PMID- 28614884 TI - ? PMID- 28614885 TI - ? PMID- 28614886 TI - Submucosal tunneling endoscopic resection of a gastric gastrointestinal stromal tumor. PMID- 28614887 TI - Successful closure of anastomotic dehiscence after colon-rectal cancer resection using the Apollo overstitch suturing system. PMID- 28614888 TI - Pull method percutaneous endoscopic gastrostomy using transnasal ultrathin endoscopy in head and neck cancer. PMID- 28614889 TI - Dysphagia from esophageal tuberculosis in a patient with undiagnosed HIV infection. PMID- 28614890 TI - A new technique for difficult biliary cannulation using endobiliary forceps in a patient with a periampullary diverticulum. PMID- 28614891 TI - Advanced technique for the treatment of chronic calculous pancreatitis using endoscopic ultrasound-guided pancreatic duct drainage. PMID- 28614892 TI - Technical aspects of placing a second lumen-apposing metal stent at a separate session for a persistent walled-off pancreatic necrosis. PMID- 28614893 TI - Traction strategy with clips and rubber band allows complete en bloc endoscopic submucosal dissection of laterally spreading tumors invading the appendix. PMID- 28614894 TI - Endoscopic extraction of a chopstick impacted in the gastric antrum. PMID- 28614895 TI - Endocuff-assisted vs. standard colonoscopy in the fecal occult blood test-based UK Bowel Cancer Screening Programme (E-cap study): a randomized trial. AB - Background and study aims Up to 25 % colorectal adenomas are missed during colonoscopy. The aim of this study was to investigate whether the endocuff could improve polyp detection in an organized bowel cancer screening program (BCSP). Patients and methods This parallel group, single-blinded, randomized controlled trial included patients with positive fecal occult blood test (FOBT) who were attending for BCSP colonoscopy. The primary outcome was the number of polyps per patient. Secondary outcomes included the number of adenomas per patient, adenoma and polyp detection rates, and withdrawal times. Results A total of 534 BCSP patients were randomized to endocuff-assisted or standard colonoscopy. The mean age was 67 years and the male to female ratio was 1.8:1. We detected no significant difference in the number of polyps per patient (standard 1.8, endocuff 1.6; P = 0.44), adenomas per patient (standard 1.4, endocuff 1.3; P = 0.54), polyp detection rate (standard 69.8 %, endocuff 70.3 %; P = 0.93), adenoma detection rate (standard 63.0 %, endocuff 60.9 %; P = 0.85), advanced adenoma detection rate (standard 18.5 %, endocuff 16.9 %; P = 0.81), and cancer detection rate (standard 5.7 %, endocuff 5.3 %; P = 0.85). The mean withdrawal time was significantly shorter among patients in the endocuff group compared with the standard colonoscopy group (16.9 vs. 19.5 minutes; P < 0.005). The endocuff had to be removed in 17/266 patients (6.4 %) because of inability to pass through the sigmoid colon. Conclusions This study did not find improved polyp or adenoma detection with endocuff-assisted colonoscopy in the FOBT-positive BCSP population. A shorter withdrawal time with endocuff may reflect improved views and stability provided by the endocuff.Trial registered at ClinicalTrials.gov (NCT02529007). PMID- 28614896 TI - [Quality of life and Potential Incriminating Factors Among Palliative Care Givers: A German Survey of the KOMPACT Working Group]. AB - Aim of the study Due to the aging population in Germany, the need for palliative care institutions will increase. Considering the lack of resources, work stress of palliative care nurses could increase significantly. It was the aim of this study to identify risk factors for job overload and work stress of palliative care nurses in the inpatient and outpatient setting. Methods In cooperation with the KOMPACT Working Group, we conducted an anonymous survey of palliative care givers in Baden-Wurttemberg, Germany. We used a paper questionnaire to inquire about job stress and workload, self-assessment of health condition and aspects about mental and emotional well-being. 167 palliative care nurses from 34 different institutions participated in the survey. Results The results showed a significant difference between inpatient and outpatient palliative care workers regarding the type and intensity of work stress. The overall stress level was significantly higher for the nurses in inpatient palliative care units (p<0.001). A high weekly working time combined with missing work experience in the field of palliative care led to a poorer compatibility of job and family. Higher stress levels resulted in a lower satisfaction with the work. Dissatisfaction with the working conditions was associated with a worse health status defined by self assessment. Mental and emotional condition of palliative care nurses was significantly worse in comparison with the norm sample, many nurses showed "strikingly" or even "seriously" high values. The survey also showed that the structural conditions in inpatient palliative care units were not optimal. Conclusion Compared to outpatient palliative care services, working conditions seem to be worse in inpatient palliative care setting, which could result in higher stress for the nurses. Interventions to reduce work-related stress appear not to be well implemented in the daily work of palliative care nurses. Standards for care as well as advanced training programs for palliative care nurses should be reevaluated. PMID- 28614897 TI - [Health Care for Refugees: Challenges and Opportunities in Hamburg]. AB - The massive increase in the number of refugees represents a great challenge to German cities. In Hamburg, 40 868 asylum seekers were registered in 2015, of which 22 315 remained in the city. The goal of the health administration is to provide primary medical care in response to specific health risks and needs of refugees while allowing them to be swiftly integrated into the standard health care system. Public authorities, charities and civil society are working hand in hand. In all reception centres in Hamburg, medical consultations with translation services are offered in fully equipped medical container practices. For every 1 000 refugees, a full-time doctor and a medical assistant are available. In addition to contractual staff, employees of contractually integrated hospitals are participating in the provision of medical care. Systematic collection of data on the health condition of the refugees as well as strengthening public health services are key factors in the planning and improvement of services in the future. Healthier living conditions and access to the standard health care system provide an opportunity to facilitate successful integration of refugees into society. PMID- 28614898 TI - Deformability of transfused red blood cells is a potent effector of transfusion induced hemoglobin increment: A study with beta-thalassemia major patients. PMID- 28614899 TI - Determination of Plasma Concentration Reference Ranges for Risperidone and Paliperidone. AB - Schizophrenia is a common disease managed by a range of interventions, with the primary treatment being antipsychotic medications (APS). Inadequate response, lack of adherence, and/or adverse events often prevent optimal therapeutic effects or therapeutic efficiency. Monitoring APS plasma concentrations can be used together with a full clinical evaluation to help improve patient care or offer better treatment options for the patient. To enable interpretation of individual risperidone and paliperidone plasma concentrations, we developed "reference ranges," which consider the expected variability in plasma concentrations between subjects across the population, rather than representing a "therapeutic range" that relates to efficacy and/or safety outcomes. The reference ranges were derived from population pharmacokinetic models, which varied based upon administration route, dose, and time after dose. Good agreement between the proposed reference ranges and external data was obtained through graphical and numerical evaluations, indicating they could be reliably used in clinical practice. PMID- 28614900 TI - Computational method for estimating boundary of abdominal subcutaneous fat for absolute electrical impedance tomography. AB - Abdominal fat accumulation is considered an essential indicator of human health. Electrical impedance tomography has considerable potential for abdominal fat imaging because of the low specific conductivity of human body fat. In this paper, we propose a robust reconstruction method for high-fidelity conductivity imaging by abstraction of the abdominal cross section using a relatively small number of parameters. Toward this end, we assume homogeneous conductivity in the abdominal subcutaneous fat area and characterize its geometrical shape by parameters defined as the ratio of the distance from the center to boundary of subcutaneous fat to the distance from the center to outer boundary in 64 equiangular directions. To estimate the shape parameters, the sensitivity of the noninvasively measured voltages with respect to the shape parameters is formulated for numerical optimization. Numerical simulations are conducted to demonstrate the validity of the proposed method. A 3-dimensional finite element method is used to construct a computer model of the human abdomen. The inverse problems of shape parameters and conductivities are solved concurrently by iterative forward and inverse calculations. As a result, conductivity images are reconstructed with a small systemic error of less than 1% for the estimation of the subcutaneous fat area. A novel method is devised for estimating the boundary of the abdominal subcutaneous fat. The fidelity of the overall reconstructed image to the reference image is significantly improved. The results demonstrate the possibility of realization of an abdominal fat scanner as a low-cost, radiation-free medical device. PMID- 28614901 TI - X-ray crystal structures of the pheromone-binding domains of two quorum-hindered transcription factors, YenR of Yersinia enterocolitica and CepR2 of Burkholderia cenocepacia. AB - The ability of LuxR-type proteins to regulate transcription is controlled by bacterial pheromones, N-acylhomoserine lactones (AHLs). Most LuxR-family proteins require their cognate AHLs for activity, and some of them require AHLs for folding and stability, and for protease-resistance. However, a few members of this family are able to fold, dimerize, bind DNA, and regulate transcription in the absence of AHLs; moreover, these proteins are antagonized by their cognate AHLs. One such protein is YenR of Yersinia enterocolitica, which is antagonized by N-3-oxohexanoyl-l-homoserine lactone (OHHL). This pheromone is produced by the OHHL synthase, a product of the adjacent yenI gene. Another example is CepR2 of Burkholderia cenocepacia, which is antagonized by N-octanoyl-l-homoserine lactone (OHL), whose synthesis is directed by the cepI gene of the same bacterium. Here, we describe the high-resolution crystal structures of the AHL binding domains of YenR and CepR2. YenR was crystallized in the presence and absence of OHHL. While this ligand does not cause large scale changes in the YenR structure, it does alter the orientation of several highly conserved YenR residues within and near the pheromone-binding pocket, which in turn caused a significant movement of a surface-exposed loop. PMID- 28614902 TI - Parental response to severe or lethal prenatal diagnosis: a systematic review of qualitative studies. AB - OBJECTIVE: A severe or lethal prenatal diagnosis places great demands on prospective parents, who face choices of far-reaching consequences, such as continuing or terminating the pregnancy. How best to support these parents is a clinical challenge. This systematic review aimed to identify and synthesize the qualitative evidence regarding prospective parents' responses to such prenatal diagnoses. METHODS: Following PRISMA guidelines, four databases were systematically searched and 28 studies met the inclusion criteria. Thematic analysis guided data extraction and synthesis of findings. The Confidence in the Evidence for Reviews of Qualitative research assessment tool was utilized to assess confidence in the findings. RESULTS: Prospective parents experienced multiple losses, for example, of the healthy child, normal pregnancy and envisioned future. After diagnosis, they requested timely and reliable information and empathetic continued interaction with clinicians. Prospective parents who continued the pregnancy wished to be acknowledged as parents and engaged in planning to obtain a sense of meaning and control. Selective disclosure and concerns about negative responses were issues both for the parents who terminated and those who continued a pregnancy. CONCLUSION: Clinicians can support parental coping following a severe prenatal diagnosis through continued dialogue and collaboration. Further research is needed on the experiences of parents who choose to terminate a pregnancy following prenatal diagnosis. (c) 2017 John Wiley & Sons, Ltd. PMID- 28614903 TI - Thiotepa-based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: A matched-pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. AB - The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long-term toxicity for patients conditioned with this regimen. Thiotepa-based conditioning is an emerging radiation-free regimen with recent publications indicative of comparable clinical outcomes to TBI-based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched-pair analysis, evaluating the outcome of adult patients with ALL who received thiotepa based conditioning (n = 180) with those receiving Cy/TBI conditioning (n = 540). The 2-year leukemia-free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for thiotepa [95% confidence interval (CI): 26.4-42.8] versus 39% for Cy/TBI (95% CI: 34.8-44.5] (P = .33) and 46.5% [95% CI: 38.6-56.1] versus 48.8% [95% CI: 44.2-54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07-2.95; P = .03) which did not affect OS. Our results indicate that thiotepa-based conditioning may not be inferior to Cy/TBI for adult patients with ALL. PMID- 28614904 TI - The AJCC/UICC eighth edition for staging head and neck cancers: Is it wise to de escalate treatment regimens in p16-positive oropharyngeal cancer patients? PMID- 28614905 TI - Long-term follow-up of chemoimmunotherapy with rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD) in patients with relapsed CD20+ B-cell non Hodgkin lymphoma: Results of a study of the Mayo Clinic Cancer Center Research Consortium (MCCRC) MC0485 now known as academic and community cancer research united (ACCRU). AB - Patients with relapsed aggressive non-Hodgkin lymphoma (NHL) are often treated with platinum-based chemoimmunotherapy regimens in preparation for autologous stem cell transplant. We sought to reduce toxicity and maintain efficacy by using oxaliplatin with rituximab, cytarabine and dexamethasone (ROAD) in a phase II clinical trial in patients who had relapsed after one prior regimen. ROAD was delivered q21 days and consisted of rituximab 375 mg/m2 IV weekly x 4 doses (cycle 1 only); dexamethasone 40 mg PO/IV d2 - 5; oxaliplatin 130 mg/m2 IV day 2; cytarabine 2000 mg/m2 IV * two doses on days 2 to 3; and pegfilgrastim 6 mg SC on day 4. Forty-five eligible patients were accrued between 2006 and 2008. Patient characteristics were a median age of 69 years; 96% had received prior rituximab; 53% were within one year of diagnosis. The median number of cycles received was 2 (range, 1-6). Forty-four % received ROAD as an outpatient. The overall response rate was 71% with 27% (12/45) CR and 44% (20/45) PR. Forty-four % (20/45) of all patients and 69% (18/26) of patients whom responded after 2 cycles proceeded to transplant. Median overall survival was 26 mos (95% CI: 7.3 mos-not reached) and median progression-free survival was 11 mos (95% CI: 6-104 mos). There was no grade 3/4 nephrotoxicity; the rate of grade 3/4 neuropathy was 4%. Forty-two percent of all patients and 69% of patients transplanted remain alive at 5 years. ROAD represents an acceptable salvage therapeutic option for patients with relapsed aggressive NHL. PMID- 28614907 TI - Relative size predicts competitive outcome through 2 million years. AB - Competition is an important biotic interaction that influences survival and reproduction. While competition on ecological timescales has received great attention, little is known about competition on evolutionary timescales. Do competitive abilities change over hundreds of thousands to millions of years? Can we predict competitive outcomes using phenotypic traits? How much do traits that confer competitive advantage and competitive outcomes change? Here we show, using communities of encrusting marine bryozoans spanning more than 2 million years, that size is a significant determinant of overgrowth outcomes: colonies with larger zooids tend to overgrow colonies with smaller zooids. We also detected temporally coordinated changes in average zooid sizes, suggesting that different species responded to a common external driver. Although species-specific average zooid sizes change over evolutionary timescales, species-specific competitive abilities seem relatively stable, suggesting that traits other than zooid size also control overgrowth outcomes and/or that evolutionary constraints are involved. PMID- 28614906 TI - Heterogeneous organization and connectivity of the chicken auditory thalamus (Gallus gallus). AB - The auditory ascending system contains parallel pathways in vertebrate brains. In chickens (Gallus gallus), three pathways arise from nucleus laminaris (NL), nucleus angularis (NA), and regio intermedius (RI) in the brainstem, innervating three subdivisions of the nucleus mesencephalicus lateralis pars dorsalis (MLd) in the midbrain. The current study reveals the segregation of these pathways in their subsequent projections to the nucleus ovoidalis (Ov) in the thalamus. Based on cytoarchitecture and myelin distribution, we identified seven Ov subregions, including five neuronal clusters within the Ov proper, the nucleus semilunaris parovoidalis (SPO), and the circum-ovoidalis (cOv). Immunocytochemistry further revealed that a ventromedial cluster of the Ov proper (Ovvm) contains unique cell types expressing alpha8 subunit nicotinic acetylcholine receptor, while SPO and cOv are characterized with expression of calcitonin-gene-related peptide and cholecystokinin. Tract tracing studies demonstrated that Ovvm is a major target of the NL-recipient zone of MLd, while the RI-recipient zone of MLd predominantly projects to a ventrolateral cluster of the Ov proper. Afferent inputs to the remaining regions of the Ov proper mostly arise from the NA-recipient zone of MLd. SPO and cOv receive a projection from the surrounding areas of MLd, named the nucleus intercollicularis. Importantly, the Ov proper, SPO and cOv all project to the Field L2 in the forebrain, the avian auditory cortex. Taken together, these results demonstrate that the avian auditory thalamus is a structurally and functionally heterogeneous structure, implicating an important role in generating novel representations for specific acoustic features. PMID- 28614908 TI - Adenoviral production of interleukin-2 at the tumor site removes the need for systemic postconditioning in adoptive cell therapy. AB - Systemic high dose interleukin-2 (IL-2) postconditioning has long been utilized in boosting the efficacy of T cells in adoptive cell therapy (ACT) of solid tumors. The resulting severe off-target toxicity of these regimens renders local production at the tumor an attractive concept with possible safety gains. We evaluated the efficacy and safety of intratumorally administered IL-2-coding adenoviruses in combination with tumor-infiltrating lymphocyte therapy in syngeneic Syrian hamsters bearing HapT1 pancreatic tumors and with T cell receptor transgenic ACT in B16.OVA melanoma bearing C57BL/6 mice. The models are complementary: hamsters are semi-permissive for human oncolytic adenovirus, whereas detailed immunological analyses are possible in mice. In both models, local production of IL-2 successfully replaced the need for systemic recombinant IL-2 (rIL-2) administration and increased the efficacy of the cell therapy. Furthermore, vectored delivery of IL-2 significantly enhanced the infiltration of CD8+ T cells, M1-like macrophages, and B-cells while systemic rIL-2 increased CD25 + FoxP3+ T cells at the tumor. In contrast with vectored delivery, histopathological analysis of systemic rIL-2-treated animals revealed significant changes in lungs, livers, hearts, spleens, and kidneys. In summary, local IL-2 production results in efficacy and safety gains in the context of ACT. These preclinical assessments provide the rationale for ongoing clinical translation. PMID- 28614909 TI - Global patterns and trends in stomach cancer incidence: Age, period and birth cohort analysis. AB - The cases of stomach cancer (SC) incidence are increasing per year and the SC burden has remained very high in some countries. We aimed to evaluate the global geographical variation in SC incidence and temporal trends from 1978 to 2007, with an emphasis on the effect of birth cohort. Joinpoint regression and age period-cohort model were applied. From 2003 to 2007, male rate were 1.5- to 3 fold higher than female in all countries. Rates were highest in Eastern Asian and South American countries. Except for Uganda, all countries showed favorable trends. Pronounced cohort-specific increases in risk for recent birth cohorts were seen in Brazil, Colombia, Iceland, New Zealand, Norway, Uganda and US white people for males and in Australia, Brazil, Colombia, Costa Rica, Czech Republic, Ecuador, Iceland, India, Malta, New Zealand, Norway, Switzerland, United Kingdom, Uganda, US black and white people for females. The cohort-specific ratio for male significantly decreased in Japan, Malta and Spain for cohorts born since 1950 and in Austria, China, Croatia, Ecuador, Russia, Switzerland and Thailand for cohorts born since 1960 and for female in Japan for cohorts born since 1950 and in Canada, China, Croatia, Latvia, Russia and Thailand for cohorts born since 1960. Disparities in incidence and carcinogenic risk persist worldwide. The favorable trends may be due to changes in environmental exposure and lifestyle, including decreased Helicobacter pylori prevalence, increased intake of fresh fruits and vegetables, the availability of refrigeration and decreased intake of salted and preserved food and smoking prevalence. PMID- 28614910 TI - TP53 mutation and survival in aggressive B cell lymphoma. AB - TP53 is mutated in 20-25% of aggressive B-cell lymphoma (B-NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 mutation to current risk models in aggressive B-NHL, we investigated TP53 gene mutations within the RICOVER-60 trial. Of 1,222 elderly patients (aged 61-80 years) enrolled in the study and randomized to six or eight cycles of CHOP-14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index-Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B-symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event-free (EFS), progression-free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI-factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed. PMID- 28614911 TI - PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. AB - The expression of PD-L1 in breast cancer is associated with estrogen receptor negativity, chemoresistance and epithelial-to-mesenchymal transition (EMT), all of which are common features of a highly tumorigenic subpopulation of cancer cells termed cancer stem cells (CSCs). Hitherto, the expression and intrinsic role of PD-L1 in the dynamics of breast CSCs has not been investigated. To address this issue, we used transcriptomic datasets, proteomics and several in vitro and in vivo assays. Expression profiling of a large breast cancer dataset (530 patients) showed statistically significant correlation (p < 0.0001, r = 0.36) between PD-L1 expression and stemness score of breast cancer. Specific knockdown of PD-L1 using ShRNA revealed its critical role in the expression of the embryonic stem cell transcriptional factors: OCT-4A, Nanog and the stemness factor, BMI1. Conversely, these factors could be induced upon PD-L1 ectopic expression in cells that are normally PD-L1 negative. Global proteomic analysis hinted for the central role of AKT in the biology of PD-L1 expressing cells. Indeed, PD-L1 positive effect on OCT-4A and Nanog was dependent on AKT activation. Most importantly, downregulation of PD-L1 compromised the self renewal capability of breast CSCs in vitro and in vivo as shown by tumorsphere formation assay and extreme limiting dilution assay, respectively. This study demonstrates a novel role for PD-L1 in sustaining stemness of breast cancer cells and identifies the subpopulation and its associated molecular pathways that would be targeted upon anti-PD-L1 therapy. PMID- 28614912 TI - Peroxisome Proliferator-Activated Receptor alpha Facilitates Osteogenic Differentiation in MC3T3-E1 Cells via the Sirtuin 1-Dependent Signaling Pathway. AB - Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by lack of insulin and high glucose levels. T2DM can cause bone loss and fracture, thus leading to diabetic osteoporosis. Promoting osteogenic differentiation of osteoblasts may effectively treat diabetic osteoporosis. We previously reported that Sirtuin 1 (Sirt1), a NAD+-dependent deacetylase, promotes osteogenic differentiation through downregulation of peroxisome proliferator-activated receptor (PPAR) gamma. We also found that miR-132 regulates osteogenic differentiation by downregulating Sirt1 in a PPARbeta/delta-dependent manner. The ligand-activated transcription factor, PPARalpha, is another isotype of the peroxisome proliferator-activated receptor family that helps maintain bone homeostasis and promot bone formation. Whether the regulatory role of PPARalpha in osteogenic differentiation is mediated via Sirt1 remains unclear. In the present study, we aimed to determine this role and the underlying mechanism by using high glucose (HG) and free fatty acids (FFA) to mimic T2DM in MC3T3-E1 cells. The results showed that HG-FFA significantly inhibited expression of PPARalpha, Sirt1 and osteogenic differentiation, but these effects were markedly reversed by PPARalpha overexpression. Moreover, siSirt1 attenuated the positive effects of PPARalpha on osteogenic differentiation, suggesting that PPARalpha promotes osteogenic differentiation in a Sirt1-dependent manner. Luciferase activity assay confirmed interactions between PPARalpha and Sirt1. These findings indicate that PPARalpha promotes osteogenic differentiation via the Sirt1 dependent signaling pathway. PMID- 28614913 TI - The Fungal Metabolite Brefeldin A Inhibits Dvl2-Plk1-Dependent Primary Cilium Disassembly. AB - The primary cilium is a non-motile microtubule-based organelle that protrudes from the surface of most human cells and works as a cellular antenna to accept extracellular signals. Primary cilia assemble from the basal body during the resting stage (G0 phase) and simultaneously disassemble with cell cycle re-entry. Defective control of assembly or disassembly causes diverse human diseases including ciliopathy and cancer. To identify the effective compounds for studying primary cilium disassembly, we have screened 297 natural compounds and identified 18 and 17 primary cilium assembly and disassembly inhibitors, respectively. Among them, the application of KY-0120, identified as Brefeldin A, disturbed Dvl2-Plk1 mediated cilium disassembly via repression of the interaction of CK1E-Dvl2 and the expression of Plk1 mRNA. Therefore, our study may suggest useful compounds for studying the cellular mechanism of primary cilium disassembly to prevent ciliopathy and cancer. PMID- 28614914 TI - IP-10 Expression in Patients with Chronic HBV Infection and Its Ability to Predict the Decrease in HBsAg Levels after Treatment with Entecavir. AB - Interferon-gamma-inducible protein 10 (IP-10), also known as chemokine C-X-C motif ligand (CXCL) 10, is closely associated with antiviral immunity and the progression of chronic hepatitis B (CHB). However, the value of baseline serological and histological IP-10 expression levels in predicting the efficacy of the antiviral response to nucleoside/nucleotide analogues (NAs) is still unknown. In our research, intrahepatic and peripheral IP-10 expression levels were systemically examined before and after treatment with entecavir (ETV). Baseline serological and histological IP-10 expression levels were significantly increased in patients with CHB, particularly in patients with higher degrees of liver inflammation and liver fibrosis. Moreover, higher baseline intrahepatic IP 10 levels indicated better prognoses in patients with CHB after entecavir therapy. The baseline IP-10 level was also positively associated with several clinical parameters, including baseline levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis B virus (HBV) DNA, and hepatitis B surface antigen (HBsAg), and with the decrease in HBsAg levels after treatment. In addition, monocyte-derived IP-10 was expressed at higher levels in patients with CHB than in patients with liver cirrhosis (LC) and healthy controls (HC). According to the results of our in vitro experiments, IP-10 directly promoted hepatocyte apoptosis. Based on these findings, baseline serological and histological IP-10 levels might predict CHB severity and the decrease in HBsAg levels after entecavir therapy. PMID- 28614915 TI - Identification of an Enhancer Critical for the ephirn-A5 Gene Expression in the Posterior Region of the Mesencephalon. AB - Ephrin-A5 has been implicated in the regulation of brain morphogenesis and axon pathfinding. In this study, we used bacterial homologous recombination to express a LacZ reporter in various ephrin-A5 BAC clones to identify elements that regulate ephrin-A5 gene expression during mesencephalon development. We found that there is mesencephalon-specific enhancer activity localized to a specific +25.0 kb to +30.5 kb genomic region in the first intron of ephrin-A5. Further comparative genomic analysis indicated that two evolutionary conserved regions, ECR1 and ECR2, were present within this 5.5 kb region. Deletion of ECR1 from the enhancer resulted in disrupted mesencephalon-specific enhancer activity in transgenic embryos. We also found a consensus binding site for basic helix-loop helix (bHLH) transcription factors (TFs) in a highly conserved region at the 3' end of ECR1. We further demonstrated that specific deletion of the bHLH TF binding site abrogated the mesencephalon-specific enhancer activity in transgenic embryos. Finally, both electrophoretic mobility shift assay and luciferase-based transactivation assay revealed that the transcription factor Ascl1 bound the bHLH consensus binding site in the mesencephalon-specific ephrin-A5 enhancer in vitro. Together, these results suggest that the bHLH TF binding site in ECR1 is involved in the positive regulation of ephrin-A5 gene expression during the development of the mesencephalon. PMID- 28614916 TI - Gestational Diabetes Affects the Growth and Functions of Perivascular Stem Cells. AB - Gestational diabetes mellitus (GDM), one of the common metabolic disorders of pregnancy, leads to functional alterations in various cells including stem cells as well as some abnormalities in fetal development. Perivascular stem cells (PVCs) have gained more attention in recent years, for the treatment of various diseases. However, the effect of GDM on PVC function has not been investigated. In our study, we isolated PVCs from umbilical cord of normal pregnant women and GDM patients and compared their phenotypes and function. There is no significant difference in phenotypic expression, response to bFGF exposure and adipogenic differentiation capacity between normal (N)-PVCs and GDM-PVCs. However, when compared with N-PVCs, early passage GDM-PVCs displayed decreased initial rates of cell yield and proliferation as well as a reduced ability to promote wound closure. These results suggest that maternal metabolic dysregulation during gestation can alter the function of endogenous multipotent stem cells, which may impact their therapeutic effectiveness. PMID- 28614917 TI - Cell Death-Associated Ribosomal RNA Cleavage in Postmortem Tissues and Its Forensic Applications. AB - Estimation of postmortem interval (PMI) is a key issue in the field of forensic pathology. With the availability of quantitative analysis of RNA levels in postmortem tissues, several studies have assessed the postmortem degradation of constitutively expressed RNA species to estimate PMI. However, conventional RNA quantification as well as biochemical and physiological changes employed thus far have limitations related to standardization or normalization. The present study focuses on an interesting feature of the subdomains of certain RNA species, in which they are site-specifically cleaved during apoptotic cell death. We found that the D8 divergent domain of ribosomal RNA (rRNA) bearing cell death-related cleavage sites was rapidly removed during postmortem RNA degradation. In contrast to the fragile domain, the 5' terminal region of 28S rRNA was remarkably stable during the postmortem period. Importantly, the differences in the degradation rates between the two domains in mammalian 28S rRNA were highly proportional to increasing PMI with a significant linear correlation observed in mice as well as human autopsy tissues. In conclusion, we demonstrate that comparison of the degradation rates between domains of a single RNA species provides quantitative information on postmortem degradation states, which can be applied for the estimation of PMI. PMID- 28614919 TI - [Effects of developmental exposure to DEHP on learning and memory of mice]. AB - Objective: To investigate the effects of developmental exposure to DEHP on learning and memory of mice. Methods: Male littermates of ICR mice randomly assigned to five experimental groups (n=14 for each condition) on PND4 to receive distilled water, vehicle and 10, 50 and 200 mg/ (kg.d) DEHP from PND5 to PND38 by gavage, weighing and recording body weight of mice. Open field task were conducted on PND 26 and Morris water maze task were begun from PND30 to PND 37 to evaluate spontaneous exploration activity and emotion, spatial learning and memory performance of pubertal mice, respectively. On PND39, all animals were killed and hippocampi were isolated on ice, then total proteins of hippocampus were extracted, followed by determining the expression of PSD95 and synapsin I by western blotting. Results: 200 mg/ (kg.d) DEHP significantly reduced the growth of body weight of mice and the time staying in the central area in open field, prolonged the time searching the hidden platform in Morris water maze (P<0.05) . 50 mg/ (kg.d) DEHP didn't change the growth of body weight and the emotion (P>0.05) , but reduced the percent of time and distance in the target quadrant during the probe trial of mice in Morris water maze (P<0.05) . The results of western blotting showed that DEHP significantly reduced the expression of PSD95 in hippocampus of mice with all dose groups (P<0.01) , but only 200 mg/ (kg.d) DEHP reduced the expression of synapsin I (P<0.05) . Conclusion: Developmental exposure to DEHP can damage the development of synapse in hippocampus, adversely impacting spatial memory performance of mice at a dose that are insufficient to significantly influence the general development and result in anxiety. PMID- 28614918 TI - The Significance of SDF-1alpha-CXCR4 Axis in in vivo Angiogenic Ability of Human Periodontal Ligament Stem Cells. AB - Periodontal ligament stem cells (PDLSCs) are multipotent stem cells derived from periodontium and have mesenchymal stem cell (MSC)-like characteristics. Recently, the perivascular region was recognized as the developmental origin of MSCs, which suggests the in vivo angiogenic potential of PDLSCs. In this study, we investigated whether PDLSCs could be a potential source of perivascular cells, which could contribute to in vivo angiogenesis. PDLSCs exhibited typical MSC-like characteristics such as the expression pattern of surface markers (CD29, CD44, CD73, and CD105) and differentiation potentials (osteogenic and adipogenic differentiation). Moreover, PDLSCs expressed perivascular cell markers such as NG2, alphasmooth muscle actin, platelet-derived growth factor receptor beta, and CD146. We conducted an in vivo Matrigel plug assay to confirm the in vivo angiogenic potential of PDLSCs. We could not observe significant vessel-like structures with PDLSCs alone or human umbilical vein endothelial cells (HU-VECs) alone at day 7 after injection. However, when PDLSCs and HUVECs were co-injected, there were vessel-like structures containing red blood cells in the lumens, which suggested that anastomosis occurred between newly formed vessels and host circulatory system. To block the SDF-1alpha and CXCR4 axis between PDLSCs and HUVECs, AMD3100, a CXCR4 antagonist, was added into the Matrigel plug. After day 3 and day 7 after injection, there were no significant vessel-like structures. In conclusion, we demonstrated the peri-vascular characteristics of PDLSCs and their contribution to in vivo angiogenesis, which might imply potential application of PDLSCs into the neovascularization of tissue engineering and vascular diseases. PMID- 28614920 TI - [Role of complement regulatory protein CD55 in the liver immune injury of trichloroethylene-sensitized mice]. AB - Objective: To explore the expression of CD55 in liver tissue of trichloroethylene sensitized mice and discuss the role of CD55 in the liver immune injury of trichloroethylene-sensitized mice. Methods: 6-8 weeks specific pathogen free female BALB/c were randomly divided into blank control group, solvent control group and TCE treatment group to establish BALB/c mice sensitized model. According to mouse skin sensitization reaction score, TCE treatment mice were divided into sensitized and non-sensitized group at 24 h after the last challenge. At 48 h after the last challenge, the blood and aseptic livers were collected. The level of serum ALT was tested by automatic biochemical analyzer and pathology of the liver was observed. C5b-9 deposition was studied by immunohistochemistry (IHC) . CD55 protein expression level in liver tissue was studied by immunohistochemistry and Western blotting. The expression of CD55 mRNA in liver tissue was detected by qRT-PCR. Results: Liver function test result showed level of serum ALT in TCE sensitized group was significantly higher than solvent control group and TCE non-sensitized group (P<0.05) . There was ballooning degeneration and necrosis of liver cells in TCE sensitized group. IHC demonstrated that TCE sensitized group had obviously increased content of C5b-9 but had reduced content of CD55 compared with solvent control group and TCE non sensitized group (P<0.05) . Western blotting also showed that TCE sensitized group had lower expression of CD55 than solvent control group and TCE non sensitized group (P<0.05) . qRT-PCR showed that CD55 mRNA expression level in liver tissue of TCE sensitized group was apparently lower than solvent control group and TCE non-sensitized group (P<0.05) . Conclusion: Complement activation may be involved in TCE-induced liver injury, and the expression change of complement regulatory protein CD55 may play essential role in the process. PMID- 28614921 TI - [The study of using cordyceps-astragalus-salvia miltiorrhiza to treat acute lung injury induced by paraquat poisoning in rats]. AB - Objective: To study the therapy of cordyceps-astragalus-salvia miltiorrhiza in treating acute lung injury and pulmonary interstitial fibrosis induced by paraquat poisoning. Methods: All 120 adult Wister male rats were randomly assigned to three groups, the paraquat poisoning group (rats were intragastric administration paraquat 50 mg/kg body weight once at the beginning) , the cordyceps-astragalus-salvia miltiorrhiza therapy group (rats were given cordyceps astragalus-salvia miltiorrhiza 90 mg/kg body weight intragastric administration half an hour after paraquat was given, then the same dose was given once a day) ; control group (rats were intragastric administration with physiological saline) . At 7th, 14th, 21st, and 28th day rats were sacrificed postanesthetic respectively after paraquat exposure, sample of lung tissue, bronchoalveolar lavage (BAL) , and venous blood were collected. GSH, SOD, TNF-alpha, TGF-beta1, and HYP in plasma, bronchoalveolar lavage (BAL) , and the lung homogenates were determined. Optical microscope was performed to examine pathological changes in lung. Results: Each experimental time point paraquat group and the treatment group rats serum SOD content significantly lower than the control group (P<0.05) . Each experimental time point the treatment group rats serum SOD levels increased significantly than that of paraquat group (P<0.05) . Each experimental time point paraquat group rats serum GSH content significantly lower than that of the control group (P<0.05) . Treatment group rats 7 days time GSH content significantly lower than that of the control group (P<0.05) . Treatment group 21 days, 28 days GSH content was increased significantly than that of the paraquat group (P<0.05) . Each experimental time point paraquat group rats alveolar lavage SOD content was significantly lower than that of the control group (P<0.05) . Treatment group 7 days, 14 days time SOD content was significantly lower than that of the control group (P<0.05) , Treatment group 21 days, 28 days SOD content was increased significantly than that of the paraquat group (P<0.05) . Each experimental time point paraquat group and the treatment group rats alveolar lavage GSH content significantly were lower than that of the control group (P<0.05) . Treatment group days 14 and 21 days, 28 days GSH content was increased significantly than that of the paraquat group (P<0.05) . Each experimental time point paraquat group rats alveolar lavage TNF alpha levels was higher than that of the control group (P<0.05) . Treatment group 7 days, 14 days the rat alveolar lavage TNF alpha levels was higher than that of the control group (P<0.05) . Treatment group 21 days, 28 days TNF alpha content significantly was decreased than that of paraquat group (P<0.05) . Paraquat group days 14 and 21 days, 28 days HYP content was significantly higher than that of control group (P<0.05) . Treatment group 21 days HYP content was significantly higher than that of control group (P<0.05) . Treatment group 28 days time HYP content in lung tissue of rats was significantly decreased than that of the paraquat group (P<0.05) . Each experimental time point paraquat group rat lung tissue (tissue homogenate) TGF beta1 content was higher than that of the control group, the difference was statistically significant (P<0.05) . Under optical microscope, the tissue damage of lung was aggravated, and reduced after cordyceps-astragalus-salvia miltiorrhiza was administrated. Conclusion: Cordyceps-astragalus-salvia miltiorrhiza can reduce inflammation factor releasing, and relieve lung injury. It has therapeutic effect on lung injury induced by paraquat poisoning. PMID- 28614922 TI - [Recombinant human tumor necrosis factor receptor type II-IgG Fc fusion protein for treatment of occupational medicamentosa-like dermatitis induced by trichloroethylene]. AB - Objective: To investigate the efficacy and safety of the recombinant human tumor necrosis factor receptor II-IgG Fc fusion protein (rhTNFR: Fc, etanercept) for the treatment of occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) . Methods: In September 2011 to February 2016, 12 patients with OMLDT were treated with etanercept 25 mg, subcutaneous injection, twice per week, doubling of first dose. The course of treatment was 6 weeks. The drug eruption area and severity index (DASI) score, the proportion of patients achieving a 50%, 75% and 90% reduction in DASI (DASI50, DASI75, DASI90) and the serum level of TNF-alpha were used to assess the efficacy at different times. Adverse reactions were also recorded and evaluated. The results were statistically analyzed by nonparametric Friedman test and repetitive measurement ANOVA using the software SPSS19.0. Results: After 4 weeks treatment, the DASI score decreased form 56.33+/-7.02 to 0.50+/-0.91 (P<0.01) . The DASI50, DASI75 and DASI90 were all increased to 12 (100%) . The serum level of TNF-alpha decreased form (43.74+/-41.62) pg/ml to (3.03+/-0.47) pg/ml (P<0.01) . Statistically significant difference was observed from the above indexes. There were no adverse reactions in clinical application. Conclusion: Recombinant human tumor necrosis factor receptor II-IgG Fc fusion protein may be a safe and effective drug in the treatment of OMLDT. PMID- 28614923 TI - [Serum levels of periostin and their influencing factors in the beta-lactam antibiotic enterprise workers]. AB - Objective: To observe serum levels of periostin, ECP, IgE in the antibiotic enterprise workers, and study the role of periostin, ECP, IgE in the development of allergic inflammation. Methods: 90 cases with asthma or rhinitis were enrolled as disease group, another 117 workers exposed to 7-ACA,6-APA dust without suffering from allergic illness, are chosen as group of dust exposed, and 192 healthy workers who didn't contact dust were chosen as control group. Questionnaires were used to learn their basic information.Lung function was determined with a portable spirometer.The expression levels of periostin,ECP and IgE in serum were measured by enzyme-linked immuno sorbent assay. Results: The exposure group and disease group had significantly lower forced vital capacity (FVC) , forced expiratory volume in 1 second (FEV(l.0)) , and FEV(l.0)/FVC ratio than the control group (P<0.05) . The disease group had significantly higher eosinophil than the control group (P<0.05) . Compared with the control group, the exposure group, the disease group, asthma subgroup, rhinitis subgroup of serum periostin and IgE increased, the differences are statistically significant (P<0.05) . Serum levels of ECP in the workers of asthma subgroup were significantly higher than that in control group (P<0.05) . Serum expression levels of periostin were positively correlated with IgE, ECP in workers (P<0.001) , serum levels of periostin were negatively correlated with FEV(1.0) in workers (P<0.05) . Multiple logistics regression analysis found that exposure to 7-ACA or 6-APA (OR=3.09, 95%CI: 1.83-5.21) , age>47years (OR=2.53, 95%CI: 1.22-5.26) , higher ECP (OR=1.04, 95%CI: 1.01-1.06) were risk factors for increased serum periostin level. Conclusion: Occupational exposure to 7-ACA or 6-APA can result in higher serum periostin level, exposure to 7-ACA or 6-APA, age>47 years, higher ECP are risk factors for increased serum periostin level. PMID- 28614924 TI - [Effects of smoking on concentration of urinary 8-hydroxydeoxyguanosine in coke oven workers]. AB - Objective: To explore the influence of smoking and polycyclic aromatic hydrocarbons (PAHs) on urinary 8-hydroxydeoxyguanosine (8-OHdG) in coke oven workers and investigate their dose-dependent relationships. Methods: A total of 436 workers exposed to coke oven emissions (COEs) and 132 controls were recruited in this study. Questionnaires were completed in a personal interview. Then their urine samples were also collected and the concentrations of urinary four OH-PAHs and 8-OHdG were determined by high performance liquid chromatography (HPLC) which was used to evaluate the levels of occupational PAHs internal exposure among workers and the DNA damage. Results: The differences of concentrations of urinary 2-NAP (2-hydroxynathalene) , 2-FLU (2-hydroxyfluorene) , 9-PHE (9 hydroxyphenanthrene) , 1-OHP (1-hydroxypyrene) between exposure group and control group were statistically significant (P<0.05) . In exposure group and control group, the level of 8-OHdG in heavy smoking workers were significantly higher than that in other groups (P<0.05) . Multivariate logistic regression analysis revealed high levels of urinary 8-OHdG were associated with a significantly increased risk of having higher urinary1-hydroxypyrene levels[OR=1.43 (95%CI: 1.06-1.94) , P<0.01] and heavy smoking [OR=1.44 (95%CI: 1.08-1.91) , P<0.01], respectively. Trend test showed that linear dose response relationship between smoking, 1-OHP in urine and higher concentrations of 8-OHdG (P<0.05) . Smoking could significant modify the effects of urinary 1-hydroxypyrene, while co exposure to both heavy smoking and high urinary 1-hydroxypyrene levels[OR=5.64 (95%CI: 2.15-14.80) , P<0.05]. Conclusion: Urinary 1-hydroxypyrene is a useful biomarker for evaluating total PAHs exposure, coke oven workers with heavy smoking present more serious DNA oxditive damage. PMID- 28614925 TI - [Investigation on standard application of industrial dust hazard classification]. AB - Objective: To investigate the application and effectiveness evaluation of the standard of GBZ/T 229.1-2010 in practice, and to explore the applicability, aiming to provide technical evidence for the revision of GBZ/T 229.1-2010. Methods: There were 2 questionnaire surveys carried out in the study, including general survey and specific survey. Databases were established and data were input with Excel 2010 and Epidata version 3.1 software. SPSS version 19.0 software was used for data cleaning and statistical analysis. Results: The general survey received 100 questionnaires, with 43 from facilities and 57 from professional expertise. There were 59 questionnaires from occupational health technical service organizations held by government, and 11 from colleges and universities. The leading three jobs using GBZ/T 229.1-2010 were the occupational hazards evaluation for constructive project (69.0%) , lecturing/training (55.0%) , occupational hazards monitoring (50.0%) , respectively. The high frequency used contents of GBZ/T 229.1-2010 were the fourth part "classification" (67.0%) , the fifth part "the principles of classification management" (59.0%) , annex A "the correct use instructions" (52.0%) , respectively. In the results of feasibility, scores of the fourth part "classification" , the fifth part "the principles of classification management" , annex A "the correct use instructions" were 3.07, 3.03, 3.23, respectively. The parts needed to be modified as priories were the fourth part "classification" (22.0%) , the fifth part "the principles of classification management" (13.0%) , annex A "the correct use instructions" (12.0%) . The specific survey received 15 questionnaires, with 12 from the employers and 3 from occupational health technical service organizations. The awareness rate of GBZ/T 229.1-2010 among occupational health professionals was 83.3%. Classification results in the employers were used for guidance on improvement measures (66.7%) , health surveillance and monitoring (58.3%) , certification for occupational health and safety management system (33.3%) , occupational disease diagnosis (33.3%) , and personal protective equipment issued (33.3%) , etc. In the results of feasibility, scores of the content of free SiO(2), occupational exposure ratio, physical labor intensity level, classification of industrial dust, principles of classification management, annex A "the correct use instructions" were 5.00, 4.33, 5.00, 5.00, 3.67, 3.67, respectively. Conclusion: GBZ/T 229.1-2010 indicates that the standard is feasible and practical. But there are still some problems, such as classification of different kinds of industrial dusts at workplace, and the interaction of occupational exposure to industrial dusts and other hazards at workplace, etc. PMID- 28614926 TI - [Investigation and analysis on occupational hazards in a carbon enterprise]. AB - Objective: To explore occupational-disease-inductive in a carbon enterprise workplace and personnel occupational health examination, providing the basis for occupational disease prevention and control of the industry. Methods: Field occupational health survey and inspection law were used to study the the situation and degree of occupational disease hazards in carbon enterprise from 2013 to 2015.Occupational health monitoring was used for workers, physical examination, detection of occupational hazard factors and physical examination results were analyzed comprehensive. Results: Dust, coal tar pitch volatiles, and noise in carbon enterprise were more serious than others. Among them, the over standard rate of coal tar pitch volatiles was 76.67%, the maximum point detection was 1.06 mg/m(3), and the maximum of the individual detection was 0.67 mg/m(3). There was no statistical difference among the 3 years (P>0.05) . There were no significant differences in the incidence of occupation health examination, chest X-ray, skin audiometry, blood routine, blood pressure, electrocardiogram between 3 years (P>0.05) , in which the skin and audiometry abnormal rate was higher than 10% per year. Conclusion: Dust, coal tar, and noise are the main occupational hazard factors of carbon enterprise, should strengthen the corresponding protection. PMID- 28614927 TI - [Study on application of two risk assessment methods in coal dust occupational health risk assessment]. AB - Objective: To evaluate the applicability of quantitative grading method (GBZ/T 229.1-2010) and occupational hazard risk index method in coal dust occupational health risk assessment. Methods: Taking 4 coal mines as the research object of risk assessment and making occupational health field testing and investigation. Based on two risk assessment methods, we analysed the health risk levels of 20 occupations which were exposed to coal dust in workplaces. Results: Coal dust working post had different risk levels in 4 coal mines, the post of higher risk level were mainly concentrated in the underground workplace of coal mine, especially the post of coal mining and tunneling system. The two risk assessment results showed that the risk levels of coal-mining machine drivers and tunneling machine drivers were the highest. The risk levels of coal dust working post used by two risk assessment methods had no significant difference (P>0.05) and were highly correlated (r=0.821, P<0.001) . Evaluation results of two risk assessment methods were supported by the field investigation and literatures. Conclusion: The two risk assessment methods can be used in coal dust occupational health risk assessment. PMID- 28614928 TI - [Analysis of inner or extra-exposure for worker in carbon and coal tar process industries]. AB - Objective: To evaluate the inner or extra-exposure of workers in carbon and coal tar process industries. Methods: In May 2015, 271 exposure and 75 non-exposure workers in two of carbon and coal tar process industries in Shandong province were selected. Coal tar pitch (CTP) was detected according to the methods of GB17054-1997. The 1-OH-Nap,2-OH-Nap,1-OH-Pyr in urine were detected by high performance liquid Chromatography (HPLC) . Results: The concentration of 1-OH Nap,2-OH-Nap,1-OH-Pyr in urine of exposure group were significant higher than that of control group (P<0.05) , respectively. The urine concentration of 1-OH Nap,2-OH-Nap,1-OH-Py in contact group tar and asphalt were 12.20, 12.55, 7.08 and 10.62, 8.73, 3.07 MUg/gCr, and the concentration of them were 7.25, 8.54, 3.00 MUg/gCr in container handle workers. Significant positive correlations were found between high or median CTP exposure and the urine concentration of 1-OH-Nap,2-OH Nap,1-OH-Pyr in exposure groups (P<0.05) . Conclusions: The inner or extra exposure level is relative and different for different type of work in these carbon and coal tar process industries. PMID- 28614929 TI - [Research of relationship between occupational exposure to coal tar pitch workers and cytogenetic damage]. AB - Objective: To investigate the effect of coal tar pitch occupational exposure on the cytogenetic damage. Methods: In July 2015, 691 workers exposed to coal tar pitch were selected as contact group. The administrative and the support crew 201 cases were selected as control group. Detect the tail DNA% and tail moment in peripheral blood lymphocyte as DNA damage degree by single cell gel electrophoresis (SCGE) . Detect the concentration of the metabolic product in urine by HPLC/MC as exposure levels. Results: The contact group were significantly higher than the control group in tail DNA% (contact group14.44%, control group 11.17%) and olive tail moment (contact group 2.85 MUm, control group 1.95 MUm) . The smoking one (contact group18.51%, control group13.43%) were significantly higher than the group not smoking (contact group12.69%, control group 11.71%) in tail DNA%. The coal tar pitch content in the air of workplace have correlation with worker, stail DNA% (r(s)=0.10) and olive tail moment (r(s)=0.11) . Conclusion: Occupational exposure to coal tar pitch and smoking can cause cytogenetic damage to workers. PMID- 28614930 TI - [Relationship between noise exposure and high frequency hearing loss in bottled beverage]. PMID- 28614931 TI - [Evaluation of "diagnostic criteria for occupational asthma" (GBZ 57?2008)]. PMID- 28614932 TI - [A group of occupational acute methyl bromide poisoning incident]. AB - Objective: To investigate a mass of occupational acute methyl bromide poisoning incident and analyzed their clinical data. Methods: To investigate an incident a mass of occupational acute methyl bromide poisoning in occurred in Shandong province in November 2016, and the clinical datas of 3 cases of severe patients with methyl bromide poisoning were analysed. Results: This event was a sudden occupational poisoning incident. Lack of vocational training and irregularities is the main reason for the accident 3 patients with nervous system, respiratory system, circulatory system, urinary system damage is given priority to, after comprehensive rescue treatment, 2 cases died and 1 case survived. Conclusions: Methyl bromide can cause severe poisoning, has high mortality in patients with acute severe poisoning. PMID- 28614933 TI - [Study on the establishment of HMLD model and the expression of KL-6/TGF-beta in rat]. AB - Objective: To establish an animal model of hard metal lung disease (HMLD) in rats, and to screen the indications for diagnosis of HMLD. Methods: The rats were randomly divided into 5 groups, each group included 8 rats: saline group, pure cobalt group, pure tungsten carbide group, silica group and hard metal (HM) group. 10 mg subjects were administered in each group by using the pulmonary endotracheal tube. After 8 week, the lung CT scan and lung tissue pathology were observed, the serum and bronchoalveolar lavage fluid (BALF) were collected for KL 6, TGF-beta1 and TGF-beta2. Results: The lung tissue structure of HM group was destroyed, a large number of nuclear giant cells and epithelial like cells appeared in the stroma, and uncommon CT scan images appeared in the lung. KL-6, TGF-beta1, TGF-beta2 expression in each group was not the same, the difference was statistically significant (P<0.05) . The expression of KL-6 and TGF-beta1 in serum was not identical in all the groups, the difference was statistically significant (P<0.05) . The expression of TGF-beta2 had no significant difference between the groups (P>0.05) . Conclusion: Rats can be successfully established HMLD model, rats in vivo lung CT scan images appear abnormal, which are provided with assistant diagnostic value for HMLD. The expression of KL-6 and TGF-beta2 in serum and BALF on HMLD rats are not highly specific, and TGF-beta1 has reference value in the rat HMLD auxiliary diagnosis. PMID- 28614934 TI - [Evaluation of clinical efficacy of tretrandrine combined with acetylcysteine effervescent tablets in the treatment of silicosis]. PMID- 28614935 TI - [Clinical observation of external diaphragm pacing in patients with pneumoconiosis complicated with chronic obstructive pulmonary disease in stable stage]. PMID- 28614936 TI - [The clinical application of SIMV+PSV during the period of extubation in whole?lung lavage]. PMID- 28614937 TI - [A case of severe allergic reaction induced by NA?DMPS]. PMID- 28614938 TI - [Investigation on the cause of death of honey poisoning]. PMID- 28614939 TI - [2 cases of acute imidacloprid poisoning clinical analysis]. PMID- 28614940 TI - [Clinical analysis of 16 occupationally server heat stroke cases]. PMID- 28614941 TI - [One case of acute respiratory distress syndrome induced by chlorine inhalation treated by combining extracorporeal membrane oxygenation and blood purification]. PMID- 28614942 TI - [Analysis of clinical data of 18 cases of carbon black pneumoconisosis in rubber industry]. PMID- 28614943 TI - [Determination of benzoquinone in occupational atmospheres by high?performance liquid chromatography]. PMID- 28614944 TI - [Quality control methods of gas chromatography?ion trap mass determine for the 2, 5?hexanedione in normal population urinary]. PMID- 28614945 TI - Selective and Fast Adsorption of Perfluorooctanesulfonate from Wastewater by Magnetic Fluorinated Vermiculite. AB - A novel magnetic fluorinated adsorbent with selective and fast adsorption of perfluorooctanesulfonate (PFOS) was synthesized via a simple ball milling of Fe3O4 and vermiculite loaded with a cationic fluorinated surfactant. The loaded Fe3O4 nanoparticles increased the dispersibility of fluorinated vermiculite (F VT) in water and allowed the magnetic separability. The nanosized Fe3O4 was homogeneously embedded into the adsorbent surfaces, improving the hydrophilicity of F-VT external surface, and this hybrid adsorbent still kept the hydrophobic fluorinated interlayer structure. With this unique property, Fe3O4-loaded F-VT has very fast and selective adsorption for PFOS in the presence of other compounds, due to the fluorophilicity of C-F chains intercalated in the adsorbent interlayers. This novel adsorbent has a high sorption capacity for PFOS, exhibiting PFOS removal from fire-fighting foam wastewater that is much higher than that of powdered activated carbon and resin due to its high selectivity for PFOS. The used Fe3O4-loaded F-VT was successfully regenerated by methanol and reused five times without reduction in PFOS removal and magnetic performance. The Fe3O4-loaded F-VT demonstrates promising application for PFOS removal from real wastewater. PMID- 28614946 TI - Tuning Band Structure of Cadmium Chalcogenide Nanoflake Arrays via Alloying for Efficient Photoelectrochemical Hydrogen Evolution. AB - Owing to their high extinction coefficient and moderate band gap, cadmium chalcogenides are known as common semiconductors for photoelectric conversion. Nevertheless, no ideal cadmium chalcogenide with proper band structure is available yet for photoelectrochemical hydrogen evolution. In this work, we modified the band structure of CdTe via alloying with Se to achieve a ternary compound (CdSe0.8Te0.2) with n-type conduction, a narrower band gap, and a more negative band position compared to those of CdSe and CdTe. This novel material exhibits strong light absorption over a wider spectrum range and generates more vigorous electrons for hydrogen reduction. As a result, a photoelectrode based on nanoflake arrays of the new material could achieve a photocurrent density 2 times that of its CdSe counterpart, outperforming similar materials previously reported in the literature. Moreover, the quick transfer of holes achieved in the novel material was found to depress photocorrosion processes, which led to improved long-term working stability. PMID- 28614948 TI - Spotlights: Volume 8, Issue 12. PMID- 28614947 TI - Catalytic Oxidation of Chlorobenzene over MnxCe1-xO2/HZSM-5 Catalysts: A Study with Practical Implications. AB - Industrial-use catalysts usually encounter severe deactivation after long-term operation for catalytic oxidation of chlorinate volatile organic compounds (CVOCs), which becomes a "bottleneck" for large-scale application of catalytic combustion technology. In this work, typical acidic solid-supported catalysts of MnxCe1-xO2/HZSM-5 were investigated for the catalytic oxidation of chlorobenzene (CB). The activation energy (Ea), Bronsted and Lewis acidities, CB adsorption and activation behaviors, long-term stabilities, and surficial accumulation compounds (after aging) were studied using a range of analytical techniques, including XPS, H2-TPR, pyridine-IR, DRIFT, and O2-TP-Ms. Experimental results revealed that the Bronsted/Lewis (B/L) ratio of MnxCe1-xO2/HZSM-5 catalysts could be adjusted by ion exchange of H* (in HZSM-5) with Mnn+ (where the exchange with Ce4+ did not distinctly affect the acidity); the long-term aged catalysts could accumulate ca. 14 organic compounds at surface, including highly toxic tetrachloromethane, trichloroethylene, tetrachloroethylene, o-dichlorobenzene, etc.; high humid operational environment could ensure a stable performance for MnxCe1-xO2/HZSM-5 catalysts; this was due to the effective removal of Cl* and coke accumulations by H2O washing, and the distinct increase of Lewis acidity by the interaction of H2O with HZSM-5. This work gives an in-depth view into the CB oxidation over acidic solid-supported catalysts and could provide practical guidelines for the rational design of reliable catalysts for industrial applications. PMID- 28614949 TI - Comparison of metrological techniques for evaluation of the impact of a cosmetic product containing hyaluronic acid on the properties of skin surface. AB - The aim of this research was to evaluate mutual interchangeability of four principally different biometric instrumental techniques designed for objective measurement of changes in the physical, mechanical, and topographical properties of the skin surface treated with commercial antiaging cosmetic products with hyaluronic acid. The following instrumental devices were used: Visioscope PC 35, Corneometer Multiprobe Adapter MPA 6, Reviscometer RVM 600, and 3D scanner Talysurf CLI 500. The comparison of the individual methods was performed using cluster analysis. The study involved 25 female volunteers aged 40-65. Measurements were taken before and after 30 daily in vivo applications of an antiaging preparation to the skin surface in the periorbital area. A slight reduction in skin surface roughness was recorded in 55% of the volunteers. On the contrary, a worsening from their initial states was detected in 25% of the subjects, while for 20%, no significant change was reported. Cluster analysis confirmed that the mentioned methodologies can be divided into two basic clusters, namely, a cluster of methods recording the changes in skin relief by means of optical techniques, and a cluster of methods investigating changes in hydration and anisotropy. In practice, the techniques in different clusters are not interchangeable and should be assessed separately. PMID- 28614950 TI - Grafting of architecture controlled poly(styrene sodium sulfonate) onto titanium surfaces using bio-adhesive molecules: Surface characterization and biological properties. AB - This contribution reports on grafting of bioactive polymers such as poly(sodium styrene sulfonate) (polyNaSS) onto titanium (Ti) surfaces. This grafting process uses a modified dopamine as an anchor molecule to link polyNaSS to the Ti surface. The grafting process combines reversible addition-fragmentation chain transfer polymerization, postpolymerization modification, and thiol-ene chemistry. The first step in the process is to synthetize architecture controlled polyNaSS with a thiol end group. The second step is the adhesion of the dopamine acrylamide (DA) anchor onto the Ti surfaces. The last step is grafting polyNaSS to the DA-modified Ti surfaces. The modified dopamine anchor group with its bioadhesive properties is essential to link bioactive polymers to the Ti surface. The polymers are characterized by conventional methods (nuclear magnetic resonance, size exclusion chromatography, and attenuated total reflection-Fourier transformed infrared), and the grafting is characterized by x-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry, and quartz crystal microbalance with dissipation monitoring. To illustrate the biocompatibility of the grafted Ti-DA-polyNaSS surfaces, their interactions with proteins (albumin and fibronectin) and cells are investigated. Both albumin and fibronectin are readily adsorbed onto Ti-DA-polyNaSS surfaces. The biocompatibility of modified Ti-DA-polyNaSS and control ungrafted Ti surfaces is tested using human bone cells (Saos-2) in cell culture for cell adhesion, proliferation, differentiation, and mineralization. This study presents a new, simple way to graft bioactive polymers onto Ti surfaces using a catechol intermediary with the aim of demonstrating the biocompatibility of these size controlled polyNaSS grafted surfaces. PMID- 28614951 TI - The diagnostic value of multimodality MRI in endometrial carcinoma staging: methodological issues to avoid misinterpretation. PMID- 28614952 TI - PHIRST Trial - pharmacist consults: prioritization of HIV-patients with a referral screening tool. AB - The role of pharmacists in HIV outpatient clinics has greatly increased in the past decades. Given the limited resources of the health system, the prioritization of pharmacist consults is now a main concern. This study aimed to create a scoring system allowing for standardized prioritization of pharmacist consults for patients living with HIV. Data was retrospectively collected from 200 HIV patients attending the Chronic Viral Illness Service at the McGill University Health Center. An expert panel consisting of four pharmacists working in the field of HIV prioritized each patient individually, after which a consensus was established and was considered as the gold standard. In order to create a scoring system, two different methods (Delphi, statistical) were used to assign a weight to each characteristic considered to be important in patient prioritization. A third method (equal weight to each characteristic) was also evaluated. The total score per patient for each method was then compared to the expert consensus in order to establish the score cut-offs to indicate the appropriate categories of delay in which to see the patient. All three systems failed to accurately prioritize patients into urgency categories ("less than 48 h", "less than 1 month", "less than 3 months", "no consult required") according to expert pharmacist consensus. The presence of high level interactions between patient characteristics, the limited number of patients and the low prevalence of some characteristics were hypothesized as the main causes for the results. Creating a prioritization tool for pharmacy consults in HIV outpatient clinics is a complex task and developing a decision tree algorithm may be a more appropriate approach in the future to take into account the importance of combinations of patient characteristic. PMID- 28614953 TI - Forced-Air Warming for Rewarming and Comfort Following Laparoscopy: A Randomized Controlled Trail. AB - We investigated the efficacy of a forced-air warming (FAW) system on postoperative rewarming and comfort in patients undergoing laparoscopic surgery. In this randomized controlled trial, a total of 127 participants were randomly divided into the FAW group ( n = 64) and control group ( n = 63). The esophageal temperature was measured every 30 min during surgery, and the tympanic temperature and comfort levels were measured preoperatively and in the postanesthesia care unit (PACU). Data analysis used the generalized estimating equation. We found that there was a lower incidence of postoperative hypothermia in the FAW group compared with the control group, as well as a higher body temperature between 30 and 180 min in the PACU, a shorter time for rewarming, and a higher comfort level. Taken together, these results suggest that FAW is an effective rewarming technique for laparoscopic patients during surgery and in the PACU that improves comfort levels. PMID- 28614954 TI - Using Visual Aids to Enhance Physician-Patient Discussions and Increase Health Literacy. AB - Health literacy refers to the comprehension required to make well-informed decisions regarding one's health. It is a critical component in helping patients to understand how to take their medications appropriately. However, many patients do not possess the comprehension necessary for medication adherence. The result of poor literacy is a higher incidence of misunderstanding medication instructions. Visual aids have the ability to transcend language and numeracy barriers and can therefore improve the effectiveness of communication and broaden target audiences. To enhance communication that is language independent, a template was created to provide instructions for proper use and explanation of risks for adverse events. This template is designed to fit on a single double sided page. This template can be adapted for use in explaining any medication using universal pictograms available from online resources. This would enable any practitioner to design information sheets for their unique use. PMID- 28614955 TI - Systemic effects after intravitreal injection of bevacizumab in new born rabbit eyes. AB - PURPOSE: To determine the systemic impact of intravitreal injection of bevacizumab (IVB), an anti-vascular endothelium growth factor antibody, in newborn rabbits. MATERIALS AND METHODS: We used four groups of rabbits. Group 1 rabbits received a single injection of IVB starting from the age of 6 weeks. Group 2 rabbits received a single injection of balanced salt solution (BSS, 0.025 ml) and served as controls for group 1. Group 3 rabbits received two consecutive injections of IVB at the ages of 6 and 10 weeks. Group 4 rabbits received two consecutive injections of BSS at the ages of 6 and 10 weeks and served as controls for group 3. During the experiment, a complete blood count (CBC), clinical biochemistry, weight gain, food intake, body temperature, blood pressure, pulse, and mortality were measured in the animals. Two months after IVB injection, the animals were sacrificed, and histology of the major organs was checked. Immunohistochemistry was assessed to explore the neurons in the central nervous system (CNS). RESULTS: We found there were no morphological or functional changes in the eyes following IVB injection. Furthermore, there were no differences in CBC, biochemistry, or other measured parameters among the four groups of animals. We checked the histology of the major organs and neurons in the CNS and they did not reveal significant differences among the four groups of animals. CONCLUSIONS: Conclusively, IVB of either one or two injections (0.625 mg) in newborn rabbit eyes is well tolerated and does not cause noticeable systemic organ pathology. PMID- 28614956 TI - Interventions for treating hyperemesis gravidarum: a Cochrane systematic review and meta-analysis. AB - INTRODUCTION: While nausea and vomiting in early pregnancy are very common, affecting approximately 80% of the pregnancies, hyperemesis gravidarum is a severe form affecting 0.3-1.0% of the pregnancies. Although hyperemesis gravidarum is rarely a source of mortality, it is a significant source of morbidity. It is one of the most common indications for hospitalization in pregnancy. Beyond the maternal and fetal consequences of malnutrition, the severity of hyperemesis symptoms causes a major psychosocial burden leading to depression, anxiety, and even pregnancy termination. The aim of this meta analysis was to examine all randomized controlled trials of interventions specifically for hyperemesis gravidarum and evaluate them based on both subjective and objective measures of efficacy, maternal and fetal/neonatal safety, and economic costs. MATERIAL AND METHODS: Randomized controlled trials were identified by searching electronic databases. We included all randomized controlled trials for the treatment of hyperemesis gravidarum. The primary outcome was intervention efficacy as defined by severity, reduction, or cessation in nausea/vomiting; number of episodes of emesis; and days of hospital admission. Secondary outcomes included other measures of intervention efficacy, adverse maternal/fetal/neonatal outcomes, quality of life measures, and economic costs. RESULTS: Twenty-five trials (2052 women) met the inclusion criteria but the majority of 18 different comparisons described in the review include data from single studies with small numbers of participants. Selected comparisons reported below: No primary outcome data were available when acupuncture was compared with placebo. There was insufficient evidence to identify clear differences between acupuncture and metoclopramide in a study with 81 participants regarding reduction/cessation in nausea or vomiting (risk ratio (RR) 1.40, 95% CI 0.79-2.49 and RR 1.51, 95% CI 0.92-2.48, respectively). Midwife-led outpatient care was associated with fewer hours of hospital admission than routine inpatient admission (mean difference (MD) - 33.20, 95% CI -46.91 to -19.49) with no difference in pregnancy-unique quantification of emesis and nausea (PUQE) score, decision to terminate the pregnancy, miscarriage, small-for-gestational age infants, or time off work when compared with routine care. Women taking vitamin B6 had a slightly longer hospital stay compared with placebo (MD 0.80 days, 95% CI 0.08-1.52). There was insufficient evidence to demonstrate a difference in other outcomes including mean number of episodes of emesis (MD 0.50, 95% CI -0.40 1.40) or side effects. A comparison between metoclopramide and ondansetron identified no clear difference in the severity of nausea or vomiting (MD 1.70, 95% CI -0.15-3.55, and MD -0.10, 95% CI -1.63-1.43; one study, 83 women, respectively). However, more women taking metoclopramide complained of drowsiness and dry mouth (RR 2.40, 95% CI 1.23-4.69, and RR 2.38, 95% CI 1.10-5.11, respectively). There were no clear differences between groups for other side effects. In a single study with 146 participants comparing metoclopramide with promethazine, more women taking promethazine reported drowsiness, dizziness, and dystonia (risk ratio (RR) 0.70, 95% CI 0.56-0.87, RR 0.48, 95% CI 0.34-0.69, and RR 0.31, 95% CI 0.11-0.90, respectively). There were no clear differences between groups for other important outcomes including quality of life and other side effects. In a single trial with 30 women, those receiving ondansetron had no difference in duration of hospital admission compared to those receiving promethazine (mean difference (MD) 0.00, 95% CI -1.39-1.39), although there was increased sedation with promethazine (RR 0.06, 95% CI 0.00-0.94). Regarding corticosteroids, in a study with 110 participants there was no difference in days of hospital admission compared to placebo (MD -0.30, 95% CI -0.70-0.10), but there was a decreased readmission rate (RR 0.69, 95% CI 0.50-0.94; 4 studies, 269 women). For hydrocortisone compared with metoclopramide, no data were available for primary outcomes and there was no difference in the readmission rate (RR 0.08, 95% CI 0.00-1.28; one study, 40 women). In a study with 80 women, compared to promethazine, those receiving prednisolone had increased nausea at 48 h (RR 2.00, 95% CI 1.08-3.72), but not at 17 days (RR 0.81, 95% CI 0.58-1.15). There was no clear difference in the number of episodes of emesis or subjective improvement in nausea/vomiting. CONCLUSIONS: While there were a wide range of interventions studied, both pharmaceutical and otherwise, there were a limited number of placebo controlled trials. In comparing the efficacy of the commonly used antiemetics, metoclopramide, ondansetron, and promethazine, the results of this review do not support the clear superiority of one over the other in symptomatic relief. Other factors such as side effect profile medication safety and healthcare costs should also be considered when selecting an intervention. PMID- 28614958 TI - Skeletons: Our Buried Bones at the Bristol M Shed (7 April to 3 Sept 2017). PMID- 28614957 TI - Associated Hematolymphoid Malignancies in Patients With Lymphomatoid Papulosis: A Canadian Retrospective Study. AB - BACKGROUND: Lymphomatoid papulosis is one of the primary cutaneous CD30+ T-cell lymphoproliferative disorders. Although considered a benign disease, lymphomatoid papulosis has been associated potentially with an increased risk of secondary hematolymphoid malignancies. OBJECTIVE: The aim of this study was to assess the clinical characteristics and histologic subtypes of lymphomatoid papulosis, identify the prevalence and types of secondary hematolymphoid malignancies, and determine the potential risk factors for development of these hematolymphoid malignancies. METHODS AND MATERIALS: A retrospective chart review was performed for all histologically confirmed cases of lymphomatoid papulosis between 1991 and 2016. RESULTS: Seventy patients with lymphomatoid papulosis were identified. Thirty patients (43%) experienced a secondary hematolymphoid malignancy. Twenty four (80%) of the hematolymphoid malignancies occurred after the onset of lymphomatoid papulosis. Older age at diagnosis of lymphomatoid papulosis, male sex, histology type B, and the presence of T-cell receptor gene rearrangement are associated with higher risk of developing hematolymphoid malignancy. CONCLUSION: Lymphomatoid papulosis is associated with increased risk of developing secondary hematolymphoid malignancies, particularly mycosis fungoides and cutaneous anaplastic large cell lymphoma. PMID- 28614959 TI - The effects of triptolide on the pharmacokinetics of sorafenib in rats and its potential mechanism. AB - CONTEXT: Combining sorafenib with triptolide could inhibit tumour growth with greater efficacy than single-agent treatment. However, their herb-drug interaction remains unknown. OBJECTIVE: This study investigates the herb-drug interaction between triptolide and sorafenib. MATERIALS AND METHODS: The effects of triptolide (10 mg/kg) on the pharmacokinetics of different doses of sorafenib (20, 50 and 100 mg/kg) in rats, and blood samples were collected within 48 h and evaluated using LC-MS/MS. The effects of triptolide on the absorption and metabolism of sorafenib were also investigated using Caco-2 cell monolayer model and rat liver microsome incubation systems. RESULTS: The results showed that the Cmax (low dose: 72.38 +/- 8.76 versus 49.15 +/- 5.46 ng/mL; medium dose: 178.65 +/- 21.05 versus 109.31 +/- 14.17 ng/mL; high dose: 332.81 +/- 29.38 versus 230.86 +/- 9.68 ng/mL) of sorafenib at different doses increased significantly with the pretreatment of triptolide, and while the oral clearance rate of sorafenib decreased. The t1/2 of sorafenib increased significant (p < 0.05) from 9.02 +/- 1.16 to 12.17 +/- 2.95 h at low dose with the pretreatment of triptolide. Triptolide has little effect on the absorption of sorafenib in Caco-2 cell transwell model. However, triptolide could significantly decrease the intrinsic clearance rate of sorafenib from 51.7 +/- 6.37 to 32.4 +/- 4.43 MUL/min/mg protein in rat liver microsomes. DISCUSSION AND CONCLUSIONS: These results indicated that triptolide could change the pharmacokinetic profiles of sorafenib in rats; these effects might be exerted via decreasing the intrinsic clearance rate of sorafenib in rat liver. PMID- 28614960 TI - Requirements on a community-based intervention for stimulating physical activity in physically disabled people: a focus group study amongst experts. AB - PURPOSE: To explore ideas experts, working in the field of physical activity for people with a disability, pose on a stimulating movement intervention for physically disabled people longer than one year post rehabilitation or not familiar with rehabilitation. METHODS: Four semi-structured focus groups were conducted with experts (n = 28). Transcripts were analysed following thematic analysis, using the integrated physical activity for people with a disability and intervention mapping model. RESULTS: Experts expressed no need for a new intervention, but, instead, a need for adapting an existing intervention, and increased collaboration between organisations. Such an adapted intervention should aim to change participants and environmental attitude towards physical activity, and to increase visibility of potential activities. Several methods were mentioned, for instance individual coaching. Potential participants should be personally approached via various intermediates. The intervention owner and government are responsible for stimulating physical activity and should finance an intervention together with health insurances and the user. CONCLUSIONS: According to experts adapting an existing intervention, together with increased collaboration between organisations, will be effective in stimulating physical activity in the target population. This study provides requirements on an intervention to stimulate physical activity, and suggestions for the approach of the target population, finance, and responsibility. Implications for Rehabilitation There is no need for designing a new intervention, but need for adaptation of an existing intervention for stimulating physical activity in physically disabled people. An intervention to stimulate physical activity in physically disabled people should aim to change participants and environmental attitude towards physical activity, and to increase the visibility of potential activities. Methods for stimulating physical activity in physically disabled people could be the use of individual coaching, feedback, a trial period, and role models. Potential participants should be personally approached via a network of intermediate organisations and via marketing, and the social environment. PMID- 28614961 TI - Greek economic crisis and impaired perinatal parameters: experience from a public maternity hospital. AB - Since 2008, Greece suffers a severe economic crisis. Adverse health outcomes have been reported, but studies on perinatal health are sparse. We aimed to examine the impact of economic crisis on perinatal parameters during early and established crisis periods. Birth records of 14 923 neonates, born in a public maternity hospital from 2005-2014, were reviewed for maternal (age, delivery mode) and neonatal (gender, birthweight, gestational age) variables. Univariable analysis tested the association of study variables with time-periods 2005-2007, 2009-2011 and 2012-2014. Multivariable logistic regression analysis identified factors independently associated with low birthweight (LBW) (<2500 g), prematurity (<37 weeks) and caesarean section (CS). During 2012-2014, compared to 2005-2007, LBW rate increased from 8.4 to 10.5% (RR 1.16; 95%CI 1.01-1.33); prematurity from 9.7 to 11.2% (RR 1.09; 95%CI 0.96-1.24), comprising mainly late preterm neonates; CS from 43.2 to 54.8% (RR 1.21; 95%CI 1.16-1.26). Maternal age >=30 years was risk factor for LBW, prematurity and CS; LBW was additional risk factor for CS. However, LBW and CSs increased during the study period, independently of maternal age. In conclusion, impaired perinatal parameters, manifested by increasing maternal age, LBW, prematurity and CS rate, were observed during the years of economic decline, with possible adverse consequences for later health. PMID- 28614962 TI - An Unusual Normal Finding in Coccygectomy Specimens. AB - Glomus coccygeum is a prominent or hyperplastic glomus structure that is located at the ventral tip of the coccyx, which frequently causes concern to pathologists that are unfamiliar with this entity. PMID- 28614963 TI - Watermelon juice concentration using ultrafiltration: Analysis of sugar and ascorbic acid. AB - Raw watermelon juice was concentrated in a laboratory-scale flat-plate ultrafiltration system incorporating polyethersulfone membranes with a molecular weight cutoff of 5 kDa. The experiments have been carried out over a wide range of transmembrane pressures (100-300 kPa). The effect of ultrafiltration with molecular weight cutoff of 5 kDa polyethersulfone membrane on concentrate properties is reported. The total soluble solid content of the permeate was found to be very good, while the ascorbic acid content was on the lower side as compared to feed. The analyses of flux decay according to fouling models reported in the literature revealed that the formation of a cake layer covering the entire surface of the membrane is the main cause of the membrane fouling. PMID- 28614964 TI - Thermosonication and optimization of stingless bee honey processing. AB - The effects of thermosonication on the quality of a stingless bee honey, the Kelulut, were studied using processing temperature from 45 to 90 C and processing time from 30 to 120 minutes. Physicochemical properties including water activity, moisture content, color intensity, viscosity, hydroxymethylfurfural content, total phenolic content, and radical scavenging activity were determined. Thermosonication reduced the water activity and moisture content by 7.9% and 16.6%, respectively, compared to 3.5% and 6.9% for conventional heating. For thermosonicated honey, color intensity increased by 68.2%, viscosity increased by 275.0%, total phenolic content increased by 58.1%, and radical scavenging activity increased by 63.0% when compared to its raw form. The increase of hydroxymethylfurfural to 62.46 mg/kg was still within the limits of international standards. Optimized thermosonication conditions using response surface methodology were predicted at 90 C for 111 minutes. Thermosonication was revealed as an effective alternative technique for honey processing. PMID- 28614965 TI - The Co-Occurrence of Autism Spectrum Disorder in Children With ADHD. AB - OBJECTIVE: Children with ADHD frequently present with autism spectrum disorder (ASD) symptomatology, yet there is a notable gap in the treatment needs of this subpopulation, including whether the presence of ASD may be associated with more severe ADHD symptoms. METHOD: Data from the 2014 National Survey of the Diagnosis and Treatment of ADHD and Tourette Syndrome ( n = 2,464) were used to compare children diagnosed with ADHD and ASD with children with ADHD, but not ASD. Children were classified as needing treatment if it was received or their parents reported it was needed, but not received. RESULTS: Approximately one in eight children currently diagnosed with ADHD was also diagnosed with ASD. Children diagnosed with both disorders had greater treatment needs, more co-occurring conditions, and were more likely to have a combined hyperactive/impulsive and inattentive ADHD subtype. CONCLUSION: These findings highlight the complexity of children diagnosed with both ADHD and ASD. PMID- 28614966 TI - Persistently elevated nuchal translucency and the fetal heart. AB - OBJECTIVE: To describe the outcome of fifteen cases with an elevated nuchal translucency (NT) which persisted into the second trimester as nuchal edema (NE) >6 mm whom underwent fetal echocardiography. MATERIALS AND METHODS: Cases were identified following retrospective review of cardiac and genetic findings in fetuses with NE. RESULTS: Minor congenital heart disease was identified in 3/15 by the second trimester. Agenesis of the ductus venosus was evident in four. Pulmonary valve stenosis was diagnosed in one fetus at the 20-week scan and hypertrophic cardiomyopathy in one. However, hypertrophic cardiomyopathy or pulmonary valve stenosis was present after birth in all surviving cases by 3 months of age. On the basis of intention to treat, 11/12 survived to delivery and 9/12 survived to 28 days. There were 6 deaths before 14 months of age as a result of severe hypertrophic cardiomyopathy. Noonan syndrome was confirmed with genetic testing in 11/15 cases. CONCLUSIONS: All fetuses with NT and NE had evidence of congenital heart disease at birth, and therefore, late gestation and postnatal review is recommended even when second trimester echocardiogram is considered normal. There is a high prevalence of Noonan syndrome and targeted genetic analysis should be considered. The outcome in these cases is poor. PMID- 28614967 TI - Bovine aortic arch: clinical significance and hemodynamic evaluation. AB - OBJECTIVE: The most common aortic arch branching variation described in literature is the common origin of the brachiocephalic trunk and left common carotid artery ("bovine arch" / type II aortic arch), with an incidence of 7.2 21.1%. The first aim of this study was to investigate the prevalence of bovine arch in the fetuses. The second aim was the hemodynamic evaluation of the epiaortic vessels. METHODS: In two years we examined 742 pregnant women and it was possible to obtain a good hemodynamic evaluation in 39 patients. Among the 39 fetuses, we found 6 with bovine arch. The blood flow of all epiaortic vessels and of MCA was evaluated. RESULTS: Among the 742 fetuses examined, the bovine aortic arch was identified in 45 patients (6.06%). The hemodynamic evaluation of the epiaortic vessels showed statistically significant differences between the bovine arch and normal aortic arch. CONCLUSION: The presence of bovine aortic arch in the fetus is characterized by some hemodynamical differences. They could have a possible relationship with the incidence of some pathologies in adult life. Prenatal knowledge of anatomic variants of the aortic arch can bring benefits to the individual's health for future possible cardiovascular investigations. PMID- 28614968 TI - Putty-like bone fillers based on CaP ceramics or Biosilicate(r) combined with carboxymethylcellulose: Characterization, optimization, and evaluation. AB - Calcium phosphates and bioactive glass ceramics have been considered promising biomaterials for use in surgeries. However, their moldability should be further enhanced. We here thereby report the handling, physicochemical features, and morphological characteristics of formulations consisting of carboxymethylcellulose-glycerol and hydroxyapatite-tricalcium phosphate or Biosilicate(r) particles. We hypothesized that combining either material with carboxymethylcellulose-glycerol would improve handling properties, retaining their bioactivity. In addition to scanning electron microscopy, cohesion, mineralization, pH, and viscoelastic properties of the novel formulations, cell culture experiments were performed to evaluate the cytotoxicity and cell proliferation. Putty-like formulations were obtained with improved cohesion and moldability. Remarkably, mineralization in simulated body fluid of hydroxyapatite tricalcium phosphate/carboxymethylcellulose-glycerol formulations was enhanced compared to pure hydroxyapatite-tricalcium phosphate. Cell experiments showed that all formulations were noncytotoxic and that HA-TCP60 and BGC50 extracts led to an increased cell proliferation. We conclude that combining carboxymethylcellulose-glycerol with either hydroxyapatite-tricalcium phosphate or Biosilicate(r) allows for the generation of moldable putties, improves handling properties, and retains the ceramic bioactivity. PMID- 28614969 TI - Short hospitalization after caesarean delivery: effects on maternal pain and stress at discharge. AB - PURPOSE: To characterize predischarge maternal pain and stress after caesarean delivery and short hospitalization. MATERIALS AND METHODS: This is a descriptive study with 60 women in the postoperative period of caesarean section and 60 control women after vaginal delivery. Pain and stress were measured by McGill Pain Questionnaire (MGPQ) and by the Stress Measure (Psychological Stress Measure (PSM)), respectively, at mother-infant dyad discharge, scheduled at 36 hours after delivery. RESULTS: Caesarean section was the delivery modality with the highest MGPQ pain and sensorial, evaluative and mixed pain descriptive categories scores. The pain location involved lower abdomen, with associated localizations at back, breast and shoulders. Conversely, vaginal delivery was the delivery modality with the highest stress scores. CONCLUSION: This study provides important information on the quality of care implications of early discharge practices in puerperae after caesarean delivery, a critical time characterized by qualitatively and quantitatively high pain and stress. PMID- 28614970 TI - Effect of Cerebrospinal Fluid Drainage on Brain Tissue Oxygenation in Traumatic Brain Injury. AB - The effectiveness of cerebrospinal fluid (CSF) drainage in lowering high intracranial pressure (ICP) is well established in severe traumatic brain injury (TBI). Recently, however, the use of external ventricular drains (EVDs) and ICP monitors in TBI has come under question. The aim of this retrospective study was to investigate the effect of CSF drainage on brain tissue oxygenation (PbtO2). Using a multi-modality monitoring system, we continuously monitored PbtO2 and parenchymal ICP during CSF drainage events via a ventriculostomy in 40 patients with severe TBI. Measurements were time-locked continuous recordings on a Component Neuromonitoring System in a neuroscience intensive care unit. We further selected for therapeutic CSF drainage events initiated at ICP values above 25 mm Hg and analyzed the 4-min periods before and after drainage for the physiologic variables ICP, cerebral perfusion pressure (CPP), and PbtO2. We retrospectively identified 204 CSF drainage events for ICP EVD-opening values greater than 25 mm Hg in 23 patients. During the 4 min of opened EVD, ICP decreased by 5.7 +/- 0.6 mm Hg, CPP increased by 4.1 +/- 1.2 mm Hg, and PbtO2 increased by 1.15 +/- 0.26 mm Hg. ICP, CPP, and PbtO2 all improved with CSF drainage at ICP EVD-opening values above 25 mm Hg. Although the average PbtO2 changes were small, a clinically significant change in PbtO2 of 5 mm Hg or greater occurred in 12% of CSF drainage events, which was correlated with larger decreases in ICP, displaying a complex relationship between ICP and PbtO2 that warrants further studies. PMID- 28614971 TI - Pilot Study of Therapy Dog Visits for Inpatient Youth With Cancer. AB - This study assessed the feasibility of studying animal-assisted activities (AAA) in inpatient pediatric oncology and collected preliminary data on potential benefits of AAA for this population. Patients at a large pediatric hospital were identified using electronic medical records and approached with physician approval. Patients completed surveys before and after a therapy dog visit in their private hospital room. Data on infections were ascertained by electronic medical record review. Provider surveys were placed in provider common areas and distributed through a link in an e-mail. We summarized resultsusing descriptive statistics and estimated mean changes in pre- and postintervention distress and conducted hypothesis tests using the paired t test. The study population (mean age = 12.9 years) consisted of 9 females and 10 males. Following the therapy dog visit, patients had lower distress and significant decreases in worry, tiredness, fear, sadness, and pain. Providers were generally supportive of the intervention. Eight patients developed infections during the 14 days after the dog visit but none could be clearly attributed to the therapy dog visit. The study's primary limitation was that there was no control group. However, results support the feasibility of and need for future studies on AAA in pediatric oncology. PMID- 28614973 TI - Comparison of an alcohol-based hand sanitation product with a traditional chlorhexidine hand scrub technique for hand hygiene preparation in an equine hospital. AB - AIMS: To investigate the efficacy of an alcohol gel-based hand antisepsis protocol compared with a traditional chlorhexidine-based protocol under conditions of routine clinical contamination, and following heavy faecal contamination. METHODS: Twelve adult participants were recruited and on four separate days completed a hand sanitation protocol using a chlorhexidine scrub or an alcohol-based gel, with hands that were grossly clean but contaminated or with faecal contamination. Bacterial samples were obtained from participants' hands before sanitation, immediately after and then 2 hours later. All samples were cultured on blood and MacConkey agar and bacterial colonies counted after 48 hours. RESULTS: for clean contaminated hands, the percentage reduction in bacterial colonies on blood agar immediately after hand sanitation was similar for both protocols (p=0.3), but was greater for the alcohol gel than chlorhexidine after 2 hours (p=0.005). For hands with faecal contamination, the percentage reduction in bacterial colonies on blood agar was similar for both protocols immediately and 2 hours after sanitation (p>0.2), but positive cultures were obtained on blood agar from samples collected after both protocols, for almost all participants. CONCLUSIONS: The results indicate equivalent efficacy of the alcohol-based gel and the pre-surgical chlorhexidine protocol. CLINICAL RELEVANCE: The alcohol-based gel protocol is an effective hand asepsis technique for grossly clean contaminated hands and those following faecal contamination, with comparable efficacy to chlorhexidine based scrub. PMID- 28614972 TI - Anti-inflammatory effects of a traditional Korean medicine: Ojayeonjonghwan. AB - OBJECTIVE: To study the anti-inflammatory properties of OJ. CONTEXT: Ojayeonjonghwan (OJ) is a traditional Korean prescription, which has been widely used for the treatment of prostatitis. However, no scientific study has been performed of the anti-inflammatory effects of OJ. MATERIALS AND METHODS: Peritoneal macrophages were isolated 3-4 days after injecting a C57BL/6J mouse with thioglycollate. They were then treated with OJ water extract (0.01, 0.1, and 1 mg/mL) for 1 h and stimulated with lipopolysaccharide (LPS) for different times. Nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and proinflammatory cytokine levels were determined by NO assay, Western blotting, RT-PCR and ELISA. RESULTS: NO generation and iNOS induction were increased in the LPS-activated mouse peritoneal macrophages. However, NO generation and iNOS induction by LPS were suppressed by treatment with OJ for the first time. The IC50 value of OJ with respect to NO production was 0.09 mg/mL. OJ did not influence LPS-stimulated COX-2 induction, but did significantly decrease LPS-stimulated secretions and mRNA expressions of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. Inhibition rates of TNF-alpha, IL-6, and IL-1beta at an OJ concentration of 1 mg/mL were 77%, 88%, and 50%, respectively. OJ also suppressed the LPS-induced nuclear translocation of NF-kappaB. High-performance liquid chromatography showed schizandrin and gomisin A are major components of OJ. CONCLUSIONS: OJ reduces inflammatory response, and this probably explains its positive impact on the prostatitis associated inflammation. PMID- 28614974 TI - Electronic consultation system demonstrates educational benefit for primary care providers. AB - Background Electronic consultation systems allow primary care providers to receive timely speciality expertise via iterative electronic communication. The use of such systems is expanding across the USA with well-documented high levels of user satisfaction. We characterise the educational impact for primary care providers of a long-standing integrated electronic consultation and referral system. Methods Primary care providers' perceptions of the educational value inherent to electronic consultation system communication and the impact on their ability to manage common speciality clinical conditions and questions were examined by electronic survey using five-point Likert scales. Differences in primary care providers' perceptions were examined overall and by primary care providers' speciality, provider type and years of experience. Results Among 221 primary care provider participants (35% response rate), 83.9% agreed or strongly agreed that the integrated electronic consultation and referral system provided educational value. There were no significant differences in educational value reported by provider type (attending physician, mid-level provider, or trainee physician), primary care providers' speciality, or years of experience. Perceived benefit of the electronic consultation and referral system in clinical management appeared stronger for laboratory-based conditions (i.e. subclinical hypothyroidism) than more diffuse conditions (i.e. abdominal pain). Nurse practitioners/physician assistants and trainee physicians were more likely to report improved abilities to manage specific clinical conditions when using the electronic consultation and/or referral system than were attending physicians, as were primary care providers with <=10 years experience, versus those with >20 years of experience. Conclusions Primary care providers report overwhelmingly positive perceptions of the educational value of an integrated electronic consultation and referral system. Nurse practitioners, physician assistants, trainee physicians and less-experienced primary care providers report the greatest clinical educational benefit, particularly for conditions involving lab based diagnosis and management. PMID- 28614975 TI - Prenatal diagnosis of fetal right and left congenital ventricular aneurysms. AB - AIM: To describe the ultrasonographic appearance of fetal ventricular aneurysm. METHODS: Ultrasound characteristics of two cases of prenatally diagnosed fetal ventricular aneurysm were reviewed. RESULTS: There was one case of left ventricular aneurysm diagnosed by prenatal ultrasound at 38 weeks of gestation. Another case of fetal right ventricular aneurysm was diagnosed prenatally at 36 weeks of gestation. Both the babies expired in the immediate post-natal period. CONCLUSION: Congenital ventricular aneurysm is a rare cardiac malformation characterized by protrusion or out pouching of a portion of the ventricular wall. It is important to differentiate an aneurysm from diverticulum, as the latter has favorable prognosis. The aneurysms are usually large and have broad-based communication with the ventricular cavity in contrast to diverticuli, which are small and connected by a narrow base. PMID- 28614976 TI - Perception of Symmetry in Aesthetic Rhinoplasty Patients: Anthropometric, Demographic, and Psychological Analysis. AB - : Visual perception of symmetry is a major determinant of satisfaction after aesthetic rhinoplasty. In this study, we sought to investigate the existence of any relationship between anthropometric characteristics of the face and visual perceptions of asymmetry among rhinoplasty patients and to evaluate tools that can shed light on patients who appear at high risk for exaggerating potential asymmetries. In the first part, 168 rhinoplasty patients were asked to fill out the demographic questionnaire, nasal shape evaluation scale, and the somatosensory amplification scale. In the second part, we examined the relationship between anthropometric characteristics of the face and visual perceptions of asymmetry using standardized photographs of 100 medical students. In the third part, patients answered the rhinoplasty outcome evaluation questionnaire 6 months after the surgery. Objectively, no symmetrical face was observed in the anthropometric evaluation. Subjectively, only 73% and 54% of the faces were considered asymmetrical by the rhinoplasty and the control groups, respectively. The rate of asymmetry perception was significantly greater in revision patients when compared with primary rhinoplasty patients. The relationship between the rate of subjective perception of asymmetry and the somatosensory amplification scale scores was statistically significant. We found a significant inverse relationship between the rate of asymmetry perception and the rhinoplasty outcome evaluation scores. Plastic surgeons should be aware of this high selectivity in asymmetry perception, which is associated with poor postoperative satisfaction. Somatosensory amplification scale may help identify rhinoplasty patients at a high risk for exaggerating potential asymmetries. LEVEL OF EVIDENCE: III. PMID- 28614979 TI - Docetaxel-induced cardiac-respiratory arrest in a patient with chronic atrial fibrillation. AB - Docetaxel has been approved by the Food and Drug Administration for the treatment of many cancer types, including breast cancer, head and neck cancer, lung cancer, and prostate cancer. Many severe to life-threatening side effects (Grades 3-5) of docetaxel have been reported in clinical trials, case reports, and Food and Drug Administration Adverse Events Reporting System. These include anaphylactic reactions, febrile neutropenia, fluid retention, acute respiratory distress, pleural effusion, pneumonia, and peripheral neuropathy. There were fewer cardiac toxicities reported for docetaxel as compared to paclitaxel, which were less severe. In this report, we present a clinical case of docetaxel-induced cardiac respiratory arrest in a 62-year-old Hispanic male patient with stable chronic atrial fibrillation, who has been recently diagnosed with metastatic prostate cancer. The cardiac event developed within 15 min of docetaxel infusion during the second cycle of chemotherapy despite using recommended premedication with corticosteroids. PMID- 28614981 TI - Nuclear-Encoded Mitochondrial mRNAs: A Powerful Force in Axonal Growth and Development. AB - Axons, their growth cones, and synaptic nerve terminals are neuronal subcompartments that have high energetic needs. As such, they are enriched in mitochondria, which supply the ATP necessary to meet these demands. To date, a heterogeneous population of nuclear-encoded mitochondrial mRNAs has been identified in distal axons and growth cones. Accumulating evidence suggests that the local translation of these mRNAs is required for mitochondrial maintenance and axonal viability. Here, we review evidence that suggests a critical role for axonal translation of nuclear-encoded mitochondrial mRNAs in axonal growth and development. Additionally, we explore the role that site-specific translation at the mitochondria itself may play in this process. Finally, we briefly review the clinical implications of dysregulation of local translation of mitochondrial related mRNAs in neurodevelopmental disorders. PMID- 28614980 TI - Meta-analysis and indirect treatment comparison of lipegfilgrastim with pegfilgrastim and filgrastim for the reduction of chemotherapy-induced neutropenia-related events. AB - Background Granulocyte colony-stimulating factors are effective at reducing the risk and duration of neutropenia. The current meta-analysis compared the neutropenia-related efficacy and safety of lipegfilgrastim to those of pegfilgrastim and filgrastim. Methods Embase was searched for trials examining the efficacy/safety of lipegfilgrastim, pegfilgrastim, or filgrastim. Outcomes included febrile neutropenia, severe neutropenia, duration of severe neutropenia, time to recovery of absolute neutrophil count, and incidence of bone pain. Direct comparisons were made using random-effects models. No trials directly compared lipegfilgrastim and filgrastim. Indirect comparisons were made between lipegfilgrastim and filgrastim with pegfilgrastim as the common comparator. Results This meta-analysis included a total of 5769 patients from 24 studies. Over all cycles, lipegfilgrastim showed a lower, nonsignificant risk of febrile neutropenia compared with pegfilgrastim. Lipegfilgrastim has a lower risk of febrile neutropenia versus filgrastim but was also not statistically significant. The risk ratio for severe neutropenia in cycle 1 was 0.80, a 20% reduction in favor of lipegfilgrastim. For cycles 2-4, the risk ratio was 0.53 (0.35, 0.79) for lipegfilgrastim versus pegfilgrastim. The risk of severe neutropenia in cycles 2-4 was also significantly lower for lipegfilgrastim (risk ratio 0.45, 0.27, 0.75, respectively). No significant differences were found for febrile neutropenia and severe neutropenia in cycle 1. However, in cycles 2-4, lipegfilgrastim was associated with significant and clinically meaningful reductions in risk of severe neutropenia versus either pegfilgrastim or filgrastim. Conclusions Compared with pegfilgrastim or filgrastim, lipegfilgrastim has a statistically significantly lower absolute neutrophil count recovery time; however, differences in duration of severe neutropenia and bone pain were nonsignificant. PMID- 28614982 TI - Intraventricular administration of tigecycline for the treatment of multidrug resistant bacterial meningitis after craniotomy: a case report. AB - BACKGROUND: Intracranial infections, especially multidrug-resistant (MDR) bacterial meningitis, are one of the most severe complications after craniotomy and may greatly impact patient outcomes. CASE PRESENTATION: We report a case of severe MDR Klebsiella pneumonia meningitis after craniotomy that was treated with three different dosages of tigecycline (Pfizer, New York, NY, U.S.A.)via a combined intravenous (IV) and intracerebroventricular (ICV) administration. Here, we discuss the pharmacokinetics (PK) of a combined IV and ICV tigecycline administration for a patient with an intracranial infection after craniotomy. CONCLUSION: In the present case, three different dosages of tigecycline were administered: 49 mg IV plus 1 mg ICV q12 h, 45 mg IV plus 5 mg ICV q12 h, 40 mg IV plus 10 mg ICV q12 h. The combined IV and ICV administration might improve CSF tigecycline concentrations, and in this case, the methods of administration were safe and effective. PMID- 28614983 TI - Second Primary Cancer in Patients with Differentiated Thyroid Cancer: Does Radioiodine Play a Role? AB - BACKGROUND: Well-differentiated thyroid cancer (WDTC) is the most common endocrine neoplasia, and its incidence is rising. Studies have reported an increased risk of second primary cancer (SPC) in WDTC survivors, but its relationship with radioiodine treatment (RAIT) and other risk factors remains controversial. This study evaluated whether RAIT is an independent risk factor for SPC in WDTC patients. METHODS: This was a retrospective single-center study. A total of 2031 patients with WDTC diagnosed between 1998 and 2009, treated and followed at the authors' tertiary cancer center, were included. RESULTS: The median age of patients was 48 years (range 5-90 years); 83% were women and 77% underwent RAIT. The median follow-up was 8.8 years (range 5.0-17.0 years). A total of 130 SPC were diagnosed: 108/1570 (6.9%) received RAIT (RAIT+) and 22/461 (4.8%) did not (RAIT-). The most common SPC was breast cancer (31%), followed by genitourinary and gastrointestinal cancer (18% each). The 10-year cumulative incidence of SPC was 8.2% in RAIT+ and 4.5% in RAIT-. The absolute risk increase in the RAIT+ group versus the RAIT- group at 10 years of follow-up was 0.039 [confidence interval (CI) 0.011-0.067] per patient-year. The number needed to harm (NNH) was 25.6 [CI 15.0-87.2], indicating that on average during a 10-year follow-up period, there is one additional case of SPC for every 26 patients receiving RAIT. When controlling for age, sex, and familial and personal histories of cancer, there was an 84% increase in the risk of SPC in the RAIT+ group compared to the RAIT- group (p = 0.026; relative risk = 1.84 [CI 1.02 3.31]). There was an association between SPC incidence and total cumulative activity administered, which was statistically significant >200 mCi. The incidence of SPC was higher in both the WDCT and the RAIT+ cohorts compared to the general population (standardized incidence ratios = 1.32 and 1.40, respectively). CONCLUSION: These results indicate that in spite of the low incidence of SPC in WDTC patients, the risk is increased after RAIT, particularly for activities >200 mCi. Thus, considering the excellent survival of patients with WDTC, clinicians need to weigh the risks and benefits of RAIT, especially in patients with low-risk thyroid cancer. PMID- 28614984 TI - TERT Promoter Mutations Were Not Found in Papillary Thyroid Microcarcinomas That Showed Disease Progression on Active Surveillance. PMID- 28614985 TI - Stimulation of abdominal and upper thoracic muscles with surface electrodes for respiration and cough: Acute studies in adult canines. AB - OBJECTIVE: To optimize maximal respiratory responses with surface stimulation over abdominal and upper thorax muscles and using a 12-Channel Neuroprosthetic Platform. METHODS: Following instrumentation, six anesthetized adult canines were hyperventilated sufficiently to produce respiratory apnea. Six abdominal tests optimized electrode arrangements and stimulation parameters using bipolar sets of 4.5 cm square electrodes. Tests in the upper thorax optimized electrode locations, and forelimb moment was limited to slight-to-moderate. During combined muscle stimulation tests, the upper thoracic was followed immediately by abdominal stimulation. Finally, a model of glottal closure for cough was conducted with the goal of increased peak expiratory flow. RESULTS: Optimized stimulation of abdominal muscles included three sets of bilateral surface electrodes located 4.5 cm dorsal to the lateral line and from the 8th intercostal space to caudal to the 13th rib, 80 or 100 mA current, and 50 Hz stimulation frequency. The maximal expired volume was 343 +/- 23 ml (n=3). Optimized upper thorax stimulation included a single bilateral set of electrodes located over the 2nd interspace, 60 to 80 mA, and 50 Hz. The maximal inspired volume was 304 +/- 54 ml (n=4). Sequential stimulation of the two muscles increased the volume to 600 +/- 152 ml (n=2), and the glottal closure maneuver increased the flow. CONCLUSIONS: Studies in an adult canine model identified optimal surface stimulation methods for upper thorax and abdominal muscles to induce sufficient volumes for ventilation and cough. Further study with this neuroprosthetic platform is warranted. PMID- 28614986 TI - Higher adherence to Mediterranean diet prior to pregnancy is associated with decreased risk for deviation from the maternal recommended gestational weight gain. AB - The present retrospective study was conducted on 1482 women in order to evaluate whether their pre-pregnancy adherence to the Mediterranean diet may affect maternal gestational weight gain (GWG). For this purpose, the study population was classified according to the Institute of Medicine (IOM) recommendations concerning GWG. Pre-pregnancy adherence to the Mediterranean diet was assessed with 11 food patterns groups based on their contribution in the Mediterranean diet pyramid. Women with high adherence to the Mediterranean diet were more frequently characterised by GWG inside the IOM recommendations. In multivariate analysis, women with low Mediterranean diet adherence were almost twice at risk in presenting deflection from recommended GWG regardless of various confounding factors. These findings suggested that high pre-pregnancy adherence to the Mediterranean diet may be associated with reduced risk for GWG outside the IOM recommendations. However, larger prospective studies are strongly recommended in order for more precise conclusions to be drawn. PMID- 28614987 TI - Role of amino acid supplementation in the prevention of necrotizing enterocolitis in preterm neonates - a review of current evidences. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is one of the most common acute and fatal gastrointestinal emergency in very low birth weight (VLBW) preterm neonates with mortality range from 15 to 30%. NEC is likely due to multifactorial process such as oxidative injury, ischemic necrosis, and over-reactive inflammatory response to intestinal microbes. AIMS: To evaluate the role of amino acid supplementation for reduction of neonatal NEC in preterm neonates. METHOD: The literature search was done for various randomized control trial (RCT) by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, Scopus, Index Copernicus, African Index Medicus (AIM), Thomson Reuters (ESCI), Chemical Abstracts Service (CAS) and other database. RESULTS: This review included 15 RCTs that fulfilled inclusion criteria. The total neonates enrolled in these different RCT are 3424 (amino acid group 1711 and control 1713). Almost all participating neonates were of VLBW or extremely low birth weight (ELBW). In two trials, birth weight was between 1500-2000 grams. The intervention was started within first few days after birth and continued up to 30th day of postnatal age in most of the trials. In two trials, intervention was continued up to 120th day of postnatal age. Arginine, glutamine and N-acetyl cysteine (NAC) were used at the dose of 1.5 mol/kg/day (261 mg/kg/day), 0.3 grams/kg/day and 16-32 mg/kg/day, respectively. CONCLUSION: Role of amino acid in the prevention of neonatal NEC is not exclusively supported by the current evidence. Only three studies were able to show reduction in the incidence of NEC with amino acid supplementation (arginine, glutamine), and the remaining studies did not report any positive effect. Amino acid supplementation was not associated with significant reduction in mortality due to any causes. However, arginine supplementation was associated with significant reduction in mortality due to NEC. Two studies on glutamine were reported significant reduction in the incidence of invasive infection. Only one study reported significant positive effects on growth parameters and less time to reach full enteral feeds. None of the studies showed any effect on the duration of hospital stay. PMID- 28614988 TI - In vitro inhibitory effects of dihydromyricetin on human liver cytochrome P450 enzymes. AB - CONTEXT: Dihydromyricetin (DHM) is the most abundant and active flavonoid component isolated from Ampelopsis grossedentata (Hand-Mazz) W.T. Wang (Vitaceae) and it possesses numerous pharmacological activities. However, whether DHM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. MATERIALS AND METHODS: The inhibitory effects of DHM on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs). RESULTS: The results showed that DHM could inhibit the activity of CYP3A4, CYP2E1 and CYP2D6, with IC50 values of 14.75, 25.74 and 22.69 MUM, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that DHM was not only a non-competitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP2E1 and CYP2D6, with Ki values of 6.06, 9.24 and 10.52 MUM, respectively. In addition, DHM is a time-dependent inhibitor for CYP3A4 with KI/Kinact value of 12.17/0.057 min-1 MUM-1. DISCUSSION AND CONCLUSION: The in vitro studies of DHM with CYP isoforms indicate that DHM has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4, CYP2E1 and CYP2D6. Further clinical studies are needed to evaluate the significance of this interaction. PMID- 28614989 TI - A challenging entity of endovascular embolization with ONYX for brainstem arteriovenous malformation: Experience from 13 cases. AB - Objective Brainstem arteriovenous malformations (AVMs) are rare lesions with a high risk of intracranial hemorrhage and are challenging to treat. We present our experience of endovascular embolization with Onyx in these aggressive lesions. Materials and methods Between 2007 and 2016, 13 patients with brainstem AVMs were embolized with Onyx at our center. Twelve patients presented with intracranial hemorrhage and one with headache. Retrospective examinations of patient demographics, clinical presentation, angiographic features, treatment modalities, postoperative complications and outcomes were carried out. Results The AVMs were in the midbrain in 10 patients (one anterior and nine posterior or dorsal), in the posterior pons in two and pontomedullary in one. Complete occlusion was achieved in three patients. Gamma knife radiosurgery was performed in six patients who were near-completely or partially embolized. Postoperative complications, including five cases of ischemia and one case of hemorrhage, resulted in four cases of neurological deterioration and two deaths. Clinical follow-up was obtained in 10 patients at a mean period of 45.2 months (range 3 to 93 months). During the follow-up, good clinical outcomes were observed in seven patients with posterior or dorsal midbrain AVMs, and one patient with a posterior pons AVM that was partially occluded died of intracranial hemorrhage. Conclusion Endovascular embolization for brainstem AVM with Onyx is a technical challenge and the reflux of Onyx may cause severe complications. Individualized treatment is needed based on the specific subtype of brainstem AVM. PMID- 28614990 TI - Screening organization and recall rate in a regional breast screening programme. AB - Objective To use results on recall rates from a regional non-population-based breast screening programme to inform practice in a planned national population based programme. Methods We analysed data on rates of recall for further assessment in 27,327 mammographic screening episodes in 2015-2016 in the breast screening programme in the city of Tbilisi, Georgia. Screening was done by two view digital mammography with double reading in women aged 40-70, and further assessment took place at the same clinic and during the same visit as the initial screening mammogram. Results The recall rates were 46% (3573/7824) in 2015 and 27% (5276/19,503) in 2016. Cancer detection rates were 8 per 1000 in 2015 and 3 per 1000 in 2016. Rates of recall were higher in younger women than in older, whereas the rates of cancer detection were higher in older women. Conclusions The recall rates, while lower in 2016 than in 2015, are still too high to manage in a nationwide population programme. The use of same-visit assessment is likely to be contributing to this. The national programme should consider separate assessment clinics and carry out audit of recalls to date. PMID- 28614991 TI - Invitation coverage and participation in Italian cervical, breast and colorectal cancer screening programmes. AB - Objectives In Italy, regional governments organize cervical, breast and colorectal cancer screening programmes, but there are difficulties in regularly inviting all the target populations and participation remains low. We analysed the determinants associated with invitation coverage of and participation in these programmes. Methods We used data on screening programmes from annual Ministry of Health surveys, 1999-2012 for cervical, 1999-2011 for breast and 2005 2011 for colorectal cancer. For recent years, we linked these data to the results of the national routine survey on preventive behaviours to evaluate the effect of spontaneous screening at Province level. Invitation and participation relative risk were calculated using Generalized Linear Models. Results There is a strong decreasing trend in invitation coverage and participation in screening programmes from North to South Italy. In metropolitan areas, both invitation coverage (rate ratio 0.35-0.96) and participation (rate ratio 0.63-0.88) are lower. An inverse association exists between spontaneous screening and both screening invitation coverage (1-3% decrease in invitation coverage per 1% spontaneous coverage increase) and participation (2% decrease in participation per 1% spontaneous coverage increase) for the three programmes. High recall rate has a negative effect on invitation coverage in the next round for breast cancer (1% decrease in invitation per 1% recall increase). Conclusions Organizational and cultural changes are needed to better implement cancer screening in southern Italy. PMID- 28614992 TI - Preimplantation genetic screening. AB - Preimplantation genetic diagnosis was first successfully performed in 1989 as an alternative to prenatal diagnosis for couples at risk of transmitting a genetic or chromosomal abnormality, such as cystic fibrosis, to their child. From embryos generated in vitro, biopsied cells are genetically tested. From the mid-1990s, this technology has been employed as an embryo selection tool for patients undergoing in vitro fertilisation, screening as many chromosomes as possible, in the hope that selecting chromosomally normal embryos will lead to higher implantation and decreased miscarriage rates. This procedure, preimplantation genetic screening, was initially performed using fluorescent in situ hybridisation, but 11 randomised controlled trials of screening using this technique showed no improvement in in vitro fertilisation delivery rates. Progress in genetic testing has led to the introduction of array comparative genomic hybridisation, quantitative polymerase chain reaction, and next generation sequencing for preimplantation genetic screening, and three small randomised controlled trials of preimplantation genetic screening using these new techniques indicate a modest benefit. Other trials are still in progress but, regardless of their results, preimplantation genetic screening is now being offered globally. In the near future, it is likely that sequencing will be used to screen the full genetic code of the embryo. PMID- 28614993 TI - A Single 10 mg Oral Dose of Biotin Interferes with Thyroid Function Tests. PMID- 28614994 TI - Are preterm-born survivors at risk of long-term respiratory disease? AB - BACKGROUND: To evaluate the long-term impact of preterm birth on respiratory function in female patients born preterm, we undertook spirometric examinations twice, as they reached the age of puberty, then follow-up examinations of part of the same cohort in adulthood. We sought evidence that preterm birth is correlated with poorer spirometric results into adulthood. METHODS: A total of 70 girls (aged 12.2 +/- 1.5 years in 1997) who had been born preterm (at 34.7 +/- 1.86 weeks, none having experienced bronchopulmonary dysplasia) took part in spriometric examinations in 1997 and again in 1998. Of those, after a gap of 17 years, a group of 12 were successfully recontacted and participated in the 2015 examination as adults (then aged 27.6 +/- 2.6 years, born at 34.5 +/- 1.92 weeks). We compared spirometric results across the adolescent and adult examinations, and compared the adult results with an adult reference group. RESULTS: The percentage values of FEV1 (forced expiratory volume in 1 s), FVC (forced vital capacity) and MVV (maximal voluntary ventilation) showed significant improvement between the two examinations in the early adolescent period. In adulthood, FEV1%pred (percentage predicted forced expiratory volume in 1 s) showed no statistically significant difference. The mean values of both FVC and FVC%pred (percentage predicted forced vital capacity) for the preterm-born group were lower than for the reference group, but this was not statistically significant. The preterm-born group showed lower values of such parameters as forced expiratory flow at 25-75% of FVC, MEF25 (maximal expiratory flow at 25% of forced vital capacity) and FEV1/FVC as compared with the reference group, but again without statistical significance. CONCLUSIONS: (1) A somewhat below-norm level of respiratory parameters among preterm-born girls entering pubescence may attest to continued negative impact on their respiratory system. (2) A significant improvement in their spirometric results 1 year later may indicate that pubescence helps compensate for the earlier negative effect of preterm birth. (3) No significant differences were seen in lung function in preterm-born adults as compared with a reference group of adults, although the preterm-born group did exhibit lower values of all parameters studied and more frequent obstructive disorders. PMID- 28614996 TI - Myeloma patients: genes increase risk for osteonecrosis of the jaw. PMID- 28614995 TI - Ease of use of tobramycin inhalation powder compared with nebulized tobramycin and colistimethate sodium: a crossover study in cystic fibrosis patients with pulmonary Pseudomonas aeruginosa infection. AB - BACKGROUND: This study assessed the ease of use of tobramycin inhalation powder (TIP) administered via T-326 inhaler versus tobramycin inhalation solution (TIS) and colistimethate sodium (COLI), both administered via nebulizers, for the treatment of chronic pulmonary Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF). METHODS: A real-world, open-label, crossover, interventional phase IV study was conducted in CF patients aged ?6 years with forced expiratory volume in 1 second (FEV1) ?25% to ?90% predicted. Patients were assigned to one of the three treatment arms in Cycle 1; all patients received TIP in Cycle 2. Each cycle consisted of 28 days on and 28 days off the treatment. RESULTS: A total of 60 patients [mean (standard deviation) age, 27.6 (8.4) years] were allocated to three treatment arms [TIS/TIP ( n = 14); COLI/TIP ( n = 28); TIP/TIP ( n = 18)] in Cycle 1. The mean total administration time, which included device setup and cleaning, in Cycle 1 versus Cycle 2 for TIS/TIP, COLI/TIP, and TIP/TIP arms were 37.0 versus 5.0 min, 16.4 versus 3.8 min, and 4.2 versus 3.4 min, respectively. The difference in mean total administration time was significantly shorter in Cycle 2 than in Cycle 1 for TIS/TIP ( p = 0.0112) and COLI/TIP ( p = 0.0016) arms. Overall, 12 patients were found to have contaminated devices across the two treatment cycles. In the TIP/TIP arm, no contamination of the T-326 inhaler was observed in either cycle. Treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication and ACCEPT(r) questionnaire, was better overall for TIP compared with TIS and COLI. There were no unexpected adverse events and most were mild or moderate in intensity. CONCLUSION: The T-326 inhaler used to deliver TIP was easy to use, required shorter total administration time, and was much less frequently contaminated than the nebulizers. The safety findings observed for TIP were generally consistent with its established safety profile. PMID- 28614997 TI - Resilience-based Diabetes Self-management Education: Perspectives From African American Participants, Community Leaders, and Healthcare Providers. AB - Purpose The purpose of this qualitative, focus group study was to further refine the Resilience-based Diabetes Self-management Education (RB-DSME) recruitment process and intervention, build greater trust in the community, and identify strategies to enhance its sustainability as a community-based intervention in African American church settings. Methods Six 2-hour focus groups (N = 55; 10 men and 45 women) were led by a trained moderator with a written guide to facilitate discussion. Two sessions were conducted with individuals diagnosed with type 2 diabetes mellitus (T2DM) who participated in previous RB-DSME pilot interventions and their family members, two sessions with local church leaders, and two sessions with community healthcare providers who care for patients with T2DM. Two independent reviewers performed content analysis to identify major themes using a grounded theory approach. The validity of core themes was enhanced by external review and subsequent discussions with two qualitative methods consultants. Results There was expressed interest and acceptability of the RB-DSME program. Church connection and pastor support were noted as key factors in building trust and enhancing recruitment, retention, and sustainability of the program. Core themes across all groups included the value of incentives, the need for foundational knowledge shared with genuine concern, teaching with visuals, dealing with denial, balancing the reality of adverse consequences with hope, the importance of social support, and addressing healthcare delivery barriers. Conclusion Focus groups documented the feasibility and potential effectiveness of RB-DSME interventions to enhance diabetes care in the African American community. In clinical practice, inclusion of these core themes may enhance T2DM self-care and treatment outcomes. PMID- 28614998 TI - A Season of American Football Is Not Associated with Changes in Plasma Tau. AB - American football athletes are routinely exposed to sub-concussive impacts over the course of the season. This study sought to examine the effect of a season of American football on plasma tau, a potential marker of axonal damage. Nineteen National Collegiate Athletic Association (NCAA) football athletes underwent serial blood sampling over the course of the 2014-2015 season at those times in which the number and magnitude of head impacts likely changed. Non-contact sport controls (NCAA men's swim athletes; n = 19) provided a single plasma sample for comparison. No significant differences were observed between control swim athletes and football athletes following a period of non-contact (p = 0.569) or a period of contact (p = 0.076). Football athletes categorized as starters (n = 11) had higher tau concentrations than non-starters (n = 8) following a period of non contact (p = 0.039) and contact (p = 0.036), but not higher than swimmers (p = 1.000 and p = 1.000, respectively). No difference was noted over the course of the season in football athletes, irrespective of starter status. Despite routine head impacts common to the sport of American football, no changes were observed over the course of the season in football athletes, irrespective of starter status. Further, no difference was observed between football athletes and non contact control swim athletes following a period of non-contact or contact. These data suggest that plasma tau is not sensitive enough to detect damage associated with repetitive sub-concussive impacts sustained by collegiate-level football athletes. PMID- 28614999 TI - Stories That Heal: Understanding the Effects of Creating Digital Stories With Pediatric and Adolescent/Young Adult Oncology Patients. AB - The purpose of this philosophical hermeneutic study was to determine if, and understand how, digital stories might be effective therapeutic tools to use with children and adolescents/young adults (AYA) with cancer, thus helping mitigate suffering. Sixteen participants made digital stories with the help of a research assistant trained in digital storytelling and were interviewed following the completion of their stories. Findings from this research revealed that digital stories were a way to have others understand their experiences of cancer, allowed for further healing from their sometimes traumatic experiences, had unexpected therapeutic effects, and were a way to reconcile past experiences with current life. Digital stories, we conclude, show great promise with the pediatric and AYA oncology community and we believe are a way in which the psychosocial effects of cancer treatment may be addressed. Recommendations for incorporating digital stories into clinical practice and follow-up programs are offered. PMID- 28615000 TI - "A Tribe Apart": Sexuality and Cancer in Adolescence. AB - This qualitative study employed hermeneutic phenomenology and narrative inquiry to examine the topic of sexuality and adolescents with cancer from the perspectives of survivors who had experienced cancer as adolescents. This investigation examined the potentially sensitive, disquieting, and often taboo issue of sexuality in the interest of optimizing wellness in young people, and, ultimately, in the health of adults. Understanding the adolescent body as a sensitive, sexual, and developing self can enrich our understanding of adolescent cancer and promote best health care and practices, examining ways that we might mitigate the long-term effects of arrested or delayed development of sexual identity. In this article, we discuss phase 1 of the study, which used hermeneutics as the method of inquiry. Findings included a general experience of adolescents having a sense of "losing themselves" while at the same time finding themselves in a new light. Other findings include the connection between sexuality, self, and identity; the unique "tribe" of adolescents with cancer; the necessity for sexuality to take a backseat to cancer; the changing mirror images from self and others; sexuality and fertility; and, ultimately, that sexuality is a relational experience. PMID- 28615001 TI - "She Was a Little Social Butterfly": A Qualitative Analysis of Parent Perception of Social Functioning in Adolescent and Young Adult Brain Tumor Survivors. AB - Psychosocial sequelae of diagnosis and treatment for childhood brain tumor survivors are significant, yet little is known about their impact on adolescent and young adult (AYA) brain tumor survivors. Interviews were conducted with parents of AYA brain tumor survivors with a focus on social functioning. Semistructured interviews were conducted with English- and Spanish-speaking parents of AYA brain tumor survivors >=10 years of age who were >2 years postdiagnosis, and analyzed using emergent themes theoretically integrated with a social neuroscience model of social competence. Twenty parents representing 19 survivors with a survivor mean age 15.7 +/- 3.3 years and 10.1 +/- 4.8 years postdiagnosis were interviewed. Several themes relevant to the social neuroscience social competence model emerged. First, parents' perceptions of their children's impaired social functioning corroborated the model, particularly with regard to poor social adjustment, social withdrawal, impaired social information processing, and developmentally inappropriate peer communication. Second, ongoing physical and emotional sequelae of central nervous system insults were seen by parents as adversely affecting social functioning among survivors. Third, a disrupted family environment and ongoing parent psychosocial distress were experienced as salient features of daily life. We document that the aforementioned framework is useful for understanding the social impact of diagnosis and treatment on AYA brain tumor survivorship. Moreover, the framework highlights areas of intervention that may enhance social functioning for AYA brain tumor survivors. PMID- 28615002 TI - Effect of a simulation-based workshop on breaking bad news for anesthesiology residents: an intervention study. AB - BACKGROUND: Breaking bad news (BBN) to patients and their relatives is a complex and stressful task. The ideal structure, training methods and assessment instruments best used to teach and assess BBN for anesthesiology residents remain unclear. The purpose of this study is to evaluate the effectiveness of an education intervention for BBN based on immersive experiences with a high fidelity simulator and role-play with standardized patients (SPs). A secondary purpose is to gather validity evidence to support the use of a GRIEV_ING instrument to assess BBN skills. METHODS: The communication skills for BBN of 16 residents were assessed via videotaped SP encounters at baseline and immediately post-intervention. Residents' perceptions about their ability and comfort for BBN were collected using pre and post workshop surveys. RESULTS: Posttest scores were significantly higher than the pretest scores for the GRIEV_ING checklist, as well as on the communication global rating. The GRIEV_ING checklist had acceptable inter-rater and internal-consistency reliabilities. Performance was not related to years of training, or previous BBN experience. CONCLUSION: Anesthesiology residents' communication skills when BBN in relation to a critical incident may be improved with educational interventions based on immersive experiences with a high fidelity simulator and role-play with SPs. PMID- 28615003 TI - 3D deep convolutional neural networks for amino acid environment similarity analysis. AB - BACKGROUND: Central to protein biology is the understanding of how structural elements give rise to observed function. The surfeit of protein structural data enables development of computational methods to systematically derive rules governing structural-functional relationships. However, performance of these methods depends critically on the choice of protein structural representation. Most current methods rely on features that are manually selected based on knowledge about protein structures. These are often general-purpose but not optimized for the specific application of interest. In this paper, we present a general framework that applies 3D convolutional neural network (3DCNN) technology to structure-based protein analysis. The framework automatically extracts task specific features from the raw atom distribution, driven by supervised labels. As a pilot study, we use our network to analyze local protein microenvironments surrounding the 20 amino acids, and predict the amino acids most compatible with environments within a protein structure. To further validate the power of our method, we construct two amino acid substitution matrices from the prediction statistics and use them to predict effects of mutations in T4 lysozyme structures. RESULTS: Our deep 3DCNN achieves a two-fold increase in prediction accuracy compared to models that employ conventional hand-engineered features and successfully recapitulates known information about similar and different microenvironments. Models built from our predictions and substitution matrices achieve an 85% accuracy predicting outcomes of the T4 lysozyme mutation variants. Our substitution matrices contain rich information relevant to mutation analysis compared to well-established substitution matrices. Finally, we present a visualization method to inspect the individual contributions of each atom to the classification decisions. CONCLUSIONS: End-to-end trained deep learning networks consistently outperform methods using hand-engineered features, suggesting that the 3DCNN framework is well suited for analysis of protein microenvironments and may be useful for other protein structural analyses. PMID- 28615004 TI - Understanding heart failure; explaining telehealth - a hermeneutic systematic review. AB - BACKGROUND: Enthusiasts for telehealth extol its potential for supporting heart failure management. But randomised trials have been slow to recruit and produced conflicting findings; real-world roll-out has been slow. We sought to inform policy by making sense of a complex literature on heart failure and its remote management. METHODS: Through database searching and citation tracking, we identified 7 systematic reviews of systematic reviews, 32 systematic reviews (including 17 meta-analyses and 8 qualitative reviews); six mega-trials and over 60 additional relevant empirical studies and commentaries. We synthesised these using Boell's hermeneutic methodology for systematic review, which emphasises the quest for understanding. RESULTS: Heart failure is a complex and serious condition with frequent co-morbidity and diverse manifestations including severe tiredness. Patients are often frightened, bewildered, socially isolated and variably able to self-manage. Remote monitoring technologies are many and varied; they create new forms of knowledge and new possibilities for care but require fundamental changes to clinical roles and service models and place substantial burdens on patients, carers and staff. The policy innovation of remote biomarker monitoring enabling timely adjustment of medication, mediated by "activated" patients, is based on a modernist vision of efficient, rational, technology mediated and guideline-driven ("cold") care. It contrasts with relationship-based ("warm") care valued by some clinicians and by patients who are older, sicker and less technically savvy. Limited uptake of telehealth can be analysed in terms of key tensions: between tidy, "textbook" heart failure and the reality of multiple comorbidities; between basic and intensive telehealth; between activated, well supported patients and vulnerable, unsupported ones; between "cold" and "warm" telehealth; and between fixed and agile care programmes. CONCLUSION: The limited adoption of telehealth for heart failure has complex clinical, professional and institutional causes, which are unlikely to be elucidated by adding more randomised trials of technology-on versus technology-off to an already-crowded literature. An alternative approach is proposed, based on naturalistic study designs, application of social and organisational theory, and co-design of new service models based on socio-technical principles. Conventional systematic reviews (whose goal is synthesising data) can be usefully supplemented by hermeneutic reviews (whose goal is deepening understanding). PMID- 28615005 TI - Development and validation of a risk score to assist screening for acute HIV-1 infection among men who have sex with men. AB - BACKGROUND: Early treatment of acute HIV-1 infection (AHI) is beneficial for patients and could reduce onward transmission. However, guidelines on whom to test for AHI with HIV-1 RNA testing are lacking. METHODS: A risk score for possible AHI based on literature and expert opinion - including symptoms associated with AHI and early HIV-1 - was evaluated using data from the Amsterdam Cohort Studies among men who have sex with men (MSM). Subsequently, we optimized the risk score by constructing two multivariable logistic regression models: one including only symptoms and one combining symptoms with known risk factors for HIV-1 seroconversion, using generalized estimating equations. Several risk scores were generated from these models and the optimal risk score was validated using data from the Multicenter AIDS Cohort Study. RESULTS: Using data from 1562 MSM with 175 HIV-1 seroconversion visits and 17,271 seronegative visits in the Amsterdam Cohort Studies, the optimal risk score included four symptoms (oral thrush, fever, lymphadenopathy, weight loss) and three risk factors (self reported gonorrhea, receptive condomless anal intercourse, more than five sexual partners, all in the preceding six months) and yielded an AUC of 0.82. Sensitivity was 76.3% and specificity 76.3%. Validation in the Multicenter AIDS Cohort Study resulted in an AUC of 0.78, sensitivity of 56.2% and specificity of 88.8%. CONCLUSIONS: The optimal risk score had good overall performance in the Amsterdam Cohort Studies and performed comparable (but showed lower sensitivity) in the validation study. Screening for AHI with four symptoms and three risk factors would increase the efficiency of AHI testing and potentially enhance early diagnosis and immediate treatment. PMID- 28615006 TI - Brief temperature stress during reproductive stages alters meiotic recombination and somatic mutation rates in the progeny of Arabidopsis. AB - BACKGROUND: Plants exposed to environmental stresses draw upon many genetic and epigenetic strategies, with the former sometimes modulated by the latter. This can help the plant, and its immediate progeny, at least, to better endure the stress. Some evidence has led to proposals that (epi) genetic changes can be both selective and sustainably heritable, while other evidence suggests that changes are effectively stochastic, and important only because they induce genetic variation. One type of stress with an arguably high level of stochasticity in its effects is temperature stress. Studies of how heat and cold affect the rates of meiotic recombination (MR) and somatic mutations (SMs, which are potentially heritable in plants) report increases, decreases, or no effect. Collectively, they do not point to any consistent patterns. Some of this variability, however, might arise from the stress being applied for such an extended time, typically days or weeks. Here, we adopted a targeted approach by (1) limiting exposure to one hour; and (2) timing it to coincide with (a) gamete, and early gametophyte, development, a period of high stress sensitivity; and (b) a late stage of vegetative development. RESULTS: For plants (Arabidopsis thaliana) otherwise grown at 22 degrees C, we measured the effects of a 1 h exposure to cold (12 degrees C) or heat (32 degrees C) on the rates of MR, and four types of SMs (frameshift mutations; intrachromosomal recombination; base substitutions; transpositions) in the F1 progeny. One parent (wild type) was stressed, the other (unstressed) carried a genetic event detector. When rates were compared to those in progeny of control (both parents unstressed) two patterns emerged. In the progeny of younger plants (stressed at 36 days; pollinated at 40 days) heat and cold either had no effect (on MR) or (for SMs) had effects that were rare and stochastic. In the progeny of older plants (stressed at 41 days; pollinated at 45 days), while effects were also infrequent, those that were seen followed a consistent pattern: rates of all five genetic events were lowest at 12 degrees C and highest at 32 degrees C, i.e. they varied in a "dose-response" manner. This pattern was strongest (or, in the case of MR, only apparent) in progeny whose stressed parent was female. CONCLUSION: While the infrequency of effects suggests the need for cautious inference, the consistency of responses in the progeny of older plants, indicate that in some circumstances the level of stochasticity in inherited genetic responses to heat or cold stress can be context-dependent, possibly reflecting life-cycle stages in the parental generation that are variably stress sensitive. PMID- 28615007 TI - Rhythm-centred music making in community living elderly: a randomized pilot study. AB - BACKGROUND: Quality of life has become an important aspect in the measurement of the health of an individual as the population ages. Rhythm-centred music making (RMM) has been shown to improve physical, psychological and social health. The purpose of this study was to explore the effects of RMM on quality of life, depressive mood, sleep quality and social isolation in the elderly. METHODS: A randomised controlled trial with cross over was conducted. 54 participants were recruited with 27 participants in each arm. In phase 1, group A underwent the intervention with group B as the control. In phase 2, group B underwent the intervention with group A as the control. The intervention involved 10 weekly RMM sessions. Patient related outcome data which included European Quality of Life-5 Dimensions (EQ5D), Geriatric Depression Scale (GDS), Pittsburg Sleep Quality Index (PSQI) and Lubben Social Network Scale (LSNS) scores were collected before the intervention, at 11th and at the 22nd week. RESULTS: A total of 31 participants were analyzed at the end of the study. The mean age was 74.65 +/- 6.40 years. In analysing the change in patient related outcome variables as a continuous measure, participation in RMM resulted in a non-significant reduction in EQ5D by 0.004 (95% CI: -0.097,0.105), GDS score by 0.479 (95% CI: 0.329,1.287), PSQI score by 0.929 (95% CI:- 0.523,2.381) and an improvement in LSNS by 1.125 (95% CI:-2.381,0.523). In binary analysis, participation in RMM resulted in a 37% (OR = 1.370, 95% CI: 0.355,5.290), 55.3% (OR = 1.553, 95% CI: 0.438,5.501), 124.1% (OR = 2.241, 95% CI = 0.677,7.419) and 14.5% (OR = 1.145, 95% CI = 0.331,3.963) non-significant increase in odds of improvement in EQ5D, GDS, PSQI and LSNS scores respectively. CONCLUSION: Participation in RMM did not show any statistically significant difference in the quality of life of the participants. It is however, an interesting alternative tool to use in the field of integrative medicine. Moving forward, a larger study could be performed to investigate the effects of RMM on the elderly with an inclusion of a qualitative component to evaluate effects of RMM that were not captured by quantitative indicators. TRIAL REGISTRATION: This trial was retrospectively registered. This trial was registered in the Australian New Zealand Clinical Trials Registry under trial number ACTRN12616001281482 on 12 September 2016. PMID- 28615008 TI - Isolated transient vertigo: posterior circulation ischemia or benign origin? AB - BACKGROUND: Isolated transient vertigo can be the only symptom of posterior circulation ischemia. Thus, it is important to differentiate isolated vertigo of a cerebrovascular origin from that of more benign origins, as patients with cerebral ischemia have a much higher risk for future stroke than do those with 'peripheral' vertigo. The current study aims to identify risk factors for cerebrovascular origin of isolated transient vertigo, and for future cerebrovascular events. METHODS: From the files of 339 outpatients with isolated transient vertigo we extracted history, clinical and technical findings, diagnosis, and follow-up information on subsequent stroke or transient ischemic attack (TIA). Risk factors were analyzed using multivariate regression models (logistic or Cox) and reconfirmed in univariate analyses. RESULTS: On first presentation, 48 (14.2%) patients received the diagnosis 'probable or definite cerebrovascular vertigo'. During follow-up, 41 patients suffered stroke or TIA (event rate 7.9 per 100 person years, 95% confidence interval (CI) 5.5-10.4), 26 in the posterior circulation (event rate 4.8 per 100 person years, 95% CI 3.0 6.7). The diagnosis was not associated with follow-up cerebrovascular events. In multivariate models testing multiple potential determinants, only the presentation mode was consistently associated with the diagnosis and stroke risk: patients who presented because of vertigo (rather than reporting vertigo when they presented for other reasons) had a significantly higher risk for future stroke or TIA (p = 0.028, event rate 13.4 vs. 5.4 per 100 person years) and for future posterior circulation stroke or TIA (p = 0.044, event rate 7.8 vs. 3.5 per 100 person years). CONCLUSIONS: We here report for the first time follow-up stroke rates in patients with transient isolated vertigo. In such patients, the identification of those with cerebrovascular origin remains difficult, and presentation mode was found to be the only consistent risk factor. Confirmation in an independent prospective sample is needed. PMID- 28615009 TI - Incidence of acute pulmonary embolism, related comorbidities and survival; analysis of a Swedish national cohort. AB - BACKGROUND: The aim of the study was to determine the incidence of acute pulmonary embolism (PE) in Sweden and any regional differences. To assess short- and long-term survival analysis after an episode of PE, before and after excluding patients with known malignancies, and to determine the most common comorbidities prior to the PE event. METHODS: All in-hospital patients, including children, diagnosed with acute PE in 2005 were retrieved from the Swedish National Patient Registry (NPR) and incidence rates were calculated. All registered comorbidities from 1998 until the index events were collected and survival up to 4 years after the event were calculated and compared to matched controls. RESULTS: There were 5793 patients of all ages diagnosed with acute PE in 2005 resulting in a national incidence of 0.6/1000/year. The mean age was 70 years and 52% were women. The most frequent comorbidities were cardiac-, vascular , infectious- and gastrointestinal diseases, injuries and malignancies. The mortality rates were more than doubled in patients with recent PE compared to that in a matched control group (49.1% vs 21.9%), and the excess mortality remained after exclusion of deaths occurring within one year and after exclusion of patients with any malignancy prior to the event. CONCLUSIONS: PE is associated with high age as well as with multiple comorbidities, and with an increased short and long-term mortality. This study highlights the importance of a proper follow up after an acute PE. PMID- 28615010 TI - Internet-based perioperative exercise program in patients with Barrett's carcinoma scheduled for esophagectomy [iPEP - study] a prospective randomized controlled trial. AB - BACKGROUND: Patients undergoing surgery for esophageal cancer have a high risk for postoperative deterioration of lung function and pulmonary complications. This is partly due to one-lung ventilation during thoracotomy. This often accounts for prolonged stay on intensive care units, delayed postoperative reconvalescence and reduced quality of life. Socioeconomic disadvantages can result from these problems. Physical preconditioning has become a crucial leverage to optimize fitness and lung function in patients scheduled for esophagectomy, in particular during the time period of neoadjuvant therapy. METHODS/STUDY DESIGN: We designed a prospective multicenter randomized-controlled trial. The objective is to evaluate the impact of an internet-based exercise program on postoperative respiratory parameters and pneumonia rates in patients with Barrett's carcinoma scheduled for esophagectomy. Patients are randomly assigned to either execute internet-based perioperative exercise program (iPEP), including daily endurance, resistance and ventilation training or treatment as usual (TAU). During neoadjuvant therapy and recovery, patients in the intervention group receive an individually designed intensive exercise program based on functional measurements at baseline. Personal feedback of the supervisor with customized training programs is provided in weekly intervals. DISCUSSION: This study will evaluate if an intensive individually adapted training program via online supervision during neoadjuvant therapy will improve cardiorespiratory fitness and reduce pulmonary complications following esophagectomy for Barrett's cancer. TRIAL REGISTRATION: NCT02478996 , registered 26 May 2015. PMID- 28615011 TI - Lessons from implementing mass drug administration for soil transmitted helminths among pre-school aged children during school based deworming program at the Kenyan coast. AB - BACKGROUND: The 2012 London declaration which committed to "sustaining, expanding and extending drug access programmes to ensure the necessary supply of drugs and other interventions to help control soil-transmitted helminths (STH) by 2020" has seen many countries in Africa roll out mass drug administration (MDA) especially among school age children. In Kenya, however, during the National school-based deworming exercise, pre-school aged children (PSAC) have to access treatment at primary schools as the pre-school teachers are not trained to carry out deworming. With studies being conducted on the effectiveness of MDAs, the experiences of key education stakeholders which could improve the programme by giving best practices, and challenges experienced have not been documented. METHODS: This was a cross-sectional qualitative study using Focus group discussions (FGDs) and Key informant interviews (KIIs). It was conducted in 4 sub counties with high STH prevalence at the Kenyan coast (Matuga, Malindi, Lunga Lunga and Msambweni) to understand best practices for implementing MDA among PSAC.FGDs categorized by gender were conducted among local community members, whereas KIIs involved pre-school teachers, primary school teachers, community health extension workers (CHEWs) and opinion leaders. Participants were purposefully selected with the saturation model determining the number of interviews and focus groups. Voice data collected was transcribed verbatim then coded and analyzed using ATLAS.Ti version 6. RESULTS: Majority of the primary school teachers and CHEWs reported that they were satisfied with the method of mobilization used and the training tools. This was however not echoed by the pre school teachers, parents and chiefs who complained of being left out of the process. Best practices mentioned included timely drug delivery, support from pre school teachers, and management of side effects. Overcrowding during the drug administration day, complexity of the forms (for instance the 'S form') and long distance between schools were mentioned as challenges. CONCLUSION: There is need to utilize better sensitization methods to include the local administration as well as the parents for better uptake of the drugs. Extending deworming training to pre-school teachers will enhance the national deworming programme. PMID- 28615012 TI - Moxifloxacin monotherapy versus combination therapy in patients with severe community-acquired pneumonia evoked ARDS. AB - BACKGROUND: We tested the hypothesis that moxifloxacin monotherapy is equally effective and safe as a betalactam antibiotic based combination therapy in patients with acute respiratory distress syndrome (ARDS) evoked by severe community acquired pneumonia (CAP). METHODS: In a retrospective chart review study of 229 patients with adult respiratory distress syndrome (ARDS) admitted to our intensive care unit between 2001 and 2011, 169 well-characterized patients were identified to suffer from severe CAP. Patients were treated with moxifloxacin alone, moxifloxacin in combination with beta-lactam antibiotics, or with another antibiotic regimen based on beta-lactam antibiotics, at the discretion of the admitting attending physician. The primary endpoint was 30-day survival. To assess potential drug-induced liver injury, we also analyzed biomarkers of liver cell integrity. RESULTS: 30-day survival (69% overall) did not differ (p = 0.89) between moxifloxacin monotherapy (n = 42), moxifloxacin combination therapy (n = 44), and other antibiotic treatments (n = 83). We found significantly greater maximum activity of aspartate transaminase (p = 0.048), alanine aminotransferase (p = 0.003), and direct bilirubin concentration (p = 0.01) in the moxifloxacin treated groups over the first 10-20 days. However, these in-between group differences faded over time, and no differences remained during the last 10 days of observation. CONCLUSIONS: In CAP evoked ARDS, moxifloxacin monotherapy and moxifloxacin combination therapy was not different to a betalactam based antibiotic regimen with respect to 30-day mortality, and temporarily increased markers of liver cell integrity had no apparent clinical impact. Thus, in contrast to the current S3 guidelines, moxifloxacin may also be safe and effective even in patients with severe CAP evoked ARDS while providing coverage of an extended spectrum of severe CAP evoking bacteria. However, further prospective studies are needed for definite recommendations. PMID- 28615013 TI - Short-term poor glycemic control and retinal microvascular changes in pediatric Type 1 Diabetes patients in Singapore: a pilot study. AB - BACKGROUND: Poor glycemic control in Type 1 Diabetes (T1D) patients is strongly associated with an increased risk of diabetes-related microvascular complications later in life, but it is unclear whether short period of poor glycemic control in children with T1D can cause evident microvascular morphological changes long before any pathological manifestation. Our study aimed to investigate the longitudinal association between poor glycemic control and subsequent changes in retinal microvasculature, in a pilot study of 55 pediatric T1D patients from Singapore after a one-year follow-up. METHODS: This is a hospital-based, exposure matched and retrospective longitudinal study. A total of 55 T1D patients were included from Singapore KK Women's and Children Hospital, 28 of whom had poor glycemic control (average glycated hemoglobin [HbA1c] >=8% during the year) while the other 27 age- and gender-matched subjects had good glycemic control (HbA1c <8%). Retinal photography was taken at diabetes annual screening and images were graded by trained graders using a semi-automated computer-based program (Singapore I Vessel Assessment [SIVA], version 4.0, Singapore Eye Research Institute, Singapore) and a spectrum of retinal vascular parameters (e.g. caliber, tortuosity, branching angle and fractal dimension) were measured quantitatively from 0.5 to 2.0 disc diameters. RESULTS: There was no significant difference in ethnicity, duration of T1D, blood pressure, body mass index (BMI) and low-density cholesterol lipoprotein (LDL) between the two groups. Retinal imaging was obtained at the end of 1 year of glycemic control assessment. In multiple linear regression adjusting for ethnicity, BMI, LDL and duration of T1D, patients with poor glycemic control tended to have marginally wider retinal arteriolar caliber (6.0 MUm, 95% CI: -0.9, 12.8) and had significantly larger retinal arteriolar branching angle (10.1 degrees, 95% CI: 1.4, 18.9) compared with their age- and gender- matched counterparts with good glycemic control. CONCLUSIONS: Our findings showed that abnormal retinal microvascular morphology was evident in pediatric patients with T1D after one-year's poor glycemic control. Such morphological abnormalities may lead to future development of microvascular complications among T1D pediatric patients with poor glycemic control. PMID- 28615014 TI - Are physicians aware enough of patient radiation protection? Results from a survey among physicians of Pavia District- Italy. AB - BACKGROUND: Radiological practices are the first anthropic sources of ionizing radiation exposure of the population. However, a review of recent publications underlines inadequate doctors' knowledge about doses imparted in medical practices and about patient protection that might explain unnecessary radiological prescriptions. We investigated the knowledge of the physicians of Pavia District (Italy) on the risk of radiation exposure. METHODS: A cross sectional study was performed involving the Medical Association of Pavia District. Data were collected with a self-administered questionnaire, available on-line with private login and password. RESULTS: Four hundred nineteen physicians fulfilled the questionnaire; 48% of participants reported training about radiation protection. The average percentage of correct answers on the knowledge on ionizing radiation was 62.29%, with a significantly higher result between radiologist. Around 5 and 13% of the responders do not know that, respectively, ultrasonography and magnetic resonance do not expose patients to ionizing radiations. Only 5% of the physicians properly identified the cancer risk rate associated to abdomen computed tomography. CONCLUSIONS: The findings show a quite good level of the general knowledge about ionizing radiations, higher that reported in literature. Nevertheless, we believe the usefulness of training on the risk linked to radiation exposure in medicine for physicians employed in every area. PMID- 28615015 TI - The gastroprotective effect of ethyl acetate fraction of hot water extract of Trichosanthes cucumerina Linn and its underlying mechanisms. AB - BACKGROUND: Antacids, anticholinergic drugs, histamine H2- receptor antagonists and irreversible proton pump inhibitors have been used for the treatment of gastric ulcers. However, prolonged use of these drugs may lead to series of adverse effects such as diarrhea, headache, rash, hypertension, muscular and joint pain. Therefore, there is an urgent need of more effective and safer treatments with fewer side effects. The aim of the present study was to scientifically evaluate the gastroprotective activity of fractions of the hot water extract of Trichosanthes cucumerina Linn (Family: Cucurbitaceae) aerial parts with a view to identifying the fraction with the best gastroprotective activity and the possible mechanism/s by which this fraction exert gastroprotection. METHODS: Gastroprotective activity of hexane fraction (HF), ethyl acetate fraction (EF), butanol fraction (BF) and aqueous fraction (AF) were evaluated by the assessment of ability to reduce the ulcer index in ethanol induced rat model and the mode of action by which the most active fraction mediating gastroprotection. RESULTS: EF showed the maximum gastroprotection effect followed by BF and AF. EF (75 mg/kg) exhibited significantly higher gastroprotection compared to the reference drugs. Further investigations with two lower doses of EF confirmed that EF can mediated a significant and dose dependent gastroprotection. The rats treated with the EF showed significant reduction in free acidity (45%), total acidity (by 48%) in the gastric juice, increased the amount of mucus produced by the rat gastro mucosa and potent antihistamine activity (by 25.6%). EF was also rich in phenolic compounds and flavonoids. CONCLUSION: Gastroprotective mechanism of EF is possibly involves inhibition of acidity, elevation in mucus content, inhibition of histamine and antioxidant mechanisms. PMID- 28615016 TI - Ex vivo susceptibility and genotyping of Plasmodium falciparum isolates from Pikine, Senegal. AB - BACKGROUND: The monitoring of Plasmodium falciparum sensitivity to anti-malarial drugs is a necessity for effective case management of malaria. This species is characterized by a strong resistance to anti-malarial drugs. In Senegal, the first cases of chloroquine resistance were reported in the Dakar region in 1988 with nearly 7% population prevalence, reaching 47% by 1990. It is in this context that sulfadoxine-pyrimethamine temporarily replaced chloroquine as first line treatment in 2003, pending the introduction of artemisinin-based combination therapy in 2006. The purpose of this study is to assess the ex vivo sensitivity to different anti-malarial drugs of the P. falciparum population from Pikine. METHODS: Fifty-four samples were collected from patients with non-complicated malaria and aged between 2 and 20 years in the Deggo health centre in Pikine in 2014. An assay in which parasites are stained with 4', 6-di-amidino-2 phenylindole (DAPI), was used to study the ex vivo sensitivity of isolates to chloroquine, amodiaquine, piperaquine, pyrimethamine, and dihydroartemisinin. High resolution melting was used for genotyping of pfdhps, pfdhfr, pfmdr1, and pfcrt genes. RESULTS: The mean IC50s of chloroquine, amodiaquine, piperaquine, dihydroartemisinin, and pyrimethamine were, respectively, 39.44, 54.02, 15.28, 2.23, and 64.70 nM. Resistance mutations in pfdhfr gene, in codon 437 of pfdhps gene, and an absence of mutation at position 540 of pfdhps were observed. Mutations in codons K76T of pfcrt and N86Y of pfmdr1 were observed at 51 and 11% population prevalence, respectively. A relationship was found between the K76T and N86Y mutations and ex vivo resistance to chloroquine. CONCLUSION: An increase in sensitivity of isolates to chloroquine was observed. A high sensitivity to dihydroartemisinin was observed; whereas, a decrease in sensitivity to pyrimethamine was observed in the parasite population from Pikine. PMID- 28615017 TI - Protocol for the effect evaluation of independent medical evaluation after six months sick leave: a randomized controlled trial of independent medical evaluation versus treatment as usual in Norway. AB - BACKGROUND: It has been discussed whether the relationship between a patient on sick leave and his/her general practitioner (GP) is too close, as this may hinder the GP's objective evaluation of need for sick leave. Independent medical evaluation involves an independent physician consulting the patient. This could lead to new perspectives on sick leave and how to follow-up the patient. METHODS/DESIGN: The current study is a randomized controlled trial in a Norwegian primary care context, involving an effect evaluation, a cost/benefit analysis, and a qualitative evaluation. Independent medical evaluation will be compared to treatment as usual, i.e., the physicians' and social insurance agencies' current management of long-term sick-listed patients. Individuals aged 18-65 years, sick listed by their GP and on full or partial sick leave for the past 6 months in Hordaland county will be included. Exclusion criteria are pregnancy, cancer, dementia or an ICD-10 diagnosis. A total sample of 3800 will be randomly assigned to either independent medical evaluation or treatment as usual. Official register data will be used to measure the primary outcome; change in sickness benefits at 7, 9 and 12 months. Sick listed in other counties will serve as a second control group, if appropriate under the "common trend" assumption. DISCUSSION: The Norwegian effect evaluation of independent medical evaluation after 6 months sick leave is a large randomized controlled trial, and the first of its kind, to evaluate this type of intervention as a means of getting people back to work after long-term sickness absence. TRIAL REGISTRATION: ClinicalTrials.gov NCT02524392 . Registered June 23, 2015. PMID- 28615018 TI - The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression. AB - BACKGROUND: Sex-specific factors play a major role in human health and disease, including responses to environmental stresses such as toxicant exposure. Increasing evidence suggests that such sex differences also exist during fetal development. In a previous report using the resources of the New Hampshire Birth Cohort Study (NHBCS), we found that low-to-moderate in utero exposure to arsenic, a highly toxic and widespread pollutant, was associated with altered expression of several key developmental genes in the fetal portion of the placenta. These associations were sex-dependent, suggesting that in utero arsenic exposure differentially impacts male and female fetuses. In the present study, we investigated the molecular basis for these sex-specific responses to arsenic. METHODS: Using NanoString technology, we further analyzed the fetal placenta samples from the NHBCS for the expression of genes encoding arsenic transporters and metabolic enzymes. Multivariable linear regression analysis was used to examine their relationship with arsenic exposure and with key developmental genes, after stratification by fetal sex. RESULTS: We found that maternal arsenic exposure was strongly associated with expression of the AQP9 gene, encoding an aquaglyceroporin transporter, in female but not male fetal placenta. Moreover, AQP9 expression associated with that of a subset of female-specific arsenic responsive genes. CONCLUSIONS: Our results suggest that AQP9 is upregulated in response to arsenic exposure in female, but not male, fetal placenta. Based on these results and prior studies, increased AQP9 expression may lead to increased arsenic transport in the female fetal placenta, which in turn may alter the expression patterns of key developmental genes that we have previously shown to be associated with arsenic exposure. Thus, this study suggests that AQP9 may play a role in the sex-specific effects of in utero arsenic exposure. PMID- 28615019 TI - Evaluation of community provision of a preventive cardiovascular programme - the National Health Service Health Check in reaching the under-served groups by primary care in England: cross sectional observational study. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of premature mortality and a major contributor of health inequalities in England. Compared to more affluent and white counterparts, deprived people and ethnic minorities tend to die younger due to preventable CVD associated with lifestyle. In addition, deprived, ethnic minorities and younger people are less likely to be served by CVD prevention services. This study assessed the effectiveness of community-based outreach providers in delivering England's National Health Services (NHS) Health Check programme, a CVD preventive programme to under-served groups. METHODS: Between January 2008 and October 2013, community outreach providers delivered a preventive CVD programme to 50,573 individuals, in their local communities, in a single consultation without prescheduled appointments. Community outreach providers operated on evenings and weekends as well as during regular business hours in venues accessible to the general public. After exclusion criteria, we analysed and compared socio-demographic data of 43,177 Health Check attendees with the general population across 38 local authorities (LAs). We assessed variation between local authorities in terms of age, sex, deprivation and ethnicity structures using two sample t-tests and within local authority variation in terms of ethnicity and deprivation using Chi squared tests and two sample t-tests respectively. RESULTS: Using Index of Multiple Deprivation, the mean deprivation score of the population reached by community outreach providers was 6.01 higher (p < 0.05) than the general population. Screened populations in 29 of 38 LAs were significantly more deprived (p < 0.05). No statistically significant difference among ethnic minority groups was observed between LAs. Nonetheless some LAs - namely Leicester, Thurrock, Sutton, South Tyneside, Portsmouth and Gateshead were very successful in recruiting ethnic minority groups. The mean proportion of men screened was 11.39% lower (p < 0.001) and mean proportion of 40-49 and 50-59 year olds was 9.98% and 3.58% higher (p < 0.0001 and p < 0.01 respectively) than the general population across 38 LAs. CONCLUSIONS: Community-based outreach providers effectively reach under-served groups by delivering preventive CVD services to younger, more deprived populations, and a representative proportion of ethnic minority groups. If the programme is successful in motivating the under-served groups to improve lifestyle, it may reduce health inequalities therein. PMID- 28615020 TI - Short-term air pollution exposure decreases lung function: a repeated measures study in healthy adults. AB - BACKGROUND: Daily changes in ambient concentrations of particulate matter, nitrogen oxides and ozone are associated with increased cardiopulmonary morbidity and mortality, with the lungs and their function being a vulnerable target. METHODS: To evaluate the association between daily changes in air pollution and lung function in healthy adults we obtained annual lung function measurements from a routine worker health surveillance program not designed for research purposes. Forced Vital Capacity (FVC), Forced Expiratory Volume in the first second (FEV1), FEV1/FVC and Peak Expiratory flow (PEF) from a cohort of 2449 employees were associated with daily measurements of PM10, NO2 and ozone at a nearby monitoring station in the North of Belgium. Repeated measures were available for the period 2011-2015. RESULTS: The mean (SD) PM10 concentration on the day of the lung function test was 24.9 (15.5) MUg/m3. A 10 MUg PM10/m3 increase on the day of the clinical examination was associated with a 18.9 ml lower FVC (95% CI: -27.5 to -10.3, p < 0.0001), 12.8 ml lower FEV1 (-19.1 to 6.5; p < 0.0001), and a 51.4 ml/s lower PEF (-75.0 to -27.0; p < 0.0001). The FEV1/FVC-ratio showed no associations. An increase of 10 MUgNO2/m3 was associated with a reduction in PEF (-66.1 ml/s (-106.6 to -25.6; p < 0.001)) on the day of the examination. CONCLUSIONS: We found negative associations between daily variations in ambient air pollution and FVC, FEV1 and PEF in healthy adults. PMID- 28615021 TI - General perception and self-practice of complementary and alternative medicine (CAM) among undergraduate pharmacy students of Bangladesh. AB - BACKGROUND: Complementary and Alternative Medicine (CAM) is a combination of herbal medicine, traditional therapies, and mind-body intervention. This descriptive study was designed to assess the knowledge, attitudes, perception and self-use of CAM among Bangladeshi undergraduate pharmacy students. The study also evaluated their opinions about its integration into the pharmacy course curriculum. METHODS: It was a cross-sectional, questionnaire-based study conducted on 250 pharmacy students of five reputed public universities of Bangladesh. RESULTS: This study revealed that majority of the pharmacy students were using or had previously used at least one type of CAM. Among the students, 59% had used homeopathy followed by Ayurveda (30%), meditation (29%), massage (13%), Unani (9%), yoga (6%) and acupuncture (2%). Students' attitudes towards CAM were influenced by family and friends, books and journals, the internet and to a lesser degree by health practitioners. A significant (p < 0.05) number of students had knowledge about CAM. A majority of the students (90%) had positive, while 10% had negative attitudes towards CAM. Lack of knowledge and trained professionals were found to be the major interruptions to CAM use. 84.45% acknowledged the importance of knowledge about CAM for them as future healthcare practitioners. Furthermore, the majority of the students also believed that ideas and methods of CAM would be beneficial for conventional medicine. CONCLUSIONS: From the findings of the study, it can be recommended that an approach should be taken to educate the students about the fundamentals of CAM use so that it may fulfill the professional needs of our future pharmacists. PMID- 28615022 TI - Correlation of retinal nerve fibre layer and macular thickness with serum uric acid among type 2 diabetes mellitus. AB - BACKGROUND: Uric acid is a final breakdown product of purine catabolism in humans. It's a potent antioxidant and can also act as a pro-oxidant that induces oxidative stress on the vascular endothelial cells, thus mediating progression of diabetic related diseases. Various epidemiological and experimental evidence suggest that uric acid has a role in the etiology of type 2 diabetes mellitus. We conducted a cross-sectional study to evaluate the correlation of retinal nerve fibre layer (RNFL) and macular thickness with serum uric acid in type 2 diabetic patients. METHODS: A cross-sectional study was conducted in the Eye Clinic, Hospital Universiti Sains Malaysia, Kelantan between the period of August 2013 till July 2015 involving type 2 diabetes mellitus patients with no diabetic retinopathy and with non-proliferative diabetic retinopathy (NPDR). An evaluation for RNFL and macular thickness was measured using Spectralis Heidelberg optical coherence tomography. Six ml of venous blood was taken for the measurement of serum uric acid and glycosylated haemoglobin (HbA1C). RESULTS: A total of 180 diabetic patients were recruited (90 patients with no diabetic retinopathy and 90 patients with NPDR) into the study. The mean level of serum uric acid for both the groups was within normal range and there was no significance difference between the two groups. Based on gender, both male and female gender showed significantly higher level of mean serum uric acid in no diabetic retinopathy group (p = 0.004 respectively). The mean serum uric acid was significantly higher in patient with HbA1C < 6.5% (p < 0.031). Patients with NPDR have thicker RNFL and macular thickness compared to patients with no diabetic retinopathy. However, only the RNFL thickness of the temporal quadrant and the macular thickness of the superior outer, inferior outer and temporal outer subfields were statistically significant (p = 0.038, p = 0.004, 0.033 and <0.001 respectively). There was poor correlation between RNFL and macular thickness with serum uric acid in both the groups. CONCLUSION: Serum uric acid showed a poor correlation with RNFL and macular thickness among type 2 diabetic patients. PMID- 28615023 TI - Access to treatment for Hepatitis C among injection drug users: results from the cross-sectional HOPE IV study. AB - BACKGROUND: Evidence suggests that Greece is among the European countries with increased trend in HCV prevalence among injecting drug users (IDUs) from 2008 to 2014. Nonetheless, the access of IDUs to treatment for Hepatitis C Virus (HCV) is very limited while the risk of co-infection and transmission remains high. In an effort to better understand the inhibitors to HCV treatment, the present study aimed to investigate the main barriers to access in a sample of IDUs. METHODS: The cross-sectional study was carried out between July and September 2015 using a 23-items questionnaire. Participants were recruited from urban primary services, mobile health vans, community health services, day-care centers as well as during street work, located in Athens, Greece. Inclusion criteria were age above 18 years, understanding and speaking Greek sufficiently, HCV diagnosis, intravenous drug use. Data collection was carried out by health professionals of Praksis, a non-governmental organization. For the comparisons of proportions chi-square and Fisher's exact tests were used. RESULTS: The study sample consisted of 101 HCV patients, 68% male. More than 80% of study participants experienced barriers in accessing their doctor and medication during the past 12 months. The most common obstacles in accessing a doctor were "delay in making the appointment and "difficulties in going to the doctor due to health condition or lack of means of transport". Access to physician or medication was not differed according to gender, but significant differences were found according to economic status and health insurance coverage. 56.1% of participants reported loss or treatment delay due to barriers to treatment. The majority of participants had deteriorated financial status, health status, access to health services and medication, higher financial burden for health services, worse mental health and lower adherence to medical instructions in 2015 compared to 2009. CONCLUSIONS: The findings from the present study revealed that the vast majority of IDUs experience significant barriers in seeking HCV care in Greece, thus highlighting the need for immediate action in this particular area due to the high risk of co-infection and transmission. PMID- 28615024 TI - Mixed methods analysis of eighteen worksite policies, programs, and environments for physical activity. AB - BACKGROUND: This study examined whether specific worksite supports for physical activity (PA) were associated with total and domain-specific PA. METHODS: A cross sectional, telephone-based study was conducted in four Missouri, USA, metropolitan areas in 2012 and 2013. Outcome variables included total PA and sub domains (leisure, work, travel) measured using the International Physical Activity Questionnaire. Logistic regression determined odds of meeting PA recommendations, given access to and use of 18 unique PA worksite supports. A subsample of 119 participants also wore hip accelerometry for seven consecutive days and maintained a wear-time diary. Access to worksite supports were associated with odds of meeting objective moderate and vigorous (MV) PA above 150 min per week. RESULTS: Among 2013 survey participants, meeting PA recommendations while performing work-related tasks was significantly associated with several supports (e.g., walking maps, stair prompts), as was meeting recommendations during travel (e.g., flextime for PA, incentives for public transportation, walking/bicycling to work). Access to 11 worksite supports increased odds of meeting PA recommendations through leisure-time PA; five supports were associated with total PA. There were significant differences between access to and use of supports. Using objective MVPA, access to worksite challenges and bike storage were significantly associated with five and three times greater odds of meeting 150 min of MVPA per week, respectively. CONCLUSIONS: Worksite wellness plans are increasing across the US and employers are eager for evidence-based supports for increasing PA. This study provides insights into the utility of multiple worksite supports for PA to increase odds that employees meet PA recommendations. PMID- 28615025 TI - Copaiba oil-resin (Copaifera reticulata Ducke) modulates the inflammation in a model of injury to rats' tongues. AB - BACKGROUND: The regeneration of integrity and tissue homeostasis after injury is a fundamental property and involves complex biological processes fully dynamic and interconnected. Although there are medications prescribed to accelerate the process of wound healing by reducing the exaggerated inflammatory response, comes the need to search for different compounds of Amazonian biodiversity that can contribute to the acceleration of the healing process. Among these products, the copaiba oil-resin is one of the most prominent feature in this scenario, as they have been reported its medicinal properties. METHODS: Aiming to evaluate the anti inflammatory and healing effect of copaiba oil-resin (Copaifera reticulata Ducke) in transfixing injury of rats' tongues first proceeded up the copaiba oil-resin oral toxicity test in 5 male mice to stipulate the therapeutic dose which was established at 200 mg/kg/day. Then it was induced transfixing injury in a total of 15 Wistar rats. The animals were randomly divided into three groups based on the treatment: control group, dexamethasone group and copaiba oil-resin group. After 7 days of treatment, histological slides stained with hematoxylin and eosin was prepared. Immunohistochemistry for CD68 (macrophage marker) was performed and analyzed by the cell counter Image J. RESULTS: The acute toxicity test showed that the oil-resin copal has low toxicity. Furthermore, copaiba oil-resin therapy modulates the inflammatory response by decreasing the chronic inflammatory infiltrate, edema and specifically the number of macrophages. CONCLUSIONS: The results indicate the potential of the Amazon region and showed up relevant because therapy with this extract modulates the inflammatory process. PMID- 28615027 TI - Influence of interradicular and palatal placement of orthodontic mini-implants on the success (survival) rate. AB - BACKGROUND: The purpose of this retrospective cohort study was to investigate the success rates of orthodontic mini-implants (OMIs) placed in different insertion sites and to analyse patient and site- related factors that influence mini implant survival. METHODS: Three hundred eighty-seven OMIs were inserted in 239 patients for orthodontic anchorage and were loaded with a force greater than 2 N. Two different insertion sites were compared: 1. buccal inter-radicular and 2. palatal, at the level of the third palatal ruga. Survival was analysed for location and select patient parameters (age, gender and oral hygiene). The level of statistical significance was set at p < 0.05. RESULTS: The overall success rate was 89.1%. There were statistically significant differences between insertion sites; success rate was 98.4% for OMIs placed in the anterior palate and 71% for OMIs inserted buccal between roots (p < 0.001). CONCLUSIONS: Success rate of OMIs was primarily affected by the insertion site. The anterior palate was a more successful location compared to buccal alveolar bone. PMID- 28615026 TI - Engaging the private sector in malaria surveillance: a review of strategies and recommendations for elimination settings. AB - BACKGROUND: In malaria elimination settings, all malaria cases must be identified, documented and investigated. To facilitate complete and timely reporting of all malaria cases and effective case management and follow-up, engagement with private providers is essential, particularly in settings where the private sector is a major source of healthcare. However, research on the role and performance of the private sector in malaria diagnosis, case management and reporting in malaria elimination settings is limited. Moreover, the most effective strategies for private sector engagement in malaria elimination settings remain unclear. METHODS: Twenty-five experts in malaria elimination, disease surveillance and private sector engagement were purposively sampled and interviewed. An extensive review of grey and peer-reviewed literature on private sector testing, treatment, and reporting for malaria was performed. Additional in depth literature review was conducted for six case studies on eliminating and neighbouring countries in Southeast Asia and Southern Africa. RESULTS: The private health sector can be categorized based on their commercial orientation or business model (for-profit versus nonprofit) and their regulation status within a country (formal vs informal). A number of potentially effective strategies exist for engaging the private sector. Conducting a baseline assessment of the private sector is critical to understanding its composition, size, geographical distribution and quality of services provided. Facilitating reporting, referral and training linkages between the public and private sectors and making malaria a notifiable disease are important strategies to improve private sector involvement in malaria surveillance. Financial incentives for uptake of rapid diagnostic tests and artemisinin-based combination therapy should be combined with training and community awareness campaigns for improving uptake. Private sector providers can also be organized and better engaged through social franchising, effective regulation, professional organizations and government outreach. CONCLUSION: This review highlights the importance of engaging private sector stakeholders early and often in the development of malaria elimination strategies. PMID- 28615028 TI - Experimentally induced subclinical mastitis: are lipopolysaccharide and lipoteichoic acid eliciting similar pain responses? AB - BACKGROUND: Pain accompanying mastitis has gained attention recently as a relevant welfare compromising aspect of disease. Adequate pain recognition and therapy are necessary in the context of a modern and ethically acceptable dairy care. For research purposes mastitis is often induced by intramammary infusion of immunogenic bacterial cell wall components. Lipopolysaccharide (LPS) from Escherichia coli and lipoteichoic acid (LTA) from Staphylococcus aureus are commonly administered to this end. While the immune response to specific immunogenic components has been well characterized, not much is known about their role on the expression of pain indicators. The aim of this study was to trial the effects of an intramammary challenge of LTA or LPS on the degree of pain and discomfort as indicated by both physiological and behavioral variables in cows. The hypothesis was that a similar degree of pain can be identified in LTA as well as in LPS induced mastitis. RESULTS: On the challenge day, compared to pre challenge, total pain index increased for all treatment groups (LPS; LTA and control), the LPS group having significantly higher values than the control group (P = 0.01). Similarly, pain visual analogue scale (VAS) increased significantly in all cows following treatment on the challenge day. Furthermore, compared to baseline, higher VAS were found 3, 4 and 5 h after the challenge in cows of the LPS group (P3h, 4h < 0.001 and P5h = 0.001) and 7 h after the challenge in cows of the LTA group (P7h = 0.002). In the control group, VAS was higher 5 h after the challenge (P5h = 0.001). On the challenge day, udder edema was higher in the LPS than in the control group (P = 0.007). Furthermore, 4 h after the challenge, milk cortisol was significantly higher than at baseline in the LPS group (P < 0.001). CONCLUSIONS: When administered at equipotent doses targeting a standard somatic cell count increase, intramammary LPS seems to be accompanied by a higher degree of pain and discomfort than LTA, as suggested by the modifications of the outcome variables total pain index, VAS, udder edema and milk cortisol. PMID- 28615030 TI - The autoimmune burden in juvenile idiopathic arthritis. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory arthritis of unknown origin which can be considered an autoimmune disease (AD). The aim of this study is to analyse the presence of two or more autoimmune diseases (polyautoimmunity) in patients suffering from JIA and to evaluate the occurrence of ADs in their families. METHODS: Seventy-nine patients diagnosed with JIA aged 0-21 years, admitted to the Paediatric Rheumatology Unit, Sant'Orsola-Malpighi Hospital, Bologna were screened for ADs. Parents were asked about the presence of ADs in the living relatives of first and second degree. RESULTS: Twelve of 79 patients (15.2%) had at least 1 AD associated with JIA. Eight patients (10.1%) suffered from autoimmune thyroid disease (AITD), three patients had celiac disease, three patients suffered from psoriasis, one from alopecia and 1 from insulin-dependent diabetes mellitus. The average age at diagnosis was 13.2 years and the cumulative incidence of AITD was 36%. Seventy six families were studied for a total of 438 relatives. The prevalence of ADs was 13%, greater in first-degree relatives (16.7%) than in second-degree ones (11.1%). The most common AD was AITD; there was no difference in JIA's age of presentation between patients with positive and negative familiarity with ADs (p > 0.05). CONCLUSION: Children and adolescents with JIA present a high autoimmunity burden, most commonly represented by AITD. Familial autoimmunity is not negligible in patients suffering from JIA (almost 50% of patients have at least one relative with an AD) and it should always be carefully examined. PMID- 28615029 TI - MicroRNAs control mRNA fate by compartmentalization based on 3' UTR length in male germ cells. AB - BACKGROUND: Post-transcriptional regulation of gene expression can be achieved through the control of mRNA stability, cytoplasmic compartmentalization, 3' UTR length and translational efficacy. Spermiogenesis, a process through which haploid male germ cells differentiate into spermatozoa, represents an ideal model for studying post-transcriptional regulation in vivo because it involves a large number of transcripts that are physically sequestered in ribonucleoprotein particles (RNPs) and thus subjected to delayed translation. To explore how small RNAs regulate mRNA fate, we conducted RNA-Seq analyses to determine not only the levels of both mRNAs and small noncoding RNAs, but also their cytoplasmic compartmentalization during spermiogenesis. RESULT: Among all small noncoding RNAs studied, miRNAs displayed the most dynamic changes in both abundance and subcytoplasmic localization. mRNAs with shorter 3' UTRs became increasingly enriched in RNPs from pachytene spermatocytes to round spermatids, and the enrichment of shorter 3' UTR mRNAs in RNPs coincided with newly synthesized miRNAs that target these mRNAs at sites closer to the stop codon. In contrast, the translocation of longer 3' UTR mRNAs from RNPs to polysomes correlated with the production of new miRNAs that target these mRNAs at sites distal to the stop codon. CONCLUSIONS: miRNAs appear to control cytoplasmic compartmentalization of mRNAs based on 3' UTR length. Our data suggest that transcripts with longer 3' UTRs tend to contain distal miRNA binding sites and are thus targeted to polysomes for translation followed by degradation. In contrast, those with shorter 3' UTRs only possess proximal miRNA binding sites, which, therefore, are targeted into RNPs for enrichment and delayed translation. PMID- 28615031 TI - Leucine-rich alpha 2 glycoprotein promotes Th17 differentiation and collagen induced arthritis in mice through enhancement of TGF-beta-Smad2 signaling in naive helper T cells. AB - BACKGROUND: Leucine-rich alpha 2 glycoprotein (LRG) has been identified as a serum protein elevated in patients with active rheumatoid arthritis (RA). Although the function of LRG is ill-defined, LRG binds with transforming growth factor (TGF)-beta and enhances Smad2 phosphorylation. Considering that the imbalance between T helper 17 (Th17) cells and regulatory T cells (Treg) plays important roles in the pathogenesis of RA, LRG may affect arthritic pathology by enhancing the TGF-beta-Smad2 pathway that is pivotal for both Treg and Th17 differentiation. The purpose of this study was to explore the contribution of LRG to the pathogenesis of arthritis, with a focus on the role of LRG in T cell differentiation. METHODS: The differentiation of CD4 T cells and the development of collagen-induced arthritis (CIA) were examined in wild-type mice and LRG knockout (KO) mice. To examine the influence of LRG on T cell differentiation, naive CD4 T cells were isolated from LRG KO mice and cultured under Treg- or Th17 polarization condition in the absence or presence of recombinant LRG. RESULTS: In the CIA model, LRG deficiency led to ameliorated arthritis and reduced Th17 differentiation with no influence on Treg differentiation. By addition of recombinant LRG, the expression of IL-6 receptor (IL-6R) was enhanced through TGF beta-Smad2 signaling. In LRG KO mice, the IL-6R expression and IL-6-STAT3 signaling was attenuated in naive CD4 T cells, compared to wild-type mice. CONCLUSIONS: Our findings suggest that LRG upregulates IL-6R expression in naive CD4 T cells by the enhancement of TGF-beta-smad2 pathway and promote Th17 differentiation and arthritis development. PMID- 28615032 TI - Evaluation of computed tomography post-processing images in postoperative assessment of Lisfranc injuries compared with plain radiographs. AB - BACKGROUND: The objective of this study is to evaluate the value of computed tomography (CT) post-processing images in postoperative assessment of Lisfranc injuries compared with plain radiographs. METHODS: A total of 79 cases with closed Lisfranc injuries that were treated with conventional open reduction and internal fixation from January 2010 to June 2016 were analyzed. Postoperative assessment was performed by two independent orthopedic surgeons with both plain radiographs and CT post-processing images. Inter- and intra-observer agreement were analyzed by kappa statistics while the differences between the two postoperative imaging assessments were assessed using the chi 2 test (McNemar's test). Significance was assumed when p < 0.05. RESULTS: Inter- and intra-observer agreement of CT post-processing images was much higher than that of plain radiographs. Non-anatomic reduction was more easily identified in patients with injuries of Myerson classifications A, B1, B2, and C1 using CT post-processing images with overall groups (p < 0.05), and poor internal fixation was also more easily detected in patients with injuries of Myerson classifications A, B1, B2, and C2 using CT post-processing images with overall groups (p < 0.05). CONCLUSIONS: CT post-processing images can be more reliable than plain radiographs in the postoperative assessment of reduction and implant placement for Lisfranc injuries. PMID- 28615033 TI - A novel frameshift mutation in the XPC gene in a Moroccan patient: a case report. AB - BACKGROUND: Xeroderma pigmentosum is an autosomal recessive inherited disease. The diagnosis is essentially based on clinical findings and the family history. This genodermatosis is genetically heterogeneous; to date, nine genes have been associated to this disorder. Based on the result of many studies, xeroderma pigmentosum complementation group C is the most common form of xeroderma pigmentosum. A founder mutation in the XPC gene was reported in the Maghreb region of northern Africa. According to these findings, the Department of Medical Genetics in Rabat offers molecular diagnosis by screening for the recurrent mutation c.1643_1644delTG which represents 74% of all the probands with xeroderma pigmentosum. CASE PRESENTATION: We describe the case of a 21-year-old Moroccan son of consanguineous parents diagnosed with xeroderma pigmentosum on the basis of sun-exposed skin abnormalities and bilateral ocular involvement. A molecular study led to the identification of a new frameshift insertion of four nucleotides in exon 9. CONCLUSIONS: To the best of our knowledge, this mutation has not been described. The sequencing of the ninth exon should be proposed as first line molecular analysis for all Moroccan patients with xeroderma pigmentosum. PMID- 28615034 TI - Novel methodologies and technologies to assess mid-palatal suture maturation: a systematic review. AB - INTRODUCTION: A reliable method to assess midpalatal suture maturation to drive clinical decision-making, towards non-surgical or surgical expansion, in adolescent and young adult patients is needed. The objectives were to systematically review and evaluate what is known regarding contemporary methodologies capable of assessing midpalatal suture maturation in humans. METHODS: A computerized database search was conducted using Medline, PubMed, Embase and Scopus to search the literature up until October 5, 2016. A supplemental hand search was completed of references from retrieved articles that met the final inclusion criteria. RESULTS: Twenty-nine abstracts met the initial inclusion criteria. Following assessment of full articles, only five met the final inclusion criteria. The number of subjects involved and quality of studies varied, ranging from an in-vitro study using autopsy material to prospective studies with in vivo human patients. Three types of evaluations were identified: quantitative, semi-quantitative and qualitative evaluations. Four of the five studies utilized computed tomography (CT), while the remaining study utilized non invasive ultrasonography (US). No methodology was validated against a histological-based reference standard. CONCLUSIONS: Weak limited evidence exists to support the newest technologies and proposed methodologies to assess midpalatal suture maturation. Due to the lack of reference standard validation, it is advised that clinicians still use a multitude of diagnostic criteria to subjectively assess palatal suture maturation and drive clinical decision-making. PMID- 28615035 TI - Unexpected consequences: exon skipping caused by CRISPR-generated mutations. AB - A new study finds that splicing disruption is a frequent consequence of mutations generated by CRISPR/Cas9 gene-editing technology, and alleles designed to be null can express aberrant proteins. This new information allows enhanced quality control procedures to select the best mutant alleles generated by CRISPR/Cas9.Please see related Method article: https://www.doi.org/10.1186/s13059 017-1237-8. PMID- 28615036 TI - Predictors of the response to etanercept in patients with juvenile idiopathic arthritis without systemic manifestations within 12 months: results of an open label, prospective study conducted at the National Scientific and Practical Center of Children's Health, Russia. AB - BACKGROUND: The aim of this study was to investigate the efficacy of etanercept treatment and to identify predictors of response to therapy within 12 months in patients with juvenile idiopathic arthritis (JIA) without systemic manifestations. METHODS: A total of 197 juvenile patients were enrolled in this study. Response to therapy was assessed using the ACRPedi 30/50/70/90 criteria, the Wallace criteria, and the Juvenile Arthritis Disease Activity Score 71 (JADAS 71). Univariate and multivariate logistic regression analyses were performed to identify potential baseline factors associated with treatment response in different JIA categories. RESULTS: One year after treatment initiation, 179 (90.9%) patients achieved ACRPedi30; 177 (89.8%) patients achieved ACRPedi50; 168 (85.3%) patients achieved ACRPedi70; and 135 (68.5%) patients achieved ACRPedi90 response. A total of 132 (67.0%) and 92 (46.7%) patients achieved inactive disease according to the Wallace criteria and the JADAS-71 cut-off point, respectively. Excellent response (achieving ACRPedi90 and clinically inactive disease according both to the Wallace criteria and the JADAS71 cut-off point) was associated with persistent oligoarticular JIA category, shorter disease duration before the start of etanercept, a lower number of DMARDs used before the introduction of etanercept, a lower number of joints with limited motion, and lower C-reactive protein at baseline. Poor response (failure to achieve ACR 70 or active disease according to both the Wallace criteria and JADAS71 even when ACR 70 was achieved) was associated with the polyarticular or enthesitis-related JIA categories, higher disease duration before the start of etanercept, and older age at disease onset. CONCLUSION: Almost half (45.7%) of the patients who initiated etanercept treatment achieved an excellent response (inactive disease and ACRPedi90) after 1 year. What may be novel is our finding that the response to etanercept therapy was strongly associated with the JIA category. The response to etanercept therapy was also associated with the disease duration before the start of etanercept treatment. PMID- 28615037 TI - High sensitivity and negative predictive value of the DETECT algorithm for an early diagnosis of pulmonary arterial hypertension in systemic sclerosis: application in a single center. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is one of the most relevant causes of death in systemic sclerosis. The aims of this study were to analyse the recently published DETECT algorithm comparing it with European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines: as screening of PAH; (2) identifying median pulmonary arterial pressure (mPAP) >=21 mmHg; and (3) determining any group of pulmonary hypertension (PH). METHODS: Eighty-three patients fulfilling LeRoy's systemic sclerosis diagnostic criteria with at least right heart catheterization were studied retrospectively. Clinical data, serological biomarkers, echocardiographic and hemodynamic features were collected. SPSS 20.0 was used for statistical analysis. RESULTS: According to right heart catheterization findings, 35 patients with PAH and 28 with no PH met the standards for DETECT algorithm analysis: 27.0% of patients presented with functional class III/IV. Applying DETECT, the sensitivity was 100%, specificity 42.9%, the positive predictive value 68.6% and the negative predictive value 100%, whereas employing the ESC/ERS guidelines these were 91.4%, 85.7%, 88.9% and 89.3%, respectively. There were no missed diagnoses of PAH using DETECT compared with three patients missed (8.5%) using ESC/ERS guidelines. The DETECT algorithm also showed greater sensitivity and negative predictive value to identify patients with mPAP >=21 mmHg or with any type of PH. CONCLUSIONS: The DETECT algorithm is confirmed as an excellent screening method due to its high sensitivity and negative predictive value, minimizing missed diagnosis of PAH. DETECT would be accurate either for early diagnosis of borderline mPAP or any group of PH. PMID- 28615038 TI - Prevalence and genetic variability of Anaplasma phagocytophilum in wild rodents from the Italian alps. AB - BACKGROUND: Human granulocytic anaplasmosis is a zoonotic bacterial disease with increasing relevance for public health in Europe. The understanding of its sylvatic cycle and identification of competent reservoir hosts are essential for improving disease risk models and planning preventative measures. RESULTS: In 2012 we collected single ear biopsy punches from 964 live-trapped rodents in the Province of Trento, Italy. Genetic screening for Anaplasma phagocytophilum (AP) was carried out by PCR amplification of a fragment of the 16S rRNA gene. Fifty two (5.4%) samples tested positive: 49/245 (20%) from the bank vole (Myodes glareolus) and 3/685 (0.4%) samples collected from the yellow-necked mouse (Apodemus flavicollis). From these 52 positive samples, we generated 38 groEL and 39 msp4 sequences. Phylogenetic analysis confirmed the existence of a distinct rodent strain of AP. CONCLUSIONS: Our results confirm the circulation of a specific strain of AP in rodents in our study area; moreover, they provide further evidence of the marginal role of A. flavicollis compared to M. glareolus as a reservoir host for this pathogen. PMID- 28615040 TI - Immunohistochemical and immunocytochemical study of mechanoreceptors in anterior cruciate ligament reconstruction with the remnant-preserving technique using Achilles tendon allografts. AB - BACKGROUND: Attempts have been made to validate the significance of remnant preservation with anterior cruciate ligament (ACL) reconstruction using immunohistochemical and immunocytochemical techniques. The purpose of this study was to examine the expression of mechanoreceptors in the remnant tissue of ACL reconstruction performed with the remnant-preserving technique. METHODS: Tissue samples were obtained from 10 patients who underwent ACL reconstruction with the remnant-preserving technique. The specimens were obtained from remnant ACL tissue and Achilles allografts superficially and at the tibial attachment. The control group consisted of three normal ACLs procured from young males who underwent partial meniscectomy. Tissues and cells from the ACL remnants and Achilles allografts were characterized using hematoxylin and eosin (H&E) staining and immunohistochemical, immunocytochemical, and immunoblotting assays. In particular, the sensitivity of neural cell validation was improved using nerve growth factor (NGF) to stimulate the expression of neural cells. RESULTS: The results are summarized as follows. (1) In H&E staining and immunohistochemical assays, no neural cells were detected in remnant or allograft tissue. (2) In the immunocytochemical study, neural cells were detected in remnant tissue. (3) The increased proliferation of remnant ACL cells with NGF treatment suggested their identity as neural cells. (4) NGF treatment also stimulated protein and RNA expression of Nestin (a specific marker for neural cells) in remnant ACL cells. CONCLUSIONS: The improved immunocytochemical methodology proved useful. Although mechanoreceptors were detected relatively less frequently than expected, the authors consider that this finding does not negate the necessity of remnant preserving ACL reconstruction. PMID- 28615039 TI - Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation. AB - BACKGROUND: Impaired T cell reconstitution remains a major deterrent in the field of bone marrow (BM) transplantation (BMT) due to pre-conditioning-induced damages inflicted to the thymi of recipient hosts. Given the previously reported thymo stimulatory property of interleukin (IL)-21, we reasoned that its use post-BMT could have a profound effect on de novo T cell development. METHODS: To evaluate the effect of IL-21 on de novo T cell development in vivo, BM derived from RAG2p GFP mice was transplanted into LP/J mice. Lymphocyte reconstitution was first assessed using a hematological analyzer and a flow cytometer on collected blood samples. Detailed flow cytometry analysis was then performed on the BM, thymus, and spleen of transplanted animals. Finally, the effect of human IL-21 on thymopoiesis was validated in humanized mice. RESULTS: Using a major histocompatibility complex (MHC)-matched allogeneic BMT model, we found that IL 21 administration improves immune reconstitution by triggering the proliferation of BM Lin-Sca1+c-kit+ (LSK) subsets. The pharmacological effect of IL-21 also culminates in the recovery of both hematopoietic (thymocytes) and non hematopoietic (stromal) cells within the thymi of IL-21-treated recipient animals. Although T cells derived from all transplanted groups proliferate, secrete various cytokines, and express granzyme B similarly in response to T cell receptor (TCR) stimulation, full regeneration of peripheral naive CD4+ and CD8+ T cells and normal TCRvbeta distribution could only be detected in IL-21-treated recipient mice. Astonishingly, none of the recipient mice who underwent IL-21 treatment developed graft-versus-host disease (GVHD) in the MHC-matched allogeneic setting while the graft-versus-tumor (GVT) effect was strongly retained. Inhibition of GVHD onset could also be attributed to the enhanced generation of regulatory B cells (B10) observed in the IL-21, but not PBS, recipient mice. We also tested the thymopoiesis-stimulating property of human IL 21 in NSG mice transplanted with cord blood (CB) and found significant improvement in de novo human CD3+ T cell development. CONCLUSIONS: In sum, our study indicates that IL-21 represents a new class of unforeseen thymopoietin capable of restoring thymic function following BMT. PMID- 28615041 TI - Epigenetic aging clocks in mice and men. AB - Epigenetic clocks provide powerful tools to evaluate nutritional, hormonal, and genetic effects on aging. What can we learn from differences between species in how these clocks tick?Please see related Research articles: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1203-5 , http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1186-2 , http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1187-1 and http://genomebiology.biomedcentral.com/articles/10.1186/s13059-017-1185-3. PMID- 28615042 TI - Locomotor circumvention strategies are altered by stroke: I. Obstacle clearance. AB - BACKGROUND: Functional locomotion requires the ability to adapt to environmental challenges such as the presence of stationary or moving obstacles. Difficulties in obstacle circumvention often lead to restricted community ambulation in individuals with stroke. The objective of this study was to contrast obstacle circumvention strategies between post-stroke (n = 12) and healthy individuals (n = 12) performing locomotor and perceptuomotor (joystick navigation) tasks with different obstacle approaches. METHODS: Participants walked and navigated with a joystick towards a central target, in a virtual environment simulating a large room, while avoiding an obstacle that either remained stationary at the pre determined point of intersection or moved from head-on or diagonally 30 degrees left/right. The outcome measures included dynamic clearance (DC), instantaneous distance from obstacle at crossing (IDC), number of collisions and preferred side of circumvention. These measures were compared between groups (stroke vs. healthy), obstacle parameter (stationary vs. moving head-on) and direction of approach (left/paretic vs. right/non-paretic). RESULTS: DC was significantly larger when circumventing a moving obstacle that approached head-on as compared to a stationary obstacle for both groups during both tasks, while not significantly different in either diagonal approach in either group. IDC was smaller in the stroke group while walking and larger in both groups during joystick navigation when avoiding moving as compared to stationary obstacle. IDC was significantly larger in the stroke group compared to controls for diagonal approaches during walking, wherein two different strategies emerged amongst individuals with stroke: circumventing to the same (Vsame n = 6) or opposite (Vopp n = 4) side of obstacle approach. This behavior was not seen in the perceptuomotor task, wherein post-stroke participants circumvented to opposite side of the obstacle approach as seen in healthy participants. In the locomotor task, the Vsame subgroup that had greater functional limitations used larger DC as compared to the Vopp subgroup and healthy individuals. The remaining two individuals with stroke collided with obstacles in >50% trials of either obstacle approach. The underlying mechanisms for collision were however different for both individuals. CONCLUSION: Avoidance strategies in individuals with stroke can vary depending on the individual locomotor capabilities and obstacle characteristics. PMID- 28615043 TI - "Like sugar in milk": reconstructing the genetic history of the Parsi population. AB - BACKGROUND: The Parsis are one of the smallest religious communities in the world. To understand the population structure and demographic history of this group in detail, we analyzed Indian and Pakistani Parsi populations using high resolution genetic variation data on autosomal and uniparental loci (Y chromosomal and mitochondrial DNA). Additionally, we also assayed mitochondrial DNA polymorphisms among ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India. RESULTS: Among present-day populations, the Parsis are genetically closest to Iranian and the Caucasus populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred ~1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement. Finally, we show that Parsis are genetically closer to Neolithic Iranians than to modern Iranians, who have witnessed a more recent wave of admixture from the Near East. CONCLUSIONS: Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7th century and in agreement with their assimilation into the Indian sub-continent's population and cultural milieu "like sugar in milk". Moreover, in a wider context our results support a major demographic transition in West Asia due to the Islamic conquest. PMID- 28615044 TI - Comparison of transportation related injury mechanisms and outcome of young road users and adult road users, a retrospective analysis on 24,373 patients derived from the TraumaRegister DGU(r). AB - BACKGROUND: Most young people killed in road crashes are known as vulnerable road users. A combination of physical and developmental immaturity as well as inexperience increases the risk of road traffic accidents with a high injury severity rate. Understanding injury mechanism and pattern in a group of young road users may reduce morbidity and mortality. This study analyzes injury patterns and outcomes of young road users compared to adult road users. The comparison takes into account different transportation related injury mechanisms. METHODS: A retrospective analysis using data collected between 2002 and 2012 from the TraumaRegister DGU(r) was performed. Only patients with a transportation related injury mechanism (motor vehicle collision (MVC), motorbike, cyclist, and pedestrian) and an ISS >= 9 were included in our analysis. Four different groups of young road users were compared to adult trauma data depending on the transportation related injury mechanism. RESULTS: Twenty four thousand three hundred seventy three, datasets were retrieved to compare all subgroups. The mean ISS was 23.3 +/- 13.1. The overall mortality rate was 8.61%. In the MVC, the motorbike and the cyclist group, we found young road users having more complex injury patterns with a higher AIS pelvis, AIS head, AIS abdomen and AIS of the extremities and also a lower GCS. Whereas in these three sub-groups the adult trauma group only had a higher AIS thorax. Only in the group of the adult pedestrians we found a higher AIS pelvis, AIS abdomen, AIS thorax, a higher AIS of the extremities and a lower GCS. DISCUSSION: This study reports on the most common injuries and injury patterns in young trauma patients in comparison to an adult trauma sample. Our analysis show that in contrast to more experienced road users our young collective refers to be a vulnerable trauma group with an increased risk of a high injury severity and high mortality rate. We indicate a striking difference in terms of the region of injury and the mechanism of injury when comparing the young versus the adult trauma collectives. CONCLUSIONS: Young drivers of cars, motorbikes and bikes were shown to be on high risk to sustain a specific severe injury pattern and a high mortality rate compared to adult road users. Our data emphasize a characteristic injury pattern of young trauma patients and may be used to improve trauma care and to guide prevention strategies to decrease injury severity and mortality due to road traffic injuries. PMID- 28615045 TI - Vigorous physical activity predicts higher heart rate variability among younger adults. AB - BACKGROUND: Baseline heart rate variability (HRV) is linked to prospective cardiovascular health. We tested intensity and duration of weekly physical activity as predictors of heart rate variability in young adults. Time and frequency domain indices of HRV were calculated based on 5-min resting electrocardiograms collected from 82 undergraduate students. Hours per week of both moderate and vigorous activity were estimated using the International Physical Activity Questionnaire. In regression analyses, hours of vigorous physical activity, but not moderate activity, significantly predicted greater time domain and frequency domain indices of heart rate variability. Adjusted for weekly frequency, greater daily duration of vigorous activity failed to predict HRV indices. CONCLUSIONS: Future studies should test direct measurements of vigorous activity patterns as predictors of autonomic function in young adulthood. PMID- 28615047 TI - Sensitivity to Sevoflurane anesthesia is decreased in mice with a congenital deletion of Guanylyl Cyclase-1 alpha. AB - BACKGROUND: Volatile anesthetics increase levels of the neurotransmitter nitric oxide (NO) and the secondary messenger molecule cyclic guanosine monophosphate (cGMP) in the brain. NO activates the enzyme guanylyl cyclase (GC) to produce cGMP. We hypothesized that the NO-GC-cGMP pathway contributes to anesthesia induced unconsciousness. METHODS: Sevoflurane-induced loss and return of righting reflex (LORR and RORR, respectively) were studied in wild-type mice (WT) and in mice congenitally deficient in the GC-1alpha subunit (GC-1-/- mice). Spatial distributions of GC-1alpha and the GC-2alpha subunit in the brain were visualized by in situ hybridization. Brain cGMP levels were measured in WT and GC-1-/- mice after inhaling oxygen with or without 1.2% sevoflurane for 20 min. RESULTS: Higher concentrations of sevoflurane were required to induce LORR in GC-1-/- mice than in WT mice (1.5 +/- 0.1 vs. 1.1 +/- 0.2%, respectively, n = 14 and 14, P < 0.0001). Similarly, RORR occurred at higher concentrations of sevoflurane in GC-1 /- mice than in WT mice (1.0 +/- 0.1 vs. 0.8 +/- 0.1%, respectively, n = 14 and 14, P < 0.0001). Abundant GC-1alpha and GC-2alpha mRNA expression was detected in the cerebral cortex, medial habenula, hippocampus, and cerebellum. Inhaling 1.2% sevoflurane for 20 min increased cGMP levels in the brains of WT mice from 2.6 +/ 2.0 to 5.5 +/- 3.7 pmol/mg protein (n = 13 and 10, respectively, P = 0.0355) but not in GC-1-/- mice. CONCLUSION: Congenital deficiency of GC-1alpha abolished the ability of sevoflurane anesthesia to increase cGMP levels in the whole brain, and increased the concentration of sevoflurane required to induce LORR. Impaired NO cGMP signaling raises the threshold for producing sevoflurane-induced unconsciousness in mice. PMID- 28615048 TI - Integrated metabolome and transcriptome analysis of Magnolia champaca identifies biosynthetic pathways for floral volatile organic compounds. AB - BACKGROUND: Magnolia champaca, commonly known as champak is a well-known tree due to its highly fragrant flowers. Champak floral scent is attributed to a complex mix of volatile organic compounds (VOCs). These aromatic flowers are widely used in flavors and fragrances industry. Despite its commercial importance, the VOC biosynthesis pathways in these flowers are largely unknown. Here, we combine metabolite and RNA sequencing (RNA-seq) analyses of fully opened champak flowers to discover the active VOC biosynthesis pathways as well as floral scent-related genes. RESULTS: Volatile collection by headspace method and analysis by gas chromatography-mass spectrometry (GC-MS) identified a total of 43 VOCs from fully opened champak flowers, of which 46.9% were terpenoids, 38.9% were volatile esters and 5.2% belonged to phenylpropanoids/benzenoids. Sequencing and de novo assembly of champak flower transcriptome yielded 47,688 non-redundant unigenes. Transcriptome assembly was validated using standard polymerase chain reaction (PCR) based approach for randomly selected unigenes. The detailed profiles of VOCs led to the discovery of pathways and genes involved in floral scent biosynthesis from RNA-seq data. Analysis of expression levels of many floral scent biosynthesis-related unigenes in flowers and leaves showed that most of them were expressed higher in flowers than in leaf tissues. Moreover, our metabolite-guided transcriptomics, in vitro and in vivo enzyme assays and transgenic studies identified (R)-linalool synthase that is essential for the production of major VOCs of champak flowers, (R)-linalool and linalool oxides. CONCLUSION: As our study is the first report on transcriptome analysis of Magnolia champaca, this transcriptome dataset that serves as an important public information for functional genomics will not only facilitate better understanding of ecological functions of champak floral VOCs, but also provide biotechnological targets for sustainable production of champak floral scent. PMID- 28615049 TI - A case of acute Sheehan's syndrome and literature review: a rare but life threatening complication of postpartum hemorrhage. AB - BACKGROUND: Sheehan's syndrome occurs because of severe postpartum hemorrhage causing ischemic pituitary necrosis. Sheehan's syndrome is a well-known condition that is generally diagnosed several years postpartum. However, acute Sheehan's syndrome is rare, and clinicians have little exposure to it. It can be life threatening. There have been no reviews of acute Sheehan's syndrome and no reports of successful pregnancies after acute Sheehan's syndrome. We present such a case, and to understand this rare condition, we have reviewed and discussed the literature pertaining to it. An electronic search for acute Sheehan's syndrome in the literature from January 1990 and May 2014 was performed. CASE PRESENTATION: A 27-year-old woman had massive postpartum hemorrhage (approximately 5000 mL) at her first delivery due to atonic bleeding. She was transfused and treated with uterine embolization, which successfully stopped the bleeding. The postpartum period was uncomplicated through day 7 following the hemorrhage. However, on day 8, the patient had sudden onset of seizures and subsequently became comatose. Laboratory results revealed hypothyroidism, hypoglycemia, hypoprolactinemia, and adrenal insufficiency. Thus, the patient was diagnosed with acute Sheehan's syndrome. Following treatment with thyroxine and hydrocortisone, her condition improved, and she was discharged on day 24. Her next pregnancy was established 2 years after her first delivery. She required induction of ovulation for the next conception. The pregnancy, delivery, and postpartum period were uneventful. An electronic search of the literature yielded 21 cases of acute Sheehan's syndrome. Presenting signs varied, including adrenal insufficiency (12 cases), diabetes insipidus (4 cases), hypothyroidism (2 cases), and panhypopituitarism (3 cases), with a median time of presentation after delivery for each of those conditions being 7.9, 4, 18, and 9 days, respectively. Serial changes in magnetic resonance imaging were reported in some cases of acute Sheehan's syndrome. CONCLUSION: Clinicians should be aware of the risk of acute Sheehan's syndrome after a massive postpartum hemorrhage in order to diagnose it accurately and treat it promptly. PMID- 28615046 TI - The association of insertions/deletions (INDELs) and variable number tandem repeats (VNTRs) with obesity and its related traits and complications. AB - BACKGROUND: Despite the fact that insertions/deletions (INDELs) are the second most common type of genetic variations and variable number tandem repeats (VNTRs) represent a large portion of the human genome, they have received far less attention than single nucleotide polymorphisms (SNPs) and larger forms of structural variation like copy number variations (CNVs), especially in genome wide association studies (GWAS) of complex diseases like polygenic obesity. This is exemplified by the vast amount of review papers on the role of SNPs and CNVs in obesity, its related traits (like anthropometric measurements, biochemical variables, and eating behavior), and its related complications (like hypertension, hypertriglyceridemia, hypercholesterolemia, and insulin resistance collectively known as metabolic syndrome). Hence, this paper reviews the types of INDELs and VNTRs that have been studied for association with obesity and its related traits and complications. These INDELs and VNTRs could be found in the obesity loci or genes from the earliest GWAS and candidate gene association studies, like FTO, genes in the leptin-proopiomelanocortin pathway, and UCP2/3. Given the important role of the brain serotonergic and dopaminergic reward system in obesity susceptibility, the association of INDELs and VNTRs in these neurotransmitters' metabolism and transport genes with obesity is also reviewed. Next, the role of INS VNTR in obesity and its related traits is questionable, since recent large-scale studies failed to replicate the earlier positive associations. As obesity results in chronic low-grade inflammation of the adipose tissue, the proinflammatory cytokine gene IL1RA and anti-inflammatory cytokine gene IL4 have VNTRs that are implicated in obesity. A systemic proinflammatory state in combination with activation of the renin-angiotensin system and decreased nitric oxide bioavailability as found in obesity leads to endothelial dysfunction. This explains why VNTR and INDEL in eNOS and ACE, respectively, could be predisposing factors of obesity. Finally, two novel genes, DOCK5 and PER3, which are involved in the regulation of the Akt/MAPK pathway and circadian rhythm, respectively, have VNTRs and INDEL that might be associated with obesity. SHORT CONCLUSION: In conclusion, INDELs and VNTRs could have important functional consequences in the pathophysiology of obesity, and research on them should be continued to facilitate obesity prediction, prevention, and treatment. PMID- 28615050 TI - Conceptualizing physical activity parenting practices using expert informed concept mapping analysis. AB - BACKGROUND: Parents are widely recognized as playing a central role in the development of child behaviors such as physical activity. As there is little agreement as to the dimensions of physical activity-related parenting practices that should be measured or how they should be operationalized, this study engaged experts to develop an integrated conceptual framework for assessing parenting practices that influence multiple aspects of 5 to 12 year old children's participation in physical activity. The ultimate goal of this study is to inform the development of an item bank (repository of calibrated items) aimed at measuring physical activity parenting practices. METHODS: Twenty four experts from 6 countries (Australia, Canada, England, Scotland, the Netherlands, & United States (US)) sorted 77 physical activity parenting practice concepts identified from our previously published synthesis of the literature (74 measures) and survey of Canadian and US parents. Concept Mapping software was used to conduct the multi-dimensional scaling (MDS) analysis and a cluster analysis of the MDS solution of the Expert's sorting which was qualitatively reviewed and commented on by the Experts. RESULTS: The conceptual framework includes 12 constructs which are presented using three main domains of parenting practices (neglect/control, autonomy support, and structure). The neglect/control domain includes two constructs: permissive and pressuring parenting practices. The autonomy supportive domain includes four constructs: encouragement, guided choice, involvement in child physical activities, and praises/rewards for their child's physical activity. Finally, the structure domain includes six constructs: co participation, expectations, facilitation, modeling, monitoring, and restricting physical activity for safety or academic concerns. CONCLUSION: The concept mapping analysis provided a useful process to engage experts in re conceptualizing physical activity parenting practices and identified key constructs to include in measures of physical activity parenting. While the constructs identified ought to be included in measures of physical activity parenting practices, it will be important to collect data among parents to further validate the content of these constructs. In conclusion, the method provided a roadmap for developing an item bank that captures key facets of physical activity parenting and ultimately serves to standardize how we operationalize measures of physical activity parenting. PMID- 28615051 TI - The pathway to consultation for rheumatoid arthritis: exploring anticipated actions between the onset of symptoms and face-to-face encounter with a healthcare professional. AB - BACKGROUND: When people first experience symptoms of rheumatoid arthritis (RA) they often delay seeking medical attention resulting in delayed diagnosis and treatment. This research assesses behaviours people might engage in prior to, or instead of, seeking medical attention and compares these with behaviours related to illnesses which are better publicised. METHODS: Thirty-one qualitative interviews with members of the general public explored intended actions in relation to two hypothetical RA vignettes (with and without joint swelling) and two non-RA vignettes (bowel cancer and angina). The interviews were audio recorded and transcribed. Analysis focused on intended information gathering and other self-management behaviours in the interval between symptom onset and help seeking. RESULTS: Participants were more likely to envision self-managing symptoms when confronted with the symptoms of RA compared to the other vignettes. Participants would look for information to share responsibility for decision making and get advice and reassurance. Others saw no need for information seeking, perceived the information available as untrustworthy or, particularly in the case of bowel cancer and angina, would not want to delay seeking medical attention. Participants further anticipated choosing not to self-manage the symptoms; actively monitoring the symptoms (angina/ bowel cancer) or engaging in self-treatment of symptom(s). DISCUSSION: These results help define targets for interventions to increase appropriate help-seeking behaviour for people experiencing the initial symptoms of RA, such as educational interventions directed at allied healthcare professionals from whom new patients may seek information on self-management techniques, or the development of authoritative and accessible informational resources for the general public. PMID- 28615052 TI - Intravenous misplacement of the nephrostomy catheter following percutaneous nephrostolithotomy: two case reports and literature review. AB - BACKGROUND: Intravenous misplacement of a nephrostomy tube after percutaneous nephrostolithotomy (PCNL) is very rare in clinical experiences. This report summarizes the characteristics and management of intravenous misplacement. CASE PRESENTATION: We present two uncommon cases of intravenous nephrostomy catheter misplacement after PCNL from among 4220 patients who underwent PCNL between January 2009 and December 2015. The tip of the tube was located in the inferior vena cava in one case and in the renal vein in the other. We preferably performed open surgery to treat the two patients, mainly to remove the residual calculi and to prepare for any possible adverse event. All patients were successfully managed and discharged uneventfully. CONCLUSION: Intravenous nephrostomy tube misplacement is an uncommon PCNL complication. Furthermore, the study illustrates the importance of prompt diagnosis of renal vein perforation and its prompt management using open surgery, similar to conservative therapies. PMID- 28615053 TI - Loci and candidate genes conferring resistance to soybean cyst nematode HG type 2.5.7. AB - BACKGROUND: Soybean (Glycine max L. Merr.) cyst nematode (SCN, Heterodera glycines I,) is a major pest of soybean worldwide. The most effective strategy to control this pest involves the use of resistant cultivars. The aim of the present study was to investigate the genome-wide genetic architecture of resistance to SCN HG Type 2.5.7 (race 1) in landrace and elite cultivated soybeans. RESULTS: A total of 200 diverse soybean accessions were screened for resistance to SCN HG Type 2.5.7 and genotyped through sequencing using the Specific Locus Amplified Fragment Sequencing (SLAF-seq) approach with a 6.14-fold average sequencing depth. A total of 33,194 SNPs were identified with minor allele frequencies (MAF) over 4%, covering 97% of all the genotypes. Genome-wide association mapping (GWAS) revealed thirteen SNPs associated with resistance to SCN HG Type 2.5.7. These SNPs were distributed on five chromosomes (Chr), including Chr7, 8, 14, 15 and 18. Four SNPs were novel resistance loci and nine SNPs were located near known QTL. A total of 30 genes were identified as candidate genes underlying SCN resistance. CONCLUSIONS: A total of sixteen novel soybean accessions were identified with significant resistance to HG Type 2.5.7. The beneficial alleles and candidate genes identified by GWAS might be valuable for improving marker assisted breeding efficiency and exploring the molecular mechanisms underlying SCN resistance. PMID- 28615054 TI - End-stage kidney disease in patient with epidermolysis bullosa - what are the treatment options? - case report. AB - BACKGROUND: Epidermolysis bullosa is a group of diseases caused by mutations in genes for proteins responsible for cells' anchorage at the dermo-epidermal junction. Their common feature are dysfunctional or even absent connections between cells. The typical clinical sign is the formation of blisters, with possible excessive scarring, in response to minimal skin irritation. End stage renal disease may be one of the comorbidities in patients with epidermolysis bullosa. The implementation of renal replacement therapy may be very difficult in this population. This is mainly due to problems in obtaining the proper dialysis access. The choice of appropriate method may be crucial for patient's survival. CASE PRESENTATION: We present a case of 29-year-old woman with Epidermolysis bullosa caused by laminin 5 gene mutation. The patient suffered from additional conditions: blindness, complete bilateral sensorineural deafness and oesophageal stenosis. When end stage renal disease was diagnosed, the problem of renal replacement therapy had to be faced. There have been few reports concerning ESRD in this specific group of patients in the available literature. In most of them the prognosis was very poor. Nevertheless, we were very determined to overcome all the difficulties. Special procedures and cooperation with the patient's family allowed us to consider kidney transplantation as a treatment option. CONCLUSION: There should be no limitations in renal replacement therapy in patients with epidermolysis bullosa. Haemodialysis, peritoneal dialysis and kidney transplantation are all possible treatment options. Nevertheless, either method requires special procedures. PMID- 28615055 TI - Small-sized newborn dogs skeletal development: radiologic, morphometric, and histological findings obtained from spontaneously dead animals. AB - BACKGROUND: Very little is known about neonatal skeletal development in small sized purebred dogs. In order to improve this knowledge, 27 spontaneously dead puppies belonging to small-sized breeds were enrolled in this study for radiologic, histological and morphometric investigations. RESULTS: The appearance of the limb secondary ossification centers and the onset of their formation were clearly observed by x rays and confirmed by histological evidences. Radiographic and anatomic measurements of limb bones length and skull length and width were positively correlated with body weight and age of the subjects and the body weight was positively correlated with radius bone mineral density, as demonstrated by dual-energy x-rays absorptiometry. CONCLUSIONS: These data provided original information on the growth of newborn small-sized breed dogs, and suggest that cadavers may be useful to study skeletal development. PMID- 28615056 TI - Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression. AB - BACKGROUND: Oct4, a key stemness transcription factor, is overexpressed in lung cancer. Here, we reveal a novel transcription regulation of long non-coding RNAs (lncRNAs) by Oct4. LncRNAs have emerged as important players in cancer progression. METHODS: Oct4 chromatin-immunoprecipitation (ChIP)-sequencing and several lncRNA databases with literature annotation were integrated to identify Oct4-regulated lncRNAs. Luciferase activity, qRT-PCR and ChIP-PCR assays were conducted to examine transcription regulation of lncRNAs by Oct4. Reconstitution experiments of Oct4 and downstream lncRNAs in cell proliferation, migration and invasion assays were performed to confirm the Oct4-lncRNAs signaling axes in promoting lung cancer cell growth and motility. The expression correlations between Oct4 and lncRNAs were investigated in 124 lung cancer patients using qRT PCR analysis. The clinical significance of Oct4/lncRNAs signaling axes were further evaluated using multivariate Cox regression and Kaplan-Meier analyses. RESULTS: We confirmed that seven lncRNAs were upregulated by direct binding of Oct4. Among them, nuclear paraspeckle assembly transcript 1 (NEAT1), metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and urothelial carcinoma associated 1 (UCA1) were validated as Oct4 transcriptional targets through promoter or enhancer activation. We showed that lung cancer cells overexpressing NEAT1 or MALAT1 and the Oct4-silenced cells reconstituted with NEAT1 or MALAT1 promoted cell proliferation, migration and invasion. In addition, knockdown of NEAT1 or MALAT1 abolished Oct4-mediated lung cancer cell growth and motility. These cell-based results suggested that Oct4/NEAT1 or Oct4/MALAT1 axis promoted oncogenesis. Clinically, Oct4/NEAT1/MALAT1 co-overexpression was an independent factor for prediction of poor outcome in 124 lung cancer patients. CONCLUSIONS: Our study reveals a novel mechanism by which Oct4 transcriptionally activates NEAT1 via promoter and MALAT1 via enhancer binding to promote cell proliferation and motility, and led to lung tumorigenesis and poor prognosis. PMID- 28615057 TI - Erratum to: Engineering an efficient and tight D-amino acid-inducible gene expression system in Rhodosporidium/Rhodotorula species. PMID- 28615058 TI - Long-term prognostic significance of rising PSA levels following radiotherapy for localized prostate cancer - focus on overall survival. AB - BACKGROUND: The aim of this study was to evaluate the long-term prognostic significance of rising PSA levels, particularly focussing on overall survival. METHODS: Two hundred ninety-five patients with localized prostate cancer were either treated with low-dose-rate (LDR) brachytherapy with I-125 seeds as monotherapy (n = 94; 145Gy), high-dose-rate (HDR) brachytherapy with Ir-192 as a boost to external beam RT (n = 66; 50.4Gy in 1.8Gy fractions EBRT + 18Gy in 9Gy fractions HDR) or EBRT alone (70.2Gy in 1.8Gy fractions; n = 135). "PSA bounce" was defined as an increase of at least 0.2 ng/ml followed by spontaneous return to pre-bounce level or lower, biochemical failure was defined according to the Phoenix definition. RESULTS: Median follow-up after the end of radiotherapy was 108 months. A PSA bounce showed to be a significant factor for biochemical control (BC) and overall survival (OS) after ten years (BC10 of 83% with bounce vs. 34% without, p < 0.01; OS10 of 82% with bounce vs. 59% without bounce, p < 0.01). The occurrence of a bounce, a high nadir and the therapy modality (LDR-BT vs. EBRT and HDR-BT + EBRT vs. EBRT) proved to be independent factors for PSA recurrence in multivariate Cox regression analysis. A bounce was detected significantly earlier than a PSA recurrence (median 20 months vs. 32 months after RT; p < 0.01; median PSA doubling time 5.5 vs. 5.0 months, not significant). PSA doubling time was prognostically significant in case of PSA recurrence (OS10 of 72% vs. 36% with PSA doubling time ? 5 months vs. <= 5 months; p < 0.01). CONCLUSIONS: Rising PSA levels within the first two years can usually be classified as a benign PSA bounce, with favourable recurrence-free and overall survival rates. PSA doubling time is an important predictor for overall survival following the diagnosis of a recurrence. PMID- 28615059 TI - Analysis of factors that affect the precision of the radiographic lateral femoral bowing angle using a three-dimensional computed tomography-based modelling technique. AB - BACKGROUND: Precise measurement of lateral femoral bowing is important to achieve postoperative lower limb alignment. We aimed to investigate factors that affect the precision of the radiographic lateral femoral bowing (RLFB) angle using three dimensional (3D) models and whether the angle affects surgery design. METHODS: Forty femurs in total were divided into two groups based on their preoperative RLFB angle. The flexion contracture angle, preoperative and postoperative RLFB angles, and intersection angle between the mechanical and anatomical axes were compared. The angle between the arc and sagittal planes, varus and valgus angles, and intersection angle between the mechanical and anatomical axes were measured on a 3D model. RESULTS: There was no significant between-group difference in 3D model measurements of the angle between the arc and sagittal planes (p = 0.327). There was no significant difference between the mechanical and anatomical axes measured by both imaging modalities (p > 0.258). When the RLFB was >5 degrees , the flexion contracture angle and radiographic femoral bowing angle were positively correlated (r = 0.535, p < 0.05). Distal femur varus and valgus angles significantly differed between the two groups (p = 0.01). After total knee arthroplasty, the radiographic femoral bowing angle decreased significantly. When the cases' radiographic femoral bowing angle is larger and the angle between the arc and sagittal planes is smaller as measured in 3D models, the angle between the arc and coronal planes is larger. CONCLUSION: The radiographic femoral bowing angle does not reflect the actual size of lateral femoral bowing, does not greatly affect surgery design, and is greatly affected by flexion contracture deformity. A RLFB angle larger than 15 degrees indicates real lateral femoral bowing. PMID- 28615060 TI - Outcome of proximal esophageal cancer after definitive combined chemo-radiation: a Swiss multicenter retrospective study. AB - OBJECTIVE: To report oncological outcomes and toxicity rates, of definitive platin-based chemoradiadiationtherapy (CRT) in the management of proximal esophageal cancer. METHODS: We retrospectively reviewed the medical records of patients with cT1-4 cN0-3 cM0 cervical esophageal cancer (CEC) (defined as tumors located below the inferior border of the cricoid cartilage, down to 22 cm from the incisors) treated between 2004 and 2013 with platin-based definitive CRT in four Swiss institutions. Acute and chronic toxicities were retrospectively scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE-NCI v.4.0). Primary endpoint was loco-regional control (LRC). We also evaluated overall survival (OS) and disease-free survival (DFS) rates. The influence of patient- and treatment related features have been calculated using the Log-rank test and multivariate Cox proportional hazards model. RESULTS: We enrolled a total of 55 patients. Median time interval from diagnosis to CRT was 78 days (6-178 days). Median radiation dose was 56Gy (28 72Gy). Induction chemotherapy (ICHT) was delivered in 58% of patients. With a median follow up of 34 months (6-110months), actuarial 3-year LRC, DFS and OS were 52% (95% CI: 37-67%), 35% (95% CI: 22-50%) and 52% (95% CI: 37-67%), respectively. Acute toxicities (dysphagia, pain, skin-toxicity) ranged from grade 0 - 4 without significant dose-dependent differences. On univariable analyses, the only significant prognostic factor for LRC was the time interval > 78 days from diagnosis to CRT. On multivariable analysis, total radiation dose >56Gy (p <0.006) and ICHT (p < 0.004) were statistically significant positive predictive factors influencing DFS and OS. CONCLUSION: Definitive CRT is a reliable therapeutic option for proximal esophageal cancer, with acceptable treatment related toxicities. Higher doses and ICHT may improve OS and DFS and. These findings need to be confirmed in further prospective studies. PMID- 28615061 TI - Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of gammadelta T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea. AB - BACKGROUND: gammadelta T cells are important for both protective immunity and immunopathogenesis during malaria infection. However, the immunological processes determining beneficial or detrimental effects on disease outcome remain elusive. The aim of this study was to examine expression and regulatory effect of the inhibitory receptor T-cell immunoglobulin domain and mucin domain 3 (TIM3) on gammadelta T cells. While TIM3 expression and function on conventional alphabeta T cells have been clearly defined, the equivalent characterization on gammadelta T cells and associations with disease outcomes is limited. This study investigated the functional capacity of TIM3+ gammadelta T cells and the underlying mechanisms contributing to TIM3 upregulation and established an association with malaria disease outcomes. METHODS: We analyzed TIM3 expression on gammadelta T cells in 132 children aged 5-10 years living in malaria endemic areas of Papua New Guinea. TIM3 upregulation and effector functions of TIM3+ gammadelta T cells were assessed following in vitro stimulation with parasite infected erythrocytes, phosphoantigen and/or cytokines. Associations between the proportion of TIM3-expressing cells and the molecular force of infection were tested using negative binomial regression and in a Cox proportional hazards model for time to first clinical episode. Multivariable analyses to determine the association of TIM3 and IL-18 levels were conducted using general linear models. Malaria infection mouse models were utilized to experimentally investigate the relationship between repeated exposure and TIM3 upregulation. RESULTS: This study demonstrates that even in the absence of an active malaria infection, children of malaria endemic areas have an atypical population of TIM3-expressing gammadelta T cells (mean frequency TIM3+ of total gammadelta T cells 15.2% +/- 12). Crucial factors required for gammadelta T cell TIM3 upregulation include IL-12/IL-18, and plasma IL-18 was associated with TIM3 expression (P = 0.002). Additionally, we show a relationship between TIM3 expression and infection with distinct parasite clones during repeated exposure. TIM3+ gammadelta T cells were functionally impaired and were associated with asymptomatic malaria infection (hazard ratio 0.54, P = 0.032). CONCLUSIONS: Collectively our data demonstrate a novel role for IL-12/IL-18 in shaping the innate immune response and provide fundamental insight into aspects of gammadelta T cell immunoregulation. Furthermore, we show that TIM3 represents an important gammadelta T cell regulatory component involved in minimizing malaria symptoms. PMID- 28615062 TI - Metabolic and transcriptional elucidation of the carotenoid biosynthesis pathway in peel and flesh tissue of loquat fruit during on-tree development. AB - BACKGROUND: Carotenoids are the main colouring substances found in orange-fleshed loquat fruits. The aim of this study was to unravel the carotenoid biosynthetic pathway of loquat fruit (cv. 'Obusa') in peel and flesh tissue during distinct on tree developmental stages through a targeted analytical and molecular approach. RESULTS: Substantial changes regarding colour parameters, both between peel and flesh and among the different developmental stages, were monitored, concomitant with a significant increment in carotenoid content. Key genes and individual compounds that are implicated in the carotenoid biosynthetic pathway were further dissected with the employment of molecular (RT-qPCR) and advanced analytical techniques (LC-MS). Results revealed significant differences in carotenoid composition between peel and flesh. Thirty-two carotenoids were found in the peel, while only eighteen carotenoids were identified in the flesh. Trans-lutein and trans-beta-carotene were the major carotenoids in the peel; the content of the former decreased with the progress of ripening, while the latter registered a 7.2-fold increase. However, carotenoid profiling of loquat flesh indicated trans beta-cryptoxanthin, followed by trans-beta-carotene and 5,8-epoxy-beta-carotene to be the most predominant carotenoids. High amounts of trans-beta-carotene in both tissues were supported by significant induction in a chromoplast-specific lycopene beta-cyclase (CYCB) transcript levels. PSY1, ZDS, CYCB and BCH were up regulated and CRTISO, LCYE, ECH and VDE were down-regulated in most of the developmental stages compared with the immature stage in both peel and flesh tissue. Overall, differential regulation of expression levels with the progress of on-tree fruit development was more evident in the middle and downstream genes of carotenoid biosynthetic pathway. CONCLUSIONS: Carotenoid composition is greatly affected during on-tree loquat development with striking differences between peel and flesh tissue. A link between gene up- or down-regulation during the developmental stages of the loquat fruit, and how their expression affects carotenoid content per tissue (peel or flesh) was established. PMID- 28615063 TI - Lineage-specific rediploidization is a mechanism to explain time-lags between genome duplication and evolutionary diversification. AB - BACKGROUND: The functional divergence of duplicate genes (ohnologues) retained from whole genome duplication (WGD) is thought to promote evolutionary diversification. However, species radiation and phenotypic diversification are often temporally separated from WGD. Salmonid fish, whose ancestor underwent WGD by autotetraploidization ~95 million years ago, fit such a 'time-lag' model of post-WGD radiation, which occurred alongside a major delay in the rediploidization process. Here we propose a model, 'lineage-specific ohnologue resolution' (LORe), to address the consequences of delayed rediploidization. Under LORe, speciation precedes rediploidization, allowing independent ohnologue divergence in sister lineages sharing an ancestral WGD event. RESULTS: Using cross-species sequence capture, phylogenomics and genome-wide analyses of ohnologue expression divergence, we demonstrate the major impact of LORe on salmonid evolution. One-quarter of each salmonid genome, harbouring at least 4550 ohnologues, has evolved under LORe, with rediploidization and functional divergence occurring on multiple independent occasions >50 million years post WGD. We demonstrate the existence and regulatory divergence of many LORe ohnologues with functions in lineage-specific physiological adaptations that potentially facilitated salmonid species radiation. We show that LORe ohnologues are enriched for different functions than 'older' ohnologues that began diverging in the salmonid ancestor. CONCLUSIONS: LORe has unappreciated significance as a nested component of post-WGD divergence that impacts the functional properties of genes, whilst providing ohnologues available solely for lineage-specific adaptation. Under LORe, which is predicted following many WGD events, the functional outcomes of WGD need not appear 'explosively', but can arise gradually over tens of millions of years, promoting lineage-specific diversification regimes under prevailing ecological pressures. PMID- 28615064 TI - Anti-Toxoplasma gondii antibodies in patients with beta-hemoglobinopathies: the first report in the Americas. AB - BACKGROUND: In Brazil, there have been no previous studies of Toxoplasma gondii infection in sickle cell anemia patients and carriers of severe forms of beta thalassemia. This study evaluated T. gondii infection in patients with beta hemoglobinopathies. METHODS: A total of 158 samples, 77 (48.7%) men and 81 (51.3%) women, were evaluated. Three groups were formed: G1 (85 patients with sickle cell disease); G2 (11 patients with homozygous beta-thalassemia; G3 (62 patients with heterozygous beta-thalassemia). ELISA was employed to identify anti T. gondii IgM and IgG antibodies, and molecular analysis was performed to determine beta-hemoglobin mutations. Fisher's exact test was used to compare frequencies of anti-T. gondii IgM and IgG antibodies in respect to gender and age. RESULTS: Anti-T. gondii IgG antibodies were found in 43.5% of individuals in G1, 18.1% in G2 and 50% in G3. All samples from G1 and G2 were seronegative for anti-T. gondii IgM antibodies, but 3.2% from G3 were seropositive. Considering anti-T. gondii IgG antibodies, no statistical significant differences were found between these groups nor in seroprevalence between genders within each group. Despite this, comparisons of the mean ages between G1, G2 and G3 were statistically significant (G2 vs. G1: p value = 0.0001; G3 vs. G1: p-value <0.0001; G3 vs. G2: p-value = 0.0001). CONCLUSION: A comparison by age of patients with sickle cell anemia showed a trend of lower risk of infection among younger individuals. Therefore, this study demonstrates that T. gondii infection occurs in patients with beta-thalassemia and sickle cell anemia in Brazil as seen by the presence of anti-T. gondii IgM and IgG antibodies. PMID- 28615065 TI - Genome wide association study and genomic prediction for fatty acid composition in Chinese Simmental beef cattle using high density SNP array. AB - BACKGROUND: Fatty acid composition of muscle is an important trait contributing to meat quality. Recently, genome-wide association study (GWAS) has been extensively used to explore the molecular mechanism underlying important traits in cattle. In this study, we performed GWAS using high density SNP array to analyze the association between SNPs and fatty acids and evaluated the accuracy of genomic prediction for fatty acids in Chinese Simmental cattle. RESULTS: Using the BayesB method, we identified 35 and 7 regions in Chinese Simmental cattle that displayed significant associations with individual fatty acids and fatty acid groups, respectively. We further obtained several candidate genes which may be involved in fatty acid biosynthesis including elongation of very long chain fatty acids protein 5 (ELOVL5), fatty acid synthase (FASN), caspase 2 (CASP2) and thyroglobulin (TG). Specifically, we obtained strong evidence of association signals for one SNP located at 51.3 Mb for FASN using Genome-wide Rapid Association Mixed Model and Regression-Genomic Control (GRAMMAR-GC) approaches. Also, region-based association test identified multiple SNPs within FASN and ELOVL5 for C14:0. In addition, our result revealed that the effectiveness of genomic prediction for fatty acid composition using BayesB was slightly superior over GBLUP in Chinese Simmental cattle. CONCLUSIONS: We identified several significantly associated regions and loci which can be considered as potential candidate markers for genomics-assisted breeding programs. Using multiple methods, our results revealed that FASN and ELOVL5 are associated with fatty acids with strong evidence. Our finding also suggested that it is feasible to perform genomic selection for fatty acids in Chinese Simmental cattle. PMID- 28615066 TI - Air pollution, cardiovascular endpoints and susceptibility by stress and material resources: a systematic review of the evidence. AB - BACKGROUND AND METHODS: Evidence shows that both the physical and social environments play a role in the development of cardiovascular disease. The purpose of this systematic review is two-fold: First, we summarize research from the past 12 years from the growing number of studies focused on effect modification of the relationships between air pollution and cardiovascular disease (CVD) outcomes by socioeconomic position (SEP) and; second, we identify research gaps throughout the published literature on this topic and opportunities for addressing these gaps in future study designs. RESULTS: We identified 30 articles that examined the modifying effects of either material resources or psychosocial stress (both related to SEP) on associations between short and long term air pollution exposure and CVD endpoints. Although 18 articles identified at least one interaction between an air pollutant and material resource indicator, 11 others did not. Support for susceptibility to air pollution by psychosocial stress was weaker; however, only three articles tested this hypothesis. Further studies are warranted to investigate how air pollution and SEP together may influence CVD. CONCLUSIONS: We recommend that such research include thorough assessment of air pollution and SEP correlations, including spatial correlation; investigate air pollution indices or multi-pollutant models; use standardized metrics of SEP to enhance comparability across studies; and evaluate potentially susceptible populations. PMID- 28615067 TI - Correspondence on Lovell et al.: identification of chicken genes previously assumed to be evolutionarily lost. AB - Through RNA-Seq analyses, we identified 137 genes that are missing in chicken, including the long-sought-after nephrin and tumor necrosis factor genes. These genes tended to cluster in GC-rich regions that have poor coverage in genome sequence databases. Hence, the occurrence of syntenic groups of vertebrate genes that have not been observed in Aves does not prove the evolutionary loss of such genes.Please see related Research article: http://dx.doi.org/10.1186/s13059-014 0565-1 and Please see response from Lovell et al: https://www.dx.doi.org/10.1186/s13059-017-1234-y. PMID- 28615068 TI - Quantitative proteomics in lung cancer. AB - Lung cancer is the most common cause of cancer-related death worldwide, less than 7% of patients survive 10 years following diagnosis across all stages of lung cancer. Late stage of diagnosis and lack of effective and personalized medicine reflect the need for a better understanding of the mechanisms that underlie lung cancer progression. Quantitative proteomics provides the relative different protein abundance in normal and cancer patients which offers the information for molecular interactions, signaling pathways, and biomarker identification. Here we introduce both theoretical and practical applications in the use of quantitative proteomics approaches, with principles of current technologies and methodologies including gel-based, label free, stable isotope labeling as well as targeted proteomics. Predictive markers of drug resistance, candidate biomarkers for diagnosis, and prognostic markers in lung cancer have also been discovered and analyzed by quantitative proteomic analysis. Moreover, construction of protein networks enables to provide an opportunity to interpret disease pathway and improve our understanding in cancer therapeutic strategies, allowing the discovery of molecular markers and new therapeutic targets for lung cancer. PMID- 28615069 TI - Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements. AB - BACKGROUND: The organisation of vertebrate genomes into topologically associating domains (TADs) is believed to facilitate the regulation of the genes located within them. A remaining question is whether TAD organisation is achieved through the interactions of the regulatory elements within them or if these interactions are favoured by the pre-existence of TADs. If the latter is true, the fusion of two independent TADs should result in the rewiring of the transcriptional landscape and the generation of ectopic contacts. RESULTS: We show that interactions within the PAX3 and FOXO1 domains are restricted to their respective TADs in normal conditions, while in a patient-derived alveolar rhabdomyosarcoma cell line, harbouring the diagnostic t(2;13)(q35;q14) translocation that brings together the PAX3 and FOXO1 genes, the PAX3 promoter interacts ectopically with FOXO1 sequences. Using a combination of 4C-seq datasets, we have modelled the three-dimensional organisation of the fused landscape in alveolar rhabdomyosarcoma. CONCLUSIONS: The chromosomal translocation that leads to alveolar rhabdomyosarcoma development generates a novel TAD that is likely to favour ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories. Rhabdomyosarcomas may therefore arise from cells which do not normally express PAX3. The borders of this novel TAD correspond to the original 5'- and 3'- borders of the PAX3 and FOXO1 TADs, respectively, suggesting that TAD organisation precedes the formation of regulatory long-range interactions. Our results demonstrate that, upon translocation, novel regulatory landscapes are formed allowing new intra-TAD interactions between the original loci involved. PMID- 28615070 TI - A randomised clinical trial of a metaphylactic treatment with tildipirosin for bovine respiratory disease in veal calves. AB - BACKGROUND: Bovine respiratory disease (BRD) is a major problem in veal calf rearing units. The objective of this randomised clinical trial was to assess the effectiveness of tildipirosin as a metaphylactic treatment in veal calves on the number of BRD treatments, lung consolidation on thoracic ultrasonography (TUS) and average daily gain (ADG). A total of 209 veal calves from a pre-weaning fattening unit were randomly allocated to receive one of two treatments (tildipirosin 4 mg/kg, subcutaneously, n = 109; placebo 0.9% saline, subcutaneously, n = 100) at day 12 after entry in the pre-weaned unit. The calves were followed for a 70-day period. Occurrence of mortality and BRD treatments were recorded during the pre-weaning period. At days 1, 12 and 30, TUS and clinical scores were performed and ADG was measured during the first and second months of feeding. RESULTS: The use of a metaphylactic treatment of tildipirosin 12 days after arrival of the veal calves was not associated with the number of BRD treatments performed by the producer, ultrasonographic lung consolidation or weight gain (P < 0,05). In this cohort of calves, the proportion of calves treated for BRD by the producer was low at 14% (29/209). However, 13% (26/209) of calves included in the study already had ultrasonographic lung consolidation lesions 12 days after their arrival, which was before treatment time, and 27% (56/209) had lung consolidation at day 30. CONCLUSION: In this study population with a low BRD prevalence, we were not able to detect any benefit of tildipirosin as a metaphylactic treatment of BRD at day 12 after arrival based on BRD treatments, TUS, and ADG. PMID- 28615071 TI - Survivin expression pattern in the intestine of normoxic and ischemic rats. AB - BACKGROUND: Survivin, a member of the inhibitor of apoptosis protein (IAP) family, regulates mitosis and chromosome segregation. The expression of survivin proceeds during embryonic development and in addition has already been demonstrated in cancer cells. However, there is also evidence of survivin expression in differentiated tissues, including the gastro-intestinal tract of adult rats. A study with human colon specimens exhibited survivin in most basal crypt epithelial cells of normal mucosa. There is rather limited information on survivin expression in the small intestine. In order to paint a more detailed and thus complete picture of survivin expression patterns in the gastrointestinal tract, we used an immunohistochemical approach in normal adult rat small intestinal and ascending colonic tissue. Moreover, to get deeper insights in the regulation of survivin expression after tissue damage, we also studied its expression in mesenteric ischemia-reperfusion (I/R) injury. METHODS: Mesenteric ischemia-reperfusion injury was induced in male Wistar rats (six animals/group) by occlusion of the superior mesenteric artery for 90 min and subsequent reperfusion for 120 min. Paraffin sections of untreated or ischemically treated tissue were assessed immunohistochemically by survivin and Ki-67 staining. RESULTS: Survivin could be detected in the small intestine and ascending colon of the normoxia group. It was expressed mainly in the epithelial cells of the crypts and only marginally in the villi. The individual small intestinal segments studied revealed comparable staining intensities. Likewise, expression of survivin was detected in the ischemically damaged small intestine and ascending colon. The expression pattern corresponded to the normoxic animals, as far as verifiable due to the existing tissue damage. Comparison of the expression pattern of Ki-67, a protein that acts as a cellular marker for proliferation, and survivin demonstrated a coincidental localization of the two proteins in the small intestinal and ascending colonic tissue. CONCLUSIONS: Survivin was expressed strongly in epithelial cells of small intestinal as well as ascending colonic tissue. Its expression was located in cells with a high proliferation rate and regenerative capacity. This further supports the decisive role of survivin in cell division. Surprisingly, the ischemically damaged small intestinal and ascending colonic tissue showed a comparably high expression level. These results suggest that there is already a maximal survivin expression under normal conditions. However, the intestine is able to maintain the regenerative capacity even in spite of an ischemic injury. These findings reflect the important relevance of an intact intestinal barrier. PMID- 28615072 TI - Chemokine receptor co-expression reveals aberrantly distributed TH effector memory cells in GPA patients. AB - BACKGROUND: Persistent expansion of circulating CD4+ effector memory T cells (TEM) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4+ TEM cell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4+ TEM cell subsets based on chemokine receptor expression in peripheral blood of GPA patients. Identification of particular circulating CD4+ TEM cells subsets may reveal distinct contributions of specific CD4+ TEM subsets to the disease pathogenesis in GPA. METHOD: Peripheral blood of 63 GPA patients in remission and 42 age- and sex-matched healthy controls was stained immediately after blood withdrawal with fluorochrome-conjugated antibodies for cell surface markers (CD3, CD4, CD45RO) and chemokine receptors (CCR4, CCR6, CCR7, CRTh2, CXCR3) followed by flow cytometry analysis. CD4+ TEM memory cells (CD3+CD4+CD45RO+CCR7-) were gated, and the expression patterns of chemokine receptors CXCR3+CCR4-CCR6-CRTh2-, CXCR3 CCR4+CCR6-CRTh2+, CXCR3-CCR4+CCR6+CRTh2-, and CXCR3+CCR4-CCR6+CRTh2- were used to distinguish TEM1, TEM2, TEM17, and TEM17.1 cells, respectively. RESULTS: The percentage of CD4+ TEM cells was significantly increased in GPA patients in remission compared to HCs. Chemokine receptor co-expression analysis within the CD4+ TEM cell population demonstrated a significant increase in the proportion of TEM17 cells with a concomitant significant decrease in the TEM1 cells in GPA patients compared to HC. The percentage of TEM17 cells correlated negatively with TEM1 cells in GPA patients. Moreover, the circulating proportion of TEM17 cells showed a positive correlation with the number of organs involved and an association with the tendency to relapse in GPA patients. Interestingly, the aberrant distribution of TEM1 and TEM17 cells is modulated in CMV- seropositive GPA patients. CONCLUSIONS: Our data demonstrates the identification of different CD4+ TEM cell subsets in peripheral blood of GPA patients based on chemokine receptor co-expression analysis. The aberrant balance between TEM1 and TEM17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse. PMID- 28615074 TI - Correspondence on Lovell et al.: response to Bornelov et al. AB - While the analysis of Bornelov et al. is informative, they provide evidence for the existence of only 3% of the reported avian missing genes set, and thus do not significantly challenge our main findings that specific groups of syntenic protein-coding genes are missing in birds.This is a response to the Correspondence article: https://www.dx.doi.org/10.1186/s13059-017-1231-1. PMID- 28615073 TI - CRISPR/Cas9-mediated genome editing induces exon skipping by alternative splicing or exon deletion. AB - CRISPR is widely used to disrupt gene function by inducing small insertions and deletions. Here, we show that some single-guide RNAs (sgRNAs) can induce exon skipping or large genomic deletions that delete exons. For example, CRISPR mediated editing of beta-catenin exon 3, which encodes an autoinhibitory domain, induces partial skipping of the in-frame exon and nuclear accumulation of beta catenin. A single sgRNA can induce small insertions or deletions that partially alter splicing or unexpected larger deletions that remove exons. Exon skipping adds to the unexpected outcomes that must be accounted for, and perhaps taken advantage of, in CRISPR experiments. PMID- 28615075 TI - Reduced RCE1 expression predicts poor prognosis of colorectal carcinoma. AB - BACKGROUND: As an end-proteolytic enzyme that cleaves the last three residues of proteins with a terminal CAAX, Ras-converting enzyme 1 (RCE1) has an essential role in multiple signaling pathways and take part in the process of differentiation, proliferation and carcinogenesis. The aim of the study is to investigate expression pattern of RCE1 and its prognosis in colorectal carcinoma (CRC). METHODS: The expression of RCE1 and phospho-MAPK family members was confirmed by immunohistochemical staining of CRC tissues. miR-RCE1 lentiviral vectors were transduced into HCT116 and SW489 cells. Reverse transcription PCR (RT-PCR) and western blot were conducted to measure the transfection efficiency. Transwell assays were used to detect the invasiveness of CRC cells. RESULTS: In the present study, we assessed RCE1 expression in 244 CRC specimens and matching adjacent, non-tumorous tissues by immunohistochemistry (IHC). Compared with the matched adjacent non-tumor tissue samples, the RCE1 reduced in the tumor tissue samples (p < 0.001). RCE1 expression was significantly decreased in 106 of 244 (43.4%) CRC cases. In univariate and multivariate analyses, Decreasing expression of RCE1 independently predicts poor prognosis for patients in both overall survival and disease-free survival. Further study indicated that RCE1 influenced tumor invasion through the p38 pathway. Knockdown of RCE1 reduced phosphorylation and significantly increased the invasive capacity of CRC cells. CONCLUSION: Taken together, the outcomes of this study indicate that RCE1 acts as a tumor suppressor in CRC, as its reduced expression may increase CRC cell invasion and independently predict an unsatisfactory prognosis in CRC patients. PMID- 28615076 TI - Dissecting the human microbiome with single-cell genomics. AB - Recent advances in genome sequencing of single microbial cells enable the assignment of functional roles to members of the human microbiome that cannot currently be cultured. This approach can reveal the genomic basis of phenotypic variation between closely related strains and can be applied to the targeted study of immunogenic bacteria in disease. PMID- 28615077 TI - Service utilization and cost of implementing a comprehensive HIV prevention and care program among people who inject drugs in Delhi, India. AB - BACKGROUND: WHO, UNODC, and UNAIDS recommend a comprehensive package for prevention, treatment, and care of HIV among people who inject drugs (PWID). We describe the uptake of services and the cost of implementing a comprehensive package for HIV prevention, treatment, and care services in Delhi, India. METHODS: A cohort of 3774 PWID were enrolled for a prospective HIV incidence study and provided the comprehensive package: HIV and hepatitis testing and counseling, hepatitis B (HB) vaccination, syndromic management of sexually transmitted infections, clean needles-syringes, condoms, abscess care, and education. Supplementary services comprising tea and snacks, bathing facilities, and medical consultations were also provided. PWID were referred to government services for antiretroviral therapy (ART), TB care, opioid substitution therapy, and drug dependence treatment/rehabilitation. RESULTS: The project spent USD 1,067,629.88 over 36 months of project implementation: 1.7% on capital costs, 3.9% on participant recruitment, 26.7% for project management, 49.9% on provision of services, and 17.8% on supplementary services. Provision of HIV prevention and care services cost the project USD 140.41/PWID/year. 95.3% PWID were tested for HIV. Of the HIV-positive clients, only 17.8% registered for ART services after repeated follow-up. Reasons for not seeking ART services included not feeling sick, need for multiple visits to the clinic, and long waiting times. 61.8% of the PWID underwent HB testing. Of the 2106 PWID eligible for HB vaccination, 81% initiated the vaccination schedule, but only 29% completed all three doses, despite intensive follow-up by outreach workers. PWID took an average of 8 clean needles-syringes/PWID/year over the project duration, with a mid-project high of 16 needles-syringes/PWID/year. PWID continued to also procure needles from other sources, such as chemists. One hundred five PWID were referred to OST services and 267 for rehabilitation services. CONCLUSIONS: A comprehensive HIV prevention, treatment, and care package is challenging to implement. Extensive efforts are needed to ensure the uptake of and retention in services for PWID; peer educators and outreach workers are required on a continuous basis. Services need to be tailored to client needs, considering clinic timing and distance from hotspots. Programs may consider provision of ART services at selected drop-in centers to increase uptake. PMID- 28615078 TI - Characterisation of Roseomonas mucosa isolated from the root canal of an infected tooth. AB - OBJECTIVE: The genus Roseomonas comprises a group of pink-pigmented, slow growing, aerobic, non-fermentative Gram-negative bacteria, which have been isolated from environmental sources such as water and soil, but are also associated with human infections. In the study presented here, Roseomonas mucosa was identified for the first time as part of the endodontic microbiota of an infected root canal and characterised in respect to growth, antibiotic susceptibility and biofilm formation. RESULTS: The isolated R. mucosa strain showed strong slime formation and was resistant to most beta-lactam antibiotics, while it was susceptible to aminoglycosides, carbapenemes, fluorochinolones, polymyxines, sulfonamides and tetracyclines. Biofilm formation on artificial surfaces (glass, polystyrene, gutta-percha) and on teeth was tested using colorimetric and fluorescence microscopic assays. While solid biofilms were formed on glass surfaces, on the hydrophobic surface of gutta-percha points, no confluent but localised, spotty biofilms were observed. Furthermore, R. mucosa was able form biofilms on dentin. The data obtained indicate that R. mucosa can support establishment of endodontic biofilms and furthermore, infected root canals might serve as an entrance pathway for blood stream infections by this emerging pathogen. PMID- 28615079 TI - Patterns of objectively measured sedentary time in 10- to 12-year-old Belgian children: an observational study within the ENERGY-project. AB - BACKGROUND: This study examined the frequency of and differences in sedentary bouts of different durations and the total time spent in sedentary bouts on a weekday, a weekend day, during school hours, during after-school hours and in the evening period in a sample of 10- to 12-year-old Belgian children. METHODS: Accelerometer data were collected as part of the ENERGY-project in Belgium (n = 577, 10.9 +/- 0.7 years, 53% girls) in 2011. Differences in total sedentary time, sedentary bouts of 2-5, 5-10, 10-20, 20-30 and >=30 min and total time accumulated in those bouts were examined on a weekday, a weekend day, during school hours, during after-school hours and in the evening period, using multilevel analyses in MLwiN 2.22. RESULTS: More than 60% of the participants' waking time was spent sedentary. Children typically engaged in short sedentary bouts of 2-5 and 5-10 min, which contributed almost 50% towards their total daily sedentary time. Although the differences were very small, children engaged in significantly fewer sedentary bouts of nearly all durations during after-school hours compared to during school hours and in the evening period. Children also engaged in significantly fewer sedentary bouts of 5-10, 10-20, and 20-30 min per hour on a weekend day than on a weekday. CONCLUSIONS: Although primary school children spend more than 60% of their waking time sedentary, they generally engaged in short sedentary bouts. Children's sedentary bouts were slightly longer on weekdays, particularly during school hours and in the evening period, although the differences were very small. These results suggest that in this age group, interventions focusing on reducing total sedentary time rather than interrupting prolonged sedentary time are needed. PMID- 28615080 TI - Locomotor circumvention strategies are altered by stroke: II. Postural Coordination. AB - BACKGROUND: Locomotor strategies for obstacle circumvention require appropriate postural coordination that depends on sensorimotor integration within the central nervous system. It is not known how these strategies are affected by a stroke. The objective of this study was to contrast postural coordination strategies used for obstacle circumvention between post-stroke participants (n = 12) and healthy controls (n = 12). METHODS: Participants walked towards a target in a virtual environment (11 * 8 m room) with cylindrical obstacles that were stationary or approaching from head-on, or diagonally 30 degrees left/right. RESULTS: Two stepping strategies for obstacle circumvention were identified: 1) side step: increase in step width by the foot ipsilateral to the side of circumvention; 2) cross step: decrease in step width by the foot contralateral to the side of circumvention. The side step strategy was favoured by post-stroke individuals in circumventing stationary and head-on approaching obstacles. In circumventing diagonally approaching obstacles, healthy controls generally veered opposite to obstacle approach (>60% trials), whereas the majority of post-stroke participants (7/12) veered to the same side of obstacle approach (Vsame). Post-stroke participants who veered to the opposite side (Vopp, 5/12) were more independent and faster ambulators who favoured the side step strategy in circumventing obstacles approaching from the paretic side and cross step strategy for obstacles approaching from the non-paretic side. Vsame participants generally favoured the side step strategy for both diagonal approaches. Segmental rotation amplitudes and latencies were largest in the Vsame group, and significantly greater in post stroke participants than controls for all obstacle conditions. All participants initiated circumvention with the feet followed by the pelvis and thorax, demonstrating a caudal-rostral sequence of reorientation. CONCLUSION: Postural coordination strategies for obstacle circumvention were altered post stroke, depending on the residual or restored functional abilities. Segmental re orientations are also affected by the motion and direction of obstacle. PMID- 28615081 TI - Clinical variables related to the diagnostic stability of demential syndromes. AB - BACKGROUND: Assigning a diagnosis to a patient with dementia is important for the present treatment of the patient and caregivers, and scientific research. Nowadays, the dementia diagnostic criteria are based on clinical information regarding medical, history, physical examination, neuropsychological tests, and supplementary exams and, therefore, subject to variability through time. METHODS: A retrospective observational study to evaluate variables related to clinical diagnostic stability in dementia syndromes in at least one year follow up. From a sample of 432 patients, from a single university center, data were collected regarding sociodemographic aspects, Clinical Dementia Rating, physical examination, neuropsychological tests, and supplementary exams including a depression triage scale. RESULTS: From this sample, 113 (26.6%) patients have their diagnosis changed, most of them adding a vascular component to initial diagnosis or depression as comorbidity or main disease. Our findings show that many factors influence the diagnostic stability including the presence of symmetric Parkinsonism, initial diagnosis of vascular dementia, presence of diabetes and hypertension, the presence of long term memory deficit in the neuropsychological evaluation, and normal neuroimaging. We discuss our findings with previous findings in the literature. CONCLUSION: Every step of the clinical diagnosis including history, vascular comorbidities and depression, physical examination, neuropsychological battery, and neuroimaging were relevant to diagnosis accuracy. PMID- 28615082 TI - DIFFERENTIAL RESPONSES IN FIRST BIRTH BEHAVIOUR TO ECONOMIC RECESSION IN THE UNITED KINGDOM. AB - Economic conditions have dramatic influences on fertility. This paper evaluates the effect of the 2008 'Great Recession' in the UK on first birth rate, which is the fertility behaviour most susceptible to external economic conditions. The key aim of the study was to assess the effect of the recession on fertility by individual-level characteristics, enabling variation in responses to economic hardship to be observed. Data were from the nationally representative UK Household Longitudinal Study (UK-HLS). Cumulative transition models were used to model the probability of first birth for women between the ages of 17 and 30 in three UK birth cohorts. The effect of the recession was captured using direct measures (local unemployment rates and individual unemployment status) and a pre /post-comparison, capturing indirect effects. In general, higher birth rates were observed among more disadvantaged women compared with advantaged groups. The effect of the recession was disaggregated by social strata; the overall effect was counter-cyclical although at a slower rate among disadvantaged women. PMID- 28615083 TI - Importance of social relationships in the association between sleep duration and cognitive function: data from community-dwelling older Singaporeans. AB - : ABSTRACTBackground:Aging is accompanied by cognitive decline that is escalated in older adults reporting extreme sleep duration. Social relationships can influence health outcomes and thus may qualify the association between sleep duration and cognitive function. The present study examines the moderating effects of marital status, household size, and social network with friends and relatives on the sleep-cognition association among older adults. METHODS: Data (N = 4,169) came from the Social Isolation, Health, and Lifestyles Survey, a nationally representative survey of community-dwelling older Singaporeans (>= 60 years). Sleep duration and social relationships were self-reported. Cognitive function was assessed with the Short Portable Mental Status Questionnaire. RESULTS: Regression analysis revealed that the inverted U-shaped association between sleep duration and cognitive function was less profound among older adults who were married (vs. unmarried) and those who had stronger (vs. weaker) social networks. In contrast, it was more prominent among individuals who had more (vs. fewer) household members. CONCLUSIONS: Being married and having stronger social networks may buffer against the negative cognitive impact of extreme sleep duration. But larger household size might imply more stress for older persons, and therefore strengthen the sleep duration-cognitive function association. We discuss the potential biological underpinnings and the policy implications of the findings. Although our findings are based on a large sample, replication studies using objective measures of sleep duration and other cognitive measures are needed. PMID- 28615084 TI - Community-wide stable isotope analysis reveals two distinct trophic groups in a service-providing carabid community. AB - Disentangling trophic interactions among species is important for elucidating mechanisms underlying ecosystem functioning and services. Carabid beetles are an important guild of predators that may regulate pest populations in arable landscapes, but their generalist feeding behavior hinders predictions about their actual contribution to pest control. In order to assess carabids' potential for pest control, we simultaneously analyzed the carbon and nitrogen stable isotope ratios of a community of 45 co-occurring species in wheat and oilseed rape fields. With the expectation to identify distinct trophic groups based on the mean and the variance of carabid isotopic signatures, we observed a high degree of overlap in trophic positions between species. However, we also observed that species could be successfully categorized into two groups according to whether or not their carbon signatures varied independently from variations in the crop baseline. We interpret these results as differential primary resource uptake or by differential mobility aptitude in foraging. Accordingly, we propose that the isotopic signal can inform us on the presence/absence of links between generalist predators and cultivated plants through the trophic networks they belong to, and consequently on their potential role as pest natural enemies. We therefore suggest the complementarity of stable isotope analysis for obtaining a time integrated assessment of carabid trophic behavior that may be combined with more direct molecular diet analysis allowing the simultaneous quantification of specific trophic links within agricultural landscapes. PMID- 28615085 TI - Contact and perspective taking improve humanness standards and perceptions of humanness of older adults and people with dementia: a cross-sectional survey study. AB - BACKGROUND: No empirical work has systematically explored perceptions of humanness of people with dementia and of older adults and the variables that could improve these perceptions. We thus investigated the role of contact and perspective taking in improving perceptions of humanness of these social groups. To do so, we developed a new concept, humanness standards, defined as the amount of evidence of ability impairment needed to conclude that elderly people and those with dementia have lost personhood. METHODS: We used a cross-sectional survey design (n = 619) to assess participants' humanness standards and perceptions of uniquely human characteristics and human nature characteristics of two social groups (people with dementia and older adults). Half the participants (n = 311) completed a survey about people with dementia and half (n = 308) assessed older adults. RESULTS: People with dementia were perceived as possessing humanness characteristics to a lesser extent than were older adults. For both groups, contact predicted enhanced perceptions of humanness characteristics. Participants' degree of contact with individuals with dementia also predicted humanness standards, but only under low perspective-taking conditions. As predicted, for older adults, participants set the highest humanness impairment thresholds in the high contact/high perspective-taking condition. CONCLUSIONS: We conclude that while social programs that bring persons with dementia and other individuals in contact could change humanness standards and perceptions of humanness characteristics of people with dementia, in the case of elderly adults, the contact must be supplemented by variables that facilitate taking the perspective of the person. PMID- 28615086 TI - The automated analysis of clustering behaviour of piglets from thermal images in response to immune challenge by vaccination. AB - An automated method of estimating the spatial distribution of piglets within a pen was used to assess huddling behaviour under normal conditions and during a febrile response to vaccination. The automated method was compared with a manual assessment of clustering activity. Huddling behaviour was partly related to environmental conditions and clock time such that more huddling occurred during the night and at lower ambient air temperatures. There were no positive relationships between maximum pig temperatures and environmental conditions, suggesting that the narrow range of air temperatures in this study was not a significant factor for pig temperature. Spatial distribution affected radiated pig temperature measurements by IR thermography. Higher temperatures were recorded in groups of animals displaying huddling behaviour. Huddling behaviour was affected by febrile responses to vaccination with increased huddling occurring 3 to 8 h post-vaccination. The automated method of assessing spatial distribution from an IR image successfully identified periods of huddling associated with a febrile response, and to changing environmental temperatures. Infrared imaging could be used to quantify temperature and behaviour from the same images. PMID- 28615087 TI - Association between intestinal helminth infections and mid-upper-arm circumference among children in Sri Lanka: A cross-sectional study. AB - Intestinal helminth infections constitute a major health problem in low socio economic communities worldwide. A cross-sectional study was conducted in children aged between 12 and 60 months. A structured questionnaire was used to collect socio-demographic data and stool samples were subjected to direct smear, stained with Lugol's iodine, and formaldehyde-ether concentration techniques to determine the prevalence of intestinal helminth infections. The circumference of each child's left mid upper arm (MUAC) was measured using standard procedures. Two hundred and six children with a mean MUAC of 14.7 cm (SD +/- 1.1) were assessed from September to December 2014. The prevalence of acute energy undernutrition was 6.3% (13/206). All of them had moderate acute undernutrition and no cases of severe acute undernutrition. Paternal occupation was significantly associated with MUAC. Intestinal helminth infections were detected in 12.6% of children. Four species of parasites were identified; Ascaris lumbricoides (9.7%) followed by Enterobius vermicularis (1.5%), Trichuris trichiura (1.0%) and hookworms (1.0%). Uninfected children aged between 1 and 2 years showed significantly higher MUAC than infected children. No statistically significant association was detected between the severity of intestinal helminth infections and MUAC. Although intestinal helminth infections are a major public health problem in this community, they are not related to MUAC. Future research, providing more insight into the nutritional impact of intestinal helminth infections, is required to determine the association between parasitic infections and physical growth in this community. PMID- 28615088 TI - Healthcare Antibiotic Resistance Prevalence - DC (HARP-DC): A Regional Prevalence Assessment of Carbapenem-Resistant Enterobacteriaceae (CRE) in Healthcare Facilities in Washington, District of Columbia. AB - OBJECTIVE Carbapenem-resistant Enterobacteriaceae (CRE) are a significant clinical and public health concern. Understanding the distribution of CRE colonization and developing a coordinated approach are key components of control efforts. The prevalence of CRE in the District of Columbia is unknown. We sought to determine the CRE colonization prevalence within healthcare facilities (HCFs) in the District of Columbia using a collaborative, regional approach. DESIGN Point-prevalence study. SETTING This study included 16 HCFs in the District of Columbia: all 8 acute-care hospitals (ACHs), 5 of 19 skilled nursing facilities, 2 (both) long-term acute-care facilities, and 1 (the sole) inpatient rehabilitation facility. PATIENTS Inpatients on all units excluding psychiatry and obstetrics-gynecology. METHODS CRE identification was performed on perianal swab samples using real-time polymerase chain reaction, culture, and antimicrobial susceptibility testing (AST). Prevalence was calculated by facility and unit type as the number of patients with a positive result divided by the total number tested. Prevalence ratios were compared using the Poisson distribution. RESULTS Of 1,022 completed tests, 53 samples tested positive for CRE, yielding a prevalence of 5.2% (95% CI, 3.9%-6.8%). Of 726 tests from ACHs, 36 (5.0%; 95% CI, 3.5%-6.9%) were positive. Of 244 tests from long-term-care facilities, 17 (7.0%; 95% CI, 4.1%-11.2%) were positive. The relative prevalence ratios by facility type were 0.9 (95% CI, 0.5-1.5) and 1.5 (95% CI, 0.9-2.6), respectively. No CRE were identified from the inpatient rehabilitation facility. CONCLUSION A baseline CRE prevalence was established, revealing endemicity across healthcare settings in the District of Columbia. Our study establishes a framework for interfacility collaboration to reduce CRE transmission and infection. Infect Control Hosp Epidemiol 2017;38:921-929. PMID- 28615089 TI - No perceptual reorganization for Limburgian tones? A cross-linguistic investigation with 6- to 12-month-old infants. AB - Despite the fact that many of the world's languages use lexical tone, the majority of language acquisition studies has focused on non-tone languages. Research on tone languages has typically investigated well-known tone languages such as Mandarin and Cantonese Chinese. The current study looked at a Limburgian dialect of Dutch that uses lexical pitch differences, albeit in a rather restricted way. Using a visual habituation paradigm, 6- to 12-month-old Limburgian and Dutch infants were tested for their ability to discriminate Limburgian tones. The results showed that both Limburgian and Dutch infants discriminate the Limburgian tones throughout their first year of life. The role of linguistic experience, acoustic salience, and the degree of similarity to the native prosodic system are discussed. PMID- 28615090 TI - Prior exercise alters the difference between arterialised and venous glycaemia: implications for blood sampling procedures. AB - Oral glucose tolerance and insulin sensitivity are common measures, but are determined using various blood sampling methods, employed under many different experimental conditions. This study established whether measures of oral glucose tolerance and oral glucose-derived insulin sensitivity (insulin sensitivity indices; ISI) differ when calculated from venous v. arterialised blood. Critically, we also established whether any differences between sampling methods are consistent across distinct metabolic conditions (after rest v. after exercise). A total of ten healthy men completed two trials in a randomised order, each consisting of a 120-min oral glucose tolerance test (OGTT), either at rest or post-exercise. Blood was sampled simultaneously from a heated hand (arterialised) and an antecubital vein of the contralateral arm (venous). Under both conditions, glucose time-averaged AUC was greater from arterialised compared with venous plasma but importantly, this difference was larger after rest relative to after exercise (0.99 (sd 0.46) v. 0.56 (sd 0.24) mmol/l, respectively; P<0.01). OGTT-derived ISIMatsuda and ISICederholm were lower when calculated from arterialised relative to venous plasma and the arterialised venous difference was greater after rest v. after exercise (ISIMatsuda: 1.97 (sd 0.81) v. 1.35 (sd 0.57) arbitrary units (au), respectively; ISICederholm : 14.76 (sd 7.83) v. 8.70 (sd 3.95) au, respectively; both P<0.01). Venous blood provides lower postprandial glucose concentrations and higher estimates of insulin sensitivity, compared with arterialised blood. Most importantly, these differences between blood sampling methods are not consistent after rest v. post exercise, preventing standardised venous-to-arterialised corrections from being readily applied. PMID- 28615091 TI - [Detection and analysis of phenotypes of tumor-associated macrophages in mouse model of spontaneous breast cancer]. AB - Objective To detect the phenotypic conversion of tumor-associated macrophages (TAMs) through analyzing the expression levels of the polarization-related genes. Methods We identified the spontaneous breast cancer mice by genotyping and characterized them into the early stage and the advanced stage groups according to their tumor size. Single cell suspension of the tumor tissues were obtained by mechanical methods and TAMs of different stages were sorted by flow cytometry. We measured the mRNA levels of M1 macrophages-related genes IL-1beta, IL-27, IL-6, CD80, CD86 and M2 macrophages-related genes arginase 1 (Arg1), IL-10, interleukin 4 receptor alpha (IL-4Ralpha), macrophage mannose receptor 1 (Mrc1), chitinase like 3 (Chil3/Ym1) by real-time quantitative PCR in order to analyze the phenotypic conversion of TAMs during the tumor progression. Results In the early stage, TAMs expressed high levels of M1-related genes, such as IL-1beta, CD80, CD86. On the contrary, TAMs of advanced stage expressed high levels of M2-related genes, including Arg1, IL-10, IL-4Ralpha as well as IL-6. Conclusion Phenotypic conversion of TAMs is present in tumor progression, and targeting the phenotypes of TAMs may provide potential therapies for breast cancer. PMID- 28615092 TI - [Purification of the recombinant Com1 and adaA of Coxiella burnetii and identification of the antigenicity]. AB - Objective To express and purify two kinds of antigens of Coxiella burnetii (C. burnetii), the main outer membrane protein Com1 and the acute disease antigen A (adaA), in prokaryotic expression system and to validate the two recombinant antigens by mass spectrometry and identify their antigenicity. Methods The gene sequences encoding Com1 and adaA were separately synthesized and constructed into the prokaryotic expression vector pET-20b(+). The constructed vectors were transformed into E.coli BL21(DE3), and the recombinant proteins were induced by IPTG. The recombinant Com1 and adaA were purified by His affinity chromatography and identified by mass spectrometry. The immunoreactivity of the two antigens was identified by Western blot analysis using Q fever positive bovine serum. Results The expression vectors pET-20b(+)-Com1 and pET-20b(+)-adaA were constructed and the recombinant Com1 and adaA were expressed and purified in a soluble form. High purity recombinant Com1 and adaA were obtained after purification, and the SDS PAGE showed that their relative molecular masses were Mr 27 000 and 25 000, respectively. The mass spectrometry confirmed the recombinant proteins were Com1 and adaA of C. burnetii. Both of the recombinant Com1 and adaA were able to react with the Q fever positive bovine serum in Western blotting, and the corresponding bands were in accordance with the SDS-PAGE. Conclusion We obtained high-purity Com1 and adaA in a soluble form and confirmed their immunoreactivity. PMID- 28615093 TI - [Overexpression of Klotho inhibits differentiation of RAW264.7 cells into osteoclasts]. AB - Objective To explore the effect of overexpression of Klotho (KL) on the differentiation of RAW264.7 cells intoosteoclasts induced by soluble receptor activator of nuclear factor-kappaB ligand ( sRANKL). Methods The RAW264.7 cells were divided into Ad-KL group, Ad-GFP group and control group. Inverted microscope was used to observe KL transfected cells. Quantitative real-time PCR (qRT-PCR) and Western blotting were used to detect mRNA and protein expression level of KL, respectively. Tartrate-resistant acidphosphatase (TRAP) staining was applied to observe the osteoclast differentiation and maturation. The qRT-PCR and Western blotting were performed to assess mRNA or protein expression levels of TRAP and cathepsin K (CTSK). Results Klotho gene was transfected into RAW264.7 cells successfully. Compared with Ad-GFP group and control group, KL mRNA and protein expression levels of Ad-KL group increased significantly. TRAP staining showed that the number and volume of TRAP-positive cells in Ad-KL group were less than those in Ad-GFP group and control group. Compared with Ad-GFP group and control group, TRAP and CTSK mRNA and protein expression levels were reduced remarkably in Ad-KL group. Conclusion Overexpression of Klotho inhibits the differentiation of RAW264.7 cells into osteoclasts. PMID- 28615094 TI - [Modified Cheng's Juanbi Decoction downregulates expression of prostaglandin E receptor 4 in synovial tissue in rats with adjuvant arthritis]. AB - Objective To investigate the effect of modified Cheng's Juanbi Decoction on the expression of prostaglandin E receptor 4 (PTGER4), the T cell receptor in the synovial tissues, in rats with adjuvant arthritis (AA). Methods A rat model of AA was established by subcutaneous injection of Freund's complete adjuvant at the vola pedis combined with ice-water bath and blowing. The degree of joint swelling and arthritis index were determined in each group. The quantitative real-time PCR was performed to assess the effect of modified Cheng's Juanbi Decoction on the mRNA expression of PTGER4in the synovial tissue. Results Cheng's Juanbi Decoction significantly alleviated the damage in the joints and synovial tissues in the AA rats. High-dose (the content of crude drug: 4 g/mL) Cheng's Juanbi Decoction significantly reduced the mRNA expression of PTGER4 in the synovial tissues. Conclusion Cheng's Juanbi Decoction can reduce the level of PTGER4 mRNA in the synovial tissue in AA rats. PMID- 28615095 TI - [Staphylococcus aureus promotes NOD2 expression in bovine mammary epithelial cells]. AB - Objective To investigate the role of nucleotide-binding oligomerization domain containing protein 2 (NOD2) in the mediate recognition of Staphylococcus aureus (S. aureus) in bovine mammary epithelial cells (BMECs). Methods We infected BMECs with living S. aureus and heat-inactivated S. aureus, respectively. When the multiplicity of infection (MOI) of living S. aureus was set for 100:1, the infection time were 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4 hours; when the MOI of living S. aureus was set for 10:1, 20:1, 40:1, 100:1, the infection time was 2 hours; on the other hand, 0, 104, 105, 106, 107, 108 colony-forming units (CFU)/mL of heat inactivated S. aureus were used to infect the cells for 2 hours separately. The expression of NOD2 was detected using real-time PCR and Western blotting. Results Levels of NOD2 mRNA and protein expression significantly increased after 0.5-4 hours of infection with living S. aureus. When the cells were infected with S. aureus at different MOI, dose-dependent accumulation of NOD2 mRNA and protein could be detected in BMECs. Levels of NOD2 mRNA and protein expression were not significantly upregulated by the stimulation with heat-inactivated S. aureus. Conclusion S. aureus infection could induce the up-regulation of NOD2 expression in BMECs. PMID- 28615096 TI - [FcgammaRIis involved in lipopolysaccharide-induced apoptosis of PC12 cells]. AB - Objective To investigate the role of IgG Fc receptorI (FcgammaRI) in lipopolysaccharide (LPS)-induced apoptosis of the rat PC12 cells. Methods PC12 cells were treated with different concentrations of LPS (50, 125, 250, 500, 1000 MUg/mL) for 24 hours and cell viability was analyzed by MTT assay. The appropriate concentration of LPS (500 MUg/mL) was chosen for the following experiments. PC12 cells in the logarithmic growth phase were divided randomly into three groups: the control group without LPS, the 500 MUg/mL LPS treated group and the 500 MUg/mL LPS plus 0.2 MUg/mL FcgammaRI neutralizer group. After24 hour different treatments, the mRNA and protein levels of FcgammaRIwere detected by quantitative real-time PCR and Western blotting, respectively. The apoptosis rate of PC12 cells was determined by flow cytometry combined with annexinV FITC/PI double staining. The protein expression levels of caspase-3, Bcl-2 and BAX were measured by immunohistochemistry. Results PC12 cell viability decreased in a LPS dose-dependent manner. Compared to the control group, the protein and mRNA expression of FcgammaRI were upregulated, the expression levels of caspase 3, Bcl-2 and BAX proteins were elevated, and the apoptosis rate of PC12 cells was raised as well in the LPS treated group. Compared to the LPS treated group, the protein and mRNA levels of FcgammaRI were significantly lower along with significantly reduced expressions of Caspase-3 and BAX and inhibited cell apoptosis in the FcgammaRIneutralizer treated group, while Bcl-2 protein expression was upregulated. Conclusion FcgammaRIis involved in the LPS-induced apoptosis in PC12 cells. PMID- 28615097 TI - [Protective effect of quercetin against seawater instillation-induced acute lung injury through preventing M1 polarization of macrophages in mice]. AB - Objective To study the protective effect of quercetin against seawater instillation-induced acute lung injury (SW-ALI) and explore the roles of M1polarization of macrophages and M1 macrophage-mediated inflammation in the protective effect. Methods Male C57BL/6 mice were randomly divided into four groups, normal control group, quercetin-treated group, SW-ALI group, SW-ALI and quercetin-treated group, with 15 mice in each group. The mice were intraperitoneally injected with 1 g/L pentobarbital sodium, and then seawater was injected into the lungs through oropharyngeal intubation at the concentration of 4 mL/kg. Quercetin (200 mg/kg) was intraperitoneally injected 0.5 hour before seawater injection. The same amount of PBS and quercetin was intraperitoneally injected in normal control group and quercetin control group, respectively. Blood gas analysis of 1 mL blood taken from abdominal aorta was performed at 0.5, 1, 2, 3, 4 hours after different treatment. Lungs were obtained at 3 days after different treatment for frozen section preparation, HE staining, dry/wet ratio (D/W) analysis and the detection of inducible nitric oxide synthase (iNOS), interleukin 4 (IL-4), IL-10, IL-1beta and tumor necrosis factor alpha (TNF-alpha) expressions by real-time quantitative PCR (qRT-PCR) and Western blotting. Results Quercetin significantly reduced the pathological changes of lung tissues, lowered PaCO2 while increased PaO2 and D/W ratio, down-regulated the expressions of iNOS, TNF-alpha, IL-1beta while up-regulated the expressions of IL-4 and IL-10 in SW ALI mice. Conclusion Quercetin can significantly improve the function of gas exchange and reduce the degree of lung injury in SW-ALI mice by inhibiting M1 polarization of macrophages and the expressions of pro-inflammatory factors. PMID- 28615098 TI - [Human EV71 invades human neuroblastoma SK-N-SH cells by clathrin-mediated endocytosis]. AB - Objective To study the mechanism ofhuman enterovirus 71 (EV71) entering human neuroblastoma SK-N-SH cells. Methods After the SK-N-SH cells were pretreated with chlorpromazine (CPZ) or nystatin (NT), real-time quantitative PCR (qRT-PCR) was employed to measure EV71 mRNA level, and indirect immunofluorescence microscopy was used to detect the expression level of viral protein 1 (VP1) in the target cells. In order to reveal the colocalization of EV71 with clathrin, laser confocal microscopy was performed on the infected cells. Results CPZ could significantly inhibit EV71 mRNA level and the expression of VP1 in the target cells, while NT had no effect on EV71 infection. Confocal microscopy showed that EV71 was colocalize with clathrin. Conclusion EV71 infects human neuroblastoma SK N-SH cells by the clathrin-mediated endocytosis. PMID- 28615099 TI - [Hyperoxia modulates the expressions of C/EBPalpha and pulmonary surfactant proteins in AECII of premature rats]. AB - Objective To explore the effect of hyperoxia on the expressions of CCAAT enhancer binding protein alpha (C/EBPalpha) and pulmonary surfactant proteins (SP-A, SP-B, SP-C, SP-D) and their correlations in primary type II alveolar epithelial cells (AECIIs) from premature rats. Methods AECIIs were divided into an air control group and a hyperoxia model group. The cells of the two groups were respectively exposed toair and 950 mL/L O2. The cells were harvested at 24, 48, and 72 hours after exposure. Inverted phase-contrast microscope was used to observe morphological changes of the cells. Real-time quantitative PCR and Western blotting were performed to measure the mRNA and protein expressions of C/EBPalpha, SP-A, SP-B, SP-C and SP-D. Cell Counting Kit-8 (CCK-8) was applied to detect the proliferation of AECIIs. Results With the prolonging incubation time, the air group showed a significantly decreasing mRNA and protein expressions of C/EBPalpha, and significantly ascending mRNAand protein expressions of SP-A, SP B, SP-C, SP-D and increasing proliferation of AECIIs. The mRNA and protein expressions of SP-A, SP-B, SP-C, SP-D and the proliferation of AECIIs in the hyperoxia group showed a trend of increasing at first and then decreasing as the culture time went on. Compared with the air group, the hyperoxia group showed significantly increased mRNA and protein expressions of C/EBPalpha and SP-A, SP B, SP-C, SP-D and enhanced proliferation of AECIIs at 48 hours. In the hyperoxia group, the protein expression of C/EBPalpha was positively correlated with the protein expressions of SP-A, SP-B, SP-C, SP-D as well as the proliferation of AECIIs(r=0.96, 0.98, 0.92, 0.97, 0.90). Conclusion In the early stage of hyperoxia exposure, C/EBPalpha can promote the secretion of pulmonary surfactant protein to participate in the body's protective regulation. However, over the time of hyperoxia exposure, C/EBPalpha loses compensatory protective effect. PMID- 28615100 TI - [The mechanism underlying the effects of tea polyphenol on epirubicin-induced autophagy and apoptosis in T24 bladder cancer cells]. AB - Objective To investigate the mechanism by which epirubicin (EPI) induces autophagy and the mechanism by which tea polyphenol (TP) regulates EPI-induced autophagy and apoptosis in T24 bladder cancer cells. Methods T24 cells weredivided into control group, EPI group, TP group and TP plus EPI group. Eight hours after corresponding treatments in different groups, transmission electron microscopy (TEM) was used to observe the image of autophagosomes. The expressions of autophagy-related protein LC3II and p62 in the cells were detected by Western blotting. Apoptotic cells were evaluated after EPI-treatment for 24 hours by flow cytometry combined with annexin V-FITC/PI staining. Western blotting was performed to determine the levels of cleaved-caspase-3 (c-caspase-3) and cleaved PARP (c-PARP). LC3II was again tested by Western blotting 8 hours after T24 cells were treated with EPI added with autophagy pathway inhibitor chloroquine and 3 methyladenine, and moreover, the levels of LC3II and p-JNK were detected by Western blotting after T24 cells were treated with EPI combined with TP or the JNK inhibitor SP for 8 hours. Results The amount of autophagosomes and the level of LC3IIin TP plus EPI group were much lower than those in EPI group. SP reduced the level of LC3II induced by EPI. EPI increased p-JNK in a time-dependent manner. TP combined with EPI reduced the activity of JNK pathway. The apoptosis rate and the levels of c-caspase-3 and c-PARP in TP plus EPI group were much higher than those in EPI group. Conclusion TP inhibits autophagy through JNK pathway to enhance EPI-induced apoptosis in T24 bladder cancer cell line. PMID- 28615101 TI - [Eukaryotic expression and localization of human MTERF2 in cervical cancer Caski cells]. AB - Objective To construct the recombinant eukaryotic expression vector of human mitochondrial transcription termination factor 2 (MTERF2) gene and determine the cellular localization by overexpressing MTERF2 in human Caski cervical cancer cells. Methods The coding sequence of MTERF2 was amplified by reverse transcription-PCR using the total RNA extracted from human cervical cancer Caski cells, and then was inserted into p3*FLAG-CMV-14 vector. After being verified by PCR and DNA sequencing, the positive recombinant plasmid was transiently transfected into Caski cells. Western blotting and immunofluorescence technique were performed to analyze the expression and distribution of human MTERF2 proteinat 24, 32 and 48 hours after transfection. Results Sequence analysis showed that the correct target gene (1158 bp) was inserted into the vector at the expected position. The target protein band was detected at Mr 44 000 as we had predicted in the transfected cells while not in the negative control group, which indicated MTERF2 expression vector could be successfully transfected and expressed in Caski cells. The p3*FLAG-MTERF2 protein was highly expressed and displayed a mitochondrial distribution at 24 hours post-transfection in Caski cells. Conclusion We successfully constructed the eukaryotic expression plasmid p3*FLAG-CMV-MTERF2 and expressed p3*FLAG tagged MTERF2 effectively in the mitochondria of Caski cells. PMID- 28615102 TI - [Effect of Golgi alpha-mannosidase 2 (GM2) gene knockdown on adhesion abilities of human gastric carcinoma cell line BGC-823 and its mechanism]. AB - Objective To investigate the effect of Golgi alpha-mannosidase II (GM2) gene knockdown on adhesion abilities of BGC-823 human gastric carcinoma cells. Methods Three plasmid vectors expressing GM2 shRNAs and a negative control plasmid vector were designed, constructed and then transfected into BGC-823 cells by LipofectamineTM 2000. After transfection, the mRNA and protein levels of GM2 in BGC-823 cells were detected by real-time quantitative PCR (qRT-PCR) and Western blotting to evaluate the transfection efficacy. The best plasmid for GM2 gene knockdown was selected and stably transfected into BGC-823 cells. Adhesion abilities of BGC-823 cells after GM2 gene silencing were observed by cell-cell, cell-matrix and cell-endothelial cell adhesion assays. At the same time, the expressions of E-cadherin, P-selectin, CD44v6 and intercellular adhesion molecule 1 (ICAM-1) proteins were detected by Western blotting after GM2 gene knockdown. Results The expression of GM2 was effectively knockdown in GM2-shRNA-2 transfected BGC-823 cells. Compared with the blank control group and the negative control group, the intercellular adhesion ability of the GM2-shRNA-2-transfected cells increased significantly, while their cell-matrix and cell-endothelium adhesion abilities markedly decreased. In GM2-shRNA-2 transfection group, E cadherin expression was significantly elevated and the P-selectin expression was significantly reduced, while the expression levels of CD44v6 and ICAM-1 were not obviously changed. Conclusion After GM2 gene knockdown, the intercellular adhesion ability of gastric carcinoma BGC-823 cells is enhanced, while the adhesion abilities with the extracellular matrix and endothelial cells are weakened. The changes might be related to the up-regulated expression of E cadherin and the down-regulation of P-selectin. PMID- 28615103 TI - [HER2 promotes cell migration via inhibiting the expression of E-cadherin in human mammary epithelial cells]. AB - Objective To study the effect of HER2 on morphology and migration of MCF10A human mammary epithelial cells and its mechanism. Methods The stable HER2 overexpressing MCF10A cells were established by lentivirus infection. Then, cell migration was analyzed by TranswellTM assay; E-cadherin expression was detected by Western blotting, real-time quantitative PCR and immunofluorescent staining. Results HER2-overexpressing MCF10A cells showed scattering growth pattern and increased migration ability. Overexpression of HER2 decreased the expression of E cadherin protein in MCF10A cells, and also reduced the membrance-associated E cadherin. In addition, HER2-induced cell scattering and migration could be significantly suppressed by re-expression of E-cadherin. Conclusion HER2 promotes the migration of human mammary epithelial cells by inhibiting the expression of E cadherin. PMID- 28615104 TI - [Mechanism of heart and lung injury induced by cerebral ischemia/reperfusion in both young and old mice]. AB - Objective To study the mechanism of heart and lung injury after cerebral ischemia/reperfusion in mice. Methods C57BL/6J mice were divided into young and old groups according to their ages, the former being 5-6 months old and the latter being 20-21 months old. Each group was divided into five subgroups subjected to sham operation, middle cerebral artery occlusion for 1-hour ischemia followed by 1-, 12-, 24-, 48-hour reperfusion. At different reperfusion time, HE and TUNEL staining were used to observe the morphological changes of heart and lung tissues; meanwhile, chemical colorimetry was performed to determine the changes of cardiac Na+-K+-ATPase and Ca2+-ATPase; the lung indexes were evaluated; the levels of nuclear factor (NF)-kappaBp65, p-NF-kappaBp65, IkappaBalpha, p-IkappaBalpha were detected by Western blotting; the levels of interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) were determined by ELISA; and the release of NO was examined by colorimetry. Results We observed inflammatory responses in the lung tissues of young and old mice at 24-hour reperfusion and 1-hour reperfusion, respectively, and hemorrhage in the heart tissues of young and old mice at 24-hour reperfusion and 12-hour reperfusion, respectively.Lung tissues showed earlier response to the stimulation of cerebral ischemia/reperfusion than heart tissues did. Meanwhile, the results of Na+-K+-ATPase, Ca2+-ATPase, lung index, NF-kappaB signaling pathway and inflammatory cytokines in young and old mice were consistent with histological changes of heart and lung tissues. Conclusion Cerebral ischemia/reperfusion can cause heart and lung tissue injury in the old mice, and energy metabolism and inflammation cascade are the main mechanisms of the injury. PMID- 28615105 TI - [Over-expression of mdr1/P-gp is associated with methotrexate resistance in patients with rheumatoid arthritis]. AB - Objective To investigate the relationship between the gene expression of multidrug resisitance 1 (mdr1)/P-glycoprotein (P-gp) in peripheral blood mononuclear cells (PBMCs) and methotrexate (MTX) resistance in patients with rheumatoid arthritis (RA). Methods According to the grades of disease activity score 28 (DAS28) after taking MTX, RA patients were divided into sensitive group and resistant group. In addition, the healthy volunteers were enrolled as a control group. Real-time PCR was adopted to detect the expression of mdrl mRNA, and flow cytometry was used to detect the level and function of P-gp in PBMCs. Using the information obtained from these detections, we compared the expression of mdr1/P-gp between the three groups. Results Compared with the healthy group, the expression of P-gp was higher in the sensitive group and resistant group. Compared with the sensitive group, both mdr1 mRNA and P-gp expressions increased in the resistant group. Conclusion The over-expression of mdr1/P-gp in RA patients is related to the MTX resistance. PMID- 28615106 TI - [Enhanced ILC2 activity contributes to metabolic syndrome multicomponent aggregation state in patients with type 2 diabetic nephropathy]. AB - Objective To study the relationship between the activity of group II innate lymphoid cells (ILC2) in maintenance hemodialysis patients with type 2 diabetic nephropathy (DN) and metabolic syndrome (MS) multicomponent aggregation state. Methods The study enrolled 30 DN patients of stable condition treated with maintenance hemodialysis over 3 months, 30 newly diagnosed untreated type 2 diabetes patients and 30 healthy volunteers as controls. Real-time quantitative PCR (qRT-PCR) was used to detect the mRNA expression levels of retinoic acid receptor-related orphan receptor alpha (RORalpha), interleukin 17 receptor B (IL 17RB), IL-33 receptor T1/ST2, IL-5 and IL-13 in peripheral blood mononuclear cells (PBMCs). The percentage of ILC2 cells in PBMCs was determined by flow cytometry. Levels of plasma IL-5 and IL-13 were tested by ELISA. The prevalence rate and number of MS in the three groups were examined and the relationship between the components and the ILC2-related factors was analyzed. Results Patients diagnosed with type 2 diabetes or DN had higher waist circumference (WC), fasting blood glucose (FBG), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG) and the number of MS components as compared with healthy controls. The prevalence rates of MS in type 2 diabetes group andDN group were 46.67% and 86.67%, respectively. The proportion of ILC2 increased and both ILC2-related transcription factor RORalpha and T1/ST2 mRNA expression levels ascended in DN patients as compared with type 2 diabetes patients and healthy controls. The correlation analysis showed that ILC2 receptor T1/ST2, IL-5, IL-13 mRNA levels were positively related to ILC2 transcription factor RORalpha mRNA levels in the DN group. IL-13 mRNA level in PBMCs was positively related to the levels of SBP, plasma total cholesterol (TC)and low density lipoprotein cholesterol (LDL-C) , and membrane receptor T1/ST2 mRNA level was positively related to the level of LDL-C. Conclusion MS multicomponent aggregation in maintenance hemodialysis patients with type 2 DN group was more obvious than that in type 2 diabetes mellitus group and healthy control group, and strengthened ILC2 activity might contribute to the formation of the state by influencing blood pressure and lipid metabolism. PMID- 28615107 TI - [Preparation and characterization of mouse polyclonal antibody against conserved region of human FOXO3]. AB - Objective To purify the recombinant protein specific to conserved region of forkhead box O3 (FOXO3) and prepare mouse anti-human FOXO3 polyclonal antibody. Methods The DNA fragment (aa290-472) encoding conserved domain of FOXO3 was amplified by PCR, and subsequently cloned into pET28a vector. Following transformation into E.coli BL21, the soluble fusion protein His-FOXO3 was induced by IPTG and purified by Ni-NTA affinity chromatography. The purified protein was used to immunize BALB/c mice to generate polyclonal antibody. The characteristics of the polyclonal antibody were assessed by ELISA, Western blotting and immunoprecipitation assays. Results We successfully prepared the expression vector pET28a-FOXO3 (aa290-472) and expressed the purified fusion protein in a soluble form. By immunizing mice with the fusion protein, we obtained anti-human FOXO3 polyclonal antibody. ELISA and Western blotting showed that the mouse antibody could recognize specifically the endogenous FOXO3 protein. Conclusion The polyclonal antibody against conserved domain of FOXO3 can identify the endogenous FOXO3 protein. It can be used to analyze the endogenous FOXO3 expression level. PMID- 28615108 TI - Kinematics of Different Components of the Posterolateral Corner of the Knee in the Lateral Collateral Ligament-intact State: A Human Cadaveric Study. AB - PURPOSE: To determine the static stabilizing effects of different anatomical structures of the posterolateral corner (PLC) of the knee in the lateral collateral ligament (LCL)-intact state. METHODS: Thirteen fresh-frozen human cadaveric knees were dissected and tested using an industrial robot with an optical tracking system. Kinematics were determined for 134 N anterior/posterior loads, 10 N m valgus/varus loads, and 5 N m internal/external rotatory loads in 0 degrees , 20 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion. The PLC structures were dissected and consecutively released: (I) intact knee joint, (II) with released posterior cruciate ligament (PCL), (III) popliteomeniscal fibers, (IV) popliteofibular ligament, (V) arcuat and popliteotibial fibers, (VI) popliteus tendon (PLT), and (VII) LCL. Repeated measures analysis of variance was performed with significance set at P < .05. RESULTS: After releasing the PCL, posterior tibial translation increased by 5.2 mm at 20 degrees to 9.4 mm at 90 degrees of joint flexion (P < .0001). A mild 1.8 degrees varus instability was measured in 0 degrees of flexion (P = .0017). After releasing the PLC structures, posterior tibial translation further increased by 2.9 mm at 20 degrees to 5.9 mm at 90 degrees of flexion (P < .05) and external rotation angle increased by 2.6 degrees at 0 degrees to 7.9 degrees at 90 degrees of flexion (P < .05, vs II). Varus stability did not decrease. Mild differences between states V and VI were found in 60 degrees and 90 degrees external rotation tests (2.1 degrees and 3.1 degrees ; P < .05). CONCLUSIONS: The connecting ligaments/fibers to the PLT act as a primary static stabilizer against external rotatory loads and a secondary stabilizer against posterior tibial loads (when PCL is injured). After releasing these structures, most static stabilizing function of the intact PLT is lost. The PLC has no varus stabilizing function in the LCL-intact knee. CLINICAL RELEVANCE: Anatomy and function of these structures for primary and secondary joint stability should be considered for clinical diagnostics and when performing surgery in the PLC. PMID- 28615109 TI - Study of guided wave propagation on a plate between two solid bodies with imperfect contact conditions. AB - In this work, fundamental symmetric Lamb wave S0 mode is characterized in terms of its velocity variation as function of the interfacial conditions between solid bodies in contact. Imperfect contact conditions are numerically and experimentally determined by using ultrasonic Lamb wave propagation parameters. For the study, an experimental system was used, formed by two solid aluminum rods (25.4mm in diameter) axially loading a thin aluminum plate to control contact interfacial stiffness. The axially applied load on the aluminum plate was varied from 0MPa to 10MPa. Experimental Lamb wave signals were excited on the plate through two longitudinal contact transducers (1MHz of central frequency) using a pitch-catch configuration. Numerical simulations of contact conditions and Lamb wave propagation were performed through Finite Element Analysis (FEA) in commercial software, ANSYS 15(r). Simulated Lamb wave signals were generated by means of a 5 cycles tone burst signals with different frequency values. Results indicate a velocity change in both, experimental and simulated Lamb wave signals as function of the applied load. Finally, a comparison between numerical results and experimental measurements was performed obtaining a good agreement. PMID- 28615110 TI - An accident at work? Traumatic lesions in the skeleton of a 4th millennium BCE "wagon driver" from Sharakhalsun, Russia. AB - The study of ante-mortem trauma is a popular and important aspect of palaeopathological analysis. The majority of publications focus on a particular assemblage, skeletal element or type of fracture, with case studies of single individuals with multiple/unusual traumata being much rarer in the literature. This paper presents the case of an adult male from the Bronze Age site of Sharakhalsun, Russia, buried, uniquely, in a sitting position on a fully assembled wagon, who displayed evidence for multiple healed ante-mortem fractures of the cranium, axial and appendicular skeleton. The mechanisms and likely etiologies of the fractures are presented, with reference to modern and 19th century clinical literature, and possible interpretations suggested: that the individual was involved in a severe accident involving a wagon or draft animals, or both, a number of years before his death. The suggestion is also made that the unique burial position of the individual was a form of commemoration by the community of the survival and recovery of the individual from such a serious incident. PMID- 28615111 TI - Synthesis and antitumor activities of 1,2,3-triazines and their benzo- and heterofused derivatives. AB - 1,2,3-Triazines are a class of biologically active compounds that exhibit a broad spectrum of activities, including antibacterial, antifungal, antiviral, antiproliferative, analgesic and anti-inflammatory properties. This review, which covers the literature from the end of last century to 2016, treats, through a comprehensive, systematic approach, the 1,2,3-triazine and related benzo- and hetero-fused derivatives possessing antitumor activity. Their efficacy, combined with a simple synthesis confers to these molecules a great potential as scaffold for the development of antitumor compounds. PMID- 28615112 TI - The evaluation of behavioural problems in the first three years of life: Comparing parents and early childhood educators. AB - The study investigates the degree of agreement between mothers, fathers and educators in the evaluation of early childhood behavioural problems, through the CBCL 11/2-5. Data analysis indicates a good level of agreement between mothers and fathers, along with a significant divergence between parents and educators. PMID- 28615113 TI - Risk Factors and Long-Term Outcomes in Patients with Low Intraocular Pressure after Trabeculectomy. AB - PURPOSE: To examine risk factors for low intraocular pressure (IOP) after trabeculectomy and to describe long-term outcomes in these eyes. DESIGN: Retrospective case-control study. PARTICIPANTS: Cases with low IOP included all patients with IOP <=5 mmHg on 3 or more consecutive visits 3 months or later after trabeculectomy. Control patients without low IOP after trabeculectomy were randomly selected at a 1:2 case-to-control ratio. METHODS: A case-control study was performed of patients undergoing trabeculectomy at the Stein Eye Institute. Covariates included demographics, history of cataract surgery, refractive error, number of glaucoma medications, family history of glaucoma, diabetes, hypertension, visual acuity (VA), IOP, number of sutures in the scleral flap, laser suture lysis, surgeon, and laterality of surgery. Logistic regression modeling was used to examine associations between each covariate and low IOP. Postoperative outcomes that were examined included reoperation, vision loss, and surgical failure. The time between trabeculectomy and each outcome was compared between cases and controls with Cox proportional hazards regression modeling. MAIN OUTCOME MEASURES: Low IOP after trabeculectomy, reoperation, vision loss, and surgical failure. RESULTS: Of 3659 total trabeculectomies performed by 5 surgeons between 1990 and 2013, 64 eyes had low IOP (1.7%), which were compared with 130 control eyes. Fifteen of the 64 eyes with low IOP had hypotony maculopathy (23.4%). After accounting for differences in baseline IOP, laser suture lysis was negatively correlated with low IOP after trabeculectomy (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.13-0.87); surgeon was correlated with high vs. low IOP after trabeculectomy (OR, 5.32; 95% CI, 1.53 18.52). There were no statistically significant associations between low IOP and time to reoperation (hazard ratio [HR], 0.73; 95% CI, 0.32-1.68), vision loss (HR, 1.77; 95% CI, 0.81-3.88) or surgical failure (HR, 1.14; 95% CI, 0.62-2.11). In patients with low IOP, there was a higher unadjusted incidence of bleb revision in patients who had maculopathy (7.6 vs. 1.9 revisions/100 person-years; for maculopathy versus no maculopathy P = 0.008). CONCLUSIONS: The absence of laser suture lysis and surgeon are factors potentially associated with low IOP after trabeculectomy. Numeric hypotony does not necessarily represent clinical failure after trabeculectomy. PMID- 28615114 TI - Experimental Assessment of Physician Modified Proximal Scalloped Stent Graft to Extend Proximal Landing Zone in the Aortic Arch. AB - OBJECTIVE/BACKGROUND: The aim of the study was to assess a model of physician modified scalloped stent graft (PMSG) on currently available thoracic aortic devices to extend the proximal landing zone in either zone 2, 1 or 0 of the aortic arch while preserving flow in the supra-aortic vessels on human cadaveric aorta. METHODS: Fresh human aortas were harvested at autopsy from adult subjects. A proximal scallop was made on the stent grafts based on direct measurements on the aortas to extend the proximal landing zone in zone 0 (n = 5), zone 1 (n = 5), and zone 2 (n = 5). A previously described benchtop closed system pulsatile flow model was used to mimic flow and pressure conditions in the aorta to deploy the stent graft as close to physiological conditions as possible. Deployment accuracy of the scallop opposite the aortic arch branch ostia was assessed by completion angiography and post-procedural analysis of the aortas. RESULTS: Fifteen proximal scalloped stent grafts were deployed in the aortic arch of 15 human cadaveric aortas under fluoroscopy. The expected proximal landing zone was achieved in all cases (zone 2 = 5; zone 1 = 5; zone 0 = 5). Post-procedural angiography and direct visual analysis showed supra-aortic vessel patency and deployment of the scallop opposite the aortic arch branch ostia in all cases. CONCLUSION: PMSG to extend the proximal landing zone in zone 2, 1, or 0 in order to treat urgent diseases of the proximal descending aorta or the inner circumference of the aortic arch by a totally endovascular approach while preserving flow in the supra aortic trunks is experimentally feasible. PMID- 28615115 TI - Circulatory collapse in a parturient undergoing cesarean delivery: a diagnostic dilemma. AB - Embolic events including thromboembolism, air embolism, and amniotic fluid embolism can cause cardiovascular collapse during cesarean delivery. Differentiation between the three conditions is challenging because they share many of the initial clinical and echocardiographic findings, but an accurate, definitive diagnosis allows the administration of specific therapy that may help in saving the life of the mother and/or the fetus. We report a case of cardiovascular collapse during cesarean delivery under general anesthesia; massive pulmonary thromboembolism was suspected and unfractionated heparin was administered. Cardiac arrest followed and was managed with standard cardiopulmonary resuscitation, resulting in return of spontaneous circulation. Postoperatively, the patient remained hemodynamically unstable in spite of heparin, norepinephrine infusions and intravenous fluids. A transthoracic echocardiogram revealed right-sided pressure overload. Thrombolysis was initiated. Streptokinase (1,500,000IU over 2hours) was administered with no clinical response, followed by infusion (100,000IU/h) for 12hours. The patient's hemodynamics improved gradually and she was successfully weaned from norepinephrine and mechanical ventilation. Significant bleeding ensued, necessitating discontinuation of anticoagulation and transfusion of red blood cells. Eventually, the patient was discharged home, in good condition, and on oral warfarin therapy. PMID- 28615116 TI - An unusual presentation of synovial chondromatosis of the knee in a 10-year-old girl. AB - Synovial chondromatosis commonly occurs in the anterior compartment of the knee joint, predominantly in middle-aged men. It is relatively unusual in female children and is rarely encountered in the synovium beneath the meniscus. The present report describes a rare case of synovial chondromatosis that developed in the synovium just inferior to both menisci of the right knee in a 10-year-old girl. At this unusual age and location, there is a greater probability of missed diagnosis, due to the lack of definite informative incidence, and difficulty in finding the lesions during arthroscopic examinations. In the present case, multiple loose bodies were hidden by the meniscus, and thus, there were no structural abnormalities in the initial arthroscopic views before probing the meniscus. After careful inspection, we found numerous cartilaginous loose bodies and removed them as much as possible with arthroscopy. PMID- 28615117 TI - Impact of COPD on outcomes in hospitalized patients with community-acquired pneumonia: Analysis of the Spanish national hospital discharge database (2004 2013). AB - AIM: To examine trends in incidence and outcomes of community-acquired pneumonia (CAP) hospitalizations among patients with or without COPD in Spain (2004-2013). METHODS: We used national hospital discharge data to select all hospital admissions for CAP. Incidence was calculated overall and according to the presence or absence of COPD. RESULTS: We identified 901,136 hospital admissions for CAP (32.25% with COPD). Incidence of hospitalizations of CAP increased significantly over time among patients with and without COPD, but it was higher among people with COPD for all years analyzed. S. pneumoniae decreased over time for both groups. Time trend analyses showed significant decreases in mortality during admission for CAP for patients with and without COPD. Factor independently associated with higher mortality in both groups included: male sex, older age, higher comorbidity, isolation of S. aureus or P. aeruginosa, use of mechanical ventilation, and readmission. The presence of COPD was associated with a lower in hospital mortality (IHM) (OR: 0.58, 95%CI 0.57-0.59). CONCLUSIONS: The incidence of hospitalizations for CAP increased over time in patients with and without COPD, being higher in the COPD population for all years analyzed. IHM decreased over time in both groups. There were no differences in mortality between COPD and non-COPD patients. PMID- 28615118 TI - Functional and biological studies of alpha-galactosidase A variants with uncertain significance from newborn screening in Taiwan. AB - Fabry disease is an X-linked disorder resulted from deficiency of alpha galactosidase A (GLA) activity. In Taiwan, a total of 792,247 newborns were screened from 2008 to 2014 in two newborn screening centers, and 13 variants of uncertain significance (VOUS) in the GLA gene were identified. To determine whether these variants were pathogenic or not, functional, biochemical, clinical and pedigree analyses were performed. In vitro functional assay was established through site-directed mutagenesis, and four in silico tools were used to predict pathogenesis. The enzyme activity of dried blood spots and plasma metabolite lyso Gb3 level from subjects with the variants were measured. Additionally, clinical manifestations were evaluated extensively from the subjects and their relatives. Our results revealed that p.G104V, p.I232T, p.D322H, and p.G360C all exhibited relatively low residual enzyme activities and elevated plasma lyso-Gb3 level. These data strongly suggest that these Fabry mutations may cause classical or later-onset phenotypes. In contrast, neither significantly clinical symptoms nor elevated lyso-Gb3 level was found in cases with p.P60S, p.A108T, p.S304T, p.R356Q, and p.P362T variants, which may be non-pathogenic or milder forms of Fabry variants. More data need to be included for the patients with p.N53D, p.P210S, p.M296L, and p.K391T variants. The established system provides us more information to classify these GLA variants. PMID- 28615119 TI - Schizophrenia and induced abortions: A national register-based follow-up study among Finnish women born between 1965-1980 with schizophrenia or schizoaffective disorder. AB - BACKGROUND: The objectives of this study were to investigate, in women with schizophrenia or schizoaffective disorder, the number and incidence of induced abortions (= pregnancy terminations performed by a physician), their demographic characteristics, use of contraceptives, plus indications of and complications related to pregnancy termination. METHODS: Using the Care Register for Health Care, we identified Finnish women born between the years 1965-1980 who were diagnosed with either schizophrenia or schizoaffective disorder during the follow up period ending 31.12.2013. For each case, five age- and place-of-birth- matched controls were obtained from the Population Register of Finland. Information about births and induced abortions were obtained from the Medical Birth Register and the Induced Abortion Register. RESULTS: The number and incidence of induced abortions per 1000 follow-up years did not differ between cases and their controls. However, due to fewer pregnancies, cases exhibited an over 2-fold increased risk of pregnancy termination (RR 2.28; 95% CI 2.20-2.36). Cases were younger, were more often without a partner at the time of induced abortion, and their pregnancies resulted more often from a lack of contraception. Among cases, the indication for pregnancy termination was more often mother-to-be's medical condition. Induced abortions after 12weeks gestation were more common among cases. However, cases had no more complications related to termination. CONCLUSIONS: The incidence of induced abortions among Finnish women with schizophrenia or schizoaffective disorder is similar to the general population, but their risk per pregnancy over two-fold. They need effective, affordable family planning services and long-term premeditated contraception. PMID- 28615120 TI - Corrigendum to "asynchrony of senescence among phenotypic traits in a wild mammal population" [Exp. Gerontol. 71 (2015) 56-68]. PMID- 28615121 TI - Implications of the getting it right first time initiative for regional knee arthroplasty services. AB - STUDY AIM: The aim of this case study of regional orthopaedic practice was to estimate the potential impact of the GIRFT recommendations (iGIRFT) of minimum unit and surgeon specific volumes to orthopaedic units within the Severn Region, UK. METHOD: Practice profiles for surgeons and units were generated using the UK National Joint Registry Surgeon and Hospital Profile Database. Minimum volume thresholds were set at 13 procedures/year for surgeons and 30 procedures/year for units. RESULTS: Five thousand five hundred seventeen knee arthroplasty procedures were recorded within the Severn Region between 1st of January and 31st December 2012 and these were performed by 94 surgeons in 18units. During this time, 4232 (76.7%) primary TKR, 751 (13.6%) primary UKR, 97 (1.7%) primary PFJR and 437 (7.9%) revision TKR were performed. Median surgeon volumes were 33 (range two to 180) for primary TKR, ten (range 2 to 64) for UKR, two (range two to 41) for PFJR and five (range two to 57) for Revision TKR. Amongst 48 surgeons performing UKR, 26 (54%) performed less than 13 procedures per year accounting for 108 (14%) procedures. Amongst 20 surgeons performing PFJR, 19 (95%) performed <13/year, accounting for 56 (58%) of cases. Fifty surgeons performed revision TKR with 37 (74%) performing <13 revisions per annum, accounting for 151 (35%) procedures. Amongst 16units performing UKR, eight (50%) performed <30/year, accounting for 16% overall. Revision TKR was performed in 15units whilst eight (53%) performed <30/year, accounting for 62 (15%) cases. CONCLUSION: We have hypothesised the impact of implementing minimum unit and surgeon volume thresholds for the organisation of regional arthroplasty services. Our analysis suggests that whilst these effects may be considerable, they may be mitigated by local rationalisation to achieve an appropriate caseload mix. PMID- 28615122 TI - In vitro and in vivo generation of heterophil extracellular traps after Salmonella exposure. AB - The release of extracellular traps (ETs) by granulocytes is a unique strategy to stop the dissemination of microbial pathogens. This study was undertaken to elucidate the potential of avian granulocytes (heterophils) to form ETs that can arrest and kill Salmonella organisms. After in vitro exposure of isolated heterophils and in vivo infection of day-old chicks with Salmonella enterica subsp. enterica serovars Infantis (SI) or Enteritidis (SE), the generation of ETs as well as the trapping and survivability of Salmonella organisms in the ET meshwork were determined by means of microscopy and spectrophotometry. In vitro, heterophils were able to form ETs within 15min after SE and SI inoculation. At 120min and with a multiplicity of infection of 1 and 5, SI induced significantly more ETs and DNA release than SE. Both SE and SI were found to be associated with the ET structures. Live-dead staining showed most of the microorganisms within the extracellular scaffold alive. In vivo, heterophils were detected in cecal lumen of SE-, but not SI-infected chicks. In cecum of the SE-exposed chicks, ET formations were scarcely detected whereas intact heterophils with phagocytosed bacteria were frequently found. The results evidence the capability of heterophils to generate ETs after SE and SI exposure in vitro. However, an infection of chicks with Salmonella did not significantly induce the formation of ET structures in cecum. Thus, the process to form ETs (ETosis) seems not to be of special relevance for Salmonella defense within the cecal lumen of young chicks. PMID- 28615123 TI - Quantification of equine immunoglobulin A in serum and secretions by a fluorescent bead-based assay. AB - Only few quantitative reports exist about the concentrations and induction of immunoglobulin A (IgA) in mucosal secretions of horses. Despite this, it is widely assumed that IgA is the predominant immunoglobulin on mucosal surfaces in the horse. Here, two new monoclonal antibodies (mAbs) against equine IgA, clones 84-1 and 161-1, were developed and characterized in detail. Both IgA mAbs specifically bound monomeric and dimeric equine IgA in different applications, such as Western blots and fluorescent bead-based assays. Cross-reactivity with other equine immunoglobulin isotypes was not observed. The new IgA mAb 84-1 was used in combination with the previously characterized anti-equine IgA mAb BVS2 for the development and validation of a fluorescent bead-based assay to quantify total IgA in equine serum and various secretions. The IgA assay's linear detection ranged from 64pg/ml to 1000ng/ml. For the quantification of IgA in serum or in secretions an IgA standard was purified from serum or nasal wash fluid (secretory IgA), respectively. The different standards were needed for accurate IgA quantification in the respective samples taking the different signal intensities of monomeric and dimeric IgA on the florescent bead-based assay into account. IgA was quantified by the bead-based assay established here in different equine samples of healthy adult individuals. In serum the median total IgA was 0.45mg/ml for Thoroughbred horses (TB, n=10) and 1.16mg/ml in Icelandic horses (ICH, n=12). In nasopharyngeal secretions of TB (n=7) 0.13mg/ml median total IgA was measured, and 0.25mg/ml for ICH (n=12). Saliva of ICH (n=6) contained a median of 0.15mg/ml, colostrum of Warmbloods (n=8) a median of 1.89mg/ml IgA. Compared to IgG1 and IgG4/7 quantified in the same samples, IgA appeared as the major immunoglobulin isotype in nasopharyngeal secretions and saliva while it is a minor isotype in serum and colostrum. The newly developed monoclonal antibodies against equine IgA and the resulting bead-based assay for quantification of total IgA can notably improve the evaluation of mucosal immunity in horses. PMID- 28615124 TI - Blood and milk polymorphonuclear leukocyte and monocyte/macrophage functions in naturally caprine arthritis encephalitis virus infection in dairy goats. AB - The exact influence of caprine arthritis encephalitis virus (CAEV) infection on blood and milk polymorphonuclear leukocytes (PMNLs) and monocyte/macrophages of goats remains unclear. Thus, the present study sought to explore the blood and milk PMNL and monocyte/macrophage functions in naturally CAEV-infected goats. The present study used 18 healthy Saanen goats that were segregated according to sera test outcomes into serologically CAEV negative (n=8; 14 halves) and positive (n=10; 14 halves) groups. All milk samples from mammary halves with milk bacteriologically positive outcomes, somatic cell count >=2*106cellsmL-1, and abnormal secretions in the strip cup test were excluded. We evaluated the percentage of blood and milk PMNLs and monocyte/macrophages, the viability of PMNLs and monocyte/macrophages, the levels of intracellular reactive oxygen species (ROS) and the nonopsonized phagocytosis of Staphylococcus aureus and Escherichia coli by flow cytometry. In the present study, a higher percentage of milk macrophages (CD14+) and milk polymorphonuclear leukocytes undergoing late apoptosis or necrosis (Annexin-V+/Propidium iodide+) was observed in CAEV infected goats; we did not find any further alterations in blood and milk PMNL and monocyte/macrophage functions. Thus, regarding our results, the goats naturally infected with CAEV did not reveal pronounced dysfunctions in blood and milk polymorphonuclear leukocytes and monocytes/macrophages. PMID- 28615125 TI - Effect of Mycoplasma bovis on bovine neutrophils. AB - Mycoplasma bovis (M. bovis) is a small bacterium that lacks a cell wall. M. bovis infection results in chronic pneumonia and polyarthritis syndrome (CPPS), otitis media, conjunctivitis, and meningitis in feedlot cattle and mastitis in dairy cattle. Numerous studies of peripheral mononuclear cells (PBMC) indicate that M. bovis evades host immunity through targeted effects on immune cell activity, including inhibition of effector function and simultaneous aberrant activation of immune cell activity that has no effect on protection against the bacterium. Few studies have addressed the interaction between M. bovis and neutrophils, one of the most important cell subsets of innate immunity. We hypothesized that M. bovis modifies specific neutrophil activities to support its persistence and systemic dissemination. In this study, we demonstrate that M. bovis enhances neutrophil apoptosis, stimulates production of pro-inflammatory cytokines, IL-12 and TNF alpha, inhibits production of nitric oxide (NO) but augments elastase release. We also show that IL-17 an inflammatory cytokine produced by Th-17 cells does not enhance the capacity of neutrophils to destroy M. bovis. These findings present novel mechanisms of mycoplasma evasion of host innate immunity and provide potential opportunities for immuno-therapeutic interventions. PMID- 28615126 TI - Unveiling the participation of avian kinin ornithokinin and its receptors in the chicken inflammatory response. AB - Vasoactive peptides are key early mediators of inflammation released through activation of different enzymatic systems. The mammalian kinin-kallikrein (K-KLK) system produces bradykinin (BK) through proteolytic cleavage of a kininogen precursor by enzymes named kallikreins. BK acts through specific ubiquitous G protein coupled receptors (B1R and B2R) to participate in physiological processes and inflammatory responses, such as activation of mononuclear phagocytes. In chickens, the BK-like nonapeptide ornithokinin (OK) has been shown to promote intracellular calcium increase in embryonic fibroblasts and to be vasodilatory in vivo. Also, one of its receptors (B2R) was already cloned. However, the participation of chicken K-KLK system components in the inflammatory response remains unknown and was therefore investigated. We first showed that B1R, B2R and kininogen 1 (KNG1) are expressed in unstimulated chicken tissues and macrophages. We next showed that chicken B1R and B2R are expressed at transcript and protein levels in chicken macrophages and are upregulated by E. coli LPS or avian pathogenic E. coli (APEC) infection. Interestingly, exogenous OK induced internalization and degradation of OK receptors protein, notably B2R. Also, OK induced intracellular calcium increase and potentiated zymosan-induced ROS production and Dextran-FITC endocytosis by chicken macrophages. Exogenous OK itself did not promote APEC killing and had no pro-inflammatory effect. However, when combined with LPS or APEC, OK upregulated cytokine/chemokine gene expression and NO production by chicken macrophages. This effect was not blocked by canonical non-peptide B1R or B2R receptor antagonists but was GPCR- and PI3K/Akt dependent. In vivo, pulmonary colibacillosis led to upregulation of OK receptors expression in chicken lungs and liver. Also, colibacillosis led to significant upregulation of OK precursor KNG1 expression in liver and in cultured hepatocytes (LMH). We therefore provide hitherto unknown information on how OK and its receptors are involved in inflammation and infection in chickens. PMID- 28615127 TI - Effect of feeding Lipopolysaccharide as an immunostimulant on immune response and immune gene expression of Labeo bata. AB - This study investigates the effects of dietary lipopolysaccharide (LPS) as an immunostimulant on hematology, innate immunity, immune gene expression and protection against Edwardsiella tarda on Labeo bata. A basal diet supplemented with 0, 50, 100 and 150mg LPS kg-1diet was fed to the four different groups for 30days. The haematological (total erythrocyte count, total leukocyte count, total serum protein, albumin and globulin), innate immune parameters (respiratory burst, serum lysozyme, myeloperoxidase and serum bactericidal activity), immune gene expression (C3, beta-2 microglobulin, lysozyme g, transferrin, IFN-1, IFN gamma) were monitored at 7th, 15th, 30th day and one day post challenge (DPC) with E. tarda. All the studied haematological, innate immune parameters and expression of immune gene increased significantly (p<=0.05) in LPS fed group in comparison with control. However the group fed 100mgkg-1 LPS in feed showed highest activity on 7th day and 1DPC. The group fed 100mgkg-1 LPS also recorded highest relative percent survivability after challenge with E. tarda. Therefore this study suggests that LPS at 100mgkg-1 could be used as an immunostimulant in feed to enhance the protection of bata during periods of increased disease risk. PMID- 28615128 TI - 17beta-Estradiol and progesterone decrease MDP induced NOD2 expression in bovine mammary epithelial cells. AB - During the periparturient period, many neuroendocrine changes develop in cows. Periparturient hormone fluxes may adversely affect mammary gland immunity and mastitis susceptibility. 17beta-Estradiol (E2) and progesterone (P4) have been reported to function on immune regulation, and their concentration fluctuates dramatically during the perinatal period. Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) mediate numerous aspects of innate immunity in humans and experimental animals. This study aimed to explore the effects of E2 and P4 on NOD2 expression in bovine mammary epithelial cells (BMECs). BMECs were isolated and purified from bovine mammary tissue and treated with E2/P4 and muramyl dipeptide (MDP). After these treatments, the mRNA levels of NOD2, receptor-interacting protein kinase (RIP) 2, interleukin (IL) 1beta, IL-6, IL-8 and tumor necrosis factor (TNF) alpha were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) respectively, and the protein levels of NOD2 were analyzed by western blotting. The results showed that E2 and P4 decreased MDP-induced transcriptional expression of NOD2 and the downstream molecules. Moreover, E2 reduced MDP-induced NOD2 protein expression levels. Our study suggests that down-regulation of NOD2 by E2 and P4 may be one of the reasons for mastitis susceptibility in periparturient dairy cows. PMID- 28615129 TI - The domestic cat antibody response to feline herpesvirus-1 increases with age. AB - Herpesviruses establish lifelong infections, normally characterized by prolonged periods of latency with intermittent episodes of viral reactivation. Feline herpesvirus-1 (FHV-1) infects domestic cats, and epidemiological studies indicate that many or most domestic cats are exposed to FHV-1, but the strength and longevity of the antibody response to FHV-1 is not fully characterized. Here we describe development of an ELISA, using lysates of cat cells infected with FHV-1, that measure feline antibodies against FHV-1. The assay is sensitive, quantitative and has a large dynamic range. We found that serum anti-FHV-1 antibodies primarily recognize FHV-1 proteins of the Late (L) class and are primarily of the IgG isotype. We then analyzed serum from a cross-sectional cohort of 100 client-owned cats that differed in age, sex and vaccination history. While there was no difference in FHV-1 antibody responses between females and males, antibody levels were significantly increased in older cats in comparison with younger animals (p=0.01). Surprisingly, as the length of time since the most recent vaccination increased, there was no corresponding drop in serum anti-FHV-1 antibody. These data suggest that FHV-1 immunity is very long lived and support the current recommendation that many cats do not require revaccination against FHV-1 annually. PMID- 28615130 TI - Different breeds, different blood: Cytometric analysis of whole blood cellular composition in chicken breeds. AB - While haematological variation is well known in birds, variation in avian breeds (distinct morphotypes of the same species) remains unexplored. Poultry breeds, in particular, may show interesting evolutionary patterns and economically-relevant physiological differences. We performed a comparative examination of blood cellular composition in five chicken (Gallus gallus domesticus) breeds: Araucana, Booted bantam, Czech, Minorca and Rosecomb bantam. In standard-environment-reared hens whole-blood flow cytometry revealed remarkable differences in most erythrocyte- and leukocyte-related parameters. We identified two extremes: Czech, a European breed, with a low heterophil/lymphocyte (H/L) ratio and high CD4+ levels, and Araucana, a South-American breed, with a high H/L ratio and high relative monocyte count. Such variation may reflect a combination of artificial and natural selection acting on health- and stress-related traits in domestic populations. Different breeds have evolved different immunological adaptations reflecting their original need to fight pathogens and physiological constraint resulting from dissimilar physiological trade-offs. PMID- 28615131 TI - Stimulation of colorectal biopsies from miniature dachshunds with inflammatory colorectal polyps with toll-like receptor ligands: A pilot study. AB - Inflammatory colorectal polyps (ICRPs) in miniature dachshunds (MDs) are a possible novel form of breed-specific canine inflammatory bowel disease (IBD). In this pilot study, we investigated the effects of different Toll like receptor (TLR2, TLR4, TLR5 and TLR9) ligands on pro-inflammatory cytokines (IL-1beta, IL 6, IL-8 and TNF-alpha) gene expression in ex vivo-cultured colorectal samples from four MDs with ICRPs and four healthy MDs. At baseline, no significant difference in the mRNA expression levels of TLRs and pro-inflammatory cytokines was observed between cases and control MDs. After 4-h incubation, the relative ratios of TNF-alpha mRNA expression in the TLR2- or TLR4-stimulated colorectal samples, and IL-1beta mRNA expression in the TLR9-stimulated colorectal samples form cases showed higher tendency compared with healthy MDs (P<0.05), although statistically not significant. The results of this pilot study using small number of cases indicated that reactivity against TLR2, TLR4 or TLR9 ligand in the production of pro-inflammatory cytokines might be enhanced in the colorectal mucosa of ICRPs. Further research is needed to perform the functional analysis of TLRs in the sole cell population using intestinal epithelial primary culture and the mononuclear cells isolated from colonic mucosa. PMID- 28615132 TI - Identification of a secondary mutation in the KIT kinase domain correlated with imatinib-resistance in a canine mast cell tumor. AB - Imatinib-resistance is a major therapeutic problem in human chronic myeloid leukemia, human gastrointestinal stromal tumors, and canine mast cell tumors. In the present study, we identified the secondary mutation c.2006C>T in c-KIT exon 14 in a mast cell tumor obtained from a dog carrying c.1663-1671del in exon 11 and showing resistance to imatinib. The mutation in exon 14 resulted in substitution of threonine with isoleucine at position 669, which was located at the center of the ATP binding site as a gatekeeper and played an important role in binding to imatinib. Transfectants were constructed to survey the functions of these mutations in exons 11 and 14. The transfectant with mutant KIT encoded by c KIT carrying c.1663-1671del showed constitutive ligand-independent phosphorylation that was suppressed by imatinib, indicating a gain-of-function mutation. Furthermore, the transfectant with mutant KIT encoded by c-KIT carrying both c.1663-1671del and c.2006C>T caused ligand-independent phosphorylation, which was not suppressed by imatinib. From these results, we concluded that the mutation c.2006C>T in c-KIT exon 14 was an imatinib-resistance mutation in a canine mast cell tumor. These findings revealed, for the first time, a mechanism of imatinib resistance in a clinical case of canine mast cell tumor. PMID- 28615133 TI - Platelet-rich plasma with keratinocytes and fibroblasts enhance healing of full thickness wounds. AB - Advances in tissue engineering led to the development of various tissue engineered skin substitutes (TESS) for the treatment of skin injuries. The majority of the autologous TESS required lengthy and costly cell expansion process to fabricate. In this study, we determine the possibility of using a low density of human skin cells suspended in platelet-rich plasma (PRP)-enriched medium to promote the healing of full-thickness skin wounds. To achieve this, full-thickness wounds of size 1.767 cm2 were created at the dorsum part of nude mice and treated with keratinocytes (2 * 104 cells/cm2) and fibroblasts (3 * 104 cells/cm2) suspended in 10% PRP-enriched medium. Wound examination was conducted weekly and the animals were euthanized after 2 weeks. Gross examination showed that re-epithelialization was fastest in the PRP+cells group at both day 7 and 14, followed by the PRP group and NT group receiving no treatment. Only the PRP+cells group achieved complete wound closure by 2 weeks. Epidermal layer was presence in the central region of the wound of the PRP+cells and PRP groups but absence in the NT group. Comparison between the PRP+cells and PRP groups showed that the PRP+cells-treated wound was more mature as indicated by the presence of thinner epidermis with single cell layer thick basal keratinocytes and less cellular dermis. In summary, the combination of low cell density and diluted PRP creates a synergistic effect which expedites the healing of full-thickness wounds. This combination has the potential to be developed as a rapid wound therapy via the direct application of freshly harvested skin cells in diluted PRP. PMID- 28615134 TI - Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2 thioglycosides. AB - In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a-4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a-4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a-8j and 9a-9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c-9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a-8j exhibited toxicity. PMID- 28615135 TI - Combined therapy for epistaxis by hereditary hemorrhagic teleangiectasia: A 3 year follow up study on 45 patients. AB - Hereditary hemorrhagic telangiectasia (HHT) is a mutilating disease associated with the majority of patients with recurrent epistaxis episodes. The aim of this study was to present a single institution experience with patients treated for nasal epistaxis using a combination of Nd:YAG laser and argon plasma coagulation (APC) vs Nd:YAG laser alone, with a minimum follow-up of 3 years. 45 patients (21 men, 24 women) aged from 15 to 84 years with the diagnosis of HHT were treated in the Department of Otolaryngology, Head and Neck Surgery in Homburg/Saar between 10/2002 and 10/2012 because of epistaxis, using a combination of Nd:YAG laser and APC or Nd:YAG laser alone. The observation period ranged from 36 to 120 months. 15 patients were treated with Nd:YAG laser alone and 30 patients with combined Nd:YAG laser and APC. A revision was necessary in three patients (20%) in the Nd:YAG laser group and in nine (33.3%) patients in the combined group. The difference between revision rates after the two therapy forms was not statistically significant (p = 0.492). Bipolar coagulation was additionally applied in 33 patients. There was no statistically significant difference (p = 1.00) in revision rates between patients who were additionally treated with bipolar coagulation and those who did not receive bipolar coagulation as part of their treatment. No case of postoperative septal perforation was observed. Nd:YAG laser therapy remains an established option for treating treat epistaxis in HHT patients. PMID- 28615136 TI - Accuracy of measurements used to quantify cranial asymmetry in deformational plagiocephaly. AB - OBJECTIVE: Various measurements are used to quantify cranial asymmetry in deformational plagiocephaly (DP), but studies validating cut-off values and comparing the accuracy of such measurements are lacking. In this study, we compared the accuracy of four different measurements in classifying children with and without DP diagnosed by visual assessment, and sought to determine their optimal cut-off values. STUDY DESIGN: Two experts rated 407 3D craniofacial images of children aged between 3 and 36 months old using the Argenta classification. We then measured the following asymmetry-related variables from the images: Oblique Cranial Length Ratio (OCLR), Diagonal Difference (DD), Posterior Cranial Asymmetry Index (PCAI), and weighted Asymmetry Score (wAS). We created receiver operating characteristic curves to evaluate the accuracy of these variables. RESULTS: All variables performed well, but OCLR consistently provided the best discrimination in terms of area under the curve values. Subject's age had no clear effect on the cut-off values for OCLR, PCAI, and wAS; however, the cut-off for DD increased monotonically with age. When subjects with discrepant expert ratings were excluded, the optimal cut-off values for DP (Argenta class >= 1) across all age-groups were 104.0% for OCLR (83% sensitivity, 97% specificity), 10.5% for PCAI (90% sensitivity, 90% specificity), and 24.5 for wAS (88% sensitivity, 90% specificity). CONCLUSION: We recommend using OCLR as the primary measurement, although PCAI and wAS may also be useful in monitoring cranial asymmetry. The threshold of relative asymmetry required for a deformation to appear clinically significant is not affected by the child's age, and DD has no additional utility in monitoring DP compared to using only OCLR. PMID- 28615137 TI - Stress measurement in surgeons and residents using a smart patch. AB - BACKGROUND: Stress may negatively affect surgeons' performance during surgical procedures, jeopardizing patient safety. For measuring stress, complex methods are used that cannot record stress real time. This study reports stress measurements in surgeons and residents using a novel patch sensor to identify activities and risk factors of stress. METHODS: In this explorative study, surgeons and residents wore the HealthPatchTM during all daily activities for 2-3 days. The patch recorded heart rate variability (HRV), and real time stress percentage using a validated algorithm of heart rate (HR) and HRV. The patch was compared with self perceived stress reporting using STAI. RESULTS: A significant increase in HRV and stress percentage was shown in twenty surgeons and residents during surgery in comparison with other activities. Consultants showed lower stress levels while operating compared to fellows and residents. Stress according to the patch did not correlate with STAI outcome. CONCLUSIONS: Continuous stress monitoring using a wearable sensor patch reveals relevant data on actual stress of surgeons and residents. Stress was highest performing an operation, particularly in fellows and residents. PMID- 28615138 TI - Wide versus narrow margins after partial hepatectomy for hepatocellular carcinoma: Balancing recurrence risk and liver function. AB - BACKGROUND: The goal of this study was to compare the outcome after partial hepatectomy for hepatocellular carcinoma (HCC) in which a margin less than or equal to 5 mm or greater than 5 mm was achieved. METHODS: A review of our 3300 patient prospective HPB database was performed from 12/2002 to 4/2015. Patients were stratified into two groups: resection margins <=5 ("narrow") and >5 mm ("wide") as measured on final pathologic assessment. RESULTS: One-hundred thirty patients were included in the analysis (margin <=5 mm, n = 41 and margin >5 mm, n = 89). At the time of analysis 54 patients had developed 56 recurrences, 15 (37%) in the narrow margin group and 41 (46%) in the wide margin group, p = 0.45. The pattern of recurrence was similar in the two groups: intrahepatic 11 (79%) versus 30 (75%), p = 1, and extra-hepatic 6 (43%) versus 17 (43%), p = 1. Median disease free survival was similar in both groups, 18.1 versus 19.5 months (p = 0.85). CONCLUSIONS: A narrow resection margin (5 mm or less) does not detract from oncologic outcomes after partial hepatectomy for HCC. Tailoring resection margins may lead to greater preservation of hepatic parenchyma. Factors other than margin status represent the driving forces for local and systemic recurrence. PMID- 28615139 TI - The impact of marriage and parenthood on male body mass index: Static and dynamic effects. AB - RATIONALE: Numerous cross-sectional studies investigated the link between marital status and BMI in the context of competing social science theories (marriage market, marriage selection, marriage protection and social obligation), frequently offering conflicting theoretical predictions and conflicting empirical findings. OBJECTIVE: This study analysed the effects of marriage, divorce, pregnancy, and parenthood on male BMI in a longitudinal setting, avoiding the estimation bias of cross-sectional studies and allowing for an analysis of BMI fluctuation over time and the dynamic effects of these events. METHOD: Using the Panel Study of Income Dynamics 1999-2013 dataset (N = 8729), this study was the first to employ a dynamic panel-data estimation to examine the static and dynamic effects of marriage, divorce, and fatherhood on male BMI. RESULTS: The study showed that married men have higher BMI, but marital status changes largely drove this static effect, namely, an increase in BMI in the period following marriage, and a decrease in BMI preceding and following divorce. CONCLUSIONS: Thus, this study found marked evidence in support of the marriage market and social obligation theories' predictions about male BMI, and supports neither marriage protection theory nor marriage selection theory. Wives' pregnancies had no significant effect on BMI; instead, men tend to have higher BMI in the periods following childbirth. Finally, analyses showed marked contemporaneous correlations between husband and wife BMI over the course of marriage. PMID- 28615140 TI - Imaging features of myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological disorders including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). These disorders show large overlap in genetic and clinical presentations, and can have many different imaging manifestations. Unusual thromboses, embolic events throughout the systemic or pulmonary vasculature, or osseous findings can often be clues to the underlying disease. There is limited literature about the imaging features of these disorders, and this may result in under-diagnosis. Multiple treatments are available for symptom control, and the development of multiple new pharmacological inhibitors has significantly improved morbidity and prognosis. Knowledge of these conditions may enable the radiologist to suggest an MPN as a possible underlying cause for certain imaging findings, particularly unexplained splanchnic venous thrombosis, i.e. in the absence of chronic liver disease or pancreatitis. The aim of the present review is to outline using examples the different categories of MPN and illustrate the variety of radiological findings associated with these diseases. PMID- 28615141 TI - Diagnostic capability of feature-tracking cardiovascular magnetic resonance to detect infarcted segments: a comparison with tagged magnetic resonance and wall thickening analysis. AB - AIM: To examine the diagnostic capabilities of feature-tracking cardiovascular magnetic resonance (FT-CMR), tagged cine magnetic resonance (MR), and wall thickening (WT) analyses to detect infarcted segments in patients with established myocardial infarction (MI). MATERIALS AND METHODS: Twenty patients with established MI were selected retrospectively and the peak endocardial circumferential strain (CS) was quantified based on the 16-segment model. According to CMR with late gadolinium enhancement, segments were categorised as transmural MI, subendocardial MI, and no MI. RESULTS: A total of 320 segments (62 transmural MI, 50 subendocardial MI, and 208 no MI) were analysed. Peak endocardial CS was significantly lower for transmural MI compared with subendocardial MI (p<0.05) and no MI (p<0.001). Cut-off values of -11.2% for CS by FTCMR, -10.9% for CS by tagged MR, and 23.8% for %WT, differentiated between infarcted and non-infarcted segments with a sensitivity of 72%, 71%, and 56%; specificity of 71%, 75%, and 67%; accuracy of 72%, 73%, and 63%; positive predictive value of 57%, 60%, and 48%; negative predictive value of 83%, 83%, and 74%; and an area-under-the-curve of 0.77, 0.79, and 0.64, respectively. CONCLUSIONS: FT-CMR was diagnostically superior to %WT, and could differentiate between subendocardial and transmural MI. Unlike tagged MR, FT-CMR did not require the acquisition of additional sequences. PMID- 28615143 TI - Monocyte/macrophage and T cell activation markers are not independently associated with MI risk in healthy individuals - results from the HUNT Study. AB - BACKGROUND: We hypothesized that circulating markers reflecting monocyte/macrophage and T cell activation are associated with increased risk of myocardial infarction (MI) in apparently healthy individuals. METHODS: Serum monocyte/macrophage and T cell activation markers soluble (s) CD163, sCD14, Gal3BP, sCD25 and sCD166 were analyzed by enzyme-immunoassay in a case-control study nested within the population-based HUNT2 cohort in Norway. Among 58,761 apparently healthy men and women followed a median 11.3years, 1587 incident MI cases were registered, and compared to 3959 age- and sex-matched controls. RESULTS: Higher serum sCD163 (Q4 vs. Q1 OR: 1.27, P-trend 0.002), sCD14 (Q4 vs. Q1 OR: 1.38, P-trend<0.001), and especially sCD25 (Q4 vs. Q1 OR: 1.45, P trend<0.001), were associated with increased MI risk in the age-and sex adjusted models. However, after additional adjustment for cardiovascular risk factors these associations were strongly attenuated (Q4 vs Q1 ORs between 1.02 and 1.12, P-trends between 0.30 and 0.58). CONCLUSIONS: sCD163, sCD14 and sCD25 may reflect leukocyte activation and inflammatory mechanisms related to atherogenesis, but do not predict MI risk above and beyond conventional cardiovascular risk factors. PMID- 28615142 TI - Overexpression of KCNJ2 in induced pluripotent stem cell-derived cardiomyocytes for the assessment of QT-prolonging drugs. AB - Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes hold great potentials to predict pro-arrhythmic risks in preclinical cardiac safety screening, although the hiPSC cardiomyocytes exhibit rather immature functional and structural characteristics, including spontaneous activity. Our physiological characterization and mathematical simulation showed that low expression of the inward-rectifier potassium (IK1) channel is a determinant of spontaneous activity. To understand impact of the low IK1 expression on the pharmacological properties, we tested if transduction of hiPSC-derived cardiomyocytes with KCNJ2, which encodes the IK1 channel, alters pharmacological response to cardiac repolarization processes. The transduction of KCNJ2 resulted in quiescent hiPSC derived cardiomyocytes, which need pacing to elicit action potentials. Significant prolongation of paced action potential duration in KCNJ2-transduced hiPSC-derived cardiomyocytes was stably measured at 0.1 MUM E-4031, although the same concentration of E-4031 ablated firing of non-treated hiPSC-derived cardiomyocytes. These results in single cells were confirmed by mathematical simulations. Using the hiPSC-derived cardiac sheets with KCNJ2-transduction, we also investigated effects of a range of drugs on field potential duration recorded at 1 Hz. The KCNJ2 overexpression in hiPSC-derived cardiomyocytes may contribute to evaluate a part of QT-prolonging drugs at toxicological concentrations with high accuracy. PMID- 28615144 TI - Obstructive acute renal failure by severe gastric distension after binge. AB - Binge eating occurs in patients with eating disorders and can result in metabolic complications, leading to gastric rupture or necrosis. However, organ failure as acute renal failure is rarely observed. We report the case of an overeating episode resulting in massive gastric dilatation and acute renal failure with abdominal pressure and bilateral ureteral obstruction. The outcome was favorable with gastric aspiration and fasting. PMID- 28615145 TI - Early initiation of low-dose hydrocortisone treatment for septic shock in adults: A randomized clinical trial. AB - BACKGROUND: Physiologic dose hydrocortisone is part of the suggested adjuvant therapies for patients with septic shock. However, the association between the corticosteroid therapy and mortality in patients with septic shock is still not clear. Some authors considered that the mortality is related to the time frame between development of septic shock and start of low dose hydrocortisone. Thus we designed a placebo-controlled, randomized clinical trial to assess the importance of early initiation of low dose hydrocortisone for the final outcome. METHODS: A total of 118 patients with septic shock were recruited in the study. All eligible patients were randomized to receive hydrocortisone (n=58) or normal saline (n=60). The study medication (hydrocortisone and normal saline) was initiated simultaneously with vasopressors. The primary end-point was 28-day mortality. The secondary end-points were the reversal of shock, in-hospital mortality and the duration of ICU and hospital stay. RESULTS: The proportion of patients with reversal of shock was similar in the two groups (P=0.602); There were no significant differences in 28-day or hospital all-cause mortality; length of stay in the ICU or hospital between patients treated with hydrocortisone or normal saline. CONCLUSION: The early initiation of low-dose of hydrocortisone did not decrease the risk of mortality, and the length of stay in the ICU or hospital in adults with septic shock. TRIAL REGISTRATION: www.clinicaltrials.govNCT02580240. PMID- 28615146 TI - Novel insights into acute kidney injury-chronic kidney disease continuum and the role of renin-angiotensin system. AB - Acute kidney injury (AKI) is an independent risk factor for chronic kidney disease (CKD). If injury is mild, a repair process can be adaptive and lead to complete renal recovery. However, severe injury will be accompanied by a maladaptive repair which usually leads to nephron loss, fibrosis, vascular rarefaction, and chronic inflammation. Although various mechanisms underlying AKI CKD transition have been explored, no intervention has been proved effective to block the transition until very recently. A lack of consensus for monitoring renal function and defining renal recovery after AKI should be the reasons for the slow advance in the discovery of a timely pharmacologic treatment to block AKI-CKD transition. Recently, animal studies have shown the activation of renin angiotensin system (RAS) after AKI. In patients with complete renal recovery after AKI defined as the decrease of serum creatinine level to within 0.3 mg/dL above the baseline, administration of RAS inhibitor can prevent the ensuing CKD. In this review, we will discuss the renal recovery after AKI and the mechanisms underlying AKI-CKD transition. We will then highlight the promising effect of RAS inhibitor on CKD prevention in patients with complete renal recovery from AKI based on the recent clinical evidence. PMID- 28615148 TI - Echocardiographic assessments of longitudinal left ventricular function in healthy English Springer spaniels. AB - OBJECTIVES: To establish reference intervals for echocardiographic measures of longitudinal left ventricular function in adult English Springer spaniel (ESS) dogs. ANIMALS: This study involved 42 healthy adult ESS. METHODS: Animals were prospectively recruited from a general practice population in the United Kingdom. Dogs were examined twice, at least 12 months apart, to exclude dogs with progressive cardiac disease. Mitral annular plane systolic excursion, tissue Doppler imaging mitral annular velocities and two-dimensional speckle-tracking echocardiographic left ventricular longitudinal strain and strain rate were measured. Intraoperator and intraobserver variability were examined and reference intervals were calculated. The potential effects of body weight, age and heart rate on these variables were examined. RESULTS: Intraoperator and intraobserver variability was <10% for all parameters except tissue Doppler imaging E' (the peak velocity of early diastolic mitral annular motion as determined by pulsed wave Doppler) and two-dimensional speckle-tracking echocardiographic variables, which were all <20%. Thirty-nine dogs were used to create reference intervals. Significant (but mostly weak) effects of age, heart rate and body weight on were detected. Reference intervals were similar to previously published values in different breeds. CLINICAL SIGNIFICANCE: Breed specific reference intervals for measures of longitudinal left ventricular function in the ESS are presented. PMID- 28615147 TI - HIV-Specific B Cell Frequency Correlates with Neutralization Breadth in Patients Naturally Controlling HIV-Infection. AB - HIV-specific broadly neutralizing antibodies (bnAbs) have been isolated from patients with high viremia but also from HIV controllers that repress HIV-1 replication. In these elite controllers (ECs), multiple parameters contribute to viral suppression, including genetic factors and immune responses. Defining the immune correlates associated with the generation of bnAbs may help in designing efficient immunotherapies. In this study, in ECs either positive or negative for the HLA-B*57 protective allele, in treated HIV-infected and HIV-negative individuals, we characterized memory B cell compartments and HIV-specific memory B cells responses using flow cytometry and ELISPOT. ECs preserved their memory B cell compartments and in contrast to treated patients, maintained detectable HIV specific memory B cell responses. All ECs presented IgG1+ HIV-specific memory B cells but some individuals also preserved IgG2+ or IgG3+ responses. Importantly, we also analyzed the capacity of sera from ECs to neutralize a panel of HIV strains including transmitted/founder virus. 29% and 21% of HLA-B*57+ and HLA B*57- ECs, respectively, neutralized at least 40% of the viral strains tested. Remarkably, in HLA-B*57+ ECs the frequency of HIV-Env-specific memory B cells correlated positively with the neutralization breadth suggesting that preservation of HIV-specific memory B cells might contribute to the neutralizing responses in these patients. PMID- 28615150 TI - Metformin in type 1 diabetes. PMID- 28615151 TI - Parkinson's disease patient preference and experience with various methods of DBS lead placement. AB - INTRODUCTION: Physiology-guided deep brain stimulation (DBS) surgery requires patients to be awake during a portion of the procedure, which may be poorly tolerated. Interventional MRI-guided (iMRI) DBS surgery was developed to use real time image guidance, obviating the need for patients to be awake during lead placement. METHODS: All English-speaking adults with PD who underwent iMRI DBS between 2010 and 2014 at our Center were invited to participate. Subjects completed a structured interview that explored perioperative preferences and experiences. We compared these responses to patients who underwent the physiology guided method, matched for age and gender. RESULTS: Eighty-nine people with PD completed the study. Of those, 40 underwent iMRI, 44 underwent physiology-guided implantation, and five underwent both methods. There were no significant differences in baseline characteristics between groups. The primary reason for choosing iMRI DBS was a preference to be asleep during implantation due to: 1) a history of claustrophobia; 2) concerns about the potential for discomfort during the awake physiology-guided procedure in those with an underlying pain syndrome or severe off-medication symptoms; or 3) non-specific fear about being awake during neurosurgery. CONCLUSION: Participants were satisfied with both DBS surgery methods. However, identification of the factors associated with a preference for iMRI DBS may allow for optimization of patient experience and satisfaction when choices of surgical methods for DBS implantation are available. PMID- 28615152 TI - A Qualitative Analysis of How Online Access to Mental Health Notes Is Changing Clinician Perceptions of Power and the Therapeutic Relationship. AB - BACKGROUND: As part of the national OpenNotes initiative, the Veterans Health Administration (VHA) provides veterans online access to their clinical progress notes, raising concern in mental health settings. OBJECTIVE: The aim of this study was to examine the perspectives and experiences of mental health clinicians with OpenNotes to better understand how OpenNotes may be affecting mental health care. METHODS: We conducted individual semi-structured interviews with 28 VHA mental health clinicians and nurses. Transcripts were analyzed using a thematic analysis approach, which allows for both inductive and deductive themes to be explored using an iterative, constant comparative coding process. RESULTS: OpenNotes is changing VHA mental health care in ways that mental health clinicians perceive as both challenging and beneficial. At the heart of these changes is a shifting power distribution within the patient-clinician relationship. Some clinicians view OpenNotes as an opportunity to better partner with patients, whereas others feel that it has the potential to undo the therapeutic relationship. Many clinicians are uncomfortable with OpenNotes, but acknowledge that this discomfort could both improve and diminish care and documentation practices. Specifically, we found that (1) OpenNotes is empowering patients, (2) OpenNotes is affecting how clinicians build and maintain the therapeutic relationship, and (3) mental health clinicians are adjusting their practices to protect patients and themselves from adverse consequences of OpenNotes. CONCLUSIONS: Our findings suggest that future research should monitor whether OpenNotes notes facilitates stronger patient-clinician relationships, enhancing patient-centered mental health care, or diminishes the quality of mental health care through disruptions in the therapeutic relationship and reduced documentation. PMID- 28615149 TI - Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. AB - BACKGROUND: Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease. METHODS: REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA1c, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560. FINDINGS: Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0.005 mm per year, 95% CI -0.012 to 0.002; p=0.1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0.013 mm per year, -0.024 to -0.003; p=0.0093). HbA1c (mean 8.1% [SD 0.9] for metformin and 8.0% [0.8] for placebo at baseline) was reduced on average over 3 years by metformin (-0.13%, 95% CI -0.22 to -0.037; p=0.0060), but this was accounted for by a reduction at the 3-month timepoint (-0.24%, -0.34 to -0.13; p<0.0001) that was not sustained thereafter (p=0.0163 for visit-by-treatment interaction). Bodyweight (-1.17 kg, 95% CI -1.66 to -0.69; p<0.0001) and LDL cholesterol (-0.13 mmol/L, -0.24 to -0.03; p=0.0117) were reduced with metformin over 3 years of treatment, and eGFR was increased (4.0 mL/min per 1.73m2, 2.19 to 5.82; p<0.0001). Insulin requirement was not reduced on average over 3 years (-0.005 units per kg, 95% CI -0.022 to 0.012; p=0.545), but there was a significant visit by-treatment interaction (p=0.0018). There was no effect on endothelial function as measured by reactive hyperaemia index, or on retinopathy. Discontinuation of treatment in 59 (27%) participants on metformin versus 26 (12%) on placebo (p=0.0002) was mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycaemia with metformin. Five deaths occurred among patients allocated to metformin and two occurred among those allocated to placebo; none were judged by site principal investigators to be related to study medication. INTERPRETATION: These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management. FUNDING: JDRF. PMID- 28615153 TI - "Click for Closer Care": A Content Analysis of Community Pharmacy Websites in Four Countries. AB - BACKGROUND: Combinations of professional and commercial communication are typically very controversial, particularly in health care communication on the Internet. Websites of licensed community pharmacies on the other hand tend to raise remarkably little controversy, although they typically contain controversial combinations of clinical and commercial services previously unprecedented in professional health care communication. OBJECTIVE: The aim of this study was to fill the void of knowledge about the combination of clinical and commercial services presented on the websites of licensed community pharmacies. METHODS: A content analysis of clinical and commercial services presented in a random sample of 200 licensed community pharmacy websites from Great Britain, the Netherlands, the Canadian provinces British Columbia and Manitoba, and the Australian states New South Wales and Western Australia was conducted. RESULTS: The top five specific services mentioned on the community pharmacy websites were cosmetic products (126/200, 63.0%), medication refill request options (124/200, 62.0%), over-the-counter medicine (115/200, 57.5%), complementary and alternative medicine (107/200, 53.5%), and home medical aids (98/200, 49.0%). On average, 72.5% (145/200) of the community pharmacy websites across the 4 countries included a combination of clinical and commercial services. A combination of clinical and commercial services was more often present on chain pharmacy websites (120/147, 82.8%) than single pharmacy websites (25/53, 47%; P<.001), and most often on the Canadian community pharmacy websites, followed by the Australian, British, and Dutch pharmacy websites, respectively (P<.02). Furthermore, more than half of the pharmacies' homepages contained a combination of clinical and commercial images (107/200, 53.5%), and almost half of the homepage menus contained a combination of clinical and commercial items (99/200, 49.5%). The latter were, again, more common on chain pharmacy than single pharmacy websites (P<.001), with significant differences between countries (P<.001). CONCLUSIONS: A considerable share of websites of licensed community pharmacies in Great Britain, the Netherlands, Canada, and Australia combine clinical services with commercial services. Previous research into the presence of a combination of commercial and professional services suggests that such a combination may lead to increased interest in commercial services that may be unnecessary or inappropriate to patients' health. PMID- 28615154 TI - Mobile Apps for Eye Care in Canada: An Analysis of the iTunes Store. AB - BACKGROUND: Mobile phone screens can facilitate stimulation to various components of the visual system and many mobile apps are accepted as a means of providing clinical assessments for the oculo-visual system. Although many of these apps are intended for use in clinical settings, there is a growing number of apps in eye care developed for self-tests and eye exercises for lay people. These and other features, however, have not yet been well described. OBJECTIVE: Our objective was to identify, describe, and categorize mobile apps related to eye care that are available to users in the Canadian iTunes market. METHODS: We conducted an extensive search of the Apple iTunes Store for apps related to eye care. We used the terms "eye," "eye care," "vision," and "eye test" and included apps that are targeted at both lay people and medical professionals. We excluded apps whose primary function is not related to eye care. Eligible apps were categorized by primary purpose, based on how they were described by their developers in the iTunes Store. RESULTS: Our search yielded 10,657 apps, of which 427 met our inclusion criteria. After removing duplicates, 355 unique apps were subject to further review. We assigned the eligible apps to three distinct categories: 39/355 apps (11.0%) were intended for use by medical professionals, 236 apps (66.5%, 236/355) were intended for use by lay people, and 80 apps (22.5%, 80/355) were intended for marketing eye care and eye-care products. We identified 9 subcategories of apps based on the descriptions of their primary functions. Apps for medical professionals fell into three subcategories: clinical calculators (n=6), clinical diagnostic tools (n=18), and education and networking apps for professionals (n=15). Apps for lay people fell into four subcategories: self testing (n=153), eye exercises (n=30), patient tools and low vision aids (n=35), and apps for patient education (n=18). Mixed-use apps (n=80) were placed into two subcategories: marketing of individual practitioners or eye-care products (n=72) and marketing of multiple eye-care products or professional services. CONCLUSIONS: The most extensive subcategory pertaining to eye care consisted of apps for use by lay people, especially for conducting self-tests (n=236). This study revealed a previously uncharacterized category of apps intended for use by doctors and patients, of which the primary goal is marketing of eye-care services and products (n=80). PMID- 28615155 TI - Experiences From Developing and Upgrading a Web-Based Surveillance System for Malaria Elimination in Cambodia. AB - Strengthening the surveillance component is key toward achieving country-wide malaria elimination in Cambodia. A Web-based upgraded malaria information system (MIS) was deemed to essentially act as the central component for surveillance strengthening. New functionality (eg, data visualization) and operational (eg, data quality) attributes of the system received particular attention. However, building from the lessons learned in previous systems' developments, other aspects unique to Cambodia were considered to be equally important; for instance, feasibility issues, particularly at the field level (eg, user acceptability at various health levels), and sustainability needs (eg, long-term system flexibility). The Cambodian process of identifying the essential changes and critical attributes for this new information system can provide a model for other countries at various stages of the disease control and elimination continuum. Sharing these experiences not only facilitates the establishment of "best practices" but also accelerates global and regional malaria elimination efforts. In this article, Cambodia's experience in developing and upgrading its MIS to remain responsive to country-specific needs demonstrates the necessity for considering functionality, operationalization, feasibility, and sustainability of an information system in the context of malaria elimination. PMID- 28615156 TI - Dr Google Is Here to Stay but Health Care Professionals Are Still Valued: An Analysis of Health Care Consumers' Internet Navigation Support Preferences. AB - BACKGROUND: The Internet offers great opportunities for consumers to be informed about their health. However, concerns have been raised regarding its impact on the traditional health consumer-health professional relationship. Our recent survey of 400 Australian adults identified that over half of consumers required some form of navigational support in locating appropriate Web-based health information. We propose that support provided by health professionals would be preferred by consumers; this preference is regardless of whether consumers have a need for navigational support. Secondary analysis of the survey dataset is presented here to quantify consumer-reported support preferences and barriers when navigating Web-based health information. OBJECTIVE: We aimed to quantitatively identify consumers' support preferences for locating Web-based health information and their barriers when navigating Web-based health information. We also aimed to compare such preferences and barriers between consumers identified as needing and not needing support when locating Web-based health information. METHODS: Chi-square (chi2) tests identified whether each listed support preference differed between subgroups of consumers classified as needing (n=205, 51.3%) or not needing (n=195, 48.8%) navigational support; degree of association, via phi coefficient (phi) tests, were also considered to ascertain the likely practical significance of any differences. This was repeated for each listed barrier. Free-text responses regarding additional support preferences were descriptively analyzed and compared with the quantitative findings to provide a richer understanding of desired support for health information searches. RESULTS: Of the 400 respondents, the most preferred mode of navigational support was involvement of health professionals; this was reported by participants identified as needing and not needing navigational support. While there was a significant difference between groups, the degree of association was small (chi21 [N=400]=13.2; P<.001; phi=.18). Qualitative data from the free-text responses supported consumers' desire for health professional involvement. The two most commonly reported barriers when navigating desired Web-based health information were (1) volume of available information and (2) inconsistency of information between sources; these were reported by participants with and without a need for navigational support. While participants identified with a need for navigational support were more likely to report volume (chi21 [N=387]= 4.40; P=.04; phi=.11) and inconsistency of information (chi21 [N=387]= 16.10, P<.001, phi=.20) as barriers, the degrees of association were small to moderate. CONCLUSIONS: Despite concerns in the literature that the popularity of the Internet could compromise the health consumer-health professional relationship, our findings suggest the contrary. Our findings showed that health professionals were found to be the most commonly preferred mode of navigational support, even among consumers classified as not needing navigational support. Further research into how health professionals could assist consumers with Web-based health information seeking could strengthen the health consumer-health professional relationship amidst the growing use of "Dr Google." PMID- 28615157 TI - Designing, Prototyping and Evaluating Digital Mindfulness Applications: A Case Study of Mindful Breathing for Stress Reduction. AB - BACKGROUND: During the past decade, there has been a rapid increase of interactive apps designed for health and well-being. Yet, little research has been published on developing frameworks for design and evaluation of digital mindfulness facilitating technologies. Moreover, many existing digital mindfulness applications are purely software based. There is room for further exploration and assessment of designs that make more use of physical qualities of artifacts. OBJECTIVE: The study aimed to develop and test a new physical digital mindfulness prototype designed for stress reduction. METHODS: In this case study, we designed, developed, and evaluated HU, a physical digital mindfulness prototype designed for stress reduction. In the first phase, we used vapor and light to support mindful breathing and invited 25 participants through snowball sampling to test HU. In the second phase, we added sonification. We deployed a package of probes such as photos, diaries, and cards to collect data from users who explored HU in their homes. Thereafter, we evaluated our installation using both self-assessed stress levels and heart rate (HR) and heart rate variability (HRV) measures in a pilot study, in order to measure stress resilience effects. After the experiment, we performed a semistructured interview to reflect on HU and investigate the design of digital mindfulness apps for stress reduction. RESULTS: The results of the first phase showed that 22 of 25 participants (88%) claimed vapor and light could be effective ways of promoting mindful breathing. Vapor could potentially support mindful breathing better than light (especially for mindfulness beginners). In addition, a majority of the participants mentioned sound as an alternative medium. In the second phase, we found that participants thought that HU could work well for stress reduction. We compared the effect of silent HU (using light and vapor without sound) and sonified HU on 5 participants. Subjective stress levels were statistically improved with both silent and sonified HU. The mean value of HR using silent HU was significantly lower than resting baseline and sonified HU. The mean value of root mean square of differences (RMSSD) using silent HU was significantly higher than resting baseline. We found that the differences between our objective and subjective assessments were intriguing and prompted us to investigate them further. CONCLUSIONS: Our evaluation of HU indicated that HU could facilitate relaxed breathing and stress reduction. There was a difference in outcome between the physiological measures of stress and the subjective reports of stress, as well as a large intervariability among study participants. Our conclusion is that the use of stress reduction tools should be customized and that the design work of mindfulness technology for stress reduction is a complex process, which requires cooperation of designers, HCI (Human-Computer Interaction) experts and clinicians. PMID- 28615158 TI - Somatosensory Modulation of Salivary Gene Expression and Oral Feeding in Preterm Infants: Randomized Controlled Trial. AB - BACKGROUND: Despite numerous medical advances in the care of at-risk preterm neonates, oral feeding still represents one of the first and most advanced neurological challenges facing this delicate population. Objective, quantitative, and noninvasive assessment tools, as well as neurotherapeutic strategies, are greatly needed in order to improve feeding and developmental outcomes. Pulsed pneumatic orocutaneous stimulation has been shown to improve nonnutritive sucking (NNS) skills in preterm infants who exhibit delayed or disordered nipple feeding behaviors. Separately, the study of the salivary transcriptome in neonates has helped identify biomarkers directly linked to successful neonatal oral feeding behavior. The combination of noninvasive treatment strategies and transcriptomic analysis represents an integrative approach to oral feeding in which rapid technological advances and personalized transcriptomics can safely and noninvasively be brought to the bedside to inform medical care decisions and improve care and outcomes. OBJECTIVE: The study aimed to conduct a multicenter randomized control trial (RCT) to combine molecular and behavioral methods in an experimental conceptualization approach to map the effects of PULSED somatosensory stimulation on salivary gene expression in the context of the acquisition of oral feeding habits in high-risk human neonates. The aims of this study represent the first attempt to combine noninvasive treatment strategies and transcriptomic assessments of high-risk extremely preterm infants (EPI) to (1) improve oral feeding behavior and skills, (2) further our understanding of the gene ontology of biologically diverse pathways related to oral feeding, (3) use gene expression data to personalize neonatal care and individualize treatment strategies and timing interventions, and (4) improve long-term developmental outcomes. METHODS: A total of 180 extremely preterm infants from three neonatal intensive care units (NICUs) will be randomized to receive either PULSED or SHAM (non-pulsing) orocutaneous intervention simultaneous with tube feedings 3 times per day for 4 weeks, beginning at 30 weeks postconceptional age. Infants will also be assessed 3 times per week for NNS performance, and multiple saliva samples will be obtained each week for transcriptomic analysis, until infants have achieved full oral feeding status. At 18 months corrected age (CA), infants will undergo neurodevelopmental follow-up testing, the results of which will be correlated with feeding outcomes in the neo-and post-natal period and with gene expression data and intervention status. RESULTS: The ongoing National Institutes of Health funded randomized controlled trial R01HD086088 is actively recruiting participants. The expected completion date of the study is 2021. CONCLUSIONS: Differential salivary gene expression profiles in response to orosensory entrainment intervention are expected to lead to the development of individualized interventions for the diagnosis and management of oral feeding in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT02696343; https://clinicaltrials.gov/ct2/show/NCT02696343 (Archived by WebCite at http://www.webcitation.org/6r5NbJ9Ym). PMID- 28615159 TI - Mobile Health in Oncology: A Patient Survey About App-Assisted Cancer Care. AB - BACKGROUND: In the last decade, the health care sector has been enriched by numerous innovations such as apps and connected devices that assist users in weight reduction and diabetes management. However, only a few native apps in the oncological context exist, which support patients during treatment and aftercare. OBJECTIVE: The objective of this study was to analyze patients' acceptance regarding app use and to investigate the functions of an oncological app that are most required, and the primary reasons for patients to refuse app-assisted cancer care. METHODS: We designed and conducted a survey with 23 questions, inquiring patients about their technical knowledge and equipment, as well as the possible advantages and disadvantages, data transfer, and general functionality of an app. RESULTS: A total of 375 patients participated; the participation rate was 60.7% (375/618). Gender distribution was about 3:4 (female:male) with a median age of 59 years (range 18-92 years). Whereas 69.6% (261/375) of patients used mobile devices, 16.3% (61/375) did not own one, and 9.1% (34/375) only used a personal computer (PC). About half of the patients rated their usability skills as very good and good (18.9% 71/375; 35.2% 132/375), 23.5% (88/375) described their skills as intermediate, and 14.4% (54/375) as bad. Of all patients, 182 (48.5%, 182/375) were willing to send data to their treating clinic via an app, that is, to a server (61.0% 111/182) or as email (33.5%, 61/182). About two-thirds (68.7%, 125/182) believed that additional and regularly sent data would be an ideal complement to the standard follow-up procedure. Additionally, 86.8% (158/182) wished to be contacted by a physician when entered data showed irregularities. Because of lack of skills (34.4%, 56/163), concerns about the use of data (35.0%, 57/163), lack of capable devices (25.8%, 42/163), and the wish for personal contact with the treating physician (47.2%, 77/163), a total of 163 (43.5%, 163/375) patients refused to use an app. Pearson correlation showed a significant but mild relationship between age and app use (P=.03, r=-.12), favoring younger age; male gender correlated as well (P=.04; r=-.11). CONCLUSIONS: The results show that the introduction of mobile apps needs to follow different strategies depending on the patients' attitude. Age and gender seem to be the strongest predictive factors. For oncology patients, our survey showed that about half of the patients were willing to send data via an app supporting their treatment. In the future, clinical data such as quality of life and treatment satisfaction recorded by mobile health (mHealth) devices could be used to evaluate and improve therapy workflow. Furthermore, apps could support classical visits, document adverse effects, and remind patients of treatment dates or drug intake. PMID- 28615160 TI - Nkx2.5 is essential to establish normal heart rate variability in the zebrafish embryo. AB - Heart rate variability (HRV) has become an important clinical marker of cardiovascular health and a research measure for the study of the cardiac conduction system and its autonomic controls. While the zebrafish (Danio rerio) is an ideal vertebrate model for understanding heart development, HRV has only recently been investigated in this system. We have previously demonstrated that nkx2.5 and nkx2.7, two homologues of Nkx2-5 expressed in zebrafish cardiomyocytes, play vital roles in maintaining cardiac chamber-specific characteristics. Given observed defects in ventricular and atrial chamber identities in nkx2.5-/- embryos coupled with conduction system abnormalities in murine models of Nkx2.5 insufficiency, we postulated that reduced HRV would serve as a marker of poor cardiac health in nkx2.5 mutants and in other zebrafish models of human congenital heart disease. Using live video image acquisition, we derived beat-to-beat intervals to compare HRV in wild-type and nkx2.5-/- embryos. Our data illustrate that the nkx2.5 loss-of-function model exhibits increased heart rate and decreased HRV when compared with wild type during embryogenesis. These findings validate HRV analysis as a useful quantitative tool for assessment of cardiac health in zebrafish and underscore the importance of nkx2.5 in maintaining normal heart rate and HRV during early conduction system development. PMID- 28615161 TI - High glucose increases action potential firing of catecholamine neurons in the nucleus of the solitary tract by increasing spontaneous glutamate inputs. AB - Glucose is a crucial substrate essential for cell survival and function. Changes in glucose levels impact neuronal activity and glucose deprivation increases feeding. Several brain regions have been shown to respond to glucoprivation, including the nucleus of the solitary tract (NTS) in the brain stem. The NTS is the primary site in the brain that receives visceral afferent information from the gastrointestinal tract. The catecholaminergic (CA) subpopulation within the NTS modulates many homeostatic functions including cardiovascular reflexes, respiration, food intake, arousal, and stress. However, it is not known if they respond to changes in glucose. Here we determined whether NTS-CA neurons respond to changes in glucose concentration and the mechanism involved. We found that decreasing glucose concentrations from 5 mM to 2 mM to 1 mM, significantly decreased action potential firing in a cell-attached preparation, whereas increasing it back to 5 mM increased the firing rate. This effect was dependent on glutamate release from afferent terminals and required presynaptic 5-HT3Rs. Decreasing the glucose concentration also decreased both basal and 5-HT3R agonist induced increase in the frequency of spontaneous glutamate inputs onto NTS-CA neurons. Low glucose also blunted 5-HT-induced inward currents in nodose ganglia neurons, which are the cell bodies of vagal afferents. The effect of low glucose in both nodose ganglia cells and in NTS slices was mimicked by the glucokinase inhibitor glucosamine. This study suggests that NTS-CA neurons are glucosensing through a presynaptic mechanism that is dependent on vagal glutamate release, 5 HT3R activity, and glucokinase. PMID- 28615162 TI - Characterization of muscle ankyrin repeat proteins in human skeletal muscle. AB - Muscle ankyrin repeat proteins (MARPs) are a family of titin-associated, stress response molecules and putative transducers of stretch-induced signaling in skeletal muscle. In cardiac muscle, cardiac ankyrin repeat protein (CARP) and diabetes-related ankyrin repeat protein (DARP) reportedly redistribute from binding sites on titin to the nucleus following a prolonged stretch. However, it is unclear whether ankyrin repeat domain protein 2 (Ankrd 2) shows comparable stretch-induced redistribution to the nucleus. We measured the following in rested human skeletal muscle: 1) the absolute amount of MARPs and 2) the distribution of Ankrd 2 and DARP in both single fibers and whole muscle preparations. In absolute amounts, Ankrd 2 is the most abundant MARP in human skeletal muscle, there being ~3.1 umol/kg, much greater than DARP and CARP (~0.11 and ~0.02 umol/kg, respectively). All DARP was found to be tightly bound at cytoskeletal (or possibly nuclear) sites. In contrast, ~70% of the total Ankrd 2 is freely diffusible in the cytosol [including virtually all of the phosphorylated (p)Ankrd 2-Ser99 form], ~15% is bound to non-nuclear membranes, and ~15% is bound at cytoskeletal sites, likely at the N2A region of titin. These data are not consistent with the proposal that Ankrd 2, per se, or pAnkrd 2-Ser99 mediates stretch-induced signaling in skeletal muscle, dissociating from titin and translocating to the nucleus, because the majority of these forms of Ankrd 2 are already free in the cytosol. It will be necessary to show that the titin associated Ankrd 2 is modified by stretch in some as-yet-unidentified way, distinct from the diffusible pool, if it is to act as a stretch-sensitive signaling molecule. PMID- 28615163 TI - Understanding mechanisms and seeking cures for Alzheimer's disease: why we must be "extraordinarily diverse". AB - After more than a century since Dr. Alois Alzheimer first described the pathological hallmarks accompanying the defining clinical features of the disease, we have yet to deliver any meaningful disease-modifying treatments to our patients. In this article, I present a rationale for the need to be "extraordinarily diverse" in seeking effective ways to treat or prevent this devastating disease. This approach is based on applying a systems-biology perspective at the population level, using a diverse array of "OMICS" methodologies to identify molecular mechanisms associated with well-established AD risk factors including systemic inflammation, obesity, and insulin resistance. We believe that applying this strategy to understand longitudinal changes in human physiology during aging is of paramount importance in identifying meaningful opportunities to intervene effectively in AD. PMID- 28615164 TI - London mayor, Sadiq Khan: how cities can act on air pollution. PMID- 28615165 TI - Most London hospitals and clinics exceed air pollution limits. PMID- 28615166 TI - Ayman Jundi: Syria never leaves you. PMID- 28615167 TI - Drugs with FDA accelerated approval often have weak evidence, study finds. PMID- 28615168 TI - Medicine is still a victim of war: we desperately need new ideas. PMID- 28615170 TI - Air pollution in the UK: better ways to solve the problem. PMID- 28615172 TI - Every breath we take. PMID- 28615173 TI - Risk of major congenital malformations in relation to maternal overweight and obesity severity: cohort study of 1.2 million singletons. AB - Objective To estimate the risks of major congenital malformations in the offspring of mothers who are underweight (body mass index (BMI) <18.5), overweight (BMI 25 to <30), or in obesity classes I (BMI 30 to <35), II (35 to <40), or III (>=40) compared with offspring of normal weight mothers (BMI 18.5 to <25) in early pregnancy.Design Population based cohort study.Setting Nationwide Swedish registries.Participants 1 243 957 liveborn singleton infants from 2001 to 2014 in Sweden. Data on maternal and pregnancy characteristics were obtained by individual record linkages.Exposure Maternal BMI at the first prenatal visit.Main outcome measures Offspring with any major congenital malformation, and subgroups of organ specific malformations diagnosed during the first year of life. Risk ratios were estimated using generalised linear models adjusted for maternal factors, sex of offspring, and birth year.Results A total of 43 550 (3.5%) offspring had any major congenital malformation, and the most common subgroup was for congenital heart defects (n=20 074; 1.6%). Compared with offspring of normal weight mothers (risk of malformations 3.4%), the proportions and adjusted risk ratios of any major congenital malformation among the offspring of mothers with higher BMI were: overweight, 3.5% and 1.05 (95% confidence interval 1.02 to 1.07); obesity class I, 3.8% and 1.12 (1.08 to 1.15), obesity class II, 4.2% and 1.23 (1.17 to 1.30), and obesity class III, 4.7% and 1.37 (1.26 to 1.49). The risks of congenital heart defects, malformations of the nervous system, and limb defects also progressively increased with BMI from overweight to obesity class III. The largest organ specific relative risks related to maternal overweight and increasing obesity were observed for malformations of the nervous system. Malformations of the genital and digestive systems were also increased in offspring of obese mothers.Conclusions Risks of any major congenital malformation and several subgroups of organ specific malformations progressively increased with maternal overweight and increasing severity of obesity. For women who are planning pregnancy, efforts should be encouraged to reduce adiposity in those with a BMI above the normal range. PMID- 28615174 TI - Supreme Court rejects Northern Irish woman's appeal for NHS abortion in England. PMID- 28615175 TI - Air pollution--a wicked problem. PMID- 28615176 TI - A Novel, 5-Minute, Multisensory Training Session to Teach High-Quality Cardiopulmonary Resuscitation to the Public: Alive in Five. PMID- 28615177 TI - Direct Transport to a Percutaneous Cardiac Intervention Center and Outcomes in Patients With Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Practice guidelines recommend regional systems of care for out-of hospital cardiac arrest. However, whether emergency medical services should bypass nonpercutaneous cardiac intervention (non-PCI) facilities and transport out-of-hospital cardiac arrest patients directly to PCI centers despite longer transport time remains unknown. METHODS AND RESULTS: Using the Cardiac Arrest Registry to Enhance Survival with geocoding of arrest location, we identified out of-hospital cardiac arrest patients with prehospital return of spontaneous circulation and evaluated the association between direct transport to a PCI center and outcomes in North Carolina during 2012 to 2014. Destination hospital was classified according to PCI center status (catheterization laboratory immediately accessible 24/7). Inverse probability-weighted logistic regression accounting for age, sex, emergency medical services response time, clustering of county, transport time to nearest PCI center, initial heart rhythm, and prehospital ECG information was performed. Of 1507 patients with prehospital return of spontaneous circulation, 1359 (90.2%) were transported to PCI centers, of whom 873 (57.9%) bypassed the nearest non-PCI hospital and 148 (9.8%) were transported to non-PCI hospitals. Discharge survival was higher among those transported to PCI centers (33.5% versus 14.6%; adjusted odds ratio, 2.47; 95% confidence interval, 2.08-2.92). Compared with patients taken to non-PCI hospitals, odds of survival were higher for patients taken to the nearest hospital with PCI center status (odds ratio, 3.07; 95% confidence interval, 1.90 4.97) and for patients bypassing closer hospitals to PCI centers (odds ratio, 3.02; 95% confidence interval, 2.01-4.53). Adjusted survival remained significantly better across transport times of 1 to 5, 6 to 10, 11 to 20, 21 to 30, and >30 minutes. CONCLUSIONS: Direct transport to a PCI center is associated with better outcomes for out-of-hospital cardiac arrest patients, even when bypassing nearest hospital and regardless of transport time. PMID- 28615178 TI - Author's reply to Singh and Devi. PMID- 28615179 TI - Do doctors have a duty to take part in pragmatic randomised trials? PMID- 28615180 TI - David Burns Moffat. PMID- 28615181 TI - Fifteen-minute consultation: Communicating with young people-how to use HEEADSSS, a psychosocial interview for adolescents. AB - Adolescents undergo a period of biological, social and psychosocial development, and each of these domains impacts each other. Psychosocial areas of concern often emerge over the adolescent period (such as mental health conditions, drug use and risky sexual behaviour); those with chronic illness being at higher risk. The paper aims to guide health practitioners on when and how to approach the psychosocial interview with young people and assess areas of risk or concern. This will include putting them at ease, developing rapport, seeing them alone and explaining confidentiality before commencing the assessment. Home, Education/Employment, Eating, Activities, Drugs, Sexuality, Suicidal ideation and Safety (HEEADSSS) is a recognised psychosocial interview framework that allows a better understanding of the young person's situation and what their specific needs may be. By exploring each section in turn briefly or more fully, it gives the professional an overall impression of the young person's life and any risky behaviours or concerns. This systematic structure should develop an easily accessible approach to adolescents as a group of patients whatever their developmental stage. PMID- 28615182 TI - Fifteen-minute consultation: Pain relief for children made simple-a pragmatic approach to prescribing oral analgesia in the postcodeine era. AB - What are the most effective doses of simple oral analgesics such as paracetamol and ibuprofen for pain relief in children? Why can't I prescribe codeine phosphate for children anymore? Is oral morphine really a safe alternative to codeine phosphate, and if so what dose should I prescribe? These questions are frequently asked by clinicians who wish to give analgesics to children for pain relief. In this article I will address these questions and describe a pragmatic approach for pain relief using oral analgesics based on the best evidence available and my experience as a consultant paediatric anaesthetist. PMID- 28615183 TI - Public health for paediatricians: promoting good health for children in the early years. PMID- 28615184 TI - Mixed methods research: expanding the evidence base. PMID- 28615185 TI - Hormone replacement treatment choices in complete androgen insensitivity syndrome: an audit of an adult clinic. AB - OBJECTIVE: To review the treatment choices of women with complete androgen insensitivity syndrome (CAIS) at a single tertiary centre. DESIGN: Retrospective review. PATIENTS: Women with CAIS identified from our database. RESULTS: The study group comprised 141 women with CAIS. Eleven percent (16/141) of women had gonads in situ, 3 of whom were under workup for gonadectomy. The age of gonadectomy in the remainder 125 women was 17 (0.1-53) years. The most common form of HRT was oral oestrogen or transdermal oestrogen in 80% (113/141). 13/141 (9%) women used vaginal oestrogens alone or together with other forms of HRT. Testosterone preparations had been used by 17% (24/141) of women and were currently used in 10% (14/141). Of those who had used testosterone, 42% (10/24) had chosen not to continue after a therapeutic trial. CONCLUSIONS: In a clinic offering individualised multidisciplinary care for women with CAIS, we found that the majority of women chose oestrogen-based treatment while a significant minority used testosterone. PMID- 28615186 TI - Subclinical hypothyroidism in paediatric population treated with levothyroxine: a real-world study on 2001-2014 Italian administrative data. AB - OBJECTIVE: To estimate the prevalence of subclinical hypothyroidism (SH) among children, by using levothyroxine low dosage as disease proxy, and to describe prescription pattern. DESIGN: An historical cohort study was performed through administrative databases of 12 Italian Local Health Units covering 3,079,141 inhabitants. A cohort of children (aged 0-13 years) was selected in the period 2001-2014. A subgroup of new users (aged 0-9 years) was identified and followed up for 5 years. METHODS: The prevalence was provided as mean value of the whole period, as annual trend, by patient gender and age. Demographic details, information on levothyroxine dosage, comorbidities and co-medications were provided. Therapy duration and medication persistence were evaluated among new users. RESULTS: 644 children treated with levothyroxine low dosage was selected, with a mean annual prevalence of 0.20 per 1000 children. The temporal trend of prevalence was stable, with a slight reduction in the 2005-2008. Prevalence by age showed an increase after 10 years. Patients were treated with an average annual dose of 4290 ug/year and 66.9% of children were affected by comorbidities. Among 197 new users, 62.9% received therapy only for one year, whereas out of those treated two or more years, 89.0% resulted persistent to the therapy. CONCLUSIONS: This study provides real-world epidemiology of SH among children, and it depicts the clinical and therapeutic characteristics of these subjects. Its findings showed that the SH treatment of this disorder was widely variable, also due to lack of evidence concerning paediatric population. PMID- 28615187 TI - Correction. PMID- 28615188 TI - Using Patient-Reported Measures in Dialysis Clinics. PMID- 28615190 TI - Sixty seconds on . . . natural caesarean. PMID- 28615191 TI - Bryan Furnass. PMID- 28615189 TI - Bar-coding neurodegeneration: identifying subcellular effects of human neurodegenerative disease proteins using Drosophila leg neurons. AB - Genetic, biochemical and histological studies have identified a number of different proteins as key drivers of human neurodegenerative diseases. Although different proteins are typically involved in different diseases, there is also considerable overlap. Addressing disease protein dysfunction in an in vivo neuronal context is often time consuming and requires labor-intensive analysis of transgenic models. To facilitate the rapid, cellular analysis of disease protein dysfunction, we have developed a fruit fly (Drosophila melanogaster) adult leg neuron assay. We tested the robustness of 41 transgenic fluorescent reporters and identified a number that were readily detected in the legs and could report on different cellular events. To test these reporters, we expressed a number of human proteins involved in neurodegenerative disease, in both their mutated and wild-type versions, to address the effects on reporter expression and localization. We observed strikingly different effects of the different disease proteins upon the various reporters with, for example, Abeta1-42 being highly neurotoxic, tau, parkin and HTT128Q affecting mitochondrial distribution, integrity or both, and Abeta1-42, tau, HTT128Q and ATX182Q affecting the F-actin network. This study provides proof of concept for using the Drosophila adult leg for inexpensive and rapid analysis of cellular effects of neurodegenerative disease proteins in mature neurons. PMID- 28615192 TI - Access to hyperacute stroke services across Canadian provinces: a geospatial analysis. AB - BACKGROUND: Canada's vast geography creates challenges for ensuring prompt transport to hospital of patients who have had a stroke. We sought to determine the proportion of people across various Canadian provinces for whom hyperacute stroke services are accessible within evidence-based time targets. METHODS: We calculated, for the 8 provinces with available data, drive-time polygons on a map of Canada that delineated the area around stroke centres and emergency medical services (EMS) base centres to which one can drive in 3.5-6 hours. We calculated the proportional area of each forward sortation area (first 3 digits of the postal code) contained within a drive-time polygon. We applied this ratio to the 2011 Canadian census population of the forward sortation area to estimate the population that can reach a stroke centre in a designated time. RESULTS: A total of 47.1%-96.4% of Canadians live within a 4.5-hour drive to a stroke centre via road EMS, and 53.3%-96.8% live within a 6-hour drive. Assuming a total travel time of 5 hours by EMS from base centre to patient and patient to hospital, 84.7% 99.8% of the population has access to a current or proposed endovascular thrombectomy site. INTERPRETATION: Most Canadians live within 6 hours' road access to a stroke centre. Geospatial mapping could be used to inform decisions for additional sites and identify gaps in service accessibility. Coordinated systems of care and ambulance bypass agreements must continue to evolve to ensure maximal access to time-sensitive emergency stroke services. PMID- 28615193 TI - Health Spending By State 1991-2014: Measuring Per Capita Spending By Payers And Programs. AB - As the US health sector evolves and changes, it is informative to estimate and analyze health spending trends at the state level. These estimates, which provide information about consumption of health care by residents of a state, serve as a baseline for state and national-level policy discussions. This study examines per capita health spending by state of residence and per enrollee spending for the three largest payers (Medicare, Medicaid, and private health insurance) through 2014. Moreover, it discusses in detail the impacts of the Affordable Care Act implementation and the most recent economic recession and recovery on health spending at the state level. According to this analysis, these factors affected overall annual growth in state health spending and the payers and programs that paid for that care. They did not, however, substantially change state rankings based on per capita spending levels over the period. PMID- 28615195 TI - A stitch in time: Replicate early and escape dosage compensation to express more. AB - The biological significance of conserved replication timing patterns in eukaryotic genomes remains a mystery. In this issue, Muller and Nieduszynski (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201701061) find that early replication is a requirement for the highest expression levels of certain genes. PMID- 28615194 TI - Fusion, fission, and transport control asymmetric inheritance of mitochondria and protein aggregates. AB - Partitioning of cell organelles and cytoplasmic components determines the fate of daughter cells upon asymmetric division. We studied the role of mitochondria in this process using budding yeast as a model. Anterograde mitochondrial transport is mediated by the myosin motor, Myo2. A genetic screen revealed an unexpected interaction of MYO2 and genes required for mitochondrial fusion. Genetic analyses, live-cell microscopy, and simulations in silico showed that fused mitochondria become critical for inheritance and transport across the bud neck in myo2 mutants. Similarly, fused mitochondria are essential for retention in the mother when bud-directed transport is enforced. Inheritance of a less than critical mitochondrial quantity causes a severe decline of replicative life span of daughter cells. Myo2-dependent mitochondrial distribution also is critical for the capture of heat stress-induced cytosolic protein aggregates and their retention in the mother cell. Together, these data suggest that coordination of mitochondrial transport, fusion, and fission is critical for asymmetric division and rejuvenation of daughter cells. PMID- 28615196 TI - Withdrawing clinically assisted nutrition and hydration (CANH) in patients with prolonged disorders of consciousness: is there still a role for the courts? AB - Currently, in England and Wales, Court of Protection's Practice Directive 9E (PD9E) requires all cases of proposed withdrawal or withholding of life sustaining treatment in relation to adults in a permanent vegetative state (PVS) or minimally conscious state be referred to the Court. This paper looks at the origins of PD9E and contrasts the routine requirement to refer cases to court with the complex clinical terrain that comprises those suffering from prolonged disorders of consciousness. We look at the role of the court in decision making in these contexts and we ask what role the courts are called on to play in these decisions. We argue that PD9E, as currently drafted, is too imprecise to achieve its purpose. With our focus always on the best interests of patients, we argue that most decisions of this nature should be made according to a strict protocol but without the need for court approval. Court overview should be reserved for cases of disagreement between those involved in the decision that cannot be resolved by other methods, where there are serious doubts about the individual's best interests or where there are legally untested aspects to the decision. PMID- 28615197 TI - Microtubule Regulation and Function during Virus Infection. AB - Microtubules (MTs) form a rapidly adaptable network of filaments that radiate throughout the cell. These dynamic arrays facilitate a wide range of cellular processes, including the capture, transport, and spatial organization of cargos and organelles, as well as changes in cell shape, polarity, and motility. Nucleating from MT-organizing centers, including but by no means limited to the centrosome, MTs undergo rapid transitions through phases of growth, pause, and catastrophe, continuously exploring and adapting to the intracellular environment. Subsets of MTs can become stabilized in response to environmental cues, acquiring distinguishing posttranslational modifications and performing discrete functions as specialized tracks for cargo trafficking. The dynamic behavior and organization of the MT array is regulated by MT-associated proteins (MAPs), which include a subset of highly specialized plus-end-tracking proteins (+TIPs) that respond to signaling cues to alter MT behavior. As pathogenic cargos, viruses require MTs to transport to and from their intracellular sites of replication. While interactions with and functions for MT motor proteins are well characterized and extensively reviewed for many viruses, this review focuses on MT filaments themselves. Changes in the spatial organization and dynamics of the MT array, mediated by virus- or host-induced changes to MT regulatory proteins, not only play a central role in the intracellular transport of virus particles but also regulate a wider range of processes critical to the outcome of infection. PMID- 28615198 TI - Polymorphic Nature of Human T-Cell Leukemia Virus Type 1 Particle Cores as Revealed through Characterization of a Chronically Infected Cell Line. AB - Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 cell-to-cell transmission is dependent on the release of infectious virus particles into the virological synapse. The HTLV-1 particle structure is still poorly understood, and previous studies analyzed viruses produced by transformed lymphocytic cell lines chronically infected with HTLV-1, particularly the MT-2 cell line, which harbors truncated proviruses and expresses aberrant forms of the Gag protein. In this study, we demonstrate that the chronically infected SP cell line harbors a relatively low number of proviruses, making it a more promising experimental system for the study of the HTLV-1 particle structure. We first identified the genomic sites of integration and characterized the genetic structure of the gag region in each provirus. We also determined that despite encoding a truncated Gag protein, only the full-length Gag protein was incorporated into virus particles. Cryo-transmission electron microscopy analyses of the purified virus particles revealed three classes of particles based upon capsid core morphology: complete cores, incomplete cores, and particles without distinct electron densities that would correlate with the capsid region of a core structure. Observed cores were generally polygonal, and virus particles were on average 115 nm in diameter. These data corroborate particle morphologies previously observed for MT-2 cells and provide evidence that the known poor infectivity of HTLV-1 particles may correlate with HTLV-1 particle populations containing few virus particles possessing a complete capsid core structure.IMPORTANCE Studies of retroviral particle core morphology have demonstrated a correlation between capsid core stability and the relative infectivity of the virus. In this study, we used cryo-transmission electron microscopy to demonstrate that HTLV-1 particles produced from a distinct chronically infected cell line are polymorphic in nature, with many particles lacking organized electron densities that would correlate with a complete core structure. These findings have important implications for infectious HTLV-1 spread, particularly in the context of cell-to-cell transmission, a critical step in HTLV-1 transmission and pathogenesis. PMID- 28615199 TI - Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. AB - HIV-1 Nef clones isolated from a rare subset of HIV-1-infected elite controllers (EC), with the ability to suppress viral load to undetectable levels in the absence of antiretroviral therapy, are unable to fully downregulate CD4 from the plasma membrane of CD4+ T cells. Residual CD4 left at the plasma membrane allows Env-CD4 interaction, which leads to increased exposure of Env CD4-induced epitopes and increases susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated largely by natural killer (NK) cells, which control their activation status through the cumulative signals received through activating and inhibitory receptors. Recently, the activating NKG2D receptor was demonstrated to positively influence ADCC responses. Since HIV 1 Nef has been reported to reduce the expression of NKG2D ligands, we evaluated the relative abilities of Nef from EC and progressors to downmodulate NKG2D ligands. Furthermore, we assessed the impact of EC and progressor Nef on the ADCC susceptibility of HIV-1-infected cells. We observed a significantly increased expression of NKG2D ligands on cells infected with viruses coding for Nef from EC. Importantly, NKG2D ligand expression levels correlated with enhanced susceptibility of HIV-1-infected cells to ADCC. The biological significance of this correlation was corroborated by the demonstration that antibody-mediated blockade of NKG2D significantly reduced ADCC of cells infected with viruses carrying Nef from EC. These results suggest the involvement of NKG2D-NKG2D ligand interactions in the enhanced susceptibility of EC HIV-1-infected cells to ADCC responses.IMPORTANCE Attenuated Nef functions have been reported in HIV-1 isolated from EC. The inability of elite controller Nef to fully remove CD4 from the surface of infected cells enhanced their susceptibility to elimination by ADCC. We now show that downregulation of NKG2D ligands by HIV-1 Nef from EC is inefficient and leaves infected cells susceptible to ADCC. These data suggest a critical role for NKG2D ligands in anti-HIV-1 ADCC responses. PMID- 28615200 TI - Kallikrein-Related Peptidase 5 Contributes to H3N2 Influenza Virus Infection in Human Lungs. AB - Hemagglutinin (HA) of influenza virus must be activated by proteolysis before the virus can become infectious. Previous studies indicated that HA cleavage is driven by membrane-bound or extracellular serine proteases in the respiratory tract. However, there is still uncertainty as to which proteases are critical for activating HAs of seasonal influenza A viruses (IAVs) in humans. This study focuses on human KLK1 and KLK5, 2 of the 15 serine proteases known as the kallikrein-related peptidases (KLKs). We find that their mRNA expression in primary human bronchial cells is stimulated by IAV infection. Both enzymes cleaved recombinant HA from several strains of the H1 and/or H3 virus subtype in vitro, but only KLK5 promoted the infectivity of A/Puerto Rico/8/34 (H1N1) and A/Scotland/20/74 (H3N2) virions in MDCK cells. We assessed the ability of treated viruses to initiate influenza in mice. The nasal instillation of only the KLK5 treated virus resulted in weight loss and lethal outcomes. The secretion of this protease in the human lower respiratory tract is enhanced during influenza. Moreover, we show that pretreatment of airway secretions with a KLK5-selective inhibitor significantly reduced the activation of influenza A/Scotland/20/74 virions, providing further evidence of its importance. Differently, increased KLK1 secretion appeared to be associated with the recruitment of inflammatory cells in human airways regardless of the origin of inflammation. Thus, our findings point to the involvement of KLK5 in the proteolytic activation and spread of seasonal influenza viruses in humans.IMPORTANCE Influenza A viruses (IAVs) cause acute infection of the respiratory tract that affects millions of people during seasonal outbreaks every year. Cleavage of the hemagglutinin precursor by host proteases is a critical step in the life cycle of these viruses. Consequently, host proteases that activate HA can be considered promising targets for the development of new antivirals. However, the specific proteases that activate seasonal influenza viruses, especially H3N2 viruses, in the human respiratory tract have remain undefined despite many years of work. Here we demonstrate that the secreted, extracellular protease KLK5 (kallikrein related peptidase 5) is efficient in promoting the infectivity of H3N2 IAV in vitro and in vivo Furthermore, we found that its secretion was selectively enhanced in the human lower respiratory tract during a seasonal outbreak dominated by an H3N2 virus. Collectively, our data support the clinical relevance of this protease in human influenza pathogenesis. PMID- 28615201 TI - The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression of SUMO/Sentrin-Specific Peptidase 6 To Facilitate Establishment of Latency. AB - Kaposi's sarcoma-associated herpesvirus (KSHV), which belongs to the Gammaherpesviridae, typically displays two different phases in its life cycle, the latent phase and the lytic phase. Latency-associated nuclear antigen (LANA), the primary viral product during latency, has been reported to bind to a series of cellular gene promoters to modulate gene transcription. To systemically elucidate the cellular genes regulated by LANA, we identified genome-wide LANA binding sites by chromatin immunoprecipitation coupled with sequencing (ChIP seq). We stratified ChIP-seq data and found that LANA might be involved in the macromolecule catabolic process. Specifically, we found and verified that LANA could directly bind to the promoter of the SUMO/sentrin-specific peptidase 6 (SENP6) gene in vivo and in vitro LANA could repress SENP6 promoter activity in a dose-dependent manner in a reporter gene assay. LANA expression was sufficient to inhibit endogenous SENP6 expression at both the RNA and protein levels. Moreover, SENP6 overexpression in KSHV-infected cells reduced LANA at the protein level. Mechanistically, we found that SENP6 could interact with LANA and reduce the formation of sumoylated LANA, which relies on the desumoylation ability of SENP6. During de novo infection, SENP6 overexpression would decrease the abundance of LANA and enhance viral gene expression, which would hamper the establishment of latency. Taken together, these data suggest that KSHV-encoded LANA could inhibit SENP6 expression to regulate the abundance of itself, which may play an important role in controlling the establishment of latency.IMPORTANCE LANA, as a key latent protein produced by KSHV, is responsible for episome persistence and regulates viral reactivation. In the present study, our results demonstrated that LANA could bind to the promoter region of the SENP6 gene and inhibit SENP6 expression while the regulated SENP6 could in turn modulate the abundance of LANA through desumoylation. This delicate regulation may provide important insights to explain the abundance of LANA during KSHV latency. PMID- 28615202 TI - Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1. AB - Follicular regulatory T (TFR) cells are a subset of CD4+ T cells in secondary lymphoid follicles. TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1 ex vivo TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 both ex vivo and in vivo This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replication in vivoIMPORTANCE In chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 both ex vivo and in vivo The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment. PMID- 28615203 TI - Phosphorylation of Serine 225 in Hepatitis C Virus NS5A Regulates Protein-Protein Interactions. AB - Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a phosphoprotein that plays key, yet poorly defined, roles in both virus genome replication and virion assembly/release. It has been proposed that differential phosphorylation could act as a switch to regulate the various functions of NS5A; however, the mechanistic details of the role of this posttranslational modification in the virus life cycle remain obscure. We previously reported (D. Ross-Thriepland, J. Mankouri, and M. Harris, J Virol 89:3123-3135, 2015, doi:10.1128/JVI.02995-14) a role for phosphorylation at serine 225 (S225) of NS5A in the regulation of JFH-1 (genotype 2a) genome replication. A phosphoablatant (S225A) mutation resulted in a 10-fold reduction in replication and a perinuclear restricted distribution of NS5A, whereas the corresponding phosphomimetic mutation (S225D) had no phenotype. To determine the molecular mechanisms underpinning this phenotype we conducted a label-free proteomics approach to identify cellular NS5A interaction partners. This analysis revealed that the S225A mutation disrupted the interactions of NS5A with a number of cellular proteins, in particular the nucleosome assembly protein 1-like protein 1 (NAP1L1), bridging integrator 1 (Bin1, also known as amphiphysin II), and vesicle-associated membrane protein-associated protein A (VAP-A). These interactions were validated by immunoprecipitation/Western blotting, immunofluorescence, and proximity ligation assay. Importantly, small interfering RNA (siRNA)-mediated knockdown of NAP1L1, Bin1 or VAP-A impaired viral genome replication and recapitulated the perinuclear redistribution of NS5A seen in the S225A mutant. These results demonstrate that S225 phosphorylation regulates the interactions of NS5A with a defined subset of cellular proteins. Furthermore, these interactions regulate both HCV genome replication and the subcellular localization of replication complexes.IMPORTANCE Hepatitis C virus is an important human pathogen. The viral nonstructural 5A protein (NS5A) is the target for new antiviral drugs. NS5A has multiple functions during the virus life cycle, but the biochemical details of these roles remain obscure. NS5A is known to be phosphorylated by cellular protein kinases, and in this study, we set out to determine whether this modification is required for the binding of NS5A to other cellular proteins. We identified 3 such proteins and show that they interacted only with NS5A that was phosphorylated on a specific residue. Furthermore, these proteins were required for efficient virus replication and the ability of NS5A to spread throughout the cytoplasm of the cell. Our results help to define the function of NS5A and may contribute to an understanding of the mode of action of the highly potent antiviral drugs that are targeted to NS5A. PMID- 28615204 TI - Human Cytomegalovirus IE2 Protein Disturbs Brain Development by the Dysregulation of Neural Stem Cell Maintenance and the Polarization of Migrating Neurons. AB - Despite the high incidence of severe defects in the central nervous system caused by human cytomegalovirus (HCMV) congenital infection, the mechanism of HCMV neuropathogenesis and the roles of individual viral genes have not yet been fully determined. In this study, we show that the immediate-early 2 (IE2) protein may play a key role in HCMV-caused neurodevelopmental disorders. IE2-transduced neural progenitor cells gave rise to neurospheres with a lower frequency and produced smaller neurospheres than control cells in vitro, indicating reduction of self-renewal and expansion of neural progenitors by IE2. At 2 days after in utero electroporation into the ventricle of the developing brain, a dramatically lower percentage of IE2-expressing cells was detected in the ventricular zone (VZ) and cortical plate (CP) compared to control cells, suggesting that IE2 concurrently dysregulates neural stem cell maintenance in the VZ and neuronal migration to the CP. In addition, most IE2+ cells in the lower intermediate zone either showed multipolar morphology with short neurites or possessed nonradially oriented processes, whereas control cells had long, radially oriented monopolar or bipolar neurites. IE2+ callosal axons also failed to cross the midline to form the corpus callosum. Furthermore, we provide molecular evidence that the cell cycle arrest and DNA binding activities of IE2 appear to be responsible for the increased neural stem cell exit from the VZ and cortical migrational defects, respectively. Collectively, our results demonstrate that IE2 disrupts the orderly process of brain development in a stepwise manner to further our understanding of neurodevelopmental HCMV pathogenesis.IMPORTANCE HCMV brain pathogenesis has been studied in limited experimental settings, such as in vitro HCMV infection of neural progenitor cells or in vivo murine CMV infection of the mouse brain. Here, we show that IE2 is a pivotal factor that contributes to HCMV-induced abnormalities in the context of the embryonic brain using an in utero gene transfer tool. Surprisingly, IE2, but not HCMV IE1 or murine CMV ie3, interferes pleiotropically with key neurodevelopmental processes, including neural stem cell regulation, proper positioning of migrating neurons, and the callosal axon projections important for communication between the hemispheres. Our data suggest that the wide spectrum of clinical outcomes, ranging from mental retardation to microcephaly, caused by congenital HCMV infection can be sufficiently explained in terms of IE2 action alone. PMID- 28615205 TI - Intrasubtype B HIV-1 Superinfection Correlates with Delayed Neutralizing Antibody Response. AB - Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses (P = 0.003 for SF-162 and P = 0.017 for NL4-3) and marginally against autologous virus (P = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection.IMPORTANCE Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some superinfected individuals. These findings will inform HIV vaccine design by providing testable correlates of protection from initial HIV infection. PMID- 28615206 TI - Plasticity and Epitope Exposure of the HIV-1 Envelope Trimer. AB - We recently showed that mutations in the HIV-1 envelope (Env) destabilize the V3 loop, rendering neutralization-resistant viruses sensitive to V3-directed monoclonal antibodies (MAbs). Here, we investigated the propagation of this effect on other Env epitopes, with special emphasis on V2 loop exposure. Wild type JR-FL and 19 mutant JR-FL pseudoviruses were tested for neutralization sensitivity to 21 MAbs specific for epitopes in V2, the CD4 binding site (CD4bs), and the CD4-induced (CD4i) region. Certain glycan mutants, mutations in the gp120 hydrophobic core, and mutations in residues involved in intraprotomer interactions exposed epitopes in the V2i region (which overlies the alpha4beta7 integrin binding site) and the V3 crown, suggesting general destabilization of the distal region of the trimer apex. In contrast, other glycan mutants, mutations affecting interprotomer interactions, and mutations affecting the CD4bs exposed V3 but not V2i epitopes. These data indicate for the first time that V3 can move independently of V2, with V3 pivoting out from its "tucked" position in the trimer while apparently leaving the V2 apex intact. Notably, none of the mutations exposed V2 epitopes without also exposing V3, suggesting that movement of V2 releases V3. Most mutations increased sensitivity to CD4bs-directed MAbs without exposure of the CD4i epitope, implying these mutations facilitate the trimers' maintenance of an intermediate energy state between open and closed conformations. Taken together, these data indicate that several transient Env epitopes can be rendered more accessible to antibodies (Abs) via specific mutations, and this may facilitate the design of V1V2-targeting immunogens.IMPORTANCE Many epitopes of the HIV envelope (Env) spike are relatively inaccessible to antibodies (Abs) compared to their exposure in the open Env conformation induced by receptor binding. However, the reduced infection rate that resulted from the vaccine used in the RV144 HIV-1 vaccine trial was correlated with the elicitation of V2- and V3-directed antibodies. Previously, we identified various mechanisms responsible for destabilizing the V3 loop; here, we determined, via mutation of numerous Env residues, which of these elements maintain the V1V2 loop in an inaccessible state and which expose V1V2 and/or V3 epitopes. Notably, our data indicate that V3 can move independently of V2, but none of the mutations studied expose V2 epitopes without also exposing V3. Additionally, V1V2 can be rendered more accessible to Abs via specific mutations, facilitating the development of engineered V2 immunogens. PMID- 28615207 TI - Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells. AB - Recent evidence indicates that inhibition of HIV-1 integrase (IN) binding to the viral RNA genome by allosteric integrase inhibitors (ALLINIs) or through mutations within IN yields aberrant particles in which the viral ribonucleoprotein complexes (vRNPs) are eccentrically localized outside the capsid lattice. These particles are noninfectious and are blocked at an early reverse transcription stage in target cells. However, the basis of this reverse transcription defect is unknown. Here, we show that the viral RNA genome and IN from ALLINI-treated virions are prematurely degraded in target cells, whereas reverse transcriptase remains active and stably associated with the capsid lattice. The aberrantly shaped cores in ALLINI-treated particles can efficiently saturate and be degraded by a restricting TRIM5 protein, indicating that they are still composed of capsid proteins arranged in a hexagonal lattice. Notably, the fates of viral core components follow a similar pattern in cells infected with eccentric particles generated by mutations within IN that inhibit its binding to the viral RNA genome. We propose that IN-RNA interactions allow packaging of both the viral RNA genome and IN within the protective capsid lattice to ensure subsequent reverse transcription and productive infection in target cells. Conversely, disruption of these interactions by ALLINIs or mutations in IN leads to premature degradation of both the viral RNA genome and IN, as well as the spatial separation of reverse transcriptase from the viral genome during early steps of infection.IMPORTANCE Recent evidence indicates that HIV-1 integrase (IN) plays a key role during particle maturation by binding to the viral RNA genome. Inhibition of IN-RNA interactions yields aberrant particles with the viral ribonucleoprotein complexes (vRNPs) eccentrically localized outside the conical capsid lattice. Although these particles contain all of the components necessary for reverse transcription, they are blocked at an early reverse transcription stage in target cells. To explain the basis of this defect, we tracked the fates of multiple viral components in infected cells. Here, we show that the viral RNA genome and IN in eccentric particles are prematurely degraded, whereas reverse transcriptase remains active and stably associated within the capsid lattice. We propose that IN-RNA interactions ensure the packaging of both vRNPs and IN within the protective capsid cores to facilitate subsequent reverse transcription and productive infection in target cells. PMID- 28615208 TI - Deficiency of the NOD-Like Receptor NLRC5 Results in Decreased CD8+ T Cell Function and Impaired Viral Clearance. AB - Pathogen recognition receptors are vital components of the immune system. Engagement of these receptors is important not only for instigation of innate immune responses to invading pathogens but also for initiating the adaptive immune response. Members of the NOD-like receptor (NLR) family of pathogen recognition receptors have important roles in orchestrating this response. The NLR family member NLRC5 regulates major histocompatibility complex class I (MHC I) expression during various types of infections, but its role in immunity to influenza A virus (IAV) is not well studied. Here we show that Nlrc5-/- mice exhibit an altered CD8+ T cell response during IAV infection compared to that of wild-type (WT) mice. Nlrc5-/- mice have decreased MHC-I expression on hematopoietic cells and fewer CD8+ T cells prior to infection. NLRC5 deficiency does not affect the generation of antigen-specific CD8+ T cells following IAV infection; however, a change in epitope dominance is observed in Nlrc5-/- mice. Moreover, IAV-specific CD8+ T cells from Nlrc5-/- mice have impaired effector functions. This change in the adaptive immune response is associated with impaired viral clearance in Nlrc5-/- mice. Collectively, our results demonstrate an important role for NLRC5 in regulation of antiviral immune responses and viral clearance during IAV infection.IMPORTANCE The NOD-like receptor family member NLRC5 is known to regulate expression of MHC-I as well as other genes required for antigen processing. In addition, NLRC5 also regulates various immune signaling pathways. In this study, we investigated the role of NLRC5 during influenza virus infection and found a major role for NLRC5 in restricting virus replication and promoting viral clearance. The observed increases in viral titers in NLRC5-deficient mice correlated with impaired effector CD8+ T cell responses. Although NLRC5-deficient mice were defective at clearing the virus, they did not show an increase in morbidity or mortality following influenza virus infection because of other compensatory immune mechanisms. Therefore, our study highlights how NLRC5 regulates multiple immune effector mechanisms to promote the host defense during influenza virus infection. PMID- 28615209 TI - In Vitro Replication of Chelonid Herpesvirus 5 in Organotypic Skin Cultures from Hawaiian Green Turtles (Chelonia mydas). AB - Fibropapillomatosis (FP) is a tumor disease of marine turtles associated with chelonid herpesvirus 5 (ChHV5), which has historically been refractory to growth in tissue culture. Here we show, for the first time, de novo formation of ChHV5 positive intranuclear inclusions in cultured green turtle cells, which is indicative of active lytic replication of the virus. The minimal requirements to achieve lytic replication in cultured cells included (i) either in vitro cultures of ChHV5-positive tumor biopsy specimens (plugs) or organotypic cultures (rafts) consisting of ChHV5-positive turtle fibroblasts in collagen rafts seeded with turtle keratinocytes and (ii) keratinocyte maturation induced by raising raft or biopsy cultures to the air-liquid interface. Virus growth was confirmed by detailed electron microscopic studies that revealed intranuclear sun-shaped capsid factories, tubules, various stages of capsid formation, nuclear export by budding into the perinuclear space, tegument formation, and envelopment to complete de novo virus production. Membrane synthesis was also observed as a sign of active viral replication. Interestingly, cytoplasmic particles became associated with keratin filaments, a feature not seen in conventional monolayer cell cultures, in which most studies of herpesvirus replication have been performed. Our findings draw a rich and realistic picture of ChHV5 replication in cells derived from its natural host and may be crucial not only to better understand ChHV5 circulation but also to eventually complete Koch's postulates for FP. Moreover, the principles described here may serve as a model for culture of other viruses that are resistant to replication in conventional cell culture.IMPORTANCE A major challenge in virology is the study of viruses that cannot be grown in the laboratory. One example is chelonid herpesvirus 5 (ChHV5), which is associated with fibropapillomatosis, a globally distributed, debilitating, and fatal tumor disease of endangered marine turtles. Pathological examination shows that ChHV5 is shed in skin. Here we show that ChHV5 will grow in vitro if we replicate the complex three-dimensional structure of turtle skin. Moreover, lytic virus growth requires a close interplay between fibroblasts and keratinocytes. Finally, the morphogenesis of herpesviral growth in three dimensional cultures reveals a far richer, and likely more realistic, array of capsid morphologies than that encountered in traditional monolayer cell cultures. Our findings have applications to other viruses, including those of humans. PMID- 28615210 TI - A Conserved Leucine Zipper Motif in Gammaherpesvirus ORF52 Is Critical for Distinct Microtubule Rearrangements. AB - Productive viral infection often depends on the manipulation of the cytoskeleton. Herpesviruses, including rhesus monkey rhadinovirus (RRV) and its close homolog, the oncogenic human gammaherpesvirus Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8), exploit microtubule (MT)-based retrograde transport to deliver their genomes to the nucleus. Subsequently, during the lytic phase of the life cycle, the maturing viral particles undergo orchestrated translocation to specialized regions within the cytoplasm, leading to tegumentation, secondary envelopment, and then egress. As a result, we hypothesized that RRV might induce changes in the cytoskeleton at both early and late stages of infection. Using confocal imaging, we found that RRV infection led to the thickening and acetylation of MTs emanating from the MT-organizing center (MTOC) shortly after viral entry and more pronounced and diffuse MT reorganization during peak stages of lytic gene expression and virion production. We subsequently identified open reading frame 52 (ORF52), a multifunctional and abundant tegument protein, as being the only virally encoded component responsible for these cytoskeletal changes. Mutational and modeling analyses indicated that an evolutionarily conserved, truncated leucine zipper motif near the N terminus as well as a strictly conserved arginine residue toward the C terminus of ORF52 play critical roles in its ability to rearrange the architecture of the MT cytoskeleton. Taken together, our findings combined with data from previous studies describing diverse roles for ORF52 suggest that it likely binds to different cellular components, thereby allowing context-dependent modulation of function.IMPORTANCE A thorough understanding of the processes governing viral infection includes knowledge of how viruses manipulate their intracellular milieu, including the cytoskeleton. Altering the dynamics of actin or MT polymerization, for example, is a common strategy employed by viruses to ensure efficient entry, maturation, and egress as well as the avoidance of antiviral defenses through the sequestration of key cellular factors. We found that infection with RRV, a homolog of the human pathogen KSHV, led to perinuclear wrapping by acetylated MT bundles and identified ORF52 as the viral protein underlying these changes. Remarkably, incoming virions were able to supply sufficient ORF52 to induce MT thickening and acetylation near the MTOC, potentially aiding in the delivery viral genomes to the nucleus. Although the function of MT alterations during late stages of infection requires further study, ORF52 shares functional and structural similarities with alphaherpesvirus VP22, underscoring the evolutionary importance of MT cytoskeletal manipulations for this virus family. PMID- 28615211 TI - Vesicular stomatitis virus pseudotyped with Ebola virus glycoprotein serves as a protective, non-infectious vaccine against Ebola virus challenge in mice. AB - The recent Ebola virus (EBOV) epidemic in West Africa demonstrates the potential for a significant public health burden caused by filoviral infections. No vaccine or antiviral is currently FDA-approved. To expand the vaccine options potentially available, we assessed protection conferred by an EBOV vaccine composed of vesicular stomatitis virus pseudovirions that lack native G glycoprotein (VSVDeltaG) and bear EBOV glycoprotein (GP). These pseudovirions mediate a single round of infection. Both single dose and prime/boost vaccination regimens protected mice against lethal challenge with mouse-adapted Ebola virus (ma-EBOV) in a dose-dependent manner. The prime/boost regimen provided significantly better protection than a single dose. As N-linked glycans are thought to shield conserved regions of the EBOV GP receptor binding domain (RBD) thereby blocking epitopes within the RBD, we also tested if VSVDeltaG bearing EBOV GPs that lack GP1 N-linked glycans provided effective immunity against challenge with ma-EBOV or a more distantly related virus, Sudan virus. Using a prime/boost strategy, high doses of GP/VSVDeltaG partially or fully denuded of N-linked glycans on GP1 protected mice against ma-EBOV challenge, but these mutants were no more effective than WT GP/VSVDeltaG and did not provide cross protection against Sudan virus. As reported for other EBOV vaccine platforms, protection conferred correlated with the quantity of EBOV GP-specific Ig produced, but not the production of neutralizing antibodies. Our results show that EBOV GP/VSVDeltaG pseudovirions serve as a successful vaccination platform in a rodent model of Ebola virus disease and GP1 N-glycan loss does not influence immunogenicity or vaccination success.IMPORTANCE The West African Ebola virus epidemic was the largest to date with more than 28,000 people infected. No FDA-approved vaccines are yet available, but in a trial vaccination strategy in West Africa, recombinant, infectious VSV encoding the Ebola virus glycoprotein effectively prevented virus-associated disease. VSVDeltaG pseudovirion vaccines may prove as efficacious and have better safety, but have not been tested to date. Thus, we test the efficacy of VSVDeltaG pseudovirions bearing Ebola virus glycoprotein as a vaccine platform. We found that wild-type Ebola virus glycoprotein, in the context of this platform, provides robust protection of EBOV challenged mice. Further, we found removal of the heavy glycan shield surrounding conserved regions of the glycoprotein does not enhance vaccine efficacy. PMID- 28615212 TI - Conserved Vdelta1 binding geometry in a setting of locus-disparate pHLA recognition by delta/alphabetaTCRs: insight into recognition of HIV peptides by TCR. AB - Given a limited set of TCR V genes which are used to create TCRs that are reactive to different ligands, such as MHC class I, MHC class II and MHC-like proteins (for example, MIC molecules and CD1 molecules), the Vdelta1 segment can be rearranged with Ddelta-Jdelta-Cdelta or Jalpha-Calpha segments, to form classical gammadeltaTCR or uncommon alphabetaTCR using a Vdelta1 segment (delta/alphabetaTCR). Here we have determined two complex structures of the delta/alphabetaTCRs (S19-2 and TU55) bound to different locus-disparate MHCIs with HIV peptides (HLA-A*2402-Nef138-10 and HLA-B*3501-Pol448-9). The overall binding modes resemble classical alphabetaTCRs, but display a strong tilt binding geometry of Vdelta1 domain towards the HLA alpha1 helix, due to a conserved extensive interaction between the CDR1delta loop and N-terminal region of alpha1 helix (mainly in position 62). The aromatic amino acids of the CDR1delta loop exploit different conformations ("aromatic-ladder" or "aromatic-hairpin") to accommodate distinct MHC helical scaffolds. This tolerance helps to explain how a particular TCR V region can similarly dock onto multiple MHC molecules, and thus, may potentially explain the nature of TCR cross-reactivity. In addition, the length of CDR3delta loop could affect the extent of tilt binding of Vdelta1 domain, and adaptively, the pairing Vbeta domains adjust their mass centers to generate differential MHC contacts, hence probably ensuring the TCR specificity to a certain peptide-MHC. Our data have provided further structural insights into the TCR recognition of classical pMHCI molecules, unifying the cross-reactivity and specificity together.IMPORTANCE The specificity of alphabeta T cell recognition is determined by the CDR loops of the alphabetaTCR and the general binding mode of alphabetaTCRs to pMHC has been established over the last decade. Due to the intrinsic genomic structure of the TCR alpha/delta chain locus, some Vdelta segments can rearrange with Calpha segment, forming a hybrid VdeltaCalphaVbetaCbeta TCR, delta/alphabetaTCR. However, the basis for the molecular recognition of such TCRs to their ligands is elusive. Here, an alphabetaTCR using Vdelta1 segment, S19-2, is isolated from a HIV-infected patient, in an HLA-A*24:02 restricted manner. Then we solved the crystal structures of S19-2 TCR and another delta/alphabetaTCR TU55 binding to their ligands respectively, revealing a conserved Vdelta1 binding feature. Further binding kinetics analysis reveals that the S19-2 and TU55 TCRs bind pHLA very tightly and long-lastingly. Our results illustrate the binding mode of a TCR using Vdelta1 segment to its ligand, virus-derived pHLA. PMID- 28615215 TI - Deconstructing a popular myth: why knee arthroscopy is no better than placebo surgery for degenerative meniscal tears. PMID- 28615213 TI - Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure. AB - BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure. PMID- 28615214 TI - Safety and Efficacy of Rivaroxaban in Patients With Cardiac Implantable Electronic Devices: Observations From the ROCKET AF Trial. AB - BACKGROUND: Although implantation of cardiac implantable electronic devices (CIEDs) in patients receiving warfarin is well studied, limited data are available on the use of oral factor Xa inhibitors in this setting. METHODS AND RESULTS: Using data from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (n=14 264), we compared baseline characteristics and clinical outcomes in patients with atrial fibrillation randomized to rivaroxaban versus warfarin who did and did not undergo CIED implantation or revision. In this post-hoc, postrandomization, on-treatment analysis, only the first intervention per patient was analyzed. During a median follow-up of 2.2 years, 453 patients (242 rivaroxaban group; 211 warfarin group) underwent de novo CIED implantation (64.2%) or revision procedures (35.8%). Patients who received CIEDs were older, more likely to be male, and more likely to have past myocardial infarction, but had similar stroke risk compared to patients who did not receive CIEDs. Most patients who received a device had study drug interrupted for the procedure and did not receive bridging anticoagulation. During the 30-day postprocedural period, 11 patients (4.55%) in the rivaroxaban group experienced bleeding complications compared with 15 (7.13%) in the warfarin group. Thromboembolic complications occurred in 3 patients (1.26%) in the rivaroxaban group and 1 (0.48%) in the warfarin group. Event rates were too low for formal hypothesis testing. CONCLUSIONS: Bleeding and thromboembolic events were low in both rivaroxaban- and warfarin-treated patients. Periprocedural use of oral factor Xa inhibitors in CIED implantation requires further study in prospective, randomized trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767. PMID- 28615216 TI - Emergency response facilities including primary and secondary prevention strategies across 79 professional football clubs in England. AB - AIM: To assess the emergency response planning and prevention strategies for sudden cardiac arrest (SCA) across a wide range of professional football clubs in England. METHODS: A written survey was sent to all professional clubs in the English football league, namely the Premiership, Championship, League 1 and League 2. Outcomes included: (1) number of clubs performing cardiac screening and frequency of screening; (2) emergency planning and documentation; (3) automated external defibrillator (AED) training and availability; and (4) provision of emergency services at sporting venues. RESULTS: 79 clubs (86%) responded to the survey. 100% clubs participated in cardiac screening. All clubs had AEDs available on match days and during training sessions. 100% Premiership clubs provided AED training to designated staff. In contrast, 30% of lower division clubs with AEDs available did not provide formal training. Most clubs (n=66; 83%) reported the existence of an emergency action plan for SCA but formal documentation was variable. All clubs in the Premiership and League 1 provided an ambulance equipped for medical emergencies on match days compared with 75% of clubs in the Championship and 66% in League 2. CONCLUSIONS: The majority of football clubs in England have satisfactory prevention strategies and emergency response planning in line with European recommendations. Additional improvements such as increasing awareness of European guidelines for emergency planning, AED training and mentorship with financial support to lower division clubs are necessary to further enhance cardiovascular safety of athletes and spectators and close the gap between the highest and lower divisions. PMID- 28615217 TI - Reconsidering current objectives for physical activity within physical education. PMID- 28615218 TI - Does leisure time physical activity protect against low back pain? Systematic review and meta-analysis of 36 prospective cohort studies. AB - BACKGROUND: There are plausible mechanisms whereby leisure time physical activity may protect against low back pain (LBP) but there have been no quality systematic reviews and meta-analyses of the subject. OBJECTIVE: This review aims to assess the effect of leisure time physical activity on non-specific LBP. METHODS: Literature searches were conducted in PubMed, Embase, Web of Science, Scopus and Google Scholar databases from their inception through July 2016. Methodological quality of included studies was evaluated. A random-effects meta-analysis was performed, and heterogeneity and publication bias were assessed. RESULTS: Thirty six prospective cohort studies (n=158 475 participants) qualified for meta analyses. Participation in sport or other leisure physical activity reduced the risk of frequent or chronic LBP, but not LBP for > 1 day in the past month or past 6-12 months. Risk of frequent/chronic LBP was 11% lower (adjusted risk ratio (RR)=0.89, CI 0.82 to 0.97, I2=31%, n=48 520) in moderately/highly active individuals, 14% lower (RR=0.86, CI 0.79 to 0.94, I2=0%, n=33 032) in moderately active individuals and 16% lower (RR=0.84, CI 0.75 to 0.93, I2=0%, n=33 032) in highly active individuals in comparison with individuals without regular physical activity. For LBP in the past 1-12 months, adjusted RR was 0.98 (CI 0.93 to 1.03, I2=50%, n=32 654) for moderate/high level of activity, 0.94 (CI 0.84 to 1.05, I2=3%, n=8549) for moderate level of activity and 1.06 (CI 0.89 to 1.25, I2=53%, n=8554) for high level of activity. CONCLUSIONS: Leisure time physical activity may reduce the risk of chronic LBP by 11%-16%. The finding, however, should be interpreted cautiously due to limitations of the original studies. If this effect size is proven in future research, the public health implications would be substantial. PMID- 28615220 TI - Confounding in ex vivo models of Diamond-Blackfan anemia. PMID- 28615219 TI - ZFP521 regulates murine hematopoietic stem cell function and facilitates MLL-AF9 leukemogenesis in mouse and human cells. AB - The concept that tumor-initiating cells can co-opt the self-renewal program of endogenous stem cells as a means of enforcing their unlimited proliferative potential is widely accepted, yet identification of specific factors that regulate self-renewal of normal and cancer stem cells remains limited. Using a comparative transcriptomic approach, we identify ZNF521/Zfp521 as a conserved hematopoietic stem cell (HSC)-enriched transcription factor in human and murine hematopoiesis whose function in HSC biology remains elusive. Competitive serial transplantation assays using Zfp521-deficient mice revealed that ZFP521 regulates HSC self-renewal and differentiation. In contrast, ectopic expression of ZFP521 in HSCs led to a robust maintenance of progenitor activity in vitro. Transcriptional analysis of human acute myeloid leukemia (AML) patient samples revealed that ZNF521 is highly and specifically upregulated in AMLs with MLL translocations. Using an MLL-AF9 murine leukemia model and serial transplantation studies, we show that ZFP521 is not required for leukemogenesis, although its absence leads to a significant delay in leukemia onset. Furthermore, knockdown of ZNF521 reduced proliferation in human leukemia cell lines possessing MLL-AF9 translocations. Taken together, these results identify ZNF521/ZFP521 as a critical regulator of HSC function, which facilitates MLL-AF9-mediated leukemic disease in mice. PMID- 28615221 TI - Coronin 1A, a novel player in integrin biology, controls neutrophil trafficking in innate immunity. AB - Trafficking of polymorphonuclear neutrophils (PMNs) during inflammation critically depends on the beta2 integrins lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) and macrophage-1 antigen (CD11b/CD18). Here, we identify coronin 1A (Coro1A) as a novel regulator of beta2 integrins that interacts with the cytoplasmic tail of CD18 and is crucial for induction of PMN adhesion and postadhesion events, including adhesion strengthening, spreading, and migration under flow conditions. Transition of PMN rolling to firm adhesion critically depends on Coro1A by regulating the accumulation of high-affinity LFA-1 in focal zones of adherent cells. Defective integrin affinity regulation in the genetic absence of Coro1A impairs leukocyte adhesion and extravasation in inflamed cremaster muscle venules in comparison with control animals. In a Helicobacter pylori mouse infection model, PMN infiltration into the gastric mucosa is dramatically reduced in Coro1A-/- mice, resulting in an attenuated gastric inflammation. Thus, Coro1A represents an important novel player in integrin biology, with key functions in PMN trafficking during innate immunity. PMID- 28615222 TI - Exploring the global landscape of genetic variation in coagulation factor XI deficiency. AB - Factor XI (FXI) deficiency is an autosomal bleeding disorder, usually posttrauma or postsurgery, characterized by reduced levels of coagulation FXI in plasma. The disease is highly prevalent in Ashkenazi Jews (heterozygote frequency, ~9%), whereas it is considered a rare condition in most populations (prevalence of the severe deficiency, 1 in 106 in the white population). So far, >190 causative mutations have been identified throughout the F11 gene. To have a global landscape of genetic variation of F11, we explored publicly available exome-based data obtained from >60 000 individuals belonging to different ethnicities (Exome Aggregation Consortium resource). This analysis revealed profound differences in heterozygote frequencies among populations (allele frequencies: African = 0.0016; East Asian = 0.0045; European = 0.0036; Finnish = 0.00030; Latino = 0.0021; South Asian = 0.0015), and a prevalence significantly higher than that reported so far (eg, the calculated prevalence of the severe deficiency in Europeans would be: 12.9 in 106). In addition, this analysis allowed us to evidence recurrent and ethnic-specific mutations: p.Phe223Leu in Africans (23.5% of all mutated alleles), p.Gln263X and p.Leu424CysfsX in East Asians (28.2% and 20.5%, respectively), and p.Ala412Thr in Latinos (25%). PMID- 28615223 TI - Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. AB - The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients. PMID- 28615225 TI - Enhanced Therapeutic Efficacy and Memory of Tumor-Specific CD8 T Cells by Ex Vivo PI3K-delta Inhibition. AB - Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating antitumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T-cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen-specific CD8+ T cells was assessed in the presence of PI3K-alpha, -beta, or -delta inhibitors. Inhibition of PI3K-delta, but not PI3K-alpha or PI3K-beta, delayed terminal differentiation of CD8+ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after ex vivo PI3K-delta inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the antitumor therapeutic activity of a tumor-specific peptide vaccine. Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function, and survival of CD8+ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies. Cancer Res; 77(15); 4135-45. (c)2017 AACR. PMID- 28615224 TI - Risk of Second Malignancies in Solid Organ Transplant Recipients Who Develop Keratinocyte Cancers. AB - Solid organ transplant recipients have increased risk for developing keratinocyte cancers, including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, keratinocyte cancers are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on keratinocyte cancer occurrence, with 15 state cancer registries. Risk of developing malignancies after keratinocyte cancer was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n = 6,169) was associated with 1.44-fold increased risk [95% confidence interval (CI), 1.31 1.59] for developing later malignancies. Risks were particularly elevated for non cutaneous SCC, including those of the oral cavity/pharynx (HR, 5.60; 95% CI, 4.18 7.50) and lung (HR, 1.66; 95% CI, 1.16-2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR, 2.77; 95% CI, 1.29-5.96) and female genital cancers (HR, 3.43; 95% CI, 1.44-8.19). In contrast, BCC (n = 3,669) was not associated with overall risk of later malignancy (HR, 0.98; 95% CI, 0.87-1.12), including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk. Cancer Res; 77(15); 4196-203. (c)2017 AACR. PMID- 28615226 TI - Raman-Encoded Molecular Imaging with Topically Applied SERS Nanoparticles for Intraoperative Guidance of Lumpectomy. AB - Intraoperative identification of carcinoma at lumpectomy margins would enable reduced re-excision rates, which are currently as high as 20% to 50%. Although imaging of disease-associated biomarkers can identify malignancies with high specificity, multiplexed imaging of such biomarkers is necessary to detect molecularly heterogeneous carcinomas with high sensitivity. We have developed a Raman-encoded molecular imaging (REMI) technique in which targeted nanoparticles are topically applied on excised tissues to enable rapid visualization of a multiplexed panel of cell surface biomarkers at surgical margin surfaces. A first ever clinical study was performed in which 57 fresh specimens were imaged with REMI to simultaneously quantify the expression of four biomarkers HER2, ER, EGFR, and CD44. Combined detection of these biomarkers enabled REMI to achieve 89.3% sensitivity and 92.1% specificity for the detection of breast carcinoma. These results highlight the sensitivity and specificity of REMI to detect biomarkers in freshly resected tissue, which has the potential to reduce the rate of re excision procedures in cancer patients. Cancer Res; 77(16); 4506-16. (c)2017 AACR. PMID- 28615227 TI - Five minutes with . . . Phil Richardson. PMID- 28615228 TI - Stronger Together: Aggregated Z-values of Traditional Quality Control Measurements and Patient Medians Improve Detection of Biases. AB - BACKGROUND: In clinical chemistry, quality control (QC) often relies on measurements of control samples, but limitations, such as a lack of commutability, compromise the ability of such measurements to detect out-of control situations. Medians of patient results have also been used for QC purposes, but it may be difficult to distinguish changes observed in the patient population from analytical errors. This study aims to combine traditional control measurements and patient medians for facilitating detection of biases. METHODS: The software package "rSimLab" was developed to simulate measurements of 5 analytes. Internal QC measurements and patient medians were assessed for detecting impermissible biases. Various control rules combined these parameters. A Westgard-like algorithm was evaluated and new rules that aggregate Z-values of QC parameters were proposed. RESULTS: Mathematical approximations estimated the required sample size for calculating meaningful patient medians. The appropriate number was highly dependent on the ratio of the spread of sample values to their center. Instead of applying a threshold to each QC parameter separately like the Westgard algorithm, the proposed aggregation of Z-values averaged these parameters. This behavior was found beneficial, as a bias could affect QC parameters unequally, resulting in differences between their Z-transformed values. In our simulations, control rules tended to outperform the simple QC parameters they combined. The inclusion of patient medians substantially improved bias detection for some analytes. CONCLUSIONS: Patient result medians can supplement traditional QC, and aggregations of Z-values are novel and beneficial tools for QC strategies to detect biases. PMID- 28615229 TI - Cardiac Troponins and Their Prognostic Importance in Patients with Suspected Acute Coronary Syndrome and Renal Dysfunction. AB - BACKGROUND: Cardiac troponin (cTn) is important for risk assessment in patients with suspected acute coronary syndrome (ACS). cTn concentrations may, however, be affected by renal dysfunction, and the clinical importance of this interrelation is not well established. We investigated the association between cTnT and cTnI (measured with conventional assays and a more sensitive assay) with the estimated glomerular filtration rate (eGFR) and also assessed the ability of cTn to predict the 1-year all-cause mortality. METHODS: This retrospective registry-based study used data from 309454 admissions to Swedish coronary care units. cTn associations with eGFR and mortality were assessed using different regression models and by calculating multivariable-adjusted c-statistics. RESULTS: cTnT concentrations exhibited stronger associations with eGFR than cTnI concentrations (conventional cTnT assay: beta = -0.113; more sensitive cTnT assay: beta= -0.186; pooled conventional cTnI assays: beta = -0.098). Overall, cTnT provided greater prognostic accuracy than cTnI. This was most evident in non-ACS patients with normal or mildly reduced eGFR when using the more sensitive assay. Despite higher mortality rates, no consistent increases in the c-statistics of cTn were seen with severely reduced eGFR irrespective of the presence of ACS or non-ACS. CONCLUSIONS: cTnT concentrations exhibited stronger associations with reduced eGFR than cTnI concentrations in patients admitted because of suspected ACS. cTnT, particularly when measured using the more sensitive assay, also tended to be a stronger prognosticator. However, the relative significance of the obtained results must be considered in the context of the severity of renal dysfunction and whether ACS is present. PMID- 28615230 TI - Rapid RHD Zygosity Determination Using Digital PCR. AB - BACKGROUND: Paternal zygosity testing is used for determining homo- or hemizygosity of RHD in pregnancies that are at a risk of hemolytic disease of the fetus and newborn. At present, this is achieved by using real-time PCR or the Rhesus box PCR, which can be difficult to interpret and unreliable, particularly for black African populations. METHODS: DNA samples extracted from 53 blood donors were analyzed using 2 multiplex reactions for RHD-specific targets against a reference (AGO1)2 to determine gene dosage by digital PCR. Results were compared with serological data, and the correct genotype for 2 discordant results was determined by long-range PCR (LR-PCR), next-generation sequencing, and conventional Sanger sequencing. RESULTS: The results showed clear and reliable determination of RHD zygosity using digital PCR and revealed that 4 samples did not match the serologically predicted genotype. Sanger sequencing and long-range PCR followed by next-generation sequencing revealed that the correct genotypes for samples 729M and 351D, which were serologically typed as R1R2 (DCe/DcE), were R2r' (DcE/dCe) for 729M and R1r" (DCe/dcE), R0ry (Dce/dCE), or RZr (DCE/dce) for 351D, in concordance with the digital PCR data. CONCLUSIONS: Digital PCR provides a highly accurate method to rapidly define blood group zygosity and has clinical application in the analysis of Rh phenotyped or genotyped samples. The vast majority of current blood group genotyping platforms are not designed to define zygosity, and thus, this technique may be used to define paternal RH zygosity in pregnancies that are at a risk of hemolytic disease of the fetus and newborn and can distinguish between homo- and hemizygous RHD-positive individuals. PMID- 28615231 TI - Single-Nucleotide Polymorphism Leading to False Allelic Fraction by Droplet Digital PCR. AB - BACKGROUND: Molecular-based diagnostics have great utility for cancer detection. We have used droplet digital PCR (ddPCR) as a platform for identifying mutations in circulating plasma tumor DNA (ptDNA). We present the unexpected finding of a spurious mutant allele fraction that was discovered to be artifactual because of the presence of a single-nucleotide polymorphism (SNP) in a patient sample. DESIGN AND METHODS: Probe and primer combinations for the K700 and V701 loci of the SF3B1 spliceosome gene were designed for ddPCR to identify the percentage of mutant and wild-type alleles. Clinical samples from patients with cancer with known SF3B1 mutations were collected and tested to evaluate the assays' ability to detect SF3B1 mutations in ptDNA. RESULTS: Patient samples showed SF3B1 K700E mutations within the ptDNA of 4 patients with acute leukemia and 3 with myelodysplastic syndrome who were known to harbor this mutation. A blood sample from a patient with lung cancer with a known SF3B1 V701F mutation was also analyzed and this mutation was successfully identified in ptDNA. However, 1 of the patients with a K700E mutation was found to have a mutational burden of 98%. After careful analysis of this locus by Sanger sequencing and ddPCR, this patient was found to have an SNP (R702R), which prevented binding of the ddPCR wild-type probe to its cognate allele. CONCLUSIONS: These results further support that ddPCR-based assays may be valuable companion diagnostics for the identification and monitoring of patients with cancer, but the results also emphasize the need to identify SNPs at loci that are being analyzed. PMID- 28615232 TI - Correction. PMID- 28615233 TI - Correction. PMID- 28615234 TI - Impact of Routine Fractional Flow Reserve on Management Decision and 1-Year Clinical Outcome of Patients With Acute Coronary Syndromes: PRIME-FFR (Insights From the POST-IT [Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease] and R3F [French FFR Registry] Integrated Multicenter Registries - Implementation of FFR [Fractional Flow Reserve] in Routine Practice). AB - BACKGROUND: Fractional flow reserve (FFR) is not firmly established as a guide to treatment in patients with acute coronary syndromes (ACS). Primary goals were to evaluate the impact of integrating FFR on management decisions and on clinical outcome of patients with ACS undergoing coronary angiography, as compared with patients with stable coronary artery disease. METHODS AND RESULTS: R3F (French FFR Registry) and POST-IT (Portuguese Study on the Evaluation of FFR-Guided Treatment of Coronary Disease), sharing a common design, were pooled as PRIME-FFR (Insights From the POST-IT and R3F Integrated Multicenter Registries - Implementation of FFR in Routine Practice). Investigators prospectively defined management strategy based on angiography before performing FFR. Final decision after FFR and 1-year clinical outcome were recorded. From 1983 patients, in whom FFR was prospectively used to guide treatment, 533 sustained ACS (excluding acute ST-segment-elevation myocardial infarction). In ACS, FFR was performed in 1.4 lesions per patient, mostly in left anterior descending (58%), with a mean percent stenosis of 58+/-12% and a mean FFR of 0.82+/-0.09. In patients with ACS, reclassification by FFR was high and similar to those with non-ACS (38% versus 39%; P=NS). The pattern of reclassification was different, however, with less patients with ACS reclassified from revascularization to medical treatment compared with those with non-ACS (P=0.01). In ACS, 1-year outcome of patients reclassified based on FFR (FFR against angiography) was as good as that of nonreclassified patients (FFR concordant with angiography), with no difference in major cardiovascular event (8.0% versus 11.6%; P=0.20) or symptoms (92.3% versus 94.8% angina free; P=0.25). Moreover, FFR-based deferral to medical treatment was as safe in patients with ACS as in patients with non-ACS (major cardiovascular event, 8.0% versus 8.5%; P=0.83; revascularization, 3.8% versus 5.9%; P=0.24; and freedom from angina, 93.6% versus 90.2%; P=0.35). These findings were confirmed in ACS explored at the culprit lesion. In patients (6%) in whom the information derived from FFR was disregarded, a dire outcome was observed. CONCLUSIONS: Routine integration of FFR into the decision-making process of ACS patients with obstructive coronary artery disease is associated with a high reclassification rate of treatment (38%). A management strategy guided by FFR, divergent from that suggested by angiography, including revascularization deferral, is safe in ACS. PMID- 28615235 TI - Percutaneous Revascularization of Chronic Total Coronary Occlusion: For Whom? PMID- 28615237 TI - Erratum. Combination Therapy With Exenatide Plus Pioglitazone Versus Basal/Bolus Insulin in Patients With Poorly Controlled Type 2 Diabetes on Sulfonylurea Plus Metformin: The Qatar Study. Diabetes Care 2017;40:325-331. PMID- 28615236 TI - Targeting mitotic pathways for endocrine-related cancer therapeutics. AB - A colossal amount of basic research over the past few decades has provided unprecedented insights into the highly complex process of cell division. There is an ever-expanding catalog of proteins that orchestrate, participate and coordinate in the exquisite processes of spindle formation, chromosome dynamics and the formation and regulation of kinetochore microtubule attachments. Use of classical microtubule poisons has still been widely and often successfully used to combat a variety of cancers, but their non-selective interference in other crucial physiologic processes necessitate the identification of novel druggable components specific to the cell cycle/division pathway. Considering cell cycle deregulation, unscheduled proliferation, genomic instability and chromosomal instability as a hallmark of tumor cells, there lies an enormous untapped terrain that needs to be unearthed before a drug can pave its way from bench to bedside. This review attempts to systematically summarize the advances made in this context so far with an emphasis on endocrine-related cancers and the avenues for future progress to target mitotic mechanisms in an effort to combat these dreadful cancers. PMID- 28615238 TI - Erratum. Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL). A Randomized Controlled Trial. Diabetes Care 2016;39:24-30. PMID- 28615239 TI - Erratum. Basal Glucose Can Be Controlled, but the Prandial Problem Persists-It's the Next Target! Diabetes Care 2017;40:291-300. PMID- 28615240 TI - Erratum. Increased Risk of Fracture and Postfracture Adverse Events in Patients With Diabetes: Two Nationwide Population-Based Retrospective Cohort Studies. Diabetes Care 2014;37:2246-2252. PMID- 28615241 TI - Erratum. Association Between Serum IGF-1 and Diabetes Among U.S. Adults. Diabetes Care 2010;33:2257-2259. PMID- 28615242 TI - Impact of Changes Over Time in Adipokines and Inflammatory Proteins on Changes in Insulin Sensitivity, beta-Cell Function, and Glycemia in Women With Previous Gestational Dysglycemia. PMID- 28615243 TI - Association Between Glycemic Variability, HbA1c, and Large-for-Gestational-Age Neonates in Women With Type 1 Diabetes. PMID- 28615244 TI - Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E2 rat model of overactive bladder. AB - Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E2 (PGE2) rat model of OAB. Cystometry experiments were conducted in 17 urethane anesthetized female Sprague-Dawley rats. The effects of intravesical PGE2 vs. vehicle and PelN stimulation after intravesical PGE2 on cystometric parameters were quantified. Intravesical infusion of PGE2 resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE2 PelN stimulation reversed the PGE2-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB. PMID- 28615245 TI - The regulatory 1alpha subunit of protein kinase A modulates renal cystogenesis. AB - The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for autosomal dominant polycystic kidney disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways. However, the role of PKA in ADPKD has not been directly ascertained in vivo, although the expression of the main regulatory subunit of PKA in cilia and other compartments (PKA-RIalpha, encoded by PRKAR1A) is increased in a mouse model orthologous to ADPKD. Therefore, we generated a kidney-specific knockout of Prkar1a to examine the consequences of constitutive upregulation of PKA on wild-type and Pkd1 hypomorphic (Pkd1RC) backgrounds. Kidney-specific loss of Prkar1a induced renal cystic disease and markedly aggravated cystogenesis in the Pkd1RC models. In both settings, it was accompanied by upregulation of Src, Ras, MAPK/ERK, mTOR, CREB, STAT3, Pax2 and Wnt signaling. On the other hand, Gli3 repressor activity was enhanced, possibly contributing to hydronephrosis and impaired glomerulogenesis in some animals. To assess the relevance of these observations in humans we looked for and found evidence for kidney and liver cystic phenotypes in the Carney complex, a tumoral syndrome caused by mutations in PRKAR1A These observations expand our understanding of the pathogenesis of ADPKD and demonstrate the importance of PRKAR1A highlighting PKA as a therapeutic target in ADPKD. PMID- 28615247 TI - Lithium-induced NDI: acetazolamide reduces polyuria but does not improve urine concentrating ability. AB - Lithium is the mainstay treatment for patients with bipolar disorder, but it generally causes nephrogenic diabetes insipidus (NDI), a disorder in which the renal urine concentrating ability has become vasopressin insensitive. Li-NDI is caused by lithium uptake by collecting duct principal cells and downregulation of aquaporin-2 (AQP2) water channels, which are essential for water uptake from tubular urine. Recently, we found that the prophylactic administration of acetazolamide to mice effectively attenuated Li-NDI. To evaluate whether acetazolamide might benefit lithium-treated patients, we administered acetazolamide to mice with established Li-NDI and six patients with a lithium induced urinary concentrating defect. In mice, acetazolamide partially reversed lithium-induced polyuria and increased urine osmolality, which, however, did not coincide with increased AQP2 abundances. In patients, acetazolamide led to the withdrawal of two patients from the study due to side effects. In the four remaining patients acetazolamide did not lead to clinically relevant changes in maximal urine osmolality. Urine output was also not affected, although none of these patients demonstrated overt lithium-induced polyuria. In three out of four patients, acetazolamide treatment increased serum creatinine levels, indicating a decreased glomerular filtration rate (GFR). Strikingly, these three patients also showed a decrease in systemic blood pressure. All together, our data reveal that acetazolamide does not improve the urinary concentrating defect caused by lithium, but it lowers the GFR, likely explaining the reduced urine output in our mice and in a recently reported patient with lithium-induced polyuria. The reduced GFR in patients prone to chronic kidney disease development, however, warrants against application of acetazolamide in Li-NDI patients without long term (pre)clinical studies. PMID- 28615246 TI - Src family kinases in chronic kidney disease. AB - Src family kinases (SFKs) belong to nonreceptor protein tyrosine kinases and have been implicated in the regulation of numerous cellular processes, including cell proliferation, differentiation, migration and invasion, and angiogenesis. The role and mechanisms of SFKs in tumorgenesis have been extensively investigated, and some SFK inhibitors are currently under clinical trials for tumor treatment. Recent studies have also demonstrated the importance of SFKs in regulating the development of various fibrosis-related chronic diseases (e.g., idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, and systemic sclerosis). In this article, we summarize the roles of SFKs in various chronic kidney diseases, including glomerulonephritis, diabetic nephropathy, human immunodeficiency virus associated nephropathy, autosomal dominant form of polycystic kidney disease, and obesity-associated kidney disease, and discuss the mechanisms involved. PMID- 28615248 TI - The transcriptome of the Didelphis virginiana opossum kidney OK proximal tubule cell line. AB - The OK cell line derived from the kidney of a female opossum Didelphis virginiana has proven to be a useful model in which to investigate the unique regulation of ion transport and membrane trafficking mechanisms in the proximal tubule (PT). Sequence data and comparison of the transcriptome of this cell line to eutherian mammal PTs would further broaden the utility of this culture model. However, the genomic sequence for D. virginiana is not available and although a draft genome sequence for the opossum Monodelphis domestica (sequenced in 2012 by the Broad Institute) exists, transcripts sequenced from both species show significant divergence. The M. domestica sequence is not highly annotated, and the majority of transcripts are predicted rather than experimentally validated. Using deep RNA sequencing of the D. virginiana OK cell line, we characterized its transcriptome via de novo transcriptome assembly and alignment to the M. domestica genome. The quality of the de novo assembled transcriptome was assessed by the extent of homology to sequences in nucleotide and protein databases. Gene expression levels in the OK cell line, from both the de novo transcriptome and genes aligned to the M. domestica genome, were compared with publicly available rat kidney nephron segment expression data. Our studies demonstrate the expression in OK cells of numerous PT-specific ion transporters and other key proteins relevant for rodent and human PT function. Additionally, the sequence and expression data reported here provide an important resource for genetic manipulation and other studies on PT cell function using these cells. PMID- 28615250 TI - An essential MIF-CD74 signaling axis in kidney tubular regeneration, with prospects for precision medicine and pharmacological augmentation. PMID- 28615249 TI - Reduction in podocyte SIRT1 accelerates kidney injury in aging mice. AB - Both the incidence and prevalence of chronic kidney disease are increasing in the elderly population. Although aging is known to induce kidney injury, the underlying molecular mechanisms remain unclear. Sirtuin 1 (Sirt1), a longevity gene, is known to protect kidney cell injury from various cellular stresses. In previous studies, we showed that the podocyte-specific loss of Sirt1 aggravates diabetic kidney injury. However, the role of Sirt1 in aging-induced podocyte injury is not known. Therefore, in this study we sought to determine the effects of podocyte-specific reduction of Sirt1 in age-induced kidney injury. We employed the inducible podocyte-specific Sirt1 knockdown mice that express shRNA against Sirt1 (Pod-Sirt1RNAi) and control mice that express shRNA for luciferase (Pod LuciRNAi). We found that reduction of podocyte Sirt1 led to aggravated aging induced glomerulosclerosis and albuminuria. In addition, urinary level of 8 hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, was markedly increased in aged Pod-Sirt1RNAi mice compared with aged Pod-LuciRNAi mice. Although podocyte-specific markers decreased in aged mice compared with the young controls, the decrease was further exacerbated in aged Pod-Sirt1RNAi compared with Pod-LuciRNAi mice. Interestingly, expression of cellular senescence markers was significantly higher in the glomeruli of Pod-Sirt1RNAi mice than Pod-LuciRNAi mice, suggesting that cellular senescence may contribute to podocyte loss in aging kidneys. Finally, we confirmed that Pod-Sirt1RNAi glomeruli were associated with reduced activation of the transcription factors peroxisome proliferator activated receptor (PPAR)-alpha coactivador-1 (PGC1alpha)/PPARgamma, forkhead box O (FOXO)3, FOXO4, and p65 NF-kappaB, through SIRT1-mediated deacetylation. Together, our data suggest that SIRT1 may be a potential therapeutic target to treat patients with aging-related kidney disease. PMID- 28615251 TI - Adjusting retinol-binding protein concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: The accurate estimation of the prevalence of vitamin A deficiency (VAD) is important in planning and implementing interventions. Retinol-binding protein (RBP) is often used in population surveys to measure vitamin A status, but its interpretation is challenging in settings where inflammation is common because RBP concentrations decrease during the acute-phase response.Objectives: We aimed to assess the relation between RBP concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and to investigate adjustment algorithms to account for these effects.Design: Cross-sectional data from 8 surveys for PSC (n = 8803) and 4 surveys for WRA (n = 4191) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to adjust RBP concentrations in PSC in inflammation and malaria settings as follows: 1) the exclusion of subjects with C-reactive protein (CRP) concentrations >5 mg/L or alpha-1-acid glycoprotein (AGP) concentrations >1 g/L, 2) the application of arithmetic correction factors, and 3) the use of a regression correction approach. The impact of adjustment on the estimated prevalence of VAD (defined as <0.7 MUmol/L) was examined in PSC.Results: The relation between estimated VAD and CRP and AGP deciles followed a linear pattern in PSC. In women, the correlations between RBP and CRP and AGP were too weak to justify adjustments for inflammation. Depending on the approach used to adjust for inflammation (CRP+AGP), the estimated prevalence of VAD decreased by a median of 11-18 percentage points in PSC compared with unadjusted values. There was no added effect of adjusting for malaria on the estimated VAD after adjusting for CRP and AGP.Conclusions: The use of regression correction (derived from internal data), which accounts for the severity of inflammation, to estimate the prevalence of VAD in PSC in regions with inflammation and malaria is supported by the analysis of the BRINDA data. These findings contribute to the evidence on adjusting for inflammation when estimating VAD with the use of RBP. PMID- 28615252 TI - Research, policy, and programmatic considerations from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - The Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project sought to inform the interpretation of iron and vitamin A biomarkers (ferritin, serum transferrin receptor, and retinol binding protein) in settings of prevalent inflammation as well as the prevention of and control strategies to address anemia. Our purpose is to comment on the contributions of the BRINDA to advance global knowledge with regard to iron and vitamin A status assessment in women and preschool children and to analyze the findings in terms of their rigor and usefulness for global nutrition research and programs. BRINDA investigators found that the acute-phase response is so prevalent that it must be assessed in surveys of iron and vitamin A status for valid interpretation of micronutrient biomarkers. Furthermore, they found that C-reactive protein and alpha-1-acid glycoprotein provide important and different information about these responses and that common survey variables cannot replace the information they provide. Developing a method for adjusting micronutrient biomarkers for the independent influence of inflammation is challenging and complex, and BRINDA has brought greater clarity to this challenge through the use of large and diverse data sets. When comparing approaches, the regression methods appear to perform best when sample sizes are sufficient and adequate statistical capacity is available. Further correction for malaria does not appear to materially alter regression-adjusted prevalence estimates. We suggest that researchers present both adjusted and unadjusted values for the micronutrient biomarkers. BRINDA findings confirm that iron deficiency is a common and consistent risk factor for anemia globally and that anemia control must combine iron interventions with control of infection and inflammation. Anemia control strategies must be informed by local data. By applying the knowledge in these studies, researchers, program planners, and evaluators working in populations with prevalent inflammation can use and interpret biomarkers with more confidence, tempered with necessary caution. PMID- 28615253 TI - Dietary calcium intake and risk of cardiovascular disease, stroke, and fracture in a population with low calcium intake. AB - Background: The role of dietary calcium intake in cardiovascular disease (CVD), stroke, and fracture is controversial. Most previous reports have evaluated populations with high calcium intake.Objective: We aimed to evaluate whether high dietary calcium intake was associated with the risk of CVD, stroke, and fracture in a population with low calcium intake.Design: In a prospective cohort study beginning in 2001 in Ansung-Ansan, Korea, 2158 men and 2153 women aged >50 y were evaluated for all-cause mortality, CVD, stroke, and fractures over a median 9-y follow-up.Results: During follow-up, 242 and 100 deaths, 149 and 150 CVD events, 58 and 82 stroke events, and 211 and 292 incident fractures occurred in men and women, respectively. The first quartiles of energy-adjusted dietary calcium intake were 249 mg/d (IQR: 169 mg/d) in men and 209 mg/d (IQR: 161 mg/d) in women. Both men and women with higher dietary calcium intake tended to have higher fat, protein, sodium, phosphorus, fruit, and vegetable intakes. In men, outcomes were not significantly associated with dietary calcium intake with or without adjustments, and CVD risk tended to increase with increasing energy adjusted dietary calcium intake, but this was not statistically significant (P = 0.078 and P = 0.093 with and without adjustment, respectively). In women, CVD risk and dietary calcium intake showed a U-shaped association; the HRs (95% CIs) without adjustment relative to the first quartile were 0.71 (0.47, 1.07), 0.57 (0.36, 0.88), and 0.52 (0.33, 0.83) for quartiles 2, 3, and 4, respectively, and the values after adjustment were 0.70 (0.45, 1.07), 0.51 (0.31, 0.81), and 0.49 (0.29, 0.83) for quartiles 2, 3, and 4, respectively.Conclusion: In Korean women, increased dietary calcium intake was associated with a decreased CVD risk, but it did not influence the risk of stroke or fracture. PMID- 28615254 TI - Methodologic approach for the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: The Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project is a multiagency and multicountry collaboration that was formed to improve micronutrient assessment and to better characterize anemia.Objectives: The aims of the project were to 1) identify factors associated with inflammation, 2) assess the relations between inflammation, malaria infection, and biomarkers of iron and vitamin A status and compare adjustment approaches, and 3) assess risk factors for anemia in preschool children (PSC) and women of reproductive age (WRA).Design: The BRINDA database inclusion criteria included surveys that 1) were conducted after 2004, 2) had target groups of PSC, WRA, or both, and 3) used a similar laboratory methodology for the measurement of >=1 biomarker of iron [ferritin or soluble transferrin receptor or vitamin A status (retinol-binding protein or retinol)] and >=1 biomarker of inflammation (alpha-1-acid glycoprotein or C-reactive protein). Individual data sets were standardized and merged into a BRINDA database comprising 16 nationally and regionally representative surveys from 14 countries. Collectively, the database covered all 6 WHO geographic regions and contained ~30,000 PSC and 27,000 WRA. Data were analyzed individually and combined with the use of a meta analysis.Results: The methods that were used to standardize the BRINDA database and the analytic approaches used to address the project's research questions are presented in this article. Three approaches to adjust micronutrient biomarker concentrations in the presence of inflammation and malaria infection are presented, along with an anemia conceptual framework that guided the BRINDA project's anemia analyses.Conclusions: The BRINDA project refines approaches to interpret iron and vitamin A biomarker values in settings of inflammation and malaria infection and suggests the use of a new regression approach as well as proposes an anemia framework to which real-world data can be applied. Findings can inform guidelines and strategies to prevent and control micronutrient deficiencies and anemia globally. PMID- 28615255 TI - Adjusting total body iron for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: Total body iron (TBI) that is calculated from ferritin and soluble transferrin receptor (sTfR) allows for the evaluation of the full range of iron status from deficiency to excess. However, both ferritin and sTfR are affected by inflammation and malaria, which may require a statistical adjustment. TBI has been used to assess iron status in the United States, but its use worldwide and in settings with inflammation has been limited.Objective: We examine whether inflammation-adjusted ferritin and sTfR concentrations affect TBI values and the prevalence of low TBI (<0 mg/kg) in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y).Design: Cross-sectional data for PSC (8 surveys; n = 8413) and WRA (4 surveys; n = 4258) from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined. TBI and the prevalence of low TBI were compared following 3 adjustment approaches for ferritin and sTfR: 1) the exclusion of individuals with inflammation (C-reactive protein concentration >5 mg/L or alpha-1-acid glycoprotein concentration >1 g/L), 2) the application of arithmetic correction factors, and 3) the use of regression correction.Results: Regardless of the method that was used to adjust ferritin and sTfR for inflammation, the adjusted mean TBI decreased in both PSC and WRA compared with unadjusted values. Subsequently, inflammation-adjusted TBI increased the prevalence of low TBI by a median of 4-14 percentage points (pps) in PSC and 1-3 pps in WRA compared with unadjusted TBI. The regression approach resulted in a greater median increase than was achieved with the exclusion or correction-factor approaches, and accounting for malaria in addition to inflammation did not have an added effect on the prevalence estimates.Conclusion: The prevalence of low TBI is underestimated if it is not adjusted by inflammation, particularly in children living in areas with a high prevalence of inflammation. PMID- 28615256 TI - Adjusting soluble transferrin receptor concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: Iron deficiency is thought to be one of the most prevalent micronutrient deficiencies globally, but an accurate assessment in populations who are frequently exposed to infections is impeded by the inflammatory response, which causes iron-biomarker alterations.Objectives: We assessed the relation between soluble transferrin receptor (sTfR) concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and investigated adjustment algorithms to account for these effects.Design: Cross-sectional data from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project from 11,913 PSC in 11 surveys and from 11,173 WRA in 7 surveys were analyzed individually and combined with the use of a meta-analysis. The following 3 adjustment approaches were compared with estimated iron-deficient erythropoiesis (sTfR concentration >8.3 mg/L): 1) the exclusion of individuals with C-reactive protein (CRP) concentrations >5 mg/L or alpha-1-acid glycoprotein (AGP) concentrations >1 g/L, 2) the application of arithmetic correction factors, and 3) the use of regression approaches.Results: The prevalence of elevated sTfR concentrations incrementally decreased as CRP and AGP deciles decreased for PSC and WRA, but the effect was more pronounced for AGP than for CRP. Depending on the approach used to adjust for inflammation, the estimated prevalence of iron deficient erythropoiesis decreased by 4.4-14.6 and 0.3-9.5 percentage points in PSC and WRA, respectively, compared with unadjusted values. The correction-factor approach yielded a more modest reduction in the estimated prevalence of iron deficient erythropoiesis than did the regression approach. Mostly, adjustment for malaria in addition to AGP did not significantly change the estimated prevalence of iron-deficient erythropoiesis.Conclusions: sTfR may be useful to assess iron deficient erythropoiesis, but inflammation influences its interpretation, and adjustment of sTfR for inflammation and malaria should be considered. More research is warranted to evaluate the proposed approaches in different settings, but this study contributes to the evidence on how and when to adjust sTfR for inflammation and malaria. PMID- 28615257 TI - Randomized controlled trial assessing the efficacy of a reusable fish-shaped iron ingot to increase hemoglobin concentration in anemic, rural Cambodian women. AB - Background: Anemia affects 45% of women of childbearing age in Cambodia. Iron supplementation is recommended in populations in which anemia prevalence is high. However, there are issues of cost, distribution, and adherence. A potential alternative is a reusable fish-shaped iron ingot, which, when added to the cooking pot, leaches iron into the fluid in which it is prepared.Objective: We sought to determine whether there was a difference in hemoglobin concentrations in rural Cambodian anemic women (aged 18-49 y) who cooked with the iron ingot or consumed a daily iron supplement compared with a control after 1 y.Design: In Preah Vihear, 340 women with mild or moderate anemia were randomly assigned to 1) an iron-ingot group, 2) an iron-supplement (18 mg/d) group, or 3) a nonplacebo control group. A venous blood sample was taken at baseline and at 6 and 12 mo. Blood was analyzed for hemoglobin, serum ferritin, and serum transferrin receptor. Hemoglobin electrophoresis was used to detect structural hemoglobin variants.Results: Anemia prevalence was 44% with the use of a portable hemoglobinometer during screening. At baseline, prevalence of iron deficiency was 9% on the basis of a low serum ferritin concentration. There was no significant difference in mean hemoglobin concentrations between the iron-ingot group (115 g/L; 95% CI: 113, 118 g/L; P = 0.850) or iron-supplement group (115 g/L; 95% CI: 113, 117 g/L; P = 0.998) compared with the control group (115 g/L; 95% CI: 113, 117 g/L) at 12 mo. Serum ferritin was significantly higher in the iron-supplement group (73 MUg/L; 95% CI: 64, 82 MUg/L; P = 0.002) than in the control group at 6 mo; however, this significance was not maintained at 12 mo (73 MUg/L; 95% CI: 58, 91 MUg/L; P = 0.176).Conclusions: Neither the iron ingot nor iron supplements increased hemoglobin concentrations in this population at 6 or 12 mo. We do not recommend the use of the fish-shaped iron ingot in Cambodia or in countries where the prevalence of iron deficiency is low and genetic hemoglobin disorders are high. This trial was registered at clinicaltrials.gov as NCT02341586. PMID- 28615258 TI - Effect of a package of health and nutrition services on sustained recovery in children after moderate acute malnutrition and factors related to sustaining recovery: a cluster-randomized trial. AB - Background: Children who recover from moderate acute malnutrition (MAM) have high rates of relapse in the year after nutritional recovery. Interventions to decrease these adverse outcomes are needed to maximize the overall effectiveness of supplemental feeding programs (SFPs).Objective: We evaluated the effectiveness of a package of health and nutrition interventions on improving the proportion of children who sustained recovery for 1 y after MAM treatment. We further explored factors related to sustained recovery.Design: We conducted a cluster-randomized clinical effectiveness trial involving rural Malawian children aged 6-62 mo who were enrolled on discharge from an SFP for MAM. We enrolled 718 children at 10 control sites and 769 children at 11 intervention sites. In addition to routine health and nutrition counseling, the intervention group received a package of health and nutrition interventions that consisted of a lipid nutrient supplement, deworming medication, zinc supplementation, a bed net, and malaria chemoprophylaxis. A survival analysis was used to determine the effectiveness of the intervention as well as to identify factors associated with sustained recovery.Results: Of 1383 children who returned for the full 12-mo follow-up period, 407 children (56%) and 347 children (53%) sustained recovery in the intervention and control groups, respectively. There was no significant difference in relapse-free survival curves between the treatment and control groups (P = 0.380; log-rank test). The risk factors for relapse or death after initial recovery were a smaller midupper arm circumference on SFP admission (P = 0.01) and discharge (P < 0.001), a lower weight-for-height z score on discharge (P < 0.01), and the receipt of ready-to-use supplementary food as opposed to ready-to-use therapeutic food during treatment (P < 0.05).Conclusion: The provision of a package of health and nutrition services in addition to traditional SFP treatment has no significant effect on improving sustained recovery in children after treatment of MAM. This trial was registered at clinicaltrials.gov as NCT02351687. PMID- 28615260 TI - Predictors of anemia in preschool children: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: A lack of information on the etiology of anemia has hampered the design and monitoring of anemia-control efforts.Objective: We aimed to evaluate predictors of anemia in preschool children (PSC) (age range: 6-59 mo) by country and infection-burden category.Design: Cross-sectional data from 16 surveys (n = 29,293) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed separately and pooled by category of infection burden. We assessed relations between anemia (hemoglobin concentration <110 g/L) and severe anemia (hemoglobin concentration <70 g/L) and individual level (age, anthropometric measures, micronutrient deficiencies, malaria, and inflammation) and household-level predictors; we also examined the proportion of anemia with concomitant iron deficiency (defined as an inflammation-adjusted ferritin concentration <12 MUg/L). Countries were grouped into 4 categories on the basis of risk and burden of infectious disease, and a pooled multivariable logistic regression analysis was conducted for each group.Results: Iron deficiency, malaria, breastfeeding, stunting, underweight, inflammation, low socioeconomic status, and poor sanitation were each associated with anemia in >50% of surveys. Associations between breastfeeding and anemia were attenuated by controlling for child age, which was negatively associated with anemia. The most consistent predictors of severe anemia were malaria, poor sanitation, and underweight. In multivariable pooled models, child age, iron deficiency, and stunting independently predicted anemia and severe anemia. Inflammation was generally associated with anemia in the high- and very high-infection groups but not in the low- and medium-infection groups. In PSC with anemia, 50%, 30%, 55%, and 58% of children had concomitant iron deficiency in low-, medium-, high-, and very high-infection categories, respectively.Conclusions: Although causal inference is limited by cross-sectional survey data, results suggest anemia control programs should address both iron deficiency and infections. The relative importance of factors that are associated with anemia varies by setting, and thus, country-specific data are needed to guide programs. PMID- 28615259 TI - Adjusting ferritin concentrations for inflammation: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: The accurate estimation of iron deficiency is important in planning and implementing interventions. Ferritin is recommended as the primary measure of iron status, but interpretability is challenging in settings with infection and inflammation.Objective: We assessed the relation between ferritin concentrations and inflammation and malaria in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y) and investigated adjustment algorithms to account for these effects.Design: Cross-sectional data from 15 surveys for PSC (n = 27,865) and 8 surveys for WRA (24,844), from the Biomarkers Reflecting the Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and combined with the use of a meta-analysis. Several approaches were explored to estimate depleted iron stores (ferritin concentration <12 MUg/L in PSC and <15 MUg/L in WRA) in inflammation and malaria settings as follows: 1) increase ferritin-concentration cutoff to <30 MUg/L; 2) exclude individuals with C-reactive protein (CRP) concentrations >5 mg/L or alpha 1-acid glycoprotein (AGP) concentrations >1 g/L; 3) apply arithmetic correction factors; and 4) use a regression correction approach.Results: Depleted iron-store estimates incrementally increased as CRP and AGP deciles decreased (4% compared with 30%, and 6% compared with 29% from highest compared with lowest CRP deciles for pooled PSC and WRA, respectively, with similar results for AGP). Depending on the approach used to adjust for inflammation (CRP plus AGP), the estimated prevalence of depleted iron stores increased by 7-25 and 2-8 absolute median percentage points for PSC and WRA, respectively, compared with unadjusted values. Adjustment for malaria in addition to CRP and AGP did not substantially change the estimated prevalence of depleted iron stores.Conclusions: Our results lend support for the use of internal regression correction to estimate the prevalence of depleted iron stores in regions with inflammation. This approach appears to mathematically reflect the linear relation of ferritin concentrations with acute phase proteins. More research is warranted to validate the proposed approaches, but this study contributes to the evidence base to guide decisions about how and when to adjust ferritin for inflammation. PMID- 28615261 TI - Increased vitamin D intake differentiated according to skin color is needed to meet requirements in young Swedish children during winter: a double-blind randomized clinical trial. AB - Background: Dark skin and low exposure to sunlight increase the risk of vitamin D insufficiency in children.Objective: The aim of the study was to evaluate the amount of vitamin D needed to ascertain that most children >4 y of age attain sufficient serum 25-hydroxyvitamin D [S-25(OH)D; i.e., >=50 nmol/L] during winter regardless of latitude and skin color.Design: In a longitudinal, double-blind, randomized, food-based intervention study, 5- to 7-y-old children from northern (63 degrees N) and southern (55 degrees N) Sweden with fair (n = 108) and dark (n = 98) skin were included. Children, stratified by skin color by using Fitzpatrick's definition, were randomly assigned to receive milk-based vitamin D3 supplements that provided 2 (placebo), 10, or 25 MUg/d during 3 winter months.Results: Mean daily vitamin D intake increased from 6 to 17 MUg and 26 MUg in the intervention groups supplemented with 10 and 25 MUg, respectively. In the intention-to-treat analysis, 90.2% (95% CI: 81.1%, 99.3%) of fair-skinned children randomly assigned to supplementation of 10 MUg/d attained sufficient concentrations, whereas 25 MUg/d was needed in dark-skinned children to reach sufficiency in 95.1% (95% CI: 88.5%, 100%). In children adherent to the study product, 97% (95% CI: 91.3%, 100%) and 87.9% (95% CI: 76.8%, 99%) of fair- and dark-skinned children, respectively, achieved sufficient concentrations if supplemented with 10 MUg/d. By using 95% prediction intervals for 30 and 50 nmol S-25(OH)D/L, intakes of 6 and 20 MUg/d are required in fair-skinned children, whereas 14 and 28 MUg/d are required in children with dark skin.Conclusion: Children with fair and dark skin require vitamin D intakes of 20 and 28 MUg/d, respectively, to maintain S-25(OH)D >=50 nmol/L, whereas intakes of 6 and 14 MUg/d, respectively, are required to maintain concentrations >=30 nmol/L during winter. This trial was registered at clinicaltrials.gov as NCT01741324. PMID- 28615262 TI - Predictors of anemia in women of reproductive age: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: Anemia in women of reproductive age (WRA) (age range: 15-49 y) remains a public health problem globally, and reducing anemia in women by 50% by 2025 is a goal of the World Health Assembly.Objective: We assessed the associations between anemia and multiple proximal risk factors (e.g., iron and vitamin A deficiencies, inflammation, malaria, and body mass index) and distal risk factors (e.g., education status, household sanitation and hygiene, and urban or rural residence) in nonpregnant WRA.Design: Cross-sectional, nationally representative data from 10 surveys (n = 27,018) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed individually and pooled by the infection burden and risk in the country. We examined the severity of anemia and measured the bivariate associations between anemia and factors at the country level and by infection burden, which we classified with the use of the national prevalences of malaria, HIV, schistosomiasis, sanitation, and water-quality indicators. Pooled multivariate logistic regression models were constructed for each infection-burden category to identify independent determinants of anemia (hemoglobin concertation <120 g/L).Results: Anemia prevalence was ~40% in countries with a high infection burden and 12% and 7% in countries with moderate and low infection burdens, respectively. Iron deficiency was consistently associated with anemia in multivariate models, but the proportion of anemic women who were iron deficient was considerably lower in the high-infection group (35%) than in the moderate- and low-infection groups (65% and 71%, respectively). In the multivariate analysis, inflammation, vitamin A insufficiency, socioeconomic status, and age were also significantly associated with anemia, but malaria and vitamin B-12 and folate deficiencies were not.Conclusions: The contribution of iron deficiency to anemia varies according to a country's infection burden. Anemia-reduction programs for WRA can be improved by considering the underlying infection burden of the population and by assessing the overlap of micronutrient deficiencies and anemia. PMID- 28615264 TI - Is the whole not greater than the sum of its parts? The case of sarcopenic obesity. PMID- 28615263 TI - Factors associated with inflammation in preschool children and women of reproductive age: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. AB - Background: In many settings, populations experience recurrent exposure to inflammatory agents that catalyze fluctuations in the concentrations of acute phase proteins and certain micronutrient biomarkers such as C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), ferritin, and retinol. Few data are available on the prevalence and predictors of inflammation in diverse settings.Objective: We aimed to assess the relation between inflammation (CRP concentration >5 mg/L or AGP concentration >1 g/L) and covariates, such as demographics, reported illness, and anthropometric status, in preschool children (PSC) (age range: 6-59 mo) and women of reproductive age (WRA) (age range: 15-49 y).Design: Cross-sectional data from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project from 29,765 PSC in 16 surveys and 25,731 WRA in 10 surveys were used to model bivariable and multivariable relations.Results: The inflammation prevalence was 6.0-40.2% in PSC and 7.9-29.5% in WRA (elevated CRP) and 21.2-64.3% in PSC and 7.1-26.7% in WRA (elevated AGP). In PSC, inflammation was consistently positively associated with recent fever and malaria but not with other recent illnesses. In multivariable models that were adjusted for age, sex, urban or rural residence, and socioeconomic status, elevated AGP was positively associated with stunting (height-for-age z score <-2) in 7 of 10 surveys. In WRA, elevated CRP was positively associated with obesity [body mass index (in kg/m2) >=30] in 7 of 9 surveys. Other covariates showed inconsistent patterns of association with inflammation. In a pooled analysis of surveys that measured malaria, stunting was associated with elevated AGP but not CRP in PSC, and obesity was associated with both elevated CRP and AGP in WRA.Conclusions: Recent morbidity and abnormal anthropometric status are consistently associated with inflammation across a range of environments, whereas more commonly collected demographic covariates were not. Because of the challenge of defining a general demographic population or environmental profile that is more likely to experience inflammation, inflammatory markers should be measured in surveys to account for their effects. PMID- 28615265 TI - Adequacy of nutritional intake from food and supplements in a cohort of pregnant women in Quebec, Canada: the 3D Cohort Study (Design, Develop, Discover). AB - Background: Assessments of the dietary intakes in various populations suggest that pregnant women have difficulty meeting all their nutritional requirements through diet alone. Few large-scale studies have considered both food sources and supplements in assessing the adequacy of nutritional intakes during pregnancy.Objective: Our study aimed to assess nutritional intakes during pregnancy by examining dietary sources and supplements. It then compared these findings with Dietary Reference Intakes.Design: We conducted a nutrition study in a large pregnancy cohort using a 3-d food record during the second trimester of pregnancy. Detailed information about supplement consumption was obtained by interview at each prenatal visit. We estimated the distribution of total usual intakes for energy, macronutrients, and micronutrients for 1533 pregnant women.Results: A third of the participants had total fat intakes that exceeded the Acceptable Micronutrient Distribution Range. A majority of women (85%) had sodium intakes above the Tolerable Upper Intake Level (UL). Median intakes for fiber and potassium were lower than Adequate Intakes. Dietary intakes of vitamin B-6, magnesium, and zinc were below the Estimated Average Requirements (EARs) for 10-15% of the women. A majority of the women had dietary intakes below the EARs for iron (97%), vitamin D (96%), and folate (70%). When we considered micronutrient intakes from both food and supplements, we found that the prevalence of inadequate intake was <10% for all nutrients except vitamin D (18%) and iron (15%), whereas 32% and 87% of the women had total intakes above the ULs for iron and folic acid, respectively.Conclusions: The level of intake of some nutrients from food alone remains low in the diets of pregnant women. Supplement use reduces the risk of inadequate intake for many micronutrients, but diet related issues during pregnancy remain and deserve to be addressed in public health interventions. This trial was registered at clinicaltrials.gov as NCT03113331. PMID- 28615266 TI - Antitumor Effects of Epidrug/IFNalpha Combination Driven by Modulated Gene Signatures in Both Colorectal Cancer and Dendritic Cells. AB - Colorectal cancer results from the progressive accumulation of genetic and epigenetic alterations. IFN signaling defects play an important role in the carcinogenesis process, in which the inability of IFN transcription regulatory factors (IRF) to access regulatory sequences in IFN-stimulated genes (ISG) in tumors and in immune cells may be pivotal. We reported that low-dose combination of two FDA-approved epidrugs, azacytidine (A) and romidepsin (R), with IFNalpha2 (ARI) hampers the aggressiveness of both colorectal cancer metastatic and stem cells in vivo and triggers immunogenic cell death signals that stimulate dendritic cell (DC) function. Here, we investigated the molecular signals induced by ARI treatment and found that this drug combination increased the accessibility to regulatory sequences of ISGs and IRFs that were epigenetically silenced in both colorectal cancer cells and DCs. Likewise, specific ARI-induced histone methylation and acetylation changes marked epigenetically affected ISG promoters in both metastatic cancer cells and DCs. Analysis by ChIP-seq confirmed such ARI induced epigenetically regulated IFN signature. The activation of this signal endowed DCs with a marked migratory capability. Our results establish a direct correlation between reexpression of silenced ISGs by epigenetic control and ARI anticancer activity and provide new knowledge for the development of innovative combined therapeutic strategies for colorectal cancer. Cancer Immunol Res; 5(7); 604-16. (c)2017 AACR. PMID- 28615267 TI - The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis. AB - Purpose: To develop an approach for the investigation of different subtypes of circulating tumor cells (CTC) and other cells to evaluate their potential prognostic value of prostate cancer.Experimental Design: Malignancy of CTCs undergoing epithelial-to-mesenchymal transition (EMT) was confirmed by repeated FISH. Subgroups of CTCs in 81 patients with prostate cancer (43 castration resistant and 38 untreated localized) were correlated to disease aggressiveness parameters. AUC analysis was applied to compare the performance for metastasis prediction between serum PSA level alone and a combined risk score using both PSA and EMTing CTC count. Circulating megakaryocytes and cancer patient survival association was performed using Cox model.Results: The majority of vimentin (VIM)+/CD45- cells were malignant, with genomic alterations in several genomic regions. The number of cytokeratin (CK)-/VIM+/CD45- CTCs correlated with disease burden, tumor aggressiveness, and poorer survival. Meanwhile, CK+/VIM+/CD45- CTCs were associated with metastases better than other subtypes of CTCs in these limited samples. Combination of PSA level and the number of CK+/VIM+/CD45- CTCs enhanced the prediction of cancer metastases [AUC, 0.921; 95% confidence interval (CI), 0.858-0.985]. The number of circulating megakaryocytes was potentially associated with good patient survival in advanced prostate cancer (HR, 0.849; 95% CI, 0.628-1.146, per cell increase), and the difference between the number of mesenchymal CTCs and megakaryocytes strongly correlated to poor survival (HR, 10.17; 95% CI, 2.164-47.789, if score >=2.0).Conclusions: This CTC analysis approach and the potential association of megakaryocytes with cancer prognosis may greatly enhance our ability to investigate the cancer metastasis process and to predict/monitor cancer progression. Clin Cancer Res; 23(17); 5112-22. (c)2017 AACR. PMID- 28615268 TI - Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. AB - OBJECTIVES: This study aims to summarise the evidence on more than 140 pharmacological and non-pharmacological treatment options for major depressive disorder (MDD) and to evaluate the confidence that patients and clinicians can have in the underlying science about their effects. DESIGN: This is a review of systematic reviews. DATA SOURCES: This study used MEDLINE, Embase, Cochrane Library, PsycINFO and Epistemonikos from 2011 up to February 2017 for systematic reviews of randomised controlled trials in adult patients with acute-phase MDD. METHODS: We dually reviewed abstracts and full-text articles, rated the risk of bias of eligible systematic reviews and graded the strength of evidence. RESULTS: Nineteen systematic reviews provided data on 28 comparisons of interest. For general efficacy, only second-generation antidepressants were supported with high strength evidence, presenting small beneficial treatment effects (standardised mean difference: -0.35; 95% CI -0.31 to -0.38), and a statistically significantly higher rate of discontinuation because of adverse events than patients on placebo (relative risk (RR) 1.88; 95% CI 1.0 to 3.28).Only cognitive behavioural therapy is supported by reliable evidence (moderate strength of evidence) to produce responses to treatment similar to those of second-generation antidepressants (45.5% vs 44.2%; RR 1.10; 95% CI 0.93 to 1.30). All remaining comparisons of non pharmacological treatments with second-generation antidepressants either led to inconclusive results or had substantial methodological shortcomings (low or insufficient strength of evidence). CONCLUSIONS: In contrast to pharmacological treatments, the majority of non-pharmacological interventions for treating patients with MDD are not evidence based. For patients with strong preferences against pharmacological treatments, clinicians should focus on therapies that have been compared directly with antidepressants. TRIAL REGISTRATION NUMBER: International Prospective Register of Systematic Reviews (PROSPERO) registration number: 42016035580. PMID- 28615269 TI - How sustainable household environment and knowledge of healthy practices relate to childhood morbidity in South Asia: analysis of survey data from Bangladesh, Nepal and Pakistan. AB - OBJECTIVES: Prevalence of diarrhoea and acute respiratory infection (ARI) is considerably high among South Asian children. The objective of this study is to compare the associations of sustainable household environment and knowledge of healthy practices with episodes of these diseases among the children in the region. DESIGN: The study analysed the latest, nationally representative and cross-sectional Demographic and Health Survey data. SETTING: Data from three countries were analysed: Bangladesh, Nepal and Pakistan. PARTICIPANTS: Women aged between 12 and 49 years living in selected households provided information on 23 940 of their children under the age of 5 years. PRIMARY OUTCOMES MEASURES: The morbidity status of the children was recorded with respect to episodes of diarrhoea and/or ARI in the 2 weeks preceding data collection. RESULTS: Consuming unhygienic drinking water increased the risks of childhood diarrhoea, and use of solid fuel for indoor cooking increased the risk of ARI, across all three countries investigated. However, far more significant were the effects of mother's education, with incomplete primary education leading to an odds of diarrhoea approaching twice that of a mother with secondary education or higher (OR 1.70 in Bangladesh, 95% CI 1.16 to 2.49). CONCLUSIONS: Results from the current research underline the importance of developing and implementing integrated strategic plans for mothers and children in the countries investigated. Promoting hygienic water and sanitation facilities can help reduce the prevalence of childhood diarrhoea. Replacing indoor solid fuel cooking arrangements with cleaner fuel or more airy conditions can help reduce the prevalence of ARI. However, these strategies need to be integrated with education for women to raise the likelihood that reduced risks are actually realised. PMID- 28615270 TI - Understanding how and why audits work: protocol for a realist review of audit programmes to improve hospital care. AB - INTRODUCTION: Many types of audits are commonly used in hospital care to promote quality improvements. However, the evidence on the effectiveness of audits is mixed. The objectives of this proposed realist review are (1) to understand how and why audits might, or might not, work in terms of delivering the intended outcome of improved quality of hospital care and (2) to examine under what circumstances audits could potentially be effective. This protocol will provide the rationale for using a realist review approach and outline the method. METHODS AND ANALYSIS: This review will be conducted using an iterative four-stage approach. The first and second steps have already been executed. The first step was to develop an initial programme theory based on the literature that explains how audits are supposed to work. Second, a systematic literature search was conducted using relevant databases. Third, data will be extracted and coded for concepts relating to context, outcomes and their interrelatedness. Finally, the data will be synthesised in a five-step process: (1) organising the extracted data into evidence tables, (2) theming, (3) formulating chains of inference from the identified themes, (4) linking the chains of inference and formulating CMO configurations and (5) refining the initial programme theory. The reporting of the review will follow the 'Realist and Meta-Review Evidence Synthesis: Evolving Standards' (RAMESES) publication standards. ETHICS AND DISSEMINATION: This review does not require formal ethical approval. A better understanding of how and why these audits work, and how context impacts their effectiveness, will inform stakeholders in deciding how to tailor and implement audits within their local context. We will use a range of dissemination strategies to ensure that findings from this realist review are broadly disseminated to academic and non-academic audiences. PROSPERO REGISTRATION NUMBER: CRD42016039882. PMID- 28615271 TI - Cost-effectiveness of a randomised trial of physical activity in Alzheimer's disease: a secondary analysis exploring patient and proxy-reported health-related quality of life measures in Denmark. AB - OBJECTIVES: To explore the cost-effectiveness of a supervised moderate-to-high intensity aerobic exercise programme in people diagnosed with Alzheimer's disease (AD) and estimate incremental cost-effectiveness ratios (ICER) using participant reported and proxy-reported measures of health-related quality of life (HRQoL) DESIGN: A cost-effectiveness analysis of economic and HRQoL data from a randomised trial delivered over 16 weeks. SETTING: Memory clinics in Denmark. PARTICIPANTS: 200 individuals with mild AD aged 50-90 years gave informed consent to participate in the study. Participants were randomised to control or intervention group. INTERVENTIONS: Control group received treatment as usual. The intervention group performed 1 hour of supervised moderate-to-high intensity aerobic exercise three times weekly for 16 weeks. PRIMARY AND SECONDARY OUTCOMES MEASURES: Different physical, functional and health measures were obtained at inclusion (baseline) and 4 and 16 weeks after. HRQoL (EuroQol-5 Dimensions-5 Levels/EQ-Visual Analogue Scale) was reported by the participants and the primary caregivers as proxy respondents. Differences in HRQOL as reported by the participant and caregiver were explored as were different values of caregiver time with respite from care tasks. RESULTS: The intervention cost was estimated at ?608 and ?496 per participant, with and without transport cost, respectively. Participants and caregivers in the intervention group reported a small, positive non-significant improvement in EQ-5D-5L and EQ-VAS after 16 weeks. The ICER was estimated at ?72 000/quality-adjusted life year using participant-reported outcomes and ?87000 using caregiver-reported outcomes. CONCLUSIONS: The findings suggest that the exercise intervention is unlikely to be cost-effective within the commonly applied threshold values. The cost of the intervention might be offset by potential savings from reduction in use of health and social care. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/ct2/show/NCT01681602. PMID- 28615272 TI - What do adolescents with asthma really think about adherence to inhalers? Insights from a qualitative analysis of a UK online forum. AB - OBJECTIVE: To explore the barriers and facilitators to inhaled asthma treatment in adolescents with asthma. DESIGN: Qualitative analysis of posts about inhaler treatment in adolescents from an online forum for people with asthma. Analysis informed by the Perceptions and Practicalities Approach. PARTICIPANTS: Fifty-four forum participants (39 adolescents >=16 years, 5 parents of adolescents, 10 adults with asthma) identified using search terms 'teenager inhaler' and 'adolescent inhaler'. SETTING: Posts from adolescents, parents and adults with asthma taking part in the Asthma UK online forum between 2006 and 2016, UK. RESULTS: Practical barriers reducing the ability to adhere included forgetfulness and poor routines, inadequate inhaler technique, organisational difficulties (such as repeat prescriptions), and families not understanding or accepting their child had asthma. Prompting and monitoring inhaler treatment by parents were described as helpful, with adolescents benefiting from self-monitoring, for example, by using charts logging adherence. Perceptions reducing the motivation to adhere included asthma representation as episodic rather than chronic condition with intermittent need of inhaler treatment. Adolescents and adults with asthma (but not parents) described concerns related to attributed side effects (eg, weight gain) and social stigma, resulting in 'embarrassment of taking inhalers'. Facilitators to adherence included actively seeking general practitioners'/consultants' adjustments if problems arose and learning to deal with the side effects and stigma. Parents were instrumental in creating a sense of responsibility for adherence. CONCLUSIONS: This online forum reveals a rich and novel insight into adherence to asthma inhalers by adolescents. Interventions that prompt and monitor preventer inhaler use would be welcomed and hold potential. In clinical consultations, exploring parents' beliefs about asthma diagnosis and their role in dealing with barriers to treatment might be beneficial. The social stigma of asthma and its role in adherence were prominent and continue to be underestimated, warranting further research and action to improve public awareness of asthma. PMID- 28615273 TI - Analysis of the potential for point-of-care test to enable individualised treatment of infections caused by antimicrobial-resistant and susceptible strains of Neisseria gonorrhoeae: a modelling study. AB - OBJECTIVE: To create a mathematical model to investigate the treatment impact and economic implications of introducing an antimicrobial resistance point-of-care test (AMR POCT) for gonorrhoea as a way of extending the life of current last line treatments. DESIGN: Modelling study. SETTING: England. POPULATION: Patients accessing sexual health services. INTERVENTIONS: Incremental impact of introducing a hypothetical AMR POCT that could detect susceptibility to previous first-line antibiotics, for example, ciprofloxacin or penicillin, so that patients are given more tailored treatment, compared with the current situation where all patients are given therapy with ceftriaxone and azithromycin. The hypothetical intervention was assessed using a mathematical model developed in Excel. The model included initial and follow-up attendances, loss to follow-up, use of standard or tailored treatment, time taken to treatment and the costs of testing and treatment. MAIN OUTCOME MEASURES: Number of doses of ceftriaxone saved, mean time to most appropriate treatment, mean number of visits per (infected) patient, number of patients lost to follow-up and total cost of testing. RESULTS: In the current situation, an estimated 33 431 ceftriaxone treatments are administered annually and 792 gonococcal infections remain untreated due to loss to follow-up. The use of an AMR POCT for ciprofloxacin could reduce these ceftriaxone treatments by 66%, and for an AMR POCT for penicillin by 79%. The mean time for patients receiving an antibiotic treatment is reduced by 2 days in scenarios including POCT and no positive patients remain untreated through eliminating loss to follow-up. Such POCTs are estimated to add L34 million to testing costs, but this does not take into account reductions in costs of repeat attendances and the reuse of older, cheaper antimicrobials. CONCLUSIONS: The introduction of AMR POCT could allow clinicians to discern between the majority of gonorrhoea-positive patients with strains that could be treated with older, previously abandoned first-line treatments, and those requiring our current last-line dual therapy. Such tests could extend the useful life of dual ceftriaxone and azithromycin therapy, thus pushing back the time when gonorrhoea may become untreatable. PMID- 28615274 TI - Detecting organisational innovations leading to improved ICU outcomes: a protocol for a double-blinded national positive deviance study of critical care delivery. AB - INTRODUCTION: There is substantial variability in intensive care unit (ICU) utilisation and quality of care. However, the factors that drive this variation are poorly understood. This study uses a novel adaptation of positive deviance approach-a methodology used in public health that assumes solutions to challenges already exist within the system to detect innovations that are likely to improve intensive care. METHODS AND ANALYSIS: We used the Philips eICU Research Institute database, containing 3.3 million patient records from over 50 health systems across the USA. Acute Physiology and Chronic Health Evaluation IVa scores were used to identify the study cohort, which included ICU patients whose outcomes were felt to be most sensitive to organisational innovations. The primary outcomes included mortality and length of stay. Outcome measurements were directly standardised, and bootstrapped CIs were calculated with adjustment for false discovery rate. Using purposive sampling, we then generated a blinded list of five positive outliers and five negative comparators.Using rapid qualitative inquiry (RQI), blinded interdisciplinary site visit teams will conduct interviews and observations using a team ethnography approach. After data collection is completed, the data will be unblinded and analysed using a cross-case method to identify themes, patterns and innovations using a constant comparative grounded theory approach. This process detects the innovations in intensive care and supports an evaluation of how positive deviance and RQI methods can be adapted to healthcare. ETHICS AND DISSEMINATION: The study protocol was approved by the Stanford University Institutional Review Board (reference: 39509). We plan on publishing study findings and methodological guidance in peer-reviewed academic journals, white papers and presentations at conferences. PMID- 28615275 TI - The burden of cancer attributable to modifiable risk factors: the Australian cancer-PAF cohort consortium. AB - PURPOSE: To estimate the Australian cancer burden attributable to lifestyle related risk factors and their combinations using a novel population attributable fraction (PAF) method that accounts for competing risk of death, risk factor interdependence and statistical uncertainty. PARTICIPANTS: 365 173 adults from seven Australian cohort studies. We linked pooled harmonised individual participant cohort data with population-based cancer and death registries to estimate exposure-cancer and exposure-death associations. Current Australian exposure prevalence was estimated from representative external sources. To illustrate the utility of the new PAF method, we calculated fractions of cancers causally related to body fatness or both tobacco and alcohol consumption avoidable in the next 10 years by risk factor modifications, comparing them with fractions produced by traditional PAF methods. FINDINGS TO DATE: Over 10 years of follow-up, we observed 27 483 incident cancers and 22 078 deaths. Of cancers related to body fatness (n=9258), 13% (95% CI 11% to 16%) could be avoided if those currently overweight or obese had body mass index of 18.5-24.9 kg/m2. Of cancers causally related to both tobacco and alcohol (n=4283), current or former smoking explains 13% (11% to 16%) and consuming more than two alcoholic drinks per day explains 6% (5% to 8%). The two factors combined explain 16% (13% to 19%): 26% (21% to 30%) in men and 8% (4% to 11%) in women. Corresponding estimates using the traditional PAF method were 20%, 31% and 10%. Our PAF estimates translate to 74 000 avoidable body fatness-related cancers and 40 000 avoidable tobacco- and alcohol-related cancers in Australia over the next 10 years (2017-2026). Traditional PAF methods not accounting for competing risk of death and interdependence of risk factors may overestimate PAFs and avoidable cancers. FUTURE PLANS: We will rank the most important causal factors and their combinations for a spectrum of cancers and inform cancer control activities. PMID- 28615276 TI - BlueHealth: a study programme protocol for mapping and quantifying the potential benefits to public health and well-being from Europe's blue spaces. AB - INTRODUCTION: Proximity and access to water have long been central to human culture and accordingly deliver countless societal benefits. Over 200 million people live on Europe's coastline, and aquatic environments are the top recreational destination in the region. In terms of public health, interactions with 'blue space' (eg, coasts, rivers, lakes) are often considered solely in terms of risk (eg, drowning, microbial pollution). Exposure to blue space can, however, promote health and well-being and prevent disease, although underlying mechanisms are poorly understood. AIMS AND METHODS: The BlueHealth project aims to understand the relationships between exposure to blue space and health and well-being, to map and quantify the public health impacts of changes to both natural blue spaces and associated urban infrastructure in Europe, and to provide evidence-based information to policymakers on how to maximise health benefits associated with interventions in and around aquatic environments. To achieve these aims, an evidence base will be created through systematic reviews, analyses of secondary data sets and analyses of new data collected through a bespoke international survey and a wide range of community-level interventions. We will also explore how to deliver the benefits associated with blue spaces to those without direct access through the use of virtual reality. Scenarios will be developed that allow the evaluation of health impacts in plausible future societal contexts and changing environments. BlueHealth will develop key inputs into policymaking and land/water-use planning towards more salutogenic and sustainable uses of blue space, particularly in urban areas. ETHICS AND DISSEMINATION: Throughout the BlueHealth project, ethics review and approval are obtained for all relevant aspects of the study by the local ethics committees prior to any work being initiated and an ethics expert has been appointed to the project advisory board. So far, ethical approval has been obtained for the BlueHealth International Survey and for community-level interventions taking place in Spain, Italy and the UK. Engagement of stakeholders, including the public, involves citizens in many aspects of the project. Results of all individual studies within the BlueHealth project will be published with open access. After full anonymisation and application of any measures necessary to prevent disclosure, data generated in the project will be deposited into open data repositories of the partner institutions, in line with a formal data management plan. Other knowledge and tools developed in the project will be made available via the project website (www.bluehealth2020.eu). Project results will ultimately provide key inputs to planning and policy relating to blue space, further stimulating the integration of environmental and health considerations into decision-making, such that blue infrastructure is developed across Europe with both public health and the environment in mind. PMID- 28615277 TI - Alterations in the brain's connectome during recovery from severe traumatic brain injury: protocol for a longitudinal prospective study. AB - INTRODUCTION: Traumatic brain injury (TBI) is considered one of the most pervasive causes of disability in people under the age of 45. TBI often results in disorders of consciousness, and clinical assessment of the state of consciousness in these patients is challenging due to the lack of behavioural responsiveness. Functional neuroimaging offers a means to assess these patients without the need for behavioural signs, indicating that brain connectivity plays a major role in consciousness emergence and maintenance. However, little is known regarding how changes in connectivity during recovery from TBI accompany changes in the level of consciousness. Here, we aim to combine cutting-edge neuroimaging techniques to follow changes in brain connectivity in patients recovering from severe TBI. METHODS AND ANALYSIS: A multimodal, longitudinal assessment of 30 patients in the subacute stage after severe TBI will be made comprising an MRI session combined with electroencephalography (EEG), a positron emission tomography session and a transcranial magnetic stimulation (TMS) combined with EEG (TMS/EEG) session. A group of 20 healthy participants will be included for comparison. Four sessions for patients and two sessions for healthy participants will be planned. Data analysis techniques will focus on whole-brain, both data driven and hypothesis-driven, connectivity measures that will be specific to the imaging modality. ETHICS AND DISSEMINATION: The project has received ethical approval by the local ethics committee of the Capital Region of Denmark and by the Danish Data Protection. Results will be published as original research articles in peer-reviewed journals and disseminated in international conferences. None of the measurements will have any direct clinical impact on the patients included in the study but may benefit future patients through a better understanding of the mechanisms underlying the recovery process after TBI. TRIAL REGISTRATION NUMBER NCT02424656; PRE-RESULTS. PMID- 28615278 TI - Individual, social and environmental determinants of sleep among women: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Sleep is important to promote optimal health and avoid negative health outcomes. Short-duration and low-quality sleep may be more common and more detrimental among women compared with men. Identifying the determinants of behaviour is one of the first steps in designing effective interventions. To our knowledge, no systematic review has identified the individual, social and environmental determinants of sleep among adult women. METHODS AND ANALYSIS: Studies reporting data on adult women from 18 to 64 years of age will be included. On the basis of ecological models of health behaviour and sleep, the types of determinants that will be included in the review are individual (eg, demographic, psychological and behavioural), social (eg, family) and environmental (eg, physical environment and policies) determinants. Observational (cross-sectional and longitudinal) and experimental studies will be included. MEDLINE/PubMed, PsycINFO, CINAHL, EMBASE and Proquest Dissertations and Theses will be investigated. Data will be extracted independently by two reviewers using a standardised data extraction form. The quality of observational studies will be assessed using the National Institute of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies and the quality of experimental studies will be assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Study. If there is a sufficient number of studies reporting data on a similar determinant among a similar population (k>5), a meta-analysis of the results will be performed with a random-effects model. If between-study heterogeneity is high (I2 >=75%), it will be investigated through sensitivity analyses and meta-regression. ETHICS AND DISSEMINATION: Formal ethical approval is not required as no primary data will be collected. The results will be published in a peer-reviewed journal. This review will provide valuable information to those interested in developing empirically based sleep interventions among women. PROSPERO REGISTRATION NUMBER: CRD42017056894. PMID- 28615279 TI - Medicines Optimisation Assessment Tool (MOAT): a prognostic model to target hospital pharmacists' input to improve patient outcomes. Protocol for an observational study. AB - INTRODUCTION: Medicines optimisation is a key role for hospital pharmacists, but with ever-increasing demands on services there is a need to increase efficiency while maintaining patient safety. The aim of this study is to develop a prognostic model, the Medicines Optimisation Assessment Tool (MOAT), which can be used to target patients most in need of pharmacists' input while in hospital. METHODS AND ANALYSIS: The MOAT will be developed following recommendations of the Prognosis Research Strategy partnership. Using a cohort study we will prospectively include 1500 adult patients from the medical wards of two UK hospitals. Data on medication-related problems (MRPs) experienced by study patients will be collected by pharmacists at the study sites as part of their routine daily clinical assessment of patients. Data on potential risk factors such as polypharmacy, renal impairment and the use of 'high risk' medicines will be collected retrospectively from the information departments at the study sites, laboratory reporting systems and patient medical records. Multivariable logistic regression models will then be used to determine the relationship between potential risk factors and the study outcome of preventable MRPs that are at least moderate in severity. Bootstrapping will be used to adjust the MOAT for optimism, and predictive performance will be assessed using calibration and discrimination. A simplified scoring system will also be developed, which will be assessed for sensitivity and specificity. ETHICS AND DISSEMINATION: This study has been approved by the Proportionate Review Service Sub-Committee of the National Health Service Research Ethics Committee Wales REC 7 (16/WA/0016) and the Health Research Authority (project ID 197298). We plan to disseminate the results via presentations at relevant patient/public, professional, academic and scientific meetings and conferences, and will submit findings for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02582463. PMID- 28615280 TI - Age-associated gene expression changes in the arcuate nucleus of male rhesus macaques. AB - The hypothalamic arcuate nucleus (ARC) represents a major component of the neuroendocrine reproductive axis and plays an important role in controlling the onset of puberty as well as age-associated reproductive senescence. Although significant gene expression changes have been observed in the ARC during sexual maturation, it is unclear what changes occur during aging, especially in males. Therefore, in the present study, we profiled the expression of reproduction related genes in the ARC of young and old male rhesus macaques, as well as old males that had received 6 months of hormone supplementation (HS) in the form of daily testosterone and dehydroepiandrosterone; we also compared morning vs night ARC gene expression in the old males. Using Affymetrix gene microarrays, we found little evidence for age-associated expression changes for genes associated with the neuroendocrine reproductive axis, whereas using qRT-PCR, we detected a similar age-associated decrease in PGR (progesterone receptor) that we previously observed in postmenopausal females. We also detected a sex-steroid-dependent and age-associated decrease in androgen receptor (AR) expression, with highest AR levels being expressed at night (i.e., coinciding with the natural peak in daily testosterone secretion). Finally, unlike previous observations made in females, we did not find a significant age-associated increase in KISS1 (Kisspeptin) or TAC3 (Neurokinin B) expression in the ARC of males, most likely because the attenuation of circulating sex-steroid levels in the males was much less than that in postmenopausal females. Taken together, the data highlight some similarities and differences in ARC gene expression between aged male and female nonhuman primates. PMID- 28615281 TI - Macrophages Promote Resistance to Checkpoint Inhibitors. AB - A study in mice suggests that macrophages produce resistance to checkpoint inhibitors by removing anti-PD-1 antibodies from T cells. Fcgamma receptors on macrophages bind to the Fc domain on the antibodies. Blocking this interaction with other antibodies produced dramatic tumor shrinkage in mice. PMID- 28615282 TI - Maternal Haploid, a Metalloprotease Enriched at the Largest Satellite Repeat and Essential for Genome Integrity in Drosophila Embryos. AB - The incorporation of the paternal genome into the zygote during fertilization requires chromatin remodeling. The maternal haploid (mh) mutation in Drosophila affects this process and leads to the formation of haploid embryos without the paternal genome. mh encodes the Drosophila homolog of SPRTN, a conserved protease essential for resolving DNA-protein cross-linked products. Here we characterize the role of MH in genome maintenance. It is not understood how MH protects the paternal genome during fertilization, particularly in light of our finding that MH is present in both parental pronuclei during zygote formation. We showed that maternal chromosomes in mh mutant embryos experience instabilities in the absence of the paternal genome, which suggests that MH is generally required for chromosome stability during embryogenesis. This is consistent with our finding that MH is abundantly present on chromatin throughout the cell cycle. Remarkably, MH is prominently enriched at the 359-bp satellite repeats during interphase, which becomes unstable without MH. This dynamic localization and specific enrichment of MH at the 359 repeats resemble that of Topoisomerase 2 (Top2), suggesting that MH regulates Top2, possibly as a protease for the resolution of Top2-DNA intermediates. We propose that maternal MH removes proteins specifically enriched on sperm chromatin. In the absence of that function, paternal chromosomes are precipitously lost. This mode of paternal chromatin remodeling is likely conserved and the unique phenotype of the Drosophila mh mutants represents a rare opportunity to gain insights into the process that has been difficult to study. PMID- 28615283 TI - Cis- and Trans-regulatory Effects on Gene Expression in a Natural Population of Drosophila melanogaster. AB - Cis- and trans-regulatory mutations are important contributors to transcriptome evolution. Quantifying their relative contributions to intraspecific variation in gene expression is essential for understanding the population genetic processes that underlie evolutionary changes in gene expression. Here, we have examined this issue by quantifying genome-wide, allele-specific expression (ASE) variation using a crossing scheme that produces F1 hybrids between 18 different Drosophila melanogaster strains sampled from the Drosophila Genetic Reference Panel and a reference strain from another population. Head and body samples from F1 adult females were subjected to RNA sequencing and the subsequent ASE quantification. Cis- and trans-regulatory effects on expression variation were estimated from these data. A higher proportion of genes showed significant cis-regulatory variation (~28%) than those that showed significant trans-regulatory variation (~9%). The sizes of cis-regulatory effects on expression variation were 1.98 and 1.88 times larger than trans-regulatory effects in heads and bodies, respectively. A generalized linear model analysis revealed that both cis- and trans-regulated expression variation was strongly associated with nonsynonymous nucleotide diversity and tissue specificity. Interestingly, trans-regulated variation showed a negative correlation with local recombination rate. Also, our analysis on proximal transposable element (TE) insertions suggested that they affect transcription levels of ovary-expressed genes more pronouncedly than genes not expressed in the ovary, possibly due to defense mechanisms against TE mobility in the germline. Collectively, our detailed quantification of ASE variations from a natural population has revealed a number of new relationships between genomic factors and the effects of cis- and trans-regulatory factors on expression variation. PMID- 28615284 TI - TCL1A Single-Nucleotide Polymorphisms and Estrogen-Mediated Toll-Like Receptor MYD88-Dependent Nuclear Factor-kappaB Activation: Single-Nucleotide Polymorphism- and Selective Estrogen Receptor Modulator-Dependent Modification of Inflammation and Immune Response. AB - In a previous genome-wide association study (GWAS) for musculoskeletal adverse events during aromatase inhibitor therapy for breast cancer, we reported that single nucleotide polymorphisms (SNPs) near the TCL1A gene were associated with this adverse drug reaction. Functional genomic studies showed that TCL1A expression was induced by estradiol, but only in cells with the variant sequence for the top GWAS SNP (rs11849538), a SNP that created a functional estrogen response element. In addition, TCL1A genotype influenced the downstream expression of a series of cytokines and chemokines and had a striking effect on nuclear factor kappaB (NF-kappaB) transcriptional activity. Furthermore, this SNP dependent regulation could be reversed by selective ER modulators (SERMs). The present study was designed to pursue mechanisms underlying TCL1A SNP-mediated, estrogen-dependent NF-kappaB activation. Functional genomic studies were performed using a panel of 300 lymphoblastoid cell lines for which we had generated genome-wide SNP and gene expression data. It is known that toll-like receptors (TLRs) can regulate NF-kappaB signaling by a process that requires the adaptor protein MYD88. We found that TLR2, TLR7, TLR9, and TLR10 expression, as well as that of MYD88, could be modulated by TCL1A in a SNP and estrogen dependent fashion and that these effects were reversed in the presence of SERMs. Furthermore, MYD88 inhibition blocked the TCL1A SNP and estrogen-dependent NF kappaB activation, as well as protein-protein interaction between TCL1A and MYD88. These observations greatly expand the range of pathways influenced by TCL1A genotype and raise the possibility that this estrogen- and SNP-dependent regulation might be altered pharmacologically by SERMs. PMID- 28615287 TI - Commentary: View from the frontline of pragmatic trials. PMID- 28615285 TI - Vaccination against Salmonella Infection: the Mucosal Way. AB - Salmonella enterica subspecies enterica includes several serovars infecting both humans and other animals and leading to typhoid fever or gastroenteritis. The high prevalence of associated morbidity and mortality, together with an increased emergence of multidrug-resistant strains, is a current global health issue that has prompted the development of vaccination strategies that confer protection against most serovars. Currently available systemic vaccine approaches have major limitations, including a reduced effectiveness in young children and a lack of cross-protection among different strains. Having studied host-pathogen interactions, microbiologists and immunologists argue in favor of topical gastrointestinal administration for improvement in vaccine efficacy. Here, recent advances in this field are summarized, including mechanisms of bacterial uptake at the intestinal epithelium, the assessment of protective host immunity, and improved animal models that closely mimic infection in humans. The pros and cons of existing vaccines are presented, along with recent progress made with novel formulations. Finally, new candidate antigens and their relevance in the refined design of anti-Salmonella vaccines are discussed, along with antigen vectorization strategies such as nanoparticles or secretory immunoglobulins, with a focus on potentiating mucosal vaccine efficacy. PMID- 28615288 TI - Correlation between Apparent Substrate Affinity and OCT2 Transport Turnover. AB - Organic cation (OC) transporter 2 (OCT2) mediates the first step in the renal secretion of many cationic drugs: basolateral uptake from blood into proximal tubule cells. The impact of this process on the pharmacokinetics of drug clearance as estimated using a physiologically-based pharmacokinetic approach relies on an accurate understanding of the kinetics of transport because the ratio of the maximal rate of transport to the Michaelis constant (i.e., Jmax/ Kt) provides an estimate of the intrinsic clearance (Clint) used in in vitro-in vivo extrapolation of experimentally determined transport data. Although the multispecificity of renal OC secretion, including that of the OCT2 transporter, is widely acknowledged, the possible relationship between relative affinity of the transporter for its diverse substrates and the maximal rates of their transport has received little attention. In this study, we determined the Jmax and apparent Michaelis constant (Ktapp) values for six structurally distinct OCT2 substrates and found a strong correlation between Jmax and Ktapp; high-affinity substrates [Ktapp values <50 uM, including 1-methyl-4-phenylpyridinium, or 1 methyl-4-phenylpyridinium (MPP), and cimetidine] displayed systematically lower Jmax values (<50 pmol cm-2 min-1) than did low-affinity substrates (Ktapp >200 uM, including choline and metformin). Similarly, preloading OCT2-expressing cells with low-affinity substrates resulted in systematically larger trans-stimulated rates of MPP uptake than did preloading with high-affinity substrates. The data are quantitatively consistent with the hypothesis that dissociation of bound substrate from the transporter is rate limiting in establishing maximal rates of OCT2-mediated transport. This systematic relationship may provide a means to estimate Clint for drugs for which transport data are lacking. PMID- 28615289 TI - Enzyme sub-functionalization driven by regulation. PMID- 28615286 TI - The Physiology of Phagocytosis in the Context of Mitochondrial Origin. AB - How mitochondria came to reside within the cytosol of their host has been debated for 50 years. Though current data indicate that the last eukaryote common ancestor possessed mitochondria and was a complex cell, whether mitochondria or complexity came first in eukaryotic evolution is still discussed. In autogenous models (complexity first), the origin of phagocytosis poses the limiting step at eukaryote origin, with mitochondria coming late as an undigested growth substrate. In symbiosis-based models (mitochondria first), the host was an archaeon, and the origin of mitochondria was the limiting step at eukaryote origin, with mitochondria providing bacterial genes, ATP synthesis on internalized bioenergetic membranes, and mitochondrion-derived vesicles as the seed of the eukaryote endomembrane system. Metagenomic studies are uncovering new host-related archaeal lineages that are reported as complex or phagocytosing, although images of such cells are lacking. Here we review the physiology and components of phagocytosis in eukaryotes, critically inspecting the concept of a phagotrophic host. From ATP supply and demand, a mitochondrion-lacking phagotrophic archaeal fermenter would have to ingest about 34 times its body weight in prokaryotic prey to obtain enough ATP to support one cell division. It would lack chemiosmotic ATP synthesis at the plasma membrane, because phagocytosis and chemiosmosis in the same membrane are incompatible. It would have lived from amino acid fermentations, because prokaryotes are mainly protein. Its ATP yield would have been impaired relative to typical archaeal amino acid fermentations, which involve chemiosmosis. In contrast, phagocytosis would have had great physiological benefit for a mitochondrion-bearing cell. PMID- 28615290 TI - A post-translational modification switch controls coactivator function of histone methyltransferases G9a and GLP. AB - Like many transcription regulators, histone methyltransferases G9a and G9a-like protein (GLP) can act gene-specifically as coregulators, but mechanisms controlling this specificity are mostly unknown. We show that adjacent post translational methylation and phosphorylation regulate binding of G9a and GLP to heterochromatin protein 1 gamma (HP1gamma), formation of a ternary complex with the glucocorticoid receptor (GR) on chromatin, and function of G9a and GLP as coactivators for a subset of GR target genes. HP1gamma is recruited by G9a and GLP to GR binding sites associated with genes that require G9a, GLP, and HP1gamma for glucocorticoid-stimulated transcription. At the physiological level, G9a and GLP coactivator function is required for glucocorticoid activation of genes that repress cell migration in A549 lung cancer cells. Thus, regulated methylation and phosphorylation serve as a switch controlling G9a and GLP coactivator function, suggesting that this mechanism may be a general paradigm for directing specific transcription factor and coregulator actions on different genes. PMID- 28615291 TI - High-affinity cooperative Ca2+ binding by MICU1-MICU2 serves as an on-off switch for the uniporter. AB - The mitochondrial calcium uniporter is a Ca2+-activated Ca2+ channel that is essential for dynamic modulation of mitochondrial function in response to cellular Ca2+ signals. It is regulated by two paralogous EF-hand proteins-MICU1 and MICU2, but the mechanism is unknown. Here, we demonstrate that both MICU1 and MICU2 are stabilized by Ca2+ We reconstitute the MICU1-MICU2 heterodimer and demonstrate that it binds Ca2+ cooperatively with high affinity. We discover that both MICU1 and MICU2 exhibit affinity for the mitochondria-specific lipid cardiolipin. We determine the minimum Ca2+ concentration required for disinhibition of the uniporter in permeabilized cells and report a close match with the Ca2+-binding affinity of MICU1-MICU2. We conclude that cooperative, high affinity interaction of the MICU1-MICU2 complex with Ca2+ serves as an on-off switch, leading to a tightly controlled channel, capable of responding directly to cytosolic Ca2+ signals. PMID- 28615292 TI - Rtt101-Mms1-Mms22 coordinates replication-coupled sister chromatid cohesion and nucleosome assembly. AB - Two sister chromatids must be held together by a cohesion process from their synthesis during S phase to segregation in anaphase. Despite its pivotal role in accurate chromosome segregation, how cohesion is established remains elusive. Here, we demonstrate that yeast Rtt101-Mms1, Cul4 family E3 ubiquitin ligases are stronger dosage suppressors of loss-of-function eco1 mutants than PCNA The essential cohesion reaction, Eco1-catalyzed Smc3 acetylation is reduced in the absence of Rtt101-Mms1. One of the adaptor subunits, Mms22, associates directly with Eco1. Point mutations (L61D/G63D) in Eco1 that abolish the interaction with Mms22 impair Smc3 acetylation. Importantly, an eco1LGpol30A251V double mutant displays additive Smc3ac reduction. Moreover, Smc3 acetylation and cohesion defects also occur in the mutants of other replication-coupled nucleosome assembly (RCNA) factors upstream or downstream of Rtt101-Mms1, indicating unanticipated cross talk between histone modifications and cohesin acetylation. These data suggest that fork-associated Cul4-Ddb1 E3s, together with PCNA, coordinate chromatin reassembly and cohesion establishment on the newly replicated sister chromatids, which are crucial for maintaining genome and chromosome stability. PMID- 28615294 TI - Pituitary stem cell regulation: who is pulling the strings? AB - The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors. PMID- 28615293 TI - Looping-out mechanism for resolution of replicative stress at telomeres. AB - Repetitive DNA is prone to replication fork stalling, which can lead to genome instability. Here, we find that replication fork stalling at telomeres leads to the formation of t-circle-tails, a new extrachromosomal structure that consists of circular telomeric DNA with a single-stranded tail. Structurally, the t-circle tail resembles cyclized leading or lagging replication intermediates that are excised from the genome by topoisomerase II-mediated cleavage. We also show that the DNA damage repair machinery NHEJ is required for the formation of t-circle tails and for the resolution of stalled replication forks, suggesting that NHEJ, which is normally constitutively suppressed at telomeres, is activated in the context of replication stress. Inhibition of NHEJ or knockout of DNA-PKcs impairs telomere replication, leading to multiple-telomere sites (MTS) and telomere shortening. Collectively, our results support a "looping-out" mechanism, in which the stalled replication fork is cut out and cyclized to form t-circle-tails, and broken DNA is religated. The telomere loss induced by replication stress may serve as a new factor that drives replicative senescence and cell aging. PMID- 28615295 TI - Burden of Recurrent and Ancestral Mutations in Families With Hypertrophic Cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy is a genetically heterogeneous myocardial disease with >1000 causal variants identified. Nonunique variants account for disease in many families. We sought to characterize nonunique variants in Australian families and determine whether they arise from common ancestral mutations or recurrent mutation events. METHODS AND RESULTS: Genetic test results of 467 index patients from apparently unrelated families with hypertrophic cardiomyopathy were evaluated. Causal variants were found in 185 of 467 (40%) families. Nonunique variants accounted for 122 of 185 (66%) families. The most common single genetic cause of hypertrophic cardiomyopathy is the recurrent MYBPC3 (myosin-binding protein-C) variant c.1504C>T, p.Arg502Trp, which was found in 13 of 185 (7%) families with a causal variant identified. Thirteen variants in MYBPC3 and MYH7 (myosin heavy chain 7) were each identified >3 times and accounted for 78 of 185 (42%) hypertrophic cardiomyopathy families with a causal variant. Haplotype analysis of these 13 variants was performed on 126 individuals from 70 Australian families, and 11 variants arose through recurrent mutation events. Two variants, MYBPC3 c.1928-2A>G and MYH7 c.2681A>G, p.Glu894Gly, were found on 1 haplotype in 6 families each, supportive of a single mutation event inherited from a common ancestor. CONCLUSIONS: The majority of families with a causal variant identified have a nonunique variant. Discovery of the genetic origins of human disease forms a fundamental basis for improved understanding of disease pathogenesis and phenotype development. PMID- 28615296 TI - Ancestry, Telomere Length, and Atherosclerosis Risk. PMID- 28615297 TI - Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas. AB - Double hit (DH) or double expressor (DE) diffuse large B-cell lymphomas (DLBCL) are aggressive non-Hodgkin's lymphomas (NHL) with translocations and/or overexpressions of MYC and BCL-2, which are difficult to treat. Aurora kinase (AK) inhibition with alisertib in DH/DE-DLBCL induces cell death in ~30%, while ~70% are aneuploid and senescent cells (AASC), a mitotic escape mechanism contributing to drug resistance. These AASCs elaborated a high metabolic rate by increased AKT/mTOR and ERK/MAPK activity via BTK signaling through the chronic active B-cell receptor (BCR) pathway. Combinations of alisertib + ibrutinib or alisertib + ibrutinib + rituximab significantly reduced AASCs with enhanced intrinsic cell death. Inhibition of AK + BTK reduced phosphorylation of AKT/mTOR and ERK-1/2, upregulated phospho-H2A-X and Chk-2 (DNA damage), reduced Bcl-6, and decreased Bcl-2 and Bcl-xL and induced apoptosis by PARP cleavage. In a DE-DLBCL SCID mouse xenograft model, ibrutinib alone was inactive, while alisertib + ibrutinib was additive with a tumor growth inhibition (TGI) rate of ~25%. However, TGI for ibrutinib + rituximab was ~50% to 60%. In contrast, triple therapy showed a TGI rate of >90%. Kaplan-Meier survival analysis showed that 67% of mice were alive at day 89 with triple therapy versus 20% with ibrutinib + rituximab. All treatments were well tolerated with no changes in body weights. A novel triple therapy consisting of alisertib + ibrutinib + rituximab inhibits AASCs induced by AK inhibition in DH/DE-DLBCL leading to a significant antiproliferative signal, enhanced intrinsic apoptosis and may be of therapeutic potential in these lymphomas. Mol Cancer Ther; 16(10); 2083-93. (c)2017 AACR. PMID- 28615298 TI - Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. AB - Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines. Orlistat is a weight loss drug that inhibits gastric lipases, but is also a potent inhibitor of fatty acid synthase (FASN), which is overexpressed in many types of cancer. NanoOrl was also investigated for its potential to synergize with taxanes in TxR cell lines. Both orlistat and NanoOrl synergistically inhibited cell viability when combined with paclitaxel, docetaxel, and cabazitaxel in PC3-TxR and DU145-TxR cells, yet these combinations were also additive in parental lines. We observed synergistic levels of apoptosis in TxR cells treated with NanoOrl and docetaxel in combination. Mechanistically, the synergy between orlistat and taxanes was independent of effects on the P-glycoprotein multidrug resistance protein, as determined by an efflux activity assay. On the other hand, immunoblot and immunofluorescence staining with an anti-detyrosinated tubulin antibody demonstrated that enhanced microtubule stability was induced by combined NanoOrl and docetaxel treatment in TxR cells. Furthermore, TxR cells exhibited higher lipid synthesis, as demonstrated by 14C-choline incorporation that was abrogated by NanoOrl. These results provide a strong rationale to assess the translational potential of NanoOrl to overcome taxane resistance. Mol Cancer Ther; 16(9); 1819-30. (c)2017 AACR. PMID- 28615300 TI - Janus-like monocytes regulate postoperative ileus. PMID- 28615299 TI - Ormeloxifene Suppresses Prostate Tumor Growth and Metastatic Phenotypes via Inhibition of Oncogenic beta-catenin Signaling and EMT Progression. AB - Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), beta-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3beta. In molecular docking analysis, ormeloxifene showed proficient docking with beta-catenin and GSK3beta. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G0-G1 phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly (P < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 MUg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving beta-catenin and EMT pathway. Mol Cancer Ther; 16(10); 2267-80. (c)2017 AACR. PMID- 28615301 TI - Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus. AB - OBJECTIVE: Postoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction. DESIGN: POI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate dextran and by measuring the excretion time of a retrogradely inserted glass ball. The impact of the microbiota on intestinal peristalsis was evaluated after oral antibiotic treatment. RESULTS: We found that Cd11c-Cre+ Irf4flox/flox mice lack CD103+CD11b+ DCs, a DC subset unique to the intestine whose function is poorly understood. Their absence in the intestinal muscularis reduced pathogenic inducible nitric oxide synthase (iNOS) production by monocytes and macrophages and ameliorated POI. Pathogenic iNOS was produced in the jejunum by resident Ly6C macrophages and infiltrating chemokine receptor 2-dependent Ly6C+ monocytes, but in the colon only by the latter demonstrating differential tolerance mechanisms along the intestinal tract. Consistently, depletion of both cell subsets reduced small intestinal POI, whereas the depletion of Ly6C+ monocytes alone was sufficient to prevent large intestinal POI. The differential role of monocytes and macrophages in small and large intestinal POI suggested a potential role of the intestinal microbiota. Indeed, antibiotic treatment reduced iNOS levels and ameliorated POI. CONCLUSIONS: Our findings reveal that CD103+CD11b+ DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI. PMID- 28615302 TI - CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus. AB - OBJECTIVE: Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility. DESIGN: IM was performed in mice with defective monocyte migration to tissues (C C motif chemokine receptor 2, Ccr2-/ - mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MPhis) during onset and resolution of ME inflammation. RESULTS: At early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2 -/- mice. However, GI transit recovery after IM was significantly delayed in Ccr2 -/- mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MPhis acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MPhi colony stimulating factor 1 enhanced monocyte recruitment and MPhi differentiation and ameliorated GI transit in Ccr2 -/- mice. CONCLUSION: Our study reveals a critical role for monocyte-derived MPhis in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MPhi physiological repair functions. PMID- 28615303 TI - Favouring modulation of circulating lipoproteins and lipid loading capacity by direct antiviral agents grazoprevir/elbasvir or ledipasvir/sofosbuvir treatment against chronic HCV infection. AB - OBJECTIVE: Lipid homoeostasis is disturbed in patients with HCV infection. Direct acting antiviral agent (DAA) treatment eradicates chronic HCV viraemia, but the dynamics of lipid components remain elusive. This study investigates the clinical manifestation and mechanistic relevance of plasma triglyceride (TG), cholesterol (Chol), lipoproteins and apolipoproteins (apos) after DAA treatment. DESIGN: Twenty-four patients with chronic genotype 1 (GT1) HCV treated with elbasvir/grazoprevir or ledipasvir/sofosbuvir for 12 weeks, and followed-up thereafter, were recruited. Their TG, Chol, apoAI and apoB levels were quantified in plasma samples and individually fractionated lipoprotein of various classes. Liver fibrosis was evaluated using the FIB-4 Score. The TG and Chol loading capacities were calculated with normalisation to apoB, which represents per very low density lipoprotein (VLDL) and LDL particle unit RESULTS: DAA treatment achieved a sustained virological response rate of 91.7% and reduced the FIB-4 Score. Relative to the baseline, the plasma TG level was reduced but the Chol level increased gradually. Plasma apoB levels and apoB/apoAI ratio were transiently downregulated as early as the first 4 weeks of treatment. The TG and Chol loading capacities in VLDL were elevated by ~20% during the period of DAA treatment and had steadily increased by 100% at follow-up. Furthermore, the TG-to Chol ratio in VLDL was increased, while the ratio in LDL was reduced, indicating an efficient catabolism. CONCLUSION: The DAA treatment of patients with chronic hepatitis C might lead to efficient HCV eradication and hepatic improvement concomitantly evolving with favouring lipoprotein/apo metabolisms. PMID- 28615304 TI - Ibuprofen exposure in early neonatal life does not affect renal function in young adolescence. AB - INTRODUCTION: Ibuprofen exposure results in acute transient renal dysfunction in preterm neonates, but we are unaware of data on long-term renal safety. METHODS: In a previously studied cohort of extreme low birth weight (ELBW, <1000 g) cases, the PREMATurity as predictor of children's Cardiovascular-renal Health study generated data on renal function (renal length, estimated glomerular filtration rate based on cystatin C (eGFRcysC) at the age of 11 years. This data set in 93 ELBW cases may also generate data on long-term drug safety on ibuprofen. In this post hoc analysis, we linked markers of renal function in young adolescence in ELBW cases with their perinatal (prenatal maternal, setting at birth, treatment modalities including drug prescription during neonatal stay, neonatal creatinine values, postdischarge growth) characteristics, including but not limited to ibuprofen exposure during neonatal stay. RESULTS: Ibuprofen exposure was not associated with significant differences in renal length or eGFRcysC. Moreover, we were unable to identify any other risk factor (perinatal characteristics, postnatal creatinine trends, postdischarge growth) on renal outcome in this cohort. CONCLUSIONS: Neonatal exposure to ibuprofen did not affect renal function. Larger studies are needed to explore the confounders of variability in renal function in former ELBW cases. This matters since ELBW relates to risk for hypertension, cardiovascular events and renal disease in later life and identification of risk factors holds the promise of secondary prevention. TRIAL REGISTRATION NUMBER: NCT02147457. PMID- 28615305 TI - Prenatal markers and longitudinal follow-up in simple and complex gastroschisis. AB - OBJECTIVE: We aimed to identify gestational-age corrected prenatal ultrasound markers of complex gastroschisis, and to compare physical growth and neurodevelopment between children with simple and complex gastroschisis. DESIGN: We included prenatally diagnosed gastroschisis patients from 2000 to 2012 who joined our longitudinal follow-up programme. Associations between complex gastroschisis and prenatal ultrasound markers collected at 30 weeks' gestation and prior to delivery were tested using logistic regression. Physical growth (SD scores (SDS)), mental and psychomotor developmental index (MDI, PDI; Bayley Scales of Infant Development) were recorded at 12 and 24 months. Data were analysed using general linear models and compared with population norms. RESULTS: Data of 61 children were analysed (82% of eligible cases). Extra-abdominal bowel dilatation at 30 weeks' gestation was significantly associated with complex gastroschisis (OR (95% CI): 5.00 (1.09 to 22.98)), with a high negative (88%) but low positive (40%) predictive value. The mean (95% CI) height SDS at 12 months ( 0.46 (-0.82 to -0.11)), and weight SDS at 12 and 24 months (-0.45 (-0.85 to 0.05), and -0.44 (-0.87 to -0.01), respectively) fell significantly below 0 SDS. MDI and PDI were significantly below 100 at 24 months; 93 (88 to 99) and 83 (78 to 87), respectively). Children with complex gastroschisis had a significantly lower PDI (76 (68 to 84)) than those with simple gastroschisis (94 (90 to 97), p<0.001). CONCLUSIONS: Prenatal ultrasound markers could not reliably distinguish between simple and complex gastroschisis. Children with complex gastroschisis may be at increased risk for delayed psychomotor development; they should be monitored more closely, and offered timely intervention. PMID- 28615306 TI - "Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension." Irene Lang, Bernhard C. Meyer, Takeshi Ogo, Hiromi Matsubara, Marcin Kurzyna, Hossein-Ardeschir Ghofrani, Eckhard Mayer and Philippe Brenot. Eur Respir Rev 2017; 26: 160119. PMID- 28615307 TI - The role of high-resolution computed tomography in the follow-up of diffuse lung disease: Number 2 in the Series "Radiology" Edited by Nicola Sverzellati and Sujal Desai. AB - High-resolution computed tomography (HRCT) of the lung is a key component of the multidisciplinary approach to diagnosis in diffuse lung disease (DLD). HRCT also plays an important role in the follow-up of patients with established DLD. In this respect, serial HRCT examinations may provide valuable information that cannot be determined from clinical history and other diagnostic tests, such as pulmonary function tests. Important roles of HRCT in this context include assisting in determining prognosis, monitoring for the efficacy of treatment, detecting progression of disease or complications, and evaluating patients with worsening or acute symptoms. Both clinicians and radiologists should be aware of the expected evolution of HRCT changes in a variety of DLDs. The goals of this paper are to discuss: 1) the expected evolution of HRCT findings over time in common DLDs; 2) the role of serial HRCT examinations in formulating an initial diagnosis; and 3) the role of HRCT in the follow-up of patients with known DLD. PMID- 28615308 TI - Mechanisms, measurement and management of exertional dyspnoea in asthma: Number 5 in the Series "Exertional dyspnoea" Edited by Pierantonio Laveneziana and Piergiuseppe Agostoni. AB - Asthma is a heterogeneous condition, with dyspnoea during exercise affecting individuals to a variable degree. This narrative review explores the mechanisms and measurement of exertional dyspnoea in asthma and summarises the available evidence for the efficacy of various interventions on exertional dyspnoea. Studies on the mechanisms of dyspnoea in asthma have largely utilised direct bronchoprovocation challenges, rather than exercise, which may invoke different physiological mechanisms. Thus, the description of dyspnoea during methacholine challenge can differ from what is experienced during daily activities, including exercise. Dyspnoea perception during exercise is influenced by many interacting variables, such as asthma severity and phenotype, bronchoconstriction, dynamic hyperinflation, respiratory drive and psychological factors. In addition to the intensity of dyspnoea, the qualitative description of dyspnoea may give important clues as to the underlying mechanism and may be an important endpoint for future interventional studies. There is currently little evidence demonstrating whether pharmacological or non-pharmacological interventions specifically improve exertional dyspnoea, which is an important area for future research. PMID- 28615309 TI - The frequent and underrecognised co-occurrence of acute exacerbated COPD and depression warrants screening: a systematic review. AB - Patients with acute exacerbated chronic obstructive pulmonary disease (AECOPD) and concurrent depression suffer significant psychological stress and decreased quality of life. The aim of this study was to collate data, guidelines and recommendations from publications on the screening and management of depressive mood disorders in patients hospitalised with AECOPD.We systematically searched four databases for publications reporting screening or management of depression in patients hospitalised for AECOPD. The identification of articles was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.Out of 1494 original articles screened, 35 met all inclusion criteria. These report a prevalence of depression in AECOPD ranging between 9.5% and 85.6%. Some studies report high postadmission mortality rates for depressive AECOPD patients, and higher readmission rates in depressive versus nondepressive AECOPD patients. Importantly, none of the 35 publications included suggestions on the screening and management of depression in AECOPD.Depression and AECOPD frequently co-occur, and this worsens outcomes. Yet we did not find recommendations on management, and few interventional studies. Patients hospitalised with AECOPD should be systematically screened for depression and treatment recommendations should be developed for these patients. Randomised studies on how to screen and treat depression in hospitalised AECOPD are necessary. PMID- 28615310 TI - Physiology in Perspective: Structure and Function-Anatomy and Physiology Are Integral. PMID- 28615311 TI - Modeling Physiological Events in 2D vs. 3D Cell Culture. AB - Cell culture has become an indispensable tool to help uncover fundamental biophysical and biomolecular mechanisms by which cells assemble into tissues and organs, how these tissues function, and how that function becomes disrupted in disease. Cell culture is now widely used in biomedical research, tissue engineering, regenerative medicine, and industrial practices. Although flat, two dimensional (2D) cell culture has predominated, recent research has shifted toward culture using three-dimensional (3D) structures, and more realistic biochemical and biomechanical microenvironments. Nevertheless, in 3D cell culture, many challenges remain, including the tissue-tissue interface, the mechanical microenvironment, and the spatiotemporal distributions of oxygen, nutrients, and metabolic wastes. Here, we review 2D and 3D cell culture methods, discuss advantages and limitations of these techniques in modeling physiologically and pathologically relevant processes, and suggest directions for future research. PMID- 28615312 TI - Stem Cells in Repair of Gastrointestinal Epithelia. AB - Among the endodermal tissues of adult mammals, the gastrointestinal (GI) epithelium exhibits the highest turnover rate. As the ingested food moves along the GI tract, gastric acid, digestive enzymes, and gut resident microbes aid digestion as well as nutrient and mineral absorption. Due to the harsh luminal environment, replenishment of new epithelial cells is essential to maintain organ structure and function during routine turnover and injury repair. Tissue-specific adult stem cells in the GI tract serve as a continuous source for this immense regenerative activity. Tissue homeostasis is achieved by a delicate balance between gain and loss of cells. In homeostasis, temporal tissue damage is rapidly restored by well-balanced tissue regeneration, whereas prolonged imbalance may result in diverse pathologies of homeostasis and injury repair. Starting with a summary of the current knowledge of GI tract homeostasis, we continue with providing models of acute injury and chronic diseases. Finally, we will discuss how primary organoid cultures allow new insights into the mechanisms of homeostasis, injury repair, and disease, and how this novel 3D culture system has the potential to translate into the clinic. PMID- 28615314 TI - Mitochondria and Reactive Oxygen Species Contribute to Neurogenic Hypertension. AB - Beyond its primary role as fuel generators, mitochondria are engaged in a variety of cellular processes, including redox homeostasis. Mitochondrial dysfunction, therefore, may have a profound impact on high-energy-demanding organs such as the brain. Here, we review the roles of mitochondrial biogenesis and bioenergetics, and their associated signaling in cellular redox homeostasis, and illustrate their contributions to the oxidative stress-related neural mechanism of hypertension, focusing on specific brain areas that are involved in the generation or modulation of sympathetic outflows to the cardiovascular system. We also highlight future challenges of research on mitochondrial physiology and pathophysiology. PMID- 28615315 TI - Hyperresponsiveness: Relating the Intact Airway to the Whole Lung. AB - We relate changes of the airway wall to the response of the intact airway and the whole lung. We address how mechanical conditions and specific structural changes for an airway contribute to hyperresponsiveness resistant to deep inspiration. This review conveys that the origins of hyperresponsiveness do not devolve into an abnormality at single structural level but require examination of the complex interplay of all the parts. PMID- 28615313 TI - Metabolic Regulation of Angiogenesis in Diabetes and Aging. AB - Impaired angiogenesis and endothelial dysfunction are hallmarks of diabetes and aging. Clinical efforts at promoting angiogenesis have largely focused on growth factor pathways, with mixed results. Recently, a new repertoire of endothelial intracellular molecules critical to endothelial metabolism has emerged as playing an important role in regulating angiogenesis. This review thus focuses on the emerging importance and therapeutic potential of these proteins and of endothelial bioenergetics in diabetes and aging. PMID- 28615317 TI - Orientation and repositioning of chromosomes correlate with cell geometry dependent gene expression. AB - Extracellular matrix signals from the microenvironment regulate gene expression patterns and cell behavior. Using a combination of experiments and geometric models, we demonstrate correlations between cell geometry, three-dimensional (3D) organization of chromosome territories, and gene expression. Fluorescence in situ hybridization experiments showed that micropatterned fibroblasts cultured on anisotropic versus isotropic substrates resulted in repositioning of specific chromosomes, which contained genes that were differentially regulated by cell geometries. Experiments combined with ellipsoid packing models revealed that the mechanosensitivity of chromosomes was correlated with their orientation in the nucleus. Transcription inhibition experiments suggested that the intermingling degree was more sensitive to global changes in transcription than to chromosome radial positioning and its orientations. These results suggested that cell geometry modulated 3D chromosome arrangement, and their neighborhoods correlated with gene expression patterns in a predictable manner. This is central to understanding geometric control of genetic programs involved in cellular homeostasis and the associated diseases. PMID- 28615316 TI - ORAI Calcium Channels. AB - In this review article, we discuss the different gene products and translational variants of ORAI proteins and their contribution to the makeup of different native calcium-conducting channels with distinct compositions and modes of activation. We also review the different modes of regulation of these distinct calcium channels and their impact on downstream cellular signaling controlling important physiological functions. PMID- 28615318 TI - Miro1-mediated mitochondrial positioning shapes intracellular energy gradients required for cell migration. AB - It has long been postulated, although never directly demonstrated, that mitochondria are strategically positioned in the cytoplasm to meet local requirements for energy production. Here we show that positioning of mitochondria in mouse embryonic fibroblasts (MEFs) determines the shape of intracellular energy gradients in living cells. Specifically, the ratio of ATP to ADP was highest at perinuclear areas of dense mitochondria and gradually decreased as more-peripheral sites were approached. Furthermore, the majority of mitochondria were positioned at the ventral surface of the cell, correlating with high ATP:ADP ratios close to the ventral membrane, which rapidly decreased toward the dorsal surface. We used cells deficient for the mitochondrial Rho-GTPase 1 (Miro1), an essential mediator of microtubule-based mitochondrial motility, to study how changes in mitochondrial positioning affect cytoplasmic energy distribution and cell migration, an energy-expensive process. The mitochondrial network in Miro1-/ MEFs was restricted to the perinuclear area, with few mitochondria present at the cell periphery. This change in mitochondrial distribution dramatically reduced the ratio of ATP to ADP at the cell cortex and disrupted events essential for cell movement, including actin dynamics, lamellipodia protrusion, and membrane ruffling. Cell adhesion status was also affected by changes in mitochondrial positioning; focal adhesion assembly and stability was decreased in Miro1-/- MEFs compared with Miro1+/+ MEFs. Consequently Miro1-/- MEFs migrated slower than control cells during both collective and single-cell migration. These data establish that Miro1-mediated mitochondrial positioning at the leading edge provides localized energy production that promotes cell migration by supporting membrane protrusion and focal adhesion stability. PMID- 28615319 TI - Retinoschisin is linked to retinal Na/K-ATPase signaling and localization. AB - Mutations in the RS1 gene cause X-linked juvenile retinoschisis (XLRS), a hereditary retinal dystrophy. We recently showed that retinoschisin, the protein encoded by RS1, regulates ERK signaling and apoptosis in retinal cells. In this study, we explored an influence of retinoschisin on the functionality of the Na/K ATPase, its interaction partner at retinal plasma membranes. We show that retinoschisin binding requires the beta2-subunit of the Na/K-ATPase, whereas the alpha-subunit is exchangeable. Our investigations revealed no effect of retinoschisin on Na/K-ATPase-mediated ATP hydrolysis and ion transport. However, we identified an influence of retinoschisin on Na/K-ATPase-regulated signaling cascades and Na/K-ATPase localization. In addition to the known ERK deactivation, retinoschisin treatment of retinoschisin-deficient (Rs1h-/Y ) murine retinal explants decreased activation of Src, an initial transmitter in Na/K-ATPase signal transduction, and of Ca2+ signaling marker Camk2. Immunohistochemistry on murine retinae revealed an overlap of the retinoschisin-Na/K-ATPase complex with proteins involved in Na/K-ATPase signaling, such as caveolin, phospholipase C, Src, and the IP3 receptor. Finally, retinoschisin treatment altered Na/K-ATPase localization in photoreceptors of Rs1h-/Y retinae. Taken together, our results suggest a regulatory effect of retinoschisin on Na/K-ATPase signaling and localization, whereas Na/K-ATPase-dysregulation caused by retinoschisin deficiency could represent an initial step in XLRS pathogenesis. PMID- 28615320 TI - Differential phosphorylation signals control endocytosis of GPR15. AB - GPR15 is an orphan G protein-coupled receptor (GPCR) that serves for an HIV coreceptor and was also recently found as a novel homing receptor for T-cells implicated in colitis. We show that GPR15 undergoes a constitutive endocytosis in the absence of ligand. The endocytosis was clathrin dependent and partially dependent on beta-arrestin in HEK293 cells, and nearly half of the internalized GPR15 receptors were recycled to the plasma membrane. An Ala mutation of the distal C-terminal Arg-354 or Ser-357, which forms a consensus phosphorylation site for basophilic kinases, markedly reduced the endocytosis, whereas phosphomimetic mutation of Ser-357 to Asp did not. Ser-357 was phosphorylated in vitro by multiple kinases, including PKA and PKC, and pharmacological activation of these kinases enhanced both phosphorylation of Ser-357 and endocytosis of GPR15. These results suggested that Ser-357 phosphorylation critically controls the ligand-independent endocytosis of GPR15. The functional role of Ser-357 in endocytosis was distinct from that of a conserved Ser/Thr cluster in the more proximal C-terminus, which was responsible for the beta-arrestin- and GPCR kinase dependent endocytosis of GPR15. Thus phosphorylation signals may differentially control cell surface density of GPR15 through endocytosis. PMID- 28615321 TI - PAR proteins regulate maintenance-phase myosin dynamics during Caenorhabditis elegans zygote polarization. AB - Establishment of anterior-posterior polarity in the Caenorhabditis elegans zygote requires two different processes: mechanical activity of the actin-myosin cortex and biochemical activity of partitioning-defective (PAR) proteins. Here we analyze how PARs regulate the behavior of the cortical motor protein nonmuscle myosin (NMY-2) to complement recent efforts that investigate how PARs regulate the Rho GTPase CDC-42, which in turn regulates the actin-myosin cortex. We find that PAR-3 and PAR-6 concentrate CDC-42-dependent NMY-2 in the anterior cortex, whereas PAR-2 inhibits CDC-42-dependent NMY-2 in the posterior domain by inhibiting PAR-3 and PAR-6. In addition, we find that PAR-1 and PAR-3 are necessary for inhibiting movement of NMY-2 across the cortex. PAR-1 protects NMY 2 from being moved across the cortex by forces likely originating in the cytoplasm. Meanwhile, PAR-3 stabilizes NMY-2 against PAR-2 and PAR-6 dynamics on the cortex. We find that PAR signaling fulfills two roles: localizing NMY-2 to the anterior cortex and preventing displacement of the polarized cortical actin myosin network. PMID- 28615322 TI - In vivo manipulation of the extracellular matrix induces vascular regression in a basal chordate. AB - We investigated the physical role of the extracellular matrix (ECM) in vascular homeostasis in the basal chordate Botryllus schlosseri, which has a large, transparent, extracorporeal vascular network encompassing an area >100 cm2 We found that the collagen cross-linking enzyme lysyl oxidase is expressed in all vascular cells and that in vivo inhibition using beta-aminopropionitrile (BAPN) caused a rapid, global regression of the entire network, with some vessels regressing >10 mm within 16 h. BAPN treatment changed the ultrastructure of collagen fibers in the vessel basement membrane, and the kinetics of regression were dose dependent. Pharmacological inhibition of both focal adhesion kinase (FAK) and Raf also induced regression, and levels of phosphorylated FAK in vascular cells decreased during BAPN treatment and FAK inhibition but not Raf inhibition, suggesting that physical changes in the vessel ECM are detected via canonical integrin signaling pathways. Regression is driven by apoptosis and extrusion of cells through the basal lamina, which are then engulfed by blood borne phagocytes. Extrusion and regression occurred in a coordinated manner that maintained vessel integrity, with no loss of barrier function. This suggests the presence of regulatory mechanisms linking physical changes to a homeostatic, tissue-level response. PMID- 28615323 TI - Generic membrane-spanning features endow IRE1alpha with responsiveness to membrane aberrancy. AB - Altered cellular lipid composition activates the endoplasmic reticulum unfolded protein response (UPR), and UPR signaling effects important changes in lipid metabolism. Secondary effects on protein folding homeostasis likely contribute to UPR activation, but deletion of the unfolded protein stress-sensing luminal domain of the UPR transducers PERK and IRE1alpha does not abolish their responsiveness to lipid perturbation. This finding suggests that PERK and IRE1alpha also directly recognize the membrane aberrancy wrought by lipid perturbation. However, beyond the need for a transmembrane domain (TMD), little is known about the features involved. Regulation of the UPR transducers entails changes in their oligomeric state and is easily corrupted by overexpression. We used CRISPR/Cas9-mediated gene editing of the Ern1 locus to study the role of the TMD in the ability of the endogenous IRE1alpha protein to recognize membrane aberrancy in mammalian cells. Conducted in the background of a point mutation that isolated the response to membrane aberrancy induced by palmitate from unfolded protein stress, our analysis shows that generic membrane-spanning features of the TMD are sufficient for IRE1alpha's responsiveness to membrane aberrancy. Our data suggest that IRE1alpha's conserved TMD may have been selected for features imparting a relatively muted response to acyl-chain saturation. PMID- 28615324 TI - HiHiMap: single-cell quantitation of histones and histone posttranslational modifications across the cell cycle by high-throughput imaging. AB - We describe High-throughput Histone Mapping (HiHiMap), a high-throughput imaging method to measure histones and histone posttranslational modifications (PTMs) in single cells. HiHiMap uses imaging-based quantification of DNA and cyclin A to stage individual cells in the cell cycle to determine the levels of histones or histone PTMs in each stage of the cell cycle. As proof of principle, we apply HiHiMap to measure the level of 21 core histones, histone variants, and PTMs in primary, immortalized, and transformed cells. We identify several histone modifications associated with oncogenic transformation. HiHiMap allows the rapid, high-throughput study of histones and histone PTMs across the cell cycle and the study of subpopulations of cells. PMID- 28615325 TI - Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis. AB - During sepsis and shock states, mitochondrial dysfunction occurs. Consequently, adaptive mechanisms, such as fission, fusion, and mitophagy, are induced to eliminate damaged portions or entire dysfunctional mitochondria. The regulatory PINK1/Parkin and DJ-1 pathways are strongly induced by mitochondrial depolarization, although a direct link between loss of mitochondrial membrane potential (DeltaPsi) and mitophagy has not been identified. Mitochondria also buffer Ca2+, and their buffering capacity is dependent on DeltaPsi Here, we characterize a role for calcium/calmodulin-dependent protein kinase (CaMK) I in the regulation of these mechanisms. Loss of DeltaPsi with either pharmacologic depolarization or LPS leads to Ca2+-dependent mitochondrial recruitment and activation of CaMKI that precedes the colocalization of PINK1/Parkin and DJ-1. CaMKI is required and serves as both a PINK1 and Parkin kinase. The mechanisms operate in both immune and nonimmune cells and are induced in in vivo models of endotoxemia, sepsis, and hemorrhagic shock. These data support the idea that CaMKI links mitochondrial stress with the PINK1/Parkin and DJ-1 mechanisms of mitophagy.-Zhang, X., Yuan, D., Sun, Q., Xu, L., Lee, E., Lewis, A. J., Zuckerbraun, B. S., Rosengart, M. R. Calcium/calmodulin-dependent protein kinase regulates the PINK1/Parkin and DJ-1 pathways of mitophagy during sepsis. PMID- 28615326 TI - Prenatal nicotinic exposure prolongs superior laryngeal C-fiber-mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation. AB - Maternal cigarette smoke, including prenatal nicotinic exposure (PNE), is responsible for sudden infant death syndrome (SIDS). The fatal events of SIDS are characterized by severe bradycardia and life-threatening apneas. Although activation of transient receptor potential vanilloid 1 (TRPV1) of superior laryngeal C fibers (SLCFs) could induce bradycardia and apnea and has been implicated in SIDS pathogenesis, how PNE affects the SLCF-mediated cardiorespiratory responses remains unexplored. Here, we tested the hypothesis that PNE would aggravate the SLCF-mediated apnea and bradycardia via up regulating TRPV1 expression and excitation of laryngeal C neurons in the nodose/jugular (N/J) ganglia. To this end, we compared the following outcomes between control and PNE rat pups at postnatal days 11-14: 1) the cardiorespiratory responses to intralaryngeal application of capsaicin (10 ug/ml, 50 ul), a selective stimulant for TRPV1 receptors, in anesthetized preparation; 2) immunoreactivity and mRNA of TRPV1 receptors of laryngeal sensory C neurons in the N/J ganglia retrogradely traced by 1,1'-dioctadecyl-3,3,3',3' tetramethylindocarbocyanine perchlorate; and 3) TRPV1 currents and electrophysiological characteristics of these neurons by using whole-cell patch clamp technique in vitro Our results showed that PNE markedly prolonged the apneic response and exacerbated the bradycardic response to intralaryngeal perfusion of capsaicin, which was associated with up-regulation of TRPV1 expression in laryngeal C neurons. In addition, PNE increased the TRPV1 currents, depressed the slow delayed rectifier potassium currents, and increased the resting membrane potential of these neurons. Our results suggest that PNE is capable of aggravating the SLCF-mediated apnea and bradycardia through TRPV1 sensitization and neuronal excitation, which may contribute to the pathogenesis of SIDS.-Gao, X., Zhao, L., Zhuang, J., Zang, N., Xu, F. Prenatal nicotinic exposure prolongs superior laryngeal C-fiber-mediated apnea and bradycardia through enhancing neuronal TRPV1 expression and excitation. PMID- 28615327 TI - Where are we now? A multicountry qualitative study to explore access to pre antiretroviral care services: a precursor to antiretroviral therapy initiation. AB - OBJECTIVE: To explore barriers and facilitators to accessing postdiagnosis HIV care in five sub-Saharan African countries. METHODS: In-depth interviews were conducted with 77 people living with HIV (PLHIV) in pre-antiretroviral therapy care or not-yet-in care and 46 healthcare workers. Participants were purposely selected from health and demographic surveillance sites in Karonga (Malawi), Manicaland (Zimbabwe), uMkhanyakude (South Africa), Kisesa (Tanzania) and Rakai and Kyamulibwa (Uganda). Thematic content analysis was conducted, guided by the constructs of affordability, availability and acceptability of care.- RESULTS: Affordability: Transport and treatment costs were a barrier to HIV care, although some participants travelled to distant clinics to avoid being seen by people who knew them or for specific services. Broken equipment and drug stock-outs in local clinics could also necessitate travel to other facilities. Availability: Some facilities did not offer full HIV care, or only offered all services intermittently. PLHIV who frequently travelled complained that care was seldom available to them in places they visited. Acceptability: Severe pain or sickness was a key driver for accessing postdiagnosis care, whereas asymptomatic PLHIV often delayed care-seeking. A belief in witchcraft was a deterrent to accessing clinical care following diagnosis. Changing antiretroviral therapy guidelines generated uncertainty among PLHIV about when to start treatment and delayed postdiagnosis care. PLHIV reported that healthcare workers' knowledge, attitudes and behaviours, and their ability to impart health education, also influenced whether they accessed HIV care. CONCLUSION: Despite efforts to decentralise services over the past decade, many barriers to accessing HIV care persist. There is a need to increase sustained access to care for PLHIV not yet on treatment, with initiatives that encompass biomedical aspects of care alongside considerations for individual and collective challenges they faced. A failure to do so may undermine efforts to achieve universal access to antiretroviral therapy. PMID- 28615328 TI - Effect of eye position during human visual-vestibular integration of heading perception. AB - Visual and inertial stimuli provide heading discrimination cues. Integration of these multisensory stimuli has been demonstrated to depend on their relative reliability. However, the reference frame of visual stimuli is eye centered while inertia is head centered, and it remains unclear how these are reconciled with combined stimuli. Seven human subjects completed a heading discrimination task consisting of a 2-s translation with a peak velocity of 16 cm/s. Eye position was varied between 0 degrees and +/-25 degrees left/right. Experiments were done with inertial motion, visual motion, or a combined visual-inertial motion. Visual motion coherence varied between 35% and 100%. Subjects reported whether their perceived heading was left or right of the midline in a forced-choice task. With the inertial stimulus the eye position had an effect such that the point of subjective equality (PSE) shifted 4.6 +/- 2.4 degrees in the gaze direction. With the visual stimulus the PSE shift was 10.2 +/- 2.2 degrees opposite the gaze direction, consistent with retinotopic coordinates. Thus with eccentric eye positions the perceived inertial and visual headings were offset ~15 degrees . During the visual-inertial conditions the PSE varied consistently with the relative reliability of these stimuli such that at low visual coherence the PSE was similar to that of the inertial stimulus and at high coherence it was closer to the visual stimulus. On average, the inertial stimulus was weighted near Bayesian ideal predictions, but there was significant deviation from ideal in individual subjects. These findings support visual and inertial cue integration occurring in independent coordinate systems.NEW & NOTEWORTHY In multiple cortical areas visual heading is represented in retinotopic coordinates while inertial heading is in body coordinates. It remains unclear whether multisensory integration occurs in a common coordinate system. The experiments address this using a multisensory integration task with eccentric gaze positions making the effect of coordinate systems clear. The results indicate that the coordinate systems remain separate to the perceptual level and that during the multisensory task the perception depends on relative stimulus reliability. PMID- 28615330 TI - The visual encoding of purely proprioceptive intermanual tasks is due to the need of transforming joint signals, not to their interhemispheric transfer. AB - To perform goal-oriented hand movement, humans combine multiple sensory signals (e.g., vision and proprioception) that can be encoded in various reference frames (body centered and/or exo-centered). In a previous study (Tagliabue M, McIntyre J. PLoS One 8: e68438, 2013), we showed that, when aligning a hand to a remembered target orientation, the brain encodes both target and response in visual space when the target is sensed by one hand and the response is performed by the other, even though both are sensed only through proprioception. Here we ask whether such visual encoding is due 1) to the necessity of transferring sensory information across the brain hemispheres, or 2) to the necessity, due to the arms' anatomical mirror symmetry, of transforming the joint signals of one limb into the reference frame of the other. To answer this question, we asked subjects to perform purely proprioceptive tasks in different conditions: Intra, the same arm sensing the target and performing the movement; Inter/Parallel, one arm sensing the target and the other reproducing its orientation; and Inter/Mirror, one arm sensing the target and the other mirroring its orientation. Performance was very similar between Intra and Inter/Mirror (conditions not requiring joint-signal transformations), while both differed from Inter/Parallel. Manipulation of the visual scene in a virtual reality paradigm showed visual encoding of proprioceptive information only in the latter condition. These results suggest that the visual encoding of purely proprioceptive tasks is not due to interhemispheric transfer of the proprioceptive information per se, but to the necessity of transforming joint signals between mirror-symmetric limbs.NEW & NOTEWORTHY Why does the brain encode goal-oriented, intermanual tasks in a visual space, even in the absence of visual feedback about the target and the hand? We show that the visual encoding is not due to the transfer of proprioceptive signals between brain hemispheres per se, but to the need, due to the mirror symmetry of the two limbs, of transforming joint angle signals of one arm in different joint signals of the other. PMID- 28615331 TI - Comparison of the VTA and LC response to methylphenidate: a concomitant behavioral and neuronal study of adolescent male rats. AB - Methylphenidate (MPD), also known as Ritalin, is a psychostimulant used to treat attention deficit hyperactivity disorder. However, it is increasingly being misused by normal adolescents for recreation and academic advantage. Therefore, it is important to elucidate the behavioral and neurophysiological effects of MPD in normal subjects. MPD inhibits the reuptake of catecholamines, mainly found in the ventral tegmental area (VTA) and locus coeruleus (LC). The VTA and LC normally mediate attention, motivation, and drug reward behaviors. Selective neuronal connections between the VTA and LC have been identified implicating regular interaction between the structures. The objective of this study was to compare the neuronal responses of the VTA and LC to MPD in normal adolescent rats. Animals were implanted with permanent electrodes in the VTA and LC, and neuronal units were recorded following acute and repetitive (chronic) saline or 0.6, 2.5, or 10.0 mg/kg MPD exposure. Animals displayed either behavioral sensitization or tolerance to all three doses of MPD. Acute MPD exposure elicited excitation in the majority of all VTA and LC units. Chronic MPD exposure elicited a further increase in VTA and LC neuronal activity in animals exhibiting behavioral sensitization and an attenuation in VTA and LC neuronal activity in animals exhibiting behavioral tolerance, demonstrating neurophysiological sensitization and tolerance, respectively. The similar pattern in VTA and LC unit activity suggests that the two structures are linked in their response to MPD. These results may help determine the exact mechanism of action of MPD, resulting in optimized treatment of patients.NEW & NOTEWORTHY The same dose of 0.6, 2.5, and 10 mg/kg methylphenidate (MPD) elicits either behavioral sensitization or tolerance in adolescent rats. There is a direct correlation between the ventral tegmental area (VTA) and locus coeruleus (LC) neuronal response to chronic MPD exposure. Both the VTA and LC are involved in the behavioral and neurophysiological effects of chronic MPD. PMID- 28615329 TI - Physiological properties of brain-machine interface input signals. AB - Brain-machine interfaces (BMIs), also called brain-computer interfaces (BCIs), decode neural signals and use them to control some type of external device. Despite many experimental successes and terrific demonstrations in animals and humans, a high-performance, clinically viable device has not yet been developed for widespread usage. There are many factors that impact clinical viability and BMI performance. Arguably, the first of these is the selection of brain signals used to control BMIs. In this review, we summarize the physiological characteristics and performance-including movement-related information, longevity, and stability-of multiple types of input signals that have been used in invasive BMIs to date. These include intracortical spikes as well as field potentials obtained inside the cortex, at the surface of the cortex (electrocorticography), and at the surface of the dura mater (epidural signals). We also discuss the potential for future enhancements in input signal performance, both by improving hardware and by leveraging the knowledge of the physiological characteristics of these signals to improve decoding and stability. PMID- 28615333 TI - Excitability and firing behavior of single slow motor axons transmitting natural repetitive firing of human motoneurons. AB - Excitability of motor axons is critically important for realizing their main function, i.e., transmitting motoneuron firing to muscle fibers. The present study was designed to explore excitability recovery and firing behavior in single slow axons transmitting human motoneuron firing during voluntary muscle contractions. The abductor digiti minimi, flexor carpi ulnaris, and tibialis anterior were investigated during threshold stimulation of corresponding motor nerves. Motor unit (MU) firing index in response to testing volleys evoking M responses was used as a physiological measure of axonal excitability and its changes throughout a target interspike interval (ISI) were explored. It was shown that axons displayed an early irresponsive period (within the first ~2-5 ms of a target ISI) that was followed by a responsive period (for the next 5-17 ms of the ISI), in which MUs fired axonal doublets, and a later irresponsive period. At the beginning of the responsive period, M-responses showed small latency delays. However, since at that ISI moment, MUs displayed excitability recovery with high firing index, slight latency changes may be considered as a functionally insignificant phenomenon. The duration of axonal doublet ISIs did not depend on motoneuron firing frequencies (range 4.3-14.6 imp/s). The question of whether or not traditionally described axonal recovery excitability cycle is realistic in natural motor control is discussed. In conclusion, the present approach, exploring, for the first time, excitability recovery in single slow axons during motoneuron natural activation, can provide further insight into axonal firing behavior in normal states and diseases.NEW & NOTEWORTHY Excitability of single slow axons was estimated by motor unit firing index in response to motor nerve stimulation, and its changes throughout a target interspike interval were explored during transmitting human motoneuron natural firing. It was found that axons exhibited early irresponsive, responsive, and later irresponsive periods. Findings question whether the traditionally described axonal excitability recovery cycle is realistic in natural motor control. PMID- 28615332 TI - Different roles for inhibition in the rhythm-generating respiratory network. AB - Unraveling the interplay of excitation and inhibition within rhythm-generating networks remains a fundamental issue in neuroscience. We use a biophysical model to investigate the different roles of local and long-range inhibition in the respiratory network, a key component of which is the pre-Botzinger complex inspiratory microcircuit. Increasing inhibition within the microcircuit results in a limited number of out-of-phase neurons before rhythmicity and synchrony degenerate. Thus unstructured local inhibition is destabilizing and cannot support the generation of more than one rhythm. A two-phase rhythm requires restructuring the network into two microcircuits coupled by long-range inhibition in the manner of a half-center. In this context, inhibition leads to greater stability of the two out-of-phase rhythms. We support our computational results with in vitro recordings from mouse pre-Botzinger complex. Partial excitation block leads to increased rhythmic variability, but this recovers after blockade of inhibition. Our results support the idea that local inhibition in the pre Botzinger complex is present to allow for descending control of synchrony or robustness to adverse conditions like hypoxia. We conclude that the balance of inhibition and excitation determines the stability of rhythmogenesis, but with opposite roles within and between areas. These different inhibitory roles may apply to a variety of rhythmic behaviors that emerge in widespread pattern generating circuits of the nervous system.NEW & NOTEWORTHY The roles of inhibition within the pre-Botzinger complex (preBotC) are a matter of debate. Using a combination of modeling and experiment, we demonstrate that inhibition affects synchrony, period variability, and overall frequency of the preBotC and coupled rhythmogenic networks. This work expands our understanding of ubiquitous motor and cognitive oscillatory networks. PMID- 28615334 TI - Diffusion-weighted tractography in the common marmoset monkey at 9.4T. AB - The common marmoset (Callithrix jacchus) is a small New World primate that is becoming increasingly popular in the neurosciences as an animal model of preclinical human disease. With several major disorders characterized by alterations in neural white matter (e.g., multiple sclerosis, Alzheimer's disease, schizophrenia), proposed to be transgenically modeled using marmosets, the ability to isolate and characterize reliably major white matter fiber tracts with MRI will be of use for evaluating structural brain changes related to disease processes and symptomatology. Here, we propose protocols for isolating major white matter fiber tracts in the common marmoset using in vivo ultrahigh field MRI (9.4T) diffusion-weighted imaging (DWI) data. With the use of a high angular-resolution DWI (256 diffusion-encoding directions) sequence, collected on four anesthetized marmosets, we provide guidelines for manually drawing fiber tracking regions of interest, based on easily identified anatomical landmarks in DWI native space. These fiber-tract isolation protocols are expected to be experimentally useful for visualization and quantification of individual white matter fiber tracts in both control and experimental groups of marmosets (e.g., transgenic models). As disease models in the marmoset advance, the determination of how macroscopic white matter anatomy is altered as a function of disease state will be relevant in bridging the existing translational gap between preclinical rodent models and human patients.NEW & NOTEWORTHY Although significant progress has been made in mapping white matter connections in the marmoset brain using ex vivo tracing techniques, the application of in vivo virtual dissection of major white matter fiber tracts has been established by few studies in the marmoset literature. Here, we demonstrate the feasibility of whole-brain diffusion weighted tractography in anesthetized marmosets at ultrahigh-field MRI (9.4T) and propose protocols for isolating nine major white matter fiber tracts in the marmoset brain. PMID- 28615335 TI - Wakefulness suppresses retinal wave-related neural activity in visual cortex. AB - In the developing visual system before eye opening, spontaneous retinal waves trigger bursts of neural activity in downstream structures, including visual cortex. At the same ages when retinal waves provide the predominant input to the visual system, sleep is the predominant behavioral state. However, the interactions between behavioral state and retinal wave-driven activity have never been explicitly examined. Here we characterized unit activity in visual cortex during spontaneous sleep-wake cycles in 9- and 12-day-old rats. At both ages, cortical activity occurred in discrete rhythmic bursts, ~30-60 s apart, mirroring the timing of retinal waves. Interestingly, when pups spontaneously woke up and moved their limbs in the midst of a cortical burst, the activity was suppressed. Finally, experimentally evoked arousals also suppressed intraburst cortical activity. All together, these results indicate that active wake interferes with the activation of the developing visual cortex by retinal waves. They also suggest that sleep-wake processes can modulate visual cortical plasticity at earlier ages than has been previously considered.NEW & NOTEWORTHY By recording in visual cortex in unanesthetized infant rats, we show that neural activity attributable to retinal waves is specifically suppressed when pups spontaneously awaken or are experimentally aroused. These findings suggest that the relatively abundant sleep of early development plays a permissive functional role for the visual system. It follows, then, that biological or environmental factors that disrupt sleep may interfere with the development of these neural networks. PMID- 28615336 TI - Prevention and reversal of latent sensitization of dorsal horn neurons by glial blockers in a model of low back pain in male rats. AB - In an animal model of nonspecific low back pain, recordings from dorsal horn neurons were made to investigate the influence of glial cells in the central sensitization process. To induce a latent sensitization of the neurons, nerve growth factor (NGF) was injected into the multifidus muscle; the manifest sensitization to a second NGF injection 5 days later was used as a read-out. The sensitization manifested in increased resting activity and in an increased proportion of neurons responding to stimulation of deep somatic tissues. To block microglial activation, minocycline was continuously administered intrathecally starting 1 day before or 2 days after the first NGF injection. The glia inhibitor fluorocitrate that also blocks astrocyte activation was administrated 2 days after the first injection. Minocycline applied before the first NGF injection reduced the manifest sensitization after the second NGF injection to control values. The proportion of neurons responsive to stimulation of deep tissues was reduced from 50% to 17.7% (P < 0.01). No significant changes occurred when minocycline was applied after the first injection. In contrast, fluorocitrate administrated after the first NGF injection reduced significantly the proportion of neurons with deep input (15.8%, P < 0.01). A block of glia activation had no significant effect on the increased resting activity. The data suggest that blocking microglial activation prevented the NGF-induced latent spinal sensitization, whereas blocking astrocyte activation reversed it. The induction of spinal neuronal sensitization in this pain model appears to depend on microglia activation, whereas its maintenance is regulated by activated astrocytes.NEW & NOTEWORTHY Activated microglia and astrocytes mediate the latent sensitization induced by nerve growth factor in dorsal horn neurons that receive input from deep tissues of the low back. These processes may contribute to nonspecific low back pain. PMID- 28615337 TI - Accumulation of methylglyoxal increases the advanced glycation end-product levels in DRG and contributes to lumbar disk herniation-induced persistent pain. AB - Lumbar disk herniation (LDH) with discogenic low back pain and sciatica is a common and complicated musculoskeletal disorder. The underlying mechanisms are poorly understood, and there are no effective therapies for LDH-induced pain. In the present study, we found that the patients who suffered from LDH-induced pain had elevated plasma methylglyoxal (MG) levels. In rats, implantation of autologous nucleus pulposus (NP) to the left lumbar 5 spinal nerve root, which mimicked LDH, induced mechanical allodynia, increased MG level in plasma and dorsal root ganglion (DRG), and enhanced the excitability of small DRG neurons (<30 MUm in diameter). Intrathecal injection of MG also induced mechanical allodynia, and its application to DRG neurons ex vivo increased the number of action potentials evoked by depolarizing current pulses. Furthermore, inhibition of MG accumulation by aminoguanidine attenuated the enhanced excitability of small DRG neurons and the mechanical allodynia induced by NP implantation. In addition, NP implantation increased levels of advanced glycation end products (AGEs) in DRG, and intrathecal injection of MG-derived AGEs induced the mechanical allodynia and DRG neuronal hyperactivity. Intrathecal injection of MG also significantly increased the expression of AGEs in DRG. Importantly, scavenging of MG by aminoguanidine also attenuated the increase in AGEs induced by NP implantation. These results suggested that LDH-induced MG accumulation contributed to persistent pain by increasing AGE levels. Thus generation of AGEs from MG may represent a target for treatment of LDH-induced pain.NEW & NOTEWORTHY Our study demonstrates that methylglyoxal accumulation via increasing advanced glycation end-product levels in dorsal root ganglion contributes to the persistent pain induced by lumbar disk herniation, which proposed potential targets for the treatment of lumbar disk herniation-induced persistent pain. PMID- 28615338 TI - Activity of primate V1 neurons during the gap saccade task. AB - When a saccadic eye movement is made toward a visual stimulus, the variability in accompanying primary visual cortex (V1) activity is related to saccade latency in both humans and simians. To understand the nature of this relationship, we examined the functional link between V1 activity and the initiation of visually guided saccades during the gap saccade task, in which a brief temporal gap is inserted between the turning off of a fixation stimulus and the appearance of a saccadic target. The insertion of such a gap robustly reduces saccade latency and facilitates the occurrence of extremely short-latency (express) saccades. Here we recorded single-cell activity from macaque V1 while monkeys performed the gap saccade task. In parallel with the gap effect on saccade latency the neural latency (time of first spike) of V1 response elicited by the saccade target became shorter, and the firing rate increased as the gap duration increased. Similarly, neural latency was shorter and firing rate was higher before express saccades relative to regular-latency saccades. In addition to these posttarget changes, the level of spontaneous spike activity during the pretarget period was negatively correlated with both neural and saccade latencies. These results demonstrate that V1 activity correlates with the gap effect and indicate that trial-to-trial variability in the state of V1 accompanies the variability of neural and behavioral latencies.NEW & NOTEWORTHY The link between neural activity in monkey primary visual cortex (V1) and visually guided behavioral response is confirmed with the gap saccade paradigm. Results indicated that the variability in neural latency of V1 spike activity correlates with the gap effect on saccade latency and that the trial-to-trial variability in the state of V1 before the onset of saccade target correlates with the variability in neural and behavioral latencies. PMID- 28615339 TI - Interhemispheric interactions between trunk muscle representations of the primary motor cortex. AB - Unilateral arm movements require trunk stabilization through bilateral contraction of axial muscles. Interhemispheric interactions between primary motor cortices (M1) could enable such coordinated contractions, but these mechanisms are largely unknown. Using transcranial magnetic stimulation (TMS), we characterized interhemispheric interactions between M1 representations of the trunk-stabilizing muscles erector spinae at the first lumbar vertebra (ES L1) during a right isometric shoulder flexion. These interactions were compared with those of the anterior deltoid (AD), the main agonist in this task, and the first dorsal interosseous (FDI). TMS over the right M1 elicited ipsilateral silent periods (iSP) in all three muscles on the right side. In ES L1, but not in AD or FDI, ipsilateral motor evoked potential (iMEP) could precede the iSP or replace it. iMEP amplitude was not significantly different whether ES L1 was used to stabilize the trunk or was voluntarily contracted. TMS at the cervicomedullary junction showed that the size of cervicomedullary evoked potential was unchanged during the iSP but increased during iMEP, suggesting that the iSP, but not the iMEP, is due to intracortical mechanisms. Using a dual-coil paradigm with two coils over the left and right M1, interhemispheric inhibition could be evoked at interstimulus intervals of 6 ms in ES L1 and 8 ms in AD and FDI. Together, these results suggest that interhemispheric inhibition is dominant when axial muscles are involved in a stabilizing task. The ipsilateral facilitation could be evoked by ipsilateral or subcortical pathways and could be used depending on the role axial muscles play in the task.NEW & NOTEWORTHY The mechanisms involved in the bilateral coordination of axial muscles during unilateral arm movement are poorly understood. We thus investigated the nature of interhemispheric interactions in axial muscles during arm motor tasks in healthy subjects. By combining different methodologies, we showed that trunk muscles receive both inhibitory and facilitatory cortical outputs during activation of arm muscles. We propose that inhibition may be conveyed mainly through interhemispheric mechanisms and facilitation by subcortical mechanisms or ipsilateral pathways. PMID- 28615342 TI - Supramodal representation of temporal priors calibrates interval timing. AB - Human timing behaviors are consistent with Bayesian inference, according to which both previous knowledge (prior) and current sensory information determine final responses. However, it is unclear whether the brain represents temporal priors exclusively for individual modalities or in a supramodal manner when temporal information comes from different modalities at different times. Here we asked participants to reproduce time intervals in either a unisensory or a multisensory context. In unisensory tasks, sample intervals drawn from a uniform distribution were presented in a single visual or auditory modality. In multisensory tasks, sample intervals from the two modalities were randomly mixed; visual and auditory intervals were drawn from two adjacent uniform distributions, with the conjunction of the two being equal to the distribution in the unisensory tasks. In the unisensory tasks, participants' reproduced times exhibited classic central tendency biases: shorter intervals were overestimated and longer intervals were underestimated. In the multisensory tasks, reproduced times were biased toward the mean of the whole distribution rather than the means of intervals in individual modalities. The Bayesian model with a supramodal prior (distribution of time intervals from both modalities) outperformed the model with modality specific priors in describing participants' performance. With a generalized model assuming the weighted combination of unimodal priors, we further obtained the relative contribution of visual intervals and auditory intervals in forming the prior for each participant. These findings suggest a supramodal mechanism for encoding priors in temporal processing, although the extent of influence of one modality on another differs individually.NEW & NOTEWORTHY Visual timing and auditory timing influence each other when time intervals in the two modalities are drawn from two adjacent distributions and are randomly intermixed. A Bayesian model with a supramodal prior (distribution of intervals from both modalities) outperforms the model using sensory-specific priors in describing participants' performance. A generalized model further reveals that the prior is represented as a weighted average of the distribution of time intervals from the two modalities, which differ individually. PMID- 28615341 TI - High-frequency epidural stimulation across the respiratory cycle evokes phrenic short-term potentiation after incomplete cervical spinal cord injury. AB - C2 spinal hemilesion (C2Hx) paralyzes the ipsilateral diaphragm, but recovery is possible through activation of "crossed spinal" synaptic inputs to ipsilateral phrenic motoneurons. We tested the hypothesis that high-frequency epidural stimulation (HF-ES) would potentiate ipsilateral phrenic output after subacute and chronic C2Hx. HF-ES (300 Hz) was applied to the ventrolateral C4 or T2 spinal cord ipsilateral to C2Hx in anesthetized and mechanically ventilated adult rats. Stimulus duration was 60 s, and currents ranged from 100 to 1,000 uA. Bilateral phrenic nerve activity and ipsilateral hypoglossal (XII) nerve activity were recorded before and after HF-ES. Higher T2 stimulus currents potentiated ipsilateral phasic inspiratory activity at both 2 and 12 wk post-C2Hx, whereas higher stimulus currents delivered at C4 potentiated ipsilateral phasic phrenic activity only at 12 wk (P = 0.028). Meanwhile, tonic output in the ipsilateral phrenic nerve reached 500% of baseline values at the high currents with no difference between 2 and 12 wk. HF-ES did not trigger inspiratory burst-frequency changes. Similar responses occurred following T2 HF-ES. Increases in contralateral phrenic and XII nerve output were induced by C4 and T2 HF-ES at higher currents, but the relative magnitude of these changes was small compared with the ipsilateral phrenic response. We conclude that following incomplete cervical spinal cord injury, HF-ES of the ventrolateral midcervical or thoracic spinal cord can potentiate efferent phrenic motor output with little impact on inspiratory burst frequency. However, the substantial increases in tonic output indicate that the uninterrupted 60-s stimulation paradigm used is unlikely to be useful for respiratory muscle activation after spinal injury.NEW & NOTEWORTHY Previous studies reported that high-frequency epidural stimulation (HF-ES) activates the diaphragm following acute spinal transection. This study examined HF-ES and phrenic motor output following subacute and chronic incomplete cervical spinal cord injury. Short-term potentiation of phrenic bursting following HF-ES illustrates the potential for spinal stimulation to induce respiratory neuroplasticity. Increased tonic phrenic output indicates that alternatives to the continuous stimulation paradigm used in this study will be required for respiratory muscle activation after spinal cord injury. PMID- 28615343 TI - Preventing hospital readmissions: the importance of considering 'impactibility,' not just predicted risk. PMID- 28615340 TI - Perspectives on classical controversies about the motor cortex. AB - Primary motor cortex has been studied for more than a century, yet a consensus on its functional contribution to movement control is still out of reach. In particular, there remains controversy as to the level of control produced by motor cortex ("low-level" movement dynamics vs. "high-level" movement kinematics) and the role of sensory feedback. In this review, we present different perspectives on the two following questions: What does activity in motor cortex reflect? and How do planned motor commands interact with incoming sensory feedback during movement? The four authors each present their independent views on how they think the primary motor cortex (M1) controls movement. At the end, we present a dialogue in which the authors synthesize their views and suggest possibilities for moving the field forward. While there is not yet a consensus on the role of M1 or sensory feedback in the control of upper limb movements, such dialogues are essential to take us closer to one. PMID- 28615344 TI - Advancing infection prevention and antimicrobial stewardship through improvement science. PMID- 28615345 TI - Variation in Leaf Respiration Rates at Night Correlates with Carbohydrate and Amino Acid Supply. AB - Plant respiration can theoretically be fueled by and dependent upon an array of central metabolism components; however, which ones are responsible for the quantitative variation found in respiratory rates is unknown. Here, large-scale screens revealed 2-fold variation in nighttime leaf respiration rate (RN) among mature leaves from an Arabidopsis (Arabidopsis thaliana) natural accession collection grown under common favorable conditions. RN variation was mostly maintained in the absence of genetic variation, which emphasized the low heritability of RN and its plasticity toward relatively small environmental differences within the sampling regime. To pursue metabolic explanations for leaf RN variation, parallel metabolite level profiling and assays of total protein and starch were performed. Within an accession, RN correlated strongly with stored carbon substrates, including starch and dicarboxylic acids, as well as sucrose, major amino acids, shikimate, and salicylic acid. Among different accessions, metabolite-RN correlations were maintained with protein, sucrose, and major amino acids but not stored carbon substrates. A complementary screen of the effect of exogenous metabolites and effectors on leaf RN revealed that (1) RN is stimulated by the uncoupler FCCP and high levels of substrates, demonstrating that both adenylate turnover and substrate supply can limit leaf RN, and (2) inorganic nitrogen did not stimulate RN, consistent with limited nighttime nitrogen assimilation. Simultaneous measurements of RN and protein synthesis revealed that these processes were largely uncorrelated in mature leaves. These results indicate that differences in preceding daytime metabolic activities are the major source of variation in mature leaf RN under favorable controlled conditions. PMID- 28615346 TI - Leaf Hydraulic Architecture and Stomatal Conductance: A Functional Perspective. PMID- 28615347 TI - Thymic stromal lymphopoietin-induced HOTAIR activation promotes endothelial cell proliferation and migration in atherosclerosis. AB - Endothelial cells' (EC) injury is a major step for the pathological progression of atherosclerosis. Recent study demonstrated that thymic stromal lymphopoietin (TSLP) exerts a protective role in atherosclerosis. However, the effect of TSLP and the exact molecular mechanism involved in EC remains unknown. In the present study, we found that long noncoding RNA (lncRNA) HOTAIR was much lower in EC from atherosclerotic plaque. Functional assays showed that HOTAIR facilitated cell proliferation and migration, and suppressed apoptosis in EC. Moreover, we demonstrated that TSLP functions upstream of HOTAIR. We found that serum level of TSLP was decreased in atherosclerosis patients and serum TSLP level positively correlated with HOTAIR expression in EC. Further investigation demonstrated that TSLP activated HOTAIR transcription through PI3K/AKT-IRF1 pathway and then regulates the EC proliferation and migration. TSLP-HOTAIR axis also plays a protective role in low-density lipoprotein (ox-LDL)-induced EC injury. Taken together, TSLP-HOTAIR may be a potential therapy for EC dysfunction in atherosclerosis. PMID- 28615348 TI - JAK2 inhibitor CEP-33779 prevents mouse oocyte maturation in vitro. AB - The inhibitor CEP-33779 is a specific selective inhibitor of Janus kinase 2 (JAK2). In most somatic cells, JAK2 plays essential roles in cellular signal transduction and in the regulation of cell cycle. Little is known regarding the effects of JAK2 on mammalian oocyte maturation. In the present study, we investigated the effects of CEP-33779 on mouse oocytes' meiosis and the possible mechanisms of JAK2 during mouse oocyte maturation. We detected the distribution of JAK2 during the mouse oocyte maturation. The results showed that JAK2 was mainly distributed in the cytoplasm during maturation. We cultured mouse oocytes with CEP-33779, examined the maturation rate, spindle morphology, and organization of microfilaments during the mouse oocyte maturation. While the rate of germinal vesicle breakdown (GVBD) did not differ between the treated and control groups, the rate of oocyte maturation decreased significantly when treated with CEP-33779. The rate of maturation was 21.14% in treated group and was 81.44% in control group. The results show that CEP-33779 inhibits the maturation of mouse oocytes. There was no obvious difference in the meiotic spindle morphology between the treated and control groups. The results show that CEP-33779 treatment did not disrupt the reorganization of microtubules. The microfilament observation shows that the microfilament did not form actin cap and the spindle stayed at the center of the oocyte in the treated group. CEP-33779 treatment inhibited the maturation of mouse oocytes which might be because of the disruption of formation of the actin cap. These results suggest that JAK2 regulated the microfilaments aggregation during the mouse oocyte maturation. PMID- 28615349 TI - CFTR protects against vascular inflammation and atherogenesis in apolipoprotein E deficient mice. AB - Atherosclerosis is a chronic inflammatory disease of the vascular wall. Dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR) has been shown to result in inflammatory responses in cystic fibrosis (CF) patients. However, little is known about the role of CFTR in vascular inflammation and atherogenesis. Our results showed that CFTR was dominantly expressed in macrophages of atherosclerotic plaque and reduced in aorta and aortic sinus from atherosclerotic apolipoprotein E-deficient (apoE-/-) mice. In vivo administration of adenovirus encoding CFTR (Ad-CFTR) with apoE-/- mice fed on high-fat diet (HFD) improved plaque stability by decreasing lipid accumulation and necrotic area and increasing smooth muscle cell content and collagen. The Ad-CFTR-treated mice also displayed reduced proinflammatory cytokines levels in aorta and peritoneal macrophages, whereas the anti-inflammatory M2 macrophage markers were increased. Confocal microscopy revealed that the infiltration of T lymphocytes, neutrophils, and macrophages in aortic sinus was markedly attenuated in Ad-CFTR treated apoE-/- mice. Moreover, in vitro experiments showed that overexpression of CFTR inhibited ox-LDL-induced the migration of peritoneal macrophages. Finally, it was observed that CFTR up-regulation suppressed NFkappaB and MAPKs activity induced by ox-LDL. Inhibition of JNK or ERK abrogated CFTR down regulation induced NFkappaB activation, whereas NFkappaB inhibitor had no effect on JNK or ERK activation. Taken together, these results demonstrate that CFTR prevents inflammation and atherogenesis via inhibition of NFkappaB and MAPKs activation. Our data suggest that CFTR may present a potential therapeutic target for the treatment of vascular inflammation and development of atherosclerotic disease. PMID- 28615350 TI - A circannual perspective on daily and total flight distances in a long-distance migratory raptor, the Montagu's harrier, Circus pygargus. AB - Long-distance migrants are particularly recognized for the distances covered on migration, yet little is known about the distances they cover during the rest of the year. GPS-tracks of 29 Montagu's harriers from breeding areas in France, The Netherlands and Denmark showed that harriers fly between 35 653 and 88 049 km yr 1, of which on average only 28.5% is on migration. Mean daily distances during migration were 296 km d-1 in autumn and 252 km d-1 in spring. Surprisingly, males' daily distances during breeding (217 km d-1) were close to those during migration, whereas breeding females moved significantly less (101 km d-1) than males. In terms of flight distance, the breeding season seemed nearly as demanding as migration periods for males. During the six winter months, both sexes moved less (114 and 128 km d-1 for females and males, respectively) than during migration. Harriers therefore covered shorter daily distances during winter which might allow birds to compensate for the more demanding phases of migration and breeding. PMID- 28615351 TI - Body shape convergence driven by small size optimum in marine angelfishes. AB - Convergent evolution of small body size occurs across many vertebrate clades and may reflect an evolutionary response to shared selective pressures. However it remains unclear if other aspects of phenotype undergo convergent evolution in miniaturized lineages. Here we present a comparative analysis of body size and shape evolution in marine angelfishes (Pomacanthidae), a reef fish family characterized by repeated transitions to small body size. We ask if lineages that evolve small sizes show convergent evolution in body shape. Our results reveal that angelfish lineages evolved three different stable size optima with one corresponding to the group of pygmy angelfishes (Centropyge). Then, we test if the observed shifts in body size are associated with changes to new adaptive peaks in shape. Our data suggest that independent evolution to small size optima have induced repeated convergence upon deeper body and steeper head profile in Centropyge These traits may favour manoeuvrability and visual awareness in these cryptic species living among corals, illustrating that functional demands on small size may be related to habitat specialization and predator avoidance. The absence of shape convergence in large marine angelfishes also suggests that more severe requirements exist for small than for large size optima. PMID- 28615352 TI - Preparatory responses to socially determined, mutually exclusive possibilities in chimpanzees and children. AB - The capacity to imagine and prepare for alternative future possibilities is central to human cognition. Recent research suggests that between age 2 and 4 children gradually begin to demonstrate a capacity to prepare for two simple, mutually exclusive alternatives of an immediate future event. When children were given the opportunity to catch a target an experimenter dropped into an inverted Y-shaped tube, 2-year olds-as well as great apes-tended to cover only one of the exits, whereas 4-year-olds spontaneously and consistently prepared for both possible outcomes. Here we gave children, age 2 to 4 years, and chimpanzees a different opportunity to demonstrate potential competence. Given that social behaviour is particularly full of uncertainty, we developed a version of the task where the outcome was still unpredictable yet obviously controlled by an experimenter. Participants could ensure they would catch the target by simply covering two tube exits. While 4-year-olds demonstrated competence, chimpanzees and the younger children instead tended to cover only one exit. These results substantiate the conclusion that the capacity for simultaneous preparation for mutually exclusive event outcomes develops relatively late in children and they are also in line with the possibility that our close animal relatives lack this capacity. PMID- 28615353 TI - Discovery of the fossil otter Enhydritherium terraenovae (Carnivora, Mammalia) in Mexico reconciles a palaeozoogeographic mystery. AB - The North American fossil otter Enhydritherium terraenovae is thought to be partially convergent in ecological niche with the living sea otter Enhydra lutris, both having low-crowned crushing teeth and a close association with marine environments. Fossil records of Enhydritherium are found in mostly marginal marine deposits in California and Florida; despite presence of very rich records of fossil terrestrial mammals in contemporaneous localities inland, no Enhydritherium fossils are hitherto known in interior North America. Here we report the first occurrence of Enhydritherium outside of Florida and California, in a land-locked terrestrial mammal fauna of the upper Miocene deposits of Juchipila Basin, Zacatecas State, Mexico. This new occurrence of Enhydritherium is at least 200 km from the modern Pacific coastline, and nearly 600 km from the Gulf of Mexico. Besides providing further evidence that Enhydritherium was not dependent on coastal marine environments as originally interpreted, this discovery leads us to propose a new east-to-west dispersal route between the Florida and California Enhydritherium populations through central Mexico. The proximity of the fossil locality to nearby populations of modern neotropical otters Lontra longicaudis suggests that trans-Mexican freshwater corridors for vertebrate species in riparian habitats may have persisted for a prolonged period of time, pre-dating the Great American Biotic Interchange. PMID- 28615355 TI - Reducing Unnecessary Imaging for Patients With Constipation in the Pediatric Emergency Department. AB - OBJECTIVES: Constipation is a common diagnosis in the pediatric emergency department (ED). Children diagnosed with constipation may undergo an abdominal radiograph (AXR) as part of their diagnostic workup despite studies that suggest that an AXR in a patient suspected of being constipated is unnecessary and potentially misleading. We aimed to decrease the percentage of low-acuity patients aged between 6 months and 18 years diagnosed with constipation who undergo an AXR in our pediatric ED from 60% to 20% over 12 months. METHODS: We conducted an interventional improvement project at a large, urban pediatric ED by using the Institute for Healthcare Improvement's Model for Improvement. The primary outcome was the proportion of patients ultimately diagnosed with constipation who had an AXR during their ED visit. Analysis was performed by using rational subgrouping and stratification on statistical process control (SPC) charts. RESULTS: Process analysis was performed by using a cause-and-effect diagram. Four plan-do-study-act cycles were completed over 9 months. Interventions included holding Grand Rounds on constipation, sharing best practices, metrics reporting, and academic detailing. Rational subgrouping and stratification on SPC charts were used to target the interventions to different ED provider groups. Over 12 months, we observed a significant and sustained decrease from a mean rate of 62% to a mean rate of 24% in the utilization of AXRs in the ED for patients with constipation. CONCLUSIONS: The use of rational subgrouping and stratification on SPC charts to study different ED provider groups resulted in a substantial and sustained reduction in the rate of AXRs for constipation. PMID- 28615354 TI - Parenting Intervention at Age 11 and Cotinine Levels at Age 20 Among African American Youth. AB - OBJECTIVES: This study was designed to test the hypothesis that African American preadolescents who participated in a family-centered parenting intervention at age 11 would show lower levels of cotinine, a biomarker for recent smoking, at age 20 than would similar participants in the control condition. The study was also designed to test the hypothesis that prevention-induced increases in supportive parenting would account for any prevention effects that emerged. METHODS: African American parents and their 11-year-old children in the rural southern United States were assigned randomly to the Strong African American Families program or to a control condition. Parents provided self-reported data on supportive parenting when the youth were 11 and 16 years of age. When the youth were 20 years of age, blood was drawn from which cotinine was assayed. RESULTS: Intervention program participants (M = 0.672, SD = 0.048) displayed significantly lower cotinine levels at age 20 years than did control participants (M = 0.824, SD = 0.059), P = .046. Mediation analyses confirmed that increases in supportive parenting accounted for intervention effects on smoking. CONCLUSIONS: We have demonstrated in this study that a randomized trial of a prevention program designed to enhance supportive parenting reduced cotinine levels among young African American adults. The developmentally appropriate family-centered intervention buffered the risk of smoking 9 years after program participation. PMID- 28615356 TI - Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. AB - A potentially useful approach for drug discovery is to connect gene expression profiles of disease-affected tissues ("disease signatures") to drug signatures, but it remains to be shown whether it can be used to identify clinically relevant treatment options. We analyzed coexpression networks and genetic data to identify a disease signature for type 2 diabetes in liver tissue. By interrogating a library of 3800 drug signatures, we identified sulforaphane as a compound that may reverse the disease signature. Sulforaphane suppressed glucose production from hepatic cells by nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and decreased expression of key enzymes in gluconeogenesis. Moreover, sulforaphane reversed the disease signature in the livers from diabetic animals and attenuated exaggerated glucose production and glucose intolerance by a magnitude similar to that of metformin. Finally, sulforaphane, provided as concentrated broccoli sprout extract, reduced fasting blood glucose and glycated hemoglobin (HbA1c) in obese patients with dysregulated type 2 diabetes. PMID- 28615358 TI - It's reticulated: Diabetes, atherosclerosis, and reticulated platelets. AB - New research describes regulatory pathways for reticulated thrombocytosis in a mouse model of diabetes. PMID- 28615357 TI - Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. AB - Primary graft dysfunction is the predominant driver of mortality and graft loss after lung transplantation. Recruitment of neutrophils as a result of ischemia reperfusion injury is thought to cause primary graft dysfunction; however, the mechanisms that regulate neutrophil influx into the injured lung are incompletely understood. We found that donor-derived intravascular nonclassical monocytes (NCMs) are retained in human and murine donor lungs used in transplantation and can be visualized at sites of endothelial injury after reperfusion. When NCMs in the donor lungs were depleted, either pharmacologically or genetically, neutrophil influx and lung graft injury were attenuated in both allogeneic and syngeneic models. Similar protection was observed when the patrolling function of donor NCMs was impaired by deletion of the fractalkine receptor CX3CR1. Unbiased transcriptomic profiling revealed up-regulation of MyD88 pathway genes and a key neutrophil chemoattractant, CXCL2, in donor-derived NCMs after reperfusion. Reconstitution of NCM-depleted donor lungs with wild-type but not MyD88-deficient NCMs rescued neutrophil migration. Donor NCMs, through MyD88 signaling, were responsible for CXCL2 production in the allograft and neutralization of CXCL2 attenuated neutrophil influx. These findings suggest that therapies to deplete or inhibit NCMs in donor lung might ameliorate primary graft dysfunction with minimal toxicity to the recipient. PMID- 28615359 TI - Immunity at the forefront of the brain: A new genetic model of FTD. AB - Functional characterization of a genetic variant linked to frontotemporal dementia in a murine model reveals deficits in cerebral immune response and metabolism. PMID- 28615360 TI - A vitamin to D-crease sunburn. AB - High doses of oral vitamin D3 attenuate skin inflammation following experimentally induced sun damage. PMID- 28615361 TI - Targeting KRAS-dependent tumors with AZD4785, a high-affinity therapeutic antisense oligonucleotide inhibitor of KRAS. AB - Activating mutations in KRAS underlie the pathogenesis of up to 20% of human tumors, and KRAS is one of the most frequently mutated genes in cancer. Developing therapeutics to block KRAS activity has proven difficult, and no direct inhibitor of KRAS function has entered clinical trials. We describe the preclinical evaluation of AZD4785, a high-affinity constrained ethyl-containing therapeutic antisense oligonucleotide (ASO) targeting KRAS mRNA. AZD4785 potently and selectively depleted cellular KRAS mRNA and protein, resulting in inhibition of downstream effector pathways and antiproliferative effects selectively in KRAS mutant cells. AZD4785-mediated depletion of KRAS was not associated with feedback activation of the mitogen-activated protein kinase (MAPK) pathway, which is seen with RAS-MAPK pathway inhibitors. Systemic delivery of AZD4785 to mice bearing KRAS mutant non-small cell lung cancer cell line xenografts or patient-derived xenografts resulted in inhibition of KRAS expression in tumors and antitumor activity. The safety of this approach was demonstrated in mice and monkeys with KRAS ASOs that produced robust target knockdown in a broad set of tissues without any adverse effects. Together, these data suggest that AZD4785 is an attractive therapeutic for the treatment of KRAS-driven human cancers and warrants further development. PMID- 28615363 TI - Neutrophils: Double agents for TB. AB - Nitric oxide restricts growth of Mycobacterium tuberculosis by repressing neutrophilic inflammation. PMID- 28615362 TI - Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. AB - Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells, we identify the CCDC6 RETI788N mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors. PMID- 28615364 TI - Common Genetic Variation and Susceptibility to Ovarian Cancer: Current Insights and Future Directions. AB - In this review, we summarize current progress in the genetic epidemiology of epithelial ovarian cancer (EOC), focusing exclusively on elucidating the role of common germline genetic variation in conferring susceptibility to EOC. We provide an overview of the more than 30 EOC risk loci identified to date by genome-wide association studies (GWAS) and describe the contribution of large-scale, cross cancer type, custom genotyping projects, such as the OncoArray and the Collaborative Oncological Gene-Environment Study, to locus discovery and replication. We discuss the histotype-specific nature of these EOC risk loci, pleiotropy, or overlapping genetic effects between EOC and other hormone-related cancer types, and the application of findings to polygenic risk prediction for EOC. The second part of the article offers a concise review of primarily laboratory-based studies that have led to the identification of several putative EOC susceptibility genes using common variants at the known EOC risk loci as starting points. More global biological insights emerging from network- and pathway-based analyses of GWAS for EOC susceptibility are also highlighted. Finally, we delve into potential future directions, including the need to identify EOC risk loci in non-European populations and the next generation of GWAS functional studies that are likely to involve genome editing to establish the cell type-specific carcinogenic effects of EOC risk variants Cancer Epidemiol Biomarkers Prev; 27(4); 395-404. (c)2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer." PMID- 28615365 TI - A Decade of GWAS Results in Lung Cancer. AB - Genome-wide association studies (GWAS) were successful to identify genetic factors robustly associated with lung cancer. This review aims to synthesize the literature in this field and accelerate the translation of GWAS discoveries into results that are closer to clinical applications. A chronologic presentation of published GWAS on lung cancer susceptibility, survival, and response to treatment is presented. The most important results are tabulated to provide a concise overview in one read. GWAS have reported 45 lung cancer susceptibility loci with varying strength of evidence and highlighted suspected causal genes at each locus. Some genetic risk loci have been refined to more homogeneous subgroups of lung cancer patients in terms of histologic subtypes, smoking status, gender, and ethnicity. Overall, these discoveries are an important step for future development of new therapeutic targets and biomarkers to personalize and improve the quality of care for patients. GWAS results are on the edge of offering new tools for targeted screening in high-risk individuals, but more research is needed if GWAS are to pay off the investment. Complementary genomic datasets and functional studies are needed to refine the underlying molecular mechanisms of lung cancer preliminarily revealed by GWAS and reach results that are medically actionable. Cancer Epidemiol Biomarkers Prev; 27(4); 363-79. (c)2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer." PMID- 28615366 TI - Significance of Ischemic Heart Disease in Patients With Heart Failure and Preserved, Midrange, and Reduced Ejection Fraction: A Nationwide Cohort Study. AB - BACKGROUND: The pathogenic role of ischemic heart disease (IHD) in heart failure (HF) with reduced ejection fraction (HFrEF; EF <40%) is well established, but its pathogenic and prognostic significance in HF with midrange (HFmrEF; EF 40%-50%) and preserved EF (HFpEF; EF >=50%) has been much less explored. METHODS AND RESULTS: We evaluated 42 987 patients from the Swedish Heart Failure Registry with respect to baseline IHD, outcomes (IHD, HF, cardiovascular events, and all cause death), and EF change during a median follow-up of 2.2 years. Overall, 23% had HFpEF (52% IHD), 21% had HFmrEF (61% IHD), and 55% had HFrEF (60% IHD). After multivariable adjustment, associations with baseline IHD were similar for HFmrEF and HFrEF and lower in HFpEF (risk ratio, 0.91 [0.89-0.93] versus HFmrEF and risk ratio, 0.90 [0.88-0.92] versus HFrEF). The adjusted risk of IHD events was similar for HFmrEF versus HFrEF and lower in HFpEF (hazard ratio, 0.89 [0.84 0.95] versus HFmrEF and hazard ratio, 0.84 [0.80-0.90] versus HFrEF). After adjustment, prevalent IHD was associated with increased risk of IHD events and all other outcomes in all EF categories except all-cause mortality in HFpEF. Those with IHD, particularly new IHD events, were also more likely to change to a lower EF category and less likely to change to a higher EF category over time. CONCLUSIONS: HFmrEF resembled HFrEF rather than HFpEF with regard to both a higher prevalence of IHD and a greater risk of new IHD events. Established IHD was an important prognostic factor across all HF types. PMID- 28615368 TI - Editor's Note. PMID- 28615367 TI - Patient Perceptions on Facilitating Follow-Up After Heart Failure Hospitalization. AB - BACKGROUND: Timely follow-up after hospitalization for heart failure (HF) is recommended. However, follow-up is suboptimal, especially in lower socioeconomic groups. Patient-centered solutions for facilitating follow-up post-HF hospitalization have not been extensively evaluated. METHODS AND RESULTS: Face-to face surveys were conducted between 2015 and 2016 among 83 racially diverse adult patients (61% African American, 34% Caucasian, and 5% Other) hospitalized for HF at a university hospital centered in a low-income area of Columbus, Ohio. Patient perceptions of methods to facilitate follow-up post-HF hospitalization and likelihood of using interventions were investigated using a Likert scale: 1=very much to 5=not at all. Results were analyzed by Wilcoxon signed-rank test with Bonferroni correction. The response rate was 82%. The annual household income was <$35 000 for 49% of patients. An appointment near the patient's home was the most desired intervention (77%), followed by reminder message (73%), transportation to appointment (63%), and elimination of copayment (59%). Interventions most likely to be used if provided were similarly ranked: reminder message (48%), appointment near home (46%), elimination of copay (46%), and transportation to appointment (39%). There were significant differences (P=0.001) in high-ranking interventions related to location (appointment near home, transportation, home appointment) and reminder for visit compared with low-ranking interventions related to time (weekend appointment, appointment after 5 pm) and telemedicine. CONCLUSIONS: Among this cohort of racially diverse low-income patients hospitalized with HF, an appointment near the patient's home and a reminder message were the most desired interventions to facilitate follow-up. Further study of similar populations nationwide is warranted. PMID- 28615369 TI - Clinical Development of PD-1/PD-L1 Immunotherapy for Gastrointestinal Cancers: Facts and Hopes. AB - Gastrointestinal (GI) cancers are among the most deadly malignancies. Although serial incremental survival benefits have been made with cytotoxic chemotherapy with metastatic disease, a plateau of achievement has been reached. Applying modern integrative genomic technology, distinct molecular subgroups have been identified in GI cancers. This not only highlighted the heterogeneity in tumors of each primary anatomical site but also identified novel therapeutic targets in distinct molecular subgroups and might improve the yield of clinical success. Molecular characteristics of tumors and their interaction with the tumor microenvironment would further affect development of combination therapy, including immunotherapy. Currently, immune checkpoint blockade attracts the most intense research, and the successful integration of these novel agents in GI cancers in the treatment paradigm requires an in-depth understanding of the diverse immune environment of these cancers. Clin Cancer Res; 23(20); 6002-11. (c)2017 AACR. PMID- 28615371 TI - A Phase Ib Open-Label Multicenter Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers. AB - Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1-amplified SQCLC cell lines and patient derived xenografts.Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1 amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 >= 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses.Results: Fifteen FGFR1-amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade >=3-related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon.Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366-73. (c)2017 AACR. PMID- 28615370 TI - Molecular Pathways: Targeting the Microenvironment of Liver Metastases. AB - Curative treatment for metastatic solid cancers remains elusive. The liver, which is nourished by a rich blood supply from both the arterial and portal venous systems, is the most common site of visceral metastases, particularly from cancers arising in the gastrointestinal tract, with colorectal cancer being the predominant primary site in Western countries. A mounting body of evidence suggests that the liver microenvironment (LME) provides autocrine and paracrine signals originating from both parenchymal and nonparenchymal cells that collectively create both pre- and prometastatic niches for the development of hepatic metastases. These resident cells and their molecular mediators represent potential therapeutic targets for the prevention and/or treatment of liver metastases (LM). This review summarizes: (i) the current therapeutic options for treating LM, with a particular focus on colorectal cancer LM; (ii) the role of the LME in LM at each of its phases; (iii) potential targets in the LME identified through preclinical and clinical investigations; and (iv) potential therapeutic approaches for targeting elements of the LME before and/or after the onset of LM as the basis for future clinical trials. Clin Cancer Res; 23(21); 6390-9. (c)2017 AACR. PMID- 28615372 TI - Preconception Micronutrient Supplementation with Iron and Folic Acid Compared with Folic Acid Alone Affects Linear Growth and Fine Motor Development at 2 Years of Age: A Randomized Controlled Trial in Vietnam. AB - Background: Maternal health and nutrition play a crucial role in early child growth and development. However, little is known about the benefits of preconception micronutrient interventions beyond the role of folic acid (FA) and neural tube defects.Objective: We evaluated the impact of weekly preconception multiple micronutrient (MM) or iron and folic acid (IFA) supplementation on child growth and development through the age of 2 y compared with FA alone.Methods: We followed 1599 offspring born to women who participated in a randomized controlled trial of preconception supplementation in Vietnam. Women received weekly supplements that contained either 2800 MUg FA, 60 mg Fe and 2800 MUg FA, or 15 MMs including IFA, from baseline until conception followed by daily prenatal IFA supplements until delivery. Child anthropometry was measured at birth and at 3, 6, 12, 18, and 24 mo. Child development was measured with the use of the Bayley Scales for Infant Development III at 24 mo.Results: The groups were similar for baseline maternal and offspring birth characteristics. At 24 mo of age, the offspring in the IFA group had significantly higher length-for-age z scores (LAZs) (0.14; 95% CI: 0.03, 0.26), reduced risk of being stunted (0.87; 95% CI: 0.76, 0.99), and smaller yearly decline in LAZs (0.10; 95% CI: 0.04, 0.15) than the offspring in the FA group. Similar trends were found for the offspring in the MM group compared with the FA group for LAZs (0.10; 95% CI: -0.02, 0.22) and the risk of being stunted (0.88; 95% CI: 0.77, 1.01). Offspring in the IFA group had improved motor development (P = 0.03), especially fine motor development (0.41; 95% CI: 0.05, 0.77), at the age of 24 mo, but there were no differences for measures of cognition or language.Conclusions: Preconception supplementation with IFA improved linear growth and fine motor development at 2 y of age compared with FA. Future studies should examine whether these effects persist and improve child health and schooling. The trial was registered at clinicaltrials.gov as NCT01665378. PMID- 28615373 TI - Yogurt Consumption as a Signature of a Healthy Diet and Lifestyle. AB - Yogurt is considered to be a nutrient-dense food that significantly contributes to the intake of several nutrients, including calcium and protein. As described in this paper, yogurt consumers have a higher nutrient intake than do nonconsumers. Yogurt consumers are also characterized by healthier dietary habits than nonconsumers, which partly explains their reduced incidence of overweight and obesity. Recent studies also suggest that yogurt consumers exhibit healthier nonnutritional behaviors, such as reduced smoking and greater participation in physical activity, than do nonconsumers. Furthermore, when greenhouse gas emissions are used as an additional criterion to categorize foods, yogurt appears to be an eco-friendly food. Compared with that of other foods, the carbon footprint of yogurt production is low to moderate and may be included as part of a healthy and sustainable diet. Based on these factors, yogurt consumption may be the signature of a healthy diet and lifestyle. PMID- 28615374 TI - A Cross-Sectional Survey in Rural Bihar, India, Indicates That Nutritional Status, Diet, and Stimulation Are Associated with Motor and Mental Development in Young Children. AB - Background: Many malnourished children in resource-poor settings fail to fulfill their developmental potential.Objective: The objectives of this analysis were to examine the nutritional, psychosocial, environmental, and household correlates of child development in Bihar, India, and identify mediators between dietary diversity and mental development.Methods: Using 2-stage cluster randomized sampling, we surveyed 4360 households with children 6-18 mo of age in the West Champaran district of Bihar. We measured motor and mental development with the use of the Developmental Milestones Checklist II. In a random subsample (n = 2838), we measured anthropometric characteristics and hemoglobin. Cluster adjusted multiple linear regression analysis was used to examine the associations between nutrition indicators and development scores. Sobel's test was used to assess significant mediators in the association between diet diversity and development scores. Analyses were stratified by children 6-11 and 12-18 mo of age.Results: In all children, length-for-age z score (LAZ), dietary diversity, and psychosocial stimulation were significant (P < 0.05) correlates of motor development scores [(beta coefficient +/- SE) in children 6-11 mo: LAZ = 0.46 +/- 0.08, dietary diversity = 0.43 +/- 0.09, and stimulation = 0.15 +/- 0.04; in children 12-18 mo: LAZ = 0.73 +/- 0.07, dietary diversity = 0.30 +/- 0.09, and stimulation = 0.31 +/- 0.05] and mental development scores [(beta coefficient +/- SE) in children 6-11 mo: LAZ = 0.57 +/- 0.10, dietary diversity = 0.84 +/- 0.13, and stimulation = 0.54 +/- 0.07; in children 12-18 mo: LAZ = 0.54 +/- 0.11, dietary diversity = 0.40 +/- 0.16, and stimulation = 0.62 +/- 0.09]. Stimulation, gross motor development, and fine motor development were significant mediators in the relation between dietary diversity and mental development.Conclusion: Strategies to improve dietary diversity and psychosocial stimulation could have important implications for child development of young North Indian children. This trial was registered at clinicaltrials.gov as NCT02593136. PMID- 28615375 TI - Inclusion of Almonds in a Cholesterol-Lowering Diet Improves Plasma HDL Subspecies and Cholesterol Efflux to Serum in Normal-Weight Individuals with Elevated LDL Cholesterol. AB - Background: Almonds may increase circulating HDL cholesterol when substituted for a high-carbohydrate snack in an isocaloric diet, yet little is known about the effects on HDL biology and function.Objective: The objective was to determine whether incorporating 43 g almonds/d in a cholesterol-lowering diet would improve HDL subspecies and function, which were secondary study outcomes.Methods: In a randomized, 2-period, crossover, controlled-feeding study, a diet with 43 g almonds/d (percentage of total energy: 51% carbohydrate, 16% protein, and 32% total and 8% saturated fat) was compared with a similar diet with an isocaloric muffin substitution (58% carbohydrate, 15% protein, and 26% total and 8% saturated fat) in men and women with elevated LDL cholesterol. Plasma HDL subspecies and cholesterol efflux from J774 macrophages to human serum were measured at baseline and after each diet period. Diet effects were examined in all participants (n = 48) and in normal-weight (body mass index: <25; n = 14) and overweight or obese (>=25; n = 34) participants by using linear mixed models.Results: The almond diet, compared with the control diet, increased alpha 1 HDL [mean +/- SEM: 26.7 +/- 1.5 compared with 24.3 +/- 1.3 mg apolipoprotein A I (apoA-I)/dL; P = 0.001]. In normal-weight participants, the almond diet, relative to the control diet, increased alpha-1 HDL (33.7 +/- 3.2 compared with 28.4 +/- 2.6 mg apoA-I/dL), the alpha-1 to pre-beta-1 ratio [geometric mean (95% CI): 4.3 (3.3, 5.7) compared with 3.1 (2.4, 4.0)], and non-ATP-binding cassette transporter A1 cholesterol efflux (8.3% +/- 0.4% compared with 7.8% +/- 0.3%) and decreased pre-beta-2 (3.8 +/- 0.4 compared with 4.6 +/- 0.4 mg apoA-I/dL) and alpha-3 (23.5 +/- 0.9 compared with 26.9 +/- 1.1 mg apoA-I/dL) HDL (P < 0.05). No diet effects were observed in the overweight or obese group.Conclusions: Substituting almonds for a carbohydrate-rich snack within a lower-saturated-fat diet may be a simple strategy to maintain a favorable circulating HDL subpopulation distribution and improve cholesterol efflux in normal-weight individuals with elevated LDL cholesterol. This trial was registered at clinicaltrials.gov as NCT01101230. PMID- 28615376 TI - Smell and Taste Dysfunction Is Associated with Higher Serum Total Cholesterol Concentrations in Chinese Adults. AB - Background: Several lipid-related hormones and peptides, such as glucagon-like peptide-1 and leptin, are involved in the regulation of taste and smell function. However, to our knowledge, it remains unknown whether these chemosensory functions are associated with lipid profiles.Objective: We examined the cross sectional association between taste and smell dysfunction and blood cholesterol concentrations.Methods: With the use of a questionnaire, we assessed chronic smell and taste dysfunction in 12,627 Chinese participants (10,418 men and 2209 women; mean age: 54.4 y) who did not take hypolipidemic agents. Participants were categorized into 3 groups based on the number of smell and taste dysfunctions, ranging from 0 (best) to 2 (worst). A general linear model was used to test differences in serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (TGs) across groups with different smell and taste status after adjusting for age, sex, education, occupation, smoking, drinking, obesity, and history of cardiovascular disease, cancer, and head injury.Results: The prevalence of smell and taste dysfunction was 2.4% and 1.2%, respectively. Worse smell and taste dysfunction was associated with higher total cholesterol concentrations (P-trend = 0.005). No significant differences were observed in LDL cholesterol, HDL cholesterol, and TG concentrations across groups with different numbers of chemosensory dysfunctions (P-trend > 0.1 for all). The associations between chemosensory dysfunction and total cholesterol concentrations were more pronounced in participants aged <=60 y and in those who were nonsmokers relative to their counterparts (P-interaction < 0.05 for all).Conclusions: In this large cross-sectional study, chemosensory dysfunction was associated with higher serum total cholesterol concentrations among Chinese adults. Prospective studies are needed to investigate the temporal relation between these chemosensory dysfunctions and hypercholesterolemia. PMID- 28615377 TI - After Mexico Implemented a Tax, Purchases of Sugar-Sweetened Beverages Decreased and Water Increased: Difference by Place of Residence, Household Composition, and Income Level. AB - Background: In January 2014, Mexico implemented a tax on sugar-sweetened beverage (SSB) purchases of 1 peso/L.Objective: We examined the heterogeneity of changes in nonalcoholic beverage (SSB and bottled water) purchases after the tax was implemented by household income, urban and rural strata, and household composition.Methods: We used 4 rounds of the National Income and Expenditure Surveys: 2008, 2010, 2012, and 2014. Changes in purchases in per capita liters per week were estimated with the use of 2-part models to adjust for nonpurchases. We compared absolute and relative differences between adjusted changes in observed purchases in 2014 with expected purchases in 2014 based on prior trends (2008-2012). The models were adjusted for sociodemographic characteristics of the households, place of residence, and lagged gross domestic product per capita.Results: We found a 6.3% reduction in the observed purchases of SSBs in 2014 compared with the expected purchases in that same year based on trends from 2008 to 2012. These reductions were higher among lower-income households, residents living in urban areas, and households with children. We also found a 16.2% increase in water purchases that was higher in low- and middle-income households, in urban areas, and among households with adults only.Conclusions: SSB purchases decreased and water purchases increased after an SSB tax was imposed in Mexico. The magnitude of these changes was greater in lower-income and urban households. PMID- 28615378 TI - Amino Acid Absorption in the Large Intestine of Humans and Porcine Models. AB - Dietary protein quality has been recognized as a critical issue by international authorities because it can affect important functions of the body. To predict protein quality, the FAO introduced the Digestible Indispensable Amino Acid Score. This score depends on ileal amino acid (AA) digestibility; therefore, the assumption is made that AAs are not absorbed in nutritionally relevant amounts from the large intestine. This article reviews the evidence for this assumption by considering the role of the mammalian large intestine in dietary protein and AA digestion and absorption, with particular reference to adult humans. Although most dietary AAs and peptides are absorbed in the small intestine, substantial amounts can enter the large intestine. Nitrogen is absorbed in the large intestine, and a series of animal experiments indicate a potential small degree of AA absorption. In humans, colonocytes have the capacity for AA absorption because AA transporters are present in the large intestine. The absorption of nutritionally relevant amounts of dietary indispensable AAs and peptides in the human large intestine has not been convincingly demonstrated, however. PMID- 28615379 TI - Daily Consumption of Lipid-Based Nutrient Supplements Containing 250 MUg Iodine Does Not Increase Urinary Iodine Concentrations in Pregnant and Postpartum Women in Bangladesh. AB - Background: Maternal iodine deficiency during pregnancy and lactation is common in Bangladesh.Objective: We evaluated the effect of lipid-based nutrient supplements for pregnant and lactating women (LNS-PL) on urinary iodine concentration (UIC).Methods: We conducted a cluster-randomized controlled effectiveness trial in which we enrolled 4011 pregnant women at <=20 gestational weeks. Women in 48 clusters received iron and folic acid (IFA; 60 mg Fe/d + 400 MUg folic acid/d) and women in 16 clusters received LNS-PL (20 g/d, 118 kcal) containing 22 vitamins and minerals (including 250 MUg I). We randomly selected a subsample of 1159 women for repeated urine sample collection, i.e., at enrollment, at 36 wk of gestation, and at 6 mo postpartum, for UIC analysis, a secondary outcome of the trial.Results: The geometric mean UIC at 36 wk of gestation and at 6 mo postpartum did not differ significantly between the IFA and LNS-PL groups. The median (quartile 1, quartile 3) UIC at 36 wk was 27.4 MUg/L (16.9, 52.7 MUg/L) in the IFA group and 30.2 MUg/L (17.7, 56.6 MUg/L) in the LNS PL group; at 6 mo, these were 23.0 MUg/L (10.0, 45.9 MUg/L) in the IFA group and 22.2 MUg/L (9.1, 50.4 MUg/L) in the LNS-PL group.Conclusion: Daily consumption of LNS-PL containing 250 MUg I did not increase the UICs of pregnant and lactating women in Bangladesh. Iodine from lipid-based nutrient supplements may have been stored in the thyroid gland or secreted in breast milk instead of being excreted in urine. Additional research that uses other biomarkers of iodine status is needed to determine how to meet the iodine requirements of pregnant and lactating women in Bangladesh and similar settings. This trial was registered at clinicaltrials.gov as NCT01715038. PMID- 28615380 TI - Leucine Differentially Regulates Gene-Specific Translation in Mouse Skeletal Muscle. AB - Background: Amino acids, especially leucine, are particularly effective in promoting protein synthesis. Leucine is known to increase the rate of protein synthesis in skeletal muscle through the mechanistic target of rapamycin complex 1-dependent, as well as -independent, signaling pathways. However, the overall translation program is poorly defined, and it is unknown how the activation of these pathways differentially controls the translation of specific mRNAs.Objective: Ribosome profiling and RNA sequencing were used to precisely define the translational program activated by an acute oral dose of leucine.Methods: Adult male C57BL/6 mice were deprived of food overnight before the delivery of an acute dose of l-leucine (9.4 mg) (n = 6) or vehicle (n = 5) and tissues collected 30 min later. Ribosome footprints and total RNA were isolated and subjected to deep sequencing. Changes in gene-specific mRNA abundance and ribosome occupancy were determined between the leucine-treated and control groups by aligning sequence reads to Reference Sequence database mRNAs and applying statistical features of the Bioconductor package edgeR.Results: Our data revealed mRNA features that confer translational control of skeletal muscle mRNAs in response to an acute dose of leucine. The subset of skeletal muscle mRNAs that are activated consists largely of terminal oligopyrimidine mRNAs (false discovery rate: <0.05), whereas those with reduced translation had 5' untranslated regions with increased length. Only the small nuclear RNAs, which are required for ribosome biogenesis, were significantly altered in RNA abundance. The inferred functional translational program activated by dietary leucine includes increased protein synthesis capacity and energy metabolism, upregulation of sarcomere-binding proteins, modulation of circadian rhythm, and suppression of select immune components.Conclusions: These results clarify the translation program acutely stimulated by leucine in mouse skeletal muscle and establish new methodologies for use in future studies of skeletal muscle disease or aging and further examination of downstream effects of leucine on gene expression. PMID- 28615381 TI - Yogurt Is a Low-Glycemic Index Food. AB - High yogurt intake is associated with a reduced risk of type 2 diabetes (T2DM). Although several mechanisms could explain this association, this paper addresses the glycemic and insulinemic impact of yogurt. There is evidence that low glycemic index (GI) and low-glycemic load (GL) diets are associated with a reduced risk of T2DM. The 93 GI values for yogurt in the University of Sydney's GI database have a mean +/- SD of 34 +/- 13, and 92% of the yogurts are low-GI (<=55). The 43 plain yogurts in the database have a lower GI than the 50 sweetened yogurts, 27 +/- 11 compared with 41 +/- 11 (P < 0.0001). This difference is not explained by sugar, per se, but rather by the higher protein-to carbohydrate ratio in plain yogurt. Although yogurt has a low GI, its insulinemic index (II) is higher than its GI. High insulin responses may be deleterious because hyperinsulinemia is associated with an increased risk of T2DM. Nevertheless, this may not be a concern for yogurt because, although its II is higher than its GI, the II of yogurt is within the range of II values for nondairy low-GI foods. In addition, mixed meals containing dairy protein elicit insulin responses similar to those elicited by mixed meals of similar composition containing nondairy protein. Because the GI of yogurt is lower than that of most other carbohydrate foods, exchanging yogurt for other protein and carbohydrate sources can reduce the GI and GL of the diet, and is in line with recommended dietary patterns, which include whole grains, fruits, vegetables, nuts, legumes, fish, vegetable oils, and yogurt. PMID- 28615383 TI - Introduction to the Fourth Global Summit on the Health Effects of Yogurt. PMID- 28615382 TI - Factors Influencing the Gut Microbiota, Inflammation, and Type 2 Diabetes. AB - The gut microbiota is a complex community of bacteria residing in the intestine. Animal models have demonstrated that several factors contribute to and can significantly alter the composition of the gut microbiota, including genetics; the mode of delivery at birth; the method of infant feeding; the use of medications, especially antibiotics; and the diet. There may exist a gut microbiota signature that promotes intestinal inflammation and subsequent systemic low-grade inflammation, which in turn promotes the development of type 2 diabetes. There are preliminary studies that suggest that the consumption of probiotic bacteria such as those found in yogurt and other fermented milk products can beneficially alter the composition of the gut microbiome, which in turn changes the host metabolism. Obesity, insulin resistance, fatty liver disease, and low-grade peripheral inflammation are more prevalent in patients with low alpha diversity in the gut microbiome than they are in patients with high alpha diversity. Fermented milk products, such as yogurt, deliver a large number of lactic acid bacteria to the gastrointestinal tract. They may modify the intestinal environment, including inhibiting lipopolysaccharide production and increasing the tight junctions of gut epithelia cells. PMID- 28615384 TI - Yogurt and Diabetes: Overview of Recent Observational Studies. AB - The effects of dairy consumption on the prevention of type 2 diabetes remain controversial and depend on the dairy subtype. Yogurt intake has received special attention because its association with health benefits is more consistent than that of other types of dairy products. In the present article, we review those observational studies that evaluated the association between yogurt consumption and type 2 diabetes. We also discuss the possible mechanisms involved in these associations. We found that 13 prospective studies evaluated the association between yogurt intake and type 2 diabetes, most of which showed an inverse association between the frequency of yogurt consumption and the risk of diabetes. In addition to the scientific evidence accumulated from individual prospective studies, several meta-analyses have shown that yogurt consumption has a potential role in diabetes prevention. The most recent analysis shows a 14% lower risk of type 2 diabetes when yogurt consumption was 80-125 g/d compared with no yogurt consumption. The intake of fermented dairy products, especially yogurt, has been inversely associated with variables of glucose metabolism. Yogurt may have probiotic effects that could modulate glucose metabolism. We conclude that yogurt consumption, in the context of a healthy dietary pattern, may reduce the risk of type 2 diabetes in healthy and older adults at high cardiovascular risk. Large scale intervention studies and randomized clinical trials are warranted to determine if yogurt consumption has beneficial effects on insulin sensitivity and reduces the risk of type 2 diabetes. PMID- 28615385 TI - Fake medical news: Is it better to be treated by a male physician or a female physician? PMID- 28615387 TI - Screening for biliary atresia: it's in the cards. PMID- 28615389 TI - Hospitalists and family physicians. PMID- 28615390 TI - Long-term benefits of weight loss? PMID- 28615391 TI - Practical approach to evaluating testicular status in infants and children. AB - OBJECTIVE: To review the differences between normal, retractile, ectopic, ascended, and undescended testes and to describe the optimal way to perform a testicular examination to distinguish one from the other, as well as to demonstrate that ultrasound imaging is not necessary and to clarify when to consider specialist referral. SOURCES OF INFORMATION: This paper is based on selected findings from a MEDLINE search on undescended testes and orchiopexy referrals, and on our experience at the Urology Clinic at the Children's Hospital of Eastern Ontario in Ottawa, including review of referrals to our clinic for undescended testes and the resultant findings of normal variants versus surgical cases. The MeSH headings used in our MEDLINE search included undescended testicle, retractile testicle, ectopic testicle, ascended testicle, referral and consultation, and orchiopexy. MAIN MESSAGE: An undescended testis is defined as the true absence of one testis (or both testes) from normal scrotal position. Ectopic and ascended testes will likewise be absent from the scrotum, the latter having been present at one point in development. Differentiating among testicular examination findings is important, as descended and retractile testes are managed conservatively, while prompt surgical intervention should be offered for ascended, ectopic, and undescended testes. Uncertainty surrounding the diagnosis of an undescended testis causes anxiety, might lead to unwarranted imaging, and might increase the wait list for specialty assessment. For this reason, avoidance of ultrasound in the evaluation of undescended testes was included in the recent Choosing Wisely Canada campaign. We seek to clarify the physical examination findings in the evaluation of possible undescended testes, the suggested referral parameters, and the subsequent management. CONCLUSION: Undescended testes and their variants are common. As decision for referral is based on the primary care physician's physical examination findings, we clarify distinguishing between normal and abnormal findings on testicular examination to aid in appropriate referral for subspecialist evaluation. Consultation, if needed, should be sought at 6 months' corrected gestational age, or at detection if later than 6 months, without delay for ultrasound imaging, as surgical management is recommended for those patients with undescended, ectopic, or ascended testes. PMID- 28615392 TI - Family medicine around the world: overview by region: The Besrour Papers: a series on the state of family medicine in the world. AB - OBJECTIVE: To demonstrate how family medicine has been recognized and integrated into primary health care systems in contrasting contexts around the world and to provide an overview of how family physicians are trained and certified. COMPOSITION OF THE COMMITTEE: Since 2012, the College of Family Physicians of Canada has hosted the Besrour Conferences to reflect on its role in advancing the discipline of family medicine globally. The Besrour Papers Working Group, which was struck at the 2013 conference, was tasked with developing a series of papers to highlight the key issues, lessons learned, and outcomes emerging from the various activities of the Besrour collaboration. The working group comprised members of various academic departments of family medicine in Canada and abroad who attended the conferences. METHODS: An initial search was conducted in PubMed using a family medicine hedge of MeSH terms, text words, and family medicine journals, combined with text words and terms representing low- and middle-income countries and the concept of family medicine training programs. A second search was completed using only family medicine terms in the CAB Direct and World Bank databases. Subsequent PubMed searches were conducted to identify articles about specific conditions or services based on suggestions from the authors of the articles selected from the second search. Additional articles were identified through reference lists of key articles and through Google searches. We then attempted to verify and augment the information through colleagues and partners. REPORT: The scope of family medicine and the nature of family medicine training vary considerably worldwide. Challenges include limited capacity, incomplete understanding of roles, and variability of standards and recognition. Opportunities for advancement might include technology, collaboration, changes in pedagogy, flexible training methods, and system-wide support. PMID- 28615394 TI - Hyperbaric oxygen therapy for children with autism spectrum disorder. AB - Question As autism spectrum disorder (ASD) is a multifactorial condition, with genetic and environmental risk factors contributing to children's unique presentation and symptom severity, a range of treatments have been suggested. Parents of children with ASD in my clinic are asking me about alternative therapies to improve their children's condition. One of those therapies is hyperbaric oxygen therapy (HBOT); commercial advertisement in the past has suggested good results with this approach. Should I recommend the use of HBOT for children with ASD? Answer Hyperbaric oxygen therapy provides a higher concentration of oxygen delivered in a chamber or tube containing higher than sea level atmospheric pressure. Case series and randomized controlled trials show no evidence to support the benefit of HBOT for children with ASD. Only 1 randomized controlled trial reported effectiveness of this treatment, and those results have yet to be repeated. PMID- 28615396 TI - Primary lung cancer presenting as foot pain: Cautionary case report. PMID- 28615397 TI - Recurrent vulvovaginal candidiasis. PMID- 28615398 TI - Porcine procedure pads: How to build a teaching tool that's a cut above. PMID- 28615399 TI - Concussion diagnosis and management: Knowledge and attitudes of family medicine residents. AB - OBJECTIVE: To assess the knowledge of, attitudes toward, and learning needs for concussion diagnosis and management among family medicine residents. DESIGN: E mail survey. SETTING: University of Toronto in Ontario. PARTICIPANTS: Family medicine residents (N = 348). MAIN OUTCOME MEASURES: To describe relationships between awareness of concussion management and lifestyle, education background, and residency placement, t tests and 2 tests were used as appropriate. Linear regression was used to compare self-reported concussion knowledge with knowledge scores. Thematic analysis was used to interpret answers to the qualitative question asking residents to describe challenges they foresee physicians facing when diagnosing and managing concussion. RESULTS: The residents who responded (n = 73, response rate 21%) correctly answered an average of 5.2 questions out of 9 (58%) regarding the diagnosis and management of concussion. Postgraduate year, sex, personal history of concussion, and clinical exposure to concussion were not significant factors in predicting the number of correct answers. Several misconceptions and knowledge gaps were revealed. Of residents who responded, 71% did not recognize chronic traumatic encephalopathy and only 63% recognized second impact syndrome as consequences of repetitive concussions. Moreover, 32% of residents did not think that every individual with a concussion should see a physician as part of management. Knowledge scores did not predict self-reported concussion knowledge. Thematic analysis revealed 4 themes related to the challenges of concussion diagnosis and management: the nonspecificity and vagueness of symptoms, lack of formal diagnostic criteria, patient compliance with management, and counseling patients with respect to return to play, work, or learning. CONCLUSION: We found substantial gaps in knowledge surrounding concussion diagnosis and management among family medicine residents. This lack of knowledge should be addressed at both the undergraduate medical education level and the residency training level to improve concussion-related care and patient outcomes. PMID- 28615400 TI - Seeing things. PMID- 28615401 TI - Indigenous medicine: Approaching the challenges with courage and humility. PMID- 28615402 TI - Evidence-based medicine resources tool kit revisited. PMID- 28615403 TI - Guidelines in family practice-help wanted. PMID- 28615406 TI - Mainpro+: One year later. PMID- 28615408 TI - Examining screening mammography participation among women aged 40 to 74. AB - OBJECTIVE: To examine participation in screening mammography among women aged 40 to 74 and identify which factors are associated with those women who participate in screening. DESIGN: Secondary analysis of the cross-sectional 2012 Canadian Community Health Survey. SETTING: Canada. PARTICIPANTS: A population-based national sample of 18 312 women aged 40 to 74. MAIN OUTCOME MEASURES: Women's participation in screening mammography in the 2 years preceding the 2012 Canadian Community Health Survey; women's preventive health activities (ie, having a regular doctor, a recent physical checkup, and a Papanicolaou test), which were adjusted for sociodemographic factors. RESULTS: Participation in recent screening mammography was highest among women aged 60 to 69 (70.3%), followed by those aged 50 to 59 (63.4%) and those aged 70 to 74 (58.4%). Almost one-third (31.4%) of women aged 40 to 49 had had a screening mammogram in the past 2 years. Having a regular doctor (odds ratio [OR] = 3.30, 95% CI 2.90 to 3.73), a physical checkup in the past year (OR = 3.06, 95% CI 2.30 to 4.08), or a Pap test in the past 3 years (OR = 3.47, 95% CI 3.18 to 3.79) more than tripled the odds that women had had a recent screening mammogram. CONCLUSION: Aside from age being a factor associated with women's participation in screening mammography, factors related to women's health care use (having a regular doctor, a recent physical checkup, and a recent Pap test) demonstrated a stronger association with women aged 40 to 74 having had recent mammograms. The association between women's participation in screening and their preventive health activities implies that the doctor's office is an appropriate venue for conversations regarding the potential benefits and harms of screening mammography. PMID- 28615409 TI - Outcome tools for diabetes-specific quality of life: Study performed in a private family practice clinic. AB - OBJECTIVE: To critically review and evaluate the psychometric properties and practical considerations of administering generic and diabetes-specific quality of-life (QoL) tools in the clinical environment and provide recommendations. DATA SOURCES AND TOOL SELECTION: A MEDLINE search was carried out from January 1950 to August 2015 using the MeSH terms diabetes, quality of life, and questionnaires. Four generic and 4 diabetes-specific tools were selected based on the frequency of their use and the existence of published evidence of strong psychometric properties in patients with diabetes (either type 1 or 2). The generic tools included the Short Form-36 (SF-36), Short Form-12 (SF-12), Sickness Impact Profile, and EuroQol EQ-5D instruments. Diabetes-specific tools included the Audit of Diabetes-Dependent Quality of Life, Diabetes Quality of Life, Appraisal of Diabetes Scale (ADS), and Diabetes Health Profile instruments. SYNTHESIS: The SF-36 is one of the most widely used general health measures in QoL research and it has proven reliability and validity. However, the SF-12 is a better option for a family practice owing to its shorter length. The SF-12 has been shown to be closely correlated with the SF-36. Of the diabetes-specific measures, the ADS is known be valid, short, and relatively straightforward in terms of scoring, thereby increasing its usefulness in routine clinical practice. The Audit of Diabetes-Dependent Quality of Life and Diabetes Quality of Life tools have been widely tested and have generally been found to be more valid and reliable than the ADS, but specific issues with feasibility make them unappealing for the clinical setting. The rationale was to find the most rigorously tested instrument within the scientific literature in terms of validity, reliability, and responsiveness. However, this was not done, as judging the quality of a measure is not simply a matter of determining its psychometric properties but rather requires qualitative judgment about the entirety of the evidence. CONCLUSION: Finding ideal tools and procedures for routine data collection in the clinic setting requires organization and groundwork that will eventually assist both clinicians and researchers by providing reliable information on QoL for patients with diabetes. Further research is necessary to assess the validity and responsiveness of these tools specifically relating to evaluation of QoL for those with diabetes. PMID- 28615410 TI - Causes and outcomes of markedly elevated C-reactive protein levels. AB - OBJECTIVE: To characterize the causes of marked elevation of C-reactive protein (CRP) levels, investigate patient outcomes, and examine factors that might influence the CRP response. DESIGN: Health records were used to retrospectively determine patient characteristics, diagnoses, and outcomes over a 2-year period (2012 to 2013). SETTING: A large referral centre in Moncton, NB. PARTICIPANTS: Adult inpatients and outpatients with a CRP level above 100 mg/L. MAIN OUTCOME MEASURES: Differences among the CRP distributions of various diagnosis categories were examined using Kruskal-Wallis tests, and factors affecting outcomes were examined using Fisher exact tests. RESULTS: Over the 2-year period, 1260 CRP levels (839 patients; 3.1% of all tests) were above 100 mg/L (range 100.1 to 576.0 mg/L). The mean age was 63 years (range 18 to 101) and 50.2% of patients were men. Infection was the most prevalent cause (55.1%), followed by rheumatologic diseases (7.5%), multiple causes (5.6%), other inflammatory conditions (5.4%), malignancy (5.1%), drug reactions (1.7%), and other conditions (2.0%). A diagnosis could not be established in 17.6% of cases. On average, infections caused higher peak CRP levels (W = 34 519, P < .001) and infection was present in 88.9% of cases with CRP levels greater than 350 mg/L. Rheumatologic causes were associated with only 5.6% of CRP levels above 250 mg/L. The overall mortality was 8.6% and was higher in patients with malignancy (37.0%), multiple diagnoses (21.0%), and leukopenia (20.7%, P = .002). CONCLUSION: Most patients had infections and the proportion of patients with infections increased with the level of CRP, although many diagnoses were associated with markedly elevated CRP levels. These data could help guide health care professionals in the evaluation and management of these patients. PMID- 28615412 TI - Insights into cortical microtubule nucleation and dynamics in Arabidopsis leaf cells. AB - Plant microtubules (MTs) are nucleated from the gamma-tubulin-containing ring complex (gammaTuRC). In cortical MT arrays of interphase plant cells, gammaTuRC is preferentially recruited to the lattice of preexisting MTs, where it initiates MT nucleation in either a branch- or bundle-forming manner, or dissociates without mediating nucleation. In this study, we analyzed how gammaTuRCs influence MT nucleation and dynamics in cotyledon pavement cells of Arabidopsis thaliana We found that gammaTuRC nucleated MTs at angles of ~40 degrees toward the plus-ends of existing MTs, or in predominantly antiparallel bundles. A small fraction of gammaTuRCs was motile and tracked MT ends. When gammaTuRCs decorated the depolymerizing MT end, they reduced the depolymerization rate. Non-nucleating gammaTuRCs associated with the MT lattice promoted MT regrowth after a depolymerization phase. These results suggest that gammaTuRCs not only nucleate MT growth but also regulate MT dynamics by stabilizing MT ends. On rare occasions, a non-MT-associated gammaTuRC was pushed in the direction of the MT minus-end, while nucleating a new MT, suggesting that the polymerizing plus-end is anchored to the plasma membrane. PMID- 28615413 TI - Breaking the color barrier - a multi-selective antibody reporter offers innovative strategies of fluorescence detection. AB - A novel bi-partite fluorescence platform exploits the high affinity and selectivity of antibody scaffolds to capture and activate small-molecule fluorogens. In this report, we investigated the property of multi-selectivity activation by a single antibody against diverse cyanine family fluorogens. Our fluorescence screen identified three cell-impermeant fluorogens, each with unique emission spectra (blue, green and red) and nanomolar affinities. Most importantly, as a protein fusion tag to G-protein-coupled receptors, the antibody biosensor retained full activity - displaying bright fluorogen signals with minimal background on live cells. Because fluorogen-activating antibodies interact with their target ligands via non-covalent interactions, we were able to perform advanced multi-color detection strategies on live cells, previously difficult or impossible with conventional reporters. We found that by fine-tuning the concentrations of the different color fluorogen molecules in solution, a user may interchange the fluorescence signal (onset versus offset), execute real-time signal exchange via fluorogen competition, measure multi-channel fluorescence via co-labeling, and assess real-time cell surface receptor traffic via pulse-chase experiments. Thus, here we inform of an innovative reporter technology based on tri-color signal that allows user-defined fluorescence tuning in live-cell applications. PMID- 28615414 TI - Loss of IP3 Receptor-Mediated Ca2+ Release in Mouse B Cells Results in Abnormal B Cell Development and Function. AB - Intracellular calcium (Ca2+) mobilization after engagement of the BCR has been proposed to play an important role in B cell development and function. BCR activation causes an initial Ca2+ release from the endoplasmic reticulum that is mediated by inositol 1,4,5-trisphosphate receptor (IP3R) and then triggers store operated Ca2+ entry once endoplasmic reticulum Ca2+ store is depleted. Store operated Ca2+ entry has been shown to regulate B cell function but is dispensable for B cell development. By contrast, the function of IP3R-mediated Ca2+ release in B cells remains to be determined. In this study, we generated a B cell specific IP3R triple-knockout (IP3R-TKO) mouse model and revealed that loss of IP3Rs increased transitional B cell numbers and reduced recirculating mature B cell numbers in bone marrow. In the peripheral tissues, the numbers of conventional B2 B cells and B1 B cells were both significantly decreased in IP3R TKO mice. Ablation of IP3Rs also dramatically reduced BCR-mediated B cell proliferation and survival. Furthermore, T cell-dependent and T cell-independent Ab responses were altered in IP3R-TKO mice. In addition, deletion of IP3Rs reduced IL-10-producing regulatory B cell numbers and led to defects in NFAT activation, which together resulted in decreased IL-10 secretion. Taken together, our study demonstrated for the first time, to our knowledge, that IP3R-mediated Ca2+ release plays an essential role in regulating B cell development, proliferation, Ab production, and B cell regulatory function in vivo. PMID- 28615415 TI - Cutting Edge: The Aging Immune System Reveals the Biological Impact of Direct Antigen Presentation on CD8 T Cell Responses. AB - The vertebrate immune system uses multiple, sometimes redundant, mechanisms to contain pathogenic microorganisms that are always evolving to evade host defenses. Thus, the cowpox virus (CPXV) uses genes encoding CPXV12 and CPXV203 to prevent direct MHC class I presentation of viral peptides by infected cells. However, CD8 T cells are effectively primed against CPXV by cross-presentation of viral Ags in young mice. Old mice accumulate defects in both CD8 T cell activation and cross-presentation. Using a double-deletion mutant (?12?203) of CPXV, we show that direct priming of CD8 T cells in old mice yields superior recall responses, establishing a key contribution of this mechanism to host antipoxvirus responses and enhancing our fundamental understanding of how viral manipulation of direct presentation impacts pathogenesis. This also provides a proof of principle that suboptimal CD8 T cell in old organisms can be optimized by manipulating Ag presentation, with implications for vaccine design. PMID- 28615416 TI - IL-17 Receptor A Maintains and Protects the Skin Barrier To Prevent Allergic Skin Inflammation. AB - Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. Although type 2 responses are implicated in AD, emerging evidence indicates a potential role for the IL-17A signaling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency (Il17ra-/- ) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra-/- mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, as well as increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin. Il17ra-/- mice have a defective skin barrier with altered filaggrin expression. The barrier dysregulation and spontaneous skin inflammation in Il17ra-/- mice was dependent on TSLP, but not the other alarmins IL-25 and IL 33. The associated skin inflammation was mediated by IL-5-expressing pathogenic effector Th2 cells and was independent of TCRgammadelta T cells and IL-22. An absence of IL-17RA in nonhematopoietic cells, but not in the hematopoietic cells, was required for the development of spontaneous skin inflammation. Skin microbiome dysbiosis developed in the absence of IL-17RA, with antibiotic intervention resulting in significant amelioration of skin inflammation and reductions in skin-infiltrating pathogenic effector Th2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signaling in regulation of the skin barrier and maintenance of skin immune homeostasis. PMID- 28615417 TI - T Cell-Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity during Cryptococcus neoformans Infection. AB - Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen but the cell signaling pathways that drive T cell responses regulating antifungal immunity are incompletely understood. Notch is a key signaling pathway regulating T cell development, and differentiation and functional responses of mature T cells in the periphery. The targeting of Notch signaling within T cells has been proposed as a potential treatment for alloimmune and autoimmune disorders, but it is unknown whether disturbances to T cell immunity may render these patients vulnerable to fungal infections. To elucidate the role of Notch signaling during fungal infections, we infected mice expressing the pan-Notch inhibitor dominant negative mastermind-like within mature T cells with C. neoformans Inhibition of T cell-restricted Notch signaling increased fungal burdens in the lungs and CNS, diminished pulmonary leukocyte recruitment, and simultaneously impaired Th1 and Th2 responses. Pulmonary leukocyte cultures from T cell Notch-deprived mice produced less IFN-gamma, IL-5, and IL-13 than wild-type cells. This correlated with lower frequencies of IFN-gamma-, IL-5-, and IL-13-producing CD4+ T cells, reduced expression of Th1 and Th2 associated transcription factors, Tbet and GATA3, and reduced production of IFN-gamma by CD8+ T cells. In contrast, Th17 responses were largely unaffected by Notch signaling. The changes in T cell responses corresponded with impaired macrophage activation and reduced leukocyte accumulation, leading to diminished fungal control. These results identify Notch signaling as a previously unappreciated regulator of Th1 and Th2 immunity and an important element of antifungal defenses against cryptococcal infection and CNS dissemination. PMID- 28615419 TI - Dimeric Fcgamma Receptor Enzyme-Linked Immunosorbent Assay To Study HIV-Specific Antibodies: A New Look into Breadth of Fcgamma Receptor Antibodies Induced by the RV144 Vaccine Trial. AB - Ab-dependent cellular cytotoxicity (ADCC) responses are of growing interest in the HIV vaccine field but current cell-based assays are usually difficult to reproduce across laboratories. We developed an ELISA and multiplex assay to model the cross-linking of Fcgamma receptors (FcgammaR) by Abs, which is required to initiate an ADCC response. Our FcgammaR dimer ELISA readily detected Abs in samples from two separate cohorts of the partially efficacious Thai RV144 HIV vaccine efficacy trial. The FcgammaR dimer-binding Abs induced by the RV144 regimen correlated well with a functional measure of ADCC as well as IgG subclasses. The high-throughput multiplex assay allowed us to simultaneously measure FcgammaR dimer-binding Abs to 32 different HIV Ags, providing a measure of the breadth of FcgammaR-binding Abs induced by the RV144 trial. FcgammaR binding Abs specific to V regions 1 and 2 were strongly associated with increased breadth of recognition of different Env proteins, suggesting anti-V regions 1 and 2 Abs may be a marker of ADCC breadth. This FcgammaR dimer provides an important tool for the further analysis and refinement of ADCC-inducing HIV and other antiviral vaccine regimens. PMID- 28615418 TI - Cutting Edge: Activation of STING in T Cells Induces Type I IFN Responses and Cell Death. AB - Stimulator of interferon genes (STING) was initially described as a sensor of intracellular bacterial and viral DNA and a promising adjuvant target in innate immune cells; more recently STING has also been shown to detect endogenous DNA and play a role in tumor immunity and autoimmune disease development. Thus far STING has been studied in macrophages and dendritic cells. In this study, to our knowledge we provide the first evidence of STING activation in T cells, in which STING agonists not only provoke type I IFN production and IFN-stimulated gene expression, mirroring the response of innate cells, but are also capable of activating cell stress and death pathways. Our results suggest a re-evaluation of STING agonist-based therapies may be necessary to identify the possible effects on the T cell compartment. Conversely, the effects of STING on T cells could potentially be harnessed for therapeutic applications. PMID- 28615420 TI - Insulin resistance among obese middle-aged is associated with decreased cerebrovascular reactivity. AB - OBJECTIVE: To evaluate differences in cerebrovascular reactivity (CVR) to mild hypercapnia in obese/overweight individuals with and without insulin resistance (IR) compared to comparable lean controls. METHODS: A total of 60 cognitively normal participants (20 lean controls and 24 obese/overweight individuals with and 16 without IR) were evaluated using a high spatial resolution arterial spin labeling MRI technique at rest and during mild hypercapnia. We analyzed group differences in CVR in cerebral cortex and ascertained the relationships between CVR, IR, and body mass index (BMI). RESULTS: Obese/overweight participants with and without IR had significantly lower CVR to hypercapnia than lean controls after controlling for age, sex, and the presence of hypertension (F2,53 = 5.578, p = 0.006 [Formula: see text] = 0.174). In the obese/overweight participants with IR, there was a significant correlation between higher CVR and a measure of insulin sensitivity, even after accounting for BMI (rp = 0.575, p = 0.004). In contrast, there was no relationship between CVR and BMI when controlling for IR. No such relationships existed for the other 2 groups. CONCLUSIONS: IR is associated with impaired CVR; the relationship appears to be driven by the degree of IR and not by obesity. These rarely reported results suggest that early forms of cerebrovascular dysfunction exist among obese middle-aged individuals with significant IR but without type 2 diabetes mellitus. These functional vascular abnormalities may help explain the associations among IR, diabetes, and dementia, and suggest that interventions aiming to improve IR or CVR may help prevent cognitive decline later in life. PMID- 28615421 TI - Outcomes of Colorado children with acute flaccid myelitis at 1 year. AB - OBJECTIVE: We describe long-term functional, neurodiagnostic, and psychosocial outcomes of a cohort of 12 children from Colorado diagnosed with acute flaccid myelitis (AFM) in 2014. METHODS: Children were assessed every 3 months for 1 year or until clinical resolution. Assessments included neurologic examination, MRI, EMG/nerve conduction studies (NCS), functional measures (Assisting Hand Assessment, Hammersmith Functional Motor Scale), and Patient-Reported Outcomes Measurement Information System questionnaires. RESULTS: Eight of 12 children completed the study. Six of 8 had persistent motor deficits at 1 year; 2 demonstrated full recovery. Four were not enrolled, 2 of whom reported full recovery. The 6 affected were weakest in proximal muscles, showing minimal to no improvement and significant atrophy at 1 year. All patients improved in distal muscle groups. Cranial nerve dysfunction resolved in 2 of 5 and improved in all. Four of 5 showed progressive functional improvement at 6 and 12 months. Two of 8 reported pain at 1 year. Three of 8 reported depressive symptoms. Repeat MRI was performed in 7 of 8 children a median of 7 months after onset and showed significant improvement or normalization in all but one child. Repeat EMG/NCS was performed on 4 children a median of 8 months after onset and showed ongoing denervation and chronic reinnervation in 3 children with persistent deficits. CONCLUSIONS: At 1 year, children with AFM demonstrated functional gains but weakness persisted. EMG changes correlated with persistent deficits better than imaging. Despite improvements, AFM had substantial long-term functional effects on affected children. PMID- 28615422 TI - Prognostic factors for chronic headache: A systematic review. AB - OBJECTIVE: To identify predictors of prognosis and trial outcomes in prospective studies of people with chronic headache. METHODS: This was a systematic review of published literature in peer-reviewed journals. We included (1) randomized controlled trials (RCTs) of interventions for chronic headache that reported subgroup analyses and (2) prospective cohort studies, published in English, since 1980. Participants included adults with chronic headache (including chronic headache, chronic migraine, and chronic tension-type headache with or without medication overuse headache). We searched key databases using free text and MeSH terms. Two reviewers independently extracted data and assessed the methodologic quality of studies and overall quality of evidence identified using appropriate published checklists. RESULTS: We identified 16,556 titles, removed 663 duplicates, and reviewed 199 articles, of which 27 were included in the review-17 prospective cohorts and 10 RCTs with subgroup analyses reported. There was moderate-quality evidence indicating that depression, anxiety, poor sleep and stress, medication overuse, and poor self-efficacy for managing headaches are potential prognostic factors for poor prognosis and unfavorable outcomes from preventive treatment in chronic headache. There was inconclusive evidence about treatment expectations, age, age at onset, body mass index, employment, and several headache features. CONCLUSIONS: This review identified several potential predictors of poor prognosis and worse outcome postinterventions in people with chronic headache. The majority of these are modifiable. The findings also highlight the need for more longitudinal high-quality research of prognostic factors in chronic headache. PMID- 28615424 TI - Epilepsy and mortality after aneurysmal subarachnoid hemorrhage. PMID- 28615423 TI - Diagnosis of DWI-negative acute ischemic stroke: A meta-analysis. AB - OBJECTIVE: To determine the prevalence of diffusion-weighted imaging (DWI) negative acute ischemic stroke (AIS) and to identify clinical characteristics of patients with DWI-negative AIS. METHODS: We systematically searched PubMed and Ovid/MEDLINE for relevant studies between 1992, the year that the DWI sequence entered clinical practice, and 2016. Studies were included based upon enrollment of consecutive patients presenting with a clinical diagnosis of AIS prior to imaging. Meta-analysis was performed to synthesize study-level data, estimate DWI negative stroke prevalence, and estimate the odds ratios (ORs) for clinical characteristics associated with DWI-negative stroke. RESULTS: Twelve articles including 3,236 AIS patients were included. The meta-analytic synthesis yielded a pooled prevalence of DWI-negative AIS of 6.8%, 95% confidence interval (CI) 4.9 9.3. In the 5 studies that reported proportion data for DWI-negative and DWI positive AIS based on the ischemic vascular territory (n = 1,023 AIS patients), DWI-negative stroke was strongly associated with posterior circulation ischemia, as determined by clinical diagnosis at hospital discharge or repeat imaging (OR 5.1, 95% CI 2.3-11.6, p < 0.001). CONCLUSIONS: A small but significant percentage of patients with AIS have a negative DWI scan. Patients with neurologic deficits consistent with posterior circulation ischemia have 5 times the odds of having a negative DWI scan compared to patients with anterior circulation ischemia. AIS remains a clinical diagnosis and urgent reperfusion therapy should be considered even when an initial DWI scan is negative. PMID- 28615427 TI - Acute flaccid myelitis and enterovirus D68: Deja vu all over again. PMID- 28615425 TI - Epilepsy-associated long-term mortality after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To elucidate the epilepsy-associated causes of death and subsequent excess long-term mortality among 12-month survivors of subarachnoid hemorrhage from saccular intracranial aneurysm (SIA-SAH). METHODS: The Kuopio SIA Database (kuopioneurosurgery.fi) includes all SIA-SAH patients admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland. The study cohort consists of 779 patients, admitted from 1995 to 2007, who were alive at 12 months after SIA-SAH. Their use of reimbursable antiepileptic drugs and the causes of death (ICD-10) were fused from the Finnish national registries from 1994 to 2014. RESULTS: The 779 12-month survivors were followed up until death (n = 197) or December 31, 2014, a median of 12.0 years after SIA-SAH. Epilepsy had been diagnosed in 121 (15%) patients after SIA-SAH, and 34/121 (28%) had died at the end of follow-up, with epilepsy as the immediate cause of death in 7/34 (21%). In the 779 patients alive at 12 months after SIA-SAH, epilepsy was an independent risk factor for mortality (hazard ratio 1.8, 95% confidence interval 1.1-3.0). CONCLUSIONS: Comorbid epilepsy in 12-month survivors of SIA-SAH is associated with increased risk of death in long-term follow-up. Survivors of SIA SAH require long-term dedicated follow-up, including identification and effective treatment of comorbid epilepsy to prevent avoidable deaths. PMID- 28615426 TI - Modulation of intrinsic resting-state fMRI networks in women with chronic migraine. AB - OBJECTIVE: To evaluate the intrinsic resting functional connectivity of the default mode network (DMN), salience network (SN), and central executive network (CEN) network in women with chronic migraine (CM), and whether clinical features are associated with such abnormalities. METHODS: We analyzed resting-state connectivity in 29 women with CM as compared to age- and sex-matched controls. Relationships between clinical characteristics and changes in targeted networks connectivity were evaluated using a multivariate linear regression model. RESULTS: All 3 major intrinsic brain networks were less coherent in CM (DMN: p = 0.030, SN: p = 0.007, CEN: p = 0.002) as compared to controls. When stratified based on medication overuse headache (MOH) status, CM without MOH (DMN: p = 0.029, SN: p = 0.023, CEN: p = 0.003) and CM with MOH (DMN: p = 0.016, SN: p = 0.016, CEN: p = 0.015) were also less coherent as compared to controls. There was no difference in CM with MOH as compared to CM without MOH (DMN: p = 0.382, SN: p = 0.408, CEN: p = 0.419). The frequency of moderate and severe headache days was associated with decreased connectivity in SN (p = 0.003) and CEN (p = 0.015), while cutaneous allodynia was associated with increased connectivity in SN (p = 0.011). CONCLUSIONS: Our results demonstrated decreased overall resting-state functional connectivity of the 3 major intrinsic brain networks in women with CM, and these patterns were associated with frequency of moderate to severe headache and cutaneous allodynia. PMID- 28615428 TI - Increased rate of venous thrombosis may be associated with inpatient dihydroergotamine treatment. AB - OBJECTIVE: To review whether the incidence of catheter-associated venous thromboses was higher in patients receiving IV dihydroergotamine compared to lidocaine. METHODS: We retrospectively reviewed all admissions at the University of California, San Francisco Headache Center from February 25, 2008, through October 31, 2014, for age, sex, diagnosis, aura, treatment dose, type of IV line used, days with line, superficial (SVT) or deep venous thrombosis (DVT), and pulmonary embolism (PE). RESULTS: A peripherally inserted central catheter (PICC) or midline catheter was placed in 315 of 589 (53%) admissions. Mean age was 38 years with a range of 6 to 79 years; 121 patients (21%) were <=18 years old. Seventy-four percent (433 of 589) of patients were female. Of 263 dihydroergotamine admissions using a PICC or midline catheter, 19 (7.2%) had either an SVT or DVT or a PE; 2 patients were diagnosed with both DVT and PE. Of 52 lidocaine admissions using a PICC or midline catheter, none had a thrombotic event (p = 0.05, Fisher exact test). Age, sex, aura, total dihydroergotamine dose, and number of days with line were not significant predictors of venous thrombosis. CONCLUSIONS: IV dihydroergotamine treatment may be associated with an increased risk of catheter-associated venous thrombosis. A low threshold for diagnostic ultrasound investigation is appropriate because anticoagulation therapy was frequently required. PMID- 28615429 TI - Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. AB - OBJECTIVE: To establish whether children with relapsing acquired demyelinating syndromes (RDS) and myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) show distinctive clinical and radiologic features and to generate a diagnostic algorithm for the main RDS for clinical use. METHODS: A panel reviewed the clinical characteristics, MOG-Ab and aquaporin-4 (AQP4) Ab, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with RDS. A neuroradiologist blinded to the diagnosis scored the MRI scans. Clinical, radiologic, and serologic tests results were compared. RESULTS: The findings showed that 56.4% of children were diagnosed with multiple sclerosis (MS), 25.4% with neuromyelitis optica spectrum disorder (NMOSD), 12.7% with multiphasic disseminated encephalomyelitis (MDEM), and 5.5% with relapsing optic neuritis (RON). Blinded analysis defined baseline MRI as typical of MS in 93.5% of children with MS. Acute disseminated encephalomyelitis presentation was seen only in the non-MS group. Of NMOSD cases, 30.7% were AQP4-Ab positive. MOG-Ab were found in 83.3% of AQP4-Ab-negative NMOSD, 100% of MDEM, and 33.3% of RON. Children with MOG-Ab were younger, were less likely to present with area postrema syndrome, and had lower disability, longer time to relapse, and more cerebellar peduncle lesions than children with AQP4-Ab NMOSD. A diagnostic algorithm applicable to any episode of CNS demyelination leads to 4 main phenotypes: MS, AQP4-Ab NMOSD, MOG-Ab-associated disease, and antibody-negative RDS. CONCLUSIONS: Children with MS and AQP4-Ab NMOSD showed features typical of adult cases. Because MOG-Ab-positive children showed notable and distinctive clinical and MRI features, they were grouped into a unified phenotype (MOG-Ab-associated disease), included in a new diagnostic algorithm. PMID- 28615431 TI - Chronic headache: What's in a name? PMID- 28615430 TI - Characterization of patients with longstanding idiopathic REM sleep behavior disorder. AB - OBJECTIVE: To evaluate the presence of prodromal markers of Parkinson disease (PD) in patients with longstanding idiopathic REM sleep behavior disorder (IRBD), a small subgroup of individuals with IRBD with long-term follow-up thought not to be at risk of developing PD. METHODS: Demographic, clinical, and neuroimaging markers of PD were evaluated in 20 patients with polysomnographic-confirmed longstanding IRBD and in 32 matched controls. RESULTS: Patients were 16 men and 4 women with mean age of 72.9 +/- 8.6 years and mean follow-up from IRBD diagnosis of 12.1 +/- 2.6 years. Patients more often had objective smell loss (35% vs 3.4%, p = 0.003), constipation (50% vs 15.6%, p = 0.008), and mild parkinsonian signs (45% vs 18.8%, p = 0.042) than controls. Unified Parkinson's Disease Rating Scale motor score was higher in patients than in controls (5.6 +/- 3.5 vs 2.0 +/- 2.1, p < 0.0001). Dopamine transporter imaging showed decreased striatal uptake in 82.4% of the patients and transcranial sonography found substantia nigra hyperechogenicity in 35.3%. alpha-Synuclein aggregates were found in 3 of 6 patients who underwent colon or submandibular gland biopsies. All 20 patients showed clinical, neuroimaging, or histologic markers of PD. Probability of prodromal PD (according to recent Movement Disorders Society research criteria) was higher in patients than in controls (<0.0001), and 45% of patients surpassed 80% probability. CONCLUSIONS: Prodromal PD markers are common in individuals with longstanding IRBD, suggesting that they are affected by an underlying neurodegenerative process. This observation may be useful for the design of disease-modifying trials to prevent PD onset in IRBD. PMID- 28615432 TI - Dento-corneal aberrant regeneration as evidence of V2 innervation of the inferior human cornea. PMID- 28615433 TI - Disease progression in C9orf72 mutation carriers. AB - OBJECTIVE: To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in C9orf72 mutation carriers (C9+) with varied clinical phenotypes. METHODS: Thirty-four unrelated participants with mutations in C9orf72 were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS-familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria. Diagnostic cognitive and motor tests were repeated at 6 and 18 months. The ALSFRS R, letter fluency, and FBI were administered at baseline and follow-up visits at 6, 12, and 18 months. RESULTS: The clinical diagnosis of most patients did not change over the follow-up. ALSFRS-R scores correlated with measures of motor function. Letter fluency correlated with FBI and cognitive tests. ALSFRS-R, letter fluency, and FBI differed among the C9+ diagnostic subgroups at enrollment and worsened over follow-up in symptomatic patients, with different slopes among the subgroups. Most patients survived to the 6-month time point after enrollment. Survival of C9+ patients with ALS and C9+ patients with ALS-FTD declined over the 12- and 18-month follow-up. CONCLUSIONS: The pattern of scores of the ALSFRS-R, letter fluency, and FBI distinguished between ALS, ALS-FTD, and FTD presentations of C9orf72 mutation carriers and asymptomatic carriers. Longitudinal changes in these measures occurred with disease progression in a manner consistent with presenting phenotype. PMID- 28615435 TI - Comment: The virtual neurologist. PMID- 28615434 TI - A randomized trial of telemedicine efficacy and safety for nonacute headaches. AB - OBJECTIVE: To evaluate long-term treatment efficacy and safety of one-time telemedicine consultations for nonacute headaches. METHODS: We randomized, allocated, and consulted nonacute headache patients via telemedicine (n = 200) or in a traditional manner (n = 202) in a noninferiority trial. Efficacy endpoints, assessed by questionnaires at 3 and 12 months, included change from baseline in Headache Impact Test-6 (HIT-6) (primary endpoint) and pain intensity (visual analogue scale [VAS]) (secondary endpoint). The primary safety endpoint, assessed via patient records, was presence of secondary headache within 12 months after consultation. RESULTS: We found no differences between telemedicine and traditional consultations in HIT-6 (p = 0.84) or VAS (p = 0.64) over 3 periods. The absolute difference in HIT-6 from baseline was 0.3 (95% confidence interval [CI] -1.26 to 1.82, p = 0.72) at 3 months and 0.2 (95% CI -1.98 to 1.58, p = 0.83) at 12 months. The absolute change in VAS was 0.4 (95% CI -0.93 to 0.22, p = 0.23) after 3 months and 0.3 (95% CI -0.94 to 0.29, p = 0.30) at 12 months. We found one secondary headache in each group at 12 months. The estimated number of consultations needed to miss one secondary headache with the use of telemedicine was 20,200. CONCLUSION: Telemedicine consultation for nonacute headache is as efficient and safe as a traditional consultation. CLINICALTRIALSGOV IDENTIFIER: NCT02270177. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a one-time telemedicine consultation for nonacute headache is noninferior to a one-time traditional consultation regarding long-term treatment outcome and safety. PMID- 28615437 TI - Chance juxtapositions and (un)biased methods in science: More efficient at inefficiency. PMID- 28615436 TI - Hospital safety among neurologic patients: A population-based cohort study of adverse events. AB - OBJECTIVE: To examine the frequency and type of adverse events (AEs) experienced by neurologic patients in hospital. METHODS: This population-based, retrospective cohort study used hospital discharge abstract data for children and adults admitted to hospital from 2009 to 2015 with 1 of 9 neurologic conditions (Alzheimer disease and related dementia, brain tumor, epilepsy, motor neuron disease, multiple sclerosis, parkinsonism/Parkinson disease, spinal cord injury, traumatic brain injury, and stroke). Neurologic conditions were identified with ICD-10-CA codes. Eighteen AEs were examined with ICD-10-CA codes. The proportion of AEs was calculated, and regression analysis was used to examine factors and outcomes associated with AEs (age, sex, comorbidity, length of stay, and mortality). RESULTS: The overall proportion of admissions associated with an AE among those with a neurologic condition was 11 per 100 admissions. Those with a spinal cord injury had the highest proportion of AEs (39.4 per 100 admissions). The most common AEs were infections and respiratory complications (32.0% and 16.7%, respectively). Age and the presence of comorbidities were associated with higher odds of an AE, while readmission was associated with lower odds of an AE. Having an AE was associated with increased length of stay and higher odds of mortality. CONCLUSIONS: This study demonstrates that neurologic patients have a high proportion of AEs in hospital. The findings provide information on the quality and safety of care for people with neurologic conditions in hospital, which can help inform future quality improvement initiatives. PMID- 28615438 TI - Cupriphication of gold to sensitize d10-d10 metal-metal bonds and near-unity phosphorescence quantum yields. AB - Outer-shell s0/p0 orbital mixing with d10 orbitals and symmetry reduction upon cupriphication of cyclic trinuclear trigonal-planar gold(I) complexes are found to sensitize ground-state Cu(I)-Au(I) covalent bonds and near-unity phosphorescence quantum yields. Heterobimetallic Au4Cu2 {[Au4(MU-C2,N3 EtIm)4Cu2(u-3,5-(CF3)2Pz)2], (4a)}, Au2Cu {[Au2(MU-C2,N3-BzIm)2Cu(u-3,5 (CF3)2Pz)], (1) and [Au2(MU-C2,N3-MeIm)2Cu(u-3,5-(CF3)2Pz)], (3a)}, AuCu2 {[Au(MU C2,N3-MeIm)Cu2(u-3,5-(CF3)2Pz)2], (3b) and [Au(MU-C2,N3-EtIm)Cu2(u-3,5 (CF3)2Pz)2], (4b)} and stacked Au3/Cu3 {[Au(MU-C2,N3-BzIm)]3[Cu(u-3,5 (CF3)2Pz)]3, (2)} form upon reacting Au3 {[Au(MU-C2,N3-(N-R)Im)]3 ((N-R)Im = imidazolate; R = benzyl/methyl/ethyl = BzIm/MeIm/EtIm)} with Cu3 {[Cu(MU-3,5 (CF3)2Pz)]3 (3,5-(CF3)2Pz = 3,5-bis(trifluoromethyl)pyrazolate)}. The crystal structures of 1 and 3a reveal stair-step infinite chains whereby adjacent dimer of-trimer units are noncovalently packed via two Au(I)?Cu(I) metallophilic interactions, whereas 4a exhibits a hexanuclear cluster structure wherein two monomer-of-trimer units are linked by a genuine d10-d10 polar-covalent bond with ligand-unassisted Cu(I)-Au(I) distances of 2.8750(8) A each-the shortest such an intermolecular distance ever reported between any two d10 centers so as to deem it a "metal-metal bond" vis-a-vis "metallophilic interaction." Density-functional calculations estimate 35-43 kcal/mol binding energy, akin to typical M-M single bond energies. Congruently, FTIR spectra of 4a show multiple far-IR bands within 65-200 cm-1, assignable to vCu-Au as validated by both the Harvey-Gray method of crystallographic-distance-to-force-constant correlation and dispersive density functional theory computations. Notably, the heterobimetallic complexes herein exhibit photophysical properties that are favorable to those for their homometallic congeners, due to threefold-to-twofold symmetry reduction, resulting in cuprophilic sensitization in extinction coefficient and solid-state photoluminescence quantum yields approaching unity (PhiPL = 0.90-0.97 vs. 0-0.83 for Au3 and Cu3 precursors), which bodes well for potential future utilization in inorganic and/or organic LED applications. PMID- 28615440 TI - Thematic Minireview Series: Inflammatory transcription confronts homeostatic disruptions. AB - In this Thematic Minireview Series, three stimulating articles are presented: one on long non-coding RNAs, another on the ligand-activated transcription factor aryl hydrocarbon receptor, and the third on how docosanoids modulate transcriptionally modulated homeostasis and ultimately cell survival in the retina and brain. PMID- 28615439 TI - Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways. AB - Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins. PMID- 28615441 TI - Iron transport proteins: Gateways of cellular and systemic iron homeostasis. AB - Cellular iron homeostasis is maintained by iron and heme transport proteins that work in concert with ferrireductases, ferroxidases, and chaperones to direct the movement of iron into, within, and out of cells. Systemic iron homeostasis is regulated by the liver-derived peptide hormone, hepcidin. The interface between cellular and systemic iron homeostasis is readily observed in the highly dynamic iron handling of four main cell types: duodenal enterocytes, erythrocyte precursors, macrophages, and hepatocytes. This review provides an overview of how these cell types handle iron, highlighting how iron and heme transporters mediate the exchange and distribution of body iron in health and disease. PMID- 28615442 TI - The heterotrimeric G protein Gbeta1 interacts with the catalytic subunit of protein phosphatase 1 and modulates G protein-coupled receptor signaling in platelets. AB - Thrombosis is caused by the activation of platelets at the site of ruptured atherosclerotic plaques. This activation involves engagement of G protein-coupled receptors (GPCR) on platelets that promote their aggregation. Although it is known that protein kinases and phosphatases modulate GPCR signaling, how serine/threonine phosphatases integrate with G protein signaling pathways is less understood. Because the subcellular localization and substrate specificity of the catalytic subunit of protein phosphatase 1 (PP1c) is dictated by PP1c-interacting proteins, here we sought to identify new PP1c interactors. GPCRs signal via the canonical heterotrimeric Galpha and Gbetagamma subunits. Using a yeast two-hybrid screen, we discovered an interaction between PP1calpha and the heterotrimeric G protein Gbeta1 subunit. Co-immunoprecipitation studies with epitope-tagged PP1c and Gbeta1 revealed that Gbeta1 interacts with the PP1c alpha, beta, and gamma1 isoforms. Purified PP1c bound to recombinant Gbeta1-GST protein, and PP1c co immunoprecipitated with Gbeta1 in unstimulated platelets. Thrombin stimulation of platelets induced the dissociation of the PP1c-Gbeta1 complex, which correlated with an association of PP1c with phospholipase C beta3 (PLCbeta3), along with a concomitant dephosphorylation of the inhibitory Ser1105 residue in PLCbeta3. siRNA-mediated depletion of GNB1 (encoding Gbeta1) in murine megakaryocytes reduced protease-activated receptor 4, activating peptide-induced soluble fibrinogen binding. Thrombin-induced aggregation was decreased in PP1calpha-/- murine platelets and in human platelets treated with a small-molecule inhibitor of Gbetagamma. Finally, disruption of PP1c-Gbeta1 complexes with myristoylated Gbeta1 peptides containing the PP1c binding site moderately decreased thrombin induced human platelet aggregation. These findings suggest that Gbeta1 protein enlists PP1c to modulate GPCR signaling in platelets. PMID- 28615443 TI - Control of immune-mediated pathology via the aryl hydrocarbon receptor. AB - Genetic and environmental factors contribute to the development of immune mediated diseases. Although numerous genetic factors contributing to autoimmunity have been identified in recent years, our knowledge on environmental factors contributing to the pathogenesis of autoimmune diseases and the mechanisms involved is still limited. In this context, the diet, microbiome, geographical location, as well as environmental pollutants have been shown to modulate autoimmune disease development. These environmental factors interact with cellular components of the immune system in distinct and defined ways and can influence immune responses at the transcriptional and protein level. Moreover, endogenous metabolites generated from basic cellular processes such as glycolysis and oxidative phosphorylation also contribute to the shaping of the immune response. In this minireview, we highlight recent progress in our understanding of the modulation of the immune response by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor whose activity is regulated by small molecules provided by diet, commensal flora, environmental pollutants, and metabolism. We focus on the role of AhR in integrating signals from the diet and the intestinal flora to modulate ongoing inflammation in the central nervous system, and we also discuss the potential therapeutic value of AhR agonists for multiple sclerosis and other autoimmune diseases. PMID- 28615444 TI - The human mitochondrial single-stranded DNA-binding protein displays distinct kinetics and thermodynamics of DNA binding and exchange. AB - The human mitochondrial ssDNA-binding protein (mtSSB) is a homotetrameric protein, involved in mtDNA replication and maintenance. Although mtSSB is structurally similar to SSB from Escherichia coli (EcoSSB), it lacks the C terminal disordered domain, and little is known about the biophysics of mtSSB ssDNA interactions. Here, we characterized the kinetics and thermodynamics of mtSSB binding to ssDNA by equilibrium titrations and stopped-flow kinetic measurements. We show that the mtSSB tetramer can bind to ssDNA in two distinct binding modes: (SSB)30 and (SSB)60, defined by DNA binding site sizes of 30 and 60 nucleotides, respectively. We found that the binding mode is modulated by magnesium ion and NaCl concentration, but unlike EcoSSB, the mtSSB does not show negative intersubunit cooperativity. Global fitting of both the equilibrium and kinetic data afforded estimates for the rate and equilibrium constants governing the formation of (SSB)60 and (SSB)30 complexes and for the transitions between the two binding modes. We found that the mtSSB tetramer binds to ssDNA with a rate constant near the diffusion limit (2 * 109 m-1 s-1) and that longer DNA (>=60 nucleotides) rapidly wraps around all four monomers, as revealed by FRET assays. We also show that the mtSSB tetramer can directly transfer from one ssDNA molecule to another via an intermediate with two DNA molecules bound to the mtSSB. In conclusion, our results indicate that human mtSSB shares many physicochemical properties with EcoSSB and that the differences may be explained by the lack of an acidic, disordered C-terminal tail in human mtSSB protein. PMID- 28615446 TI - Lysosome-mediated degradation of a distinct pool of lipid droplets during hepatic stellate cell activation. AB - Activation of hepatic stellate cells (HSCs) is a critical step in the development of liver fibrosis. During activation, HSCs lose their lipid droplets (LDs) containing triacylglycerols (TAGs), cholesteryl esters, and retinyl esters (REs). We previously provided evidence for the presence of two distinct LD pools, a preexisting and a dynamic LD pool. Here we investigate the mechanisms of neutral lipid metabolism in the preexisting LD pool. To investigate the involvement of lysosomal degradation of neutral lipids, we studied the effect of lalistat, a specific lysosomal acid lipase (LAL/Lipa) inhibitor on LD degradation in HSCs during activation in vitro The LAL inhibitor increased the levels of TAG, cholesteryl ester, and RE in both rat and mouse HSCs. Lalistat was less potent in inhibiting the degradation of newly synthesized TAG species as compared with a more general lipase inhibitor orlistat. Lalistat also induced the presence of RE containing LDs in an acidic compartment. However, targeted deletion of the Lipa gene in mice decreased the liver levels of RE, most likely as the result of a gradual disappearance of HSCs in livers of Lipa-/- mice. Lalistat partially inhibited the induction of activation marker alpha-smooth muscle actin (alpha SMA) in rat and mouse HSCs. Our data suggest that LAL/Lipa is involved in the degradation of a specific preexisting pool of LDs and that inhibition of this pathway attenuates HSC activation. PMID- 28615445 TI - Iron-sulfur cluster biogenesis and trafficking in mitochondria. AB - The biogenesis of iron-sulfur (Fe/S) proteins in eukaryotes is a multistage, multicompartment process that is essential for a broad range of cellular functions, including genome maintenance, protein translation, energy conversion, and the antiviral response. Genetic and cell biological studies over almost 2 decades have revealed some 30 proteins involved in the synthesis of cellular [2Fe 2S] and [4Fe-4S] clusters and their incorporation into numerous apoproteins. Mechanistic aspects of Fe/S protein biogenesis continue to be elucidated by biochemical and ultrastructural investigations. Here, we review recent developments in the pursuit of constructing a comprehensive model of Fe/S protein assembly in the mitochondrion. PMID- 28615447 TI - Human retinal pigment epithelial cells prefer proline as a nutrient and transport metabolic intermediates to the retinal side. AB - Metabolite transport is a major function of the retinal pigment epithelium (RPE) to support the neural retina. RPE dysfunction plays a significant role in retinal degenerative diseases. We have used mass spectrometry with 13C tracers to systematically study nutrient consumption and metabolite transport in cultured human fetal RPE. LC/MS-MS detected 120 metabolites in the medium from either the apical or basal side. Surprisingly, more proline is consumed than any other nutrient, including glucose, taurine, lipids, vitamins, or other amino acids. Besides being oxidized through the Krebs cycle, proline is used to make citrate via reductive carboxylation. Citrate, made either from 13C proline or from 13C glucose, is preferentially exported to the apical side and is taken up by the retina. In conclusion, RPE cells consume multiple nutrients, including glucose and taurine, but prefer proline, and they actively synthesize and export metabolic intermediates to the apical side to nourish the outer retina. PMID- 28615448 TI - Structural and biochemical analyses reveal insights into covalent flavinylation of the Escherichia coli Complex II homolog quinol:fumarate reductase. AB - The Escherichia coli Complex II homolog quinol:fumarate reductase (QFR, FrdABCD) catalyzes the interconversion of fumarate and succinate at a covalently attached FAD within the FrdA subunit. The SdhE assembly factor enhances covalent flavinylation of Complex II homologs, but the mechanisms underlying the covalent attachment of FAD remain to be fully elucidated. Here, we explored the mechanisms of covalent flavinylation of the E. coli QFR FrdA subunit. Using a DeltasdhE E. coli strain, we show that the requirement for the assembly factor depends on the cellular redox environment. We next identified residues important for the covalent attachment and selected the FrdAE245 residue, which contributes to proton shuttling during fumarate reduction, for detailed biophysical and structural characterization. We found that QFR complexes containing FrdAE245Q have a structure similar to that of the WT flavoprotein, but lack detectable substrate binding and turnover. In the context of the isolated FrdA subunit, the anticipated assembly intermediate during covalent flavinylation, FrdAE245 variants had stability similar to that of WT FrdA, contained noncovalent FAD, and displayed a reduced capacity to interact with SdhE. However, small-angle X-ray scattering (SAXS) analysis of WT FrdA cross-linked to SdhE suggested that the FrdAE245 residue is unlikely to contribute directly to the FrdA-SdhE protein protein interface. We also found that no auxiliary factor is absolutely required for flavinylation, indicating that the covalent flavinylation is autocatalytic. We propose that multiple factors, including the SdhE assembly factor and bound dicarboxylates, stimulate covalent flavinylation by preorganizing the active site to stabilize the quinone-methide intermediate. PMID- 28615449 TI - Equilibrium and ultrafast kinetic studies manipulating electron transfer: A short lived flavin semiquinone is not sufficient for electron bifurcation. AB - Flavin-based electron transfer bifurcation is emerging as a fundamental and powerful mechanism for conservation and deployment of electrochemical energy in enzymatic systems. In this process, a pair of electrons is acquired at intermediate reduction potential (i.e. intermediate reducing power), and each electron is passed to a different acceptor, one with lower and the other with higher reducing power, leading to "bifurcation." It is believed that a strongly reducing semiquinone species is essential for this process, and it is expected that this species should be kinetically short-lived. We now demonstrate that the presence of a short-lived anionic flavin semiquinone (ASQ) is not sufficient to infer the existence of bifurcating activity, although such a species may be necessary for the process. We have used transient absorption spectroscopy to compare the rates and mechanisms of decay of ASQ generated photochemically in bifurcating NADH-dependent ferredoxin-NADP+ oxidoreductase and the non bifurcating flavoproteins nitroreductase, NADH oxidase, and flavodoxin. We found that different mechanisms dominate ASQ decay in the different protein environments, producing lifetimes ranging over 2 orders of magnitude. Capacity for electron transfer among redox cofactors versus charge recombination with nearby donors can explain the range of ASQ lifetimes that we observe. Our results support a model wherein efficient electron propagation can explain the short lifetime of the ASQ of bifurcating NADH-dependent ferredoxin-NADP+ oxidoreductase I and can be an indication of capacity for electron bifurcation. PMID- 28615450 TI - Cellular requirements for iron-sulfur cluster insertion into the antiviral radical SAM protein viperin. AB - Viperin (RSAD2) is an interferon-stimulated antiviral protein that belongs to the radical S-adenosylmethionine (SAM) enzyme family. Viperin's iron-sulfur (Fe/S) cluster is critical for its antiviral activity against many different viruses. CIA1 (CIAO1), an essential component of the cytosolic iron-sulfur protein assembly (CIA) machinery, is crucial for Fe/S cluster insertion into viperin and hence for viperin's antiviral activity. In the CIA pathway, CIA1 cooperates with CIA2A, CIA2B, and MMS19 targeting factors to form various complexes that mediate the dedicated maturation of specific Fe/S recipient proteins. To date, however, the mechanisms of how viperin acquires its radical SAM Fe/S cluster to gain antiviral activity are poorly understood. Using co-immunoprecipitation and 55Fe radiolabeling experiments, we therefore studied the roles of CIA2A, CIA2B, and MMS19 for Fe/S cluster insertion. CIA2B and MMS19 physically interacted with the C terminus of viperin and used CIA1 as the primary viperin-interacting protein. In contrast, CIA2A bound to viperin's N terminus in a CIA1-, CIA2B-, and MMS19 independent fashion. Of note, the observed interaction of both CIA2 isoforms with a single Fe/S target protein is unprecedented in the CIA pathway. 55Fe radiolabeling experiments with human cells depleted of CIA1, CIA2A, CIA2B, or MMS19 revealed that CIA1, but none of the other CIA factors, is predominantly required for 55Fe/S cluster incorporation into viperin. Collectively, viperin maturation represents a novel CIA pathway with a minimal requirement of the CIA targeting factors and represents a new paradigm for the insertion of the Fe/S cofactor into a radical SAM protein. PMID- 28615451 TI - Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection. AB - Docosahexaenoic acid, enriched in the brain and retina, generates docosanoids in response to disruptions of cellular homeostasis. Docosanoids include neuroprotectin D1 (NPD1), which is decreased in the CA1 hippocampal area of patients with early-stage Alzheimer's disease (AD). We summarize here how NPD1 elicits neuroprotection by up-regulating c-REL, a nuclear factor (NF)-kappaB subtype that, in turn, enhances expression of BIRC3 (baculoviral inhibitor of apoptosis repeat-containing protein 3) in the retina and in experimental stroke, leading to neuroprotection. Elucidating the mechanisms of action of docosanoids will contribute to managing diseases, including stroke, AD, age-related macular degeneration, traumatic brain injury, Parkinson's disease, and other neurodegenerations. PMID- 28615452 TI - Interplay of the iron-regulated metastasis suppressor NDRG1 with epidermal growth factor receptor (EGFR) and oncogenic signaling. AB - The iron-regulated metastasis suppressor N-myc downstream-regulated gene 1 (NDRG1) has been shown to inhibit numerous oncogenic signaling pathways in cancer cells. Recent findings have demonstrated that NDRG1 inhibits the ErbB family of receptors, which function as key inducers of carcinogenesis. NDRG1 attenuates ErbB signaling by inhibiting formation of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) and HER2/HER3 heterodimers and by down-regulating EGFR via a mechanism involving its degradation. Understanding the complex interplay between NDRG1, iron, and ErbB signaling is vital for identifying novel, more effective targets for cancer therapy. PMID- 28615453 TI - Long non-coding RNAs (lncRNAs) and their transcriptional control of inflammatory responses. AB - Long non-coding RNAs (lncRNAs) have emerged as potential key regulators of the inflammatory response, particularly by modulating the transcriptional control of inflammatory genes. lncRNAs may act as an enhancer or suppressor to inflammatory transcription, function as scaffold molecules through interactions with RNA binding proteins in chromatin remodeling complexes, and modulate dynamic and epigenetic control of inflammatory transcription in a gene-specific and time dependent fashion. Here, we will review recent literature regarding the role of lncRNAs in transcriptional control of inflammatory responses. Better understanding of lncRNA regulation of inflammation will provide novel targets for the development of new therapeutic strategies. PMID- 28615455 TI - Introduction to Metals in Biology 2017: Iron transport, storage, and the ramifications. AB - In this tenth Thematic Series in Metals in Biology, six Minireviews deal with aspects of iron metabolism. A number of important proteins control iron homeostasis, including hepcidin and ferroportin, in various cells. Other aspects of iron dealt with here include biogenesis of iron-sulfur proteins and chaperones that deliver iron cofactors in cells. Additionally, an iron-regulated metastasis suppressor interacts with the epidermal growth factor receptor and mediates its downstream signaling activity. PMID- 28615454 TI - Cytosolic iron chaperones: Proteins delivering iron cofactors in the cytosol of mammalian cells. AB - Eukaryotic cells contain hundreds of metalloproteins that are supported by intracellular systems coordinating the uptake and distribution of metal cofactors. Iron cofactors include heme, iron-sulfur clusters, and simple iron ions. Poly(rC)-binding proteins are multifunctional adaptors that serve as iron ion chaperones in the cytosolic/nuclear compartment, binding iron at import and delivering it to enzymes, for storage (ferritin) and export (ferroportin). Ferritin iron is mobilized by autophagy through the cargo receptor, nuclear co activator 4. The monothiol glutaredoxin Glrx3 and BolA2 function as a [2Fe-2S] chaperone complex. These proteins form a core system of cytosolic iron cofactor chaperones in mammalian cells. PMID- 28615456 TI - Iron homeostasis: An anthropocentric perspective. AB - The regulation of iron metabolism in biological systems centers on providing adequate iron for cellular function while limiting iron toxicity. Because mammals cannot excrete iron, mechanisms have evolved to control iron acquisition, storage, and distribution at both systemic and cellular levels. Hepcidin, the master regulator of iron homeostasis, controls iron flows into plasma through inhibition of the only known mammalian cellular iron exporter ferroportin. Hepcidin is feedback-regulated by iron status and strongly modulated by inflammation and erythropoietic demand. This review highlights recent advances that have changed our understanding of iron metabolism and its regulation. PMID- 28615458 TI - Heartbeat: Anatomy versus physiology for diagnosis of coronary artery disease. PMID- 28615457 TI - Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing. AB - AMP-activated protein kinase (AMPK) is a central cellular energy sensor that adapts metabolism and growth to the energy state of the cell. AMPK senses the ratio of adenine nucleotides (adenylate energy charge) by competitive binding of AMP, ADP, and ATP to three sites (CBS1, CBS3, and CBS4) in its gamma-subunit. Because these three binding sites are functionally interconnected, it remains unclear how nucleotides bind to individual sites, which nucleotides occupy each site under physiological conditions, and how binding to one site affects binding to the other sites. Here, we comprehensively analyze nucleotide binding to wild type and mutant AMPK protein complexes by quantitative competition assays and by hydrogen-deuterium exchange MS. We also demonstrate that NADPH, in addition to the known AMPK ligand NADH, directly and competitively binds AMPK at the AMP sensing CBS3 site. Our findings reveal how AMP binding to one site affects the conformation and adenine nucleotide binding at the other two sites and establish CBS3, and not CBS1, as the high affinity exchangeable AMP/ADP/ATP-binding site. We further show that AMP binding at CBS4 increases AMP binding at CBS3 by 2 orders of magnitude and reverses the AMP/ATP preference of CBS3. Together, these results illustrate how the three CBS sites collaborate to enable highly sensitive detection of cellular energy states to maintain the tight ATP homeostastis required for cellular metabolism. PMID- 28615459 TI - Cardiovascular highlights from non-cardiology journals. PMID- 28615460 TI - Re: The National Institute for Health and Care Excellence update for stable chest pain: poorly reasoned and risky for patients. PMID- 28615461 TI - The true value of The National Institute for Health and Care Excellence guidance. PMID- 28615462 TI - Posttranslational Modification as a Critical Determinant of Cytoplasmic Innate Immune Recognition. AB - Cell surface innate immune receptors can directly detect a variety of extracellular pathogens to which cytoplasmic innate immune sensors are rarely exposed. Instead, within the cytoplasm, the environment is rife with cellular machinery and signaling pathways that are indirectly perturbed by pathogenic microbes to activate intracellular sensors, such as pyrin, NLRP1, NLRP3, or NLRC4. Therefore, subtle changes in key intracellular processes such as phosphorylation, ubiquitination, and other pathways leading to posttranslational protein modification are key determinants of innate immune recognition in the cytoplasm. This concept is critical to establish the "guard hypothesis" whereby otherwise homeostatic pathways that keep innate immune sensors at bay are released in response to alterations in their posttranslational modification status. Originally identified in plants, evidence that a similar guardlike mechanism exists in humans has recently been identified, whereby a mutation that prevents phosphorylation of the innate immune sensor pyrin triggers a dominantly inherited autoinflammatory disease. It is also noteworthy that even when a cytoplasmic innate immune sensor has a direct ligand, such as bacterial peptidoglycan (NOD1 or NOD2), RNA (RIG-I or MDA5), or DNA (cGAS or IFI16), it can still be influenced by posttranslational modification to dramatically alter its response. Therefore, due to their existence in the cytoplasmic milieu, posttranslational modification is a key determinant of intracellular innate immune receptor functionality. PMID- 28615463 TI - Low-Density Lipoprotein Receptor-Related Proteins in Skeletal Development and Disease. AB - The identification of the low-density lipoprotein receptor (LDLR) provided a foundation for subsequent studies in lipoprotein metabolism, receptor-mediated endocytosis, and many other fundamental biological functions. The importance of the LDLR led to numerous studies that identified homologous molecules and ultimately resulted in the description of the LDL-receptor superfamily, a group of proteins that contain domains also found in the LDLR. Subsequent studies have revealed that members of the LDLR-related protein family play roles in regulating many aspects of signal transduction. This review is focused on the roles of selected members of this protein family in skeletal development and disease. We present background on the identification of this subgroup of receptors, discuss the phenotypes associated with alterations in their function in human patients and mouse models, and describe the current efforts to therapeutically target these proteins to treat human skeletal disease. PMID- 28615464 TI - Corrigendum. PMID- 28615465 TI - Emergency Department Urinary Antibiograms Differ by Specific Patient Group. AB - Patients presenting to the emergency department (ED) represent a heterogeneous population comprised of all ages, various backgrounds, such as from the community and skilled-nursing facilities (SNFs), and at various risks for resistant pathogens. The aim of this study was to compare patient group-specific urinary antibiograms in the ED. Adults presented to the ED with an ICD 9/10 code urinary tract infection (UTI) diagnosis during July 2015 to June 2016 were randomly selected (n = 500) to extract relevant demographic, laboratory, and clinical data from the medical record. Urinary Escherichia coli antibiograms were compared between institutional versus ED and among ED patients (male versus female; age of 18 to 64 years versus >=65 years; female aged 18 to 50 years versus >50 years; home versus SNF; and admitted versus discharged). E. coli grew from 56% (145/259) of the positive urine cultures. Overall ciprofloxacin (CIP), trimethoprim sulfamethoxazole (SXT), and cefazolin (CFZ) susceptibilities were <71%. Differences in antibiograms were the following: lower CFZ and SXT susceptibilities in ED versus institutional (CFZ, 67% versus 86% [P = 0.001]; SXT, 66% versus 74% [P = 0.02]), lower ampicillin and gentamicin susceptibilities in females aged 18 to 50 years versus >50 years (32% versus 52% [P = 0.04]; 78% versus 93% [P = 0.02]), lower CIP susceptibilities in the elderly (64% versus 81%; P = 0.03), SNF versus home (35% versus 77%; P < 0.001), admitted versus discharged (63% versus 78%; P = 0.04), and lower SXT susceptibilities in patients aged <65 years versus the elderly (58% versus 71%; P = 0.01). Nitrofurantoin showed >80% susceptibility in all groups. Patient group-specific urinary antibiograms revealed distinct differences in E. coli susceptibility and should be developed to better inform empirical UTI therapy selection in the ED. PMID- 28615467 TI - Evaluation of the BD Max StaphSR Assay for Detecting Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible S. aureus (MSSA) in ESwab-Collected Wound Samples. PMID- 28615468 TI - Biographical Feature: Paul C. Schreckenberger, Ph.D. PMID- 28615466 TI - "Pathotyping" Multiplex PCR Assay for Haemophilus parasuis: a Tool for Prediction of Virulence. AB - Haemophilus parasuis is a diverse bacterial species that is found in the upper respiratory tracts of pigs and can also cause Glasser's disease and pneumonia. A previous pangenome study of H. parasuis identified 48 genes that were associated with clinical disease. Here, we describe the development of a generalized linear model (termed a pathotyping model) to predict the potential virulence of isolates of H. parasuis based on a subset of 10 genes from the pangenome. A multiplex PCR (mPCR) was constructed based on these genes, the results of which were entered into the pathotyping model to yield a prediction of virulence. This new diagnostic mPCR was tested on 143 field isolates of H. parasuis that had previously been whole-genome sequenced and a further 84 isolates from the United Kingdom from cases of H. parasuis-related disease in pigs collected between 2013 and 2014. The combination of the mPCR and the pathotyping model predicted the virulence of an isolate with 78% accuracy for the original isolate collection and 90% for the additional isolate collection, providing an overall accuracy of 83% (81% sensitivity and 93% specificity) compared with that of the "current standard" of detailed clinical metadata. This new pathotyping assay has the potential to aid surveillance and disease control in addition to serotyping data. PMID- 28615469 TI - Is This the Carbapenemase Test We've Been Waiting for? A Multicenter Evaluation of the Modified Carbapenem Inactivation Method. AB - A plethora of phenotypic methods exist for the detection of carbapenemases; however, clinical laboratories have struggled for years with accurate, objective phenotypic detection of carbapenemase activity in Enterobacteriaceae In this issue of the Journal of Clinical Microbiology, V. M. Pierce et al. (J Clin Microbiol 55:2321-2333, 2017, https://doi.org/10.1128/JCM.00193-17) report on a multicenter evaluation of the modified carbapenem inactivation method (mCIM). The high sensitivity, specificity, reproducibility, and ease of interpretation associated with the mCIM for Enterobacteriaceae will likely lead to its adoption by clinical laboratories. PMID- 28615470 TI - Identification of Group B Streptococcus Capsule Type by Use of a Dual Phenotypic/Genotypic Assay. AB - The group B streptococcus (GBS) capsular polysaccharide (CPS) is an important virulence factor which is also used for GBS typing. There are 10 CPS types (Ia, Ib, and II to IX). GBS that do not phenotypically type are considered nontypeable. All genes required for CPS synthesis are found on the GBS cps operon, which contains a highly variable CPS-determining region (cpsG-cpsK). The objective of this study was development of an assay to detect sialic acid on the GBS cell surface, followed by a genotypic PCR CPS typing assay. Sialic acid is located at the terminal end of the side chain of all known GBS CPS types. Sialic acid can be bound to commercially available lectins such as slug Limax flavus lectin. Biotinylated L. flavus-streptavidin-peroxidase complex was used in an enzyme immunoassay and dot blot assay to detect sialic acid. This was followed by a PCR typing scheme that was developed to target the serotype-determining region of the cps locus for Ia, Ib, and II to IX. Sialic acid from the CPS types Ia, Ib, and II to IX was detectable on the GBS cell surfaces of all previously identified CPS-typed GBS strains assayed. This was followed by the real-time PCR typing assay which successfully identified CPS Ia, Ib, and II to IX types. The combination of phenotypic and genotypic assays provides an accurate tool for detection of CPS expression and assignment of CPS typing. These assays have the potential to be used for CPS typing in large-scale epidemiological studies. PMID- 28615471 TI - Clostridium difficile PCR Cycle Threshold Predicts Free Toxin. AB - There is no stand-alone Clostridium difficile diagnostic that can sensitively and rapidly detect fecal free toxins. We investigated the performance of the C. difficile PCR cycle threshold (CT ) for predicting free toxin status. Consecutive stool samples (n = 312) positive for toxigenic C. difficile by the GeneXpert C. difficile/Epi tcdB PCR assay were tested with the rapid membrane C. Diff Quik Chek Complete immunoassay (RMEIA). RMEIA toxin-negative samples were tested with the cell cytotoxicity neutralization assay (CCNA) and tgcBIOMICS enzyme-linked immunosorbent assay (ELISA). Using RMEIA alone or in combination with CCNA and/or ELISA as the reference method, the accuracy of CT was measured at different CT cutoffs. Using RMEIA as the reference method, a CT cutoff of 26.35 detected toxin positive samples with a sensitivity, specificity, positive predictive value, and negative predictive value of 96.0% (95% confidence interval [CI], 90.2% to 98.9%), 65.9% (95% CI, 59.0% to 72.2%), 57.4% (95% CI, 52.7% to 62%), and 97.1% (95% CI, 92.8% to 98.9), respectively. Inclusion of CCNA in the reference method improved CT specificity to 78.0% (95% CI, 70.7% to 84.2%). Intercartridge lot CT variability measured as the average coefficient of variation was 2.8% (95% CI, 1.2% to 3.2%). Standardizing the input stool volume did not improve CT toxin specificity. The median CT values were not significantly different between stool samples with Bristol scores of 5, 6, and 7, between pediatric and adult samples, or between presumptive 027 and non-027 strains. In addition to sensitively detecting toxigenic C. difficile in stool, on-demand PCR may also be used to accurately predict toxin-negative stool samples, thus providing additional results in PCR-positive stool samples to guide therapy. PMID- 28615472 TI - Neuronal circadian clock protein oscillations are similar in behaviourally rhythmic forager honeybees and in arrhythmic nurses. AB - Internal clocks driving rhythms of about a day (circadian) are ubiquitous in animals, allowing them to anticipate environmental changes. Genetic or environmental disturbances to circadian clocks or the rhythms they produce are commonly associated with illness, compromised performance or reduced survival. Nevertheless, some animals including Arctic mammals, open sea fish and social insects such as honeybees are active around-the-clock with no apparent ill effects. The mechanisms allowing this remarkable natural plasticity are unknown. We generated and validated a new and specific antibody against the clock protein PERIOD of the honeybee Apis mellifera (amPER) and used it to characterize the circadian network in the honeybee brain. We found many similarities to Drosophila melanogaster and other insects, suggesting common anatomical organization principles in the insect clock that have not been appreciated before. Time course analyses revealed strong daily oscillations in amPER levels in foragers, which show circadian rhythms, and also in nurses that do not, although the latter have attenuated oscillations in brain mRNA clock gene levels. The oscillations in nurses show that activity can be uncoupled from the circadian network and support the hypothesis that a ticking circadian clock is essential even in around-the clock active animals in a constant physical environment. PMID- 28615473 TI - Forkhead box transcription factor L2 activates Fcp3C to regulate insect chorion formation. AB - Most animals are oviparous. However, the genes regulating egg shell formation remain not very clear. In this study, we found that Nilaparvata lugens Forkhead box transcription factor L2 (NlFoxL2) directly activated follicle cell protein 3C (NlFcp3C) to regulate chorion formation. NlFoxL2 and NlFcp3C had a similar expression pattern, both highly expressed in the follicular cells of female adults. Knockdown of NlFoxL2 or NlFcp3C also resulted in the same phenotypes: obesity and female infertility. RNA interference (RNAi) results suggested that NlFcp3C is a downstream gene of NlFoxL2 Furthermore, transient expression showed that NlFoxL2 could directly activate the NlFcp3C promoter. These results suggest that NlFcp3C is a direct target gene of NlFoxL2. Depletion of NlFoxL2 or NlFcp3C prevented normal chorion formation. Our results first revealed the functions of Fcp3C and FoxL2 in regulation of oocyte maturation in an oviparous animal. PMID- 28615474 TI - Regulation of expression of human RNA polymerase II-transcribed snRNA genes. AB - In addition to protein-coding genes, RNA polymerase II (pol II) transcribes numerous genes for non-coding RNAs, including the small-nuclear (sn)RNA genes. snRNAs are an important class of non-coding RNAs, several of which are involved in pre-mRNA splicing. The molecular mechanisms underlying expression of human pol II-transcribed snRNA genes are less well characterized than for protein-coding genes and there are important differences in expression of these two gene types. Here, we review the DNA features and proteins required for efficient transcription of snRNA genes and co-transcriptional 3' end formation of the transcripts. PMID- 28615477 TI - Correction: Joiner and Green et al., "Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium". PMID- 28615476 TI - A Role for AnkyrinG in Maturation and Maintenance of the Nodes of Ranvier. PMID- 28615475 TI - Infantile Amnesia: A Critical Period of Learning to Learn and Remember. AB - Infantile amnesia, the inability of adults to recollect early episodic memories, is associated with the rapid forgetting that occurs in childhood. It has been suggested that infantile amnesia is due to the underdevelopment of the infant brain, which would preclude memory consolidation, or to deficits in memory retrieval. Although early memories are inaccessible to adults, early-life events, such as neglect or aversive experiences, can greatly impact adult behavior and may predispose individuals to various psychopathologies. It remains unclear how a brain that rapidly forgets, or is not yet able to form long-term memories, can exert such a long-lasting and important influence. Here, with a particular focus on the hippocampal memory system, we review the literature and discuss new evidence obtained in rats that illuminates the paradox of infantile amnesia. We propose that infantile amnesia reflects a developmental critical period during which the learning system is learning how to learn and remember. PMID- 28615478 TI - Correction: Joo et al., "Separate Perceptual and Neural Processing of Velocity- and Disparity-Based 3D Motion Signals". PMID- 28615484 TI - Join the Conversation: focus on early career researchers. PMID- 28615485 TI - Early career researchers: an interview with Caroline Williams. AB - Caroline Williams is an Assistant Professor at the University of California, Berkeley, USA, where she studies evolution of metabolic physiology in ectotherms. She grew up in New Zealand, where she received Bachelor's and Master's degrees in Zoology from the University of Otago in Dunedin. After travelling and working in Asia, she moved to Western University, Canada, for her PhD in the laboratory of Brent Sinclair, before joining Dan Hahn at the University of Florida as a postdoctoral research fellow. In 2010 she received the Scholander Award from the American Physiological Society. PMID- 28615486 TI - Acid-base physiology, neurobiology and behaviour in relation to CO2-induced ocean acidification. AB - Experimental exposure to ocean and freshwater acidification affects the behaviour of multiple aquatic organisms in laboratory tests. One proposed cause involves an imbalance in plasma chloride and bicarbonate ion concentrations as a result of acid-base regulation, causing the reversal of ionic fluxes through GABAA receptors, which leads to altered neuronal function. This model is exclusively based on differential effects of the GABAA receptor antagonist gabazine on control animals and those exposed to elevated CO2 However, direct measurements of actual chloride and bicarbonate concentrations in neurons and their extracellular fluids and of GABAA receptor properties in aquatic organisms are largely lacking. Similarly, very little is known about potential compensatory mechanisms, and about alternative mechanisms that might lead to ocean acidification-induced behavioural changes. This article reviews the current knowledge on acid-base physiology, neurobiology, pharmacology and behaviour in relation to marine CO2 induced acidification, and identifies important topics for future research that will help us to understand the potential effects of predicted levels of aquatic acidification on organisms. PMID- 28615487 TI - Cognitive specialization for learning faces is associated with shifts in the brain transcriptome of a social wasp. AB - The specialized ability to learn and recall individuals based on distinct facial features is known in only a few, large-brained social taxa. Social paper wasps in the genus Polistes are the only insects known to possess this form of cognitive specialization. We analyzed genome-wide brain gene expression during facial and pattern training for two species of paper wasps (P. fuscatus, which has face recognition, and P. metricus, which does not) using RNA sequencing. We identified 237 transcripts associated with face specialization in P. fuscatus, including some transcripts involved in neuronal signaling (serotonin receptor and tachykinin). Polistes metricus that learned faces (without specialized learning) and P. fuscatus in social interactions with familiar partners (from a previous study) showed distinct sets of brain differentially expressed transcripts. These data suggest face specialization in P. fuscatus is related to shifts in the brain transcriptome associated with genes distinct from those related to general visual learning and social interactions. PMID- 28615488 TI - Hotter nests produce hatchling lizards with lower thermal tolerance. AB - In many regions, the frequency and duration of summer heatwaves is predicted to increase in future. Hotter summers could result in higher temperatures inside lizard nests, potentially exposing embryos to thermally stressful conditions during development. Potentially, developmentally plastic shifts in thermal tolerance could allow lizards to adapt to climate warming. To determine how higher nest temperatures affect the thermal tolerance of hatchling geckos, we incubated eggs of the rock-dwelling velvet gecko, Amalosia lesueurii, at two fluctuating temperature regimes to mimic current nest temperatures (mean 23.2 degrees C, range 10-33 degrees C, 'cold') and future nest temperatures (mean 27.0 degrees C, range 14-37 degrees C, 'hot'). Hatchlings from the hot incubation group hatched 27 days earlier and had a lower critical thermal maximum (CTmax 38.7 degrees C) and a higher critical thermal minimum (CTmin 6.2 degrees C) than hatchlings from cold incubation group (40.2 and 5.7 degrees C, respectively). In the field, hatchlings typically settle under rocks near communal nests. During the hatching period, rock temperatures ranged from 13 to 59 degrees C, and regularly exceeded the CTmax of both hot- and cold-incubated hatchlings. Because rock temperatures were so high, the heat tolerance of lizards had little effect on their ability to exploit rocks as retreat sites. Instead, the timing of hatching dictated whether lizards could exploit rocks as retreat sites; that is, cold-incubated lizards that hatched later encountered less thermally stressful environments than earlier hatching hot-incubated lizards. In conclusion, we found no evidence that CTmax can shift upwards in response to higher incubation temperatures, suggesting that hotter summers may increase the vulnerability of lizards to climate warming. PMID- 28615489 TI - Ovarian fluid impacts flagellar beating and biomechanical metrics of sperm between alternative reproductive tactics. AB - Alternative reproductive tactics (ARTs) are prevalent in nature, where smaller parasitic males typically have better sperm quality than larger territorial guard males. At present, it is unclear what is causing this phenomenon. Our objective was to gain insights into sperm form and function by examining flagellar beating patterns (beat frequency, wave amplitude, bend length, bend angle, wave velocity) and biomechanical sperm metrics (velocity, hydrodynamic power output, propulsive efficiency) of wild spawning Chinook salmon ARTs. Ovarian fluid and milt were collected to form a series of eight experimental blocks, each composed of ovarian fluid from a unique female and sperm from a unique pair of parasitic jack and guard hooknose males. Sperm from each ART were activated in river water and ovarian fluid. Flagellar parameters were evaluated from recordings using high speed video microscopy and biomechanical metrics were quantified. We show that ART has an impact on flagellar beating, where jacks had a higher bend length and bend angle than hooknoses. Activation media also impacted the pattern of flagellar parameters, such that beat frequency, wave velocity and bend angle declined, while wave amplitude of flagella increased when ovarian fluid was incorporated into activation media. Furthermore, we found that sperm from jacks swam faster than those from hooknoses and required less hydrodynamic power output to propel themselves in river water and ovarian fluid. Jack sperm were also more efficient at swimming than hooknose sperm, and propulsive efficiency increased when cells were activated in ovarian fluid. The results demonstrate that sperm biomechanics may be driving divergence in competitive reproductive success between ARTs. PMID- 28615490 TI - Hunting with sticky tape: functional shift in silk glands of araneophagous ground spiders (Gnaphosidae). AB - Foraging is one of the main evolutionary driving forces shaping the phenotype of organisms. In predators, a significant, though understudied, cost of foraging is the risk of being injured by struggling prey. Hunting spiders that feed on dangerous prey like ants or other spiders are an extreme example of dangerous feeding, risking their own life over a meal. Here, we describe an intriguing example of the use of attachment silk (piriform silk) for prey immobilization that comes with the costs of reduced silk anchorage function, increased piriform silk production and additional modifications of the extrusion structures (spigots) to prevent their clogging. We show that the piriform silk of gnaphosids is very stretchy and tough, which is an outstanding feat for a functional glue. This is gained by the combination of an elastic central fibre and a bi-layered glue coat consisting of aligned nanofibrils. This represents the first tensile test data on the ubiquitous piriform gland silk, adding an important puzzle piece to the mechanical catalogue of silken products in spiders. PMID- 28615491 TI - Enhanced osteointegration of poly(methylmethacrylate) bone cements by incorporating strontium-containing borate bioactive glass. AB - Although poly(methylmethacrylate) (PMMA) cements are widely used in orthopaedics, they have numerous drawbacks. This study aimed to improve their bioactivity and osseointegration by incorporating strontium-containing borate bioactive glass (SrBG) as the reinforcement phase and bioactive filler of PMMA cement. The prepared SrBG/PMMA composite cements showed significantly decreased polymerization temperature when compared with PMMA and retained properties of appropriate setting time and high mechanical strength. The bioactivity of SrBG/PMMA composite cements was confirmed in vitro, evidenced by ion release (Ca, P, B and Sr) from SrBG particles. The cellular responses of MC3T3-E1 cells in vitro demonstrated that SrBG incorporation could promote adhesion, migration, proliferation and collagen secretion of cells. Furthermore, our in vivo investigation revealed that SrBG/PMMA composite cements presented better osseointegration than PMMA bone cement. SrBG in the composite cement could stimulate new-bone formation around the interface between the composite cement and host bone at eight and 12 weeks post-implantation, whereas PMMA bone cement only stimulated development of an intervening connective tissue layer. Consequently, the SrBG/PMMA composite cement may be a better alternative to PMMA cement in clinical applications and has promising orthopaedic applications by minimal invasive surgery. PMID- 28615492 TI - Macromolecular crowding directs the motion of small molecules inside cells. AB - It is now well established that cell interiors are significantly crowded by macromolecules, which impede diffusion and enhance binding rates. However, it is not fully appreciated that levels of crowding are heterogeneous, and can vary substantially between subcellular regions. In this article, starting from a microscopic model, we derive coupled nonlinear partial differential equations for the concentrations of two populations of large and small spherical particles with steric volume exclusion. By performing an expansion in the ratio of the particle sizes, we find that the diffusion of a small particle in the presence of large particles obeys an advection-diffusion equation, with a reduced diffusion coefficient and a velocity directed towards less crowded regions. The interplay between advection and diffusion leads to behaviour that differs significantly from Brownian diffusion. We show that biologically plausible distributions of macromolecules can lead to highly non-Gaussian probability densities for the small particle position, including asymmetrical and multimodal densities. We confirm all our results using hard-sphere Brownian dynamics simulations. PMID- 28615494 TI - Correction: Analysis of unstable modes distinguishes mathematical models of flagellar motion. PMID- 28615493 TI - Optically ambidextrous circularly polarized reflection from the chiral cuticle of the scarab beetle Chrysina resplendens. AB - The evolution of structural colour mechanisms in biological systems has given rise to many interesting optical effects in animals and plants. The instance of the scarab beetle Chrysina resplendens is particularly distinctive. Its exoskeleton has a bright, golden appearance and reflects both right-handed and left-handed circularly polarized light concurrently. The chiral nanostructure responsible for these properties is a helicoid, in which birefringent dielectric planes are assembled with an incremental rotation. This study correlates details of the beetle's circularly polarized reflectance spectra directly with physical aspects of its structural morphology. Electron micrography is used to identify and measure the physical dimensions of the key constituent components. These include a chiral multilayer configuration comprising two chirped, left-handed helicoids that are separated by a birefringent retarder. A scattering matrix technique is used to simulate the system's optical behaviour in which the roles of each component of the morphological substructure are elucidated by calculation of the fields throughout its depth. PMID- 28615495 TI - A Bayesian approach to estimating hidden variables as well as missing and wrong molecular interactions in ordinary differential equation-based mathematical models. AB - Ordinary differential equations (ODEs) are a popular approach to quantitatively model molecular networks based on biological knowledge. However, such knowledge is typically restricted. Wrongly modelled biological mechanisms as well as relevant external influence factors that are not included into the model are likely to manifest in major discrepancies between model predictions and experimental data. Finding the exact reasons for such observed discrepancies can be quite challenging in practice. In order to address this issue, we suggest a Bayesian approach to estimate hidden influences in ODE-based models. The method can distinguish between exogenous and endogenous hidden influences. Thus, we can detect wrongly specified as well as missed molecular interactions in the model. We demonstrate the performance of our Bayesian dynamic elastic-net with several ordinary differential equation models from the literature, such as human JAK-STAT signalling, information processing at the erythropoietin receptor, isomerization of liquid alpha-Pinene, G protein cycling in yeast and UV-B triggered signalling in plants. Moreover, we investigate a set of commonly known network motifs and a gene-regulatory network. Altogether our method supports the modeller in an algorithmic manner to identify possible sources of errors in ODE-based models on the basis of experimental data. PMID- 28615497 TI - Excavation and aggregation as organizing factors in de novo construction by mound building termites. AB - Termites construct complex mounds that are orders of magnitude larger than any individual and fulfil a variety of functional roles. Yet the processes through which these mounds are built, and by which the insects organize their efforts, remain poorly understood. The traditional understanding focuses on stigmergy, a form of indirect communication in which actions that change the environment provide cues that influence future work. Termite construction has long been thought to be organized via a putative 'cement pheromone': a chemical added to deposited soil that stimulates further deposition in the same area, thus creating a positive feedback loop whereby coherent structures are built up. To investigate the detailed mechanisms and behaviours through which termites self-organize the early stages of mound construction, we tracked the motion and behaviour of major workers from two Macrotermes species in experimental arenas. Rather than a construction process focused on accumulation of depositions, as models based on cement pheromone would suggest, our results indicated that the primary organizing mechanisms were based on excavation. Digging activity was focused on a small number of excavation sites, which in turn provided templates for soil deposition. This behaviour was mediated by a mechanism of aggregation, with termites being more likely to join in the work at an excavation site as the number of termites presently working at that site increased. Statistical analyses showed that this aggregation mechanism was a response to active digging, distinct from and unrelated to putative chemical cues that stimulate deposition. Agent-based simulations quantitatively supported the interpretation that the early stage of de novo construction is primarily organized by excavation and aggregation activity rather than by stigmergic deposition. PMID- 28615496 TI - Experimental evidence that primate trichromacy is well suited for detecting primate social colour signals. AB - Primate trichromatic colour vision has been hypothesized to be well tuned for detecting variation in facial coloration, which could be due to selection on either signal wavelengths or the sensitivities of the photoreceptors themselves. We provide one of the first empirical tests of this idea by asking whether, when compared with other visual systems, the information obtained through primate trichromatic vision confers an improved ability to detect the changes in facial colour that female macaque monkeys exhibit when they are proceptive. We presented pairs of digital images of faces of the same monkey to human observers and asked them to select the proceptive face. We tested images that simulated what would be seen by common catarrhine trichromatic vision, two additional trichromatic conditions and three dichromatic conditions. Performance under conditions of common catarrhine trichromacy, and trichromacy with narrowly separated LM cone pigments (common in female platyrrhines), was better than for evenly spaced trichromacy or for any of the dichromatic conditions. These results suggest that primate trichromatic colour vision confers excellent ability to detect meaningful variation in primate face colour. This is consistent with the hypothesis that social information detection has acted on either primate signal spectral reflectance or photoreceptor spectral tuning, or both. PMID- 28615498 TI - Antagonistically pleiotropic allele increases lifespan and late-life reproduction at the cost of early-life reproduction and individual fitness. AB - Evolutionary theory of ageing maintains that increased allocation to early-life reproduction results in reduced somatic maintenance, which is predicted to compromise longevity and late-life reproduction. This prediction has been challenged by the discovery of long-lived mutants with no loss of fecundity. The first such long-lived mutant was found in the nematode worm Caenorhabditis elegans Specifically, partial loss-of-function mutation in the age-1 gene, involved in the nutrient-sensing insulin/insulin-like growth factor signalling pathway, confers longevity, as well as increased resistance to pathogens and to temperature stress without appreciable fitness detriment. Here, we show that the long-lived age-1(hx546) mutant has reduced fecundity and offspring production in early-life, but increased fecundity, hatching success, and offspring production in late-life compared with wild-type worms under standard conditions. However, reduced early-life performance of long-lived mutant animals was not fully compensated by improved performance in late-life and resulted in reduced individual fitness. These results suggest that the age-1(hx546) allele has opposing effects on early-life versus late-life fitness in accordance with antagonistic pleiotropy (AP) and disposable soma theories of ageing. These findings support the theoretical conjecture that experimental studies based on standing genetic variation underestimate the importance of AP in the evolution of ageing. PMID- 28615499 TI - The importance of individual and species-level traits for trophic niches among herbivorous coral reef fishes. AB - Resolving how species compete and coexist within ecological communities represents a long-standing challenge in ecology. Research efforts have focused on two predominant mechanisms of species coexistence: complementarity and redundancy. But findings also support an alternative hypothesis that within species variation may be critical for coexistence. Our study focuses on nine closely related and ecologically similar coral reef fish species to test the importance of individual- versus species-level traits in determining the size of dietary, foraging substrate, and behavioural interaction niches. Specifically, we asked: (i) what level of biological organization best describes individual-level niches? and (ii) how are herbivore community niches partitioned among species, and are niche widths driven by species- or individual-level traits? Dietary and foraging substrate niche widths were best described by species identity, but no level of taxonomy explained behavioural interactions. All three niches were dominated by only a few species, contrasting expectations of niche complementarity. Species- and individual-level traits strongly drove foraging substrate and behavioural niches, respectively, whereas the dietary niche was described by both. Our findings underscored the importance of species-level traits for community-level niches, but highlight that individual-level trait variation within a select few species may be a key driver of the overall size of niches. PMID- 28615500 TI - Evolvability meets biogeography: evolutionary potential decreases at high and low environmental favourability. AB - Understanding and forecasting the effects of environmental change on wild populations requires knowledge on a critical question: do populations have the ability to evolve in response to that change? However, our knowledge on how evolution works in wild conditions under different environmental circumstances is extremely limited. We investigated how environmental variation influences the evolutionary potential of phenotypic traits. We used published data to collect or calculate 135 estimates of evolvability of morphological traits of European wild bird populations. We characterized the environmental favourability of each population throughout the species' breeding distribution. Our results suggest that the evolutionary potential of morphological traits decreases as environmental favourability becomes high or low. Strong environmental selection pressures and high intra-specific competition may reduce species' evolutionary potential in low- and high- favourability areas, respectively. This suggests that species may be least able to adapt to new climate conditions at their range margins and at the centre. Our results underscore the need to consider the evolutionary potential of populations when studying the drivers of species distributions, particularly when predicting the effects of environmental change. We discuss the utility of integrating evolutionary dynamics into a biogeographical perspective to understand how environmental variation shapes evolutionary patterns. This approach would also produce more reliable predictions about the effect of environmental change on population persistence and therefore on biodiversity. PMID- 28615501 TI - X-ray micro-CT scanning reveals temporal separation of male harm and female kicking during traumatic mating in seed beetles. AB - In the seed beetle Callosobruchus maculatus, the male intromittent organ is covered in sharp spines that pierce the female copulatory tract wall during mating. Although the fitness consequences of traumatic mating are well studied in this species, we know much less about how the male and female genitalia interact during mating. This is partly due to the fact that genital interactions occur primarily inside the female, and so are difficult to observe. In this study, we use X-ray micro-CT scanning to examine the proximate mechanisms of traumatic mating in C. maculatus in unprecedented detail. We show that this technique can be used to identify female tissue damage before the melanization of wound sites. We visualize the positioning of the male intromittent organ inside the female copulatory tract during mating, and show how this relates to tract wounding in three dimensions. By scanning pairs flash-frozen at different times during mating, we show that significant tract wounding occurs before the onset of female kicking. There is thus some degree of temporal separation between the onset of wounding and the onset of kicking, which supports recent suggestions that kicking is not an effective female counter-adaptation to reduce copulatory wounding in this species. We also present evidence that the sharp teeth protruding from the female tract wall are able to pierce the spermatophore as it is deposited, and may thus function to aid sperm release. PMID- 28615502 TI - Empirical links between natural mortality and recovery in marine fishes. AB - Probability of species recovery is thought to be correlated with specific aspects of organismal life history, such as age at maturity and longevity, and how these affect rates of natural mortality (M) and maximum per capita population growth (rmax). Despite strong theoretical underpinnings, these correlates have been based on predicted rather than realized population trajectories following threat mitigation. Here, we examine the level of empirical support for postulated links between a suite of life-history traits (related to maturity, age, size and growth) and recovery in marine fishes. Following threat mitigation (medium time since cessation of overfishing = 20 years), 71% of 55 temperate populations had fully recovered, the remainder exhibiting, on average, negligible change (impaired recovery). Singly, life-history traits did not influence recovery status. In combination, however, those that jointly reflect length-based mortality at maturity, Malpha , revealed that recovered populations have higher Malpha , which we hypothesize to reflect local adaptations associated with greater rmax But, within populations, the smaller sizes at maturity generated by overfishing are predicted to increase Malpha , slowing recovery and increasing its uncertainty. We conclude that recovery potential is greater for populations adapted to high M but that temporal increases in M concomitant with smaller size at maturity will have the opposite effect. The recovery metric documented here (Malpha ) has a sound theoretical basis, is significantly correlated with direct estimates of M that directly reflect rmax, is not reliant on data-intensive time series, can be readily estimated, and offers an empirically defensible correlate of recovery, given its clear links to the positive and impaired responses to threat mitigation that have been observed in fish populations over the past three decades. PMID- 28615503 TI - The scaling of population persistence with carrying capacity does not asymptote in populations of a fish experiencing extreme climate variability. AB - Despite growing concerns regarding increasing frequency of extreme climate events and declining population sizes, the influence of environmental stochasticity on the relationship between population carrying capacity and time-to-extinction has received little empirical attention. While time-to-extinction increases exponentially with carrying capacity in constant environments, theoretical models suggest increasing environmental stochasticity causes asymptotic scaling, thus making minimum viable carrying capacity vastly uncertain in variable environments. Using empirical estimates of environmental stochasticity in fish metapopulations, we showed that increasing environmental stochasticity resulting from extreme droughts was insufficient to create asymptotic scaling of time-to extinction with carrying capacity in local populations as predicted by theory. Local time-to-extinction increased with carrying capacity due to declining sensitivity to demographic stochasticity, and the slope of this relationship declined significantly as environmental stochasticity increased. However, recent 1 in 25 yr extreme droughts were insufficient to extirpate populations with large carrying capacity. Consequently, large populations may be more resilient to environmental stochasticity than previously thought. The lack of carrying capacity-related asymptotes in persistence under extreme climate variability reveals how small populations affected by habitat loss or overharvesting, may be disproportionately threatened by increases in extreme climate events with global warming. PMID- 28615504 TI - Biological markets in cooperative breeders: quantifying outside options. AB - A major aim in evolutionary biology is to understand altruistic help and reproductive partitioning in cooperative societies, where subordinate helpers forego reproduction to rear dominant breeders' offspring. Traditional models of cooperation in these societies typically make a key assumption: that the only alternative to staying and helping is solitary breeding, an often unfeasible task. Using large-scale field experiments on paper wasps (Polistes dominula), we show that individuals have high-quality alternative nesting options available that offer fitness payoffs just as high as their actual chosen options, far exceeding payoffs from solitary breeding. Furthermore, joiners could not easily be replaced if they were removed experimentally, suggesting that it may be costly for dominants to reject them. Our results have implications for expected payoff distributions for cooperating individuals, and suggest that biological market theory, which incorporates partner choice and competition for partners, is necessary to understand helping behaviour in societies like that of P. dominula Traditional models are likely to overestimate the incentive to stay and help, and therefore the amount of help provided, and may underestimate the size of reproductive concession required to retain subordinates. These findings are relevant for a wide range of cooperative breeders where there is dispersal between social groups. PMID- 28615505 TI - Topological features of a gene co-expression network predict patterns of natural diversity in environmental response. AB - Molecular interactions affect the evolution of complex traits. For instance, adaptation may be constrained by pleiotropic or epistatic effects, both of which can be reflected in the structure of molecular interaction networks. To date, empirical studies investigating the role of molecular interactions in phenotypic evolution have been idiosyncratic, offering no clear patterns. Here, we investigated the network topology of genes putatively involved in local adaptation to two abiotic stressors-drought and cold-in Arabidopsis thaliana Our findings suggest that the gene-interaction topologies for both cold and drought stress response are non-random, with genes that show genetic variation in drought expression response (eGxE) being significantly more peripheral and cold response genes being significantly more central than genes which do not show GxE. We suggest that the observed topologies reflect different constraints on the genetic pathways involved in environmental response. The approach presented here may inform predictive models linking genetic variation in molecular signalling networks with phenotypic variation, specifically traits involved in environmental response. PMID- 28615506 TI - Modified protocol for enhanced recovery after surgery is beneficial for Chinese cancer patients undergoing pancreaticoduodenectomy. AB - Radical surgical resection remains the only effective treatment for advanced pancreatic cancer. Effective protocols for recovery from post-operative complications that result in high rates of morbidity and mortality are therefore essential. The enhanced recovery after surgery (ERAS) protocol is an interdisciplinary multimodal concept based on modern anesthesia and analgesia combined with other fast rehabilitation parameters. It was first applied in the field of elective colorectal surgery, and eventually extended to several surgical diseases. In this study, we investigated the feasibility and safety of implementing the ERAS protocol in patients undergoing pancreaticoduodenectomy (PD). We randomly divided 159 patients who underwent PD into two groups who were managed using either ERAS or the conventional protocol. We observed that in those treated with the ERAS protocol several post-operative recovery factors were greatly improved, and there were no complications requiring readmission. We therefore propose that ERAS can improve post-operative recovery of PD patients and shorten the waiting time to chemotherapy, which may improve the overall survival of surgically treated pancreatic cancer patients. PMID- 28615517 TI - mTOR signaling mediates resistance to tankyrase inhibitors in Wnt-driven colorectal cancer. AB - Activation of Wnt/beta-catenin signaling is essential for colorectal carcinogenesis. Tankyrase, a member of the poly(ADP-ribose) polymerase (PARP) family, is a positive regulator of the Wnt/beta-catenin signaling. Accordingly, tankyrase inhibitors are under preclinical development for colorectal cancer (CRC) therapy. However, Wnt-driven colorectal cancer cells are not equally sensitive to tankyrase inhibitors, and cellular factors that affect tankyrase inhibitor sensitivity remain elusive. Here, we established a tankyrase inhibitor resistant cell line, 320-IWR, from Wnt/beta-catenin-dependent CRC COLO-320DM cells. 320-IWR cells exhibited resistance to tankyrase inhibitors, IWR-1 and G007 LK, but remained sensitive to a PARP-1/2 inhibitor, olaparib, and several anti CRC agents. In 320-IWR cells, nuclear localization of active beta-catenin was decreased and expression of beta-catenin target genes was constitutively repressed, suggesting that these cells repressed the Wnt/beta-catenin signaling and were dependent on alternative proliferation pathways. 320-IWR cells exhibited upregulated mTOR signaling and were more sensitive to mTOR inhibition than the parental cells. Importantly, mTOR inhibition reversed resistance to tankyrase inhibitors and potentiated their anti-proliferative effects in 320-IWR cells as well as in CRC cell lines in which the mTOR pathway was intrinsically activated. These results indicate that mTOR signaling confers resistance to tankyrase inhibitors in CRC cells and suggest that the combination of tankyrase and mTOR inhibitors would be a useful therapeutic approach for a subset of CRCs. PMID- 28615518 TI - Estrogen-activated MDM2 disrupts mammary tissue architecture through a p53 independent pathway. AB - The Cancer Genome Atlas (TCGA) data indicate that high MDM2 expression correlates with all subtypes of breast cancer. Overexpression of MDM2 drives breast oncogenesis in the presence of wild-type or mutant p53 (mtp53). Importantly, estrogen-receptor positive (ER+) breast cancers overexpress MDM2 and estrogen mediates this expression. We previously demonstrated that this estrogen-MDM2 axis activates the proliferation of breast cancer cell lines T47D (mtp53 L194F) and MCF7 (wild-type p53) in a manner independent of increased degradation of wild type p53 (ie, p53-independently). Herein we present data supporting the role of the estrogen-MDM2 axis in regulating cell proliferation and mammary tissue architecture of MCF7 and T47D cells in a p53-independent manner. Inducible shRNA mediated MDM2 knockdown inhibited colony formation in soft agar, decreased mass size and induced lumen formation in matrigel and also significantly reduced mitosis as seen by decreased phospho-histone H3 positive cells. The knockdown of MDM2 in both cell lines decreased Rb phosphorylation and the level of E2F1 protein. This signaling was through the estrogen receptor because fulvestrant (a selective estrogen receptor degrader) decreased MDM2 protein levels and decreased phosphorylation of Rb. Taken together these data indicate that in some ER+ breast cancers the estrogen-MDM2-Rb-E2F1 axis is a central hub for estrogen-mediated p53 independent signal transduction. This is the first indication that estrogen signaling utilizes the estrogen-MDM2 axis to provoke phosphorylation of Rb and increase E2F1 while promoting abnormal mammary architecture. PMID- 28615526 TI - Identifying prognostic signature in ovarian cancer using DirGenerank. AB - Identifying the prognostic genes in cancer is essential not only for the treatment of cancer patients, but also for drug discovery. However, it's still a big challenge to select the prognostic genes that can distinguish the risk of cancer patients across various data sets because of tumor heterogeneity. In this situation, the selected genes whose expression levels are statistically related to prognostic risks may be passengers. In this paper, based on gene expression data and prognostic data of ovarian cancer patients, we used conditional mutual information to construct gene dependency network in which the nodes (genes) with more out-degrees have more chances to be the modulators of cancer prognosis. After that, we proposed DirGenerank (Generank in direct netowrk) algorithm, which concerns both the gene dependency network and genes' correlations to prognostic risks, to identify the gene signature that can predict the prognostic risks of ovarian cancer patients. Using ovarian cancer data set from TCGA (The Cancer Genome Atlas) as training data set, 40 genes with the highest importance were selected as prognostic signature. Survival analysis of these patients divided by the prognostic signature in testing data set and four independent data sets showed the signature can distinguish the prognostic risks of cancer patients significantly. Enrichment analysis of the signature with curated cancer genes and the drugs selected by CMAP showed the genes in the signature may be drug targets for therapy. In summary, we have proposed a useful pipeline to identify prognostic genes of cancer patients. PMID- 28615536 TI - Antagonistic effects of lycopene on cadmium-induced hippocampal dysfunctions in autophagy, calcium homeostatis and redox. AB - Cadmium (Cd), a widely existed environmental contaminant, was shown to trigger neurotoxicity by regulating autophagy, ion homeostasis and redox. Lycopene (LYC) is a natural substance with potent antioxidant capacity. Nevertheless, little is known about i) the relationship of Cd-induced neurotoxicity and autophagy, ion homeostasis as well as redox in the hippocampus; ii) the role of LYC in the regulation of hippocampal autophagy, ionic balance and antioxidant capacity during Cd exposure. Therefore, this study sought to investigate the Cd exposure induced hippocampal dysfunctions for neurotoxicity, and the preventive potential of LYC on the hippocampus impairment by reversing the dysfunctions during the exposure. In vivo study with mice model demonstrated that Cd exposure increased gene expression of a wide spectrum of autophagy-related gene (ATG) and gene regulating autophagy in hippocampus. This suggests the activation of hippocampal autophagy mediated by Cd. Cd exposure also decreased Ca2+-ATPase activity, thus increasing intracellular Ca2+ concentration in hippocampus, indicating the possibility that Cd-induced autophagy requires the Ca2+ signaling. Moreover, Cd exposure triggered redox stress in hippocampus cells, as antioxidant enzyme activities were decreased while oxidative productions were promoted. Cd exposure led to severe cytotoxicity in hippocampus cells. Of important note, all the hippocampal dysfunctions upon Cd exposure were reversed by LYC treatment to normal situations, and exposure-induced neurotoxicity was abrogated. The in vivo findings were recapitulated relevantly in the mouse hippocampal neuronal cell line, TH22. In all, the above data imply that LYC could be a potent therapeutic agent in treating Cd-triggered hippocampal dysfunctions and subsequent cell damage. PMID- 28615542 TI - Headphone listening habits and hearing thresholds in swedish adolescents. AB - INTRODUCTION: The aim of this study was to investigate self-reported hearing and portable music listening habits, measured hearing function and music exposure levels in Swedish adolescents. The study was divided into two parts. MATERIALS AND METHODS: The first part included 280 adolescents, who were 17 years of age and focused on self-reported data on subjective hearing problems and listening habits regarding portable music players. From this group, 50 adolescents volunteered to participate in Part II of the study, which focused on audiological measurements and measured listening volume. RESULTS: The results indicated that longer lifetime exposure in years and increased listening frequency were associated with poorer hearing thresholds and more self-reported hearing problems. A tendency was found for listening to louder volumes and poorer hearing thresholds. Women reported more subjective hearing problems compared with men but exhibited better hearing thresholds. In contrast, men reported more use of personal music devices, and they listen at higher volumes. DISCUSSION: Additionally, the study shows that adolescents listening for >=3 h at every occasion more likely had tinnitus. Those listening at >=85 dB LAeq, FF and listening every day exhibited poorer mean hearing thresholds, reported more subjective hearing problems and listened more frequently in school and while sleeping. CONCLUSION: Although the vast majority listened at moderate sound levels and for shorter periods of time, the study also indicates that there is a subgroup (10%) that listens between 90 and 100 dB for longer periods of time, even during sleep. This group might be at risk for developing future noise induced hearing impairments. PMID- 28615541 TI - Self-reported occupational noise may be associated with prevalent chronic obstructive pulmonary disease in the us general population. AB - INTRODUCTION: Occupational noise exposure and chronic obstructive pulmonary disease (COPD) are common in the United States, but so far their association has not been explored. Given the neuroimmunological effects of noise, such an association seems plausible. Thus, the present study aimed to explore the association of occupational noise exposure with prevalent COPD in the US general population. MATERIALS AND METHODS: We used data from the population-based National Health Interview Survey (NHIS) 2014. The cross-sectional association of self-reported duration of exposure to very loud noise during participants' occupational lifetime with self-reported COPD and emphysema was explored using weighted logistic regression. RESULTS AND DISCUSSION: The fully adjusted model yielded odds ratio (OR)>=15 years = 1.68 [95% confidence interval (CI): 1.28, 2.21] for COPD and OR>=15 years = 1.61 (95% CI: 1.13, 2.30) for emphysema. Race/ethnicity was a significant effect modifier. In sensitivity analysis with cumulative noise exposure based on a job exposure matrix, we found no effect. CONCLUSION: In conclusion, we found a relationship between self-reported occupational noise exposure and the risk of prevalent COPD in the US general population, but none with objective noise levels. Being the first study on the subject matter, and given the design limitations, these findings are tentative and should be treated with caution. PMID- 28615543 TI - Time course of cell death due to acoustic overstimulation in the mouse medial geniculate body and primary auditory cortex. AB - It has previously been shown that acoustic overstimulation induces cell death and extensive cell loss in key structures of the central auditory pathway. A correlation between noise-induced apoptosis and cell loss was hypothesized for the cochlear nucleus and colliculus inferior. To determine the role of cell death in noise-induced cell loss in thalamic and cortical structures, the present mouse study (NMRI strain) describes the time course following noise exposure of cell death mechanisms for the ventral medial geniculate body (vMGB), medial MGB (mMGB), and dorsal MGB (dMGB) and the six histological layers of the primary auditory cortex (AI 1-6). Therefore, a terminal deoxynucleotidyl transferase dioxyuridine triphosphate nick-end labeling assay (TUNEL) was performed in these structures 24 h, 7 days, and 14 days after noise exposure (3 h, 115 dB sound pressure level, 5-20 kHz), as well as in unexposed controls. In the dMGB, TUNEL was statistically significant elevated 24 h postexposure. AI-1 showed a decrease in TUNEL after 14 days. There was no statistically significant difference between groups for the other brain areas investigated. dMGB's widespread connection within the central auditory pathway and its nontonotopical organization might explain its prominent increase in TUNEL compared to the other MGB subdivisions and the AI. It is assumed that the onset and peak of noise-induced cell death is delayed in higher areas of the central auditory pathway and takes place between 24 h and 7 days postexposure in thalamic and cortical structures. PMID- 28615545 TI - Inhibitory effects of low decibel infrasound on the cardiac fibroblasts and the involved mechanism. AB - INTRODUCTION: Infrasound is a mechanical vibration wave with frequency between 0.0001 and 20 Hz. It has been established that infrasound of 120 dB or stronger is dangerous to humans. However, the biological effects of low decibel infrasound are largely unknown. The purpose of this study was to investigate the effects of low decibel infrasound on the cardiac fibroblasts. MATERIALS AND METHODS: The cardiac fibroblasts were isolated and cultured from Sprague-Dawley rats. The cultured cells were assigned into the following four groups: control group, angiotensin II (Ang II) group, infrasound group, and Ang II+infrasound group. The cell proliferation and collagen synthesis rates were evaluated by means of [3H] thymidine and [3H]-proline incorporation, respectively. The levels of TGF-beta were determined by enzyme-linked immunosorbent assay. Moreover, RNAi approaches were used for the analysis of the biological functions of miR-29a, and the phosphorylation status of Smad3 was detected using western blotting analysis. RESULTS: The results showed that low decibel infrasound significantly alleviated Ang II-induced enhancement of cell proliferation and collagen synthesis. DISCUSSION: Compared with the control, Ang II markedly decreased the expression of miR-29a levels and increased the secretion of TGF-beta and phosphorylation of Smad3, which was partly reversed by the treatment with low decibel infrasound. Importantly, knockdown of miR-29a diminished the effects of infrasound on the cardiac fibroblasts. In conclusion, low decibel infrasound inhibits Ang II stimulated cardiac fibroblasts via miR-29a targeting TGF-beta/Smad3 signaling. PMID- 28615544 TI - Evidence of associations between brain-derived neurotrophic factor (BDNF) serum levels and gene polymorphisms with tinnitus. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. MATERIALS AND METHODS: In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA) samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. RESULTS: Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. CONCLUSIONS: This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results. PMID- 28615547 TI - Newborn survival - the forgotten milestone for achieving MDG 4. PMID- 28615548 TI - Dengue fever: Pakistan's worst nightmare. PMID- 28615546 TI - Assessment of spatial and physical neighborhood characteristics that influence sound quality and herewith well-being and health. AB - Environmental noise and health studies seldom address the positive effect of environments with high acoustic quality. Sound quality, in turn, is influenced by a large number of factors, including the spatial-physical characteristics of a neighborhood. In general, these characteristics cannot be retrieved from existing databases. In this article, we describe the design of an audit instrument and demonstrate its value for gathering information about these characteristics of neighborhoods. The audit instrument used was derived from research in other fields than environmental health. The instrument was tested in 33 neighborhoods in the Dutch cities of Amsterdam, Rotterdam, and Arnhem. In these neighborhoods, more or less homogeneous subareas were identified that were subject of the audit. The results show that the audit approach is suitable to gather neighborhood data that are relevant for the sound quality of neighborhoods. Together with survey data, they provide information that could further the field of soundscape and health. Several suggestions for improvement of the audit instrument were made. PMID- 28615549 TI - Pesticide exposure during pregnancy and low birth weight. AB - BACKGROUND: Limited epidemiologic studies have investigated the effects of pesticide exposure during pregnancy on low birth weight in offspring in rural China. METHODS: A survey of a total of 503 women was conducted in Ling county of Shandong Province of China following delivery from 1 November 2009 to 8 February 2010. RESULTS: After adjustment for confounding and compared with no pesticide exposure, multiple logistic regression showed a non-significant increased likelihood of low birth weight for both children of mothers exposed to pesticides when not pregnant (OR = 1.80, 95% CI: 0.62, 5.22) and mothers exposed to pesticides during pregnancy (OR = 2.42, 95% CI: 0.73, 8.08); multiple linear regression showed a non-significant reduced birth weight for both children of mothers exposed to pesticides when not pregnant (beta=-0.59, p=0.28) and mothers exposed to pesticides during pregnancy (beta=-0.89, p=0.15). CONCLUSIONS: Exposure to pesticides during pregnancy was associated with a non-significant increase in low birth weight in this rural Chinese population. Future studies using larger sample sizes and longer follow-up periods are warranted. PMID- 28615550 TI - A systematic review of the burden of neonatal mortality and morbidity in the ASEAN Region. AB - Neonatal morbidity and mortality are major global public health challenges representing an increasing proportion of overall under-5 child mortality, with the vast majority of neonatal deaths occurring in resource-limited settings. In the Association of Southeast Asian Nations (ASEAN) region, it is estimated that approximately 200 000 neonatal deaths occur annually with reported estimates of the neonatal mortality rate ranging from 1 to over 30 per 1000 live-births, depending on the setting. The aim of this study is to conduct a systematic review of published data on neonatal morbidity and mortality from the ASEAN region over the last 10 years. Very few published studies reporting neonatal morbidity and mortality in this region were found. Importantly, data are available from just a few countries, with an underrepresentation of the most resource-limited settings. The majority of the studies describing mortality and morbidity were retrospective surveys or focussed on a specific cause of neonatal morbidity. Studies included findings from a range of settings, from neonatal intensive care to community settings utilizing verbal autopsy. Therefore, comprehensive and prospective data are needed to inform priorities and potential interventions to improve neonatal care and reduce neonatal mortality in this region. PMID- 28615551 TI - Factors associated with knowledge about breastfeeding among female garment workers in Dhaka city. AB - BACKGROUND: Knowledge about breastfeeding among women is very important for healthy children. The present study aims to determine the level of knowledge and factors associated with knowledge on breastfeeding among female garment workers in a selected garment factory in Dhaka city. METHODS: A cross-sectional study was conducted among 200 female garment workers in the reproductive age group (15-49 years). Data were collected through a pre-tested questionnaire using the face-to face interview method. Bivariate and multivariate analysis was done to determine the association between sociodemographic variables and knowledge on breastfeeding. RESULTS: The study showed that, overall the level of knowledge regarding breastfeeding is very poor (88%) among the study subjects. Most of the respondents have very poor knowledge regarding advantages of exclusive breastfeeding (89%) and breastfeeding (100%). In contrast, a majority have good knowledge on duration of exclusive breastfeeding (74%) and breastfeeding (66%). No significant association was found between the knowledge score of breastfeeding with remaining socio-demographic variables like age, marital status, family income and expenditure. Education is significantly (p<0.001) associated with a higher total knowledge score of breastfeeding. Women with secondary level of education had a significantly higher (p<0.001) level of total knowledge score than other categories (illiterate, primary and higher secondary) of education. CONCLUSION: A large proportion of female garment workers had inadequate knowledge regarding breastfeeding. It is also important that health education on breastfeeding is urgently provided to the female garments workers of Bangladesh. PMID- 28615552 TI - Challenges faced by visually disabled people in use of medicines, self-adopted coping strategies and medicine-related mishaps. AB - BACKGROUND: Difficulties faced by visually disabled people when using medicines, self-adopted coping strategies, and medicine-related mishaps have been under explored locally and internationally. The objective of this study was to gain insight regarding this long-neglected issue. METHODS: A descriptive cross sectional study, using an interviewer administered questionnaire on 63 visually disabled adults was carried out at a vocational training centre and a school for visually disabled students in Sri Lanka. RESULTS: Among 63 participants, 71% wanted to be independent in medicine use and 79% in spite of difficulties had self-administered medicines. They had difficulty in locating medicines (25.39%), identifying medicines and medicine containers (17.46%), and administering liquid medications (25.39%). These difficulties led to inaccurate dosing (14.28%), missed doses (39.68%), and discontinuation of treatment prematurely (28.57%). Self-adopted coping strategies to overcome these difficulties included using different sized and shaped containers, tying medicines to the attire, and dipping their finger into a measuring cup while measuring liquid medicines. Mishaps related to medicines such as taking vinegar instead of gripe mixture and, putting ear drops into eyes were disclosed. CONCLUSIONS: There were many challenges for visually disabled people in taking medicines and some self-adopted coping strategies were inadequate to overcome these. PMID- 28615553 TI - Knowledge of antiretrovirals in preventing parentto-child-transmission of HIV: a cross-sectional study among women living with HIV in Tamil Nadu, India. AB - BACKGROUND: India is amongst the top 10 countries in the world currently with the highest burden of pregnant women living with HIV and nearly 80% of these women do not receive antiretroviral (ARV) drugs to prevent parent-to-child transmission (PTCT) of HIV. The aim of this study was to estimate HIV-infected women's awareness on PTCT and knowledge of ARVs as a measure to prevent PTCT. METHODS: This was a descriptive, cross-sectional study in which a total of 986 women with HIV aged 18 years and above were interviewed in 13 high HIV prevalence districts of Tamil Nadu, South India. Data were analysed using descriptive, bivariate and multivariate methods. RESULTS: Nearly one fifth (18.8%) of the women with HIV had not heard of PTCT and 40% did not know that ARVs could prevent PTCT. In addition, 39.3% were not aware of the timing of PTCT; 50.4% reported intrauterine and intrapartum and 13.7% mentioned breastfeeding period as the possible timings of PTCT of HIV. Multivariate analysis showed that single/never married women had lower knowledge of PTCT. Also, those who had undergone a prior training on reproductive and child health (RCH) and those who discussed RCH issues with their partners were more likely to have higher knowledge. CONCLUSION: Considering the risk of HIV transmission from HIV-infected women to their children, the knowledge level of PTCT among them is low. Appropriate strategies to generate awareness among women with HIV need be introduced to help them make informed decisions. PMID- 28615554 TI - India's progress towards the Millennium Development Goals 4 and 5 on infant and maternal mortality. AB - BACKGROUND: India is in a race against time to achieve the Millennium Development Goals (MDGs) 4 and 5, to reduce Infant Mortality Rate (IMR) to '28' and Maternal Mortality Ratio (MMR) to '109', by 2015. This study estimates the percent net contribution of the states and the periods in shaping India's IMR/MMR, and predicts future levels. METHODS: A standardized decomposition technique was used to estimate each state's and period's percent share in shaping India's decline in IMR/MMR between two time points. Linear and exponential regression curves were fitted for IMR/MMR values of the past two decades to predict IMR/MMR levels for 2015 for India and for the 15 most populous states. RESULTS: Due to favourable maternal mortality reduction efforts in Bihar/Jharkhand (19%) and Madhya Pradesh/Chhattisgarh (11%), Uttar Pradesh (33%) - India is predicted to attain the MDG-5 target by 2016, assuming the pace of decline observed in MMR during 1997-2009 continues to follow a linear-trend, while the wait may continue until 2023-2024 if the decline follows an exponential- trend. Attaining MDG-4 may take until 2023-2024, due to low acceleration in IMR drop in Bihar/ Jharkhand, Uttar Pradesh/Uttarakhand and Rajasthan. The maximum decline in MMR during 2004-2009 coincided with the launch and uptake of the National Rural Health Mission (NRHM). CONCLUSIONS: Even though India as a nation is not predicted to attain all the MDG 4 and 5 targets, at least four of its 15 most populous states are predicted to do so. In the past two decades, MMR reduction efforts were more effective than IMR reduction efforts. PMID- 28615555 TI - Promoting antenatal care services for early detection of pre-eclampsia. AB - A prospective, quasi-experimental study was carried out in 2009 at urban health centres (UHCs) of five townships of Mandalay, Myanmar, to improve the skill of midwives (MWs) in diagnosis and referral of pre-eclampsia (PE) from UHC to the Central Women's Hospital (CWH) and to enhance the supervision of midwives by lady health visitors (LHVs). The intervention was training on quality antenatal care focusing on PE using an updated training manual. Altogether, 75 health care providers (MWs & LHVs) participated. In this study, data were extracted from patient registers and monthly reports of UHCs and CWH. Interviewers were trained regarding the conduct of semi-structured questionnaires to elicit knowledge and to use checklists in observation of skills in screening of PE, measuring blood pressure and urine protein (dipstick test). A guide for LHVs was also used to obtain data, and data was collected six months prior to and after the intervention. Significant improvements from baseline to endline survey occurred in the knowledge (p<0.001) and skill levels (p<0.001) including skills for screening, measuring blood pressure and urine protein. At CWH, there was an increase in referred cases of PE after the intervention, from 1.25% to 2.56% (p<0.001). In conclusion, this study highlights the early detection of pre eclampsia by widespread use of quality antenatal care, education and training of health-care providers to improve their performance and increase human resources for health care, in order to enable women in our society to have healthy pregnancies and healthy babies. PMID- 28615556 TI - Haemoglobinopathies - major associating determinants in prevalence of anaemia among adolescent girl students of Assam, India. AB - Prevalence of anaemia among adolescent girl students of Assam, a north-eastern state of India, was evaluated along with its associating determinants. The present study revealed that anaemia is a major public health problem among adolescent girl students of Assam. The overall prevalence of anaemia among adolescent girl students of Assam is as high as 71.5%. Non-nutritional factors such as infection due to helminths was substantially low (24.71%). Ascaris lumbricoides was the most frequent infection (10.6%), followed by Trichuris trichiura (6.2%), and hookworm infestations (3.9%). Polyparasitic infection (A. lumbricoides, T. trichiura and hookworm) was observed in 0.5% of the study subjects. While coinfection due to A. lumbricoides and T. trichiura was 2.3%, A. lumbricoides and hookworm was 1.1% and T. trichiura and hookworm was 0.9%. Serum ferritin level in a subgroup of samples was in the lower normal range. Malaria parasite was not detected in any of the slides. We have observed a gene frequency of 0.188 for betaE-globin gene among the adolescent girl students of Assam. The gene frequency for betaE-globin gene ranged from 0.071 to 0.266. Statistically significant difference (F=3.471; P=0.001) of mean haemoglobin level was observed in different types of haemoglobin variants. Multiple regression analysis, in a sub-set of samples having information on Hb levels (g/dl), helminthic infestation (A. lumbricoides, T. trichuria and hookworm), haemoglobin type, revealed haemoglobin type (Hb E) was the important determinant of anaemia among adolescent girl students in the present study. PMID- 28615557 TI - Early discontinuation of intrauterine device in Nepal - a retrospective study. AB - BACKGROUND: The Intrauterine Device (IUD) is the least popular method of contraception for family planning in Nepal. In addition, discontinuation in the early days after insertion is very high and information related to factors affecting early discontinuation is very limited. METHODS: A retrospective study was carried out over a 5-year period to determine the associated factors for early discontinuation of the IUD. Insertion, consultation and removal records of IUD users of Kshetrapati Family Welfare Centre, Kathmandu, were reviewed. Removal within 12 months of insertion is defined as early discontinuation. The study participants were selected randomly. Uni-variate and logistic regression analysis were used to analyse predictors of early discontinuation of IUD. RESULTS: The results showed that one fifth of the 230 women using IUD discontinued within the first year of insertion. Side-effects were the main reason for early discontinuation followed by expulsion. Woman's occupational status, husband's occupational status, husband's educational status, experience of side-effects and follow-up practice were associated with early discontinuation of IUD. Menstrual disorder and abnormal vaginal discharge were also associated with early discontinuation. CONCLUSION AND RECOMMENDATION: Risks of IUD discontinuation were found to be very high during the early days of insertion and side-effects were identified as the major cause. So, proper management of side-effects would be very important to reduce early discontinuation of IUD. PMID- 28615558 TI - Screening high-risk population for hypertension and type 2 diabetes among Thais. AB - BACKGROUND: waist circumference (WC) and body mass index (BMI) are simple screening tools for hypertension (HT) and type 2 diabetes (DM). Cutoffs of WC for BMI for Asians have been discussed. This study aimed to assess the accuracy of screening tools and associations of WC, BMI with HT and DM. METHODS: Data from the national screening programme for metabolic syndrome conducted in 2010 in 21 provinces in the central region of Thailand were analysed. A total of 10 748 participants aged >35 years were included in the analysis with cutoffs of WC set at 90 cm for men, 80 cm for women, and BMI at 23 kg/m2 for both sexes. RESULTS: WC produced low sensitivity and high specificity among male participants, and moderate sensitivity and specificity among female participants, while BMI produced moderate sensitivity and specificity in both sexes. Significant associations were found among those who had high WC only, high BMI only, and both high WC and BMI with HT and DM in both sexes. (males for HT, OR=1.63, 95%CI: 1.15 2.33, OR=1.22, 95%CI: 1.03-1.44 and OR=2.03, 95%CI: 1.07-2.42; males for DM, OR=1.39, 95%CI: 1.05-1.83), OR=1.77, 95%CI: 1.07-2.94 and OR= 2.05, 95%CI: 1.57 2.69, females for HT, OR=1.69: 95%CI 1.38-2.07, OR=1.32; 95%CI: 1.09-1.60 and OR=2.54, 95%CI: 2.11-2.91; females for DM, OR=1.45, 95%CI: 1.08-1.94, OR=1.45, 95%CI: 1.09-1.91 and OR=1.70, 95%CI: 1.39-2.09). When the cutoff WC was lowered among male participants to 85 cm, sensitivity increased, and significant strengths of associations with HT and DM were nearly the same. CONCLUSION: For Thailand, WC and BMI with appropriate cutoffs can be effective screening tools to recruit high-risk populations into health promotion programmes. However, WC and BMI should be implemented with other screening tools for other risk factors because of their moderate accuracy. PMID- 28615559 TI - Oral health status of 12-year-old children with disabilities and controls in Southern India. AB - BACKGROUND: This study explores the association of disabilities and oral health. The aim of the study was to compare and assess oral health status of 12-year-old children with disabilities with healthy controls in Karnataka, Southern India. METHODS: A total of 191 schoolchildren with disabilities were examined from 12 year age group. For comparison, 203 healthy children were randomly selected from other government schools. Clinical data were collected on periodontal status, dental caries, treatment needs and dental malocclusion using WHO criteria. A chi squared test was used to compare between categorical variables. Linear and logistic regression analysis was performed to determine the importance of the factors associated with caries status. RESULTS: Significant differences were noted in the frequency of sugar consumption between subjects with disabilities and their healthy controls. Subjects with disabilities had significantly higher CPI (community periodontal index) scores than their healthy counterparts (p<0.001). Dental caries was present in 89.8% children from special schools as compared with 58.6% from the control group. Mean DMFT (decayed, missing, filled teeth) values for special school children and healthy controls were 2.52 +/- 2.61 and 0.61 +/- 1.12, respectively. Higher prevalence of malocclusion was seen in subjects with special healthcare needs, with 66.4% having definite malocclusion and 17.4% of controls having malocclusion (p<0.001). The mean values for treatment needs were higher in subjects with disabilities. Regression analysis showed that, type of school, male gender, low frequency of brushing, increased frequency of sugar consumption between meals and dental malocclusion were significantly related to dental caries. CONCLUSION: Poor oral health of children with disabilities as compared with their healthy controls in terms of periodontal status, dentition status, treatment needs, and dentofacial anomalies was found in our study, which confirms a need for preventive treatment for these children. PMID- 28615560 TI - Mental health care in Bhutan: policy and issues. AB - The Royal Government of Bhutan pursues and promotes a policy of providing well integrated, equitable, cost-effective and balanced health services consisting of preventive, promotive, curative and rehabilitative programmes through its primary health care system. The government has accorded high priority to social sectors like health and education. However, there are serious concerns regarding the quality of care provided to persons with mental disorder, who on this account are subjected to stigma, discrimination and human rights abuses. This article aims to analyse, examine and highlight the policy and issues of the mental healthcare system in Bhutan. It focuses on the mental healthcare system with reference to services, policies and issues and to advocate for better policy development for mental health. PMID- 28615561 TI - A decade of health-care decentralization in Thailand: what lessons can be drawn? AB - This paper reviews the progress of implementation of health-care decentralization in Thailand since the promulgation of the Decentralization Act 1999, draws lessons learnt and provides recommendations. This review was carried out because of the delay in health-care decentralization, as compared with what was indicated in the Decentralization Action Plan, and to identify the possible causes of delay. The review also analyses other issues that affected implementation of this policy such as consensus on models of health-care decentralization, and other government policies being implemented during the same period. It is recommended that decentralization is not a panacea for health system development and its concept should be applied carefully, based on the country context. PMID- 28615562 TI - Laboratory diagnosis of epidermolysis bullosa. PMID- 28615563 TI - Role of oral vitamin D3 analogues in the treatment of psoriasis. AB - Oral vitamin D3 analogues 1 alpha hydroxy cholecalciferol and 1,25 dihydroxy cholecalciferol were compared with placebo in the treatment of psoriasis. Three groups of 15 patients each were given 1 alpha hydroxy cholecalciferol at 1 ug/ day 1,25 dihydroxy cholecalciferol at 0.5 ug/d and multi vitamins other than Vit A and Vit D, respectively. Patients were followed up for 3-6 months. Assessment of severity and response was done by Psoriasis Area Severity Index (PASI). Both Vit D, analogues 1 alpha hydroxy vitamins D3 and 1,25 (OH)2 D3 were found to be effective. Serum and urinary calcium remained within normal limits. PMID- 28615564 TI - Treatment of benign vascular skin lesions with carbon dioxide laser. AB - Fifteen patients, 10 males and 5 females, between 10-27 years age with different benign vascular skin lesions i.e.haemangioma (3) and lymphangioma circumscriptum (2) were taken up for this study. The lesions in all the patients were vaporized/excised with the indigeneously developed carbon dioxide laser. The patients were evaluated at 1,2,4,8 and 12 weekly visits to assess the overall response to the treatment and the side effects. All the patients responded to the treatment. The patients with granuloma pyogenicum showed excellent response with complete disappearance of the lesions while the patients with haemangiomas, lymphangio-haemangiomas and lymphangioma circumscriptum improved by 70-90%. Transient hypopigmentation and mild scarring were seen in all the patients except in patienls with granuloma pyogenieum. There were no other significant side effects in any of the patients. PMID- 28615565 TI - Peripheral T-lymphocyte counts in seborrhoeic keratosis. AB - One hundred and forty-eight cases of clinically diagnosed seborrhoeic keratoses and 12 of stuccokeratoses were selected from Dermato Venereology department of Rajendra Hospital, Patiala, during a period of 15 months. Histopathology confirmed that 123 out of 148 cases were of seborrhoeic keratosis and 8 out of 12 were of stuccokeratosis. T-lymphocyte counts in histopathologically confirmed cases were done by Thomson's E-rosette method (1977). Peripheral T-lymphocyte counts were statistically significantly increased in both seborrhoeic keratosis and stucco keratosis, thus revealing important role of cell mediated immunity in seborrhoeic keralosis. PMID- 28615566 TI - Vegetable and fruit contact dermatitis among housewives-study of 25 cases. AB - Almost all women have to handle vegetables and fruits, so vegetable and fruit contact dermatitis in females has surfaced as a dermatological problem. This study was therefore undertaken to evaluate the contact sensitization pattern of various vegetables and fruits in housewives in north-west Rajasthan. Thirty-eight commonly used vegetables and fruits extracted/crushed allergen's patch tests were applied as such over back of 25 women having eczema of thumhs, index and middle fingers, 1st and 2nd web spaces, palmar and dorsal aspect of hands. Patch tests were read after 48 and 72 hours and graded as ICDRG. Out of them we obtained positive results in 20(80%), with single allergen positivity in 6 (24%) an11 multiple allergen positivity in 14 (56%). PMID- 28615567 TI - Bacteriology of primary pyodermas and comparative efficacy of topical application of mupirocin and sodium fusidate ointments in their treatment. AB - A study to compare the efficacy of topical 2% mupirocin ointment and 2% topical sodium fusidate ointment in the treatment of primary pyodermas was done. Out of one hundred cases of primary pyodermas, fifty were randomly treated with 2% topical mupirocin ointment and fifty were given 2% topical sodium fusidate ointment. Patients were evaluated after four days and seven days of treatment. At the end of seven days. both the agents were found to be equally effective and side effects were insignificant in both the groups. PMID- 28615569 TI - Chancroid. PMID- 28615568 TI - A double - blind randomised multicentre controlled study of topical 0.05% clobetasol propionate with 2.5% zinc sulphate preparation. AB - The aim of this study was to compre the efficacy and safety of topical clobetasol propionate and clobetasol propionate with zinc sulphate cream preparation. Steroid responsive dermatoses were primarily considered in both the treatment groups. From thc analysis of 291 patients, from five different centres, it wasnoted that though the out come was Positive in both the trial groups significant differences existed in the treatment group which received clobetasol propionate with zinc sulphate preparation. During evaluation the outcome was even between both treatment groups on the day 7. However towards the end of the study significant differences existed. Interestingly both the treatment groups did not have any adverse effects. PMID- 28615570 TI - Periumbilical pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum is an inherited connective tissue disorder affecting skin, ocular and vascular systems. We report an unusual case with cutaneous lesions simulating PXE localized to the periumbilical region with no systemic involvement. Two entities having localized PXE-like skin changes namely perforating calcific elastosis and papillary dermal elastolysis are discussed. PMID- 28615571 TI - AIDS related kaposi's sarcoma. AB - A case report of a 22-year-old HIV-infected heterosexual man with Kaposi's sarcoma is described. The need for high index of suspicion and new mode of therapy are discussed. PMID- 28615572 TI - Tuberculous panniculitis. AB - A rare case of tuberculous panniculitis in a 2-year-old girl who presented with a progressively increasing large nodular plaque over the back of 2 months duration is being reported. Diagnosis was confirmed histopathologically and on the basis of a positive accelerated BCG test. PMID- 28615573 TI - Pityriasis rotunda - report of three cases. AB - Pityriasis rounda is a very rare disorder of keratinization. Here is a report of three such cases. PMID- 28615574 TI - Angina bullosa hemorrhagica (recurrent oral haemophlyctenosis). AB - A case of recurrent oral haemophlyctenosis, characterized by sudden onset of tense blisters on the tongue is being reported. The blisters were fillcd with haemorrhagic fluid and healed within a week. PMID- 28615575 TI - Oral condylomata acuminata. AB - A case of oral condylomata acuminata in a boy aged 14 years is reported for its uncommon presentation, which warrants a high index of suspicion for diagnosis. PMID- 28615576 TI - Primary cutaneous mucin producing squamous cell carcinoma. AB - Variants of squamous cell carcinoma are often rare but they an aggressive tumours with a potential for local recurrence and metastasis. A deeply invasive primary mucin producing squamous cell carcinoma of skin is one such rare variant. PMID- 28615577 TI - Facial pseudochromhidrosis induced by lead. AB - A young girl presented with dark blue black smoky pigmentation on her face which she presumed started after chloroquine therapy for malaria. Histology revealed a normal picture except some yellow brown granules in the superficial part of the stratum corneum. A strict vigilance on the patient after admission revealed that she had been applying lead pencil powder on her face to gain sympathy from her parents. An unusual presentation of pseudochromhidrosis is reported with relevant review of literature. PMID- 28615578 TI - Sebaceous hyperplasia resembling lymphangioma circumscriptum. AB - A young boy presented with multiple soft linear papules on left ear of short duration with associated psoriasiform dermatitis of scalp. The lesions clinically resembled lymphangioma circumscriptum. Histology revealed multiple hyperplastic sebaceous glands branching from a single duct and dilated hair follieles suggesting sebaceous hyperplasia. The case is presented with review of the relevant literaturs. PMID- 28615579 TI - Porokeratosis of mibelli: Disseminated non actinic form. AB - Two cases of nonactinic - disseminated porokeratosis of Mibelli are reported. Autosomal dominant mode of inheritance was observed in one case. PMID- 28615580 TI - Papuloerythroderma of ofuji. AB - A 60-year old male with papulo erythroderma of Ofuji is presented here for its rarity. The characteristic 'deck chair' sign was present. Response to PUVA therapy was noted. PMID- 28615581 TI - Herpes labials and genitalis in a hiv positive patient. AB - A 22-year-old man who was HIV positive, presented with recurrent oral and genital losions simultaneously. PMID- 28615582 TI - Contact depigmentation caused by henna. PMID- 28615583 TI - Toxic epidermal necrolysis. PMID- 28615584 TI - Trichomonas vaglnalls. PMID- 28615585 TI - Sildenafil nitrate : Its prescription. PMID- 28615586 TI - Why do women deliver in facilities, or not? PMID- 28615587 TI - Unintended consequences of regulating traditional medicine. AB - The World Health Organization (WHO) has the noble goals of advancing traditional medicine and simultaneously promoting the regulation and professionalization of traditional healers. However, such regulation has the unintended consequence of withholding power from traditional practitioners. This review explores this concept through a historical analysis of traditional medicine in both India and Zimbabwe. During the post-colonial period in both countries, traditional medicine contributed to the creation of national identity. In the process of nationalizing traditional medicine, regulations were set in place that led to a rise in the university-style teaching of traditional healing. This period of professionalization of traditional healers resulted in certain types of traditional medicine being marginalized, as they were neither included in regulation nor taught at university. Since then, the current era of globalization has commoditizedtraditional healing. Private industries like ZEPL and Dabur have rapidly and vastly altered the role of traditional healers. Consumers can now buy traditional medication directly from companies without visiting a healer. Additionally, disputes over patents and other intellectual property rights have led to important questions regarding ownership of certain plants traditionally known for healing properties. Through regulation and commercialization of traditional medicine, healers have lost some of their independence to practise. PMID- 28615588 TI - Why women do not utilize maternity services in Nepal: a literature review. AB - The structure and provision mechanism of maternity services in Nepal appears to be good, with adequate coverage and availability. Utilization of maternity services has also improved in the past decade. However, this progress may not be adequate to achieve the Millennium Development Goal to improve maternal health (MDG 5) in Nepal. This paper reviews the factors that impede women from utilizing maternity services and those that encourage such use. Twenty-one articles were examined in-depth with results presented under four headings: (i) sociocultural factors; (ii) perceived need/benefit of skilled attendance; (iii) physical accessibility; and (iv) economic accessibility. The majority of the studies on determinants of service use were cross-sectional focusing on sociocultural, economic and physical accessibility factors. In general, the education of couples, their economic status and antenatal check-ups appeared to have positive influences. On the other hand, traditional beliefs and customs, low status of women, long distance to facilities, low level of health awareness and women's occupation tended to impact negatively on service uptake. More analytical studies are needed to assess the effectiveness of the Safer Mother Programme, expansion of rural birth centres and birth-preparedness packages on delivery-service use. Moreover, it is important to investigate women's awareness of the need of facility delivery and their perception of the quality of health facilities in relation to actual usage. PMID- 28615589 TI - Appropriate anthropometric indices to identify cardiometabolic risk in South Asians. AB - BACKGROUND: South Asians show an elevated cardiometabolic risk compared to Caucasians. They are clinically metabolically obese but are considered normal weight based on current international cut-off levels of several anthropometric indices. This study has two main objectives: (i) to predict the most sensitive anthropometric measures for commonly studied cardiometabolic risk factors, and (ii) to determine optimal cut-off levels of each of the anthropometric indices in relation to these cardiometabolic risk factors in South Asians. METHODS: The study was conducted on a random sample of 1178 adults of 20-80 years of age from an urban population of eastern India. Obesity, as evaluated by standard anthropometric indices of BMI (body mass index), WC (waist circumference), WHpR (waist-to-hip ratio) and WHtR (waist-to-height ratio), was individually correlated with cardiometabolic risk factors. Receiver operating characteristic (ROC) curve analyses were performed which includes: (i) the area under the receiver operating characteristic curve (AUROC) analysis to assess the predictive validity of each cardiometabolic risk factor; and (ii) Youden index to determine optimal cut-off levels of each of the anthropometric indices. RESULTS: Overall, AUROC values for WHtR were the highest, but showed variations within the sexes for each of the cardiometabolic risk factors studied. Further, WHpR cut-offs were higher for men (0.93-0.95) than women (0.85-0.88). WC cut-offs were 84.5-89.5 cm in men and 77.5-82.0 cm in women. For both sexes the optimal WHtR cut-off value was 0.51-0.55. The optimal BMI cut-offs were 23.4-24.2 kg/m2 in men and 23.6-25.3 kg/m2 in women. CONCLUSION: WHtR may be a better anthropometric marker of cardiometabolic risks in South Asian adults than BMI, WC or WHpR. PMID- 28615590 TI - Diabetes in rural Pondicherry, India: a population-based studyof the incidence and risk factors. AB - BACKGROUND: For India, the 'diabetes capital' of the world, it is essential to know the incidence of type 2 diabetes mellitus (T2DM) and its key determinants. As two thirds of Indians live in rural areas, a study was undertaken to assess the incidence and risk factors of T2DM in rural Pondicherry, India. METHODS: In a population-based cohort study initiated in 2007, a sample of 1223 adults > 25 years ofage from two villages of Pondicherry were selected using cluster random sampling. Data on risk factor exposure were collected using a structured questionnaire, anthropometric tests and fasting blood glucose assessment. During house visits, 1223 of 1403 invited subjects participated. Of these, 71 (5.8%) were found to have diabetes. In 2010-2011, 85% of the non-diabetics (979/1152) were followed up using the same protocol. We calculated the risk of T2DM per annum standardized by age and sex. Population estimates of the risk factors associated with T2DM were analysed using the Generalized Estimating Equation model and the Population Attributable Risk (PAR) for T2DM calculated. RESULTS: During 2937 person-years (PY) of follow-up, 63 new cases of T2DM occurred, giving an incidence rate of 21.5/1000 PY. Almost one third (31.7%) of cases occurred in people aged below 40 years. The incidence was double among males (28.7/1000 PY; 95% confidence interval (CI): 21.0-38.7) compared with females (14.6/1000 PY; 95% CI: 9.4-21.7). Applying these rates to rural populations, it is estimated that each year 8.7 million people develop T2DM in rural India. Nearly half of the T2DM incidence was attributed to overweight/obesity and alcohol usage. CONCLUSION: T2DM incidence was 2% per year in adults in rural Pondicherry, India, with the rate increasing twice as fast in men. Increasing age, obesity, alcohol use and a family history of T2DM independently predicted the development of diabetes. As half of T2DM incidence was attributed to overweight/obesity and alcohol use, health promotion interventions focusing on maintaining an optimal weight and decreasing alcohol consumption may be effective in reducing the rise in T2DM cases. PMID- 28615591 TI - Effects of education and income on cognitive functioning among Indians aged 50 years and older: evidence from the Study on Global Ageing and Adult Health (SAGE) Wave 1 (2007-2010). AB - OBJECTIVES: Relatively little is known about socioeconomic predictors of cognitive health among middle-aged and elderly Indians. The primary objective of this study was to examine the extent to which education and income influence cognitive functioning after adjusting for demographic characteristics, health risk factors and transgenerational factors such as parental education. The study also examined gender disparities in cognitive functioning across geographic regions in India. METHODS: Using cross-sectional data from the World Health Organization Study on Global Ageing and Adult Health (SAGE) Wave 1 (2007-2010) in a national sample of adults aged 50 years or older, a generalized linear model was used to examine the impacts of education and per-capita income on overall cognitive functioning. The generalized estimating equation approach was utilized to quantify these impacts on respondents' overall cognitive performance score. This technique accounted for any correlation of responses of individuals within the same household. RESULTS: Respondents with primary or secondary education and those with education above secondary level scored 3.8 and 6 points (P < 0.001) respectively more than respondents who had no formal education. In a similar vein, individuals in higher per-capita income quartiles scored 0.4,1.0 and 1.8 (P < 0.001) more than respondents in the lowest income quartile. Although respondents in northern states scored 1.8 points higher than those from other geographic locations (P < 0.001), females in northern states had the worst cognitive performance (1.9 points lower) compared with females in other Indian states. In addition, early and adult life characteristics such as parental education, physical activity and a history of depression were found to be significant predictors of overall cognitive functioning. CONCLUSION: Education and income play important roles in influencing overall cognitive performance among middle-aged and elderly Indians. In addition, cognitive performance scores varied across geographic regions, and female disadvantage was observed in northern Indian states. Policies directed towards greater educational opportunities, particularly for women in northern Indian states, or promotion of physical activity programmes, have potential to improve cognitive performance and enhance cognitive health among middle-aged and older adults in India. PMID- 28615592 TI - Integrating adolescent-friendly health services into the public health system: an experience from rural India. AB - BACKGROUND: Although India's health policy is directed toward improving adolescent reproductive health, adolescent-friendly health services are scarce. The intervention for "integrating adolescent-friendly health services into the public health system" is an effort to improve the health status of adolescents in rural areas of the Varanasi (Arajiline) and Bangalore (Hosakote) districts in India. The purpose of this article is to describe the features of the intervention and investigate the impact on improving awareness and utilization of services by adolescent as well as quality of ARSH services in the intervention districts. METHODS: Data from project monitoring, community survey (737 adolescents), exit interviews (120 adolescents), assessment of adolescent sexual and reproductive health clinics (n = 4), and health service statistics were used. Descriptive analyses and paired t-tests were used to compare the two intervention districts. RESULTS: Overall, the percentage of adolescents who were aware of the services being offered at a health-care facility was higher in Hosakote (range: 56.2% to 74.7%) as compared to Arajiline (range: 67.3% to 96.9); 23.3% and 42.6% of adolescents in Arajiline and Hosakote typically sought multiple services at any one visit. A large percentage of clients (Arajiline: 81.7%; Hosakote: 95.0%) were satisfied with the services they received from the facility. The relative change in uptake of services from the first quarter (January to March 2009) to the last quarter (October to December 2010) was significantly higher in Arajiline (7.93, P = 0.020) than in Hosakote (0.78, P = 0.007). CONCLUSION: The intervention had positive results for the public health system and the services are being scaled up to different blocks of the districts, under a public-private partnership. PMID- 28615594 TI - Oseltamivir-resistant influenza A(H1N1) pdm09 virus: first reported case from India. AB - BACKGROUND: Recent studies on antiviral susceptibiliy from South-East Asia, Europe and the United States have shown sporadic neuraminidase inhibitor (NAI) resistance in A(H1N1)pdm09 viruses. We undertook a study to evaluate NAI resistance in these viruses isolated in India. METHODS: Pandemic influenza viruses, isolated from 2009 to 2013, along with clincal samples were genetically analysed for known resistance markers in the neuraminidase (NA) gene. Clinical samples (n=1524) were tested for H275Y (N1 numbering; H274Y in N2 numbering) mutation by real time reverse transcriptase PCR (rRT-PCR). One hundred and ten randomly selected resistant and sensitive viruses were analysed by phenotypic assay. RESULTS: All but one of the 2013 A(H1N1)pdm09 isolates were sensitive to oseltamivir. Genetic analysis of this isolate as well as the original clinical material showed that the presence of H275Y mutation was responsible for reduced susceptibility to oseltamivir in the patient. This was confirmed by phenotypic assay. CONCLUSION: The emergence of a pandemic influenza strain resistant to oseltamivir emphasizes the need for monitoring antiviral resistance as part of the National Influenza Programme in India. PMID- 28615593 TI - Knowledge and opinion about smoke-free laws and second-hand smoke among hospitality venue managers in Gujarat and Andhra Pradesh, India. AB - BACKGROUND: India's Smoke-Free Law (SFL) was implemented in 2004 and reinforced on 2nd October 2008. This research attempts to understand the knowledge and opinion of hospitality venue (HV) managers about second-hand smoke (SHS) and SFL as well as self-reported compliance with SFL in two Indian states. METHODS: A survey was conducted among 804 randomly sampled HVs from project STEPS (Strengthening of tobacco control efforts through innovative partnerships and strategies) in Gujarat and Andhra Pradesh, India. Four hundred and three HVs from two districts in Gujarat and 401 HVs from six districts in Andhra Pradesh were selected. The owner, manager or supervisor of each HV was interviewed using a pre tested structured interview schedule. Association of opinion scales with respondents' background characteristics was assessed through the analysis of variance (ANOVA) method. RESULTS: Out of the 403 respondents in Gujarat and 401 in Andhra Pradesh, 56.1% and 84.3% had knowledge about SFL respectively. Compliance of HVs with SFL was 21.8% in Gujarat and 31.2% in Andhra Pradesh as reported by the managers. Knowledge about SHS was noted among 39.7% of respondents in Gujarat and 25.4% in Andhra Pradesh. Bivariate results indicated that more educated HV managers showed higher support for smoke-free public places (P < 0.001) and were more concerned about the health effects of SHS exposure (P = 0.002). CONCLUSION: Complete self-reported compliance with, and knowledge of SFL as well as SHS was not found in Gujarat and Andhra Pradesh. The education level of HV managers is an important determinant to ensure compliance with SFL in public places. PMID- 28615595 TI - Tetanus: still a public health problem in India - observations in an infectious diseases hospital in Kolkata. AB - BACKGROUND: Tetanus is a major health problem in many developing countries, including India, with significant morbidity and mortality due to lack of environmental hygiene and health education, incomplete vaccination, high case prevalence and inadequate intensive care facilities. OBJECTIVES: To observe the demography, clinical profile and outcomes of tetanus patients. MATERIALS AND METHODS: A total of 282 tetanus patients were screened and closely observed prospectively from January 2010 to December 2011. RESULTS: The mean age of the study patients was 31.15 years (+/- 14.26) and the majority were unvaccinated or incompletely vaccinated against tetanus. Patients were mainly farmers (140, 49.64%) and children (102, 36.17%). The sources of infection identified were mainly thorn/pin prick in 129 cases (45.7%), cut/lacerated injury in 83 cases (29.4%) and ear infection in 47 cases (16.7%), while definite injurywas not detected/remembered in 42 cases (14.8%). The average duration of hospital stay was 17.2 +/- (4.7) days and autonomic nervous system dysfunction was the most common complication observed in this study. Death was the outcome in a total of 58 patients (20.6%) mostly due to aspiration pneumonia-induced sepsis, respiratory failure or cardiac complications. CONCLUSION: Environmental hygiene, basic health education, increased in immunization coverage, proper wound care - even following minor injuries - and more facilities for intensive care units, may reduce the overall incidence of tetanus and mortality following onset of the disease. PMID- 28615596 TI - Veterinary public health capacity-building in India: a grim reflection of the developing world's underpreparedness to address zoonotic risks. AB - Veterinary public health (VPH) is ideally suited to promote convergence between human, animal and environmental sectors. Recent zoonotic and emerging infectious disease events have given rise to increasing calls for efforts to build global VPH capacities. However, even with their greater vulnerability to such events, including their economic and livelihood impacts, the response from low-and middle income countries such as India has been suboptimal, thereby elevating global health risks. Addressing risks effectively at the human-animal interface in these countries will require a clear vision, consistent policies, strategic approach and sustained political commitment to reform and refine the current VPH capacity building efforts. Only then can the discipline serve its goal of disease prevention, poverty alleviation and support for sustainable livelihoods through improvements in human and animal health. PMID- 28615597 TI - Knowledge brokering for evidence-based urban health policy: a proposed framework. AB - This paper presents a multidimensional approach to examining the urban evidence policy interface in low- and middle-income countries (LMICs), and applies this approach to a case study from Pakistan. Key features of urban health policy and the significance of the evidence-policy interface in rapidly changing LMICs are articulated; characteristics of evidence that has been successfully incorporated into health policy are also defined. An urban health evidence-to-policy exploratory framework for LMICs based on innovative multidisciplinary thinking and pivotal knowledge brokering is presented. Application of the framework to a case study on road transport and health in urban Pakistan underscores the opportunities and utility of knowledge brokering. Public health practitioners can become knowledge brokers at the evidence-policy interface to develop a concerted, coordinated and informed response to urban health challenges in LMICs. PMID- 28615598 TI - Fiscal competition in health spending among local governments in the Philippines. AB - The Philippines is one of several Asian countries that has decentralized the provision of health care to its local governments in recent decades. In the context of decentralization, a few studies have previously examined the issue of fiscal competition among local governments in the developing world. This report presents a summary of a published study that examined the existence of inter jurisdictional competition in health-care spending in the Philippines. The results indicate the presence of positive fiscal "spillovers" in health spending, consistent with municipalities/cities competing to outspend their neighbours. Several potential explanations forthis finding are discussed. PMID- 28615599 TI - Trends in tobacco use in Nepal. PMID- 28615600 TI - Success of tuberculosis and HIV collaboration. PMID- 28615601 TI - Janani Suraksha Yojana: the conditional cash transfer scheme to reduce maternal mortality in India - a need for reassessment. AB - Alongside endorsing Millennium Development Goal 5 in 2000, India launched its National Population Policy in 2000 and the National Health Policy in 2002. However, these have failed thus far to reduce the maternal mortality ratio (MMR) by the targeted 5.5% per annum. Under the banner of the National Rural Health Mission, the Government of India launched a national conditional cash transfer (CCT) scheme in 2005 called Janani Suraksha Yojana (JSY), aimed to encourage women to give birth in health facilities which, in turn, should reduce maternal deaths. Poor prenatal care in general, and postnatal care in particular, could be considered the causes of the high number of maternal deaths in India (the highest in the world). Undoubtedly, institutional delivery in India has increased and MMR has reduced over time as a result of socioeconomic development coupled with advancement in health care including improved women's education, awareness and availability of health services. However, in the light of its performance, we argue that the JSY scheme was not well enough designed to be considered as an effective pathway to reduce MMR. We propose that the service-based CCT is not the solution to avoid/reduce maternal deaths and that policy-makers and programme managers should reconsider the 'package' of continuum of care and maternal health services to ensure that they start from adolescence and the pre-pregnancy period, and extend to delivery, postnatal and continued maternal health care. PMID- 28615602 TI - Pandemic influenza preparedness planning: lessons from Cambodia. PMID- 28615603 TI - A review of Japanese encephalitis in Uttar Pradesh, India. AB - BACKGROUND: Japanese encephalitis (JE) is a major public health problem in India. When the first case was reported in 1955, the disease was restricted to south India. The disease spread to north India in 1978 from where extensive and recurrent outbreaks of JE have been reported ever since. An attempt has been made to review the epidemiology of JE over the past 30 years and suggestions made for its prevention and control. METHODS: An epidemiological profile of JE (1978-2009) has been compiled and analysed to understand the trend and status of the disease. RESULTS: In India, while 24 states are endemic for JE, Uttar Pradesh contributed more than 75% of cases during the recent past. Over the years, the seasonal trend has changed and the epidemic peak of the disease has advanced by one month. CONCLUSION: JE is closely associated with the pattern of precipitation, flooding and rice production systems. Analysis of trends and influencing factors will help in designing suitable strategies for the prevention and control of JE in the country. Continuous monitoring of vector populations and JE virus infection rates in vector mosquitoes will help in predicting an outbreak and in taking effective intervention measures. PMID- 28615604 TI - A study on delay in treatment of kala-azar patients in Bangladesh. AB - Visceral leishmaniasis (kala-azar) continues to be a major rural public health problem in Bangladesh. A cross-sectional study was carried out in two subdistricts of Mymensingh district from January 2006 to June 2007 to evaluate the delay kala-azar treatment. Suspected patients who attended to out patient department (OPD) were subjected to a dipstick test (RK39) for kala-azar. Sixty five from Bhaluka and 60 positive patients from Gafargaon subdistrict were enrolled. Most of the patients (80%) first visited nonqualified private practitioners, while only 15.2% consulted registered doctors. Fifty per cent were referred to the Upazilla health complex (UZHC) by the family members or relatives. About 49% and 43% patients required third and second health-care providers for kala-azar treatment, respectively. Patient delay ranged from 2 to 30 days; median 4 (IQR 3 to 7 days), the system delay ranged from 0 days to 225 days; median 54 (IQR 40-66 days). Residential status (p value <0.05) had impact on patient delay. Educational status and number of treatment providers had impact on system delay (p<0.05). System delay rather than patient delay is the important weakness of the kala-azar control programme in Bangladesh. Residence in rural areas, low educational background and treatment providers are associated with these delays. A proper educational programme may reduce the delay. PMID- 28615605 TI - Factors associated with high prevalence of pulmonary tuberculosis in HIV-infected people visiting for assessment of eligibility for highly active antiretroviral therapy in Kathmandu, Nepal. AB - BACKGROUND: Tuberculosis is the leading cause of deaths among HIV patients. In this study, we estimated the prevalence of pulmonary tuberculosis (PTB) and identified the factors/co-morbidities associated with active PTB in HIV-infected people visiting the national public health laboratory to assess their eligibility to receive highly active antiretroviral therapy. METHODS: A cross-sectional study was conducted to measure the prevalence of pulmonary tuberculosis. Data on probable risk factors in patients with and without PTB were compared, calculating the odds ratio as a measure of association. Factors showing significant association in univariate analyses were included in a stepwise backward logistic regression model to adjust for confounding. RESULTS: The prevalence of pulmonary tuberculosis was 32.4 % (95% confidence interval (CI) 30.25-34.56). In the univariate analysis, patients with PTB were more likely to be older, married, and have a longer duration since the diagnosis of HIV, diarrhoea, parasitic infection, lower CD4 T-cell counts, and lower CD4/CD8 ratio. However, the backward stepwise logistic regression revealed that only the CD4 T-cell count < 200/MUL (AOR 11.69, 95% CI 6.23-21.94), CD4 T-cell count 200-350/MUL (AOR 2.52, 95% CI 1.30-4.89), diarrhoea (AOR 2.77, 95% CI 1.78-4.31), parasitic infection (AOR 3.34, 95% CI 2.02-5.50) and 'sex with partner' as probable modes of transmission (AOR 0.44, 95% CI 0.20-0.93) were independently associated with pulmonary tuberculosis. CONCLUSION: A high prevalence of pulmonary tuberculosis was observed. Participants with tuberculosis were significantly more likely to have lower CD4 counts, diarrhoea, and parasitic infections. HIV treatment programmes should consider these factors for better outcomes. PMID- 28615606 TI - Compliance of off-premise alcohol retailers with the minimum purchase age law. AB - BACKGROUND: In Thailand, the 2008 Alcoholic Beverages Control Act set the minimum purchase age (MPA) at 20 years old in order to limit new drinkers as part of the overall alcohol control effort. This study aims to assess the compliance of off premise alcohol retailers with MPA restrictions and to identify factors affecting sales to adolescents. METHODS: A decoy protocol was used to quantify compliance of 417 alcohol retailers from three categories, namely grocers, modern minimarts and department stores. Multi-stage sampling was applied to obtain the samples in four provinces: Bangkok, Nakorn Sawan, Songkhla and Surin. Each alcohol retailer was visited twice by 17-19 year-old male and female adolescents who tried to buy alcohol. Information collected from focus groups and in-depth interviews with vendors and management officers were analysed for the qualitative methodology. RESULTS: Of all 834 buying attempts undertaken by the underage adolescent, 98.7% were successful in buying alcohol. Only 0.9% were asked for age and 0.1% were requested to show an ID card. Age and ID verifications were statistically significant to buying success as well as province, while number of vendors, gender and age of vendors and buyers, type of outlet, law cautions and advertisement signs in the outlet demonstrated no significant association. CONCLUSIONS: The results showed that vendors fail to comply with the law despite the fact that they know the law. Enforcement needs to be strengthened to effectively limit new drinkers. PMID- 28615607 TI - External quality assessment in blood group serology in the World Health Organization South-East Asia Region. AB - BACKGROUND: The quality of blood transfusion services (BTS) is essential for the treatment of patients who need blood or blood products. BTS involve several steps, including the acquisition of the donor's blood, blood grouping, unexpected antibody screening, blood storage, transfusion, etc. There is a need to check the effectiveness of all elements in the BTS can be assessed and monitored by an external quality assessment. AIM: To assess and evaluate the performance of ABO and Rh(D) blood grouping and unexpected antibody screening of the selected World Health Organization (WHO) South-East Asia Region Member country laboratories. METHODS: WHO Collaborating Centre on Strengthening Quality of Health Laboratories (Thailand) organized a regional external quality assessment scheme for blood group serology (REQAS-BGS) between 2002 and 2008 for laboratories in countries of the WHO South-East Asia Region. Test items for ABO and Rh(D) blood groupings and unexpected antibody screening and identification were distributed three cycles per year to BTS laboratories in Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka and Thailand. By the end of the project, a total of 20 BTS laboratories had participated for differing lengths of time. RESULTS: It was found that 87.5%, 93.3%, 81.3%, 92.3%, 100% and 87.5% of laboratories returned the test results in 2002, 2003, 2004, 2006, 2007 and 2008, respectively. Laboratories with excellent quality or a trend of quality improvement for ABO and Rh(D) blood grouping, unexpected antibody screening and identification during the six years were 60% (12/20), 50% (10/20), 52.9% (9/17) and 81.8% (9/11), respectively. At the initiation of the scheme, most laboratories were using substandard methods for ABO and Rh blood groupings, i.e. performing only direct blood grouping alone but subsequently adopted the standard methods, i.e. performing both direct and reverse blood groupings. CONCLUSION: REQAS-BGS in South-East Asia countries has been useful for assessing, monitoring and improving the quality of testing. Challenges such as high costs and regulatory requirements for international shipment of blood samples could be solved by amending the regulation(s) for shipment, or establishing a national EQAS. PMID- 28615608 TI - Prevalence of group A genotype human rotavirus among children with diarrhoea in Nepal, 2009-2011. AB - BACKGROUND: Rotavirus as a causative agent of childhood diarrhea is known to cause serious illness among children less than 5 years of age. This study examined the epidemiology of rotavirus disease burden and diversity of G and P genotypes of rotavirus in Nepal. METHODS: Stool samples were tested for rotavirus by Enzyme Immuno Assay and Group A rotaviruses were detected by using both ELISA and RT-PCR in 2718 samples between 2009 and 2011. RESULTS: Rotavirus was more frequently detected among inpatients (28.5%) than outpatients (15.2%). Over the three-year study period, 653 (24.4%) cases were positive for rotavirus by ELISA. Genotyping by RT-PCR was done on 638 samples. The most prevalent genotype was G12P [6] (60.4%). Mixed infections were not uncommon (14% in 2009, 29% in 2010 an 7% in 2011). However, 41 were partially typed and 23 were completely untyped over the study period. CONCLUSIONS: This study highlights the rotavirus disease burden and diversity of rotavirus strains circulating in Nepal. Continued sentinel surveillance will provide useful information to policy makers with regard to rotavirus vaccine introduction. PMID- 28615609 TI - Evidence of HPV subtypes linked with cervical cancer in Nepal. AB - OBJECTIVES: Cervical cancer is the commonest malignancy among women in Nepal but data are limited on which subtypes of human papillomavirus (HPV) are associated with cancer in this population. Now that vaccines against HPV types 16 and 18 are available, this evidence is of vital importance in obtaining further support for a vaccination programme. METHODS: Cervical swabs from 44 histologically confirmed invasive cervical cancer cases were obtained from two tertiary referral hospitals in Nepal. Evidence of HPV subtypes was identified using an HPV multiplex polymerase chain reaction (PCR), and confirmed at the Scottish HPV Virus Reference Laboratory. RESULTS: HPV types 16 and 18 were present in 70% of samples, along with other high-risk subtypes. HPV 6 and 11 were not observed. Epidemiological data assessment appeared to indicate that patient age, age of marriage and age of first pregnancy were associated with increased HPV infection in patients. CONCLUSIONS: This study provides further evidence of the importance of HPV types 16 and 18 in cervical cancer in Nepal and adds support to a nationwide vaccination programme and the use of HPV detection in screening programmes. PMID- 28615610 TI - Institutionalizing district level infant death review: an experience from southern India. AB - BACKGROUND: An Infant Death Review (IDR) programme was developed and implemented in two districts of Karnataka. OBJECTIVE: We explored the processes that led to the development of the IDR programme with a view to improving the existing pilot programme and to ensuring its sustainability. METHODS: A sequential mixed-methods design was followed in which quantitative data collection (secondary data) was followed by qualitative data collection (in-depth interviews). Quantitative data were entered using EpiInfo (version 3.5.1) software and qualitative data were analysed manually. RESULTS: Apart from ascertaining the cause of infant deaths, the IDR Committee discusses social, economic, behavioural and health system issues that potentially contribute to the deaths. As a result of the IDR programme, key actors perceived an improvement in infant death reporting at district level, the development of a rapport with the local community, and elaboration of a feedback system for corrective actions. This has led to improved health care during pregnancy. CONCLUSIONS: We found that involvement of the different stakeholders in planning and implementing the IDR programme offered a platform for collective learning and action. Impediments to the success of the programme need to be addressed by corrective actions at all levels for its future sustainability. PMID- 28615611 TI - Health systems responsiveness and its correlates: evidence from family planning service provision in Sri Lanka. AB - BACKGROUND: The World Health Organization has described health systems responsiveness (HSR) as a multi-domain concept encompassing eight non-medical expectations of health-care service seekers. HSR is a valuable measure of health systems performance, providing policy-makers and service providers much information to improve services. This paper presents findings of a cross sectional survey conducted to assess HSR and its correlates through family planning (FP) services in Colombo district, Sri Lanka. METHODS: A Health Systems Responsiveness Assessment Questionnaire, developed and validated in Sri Lanka, was used. Trained interviewers administered the questionnaire in 38 FP clinics randomly selected to sample 1520 clients. RESULTS: The rating of responsiveness as 'good' for six domains ranged from 88% (n=1338) to 72% (n=1094). The overall HSR was rated to be 'good' by 83.4% (1268). Ethnicity being majority Sinhalese, persons who were currently employed and those using oral contraceptive pills (OCP) or condoms were negatively associated with rating of HSR. Positive associations with the HSR assessment were a family income of less than Rs 40 000 (US$ 303) per month, satisfaction with current FP method, use of only one method within the past year, use of only one FP clinic within the past year, health service provider being a medical officer, intention to use the FP clinic services in future, and satisfaction with overall services of the clinic. CONCLUSIONS: Though overall HSR was rated by the majority as 'good', some aspects need more attention in delivering FP services. PMID- 28615612 TI - Challenges faced by skilled birth attendants in providing antenatal and intrapartum care in selected rural areas of Myanmar. AB - BACKGROUND: In Myanmar a large proportion of antenatal and intrapartum care in rural areas is provided by skilled birth attendants (SBAs), this study assessed the coverage by these health workers of all births, their adherence to service guidelines, and community opinion on the antenatal and delivery care they give in two rural health centres in Pathein Township, Ayeyarwaddy Region to identify the challenges and improve antenatal and intrapartum service delivery provided by the SBAs. METHOD: A structured questionnaire was used to interview 304 women who had infants under one year of age, and in-depth interviews were held with 12 SBAs and 10 community members. RESULTS: Of the 304 pregnancies, 93% had received antenatal care (ANC); 97% of these were covered by SBAs at an average 15 weeks' gestation. The average frequency of ANC visits was 9. Rates of home and hospital deliveries were 84.5% and 13.8% respectively. Among home deliveries, use rate of SBA was 51.4%, while for postnatal care, 31.3% was given by unskilled providers (traditional birth attendants (TBAs) 17.5%, auxiliary midwives (AMWs),13.8%). Multivariate analysis showed that interviewees aged 30 years and below (OR=0.468, P=0.046), with an education at primary level and below that of husband (OR=0.391, P=0.007) or not residing in the village of the rural/station health centre (OR=0.457, P=0.011) were significantly less likely to use SBAs. The categories of supervision, referral, and health education activities of SBAs were not in line with service guidelines. The main reasons were lack of access and community acceptance of TBAs. CONCLUSION: Heavy workload, geographical location, transportation and financial concerns were major challenges for SBAs, along with community compliance and mutual coordination. Good communication and service management skills were important to overcome these challenges. PMID- 28615613 TI - Epidemiologic investigation of excess maternal and neonatal deaths and evidence based low-cost public health interventions - Ignaz Semmelweis: the etiology, concept and prophylaxis of child bed fever[1]. PMID- 28615614 TI - Effects of Connexin43 Overexpression on U251 Cell Growth, Migration, and Apoptosis. AB - BACKGROUND Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with a high incidence in adults. Connexin43 (Cx43) has general roles in tumorigenesis and is expressed in U251 glioma cells. Accordingly, the effects of Cx43 on the growth, migration, and apoptosis and the underlying mechanisms mediating Cx43-dependent migration and apoptosis were examined in U251 cells. MATERIAL AND METHODS A Cx43-overexpressing U251 cell line was generated to analyze the effects of Cx43 overexpression on cell growth, wound healing, and apoptosis-related protein expression after treatment with temozolomide. RESULTS The growth rate of U251 cells overexpressing Cx43 was significantly lower than that of parental wild-type cells, and cell morphology was considerably altered. The expression level of Bcl-2 was higher and the expression levels of Bax and caspase-3 were lower in cells overexpressing Cx43 than in wild-type cells. Additionally, the Bax/Bcl-2 ratio decreased. CONCLUSIONS Cx43 inhibited the growth of U251 cells, promoted morphological changes and migration, and inhibited apoptosis via a mitochondria-associated pathway. PMID- 28615615 TI - STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis. AB - BACKGROUND Macrophages are highly heterogeneous and plastic cells that are involved in all stages of atherogenesis. They can undergo polarization by shifting between M1 and M2 functional phenotypes. However, the role of macrophage polarization and the molecular mechanism in modulating atherosclerotic plaque stability remain incompletely understood. Our study investigated the role of STAT6 in regulating macrophage phenotypes to affect atherosclerotic plaque stability. MATERIAL AND METHODS A murine atherosclerosis model with vulnerable plaques was induced with high-cholesterol diet and PCCP surgeries in ApoE-/- mice. Murine macrophages RAW264.7 treated with ox-LDL or IL-4 were used to simulate the in vitro process. pcDNA3.1(-)/STAT6-expressing vectors were transfected into RAW264.7 to evaluate its effect on cell polarization and the involved molecules. RESULTS Unstable plaques presented significantly increased M1 markers (CD86 and iNOS) and less M2 markers (Arg-1 and TGF-beta) than the stable plaques. Moreover, we found that STAT6 and p-STAT6 were greatly decreased in the vulnerable plaques and ox-LDL-induced macrophages, while their expression was elevated after IL-4 stimulation. The overexpression of STAT6 substantially reversed the ox-LDL-stimulated macrophage apoptosis and lipid accumulation. STAT6 upregulation promoted the differentiation of macrophage to M2 subtype as reflected by the increased expression of Arg-1 and TGF-beta. Furthermore, we found that STAT6 overexpression activated the Wnt-beta-catenin signaling by enhancing the translocation of beta-catenin, while beta-catenin suppression inhibited STAT6 overexpression-induced M2 polarization. CONCLUSIONS STAT6 facilitated atherosclerotic plaque stabilization by promoting the polarization of macrophages to M2 subtype and antagonizing ox-LDL-induced cell apoptosis and lipid deposition in a Wnt-beta-catenin-dependent manner. PMID- 28615616 TI - Early-Stage Mucinous Ovarian Adenocarcinoma with Extensive Clotting in a Previously Healthy Young Female Patient: An Uncommon Presentation of a Relatively Uncommon Disease. AB - BACKGROUND Mucinous ovarian adenocarcinoma is one of the less common epithelial cancers of the ovaries, and typically does not occur in younger women. Nearly all mucinous ovarian adenocarcinomas present with early-stage disease without significant sequelae of cancer, such as clotting. Anchoring bias is a common problem in medicine that has been shown to significantly affect physician decision-making. CASE REPORT We present the case of a 24-year-old healthy female Chinese immigrant with no significant past medical history, who presented with a subacute history of nonproductive cough and shortness of breath with exertion. Initial workup was directed towards diagnosis of tuberculosis and other infectious etiologies due to anchoring to patient's nationality and her positive family history for tuberculosis. She was eventually diagnosed with extensive bilateral pulmonary emboli and bilateral deep vein thromboses as well as a right ventricular thrombus. This extensive clot burden helped lead to the diagnosis of mucinous ovarian adenocarcinoma. CONCLUSIONS This case is significant not only because the diagnosis of mucinous ovarian adenocarcinoma is uncommon in healthy young females under the age of 25, but, more importantly, because such extensive pulmonary emboli and deep vein thromboses in a young female with local/early stage ovarian cancer is very rare. This case is also significant because it serves as an important reminder of the risks of anchoring bias in skewing perceptions and delaying the correct diagnosis by physicians. PMID- 28615617 TI - Flexible integration of free-standing nanowires into silicon photonics. AB - Silicon photonics has been developed successfully with a top-down fabrication technique to enable large-scale photonic integrated circuits with high reproducibility, but is limited intrinsically by the material capability for active or nonlinear applications. On the other hand, free-standing nanowires synthesized via a bottom-up growth present great material diversity and structural uniformity, but precisely assembling free-standing nanowires for on demand photonic functionality remains a great challenge. Here we report hybrid integration of free-standing nanowires into silicon photonics with high flexibility by coupling free-standing nanowires onto target silicon waveguides that are simultaneously used for precise positioning. Coupling efficiency between a free-standing nanowire and a silicon waveguide is up to ~97% in the telecommunication band. A hybrid nonlinear-free-standing nanowires-silicon waveguides Mach-Zehnder interferometer and a racetrack resonator for significantly enhanced optical modulation are experimentally demonstrated, as well as hybrid active-free-standing nanowires-silicon waveguides circuits for light generation. These results suggest an alternative approach to flexible multifunctional on-chip nanophotonic devices.Precisely assembling free-standing nanowires for on-demand photonic functionality remains a challenge. Here, Chen et al. integrate free-standing nanowires into silicon waveguides and show all optical modulation and light generation on silicon photonic chips. PMID- 28615619 TI - Excess reciprocity distorts reputation in online social networks. AB - The peer-to-peer (P2P) economy relies on establishing trust in distributed networked systems, where the reliability of a user is assessed through digital peer-review processes that aggregate ratings into reputation scores. Here we present evidence of a network effect which biases digital reputation, revealing that P2P networks display exceedingly high levels of reciprocity. In fact, these are much higher than those compatible with a null assumption that preserves the empirically observed level of agreement between all pairs of nodes, and rather close to the highest levels structurally compatible with the networks' reputation landscape. This indicates that the crowdsourcing process underpinning digital reputation can be significantly distorted by the attempt of users to mutually boost reputation, or to retaliate, through the exchange of ratings. We uncover that the least active users are predominantly responsible for such reciprocity induced bias, and that this fact can be exploited to obtain more reliable reputation estimates. Our findings are robust across different P2P platforms, including both cases where ratings are used to vote on the content produced by users and to vote on user profiles. PMID- 28615618 TI - Comparative genomics and transcriptomics of Escherichia coli isolates carrying virulence factors of both enteropathogenic and enterotoxigenic E. coli. AB - Escherichia coli that are capable of causing human disease are often classified into pathogenic variants (pathovars) based on their virulence gene content. However, disease-associated hybrid E. coli, containing unique combinations of multiple canonical virulence factors have also been described. Such was the case of the E. coli O104:H4 outbreak in 2011, which caused significant morbidity and mortality. Among the pathovars of diarrheagenic E. coli that cause significant human disease are the enteropathogenic E. coli (EPEC) and enterotoxigenic E. coli (ETEC). In the current study we use comparative genomics, transcriptomics, and functional studies to characterize isolates that contain virulence factors of both EPEC and ETEC. Based on phylogenomic analysis, these hybrid isolates are more genomically-related to EPEC, but appear to have acquired ETEC virulence genes. Global transcriptional analysis using RNA sequencing, demonstrated that the EPEC and ETEC virulence genes of these hybrid isolates were differentially expressed under virulence-inducing laboratory conditions, similar to reference isolates. Immunoblot assays further verified that the virulence gene products were produced and that the T3SS effector EspB of EPEC, and heat-labile toxin of ETEC were secreted. These findings document the existence and virulence potential of an E. coli pathovar hybrid that blurs the distinction between E. coli pathovars. PMID- 28615620 TI - Understanding 'saturation' of radar signals over forests. AB - There is an urgent need to quantify anthropogenic influence on forest carbon stocks. Using satellite-based radar imagery for such purposes has been challenged by the apparent loss of signal sensitivity to changes in forest aboveground volume (AGV) above a certain 'saturation' point. The causes of saturation are debated and often inadequately addressed, posing a major limitation to mapping AGV with the latest radar satellites. Using ground- and lidar-measurements across La Rioja province (Spain) and Denmark, we investigate how various properties of forest structure (average stem height, size and number density; proportion of canopy and understory cover) simultaneously influence radar backscatter. It is found that increases in backscatter due to changes in some properties (e.g. increasing stem sizes) are often compensated by equal magnitude decreases caused by other properties (e.g. decreasing stem numbers and increasing heights), contributing to the apparent saturation of the AGV-backscatter trend. Thus, knowledge of the impact of management practices and disturbances on forest structure may allow the use of radar imagery for forest biomass estimates beyond commonly reported saturation points. PMID- 28615621 TI - Combination of scanning probe technology with photonic nanojets. AB - Light focusing through a microbead leads to the formation of a photonic nanojet functional for enhancing the spatial resolution of traditional optical systems. Despite numerous works that prove this phenomenon, a method to appropriately translate the nanojet on top of a region of interest is still missing. Here, by using advanced 3D fabrication techniques we integrated a microbead on an AFM cantilever thus realizing a system to efficiently position nanojets. This fabrication approach is robust and can be exploited in a myriad of applications, ranging from microscopy to Raman spectroscopy. We demonstrate the potential of portable nanojets by imaging different sub-wavelength structures. Thanks to the achieved portability, we were able to perform a detailed optical characterization of the resolution enhancement induced by the microbead, which sheds light into the many contradictory resolution claims present in literature. Our conclusions are strongly supported by rigorous data analysis and by numerical simulations, all in perfect agreement with experimental results. PMID- 28615622 TI - A Russian Dolls ordering of the Hadamard basis for compressive single-pixel imaging. AB - Single-pixel imaging is an alternate imaging technique particularly well-suited to imaging modalities such as hyper-spectral imaging, depth mapping, 3D profiling. However, the single-pixel technique requires sequential measurements resulting in a trade-off between spatial resolution and acquisition time, limiting real-time video applications to relatively low resolutions. Compressed sensing techniques can be used to improve this trade-off. However, in this low resolution regime, conventional compressed sensing techniques have limited impact due to lack of sparsity in the datasets. Here we present an alternative compressed sensing method in which we optimize the measurement order of the Hadamard basis, such that at discretized increments we obtain complete sampling for different spatial resolutions. In addition, this method uses deterministic acquisition, rather than the randomized sampling used in conventional compressed sensing. This so-called 'Russian Dolls' ordering also benefits from minimal computational overhead for image reconstruction. We find that this compressive approach performs as well as other compressive sensing techniques with greatly simplified post processing, resulting in significantly faster image reconstruction. Therefore, the proposed method may be useful for single-pixel imaging in the low resolution, high-frame rate regime, or video-rate acquisition. PMID- 28615623 TI - Proboscis infection route of Beauveria bassiana triggers early death of Anopheles mosquito. AB - Entomopathogenic fungi are known to control vector mosquito populations. Thus, understanding the infection dynamics of entomopathogenic fungi is crucial for the effective control of insect pests such as mosquitoes. We investigated the dynamics of Beauveria bassiana s.l. 60-2 infection of Anopheles stephensi by exposing the mosquito to fungus-impregnated filter paper through two infection routes and then comparing the mortality and extent of infection. Fungal development was observed after using this inoculation method with both the tarsus route and the proboscis route, but early mosquito death occurred only after infection through the proboscis route. Fungal hyphae invaded almost all the tissues and organs before or after the death of the host, and fungal invasion of the brain was highly correlated with mortality. Moreover, although all mosquitoes that were alive at various time points after inoculation showed no fungal infection in the brain, fungal infection was detected in the brain in all dead mosquitoes. Our results suggest that fungal invasion of the brain represents one of the factors affecting mortality, and that the proboscis route of infection is critical for the early death of vector mosquitoes. PMID- 28615624 TI - Circulation of HAdV-41 with diverse genome types and recombination in acute gastroenteritis among children in Shanghai. AB - Human adenovirus F (HAdV-F) is one of the major causative species detected in acute gastroenteritis in children worldwide. HAdV-F is composed of serotypes 40 and 41. Most studies have reported the prevalence of HAdV-41 and focused on its epidemiologic characteristics. In this study, seventeen samples were identified as HAdV-41 out of 273 fecal specimens from children with acute diarrhea in Shanghai. Five isolates were isolated and subjected to whole genome sequencing and analysis to characterize the genetic variation and evolution. Full genome analysis revealed low genetic variation (99.07-99.92% identity) among the isolates, and InDels are observed in the E2A gene and the hexon gene compared to the reference strain NIVD103. Phylogenetic analysis showed that all isolates mainly formed two genome-type clusters but with incongruence in the trees of whole genomes and individual genes. The recombination breakpoints of the five isolates were inferred by the Recombination Detection Program (RDP) and varied in the number and location of the recombination events, indicating different evolution origins. Overall, our study highlights the genetic diversity of HAdV-41 isolates circulating in Shanghai, which may have evolved from inter-strain recombination. PMID- 28615625 TI - Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules. AB - In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp70 proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp90 (geldanamycin) or Abl kinase (imatinib). The results of NMR studies revealed that Az associates with an ATPase domain of Hsc70 and thus blocks ATP binding to the protein. Observations made in the cell study indicated that Az treatment promotes leukemia cell death by activating caspase dependent apoptosis without affecting the caspase-independent apoptotic pathway. Importantly, the hybrids composed of Az and geldanamycin, which have high inhibitory activities towards both Hsp70 and Hsp90, exhibit enhanced anti leukemia activity relative to the individual inhibitors. However, the Az and imatinib hybrids have weak inhibitory activities towards Hsp70 and Abl, and display lower cytotoxicity against leukemia cells compared to those of the individual constituents. The results of a mechanistic study showed that the active hybrid molecules promote leukemia cell death through a caspase-dependent apoptotic pathway. Taken together, the findings suggest that Hsp70 inhibitors as well as their hybrids can serve as potential anti-leukemia agents. PMID- 28615626 TI - Neuronal P2X7 receptor-induced reactive oxygen species production contributes to nociceptive behavior in mice. AB - ATP can activate a variety of pathways through P2 purinoreceptors, leading to neuroprotection and pathology in the CNS. Among all P2X receptors, the P2X7 receptor (P2X7R) is a well-defined therapeutic target for inflammatory and neuropathic pain. Activation of P2X7R can generate reactive oxygen species (ROS) in macrophages and microglia. However, the role of ROS in P2X7R-induced pain remains un explored. Here, we investigated the downstream effects of neuronal P2X7R activation in the spinal cord. We found that ATP induces ROS production in spinal cord dorsal horn neurons, an effect eliminated by ROS scavenger N-tert butyl-alpha-phenylnitrone (PBN) and P2X7R antagonist A438079. A similar effect was observed with a P2X7R agonist, BzATP, and was attenuated by a NADPH oxidase inhibitor apocynin. Intrathecal administration of BzATP resulted in ROS production in the spinal cord and oxidative DNA damage in dorsal horn neurons. BzATP also induced robust biphasic spontaneous nociceptive behavior. Pre treatment with A438079 abolished all BzATP-induced nociceptive behaviors, while ROS scavengers dose-dependently attenuated the secondary response. Here, we provide evidence that neuronal P2X7R activation leads to ROS production and subsequent nociceptive pain in mice. Together, the data indicate that P2X7R induced ROS play a critical role in the P2X7R signaling pathway of the CNS. PMID- 28615627 TI - Reduction in Migratory Phenotype in a Metastasized Breast Cancer Cell Line via Downregulation of S100A4 and GRM3. AB - To investigate phenotypic and genotypic alterations before and after bone metastasis, we conducted genome-wide mRNA profiling and DNA exon sequencing of two cell lines (TMD and BMD) derived from a mouse xenograft model. TMD cells were harvested from the mammary fat pad after transfecting MDA-MB-231 breast cancer cells, while BMD cells were isolated from the metastasized bone. Compared to BMD cells, TMD cells exhibited higher cellular motility. In contrast, BMD cells formed a spheroid with a smoother and more circular surface when co-cultured with osteoblasts. In characterizing mRNA expression using principal component analysis, S100 calcium-binding protein A4 (S100A4) was aligned to a principal axis associated with metastasis. Partial silencing of S100A4 suppressed migratory capabilities of TMD cells, while Paclitaxel decreased the S100A4 level and reduced TMD's cellular motility. DNA mutation analysis revealed that the glutamate metabotropic receptor 3 (GRM3) gene gained a premature stop codon in BMD cells, and silencing GRM3 in TMD cells altered their spheroid shape closer to that of BMD cells. Collectively, this study demonstrates that metastasized cells are less migratory due in part to the post-metastatic downregulation of S100A4 and GRM3. Targeting S100A4 and GRM3 may help prevent bone metastasis. PMID- 28615628 TI - Glucocorticoids ameliorate TGF-beta1-mediated epithelial-to-mesenchymal transition of airway epithelium through MAPK and Snail/Slug signaling pathways. AB - Chronic rhinosinusitis with nasal polyps (CRSwNP) is closely associated with tissue remodeling. Epithelial-to-mesenchymal transition (EMT), a process of tissue remodeling, can be a therapeutic target of CRSwNP. Glucocorticoids are a type of steroid hormone that is used primarily in medical therapy for patients with CRSwNP; however, their effects on EMT in the airway epithelium remain unknown. To investigate the effects of dexamethasone and fluticasone propionate, a class of glucocorticoids, on transforming growth factor-beta1 (TGF-beta1) induced EMT, we used A549 cells, human primary nasal epithelial cells (hPNECs) and ex vivo organ culture of the inferior turbinate. TGF-beta1 induced changes in cell morphology, suppressed the expression of E-cadherin and enhanced the expression of a-smooth muscle actin, vimentin and fibronectin in A549 cells. However, glucocorticoids inhibited EMT, migration and invasion enhancement by TGF beta1. We found that the induction of phosphorylated ERK, p38 and the activity of Snail and Slug transcription factors by TGF-beta1 were suppressed by glucocorticoids. Glucocorticoids also had a similar effect in hPNECs and ex vivo organ cultures of the inferior turbinate. These findings suggest that glucocorticoids might be a useful therapy for preventing tissue remodeling by blocking the EMT initiated by TGF-beta1-induced MAPK and Snail/Slug signaling pathways in CRSwNP. PMID- 28615629 TI - Effect Of Microgravity On Aromatase Expression In Sertoli Cells. AB - Cytochrome P450-aromatase catalyzes estrogen biosynthesis from C19 steroids. In the testis, Sertoli cells express P450-aromatase and represent the primary source of estrogen during prepuberal age. This study focused on the effect of simulated microgravity (SM) on aromatase expression in primary mouse Sertoli cells. When cultured in Rotary Cell Culture System (RCCS), Sertoli cells, formed multicellular three dimensional spheroids (3D). Biological properties were first analyzed in terms of viability, cell cycle, expression of cytoskeletal components and growth factors in comparison to Sertoli cells cultured in spheroids at unit gravity (G). SM did not affect cell viability and proliferation, nor expression of the main cytoskeleton proteins and of growth factors like Kit Ligand (KL) and glial derived neurotrophic factor (GDNF). On the other hand, SM caused a strong increase in P450 aromatase mRNA and protein expression. Interestingly, P450 aromatase was no more inducible by 8-Br-cAMP. The presence of a functional aromatase was confirmed by enrichment of 17beta-estradiol released in the medium by androgen precursors. We concluded that SM causes a significant upregulation of aromatase gene expression in Sertoli cells, leading to a consequent increase in 17beta-estradiol secretion. High level of 17beta-estradiol in the testis could have potentially adverse effects on male fertility and testicular cancer. PMID- 28615630 TI - Non-muscle myosin II is required for correct fate specification in the Caenorhabditis elegans seam cell divisions. AB - During development, cell division often generates two daughters with different developmental fates. Distinct daughter identities can result from the physical polarity and size asymmetry itself, as well as the subsequent activation of distinct fate programmes in each daughter. Asymmetric divisions are a feature of the C. elegans seam lineage, in which a series of post-embryonic, stem-like asymmetric divisions give rise to an anterior daughter that differentiates and a posterior daughter that continues to divide. Here we have investigated the role of non-muscle myosin II (nmy-2) in these asymmetric divisions. We show that nmy-2 does not appear to be involved in generating physical division asymmetry, but nonetheless is important for specifying differential cell fate. While cell polarity appears normal, and chromosome and furrow positioning remains unchanged when nmy-2 is inactivated, seam cell loss occurs through inappropriate terminal differentiation of posterior daughters. This reveals a role for nmy-2 in cell fate determination not obviously linked to the primary polarity determination mechanisms it has been previously associated with. PMID- 28615631 TI - Inverse problem for multi-body interaction of nonlinear waves. AB - The inverse problem is studied in multi-body systems with nonlinear dynamics representing, e.g., phase-locked wave systems, standard multimode and random lasers. Using a general model for four-body interacting complex-valued variables we test two methods based on pseudolikelihood, respectively with regularization and with decimation, to determine the coupling constants from sets of measured configurations. We test statistical inference predictions for increasing number of sampled configurations and for an externally tunable temperature-like parameter mimicing real data noise and helping minimization procedures. Analyzed models with phasors and rotors are generalizations of problems of real-valued spherical problems (e.g., density fluctuations), discrete spins (Ising and vectorial Potts) or finite number of states (standard Potts): inference methods presented here can, then, be straightforward applied to a large class of inverse problems. The high versatility of the exposed techniques also concerns the number of expected interactions: results are presented for different graph topologies, ranging from sparse to dense graphs. PMID- 28615633 TI - Local particle-hole pair excitations by SU(2) symmetry fluctuations. AB - Understanding the pseudo-gap phase which opens in the under-doped regime of cuprate superconductors is one of the most enduring challenges of the physics of these compounds. A depletion in the electronic density of states is observed, which is gapping out part of the Fermi surface, leading to the formation of mysterious lines of massless excitations- the Fermi arcs. Here we give a new theoretical account of the physics of the pseudo-gap phase in terms of the emergence of local patches of particle-hole pairs generated by SU(2) symmetry fluctuations. The proliferation of these local patches accounts naturally for the robustness of the pseudo-gap phase to disturbances like disorder or magnetic field and is shown to gap out part of the Fermi surface, leading to the formation of the Fermi arcs. Most noticeably, we show that these patches induce a modulated charge distribution on the Oxygen atoms, in remarkable agreement with recent X ray and STM observations. PMID- 28615632 TI - Genome-wide analysis suggests a differential microRNA signature associated with normal and diabetic human corneal limbus. AB - Small non-coding RNAs, in particular microRNAs (miRNAs), regulate fine-tuning of gene expression and can impact a wide range of biological processes. However, their roles in normal and diseased limbal epithelial stem cells (LESC) remain unknown. Using deep sequencing analysis, we investigated miRNA expression profiles in central and limbal regions of normal and diabetic human corneas. We identified differentially expressed miRNAs in limbus vs. central cornea in normal and diabetic (DM) corneas including both type 1 (T1DM/IDDM) and type 2 (T2DM/NIDDM) diabetes. Some miRNAs such as miR-10b that was upregulated in limbus vs. central cornea and in diabetic vs. normal limbus also showed significant increase in T1DM vs. T2DM limbus. Overexpression of miR-10b increased Ki-67 staining in human organ-cultured corneas and proliferation rate in cultured corneal epithelial cells. MiR-10b transfected human organ-cultured corneas showed downregulation of PAX6 and DKK1 and upregulation of keratin 17 protein expression levels. In summary, we report for the first time differential miRNA signatures of T1DM and T2DM corneal limbus harboring LESC and show that miR-10b could be involved in the LESC maintenance and/or their early differentiation. Furthermore, miR-10b upregulation may be an important mechanism of corneal diabetic alterations especially in the T1DM patients. PMID- 28615634 TI - Transcriptome profiling of Cucumis metuliferus infected by Meloidogyne incognita provides new insights into putative defense regulatory network in Cucurbitaceae. AB - Root-knot nematodes (RKN) represent extensive challenges to Cucurbitaceae crops. However, Cucumis metuliferus (Cm) is known to be resistant to Meloidogyne incognita (Mi) infections. Thus, analysis of differentially expressed genes may lead to a comprehensive gene expression profiling of the incompatible Cm-Mi interaction. In this study, the time-course transcriptome of Cm against Mi infection was monitored using RNA-Seq. More than 170000 transcripts were examined in Cm roots, and 2430 genes were subsequently identified as differentially expressed in response to Mi infection. Based on function annotation and orthologs finding, the potential mechanism of transcriptional factor, cytoskeleton, pathogen-related genes and plant hormone were assessed at the transcription level. A comparison of gene expression levels between Mi-infected Cm and cucumber plants revealed that cytoskeleton-related genes are key regulators of Cm resistance to Mi. We herein discuss the dual nature of cytoskeleton-related genes in the susceptibility and resistance of plant hosts to Mi. Our observations provide novel insights into the responses of Cm to Mi at the transcriptome level. The data generated in this study may be useful for elucidating the mechanism underlying resistance to RKNs in cucurbitaceous crops. PMID- 28615635 TI - DNA Backbone Sulfur-Modification Expands Microbial Growth Range under Multiple Stresses by its anti-oxidation function. AB - DNA phosphorothioate (PT) modification is a sulfur modification on the backbone of DNA introduced by the proteins DndA-E. It has been detected within many bacteria isolates and metagenomic datasets, including human pathogens, and is considered to be widely distributed in nature. However, little is known about the physiological function of this modification, and thus its evolutionary significance and application potential remains largely a mystery. In this study, we focused on the advantages of DNA PT modification to bacterial cells coping with environmental stresses. We show that the mesophile Escherichia coli and the extremophile Shewanella piezotolerans both expanded their growth ranges following exposure to extreme temperature, salinity, pH, pressure, UV, X-ray and heavy metals as a result of DNA phophorothioation. The phophorothioated DNA reacted to both H2O2 and hydroxyl radicals in vivo, and protected genomic DNA as well as sensitive enzymes from intracellular oxidative damage. We further demonstrate that this process has evolved separate from its associated role in DNA restriction and modification. These findings provide a physiological role for a covalent modification widespread in nature and suggest possible applications in biotechnology and biomedicine. PMID- 28615636 TI - Autotransporter domain-dependent enzymatic analysis of a novel extremely thermostable carboxylesterase with high biodegradability towards pyrethroid pesticides. AB - The EstPS1 gene, which encodes a novel carboxylesterase of Pseudomonas synxantha PS1 isolated from oil well-produced water, was cloned and sequenced. EstPS1 has an open reading frame of 1923 bp and encodes the 640-amino acid carboxylesterase (EstPS1), which contains an autotransporter (AT) domain (357-640 amino acids). Homology analysis revealed that EstPS1 shared the highest identity (88%) with EstA from Pseudomonas fluorescens A506 (NCBI database) and belonged to the carboxylesterase family (EC 3.1.1.1). The optimum pH and temperature of recombinant EstPS1 were found to be 8.0 and 60 degrees C, respectively. EstPS1 showed high thermostability, and the half-lives (T1/2 thermal inactivation) at 60, 70, 80, 90, and 100 degrees C were 14 h, 2 h, 31 min, 10 min, and 1 min, respectively. To understand the role of the AT domain in carboxylesterase, AT domain-truncated carboxylesterase (EstPS1DeltaAT) was generated. EstPS1DeltaAT showed a clearly decreased secretion rate, owing to the AT domain strongly improved secretory expression in the heterogeneous system. EstPS1 degraded various pyrethroid pesticides, and hydrolysis efficiencies were dependent on the pyrethroid molecular structure. EstPS1 degraded all the tested pyrethroid pesticides and hydrolysed the p-nitrophenyl esters of medium-short-chain fatty acids, indicating that EstPS1 is an esterase with broad specificity. PMID- 28615637 TI - Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. AB - Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion. PMID- 28615638 TI - Pharmacodynamic and pharmacokinetic assessment of pulmonary rehabilitation mixture for the treatment of pulmonary fibrosis. AB - Pulmonary rehabilitation mixture (PRM), a Chinese herbal medicine formula, has been used to treat pulmonary fibrosis for decades. In this study, we systematically evaluated the pharmacodynamic and pharmacokinetic performance of PRM. The pharmacodynamic results showed that PRM could improve the condition of CoCl2-stimulated human type II alveolar epithelial cells, human pulmonary microvascular endothelial cells, human lung fibroblasts and pulmonary fibrosis rats induced by bleomycin, PRM treatment reduced the expression of platelet derived growth factor, fibroblast growth factor, toll-like receptor 4, high mobility group box protein 1 and hypoxia-inducible factor 1alpha. In the pharmacokinetic study, an accurate and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method was developed and validated for the simultaneous determination of calycosin, calycosin-7-O-glucoside, formononetin, ononin and mangiferin of PRM in the rat plasma for the first time. The method was then successfully applied to the comparative pharmacokinetic study of PRM in normal and pulmonary fibrosis rats. The five constituents could be absorbed in the blood after the oral administration of PRM and exhibited different pharmacokinetic behaviors in normal and pulmonary fibrosis rats. In summary, PRM exhibited a satisfactory pharmacodynamic and pharmacokinetic performance, which highlights PRM as a potential multi-target oral drug for the treatment of pulmonary fibrosis. PMID- 28615639 TI - Population-based study of effectiveness of neoadjuvant radiotherapy on survival in US rectal cancer patients according to age. AB - Recent cancer researches pay more attention to younger patients due to the variable treatment response among different age groups. Here we investigated the effectiveness of neoadjuvant radiation on the survival of younger and older patients in stage II/III rectal cancer. Data was obtained from Surveillance, Epidemiology, and End Results (SEER) database (n = 12801). Propensity score matching was used to balance baseline covariates according to the status of neoadjuvant radiation. Our results showed that neoadjuvant radiation had better survival benefit (Log-rank P = 3.25e-06) and improved cancer-specific 3-year (87.6%; 95% CI: 86.4-88.7% vs. 84.1%; 95% CI: 82.8-85.3%) and 5-year survival rates (78.1%; 95% CI: 76.2-80.1% vs. 77%; 95% CI: 75.3-78.8%). In older groups (>50), neoadjuvant radiation was associated with survival benefits in stage II (HR: 0.741; 95% CI: 0.599-0.916; P = 5.80e-3) and stage III (HR: 0.656; 95% CI 0.564-0.764; P = 5.26e-08). Interestingly, neoadjuvant radiation did not increase survival rate in younger patients (< = 50) both in stage II (HR: 2.014; 95% CI: 0.9032-4.490; P = 0.087) and stage III (HR: 1.168; 95% CI: 0.829-1.646; P = 0.372). Additionally, neoadjuvant radiation significantly decreased the cancer specific mortality in older patients, but increased mortality in younger patients. Our results provided new insights on the neoadjuvant radiation in rectal cancer, especially for the younger patients. PMID- 28615640 TI - Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices. AB - The benzodiazepine midazolam is widely used in critical care medicine. Midazolam has a clinically active metabolite, 1-hydroxymidazolam. The contribution of 1 hydroxymidazolam to the effects of midazolam is controversial. The aim of the current study was to compare the actions of midazolam and 1-hydroxymidazolam on network activity of cortical neurons. Midazolam depressed neuronal activity at a low concentration of 5 nM. When midazolam concentration was increased, it depressed neuronal discharge rates in a biphasic manner. In comparison, 1 hydroxymidazolam did not depress the cortical network activity at low nanomolar concentrations. Higher concentrations of 1-hydroxymidazolam consistently inhibited neuronal activity. Moreover, midazolam shortened cortical up states at low, but not at high concentrations, while the opposite effect was observed with 1-hydroxymidazolam. The network depressant action of midazolam at low concentrations was absent in slices from GABAA receptor alpha1(H101R)mutant mice. The alpha1(H101R)mutation renders alpha1-subunit containing GABAA receptors insensitive towards benzodiazepines. This GABAA receptor subtype is thought to mediate sedation. As midazolam is more potent than its metabolite 1 hydroxymidazolam, the major clinical effects are thus likely caused by midazolam itself. However, 1-hydroxymidazolam could add to the effects of midazolam, especially after the application of high doses of midazolam, and in case of impaired drug metabolism. PMID- 28615641 TI - An earlier revolution: genetic and genomic analyses reveal pre-existing cultural differences leading to Neolithization. AB - Archaeological evidence shows that, in the long run, Neolitization (the transition from foraging to food production) was associated with demographic growth. We used two methods (patterns of linkage disequilibrium from whole-genome SNPs and MSMC estimates on genomes) to reconstruct the demographic profiles for respectively 64 and 24 modern-day populations with contrasting lifestyles across the Old World (sub-Saharan Africa, south-eastern Asia, Siberia). Surprisingly, in all regions, food producers had larger effective population sizes (N e) than foragers already 20 k years ago, well before the Neolithic revolution. As expected, this difference further increased ~12-10 k years ago, around or just before the onset of food production. Using paleoclimate reconstructions, we show that the early difference in N e cannot be explained by food producers inhabiting more favorable regions. A number of mechanisms, including ancestral differences in census size, sedentism, exploitation of the natural resources, social stratification or connectivity between groups, might have led to the early differences in Ne detected in our analyses. Irrespective of the specific mechanisms involved, our results provide further evidence that long term cultural differences among populations of Palaeolithic hunter-gatherers are likely to have played an important role in the later Neolithization process. PMID- 28615642 TI - Skin sloughing in susceptible and resistant amphibians regulates infection with a fungal pathogen. AB - The fungal pathogen Batrachochytrium dendrobatidis (Bd) has been implicated in amphibian population declines globally. Given that Bd infection is limited to the skin in post-metamorphic amphibians, routine skin sloughing may regulate infection. Skin sloughing has been shown to reduce the number of cultivatable microbes on amphibian skin, and Bd infection increases skin sloughing rates at high loads. However, it is unclear whether species specific differences in skin sloughing patterns could regulate Bd population growth on the skin, and influence subsequent infection dynamics. We exposed five Australian frog species to Bd, and monitored sloughing rates and infection loads over time. Sloughing reduced Bd load on the ventral skin surface, in all five species, despite wide variation in susceptibility to disease. In the least susceptible species, an increase in sloughing rate occurred at lower infection loads, and sloughing reduced Bd load up to 100%, leading to infection clearance. Conversely, the drop in Bd load with sloughing was only temporary in the more susceptible species. These findings indicate that the ability of sloughing to act as an effective immune defence is species specific, and they have implications for understanding the pattern of Bd population growth on individual hosts, as well as population-level effects. PMID- 28615643 TI - Family aggression in a social lizard. AB - The evolution of family living is underpinned by conflict and cooperation between family members. While family groups can be maintained by reducing conflict between parents and offspring, interactions between siblings may play an equally important role. Here, we compared the level of aggressive interactions between siblings to that between parents and their offspring in the family living skink Liopholis whitii. Aggressive interactions occurred much more frequently between siblings and between fathers and offspring than between mothers and their offspring. These results suggest that ecological and social conditions that reduce conflict between siblings and between males and offspring will be fundamental in the evolutionary maintenance and diversification of family living in these lizards. PMID- 28615644 TI - miRNA profiling during antigen-dependent T cell activation: A role for miR-132 3p. AB - microRNAs (miRNAs) are tightly regulated during T lymphocyte activation to enable the establishment of precise immune responses. Here, we analyzed the changes of the miRNA profiles of T cells in response to activation by cognate interaction with dendritic cells. We also studied mRNA targets common to miRNAs regulated in T cell activation. pik3r1 gene, which encodes the regulatory subunits of PI3K p50, p55 and p85, was identified as target of miRNAs upregulated after T cell activation. Using 3'UTR luciferase reporter-based and biochemical assays, we showed the inhibitory relationship between miR-132-3p upregulation and expression of the pik3r1 gene. Our results indicate that specific miRNAs whose expression is modulated during T cell activation might regulate PI3K signaling in T cells. PMID- 28615645 TI - Intravascular forward-looking ultrasound transducers for microbubble-mediated sonothrombolysis. AB - Effective removal or dissolution of large blood clots remains a challenge in clinical treatment of acute thrombo-occlusive diseases. Here we report the development of an intravascular microbubble-mediated sonothrombolysis device for improving thrombolytic rate and thus minimizing the required dose of thrombolytic drugs. We hypothesize that a sub-megahertz, forward-looking ultrasound transducer with an integrated microbubble injection tube is more advantageous for efficient thrombolysis by enhancing cavitation-induced microstreaming than the conventional high-frequency, side-looking, catheter-mounted transducers. We developed custom miniaturized transducers and demonstrated that these transducers are able to generate sufficient pressure to induce cavitation of lipid-shelled microbubble contrast agents. Our technology demonstrates a thrombolysis rate of 0.7 +/- 0.15 percent mass loss/min in vitro without any use of thrombolytic drugs. PMID- 28615646 TI - Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis. AB - Hydrogen sulfide (H2S) has been recognized as a signalling molecule which affects the activity of ion channels and transporters in epithelial cells. The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial anion channel and a key regulator of electrolyte and fluid homeostasis. In this study, we investigated the regulation of CFTR by H2S. Human CFTR was heterologously expressed in Xenopus oocytes and its activity was electrophysiologically measured by microelectrode recordings. The H2S-forming sulphur salt Na2S as well as the slow-releasing H2S-liberating compound GYY4137 increased transmembrane currents of CFTR-expressing oocytes. Na2S had no effect on native, non-injected oocytes. The effect of Na2S was blocked by the CFTR inhibitor CFTR_inh172, the adenylyl cyclase inhibitor MDL 12330A, and the protein kinase A antagonist cAMPS-Rp. Na2S potentiated CFTR stimulation by forskolin, but not that by IBMX. Na2S enhanced CFTR stimulation by membrane-permeable 8Br-cAMP under inhibition of adenylyl cyclase-mediated cAMP production by MDL 12330A. These data indicate that H2S activates CFTR in Xenopus oocytes by inhibiting phosphodiesterase activity and subsequent stimulation of CFTR by cAMP-dependent protein kinase A. In epithelia, an increased CFTR activity may correspond to a pro-secretory response to H2S which may be endogenously produced by the epithelium or H2S-generating microflora. PMID- 28615647 TI - Differential synchrotron X-ray imaging markers based on the renal microvasculature for tubulointerstitial lesions and glomerulopathy. AB - High resolution synchrotron microtomography capable of revealing microvessels in three dimensional (3D) establishes distinct imaging markers of mouse kidney disease strongly associated to renal tubulointerstitial (TI) lesions and glomerulopathy. Two complementary mouse models of chronic kidney disease (CKD), unilateral ureteral obstruction (UUO) and focal segmental glomerulosclerosis (FSGS), were used and five candidates of unique 3D imaging markers were identified. Our characterization to differentially reflect the altered microvasculature of renal TI lesions and/or glomerulopathy demonstrated these image features can be used to differentiate the disease status and the possible cause therefore qualified as image markers. These 3D imaging markers were further correlated with the histopathology and renal microvessel-based molecular study using antibodies against vascular endothelial cells (CD31), the connective tissue growth factor or the vascular endothelial growth factor. We also found that these 3D imaging markers individually characterize the development of renal TI lesions or glomerulopathy, quantitative and integrated use of all of them provide more information for differentiating the two renal conditions. Our findings thus establish a practical strategy to characterize the CKD-associated renal injuries by the microangiography-based 3D imaging and highlight the impact of dysfunctional microvasculature as a whole on the pathogenesis of the renal lesions. PMID- 28615649 TI - Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis. AB - Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-kappaB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the effects of ANDRO in NASH and its influence on inflammasome activation in this setting. Thus, mice were fed a choline-deficient-amino-acid-defined (CDAA) diet with/without concomitant ANDRO administration (1 mg/kg, 3-times/week). Also, we assessed serum levels of alanine-aminotransferase (ALT), liver histology, hepatic triglyceride content (HTC) and hepatic expression of pro-inflammatory, pro-fibrotic and inflammasome genes. Inflammasome activation was also evaluated in fat-laden HepG2 cells. Our results showed that ANDRO administration decreased HTC and attenuated hepatic inflammation and fibrosis in CDAA-fed mice. ANDRO treatment determined a strong reduction in hepatic macrophage infiltration and reduced hepatic mRNA levels of both pro-inflammatory and pro-fibrotic genes. In addition, mice treated with ANDRO showed reduced expression of inflammasome genes. Finally, ANDRO inhibited LPS-induced interleukin-1beta expression through NF-kappaB inhibition in fat-laden HepG2 cells and inflammasome disassembly. In conclusion, ANDRO administration reduces inflammation and fibrosis in experimental NASH. Inflammasome modulation by a NF-kappaB-dependent mechanism may be involved in the therapeutic effects of ANDRO. PMID- 28615650 TI - Experimental design approach for deposition optimization of RF sputtered chalcogenide thin films devoted to environmental optical sensors. AB - The development of the optical bio-chemical sensing technology is an extremely important scientific and technological issue for diagnosis and monitoring of diseases, control of industrial processes, environmental detection of air and water pollutants. Owing to their distinctive features, chalcogenide amorphous thin films represent a keystone in the manufacture of middle infrared integrated optical devices for a sensitive detection of biological or environmental variations. Since the chalcogenide thin films characteristics, i.e. stoichiometric conformity, structure, roughness or optical properties can be affected by the growth process, the choice and control of the deposition method is crucial. An approach based on the experimental design is undoubtedly a way to be explored allowing fast optimization of chalcogenide film deposition by means of radio frequency sputtering process. Argon (Ar) pressure, working power and deposition time were selected as potentially the most influential factors among all possible. The experimental design analysis confirms the great influence of the Ar pressure on studied responses: chemical composition, refractive index in near-IR (1.55 um) and middle infrared (6.3 and 7.7 um), band-gap energy, deposition rate and surface roughness. Depending on the intended application and therefore desired thin film characteristics, mappings of the experimental design meaningfully help to select suitable deposition parameters. PMID- 28615648 TI - Embryonic exposure to the widely-used herbicide atrazine disrupts meiosis and normal follicle formation in female mice. AB - The widely-used herbicide atrazine (ATZ) is detected in ground and surface water in many countries. Several studies in animals have demonstrated that ATZ has endocrine-disrupting effects on male and female reproduction in many vertebrate species. In this study, we investigated the effects of ATZ exposure on meiosis, a key step in gametogenesis in mammals. The treatment was initiated before oocyte entry into meiosis, which occurs during the embryonic period in females. We found that embryonic exposure to ATZ increases the level of 8-oxo-guanine in the nucleus of meiotic cells, reflecting oxidative stress and affecting meiotic double-strand break repair, chromosome synapsis and crossover numbers. Finally, embryonic exposure to ATZ reduces the number of primordial follicles and increases the incidence of multi-oocyte follicles in adult mice. Our data demonstrate that embryonic exposure to ATZ disrupts prophase I of meiosis and affects normal follicle formation in female mice. PMID- 28615651 TI - Cognitive and Metacognitive Mechanisms of Change in Metacognitive Training for Depression. AB - Metacognitive Training for Depression (D-MCT), a low-threshold group intervention, has been shown to improve depressive symptoms. It aims at the reduction of depression by changing dysfunctional cognitive as well as metacognitive beliefs. The purpose of the present study was to investigate whether the mechanisms of change in D-MCT are cognitive (and thus primarily concern the content of cognition) or metacognitive in nature. Eighty-four outpatients with depression were included in a randomized controlled trial comparing D-MCT to an active control intervention. Level of depression, dysfunctional cognitive beliefs (DAS), and metacognitive beliefs (MCQ subscales: Positive Beliefs, Negative Beliefs, Need for Control) were assessed before (t0) and after treatment (t1). Severity of depression was also assessed 6 months later (t2). Linear regression analyses were used to determine whether change in depression from t0 to t2 was mediated by change in cognitive vs. metacognitive beliefs from t0 to t1. D-MCT's effect on change in depression was mediated by a decrease in dysfunctional metacognitive beliefs, particularly 'need for control'. Our findings underline that one of the key mechanisms of improvement in D-MCT is the change in metacognitive beliefs. The current study provides further support for the importance of metacognition in the treatment of depression. PMID- 28615652 TI - Development of a computer-aided design and finite-element analysis combined method for customized Nuss bar in pectus excavatum surgery. AB - Pectus excavatum (PEX) is the most common chest deformity in children, which is usually corrected by using the minimally invasive Nuss method. The orthopedic effect of the Nuss operation is mainly evaluated by both the Haller index and the appearance of the chest wall configuration, which is dependent on the operator's clinical experience to a great extent. To improve the orthopedic effect, we proposed a novel method to individually design and optimize the shape of the Nuss bar and to advise its location as well as the incisions. By using the CT imaging data, the three-dimensional model of the PEX thoracic structure is reconstructed, which is further employed in finite element analysis to determine the operation plan. By referring to a healthy person who has similar chest dimensions to the PEX patient, the Nuss bar shape is designed, and according to the finding that the healthy chest wall boundary is almost convex with positive curvature, the Nuss bar shape is tuned to be a convex curve to ensure the orthopedic effect. Finite element analysis is employed to analyze the orthopedic effect and to determine the incision position of the Nuss bar. Experiments were carried out to verify the orthopedic effect of the customized Nuss bar, which showed that this method is more accurate and individualized, compared to conventional methods. PMID- 28615653 TI - Electrophoresis assisted time-of-flow mass spectrometry using hollow nanomechanical resonators. AB - This report discusses the first demonstration of electrophoresis assisted time-of flow mass spectrometry using 'U' shaped hollow nanomechanical resonators (HNR). Capillary electrophoresis was coupled with the HNR based mass detection to overcome low ionic conductivity of channels embedded in the HNR preventing direct in-situ electrophoretic separation. The flow of analytes through the HNR was achieved by balancing the hydrodynamic pressure to override the electromotive force and inhibit the motion of analytes towards the anode for capillary electrophoresis. The resonance frequency shifts of the HNR vibrating around 1.5 MHz were correlated with the time of the passage of the protein bands to construct the mass spectrum. The proposed concept was demonstrated by constructing a mass spectrum of egg white proteins in the molecular weight range of 14-250 kDa. When compared to regular polyacrylamide gel electrophoresis, our method not only provides a precise and fast readout but also avoids the use of chemical staining. This study paves a new route for low-cost and on-chip mass spectrometers with ultra-miniaturized dimensions. PMID- 28615654 TI - 6.2-GHz modulated terahertz light detection using fast terahertz quantum well photodetectors. AB - The fast detection of terahertz radiation is of great importance for various applications such as fast imaging, high speed communications, and spectroscopy. Most commercial products capable of sensitively responding the terahertz radiation are thermal detectors, i.e., pyroelectric sensors and bolometers. This class of terahertz detectors is normally characterized by low modulation frequency (dozens or hundreds of Hz). Here we demonstrate the first fast semiconductor-based terahertz quantum well photodetectors by carefully designing the device structure and microwave transmission line for high frequency signal extraction. Modulation response bandwidth of gigahertz level is obtained. As an example, the 6.2-GHz modulated terahertz light emitted from a Fabry-Perot terahertz quantum cascade laser is successfully detected using the fast terahertz quantum well photodetector. In addition to the fast terahertz detection, the technique presented in this work can also be used for optically characterizing the frequency stability of terahertz quantum cascade lasers, heterodyne detections and photomixing applications. PMID- 28615655 TI - Secreted IgM deficiency leads to increased BCR signaling that results in abnormal splenic B cell development. AB - Mice lacking secreted IgM (sIgM -/-) antibodies display abnormal splenic B cell development, which results in increased marginal zone and decreased follicular B cell numbers. However, the mechanism by which sIgM exhibit this effect is unknown. Here, we demonstrate that B cells in sIgM -/- mice display increased B cell receptor (BCR) signaling as judged by increased levels of phosphorylated Bruton's tyrosine kinase (pBtk), phosphorylated Spleen tyrosine kinase (pSyk), and nuclear receptor Nur77. Low dosage treatment with the pBtk inhibitor Ibrutinib reversed the altered B cell development in the spleen of sIgM -/- mice, suggesting that sIgM regulate splenic B cell differentiation by decreasing BCR signaling. Mechanistically, we show that B cells, which express BCRs specific to hen egg lysozyme (HEL) display diminished responsiveness to HEL stimulation in presence of soluble anti-HEL IgM antibodies. Our data identify sIgM as negative regulators of BCR signaling and suggest that they can act as decoy receptors for self-antigens that are recognized by membrane bound BCRs. PMID- 28615656 TI - The CCAAT-Binding Complex Controls Respiratory Gene Expression and Iron Homeostasis in Candida Glabrata. AB - The CCAAT-binding complex (CBC) is a heterotrimeric transcription factor which is widely conserved in eukaryotes. In the model yeast S. cerevisiae, CBC positively controls the expression of respiratory pathway genes. This role involves interactions with the regulatory subunit Hap4. In many pathogenic fungi, CBC interacts with the HapX regulatory subunit to control iron homeostasis. HapX is a bZIP protein which only shares with Hap4 the Hap4Like domain (Hap4L) required for its interaction with CBC. Here, we show that CBC has a dual role in the pathogenic yeast C. glabrata. It is required, along with Hap4, for the constitutive expression of respiratory genes and it is also essential for the iron stress response, which is mediated by the Yap5 bZIP transcription factor. Interestingly, Yap5 contains a vestigial Hap4L domain. The mutagenesis of this domain severely reduced Yap5 binding to its targets and compromised its interaction with Hap5. Hence, Yap5, like HapX in other species, acts as a CBC regulatory subunit in the regulation of iron stress response. This work reveals new aspects of iron homeostasis in C. glabrata and of the evolution of the role of CBC and Hap4L-bZIP proteins in this process. PMID- 28615657 TI - Bone morphogenetic protein 4 promotes the survival and preserves the structure of flow-sorted Bhlhb5+ cochlear spiral ganglion neurons in vitro. AB - SGNs are the primary auditory neurons, and damage or loss of SGNs leads to sensorineural hearing loss. BMP4 is a growth factor that belongs to the TGF-beta superfamily and has been shown to play a key role during development, but little is known about its effect on postnatal cochlear SGNs in mice. In this study, we used the P3 Bhlhb5-cre/tdTomato transgenic mouse model and FACS to isolate a pure population of Bhlhb5+ SGNs. We found that BMP4 significantly promoted SGN survival after 7 days of culture. We observed fewer apoptotic cells and decreased expression of pro-apoptotic marker genes after BMP4 treatment. We also found that BMP4 promoted monopolar neurite outgrowth of isolated SGNs, and high concentrations of BMP4 preserved the number and the length of neurites in the explant culture of the modiolus harboring the SGNs. We showed that high concentration of BMP4 enhanced neurite growth as determined by the higher average number of filopodia and the larger area of the growth cone. Finally, we found that high concentrations of BMP4 significantly elevated the synapse density of SGNs in explant culture. Thus, our findings suggest that BMP4 has the potential to promote the survival and preserve the structure of SGNs. PMID- 28615658 TI - Serotyping dengue virus with isothermal amplification and a portable sequencer. AB - The recent development of a nanopore-type portable DNA sequencer has changed the way we think about DNA sequencing. We can perform sequencing directly in the field, where we collect the samples. Here, we report the development of a novel method to detect and genotype tropical disease pathogens, using dengue fever as a model. By combining the sequencer with isothermal amplification that only requires a water bath, we were able to amplify and sequence target viral genomes with ease. Starting from a serum sample, the entire procedure could be finished in a single day. The analysis of blood samples collected from 141 Indonesian patients demonstrated that this method enables the clinical identification and serotyping of the dengue virus with high sensitivity and specificity. The overall successful detection rate was 79%, and a total of 58 SNVs were detected. Similar analyses were conducted on 80 Vietnamese and 12 Thai samples with similar performance. Based on the obtained sequence information, we demonstrated that this approach is able to produce indispensable information for etiologically analyzing annual or regional diversifications of the pathogens. PMID- 28615659 TI - Invisible noise obscures visible signal in insect motion detection. AB - The motion energy model is the standard account of motion detection in animals from beetles to humans. Despite this common basis, we show here that a difference in the early stages of visual processing between mammals and insects leads this model to make radically different behavioural predictions. In insects, early filtering is spatially lowpass, which makes the surprising prediction that motion detection can be impaired by "invisible" noise, i.e. noise at a spatial frequency that elicits no response when presented on its own as a signal. We confirm this prediction using the optomotor response of praying mantis Sphodromantis lineola. This does not occur in mammals, where spatially bandpass early filtering means that linear systems techniques, such as deriving channel sensitivity from masking functions, remain approximately valid. Counter-intuitive effects such as masking by invisible noise may occur in neural circuits wherever a nonlinearity is followed by a difference operation. PMID- 28615660 TI - Scanning tunnelling microscope light emission: Finite temperature current noise and over cut-off emission. AB - The spectral distribution of light emitted from a scanning tunnelling microscope junction not only bears its intrinsic plasmonic signature but is also imprinted with the characteristics of optical frequency fluc- tuations of the tunnel current. Experimental spectra from gold-gold tunnel junctions are presented that show a strong bias (V b ) dependence, curiously with emission at energies higher than the quantum cut-off (eV b ); a component that decays monotonically with increasing bias. The spectral evolution is explained by developing a theoretical model for the power spectral density of tunnel current fluctuations, incorporating finite temperature contribution through consideration of the quantum transport in the system. Notably, the observed decay of the over cut-off emission is found to be critically associated with, and well explained in terms of the variation in junction conductance with V b . The investigation highlights the scope of plasmon-mediated light emission as a unique probe of high frequency fluctuations in electronic systems that are fundamental to the electrical generation and control of plasmons. PMID- 28615661 TI - Increased levels of ascorbic acid in the cerebrospinal fluid of cognitively intact elderly patients with major depression: a preliminary study. AB - Major depressive disorder (MDD) in the elderly is a risk factor for dementia, but the precise biological basis remains unknown, hampering the search for novel biomarkers and treatments. In this study, we performed metabolomics analysis of cerebrospinal fluid (CSF) from cognitively intact elderly patients (N = 28) with MDD and age- and gender-matched healthy controls (N = 18). The CSF levels of 177 substances were measured, while 288 substances were below the detection limit. Only ascorbic acid was significantly different, with higher levels in the MDD group at baseline. There were no correlations between CSF ascorbic acid levels and clinical variables in MDD patients at baseline. At the 3-year follow-up, there was no difference of CSF ascorbic acid levels between the two groups. There was a negative correlation between CSF ascorbic acid and CSF amyloid-beta42 levels in all subjects. However, there were no correlations between ascorbic acid and other biomarkers (e.g., amyloid-beta40, total and phosphorylated tau protein). This preliminary study suggests that abnormalities in the transport and/or release of ascorbic acid might play a role in the pathogenesis of late life depression. PMID- 28615662 TI - Engineering of many-body Majorana states in a topological insulator/s-wave superconductor heterostructure. AB - We study a vortex chain in a thin film of a topological insulator with proximity induced superconductivity-a promising platform to realize Majorana zero modes (MZMs)-by modeling it as a two-leg Majorana ladder. While each pair of MZMs hybridizes through vortex tunneling, we hereby show that MZMs can be stabilized on the ends of the ladder with the presence of tilted external magnetic field and four-Majorana interaction. Furthermore, a fruitful phase diagram is obtained by controlling the direction of magnetic field and the thickness of the sample. We reveal many-body Majorana states and interaction-induced topological phase transitions and also identify trivial-superconducting and commensurate/incommensurate charge-density-wave states in the phase diagram. PMID- 28615664 TI - Investigation of material removal in inner-jet electrochemical grinding of GH4169 alloy. AB - Electrochemical grinding (ECG) is a low-cost and highly efficient process for application to difficult-to-machine materials. In this process, the electrolyte supply mode directly affects machining stability and efficiency. This paper proposes a flow channel structure for an abrasive tool to be used for inner-jet ECG of GH4169 alloy. The tool is based on a dead-end tube with electrolyte outlet holes located in the sidewall. The diameter and number of outlet holes are determined through numerical simulation with the aim of achieving uniform electrolyte flow in the inter-electrode gap. Experiments show that the maximum feed rate and material removal rate are both improved by increasing the diamond grain size, applied voltage, electrolyte temperature and pressure. For a machining depth of 3 mm in a single pass, a feed rate of 2.4 mm min-1 is achieved experimentally. At this feed rate and machining depth, a sample is produced along a feed path under computer numerical control, with the feed direction changing four times. Inner-jet ECG with the proposed abrasive tool shows good efficiency and flexibility for processing hard-to-cut metals with a large removal depth. PMID- 28615663 TI - Hydrostatic pressure effects on the static magnetism in Eu(Fe0.925Co0.075)2As2. AB - EuFe2As2-based iron pnictides are quite interesting compounds, due to the two magnetic sublattices in them and the tunability to superconductors by chemical doping or application of external pressure. The effects of hydrostatic pressure on the static magnetism in Eu(Fe0.925Co0.075)2As2 are investigated by complementary electrical resistivity, ac magnetic susceptibility and single crystal neutron diffraction measurements. A specific pressure-temperature (P-T) phase diagram of Eu(Fe0.925Co0.075)2As2 is established. The structural phase transition, as well as the spin-density-wave order of Fe sublattice, is suppressed gradually with increasing pressure and disappears completely above 2.0 GPa. In contrast, the magnetic order of Eu sublattice persists over the whole investigated pressure range up to 14 GPa, yet displaying a non-monotonic variation with pressure. With the increase of the hydrostatic pressure, the magnetic state of Eu evolves from the canted antiferromagnetic structure in the ground state, via a pure ferromagnetic structure under the intermediate pressure, finally to an "unconfirmed" antiferromagnetic structure under the high pressure. The strong ferromagnetism of Eu coexists with the pressure-induced superconductivity around 2 GPa. Comparisons between the P-T phase diagrams of Eu(Fe0.925Co0.075)2As2 and the parent compound EuFe2As2 were also made. PMID- 28615665 TI - Trilocular phenotype in Brassica juncea L. resulted from interruption of CLAVATA1 gene homologue (BjMc1) transcription. AB - As a desirable agricultural trait, multilocular trait of rapeseed (Brassica rapa; Brassica napus; Brassica juncea), always represents higher yield per plant compared with bilocular plants. We previously isolated a trilocular gene locus, Bjmc1, and identified a set of molecular markers linked to the trilocular gene. With a map-based cloning, we identified that the BjMc1 was located in B genome of Brassica juncea, and it was a CLAVATA1 (CLV1) gene homologue. The insertion of a copia-LTR retrotransposable element 1 (RTE1) into the coding region of BjMc1 interrupted its transcription in rapeseed, leading to the trilocular phenotype. Phylogenetic analysis showed that Mc1 genes were conserved and widespread in land plants. Two amino acid sites had undergone positive selection in the ancestor of Mc1 genes, and then purifying selection was the dominant force after the divergence of dicots and monocots from their common ancestor in the evolutionary process, indicating that Mc1 genes are conserved in modern land plants. Our results provided new insights in molecular regulatory mechanism of multilocularity in rapeseed, and better understanding of molecular mechanism in crop yield improvement. PMID- 28615666 TI - A sex-specific reconstitution bias in the competitive CD45.1/CD45.2 congenic bone marrow transplant model. AB - Allelic variants of the pan-haematopoietic cell marker CD45, identified as CD45.1 and CD45.2, have been established as a marker system to track haematopoietic cells following congenic mouse bone marrow transplants. Despite the frequent use of this model for studying the impact of genetic modifications on relative differentiation potential, it is now evident that a bias exists in CD45.1 versus CD45.2 cell reconstitution. While this bias has been demonstrated by reduced reconstitution potential in B cells of CD45.1 origin, differences in the development of other lymphocytes, as well as the impact of sex on this bias, remain uncertain. We performed bone marrow transplants with wild-type CD45.1 and CD45.2 donor cells, and characterised haematopoietic cell reconstitution in dual expressing CD45.1/2 host mice. We report an increase in CD45.2 reconstitution in the bone marrow that persists in the spleen, thymus and blood. Through the use of CD45.1/2 hosts, we demonstrate the intrinsic bias towards CD45.2 reconstitution is independent of an immunogenic response to the CD45.1 epitope. Furthermore, we identify a sex-specific difference in reconstitution efficiencies, with female mice exhibiting a greater bias towards CD45.2 reconstitution than males. This work sheds new light on the limitations of the CD45.1/CD45.2 congenic system for tracking lymphocyte development. PMID- 28615667 TI - IL-6 secretion in osteoarthritis patients is mediated by chondrocyte-synovial fibroblast cross-talk and is enhanced by obesity. AB - Increasing evidence suggests that inflammation plays a central role in driving joint pathology in certain patients with osteoarthritis (OA). Since many patients with OA are obese and increased adiposity is associated with chronic inflammation, we investigated whether obese patients with hip OA exhibited differential pro-inflammatory cytokine signalling and peripheral and local lymphocyte populations, compared to normal weight hip OA patients. No differences in either peripheral blood or local lymphocyte populations were found between obese and normal-weight hip OA patients. However, synovial fibroblasts from obese OA patients were found to secrete greater amounts of the pro-inflammatory cytokine IL-6, compared to those from normal-weight patients (p < 0.05), which reflected the greater levels of IL-6 detected in the synovial fluid of the obese OA patients. Investigation into the inflammatory mechanism demonstrated that IL-6 secretion from synovial fibroblasts was induced by chondrocyte-derived IL-6. Furthermore, this IL-6 inflammatory response, mediated by chondrocyte-synovial fibroblast cross-talk, was enhanced by the obesity-related adipokine leptin. This study suggests that obesity enhances the cross-talk between chondrocytes and synovial fibroblasts via raised levels of the pro-inflammatory adipokine leptin, leading to greater production of IL-6 in OA patients. PMID- 28615668 TI - Improving the detection of pathways in genome-wide association studies by combined effects of SNPs from Linkage Disequilibrium blocks. AB - Genome-wide association studies (GWAS) have successfully identified single variants associated with diseases. To increase the power of GWAS, gene-based and pathway-based tests are commonly employed to detect more risk factors. However, the gene- and pathway-based association tests may be biased towards genes or pathways containing a large number of single-nucleotide polymorphisms (SNPs) with small P-values caused by high linkage disequilibrium (LD) correlations. To address such bias, numerous pathway-based methods have been developed. Here we propose a novel method, DGAT-path, to divide all SNPs assigned to genes in each pathway into LD blocks, and to sum the chi-square statistics of LD blocks for assessing the significance of the pathway by permutation tests. The method was proven robust with the type I error rate >1.6 times lower than other methods. Meanwhile, the method displays a higher power and is not biased by the pathway size. The applications to the GWAS summary statistics for schizophrenia and breast cancer indicate that the detected top pathways contain more genes close to associated SNPs than other methods. As a result, the method identified 17 and 12 significant pathways containing 20 and 21 novel associated genes, respectively for two diseases. The method is available online by http://sparks lab.org/server/DGAT-path . PMID- 28615669 TI - Differential effects of a post-anthesis heat stress on wheat (Triticum aestivum L.) grain proteome determined by iTRAQ. AB - Heat stress, a major abiotic stressor of wheat (Triticum aestivum L.), often results in reduced yield and decreased quality. In this study, a proteomic method, Tags for Relative and Absolute Quantitation Isobaric (iTRAQ), was adopted to analyze the protein expression profile changes among wheat cultivar Jing411 under heat stress. Results indicated that there were 256 different proteins expressed in Jing411 under heat stress. According to the result of gene annotation and functional classification, 239 proteins were annotated by 856 GO function entries, including growth and metabolism proteins, energy metabolism proteins, processing and storage proteins, defense-related proteins, signal transduction, unknown function proteins and hypothetical proteins. GO enrichment analysis suggested that the differentially expressed proteins in Jing411 under heat stress were mainly involved in stimulus response (67), abiotic stress response (26) and stress response (58), kinase activity (12), and transferase activity (12). Among the differentially expressed proteins in Jing411, 115 were attributed to 119 KEGG signaling/metabolic pathways. KEGG pathway enrichment analysis in Jing411 showed that heat stress mainly affected the starch and sucrose metabolism as well as protein synthesis pathway in the endoplasmic reticulum. The protein interaction network indicated that there were 8 differentially expressed proteins that could form an interaction network in Jing411. PMID- 28615670 TI - Optic Disc Hemorrhage and Lamina Cribrosa Defects in Glaucoma Progression. AB - Both disc hemorrhages (DH) and focal lamina cribrosa (LC) defects are recently considered as a progression factor in glaucoma. However, the clinical relevance of the presence of LC findings at the site of the DH has not yet been determined. We conducted a prospective study enrolling a total of 98 glaucoma eyes with DH and 37 OAG eyes with focal LC defect without DH to determine whether visual field (VF) progression differs according to the findings of the LC that had been evaluated by enhanced depth imaging (EDI) of optical coherence tomography (OCT) and its relationship with DH. Only the presence of focal LC defects was significantly different between the progressing and stable patients (P < 0.001). Baseline intraocular pressure (hazard ratio [HR], 1.076; P = 0.098) and the presence of focal LC defects at the DH site (HR, 2.620; P = 0.002) were found to be associated with VF progression. Glaucoma eyes with DH at the site of focal LC defects showed frequent and faster VF progression compared with DH not accompanied by LC alterations or LC alterations not accompanied by DH. Evaluating LC alterations in glaucoma eyes with DH may be important in predicting the progression of glaucoma. PMID- 28615671 TI - Universal fractality of morphological transitions in stochastic growth processes. AB - Stochastic growth processes give rise to diverse and intricate structures everywhere in nature, often referred to as fractals. In general, these complex structures reflect the non-trivial competition among the interactions that generate them. In particular, the paradigmatic Laplacian-growth model exhibits a characteristic fractal to non-fractal morphological transition as the non-linear effects of its growth dynamics increase. So far, a complete scaling theory for this type of transitions, as well as a general analytical description for their fractal dimensions have been lacking. In this work, we show that despite the enormous variety of shapes, these morphological transitions have clear universal scaling characteristics. Using a statistical approach to fundamental particle cluster aggregation, we introduce two non-trivial fractal to non-fractal transitions that capture all the main features of fractal growth. By analyzing the respective clusters, in addition to constructing a dynamical model for their fractal dimension, we show that they are well described by a general dimensionality function regardless of their space symmetry-breaking mechanism, including the Laplacian case itself. Moreover, under the appropriate variable transformation this description is universal, i.e., independent of the transition dynamics, the initial cluster configuration, and the embedding Euclidean space. PMID- 28615672 TI - Reconstruction of pathway modification induced by nicotinamide using multi-omic network analyses in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is characterized by an aggressive biological behavior in the absence of a specific target agent. Nicotinamide has recently been proven to be a novel therapeutic agent for skin tumors in an ONTRAC trial. We performed combinatory transcriptomic and in-depth proteomic analyses to characterize the network of molecular interactions in TNBC cells treated with nicotinamide. The multi-omic profiles revealed that nicotinamide drives significant functional alterations related to major cellular pathways, including the cell cycle, DNA replication, apoptosis and DNA damage repair. We further elaborated the global interaction networks of molecular events via nicotinamide inducible expression changes at the mRNA and functional protein levels. This approach indicated that nicotinamide treatment rewires interaction networks toward dysfunction in DNA damage repair and away from a pro-growth state in TNBC. To our knowledge, the high-resolution network interactions identified in the present study provide the first evidence to comprehensively support the hypothesis of nicotinamide as a novel therapeutic agent in TNBC. PMID- 28615673 TI - Phototaxis beyond turning: persistent accumulation and response acclimation of the microalga Chlamydomonas reinhardtii. AB - Phototaxis is an important reaction to light displayed by a wide range of motile microorganisms. Flagellated eukaryotic microalgae in particular, like the model organism Chlamydomonas reinhardtii, steer either towards or away from light by a rapid and precisely timed modulation of their flagellar activity. Cell steering, however, is only the beginning of a much longer process which ultimately allows cells to determine their light exposure history. This process is not well understood. Here we present a first quantitative study of the long timescale phototactic motility of Chlamydomonas at both single cell and population levels. Our results reveal that the phototactic strategy adopted by these microorganisms leads to an efficient exposure to light, and that the phototactic response is modulated over typical timescales of tens of seconds. The adaptation dynamics for phototaxis and chlorophyll fluorescence show a striking quantitative agreement, suggesting that photosynthesis controls quantitatively how cells navigate a light field. PMID- 28615675 TI - A commentary on homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. PMID- 28615676 TI - A reply to a commentary on homozygous p.(Glu87Lys) variant in ISCA1 is associated with a multiple mitochondrial dysfunctions syndrome. PMID- 28615674 TI - Meta-analysis of genome-wide SNP- and pathway-based associations for facets of neuroticism. AB - Neuroticism is a heritable personality trait that is comprised of distinct sub factors, or facets. Sub-factors of neuroticism are linked to different emotional states or psychiatric symptoms and studying the genetic variants associated with these facets may help reveal the biological mechanisms underlying psychiatric disorders. In the present study, a meta-analysis of genome-wide association studies for six facets of neuroticism was performed in 5584 participants from three cohorts. Additionally, a Gene Set Enrichment Analysis was conducted to find biological pathways associated with each facet. Six neuroticism facets (N1: anxiety, N2: angry hostility, N3: depression, N4: self-consciousness, N5: impulsivity and N6: vulnerability) were assessed using the Korean version of the Revised NEO Personality Inventory. In the single-nucleotide polymorphism-based analysis, results showed genome-wide significance for N2 within the MIR548H3 gene (rs1360001, P=4.14 * 10-9). Notable genes with suggestive associations (P<1.0 * 10-6) were ITPR1 for N1, WNT7A for N2, FGF10 and FHIT for N3, DDR1 for N4, VGLL4 for N5 and PTPRD for N6. In the pathway-based analysis, the axon guidance pathway was identified to be associated with multiple facets of neuroticism (N2, N4 and N6). The focal adhesion and extracellular matrix receptor interaction pathways were significantly associated with N2 and N3. Our findings revealed genetic influences and biological pathways that are associated with facets of neuroticism. PMID- 28615678 TI - Small head size and delayed body weight growth in wild Japanese monkey fetuses after the Fukushima Daiichi nuclear disaster. AB - To evaluate the biological effect of the Fukushima Daiichi nuclear disaster, relative differences in the growth of wild Japanese monkeys (Macaca fuscata) were measured before and after the disaster of 2011 in Fukushima City, which is approximately 70 km from the nuclear power plant, by performing external measurements on fetuses collected from 2008 to 2016. Comparing the relative growth of 31 fetuses conceived prior to the disaster and 31 fetuses conceived after the disaster in terms of body weight and head size (product of the occipital frontal diameter and biparietal diameter) to crown-rump length ratio revealed that body weight growth rate and proportional head size were significantly lower in fetuses conceived after the disaster. No significant difference was observed in nutritional indicators for the fetuses' mothers. Accordingly, radiation exposure could be one factor contributed to the observed growth delay in this study. PMID- 28615677 TI - Associations between radiologist-defined semantic and automatically computed radiomic features in non-small cell lung cancer. AB - Tumor phenotypes captured in computed tomography (CT) images can be described qualitatively and quantitatively using radiologist-defined "semantic" and computer-derived "radiomic" features, respectively. While both types of features have shown to be promising predictors of prognosis, the association between these groups of features remains unclear. We investigated the associations between semantic and radiomic features in CT images of 258 non-small cell lung adenocarcinomas. The tumor imaging phenotypes were described using 9 qualitative semantic features that were scored by radiologists, and 57 quantitative radiomic features that were automatically calculated using mathematical algorithms. Of the 9 semantic features, 3 were rated on a binary scale (cavitation, air bronchogram, and calcification) and 6 were rated on a categorical scale (texture, border definition, contour, lobulation, spiculation, and concavity). 32-41 radiomic features were associated with the binary semantic features (AUC = 0.56-0.76). The relationship between all radiomic features and the categorical semantic features ranged from weak to moderate (|Spearmen's correlation| = 0.002-0.65). There are associations between semantic and radiomic features, however the associations were not strong despite being significant. Our results indicate that radiomic features may capture distinct tumor phenotypes that fail to be perceived by naked eye that semantic features do not describe and vice versa. PMID- 28615679 TI - Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1. AB - Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER) negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT 549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers. PMID- 28615680 TI - Interval Optimization Model Considering Terrestrial Ecological Impacts for Water Rights Transfer from Agriculture to Industry in Ningxia, China. AB - In this study, an interval optimization model is developed to maximize the benefits of a water rights transfer system that comprises industry and agriculture sectors in the Ningxia Hui Autonomous Region in China. The model is subjected to a number of constraints including water saving potential from agriculture and ecological groundwater levels. Ecological groundwater levels serve as performance indicators of terrestrial ecology. The interval method is applied to present the uncertainty of parameters in the model. Two scenarios regarding dual industrial development targets (planned and unplanned ones) are used to investigate the difference in potential benefits of water rights transfer. Runoff of the Yellow River as the source of water rights fluctuates significantly in different years. Thus, compensation fees for agriculture are calculated to reflect the influence of differences in the runoff. Results show that there are more available water rights to transfer for industrial development. The benefits are considerable but unbalanced between buyers and sellers. The government should establish a water market that is freer and promote the interest of agriculture and farmers. Though there has been some success of water rights transfer, the ecological impacts and the relationship between sellers and buyers require additional studies. PMID- 28615681 TI - Genome-wide analysis of banana MADS-box family closely related to fruit development and ripening. AB - Proteins encoded by MADS-box genes are important transcription factors involved in the regulation of flowering plant growth and development. Currently, no systematic information exists regarding the MADS-box family in the important tropical fruit banana. Ninety-six MADS-box genes were identified from the banana (Pahang) A genome. Phylogenetic analysis indicated that Musa acuminata MCM1 AGAMOUS- DEFICIENS-SRF (MaMADS) could be divided into MIKCc, MIKC*, Malpha/beta and Mgamma groups. MIKCc could be further divided into 11 subfamilies, which was further supported by conserved motif and gene structure analyses. Transcriptome analysis on the Feng Jiao (FJ) and BaXi Jiao (BX) banana cultivars revealed that MaMADS genes are differentially expressed in various organs, at different fruit development and ripening stages, indicating the involvement of these genes in fruit development and ripening processes. Interactive network analysis indicated that MaMADS24 and 49 not only interacted with MaMADS proteins themselves, but also interacted with hormone-response proteins, ethylene signal transduction and biosynthesis-related proteins, starch biosynthesis proteins and metabolism related proteins. This systematic analysis identified candidate MaMADS genes related to fruit development and ripening for further functional characterization in plants, and also provided new insights into the transcriptional regulation of MaMADS genes, facilitating the future genetic manipulation of MADS-mediated fruit development and ripening. PMID- 28615682 TI - Improved retinal function in RCS rats after suppressing the over-activation of mGluR5. AB - Muller cells maintain retinal synaptic homeostasis by taking up glutamate from the synaptic cleft and transporting glutamine back to the neurons. To study the interaction between Muller cells and photoreceptors, we injected either DL-alpha aminoadipate or L-methionine sulfoximine-both inhibitors of glutamine synthetase subretinally in rats. Following injection, the a-wave of the electroretinogram (ERG) was attenuated, and metabotropic glutamate receptor 5 (mGluR5) was activated. Selective antagonism of mGluR5 by 2-methyl-6-(phenylethynyl)-pyridine increased the ERG a-wave amplitude and also increased rhodopsin expression. Conversely, activation of mGluR5 by the agonist, (R,S)-2-chloro-5 hydroxyphenylglycine, decreased both the a-wave amplitude and rhodopsin expression, but upregulated expression of Gq alpha subunit and phospholipase C betaIII. Overexpression of mGluR5 reduced the inward-rectifying potassium ion channel (Kir) current and decreased the expression of Kir4.1 and aquaporin-4 (AQP4). Further experiments indicated that mGluR5 formed a macromolecular complex with these two membrane channels. Lastly, increased expression of mGluR5 was found in Royal College of Surgeons rats-a model of retinitis pigmentosa (RP). Inhibition of mGluR5 in this model restored the amplitude of ERG features, and reduced the expression of glial fibrillary acidic protein. These results suggest that mGluR5 may be worth considering as a potential therapeutic target in RP. PMID- 28615684 TI - Flat Terahertz Reflective Focusing Metasurface with Scanning Ability. AB - The ability to manipulate the propagation properties of electromagnetic waves, e.g., divergence, focusing, holography or deflection, is very significant in terahertz applications. Metasurfaces with flat structures are attractive for achieving such manipulations in terahertz band, as they feature low profile, lightweight, and ease of design and installation. Several types of terahertz reflective or transmitting metasurfaces with focusing function have been implemented recently, but none of them can provide scanning ability with controllable focus. Here, a flat reflective metasurface featuring controllable focal shift is proposed and experimentally demonstrated. Furthermore, the principle of designing a focus scanning reflective metasurface is presented and the focusing characteristics are discussed, including focus scanning along a line parallel or orthogonal to the metasurface with a large bandwidth. These interesting properties indicate that this flat reflective metasurface could play a key role in many terahertz imaging and detection systems. PMID- 28615683 TI - Bacteriocin Gene-Trait matching across the complete Lactobacillus Pan-genome. AB - Lactobacilli constitute a large genus of Gram-positive lactic acid bacteria which have widespread roles ranging from gut commensals to starters in fermented foods. A combination of in silico and laboratory-based screening allowed us to determine the overall bacteriocin producing potential of representative strains of each species of the genus. The genomes of 175 lactobacilli and 38 associated species were screened for the presence of antimicrobial producing genes and combined with screening for antimicrobial activity against a range of indicators. There also appears to be a link between the strains' environment and bacteriocin production, with those from the animal and human microbiota encoding over twice as many bacteriocins as those from other sources. Five novel bacteriocins were identified belonging to differing bacteriocin classes, including two-peptide bacteriocins (muricidin and acidocin X) and circular bacteriocins (paracyclicin). In addition, there was a clear clustering of helveticin type bacteriolysins in the Lactobacillus acidophilus group of species. This combined in silico and in vitro approach to screening has demonstrated the true diversity and complexity of bacteriocins across the genus. It also highlights their biological importance in terms of communication and competition between closely related strains in diverse complex microbial environments. PMID- 28615685 TI - Repeated evolution of camouflage in speciose desert rodents. AB - There are two main factors explaining variation among species and the evolution of characters along phylogeny: adaptive change, including phenotypic and genetic responses to selective pressures, and phylogenetic inertia, or the resemblance between species due to shared phylogenetic history. Phenotype-habitat colour match, a classic Darwinian example of the evolution of camouflage (crypsis), offers the opportunity to test the importance of historical versus ecological mechanisms in shaping phenotypes among phylogenetically closely related taxa. To assess it, we investigated fur (phenotypic data) and habitat (remote sensing data) colourations, along with phylogenetic information, in the species-rich Gerbillus genus. Overall, we found a strong phenotype-habitat match, once the phylogenetic signal is taken into account. We found that camouflage has been acquired and lost repeatedly in the course of the evolutionary history of Gerbillus. Our results suggest that fur colouration and its covariation with habitat is a relatively labile character in mammals, potentially responding quickly to selection. Relatively unconstrained and substantial genetic basis, as well as structural and functional independence from other fitness traits of mammalian colouration might be responsible for that observation. PMID- 28615686 TI - Formation and electronic properties of palladium hydrides and palladium-rhodium dihydride alloys under pressure. AB - We present the formation possibility for Pd-hydrides and Pd-Rh hydrides system by density functional theory (DFT) in high pressure upto 50 GPa. Calculation confirmed that PdH2 in face-centered cubic (fcc) structure is not stable under compression that will decomposition to fcc-PdH and H2. But it can be formed under high pressure while the palladium is involved in the reaction. We also indicate a probably reason why PdH2 can not be synthesised in experiment due to PdH is most favourite to be formed in Pd and H2 environment from ambient to higher pressure. With Rh doped, the Pd-Rh dihydrides are stabilized in fcc structure for 25% and 75% doping and in tetragonal structure for 50% doping, and can be formed from Pd, Rh and H2 at high pressure. The electronic structural study on fcc type Pd x Rh1 xH2 indicates the electronic and structural transition from metallic to semi metallic as Pd increased from x = 0 to 1. PMID- 28615688 TI - Interaction-induced edge states in anisotropic non-Fermi liquids. AB - We devise an approach to calculation of scaling dimensions of generic operators describing scattering within multi-channel Luttinger liquid. The local impurity scattering in arbitrary configuration of conducting and insulating channels is investigated and the problem is reduced to a single algebraic matrix equation. The application to a semi-infinite array of chains described by Luttinger liquid models demonstrates that for a weak inter-chain hybridisation and intra-channel electron-electron attraction the edge wire is robust against disorder whereas bulk wires, on contrary, become insulating in some region of inter-chain interaction parameters. This result proves that the edge states may exist in disordered anisotropic strongly correlated systems without time-reversal symmetry breaking or spin-orbit interaction and provide quantized low-temperature transport. PMID- 28615687 TI - Multi-drug resistant Klebsiella pneumoniae strains circulating in hospital setting: whole-genome sequencing and Bayesian phylogenetic analysis for outbreak investigations. AB - Carbapenems resistant Enterobacteriaceae infections are increasing worldwide representing an emerging public health problem. The application of phylogenetic and phylodynamic analyses to bacterial whole genome sequencing (WGS) data have become essential in the epidemiological surveillance of multi-drug resistant nosocomial pathogens. Between January 2012 and February 2013, twenty-one multi drug resistant K. pneumoniae strains, were collected from patients hospitalized among different wards of the University Hospital Campus Bio-Medico. Epidemiological contact tracing of patients and Bayesian phylogenetic analysis of bacterial WGS data were used to investigate the evolution and spatial dispersion of K. pneumoniae in support of hospital infection control. The epidemic curve of incident K. pneumoniae cases showed a bimodal distribution of cases with two peaks separated by 46 days between November 2012 and January 2013. The time scaled phylogeny suggested that K. pneumoniae strains isolated during the study period may have been introduced into the hospital setting as early as 2007. Moreover, the phylogeny showed two different epidemic introductions in 2008 and 2009. Bayesian genomic epidemiology is a powerful tool that promises to improve the surveillance and control of multi-drug resistant pathogens in an effort to develop effective infection prevention in healthcare settings or constant strains reintroduction. PMID- 28615689 TI - Nomogram model to predict postoperative infection after mandibular osteoradionecrosis surgery. AB - Osteoradionecrosis of the mandible (ORNM) is one of the most dreaded complications of radiotherapy. The poor healing capacity of soft tissue after radiation may lead to surgical failure. The current study was designed to identify prognostic factors for postoperative infection (PPI) and propose corresponding prophylaxis and intervention protocols. A retrospective study was conducted concerning ORNM patients from 2000 to 2015. A risk-stratification score and nomogram model were established to predict the risk of PPI. A total of 257 patients were analyzed, and the total incidence of PPI was 23.3% (60/257). In multiple logistic regression analysis, radiation dose [Formula: see text]80 Gy (versus <80 Gy, OR = 2.044, P = 0.035, 95% CI: 1.05-3.979), bilateral ORNM (versus unilateral, OR = 4.120, P = 0.006, 95% CI: 1.501-11.307), skin fistula (versus none, OR = 3.078, P = 0.040, 95% CI: 1.05-9.023), and implant utilization (versus none, OR = 2.115, P = 0.020, 95% CI: 1.125-3.976) were significantly associated with PPI. The susceptibility to PPI in patients with risk stratification scores of 14-22 was 2.833 times that of patients with scores of 7 13, and 7.585 times that of cases defined as scores of 0-6. The discrimination capability of the nomogram model was estimated using a ROC curve with an AUC of 0.708, revealing potentially useful predictive abilities. In conclusion, current risk-stratification scores and nomogram models effectively predicted the risk of PPI in ORNM patients. PMID- 28615690 TI - Cathepsin D regulates lipid metabolism in murine steatohepatitis. AB - : Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism. CONCLUSION: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH. PMID- 28615691 TI - Human myogenic reserve cells are quiescent stem cells that contribute to muscle regeneration after intramuscular transplantation in immunodeficient mice. AB - Satellite cells, localized within muscles in vivo, are Pax7+ muscle stem cells supporting skeletal muscle growth and regeneration. Unfortunately, their amplification in vitro, required for their therapeutic use, is associated with reduced regenerative potential. In the present study, we investigated if human myogenic reserve cells (MRC) obtained in vitro, represented a reliable cell source for muscle repair. For this purpose, primary human myoblasts were freshly isolated and expanded. After 2 days of differentiation, 62 +/- 2.9% of the nuclei were localized in myotubes and 38 +/- 2.9% in the mononucleated non-fusing MRC. Eighty percent of freshly isolated human MRC expressed a phenotype similar to human quiescent satellite cells (CD56+/Pax7+/MyoD-/Ki67- cells). Fourteen days and 21 days after cell transplantation in immunodeficient mice, live human cells were significantly more numerous and the percentage of Pax7+/human lamin A/C+ cells was 2 fold higher in muscles of animals injected with MRC compared to those injected with human myoblasts, despite that percentage of spectrin+ and lamin A/C+ human fibers in both groups MRC were similar. Taken together, these data provide evidence that MRC generated in vitro represent a promising source of cells for improving regeneration of injured skeletal muscles. PMID- 28615692 TI - Wnt5a is associated with right ventricular dysfunction and adverse outcome in dilated cardiomyopathy. AB - The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling. PMID- 28615693 TI - The CCR4-NOT complex contributes to repression of Major Histocompatibility Complex class II transcription. AB - The multi-subunit CCR4 (carbon catabolite repressor 4)-NOT (Negative on TATA) complex serves as a central coordinator of all different steps of eukaryotic gene expression. Here we performed a systematic and comparative analysis of cells where the CCR4-NOT subunits CNOT1, CNOT2 or CNOT3 were individually downregulated using doxycycline-inducible shRNAs. Microarray experiments showed that downregulation of either CNOT subunit resulted in elevated expression of major histocompatibility complex class II (MHC II) genes which are found in a gene cluster on chromosome 6. Increased expression of MHC II genes after knock-down or knock-out of either CNOT subunit was seen in a variety of cell systems and also in naive macrophages from CNOT3 conditional knock-out mice. CNOT2-mediated repression of MHC II genes occurred also in the absence of the master regulator class II transactivator (CIITA) and did not cause detectable changes of the chromatin structure at the chromosomal MHC II locus. CNOT2 downregulation resulted in an increased de novo transcription of mRNAs whereas tethering of CNOT2 to a regulatory region governing MHC II expression resulted in diminished transcription. These results expand the known repertoire of CCR4-NOT members for immune regulation and identify CNOT proteins as a novel group of corepressors restricting class II expression. PMID- 28615694 TI - Selective serotonin reuptake inhibitor, fluoxetine, impairs E-cadherin-mediated cell adhesion and alters calcium homeostasis in pancreatic beta cells. AB - Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mood disorders. Long term use of SSRIs is associated with an increased risk of diabetes, but the underlying mechanism(s) remains elusive. E-cadherin mediated cell-cell adhesion and elevated [Ca2+]i are important for insulin release and pancreatic beta cell functions. This study aims to investigate whether a SSRI, fluoxetine (Prozac), induces pancreatic beta cell dysfunction through affecting E-cadherin and/or [Ca2+]i. Here we show that fluoxetine significantly reduces glucose stimulated insulin secretion (GSIS). MIN6 cells, an established murine immortalized beta cell line, form smaller colonies of loosely packed cells with reduced cell-cell contact after fluoxetine treatment. Immunofluorescence staining reveals that fluoxetine increases cytoplasmic accumulation of E-cadherin and reduces the membrane-localized E-cadherin probably due to increase of its endocytosis. Fluoxetine inhibits spreading of beta cells on E-cad/Fc coated slides and also disrupts E-cadherin-mediated actin filaments. Additionally, fluoxetine significantly suppresses endoplasmic reticulum (ER) calcium release and store-operated calcium entry (SOCE) activation, probably through reduction of ER calcium storage and inhibition of stromal interaction molecule 1 (STIM1) trafficking. These data suggest that exposure to fluoxetine results in impaired beta cell functions, occurring in concert with reduction of E cadherin-dependent cell adhesion and alterations of calcium homeostasis. PMID- 28615695 TI - Brain-derived neurotrophic factor is regulated via MyD88/NF-kappaB signaling in experimental Streptococcus pneumoniae meningitis. AB - Streptococcus pneumoniae meningitis is an intractable disease of the central nervous system (CNS). Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophic family and found to participate in the immune inflammatory response. In this study, we investigated if activation of the classical inflammatory signaling pathway, myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-kappaB), regulates BDNF expression in experimental S. pneumoniae meningitis. MyD88 knockout (myd88-/-) mice and wild-type littermates were infected intracisternally with S. pneumoniae suspension. Twenty-four hours after inoculation, histopathology of brains was evaluated. Cytokine and chemokine in brains and spleens was analyzed using ELISA. NF-kappaB activation was evaluated using EMSA. Cortical and hippocampal BDNF was assessed using RT-PCR and ELISA, respectively. BDNF promoter activity was evaluated using ChIP-PCR. myd88-/- mice showed an obviously weakened inflammatory host response. This diminished inflammation was consistent with worse clinical parameters, neuron injury, and apoptosis. Deficiency in MyD88 was associated with decreased BDNF expression. Furthermore, we identified a valid kappaB-binding site in the BDNF promoter, consistent with activation of NF-kappaB induced by inflammation. To sum up, MyD88/NF-kappaB signaling has a crucial role in up-regulating BDNF, which might provide potential therapeutic targets for S. pneumoniae meningitis. PMID- 28615696 TI - Intraoperative imaging of hepatic cancers using gamma-glutamyltranspeptidase specific fluorophore enabling real-time identification and estimation of recurrence. AB - gamma-Glutamyltranspeptidase (GGT) is upregulated in a variety of human cancers including primary and secondary hepatic tumors. This motivated us to use gamma glutamyl hydroxymethyl rhodamine green (gGlu-HMRG), a novel fluorophore emitting light at around 520 nm following enzymatic reaction with GGT, as a tool for the intraoperative identification of hepatic tumors. gGlu-HMRG was topically applied to 103 freshly resected hepatic specimens. Fluorescence imaging using gGlu-HMRG identified hepatic tumors with the sensitivity/specificity of 48%/96% for hepatocellular carcinoma, 100%/100% for intrahepatic cholangiocarcinoma, and 87%/100% for colorectal liver metastasis. High gGlu-HMRG fluorescence intensity was positively associated with the incidence of microscopic vascular invasion in HCC and the risk of early postoperative recurrence in CRLM. These results suggest that gGlu-HMRG imaging could not only be a useful intraoperative navigation tool but also provide information related to postoperative disease recurrence. PMID- 28615697 TI - Remodeling of the cycling transcriptome of the oyster Crassostrea gigas by the harmful algae Alexandrium minutum. AB - As a marine organism, the oyster Crassostrea gigas inhabits a complex biotope governed by interactions between the moon and the sun cycles. We used next generation sequencing to investigate temporal regulation of oysters under light/dark entrainment and the impact of harmful algal exposure. We found that ~6% of the gills' transcriptome exhibits circadian expression, characterized by a nocturnal and bimodal pattern. Surprisingly, a higher number of ultradian transcripts were also detected under solely circadian entrainment. The results showed that a bloom of Alexandrium minutum generated a remodeling of the bivalve's temporal structure, characterized by a loss of oscillations, a genesis of de novo oscillating transcripts, and a switch in the period of oscillations. These findings provide unprecedented insights into the diurnal landscape of the oyster's transcriptome and pleiotropic remodeling due to toxic algae exposure, revealing the intrinsic plasticity of the cycling transcriptome in oysters. PMID- 28615698 TI - Divergent Anabolic Signalling responses of Murine Soleus and Tibialis Anterior Muscles to Chronic 2G Hypergravity. AB - The purpose of the study was to assess the rate of protein synthesis (PS) and elucidate signalling pathways regulating PS in mouse soleus (Sol) and tibialis anterior (TA) muscles following chronic hypergravity (30-day centrifugation at 2G). The content of the key signalling proteins of the various anabolic signalling pathways was determined by Western-blotting. The rate of PS was assessed using in-vivo SUnSET technique. An exposure to 2G centrifugation did not induce any significant changes in the rate of PS as well as phosphorylation status of the key anabolic markers (AKT, p70s6k, 4E-BP1, GSK-3beta, eEF2) in Sol. On the contrary, a significant 55% increase in PS (p < 0.05) was found in TA. The cause of such a rise in PS could be associated with an increase in AKT (+72%, p < 0.05), GSK-3beta (+60%, p < 0.05) and p70s6k (+40%, p < 0.05) phosphorylation, as well as a decrease in eEF2 phosphorylation (-46%, p < 0.05) as compared to control values. Thus, the results of our study indicate that 30-day 2G centrifugation induces a distinct anabolic response in mouse Sol and TA muscles. The activation of the PS rate in TA could be linked to an up-regulation of both mTORC1-dependent and mTORC1-independent signalling pathways. PMID- 28615700 TI - Urban conservation hotspots: predation release allows the grassland-specialist burrowing owl to perform better in the city. AB - Although habitat transformation is one of the main causes of biodiversity loss, there are many examples of species successfully occupying and even proliferating in highly human-modified habitats such are the cities. Thus, there is an increasing interest in understanding the drivers favoring urban life for some species. Here, we show how the low richness and abundance of predators in urban areas may explain changes in the habitat selection pattern of a grassland specialist species, the burrowing owl Athene cunicularia, toward urban habitats. Predation release improves the demographic parameters of urban individuals, thus favoring an increment in the breeding density of the species in urban areas that accounts for the apparent positive selection of this habitat in detriment of the more natural ones that are avoided. These results suggest that traditional habitat selection analyses do not necessarily describe habitat choice decisions actively taken by individuals but differences in their demographic prospects. Moreover, they also highlight that cites, as predator-free refuges, can become key conservation hotspots for some species dependent on threatened habitats such as the temperate grasslands of South America. PMID- 28615699 TI - Novel regulatory mechanism of serine biosynthesis associated with 3 phosphoglycerate dehydrogenase in Arabidopsis thaliana. AB - The proteinogenic amino acid L-serine is a precursor for various essential biomolecules in all organisms. 3-Phosphoglycerate dehydrogenase (PGDH) is the first committed enzyme of the phosphorylated pathway of L-serine biosynthesis, and is regulated by negative feedback from L-serine in bacteria and plants. In the present study, two Arabidopsis PGDH isoforms were inhibited by L-serine but were activated by L-amino acids such as L-homocysteine in vitro. Activation and inhibition by these amino acids was cooperative, suggesting an allosteric mechanism. Moreover, the half maximal effective concentration of L-homocysteine was 2 orders of magnitude lower than that of L-serine, suggesting greater regulatory potency. These are the first data to show that PGDH is activated by various biomolecules and indicate that serine biosynthesis is regulated by multiple pathways. PMID- 28615701 TI - Revisiting Zika (and Rubella). AB - Three months after the World Health Organization declared the epidemic of Zika virus infections to be a Public Health Emergency of International Concern, we can look back at what we have learned and prospects for controlling the disease. Although Zika virus infections may explain many cases of brain damage in newborns, it may not be the only cause. We need a clear association between confirmed cases of Zika infections in pregnant women and microcephaly in newborns. Until we reach a firm conclusion, past experience with another virus that causes damage to newborns offers some hope. The development and almost universal use of rubella vaccine has all but eliminated the congenital rubella syndrome in the world. Rapid development of Zika virus vaccine might well do the same for this epidemic. PMID- 28615702 TI - Violence, health, and the 2030 agenda: merging evidence and implementation : A Sponsored Special Issue. PMID- 28615703 TI - Building codes and public health on both sides of the Atlantic. PMID- 28615704 TI - The early metabolomic response of adipose tissue during acute cold exposure in mice. AB - To maintain core body temperature in cold conditions, mammals activate a complex multi-organ metabolic response for heat production. White adipose tissue (WAT) primarily functions as an energy reservoir, while brown adipose tissue (BAT) is activated during cold exposure to generate heat from nutrients. Both BAT and WAT undergo specific metabolic changes during acute cold exposure. Here, we use an untargeted metabolomics approach to characterize the initial metabolic response to cold exposure in multiple adipose tissue depots in mice. Results demonstrate dramatically distinct metabolic responses during cold exposure in BAT and WAT. Amino acids, nucleotide pathways, and metabolites involved in redox regulation were greatly affected 4 hours post-exposure in BAT, while no polar metabolites were observed to significantly change in WAT depots up to 6 hours post exposure. Lipid metabolism was activated early (2 hours) in both BAT and the subcutaneous WAT depots, with the most striking change being observed in the modulation of diglyceride and monoglyceride levels in BAT. Overall, these data provide a timeline of global thermogenic metabolism in adipose depots during acute cold exposure. We have highlighted differences in visceral and subcutaneous WAT thermogenic metabolism and demonstrate the distinct metabolism of BAT during cold exposure. PMID- 28615705 TI - A Long-Term and Slow-Releasing Hydrogen Sulfide Donor Protects against Myocardial Ischemia/Reperfusion Injury. AB - Hydrogen sulfide (H2S) has been recognized as an important gasotransmitter exerting various physiological effects, especially in the cardiovascular system. Herein we investigated the cardioprotective effects of a novel long-term and slow releasing H2S donor, DATS-MSN, using in vivo myocardial ischemia/reperfusion (I/R) models and in vitro hypoxia/reoxygenation cardiomyocyte models. Unlike the instant-releasing pattern of sodium hydrosulphide (NaHS), the release of H2S from DATS-MSN was quite slow and continuous both in the cell culture medium and in rat plasma (elevated H2S concentrations during 24 h and 72 h reperfusion). Correspondingly, DATS-MSN demonstrated superior cardioprotective effects over NaHS in I/R models, which were associated with greater survival rates, reduced CK MB and troponin I levels, decreased cardiomyocyte apoptosis index, increased antioxidant enzyme activities, inhibited myocardial inflammation, greater reduction in the infarct area and preserved cardiac ejection fraction. Some of these effects of DATS-MSN were also found to be superior to classic slow releasing H2S donor, GYY4137. In in vitro experiments, cardiomyocytes injury was also found to be relived with the use of DATS-MSN compared to NaHS after the hypoxia/reoxygenation processes. The present work provides a novel long-term and slow-releasing H2S donor and an insight into how the release patterns of H2S donors affect its physiological functionality. PMID- 28615706 TI - Channel branching and zigzagging in negative cloud-to-ground lightning. AB - A fundamental question in lightning flash concerns why the discharge channel propagates in a zig-zag manner and produces extensive branches. Here we report the optical observation of two negative cloud-to-ground lightning discharges with very high temporal resolution of 180,000 frames per second, which shows in detail the dependence of channel branching and tortuous behavior on the stepping process of the leader development. It is found that the clustered space leaders formed in parallel ahead of the channel tip during an individual step process. The leader branching is due to the multiple connection of the clustered space leaders with the same root channel tip, which occur almost simultaneously, or successively as some space leaders/stems resurrect after interruption. Meanwhile, the irregularity of angles between the clustered space leaders and the advancing direction of leader tip is the origin of channel tortuosity. The statistical analysis on 96 steps shows a geometric-mean value of 4.4 m for the step length, ranging between 1.3 and 8.6 m, while the distance from the center of space leader to the channel is 3.6 m, ranging between 2.1 and 6.9 m. More than 50% steps occurred within an angle range of +/-30 degrees from the advancing direction of the leader. PMID- 28615707 TI - 99mTc-labeled bevacizumab for detecting atherosclerotic plaque linked to plaque neovascularization and monitoring antiangiogenic effects of atorvastatin treatment in ApoE-/- mice. AB - Atherosclerotic neovascularization plays a significant role in plaque instability as it provides additional lipids and inflammatory mediators to lesions, and resulting in intraplaque hemorrhage. Vascular endothelial growth factor-A (VEGF A) is considered the predominant proangiogenic factor in angiogenesis. Bevacizumab, a humanized monoclonal antibody, specifically binds to all VEGF-A isoforms with high affinity. Therefore, in this study, we designed 99mTc-MAG3 bevacizumab as a probe, and then investigated its usefulness as a new imaging agent for the detection of plaque neovessels, while also assessing the therapeutic effect of atorvastatin treatment. The ApoE-/- mice treated with atorvastatin were used as the treatment group, and C57BL/6 J mice were selected as the control group. 99mTc-MAG3-bevacizumab uptake was visualized on atherosclerotic lesions by non-invasive in-vivo micro-SPECT/CT and ex-vivo BSGI planar imaging. The value of P/B in each part of the aorta of ApoE-/- mice was higher than in the treatment group and the C57BL/6 J mice, which was confirmed by Oil Red O staining, CD31 staining and VEGF immunohistochemistry staining. 99mTc MAG3-bevacizumab imaging allowed for the non-invasive diagnosis and assessment of plaque neovascularization. Furthermore, this probe may be used as a new molecular imaging agent to assess the antiangiogenic effect of atorvastatin. PMID- 28615709 TI - Programmable Deployment of Tensegrity Structures by Stimulus-Responsive Polymers. AB - Tensegrity structures with detached struts are naturally suitable for deployable applications, both in terrestrial and outer-space structures, as well as morphing devices. Composed of discontinuous struts and continuous cables, such systems are only structurally stable when self-stress is induced; otherwise, they lose the original geometrical configuration (while keeping the topology) and thus can be tightly packed. We exploit this feature by using stimulus responsive polymers to introduce a paradigm for creating actively deployable 3D structures with complex shapes. The shape-change of 3D printed smart materials adds an active dimension to the configurational space of some structural components. Then we achieve dramatic global volume expansion by amplifying component-wise deformations to global configurational change via the inherent deployability of tensegrity. Through modular design, we can generate active tensegrities that are relatively stiff yet resilient with various complexities. Such unique properties enable structural systems that can achieve gigantic shape change, making them ideal as a platform for super light-weight structures, shape-changing soft robots, morphing antenna and RF devices, and biomedical devices. PMID- 28615708 TI - Epitope mapping and kinetics of CD4 T cell immunity to pneumonia virus of mice in the C57BL/6 strain. AB - Pneumonia virus of mice (PVM) infection has been widely used as a rodent model to study the closely related human respiratory syncytial virus (hRSV). While T cells are indispensable for viral clearance, they also contribute to immunopathology. To gain more insight into mechanistic details, novel tools are needed that allow to study virus-specific T cells in C57BL/6 mice as the majority of transgenic mice are only available on this background. While PVM-specific CD8 T cell epitopes were recently described, so far no PVM-specific CD4 T cell epitopes have been identified within the C57BL/6 strain. Therefore, we set out to map H2-IAb restricted epitopes along the PVM proteome. By means of in silico prediction and subsequent functional validation, we were able to identify a MHCII-restricted CD4 T cell epitope, corresponding to amino acids 37-47 in the PVM matrix protein (M37 47). Using this newly identified MHCII-restricted M37-47 epitope and a previously described MHCI-restricted N339-347 epitope, we generated peptide-loaded MHCII and MHCI tetramers and characterized the dynamics of virus-specific CD4 and CD8 T cell responses in vivo. The findings of this study can provide a basis for detailed investigation of T cell-mediated immune responses to PVM in a variety of genetically modified C57BL/6 mice. PMID- 28615710 TI - An alternative conformation of ERbeta bound to estradiol reveals H12 in a stable antagonist position. AB - The natural ligand 17beta-estradiol (E2) is so far believed to induce a unique agonist-bound active conformation in the ligand binding domain (LBD) of the estrogen receptors (ERs). Both subtypes, ERalpha and ERbeta, are transcriptionally activated in the presence of E2 with ERbeta being somewhat less active than ERalpha under similar conditions. The molecular bases for this intriguing behavior are mainly attributed to subtype differences in the amino terminal domain of these receptors. However, structural details that confer differences in the molecular response of ER LBDs to E2 still remain elusive. In this study, we present a new crystallographic structure of the ERbeta LBD bound to E2 in which H12 assumes an alternative conformation that resembles antagonist ERs structures. Structural observations and molecular dynamics simulations jointly provide evidence that alternative ERbeta H12 position could correspond to a stable conformation of the receptor under physiological pH conditions. Our findings shed light on the unexpected role of LBD in the lower functional response of ERbeta subtype. PMID- 28615711 TI - Identification and characterization of a rich population of CD34+ mesenchymal stem/stromal cells in human parotid, sublingual and submandibular glands. AB - Mesenchymal stem/stromal cells (MSCs) play crucial roles in maintaining tissue homeostasis during physiological turnovers and injuries. Very little is known about the phenotype, distribution and molecular nature of MSCs in freshly isolated human salivary glands (SGs) as most reports have focused on the analysis of cultured MSCs. Our results demonstrate that the cell adhesion molecule CD34 was widely expressed by the MSCs of human major SGs, namely parotid (PAG), sublingual (SLG) and submandibular (SMG) glands. Further, gene expression analysis of CD34+ cells derived from fetal SMGs showed significant upregulation of genes involved in cellular adhesion, proliferation, branching, extracellular matrix remodeling and organ development. Moreover, CD34+ SMG cells exhibited elevated expression of genes encoding extracellular matrix, basement membrane proteins, and members of ERK, FGF and PDGF signaling pathways, which play key roles in glandular development, branching and homeostasis. In vitro CD34+ cell derived SG-MSCs revealed multilineage differentiation potential. Intraglandular transplantation of cultured MSCs in immunodeficient mice led to their engraftment in the injected and uninjected contralateral and ipsilateral glands. Engrafted cells could be localized to the stroma surrounding acini and ducts. In summary, our data show that CD34+ derived SG-MSCs could be a promising cell source for adoptive cell-based SG therapies, and bioengineering of artificial SGs. PMID- 28615712 TI - Cell-specific expression of aquaporin-5 (Aqp5) in alveolar epithelium is directed by GATA6/Sp1 via histone acetylation. AB - Epigenetic regulation of differentiation-related genes is poorly understood. We previously reported that transcription factors GATA6 and Sp1 interact with and activate the rat proximal 358-bp promoter/enhancer (p358P/E) of lung alveolar epithelial type I (AT1) cell-specific gene aquaporin-5 (Aqp5). In this study, we found that histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) increased AQP5 expression and Sp1-mediated transcription of p358P/E. HDAC3 overexpression inhibited Sp1-mediated Aqp5 activation, while HDAC3 knockdown augmented AQP5 protein expression. Knockdown of GATA6 or transcriptional co activator/histone acetyltransferase p300 decreased AQP5 expression, while p300 overexpression enhanced p358P/E activation by GATA6 and Sp1. GATA6 overexpression, SAHA treatment or HDAC3 knockdown increased histone H3 (H3) but not histone H4 (H4) acetylation within the homologous p358P/E region of mouse Aqp5. HDAC3 binds to Sp1 and HDAC3 knockdown increased interaction of GATA6/Sp1, GATA6/p300 and Sp1/p300. These results indicate that GATA6 and HDAC3 control Aqp5 transcription via modulation of H3 acetylation/deacetylation, respectively, through competition for binding to Sp1, and suggest that p300 modulates acetylation and/or interacts with GATA6/Sp1 to regulate Aqp5 transcription. Cooperative interactions among transcription factors and histone modifications regulate Aqp5 expression during alveolar epithelial cell transdifferentiation, suggesting that HDAC inhibitors may enhance repair by promoting acquisition of AT1 cell phenotype. PMID- 28615713 TI - Exosomal microRNAs in giant panda (Ailuropoda melanoleuca) breast milk: potential maternal regulators for the development of newborn cubs. AB - The physiological role of miRNAs is widely understood to include fine-tuning the post-transcriptional regulation of a wide array of biological processes. Extensive studies have indicated that exosomal miRNAs in the bodily fluids of various organisms can be transferred between living cells for the delivery of gene silencing signals. Here, we illustrated the expression characteristics of exosomal miRNAs in giant panda breast milk during distinct lactation periods and highlighted the enrichment of immune- and development-related endogenous miRNAs in colostral and mature giant panda milk. These miRNAs are stable, even under certain harsh conditions, via the protection of extracellular vesicles. These findings indicate that breast milk may facilitate the dietary intake of maternal miRNAs by infants for the regulation of postnatal development. We also detected exogenous plant miRNAs from the primary food source of the giant panda (bamboo) in the exosomes of giant panda breast milk that were associated with regulatory roles in basic metabolism and neuron development. This result suggested that dietary plant miRNAs are absorbed by host cells and subsequently secreted into bodily fluids as potential cross-kingdom regulators. In conclusion, exosomal miRNAs in giant panda breast milk may be crucial maternal regulators for the development of intrinsic 'slink' newborn cubs. PMID- 28615714 TI - Platelet distribution width correlates with prognosis of non-small cell lung cancer. AB - Platelets play a multifaceted role in cancer progression and metastasis. Mean platelet volume (MPV) and platelet distribution width (PDW) are commonly used platelet parameters from routine blood test. The aim of the present study was to investigate the correlation between platelet indices and prognosis in patients with non-small cell lung cancer (NSCLC). A total of 270 patients who were diagnosed with NSCLC between January 2009 and December 2009 were retrospectively analyzed. Patients' characteristics and hematologic tests data at initial diagnosis were collected. The overall survival rate was estimated using Kaplan Meier method. The prognostic analysis was carried out with univariate and multivariate Cox regressions model. Reduced PDW was significantly correlated with T stage, N stage, TNM stage, and histological type of the disease. Moreover, survival analysis showed that the overall survival of patients with PDW >= 16.3% was significantly longer than that of those with PDW < 16.3% (P < 0.001). In multivariate Cox regression model, age, sex, TNM stage, and PDW were identified as independent prognostic factors for overall survival (for PDW, P < 0.001). In conclusion, reduced PDW is an unfavorable predictive factor of NSCLC patient survival. Further studies are warranted. PMID- 28615715 TI - RNAseq based transcriptomics study of SMCs from carotid atherosclerotic plaque: BMP2 and IDs proteins are crucial regulators of plaque stability. AB - Carotid artery atherosclerosis is a risk factor to develop cerebrovascular disease. Atheroma plaque can become instable and provoke a cerebrovascular event or else remain stable as asymptomatic type. The exact mechanism involved in plaque destabilization is not known but includes among other events smooth muscle cell (SMC) differentiation. The goal of this study was to perform thorough analysis of gene expression differences in SMCs isolated from carotid symptomatic versus asymptomatic plaques. Comparative transcriptomics analysis of SMCs based on RNAseq technology identified 67 significant differentially expressed genes and 143 significant differentially expressed isoforms in symptomatic SMCs compared with asymptomatic. 37 of top-scoring genes were further validated by digital PCR. Enrichment and network analysis shows that the gene expression pattern of SMCs from stable asymptomatic plaques is suggestive for an osteogenic phenotype, while that of SMCs from unstable symptomatic plaque correlates with a senescence-like phenotype. Osteogenic-like phenotype SMCs may positively affect carotid atheroma plaque through participation in plaque stabilization via bone formation processes. On the other hand, plaques containing senescence-like phenotype SMCs may be more prone to rupture. Our results substantiate an important role of SMCs in carotid atheroma plaque disruption. PMID- 28615716 TI - Lipid vesicles containing transferrin receptor binding peptide TfR-T12 and octa arginine conjugate stearyl-R8 efficiently treat brain glioma along with glioma stem cells. AB - Surgery and radiotherapy cannot fully remove brain glioma; thus, chemotherapy continues to play an important role in treatment of this illness. However, because of the restriction of the blood-brain barrier (BBB) and the regeneration of glioma stem cells, post-chemotherapy relapse usually occurs. Here, we report a potential solution to these issues that involves a type of novel multifunctional vinblastine liposomes equipped with transferrin receptor binding peptide TfR-T12 and octa-arginine conjugate stearyl-R8. Studies were performed on brain glioma and glioma stem cells in vitro and were verified in brain glioma-bearing mice. The liposomes were transported across the BBB, killing brain glioma and glioma stem cells via the induction of necrosis, apoptosis and autophagy. Furthermore, we reveal the molecular mechanisms for treating brain glioma and glioma stem cells via functionalized drug lipid vesicles. PMID- 28615717 TI - Image based Machine Learning for identification of macrophage subsets. AB - Macrophages play a crucial rule in orchestrating immune responses against pathogens and foreign materials. Macrophages have remarkable plasticity in response to environmental cues and are able to acquire a spectrum of activation status, best exemplified by pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes at the two ends of the spectrum. Characterisation of M1 and M2 subsets is usually carried out by quantification of multiple cell surface markers, transcription factors and cytokine profiles. These approaches are time-consuming, require large numbers of cells and are resource intensive. In this study, we used machine learning algorithms to develop a simple and fast imaging-based approach that enables automated identification of different macrophage functional phenotypes using their cell size and morphology. Fluorescent microscopy was used to assess cell morphology of different cell types which were stained for nucleus and actin distribution using DAPI and phalloidin respectively. By only analysing their morphology we were able to identify M1 and M2 phenotypes effectively and could distinguish them from naive macrophages and monocytes with an average accuracy of 90%. Thus we suggest high-content and automated image analysis can be used for fast phenotyping of functionally diverse cell populations with reasonable accuracy and without the need for using multiple markers. PMID- 28615718 TI - Genome-wide analyses of SWEET family proteins reveal involvement in fruit development and abiotic/biotic stress responses in banana. AB - Sugars Will Eventually be Exported Transporters (SWEET) are a novel type of sugar transporter that plays crucial roles in multiple biological processes. From banana, for the first time, 25 SWEET genes which could be classified into four subfamilies were identified. Majority of MaSWEETs in each subfamily shared similar gene structures and conserved motifs. Comprehensive transcriptomic analysis of two banana genotypes revealed differential expression patterns of MaSWEETs in different tissues, at various stages of fruit development and ripening, and in response to abiotic and biotic stresses. More than 80% MaSWEETs were highly expressed in BaXi Jiao (BX, Musa acuminata AAA group, cv. Cavendish), in sharp contrast to Fen Jiao (FJ, M. acuminata AAB group) when pseudostem was first emerged. However, MaSWEETs in FJ showed elevated expression under cold, drought, salt, and fungal disease stresses, but not in BX. Interaction networks and co-expression assays further revealed that MaSWEET-mediated networks participate in fruit development signaling and abiotic/biotic stresses, which was strongly activated during early stage of fruit development in BX. This study provides new insights into the complex transcriptional regulation of SWEETs, as well as numerous candidate genes that promote early sugar transport to improve fruit quality and enhance stress resistance in banana. PMID- 28615719 TI - Thermal and structural studies of carbon coated Mo2C synthesized via in-situ single step reduction-carburization. AB - Carbon coated nano molybdenum carbide (Mo2C) has been synthesized at 800 degrees C through single step reduction route using molybdenum trioxide (MoO3) as a precursor, polypropylene (P.P) as a carbon source and magnesium (Mg) as a catalyst in an autoclave. The synthesized samples were characterized by X-ray diffraction (XRD), thermal analysis techniques (TG/DTA/DTG), field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). Williamson- Hall (W-H) analysis has been done to estimate various parameters like strain, stress and strain energy density. Multi-stage kinetic analysis of the product phase has been studied to establish the nature of the thermal decomposition. Coats-Redfern method applied to determine the mechanism involved in the decomposition of the product phase shows that initial and final stage follow F1 mechanism whereas middle stage follow F3 mechanism. The activation energy (E a) and pre-exponential factor (A) has also been determined. The morphological studies shows that the particles have partially spherical/faceted shape, with carbon coated having wide particle size distribution. The surface chemistry and surface area analysis were studied by X-ray photoelectron spectroscopy (XPS) and Brunauer-Emmet-Teller (BET), respectively. The formation mechanism of carbon coated Mo2C nano particles has been predicted based on the XRD, TG/DTA & DTG and microstructural results. PMID- 28615721 TI - Spatio-temporal variability of trace elements fingerprints in cockle (Cerastoderma edule) shells and its relevance for tracing geographic origin. AB - Understanding spatio-temporal variability of trace elements fingerprints (TEF) in bivalve shells is paramount to determine the discrimination power of this analytical approach and secure traceability along supply chains. Spatio-temporal variability of TEF was assessed in cockle (Cerastoderma edule) shells using inductively coupled plasma-mass spectrometry (ICP-MS). Four elemental ratios (Mg/Ca, Mn/Ca, Sr/Ca and Ba/Ca) were measured from the shells of specimens originating from eight different ecosystems along the Portuguese coast, as well as from four different areas, within one of them, over two consecutive years (2013 and 2014). TEF varied significantly in the shells of bivalves originating from the eight ecosystems surveyed in the present study. Linear discriminant function analyses assigned sampled cockles to each of the eight ecosystems with an average accuracy of 90%. Elemental ratios also displayed significant differences between the two consecutive years in the four areas monitored in the same ecosystem. Overall, while TEF displayed by cockle shells can be successfully used to trace their geographic origin, a periodical verification of TEF (>6 months and <1 year) is required to control for temporal variability whenever comparing specimens originating from the same area collected more than six months apart. PMID- 28615720 TI - ARC6-mediated Z ring-like structure formation of prokaryote-descended chloroplast FtsZ in Escherichia coli. AB - Plant chloroplasts proliferate through binary fission, and the stromal-side molecules that are involved in chloroplast division are bacterial derivatives. As in bacteria, the prokaryotic tubulin homolog FtsZ assembles into a ring-like structure (Z ring) at mid-chloroplast, and this process is followed by constriction. However, the properties of chloroplast FtsZs remain unclarified. Here, we employed Escherichia coli as a novel heterologous system for expressing chloroplast FtsZs and their regulatory components. Fluorescently labelled Arabidopsis FtsZ2 efficiently assembled into long filaments in E. coli cells, and artificial membrane tethering conferred FtsZ2 filaments with the ability to form Z ring-like structures resembling the bacterial Z ring. A negative regulator of chloroplast FtsZ assembly, ARC3, retained its inhibitory effects on FtsZ2 filamentation and Z ring-like structure formation in E. coli cells. Thus, we provide a novel heterologous system by using bacterial cells to study the regulation of the chloroplast divisome. Furthermore, we demonstrated that the FtsZ2-interacting protein ARC6, which is a potential candidate for Z ring tethering to the chloroplast inner envelope membrane, genuinely targeted FtsZ2 to the membrane components and supported its morphological shift from linear filaments to Z ring-like structures in a manner dependent on the C-terminal ARC6 interacting domain of FtsZ2. PMID- 28615722 TI - A novel, simple and rapid route to the synthesis of boron cabonitride nanosheets: combustive gaseous unfolding. AB - The ternary compound boron carbonitride (BCN) was synthesized in the form of few layer nanosheets through a mechanically induced self-sustaining reaction (MSR). Magnesium was used to reduce boron trioxide in the presence of melamine in a combustive manner. The process to form the nanostructured material was very rapid (less than 40 min). The prepared powder was investigated by various techniques such as X-ray diffraction (XRD), Fourier Transform infrared (FTIR), Micro-Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), high-resolution transmission electron microscopy (HRTEM), and electron energy loss spectroscopy (EELS). The thermal stability and the optical behavior of the BCN nanosheets were also studied by thermal analysis and UV-vis spectroscopy, respectively. The formation mechanism of the nanosheet morphology was described in detail. PMID- 28615723 TI - Core-multishell globular oxidation in a new TiAlNbCr alloy at high temperatures. AB - Oxidation resistance is one of key properties of titanium aluminide (TiAl) based alloys for high-temperature applications such as in advanced aero-engines and gas turbines. A new TiAlNbCr alloy with micro-addition of yttrium has been developed, but its oxidation behavior is unknown. To provide some fundamental insights, high temperature oxidation characteristics of this alloy are examined via scanning electron microscopy, transmission electron microscopy, electron probe microanalysis, and X-ray diffraction. We show that distinctive core-multishell globular oxidation and "daisy" flower-like oxidation occur exclusively around Y2O3 particles. Globular oxides exhibit multi-layered Y2O3/TiO2/Al2O3-rich/TiO2 rich shell structures from the inside to outside. Flower-like inner oxides consist of core Y2O3 particles surrounded by divergent Al2O3 and oxygen-rich alpha2-Ti3Al in the near-scale substrate. As the scale-substrate interface moves inward, the inner oxide structures suffer deeper oxidation and transform into the globular oxide structures. Our results demonstrate that the unique oxidation characteristics and the understanding of formation mechanisms pave the way for the exploration and development of advanced oxidation-resistant TiAl-based materials. PMID- 28615724 TI - Tunable transport property of oxygen ion in metal oxide thin film: Impact of electrolyte orientation on conductivity. AB - Quest for efficient ion conducting electrolyte thin film operating at intermediate temperature (~600 degrees C) holds promise for the real-world utilization of solid oxide fuel cells. Here, we report the correlation between mixed as well as preferentially oriented samarium doped cerium oxide electrolyte films fabricated by varying the substrate temperatures (100, 300 and 500 degrees C) over anode/ quartz by electron beam physical vapor deposition. Pole figure analysis of films deposited at 300 degrees C demonstrated a preferential (111) orientation in out-off plane direction, while a mixed orientation was observed at 100 and 500 degrees C. As per extended structural zone model, the growth mechanism of film differs with surface mobility of adatom. Preferential orientation resulted in higher ionic conductivity than the films with mixed orientation, demonstrating the role of growth on electrochemical properties. The superior ionic conductivity upon preferential orientation arises from the effective reduction of anisotropic nature and grain boundary density in highly oriented thin films in out-of-plane direction, which facilitates the hopping of oxygen ion at a lower activation energy. This unique feature of growing an oriented electrolyte over the anode material opens a new approach to solving the grain boundary limitation and makes it as a promising solution for efficient power generation. PMID- 28615726 TI - Microfluidic co-cultures of retinal pigment epithelial cells and vascular endothelial cells to investigate choroidal angiogenesis. AB - Angiogenesis plays a critical role in many diseases, including macular degeneration. At present, the pathological mechanisms remain unclear while appropriate models dissecting regulation of angiogenic processes are lacking. We propose an in vitro angiogenesis process and test it by examining the co-culture of human retinal pigmental epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVEC) inside a microfluidic device. From characterisation of the APRE-19 monoculture, the tight junction protein (ZO-1) was found on the cells cultured in the microfluidic device but changes in the medium conditions did not affect the integrity of monolayers found in the permeability tests. Vascular endothelial growth factor (VEGF) secretion was elevated under low glucose and hypoxia conditions compared to the control. After confirming the angiogenic ability of HUVEC, the cell-cell interactions were analyzed under lowered glucose medium and chemical hypoxia by exposing ARPE-19 cells to cobalt (II) chloride (CoCl2). Heterotypic interactions between ARPE-19 and HUVEC were observed, but proliferation of HUVEC was hindered once the monolayer of ARPE-19 started breaking down. The above characterisations showed that alterations in glucose concentration and/or oxygen level as induced by chemical hypoxia causes elevations in VEGF produced in ARPE-19 which in turn affected directional growth of HUVEC. PMID- 28615725 TI - Transcriptome analysis reveals similarities between human blood CD3- CD56bright cells and mouse CD127+ innate lymphoid cells. AB - For many years, human peripheral blood natural killer (NK) cells have been divided into functionally distinct CD3- CD56bright CD16- and CD3- CD56dim CD16+ subsets. Recently, several groups of innate lymphoid cells (ILC), distinct from NK cells in development and function, have been defined in mouse. A signature of genes present in mouse ILC except NK cells, defined by Immunological Genome Project studies, is significantly over-represented in human CD56bright cells, by gene set enrichment analysis. Conversely, the signature genes of mouse NK cells are enriched in human CD56dim cells. Correlations are based upon large differences in expression of a few key genes. CD56bright cells show preferential expression of ILC-associated IL7R (CD127), TNFSF10 (TRAIL), KIT (CD117), IL2RA (CD25), CD27, CXCR3, DPP4 (CD26), GPR183, and MHC class II transcripts and proteins. This could indicate an ontological relationship between human CD56bright cells and mouse CD127+ ILC, or conserved networks of transcriptional regulation. In line with the latter hypothesis, among transcription factors known to impact ILC or NK cell development, GATA3, TCF7 (TCF-1), AHR, SOX4, RUNX2, and ZEB1 transcript levels are higher in CD56bright cells, while IKZF3 (AIOLOS), TBX21 (T-bet), NFIL3 (E4BP4), ZEB2, PRDM1 (BLIMP1), and RORA mRNA levels are higher in CD56dim cells. PMID- 28615727 TI - Oestrogen Inhibits Arterial Calcification by Promoting Autophagy. AB - Arterial calcification is a major complication of cardiovascular disease. Oestrogen replacement therapy in postmenopausal women is associated with lower levels of coronary artery calcification, but its mechanism of action remains unclear. Here, we show that oestrogen inhibits the osteoblastic differentiation of vascular smooth muscle cells (VSMCs) in vitro and arterial calcification in vivo by promoting autophagy. Through electron microscopy, GFP-LC3 redistribution, and immunofluorescence analyses as well as measurement of the expression of the autophagosome marker light-chain I/II (LC3I/II) and autophagy protein 5 (Atg5), we show that autophagy is increased in VSMCs by oestrogen in vitro and in vivo. The inhibitory effect of oestrogen on arterial calcification was counteracted by 3-methyladenine (3MA) or knockdown of Atg5 and was increased by rapamycin. Furthermore, the inhibitory effect of oestrogen on arterial calcification and the degree of autophagy induced by oestrogen were blocked by a nonselective oestrogen receptor (ER) antagonist (ICI 182780), a selective oestrogen receptor alpha (ERalpha) antagonist (MPP), and ERalpha-specific siRNA. Our data indicate that oestrogen inhibits the osteoblastic differentiation of VSMCs by promoting autophagy through the ERalpha signalling pathway in vitro and arterial calcification in vivo by increasing autophagy. Our findings provide new insights into the mechanism by which oestrogen contributes to vascular calcification in vitro and in vivo. PMID- 28615728 TI - Violation of the virial theorem and generalized equipartition theorem for logarithmic oscillators serving as a thermostat. AB - A logarithmic oscillator has been proposed to serve as a thermostat recently since it has a peculiar property of infinite heat capacity according to the virial theorem. In order to examine its feasibility in numerical simulations, a modified logarithmic potential has been applied in previous studies to eliminate the singularity at the origin. The role played by the modification has been elucidated in the present study. We argue that the virial theorem is practically violated in finite-time simulations of the modified log-oscillator illustrated by a linear dependence of kinetic temperature on energy. Furthermore, as far as a thermalized log-oscillator is concerned, our calculation based on the canonical ensemble average shows that the generalized equipartition theorem is broken if the temperature is higher than a critical temperature. Finally, we show that log oscillators fail to serve as thermostats for their incapability of maintaining a nonequilibrium steady state even though their energy is appropriately assigned. PMID- 28615729 TI - Systemic lupus erythematosus: BAFF emerges from the genetic shadows. PMID- 28615731 TI - The role of IL-6 in host defence against infections: immunobiology and clinical implications. AB - IL-6 is a pleiotropic cytokine with broad-ranging effects within the integrated immune response. One of the roles of IL-6 is to support immunocompetence, defined as the ability of a host to respond to infections. Understanding the precise role of this cytokine in immunocompetence requires a critical appraisal of data derived from both preclinical and clinical studies. Primary immunodeficiency diseases involving IL-6 or its signalling pathways reveal that IL-6 is critical in the defence against numerous types of pathogens. Studies of IL-6 signalling in preclinical models reveal that selective inhibition of either classic IL-6 signalling or IL-6 trans-signalling has differential effects on the host response to different types of infections. Knowledge of such variation might inform bioengineering of new IL-6-targeting molecules and potentially enable modulation of their toxicity. Clinical studies of IL-6 inhibitors, mainly tocilizumab, reveal that their use is associated with an increased rate of both serious and opportunistic infections generally in the range observed with other non-IL-6 directed biologic therapies. Targeting IL-6 has several other important clinical implications related to diagnosis, management and prevention of infectious diseases. PMID- 28615732 TI - Managing rheumatic and musculoskeletal diseases - past, present and future. AB - Progress in rheumatology has been remarkable in the past 70 years, favourably affecting quality of life for people with rheumatic and musculoskeletal diseases. Therapeutics have advanced considerably in this period, from early developments such as the introduction of glucocorticoid therapy to the general use of methotrexate and other disease-modifying agents, followed by the advent of biologic DMARDs and, most recently, small-molecule signalling inhibitors. Novel strategies for the use of such agents have also transformed outcomes, as have multidisciplinary nonpharmacological approaches to the management of rheumatic musculoskeletal disease including surgery, physical therapy and occupational therapy. Breakthroughs in our understanding of disease pathogenesis, diagnostics and the use of 'big data' continue to drive the field forward. Critically, the patient is now at the centre of management strategies as well as the future research agenda. PMID- 28615730 TI - Pain in ankylosing spondylitis: a neuro-immune collaboration. AB - Clinicians have commonly differentiated chronic back pain into two broad subsets: namely, non-inflammatory (or mechanical) back pain and inflammatory back pain. As the terminology suggests, the latter category, in which ankylosing spondylitis (AS) is prominent, presupposes a close link between pain and inflammation. Advances in research into the genetics and immunology of AS have improved our understanding of the inflammatory processes involved in this disease, and have led to the development of potent anti-inflammatory biologic therapeutic agents. However, evidence from clinical trials and from biomarker and imaging studies in patients with AS indicate that pain and inflammation are not always correlated. Thus, the assumption that pain in AS is a reliable surrogate marker for inflammation might be an over-simplification. This Review provides an overview of current concepts relating to neuro-immune interactions in AS and summarizes research that reveals an increasingly complex interplay between the activation of the immune system and pain pathways in the nervous system. The different types of pain experienced by patients with AS, insights from brain imaging studies, neurological mechanisms of pain, sex bias in pain and how the immune system can modify pain in patients with AS are also discussed. PMID- 28615735 TI - Mediational Analysis in a Planned Missingness Data Design: Alternative Model Specifications and Power of the Mediated Effect. PMID- 28615733 TI - Why location matters - site-specific factors in rheumatic diseases. AB - Rheumatic diseases follow a characteristic anatomical pattern of joint and organ involvement. This Review explores three interconnected mechanisms that might be involved in the predilection of specific joints for developing specific forms of arthritis: site-specific local cell types that drive disease; systemic triggers that affect local cell types; and site-specific exogenous factors, such as focal mechanical stress, that activate cells locally. The embryonic development of limbs and joints is also relevant to the propensity of certain joints to develop arthritis. Additionally, location-specific homeostasis and disease occurs in skin and blood vessels, thereby extending the concept of site-specificity in human diseases beyond rheumatology. Acknowledging the importance of site-specific parameters increases the complexity of current disease paradigms and brings us closer to understanding why particular disease processes manifest at a particular location. PMID- 28615734 TI - The role of organic acids on microbial deterioration in the Radix pseudostellariae rhizosphere under continuous monoculture regimes. AB - A three-year field monoculture trial of Radix pseudostellariae and complementary laboratory studies were conducted to further elucidate the underlying mechanism responsible for significant decreases in the biomass yield and quality of R. pseudostellariae under continuous monoculture regimes. HPLC analysis indicated that continuous monoculture soil was rich in organic acids, which had cumulative effects over time. Further analysis suggested that the application of a mixture of organic acids significantly promoted growth of pathogenic fungi, and increased the expression of chemotaxis-related gene (cheA) and biofilm formation of the specific pathogenic Kosakonia sacchari. However, opposite reactions were observed in the case of Bacillus megaterium and Bacillus pumilus. Concurrently, the present results revealed that the mixed organic acids stimulated the production of toxins, as well as H2O2 in the pathogenic fungi. Furthermore, the presence of organic acids reflecting environmental conditions under monocropping had negative effects on the expression of the biocontrol-related genes, which resulted in attenuated antagonistic activities of plant growth-promoting rhizobacteria (PGPR) to suppress mycelial growth of the pathogenic fungi. These results help to unveil the mechanisms associated with how accumulated organic acids differentially mediate deterioration of soil microbial composition and structure in monocropping system. PMID- 28615736 TI - An analysis of the Rayleigh-Stokes problem for a generalized second-grade fluid. AB - We study the Rayleigh-Stokes problem for a generalized second-grade fluid which involves a Riemann-Liouville fractional derivative in time, and present an analysis of the problem in the continuous, space semidiscrete and fully discrete formulations. We establish the Sobolev regularity of the homogeneous problem for both smooth and nonsmooth initial data [Formula: see text], including [Formula: see text]. A space semidiscrete Galerkin scheme using continuous piecewise linear finite elements is developed, and optimal with respect to initial data regularity error estimates for the finite element approximations are derived. Further, two fully discrete schemes based on the backward Euler method and second-order backward difference method and the related convolution quadrature are developed, and optimal error estimates are derived for the fully discrete approximations for both smooth and nonsmooth initial data. Numerical results for one- and two dimensional examples with smooth and nonsmooth initial data are presented to illustrate the efficiency of the method, and to verify the convergence theory. PMID- 28615737 TI - Automatic integration using asymptotically optimal adaptive Simpson quadrature. AB - We present a novel theoretical approach to the analysis of adaptive quadratures and adaptive Simpson quadratures in particular which leads to the construction of a new algorithm for automatic integration. For a given function [Formula: see text] with [Formula: see text] and possible endpoint singularities the algorithm produces an approximation to [Formula: see text] within a given [Formula: see text] asymptotically as [Formula: see text]. Moreover, it is optimal among all adaptive Simpson quadratures, i.e., needs the minimal number [Formula: see text] of function evaluations to obtain an [Formula: see text]-approximation and runs in time proportional to [Formula: see text]. PMID- 28615738 TI - A massively parallel nonoverlapping additive Schwarz method for discontinuous Galerkin discretization of elliptic problems. AB - A second order elliptic problem with discontinuous coefficient in 2-D or 3-D is considered. The problem is discretized by a symmetric weighted interior penalty discontinuous Galerkin finite element method with nonmatching simplicial elements and piecewise linear functions. The resulting discrete problem is solved by a two level additive Schwarz method with a relatively coarse grid and with local solves restricted to subdomains which can be as small as single element. In this way the method has a potential for a very high level of fine grained parallelism. Condition number estimate depending on the relative sizes of the underlying grids is provided. The rate of convergence of the method is independent of the jumps of the coefficient if its variation is moderate inside coarse grid substructures or on local solvers' subdomain boundaries. Numerical experiments are reported which confirm theoretical results. PMID- 28615739 TI - Mixed finite elements for global tide models. AB - We study mixed finite element methods for the linearized rotating shallow water equations with linear drag and forcing terms. By means of a strong energy estimate for an equivalent second-order formulation for the linearized momentum, we prove long-time stability of the system without energy accumulation-the geotryptic state. A priori error estimates for the linearized momentum and free surface elevation are given in [Formula: see text] as well as for the time derivative and divergence of the linearized momentum. Numerical results confirm the theoretical results regarding both energy damping and convergence rates. PMID- 28615740 TI - Backward error analysis of the shift-and-invert Arnoldi algorithm. AB - We perform a backward error analysis of the inexact shift-and-invert Arnoldi algorithm. We consider inexactness in the solution of the arising linear systems, as well as in the orthonormalization steps, and take the non-orthonormality of the computed Krylov basis into account. We show that the computed basis and Hessenberg matrix satisfy an exact shift-and-invert Krylov relation for a perturbed matrix, and we give bounds for the perturbation. We show that the shift and-invert Arnoldi algorithm is backward stable if the condition number of the small Hessenberg matrix is not too large. This condition is then relaxed using implicit restarts. Moreover, we give notes on the Hermitian case, considering Hermitian backward errors, and finally, we use our analysis to derive a sensible breakdown condition. PMID- 28615741 TI - Runge-Kutta time semidiscretizations of semilinear PDEs with non-smooth data. AB - We study semilinear evolution equations [Formula: see text] posed on a Hilbert space [Formula: see text], where A is normal and generates a strongly continuous semigroup, B is a smooth nonlinearity from [Formula: see text] to itself, and [Formula: see text], [Formula: see text], [Formula: see text]. In particular the one-dimensional semilinear wave equation and nonlinear Schrodinger equation with periodic, Neumann and Dirichlet boundary conditions fit into this framework. We discretize the evolution equation with an A-stable Runge-Kutta method in time, retaining continuous space, and prove convergence of order [Formula: see text] for non-smooth initial data [Formula: see text], where [Formula: see text], for a method of classical order p, extending a result by Brenner and Thomee for linear systems. Our approach is to project the semiflow and numerical method to spectral Galerkin approximations, and to balance the projection error with the error of the time discretization of the projected system. Numerical experiments suggest that our estimates are sharp. PMID- 28615742 TI - Restarting iterative projection methods for Hermitian nonlinear eigenvalue problems with minmax property. AB - In this work we present a new restart technique for iterative projection methods for nonlinear eigenvalue problems admitting minmax characterization of their eigenvalues. Our technique makes use of the minmax induced local enumeration of the eigenvalues in the inner iteration. In contrast to global numbering which requires including all the previously computed eigenvectors in the search subspace, the proposed local numbering only requires a presence of one eigenvector in the search subspace. This effectively eliminates the search subspace growth and therewith the super-linear increase of the computational costs if a large number of eigenvalues or eigenvalues in the interior of the spectrum are to be computed. The new restart technique is integrated into nonlinear iterative projection methods like the Nonlinear Arnoldi and Jacobi Davidson methods. The efficiency of our new restart framework is demonstrated on a range of nonlinear eigenvalue problems: quadratic, rational and exponential including an industrial real-life conservative gyroscopic eigenvalue problem modeling free vibrations of a rolling tire. We also present an extension of the method to problems without minmax property but with eigenvalues which have a dominant either real or imaginary part and test it on two quadratic eigenvalue problems. PMID- 28615743 TI - Edge-based nonlinear diffusion for finite element approximations of convection diffusion equations and its relation to algebraic flux-correction schemes. AB - For the case of approximation of convection-diffusion equations using piecewise affine continuous finite elements a new edge-based nonlinear diffusion operator is proposed that makes the scheme satisfy a discrete maximum principle. The diffusion operator is shown to be Lipschitz continuous and linearity preserving. Using these properties we provide a full stability and error analysis, which, in the diffusion dominated regime, shows existence, uniqueness and optimal convergence. Then the algebraic flux correction method is recalled and we show that the present method can be interpreted as an algebraic flux correction method for a particular definition of the flux limiters. The performance of the method is illustrated on some numerical test cases in two space dimensions. PMID- 28615744 TI - Regularity of non-stationary subdivision: a matrix approach. AB - In this paper, we study scalar multivariate non-stationary subdivision schemes with integer dilation matrix M and present a unifying, general approach for checking their convergence and for determining their Holder regularity (latter in the case [Formula: see text]). The combination of the concepts of asymptotic similarity and approximate sum rules allows us to link stationary and non stationary settings and to employ recent advances in methods for exact computation of the joint spectral radius. As an application, we prove a recent conjecture by Dyn et al. on the Holder regularity of the generalized Daubechies wavelets. We illustrate our results with several examples. PMID- 28615745 TI - On the interconnection between the higher-order singular values of real tensors. AB - A higher-order tensor allows several possible matricizations (reshapes into matrices). The simultaneous decay of singular values of such matricizations has crucial implications on the low-rank approximability of the tensor via higher order singular value decomposition. It is therefore an interesting question which simultaneous properties the singular values of different tensor matricizations actually can have, but it has not received the deserved attention so far. In this paper, preliminary investigations in this direction are conducted. While it is clear that the singular values in different matricizations cannot be prescribed completely independent from each other, numerical experiments suggest that sufficiently small, but otherwise arbitrary perturbations preserve feasibility. An alternating projection heuristic is proposed for constructing tensors with prescribed singular values (assuming their feasibility). Regarding the related problem of characterising sets of tensors having the same singular values in specified matricizations, it is noted that orthogonal equivalence under multilinear matrix multiplication is a sufficient condition for two tensors to have the same singular values in all principal, Tucker-type matricizations, but, in contrast to the matrix case, not necessary. An explicit example of this phenomenon is given. PMID- 28615746 TI - Local two-sided bounds for eigenvalues of self-adjoint operators. AB - We examine the equivalence between an extension of the Lehmann-Maehly-Goerisch method developed a few years ago by Zimmermann and Mertins, and a geometrically motivated method developed more recently by Davies and Plum. We establish a general framework which allows sharpening various previously known results in these two settings and determine explicit convergence estimates for both methods. We demonstrate the applicability of the method of Zimmermann and Mertins by means of numerical tests on the resonant cavity problem. PMID- 28615747 TI - Scattered manifold-valued data approximation. AB - We consider the problem of approximating a function f from an Euclidean domain to a manifold M by scattered samples [Formula: see text], where the data sites [Formula: see text] are assumed to be locally close but can otherwise be far apart points scattered throughout the domain. We introduce a natural approximant based on combining the moving least square method and the Karcher mean. We prove that the proposed approximant inherits the accuracy order and the smoothness from its linear counterpart. The analysis also tells us that the use of Karcher's mean (dependent on a Riemannian metric and the associated exponential map) is inessential and one can replace it by a more general notion of 'center of mass' based on a general retraction on the manifold. Consequently, we can substitute the Karcher mean by a more computationally efficient mean. We illustrate our work with numerical results which confirm our theoretical findings. PMID- 28615748 TI - Discontinuous Galerkin methods for nonlinear scalar hyperbolic conservation laws: divided difference estimates and accuracy enhancement. AB - In this paper, an analysis of the accuracy-enhancement for the discontinuous Galerkin (DG) method applied to one-dimensional scalar nonlinear hyperbolic conservation laws is carried out. This requires analyzing the divided difference of the errors for the DG solution. We therefore first prove that the [Formula: see text]-th order [Formula: see text] divided difference of the DG error in the [Formula: see text] norm is of order [Formula: see text] when upwind fluxes are used, under the condition that [Formula: see text] possesses a uniform positive lower bound. By the duality argument, we then derive superconvergence results of order [Formula: see text] in the negative-order norm, demonstrating that it is possible to extend the Smoothness-Increasing Accuracy-Conserving filter to nonlinear conservation laws to obtain at least [Formula: see text]th order superconvergence for post-processed solutions. As a by-product, for variable coefficient hyperbolic equations, we provide an explicit proof for optimal convergence results of order [Formula: see text] in the [Formula: see text] norm for the divided differences of DG errors and thus [Formula: see text]th order superconvergence in negative-order norm holds. Numerical experiments are given that confirm the theoretical results. PMID- 28615749 TI - Optimal convergence for adaptive IGA boundary element methods for weakly-singular integral equations. AB - In a recent work (Feischl et al. in Eng Anal Bound Elem 62:141-153, 2016), we analyzed a weighted-residual error estimator for isogeometric boundary element methods in 2D and proposed an adaptive algorithm which steers the local mesh refinement of the underlying partition as well as the multiplicity of the knots. In the present work, we give a mathematical proof that this algorithm leads to convergence even with optimal algebraic rates. Technical contributions include a novel mesh-size function which also monitors the knot multiplicity as well as inverse estimates for NURBS in fractional-order Sobolev norms. PMID- 28615750 TI - The first description of a microtrombidiid mite (Actinotrichida: Prostigmata, Microtrombidiidae) from Baltic amber, with notes on related extant genera and species. AB - Discovery of parasitengone mites (Acari) in the Gulf of Gdansk deposits of Baltic amber ("Blue Earth" sediment) resulted in the first description of a fossil representative of Microtrombidiidae. The new species, based on larvae, displays affinity to recent members of Montenegtrombium Saboori and Pesic, 2006, Persianthrombium Sedghi, Saboori and Hakimitabar (in Sedghi et al. 2010) and Porttrombidium Haitlinger, 2000, known from the southwestern Palaearctic. A comparison with related genera and species places the newly described taxon in Porttrombidium (as Porttrombidium gedanense sp. nov.). Montenegtrombium is regarded as a junior synonym of Porttrombidium. PMID- 28615751 TI - The sponge genus Ephydatia from the high-latitude middle Eocene: environmental and evolutionary significance. AB - The freshwater sponge species Ephydatia cf. facunda Weltner, 1895 (Spongillida, Spongillidae) is reported for the first time as a fossil from middle Eocene lake sediments of the Giraffe kimberlite maar in northern Canada. The sponge is represented by birotule gemmuloscleres as well as oxea megascleres. Today, E. facunda inhabits warm-water bodies, so its presence in the Giraffe locality provides evidence of a warm climate at high latitudes during the middle Eocene. The morphological similarity of the birotules to modern conspecific forms suggests protracted morphological stasis, comparable to that reported for other siliceous microfossils from the same locality. PMID- 28615752 TI - Icriodus marieae, a new icriodontid conodont species from the Middle Devonian. AB - A new conodont species, Icriodus marieae, is described from pelagic limestone beds of the Carnic Alps (Austria). Specimens are obtained from the upper part of the Valentin Formation (Central Carnic Alps) and range from the latest Eifelian to middle Givetian. Significantly differing from other icriodontid conodonts is that the icriodontan element of the new species develops only three denticles on either lateral denticle row, which are constricted to the central part of the element. The anterior part of the element is free of lateral row denticles and consists of two to four denticles, which have a fan-shaped outline in lateral view. The anterior part as well as the posterior part (consisting of cusp and two to three pre-cusp denticles) is higher than the denticles of the central part of the element. Shape analysis confirms that the parameters chosen for landmarks (element size relation and denticle setting) show little variation between different specimens. PMID- 28615753 TI - Pharmacological Advances in the Management of Sexual Dysfunction. PMID- 28615755 TI - Role of Electroencephalography in the Diagnosis and Treatment of Neuropsychiatric Border Zone Syndromes. AB - Border zone disorders involve neurological disorders with psychiatric symptoms and signs as well as psychiatric disorders with soft neurological features. This becomes a cause for great diagnostic and therapeutic concerns. We, in this paper, analyzed some of the imitators such as epilepsy, dementia, some forms of encephalitis, and pure psychiatric diseases which produce problems in decision making due to soft neurological features and the utility of electroencephalography (EEG) as a simple diagnostic tool in differentiating some of these conditions from each other as well as the therapeutic role of EEG in some of these disorders. We retrospectively took index cases which produced problems for us in decision making in the last 5 years and correlated with the final diagnosis, EEG parameters as well as literature available by PubMed search using specific key words based on the conditions identified. EEG can be normal in organic diseases and abnormal in psychiatric diseases. Typical EEG findings in neuropsychiatric syndromes point to specific diagnosis. Soft EEG changes are common in psychiatric disorders and do not indicate organicity. EEG can be used to assess efficacy and toxicity of therapeutic agents in psychiatry. Biofeedback based training to keep the brain in particular rhythm is of use in psychiatric disorders as a pharmaco-sparing agent. PMID- 28615754 TI - Telepsychiatry in India - Where Do We Stand? A Comparative Review between Global and Indian Telepsychiatry Programs. AB - A wide discrepancy exists in India between the existing mental healthcare repertoire and the alarmingly high burden of individuals requiring immediate attention from requisite mental healthcare services. Providing equitable mental healthcare across a vast country characterized by profound cultural variations and territorial caveats has remained a major public health concern. Against this gloomy backdrop, the emergence of distant communications technology offers solace and optimism as an ingenious approach to bridge the existing gap between clients and mental health professionals. Using inexpensive equipment and basic technical knowhow, telepsychiatry expands the scope of the discipline to distant and hazy suburbs and villages from its urban centers of excellence. The current academic endeavor intends to perform a systematic review of relevant literature from India as well as from other countries. The various models of telepsychiatry-both asynchronous and synchronous models-in practice have been elaborated on with a focus on effectiveness, feasibility and acceptability of this latest modality. A sincere attempt to chronicle the remarkable journey of telepsychiatry in India, beginning in the dawn of the 21st century to the current Indian scenario, has been made. The legal and ethical issues, along with a few words of caution and contemplation, have been briefly touched on. A set of recommendations has been provided with the hope that policy makers and administrators in the domain of mental health may benefit from them. It is anticipated that telepsychiatry will be adequately utilized in India to tackle the raging menace of inadequate mental healthcare services. PMID- 28615757 TI - An Audit of Indian Health Insurance Claims for Mental Illness from Pooled Insurance Information Bureau's Macroindicator Data. AB - INTRODUCTION: Information on the social and voluntary insurance coverage of mental illness in India is scarce. We attempted to address this lacuna, utilizing a secondary macrodata approach for 3 years. Mental illness per se is not covered by most of existing Indian health insurance policies. MATERIALS AND METHODS: Publicly available de-identified claim macrodata for all health (nonlife) insurance for Indian financial year from 2011-2012 to 2013-2014 were collected. The age group, gender, amount of claims, proportion of claims, and details of number of days of hospitalization were collected and analyzed. Descriptive statistics, Chi-square test, and Wilcoxon tests were used appropriately. P <= 0.05 was considered statistically significant. RESULTS: In 2011-2012, there were 2864 claims from the registered 2,591,781 members citing mental illness (0.11%) which decreased to 0.03% in 2012-2013 and marginally rose to 0.07% of all claims. The total amount of claims paid for mental illness was Rs. 51.7 millions in 2011 2012, Rs. 97.2 million in 2012-2013, and Rs. 150 million in 2013-2014. Statistically significant difference emerged in terms of age group, gender, amount and proportion of claim, and number of days of hospitalization. CONCLUSION: The penetration of health insurance is low and claim for mental illness remains low. The difference in patterns of age, gender, amount of claims, and number of days for mental illness provides detailed relevant information to formulate future policies. PMID- 28615756 TI - Neurocognitive Impairments in Unaffected First-degree Relatives of Schizophrenia. AB - BACKGROUND: Neurocognitive impairments of attention and executive functioning are trait abnormalities in schizophrenia, and these are considered to be endophenotypes. These deficits have been convincingly linked to prefrontal cortical functioning. In this study, we examined the cognitive performance in the domains of attention and executive functioning among first-degree relatives of Indian people with schizophrenia (high-risk [HR] patients) compared to healthy controls (HC). MATERIALS AND METHODS: Siblings of patients with DSM-IV schizophrenia, HR patients (n = 17), were compared with HC (n = 30) (matched as a group for age, sex, years of education, and handedness) using the following neurocognitive tests for attention and executive function - digit span test (DST), trail making test, letter-number sequencing (LNS), and spatial span test. RESULTS: HR patients had significantly deficient performance in attention and executive function tasks (DST-forward [P < 0.001], DST-backward [P < 0.001], spatial span-forward [P < 0.001], spatial span-backward [P < 0.001], and LNS [P < 0.001]). CONCLUSIONS: This study replicates the findings that neurocognitive deficits involving executive function task performance, attention, and working memory, which are considered as principal features in patients with schizophrenia, are also significantly present in the first-degree relatives of patients. Thus, these neurocognitive parameters can be considered as potential endophenotypes in schizophrenia. PMID- 28615758 TI - Regional Cerebral Glucose Metabolism and its Association with Phenotype and Cognitive Functioning in Patients with Autism. AB - INTRODUCTION: In spite of three decades of neuroimaging, we are unable to find consistent and coherent anatomical or pathophysiological basis for autism as changes are subtle and there are no studies from India. AIM: To study the regional cerebral glucose metabolism in children with autism using positron emission tomography (PET) scan and to study the behavior and cognitive functioning among them. MATERIALS AND METHODS: Ten subjects (8-19 years) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for autism were evaluated on Childhood Autism Rating Scale (CARS), trail making test (TMT) A and B, Wisconsin card sorting test, Raven's progressive matrices, and PET scan. A control group of 15 matched subjects without any brain pathology or neurological disorder was similarly studied. RESULTS: Four out of the ten patients with autism had abnormal PET scan findings, and in contrast, none of the patients in the control group had abnormal PET scan. Of the four patients with abnormality in the PET scan, two patients had findings suggestive of hypometabolism in cerebellum bilaterally; one patient showed bilateral hypometabolism in anterior temporal cortices and cerebellum, and the fourth patient had hypermetabolism in the bilateral frontal cortices and medial occipital cortices. Subjects with autism performed poorly on neuropsychological testing. Patients with abnormal PET scan findings had significantly higher scores on the "body use" domain of CARS indicating more stereotypy. CONCLUSION: Findings of this study support the view of altered brain functioning in subjects with autism. PMID- 28615759 TI - Telepsychiatry as an Economically Better Model for Reaching the Unreached: A Retrospective Report from South India. AB - AIM: In a resource-poor country such as India, telepsychiatry could be an economical method to expand health-care services. This study was planned to compare the costing and feasibility of three different service delivery models. The end user was a state-funded long-stay Rehabilitation Center (RC) for the homeless. METHODOLOGY: Model A comprised patients going to a tertiary care center for clinical care, Model B was community outreach service, and Model C comprised telepsychiatry services. The costing included expenses incurred by the health system to complete a single consultation for a patient on an outpatient basis. It specifically excluded the cost borne by the care-receiver. No patients were interviewed for the study. RESULTS: The RC had 736 inmates, of which 341 had mental illness of very long duration. On comparing the costing, Model A costed 6047.5 INR (100$), Model B costed 577.1 INR (9.1$), and Model C costed 137.2 INR (2.2$). Model C was found fifty times more economical when compared to Model A and four times more economical when compared to Model B. CONCLUSION: Telepsychiatry services connecting tertiary center and a primary health-care center have potential to be an economical model of service delivery compared to other traditional ones. This resource needs to be tapped in a better fashion to reach the unreached. PMID- 28615760 TI - Use of Mobile Phone Technology to Improve follow-up at a Community Mental Health Clinic: A Randomized Control Trial. AB - BACKGROUND: Mobile phone technology is being used worldwide to improve follow-ups in health care. AIM: Aim of the study is to evaluate whether the use of mobile technology will improve or not the follow-up of Indian patients from a community mental health center. MATERIALS AND METHODS: Patients or caregivers having mobile phones and consenting for study were enrolled, and sociodemographic and clinical details of patients were taken. Participants were randomized into two groups (short message service [SMS] vs. non-SMS group). At first intervention level, a SMS was sent to SMS group (not in non-SMS group) 1 day before their appointment. At second-level intervention (voice call level), patients from both groups who missed their first appointment were given a voice call requesting them to come for follow-up, and the reasons for first missed appointments (MA) were also elicited. The effect of these two intervention levels (first SMS for SMS group and next voice calls for both groups) on follow-up was evaluated. RESULTS: A total of 214 patients were enrolled in the study. At first SMS intervention level of SMS group (n = 106), 62.26% of participants reached appointment-on-time (RA), while in the non-SMS/as usual group (n = 108), 45.37% of patients RA. The difference of these groups is statistically significant. At second-level intervention (voice call), 66 of 88 (another 15 were unable to contact) were came for follow-up consultation within 2 days of MA. Distance and diagnosis of alcohol dependence were significantly associated with MA. Social reasons were most common reasons for first MA. CONCLUSION: The use of mobile phone technology in an outpatient community psychiatric clinic improved follow-up significantly. PMID- 28615761 TI - Prediction of Risk for Boys' Involvement in Drug Use Based on Levels of Self evaluations in Russia. AB - BACKGROUND: Adolescents often experiment with drug use, which can impact on their health and well-being and increase the probability of problem drug use. Yet, not enough is known about which psychological indicators is related with the initiation of drug use among young adults and have predictive power. MATERIALS AND METHODS: Participants in this study were 311 boys (school and college students) aged 15-17. Data were collected in the towns of Moscow region. A modified version of Dembo-Rubinstein test was used to assess the self-evaluation (SE). A questionnaire and detection of drugs in urine were used to identify drug users. Binary logistic regression analysis based on SE with the inclusion of interactive effects between predictors was used for prediction of drug use. RESULTS: Drug users, compared to nondrug users, are characterized by lower actual SE of health, happiness, success in learning, mind and desired SE of appearance, and higher desired SE of relationships with friends. The developed nonlinear regression model for prediction of boys' involvement in drug use among young boys in the towns of Moscow region has a sensitivity of 82.7% at a specificity of 79.0%. CONCLUSIONS: Dembo-Rubinstein test of SE is a sensitive measure to identify boys at risk of involvement in drug use. Application of the regression model based on SE may contribute to the useful solution in preventing any onset of early drug use. PMID- 28615762 TI - Prevalence of Depression among School-going Adolescents in an Urban Area of Bihar, India. AB - INTRODUCTION: Depression is one of the under-recognized health problems in adolescents. Emotional instability resulted from childhood to adulthood transition makes adolescents vulnerable to depression. AIMS: The aim of the study was to explore the prevalence of depression and its associated sociodemographic factors among school-going adolescents. MATERIALS AND METHODS: This cross sectional study was undertaken from January 2016 to June 2016 in adolescents studying in 9-12th standard from forty schools located in an urban area of Patna, Bihar. The self-administered questionnaire of Beck's Depression Inventory II was utilized to assess the prevalence of depression. Statistical analysis was done with Pearson's Chi-square test using SPSS software version 21.0. RESULTS: Among the 1412 selected students, the prevalence of depression was found to be 49.2%, wherein the prevalence of severe depression was 7.7%. The overall prevalence of depression was significantly (P < 0.001) higher among girls (55.1%) than boys (45.8%). The prevalence of depression was found to be higher among students belonging to minorities (Buddhism, Jainism, etc.) (63.3%, P < 0.001). Elder students were found to be more depressed than younger students. Depression was found to be statistically significantly associated with gender and religion (P < 0.005). Guilty feeling (69.48%) was one of the most prominent clinical factors associated with depression followed by pessimism (58.14%), sadness (56.52%), and past failure (55.81%). CONCLUSIONS: Mental health is one of the most neglected aspects of our society. There is a need to increase awareness about depression among teachers and parents to identify and help depressed adolescents in the school. PMID- 28615763 TI - Adverse Drug Reactions and their Impact on Quality of Life in Patients on Antipsychotic Therapy at a Tertiary Care Center in Delhi. AB - CONTEXT: Adverse drug reactions (ADR) due to antipsychotic therapy have significant impact on a psychiatric patient's quality of life. Few studies have been conducted in India to monitor adverse drug reactions due to antispsychotics and none has been done to determine their impact on quality of life. AIMS: The present study was conducted to monitor ADRs due to antipsychotics and ascertain the impact of ADRs on quality of life. SETTINGS AND DESIGN: This prospective observational study was conducted in the psychiatry outpatients department in New Delhi for 1 year. PATIENTS AND METHODS: A total of 224 patients enrolled were followed up for a period of 3 months. ADRs were monitored using the standard form of the Central Drugs Standard Control Organization and causality was determined using the Naranjo algorithm. The WHO Quality of Life BREF (WHOQOL-BREF) scale was used to study the effect of ADR on the quality of life. STATISTICAL ANALYSIS USED: The data were entered and analyzed using the statistical software SPSS 17.0. Unpaired t-test was used to compare the quality of life of patients who encountered ADRs and those who did not. P < 0.05 was considered statistically significant. RESULTS: Of the total 224 patients, 38 adverse drug events occurred. Adverse drug events were mostly with risperidone (10), followed by olanzapine (8) owing to high usage. Majority of the events were classified as probable (34). The occurrence of adverse drug events decreased the scores on physical and psychological domain scores of WHO-QOL BREF at 3 months compared to baseline. CONCLUSIONS: The study provides information on the existing incidence of ADRs in the setup with an established pharmacovigilance center. The nature of ADRs correlates with the prevalence pattern of usage of atypical antipsychotics. Clinicians need to weigh benefit versus the impact on quality of life while prescribing antipsychotics. PMID- 28615764 TI - Evaluation of Antioxidant Status, High Sensitivity C-reactive Protein, and Insulin Resistance in Male Chronic Opiate Users Without Comorbidities. AB - BACKGROUND: There is a paucity of data on frequency of metabolic syndrome (MS), insulin resistance (IR), and oxidative stress in Indian opiate users without comorbidities. OBJECTIVES: To determine the influence of opiate use on frequency of MS, homeostasis model assessment for IR (HOMA-IR), high-sensitivity C-reactive protein (hs-CRP), and oxidative stress in opiate-dependent male patients without comorbidities. METHODS: Participants (n = 120) were grouped as controls (Group I), pure opiate dependents (Group II), opiate + tobacco dependents (Group III), and tobacco dependents (Group IV) with a minimum of 1-year dependence participated in the study. Participants were evaluated for anthropometric parameters, blood pressure (BP), fasting blood sugar, insulin, HOMA-IR, lipid profile, hs-CRP, and total antioxidant status (TAS). Frequency of MS was determined based on modified Adult Treatment Panel-III. The data were analyzed using one-way ANOVA, multiple regression by SPSS 21. RESULTS: Frequency of MS in opiate dependents was higher than control. There was a significant difference in serum insulin, HOMA-IR, and TAS levels of the study groups. Multiple regression analysis showed dependence years, body mass index, waist-hip ratio, systolic blood pressure, diastolic blood pressure (DBP), HOMA-IR, and hs-CRP to be significant independent predictors of TAS in Group II and III patients with MS after adjusting for age and education years. TAS and DBP significantly predicted hs-CRP after adjusting for age and education years in Group II and III patients with MS. No such relation was seen in Group I and IV. CONCLUSIONS: Chronic opiate dependent males without comorbidity are a unique group that shows low-grade inflammation, oxidative stress, and prevalence of MS predisposing them to future risk of cardiovascular diseases. PMID- 28615766 TI - Psychosocial Factors Associated with Relapse in Patients with Alcohol Dependence. AB - INTRODUCTION: Despite the recent developments in the biology of addiction, a significant part of relapse and its management is still influenced by psychosocial factors and the interplay between them. This study aims at finding the extent of association of various psychosocial factors with relapse in patients of alcohol dependence. MATERIALS AND METHODS: It is a cross-sectional study of two groups of alcohol dependence patients: abstinence (n = 31) and relapse (n = 35). Demographic, clinical, and psychosocial variables were compared between the two groups. Statistical analyses were aimed at finding the extent of association between various factors and relapse. RESULTS: Demographic variables such as family history of substance dependence (odds ratio [OR] =2.09; confidence interval [CI] =0.74-5.90) and past history of >=2 relapses (OR = 2.71; CI = 0.83 8.87) were associated with relapse in alcohol dependence. Clinical variables such as younger age of onset of dependence (Mean difference = -3.93; 95% CI = -7.66 - 0.21; P = 0.038) and shorter time to develop dependence (Mean difference = -3.08; 95% CI = -5.53 --0.63; P = 0.014) were significantly associated with relapse. Of the psychosocial variables, coping behavior (OR = 6.54; CI = 1.17-36.74) had the highest association with relapse followed by relapse precipitants (OR = 1.42; CI = 1.16-1.74). CONCLUSION: Coping behaviors to adverse situations have greater association with relapse among psychosocial variables than the number of high risk situations a patient experiences. Interventions targeted at improving coping skills can help patients stay abstinent. PMID- 28615765 TI - Adverse Drug Reaction Monitoring in a Tertiary Care Psychiatry Setting: A Comparative Study between Inpatients and Outpatients. AB - BACKGROUND: Psychotropic medications are the mainstay of treatment in psychiatric disorders and are associated with ADRs which affect the compliance and treatment course. Previous studies have looked at the frequency, profile of ADRs and their management aspects. However, the systematic comparison between IP and OP was lacking even though there is a prescription pattern difference. Hence this study was aimed to compare the proportion, pattern, severity and resolution of ADRs once detected. METHODS: This is a hospital based, prospective follow up study done in the psychiatry ward and outpatient setting for a period of 6 months. A total of 491 patients (200 IP, 291 OP) who received psychotropics were monitored in the study. UKU side effect rating scale was used to detect ADRs, WHO - UMC scale for causality, Modified Hartwig and Siegel Scale to assess severity of ADR and CDSCO suspected ADR form for reporting it. RESULTS: Out of 491 patients who were recruited for the study, 83 patients developed ADRs (34 IP, 49 OP, P = 0.963). The mean number of ADRs per patient was found to be higher in IP (IP 2.17+/-1.14, OP-1.65+/-1.12, P-0.01). Severe ADRs were observed to be higher IP (IP-67.64%, OP-38.7%, P-0.014) which was statistically significant. There is no statistically significant difference in distribution of ADRs across all age groups (P-0.475). CONCLUSION: The study results emphasises the need for active pharmacovigilance so that ADRs are detected and managed at the earliest, hence reducing the morbidity and improving compliance. There is also need for systematic long term, multicentric study to further examine and correlatethe observations of our study. PMID- 28615767 TI - Do Life Events and Social Support Vary across Depressive Disorders? AB - BACKGROUND: Social support and life events moderate the expression of depression though studies have shown contradictory results. The objective was to study the stressful life events and perceived social support in patients with adjustment disorder, first-episode depression, and recurrent depressive disorder (RDD). SUBJECTS AND METHODS: One hundred and forty-six patients aged 18-60 years with adjustment disorder, first-episode depression, or RDD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision were evaluated using the presumptive stressful life events scale and Multidimensional Scale of Perceived Social Support. RESULTS: There was no difference in mean number of total life events and subgroups as well as perceived stress score in the past 1 year between the groups. There was no difference in the perceived social support scale total score, as well as from family and friends, across the three groups. However, the mean perceived social support from significant others in those with RDD was lower as compared to those with adjustment disorder. CONCLUSION: Stressful life events do not differ in adjustment disorder, first episode depression, and RDD. Furthermore, the perceived social support was similar across the three groups, except for perceived social support from significant others, which was less in those with RDD. PMID- 28615768 TI - The Phenomenology and Treatment Response in Catatonia: A Hospital Based Descriptive Study. AB - BACKGROUND: Literatures regarding clinical symptomatology and treatment response of catatonia are very few. OBJECTIVE: To assess onset, clinical profile, diagnostic break up, treatment response and outcome in patients diagnosed as Catatonia, reported to a tertiary care hospital. METHODS: The present study was a cross-sectional descriptive study conducted in indoor of Mental Health Institute (Centre of Excellence), S.C.B. Medical College, between March 2015 to March 2016. A total of 34 patients were included in the study who reported at outdoor department of Mental Health Institute with catatonic symptoms. All patients admitted in inpatient department were routinely assessed through a detailed semi structured interview. The diagnosis of catatonia was made if the patients present with three or more symptoms out of twelve symptoms fulfilling the criteria of DSM 5. All the patients were assessed through Bush-Francis Catatonia Rating Scale. They were initially given parental lorazepam at the doses ranging from 4-12 mg per day as per requirement. Patients who did not respond to lorazepam trial were given ECT. RESULTS: The patients were predominantly presented with retarded symptoms of catatonia such as staring, mutism, withdrawal, posturing and negativism. Schizophrenia and other psychotic spectrum disorders were more commonly presented as catatonia as compared to mood disorders. Younger age group patients were mainly responded to lorazepam only, whereas older age group patients responded to both ECT and lorazepam. CONCLUSION: This study has came out with very important insights in the age of incidence, phenomenology, clinical profile, source of referral, diagnostic break up and treatment response with lorazepam and ECT in catatonic patients following mental disorder. PMID- 28615770 TI - The Mood Spectrum and Temperamental Instability in Unipolar and Bipolar Disorder. AB - BACKGROUND: The current categorical split of mood disorders in bipolar (BP) disorders and depressive disorders has recently been questioned. The presence of a significant number of manic/hypomanic symptoms in patients with recurrent unipolar depression seems to challenge the traditional dichotomy of unipolar-BP disorder. Two highly unstable personality features, i.e., the cyclothymic temperament (CT) and borderline personality disorder, have been found to be more common in BP disorder than in major depressive disorder. AIM: The aim was to assess the distributions of the number of mood spectrum, CT, and borderline personality items between two groups. Finding no bimodal distribution (a "zone of rarity") of these items would support a continuity between the two disorders. METHODS: Forty euthymic BP disorder patients and forty unipolar depression patients were administered the Structured Clinical Interview for the Mood Spectrum, which assesses lifetime symptoms, traits, and lifestyles that characterize threshold and subthreshold mood episodes. CT was assessed using Temperament Evaluation of Memphis, Pisa, Paris and San Diego-A relative to CT and borderline personality trait (BPT) was assessed using Structured Clinical Interview for DSM Disorders II personality questionnaire relative to BPT. The distribution of the number of CT and BPT items was studied by Kernel density estimate. RESULT: Patient with recurrent depression endorsed manic/hypomanic items though less than BP group. However, the Kernel density estimates distributions of the number of hypomanic/manic items, CT and BPT items in the entire sample had a normal-like shape (i.e. no bimodality). CONCLUSION: Normal like curves in the distributions of mood symptoms, number of CT and BPT items in the entire sample, suggest significant amount of overlap of these characteristic in both the groups. Using the bimodality approach, continuity between BP and major depressive disorder (MDD) seems to be supported, questioning the current categorical splitting of BP and MDD based on classic diagnostic validators. PMID- 28615769 TI - Gender, Life Events, and Depression: An Exploratory Study. AB - CONTEXT: Literature is inconsistent about the role of gender in mediating the relationship between life events and depression. AIM: Our objective was to explore gender differences in patterns and frequencies of stressful life events before onset of a depressive episode. SETTING AND DESIGN: Cross-sectional study at a tertiary care center. SUBJECTS AND METHODS: One hundred patients fulfilling Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria for current major depression (50 males and 50 females) were recruited for the study. Structured instruments were used to assess psychiatric comorbidity, episode severity, and stressful life events. We compared the number and frequency of stressful life events between genders and their relationship with demographic and clinical variables. STATISTICAL ANALYSIS USED: Mann-Whitney U-test and Chi-square test. RESULTS: Women with depression were older, more likely to be married (P < 0.01), had lower rates of comorbid panic disorder (P < 0.01) and nicotine dependence (P = 0.016) compared to men. Total stress scores and median number of stressful events in the year before onset of depression were significantly lower in women (P < 0.01). Getting married, job or property-related stressors, and breakup of friendship were more commonly reported stressors among males while more females reported dowry-related issues before symptom onset. In stratified analysis, these gender differences continued to hold good only in those with comorbid dysthymia. CONCLUSION: There appears to be a sex-specific effect of certain life events on depression. Comorbid dysthymia may play an important role in mediating this differential stress sensitivity across genders. PMID- 28615771 TI - Comparative Study of Psychiatric Manifestations among Type I and Type II Diabetic Patients. AB - BACKGROUND: Anxiety and depressive disorders belong to the most common psychiatric disorders worldwide. They are generally seen in individuals who suffer from chronic diseases, such as diabetes mellitus (DM). The prevalence of depression among diabetics ranges from 8.5% to 32.5%, while that for anxiety it is up to 30%. In this study, we try to compare the mental health problems faced by those with Type I and Type II DM. MATERIALS AND METHODS: Fifty patients diagnosed with Type I diabetes (T1D) and Type II diabetes each presenting to Medicine and Endocrinology Department were assessed with Hamilton Depression Rating Scale (HAM-D) for depression and Hamilton Anxiety Rating Scale (HAM-A) for anxiety. Patients were assessed on sociodemographic profile, duration of illness, type of treatment and then the data were analyzed on different domains. RESULTS: On the assessment of patients with HAM-D a total of 38% with T1D were found to be depressed, and 42% patients with Type II diabetes had depression. Similarly, on assessment of anxiety with HAM-A, a total of 44% with T1D had anxiety. In patients with Type II diabetes, a total of 34% patients suffer from anxiety. CONCLUSION: The study concludes that Type I and Type II are slightly different in terms of associated psychiatric illnesses. In those with psychiatric illness, they do less well in terms of improving their overall diabetes control. The wider implication is that all the patients with diabetes should be regularly assessed for psychological problems. There needs to be greater psychological/psychiatric support available to intensive diabetes clinics. PMID- 28615772 TI - Postherpetic Neuralgia Presenting as Delusional Parasitosis: A Case Series. AB - Delusional parasitosis (DP) or Ekbom's disease is a rare psychiatric condition where the sufferers have a firm-fixed belief of insects crawling over their skin. The condition may be primary monosymptomatic hypochrondrical delusion or secondary to an underlying psychiatric or organic condition. We present two cases of elderly men presenting with classical symptomatology of DP, which is found to be secondary to postherpetic neuralgia following an acute episode of shingles or herpes zoster infection. One patient responded to a combination of antipsychotic, olanzapine, and pregabalin, used for neuropathic pain, and the other patient responded completely with medications used for neuropathic pain only without any antipsychotic use. PMID- 28615773 TI - Cabergoline-induced Mania in a Patient of Pituitary Microadenoma. AB - Cabergoline, a dopamine agonist agent, is commonly used in the treatment of hyperprolactinemia, Parkinson's disease, restless leg syndrome, and antipsychotic induced prolactin elevation. It is generally well tolerated as compared to other dopamine agonist agents due to its more selective D2 receptor agonistic effect. We present a case of a 25-year-old female who developed manic episode, following the use of cabergoline for treatment of pituitary microadenoma. We suggest that physicians should carefully screen patients before initiating cabergoline therapy and at-risk patients may benefit from more frequent monitoring and cessation of therapy at the earliest safe juncture. PMID- 28615774 TI - Hypokalemia with Trifluoperazine at Therapeutic Dose. AB - This case report outlines a rare presentation of hypokalemia with therapeutic doses of trifluoperazine in a patient with schizophrenia. Although there was comorbid diabetes mellitus in the patient, its effect was ruled out subsequently. On recovery, rechallenge with trifluoperazine resulted in the same effect at a milder level. No cardiac abnormalities were detected with the presentation. Naranjo adverse drug reaction probability scale reported definite relation with the drug. PMID- 28615775 TI - Online Methods of Managing Auditory Hallucinations: A New Trend to Understand Psychopathology. AB - Treatment seekers use various coping methods to reduce the distress associated with auditory hallucinations. With the increase use of technology, the technology means are also in use to manage the auditory hallucination. The current report documents the implications of technology means for the management of auditory hallucinations. The user was assessed using clinical interview, internet addiction test, problematic online gaming questionnaire, and screening questions for technology addiction. It showed the use of technology to manage the auditory hallucinations. Psychotherapy work revealed a reduction in their use of technology means at follow-up. It implies to evolve the therapeutic use of technology means and development of alternative therapeutic means to manage the auditory hallucinations. PMID- 28615776 TI - Sleeping Beauty Syndrome: A Case Report and Review of Female Cases Reported from India. AB - Kleine-Levin syndrome (KLS), also called "Sleeping beauty syndrome" is a rare, disorder predominantly reported in adolescent males, characterized by recurrent episodes of hypersomnia and to various degrees, hyperphagia, cognitive disturbances, and hypersexuality. Here, we are reporting a case of a middle-aged female, with 16 years delay in diagnosing KLS, poor response to most of the psychotropics, except good response to a combination of lithium, sertraline, and modafinil for last 12 months and also reviewing other female cases with KLS reported from India. PMID- 28615777 TI - Rumination Disorder: An Unexplained Case of Recurrent Vomiting. AB - Rumination disorder or rumination syndrome is an infrequent clinical presentation reported in infants and young children as well as adults worldwide. Studies calculating prevalence and etiological considerations are very few, and the scientific literature mostly consists of anecdotal case reports and series. Awareness of this clinical entity is obscured by presentations mimicking upper gastrointestinal disorders, mostly recurrent vomiting. The repetitive, voluntary, habitual nature of this disorder is vulnerable to be missed out if not looked for specifically in the history. Here lies the importance of increasing the awareness about diagnosis of this disorder and the need to operationalize treatment guidelines for this disorder which has long-term physical, psychological, and economic consequences if not treated early in its course. PMID- 28615778 TI - Olanzapine-induced Neuroleptic Malignant Syndrome. AB - Neuroleptic malignant syndrome (NMS) is a life-threatening adverse effect usually seen with typical antipsychotic drugs. Rarely, NMS can occur with atypical antipsychotics also. A 19-year-old male diagnosed as a case of acute and transient psychotic disorder developed NMS, following the treatment with an atypical antipsychotic, olanzapine 20 mg/day. The patient was diagnosed NMS, an offending agent olanzapine was immediately withdrawn, and prompt treatment by maintaining hydration and giving bromocriptine produced recovery. PMID- 28615779 TI - Multimodal Hallucinations in a Visually Impaired Elderly Female: Is it a Variant of Charles Bonnet Syndrome? AB - Charles Bonnet Syndrome (CBS) is a common cause of visual hallucinations seen in elderly people with visual impairment. Well-formed visual hallucinations in clear consciousness with preserved insight are commonly reported in literature. We report a case of CBS having multisensory hallucinations. An elderly patient with visual impairment fulfilling the criteria of CBS presents with various modalities of hallucinations viz. visual, auditory and tactile hallucinations improved completely with low dose of antipsychotics. Atypical features are common in CBS and thus often make it difficult to diagnose this condition. PMID- 28615780 TI - Converging Neurobiological Evidence In Primary Polydipsia Resembling Obsessive Compulsive Disorder. AB - Compulsive water drinking can have phenomenological and pharmacotherapeutic similarities with obsessive-compulsive disorder (OCD). Substantiating neurobiological evidence is lacking for such an association. We report a patient who was referred with a diagnosis of primary polydipsia with no signs of organic pathology in structural neuroimaging. However, positron emission tomography revealed basal ganglia hypometabolism indicating that primary polydipsia with compulsive water drinking is neurobiologically related to OCD. The diagnostic complexities displayed by primary polydipsia and the use of systematic evaluation with supporting neuroimaging evidence in reaching a reliable diagnosis are discussed. The neurobiological evidence will foster the treatment decisions for starting anti-OCD measures when clinicians encounter patients with primary polydipsia exhibiting compulsive patterns of drinking. Nevertheless, such findings need to be replicated in future studies with a larger sample size. PMID- 28615781 TI - "Radio Inside My Head": A Curious Case of Early Onset "Stuck Song Syndrome" or Obsessive-Compulsive Disorder with Predominant Musical Obsession. AB - Musical obsessions also called "stuck song syndrome" is a topic of limited research. It is among the most poorly understood and rare phenomenology. There are only a few cases reported across the world which describes it. Subjects usually present with complaints of continuous play of a musical tune in the head which the subject is unable to remove. Because of its similarity in presentation with auditory musical hallucination, it presents a diagnostic dilemma to the clinician. Here, we present the case of a 25-year-old man who presented with this particular phenomenon, and the approach we took to manage it. PMID- 28615782 TI - Comment On: Dance-like Movements in Obsessive Compulsive Disorder. PMID- 28615783 TI - Premature Ejaculation: A Redundant Entity in the Era of Somatic Symptom Disorder? PMID- 28615784 TI - Reasons of Disciplinary Discharges from a Tertiary Care De-addiction Setting in India. PMID- 28615785 TI - Is Low Body Mass Index a Risk Factor for Postinjection Delirium/Sedation Syndrome? PMID- 28615786 TI - Bipolar in Women: Any Gender-based Difference? PMID- 28615787 TI - Pimozide: An Old Wine in a New Bottle! PMID- 28615788 TI - Shared or Induced Obsessive Compulsive Disorder: A Case Report with Critical Review. PMID- 28615789 TI - Smartphone App for Management of Mental Disorder: Comment on Usefulness in Specific Case of Posttraumatic Stress Disorder. PMID- 28615790 TI - Baclofen and Back Pain: A Paradoxical Phenomena. PMID- 28615791 TI - Monte Carlo investigation of backscatter point spread function for X-ray imaging examinations. AB - X-ray imaging examinations, especially complex interventions, may result in relatively high doses to the patient's skin inducing skin injuries. A method was developed to determine the skin-dose distribution for non-uniform x-ray beams by convolving the backscatter point-spread-function (PSF) with the primary-dose distribution to generate the backscatter distribution that, when added to the primary dose, gives the total-dose distribution. This technique was incorporated in the dose-tracking system (DTS), which provides a real-time color-coded 3D mapping of skin dose during fluoroscopic procedures. The aim of this work is to investigate the variation of the backscatter PSF with different parameters. A backscatter PSF of a 1-mm x-ray beam was generated by EGSnrc Monte-Carlo code for different x-ray beam energies, different soft-tissue thickness above bone, different bone thickness and different entrance-beam angles, as well as for different locations on the SK-150 anthropomorphic head phantom. The results show a reduction of the peak scatter to primary dose ratio of 48% when X-ray beam voltage is increased from 40 keV to 120 keV. The backscatter dose was reduced when bone was beneath the soft tissue layer and this reduction increased with thinner soft tissue and thicker bone layers. The backscatter factor increased about 21% as the angle of incidence of the beam with the entrance surface decreased from 90 degrees (perpendicular) to 30 degrees . The backscatter PSF differed for different locations on the SK-150 phantom by up to 15%. The results of this study can be used to improve the accuracy of dose calculation when using PSF convolution in the DTS. PMID- 28615792 TI - A CMOS-based high resolution fluoroscope (HRF) detector prototype with 49.5 MUm pixels for use in endovascular image guided interventions (EIGI). AB - X-ray detectors to meet the high-resolution requirements for endovascular image guided interventions (EIGIs) are being developed and evaluated. A new 49.5-micron pixel prototype detector is being investigated and compared to the current suite of high-resolution fluoroscopic (HRF) detectors. This detector featuring a 300 micron thick CsI(Tl) scintillator, and low electronic noise CMOS readout is designated the HRF-CMOS50. To compare the abilities of this detector with other existing high resolution detectors, a standard performance metric analysis was applied, including the determination of the modulation transfer function (MTF), noise power spectra (NPS), noise equivalent quanta (NEQ), and detective quantum efficiency (DQE) for a range of energies and exposure levels. The advantage of the smaller pixel size and reduced blurring due to the thin phosphor was exemplified when the MTF of the HRF-CMOS50 was compared to the other high resolution detectors, which utilize larger pixels, other optical designs or thicker scintillators. However, the thinner scintillator has the disadvantage of a lower quantum detective efficiency (QDE) for higher diagnostic x-ray energies. The performance of the detector as part of an imaging chain was examined by employing the generalized metrics GMTF, GNEQ, and GDQE, taking standard focal spot size and clinical imaging parameters into consideration. As expected, the disparaging effects of focal spot unsharpness, exacerbated by increasing magnification, degraded the higher-frequency performance of the HRF-CMOS50, while increasing scatter fraction diminished low-frequency performance. Nevertheless, the HRF-CMOS50 brings improved resolution capabilities for EIGIs, but would require increased sensitivity and dynamic range for future clinical application. PMID- 28615793 TI - Classification of Clinical Significance of MRI Prostate Findings Using 3D Convolutional Neural Networks. AB - Prostate cancer (PCa) remains a leading cause of cancer mortality among American men. Multi-parametric magnetic resonance imaging (mpMRI) is widely used to assist with detection of PCa and characterization of its aggressiveness. Computer-aided diagnosis (CADx) of PCa in MRI can be used as clinical decision support system to aid radiologists in interpretation and reporting of mpMRI. We report on the development of a convolution neural network (CNN) model to support CADx in PCa based on the appearance of prostate tissue in mpMRI, conducted as part of the SPIE-AAPM-NCI PROSTATEx challenge. The performance of different combinations of mpMRI inputs to CNN was assessed and the best result was achieved using DWI and DCE-MRI modalities together with the zonal information of the finding. On the test set, the model achieved an area under the receiver operating characteristic curve of 0.80. PMID- 28615794 TI - DeepInfer: Open-Source Deep Learning Deployment Toolkit for Image-Guided Therapy. AB - Deep learning models have outperformed some of the previous state-of-the-art approaches in medical image analysis. Instead of using hand-engineered features, deep models attempt to automatically extract hierarchical representations at multiple levels of abstraction from the data. Therefore, deep models are usually considered to be more flexible and robust solutions for image analysis problems compared to conventional computer vision models. They have demonstrated significant improvements in computer-aided diagnosis and automatic medical image analysis applied to such tasks as image segmentation, classification and registration. However, deploying deep learning models often has a steep learning curve and requires detailed knowledge of various software packages. Thus, many deep models have not been integrated into the clinical research workflows causing a gap between the state-of-the-art machine learning in medical applications and evaluation in clinical research procedures. In this paper, we propose "DeepInfer" - an open-source toolkit for developing and deploying deep learning models within the 3D Slicer medical image analysis platform. Utilizing a repository of task specific models, DeepInfer allows clinical researchers and biomedical engineers to deploy a trained model selected from the public registry, and apply it to new data without the need for software development or configuration. As two practical use cases, we demonstrate the application of DeepInfer in prostate segmentation for targeted MRI-guided biopsy and identification of the target plane in 3D ultrasound for spinal injections. PMID- 28615795 TI - Quantitative comparison using Generalized Relative Object Detectability (G-ROD) metrics of an amorphous selenium detector with high resolution Microangiographic Fluoroscopes (MAF) and standard flat panel detectors (FPD). AB - A novel amorphous selenium (a-Se) direct detector with CMOS readout has been designed, and relative detector performance investigated. The detector features include a 25MUm pixel pitch, and 1000MUm thick a-Se layer operating at 10V/MUm bias field. A simulated detector DQE was determined, and used in comparative calculations of the Relative Object Detectability (ROD) family of prewhitening matched-filter (PWMF) observer and non-prewhitening matched filter (NPWMF) observer model metrics to gauge a-Se detector performance against existing high resolution micro-angiographic fluoroscopic (MAF) detectors and a standard flat panel detector (FPD). The PWMF-ROD or ROD metric compares two x-ray imaging detectors in their relative abilities in imaging a given object by taking the integral over spatial frequencies of the Fourier transform of the detector DQE weighted by an object function, divided by the comparable integral for a different detector. The generalized-ROD (G-ROD) metric incorporates clinically relevant parameters (focal-spot size, magnification, and scatter) to show the degradation in imaging performance for detectors that are part of an imaging chain. Preliminary ROD calculations using simulated spheres as the object predicted superior imaging performance by the a-Se detector as compared to existing detectors. New PWMF-G-ROD and NPWMF-G-ROD results still indicate better performance by the a-Se detector in an imaging chain over all sphere sizes for various focal spot sizes and magnifications, although a-Se performance advantages were degraded by focal spot blurring. Nevertheless, the a-Se technology has great potential to provide breakthrough abilities such as visualization of fine details including of neuro-vascular perforator vessels and of small vascular devices. PMID- 28615796 TI - Focal Spot Deblurring for High Resolution Direct Conversion X-ray Detectors. AB - Small pixel high resolution direct x-ray detectors have the advantage of higher spatial sampling and decreased blurring characteristic. The limiting factors for such systems becomes the degradation due to the focal spot size. One solution is a smaller focal spot; however, this can limit the output of the x-ray tube. Here a software solution of deconvolving with an estimated focal spot blur is presented. To simulate images from a direct detector affected with focal-spot blur, first a set of high-resolution stent images (FRED from Microvention, Inc., Tustin, CA) were acquired using a 75MUm pixel size Dexela-Perkin-Elmer detector and frame averaged to reduce quantum noise. Then the averaged image was blurred with a known Gaussian blur. To add noise to the blurred image a flat-field image was multiplied with the blurred image. Both the ideal and the noisy-blurred images were then deconvolved with the known Gaussian function using either threshold-based inverse filtering or Weiner deconvolution. The blur in the ideal image was removed and the details were recovered successfully. However, the inverse filtering deconvolution process is extremely susceptible to noise. The Weiner deconvolution process was able to recover more of the details of the stent from the noisy-blurred image, but for noisier images, stent details are still lost in the recovery process. PMID- 28615797 TI - 3D Printed Cardiac Phantom for Procedural Planning of a Transcatheter Native Mitral Valve Replacement. AB - : 3D printing an anatomically accurate, functional flow loop phantom of a patient's cardiac vasculature was used to assist in the surgical planning of one of the first native transcatheter mitral valve replacement (TMVR) procedures. CTA scans were acquired from a patient about to undergo the first minimally-invasive native TMVR procedure at the Gates Vascular Institute in Buffalo, NY. A python scripting library, the Vascular Modeling Toolkit (VMTK), was used to segment the 3D geometry of the patient's cardiac chambers and mitral valve with severe stenosis, calcific in nature. A stereolithographic (STL) mesh was generated and AutoDesk Meshmixer was used to transform the vascular surface into a functioning closed flow loop. A Stratasys Objet 500 Connex3 multi-material printer was used to fabricate the phantom with distinguishable material features of the vasculature and calcified valve. The interventional team performed a mock procedure on the phantom, embedding valve cages in the model and imaging the phantom with a Toshiba Infinix INFX-8000V 5-axis C-arm bi-Plane angiography system. RESULTS: After performing the mock-procedure on the cardiac phantom, the cardiologists optimized their transapical surgical approach. The mitral valve stenosis and calcification were clearly visible. The phantom was used to inform the sizing of the valve to be implanted. CONCLUSION: With advances in image processing and 3D printing technology, it is possible to create realistic patient specific phantoms which can act as a guide for the interventional team. Using 3D printed phantoms as a valve sizing method shows potential as a more informative technique than typical CTA reconstruction alone. PMID- 28615798 TI - Are civil-law notaries rent-seeking monopolists or essential market intermediaries? Endogenous development of a property rights institution in Mexico. AB - As the fourth contribution in the 'Land' section, this paper forms a research 'diptych' with the next paper by Levy. Whereas she focuses on the notarial institution in mid-nineteenth century Mexico, this contribution examines it in a contemporary context. The notary is one of the chief components of property rights protection in civil-law systems, performing various public functions such as writing deeds for real estate property. Yet notaries are considered an 'inefficient' institution by many, due to the perception of rent-seeking behavior enabled by their near-monopoly over validating property rights claims. This study examines notaries in Mexico to unpack the apparent contradiction in the role of notaries in economic development. I use a combination of interviews with notaries and clients, and data on notarial practice and bureaucratic outcomes across the country, to examine notaries' social function. The theoretical lens of endogenous development and institutional functionalism reveals an alternate explanation for their seemingly high-cost services, as well as their role in economic development. Mexican notaries have a dual social function: public representative and private service provider. They perform diverse and essential activities, which in other countries are performed by multiple actors such as real estate agents, escrow offices and title insurance companies. Thus, what is perceived as inefficiency by some can be interpreted as an efficient response to the context in which they operate, and their semi-privatized nature can overcome problems found in other bureaucratic arrangements. PMID- 28615799 TI - Monochromatic Clique Decompositions of Graphs. AB - Let G be a graph whose edges are colored with k colors, and H=(H1,?,Hk) be a k tuple of graphs. A monochromatic H-decomposition of G is a partition of the edge set of G such that each part is either a single edge or forms a monochromatic copy of Hi in color i, for some 1<=i<=k. Let phik(n,H) be the smallest number phi, such that, for every order-n graph and every k-edge-coloring, there is a monochromatic H-decomposition with at most phi elements. Extending the previous results of Liu and Sousa [Monochromatic Kr-decompositions of graphs, J Graph Theory 76 (2014), 89-100], we solve this problem when each graph in H is a clique and n>=n0(H) is sufficiently large. PMID- 28615800 TI - Question mark ear deformity-revisited. AB - : We report on two unusual cases of Cosman (question mark) ear; both required modifications of the standard techniques for surgical correction. The first patient presented with a unilateral question mark ear and concurrent ear prominence and bulging of the cartilage of the anti-helix. Simultaneous correction was done using a combination of cartilage suturing/scoring (for the prominence and the cartilage bulge) as well as Al-Qattan's "v-y skin flap cartilage graft-z-plasty" technique (for the correction of the ear cleft deformity). The second patient had aurico-condylar syndrome with bilateral ear deformity and complete separation of ear lobes from the external ear. Staged transposition followed by Al-Qattan's technique resulted in a satisfactory outcome. LEVEL OF EVIDENCE: Level V, therapeutic study. PMID- 28615801 TI - A New Impulse for Neuropsychology in Europe: The Federation of the European Societies of Neuropsychology. PMID- 28615802 TI - Publish or perish? PMID- 28615803 TI - Dr. Behman Minoo Daver (1939-2015). PMID- 28615804 TI - The neurochemistry of peripheral nerve regeneration. AB - Peripheral nerve injuries (PNIs) can be most disabling, resulting in the loss of sensitivity, motor function and autonomic control in the involved anatomical segment. Although injured peripheral nerves are capable of regeneration, sub optimal recovery of function is seen even with the best reconstruction. Distal axonal degeneration is an unavoidable consequence of PNI. There are currently few strategies aimed to maintain the distal pathway and/or target fidelity during regeneration across the zone of injury. The current state of the art approaches have been focussed on the site of nerve injury and not on their distal muscular targets or representative proximal cell bodies or central cortical regions. This is a comprehensive literature review of the neurochemistry of peripheral nerve regeneration and a state of the art analysis of experimental compounds (inorganic and organic agents) with demonstrated neurotherapeutic efficacy in improving cell body and neuron survival, reducing scar formation and maximising overall nerve regeneration. PMID- 28615805 TI - Free anteromedial thigh perforator flap: Complementing and completing the anterolateral thigh flap. AB - OBJECTIVE: Theobjective of this study was to determine the indications, utility, advantages and surgical approach for the anteromedial thigh (AMT) flap. MATERIALS AND METHODS: We reviewed the records of the patients in whom the AMT flap was used for head and neck reconstruction. We use an anterior approach to harvest the anterolateral thigh (ALT) flap with a non-committal straight line incision. This preserves both ALT and AMT flap territories intact, and further decision is based on the intraoperative anatomy of perforator and pedicle. The ALT flap was usually used as the first choice when available and suitable. RESULTS: Free AMT skin flaps were harvested in 24 patients. All flaps were used for the head and neck reconstruction. Two flaps had marginal flap necrosis. One flap was lost due to venous thrombosis. DISCUSSION: The thigh is an excellent donor site as it has large available skin territory, expendable lateral circumflex femoral artery system and low donorsite morbidity. The ALT flap is the most commonly used flap for reconstruction of soft-tissue defects. However, it is characterised by variable vascular pedicle and perforator anatomy. The AMT flap is an excellent alternative when the ALT flap is not available due to variable perforator anatomy, injury to perforator, when an intermediate thickness is needed between distal and proximal thigh or a chimeric flap is needed. CONCLUSION: The AMT flap offers all the advantages of the ALT flap without increasing donor-site morbidity. The anterior non-committal approach keeps both the ALT and the AMT flap options viable. PMID- 28615806 TI - Proposal of a new classification scheme for periocular injuries. AB - BACKGROUND: Eyelids are important structures and play a role in protecting the globe from trauma, brightness, in maintaining the integrity of tear films and moving the tears towards the lacrimal drainage system and contribute to aesthetic appearance of the face. Ophthalmic trauma is an important cause of morbidity among individuals and has also been responsible for additional cost of healthcare. Periocular trauma involving eyelids and adjacent structures has been found to have increased recently probably due to increased pace of life and increased dependence on machinery. A comprehensive classification of periocular trauma would help in stratifying these injuries as well as study outcomes. MATERIAL AND METHODS: This study was carried out at our institute from June 2015 to Dec 2015. We searched multiple English language databases for existing classification systems for periocular trauma. We designed a system of classification of periocular soft tissue injuries based on clinico-anatomical presentations. This classification was applied prospectively to patients presenting with periocular soft tissue injuries to our department. RESULTS: A comprehensive classification scheme was designed consisting of five types of periocular injuries. A total of 38 eyelid injuries in 34 patients were evaluated in this study. According to the System for Peri-Ocular Trauma (SPOT) classification, Type V injuries were most common. SPOT Type II injuries were more common isolated injuries among all zones. DISCUSSION: Classification systems are necessary in order to provide a framework in which to scientifically study the etiology, pathogenesis, and treatment of diseases in an orderly fashion. The SPOT classification has taken into account the periocular soft tissue injuries i.e., upper eyelid, lower eyelid, medial and lateral canthus injuries., based on observed clinico-anatomical patterns of eyelid injuries. CONCLUSION: The SPOT classification seems to be a reliable system to address eyelid injuries. This classification scheme would guide the ophthalmic and facial reconstructive surgeons to provide optimal outcomes in eyelid injuries. Based on the classification scheme and review of existing literature, an algorithm is presented to facilitate repair and reconstruction. PMID- 28615807 TI - Soft embalming of cadavers for training purposes: Optimising for long-term use in tropical weather. AB - BACKGROUND: Surgical and anatomical training has been found to be most optimally simulated in a cadaver than any other available methods. Soft embalming methods have made the bodies more 'lifelike' and better suited for training. The widely accepted soft embalming techniques, including Thiel embalming, are designed for temperate climates. Their use in tropical locations has been found to be associated with poor short-term and long-term preservation of the bodies. In fact, adequate reports from tropical countries on effective methods for soft embalming are lacking. MATERIALS AND METHODS: This article details the modifications made in the Thiel embalming technique over a period of 2 years which has enabled us to preserve the anatomical features of bodies in an optimal way for longer periods in tropical conditions. This study was carried out in a tertiary care referral centre located in a tropical climate zone. A total of 13 frozen and thawed cadavers were used over a period of 2 years for developing such soft embalming technique. The efficacy of the technique was tested using these cadavers for varying types of surgical exercises on multiple occasions. RESULTS: The conventionally described technique of Thiel embalming did not provide desired results. Hence, various modifications to this technique were instituted which helped us to get superior quality of soft-embalmed cadavers. In the final year, these cadavers were used successfully for workshops in flap dissection. Head and neck access surgery, arthroscopic and laparoscopic procedures as well as mock face and hand transplant dissections. CONCLUSIONS: The Theil embalming technique for obtaining soft embalmed cadavers, even though found to be best in many centres in the world, has not been found to be suitable to tropical weather. By modifying it, we have succeeded in developing a technique suitable to the tropical weather. This technique yields cadavers suitable for various surgical simulation exercises. This technique also allows the body to be optimally used over several months in multiple occasions. These modifications are very simple and have been described in detail enabling it to be adopted by any surgical skill laboratory in the tropical countries. PMID- 28615808 TI - Triceps to biceps transfer for restoration of elbow flexion following upper brachial plexus injury. AB - INTRODUCTION: Upper brachial plexus injury in adults causes loss of elbow fl exion; when the primary nerve surgery has failed or the patient seeks treatment after 12 months of injury and pedicled muscle transfers are required. Most commonly, the latissimus dorsi or the Steindler flexorplasty is used. MATERIAL AND METHODS: We have transferred one of the heads of triceps muscle to restore the elbow flexion in such cases. In addition to return of elbow flexion, extension of elbow following surgery is retained. Ten patients suffering from upper brachial plexus injuries underwent transfer of one head of triceps to biceps tendon between December 2011 and August 2015. RESULTS: The recovery of elbow flexion was Grade 5 in 1, Grade 4 in 4 and Grade 3 in 2; only three of the ten patients had no functionally useful elbow flexion. Seven of the ten patients had an adequate elbow extension following the procedure. PMID- 28615809 TI - Role of customised negative-pressure wound therapy in the integration of split thickness skin grafts: A randomised control study. AB - BACKGROUND: Split-thickness skin grafting (STSG) is a time-tested technique in wound cover, but many factors lead to suboptimal graft take. Role of custom-made negative-pressure wound therapy (NPWT) is compared with conventional dress in the integration of STSG and its cost is compared with widely used commercially available NPWT. MATERIALS AND METHODS: This is a parallel group randomised control study. Block randomisation of 100 patients into one of the two groups (NPWT vs. non-NPWT; 50 patients each) was done. Graft take/loss, length of hospital stay post-grafting, need for regrafting and cost of custom-made negative pressure wound therapy (NPWT) dressings as compared to widely used commercially available NPWT were assessed. RESULTS: Mean graft take in the NPWT group was 99.74% +/- 0.73% compared to 88.52% +/- 9.47% in the non-NPWT group (P = 0.004). None of the patients in the NPWT group required second coverage procedure as opposed to six cases in the non-NPWT group (P = 0.035). All the patients in the NPWT group were discharged within 4-9 days from the day of grafting. No major complication was encountered with the use of custom-made NPWT. Custom-made NPWT dressings were found to be 22 times cheaper than the widely used commercially available NPWT. CONCLUSIONS: Custom-made NPWT is a safe, simple and effective technique in the integration of STSG as compared to the conventional dressings. We have been able to reduce the financial burden on the patients as well as the hospital significantly while achieving results at par with other studies which have used commercially available NPWT. PMID- 28615810 TI - Computed tomography angiographic study of internal mammary perforators and their use as recipient vessels for free tissue transfer in breast reconstruction. AB - CONTEXT: The internal mammary artery perforator vessels (IMPV) as a recipient in free flap breast reconstruction offer advantages over the more commonly used thoracodorsal vessels and the internal mammary vessels (IMV). AIMS: This study was designed to assess the anatomical consistency of the IMPV and the suitability of these vessels for use as recipients in free flap breast reconstruction. PATIENTS AND METHODS: Data from ten randomly selected female patients who did not have any chest wall or breast pathology but had undergone a computed tomography angiography (CTA) for unrelated diagnostic reasons from April 2013 to October 2013 were analysed. Retrospective data of seven patients who had undergone mastectomy for breast cancer and had been primarily reconstructed with a deep inferior epigastric artery perforator free flap transfer using the IMPV as recipient vessels were studied. RESULTS: The CTA findings showed that the internal mammary perforator was consistently present in all cases bilaterally. In all cases, the dominant perforator arose from the upper four intercostal spaces (ICS) with the majority (55%) arising from the 2nd ICS. The mean distance of the perforators from the sternal border at the level of pectoralis muscle surface on the right side was 1.86 cm (range: 0.9-2.5 cm) with a mode value of 1.9 cm. On the left side, a mean of 1.77 cm (range: 1.5-2.1 cm) and a mode value of 1.7 cm were observed. Mean perforator artery diameters on the right and left sides were 2.2 mm and 2.4 mm, respectively. CONCLUSIONS: Though the internal mammary perforators are anatomically consistent, their use as recipients in free tissue transfer for breast reconstruction eventually rests on multiple variables. PMID- 28615811 TI - Adipokine concentrations in lipoaspirates may have a role in wound healing. AB - OBJECTIVES: In addition to its use as a volume filler, fat grafting may have a potential role in wound healing based on the concentration of growth factors in the lipoaspirate. In this study, we compare the quantitative and qualitative concentration of the various growth factors and adipokines using the Shippert or the Coleman techniques to prepare the lipoaspirate. METHODS: We measured leptin, adiponectin and the growth factors, i.e., acidic fibroblast growth factor (aFGF), basic FGF (bFGF), keratinocyte growth factor (KGF), bone morphogenetic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) by ELISA in solid and liquid fractions obtained with both techniques in human fat obtained with Coleman technique and Shippert technique. RESULTS: All of these peptides, except BMP-2, were detected in relevant quantities in the solid fraction. The Coleman but not the Shippert technique resulted in statistically higher adiponectin concentrations in the solid tissue fraction. The other four growth factors occurred in significantly higher concentrations in the solid fractions compared to the liquid fractions, independent of the processing technique. CONCLUSION: In summary, we demonstrated that KGF, aFGF, bFGF and VEGF, as well as leptin and adiponectin, are contained in fat suspensions obtained by liposuction and in the supernatant. Only the concentration of adiponectin was in the range reported to contribute to wound healing. PMID- 28615812 TI - Optimising aesthetic outcome after nipple-areola complex-sparing mastectomy and immediate one-stage prosthetic reconstruction: A simple surgical trick to fix nipple-areola complex position. AB - BACKGROUND: Nipple-areola complex (NAC) sparing mastectomy (NSM) is mostly indicated in patients with small-/medium-sized and non-ptotic breasts, while skin reducing mastectomy is used in patients with medium or large breasts with severe ptosis. NAC location on the reconstructed breast is one of the major factors in determining the final aesthetic result and patients' satisfaction. An optimum result obtained at the end of surgical procedure may be altered and compromised by skin redistribution and consequently NAC depositioning during the post operative period in patients with medium-sized breasts and a moderate degree of ptosis. AIMS: In the present study, we propose a simple surgical trick to fix the NAC in the desired position with a long-lasting result. METHODS: We selected 35 patients undergoing NAC sparing mastectomy for breast cancer and immediate one stage prosthetic reconstruction and we performed a single suture to fix NAC in the desired position before closing the skin envelope. We evaluated NAC complex position stability overtime comparing pre-operative standard photographs with early (3 weeks after surgery) and late (1 year after surgery). RESULTS: In all patients, we were able to place the NAC complex on the desired position, and the result was stable at 1 year follow-up. The aesthetic outcome was satisfactory in all patients with no change in the complication rate. CONCLUSIONS: This simple surgical trick has been shown to be safe and effective in optimising the aesthetic outcome in a patient undergoing NAC sparing mastectomy and immediate one-stage prosthetic reconstruction. Level IV: evidence obtained from multiple time series with or without the intervention, such as case studies. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. PMID- 28615813 TI - Modified Cantwell-Ransley repair for isolated continent epispadias in adult: Our experience. AB - PURPOSE: We evaluate here our experience with modified Cantwell-Ransley technique described by Gearhart for correction of isolated continent epispadias in adults with respect to its long-term functional outcome and complications. INTRODUCTION: Isolated male epispadias is a rare anomaly with a reported incidence of 1 in 11,700 males. Many surgical techniques with various modifications described to correct epispadias as treatment are debatable and challenging. The majority of the cases are treated at childhood as clinical presentation is striking at birth; hence, presentation in adulthood is extremely rare. MATERIALS AND METHODS: During the past 5 years, modified Cantwell-Ransley technique described by Gearhart was performed in five cases of isolated continent epispadias which includes two cases of proximal penile, two distal penile and one penopubic. All cases were fresh except one had prior failed repair. Corporal rotation was done by delayed absorbable sutures without incision and anastomosis and suprapubic diversions placed in all the cases. RESULTS: All cases followed up ranging from 6 months to 5 years and were having horizontal and downwards angled penis. No case had urethrocutaneous fistula or stricture. One case had superficial skin infection which healed by secondary intention did not require any secondary procedure. All cases maintained erection post-operatively too. Catheterisation with soft tube revealed easily negotiable channel in all cases on follow-up. CONCLUSION: Modified Cantwell-Ransley repair described by Gearhart has excellent cosmetic, functional and anatomical results in isolated continent epispadias in the adult. PMID- 28615814 TI - An Anatomical study for localisation of Zygomatic branch of Facial nerve and Masseteric nerve - An aid to nerve coaptation for facial reanimation surgery: A cadaver based study in Eastern India. AB - CONTEXT: In cases of chronic facial palsy, where direct neurotisation is possible, ipsilateral masseteric nerve is a very suitable motor donor. We have tried to specifically locate the masseteric nerve for this purpose. AIMS: Describing an approach of localisation and exposure of both the zygomatic branch of Facial nerve and the nerve to masseter, with respect to a soft tissue reference point over face. SETTINGS AND DESIGN: Observational cross sectional study, conducted on 12 fresh cadavers. SUBJECTS AND METHODS: A curved incision was given, passing about 0.5cms in front of the tragal cartilage. A reference point "R" was pointed out. The zygomatic branch of facial nerve and masseteric nerve were dissected out and their specific locations were recorded from fixed reference points with help of copper wire and slide callipers. STATISTICAL ANALYSIS USED: Central Tendency measurements and Unpaired "t" test. RESULTS: Zygomatic branch of the Facial nerve was located within a small circular area of radius 1 cm, the centre of which lies at a distance of 1.1 cms (+/-0.4cm) in males and 0.2cm (+/-0.1cm) in females from the point, 'R', in a vertical (coronal) plane. The nerve to masseter was noted to lie within a circular area of 1 cm radius, the centre of which was at a distance of 2.5cms (+/-0.4cm) and 1.7cms (+/-0.2cm) from R, in male and female cadavers, respectively. Finally, Masseteric nerve's depth, from the masseteric surface was found to be 1cm (+/ 0.1cm; male) and 0.8cm (+/-0.1cm; female). CONCLUSIONS: This novel approach can reduce the post operative cosmetic morbidity and per-operative complications of facial reanimation surgery. PMID- 28615815 TI - Harvesting split thickness costal cartilage graft. AB - AIM: There are few complications associated with harvesting of full thickness coastal cartilage grafts i.e., pneumothorax (0.9%), contour deformities and prolonged post-operative pain. To address these issues, authors devised special scalpel to harvest split-thickness costal cartilage grafts. MATERIALS AND METHODS: Standard inframammary incision was used for harvesting rib. Incision was made directly over the desired rib. Specially designed scalpel was used to cut through the rib cartilage to the half of the thickness. The study was conducted in two parts - cadaveric and clinical. RESULTS: There was significantly less pain and no pneumothorax in the patients in whom the split thickness graft was harvested. Wounds healed without any complication. DISCUSSION: Thus, newly devised angulated scalpel used in the current study, showed the potential to supply the reconstructive surgeon with split thickness rib graft without risk of complications such as pneumothorax or warping contour deformities and post operative pain. PMID- 28615816 TI - Use of selfie sticks and iPhones to record operative photos and videos in plastic surgery. AB - Use of smartphone has become ubiquitous. With smartphone cameras becoming powerful, they are replacing digital cameras and digital SLRs as primary instruments to take photos and record videos. It is natural even for plastic surgeons that smartphones are handy to take still photographs and even record high-definition or 4K videos. Another invention which has become popular with smartphone photography is a selfie stick. We explain the possibility and methodology of using an iPhone and selfie stick to take operative photographs and high-quality videos. PMID- 28615817 TI - Advocacy and mass education in plastic surgery: Efforts and outcomes. AB - BACKGROUND: Awareness of plastic surgery is lacking. Be it reconstructive surgery, or aesthetic surgery, public education and awareness regarding the spectrum is the need of the hour. MATERIALS AND METHODS: We undertook a string of activities for patient awareness and education for burn prevention, occupational hand injuries prevention, skin banking awareness and various other conditions relevant to us as plastic surgeons. Use of social media helped us for increasing the reach of our projects. OBSERVATION AND RESULTS: Some of the projects we started, we are still pursuing with sincerity, and some never really picked up. A wide range and spectrum of activities were undertaken, and we would like to think that we have made some impact towards advocacy of plastic surgery; however, the measurable impact of these initiatives is questionable. CONCLUSION: Collective efforts for promotion of the speciality using innovative methods, use of celebrities for awareness and social media amongst other things must be undertaken to make a sustained and demonstrable impact towards advocacy of plastic surgery. PMID- 28615818 TI - Minimising the donor area morbidity of radial forearm phalloplasty using prefabricated thigh flap: A new technique. AB - Phalloplasty is indicated in various conditions of penile loss or absence. There are numerous techniques for phalloplasty including the pedicle and free flaps with the ultimate goal of micturition in standing position, attaining adequate size, aesthesis and sensations for sexual intercourse. Radial forearm phalloplasty is the gold standard flap to achieve above results but gives a very bad scar on the forearm. We present a technique of using prefabricated thigh flap to reduce the morbidity of donor area. The descending branch of lateral circumflex femoral pedicle was placed in a subcutaneous plane over tissue expander. After attaining an adequate size of flap with tissue expansion, it was delayed 3 weeks before phalloplasty. Prefabricated flap was thin and of large size replicating the radial forearm flap used for phalloplasty. Whole forearm defect was covered with the thigh flap, and the thigh could be closed primarily. This new technique of using prefabricated thigh flap has significantly reduced the donor site morbidity both aesthetically and functionally without the use of skin grafting in the whole procedure. PMID- 28615819 TI - Columella reconstruction with an inferiorly-based philtral advancement flap in a cocaine abuser. AB - Nasal columella defects can significantly impair aesthetic appearance. Columella reconstruction can be very challenging for surgeons, especially if due to cocaine abuse. The case of a 32-year-old male patient with subtotal columellar necrosis secondary to cocaine abuse is presented. An inferiorly based philtral advancement flap was performed to cover the defect. Aesthetic outcome was the primary goal of surgery. Reconstruction led to good aesthetic and functional results. PMID- 28615820 TI - From wheelchair to walking: First case report of post-electrical burn destruction of patellar ligament with its one-stage reconstruction and restoration of function. AB - Electrical burn injury causing bilateral patellar ligament destruction leading to complete loss of knee extension is a very rare injury. In such situation, surgical repair or reconstruction of the patellar ligament becomes necessary to restore knee functions. Here, we present such a case of an 8-year-old boy, whose both patellar ligaments were destroyed throughout its length due to high-voltage electrical injury. His left knee joint cavity was exposed and grossly infected, but the right knee joint cavity was apparently intact. The right-sided patellar ligament was reconstructed with an ipsilateral and looped semitendinosus tendon graft and covered with a medial gastrocnemius musculocutaneous flap. The patient had an uneventful recovery, and full range of motion in the right knee joint along with good bipedal locomotion was achieved successfully. PMID- 28615821 TI - Pyogenic granuloma-like lesion in children: Should we wait? AB - Malignant melanoma is a potentially lethal cutaneous malignancy. Melanoma in paediatrics is rare as compared to adult melanoma. The clinicopathological characteristics of paediatric melanoma are different from adult melanoma, and the presence of melanoma mimics which occurs frequently in children (Spitz naevi) resulted in diagnosis uncertainty. We reported a 9-year-old girl who presented with a slow-growing, pyogenic granuloma-like lesion which was diagnosed with melanoma. It is important to have a high index of suspicion in paediatric skin lesion that would usually be deemed benign. Early tissue biopsy in a suspicious lesion prevents delayed diagnosis and treatment. PMID- 28615822 TI - A new method of salvaging nipple projection after secondary nipple reconstruction using locoregional flap. PMID- 28615823 TI - Bilateral superficial brachioulnar artery in a cadaver along with bilateral absence of palmaris longus. PMID- 28615824 TI - Absence of flexor carpi radialis: A rare anatomical variation with clinical significance. PMID- 28615825 TI - Novel use of preputial flap. PMID- 28615826 TI - Mnemonics for gillies principles of plastic surgery and it importance in residency training programme. PMID- 28615827 TI - Selfie stick: An extension of the photographer's hand in operation room conditions. PMID- 28615828 TI - Simple way of splinting the arm following vascular anastomosis in the axilla. PMID- 28615829 TI - Primary management of post-burn contracture neck with tracheostomy: A surgeon and an anaesthetist's perspective. PMID- 28615830 TI - Pedicled transverse rectus abdominis myocutaneous flap: A method for tunnelling with Dilson Luz vascular dilation wands for breast reconstruction. PMID- 28615831 TI - Species diversity of the genus Thelohanellus Kudo, 1933 (Myxozoa: Bivalvulida) parasitizing fishes in Indian subcontinent. AB - A synopsis of 52 nominal species of the genus Thelohanellus Kudo, 1933 reported to infect freshwater fishes in India is presented. These species infect various organs such as gills, fins, scales, skin, muscles, gall bladder, kidney etc. The diagnostic features of the genus include tear-shaped myxospores with smooth shell valves and single polar capsule. The members are histozoic in their nature of parasitism infecting fresh water fishes. The present manuscript is aimed to compile the list of reported species in India along with essential information on morphometrics of vegetative stage, host, organ preference and pathogenic effects if any. Maximum number of species are recorded from state of West Bengal (25) followed by 23 in Punjab (out of which 8 were already reported from other states of India), Andhra Pradesh (7), Orissa (3), Manipur (1) and Haryana (1). Majority of the species have been recorded to infect major and minor carps (43 species) and 9 species in cat fishes. Out of 43 species infecting Indian major carps, T. batae infected the epithelial lining of gill filament of Labeo bata and also the wall of the duodenum and pectoral fin of Wallago attu in Harike Wetland (Punjab). Organ distribution of the species belonging to the genus Thelohanellus indicated that the plasmodia of 27 species were located in the gills, 14 species in the fins, 7 species in the gall bladder, 4 species in muscles and 3 species in kidney, 2 each in scale and skin on the head region and 1 species each in brain, eye, spleen, liver and wall of the duodenum. Recent studies conducted by the authors and also by few earlier studies in West Bengal have documented many species of Thelohanellus to cause serious gill haemorrhagic disease and dermal lesions. Histological studies on the gills of cultured carps in Punjab infected with members of Thelohanellus have indicated that these parasites cause 15-20 % damage to respiratory surface leading to localized loss of function. PMID- 28615832 TI - A new species of Quadruspinospora Sarkar and Chakravarty, 1969 (Apicomplexa:Conoidasida) from Orthopteran Insects of Manipur, India. AB - The description of a new species of cephaline gregarine Quadruspinosporaoxyae sp.nov from a grasshopper (Orthoptera:Acrididae) is presented. Trophozoite has an elongated body measuring 120-163.6 (146 +/- 14.1) um with digitiform epimerite that is in the form of a question mark, measuring 6.5-23.6 (13.8 +/- 5.3) um in average. The mature sporadins associate sidewise in pairs and move together. Spherical Gametocyst measuring 90-129.7 (116 +/- 11.1) um * 59.7-97.4 (74.4 +/- 13.4) um in dimensions are present. Oocysts are oval, measuring 7.2 * 11.5 um in length. Length of spores 19.5-21.5 um, provided with four long spines, two at each pole, which is a characteristic of the genus Quadruspinospora Sarkar et Chakravarty, 1969. PMID- 28615834 TI - Aphelenchoides meghalayensis sp. nov. (Nematoda: Aphelenchoididae) from Meghalaya, India. AB - During a survey for the aphelenchid nematodes of North Eastern States of India, a new species of Aphelenchoides nematode was found from Cherrapunji, Meghalaya. The morphological and morphometric characteristics of the species were studied using light and SEM microscopy. Aphelenchoides meghalayensis sp. nov. is characterized by having 493.03-681.62 (604.0 +/- 80.52) um long body, strong stylet of 8.65 10.38 (9.8 +/- 0.81) um long with small basal swellings, six lateral lines, elongated uterine sac and tail which is slightly arcuate, gradually become cylindroids and bluntly pointed, 28.24-44.96 (37.09 +/- 6.86) um long with a strong and elongated curved mucro situated ventrally. PMID- 28615833 TI - Prevalence and organwise distribution of sarcocystiosis in buffaloes of Mohali, Punjab. AB - The study was carried at Mirha Exports private limited at Mohali, Punjab, from December 2012 to May 2013 during which 1000 buffaloes of 2-3 years of age slaughtered for meat purposes were screened for the Sarcocystis species. Most of the animals examined at anti-mortem appeared normal and clinically healthy. However, at slaughtering, the gross and microscopic examination of representative samples of striated muscles collected from slaughtered buffaloes revealed 95.50 % prevalence of Sarcocystis species. Out of 1000 samples examined, 955 samples (95.55 %) were infected with microscopic cysts with size ranging from 19.1 to 95.9 * 10.2 to 68.9 MUm cyst, while 6 samples (0.60 %) had mixed infection with macroscopic cyst with size ranging from 1270 to 19,000 * 700 to 7000 MUm cyst of white or creamy colour and microscopic cysts. Among the muscles infected with cysts, highest number of cysts were recorded in tongue muscles (87.40 %) followed by oesophageal muscles (83.60 %), cardiac muscles (53 %) and diaphragmatic muscles (31.30 %). PMID- 28615835 TI - Haematological changes in South Indian fresh water murrel, Channa punctatus have both EUS and A. hydrophila infection. AB - The mixed infection in fishes is a common feature and in this Pathogens like Bacteria, Fungi and Protozoan's are found together to cause ill health to the fishes known as Epizootic Ulcerative Syndrome (EUS). In this syndrome the low temperature and aquatic pollution aggravates the infection in fishes. In the present study the fresh water edible fish, Channa punctatus (Murrel) was found infected with the bacteria namely, Aeromonas hydrophila, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella salmonicida. The fungi, Aphanomyces invadans was also found. The major objective of this study is to understand the microbial intensity in various organs of fish and hematological variations in both control and EUS infected fish. The highest microbial load of 8.2 +/- 0.12 * 107 cfu g-1was observed in the skin where as the lowest load of 3.2 +/- 0.8 * 103 cfu g-1 was found in the pancreas. From the microbial diagnosis, A. hydrophila has been isolated from different organs indicating its predominant presence. In comparison with the control the haemotological indices like WBC, MCV, Lymophocytes, Eosinophils and Basophils were found increased in the infected by (17 %), (16 %), (5 %), (58 %) and (27 %) respectively. The variations in microbial load found in fish in the study can be attributed to feeding habits, behavior, fish adaptations among the different fish species. These conditions are being caused by the presence of environmental pollution and are high in heavy native fishes. Thus the results showed that low of Haemoglobin value Packed Cell Volume and Red Blood Corpuscles indicated the presence of anemic conditions in the EUS infected fish found in Warangal. PMID- 28615836 TI - Molecular identification of an old clinical isolate of Indian Kala-azar. AB - Molecular characterization is an important task for species identification of the isolates belonging to different Leishmania species. Clinical symptoms, tissue tropism, vector preference, reservoir and geographical distribution may act as distinguishing parameters but not always decisive. On the other hand, modern taxonomic tools employed to divulge characteristics of the genome or protein molecules of the parasite would be convincing and for Leishmania sp., they include nuclear and kDNA buoyant density, multi locus enzyme electrophoresis (MLEE), RAPD, RFLP or use of monoclonal antibodies etc. In the present study, we intend to establish the identification of an old clinical isolate of Indian Kala azar, familiarly known as 'UR6' by MLEE, RAPD, RFLP and species specific monoclonal antibodies. UR6 has been isolated from a confirmed Kala-azar patient admitted in Calcutta School of Tropical Medicine, Kolkata in 1978. From then it is being regularly used for various scientific studies by the Leishmania Research Group of India and abroad. The isozyme profile of UR6 showed similar electrophoretic mobility that of WHO reference strain for Leishmania tropica, K27. Similar findings were obtained in the RAPD and RFLP assays. Screening with species specific monoclonal antibodies showed its strong reactivity towards L. tropica. The Jaccard's Similarity Indices were calculated. PMID- 28615837 TI - Trypanocidal action of Lippia alba and Lippia origanoides essential oils against Trypanosoma evansi in vitro and in vivo used mice as experimental model. AB - Parasitic diseases have an enormous health and economic impact and are a particular problem in tropical regions of the world. Disease caused by protozoa, such as trypanosomiasis, are the cause of most parasite related morbidity and mortality. Thus, the aim of this study was to verify the trypanocidal effectiveness of Lippia alba and Lippia origanoides against Trypanosoma evansi in vitro and in vivo. L. alba and L. origanoides were used in vitro on trypomastigotes at different concentrations (0.5, 1.0 and 2.0 %) and exposure times (0, 1, 3, 6 and 9 h). The three concentrations tested showed trypanocidal activity in vitro, completely eliminating the parasites in small concentration after 6 h of assay. In vivo tests were performed using mice as the experimental model. T. evansi infected mice were treated with L. alba and L. origanoides with dose of 1.5 mL kg-1 during 5 days. These protocols did not provide curative efficacy, however the mice treated with L. origanoides showed a significant increase in the longevity when compared to control group. Active compounds present in essential oils, such as L. origanoides, may potentiate the treatment of trypanosomosis when associated with other trypanocidal drugs. PMID- 28615838 TI - Immunodiagnosis of Haemonchus contortus infection in sheep by counter immuno electrophoresis using somatic antigen. AB - The present study was undertaken for the immuno-diagnosis of Haemonchus contortus infection in sheep by counter immuno-electrophoresis (CIEP) using crude somatic antigen. Adult worms of H. contortus were found in 57 out of 100 abomasums screened. A total of 250 serum samples which includes, 100 serum from local abattoir in and around Shimoga region from the sheep from which the abomasums were collected for H. contortus worms and 150 serum from the migratory sheep were collected to detect the circulating antibody of H. contortus by CIEP using crude whole worm somatic antigen. Out of 100 abomasums screened, 18 were heavily infected with adult worms of H. contortus and their serum samples showed positive reaction with clear thick precipitin line with crude somatic antigen of H. contortus by CIEP and 39 samples showed light precipitin line, which were moderately infected with adult worms of H. contortus during necropsy. However, the 12 serum samples showed positive reaction with clear precipitin line, but their abomasums did not show H. contortus and the remaining 31 were not harbouring any adult worms of H. contortus and no precipitin line observed by CIEP. The sensitivity and specificity of CIEP was found 100 and 72.09 %, respectively. In the present study, 62 % sero-prevalence was observed with CIEP among 150 serum samples from migratory sheep screened for antibodies of H. contortus using crude whole worm somatic antigen of H. contortus. PMID- 28615839 TI - Epidemiological and clinical aspects of patients with hydatid cyst in Iran. AB - Hydatid cyst is one of the most common Zoonotic diseases occurs due to infection with larval stage of Echinococcus granulosus parasite. Based on epidemiological reasons, World Health Organization has introduced Iran as a hyperendemic region. This study aims to investigate the clinico-epidemiological characteristics of patients with hydatid cyst in Iran. We used information registered in the surveillance system of the Iranian Ministry of Health and Medical Education attributed to Mazandaran province. Data were entered into SPSS software V.20 after refinement and analyzed using percent frequency, mean, standard deviation and statistical tests such as Chi-square and Exact Fisher tests. Mean (SD), minimum and maximum ages of the participants were 42.2 (17.2), 6 and 72 years respectively. Most of them were female (63.4 %) and mean (SD) number of cysts was 1.6 +/- 0.8. Of them, 51.2 % living in rural areas and 58.5 % of them were housewives. Liver was the most common organ involved. The main diagnostic procedures were radiography and CT scanning. The majority of participants (73.2 %) consumed unsterilized vegetables. This study showed women more susceptible compared to men probably because of more exposure to parasites through vegetables. We also found the liver as the most affected organ in hydatid cyst patients. PMID- 28615840 TI - Observation on Monocystis kuidongae sp. nov. (Apicomplexa: Eugregarinida) from an Indian earthworm Perionyx excavatus Perrier (Annelida: Oligochaeta). AB - A survey to know the diversity of endoparasitic protozoan parasites of the earthworms of West Bengal, revealed a new species of the genus Monocystis Stein, 1848, that resides in the seminal vesicle of the earthworm Perionyx excavatus Perrier. Monocystis kuidongae sp. nov. is characterized by ovoidal gamonts (trophozoites) with inconspicuous mucron and measure 69.53-102.25 (86.29 +/- 11.48) MUm * 24.54-61.35 (35.17 +/- 12.82) MUm. Shape of the gametocysts are almost rounded and measure 81.80-110.43 (96.11 +/- 8.85) MUm in diameter. Oocysts are navicular with pointed ends and measure 11.55-12.32 (11.78 +/- 0.36) um * 5.00-5.77 (5.39 +/- 0.25) um. PMID- 28615841 TI - Cobboldia elephantis (Cobbold, 1866) larval infestation in an Indian elephant (Elephas maximus). AB - In the present study, post-mortem was conducted on a female elephant aged about 37 years died at Rajeev Gandhi National Park, Hunsur, Mathigoodu Elephant Camp, Karnataka state. The animal suffered with diarrhoea, anorexia, dehydration and was unable to walk for about one week before death and was treated with antibiotics and fluid therapy for three days. The post-mortem examination revealed that, the gastric mucosa was severely congested, hyperaemic and numerous stomach bots attached to the mucosa. The bots were recovered from the gastric mucosa and processed for species identification. The posterior spiracles of the bots showed three longitudinal parallel slits in each spiracle, the abdominal segments had a row of belt like triangular shaped spines and the anterior end had two powerful oral hooks with cephalo-pharyngeal skeleton. Based on the above said morphological characters, the bots were identified as Cobboldia elephantis. This seems to be the first report of C. elephantis in free range wild elephant from Karnataka state. PMID- 28615842 TI - Retro-bulbar cyst of Coenurus gaigeri in Barbari goats. AB - Two adult Barbari goats were presented to the Division of Animal Health of the Institute with the history of unilateral protrusion of the left eye ball, blepharitis and congestion of the conjunctival membrane. Physical and ultrasonographical examination revealed large fluctuating fluid filled bladder with distinct dimensions. The cysts were successfully removed along with its membrane and parasitological examination revealed it as a Coenurus gaigeri, the intermediate stage of T. multiceps gaigeri. The present report describes the retro-bulbar cyst of Coenurus gaigeri in two Barbari goats. This is the first report of retro-bulbar cyst of Coenurus gaigeri in goats. PMID- 28615843 TI - In vitro adaptability of Plasmodium falciparum to different fresh serum alternatives. AB - To reduce the dependency on fresh AB+ serum in continuous culture of Plasmodium falciparum, a comparative study was undertaken to assess the in vitro adaptability of P. falciparum to media supplemented with fresh AB+ serum from whole blood, AB+ plasma, serum derived from AB+ plasma, AB+ human serum from Sigma, Albumax II, fetal bovine serum and new born calf serum, independently and in different combinations. Combinations were used to analyze whether two different substitutes demonstrate any synergistic effect on the growth of the parasites. Our findings exhibited that the combination of fresh human serum and Albumax II showed good growth pattern in comparison to that of fresh serum and can thereby be instrumental in reducing the role of fresh human serum in continuous parasite maintenance. Culture maintained with Albumax II with or without hypoxanthine showed average growth. PMID- 28615844 TI - The antileishmanial effects of Lowsonia inermis and Cedrus libani on Leishmania major promastigotes: an in vitro study. AB - Leishmaniasis is a parasitic disease caused by different species of protozoan parasites belonging to the genus Leishmania. In this study, Leishmania major (MRHO/IR/75/ER) promastigotes were cultured at 23-25 degrees C in brain heart infusion (BHI) medium supplemented with 10 % heat-inactivated fetal bovine serum (FBS) and penicillin and streptomycin. Antileishmanial effects of Lowsonia inermis and Cedrus libani methanolic extracts (0.07, 0.15, 0.31, 0.62, 1.25, 2.5, 5, 10 mg/mL) on Leishmania major promastigotes were evaluated using the MTT (3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. All experiments were repeated at least three times. Cedrus libani methanolic extract did not show any activity while Lowsonia inermis methanolic extract inhibited the growth of promastigote forms of L. major in vitro after 72 h of incubation and had a 50 % inhibitory concentration (IC50) of 1.25 mg/mL. The methanolic extract of Lawsonia inermis (henna) can be a promising antileishmanial agent in the future. Further experiments are needed for isolation of active fractions and identification of the active components of methanolic extract. PMID- 28615845 TI - Efficacy of ivermectin, closantel and fenbendazole against gastrointestinal nematodes of sheep in Kashmir valley. AB - The present work was undertaken to evaluate the therapeutic efficacy of ivermectin, closantel and fenbendazole under field conditions against Gastrointestinal Nematodes (GIN) of cross bred merino sheep in Budgam area of Kashmir Valley. A total of 115 sheep having Egg per gram of faeces (EPG) greater than or equal to 150 (mean EPG 258.89) were selected. The animals were randomly divided into four groups comprising of 30 animals each in three treatment groups (ivermectin, closantel and fenbendazole) and twenty-five in fourth untreated infected control group. Faecal samples from the selected animals were collected on day '0' pre treatment and on days 8th and 14th post treatment. Based on Faecal Egg Count Reduction Test (FECRT), ivermectin was found to be 98.80 % effective against strongyles on 8th day post treatment, however an efficacy of 100 % was seen against strongyle worms on 14th day post treatment. 98.80 and 100 % efficacy was observed on day 8th post treatment against strongyles in case of closantel and fenbendazole respectively, however efficacy decreased to 97.60 and 98.8 % respectively on 14th day post treatment. There was no evidence of development of resistance by GIN of cross bred merino sheep in District Budgam of Kashmir Valley to ivermectin, closantel and fenbendazole. PMID- 28615846 TI - Incidence of fur mite infestation in laboratory rodents. AB - Incidence of fur mites in laboratory rodents is reported. Among mice, infestation was found to be highest in male Swiss Albino mice followed by female Swiss Albino mice, male Balb C mice and female Balb C mice. Infestation in Guinea pigs was 50 %. None of the rats screened were found to be positive for fur mites. Species of fur mites identified were Myocoptesmusculinus in mice and Chirodiscoidescaviae in Guinea pigs. Clinical signs in affected animals are also reported. PMID- 28615847 TI - Larvicidal potency of marine actinobacteria isolated from mangrove environment against Aedes aegypti and Anopheles stephensi. AB - The marine soil samples were collected from different locations of Parangipettai mangrove ecosystem, Vellar estuary, southeast coast of India. Totally 30 different marine actinobacteria were isolated by serial dilution plate technique on starch casein agar medium. The isolated actinobacteria were investigated for their larvicidal activity against Aedes aegypti and Anopheles stephensi mosquitoes. Streptomyces fungicidicus, S. griseus, S. albus, S. alboflavus and S. rochei were identified as potential biocide producers. Based on the antimicrobial activity, five strains were chosen for larvicidal and pupicidal activity. Among the crude extracts tested, the S. alboflavus extract showed significant activity against Ae. aegypti (LC50 1.48 +/- 0.09 and LC90 3.33 +/- 0.22) and An. stephensi (LC50 1.30 +/- 0.09 and LC90 3.13 +/- 0.21). Five isolates have shown a most significant mortality rate of the Ae. aegypti and An. stephensi mosquito larvae. This is an ideal eco-friendly approach for the control of Japanese encephalitis vectors, Ae. aegypti and malarial vector An. stephensi. PMID- 28615848 TI - Therapeutic management of canine ehrlichiosis with aid of blood transfusion: a case report. AB - An adult female Labrador Retriever dog was presented at referral veterinary polyclinic, IVRI in lateral recumbency with history of anorexia, high fever, severe panting, heavy tick infestation, and not responding to cephalosporins and fluoroquinolones since last 1 week. Clinical examination showed pale conjunctiva, enlarged popliteal lymph node however, electrocardiogram (ECG) report found to be normal. Haematological finding showed marked anaemia and thrombocytopenia. Parasitological examination found it to be positive for Ehrlichia canis and confirmed ticks to be Rhipicephalus sanguineus. Dog was treated with doxycycline @ 10 mg/kg for 28 days in divided dose with supportive therapy. Blood transfusion was done on second day to avoid complication. Dog showed marked recovery after 15 days and re-examination of blood revealed no parasitemia. PMID- 28615849 TI - In-vivo antimalarial activity of aqueous leaf and bark extracts of Trema orientalis against Plasmodium berghei in mice. AB - The control of malaria relies on the use of chemical antimalarial, but the development of resistance necessitates research into alternatives. Trema orientalis (L.) Blume is used in Nigerian folklore medicine for the treatment of malaria. This study investigates the in vivo antiplasmodial activity of aqueous leaf and bark extracts of T. orientalis in rodent model. Swiss Albino mice weighing 23-27 g were intraperitoneally infected with Plasmodium berghei. The lethal dose in mice was estimated to be greater than 5000 mg/kg based on toxicity signs and death. Aqueous crude leaf and bark extracts were administered at 400, 800 and 1600 mg/kg. Chloroquine was used as positive control while the negative control was treated with distilled water. Parasitemia, parasite inhibition, body weight and packed cell volume (PCV) were determined. The parasite inhibition of the leaf extracts at 400, 800 and 1600 mg/kg was 51.55, 62.78 and 76.08 % while that of the bark extract was 44.3, 65.82 and 74.23 % respectively. The percentage parasitemia of the leaf extract at 400, 800 and 1600 mg/kg decreased by 45.0, 70.3 and 74.7 % while that of the bark decreased by 37.4, 53.0 and 52.0 % respectively. The PCV of mice treated with 400, 800 and 1600 mg/kg leaf extract were 48.85, 49.88 and 50.99 % while that of the bark extract was 49.38, 48.88 and 51.94 % respectively. The results indicate that the plant has a promising antiplasmodial activity against P. berghei, which validates its folkloric use. PMID- 28615851 TI - Gastrointestinal helminthosis: prevalence and associated determinants in goats of Jabalpur, India. AB - A total of 632 faecal samples of goats of Jabalpur district of Madhya Pradesh state were examined during three years of the study period (November 2012-October 2015), out of which 82.75 % samples were positive for helminthic infections. Among various helminths, maximum prevalence was of strongyles (32.59 %) followed by amphistomes (14.40 %), Moniezia spp. (12.50 %), Strongyloides spp. (0.79 %), Trichuris spp. (0.47 %) and Fasciolagigantica (0.32 %). Year wise prevalence revealed a highly significant (p < 0.01) decrease in prevalence of helminths. Except Trichuris and Moniezia spp., the effect of year was significant for prevalence of all other gastro-intestinal helminths observed during the study. Significantly higher (p < 0.05) helminth infections were observed in monsoon (87.97 %) as compared to that of winter (81.48 %) or summer (79.03 %) season. The seasonal difference in prevalence was found significant for strongyles, Strongyloides spp., amphistomes and Moniezia spp. There was no significant variation in Trichuris spp. and Fasciola gigantica infections in relation to season. Age wise prevalence of helminths was non-significantly higher in kids (83.13 %) than in adults (82.62 %). Except Moniezia spp., age wise observations did not reveal any significant difference (p > 0.05) in prevalence of other gastrointestinal helminths. PMID- 28615850 TI - Prevalence of Giardiaduodenalis among children from a central region of Cuba: molecular characterization and associated risk factors. AB - Giardia duodenalis is one of the most frequent intestinal parasitic infections in children worldwide. To date, eight main assemblages of G. duodenalis have been described, but only A and B genetic groups are known to infect humans. A cross sectional study was conducted to determine the prevalence and risk factors of Giardia duodenalis infection in 417 preschool children from the Fomento municipality in the central region of Cuba between January and June 2013. The overall prevalence of Giardia infection was 10.79 %. Assemblage identification was carried out by the amplification of a fragment of the triose phosphate isomerase (tpi) gene. DNA from 36 of 45 (80 %) samples was successfully amplified by PCR-tpi. Assemblage B and mixed assemblages A + B represented 52.78 and 36.11 % respectively, of genotyped samples. Assemblage A accounts for only 11.11 %. Children who were cared for at home were associated with diarrhea caused by assemblage B. No associations were found between other clinical variables with infecting assemblage of Giardia. Univariate analysis identified the use of unsafe water resources (OR 2.9; CI 1.2-6.8) and-even more interestingly-keeping dogs indoor (OR 2.5; CI 1.2-5.4) were significant risk factors associated with Giardia infection among children. Multivariate analysis using introduction test logistic regression ratified the association of these two risk factors: kept dogs indoor (OR 2.8, CI 1.1-5.3), and untreated water (OR 1.4, CI 1.4-4.9) with Giardia infection. This information may be useful for an effective prevention and control programme of giardiasis in this population. PMID- 28615852 TI - Therapecutic efficacy of the leaf extract of Croton joufra Roxb. against experimental cestodiasis in rats. AB - The leaves of Croton joufra have been used as a traditional medicine in Assam (Northeast India) to treat the intestinal helminthic infections. The aim of this study was to establish the in vitro and in vivo anthelmintic efficacy of the leaf extract of this plant on Hymenolepis diminuta, a zoonotic tapeworm. The plant extract was also screened for its chemical constituents. The in vitro anthelmintic efficacy of the plant was evaluated by physical motility test on adult cestodes, following their exposure to 10, 20, 30 mg/ml concentrations of the crude leaf extract, while the in vivo effect was determined based on the eggs per gram (EPG) counts and worm recovery rates, using an experimentally induced model of H. diminuta infections in Wistar rats. The in vitro study results showed a dose-dependent effect on the parasite and the highest concentration of the extract (30 mg/ml) caused mortality of the worms in 1.53 +/- 0.12 h as compared to 3.46 +/- 0.10 h shown by 1 mg/ml concentration of the reference drug, praziquantel (PZQ). The in vivo results showed that a single 800 mg/kg dose of the extract, given for 3 days, was highly efficacious against adult parasites as it reduced the EPG count and worm burdens of rats by 94.74 and 75 %, respectively. The extract also showed almost similar degree of effects against the larval stage of the parasite. As ascertained by the qualitative screening tests, the leaf extract of C. joufra contains terpenoids, tannins, alkaloids, flavonoids, glycosides and reducing sugar. The overall findings of this study suggest that C. joufra leaf extract possesses significant anthelmintic efficacy and support its traditional anthelmintic claims. PMID- 28615853 TI - Genotoxic potential of Fasciolagigantica infection in experimentally infected rabbits. AB - A number of parasitic platyhelminthes are known to cause genotoxicity in humans and animals. However no such information is available on tropical liver fluke, Fasciola gigantica, which incurs huge economic losses worldwide. In the present study the genotoxic potential of F. gigantica infection in rabbits, experimentally infected with the metacercarial cysts of this parasite, has been investigated using the standard comet assay and micronucleus (MNi) test on the isolated hepatocytes and the whole blood from the infected rabbits. The tail length of the comet in both hepatocytes and reticulocytes from the infected animals was significantly prominent (p < 0.05) as compared to the controls. About 61.17 % of the hepatocytes from the infected rabbits were positive for MNi formation. A number of blood cells also showed cellular deformities, which were recognised as spicule type, schistocytes, tear drop type, acanthocytes and dumbbell type. It is possible that during the establishment of host-parasite relationship the worms might have released some products which could have contributed to the induction of cellular and DNA damage. However, long term studies are required to understand the serious implications of such an effect caused by F. gigantica, though hepatic carcinoma has not been reported so far due to fasciolosis, however, considering the present results the possibility may not be rule out for the disease progression in this direction. PMID- 28615854 TI - Sarcoptic mange infestation in rabbits in an organized farm at Tamil Nadu. AB - Sarcoptes scabiei are burrowing mites which causes major constraints in rabbit production. Eighty-eight rabbits were examined for mange infestation at University Research Farm, Tamil Nadu. Overall incidence of mange infestation in rabbit was 23.6 %. On microscopical examination, the mite was identified as Sacoptes scabiei var cuniculi. Among the breeds, Soviet Chinchilla were found to be infested more (57.14 %) followed by New Zealand White (28.57 %) and White Giant (28.57 %). Among the age groups, adults (33.33 %) were heavily infested than the grower (21.88 %) whereas, suckling had no infestation of mange. Among the sex, males (21.95 %) were heavily infested than the females (14.89 %). Lesions were mostly found on the edges of ear, nose, face and legs and characterized by loss of hair, thickening of the skin, irregular dried dirty encrusted scabs with erythema and disfigurement of face and ear. PMID- 28615855 TI - Genetic diversity among Trypanosoma vivax strains detected in naturally infected cattle in Nigeria based on ITS1 of rDNA and diagnostic antigen gene sequences. AB - Trypanosoma vivax (sub-genus Duttonella) is largely responsible for non profitable livestock production in sub-Sahara Africa. In Nigeria, no study has addressed the molecular characteristic of T. vivax except Y486. Hence, we characterized and assessed the genetic diversity among T. vivax detected in naturally infected cattle in Nigeria using internal transcribed spacer 1 (ITS1) of ribosoma DNA (rDNA) and diagnostic antigen gene (DAG) sequences. The length of ITS1 and DAG sequences range from 215-220 to 257-338 bp, respectively and the mean G-C contents were 60 and 61.5 %. Homology search revealed 93-99 and 95-100 % homologies to T. vivax DAG and ITS1 sequences from GenBank. Aligned sequences revealed both ITS1 rDNA and DAG to be less polymorphic but DAG sequences of the Y486 strain and its clone showed marked variation from autochthonous strains. Phylogenetic analysis yielded tree that grouped T. vivax ITS1rDNA gene and DAG sequences into two main clades each. Considering the ITI1 rDNA sequences, clade A contained autochthonous T. vivax within which the South American sequences clustered, clade B contained the sequences of T. vivax from East Africa. Analysis of DAG revealed that the clade A contains autochthonous T. vivax sequences but clade B contained the Y486 and its clones. In conclusion, the diagnostic antigen gene sequences of the T. vivax detected in this study may have undergone considerable gene recombination through time and suggests that more than one strain of T. vivax exist among cattle population in Nigeria. PMID- 28615856 TI - A rare case of Theileria annulata induced corneal opacity in a calf. AB - A 10 months old male cross-bred calf was presented in OPD Medicine, Referral Veterinary Polyclinic, ICAR-Indian Veterinary Research Institute, Izatnagar with the history of anorexia, impaired vision, heavy tick infestation and diarrhoea for the last 1 week. The clinical examination revealed enlarged pre-scapular lymph nodes, prominent cloudiness in eyes and exophthalmos. The presence of Koch blue bodies in biopsied lymph nodes and a PCR assay confirmed it to be bovine tropical theileriosis associated with unique corneal opacity. Treatment with buparvaquone at a dose of 2.5 mg/kg i.m. two doses 48 h apart was successful and typical ocular manifestations completely subsided after 2 weeks of therapy. PMID- 28615857 TI - Alteration of Direct Agglutination Test (DAT) results in Iranian Kala-Azar patients: a case series. AB - The early diagnosis of visceral leishmaniasis (VL) using Direct Agglutination Tests (DAT) and its treatment and control are essential actions taken in rural health centers in endemic foci of the infection based on the national protocols set by the Iranian Ministry of Health and Medical Education. Eleven clinically confirmed VL patients with typical VL symptoms and negative results of DAT, admitted to the pediatrics department of Valiasr Hospital in Meshkinshahr underwent parasitological tests. 7 of the total of 11 patients had positive result of bone marrow puncture smears and all of them had negative results of DAT. Thus factors that had led to false negative DAT results were examined. The patients' blood samples were collected in microhematocrit tubes using the finger prick technique, centrifuged and their plasma then separated. The complete medical history of the patients was taken using a questionnaire. The laboratory staff therefore checked the quality of anti-leishmania antigen, materials and equipment used. The patients' medical history showed that they had all been administered corticosteroid medications such as dexamethasone or hydrocortisone prior to visiting the laboratory. The DAT was repeated in these patients 2-3 weeks after their last administration of corticosteroids. The antibody titers were positive this time. A total of 3 of the collected specimens (27.3 %) showed a titer of 1.3200, 5 (46 %) showed a titer of 1.1600 and 3 (27.3 %) a titer of 1.800. Due to the effects of some medications, particularly corticosteroids, on serological tests, the patients' full medical history should be taken prior to performing this test and physicians working at endemic regions of this infection should be notified about these drug interactions. PMID- 28615858 TI - Molecular diagnosis of cattle trypanosomes in Venezuela: evidences of Trypanosoma evansi and Trypanosoma vivax infections. AB - In South America Trypanosoma evansi has been determined by molecular methods in cattle from Bolivia, Brazil, Colombia and Peru, reason for which the presence of this parasite is not excluded in Venezuelan livestock. Therefore, the aim of this study was to perform parasitological and molecular diagnosis of cattle trypanosomosis in small livestock units from two regions in this country. The parasitological diagnosis was carried out by MHCT and the molecular by PCR using genus-specific ITS1 primers that differentiate T. vivax and T. evansi infections. 47 cattle were evaluated in the "Laguneta de la Montana" sector, Miranda State, where 3 animals were diagnosed as positive (6.4 %) by MHCT and 14 (30 %) by PCR as Trypanosoma spp., out of which 9 animals resulted positive for T. vivax, 3 for T. evansi and 2 with double infections. Whilst in the "San Casimiro" sector, State of Aragua, out of the 38 cattle evaluated 7 animals were diagnosed as positive (18.4 %) by MHCT and 19 (50 %) by PCR, determining only the presence of T. evansi in this locality. The molecular diagnosis by PCR using ITS1 primers allowed T. evansi detection in cattle field populations, which suggests the possible role of these animals as reservoirs in the epidemiology of the disease caused by T. evansi in Venezuela. PMID- 28615859 TI - Molecular identification of Babesia spp. in naturally infected dogs of Kerala, South India. AB - Canine babesiosis is a tick borne haemoprotozoan disease caused by large and small intraerythrocytic apicomplexan piroplasms of the genus Babesia spp. The clinical manifestations of the disease vary from inapparent subclinical form to hyperacute shock related haemolytic crisis. Microscopic examination of blood smears from suspected dogs revealed Babesia canis and B. gibsoni in 3.45 and 25.86 % of samples respectively. A seminested PCR based on previously published species specific primers targeting the 18S rRNA gene was utilized to identify the Babesia species infecting dogs of Kerala at the sub species level. The study revealed 57.5 % prevalence of Babesia spp. among dogs. This report also presents the first molecular evidence of Babesia canis vogeli and B. gibsoni among naturally infected dogs in Kerala, South India. Molecular survey revealed a high prevalence of B. gibsoni infections when compared with B. canis vogeli infections among canines of the state. Preliminary survey of the tick population revealed the presence of Rhipicephalus sanguineus, R. haemaphysaloides and Haemaphysalis bispinosa in infected animals. Further studies need be directed towards utilizing the PCR protocol for confirming the vectors of these species in the region. PMID- 28615860 TI - Detection of anthelmintic resistance in sheep and goat against fenbendazole by faecal egg count reduction test. AB - Anthelmintic resistance against commonly used anthelmintic fenbendazole was evaluated by employing faecal egg count reduction test (FECRT) in naturally occurring gastrointestinal (GI) nematodes in the semi organized sheep and goat farms of Ludhiana and Amritsar districts. A total of 80 animals (20 each for sheep and goat in both districts) were randomly selected and their faecal samples were examined by qualitative and quantitative parasitological techniques. Results indicate presence of high level of resistance against fenbendazole in both sheep and goat population of Ludhiana and Amritsar districts. More resistance was observed in the GI nematodes from animals reared in Amritsar district as compared to Ludhiana district. The level of anthelmintic resistance observed was apparently more in sheep than goats. PMID- 28615861 TI - In vitro ovicidal activity of Peganum harmala seeds extract on the eggs of Fasciola hepatica. AB - Peganum harmala seeds extract has been previously reported to have antimicrobial and other medicinal properties. The aim of this study was to evaluate the ovicidal activity of the methanolic extract of P. harmala seeds against the eggs of F. hepatica. The phenolic compounds of the methanolic extract of P. harmala seeds were identified by HPLC analysis. Catechin, rutin, p-Coumaric acid, chloregenic acid and hesperetin were found to be the major phenolic compounds. F. hepatica eggs were collected from the gall bladder of naturally infected sheep. The eggs were exposed to two concentrations of P. harmala seeds extract (1 and 3 mg/mL) for 24 and 48 h. To investigate the effect of the P. harmala seeds extract on the miracidial formation, the treated eggs were incubated at 28 degrees C for 14 days. The results indicated that F. hepatica eggs were susceptible to the methanolic extract of P. harmala seeds. Following 24 h exposure of the eggs to P. harmala seeds extract with concentrations of 1 and 3 mg/mL, the miracidial formation reduced to 5 and 2.2 % respectively (compared with 60 % for the control group). Following 48 h of exposure of the eggs to P. harmala seeds extract with 1 mg/mL concentration, the miracidial formation reduced to 0.5 %. In this exposure time, no miracidial formation was observed in the eggs exposed to P. harmala seeds extract with concentration of 3 mg/mL. Therefore, the results of this study indicated that P. harmala seeds extract has high ovicidal activity against the eggs of F. hepatica. Accordingly, this extract may have the potential flukicidal activity against the immature and mature F. hepatica. PMID- 28615862 TI - Incidence of Onchocerca gibsoni in subcutaneous nodules of cross bred Jersey cows: case report. AB - Onchocerca gibsoni subcutaneous nodules in four cross bred Jersey cows aged 5-6 years brought for post mortem with calcified and caseated skin nodules in the lateral flank region is reported. Examination and dissection of these nodules revealed that they were "worm nests" of Onchocerca sp. of filarid nematodes. The worm nests were carefully dissected and filarid worms were extracted out. Multiple numbers of worms were recovered from each nodule ranging from 15 to 20. Female worms were found inside the worm nests and were found to be filled with microfilariae. The nodules weighed 2-3 g. Based on the morphological features the worms were identified as O. gibsoni. PMID- 28615863 TI - Prevalence and microscopic studies of Sarcocystis infection in naturally infected water buffaloes (Bubalus bubalis) of Andhra Pradesh. AB - Sarcocystis species are the obligate tissue protozoan parasites of livestock causing clinical and subclinical disease resulting in downgrading of the meat and their products thereby leading to economic losses. The present study reveals the prevalence and distribution of sarcocystosis in water buffaloes (Bubalus bubalis) slaughtered at local abattoirs in A.P for a period of 1 year from June 2014 to May 2015. A total of 137 buffalo carcasses were screened grossly and microscopically organ wise viz., esophagus, tongue, heart, diaphragm and intercostal muscles. Out of 137 screened, 91 were infected with an overall prevalence of 66.42 %. Age wise analysis of 89 young male calves aged about 18-36 months old revealed 65.16 % (58/89) and 48 old she buffaloes (5-8 years) showed 68.75 % (33/48). The organ wise prevalence was highest in esophagus (51.82 %) followed by tongue (47.44 %), heart (29.92 %), diaphragmatic muscles (28.46 %) and intercostal muscles (18.24 %), respectively. Morphometric studies revealed the presence of two Sarcocystis species, i.e., S.levinei and S.fusiformis infection with a prevalence of 43.79 and 22.62 %, respectively, along with mixed infection rate of 43.06 %. Microscopic studies of S.levinei showed sarcocyst length/width/cyst wall thickness ranged between 0.31-0.69/0.09-0.12 mm/<1 um, respectively, and bradyzoites with an average of 6.25 um length/2.5 um width. Similarly, S.fusiformis cyst ranged between 2 and 8.5 mm/1-3 mm/2-5 um and bradyzoites with an average of 10 um length/2.5 um width. The histopathological studies revealed congestion and degenerative changes of myocytes along with infiltration of mononuclear cells. PMID- 28615864 TI - Prevalence of gastro intestinal parasites in pigs in Punjab, India. AB - Gastrointestinal parasites are a common problem in pigs in India. The important risk factors include coprophagic behaviour of pigs and their free access to garbage. To investigate the gastrohelmenthic spectrum in pigs of Punjab, we examined 265 faecal samples from farm (n = 47) and scavenging pigs (n = 218) using faecal floatation method. Ascaris suum, unsporulated oocysts, Trichuris spp. and Strongyloides were recorded in 27.5, 15.4, 1.8 and 4.5 % of the pig faecal samples, respectively. Overall prevalence was significantly higher in pigs >1 year (56.5 %) than pigs <=1 year (39.6; p = 0.01) Parasite positivity was neither significantly related with location (p = 0.309) nor with management practices (p = 0.69). High prevalence of gastro intestinal parasites in pigs in Punjab warrants intervention policies to control this problem. PMID- 28615865 TI - Epidemiological studies on trichinellosis in pigs (Sus scofa) in India. AB - The present study was conducted to determine the prevalence of trichinellosis in domestic pigs (Sus scrofa) in India. A total of 319 tissue and 279 serum samples were collected from 279 slaughter pigs. The samples were collected from small slaughter shops located in Assam, Chandigarh (Union territory), Punjab and Uttarakhand states of the country. The presence of Trichinella spp. antibodies in serum was determined using a commercially available enzyme-linked immunosorbent assay (ELISA) kit and tissue samples were digested using the OIE recommended pepsin-HCl digestion method. The overall seroprevalence of trichinellosis was found to be 2.87 %. The age wise seroprevalence was found to be 2.83 % in pigs aged more than 6 months and 3.12 % in pigs <6 months of age. The seroprevalence was more in male (3.38 %) than female (1.96 %) pigs. None of the samples were found positive using pepsin-HCl digestion method. Since none of the samples was found positive for Trichinella, PCR assay could not be employed in the current study. The age, sex and management practices of the animals were not significantly (p > 0.05) associated with seroprevalence. The current research confirms that trichinellosis remains a rare zoonosis in India. However, extensive studies must be carried out in wildlife to identify reservoir hosts in the country. PMID- 28615866 TI - Virulence assay and role of Bacillus thuringiensis TS110 as biocontrol agent against the larval stages of rice leaffolder Cnaphalocrocis medinalis. AB - The bacterial isolate Bacillus thuringiensis TS110 was isolated from the rice field soil of Burdwan district, West Bengal, India. Bioassay test of the bacteria TS110 against 3rd, 4th and 5th instar larvae of Cnaphalocrocis medinalis was carried out. Cut leaf assay, potted plant assay and field assay were done. During filed assay, it has been observed that the LC50 (*107) values of TS110 against 3rd, 4th and 5th instar larvae of C. medinalis were 3.77, 5.29, 4.83 and 4.93, 4.42, 4.72 in dry and wet season, respectively. The morphological, biochemical and phylogenetic analysis of the isolate TS110 were done. TS110 was positive for catalase, nitrate reductase, methyl red, voges-proskauer, oxidase, urease, indole, citrate utilization, arginine dihydrolase test, starch, lipid, gelatin, casein, and lecithin hydrolysis test. TS110 showed fermentation test positive for glucose, fructose, mannose, arabinose and trehalose in nutrient broth medium. The antibiotic sensitivity test showed that the bacterial isolate was sensitive to kanamycin (30 ug/disc), nalidixic acid (30 ug/disc), rifampicin (5 MUg/disc), doxycycline (30 ug/disc), gatifloxacin (10 ug/disc), vancomycin (30 ug/disc), gentamycin (10 ug/disc), ampicillin (10 ug/disc), ofloxacin (5 MUg/disc), levofloxacin (5 MUg/disc), streptomycin (10 ug/disc), gentamycin (10 ug/disc). The phylogenetic analysis revealed that TS110 was closely related to different species of B. thuringiensis submitted to the GenBank. On the basis of morpho physiological and molecular characterization, the bacterial isolate was identified as B. thuringiensis. PMID- 28615867 TI - First record of a rare transversotrematid cercaria larva (Trematoda: Digenea) from Rajasthan, India: focus on seasonal occurrence and host-specificity of diverse cercariae. AB - During the survey of freshwater snail hosts and their digenean larval trematode parasites, a rare cercaria larva belonging to family Transversotrematidae and subclass Digenea (Trematoda) was recovered from the snail species Melanoides striatella tuberculata inhabiting perennial Som river of Udaipur district, Rajasthan, India. More than 28 % mature specimens of these snails were found to be infected with transversotrematid cercaria larvae in the spring season. Body of this cercaria is large, bowl-shaped, biocellate, spinose, transparent and laterally extended having two pigmented eye spots, two hold fast organs extended from the junction of body and tail, large tail with two foliated furcal rami, and cyclocoel intestinal caeca. As far as the authors are aware, this is the first record of a transversotrematid larva from Rajasthan, India. Simultaneously, other forms of cercariae viz., amphistome, echinostome, monostome, gymnocephalous, furcocercous and xiphidiocercous cercariae were also recovered from fifteen species of pulmonate and operculate snails including Lymnaea acuminata f. patula, L. acuminata f. chlamys, L. acuminata f. typica, L. acuminata f. rufescens, L. luteola f. australis, L. luteola f. typica, L. luteola f. impura, Planorbis (Indoplanorbis) exustus, and Anisus (Gyraulus) convexiusculus, Faunus ater, Melania (Plotia) scabra, Thiara (Tarebia) lineata, Melanoides striatella tuberculata, Vivipara bengalensis race gigantica and V. bengalensis race mandiensis. The seasonal occurrence and host-specificity of diverse trematode cercaria larvae are also discussed besides the first record of a rare transversotrematid cercaria larva from Rajasthan, India. PMID- 28615868 TI - Some probable factors affecting the malaria situation before and at the beginning of a pre-elimination program in southeastern Iran. AB - The area southeast of Iran still copes with malaria as an unstable infectious disease and includes the most autochthonous malaria reports in the country. This comprehensive study was carried out for the evaluation of environmental factors, welfare indicators and health facilities on the malaria situation before and at the beginning of a pre-elimination programme in this area. The probable factors affecting the malaria situation, including the water-pipe network, electricity, rainfall, long-lasting integrated nets (LLINs), indoor residual spraying and malaria diagnosis-treatment centres were analysed using SPSS software. The Pearson correlation test showed no significant correlation between some factors such as piped water networks, annual precipitation, number of sprayed villages and autochthonous cases as well as autochthonous foci. But a significant correlation between electricity coverage, number of diagnoses of malaria treatment centres and autochthonous cases?foci was observed. Also, the number of distributed LLINs didn't have any correlation with the number of total malaria cases, but a significant correlation between LLINs and autochthonous foci was seen. Detailed studies on the correlation of various variables, such as piped water, spraying coverage and number of malaria diagnosis centres, with the malaria situation is limited in Asia and other parts of the world. This study and others like it can help malaria managers and directors in the more accurate allocation of financial resources. PMID- 28615869 TI - Coenurus cerebralis and its pathology in an organized farm of Tamil Nadu. AB - Coenurosis is a disease of the central nervous system in sheep. A survey was carried out to assess the occurrence of Coenurus cerebralis in Madras red sheep. A prevalence rate of 12.30 % observed when 122 slaughtered Madras red sheep were examined in an organized farm during 2002 to 2007 at Livestock Research Station, Kattupakkam, Tamil Nadu, India. The skulls of the animals were opened to know the prevalence of Coenurus cyst in the brain. Out of 12.30 %, only 3.28 % sheep showed clinical signs while the remaining were apparently healthy (9.02 %). C. cerebralis cysts were observed in cerebrum, cerebellum and on spinal cord, averaging 66.67, 26.67 and 6.66 %, respectively. Among different age groups of sheep, highest infection rate was observed in rams (20.69 %) followed by ewes (10.00 %), young males (9.09 %) and young females (8.33 %). Males (17.50 %, 7/40) were more infected compared to the female sheep (9.76 %, 8/82). Grossly, ventral cerebrum was congested and depression in sulci was noticed. Posterior portion of the skull showed severe congestion and haemorrhage. Severe congestion was also noticed on the gyri of right cerebral hemisphere. PMID- 28615870 TI - Buparvaquone therapy in a rock pigeon infected with Haemoproteus columbae showing torticollis. AB - A clinical Haemoproteus columbae infection in a two months rock pigeon was diagnosed on the basis of outward signs and blood smear examination. The clinical signs suggestive of pigeon malaria were anorexia, depression, inability to fly, circling movements and episodes of torticollis. The characteristic halter shaped gametocytes were seen, in thin blood smear, encircling the nucleus of erythrocytes. Buparvaquone therapy, two intramuscular injections at the rate of 5 mg/kg at 72 h interval, was successful. Supplementation of multivitamin helped in speedy recovery and clinical signs along with uncommon torticollis, completely disappeared in one week. PMID- 28615871 TI - Morphometric and scanning electron microscopy based identification of Ancylostoma caninum parasites in dog. AB - Ancylostoma caninum, a blood feeding nematode parasite (Family: Ancylostomatidae, Superfamily: Ancylostomatoidea) can cause anaemia, dark reddish-brown to black haemorrhagic diarrhoea, dehydration, wasting and deaths due to heavy blood loss. Adult hook worm parasites recovered from the intestine of a stray dog at the time of necropsy were identified as A. caninum based on morphological characters and morphometric observations involving scanning electron microscopy (SEM). Different developmental stages of hookworm eggs viz. 8 cell stage, morula, gastrula and vermiform were observed during the culture process of faecal sample. High quality SEM photographs showed teeth of dimensions 52.5, 42.3 and 23.5 MUm on one side and 55.4, 43.8 and 21.0 MUm on the other side along with the presence of characteristic transverse cuticular striations on body surface of A. caninum parasites. PMID- 28615872 TI - Seasonal incidence of protozoan parasitic infestation in ornamental fishes of West Bengal, India. AB - The communication, dealing with the prevalence of protozoan parasites of the ornamental fish of West Bengal. During the study more than five hundred fish have been examined from five districts namely, Nadia, Hooghly, Howrah, North 24 pargana and South 24-pargana of West Bengal during pre-monsoon, monsoon and post monsoon season. The study reveals that the intensity of infection is more in case of ciliate parasites. The highest ectoparasitic infection has been recorded during post-monsoon season, i.e. from November to February, followed by the pre monsoon period while the lowest infection was recorded during monsoon i.e. from July to October which may lead to the conclusion that environmental factors are responsible for spreading infection. PMID- 28615873 TI - Molecular characterization of internal transcribed spacer 1 (ITS 1) region of different Trypanosoma evansi isolates of India. AB - Six Trypanosoma evansi isolates collected from ponies (PH1 and PK6), camel (CB2), donkeys (DJ3 and DH4) and cattle (CK5) from Haryana, Rajasthan, Uttar Pradesh and Gujarat states of India were used for molecular characterization of internal transcribed spacer 1 (ITS 1). The DNA was isolated from purified trypanosomes of these six isolates after propagation in mice model. ITS1-PCR of purified parasite DNA yielded an amplification product approximately 540 bp in size. Nucleotide sequence of ITS1 gene of CB2 isolate had 530 bp while CK5, DH4, DJ3, and PH1 isolates had 532 bp, whereas, PK6 isolates had 533 bp size. Blast data of the Indian isolates revealed 99 % homology with other available sequences of T. evansi. Multiple alignment of nucleotide sequence of ITS1 gene variants from Indian T. evansi isolates with selected homologous sequences from GenBank revealed that nucleotide substitution mostly occurred at the position of 101-103, 218-223, 243-244, 301-396 and 470-480. The isolates PH1, CK5, DH4 and DJ3 were found more associated with T. evansi isolates from the Philippines, Thailand, Iran, Egypt and China, whereas, PK6 and CB2 isolates were related to each other and were phylogenetically distant from rest of the Indian isolates used in this study. Based on the ITS1 rDNA sequence, the Neighbour-Joining consensus tree indicated clear evidence of existence of genetic diversity among T. evansi isolates from India. PMID- 28615874 TI - Cyathostomum catinatum infection in a mule of Palam Valley, India: a case report. AB - The small strongyles also called as cyathostomes, cyathostomins or trichonemes, affect the health status of equines, leading to morbidity and mortality in heavily infested individuals. The present study was carried out with the aim to identify the cause of colic in a mule of Palam valley, Himachal Pradesh, India. The detailed faecal sample examination revealed heavy intensity of strongyle eggs with an egg per gram value of 2300. The collected faecal sample also exhibited presence of adult worms. The morphological observations after clearing the retrieved parasites revealed the presence of adults of Cyathostomum catinatum species. The haematological and serum biochemical studies revealed alterations related to parasitic invasion. Fenbendazole used for the treatment proved completely effective. To the best of our knowledge and thorough literature search this is the first report of C. catinatum infestation in equines of India. PMID- 28615875 TI - Haematological and biochemical indicators of tropical theileriosis diseased cattle in wilaya of Setif (North East Algeria). AB - The authors investigated biochemical and haematological parameters in 40 healthy and 40 tropical theileriosis (Theileria annulata) clinically infected cattle in El Eulma region (North East Algeria). The mean haematological and biochemical parameters including the number of erythrocytes, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin concentration and mean corpuscular haemoglobin were estimated. The mean hematological and biochemical parameters including the number of leukocytes, erythrocytes, hemoglobin, hematocrit, glucose, albumin, total proteins decreased significantly (p = 0.005; 0.008; 0.03 0.048; 0.002; 0.027 and 0.018; respectively) in Montbeliard breed clinically infected with T. annulata. In all diseased animals, the concentration of total and direct bilirubin increased significantly (p < 0.001). In cross breed cattle, the erythrocytes, hemoglobin, hematocrit means decreased significantly (p = 0.027; 0.003 and <0.001, respectively). Two types of anemia were detected: a microcytic hypochromic anemia in Montbeliard breed clinically infected cattle and normocytic normochromic anemia in local and cross breed cattle. Tropical theileriosis induces severe biochemical and haematological alterations that should be taken into consideration by field veterinarians for both the diagnosis of the disease and its treatment. PMID- 28615876 TI - Microscopic investigation to determine the effect of Beauveria bassiana (Bals.) Vuill. and Cymbopogon citratus (DC.) Stapf. treatment on different life stages of Musca domestica (L.). AB - Microscopic investigation was done to determine the effect of entomopathogenic fungi, Beauveria bassiana and essential oil of Cymbopogon citratus on different life stages of Musca domestica. Scanning electron microscopy investigation of fungal infected larvae showed sluggish movement, rigor, and failure of body to balance in water. Treated larvae also revealed varied level of cuticle shrinkage and extreme dehydration. Surface of B. bassiana infected pupae showed varied stage of mycelial growth, while the cadaver of adult fly was observed to have extensive fungal growth covering their entire body surface. The application of C. citratus oils on M. domestica larvae resulted in skin shrinkage, spinous cells proliferation and bleb formation, while the treated pupae showed high incidence of incomplete emergence and malformation in emerged adult flies. The current study establishes effect of C. citratus essential oil and B. bassiana infection on different life stages of M. domestica. PMID- 28615877 TI - PCR-RFLP based genotyping of Indian isolates of Toxoplasma gondii. AB - Toxoplasma gondii is an apicomplexan parasite capable of infecting a wide variety of warm-blooded animals, including birds and humans and is zoonotically important too. Felidae serve its definitive hosts and most infections are inoccous while in various intermediate hosts (e.g. sheep), it is responsible for abortion, still births. Humans which are immune compromised are also susceptible to toxoplasmosis. Most of the epidemiological studies have revealed it to be belonging to three clonal types with exceptions in South Africa having atypical isolates. Current genotyping was carried out at 11 genetic loci (SAG1, 5'-SAG2, 3'-SAG2, alt. SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358 and PK1) using multiplex nested polymerase chain reaction restriction fragment length polymorphism (Mn-PCR RFLP). SAG1, alt SAG2, SAG3, BTUB, GRA6, C22-8, C29-2, L358 and PK1 could differentiate our strain/isolates as type I (T. gondii RH) and type III (T. gondii isolates from Chennai and Izatnagar). 5'SAG2 and 3'SAG2 in combination confirmed these as above mentioned genotypes. Further, the T. gondii RH was assigned Toxo DB#10 and local isolates of T. gondii were assigned Toxo DB#2. The present study is the first report on existence of Type III T. gondii lineage from animal population of Indian subcontinent based on PCR-RFLP. PMID- 28615878 TI - Prevalence and risk assessment of gastrointestinal helminthoses in dairy animals of Bikaner, Rajasthan. AB - A total of 715 faecal sampleswere collected fromdairy animals ofeight tehsils ofBikaner district, Rajasthan during March 2015 to January 2016. An overall prevalence rate of 54.12 % was recorded for gastrointestinal helminthoses with highly statistical difference among dairy animals (p < 0.01). Quantitative analysis revealed mild to high severity of strongyle and Strongyloides sp. infections in cattle population, respectively whereas, mild severities of same infections were reported from the buffalo population of the region. Seasonal analysis revealed a non-significant difference with highest prevalence in rainy season (59.18 %). The tehsil wise analysis revealed a significant difference (p < 0.05) among tehsils with highest prevalence in Chhatargarh (69.70 %). Multivariate binary regression model revealed rainy season as the most favorable season and Chattargarh as the tehsil with maximum risk for GI helminth infections.On coproculture of positive samples, the nematode infections in decreasing order of prevalence were Haemonchus sp. (36.33 %); Oesophagostomum sp. (26.33 %); Strongyloides sp. (13.67 %); Trichostrongylus sp. (11.67 %); Bunostomum sp. (7.33 %) and Cooperia sp. (4.67 %). Thebaseline data on the prevalence of various GI Helminths of dairy animals generated in the current study would be of immense help in formulating control strategies against infections inBikaner district. PMID- 28615879 TI - The eggshell morphology of Rallicola unguiculatus Piaget, 1880 (Ischnocera: Phthiraptera). AB - The egg chorion of the greater coucal louse, Rallicola unguiculatus bears hexagonal ridges. The hat shaped opercular disc also shows hexagonal marks. Twenty to twenty-three button shaped micropyles occur along the opercular rim. The stigma remained obscured under the cementing material. PMID- 28615880 TI - Records of new localities and hosts for crustacean parasites in fish from the eastern Amazon in northern Brazil. AB - The aim of this study was to investigate parasites crustacean fauna in Arapaima gigas, Cichla monoculus, Cichla ocellaris, Cichla jariina, Satanoperca jurupari, Leporinus friderici, Leporinus fasciatus, Hoplias malabaricus, Phractocephalus hemioliopterus, Serrasalmus altispinis, Pseudoplatystoma tigrinum and Potamotrygon motoro of the State Amapa and Para, in northern Brazil. A total of 242 parasites, including Argulus elongatus, Argulus multicolor,Argulus juparanaensis, Argulus nattereri, Dolops discoidalis, Dolops longicauda, Braga patagonica, Braga fluviatilis, Livoneca guianensis and undetermined Lernaeidae, were collected from these hosts. The Argulus species had the greatest richness among the community of parasitic crustaceans. There was a low abundance of parasites among the hosts, other than D. discoidalis, was most abundant in the integument of A. gigas and P. tigrinum. Finally, the present study reported nine new hosts for the crustacean parasite species and expanded knowledge of the occurrence of some parasite species in the Jari River basin, in eastern Amazon. PMID- 28615881 TI - Aphelenchus assamensis sp. nov. (Nematoda: Aphelenchida: Aphelenchoidea: Aphelenchidae) from Assam, North East India. AB - During a survey for the aphelenchid nematodes of North Eastern States of India, a new species of Aphelenchus nematode was found from Kahilipara, Assam associating with the decaying plant materials of Areca catechu. The morphological and morphometric characteristics of the species were studied using light and Scanning Electron microscopy. Aphelenchus assamenensis sp. nov. is characterized by having 700.65-776.77 (733.30 +/- 28.85) um long body, stylet 12.11 um long without basal swellings, two lateral lines, elongated narrow uterine sac and a cylindrical 20.76-36.33 (27.03 +/- 5.03) um long tail or about 1.36-2.37 (1.94 +/- 0.43) times anal body widths long. PMID- 28615882 TI - Isolated cysticercosis involving the anterior abdominal wall: a rare case report. AB - Isolated cysticercosis of anterior abdominal wall without parasitosis of central nervous system is very rare and may mimic a tumor leading to diagnostic and therapeutic dilemma. Histopathological examination plays an important role in making a definitive diagnosis. Here we report a case of a 13-year old Muslim girl presenting with swelling and pain in left lower abdomen which was clinically diagnosed as lipoma. On histopathological examination cysticercus with surrounding inflammation was seen. Since cysticercosis is a preventable disease, early and accurate diagnosis is necessary for the reduction of disease burden in the endemic areas. PMID- 28615883 TI - Clinicobiochemical changes in ivermectin toxicity in Doberman pinscher pups. AB - This study is based on naturally intoxicated Doberman pinscher pups. Six Doberman pinscher pups were overdosed 50 times of recommended ivermectin dose by the pet owner and presented to Referral Veterinary Polyclinic section of this institute in a state of coma. The pups were unable to hold their head up and had no pupillary reflex. The pups were examined clinically and samples of blood were taken for haemato-biochemical studies, before and after treatment. During intoxication there was marked haemoconcentration, increase in values of serum creatinine phosphokinase, gamma glutamyl transpeptidase but decrease in serum glucose levels. These pups were treated with isotonic dextrose normal saline, 1.0 mg/kg physostigmine and 3 mg/kg dexamethasone. Clinical improvement occurred in remaining 2 pups after 12 h of treatment. These pups were able to take a liquid diet after 3 day and became clinically normal after 2 week. The serum biochemical values gradually reached to normal in recovered pups after 2 weeks of treatment. It took a month for complete recovery from depression and blindness. PMID- 28615884 TI - Intestinal parasitic infestation among paediatric diarrhoea patients attending hospitals in Port Blair, Andaman and Nicobar Islands. AB - Acute childhood diarrhoea remains one of the leading causes of childhood morbidity and mortality in developing countries. The present study was conducted to estimate the prevalence of various intestinal parasitic infestation among children aged 5 years and less suffering from acute diarrhoea disease attending hospitals in Andaman Islands. During the period from January 2012 to December 2013, a total of 675 acute diarrhoea patients were included in the study. Among these samples, 476 (70.5, 95 % CI 66.9, 73.9) harboured ova/cyst of one or more intestinal parasites. Ova/cyst and trophozite of intestinal protozoan parasite was present in the stool samples of 390 (57.8, 95 % CI 54.0, 61.5) children whereas ova of helminth parasite was observed in the stool samples of 105 (15.6, 95 % CI 12.9, 18.5) children. Among all the parasites, Giardia lamblia trophozite had the highest prevalence of 30.5 % followed by Entamoeba histolitica cyst (21.0 %). The high prevalence of intestinal protozoan parasites is an indicator of a probably high carrier rate of these parasites in the community. The study is two issues that are important from public health points of view. Protozoan infestations could be the cause of diarrhoea, particularly watery diarrhoea, in a substantial proportion of the childhood diarrhoea patients attending the hospitals and anti-protozoan therapy needs to be part of the treatment regimen for watery diarrhoea among childhood diarrhoea patients. The second is the need for instituting a community based programme for controlling intestinal protozoan carriage in children as well as in adults as a step towards diarrhoea control. PMID- 28615885 TI - Nyctotherus sp. infection in pet turtle: a case report. AB - The present clinical case represents the successful therapeutic management of Nyctotherus sp. protozoan infection in turtles. Two pet turtles were presented with history of diarrhea, dehydration, weight loss and passage of undigested food in the faeces. Direct faecal examination and Giemsa staining revealed the presence of cysts of Nyctotherus sp. Treatment was initiated with antiprotozoal drug, Metronidazole at the rate of 25 mg/kg body weight per-oral consecutively for 5 days, and Vimeral suspension at rate of 10-20 mg/kg per-oral for 8 days. After 10 days of intensive care and management with antiprotozoal drug, multivitamin under proper sanitary measures, the case showed gradual improvement in condition. During medication, the fecal samples were checked on every alternative day for the presence of ciliated trophozoites of Nyctotherus sp. After 4th day, there was no trophozoites observed by both the techniques examined and the animal was quite healthy and active and started taking food. Improvement was noticed with resumption of normal appetite. Incessant patient monitoring and initiation of suitable need based therapeutic strategy is most important in management and control of Nyctotherus sp. infection. PMID- 28615886 TI - First record on the occurrence of Ryukyua circularis (Pillai, 1954), a parasitic cymothoid (Crustacean: Isopoda) infesting the clupeid fish Amblygaster sirm (Walbaum) from Andaman Islands, India. AB - In the present study, occurrence of branchial parasitic cymothoid, Ryukyua circularis from the marine finfish, Amblygaster sirm is reported for the first time from Andaman Islands. Morphological characterization was carried out which confirmed the parasite as R. circularis. Molecular characterization using 28S rDNA revealed 443 bp sequence which has been submitted to NCBI GenBank under the accession no. KX090447. Ten female and one male parasite (R. circularis) were collected from the branchial cavity of the individual host fishes (A. sirm). The displacement of gill filament and cavity formation in the gill chamber of the host fish was observed. The report of this species from Andaman Islands gives further information on its geographic range extension, since they are currently known from West coast of India and Thailand. PMID- 28615887 TI - An unusual cause of chest discomfort: case report of oesophageal hirudiniasis. AB - Hirudiniasis is caused by sanguivorous leeches feeding on mucous membranes with possible severe obstructive or haemorrhagic manifestations. Few cases have been reported in humans, and most occur in tropical countries. A seventy-year-old female patient presented to our Emergency Department (ED) with retrosternal discomfort. She was taking warfarin for a mechanical prosthetic heart valve. While in the ED, a leech was spontaneously extruded from her mouth, with symptomatic resolution. Endoscopy revealed an area of previous leech attachment in the distal oesophageal, without severe bleeding. Albeit uneventful, this case could have had a devastating outcome. PMID- 28615888 TI - Helminth infections of the brown rat (Rattus norvegicus Berkenhout, 1769) in the biocenoses of South-West Belarus. AB - The result of helminthological examination of 20 brown rats from various biocenoses of South-West Belarus during 1996-2011 is presented. Twelve animals were infected. Six species of helminths were found: 1 trematode species, 3 cestode species and 2 nematode species. The most often, the brown rat infected with mesocercariae of trematode Alaria alata (Goeze, 1782). The helminth fauna of brown rats living in the biocenoses are specified for the first time in Belarus. PMID- 28615889 TI - Helminth parasites of the Eurasian water shrew (Neomys fodiens pennant, 1771) in South-West Belarus. AB - The result of helminthological investigation of 25 Eurasian water shrews during 1996-2011 in South-West Belarus is presented. Sixteen species of helminths (8 species of trematodes, 3 species of cestodes and 5 species of nematodes) were discovered in 92.0 % of animals (23 infected individuals). The most common species is the trematode Neoglyphe locellus (Kossack, 1910). The cestode Triodontolepis sumavensis (Prokopic, 1957), nematodes Capillaria konstantini Romashov, 1999 and Longistriata neomi Lubarskaja, 1962 is specified in Belarus for the first time. Twenty-one species of helminths in total were found by helminthologists in this mammal in South-West Belarus in the period 1960-2011. PMID- 28615890 TI - Helminth fauna of the northern white-breasted hedgehog (Erinaceus roumanicus) in Serbia. AB - The result of helminthological examination of 28 hedgehogs died at traffic accident and 12 samples of feces collected from pets hedgehogs during 2013-2015 were presented. Three species of helminths were found: Crenosoma striatum, Hymenolepis erinacei and Aonchotheca erinacei. This is the first research of parasitic fauna of hedgehogs in Serbia. PMID- 28615891 TI - Limb-girdle Muscular Dystrophies in India: A Review. AB - Limb-girdle muscular dystrophies (LGMDs) are common in India. Information on LGMDs has been gradually evolving in the recent years. This information is scattered in case series and case studies. The aim of this study is to collate available Indian information on LGMDs and put it in perspective. PubMed search using keywords such as limb-girdle muscular dystrophies in India, sarcoglycanopathies, dysferlinopathy, calpainopathy, and GNE myopathy was carried out. The published information on LGMDs in Indian context suggests that dysferlinopathy, calpainopathy, sarcoglycanopathies, and other myopathies such as GNE myopathy are frequently seen in India. Besides these, anecdotal reports of many other forms are available, some with genetic support and others showing immunocytochemical defects. The genotypic information on LGMDs is gradually evolving and founder mutations have been detected in selected populations. Further multicenter studies are necessary to document the incidence and prevalence of these common conditions in India. PMID- 28615893 TI - Frederic Andrews Gibbs and the Assassination of John Fitzgerald Kennedy. AB - Frederic Gibbs, the peerless expert on electroencephalogrphy was summoned to provide opinion on the EEG tracing of Jack Ruby, who murdered Lee Harvey Oswald, the assassin of John Fitzgerald Kennedy, the American President, in 1963. Gibbs pleaded that the tracing suggested features indicative of psychomotor epilepsy and Ruby killed Oswald in a state of fugue. His view was not agreed upon but Gibbs stood his ground unflinchingly. Subsequent appeals to the higher court spared Ruby from imminent execution and finally he died a natural death from metastatic complications of carcinoma of the lung in 1967. PMID- 28615892 TI - Molecular Genetics of Epilepsy: A Clinician's Perspective. AB - Epilepsy is a common neurological problem, and there is a genetic basis in almost 50% of people with epilepsy. The diagnosis of genetic epilepsies makes the patient assured of the reasons of his/her seizures and avoids unnecessary, expensive, and invasive investigations. Last decade has shown tremendous growth in gene sequencing technologies, which have made genetic tests available at the bedside. Whole exome sequencing is now being routinely used in the clinical setting for making a genetic diagnosis. Genetic testing not only makes the diagnosis but also has an effect on the management of the patients, for example, the role of sodium channels blockers in SCN1A+ Dravet syndrome patients and usefulness of ketogenic diet therapy in SLC2A1+ generalized epilepsy patients. Many clinicians in our country have no or limited knowledge about the molecular genetics of epilepsies, types of genetic tests available, how to access them and how to interpret the results. The purpose of this review is to give an overview in this direction and encourage the clinicians to start considering genetic testing as an important investigation along with electroencephalogram and magnetic resonance imaging for better understanding and management of epilepsy in their patients. PMID- 28615894 TI - Unknown Patients and Neurology Casualty Services in an Indian Metropolitan City: A Decades Experience. AB - OBJECTIVES: A large number of unknown patients without any personal, family, or other identification details represent a unique problem in the neurological emergency services of developing countries like India in a context of legal, humanitarian, and treatment issues. These patients pose a diagnostic and management challenge to treating physicians and staff. There are sparse data on these patients. The objective of this study was to know the clinical, socio demographic, and investigational profile of "unknown" patients. MATERIALS AND METHODS: We did retrospective chart review of all "Unknown" patients from January 2002 to December 2011, who was admitted under Neurology Emergency Service at a Tertiary Care Neuropsychiatry Center in South Indian Metropolitan City. Clinical and sociodemographic characteristics and clinical outcome of the sample were analyzed. RESULTS: A total of 151 unknown patients were admitted during the 10 years. Out of these, 134 (88.7%) were males with the mean age of 43.8 +/- 14.8 years and 95 (63%) were aged >40 years. Among them, 147 (97.4%) were from the urban vicinity, 126 (83.6%) were brought by police and 75 (49.7%) were registered as medico-legal cases. Out of these, only 3 (2%) patients had normal sensorium, whereas 101 (66.9%) presented with loss of consciousness. Forty-one (27.2%) unknown patients had a seizure disorder, 37 (24.5%) had metabolic encephalopathy, 26 (17.2%) had a stroke, 9 (6%) had neuro-infection, and 17 (11.3%) had a head injury. Deranged liver functions were seen in 65 (43%), renal derangement in 37 (24.5%), dyselectrolytemia in 42 (27.8%), and abnormal brain imaging finding in 95 (62.9%) patients. Furthermore, there were 14 (9.3%) deaths. CONCLUSIONS: Our findings demonstrate seizures, metabolic causes, and neuro-infections were the primary reasons for admission of unknown patients to neuro-emergency service. This novel Indian study data show the common causes of admission of unknown patients in neurology. This pattern can be useful to guide the approach of healthcare providers in India. PMID- 28615896 TI - Maintenance of Normoglycemia May Improve Outcome in Acute Ischemic Stroke. AB - INTRODUCTION: Several studies have shown that high admission glucose is associated with poor outcomes after stroke, but the impact of maintenance of normoglycemia on functional outcome during hospitalization for acute ischemic stroke is less well established. AIMS: The aim of this study was to examine the independent association of postadmission glycemic status in the 1st week with 3 month functional outcome in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke admitted within 48 h of symptom onset with National Institutes of Health Stroke Scale (NIHSS) of >=4 were selected from a prospectively maintained database by chart review. Demographic data, risk factors, NIHSS, and blood glucose values in the 1st week were collected. The primary outcome was Modified Rankin Scale (mRS) score at 3 months (good outcome mRS <=2). RESULTS: Over 3 years, 342 patients were enrolled with 220 (64.32%) males. Mean age was 60.5 +/- 13.4 years, and median admission score on NIHSS was 10 (interquartile range: 6-16). Blood glucose values persistently <140 mg/dl in the 1st week were associated with a good 3-month functional outcome in univariate analysis (P = 0.036). Hypoglycemic episodes occurred only in 11 (3.22%) patients. CONCLUSIONS: Blood glucose values persistently below 140 mg/dl in the 1st week after acute ischemic stroke were associated with a favorable outcome in our study. Future clinical trials are needed to confirm these findings. PMID- 28615895 TI - Study of Refractory Status Epilepticus from a Tertiary Care Center. AB - OBJECTIVES: To determine the proportion of refractory status epilepticus (RSE) and super-RSE (SRSE) among patients with status epilepticus (SE) and to analyze RSE and non-RSE (NRSE) in terms of etiology and predictors for RSE. MATERIALS AND METHODS: Patients were identified from discharge summaries database with keywords of SE and records of the portable electroencephalogram (EEG) machine from January 2011 to March 2016. RESULTS: Two hundred and eighteen events were included in the study with 114 (52.3%) males, bimodal age preponderance age <5 years 30%, and second peak in age 15-65 years 52.8%, preexisting seizures were present in 34.4% (n = 75). Nearly 77.1% had NRSE (n = 168) and 22.9% had RSE (n = 50). This included 17 patients with SRSE (n = 17, 7.8% of all SE). Central nervous system (CNS) infection was a single largest etiological group in SE (69/218, 31.7%). In RSE, autoimmune encephalitis (17/50) and CNS infection (13/50) were the largest groups. De novo seizures (P = 0.007), low sensorium at admission (P = 0.001), low albumin at admission (P = 0.002), and first EEG being abnormal (P = 0.001) were risk factors on bivariate analysis. An unfavorable status epilepticus severity score (STESS) was predictive for RSE (P = 0.001). On multivariate analysis, de novo seizures (P = 0.009) and abnormal EEG at admission (P = 0.03) were predictive for RSE. CONCLUSIONS: Fifty patients had RSE (22.9%), of which 17 went on to become SRSE (7.8%). Unfavorable STESS score was predictive for RSE on bivariate analysis. On multivariate analysis, de novo seizures and abnormal initial EEG were predictors of RSE. PMID- 28615897 TI - Dorsal Sural Sensory Nerve Action Potential: A Study for Reference Values. AB - BACKGROUND: Dorsal sural sensory nerve action potential (SNAP) could help diagnose early or subclinical peripheral neuropathy. OBJECTIVES: To establish reference data for dorsal sural SNAP amplitude, latency, and velocity in healthy participants. MATERIALS AND METHODS: A prospective study was conducted in 45 nerves from healthy participants between 18 and 90 years and stratified into three age groups (a = 18-40 years, b = 41-60 years, and c>60 years). StataCorp 12.2 statistical program was used for all statistical analyses. Mean-2 standard deviation was used to generate reference values for the lower limit of amplitude and velocity in each age group. ANOVA with Bonferroni correction was used for intergroup comparisons of amplitude and velocity. Regression analysis was used to compute an equation for the predicted amplitude with age, height, and weight as the covariates. RESULTS: The lower limit for amplitude (uv) in Groups a, b, and c was 2.57, 1.97, and 1.01, respectively. The lower limit for velocity (m/s) was 33.6, 32, and 22.8, respectively. Statistical significance was noted between the amplitudes of participants in Groups b and c (P = 0.039) and a and c (P = 0.001). Similarly, velocity was significantly different between Groups b and c (P = 0.04) and a and c (P = 0.008). Age was the covariate with maximum effect on the dorsal sural amplitude. Gender and side-to-side comparison did not show statistical significance for amplitude and velocity measurements. Linear regression analysis of the transformed amplitude gave the predictive equation as (y) =3.338 + age ( 0.0167) + height in meters (-0.209) + weight (0.001). CONCLUSION: This study provides reference data for dorsal sural SNAP in Indian population stratified by age. PMID- 28615899 TI - Clinical and Imaging Study of Isolated and Mixed Rest and Action Tremor-Essential Tremor versus Parkinson's Disease. AB - BACKGROUND: Some patients present an unusual association of both action tremor (AT) and rest tremor (RT) making the differential diagnosis between essential tremor (ET) and Parkinson's disease (PD) difficult. AIM: To investigate this particular clinical picture trying to focus on possible peculiar clinical inferences. PATIENTS AND METHODS: Twenty-three patients with atypical tremor syndrome were selected for the study. They underwent neurological examination, neuroimaging study, and brain DaTSCAN single-photon emission computed tomography. RESULTS: Twenty-three patients were evaluated; 17 presented mixed-tremor syndrome, while six patients showed only isolated AT or RT. DaTSCAN was pathological in 19 patients and normal in 3 patients. The emerging statistical data highlighted a positive correlation between disease duration and DaTSCAN abnormalities; Fisher's exact test showed a marked difference in evolution toward a dysfunction of dopaminergic pathways in patients with both AT and RT phenotype. CONCLUSION: The possible correlation between PD and ET has often been discussed without any clear findings. Are these patients suffering from ET prone to develop PD? Or are they the expression of a specific clinical phenotype? Our clinical survey has not led to absolute considerations; however, it seeks to highlight the clinical markers that might arouse the suspicion of extrapyramidal disease in patients with atypical tremor syndrome. PMID- 28615898 TI - Teratogenic Effects of Carbamazepine in Mice. AB - OBJECTIVES: The aim of this study was to determine the teratogenic effects of carbamazepine (CBZ) in BALB/c mice. MATERIALS AND METHODS: Mature female and male BALB/c mice (25-30 g) were used for all experiments. After standardization of administration and dose of CBZ, animals in the CBZ-treated groups (CBZ 450 mg/kg and 600 mg/kg) were fed on medicinal diet. The dams in the control group were mated on the same day as that of the CBZ-treated dams. After cesarean section (CS), fetal viability status and weights were recorded. Gross histopathological examination of fetuses was conducted to identify alterations in morphology and external or internal organs due to in utero exposure of CBZ. RESULTS: Out of the nine female animals (three treated on CBZ 450 mg/kg, three treated on CBZ 600 mg/kg and three controls), seven were pregnant, and two (one each from the two CBZ-treated groups) were nonpregnant. All fetuses of the control group (n = 31) and CBZ 450 mg/kg treated group (n = 24) were live, but eight out of the twenty fetuses (40%) of CBZ 600 mg/kg treated group were dead at CS. The birth weight of the fetuses antenatally exposed to CBZ was drastically reduced (0.71 +/- 0.06) when compared to control fetuses (1.67 +/- 0.12) (P < 0.0001). All the fetuses of the CBZ-treated groups showed stunted physical development. CONCLUSION: Although oral administration of CBZ to mice is a convenient model to study the effect of CBZ to pregnancy, higher oral dose was associated with increased fetal loss. Some of the fetuses exposed to CBZ demonstrated structural abnormalities and low body weight. PMID- 28615900 TI - Predictors of Outcome in Children with Status Epilepticus during Resuscitation in Pediatric Emergency Department: A Retrospective Observational Study. AB - OBJECTIVES: To study the clinical profile and predictors of outcome in children with status epilepticus (SE) during resuscitation in pediatric emergency department. MATERIALS AND METHODS: This retrospective study was carried out in a tertiary care teaching hospital. Admission and resuscitation data of children, aged between 1 month and 12 years, treated for SE, between September 2013 and August 2014, were extracted using a standard data collection form. Our SE management protocol had employed a modified pediatric assessment triangle to recognize and treat acute respiratory failure, cardiovascular dysfunction (CD), and subtle SE until all parameters resolved. Continuous positive airway pressure, fluid boluses based on shock etiology, inotropes, and cardiac safe anticonvulsants were the other modifications. Risk factors predicting mortality during resuscitation were analyzed using univariate and penalized logistic regression. RESULTS: Among 610 who were enrolled, 582 (95.4%) survived and 28 (4.6%) succumbed. Grunt odds ratio (OR): 3.747 (95% confidence interval [CI]: 1.035-13.560), retractions OR: 2.429 (95% CI: 1.036-5.698), rales OR: 10.145 (95% CI: 4.027-25.560), prolonged capillary refill time OR: 3.352 (95% CI: 1.339 8.388), and shock requiring >60 mL/kg fluids OR: 2.439 (95% CI 1.040-5.721) were associated with 2-3 times rise in mortality. Inappropriate prehospital treatment and CD were the significant predictors of mortality OR: 7.82 (95% CI 2.10-29.06) and 738.71 (95% CI: 97.11-999), respectively. Resolution of CD was associated with improved survival OR: 0.02 (95% CI: 0.003-0.17). CONCLUSION: Appropriate prehospital management and treatment protocol targeting resolution of CD during resuscitation could reduce mortality in children with SE. PMID- 28615901 TI - Varicella Zoster Virus Infection of the Central Nervous System - 10 Year Experience from a Tertiary Hospital in South India. AB - INTRODUCTION: Varicella zoster virus is an exclusively human neurotrophic virus. The primary infection with the virus causes varicella. The virus remains latent in nervous tissue and upon secondary activation causes a variety of syndromes involving the central nervous system (CNS) including meningoencephalitis and cerebellitis. MATERIALS AND METHODS: In this study, we looked at the epidemiology, clinical and laboratory features, and outcomes of patients who were admitted with varicella zoster of the CNS from 2005 to 2014. RESULTS: There were 17 patients. Fever was present in 13 patients, seizures in 9 patients and headache and vomiting in 4 patients each. A generalized varicella rash was present in 8 out of 17 patients. A single dermatomal herpes zoster was present in seven patients. Two patients had no rash. Varicella zoster polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) was done in 5 patients of which 4 were positive and 1 was negative. Nine patients had diabetes with an average glycated hemoglobin of 8.6%. Total number of deaths was five. CONCLUSIONS: Patients with diabetes who develop varicella or herpes zoster may be at risk for CNS complications. The diagnosis of varicella encephalitis has to rest on a combination of clinical findings and CSF PCR, as neither the rash nor the PCR is sensitive enough to diagnose all the cases with varicella encephalitis. PMID- 28615902 TI - Translation and Adaptation of Stroke Aphasia Depression Questionnaire-10 to Hindi. AB - BACKGROUND: Depression is one of the most researched emotional responses after stroke and shows that the emotional impact of aphasia can have a marked negative impact on recovery, response to rehabilitation, and psychosocial adjustment. There is an evident dearth of validated instruments to assess depression in people with aphasia including Hindi, the national language of the country. AIMS: The aim of this study was to translate and adapt the original English version of widely used hospital version of Stroke Aphasia Depression Questionnaire (SADQ-10) to Hindi. SUBJECTS AND METHODS: English version of SADQ-10 was translated and adapted for the use in Hindi-speaking population in concordance to the WHO guidelines. STATISTICAL ANALYSIS USED: The intraclass correlation coefficient (ICC) analysis of the data was performed using SPSS, version 16, to compute the test-retest reliability. RESULTS: The Hindi version of SADQ-10 yielded an overall high test-retest reliability (ICC = 0.91) as well as internal consistency (alpha = 0.98), which in turn were comparable to the original instrument in English. CONCLUSIONS: SADQ10-Hindi may assist the identification of depressed mood in patients with speech and language impairment in an Indian population as well. It is an easy to administer and quick test which can be used by health-care professionals in a hospital- or community-based settings. PMID- 28615903 TI - Turf Wars in Stroke Medicine: Why Should Patients Suffer. PMID- 28615904 TI - Endovascular Stroke Treatment: Is it "Everybody's Cup of Tea?" PMID- 28615905 TI - Paradigm Shift in Stroke Prevention: Need of the Hour. PMID- 28615906 TI - Direct Mechanical Thrombectomy with Thromboaspiration in Cerebral Venous Sinus Thrombosis. PMID- 28615907 TI - Successful Revascularization of Acute Middle Cerebral Artery Occlusion by Intravenous Thrombolysis While on Apixaban. PMID- 28615908 TI - Right- versus Left-onset Parkinson's Disease: Other Psychometric Parameters. PMID- 28615909 TI - A Case of Kennedy's Disease from India. PMID- 28615910 TI - Molecular Diagnosis of Limb-girdle Muscular Dystrophy Type 2A by Next-generation Sequencing. PMID- 28615911 TI - Bupropion and Iron for Restless Leg Syndrome: Do They Have Efficacy Similar to Ropinirole? PMID- 28615912 TI - Carbamazepine: A Symptomatic Treatment of the Paresthesiae Associated with Lhermitte's Sign. PMID- 28615913 TI - Response to Reader's Queries. PMID- 28615914 TI - Piloerection: A Rare Ictal Phenomenon - Case Report and Review of Literature. PMID- 28615915 TI - An Eminently Treatable Dropped Head Syndrome. PMID- 28615916 TI - Weak convergence theorem for a class of split variational inequality problems and applications in a Hilbert space. AB - In this paper, we consider the algorithm proposed in recent years by Censor, Gibali and Reich, which solves split variational inequality problem, and Korpelevich's extragradient method, which solves variational inequality problems. As our main result, we propose an iterative method for finding an element to solve a class of split variational inequality problems under weaker conditions and get a weak convergence theorem. As applications, we obtain some new weak convergence theorems by using our weak convergence result to solve related problems in nonlinear analysis and optimization. PMID- 28615917 TI - High Dimensional EM Algorithm: Statistical Optimization and Asymptotic Normality. AB - We provide a general theory of the expectation-maximization (EM) algorithm for inferring high dimensional latent variable models. In particular, we make two contributions: (i) For parameter estimation, we propose a novel high dimensional EM algorithm which naturally incorporates sparsity structure into parameter estimation. With an appropriate initialization, this algorithm converges at a geometric rate and attains an estimator with the (near-)optimal statistical rate of convergence. (ii) Based on the obtained estimator, we propose new inferential procedures for testing hypotheses and constructing confidence intervals for low dimensional components of high dimensional parameters. For a broad family of statistical models, our framework establishes the first computationally feasible approach for optimal estimation and asymptotic inference in high dimensions. Our theory is supported by thorough numerical results. PMID- 28615918 TI - Lung Cancer Pathological Image Analysis Using a Hidden Potts Model. AB - Nowadays, many biological data are acquired via images. In this article, we study the pathological images scanned from 205 patients with lung cancer with the goal to find out the relationship between the survival time and the spatial distribution of different types of cells, including lymphocyte, stroma, and tumor cells. Toward this goal, we model the spatial distribution of different types of cells using a modified Potts model for which the parameters represent interactions between different types of cells and estimate the parameters of the Potts model using the double Metropolis-Hastings algorithm. The double Metropolis Hastings algorithm allows us to simulate samples approximately from a distribution with an intractable normalizing constant. Our numerical results indicate that the spatial interaction between the lymphocyte and tumor cells is significantly associated with the patient's survival time, and it can be used together with the cell count information to predict the survival of the patients. PMID- 28615919 TI - Sequence Analysis and Phylogenetic Studies of Hypoxia-Inducible Factor-1alpha. AB - Hypoxia-inducible factors (HIF) belong to the basic helix loop helix-PER ARNT SIM (bHLH-PAS) family of transcription factors that induce metabolic reprogramming under hypoxic condition. The phylogenetic studies of hypoxia-inducible factor 1alpha (HIF-1alpha) sequences across different organisms/species may leave a clue on the evolutionary relationships and its probable correlation to tumorigenesis and adaptation to low oxygen environments. In this study, we have aimed at the evolutionary investigation of the protein HIF-1alpha across different species to decipher their sequence variations/mutations and look into the probable causes and abnormal behaviour of this molecule under exotic conditions. In total, 16 homologous sequences for HIF-1alpha were retrieved from the National Center for Biotechnology Information. Sequence identity was performed using the Needle program. Multiple aligned sequences were used to construct the phylogeny using the neighbour-joining method. Most of the changes were observed in oxygen dependent degradation domain and inhibitory domain. Sixteen sequences were clustered into 5 groups. The phylogenetic analysis clearly highlighted the variations that were observed at the sequence level. Comparisons of the HIF 1alpha sequence among cancer-prone and cancer-resistant animals enable us to find out the probable clues towards potential risk factors in the development of cancer. PMID- 28615920 TI - Immune Checkpoint Inhibition and the Prevalence of Autoimmune Disorders Among Patients With Lung and Renal Cancer. AB - PURPOSE: Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab. METHODS: An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients for diagnosis of autoimmune diseases 1 year prior to or after diagnosis of cancer using International Classification of Diseases, Ninth Revision codes for 41 autoimmune diseases. Baseline characteristics and other comorbid conditions were recorded. RESULTS: More than 25% of patients with both lung and renal cancer had a comorbid autoimmune condition between 2010 and 2013 and were more likely to be women, older, and have more baseline comorbidities. CONCLUSIONS: This population presents a dilemma to physicians when deciding to treat with immune checkpoint inhibitors and risk immune-related adverse events. Future evaluation of real world use of immune checkpoint inhibitors in patients with cancer with autoimmune diseases will be needed. PMID- 28615921 TI - Data-Independent Acquisition and Parallel Reaction Monitoring Mass Spectrometry Identification of Serum Biomarkers for Ovarian Cancer. AB - A data-independent acquisition (DIA)/parallel reaction monitoring (PRM) workflow was implemented to identify improved ovarian cancer biomarkers. Data-independent acquisition on ovarian cancer versus control sera and literature searches identified 50 biomarkers and indicated that apolipoprotein A-IV (ApoA-IV) is the most significantly differentially regulated protein. Parallel reaction monitoring with Targeted Ovarian Cancer Proteome Assay validated differential ApoA-IV expression and quantified 9 other biomarkers. Random Forest (RF) analyses achieved 92.3% classification accuracy and confirmed ApoA-IV as the leading biomarker. Indeed, all samples were classified correctly with an [ApoA-IV] breakpoint. The next best biomarkers were C-reactive protein, transferrin, and transthyretin. The Targeted Ovarian Cancer Proteome Assay suggests that ApoA-IV is a more reliable biomarker than had been determined by immunological assays and it is a better biomarker than ApoA-I, which is in the OVA1 test for ovarian cancer. This research provides a PRM/RF approach together with 4 promising biomarkers to speed the development of a clinical assay for ovarian cancer. PMID- 28615922 TI - Influence of Circulating Endothelin-1 and Asymmetric Dimethylarginine on Whole Brain Circulation Time in Multiple Sclerosis. AB - Blood-brain barrier (BBB) breakdown, inflammatory and immune cell activation, and chronic cerebral hypoperfusion are features of multiple sclerosis (MS). The aim is to determine the influence of endothelin-1 (ET1) and asymmetric dimethylarginine (ADMA) on cerebral circulation time (CCT) in patients with MS. In all, 64 patients with MS (39 relapsing-remitting [RR]-MS; 25 secondary progressive [SP]-MS subtype) and 37 controls (C) were studied. Cerebral circulation time was obtained by angiography. Plasmatic ET1 and ADMA were measured by enzyme-linked immunosorbent assay. Lesion load (LL) and brain volume (BV) were obtained by magnetic resonance imaging. Cerebral circulation time was correlated to ET1, ADMA, LL, BV, disease duration (DD), and Expanded Disability Status Scale (EDSS). In MS, both ET1 and ADMA were significantly higher than C (P < .0001); CCT was approximately 2 times lower than C (P < .0001) and significantly slower in SP than in RR-MS (P = .0215). Cerebral circulation time significantly correlated with ET1 in SP-MS (r = 0.38), whereas in RR-MS CCT significantly correlated with DD (r = 0.75). The LL, BV, and EDSS did not correlate with CCT. Endothelin-1 significantly influences CCT delay in SP-MS. Diversely, CCT in RR-MS is independent of ET1 and correlates significantly with DD. We conclude that in RR-MS, DD responds to neurovascular damage accumulation. It is supposed that high ET1 and ADMA levels stem from a protective response to early insults, aimed at opposing nitric oxide overproduction, whereas persistent pathological ET1 and ADMA levels translate into detrimental long-term effects, due to increased brain micro-vessel resistance. PMID- 28615923 TI - Changes in meibomian gland morphology and ocular higher-order aberrations in eyes with chalazion. AB - PURPOSE: To examine the changes in meibomian gland morphology and ocular higher order aberrations (HOAs) in eyes with chalazion and its excision. METHODS: Seven male patients with previous history of chalazion excision and seven control male subjects were enrolled. Changes in meibomian gland morphology (meiboscores, gland dropout, and shortening) were evaluated by using meibography equipped in a wavefront analyzer KR-1W and in a slit-lamp device BG-4M. Ocular HOAs were measured sequentially with KR-1W. The tear film breakup time (BUT) was measured. RESULTS: Both KR-1W and BG-4M visualized meibomian gland as clear similar images. The tear film BUT (mean +/- SD, 5.6+/-3.0 vs 9.4+/-2.3 seconds, P=0.025), the total meiboscore (median [interquartile range], 2 (2-3) vs 0 (0-1), P=0.007) as well as the meibomian gland dropout rate (86% vs 14%, P=0.008) and shortening rate (100% vs 29%, P=0.031) differed significantly between the patient and control groups. The first total ocular HOAs (0.142+/-0.063 vs 0.130+/-0.015, P=0.80) were similar in both groups, whereas the stability index of the total HOAs over time (0.0041+/-0.0048 vs -0.0012+/-0.0020, P=0.030) differed significantly between the patient and control groups. CONCLUSIONS: Chalazion and its excision were associated with dropout and shortening rate of meibomian glands. The morphological changes of meibomian glands in chalazion may be associated to instability of the tear film, which was suggested by the tear film BUT and the stability of ocular HOAs. PMID- 28615924 TI - Comparison of the frequency of use of a pupil expansion device with and without an intracameral phenylephrine and ketorolac injection 1%/0.3% at the time of routine cataract surgery. AB - PURPOSE: The objective of this study is to evaluate whether a phenylephrine and ketorolac injection 1%/0.3% (phenyl/keto injection) (Omidria(r)) prior to capsulotomy decreases the need for the Malyugin Ring(r) to manage small pupils. SETTING: Bucci Laser Vision Institute, Wilkes-Barre, PA, USA. DESIGN: Retrospective analysis of cataract surgeries performed by a single surgeon at a single center. METHODS: A historical control group of 1,004 consecutive cases (December 2013 to February 2015) did not receive a phenyl/keto intracameral injection prior to capsulotomy and were compared with 915 consecutive cases in the treatment group (June 2015 to April 2016) for the rate of use of the Malyugin Ring. Epinephrine injections were selectively used in the control group as per surgeon judgment. Use of the femtosecond laser was recorded for both groups. The incidence of alpha-1 blocker patients and the use of the femtosecond laser were recorded for both groups. RESULTS: In the 1,004 cases performed in the historical control group without a phenyl/keto injection, the surgeon chose to use the Malyugin Ring 79 times (7.87%). In the 915 cases performed in the treatment group, the surgeon chose to use the Malyugin Ring 27 times (2.95%). The surgeon selectively used intracameral injections of epinephrine in the control group 64 times (6.47%). There was no significant difference in the use of the femtosecond laser in the control group (15.04%) versus the treatment group (16.28%); however, 4 (2.65%) femtosecond patients in the control group required a Malyugin Ring, while zero patients needed the ring in the femtosecond treatment group. The incidence of Malyugin Ring use in alpha-1 blocker patients was 12/49 (24.49%) in the control group and 6/49 (12.74%) in the treatment group (P=0.05). CONCLUSION: The frequency of use of the Malyugin Ring was significantly reduced (P<0.001) from 7.87% to 2.95% with this treatment. These results strongly suggest that the antimiotic/anti-inflammatory effects of this phenyl/keto injection reduced facility costs, surgical time, and other complexities related to the use of the Malyugin Ring during phacoemulsification. PMID- 28615925 TI - Anterior lamina cribrosa surface depth in healthy Saudi females. AB - PURPOSE: This study was conducted to determine normative profile of anterior lamina cribrosa surface depth (ALCSD) in healthy Saudi females using Topcon Three Dimensional (3D) Optical Coherence Tomography (OCT) 2000 - Spectral Domain (SD OCT). In addition, the correlation between ALCSD and other clinical factors such as age, refractive error, intraocular pressure (IOP), central corneal thickness, anterior chamber depth, axial length, retinal nerve fiber layer thickness, and disk area was also assessed. DESIGN: This study was a prospective, nonrandomized, cross-sectional, observational, and quantitative study. METHODS: This study included 191 eyes of 191 healthy Saudi females from the College of Applied Medical Sciences of King Saud University. Stereoscopic disk photographs were reconstructed using Topcon 3D OCT-2000 for all subjects. ALCSD was measured at three planes (superior, middle, and inferior) and defined as the distance from Bruch's membrane opening level (reference line) to anterior lamina cribrosa surface. Average of ALCSD at all planes was defined as mean ALCSD of the eye. Correlation between ALCSD and all the clinical factors was performed by linear regression analysis. Paired t-test was performed in order to compare ALCSD at all planes. RESULTS: In this study, the average ALCSD was 371.88+/-114.62 MUm (range, 155-647.6 MUm). Paired t-test showed a significant difference between superior and middle planes (P=0.004) and middle and inferior planes (P=0.013). Using the same test, no significant difference between superior and inferior planes (P=0.820) was observed. Generally, the largest ALCSD was in the middle plane. In addition, linear regression analysis showed no significant correlation between ALCSD and associated clinical factors. CONCLUSION: This work is the first to provide the normative profile of ALCSD in Saudi females using Topcon 3D OCT-2000. Further studies are recommended for males, different ethnic populations, high myopic eyes, and different age groups using advanced imaging techniques such as enhanced depth imaging OCT. PMID- 28615927 TI - p-TSA-promoted syntheses of 5H-benzo[h] thiazolo[2,3-b]quinazoline and indeno[1,2 d] thiazolo[3,2-a]pyrimidine analogs: molecular modeling and in vitro antitumor activity against hepatocellular carcinoma. AB - In our efforts to address the rising incidence of hepatocellular carcinoma (HCC), we have made a commitment to the synthesis of novel molecules to combat Hep-G2 cells. A facile and highly efficient one-pot, multicomponent reaction has been successfully devised utilizing a p-toluenesulfonic acid (p-TSA)-catalyzed domino Knoevenagel/Michael/intramolecular cyclization approach for the synthesis of novel 5H-benzo[h]thiazolo[2,3-b]quinazoline and indeno[1,2-d] thiazolo[3,2 a]pyrimidine analogs bearing a bridgehead nitrogen atom. This domino protocol constructed one new ring by the concomitant formation of multiple bonds (C-C, C N, and C=N) involving multiple steps without the use of any metal catalysts in one-pot, with all reactants effi-ciently exploited. All the newly synthesized compounds were authenticated by means of Fourier transform infrared spectroscopy, liquid chromatography-mass spectrometry, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy, together with elemental analysis, and their antitumor activity was evaluated in vitro on a Hep-G2 human cancer cell line by sulforhodamine B assay. Computational molecular modeling studies were carried out on cancer-related targets, including interleukin-2, interleukin-6, Caspase-3, and Caspase-8. Two compounds (4A and 6A) showed growth inhibitory activity comparable to the positive control Adriamycin, with growth inhibition of 50% <10 MUg/mL. The results of the comprehensive structure-activity relationship study confirmed the assumption that two or more electronegative groups on the phenyl ring attached to the thiazolo[2,3 b]quinazoline system showed the optimum effect. The in silico simulations suggested crucial hydrogen bond and pi-pi stacking interactions, with a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and molecular dynamics, in order to explore the molecular targets of HCC which were in complete agreement with the in vitro findings. Considering their significant anticancer activity, 4A and 6A are potential drug candidates for the management of HCC. PMID- 28615928 TI - Using a multidimensional unfolding approach to assess multiple sclerosis patient preferences for disease-modifying therapy: a pilot study. AB - PURPOSE: Multidimensional unfolding is a multivariate method to assess preferences using a small sample size, a geometric model locating individuals and alternatives as points in a joint space. The objective was to evaluate relapsing remitting multiple sclerosis (RRMS) patient preferences toward key disease modifying therapy (DMT) attributes using multidimensional unfolding. PATIENTS AND METHODS: A cross-sectional pilot study in RRMS patients was conducted. Drug attributes included relapse prevention, disease progression prevention, side effect risk and route and schedule of administration. Assessment of preferences was performed through a five-card game. Patients were asked to value attributes from 1 (most preferred) to 5 (least preferred). RESULTS: A total of 37 patients were included; the mean age was 38.6 years, and 78.4% were female. Disease progression prevention was the most important factor (51.4%), followed by relapse prevention (40.5%). The frequency of administration had the lowest preference rating for 56.8% of patients. Finally, 19.6% valued the side-effect risk attribute as having low/very low importance. CONCLUSION: Patients' perspective for DMT attributes may provide valuable information to facilitate shared decision making. Efficacy attributes were the most important drug characteristics for RRMS patients. Multidimensional unfolding seems to be a feasible approach to assess preferences in multiple sclerosis patients. Further elicitation studies using multidimensional unfolding with other stated choice methods are necessary to confirm these findings. PMID- 28615926 TI - Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses. AB - Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI. PMID- 28615929 TI - Impact of serum-derived bovine immunoglobulin/protein isolate therapy on irritable bowel syndrome and inflammatory bowel disease: a survey of patient perspective. AB - BACKGROUND: Patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD) commonly experience diarrhea, abdominal pain, bloating, and urgency. These symptoms significantly compromise the patient's quality of life (QoL) by limiting participation in normal daily activities and adversely affect work productivity and performance. PURPOSE: The aim of this study was to understand from the patient's perspective how oral serum-derived bovine immunoglobulin/protein isolate (SBI) impacts bowel habits, management of condition, and basic QoL. METHODS: A 1-page questionnaire was distributed randomly to >14,000 patients who were prescribed SBI (EnteraGam(r)) for relevant intended uses. The survey was designed to collect data related to the influence of IBS or IBD on daily life activities and the impact of SBI usage on daily stool frequency, management of their condition, and QoL. Patient-reported responses were analyzed using a paired t-test to compare mean change in daily stool output and descriptive statistics for continuous variables. RESULTS: A total of 1,377 patients returned the surveys. Results from 595 surveys were analyzed with a focus on patients with IBS or IBD who had provided numeric responses regarding daily stool frequency. Respondents with IBS who reported having a normal stool frequency (<=4 stools per day) increased from 35% prior to using SBI to 91% while using SBI. A similar change toward normal stool frequency was reported by IBD respondents. Mean daily stool numbers decreased for respondents in the combined IBS and IBD groups (P=0.0001) from 6.5+/-4.3 before SBI to 2.6+/-1.9 following SBI use. The majority of respondents agreed strongly or very strongly that SBI helped them manage their condition (66.9%) and helped them return to the activities they enjoyed (59.1%). CONCLUSION: Results from this patient survey suggest that SBI use can lead to clinically relevant decreases in daily stool frequency in patients with IBS or IBD along with improvements in the overall management of their condition and aspects of QoL. PMID- 28615930 TI - Prevention of Influenza A(H7N9) and Bacterial Infections in Mice Using Intranasal Immunization With Live Influenza Vaccine and the Group B Streptococcus Recombinant Polypeptides. AB - We investigate the protective effect of combined vaccination based on live attenuated influenza vaccine (LAIV) and group B streptococcus (GBS) recombinant polypeptides against potential pandemic H7N9 influenza infection followed by GBS burden. Mice were intranasally immunized using 107 50% egg infectious dose (EID50) of H7N3 LAIV, the mix of the 4 GBS peptides (group B streptococcus vaccine [GBSV]), or combined LAIV + GBSV vaccine. The LAIV raised serum hemagglutination-inhibition antibodies against H7N9 in higher titers than against H7N3. Combined vaccination provided advantageous protection against infections with A/Shanghai/2/2013(H7N9)CDC-RG influenza and serotype II GBS. Combined vaccine significantly improved bacterial clearance from the lungs after infection compared with other vaccine groups. The smallest lung lesions due to combined LAIV + GBSV vaccination were associated with a prevalence of lung interferon gamma messenger RNA expression. Thus, combined viral and bacterial intranasal immunization using H7N3 LAIV and recombinant bacterial polypeptides induced balanced adaptive immune response, providing protection against potential pandemic influenza H7N9 and bacterial complications. PMID- 28615932 TI - Expanding The INSPIRED COPD Outreach ProgramTM to the emergency department: a feasibility assessment. AB - BACKGROUND: The Halifax-based INSPIRED COPD Outreach ProgramTM is a facility-to community home-based novel clinical initiative that through improved care transitions, self-management, and engagement in advance care planning has demonstrated a significant (60%-80%) reduction in health care utilization with substantial cost aversion. By assessing the feasibility of expanding INSPIRED into the emergency department (ED) we anticipated extending reach and potential for positive impact of INSPIRED to those with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) who avoid hospital admission. METHODS: Patients were eligible for the INSPIRED-ED study if >40 years of age, diagnosed with AECOPD and discharged from the ED, willing to be referred, community dwelling with at least one of: previous use of the ED services, admission to Intermediate Care Unit/Intensive Care Unit, or admission to hospital with AECOPD in the past year. We set feasibility objectives for referral rates, completion of action plans, advance care planning participation, and reduction in ED visit frequency. RESULTS: Referral rates were 0.5/week. Among eligible patients (n=174) 33 (19%) were referred of whom 15 (M=4, F=11) enrolled in INSPIRED-ED. Mean (SD) age was 68 (7) years, post-bronchdilator FEV1 44.2 (15.5) % predicted, and Medical Research Council (MRC) dyspnea score 3.8 (0.41). We met feasibility objectives for action plan and advance care planning completion. Frequency of subsequent ED visits fell by 54%. Mean (SD) Care Transition Measure (CTM-3) improved from 8.6 (2.0) to 11.3 (1.3), P=0.0004, and of 14 patients responding 12 (86%) found the program very helpful. An additional 34 patients were enrolled to our regular program from those referred but ineligible for INSPIRED-ED (n=27) or unwilling to participate (n=7). CONCLUSIONS: INSPIRED-ED outcomes were generally positive, however referral and enrollment rates were lower than anticipated. Despite the potential of early self-management education, the ED may not be the ideal recruitment setting for home-based programs. Our findings underline the importance of conducting preliminary work to ascertain best settings for implementing new self-management education initiatives. PMID- 28615931 TI - Inhaled indacaterol for the treatment of COPD patients with destroyed lung by tuberculosis and moderate-to-severe airflow limitation: results from the randomized INFINITY study. AB - BACKGROUND AND OBJECTIVE: Pulmonary tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD); however, few clinical studies have investigated treatment effectiveness in COPD patients with destroyed lung by TB. The Indacaterol effectiveness in COPD patients with Tuberculosis history (INFINITY) study assessed the efficacy and safety of once-daily inhaled indacaterol 150 ug for the treatment of Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation. METHODS: This was a multicenter, double-blind, parallel-group study, in which eligible patients were randomized (1:1) to receive either once-daily indacaterol 150 ug or placebo for 8 weeks. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s at Week 8; the secondary endpoints included changes in transition dyspnea index score and St George's Respiratory Questionnaire for COPD score at Week 8. Safety was evaluated over 8 weeks. RESULTS: Of the 136 patients randomized, 119 (87.5%) completed the study treatment. At Week 8, indacaterol significantly improved trough forced expiratory volume in 1 s versus placebo (treatment difference [TD] 140 mL, P<0.001). Statistically significant improvement in transition dyspnea index score (TD =0.78, P<0.05) and numerical improvement in St George's Respiratory Questionnaire for COPD score (TD =-2.36, P=0.3563) were observed with indacaterol versus placebo at Week 8. Incidence of adverse events was comparable between the treatment groups. CONCLUSION: Indacaterol provided significantly superior bronchodilation, significant improvement in breathlessness and improved health status with comparable safety versus placebo in Korean COPD patients with destroyed lung by TB and moderate-to severe airflow limitation. PMID- 28615933 TI - Development of a nomogram for predicting in-hospital mortality of patients with exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) often experience exacerbations of their disease, sometimes requiring hospital admission and being associated with increased mortality. Although previous studies have reported mortality from exacerbations of COPD, there is limited information about prediction of individual in-hospital mortality. We therefore aimed to use data from a nationwide inpatient database in Japan to generate a nomogram for predicting in-hospital mortality from patients' characteristics on admission. METHODS: We retrospectively collected data on patients with COPD who had been admitted for exacerbations and been discharged between July 1, 2010 and March 31, 2013. We performed multivariable logistic regression analysis to examine factors associated with in-hospital mortality and thereafter used these factors to develop a nomogram for predicting in-hospital prognosis. RESULTS: The study comprised 3,064 eligible patients. In-hospital death occurred in 209 patients (6.8%). Higher mortality was associated with older age, being male, lower body mass index, disturbance of consciousness, severe dyspnea, history of mechanical ventilation, pneumonia, and having no asthma on admission. We developed a nomogram based on these variables to predict in hospital mortality. The concordance index of the nomogram was 0.775. Internal validation was performed by a bootstrap method with 50 resamples, and calibration plots were found to be well fitted to predict in-hospital mortality. CONCLUSION: We developed a nomogram for predicting in-hospital mortality of exacerbations of COPD. This nomogram could help clinicians to predict risk of in-hospital mortality in individual patients with COPD exacerbation. PMID- 28615934 TI - Radiologic features of precancerous areas of the lungs in chronic obstructive pulmonary disease. AB - BACKGROUND: Only a few studies have evaluated the radiologic features of pre existing structural abnormalities where lung cancer may develop. This study aimed to analyze the computed tomography (CT) images of lung areas where new cancer developed in chronic obstructive pulmonary disease (COPD) patients. PATIENTS AND METHODS: We conducted a multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research, to assess the incidence of lung cancer. Emphysema and interstitial abnormalities were evaluated in 240 COPD patients who had baseline CT scans applicable for further digital analyses. For patients who developed lung cancer during the 3-year follow-up period, the local spherical lung density of the precancerous area was individually quantified. RESULTS: Lung cancer was newly diagnosed in 21 participants (2.3% per year). The percent-age of low attenuation area in patients who developed lung cancer was higher than that of the other patients (20.0% vs 10.4%, P=0.014). The presence of emphysema (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.0-29.0, P=0.049) or interstitial lung abnormalities (OR 15.6, 95% CI 4.4-65.4, P<0.0001) independently increased the risk for lung cancer. Compared with the density of the entire lung, the local density of the precancerous area was almost the same in patients with heterogeneous emphysema, but it was higher in most patients with interstitial abnormalities. CONCLUSION: The presence of emphysema or interstitial abnormalities or a combination of both were independent predictors of lung cancer development in COPD patients. Furthermore, lung cancer most often developed in non-emphysematous areas or in interstitial abnormalities. PMID- 28615935 TI - Serum inflammatory biomarkers and clinical outcomes of COPD exacerbation caused by different pathogens. AB - BACKGROUND AND OBJECTIVE: COPD exacerbation is characterized by worsening of symptoms, warranting change in treatment. Systemic and airway inflammation play roles in the pathogenesis of COPD exacerbation. We hypothesized whether increased serum inflammatory biomarkers are associated with the clinical outcomes of COPD exacerbation caused by different infectious pathogens. METHODS: COPD patients with exacerbation were recruited from a hospital emergency department during 2014 2015. Serum procalcitonin (PCT) and C-reactive protein (CRP) were measured. Dyspnea, eosinopenia, consolidation, acidemia, and atrial fibrillation (DECAF) score was calculated for predicting mortality. Multiplex polymerase chain reaction was carried out for respiratory viral assay from nasopharyngeal swabs, and sputum bacterial culture was also performed. Hospital mortality, invasive mechanical ventilation requirement, and length of hospital stay (LOS) were evaluated, and their associations with clinical characteristics, DECAF score, and serum biomarkers were examined. RESULTS: A total of 62 COPD patients were enrolled. These patients were classified as Global Initiative for Obstructive Lung Disease (GOLD) stage 2, 3, and 4 in 12.9%, 6.4%, and 80.7% of cases, respectively. Isolated bacterial exacerbation was recovered in 30.6% of exacerbation episodes: Klebsiella pneumoniae was the most commonly identified bacteria. Viral pathogens and coinfections were noted in 9.6% and 16.1% of exacerbated patients, respectively. Influenza was the most commonly detected viral pathogen. Serum biomarkers and DECAF score for viruses, bacteria, coinfection, and noninfectious causes of exacerbations were similar. Neither DECAF score nor serum biomarkers were able to differentiate patients with and without mortality or requiring mechanical ventilation. Increased serum PCT was noted in patients with LOS >=7 days when compared with those with LOS <7 days (0.38 ng/mL vs 0.1 ng/mL; P=0.035). CONCLUSION: Increased serum PCT is associated with longer LOS in COPD exacerbation. However, CRP and DECAF score play limited roles in predicting clinical outcome and lack an association with causes of exacerbation. PMID- 28615936 TI - Comparison of distinctive models for calculating an interlobar emphysema heterogeneity index in patients prior to endoscopic lung volume reduction. AB - BACKGROUND: The degree of interlobar emphysema heterogeneity is thought to play an important role in the outcome of endoscopic lung volume reduction (ELVR) therapy of patients with advanced COPD. There are multiple ways one could possibly define interlobar emphysema heterogeneity, and there is no standardized definition. PURPOSE: The aim of this study was to derive a formula for calculating an interlobar emphysema heterogeneity index (HI) when evaluating a patient for ELVR. Furthermore, an attempt was made to identify a threshold for relevant interlobar emphysema heterogeneity with regard to ELVR. PATIENTS AND METHODS: We retrospectively analyzed 50 patients who had undergone technically successful ELVR with placement of one-way valves at our institution and had received lung function tests and computed tomography scans before and after treatment. Predictive accuracy of the different methods for HI calculation was assessed with receiver-operating characteristic curve analysis, assuming a minimum difference in forced expiratory volume in 1 second of 100 mL to indicate a clinically important change. RESULTS: The HI defined as emphysema score of the targeted lobe (TL) minus emphysema score of the ipsilateral nontargeted lobe disregarding the middle lobe yielded the best predicative accuracy (AUC =0.73, P=0.008). The HI defined as emphysema score of the TL minus emphysema score of the lung without the TL showed a similarly good predictive accuracy (AUC =0.72, P=0.009). Subgroup analysis suggests that the impact of interlobar emphysema heterogeneity is of greater importance in patients with upper lobe predominant emphysema than in patients with lower lobe predominant emphysema. CONCLUSION: This study reveals the most appropriate ways of calculating an interlobar emphysema heterogeneity with regard to ELVR. PMID- 28615937 TI - Patient-perceived treatment burden of chronic obstructive pulmonary disease. AB - BACKGROUND: While chronic morbidity and mortality from COPD is well documented, little is known about the treatment burden faced by patients with COPD. SUBJECTS AND METHODS: Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] <50% predicted) representing different age-groups, sex, and number of comorbidities participated in a semistructured interview. Interviews were conducted until thematic saturation was reached. Interviews were recorded, transcribed, and analyzed thematically using an established treatment-burden framework. RESULTS: A total of 26 patients (42% male, mean age 66.7+/-9.8 years) with severe (n=15) or very severe (n=11) airflow limitation (mean FEV1 32.1%+/ 9.65% predicted) were interviewed. Participants struggled with various treatment burden domains, predominantly with changing health behaviors, such as smoking cessation and exercise. Interviewees often only ceased smoking after a major health event, despite being advised to do so earlier by a doctor. Recommended exercise regimens, such as pulmonary rehabilitation classes, were curtailed, although some patients replaced them with light home-based exercise. Interviewees had difficulty attending medical appointments, often relying on others to transport them. Overall, COPD patients indicated they were not willing to accept the burden of treatments where they perceived minimal benefit. CONCLUSION: This study describes the substantial treatment burden experienced by patients with COPD. Medical advice may be rejected by patients if the benefit of following the advice is perceived as insufficient. Health professionals need to recognize treatment burden as a source of nonadherence, and should tailor treatment discussions to fit patients' values and capacity to achieve optimal patient outcomes. PMID- 28615939 TI - Effect of carbon ion implantation on the tribology of metal-on-metal bearings for artificial joints. AB - Metal-on-metal (MoM) bearings have become popular due to a major advantage over metal-on-polymer bearings for total hip arthroplasty in that the larger femoral head and hydrodynamic lubrication of the former reduce the rate of wear. However, concerns remain regarding adverse reactions to metal debris including metallosis caused by metal wear generated at the taper-head interface and another modular junction. Our group has hypothesized that carbon ion implantation (CII) may improve metal wear properties. The purpose of this study was to investigate the wear properties and friction coefficients of CII surfaces with an aim to ultimately apply these surfaces to MoM bearings in artificial joints. CII was applied to cobalt-chromium-molybdenum (Co-Cr-Mo) alloy substrates by plasma source ion implantation. The substrates were characterized using scanning electron microscopy and a 3D measuring laser microscope. Sliding contact tests were performed with a simple geometry pin-on-plate wear tester at a load of 2.5 N, a calculated contact pressure of 38.5 MPa (max: 57.8 MPa), a reciprocating velocity of 30 mm/s, a stroke length of 60 mm, and a reciprocating cycle count of 172,800 cycles. The surfaces of the CII substrates were generally featureless with a smooth surface topography at the same level as untreated Co-Cr-Mo alloy. Compared to the untreated Co-Cr-Mo alloy, the CII-treated bearings had lower friction coefficients, higher resistance to catastrophic damage, and prevented the adhesion of wear debris. The results of this study suggest that the CII surface stabilizes the wear status due to the low friction coefficient and low infiltration of partner materials, and these properties also prevent the adhesion of wear debris and inhibit excessive wear. Carbon is considered to be biologically inert; therefore, CII is anticipated to be applicable to the bearing surfaces of MoM prostheses. PMID- 28615940 TI - Killing malignant melanoma cells with protoporphyrin IX-loaded polymersome mediated photodynamic therapy and cold atmospheric plasma. AB - Traditional cancer treatments contain several limitations such as incomplete ablation and multidrug resistance. It is known that photodynamic therapy (PDT) is an effective treatment for several tumor types especially melanoma cells. During the PDT process, protoporphyrin IX (PpIX), an effective photosensitizer, can selectively kill cancer cells by activating a special light source. When tumor cells encapsulate a photosensitizer, they can be easily excited into an excited state by a light source. In this study, cold atmospheric plasma (CAP) was used as a novel light source. Results of some studies have showed that cancer cells can be effectively killed by using either a light source or an individual treatment due to the generation of reactive oxygen species and electrons from a wide range of wavelengths, which suggest that CAP can act as a potential light source for anticancer applications compared with UV light sources. Results of the present in vitro study indicated for the first time that PpIX can be successfully loaded into polymersomes. Most importantly, cell viability studies revealed that PpIX loaded polymersomes had a low toxicity to healthy fibroblasts (20% were killed) at a concentration of 400 ug/mL, but they showed a great potential to selectively kill melanoma cells (almost 50% were killed). With the application of CAP posttreatment, melanoma cell viability significantly decreased (80% were killed) compared to not using a light source (45% were killed) or using a UV light source (65% were killed). In summary, these results indicated for the first time that PpIX-loaded polymersomes together with CAP posttreatment could be a promising tool for skin cancer drug delivery with selective toxicity toward melanoma cells sparing healthy fibroblasts. PMID- 28615938 TI - High drug-loading nanomedicines: progress, current status, and prospects. AB - Drug molecules transformed into nanoparticles or endowed with nanostructures with or without the aid of carrier materials are referred to as "nanomedicines" and can overcome some inherent drawbacks of free drugs, such as poor water solubility, high drug dosage, and short drug half-life in vivo. However, most of the existing nanomedicines possess the drawback of low drug-loading (generally less than 10%) associated with more carrier materials. For intravenous administration, the extensive use of carrier materials might cause systemic toxicity and impose an extra burden of degradation, metabolism, and excretion of the materials for patients. Therefore, on the premise of guaranteeing therapeutic effect and function, reducing or avoiding the use of carrier materials is a promising alternative approach to solve these problems. Recently, high drug loading nanomedicines, which have a drug-loading content higher than 10%, are attracting increasing interest. According to the fabrication strategies of nanomedicines, high drug-loading nanomedicines are divided into four main classes: nanomedicines with inert porous material as carrier, nanomedicines with drug as part of carrier, carrier-free nanomedicines, and nanomedicines following niche and complex strategies. To date, most of the existing high drug-loading nanomedicines belong to the first class, and few research studies have focused on other classes. In this review, we investigate the research status of high drug loading nanomedicines and discuss the features of their fabrication strategies and optimum proposal in detail. We also point out deficiencies and developing direction of high drug-loading nanomedicines. We envision that high drug-loading nanomedicines will occupy an important position in the field of drug-delivery systems, and hope that novel perspectives will be proposed for the development of high drug-loading nanomedicines. PMID- 28615941 TI - Development and optimization of an injectable formulation of copper diethyldithiocarbamate, an active anticancer agent. AB - Copper diethyldithiocarbamate (Cu(DDC)2) is the active anticancer agent generated when disulfiram (DSF) is provided in the presence of copper. To date, research directed toward repurposing DSF as an anticancer drug has focused on administration of DSF and copper in combination, efforts that have proven unsuccessful in clinical trials. This is likely due to the inability to form Cu(DDC)2 at relevant concentrations in regions of tumor growth. Little effort has been directed toward the development of Cu(DDC)2 because of the inherent aqueous insolubility of the complex. Here, we describe an injectable Cu(DDC)2 formulation prepared through a method that involves synthesis of Cu(DDC)2 inside the aqueous core of liposomes. Convection-enhanced delivery of a Cu(DDC)2 formulation prepared using 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/cholesterol liposomes into a rat model of F98 glioma engendered a 25% increase in median survival time relative to vehicle-treated animals. In a murine subcutaneous MV-4 11 model, treatment resulted in a 45% reduction in tumor burden when compared to controls. Pharmacokinetic studies indicated that the Cu(DDC)2 was rapidly eliminated after intravenous administration while the liposomes remained in circulation. To test whether liposomal lipid composition could increase Cu(DDC)2 circulation lifetime, a number of different formulations were evaluated. Studies demonstrated that liposomes composed of DSPC and 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-n-(carboxy[polyethylene glycol]-2000) (95:5) enhanced Cu(DDC)2 concentrations in the circulation as reflected by a 4.2-fold increase in plasma AUC(0-infinity) relative to the DSPC/cholesterol formulation. The anticancer activity of this Cu(DDC)2 formulation was subsequently evaluated in the MV-4-11 model. At its maximum tolerated dose, this formulation exhibited comparable activity to the DSPC/cholesterol formulation. This is the first report demonstrating the therapeutic effects of an injectable Cu(DDC)2 formulation in vivo. PMID- 28615942 TI - iRGD-modified lipid-polymer hybrid nanoparticles loaded with isoliquiritigenin to enhance anti-breast cancer effect and tumor-targeting ability. AB - Isoliquiritigenin (ISL), a natural anti-breast cancer dietary compound, has poor delivery characteristics and low bioavailability. In order to promote the therapeutic outcome of ISL, a tumor-targeting lipid-polymer hybrid nanoparticle (NP) system modified by tumor-homing iRGD peptides has been developed. The hybrid NPs were prepared by a modified single-step nanoprecipitation method to encapsulate ISL. iRGD peptides were anchored on the surface by a postinsertion method (ISL-iRGD NPs). The stable lipid-polymer structure of ISL-iRGD NPs, with high encapsulation and loading efficiency, was confirmed. Compared to free ISL and non-iRGD-modified counterparts, ISL-iRGD NPs showed higher cytotoxicity and cell apoptosis against the different type of breast cancer cells. This was attributable to higher cellular accumulation mediated by the iRGD-integrin recognition and the nanoscale effect. More importantly, based on the active tumor tissue accumulation by iRGD peptides and the prolonged in vivo circulation by the stealth nanostructure, ISL-iRGD NPs displayed higher tumor-growth inhibition efficiency in 4T1-bearing breast-tumor mouse models. Therefore, the constructed iRGD modified lipid-polymer hybrid NPs would provide a promising drug-delivery strategy to improve ISL in anti-breast cancer efficacy. PMID- 28615943 TI - The use of functional epirubicin liposomes to induce programmed death in refractory breast cancer. AB - Currently, chemotherapy is less efficient in controlling the continued development of breast cancer because it cannot eliminate extrinsic and intrinsic refractory cancers. In this study, mitochondria were modified by functional epirubicin liposomes to eliminate refractory cancers through initiation of an apoptosis cascade. The efficacy and mechanism of epirubicin liposomes were investigated on human breast cancer cells in vitro and in vivo using flow cytometry, confocal microscopy, high-content screening system, in vivo imaging system, and tumor inhibition in mice. Mechanistic studies revealed that the liposomes could target the mitochondria, activate the apoptotic enzymes caspase 8, 9, and 3, upregulate the proapoptotic protein Bax while downregulating the antiapoptotic protein Mcl-1, and induce the generation of reactive oxygen species (ROS) through an apoptosis cascade. In xenografted mice bearing breast cancer, the epirubicin liposomes demonstrated prolonged blood circulation, significantly increased accumulation in tumor tissue, and robust anticancer efficacy. This study demonstrated that functional epirubicin liposomes could significantly induce programmed death of refractory breast cancer by activating caspases and ROS-related apoptotic signaling pathways, in addition to the direct killing effect of the anticancer drug itself. Thus, we present a simple nanomedicine strategy to treat refractory breast cancer. PMID- 28615945 TI - Ictal blinking, an under-recognized phenomenon: our experience and literature review. AB - Ictal blinking (IB) is a very rare disease manifesting as an epileptic motor event in children and adults. Until now it has not been included in any classification of focal seizures of the International League Against Epilepsy Commission. It could be unilateral or bilateral, isolated or in association with other motor manifestations such as limbs' clonus and spasms. Its pathogenesis has not been clearly established: paroxysmal discharges from different areas of the brain could cause IB by activation of trigeminal fibers. Herein authors report three infants and a child with IB, observed in three pediatric centers in two different countries. We also performed a review of literature data, suggesting IB as a seizure type to be included in international classifications, and describing the specific electroencephalographic pattern of this condition. PMID- 28615944 TI - The interactions of single-wall carbon nanohorns with polar epithelium. AB - Single-wall carbon nanohorns (SWCNHs), which have multitudes of horn interstices, an extensive surface area, and a spherical aggregate structure, offer many advantages over other carbon nanomaterials being used as a drug nanovector. The previous studies on the interaction between SWCNHs and cells have mostly emphasized on cellular uptake and intracellular trafficking, but seldom on epithelial cells. Polar epithelium as a typical biological barrier constitutes the prime obstacle for the transport of therapeutic agents to target site. This work tried to explore the permeability of SWCNHs through polar epithelium and their abilities to modulate transcellular transport, and evaluate the potential of SWCNHs in drug delivery. Madin-Darby canine kidney (MDCK) cell monolayer was used as a polar epithelial cell model, and as-grown SWCNHs, together with oxidized and fluorescein isothiocyanate-conjugated bovine serum albumin-labeled forms, were constructed and comprehensively investigated in vitro and in vivo. Various methods such as transmission electron microscopy and confocal imaging were used to visualize their intracellular uptake and localization, as well as to investigate the potential transcytotic process. The related mechanism was explored by specific inhibitors. Additionally, fast multispectral optoacoustic tomography imaging was used for monitoring the distribution and transport process of SWCNHs in vivo after oral administration in nude mice, as an evidence for their interaction with the intestinal epithelium. The results showed that SWCNHs had a strong bioadhesion property, and parts of them could be uptaken and transcytosed across the MDCK monolayer. Multiple mechanisms were involved in the uptake and transcytosis of SWCNHs with varying degrees. After oral administration, oxidized SWCNHs were distributed in the gastrointestinal tract and retained in the intestine for up to 36 h probably due to their surface adhesion and endocytosis into the intestinal epithelium. Overall, this comprehensive investigation demonstrated that SWCNHs can serve as a promising nanovector that can cross the barrier of polar epithelial cells and deliver drugs effectively. PMID- 28615946 TI - Treatment and outcome of intestinal perforation after liver transplant surgery in adults: a single-center experience. AB - OBJECTIVE: Intestinal perforation is a rare complication after liver transplantation. This study was designed to calculate the incidence and investigate the outcomes of intestinal perforation in adult liver transplant patients. MATERIALS AND METHODS: The clinical records of liver transplant recipients between January 2014 and June 2016 were obtained. The incidence of intestinal perforation was calculated, and high risk factors were analyzed. RESULTS: The mean operative time was 8.5 h (range: 6-11 h). The mean portal vein occlusion time was 66.5 min (range: 58-72 min), and the mean cold ischemia time was 7.9 h (range: 6.5-9.5 h). Four (2.7%) patients developed intestinal perforation from 9 to 14 days postliver transplant. All perforations were single and repaired by interrupted silk sutures. Two patients uneventfully recovered, but intestinal perforation recurred in two other patients. Simple repair was undertaken in one patient, and terminal ileum resection and ileostomy were performed in the other patient. There were no perioperative deaths. CONCLUSION: The incidence of intestinal perforation after liver transplantation is low. Prompt diagnosis and treatment should be carried out to reduce comorbidities and mortality. PMID- 28615947 TI - Treatment of secondary hyperparathyroidism: the clinical utility of etelcalcetide. AB - Secondary hyperparathyroidism (SHPT), a very frequent, severe, and worsening complication of chronic kidney disease, is characterized by high serum parathyroid hormone (PTH), parathyroid gland hyperplasia, and disturbances in mineral metabolism. Clinically, SHPT shows renal osteodystrophy, vascular calcification, cardiovascular damage, and fatal outcome. Calcium-sensing receptor (CaSR) is the main physiological regulator of PTH secretion; its activation by calcium rapidly inhibits PTH. Another important player in regulating mineral metabolism is vitamin D receptor (VDR), which is under the influence of vitamin D and influences the intestinal absorption of calcium and phosphate, PTH gene expression, and bone calcium mobilization. Serum phosphate levels influence fibroblast growth factor 23 (FGF-23) production, a phosphatonin that modulates serum phosphate reabsorption, PTH synthesis, and vitamin D production. Current therapeutic approaches consist of 1) phosphate intake control by diet or phosphate binders, 2) vitamin D by VDR activation, and 3) calcimimetic agents that activate CaSR. Recently, a new long-acting peptide (etelcalcetide) belonging to the calcimimetics class was approved for intravenous use in hemodialysis patients with SHPT. Etelcalcetide binds directly to CaSR, by a sulfide bond, inhibiting the production and secretion of PTH by parathyroid glands. After intravenous administration in rats, etelcalcetide is quickly distributed to the tissues and eliminated by kidneys, while in uremic animals the nonrenal excretion is only 1.2%. In hemodialysis patients, the treatment itself is the main route of elimination. Etelcalcetide in hemodialysis patients with SHPT was more effective than placebo and cinacalcet, with a PTH reduction of >30% in 76% of patients with etelcalcetide versus 10% with placebo. Particular attention was paid to the safety of the drug; the most common adverse event was asymptomatic blood calcium reduction, similar to cinacalcet, while gastrointestinal symptoms were less frequent. This promising new drug available for better control of SHPT will, together with drugs already in use, optimize the treatment to normalize the biochemical parameters. PMID- 28615948 TI - Marijuana Use, Recent Marijuana Initiation, and Progression to Marijuana Use Disorder Among Young Male and Female Adolescents Aged 12-14 Living in US Households. AB - Marijuana initiation during adolescence, and early adolescence in particular, is associated with adverse health consequences. Our study used 2005-2014 data from the annual, cross-sectional National Survey on Drug Use and Health to study the prevalence and correlates of marijuana initiation, use, and marijuana use disorder (MUD; abuse or dependence) among 12- to 14-year olds living in civilian US households (n = 84 954). Examined correlates included age, sex, race/ethnicity, poverty status, metropolitan status, year of survey, depression, tobacco use, alcohol use, and fighting at school. Sex differences in the correlates of lifetime use and past year marijuana initiation were tested via interaction. Lifetime prevalence of marijuana use was 5.5%; 3.2% reported past year initiation. About 1 in 6 (16.8%) past year initiates progressed to MUD within 12 months of first use. Although men had higher prevalence of lifetime use than women, past year initiation did not differ by sex. On examining the sex*race/ethnicity interaction effects, findings determined that non-Hispanic black and Hispanic men had higher prevalence estimates of ever using marijuana and incidence of past year initiation as compared with non-Hispanic white men; these race/ethnicity differences were not found among women. Identifying correlates of initiation and progression to MUD among young adolescents is critical to improve prevention and treatment program targets. PMID- 28615949 TI - Contextual Effects of Neighborhoods and Schools on Adolescent and Young Adult Marijuana Use in the United States. AB - Little is known about the unique contribution of schools vs neighborhoods in driving adolescent marijuana use. This study examined the relative contribution of each setting and the influence of school and neighborhood socioeconomic status on use. We performed a series of cross-classified multilevel logistic models predicting past 30-day adolescent (N = 18 329) and young adult (N = 13 908) marijuana use using data from Add Health. Marijuana use differed by age, sex, race/ethnicity, and public assistance in adjusted models. Variance parameters indicated a high degree of clustering by school (sigma2 = 0.30) and less pronounced clustering by neighborhood (sigma2 = 0.06) in adolescence when accounting for both levels simultaneously in a cross-classified multilevel model. Clustering by school persisted into young adulthood (sigma2 = 0.08). Parental receipt of public assistance increased the likelihood of use during adolescence (odds ratio = 1.39; 95% confidence interval: 1.19-1.59), and higher parental education was associated with increased likelihood of use in young adulthood. These findings indicate that both contexts may be promising locations for intervention. PMID- 28615950 TI - Utilizing Big Data and Twitter to Discover Emergent Online Communities of Cannabis Users. AB - Large shifts in medical, recreational, and illicit cannabis consumption in the United States have implications for personalizing treatment and prevention programs to a wide variety of populations. As such, considerable research has investigated clinical presentations of cannabis users in clinical and population based samples. Studies leveraging big data, social media, and social network analysis have emerged as a promising mechanism to generate timely insights that can inform treatment and prevention research. This study extends a novel method called stochastic block modeling to derive communities of cannabis consumers as part of a complex social network on Twitter. A set of examples illustrate how this method can ascertain candidate samples of medical, recreational, and illicit cannabis users. Implications for research planning, intervention design, and public health surveillance are discussed. PMID- 28615951 TI - Long-Term Cause-Specific Mortality After Surgery for Women With Breast Cancer: A 20-Year Follow-Up Study From Surveillance, Epidemiology, and End Results Cancer Registries. AB - BACKGROUND: Research into long-term cause-specific mortality of women diagnosed with breast cancer is important because it allows for the splitting of the population into patients who eventually die from breast cancer and from other causes. The adoption of this approach helps to identify patients with an elevated risk of eventual death from breast cancer. OBJECTIVE: The primary aim of this study was to examine the associations between both sociodemographic and clinicopathologic characteristics and the underlying risks of death from breast cancer and from other causes for women diagnosed with breast cancer. A second aim was to propose a predictive biomarker of cause-specific mortality in terms of treatment and several important characteristics of a patient. METHODS: A cohort of 16 511 female patients diagnosed with breast cancer in 1990 was obtained from the Surveillance, Epidemiology, and End Results cancer registries and followed for 20 years. A mixture model for the regression analysis of competing risks was used to identify factors and confounders that affected either the eventual cause specific mortality or conditional cause-specific hazard rates, or both. Missing data were handled with multiple imputation. RESULTS: Curvilinear relationships of age at diagnosis along with race, marital status, breast cancer type, tumor size, estrogen receptor status, extension, lymph node status, type of surgery, and radiotherapy status were significant risk factors for the cause-specific mortality, with extension and lymph node status appearing to be confounded with the effects of both type of surgery and radiotherapy status. The score obtained from combining a set of predictors showed to be an accurate predictive biomarker. CONCLUSIONS: In cause-specific mortality of women diagnosed breast cancer, prognosis appears to depend on both sociodemographic and clinicopathologic factors. The predictive biomarker proposed in this study may help identifying the level of seriousness of the disease earlier than traditional methods, potentially guiding future allocation of resources for better patient care and management strategies. PMID- 28615952 TI - Assessment of Dithiocarbamate Residues on Tomatoes Conventionally Grown in Uganda and the Effect of Simple Washing to Reduce Exposure Risk to Consumers. AB - Pesticide misuse by farmers poses health risks to consumers. This study assessed the level of dithiocarbamate residues in tomatoes acquired from 20 farmers and 25 market vendors in Wakiso District, how simple washing affects these residues, and the potential chronic health risk for Ugandans eating such tomatoes. Results revealed that mancozeb was the only reported dithiocarbamate, and 47.4% and 14% of farm and market samples, respectively, had dithiocarbamate residues exceeding the Codex alimentarius maximum residue limit of 2 mgCS2/kg. Mixing concentration had a positive significant effect on dithiocarbamate residue levels (P = 0.004). Washing reduced dithiocarbamate residues by a factor of 0.3. Dietary risk assessment revealed no chronic health risk to both children and general population when a national daily per capita consumption of 1.0 g is considered. This study recommends comprehensive research into Uganda's food production and consumption patterns and establishment of a national pesticide residue surveillance program. PMID- 28615953 TI - Characteristics of Pesticide Poisoning in Rural and Urban Settings in Uganda. AB - Pesticide poisoning is a significant burden on health care systems in many low income countries. This study evaluates cases of registered pesticide poisonings treated in selected rural (N = 101) and urban (N = 212) health facilities in Uganda from January 2010 to August 2016. In the urban setting, pesticides were the most prevalent single poison responsible for intoxications (N = 212 [28.8%]). Self-harm constituted a significantly higher proportion of the total number of poisonings in urban (63.3%) compared with rural areas (25.6%) where unintentional poisonings prevailed. Men were older than women and represented a majority of around 60% of the cases in both the urban and rural settings. Unintentional cases were almost the only ones seen below the age of 10, whereas self-harm dominated among adolescents and young persons from 10 to 29 years of age. Organophosphorus insecticides accounted for 73.0% of the poisonings. Urban hospitals provided a more intensive treatment and had registered fever complications than rural health care settings. To minimize self-harm with pesticides, a restriction of pesticide availability as shown to be effective in other low-income countries is recommended. Training of health care workers in proper diagnosis and treatment of poisonings and improved equipment in the health care settings should be strengthened. PMID- 28615954 TI - Response to LiPuma and DeMarco's Article on "Hastening Death". AB - The paper "Palliative care and patient autonomy: moving beyond prohibitions against hastening death" by LiPuma and DeMarco deals with an aspect of end of life care which is the source of considerable disagreement. It is important to emphasize that autonomy is not the unique feature for end of life care. There is always a medical and ethical commitment to care, i.e. beneficence and nonmaleficence. All of these aspects have to be taken into account when treating patients at the very end of life. There is considerable scientific proof indicating that most patients and families can experience a death in dignity when being cared for in palliative care or hospice units. PMID- 28615955 TI - Reply to Commentary on Our Paper "Palliative Care and Patient Autonomy." PMID- 28615956 TI - The role of long noncoding RNA-LET in cell proliferation and invasion of nasopharyngeal carcinoma and its mechanism. AB - LncRNA-LET, a recently identified long noncoding RNA, has been shown to act as a tumor suppressor; however, its biological function and mechanism have not been fully investigated. Our research found that there was less expression of LET in nasopharyngeal carcinoma (NPC) tissues than normal tissues and that LET might inhibit proliferation, adhesion and invasion of NPC in vitro by enhancing its expression. By contrast, decreased LET expression could promote the proliferation, adhesion and invasion of NPC. In addition, the expression profiles of related genes and MAPK/ERK pathway were also regulated effectively via overexpression or silencing of LET. This result provides comprehensive evidence of LET's antitumor effect on NPC in vitro, which might provide a new approach for clinical treatment. PMID- 28615957 TI - Erratum: Isoorientin induces apoptosis, decreases invasiveness, and downregulates VEGF secretion by activating AMPK signaling in pancreatic cancer cells [Corrigendum]. AB - [This corrects the article on p. 7481 in vol. 9, PMID: 28003763.]. PMID- 28615958 TI - The critical role of EGF-beta-catenin signaling in the epithelial-mesenchymal transition in human glioblastoma. AB - To date, beta-catenin has been reported to be implicated in mediating the epithelial-mesenchymal transition (EMT) in a variety of human cancers, which can be triggered by EGF. However, the mechanisms underlying EGF-beta-catenin pathway induced EMT of glioblastoma multiforme (GBM) have not been reported previously. In the present study, immunohistochemistry, reverse transcription polymerase chain reaction, and Western blot were applied to investigate the effect of EGF beta-catenin pathway on EMT of GBM. Here, we identified that beta-catenin mRNA and protein levels were up-regulated in GBM tissues and four kinds of glioblastoma cell lines, including T98G, A172, U87, and U251 cells, compared with normal brain tissue and astrocytes. In U87 cell line, inhibition of beta-catenin by siRNA suppressed EGF-induced proliferation, migration, invasiveness, and the expression of EMT activators (Snail and Slug). In addition, the expression of epithelial markers (E-cadherin) was up-regulated and the expression of mesenchymal markers (N-cadherin and MMP9) was down-regulated. Finally, inhibitor of PI3K/Akt signaling pathways inactivated the EGF-beta-catenin-induced EMT. In conclusion, beta-catenin-EMT pathway induced by EGF is important for GBM progression by the PI3K/Akt pathways. Inhibition of beta-catenin leads to suppression of EGF pathway-induced EMT, which provides a new way to treat GBM patients. PMID- 28615959 TI - Severe forms of fibromyalgia with acute exacerbation of pain: costs, comorbidities, and length of stay in inpatient care. AB - BACKGROUND AND PURPOSE: As a disease of the musculoskeletal system, fibromyalgia is becoming increasingly important, because of the direct and indirect costs to health systems. The purpose of this study of health economics was to obtain information about staff costs differentiated by service provider, and staff and material costs of the nonmedical infrastructure in inpatient care. PATIENTS AND METHODS: This study looked at 263 patients who received interdisciplinary inpatient treatment for severe forms of fibromyalgia with acute exacerbation of pain between 2011 and 2014. Standardized cost accounting and an analysis of additional diagnoses were performed. RESULTS: The average cost per patient was ?3,725.84, with staff and material costs of the nonmedical infrastructure and staff costs of doctors and nurses accounting for the highest proportions of the costs. Each fibromyalgia patient had an average of 6.1 additional diagnoses. CONCLUSION: Severe forms of fibromyalgia are accompanied by many concomitant diseases and associated with both high clinical staff costs and high medical and nonmedical infrastructure costs. Indication-based cost calculations provide important information for health policy and hospital managers if they include all elements that incur costs in both a differentiated and standardized way. PMID- 28615960 TI - Personalized multistep cognitive behavioral therapy for obesity. AB - Multistep cognitive behavioral therapy for obesity (CBT-OB) is a treatment that may be delivered at three levels of care (outpatient, day hospital, and residential). In a stepped-care approach, CBT-OB associates the traditional procedures of weight-loss lifestyle modification, ie, physical activity and dietary recommendations, with specific cognitive behavioral strategies that have been indicated by recent research to influence weight loss and maintenance by addressing specific cognitive processes. The treatment program as a whole is delivered in six modules. These are introduced according to the individual patient's needs in a flexible and personalized fashion. A recent randomized controlled trial has found that 88 patients suffering from morbid obesity treated with multistep residential CBT-OB achieved a mean weight loss of 15% after 12 months, with no tendency to regain weight between months 6 and 12. The treatment has also shown promising long-term results in the management of obesity associated with binge-eating disorder. If these encouraging findings are confirmed by the two ongoing outpatient studies (one delivered individually and one in a group setting), this will provide evidence-based support for the potential of multistep CBT-OB to provide a more effective alternative to standard weight-loss lifestyle-modification programs. PMID- 28615961 TI - The role of novel biomarkers in childhood idiopathic nephrotic syndrome: a narrative review of published evidence. AB - Two histological subtypes of idiopathic nephrotic syndrome are commonly recognized in children, namely minimal change nephropathy and focal segmental glomerulosclerosis. Children with minimal change nephropathy (the majority of whom are steroid-sensitive) and focal segmental glomerulosclerosis (the majority of whom are steroid-resistant) require early identification in order to ensure appropriate therapeutic intervention and better outcome. Although renal biopsy and histology remain the ideal diagnostic steps to identify these histological subtypes, reports indicate that serum and urinary biomarkers are now being utilized in the investigation of childhood idiopathic nephrotic syndrome. This paper aims to review the diagnostic and prognostic utility of novel biomarkers in childhood idiopathic nephrotic syndrome and to highlight their role in differentiating steroid-sensitive nephrotic syndrome (SRNS) from steroid resistant nephrotic syndrome (SSNS). Using the terms "idiopathic nephrotic syndrome," "children," and "biomarkers" the PubMed database was searched for relevant studies related to the topic. Biomarkers such as adiponectin, neopterin, beta2-microglobulin, and N-acetyl-beta-D glucosaminidase were reported as diagnostic markers. In addition to neopterin and N-acetyl-beta-D glucosaminidase, urine vitamin D-binding protein and alpha1beta-glycoprotein were shown to differentiate SRNS from SSNS while N-acetyl-beta-D glucosaminidase and beta2 microglobulin could predict steroid responsiveness and renal outcome in SRNS. Although progress has been made in demonstrating the diagnostic and prognostic utility of these biomarkers, their limited availability in most laboratories has precluded a complete paradigm shift from the conventional renal biopsy. Nevertheless, further longitudinal studies are required to establish their usefulness as noninvasive predictors of disease response to immunosuppressive therapy. PMID- 28615962 TI - Sensitivity to Pain Traumatization Scale: development, validation, and preliminary findings. AB - BACKGROUND: This article reports three studies describing the development and validation of the 12-item Sensitivity to Pain Traumatization Scale (SPTS-12). SPT refers to the anxiety-related cognitive, emotional, and behavioral reactions to pain that resemble the features of a traumatic stress reaction. METHODS: In Study 1, a preliminary set of 79 items was administered to 116 participants. The data were analyzed by using combined nonparametric and parametric item response theory resulting in a 12-item scale with a one-factor structure and good preliminary psychometric properties. Studies 2 and 3 assessed the factor structure and psychometric properties of the SPTS-12 in a community sample of 823 participants (268 with chronic pain and 555 pain-free) and a clinical sample of 345 patients (126 with chronic post-surgical pain, 92 with other nonsurgical chronic pain, and 127 with no chronic pain) at least 6 months after undergoing coronary artery bypass graft surgery, respectively. RESULTS: The final SPTS-12 derived from Study 1 comprised 12 items that discriminated between individuals with different levels of SPT, with the overall scale showing good to very good reliability and validity. The results from Studies 2 and 3 revealed a one-factor structure for chronic pain and pain-free samples, excellent reliability and concurrent validity, and moderate convergent and discriminant validity. CONCLUSION: The results of the three studies provide preliminary evidence for the validity and reliability of the SPTS-12. PMID- 28615963 TI - Frequency-dependent changes in sensorimotor and pain affective systems induced by empathy for pain. AB - BACKGROUND: Empathy for pain helps us to understand the pain of others indirectly. To better comprehend the processing of empathic pain, we report the frequency-dependent modulation of cortical oscillations induced by watching movies depicting pain using high-density electroencephalography (EEG), magnetoencephalography (MEG), and motor evoked potentials (MEP). METHODS: Event related desynchronization of EEG and MEG was assessed while participants viewed videos of painful (needle) or neutral (cotton swab) situations. The amplitudes of MEPs were also compared between the needle and cotton swab conditions. RESULTS: The degree of suppression in alpha/beta band power was significantly increased, whereas that of gamma band power was significantly decreased, in the needle condition compared with the cotton swab condition. EEG revealed that significant differences in alpha/beta band were distributed in the right frontocentral and left parietooccipital regions, whereas significant gamma band differences were distributed predominantly over the right hemisphere, which were confirmed by source estimation using MEG. There was a significant positive correlation between the difference in gamma power of the two conditions and the visual analog scale subjective rating of aversion, but not in the alpha/beta band. The amplitude of MEPs decreased in the needle condition, which confirmed the inhibition of the primary motor cortex. CONCLUSION: MEP suppression supports that modulation of cortical oscillations by viewing movies depicting pain involves sensorimotor processing. Our results suggest that alpha/beta oscillations underlie the sensory qualities of others' pain, whereas the gamma band reflects the cognitive aspect. Therefore, alpha/beta and gamma band oscillations are differentially involved in empathic pain processing under the condition of motor cortical suppression. PMID- 28615964 TI - Development and performance of a diagnostic/prognostic scoring system for breakthrough pain. AB - OBJECTIVES: Variable prevalence and treatment of breakthrough pain (BTP) in different clinical contexts are partially due to the lack of reliable/validated diagnostic tools with prognostic capability. We report the statistical basis and performance analysis of a novel BTP scoring system based on the naive Bayes classifier (NBC) approach and an 11-item IQ-BTP validated questionnaire. This system aims at classifying potential BTP presence in three likelihood classes: "High," "Intermediate," and "Low." METHODS: Out of a training set of n=120 mixed chronic pain patients, predictors associated with the BTP likelihood variables (Pearson's chi2 and/or Fisher's exact test) were employed for the NBC planning. Adjusting the binary classification to a three-likelihood classes case enabled the building of a scoring algorithm and to retrieve the score of each predictor's answer options and the Patient's Global Score (PGS). The latter medians were used to establish the NBC thresholds, needed to evaluate the scoring system performance (leave-one-out cross-validation). RESULTS: Medians of PGS in the "High," "Intermediate," and "Low" likelihood classes were 3.44, 1.53, and -2.84, respectively. Leading predictors for the model (based on score differences) were flair frequency (DeltaS=1.31), duration (DeltaS=5.25), and predictability (DeltaS=1.17). Percentages of correct classification were 63.6% for the "High" and of 100.0% for either the "Intermediate" and "Low" likelihood classes; overall accuracy of the scoring system was 90.9%. CONCLUSION: The NBC-based BTP scoring system showed satisfactory performance in classifying potential BTP in three likelihood classes. The reliability, flexibility, and simplicity of this statistical approach may have significant relevance for BTP epidemiology and management. These results need further impact studies to generalize our findings. PMID- 28615965 TI - Impact of a value-based insurance design for physical therapy to treat back pain on care utilization and cost. AB - OBJECTIVE: To assess the impact of a value-based insurance design providing enhanced access to physical therapy (PT) for treatment of back pain on treatment patterns and cost of care. STUDY DESIGN: A retrospective analysis of claims data obtained from Geisinger Health Plan (GHP). In April 2013, GHP began offering "PT bundle" - i.e., a bundle of up to five PT visits for a single one-time copay that can be renewed for another bundle of five PT visits - for its employer-based plan members with back pain. METHODS: A cohort of GHP members who were preauthorized for the PT bundle were compared against a contemporaneous cohort of GHP members who were preauthorized for PT under the standard per-visit copay arrangement between January 2013 and October 2014. RESULTS: Among the PT bundle cohort, the PT visit rate during the first 9 months since the PT preauthorization date had dramatically increased and then gradually decreased in subsequent months. The PT bundle was also associated with 29%-35% short-term reductions in emergency department visits and with 12%-20% reductions in primary care visits after 6 months. No significant impact on hospitalization or cost was observed. CONCLUSION: Implementation of the PT bundle appears to have led to a change in the treatment pattern of back pain that is more consistent with the recommended guidelines to use more conservative management such as PT as the first-line treatment for back pain. PMID- 28615966 TI - Acute physiological and electrical accentuation of vagal tone has no effect on pain or gastrointestinal motility in chronic pancreatitis. AB - BACKGROUND: The effective management of pain in chronic pancreatitis (CP) remains a therapeutic challenge. Analgesic drugs, such as opioids, and the underlying pathology can impair gut function. The autonomic nervous system influences hormone secretion and gut motility. In healthy volunteers, electrical (using noninvasive transcutaneous vagal nerve stimulation [t-VNS]) and physiological (using deep slow breathing [DSB]) modulation of parasympathetic tone results in pain attenuation and enhanced gut motility. Thus, the aims were to investigate whether t-VNS and DSB could enhance the parasympathetic tone, decrease pain sensitivity and improve gut motility in CP. PATIENTS AND METHODS: A total of 20 patients (12 males, mean age=61 years, range: 50-78 years) with CP were randomized to short-term (60 minutes) t-VNS and DSB, or their placebo equivalent, in a crossover design. Cardiometrically derived parameters of autonomic tone, quantitative sensory testing of bone and muscle pain pressure, conditioned pain modulation (CPM) and assessments of gastroduodenal motility with ultrasound were performed. RESULTS: In comparison to sham, t-VNS and DSB increased cardiac vagal tone (CVT) (P<0.001). However, no changes in pain pressure thresholds for bone (P=0.95) or muscle (P=0.45) were seen. There was diminished CPM (P=0.04), and no changes in gastroduodenal motility were observed (P=0.3). CONCLUSION: This explorative study demonstrated that t-VNS and DSB increased CVT in patients with CP. However, this short-lasting increase did not affect pain sensitivity to musculoskeletal pain or gastroduodenal motility. The chronic pain in CP patients is complex, and future trials optimizing neuromodulation for pain relief and improved motility are needed. PMID- 28615967 TI - Assessment of direct analgesic effect of duloxetine for chronic low back pain: post hoc path analysis of double-blind, placebo-controlled studies. AB - BACKGROUND: Comorbid depression and depressive symptoms are common in patients with chronic low back pain (CLBP). Duloxetine is clinically effective in major depressive disorder and several chronic pain states, including CLBP. The objective of this post hoc meta-analysis was to assess direct and indirect analgesic efficacy of duloxetine for patients with CLBP in previous clinical trials. METHODS: Post hoc path analyses were conducted of 3 randomized, double blind, clinical studies of patients receiving duloxetine or placebo for CLBP. The primary outcome measure for pain was the Brief Pain Inventory, average pain score. A secondary outcome measure, the Beck Depression Inventory-II, was used for depressive symptoms. The changes in score from baseline to endpoint were determined for each index. Path analyses were employed to calculate the proportion of analgesia that may be attributed to a direct effect of duloxetine on pain. RESULTS: A total of 851 patients (400 duloxetine and 451 placebo) were included in this analysis. Duloxetine significantly improved pain scores compared with placebo (p<0.001). It also significantly improved depressive scores compared with placebo (p=0.015). Path analyses showed that 91.1% of the analgesic effect of duloxetine could be attributed to a direct analgesic effect, and 8.9% to its antidepressant effect. Similar results were obtained when data were evaluated at weeks 4 and 7, and when patients were randomized to subgroups based on baseline pain scores, baseline depressive symptoms scores, and gender. CONCLUSION: Duloxetine significantly improved pain in patients with CLBP. Path analyses results suggest that duloxetine produced analgesia mainly through mechanisms directly impacting pain modulation rather than lifting depressive symptoms. This effect was consistent across all subgroups tested. PMID- 28615968 TI - Effects of dezocine on prevention of propofol injection pain: a meta-analysis. AB - OBJECTIVE: The objective of this study was to evaluate the effects of dezocine on the prevention of propofol injection pain. MATERIALS AND METHODS: We searched for randomized controlled trials (RCTs) of dezocine in preventing propofol injection pain, from inception to April 2016, in PubMed, Embase, Cochrane Library, and CNKI. Next, two reviewers independently screened literature, extracted data, and assessed quality in accordance with the inclusion and exclusion criteria. Finally, RevMan 5.2 software was used to conduct a meta-analysis. RESULTS: Seven RCTs totaling 630 patients were included in this meta-analysis. The meta-analysis study showed: 1) compared with the control group (relative risk [RR] =0.32, 95% CI [0.26, 0.39], P<0.00001), the dezocine group showed a decreasing incidence of propofol injection pain; 2) for severity of propofol injection pain, incidences of mild pain (RR =0.55, 95% CI [0.40, 0.75], P=0.0001), moderate pain (RR =0.28, 95% CI [0.18, 0.43], P<0.00001), and severe pain (RR =0.11, 95% CI [0.06, 0.23], P<0.00001) were considerably lower in the dezocine group than in the control group; 3) when comparing the incidence of propofol injection pain in the dezocine group with that of the lidocaine group, no statistically significant differences were found (RR =0.86, 95% CI [0.66, 1.13], P=0.29); and 4) subgroup analysis indicated a significant reduction in the incidence of propofol injection. CONCLUSION: Dezocine can both prevent propofol injection pain and mitigate its severity, and its efficacy shows no significant difference from that of lidocaine. PMID- 28615969 TI - A Behavioral Survey of the Effects of Kavalactones on Caenorhabditis elegans Neuromuscular Transmission. AB - Kava is a plant root extract that is widely consumed by Pacific Islanders. Kava contains a class of lactone compounds called kavalactones. The sedative and anxiolytic effects of kava are likely attributed to the efficacies of kavalactones on the nervous system. Although some studies have implicated the potencies of certain kavalactone species on gamma-aminobutyric acid transmission, evidence supporting the action of kavalactones on the eukaryotic neuromuscular junction (NMJ) and acetylcholine (ACh) transmission is scant. Here, we used behavioral assays to demonstrate the effects of kavalactones at the Caenorhabditis elegans NMJ. Our results suggest that kavalactones disrupt the inhibitory-excitatory balance at the NMJ. Such perturbation of NMJ activity is likely due to excess or prolonged ACh transmission. In addition, we found that kavain, a major constituent of kava, induced worm paralysis but not convulsions. Hence, the modulatory action of kavain could be distinct from the other kavalactone species. PMID- 28615970 TI - Changes in pulmonary function tests in breast carcinoma patients treated with locoregional post-mastectomy radiotherapy: results of a pilot study. AB - BACKGROUND: The aim of present pilot study was to evaluate the changes in pulmonary function tests (PFTs) after locoregional post-mastectomy radiotherapy (PMRT) in breast cancer patients. MATERIALS AND METHODS: Twenty consecutive patients with histopathologically confirmed breast carcinoma stages T1-T4, N1-N2, who were treated with modified radical mastectomy with neoadjuvant or adjuvant chemotherapy underwent PFTs, including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced expiratory flow at 50%, and peak expiratory flow rate, maximum mid expiratory flow (MMEF25-75), maximal oxygen consumption (VO2max), and carbon monoxide diffusing capacity (DLCO) before, at 30 days, and at 90 days after locoregional PMRT. A two-tailed paired Student's t test was used to compare mean values among the variables between the groups. RESULTS: A significant drop in FVC, FEV1, and DLCO was noticed at day 90 after the completion of locoregional PMRT with P-values 0.033, 0.042, and 0.031, respectively, while MMEF25-75 and VO2max were not significantly affected (P values 0.075 and 0.062, respectively) favoring a restrictive lung injury pattern. However, no patient was found to be symptomatic. CONCLUSION: A significant drop in reduction in PFTs occurred at day 90 after the completion of locoregional PMRT. PFTs shall be performed in all breast cancer patients receiving locoregional PMRT for early detection of radiation-induced lung toxicity as all patients in our cohort were found asymptomatic. PMID- 28615971 TI - Clinical use of the Oncotype DX genomic test to guide treatment decisions for patients with invasive breast cancer. AB - Implementation of the Oncotype DX assay has led to a change in the manner in which chemotherapy is utilized in patients with early stage, estrogen receptor (ER)-positive, node-negative breast cancer; ensuring that patients at highest risk of recurrence are prescribed systemic treatment, while at the same time sparing low-risk patients potential adverse events from therapy unlikely to influence their survival. This test generates a recurrence score between 0 and 100, which correlates with probability of distant disease recurrence. Patients with low-risk recurrence scores (0-17) are unlikely to derive significant survival benefit with adjuvant chemotherapy and hormonal agents derived from using adjuvant hormonal therapy only. Conversely, adjuvant chemotherapy has been shown to significantly improve survival in patients with high-risk recurrence scores (>=31). Trials are ongoing to determine how best to manage patients with recurrence scores in the intermediate range. This review outlines the introduction and impact of Oncotype DX testing on practice; ongoing clinical trials investigating its utility; and challenging clinical scenarios where the absolute recurrence score may require careful interpretation. We also performed a bibliometric analysis of publications on the topics of breast cancer and Oncotype DX as a surrogate marker of acceptability and incorporation of the assay into the management of patients with breast cancer. PMID- 28615972 TI - Single nucleotide polymorphisms and unacceptable late toxicity in breast cancer adjuvant radiotherapy: a case report. AB - BACKGROUND: There has recently been a strong interest in the inter-individual variation in normal tissue and tumor response to radiotherapy (RT), because tissue radiosensitivity seems to be under genetic control. Evidence is accumulating on the role of polymorphic genetic variants, such as single nucleotide polymorphisms (SNPs) that could influence normal tissue response after radiation. The most studied SNPs include those in genes involved in DNA repair (single- and double-strand breaks, and base excision) and those active in the response to oxidative stress. CASE REPORT: We present the case report of a 60 year-old woman with early breast cancer who underwent adjuvant hormone therapy and conventional radiotherapy, and subsequently developed unacceptable cosmetic toxicities of the irradiated breast requiring a genetic test of genes involved in DNA repair mechanisms. The patient was found to be heterozygous for G28152A (T/C) and C18067T (A/G) mutations in X-ray repair cross-complementing group 1 (XRCC1) and 3 (XRCC3), respectively, homozygous for A313G (G/G) mutation in glutathione S transferase Pi 1 (GSTP1), and wild-type for A4541G (A/A) in XRCC3 and G135C (G/G) in RAD51 recombinase. CONCLUSION: The role of SNPs should be taken into account when a severe phenomenon appears in normal tissues after radiation treatment, because understanding the molecular basis of individual radiosensitivity may be useful for identifying moderately or extremely radiosensitive patients who may need tailored therapeutic strategies. PMID- 28615973 TI - Can biosimilars help achieve the goals of US health care reform? AB - The US Patient Protection and Affordable Care Act (ACA) aims to expand health care coverage, contain costs, and improve health care quality. Accessibility and affordability of innovative biopharmaceuticals are important to the success of the ACA. As it is substantially more difficult to manufacture them compared with small-molecule drugs, many of which have generic alternatives, biologics may increase drug costs. However, biologics offer demonstrated improvements in patient care that can reduce expensive interventions, thus lowering net health care costs. Biosimilars, which are highly similar to their reference biologics, cost less than the originators, potentially increasing access through reduced prescription drug costs while providing equivalent therapeutic results. This review evaluates 1) the progress made toward enacting health care reform since the passage of the ACA and 2) the role of biosimilars, including the potential impact of expanded biosimilar use on access, health care costs, patient management, and outcomes. Barriers to biosimilar adoption in the USA are noted, including low awareness and financial disincentives relating to reimbursement. The evaluated evidence suggests that the ACA has partly achieved some of its aims; however, the opportunity remains to transform health care to fully achieve reform. Although the future is uncertain, increased use of biosimilars in the US health care system could help achieve expanded access, control costs, and improve the quality of care. PMID- 28615974 TI - Presurgical cleft lip and palate orthopedics: an overview. AB - Patients with cleft lip and/or palate go through a lifelong journey of multidisciplinary care, starting from before birth and extending until adulthood. Presurgical orthopedic (PSO) treatment is one of the earliest stages of this care plan. In this paper we provide a review of the PSO treatment. This review should help general and specialist dentists to better understand the cleft patient care path and to be able to answer patient queries more efficiently. The objectives of this paper were to review the basic principles of PSO treatment, the various types of techniques used in this therapy, and the protocol followed, and to critically evaluate the advantages and disadvantages of some of these techniques. In conclusion, we believe that PSO treatment, specifically nasoalveolar molding, does help to approximate the segments of the cleft maxilla and does reduce the intersegment space in readiness for the surgical closure of cleft sites. However, what we remain unable to prove equivocally at this point is whether the reduction in the dimensions of the cleft presurgically and the manipulation of the nasal complex benefit our patients in the long term. PMID- 28615975 TI - Pre-exposure prophylaxis for HIV prevention in women: current perspectives. AB - There are ~900,000 new HIV infections among women every year, representing nearly half of all new HIV infections globally. In the US, nearly one-fifth of all new HIV infections occur among women, and women from racial and ethnic minority communities experience disproportionately high rates of new HIV infections. Thus, there is a need to develop and implement effective HIV prevention strategies for women in the US and internationally, with a specific need to advance strategies in minority communities. Previous studies have demonstrated that oral HIV pre exposure prophylaxis (PrEP), the use of antiretroviral medications by HIV uninfected persons to prevent HIV acquisition, can reduce HIV incidence among women who are adherent to PrEP. However, to date, awareness and uptake of PrEP among women have been very limited, suggesting a need for innovative strategies to increase the knowledge of and access to PrEP among women in diverse settings. This narrative review summarizes the efficacy and safety data of PrEP in women, discusses considerations related to medication adherence for women who use PrEP, and highlights behavioral, social, and structural barriers to maximize the effectiveness of PrEP in women. It also reviews novel modalities for PrEP in women which are being developed and tested, including topical formulations and long-acting injectable agents that may offer advantages as compared to oral PrEP and proposes a community-oriented, social networking framework to increase awareness of PrEP among women. If women are provided with access to PrEP and support to overcome social and structural barriers to adhere to PrEP, this prevention strategy holds great promise to impact the HIV epidemic among women in the US and globally. PMID- 28615976 TI - Clinical utility of neurostimulation devices in the treatment of overactive bladder: current perspectives. AB - OBJECTIVES: This review describes the evidence from established and experimental therapies that use electrical nerve stimulation to treat lower urinary tract dysfunction. METHODS: Clinical studies on established treatments such as percutaneous posterior tibial nerve stimulation (P-PTNS), transcutaneous electrical nerve stimulation (TENS), sacral nerve stimulation (SNS) and sacral anterior root stimulation (SARS) are evaluated. In addition, clinical evidence from experimental therapies such as dorsal genital nerve (DGN) stimulation, pudendal nerve stimulation, magnetic nerve stimulation and ankle implants for tibial nerve stimulation are evaluated. RESULTS: SNS and P-PTNS have been investigated with high-quality studies that have shown proven efficacy for the treatment for overactive bladder (OAB). SARS has proven evidence-based efficacy in spinal cord patients and increases the quality of life. TENS seems inferior to other OAB treatments such as SNS and P-PTNS but is noninvasive and applicable for ambulant therapy. Results from studies on experimental therapies such as pudendal nerve stimulation seem promising but need larger study cohorts to prove efficacy. CONCLUSION: Neurostimulation therapies have proven efficacy for bladder dysfunction in patients who are refractory to other therapies. SIGNIFICANCE: Refinement of neurostimulation therapies is possible. The aim should be to make the treatments less invasive, more durable and more effective for the treatment of lower urinary tract dysfunction. PMID- 28615977 TI - High lateral plantar pressure is related to an increased tibialis anterior/fibularis longus activity ratio in patients with recurrent lateral ankle sprain. AB - INTRODUCTION: Center of pressure (COP) is a sudden displacement at the time of a lateral ankle sprain (LAS). It has been suggested that the distribution of plantar pressure and the quantity of COP displacement are important for assessing the risk of LAS. Therefore, we evaluated the plantar pressure during a single-leg balance test with eyes closed (SLB-C) to identify the factors and characteristics of plantar pressure in people with repeated cases of LAS. METHODS: We recruited 22 collegiate athletes and divided them into an instability group (IG; n=11) and a control group (CG; n=11). We measured the distribution of plantar pressure and lower extremity muscle activity during a SLB-C along with static alignment and isometric ankle strength. RESULTS: The fibularis longus (FL) activity was significantly lower in the IG than in the CG. The lateral plantar pressure (LPP)/medial plantar pressure (MPP) ratio was also higher in the IG than in the CG. In addition, the LPP/MPP ratio was correlated with the tibialis anterior (TA)/FL ratio. CONCLUSION: These results suggest that increased lateral plantar pressure is related to decreased FL activity and increased TA/FL ratio. PMID- 28615978 TI - Clinical characteristics and outcomes of cancer patients with post-chemotherapy arthritis: a retrospective case series report. AB - OBJECTIVE: The objective of this report was to describe the demographics, clinical characteristics and outcomes of patients with cancer presenting with arthritis following chemotherapy in Jeddah, Saudi Arabia. PATIENTS AND METHODS: This is a retrospective case series report. We included any patient >=18 years of age with an established diagnosis of cancer who had received standard therapeutic intervention and was subsequently diagnosed with arthritis after developing rheumatic symptoms either during or after treatment. Patients with clinical evidence of arthritis at the time of their cancer diagnosis were excluded. RESULTS: Seven cases from different centers were identified. Breast cancer was the most common type of cancer reported. The diagnosis of arthritis was established by a rheumatologist. Bilateral involvement of the metacarpophalangeal and proximal interphalangeal joints was the most common presentation. The knee, back, shoulder and wrist joints were less affected. Following treatment, one patient experienced complete resolution of symptoms, four patients symptomatically improved and one patient had no improvement. CONCLUSION: Arthritis can develop both during and after treatment of a malignancy. Solid tumors seem to be more commonly associated with this phenomenon. In this case series, the prognosis was poor as the majority of patients developed persistent arthritis. PMID- 28615979 TI - Erratum: Gender stereotypes in occupational choice: a cross-sectional study on a group of Italian adolescents [Erratum]. AB - [This corrects the article on p. 109 in vol. 10, PMID: 28458587.]. PMID- 28615980 TI - Household flood preparedness and associated factors in the flood-prone community of Dembia district, Amhara National Regional State, northwest Ethiopia. AB - BACKGROUND: Flood preparedness empowers the community to respond effectively to related hazards. However, there was no research done in the country concerning household flood preparedness. Therefore, the aim of this study was to assess household flood preparedness and associated factors in the flood-prone community of Dembia district, northwest Ethiopia. METHODS: A community-based cross sectional study was conducted from March to April 2014 in the Dembia district. A two-stage sampling technique was used. The study was conducted using 806 flood prone participants. An interviewer-administered questionnaire was used to collect data. The collected data were entered using Epi info version 3.5.1 and transported into SPSS version 16 for further analysis. Descriptive and analytic statistics were computed. Variables having association with the outcome variable were reported using odds ratio with 95% confidence interval (CI). Model fitness was checked by Hosmer and Lemeshew chi-square test. RESULTS: Household flood preparedness was found to be 24.4%. The age group of >= 46 years (adjusted odds ratio [AOR]=2.62; 95% CI: 1.12, 6.00) above, monthly household income >893 Ethiopian Birr, (AOR=6.72; 95% CI: 2.2 7, 19.88) attending primary level education (AOR=22.08; 95% CI: 8.16, 59.74), warning system in household (AOR=5.41; 95% CI: 2.38, 12.32), knowledge of flood prevention, (AOR=2.52; 95% CI: 1.43, 5.57) were positively associated with household flood preparedness. CONCLUSION AND RECOMMENDATION: This study has demonstrated that household flood preparedness was found to be low in the study area. Household flood preparedness was significantly associated with the older age group, attending primary level education, having a higher monthly income, receive household level warning messages, having knowledge on preparedness, prior exposure to a flood, and length of flood >6 days. Strengthening household flood preparedness in advance is important in order to prevent flood and its related consequences. PMID- 28615981 TI - Human taeniasis: current insights into prevention and management strategies in endemic countries. AB - Human taeniasis is a zoonotic condition resulting from infection with the adult stages of Taenia saginata ("beef tapeworm"), Taenia solium ("pork tapeworm") or Taenia asiatica ("Asian tapeworm"). Although these parasites have a worldwide distribution, the overwhelming burden is felt by communities in low- and middle income countries. This is particularly true for T. solium, whereby infection of the central nervous system with the larval stage of the parasite (neurocysticercosis) is a major cause of acquired epilepsy in low-resource settings. With a focus on endemic countries, this review provides an insight into the prevention and management of human taeniasis, concluding with some recent case studies describing their implementation. Discussion of the opportunities and challenges regarding current fecal and serological diagnostic assays for detecting Taenia spp. highlights the importance of accurate and accessible diagnostic options for the field situation. The lack of long-term impact on the parasites' lifecycle from human anthelmintic treatment, coupled with the propensity for adverse reactions, highlights the importance of a "two-pronged" approach that considers the relevant animal hosts, particularly in the case of T. solium. Aside from the therapeutic options, this review reiterates the importance of adequate assessment and consideration of the associated behavioral and policy aspects around sanitation, hygiene and meat inspection that have been shown to support parasite control, and potential elimination, in endemic regions. PMID- 28615983 TI - Legionnaires' Disease: Clinicoradiological Comparison of Sporadic Versus Outbreak Cases. AB - BACKGROUND: In 2015, New York City experienced the worst outbreak of Legionnaires' disease in the history of the city. We compare patients seen during the 2015 outbreak with sporadic cases of Legionella during the past 5 years. METHODS: We conducted a retrospective chart review of 90 patients with Legionnaires' disease, including sporadic cases of Legionella infection admitted from 2010 to 2015 (n = 55) and cases admitted during the 2015 outbreak (n = 35). RESULTS: We saw no significant differences between the 2 groups regarding demographics, smoking habits, alcohol intake, underlying medical disease, or residence type. Univariate and multivariate analyses showed that patients with sporadic case of Legionella had a longer stay in the hospital and intensive care unit as well as an increased stay in mechanical ventilation. Short-term mortality, discharge disposition, and most clinical parameters did not differ significantly between the 2 groups. CONCLUSIONS: We found no specific clinicoradiological characteristics that could differentiate sporadic from epidemic cases of Legionella. Early recognition and high suspicion for Legionnaires' disease are critical to provide appropriate treatment. Cluster of cases should increase suspicion for an outbreak. PMID- 28615982 TI - Family-based treatment of eating disorders in adolescents: current insights. AB - Eating disorders are serious illnesses associated with significant morbidity and mortality. Family-based treatment (FBT) has emerged as an effective intervention for adolescents with anorexia nervosa, and preliminary evidence suggests that it may be efficacious in the treatment of adolescents with bulimia nervosa. Multifamily therapy for anorexia nervosa provides a more intensive experience for families needing additional support. This review outlines the three phases of treatment, key tenets of family-based treatment, and empirical support for FBT. In addition, FBT in higher levels of care is described, as well as challenges in the implementation of FBT and recent adaptations to FBT, including offering additional support to eating-disorder caregivers. Future research is needed to identify families for whom FBT does not work, determine adaptations to FBT that may increase its efficacy, develop ways to improve treatment adherence among clinicians, and find ways to support caregivers better during treatment. PMID- 28615984 TI - Papillary Thyroid Microcarcinoma Arising Within a Mature Ovarian Teratoma: Case Report and Review of the Literature. AB - Mature cystic teratoma is the most common kind of ovarian germ cell tumor. Malignant transformation is uncommon, with thyroid cancer rarely found. Papillary thyroid microcarcinoma has rarely been described as associated with ovarian teratomas. We report a case of a 34-year-old woman who presented with abdominal pain and an ovarian mass. After surgery, the patient was diagnosed with a follicular variant papillary thyroid microcarcinoma that arose within a mature cystic ovarian teratoma. Based on the small size of the primary lesion and patient preferences, no further treatment was performed. To our knowledge, this is the third reported case of papillary thyroid microcarcinoma arising within a mature ovarian teratoma without struma ovarii. There is no consensus on the surgical approach and postoperative management of this condition. Whether further therapy with total thyroidectomy and radioiodine ablation may be beneficial is unknown. In conclusion, papillary thyroid microcarcinoma can also arise within mature ovarian teratomas. Although a favorable prognosis is anticipated, there is limited information about its history or prognosis. PMID- 28615985 TI - Treatment of Movement Disorders With Focused Ultrasound. AB - Although the use of ultrasound as a potential therapeutic modality in the brain has been under study for several decades, relatively few neuroscientists or neurologists are familiar with this technology. Stereotactic brain lesioning had been widely used as a treatment for medically refractory patients with essential tremor (ET), Parkinson disease (PD), and dystonia but has been largely replaced by deep brain stimulation (DBS) surgery, with advantages both in safety and efficacy. However, DBS is associated with complications including intracerebral hemorrhage, infection, and hardware malfunction. The occurrence of these complications has spurred interest in less invasive stereotactic brain lesioning methods including magnetic resonance imaging-guided high intensity-focused ultrasound (FUS) surgery. Engineering advances now allow sound waves to be targeted noninvasively through the skull to a brain target. High intensities of sonic energy can create a coagulation lesion similar to that of older radiofrequency stereotactic methods, but without opening the skull, recent Food and Drug Administration approval of unilateral thalamotomy for treatment of ET. Clinical studies of stereotactic FUS for aspects of PD are underway. Moderate intensity, pulsed FUS has also demonstrated the potential to safely open the blood-brain barrier for localized delivery of therapeutics including proteins, genes, and cell-based therapy for PD and related disorders. The goal of this review is to provide basic and clinical neuroscientists with a level of understanding to interact with medical physicists, biomedical engineers, and radiologists to accelerate the application of this powerful technology to brain disease. PMID- 28615986 TI - Mortality, stroke, and heart failure in atrial fibrillation cohorts after ablation versus propensity-matched cohorts. AB - BACKGROUND: We sought to determine from key clinical outcomes whether catheter ablation of atrial fibrillation (AF) is associated with increased survival. METHODS AND RESULTS: Using routinely collected hospital data, ablation patients were matched to two control cohorts using direct and propensity score methodology. Four thousand nine hundred ninety-one ablation patients were matched 1:1 with general AF controls without ablation. Five thousand four hundred seven ablation patients were similarly matched to controls who underwent cardioversion. We examined the rates of ischemic stroke or transient ischemic attack (stroke/TIA), heart failure hospitalization, and death. Matched populations had very similar comorbidity profiles, including nearly identical CHA2DS2-VASc risk distribution (p=0.6948 and p=0.8152 vs general AF and cardioversion cohorts). Kaplan-Meier models showed increased survival after ablation for all outcomes compared with both control cohorts (p<0.0001 for all outcomes vs general AF, p=0.0087 for stroke/TIA, p<0.0001 for heart failure, and p<0.0001 for death vs cardioversion). Cox regression models also showed improved survival after ablation for all outcomes compared with the general AF cohort (hazard ratio [HR]=0.4, 95% confidence interval [95% CI]: 0.3-0.6, p<0.0001 for stroke/TIA; HR=0.4, 95% CI: 0.2-0.6, p<0.0001 for heart failure; HR=0.1, 95% CI: 0.1-0.1, p<0.0001 for death) and the cardioversion cohort (HR=0.6, 95% CI: 0.4-0.9, p=0.0111 for stroke/TIA; HR=0.4, 95% CI: 0.3-0.6, p<0.0001 for heart failure; HR=0.3, 95% CI:0.2-0.5, p<0.0001 for death). CONCLUSIONS: Catheter ablation of AF was associated with very significant reductions in mortality, stroke/TIA, and heart failure compared with a matched general AF population and a matched population who underwent cardioversion. Potential confounding of outcomes was minimized by very tight cohort matching. PMID- 28615987 TI - Stroke rates before and after ablation of atrial fibrillation and in propensity matched controls in the UK. AB - BACKGROUND: We sought to determine whether catheter ablation of atrial fibrillation (AF) is associated with reduced occurrence of ischemic cerebrovascular events. METHODS AND RESULTS: Using routinely collected hospital data, ablation patients were matched to two control cohorts via direct and propensity score matching. A total of 4,991 ablation patients were matched 1:1 to general AF controls with no ablation, and 5,407 ablation patients were similarly matched to controls who underwent cardioversion. Yearly rates of ischemic stroke or transient ischemic attack (stroke/TIA) before and after an index date were compared between cohorts. Index date was defined as the first ablation, the first cardioversion, or the second AF event in the general AF cohort. Matched populations had very similar demographic and comorbidity profiles, including nearly identical CHA2DS2-VASc risk distribution (p-values 0.6948 and 0.8152 vs general AF and cardioversion cohorts). Statistical models of stroke/TIA risk in the preindex period showed no difference in annual event rates between cohorts (mean+/-standard error 0.30% +/- 0.08% ablation vs 0.28% +/- 0.07% general AF, p=0.8292; 0.37% +/- 0.09% ablation vs 0.42% +/- 0.08% cardioversion, p=0.5198). Postindex models showed significantly lower annual rates of stroke/TIA in ablation patients compared with each control group over 5 years (0.64% +/- 0.11% ablation vs 1.84% +/- 0.23% general AF, p<0.0001; 0.82% +/- 0.15% ablation vs 1.37% +/- 0.18% cardioversion, p=0.0222). CONCLUSION: Matching resulted in cohorts having the same baseline risks and rates of ischemic cerebrovascular events. After the index date, there were significantly lower yearly event rates in the ablation cohort. These results suggest the divergence in outcome rates stems from variance in the treatment pathways beginning at the index date. PMID- 28615988 TI - Identification and control of an isolated, but intense focus of lymphatic filariasis on Satawal Island, Federated States of Micronesia, in 2003. AB - BACKGROUND: There is very limited data available on the prevalence of Bancroftian filariasis in the Federated States of Micronesia (FSM). Considerable attempts to eliminate the disease had occurred in the Pacific region by the year 2003, and the prevalence in FSM was thought to be sufficiently low that the region was considered non-endemic. However, a survey conducted in 2003 on an isolated atoll of FSM, Satawal Island, challenged that assumption. METHODS: Participants on Satawal Island were recruited and their blood tested for Wuchereria bancrofti antigen by the filariasis immunochromatographic test (ICT) card and circulating microfilaria by Knott's concentration technique. A survey for active cases of lymphoedema, elephantiasis and hydrocoele was performed and mosquitoes were trapped and dissected to detect larvae of W. bancrofti. RESULTS: A total of 104 males and 149 females from early teens to mid-80s were tested. Men had a significantly higher prevalence of infection than women in both the ICT test (53 vs 28%; p < 0.001) and by Knott's concentration results (37 vs 11%; p < 0.001). Microfilaria prevalence was higher in subjects <=25 than in those >25 years of age. All persons sampled were treated for LF. No cases of elephantiasis or hydrocoele were detected. No Aedes dissected were positive but three of nine culicine mosquitoes were positive for L1-3 larval stages of W. bancrofti by microscopy. In depth interviews were conducted with residents and chiefs. CONCLUSIONS: This survey showed that even in regions thought to be close to elimination, isolated high intensity foci of lymphatic filariasis may occur. These need to be recognized and control measures instituted such as local MDA as in the current study. PMID- 28615989 TI - Factors that influence the clinical utilization of the nursing process at a hospital in Accra, Ghana. AB - BACKGROUND: The nursing process is a tool that is recommended for use by all professional nurses working in Ghana, in order to provide nursing care. However, there is currently a limited use of this tool by nurses in Ghana. The purpose of this research study was to explore the various factors that influence the utilization of this nursing process. METHOD: An exploratory descriptive qualitative-research design was employed. Ten participants were involved by using the purposive sampling method. A semi-structured interview guide was used to collect the data from the research participants; and the data were analysed by using content analysis. One main theme, with five subthemes, emerged from the analysis. RESULTS: It was found that there are factors, such as nurses not having a better understanding of the nursing process, whilst in school; the absence of the care plan in the ward, as well as the lack of adequate staff, with limited time being available for coping with contributed to the non-usage of the nursing process. CONCLUSIONS: We conclude that the clinical utilization of the Nursing process at the clinical setting is influenced by lack of understanding of Nurses on the Nursing process and care plan as well as lack of adequate nurses and time. We recommend that the care-plan form be made officially a part of the admission documents. Furthermore, the nursing administration should put measures in place to provide nurses with the needed resources to implement the nursing process. Additionally, they should ensure that the care-plan forms and other resources needed by the nurses are regularly and adequately provided. Nurses should further see the nursing process as a means of providing comprehensive care to their patients and addressing their specific problems. They should therefore make time despite their busy schedules to use it in order to improve quality of care and the image of nursing in Ghana. PMID- 28615990 TI - The challenges and opportunities of translating best practice immunisation strategies among low performing general practices to reduce equity gaps in childhood immunisation coverage in New Zealand. AB - BACKGROUND: Immunisation coverage rates vary considerably at the local level across New Zealand and challenges remain with effectively translating best available research evidence into public health practice. This study aimed to translate best practices from high performing general practices into strategies to improve childhood immunisation coverage among low performing practices. METHODS: An intervention study was undertaken of general practices with low immunisation coverage rates and a high percentage of the enrolled population being of Maori ethnicity. Intervention groups received customised action plans and support for a 12 month period while control groups received 'business as usual' support. Structured interviews were conducted with key informants from all participating practices to understand current aspects related to childhood immunisation delivery and surveys were conducted to understand how the intervention worked. Collected data were thematically analysed. RESULTS: Ten sites were randomised to either intervention (n = 6) or control group (n = 4). Positive aspects of childhood immunisation delivery included high prioritisation at the practice and staff being pro-immunisation and knowledgeable. Key challenges experienced included inaccurate family contact information and discrepancies with referral processes to other providers. Other challenges noted were building rapport with families and vaccine hesitancy. The action plans included various strategies aimed to improve processes at the practice, contact and engagement with parents, and partnership development with local service providers. CONCLUSIONS: Creating customised action plans and providing support to providers were considered as helpful approaches when attempting to improve childhood immunisation coverage rates. Our study supports the notion that one strategy will not solely by itself improve childhood immunisation rates and highlights the importance of having a toolkit of strategies from which to draw from. PMID- 28615991 TI - MiR-34a and miR-206 act as novel prognostic and therapy biomarkers in cervical cancer. AB - BACKGROUND: Recent evidence indicated that the aberrant expression of microRNA plays a crucial role in the development of cervical cancer. The overall shorter survival was strongly related to the abnormal expression of microRNA-34a (miR 34a) and microRNA-206 (miR-206), which target B cell lymphoma-2(Bcl2) and c-Met. Hepatocyte growth factor (HGF)/c-Met pathway is related to the occurrence, development and prognosis of cervical cancer, and c-Met is significantly overexpressed in cervical squamous cell carcinoma. Bcl2 is also considered to be a promising target for developing novel anticancer treatments. METHODS: In this study, we detect the expression of miR-34a and miR-206 in the cervical cancer tissue through quantificational real-time polymerase chain reaction (qRT-PCR) assay, and the expression of Bcl2 and c-Met from cervical cancer tissue were detected by immunohistochemistry. RESULTS: The expression of miR-34a and miR-206 were down-regulated in the cervical cancer tissue through qRT-PCR assay. As target genes of miR-34a and miR-206, Bcl2 and c-Met were up-regulated in cervical cancer tissues through qRT-PCR assay and immunohistochemistry. Kaplan-Meier and log-rank analysis revealed that down-regulated expression of miR-34a and miR-206 were strongly related to shorter overall survival. Multivariate Cox proportional hazards model for all variables that were statistically significant in the univariate analysis demonstrated that miR-34a (P = 0.038) and miR-206 (P = 0.008) might be independent prognostic factors for overall survival of patients suffering from cervical cancer. CONCLUSIONS: The up-regulation of Bcl2 and c-Met promotes the cervical cancer's progress, and the expression of miR-34a and miR 206 significantly correlated with the progression and prognosis in cervical cancer. All of these suggested that miR-34a and miR-206 might be the novel prognostic and therapy tools in cervical cancer. PMID- 28615992 TI - Overexpression of lncRNA HOXA11-AS promotes cell epithelial-mesenchymal transition by repressing miR-200b in non-small cell lung cancer. AB - BACKGROUND: Recent studies have verified that long noncoding RNAs (lncRNAs) involved in many biological functions and play crucial roles in human cancers progression, the study aimed to detect the association between long non-coding RNA HOXA11-AS and epithelial-mesenchymal transition (EMT) process in non-small cell lung cancer (NSCLC). METHODS: The lncRNA HOXA11-AS expression levels were determined by quantitative real-time polymerase chain reaction (qRT-PCR) assays in 78 paired of tumor tissue and adjacent normal tissue samples in NSCLC patients. Kaplan-Meier survival curves and log-rank test was used to examine the association between lncRNA HOXA11-AS expression and the over survival time in NSCLC patients. Transwell invasion assay was performed to detect the cell invasion ability. QRT-PCR and western-blot analysis detected the mRNA and protein expression of EMT related transcription factors ZEB1/ZEB2, Snail1/2 and EMT marker E-cadherin and N-cadherin in NSCLC cells. RIP and Chromatin immunoprecipitation assays were performed to analyze the association between lncRNA HOXA11-AS and miR-200b expression in NSCLC cells. RESULTS: The lncRNA HOXA11-AS expression levels were significantly higher in NSCLC tissues compared with adjacent normal tissues and higher HOXA11-AS expression levels had a poor prognosis in NSCLC patients. Furthermore, knockdown of lncRNA HOXA11-AS in A549 and H1299 cells dramatically inhibited cell invasive abilities. Besides, the transcription levels and protein levels of EMT related transcription factors ZEB1/ZEB2, Snail1/2, and EMT maker N-cadherin were down-regulated after lncRNA HOXA11-AS was knocked down, but the mRNA and protein expression levels of EMT maker E-cadherin was increasing in A549 and H1299 cells. The mechanistic findings showed demonstrated that HOXA11-AS interacted with EZH2 and DNMT1 and recruited them to the miR-200b promoter regions to repress miR-200b expression in NSCLC cells, which promoted cell EMT in NSCLC. CONCLUSIONS: Our results showed that up regulation of lncRNA HOXA11-AS predicted a poor prognosis and lncRNA HOXA11-AS promoted cell epithelial-mesenchymal transition (EMT) by inhibiting miR-200b expression in NSCLC. PMID- 28615993 TI - Resveratrol protects against ICV collagenase-induced neurobehavioral and biochemical deficits. AB - BACKGROUND: Indeed, intracerebral hemorrhage (ICH) account for only 15% of all strokes but it is one of the most devastating subtype of stroke associated with behavioral, cognitive and neurological deficits. The primary cause of neurological deficits in ICH is the hematoma growth, generation of free radicals, inflammatory cytokines and exhausting endogenous anti-oxidant machinery. It has been found that neuroinflammation following ICH leads to exaggeration of hallmarks of ICH. With this background, the study was aimed to evaluate the protective effect of resveratrol (RSV) in intracerebroventricular (ICV) collagenase (COL) induced neurological deficits in rats. METHODS: The present study was designed to explore the protective effects of resveratrol (5, 10, 20 mg/kg) against ICV-COL induced ICH. Animals were subjected to a battery of behavioral tests to access behavioral changes, including neurological scoring tests (cylinder test, spontaneous motility, righting reflex, horizontal bar test, forelimb flexion), actophotometer, rotarod, Randall Sellito and von Frey. Post stroke depression was estimated using forced swim test (FST). Memory deficit was monitored using Morris water maze (MWM). RESULTS: Chronic treatment with RSV (20 mg/kg) for 21 days restored various behavioral changes, including neurological scoring tests (cylinder test, spontaneous motility, righting reflex, horizontal bar test, forelimb flexion), actophotometer, rotarod, Randall Sellito and Von Frey. RSV also restores increase in immobility time forced swim test used to evaluate post stroke depression and impaired memory deficit in Morris water maze. RSV administration also attenuated increased nitro-oxidative stress and TNF-alpha level. RSV being a potent antioxidant also restores changes in endogenous anti oxidant levels. CONCLUSION: In conclusion, our research demonstrates that RSV has a protective effect against ICH by virtue of its anti-inflammatory property and antioxidant and nitrosative stress restoring property. PMID- 28615995 TI - Additive Enhanced Creeping of Sodium Chloride Crystals. AB - This article investigates the mechanism behind the creeping of sodium chloride induced by additives. Here, an experimental approach is complemented with theoretical considerations to describe how creeping patterns of brine evolve and how the introduction of additives into the solution affects the morphology of the resultant crystals. We have found that these additives cause kinetic roughening and morphological instability mainly due to the reduction of surface free energy. There was also a marked increase in three-dimensional nucleation of the NaCl crystals and thus branching. PMID- 28615994 TI - Characterisation of the circulating acellular proteome of healthy sheep using LC MS/MS-based proteomics analysis of serum. AB - BACKGROUND: Unlike humans, there is currently no publicly available reference mass spectrometry-based circulating acellular proteome data for sheep, limiting the analysis and interpretation of a range of physiological changes and disease states. The objective of this study was to develop a robust and comprehensive method to characterise the circulating acellular proteome in ovine serum. METHODS: Serum samples from healthy sheep were subjected to shotgun proteomic analysis using nano liquid chromatography nano electrospray ionisation tandem mass spectrometry (nanoLC-nanoESI-MS/MS) on a quadrupole time-of-flight instrument (TripleTOF(r) 5600+, SCIEX). Proteins were identified using ProteinPilotTM (SCIEX) and Mascot (Matrix Science) software based on a minimum of two unmodified highly scoring unique peptides per protein at a false discovery rate (FDR) of 1% software by searching a subset of the Universal Protein Resource Knowledgebase (UniProtKB) database (http://www.uniprot.org). PeptideShaker (CompOmics, VIB-UGent) searches were used to validate protein identifications from ProteinPilotTM and Mascot. RESULTS: ProteinPilotTM and Mascot identified 245 and 379 protein groups (IDs), respectively, and PeptideShaker validated 133 protein IDs from the entire dataset. Since Mascot software is considered the industry standard and identified the most proteins, these were analysed using the Protein ANalysis THrough Evolutionary Relationships (PANTHER) classification tool revealing the association of 349 genes with 127 protein pathway hits. These data are available via ProteomeXchange with identifier PXD004989. CONCLUSIONS: These results demonstrated for the first time the feasibility of characterising the ovine circulating acellular proteome using nanoLC-nanoESI-MS/MS. This peptide spectral data contributes to a protein library that can be used to identify a wide range of proteins in ovine serum. PMID- 28615998 TI - In anesthesia and pain medicine, do we need Arabic version of the English language questionnaires? PMID- 28615997 TI - Serum concentration of several trace metals and physical training. AB - BACKGROUND: The aim of this study was to observe the concentrations of trace metals boron, lithium, rubidium, antimony, tin and strontium in the serum of athletes from different modalities and sedentary subjects and the possible influence that different energy sports training modalities can have on their concentration. METHODS: Eighty professional athletes and 31 sedentary males participated in the present survey. All of them were living in Caceres (Spain). Serum boron, lithium, rubidium, antimony, tin and strontium analysis was performed by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). RESULTS: The results show higher concentrations in athletes on tin (p < 0.01), rubidium and antimony (p < 0.001) than the control group. In the case of tin, this item had the highest concentrations only in aerobic sports modalities. Regarding rubidium and antimony, the highest concentrations are found in athletes with lower oxygen consumption (aerobic-anaerobic) (p < 0.001), followed by anaerobic group (p < 0.001). CONCLUSION: Our research shows that, probably due to increased water and air intake, especially, trace elements rubidium, antimony and tin reveal major differences in serum concentration of athletes in relation to sedentary subjects. On the other hand, physical training does not change the serum concentration of Boron, Lithium and strontium. PMID- 28615999 TI - Development and validation of Arabic version of the Short-Form McGill Pain Questionnaire. AB - INTRODUCTION: The Short-Form McGill Pain Questionnaire (SF-MPQ) is a widely used tool for qualitative and quantitative pain assessment. Our aim was to translate, culturally adapt, and validate the SF-MPQ in Arabic. METHODS: A systematic translation process was used to translate the original English SF-MPQ into Arabic. After the pilot study, we validated our version in patients with chronic pain at two tertiary care centers. We tested the reliability of our version using internal consistency and test-retest reliability. We examined the validity by assessing construct validity, concurrent validity (by investigating the associations between SF-MPQ, Brief Pain Inventory [BPI], and Self-completed Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS]), and face validity. The questionnaire was administered twice to examine responsiveness. RESULTS: A total of 142 participants (68 men and 74 women) were included in this study. Cronbach's alpha was 0.85 (95% confidence interval: 0.81 - 0.89), and interclass correlation coefficients were 0.71 (0.62-0.79) for the whole scale. SF-MPQ was moderately associated with patients' present pain (r = 0.55, P < 0.001) and the numerical rating scale (r = 0.42, P < 0.001). The total pain score was moderately correlated with pain severity and interference assessed with the BPI (rs = 0.39 to 0.49, all Ps < 0.001). SF-MPQ total pain score was weakly associated with neuropathic pain assessed with S-LANSS (r = 0.26, P < 0.01). Most patients found the SF-MPQ questions to be clear and easy to understand and thought the questionnaire items covered all their problem areas regarding their pain. CONCLUSION: Our translated version of SF-MPQ was reliable and valid for use among Arabic-speaking patients. The SF-MPQ is a good qualitative and quantitative assessment tool for pain but is only weakly associated with neuropathic pain. PMID- 28616000 TI - Development and validation of Arabic version of the Hospital Anxiety and Depression Scale. AB - INTRODUCTION: The Hospital Anxiety and Depression Scale (HADS) is widely used to predict and diagnose hospital anxiety and depression. It has been translated and validated in many languages, but the existing Arabic version was not validated in hospitalized patients. The aim was to translate, culturally adapt, and validate the HADS Questionnaire into Arabic language for in-patient use, especially for surgical wards. METHODS: A systematic translation process was used to translate the original English HADS into Arabic. After the pilot study, we validated our version in surgical patients at two tertiary care centers. We tested the reliability of our version using internal consistency. We examined the validity by assessing construct validity, concurrent validity (by testing the associations between HADS, Generalized Anxiety Disorder 7-item scale [GAD-7], and Major Depression Inventory [MDI]), and face validity. The questionnaire was administered before and after surgery to examine responsiveness. RESULTS: A total of 110 patients (22 men, 88 women) were included in the study. Cronbach's alphas for the HADS anxiety subscale were 0.83 (95% confidence interval: 0.79- 0.88) and for the HADS depression subscale were 0.77 (0.7-0.83). Nearly 36% of the patients reported symptoms indicative of borderline or case anxiety before surgery, which decreased to 25% 1 week after surgery. HADS anxiety score was strongly correlated with GAD-7, and HADS depression score was strongly associated with MDI. Patients with higher American Society of Anesthesiologists Physical Status and those who remained hospitalized for more than 5 days were more likely to report depression symptoms. Most patients found the HADS questions to be clear and easy to understand, and thought the questionnaire items covered all their problem areas regarding their hospital anxiety and depression. CONCLUSIONS: Our Arabic version of HADS is a reliable and valid tool to assess the mood states in hospitalized patients. PMID- 28616001 TI - Development and validation of Arabic version of the postoperative quality of recovery scale. AB - INTRODUCTION: The postoperative quality of recovery scale (PostopQRS) is a widely used tool to assess the postoperative quality of recovery. Our aim was to translate, culturally adapt, and validate the PostopQRS questionnaire in Arabic. METHODOLOGY: A systematic translation process was used to translate the original English PostopQRS into Arabic. After the pilot study, the translated version was validated among patients who underwent different types of surgeries. We examined the reliability (using internal consistency) and validity of the translated version. To examine the responsiveness of the translated PostopQRS, the questionnaire was administered 6 times among the same group of patients (once before surgery as baseline measure, and 5 times after surgery, up to 1 week after surgery). RESULTS: A total of 190 patients (10 men, 180 women) were included. Internal consistencies vary across each domain and overtime, with mostly good to excellent reliability. Most patients found the PostopQRS questions to be clear and easy to understand and thought the questionnaire items covered all their problem areas regarding their quality of recovery. In general, patients showed recovery across all five domains starting from postoperative day 1 (POD1). Patients showed the fastest recovery in the emotional domain, and the proportion of recovered patients remained stable over time. Most patients were recovered in the cognitive domain by POD1. Although only a small proportion of patients were recovered in the physiological and activities of daily living domains in POD1, most patients were recovered by POD3. The proportion of patients recovered in the nociceptive domain declined initially, but more patients showed recovery by POD3 and most were recovered by POD7. Furthermore, quality of recovery was related to the extent of surgery (major vs. minor). CONCLUSION: Our translated version of PostopQRS was reliable and valid for use among Arabic-speaking patients. In addition, we showed that the PostopQRS was able to track the changes in recovery among patients in our study. PMID- 28615996 TI - International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. AB - Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson's, Huntington's disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads. Additionally, researchers have identified a number of potentially beneficial clinical uses of creatine supplementation. These studies show that short and long-term supplementation (up to 30 g/day for 5 years) is safe and well-tolerated in healthy individuals and in a number of patient populations ranging from infants to the elderly. Moreover, significant health benefits may be provided by ensuring habitual low dietary creatine ingestion (e.g., 3 g/day) throughout the lifespan. The purpose of this review is to provide an update to the current literature regarding the role and safety of creatine supplementation in exercise, sport, and medicine and to update the position stand of International Society of Sports Nutrition (ISSN). PMID- 28616002 TI - Development and validation of Arabic version of the douleur neuropathique 4 questionnaire. AB - INTRODUCTION: The douleur neuropathique 4 (DN4) questionnaire is a widely used tool for diagnosis of neuropathic pain (NP). The aim was to translate, culturally adapt, and validate the DN4 questionnaire in Arabic. METHODS: A systematic translation process was used to translate the original English DN4 into Arabic. After the pilot study, the Arabic version was validated among patients with chronic pain in two tertiary care centers. The reliability of the translated version was examined using internal consistency, test-retest reliability, and intraclass correlation coefficients. We examined the validity of the Arabic DN4 via construct validity, concurrent validity (associations with the numeric rating scale, brief pain inventory, and Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS]), face validity, and diagnostic validity. To investigate the responsiveness, the translated DN4 was administered twice among the same group of patients. RESULTS: A total of 142 subjects (68 men, 74 women) were included in the study. Cronbach's alpha was 0.67 (95% confidence interval [CI]: 0.59-0.75), and interclass correlation coefficients was 0.81 (95% CI: 0.76 0.87). The DN4 was moderately associated with the S-LANSS questionnaire. Results showed our Arabic DN4 to have good diagnostic accuracy, with area under the curve of 0.88 (95% CI: 0.82-0.94). As with the original version, a score of >=4 was found to be the best cut-off for the diagnosis of NP, with a sensitivity of 88.31%, specificity of 74.47%, a positive predictive value of 85%, and a negative predictive value of 80%. Most patients found the DN4 questionnaire to be clear and easy to understand, and thought the questionnaire items covered all their problem areas regarding their pain. CONCLUSION: Our Arabic version of the DN4 is a reliable and valid screening tool that can be easily administered among patients to differentiate between NP and non-NP. PMID- 28616003 TI - Development and validation of Arabic version of the postoperative quality of recovery-40 questionnaire. AB - INTRODUCTION: The postoperative quality of recovery-40 (QoR-40) is one of the most frequently used tools to assess the quality of recovery after surgery. The aim of the current study was to translate, culturally adapt, and validate the QoR 40 questionnaire in Arabic. METHODS: A systematic translation process was used to translate the original English QoR-40 into Arabic. After the pilot study, the translated version was validated among patients who underwent different types of surgeries. The reliability (using internal consistency) and validity of our translated Arabic version was examined. To investigate the responsiveness of the translated QoR-40, the questionnaire was administered five times among the same group of patients (once before surgery as baseline measure, and four times after surgery, up to 1 week after surgery). RESULTS: A total of 182 participants (7 men, 175 women) were included in the study. The QoR-40 total scale and all subscales showed excellent internal consistencies over time, with the exception of the QoR-40 pain subscale at postoperative day 1. The QoR-40 total and subscale scores were inversely associated with patients' self-report pain scores but positively correlated with patients' self-report recovery scores. Patients' QoR 40 total, comfort, emotions, and physical subscale scores increased over time after surgery, indicating a general trend of recovery over time. Patients' scores in the QoR-40 pain and support subscales remained stable over time, suggesting no substantial changes were reported in these two domains. Quality of recovery was also found to be related to patients' ages, American Society of Anesthesiologists Physical Status, and the extent of surgery (major vs. minor). Most patients found the Arabic QoR-40 questions to be clear and easy to understand and thought the questionnaire items covered all their problem areas regarding their quality of recovery. CONCLUSION: Our translated version of QoR-40 was reliable and valid for use among Arabic-speaking patients. In addition, the QoR-40 was able to assess the quality of recovery in several domains among patients who underwent surgical procedures. PMID- 28616004 TI - Development and validation of Arabic version of the Neuropathic Pain Questionnaire-Short Form. AB - INTRODUCTION: The Neuropathic Pain Questionnaire-Short Form (NPQ-SF) is the shortest diagnostic tool for the assessment of neuropathic pain, designed with the goal to differentiate between neuropathic and nonneuropathic pain. The aim of this study was to translate, culturally adapt, and validate the NPQ-SF questionnaire in Arabic. METHODS: A systematic translation process was used to translate the original English NPQ-SF into Arabic. After the pilot study, the Arabic version was validated among patients with chronic pain in two tertiary care centers. Reliability of the translated version was examined using internal consistency, test-retest reliability, and intraclass correlation coefficient (ICC). We examined the validity of the Arabic NPQ-SF via construct validity, concurrent validity (associations with the numeric pain scale, Brief Pain Inventory, and Self-completed Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS]), face validity, and diagnostic validity. To investigate the responsiveness, the translated NPQ-SF questionnaire was administered twice among the same group of patients. RESULTS: A total of 142 subjects (68 men, 74 women) were included in the study. Cronbach's alpha were 0.45 (95% CI: 0.29, 0.61) and 0.48 (95% CI: 0.33, 0.63), and the ICC was 0.78 (95% CI: 0.72, 0.85). The NPQ-SF was moderately to strongly associated with the S-LANSS questionnaire. Results showed our Arabic NPQ-SF to have good diagnostic accuracy, with area under the curve of 0.76 (95% CI: 0.67, 0.84). Results from the receiver operating characteristic analysis identified a cut-off score of >=0.52 as the best score to distinguish between patients with or without neuropathic pain, which was higher than the recommended cut-off score (>=0) in the original study. With both sensitivity and specificity of 71%. Most patients found the NPQ-SF questionnaire to be clear and easy to understand. CONCLUSION: Our translated version of NPQ-SF is reliable and valid for use, thus providing physicians a new tool with which to evaluate and diagnose neuropathic pain among Arabic-speaking patients. PMID- 28616005 TI - Development and validation of Arabic version of the pain catastrophizing scale. AB - INTRODUCTION: The pain catastrophizing scale (PCS) is the most widely used tool to assess pain catastrophizing. The aim of this study was to translate, culturally adapt, and validate the PCS questionnaire in Arabic. METHODS: A systematic translation process was used to translate the original English PCS into Arabic. After the pilot study, we validated our version among patients with chronic pain at two tertiary care centers. We tested the reliability of our version using internal consistency and test-retest reliability. We examined the validity by assessing construct validity, concurrent validity (by investigating the associations with Brief Pain Inventory [BPI]), and face validity. RESULTS: A total of 113 subjects (50 men, 63 women) were included in the study. Cronbach's alpha was 0.94 (95% confidence interval [CI]: 0.92-0.96), and interclass correlation coefficients was 0.83 (95% CI: 0.77-0.89) for the total scale. There was no statistically significant difference in the total PCS scores between patients who reported experiencing current pain and those who did not. Among patients who reported having current pain, pain severity was weakly associated with the total PCS scores (r = 0.22, P = 0.03). PCS and its subscales were not statistically significantly associated with any of the BPI items. Nonetheless, patients who were diagnosed with neuropathic pain had statistically significantly higher scores on the total PCS, rumination, and helplessness subscales. Most patients found the PCS questions to be clear and easy to understand, and thought the questionnaire items covered all their problem areas regarding their pain catastrophizing. CONCLUSION: Our translated version of PCS is reliable and valid for use among Arabic-speaking patients. PMID- 28616006 TI - The burden of chronic pain after major head and neck tumor therapy. AB - INTRODUCTION: Little is known about the burden of chronic pain after major head and neck tumors' therapy. In this study, we aimed to estimate the prevalence of chronic pain, explore the factors associated with the presence of chronic pain, and assess the consequences of chronic pain on the patients' quality of life. METHODOLOGY: This was a cross-sectional survey among patients who had completed their therapy (e.g., surgery, radiotherapy, and chemotherapy) for major head and neck (larynx, nasopharynx, oropharynx, hypopharynx, oral cavity, tongue, and sinuses) tumors after at least 3 months. We collected relevant demographic and clinical data and administered the Brief Pain Inventory-Short Form, Neuropathic Pain Questionnaire-Short Form, and Pain Catastrophizing Scale questionnaires. Possible risk factors were explored using a classification tree model. RESULTS: A total of 102 patients (59 men, 42 women) were enrolled in this study between 3 and 72 months after tumor treatment. 30% of the patients reported having chronic pain after their major head and neck tumors' therapy. The average pain score in the last 24-hr was 3.4 (standard deviation = 2.7). The prevalence of patients with chronic pain was higher (42%) among those who had surgery. Factors associated with chronic pain were female sex, older age, surgery, advanced cancer stage, and radiotherapy. Patients who reported having chronic pain also reported having a lower quality of life manifested by impairments in general activity, mood, walking ability, normal work, and sleeping. Patients who reported having chronic pain had higher Pain Catastrophizing Scale scores. CONCLUSION: Our study highlighted the high burden of chronic pain after therapy for major head and neck tumors. We identified demographic and clinical factors that are associated with the presence of chronic pain. Further studies are required to better understand the risk factors to implement strategies to prevent, alleviate, and treat chronic pain associated with major head and neck tumor therapies. PMID- 28616007 TI - Guidelines for developing, translating, and validating a questionnaire in perioperative and pain medicine. AB - The task of developing a new questionnaire or translating an existing questionnaire into a different language might be overwhelming. The greatest challenge perhaps is to come up with a questionnaire that is psychometrically sound, and is efficient and effective for use in research and clinical settings. This article provides guidelines for the development and translation of questionnaires for application in medical fields, with a special emphasis on perioperative and pain medicine. We provide a framework to guide researchers through the various stages of questionnaire development and translation. To ensure that the questionnaires are psychometrically sound, we present a number of statistical methods to assess the reliability and validity of the questionnaires. PMID- 28616008 TI - Corrigendum: ToolConnect: A Functional Connectivity Toolbox for In vitro Networks. AB - [This corrects the article on p. 13 in vol. 10, PMID: 27065841.]. PMID- 28616009 TI - Corrigendum: Shape Perception and Navigation in Blind Adults. AB - [This corrects the article on p. 10 in vol. 8, PMID: 28144226.]. PMID- 28616010 TI - Corrigendum: The N400 Effect during Speaker-Switch-Towards a Conversational Approach of Measuring Neural Correlates of Language. AB - [This corrects the article on p. 1854 in vol. 7, PMID: 27965604.]. PMID- 28616011 TI - Corrigendum: Picture-induced semantic interference reflects lexical competition during object naming. AB - [This corrects the article on p. 28 in vol. 3, PMID: 22363304.]. PMID- 28616012 TI - Corrigendum: From Vineyard Soil to Wine Fermentation: Microbiome Approximations to Explain the "terroir" Concept. AB - [This corrects the article on p. 821 in vol. 8, PMID: 28533770.]. PMID- 28616013 TI - Corrigendum: Zebra Fish Lacking Adaptive Immunity Acquire an Antiviral Alert State Characterized by Upregulated Gene Expression of Apoptosis, Multigene Families, and Interferon-Related Genes. AB - [This corrects the article on p. 121 in vol. 8, PMID: 28243233.]. PMID- 28616014 TI - Corrigendum: Seed Embryo Development Is Regulated via an AN3-MINI3 Gene Cascade. AB - [This corrects the article on p. 1645 in vol. 7, PMID: 27857719.]. PMID- 28616015 TI - Correction: The translational importance of establishing biomarkers of human spinal cord injury. AB - [This corrects the article on p. 385 in vol. 12, PMID: 28469645.]. PMID- 28616017 TI - Inhibition and enhancement of neural regeneration by chondroitin sulfate proteoglycans. AB - The current dogma in neural regeneration research implies that chondroitin sulfate proteoglycans (CSPGs) inhibit plasticity and regeneration in the adult central nervous system (CNS). We argue that the role of the CSPGs can be reversed from inhibition to activation by developmentally expressed CSPG-binding factors. Heparin-binding growth-associated molecule (HB-GAM; also designated as pleiotrophin) has been studied as a candidate molecule that might modulate the role of CSPG matrices in plasticity and regeneration. Studies in vitro show that in the presence of soluble HB-GAM chondroitin sulfate (CS) chains of CSPGs display an enhancing effect on neurite outgrowth. Based on the in vitro studies, we suggest a model according to which the HB-GAM/CS complex binds to the neuron surface receptor glypican-2, which induces neurite growth. Furthermore, HB-GAM masks the CS binding sites of the neurite outgrowth inhibiting receptor protein tyrosine phosphatase sigma (PTPsigma), which may contribute to the HB-GAM-induced regenerative effect. In vivo studies using two-photon imaging after local HB-GAM injection into prick-injury of the cerebral cortex reveal regeneration of dendrites that has not been previously demonstrated after injuries of the mammalian nervous system. In the spinal cord, two-photon imaging displays HB-GAM induced axonal regeneration. Studies on the HB-GAM/CS mechanism in vitro and in vivo are expected to pave the way for drug development for injuries of brain and spinal cord. PMID- 28616018 TI - Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration. AB - Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2 (CRMP2) might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases. PMID- 28616016 TI - Neurological and neuropsychological consequences of electrical and lightning shock: review and theories of causation. AB - Injuries from lightning and electrical injuries involve multiple systems of the body, however neurological symptoms are very widely reported. A disabling neuropsychological syndrome is also noted. This paper presents a comprehensive review of neurological and neuropsychological symptoms. Partial theories of causation for these injuries have been advanced, however, there is no convincing explanation for both delay in onset of symptoms and also the genesis of the neuropsychological syndrome. A theory of causation is proposed which satisfies both these constraints. This theory suggests circulating hormones such as cortisol, together with nitric oxide and oxidant free radicals from glutamatergic hyper-stimulation, act on tissues remote from the injury path including the hippocampus. This theory opens a research path to explore treatment options. PMID- 28616019 TI - Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury. AB - Mild traumatic brain injury (TBI), also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO), the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1alpha), a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1alpha is regulated by NO via the mechanism of S-nitrosylation of HIF-1alpha. S nitrosylation is dynamically regulated by NO metabolites such as S nitrosoglutathione (GSNO) and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1alpha. Exogenously administered GSNO was found not only to stabilize HIF-1alpha and to induce HIF-1alpha-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals. PMID- 28616021 TI - MRI analysis and clinical significance of lower extremity muscle cross-sectional area after spinal cord injury. AB - Shortly after spinal cord injury (SCI), the musculoskeletal system undergoes detrimental changes in size and composition, predominantly below the level of injury. The loss of muscle size and strength, along with increased immobility, predisposes persons with SCI to rapid and severe loss in bone mineral density and other health related consequences. Previous studies have highlighted the significance of measuring thigh muscle cross-sectional area, however, measuring the size and composition of muscles of the lower leg may provide insights on how to decrease the risk of various comorbidities. The purpose of the current review was to summarize the methodological approach to manually trace and measure the muscles of the lower leg in individuals with SCI, using magnetic resonance imaging. We also intend to highlight the significance of analyzing lower leg muscle cross-sectional area and its relationship to musculoskeletal and vascular systems in persons with SCI. PMID- 28616020 TI - Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. AB - Minocycline hydrochloride (MH), a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways as well as inhibition of matrix metalloproteinases (MMPs). Additionally, MH can directly inhibit calcium influx through the N-methyl-D aspartate (NMDA) receptors, mitochondrial calcium uptake, poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury. PMID- 28616023 TI - Genetically modifying transcription factors to promote CNS axon regeneration. PMID- 28616024 TI - Chronically denervated distal nerve stump inhibits peripheral nerve regeneration. PMID- 28616022 TI - Therapeutic opportunities and challenges of induced pluripotent stem cells derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease. AB - Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro "disease in dish" and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs. PMID- 28616025 TI - Age-at-injury effects of microglial activation following traumatic brain injury: implications for treatment strategies. PMID- 28616026 TI - Antioxidant-induced reductive stress has untoward consequences on the brain microvasculature. PMID- 28616027 TI - The role of motor network reorganization during rehabilitation. PMID- 28616028 TI - Need for multiple biomarkers to adjust parameters of closed-loop deep brain stimulation for Parkinson's disease. PMID- 28616029 TI - P2X7 receptor antagonism in amyotrophic lateral sclerosis. PMID- 28616031 TI - Polyethylene glycol restores axonal conduction after corpus callosum transection. AB - Polyethylene glycol (PEG) has been shown to restore axonal continuity after peripheral nerve transection in animal models. We hypothesized that PEG can also restore axonal continuity in the central nervous system. In this current experiment, coronal sectioning of the brains of Sprague-Dawley rats was performed after animal sacrifice. 3Brain high-resolution microelectrode arrays (MEA) were used to measure mean firing rate (MFR) and peak amplitude across the corpus callosum of the ex-vivo brain slices. The corpus callosum was subsequently transected and repeated measurements were performed. The cut ends of the corpus callosum were still apposite at this time. A PEG solution was applied to the injury site and repeated measurements were performed. MEA measurements showed that PEG was capable of restoring electrophysiology signaling after transection of central nerves. Before injury, the average MFRs at the ipsilateral, midline, and contralateral corpus callosum were 0.76, 0.66, and 0.65 spikes/second, respectively, and the average peak amplitudes were 69.79, 58.68, and 49.60 MUV, respectively. After injury, the average MFRs were 0.71, 0.14, and 0.25 spikes/second, respectively and peak amplitudes were 52.11, 8.98, and 16.09 MUV, respectively. After application of PEG, there were spikes in MFR and peak amplitude at the injury site and contralaterally. The average MFRs were 0.75, 0.55, and 0.47 spikes/second at the ipsilateral, midline, and contralateral corpus callosum, respectively and peak amplitudes were 59.44, 45.33, 40.02 MUV, respectively. There were statistically differences in the average MFRs and peak amplitudes between the midline and non-midline corpus callosum groups (P < 0.01, P < 0.05). These findings suggest that PEG restores axonal conduction between severed central nerves, potentially representing axonal fusion. PMID- 28616030 TI - Time-lapse changes of in vivo injured neuronal substructures in the central nervous system after low energy two-photon nanosurgery. AB - There is currently very little research regarding the dynamics of the subcellular degenerative events that occur in the central nervous system in response to injury. To date, multi-photon excitation has been primarily used for imaging applications; however, it has been recently used to selectively disrupt neural structures in living animals. However, understanding the complicated processes and the essential underlying molecular pathways involved in these dynamic events is necessary for studying the underlying process that promotes neuronal regeneration. In this study, we introduced a novel method allowing in vivo use of low energy (less than 30 mW) two-photon nanosurgery to selectively disrupt individual dendrites, axons, and dendritic spines in the murine brain and spinal cord to accurately monitor the time-lapse changes in the injured neuronal structures. Individual axons, dendrites, and dendritic spines in the brain and spinal cord were successfully ablated and in vivo imaging revealed the time-lapse alterations in these structures in response to the two-photon nanosurgery induced lesion. The energy (less than 30 mW) used in this study was very low and caused no observable additional damage in the neuronal sub-structures that occur frequently, especially in dendritic spines, with current commonly used methods using high energy levels. In addition, our approach includes the option of monitoring the time-varying dynamics to control the degree of lesion. The method presented here may be used to provide new insight into the growth of axons and dendrites in response to acute injury. PMID- 28616032 TI - Dose-dependent neuroprotective effect of enoxaparin on cold-induced traumatic brain injury. AB - Recent evidence exists that enoxaparin can reduce brain injury because of its anticoagulant activity. To investigate the potential therapeutic effect of enoxaparin on cold-induced traumatic brain injury, at 20 minutes after modeling, male BALB/c mouse models of cold-induced traumatic brain injury were intraperitoneally administered 3 and 10 mg/kg enoxaparin or isotonic saline solution. Twenty-four hours later, enoxaparin at 10 mg/kg greatly reduced infarct volume, decreased cell apoptosis in the cortex and obviously increased serum level of total antioxidant status. By contrast, administration of enoxaparin at 3 mg/kg did not lead to these changes. These findings suggest that enoxaparin exhibits neuroprotective effect on cold-induced traumatic brain injury in a dose dependent manner. PMID- 28616033 TI - Exercise-induced muscle fatigue in the unaffected knee joint and its influence on postural control and lower limb kinematics in stroke patients. AB - This study aimed to investigate the effects of exercise-induced muscle fatigue in the unaffected knee joint on postural control and kinematic changes in stroke patients. Forty participants (20 stroke patients, 20 age-matched healthy participants) were recruited. To induce fatigue, maximum voluntary isometric contractions were performed in the unaffected knee joint in a Leg Extension Rehab exercise machine using the pneumatic resistance. We measured static and dynamic balance and lower-limb kinematics during gait. Changes in postural control parameters anteroposterior sway speed and total center of pressure distance differed significantly between the stroke and control groups. In addition, changes in gait kinematic parameters knee and ankle angles of initial contact differed significantly between stroke (paretic and non-paretic) and control groups. Muscle fatigue in the unaffected knee and ankle impaired postural control and debilitates kinematic movement of ipsilateral and contralateral lower limbs, and may place the fatigued stroke patients at greater risk for falls. PMID- 28616034 TI - Acupuncture with reinforcing and reducing twirling manipulation inhibits hippocampal neuronal apoptosis in spontaneously hypertensive rats. AB - To observe the effects of different acupuncture manipulations on blood pressure and target organ damage in spontaneously hypertensive rats (SHRs), this study used the reinforcing twirling method (1.5-2-mm depth; rotating needle clockwise for 360 degrees and then counter clockwise for 360 degrees , with the thumb moving heavily forward and gently backward, 60 times per minute for 1 minute, and retaining needle for 9 minutes), the reducing twirling method (1.5-2-mm depth; rotating needle counter clockwise for 360 degrees and then clockwise for 360 degrees , with the thumb moving heavily backward and gently forward, 60 times per minute for 1 minute, and retaining needle for 9 minutes), and the needle retaining method (1.5-2-mm depth and retaining the needle for 10 minutes). Bilateral Taichong (LR3) was treated by acupuncture using different manipulations and manual stimulation. Reinforcing twirling, reducing twirling, and needle retaining resulted in a decreased number of apoptotic cells, reduced Bax mRNA and protein expression, and an increased Bcl-2/Bax ratio in the hippocampus compared with the SHR group. Among these groups, the Bcl-2/Bax protein ratio was highest in the reducing twirling group, and the Bcl-2/Bax mRNA ratio was highest in the needle retaining group. These results suggest that reinforcing twirling, reducing twirling, and needle retaining methods all improve blood pressure and prevent target organ damage by increasing the hippocampal Bcl-2/Bax ratio and inhibiting cell apoptosis in the hippocampus in SHR. PMID- 28616035 TI - Neuroprotective effects of Activin A on endoplasmic reticulum stress-mediated apoptotic and autophagic PC12 cell death. AB - Activin A, a member of the transforming growth factor-beta superfamily, plays a neuroprotective role in multiple neurological diseases. Endoplasmic reticulum (ER) stress-mediated apoptotic and autophagic cell death is implicated in a wide range of diseases, including cerebral ischemia and neurodegenerative diseases. Thapsigargin was used to induce PC12 cell death, and Activin A was used for intervention. Our results showed that Activin A significantly inhibited morphological changes in thapsigargin-induced apoptotic cells, and the expression of apoptosis-associated proteins [cleaved-caspase-12, C/EBP homologous protein (CHOP) and cleaved-caspase-3] and biomarkers of autophagy (Beclin-1 and light chain 3), and downregulated the expression of thapsigargin-induced ER stress associated proteins [inositol requiring enzyme-1 (IRE1), tumor necrosis factor receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38]. The inhibition of thapsigargin induced cell death was concentration-dependent. These findings suggest that administration of Activin A protects PC12 cells against ER stress-mediated apoptotic and autophagic cell death by inhibiting the activation of the IRE1 TRAF2-ASK1-JNK/p38 cascade. PMID- 28616036 TI - Correlation between white matter damage and gray matter lesions in multiple sclerosis patients. AB - We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. We analyzed the correlation between fractional anisotropy values and changes in whole-brain gray matter volume. The participants included 20 patients with relapsing-remitting multiple sclerosis and 20 healthy volunteers as controls. All subjects underwent head magnetic resonance imaging and diffusion tensor imaging. Our results revealed that fractional anisotropy values decreased and gray matter volumes were reduced in the genu and splenium of corpus callosum, left anterior thalamic radiation, hippocampus, uncinate fasciculus, right corticospinal tract, bilateral cingulate gyri, and inferior longitudinal fasciculus in multiple sclerosis patients. Gray matter volumes were significantly different between the two groups in the right frontal lobe (superior frontal, middle frontal, precentral, and orbital gyri), right parietal lobe (postcentral and inferior parietal gyri), right temporal lobe (caudate nucleus), right occipital lobe (middle occipital gyrus), right insula, right parahippocampal gyrus, and left cingulate gyrus. The voxel sizes of atrophic gray matter positively correlated with fractional anisotropy values in white matter association fibers in the patient group. These findings suggest that white matter fiber bundles are extensively injured in multiple sclerosis patients. The main areas of gray matter atrophy in multiple sclerosis are the frontal lobe, parietal lobe, caudate nucleus, parahippocampal gyrus, and cingulate gyrus. Gray matter atrophy is strongly associated with white matter injury in multiple sclerosis patients, particularly with injury to association fibers. PMID- 28616037 TI - Correlation between photoreceptor injury-regeneration and behavior in a zebrafish model. AB - Direct exposure to intensive visible light can lead to solar retinopathy, including macular injury. The signs and symptoms include central scotoma, metamorphopsia, and decreased vision. However, there have been few studies examining retinal injury due to intensive light stimulation at the cellular level. Neural network arrangements and gene expression patterns in zebrafish photoreceptors are similar to those observed in humans, and photoreceptor injury in zebrafish can induce stem cell-based cellular regeneration. Therefore, the zebrafish retina is considered a useful model for studying photoreceptor injury in humans. In the current study, the central retinal photoreceptors of zebrafish were selectively ablated by stimulation with high-intensity light. Retinal injury, cell proliferation and regeneration of cones and rods were assessed at 1, 3 and 7 days post lesion with immunohistochemistry and in situ hybridization. Additionally, a light/dark box test was used to assess zebrafish behavior. The results revealed that photoreceptors were regenerated by 7 days after the light induced injury. However, the regenerated cells showed a disrupted arrangement at the lesion site. During the injury-regeneration process, the zebrafish exhibited reduced locomotor capacity, weakened phototaxis and increased movement angular velocity. These behaviors matched the morphological changes of retinal injury and regeneration in a number of ways. This study demonstrates that the zebrafish retina has a robust capacity for regeneration. Visual impairment and stress responses following high-intensity light stimulation appear to contribute to the alteration of behaviors. PMID- 28616038 TI - Electroacupuncture at Fengchi (GB20) inhibits calcitonin gene-related peptide expression in the trigeminovascular system of a rat model of migraine. AB - Most migraine patients suffer from cutaneous allodynia; however, the underlying mechanisms are unclear. Calcitonin gene-related peptide (CGRP) plays an important role in the pathophysiology of migraine, and it is therefore, a potential therapeutic target for treating the pain. In the present study, a rat model of conscious migraine, induced by repeated electrical stimulation of the superior sagittal sinus, was established and treated with electroacupuncture at Fengchi (GB20) (depth of 2-3 mm, frequency of 2/15 Hz, intensity of 0.5-1.0 mA, 15 minutes/day, for 7 consecutive days). Electroacupuncture at GB20 significantly alleviated the decrease in hind paw and facial withdrawal thresholds and significantly lessened the increase in the levels of CGRP in the trigeminal ganglion, trigeminal nucleus caudalis and ventroposterior medial thalamic nucleus in rats with migraine. No CGRP-positive cells were detected in the trigeminal nucleus caudalis or ventroposterior medial thalamic nucleus by immunofluorescence. Our findings suggest that electroacupuncture treatment ameliorates migraine pain and associated cutaneous allodynia by modulating the trigeminovascular system ascending pathway, at least in part by inhibiting CGRP expression in the trigeminal ganglion. PMID- 28616039 TI - The brain activation pattern of the medial temporal lobe during chewing gum: a functional MRI study. PMID- 28616040 TI - Stem cell transplantation for spinal cord injury: a meta-analysis of treatment effectiveness and safety. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of stem cell transplantation for spinal cord injury (SCI). DATA SOURCES: PubMed, EMBASE, Cochrane, China National Knowledge Infrastructure, China Science and Technology Journal, Wanfang, and SinoMed databases were systematically searched by computer to select clinical randomized controlled trials using stem cell transplantation to treat SCI, published between each database initiation and July 2016. DATA SELECTION: Randomized controlled trials comparing stem cell transplantation with rehabilitation treatment for patients with SCI. Inclusion criteria: (1) Patients with SCI diagnosed according to the American Spinal Injury Association (ASIA) International standards for neurological classification of SCI; (2) patients with SCI who received only stem cell transplantation therapy or stem cell transplantation combined with rehabilitation therapy; (3) one or more of the following outcomes reported: outcomes concerning neurological function including sensory function and locomotor function, activities of daily living, urination functions, and severity of SCI or adverse effects. Studies comprising patients with complications, without full-text, and preclinical animal models were excluded. Quality of the included studies was evaluated using the Cochrane risk of bias assessment tool and RevMan V5.3 software, provided by the Cochrane Collaboration, was used to perform statistical analysis. OUTCOME MEASURES: ASIA motor score, ASIA light touch score, ASIA pinprick score, ASIA impairment scale grading improvement rate, activities of daily living score, residual urine volume, and adverse events. RESULTS: Ten studies comprising 377 patients were included in the analysis and the overall risk of bias was relatively low level. Four studies did not detail how random sequences were generated, two studies did not clearly state the blinding outcome assessment, two studies lacked blinding outcome assessment, one study lacked follow-up information, and four studies carried out selective reporting. Compared with rehabilitation therapy, stem cell transplantation significantly increased the lower limb light touch score (odds ratio (OR) = 3.43, 95% confidence interval (CI): 0.01 - 6.86, P = 0.05), lower limb pinprick score (OR = 3.93, 95%CI: 0.74 - 7.12, P = 0.02), ASI grading rate (relative risk (RR) = 2.95, 95%CI: 1.64 - 5.29, P = 0.0003), and notably reduced residual urine volume (OR = -8.10, 95%CI: -15.09 to -1.10, P = 0.02). However, stem cell transplantation did not significantly improve motor score (OR = 1.89, 95%CI: -0.25 to 4.03, P = 0.08) or activities of daily living score (OR = 1.12, 95%CI: -1.17 to 4.04, P = 0.45). Furthermore, stem cell transplantation caused a high rate of mild adverse effects (RR = 14.49, 95%CI: 5.34 - 34.08, P < 0.00001); however, these were alleviated in a short time. CONCLUSION: Stem cell transplantation was determined to be an efficient and safe treatment for SCI and simultaneously improved sensory and bladder functions. Although associated minor and temporary adverse effects were observed with transplanted stem cells, spinal cord repair and axon remyelination were apparent. More randomized controlled trials with larger sample sizes and longer follow-up times are needed to further validate the effectiveness of stem cell transplantation in the treatment of SCI. PMID- 28616041 TI - Efficacy of intraorbital electroacupuncture for diabetic abducens nerve palsy: study protocol for a prospective single-center randomized controlled trial. AB - Abducens nerve palsy (ANP) is commonly seen in patients with diabetes mellitus. The validity of acupuncture as a traditional Chinese medicine method in peripheral nerve repair is well established. However, its efficacy in randomized controlled trials remains unclear. Herein, we designed a protocol for a prospective, single-center, randomized controlled trial to investigate the effect of intraorbital electroacupuncture on diabetic ANP. We plan to recruit 60 patients with diabetic ANP, and randomly divide them into treatment and control groups. Patients in both groups will continue their glucose-lowering therapy. A neural nutrition drug will be given to both groups for six weeks. The treatment group will also receive intraorbital electroacupuncture therapy. We will assess efficacy of treatment, eyeball movement, diplopia deviation and the levels of fasting blood-glucose and glycosylated hemoglobin before treatment at 2, 4, and 6 weeks after treatment. The efficacy and recurrence will be investigated during follow-up (1 month after intervention). This protocol was registered at Chinese Clinical Trial Registry on 16 January 2015 (ChiCTR-IPR-15005836). This study was approved by the Ethics Committee of First Affiliated Hospital of Harbin Medical University of China (approval number: 201452). All protocols will be in accordance with Declaration of Helsinki, formulated by the World Medical Association. Written informed consent will be provided by participants. We envisage that the results of this clinical trial will provide evidence for promoting clinical use of this new therapy for management of ANP. PMID- 28616042 TI - Cerebral mechanism of puncturing at He-Mu point combination for functional dyspepsia: study protocol for a randomized controlled parallel trial. AB - Acupuncture is widely used to treat functional dyspepsia with satisfactory outcomes. Combination of the He and Mu acupoints is commonly used and has a synergistic effect on functional dyspepsia; however, its underlying mechanisms remain unclear. Therefore, a randomized controlled parallel clinical trial is currently underway at Chengdu University of Traditional Chinese Medicine, China. This trial is designed to explore the efficacy of and central responses to the He Mu point combination in patients with functional dyspepsia using functional magnetic resonance imaging. A total of 105 patients with functional dyspepsia will be allocated into 3 groups: the low-He point group (puncturing at Zusanli (ST36)), Mu point group (puncturing at Zhongwan (CV12)), and He-Mu point combination group (puncturing at ST36 and CV12). Every participant will receive 20 sessions of manual acupuncture for 4 weeks. The needles will be inserted perpendicularly to a depth of 1 to 2 cun. The angle of rotation and twisting will range from 90 to 180 degrees, while lifting and thrusting will range from 0.3 to 0.5 cm. The various manipulations will be performed 60 to 90 times per minute. The needles will remain in place for 30 minutes, during which manipulation will be applied every 10 minutes. Magnetic resonance imaging will be performed before and after 20 sessions of acupuncture. The primary outcome is symptom improvement according to the Chinese version of the Nepean Dyspepsia Index. Secondary outcomes include the Leeds dyspepsia questionnaire, Self-Rating Anxiety Scale, Self-Rating Depression Scale, Beck Anxiety Inventory, Beck Depression Inventory, and visual analogue scale scores before and after 10 and 20 sessions of acupuncture. Needle sensation and adverse events will be used to assess the therapeutic effects. This study will promote more widespread awareness of the benefits of acupoint combination in the clinical setting and provide a further explanation of the neuromechanism by which acupuncture at the He-Mu point combination for functional dyspepsia. Registration: Chinese Clinical Trial Registry, ChiCTR-IOR-15006402. PMID- 28616043 TI - Angioedema suppressed by a combination of anti-histamine and leukotriene modifier. AB - RATIONALE: Angioedema without co-existent urticaria is due to a limited number of causes, including hereditary and acquired C1 esterase inhibitor deficiency, drug induced angioedema or idiopathic histaminergic or non-histaminergic angioedema. We describe a cohort of patients with recurrent angioedema whose clinical features and response to medications are distinct from the causes above. METHODS: Patients were accrued retrospectively from an academic allergy practice between 2007 and 2014. After institutional research ethics board approval, patients' charts were reviewed and demographic, clinical and laboratory data were extracted. RESULTS: A total of 11 patients were recruited. The mean age at presentation was 54.9 years (range 19-70 years) and 6 of 11 were male. The mean number of episodes per year was 18.7 (range 2-60) and mean duration of episodes was 22.4 h (range 4-96). About half of episodes (52%) began overnight. Areas of involvement were lips (73%), tongue (64%), eyelids (18%), feet (36%) and hands (27%). None of the patients had low C3, C4, or CH50; none had significantly positive ANA; C1 esterase inhibitor level and function and C1q were normal in all patients tested. In these 11 patients, complete suppression of recurrences by the combination of cetirizine 20 mg daily and montelukast 10 mg daily was reported by 9 (82%) of patients; whereas 2 (18%) of patients had a partial response to this combination of medications. CONCLUSIONS: Herein, we report a form of angioedema without urticaria, mediated by a combination of histamine and leukotrienes. Clinical, demographic and therapeutic characteristics differentiate this from other recognized causes of angioedema. PMID- 28616044 TI - Decreased fibrinolytic activity is associated with carotid artery stiffening in arterial hypertension. AB - BACKGROUND: A prothrombotic state is associated with the presence and severity of organ damage in hypertensive patients. In these patients, evidence of subclinical carotid functional changes anticipates major cardiovascular events. The aim of this study was to investigate the association of hemostatic markers with carotid artery stiffness in hypertension. MATERIALS AND METHODS: In 116 untreated essential hypertensive patients recruited at a referral center in the University of Udine, we assessed common carotid artery stiffness by B-mode ultrasonography and measured plasma fibrinogen, D-dimer, plasminogen activator inhibitor-1 (PAI 1), and homocysteine by the currently available methods. For statistical reasons, the patients were divided according to the median value of each index of carotid stiffness, and continuous variables were further analyzed by univariate correlation and stepwise multivariate regression analysis. RESULTS: PAI-1 levels were significantly higher in patients with low coefficient of distensibility (P = 0.018) and high Young's elastic modulus (P = 0.012), whereas no association of fibrinogen, D-dimer, and homocysteine levels was observed with carotid coefficient of distensibility, Young's elastic modulus, and beta-stiffness. On univariate analysis, Young's elastic modulus was significantly and positively correlated with PAI-1 levels (r = 0.286, P = 0.002), a correlation that on multivariate regression resulted to be independent of other confounders (beta = 0.289, P = 0.028). CONCLUSION: An independent association of plasma PAI-1 levels with carotid artery stiffness suggests a possible contribution of decreased fibrinolytic activity to the early functional abnormalities of arterial vessels in hypertensive patients. This contribution might be relevant for subsequent development of hypertension-related cardiovascular complications. PMID- 28616045 TI - Development of the Persian version of the Vertigo Symptom Scale: Validity and reliability. AB - BACKGROUND: Vertigo Symptom Scale (VSS) is a proper instrument for assessing the patient status, clarifying the symptoms, and examining the relative impact of the vertigo and anxiety on reported handicap. Our aim is the translation and cross cultural adaptation of the VSS into Persian language (VSS-P) and investigating its validity and reliability in patients with peripheral vestibular disorders. MATERIALS AND METHODS: VSS was translated into Persian. Cross-cultural adaptation was carried out on 101 patients with peripheral vestibular disorders and 34 participants with no history of vertigo. They completed the Persian versions of VSS, dizziness handicap inventory (DHI), and Beck anxiety inventory (BAI). Internal, discriminant, and convergent validities, internal consistency, and test retest reliability were determined. RESULTS: The VSS-P showed good face validity. Internal validity was confirmed and demonstrated the presence of two vertigo (VSS VER) and autonomic-anxiety (VSS-AA) subscales. Significant difference between the median scores for patient and healthy groups was reported in discriminate validity (P <0.001). Convergent validity revealed high correlation between both BAI and DHI with VSS-P. There was a high test-retest reliability; with intraclass correlation coefficient of 0.89, 0.86, and 0.91 for VSS-AA, VER, and VSS-P, respectively. The internal consistency was good with Cronbach's alpha 0.90 for VER subscale, 0.86 for VSS-AA subscale, and 0.92 for the overall VSS-P. CONCLUSION: The Persian version of the VSS could be used clinically as a valid and reliable tool. Thus, it is a key instrument to focus on the symptoms associated with dizziness. PMID- 28616046 TI - Encouraging collaborative efforts between environment and health sector to arrest climate deterioration. PMID- 28616047 TI - Modeling birth weight neonates and associated factors. AB - BACKGROUND: Neonate with abnormal weight is at risk of increased mortality and morbidity. Many factors affect pregnancy outcome. Because of the importance and vital role in birth weight, in this study, some of the factors associated with birth weight in a sample of Iranians neonates were investigated. MATERIALS AND METHODS: In this cross-sectional study, 245 newborns in a sample of Iranians neonates in the year 2013 were selected, and characteristics of neonate and their mothers were derived. Birth weights were registered by the neonatal scale. To identify the direct and indirect factors affecting birth weight, we used path analysis (PA) and IBM AMOS and SPSS software. RESULTS: The mean +/- standard deviation of weight in girls (3200 +/- 421) g less than boys (3310 +/- 444) g significantly (P = 0.04). Gestational age (P < 0.001), birth rank (P = 0.012), distance from a previous pregnancy (P = 0.028), and mother weight (P = 0.04) had a statistical significant relationship with birth weight. In the final PA model, gestational age has a highest total effect, type of delivery with gestational age mediated had the highest indirect effect and type of delivery, and gestational age had the greatest total impact on the birth weight. CONCLUSION: Gestational age, sex, distance from a previous pregnancy, maternal weight, type of delivery, number of abortion, and birth rank were related with birth weight. Due to the termination of pregnancy and avoid unnecessary deliveries through cesarean section and other related factors should be further consideration by childbirth experts. In addition, factors affecting these variables are carefully identified and prevented as much as possible. PMID- 28616048 TI - Molecular biology of frozen shoulder-induced limitation of shoulder joint movements. AB - Frozen shoulder is a chronic condition characterized by pain in the shoulder and restriction of movements in all directions. Some patients are left with long-term limitation of shoulder joint activity with various severities, which results in reduced quality of life. Currently, there is a paucity of literature on the molecular biology of frozen shoulder, and the molecular biological mechanism for periarthritis-induced limitation of shoulder joint movements remains unclear. Research in this field is focused on inflammation and cytokines associated with fibrosis. Repeated investigations confirmed alterations of specified inflammatory mediators and fibrosis-associated cytokines, which might be involved in the pathogenesis of frozen shoulder by causing structural changes of the shoulder joint and eventually the limitation of shoulder movements. The aim of this article is to review studies on molecular biology of frozen shoulder and provide a reference for subsequent research, treatment, and development of new drugs. PMID- 28616050 TI - Occult cancer in patients with deep-vein thrombosis in a general hospital at Mexico City: A pilot study. AB - BACKGROUND: We aimed to explore the frequency of occult cancer in patients with deep-vein thrombosis (DVT) at a general hospital in Mexico City. MATERIALS AND METHODS: From March 2012 to February 2015, all patients with primary DVT of lower extremities attended in the emergency department of our hospital were studied. Initially, all patients were evaluated with clinical history, physical examination, basic laboratories, abdominal ultrasound, chest X-ray, and duplex venous ultrasonography. In a case-by-case approach, if necessary, computed tomography, endoscopy, colonoscopy, and tumor markers were done. RESULTS: From 182 patients with primary DVT, 30 (16.5%) presented occult cancer: Thirteen males and 17 females, with an average age of 61 years. In males, prostate cancer prevailed (6/13, 46%); meanwhile, in females, pelvic gynecologic cancers predominated (7/17, 41%). CONCLUSION: Our results suggest that in Mexican patients with primary DVT, occult cancer is frequent. PMID- 28616049 TI - Cytokine profiles at birth and the risk of developing severe respiratory distress and chronic lung disease. AB - BACKGROUND: Neonates with the diagnosis of respiratory distress syndrome (RDS) were studied to investigate possible associations between cytokine levels at birth and developing severe RDS or chronic lung disease (CLD). MATERIALS AND METHODS: This was a cross-sectional study on serum and bronchoalveolar lavage (BAL) samples collected within hours of birth from infants with moderate and severe RDS. Twenty infants with moderate RDS and 20 infants with severe RDS were studied. RDS was diagnosed on the basis of radiographic findings, respiratory distress, and an increasing oxygen requirement. RDS severity was graded based on the radiological findings and Downe's Score. CLD was diagnosed when infants were still on supplemented O2 by at least 28 days of age. Levels of the cytokines interleukin (IL)-1beta, IL-6, IL-8, IL-10, and tumor necrosis factor alpha were measured using enzyme-linked immunosorbent assay. "Statistical analysis was performed using the SPSS for Windows, (SPSS Inc., Chicago, IL, USA)." RESULTS: Levels of the proinflammatory cytokines IL-8 and IL-1beta were significantly higher in BAL of infants with severe RDS than those with moderate RDS (P = 0.007 and P = 0.02, respectively). IL-8 levels were also significantly higher in BAL and serum of infants who later progressed to CLD than in those who did not (P = 0.03 for both). The IL-8/IL-10 cytokine ratio was significantly higher in the BAL of severe RDS infants than in moderate RDS (P = 0.01) and in the serum of infants who progressed to CLD than in those who did not (P = 0.03). CONCLUSION: Levels of IL-8 and the IL-8/IL-10 ratio measured soon after birth were associated with severity of RDS as well as progression to CLD. Early measurement of cytokines levels and ratios may contribute to the prognosis and management of RDS and CLD. PMID- 28616051 TI - Omega-3 supplementation effects on polycystic ovary syndrome symptoms and metabolic syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder with unknown etiology and with different complications. The aim of this study was to evaluate the effect of omega-3 supplementation on PCOS symptoms and metabolic syndrome. MATERIALS AND METHODS: This double-blind clinical trial was performed in 2015 in Alzahra and Shahid Beheshti Hospitals, Isfahan, Iran, on 88 patients with PCOS. Intervention group took omega-3 supplements with dose of 2 g/day for 6 months (two capsules), but control group received two olive oil capsules. Finally, ultrasound and laboratory findings and the recovery rate of menstrual disorders in both groups were compared. RESULTS: After 6 months' intervention, waist circumference (WC) was significantly lower in omega-3 as compared to control (81.18 +/- 2.87 vs. 84.22 +/- 2.61 cm, respectively, P < 0.0001). High-density lipoprotein was increased (47.2 +/- 1.37 vs. 41.56 +/- 1.34 mg/dl, respectively, P < 0.0001) while low-density lipoprotein (107.79 +/- 1.68 vs. 117.4 +/- 1.57 mg/dl, respectively), triglyceride (116.02 +/- 3.13 vs. 125.06 +/- 2.91 mg/dl, respectively), and cholesterol (180.34 +/- 6.34 vs. 189.56 +/- 5.93 mg/dl, respectively) in omega-3 were significantly lower than control (P < 0.0001). The interval between periods in omega-3 was significantly shorter than control (29.83 +/- 4.68 vs. 47.11 +/- 8.72 days, respectively, P < 0.001). CONCLUSION: Omega-3 decrease lipid profiles, WC, and interval between periods while weight, hip circumference, fasting blood sugar, number of ovarian follicle, size of ovary, bleeding volume, menstrual bleeding, and hirsutism score did not change by administration of omega-3. PMID- 28616052 TI - New emerging biological markers of neonatal sepsis. PMID- 28616053 TI - What we should know about health problems in people with intellectual disability: Implications for health policy. PMID- 28616054 TI - An investigation on non-invasive fungal sinusitis; Molecular identification of etiologic agents. AB - BACKGROUND: Fungal sinusitis is increasing worldwide in the past two decades. It is divided into two types including invasive and noninvasive. Noninvasive types contain allergic fungal sinusitis (AFS) and fungus ball. AFS is a hypersensitivity reaction to fungal allergens in the mucosa of the sinonasal tract in atopic individuals. The fungus ball is a different type of noninvasive fungal rhinosinusitis which is delineated as an accumulation of debris and fungal elements inside a paranasal sinus. Fungal sinusitis caused by various fungi such as Aspergillus species, Penicillium, Mucor, Rhizopus, and phaeohyphomycetes. The aim of the present study is to identify fungal species isolated from noninvasive fungal sinusitis by molecular methods. MATERIALS AND METHODS: During 2015-2016, a total of 100 suspected patients were examined for fungal sinusitis. Functional endoscopic sinus surgery was performed using the Messerklinger technique. Clinical samples were identified by phenotypic and molecular methods. Polymerase chain reaction (PCR) sequencing of ITS1-5.8S-ITS2 region and PCR-restriction fragment length polymorphism with MspI restriction enzyme was performed for molecular identification of molds and yeasts, respectively. RESULTS: Twenty-seven out of 100 suspected cases (27%) had fungal sinusitis. Nasal congestion (59%) and headache (19%) were the most common clinical signs among patients. Fifteen patients (55.5%) were male and 12 patients (44.5%) were female. Aspergillus flavus was the most prevalent fungal species (26%), followed by Penicillium chrysogenum (18.5%) and Candida glabrata species complex (15%). CONCLUSION: Since clinical manifestations, computed tomography scan, endoscopy, and histopathological findings are very nonspecific in AFS and fungus ball; therefore, molecular investigations are compulsory for precise identification of etiologic agents and appropriate management of these fungal infections. PMID- 28616055 TI - Evaluation of ovarian function after hysterectomy with or without salpingectomy: A feasible study. AB - BACKGROUND: Prophylactic salpingectomy for the prevention of ovarian cancer has been recommended strongly. The aim of this study was to compare ovarian function in patients who undergo hysterectomy for benign reasons with or without bilateral salpingectomy. MATERIALS AND METHODS: This was a clinical-trial study on patients undergone hysterectomy with/without bilateral salpingectomy in Al-Zahra Hospital, in 2015-2016. Demographic information (age, height, and weight) were recorded. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured in 2-5 days of menstrual cycle before operation. Patients were asked to refer in 6 months for follow-up, including FSH and LH re-measurement and also menopausal status examination. Patients were divided into age groups of 39-45, 46-50, and >=51 and also groups of body mass index including 18.5-24.9, 25-29.9, and 30 34.9. RESULTS: A total of 37 patients divided into two groups, including 22 patients undergone hysterectomy without salpingectomy (H) and 15 undergone hysterectomy with bilateral salpingectomy (H-bS). The mean age (standard deviation) of Group H was 47.77 (3.03) and Group H-bS was 48.47 (2.03) (P > 0.05). Furthermore, the mean level of FSH and LH before surgery was not significantly different (P > 0.05). The mean level of FSH and LH changes was not significant between H and H-bS groups (P = 0.17), (P = 0.16). CONCLUSION: Bilateral salpingectomy during hysterectomy did not increase the risk of ovarian dysfunction after 6 months follow-up. PMID- 28616056 TI - Ertapenem for multiple beta-lactamases producing Gram-negative bacteria causing urinary tract infections in HIV patients. PMID- 28616057 TI - Serum omentin-1, vaspin, and apelin levels and central obesity in patients with nonalcoholic fatty liver disease. AB - BACKGROUND: Omentin-1, vaspin, and apelin are novel adipokines which closely associate with obesity, nonalcoholic fatty liver disease (NAFLD), and inflammation. The aim of this study was to investigate the circulating levels of omentin-1, vaspin, and apelin in NAFLD patients and to clarify their relationship with biochemical parameters, abdominal obesity, and high sensitive C-reactive protein. MATERIALS AND METHODS: In a case-control study, serum levels of omentin 1, vaspin, and apelin were measured in 41 NAFLD patients and 41 healthy volunteers. The study was performed in the outpatients' clinic of Imam-Ali Hospital in Zahedan, Iran, during February to July 2015. Fatty liver was confirmed by ultrasonography. The association of the adipokines with lipid profile and anthropometric parameters was assessed using multivariable linear regression models. In this model, those variables that showed P < 0.05 were included in the study. RESULTS: NAFLD patients presented a significantly higher apelin levels compared to the controls (P < 0.01), whereas serum omentin-1 and vaspin levels did not differ between two groups (both P > 0.05). Multiple regression analysis showed that the serum levels of apelin and vaspin correlated positively with waist circumference (WC) (P < 0.01 and P < 0.05, respectively) and low-density lipoprotein (P < 0.05 and P < 0.01, respectively) while serum omentin-1 was inversely correlated with WC (P < 0.01) and positively corrected with high-density lipoprotein (P < 0.05). CONCLUSION: The findings showed that among the analyzed adipokines only apelin was different in patients with NAFLD when compared to controls. Considering the multivariate regression analysis, apelin seems be more suitable diagnostic marker in predicting of NAFLD and omentin might be considered as a protective factor in occurrence of NAFLD, particularly in those with central obesity. PMID- 28616058 TI - Getting fat or getting help? How female mammals cope with energetic constraints on reproduction. AB - BACKGROUND: Fat deposits enable a female mammal to bear the energy costs of offspring production and thus greatly influence her reproductive success. However, increasing locomotor costs and reduced agility counterbalance the fitness benefits of storing body fat. In species where costs of reproduction are distributed over other individuals such as fathers or non-breeding group members, reproductive females might therefore benefit from storing less energy in the form of body fat. RESULTS: Using a phylogenetic comparative approach on a sample of 87 mammalian species, and controlling for possible confounding variables, we found that reproductive females of species with allomaternal care exhibit reduced annual variation in body mass (estimated as CV body mass), which is a good proxy for the tendency to store body fat. Differential analyses of care behaviours such as allonursing or provisioning corroborated an energetic interpretation of this finding. The presumably most energy-intensive form of allomaternal care, provisioning of the young, had the strongest effect on CV body mass. In contrast, allonursing, which involves no additional influx of energy but distributes maternal help across different mothers, was not correlated with CV body mass. CONCLUSIONS: Our results suggest that reproducing females in species with allomaternal care can afford to reduce reliance on fat reserves because of the helpers' energetic contribution towards offspring rearing. PMID- 28616059 TI - Supramolecular structure of dietary fat in early life modulates expression of markers for mitochondrial content and capacity in adipose tissue of adult mice. AB - BACKGROUND: Previous studies have shown that early life nutrition can modulate the development of white adipose tissue and thereby affect the risk on obesity and metabolic disease later in life. For instance, postnatal feeding with a concept infant milk formula with large, phospholipid coated lipid droplets (Concept, Nuturis(r)), resulted in reduced adiposity in adult mice. The present study investigated whether differences in cell energy metabolism, using markers of mitochondrial content and capacity, may contribute to the observed effects. METHODS: C57Bl/6j male mice were exposed to a rodent diet containing the Concept (Concept) or standard (CTRL) infant milk formula from postnatal day 16 until postnatal day 42, followed by a western style diet challenge until postnatal day 98. Markers for mitochondrial content and capacity were analyzed in retroperitoneal white adipose tissue and gene expression of metabolic markers was measured in both retroperitoneal white adipose tissue and muscle tibialis (M. tibialis) at postnatal day 98. RESULTS: In retroperitoneal white adipose tissue, the Concept group showed higher citrate synthase activity and mitochondrial DNA expression compared to the CTRL group (p < 0.05). In addition, protein expression of mitochondrial cytochrome c oxidase subunit I of the oxidative phosphorylation pathway/cascade was increased in the Concept group compared to CTRL (p < 0.05). In the M. tibialis, gene expression of uncoupling protein 3 was higher in the Concept compared to the CTRL group. Other gene and protein expression markers for mitochondrial oxidative capacity were not different between groups. CONCLUSION: Postnatal feeding with large, phospholipid coated lipid droplets generating a different supramolecular structure of dietary lipids enhances adult gene and protein expression of specific mitochondrial oxidative capacity markers, indicative of increased substrate oxidation in white adipose tissue and skeletal muscle. Although functional mitochondrial capacity was not measured, these results may suggest that adaptations in mitochondrial function via early feeding with a more physiological structure of dietary lipids, could underlie the observed beneficial effects on later life adiposity. PMID- 28616060 TI - Early recognition of methicillin-resistant Staphylococcus aureus surgical site infections using risk and protective factors identified by a group of Italian surgeons through Delphi method. AB - BACKGROUND: Surgical site infections (SSIs) constitute a major clinical problem in terms of morbidity, mortality, duration of hospital stay, and overall costs. The bacterial pathogens implicated most frequently are Streptococcus pyogenes (S. pyogenes) and Staphylococcus aureus (S. aureus). The incidence of methicillin resistant S. aureus (MRSA) SSIs is increasing significantly. Since these infections have a significant impact on hospital budgets and patients' health, their diagnosis must be anticipated and therapy improved. The first step should be to evaluate risk factors for MRSA SSIs. METHODS: Through a literature review, we identified possible major and minor risk factors for, and protective factors against MRSA SSIs. We then submitted statements on these factors to 228 Italian surgeons to determine, using the Delphi method, the degree of consensus regarding their importance. The consensus was rated as positive if >80% of the voters agreed with a statement and as negative if >80% of the voters disagreed. In other cases, no consensus was reached. RESULTS: There was positive consensus that sepsis, >2 weeks of hospitalization, age >75 years, colonization by MRSA, and diabetes were major risk factors for MRSA SSIs. Other possible major risk factors, on which a consensus was not reached, e.g., prior antibiotic use, were considered minor risk factors. Other minor risk factors were identified. An adequate antibiotic prophylaxis, laparoscopic technique, and infection committee surveillance were considered protective factors against MRSA SSIs. All these factors might be used to build predictive criteria for identifying SSI due to MRSA. CONCLUSIONS: In order to help to recognize and thus promptly initiate an adequate antibiotic therapy for MRSA SSIs, we designed a gradation of risk and protective factors. Validation, ideally prospective, of this score is now required. In the case of a SSI, if the risk that the infection is caused by MRSA is high, empiric antibiotic therapy should be started after debriding the wound and collecting material for culture. PMID- 28616061 TI - Penetrating cardiac trauma: analysis of 240 cases from a hospital in Bogota, Colombia. AB - BACKGROUND: Trauma characteristics and its management is influenced by socioeconomic context. Cardiac trauma constitutes a challenge for surgeons, and outcomes depend on multiple factors including initial care, characteristics of the wounds, and surgical management. METHODS: This is a retrospective cross sectional case series of patients with penetrating cardiac injuries (PCI) from January 1999 to October 2009 who underwent surgery in a trauma referral center in Bogota, Colombia. Demographic variables, trauma characteristics, treatment, and outcomes were analyzed. RESULTS: The study included 240 cases: 96.2% males, mean age of 27.8 years. Overall mortality was 14.6%: 11.7% from stab wounds and 41.2% from gunshot wounds. Upon admission, 44% had a normal hemodynamic status and 67% had cardiac tamponade. About 32% had Grade II injuries and 29% Grade IV injuries. In 85% of the cases, there were ventricular compromise and 55% of patients had associated lesions. In 150 cases, a pericardial window was performed. Highest mortality occurred in wounds to the right atrium. In tamponade patients, mortality was 20% being higher for gunshot wounds (54.5%) than for stab wounds (18%) (p = 0.0120). CONCLUSIONS: The study evidenced predominance of stab wounds. Based on characteristics of the trauma, patients, and survival rate, there is most likely a high pre-hospitalization mortality rate. The difference in mortality due to stab wounds and those produced by gunshots was more related to technical difficulties of the surgical repair than with the type of injury established by the Injury Grading Scale. Mortality was higher in patients with cardiac tamponade. Surgical management was satisfactory using pericardial window as the diagnostic method and sternotomy as the surgical approach. PMID- 28616062 TI - Severe consequences of habitat fragmentation on genetic diversity of an endangered Australian freshwater fish: A call for assisted gene flow. AB - Genetic diversity underpins the ability of populations to persist and adapt to environmental changes. Substantial empirical data show that genetic diversity rapidly deteriorates in small and isolated populations due to genetic drift, leading to reduction in adaptive potential and fitness and increase in inbreeding. Assisted gene flow (e.g. via translocations) can reverse these trends, but lack of data on fitness loss and fear of impairing population "uniqueness" often prevents managers from acting. Here, we use population genetic and riverscape genetic analyses and simulations to explore the consequences of extensive habitat loss and fragmentation on population genetic diversity and future population trajectories of an endangered Australian freshwater fish, Macquarie perch Macquaria australasica. Using guidelines to assess the risk of outbreeding depression under admixture, we develop recommendations for population management, identify populations requiring genetic rescue and/or genetic restoration and potential donor sources. We found that most remaining populations of Macquarie perch have low genetic diversity, and effective population sizes below the threshold required to retain adaptive potential. Our simulations showed that under management inaction, smaller populations of Macquarie perch will face inbreeding depression within a few decades, but regular small-scale translocations will rapidly rescue populations from inbreeding depression and increase adaptive potential through genetic restoration. Despite the lack of data on fitness loss, based on our genetic data for Macquarie perch populations, simulations and empirical results from other systems, we recommend regular and frequent translocations among remnant populations within catchments. These translocations will emulate the effect of historical gene flow and improve population persistence through decrease in demographic and genetic stochasticity. Increasing population genetic connectivity within each catchment will help to maintain large effective population sizes and maximize species adaptive potential. The approach proposed here could be readily applicable to genetic management of other threatened species to improve their adaptive potential. PMID- 28616063 TI - Benefits of gene flow are mediated by individual variability in self compatibility in small isolated populations of an endemic plant species. AB - Many rare and endemic species experience increased rates of self-fertilization and mating among close relatives as a consequence of existing in small populations within isolated habitat patches. Variability in self-compatibility among individuals within populations may reflect adaptation to local demography and genetic architecture, inbreeding, or drift. We use experimental hand pollinations under natural field conditions to assess the effects of gene flow in 21 populations of the central Appalachian endemic Trifolium virginicum that varied in population size and degree of isolation. We quantified the effects of distance from pollen source on pollination success and fruit set. Rates of self compatibility varied dramatically among maternal plants, ranging from 0% to 100%. This variation was unrelated to population size or degree of isolation. Nearly continuous variation in the success of selfing and near-cross-matings via hand pollination suggests that T. virginicum expresses pseudo-self-fertility, whereby plants carrying the same S-allele mate successfully by altering the self incompatibility reaction. However, outcrossing among populations produced significantly higher fruit set than within populations, an indication of drift load. These results are consistent with strong selection acting to break down self-incompatibility in these small populations and/or early-acting inbreeding depression expressed upon selfing. PMID- 28616064 TI - Plasticity in gene transcription explains the differential performance of two invasive fish species. AB - Phenotypic plasticity buffers organisms from environmental change and is hypothesized to aid the initial establishment of nonindigenous species in novel environments and postestablishment range expansion. The genetic mechanisms that underpin phenotypically plastic traits are generally poorly characterized; however, there is strong evidence that modulation of gene transcription is an important component of these responses. Here, we use RNA sequencing to examine the transcriptional basis of temperature tolerance for round and tubenose goby, two nonindigenous fish species that differ dramatically in the extent of their Great Lakes invasions despite similar invasion dates. We used generalized linear models of read count data to compare gene transcription responses of organisms exposed to increased and decreased water temperature from those at ambient conditions. We identify greater response in the magnitude of transcriptional changes for the more successful round goby compared with the less successful tubenose goby. Round goby transcriptional responses reflect alteration of biological function consistent with adaptive responses to maintain or regain homeostatic function in other species. In contrast, tubenose goby transcription patterns indicate a response to stressful conditions, but the pattern of change in biological functions does not match those expected for a return to homeostatic status. Transcriptional plasticity plays an important role in the acute thermal tolerance for these species; however, the impaired response to stress we demonstrate in the tubenose goby may contribute to their limited invasion success relative to the round goby. Transcriptional profiling allows the simultaneous assessment of the magnitude of transcriptional response as well as the biological functions involved in the response to environmental stress and is thus a valuable approach for evaluating invasion potential. PMID- 28616065 TI - Human management and hybridization shape treegourd fruits in the Brazilian Amazon Basin. AB - Local people's perceptions of cultivated and wild agrobiodiversity, as well as their management of hybridization are still understudied in Amazonia. Here we analyze domesticated treegourd (Crescentia cujete), whose versatile fruits have technological, symbolic, and medicinal uses. A wild relative (C. amazonica) of the cultivated species grows spontaneously in Amazonian flooded forests. We demonstrated, using whole chloroplast sequences and nuclear microsatellites, that the two species are strongly differentiated. Nonetheless, they hybridize readily throughout Amazonia and the proportions of admixture correlate with fruit size variation of cultivated trees. New morphotypes arise from hybridization, which are recognized by people and named as local varieties. Small hybrid fruits are used to make the important symbolic rattle (maraca), suggesting that management of hybrid trees is an ancient human practice in Amazonia. Effective conservation of Amazonian agrobiodiversity needs to incorporate this interaction between wild and cultivated populations that is managed by smallholder families. Beyond treegourd, our study clearly shows that hybridization plays an important role in tree crop phenotypic diversification and that the integration of molecular analyses and farmers' perceptions of diversity help disentangle crop domestication history. PMID- 28616066 TI - The evolutionary trade-off between stem cell niche size, aging, and tumorigenesis. AB - Many epithelial tissues within multicellular organisms are continually replenished by small independent populations of stem cells largely responsible for maintaining tissue homeostasis. These continually dividing populations are subject to mutations that can lead to tumorigenesis but also contribute to aging. Mutations accumulate in stem cell niches and change the rate of cell division and differentiation; the pace of this process and the fate of specific mutations depend strongly on niche population size. Here, we create a mathematical model of the intestinal stem cell niche, crypt system, and epithelium. We calculate the expected effect of fixed mutations in stem cell niches and their effect on tissue homeostasis throughout the intestinal epithelium over organismal lifetime. We find that, due to the small population size of stem cell niches, mutations predominantly fix via genetic drift and decrease stem cell fitness, leading to niche and tissue attrition, and contributing to organismal aging. We also explore mutation accumulation at various stem cell niche sizes and demonstrate that an evolutionary trade-off exists between niche size, tissue aging, and the risk of tumorigenesis. Further, mouse and human niches exist at a size that minimizes the probability of tumorigenesis, at the expense of accumulating deleterious mutations due to genetic drift. Finally, we show that the trade-off between the probability of tumorigenesis and the extent of aging depends on whether or not mutational effects confer a selective advantage in the stem cell niche. PMID- 28616067 TI - Selection by higher-order effects of salinity and bacteria on early life-stages of Western Baltic spring-spawning herring. AB - Habitat stratification by abiotic and biotic factors initiates divergence of populations and leads to ecological speciation. In contrast to fully marine waters, the Baltic Sea is stratified by a salinity gradient that strongly affects fish physiology, distribution, diversity and virulence of important marine pathogens. Animals thus face the challenge to simultaneously adapt to the concurrent salinity and cope with the selection imposed by the changing pathogenic virulence. Western Baltic spring-spawning herring (Clupea harengus) migrate to spawning grounds characterized by different salinities to which herring are supposedly adapted. We hypothesized that herring populations do not only have to cope with different salinity levels but that they are simultaneously exposed to higher-order effects that accompany the shifts in salinity, that is induced pathogenicity of Vibrio bacteria in lower saline waters. To experimentally evaluate this, adults of two populations were caught in their spawning grounds and fully reciprocally crossed within and between populations. Larvae were reared at three salinity levels, representing the spawning ground salinity of each of the two populations, or Atlantic salinity conditions resembling the phylogenetic origin of Clupea harengus. In addition, larvae were exposed to a Vibrio spp. infection. Life-history traits and gene expression analysis served as response variables. Herring seem adapted to Baltic Sea conditions and cope better with low saline waters. However, upon a bacterial infection, herring larvae suffer more when kept at lower salinities implying reduced resistance against Vibrio or higher Vibrio virulence. In the context of recent climate change with less saline marine waters in the Baltic Sea, such interactions may constitute key future stressors. PMID- 28616068 TI - Genetic diversity and structure of Lolium perenne ssp. multiflorum in California vineyards and orchards indicate potential for spread of herbicide resistance via gene flow. AB - Management of agroecosystems with herbicides imposes strong selection pressures on weedy plants leading to the evolution of resistance against those herbicides. Resistance to glyphosate in populations of Lolium perenne L. ssp. multiflorum is increasingly common in California, USA, causing economic losses and the loss of effective management tools. To gain insights into the recent evolution of glyphosate resistance in L. perenne in perennial cropping systems of northwest California and to inform management, we investigated the frequency of glyphosate resistance and the genetic diversity and structure of 14 populations. The sampled populations contained frequencies of resistant plants ranging from 10% to 89%. Analyses of neutral genetic variation using microsatellite markers indicated very high genetic diversity within all populations regardless of resistance frequency. Genetic variation was distributed predominantly among individuals within populations rather than among populations or sampled counties, as would be expected for a wide-ranging outcrossing weed species. Bayesian clustering analysis provided evidence of population structuring with extensive admixture between two genetic clusters or gene pools. High genetic diversity and admixture, and low differentiation between populations, strongly suggest the potential for spread of resistance through gene flow and the need for management that limits seed and pollen dispersal in L. perenne. PMID- 28616069 TI - Population genetic and field-ecological analyses return similar estimates of dispersal over space and time in an endangered amphibian. AB - The explosive growth of empirical population genetics has seen a proliferation of analytical methods leading to a steady increase in our ability to accurately measure key population parameters, including genetic isolation, effective population size, and gene flow, in natural systems. Assuming they yield similar results, population genetic methods offer an attractive complement to, or replacement of, traditional field-ecological studies. However, empirical assessments of the concordance between direct field-ecological and indirect population genetic studies of the same populations are uncommon in the literature. In this study, we investigate genetic isolation, rates of dispersal, and population sizes for the endangered California tiger salamander, Ambystoma californiense, across multiple breeding seasons in an intact vernal pool network. We then compare our molecular results to a previously published study based on multiyear, mark-recapture data from the same breeding sites. We found that field and genetic estimates of population size were only weakly correlated, but dispersal rates were remarkably congruent across studies and methods. In fact, dispersal probability functions derived from genetic data and traditional field ecological data were a significant match, suggesting that either method can be used effectively to assess population connectivity. These results provide one of the first explicit tests of the correspondence between landscape genetic and field-ecological approaches to measuring functional population connectivity and suggest that even single-year genetic samples can return biologically meaningful estimates of natural dispersal and gene flow. PMID- 28616070 TI - Persistence of antibiotic resistance plasmids in bacterial biofilms. AB - The emergence and spread of antibiotic resistance is a crisis in health care today. Antibiotic resistance is often horizontally transferred to susceptible bacteria by means of multidrug resistance plasmids that may or may not persist in the absence of antibiotics. Because bacterial pathogens often grow as biofilms, there is a need to better understand the evolution of plasmid persistence in these environments. Here we compared the evolution of plasmid persistence in the pathogen Acinetobacter baumannii when grown under antibiotic selection in biofilms versus well-mixed liquid cultures. After 4 weeks, clones in which the plasmid was more stably maintained in the absence of antibiotic selection were present in both populations. On average plasmid persistence increased more in liquid batch cultures, but variation in the degree of persistence was greater among biofilm-derived clones. The results of this study show for the first time that the persistence of MDR plasmids improves in biofilms. PMID- 28616071 TI - Combined "de novo" and "ex novo" lipid fermentation in a mix-medium of corncob acid hydrolysate and soybean oil by Trichosporon dermatis. AB - BACKGROUND: Microbial oil is one important bio-product for its important function in energy, chemical, and food industry. Finding suitable substrates is one key issue for its industrial application. Both hydrophilic and hydrophobic substrates can be utilized by oleaginous microorganisms with two different bio-pathways ("de novo" lipid fermentation and "ex novo" lipid fermentation). To date, most of the research on lipid fermentation has focused mainly on only one fermentation pathway and little work was carried out on both "de novo" and "ex novo" lipid fermentation simultaneously; thus, the advantages of both lipid fermentation cannot be fulfilled comprehensively. RESULTS: In this study, corncob acid hydrolysate with soybean oil was used as a mix-medium for combined "de novo" and "ex novo" lipid fermentation by oleaginous yeast Trichosporon dermatis. Both hydrophilic and hydrophobic substrates (sugars and soybean oil) in the medium can be utilized simultaneously and efficiently by T. dermatis. Different fermentation modes were compared and the batch mode was the most suitable for the combined fermentation. The influence of soybean oil concentration, inoculum size, and initial pH on the lipid fermentation was evaluated and 20 g/L soybean oil, 5% inoculum size, and initial pH 6.0 were suitable for this bioprocess. By this technology, the lipid composition of extracellular hydrophobic substrate (soybean oil) can be modified. Although adding emulsifier showed little beneficial effect on lipid production, it can modify the intracellular lipid composition of T. dermatis. CONCLUSIONS: The present study proves the potential and possibility of combined "de novo" and "ex novo" lipid fermentation. This technology can use hydrophilic and hydrophobic sustainable bio-resources to generate lipid feedstock for the production of biodiesel or other lipid-based chemical compounds and to treat some special wastes such as oil-containing wastewater. PMID- 28616072 TI - The advanced strategy for enhancing biobutanol production and high-efficient product recovery with reduced wastewater generation. AB - BACKGROUND: Butanol as an important chemical and potential fuel could be produced via ABE fermentation from lignocellulosic biomass. The use of food-related feedstocks such as maize and sugar cane may not be a sustainable solution to world's energy needs. Recently, Jerusalem artichoke tubers containing inulin have been used as feedstock for butanol production, but this bioprocess is not commercially feasible due to the great value of inulin as functional food. Till now, there is a gap on the utilization of Jerusalem artichoke stalk (JAS) as feedstock for microbial butanol production. RESULTS: Biobutanol production from JAS was investigated in order to improve cellulose digestibility and efficient biobutanol fermentation. Compared with 9.0 g/L butanol (14.7 g/L ABE) production by 2% NaOH pretreatment of JAS, 11.8 g/L butanol (17.6 g/L ABE) was produced in the best scenario conditions of NaOH-H2O2 pretreatment, washing times and citrate buffer strengths etc. Furthermore, more than >64% water in washing pretreated JAS process could be saved, with improving butanol production by >25.0%. To mimic in situ product recovery for ABE fermentation, the vapor stripping-vapor permeation (VSVP) process steadily produced 323.4-348.7 g/L butanol (542.7-594.0 g/L ABE) in condensate, which showed more potentials than pervaporation for butanol recovery. CONCLUSIONS: Therefore, the present study demonstrated an effective strategy on efficient biobutanol production using lignocellulosic biomass. The process optimization could contribute to significant reduction of wastewater emission and the improvement of lignocellulosic biomass digestibility and biobutanol production, which makes biobutanol production more efficient using JAS. PMID- 28616073 TI - The transcription factor PDR-1 is a multi-functional regulator and key component of pectin deconstruction and catabolism in Neurospora crassa. AB - BACKGROUND: Pectin is an abundant component in many fruit and vegetable wastes and could therefore be an excellent resource for biorefinery, but is currently underutilized. Fungal pectinases already play a crucial role for industrial purposes, such as for foodstuff processing. However, the regulation of pectinase gene expression is still poorly understood. For an optimal utilization of plant biomass for biorefinery and biofuel production, a detailed analysis of the underlying regulatory mechanisms is warranted. In this study, we applied the genetic resources of the filamentous ascomycete species Neurospora crassa to screen for transcription factors that play a major role in pectinase induction. RESULTS: The pectin degradation regulator-1 (PDR-1) was identified through a transcription factor mutant screen in N. crassa. The Deltapdr-1 mutant exhibited a severe growth defect on pectin and all tested pectin-related poly- and monosaccharides. Biochemical as well as transcriptional analyses of WT and the Deltapdr-1 mutant revealed that while PDR-1-mediated gene induction was dependent on the presence of l-rhamnose, it also strongly affected the degradation of the homogalacturonan backbone. The expression of the endo-polygalacturonase gh28-1 was greatly reduced in the Deltapdr-1 mutant, while the expression levels of all pectate lyase genes increased. Moreover, a pdr-1 overexpression strain displayed substantially increased pectinase production. Promoter analysis of the PDR-1 regulon allowed refinement of the putative PDR-1 DNA-binding motif. CONCLUSIONS: PDR-1 is highly conserved in filamentous ascomycete fungi and is present in many pathogenic and industrially important fungi. Our data demonstrate that the function of PDR-1 in N. crassa combines features of two recently described transcription factors in Aspergillus niger (RhaR) and Botrytis cinerea (GaaR). The results presented in this study contribute to a broader understanding of how pectin degradation is orchestrated in filamentous fungi and how it could be manipulated for optimized pectinase production. PMID- 28616074 TI - Thermodynamics and economic feasibility of acetone production from syngas using the thermophilic production host Moorella thermoacetica. AB - BACKGROUND: Syngas fermentation is a promising option for the production of biocommodities due to its abundance and compatibility with anaerobic fermentation. Using thermophilic production strains in a syngas fermentation process allows recovery of products with low boiling point from the off-gas via condensation. RESULTS: In this study we analyzed the production of acetone from syngas with the hypothetical production host derived from Moorella thermoacetica in a bubble column reactor at 60 degrees C with respect to thermodynamic and economic feasibility. We determined the cost of syngas production from basic oxygen furnace (BOF) process gas, from natural gas, and from corn stover and identified BOF gas as an economically interesting source for syngas. Taking gas liquid mass transfer limitations into account, we applied a thermodynamics approach to derive the CO to acetone conversion rate under the process conditions. We estimated variable costs of production of 389 $/t acetone for a representative production scenario from BOF gas with costs for syngas as the main contributor. In comparison, the variable costs of production from natural gas- and corn stover-derived syngas were determined to be higher due to the higher feedstock costs (1724 and 2878 $/t acetone, respectively). CONCLUSION: We applied an approach of combining thermodynamic and economic assessment to analyze a hypothetical bioprocess in which the volatile product acetone is produced from syngas with a thermophilic microorganism. Our model allowed us to identify process metrics and quantify the variable production costs for different scenarios. Economical production of bulk chemicals is challenging, making rigorous thermodynamic/economic modeling critical before undertaking an experimental program and as an ongoing guide during the program. We intend this study to give an incentive to apply the demonstrated approach to other bioproduction processes. PMID- 28616075 TI - Proximity ligation scaffolding and comparison of two Trichoderma reesei strains genomes. AB - BACKGROUND: The presence of low complexity and repeated regions in genomes often results in difficulties to assemble sequencing data into full chromosomes. However, the availability of full genome scaffolds is essential to several investigations, regarding for instance the evolution of entire clades, the analysis of chromosome rearrangements, and is pivotal to sexual crossing studies. In non-conventional but industrially relevant model organisms, such as the ascomycete Trichoderma reesei, a complete genome assembly is seldom available. RESULTS: The chromosome scaffolds of T. reesei QM6a and Rut-C30 strains have been generated using a contact genomic/proximity ligation genomic approach. The original reference assembly, encompassing dozens of scaffolds, was reorganized into two sets of seven chromosomes. Chromosomal contact data also allowed to characterize 10-40 kb, gene-free, AT-rich (76%) regions corresponding to the T. reesei centromeres. Large chromosomal rearrangements (LCR) in Rut-C30 were then characterized, in agreement with former studies, and the position of LCR breakpoints used to assess the likely chromosome structure of other T. reesei strains [QM9414, CBS999.97 (1-1, re), and QM9978]. In agreement with published results, we predict that the numerous chromosome rearrangements found in highly mutated industrial strains may limit the efficiency of sexual reproduction for their improvement. CONCLUSIONS: The GRAAL program allowed us to generate the karyotype of the Rut-C30 strain, and from there to predict chromosome structure for most T. reesei strains for which sequence is available. This method that exploits proximity ligation sequencing approach is a fast, cheap, and straightforward way to characterize both chromosome structure and centromere sequences and is likely to represent a popular convenient alternative to expensive and work-intensive resequencing projects. PMID- 28616077 TI - Hydrocarbon bio-jet fuel from bioconversion of poplar biomass: techno-economic assessment. AB - BACKGROUND: Infrastructure compatible hydrocarbon biofuel proposed to qualify as renewable transportation fuel under the U.S. Energy Independence and Security Act of 2007 and Renewable Fuel Standard (RFS2) is evaluated. The process uses a hybrid poplar feedstock, which undergoes dilute acid pretreatment and enzymatic hydrolysis. Sugars are fermented to acetic acid, which undergoes conversion to ethyl acetate, ethanol, ethylene, and finally a saturated hydrocarbon end product. An unfermentable lignin stream may be burned for steam and electricity production, or gasified to produce hydrogen. During biofuel production, hydrogen gas is required and may be obtained by various methods including lignin gasification. RESULTS: Both technical and economic aspects of the biorefinery are analyzed, with different hydrogen sources considered including steam reforming of natural gas and gasification of lignin. Cash operating costs for jet fuel production are estimated to range from 0.67 to 0.86 USD L-1 depending on facility capacity. Minimum fuel selling prices with a 15 % discount rate are estimated to range from 1.14 to 1.79 USD L-1. Capacities of 76, 190, and 380 million liters of jet fuel per year are investigated. Capital investments range from 356 to 1026 million USD. CONCLUSIONS: A unique biorefinery is explored to produce a hydrocarbon biofuel with a high yield from bone dry wood of 330 L t-1. This yield is achieved chiefly due to the use of acetogenic bacteria that do not produce carbon dioxide as a co-product during fermentation. Capital investment is significant in the biorefinery in part because hydrogen is required to produce a fully de-oxygenated fuel. Minimum selling price to achieve reasonable returns on investment is sensitive to capital financing options because of high capital costs. Various strategies, such as producing alternative, intermediate products, are investigated with the intent to reduce risk in building the proposed facility. It appears that producing and selling these intermediates may be more profitable than converting all the biomass into aviation fuel. With variability in historical petroleum prices and environmental subsidies, a high internal rate of return would be required to attract investors. PMID- 28616078 TI - Role of surface tryptophan for peroxidase oxidation of nonphenolic lignin. AB - BACKGROUND: Despite claims as key enzymes in enzymatic delignification, very scarce information on the reaction rates between the ligninolytic versatile peroxidase (VP) and lignin peroxidase (LiP) and the lignin polymer is available, due to methodological difficulties related to lignin heterogeneity and low solubility. RESULTS: Two water-soluble sulfonated lignins (from Picea abies and Eucalyptus grandis) were chemically characterized and used to estimate single electron-transfer rates to the H2O2-activated Pleurotus eryngii VP (native enzyme and mutated variant) transient states (compounds I and II bearing two- and one electron deficiencies, respectively). When the rate-limiting reduction of compound II was quantified by stopped-flow rapid spectrophotometry, from fourfold (softwood lignin) to over 100-fold (hardwood lignin) lower electron-transfer efficiencies (k3app values) were observed for the W164S variant at surface Trp164, compared with the native VP. These lignosulfonates have ~20-30 % phenolic units, which could be responsible for the observed residual activity. Therefore, methylated (and acetylated) samples were used in new stopped-flow experiments, where negligible electron transfer to the W164S compound II was found. This revealed that the residual reduction of W164S compound II by native lignin was due to its phenolic moiety. Since both native lignins have a relatively similar phenolic moiety, the higher W164S activity on the softwood lignin could be due to easier access of its mono-methoxylated units for direct oxidation at the heme channel in the absence of the catalytic tryptophan. Moreover, the lower electron transfer rates from the derivatized lignosulfonates to native VP suggest that peroxidase attack starts at the phenolic lignin moiety. In agreement with the transient-state kinetic data, very low structural modification of lignin, as revealed by size-exclusion chromatography and two-dimensional nuclear magnetic resonance, was obtained during steady-state treatment (up to 24 h) of native lignosulfonates with the W164S variant compared with native VP and, more importantly, this activity disappeared when nonphenolic lignosulfonates were used. CONCLUSIONS: We demonstrate for the first time that the surface tryptophan conserved in most LiPs and VPs (Trp164 of P. eryngii VPL) is strictly required for oxidation of the nonphenolic moiety, which represents the major and more recalcitrant part of the lignin polymer. PMID- 28616079 TI - Surgical site infection and its associated factors following cesarean section: a cross sectional study from a public hospital in Ethiopia. AB - BACKGROUND: A cesarean section is a surgical procedure in which incisions are made through a woman's abdomen and uterus to deliver her baby. Surgical site infections are a common surgical complication among patients delivered with cesarean section. Further it caused to increase maternal morbidity, stay of hospital and the cost of treatment. METHODS: Hospital based cross-sectional study was conducted to assess the magnitude of surgical site infection following cesarean Site Infections and its associated factors at Lemlem Karl hospital July 1, 2013 to June 30, 2016. Retrospective card review was done on 384 women who gave birth via cesarean section at Lemlem Karl hospital from July 1, 2013 to June 30, 2016. Systematic sampling technique was used to select patient medical cards. The data were entered by Epi info version 7.2 then analyzed using Statistical Package for Social Sciences windows version 20. Both bivariate and multivariate logistic regression was done to test association between predictors and dependent variables. P value of < 0.05 was considered to declare the presence of statistically significantly association. RESULTS: Among 384 women who performed cesarean section, the magnitude of surgical site infection following cesarean section Infection was 6.8%. The identified independent risk factors for surgical site infections were the duration of labor AOR=3.48; 95%CI (1.25, 9.68), rupture of membrane prior to cesarean section AOR=3.678; 95%CI (1.13, 11.96) and the abdominal midline incision (AOR=5.733; 95%CI (2.05, 16.00). CONCLUSIONS: The magnitude of surgical site infection following cesarean section is low compare to other previous studies. The independent associated factors for surgical site infection after cesarean section in this study: Membranes rupture prior to cesarean section, duration of labor and sub umbilical abdominal incision. In addition to ensuring sterile environment and aseptic surgeries, use of WHO surgical safety checklist would appear to be a very important intervention to reduce surgical site infections. PMID- 28616080 TI - Pedobarography as a clinical tool in the management of diabetic feet in New Zealand: a feasibility study. AB - BACKGROUND: The peripheral complications of diabetes mellitus remain a significant risk to lower-limb morbidity. In New Zealand, risk of diabetes, comorbidity and lower-limb amputation are highly-differential between demographic groups, particularly ethnicity. There is growing and convincing evidence that the use of pedobarography - or plantar pressure measurement - can usefully inform diabetic foot care, particularly with respect to the prevention of re-ulceration among high-risk patients. METHODS: For the current feasibility study, we embedded pedobarographic measurements into three unique diabetic foot clinic settings in the New Zealand context, and collected pedobarographic data from n = 38 patients with diabetes using a platform-based (Novel Emed) and/or in-shoe-based system (Novel Pedar). Our aim was to assess the feasibility of incorporating pedobarographic testing into the clinical care of diabetic feet in New Zealand. RESULTS AND CONCLUSIONS: We observed a high response rate and positive self reported experience from participants. As part of our engagement with participants, we observed a high degree of lower-limb morbidity, including current ulceration and chronic foot deformities. The median time for pedobarographic testing (including study introduction and consenting) was 25 min. Despite working with a high-risk population, there were no adverse events in this study. In terms of application of pedobarography as a clinical tool in the New Zealand context, the current feasibility study leads us to believe that there are two avenues that deserve further investigation: a) the use of pedobarography to inform the design and effectiveness of offloading devices among high-risk diabetic patients; and b) the use of pedobarography as a means to increase offloading footwear and/or orthoses compliance among high-risk diabetic patients. Both of these objectives deserve further examination in New Zealand via clinical trial. PMID- 28616076 TI - Regulators of plant biomass degradation in ascomycetous fungi. AB - Fungi play a major role in the global carbon cycle because of their ability to utilize plant biomass (polysaccharides, proteins, and lignin) as carbon source. Due to the complexity and heterogenic composition of plant biomass, fungi need to produce a broad range of degrading enzymes, matching the composition of (part of) the prevalent substrate. This process is dependent on a network of regulators that not only control the extracellular enzymes that degrade the biomass, but also the metabolic pathways needed to metabolize the resulting monomers. This review will summarize the current knowledge on regulation of plant biomass utilization in fungi and compare the differences between fungal species, focusing in particular on the presence or absence of the regulators involved in this process. PMID- 28616081 TI - Anaerobic adaptation of Mycobacterium avium subspecies paratuberculosis in vitro: similarities to M. tuberculosis and differential susceptibility to antibiotics. AB - BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of Johne's disease in ruminants and is associated with Crohn's disease (CD) in humans, although the latter remains controversial. In this study, we investigated the ability of MAP to adapt to anaerobic growth using the "Wayne" model of non-replicating persistence (NRP) developed for M. tuberculosis. RESULTS: All strains adapted to anaerobiosis over time in a manner similar to that seen with MTB. Susceptibility to 12 antibiotics varied widely between strains under aerobic conditions. Under anaerobic conditions, no drugs caused significant growth inhibition (>0.5 log) except metronidazole, resulting in an average decrease of ~2 logs. CONCLUSIONS: These results demonstrate that MAP is capable of adaptation to NRP similar to that observed for MTB with differential susceptibility to antibiotics under aerobic versus anaerobic conditions. Such findings have significant implications for our understanding of the pathogenesis of MAP in vivo and the treatment of CD should this organism be established as the causative agent. PMID- 28616082 TI - Prevalence of pks-positive Escherichia coli in Japanese patients with or without colorectal cancer. AB - BACKGROUND: Recent studies show that some Escherichia coli strains possessing a gene cluster named the pks island might have a causative role in the development of human colorectal cancer (CRC). In several reports from Europe, they are found more prevalently in colon tissue specimens derived from CRC patients compared to those from controls. In this study we sought to clarify the difference in pks prevalence between CRC patients and non-CRC controls in the Japanese population, by using non-invasive sample collection technique during colonoscopy. METHODS: Colonic lavage samples were collected during diagnostic colonoscopy, and bacterial DNA within each sample was extracted. Fecal DNA samples were then examined for pks island genes using conventional qualitative PCR and real-time quantitative PCR. In some patients biopsy samples were also collected in the same session of colonoscopy, and the correlation between the pks status of the colonic lavage sample and the biopsy sample of the same patients was evaluated. RESULTS: Twelve out of thirteen patients (92%) showed the same pks status by colonic lavage sample and biopsy sample, suggesting the usefulness of colonic lavage samples as a surrogate for biopsy samples. A total of 98 colonic lavage samples were collected, which included 35 from CRC patients, 37 from adenoma patients, and 26 from controls. The pks-positive bacterial DNA was detected in 43, 51, and 46% of colonic lavage samples from CRC, adenoma, and control patients, respectively, and there was no significant difference among diseases. Real-time quantitative PCR showed no significant difference in the relative concentrations of pks-positive bacterial DNA among diseases. Age, gender, location of CRC, CRC staging, or k-ras gene status was not associated with pks prevalence. CONCLUSIONS: Although the method of collecting fecal DNA from colonic lavage samples was safe and technically feasible, factors other than pks-positive bacteria appear to play more important roles in CRC development in this cohort. PMID- 28616084 TI - Interdisciplinary perspectives. PMID- 28616085 TI - Helicobacter pylori infection: old and new. AB - Helicobacter pylori is a spiral-shaped bacterium that grows in the digestive tract and may be present in more than half of the world's population. The clinical features of Helicobacter pylori range from asymptomatic gastritis to gastrointestinal malignancy. Mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade B-cell marginal zone lymphoma and Helicobacter pylori has been detected in more than 75% of the patients with MALT lymphoma. Many tests for the detection of Helicobacter pylori are available, including antibody tests, urea breath tests, stool antigen tests and endoscopic biopsies. The eradication of Helicobacter pylori usually prevents the return of ulcers and ulcer complications even after appropriate medications such as PPIs are stopped. The eradication of Helicobacter pylori is important in the treatment of the rare condition of the stomach known as MALT lymphoma. The treatment of Helicobacter pylori to prevent stomach cancer is controversial. Confirmation of eradication is recommended in associated ulcers, persistent dyspepsia despite a test-and-treat approach, MALT lymphoma, and previous treatment for early-stage gastric cancer. The urea breath test and stool antigen test can be used to confirm the eradication and should be performed at least 4 weeks after the completion of therapy. Several diseases have been reported to be associated with Helicobacter pylori infection, including hematologic diseases, such as ITP, idiopathic iron deficiency anemia and vitamin B12 deficiency. There is a positive trend in the association between Helicobacter pylori infection and neurodegenerative disorders and new data showed a reduced risk of death due to stroke and lung cancer but an increased risk of preeclampsia in infected women, which requires further investigations. PMID- 28616083 TI - Outer membrane phospholipase A's roles in Helicobacter pylori acid adaptation. AB - BACKGROUND: The pH of the human gastric mucosa varies around 2.5 so that only bacteria with strong acidic stress tolerance can colonize it. The ulcer causing Helicobacter pylori thrives in the gastric mucosa. We analyse the roles of the key outer membrane protein OMPLA in its roles in acid tolerance. RESULTS: The homology model of Helicobacter pylori outer membrane phospholipase A (OMPLA) reveals a twelve stranded beta-barrel with a pore that allows molecules to pass with a diameter up to 4 A. Structure based multiple sequence alignments revealed the functional roles of many amino acids, and led to the suggestion that OMPLA has multiple functions. Besides its role as phospholipase it lets urea enter and ammonium exit the periplasm. Combined with an extensive literature study, our work leads to a comprehensive model for H. pylori's acid tolerance. This model is based on the conversion of urea into ammonium, and it includes multiple roles for OMPLA and involves two hitherto little studied membrane channels in the OMPLA operon. CONCLUSION: The three-dimensional model of OMPLA predicts a transmembrane pore that can aid H. pylori's acid tolerance through urea influx and ammonium efflux. After urea passes through OMPLA into the periplasm, it passes through the pH-gated inner membrane channel UreI into the cytoplasm where urease hydrolyses it into NH3 and CO2. Most of the NH3 becomes NH4+ that is likely to need an inner membrane channel to reach the periplasm. Two genes that are co-regulated with OMPLA in gastric Helicobacter operons could aid this transport. The NH4+ that might leave the cell through the OMPLA pore has been implicated in H. pylor's pathogenesis. PMID- 28616086 TI - Homeopathic treatment for prolonged postoperative coma: a case report. AB - Coma is the state of unrousable unconsciousness. There are variations in the degree of coma and the findings and signs found on the patient's clinical examination depend on the underlying cause of the disorder. The Glasgow Coma scale evaluates the best motor, verbal and eye answers of the patient. A patient is considered to be in a coma if his Glasgow Coma Scale is below 8 points. The progress that we have made throughout the years has also led to complications that can culminate in a major catastrophe like death, permanent brain damage, coma. A study performed reached the conclusion that prior comorbidity, older age, intraoperative hypotension, and cardiovascular surgery may predispose patients to postoperative coma. The article presents a case of postoperative coma treated successfully with homeopathy. Although a rare complication, postoperative coma is a severe, death-leading condition, causing immense suffering on both the patient and the patient's family. A multidisciplinary and thorough approach is necessary for these patients, but even after a well-conducted therapy, this condition leads to the death of the patient. PMID- 28616087 TI - Acute rheumatic fever: clinical profile in children in western Ukraine. AB - : Acute rheumatic fever (ARF) may have different clinical manifestations in different countries according to the genetic predisposition, prevalence of rheumatogenic strains, social and economic conditions. The purpose of this study was to determine the clinical characteristics of ARF in Western Ukraine and to improve the detection of the cases. A retrospective analysis of 85 medical clinical cases of in-hospital patients aged from 4 to 17 years old was performed. The cases covered patients who underwent treatment in the City Children's Hospital of Ternopil during 2000 and 2013 with the ARF diagnosis, which was established according to Jones criteria. 65.9% of the ARF patients were admitted to the hospital from October to March. Fever (65.9%) and joint syndrome (78.8%) were the most common causes for admission to the medical care. The admission diagnosis was wrong in 34 (40.0%) children who underwent the treatment. The most frequent major Jones criteria of ARF were carditis (84.7%) and polyarthritis (54.1%). Chorea was significantly less common than carditis (r < 0,001). The adequate treatment of the preceding streptococcal infection was administered in 25 children (53.2%). CONCLUSIONS: The significant incidence of misdiagnoses in the ARF children during admission to the hospital, especially the interpretation of joint syndrome, indicates that physicians need an extra awareness. The lack of specific clinical signs of rheumatic carditis makes it a diagnostic challenge. The revised Jones criteria (2015) for the diagnosis of ARF can improve carditis detection. The adequate treatment of the preceding streptococcal infection may prevent ARF. Abbreviations: ARF = acute rheumatic fever. PMID- 28616088 TI - Effect of prophylactic administration of Novafen for periodontal surgery on postoperative pain relief. AB - Pain is a subjective feeling and one of the defense and alerting mechanisms of the body, which is distinguished from the body senses, including touch sensation and perception of heat, cold, pressure, etc. Pain, discomfort, and edema are very common after dental procedures, especially after periodontal surgeries, usually occurring during the first 24 hours after surgery; such pains are classified as medium to severe pains. Generally, medications are used to manage patients' pain and discomfort. One of the most commonly used medications for pain control is Ibuprofen, which is one of the NSAIDs and is a simple derivative of phenylpropionic acid. There is evidence that caffeine alone or in association with Acetaminophen, Ibuprofen, or Aspirin can increase their analgesic effects. Novafen is a new drug which consists of Acetaminophens, Ibuprofen and caffeine and has been marketed in Iran in recent years. 70 subjects referring to the Department of Oral and Maxillofacial Surgery, Tabriz Faculty of Dentistry, who were candidates for crown lengthening procedure, were randomly selected and included in the present study, based on inclusion and exclusion criteria. No significant differences were detected in pain severity between the two groups either clinically or statistically at 30-minutes postoperative interval. Pain, discomfort, and edema are very common after dental procedures, especially after periodontal surgeries. Such conditions usually occur during the first 24-hours postoperative interval and are considered moderate to severe pains. Although in the present study, the administration of Novafen before periodontal surgery resulted in the relief of postoperative pain, further studies are recommended on the subject, The administration of Novafen before periodontal surgeries resulted in pain relief after surgery. PMID- 28616089 TI - Severe pulmonary arterial hypertension associated with congenital cardiac shunts: evolution under specific treatment. AB - Objective: The aim of this study was to compare the effects of Sildenafil, Bosentan and combined therapy in patients with congenital cardiac shunts associated pulmonary artery hypertension (CCS-PAH). Design: Prospective observational study (February 2011 - January 2014) with a historical control group (January 2009 - January 2011). Setting: "CC Iliescu" Institute for Emergency Cardiovascular Diseases of Bucharest, a tertiary university-affiliated center. Patients: All cases with CCS-PAH. Interventions: Specific vasodilatory therapy: Sildenafil, Bosentan or combined therapy. Outcome Measures: The primary outcome was the overall survival at 24 months. Results: Out of 108 patients with pulmonary arterial hypertension, there were 79 patients with CCS-PAH, 55 presenting a severe form of the disease. The mean age of the patients was 34.42+/ 21.15 years, with 37 (67,3%) female patients. 23 patients received specific vasodilatory treatment (thirteen Sildenafil, seven Bosentan, three combined treatment), with 32 patients in the control group, without specific vasodilatory therapy. The specific vasodilatory therapy was associated with improved WHO/ NYHA functional class (p=0.025), oxygen saturation at the end of the six-minute walk test (p=0.011), decreased pulmonary artery systolic (p=0.002) and diastolic (p=0.004) pressures, and an increased S' wave in Tissue Doppler Imaging (p=0.008). Conclusions: Despite the complexity of CCS-PAH, with a complex constellation of underlying congenital heart defects, there are short-term benefits of a specific vasodilatory therapy. PMID- 28616090 TI - Histochemical and immunohistochemical study of mucinous rectal carcinoma. AB - Colorectal cancer (CRC) is a major health problem worldwide. The objective of our study was to assess the histopathological (HP) and immunohistochemical (IHC) profile of mucins from signet ring (SR) and mucinous rectal carcinoma, while evaluating their value as a prognostic factor and muco-secretive ability. The HP study (76 cases) included 4 categories of patients: pure mucinous (PM), mixed mucinous components (MM) (50-80% of the tumor cells), mixed mucinous components (Mm) (< 50% of the tumor cells) and signet ring (SR). The IHC study consisted of a total of 30 cases of MRC and was processed by the ABC/ HRP technique. The antibodies used have addressed their muco-secretive capacity: MUC1, 2 and MUC5AC. MRC cases were more frequent in the sixth decade, with a median age of 57.3 years. It could be noted that MRC tended to develop at younger ages. For the MP variant, the gender ratio was 1.37 in favor of men, while for the MM variant it was 1.16, 1.31 for the Mm and 1.6 in the case of signet ring type. Most of the MRC were moderately differentiated forms, except for the SR form, poorly differentiated forms predominating. Well-differentiated forms were the most underrepresented, being more common in the Mm version. Regarding the biochemical type of mucin, MP and SR were characterized by acid mucins and sialomucin, while in the Mm type, there was a balance of acidic and neutral mucins. The prevalence of mucin acids, respectively sulfomucin, was characteristic to younger ages and poor prognosis. PMID- 28616091 TI - Price and distribution policies in healthcare marketing in Romania. AB - There is a principle similar to the theory of exchange in the marketing of health services, meaning that what is delivered to the target market (i.e. the beneficiaries) must be equal to or greater than what is to be received (i.e. the price). The price level in the marketing mix is influenced by how the consumer perceives the respective medical service and is quantified in the profit and the turnover of the organization respectively. The cost of the medical act as a whole is the value of all the tangible and intangible variables associated with it, and the planning, distribution and promotion of the product must be taken into account in the price setting. PMID- 28616092 TI - Vascularization from Flexible Imaging Color Enhancement (FICE) for polyp localization. AB - Background. Virtual chromoendoscopy is an imaging technology that helps in better visualizing the gastrointestinal tract effectively. Recently, the flexible imaging color enhancement (FICE) technique developed by Fijifilm has been considered an alternative to traditional dye spraying. This results in a clearer visualization of the vascular patterns than through the traditional white light endoscopy imaging methods. The performance of vasculature based polyp localization in both traditional and corresponding virtual coloration by FICE was analyzed. Conclusion. Our analysis showed that FICE based images vascularization features provides a better discrimination of polyps than the traditional white light endoscopy images. PMID- 28616093 TI - Hepatitis E immunosuppressed patients and assisted pregnancy: Is it time to discuss neglected issues? PMID- 28616094 TI - Arbaclofen in fragile X syndrome: results of phase 3 trials. AB - BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. PMID- 28616095 TI - Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety. AB - BACKGROUND: Fragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene (FMR1) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule's calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the Fmr1-/y (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments. METHODS: Fmr1 KO mice and their wild type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl2 treatment on behavior and nuclear ERK1/2 activation. RESULTS: Acamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation. CONCLUSIONS: These data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances. PMID- 28616098 TI - Translation in fragile X: no home runs in the first at-bat. PMID- 28616096 TI - Fragile X targeted pharmacotherapy: lessons learned and future directions. AB - Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts. PMID- 28616100 TI - An ultrasonic caliper device for measuring acoustic nonlinearity. AB - In medical and industrial ultrasound, it is often necessary to measure the acoustic properties of a material. A specific medical application requires measurements of sound speed, attenuation, and nonlinearity to characterize livers being evaluated for transplantation. For this application, a transmission-mode caliper device is proposed in which both transmit and receive transducers are directly coupled to a test sample, the propagation distance is measured with an indicator gage, and receive waveforms are recorded for analysis. In this configuration, accurate measurements of nonlinearity present particular challenges: diffraction effects can be considerable while nonlinear distortions over short distances typically remain small. To enable simple estimates of the nonlinearity coefficient from a quasi-linear approximation to the lossless Burgers' equation, the calipers utilize a large transmitter and plane waves are measured at distances of 15-50 mm. Waves at 667 kHz and pressures between 0.1 and 1 MPa were generated and measured in water at different distances; the nonlinearity coefficient of water was estimated from these measurements with a variability of approximately 10%. Ongoing efforts seek to test caliper performance in other media and improve accuracy via additional transducer calibrations. PMID- 28616099 TI - Epigenetic silencing of SALL3 is an independent predictor of poor survival in head and neck cancer. AB - BACKGROUND: This study examined Sal-like protein (SALL)3 methylation profiles of head and neck cancer (HNSCC) patients at diagnosis and follow-up and evaluated their prognostic significance and value as a biomarker. SALL3 expression was examined in a panel of cell lines by quantitative reverse transcription polymerase chain reaction (RT-PCR). The methylation status of the SALL3 promoter was examined by quantitative methylation-specific PCR. RESULTS: SALL3 promoter methylation was associated with transcriptional inhibition and was correlated with disease recurrence in 64.8% of cases, with an odds ratio of 1.914 (95% confidence interval: 1.157-3.164; P = 0.011) by multivariate Cox proportional hazard regression analysis. SALL3 promoter hypermethylation showed highly discriminatory receiver operator characteristic curve profiles that clearly distinguished HNSCC from adjacent normal mucosal tissue, and was correlated with reduced disease-free survival (DFS) (log-rank test, P = 0.01). Hypermethylation of tumor-related genes was higher among patients with SALL3 methylation than among those without methylation (P < 0.001). Furthermore, SALL3 hypermethylation was associated with expression of TET1, TET2, and DNMT3A genes. CONCLUSIONS: This study suggests that CpG hypermethylation is a likely mechanism of SALL3 gene inactivation, supporting the hypothesis that the SALL3 gene may play a role in the tumorigenesis of HNSCC and may serve as an important biomarker. PMID- 28616102 TI - Female stress urinary incontinence: What's old is new again? PMID- 28616101 TI - The influence of gastric digestion on the development of food allergy. AB - Food allergy represents an increasing health concern worldwide. To identify mechanisms and risk factors associated with food allergy development major research efforts are ongoing. For a long time only food allergens that are resistant to gastric enzymes were accepted to harbor sensitizing capacity via the oral route. However, over the past years several studies reported that even important food allergens can be readily degraded by digestive enzymes. Interestingly, a number of in vitro experiments confirmed that impairment of physiological gastric digestion by elevating gastric pH levels was associated with protein resistance. Additionally, pharmacological gastric acid suppression was found to be a risk factor for food allergy induction. In contrast, protein modifications resulting in increased susceptibility to digestive enzymes were reported to decrease the sensitization capacity via the oral route. The here reviewed data highlight the important gate keeping function of physiological gastric digestion in food allergy. PMID- 28616097 TI - Updated report on tools to measure outcomes of clinical trials in fragile X syndrome. AB - OBJECTIVE: Fragile X syndrome (FXS) has been the neurodevelopmental disorder with the most active translation of preclinical breakthroughs into clinical trials. This process has led to a critical assessment of outcome measures, which resulted in a comprehensive review published in 2013. Nevertheless, the disappointing outcome of several recent phase III drug trials in FXS, and parallel efforts at evaluating behavioral endpoints for trials in autism spectrum disorder (ASD), has emphasized the need for re-assessing outcome measures and revising recommendations for FXS. METHODS: After performing an extensive database search (PubMed, Food and Drug Administration (FDA)/National Institutes of Health (NIH)'s www.ClinicalTrials.gov, etc.) to determine progress since 2013, members of the Working Groups who published the 2013 Report evaluated the available outcome measures for FXS and related neurodevelopmental disorders using the COSMIN grading system of levels of evidence. The latter has also been applied to a British survey of endpoints for ASD. In addition, we also generated an informal classification of outcome measures for use in FXS intervention studies as instruments appropriate to detect shorter- or longer-term changes. RESULTS: To date, a total of 22 double-blind controlled clinical trials in FXS have been identified through www.ClinicalTrials.gov and an extensive literature search. The vast majority of these FDA/NIH-registered clinical trials has been completed between 2008 and 2015 and has targeted the core excitatory/inhibitory imbalance present in FXS and other neurodevelopmental disorders. Limited data exist on reliability and validity for most tools used to measure cognitive, behavioral, and other problems in FXS in these trials and other studies. Overall, evidence for most tools supports a moderate tool quality grading. Data on sensitivity to treatment, currently under evaluation, could improve ratings for some cognitive and behavioral tools. Some progress has also been made at identifying promising biomarkers, mainly on blood-based and neurophysiological measures. CONCLUSION: Despite the tangible progress in implementing clinical trials in FXS, the increasing data on measurement properties of endpoints, and the ongoing process of new tool development, the vast majority of outcome measures are at the moderate quality level with limited information on reliability, validity, and sensitivity to treatment. This situation is not unique to FXS, since reviews of endpoints for ASD have arrived at similar conclusions. These findings, in conjunction with the predominance of parent-based measures particularly in the behavioral domain, indicate that endpoint development in FXS needs to continue with an emphasis on more objective measures (observational, direct testing, biomarkers) that reflect meaningful improvements in quality of life. A major continuous challenge is the development of measurement tools concurrently with testing drug safety and efficacy in clinical trials. PMID- 28616103 TI - Canadian Urological Association position statement on the use of transvaginal mesh. AB - Stress incontinence (SUI) and pelvic organ prolapse (POP) are common conditions. There is high-level evidence that midurethral mesh slings for stress incontinence are effective and safe; however, the rare but serious potential risks of this surgery must be discussed with the patient. The use of transvaginal mesh for prolapse repair does not appear to be supported by the current evidence, and its use should be restricted to specialized pelvic floor surgeons and specific clinical situations. PMID- 28616104 TI - Medicolegal basics and update on transvaginal mesh in Canada. AB - In recent years, midurethral slings (MUS) and transvaginal mesh procedures have experienced blazing growth and popularity. However, the US Food and Drug Administration (FDA) and Health Canada regulatory advisories threw water on that fire and created a confusing environment surrounding their continued usage. MUS usage has continued in Canada and transvaginal mesh kits for pelvic organ prolapse have become a rarity. Several large organizations (the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction [SUFU], the American Urogynecologic Society [AUGS], and the Canadian Urological Association [CUA]) have developed "mesh statements" to clarify the issues surrounding mesh for patients and medical professionals; however, often the legal system sees things differently in either individual cases or class action lawsuits. In this update, some medicolegal basics are outlined and Canadian context on legal proceedings are highlighted. This summary does not constitute legal advice and physicians should contact experts in legal matters for help with consents, complaints, litigation, or questions. PMID- 28616105 TI - "The road to hell is paved with good intentions" (St. Bernard of Clairvaux, c. 1150). PMID- 28616106 TI - The role of preoperative urodynamics in stress urinary incontinence surgery. AB - The routine use of urodynamics prior to incontinence surgery continues to be debated. The evidence available from randomized, control trials suggests that preoperative urodynamics do not improve surgical outcomes and are not cost effective. PMID- 28616107 TI - Decisions regarding use of urodynamic studies in stress urinary incontinence must be made on a case-by-case basis. PMID- 28616108 TI - Advances in basic science methodologies for clinical diagnosis in female stress urinary incontinence. AB - We provide an overview of advanced imaging techniques currently being explored to gain greater understanding of the complexity of stress urinary incontinence (SUI) through better definition of structural anatomic data. Two methods of imaging and analysis are detailed for SUI with or without prolapse: 1) open magnetic resonance imaging (MRI) with or without the use of reference lines; and 2) 3D reconstruction of the pelvis using MRI. An additional innovative method of assessment includes the use of near infrared spectroscopy (NIRS), which uses non invasive photonics in a vaginal speculum to objectively evaluate pelvic floor muscle (PFM) function as it relates to SUI pathology. Advantages and disadvantages of these techniques are described. The recent innovation of open configuration magnetic resonance imaging (MRO) allows images to be captured in sitting and standing positions, which better simulates states that correlate with urinary leakage and can be further enhanced with 3D reconstruction. By detecting direct changes in oxygenated muscle tissue, the NIRS vaginal speculum is able to provide insight into how the oxidative capacity of the PFM influences SUI. The small number of units able to provide patient evaluation using these techniques and their cost and relative complexity are major considerations, but if such imaging can optimize diagnosis, treatment allocation, and selection for surgery enhanced imaging techniques may prove to be a worthwhile and cost-effective strategy for assessing and treating SUI. PMID- 28616109 TI - The management of mixed urinary incontinence in women. AB - Mixed urinary incontinence is a common diagnosis among women with urinary leakage and is often present in women who are unable to characterize their incontinence. Research and optimized clinical treatment of these patients is limited by the challenges in objectively defining and stratifying this population. The evaluation of these patients should follow the same general principles as any assessment of any women with incontinence; however, it is essential to define whether urge or stress incontinence is the predominant symptom. Urodynamics (UDS) may be helpful in this regard and may help predict surgical outcomes. Behavioural therapy, weight loss, and pelvic floor muscle therapy are usually appropriate initial management strategies. In postmenopausal women, vaginal estrogen can be considered, and in women with equal parts stress and urge incontinence or urge predominant mixed incontinence, a trial of anticholinergics or beta-3 agonists is appropriate. In women with stress-predominant or equal parts stress and urge incontinence, stress incontinence surgery can be considered, with the caveat that outcomes are generally worse among women with more severe levels of urgency, success rates may not be as durable, and a significant proportion of women may need additional medical therapy. PMID- 28616110 TI - Pelvic organ prolapse: A primer for urologists. AB - Pelvic organ prolapse (POP) results from weakness or injury of the pelvic floor supports with resulting descent of one or more vaginal compartments (anterior, apical and/or posterior). Women typically become symptomatic from the bulging vaginal wall or related organ dysfunction once this descent reaches the introitus. POP is a common condition, affecting more than half of adult women. Many women presenting to an urologist for stress urinary incontinence or overactive bladder will have associated POP; therefore, it is important for urologists who treat these conditions to be familiar with its diagnosis and management. While POP is part of the core urology training curriculum in some jurisdictions, it is not in Canada.1 This article reviews the diagnosis of POP, including pertinent symptoms to query in the history, important facets of a systematic pelvic examination, and the appropriate use of ancillary tests. Treatment options are also discussed, including conservative measures, pessaries, and various reconstructive and obliterative techniques. PMID- 28616111 TI - Urologists should have a working knowledge of the evaluation and management of POP. PMID- 28616112 TI - Choosing the right sling for your patient. AB - Recent data has demonstrated a one in five lifetime risk of a woman requiring stress urinary incontinence (SUI) surgery. Currently, most women opt for a synthetic midurethral sling (MUS), with over 3.6 million placed worldwide. This article attempts to identify whether a gold standard exists with regards to surgical correction of female SUI. When considering which sling type to use for which incontinent woman, the published data demonstrates excellent results for both synthetic mesh (retropubic or transobturator routes) and fascial pubovaginal slings for most patients. Intrinsic sphincter deficiency does appear to be better treated with the use of a retropubic approach, although still with less than stellar results. With little to differentiate, the treatment of most female SUI may be solely based on which sling the surgeon feels most comfortable performing. Currently, most urologists and gynecologists favour synthetic MUS over fascial slings in surgical-naive patients; however, recent U.S Food and Drug Administration (FDA) warnings concerning the use of mesh in transvaginal surgery have patients questioning the safety of synthetic MUS for the treatment of SUI. PMID- 28616113 TI - Prevention, diagnosis, and management of midurethral mesh sling complications. AB - Midurethral slings (MUS) are a proven effective treatment option for stress urinary incontinence (SUI) and have become the gold standard in most centres in North America. MUS implantation can be associated with risks that are common to all anti-incontinence surgeries, and others which are unique. This article reviews the intraoperative and the early and late postoperative risks associated with these procedures, with insights into their prevention, diagnosis, and management drawn from the literature and expert opinion. In most cases, careful patient counselling before and after surgery, along with meticulous surgical technique, can mitigate risk and patient concern. Even in the best of hands, however, complications will occur, so surgeons must have a high index of suspicion and a low threshold to investigate. PMID- 28616114 TI - Midurethral sling complications. PMID- 28616115 TI - Management of patients with stress urinary incontinence after failed midurethral sling. AB - Surgical failure rates after midurethral sling (MUS) procedures are variable and range from approximately 8-57% at five years of followup. The disparity in long term failure rates is explained by a lack of long-term followup and lack of a clear definition of what constitutes failure. A recent Cochrane review illustrates that no high-quality data exists to recommend or refute any of the different management strategies for recurrent or persistent stress urinary incontinence (SUI) after failed MUS surgery. Clinical evaluation requires a complete history, physical examination, and establishment of patient goals. Conservative treatment measures include pelvic floor physiotherapy, incontinence pessary dish, commercially available devices (Uresta(r), Impressa(r)), or medical therapy. Minimally invasive therapies include periurethral bulking agents (bladder neck injections) and sling plication. Surgical options include repeat MUS with or without mesh removal, salvage autologous fascial sling or Burch colposuspension, or salvage artificial urinary sphincter insertion. In this paper, we present the available evidence to support each of these approaches and include the management strategy used by our review panel for patients that present with SUI after failed midurethral sling. PMID- 28616116 TI - The pubovaginal sling: Reintroducing an old friend. AB - The surgical management of female stress urinary incontinence (SUI) has evolved over the past century, using various techniques of retropubic colposuspensions and sling procedures. In the past two decades, the sling has become the mainstay of surgical treatment of SUI, with the synthetic midurethral sling (MUS) leading the way. With the recent concerns raised by the U.S. Food and Drug Administration (FDA) and Health Canada about the safety of vaginal surgery using mesh implants, including the MUS, urologists and gynecologists should be familiar with suitable alternatives, including the pubovaginal sling (PVS), which often incorporates autologous fascia. Surgeons should be expected to discuss the surgical options to patients in more detail so that an informed decision can be made by both parties on which surgery to choose. Despite the MUS still being considered the "gold standard" by many, both the urologist and gynecologist who manage SUI should understand the indications for a PVS with autologous fascia, as well as its surgical technique and outcomes. This knowledge is required to aid in the decision-making of both the patient and her surgeon. In this article, the role of the PVS and the description of its surgical technique are presented. PMID- 28616117 TI - Periurethral bulking agents for female stress urinary incontinence in Canada. AB - Urethral bulking aims to improve urethral mucosal coaptation, and thus outlet resistance, in an effort to limit stress-induced leakage. While efforts have been made to employ bulking agents to treat stress urinary incontinence (SUI) for more than 100 years, we remain wanting for the perfect injectable. Regardless of the agent studied, efficacy is modest at best, repeat injections are the norm, and long-term followup is conspicuously lacking. This treatment, however, fills an important need in our armamentarium against SUI, serving those patients who are not candidates for more invasive interventions and those with multiple prior failed surgeries. This review offers a contemporary discussion on the role of periurethral bulking therapy in Canada, along with practical aspects of its application. PMID- 28616118 TI - Stress urinary incontinence in women: Current and emerging therapeutic options. AB - Surgical management of stress urinary incontinence (SUI) is most commonly achieved by midurethral synthetic sling (MUS) insertion as a first-line surgical option. A great deal of research continues to evolve new management strategies to reach an optimal balance of high efficacy and minimal adverse events. This expert opinion review provides a brief and comprehensive discussion of recent advances and ongoing research in the management of SUI, with an emphasis on single incision mini-slings, vaginal laser treatment, and cell-based therapy. It is based on data obtained from numerous published meta-analyses and original studies identified through literature search. Single-incision mini-slings appear equally effective initially compared with standard MUS (retropubic or transobturator) for the treatment of female SUI; however, this efficacy lacks durability evidence beyond one-year followup. There is a lack of sufficient clinical evidence to currently confirm long-term safety and effectiveness of cell-therapy and non ablative vaginal laser therapy, besides suggestion of apparent initial safety. There are still significant challenges to overcome before widespread clinical practice of the latter two modalities. Future research should be aimed at identifying groups of patients who might benefit from these minimally invasive therapeutic options. PMID- 28616119 TI - New research in bladder cancer, ASCO-GU 2017. PMID- 28616120 TI - New research in kidney cancer, ASCO-GU 2017. PMID- 28616121 TI - New research in prostate cancer, ASCO-GU 2017. PMID- 28616122 TI - New research in testicular cancer, ASCO-GU 2017. PMID- 28616123 TI - The Unexpected Hand Patient: Invited Commentary. PMID- 28616124 TI - Psychoneuroimmunoendocrinology: clinical implications. AB - Psychoneuroimmunoendocrinology, which was first described in 1936, is the study of the interactions between the psyche, neural and endocrine functions and immune responses. The aim of psychoneuroimmunoendocrinology is to apply medical knowledge to the treatment of different allergic, immune, autoimmune, rheumatic, neoplastic, endocrine, cardiovascular and dental pathologies, among other disorders. Epigenetic factors and major stresses from different types of stimuli acting through distinct pathways and neurotransmitters are highly involved in altering the psychoneuroimmunoendocrine axis, resulting in the emergence of disease. The main purpose of this report is to expand the understanding of psychoneuroimmunoendocrinology and to demonstrate the importance of the above mentioned interactions in the etiology of multiple pathologies. In this review, a search of the medical literature using PubMed (free access search engine for the Medline database of the National Library of Medicine of the United States) over the years 1936 to 2016 was conducted, and descriptive and experimental studies and reviews of the scientific literature were included. PMID- 28616125 TI - Mechanisms of Neurotoxic Symptoms as a Result of Breast Cancer and Its Treatment: Considerations on the Contribution of Stress, Inflammation, and Cellular Bioenergetics. AB - PURPOSE OF REVIEW: Breast cancer and its treatment are associated with a range of neurotoxic symptoms, such as fatigue, cognitive impairment, and pain. Although these symptoms generally subside after treatment completion, they become chronic in a significant subset of patients. We here summarize recent findings on neuroinflammation, stress, and mitochondrial dysfunction as mechanistic pathways leading to neurotoxic symptom experience in breast cancer patients and survivors. RECENT FINDINGS: Neuroinflammation related to stress or cancer treatment and stress resulting from diagnosis, treatment, or (cancer-related) worrying are important predictors of a neurotoxic symptom experience, both during and after treatment for breast cancer. Both inflammation and stress hormones, as well as cancer treatment, can induce mitochondrial dysfunction resulting in reduced cellular energy. SUMMARY: We propose reduced cellular energy (mitochondrial dysfunction) induced by inflammation, oxygen radical production, and stress as a result of cancer and/or cancer treatment as a final mechanism underlying neurotoxic symptoms. PMID- 28616126 TI - Autistic traits affect interpersonal motor coordination by modulating strategic use of role-based behavior. AB - BACKGROUND: Despite the fact that deficits in social communication and interaction are at the core of Autism Spectrum Conditions (ASC), no study has yet tested individuals on a continuum from neurotypical development to autism in an on-line, cooperative, joint action task. In our study, we aimed to assess whether the degree of autistic traits affects participants' ability to modulate their motor behavior while interacting in a Joint Grasping task and according to their given role. METHODS: Sixteen pairs of adult participants played a cooperative social interactive game in which they had to synchronize their reach-to-grasp movements. Pairs were comprised of one ASC and one neurotypical with no cognitive disability. In alternate experimental blocks, one participant knew what action to perform (instructed role) while the other had to infer it from his/her partner's action (adaptive role). When in the adaptive condition, participants were told to respond with an action that was either opposite or similar to their partner. Participants also played a non-social control game in which they had to synchronize with a non-biological stimulus. RESULTS: In the social interactive task, higher degree of autistic traits predicted less ability to modulate joint action according to one's interactive role. In the non-social task, autistic traits did not predict differences in movement preparation and planning, thus ruling out the possibility that social interactive task results were due to basic motor or executive function difficulties. Furthermore, when participants played the non-social game, the higher their autistic traits, the more they were interfered by the non-biological stimulus. CONCLUSIONS: Our study shows for the first time that high autistic traits predict a stereotypical interaction style when individuals are required to modulate their movements in order to coordinate with their partner according to their role in a joint action task. Specifically, the infrequent emergence of role-based motor behavior modulation during on-line motor cooperation in participants with high autistic traits sheds light on the numerous difficulties ASC have in nonverbal social interactions. PMID- 28616127 TI - New coordination features; a bridging pyridine and the forced shortest non covalent distance between two CO32- species. AB - The aerobic reaction of the multidentate ligand 2,6-bis-(3-oxo-3-(2 hydroxyphenyl)-propionyl)-pyridine, H4L, with Co(ii) salts in strong basic conditions produces the clusters [Co4(L)2(OH)(py)7]NO3 (1) and [Co8Na4(L)4(OH)2(CO3)2(py)10](BF4)2 (2). Analysis of their structure unveils unusual coordination features including a very rare bridging pyridine ligand or two trapped carbonate anions within one coordination cage, forced to stay at an extremely close distance (dO...O = 1.946 A). This unprecedented non-bonding proximity represents a meeting point between long covalent interactions and "intermolecular" contacts. These original motifs have been analysed here through DFT calculations, which have yielded interaction energies and the reduced repulsion energy experimented by both CO32- anions when located in close proximity inside the coordination cage. PMID- 28616128 TI - Establishing hierarchy: the chain of events leading to the formation of silicalite-1 nanosheets. AB - In applying a multi-scale spectroscopic and computational approach, we demonstrate that the synthesis of stacked zeolite silicalite-1 nanosheets, in the presence of a long-tail diquaternary ammonium salt surfactant, proceeds through a pre-organised phase in the condensed state. In situ small-angle X-ray scattering, coupled to paracrystalline theory, and backed by electron microscopy, shows that this phase establishes its meso-scale order within the first five hours of hydrothermal synthesis. Quasi in situ vibrational and solid-state NMR spectroscopy reveal that this meso-shaped architecture already contains some elementary zeolitic features. The key to this coupled organisation at both micro- and meso-scale, is a structure-directing agent that is ambifunctional in shaping silica at the meso-scale whilst involved in molecular recognition at the micro scale. The latter feature is particularly important and requires the structure directing agent to reside within the silica matrix already at early stages of the synthesis. From here, molecular recognition directs stabilization of precursor species and their specific embedding into a lattice, as shown by force-field molecular dynamics calculations. These calculations, in line with experiment, further show how it is possible to subtly tune both the zeolite topology and aspect ratio of the condensating crystals, by modifying the headgroup of the structure-directing agent. PMID- 28616129 TI - Non-local real-space analysis of chiral optical signals. AB - A spatially non-local response tensor description of linear chiral signals such as circular dichroism is developed. By working directly with the vector potential rather that the electric and magnetic fields, we recast the signals in terms of correlation functions of charge and current densities and avoid the tedious expansion in multipoles. PMID- 28616130 TI - Quantitative investigation of human cell surface N-glycoprotein dynamics. AB - Surface glycoproteins regulate nearly every extracellular event and they are dynamic for cells to adapt to the ever-changing extracellular environment. These glycoproteins contain a wealth of information on cellular development and disease states, and have significant biomedical implications. Systematic investigation of surface glycoproteins will result in a better understanding of surface protein functions, cellular activities and the molecular mechanisms of disease. However, it is extraordinarily challenging to specifically and globally analyze surface glycoproteins. Here we designed the first method to systematically analyze surface glycoprotein dynamics and measure their half-lives by integrating pulse chase labeling, selective enrichment of surface glycoproteins, and multiplexed proteomics. The current results clearly demonstrated that surface glycoproteins with catalytic activities were more stable than those with binding and receptor activities. Glycosylation sites located outside of any domain had a notably longer median half-life than those within domains, which strongly suggests that glycans within domains regulate protein interactions with other molecules while those outside of domains mainly play a role in protecting the protein from degradation. This method can be extensively applied to biological and biomedical research. PMID- 28616131 TI - Size-dependence of carbon nanotube confinement in catalysis. AB - An increasing number of studies have demonstrated that confinement within carbon nanotubes (CNTs) provides an effective approach for the modulation of catalysis. It was generally predicted that confinement became stronger with a decreasing diameter of CNTs. However, our present study here overturns the previous expectation: the influence on catalysis is not monotonic. Instead, it exhibits a volcano relationship with CNT diameter. Taking Pt catalyzing O2 conversion and Re catalyzing N2 conversion as probes using density functional theory, we show that only within tubes with an i.d. of ~1 nm can the activity of metal clusters be enhanced to its maximum. Furthermore, confinement only enhances the catalytic activity of metals with strong intrinsic binding with reactants, whereas it is suppressed for those with weak binding. These findings shed further light on the fundamental effects of confinement on catalysis, and could guide more rational design of confined catalysts. PMID- 28616132 TI - Pressure induced polymerization of acetylide anions in CaC2 and 107 fold enhancement of electrical conductivity. AB - Transformation between different types of carbon-carbon bonding in carbides often results in a dramatic change of physical and chemical properties. Under external pressure, unsaturated carbon atoms form new covalent bonds regardless of the electrostatic repulsion. It was predicted that calcium acetylide (also known as calcium carbide, CaC2) polymerizes to form calcium polyacetylide, calcium polyacenide and calcium graphenide under high pressure. In this work, the phase transitions of CaC2 under external pressure were systematically investigated, and the amorphous phase was studied in detail for the first time. Polycarbide anions like C66- are identified with gas chromatography-mass spectrometry and several other techniques, which evidences the pressure induced polymerization of the acetylide anions and suggests the existence of the polyacenide fragment. Additionally, the process of polymerization is accompanied with a 107 fold enhancement of the electrical conductivity. The polymerization of acetylide anions demonstrates that high pressure compression is a viable route to synthesize novel metal polycarbides and materials with extended carbon networks, while shedding light on the synthesis of more complicated metal organics. PMID- 28616133 TI - Naked eye detection of multiple tumor-related mRNAs from patients with photonic crystal micropattern supported dual-modal upconversion bioprobes. AB - Development of a portable device for the detection of multiple mRNAs is a significant need in the early diagnosis of cancer. We have designed a biochip based mRNA detection device by combining a hydrophilic-hydrophobic micropattern with upconversion luminescence (UCL) probes. The device achieves highly sensitive detection, using the naked eye, of multiple mRNAs among patient samples. The high sensitivity is attributed to enrichment of the target concentration and a fluorescence enhancement effect. In addition, since the photonic crystal (PC) dot biochip is functionalized with dual-wavelength excitation UCL probes, two kinds of mRNAs in the heterogeneous biological samples are detected simultaneously, and the corresponding luminescence signals are captured using an unmodified camera phone. The biochip-based mRNA detection device reported here demonstrates that multiple mRNAs extracted from patient samples can be simultaneously and sensitively detected in a visual way without sophisticated instrumentation. Therefore, this device is promising for real-time detection of multiple biomarkers in patient samples, and it is anticipated that it will provide a powerful tool for convenient early diagnosis of cancer. PMID- 28616134 TI - Photodriven hydrogen evolution by molecular catalysts using Al2O3-protected perylene-3,4-dicarboximide on NiO electrodes. AB - The design of efficient hydrogen-evolving photocathodes for dye-sensitized photoelectrochemical cells (DSPECs) requires the incorporation of molecular light absorbing chromophores that are capable of delivering reducing equivalents to molecular proton reduction catalysts at rates exceeding those of charge recombination events. Here, we report the functionalization and kinetic analysis of a nanostructured NiO electrode with a modified perylene-3,4-dicarboximide chromophore (PMI) that is stabilized against degradation by atomic layer deposition (ALD) of thick insulating Al2O3 layers. Following photoinduced charge injection into NiO in high yield, films with Al2O3 layers demonstrate longer charge separated lifetimes as characterized via femtosecond transient absorption spectroscopy and photoelectrochemical techniques. The photoelectrochemical behavior of the electrodes in the presence of Co(ii) and Ni(ii) molecular proton reduction catalysts is examined, revealing reduction of both catalysts. Under prolonged irradiation, evolved H2 is directly observed by gas chromatography supporting the applicability of PMI embedded in Al2O3 as a photocathode architecture in DSPECs. PMID- 28616135 TI - Carbon dioxide binding at a Ni/Fe center: synthesis and characterization of Ni(eta1-CO2-kappaC) and Ni-MU-CO2-kappaC:kappa2O,O'-Fe. AB - The degree of CO2 activation can be tuned by incorporating a distinct electronic coordination environment at the nickel center. A mononuclear nickel carboxylate species (Ni-CO2, 3) and a dinuclear nickel-iron carboxylate species (Ni-CO2-Fe, 5) were prepared. The structure of 3 reveals a rare eta1-kappaC binding mode of CO2, while that of 5 shows bridging CO2 binding (MU2-kappaC:kappa2O,O') between the nickel and iron, presented as the first example of a nickel-MU-CO2-iron species. The structural analyses of 3 and 5 based on XRD and DFT data reveal a higher degree of CO2 activation in 5, imparted by the additional interaction with an iron ion. PMID- 28616136 TI - Highly selective olefin-assisted palladium-catalyzed oxidative carbocyclization via remote olefin insertion. AB - A highly selective olefin-assisted palladium-catalyzed oxidative carbocyclization via remote olefin insertion to afford cyclohexenes has been developed. It was shown that the assisting olefin moiety was indispensable for the formation of the cyclohexene product. Furthermore, preliminary studies on chiral anion-induced asymmetrical carbocyclization-borylation of enallenes have been carried out. PMID- 28616137 TI - Multi-stimuli responsive and multi-functional oligoaniline-modified vitrimers. AB - Smart polymers have been playing indispensable roles in our lives. However, it is challenging to combine more than three stimuli-responses or functionalities into one polymer, not to mention integrating multi-stimuli responsivity and multi functionality at the same time. Vitrimers, an emerging type of materials, are covalently crosslinked networks that can be reprocessed but are still infusible and insoluble. Herein, we show that simply introducing oligoaniline into a vitrimer results in a covalently crosslinked material that can respond to six different stimuli (heat, light, pH, voltage, metal ions and redox chemicals) and perform six functions (shape memory, welding, healing, recycling, electro chromism and adsorption of metal ions). New properties, which cannot be found in either neat vitrimers or oligoanilines, are generated, including photo-heal ability, photo-weldability, pH-induced shape memory, enhancement of the photo thermal effect due to metal ions absorption and simultaneous multi-tasking operations. Furthermore, the material is low-cost and suitable for large-scale mass production. PMID- 28616138 TI - The HOF structures of nitrotetraphenylethene derivatives provide new insights into the nature of AIE and a way to design mechanoluminescent materials. AB - This study probes the effect of intramolecular rotations on aggregation-induced emission (AIE) and leads to a kind of supramolecular mechanoluminescent material. Two hydrogen-bonded organic frameworks (HOFs), namely HOFTPE3N and HOFTPE4N, have been constructed from nitro-substituted tetraphenylethene (TPE) building blocks, namely tris(4-nitrophenyl)phenylethene (TPE3N) and tetrakis(4-nitrophenyl)ethene (TPE4N). Using single-crystal X-ray diffraction analysis, two types of pores are observed in the HOFTPE4N supramolecular structure. The pore sizes are 5.855 A * 5.855 A (alpha pores) and 7.218 A * 7.218 A (beta pores). Powder X-ray diffraction and differential scanning calorimetry studies further reveal that the alpha pores, which contain nitrophenyl rings, quench the emission of HOFTPE4N. This emission can be turned on by breaking the alpha pores in the HOFs by grinding the sample. Temperature-dependent emission studies demonstrate that the emission quenching of HOFTPE4N is attributed to the intramolecular rotations of nitro-substituted phenyl units within the space of the alpha pores. These results clearly reveal AIE by controlling the intramolecular rotations, which can serve as a basis for developing mechanoluminescent materials. PMID- 28616139 TI - Rh(iii)-catalyzed double C-H activation of aldehyde hydrazones: a route for functionalized 1H-indazole synthesis. AB - A novel and straightforward strategy for functionalized 1H-indazoles is realized by the Rh(iii)-catalyzed double C-H activation and C-H/C-H cross coupling of readily available aldehyde phenylhydrazones. The reaction is scalable and various 1H-indazoles could be afforded in moderate to high yields with good functional group compatibility. Mechanism experiments and DFT calculations suggest the distinctive Rh(iii)-catalyzed C-H/C-H cross coupling reaction underwent a cascade C(aryl)-H bond metalation, C(aldhyde)-H bond insertion and reductive elimination process. PMID- 28616140 TI - Photochromic benzo[b]phosphole oxide with excellent thermal irreversibility and fatigue resistance in the thin film solid state via direct attachment of dithienyl units to the weakly aromatic heterocycle. AB - A novel photochromic benzo[b]phosphole oxide has been demonstrated to display photochromic properties with excellent fatigue resistance and thermal irreversibility in polymethylmethacrylate (PMMA) thin film under ambient conditions. The remarkable photochromic behaviour can be achieved by rational molecular design, in which the weakly aromatic phosphole oxide is directly incorporated into the photo-responsive dithienylethene units. Photopatterning via photoinduced colouration and decolouration has been performed to demonstrate the repeatable and distinct transformation between the bistable states, making it a promising candidate with photoswitching properties for optoelectronic applications. PMID- 28616141 TI - A general strategy for colloidal stable ultrasmall amorphous mineral clusters in organic solvents. AB - While nature exerts precise control over the size and chemical composition of minerals, this is still a challenging task for artificial syntheses. Despite its significance, until now, there are still no reports on colloidal mineral nanoparticles in the subnanometer range. Here we developed a general gas diffusion strategy using 10,12-pentacosadiynoic acid as a ligand and ethanol as a solvent to fabricate stable amorphous mineral clusters with a core size of less than 2 nm. First discovered for CaCO3, the method was successfully extended to produce monolayer protected clusters of MgCO3, SrCO3, Eu2(CO3)3, Tb2(CO3)3, Ce2(CO3)3, Ca x (PO4) y , CaC2O4 and their hybrid minerals, Ca x Mg y (CO3) z and Ca x (CO3) y (PO4) z . All the mineral clusters can be well dispersed in organic solvents like toluene, and are stable for a long period without further crystallization. Our work paves a way for the artificial synthesis of colloidal mineral clusters, which may have various uses in both fundamental research and industry. PMID- 28616142 TI - Alkene hydrogenation activity of enoate reductases for an environmentally benign biosynthesis of adipic acid. AB - Adipic acid, a precursor for Nylon-6,6 polymer, is one of the most important commodity chemicals, which is currently produced from petroleum. The biosynthesis of adipic acid from glucose still remains challenging due to the absence of biocatalysts required for the hydrogenation of unsaturated six-carbon dicarboxylic acids to adipic acid. Here, we demonstrate the first enzymatic hydrogenation of 2-hexenedioic acid and muconic acid to adipic acid using enoate reductases (ERs). ERs can hydrogenate 2-hexenedioic acid and muconic acid producing adipic acid with a high conversion rate and yield in vivo and in vitro. Purified ERs exhibit a broad substrate spectrum including aromatic and aliphatic 2-enoates and a significant oxygen tolerance. The discovery of the hydrogenation activity of ERs contributes to an understanding of the catalytic mechanism of these poorly characterized enzymes and enables the environmentally benign biosynthesis of adipic acid and other chemicals from renewable resources. PMID- 28616143 TI - Highly enantioselective metallation-substitution alpha to a chiral nitrile. AB - We report the deprotonation of a chiral nitrile and reaction of the resulting chiral organometallic species with a variety of electrophiles to give highly enantiomerically enriched 2-substituted nitrile products. The nitrile was treated with TMPMgCl and the resulting anion, an asymmetric alpha cyano Grignard species, was found to be configurationally stable at low temperature for a short time (half-life several minutes at -104 degrees C). PMID- 28616144 TI - Mechanistic study of the rhodium-catalyzed carboxylation of simple aromatic compounds with carbon dioxide. AB - A detailed mechanism of the Rh(i)-catalyzed carboxylation of simple aromatic compounds via C-H bond activation was investigated. Kinetic studies with model compounds of the postulated key intermediates revealed that 14-electron complexes, RhMe(dcype) and RhPh(dcype), participated in the C-H bond activation step and the carboxylation step, respectively. Interestingly, the undesired carboxylation of RhMe(dcype) to give acetic acid was found to be much faster than the desired C-H bond activation reaction under stoichiometric conditions, however, the C-H bond activation reaction could occur under catalytic conditions. Careful controlled experiments revealed that C-H bond activation using RhMe(dcype) became competitive with its direct carboxylation under the condition that the concentration of CO2 in the liquid phase was rather low. This factor could be controlled to some extent by mechanical factors such as the stirring rate and the shape of the reaction vessel. The resting state of the rhodium species under catalytic conditions was found to be [RhCl(dcype)]2, and the proposed intermediates such as RhMe(dcype) and Rh(OBz)(dcype) were readily converted to the most stable state, [RhCl(dcype)]2, via transmetallation with [Al]-Cl species, thus preventing the decomposition of the active catalytic species. PMID- 28616145 TI - A family of cis-macrocyclic diphosphines: modular, stereoselective synthesis and application in catalytic CO2/ethylene coupling. AB - A family of cis-macrocyclic diphosphines was prepared in just three steps from white phosphorus and commercial materials using a modular synthetic approach. Alkylation of bicyclic diphosphane 3,4,8,9-tetramethyl-1,6 diphosphabicyclo(4.4.0)deca-3,8-diene, or P2(dmb)2, produced phosphino phosphonium salts [R-P2(dmb)2]X, where R is methyl, benzyl and isobutyl, in yields of 90-96%. Treatment of these salts with organolithium or Grignard reagents yielded symmetric and unsymmetric macrocyclic diphosphines of the form cis-1-R-6-R'-3,4,8,9-tetramethyl-2,5,7,10-tetrahydro-1,6-DiPhospheCine, or R,R' DPC, in which R' is methyl, cyclohexyl, phenyl or mesityl, in yields of 46-94%. Alternatively, symmetric diphosphine Cy2-DPC was synthesized in 74% yield from the dichlorodiphosphine Cl2P2(dmb)2. As a first application, these cis macrocyclic diphosphines were used as ligands in the nickel-catalyzed synthesis of acrylate from CO2 and ethylene, for which they showed promising catalytic activity. PMID- 28616146 TI - Infrared spectroscopy of the nitrogenase MoFe protein under electrochemical control: potential-triggered CO binding. AB - We demonstrate electrochemical control of the nitrogenase MoFe protein, in the absence of Fe protein or ATP, using europium(iii/ii) polyaminocarboxylate complexes as electron transfer mediators. This allows the potential dependence of proton reduction and inhibitor (CO) binding to the active site FeMo-cofactor to be established. Reduction of protons to H2 is catalyzed by the wild type MoFe protein and beta-98Tyr->His and beta-99Phe->His variants of the MoFe protein at potentials more negative than -800 mV (vs. SHE), with greater electrocatalytic proton reduction rates observed for the variants compared to the wild type protein. Electrocatalytic proton reduction is strongly attenuated by carbon monoxide (CO), and the potential-dependence of CO binding to the FeMo-cofactor is determined by in situ infrared (IR) spectroelectrochemistry. The vibrational wavenumbers for CO coordinated to the FeMo-cofactor are consistent with earlier IR studies on the MoFe protein with Fe protein/ATP as reductant showing that electrochemically generated states of the protein are closely related to states generated with the native Fe protein as electron donor. PMID- 28616147 TI - Stereodivergent, Diels-Alder-initiated organocascades employing alpha,beta unsaturated acylammonium salts: scope, mechanism, and application. AB - Chiral alpha,beta-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels-Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic gamma- and delta-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Bronsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol-Bronsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects. PMID- 28616148 TI - The structural assembly switch of cell division protein FtsZ probed with fluorescent allosteric inhibitors. AB - FtsZ is a widely conserved tubulin-like GTPase that directs bacterial cell division and a new target for antibiotic discovery. This protein assembly machine cooperatively polymerizes forming single-stranded filaments, by means of self switching between inactive and actively associating monomer conformations. The structural switch mechanism was proposed to involve a movement of the C-terminal and N-terminal FtsZ domains, opening a cleft between them, allosterically coupled to the formation of a tight association interface between consecutive subunits along the filament. The effective antibacterial benzamide PC190723 binds into the open interdomain cleft and stabilizes FtsZ filaments, thus impairing correct formation of the FtsZ ring for cell division. We have designed fluorescent analogs of PC190723 to probe the FtsZ structural assembly switch. Among them, nitrobenzoxadiazole probes specifically bind to assembled FtsZ rather than to monomers. Probes with several spacer lengths between the fluorophore and benzamide moieties suggest a binding site extension along the interdomain cleft. These probes label FtsZ rings of live Bacillus subtilis and Staphylococcus aureus, without apparently modifying normal cell morphology and growth, but at high concentrations they induce impaired bacterial division phenotypes typical of benzamide antibacterials. During the FtsZ assembly-disassembly process, the fluorescence anisotropy of the probes changes upon binding and dissociating from FtsZ, thus reporting open and closed FtsZ interdomain clefts. Our results demonstrate the structural mechanism of the FtsZ assembly switch, and suggest that the probes bind into the open clefts in cellular FtsZ polymers preferably to unassembled FtsZ in the bacterial cytosol. PMID- 28616149 TI - Is iron unique in promoting electrical conductivity in MOFs? AB - Identifying the metal ions that optimize charge transport and charge density in metal-organic frameworks is critical for systematic improvements in the electrical conductivity in these materials. In this work, we measure the electrical conductivity and activation energy for twenty different MOFs pertaining to four distinct structural families: M2(DOBDC)(DMF)2 (M = Mg2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+); H4DOBDC = 2,5-dihydroxybenzene-1,4-dicarboxylic acid; DMF = N,N-dimethylformamide), M2(DSBDC)(DMF)2 (M = Mn2+, Fe2+; H4DSBDC = 2,5-disulfhydrylbenzene-1,4-dicarboxylic acid), M2Cl2(BTDD)(DMF)2 (M = Mn2+, Fe2+, Co2+, Ni2+; H2BTDD = bis(1H-1,2,3-triazolo[4,5-b],[4',5' i]dibenzo[1,4]dioxin), and M(1,2,3-triazolate)2 (M = Mg2+, Mn2+, Fe2+, Co2+, Cu2+, Zn2+, Cd2+). This comprehensive study allows us to single-out iron as the metal ion that leads to the best electrical properties. The iron-based MOFs exhibit at least five orders of magnitude higher electrical conductivity and significantly smaller charge activation energies across all different MOF families studied here and stand out materials made from all other metal ions considered here. We attribute the unique electrical properties of iron-based MOFs to the high-energy valence electrons of Fe2+ and the Fe3+/2+ mixed valency. These results reveal that incorporating Fe2+ in the charge transport pathways of MOFs and introducing mixed valency are valuable strategies for improving electrical conductivity in this important class of porous materials. PMID- 28616150 TI - Pitch Perception in Tone Language-Speaking Adults With and Without Autism Spectrum Disorders. AB - Enhanced low-level pitch perception has been universally reported in autism spectrum disorders (ASD). This study examined whether tone language speakers with ASD exhibit this advantage. The pitch perception skill of 20 Cantonese-speaking adults with ASD was compared with that of 20 neurotypical individuals. Participants discriminated pairs of real syllable, pseudo-syllable (syllables that do not conform the phonotactic rules or are accidental gaps), and non-speech (syllables with attenuated high-frequency segmental content) stimuli contrasting pitch levels. The results revealed significantly higher discrimination ability in both groups for the non-speech stimuli than for the pseudo-syllables with one semitone difference. No significant group differences were noted. Different from previous findings, post hoc analysis found that enhanced pitch perception was observed in a subgroup of participants with ASD showing no history of delayed speech onset. The tone language experience may have modulated the pitch processing mechanism in the speakers in both ASD and non-ASD groups. PMID- 28616152 TI - Magnetically levitated mesenchymal stem cell spheroids cultured with a collagen gel maintain phenotype and quiescence. AB - Multicellular spheroids are an established system for three-dimensional cell culture. Spheroids are typically generated using hanging drop or non-adherent culture; however, an emerging technique is to use magnetic levitation. Herein, mesenchymal stem cell spheroids were generated using magnetic nanoparticles and subsequently cultured within a type I collagen gel, with a view towards developing a bone marrow niche environment. Cells were loaded with magnetic nanoparticles, and suspended beneath an external magnet, inducing self-assembly of multicellular spheroids. Cells in spheroids were viable and compared to corresponding monolayer controls, maintained stem cell phenotype and were quiescent. Interestingly, core spheroid necrosis was not observed, even with increasing spheroid size, in contrast to other commonly used spheroid systems. This mesenchymal stem cell spheroid culture presents a potential platform for modelling in vitro bone marrow stem cell niches, elucidating interactions between cells, as well as a useful model for drug delivery studies. PMID- 28616153 TI - A multidisciplinary approach to the successful management of Gorlin syndrome. AB - Gorlin-Goltz syndrome (GGS) is a rare genetic syndrome with variable expressivity and autosomal dominant inheritance. The major features of GGS include numerous basal cell carcinomas (BCCs), keratocysts of the jaw, palmar/plantar pits and calcification of the falx cerebri. Authors report the case of a 51-year-old male with a 19-year history of GGS and multiple BCCs of the head and neck. He presented with a large ulcerating lesion on the right side of his face involving cutaneous, subcutaneous and muscular tissues of the temporal and orbital region. Additionally, magnetic resonance imaging revealed involvement of the right zygomatic bone, infratemporal fossa and mandible. This case is notable in that BCC invasion of the facial bones is rare. Extensive resection and reconstruction with a latissimus dorsi microvascular free muscle flap was performed. The success of this challenging case exemplifies the need for a multidisciplinary team that included dermatology, plastic surgery, oculoplastics and otolaryngology. PMID- 28616151 TI - Therapeutic potential of dental stem cells. AB - Stem cell biology has become an important field in regenerative medicine and tissue engineering therapy since the discovery and characterization of mesenchymal stem cells. Stem cell populations have also been isolated from human dental tissues, including dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla, dental follicle progenitor cells, and periodontal ligament stem cells. Dental stem cells are relatively easily obtainable and exhibit high plasticity and multipotential capabilities. The dental stem cells represent a gold standard for neural-crest derived bone reconstruction in humans and can be used for the repair of body defects in low-risk autologous therapeutic strategies. The bioengineering technologies developed for tooth regeneration will make substantial contributions to understand the developmental process and will encourage future organ replacement by regenerative therapies in a wide variety of organs such as the liver, kidney, and heart. The concept of developing tooth banking and preservation of dental stem cells is promising. Further research in the area has the potential to herald a new dawn in effective treatment of notoriously difficult diseases which could prove highly beneficial to mankind in the long run. PMID- 28616154 TI - Cutaneous presentation of gastrointestinal adenocarcinoma. AB - Seeding of a central nervous system malignancy to the abdominal cavity is an uncommon but well documented complication of a ventriculoperitoneal (VP) shunt. However, the metastasis of a primary gastrointestinal cancer to the skin via a VP shunt is extremely rare. We report the clinical case of an 85-year-old male who presented with a right upper quadrant nodule over his shunt, which on histopathology and tumour marker profile was diagnosed as an adenocarcinoma of likely upper gastrointestinal origin. This case illustrates the importance of proceeding to biopsy to inform prognosis and management, despite the risks of shunt infection. PMID- 28616155 TI - Severe pelvic fracture with profound hypotension: a case report and treatment algorithm. AB - Approximately 9% of all blunt trauma patients suffer pelvic fractures. These fractures can range from insignificant and requiring almost no therapy to massive destruction of the pelvic ring with associated with multisystem injury and life threatening hypotension which mandates the attention of the trauma surgeon, the orthopedic surgeon, the interventional radiologists and possibly other subspecialists. We present a case of a patient who presented to the emergency room in extremis from massive bleeding from a complex pelvic fracture. The patient developed abdominal compartment syndrome. The patient was emergently taken to the operating room but we were unable to control his pelvic bleeding. We propose an algorithm which might be helpful in these critically ill patients. PMID- 28616156 TI - Primary solitary peritoneal tumor of the abdominal wall-report of a rare case and review of the literature. AB - Abdominal wall tumors are sometimes diagnosed as metastases of ovarian cancer, however, primary peritoneal tumors should be taken into consideration in the final diagnosis. A 49-year-old female patient was admitted in our Department for the excision of a pulpable abdominal wall lump, with no other abnormalities shown on imaging investigation. On histology examination, the excised specimen revealed characteristics of metastatic high-grade serous ovarian carcinoma. Total hysterectomy, bilateral oophorectomy, omentectomy and appendectomy were performed. No signs of malignancy were proved on histology, leading to the final diagnosis of a primary serous peritoneal tumor. This is the third described case of solitary primary serous peritoneal tumor located in the abdominal wall. This condition should be included in the differential diagnosis of a probable metastatic ovarian carcinoma, as both present similar histologic characteristics. PMID- 28616157 TI - Constant maintenance of an alternative route of coronary flow in radical surgery for gastric cancer following coronary artery bypass grafting involving the right gastroepiploic artery: a case report. AB - We describe a 64-year-old man diagnosed as having gastric cancer with a patent right gastroepiploic artery (RGEA) used for coronary artery bypass grafting (CABG). Before gastrectomy, the native coronary artery was revascularized to safely dissect the infrapyloric lymphatic tissue along the layer recently identified as an appropriate layer for radical lymphadenectomy, in anticipation of preserving the radically skeletonized RGEA. The perioperative strategy was feasible. Postoperatively, hemorrhage extended the stopping period of antiplatelet therapy. However, since the RGEA was preserved, an alternative route was available for coronary flow. After a 41-month postoperative follow-up, the patient remained in good health, with no recurrence or cardiac ischemia. In this case, the alternative route of coronary flow could be constantly maintained, although radical infrapyloric lymphadenectomy had been performed. Preoperative revascularization and preserving the RGEA with radical skeletonization can be a safe yet permissibly radical strategy for gastric cancer treatment following CABG involving the RGEA. PMID- 28616158 TI - Synchronous contralateral adrenal metastasis of colorectal cancer: case report. AB - The most frequent sites of distant metastasis of colorectal cancer (CRC) are primarily liver and lung, followed by brain and bone metastases. Infrequently, metastases are found in the adrenal glands. They usually have a metachronous and homolateral character. We present a case of contralateral synchronic adrenal metastasis of CRC and its surgical resolution. PMID- 28616159 TI - Thoracic outlet syndrome as a consequence of isolated atraumatic first rib fracture. AB - Neurogenic thoracic outlet syndrome (nTOS) resulting from an isolated first rib fracture is extremely infrequent. We report a case of performance limiting nTOS in a college athlete who was initially evaluated and treated for upper extremity ligamentous injury with only transient improvement. Subsequent noninvasive studies were consistent with TOS physiology and MRA showed a large hypertrophic callus on the first rib adjacent to the brachial plexus. With continued athletic limitations and radiographic findings consistent with TOS, surgical decompression was performed resulting in resolution of symptoms. Although apparent atraumatic isolated first rib fractures are infrequently reported etiologies for TOS in athletes, they are a reasonable consideration in this population with corresponding presentations. PMID- 28616160 TI - Cardiopulmonary arrest in primary care clinics: more holes than cheese: a survey of the knowledge and attitudes of primary care physicians regarding resuscitation. AB - BACKGROUND: Patients experiencing pre-arrest symptoms may first refer to their primary care physician. The study's aim was to determine the likelihood that a patient undergoing out-of-hospital cardiac arrest will receive appropriate resuscitation efforts in a primary care clinic in a country with a directive that clinics maintain resuscitation equipment and physicians undergo periodic resuscitation training. METHODS: An anonymous, 23-question online cross-sectional survey was created and administered to primary care physicians working in community clinics (10/1/2015-5/3/2015). Recruitment was accomplished by posting a link to the survey to all physicians listed as registered Society of Family Medicine members and in other online forums dedicated to residents and board certified specialists in family medicine in Israel. The primary outcome measure was the proportion of respondents whose responses indicate that they fulfill all conditions for performing resuscitation. RESULTS: Of approximately 2400 potential respondents, 185 replied to the survey; the study's findings should be viewed as preliminary. Respondents' characteristics were generally similar to those of the study population, but respondents had a higher rate of family medicine specialists. Respondents were mostly female (n = 108, 58%) Israeli graduates who have practiced medicine for > 10 years (72%, n = 134). 55% (n = 101) had undergone basic life support (BLS) training within < 2 years. Although just 5% (n = 10) estimated call-to-Emergency Medical Service (EMS) arrival time to their clinic to be <5 min, only 64% (n = 119) knew the telephone number for summoning EMS. Most confirmed the existence of a resuscitation cart in their clinic (85%, n = 157); 68% confirmed the presence of a defibrillator (n = 126). Most respondents were aware of the location of the defibrillator in their clinic (67%, n = 123), stated its accessibility during working hours (63%, n = 116), and 56% (n = 103) knew how to use it. Only 28% of the questionnaires indicated that all requirements for mounting an effective BLS response had been fulfilled. CONCLUSIONS: The study suggests that many primary care clinics are under-equipped and their physicians are under-prepared to initiate life-saving services. Steps must be taken to rectify this situation. In addition, to develop more reliable estimates of the phenomena reported in this preliminary study, these issues should be re-examined in the context of a high response rate physician survey. PMID- 28616161 TI - Geographical and climatic gradients of evergreen versus deciduous broad-leaved tree species in subtropical China: Implications for the definition of the mixed forest. AB - Understanding climatic influences on the proportion of evergreen versus deciduous broad-leaved tree species in forests is of crucial importance when predicting the impact of climate change on broad-leaved forests. Here, we quantified the geographical distribution of evergreen versus deciduous broad-leaved tree species in subtropical China. The Relative Importance Value index (RIV) was used to examine regional patterns in tree species dominance and was related to three key climatic variables: mean annual temperature (MAT), minimum temperature of the coldest month (MinT), and mean annual precipitation (MAP). We found the RIV of evergreen species to decrease with latitude at a lapse rate of 10% per degree between 23.5 and 25 degrees N, 1% per degree at 25-29.1 degrees N, and 15% per degree at 29.1-34 degrees N. The RIV of evergreen species increased with: MinT at a lapse rate of 10% per degrees C between -4.5 and 2.5 degrees C and 2% per degrees C at 2.5-10.5 degrees C; MAP at a lapse rate of 10% per 100 mm between 900 and 1,600 mm and 4% per 100 mm between 1,600 and 2,250 mm. All selected climatic variables cumulatively explained 71% of the geographical variation in dominance of evergreen and deciduous broad-leaved tree species and the climatic variables, ranked in order of decreasing effects were as follows: MinT > MAP > MAT. We further proposed that the latitudinal limit of evergreen and deciduous broad-leaved mixed forests was 29.1-32 degrees N, corresponding with MAT of 11 18.1 degrees C, MinT of -2.5 to 2.51 degrees C, and MAP of 1,000-1,630 mm. This study is the first quantitative assessment of climatic correlates with the evergreenness and deciduousness of broad-leaved forests in subtropical China and underscores that extreme cold temperature is the most important climatic determinant of evergreen and deciduous broad-leaved tree species' distributions, a finding that confirms earlier qualitative studies. Our findings also offer new insight into the definition and distribution of the mixed forest and an accurate assessment of vulnerability of mixed forests to future climate change. PMID- 28616162 TI - Insularity effects on bird immune parameters: A comparison between island and mainland populations in West Africa. AB - Oceanic islands share several environmental characteristics that have been shown to drive convergent evolutionary changes in island organisms. One change that is often assumed but has seldom been examined is the evolution of weaker immune systems in island species. The reduction in species richness on islands is expected to lead to a reduced parasite pressure and, given that immune function is costly, island animals should show a reduced immune response. However, alternative hypotheses exist; for example, the slower pace of life on islands could favor the reorganization of the immune system components (innate vs. acquired immunity) on islands. Thus far, few island species have been studied and no general patterns have emerged. Here, we compared two immune parameters of birds from Sao Tome and Principe islands to those of their close relatives at similar latitudes on the mainland (Gabon, West Africa). On islands, the acquired humoral component (total immunoglobulins) was lower for most species, whereas no clear pattern was detected for the innate component (haptoglobin levels). These different responses did not seem to arise from a reorganization of the two immune components, as both total immunoglobulins and haptoglobin levels were positively associated. This work adds to the few empirical studies conducted so far which suggest that changes in immune parameters in response to insularity are not as straightforward as initially thought. PMID- 28616164 TI - Elevational gradient and human effects on butterfly species richness in the French Alps. AB - We examined how butterfly species richness is affected by human impact and elevation, and how species ranges are distributed along the elevational gradient (200-2700 m) in the Isere Department (French Alps). A total of 35,724 butterfly observations gathered in summer (May-September) between 1995 and 2015 were analyzed. The number of estimated species per 100-m elevational band was fitted to the elevational gradient using a generalized additive model. Estimations were also performed on a 500 m * 500 m grid at low altitude (200-500 m) to test for the human impact on species richness using generalized least squares regression models. Each species elevational range was plotted against the elevational gradient. Butterfly richness along the elevational gradient first increased (200 500 m) to reach a maximum of 150 species at 700 m and then remained nearly constant till a sharp decrease after 1900 m, suggesting that after some temperature threshold, only few specialized species can survive. At low elevation, urbanization and arable lands had a strongly negative impact on butterfly diversity, which was buffered by a positive effect of permanent crops. Butterfly diversity is exceptionally high (185 species) in this alpine department that represents less than 5% of the French territory and yet holds more than 70% of all the Rhopalocera species recorded in France. Both climate and habitat shape the distribution of species, with a negative effect of anthropization at low altitude and strong climatic constraints at high altitude. PMID- 28616163 TI - A genomic assessment of species boundaries and hybridization in a group of highly polymorphic anoles (distichus species complex). AB - Delimiting young species is one of the great challenges of systematic biology, particularly when the species in question exhibit little morphological divergence. Anolis distichus, a trunk anole with more than a dozen subspecies that are defined primarily by dewlap color, may actually represent several independent evolutionary lineages. To test this, we utilized amplified fragment length polymorphisms (AFLP) genome scans and genetic clustering analyses in conjunction with a coalescent-based species delimitation method. We examined a geographically widespread set of samples and two heavily sampled hybrid zones. We find that genetic divergence is associated with a major biogeographic barrier, the Hispaniolan paleo-island boundary, but not with dewlap color. Additionally, we find support for hypotheses regarding colonization of two Hispaniolan satellite islands and the Bahamas from mainland Hispaniola. Our results show that A. distichus is composed of seven distinct evolutionary lineages still experiencing a limited degree of gene flow. We suggest that A. distichus merits taxonomic revision, but that dewlap color cannot be relied upon as the primary diagnostic character. PMID- 28616165 TI - Natural expansion versus translocation in a previously human-persecuted bird of prey. AB - Many threatened species in Europe have been expanding their distributions during recent decades owing to protection measures that overcome historical human activity that has limited their distributions. Range expansion has come about via two processes, natural expansion from existing range and reintroductions to new ranges. Reintroductions may prove to be a better way to establish populations because individuals are less subject to competitive relationships lowering breeding success than individuals expanding from existing populations. Whether this is true, however, remains uncertain. We compared success of breeding pairs of an expanding and a reintroduced population of spanish imperial eagles monitored for over 15 years in the south of Spain. We found significant differences in productivity between breeding pairs of each population. Newly established territories in reintroduction areas were almost three times more productive than new territories established as individuals expanded out from an existing population. We conclude that among these eagle populations reintroduced to new areas may fare as well or better than individuals expanding out form existing populations. PMID- 28616166 TI - Gregariousness does not vary with geography, developmental stage, or group relatedness in feeding redheaded pine sawfly larvae. AB - Aggregations are widespread across the animal kingdom, yet the underlying proximate and ultimate causes are still largely unknown. An ideal system to investigate this simple, social behavior is the pine sawfly genus Neodiprion, which is experimentally tractable and exhibits interspecific variation in larval gregariousness. To assess intraspecific variation in this trait, we characterized aggregative tendency within a single widespread species, the redheaded pine sawfly (N. lecontei). To do so, we developed a quantitative assay in which we measured interindividual distances over a 90-min video. This assay revealed minimal behavioral differences: (1) between early-feeding and late-feeding larval instars, (2) among larvae derived from different latitudes, and (3) between groups composed of kin and those composed of nonkin. Together, these results suggest that, during the larval feeding period, the benefits individuals derive from aggregating outweigh the costs and that this cost-to-benefit ratio does not vary dramatically across space (geography) or ontogeny (developmental stage). In contrast to the feeding larvae, our assay revealed a striking reduction in gregariousness following the final larval molt in N. lecontei. We also found some intriguing interspecific variation: While N. lecontei and N. maurus feeding larvae exhibit significant aggregative tendencies, feeding N. compar larvae do not aggregate at all. These results set the stage for future work investigating the proximate and ultimate mechanisms underlying developmental and interspecific variation in larval gregariousness across Neodiprion. PMID- 28616167 TI - Species-specific regulation of herbivory-induced defoliation tolerance is associated with jasmonate inducibility. AB - Induced changes in root carbohydrate pools are commonly assumed to determine plant defoliation tolerance to herbivores. However, the regulation and species specificity of these two traits are not well understood. We determined herbivory induced changes in root carbohydrates and defoliation tolerance in seven different solanaceous plant species and correlated the induced changes in root carbohydrates and defoliation tolerance with jasmonate inducibility. Across species, we observed strong species-specific variation for all measured traits. Closer inspection revealed that the different species fell into two distinct groups: Species with a strong induced jasmonic acid (JA) burst suffered from a reduction in root carbohydrate pools and reduced defoliation tolerance, while species with a weak induced JA burst maintained root carbohydrate pools and tolerated defoliation. Induced JA levels predicted carbohydrate and regrowth responses better than jasmonoyl-L-isoleucine (JA-Ile) levels. Our study shows that induced JA signaling, root carbohydrate responses, and defoliation tolerance are closely linked, but highly species specific, even among closely related species. We propose that defoliation tolerance may evolve rapidly via changes in the plant's defense signaling network. PMID- 28616168 TI - Does selection on horn length of males and females differ in protected and hunted populations of a weakly dimorphic ungulate? AB - Weaponry in ungulates may be costly to grow and maintain, and different selective pressures in males and females may lead to sex-biased natural survival. Sexual differences in the relationship between weapon growth and survival may increase under anthropogenic selection through culling, for example because of trophy hunting. Selection on weaponry growth under different scenarios has been largely investigated in males of highly dimorphic ungulates, for which survival costs (either natural or hunting related) are thought to be greatest. Little is known, however, about the survival costs of weaponry in males and females of weakly dimorphic species. We collected information on horn length and age at death/shooting of 407 chamois Rupicapra rupicapra in a protected population and in two hunted populations with different hunting regimes, to explore sexual differences in the selection on early horn growth under contrasting selective pressures. We also investigated the variation of horn growth and body mass in yearling males (n = 688) and females (n = 539) culled in one of the hunted populations over 14 years. The relationship between horn growth and survival showed remarkable sexual differences under different evolutionary scenarios. Within the protected population, under natural selection, we found no significant trade-off in either males or females. Under anthropogenic pressure, selection on early horn growth of culled individuals showed diametrically opposed sex-biased patterns, depending on the culling regime and hunters' preferences. Despite the selective bias between males and females in one of the hunted populations, we did not detect significant sex-specific differences in the long-term pattern of early growth. The relationship between early horn growth and natural survival in either sex might suggest stabilizing selection on horn size in chamois. Selection through culling can be strongly sex-biased also in weakly dimorphic species, depending on hunters' preferences and hunting regulations, and long-term data are needed to reveal potential undesirable evolutionary consequences. PMID- 28616169 TI - Host sympatry and body size influence parasite straggling rate in a highly connected multihost, multiparasite system. AB - Parasite lineages commonly diverge when host lineages diverge. However, when large clades of hosts and parasites are analyzed, some cases suggest host switching as another major diversification mechanism. The first step in host switching is the appearance of a parasite on an atypical host, or "straggling." We analyze the conditions associated with straggling events. We use five species of colonially nesting seabirds from the Galapagos Archipelago and two genera of highly specific ectoparasitic lice to examine host switching. We use both genetic and morphological identification of lice, together with measurements of spatial distribution of hosts in mixed breeding colonies, to test: (1) effects of local host community composition on straggling parasite identity; (2) effects of relative host density within a mixed colony on straggling frequency and parasite species identity; and (3) how straggling rates are influenced by the specifics of louse attachment. Finally, we determine whether there is evidence of breeding in cases where straggling adult lice were found, which may indicate a shift from straggling to the initial stages of host switching. We analyzed more than 5,000 parasite individuals and found that only ~1% of lice could be considered stragglers, with ~5% of 436 host individuals having straggling parasites. We found that the presence of the typical host and recipient host in the same locality influenced straggling. Additionally, parasites most likely to be found on alternate hosts are those that are smaller than the typical parasite of that host, implying that the ability of lice to attach to the host might limit host switching. Given that lice generally follow Harrison's rule, with larger parasites on larger hosts, parasites infecting the larger host species are less likely to successfully colonize smaller host species. Moreover, our study supports the general perception that successful colonization of a novel host is extremely rare, as we found only one nymph of a straggling species, which may indicate successful reproduction. PMID- 28616170 TI - Variation in species-level plant functional traits over wetland indicator status categories. AB - Wetland indicator status (WIS) describes the habitat affinity of plant species and is used in wetland delineations and resource inventories. Understanding how species-level functional traits vary across WIS categories may improve designations, elucidate mechanisms of adaptation, and explain habitat optima and niche. We investigated differences in species-level traits of riparian flora across WIS categories, extending their application to indicate hydrologic habitat. We measured or compiled data on specific leaf area (SLA), stem specific gravity (SSG), seed mass, and mature height of 110 plant species that occur along the Colorado River in Grand Canyon, Arizona. Additionally, we measured leaf delta13C, delta15N, % carbon, % nitrogen, and C/N ratio of 56 species with C3 photosynthesis. We asked the following: (i) How do species-level traits vary over WIS categories? (ii) Does the pattern differ between herbaceous and woody species? (iii) How well do multivariate traits define WIS categories? (iv) Which traits are correlated? The largest trait differences among WIS categories for herbaceous species occurred for SSG, seed mass, % leaf carbon and height, and for woody species occurred for height, SSG, and delta13C. SSG increased and height decreased with habitat aridity for both woody and herbaceous species. The delta13C and hence water use efficiency of woody species increased with habitat aridity. Water use efficiency of herbaceous species increased with habitat aridity via greater occurrence of C4 grasses. Multivariate trait assemblages differed among WIS categories. Over all species, SLA was correlated with height, delta13C, % leaf N, and C/N; height was correlated with SSG and % leaf C; SSG was correlated with % leaf C. Adaptations of both herbaceous and woody riparian species to wet, frequently inundated habitats include low-density stem tissue. Adaptations to drier habitats in the riparian zone include short, high-density cavitation-resistant stem tissue, and high water use efficiency. The results enhance understanding about using traits to describe plant habitat in riparian systems. PMID- 28616171 TI - Is bigger really better? Relative and absolute body size influence individual growth rate under competition. AB - Models suggest that the mechanism of competition can influence the growth advantage associated with being large (in absolute body size or relative to other individuals in the population). Large size is advantageous under interference, but disadvantageous under exploitative competition. We addressed this prediction in a laboratory experiment on Rana temporaria tadpoles competing for limited food. There were 166 target individuals spanning a 10-fold range in body mass reared for 3 days with three other individuals that were either the same size, half as large, or twice as large as the target. Relative growth rate (proportion per day) declined with size, and absolute growth rate (mass per day) reached a peak at intermediate size and declined thereafter. Tadpoles grew slowly if they were large relative to their competitors, although relative body size was less important than absolute size. As a result, size variation declined in groups that were initially composed of individuals of variable size. Thus, bigger was not better under exploitative competition. Our results help connect individual-level behavior with individual growth and the size distribution of the population. PMID- 28616172 TI - Developing approaches for linear mixed modeling in landscape genetics through landscape-directed dispersal simulations. AB - Dispersal can impact population dynamics and geographic variation, and thus, genetic approaches that can establish which landscape factors influence population connectivity have ecological and evolutionary importance. Mixed models that account for the error structure of pairwise datasets are increasingly used to compare models relating genetic differentiation to pairwise measures of landscape resistance. A model selection framework based on information criteria metrics or explained variance may help disentangle the ecological and landscape factors influencing genetic structure, yet there are currently no consensus for the best protocols. Here, we develop landscape-directed simulations and test a series of replicates that emulate independent empirical datasets of two species with different life history characteristics (greater sage-grouse; eastern foxsnake). We determined that in our simulated scenarios, AIC and BIC were the best model selection indices and that marginal R2 values were biased toward more complex models. The model coefficients for landscape variables generally reflected the underlying dispersal model with confidence intervals that did not overlap with zero across the entire model set. When we controlled for geographic distance, variables not in the underlying dispersal models (i.e., nontrue) typically overlapped zero. Our study helps establish methods for using linear mixed models to identify the features underlying patterns of dispersal across a variety of landscapes. PMID- 28616173 TI - Modeling connectivity to identify current and future anthropogenic barriers to movement of large carnivores: A case study in the American Southwest. AB - This study sought to identify critical areas for puma (Puma concolor) movement across the state of Arizona in the American Southwest and to identify those most likely to be impacted by current and future human land uses, particularly expanding urban development and associated increases in traffic volume. Human populations in this region are expanding rapidly, with the potential for urban centers and busy roads to increasingly act as barriers to demographic and genetic connectivity of large-bodied, wide-ranging carnivores such as pumas, whose long distance movements are likely to bring them into contact with human land uses and whose low tolerance both for and from humans may put them at risk unless opportunities for safe passage through or around human-modified landscapes are present. Brownian bridge movement models based on global positioning system collar data collected during bouts of active movement and linear mixed models were used to model habitat quality for puma movement; then, a wall-to-wall application of circuit theory models was used to produce a continuous statewide estimate of connectivity for puma movement and to identify pinch points, or bottlenecks, that may be most at risk of impacts from current and future traffic volume and expanding development. Rugged, shrub- and scrub-dominated regions were highlighted as those offering high quality movement habitat for pumas, and pinch points with the greatest potential impacts from expanding development and traffic, although widely distributed, were particularly prominent to the north and east of the city of Phoenix and along interstate highways in the western portion of the state. These pinch points likely constitute important conservation opportunities, where barriers to movement may cause disproportionate loss of connectivity, but also where actions such as placement of wildlife crossing structures or conservation easements could enhance connectivity and prevent detrimental impacts before they occur. PMID- 28616174 TI - Spatial overlap of shark nursery areas and the salmon farming industry influences the trophic ecology of Squalus acanthias on the southern coast of Chile. AB - Potential interactions between marine predators and humans arise in the southern coast of Chile where predator feeding and reproduction sites overlap with fisheries and aquaculture. Here, we assess the potential effects of intensive salmon aquaculture on food habits, growth, and reproduction of a common predator, the spiny dogfish-identified as Squalus acanthias via genetic barcoding. A total of 102 (89 females and 13 males) individuals were collected during winter and summer of 2013-2014 from the Chiloe Sea where salmon aquaculture activities are concentrated. The low frequency of males in our study suggests spatial segregation of sex, while immature and mature females spatially overlapped in both seasons. Female spiny dogfish showed a functional specialist behavior as indicated by the small number of prey items and the relative high importance of the austral hake and salmon pellets in the diet. Immature sharks fed more on pellets and anchovies than the larger hake-preferring mature females. Our results also indicate that spiny dogfish switch prey (anchovy to hake) to take advantage of seasonal changes in prey availability. Despite differences in the trophic patterns of S. acanthias due to the spatial association with intensive salmon farming, in this region, there appears to be no difference in fecundity or size at maturity compared to other populations. Although no demographic effects were detected, we suggest that a range of additional factors should be considered before concluding that intensive aquaculture does not have any impact on these marine predators. PMID- 28616175 TI - Seasonal habitat use by Elephants (Loxodonta africana) in the Mole National Park of Ghana. AB - To avoid unnecessary waste of limited resources and to help prioritize areas for conservation efforts, this study aimed to provide information on habitat use by elephants between the wet and dry seasons in the Mole National Park (MNP) of Ghana. We compiled coordinates of 516 locations of elephants' encounters, 256 for dry season and 260 for wet season. Using nine predictor variables, we modeled the probability of elephant's distribution in MNP. We threshold the models to "suitable" and "nonsuitable" regions of habitat use using the equal training sensitivity and specificity values of 0.177 and 0.181 for the dry and wet seasons, respectively. Accuracy assessment of our models revealed a sensitivity score of 0.909 and 0.974, and a specificity of 0.579 and 0.753 for the dry and wet seasons, respectively. A TSS of 0.488 was also recorded for the dry season and 0.727 for the wet season indicating a good model agreement. Our model predicts habitat use to be confined to the southern portion of MNP due to elevation difference and a relatively steep slope that separates the northern regions of the park from the south. Regions of habitat use for the wet season were 856 km2 and reduced significantly to 547.68 km2 in the dry season. We observed significant overlap (327.24 km2) in habitat use regions between the wet and dry seasons (Schoener's D = 0.922 and Hellinger's-based I = 0.991). DEM, proximity to waterholes, and saltlicks were identified as the key variables that contributed to the prediction. We recommend construction of temporal camps in regions of habitat use that are far from the headquarters area for effective management of elephants. Also, an increase in water point's density around the headquarters areas and selected dry areas of the park will further decrease elephant's range and hence a relatively less resource use in monitoring and patrols. PMID- 28616176 TI - Adaptation to fluctuating environments in a selection experiment with Drosophila melanogaster. AB - A fundamental question in life-history evolution is how organisms cope with fluctuating environments, including variation between stressful and benign conditions. For short-lived organisms, environments commonly vary between generations. Using a novel experimental design, we exposed wild-derived Drosophila melanogaster to three different selection regimes: one where generations alternated between starvation and benign conditions, and starvation was always preceded by early exposure to cold; another where starvation and benign conditions alternated in the same way, but cold shock sometimes preceded starvation and sometimes benign conditions; and a third where conditions were always benign. Using six replicate populations per selection regime, we found that selected flies increased their starvation resistance, most strongly for the regime where cold and starvation were reliably combined, and this occurred without decreased fecundity or extended developmental time. The selected flies became stress resistant, displayed a pronounced increase in early life food intake and resource storage. In contrast to previous experiments selecting for increased starvation resistance in D. melanogaster, we did not find increased storage of lipids as the main response, but instead that, in particular for females, storage of carbohydrates was more pronounced. We argue that faster mobilization of carbohydrates is advantageous in fluctuating environments and conclude that the phenotype that evolved in our experiment corresponds to a compromise between the requirements of stressful and benign environments. PMID- 28616177 TI - The effects of elevated temperature and dissolved rhoCO2 on a marine foundation species. AB - Understanding how climate change and other environmental stressors will affect species is a fundamental concern of modern ecology. Indeed, numerous studies have documented how climate stressors affect species distributions and population persistence. However, relatively few studies have investigated how multiple climate stressors might affect species. In this study, we investigate the impacts of how two climate change factors affect an important foundation species. Specifically, we tested how ocean acidification from dissolution of CO 2 and increased sea surface temperatures affect multiple characteristics of juvenile eastern oysters (Crassostrea virginica). We found strong impacts of each stressor, but no interaction between the two. Simulated warming to mimic heat stressed summers reduced oyster growth, survival, and filtration rates. Additionally, we found that CO 2-induced acidification reduced strength of oyster shells, which could potentially facilitate crab predation. As past studies have detected few impacts of these stressors on adult oysters, these results indicate that early life stages of calcareous marine organisms may be more susceptible to effects of ocean acidification and global warming. Overall, these data show that predicted changes in temperature and CO 2 can differentially influence direct effects on individual species, which could have important implications for the nature of their trophic interactions. PMID- 28616178 TI - Population differences in host plant preference and the importance of yeast and plant substrate to volatile composition. AB - Divergent selection between environments can result in changes to the behavior of an organism. In many insects, volatile compounds are a primary means by which host plants are recognized and shifts in plant availability can result in changes to host preference. Both the plant substrate and microorganisms can influence this behavior, and host plant choice can have an impact on the performance of the organism. In Drosophila mojavensis, four geographically isolated populations each use different cacti as feeding and oviposition substrates and identify those cacti by the composition of the volatile odorants emitted. Behavioral tests revealed D. mojavensis populations vary in their degree of preference for their natural host plant. Females from the Mojave population show a marked preference for their host plant, barrel cactus, relative to other cactus choices. When flies were given a choice between cacti that were not their host plant, the preference for barrel and organ pipe cactus relative to agria and prickly pear cactus was overall lower for all populations. Volatile headspace composition is influenced by the cactus substrate, microbial community, and substrate-by-microorganism interactions. Differences in viability, developmental time, thorax length, and dry body weight exist among populations and depend on cactus substrate and population-by-cactus interactions. However, no clear association between behavioral preference and performance was observed. This study highlights a complex interplay between the insect, host plant, and microbial community and the factors mediating insect host plant preference behavior. PMID- 28616179 TI - Prediction of harmful variants on mitochondrial genes: Test of habitat-dependent and demographic effects in a euryhaline fish. AB - Both effective population size and life history may influence the efficacy of purifying selection, but it remains unclear if the environment affects the accumulation of weakly deleterious nonsynonymous polymorphisms. We hypothesize that the reduced energetic cost of osmoregulation in brackish water habitat may cause relaxation of selective constraints at mitochondrial oxidative phosphorylation (OXPHOS) genes. To test this hypothesis, we analyzed 57 complete mitochondrial genomes of Pungitius pungitius collected from brackish and freshwater habitats. Based on inter- and intraspecific comparisons, we estimated that 84% and 68% of the nonsynonymous polymorphisms in the freshwater and brackish water populations, respectively, are weakly or moderately deleterious. Using in silico prediction tools (MutPred, SNAP2), we subsequently identified nonsynonymous polymorphisms with potentially harmful effect. Both prediction methods indicated that the functional effects of the fixed nonsynonymous substitutions between nine- and three-spined stickleback were weaker than for polymorphisms within species, indicating that harmful nonsynonymous polymorphisms within populations rarely become fixed between species. No significant differences in mean estimated functional effects were identified between freshwater and brackish water nine-spined stickleback to support the hypothesis that reduced osmoregulatory energy demand in the brackish water environment reduces the strength of purifying selection at OXPHOS genes. Instead, elevated frequency of nonsynonymous polymorphisms in the freshwater environment (Pn/Ps = 0.549 vs. 0.283; Fisher's exact test p = .032) suggested that purifying selection is less efficient in small freshwater populations. This study shows the utility of in silico functional prediction tools in population genetic and evolutionary research in a nonmammalian vertebrate and demonstrates that mitochondrial energy production genes represent a promising system to characterize the demographic, life history and potential habitat-dependent effects of segregating amino acid variants. PMID- 28616180 TI - Sustained functional composition of pollinators in restored pastures despite slow functional restoration of plants. AB - Habitat restoration is a key measure to counteract negative impacts on biodiversity from habitat loss and fragmentation. To assess success in restoring not only biodiversity, but also functionality of communities, we should take into account the re-assembly of species trait composition across taxa. Attaining such functional restoration would depend on the landscape context, vegetation structure, and time since restoration. We assessed how trait composition of plant and pollinator (bee and hoverfly) communities differ between abandoned, restored (formerly abandoned) or continuously grazed (intact) semi-natural pastures. In restored pastures, we also explored trait composition in relation to landscape context, vegetation structure, and pasture management history. Abandoned pastures differed from intact and restored pastures in trait composition of plant communities, and as expected, had lower abundances of species with traits associated with grazing adaptations. Further, plant trait composition in restored pastures became increasingly similar to that in intact pastures with increasing time since restoration. On the contrary, the trait composition of pollinator communities in both abandoned and restored pastures remained similar to intact pastures. The trait composition for both bees and hoverflies was influenced by flower abundance and, for bees, by connectivity to other intact grasslands in the landscape. The divergent responses across organism groups appeared to be mainly related to the limited dispersal ability and long individual life span in plants, the high mobility of pollinators, and the dependency of semi-natural habitat for bees. Our results, encompassing restoration effects on trait composition for multiple taxa along a gradient in both time (time since restoration) and space (connectivity), reveal how interacting communities of plants and pollinators are shaped by different trait-environmental relationships. Complete functional restoration of pastures needs for more detailed assessments of both plants dispersal in time and of resources available within pollinator dispersal range. PMID- 28616181 TI - Incorporating breeding abundance into spatial assignments on continuous surfaces. AB - Determining the geographic connections between breeding and nonbreeding populations, termed migratory connectivity, is critical to advancing our understanding of the ecology and conservation of migratory species. Assignment models based on stable isotopes historically have been an important tool for studying migratory connectivity of small-bodied species, but the low resolution of these assignments has generated interest into combining isotopes with other sources in information. Abundance is one of the most appealing data sources to include in isotope-based assignments, but there are currently no statistical methods or guidelines for optimizing the contribution of stable isotopes and abundance for inferring migratory connectivity. Using known-origin stable hydrogen isotope samples of six Neotropical migratory bird species, we rigorously assessed the performance of assignment models that differentially weight the contribution of the isotope and abundance data. For two species with adequate sample sizes, we used Pareto optimality to determine the set of models that simultaneously minimized both assignment error rate and assignment area. We then assessed the ability of the top models from these two species to improve assignments of the remaining four species compared to assignments based on isotopes alone. We show that the increased precision of models that include abundance is often offset by a large increase in assignment error. However, models that optimally weigh the abundance data relative to the isotope data can result in higher precision and, in some cases, lower error than models based on isotopes alone. The top models, however, depended on the distribution of relative breeding abundance, with patchier distributions requiring stronger downweighting of abundance, and we present general guidelines for future studies. These results confirm that breeding abundance can be an important source of information for studies investigating broad-scale movements of migratory birds and potentially other taxa. PMID- 28616182 TI - Terrestrial capture of prey by the reedfish, a model species for stem tetrapods. AB - Due to morphological resemblance, polypterid fishes are used as extant analogues of Late Devonian lobe-finned sarcopterygians to identify the features that allowed the evolution of a terrestrial lifestyle in early tetrapods. Previous studies using polypterids showed how terrestrial locomotion capacity can develop, and how air ventilation for breathing was possible in extinct tetrapodomorphs. Interestingly, one polypterid species, the reedfish Erpetoichthys calabaricus, has been noted being capable of capturing prey on land. We now identified the mechanism of terrestrial prey-capture in reedfish. We showed that this species uses a lifted trunk and downward inclined head to capture ground-based prey, remarkably similar to the mechanism described earlier for eel-catfish. Reedfish similarly use the ground support and flexibility of their elongated body to realize the trunk elevation and dorsoventral flexion of the anterior trunk region, without a role for the pectoral fins. However, curving of the body to lift the trunk may not have been an option for the Devonian tetrapodomorphs as they are significantly less elongated than reedfish and eel-catfish. This would imply that, in contrast to the eel-like extant species, evolution of the capacity to capture prey on land in early tetrapods may be linked to the evolution of the pectoral system to lift the anterior part of the body. PMID- 28616183 TI - Dissecting spatiotemporal patterns of functional diversity through the lens of Darwin's naturalization conundrum. AB - Darwin's naturalization conundrum describes the paradigm that community assembly is regulated by two opposing processes, environmental filtering and competitive interactions, which predict both similarity and distinctiveness of species to be important for establishment. Our goal is to use long-term, large-scale, and high resolution temporal data to examine diversity patterns over time and assess whether environmental filtering or competition plays a larger role in regulating community assembly processes. We evaluated Darwin's naturalization conundrum and how functional diversity has changed in the Laurentian Great Lakes fish community from 1870 to 2010, which has experienced frequent introductions of non-native species and extirpations of native species. We analyzed how functional diversity has changed over time by decade from 1870 to 2010 at three spatial scales (regional, lake, and habitat) to account for potential noninteractions between species at the regional and lake level. We also determined which process, environmental filtering or competitive interactions, is more important in regulating community assembly and maintenance by comparing observed patterns to what we would expect in the absence of an ecological mechanism. With the exception of one community, all analyses show that functional diversity and species richness has increased over time and that environmental filtering regulates community assembly at the regional level. When examining functional diversity at the lake and habitat level, the regulating processes become more context dependent. This study is the first to examine diversity patterns and Darwin's conundrum by integrating long-term, large-scale, and high-resolution temporal data at multiple spatial scales. Our results confirm that Darwin's conundrum is highly context dependent. PMID- 28616184 TI - Reindeer habitat use in relation to two small wind farms, during preconstruction, construction, and operation. AB - Worldwide there is a rush toward wind power development and its associated infrastructure. In Fennoscandia, large-scale wind farms comprising several hundred windmills are currently built in important grazing ranges used for Sami reindeer husbandry. In this study, reindeer habitat use was assessed using reindeer fecal pellet group counts in relation to two relatively small wind farms, with 8 and 10 turbines, respectively. In 2009, 1,315 15-m2 plots were established and pellet groups were counted and cleaned from the plots. This was repeated once a year in May, during preconstruction, construction, and operation of the wind farms, covering 6 years (2009-2014) of reindeer habitat use in the area. We modeled the presence/absence of any pellets in a plot at both the local (wind farm site) and regional (reindeer calving to autumn range) scale with a hierarchical logistic regression, where spatial correlation was accounted for via random effects, using vegetation type, and the interaction between distance to wind turbine and time period as predictor variables. Our results revealed an absolute reduction in pellet groups by 66% and 86% around each wind farm, respectively, at local scale and by 61% at regional scale during the operation phase compared to the preconstruction phase. At the regional, scale habitat use declined close to the turbines in the same comparison. However, at the local scale, we observed increased habitat use close to the wind turbines at one of the wind farms during the operation phase. This may be explained by continued use of an important migration route close to the wind farm. The reduced use at the regional scale nevertheless suggests that there may be an overall avoidance of both wind farms during operation, but further studies of reindeer movement and behavior are needed to gain a better understanding of the mechanisms behind this suggested avoidance. PMID- 28616185 TI - Asymmetry matters: A genomic assessment of directional biases in gene flow between hybridizing spruces. AB - Assessing directional bias in interspecific gene flow might be important in determining the evolutionary trajectory of closely related species pairs. Using a set of 300 single nucleotide polymorphisms (SNPs) having variable propensity to cross species boundary, we evaluated the genomic extent and direction of interspecific gene flow in a progenitor-derivative spruce species pair (black spruce and red spruce). A higher rate of gene flow was found from black spruce toward red spruce purebreds than vice versa. This asymmetry could reflect the historical gene flow between the two taxa at the time of species inception and during postglacial colonization. A clear asymmetry in introgression was depicted by a greater gene flow between red spruce and hybrids than between black spruce and hybrids. While backcrossing toward red spruce was invariably high across the genome, the actual species boundary is between hybrids and black spruce where gene flow is impeded at those genomic regions impermeable to introgression. Associations between hybrid index and climatic variables (total annual precipitation and mean annual temperature) were tested, as these might indicate a role for exogenous selection in maintaining the species boundary. While an apparent association was found between the hybrid index and precipitation, it collapsed when considered in light of the directional bias in interspecific gene flow. Hence, considering asymmetrical patterns of introgression allowed us to falsify an apparent role for exogenous selection. Although this was not formerly tested here, we suggest that this pattern could result from asymmetrical endogenous selection, a contention that deserves further investigations. PMID- 28616186 TI - At-sea distribution and habitat use in king penguins at sub-Antarctic Marion Island. AB - King penguins make up the bulk of avian biomass on a number of sub-Antarctic islands where they have a large functional effect on terrestrial and marine ecosystems. The same applies at Marion Island where a substantial proportion of the world population breeds. In spite of their obvious ecological importance, the at-sea distribution and behavior of this population has until recently remained entirely unknown. In addressing this information deficiency, we deployed satellite-linked tracking instruments on 15 adult king penguins over 2 years, April 2008 and 2013, to study their post-guard foraging distribution and habitat preferences. Uniquely among adult king penguins, individuals by and large headed out against the prevailing Antarctic Circumpolar Current, foraging to the west and southwest of the island. On average, individuals ventured a maximum distance of 1,600 km from the colony, with three individuals foraging close to, or beyond, 3,500 km west of the colony. Birds were mostly foraging south of the Antarctic Polar Front and north of the southern boundary of the Antarctic Circumpolar Current. Habitat preferences were assessed using boosted regression tree models which indicated sea surface temperate, depth, and chorophyll a concentration to be the most important predictors of habitat selection. Interestingly, king penguins rapidly transited the eddy-rich area to the west of Marion Island, associated with the Southwest Indian Ocean Ridge, which has been shown to be important for foraging in other marine top predators. In accordance with this, the king penguins generally avoided areas with high eddy kinetic energy. The results from this first study into the behavioral ecology and at-sea distribution of king penguins at Marion Island contribute to our broader understanding of this species. PMID- 28616187 TI - Ecological effects of dams, alien fish, and physiochemical environmental factors on homogeneity/heterogeneity of fish community in four tributaries of the Pearl River in China. AB - In this study, we aimed to characterize the fish community structure and identify the drivers contributing to homogenization/differentiation processes in four tributaries to the Pearl River, Guangxi Province, China, over the past few decades. We sampled 22 sites seasonally from 2013 through 2015, and these sites were selected based on archived records of previous sampling conducted in the 1980s. Jaccard's faunal similarity index, cluster analysis, and canonical correspondence analysis (CCA) were applied to describe the homogenization/differentiation of fish community and illustrate the potential effectors. The number of fish species present in three of the four sampled tributaries declined dramatically over the past 30 years, leading toward a trend of increased fish community homogeneity throughout the watershed. Results from multidimensional scaling and cluster analyses allowed us to divide the study area into two distinct ecoregions. Four species (yellow catfish Pelteobagrus fulvidraco, pond loach Misgurnus anguillicaudatus, Nile tilapia Oreochromis niloticus, and sharpbelly Hemiculter leucisculus) were considered to be indicative fish species contributing more than 5% of the dissimilarity between the two eco-regions according to the results of similarity percentage procedure. Results from CCA revealed that pH and latitude corresponded with the dominant fish species of each respective tributary. More specifically, CCA results allowed us to classify dominant fish species into three distinct groups. The first group was mainly located in Guijiang characterized by higher latitudes and lower pH values, the second group was widespread in the four tributaries, and the last group was primarily distributed in Yujiang, Youjiang, and Zuojiang characterized by lower latitudes and higher pH values. Spatial differentiation of fish community structure and temporal homogeneity of species composition were attributed to the joint actions of human interventions including construction of dams and introductions of exotic fish species that led to habitat degeneration and fragmentation, and unequal interspecies competitions. PMID- 28616189 TI - The combined effects of reactant kinetics and enzyme stability explain the temperature dependence of metabolic rates. AB - A mechanistic understanding of the response of metabolic rate to temperature is essential for understanding thermal ecology and metabolic adaptation. Although the Arrhenius equation has been used to describe the effects of temperature on reaction rates and metabolic traits, it does not adequately describe two aspects of the thermal performance curve (TPC) for metabolic rate-that metabolic rate is a unimodal function of temperature often with maximal values in the biologically relevant temperature range and that activation energies are temperature dependent. We show that the temperature dependence of metabolic rate in ectotherms is well described by an enzyme-assisted Arrhenius (EAAR) model that accounts for the temperature-dependent contribution of enzymes to decreasing the activation energy required for reactions to occur. The model is mechanistically derived using the thermodynamic rules that govern protein stability. We contrast our model with other unimodal functions that also can be used to describe the temperature dependence of metabolic rate to show how the EAAR model provides an important advance over previous work. We fit the EAAR model to metabolic rate data for a variety of taxa to demonstrate the model's utility in describing metabolic rate TPCs while revealing significant differences in thermodynamic properties across species and acclimation temperatures. Our model advances our ability to understand the metabolic and ecological consequences of increases in the mean and variance of temperature associated with global climate change. In addition, the model suggests avenues by which organisms can acclimate and adapt to changing thermal environments. Furthermore, the parameters in the EAAR model generate links between organismal level performance and underlying molecular processes that can be tested for in future work. PMID- 28616188 TI - Life-history predicts past and present population connectivity in two sympatric sea stars. AB - Life-history traits, especially the mode and duration of larval development, are expected to strongly influence the population connectivity and phylogeography of marine species. Comparative analysis of sympatric, closely related species with differing life histories provides the opportunity to specifically investigate these mechanisms of evolution but have been equivocal in this regard. Here, we sample two sympatric sea stars across the same geographic range in temperate waters of Australia. Using a combination of mitochondrial DNA sequences, nuclear DNA sequences, and microsatellite genotypes, we show that the benthic-developing sea star, Parvulastra exigua, has lower levels of within- and among-population genetic diversity, more inferred genetic clusters, and higher levels of hierarchical and pairwise population structure than Meridiastra calcar, a species with planktonic development. While both species have populations that have diverged since the middle of the second glacial period of the Pleistocene, most P. exigua populations have origins after the last glacial maxima (LGM), whereas most M. calcar populations diverged long before the LGM. Our results indicate that phylogenetic patterns of these two species are consistent with predicted dispersal abilities; the benthic-developing P. exigua shows a pattern of extirpation during the LGM with subsequent recolonization, whereas the planktonic developing M. calcar shows a pattern of persistence and isolation during the LGM with subsequent post-Pleistocene introgression. PMID- 28616190 TI - Insight into the roles of selection in speciation from genomic patterns of divergence and introgression in secondary contact in venomous rattlesnakes. AB - Investigating secondary contact of historically isolated lineages can provide insight into how selection and drift influence genomic divergence and admixture. Here, we studied the genomic landscape of divergence and introgression following secondary contact between lineages of the Western Diamondback Rattlesnake (Crotalus atrox) to determine whether genomic regions under selection in allopatry also contribute to reproductive isolation during introgression. We used thousands of nuclear loci to study genomic differentiation between two lineages that have experienced recent secondary contact following isolation, and incorporated sampling from a zone of secondary contact to identify loci that are resistant to gene flow in hybrids. Comparisons of patterns of divergence and introgression revealed a positive relationship between allelic differentiation and resistance to introgression across the genome, and greater-than-expected overlap between genes linked to lineage-specific divergence and loci that resist introgression. Genes linked to putatively selected markers were related to prominent aspects of rattlesnake biology that differ between populations of Western Diamondback rattlesnakes (i.e., venom and reproductive phenotypes). We also found evidence for selection against introgression of genes that may contribute to cytonuclear incompatibility, consistent with previously observed biased patterns of nuclear and mitochondrial alleles suggestive of partial reproductive isolation due to cytonuclear incompatibilities. Our results provide a genome-scale perspective on the relationships between divergence and introgression in secondary contact that is relevant for understanding the roles of selection in maintaining partial isolation of lineages, causing admixing lineages to not completely homogenize. PMID- 28616191 TI - Towards the co-ordination of terrestrial ecosystem protocols across European research infrastructures. AB - The study of ecosystem processes over multiple scales of space and time is often best achieved using comparable data from multiple sites. Yet, long-term ecological observatories have often developed their own data collection protocols. Here, we address this problem by proposing a set of ecological protocols suitable for widespread adoption by the ecological community. Scientists from the European ecological research community prioritized terrestrial ecosystem parameters that could benefit from a more consistent approach to data collection within the resources available at most long-term ecological observatories. Parameters for which standard methods are in widespread use, or for which methods are evolving rapidly, were not selected. Protocols were developed by domain experts, building on existing methods where possible, and refined through a process of field testing and training. They address above ground plant biomass; decomposition; land use and management; leaf area index; soil mesofaunal diversity; soil C and N stocks, and greenhouse gas emissions from soils. These complement existing methods to provide a complete assessment of ecological integrity. These protocols offer integrated approaches to ecological data collection that are low cost and are starting to be used across the European Long Term Ecological Research community. PMID- 28616192 TI - Sex-specific floral morphology, biomass, and phytohormones associated with altitude in dioecious Populus cathayana populations. AB - Relationships between sex-specific floral traits and endogenous phytohormones associated with altitude are unknown particularly in dioecious trees. We thus examined the relationships between floral morphology or biomass and phytohormones in male and female flowers of dioecious Populus cathayana populations along an altitudinal gradient (1,500, 1,600, and 1,700 m above sea level) in the Xiaowutai Nature Reserve in northern China. The female and male flowers had the most stigma and pollen at 1,700 m, the largest ovaries and least pollen at 1,500 m, and the smallest ovaries and greater numbers of anthers at 1,600 m altitude. The single flower biomass was significantly greater in males than in females at 1,600 or 1,700 m, but the opposite was true at 1,500 m altitude. The biomass percentages were significantly higher in anthers than in stigmas at each altitude, while significantly greater gibberellin A3 (GA 3), zeatin riboside (ZR), indoleacetic acid (IAA), and abscisic acid (ABA) concentrations were found in female than in male flowers. Moreover, most flower morphological traits positively correlated with IAA in females but not in males. The biomass of a single flower was significantly positively correlated with ABA or IAA in males but negatively with ZR in females and was not correlated with GA 3 in both females and males. Our results demonstrate a distinct sexual adaptation between male and female flowers and that phytohormones are closely related to the size, shape, and biomass allocation in the pollination or fertilization organs of dioecious plants, although with variations in altitude. PMID- 28616193 TI - Concentration and retention of chlorophyll around the extrafloral nectary of Mallotus japonicus. AB - Plants need to allocate some of their limited resources for defense against herbivores as well as for growth and reproduction. However, the priority of resource allocation within plants has not been investigated. We hypothesized that plants with extrafloral nectaries (EFNs) invest more chlorophyll around their EFNs-to support a high rate of carbon fixation there-than in other leaf parts of young leaves. Additionally, this chlorophyll may remain around EFNs rather than in the other leaf parts. We used Mallotus japonicus plants to investigate the chlorophyll content at leaf centers and edges and around EFNs at four stages of leaf development: middle-expanded young leaves, fully expanded mature leaves, senior leaves, and leaves prior to abscission. These four stages of development were located at the third, fifth, eighth, and eleventh leaf positions from the apex, respectively. The results revealed that the chlorophyll content around the EFN side of the third-position leaves was higher than that at the leaf center or edge. Although the chlorophyll content in the fifth-position leaves did not differ between those at the leaf edge and around EFNs, the chlorophyll content around EFNs in the eighth-position leaves was higher than that at the leaf centre and edge. The volume of EF nectar was positively correlated with the chlorophyll content around EFN during the leaf stage, but it was not correlated with the chlorophyll content in the leaf center and edge, except in fifth-position leaves. These findings suggest that M. japonicus plants facilitate and maintain secretion of EF nectar in their young and old leaves, respectively, through the concentration and retention of chlorophyll around EFNs. PMID- 28616194 TI - Habitat use and spatial fidelity of male South American sea lions during the nonbreeding period. AB - Conditions experienced during the nonbreeding period have profound long-term effects on individual fitness and survival. Therefore, knowledge of habitat use during the nonbreeding period can provide insights into processes that regulate populations. At the Falkland Islands, the habitat use of South American sea lions (Otaria flavescens) during the nonbreeding period is of particular interest because the population is yet to recover from a catastrophic decline between the mid-1930s and 1965, and nonbreeding movements are poorly understood. Here, we assessed the habitat use of adult male (n = 13) and juvenile male (n = 6) South American sea lions at the Falkland Islands using satellite tags and stable isotope analysis of vibrissae. Male South American sea lions behaved like central place foragers. Foraging trips were restricted to the Patagonian Shelf and were typically short in distance and duration (127 +/- 66 km and 4.1 +/- 2.0 days, respectively). Individual male foraging trips were also typically characterized by a high degree of foraging site fidelity. However, the isotopic niche of adult males was smaller than juvenile males, which suggested that adult males were more consistent in their use of foraging habitats and prey over time. Our findings differ from male South American sea lions in Chile and Argentina, which undertake extended movements during the nonbreeding period. Hence, throughout their breeding range, male South American sea lions have diverse movement patterns during the nonbreeding period that intuitively reflects differences in the predictability or accessibility of preferred prey. Our findings challenge the long-standing notion that South American sea lions undertake a winter migration away from the Falkland Islands. Therefore, impediments to South American sea lion population recovery likely originate locally and conservation measures at a national level are likely to be effective in addressing the decline and the failure of the population to recover. PMID- 28616195 TI - Assessing vulnerability of giant pandas to climate change in the Qinling Mountains of China. AB - Climate change might pose an additional threat to the already vulnerable giant panda (Ailuropoda melanoleuca). Effective conservation efforts require projections of vulnerability of the giant panda in facing climate change and proactive strategies to reduce emerging climate-related threats. We used the maximum entropy model to assess the vulnerability of giant panda to climate change in the Qinling Mountains of China. The results of modeling included the following findings: (1) the area of suitable habitat for giant pandas was projected to decrease by 281 km2 from climate change by the 2050s; (2) the mean elevation of suitable habitat of giant panda was predicted to shift 30 m higher due to climate change over this period; (3) the network of nature reserves protect 61.73% of current suitable habitat for the species, and 59.23% of future suitable habitat; (4) current suitable habitat mainly located in Chenggu, Taibai, and Yangxian counties (with a total area of 987 km2) was predicted to be vulnerable. Assessing the vulnerability of giant panda provided adaptive strategies for conservation programs and national park construction. We proposed adaptation strategies to ameliorate the predicted impacts of climate change on giant panda, including establishing and adjusting reserves, establishing habitat corridors, improving adaptive capacity to climate change, and strengthening monitoring of giant panda. PMID- 28616196 TI - Geographic characteristics of sable (Martes zibellina) distribution over time in Northeast China. AB - Understanding historical context can help clarify the ecological and biogeographic characteristics of species population changes. The sable (Martes zibellina) population has decreased dramatically in Northeast China since the l950s, and understanding the changes in its distribution over time is necessary to support conservation efforts. To achieve this goal, we integrated ecological niche modeling and historical records of sables to estimate the magnitude of change in their distribution over time. Our results revealed a 51.71% reduction in their distribution in 2000-2016 compared with the potential distribution in the 1950s. This reduction was related to climate change (Pearson's correlation: Bio1, -.962, p < .01; Bio2, -.962, p < .01; Bio5, .817, p < .05; Bio6, .847, p < .05) and human population size (-.956, p < .01). The sable population tended to migrate in different directions and elevations over time in different areas due to climate change: In the Greater Khingan Mountains, they moved northward and to lower elevations; in the Lesser Khingan Mountains, they moved northward; and in the Changbai Mountains, they move southward and to higher elevations. Active conservation strategies should be considered in locations where sable populations have migrated or may migrate to. PMID- 28616197 TI - Production of plumage ornaments among males and females of two closely related tropical passerine bird species. AB - The evolution of elaborate secondary sexual traits (i.e., ornaments) is well studied in males but less so in females. Similarity in the appearance of ornaments between males and females supports the view that female ornaments arise as a neutral byproduct of selection on male traits due to genetic correlation between sexes, but recent research suggests an adaptive function of female ornaments in at least some contexts. Information on the degree to which production of ornaments differs between the sexes can shed light on these alternative perspectives. We therefore characterized the structural underpinnings of melanin-based plumage production in males and females of two closely related passerine bird species (genus Malurus). Importantly, both ornamented and unornamented phenotypes in each sex are present between these two species, providing an opportunity to test the null expectation of equivalent modes of production in male and female ornamented phenotypes. In Malurus alboscapulatus, ornamented females are qualitatively similar to males, but we describe a distinctive ornamented female phenotype that differs from that of males in lacking a blue sheen and in lower feather barbule density. In M. melanocephalus, unornamented males and females are also similar in appearance, and we describe a similarity between unornamented phenotypes of males and females in both color and underlying feather barbule structure and pigment composition. Unornamented male M. melanocephalus can flexibly transition to the ornamented phenotype in weeks, and we found extreme differences in color and feather structure between these two alternative male phenotypes. These results contradict the idea that female ornaments have evolved in this system following a simple switch to male-like plumage by demonstrating greater complexity in the production of the ornamented phenotype in males than in females. PMID- 28616198 TI - Seed dispersal of Diospyros virginiana in the past and the present: Evidence for a generalist evolutionary strategy. AB - Several North American trees are hypothesized to have lost their co-evolved seed disperser during the late-Pleistocene extinction and are therefore considered anachronistic. We tested this hypothesis for the American persimmon (Diospyros virginiana) by studying the effects of gut passage of proposed seed dispersers on seedling survival and growth, natural fruiting characteristics, and modern animal consumption patterns. We tested gut passage effects on persimmon seeds using three native living species, the raccoon (Procyon lotor), Virginia opossum (Didelphis virginiana), and coyote (Canis latrans), and two Pleistocene analogs; the Asian elephant (Elephas maximus) and alpaca (Vicugna pacos). Persimmon seeds excreted by raccoons, coyotes, and elephants survived gut transit. Gut passage did not affect sprouting success, but did tend to decrease time to sprout and increase seedling quality. Under field conditions, persimmon fruits were palatable on the parent tree and on the ground for an equal duration, but most fruits were consumed on the ground. Seven vertebrate species fed upon persimmon fruits, with the white-tailed deer (Odocoileus virginianus)-a species not capable of dispersing persimmon seeds-comprising over 90% of detections. Conversely, potential living seed dispersers were rarely detected. Our results suggest the American persimmon evolved to attract a variety of seed dispersers and thus is not anachronistic. However, human-induced changes in mammal communities could be affecting successful seed dispersal. We argue that changes in the relative abundance of mammals during the Anthropocene may be modifying seed dispersal patterns, leading to potential changes in forest community composition. PMID- 28616199 TI - Global realized niche divergence in the African clawed frog Xenopus laevis. AB - Although of crucial importance for invasion biology and impact assessments of climate change, it remains widely unknown how species cope with and adapt to environmental conditions beyond their currently realized climatic niches (i.e., those climatic conditions existing populations are exposed to). The African clawed frog Xenopus laevis, native to southern Africa, has established numerous invasive populations on multiple continents making it a pertinent model organism to study environmental niche dynamics. In this study, we assess whether the realized niches of the invasive populations in Europe, South, and North America represent subsets of the species' realized niche in its native distributional range or if niche shifts are traceable. If shifts are traceable, we ask whether the realized niches of invasive populations still contain signatures of the niche of source populations what could indicate local adaptations. Univariate comparisons among bioclimatic conditions at native and invaded ranges revealed the invasive populations to be nested within the variable range of the native population. However, at the same time, invasive populations are well differentiated in multidimensional niche space as quantified via n-dimensional hypervolumes. The most deviant invasive population are those from Europe. Our results suggest varying degrees of realized niche shifts, which are mainly driven by temperature related variables. The crosswise projection of the hypervolumes that were trained in invaded ranges revealed the south-western Cape region as likely area of origin for all invasive populations, which is largely congruent with DNA sequence data and suggests a gradual exploration of novel climate space in invasive populations. PMID- 28616201 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/ece3.2863.]. PMID- 28616200 TI - Season-modulated responses of Neotropical bats to forest fragmentation. AB - Seasonality causes fluctuations in resource availability, affecting the presence and abundance of animal species. The impacts of these oscillations on wildlife populations can be exacerbated by habitat fragmentation. We assessed differences in bat species abundance between the wet and dry season in a fragmented landscape in the Central Amazon characterized by primary forest fragments embedded in a secondary forest matrix. We also evaluated whether the relative importance of local vegetation structure versus landscape characteristics (composition and configuration) in shaping bat abundance patterns varied between seasons. Our working hypotheses were that abundance responses are species as well as season specific, and that in the wet season, local vegetation structure is a stronger determinant of bat abundance than landscape-scale attributes. Generalized linear mixed-effects models in combination with hierarchical partitioning revealed that relationships between species abundances and local vegetation structure and landscape characteristics were both season specific and scale dependent. Overall, landscape characteristics were more important than local vegetation characteristics, suggesting that landscape structure is likely to play an even more important role in landscapes with higher fragment-matrix contrast. Responses varied between frugivores and animalivores. In the dry season, frugivores responded more to compositional metrics, whereas during the wet season, local and configurational metrics were more important. Animalivores showed similar patterns in both seasons, responding to the same group of metrics in both seasons. Differences in responses likely reflect seasonal differences in the phenology of flowering and fruiting between primary and secondary forests, which affected the foraging behavior and habitat use of bats. Management actions should encompass multiscale approaches to account for the idiosyncratic responses of species to seasonal variation in resource abundance and consequently to local and landscape scale attributes. PMID- 27335636 TI - Referencing cross-reactivity of detection antibodies for protein array experiments. AB - Protein arrays are frequently used to profile antibody repertoires in humans and animals. High-throughput protein array characterisation of complex antibody repertoires necessitates the use of extensively validated secondary detection antibodies. This article details the validation of an affinity-isolated anti chicken IgY antibody produced in rabbit and a goat anti-rabbit IgG antibody conjugated with alkaline phosphatase using protein arrays consisting of 7,390 distinct human proteins. Probing protein arrays with secondary antibodies in absence of chicken serum revealed non-specific binding to 61 distinct human proteins. Despite the identified non-specific binding, the tested antibodies are well suited for use in protein array experiments as the cross-reactive binding partners can be readily excluded from further analysis. The evident cross reactivity of the tested secondary detection antibodies points towards the necessity of platform-specific antibody characterisation studies for all secondary immunoreagents. Furthermore, secondary antibody characterisation using protein arrays enables the generation of reference lists of cross-reactive proteins, which can be then marked as potential false positives in follow-up experiments. Providing such cross-reactivity reference lists accessible to the wider research community may help to interpret data generated with the same antibodies in applications not only related to protein arrays such as immunoprecipitation, Western blots or other immunoassays. PMID- 28616203 TI - Reduced rate of intensive care unit acquired gram-negative bacilli after removal of sinks and introduction of 'water-free' patient care. AB - BACKGROUND: Sinks in patient rooms are associated with hospital-acquired infections. The aim of this study was to evaluate the effect of removal of sinks from the Intensive Care Unit (ICU) patient rooms and the introduction of 'water free' patient care on gram-negative bacilli colonization rates. METHODS: We conducted a 2-year pre/post quasi-experimental study that compared monthly gram negative bacilli colonization rates pre- and post-intervention using segmented regression analysis of interrupted time series data. Five ICUs of a tertiary care medical center were included. Participants were all patients of 18 years and older admitted to our ICUs for at least 48 h who also received selective digestive tract decontamination during the twelve month pre-intervention or the twelve month post-intervention period. The effect of sink removal and the introduction of 'water-free' patient care on colonization rates with gram negative bacilli was evaluated. The main outcome of this study was the monthly colonization rate with gram-negative bacilli (GNB). Yeast colonization rates were used as a 'negative control'. In addition, colonization rates were calculated for first positive culture results from cultures taken >=3, >=5, >=7, >=10 and >=14 days after ICU-admission, rate ratios (RR) were calculated and differences tested with chi-squared tests. RESULTS: In the pre-intervention period, 1496 patients (9153 admission days) and in the post-intervention period 1444 patients (9044 admission days) were included. Segmented regression analysis showed that the intervention was followed by a statistically significant immediate reduction in GNB colonization in absence of a pre or post intervention trend in GNB colonization. The overall GNB colonization rate dropped from 26.3 to 21.6 GNB/1000 ICU admission days (colonization rate ratio 0.82; 95%CI 0.67-0.99; P = 0.02). The reduction in GNB colonization rate became more pronounced in patients with a longer ICU-Length of Stay (LOS): from a 1.22-fold reduction (>=2 days), to a 1.6-fold (>=5 days; P = 0.002), 2.5-fold (for >=10 days; P < 0.001) to a 3.6 fold (>=14 days; P < 0.001) reduction. CONCLUSIONS: Removal of sinks from patient rooms and introduction of a method of 'water-free' patient care is associated with a significant reduction of patient colonization with GNB, especially in patients with a longer ICU length of stay. PMID- 28616204 TI - Comparison of subsequent infection in methicillin-resistant Staphylococcus aureus nasal carriers between ST72 community-genotype and hospital genotypes: a retrospective cohort study. AB - BACKGROUND: Carriage of methicillin-resistant Staphylococcus aureus (MRSA) is an important risk factor of subsequent infection. The purpose of our study was to compare the rates of subsequent infection among newly-admitted patients carrying MRSA between community-genotype and hospital-genotypes. METHODS: In this retrospective cohort study, we compared the rates of subsequent MRSA infection, time to subsequent infection and mortality in the following 6 months between the community-genotype ST72 MRSA cohort and the hospital-genotypes ST5 / ST239 MRSA cohort. RESULTS: We identified 198 patients carrying ST72 and 156 patients carrying ST5 or ST239. There was no difference in the rates of subsequent infection between ST72 cohort and ST5 / ST239 cohort (13.1% vs. 12.8%; P = 0.931). The median time to development of subsequent infection was not significantly different (27 days vs. 88 days; P = 0.0877). The Kaplan-Meier method showed no difference in the cumulative rate of being free of subsequent infection between the cohorts (P = 0.9209). Overall mortality rates at 6 months did not differ (1.5% vs. 1.9%; P = 1.000). CONCLUSIONS: We found no evidence that rates of subsequent MRSA infection were different between newly-admitted patients carrying community-genotype ST72 MRSA and those whom carrying hospital-genotypes ST5 or ST239 MRSA. PMID- 28616205 TI - Appearance and rapid evolution of thoraco-abdominal intramural hematoma after TEVAR. AB - Some studies consider the different physical properties of the stent graft when compared with the blood vessel on the basis of vascular lesions that may require further intervention. We present a case in which a patient developed an intramural hematoma at the distal landing of previous thoracic endovascular aortic repair (TEVAR) that required the relining with a flared prosthesis. During follow-up, we observed the appearance of more caudal hematoma. We decided to observe this lesion with close radiological controls. In order to prevent serious complication after the induction of TEVAR, accurate planning of the procedure is very important to study the impact of the prosthesis implanted in the cardiovascular system. In particular, oversize, radial forces and length of coverage have been taken into account. The adherence to follow-up is very important to precociously detect the lesions to avoid the onset of complication. PMID- 28616206 TI - A systematic review and meta-analysis of genetic association studies for the role of inflammation and the immune system in diabetic nephropathy. AB - Background: Despite the certain contribution of metabolic and haemodynamic factors in diabetic nephropathy (DN), many lines of evidence highlight the role of immunologic and inflammatory mechanisms. To elucidate the contribution of the immune system in the development of DN, we explored the contribution of gene variants (polymorphisms) in relevant pathophysiologic pathways. Methods: We selected six major pathways related to immune response from the Kyoto Encyclopaedia of Genes and Genomes database and thereafter we traced all available genetic association studies (GASs) involving gene variants in these pathways from PubMed and HuGE Navigator. Finally, we used meta-analytic methods for synthesizing the results of the GASs. Results: One hundred three GASs were retrieved that included 443 variants from 75 genes. Of those variants, 138 were meta-analysed and 61 produced significant results; seven variants were investigated in single GASs and showed significant association. Variants in CCL2, CCR5, IL6, IL8, EPO, IL1A, IL1B, IL100, IL1RN, GHRL, MMP9, TGFB1, VEGFA, MMP3, MMP12, IL12RB1, PRKCE, TNF and TNFRSF19 genes were associated with an increased risk of DN. Conclusions: There is evidence that variants related with immunologic response affect the course of DN. However, the present results should be interpreted with caution since the current number of available GASs is limited. PMID- 28616207 TI - Changes in metformin use in chronic kidney disease. AB - Metformin is one of the oldest and most widely prescribed antidiabetic medicines worldwide. It is the only such medicine that has shown a reduction of cardiovascular mortality in diabetes mellitus type 2. Since many diabetic patients have chronic kidney disease, its use is often curtailed by practitioners due to fear of lactic acidosis and the US Food and Drug Administration (FDA) warnings that, until recently, had been in place for decades. Current guidelines, though somewhat vague regarding dosages, clearly pave the way for spreading the use of metformin in patients with lower glomerular filtration rates. These guidelines also suggest moving away from just looking at serum creatinine to create a cut-off. Metformin's costs are lower, and in many underdeveloped countries this is the only medicine available for poor patients. More widespread use of metformin will further help with health care costs, as well as obesity. It will simplify the use of diabetes mellitus type 2 management with lower incidences of hypoglycemia. With all the mounting evidence, the FDA is finally requiring labeling changes regarding recommendations, to allow the use of metformin in patients with much reduced kidney function. PMID- 28616208 TI - Patient Survey of current water Intake practices in autosomal dominant Polycystic kidney disease: the SIPs survey. AB - Background: Autosomal dominant polycystic kidney disease (ADPKD) affects 12.5 million worldwide. Vasopressin drives cysts growth and in animal models can be suppressed through high water intake. A randomized controlled trial of 'high' versus 'standard' water intake in ADPKD is essential to determine if this intervention is beneficial. We conducted an ADPKD patient survey to gain an understanding of current fluid intake practices and the design challenges of a randomized water intake trial. Methods: In collaboration with the PKD Charity, we developed and distributed an online survey to ADPKD patients over age 16 years and not on renal replacement therapy. Results: Of the 2377 invited, 89 ADPKD patients completed the Survey of current water Intake practices in autosomal dominant Polycystic kidney disease (SIPs) online questionnaire. Most were female (65, 73%) and white (84, 94%), with a median age group of 45-49 years. The risk of contamination between treatment arms was highlighted by the survey as the majority (70, 79%) routinely discussed ADPKD management with family despite only 17% sharing the same household. More participants reported drinking beyond thirst (65, 73%) than those actually indicating a daily fluid intake of >2 L (54, 61%). This discrepancy emphasizes inaccuracies of fluid intake estimates and the requirement for objective methods of measuring water intake. Overall, only 51% believed high water intake was beneficial, while 91% were willing to participate in research evaluating this. Conclusion: ADPKD poses unique design challenges to a randomized water intake trial. However, the trial is likely to be supported by the ADPKD community and could impact significantly on PKD management and associated healthcare costs. PMID- 28616209 TI - Should eculizumab be discontinued in patients with atypical hemolytic uremic syndrome? AB - Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disorder for which prompt diagnosis and eculizumab treatment is indicated. The time for relapse and patients at risk for relapse after eculizumab discontinuation are unknown. While some authors believe there is no clinical evidence supporting eculizumab discontinuation, which may be associated with high collateral risks such as loss of renal function, other authors believe that the drug can be safely discontinued with close patient monitoring. In this editorial, we update the pros and cons for eculizumab discontinuation in aHUS. PMID- 28616210 TI - Acute kidney injury-an overview of diagnostic methods and clinical management. AB - Acute kidney injury (AKI) is a common condition in multiple clinical settings. Patients with AKI are at an increased risk of death, over both the short and long term, and of accelerated renal impairment. As the condition has become more recognized and definitions more unified, there has been a rapid increase in studies examining AKI across many different clinical settings. This review focuses on the classification, diagnostic methods and clinical management that are available, or promising, for patients with AKI. Furthermore, preventive measures with fluids, acetylcysteine, statins and remote ischemic preconditioning, as well as when dialysis should be initiated in AKI patients are discussed. The classification of AKI includes both changes in serum creatinine concentrations and urine output. Currently, no kidney injury biomarkers are included in the classification of AKI, but proposals have been made to include them as independent diagnostic markers. Treatment of AKI is aimed at addressing the underlying causes of AKI, and at limiting damage and preventing progression. The key principles are: to treat the underlying disease, to optimize fluid balance and optimize hemodynamics, to treat electrolyte disturbances, to discontinue or dose-adjust nephrotoxic drugs and to dose-adjust drugs with renal elimination. PMID- 28616211 TI - Acute kidney injury in patients with severe sepsis or septic shock: a comparison between the 'Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease' (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO) classifications. AB - PURPOSE: Using the Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO) systems, the incidence of acute kidney injury (AKI) and their ability to predict in-hospital mortality in severe sepsis or septic shock was compared. MATERIALS AND METHODS: We performed a retrospective analysis of 457 critically ill patients with severe sepsis or septic shock hospitalized between January 2008 and December 2014. Multivariate logistic regression was employed to evaluate the association between the RIFLE, AKIN and KDIGO systems with in-hospital mortality. Model fit was assessed by the goodness of-fit test and discrimination by the area under the receiver operating characteristic (AUROC) curve. Statistical significance was defined as P < 0.05. RESULTS: RIFLE (84.2%) and KDIGO (87.5%) identified more patients with AKI than AKIN (72.8%) (P < 0.001). AKI defined by AKIN and KDIGO was associated with in hospital mortality {AKIN: adjusted odds ratio [OR] 2.3[95% confidence interval (CI) 1.3-4], P = 0.006; KDIGO: adjusted OR 2.7[95% CI 1.2-6.2], P = 0.021} while AKI defined by RIFLE was not [adjusted OR 2.0 (95% CI 1-4), P = 0.063]. The AUROC curve for in-hospital mortality was similar between the three classifications (RIFLE 0.652, P < 0.001; AKIN 0.686, P < 0.001; KDIGO 0.658, P < 0.001). CONCLUSIONS: RIFLE and KDIGO diagnosed more patients with AKI than AKIN, but the prediction ability for in-hospital mortality was similar between the three systems. PMID- 28616212 TI - Hypophosphatemia in critically ill patients with acute kidney injury treated with hemodialysis is associated with adverse events. AB - Background. Hypophosphatemia in critically ill patients may be exacerbated by renal replacement therapy (RRT). We aimed to identify risk factors and adverse outcomes associated with hypophosphatemia in intensive care patients treated with RRT for acute kidney injury (AKI). Methods. This was a secondary analysis of data from a single-center prospective cohort study of medical and surgical intensive care patients with RRT for AKI between 18 December 2010 and 3 April 2013. Demographic, comorbidity, laboratory and RRT data were retrieved from patient case notes and electronic medical records. Outcomes assessed were hypophosphatemia (serum phosphate <0.94 mmol/L) during RRT, intensive care unit (ICU) mortality, and duration of mechanical ventilation and vasopressor support. Results. Among 96 patients who received acute RRT, 25 (26.0%) developed hypophosphatemia. On multivariate logistic regression, serum phosphate at RRT initiation [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) (0.09, 0.91), P = 0.03] was independently associated with hypophosphatemia during acute RRT. Patients with hypophosphatemia during RRT required longer ventilatory support [median 12 (interquartile range: 8, 17) days versus 5 (3, 9) days, P < 0.001] and vasopressor support [5 (4, 15) days versus 2 (2, 6) days, P = 0.003] compared with those without hypophosphatemia but there was no significant difference in ICU mortality [5 patients (20.0%) versus 24 patients (33.8%), P = 0.20]. Hypophosphatemia during RRT was independently associated with prolonged mechanical ventilation (>=7 days) [adjusted OR 14.0, 95% CI (1.37, 143.90), P = 0.03]. Conclusion. Hypophosphatemia is common during acute RRT for critically ill patients and was associated with adverse clinical outcomes. PMID- 28616213 TI - Postoperative goal-directed therapy and development of acute kidney injury following major elective noncardiac surgery: post-hoc analysis of POM-O randomized controlled trial. AB - Background: The role of goal-directed therapy (GDT) in preventing creatinine rise following noncardiac surgery is unclear. We performed a post-hoc analysis of a randomized controlled trial to assess the relationship between postoperative optimization of oxygen delivery and development of acute kidney injury (AKI)/creatinine rise following noncardiac surgery. Methods: Patients were randomly assigned immediately postoperatively to receive either fluid and/or dobutamine therapy to maintain/restore their preoperative oxygen delivery, or protocolized standard care (oxygen delivery only recorded). Primary end point was serial changes in postoperative creatinine within 48 h postoperatively. Secondary outcomes were development of AKI (KDIGO criteria) and minimal creatinine rise (MCR; no decline from preoperative creatinine), related to all-cause morbidity and length of stay. Results: Postoperative reductions in serum creatinine were similar (P = 0.76) in patients randomized to GDT [10 umol/L (95% confidence interval, CI: 17 to -1); n = 95] or protocolized care [8 umol/L (95% CI: 17 to 6); n = 92]. Postoperative haemodynamic management was not associated with the development of MCR [78/187 (41.7%)] or AKI [13/187; (7.0%)]. Intraoperative requirement for norepinephrine was more likely in patients who developed postoperative rises in creatinine [relative risk (RR): 1.66 (95% CI: 1.04-2.67); P = 0.04], despite similar volumes of intraoperative fluid being administered. Persistently higher lactate during the intervention period was associated with AKI (mean difference: 1.15 mmol/L (95% CI: 0.48-1.81); P = 0.01]. Prolonged hospital stay was associated with AKI but not MCR [RR: 2.71 (95% CI: 1.51-4.87); P = 0.0008]. Conclusion: These data provide further insights into how perioperative haemodynamic alterations relate to postoperative increases in creatinine once systemic inflammation is established. PMID- 28616214 TI - High-dose hydroxocobalamin for vasoplegic syndrome causing false blood leak alarm. AB - Blood leak alarms are important safety features in a hemodialysis machine to protect patients from loss of blood through a rupture in the dialyzer membrane (true alarms). A false blood leak alarm can be triggered by air bubbles or detector malfunction (such as deposits of grease or scale). Hydroxocobalamin is an injectable form of vitamin B12 approved by the US Food and Drug Administration for the treatment of confirmed or suspected cyanide toxicity. Due to observations of an increase in arterial pressure after high-dose hydroxocobalamin infusion for the treatment of acute cyanide poisoning, it has recently been reported as an off label rescue treatment for post-cardiopulmonary bypass vasoplegic syndrome. We report an 83-year-old man who received hydroxocobalamin following cardiac surgery for treatment of vasoplegic syndrome. The patient developed severe acute kidney injury with volume overload. Hydroxocobalamin interference with the blood leak detector compromised his dialysis treatment. We describe the use of continuous renal replacement therapy to overcome the hydroxocobalamin-related interference with hemodialysis. As the utility of hydroxocobalamin potentially expands, physicians must be aware of its inadvertent effect on renal replacement therapy. PMID- 28616215 TI - The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients. AB - Background: The aim of this study was to assess the impact of follow-up in renal protection clinics on the prescription of and adherence to cardioprotective drugs in patients with chronic kidney disease (CKD). Methods: We studied stage 4 and 5 CKD patients who initiated follow-up in three renal protection clinics. The prescription pattern of antihypertensive agents (AHA) and lipid-lowering agents (LLAs) was measured as the percentage of patients who are prescribed the agents of interest at a given time. Adherence to drug therapy was defined as the percentage of days, during a pre-defined observation period, in which patients have an on-hand supply of their prescribed medications. Results: A total of 259 CKD patients were enrolled and followed for up to 1 year after referral to renal protection clinics. There was a significant increase in the prescription of angiotensin-converting enzyme inhibitors (34-39%), angiotensin II receptor blockers (11-14%), beta-blockers (40-51%), calcium channel blockers (62-74%), diuretics (66-78%) and LLAs (39-47%) during follow-up in the renal protection clinic compared with baseline (P-values <0.01 for all comparisons). The proportions of patients with good (>= 80%) and poor (< 80%) adherence to AHA (P = 0.41) and LLAs (P = 0.11) were similar in the year preceding and the year following the first visit to the renal protection clinics. Conclusion: Our results suggest that referral and follow-up in a renal protection clinic may increase the prescription of cardioprotective agents in CKD patients, but does not appear to improve adherence to these medications. PMID- 28616216 TI - Warfarin-related nephropathy induced by three different vitamin K antagonists: analysis of 13 biopsy-proven cases. AB - Background: Acute kidney injury (AKI) with renal tubular obstruction by red blood cell casts (RBCC) has been described in patients treated with warfarin and is known as warfarin-related nephropathy (WRN). Methods: To determine whether other vitamin K antagonists (VKA) cause WRN, we retrospectively collected and analyzed the clinical and histological data of 13 patients treated with different VKA (seven with fluindione, four with warfarin and two with acenocoumarol) in seven French hospitals. Results: They all developed gross hematuria following overanticoagulation complicated by severe AKI (median serum creatinine concentration = 693 MUmol/L). Histological analysis of the kidney biopsies highlighted the presence of intratubular RBCC and acute tubular necrosis in all patients and of an underlying kidney disease in 12 patients. WRN was suspected in patients treated with warfarin; however, the initial diagnosis was incorrect in six of the nine patients treated with other VKA. Nine patients progressed to chronic kidney disease, one fully recovered renal function, two died and one still needs dialysis. Conclusions: This is the first report of AKI caused by fluindione. In agreement with the recent publication on AKI in two patients treated with dabigatran, we suggest that the term 'anticoagulant-related nephropathy' is more appropriate than WRN. Gross hematuria in patients with an underlying kidney disease and treated with VKA requires rapid control of the international normalized ratio and renal function monitoring. PMID- 28616217 TI - Is chronic kidney disease-mineral and bone disorder associated with the presence of endothelial progenitor cells with a calcifying phenotype? AB - Background: Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been implicated in vascular calcification pathogenesis. CKD-MBD results in alterations in the number and function of circulating endothelial progenitor cells (EPCs), physiological regulators of angiogenesis and vessel repair, commonly defined as proangiogenic progenitor cells (PACs) by the antigen pattern CD34+CD133+KDR+CD45- and putative EPCs by the pattern CD34+CD133-KDR+CD45-. These cells might acquire a calcifying phenotype in CKD-MBD, expressing mineralization biomarkers. We investigated the expression of vitamin D receptor (VDR) and osteocalcin (OC) on EPCs of healthy individuals and haemodialysis patients, and their possible associations with circulating biomarkers of inflammation and vascular calcification. Methods: We compared EPC counts, expressing VDR or OC, in 23 healthy subjects versus 53 haemodialysis patients, 17 of them without vitamin D receptor agonist (VDRA) therapy and 35 treated with calcitriol (n = 17) or paricalcitol (n = 18). The correlations with serum levels of inflammatory and calcification indexes were also analysed. Results: All subsets expressing VDR or OC were significantly higher in haemodialysis patients compared with healthy controls, but PACs were increased only in VDRA treatment subgroup, while putative EPCs showed a similar rise also in untreated patients. In VDRA-untreated patients, OC+ PACs correlated positively with calcium levels, while in VDRA treated patients, VDR+ PACs correlated positively with interleukin 6 levels, and OC+ PACs correlated positively 25-hydroxyvitamin D levels. Conclusions: Our data suggest that in CKD-MBD, EPCs undergo an endothelial-to-procalcific shift, representing a risk factor for vascular calcification. A link between mineral disorders and vitamin D replacement therapy emerged, with potential adverse effects for CKD patients. PMID- 28616218 TI - Soluble klotho may be a marker of phosphate reabsorption. AB - Background: Membrane-bound alpha-klotho functions as a co-receptor with fibroblast growth factor receptor at the renal tubule conferring specificity to fibroblast growth factor-23 (FGF-23), allowing it to inhibit tubular phosphate reabsorption at physiological concentrations. alpha-klotho also exists as a soluble protein. However, the complex interrelationships between soluble alpha klotho (sKl), FGF-23 and phosphate reabsorption are poorly understood, with little known about the links between sKl, FGF-23 and phosphate reabsorption in chronic kidney disease (CKD). This study addresses this issue in a cohort of patients with and without CKD. Methods: We conducted a single-centre, cross sectional study of contemporaneously obtained samples of blood and 24-h urine biochemistry along with sKl and intact FGF-23 (iFGF-23) from non-dialysis dependent CKD patients and healthy volunteers. Pearson's correlation coefficients were used to determine correlations between natural log-transformed (Ln) sKl and iFGF-23 with other parameters of interest. Backward multivariate analysis was undertaken to evaluate the relationship between mineral parameters. Results: One hundred and sixteen participants (77 with CKD and 39 healthy volunteers) were studied, of which 74 (63.8%) were male. The median age was 61 (interquartile range 49-71) years. Those with CKD had lower sKl (408 versus 542 pg/mL), higher iFGF-23 (94 versus 41 pg/mL), higher fractional excretion of phosphate (25.05 versus 10.98%) and lower daily urinary phosphate excretion (UPE) (24.8 versus 32.3 mmol/L) compared with healthy volunteers (all P <= 0.002). Age correlated inversely and estimated glomerular filtration rate (eGFR) correlated positively with phosphate reabsorption and Ln(sKl), while the opposite was seen with Ln(iFGF23). Upon multivariate analysis, eGFR, Ln(sKl) and parathyroid hormone were independently associated with phosphate reabsorption, whereas Ln(iFGF-23) was not, after adjustment for age. Conclusions: Abnormalities in phosphate regulatory pathways are disturbed early in CKD. While iFGF-23 is associated with phosphate excretion on univariate analyses, sKl demonstrates a significant association with phosphate reabsorption independent of iFGF-23, and this relationship deserves further exploration. PMID- 28616219 TI - Proliferative glomerulonephritis with monoclonal IgG deposits in two kidney allografts successfully treated with rituximab. AB - Proliferative glomerulonephritis with monoclonal immunoglobulin G deposit (PGNMID), a recently described pathologic entity in native kidneys, has been recognized in kidney transplant patients, where it can present as either recurrent or de novo disease. There is no definitive treatment to date, in either population. Here, we present two cases of PGNMID in kidney allografts that illustrate the challenges of diagnostic approach and highlight the allograft outcome after treatment with rituximab as a potential treatment of this condition. PMID- 28616220 TI - Impact of seasonality on the dynamics of native Vitamin D repletion in long-term renal transplant patients. AB - Background: Renal transplant recipients (RTRs) are often Vitamin D (VitD) depleted as a result of both chronic kidney disease and mandated sun avoidance behaviours. Repleting VitD may be warranted, but how, and for how long, is unknown, as is the impact of seasonality on the success of repletion. We investigated the impact of seasonality on VitD status following VitD repletion in a large cohort of stable, long-term RTRs. Methods: Serum 25-hydroxyvitamin D [25(OH)D] concentrations and bone biochemistry parameters were analysed from 102 VitD repletion courses in 98 RTRs that had undergone VitD repletion. Repletion was delivered over 6 months with either 240 000 IU colecalciferol if pre repletion serum VitD was between 20 and 50 nmol/L, or with 360 000 IU if VitD was <20 nmol/L. Twelve months post-repletion 25(OH)D and parathyroid hormone (PTH) were available for 75 patients. Results: At baseline, 25(OH)D was 20.1 +/- 1.0 nmol/L, increasing to 65.4 +/- 1.8 nmol/L following repletion (+7.55 nmol/L/month, P < 0.0001). Twelve months post-repletion and after no further VitD administration, 25(OH)D fell to 35.4 +/- 1.8 nmol/L (14.2 +/- 0.7 ng/mL; -2.50 nmol/L/month, P < 0.0001). PTH followed the opposite trend with baseline, repletion-end and post-repletion values being 144.2 +/- 12.0, 109.6 +/- 7.5 and 129.2 +/- 11.4 ng/L, respectively. VitD repletion during the summer was associated with significantly higher at repletion-end 25(OH)D compared with any other time of year [summer 80.9 +/- 4.0, autumn 64.1 +/- 3.0 (P = 0.002), winter 48.9 +/- 3.0 (P <0.001), spring 63.8 +/- 2.5 nmol/L (P <0.001)]. There was no hypercalcaemia during repletion and renal transplant function remained stable without any evidence of allograft rejection. Conclusions: VitD repletion can safely and effectively be achieved in the majority of chronic stable RTRs using a 6-month bolus intermediate-dose schedule. Winter repletion is associated with an inadequate response in 25(OH)D; however, all patients experience a post-repletion fall towards deficiency in the absence of maintenance supplementation, irrespective of the season of repletion. PMID- 28616221 TI - Time, timing, talking and training: findings from an exploratory action research study to improve quality of end of life care for minority ethnic kidney patients. AB - Background. With an ageing and increasingly diverse population at risk from rising levels of obesity, diabetes and cardiovascular disease, including kidney complications, there is a need to provide quality care at all stages in the care pathway including at the end of life and to all patients. Aim. This study purposively explored South Asian patients' experiences of kidney end of life care to understand how services can be delivered in a way that meets diverse patient needs. Methods. Within an action research design 14 focus groups (45 care providers) of kidney care providers discussed the recruitment and analysis of individual interviews with 16 South Asian kidney patients (eight men, eight women). Emergent themes from the focus groups were analysed thematically. The research took place at four UK centres providing kidney care to diverse populations: West London, Luton, Leicester and Bradford. Results. Key themes related to time and the timing of discussions about end of life care and the factors that place limitations on patients and providers in talking about end of life care. Lack of time and confidence of nurses in areas of kidney care, individual attitudes and workforce composition influence whether and how patients have access to end of life care through kidney services. Conclusion. Training, team work and time to discuss overarching issues (including timing and communication about end of life) with colleagues could support service providers to facilitate access and delivery of end of life care to this group of patients. PMID- 28616222 TI - A case report of an unusual cause of postoperative leg pain after posterior lumbar fusion. AB - We report the case of a 36-year old man who underwent elective posterior lumbar spinal fusion after presenting with bilateral leg pain with associated back pain. He had undergone a L5/S1 discectomy in 2001, which provided good symptomatic relief. On this admission, he underwent elective L4-S1 posterolateral fusion and bilateral L4/5 and L5/S1 decompression. Intra-operatively a pedicle screw had to be re-inserted after fluoroscopy confirmed a lateral breech. The patient had no major postoperative complications until the sixth day when the patient re presented with acute leg pain and weakness. Following a local multidisciplinary meeting (MDT) an MRI showed a large haematoma at the right psoas muscle. CT angiogram confirmed a bleeding lumbar segmental vessel at the site of the previous misplaced screw and an emergency fluoroscopic guided embolisation of the vessel was performed. The patient recovered well post operatively and was discharged back to the community 12 days later. Haemorrhage, as in this case a psoas haematoma should be considered as one of the differentials in patients with recurrent post-operative radiculopathy following posterior lumbar spine fusion. This should be suspected particularly if there has been a misplacement of one or more screws as this can cause injury to blood vessels and be fatal for the patient. PMID- 28616223 TI - Clinical outcomes of self-expandable metal stent (SEMS) placement as palliative treatment for malignant colorectal obstruction: A single-center study from Japan. AB - OBJECTIVES: We aimed to assess the efficacy of self-expanding metal stent (SEMS) implantation as palliative treatment for malignant colorectal obstruction. METHODS: We retrospectively reviewed the records of patients with malignant colorectal obstruction who underwent SEMS insertion as palliative treatment in our hospital between March 2013 and December 2016. We analyzed demographic, clinical, and operative characteristics. RESULTS: A total of 13 patients (8 males, 5 females; median age, 80.1 years) were reviewed. Tumor location included the left colon, rectum, and right colon in 38.5%, 38.5%, and 23% of the patients, respectively. Advanced and early colorectal cancer were noted in 7 (63.6%) and 4 (36.4%) cases, respectively. The mean ColoRectal Obstruction Scoring System score was 0.92 before stenting and 3.92 after stenting. Oral intake was resumed at a median of 2.1 days after SEMS placement. Median stent patency was 7.6 months, and 69.2% of patients maintained stent patency until death or the end of follow-up. Stent-related adverse effects included: re-occlusion (4 cases, 30.8%); stent migration (1 case, 7.7%), and pain with tenesmus (2 cases, 15.4%). In patients with re-occlusion (median follow-up interval, 1.3 months), stent patency was maintained for a median of 10.3 months (early failure, within 3 months; late failure, >11 months). CONCLUSION: SEMS placement as a palliative treatment is likely to fail within a year, leading to re-occlusion. It is very important to maintain vigilant monitoring using X-ray, CT, and colonoscopy after SEMS placement, with close cooperation between the endoscopist and surgeon. A logistic framework involving careful follow-up, even in the absence of symptoms, and a combined team involving endoscopists and surgeons should be established to support re-intervention and surgery. We recommend vigilant monitoring of patients who received SEMS placement for palliation of malignant colorectal obstruction. PMID- 28616224 TI - Semiparametric Bayes conditional graphical models for imaging genetics applications. AB - Motivated by the need for understanding neurological disorders, large-scale imaging genetic studies are being increasingly conducted. A salient objective in such studies is to identify important neuroimaging biomarkers such as the brain functional connectivity, as well as genetic biomarkers, which are predictive of disorders. However, typical approaches for estimating the group level brain functional connectivity do not account for potential variation, resulting from demographic and genetic factors, while usual methods for discovering genetic biomarkers do not factor in the influence of the brain network on the imaging phenotype. We propose a novel semiparametric Bayesian conditional graphical model for joint variable selection and graph estimation, which simultaneously estimates the brain network after accounting for heterogeneity, and infers significant genetic biomarkers. The proposed approach specifies priors on the regression coefficients, which clusters brain regions having similar activation patterns depending on covariates, leading to dimension reduction. A novel graphical prior is proposed, which encourages modularity in brain organization by specifying denser and sparse connections within and across clusters, respectively. The posterior computation proceeds via a Markov chain Monte Carlo. We apply the approach to data obtained from the Alzheimer's disease neuroimaging initiative and demonstrate numerical advantages via simulation studies. PMID- 28616225 TI - Effect of three lactobacilli with strain-specific activities on the growth performance, faecal microbiota and ileum mucosa proteomics of piglets. AB - BACKGROUND: The beneficial effects of Lactobacillus probiotics in animal production are often strain-related. Different strains from the same species may exert different weight-gain effect on hosts in vivo. Most lactobacilli are selected based on their in vitro activities, and their metabolism and regulation on the intestine based on strain-related characters are largely unexplored. The objective of the present study was to study the in vivo effects of the three lactobacilli on growth performance and to compare the differential effects of the strains on the faecal microbiota and ileum mucosa proteomics of piglets. METHODS: Three hundred and sixty piglets were assigned to one of four treatments, which included an antibiotics-treated control and three experimental groups supplemented with the three lactobacilli, L. salivarius G1-1, L. reuteri G8-5 and L. reuteri G22-2, respectively. Piglets were weighed and the feed intake was recorded to compare the growth performance. The faecal lactobacilli and coliform was quantified using quantitative PCR and the faecal microbiota was profiled by denaturing gradient gel electrophoresis (DGGE). The proteomic approach was applied to compare the differential expression of proteins in the ileum mucosa. RESULTS: No statistical difference was found among the three Lactobacillus treated groups in animal growth performance compared with the antibiotics-treated group (P > 0.05). Supplementation of lactobacilli in diets significantly increased the relative 16S rRNA gene copies of Lactobacillus genus on both d 14 and d 28 (P < 0.05)., and the bacterial community profiles based on DGGE from the lactobacilli-treated groups were distinctly different from the antibiotics treated group (P < 0.05). The ileum mucosa of piglets responded to all Lactobacillus supplementation by producing more newly expressed proteins and the identified proteins were all associated with the functions beneficial for stabilization of cell structure. Besides, some other up-regulated and down regulated proteins in different Lactobacillus-treated groups showed the expression of proteins were partly strain-related. CONCLUSIONS: All the three lactobacilli in this study show comparable effects to antibiotics on piglets growth performance. The three lactobacilli were found able to modify intestinal microbiota and mucosa proteomics. The regulation of protein expression in the intestinal mucosa are partly associated with the strains administrated in feed. PMID- 28616226 TI - Child wasting is a severe public health problem in the predominantly rural population of Ethiopia: A community based cross-sectional study. AB - BACKGROUND: In Ethiopia, child wasting has remained a public health problem for a decade's, suggesting the need to further monitoring of the problem. Hence, this study aimed at assessing the prevalence of wasting and associated factors among children aged 6-59 months at Dabat District, northwest Ethiopia. METHODS: A Community based cross-sectional study was undertaken from May to June, 2015, in Dabat District, northwest Ethiopia. A total of 1184 children aged under five years and their mothers/caretakers were included in the study. An interviewer administered, pre-tested, and structured questionnaire was used to collect data. Standardized anthropometric body measurements were employed to assess the height and weight of the participants. Anthropometric body measurements were analyzed by the WHO Anthro Plus software version 1.0.4. Wasting was defined as having a weight-for-height of Z-score lower than two standard deviations (WHZ < -2 SD) compared to the WHO reference population of the same age and sex group. In the binary logistic regression, both bivariate and multivariate analyses were done to list out factors associated with wasting. All variables with P-values of < 0.2 in the bivariate analysis were earmarked for the multivariate analysis. Both Crude Odds Ratio (COR) and Adjusted Odds Ratio (AOR) at 95% Confidence Interval (CI) were computed to determine the strength of association. In the multivariate analysis, variables at P-values of < 0.05 were identified as determinants of wasting. RESULTS: The overall prevalence of wasting was 18.2%; 10.3% and 7.9% of the children were moderately and severely wasted, respectively. Poor dietary diversity [AOR = 2.08, 95% CI: 1.53, 4.46], late initiation of breastfeeding [AOR = 1.43, 95% CI: 1.04, 1.95], no postnatal vitamin-A supplementation [AOR = 1.55, 95% CI: 1.04, 2.30], and maternal occupational status [AOR = 2.31, 95% CI: 1.56, 3.42] were independently associated with wasting in the study area. CONCLUSION: Wasting is a severe public health problem in Dabat District. Therefore, there is a need to strengthen the implementation of optimal breastfeeding practice and dietary diversity. In addition, improving the coverage of mothers' postnatal vitamin-A supplementation is essential to address the burden of child wasting. PMID- 28616227 TI - Bridging the gap between climate models and impact studies: the FORESEE Database. AB - Studies on climate change impacts are essential for identifying vulnerabilities and developing adaptation options. However, such studies depend crucially on the availability of reliable climate data. In this study, we introduce the climatological database called FORESEE (Open Database for Climate Change Related Impact Studies in Central Europe), which was developed to support the research of and adaptation to climate change in Central and Eastern Europe: the region where knowledge of possible climate change effects is inadequate. A questionnaire-based survey was used to specify database structure and content. FORESEE contains the seamless combination of gridded daily observation-based data (1951-2013) built on the E-OBS and CRU TS datasets, and a collection of climate projections (2014 2100). The future climate is represented by bias-corrected meteorological data from 10 regional climate models (RCMs), driven by the A1B emission scenario. These latter data were developed within the frame of the ENSEMBLES FP6 project. Although FORESEE only covers a limited area of Central and Eastern Europe, the methodology of database development, the applied bias correction techniques, and the data dissemination method, can serve as a blueprint for similar initiatives. PMID- 28616228 TI - A daily Azores-Iceland North Atlantic Oscillation index back to 1850. AB - We present the construction of a continuous, daily (09:00 UTC), station-based (Azores-Iceland) North Atlantic Oscillation (NAO) Index back to 1871 which is extended back to 1850 with additional daily mean data. The constructed index more than doubles the length of previously existing, widely available, daily NAO time series. The index is created using entirely observational sea-level pressure (SLP) data from Iceland and 73.5% of observational SLP data from the Azores - the remainder being filled in via reanalysis (Twentieth Century Reanalysis Project and European Mean Sea Level Pressure) SLP data. Icelandic data are taken from the Southwest Iceland pressure series. We construct and document a new Ponta Delgada SLP time series based on recently digitized and newly available data that extend back to 1872. The Ponta Delgada time series is created by splicing together several fractured records (from Ponta Delgada, Lajes, and Santa Maria) and filling in the major gaps (pre-1872, 1888-1905, and 1940-1941) and occasional days (145) with reanalysis data. Further homogeneity corrections are applied to the Azores record, and the daily (09:00 UTC) NAO index is then calculated. The resulting index, with its extended temporal length and daily resolution, is the first reconstruction of daily NAO back into the 19th Century and therefore is useful for researchers across multiple disciplines. PMID- 28616229 TI - Datasets related to in-land water for limnology and remote sensing applications: distance-to-land, distance-to-water, water-body identifier and lake-centre co ordinates. AB - Datasets containing information to locate and identify water bodies have been generated from data locating static-water-bodies with resolution of about 300 m (1/360?) recently released by the Land Cover Climate Change Initiative (LC CCI) of the European Space Agency. The LC CCI water-bodies dataset has been obtained from multi-temporal metrics based on time series of the backscattered intensity recorded by ASAR on Envisat between 2005 and 2010. The new derived datasets provide coherently: distance to land, distance to water, water-body identifiers and lake-centre locations. The water-body identifier dataset locates the water bodies assigning the identifiers of the Global Lakes and Wetlands Database (GLWD), and lake centres are defined for in-land waters for which GLWD IDs were determined. The new datasets therefore link recent lake/reservoir/wetlands extent to the GLWD, together with a set of coordinates which locates unambiguously the water bodies in the database. Information on distance-to-land for each water cell and the distance-to-water for each land cell has many potential applications in remote sensing, where the applicability of geophysical retrieval algorithms may be affected by the presence of water or land within a satellite field of view (image pixel). During the generation and validation of the datasets some limitations of the GLWD database and of the LC CCI water-bodies mask have been found. Some examples of the inaccuracies/limitations are presented and discussed. Temporal change in water-body extent is common. Future versions of the LC CCI dataset are planned to represent temporal variation, and this will permit these derived datasets to be updated. PMID- 28616230 TI - Predictors of Adamkiewicz artery and anterior spinal artery detection through computerized tomographic angiography. AB - BACKGROUND: The detection of the Adamkiewicz artery and the anterior spinal artery has been associated with the ability to prevent adverse spinal cord outcomes after aortic surgical procedures. Yet, to our knowledge, no previous studies have attempted to use modern predictive models to identify the most important variables in determining artery detectability. AIMS: To develop a model to predict the odds of visualizing the Adamkiewicz artery or anterior spinal artery in patients undergoing computerized tomographic angiography. METHODS: We conducted a prospective, cross-sectional study. Outcomes of interest were the non detection of the Adamkiewicz artery and anterior spinal artery, and their corresponding level of origin. Axial images were inspected in high definition in search of two dense spots characterizing the Adamkiewicz artery and anterior spinal artery. A multiplanar three-dimensional reconstruction was then performed using the OsiriX(r) software. RESULTS: A total of 110 participants were part of this analysis. When evaluating risks for the Adamkiewicz artery being undetectable, significant factors could be classified into three broad categories: risk factors for arterial disease, established arterial disease, and obesity. Factors in the former category included metabolic syndrome, hypertension, and smoking status, while factors in the arterial disease included descending aortic aneurysm, mural thrombi, aortic aneurysm without a dissection, and aortic disease in general. In relation to anterior spinal artery not being detectable, significant risk factors included hypertension, smoking status, and metabolic syndrome, while those associated with arterial disease involved aortic disease and arterial thrombi. When evaluating the importance of individual clinical factors, the presence of higher body mass index was the single most important risk factor. CONCLUSION: Arterial disease, established arterial disease, and increased body mass index are risk factors in the detection of Adamkiewicz artery and anterior spinal artery. Specific diagnostic protocols should be in place for patients with these underlying conditions, thus enhancing the likelihood of detection when the Adamkiewicz artery is indeed present. PMID- 28616231 TI - Lymph node transfer for refractory infectious sites caused by trauma. AB - OBJECTIVE: In this report, we placed focus on the immunological function of lymph nodes and performed lymph node transfer via a free flap to a site of refractory infection. CASE AND RESULTS: Case 1 describes a 34-year-old male suffering from compound fractures with severe crush injuries and burns in the right ankle joint. A 20 * 15 cm skin defect was observed around the right malleolus medialis, along with denuded tendons with bacterial infection. After conservative treatment, we transferred a lymph-node-containing free superficial circumflex iliac artery perforator flap to the region, with minimum debridement. No recurrence of wound infection appeared. Case 2 describes a 73-year-old male patient suffering from extensive contused wound in the right crus. Despite conservative treatment, the tibia gradually became denuded with computed tomography and magnetic resonance imaging revealing degeneration of the tibial cortex. We performed a free superficial circumflex iliac artery perforator flap containing lymph nodes to the chronic infection area. The wound area healed successfully. CONCLUSION: In conclusion, lymph node transfer has a potential of treatment infection sites. PMID- 28616232 TI - Treatment of sudden hearing loss using electro-acupuncture. AB - OBJECTIVES: Sudden neurosensory deafness is the second debilitating disease in China. In fact, the current treatment is limited to hearing aids, assistive devices and cochlear implants. However, some patients might not be suitable for surgery or even hearing aids. METHODS: Hereby, we report a pediatric case of sudden sensorineural hearing loss accompanied by otalgia and blocked ear sensation. RESULTS: He firstly failed with conventional treatment but later his hearing symptoms were improved with our electro-acupuncture therapy according to pure tone audiometry findings and clinical responses. CONCLUSIONS: It may be worth trying in patients with sudden neurosensory deafness, who do not respond to routine medical treatment. In line with previous studies, the current report indicates that future observational studies or even clinical trials are needed to prove the efficacy of acupuncture on hearing loss and the accompanying symptoms. PMID- 28616233 TI - Long-standing aggressive angiomyxoma as a paratesticular mass: A case report and review of literature. AB - OBJECTIVES: Aggressive angiomyxoma is known as a mesenchymal tumor of premenopausal women and it is extremely rare in men. METHODS: Herein, we report a 66-year-old male with a firm scrotal mass that had gradually enlarged over 20 years. RESULTS: Radiological studies revealed 10 x 15 cm mass lesion confined to right scrotum with neither local invasion nor distant metastasis. Inguinal orchiectomy was performed and histopathology showed characteristic features of an aggressive angiomyxoma occupying paratesticular region, which was a challenging diagnosis due to its unexpected occurrence in the male gender. CONCLUSION: Aggressive angiomyxoma is mostly considered as a benign tumor in females despite its propensity for local recurrence. Whether it may show a divergent biological behavior in men is unknown as the reported cases are too few. PMID- 28616234 TI - All that glitters is not gold: A case of lanthanum carbonate aspiration. AB - INTRODUCTION: Foreign body aspiration is a significant cause of morbidity and mortality in elderly hospitalized patients. These are typically small items that patients have access to, including small coins. CASE PRESENTATION: This is a case report of a 75-year-old man recently bedridden from a large hemispheric stroke with sudden onset of hoarseness, cough and dysphagia. A chest X-ray was obtained which showed a radiopaque coin-shaped foreign body, presumably a coin in his aerodigestive tract. He was promptly taken to the endoscopy suite for upper endoscopy. During endoscopy, it was determined that the foreign body was a radiopaque medication that he had been given. It was easily and safely able to be crushed and lavaged down into his stomach and later determined to be lanthanum carbonate, a commonly used phosphate binder. Following endoscopy, the patient's cough, hoarseness and dysphagia resolved with no long-term complications. DISCUSSION: Lanthanum carbonate is a phosphate-binding medication used in the management and treatment of hyperphosphatemia commonly seen in patients with end stage renal disease, which is radiopaque. There are few published reports and images of radiopaque fragments of medication in the gastrointestinal tract but none causing aspiration by masquerading as a coin-like density in the aerodigestive tract as we present here. PMID- 28616235 TI - Exacerbation of alopecia areata: A possible complication of sodium tetradecyl sulphate foam sclerotherapy treatment for varicose veins. AB - A 40-year-old woman with a history of alopecia areata related to stress or hormonal changes was treated for bilateral primary symptomatic varicose veins (CEAP clinical score C2S) of pelvic origin, using a staged procedure. Her first procedure entailed pelvic vein embolisation of three pelvic veins using 14 coils and including foam sclerotherapy of the tributaries, using 3% sodium tetradecyl sulphate. Following this procedure, she had an exacerbation of alopecia areata with some moderate shedding of hair. Subsequently, she underwent endovenous laser ablation under local anaesthetic without incident. Seven months after the pelvic vein embolisation, she underwent foam sclerotherapy of leg and labial varicose veins using sodium tetradecyl sulphate. Two days following this procedure, she had a severe exacerbation of alopecia areata with gross shedding of hair. These two episodes of exacerbation of alopecia areata appear to be associated with sodium tetradecyl sulphate foam sclerotherapy of veins. PMID- 28616236 TI - Effect of applied energy in renal sympathetic denervation with magnetic resonance guided focused ultrasound in a porcine model. AB - BACKGROUND: Past catheter-based and focused ultrasound renal denervation studies have indicated that procedure efficacy is related to the number of ablations performed or the amount of energy used for the ablation. This study extends those prior results and investigates energy level effects on the efficacy of MR guided focused ultrasound renal denervation performed in a porcine model. METHODS: Twenty-four normotensive pigs underwent unilateral denervation at three intensity levels. The applied intensity level was retrospectively de-rated to account for variability in animal size. Efficacy was assessed through evaluating the norepinephrine present in the kidney medulla and through histological analysis. The treatment was performed under MRI guidance including pre- and post-procedure T1-weighted and quantitative T1 and T2 imaging. During treatment, the temperature in the near field of the ultrasound beam was monitored in real time with MR temperature imaging. Energy delivery in the regions surrounding the renal artery was independently confirmed through an invasive fiberoptic temperature probe placed in the right renal artery. RESULTS: Animals that underwent denervation at a de-rated acoustic intensity of greater than 1.2 kW/cm2 had a significantly lower norepinephrine concentration in the kidney indicating successful denervation. Images obtained during the treatment indicated no tissue changes in the kidneys as a function of the procedure but there were significant T1 changes present in the right lumbar muscles, although only one animal had indication of muscle damage at the time of necropsy. CONCLUSIONS: While MR guided focused ultrasound renal denervation was found to be safe and effective in this normotensive animal model, the results indicated the need to incorporate patient specific details in the treatment planning of MRgFUS renal denervation procedure. PMID- 28616237 TI - Higher serum concentrations of vimentin and DAKP1 are associated with aggressive breast tumour phenotypes in Ghanaian women. AB - BACKGROUND: Breast cancer, the most commonly diagnosed cancer among women and leading cause of cancer-related deaths worldwide, exhibits aggressive behavior in indigenous African women evidenced by high histologic grade tumours with low hormone receptor positivity. Aggressive breast cancers grow quickly, easily metastasize and recur and often have unfavourable outcomes. The current study investigated candidate genes that may regulate tumour aggression in Ghanaian women. We hypothesize that increased expression and function of certain genes other than the widely-held view attributing breast cancer aggression in African populations to their younger population age may be responsible for the aggressive nature of tumours. METHODS: Employing ELISA, we assayed for vimentin and death associated protein kinase 1 (DAPK1) from thawed archived (stored at -80 degrees C) serum samples obtained from 40 clinically confirmed Ghanaian breast cancer patients and 40 apparently healthy controls. Patients' clinical records and tumour parameters matching the samples were retrieved from the database of the hospital. ANOVA was used to compare means of serum protein concentration among groups while Chi-square analysis was used for the categorical data sets with p value <=0.05 considered significant. Multiple logistic regression analysis was conducted to determine the association between protein concentration and tumour parameters. RESULTS: Of the 80 samples, 27 (33.8%) and 53 (66.2%) were from young (<35 years) and old (>=35 years), respectively. Vimentin and DAPK1 concentration were higher in patients than controls with higher levels in "young" age group than "old" age group. Vimentin concentration was highest in grade 3 tumours followed by grade 2 and 1 but that for DAPK1 was not significant. For vimentin, tumour area strongly correlated with tumour grade (r = 0.696, p < 0.05) but weakly correlated with tumour stage (r = 0.420, p < 0.05). Patient's age correlated with DAPK1 concentration (r = 0.393, p < 0.05). DAPK1 serum levels weakly correlated with cancer duration (r = 0.098, p = 0.27) and tumour size (r = 0.40, p < 0.05). CONCLUSION: Serum concentration of Vimentin and DAPK1 are elevated in Ghanaian breast cancer patients. This may be partly responsible for aggressive nature of the disease among the population. Vimentin and DAPK1 should be explored further as potential breast cancer biomarkers in Africans. PMID- 28616238 TI - Validation of a portable, waterproof blood pH analyser for elasmobranchs. AB - Quantifying changes in blood chemistry in elasmobranchs can provide insights into the physiological insults caused by anthropogenic stress, and can ultimately inform conservation and management strategies. Current methods for analysing elasmobranch blood chemistry in the field are often costly and logistically challenging. We compared blood pH values measured using a portable, waterproof pH meter (Hanna Instruments HI 99161) with blood pH values measured by an i-STAT system (CG4+ cartridges), which was previously validated for teleost and elasmobranch fishes, to gauge the accuracy of the pH meter in determining whole blood pH for the Cuban dogfish (Squalus cubensis) and lemon shark (Negaprion brevirostris). There was a significant linear relationship between values derived via the pH meter and the i-STAT for both species across a wide range of pH values and temperatures (Cuban dogfish: 6.8-7.1 pH 24-30 degrees C; lemon sharks: 7.0 7.45 pH 25-31 degrees C). The relative error in the pH meter's measurements was ~+/-2.7%. Using this device with appropriate correction factors and consideration of calibration temperatures can result in both a rapid and accurate assessment of whole blood pH, at least for the two elasmobranch species examined here. Additional species should be examined in the future across a wide range of temperatures to determine whether correction factors are universal. PMID- 28616239 TI - Reflex impairment and physiology as predictors of delayed mortality in recreationally caught yellowtail snapper (Ocyurus chrysurus). AB - Yellowtail snapper (Ocyurus chrysurus) is an important part of the reef fish assemblage in the western, tropical Atlantic and is caught by both recreational and commercial fisheries in south Florida and the Bahamas. It is estimated that 80% of snapper caught within southeastern Florida waters are discarded due to minimum size restrictions. Neglecting to include information on delayed mortality of undersized fish has the potential for fishery managers to overestimate the abundance of smaller size classes and introduce bias into stock assessments. This study examines associations between reflex impairment, traditional physiological parameters and post-release mortality of undersized yellowtail snapper. Laboratory experiments exposed yellowtail snapper to a gradient, simulating capture conditions. Blood draws were obtained from a sub-sample of fish. There was a significant relationship between delayed mortality and the proportion of reflex impairment for both individual fish and groups of fish (P < 0.001 and P = 0.03). Within the sub-sample of blood-sampled fish, base excess and pH were significantly correlated to reflex impairment. Delayed mortality was significantly correlated to pH, base excess and lactate concentration. Results suggest that discarded, undersized yellowtail with more than 29% of their reflexes impaired will not survive. PMID- 28616240 TI - Metastatic pancreatic carcinoma masquerading as cystic lung disease: a rare presentation. AB - This 52-year-old male ex-smoker presented with a six-month history of progressive breathlessness and weight loss. He deteriorated acutely, and was admitted with severe type 1 respiratory failure. Apart from diffuse coarse crackles on chest auscultation, physical examination was unremarkable. High-resolution computed tomography (HRCT) showed diffuse cystic changes throughout the lungs. A diagnosis of pulmonary Langerhans cell histiocytosis (PLCH) was considered. Further workup identified a coincidental pancreatic lesion of uncertain significance, which remained indeterminate on magnetic resonance imaging (MRI) and on positron emission tomography (PET). Transbronchial biopsy revealed enteric differentiated adenocarcinoma exhibiting lepidic spread, and autopsy later confirmed primary pancreatic malignancy. This case demonstrates that metastatic pancreatic malignancy can present with severe respiratory failure and masquerade as cystic lung disease. PMID- 28616241 TI - Passive leg raising test with minimally invasive monitoring: the way forward for guiding septic shock resuscitation? AB - BACKGROUND: Swift and adequate fluid loading is a cornerstone of septic shock therapy. Yet, careful assessment of volume responsiveness and volume amount during the resuscitation process is a prerequisite. Both overzealous initial fluid administration and late fluid overload are harmful and may be associated with increased mortality. MAIN BODY: Static (i.e., central venous or pulmonary artery occlusion) pressure readings are erroneous for monitoring fluid resuscitation and should be abandoned. Dynamic measurements (i.e., stroke volume and pulse pressure variation) better predict fluid responsiveness than static filling pressures but the conditions necessary for these parameters to correctly evaluate preload dependency are frequently not met. The passive leg raising maneuver as a means to alter biventricular preload in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management and to avoid fluid overload during early septic shock treatment. Moreover, PLR may also be particularly useful to assist various treatments that trigger fluid removal during the "de-resuscitation" phase of septic shock. CONCLUSIONS: The passive leg raising maneuver in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management during septic shock. PMID- 28616242 TI - First complete genome sequence of canine bocavirus 2 in mainland China. AB - We obtained the first full-length genome sequence of canine bocavirus 2 (CBoV2) from the faeces of a healthy dog in Guangzhou city, Guangdong province, mainland China. The genome of GZHD15 consisted of 5059 nucleotides. Sequence analysis suggested that GZHD15 was close to a previously circulated Hong Kong isolate. PMID- 28616243 TI - A global, cross cultural study examining the relationship between employee health risk status and work performance metrics. AB - BACKGROUND: Health risk assessments (HRA) are used by many organisations as a basis for developing relevant and targeted employee health and well-being interventions. However, many HRA's have a western-centric focus and therefore it is unclear whether the results can be directly extrapolated to those from non western countries. More information regarding the differences in the associations between country status and health risks is needed along with a more global perspective of employee health risk factors and well-being overall. Therefore we aimed to i) quantify and compare associations for a number of health risk factors based on country status, and then ii) explore which characteristics can aid better prediction of well-being levels and in turn workplace productivity globally. METHODS: Online employee HRA data collected from 254 multi-national companies, for the years 2013 through 2016 was analysed (n = 117,274). Multiple linear regression models were fitted, adjusting for age and gender, to quantify associations between country status and health risk factors. Separate regression models were used to assess the prediction of well-being measures related to productivity. RESULTS: On average, the developing countries were comprised of younger individuals with lower obesity rates and markedly higher job satisfaction compared to their developed country counterparts. However, they also reported higher levels of anxiety and depression, a greater number of health risks and lower job effectiveness. Assessment of key factors related to productivity found that region of residency was the biggest predictor of presenteeism and poor pain management was the biggest predictor of absenteeism. CONCLUSIONS: Clear differences in health risks exist between employees from developed and developing countries and these should be considered when addressing well-being and productivity in the global workforce. PMID- 28616244 TI - Macrophages and fibroblasts during inflammation and tissue repair in models of organ regeneration. AB - This review provides a concise summary of the changing phenotypes of macrophages and fibroblastic cells during the local inflammatory response, the onset of tissue repair, and the resolution of inflammation which follow injury to an organ. Both cell populations respond directly to damage and present coordinated sequences of activation states which determine the reparative outcome, ranging from true regeneration of the organ to fibrosis and variable functional deficits. Recent work with mammalian models of organ regeneration, including regeneration of full-thickness skin, hair follicles, ear punch tissues, and digit tips, is summarized and the roles of local immune cells in these systems are discussed. New investigations of the early phase of amphibian limb and tail regeneration, including the effects of pro-inflammatory and anti-inflammatory agents, are then briefly discussed, focusing on the transition from the normally covert inflammatory response to the initiation of the regeneration blastema by migrating fibroblasts and the expression of genes for limb patterning. PMID- 28616245 TI - Regulation of dorso-ventral polarity by the nerve cord during annelid regeneration: A review of experimental evidence. AB - An important goal for understanding regeneration is determining how polarity is conferred to the regenerate. Here we review findings in two groups of polychaete annelids that implicate the ventral nerve cord in assigning dorso-ventral polarity, and specifically ventral identity, to the regenerate. In nereids, surgical manipulations indicate that parapodia develop where dorsal and ventral body wall territories contact. Without a nerve cord at the wound site, the regenerate differentiates no evident polarity (with no parapodia) and only dorsal identity, while with two nerve cords the regenerate develops a twinned dorso ventral axis (with four parapodia per segment instead of the normal two). In sabellids, a striking natural dorso-ventral inversion in parapodial morphology occurs along the body axis and this inversion is morphologically correlated with the position of the nerve cord. Parapodial inversion also occurs in segments in which the nerve cord has been removed, even without any segment amputation. Together, these data strongly support a role for the nerve cord in annelid dorso ventral pattern regulation, with the nerve cord conferring ventral identity. PMID- 28616246 TI - Fibroblast reticular cells engineer a blastema extracellular network during digit tip regeneration in mice. AB - The regeneration blastema which forms following amputation of the mouse digit tip is composed of undifferentiated cells bound together by an organized network of fibers. A monoclonal antibody (ER-TR7) that identifies extracellular matrix (ECM) fibers produced by fibroblast reticular cells during lymphoid organogenesis was used to characterize the ECM of the digit, the blastema, and the regenerate. Digit fibroblast reticular cells produce an ER-TR7+ ECM network associated with different tissues and represent a subset of loose connective tissue fibroblasts. During blastema formation there is an upregulation of matrix production that returns to its pre-existing level and anatomical pattern in the endpoint regenerate. Co-localization studies demonstrate a strong spatial correlation between the ER-TR7 antigen and collagen type III (COL3) in histological sections. ER-TR7 and COL3 are co-induced in cultured digit fibroblasts following treatment with tumor necrosis factor alpha and a lymphotoxin beta receptor agonist. These results provide an initial characterization of the ECM during digit regeneration and identify a subpopulation of fibroblasts involved in producing the blastema provisional matrix that is remodeled during the regeneration response. PMID- 28616248 TI - Lymphangioleiomyomatosis: an explosive presentation of a rare disease. AB - Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease, commonly affecting women in the reproductive age group. Exacerbation of pre-existing disease is common during pregnancy likely due to the up-regulation of estrogen and progesterone receptors present within the proliferating smooth muscle cells. This case highlights a dramatic presentation of LAM for the first time in pregnancy, its rapid progression during gestation, and a partial resolution with delivery. The unusual radiographic imaging in this patient, lacked the characteristic cystic lesions commonly associated with LAM, but instead demonstrated a dense interstitial pattern with micronodular expansion of the interlobular septa suggesting severe lymphatic obstruction. PMID- 28616247 TI - Planarian regeneration in space: Persistent anatomical, behavioral, and bacteriological changes induced by space travel. AB - Regeneration is regulated not only by chemical signals but also by physical processes, such as bioelectric gradients. How these may change in the absence of the normal gravitational and geomagnetic fields is largely unknown. Planarian flatworms were moved to the International Space Station for 5 weeks, immediately after removing their heads and tails. A control group in spring water remained on Earth. No manipulation of the planaria occurred while they were in orbit, and space-exposed worms were returned to our laboratory for analysis. One animal out of 15 regenerated into a double-headed phenotype-normally an extremely rare event. Remarkably, amputating this double-headed worm again, in plain water, resulted again in the double-headed phenotype. Moreover, even when tested 20 months after return to Earth, the space-exposed worms displayed significant quantitative differences in behavior and microbiome composition. These observations may have implications for human and animal space travelers, but could also elucidate how microgravity and hypomagnetic environments could be used to trigger desired morphological, neurological, physiological, and bacteriomic changes for various regenerative and bioengineering applications. PMID- 28616249 TI - Quality of Care for Patients With Chronic Kidney Disease in the Primary Care Setting: A Retrospective Cohort Study From Ontario, Canada. AB - BACKGROUND: Patients with chronic kidney disease may not be receiving recommended primary renal care. OBJECTIVE: To use recently established primary care quality indicators for chronic kidney disease to determine the proportion of patients receiving recommended renal care. DESIGN: Retrospective cohort study using administrative data with linked laboratory information. SETTING: The study was conducted in Ontario, Canada, from 2006 to 2012. PATIENTS: Patients over 40 years with chronic kidney disease or abnormal kidney function in primary care were included. MEASUREMENTS: In total, 11 quality indicators were assessed for chronic kidney disease identified through a Delphi panel in areas of screening, monitoring, drug prescribing, and laboratory monitoring after initiating an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). METHODS: We calculated the proportion and cumulative incidence at the end of follow-up of patients meeting each indicator and stratified results by age, sex, cohort entry, and chronic kidney disease stage. RESULTS: Less than half of patients received follow-up tests after an initial abnormal kidney function result. Most patients with chronic kidney disease received regular monitoring of serum creatinine (91%), but urine albumin-to-creatinine monitoring was lower (70%). A total of 84% of patients age 66 and older did not receive a non steroidal anti-inflammatory drug prescription of at least 2-week duration. Three quarters of patients age 66 and older were on an ACE inhibitor or ARB, and 96% did not receive an ACE inhibitor and ARB concurrently. Among patients 66 to 80 years of age with chronic kidney disease, 65% were on a statin. One quarter of patients age 66 and older who initiated an ACE inhibitor or ARB had their serum creatinine and potassium monitored within 7 to 30 days. LIMITATIONS: This study was limited to people in Ontario with linked laboratory information. CONCLUSIONS: There was generally strong performance across many of the quality of care indicators. Areas where more attention may be needed are laboratory testing to confirm initial abnormal kidney function test results and monitoring serum creatinine and potassium after initiating a new ACE inhibitor or ARB. PMID- 28616251 TI - Physical micro-environment interventions for healthier eating in the workplace: protocol for a stepped wedge randomised controlled pilot trial. AB - BACKGROUND: An estimated one third of energy is consumed in the workplace. The workplace is therefore an important context in which to reduce energy consumption to tackle the high rates of overweight and obesity in the general population. Altering environmental cues for food selection and consumption-physical micro environment or 'choice architecture' interventions-has the potential to reduce energy intake. The first aim of this pilot trial is to estimate the potential impact upon energy purchased of three such environmental cues (size of portions, packages and tableware; availability of healthier vs. less healthy options; and energy labelling) in workplace cafeterias. A second aim of this pilot trial is to examine the feasibility of recruiting eligible worksites, and identify barriers to the feasibility and acceptability of implementing the interventions in preparation for a larger trial. METHODS: Eighteen worksite cafeterias in England will be assigned to one of three intervention groups to assess the impact on energy purchased of altering (a) portion, package and tableware size (n = 6); (b) availability of healthier options (n = 6); and (c) energy (calorie) labelling (n = 6). Using a stepped wedge design, sites will implement allocated interventions at different time periods, as randomised. DISCUSSION: This pilot trial will examine the feasibility of recruiting eligible worksites, and the feasibility and acceptability of implementing the interventions in preparation for a larger trial. In addition, a series of linear mixed models will be used to estimate the impact of each intervention on total energy (calories) purchased per time frame of analysis (daily or weekly) controlling for the total sales/transactions adjusted for calendar time and with random effects for worksite. These analyses will allow an estimate of an effect size of each of the three proposed interventions, which will form the basis of the sample size calculations necessary for a larger trial. TRIAL REGISTRATION: ISRCTN52923504. PMID- 28616252 TI - Important considerations for feasibility studies in physical activity research involving persons with multiple sclerosis: a scoping systematic review and case study. AB - BACKGROUND: Much research has been undertaken to establish the important benefits of physical activity in persons with multiple sclerosis (MS). There is disagreement regarding the strength of this research, perhaps because the majority of studies on physical activity and its benefits have not undergone initial and systematic feasibility testing. We aim to address the feasibility processes that have been examined within the context of physical activity interventions in MS. METHOD: A systematic scoping review was conducted based on a literature search of five databases to identify feasibility processes described in preliminary studies of physical activity in MS. We read and extracted methodology from each study based on the following feasibility metrics: process (e.g. recruitment), resource (e.g. monetary costs), management (e.g. personnel time requirements) and scientific outcomes (e.g. clinical/participant reported outcome measures). We illustrate the use of the four feasibility metrics within a randomised controlled trial of a home-based exercise intervention in persons with MS. RESULTS: Twenty-five studies were identified. Resource feasibility (e.g. time and resources) and scientific outcomes feasibility (e.g. clinical outcomes) methodologies were applied and described in many studies; however, these metrics have not been systematically addressed. Metrics related to process feasibility (e.g. recruitment) and management feasibility (e.g. human and data management) are not well described within the literature. Our case study successfully enabled us to address the four feasibility metrics, and we provide new information on management feasibility (i.e. estimate data completeness and estimate data entry) and scientific outcomes feasibility (i.e. determining data collection materials appropriateness). CONCLUSION: Our review highlights the existing research and provides a case study which assesses important metrics of study feasibility. This review serves as a clarion call for feasibility trials that will substantially strengthen the foundation of research on exercise in MS. PMID- 28616253 TI - Necessary but not sufficient: unique author identifiers. PMID- 28616250 TI - Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy. AB - PURPOSE OF REVIEW: Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. OBJECTIVE: In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. METHODS: We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. KEY FINDINGS: In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. LIMITATIONS: Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. IMPLICATIONS: Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of developing kidney diseases. PMID- 28616254 TI - In vitro ion adsorption and cytocompatibility of dicalcium phosphate ceramics. AB - BACKGROUND: In vitro cell testing of degradable bioceramics such as brushite or monetite is often challenging due to the ion release into or adsorption from the culture medium. These ionic changes are then mostly responsible for cell proliferation and activity, which prohibits the investigation of effects originating from surface topography or further material modifications. METHODS: Here, we aimed to solve this problem by developing a pre-conditioning regime following the repeated immersion of brushite and monetite samples in various Ca2+, Mg2+ and PO43- containing electrolytes, followed by studying ion adsorption / release as well as changes in phase composition and in vitro cytocompatibility with MG63 cells. RESULTS: The results demonstrated that by using DMEM cell culture medium in a ratio of 10 ml/sample was sufficient to minimize changes of ionic composition after 7 d with a daily change of the medium. This leads to changes of the surface composition with dissolution of the brushite phase. In turn, this also positively influences the in vitro cytocompatibility with a 2-3 fold higher cell number and cell activity on the DMEM pretreated surfaces. CONCLUSIONS: Controlled sample washing prior to cell testing using DMEM medium seems to be a valuable procedure not only to stabilize the pH during cell culture but also to maintain ion concentrations within a cell friendly range. PMID- 28616255 TI - Global health governance in the sustainable development goals: Is it grounded in the right to health? AB - This paper explores the extent to which global health governance - in the context of the early implementation of the Sustainable Development Goals is grounded in the right to health. The essential components of the right to health in relation to global health are unpacked. Four essential functions of the global health system are assessed from a normative, rights-based, analysis on how each of these governance functions should operate. These essential functions are: the production of global public goods, the management of externalities across countries, the mobilization of global solidarity, and stewardship. The paper maps the current reality of global health governance now that the post-2015 Sustainable Development Goals are beginning to be implemented. In theory, the existing human rights legislation would enable the principles and basis for the global governance of health beyond the premise of the state. In practice, there is a governance gap between the human rights framework and practices in global health and development policies. This gap can be explained by the political determinants of health that shape the governance of these global policies. Current representations of the right to health in the Sustainable Development Goals are insufficient and superficial, because they do not explicitly link commitments or right to health discourse to binding treaty obligations for duty bearing nation states or entitlements by people. If global health policy is to meaningfully contribute to the realization of the right to health and to rights based global health governance then future iterations of global health policy must bridge this gap. This includes scholarship and policy debate on the structure, politics, and agency to overcome existing global health injustices. PMID- 28616256 TI - Extremely Cost-Effective and Efficient Solar Vapor Generation under Nonconcentrated Illumination Using Thermally Isolated Black Paper. AB - Passive solar vapor generation represents a promising and environmentally benign method of water purification/desalination. However, conventional solar steam generation techniques usually rely on costly and cumbersome optical concentration systems and have relatively low efficiency due to bulk heating of the entire liquid volume. Here, an efficient strategy using extremely low-cost materials, i.e., carbon black (powder), hydrophilic porous paper, and expanded polystyrene foam is reported. Due to the excellent thermal insulation between the surface liquid and the bulk volume of the water and the suppressed radiative and convective losses from the absorber surface to the adjacent heated vapor, a record thermal efficiency of ~88% is obtained under 1 sun without concentration, corresponding to the evaporation rate of 1.28 kg (m2 h)-1. When scaled up to a 100 cm2 array in a portable solar water still system and placed in an outdoor environment, the freshwater generation rate is 2.4 times of that of a leading commercial product. By simultaneously addressing both the need for high efficiency operation as well as production cost limitations, this system can provide an approach for individuals to purify water for personal needs, which is particularly suitable for undeveloped regions with limited/no access to electricity. PMID- 28616258 TI - The comparison of multimodal imaging findings of central serous chorioretinopathy patients in regard to the early anatomically treatment response to half-fluence photodynamic therapy: a retrospective case-control study. AB - BACKGROUND: To compare the multimodal imaging findings of chronic central serous chorioretinopathy (CSC) patients who are good or poor responders to low-fluence photodynamic therapy (PDT). METHODS: Retrospective, interventional comparative study. The CSC patients who were admitted to our clinic for the first time between January 2013 and December 2015 were included in the study. Patients were treated with PDT only if they did not show any sign of resolution after at least 6 months from the initial signs of the disease. The patients who showed full or partial response to PDT after 3 months of treatment were accepted as good responders, those who did not show any sign of resolution were accepted as poor responders. The optical coherence tomography (OCT), fluorescein angiography (FA), and indocyanine green angiography (ICGA) findings were compared between the two groups. RESULTS: A total of 101 eyes of 101 patients were included: 76 eyes (75.2%) were considered as good responders and 25 eyes (24.8%) as poor responders. In regards to OCT and FA findings there was not a significant difference between the two groups for all of the evaluated findings (p > 0.05 for all). In regards to ICGA findings, there was a statistically difference in the percentage of intense midphase hypercyanescence (p < 0.0001). CONCLUSIONS: The multimodal imaging findings of CSC patients were compared in regard to their PDT response. The presence of midphase hypercyanescence in ICGA seemed to be positive predictive factor for the PDT response in CSC patients. PMID- 28616259 TI - Hyperphosphatemia in a patient with spinal cord injury who received etidronate for the treatment of heterotopic ossification. AB - INTRODUCTION: Heterotopic ossification (HO) is defined as ectopic bone formation around peripheral joints and in soft tissues. HO is a common complication of diseases of the central nervous system, such as spinal cord injury (SCI) and traumatic brain injury. HO is seen in up to 50% of patients with SCI and typically occurs in the first 12 weeks after onset of injury. Although no treatment method is proven to be curative, nonsteroidal anti-inflammatory drugs, irradiation of the involved body part and bisphosphonates are commonly used in the management of HO. CASE PRESENTATION: Here we present a 27-year-old male patient with a T10 ASIA Impairment Scale (AIS) A SCI, who developed hyperphosphatemia as a complication of bisphosphonate therapy initiated for the treatment of HO during the 6th post-operative week. After cessation of etidronate use, phosphate levels gradually returned to normal over 2 weeks. DISCUSSION: Hyperphosphatemia is a rare complication of etidronate use. It is speculated to result from increased renal tubular phosphate reabsorption and is usually asymptomatic. Although mostly asymptomatic, this complication must be kept in mind while administering etidronate to SCI patients and blood phosphate levels should be monitored in the early weeks of treatment. PMID- 28616260 TI - The therapeutic effects of ablative neurosurgical procedures on the spinal cord for intractable spinal spasticity. AB - STUDY DESIGN: This research is a retrospective study. OBJECTIVE: To study the therapeutic effects of operative procedures, including dorsal longitudinal myelotomy (DLM) and dorsal root entry zone lesion (DREZL) on spasticity and associated aspects. SETTING: Tertiary university hospital in Bangkok, Thailand. METHODS: Eighteen patients with refractory spasticity of spinal origin who underwent the operations were recruited. Clinical parameters for evaluating severity of spasticity and ambulatory status were compared between before and after surgery, and between surgeries. RESULTS: A statistically significant reduction of spasticity as measured by the Modified Ashworth Scale (MAS), Adductor Tone Rating Scale (ATRS) and Penn Spasm Frequency Scale (PSFS) was found after surgeries and in the overall analysis (p < 0.05). Chronic pressure ulcers disappeared postoperatively in 11 cases. All of 7 bed-ridden subjects experienced improvement in their ambulatory status postoperatively. DLM was found to be more effective than DREZL in reduction of spasticity. CONCLUSION: Ablative neurosurgery on the spinal cord is still valuable in situations when intrathecal baclofen is unavailable. These operations are potentially effective in the treatment of intractable spasticity of spinal origin. PMID- 28616261 TI - Nerve entrapment as a cause of shoulder pain in the spinal cord injured patient. AB - INTRODUCTION: Many people with chronic spinal cord injury (SCI) develop shoulder pain, which can adversely impact transfers and independence. Yet effective treatments remain elusive. CASE PRESENTATION: This report presents two patients with tetraplegia who had long-standing shoulder pain. Our exam showed muscle weakness and point tenderness, suggestive of nerve entrapments of the radial and axillary nerves in the posterior shoulder. These nerves were surgically decompressed and post-operatively the patients' pain resolved. DISCUSSION: Shoulder nerve entrapments are uncommon but SCI patients may be at more risk due to their unique upper extremity demands. SCI providers should consider proximal nerve entrapments as a possible cause of shoulder pain. PMID- 28616262 TI - RASSF1A methylation, YAP1 activation and metastasis: a new role for an old foe in lung cancer. PMID- 28616263 TI - Balancing the paradox of medical-surgical advances: a historical perspective on the current situation in thoracic surgery. PMID- 28616264 TI - Optimal revascularization for left main coronary artery disease-coronary artery bypass grafting versus percutaneous coronary intervention. PMID- 28616265 TI - The use of transcatheter mitral valve system: can we make mitral regurgitation better again? PMID- 28616266 TI - From biological mechanisms to clinical implications: the role of mineral dust induced gene in lung cancers. PMID- 28616267 TI - Log odds of positive lymph nodes is a novel prognostic indicator for advanced ESCC after surgical resection. AB - BACKGROUND: To investigate the prognostic value of the log odds of positive lymph nodes (LODDS) in patients with advanced esophageal squamous cell carcinoma (ESCC) after surgical resection. METHODS: Clinical data of 260 patients with advanced ESCC undergoing surgical resection were retrospectively reviewed. Univariate and multivariate analysis were done using the chi-square test and Cox regression model. Receiver-operating-characteristic (ROC) curve was used to compare the association of pathologic nodal (pN) and LODDS with 3- or 5-year overall survival (OS). The cut-point analyses were performed to determine whether there was a cutoff LODDS related to the greatest OS difference. RESULTS: The mean follow-up duration was 30 months (range, 3 to 106 months). The 1-, 3-, 5-year OS rates were 70.0%, 41.9% and 30.3%, respectively. Univariate analyses indicated that the 5 year OS rates were 51.2%, 30.5%, 24.6%, and 14.2% in LODDS1, LODDS2, LODDS3, and LODDS4, respectively, and the median survival times were 68.7, 34.6, 24.0, and 14.6 months, respectively (P=0.000) for all patients, and subgroup analysis showed the effect did not change in 155 patients without lymph node (LN) metastasis (P=0.024). Multivariate analysis showed that LODDS [hazard ratio (HR) =1.309, P=0.003] to be independent and significant prognostic factors for all patients, so as in node-negative patients LODDS (HR =1.610, P=0.038). The AUC of LODDS stage (AUC =0.630) was larger than that of pN stage (AUC =0.621) in prediction of 3-year OS, however LODDS were smaller in prediction of 5-year OS (AUC =0.620, 0.631, respectively), and the differences were not statistically significant (P>0.05 all). Lastly, the step analysis identified the best cut-off point for LODDS as -1.2 that is significantly associated with the prognosis of the node-negative patients (P=0.024), and the ROC analysis also indicated that a cut-off value of -1.2 for LODDS provided the highest sensitivity and specificity interestingly. CONCLUSIONS: LODDS may be suitable for evaluation of OS in advanced ESCC patients without LN metastasis. PMID- 28616268 TI - Tumor invasiveness defined by IASLC/ATS/ERS classification of ground-glass nodules can be predicted by quantitative CT parameters. AB - BACKGROUND: To investigate the potential value of CT parameters to differentiate ground-glass nodules between noninvasive adenocarcinoma and invasive pulmonary adenocarcinoma (IPA) as defined by IASLC/ATS/ERS classification. METHODS: We retrospectively reviewed 211 patients with pathologically proved stage 0-IA lung adenocarcinoma which appeared as subsolid nodules, from January 2012 to January 2013 including 137 pure ground glass nodules (pGGNs) and 74 part-solid nodules (PSNs). Pathological data was classified under the 2011 IASLC/ATS/ERS classification. Both quantitative and qualitative CT parameters were used to determine the tumor invasiveness between noninvasive adenocarcinomas and IPAs. RESULTS: There were 154 noninvasive adenocarcinomas and 57 IPAs. In pGGNs, CT size and area, one-dimensional mean CT value and bubble lucency were significantly different between noninvasive adenocarcinomas and IPAs on univariate analysis. Multivariate regression and ROC analysis revealed that CT size and one-dimensional mean CT value were predictive of noninvasive adenocarcinomas compared to IPAs. Optimal cutoff value was 13.60 mm (sensitivity, 75.0%; specificity, 99.6%), and -583.60 HU (sensitivity, 68.8%; specificity, 66.9%). In PSNs, there were significant differences in CT size and area, solid component area, solid proportion, one-dimensional mean and maximum CT value, three-dimensional (3D) mean CT value between noninvasive adenocarcinomas and IPAs on univariate analysis. Multivariate and ROC analysis showed that CT size and 3D mean CT value were significantly differentiators. Optimal cutoff value was 19.64 mm (sensitivity, 53.7%; specificity, 93.9%), -571.63 HU (sensitivity, 85.4%; specificity, 75.8%). CONCLUSIONS: For pGGNs, CT size and one-dimensional mean CT value are determinants for tumor invasiveness. For PSNs, tumor invasiveness can be predicted by CT size and 3D mean CT value. PMID- 28616269 TI - Elevated serum levels of immunoglobulin A correlate with the possibility of readmission in patients with microscopic polyangiitis. AB - BACKGROUND: The evidence for the short-term prognosis of patients with microscopic polyangiitis (MPA) is weak, and the objective of this study was to analyze the clinical features of the disease and evaluate the risk factors for readmission in patients with MPA. METHODS: Fifty-seven patients with MPA were recruited into this study. The clinical data of these MPA patients were collected. Clinical manifestations, laboratory results, and imaging results were analyzed. Patients who were readmitted to our hospital within 6 months after their first diagnosis and treatment of MPA were defined as the readmission group; the remaining patients were defined as the control group. RESULTS: Respiratory symptoms, including cough, dyspnea (87.72%), and hemoptysis (3.51%), seemed to be the initial symptoms in many patients with MPA. Systemic symptoms included fever (71.93%), hearing loss (12.28%), vision loss (3.51%), and joint involvement (5.27%). The D-dimer levels of 43 patients (75.44%) were >500 ng/dL, and only three of these patients had venous thrombosis. Age and immunoglobulin A (IgA) were the risk factors for readmission in patients with MPA, with odds ratios (ORs) of 1.162 [95% confidence interval (CI): 1.025-1.317, P=0.019] and 1.010 (95% CI: 1.001-1.018, P=0.028). The days of hospitalization and the a2-globulin level were protective factors with ORs of 0.849 (95% CI: 0.725-0.993 P=0.041) and 0.789 (95% CI: 0.64-0.971, P=0.025), respectively. IgA levels were positively correlated with the number of hospitalizations, with a correlation coefficient of 0.428 (P=0.002). Receiver operating characteristic curve analysis showed that the possibility of readmission increases when the serum levels of IgA were >217.5 mg/dL. CONCLUSION: The level of serum IgA is a risk factor for the readmission of patients with MPA, and correlated with the number of hospitalizations in these patients. PMID- 28616270 TI - Urinothorax: a systematic review. AB - BACKGROUND: The characteristics of patients with urinothorax (UT) are poorly defined. METHODS: A systematic review was performed searching for studies reporting clinical findings, pleural fluid (PF) characteristics, and the most effective treatment of UT. Case descriptions and retrospective studies were included. RESULTS: The review included 78 studies with a total of 88 patients. Median age was 45 years, male/female ratio was 1.6:1 and in 76% of cases the etiology was trauma. Pleural effusion (PE) was predominantly unilateral (87%) and occupied over 2/3 of the hemithorax in most cases (64.4%). PF was straw-colored (72.7%) or hematic (27.3%) with urine-like odor in all cases. PF was transudate in 56.2% of cases (18/32) and among 14 exudates (43.8%), 3 were concordant exudates, 1 protein-discordant and 10 LDH-discordant, with lymphocyte (44.4%) and neutrophil (38.5%) predominance. The PF/serum (PF/S) creatinine ratio was >1 in all cases except one (97.9%). The diagnosis was established on the basis of PF/S creatinine ratio >1 (56.6%), urinary tract contrast extravasation (12%), abnormal computed tomography (8.4%), laparotomy findings (6%), and association of obstructive uropathy with PE (6%). The outcome was favorable (74/77; 96.1%) when treatment was direct towards the uropathy (alone or associated with thoracentesis/thoracic drainage). Outcome was unfavorable in the 15 patients who were only treated with thoracentesis/thoracic drainage. CONCLUSIONS: UT is usually traumatic, unilateral, and PF does not have a specific pattern or cellularity predominance, with a PF/S creatinine ratio almost always >1. Treatment should include the uropathy, with or without PF evacuation. PMID- 28616271 TI - Prolonged air leak after video-assisted thoracic surgery lung cancer resection: risk factors and its effect on postoperative clinical recovery. AB - BACKGROUND: Prolonged air leak (PAL) is one of the most common postoperative complications after pulmonary resection. The aim of this study was to reveal the incidence and risk factors of PAL in video-assisted thoracic surgery (VATS) lung cancer resection, and to evaluate the effect of PAL on postoperative complications, postoperative length of stay (PLOS), and medical costs. METHODS: Continuous patients who underwent VATS major pulmonary resection for lung cancer between January 2014 and December 2015 were studied. Clinical data of these patients were obtained from the Western China Lung Cancer Database. PAL was defined as air leak more than 5 days after surgery. The risk factors for PAL were analyzed, as well as the effect of PAL on postoperative clinical recovery. RESULTS: A total of 1,051 patients were enrolled in this study. The incidence of PAL was 10.6% (111/1,051). Pleural adhesion [odds ratio (OR), 2.38 for extensive vs. none, P=0.001] was identified as the only independent risk factors for PAL through multivariate analysis. The incidence of overall complications and pneumonia were significantly higher in patients with PAL (PAL group) than those without PAL (non-PAL group) (OR, 6.77, P=0.000; OR, 2.41, P=0.010, respectively). PAL was found to be associated with longer PLOS (11.7+/-6.6 vs. 6.5+/-3.6 days; P=0.000) and higher medical costs (Y62,042.5+/-18,072.0 vs. Y52,291.3+/-13,845.5, P=0.000). CONCLUSIONS: Pleural adhesion was associated with increased risk of PAL after VATS lung cancer resection. Those patients with PAL had more postoperative complications, stayed longer in the hospital after surgery, and paid higher medical costs. PMID- 28616272 TI - The effects of additional ezetimibe treatment to baseline rosuvastatin on circulating PCSK9 among patients with stable angina. AB - BACKGROUND: Blood lipid management is one of the effective strategies for coronary heart disease, and statins are the first-line lipid-lowering drugs. Low density lipoprotein cholesterol (LDL-C) drop brings about cardioprotective effects. Proprotein convertase subtilisin kexin type 9 (PCSK9) is known to increase LDL-C, thus hazarding LDL-C reduction-induced benefits. To date, how PCSK9 responds to various lipid-lowering strategies has not been fully clarified. METHODS: This study involves patients with stable angina and aims to explore and clarify the short-term impacts of rosuvastatin and ezetimibe, alone or in combination, on circulating PCSK9. A total of 68 patients with stable angina were enrolled and 60 eligible patients were randomly assigned into 3 groups (20 subjects in each). Patients in different groups were treated for a period of 14 days with rosuvastatin 10 mg/d, ezetimibe 10 mg/d, and rosuvastatin 10 mg/d plus ezetimibe 10 mg/d, respectively. Concentrations of blood LDL-C and PCSK9 levels were measured at baseline and at the 14th day after treatment. RESULTS: Both rosuvastatin and ezetimibe could reduce the LDL-C levels, and rosuvastatin displayed a stronger cholesterol-lowering effect than ezetimibe. Moreover, when combined, they yielded even greater efficacy in lowering LDL-C, as compared with either rosuvastatin or ezetimibe mono-treatment (P<0.05). Rosuvastatin therapy (alone or combined with ezetimibe) caused significant rise in circulating PCSK9. Nevertheless, no significant growth of PCSK9 levels (P=0.558) was observed during ezetimibe treatment. At the 14th day, no difference in PCKS9 levels was observed between the rosuvastatin group and the combination-therapy group (P=0.906). CONCLUSIONS: Rosuvastatin plus ezetimibe therapy is more effective in reducing LDL-C levels as compared with either rosuvastatin or ezetimibe mono-medication. Meanwhile, such combination strategy does not further increase the levels of circulating PCSK9 compared to rosuvastatin mono-intervention, thus maintaining maximal clinical benefits from lipid-lowering. PMID- 28616273 TI - Mid- to long-term outcomes of bovine jugular vein conduit implantation in Chinese children. AB - BACKGROUND: Bovine jugular vein (BJV) conduits are widely applied for surgical reconstruction of the right ventricular outflow tract (RVOT). However, relevant studies of valve failure rates and the related risk factors are limited in China. The aim of this study was to assess the BJV prognosis after medium- to long-term follow-up. METHODS: Fifty-three hospital patients implanted with BJV conduits from January 2002 to December 2013 were recruited. Patient information and follow up prognosis were reviewed retrospectively. Conduit stenosis and failure as well as endocarditis were diagnosed. RESULTS: The total person years was 345.5, and the median follow-up time was 6.3 years. Early mortality occurred in two patients, and there was no late mortality. BJV conduit failure occurred in 15 patients (29.4%) due to severe stenosis (n=10), stenosis plus regurgitation (n=3), and regurgitation alone (n=2). The proportion of patients who were free of BJV conduit failure at 1, 3, 5, and 7 years was 98.0%, 85.8%, 76.8%, and 62.1%, respectively. There were nine cases of endocarditis (17.0%). Multivariate logistic regression analysis showed that endocarditis was a significant risk factor associated with BJV conduit failure (OR: 6.735; 95% CI: 1.348-33.647). CONCLUSIONS: The durability of BJV conduits was suboptimal after a mid-term follow-up period. Endocarditis was found to be a significant risk factor that accelerates BJV conduit deterioration. PMID- 28616274 TI - Remedial localization after dislodgement of primary mechanical localization in lung surgery. AB - BACKGROUND: Unhooking or displacement of hookwire or microcoil due to technical failures is rather common. We aim to establish a new technique for remedial localization in the case of displacement or unhooking of primary mechanical localization during lung surgery. METHODS: From February 2014 to September 2015, 18 consecutive cases of intraoperative dislodgement during video-assisted thoracoscopic surgery (VATS) were enrolled. Nodule's projection on body surface was located by analyzing computed tomography (CT) images, and a needle was inserted into thoracic cavity through this point. The lung was then inflated, and a small burn was made where the needle tip touched the visceral plural. Wedge resections were subsequently performed for these impalpable small lesions. RESULTS: Eighteen solitary pulmonary nodules (SPNs) from 18 patients were scheduled for VATS wedge resections in this series, including 6 (33.3%) hookwire localization and 12 (66.7%) microcoil localization. Fifteen (83.3%) of 18 nodules were pure ground glass opacity (pGGO) and 3 (16.7%) mixed ground glass opacity (mGGO). The mean diameter of SPNs was 7.7+/-3.6 mm. The mean distance from SPN to pleura was 12.2+/-10.9 mm. During remedial localization, 17 (94.4%) nodules were removed successfully by wedge resection, and segmentectomy was performed only in one case with failed outcome. Paraffin pathology showed 2 (11.1%) atypical adenomatous hyperplasia (AAH), 11 (61.1%) adenocarcinoma in situ (AIS), 4 (22.2%) minimally invasive adenocarcinoma (MIA), and 1 (5.6%) inflammatory disease. CONCLUSIONS: This remedial localization technique is practical and reliable. It is a good backup plan in the case of dislodgement, and it can help prevent extended lung resection. PMID- 28616275 TI - Transthoracic echocardiography is a safe alternative for assessment and guidance of transcatheter closure of secundum atrial septal defect in children. AB - BACKGROUND: 2D-transesophageal echocardiography (TEE) is routinely performed to guide percutaneous ASD closure in children. We aimed to assess whether two dimensional (2D)-transthoracic echocardiography (TTE) is a safe alternative for assessment and guidance of atrial septal defect (ASD) closure in unselected children. METHODS: We performed a retrospective single-center study including 389 consecutive children aged less than 15-year-old who underwent percutaneous ASD closure under 2D-TEE (1998-2005, n=133) or 2D-TTE (2005-2014, n=256). A balloon calibration was performed in all cases for the Amplatz Septal Occluder choice. RESULTS: ASDs were larger and rims deficiencies were more frequent in the TTE guided group. The procedure was successful in 376 patients [96.7%; 95% confidence interval (CI), 94.4-98.2%]. The success rate tended to be higher in the TTE- versus TEE-guided group (98.0% versus 94.0%, P=0.069). Device migration occurred in 4 patients (1.0%; 95% CI: 0.3-1.6%), all after TEE-guided procedure (P=0.013). Early major adverse events were observed in 5 patients (1.3%; 95% CI: 0.4-3.0%), all in the TEE group (P=0.004). Fluroroscopic time and irradiation dose were not different among the 2 groups (P=0.450 and P=0.130 respectively). After a median follow-up of 7 years (range, 1-16 years), no adverse events was reported. One (0.3%, 95% CI: 0-1.4%) 12-year-old patient developed atrial fibrillation 5 years after the procedure. Pregnancies were uneventful in 72 cases. CONCLUSIONS: When a balloon sizing is performed, 2D-TTE imaging is as efficient as 2D-TEE to guide percutaneous ASD closure in children. The procedure can safely be done in spontaneously breathing children under TTE guidance alone in experienced centers. PMID- 28616276 TI - Benefits of postoperative thoracic radiotherapy for small cell lung cancer subdivided by lymph node stage: a systematic review and meta-analysis. AB - BACKGROUND: Whether postoperative thoracic radiotherapy (PORT) is beneficial for small cell lung cancer (SCLC) of different lymph node stages remains uncertain; therefore, the purpose of this meta-analysis was to explore the clinical significance of PORT for SCLC patients subdivided by lymph node status. METHODS: The PubMed, OVID, Web of SCI, EMBASE, Google Scholar, Cochrane Library, Chinese National Knowledge Infrastructure and Wanfang databases were systematically searched to identify eligible studies where SCLC patients received PORT based on lymph node stage. The main outcome measures were 1-, 3- and 5-year overall survival (OS) rates, as well as 1-, 2- and 3-year local regional recurrence (LRR) rates. All data were analyzed using STATA 12.0 and expressed as risk ratios (RR) with their corresponding 95% confidence intervals (95% CI). RESULTS: Five cohort studies, including 3,497 SCLC patients (578 receiving PORT and 2,919 not) were included in this study. PORT significantly decreased the 1-, 2- and 3-year LRR rates (RR =0.14, 0.28 and 0.27, respectively; Pall<0.05), but did not improve the 1-, 3- or 5-year OS rates when all patients were analyzed together. However, subgroup analysis showed that in the pN0 group PORT did not improve the 1-, 3- or 5-year OS rates or decrease the 1-, 2- or 3-year LRR rates; in the pN1 group PORT reduced the 1-, 2- and 3-year LRR rates (RR =0.11, 0.16 and 0.17, respectively; Pall<0.05) and improved the 1-year OS rate (RR =0.40; P<0.001), but not the 3- or 5-year OS rates; in the pN2 group PORT significantly reduced the 1-, 2- and 3 year LRR rates (RR =0.14, 0.15 and 0.15 respectively; Pall<0.05) and improved the 1-, 3- and 5-year OS rates (RR =0.46, 0.72 and 0.85, respectively; Pall<0.05). CONCLUSIONS: This is the first meta-analysis of the benefits of PORT for SCLC patients. Although derived from retrospective cohort studies, the data showed that PORT significantly reduced the risk of recurrence and improved survival for patients with pN2-SCLC; however, patients with pN0-SCLC did not benefit from PORT, whereas for patients with pN1-SCLC, PORT reduced the LRR rates and improved the 1-year survival rate. The long-term survival benefits of PORT remain unclear and will require further prospective studies. PMID- 28616277 TI - Barbed suture material technique for wound closure and concomitant tube placement in uniportal VATS for pneumothorax. AB - BACKGROUND: Uniportal video-assisted thoracoscopic surgery (VATS) is an alternative modality for treatment of primary spontaneous pneumothorax (PSP) with its less invasiveness and acceptable surgical outcomes. However, a few reports have been introduced for wound management to achieve better cosmetic wound healing and for placement of the chest tube in uniportal VATS. Thus, we aimed to evaluate the feasibility of our novel method for wound closure and concomitant tube placement using continuous barbed suture material in uniportal VATS for PSP. METHODS: Between July 2012 and December 2015, consecutive 31 patients (22 males) underwent uniportal VATS to treat PSP. Bilateral approaches were performed in four patients, thus total 35 cases were enrolled. We divided them into two groups with one group of 17 (48.5%) cases (group A), using barbed absorbable wound closure device for knotless continuous wound closure and subsequent chest tube anchoring, and the other group of 18 (51.4%) cases (group B), using conventional suture anchoring after skin closure using absorbable suture device. Postoperative surgical outcomes were compared to assess the feasibility of this technique. RESULTS: Demographic data demonstrate no significant difference in both groups. There was no significant difference in length of hospital stay (3.7+/-1.2 vs. 4.1+/-1.2 days, P=0.267) and in median chest tube indwelling time (2.4+/-0.9 vs. 3.1+/-1.2 days, P=0.066), respectively. Operation time in group A was shorter than in group B but there was no significant difference (41.7+/-11.8 vs. 45.6+/ 16.0 minutes, P=0.415). There was neither conversion to two or three port VATS in all cases. In group A, all chest tubes were removed with concomitant sealing the tube removal site by pulling the thread. Residual knots do not exist that stitch out procedure is not required. There was no wound complication in both groups during the median follow-up period of 18 months. CONCLUSIONS: Knotless, barbed suture material technique for continuous wound closure with concomitant chest tube placement achieved equivocal outcomes in comparison to the conventional suture anchoring method. We suggest this simple technique for wound closure and easy tube removal with cosmetic wound healing in uniportal VATS for PSP. PMID- 28616278 TI - Management of the vertebral artery during thoracic endovascular aortic repair with coverage of the left subclavian artery. AB - BACKGROUND: The application of thoracic endovascular aortic repair (TEVAR), a minimally invasive operation, in the aortic arch has been a challenge of cardiovascular surgery in recent years. This study aimed to investigate management of the vertebral artery with coverage of the left subclavian artery (LSA) during TEVAR. METHODS: From January 2007 to September 2014 in the Department of Cardiothoracic Surgery at Wuhan General Hospital of Guangzhou Military Region, 160 patients underwent LSA closure or partial coverage during TEVAR of an aortic lesion near the LSA. The vertebral artery treatment, the reason for the surgical approach selection, and the prognosis were analyzed. RESULTS: In 94 patients with partial LSA coverage during TEVAR, no treatment was provided for the vertebral arteries, revealing blood flow of the left vertebral artery forward into the skull after surgery. For 66 patients with full LSA coverage (closure) during TEVAR, right carotid artery-left common carotid artery bypass surgery was performed before TEVAR in ten patients, without any treatment for the vertebral artery, showing reverse blood flow of the left vertebral artery after surgery. Left common carotid artery-LSA bypass surgery was performed before TEVAR in four patients; right common carotid artery-left common carotid artery LSA bypass surgery was performed before TEVAR in three cases, and 6 out of these 7 patients underwent proximal LSA ligation, showing no obvious blood flow in the left vertebral artery. The closure of the LSA aortic arch opening using an occluder was performed in one patient, preserving the forward blood flow in the left vertebral artery. Among the 160 patients in this study, postoperative recurrent laryngeal nerve injury occurred in one patient after right common carotid artery-left common carotid artery-LSA bypass surgery, and the remaining 159 patients had no significant severe complications or death within 1 postoperative month. CONCLUSIONS: Appropriate management of the aortic arch branch vessels may expand the application of TEVAR to the aortic arch and reduce complications, especially for high-risk patients who have a difficult time tolerating thoracotomy. PMID- 28616279 TI - Benefits of a right anterolateral minithoracotomy rather than a median sternotomy in isolated tricuspid redo procedures. AB - BACKGROUND: To compare results of tricuspid valve (TV) reoperation between incision via a right anterolateral minithoracotomy (RAMT) and median sternotomy (MS). METHODS: We performed a retrospective analysis of 49 patients who underwent isolated TV surgery as a reoperation at our institution between 2006 and 2015. Previous cardiac operations included mitral, aortic, and TV surgeries, atrial septal defect repair, and pericardiectomy. The mean age of the patients was 51.9+/-12.8 years, 14 (28%) were male and 35 (72%) were female. Follow-up was 95% (38/40) complete, with a mean duration of 41.3+/-19.5 months. RESULTS: Perioperative demographic and laboratory tests did not show any significant differences between the RAMT and MS groups. The drainage volume, total red cell unit, total serum volume and platelet were significantly different 1150+/ 803.5/2,270+/-1,920, 4.8+/-4.1/8.7+/-8.9, 478.2+/-488.9/950.0+/-857.6, 0.04+/ 0.21/0.38+/-0.64 (P<0.05), while other perioperative data were similar. There were no significant differences in early postoperative death and complications between the RAMT and MS groups. A multivariate linear regression analysis predicted that serum creatinine (Scr), age, and MS group were independent risk factors for bleeding. The Cox regression demonstrated that the MS group had a longer drainage duration (P<0.05) and had a relative hazardous risk (HR) of 2.691 (1.328, 5.450 CI) compared with the RAMT group. CONCLUSIONS: The RAMT approach is an alternative, safe, and feasible procedure for isolated TV reoperation. It has the advantages of less drainage and reduced requirement for blood products. PMID- 28616280 TI - Identifying patients at higher risk of pneumonia after lung resection. AB - BACKGROUND: Pneumonia is considered as one of the most common and serious complications after lung resection. The purpose of this study was to identify the risk factors associated with postoperative pneumonia (POP) after lung resection and to develop a scoring system to stratify patients with increased risk of POP. METHODS: A retrospective review of a prospective database of patients between September 2014 and June 2016 was carried out. Logistic regression analysis was used to examine the risk factors for POP. Bootstrap resampling analysis was used for internal validation. Regression coefficients were used to develop weighted risk scores for POP. RESULTS: Results revealed that age >=64 years, smoking (current or previous), high pathological stage, and extent of excision of more than one lobe as risk factors. Logistic regression analysis showed that the predictors of POP were as follows: age >=64 years, smoking, extent of excision of more than one lobe. A weighted score based on these factors was developed which was follows: smoking (three points), age >=64 years (four points), and extent of excision of more than one lobe (five points). POP score >5 points offered the best combination of sensitivity (64.7%) and specificity (83.3%), and an area under receiver operating characteristic (ROC) curve (AUC) of 0.830 [95% confidence interval (CI): 0.746-0.914]. CONCLUSIONS: Patients with older age, smoking and extent of excision of more than one lobe have a higher risk for pneumonia after lung cancer surgery. Also, the scoring system helps to guide decision making of POP risk reduction. PMID- 28616281 TI - Clinicopathological factors influenced the prognosis of surgically resected pulmonary pleomorphic carcinoma. AB - BACKGROUND: Pulmonary pleomorphic carcinoma has made an unfavorable prognosis because of its properties of resisting radiation and chemotherapy, and its aggressive growth. The correlation between clinicopathological factors and prognosis about pulmonary pleomorphic carcinoma patients who received its surgical resection has not been clearly identified. METHODS: We retrospectively investigated the clinical records of 24 pulmonary pleomorphic carcinoma patients who had a surgical resection from January 2004 to December 2013 at our institute. We examined the correlation between their clinicopathological factors and therapeutic effects including their prognosis. RESULTS: The median follow up time was 2.3 years. The 5-year survival was 54.7% and the 5-year progression free survival was 52.4%. In comparison with other tissue types of lung cancer, the prognosis was not so poor even taking into consideration the survival curve including several progression stages. We analyzed the 21 clinicopathological factors in order to clarify the factors connected with the prognosis and disease progression. As a result, we found that both vascular invasion evaluated by immunohistochemistry and lymph node metastasis were connected closely with the overall survival. We found another strong link between the tissue type of epithelial components, vascular invasion evaluated by immunohistochemistry and lymph nodal metastasis with the progression free survival. CONCLUSIONS: Pulmonary pleomorphic carcinoma patients with lymph node metastasis and vascular invasion had worse prognosis after their surgical resections. We have to find an effective chemotherapeutic drug or molecular targeted drug. PMID- 28616282 TI - Pressure-controlled versus volume-controlled ventilation during one-lung ventilation for video-assisted thoracoscopic lobectomy. AB - BACKGROUND: It is controversial as to which ventilation mode is better during one lung ventilation (OLV). This study was designed to figure out whether there was any difference between volume controlled ventilation (VCV) and pressure controlled ventilation (PCV) on oxygenation and postoperative complications under the condition of protective ventilation (PV). METHODS: Sixty-five patients undergoing video-assisted thoracoscopic lobectomy were randomized into two groups. Patients in group V received VCV mode during OLV while patients in group P received PCV. The tidal volume (VT) in both groups was 6 mL per predicted body weight (PBW). Positive end-expiratory pressure (PEEP) was set at the level of 5 cmH2O in both groups. Arterial gas analysis were performed preoperatively with room air (T0), at 15 mins (T1) and 1 h (T2) after OLV, at the end of OLV (T3), 30 min after PACU admission (T4), 24 h after surgery (post-operative day 1, POD1) and 48 h after surgery (post-operative day 2, POD2). Peak inspiratory airway pressure (Ppeak) and plateau airway pressure (Pplat) were recorded at T1, T2 and T3. The perioperative complications were also recorded. RESULT: Sixty-four patients completed this study. Ppeak in group V was significantly higher than that in group P (T1 22.3+/-2.9 vs. 18.7+/-2.1 cmH2O; T2 22.2+/-2.8 vs. 18.7+/-2.6 cmH2O). There were no differences with Pplat and intraoperative oxygenation index (T1 203.3+/-109.7 vs. 198.1+/-93.4; T2 216.8+/-79.1 vs. 232.1+/-101.4). The postoperative oxygenation index (T4 525.0+/-160.9 vs. 520.7+/-127.1, post operative day 1 (POD1) 452.1+/-161.3 vs. 446.1+/-109.1; post-operative day 2 (POD2) 403.8+/-93.4 vs. 396.7+/-92.8) and postoperative complications were also comparable between these two groups. CONCLUSIONS: When they were utilized during OLV, PCV and VCV had the same performance on the intraoperative oxygenation and postoperative complications under the condition of PV. PMID- 28616283 TI - The use of thrombolytics in the management of complex pleural fluid collections. AB - BACKGROUND: To determine the efficacy of thrombolytics for the management of complex pleural fluid collections. METHODS: We reviewed patients that received alteplase for persistent loculated pleural fluid collections after simple tube drainage between July 01, 2007 and November 01, 2012. Our alteplase protocol is 6 mg of alteplase in 50 mL of normal saline injected into the pleural chest tube. The chest tube is clamped for four hours and then opened. Normally this is repeated daily for 2 to 3 days (d). RESULTS: One hundred and three [103] patients were identified with 110 interventions. Sixty-eight (66%) of the patients were male, with ages ranging from 20-91 years (y), mean 57.2 y. Twenty (18.2%) patients were trauma patients, 60 (55%) had hypertension and 32 (35%) were smokers. Most patients had one of the following diagnoses: 79.6% (82/110) loculated pleural fluid collection as a result of an empyema or 20.4% (21/110) retained hemothorax. The mean time from diagnosis to alteplase treatment for a hemothorax was 12.8 days (range, 1-32 days) and 16.2 days (range, 4-48 days) for an empyema. The mean duration of therapy was 2.2+/-1.4 days (1-11 days). The time from alteplase to chest tube removal was 4.5 days (1-21 days). Eleven of 103 (10.7%) patients required surgery including 3 video assisted decortications. The others had adequate radiographic resolution. Seventeen patients (16.5%) died, in the hospital of: sepsis, respiratory failure, aortic injury, and cardiac arrest. CONCLUSIONS: Alteplase therapy is an effective alternative to surgery in most complex pleural fluid collections. PMID- 28616284 TI - Intrapleural perfusion thermo-chemotherapy for pleural effusion caused by lung carcinoma under VATS. AB - BACKGROUND: The aim of this study was to assess the effectiveness of intrapleural perfusion thermo-chemotherapy (IPTC) under video-assisted thoracoscopic surgery (VATS) for malignant pleural effusion (MPE) caused by lung carcinoma. METHODS: In this retrospective study, fifty-four patients with moderate or large amounts of ipsilateral MPE secondary to non-small cell lung cancer (NSCLC) underwent pleural biopsy and IPTC under VATS. IPTC was performed by perfusing the pleural cavity with 43.0 degrees C saline solution containing cisplatin (200 mg/m2) using a devised circuit through mechanical circulation for 60 minutes. Blood pressure, heart rate, oxygen saturation (SpO2), and esophageal and rectal temperatures were monitored throughout the surgery. At the end of the perfusion, pleural biopsy was performed again for histological analysis. RESULTS: The temperature at the pleural surface was stabilized at 43 degrees C, and pleural effusion was controlled in all patients. KPS scores increased in 89.3% of patients. No patient developed bone marrow suppression reactions with noticeable bleeding after treatment, and no liver and kidney malfunctions were observed. Apoptosis was detected by light and electron microscopy after IPTC. CEA markedly decreased in all patients 1 month after IPTC. The median survival time was 21.7 months, with a one-year survival rate of 74.1%. CONCLUSIONS: IPTC under VATS is a new, safe, less invasive and more effective approach for MPE caused by lung carcinoma. PMID- 28616285 TI - Long-term statin therapy could be efficacious in reducing the lipoprotein (a) levels in patients with coronary artery disease modified by some traditional risk factors. AB - BACKGROUND: Lipoprotein (a) [Lp (a)] is a well-established risk factor for coronary artery disease (CAD). However, up till now, treatment of patients with higher Lp (a) levels is challenging. This current study aimed to investigate the therapeutic effects of short-, medium and long-term statin use on the Lp (a) reduction and its modifying factors. METHODS: The therapeutic duration was categorized into short-term (median, 39 days), medium term (median, 219 days) and long-term (median, 677 days). The lipid profiles before therapy served as baselines. Patients at short-, medium or long-term exactly matched with those at baseline. Every patient's lipid profiles during the follow-ups were compared to his own ones at baselines. RESULTS: The current study demonstrated that long-term statin therapy significantly decreased the Lp (a) levels in CAD patients while short-term or medium term statin therapy didn't. When grouped by statin use, only long-term simvastatin use significantly decreased the Lp (a) levels while long term atorvastatin use insignificantly decreased the Lp (a) levels. Primary hypertension (PH), DM, low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) could modify the therapeutic effects of statin use on the Lp (a) levels in CAD patients. CONCLUSIONS: The long-term statin therapy could be efficacious in reducing the Lp (a) levels in CAD patients, which has been modified by some traditional risk factors. In the era of commercial unavailability of more reliable Lp (a) lowering drugs, our findings will bolster confidence in fighting higher Lp (a) abnormalities both for patients and for doctors. PMID- 28616286 TI - Severe and uncontrolled asthma in China: a cross-sectional survey from the Australasian Severe Asthma Network. AB - BACKGROUND: Severe asthma is largely unexplored in the Chinese population. Patients with asthma underwent systematic evaluation, by investigating the characteristics of uncontrolled asthma and of asthma treated with three different controller therapies. METHODS: This multi-centre, real-world study was conducted from March 2014 to September 2015. Adults with stable asthma underwent assessment of medication use, asthma control, quality of life, psychological symptoms, work productivity and activity impairment, bronchodilator response and sputum induction. RESULTS: Participants (n=379) had a mean (SD) age of 47.4 (14.0) years, and 57.0% were female. There were 14.8% (n=56) of patients receiving treatment with Step 4/5 as severe asthma, but only 13 (3.4%) met ERS/ATS severe refractory asthma criteria. The patients with severe asthma usually used triple controller therapy: ICS/LABA, additional leukotriene modifier or theophylline, and reported better asthma control. Two fifths of patients (n=147) had uncontrolled asthma, with worse symptoms, psychological symptoms (both P<0.001), health-related work productivity and activity impairment, increased eosinophilic inflammation in sputum [1.68% (0.0, 17.1%) vs. 0.2% (0.0, 1.3%), P<0.0001] and more exacerbations (P<0.05). Multiple regression analysis indicated that triple controller therapy significantly reduced the risk of uncontrolled asthma [OR =0.32, 95% CI =(0.14, 0.75)]. CONCLUSIONS: Although there is a relatively low proportion of severe refractory asthma based on ERS/ATS criteria, two of five patients with asthma in China are uncontrolled, displaying more psychological symptoms and reduced work productivity. Substantial gain in asthma control is obtained by triple controller therapy and this may be a promising therapeutic option for persistent asthma. PMID- 28616287 TI - Statin-ezetimibe versus statin lipid-lowering therapy in patients with acute coronary syndromes undergoing percutaneous coronary intervention. AB - BACKGROUND: Studies comparing the clinical efficacy and safety of intensive statin therapy with ezetimibe-statin combination therapy are still rare at present, especially in Asian population. METHODS: We enrolled 202 patients who suffered acute coronary syndrome (ACS) and underwent percutaneous coronary intervention (PCI) between May and July in 2016. Patients were allocated into three groups based on the lipid lowering strategy: moderate-intensity statin group (n=118), ezetimibe combined with moderate-intensity statin group (ezetimibe statin combination, n=55) and intensive statin group (n=29). The lipid profiles and side effects were analyzed and compared among the patients in three groups at admission, 1 month and 3 months after PCI. The clinical outcomes of the patients were observed through 6-month follow-up. RESULTS: One month after PCI, the level of non-high density lipoprotein-cholesterol (non-HDL-C) was decreased by 41.9%, 21.6% and 29.8% by ezetimibe-statin combination therapy, moderate-intensity statin therapy and intensive statin therapy, respectively (P<0.05). The reduction percentages of TC and LDL-C were significantly higher in ezetimibe-statin combination group than in moderate-intensity statin group (P<0.001). The proportion of patients reaching LDL-C goal was higher in ezetimibe-statin combination group (69.1%, P=0.007) and intensive statin group (67.9%, P=0.047) compared with moderate-intensity statin group (46.9%) at 1 month after PCI. There was no significant difference among the three groups with respect to hepatic enzymes level, creatine kinase (CK) level and incidence of muscle symptoms. CONCLUSIONS: The reduction percentage of non-HDL-C was larger in ezetimibe-statin combination group than intensive statin group. This finding suggested that statin/ezetimibe combination therapy could be an alternative to intensive statin therapy in Chinese patients with atherosclerotic cardiovascular disease. PMID- 28616288 TI - Decreased expression of perforin in CD8+ T lymphocytes in patients with Mycobacterium tuberculosis infection and its potential value as a marker for efficacy of treatment. AB - BACKGROUND: Cytolytic activity against mycobacteria tuberculosis (MTB) within the infected macrophage is a crucial step in the immunity against TB infection, as MTB is an intracellular bacterium. Cytotoxic molecules such as perforin and granzymes produced by cytolytic T cells directly participate in this process. In this study, we evaluated the cytotoxicity function employing flow cytometry analysis of the level of expression of interferon-gamma (IFN-gamma), perforin and granzyme B in CD8+ T cells from patients with active pulmonary TB (PTB), stable PTB and healthy controls, and explored whether MTB antigen (MTB Ag)-stimulated cytotoxic molecules would be useful for monitoring responses to anti-TB treatment. METHODS: Intracellular IFN-gamma, perforin, and granzyme B were measured by flow cytometry in CD8+ T lymphocyte populations from peripheral blood mononuclear cells before and after stimulation with ESAT-6 and CFP-10 peptides for 72 hours. A total of 38 healthy controls, 52 PTB patients after treatment for 2 months and 58 patients with active PTB were enrolled. RESULTS: The positive rate of IFN-gamma+ CD8+ T cells was expressed higher in active PTB patients and stable PTB compared to healthy controls. Expression of perforin in CD8+ T lymphocytes was lower in the active PTB than the stable PTB. Positive downregulation of perforin and granzyme B after stimulation with ESAT-6 and CFP 10 peptides in active PTB and stable PTB was seen. IFN-gamma was upregulated after stimulation. ROC curve analysis showed that the area under the curve (AUC) of perforin and perforin + IFN-gamma after stimulation were 0.766 (P=0.000), 0.802 (P=0.000), respectively. CONCLUSIONS: Our results show that expression of perforin in CD8+ T lymphocytes is downregulated in PTB infection and ESAT-6 and CFP-10 peptides might participate in the downregulation process. This finding cautiously suggests that MTB Ag-stimulated perforin downregulation and IFN-gamma upregulation might be a potential index for monitoring therapy response in active PTB patients. PMID- 28616289 TI - The bronchoscopic interventions for chronic obstructive pulmonary disease according to different phenotypes. AB - Bronchoscopic interventions are valuable adjuncts to the pharmacologic therapy for chronic obstructive pulmonary disease (COPD). But different phenotypes of COPD patients showed different clinical responses to the same or similar therapy. The optimal selection of bronchoscopic interventions for COPD patients also needs to be based on the phenotypes. According to the different phenotypes, novel interventional pulmonology techniques which were used for COPD treatments in daily clinical practice or clinical trials have been described extensively throughout our current review. PMID- 28616290 TI - Quick spontaneous remodelling of thrombosed false lumen in acute type-A aortic dissection. AB - Natural history of acute Stanford type A aortic dissection (AAAD) implies the need of emergent surgical treatment in the vast majority of cases. Nevertheless, conservative treatment has been described to yield acceptable outcomes, when compared to surgery, in selected high risk cases of thrombosed false lumen. We report a significant quick remodelling of the false lumen occurred in an 85-year old female 6 days after conservative treatment. PMID- 28616291 TI - Intensive blood pressure control in patients with acute type B aortic dissection (RAID): study protocol for randomized controlled trial. AB - BACKGROUND: Blood pressure control is an essential therapy for patients with acute type B aortic dissection (ABAD) and should be maintained throughout the entire treatment. Thus, vast majority current guidelines recommend control the blood pressure to lower than 140/90 mmHg. Theoretically, a much lower target may further decrease the risk of propagation of dissection. However, some argued that too lower blood pressure would compromise the organ perfusion. Thus, there is no unanimous optimal target for blood pressure in patients with ABAD so far. The present study aimed to investigate the optimal blood pressure target for patients with ABAD, in the hope that the result would optimize the treatment of aortic dissection (AD). METHODS: The study is a multi-center randomized controlled clinical trial. Study population will include patients with new diagnosed ABAD and hypertension. Blocked randomization was performed where intensive blood pressure control (<120 mmHg) with conventional blood pressure control (<140 mmHg) were allocated at random in a ratio of 1:1 in blocks of sizes 4, 6, 8, and 10 to 360 subjects. Interim analysis will be performed. The primary outcome is a composite in-hospital adverse outcome, including death, permanent paraplegia or semi- paralysis during the hospitalization, and renal failure requiring hemodialysis at discharge. While the secondary outcomes include the aortic size, lower extremity or visceral ischemia, retrograde propagation into aortic arch or ascending aorta, mortality in 6 months and 1 year, intensive care unit (ICU) length of stay, total length of hospital stay, creatinine level, and surgical or endovascular intervention. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of Sir Run Run Shaw Hospital (approval number: 20160920-9). Informed consent will be obtained from participants or their next-of kin. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION: NCT03001739 (https://register.clinicaltrials.gov/). PMID- 28616292 TI - Uniportal video-assisted thoracoscopic surgery left upper lobectomy and systematic lymph node dissection with fused fissure. AB - As surgical proficiency and the development of medical techniques have improved, uniportal video-assisted thoracoscopic surgery (VATS) has emerged as a minimally invasive alternative in the surgical management of lung cancer. The spectrum of uniportal VATS indications is now almost equal to that of conventional VATS. Recent decades have witnessed the emergence of numerous uniportal VATS techniques. A significant proportion of these have to be converted into a multiport approach and even open thoracotomy due to the difficulty of managing the upper lobe vein and bronchus, particularly for the technically challenging left upper lobectomy. Although many successfully uniportal VATS left upper lobectomies have been reported, their procedures were modularized without describing refined techniques or operative improvements. This report describes a patient who was clinically diagnosed with stage IB (T2aN0M0) primary lung cancer of the left upper lobe (LUL), and who underwent left upper lobectomy and systematic lymph node dissection. During the operation, the placement of a single incision was readjusted to obtain optimal angulation; the versatile electrocautery hook and curved suction tube were used in conjunction with each other; accessible, cost-effective modified instruments were used; and new operative tricks were created; in addition, the operative sequence was alternated and the nerves were preserved to ensure a smooth procedure, improve efficiency, embody tumor-free operation and ensure safety. These are all good ideas that are worth disseminating. PMID- 28616293 TI - Video-assisted thoracoscopic completion thymectomy based on mediastinal pleura guidance. AB - We describe a practical video-assisted thoracoscopic surgery (VATS) technique for the en bloc resection of the thymoma, thymus, and bilateral mediastinum lipid based on mediastinal pleura guidance. By taking advantage of single-lumen endotracheal tube (SLET) anesthesia and artificial pneumothorax, we acquired excellent exposure of the anterior mediastinum operative field. In addition, our limited data showed that this surgical approach might have a potential tendency on reducing the blood loss and the operative times. Moreover, no complication of phrenic nerve paralysis or signs of myasthenia gravis were observed at the 6 month follow-up. PMID- 28616294 TI - Optical imaging of tissue obtained by transbronchial biopsies of peripheral lung lesions. AB - BACKGROUND: Bronchoscopic procedures have been increasingly used for the diagnosis of peripheral lung cancers, but the yield remains moderately low. The aim of this study is to assess the feasibility and ability of a custom-built bimodal optical spectroscopy system to enhance the on-site discrimination between malignant and benign specimens obtained from the transbronchial lung biopsies (TBLB) of peripheral lung lesions. METHODS: We conducted a prospective and single center pilot study to examine the TBLB specimens obtained from peripheral lung lesions. Diffuse reflectance spectroscopy (DRS) and diffuse fluorescence spectroscopy (DFS) parameters were used to analyze the optical characteristics of these specimens. RESULTS: One hundred and sixteen biopsy specimens from 15 patients were analyzed using optical imaging. All specimens had a confirmed pathologic diagnosis. Notably, 22 of the 116 specimens were malignant, and 10 of the 94 non-malignant specimens were necrotic biopsies. Individual parameters showed significant difference between the three groups (malignant, non-malignant and necrosis). Multivariate analysis of the blood, scattering and fluorescence parameters demonstrated a sensitivity of 77.3% and specificity of 73.1% in differentiating between malignant and benign specimens and a sensitivity of 90.9% and specificity of 100% in differentiating malignant from necrotic specimens. CONCLUSIONS: We conclude that optical spectroscopy is a feasible modality for on site discrimination between malignant and benign as well as malignant and necrotic TBLB specimens of peripheral lung lesions. PMID- 28616295 TI - Malignant tracheal necrosis and fistula formation following palliative chemoradiotherapy: a case report. AB - Concurrent chemoradiotherapy is an essential treatment strategy for inoperable locally advanced non-small cell lung cancer (NSCLC). Although supportive care has improved, unexpected complications due to the disease or treatment can occur. Tracheomediastinal fistulas are very rare but can be a serious problem. Herein, we report a case of severe chondronecrosis of the distal trachea with formation of a fistula into a metastatic lymphadenopathy in a patient with stage IIIB NSCLC. The patient received external beam radiotherapy with a total dose of 35 Gy in 14 fractions, which was approximately half of the conventional therapeutic radiotherapy dose, along with concurrent cisplatin based chemotherapy. Careful evaluation, early detection, and timely intervention are essential to prevent and appropriately treat chondronecrosis, even in cases of low-dose radiotherapy application to central tumors. PMID- 28616296 TI - Traumatic esophageal perforation by a self bougienage. AB - The case report describes a 75-year-old female with esophageal perforation by a self bougienage. From a decade ago, she had performed an esophageal bougienage by herself with a 70 cm long self-made bougie whenever she suffered from food impaction. On the day of the accident, she went on an outing without carrying the bougie, she pushed a broken bough into her esophagus, eventually the bough perforated her thoracic esophagus. We found some food particles in a large mediastinal abscess cavity, and the perforated esophagus was repaired by interrupted sutures and reinforced with a pedicled intercostal musculopleural flap. We report an extremely rare case of esophageal perforation by a self bougienage. PMID- 28616297 TI - Mediastinal hemangioma presenting with a characteristic feature on dynamic computed tomography images. AB - Hemangiomas are uncommon benign tumors of the mediastinum. The definite diagnosis is sometimes difficult to make because of usually nonspecific features on single phase contrast-enhanced computed tomography (CT) images. We described a 60-year old woman suffering from a neck mass with progressive enlargement. On the dynamic CT study, the tumor showed peripheral nodular enhancement on early phase images and progressive centripetal fill-in on delayed phase images. Hemangioma was preoperatively diagnosed on the basis of this characteristic CT appearance. PMID- 28616299 TI - Rupture of right sinus of Valsalva aneurysm protruding into the pulmonary artery with aortic and pulmonary valve endocarditis. AB - Rupture of right sinus of Valsalva aneurysm (SVA) protruding into the pulmonary artery with aortic and pulmonary valve endocarditis is rare. A 42-year-old man was admitted with fever and dyspnea. He was diagnosed with right sinus of Valsalva rupture with ventricular septal defect (VSD) and vegetation on both aortic and pulmonary valves. Dual exposure technique was performed. The base of the aneurysm sac was closed off, and, together with the VSD, was covered by a Gore-Tex patch. Aortic and pulmonary valves were replaced with mechanical valves. After surgery, antibiotics were administered for 5 weeks, and patient was discharged without complications. PMID- 28616298 TI - Imaging-guided thoracoscopic resection of a ground-glass opacity lesion in a hybrid operating room equipped with a robotic C-arm CT system. AB - The intraoperative identification of small pulmonary nodules through video assisted thoracoscopic surgery remains challenging. Although preoperative CT guided nodule localization is commonly used to detect tumors during video assisted thoracoscopic surgery (VATS), this approach carries inherent risks. We report the case of a patient with stage I lung cancer presenting as an area of ground-glass opacity (GGO) in the right upper pulmonary lobe. He successfully underwent a single-stage, CT-guided localization and removal of the pulmonary nodule within a hybrid operating room (OR) equipped with a robotic C-arm. PMID- 28616300 TI - Late cardiac tamponade following Nuss procedure for pectus excavatum. AB - The Nuss procedure is a recently developed technique for correction of pectus excavatum. A 23-year-old female patient presented at our emergency department with clinical signs of cardiac tamponade, which required an emergency procedure. Sixteen months ago, she underwent the Nuss procedure with a single bar. Her preoperative Haller index was 5. We report on a case of delayed recurrent cardiac tamponade that occurred 16 and 18 months after the patient underwent the Nuss procedure; in this case, we treated the patient with pericardiocentesis the first time and performed pericardial window creation with bar removal the second time. She was discharged on day 10 in good condition and follow-up chest radiographs showed no fluid collection. PMID- 28616301 TI - Successful thoracoscopic resection of a large mediastinal angiomyolipoma. AB - An angiomyolipoma (AML) is a benign mesenchymal tumor characterized by proliferation of mature vessels, smooth muscle, and adipose tissue. AMLs most commonly occur in the kidney but have been reported in a variety of extrarenal sites. Mediastinal AMLs are extremely rare. We herein present a case of a large AML of the mediastinum that was successfully treated by thoracoscopic resection. PMID- 28616302 TI - Esophagogastric junction outflow obstruction-related functional chest pain treated using robotic-assisted thoracoscopic esophageal myotomy. AB - Elevated relaxation pressure in combination with intact or weak peristalsis characterizes esophagogastric junction (EGJ) outflow obstruction. Symptoms of EGJ outflow obstruction include dysphagia and atypical chest pain. EGJ outflow obstruction can be diagnosed using high-resolution manometry (HRM), but there is a lack of consensus regarding treatment. We present a case report of a 43-year old man with a history of headache and mitral valve disorder who suffered from intermittent atypical chest pain for 20 years. A diagnosis of EGJ outflow obstruction was made using esophageal HRM. Due to medication intolerance, robotic assisted esophageal myotomy and Belsey-Mark IV fundoplication were performed. The symptoms went into complete remission and no motility disorders were detected on postoperative HRM. HRM is a useful diagnostic examination for EGJ outflow obstruction. The robotic systems-assisted long segment myotomy may potentially play an important role in the treatment of EGJ outflow obstruction-related functional chest pain. PMID- 28616303 TI - Stop the LVAD bleeding. PMID- 28616304 TI - Tailored antiplatelet therapy in high-risk ACS patients treated with PCI stenting: lessons from the ANTARCTIC trial. PMID- 28616305 TI - Paradigm shift in anticoagulation therapy, fueling the pump and preventing rhythm crisis. PMID- 28616306 TI - What is the optimal first-line treatment for advanced anaplastic lymphoma kinase rearranged non-small cell lung cancer? PMID- 28616307 TI - PCI or CABG for severe unprotected left main coronary artery disease: making sense of the NOBLE and EXCEL trials. PMID- 28616308 TI - HeartMate 3-a "Step" in the right direction. PMID- 28616309 TI - Non-cardiac surgery following drug-eluting coronary stent implantation-a question of timing? PMID- 28616310 TI - Intratumoral heterogeneity of esophageal squamous cell carcinoma. PMID- 28616311 TI - Neutrophils dominate the immune landscape of non-small cell lung cancer. PMID- 28616312 TI - PD-L1 protein expression in non-small cell lung cancer based on different immunohistochemical antibodies. PMID- 28616313 TI - MYCing and YAPing the escape of tumor cell growth arrest after chronic PI3K/mTOR inhibition. PMID- 28616314 TI - Echocardiography is a feasible tool for assessing volume responsiveness. PMID- 28616315 TI - Examined lymph node count in non-small-cell lung cancer: will it be a decision making approach in treatment of NSCLC? PMID- 28616316 TI - What is the role of stereotactic ablative radiotherapy in the management of surgically resectable and operable stage I non-small cell lung cancer? PMID- 28616317 TI - Modifiable risk factors and the role of driving pressure in acute respiratory distress syndrome. PMID- 28616318 TI - Is tumor location an independent prognostic factor in locally advanced non-small cell lung cancer treated with trimodality therapy? PMID- 28616319 TI - The evolution of left ventricular assist devices-a moment to reflect. PMID- 28616320 TI - Imaging homeostatic sleep pressure and circadian rhythm in the human brain. PMID- 28616321 TI - Comment on prognostic value of epidermal growth factor receptor mutation subtypes in surgically resected non-small cell lung cancer. PMID- 28616322 TI - Gender differences in cardiovascular risk factors in patients with coronary artery disease and those with type 2 diabetes. PMID- 28616323 TI - The emerging role of YAP/TAZ in mechanotransduction. PMID- 28616324 TI - Congenital heart disease in a dish: progress toward understanding patient specific mutations. PMID- 28616325 TI - Minimally invasive aortic valve replacement-where are we? PMID- 28616326 TI - Immunotherapy supplanting chemotherapy for upfront treatment of advanced non small cell lung cancer: what's next? PMID- 28616327 TI - Intra-aortic balloon pump during venoarterial extracorporeal membrane oxygenation: still a matter of debate? Contemporary multi-device approach to cardiogenic shock. PMID- 28616328 TI - Tuberculosis control programs and challenges in developed cities with intermediate disease burden: China experience. PMID- 28616329 TI - Reintervention after thoracic endovascular aortic repair deserves more attention. PMID- 28616330 TI - The 2017 Annual Meeting of the Thoracic Surgery Branch of Guangdong Medical Doctor Association and the 5th Summit Forum on Diagnosis and Treatment of Thoracic Surgery ended successfully on 25th March 2017. PMID- 28616331 TI - Professor Gang Chen: enhance the development of thoracic surgery techniques and serve for people's healthcare. PMID- 28616332 TI - Erratum to totally thoracoscopic pulmonary anatomic segmentectomies: technical considerations. AB - [This corrects the article on p. S200 in vol. 5, PMID: 24040524.]. PMID- 28616333 TI - Aortic diseases. PMID- 28616334 TI - Surgeons, high risk interventions and the birth of the Star Chamber. PMID- 28616335 TI - Cannulation strategies for aortic surgery: which is the best one? PMID- 28616336 TI - The great challenge of the public health system in Spain. PMID- 28616337 TI - Strategies to prevent aortic complications in Marfan syndrome. PMID- 28616338 TI - Transcatheter aortic valve replacement in patients with high aortic anguation. PMID- 28616339 TI - Routinary use of preoperative transthoracic echocardiography in abdominal aortic aneurysm, does it solve problems? PMID- 28616340 TI - Measuring the aorta in the era of multimodality imaging: still to be agreed. PMID- 28616341 TI - Ascending aorta reinterventions. AB - Ascending aorta reinterventions present a challenge for surgeons as the technical difficulties of the procedure and the complex strategic approach can complicate successful treatment. These patients should be treated by surgical teams with ample experience in aortic diseases as they can be at high risk of mortality. The number of interventions on the ascending aorta and aortic arch and the use of biological conducts (lung autograft, homograft, etc.) have increased in recent years; therefore, the number of reinterventions can also be expected to increase, representing 10% of aortic surgical procedures. This article reviews the current status of ascending aorta reinterventions, analyzing the principal aspects of indication and surgical strategy, as well as the results published in the largest studies. PMID- 28616342 TI - Bicuspid aortic valve syndrome: a multidisciplinary approach for a complex entity. AB - Bicuspid aortic valve (BAV) or bicuspid aortopathy is the most common congenital heart disease. It can be clinically silent and it is often identified as an incidental finding in otherwise healthy, asymptomatic patients. However, it can be dysfunctioning at birth, even requiring neonatal intervention, or, in time, lead to aortic stenosis, aortic insufficiency, and endocarditis, and also be associated with aortic aneurysm and aortic dissection. Given its prevalence and significant complications, it is estimated that BAV is responsible for more deaths and morbidity than the combined effects of all the other congenital heart defects. Pathology of BAV is still not well known and many questions are unresolved. In this manuscript we review some aspects on bicuspid aortopathy, a heterogeneous and frequent disease in which like some authors have previously described, complex gene environment are present. Further investigations and, what is more, multidisciplinary teams are needed to improve our knowledge on this really fascinating disease. PMID- 28616343 TI - Debranching aortic surgery. AB - Conventional open surgery still remains as the gold standard of care for aortic arch and thoracoabdominal pathology. In centers of excellence, open repair of the arch has been performed with 5% immediate mortality and a low rate of complications; however overall mortality rates are around 15%, being up to 40% of all patients rejected for treatment due to their age or comorbidities. For thoracoabdominal aortic pathology, data reported from centers of excellence show immediate mortality rates from 5% to 19%, spinal cord ischemia from 2.7% to 13.2%, and renal failure needing dialysis from 4.6% to 5.6%. For these reasons, different alternatives that use endovascular techniques, including debranching procedures, have been developed. The reported results for hybrid debranching procedures are controversial and difficult to interpret because series are retrospective, heterogenic and including a small number of patients. Clearly, an important selection bias exists: debranching procedures are performed in elderly patients with more comorbidities and with thoracoabdominal aortic aneurysms that have more complex and extensive disease. Considering this fact, debranching procedures still remain a useful alternative: for aortic arch pathology debranching techniques can avoid or reduce the time of extracorporeal circulation (ECC) or cardiac arrest which may be beneficial in high-risk patients that otherwise would be rejected for treatment. And compared to pure endovascular techniques, they can be used in emergency cases with applicability in a wide range of anatomies. For thoracoabdominal aortic aneurysms, they are mainly useful when other lesser invasive endovascular options are not feasible due to anatomical limitations or when they are not available in cases where delaying the intervention is not an option. PMID- 28616344 TI - Vascular approaches for transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) is a rapidly evolving therapeutic modality currently available for patients with severe aortic stenosis (AS) that are unsuitable for surgery because of technical/anatomical issues or high estimated surgical risk. Transfemoral approach is the preferred TAVI delivery route when possible. Alternative non-transfemoral access options include transaortic, trans-subclavian and transapical access. Other approaches are also feasible (transcarotid, transcaval, and antegrade aortic) but are restricted to operators and hospitals with experience. The peculiarities of each of the vascular approaches designed for TAVI delivery make it necessary to carefully assess patient's atherosclerotic load and location, arterial size and tortuosity, and presence of mural thrombus. Several clinical trials are currently ongoing and in the near future the indications for these approaches will likely be better defined and extended to a broader spectrum of TAVI candidates. PMID- 28616345 TI - Wrapping of the ascending aorta revisited-is there any role left for conservative treatment of ascending aortic aneurysm? AB - Dilatation of the ascending aorta (AA) is a common finding in patients with aortic valve disease. The clinical practice guidelines recommend replacing the AA whenever the diameter exceeds 45 mm. However, no consensus has been reached regarding the approach when the aorta is only moderately dilated. Although the risk in aorta replacement is generally low, it may be higher when associated with other complex surgical procedures or it is carried out in elderly patients or patients with significant comorbidity. This would justify the use of alternative surgical techniques, which reduce surgical risk and guarantee a durable correction of the aortic pathology. Conservative treatment of aneurysms of the AA via wrapping with different synthetic materials has been implemented for many years. The most commonly used technical variant is wrapping the dilated aorta with a vascular prosthesis with a predetermined diameter. When this technique is adequately applied, it immediately reduces the diameter of the AA and, to a lesser degree, the diameter of the aortic root and arch, while at the same time it reinforces the weak aortic wall. These effects lead to a drop-in wall shear stress and in the risk of aortic dissection and rupture, and persist over time. Although the low elasticity of the external support causes significant changes in the histologic structure of the aortic wall, mainly atrophy and alterations typical of a foreign body-induced reaction, this does not seem to involve a higher risk of complications. In some selected patients, this technique may be used in cases other than post-stenotic aortopathy, and also in aortas with a larger diameter. PMID- 28616346 TI - Emergent aortic surgery in octogenarians: is the advanced age a contraindication? AB - Surgery of both the ascending and descending aortic segments in the context of an acute aortic syndrome is one of the greatest challenges for the cardiac surgeon. In the case of surgery of the descending aorta, surgical risk increases due to the technical complexity, the required aggressive approach and because surgical indication is usually established as a result of complications and therefore involves, almost always, critically ill patients. The aging of the population is causing such surgery to be considered in an increasing number of octogenarians. The present review analyzes the available scientific evidence on the surgical indications and outcomes of these complex procedures in this population, particularly in the emergent scenario. Ascending and descending thoracic aortic diseases are reviewed separately, and the role of both the current risk scores and frailty assessments are comprehensively discussed. PMID- 28616348 TI - Predictive risk models for proximal aortic surgery. AB - Predictive risk models help improve decision making, information to our patients and quality control comparing results between surgeons and between institutions. The use of these models promotes competitiveness and led to increasingly better results. All these virtues are of utmost importance when the surgical operation entails high-risk. Although proximal aortic surgery is less frequent than other cardiac surgery operations, this procedure itself is more challenging and technically demanding than other common cardiac surgery techniques. The aim of this study is to review the current status of predictive risk models for patients who undergo proximal aortic surgery, which means aortic root replacement, supracoronary ascending aortic replacement or aortic arch surgery. PMID- 28616347 TI - Intraoperative care for aortic surgery using circulatory arrest. AB - The total circulatory arrest (CA) is necessary to achieve optimal surgical conditions in certain aortic pathologies, especially in those affecting the ascending aorta and aortic arch. During this procedure it is necessary to protect all the organs of ischemia, especially those of the central nervous system and for this purpose several strategies have been developed. The first and most important protective method is systemic hypothermia. The degree of hypothermia and the route of application have been evolving and currently tend to use moderate hypothermia (MH) (20.1-28 degrees C) associated with unilateral or bilateral selective cerebral perfusion methods. In this way the neurological results are better, the interval of security is greater and the times of extracorporeal circulation are smaller. Even so, it is necessary to take into account that there is the possibility of ischemia in the lower part of the body, especially of the abdominal viscera and the spinal cord, therefore the time of circulatory stop should be limited and not to exceed 80 minutes. Evidence of possible neurological drug protection is very weak and only mannitol, magnesium, and statins can produce some benefit. Inhalational anesthetics and some intravenous seem to have advantages, but more studies would be needed to test their long-term benefit. Other important parameters to be monitored during these procedures are blood glucose, anemia and coagulation disorders and acid-base balance. The recommended monitoring is common in complex cardiovascular procedures and it is of special importance the neurological monitoring that can be performed with several techniques, although currently the most used are Bispectral Index (BIS) and Near-Infrared Spectroscopy (NIRS). It is also essential to monitor the temperature routinely at the nasopharyngeal and bladder level and it is important to control coagulation with rotational thromboelastometry (ROTEM). PMID- 28616349 TI - Sparing aortic valve techniques. AB - Prosthetic valve implantation is the most widely used therapeutic option for aortic regurgitation (AR), but complications associated with prosthetic valves, with an incidence of 3-5% patient/year, and the need for anticoagulation in mechanical valves, force us to consider aortic valve repair as an alternative to the prosthetic implant, especially in young people with many potential years of life for these complications. Aortic valve repair techniques are not excessively complicated, but there is no standardization, so they are not reproducible in all medical centers. There are multiple repair procedures, but to study them we can divide, arbitrarily, into two large groups, techniques for treatment of aortic root dilatation (reimplantation and remodeling); and repair techniques without treatment of the aortic root, that act on annulus and on aortic leaflets. The two sets of techniques are often used together, but it is easier to understand them if this arbitrary division is made. Our goal is to publish our experience and knowledge of repair techniques to facilitate their learning by other professionals. In this article, we will focus on the procedures on the aortic annulus and leaflets, because they can be applied in patients without aortic root dilatation, but they are also complementary to the reimplantation and remodeling techniques. We will present the procedures describing them individually, with an explanation in text accompanied by three videos in which the application of each technique is visualized in several cases. The standardization of sparing aortic valve techniques is difficult, because each patient requires its individualized application, yet we have tried to illustrate reproducible procedures so that professionals have more tools to deal with aortic valve-preserving surgery. PMID- 28616350 TI - Anomalous right coronary artery origin with interarterial pathway-importance of morphological origin assessment and the role of percutaneous interventionism. AB - Anomalies in coronary arteries (CA) are an important issue in cardiology and cardiovascular surgery. Specifically the anomalous origin of the right coronary artery (RCA) is of special importance because it is the most frequent anomaly. Clinical practice guidelines recommend the revascularization treatment in cases of interarterial pathway and documented myocardial ischemia and when hypoplasia, compression or obstruction is evident. We report two different cases of patients with anomalous origin of RCA and associated interarterial pathway. With them we want to highlight the different presentation forms of these patients and the different diagnostic alternatives available in each of the steps. In the patient with anomalous origin of the RCA and associated interarterial pathway, the first step after establishing the diagnosis is to rule out the presence of inducible ischemia. In those patients in whom ischemia induction tests are negative, the second step is to adequately assess the interarterial pathway, in order to rule out obstructions or compressions that also justify revascularization. In those cases in which all the tests are negative, the current evidence does not recommend revascularization, but adequate periodic follow-up is recommended. For this reason, we believe that the stress echocardiogram and exercise perfusion scintigraphy (based on availability and experience in each center) are fundamental because of their high sensitivity and specificity. We would also like to highlight the role that percutaneous interventionism can play in this type of clinical cases. Especially with patients of high surgical risk and in whom the percutaneous approach is feasible. PMID- 28616351 TI - Hybrid aortic repair with antegrade supra-aortic and renovisceral debranching from ascending aorta. AB - Aortic dissection is a life threatening condition. Hybrid repair has been described for the treatment of complex aortic pathology such as thoracoabdominal aortic aneurysms (TAAA) and type A and B dissections, although open and total endovascular repair are also possible. Open surgery is still associated with substantial perioperative morbi-mortality rates, thus less invasive techniques such as endovascular repair and hybrid procedures can achieve good results in centers with experience. We present the case of a patient with a chronic type B dissection and TAAA degeneration that was treated in a single stage hybrid procedure with antegrade supra-aortic and renovisceral debranching from the ascending aorta and TEVAR. At three-year follow up, the patient is free of intervention-related complications. PMID- 28616352 TI - Aortic polyaneurysmal disease: case report. AB - We report a 78-year-old man who presents progression of his aneurysmatic pathology with previous abdominal infrarenal aortic surgery 20 years later. The computed tomography (CT) scan showed proximal degeneration of the infrarenal aorta, left iliac aneurysm and a new descending thoracic aneurysm close to the aortic arch. The surgical treatment was staged in two times due to the evolution of the aneurysm measures. First, the thoracic and the infrarenal aneurysms were covered each one with endoprosthesis. Four years later the iliac disease was solved with a branched specific iliac endograft. PMID- 28616353 TI - Double pseudoaneurysm, recurrent subvalvular aortic membrane and small left ventricular outflow tract in the same patient: who dares? AB - Patients with pseudoaneurysm in the left ventricular outflow tract (LVOT) commonly present vague and nonspecific symptoms making the diagnosis difficult. We present the case of a 37-year-old patient with two subvalvular pseudoaneurysms in whom a combined resection surgery, enlargement of the LVOT, aortic valve replacement (AVR) and aortic root replacement were performed using the technique of Cabrol. PMID- 28616354 TI - Comparing American, European and Asian practice guidelines for aortic diseases. AB - The aortic disease comprises a group of different pathologies of high prevalence, seriousness and ever changing by the medical and surgical investigations. Therefore cardiovascular scientific societies in USA, Europe and Asia have created Task Force on practice guidelines (PG) to develop, update and revise PG for aortic diseases. These documents issue recommendations on the diagnosis and management of different aortic diseases. The three societies agree on the recommendations about diagnostic tests and on the value of computed tomography and magnetic resonance as the main tools for the diagnosis and follow-up of aortic disease. Concerning to acute aortic syndromes (AAS), American and European GPs recognize intramural hematoma (IMH) as a type of AAS with surgery indication; however Asian guidelines consider IMH a pathological process different from AAS and indicate medical treatment. In thoracic aortic aneurysms (TAA), all express the need for an adequate control of cardiovascular risk factors, emphasizing strict control of blood pressure, smoking cessation and recommend the use of beta blockers and statins. The threshold for asymptomatic repair is 5.5 cm in European and American and 6 cm for Asian PG, with lower thresholds in Marfan and bicuspid aortic valve (BAV). As regards the abdominal aortic aneurysms (AAA), the PGs recognize the adequate control of cardiovascular risk factors, but there are differences in class of recommendation on statins, angiotensin-converting enzyme inhibitors or beta-blockers to prevent progression of AAA. For intervention, the threshold diameter in asymptomatic is 5.5 cm but can be reduced to 5 cm in women as recommended by Asian PG. Moreover the specific diseases such as Marfan, BAV, pregnancy or atherosclerosis aortic present specific recommendations with small differences between PGs. In conclusion, PGs are interesting and appropriate documents at present. They issue recommendations based on evidence that help the clinician and surgeon in their daily approach to aortic pathology. PMID- 28616355 TI - Activation of Natural Killer Cells by Probiotics. AB - During the last decade, probiotics have been established to be important mediators of host immunity. Their effects on both innate and adaptive immunity have been documented in the literature. Although several reports have correlated different strains of bacteria as probiotics, their effects on immunity vary. Clearly, there is a complex interplay between various constituents of probiotics and the immune response in humans. The role of probiotics on natural killer (NK) cells in the gut has been the subject of a few reports. In this review, we summarize the reported findings on the role of probiotics in the activation of gut-associated NK cells and the response of NK cells to stimuli elicited by probiotics and their microenvironment. The effects of probiotics on the activation of NK cells and their secretion of immune factors (e.g., interferon gamma, tumor necrosis factor-alpha, interleukin-2, etc.) are discussed in regard to their clinical significance in various diseases. Current investigations are being pursued, in particular, on the role of probiotics-activated NK cells in promoting the adaptive immune response against pathogens. PMID- 28616356 TI - Challenges and Innovations in Phase I Dose-Finding Designs for Molecularly Targeted Agents and Cancer Immunotherapies. AB - Phase I oncology trials are designed to identify a safe dose with an acceptable toxicity profile. In traditional phase I dose-finding design, the dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle. The recent development of molecularly targeted agents and cancer immunotherapies call for new innovations in phase I designs, because of prolonged treatment cycles often involved. Various phase I designs using toxicity and efficacy endpoints from multiple treatment cycles have been developed for these new treatment agents. Here, we will review the novel endpoints and designs for the phase I oncology clinical trials. PMID- 28616357 TI - Improvement of Post-hypoxic Myoclonus with Bilateral Pallidal Deep Brain Stimulation: A Case Report and Review of the Literature. AB - BACKGROUND: Post-hypoxic myoclonus (PHM) is a syndrome that occurs when a patient has suffered hypoxic brain injury. The myoclonus is usually multifocal and generalized, often stemming from both cortical and subcortical origins. In severe cases, pharmacological treatments with antiepileptic medications may not satisfactorily control the myoclonus. METHODS: We present a case of a 23-year-old male with chronic medication refractory PHM following a cardiopulmonary arrest related to an asthmatic attack who improved with bilateral globus pallidus internus (GPi) deep brain stimulation (DBS). We review the clinical features of PHM, as well as the preoperative and postoperative Unified Myoclonus Rating Scale scores and DBS programming parameters in this patient and compare them with the three other published PHM-DBS cases in the literature. RESULTS: This patient experienced an alleviation of myoclonic jerks at rest and a 39% reduction in action myoclonus with improvement in both positive and negative myoclonus with bilateral GPi-DBS. High frequency stimulation (130 Hz) with amplitudes >2.5 V were needed for the therapeutic response. DISCUSSION: We demonstrate a robust improvement in a medication refractory PHM patient with bilateral GPi-DBS, and suggest that it is a viable therapeutic option for debilitating post-hypoxic myoclonus. PMID- 28616358 TI - Parkinsonism and Tremor in a Patient with Plasmodium vivax Malaria. AB - BACKGROUND: A 57-year-old male diagnosed with Plasmodium vivax malaria presented with a subacute onset of hand tremor, slowness, and gait difficulty. PHENOMENOLOGY: A bilateral upper extremity kinetic tremor was seen, as well as a right upper extremity rigidity and body bradykinesia. EDUCATIONAL VALUE: Parkinsonism and tremor are neurological manifestations that may occur in malaria as a result of globus pallidi and dentate nuclei involvement. PMID- 28616359 TI - Bioactive Antimicrobial Peptides as Therapeutics for Corneal Wounds and Infections. AB - Significance: More than 2 million eye injuries and infections occur each year in the United States that leave civilians and military members with reduced or complete vision loss due to the lack of effective therapeutics. Severe ocular injuries and infections occur in varied settings including the home, workplace, and battlefields. In this review, we discuss the potential of developing antimicrobial peptides (AMPs) as therapeutics for the treatment of corneal wounds and infections for which the current treatment options are inadequate. Recent Advances: Standard-of-care employs the use of fluorescein dye for the diagnosis of ocular defects and is followed by the use of antibiotics and/or steroids to treat the infection and reduce inflammation. Recent advances for treating corneal wounds include the development of amniotic membrane therapies, wound chambers, and drug-loaded hydrogels. In this review, we will discuss an innovative approach using AMPs with the dual effect of promoting corneal wound healing and clearing infections. Critical Issues: An important aspect of treating ocular injuries is that treatments need to be effective and administered expeditiously. This is especially important for injuries that occur during combat and in individuals who demonstrate delayed wound healing. To overcome gaps in current treatment modalities, bioactive peptides based on naturally occurring cationic antimicrobial proteins are being investigated as new therapeutics. Future Directions: The development of new therapeutics that can treat ocular infections and promote corneal wound healing, including the healing of persistent corneal epithelial defects, would be of great clinical benefit. PMID- 28616361 TI - Hyperbaric Oxygen Therapy: Side Effects Defined and Quantified. AB - Significance: Hyperbaric oxygen therapy (HBOT) is an important advanced therapy in the treatment of problem wounds, including diabetic foot ulcers and late effect radiation injury. HBOT remains among the safest therapies used today. Nonetheless, there are side effects associated with HBOT. It is important for providers to be able to identify, understand, and quantify these side effects for prevention, management, and informed consent. Recent Advances: The past two decades have seen significant advancements in our understanding of the underlying mechanisms of HBOT. This has led to a better understanding of the underlying reason for clinical benefit. It has also led to a better understanding of its side effects. Moreover, more recent literature allows for better quantification of these side effects. This review will highlight these side effects. Critical Issues: Wound healing in the case of problem nonhealing wounds requires the use of various advanced treatment modalities, including HBOT. HBOT has been shown to significantly improve healing rates in certain problem wounds, including advanced diabetic foot ulcers and late effect radiation injury. It is provided in a variety of clinical settings by providers with varying levels of expertise. It is important for those providing this therapy to understand the potential side effects. Future Directions: Research in HBOT has led to significant advancements in the area of wound healing. At the same time, there remains a variety of treatment protocols used at different institutions. It is important to quantify risk and benefit at different treatment pressures and times to better standardize treatment and improve patient care. PMID- 28616360 TI - Current Advancements and Strategies in Tissue Engineering for Wound Healing: A Comprehensive Review. AB - Significance: With an aging population leading to an increase in diabetes and associated cutaneous wounds, there is a pressing clinical need to improve wound healing therapies. Recent Advances: Tissue engineering approaches for wound healing and skin regeneration have been developed over the past few decades. A review of current literature has identified common themes and strategies that are proving successful within the field: The delivery of cells, mainly mesenchymal stem cells, within scaffolds of the native matrix is one such strategy. We overview these approaches and give insights into mechanisms that aid wound healing in different clinical scenarios. Critical Issues: We discuss the importance of the biomimetic niche, and how recapitulating elements of the native microenvironment of cells can help direct cell behavior and fate. Future Directions: It is crucial that during the continued development of tissue engineering in wound repair, there is close collaboration between tissue engineers and clinicians to maintain the translational efficacy of this approach. PMID- 28616362 TI - Assessing the Accuracy of Foveal Avascular Zone Measurements Using Optical Coherence Tomography Angiography: Segmentation and Scaling. AB - PURPOSE: The foveal avascular zone (FAZ) is altered in numerous diseases. We assessed factors (axial length, segmentation method, age, sex) impacting FAZ measurements from optical coherence tomography (OCT) angiography images. METHODS: We recruited 116 Caucasian subjects without ocular disease, and acquired two 3 * 3 mm AngioVue scans per each right eye (232 total scans). In images of the superficial plexus, the FAZ was segmented using the AngioVue semiautomatic nonflow measurement tool and ImageJ manual segmentation. In images from the full retinal thickness, the FAZ was segmented using the AngioAnalytics automatic FAZ tool. Repeatability, reliability, and reproducibility were calculated for FAZ measurements (acircularity, area). RESULTS: FAZ area (mean +/- SD) for manual segmentation was 0.240 +/- 0.0965 mm2, greater than both semiautomatic (0.216 +/- 0.0873 mm2) and automatic (0.218 +/- 0.0869 mm2) segmentation (P < 0.05). Not correcting for axial length introduced errors up to 25% in FAZ area. Manual area segmentation had better repeatability (0.020 mm2) than semiautomatic (0.043 mm2) or automatic (0.056 mm2). FAZ acircularity had better repeatability with automatic than manual segmentation (0.086 vs. 0.114). Reliability of all area measurements was excellent (intraclass correlation coefficient [ICC] = 0.994 manual, 0.969 semiautomatic, 0.948 automatic). Reliability of acircularity measurements was 0.879 for manual and 0.606 for automatic. CONCLUSION: We identified numerous factors affecting FAZ measurements. These errors confound comparisons across studies and studies examining factors that may correlate with FAZ measures. TRANSLATIONAL RELEVANCE: Using FAZ measurements as biomarkers for disease progression requires assessing and controlling for different sources of error. Not correcting for ocular magnification can result in significant inaccuracy in FAZ measurements, while choice of segmentation method affects both repeatability and accuracy. PMID- 28616363 TI - Insights from Global Analyses of Long Noncoding RNAs in Breast Cancer. AB - PURPOSE OF REVIEW: The goal of this review was to compare and contrast the results and implications from several recent transcriptomic studies that analyzed the expression of lncRNAs in breast cancer. How many lncRNAs are dysregulated in breast cancer? Do dysregulated lncRNAs contribute to breast cancer etiology? Are lncRNAs viable biomarkers in breast cancer? RECENT FINDINGS: Transcriptomic profiling of breast cancer tissues, mostly from The Cancer Genome Atlas, identified thousands of long noncoding RNAs that are expressed and dysregulated in breast cancer. The expression of lncRNAs alone can divide patients into molecular subtypes. Subsequent functional studies demonstrated that several of these lncRNAs have important roles in breast cancer cell biology. SUMMARY: Thousands of lncRNAs are dysregulated in breast cancer that can be developed as biomarkers for prognostic or therapeutic purposes. The reviewed reports provide a roadmap to guide functional studies to discover lncRNAs with critical biological functions relating to breast cancer development and progression. PMID- 28616364 TI - Recurrent Acute Otitis Media: What Are the Options for Treatment and Prevention? AB - PURPOSE OF REVIEW: To survey current strategies for treatment and prevention of recurrent acute otitis media (rAOM). RECENT FINDINGS: Treatment with systemic antibiotics is required in recurrent episodes of acute otitis media. A cautious attitude is recommended due to antibiotic resistance. Antibiotics also provide effective prophylaxis for rAOM. Topical treatment with ear drops is recommended in rAOM with otorrhea from tympanostomy tubes. Pneumococcal conjugated vaccines seem to have a moderate reductive effect on overall otitis media. The effect on rAOM is still unclear. Different administrations of immunoglobulins have not been effective against rAOM. Breastfeeding had a protective effect against rAOM. A recommendation against cigarette smoke exposure as a measure to prevent otitis seems warranted. An effect for adenoidectomy in children <2 years old with rAOM has been suggested. There is a strong genetic connection with rAOM. Probiotics and nasal spray with Streptococci might offer future opportunities as prophylaxis. Too little is known about complimentary treatments to give any recommendations. SUMMARY: Systemic antibiotics are still needed as treatment against episodes of AOM in rAOM children. There are several preventive measures that can be taken to reduce the burden of AOM but they all have a small-moderate effect. Systemic antibiotics provide effective prophylaxis in rAOM, but must be used with extreme caution due to the emerging antibiotic resistance. PMID- 28616365 TI - Streptococcus pneumoniae Otitis Media Pathogenesis and How It Informs Our Understanding of Vaccine Strategies. AB - PURPOSE OF REVIEW: This study aimed to review the literature regarding the mechanisms of transition from asymptomatic colonization to induction of otitis media and how the insight into the pathogenesis of otitis media has the potential to help design future otitis media-directed vaccines. RECENT FINDINGS: Respiratory viruses have long been shown to predispose individuals to bacterial respiratory infections, such as otitis media. Recent information suggests that Streptococcus pneumoniae, which colonize the nasopharynx asymptomatically, can sense potentially "threatening" changes in the nasopharyngeal environment caused by virus infection by upregulating specific sets of genes involved in biofilm release, dissemination from the nasopharynx to other sites, and protection against the host immune system. Furthermore, an understanding of the transcriptional and proteomic changes occurring in bacteria during transition to infection has led to identification of novel vaccine targets that are disease specific and will not affect asymptomatic colonization. This approach will avoid major changes in the delicate balance of microorganisms in the respiratory tract microbiome due to elimination of S. pneumoniae. SUMMARY: Our recent findings are reviewed in the context of the current literature on the epidemiology and pathogenesis of otitis media. We also discuss how other otopathogens, such as Haemophilus influenzae and Moraxella catarrhalis, as well as the normal respiratory microbiome, can modulate the ability of pneumococci to cause infection. Furthermore, the unsatisfactory protection offered by the pneumococcal conjugate vaccines is highlighted and we review potential future strategies emerging to confer a more specific protection against otitis media. PMID- 28616366 TI - Increased Energy Cost of Mobility in Chronic Stroke. AB - The purpose of this study was to compare the energy cost of completing mobility related activities in chronic stroke to the estimated energy cost found in the compendium of physical activities, a resource that estimates and classifies energy cost of various human physical activities. Men (n=18) and women (n=10) with chronic hemiparetic gait (stroke latency: 4 +/- 2 years, age: 60.4 +/- 1.6 years, BMI: 31.5 +/- 1.1 kg/m2) participated in the study. Portable energy cost monitoring (COSMED K4b2) was performed during five mobility activities of varying intensity to determine metabolic equivalents (METs, or oxygen consumption in multiples of resting level) for each activity. The METs achieved during the five activities were compared to the following compendium MET values for: 1) floor sweeping; 2) stepping in place; 3) over-ground walking; 4) lower speed treadmill walking (1.0 mph at 4% incline); and 5) higher speed treadmill walking (2.0 mph at 4% incline). Measurements were obtained for 10 min at rest and 5 minutes during each of the five activities. The energy cost of rest was only 85% of Compendium METS, while mobility-related activities were ~1.25-1.50 fold greater when measured in stroke vs. Compendium METS for all measures (P's<0.05), except floor sweeping, which was similar between groups. These data indicate that MET levels provided in the compendium are not applicable to chronic stroke survivors as they overestimate energy expenditure at rest and underestimate energy expenditure during physical activity, indicating poor efficiency in movement, thus elevating the oxygen cost of completing general daily activities. PMID- 28616367 TI - Correction: The scavenger receptor repertoire in six cnidarian species and its putative role in cnidarian-dinoflagellate symbiosis. AB - [This corrects the article DOI: 10.7717/peerj.2692.]. PMID- 28616368 TI - Correction: Insights of the dental calculi microbiome of pre-Columbian inhabitants from Puerto Rico. AB - [This corrects the article DOI: 10.7717/peerj.3277.]. PMID- 28616369 TI - Management of an Obstructed Tracheostomy in a Limited-Resource Setting. AB - Obstruction of a tracheostomy tube is a common cause of respiratory compromise in adults and pediatric patients, which can lead to a life-threatening emergency if it is not properly managed. Compromised airway patency has many potential etiologies; however, the scenario described in this technical report focuses specifically on the management of tracheostomy obstruction through the presence of a mucus plug, blood clot, or highly viscous secretions. The simulation described in this technical report was written to be conducted as an in-situ simulation within the intensive care unit (ICU) at Mzuzu Central Hospital, Malawi. The novel aspect of this report is that it depicts the integration of low tech simulation with a deteriorating patient scenario educational methodology. This integration enables the use of affordable and sustainable simulation materials in Malawi context to deliver learning objectives that are otherwise not achievable. It was designed to train nurses, clinical officers, and nursing students from the ICU and male/female surgical wards. It can be utilized to train similar learners in other resource-poor regions of the world, as well as remote areas of the more developed countries. PMID- 28616370 TI - Editorial Comment: Cost-Effectiveness Analysis for Prioritization of Limited Public Health Resources - Tuberculosis Interventions in Texas. AB - Public health departments have limited evidence to understand and analyze the costs and benefits of different health programs, including tuberculosis control and prevention programs. The study by Miller et. al addresses this challenge to estimate costs and benefits of tuberculosis prevention programs in Texas and identify cost-effective diagnostic and treatment combinations, thereby improving the evidence-based decision making power of the public health departments. PMID- 28616371 TI - Tactile Sensing with Whiskers of Various Shapes: Determining the Three Dimensional Location of Object Contact Based on Mechanical Signals at the Whisker Base. AB - Almost all mammals use their mystacial vibrissae (whiskers) as important tactile sensors. There are no sensors along the length of a whisker: all sensing is performed by mechanoreceptors at the whisker base. To use artificial whiskers as a sensing tool in robotics, it is essential to be able to determine the three dimensional (3D) location at which a whisker has made contact with an object. With the assumption of quasistatic, frictionless, single-point contact, previous work demonstrated that the 3D contact point can be uniquely determined if all six components of force and moment are measured at the whisker base, but these measurements require a six-axis load cell. Here, we perform simulations to investigate the extent to which each of the 20 possible "triplet" combinations of the six mechanical signals at the whisker base uniquely determine 3D contact point location. We perform this analysis for four different whisker profiles (shapes): tapered with and without intrinsic curvature, and cylindrical with and without intrinsic curvature. We show that whisker profile has a strong influence on the particular triplet(s) of signals that uniquely map to the 3D contact point. The triplet of bending moment, bending moment direction, and axial force produces unique mappings for tapered whiskers. Four different mappings are unique for a cylindrical whisker without intrinsic curvature, but only when large deflections are excluded. These results inform the neuroscience of vibrissotactile sensing and represent an important step toward the development of artificial whiskers for robotic applications. PMID- 28616372 TI - Ionization Capabilities of Hydronium Ions and High Electric Fields Produced by Atmospheric Pressure Corona Discharge. AB - Atmospheric pressure corona discharge (APCD) was applied to the ionization of volatile organic compounds. The mass spectra of analytes having aromatic, phenolic, anilinic, basic and aliphatic in nature were obtained by using vapor supply and liquid smear supply methods. The vapor supply method mainly gave protonated analytes [A+H]+ caused by proton transfer from hydronium ion H3O+, except for benzene, toluene and n-hexane that have lower proton affinity. The use of the liquid smear supply method resulted in the formation of molecular ion A.+ and/or dehydride analyte [A-H]+, according to the nature of analytes used. The formation of A.+ without fragment ions could be explained by the electron tunneling via high electric fields 108 V/m at the tip of the corona needle. The dehydride analytes [A-H]+ observed in the mass spectra of n-hexane, di- and tributylamines may be explained by the hydride abstraction from the alkyl chains by the hydronium ion. The hydronium ion can play the two-roles for analytes, i.e., the proton donor to form [A+H]+ and the hydride acceptor to form [A-H]+. PMID- 28616373 TI - Development of Remote Sampling ESI Mass Spectrometry for the Rapid and Automatic Analysis of Multiple Samples. AB - We report on combining a self-aspirated sampling probe and an ESI source using a single metal capillary which is electrically grounded and safe for use by the operator. To generate an electrospray, a negative H.V. is applied to the counter electrode of the ESI emitter to operate in positive ion mode. The sampling/ESI capillary is enclosed within another concentric capillary similar to the arrangement for a standard pneumatically assisted ESI source. The suction of the liquid sample is due to the Venturi effect created by the high-velocity gas flow near the ESI tip. In addition to serving as the mechanism for suction, the high velocity gas flow also assists in the nebulization of charged droplets, thus producing a stable ion signal. Even though the potential of the ion source counter electrode is more negative than the mass spectrometer in the positive ion mode, the electric field effect is not significant if the ion source and the mass spectrometer are separated by a sufficient distance. Ion transmission is achieved by the viscous flow of the carrier gas. Using the present arrangement, the user can hold the ion source in a bare hand and the ion signal appears almost immediately when the sampling capillary is brought into contact with the liquid sample. The automated analysis of multiple samples can also be achieved by using motorized sample stage and an automated ion source holder. PMID- 28616374 TI - Five things to know about diagnostic error. AB - Diagnostic error represents an important patient safety issue. Herein, we summarize five important things to know about this topic. 1) At least 1 in 20 adults are affected by diagnostic errors annually. 2) The root causes for diagnostic errors are typically multifactorial. 3) Cognitive errors are found in the majority of cases. 4) Most missed diagnoses involve common conditions. 5) Advancements in policy, education, and health information technologies hold promise for improving diagnostic safety. PMID- 28616375 TI - Geometric and electronic structures of monolayer hexagonal boron nitride with multi-vacancy. AB - Hexagonal boron nitride (h-BN) is an electrical insulator with a large band gap of 5 eV and a good thermal conductor of which melting point reaches about 3000 degrees C. Due to these properties, much attention was given to the thermal stability rather than the electrical properties of h-BN experimentally and theoretically. In this study, we report calculations that the electronic structure of monolayer h-BN can be influenced by the presence of a vacancy defect which leads to a geometric deformation in the hexagonal lattice structure. The vacancy was varied from mono- to tri-vacancy in a supercell, and different defective structures under the same vacancy density were considered in the case of an odd number of vacancies. Consequently, all cases of vacancy defects resulted in a geometric distortion in monolayer h-BN, and new energy states were created between valence and conduction band with the Fermi level shift. Notably, B atoms around vacancies attracted one another while repulsion happened between N atoms around vacancies, irrespective of vacancy density. The calculation of formation energy revealed that multi-vacancy including more B-vacancies has much lower formation energy than vacancies with more N-vacancies. This work suggests that multi-vacancy created in monolayer h-BN will have more B-vacancies and that the presence of multi-vacancy can make monolayer h-BN electrically conductive by the new energy states and the Fermi level shift. PMID- 28616377 TI - Blue after splenectomy. AB - INTRODUCTION: We present a 51 year old, African American, female who presented with persistent hypoxemia. She had been taking dapsone for many years for prophylaxis against Pneumocystic Jiroveci with no symptoms but eventually developed methemoglobinemia only after a splenectomy. From our literature review there are no documented cases that have demonstrated this relationship between dapsone, splenic function and methemoglobin and we hope to share our perplexing case and shed light on the interaction. DESCRIPTION: Our patient has type 1 diabetes and underwent multiple pancreas transplants and an initial kidney transplant during her disease course. One year prior to her presentation she underwent a distal pancreatectomy and an incidental splenectomy during the same procedure. She had been taking dapsone for approximately 17 years due to her allergy to sulfamethoxazole/trimethoprim and her immunosuppressive regimen included tacrolimus, sirolimus, and low dose prednisone. She had presented for a routine, post-surgery follow up visit when she was diagnosed with hypoxemia. After an extensive but unsuccessful work up for persistent hypoxemia, she presented to our clinic for a second opinion. Repeat testing of the arterial blood gas in clinic showed a significant methemoglobin (MHb) level of 16.6 mg/dl. DISCUSSION: Although methemoglobinemia is a well-known risk of dapsone exposure, we report a case that suggests that splenectomy can interact with dapsone to further increase the risk of methemobloginemia. We believe that our patient did not develop methemoglobinemia initially, despite being on dapsone for many years because her spleen was able to remove older more susceptible erythrocytes from the circulation leaving the more robust younger erythrocytes. With the splenectomy, the number of older erythrocytes in the peripheral circulation increased and resulted in an accumulation of MHb leading to the low oxygen saturations. Her dapsone was immediately stopped and she was started on vitamin C with a 3 day follow up revealing resolution of her methemoglobinemia and normal oxygen saturation on room air. PMID- 28616378 TI - Primary ciliary dyskinesia presenting with spontaneous pneumothorax: Case report and review of the literature. AB - BACKGROUND: Primary ciliary dyskinesia (PCD) is an autosomal recessive heterogeneous group of conditions with variable clinical findings. CASE PRESENTATION: A 36-year-old nonsmoking Chinese man present to the emergency department of our hospital with acute-onset breathlessness and sudden-onset left sided chest pain. The patient had 6 years primary infertility and suffered from recurrent episodes of respiratory tract infections since childhood. Chest X-ray was performed, which showed a left-sided pneumothorax with lung collapse. His conditions improved in clinical symptoms after 3 days of closed thoracic drainage. Radiographic findings after lung recruitment revealed bronchiectasis and bronchiolitis but no situs inversus. Paranasal sinus computed tomography (CT) showed maxillary sinusitis and ethmoid sinusitis. Pulmonary function tests demonstrated severe obstructive ventilation functional impairment. Bronchial mucosal cilia showed the absence of both outer and inner dynein arms of the microtubules (ODA and IDA). A culture of bronchoalveolar lavage fluid was positive for Pseudomonas aeruginosa. His clinical symptoms and CT images showed improvement after 1 month of treatment. A literature review revealed that few patients are diagnosed with PCD complicated with spontaneous pneumothorax. Within one year of follow-up, the patient showed good responses to local ICS+ LA beta2 agonist combined with oral carbocistein. CONCLUSIONS: Pneumothorax might be one of the complications of the PCD. Combination therapy including ICS+ LA beta2 agonist and carbocistein could be a potential therapy to reduce the frequency of acute exacerbations and delay progression of PCD. PMID- 28616376 TI - Genome Editing and Muscle Stem Cells as a Therapeutic Tool for Muscular Dystrophies. AB - PURPOSE OF REVIEW: Muscular dystrophies are a group of severe degenerative disorders characterized by muscle fiber degeneration and death. Therapies designed to restore muscle homeostasis and to replace dying fibers are being experimented, but none of those in clinical trials are suitable to permanently address individual gene mutation. The purpose of this review is to discuss genome editing tools such as CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated), which enable direct sequence alteration and could potentially be adopted to correct the genetic defect leading to muscle impairment. RECENT FINDINGS: Recent findings show that advances in gene therapy, when combined with traditional viral vector-based approaches, are bringing the field of regenerative medicine closer to precision-based medicine. SUMMARY: The use of such programmable nucleases is proving beneficial for the creation of more accurate in vitro and in vivo disease models. Several gene and cell-therapy studies have been performed on satellite cells, the primary skeletal muscle stem cells involved in muscle regeneration. However, these have mainly been based on artificial replacement or augmentation of the missing protein. Satellite cells are a particularly appealing target to address these innovative technologies for the treatment of muscular dystrophies. PMID- 28616379 TI - Re-biopsy after relapse of targeted therapy. T790M after epidermal growth factor mutation, where and why based on a case series. AB - Guidelines for the treatment of non-small cell lung cancer adenocarcinoma positive in epidermal growth factor mutations indicate tyrosine kinase inhibitors. There are currently three tyrosine kinase inhibitors that can be used as first line treatment: gefitinib, erlotinib and afatinib. Regarding erlotinib and afatinib dosage can be modified in the case of severe adverse effects. In the case of disease relapse investigation for T790M mutation has to be made either with re-biopsy or liquid biopsy and osimertinib has to be administered when T790M is diagnosed. Based on a case series we indicate which is the best approach for T790M mutation. PMID- 28616380 TI - Rare case of pulmonary histoplasmosis complicated with bronchocentric granulomatosis in a non endemic area. AB - BACKGROUND: Pulmonary histoplasmosis is a fungal infection caused by histoplasma capsulatum, rarely diagnosed in non endemic areas and/or immunocompromised patients. Complication of pulmonary histoplasmosis with bronchocentric granulomatosis is extremely rare. CASE REPORT: A 48-year-old man with prolonged fever and nausea was admitted to our hospital. Clinical examination revealed pathological auscultatory sounds to the left lung. Computed tomography was performed and revealed a large solid mass of the left upper lobe, limited pleural and pericardial effusion and calcified lymphadenopathy of mediastinum. A computed tomography guided core biopsy of the lung lesion was performed and three samples were obtained. Culture and polymerase chain reaction (PCR) revealed Histoplasma capsulatum. Histological findings were compatible with bronchocentric granulomatosis. Extended laboratory investigation excluded immunosuppresion. Our patient although immunocompetent was diagnosed with chronic pulmonary histoplasmosis complicated with bronchocentric granulomatosis and treatment with antifungal medication and methylprednisoline started. CONCLUSION: Description of a rare case of chronic pulmonary histoplasmosis in a non endemic area like Greece, with atypical radiological findings, complicated with bronchocentric granulomatosis. PMID- 28616381 TI - Anosognosia for memory deficits in mild cognitive impairment: Insight into the neural mechanism using functional and molecular imaging. AB - Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer's disease (AD). Previous findings in AD dementia patients suggest that anosognosia is due to both functional metabolic changes within cortical midline structures involved in self-referential processes, as well as functional disconnection between these regions. The present study aims to extend these findings by investigating the neural correlates of anosognosia in the prodromal stage of AD. Here, we used regional brain metabolism (resting state 18 F fluorodeoxyglucose positron emission tomography (FDG-PET)) to unravel the metabolic correlates of anosognosia in subjects with amnestic mild cognitive impairment (aMCI) and subsequently resting state functional magnetic resonance imaging (rs-fMRI) to investigate the intrinsic connectivity disruption between brain regions. Thirty-one subjects (mean age: 74.1; Clinical Dementia Rating (CDR) global score: 0.5) with aMCI, and 251 cognitively normal (CN) older adults (mean age: 73.3; CDR: 0) were included as a reference group for behavioral and FDG data. An anosognosia index was obtained by calculating a discrepancy score between subjective and objective memory scores. All subjects underwent FDG-PET for glucose metabolism measurement, and aMCI subjects underwent additional rs fMRI for intrinsic connectivity measurement. Voxel-wise correlations between anosognosia and neuroimaging data were conducted in the aMCI subjects. Subjects with aMCI had significantly decreased memory awareness as compared to the CN older adults. Greater anosognosia in aMCI subjects was associated with reduced glucose metabolism in the posterior cingulate (PCC) cortices and hippocampus. Intrinsic connectivity analyses revealed a significant association between anosognosia and attenuated functional connectivity between the PCC seed region and orbitofrontal cortex (OFC) as well as bilateral inferior parietal lobes (IPL). These findings provide further evidence that implicates cortical midline structures and hippocampus in the awareness of memory deficits. Investigating neuroimaging changes that co-vary with memory awareness may improve our ability to identify the cause of anosognosia and ultimately increase our chances for its treatment. PMID- 28616382 TI - Improving language mapping in clinical fMRI through assessment of grammar. AB - INTRODUCTION: Brain surgery in the language dominant hemisphere remains challenging due to unintended post-surgical language deficits, despite using pre surgical functional magnetic resonance (fMRI) and intraoperative cortical stimulation. Moreover, patients are often recommended not to undergo surgery if the accompanying risk to language appears to be too high. While standard fMRI language mapping protocols may have relatively good predictive value at the group level, they remain sub-optimal on an individual level. The standard tests used typically assess lexico-semantic aspects of language, and they do not accurately reflect the complexity of language either in comprehension or production at the sentence level. Among patients who had left hemisphere language dominance we assessed which tests are best at activating language areas in the brain. METHOD: We compared grammar tests (items testing word order in actives and passives, wh subject and object questions, relativized subject and object clauses and past tense marking) with standard tests (object naming, auditory and visual responsive naming), using pre-operative fMRI. Twenty-five surgical candidates (13 females) participated in this study. Sixteen patients presented with a brain tumor, and nine with epilepsy. All participants underwent two pre-operative fMRI protocols: one including CYCLE-N grammar tests (items testing word order in actives and passives, wh-subject and object questions, relativized subject and object clauses and past tense marking); and a second one with standard fMRI tests (object naming, auditory and visual responsive naming). fMRI activations during performance in both protocols were compared at the group level, as well as in individual candidates. RESULTS: The grammar tests generated more volume of activation in the left hemisphere (left/right angular gyrus, right anterior/posterior superior temporal gyrus) and identified additional language regions not shown by the standard tests (e.g., left anterior/posterior supramarginal gyrus). The standard tests produced more activation in left BA 47. Ten participants had more robust activations in the left hemisphere in the grammar tests and two in the standard tests. The grammar tests also elicited substantial activations in the right hemisphere and thus turned out to be superior at identifying both right and left hemisphere contribution to language processing. CONCLUSION: The grammar tests may be an important addition to the standard pre-operative fMRI testing. PMID- 28616383 TI - Multiparametric MRI to distinguish early onset Alzheimer's disease and behavioural variant of frontotemporal dementia. AB - This prospective study explored whether an approach combining structural [cortical thickness and white matter (WM) microstructure] and resting state functional MRI can aid differentiation between 62 early onset Alzheimer's disease (EOAD) and 27 behavioural variant of frontotemporal dementia (bvFTD) patients. Random forest and receiver operator characteristic curve analyses assessed the ability of MRI in classifying the two clinical syndromes. All patients showed a distributed pattern of brain alterations relative to controls. Compared to bvFTD, EOAD patients showed bilateral inferior parietal cortical thinning and decreased default mode network functional connectivity. Compared to EOAD, bvFTD patients showed bilateral orbitofrontal and temporal cortical thinning, and WM damage of the corpus callosum, bilateral uncinate fasciculus, and left superior longitudinal fasciculus. Random forest analysis revealed that left inferior parietal cortical thickness (accuracy 0.78, specificity 0.76, sensitivity 0.83) and WM integrity of the right uncinate fasciculus (accuracy 0.81, specificity 0.96, sensitivity 0.43) were the best predictors of clinical diagnosis. The combination of cortical thickness and DT MRI measures was able to distinguish patients with EOAD and bvFTD with accuracy 0.82, specificity 0.76, and sensitivity 0.96. The diagnostic ability of MRI models was confirmed in a subsample of patients with biomarker-based clinical diagnosis. Multiparametric MRI is useful to identify brain alterations which are specific to EOAD and bvFTD. A severe cortical involvement is suggestive of EOAD, while a prominent WM damage is indicative of bvFTD. PMID- 28616384 TI - Comparison of large-scale human brain functional and anatomical networks in schizophrenia. AB - Schizophrenia is a disease with disruptions in thought, emotion, and behavior. The dysconnectivity hypothesis suggests these disruptions are due to aberrant brain connectivity. Many studies have identified connectivity differences but few have been able to unify gray and white matter findings into one model. Here we develop an extension of the Network-Based Statistic (NBS) called NBSm (Multimodal Network-based statistic) to compare functional and anatomical networks in schizophrenia. Structural, resting functional, and diffusion magnetic resonance imaging data were collected from 29 chronic patients with schizophrenia and 29 healthy controls. Images were preprocessed, and average time courses were extracted for 90 regions of interest (ROI). Functional connectivity matrices were estimated by pairwise correlations between wavelet coefficients of ROI time series. Following diffusion tractography, anatomical connectivity matrices were estimated by white matter streamline counts between each pair of ROIs. Global and regional strength were calculated for each modality. NBSm was used to find significant overlap between functional and anatomical components that distinguished health from schizophrenia. Global strength was decreased in patients in both functional and anatomical networks. Regional strength was decreased in all regions in functional networks and only one region in anatomical networks. NBSm identified a distinguishing functional component consisting of 46 nodes with 113 links (p < 0.001), a distinguishing anatomical component with 47 nodes and 50 links (p = 0.002), and a distinguishing intermodal component with 26 nodes (p < 0.001). NBSm is a powerful technique for understanding network-based group differences present in both anatomical and functional data. In light of the dysconnectivity hypothesis, these results provide compelling evidence for the presence of significant overlapping anatomical and functional disruption in people with schizophrenia. PMID- 28616385 TI - Neurophysiological evidence of preserved connectivity in tuber tissue. AB - We present a case of preserved corticospinal connectivity in a cortical tuber, in a 10 year-old boy with intractable epilepsy and tuberous sclerosis complex (TSC). The patient had multiple subcortical tubers, one of which was located in the right central sulcus. In preparation for epilepsy surgery, motor mapping, by neuronavigated transcranial magnetic stimulation (nTMS) coupled with surface electromyography (EMG) was performed to locate the primary motor cortical areas. The resulting functional motor map revealed expected corticospinal connectivity in the left precentral gyrus. Surprisingly, robust contralateral deltoid and tibialis anterior motor evoked potentials (MEPs) were also elicited with direct stimulation of the cortical tuber in the right central sulcus. MRI with diffusion tensor imaging (DTI) tractography confirmed corticospinal fibers originating in the tuber. As there are no current reports of preserved connectivity between a cortical tuber and the corticospinal tract, this case serves to highlight the functional interdigitation of tuber and eloquent cortex. Our case also illustrates the widening spectrum of neuropathological abnormality in TSC that is becoming apparent with modern MRI methodology. Finally, our finding underscores the need for further study of preserved function in tuber tissue during presurgical workup in patients with TSC. PMID- 28616386 TI - Extreme delta brush evolving into status epilepticus in a patient with anti-NMDA encephalitis. AB - Extreme delta brush (EDB) is an EEG pattern unique to anti-NMDA encephalitis. It is correlated with seizures and status epilepticus in patients who have a prolonged course of illness. The etiology of the underlying association between EDB and seizures is not understood. We present a patient with anti-NMDA encephalitis who developed status epilepticus evolving from the high frequency activity of the extreme delta brush. This case demonstrates that EDB is not only a marker for a greater propensity for seizures but also directly implicated in seizure generation. PMID- 28616387 TI - Biosecurity and geospatial analysis of mycoplasma infections in poultry farms at Al-Jabal Al-Gharbi region of Libya. AB - Geospatial database of farm locations and biosecurity measures are essential to control disease outbreaks. A study was conducted to establish geospatial database on poultry farms in Al-Jabal Al-Gharbi region of Libya, to evaluate the biosecurity level of each farm and to determine the seroprevalence of mycoplasma and its relation to biosecurity level. A field team of 7 Veterinarians belongs to the National Center of Animal Health was assigned for data recording and collection of blood samples. Personal information of the producers, geographical locations, biosecurity measures and description of the poultry farms were recorded. The total number of poultry farms in Al-Jabal Al-Gharbi Region is 461 farms distributed in 13 cities. Out of these, 102 broiler farms and one broiler breeder farm (10 houses) which were in operation during team visit were included in this study. Following collection of blood, sera were separated and tested by Enzyme-linked immunosorbent assay (ELISA) for the presence of antibodies against Mycoplasma (General antigen for M. gallisepticum and M. synoviae). The seroprevalence of Mycoplasma in the region was 28% (29 poultry farms out of 103 were infected). About 50% (23 out of 47) of poultry farms located in Garian city were infected with Mycoplasma and one significant cluster of Mycoplasma infection in the city was identified. Low level of biosecurity was found in poultry farms of the region. Out of the 103 farms included, 63% of poultry houses has a ground of soil and 44% of them has uncoated walls which may influence the proper cleaning and disinfection. Almost 100% of the farms are at risk of exposure to diseases transmitted by wild birds such as avian influenza and Newcastle disease due to absence of wild birds control program. Although, 81% of the farms have entry restrictions, only 20% have disinfectants at entry which increase the risk of exposure to pathogens. The results of this study highlight the weakness points of biosecurity measures in poultry farms of Al-Jabal Al-Gharbi region and high seroprevalence of mycoplasma. Data collected in this study will assist the Veterinary authorities to apply effective disease control strategies. PMID- 28616388 TI - Unusual haemodynamics in two dogs and two cats with portosystemic shunt - implications for distinguishing between congenital and acquired conditions. AB - Extrahepatic porto-systemic shunt (PSS) in small animals can be congenital (CPSS) or acquired (APSS) as a consequence of portal hypertension (PH), and are distinguished on the bases of their anatomical pattern. A precise morphologic imaging assessment, along with clinical and histopathologic findings, is important for distinguishing patients with PH from those with congenital PSSs, which require different therapeutic approach. Expected findings in patients with PH are presence of ascites, multiple APSS, and a confirmed cause of portal flow obstruction. On the other hand, a single PSS, absence of ascites and no evidence of portal vein, caudal vena cava or hepatic disorders are typical findings of CPSS patients. This paper describes four cases of PSSs in which the combination of the computed tomographic imaging findings did not match the standards for APSS nor for CPSS: one dog had chronic hepatitis causing PH and ascites and a splenoazygos PSS, to date considered a CPSS pattern. One dog showed a left splenogonadal PSS and porto-caval varices, to date considered an APSS pattern, without ascites, portal vein obstruction, primary structural hepatic disorders nor evidence of PH. Two cats, with and without diffuse hepatic structural disorders respectively, had a single left splenogonadal PSS without ascites. Possible interpretation of such unusual haemodynamic conditions and clinical repercussion, especially for orientation of treatment choice, are discussed. PMID- 28616389 TI - Fibrosarcoma of the eyelid in two sibling Czech wolfdogs. AB - Most canine tumors of the eyelid are tumors generally encountered in the skin. They are most commonly of epithelial origin and benign. In this report, we describe the cases of two sibling Czech wolfdogs presented, one year apart, with a subcutaneous mass involving the left eyelid. Both lesions were histologically consistent with a diagnosis of subcutaneous fibrosarcoma. Immunohistochemical analyses of the tumors revealed a mild positivity for vimentin and negativity for GFAP, desmin, alphaSMA, myoglobin, S100, PNL2 and calponin, excluding all differential diagnosis (i.e. peripheral nerve sheath tumor, melanoma, perivascular sarcoma, myofibroblastic sarcoma, rhabdomyosarcoma). To the best of authors' knowledge, this is the first report of canine eyelid fibrosarcoma. Since this rare tumor has been observed in two full siblings, we could speculate the existence of some genetic predisposition to sarcoma, however the present data did not allow any definite conclusion on the etiopathogenesis or genetic basis of these tumors. PMID- 28616390 TI - Encephalomyocarditis virus in a captive Malayan tapir (Tapirus indicus). AB - A 5-month-old female captive Malayan tapir (Tapirus indicus) died suddenly without preceding symptoms. Gross necropsy revealed numerous white circular and linear foci in the myocard. Differential diagnosis all turned out negative, except for encephalomyocarditis virus. Histopathology revealed mineralisation of myocardial cells and interstitial infiltration of lymphocytes, plasma cells and less neutrophils. Encephalomyocarditis virus was detected by PCR. Although encephalomyocarditis virus occurs in many mammals, this is the first published description of this virus in a Malayan tapir. PMID- 28616391 TI - Opioid-free anaesthesia in three dogs. AB - Opioid-free anaesthesia (OFA) is a relatively new and growing field in human medicine. There are multiple motivations behind this emerging practice with the recognition of several serious potential opioid-related adverse effects including opioid induced hyperalgesia, opioid tolerance and immunomodulatory effects of opioids. Opioids have long been the mainstay of veterinary anaesthesia and pain management practice. The feasibility of OFA in veterinary patients is presented here. A case series of three dogs that underwent OFA for canine ovariohysterectomy is reported. The authors conclude OFA is possible in veterinary medicine; however the move away from the familiar effects of opioids perioperatively is challenging. Gaining experience with these types of protocols for standard procedures in healthy animals, such as neutering, will provide the anaesthetist with the building blocks for more invasive surgeries. PMID- 28616392 TI - Catastrophic complication following injection and extracorporeal shock wave therapy of a medial femoral condyle subchondral cystic lesion in a 14 year old Arabian mare. AB - This report describes fibrous cyst lining injection and extracorporeal shock wave therapy (ESWT) of a medial femoral condyle (MFC) subchondral cystic lesion (SCL) resulting in catastrophic MFC fracture in an Arabian mare. The mare was presented for evaluation of a severe hind limb lameness of approximately 4 months duration. On presentation, a non-weight bearing lameness of the left hind limb with severe effusion and soft tissue swelling of the stifle region was noted. Radiographic evaluation of the stifle revealed a large SCL of the MFC with associated osteoarthritis. Arthroscopic guided intra-lesional injection of the SCL with corticosteroids and autologous bone marrow concentrate was performed followed by ESWT of the MFC. The mare was discharged walking comfortably 48-hours post operatively. An acute increase in lameness was noted 14 days post-operatively. Imaging revealed catastrophic fracture of the left MFC. Possible mechanisms leading to failure of the MFC secondary to the described treatment are discussed. PMID- 28616393 TI - Tear production and intraocular pressure in canine eyes with corneal ulceration. AB - This study aimed to evaluate changes in lacrimation and intraocular pressure (IOP) in dogs with unilateral corneal ulceration using the Schirmer tear test (STT) and rebound (TonoVet(r)) tonometry. IOP and STT values were recorded in both ulcerated and non-ulcerated (control) eyes of 100 dogs diagnosed with unilateral corneal ulceration. Dogs presented with other ocular conditions as their primary complaint were excluded from this study. The mean +/- standard deviation for STT values in the ulcerated and control eyes were 20.2+/-4.6 mm/min and 16.7+/-3.5 mm/min respectively. The mean +/- standard deviation for IOP in the ulcerated and control eyes were 11.9+/-3.1 mmHg and 16.7+/-2.6 mmHg respectively. STT values were significantly higher (p<0.000001) in the ulcerated eye compared to the control eye while IOP was significantly lower (p<0.0001). There is an increase in lacrimation and a decrease in IOP in canine eyes with corneal ulceration. The higher tear production in ulcerated eyes shows the importance of measuring STT in both eyes in cases of corneal ulceration, since this increased lacrimation may mask an underlying keratoconjunctivitis sicca only evident in the contralateral eye. The lower IOP in ulcerated eyes is likely to relate to mild uveitic change in the ulcerated eye with a concomitant increase in uveoscleral aqueous drainage. While these changes in tear production and IOP in ulcerated eyes are widely recognised in both human and veterinary ophthalmology, it appears that this is the first controlled documented report of these changes in a large number of individuals. PMID- 28616395 TI - Endoscopic therapies are ever-changing strategies and neverending challenges for gastroenterological neoplasia and the refractory conditions. PMID- 28616394 TI - New method of sudomotor function measurement to detect microvascular disease and sweat gland nerve or unmyelinated C fiber dysfunction in adults with retinopathy. AB - BACKGROUND: Diabetes-associated microvascular complications such as retinopathy and neuropathy often lead to end-organ and tissue damage. Impaired skin microcirculation often precedes the detection of other advanced diabetic complications. The ANS-1 system contains a redesigned sympathetic skin response (ANS-1 SSR) device that measures sudomotor function, a photoplethysmography sensor, and a blood pressure device to comprehensively assess cardiac autonomic neuropathy and endothelial dysfunction. The purpose of this study was to determine the relationships between the ANS-1 SSR amplitude measured at the: (a) negative electrode (Nitric Oxide [NO] Sweat Peak) with microvascular diseases and associated vascular blood markers and (b) positive electrode (iSweat Peak) with C fiber function. METHODS: All participants (healthy controls n = 50 and retinopathy patients n = 50) completed the ANS-1 system evaluation and a basic sociodemographic and medical history questionnaire, including a quality of life measure (SF-36). A small sample of blood was drawn to determine levels of homocysteine, blood urea nitrogen (BUN), C-reactive protein (CRP), and fibrinogen. Symptoms of peripheral foot neuropathy were assessed with a scale from 1 (none) to 10 (the worst). We used Spearman rank correlations, independent samples t-tests, and receiver operating characteristic curves to determine the specificity and sensitivity of the NO Sweat Peak as a potential screening marker of retinopathy. RESULTS: The ANS-1 System Cardiometabolic Risk Score and all indicators of quality of life on the SF-36, other than Emotional Role Functioning, were significantly worse in the retinopathy patients. The sudomotor response marker NO Sweat Peak had a sensitivity of 88% and a specificity of 68% (Area Under the Curve = 0.81, p < 0.0001) to detect retinopathy. The NO Sweat Peak response marker inversely correlated with BUN (rho = -0.41, p < 0.0001), homocysteine (rho = -0.44, p < 0.0001), fibrinogen (rho = -0.41, p < 0.0001), the Cardiac Autonomic Neuropathy score (rho = -0.68, p < 0.0001), and the heart rate variability Total Power (rho = -0.57, p < 0.0001), and it positively correlated with the Photoplethysmography Index (PTGi; rho = 0.53 p < 0.0001). The ANS-1 system sudomotor response marker iSweat Peak inversely correlated with the severity of symptoms on the peripheral neuropathy scale (rho = -0.56, p < 0.0001). CONCLUSION: The results of the study show that this new method of measuring sympathetic skin response should be useful for detecting the earliest manifestations of microvascular disease and symptoms of C fiber dysfunction. PMID- 28616396 TI - Management for non-variceal upper gastrointestinal bleeding in elderly patients: the experience of a tertiary university hospital. AB - BACKGROUND: Peptic ulcer bleeding (PUB) is the main cause of non-variceal upper gastrointestinal bleeding (UGIB). Endoscopic treatment and acid suppression with proton-pump inhibitors (PPIs) are most important in the management of PUB and these treatments have reduced mortality. However, elderly patients sometimes have a poor prognostic outcome due to severe comorbidities. METHODS: A retrospective study was performed on 504 cases with acute non-variceal UGIB who were examined in our hospital, in order to reveal the risk factor of a poor outcome in elderly patients. RESULTS: Two hundred and thirty-four cases needed hemostasis; 11 cases had unsuccessful endoscopic treatments; 31 cases had re-bleeding after endoscopic hemostasis. Forty-three cases died within 30 days after the initial urgent endoscopy, but only seven cases died from bleeding. Elderly patients aged over 65 years had more severe comorbidities, and were prescribed non-steroidal anti inflammatory drugs (NSAIDs), antiplatelet agents and/or anticoagulation agents, more frequently, compared with non-elderly patients. The significant risk factor of needing hemostatic therapy was the taking of two or more NSAIDs, antiplatelet agents and/or anticoagulation agents. The most important risk of a poor outcome in elderly patients was various kinds of severe comorbidities. And so, it is important to predict such an outcome in these cases. AIMS65 is a simple and relatively useful scoring system that predicts the risk of a poor outcome in UGIB. High-score patients via AIMS65 were associated with a high mortality rate because of death from comorbidities. CONCLUSIONS: The elderly patients in whom were prescribed two or more NSAIDs, antiplatelet agents and/or anticoagulation agents, should have UGIB prevented using a PPI. The most significant risk of a poor outcome in elderly patients was severe comorbidities. We recommend that elderly patients with UGIB should be estimated as having a poor outcome as soon as possible via the risk scoring system AIMS65. PMID- 28616397 TI - Development and use of a non-biomaterial model for hands-on training of endoscopic procedures. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) and peroral endoscopic myotomy (POEM) are recently developed techniques that have the potential to significantly improve clinical outcomes. However, training opportunities on these techniques remain limited. To address this issue, we developed a novel ex-vivo ESD/POEM training model. Our aim in this paper is to describe the model and provide preliminary evidence of promising feasibility to improve access to ESD/POEM training. METHODS: The model was developed using polyvinyl alcohol hydrogel, which can easily be modified to reproduce the stiffness of the different intestinal layers, namely the mucosa, submucosa, and muscle layer. RESULTS: A training workshop, using our ex-vivo model, was held for 28 residents. Satisfaction and feasibility in using the ex-vivo model for endoscopic training were evaluated by using a self-report questionnaire. All participants were satisfied with their training experience (100% satisfaction rate), with 27 of the 28 participants reporting that the model was feasible in replicating all components of the ESD/POEM technique (96.4% feasibility rate). CONCLUSIONS: Based on this feedback, we propose that our non-biomaterial model has the feasibility to provide an effective endoscopy education tool and a satisfactory training experience. PMID- 28616398 TI - New photodynamic therapy with next-generation photosensitizers. AB - Photodynamic therapy (PDT) is a non-invasive antitumor treatment that uses the combination of a photosensitizer, tissue oxygen, and visible light irradiation to produce cytotoxic reactive oxygen species, predominantly singlet oxygen. Currently, first-generation PDT using porfimer sodium with an excimer dye laser, and second-generation PDT using talaporfin sodium PDT with a semiconductor laser are approved by health insurance for use in Japan. However, the cancer cell specificity and selectivity of these treatments are inadequate. Cancer cells consume higher levels of glucose than normal cells and this phenomenon is known as the Warburg effect. Thus, we developed a third-generation PDT, based on the Warburg effect, by synthesizing a novel photosensitizer, sugar-conjugated chlorin, with increased cancer cell-selective accumulation. Glucose-conjugated chlorin (G-chlorin) PDT showed significantly stronger antitumor effects than second-generation talaporfin PDT. We also found that PDT with G-chlorin induced immunogenic cell death which is characterized by the secretion, release, or surface exposure of damage-associated molecular patterns (DAMPs), including calreticulin (CRT) and the high-mobility group box 1 (HMGB1) protein. Mannose conjugated chlorin (M-chlorin) PDT which targets the mannose receptors on the surface of cancer cells and tumor-associated macrophages (TAMs) in cancer tissue stroma also showed very strong antitumor effects. These novel PDTs using glucose or M-chlorins stand as new candidates for very effective, next-generation PDTs. PMID- 28616399 TI - Management of strictures after endoscopic submucosal dissection for superficial esophageal cancer. AB - Endoscopic resection of early esophageal cancer has a high therapeutic effect while being minimally invasive. Especially, the establishment of the endoscopic submucosal dissection (ESD) procedure has made it possible to resect large lesions in an en-bloc manner. As a result, accurate pathology evaluation became possible, and the risk of local recurrence was extremely low. On the other hand, esophageal strictures after endoscopic treatment of an extensive circumferential lesion are a potential problem. Previously, for the prevention and treatment of esophageal strictures, patients had to undergo painful endoscopic balloon dilation (EBD) many times. It is, however, associated with complications (perforation, bleeding, etc.). For this, oral intake and/or a local injection of steroids were given and EBD sessions were less frequently or even unnecessarily performed. Furthermore, oral mucosa epithelial cell sheet transplantation and biodegradable stents are applied for controlling post-ESD stricture. Nevertheless, EBD was still the treatment option for refractory cases of stenosis. Recently, endoscopic radial incision and cutting methods have been applied to esophageal post-procedural strictures and even for anastomotic strictures following surgery. Thus, it is now becoming possible to treat circumferential lesions with ESD and to control the resultant stenosis. PMID- 28616400 TI - Tips for safety in endoscopic submucosal dissection for colorectal tumors. AB - In Japan, endoscopic submucosal dissection (ESD) becomes one of standard therapies for large colorectal tumors. Recently, the efficacy of ESD has been reported all over the world. However, it is still difficult even for Japanese experts in some situations. Right-sided location, large tumor size, high degree of fibrosis, difficult manipulation is related with the difficulty. However, improvements on ESD devices, suitable strategies, and increase of operators' experiences enable us to solve these problems. In this chapter, we introduce recent topics about various difficult factors of colorectal ESD and the tips such as strategy, devices, injection, and traction method [Pocket-creation method (PCM) etc.]. PMID- 28616401 TI - Recent advancements in stent therapy in patients with malignant gastroduodenal outlet obstruction. AB - Gastric outlet obstruction (GOO) is one of severe comorbidities caused by many kinds of malignant diseases and is associated with not only degradation of patients' quality of life but also mortality. Although surgical bypass is one of the main therapies for malignant GOO, it is often difficult to perform in end stage patients. The deployment of self-expandable metallic stents (SEMSs) has recently become a viable alternative to surgical bypass for malignant GOO. This technique is less invasive and more effective, particularly in patients with poor prognoses. Many reports have referred to the feasibility, effectiveness, and safety of the placement of SEMSs for malignant GOO. According to these reports, the rates of technical and clinical success were reported to be relatively high and the rate of adverse events to be acceptable. However, precautions against severe adverse events such as massive bleeding and perforation are necessary. Several reports have described the differences in clinical results among different kinds of SEMSs. The presence of a covered design for SEMSs may affect the patency of SEMSs and the rate of stent dysfunction. Selection of the SEMS according to axial force may affect successful achievement of long patency of SEMSs and avoidance of gastroduodenal perforation at the bending site of the duodenum. Compared with high technical success rates nearing 100%, clinical success rates were usually lower than technical success. Therefore, determination of predictive factors for failure of clinical success is important. Several papers reported that low performance status could be associated with failure of clinical success. However, the association of clinical success with other factors such as carcinomatosa and ascites remains controversial, which is a problem to be solved. Reintervention with SEMS using the stent-in-stent method after stent dysfunction can be performed effectively as well as placement of the first SEMS. PMID- 28616402 TI - Laparoscopic and endoscopic cooperative surgery for gastrointestinal tumor. AB - With technological progress of endoscopic submucosal dissection (ESD) in the last decade, several laparoscopic and endoscopic cooperative surgeries (LECS) for gastrointestinal tumor have recently been developed. LECS is definitely favorable to the minimization of surgical margin, which leads to functional and anatomical preservation of gastrointestinal tract. LECS for gastrointestinal tumor is mainly sorted by two categories: exposure procedures and non-exposure procedures between endoluminal and extraluminal spaces. Exposure procedures have the potential risk of gastric contents or tumor cells spilling out over the abdominal cavity, because the stomach wall has to be perforated intentionally during the procedure. In order to avoid the potential these risks, non-exposure procedures have been developed. Currently, the LECS concept has rapidly permeated for treatment of gastrointestinal tumor due to its certainty and safety, although there is still room for improvement to lessen its technical difficulty. This review describes the current LECS for gastrointestinal tumor based on the several articles. PMID- 28616403 TI - Endoscopic submucosal dissection for duodenal tumors. AB - Recently, endoscopic submucosal dissection (ESD) for the duodenal tumors has come to be treated in many institutions, but has also showed many problems of feasibility and safety compared with endoscopic mucosal resection (EMR). Although duodenal ESD is expected to be more effective for the prevention of postoperative local recurrence, high incidence rate of duodenal perforation and emergency surgical rescue are big problem. Prophylactic mucosal closure by clipping device, polyglycolic acid sheets shielding, and the laparoscopic and endoscopic cooperative surgery are reported to be effective measures to overwhelm the various problems associated with duodenal ESD. However, duodenal ESD still has quite a bit of room for improvement of the procedure, and currently the indication should be well discussed before treatment in consideration of the expected therapeutic effect and complications. PMID- 28616404 TI - Complications following endoscopic submucosal dissection for gastric, esophageal, and colorectal cancer: a review of studies based on nationwide large-scale databases. AB - Endoscopic submucosal dissection (ESD) is a relatively new procedure used for the treatment of early gastrointestinal cancers regardless of the lesion size and configuration, and it has gradually acquired popularity because of its minimally invasive nature. As compared to conventional endoscopic resection, ESD is a more complex procedure and requires a higher level of technical skill. Therefore, it is associated with a higher complication rate. Many previous studies that investigated the complication rates following ESD analyzed data from a limited number of specialized centers, possibly leading to an underestimation of the complication rates. Further, the relationship between hospital volume and complication rates is poorly understood. In the present study, we searched the MEDLINE and the Cochrane Library databases for studies that have reported on ESD related complications and the relationship between hospital volume and ESD related complication rates in a nationwide setting. The complication rates (including perforation, peritonitis, and bleeding) were 3.5% for gastric ESD, 3.3% for esophageal ESD, and 4.6% for colorectal ESD. The studies reviewed showed that ESD-related complication rates were permissibly low, and that there was a linear association between a higher hospital volume and a lower frequency of complications following ESD. PMID- 28616405 TI - Endoscopic treatment for distal malignant biliary obstruction. AB - Distal malignant biliary obstruction (MBO) leads to obstructive jaundice as a result of when the bile excretion from the liver is disturbed and induces hepatic failure and sepsis, which when complicated with cholangitis, it becomes necessary to perform drainage for the MBO. For biliary drainage, we can perform a surgical bypass operation, percutaneous transhepatic biliary drainage (PTBD), endoscopic biliary drainage (EBD) via duodenal papilla, or endoscopic ultrasound (EUS) guided biliary drainage (EUS-BD), which is a transgastrointestinal biliary drainage. Although currently we usually perform EBD for distal MBO to begin with, the choice is different for biliary drainage in patients in whom EBD has failed in a preoperative case or an unresectable case. In other words, we choose PTBD for preoperative cases, and PTBD or EUS-BD according to the ability of the institution for their procedures when EBD has failed. It is desirable not to choose a plastic stent (PS) but a self-expandable metallic stent (SEMS), in particular for the unresectable cases of pancreatic cancer it is desirable not to choose an uncovered SEMS but a covered SEMS in EBD. Nevertheless, further examinations are expected to decide which, a covered or uncovered SEMS, we should choose in unresectable biliary tract cancer (BTC) and whether we should select PS, SEMS or ENBD in preoperative cases. PMID- 28616406 TI - New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease. AB - Fibrosis continues to be paid a great attention in not only basic research but also clinical practice, especially for the development of novel therapeutics in various fibrotic diseases. However, there remain several obstacles to translation in developing anti-fibrosis therapy. The present review documents our translational practice from target discovery to first-in-patient studies in the development of anti-fibrosis therapy for inflammatory bowel disease (IBD). First topic is a target selection. We have focused on the target that has an ability to regulate multifactorial cascades of fibrosis. Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling during injury. Small interfering RNA (siRNA) targeting CHST15 inhibited activation of fibroblasts in vitro and reduced fibrosis in vivo. Second topic is a clinically feasible application. We established a safe and novel pancolonic delivery of siRNA, which is achieved by direct injection to extracellular matrix (ECM) through endoscope. Third topic is an endpoint for both nonclinical and clinical studies. We have focused on tissue specific findings for co-existence of fibrosis in ulcerative lesions in IBD and investigated whether the balance of mucosal healing (MH) and fibrosis, which is evaluated by endoscopy and histology respectively, can be used for study endpoints. Phase 1 clinical trial of STNM01, a synthesized CHST15 siRNA, by a single dose endoscopic submucosal injection for non-healer patients with Crohn's disease showed high rates of MH. Analyses of biopsy specimens revealed that STNM01 reduced CHST15 expression at local lesions, repressed pre-existing fibrosis and repaired the damaged crypts. Thus, blockade of multifactorial modulator CHST15 in ECM showed a potential to treat tissue remodeling and skew fibrosis toward mucosal repair. Our practice suggests that target- and tissue specific findings-based strategy would be a key to translation in developing anti fibrosis therapy. PMID- 28616407 TI - Peroral endoscopic myotomy (POEM) for treating esophageal motility disorders. AB - Pneumatic dilatation and Heller myotomy have been thoroughly studied as the most viable treatment options for achalasia. The pendulum, however, is shifting to the minimally invasive approach. Since Inoue et al. published the experience of the first 17 cases of peroral endoscopic myotomy (POEM) in 2010, there have been at least 5,000 cases performed worldwide and the number is increasing exponentially. Experts across the globe have been extending the indications to various esophageal motility disorders, to patients of extremes of age, sigmoidal esophagus and re-operated patients. There are a few variations in technique across different centers in defining the gastroesophageal junction (GEJ) and adequacy of myotomy, the optimal length, site of myotomy and whether the full thickness of the muscle wall should be cut. Large case series demonstrated its promising efficacy & reasonable complication profile. Randomized controlled trial in comparison with the gold standard, Heller myotomy, is ongoing. The future application of submucosal tunnelling technique is thrilling with its extension in tumour resection, antropyloromyotomy and other natural orifice transluminal endoscopic surgery (NOTES). PMID- 28616408 TI - Breastfeeding and respiratory tract infections during the first 2 years of life. AB - Breastfeeding and respiratory tract infections http://ow.ly/Isd9309JS69. PMID- 28616409 TI - Awareness and perceptions regarding common cancers among adult population in a rural area of Puducherry, India. AB - BACKGROUND: Awareness regarding cancer signs and symptoms and their screening and treatment method was low in India. OBJECTIVES: To assess the awareness level of common cancers, perception regarding prevention and treatment of common cancers, association between sociodemographic variables with the awareness level of common cancers in the adult population. MATERIALS AND METHODS: A cross-sectional study was conducted among 299 adults from the field practice areas of Our Rural Health Centre, Puducherry, during April-May 2014. Using systematic random sampling, 299 adults were interviewed through a pretested semi-structured questionnaire. Data were entered into EpiData version 3.1 and were analyzed by Statistical Package for Social Sciences version 20. Chi-square test was used. RESULTS: Nearly, 64% were in the age group of >=40 years, the majorities were females (56.2%) and 64% were in lower socioeconomic class. Symptoms reported majorities were unusual bleeding (41.6%), followed by nagging cough (34.1%). Risk factors reported majorities were smoking (65%), chewing tobacco (59%) followed by alcohol use (46.5%). Only 10% reported cancer could be diagnosed early and 27% perceived cancer could be preventable. Only 6% perceived cancer could be cured fully. The adequate awareness level regarding lung and oral cancer were 14%, but breast and cervical cancer were <5%. The younger age group (<40 years) had more adequate awareness level compared to age group >=40 years (P < 0.05). CONCLUSION: The awareness level of common cancers was very poor. Vigorous health education program should improve the status of early diagnosis and proper treatment for common cancers such as oral, breast, and cervical cancer. PMID- 28616410 TI - Assessing effects of BL67 points stimulation on fetal heart rate parameters and fetal movements during nonstress test. AB - CONTEXT: One of the main goals of antenatal testing is to identify fetuses at the risk of neurologic injury or death so that these adverse outcomes can be prevented. We want to assess the effects of BL67 points' stimulation on fetal heart rate parameters and fetal movements during nonstress test (NST). We did a quasi-experimental design in Shahid Beheshti Hospital in Isfahan in 2011. AIMS: This study aims to assessment of the effects of BL67 points' stimulation on fetal heart rate parameters and fetal movements. SETTINGS AND DESIGN: We did a randomized controlled clinical trial in Shahid Beheshti Hospital in Isfahan in 2011. SUBJECTS AND METHODS: This study is a quasi-experimental design that was conducted in one group and the two steps (before-after study). Participants were pregnant women (primigravida) who were 35-18 years that refer to Shahid Beheshti Hospital in Isfahan in 2011 to receive routine prenatal care. The 32 pregnant women were selected for acupressure during the second NST. STATISTICAL ANALYSIS USED: The statistical processing was performed by descriptive, paired t-test through SPSS version 20. RESULTS: There was no significant difference in mean number of accelerations in fetal heart rate and mean number of fetal movement before and after intervention; however, there was a significant difference in mean time to the second acceleration before and after the intervention (P = 0.04). CONCLUSIONS: No difference between parameters of the fetal heart rate before and after stimulation and lack of uterine response by this method is a significant advantage and is probably why stimulating this point could not create a risk to the fetuses. PMID- 28616411 TI - Identification of etiologic agents of cutaneous Leishmaniasis in palpebral position followed by effective therapy. AB - CONTEXT: Cutaneous Leishmaniasis (CL) is a self-healing lesion but prevention of complications and involvement of vital organs such as palpebra requires proper treatment. AIMS: The main objectives were to detect agents of CL in palpebral region and estimate the proportion of palpebral lesion also possible complications among CL patients in a zoonotic CL endemic area. SETTINGS AND DESIGN: The study was performed from April 2012 to March 2013 in a total of 1613 CL suspected patients by interview and physically exam. SUBJECTS AND METHODS: The samples were used for direct smear using Giemsa stain method, or cultured in Novy McNeal-Nicol medium. For further checked, nested polymerase chain reaction (PCR) was used for negative palpebral samples. Of the 1613 examined samples, 848 (81.4%) by direct smear, 188 (18%) by culture and 6 (0.6%) by nested PCR were positive, respectively. A total of 233 of the patients showed lesions on the face of whom 15 (male = 5, female = 10, 1.43% of all and 6.43% of facial lesions) presented with palpebral CL. The results of nested PCR indicated that all the palpebral cases were due to Leishmania major. CONCLUSIONS: About 93% of the patients with palpebral lesion were under 5 years old and were infected in the hyper endemic regions, but no ocular complication was seen in any of them. Based on the results, it seems that early referring to the medical center for proper diagnosis and treatment is the main reason for prevention of further complications. PMID- 28616412 TI - Assessing the presence of Chlamydia trachomatis genome in pregnant women with spontaneous abortion using polymerase chain reaction method in Yasuj: First report from Southwest of Iran. AB - CONTEXT: Chlamydia trachomatis is one of the most prevalent factors of sexually transmitted diseases worldwide, which causes abortion, premature rupture of membrane, uterine cervicitis, pelvic inflammatory diseases, and ectopic pregnancy. AIMS: The aim of this study was to investigate the presence of C. trachomatis genome in pregnant women with abortion in Yasuj, Iran. SETTINGS AND DESIGN: This is a descriptive-analytical study in Shahid Mofateh Gyneco obstetrics clinic and Emam sajjad Hospital. SUBJECTS AND METHODS: Specimens of cervix, urine, placenta, and blood of 107 pregnant women were simultaneously collected at maternity ward and operation room and were stored for molecular tests. The molecular tests were performed, and the results were analyzed. STATISTICAL ANALYSIS USED: Analysis was performed using SPSS software 9.1 (IBM, Illinois, Chicago, USA) with descriptive-analytical statistics. RESULTS: Of 107 women, 15 had polymerase chain reaction-positive tests for C. trachomatis. The age of the studied individuals was 15-38 years with mean age of 26.6 years. The highest infection rates were in the age group of 21-25 years (7.47%), and the lowest frequency was in the age group of 36-40 years. A significant difference was noted between the number of first abortions in the case and control groups. CONCLUSIONS: Our results showed that C. trachomatis as a sexually transmitted agent causes severe complications such as abortion; thus, it is important to screen pregnant and sexually active women who are craving to carry a baby. PMID- 28616413 TI - The condition of interdisciplinary communication among various Educational and Research Departments of Isfahan University of Medical Sciences. AB - BACKGROUND: The study aimed to assess interdisciplinary communication among various Educational and Research Departments of Isfahan University of Medical Sciences (IUMS) in clinical medical sciences using social network analysis. MATERIALS AND METHODS: The study was carried out using scientometrics method and interdisciplinary communication network analysis. Interdisciplinary network of 1298 articles in medical sciences published in Journal of Isfahan Medical School was evaluated using macro- and micro-level criteria of network analysis. Ravar Matrix, UCINET, and VOSviewer software were used to analyze the interdisciplinary network of medical sciences articles. RESULTS: Findings showed that "Students Research Committee" and "School of Medicine," the affiliations of the medical students in general practice with scores of 272 and 197, "Epidemiology and Biostatistics," "Community Medicine," and "Internal Medicine" with 170, 101, and 99, respectively, possessed the first ranking of productivity index in scientific communication. Furthermore, in betweenness centrality index, "Epidemiology and Biostatistics" (3427.807), "Students Research Committee" (2967.180), and "Community Medicine" (1770.300) have an appropriate position in the network. Based on the centrality index, "Epidemiology and Biostatistics" (22.412), "Students Research Committee" (22.185) as well as "Community Medicine" and "School of Medicine" (both 21.554) acquired the least amount of distance with other nodes in network. CONCLUSION: Given the increased specialization in medical fields in recent years, communication between researchers with various specializations and creation of interdisciplinary or multidisciplinary departments had turned into an undeniable necessity. Therefore, communication between educational or research departments can facilitate the flow of information between researchers; and consequently, the top ranking departments in this study had more participation in scientific production of IUMS and getting more scores in annual evaluation by scientometrics department. This network analysis showed that researchers in various medical fields closely collaborate with each other and are able to connect with <2 intermediates. PMID- 28616414 TI - BASNEF Model intervention on blood pressure modification among hypertensive diabetic patients. AB - BACKGROUND: Prevalence of hypertension in patients with type 2 diabetes is two to three times more than nondiabetic patients. This study aimed at assessing the impacts of an educational program based on BASNEF Model on blood pressure modification among diabetic patients with hypertension. MATERIALS AND METHODS: Two hundred patients with type 2 diabetes were recruited in an educational intervention study among two groups. The intervention group attended a 3-month self-care educational program regarding hypertension control in addition to the regular care presented for both the groups. Another group received no extra program except regular treatment. To collect information about demographic characteristics, type 2 diabetes-related variables, and BASNEF Model construct items, a self-designed questionnaire was utilized. Data analyzed by SPSS version 16 using Chi-square, independent t-test, and paired t-test. RESULTS: Knowledge, behavioral beliefs, attitude to action, enabling factors, subjective norms, and practice were significantly higher in intervention group as compared to the controls (P < 0.001). In addition, blood pressure revealed significant differences in intervention group before and after program using paired t-test (P = 0.001) while in the control group, there was no significant difference in blood pressure (P = 0.54). DISCUSSION: The study results revealed a significant change in blood pressure and model constructs in intervention group compared to control. This research suggested intervention program based on BASNEF Model has essentially effectiveness in blood pressure modification among diabetic patients. CONCLUSION: BASNEF Model has effectiveness to high blood modification among diabetic patients with hypertension. PMID- 28616415 TI - Quality evaluation of Persian nutrition and diet therapy websites. AB - INTRODUCTION: Nowadays websites are among the most important information sources used by most people. With the spread of websites, especially those related to health issues, the number of their visitors also increases, more than half of which are about nutritional information. Therefore, quality analysis of nutrition and diet therapy websites is of outmost importance. This study aims to evaluate the quality of Persian nutrition and diet therapy websites. METHODS: The current work is a survey study and uses an applied study method. The statistical population consists of 51 Persian websites about nutrition and diet therapy and census method was used in order to study them. Data gathering was done using a checklist and with direct visit to each website. Descriptive and analytical statistics were used to analyse the gathered data with the help of SPSS 21 software. RESULTS: Findings showed that content (66.7%), organization (82.4%), user friendly interfaces (52.9%) and total quality (70.6%) of most websites had a mediocre score while the design score for most of the websites (70.6%) was acceptable also organizational websites had better design, organization and quality compared to private websites. The three websites with the highest general quality score were the websites of "Novel Diet Therapy," "Behsite" and "Dr. BehdadiPour" (jointly) and "Dr. Kermani" respectively. Also in the dimension of content the factors of goal, relevance and credibility, in the dimension of design the factors of color, text and sound, pictures and videos, in the dimension of organization the factors of stability and indexing and in the dimension of user friendliness the factors of confidentiality, credibility and personalization had the highest scores. CONCLUSION: The results showed that the design score was higher than other scores. Also the general quality score of the websites was mediocre and was not desirable. Also websites didn't have suitable scores in every factor. Since most people search the internet for nutritional and diet therapy information, the creators of these websites should endeavor to fix the shortcomings of their websites and increase the quality of their websites in several different areas. PMID- 28616416 TI - Iranian parent-staff communication and parental stress in the neonatal Intensive Care Unit. AB - INTRODUCTION: The birth of an infant requiring hospitalization in the neonatal Intensive Care Unit (NICU) uniformly is reported to be stressful for parents and family members. This study aimed to determine parent-staff communication in the NICU and its relationship to parent stress. MATERIALS AND METHODS: Two hundred and three Iranian parents with preterm infants hospitalized in the NICU participated in this descriptive-correlational study. The participants were selected by the quota sampling method. Data collected included a three-part: questionnaire, the first part covered demographic parent and infant information, the second was the Parent-Staff Communication Scale (the score of which ranged from 0 to 180), and the third was the Parental Stress Scale (the score of which ranged from 0 to 102). Descriptive and inferential statistics including the Pearson's correlation coefficient test were applied to the data, using SPSS software Version 16. RESULTS: This study revealed that fathers and mothers' stress and communication scores were almost comparable and both higher than expected. The total mean score of the two main variables, i.e., parent-staff communication and parental stress were, respectively, 100.72 +/- 18.89 and 75.26 +/- 17.6. A significant inverse correlation was found between parental stress and parent-staff communication scores (r = -0.144, P = 0.041). CONCLUSIONS: Based on this study finding showed that better parent-staff communication is related to lower parent stress scores, it is recommended that nurses and physicians receive specific skill training for the establishment of effective parent-staff communication. It is anticipated that such improved staff skills will help decrease parent stress and therewith likely promote parent and infant health in the NICU. PMID- 28616418 TI - Researcher's experiences about their publication in ISI journals: A qualitative study in Isfahan University of Medical Sciences. AB - BACKGROUND: As one of the indicators of actual growth and scientific development capacity of countries, the importance of the research is steadily increasing. Knowing that success depends on the work done by researchers so identified identify these barriers and pave the way for one of the concerned authorities of their research. METHODS: This qualitative study using analysis of the theme. Semi structured interviews were used to collect the data. Participants include people who are experienced and knowledgeable in the field. Sampling was purposeful and continued until data saturation. The criteria of "reliability", "trustworthiness", "reliability" and "significant consolidation" of data were considered. RESULTS: Data analysis led to the extraction of code 600, 5, and 35 issues were Zyrmvzv. Five topics including motivation, success factors, barriers and problems, reflections and strategies, respectively. CONCLUSION: Discussion interest, innovation, the ability to apply research methods, specializes in the research literature and English language skills of researchers successfully in printing paper. Creating strong incentives to improve the material and spiritual encouragement and removal of obstacles, increase the amount of scientific publications and its opposite, although the force can cause increased production of scientific publications, but the negative consequences of such unhealthy competition and robbery also will follow. As a result, universities have to go through proper planning and management in the areas of research and teaching more responsible to pay it. PMID- 28616417 TI - The comparison the effect of training by means of simulation and oral method on midwives' skill in management of shoulder dystocia. AB - INTRODUCTION: Shoulder dystocia is one of the obstetric emergencies that are accompanied to serious risks for mother and fetus. It necessitates making the method of training of shoulder dystocia management more efficient, i.e., better management and giving services with higher quality. Thus, this study was carried out to compare the impact of training by simulation and oral technique on the skill of the employed midwives in obstetric clinics at Mashhad city (Iran) in shoulder dystocia management during 2012. METHODS: The current research is a double-group clinical trial that was conducted on 51 members of the employed midwives in the obstetric clinic at Mashhad city in 2012. The questionnaire of personal specification and awareness about shoulder dystocia and practical examination (objective-structured clinical examination) were employed as tools for data collection. The learners were divided into two groups by randomized allocation. Training was done by the presentation of lecture in the oral content group and a short movie was displayed at the end of it. The shoulder dystocia management technique was simulated in another group and through role-playing of instructor application of moulage (station) training was conducted. The period of the training course (4 h) and content of the educational workshop was identical for both groups. The practical examination was held for the learners before and immediately after training course. The given data were analyzed by means of statistical descriptive tests including Mann-Whitney U-test and Wilcoxon test via SPSS software (version 16). The significance level was considered as (P < 0.05) in all cases. RESULTS: The total mean score was significantly increased for the variable of shoulder dystocia management skill after intervention in both groups (P < 0.0001). Similarly, the results of Mann-Whitney U-test statistical tests indicated that total mean score for the variable of shoulder dystocia management skill after the intervention was significantly greater in simulation group than in an oral group (P = 0.040). CONCLUSION: Training in simulated delivery room by means of role-playing is an efficient method for training shoulder dystocia management skill, so it is recommended to use this program in the training of this skill. PMID- 28616419 TI - Economic planning and equilibrium growth of human resources and capital in health care sector: Case study of Iran. AB - CONTEXT: During different planning periods, human resources factor has been considerably increased in the health-care sector. AIMS: The main goal is to determine economic planning conditions and equilibrium growth for services level and specialized workforce resources in health-care sector and also to determine the gap between levels of health-care services and specialized workforce resources in the equilibrium growth conditions and their available levels during the periods of the first to fourth development plansin Iran. MATERIALS AND METHODS: In the study after data collection, econometric methods and EViews version 8.0 were used for data processing. The used model was based on neoclassical economic growth model. RESULTS: The results indicated that during the former planning periods, although specialized workforce has been increased significantly in health-care sector, lack of attention to equilibrium growth conditions caused imbalance conditions for product level and specialized workforce in health-care sector. CONCLUSIONS: In the past development plans for health services, equilibrium conditions based on the full employment in the capital stock, and specialized labor are not considered. The government could act by choosing policies determined by the growth model to achieve equilibrium level in the field of human resources and services during the next planning periods. PMID- 28616420 TI - Investigation effect of oral chamomilla on sleep quality in elderly people in Isfahan: A randomized control trial. AB - BACKGROUND: Elderly people often suffer from sleep disorders. Chamomile due to the many health benefits such as sedation may be effective in improving sleep quality in elderly people. This study aimed to determine the effect of Matricaria chamomilla extract on sleep quality in elderly people admitted to nursing homes of Isfahan in 2014. MATERIALS AND METHODS: The present study is a quasi experimental clinical trial. The study population was 77 cases of elderly hospitalized in nursing homes. Participants were selected through random continuous sampling and divided into intervention and control groups. The intervention group received 400 mg oral capsules of chamomile twice daily, after lunch and after dinner for 4 weeks. The control group did not receive the intervention. Sleep quality in older adults before and after intervention were compared using the Pittsburgh Sleep Quality Index questionnaire. Data were analyzed using descriptive statistics and paired t- and independent t-tests, one way analysis of variance and liner regression analysis, using SPSS software version 17. RESULTS: Before intervention, the mean score of sleep quality both experimental and control groups showed no significant difference (P > 0.05). After intervention, the mean score of sleep quality was a significant difference between experimental and control groups (P < 0.001). CONCLUSIONS: Oral administration of chamomile extract has sedative properties in sleep quality of hospitalized elderly patients in nursing homes. Therefore, it can be used in similar cases and nursing care. PMID- 28616421 TI - Cystic fibrosis prevalence among a group of high-risk children in the main referral children hospital in Iran. AB - BACKGROUND: Knowledge about cystic fibrosis (CF) in Iran is very limited. The objective of this study was to determine the prevalence of CF among a group of high-risk children with suggestive clinical features in the main referral hospital in Iran. MATERIALS AND METHODS: This study children consisted of 505 patients who had presented with one or more of the following symptoms: chronic or recurrent respiratory symptoms, gastrointestinal symptoms as rectal prolapse, steatorrhea, hepatobiliary disease as prolonged jaundice, failure to thrive, hyperglycemia and glycosuria, hypochloremic metabolic alkalosis, hypoprothrombinemia, anemia or edema, and positive family history of CF. Patients were screened using pilocarpine iontophoresis to collect sweat and chemical analysis of its chloride content with classic Gibson and Cooke technique. RESULTS: Of 505 patients, 89 (17.6%) had positive sweat chloride screening test. Five (1%) patients had required cystic fibrosis transmembrane conductive regulator protein mutation analysis to confirm CF. CONCLUSION: Our findings suggest that in Iran, CF is more common than what previously anticipated. Larger studies are warranted to identify the incidence, molecular basis, and clinical pattern of CF in the Iranian population. PMID- 28616422 TI - Evaluation of educational program in the Master of Medical Education by Eisner's educational connoisseurship and criticism model. AB - INTRODUCTION: To be more successful in medical education and identify the strengths and weaknesses of the curriculum in this field, assessment of the students' views, graduates, professors, and experts is essential. The aim of this qualitative assessment was to identify the strengths and weaknesses of the medical education curriculum. SUBJECTS AND METHODS: This research is a qualitative study using the Eisner's educational connoisseurship and criticism model that was conducted in Shiraz Medical Sciences University in 2014. In this research, graduate medical education curriculum was criticized by a team of educational experts. Fifteen professors in the first stage of the focus group meeting addressed the three stages of educational criticism. In the second stage, several interviews were conducted with the above-mentioned people. In the third phase, the implementation of video recordings from the focus group meeting was performed in written form. In the fourth stage, conventional content analysis was used to analyze the qualitative data. RESULTS: This curriculum has advantages and disadvantages in the constituent elements of the program. Its weaknesses include lack of written a guide for practical courses, lack of consideration of joint practical exercise to make integrate between lessons, lack of sufficient attention to aspects of practical and functional knowledge in this field, lack of attention to performance evaluation and development, and lack of routine review of the curriculum. On the other hand, the strengths of this study include the suitability of this field for professors and its positive impact on professors and students performance in the classroom. CONCLUSION: As medical education is partly an emerging field in Iran and considering the weaknesses, reviewing the curriculum based on the main part of program, the outcomes, curriculum content, teaching strategies, student assessment, and course management are recommended. PMID- 28616423 TI - The relationship between sexual dysfunction and quality of marital relationship in genital and breast cancers women. AB - INTRODUCTION: The concept of sexual dysfunction is dysfunction in desire and emotional - social that it is Impact on the sexual response cycle and can cause stress and interpersonal difficulties. Quality of marital relationship is one of the important factors predicting sexual function disorders, which varies among different cancers. The purpose of this study is to determine the relationship between sexual dysfunction and quality of marital relationship in genital and breast cancers in women. METHODS: This correlational study was conducted on 150 breast and genital cancers in women referred to Sayedoshohada and Milad hospitals in Isfahan city through a two-stage sampling method. Participants completed questionnaires about demographic/disease and sexual function questionnaire (44 questions) and quality of marital relationship (11 questions). Collected data were analyzed using SPSS version 14 software, statistical test such as, Pearson correlation coefficient tests independent t- student, one way ANOVA. RESULTS: The results showed that 70.7% of women had breast cancer and 29.3% had gynaecological cancer. 60% of patient had good quality of marital relationship and 19.3% sexual dysfunction. There was a significant correlation between sexual function and quality of marital relationship (P = <0.001). CONCLUSION: There was a significant correlation between sexual function disorder and quality of marital relationship. The inclusion of patients educational programs and couple therapy in cancer disease rehabilitation program is important in order to improve the quality of marital relationship and subsequent sexual dysfunction in cancer patients. PMID- 28616424 TI - Evaluation of 1-year-old children development in Isfahan City and its effective factors using ages and stages questionnaire, in 2014. AB - BACKGROUND AND AIMS: Attention to the development of children as the future generation that leads to the upbringing of productive human resources is an important subject. Development has dimensions that a child should acquire the skills related to them in proper age. Otherwise, he may be affected by developmental delays. There are different factors influencing children's developmental delays and this study is carried out to evaluate the developmental conditions of 1-year-old children in the Isfahan and its effective factors. MATERIALS AND METHODS: In a historical cohort, 725 children born in 2013 were selected using multi-stage random sampling from health centers licensed by Isfahan Medical University and followed up to 1-year and their related specifications were extracted from ages and stages questionnaire and their families' files. SPSS 20 software and Pearson and Spearman correlation coefficients, independent t-tests, ANOVA, multiple linear regression and analysis of covariance were used for analyzing the data. RESULTS: The minimum and maximum scores of development were observed in the personal-social domain (52.38 +/- 9.1) and fine motor (56.06 +/- 5.9), respectively. The results showed that the child spacing has direct relation with development in fine motor domain (r = 0.2, P < 0.001), personal-social development (r = 0.197, P = 0.001), and problem solving domain (r = 0.18, P = 0.002). The score for the development in gross motor skills had a direct correlation with the weight at birth (r = 0.129, P < 0.001). Breastfeeding also improved personal-social development (P = 0.024). Sex (P = 0.024) and living place with communication skills also showed significant relations (P < 0.001). CONCLUSION: The factors such as the child's sex, feeding in the first 6 months of age, living in urban or rural areas are effective in delayed development. Considering these factors to prevent adverse effects of the elements and rapid identification of children with delayed development as well as timely therapeutic interventions are essential in the health care system. PMID- 28616425 TI - Medical radiation workers' knowledge, attitude, and practice to protect themselves against ionizing radiation in Tehran Province, Iran. AB - BACKGROUND: Medical radiation workers are potentially at a risk of unwanted ionizing radiation exposures. This study assessed the radiation protection knowledge, attitude, and practice (RP-KAP) of health-care workers who are occupationally exposed to radiation regarding protecting themselves from radiation. MATERIALS AND METHODS: This study was cross-sectional in design and was carried out in 16 hospitals affiliated to the Tehran University of Medical Sciences between May and September 2014. Total health-care workers who were occupationally exposed to radiation comprising 670 individuals were included in the study based on census sampling method. In total, 413 individuals consented to complete an anonymous 32-item questionnaire comprising single best choice questions with a numerical value assigned to each correct answer. Each set of RP KAP questions was scored and categorized as poor, medium, and good. The effect of independent variables for prediction of RP-KAP was explored using linear regression analyses. RESULTS: A significant number of participants had poor RP knowledge (78.9%), RP-attitude (70.7%), and RP-practice (32.4%). Based on linear regression analyses, it was found that field of study (beta = 0.1, P = 0.001), marital status (beta = -0.14, P = 0.01), and level of education (beta = 0.2, P < 0.001) were the predictors of higher RP-knowledge. In-service RP-training (beta = 0.1, P = 0.04) was associated with an increased RP-attitude. Being a woman (beta = 0.2, P < 0.001) and longer years of experience with radiation (beta = 0.2, P < 0.001) were significantly related to better practice. CONCLUSION: In-service training with appropriate qualified and up-to-date materials based on radiation workers' educational needs and approved protocols and guidelines is recommended. PMID- 28616426 TI - Cytologic diagnosis of atypical teratoid rhabdoid tumor based on touch imprint study: Report of a case with review of literature. AB - Atypical teratoid rhabdoid tumor (ATRT) is a rare malignant tumor with gloom destiny. Our case was a 4-year-old boy with a temporal lobe tumor that was then became evident of ATRT with recurrent happening. In a retrospective review of all cytologic slides, we found unique rhabdoid cells that are morphologically evident cells for ATRT in both times. Unfortunately, the cells were overlooked at the first time. We conclude if the pathologist is experienced to see rhabdoid cells noticing these cells is highly helpful for diagnosis ATRT, especially in frozen sectioning. PMID- 28616427 TI - Specific Genes Associated with Adverse Events of Methylphenidate Use in the Pediatric Population: A Systematic Literature Review. AB - The aim of this study was to review empirical studies examining associations between candidate genes and adverse events (AEs) from methylphenidate (MPH) use in children and adolescents. The PubMed, EMBASE, CINAHL, and Web of Science databases were searched from their inception until March 2017. We included empirically based articles on pharmacogenetic studies in 0-17-year-old patients that investigated associations between specific candidate genes, their polymorphisms, and reported AEs. We extracted information about study design, setting, type of AE reporter, studied genes and their polymorphisms, age and gender, administered doses, method of genotyping, outcome measures, and main findings. A total of nine articles reporting information about four double-blind, placebo-controlled, cross-over studies and five open-label cohort studies were eligible for inclusion. Studies were published from 2006 onward and included a total of 998 patients (3-17-year-olds) diagnosed with attention-deficit hyperactivity disorder (ADHD). Studies predominantly involved males and lasted from 1 to 12 weeks. Studies used polymerase chain reaction and single nucleotide polymorphism genotyping methodology. Reported AEs were significantly associated with the following genes: appetite reduction (CES1*G); buccal-lingual movements (T1065G); diastolic blood pressure (ADRA2A Mspl C/C-GC); emotionality (DAT1*9/9); irritability (SNAP25 T1065G); picking (DRD4*7/DRD4*4); social withdrawal (DRD4*7/DRD4*4); somatic complaints (DAT1*10/10); tics (5-HTTLRP*S/L*L/L; SNAP25 T1065G); sadness (CES1*rsl12443580); and vegetative symptoms (5-HTTLPR). In conclusion, only few MPH pediatric pharmacogenetic studies were located, and large between-study heterogeneity was found. Studies were of naturalistic design and of short duration. They included small patient samples, poorly standardized treatment regimens, and limited outcome assessments. In the future, more pharmacogenomic studies in ADHD are needed, preferably using randomized, controlled study designs and of longer duration (more than 6 months). PMID- 28616428 TI - Severity of Gastrointestinal Side Effects of Metformin Tablet Compared to Metformin Capsule in Type 2 Diabetes Mellitus Patients. AB - OBJECTIVE: This study was designed to compare the severity of gastrointestinal (GI) side effects in Type 2 diabetes mellitus (DM) patients receiving tablet or capsule forms of metformin. METHODS: In this prospective interventional study, patients were evaluated from June to November 2016 at DM clinics affiliated to Isfahan University of Medical Sciences, Isfahan, Iran. Adult patients with Type 2 DM who were eligible for inclusion criteria switched from metformin tablet to metformin capsule. Hemoglobin A1c (HbA1c), GI side effects, and patient satisfaction based on visual analog scale (VAS) were assessed during a 6-week follow-up of receiving metformin capsule. FINDINGS: One hundred and three patients were evaluated, and 75 patients participated in this study. At the baseline, 40 patients (53.3%) had GI side effects due to metformin tablet which was reduced to 16 patients (21.3%) after switching to metformin capsule (P = 0.001). There was also an improvement in HbA1c (from 7 to 6.8,P < 0.0001). The results of patients' satisfaction based on VAS and numeric rating scale indicated that in 59 patients (78.67%), GI side effects were reduced after switching to metformin capsule (mean score: 7.2 with the range of 6-9) while 16 patients stated no treatment preference. CONCLUSION: Switching to metformin capsule may result in less GI side effects, with no further side effect complications. PMID- 28616429 TI - Evaluation of the Interaction of Intravenous and Oral Voriconazole with Oral Cyclosporine in Iranian HSCT Patients. AB - OBJECTIVE: Voriconazole as a triazole antifungal agent is widely used for prophylaxis or treatment of fungal infections in allogeneic hematopoietic stem cell transplantation (HSCT). It can increase blood concentrations of other medications including cyclosporine A (CsA) which are substrates for cytochrome P450 3A4. The aim of this study was to evaluate comparatively the interaction between oral/intravenous (IV) voriconazole and oral CsA. METHODS: Twenty-nine recipients of allogeneic HSCT who had been already on a steady dose of CsA and were started on oral or IV voriconazole were evaluated in a prospective cohort study. Blood concentration of CsA was determined before and 5-8 days after voriconazole initiation. Plasma concentration of voriconazole was measured in steady state. The changes in blood concentration of CsA after administration of voriconazole were evaluated. FINDINGS: The concentration/dose (C/D) ratio of CsA increased significantly (P < 0.001) after voriconazole initiation in both routes of administration (8.40%-174.10% increase in C/D ratio). The C/D ratio alteration of CsA did not differ significantly between oral and IV voriconazole group (P = 0.405). There was a significant correlation in all patients between plasma concentration of voriconazole and percentage of CsA C/D ratio increment (P = 0.046). CONCLUSION: There was a significant intrapatient variability in the magnitude of CsA blood concentration increment after voriconazole initiation. We also demonstrated that magnitude of drug interaction did not differ in IV and oral voriconazole administration. Furthermore, we found that the magnitude of drug interaction was correlated with plasma concentration of voriconazole. PMID- 28616431 TI - Comparing the Effects of Zinc Sulfate, Calcium Pantothenate, Their Combination and Minoxidil Solution Regimens on Controlling Hair Loss in Women: A Randomized Controlled Trial. AB - OBJECTIVE: This study was conducted to evaluate the combination of oral supplements with 2% minoxidil solution in four groups of women with hair loss. METHODS: A prospective, randomized controlled trial was conducted from July to December 2016 in dermatology clinics affiliated to Isfahan University of Medical Sciences. A total of 73, 15-45-year-old, women with hair loss participated in this 4-month study. Simple randomization using Random Allocation Software was done to put the participants in four groups to receive coadministration of zinc sulfate and calcium pantothenate, zinc sulfate, calcium pantothenate, and 2% minoxidil solution. The primary endpoint was the change in hair density and diameter measured by dermatoscope. Secondary endpoints included the researcher's evaluation, dermatologist's opinion - which was blinded to the study - from comparing the participants' photographs before and after treatment and finally, overall changes in hair density measured by participants' self-assessment. FINDINGS: Seventy-three women participated in this study. Primary hair count and thickness were 118.5 +/- 10 hairs/cm2 and 58.8 +/- 5.8 MU that changed to 124 +/- 11 hairs/cm2 and 62.3 +/- 4.3 MU respectively (P < 0.001) which in the zinc plus pantothenate group these changes were from 118.6 +/- 9.9 hairs/cm2 to 121.9 +/- 11.1 hairs/cm2 (P = 0.042) and from 62.2 +/- 6.6 MU to 64.0 +/- 5.0 MU (P = 0.126), respectively. Hair density increments were more obvious in the minoxidil group, and hair thickness increments were more obvious in pantothenate group. Participants' satisfaction was 85% in the combination therapy which was more than other groups. Participants' satisfaction, author's and blind dermatologist's opinion showed a significant correlation (P = 0.0001). CONCLUSION: Based on the participants' satisfaction, the combination of zinc sulfate and calcium pantothenate when administered in a pulse therapy way could be a good choice for hair loss controlling in initial stages. PMID- 28616430 TI - Training and Validation of Standardized Patients for Assessing Communication and Counseling Skills of Pharmacy Students: A Pilot Study. AB - OBJECTIVE: The objective of this study is to describe the process of training valid simulated patients (SPs) for assessing communication and counseling skills of pharmacy students' performance. METHODS: This is a cross-sectional and correlational study. Psychometric properties of checklist and SPs' portrayals and their filling of the checklist regarding assessing pharmacy students were assessed. Five SPs who were working in the simulated patient's pool were volunteered to take part in the project, which one of the SPs failed. Three scenarios, along with corresponding checklists, were developed based on the usual medications of different diseases consisting of asthma, respiratory infections, and osteoporosis. The SPs' role-play performance was video-recorded and rated independently by two experts according to an observational rating scale to assess validity. The role-play was repeated after 1 week with the same scenario and the same doctor, to assess test-retest reliability. The inter-rater agreement between SPs and experts was determined by calculating the intraclass correlation coefficient and kappa coefficient. FINDINGS: The four eligible SPs were all women, with an average age of 37 years. The correlation between mean scores of raters and mean scores of SPs was 0.91 and 0.85, respectively. The Pearson's correlation between mean scores of raters with SPs was 0.75. The checklists' reliability, Cronbach's alpha, was calculated to be 0.72. The measured weighted Cohen's kappa for the ratings of by each SP, and the gold standard was between 0.53 and 0.57, indicating a moderate agreement. The inter-rater reliability kappa coefficient between raters was 0.75 (P = 0.01). CONCLUSION: The authors have demonstrated the technique of using standardized patients to evaluate communication and counseling skills of pharmacy students. The findings indicated that trained SPs can be used as an effective tool to assess pharmacy students' communication and counseling skills. PMID- 28616432 TI - Effect of Pretreatment with Omega-3 Supplement on Cardiac Necrosis Markers in Chronic Kidney Disease Patients Undergoing Elective Percutaneous Coronary Intervention. AB - OBJECTIVE: Studies have demonstrated the direct relation between elevation in cardiac necrosis markers and increased risk of cardiovascular complications after percutaneous coronary intervention (PCI) in chronic kidney disease (CKD) patients. In this study, we sought to evaluate the effect of omega-3 on creatine kinase-MB (CK-MB) and troponin-I in CKD patients undergoing elective PCI. METHODS: Eighty CKD patients, candidate for elective PCI, were randomly assigned into two groups: Group A - receiving omega-3 (2.5 g, 12 h before PCI) plus standard treatment (n = 37) and Group B - control group, receiving only standard therapy (aspirin 325 mg and clopidogrel 600 mg loading dose and weight-adjusted intravenous heparin) (n = 43). Blood samples were collected before and 24 h after PCI for measuring CK-MB and troponin-I. The primary endpoint was considered to be postprocedural variations of CK-MB and troponin-I levels in both groups. The secondary endpoint was the percentage of pre-procedural myocardial infarction (PMI) occurrence, defined as the elevation of post-PCI troponin-I, between study groups. FINDINGS: Both the baseline and 24-h CK-MB were significantly higher in omega-3 group. Although 24-h troponin-I increased less in omega-3-treated arm compared to the control group, no statistically significant variation was observed between the two groups. With regard to PMI occurrence, no significant difference was detected among study groups. CONCLUSION: Despite the beneficial but nonsignificant effects of omega-3 on decreasing post-PCI elevation of troponin-I and PMI occurrence, further investigations with bigger study population, higher doses of omega-3 and longer duration of treatment, and long term follow-up of patients are required to better test the potential effects of omega-3 in improving clinical outcomes in CKD patients undergoing PCI. PMID- 28616433 TI - Medication Errors in Patients with Enteral Feeding Tubes in the Intensive Care Unit. AB - OBJECTIVE: Most patients admitted to Intensive Care Units (ICU) have problems in using oral medication or ingesting solid forms of drugs. Selecting the most suitable dosage form in such patients is a challenge. The current study was conducted to assess the frequency and types of errors of oral medication administration in patients with enteral feeding tubes or suffering swallowing problems. METHODS: A cross-sectional study was performed in the ICU of Shahid Sadoughi Hospital, Yazd, Iran. Patients were assessed for the incidence and types of medication errors occurring in the process of preparation and administration of oral medicines. FINDINGS: Ninety-four patients were involved in this study and 10,250 administrations were observed. Totally, 4753 errors occurred among the studied patients. The most commonly used drugs were pantoprazole tablet, piracetam syrup, and losartan tablet. A total of 128 different types of drugs and nine different oral pharmaceutical preparations were prescribed for the patients. Forty-one (35.34%) out of 116 different solid drugs (except effervescent tablets and powders) could be substituted by liquid or injectable forms. The most common error was the wrong time of administration. Errors of wrong dose preparation and administration accounted for 24.04% and 25.31% of all errors, respectively. CONCLUSION: In this study, at least three-fourth of the patients experienced medication errors. The occurrence of these errors can greatly impair the quality of the patients' pharmacotherapy, and more attention should be paid to this issue. PMID- 28616434 TI - Developing an Economic Case of Clinical Pharmacists' Interventions on Venous Thromboembolism Prophylaxis Through Service Evaluation. AB - OBJECTIVE: Venous thromboembolism (VTE) has become a huge health problem as well as a financial burden for the National Health Service. The objective of this study was to characterize current practice of VTE prophylaxis (VTEP) and evaluate the economic impact of clinical pharmacists' interventions (CPIs) on VTEP. METHODS: A prospective service evaluation was conducted in a medical and surgical ward at a tertiary teaching hospital in London from 23 May to 08 June 2016. Appropriateness of risk assessment (RA) and VTEP and CPIs were categorized and assessed. Based on the results of the service evaluation, a pharmacoeconomic analysis was undertaken to estimate the cost savings by CPIs for inappropriate pharmacological VTEP. FINDINGS: A total of 203 cases were analyzed. The rates of appropriateness for RA on admission, RA at 24 h and pharmacological VTEP were 58.6%, 39.7%, and 75.4%, respectively. In the medical ward, there was a significant difference of appropriate RAs between on admission and at 24 h (70.3% vs. 23.8%, respectively). Whereas, the rate of appropriate pharmacological VTEP accounted for 75.4% and the rate of appropriate prophylaxis was significantly higher in the medical ward than surgical ward (80.5% vs. 68.2%, P = 0.045). Of 50 cases of inappropriate pharmacological prophylaxis, 39 cases (78.0%) were corrected by clinical pharmacists. These CPIs resulted in L1,286.23 cost savings during the study and it was estimated to be L517,522/annum. CONCLUSION: CPIs had significant positive clinical and economic impacts on VTEP. There is more scope for the improvement of RA at 24 h through CPIs. PMID- 28616435 TI - Impact of Pharmacist Intervention on Appropriate Insulin Pen Use in Older Patients with Type 2 Diabetes Mellitus in a Rural Area in Iran. AB - OBJECTIVE: The aim of this study was to evaluate the impact of pharmacist conducted educational intervention on reducing errors related to inappropriate insulin pen use. METHODS: This was a prospective, before-after study with an educational intervention component. The study was conducted on 122 elderly diabetic patients. Data were collected through interviews using researcher administered questionnaires as well as patients' medical records. Patients were asked about the preparation, injection, and storage techniques, they followed when using insulin pens. Blood glucose parameters were extracted from laboratory records. After the detection of errors, patients and their caregivers were instructed about the insulin pen use by the pharmacist. Patients were reevaluated after 12 weeks. FINDINGS: Patients' mean age was 67.2 +/- 3.5 with male: female ratio of 71:51. Mean diabetes duration was 7.1 +/- 2.8 years. Fifty-four patients (44.2%) stated that they had received instructions for insulin pen use previously. The majority of this group (24 cases, 44.4%) reported that the instructions were given by a pharmacist. The mean number of errors decreased from 3.99 +/- 0.22 errors per patient to 1.49 +/- 0.13 errors (odds ratio: 0.28, 95% confidence interval: 0.23-0.33,P < 0.05). Of eleven evaluated insulin pen-related medication error items, nine items experienced a significant decrease after patient education. Fasting plasma glucose (FPG) levels decreased significantly from 161.7 +/- 12.5 to 147.3 +/- 13.1 mg/dL (P < 0.05). However, glycated hemoglobin levels did not change significantly after 3 months (P = 0.18). Controlled FPG had a significant rise from 45% before education to 63.9% postintervention (P < 0.05). CONCLUSION: Pharmacists can play an important role in safe and efficient use of insulin pen in elderly diabetic patients by minimizing the likelihood of medication errors associated with insulin pen use. PMID- 28616436 TI - Initiatives to Reduce Nonprescription Sales and Dispensing of Antibiotics: Findings and Implications. AB - OBJECTIVE: Irrational use of antimicrobials is a major driver of antimicrobial resistance, exacerbated by dispensing antibiotics without a prescription. Our previous study suggested this was a problem in the Republic of Srpska despite legislation. Since then, a number of activities have been initiated. Consequently, the study aimed to ascertain whether these multiple initiatives had reduced this. METHODS: Patients visiting all community pharmacies in the Republic from October 2014 to July 2015 presenting with symptoms typical of an acute, viral, and mostly uncomplicated upper respiratory tract infection, with results compared to the previous study. If an antibiotic was suggested, the maximum allowance was ?3/pack. FINDINGS: Self-medication with antibiotics significantly decreased from 58% to 18.5% of pharmacies. In both studies, most patients were offered over-the-counter medication. The most common reason for not dispensing an antibiotic was "antibiotics can be dispensed with a prescription only." The penicillins were the most dispensed antibiotic. Fewer patients than the previous study were given instructions about antibiotic use and no discussion on their side effects. CONCLUSION: While encouraging that self-medication decreased significantly, 18.5% were disappointing given recent initiatives. Fewer instructions about antibiotics if an antibiotic was dispensed were also disappointing. This suggests the need for even stronger enforcement of the laws as well as further training of pharmacy personnel to ensure the future appropriate use of medicines. PMID- 28616437 TI - An Audit of Perioperative Antimicrobial Prophylaxis: Compliance with the International Guidelines. AB - OBJECTIVE: Antimicrobial prophylaxis has been demonstrated to lower the incidence of postoperative infection in nearly all types of surgery. The American Society of Health-System Pharmacists (ASHP) guideline summarizes current data on the appropriate use of antibiotic for surgical prophylaxis. The objective of this study was to assess and audit the use of antibiotics in a tertiary care center according to the recommendation of ASHP guideline. METHODS: This cross-sectional study was performed using prospective data gathered from April to September 2015 in the surgical wards of Al Zahra Hospital, Isfahan, Iran. Antibiotic indication and choice, dose, dosing interval, route of administration, and timing of first administration and duration of prophylaxis were compared with the ASHP guideline recommendations. FINDINGS: A total of 100 patients with the mean age of 49.8 +/- 18.2 years were recruited for this study. About 22% of procedures had full compliance with all guideline recommendations. The most frequently encounter noncompliance type were the duration of prophylaxis (14%) and appropriate agent choice (35%). Timing of the initial dose was appropriate in most of the procedures (42%). CONCLUSION: This study revealed that most of the prescribed antibiotics for surgical prophylaxis are not in accordance with standard treatment guideline. The density of antimicrobial use for preoperative antimicrobial prophylaxis is very high. Furthermore, the hospital should develop a formal strategy, including a local guideline for antimicrobial prophylaxis in surgical procedures. PMID- 28616438 TI - Drug Reaction with Eosinophilia and Systemic Symptom in a Patient with Pneumonia and Hyperthyroidism. AB - Drug rash with eosinophilia and systemic symptoms syndrome is an idiosyncratic drug reaction characterized by fever, skin eruption, lymph node enlargement, and internal organ involvement. We report a case of a patient with pneumonia who developed clinical manifestations of fever, rash, lymphadenopathy, hypereosinophilia, and visceral involvement (renal failure and eosinophilic pneumonitis) caused by methimazole. The patient improved remarkably with drug withdrawal. A high index of clinical suspicion is emphasized to facilitate prompt diagnosis of medication-related adverse effect and its discontinuation. PMID- 28616439 TI - Erratum: A Copmarative Review of Electronic Prescription Systems: Lessons Learned from Developed Countries. AB - [This corrects the article on p. 3 in vol. 6, PMID: 28331859.]. PMID- 28616440 TI - Cardiomyopathy Related to a Weight Loss Supplement: A Case Report and Review of Literature. AB - There are various etiologies of dilated cardiomyopathy. However, in young patients without a strong family history of cardiovascular disease, alcohol or drug abuse, viral infections, and absence of endocrine and metabolic abnormalities, ischemia is an unlikely cause. We present an interesting case of a young female without traditional risk factors who developed dilated cardiomyopathy following administration of a weight loss supplement xenadrine and had resolution of symptoms after discontinuation of the supplement. PMID- 28616441 TI - Is Firearm Threat in Intimate Relationships Associated with Posttraumatic Stress Disorder Symptoms Among Women? AB - In the context of intimate partner violence (IPV), firearms may be used to threaten, coerce, and intimidate. Yet, what little research exists on firearms among IPV victims has focused almost exclusively on homicide or near homicide. Thus, the deleterious health consequences of firearms more broadly remain unknown. The goals of the current study were (1) to document the prevalence of firearm threat in a community sample of female IPV victims, and (2) to identify the extent to which threat with a firearm, independent of other forms of IPV, is related to women's posttraumatic stress disorder (PTSD) symptom severity. Participants were 298 women who had been a victim in a criminal domestic violence case with a male intimate partner (Mage = 36.39 years; 50.0% African American; 51.3% unemployed). Retrospective data on firearm threat, fear of firearm violence, other IPV victimization (i.e., physical, psychological, and sexual), and PTSD symptoms were collected during in-person individual interviews. Approximately one-quarter of the sample (24.2%) experienced threat with a firearm during the course of their relationship, and 12.5% were afraid that their partners would use a firearm against them in the 30 days prior to the study interview. Firearm threat and fear of firearm violence emerged as significant and unique predictors of PTSD symptom severity, controlling for age and physical, psychological, and sexual IPV victimization severity. The findings underscore firearm threat as a key factor for identifying and intervening with criminal justice involved women who experience IPV. PMID- 28616442 TI - Human Coronavirus-HKU1 Infection Among Adults in Cleveland, Ohio. AB - BACKGROUND: Human coronaviruses (CoV) have been long recognized as a common cause of respiratory tract disease including severe respiratory tract illness. Coronavirus-HKU1 has been described predominantly among children less than 5 years of age in the United States with few studies characterizing the disease spectrum among adults. METHODS: Nasopharyngeal specimens of patients with respiratory symptoms were analyzed for CoV-HKU1 by NxTAG Respiratory Pathogen Panel multiplex assay from February 7, 2016 to April 30, 2016. Epidemiologic, clinical, and laboratory data were collected on adults (patients >18 years) whose samples screened positive. RESULTS: Of 832 adult respiratory specimens screened, 13 (1.6%) cases of CoV-HKU1 were identified. Adults age ranged between 23 and 75 years and 6 (46%) were males. All of whom had 1 or more respiratory symptoms, and 5 (38%) also reported 1 or more gastrointestinal symptoms. Eleven (85%) reported history of smoking and 5 (38%) used inhaled steroids. Seven (54%) required hospitalization, 5 (71%) of these needed supplemental oxygen, and 2 (29%) were admitted to intensive care. Median length of hospitalization was 5 days. Eight (62%) received antibiotics despite identification of CoV-HKU1. Infectious work-up in 1 patient who died did not reveal any other pathogen. In 2 (15%) CoV-HKU1 positive adults, the only viral coinfection detected was influenza A. CONCLUSIONS: Coronavirus-HKU1 accounted for 1.6% of adult respiratory infections and should be considered in differential diagnosis of severe respiratory illnesses among adults. PMID- 28616443 TI - Elevated Spontaneous Interferon-gamma Secretion in Human Immunodeficiency Virus Infected Persons. AB - Immune activation in human immunodeficiency virus (HIV) is a well described phenomenon. We found that HIV patients have higher secretion of interferon (IFN) gamma compared with non-HIV subjects, as measured by the "nil" value in the QuantiFERON-TB Gold test, even when viral loads are low. This may reflect ongoing immune activation, even with optimal HIV management. PMID- 28616445 TI - Nitroxide Labeling of Proteins and the Determination of Paramagnetic Relaxation Derived Distance Restraints for NMR Studies. AB - Site-specific attachment of paramagnetic spin labels to biomolecules causes distance-dependent line-broadening effects, which can be exploited to study the structure and dynamics of these molecules in solution. This protocol describes how to attach nitroxide spin labels to proteins and how to collect and analyze NMR data using these labeled samples. We also explain how to derive distance restraints for paramagnetic relaxation enhancement nuclear magnetic resonance (PRE-NMR) studies. PMID- 28616444 TI - Incidence of Hepatitis C Virus Infection in the Human Immunodeficiency Virus Outpatient Study Cohort, 2000-2013. AB - BACKGROUND: There are few recent studies of incident hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected patients in the United States. METHODS: We studied HIV Outpatient Study (HOPS) participants seen in 9 HIV-specialty clinics who had >=1 clinical encounter during 2000-2013 and >=2 HCV-related tests, the first of which was a negative HCV antibody test (Ab). Hepatitis C virus incident cases were identified by first positive HCV Ab, viral load, or genotype. We assessed rates of incident HCV overall, by calendar intervals, and by demographic and HIV risk strata, and we explored risk factors for incident HCV using Cox proportional hazards models. RESULTS: The 1941 eligible patients (median age 40 years, 23% female, 61% men who had sex with men [MSM], and 3% persons who injected drugs [PWID]) experienced 102 (5.3%) incident HCV infections for an overall incidence of 1.07 (95% confidence interval [CI], 0.87-1.30) per 100 person-years (py). Hepatitis C virus incidence decreased from 1.83 in 2000-2003 to 0.88 in 2011-2013 (P = .024), with decreases observed (P < .05) among PWID and heterosexuals, but not among MSM. Overall, MSM comprised 59% of incident cases, and PWID were at most risk for incident HCV infection (adjusted hazard ratio [aHR] for PWID = 4.62 and 95% CI = 2.11-10.13; for MSM, aHR = 1.48 and 95% CI = 0.86-2.55 compared with heterosexuals). CONCLUSIONS: Among HIV-infected patients in care during 2000-2013, incidence of HCV infection exceeded 1 case per 100 py. Our findings support recommendations for annual HCV screenings for HIV-infected persons, including persons with only MSM risk, to enable HCV diagnosis and treatment for coinfected individuals. PMID- 28616446 TI - Treatment with anti-FcepsilonRIalpha antibody exacerbates EAE and T-cell immunity against myelin. AB - OBJECTIVE: To investigate the effects of targeting the high-affinity receptor for immunoglobulin E (FcepsilonRI), that plays a central role in allergic responses and is constitutively expressed on mast cells and basophils, in clinical disease and autoimmune T-cell response in experimental MS. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein 35-55. Anti-FcepsilonRI alpha-chain antibody was administered intraperitoneally. CNS immunohistochemistry, flow cytometry analysis of immune cell populations, IgE and histamine serum concentration, immune cell proliferation, and cytokine measurement were performed. In BALB/c mice, EAE was induced by immunization with myelin proteolipid protein 185-206. RESULTS: Treatment with anti-FcepsilonRIalpha antibody resulted in exacerbation of EAE and increased CNS inflammation in C57BL/6 mice. Treated mice displayed long-lasting complete depletion of basophils in the blood stream and peripheral lymphoid organs and increased antigen-induced immune cell proliferation and production of interferon-gamma, interleukin (IL) 17, IL-6, and granulocyte-macrophage colony-stimulating factor. In BALB/c mice, which are T-helper (Th) 2 prone and resistant to EAE, treatment with anti FcepsilonRIalpha antibody restored susceptibility to EAE. CONCLUSION: Our observations that anti-FcepsilonRIalpha antibody increases Th1 and Th17 responses against myelin antigen and exacerbates EAE suggest that FcepsilonRI, basophils, and possibly other FcepsilonRI-bearing cells that might be affected by this antibody play important roles in influencing the severity of CNS autoimmunity. PMID- 28616447 TI - Natalizumab-PML survivors with subsequent MS treatment: Clinico-radiologic outcome. AB - OBJECTIVE: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving disease-modifying therapy (DMT). METHODS: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression. RESULTS: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up. CONCLUSION: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy. PMID- 28616448 TI - Adaptive statistical iterative reconstruction improves image quality without affecting perfusion CT quantitation in primary colorectal cancer. AB - OBJECTIVES: To determine the effect of Adaptive Statistical Iterative Reconstruction (ASIR) on perfusion CT (pCT) parameter quantitation and image quality in primary colorectal cancer. METHODS: Prospective observational study. Following institutional review board approval and informed consent, 32 patients with colorectal adenocarcinoma underwent pCT (100 kV, 150 mA, 120 s acquisition, axial mode). Tumour regional blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface area product (PS) were determined using identical regions-of-interests for ASIR percentages of 0%, 20%, 40%, 60%, 80% and 100%. Image noise, contrast-to-noise ratio (CNR) and pCT parameters were assessed across ASIR percentages. Coefficients of variation (CV), repeated measures analysis of variance (rANOVA) and Spearman' rank order correlation were performed with statistical significance at 5%. RESULTS: With increasing ASIR percentages, image noise decreased by 33% while CNR increased by 61%; peak tumour CNR was greater than 1.5 with 60% ASIR and above. Mean BF, BV, MTT and PS differed by less than 1.8%, 2.9%, 2.5% and 2.6% across ASIR percentages. CV were 4.9%, 4.2%, 3.3% and 7.9%; rANOVA P values: 0.85, 0.62, 0.02 and 0.81 respectively. CONCLUSIONS: ASIR improves image noise and CNR without altering pCT parameters substantially. PMID- 28616449 TI - Cyclic deformation and fatigue data for Ti-6Al-4V ELI under variable amplitude loading. AB - This article presents the strain-based experimental data for Ti-6Al-4V ELI under non-constant amplitude cyclic loading. Uniaxial strain-controlled fatigue experiments were conducted under three different loading conditions, including two-level block loading (i.e. high-low and low-high), periodic overload, and variable amplitude loading. Tests were performed under fully-reversed, and mean strain/stress conditions. For each test conducted, two sets of data were collected; the cyclic stress-strain response (i.e. hysteresis loops) in log10 increments, and the peak and valley values of stress and strain for each cycle. Residual fatigue lives are reported for tests with two-level block loading, while for periodic overload and variable amplitude experiments, fatigue lives are reported in terms of number of blocks to failure. PMID- 28616450 TI - Climate, weather, socio-economic and electricity usage data for the residential and commercial sectors in FL, U.S. AB - This paper presents the data that is used in the article entitled "Climate sensitivity of end-use electricity consumption in the built environment: An application to the state of Florida, United States" (Mukhopadhyay and Nateghi, 2017) [1]. The data described in this paper pertains to the state of Florida (during the period of January 1990 to November 2015). It can be classified into four categories of (i) state-level electricity consumption data; (ii) climate data; (iii) weather data; and (iv) socio-economic data. While, electricity consumption data and climate data are obtained at monthly scale directly from the source, the weather data was initially obtained at daily-level, and then aggregated to monthly level for the purpose of analysis. The time scale of socio economic data varies from monthly-level to yearly-level. This dataset can be used to analyze the influence of climate and weather on the electricity demand as described in Mukhopadhyay and Nateghi (2017) [1]. PMID- 28616451 TI - Dataset on potential large scale production of biosurfactant using Bacillus sp. AB - Surfactants are very important in industry. The cost of commercial surfactant production is still high and the surfactant demand is constantly increasing. Microbial production of surfactant known as biosurfactant shows commercial potency. Utilization of Bacillus sp. strain on glucose fermentation for biosurfactant production was then studied. This type of microbe was isolated from soil contaminated with palm oil. The selection of the strain was based on its ability to form emulsifying zone around the colony and its capability to grow compared with those for commercial bacteria of Bacillus pumilus JCM 2508. The results showed a potentially promising strain with high biosurfactant yields and low surface tension. For further scale-up development, the microbe performance in a fermentor was compared with those in a flask and a proposed model to predict the kinetic profiles of cell mass, biosurfactant and surface tension were also described. The data presented here are related to the research article entitled "Kinetic study and modeling of biosurfactant production using Bacillus sp." (Heryani and Putra, 2017) [1]. PMID- 28616452 TI - Datasets on the genomic positions of the MLL1 morphemes, the ZFP57 binding site, and ZFBS-Morph overlaps in the build mm9 of the mouse genome. AB - While MLL1 activates gene expression in most tissues, ZFP57 represses transcription. MLL1 selectively interacts with a group of nonmethylated DNA sequences known as the MLL1 morphemes. ZFP57 associates with a methylated hexamer (ZFBS), dispersed in the genomic DNA segments known as Imprinted Control Regions (ICRs) and germline Differentially Methylated Regions (gDMRs), to maintain allele specific gene repression. We have identified a set of composite DNA elements (ZFBS-Morph overlaps) that provides the sequence context of ZFBS in the canonical ICRs/gDMRs. This report provides tables listing the nucleotide sequences of the MLL1 morphemes and ZFBS-Morph overlaps. The report also offers links to the data repository at Purdue University, for downloading the positions of the MLL1 morphemes, the ZFP57 binding site, and the ZFBS-Morph overlaps in the mouse genome. PMID- 28616453 TI - Reproducibility discrepancies following reanalysis of raw data for a previously published study on diisononyl phthalate (DINP) in rats. AB - A 2011 publication by Boberg et al. entitled "Reproductive and behavioral effects of diisononyl phthalate (DINP) in perinatally exposed rats" [1] reported statistically significant changes in sperm parameters, testicular histopathology, anogenital distance and retained nipples in developing males. Using the statistical methods as reported by Boberg et al. (2011) [1], we reanalyzed the publically available raw data ([dataset] US EPA (United States Environmental Protection Agency), 2016) [2]. The output of our reanalysis and the discordances with the data as published in Boberg et al. (2011) [1] are highlighted herein. Further discussion of the basis for the replication discordances and the insufficiency of the Boberg et al. (2011) [1] response to address them can be found in a companion letter of correspondence (doi: 10.1016/j.reprotox.2017.03.013.; (Morfeld et al., 2011) [3]). PMID- 28616454 TI - Data on blueberry peroxidase kinetic characterization and stability towards thermal and high pressure processing. AB - The data presented in this article are related to a research article entitled 'Thermal and high pressure inactivation kinetics of blueberry peroxidase' (Terefe et al., 2017) [1]. In this article, we report original data on the activity of partially purified blueberry peroxidase at different concentrations of hydrogen peroxide and phenlylenediamine as substrates and the effects of thermal and high pressure processing on the activity of the enzyme. Data on the stability of the enzyme during thermal (at temperatures ranging from 40 to 80 degrees C) and combined thermal-high pressure processing (100-690 MPa, 30-90 degrees C) are included in this report. The data are presented in this format in order to facilitate comparison with data from other researchers and allow statistical analyses and modeling by others in the field. PMID- 28616455 TI - Ultra high-field (7 T) multi-resolution fMRI data for orientation decoding in visual cortex. AB - Multivariate pattern classification methods have been successfully applied to decode orientation of visual grating stimuli from BOLD fMRI activity recorded in human visual cortex (Kamitani and Tong, 2005; Haynes and Rees, 2005) [12], [10]. Though there has been extensive research investigating the true spatial scale of the orientation specific signals (Op de Beeck, 2010; Swisher et al., 2010; Alink et al., 2013; Freeman et al., 2011, 2013) [2], [15], [1], [4], [5], it remained inconclusive what spatial acquisition resolution is required, or is optimal, for decoding analyses. The research article entitled "The effect of acquisition resolution on orientation decoding from V1 BOLD fMRI at 7 T" Sengupta et al. (2017) [14] studied the effect of spatial acquisition resolution and also analyzed the strength and spatial scale of orientation discriminating signals. In this article, for the first time, we present empirical ultra high-field fMRI data, obtained as a part of the aforementioned study, which were recorded at four spatial resolutions (0.8 mm, 1.4 mm, 2 mm, and 3 mm isotropic voxel size) for orientation decoding in visual cortex. The dataset is compliant with the BIDS (Brain Imaging Data Structure) format, and freely available from the OpenfMRI portal (dataset accession number: http://openfmri.org/dataset/ds000113c ds000113c). PMID- 28616456 TI - Experimental data of deformation and cracking behaviour of concrete ties reinforced with multiple bars. AB - The data presented in this article are related to the research article entitled "Experimental Investigation of cracking and deformations of concrete ties reinforced with multiple bars" (Rimkus and Gribniak, 2017) [1]. The article provides data on deformation and cracking behaviour of 22 concrete ties reinforced with multiple bars. The number and diameter of the steel bars vary from 4 to 16 and from 5 mm to 14 mm, respectively. Two different covers (30 mm and 50 mm) are considered as well. The test recordings include average stains of the reinforcement and the concrete surface, the mean and maximum crack spacing, final crack patterns, and crack development schemes obtained using digital image correlation (DIC) system. The reported original data set is made publicity available for ensuring critical or extended analyses. PMID- 28616457 TI - Cervical cancer screening at a tertiary care center in Rwanda. AB - In limited resource settings such as Rwanda, visual inspection with acetic acid (VIA) is the primary model for cervical cancer screening. The objective of this study was to describe clinical characteristics and outcomes for women presenting for cervical cancer screening. A prospective, observational study was conducted between September 2015 and February 2016 at Kigali University Teaching Hospital (CHUK). Women referred to the VIA clinic were enrolled and completed a semi structured questionnaire. During the six-month study period, 150 women were enrolled and evaluated with VIA followed by colposcopy directed biopsy for VIA positive. The median age was 42 years (IQR 36-49). Only 20 (13.3%) asymptomatic women presented for screening exam, whereas 126 (84%) were symptomatic. Among symptomatic patients, more than one-third had never had a speculum exam prior to referral (n = 43). Twenty-two (14.7%) women were VIA positive, and 8 (5.3%) had lesions suspicious for cancer, while 120 (80%) were found to be VIA negative. Among women undergoing biopsy (n = 30), 11 were normal (36.7%), 5 cases showed CIN 1 (16.6%), 4 cases showed CIN 2 (13.3%), 2 cases showed CIN 3 (6.7%) and 8 were confirmed cervical cancers (26.7%). In Rwanda, VIA is the current method for cervical cancer screening. In this study, few asymptomatic patients presented for cervical cancer screening. Increasing knowledge about cervical cancer screening and expanding access are key elements to improving cervical cancer control in Rwanda. PMID- 28616458 TI - Malignant Brenner tumor associated with a germline BRCA2 mutation. AB - *The first woman with a Malignant Brenner tumor and a BRCA2 mutation is described.*Not all women with epithelial ovarian cancers are referred for genetic counseling.*Women should be referred for genetics regardless of how rare the histology. PMID- 28616459 TI - This could be the start of something big-20 years since the identification of bats as the natural host of Hendra virus. AB - Hendra virus was first described in 1994 in Australia, causally associated with a cluster of fatal equine and human cases at a thoroughbred racing stable in the Brisbane suburb of Hendra. This year marks the twentieth anniversary of the identification of pteropid bats (flying-foxes) as the natural host of the virus, and it is timely to reflect on a pivotal meeting of an eclectic group of scientists in that process. They included animal and public health experts, environmental scientists, veterinary and horse industry representatives, and wildlife experts. The task was to review and prioritise wildlife surveillance seeking the origin of the previously unknown virus. The group determined that the likely reservoir must occur in disparate locations, and be capable of moving between locations, or exist in continuous, overlapping populations spanning multiple locations. Flying-foxes were considered to be a more probable source of the novel virus than birds. Within weeks, antibodies were detected in several species of flying-fox, and the virus was subsequently isolated. While the identification of the natural host of Hendra virus within 18 months of its description was remarkable in itself, a broader legacy followed. In the subsequent years, a suite of zoonotic viruses including Australian bat lyssavirus, Nipah virus, SARS coronavirus, and Ebola and Marburg viruses have been detected in bats. Bats are now the "go to" taxa for novel viruses. History has repeatedly demonstrated that knowledge begets knowledge. This simple notion of bringing a diverse group of people together in an environment of mutual respect reinforced this principle and proves that the sum is often so much more powerful than the parts. PMID- 28616460 TI - Redefining disease emergence to improve prioritization and macro-ecological analyses. AB - Microbial infections are as old as the hosts they sicken, but interest in the emergence of pathogens and the diseases they cause has been accelerating rapidly. The term 'emerging infectious disease' was coined in the mid-1900s to describe changes in disease dynamics in the modern era. Both the term and the phenomena it is meant to characterize have evolved and diversified over time, leading to inconsistencies and confusion. Here, we review the evolution of the term 'emerging infectious disease' (EID) in the literature as applied to human hosts. We examine the pathways (e.g., speciation or strain differentiation in the causative agent vs. rapid geographic expansion of an existing pathogen) by which diseases emerge. We propose a new framework for disease and pathogen emergence to improve prioritization. And we illustrate how the operational definition of an EID affects conclusions concerning the pathways by which diseases emerge and the ecological and socioeconomic drivers that elicit emergence. As EIDs appear to be increasing globally, and resources for science level off or decline, the research community is pushed to prioritize its focus on the most threatening diseases, riskiest potential pathogens, and the places they occur. The working definition of emerging infectious diseases and pathogens plays a crucial role in prioritization, but we argue that the current definitions may be impeding these efforts. We propose a new framework for classifying pathogens and diseases as "emerging" that distinguishes EIDs from emerging pathogens and novel potential pathogens. We suggest prioritization of: 1) EIDs for adaptation and mitigation, 2) emerging pathogens for preventive measures, and 3) novel potential pathogens for intensive surveillance. PMID- 28616461 TI - Flying-foxes in the Australian urban environment-community attitudes and opinions. AB - The urban presence of flying-foxes (pteropid bats) in eastern Australia has increased in the last 20 years, putatively reflecting broader landscape change. The influx of large numbers often precipitates community angst, typically stemming from concerns about loss of social amenity, economic loss or negative health impacts from recently emerged bat-mediated zoonotic diseases such as Hendra virus and Australian bat lyssavirus. Local authorities and state wildlife authorities are increasingly asked to approve the dispersal or modification of flying-fox roosts to address expressed concerns, yet the scale of this concern within the community, and the veracity of the basis for concern are often unclear. We conducted an on-line survey to capture community attitudes and opinions on flying-foxes in the urban environment to inform management policy and decision-making. Analysis focused on awareness, concerns, and management options, and primarily compared responses from communities where flying-fox management was and was not topical at the time of the survey. While a majority of respondents indicated a moderate to high level of knowledge of both flying-foxes and Hendra virus, a substantial minority mistakenly believed that flying-foxes pose a direct infection risk to humans, suggesting miscommunication or misinformation, and the need for additional risk communication strategies. Secondly, a minority of community members indicated they were directly impacted by urban roosts, most plausibly those living in close proximity to the roost, suggesting that targeted management options are warranted. Thirdly, neither dispersal nor culling was seen as an appropriate management strategy by the majority of respondents, including those from postcodes where flying-fox management was topical. These findings usefully inform community debate and policy development and demonstrate the value of social analysis in defining the issues and options in this complex human wildlife interaction. The mobile nature of flying-foxes underlines the need for a management strategy at a regional or larger scale, and independent of state borders. PMID- 28616462 TI - Comparative Usutu and West Nile virus transmission potential by local Culex pipiens mosquitoes in north-western Europe. AB - Originating from Africa, Usutu virus (USUV) first emerged in Europe in 2001. This mosquito-borne flavivirus caused high mortality rates in its bird reservoirs, which strongly resembled the introduction of West Nile virus (WNV) in 1999 in the United States. Mosquitoes infected with USUV incidentally transmit the virus to other vertebrates, including humans, which can result in neuroinvasive disease. USUV and WNV co-circulate in parts of southern Europe, but the distribution of USUV extends into central and northwestern Europe. In the field, both viruses have been detected in the northern house mosquito Culex pipiens, of which the potential for USUV transmission is unknown. To understand the transmission dynamics and assess the potential spread of USUV, we determined the vector competence of C. pipiens for USUV and compared it with the well characterized WNV. We show for the first time that northwestern European mosquitoes are highly effective vectors for USUV, with infection rates of 11% at 18 degrees C and 53% at 23 degrees C, which are comparable with values obtained for WNV. Interestingly, at a high temperature of 28 degrees C, mosquitoes became more effectively infected with USUV (90%) than with WNV (58%), which could be attributed to barriers in the mosquito midgut. Small RNA deep sequencing of infected mosquitoes showed for both viruses a strong bias for 21-nucleotide small interfering (si)RNAs, which map across the entire viral genome both on the sense and antisense strand. No evidence for viral PIWI-associated RNA (piRNA) was found, suggesting that the siRNA pathway is the major small RNA pathway that targets USUV and WNV infection in C. pipiens mosquitoes. PMID- 28616463 TI - Sentinel California sea lions provide insight into legacy organochlorine exposure trends and their association with cancer and infectious disease. AB - BACKGROUND: Organochlorine contaminants (OCs), like polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethanes (DDTs), are widespread marine pollutants resulting from massive historical use and environmental persistence. Exposure to and health effects of these OCs in the marine environment may be examined by studying California sea lions (Zalophus californianus), which are long lived, apex predators capable of accumulating OCs. METHODS: We evaluated PCB and DDT levels in 310 sea lions sampled between 1992 and 2007: 204 individuals stranded along the coast of central California, 60 healthy males from Washington State, and 46 healthy females from southern California. Lipid-normalized contaminant concentrations were analyzed using general linear models and logistic regression to ascertain temporal trends; differences between stranded and healthy sea lions; and association of organochlorines with sex, age, and presence of cancer or fatal infectious disease. RESULTS: Concentrations of the contaminants in stranded adults decreased over time in the study period (adjusted for sex, as adult males had higher mean blubber concentrations than adult females and juveniles). Cancer was almost eight and six times more likely in animals with higher summed PCBs and DDTs, compared to those with lower levels (95% CI 5.55 10.51 and 4.54-7.99, respectively). Fatal infectious diseases were similarly seven and five times more likely in animals with higher contaminant burdens (95% CI 4.20-10.89 and 3.27-7.86, respectively). Mean contaminant loads were significantly higher in stranded sea lions than in healthy live captured animals (p < 0.001). CONCLUSION: Organochlorine contamination has significant associations with health outcomes in California sea lions, raising concerns for humans and other animals eating tainted seafood. While environmental exposure to these organochlorines appears to be decreasing over time based on levels in sea lion tissues, their persistence in the environment and food web for all predators, including humans, and the associated serious health risks, warrant monitoring, possibly through sentinel species like marine mammals. PMID- 28616464 TI - A framework to promote collective action within the One Health community of practice: Using participatory modelling to enable interdisciplinary, cross sectoral and multi-level integration. AB - As Southeast Asia (SEA) is characterized by high human and domestic animal densities, growing intensification of trade, drastic land use changes and biodiversity erosion, this region appears to be a hotspot to study complex dynamics of zoonoses emergence and health issues at the Animal-Human-Environment interface. Zoonotic diseases and environmental health issues can have devastating socioeconomic and wellbeing impacts. Assessing and managing the related risks implies to take into account ecological and social dynamics at play, in link with epidemiological patterns. The implementation of a One Health (OH) approach in this context calls for improved integration among disciplines and improved cross sectoral collaboration, involving stakeholders at different levels. For sure, such integration is not achieved spontaneously, implies methodological guidelines and has transaction costs. We explore pathways for implementing such collaboration in SEA context, highlighting the main challenges to be faced by researchers and other target groups involved in OH actions. On this basis, we propose a conceptual framework of OH integration. Throughout 3 components (field based data management, professional training workshops and higher education), we suggest to develop a new culture of networking involving actors from various disciplines, sectors and levels (from the municipality to the Ministries) through a participatory modelling process, fostering synergies and cooperation. This framework could stimulate long-term dialogue process, based on the combination of case studies implementation and capacity building. It aims for implementing both institutional OH dynamics (multi-stakeholders and cross-sectoral) and research approaches promoting systems thinking and involving social sciences to follow-up and strengthen collective action. PMID- 28616465 TI - Cross-species transmission of canine distemper virus-an update. AB - Canine distemper virus (CDV) is a pantropic morbillivirus with a worldwide distribution, which causes fatal disease in dogs. Affected animals develop dyspnea, diarrhea, neurological signs and profound immunosuppression. Systemic CDV infection, resembling distemper in domestic dogs, can be found also in wild canids (e.g. wolves, foxes), procyonids (e.g. raccoons, kinkajous), ailurids (e.g. red pandas), ursids (e.g. black bears, giant pandas), mustelids (e.g. ferrets, minks), viverrids (e.g. civets, genets), hyaenids (e.g. spotted hyenas), and large felids (e.g. lions, tigers). Furthermore, besides infection with the closely related phocine distemper virus, seals can become infected by CDV. In some CDV outbreaks including the mass mortalities among Baikal and Caspian seals and large felids in the Serengeti Park, terrestrial carnivores including dogs and wolves have been suspected as vectors for the infectious agent. In addition, lethal infections have been described in non-carnivore species such as peccaries and non-human primates demonstrating the remarkable ability of the pathogen to cross species barriers. Mutations affecting the CDV H protein required for virus attachment to host-cell receptors are associated with virulence and disease emergence in novel host species. The broad and expanding host range of CDV and its maintenance within wildlife reservoir hosts considerably hampers disease eradication. PMID- 28616466 TI - Modeling the burden of poultry disease on the rural poor in Madagascar. AB - Livestock represent a fundamental economic and nutritional resource for many households in the developing world; however, a high burden of infectious disease limits their production potential. Here we present an ecological framework for estimating the burden of poultry disease based on coupled models of infectious disease and economics. The framework is novel, as it values humans and livestock as co-contributors to household wellbeing, incorporating feedbacks between poultry production and human capital in disease burden estimates. We parameterize this coupled ecological-economic model with household-level data to provide an estimate of the overall burden of poultry disease for the Ifanadiana District in Madagascar, where over 72% of households rely on poultry for economic and food security. Our models indicate that households may lose 10-25% of their monthly income under current disease conditions. Results suggest that advancements in poultry health may serve to support income generation through improvements in both human and animal health. PMID- 28616467 TI - Primate malarias: Diversity, distribution and insights for zoonotic Plasmodium. AB - Protozoans within the genus Plasmodium are well-known as the causative agents of malaria in humans. Numerous Plasmodium species parasites also infect a wide range of non-human primate hosts in tropical and sub-tropical regions worldwide. Studying this diversity can provide critical insight into our understanding of human malarias, as several human malaria species are a result of host switches from non-human primates. Current spillover of a monkey malaria, Plasmodium knowlesi, in Southeast Asia highlights the permeability of species barriers in Plasmodium. Also recently, surveys of apes in Africa uncovered a previously undescribed diversity of Plasmodium in chimpanzees and gorillas. Therefore, we carried out a meta-analysis to quantify the global distribution, host range, and diversity of known non-human primate malaria species. We used published records of Plasmodium parasites found in non-human primates to estimate the total diversity of non-human primate malarias globally. We estimate that at least three undescribed primate malaria species exist in sampled primates, and many more likely exist in unstudied species. The diversity of malaria parasites is especially uncertain in regions of low sampling such as Madagascar, and taxonomic groups such as African Old World Monkeys and gibbons. Presence-absence data of malaria across primates enables us to highlight the close association of forested regions and non-human primate malarias. This distribution potentially reflects a long coevolution of primates, forest-adapted mosquitoes, and malaria parasites. The diversity and distribution of primate malaria are an essential prerequisite to understanding the mechanisms and circumstances that allow Plasmodium to jump species barriers, both in the evolution of malaria parasites and current cases of spillover into humans. PMID- 28616468 TI - Absence of MERS-CoV antibodies in feral camels in Australia: Implications for the pathogen's origin and spread. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) infections continue to be a serious emerging disease problem internationally with well over 1000 cases and a major outbreak outside of the Middle East region. While the hypothesis that dromedary camels are the likely major source of MERS-CoV infection in humans is gaining acceptance, conjecture continues over the original natural reservoir host(s) and specifically the role of bats in the emergence of the virus. Dromedary camels were imported to Australia, principally between 1880 and 1907 and have since become a large feral population inhabiting extensive parts of the continent. Here we report that during a focussed surveillance study, no serological evidence was found for the presence of MERS-CoV in the camels in the Australian population. This finding presents various hypotheses about the timing of the emergence and spread of MERS-CoV throughout populations of camels in Africa and Asia, which can be partially resolved by testing sera from camels from the original source region, which we have inferred was mainly northwestern Pakistan. In addition, we identify bat species which overlap (or neighbour) the range of the Australian camel population with a higher likelihood of carrying CoVs of the same lineage as MERS-CoV. Both of these proposed follow-on studies are examples of "proactive surveillance", a concept that has particular relevance to a One Health approach to emerging zoonotic diseases with a complex epidemiology and aetiology. PMID- 28616469 TI - Periodic global One Health threats update. AB - Emerging infectious diseases continue to impose unpredictable burdens on global health and economy. Infectious disease surveillance and pandemic preparedness are essential to mitigate the impact of future threats. Global surveillance networks provide unprecedented monitoring data on plant, animal and human infectious diseases. Using such sources, we report on current major One Health threats and update on their epidemiological status. PMID- 28616470 TI - Global Solutions to Regional Challenges: Bridging the One Health Divide in the Caribbean. AB - Ross University School of Veterinary Medicine, located on the Caribbean island of St. Kitts in the West Indies, hosted a multi-national, transdisciplinary One Health conference in St. Kitts and Nevis. Historically the many countries of the Caribbean carry a high burden of chronic and infectious disease and struggle with complex economic and developmental issues that continuously pressurize inhabitants and their natural environment. Considering these vast regional challenges, presentations covered diverse topics including community-based approaches for zoonotic disease control and prevention and mitigation of problems at the interface of wildlife, domestic animals, and humans. In two workshops the participants suggested a framework for practicing One Health in the Caribbean that emphasized capacity building and sustainability. Four structural components to the One Health paradigm were discussed including: identification of common problems, the necessity of comprehensive needs assessment, regional mobilization of resources, and building trust among all One Health stakeholders and the public. PMID- 28616472 TI - The 'One Health' journal: Filling a niche. PMID- 28616471 TI - Methicillin-resistant Staphylococcus aureus from infections in horses in Germany are frequent colonizers of veterinarians but rare among MRSA from infections in humans. AB - A total of 272 methicillin-resistant Staphylococcus aureus (MRSA) from equine infections originating from 17 equine hospitals and 39 veterinary practices in Germany as well as 67 isolates from personnel working at equine clinics were subjected to molecular typing. The majority of isolates from horses was attributed to clonal complex (CC) 398 (82.7%). Within CC398, 66% of isolates belonged to a subpopulation (clade) of CC398, which is associated with equine clinics. MRSA attributed to CC8 (ST254, t009, t036, SCCmecIV; ST8, t064, SCCmecIV) were less frequent (16.5%). Single isolates were attributed to ST1, CC22, ST130, and ST1660. The emergence of MRSA CC22 and ST130 in horses was not reported so far. Nasal MRSA colonization was found in 19.5% of veterinary personnel with occupational exposure to horses. The typing characteristics of these isolates corresponded to isolates from equine infections. Comparing typing characteristics of equine isolates with those of a substantial number of isolates from human infections typed at the German Reference Center for Staphylococci and Enterococci (2006-2014; n = 10864) yielded that the proportion of isolates exhibiting characteristics of MRSA from equine medicine is very low (< 0.5%). As this low proportion was also found among MRSA originating from nasal screenings of human carriers not suffering from a staphylococcal infection (n = 5546) transmission of MRSA from equine clinics to the community seems to be rare so far. PMID- 28616473 TI - Ten years of the Tiger: Aedes albopictus presence in Australia since its discovery in the Torres Strait in 2005. AB - The "Asian tiger mosquito", Aedes albopictus, is highly invasive, an aggressive biter and a major arbovirus vector. It is not currently present on mainland Australia despite being intercepted on numerous occasions at international ports and infesting the Torres Strait of Australia since at least 2004. In the current paper, we describe the invasion and current status of Ae. albopictus in the Torres Strait, as well as research conducted to assess the threat of this species becoming established in arbovirus transmission cycles on the Australian mainland. Genetic analysis of the invading population demonstrated that the Indonesian region was the likely origin of the invasion and not Papua New Guinea (PNG) as initially suspected. There was also intermixing between Torres Strait, PNG and Indonesian populations, indicating that the species could be re-introduced into the Torres Strait compromising any successful eradication programme. Vector competence experiments with endemic and exotic viruses revealed that Ae. albopictus from the Torres Strait are efficient alphavirus vectors, but less efficient flavivirus vectors. Ae.albopictus obtains blood meals from a range of vertebrate hosts (including humans), indicating that it could play a role in both zoonotic and human-mosquito arbovirus transmission cycles in Australia. Predictive models coupled with climate tolerance experiments suggest that a Torres Strait strain of Ae. albopictus could colonise southern Australia by overwintering in the egg stage before proliferating in the warmer months. Cohabitation experiments demonstrated that the presence of Aedes notoscriptus larvae in containers would not prevent the establishment of Ae. albopictus. Evidence from these studies, coupled with global experience suggests that we need to be prepared for the imminent invasion of Australia by Ae. albopictus by thoroughly understanding its biology and being willing to embrace emerging control technologies. PMID- 28616474 TI - Serological tools for detection of Trichinella infection in animals and humans. AB - Trichinellosis is a serious foodborne zoonotic disease. It is an important threat to public health in both developing and developed countries. Human infections are strongly associated with consuming undercooked meat containing infective Trichinella larvae. The development of serological tools has enabled seroepidemiological studies and contributed to our knowledge on the importance of this parasite. Serological tests can also help the diagnosis of parasite infections in humans and the surveillance of animals. Generally speaking, serological techniques include detection methods for specific antibodies and for circulating parasite antigens in the serum or tissue fluids. Here, we present a comprehensive review of various methods used in the detection of antibodies against Trichinella and circulating parasite antigens in animals and humans. PMID- 28616475 TI - Clonal diversity of methicillin-sensitive Staphylococcus aureus from South Australian wallabies. AB - Seven methicillin-sensitive Staphylococcus aureus nasal isolates from apparently healthy captive and wild wallabies were characterised by DNA microarray and antibiotic susceptibility assays. Isolates were found to belong to uncommon clonal complexes including those previously associated with birds, pigs and humans. PMID- 28616476 TI - Proteobacteria from the human skin microbiota: Species-level diversity and hypotheses. AB - The human skin microbiota is quantitatively dominated by Gram-positive bacteria, detected by both culture and metagenomics. However, metagenomics revealed a huge variety of Gram-negative taxa generally considered from environmental origin. For species affiliation of bacteria in skin microbiota, clones of 16S rRNA gene and colonies growing on diverse culture media were analyzed. Species-level identification was achieved for 81% of both clones and colonies. Fifty species distributed in 26 genera were identified by culture, mostly belonging to Actinobacteria and Firmicutes, while 45 species-level operational taxonomic units distributed in 30 genera were detected by sequencing, with a high diversity of Proteobacteria. This mixed approach allowed the detection of 100% of the genera forming the known core skin Gram-negative microbiota and 43% of the known diversity of Gram-negative genera in human skin. The orphan genera represented 50% of the current skin pan-microbiota. Improved culture conditions allowed the isolation of Roseomonas mucosa, Aurantimonas altamirensis and Agrobacterium tumefaciens strains from healthy skin. For proteobacterial species previously described in the environment, we proposed the existence of skin-specific ecotypes, which might play a role in the fine-tuning of skin homeostasis and opportunistic infections but also act as a shuttle between environmental and human microbial communities. Therefore, skin-associated proteobacteria deserve to be considered in the One-Health concept connecting human health to the health of animals and the environment. PMID- 28616477 TI - Is there a Lyme-like disease in Australia? Summary of the findings to date. AB - Lyme Borreliosis is a common tick-borne disease of the northern hemisphere caused by the spirochaetes of the Borrelia burgdorferi sensu lato (B. burgdorferi s. l.) complex. It results in multi-organ disease with arthritic, cardiac, neurological and dermatological manifestations. In the last twenty-five years there have been over 500 reports of an Australian Lyme-like syndrome in the scientific literature. However, the diagnoses of Lyme Borreliosis made in these cases have been primarily by clinical presentation and laboratory results of tentative reliability and the true cause of these illnesses remains unknown. A number of animals have been introduced to Australia that may act as B. burgdorferi s. l. reservoirs in Lyme-endemic countries, and there are some Australian Ixodes spp. and Haemaphysalis spp. ticks whose geographical distribution matches that of the Australian Lyme-like cases. Four published studies have searched for Borrelia in Australian ticks, with contradicting results. The cause of the potential Lyme like disease in Australia remains to be defined. The evidence to date as to whether these illnesses are caused by a Borrelia species, another tick borne pathogen or are due to a novel or unrelated aetiology is summarised in this review. PMID- 28616478 TI - Human-livestock contacts and their relationship to transmission of zoonotic pathogens, a systematic review of literature. AB - BACKGROUND: Micro-organisms transmitted from vertebrate animals - including livestock - to humans account for an estimated 60% of human pathogens. Micro organisms can be transmitted through inhalation, ingestion, via conjunctiva or physical contact. Close contact with animals is crucial for transmission. The role of intensity and type of contact patterns between livestock and humans for disease transmission is poorly understood. In this systematic review we aimed to summarise current knowledge regarding patterns of human-livestock contacts and their role in micro-organism transmission. METHODS: We included peer-reviewed publications published between 1996 and 2014 in our systematic review if they reported on human-livestock contacts, human cases of livestock-related zoonotic diseases or serological epidemiology of zoonotic diseases in human samples. We extracted any information pertaining the type and intensity of human-livestock contacts and associated zoonoses. RESULTS: 1522 papers were identified, 75 were included: 7 reported on incidental zoonoses after brief animal-human contacts (e.g. farm visits), 10 on environmental exposures and 15 on zoonoses in developing countries where backyard livestock keeping is still customary. 43 studies reported zoonotic risks in different occupations. Occupations at risk included veterinarians, culling personnel, slaughterhouse workers and farmers. For culling personnel, more hours exposed to livestock resulted in more frequent occurrence of transmission. Slaughterhouse workers in contact with live animals were more often positive for zoonotic micro-organisms compared to co-workers only exposed to carcasses. Overall, little information was available about the actual mode of micro-organism transmission. CONCLUSIONS: Little is known about the intensity and type of contact patterns between livestock and humans that result in micro-organism transmission. Studies performed in occupational settings provide some, but limited evidence of exposure response-like relationships for livestock-human contact and micro-organism transmission. Better understanding of contact patterns driving micro-organism transmission from animals to humans is needed to provide options for prevention and thus deserves more attention. PMID- 28616479 TI - Human Q fever incidence is associated to spatiotemporal environmental conditions. AB - Airborne pathogenic transmission from sources to humans is characterised by atmospheric dispersion and influence of environmental conditions on deposition and reaerosolisation. We applied a One Health approach using human, veterinary and environmental data regarding the 2009 epidemic in The Netherlands, and investigated whether observed human Q fever incidence rates were correlated to environmental risk factors. We identified 158 putative sources (dairy goat and sheep farms) and included 2339 human cases. We performed a high-resolution (1 * 1 km) zero-inflated regression analysis to predict incidence rates by Coxiella burnetii concentration (using an atmospheric dispersion model and meteorological data), and environmental factors - including vegetation density, soil moisture, soil erosion sensitivity, and land use data - at a yearly and monthly time resolution. With respect to the annual data, airborne concentration was the most important predictor variable (positively correlated to incidence rate), followed by vegetation density (negatively). The other variables were also important, but to a less extent. High erosion sensitive soils and the land-use fractions "city" and "forest" were positively correlated. Soil moisture and land-use "open nature" were negatively associated. The geographical prediction map identified the largest Q fever outbreak areas. The hazard map identified highest hazards in a livestock dense area. We conclude that environmental conditions are correlated to human Q fever incidence rate. Similar research with data from other outbreaks would be needed to more firmly establish our findings. This could lead to better estimations of the public health risk of a C. burnetii outbreak, and to more detailed and accurate hazard maps that could be used for spatial planning of livestock operations. PMID- 28616481 TI - Evidence of exposure to Rickettsia felis in Australian patients. AB - Rickettsia felis is an emerging zoonosis, causing flea-borne spotted fever (FBSF). Serological diagnosis is typically confounded by cross-reactivity with typhus group rickettsiae and prior to the development of specific serological methods, cases of FBSF in Australia were misdiagnosed. Patient sera tested between August 2010 and December 2013 and known to be seropositive to R. typhi by immunofluorescence antibody testing (IFAT) were subsequently retested against R. felis using an R. felis-specific IFAT. Sera of 49 patients were of a sufficient quality to be included in re-analysis. A classification of FBSF and murine typhus (MT) was attributed to fourteen and seven patients respectively, based on a minimum four-fold higher antibody titre to R. felis than to R. typhi and vice versa. Twenty-eight patients were classified as indeterminate for either R. felis or R. typhi (antibody titres within two-fold of one another). Historically, it is likely that Australian patients clinically ill with FBSF were misdiagnosed. It is important that medical practitioners consider FBSF as part of their differential diagnoses, and obtain relevant history with regard to patient's exposure to domestic pets and their fleas. Australian microbiology diagnostic laboratories should include serological testing for R. felis as part of the diagnostic panel for febrile diseases. Veterinarians are encouraged to increase their awareness of this emerging zoonosis and advocate flea control in pets. PMID- 28616480 TI - Culex pipiens and Culex torrentium populations from Central Europe are susceptible to West Nile virus infection. AB - West Nile virus (WNV), a Flavivirus with an avian primary host, is already widespread in Europe and might also pose an infection risk to Germany, should competent mosquito vectors be present. Therefore, we analysed the ability of WNV to infect German Culex mosquitoes with special emphasis on field collected specimens of Culex torrentium and Culex pipiens biotype pipiens. We collected egg rafts of Culex mosquitoes over two subsequent seasons at two geographically distinct sampling areas in Germany and differentiated the samples by molecular methods. Adult females, reared from the various egg rafts, were challenged with WNV by feeding of artificial blood meals. WNV infection was confirmed by real time RT-PCR and virus titration. The results showed that field collected C. pipiens biotype pipiens and C. torrentium mosquitoes native to Germany are susceptible to WNV infection at 25 degrees C as well as 18 degrees C incubation temperature. C. torrentium mosquitoes, which have not been established as WNV vector so far, were the most permissive species tested with maximum infection rates of 96% at 25 degrees C. Furthermore, a disseminating infection was found in up to 94% of tested C. pipiens biotype pipiens and 100% of C. torrentium. Considering geographical variation of susceptibility, C. pipiens biotype pipiens mosquitoes from Southern Germany were more susceptible to WNV infection than corresponding populations from Northern Germany. All in all, we observed high infection and dissemination rates even at a low average ambient temperature of 18 degrees C. The high susceptibility of German Culex populations for WNV indicates that an enzootic transmission cycle in Germany could be possible. PMID- 28616482 TI - A brief historical overview of emerging infectious disease response in China and the need for a One Health approach in future responses. PMID- 28616483 TI - The control of East Coast fever of cattle by live parasite vaccination: A science to-impact narrative. AB - There is an increasing interest in determining the impact of vaccine technologies developed using public funding targeted at international development, and understanding the factors and ingredients which contribute to the success and impacts of such vaccines. This paper chronicles the development of a live vaccine against East Coast fever, a tick-borne disease of cattle caused by Theileria parva. The paper describes the technological innovation, commonly known as infection-and-treatment, which was developed some 40 years ago, explores the institutional settings in which the vaccine was developed and refined, and discusses the political dynamics of both during the decades from first development to field deployment and impacts. The paper also analyses the direct and indirect indicators of success of ITM and the many qualifiers of these, the impacts that the emerging technology has had, both in positive and negative terms, and maps the key contributors and milestones on the research-to-impact pathway. PMID- 28616484 TI - Climatic suitability influences species specific abundance patterns of Australian flying foxes and risk of Hendra virus spillover. AB - Hendra virus is a paramyxovirus of Australian flying fox bats. It was first detected in August 1994, after the death of 20 horses and one human. Since then it has occurred regularly within a portion of the geographical distribution of all Australian flying fox (fruit bat) species. There is, however, little understanding about which species are most likely responsible for spillover, or why spillover does not occur in other areas occupied by reservoir and spillover hosts. Using ecological niche models of the four flying fox species we were able to identify which species are most likely linked to spillover events using the concept of distance to the niche centroid of each species. With this novel approach we found that 20 out of 27 events occur disproportionately closer to the niche centroid of two species (P. alecto and P. conspicillatus). With linear regressions we found a negative relationship between distance to the niche centroid and abundance of these two species. Thus, we suggest that the bioclimatic niche of these two species is likely driving the spatial pattern of spillover of Hendra virus into horses and ultimately humans. PMID- 28616485 TI - Evidence of canine parvovirus transmission to a civet cat (Paradoxurus musangus) in Singapore. AB - Cross-species transmission can often lead to deleterious effects in incidental hosts. Parvoviruses have a wide host range and primarily infect members of the order Carnivora. Here we describe juvenile common palm civet cats (Paradoxurus musangus) that were brought to the Singapore zoo and fell ill while quarantined. The tissues of two individual civets that died tested PCR-positive for parvovirus infection. Phylogenetic analysis revealed this parvovirus strain falls in a basal position to a clade of CPV that have infected dogs in China and Uruguay, suggesting cross-species transmission from domestic to wild animals. Our analysis further identified these viruses as genotype CPV-2a that is enzootic in carnivores. The ubiquity of virus infection in multiple tissues suggests this virus is pathogenic to civet cats. Here we document the cross-species transmission from domestic dogs and cats to wild civet populations, highlighting the vulnerability of wildlife to infectious agents in companion animals. PMID- 28616486 TI - Goat farm management and Brucella serological test among goat keepers and livestock officers, 2011-2012, Nakhon Si Thammarat Province, southern Thailand. AB - Brucellosis, a zoonotic disease particularly affecting goats, emerged in Thailand in 2003, resulting in both an occupational hazard for goat keepers and livestock officers, and production losses. Farm management practices have been identified as risk factors associated with Brucella sero-positivity in many studies. Our finding in this study should be considered in order to strengthen the system of biosecurity control in farm animals as one health approach. The objectives of the study were to describe the distribution of potential risk factors by types of goat farms and to document the prevalence of human Brucella sero-positivity among goat keepers and livestock officers in Nakhon Si Thammarat, Thailand. A cross sectional study was conducted from September to December 2012. The study population included three types of goat farms: standard, community enterprise and private goat farms that were located in Nakhon Si Thammmarat Province in southern Thailand. Information on whether the farm had any Brucella sero-positivity goats since 2011 was retrieved from the local livestock office records. Information on farming management was also traced back to 2011. Field researchers collected information from goat keepers of the selected farms using a structured questionnaire. Goat keepers on all farms pre-identified (January to June 2012) as having had at least one positive goat were considered to have been exposed. Goat keepers on a random sample of farms having all goats with negative results were considered to be unexposed. Venous blood samples were collected from goat keepers exposed and unexposed and from livestock officers and the samples were tested by IgG ELISA. Statistical analysis was done under the complex survey design in R software. Fourteen standard farms, 66 community enterprise farms and 68 private farms participated in the study; 82.4% (122/148) used public pasture and 53.4% (79/148) shared breeder goats with other farms. Farm management practices corresponding to pre-identified risk factors were more common in private farms. Large herd size (>= 51 goats) and having dogs and/or rats on the farm were significantly associated with Brucella infection in animals (P < 0.05). Similar proportions of goat keepers in positive goat farm and livestock officers were positive for Brucella antibody (8.3% and 8.8% respectively). Several goat farming management practices in the study area may increase the risk of Brucella infection in animals. Livestock officers in the area have a high risk of being infected with Brucella. Improving goat farm biosecurity practices in needed to reduce the risk of brucellosis in this area. PMID- 28616487 TI - Wild snakes harbor West Nile virus. AB - West Nile virus (WNV) has a complex eco-epidemiology with birds acting as reservoirs and hosts for the virus. Less well understood is the role of reptiles, especially in wild populations. The goal of our study was to determine whether a wild population of snakes in Pennsylvania harbored WNV. Six species of snakes were orally sampled in the summer of 2013 and were tested for the presence of WNV viral RNA using RT-PCR. Two Eastern Garter Snakes, Thamnophis sirtalis sirtalis tested positive for viral RNA (2/123, 1.62%). These results indicate a possible role for snakes in the complex transmission cycle of WNV. PMID- 28616488 TI - Building bridges to operationalise one health - A Sino-Swedish collaboration to tackle antibiotic resistance. AB - Antibiotic resistance is a complex global health challenge. The recent Global Action Plan on antimicrobial resistance highlights the importance of adopting One Health approaches that can cross traditional disciplinary boundaries. We report on the early experiences of a multisectoral Sino-Swedish research project that aims to address gaps in our current knowledge and seeks to improve the situation through system-wide interventions. Our research project is investigating antibiotic use and resistance in a rural area of China through a combination of epidemiological, health systems and laboratory investigations. We reflect here on the challenges inherent in conducting long distance cross-disciplinary collaborations, having now completed data and sample collection for a baseline situation analysis. In particular, we recognise the importance of investing in aspects such as effective communication, shared conceptual frameworks and leadership. We suggest that our experiences will be instructive to others planning to develop similar international One Health collaborations. PMID- 28616489 TI - Multistate outbreak of human Salmonella Typhimurium infections linked to live poultry from agricultural feed stores and mail-order hatcheries, United States 2013. AB - Live poultry-associated salmonellosis is an emerging public health issue in the United States. Public and animal health officials collaborated to investigate one of the largest (356 cases, 39 states) of these outbreaks reported to date. A case was defined as illness in a person infected with the outbreak strain of Salmonella Typhimurium with illness onset between 1 March and 22 October 2013. The median patient age was seven years (range: < 1-87 years); 58% of ill persons were children <= 10 years, 51% were female, 25% were hospitalized; 189 (76%) of 250 patients reported live poultry exposure in the week before illness; and 149 (95%) of 157 reported purchasing live poultry from agricultural feed stores. Traceback investigations identified 18 live poultry sources, including 16 mail order hatcheries. Environmental sampling was conducted at two mail-order hatcheries. One (2.5%) of 40 duplicate samples collected at one hatchery yielded the outbreak strain. Live poultry are an important source of human salmonellosis, particularly among children, highlighting the need for educational campaigns and comprehensive interventions at the mail-order hatchery and agricultural feed store levels. Prevention and control efforts depend on a One Health approach, involving cooperation between public and animal health officials, industry, health professionals, and consumers. PMID- 28616490 TI - One Health and the International Fund for Agriculture Development. PMID- 28616491 TI - Climate change projections and public health systems: Building evidence-informed connections. PMID- 28616492 TI - The role of environmental health in One Health: A Uganda perspective. AB - BACKGROUND: One Health is the integrative effort of multiple disciplines working locally, nationally and globally to attain optimal health for people, animals and the environment. As the human population continues to increase across the world, the interface of people, animals and the environment becomes more significant and impactful. For the past few years, the One Health concept has brought together experts in the areas of animal and human health. It has provided a new synthesis for public health and veterinary communities across the world. One Health initiatives have majorly focused on veterinarians, medical doctors and public health professionals. However, the Environmental Health profession has a major role to play in One Health activities based on Uganda's experiences. CONTRIBUTION OF ENVIRONMENTAL HEALTH TO ONE HEALTH: In Uganda, Environmental Health Practitioners (EHPs) carry out several duties that contribute towards One Health. These include: inspection of animals before slaughter (antemortem) and meat in abattoirs (postmortem); inspection of meat in butcheries; destruction of condemned meat; disease surveillance; outbreak investigation and control of zoonoses; control of vectors and vermin such as rats, fleas, mosquitoes and monkeys; health education on pertinent issues such as vaccination of dogs; and food safety including meat and milk. EHPs also play an important role in prevention, detection and abatement of microbial and chemical pollution of land, air and water sources that have created new threats to the health of both animals and humans. EHPs carry out house to house inspections on water, sanitation and hygiene hence involved in abating nuisances at households that could pose a threat to public health. Such threats could be emerging from the environment including animals. Enforcement of public health legislation is also a key contribution of EHPs to One Health in Uganda. CONCLUSION: EHPs play an important role in disease surveillance, prevention and control. Therefore, Environmental Health professionals should be involved as stakeholders in local, national and global One Health initiatives. PMID- 28616493 TI - Leadership, governance and partnerships are essential One Health competencies. AB - One Health is held as an approach to solve health problems in this era of complexity and globalization, but inadequate attention has been paid to the competencies required to build successful teams and programs. Most of the discussion on developing One Health teams focuses on creating cross-disciplinary awareness and technical skills. There is, however, evidence that collaborative, multi-disciplinary teams need skills, processes and institutions that enable policy and operations to be co-managed and co-delivered across jurisdictions. We propose that competencies in leadership and human resources; governance and infrastructure; and partnership and stakeholder engagement are essential, but often overlooked One Health attributes. Competencies in these staple attributes of leadership and management need to be more prominent in training and One Health capacity development. Although One Health has been in existence for over a decade, there has been no systematic evaluation of the essential attributes of successful and sustainable One Health programs. As such, much of this paper borrows from experience in other sectors dealing with complex, cross and inter sectoral problems. Our objective is to advocate for increased investment in One Health leadership, governance and partnership skills to balance the focus on creating cross-disciplinary awareness and technical proficiency in order to maintain One Health as a viable approach to health issues at the human-animal environment interface. PMID- 28616494 TI - Community-based surveillance of zoonotic parasites in a 'One Health' world: A systematic review. AB - The One Health (OH) concept provides an integrated framework for observing and improving health issues involving human, animal, and environmental factors, and has been applied in particular to zoonotic disease problems. We conducted a systematic review of English and Chinese language peer-reviewed and grey literature databases to identify zoonotic endoparasite research utilizing an OH approach in community-based settings. Our review identified 32 articles where specimens collected simultaneously from all three OH domains (people, animals, and the environment) were assessed for endoparasite infection or exposure. Study sites spanned 23 countries, and research teams brought together an average of seven authors from two countries. Surveillance of blood-borne and gastrointestinal protozoa were most frequently reported (19 of 32; 59%), followed by trematodes, nematodes, and cestodes. Laboratory techniques varied greatly between studies, and only 16 identified parasites using Polymerase Chain Reaction (PCR) in all three OH domains. Our review identified important gaps in parasitology research operating under an OH framework. We recommend that investigators working in the realm of zoonotic disease strive to evaluate all three OH domains by integrating modern molecular tools as well as techniques provided by economists and social scientists. PMID- 28616495 TI - Zoos and public health: A partnership on the One Health frontier. AB - Today, accredited zoos are not just places for entertainment, they are actively involved in research for conservation and health. During recent decades in which the challenges for biodiversity conservation and public health have escalated, zoos have made significant changes to address these difficulties. Zoos increasingly have four key areas of focus: education, recreation, conservation, and research. These key areas are important in addressing an interrelated global conservation (i.e. habitat and wildlife loss) and public health crisis. Zoo and public health professionals working together within a One Health framework represent a powerful alliance to address current and future conservation and public health problems around the world. For researchers, practitioners, and students, the collaboration between zoos and public health institutions offers the opportunity to both teach and operationalize this transdisciplinary approach. Using examples from our programs, we give a template for moving forward with collaborative initiatives and sustainable solutions involving partners in both zoos and public health institutions. We provide examples of cooperative programs and suggest a model for consideration in the development of further activities in this area. PMID- 28616496 TI - Evaluating one health: Are we demonstrating effectiveness? AB - The perceived benefits of a One Health approach are largely hinged on increasing public health efficiency and cost effectiveness through a better understanding of disease risk-through shared control and detection efforts, and results that benefit human, animal and ecosystem health. However, there have been few efforts to identify and systematize One Health metrics to assess these perceived efficiencies. Though emphasis on the evaluation of One Health has increased, widely cited benefits of One Health approaches have mainly been based on modeled projections, rather than outcomes of implemented interventions. We conducted a review of One Health literature to determine the current status of One Health frameworks and case studies reporting One Health metrics. Of 1839 unique papers, only 7 reported quantitative outcomes; these assessments did not follow shared methodology and several reviewed only intermediate outcomes. For others, the effectiveness of One Health approaches was often assumed without supporting evidence or determined subjectively. The absence of a standardized framework to capture metrics across disciplines, even in a generic format, may hinder the more widespread adoption of One Health among stakeholders. We review possible outcome metrics suitable for the future evaluation of One Health, noting the relevance of cost outcomes to the three main disciplines associated with One Health. PMID- 28616497 TI - MERS-coronavirus: From discovery to intervention. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) still causes outbreaks despite public awareness and implementation of health care measures, such as rapid viral diagnosis and patient quarantine. Here we describe the current epidemiological picture of MERS-CoV, focusing on humans and animals affected by this virus and propose specific intervention strategies that would be appropriate to control MERS-CoV. One-third of MERS-CoV patients develop severe lower respiratory tract infection and succumb to a fatal outcome; these patients would require effective therapeutic antiviral therapy. Because of the lack of such intervention strategies, supportive care is the best that can be offered at the moment. Limiting viral spread from symptomatic human cases to health care workers and family members, on the other hand, could be achieved through prophylactic administration of MERS-CoV neutralizing antibodies and vaccines. To ultimately prevent spread of the virus into the human population, however, vaccination of dromedary camels - currently the only confirmed animal host for MERS-CoV - may be the best option to achieve a sustained drop in human MERS cases in time. In the end, a One Health approach combining all these different efforts is needed to tackle this zoonotic outbreak. PMID- 28616498 TI - Xenotransplantation - A special case of One Health. AB - The chronic shortage of human transplants to treat tissue and organ failure has led to the development of xenotransplantation, the transplantation of cells, tissues and organs from another species to human recipients. For a number of reasons, pigs are best suited as donor animals. Successful, routine xenotransplantation would have an enormous impact on the health of the human population, including the young, who sometimes require a replacement organ or islet cells, but especially the elderly, who more often suffer the consequences of organ failure. The first form of xenotransplantation applied to humans is the use of pig islet cells to treat insulin-dependent diabetes, a procedure that will have a significant economic impact. However, although xenotransplantation using pig cells, tissues and organs may save and prolong the lives of patients, it may also be associated with the transmission of porcine microorganisms to the recipient, eventually resulting in emerging infectious diseases. For this reason, the health of both the donor animals and the human recipients represents a special and sensitive case of the One Health concept. Basic research leading to strategies how to prevent transmission of porcine microorganisms by selection of virus-free animals, treatment of donor pigs by antiviral drugs, vaccines, colostrum deprivation, early weaning, Caesarean delivery, embryo transfer and/or gene editing should be undertaken to supply an increasing number of potential recipients with urgently required transplants. The methods developed for the detection and elimination of porcine microorganisms in the context of xenotransplantation will also contribute to an improvement in the health of pig populations in general and an increase in the quality of meat products. At present, there is evidence for transmission of porcine viruses to humans eating pork and having contact with pigs, however the impact of these viruses on public health is still unknown. PMID- 28616499 TI - Emergence of Wesselsbron virus among black rat and humans in Eastern Senegal in 2013. AB - Wesselsbron disease is a neglected mosquito transmitted Flavivirus infection that causes abortions and has teratogenic effects on sheep and cattle in Africa. Human can also be infected. The detection of human or animal cases is complicated by the non-specific symptoms close to Rift Valley Fever (RVF) in domestic livestock species or Dengue like syndrome in humans. Then, these detections are usually made during RVF investigations in sheep. These domestic animals should take a role in the life cycle of the virus but some evidences of Wesselsbron virus (WSLV) presence in wild animals suggest that the latter may be involved in the virus maintenance in nature. However, the reservoir status of wild vertebrate in general and rodents particularly for WSLV is only based on an isolation from a Cape short-eared gerbil in southern Africa. Most of WSLV isolations are from southern parts of Africa even if it has been found in western and central Africa or Madagascar. In Senegal, there are serological evidences of WSLV circulation in human since the 1970s and some isolations, the last one of which dates back in 1992. Despite the detection of the virus on mosquitoes until the 2000s in different parts of the country, no new human case has been noted. In this paper, we report the WSLV re-emergence in eastern Senegal in 2013 with 2 human cases and its first isolation from a black rat Rattus rattus. Sequencing analyses show the circulation of the same strain between these humans and the commensal rodent. The putative impact on WSLV transmission to human populations could be more important if the reservoir status of the black rat is confirmed. Focused survey in human populations, specific entomological and mammalogical investigations would permit a better understanding of the life cycle of the virus and its impact on public health. PMID- 28616500 TI - An outbreak of psittacosis at a veterinary school demonstrating a novel source of infection. AB - In November 2014, New South Wales Health was notified of a cluster of respiratory illness in a veterinary school. Active case finding identified another case at a local equine stud. All cases had exposure to the equine fetal membranes of Mare A. This tissue subsequently tested positive for Chlamydia psittaci using quantitative real-time polymerase chain reaction. We conducted a cohort study of the university and stud farm staff to determine risk factors for disease. Nine people were exposed to the fetal membranes of Mare A. Of these, five cases of psittacosis were identified. Two required hospital admission. Contact with birds was not associated with illness (RR = 0.5, 95% CI = 0.09-2.73). People who had direct contact with the abnormal fetal membranes were more likely to develop disease (RR = 11.77, 95% CI = 1.02-infinity). The emergence of an association between horse exposure and C. psittaci infection has important implications for the prevention and control of psittacosis. Article summary line: Investigation of an outbreak of psittacosis in a rural veterinary school demonstrates novel source of infection for psittacosis through exposure to abnormal equine fetal membranes. PMID- 28616501 TI - Searching for animal models and potential target species for emerging pathogens: Experience gained from Middle East respiratory syndrome (MERS) coronavirus. AB - Emerging and re-emerging pathogens represent a substantial threat to public health, as demonstrated with numerous outbreaks over the past years, including the 2013-2016 outbreak of Ebola virus in western Africa. Coronaviruses are also a threat for humans, as evidenced in 2002/2003 with infection by the severe acute respiratory syndrome coronavirus (SARS-CoV), which caused more than 8000 human infections with 10% fatality rate in 37 countries. Ten years later, a novel human coronavirus (Middle East respiratory syndrome coronavirus, MERS-CoV), associated with severe pneumonia, arose in the Kingdom of Saudi Arabia. Until December 2016, MERS has accounted for more than 1800 cases and 35% fatality rate. Finding an animal model of disease is key to develop vaccines or antivirals against such emerging pathogens and to understand its pathogenesis. Knowledge of the potential role of domestic livestock and other animal species in the transmission of pathogens is of importance to understand the epidemiology of the disease. Little is known about MERS-CoV animal host range. In this paper, experimental data on potential hosts for MERS-CoV is reviewed. Advantages and limitations of different animal models are evaluated in relation to viral pathogenesis and transmission studies. Finally, the relevance of potential new target species is discussed. PMID- 28616502 TI - Dromedary camels in northern Mali have high seropositivity to MERS-CoV. AB - A high percentage (up to 90%) of dromedary camels in the Middle East as well as eastern and central Africa have antibodies to Middle East respiratory syndrome coronavirus (MERS-CoV). Here we report comparably high positivity of MERS-CoV antibodies in dromedary camels from northern Mali. This extends the range of MERS CoV further west in Africa than reported to date and cautions that MERS-CoV should be considered in cases of severe respiratory disease in the region. PMID- 28616503 TI - A framework for One Health research. AB - The need for multidisciplinary research to address today's complex health and environmental challenges has never been greater. The One Health (OH) approach to research ensures that human, animal, and environmental health questions are evaluated in an integrated and holistic manner to provide a more comprehensive understanding of the problem and potential solutions than would be possible with siloed approaches. However, the OH approach is complex, and there is limited guidance available for investigators regarding the practical design and implementation of OH research. In this paper we provide a framework to guide researchers through conceptualizing and planning an OH study. We discuss key steps in designing an OH study, including conceptualization of hypotheses and study aims, identification of collaborators for a multi-disciplinary research team, study design options, data sources and collection methods, and analytical methods. We illustrate these concepts through the presentation of a case study of health impacts associated with land application of biosolids. Finally, we discuss opportunities for applying an OH approach to identify solutions to current global health issues, and the need for cross-disciplinary funding sources to foster an OH approach to research. PMID- 28616504 TI - Q fever in an endemic region of North Queensland, Australia: A 10 year review. AB - BACKGROUND: Q fever is a zoonotic infection caused by Coxiella burnetii. Endemic Q fever has long been recognised in north Queensland, with north Queensland previously acknowledged to have the highest rate of notification in Australia. In this retrospective study, we reviewed the demographics and exposure of patients diagnosed with Q fever in an endemic region of north Queensland, to identify trends and exposure factors for the acquisition of Q fever. METHODS: A retrospective study looking at patients in the region that had tested positive for Q fever by case ascertainment between 2004 and 2014. This involved both a chart review and the completion of a patient questionnaire targeting demographics, clinical presentation, risk factors and outcomes. RESULTS: There were 101 patients with a positive Q fever serology and/or PCR that were identified in the region of north Queensland that was studied, between 2004 and 2014. The cohort was residents of Mackay Hospital and Health Service. Of these, 4 patients were excluded and 63 patients successfully completed a questionnaire on demographic and risk factors. Out of the 63 patients, the highest prevalence was in the patients residing in the coastal region of Proserpine (42/100,000 people per year) followed by the Whitsundays region (14.8/100,000 people per year). A significantly higher proportion of patients were reportedly exposed to macropods (69.8%) and possums (66.7%) as compared to cattle (23.8%). A trend between increased cases of Q fever infection and high seasonal rainfall was noted. CONCLUSIONS: In this endemic region of north Queensland, exposure to wildlife and seasonal rainfall may be substantial exposure factors for the development of Q fever. The region studied is a popular tourist destination. An understanding of risk factors involved can help practitioners who see residents or returned travelers from the region, with an undifferentiated fever. PMID- 28616505 TI - One Health in food safety and security education: Subject matter outline for a curricular framework. AB - Educating students in the range of subjects encompassing food safety and security as approached from a One Health perspective requires consideration of a variety of different disciplines and the interrelationships among disciplines. The Western Institute for Food Safety and Security developed a subject matter outline to accompany a previously published One Health in food safety and security curricular framework. The subject matter covered in this outline encompasses a variety of topics and disciplines related to food safety and security including effects of food production on the environment. This subject matter outline should help guide curriculum development and education in One Health in food safety and security and provides useful information for educators, researchers, students, and public policy-makers facing the inherent challenges of maintaining and/or developing safe and secure food supplies without destroying Earth's natural resources. PMID- 28616506 TI - The hookworm Ancylostoma ceylanicum: An emerging public health risk in Australian tropical rainforests and Indigenous communities. AB - Ancylostoma ceylanicum is the common hookworm of domestic dogs and cats throughout Asia, and is an emerging but little understood public health risk in tropical northern Australia. We investigated the prevalence of A. ceylanicum in soil and free-ranging domestic dogs at six rainforest locations in Far North Queensland that are Indigenous Australian communities and popular tourist attractions within the Wet Tropics World Heritage Area. By combining PCR-based techniques with traditional methods of hookworm species identification, we found the prevalence of hookworm in Indigenous community dogs was high (96.3% and 91.9% from necropsy and faecal samples, respectively). The majority of these infections were A. caninum. We also observed, for the first time, the presence of A. ceylanicum infection in domestic dogs (21.7%) and soil (55.6%) in an Indigenous community. A. ceylanicum was present in soil samples from two out of the three popular tourist locations sampled. Our results contribute to the understanding of dogs as a public health risk to Indigenous communities and tourists in the Wet Tropics. Dog health needs to be more fully addressed as part of the Australian Government's commitments to "closing the gap" in chronic disease between Indigenous and other Australians, and encouraging tourism in similar locations. PMID- 28616507 TI - The first report of Escherichia fergusonii isolated from non-human primates, in Africa. AB - The aim of this study was to determine the resistance phenotypes of selected enteric bacteria isolated from non-human primates at a wildlife-human interface. Bacterial isolates from faecal samples of non-human primates at two wildlife rehabilitation centres in South Africa were screened for the presence of Escherichia coli. The biochemical characterisation of E. coli and E. coli-like bacteria revealed both adonitol positive and sorbitol negative strains - a unique characteristic of Escherichia fergusonii and Escherichia coli K99. Further tests were carried out to identify the isolates, namely growth on Simmons citrate agar supplemented with 2% adonitol and biochemical tests based on their ability to ferment cellobiose and d-arabitol. Antimicrobial sensitivity was determined with microbroth dilution tests employing microtitre plates with 21 different antimicrobial drugs. Molecular characterisation was done with a duplex polymerase chain reaction (PCR) assay that targeted the yliE and EFER_1569 genes. E. fergusonii strains were confirmed by the presence of a 233 bp segment of the yliE gene and a 432 bp segment of the EFER_1569 gene. Twenty-three E. coli-like bacteria were confirmed as E. fergusonii based on the confirmatory tests and they were in 100% agreement. Approximately 87% of them were resistant to polymyxins B and E (colistin) as well as the carbapenem group with occasional resistance to amikacin. This is the first reported isolation and identification of E. fergusonii strains in non-human primates. The findings point to E. fergusonii as a possible emerging pathogen of zoonotic importance. PMID- 28616508 TI - Non-invasive estimation of pulmonary outflow tract obstruction: A comparative study of cardiovascular phase contrast magnetic resonance and Doppler echocardiography versus cardiac catheterization. AB - AIM: To compare estimated pressure gradients from routine follow-up cardiovascular phase-contrast magnetic resonance (PC-MR) with those from Doppler echocardiography and invasive catheterization in patients with congenital heart disease (CHD) and pulmonary outflow tract obstruction. METHODS: In 75 patients with pulmonary outflow tract obstruction maximal and mean PC-MR gradients were compared to maximal and mean Doppler gradients. Additionally, in a subgroup of 31 patients maximal and mean PC-MR and Doppler pressure gradients were compared to catheter peak-to-peak pressure gradients (PPG). RESULTS: Maximal and mean PC-MR gradients underestimated pulmonary outflow tract obstruction as compared to Doppler (max gradient: bias = + 8.4 mm Hg (+ 47.6%), r = 0.89, p < 0.001; mean gradient: + 4.3 mm Hg (+ 49.0%), r = 0.88, p < 0.001). However, in comparison to catheter PPG, maximal PC-MR gradients (bias = + 1.8 mm Hg (+ 8.8%), r = 0.90, p = 0.14) and mean Doppler gradients (bias = - 2.3 mm Hg (- 11.2%), r = 0.87, p = 0.17) revealed best agreement. Mean PC-MR gradients underestimated (bias = - 7.7 mm Hg (- 55.6%), r = 0.90, p < 0.001) while maximal Doppler gradients systematically overestimated catheter PPG (bias = + 13.9 mm Hg (+ 56.5%), r = 0.88, p < 0.001). CONCLUSIONS: Estimated maximal PC-MR pressure gradients from routine CHD follow-up agree well with invasively assessed peak-to-peak pressure gradients. Estimated maximal Doppler pressure gradients tend to overestimate, while Doppler mean gradients agree better with catheter PPG. Therefore, our data provide reasonable arguments to either apply maximal PC-MR gradients or mean Doppler gradients to non-invasively evaluate the severity of pulmonary outflow tract obstruction in the follow-up of CHD. PMID- 28616509 TI - Predictors and outcome of no-reflow post primary percutaneous coronary intervention for ST elevation myocardial infarction. AB - BACKGROUND: No-reflow (TIMI < 3) during primary PCI (PCI) for STEMI occurs in 11 41% of cases, indicates poor myocardial tissue perfusion, and is associated with a poor outcome. We aimed to determine predictors and 12 month outcomes of patients who developed no-reflow. METHODS: We analysed the PCI database of The Canberra Hospital and identified 781 patients who underwent primary PCI during 2008-2012. Follow-up at 12 months was with letter, phone call and review of hospital records. RESULTS: No-reflow was observed in 189 patients (25%) at the end of the procedure. Patients with no-reflow were older (64 vs. 61 years, p = 0.03). No-reflow patients were more likely to have initial TIMI flow < 3 (89% vs. 79%, p = 0.001), thrombus score >= 4 (83% vs. 69%, p = 0.0001), higher use of glycoprotein IIb/IIIa inhibitors (57% vs. 48%, p = 0.03) and longer median symptom to balloon time (223 min vs. 192 min, p = 0.004). No-reflow was an independent predictor of mortality (HR 1.95, CI 1.04-3.59, p = 0.037) during 12 month follow-up. On multivariate analysis, age > 60 years, thrombus score >= 4 and symptom to balloon time > 360 min were independent predictors of no-reflow. In 17% of cases of no reflow, it occurred only after stent insertion. CONCLUSIONS: No-reflow occurred in 25% of STEMI patients undergoing primary PCI and was more likely with older age, high thrombus burden and delayed presentation. No-reflow was associated with a higher risk of death at 12 month follow-up. PMID- 28616510 TI - Red cell distribution width (RDW) correlates with markers of diastolic dysfunction in patients with impaired left ventricular systolic function. AB - OBJECTIVE: Red-cell distribution width (RDW) has been identified as a novel prognostic marker in a heterogeneous group of heart failure patients. In this group, diastolic dysfunction is associated with worse outcome. As the evidence is limited, the aim of the present study was to assess the relationship of RDW to diastolic markers in patients with left ventricular dysfunction (LVD) diagnosed during cardiac catheterization. METHODS: Clinical and angiographic data were collected retrospectively on a total of 291 stable patients (mean age 62 years, 199 males) with systolic dysfunction documented during cardiac catheterization in a regional medical center between January 2006 and December 2010. RESULTS: Positive association was seen between RDW and Left ventricular end diastolic pressure (LVEDP), estimated systolic pulmonary arterial pressure(sPAP), and left atrial dimension (LAD) (r: 0.18, 0.24, 0.28, respectively; p:<0.05).Three year retrospective survival analysis for 108 patients admitted in the first 2 years showed a statistically significant decrease in survival patients with high RDW(> 14.5) vs. normal RDW (73%vs.88%;log rank p:0.03). This was seen even in the asymptomatic subgroup (71% vs. 94%; log rank p: 0.01). CONCLUSION: RDW correlates with markers of diastolic dysfunction in patients with LVD. Additionally, in patients asymptomatic LVD, high RDW is still associated with lower survival. PMID- 28616511 TI - One-year outcomes following drug-eluting balloon use for coronary ostial restenosis. AB - AIMS: The management of ostial lesions is one of the challenges of percutaneous coronary intervention (PCI) in recent medicine. Although stent implantation has increased the accuracy of the results and improved long-term outcomes, in-stent restenosis (ISR) occurs more frequency following the treatment of ostial lesions than the treatment of non-ostial lesions. When additional stenting is not desirable, PCI with drug-eluting balloons (DEBs) has emerged as an adjunctive strategy. However, little data regarding the effects of DEBs in ostial ISR lesions are available. Our study aimed to assess the efficacy of the use of DEBs in coronary ostial instent restenotic lesions. METHODS AND RESULTS: From November of 2011 to May of 2014, 85 patients were diagnosed with coronary ostial ISR in our hospital. A total of 93 coronary ostial ISR lesions were treated with DEBs. More than half of the study patients had comorbidities, including hypertension, diabetes, and hyperlipidemia, 77.6% of the study patients had triple vessel coronary artery disease, and 54.1% of the study patients had left main coronary artery disease. In our study, target lesion revascularization were performed in 19.2% in all groups; 11.5% were in the ostial left anterior descending artery, 29.0% were in the ostial left circumflex artery, and 21.4% were in the ostial right coronary artery. Across all of the groups, 24.4% of the patients experienced major adverse cardiac cerebral events. CONCLUSION: Percutaneous coronary intervention with drug-eluting balloons is an alternative strategy for coronary ostial instent restenosis when additional stenting is not desirable. PMID- 28616512 TI - High prevalence of coronary artery events and non-coronary events in patients with coronary artery aneurysm in the observational group. AB - BACKGROUND: Coronary artery aneurysm (CAA) is occasionally detected on a small percentage of coronary angiography or multi-detector computed tomography (MDCT). CAA itself is considered benign entity despite the potential risks of rupture, thromboembolism, and compression of surrounding structures. However, the optimal management including other vascular comorbidity has yet to be fully clarified. OBJECTIVE: The aim of this study was to evaluate cardiovascular events in the patients with CAA in the observational group. METHODS: Between January 2010 and August 2015, 48 CAAs were identified in 37 patients out of consecutive 10,010 patients (0.37%) by MDCT. Twenty-eight patients treated conservatively were included in this study. Their major adverse cardiovascular events (MACE) were evaluated retrospectively: death, non-fatal myocardial infarction (MI), revascularizations; coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), and other vascular events. RESULTS: The average age was 62.0 +/- 15.5 year sold, and median follow-up period was 49.6 months (IQR 23.6 to 78.1). Mean CAA diameter was 7.5 +/- 2.8 mm. Twenty-two MACE occurred in 15 patients (53.6%): 1 sudden death, 4 MI, 1 CABG for CAA, 3 PCI for CAA, 7 PCI for non-CAA lesions, and 6 other vascular treatments for aorta and cerebral and peripheral artery. Follow-up MDCT was performed for 22 CAAs in 16 patients. In 9 CAAs of them, the maximal diameter increased significantly (Delta diameter: 1.5 +/- 1.1 mm). CONCLUSIONS: Presence of CAA may be associated with adverse vascular events including non-coronary diseases. This study could suggest the management for CAA should include the evaluation of not only CAA itself but also other vascular diseases. PMID- 28616513 TI - Post-valvular surgery multi-vessel coronary artery spasm - A literature review. AB - Coronary artery spasm (CAS) refers to the spontaneous or stimuli-induced transient, often localized and intense subtotal or total constriction/occlusion of the epicardial coronary artery, usually concomitant with angina pectoris with associated elevation of the ST segment on electrocardiogram (ECG). In this article, we present a literature review on post-valvular surgery CAS and report the clinical case of a 77 year-old man who experienced severe early post-aortic surgery chest pain and hemodynamic instability. Emergent coronary angiography revealed severe occlusion of multiple branches of both coronary arteries. The CAS was alleviated with intracoronary infusion of nitroglycerin. PMID- 28616514 TI - Mitral valve prolapse syndrome and MASS phenotype: Stability of aortic dilatation but progression of mitral valve prolapse. AB - BACKGROUND: Mitral valve prolapse syndrome (MVPS) and MASS phenotype (MASS) are Marfan-like syndromes that exhibit aortic dilatation and mitral valve prolapse. Unlike in Marfan syndrome (MFS), the presence of ectopia lentis and aortic aneurysm preclude diagnosis of MVPS and MASS. However, it is unclear whether aortic dilatation and mitral valve prolapse remain stable in MVPS or MASS or whether they progress like in MFS. METHODS: This retrospective longitudinal observational study examines clinical characteristics and long-term prognosis of 44 adults with MVPS or MASS (18 men, 26 women aged 38 +/- 17 years) as compared with 81 adults with Marfan syndrome (MFS) with similar age and sex distribution. The age at final contact was 42 +/- 15 years with mean follow-up of 66 +/- 49 months. RESULTS: At baseline, ectopia lentis and aortic sinus aneurysm were absent in MVPS and MASS, and systemic scores defined by the revised Ghent nosology were lower than in MFS (all P < .001). Unlike in MFS, no individual with MVPS and MASS developed aortic complications (P < .001). In contrast, the incidence of endocarditis (P = .292), heart failure (P = .644), and mitral valve surgery (P = .140) was similar in all syndromes. Cox regression analysis identified increased LV end-diastolic (P = .013), moderate MVR (P = .019) and flail MV leaflet (P = .017) as independent predictors of mitral valve surgery. CONCLUSIONS: The study provides evidence that MVPS and MASS are Marfan-like syndromes with stability of aortic dilatation but with progression of mitral valve prolapse. Echocardiographic characteristics of mitral valve disease rather than the type of syndrome, predict clinical progression of mitral valve prolapse. PMID- 28616515 TI - Coronary artery spasm: Current knowledge and residual uncertainties. AB - Myocardial ischaemia results from a direct mismatch between oxygen supply and demand, commonly arising as a result of coronary atherosclerosis, microvascular dysfunction or acute thrombosis and luminal obstruction. However, transient ischaemia may also occur due to coronary spasm leading to acute and unexpected myocardial ischaemia without obvious visible coronary pathology. Aside from symptoms of chest pain, coronary spasm can cause infarction, LV impairment, promote life threatening arrhythmias and ultimately sudden cardiac death. While therapeutic options are available, controversies exist around diagnosis, pathology, management and prognosis. This review summarises some of the common questions in this area. In particular we explore and discuss the available evidence for the pharmacological treatment of coronary spasm, and strategies for identification and management of very high risk patients to try and reduce the incidence of sudden premature death. PMID- 28616516 TI - Cardiac magnetic resonance imaging characteristics and pregnancy outcomes in women with Mustard palliation for complete transposition of the great arteries. AB - BACKGROUND: Women with transposition of the great arteries (TGA) following atrial redirection surgery are at risk of pregnancy-associated arrhythmia and heart failure. The cardiovascular magnetic resonance imaging (CMR) characteristics of these women and the relationship of CMR findings to pregnancy outcomes have not been described. METHODS: We included 17 women with atrial redirection surgery and CMR within 2 years of delivery. RESULTS: All women were asymptomatic at baseline (New York Heart Association Class 1). CMR studies were completed pre-pregnancy in 3, antepartum/peripartum in 2, and postpartum in 12 women. Three women (3/17, 18%) experienced major cardiovascular events related to pregnancy: cardiac arrest (n = 1) and symptomatic atrial arrhythmia (n = 2). Median gestational age at delivery was 38 weeks (24-39 weeks) and birth weight was 2770 g (2195-3720 g). Complications were seen in 3 offspring (3/17, 18%): death (n = 1) and prematurity (n = 2). CMR characteristics included median right ventricular end diastolic volume 119 mL/m2 (range 85-214 mL/m2) and median right ventricular ejection fraction (RVEF) 37% (range 30-51%). All women with cardiovascular complications had an RVEF < 35% (range 32-34%). The association between RVEF < 35% and cardiovascular complications trended towards statistical significance (p = 0.05). No statistically significant differences in CMR measurements were found between those with and without neonatal complications. CONCLUSIONS: While the majority of women in this cohort had successful outcomes following pregnancy, important cardiovascular complications were seen in a significant minority, all of whom had an RVEF < 35%. The preliminary findings of our study provide impetus for a larger prospective study to evaluate the prognostic role of CMR in pregnant women with atrial redirection surgery. PMID- 28616517 TI - High perfusion pressure as a predictor of reperfusion pulmonary injury after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Clinical efficacy of balloon pulmonary angioplasty (BPA) to the patients with non-operable chronic thromboembolic pulmonary hypertension (CTEPH) for improving pulmonary hemodynamics and exercise tolerance has been reported in these several years. However, reperfusion pulmonary injury (RPI) remains to be a major complication of BPA to overcome. This study elucidated the local predictor of RPI. METHODS: Twenty-eight consecutive patients with non-operable CTEPH underwent BPA for lesions in the segmental or sub-segmental vessels. Pre- and post-BPA pulmonary arterial pressures at proximal (Pp) and distal (Pd) to the stenosis were measured by a 0.014-in. pressure wire. Positive or negative RPI was evaluated by chest computed tomography in each re-perfused segment separately 4 h after BPA. RESULTS: Pressure measurements pre- and post-BPA were obtained from 110 lesions, where Pd and pressure ratio (Pd/Pp) increased after BPA in all lesions. Among them, RPI was observed in 49 lesions (44.5%). In the RPI-positive lesions, post-BPA Pd and post-BPA Pd/Pp were higher compared with the RPI negative lesions. Multivariate logistic analysis revealed that the post-BPA Pd was independently associated with RPI incidence. Receiver operating characteristic curve analysis demonstrated the best cut-off value of 19.5 mm Hg for post-BPA Pd to predict RPI. CONCLUSIONS: High reperfusion pressure after BPA could be a predictor of RPI. Monitoring local pressure during BPA procedure may have a potential to reduce the incidence of RPI. PMID- 28616518 TI - Relationship between electrocardiographic findings and Cardiac Magnetic Resonance phenotypes in patients with Hypertrophic Cardiomyopathy. AB - BACKGROUND: Q waves and negative T waves are common electrocardiographic (ECG) abnormalities in patients with Hypertrophic Cardiomyopathy (HCM). Several studies correlated ECG findings with presence and extent of fibrosis and hypertrophy; however, their significance remains incompletely clarified. Our study aimed to explain the mechanism behind Q and negative T waves by comparing their positions on a 12-lead ECG with phenotypes observed at Late Gadolinium Enhancement (LGE) Cardiac Magnetic Resonance (CMR). METHODS: 12-lead ECG and LGE-CMR were performed in 88 consecutive patients with HCM (42 SD 16 years, 65 males). Using Delta Thickness ratio (DT ratio), and "global" and "parietal" LGE at CMR, the extent and distribution of myocardial hypertrophy and fibrosis were studied in correlation with ECG abnormalities. RESULTS: Q waves in different leads were not associated with "parietal" LGE score. Lateral Q waves correlated with an increased DT ratio Inferior Septum/Lateral wall (p = 0.01). A similar correlation between inferior Q waves and an increased DT Ratio Anterior wall/Inferior wall was of borderline statistical significance (p = 0.06). As expected, ECG signs of LV hypertrophy related to a raised Left Ventricular Mass Index (LVMI) (p < 0.0001) and mean wall thickness (p = 0.01). Depolarization disturbances, including negative T waves in lateral (p = 0.044) and anterior (p = 0.031) leads correlated with "parietal" LGE scores while QT dispersion (p = 0.0001) was associated with "global" LGE score. CONCLUSION: In HCM patients, Q waves are generated by asymmetric hypertrophy rather than by myocardial fibrosis, while negative T waves result from local LGE distribution at CMR. PMID- 28616519 TI - Cardiovascular changes in patients with non-severe Plasmodium vivax malaria. AB - BACKGROUND: Cardiovascular system involvement in patients with Plasmodium vivax malaria has been poorly addressed. The aim of this study was to evaluate cardiac structures and function, and serum markers of cardiovascular injury in patients with the non-severe form of vivax malaria in Manaus, Amazonas State, Brazil. METHODS AND RESULTS: We prospectively evaluated 26 patients with vivax malaria in an outpatient referral hospital and compared results with a control group of 25 gender- and age-matched healthy individuals. Patients underwent clinical evaluation, laboratory tests, and transthoracic echocardiography at first evaluation (day zero, D0) and seven days (D7) after malaria diagnosis. At D0 echocardiography showed higher left ventricular (LV) systolic diameter (28.8 +/- 2.82 vs 30.9 +/- 4.03 mm; p = 0.037) and LV diastolic volume (82.4 +/- 12.3 vs 93.8 +/- 25.9 ml; p = 0.05), and lower LV ejection fraction (Teicholz method: 73.2 +/- 6.59 vs 68.4 +/- 4.87%; p = 0.004) in patients compared to controls. Right ventricle (RV) fractional area change (54.7 +/- 5.11 vs 50.5 +/- 6.71%; p = 0.014) was lower, and RV myocardial performance index (0.21 +/- 0.07 vs 0.33 +/- 0.19; p = 0.007), and pulmonary vascular resistance (1.13 +/- 0.25 vs 1.32 +/- 0.26 Woods unit; p = 0.012) were higher in patients than controls. Patients presented higher serum levels of unconjugated bilirubin (0.24 +/- 0.15 vs 1.30 +/ 0.89 mg/dL; p < 0.001), soluble vascular cell adhesion molecule-1 (sVCAM-1; 453 +/- 143 vs 1983 +/- 880 ng/mL; p < 0.001), N-terminal prohormone brain natriuretic peptide (0.59 +/- 0.86 vs 1.08 +/- 0.81 pg/mL; p = 0.045), and troponin T (861 +/- 338 vs 1037 +/- 264 pg/mL; p = 0.045), and lower levels of plasma nitrite (13.42 +/- 8.15 vs 8.98 +/- 3.97 MUM; p = 0.016) than controls. Most alterations had reversed by D7. CONCLUSION: Patients with non-severe Plasmodium vivax malaria present subclinical reversible cardiovascular changes. PMID- 28616520 TI - More haste, less speed: Cardiac perforation by a thoracentesis catheter. PMID- 28616521 TI - Predictors of subjective health status 10 years post-PCI. AB - BACKGROUND: Subjective health status is an increasingly important parameter to assess the effect of percutaneous coronary intervention (PCI) in clinical practice. Aim of this study was to determine medical and psychosocial predictors of poor subjective health status over a 10 years' post-PCI period. METHODS: We included a series of consecutive PCI patients (n = 573) as part of the RESEARCH registry, a Dutch single-center retrospective cohort study. RESULTS: These patients completed the 36-item Short-Form Health Survey (SF-36) at baseline and 10 years post-PCI. We found 6 predictors of poor subjective health status 10 years post-PCI: SF-36 at baseline, age, previous PCI, obesity, acute myocardial infarction as indication for PCI, and diabetes mellitus (arranged from most to least numbers of sub domains). CONCLUSIONS: SF-36 scores at baseline, age, and previous PCI were significant predictors of subjective health status 10 years post-PCI. Specifically, the SF-36 score at baseline was an important predictor. Thus assessment of subjective health status at baseline is useful as an indicator to predict long-term subjective health status. Subjective health status becomes better by optimal medical treatment, cardiac rehabilitation and psychosocial support. This is the first study determining predictors of subjective health status 10 years post-PCI. PMID- 28616522 TI - The experimental model of transition from compensated cardiac hypertrophy to failure created by transverse aortic constriction in mice. AB - BACKGROUND: Transverse aortic constriction (TAC) operation is used as an experimental model of left ventricular (LV) hypertrophy and LV failure in mice. The severity of LV remodeling or failure may depend on the degree of TAC, but is variable among operated animals. Therefore, we tried to identify the optimal diameter of TAC to create this model with ease and high reproducibility. METHODS AND RESULTS: To produce TAC in C57BL/6J mice (7-9 weeks, body weight 19-26 g, n = 109), a 7-0 nylon suture ligature was tightly tied around the transverse aorta against needles with 3 different diameters (mm); 0.40, 0.385 and 0.375. LV wall thickness, end-diastolic dimension, fractional shortening were measured by echocardiography. At 4 weeks after TAC, no mouse with the 0.400 mm gauge progressed in LV failure. The 0.385 mm pin gauge mouse kept a more survival rate compared with the 0.375 mm (59% vs 48%), representing same efficient in LV failure. With the 0.385 mm pin gauge, hearts of mice remained LV hypertrophy at 1 week after TAC, followed by LV failure at 4 weeks. CONCLUSION: TAC with the diameter of 0.385 mm can effectively induce the transition from LV hypertrophy to failure in mice with relatively preserved survival. PMID- 28616523 TI - Safety and feasibility of transcatheter renal sympathetic denervation using different types of catheter and various radiofrequency settings. AB - BACKGROUND: To evaluate in vivo the feasibility and safety of renal sympathetic denervation (RSD) with different catheters and various radiofrequency protocols. METHODS AND RESULTS: Twenty-two pigs were included. First 2 pigs were enrolled in a feasibility protocol using one catheter and power from 5 W to 20 W. The next 10 pigs underwent RSD with three different catheters and four different RF-power settings of 5 W, 8 W, 10 W and 12 W in one minute per lesion (Protocol 1). The following 10 (Pigs 13 to 22) underwent RSD with five types of catheters (including the Symplicity(r) catheter), powers of 8 W and 10 W and two minutes RF application (Protocol 2). Angiographic data were obtained at baseline, during and after RSD. At last, renal arteries were excised and analyzed macroscopically. The first pig developed severe renal stenoses with lesions of 15 to 20 W correlated with macroscopic alterations. The second feasibility pig did not develop renal stenosis with 5 and 8 W. In Protocol 1 from 60 RF-lesions, we observed 7 stenoses (>= 30%). Three were severe (one of 80% with 10 W and two of 80% with 12 W). In Protocol 2 from 57 lesions we observed only 1 stenosis of 50% with 8 W with Symplicity(r) catheter. Severe stenosis was not observed. CONCLUSION: In this study, renal sympathetic denervation showed safety using five types of catheters when applying RF-energy less than 10 W, within main stems of arteries larger than 3.0 mm diameter and a distance between lesions of at least 1 time catheter tip length. PMID- 28616524 TI - Coronary plaque morphology on multi-modality imagining and periprocedural myocardial infarction after percutaneous coronary intervention. AB - Percutaneous coronary intervention (PCI) may be complicated by periprocedural myocardial infarction (PMI) as manifested by elevated cardiac biomarkers such as creatine kinase (CK)-MB or troponin T. The occurrence of PMI has been shown to be associated with worse short- and long-term clinical outcome. However, recent studies suggest that PMI defined by biomarker levels alone is a marker of atherosclerosis burden and procedural complexity but in most cases does not have independent prognostic significance. Diagnostic multi-modality imaging such as intravascular ultrasound, optical coherence tomography, coronary angioscopy, near infrared spectroscopy, multidetector computed tomography, and magnetic resonance imaging can be used to closely investigate the atherosclerotic lesion in order to detect morphological markers of unstable and vulnerable plaques in the patients undergoing PCI. With the improvement of technical aspects of multimodality coronary imaging, clinical practice and research are increasingly shifting toward defining the clinical implication of plaque morphology and patients outcomes. There were numerous published data regarding the relationship between pre-PCI lesion subsets on multi-modality imaging and post-PCI biomarker levels. In this review, we discuss the relationship between coronary plaque morphology estimated by invasive or noninvasive coronary imaging and the occurrence of PMI. Furthermore, this review underlies that the value of the multimodality coronary imaging approach will become the gold standard for invasive or noninvasive prediction of PMI in clinical practice. PMID- 28616526 TI - Repeat remote ischaemic pre-conditioning for improved cardiovascular function in humans: A systematic review. AB - BACKGROUND: Single exposure to remote ischaemic pre-conditioning (RIPC) has been shown to be effective in reducing major adverse events during cardiac surgery. We evaluated the efficacy of repeated exposure RIPC to elicit improvements in cardiovascular function. METHODS: A systematic search was conducted up until May 1st, 2015, using the following databases: EMBASE, PubMed (Medline), Web of Science and the Cochrane Central Registry of Controlled Trials (CENTRAL). Data was extracted and synthesized from published studies of repeat RIPC. RESULTS: Data from seven studies showed evidence of improvements in vascular function and anti-hypertensive effects of systolic, diastolic and mean arterial blood pressure following repeat RIPC. Currently existing work justifies a systematic review but not data pooling of individual study data. Repeat RIPC has also produced evidence of improvements in endothelial dependent vasodilation, but not non-endothelial dependent vasodilation, cutaneous vascular conductance or cardiorespiratory fitness. CONCLUSION: Repeated RIPC exposure has produced evidence of improvements in endothelial dependent vasodilation, ulcer healing and blood pressure but no benefit in non-endothelial dependent vasodilation, cutaneous vascular conductance or cardiorespiratory fitness. The optimal delivery of RIPC remains unclear, but at least 3 or preferably 4, 5 min exposures appears to be most beneficial, at least for reducing blood pressure. Aside from those undertaking cardiac surgery, other study populations with endothelial dysfunction may benefit from repeat exposure to RIPC. PMID- 28616525 TI - Thrombolytics in VAD management - A single-center experience. AB - BACKGROUND: With continued increase in the use of mechanical circulatory support, the incidence of device thrombus remains a challenge. This study is a retrospective analysis of data at a single center to assess the safety and efficacy of thrombolytic use in durable mechanical assist devices. METHODS: Data was analyzed retrospectively from 154 patients who underwent left ventricular assist device (LVAD) implantation from 1/1/2005 to 6/30/2014. The HMII device was implanted in 131 patients while 23 received the HVAD. LVAD thrombus was diagnosed when lactate dehydrogenase levels exceeded 1000 units/l accompanied by clinical signs of hemolysis and heart failure, echocardiographic data and surges in pump power. TPA (tissue plasminogen activator) protocol consisted of a 5 mg intravenous bolus followed by 3 mg/h infusion in normal saline for 10 h. If symptoms persisted another cycle of TPA at 1 mg/h was continued up to 48 h. RESULTS: The TPA group had a 70% success rate. Success was defined as complete resolution of hemolysis and clinical symptoms with no requirement for LVAD exchange at 30 days. 95% survival was noted at 30 days and 90% were free of a hemorrhagic stroke in the TPA group. The rates of hemorrhagic strokes in the TPA group and the control group were not different (OR = 0.92). CONCLUSION: The TPA protocol described here was successful consistently. Though this study is limited by its size and retrospective nature it leads the way for larger studies to generate more robust comparisons between different types of mechanical assist devices as well as the tailored use of thrombolytics in this patient population. PMID- 28616527 TI - The renin-angiotensin-aldosterone-system and right heart failure in congenital heart disease. AB - Adults with congenital heart disease represent a rapidly growing patient group. Dysfunction of the right ventricle is often present, and right heart failure constitutes the main cause of death. Heart failure therapies used in acquired left heart failure are often initiated in adults with right heart failure due to congenital heart disease, but the right ventricle differs substantially from the left ventricle, and the clinical evidence for this treatment strategy is lacking. In this review, we identified existing clinical studies evaluating the effects of ACE inhibitors, angiotensin II receptor blockers and aldosterone antagonists in adults with congenital heart disease by a systematic literature search. From 13 identified studies no clear evidence of beneficial effects was found, but the design of the studies limits the validity of the results. The studies in general include low numbers of patients, have short follow-up periods and evaluate surrogate endpoints instead of hard clinical endpoints. Specific evaluation of symptomatic patients with a systemic right ventricle indicates that these patients may benefit from RAAS inhibitory treatments, but this requires further investigation. To conclude, existing studies do not support the use of RAAS inhibitory treatments in right heart failure due to congenital heart disease but contain important limitations. Hence, there is a need for new well-designed trials including higher numbers of patients and validated endpoints to optimize and guide future treatment of this patient group. PMID- 28616529 TI - Intima-media thickness of the descending aorta in patients with bicuspid aortic valve. AB - OBJECTIVE: A bicuspid aortic valve (BAV) is associated with accelerated aortic valve disease (AVD) and abnormalities in aortic elasticity. We investigated the intima-media thickness of the descending aorta (AoIMT) in patients with AVD with or without an ascending aortic aneurysm (AscAA), in relation to BAV versus tricuspid aortic valve (TAV) phenotype, type of valve disease, cardiovascular risk factors, and single-nucleotide polymorphisms (SNPs) with a known association with carotid IMT. METHODS AND RESULTS: 368 patients (210 with BAV, 158 with TAV,); mean age 64 +/- 13 years) were examined using transesophageal echocardiography (TEE) before valvular and/or aortic surgery. No patient had a coronary disease (CAD). The AoIMT was measured on short-axis TEE images of the descending aorta using a semi-automated edge-detection technique. AoIMT was univariately (P < 0.05) related to age, blood pressure, smoking, creatinine, highly sensitive C-reactive protein, HDL, valve hemodynamics and BAV. In the TAV subgroup it was also associated with the rs200991 SNP. Using multivariate regression analysis, age was the main determinant for AoIMT (P < 0.001), followed by male gender (P = 0.02), BAV was no longer a significant predictor of AoIMT. AoIMT was still related to the rs200991 SNP in TAV (P = 0.034), and to creatinine in BAV (P = 0.019), when other variables were accounted for. CONCLUSIONS: Intima media thickness of the descending aorta is not affected by aortic valve morphology (BAV/TAV); age is the main determinant of AoIMT. Genetic markers (SNPs) known to influence IMT in the carotid artery seem to correlate to IMT in the descending aorta only in patients with TAV. PMID- 28616528 TI - Acute contractile recovery extent during biventricular pacing is not associated with follow-up in patients undergoing resynchronization. AB - BACKGROUND: It has been reported that contractility, as assessed using dobutamine infusion, is independently associated with reverse remodeling after CRT. Controversy, however, exists about the capacity of this approach to predict a long-term clinical response. This study's purpose was to assess whether long-term CRT clinical effects can be predicted according to acute inotropic response induced by biventricular stimulation (CRT on), as compared with AAI-VVI right stimulation pacing mode (CRT off), quantified at the time of implantation. METHODS: In 98 patients (ejection fraction 29 +/- 10%), acute changes in left ventricular (LV) elastance (Ees), arterial elastance (Ea), and Ees/Ea, as assessed from slope changes of the force-frequency relation obtained when the heart rate increased, and also assessed while measuring triplane LV volumes and continuous noninvasive blood pressure, were related to death or rehospitalization during a 3-year follow-up. Other covariances tested were age, gender, disease etiology, QRS duration, amount of mitral regurgitation, LV diastolic volume, ejection fraction, and the degree of asynchrony and longitudinal strain at baseline. RESULTS: There was a marked increment in the Ees slope with CRT (interaction P = 0.004), no Ea change, and modest Ees/Ea increase (interaction P < 0.05). In Cox analysis, however, neither slope changes nor baseline values of Ees, Ea, and Ees/Ea were associated with long-term follow-up. Only ventricular diastolic volume (direct relation P = 0.002) and QRS duration (inverse relation P = 0.009) predicted death/rehospitalization. CONCLUSIONS: Acute contractile recovery in CRT patients is not associated with 3 years prognosis. Instead, death or rehospitalization can be predicted from QRS duration and LV diastolic volume at baseline. PMID- 28616530 TI - Resistance to renal denervation therapy - Identification of underlying mechanisms by analysis of differential DNA methylation. AB - BACKGROUND: Factors causing resistance to renal denervation (RDN) for treatment of arterial hypertension are not known. In the current study, we sought to determine mechanisms involved in responsiveness to renal denervation therapy in patients with difficult-to-control and resistant hypertension. METHODS AND RESULTS: We evaluated the differential CpG methylation of genes in blood samples isolated from patients of a recently described cohort of responders or non responders to renal denervation using microarray technique and measured protein levels of identified downstream effectors in blood samples of these patients by ELISA. Our analysis revealed up to 6103 methylation sites differing significantly between non-responders and responders to renal denervation therapy. Software based analysis showed several of these loci to be relevant for arterial hypertension and sympathetic nervous activity. Particularly, genes involved in glutamate synthesis, degradation and glutamate signaling pathways were differently methylated between both groups. For instance, genes for glutamate dehydrogenase 1 and 2 central to glutamate metabolism, genes for ionotropic (AMPA, NMDA) and metabotropic glutamate receptors as well as glutamate transporters revealed significant differences in methylation correlating with responsiveness to RDN. To underline their potential relevance for responsiveness to RDN, we measured plasma protein levels of norepinephrine, a downstream effector of the glutamate receptor pathway, which were significantly lower in non responders to RDN. CONCLUSIONS: The present study describes novel molecular targets potentially contributing to reduction of blood pressure after RDN in some patients. Identifying patients with a high responsiveness to RDN could contribute to an individualized therapy in drug resistant hypertension. PMID- 28616531 TI - Pulmonary hypertension: prevalence and risk factors. AB - INTRODUCTION: Pulmonary arterial hypertension (PAH), defined as a systolic pulmonary artery pressure above 35 mm Hg, is another vascular disease entity recently described in patients receiving hemodialysis. It is a major problem due to its high prevalence and morbidity and mortality. Its pathophysiological mechanism is just known and the strategies for its supported not yet defined. AIMS: To determine the prevalence of PAH in our hemodialysis patients and its risk factors. METHODOLOGY: Single center descriptive and analytical cross sectional study, including 111 hemodialysis patients who had benefit from a trans thoracic cardiac Doppler ultrasound during 2014. A value greater than or equal to 35 mm Hg is considered PAH and classified as follows: mild PAH (35 50 mm Hg), moderate PAH (50 70 mm Hg), and severe pulmonary hypertension (> 70 mm Hg). Patients with a high probability of secondary PAH, especially those with the following history: chronic obstructive pulmonary disease, pulmonary embolism, were not included. RESULTS: The mean age was 44.3 +/- 14.2 years. Among the 111 patients, 18 had pulmonary arterial pressure above 35 mm Hg corresponding to 16.22% of PAH prevalence. The average pressure was 45 mm Hg. Of these 18 patients, 11.8% had mild PAH, 3.4% moderate PAH and 0.8% severe PAH. The average hemodialysis duration was significantly associated with PAH (p = 0.003); as well as valvular calcification (p = 0.000), mitral regurgitation (p = 0.001) and tricuspid regurgitation (p = 0.002). CONCLUSION: Primary pulmonary hypertension is a major problem among our hemodialysis because of its high prevalence and its risk factors. PMID- 28616532 TI - Impact and evolution of right ventricular dysfunction after successful MitraClip implantation in patients with functional mitral regurgitation. AB - BACKGROUND: Right ventricular dysfunction (RVdysf) is a predictor of poor outcome in patients with heart failure and valvular disease. The aim of this study was to evaluate the evolution and the impact of RVdysf in patients with moderate-severe functional mitral regurgitation (FMR) successfully treated with MitraClip. METHODS AND RESULTS: From October 2008 to July 2014, 60 consecutive high surgical risk FMR patients were evaluated and stratified into two groups: RVdysf group (TAPSE < 16 mm and/or S'TDI < 10 cm/s, 21 patients) and No-RVdysf group (38 patients). The overall mean age of patients was 73 +/- 8 (83% male). Ischemic FMR etiology was present in 67%. Mean LVEF was 30 +/- 10%. Overall mean time follow up was 565 +/- 310 days. The only significant difference between the two groups was a greater prevalence of stroke, ICD and use of aldosterone antagonist in RVdysf group. Acute procedural success was achieved in 90% of patients. At 6 month echo-matched analysis significant RV function improvement was observed in patients with baseline RVdysf (TAPSE 15 +/- 3.0 vs. 19 +/- 4.5, p = 0.007; S'TDI 7 +/- 1.2 vs. 11 +/- 2.8, p < 0.0001; baseline vs. 6-month, respectively). The mean improvement in the 6-min walking test was significant in both groups (120 and 143 m, RVdysf and No-RVdysf groups, respectively). At Kaplan-Meier analysis, the presence of RVdysf did not affect the outcome in terms of freedom from composite efficacy endpoint. CONCLUSIONS: This study shows that successful MitraClip implantation in patients with FMR and concomitant right ventricular dysfunction yields significant improvement of RV function at mid-term follow-up. Further data on larger population will be required to confirm our observations. PMID- 28616533 TI - Differences between Takotsubo cardiomyopathy and reverse Takotsubo cardiomyopathy associated with subarachnoid hemorrhage. AB - BACKGROUND: Both Takotsubo cardiomyopathy (TTC) and reverse TTC (r-TTC) are characterized by reversible regional wall motion abnormalities of the heart unrelated to coronary artery pathology. It remains unclear whether and/or how r TTC differs from TTC. Subarachnoid hemorrhage (SAH) is occasionally causative of TTC/r-TTC, and this study was conducted to detect possible differences between TTC and r-TTC associated with SAH. METHODS: A single-center retrospective study was conducted on 328 consecutive SAH patients. They routinely underwent transthoracic echocardiography (TTE), ECG, and measurements of plasma catecholamines and other cardiac biomarkers within 24 h of admission. Demographic, echocardiographic, electrocardiographic and neurochemical profiles were compared between patients with TTC and r-TTC. The diagnosis of TTC/r-TTC was based on the revised Mayo Clinic Criteria. RESULTS: Data of 21 SAH-induced TTC and 10 SAH-induced r-TTC patients admitted between January 2009 and December 2014 were analyzed. The patients with r-TTC were significantly younger than those with TTC (51.8 +/- 10.9 vs. 63.5 +/- 14.4 years, p = 0.04). The former exhibited significantly higher plasma epinephrine levels than the latter (809 +/- 710 vs. 380 +/- 391 pg/mL, p = 0.04). Plasma norepinephrine levels did not differ significantly (2421 +/- 1374 vs. 1724 +/- 1591 pg/mL, p = 0.25). No significant differences were observed in other demographic/physiologic variables, echocardiographic parameters, frequency of ECG abnormalities, and 90-day mortality. Moreover, none of the patients who underwent a follow-up TTE exhibited morphologic change from one type to the other. CONCLUSIONS: The pathomechanisms in TTC and r-TTC may not be identical: however, distinguishing the two conditions may not have great importance from the standpoint of clinical management and prognostication. PMID- 28616534 TI - Comparison of circadian, weekly, and seasonal variations of electrical storms and single events of ventricular fibrillation in patients with Brugada syndrome. AB - In patients with Brugada syndrome (BS), VF occurred predominantly during the nocturnal period. Some patients also developed ESs. In addition to the circadian rhythm, patients showed weekly and seasonal patterns. The patients with ESs had peak episodes of VF on Saturday and in the winter and spring, while episodes of VF in patients with single VF events occurred most often on Monday with smaller seasonal variation. Except for age, there was no difference in the clinical or ECG characteristics between the patients with ESs and those with single VF episodes. PMID- 28616535 TI - Effect of intravenous infusion of iodinated contrast media on the coronary blood flow in dogs. AB - BACKGROUND: Coronary computed tomography angiography (CCTA) is obtained using peripheral intravenous iodinated contrast agents (ICA) injection. There is continuing attempts to derive coronary physiological information like coronary blood flow (CBF) and/or fractional flow reserve from CCTA images. However, no data is available regarding the effect of peripheral intravenous injection of ICA on CBF. METHODS: A series of 4 experiments was performed using healthy mongrel dogs. All dogs underwent anesthesia and open thoracotomy with placement of ultrasound flowmeter to one of the coronary artery to provide real time absolute CBF measurements. Different infusion protocols of Isovue-370 and Visipaque-320 were injected into a peripheral vein. Similar doses of normal saline injection were performed to be used as controls. The effect of iodinated contrast media injection on absolute coronary blood flow was monitored and recorded. RESULTS: Injection of normal saline in the peripheral vein did not produce any significant increase in CBF. Peripheral intravenous injection of ICA resulted in a consistent increase of 40-73% in absolute CBF as recorded 5 minutes post-contrast administration. The contrast effect starts about 30 seconds and peaks at about 2 minutepost-contrast injection then slowly fades away in the following 10-15 min. The increase in the CBF was dose related. There was greater increase in the CBF to 50 ml infusion compared to 25 ml infusion of both Visipaque and Isovue. CONCLUSIONS: Peripheral venous administration of iodinated contrast-media in dogs results in a dose related, significant and prolonged increase in CBF. PMID- 28616536 TI - NT-proBNP and diastolic left ventricular function in patients with Marfan syndrome. AB - AIMS: Subclinical diastolic dysfuntion in patients with preclinical heart failure with preserved ejection fraction (HFpEF) has been demonstrated in patients with Marfan syndrome (MFS). We investigated the relationship between diastolic dysfunction and NT-proBNP levels in patients with MFS. METHODS AND RESULTS: NT proBNP, C-reactive protein (CRP) and diastolic function were assessed in 217 patients with MFS (31 +/- 16 y, 110 f. and in 339 patients referred for suspected MFS in whom the diagnosis was ruled out according to the Ghent nosology (30 +/- 15 y, 154 f). Assessment of cardiovascular remodeling, diastolic function in echocardiography, and NT-proBNP was analyzed with univariate analysis and multi parameter analysis of covariance (MANCOVA). NT-proBNP was 70.6 +/- 74.8 pg/ml in patients with Marfan syndrome and 58.4 +/- 100.3 pg/ml in controls (p = 0.002, Kolmogorov-Smirnov). There were significant intergroup differences regarding end diastolic left ventricular volume (p < 0.001), and aortic diameter (p < 0.001). The ratio of early diastolic mitral flow velocity (E) to early relaxation velocity in tissue Doppler (e'), E/e' (p < 0.001) was significantly higher in patients with Marfan syndrome than in controls, whereas e' (p < 0.001) and the ratio of E to inflow velocity during atrial contraction (A), E/A (p = 0.012) was significantly lower. Besides age and gender, diagnosis of MFS, diastolic function (e' and E/e'), Z-Score of aortic diameter, and left ventricular size were identified as significant independent parameters with impact on NT-proBNP levels. CONCLUSIONS: MFS patients presenting with normal ejection fraction show disturbed diastolic function and higher NT-proBNP levels, which is partly explained by aortic Z-score. Assessment of diastolic function and NT-proBNP levels may therefore detect early abnormalities and guide surveillance and prevention management of patients with MFS. PMID- 28616537 TI - Congenital arch vessel anomalies in CHARGE syndrome: A frequent feature with risk for co-morbidity. AB - BACKGROUND: CHARGE syndrome is a complex multiple congenital malformation disorder with variable expression that is caused by mutations in the CHD7 gene. Variable heart defects occur in 74% of patients with a CHD7 mutation, with an overrepresentation of atrioventricular septal defects and conotruncal defects - including arch vessel anomalies. METHODS AND RESULTS: We report an index patient with an arch vessel anomaly underlying serious feeding problems that resolved after arch vessel surgery. This led us to examine the incidence of arch vessel anomalies in our previously studied cohort of 299 patients with a CHD7 mutation. Forty-two patients (14%) had an aortic arch anomaly, mostly aberrant subclavian artery or right aortic arch, which usually occurred in combination with other congenital heart defects (81%). The majority of these patients also had feeding problems that may be linked to their arch anomaly, but insufficient information was available to exclude other causes. CONCLUSIONS: Arch vessel anomalies occur in a significant proportion of patients with a CHD7 mutation, and these anomalies may cause morbidity due to compression of the esophagus or trachea. Since symptoms of vascular compression can mimic those caused by other abnormalities in CHARGE syndrome, it is important to be aware of arch vessel anomalies in this complex patient category. Whether a solitary arch vessel anomaly is an indicator for CHARGE syndrome still needs to be studied, but doctors should look out for other CHARGE syndrome features in patients with arch vessel anomalies. PMID- 28616538 TI - Aorto-ostial atherosclerotic coronary artery disease-Risk factor profiles, demographic & angiographic features. AB - BACKGROUND: The risk factors along with demographic and angiographic features associated with aorto-ostial atherosclerotic coronary artery disease usually differ from that of non-aorto-ostial atherosclerotic coronary artery disease. OBJECTIVES: This study was designed to evaluate etiology of aorto-ostial atherosclerotic coronary artery disease involving left main coronary artery (LMCA), right coronary artery or both with consideration of clinical risk factors, demographic and angiographic features. METHODS: A total of 7356 angiograms over 2 years in continuation were analyzed. RESULTS: 116 patients were found to have aorto-ostial coronary artery disease with prevalence of 1.5. A total of 95 patients who have complete data were analyzed. Mean age was 59 +/- 10 years. Prevalence in males was 5.7 times greater than female. Isolated ostial LMCA was 2 times more prevalent than isolated ostial RCA. Hypertension, diabetes and smoking were the main risk factors. 34.7% of the patients had hypercholesterolemia (> 180 mg/dl) and 26.3% of the patients had hypertriglyceridemia (> 150 mg/dl). High TC/HDL (> 3.5) ratio was seen in 77.9% of the patients. When ostial LMCA group was compared with ostial RCA group hypertriglyceridemia (Odds ratio 9.8, 95% CI, 1.7-4.2, P < 0.001) and hypercholesterolemia (Odds ratio 7.05, 95% CI, 1.7-5.7, P < 0.001) emerged as independent risk factors for ostial LMCA disease. CONCLUSION: Overall there is 1.5% prevalence of atherosclerotic aorto-ostial disease of coronary arteries among patients of atherosclerotic coronary artery disease and higher proportions of patients are of male sex. Hypercholesterolemia, hypertriglyceridemia and high TC/HDL ratio can be considered as risk factors for aorto-ostial atherosclerotic coronary artery disease. PMID- 28616539 TI - Idiopathic sensorineural hearing loss is associated with endothelial dysfunction. PMID- 28616540 TI - The fate of small side branches following drug eluting stent implantation. AB - OBJECTIVES: Although drug eluting stents (DES) have documented convenience in bifurcation lesions, possible unfavorable effects on small side branch ostium (SBO) remain a question. We aimed to explore the effects of DES on small jailed SBs (1.5-2.25 mm) which originated from the lesion on the main vessel and were not treated with either stenting or balloon dilatation. METHODS: Angiographic data of 107 consecutive patients (129 SB) with Medina 1,1,1 or 1,1,0 lesions were evaluated at the time of procedure and at the follow-up. RESULTS: Of all DES used, 70 (54.7%) was sirolimus-eluting, 39 (30.5%) was paclitaxel-eluting and 20 (14.8%) was zotarolimus-eluting. The diameter of SBs was 1.84 +/- 0.41 mm with a stenosis of 20.7 +/- 26.6% at SBO at baseline. The lesion at the SBO had progressed after the procedure when the pre vs postprocedure values and follow-up vs pre-procedure values are compared (20.7 +/- 26.6% vs 29.4 +/- 27.4%; p < 0.0001 and 25.4 +/- 25.1 vs 20.7 +/- 26.6%; p = 0.004 respectively). A significant reduction in stenosis was revealed over the follow-up (29.4 +/- 27.4 vs 25.4 +/- 25.1 respectively; p = 0.013). The severity of the disease at the SBO at baseline was the only parameter that affected the severity of SB stenosis in acute, longterm and follow-up. Additional parameters with influence on SB patency at different times were female gender, stent deployment with low pressure, cTFC of the main lesion, age, cTFC of the lesion, late loss index and the preprocedure TIMI flow grade of the SB. CONCLUSIONS: Although there was a significant deterioration of SBO immediately after stenting, follow-up data showed that the lesion at SBO improved but remained worse than baseline. PMID- 28616541 TI - Accuracy of quantitative echocardiographic measures of right ventricular function as compared to cardiovascular magnetic resonance. AB - BACKGROUND: Many echocardiographic parameters have been proposed to evaluate right ventricular (RV) systolic function. We comprehensively assessed a wide range of quantitative echocardiographic parameters in a single cohort compared with same-day cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: 92 subjects were examined prospectively: Group 1 consisted of 46 healthy controls (21 males, 33.4 +/- 11.4 years), Group 2 consisted of 46 patients (20 males, 38.5 +/- 18.9 years) undergoing RV functional assessment by CMR (1.5 T). Echocardiography was performed on the same day as CMR; fractional area change (RVFAC), myocardial performance index via spectral Doppler (RVMPI), RVMPI via Doppler tissue imaging (RVMPI-DTI), peak systolic myocardial velocity by DTI (RVSm), tricuspid annular plane systolic excursion (TAPSE), speckle tracking strain, and three dimensional right ventricular ejection fraction (3DE-RV). Linear regression, Bland-Altman and receiver-operator-characteristic (ROC) analyses were performed. At ROC analysis, the most predictive echocardiographic methods were; RVFAC (AUC = 0.892), RVMPI (AUC 0.785), TAPSE (AUC 0.849) and 3DE RV (AUC 0.909). 3DE-RV appeared the most accurate compared to CMR, although underestimated true RV volumes. CONCLUSION: As compared to CMR; 3DE-RV, RVFAC, TAPSE and RVMPI were the most reliable predictors of RV function. These parameters can be recommended for clinical use. PMID- 28616542 TI - Assessment of pulmonary artery pressure by echocardiography-A comprehensive review. AB - Pulmonary hypertension is a pathological haemodynamic condition defined as an increase in mean pulmonary arterial pressure >= 25 mmHg at rest, assessed using gold standard investigation by right heart catheterisation. Pulmonary hypertension could be a complication of cardiac or pulmonary disease, or a primary disorder of small pulmonary arteries. Elevated pulmonary pressure (PAP) is associated with increased mortality, irrespective of the aetiology. The gold standard for diagnosis is invasive right heart catheterisation, but this has its own inherent risks. In the past 30 years, immense technological improvements in echocardiography have increased its sensitivity for quantifying pulmonary artery pressure (PAP) and it is now recognised as a safe and readily available alternative to right heart catheterisation. In the future, scores combining various echo techniques can approach the gold standard in terms of sensitivity and accuracy, thereby reducing the need for repeated invasive assessments in these patients. PMID- 28616543 TI - Transcatheter aortic valve implantation with the new-generation Evolut RTM: Comparison with CoreValve(r) in a single center cohort. AB - BACKGROUND: The Medtronic Evolut R (EVR) is a novel transcatheter heart valve designed to allow precise implantation at the intended position and to minimize prosthesis dysfunction as well as procedural complications. Our aim was to compare short-term functional and clinical outcomes of the new EVR with the established Medtronic CoreValve (CV) system. METHODS AND RESULTS: Of 151 patients undergoing transfemoral transcatheter aortic valve implantation with a self expanding valve at our institution between January 2013 and January 2016, 86 were treated with EVR and 65 with CV. Patients treated with EVR had a significantly lower rate of more-than-mild aortic regurgitation and a higher rate of device success. Recapture maneuvers to optimize valve deployment were performed in 22.1% of the EVR procedures. Transvalvular post-procedural gradients were slightly higher in the EVR group, while no differences were observed in the incidence of safety endpoints at 30 days, vascular complications, or need for permanent pacemaker implantation following asystole or complete atrioventricular block. CONCLUSIONS: These initial single-center experience data on the short-term outcomes after EVR valve implantation show a substantially reduced rate of more than-mild paravalvular regurgitation and higher device success, while 30-day safety outcomes were similar to the CV system. Clinical outcome data from long term follow-up and larger scale multicenter experience are now necessary. PMID- 28616544 TI - Dental care before cardiac valve surgery: Is it important to prevent infective endocarditis? AB - BACKGROUND: Infective endocarditis (IE) is a serious disease that affects the surface of the endocardium. The spread of microorganisms from the oral cavity has been associated with the occurrence of IE. OBJECTIVE: To analyze whether dental treatment before cardiac valve surgery (CVS) influenced the occurrence of IE. METHODS: We performed a retrospective analysis of the medical and dental histories of patients undergoing CVS from 2004 to 2014. The sample consisted of 481 patients who underwent CVS divided into two groups: patients submitted to dental treatment prior to CVS (n = 110) and patients undergoing CVS without dental treatment (n = 371). RESULTS: Of the total sample, 38 patients (8%) were diagnosed with IE. No significant difference was detected (p = 0.496) in comparing the occurrence of IE in the group with dental preparation (6.4%) and without dental preparation (8.4%). The logistic regression model confirmed that dental treatment did not change the IE risk (p = 0.504) and indicated that age (p < 0.003) and gender (p = 0.013) were significant risk factors for IE. There was a high demand for dental procedures in the group receiving dental preparation, with no significant differences between the patients with or without IE. Hemoculture indicated qualitative differences in comparing patients with and without dental treatment, especially in the frequency of Staphylococcus and Streptococcus. CONCLUSIONS: The results did not allow for the determination of the impact of dental treatment before CVS on IE outcomes. However, it was not possible to exclude the potential beneficial effects of dental treatment in the prevention of IE. PMID- 28616545 TI - Assessment of various parameters using simple non-invasive tests in patients with cardiovascular diseases with or without cardiac rehabilitation. AB - Cardiac rehabilitation (CR) improves cardiac function and exercise capacity in patients with cardiovascular disease (CVD). Simpler techniques are needed for use by physicians in the examination room to assess the usefulness of CR. We enrolled 46 consecutive CVD patients in a CR program (CR group) and prospectively followed them for 3 months. We compared them to 18 age-, gender- and body mass index matched CVD patients without CR (non-CR group). Various parameters were measured at baseline and after 3 months using 3 simple non-invasive tests: severity of atherosclerosis [arterial velocity pulse index and arterial pressure volume index (API)] were determined using PASESA(r), an autonomic nerve total activity amount index and a coefficient of variation of the R-R interval (CVRR) were determined using eHEART(r), and peripheral resistance index, pressure rate product, stroke volume and cardiac index were determined using nico(r)]. There were no significant differences in patient characteristics including percentages (%) of ischemic heart disease and heart failure between the non-CR and CR groups. Systolic blood pressure (SBP), diastolic BP, heart rate and API at baseline significantly decreased and CVRR at baseline significantly increased after 3 months in the CR group, but not in the non-CR group. In addition, DeltaAPI (Delta = the value after 3 months minus the value at baseline) was positively associated with DeltaSBP in the CR group. In conclusion, CR significantly decreased BP and improved atherosclerosis and sympathetic nerve activity. These findings suggest that simple non-invasive tests may be useful for assessing the effects of CR. PMID- 28616546 TI - Late gadolinium enhancement does occur in Tako-tsubo cardiomyopathy - A quantitative cardiac magnetic resonance and speckle tracking strain study. AB - BACKGROUND: Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) has been recommended to distinguish Tako-tsubo cardiomyopathy (TTC) from either acute myocardial infarction or myocarditis. METHOD: 44 consecutive patients with confirmed Mayo Clinic criteria for TTC underwent CMR imaging at 1.5 Tesla during the acute phase. 10 patients who had CMRI to exclude scar related ventricular tachycardia, and had negative studies, were used as negative controls. LGE was quantitated at two signal intensity thresholds (CircleCVi software) at > 2 and > 5 standard-deviations (SD) above reference myocardium, and compared to biomarkers. FINDINGS: Mean door-to-CMR time was 57 hours. 18 patients (41%) had LGE > 2 SD localized to the area of abnormal wall motion, representing 28.9 +/- 11.2% LV mass. In 16 of these 18 patients (89%) LGE signal intensity was > 5 SD above normal myocardium, representing 12.1 +/- 10% LV mass. LGE signal intensity was significantly greater in TTC than in matched controls (p < 0.05) but lower than in STEMI patients (p < 0.05). Mean troponin was significantly higher in LGE positive patients (2.5 +/- 1.8 vs 4.4 +/- 6.9, p = 0.001). Mean ejection fraction (EF) by CMR was 45% +/- 8.7 in LGE-negative, and 40% +/- 7.1 in LGE-positive patients (p = 0.37). Recovery of segmental function was confirmed at follow-up, mean EF was 59% in both groups. CONCLUSION: LGE was present in 41% of cases of TTC, 89% of which had intense enhancement > 5 SD above normal myocardium. Presence of LGE was associated with worse myocardial injury in the acute setting, with no difference in recovery of function. PMID- 28616547 TI - Predictors of tamponade and constriction in patients with pericardial disease undergoing interventional and surgical treatment. AB - OBJECTIVE: The aim of our study was to define predictors of cardiac compression development including clinical, electrocardiographic, echocardiographic, chest-X ray and perioperative parameters and their diagnostic value. METHODS: Overall 243 patients with pericardial disease, among them 123 with compression (tamponade, constriction) and 120 without signs of compression were included in the study. Clinical, laboratory, electrocardiographic, chest-X-Ray, echocardiographic and perioperative data were included in the logistic regression analysis to define predictors of tamponade/constriction development. RESULTS: Logistic regression analysis demonstrated large effusion (> 20 mm) (OR 5.393, 95%CI 1.202-24.199, p = 0.028), cardiac chamber collapse (OR 31.426, 95%CI 1.609-613-914, p = 0.023) and NYHA class > 3 (OR 8.671, 95%CI 1.730-43.451, p = 0.009) were multivariable predictors of compression development. The model including these three variables allowed predicting compression in 91.7% of cases. ROC analyses demonstrated that all three variables had significant diagnostic value with sensitivity of 75.6% and specificity of 74.2% for large effusion, low sensitivity and high specificity for cardiac chamber collapse (35% and 92%) and NYHA class (32.5% and 94.2%). CONCLUSION: The independent predictors of compression development are presence of large effusion > 20 mm, cardiac chamber collapse and high NYHA class. The model including all three parameters allows correctly predicting compression in 91.4% of cases. The diagnostic accuracy of each parameter is characterized by high sensitivity and specificity of large effusion, high specificity of cardiac chamber collapse and NYHA class. PMID- 28616548 TI - A case of massive aortic mural thrombus in the absence of atherosclerotic or aneurysmal disease. PMID- 28616549 TI - Changes in the risk factors for coronary spasm. PMID- 28616550 TI - Is HATCH score a reliable predictor of atrial fibrillation after cavotricuspid isthmus ablation for typical atrial flutter? AB - OBJECTIVE: We determined the effectiveness of the HATCH score in patients with typical atrial flutter (AFl) undergoing cavotricuspid isthmus (CTI) ablation to predict long-term atrial fibrillation (AF). METHODS: We conducted an observational retrospective single-center cohort study including all patients admitted to our hospital for a CTI ablation between 1998 and 2010. The patients were divided into four categories: 1) new-onset AF (no prior AF and AF during follow-up (FU)); 2) old AF (prior AF and no AF during FU); 3) prior and post AF (AF prior and post CTI ablation); and 4) no AF. RESULTS: Four hundred and eight patients were included. In patients without prior AF, the hazard ratio (HR) for new-onset AF during FU was 0.98 (CI 95%: 0.65-1.50; p = 0.95) and 1.00 (CI 95%: 0.57-1.77; p = 0.98) for HATCH >= 2 and HATCH >= 3, respectively. In patients with prior AF, the HR for AF was 1.41 (CI 95%: 0.87-2.28; p = 0.17) and 1.79 (CI 95%: 0.96-3.35; p = 0.06), for HATCH >= 2 and HATCH >= 3, respectively. Left atrial enlargement was positively correlated with the occurrence of AF during FU, especially in the subgroup without prior AF, which had a HR of 2.44 (CI 95%: 1.35 4.40; p = 0.003), a HR of 2.88 (CI 95%: 1.36-6.10; p = 0.006) and a HR of 3.68 (CI 95%: 1.71-7.94; p = 0.001), for slight, moderate and severely dilated left atrial dimension, respectively, compared with a normal value. CONCLUSIONS: HATCH score did not predict AF in patients with typical AFl who underwent CTI ablation. Basal left atrium dimension could help predict new-onset AF. PMID- 28616551 TI - Letter to Editor. PMID- 28616552 TI - Effectiveness of renal sympathetic denervation in renal function and blood pressure in CKD and non-CKD patients with controlled vs. uncontrolled hypertension. PMID- 28616553 TI - Femoral arterial closure using ProGlide(r) is more efficacious and cost-effective when ambulating early following cardiac catheterization. AB - OBJECTIVE: This was a prospective, single-center study evaluating the efficacy and cost-effectiveness of early ambulation (within 30 min) following femoral artery closure with the ProGlide(r) suture-mediated vascular closure device (PD) in patients undergoing diagnostic cardiac catheterization compared with manual compression. BACKGROUND: It is unclear whether early ambulation with ProGlide is safe or is associated with patient satisfaction and cost savings as compared with manual compression (MC). METHODS AND RESULTS: Inclusion criteria were met in 170 patients (85 PD and 85 MC patients). Patients ambulated 20 ft. within 30 min (PD) or after the requisite 4 h recumbent time (MC) if feasible. Primary endpoint was time-to-ambulation (TTA) following device closure. We also directly compared the safety of closure, times-to-hemostasis (TTH), -ambulation (TTA) and -discharge (TTD) with MC and, using a fully allocated cost model, performed cost analysis for both strategies. Multivariate analysis was used to determine predictors of patient satisfaction. The primary endpoint of safe, early ambulation was achieved following closure (mean of 27.1 +/- 14.9 min; 95% confidence interval [CI] 25.2 30.2). Predictors of patient satisfaction in the PD group were absence of pain during closure, decreased TTA, and drastic reductions in TTD; the latter contributed indirectly to significant cost savings in the PD group (1250.3 +/- 146.4 vs. 2248.1 +/- 910.2 dollars, respectively; P < 0.001) and incremental cost savings by strategy also favored closure over MC ($84,807). CONCLUSIONS: ProGlide is safe and effective for femoral artery closure in patients who ambulate within 30 min after cardiac catheterization; translating into improved patient satisfaction and substantial cost savings. PMID- 28616554 TI - Alpha2A-adrenergic receptor and eNOS genetic polymorphisms are associated with exercise muscle vasodilatation in apparently healthy individuals. AB - PURPOSE: Muscle vasodilatation during exercise has been associated with cardiovascular health and may be influenced by genetic variability. The purpose of this study was to evaluate functional genetic polymorphisms of physiologic pathways related to the regulation of the cardiovascular function (alpha adrenergic receptors, endothelial nitric oxide synthase and bradykinin B2 receptor) and exercise muscle vasodilatation in apparently healthy men and women. METHODS: We enrolled 689 individuals without established cardiovascular disease that had attended a check-up program. The vasodilatation was studied with venous occlusion plethysmography and determined by the increase of vascular conductance during handgrip exercise. Genotypes for ADRA1A Arg347Cys (rs1048101), ADRA2A 1780 C > T (rs553668), ADRA2B Del 301-303 (rs28365031), eNOS 786 T > C (rs2070744), eNOS Glu298Asp (rs1799983) and BDKRB2 (rs5810761) polymorphisms were assessed by polymerase chain reaction followed by high resolution melting analysis. RESULTS: The eNOS rs2070744 polymorphism was significantly associated with forearm vascular conductance during exercise in women. Women with CC genotype showed higher vasodilatation than carriers of TC and TT genotypes (p = 0.043). The ADRA2A rs553668 polymorphism was significantly associated with forearm vascular conductance during exercise in men. Men with TT genotype had higher vasodilatation than carriers of CT and CC genotypes (p = 0.025). CONCLUSIONS: eNOS rs207074 polymorphism in women and ADRA2A rs553668 polymorphism in men were associated with the increase of forearm vascular conductance during handgrip exercise. These findings suggest that eNOS and ADRA2A genetic polymorphisms may be potential markers of exercise muscle vasodilatation. PMID- 28616555 TI - MTRR rs326119 polymorphism is associated with plasma concentrations of homocysteine and cobalamin, but not with congenital heart disease or coronary atherosclerosis in Brazilian patients. AB - BACKGROUND: Differences in the distribution of the MTRR rs326119 polymorphism (c.56 + 781 A > C) between patients with congenital heart disease (CHD) and controls have been described in Chinese individuals. The association is thought to be due to deregulation of homocysteine-cobalamin pathways. This has not been replicated in other populations. The primary objective of this study was to assess the influence of the MTRR rs326119 polymorphism on biochemical parameters of vitamin B12 metabolism, coronary lesions, and congenital heart disease in Brazilian subjects. METHODS: We selected 722 patients with CHD, 1432 patients who underwent coronary angiography, and 156 blood donors. Genotyping for the MTRR polymorphism was evaluated by high-resolution melting analysis, and biochemical tests of vitamin B12 metabolism were measured. RESULTS: Subjects carrying the AC or CC genotypes had higher homocysteine concentrations (9.7 +/- 0.4 MUmol/L and 10.1 +/- 0.6 MUmol/L) and lower cobalamin concentrations (260.5 +/- 13.3 pmol/L and 275.6 +/- 19.9 pmol/L) compared with the subjects carrying the AA genotype (8.7 +/- 0.5 MUmol/L and 304.8 +/- 14.7 pmol/L), respectively. A multiple linear regression model also identified a significant association between the number of C variant alleles with the concentrations of homocysteine and cobalamin. Nonetheless, the allelic and genotypic distributions for MTRR rs326119 were not associated with CHD or coronary atherosclerosis in the studied samples. CONCLUSION: Our findings indicate that the MTRR rs326119 variant might be a genetic marker associated with homocysteine and cobalamin concentrations, but not a strong risk factor for CHD or coronary atherosclerosis in the Brazilian population. PMID- 28616556 TI - The role of optical coherence tomography in decision making during the acute phase of spontaneous coronary artery dissection. PMID- 28616557 TI - Dipyridamole-induced adverse effects in myocardial perfusion scans: Dynamic evaluation. AB - AIM AND BACKGROUND: Dipyridamole-induced stress myocardial perfusion scans (MPS) has been widely used for management of coronary artery disease. The adverse effects of dipyridamole and other stress agents have been evaluated. The aim of this research is to confirm the dynamic data on dipyridamole side effects during MPS. METHODS: We collected data of 183 patients who underwent dipyridamole induced stress MPS by retrospectively reviewing their clinical records, which included the severity of dipyridamole side effects in 3 min, 10 min, and 20 min after infusion. The incidence and severity at all three points, including the effect of age and gender, were obtained. RESULTS: Adverse effects occurred in 96 patients (69.6%). The most frequent symptoms were dizziness (42.8%), chest tightness (24.6%), abdominal pain (18.1%), and headache (15.2%). Most symptoms were Grade 1 to 2, according to the grading system for common terminology criteria. The median duration of symptom persistence was 36 min, not significantly different among age and gender. CONCLUSION: This study demonstrates that the adverse effects of dipyridamole were generally minimal and its duration was acceptable for clinical usage. PMID- 28616558 TI - Left ventricular diastolic gradient in hypertrophic cardiomyopathy. PMID- 28616559 TI - Gender differences in the prevalence of coronary artery tortuosity and its association with coronary artery disease. AB - BACKGROUND: Little is known about the significance of severe coronary tortuosity (SCT) despite it being a relatively common finding on coronary angiography. We examined whether the presence of tortuosity was influenced by gender or cardiac risk factors. METHODS AND RESULTS: We examined 870 patients (Men = 589, Women = 281) who presented to Westmead Hospital, Sydney, Australia for invasive coronary angiography for the assessment of chest pain due to suspected CAD. Female gender and age were significantly associated with SCT (p < 0.001 for age) with 45.2% of women having SCT as opposed to 19.7% of men (p < 0.001). Men with SCT had lower Extent scores only compared than those without tortuosity (22.4 vs. 32.4, p = 0.003). However, women with SCT had less severe coronary artery disease than those with no SCT as measured by both the Extent score (12.4 vs. 19.1, p = 0.03) and Gensini score (10.4 vs. 15.5, p = 0.02). CONCLUSION: There is a significant relationship between coronary artery tortuosity and gender. Women with severe tortuosity are more likely to have normal coronary arteries or less severe disease than men despite presenting with chest pain. PMID- 28616560 TI - Successful revascularization improves long-term clinical outcome in patients with chronic coronary total occlusion. AB - BACKGROUND: Following the development of breakthrough techniques for percutaneous coronary intervention (PCI) in the treatment of chronic total occlusions (CTO), the initial success rate of PCI in CTO lesions (CTO-PCI) has improved; however, there are few reports regarding the effects of successful CTO revascularization on long-term mortality in Japan. The aim of this study was to compare the long term clinical outcomes of patients with successful versus failed CTO recanalization and to identify related factors. METHODS AND RESULTS: From all PCI procedures performed in our hospital between 2006 and 2013, CTO-PCIs were extracted and classified into two groups: PCI success (n = 656 patients) and PCI failure (n = 82 patients). Patients with successful procedures only on a second attempt, CTO-PCI in small branches, or CTOs in more than one vessel were excluded. Survival was determined from a telephone interview or the consultation history in the outpatient clinic. Initial angiographic success was achieved in 88.9% of the patients. A Kaplan-Meier plot with log-rank analysis showed that cumulative all-cause death was significantly lower in the success group than in the failure group (p = 0.0003; average follow-up duration in success group vs. failure group was 1531.3 +/- 33.5 vs. 1565.3 +/- 97.5 days, p = 0.7). Moreover, the rate of evident cardiac death was significantly lower in the success group than in the failure group (3.5% [23/656] vs. 15.9% [13/82], p < 0.0001). CONCLUSIONS: This study suggests that successful revascularization in patients with CTO improves their long-term clinical outcomes. PMID- 28616561 TI - Left atrial appendage function assessment and thrombus identification. AB - BACKGROUND: The diagnosis of thrombus in the left atrium in patients with persistent atrial fibrillation (AF) and may be inconsistent because of variability in thrombus morphology. In some cases it is challenging and requires unusual approach. New Doppler-derived methods might be helpful to identify such thrombi. We evaluated quantitative differences in mechanical function of the left atrial appendage (LAA) basal segments using tissue Doppler imaging (TDI)and speckle tracking echocardiography (STE) in patients with non-valvular AF with and without LAA thrombus and compared them with SR patients. METHODS: A total of 80 patients with normal left ventricular ejection fraction underwent transesophageal echocardiography (40 patients with SR and 40 patients with AF on oral anticoagulants including patients with LAA thrombus). We analyzed the basal segments of LAA including left lateral ridge (LLR) and baso-medial appendage segment (BMAS). Quantitative analysis was used to calculate peak velocity, average velocity, strain, strain rate and deformation. RESULTS: In patients with AF the lower LLR strain rate was the sole new STE significant parameter differentiating patients with and without LAA thrombi: - 0.9(- 1.2; - 0.1)s- 1 vs. - 1.6(- 1.9; - 1.3)s- 1, (p = 0.004). Additionally, patients in SR demonstrated significantly better peak velocity, average velocity, strain, strain rate and deformation than those with AF (p < 0.001). CONCLUSIONS: LLR appeared to be an appropriate site for measuring Doppler derived parameters. It is possible that the strain rate in LLR area may be a novel parameter correlating with the presence of thrombus in patients with AF. PMID- 28616562 TI - Coronary calcification compromises myocardial perfusion irrespective of luminal stenosis. AB - AIM: The aim of this study was to evaluate the relationship between coronary artery calcification (CAC) assessed by multi-detector computed tomography (MDCT) and myocardial perfusion assessed by cardiac magnetic resonance imaging (CMR) in a group of symptomatic patients. METHOD: Retrospective analysis of 120 patients (age 65.1 +/- 8.9 years, 88 males) who presented with atypical chest pain to Bethanien Hospital, Frankfurt, Germany, between 2007 and 2010 and who underwent CAC scoring using MDCT, CMR, and conventional coronary angiography. Patients were divided into those with high-grade (HG) stenosis (n = 67, age 65.1 +/- 9.4 years) and those with no-HG stenosis (n = 53, age 65.1 +/- 8.6 years). RESULTS: There were more males with HG stenosis (82.1% vs. 62.3%, p = 0.015), in whom the percentage and number of abnormal perfusion segments were higher at rest (37.3% vs. 17%, p = 0.014) but not different with stress (p = 0.83) from those with no HG stenosis. Thirty-four patients had myocardial perfusion abnormalities at rest and 26 patients developed perfusion defects with stress. Stress-induced myocardial perfusion defects were 22.4% sensitive and 79.2% specific for detecting HG stenosis. The CAC score was lower in patients with no-HG stenosis compared to those with HG stenosis (p < 0.0001). On the ROC curve, a CAC score of 293 had a sensitivity of 71.6% and specificity of 83% in predicting HG stenosis [(AUC 0.80 (p < 0.0001)]. A CAC score of 293 or the presence of at least 1 segment myocardial perfusion abnormality was 74.6% sensitive and 71.7% specific in detecting HG stenosis, the respective values for the 2 abnormalities combined being 19.4% and 90.6%. The severity of CAC correlated with the extent of myocardial perfusion in the patient group as a whole with stress (r = 0.22, p = 0.015), particularly in those with no-HG stenosis (r = 0.31, p = 0.022). A CAC score of 293 was 31.6% sensitive and 87.3% specific in detecting myocardial perfusion abnormalities. CONCLUSION: In a group of patients with exertional angina, coronary calcification is more accurate in detecting high-grade luminal stenosis than myocardial perfusion defects. In addition, in patients with no stenosis, the incremental relationship between coronary calcium score and the extent of myocardial perfusion suggests coronary wall hardening as an additional mechanism for stress-induced angina other than luminal narrowing. These preliminary findings might have a clinical impact on management strategies of these patients other than conventional therapy. PMID- 28616563 TI - Low rate of access site complications after transradial coronary catheterization: A prospective ultrasound study. AB - BACKGROUND: Transradial artery (TRA) left heart catheterization is an increasingly used technique for both diagnostic and interventional coronary procedures. This study evaluates the incidence of access site complications in the current interventional era. METHODS AND RESULTS: A total of 507 procedures were performed under standardized conditions. Each procedure was performed using high levels of anticoagulation, hydrophilic sheaths, and short post-procedural compression times. Vascular complications were assessed one day after TRA catheterization using Duplex sonography and classified according to the necessity of additional medical intervention. A simple questionnaire helped identifying upper extremity neurologic or motor complications. Vascular complications were detected in 12 patients (2.36%): radial artery occlusion was detected in 9 patients (1.77%), 1 patient developed an AV-fistula (0.19%), and 2 patients had pseudoaneurysms (0.38%). None of the patients required specialized medical or surgical intervention. Under our procedural conditions, small radial artery diameter was the only significant predictor for the development of post procedural vascular complications (2.11 +/- 0.42 mm vs 2.52 +/- 0.39 mm, p = 0.001). None of the previously reported risk factors, namely, advanced renal failure, diabetes, acuteness/complexity of procedure, or sheath and catheter size significantly influenced the rate of vascular complications. No major hematoma or local neurologic or motor complications were identified. CONCLUSIONS: Using current techniques and materials, we report a very low rate of local complications associated with TRA catheterization. PMID- 28616564 TI - Regression of cardiac amyloidosis following stem cell transplantation: a comparison between echocardiography and cardiac magnetic resonance imaging in long-term survivors. AB - BACKGROUND: AL amyloidosis and multiple myeloma result in extracellular deposition of insoluble fibrillary protein in tissue and organs. Untreated median survival is very poor, and even worse with cardiac involvement. Chemotherapy and peripheral blood stem cell transplantation (PBSCT) have been shown to dramatically improve survival, with hematologic remission documented. Regression of cardiac changes has previously been shown, as assessed by echocardiography (TTE) and cardiac magnetic resonance imaging (CMR). This study is a comparison of TTE and CMR in long-term survivors of cardiac amyloidosis with regression. RESULTS: Four long-term survivors with cardiac amyloidosis and regression of cardiac features on TTE were identified. Mean age was 60 years and average survival was 139 months from the time of diagnosis of cardiac involvement. Statistically significant regression of the cardiac features of cardiac amyloidosis were demonstrated on TTE. In these survivors, post-PBSCT structural assessments were similar between TTE and CMR. Classical strain imaging features of cardiac amyloidosis were only present in 50%. All patients had diffuse, patchy gadolinium enhancement on CMR after PBSCT. CONCLUSIONS: Treatment of cardiac amyloidosis with chemotherapy and PBSCT may result in regression of abnormalities on TTE with marked improvement in survival. Post treatment, TTE and CMR structural assessments appear similar. Gadolinium imaging suggests that microscopic residual infiltration persists despite macroscopic regression. Significant cardiac improvements with prolonged survival are seen nonetheless. Multimodality imaging has a vital role in the management of cardiac amyloidosis. PMID- 28616565 TI - Lactated Ringer's solution for preventing myocardial reperfusion injury. AB - Reperfusion of ischemic myocardium is crucial for salvaging myocardial cells from ischemic cell death. However, reperfusion itself induces various deleterious effects on the ischemic myocardium. These effects, known collectively as reperfusion injury, comprise stunned myocardium, reperfusion-induced arrhythmia, microvascular reperfusion injury, and lethal reperfusion injury. No approach has proven successful in preventing any of these injuries in the clinical setting. My colleagues and I recently proposed a new postconditioning protocol, postconditioning with lactate-enriched blood (PCLeB), for the prevention of reperfusion injury. This new approach consists of intermittent reperfusion and timely coronary injections of lactated Ringer's solution, aiming to achieve controlled reperfusion with cellular oxygenation and minimal lactate washout from the cells. This approach appeared to be effective in preventing all types of reperfusion injury in patients with ST-segment elevation myocardial infarction (STEMI), and we have already reported excellent in-hospital outcomes of patients with STEMI treated using PCLeB. In this review article, I discuss a possible mechanism of reperfusion injury, which we believe to be valid and which we targeted using this new approach, and I report how the approach worked in preventing each type of reperfusion injury. PMID- 28616566 TI - The effects of fibrinolytic before referring STEMI patients: A systematic review and meta-analysis. AB - BACKGROUND: Accessibility of primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) in primary care settings is limited. Referring patients to PCI-capable hospitals might increase cardiac events. Hence, fibrinolytic injection before referring patients to PCI capable settings decreases cardiac events, however, the effect of fibrinolytic injection before the referral has not been systematically evaluated. This study aimed to systematically review the effect of fibrinolytic injection before referring patients with STEMI to PCI-capable settings. METHODS: A systematic search with Embase, Cochrane CENTRAL, Google scholar, and PubMed was conducted. Studies conducted in patients with STEMI presented to non PCI-capable settings and compared fibrinolytic injection with no injection before referring patients to PCI-capable settings were included. The primary outcome was the composite outcomes of major adverse cardiac events (MACEs) at 30 days. Meta-analyses were performed using random-effect model. RESULTS: Of 912 articles, three RCTs and three non-RCTs were included. Based on RCTs, fibrinolytic injection before the referral has failed to decrease MACEs compared to non-fibrinolytic injection [relative risk (RR) 1.18; 95% confidence interval (CI), 0.89-1.57, p = 0.237]. Fibrinolytic injection has also failed to decrease mortality, re-infarction, and ischemic stroke. On the other hand, fibrinolytic injection was associated with a higher risk of major bleeding. CONCLUSIONS: In non PCI-capable settings, fibrinolytic injection before referring patients with STEMI to PCI-capable settings has no clinical benefit but could increase risk of major bleeding. Clinicians might more carefully consider whether fibrinolytic injection should be used in patients with STEMI before the referral. PMID- 28616567 TI - CYP2C19 variants and epoxyeicosatrienoic acids in patients with microvascular angina. AB - BACKGROUND: Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the impact of CYP2C19 polymorphisms and EETs on the patients with microvascular angina (MVA) caused by coronary microvascular dysfunction. METHODS AND RESULTS: We examined CYP2C19 genotypes in patients with MVA (n = 81). MVA was defined as absence of coronary artery stenosis and epicardial spasms, and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. In MVA, the patients with CYP2C19 PM were 34.6% and high sense C-reactive protein (hs-CRP) levels in CYP2C19 PM were significantly higher than that of non-PM group (0.165 +/- 0.116 vs. 0.097 +/- 0.113 mg/dL, P = 0.026). Moreover, DHET levels in CYP2C19 PM were significantly lower than that of non-PM (10.4 +/- 4.58 vs. 15.6 +/- 11.1 ng/mL, P = 0.003 (11,12-DHET); 12.1 +/- 3.79 vs. 17.3 +/- 6.49 ng/mL, P = 0.019 (14,15-DHET)). CONCLUSIONS: The decline of EET owing to CYP2C19 variants may affects coronary microvascular dysfunction via chronic inflammation. PMID- 28616568 TI - Clinical evaluation of R860Q semi-conservative amino acid substitution in CACNA1C gene in association with long QT syndrome. PMID- 28616569 TI - Successful conservative treatment of myocardial infarction in a teenager with MTHFR mutation. PMID- 28616570 TI - A study of spectrum of rheumatic heart disease in a tertiary care hospital in Central Nepal. AB - BACKGROUND AND AIMS: Rheumatic heart disease is one of the most common cause for heart failure and associated mortalities/morbidities in the young population in developing countries like Nepal imparting huge familial, social and manpower burden. MATERIALS AND METHODS: This is a hospital based descriptive cross sectional study during June 2014 to April 2016 over a period of 22 months at College of Medical Sciences-Bharatpur including 235 patients with clinical and/or echocardiographic evidence of definite rheumatic heart disease. RESULTS: The age of the patients ranged from 7 to 76 years with mean age 39.82 +/- 4.2 years with female preponderance (F:M = 2.1:1) (p < 0.01). Majority of the rheumatic heart disease patients belonged to 30-44 years (28.78%) followed by 15-29 years (25.75%) and 45-59 years (25.00%). Majority belonged to the low socioeconomic status (60.60%) (p < 0.05). The predominantly involved isolated valve was mitral in 110 patients (46.80%) followed by isolated aortic valve in 22 patients (9.36%) and 79 (33.62%) had dual valvular involvement. The common rheumatic valvular lesions were pure mitral stenosis in 32 (13.61%), isolated mitral regurgitation in 58 (24.68%), combined mitral stenosis/regurgitation in 36 (15.32%), combined mitral/aortic regurgitation in 23 (9.78%) and combined aortic stenosis/regurgitation in 18 (7.66%) patients with few overlappings. The common complications encountered were heart failure in 90 (38.30%) and arrhythmias in 124 (51.00%) patients.130 patients (55.32%) received injectable benzathine penicillin whereas 45 patients (19.15%) preferred oral penicillin V. Surgical intervention was done in 54 (22.97%) patients. 12 (5.10%) expired in the CCU during the course of treatment. CONCLUSION: RHD is a leading cause of heart failure among young populations with requirement of prolonged duration of medical treatment and many of them requiring surgery. PMID- 28616571 TI - A time out for CENP-A. AB - Proper chromosome segregation relies on a functional centromere-kinetochore interface. We showed that chromatin containing CENtromere Protein A (CENP-A) is essential for centromere assembly, but dispensable for chromosome segregation in the presence of CENP-B-bound DNA sequences. This demonstrates the existence of two contact points between the DNA and the kinetochore to mediate successful chromosome segregation. PMID- 28616572 TI - Reversible lysine acetylation regulates nuclear translocation of TyrRS to counteract genotoxic oxidative stress. AB - Aminoacyl-tRNA synthetases, catalyzing the first step of protein synthesis, have been shown to involve with multiple additional physiologic responses. Here, we summarize our findings that p300/CBP-Associated Factor and Sirtuin 1 play the reversible acetylation role in regulating the nuclear translocation of Tyrosyl tRNA synthetase and activating transcription factor E2F1, thus facilitating the repair of damaged DNA. PMID- 28616574 TI - Therapeutic arginine starvation in ASS1-deficient cancers inhibits the Warburg effect. AB - Argininosuccinate Synthetase 1 deficiency induces dependence on extracellular arginine for continued cellular growth and survival. Arginine starvation inhibits the Warburg effect and diverts glucose into serine biosynthesis, while simultaneously increasing glutamine metabolism via the tricarboxylic acid cycle. Simultaneous arginine deprivation and inhibition of the subsequent metabolic adaptations induce synthetic lethality. PMID- 28616573 TI - YAP and the Hippo pathway in pediatric cancer. AB - The Hippo pathway is an important signaling pathway that controls cell proliferation and apoptosis. It is evolutionarily conserved in mammals and is stimulated by cell-cell contact, inhibiting cell proliferation in response to increased cell density. During early embryonic development, the Hippo signaling pathway regulates organ development and size, and its functions result in the coordinated balance between proliferation, apoptosis, and differentiation. Its principal effectors, YAP and TAZ, regulate signaling by the embryonic stem cells and determine cell fate and histogenesis. Dysfunction of this pathway contributes to cancer development in adults and children. Emerging studies have shed light on the upregulation of Hippo pathway members in several pediatric cancers and may offer prognostic information on rhabdomyosarcoma, osteosarcoma, Wilms tumor, neuroblastoma, medulloblastoma, and other brain gliomas. We review the results of such published studies and highlight the potential clinical application of this pathway in pediatric oncologic and pathologic studies. These studies support targeting this pathway as a novel treatment strategy. PMID- 28616575 TI - Multiple functions of protein phosphatases in receptor tyrosine kinase signaling revealed by interactome analysis. AB - To obtain a global picture of how protein phosphatases are involved in receptor tyrosine kinase (RTK) signaling, we mapped the RTK-phosphatase interactome. Analyses of selected interactions revealed detailed mechanisms of their actions. This study provides new knowledge to better understand cancer development and to identify novel therapeutic targets. PMID- 28616576 TI - Escaping mTOR inhibition for cancer therapy: Tumor suppressor functions of mTOR. AB - A master promoter of cell growth, mammalian target of rapamycin (mTOR) is upregulated in a large percentage of cancer cells. Still, targeting mTOR using rapamycin has a limited outcome in patients. Our recent results highlight the additional role of mTOR as a tumor suppressor, explaining these modest results in the clinic. PMID- 28616577 TI - Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells. AB - Mitotic catastrophe is an oncosuppressive mechanism that targets cells experiencing defective mitoses via the activation of specific cell cycle checkpoints, regulated cell death pathways and/or cell senescence. This prevents the accumulation of karyotypic aberrations, which otherwise may drive oncogenesis and tumor progression. Here, we summarize experimental evidence confirming the role of caspase 2 (CASP2) as the main executor of mitotic catastrophe, and we discuss the signals that activate CASP2 in the presence of mitotic aberrations. In addition, we summarize the main p53-dependent and -independent effector pathways through which CASP2 limits chromosomal instability and non-diploidy, hence mediating robust oncosuppressive functions. PMID- 28616578 TI - Senescent cells: New target for an old treatment? AB - Many genotoxic chemotherapies have debilitating side effects and induce cellular senescence in normal tissues. Senescent cells acquire a pro-inflammatory phenotype which contributes to local and systemic inflammation. Eliminating senescent cells reduce several short- and long-term effects of the drugs, providing a new target to reduce the toxicity of anticancer treatments. PMID- 28616579 TI - Common genetic variation in the germline influences where and how tumors develop. AB - Germline variation contributes to individual risk for developing specific types of cancer. Analyzing thousands of tumors, we found evidence that the germline also influences vulnerable tissue sites and the mutations that arise in tumor genomes. These associations provide new clues to unravel the biologic mechanisms underlying cancer predisposition. PMID- 28616580 TI - Ferroptosis-like death in plant cells. AB - Ferroptosis is an iron-dependent, oxidative, non-apoptotic form of cell death initially described in mammalian cells. We recently reported that a ferroptosis like cell death process can be triggered by heat shock in Arabidopsis thaliana. Thus, ferroptosis may be a form of cell death conserved between animals and plants. PMID- 28616581 TI - The enigma of RIPK1 in the liver: More than just a kinase. AB - Receptor interacting protein kinase 1 (RIPK1) represents a key molecule in cell death. Here, we discuss our recent data on RIPK1 in liver injury and hepatocellular carcinoma development and put these into relation to previous experimental findings to underpin that it exerts opposing kinase-dependent and kinase independent functions in liver cells. PMID- 28616582 TI - A new duet in cancer biology: AMPK the typical and UBE2O the atypical. AB - Ubiquitin-conjugating enzyme E2O (UBE2O) is upregulated in human cancers. We have demonstrated that genetic deletion or pharmacological blockade of UBE2O reduces tumorigenesis through inhibiting the mammalian target of rapamycin complex 1 hypoxia-inducible factor 1-alpha pathway. Critically, UBE2O targets adenosine monophosphate (AMP)-activated protein kinase-alpha 2 (AMPKalpha2) for ubiquitination and degradation. We thus suggest the UBE2O-AMPKalpha2 axis as a potential therapeutic target for cancer. PMID- 28616583 TI - MNK inversely regulates TELO2 vs. DEPTOR to control mTORC1 signaling. AB - mTORC1 is the major homeostatic nutrient sensor for the cell. As such, it is integrated into diverse signaling networks and co-factor interactions that determine its activity. Our recent work implicates the mTORC1 co-factor and PI3K related Kinase (PIKK) stabilizer, TELO2, in regulating mTORC1 activity in a MAPK Interacting Kinase (MNK) responsive manner during mitogenic stimulation of cancer cells and T cell activation. PMID- 28616584 TI - BAK regulates catalase release from peroxisomes. AB - Loss of voltage-dependent anion channel 2 (VDAC2) leads to impaired peroxisome biogenesis in mammalian cells. Knockdown of BAK restores peroxisomal biogenesis in VDAC2-deficient cells, where BAK localization shifts from mitochondria to peroxisomes. Moreover, overexpression of BAK activators in wild-type cells permeabilizes peroxisomes in a BAK-dependent manner. Together, BAK most likely regulates peroxisomal membrane permeability. PMID- 28616585 TI - Co-targeting cancer stem-like cells and bulk cancer cells with a bispecific antibody. AB - Epidermal growth factor receptor (EGFR) is a widely recognized target for tumors, but resistance is commonly reported. Recently, we reported that dual targeting of EGFR and NOTCH2/3 receptors with antibody CT16 showed a strong anti-stem effect both in vitro and in vivo to overcome resistance of EGFR inhibitors and radiation. PMID- 28616586 TI - The autotaxin-lysophosphatidic acid pathway emerges as a therapeutic target to prevent liver cancer. AB - Using transcriptome meta-analysis, we recently identified the autotaxin (ATX) lysophosphatidic acid (LPA) pathway as a regulator of hepatocellular carcinoma (HCC) risk in human cirrhosis patients. Pharmacological targeting of this pathway reduced fibrosis progression and HCC development in animals, identifying ATX-LPA signaling as a novel chemoprevention strategy for cirrhosis and HCC. PMID- 28616587 TI - Notch signaling facilitates crossing of endothelial barriers by tumor cells. AB - Blood vessels supply tumor cells with oxygen and nutrients and provide the basis for metastatic dissemination. In addition, endothelial cells can provide factors that orchestrate the behavior of tumor cells. Here, we expand upon our previous findings that link activation of Notch signaling in the endothelium to cellular senescence, weakening of cell junctions, and expression of adhesion molecules, which facilitates tumor and immune cell migration across the vessel wall and homing at distant sites. PMID- 28616588 TI - All for one and FOSL1 for all: FOSL1 at the crossroads of lung and pancreatic cancer driven by mutant KRAS. AB - KRAS proto-oncogene, GTPase (KRAS) remains refractory to current therapies. We devised an integrative cross-tumor approach to expose common core elements up regulated in mutant KRAS cancers that could provide new treatment opportunities. This approach identified FOSL1 (Fos-like antigen 1) as a clinically and functionally relevant gene in mutant KRAS-driven lung and pancreatic cancers, and unveiled downstream transcriptional targets amenable to pharmacological inhibition. PMID- 28616589 TI - miR-145: Revival of a Dragon in Pancreatic Cancer. AB - Emergence of the role of MicroRNA-145 (miR-145) as a tumor suppressor in pancreatic cancer, offers its potential for novel therapeutic interventions. Our recently published studies demonstrate clinical significance of miR-145 in pancreatic cancer and suggest that the dysregulation of miR-145 in human pancreatic tumors draws in parallel with the aberrant expression of an oncogenic mucin, MUC13. These studies also present a novel therapeutic strategy of restoring the downregulated levels of miR-145 in pancreatic cancer via nanoparticle mediated efficient delivery system. PMID- 28616590 TI - Combination of Extracorporeal Shockwave Lithotripsy and Ureteroscopy for Large Staghorn Calculi in a Pediatric Patient: Case Report. AB - Background: Extracorporeal shockwave lithotripsy (SWL) is a procedure commonly performed to treat nephrolithiasis, with promising results in pediatric patients. However, increasing renal calculi size is directly related to worsening stone free rates. There are few reports in the literature of >2-cm staghorn calculi that expound on the exact mechanism of treatment in the pediatric population. Case Presentation: We present a case report of a 3-year-old boy who presented with a large 3-cm staghorn calculi effectively treated with one session of SWL followed by a planned staged ureteroscopy for definitive treatment. Conclusion: Despite the numerous studies limiting the use of SWL to treat stones <2 cm, if used in softer composition stones, coupled with the larger focal volume involved with smaller patients, SWL when used in combination with adjunctive ureteroscopy is a safe and effective treatment option. PMID- 28616591 TI - Retained Double J Stent with Huge Renal and Bladder Calculi Extracted by Percutaneous Nephrolithotomy and Percutaneous Cystolitholapaxy in a Single Encounter. AB - We report a case of retained Double J ureteral stent with huge, multiple calculi at both ends in a 10-year-old female child. The renal and bladder calculi were managed by percutaneous nephrolithotomy and percutaneous cystolitholapaxy in a single sitting. PMID- 28616592 TI - French validation of the Brace Questionnaire (BrQ). AB - BACKGROUND: Quality of Life (QoL) scales have to be introduced in the treatment evaluation of our patients with adolescent idiopathic scoliosis. Vasiliadis et. al. created the Brace Questionnaire (BrQ), which is specific for brace-treated adolescents. This tool was developed and validated in Greek. The aim of our study was to undertake the process of cultural adaptation of the Brace Questionnaire (BrQ) into French. METHODS: The BrQ is made of 34 items on Likert scale, divided in eight domains. The questionnaire was developed for self-completion by the children and is adapted for 9 to 18-year-old patients. The process of cultural adaptation of the questionnaire was in accordance with the International Quality of Life Assessment (IQOLA) guidelines. In the first place, descriptive statistics were used to calculate mean scores and standard deviations for a given question and a domain. The second level was comparative, concerning reliability and validity. RESULTS: The internal consistency was satisfactory; Cronbach's alpha coefficient was 0.85. There were no floor or ceiling effects. CONCLUSIONS: The French version of the BrQ (F-BrQ) is reliable and reproducible, and can therefore be used to evaluate the quality of life of children and adolescents treated with a brace for idiopathic scoliosis. PMID- 28616593 TI - Neck and back problems in adults with idiopathic scoliosis diagnosed in youth: an observational study of prevalence, change over a mean four year time period and comparison with a control group. AB - BACKGROUND: The knowledge is sparse concerning neck problems in patients with idiopathic scoliosis. This is an observational study including a control group which aims to describe the prevalence of neck problems and the association with back problems among adult individuals with and without idiopathic scoliosis. METHODS: One thousand sixty-nine adults with a mean age of 40 years, diagnosed with idiopathic scoliosis in youth, answered a questionnaire on neck and back problems. Eight hundred seventy of these answered the same questionnaire at a second occasion in a mean of 4 years later. Comparisons were made with a cross sectional population-based survey of 158 individuals. Statistical analyses were made with logistic regression or analysis of variance, adjusted for age, smoking status, and sex. RESULTS: Individuals with scoliosis were previously untreated (n = 374), brace treated (n = 451), or surgically treated (n = 244). Of the individuals with scoliosis, 42% (n = 444) had neck problems compared to 20% (n = 32) of the controls (p = 0.001). The prevalence of neck problems was not affected by the type of treatment (p = 0.67) or onset of scoliosis; juvenile (n = 159) or adolescent (n = 910; p = 0.68). Neck and/or back problems were experienced by 72% of the individuals with scoliosis and 37% of the controls (p < 0.001). Of the individuals with scoliosis having neck problems, 81% also reported back problems, compared to 59% of the individuals in the control group (p < 0.001). The prevalence of neck and back problems was similar at the second survey. CONCLUSIONS: Neck problems are more prevalent and more often coexist with back problems in individuals with idiopathic scoliosis than in controls. The majority of individuals have persisting problems over time. PMID- 28616594 TI - Pattern of c-Fos expression induced by tail suspension test in the mouse brain. AB - The tail suspension test (TST) has been widely used as a screening assay for antidepressant drugs. However, the neural substrates underlying the stress response and antidepressant-like effect during the TST remain largely unknown despite the prevalence of this test. In the present study, we used immunohistochemistry to examine alterations in c-Fos expression as a measure of neuronal activity in the mouse brain after acute administration of the antidepressant drugs nortriptyline or escitalopram (or saline as a control) with or without a subsequent TST session. We found that without the TST session, nortriptyline administration enhanced the density of c-Fos-immunoreactive cells in regions of the central extended amygdala, paraventricular hypothalamic nucleus, and relevant regions of the brain stem, whereas escitalopram did not change c-Fos expression in any region. Following the TST in the absence of antidepressant drugs, we observed a significant increase in c-Fos-positive cell density in a number of brain regions within the limbic telencephalon, hypothalamus, and brain stem. We detected a statistically significant interaction using an analysis of variance between the main effects of the drug and stress response in four regions: the infralimbic cortex, lateral septal nucleus (intermediate part), ventrolateral preoptic nucleus, and solitary nucleus. Following the TST, escitalopram but not nortriptyline increased c-Fos-positive cell density in the infralimbic cortex and ventrolateral preoptic nucleus, whereas nortriptyline but not escitalopram increased c-Fos expression in the solitary nucleus. Both antidepressants significantly increased c-Fos expression in the lateral septal nucleus (intermediate part). The present results indicate that neuronal activity increases in septo-hypothalamic regions and related structures, especially the lateral septal nucleus, following administration of drugs producing an antidepressant-like effect in mice subjected to the TST. PMID- 28616595 TI - A rare case of anal carcinosarcoma with human papilloma virus infection in both biphasic tumor elements: An immunohistochemical, molecular and ultrastructural study. AB - Carcinosarcoma of the anus is rare and has yet to be reportedly associated with the keratinocyte-specific Human Papilloma Virus (HPV). We describe a case of anal carcinosarcoma with HPV infection in both the epithelial and mesenchymal components of the tumor by immunohistochemistry, chromogenic in-situ hybridization (CISH) and further supported by electron microscopy (EM). Microscopic examination of the tumor showed nests of poorly-differentiated invasive squamous cell carcinoma with basaloid features intermixed with a hypercellular, atypical spindle cell proliferation. Immunohistochemistry demonstrated that the epithelial component was positive for AE1/AE3, p63, CK5/6 and p16, whilst the mesenchymal component was positive for smooth muscle actin, vimentin, and focally positive for desmin and p16, consistent with carcinosarcoma. The tumor was negative for GATA-3, CK7 and CK20. CISH demonstrated that the tumor was positive for high risk HPV (subtype 16/18) in both tumor components. EM further supported the presence of intracellular virus particles (~50 nm) that is compatible with HPV infection. Infection of both epithelial and mesenchymal tumor components by HPV has not been previously observed in the gastrointestinal tract. This finding may represent initial epithelial HPV infection with subsequent divergent tumoral differentiation and suggests the presence of viral replication in both biphasic tumor components. PMID- 28616596 TI - Laparoscopic endoscopic cooperative surgery (LECS) for the upper gastrointestinal tract. AB - We developed the laparoscopic and endoscopic cooperative surgery (LECS) technique, which combines endoscopic submucosal dissection (ESD) and laparoscopic gastric resection to resect gastric submucosal tumors (SMTs). Many researchers have reported LECS to be a feasible technique for gastric submucosal tumor resection regardless of tumor location, including the esophagogastric junction (EGJ). Recently, the Japanese National Health Insurance system approved LECS for insurance coverage, and it is now widely applied for gastric submucosal tumor resection. Initially, we applied LECS to gastric SMTs without ulcerative lesions due to concern about the possibility of tumor cells seeding into the peritoneal cavity, in a procedure termed "classical LECS". To expand the indication of LECS for gastric epithelial neoplasms, modified LECS procedures such as inverted LECS, non-exposed endoscopic wall-inversion surgery (NEWS), combination of laparoscopic and endoscopic approaches to neoplasia with non-exposure technique (CLEAN-NET), and closed laparoscopic and endoscopic cooperative surgery (closed-LECS) have been developed and applied to patients with gastric epithelial neoplasms. As a future perspective of LECS, we plan to combine the modified LECS procedure and sentinel node (SN) navigation surgery (SNNS) for clinical (c)Stage IA gastric cancer resection. This strategy could be a minimally invasive surgical technique for cStage IA early gastric cancer. PMID- 28616597 TI - Reconstruction after LATG: technical tips and pitfalls. AB - Since the launching of laparoscopic radical gastrectomy in 1990s, the technique of laparoscopy has become more mature, and it has gradually been applied from distal gastrectomy to total gastrectomy. Laparoscopic distal gastrectomy is an accepted option for gastric cancer surgery; however, laparoscopic total gastrectomy is not widely performed, because of the difficulty of reconstruction of the digestive tract. Efforts have been made to establish an intracorporeal anatomic technique for esophagojejunostomy. There have been several techniques for esophagojejunostomy reported using either circular or lineal staplers. This article is to introduce these techniques and try to analysis the technical tips and pitfalls of them. PMID- 28616598 TI - Laparoscopic sentinel node navigation surgery for early gastric cancer. AB - Currently, the most accurate method for identifying lymph node metastasis is intraoperative diagnosis by sentinel node (SN) biopsy. Based on the SNNS study-a recent large-scale, nationwide, multicenter prospective study-the SN concept seems to be scientifically valid in patients with early gastric cancer. SN biopsy is a multistep technique consisted of six essential elements: indication, the selection of a tracer, a proper tracer injection method, the objective detection of SNs, a reliable biopsy technique, and the precise detection of nodal metastasis. For SN biopsy of gastric cancer, these elements have been validated as follows: the indication should be limited to clinical T1 less than 4 cm in diameter; combination mapping with radioactive colloid and blue dye is used as the standard; and endoscopic submucosal injection is the standard tracer injection. Detection of SNs and a reliable biopsy technique are enabled by adaptation of lymphatic basin dissection, a proper biopsy technique for gastric cancer. Lymphatic basin dissection is a selective lymphadenectomy procedure for dissecting basins en bloc, collecting lymph nodes and lymphatic vessels stained with dye. Lymphatic basin dissection is superior to the ordinary pick-up method, not only for minimizing the rate of missed SNs, but also in terms of oncological safety as it complements an intraoperative frozen section diagnosis by serving as a backup dissection. Moreover, indocyanine green (ICG) fluorescence mapping has been developed in recent years. ICG fluorescence mapping is superior because of its high sensitivity and signal stability. Moreover, it is feasible for both open and laparoscopic gastrectomy in treating early gastric cancer. SN biopsy has brought dramatic changes to laparoscopic surgery for early gastric cancer. With laparoscopic SN biopsy using ICG fluorescence navigation, laparoscopic surgery for early gastric cancer has changed from the uniform standard gastrectomy with D1+ into a tailor-made function-preserving surgical procedure, such as local resection with lymphatic basin dissection. PMID- 28616599 TI - Current status and future perspectives of laparoscopic radical surgery for advanced gastric cancer. AB - Laparoscopic radical gastrectomy with lymph node dissection has widely penetrated to East Asian countries, where incidence of gastric cancer occurrence is higher than the rest of the world. Laparoscopic distal gastrectomy for cStageI disease is regarded as one of the option in daily practice in the latest Japanese guidelines; however its applicability to more advanced disease (Stage II/III) is still under debate. Actually, operative techniques of laparoscopic D2 dissection is being matured, but still, necessity of total omentectomy, splenic hilar dissection, management of bulky nodes or large primary tumor, high-level anastomosis in esophageal invasion cases, and extensive peritoneal lavage can be raised as technical limitations. In the future perspective, further technological innovation, including next generation surgical robot, may help surgeons overcome these difficulties. Currently, three large-scaled randomized phase-III clinical trials are ongoing in East Asia, in which patients' accruals have been already completed. With coming long-term outcomes of these well-designed studies, oncological validity of laparoscopic approach will be adequately elucidated. PMID- 28616600 TI - Minimally invasive surgery for gastric cancer in UK: current status and future perspectives. AB - The aim of this study is to review the literature and report the various minimally invasive methods used to treat gastric cancer in the UK and compare it with worldwide practice. Published randomised studies, non-randomised studies and case series reporting the use of minimal invasive approach to treat gastric cancer were retrieved from the search of standard medical electronic databases and their outcomes were highlighted suggesting their effectiveness. Several randomised, controlled trials and meta-analyses have proven the clinical and oncological safety of the laparoscopic gastrectomy for gastric cancer. Similarly, robot-assisted gastrectomy, EMR (endoscopic mucosal resection) and ESD (endoscopic sub-mucosal dissection) have also been proven feasible and safe to treat gastric cancer of various stages in prospective and retrospective comparative studies. However, UK based studies on minimally invasive surgery to treat gastric cancer is scarce and the paucity of trials led to uncertain outcomes. Laparoscopic gastrectomy, robot-assisted gastrectomy, EMR and ESD are feasible procedures in terms of clinical and oncological safety but mainly being practiced in Asian countries with high prevalence of stomach cancer. The UK based practice is still small and limited but the introduction of MIGOCS and STOMACH trial might help to widen the application of this technique. PMID- 28616601 TI - Minimally invasive surgery for gastric cancer in Brazil: current status and perspectives-a report from the Brazilian Laparoscopic Oncologic Gastrectomy Group (BLOGG). AB - The minimally invasive surgery for gastric cancer in Brazil has begun about two years after the first laparoscopic gastrectomy (LG) performed by Kitano in Japan, in 1991. Although the report of first surgeries shows the year of 1993, there was no dissemination of the technique until the years 2010. At that time with the improvement of optical devices, laparoscopic instruments and with the publications coming from Asia, several Brazilian surgeons felt encouraged to go to Korea and Japan to learn the standardization of the LG. After that there was a significant increase in that type of surgery, especially after the IRCAD opened a branch in Brazil. The growing interest for the subject led some services to begin their own experience with the LG and, since the beginning, the results were similar with those found in the open surgery. Nevertheless, there were some differences with the papers published initially in Japan and Korea. In those countries, the surgeries were laparoscopic assisted, meaning that, in the majority of cases, the anastomoses were done through a mini-incision in the end of the procedure. In Brazil since the beginning it was performed completely through laparoscopic approach due to the skills acquired by Brazilian surgeons in bariatric surgeries. Another difference was the stage. While in the east the majority of cases were done in T1 patients, in Brazil, probably due to the lack of early cases, the surgeries were done also in advanced cases. The initial experience of Zilberstein et al. revealed low rates of morbidity without mortality. Comparing laparoscopic and open surgery, the group from Barretos/IRCAD showed shorter surgical time (216*255 minutes), earlier oral or enteral feeding and earlier hospital discharge, with a smaller number of harvested lymph nodes (28 in laparoscopic against 33 in open surgery). There was no significant difference regarding morbidity, mortality and reoperation rate. In the first efforts to publish a multicentric study the Brazilian Gastric Cancer Association (BGCA) collected data from three institutions analyzing 148 patients operated from 2006 to 2016. There were 98 subtotal, 48 total and 2 proximal gastrectomies. The anastomoses were totally laparoscopic in 105, laparoscopic assisted in 21, cervical in 2, and 20 open (after conversion). The reconstruction methods were: 142 Roux-en-Y, two Billroth I, and three other types. The conversion rate was 13.5% (20/148). The D2 dissection was performed in 139 patients. The mean number of harvested lymph nodes was 34.4. If we take only the D2 cases the mean number was 39.5. The morbidity rate was 22.3%. The mortality was 2.7%. The stages were: IA-59, IB-14, IIA-11, IIB-15, IIIA-9, IIIB-19, IIIC-11 and stage IV-three cases. Four patients died from the disease and 10 are alive with disease. The participating services have already begun the robotic gastrectomy with satisfactory results. The intention of this group is to begin now a prospective multicentric study to confirm the data already obtained with the retrospective studies. PMID- 28616602 TI - Histopathological regression after taxane based neoadjuvant chemotherapy in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma. PMID- 28616603 TI - Current practice for gastric cancer treatment in Ukraine. AB - Ukraine registers more than 8,000 new cases of gastric cancer (GC) annually. The disease is usually diagnosed at stage III-IV (65% of cases) and 62.2% of patients die within 1 year. About 70% of patients with GC need chemotherapy, and for most of them, this is the only way to increase their life expectancy. An unsolved problem of nationwide importance is achieving the early diagnosis of GC, which predetermines the treatment outcome. The 5-year survival rate for GC patients in Ukraine is only 13%, while early diagnosed GC is almost totally curable using surgery. Another important task is the development of national diagnosis and treatment standards, which will be based on national breakthroughs and will meet modern international requirements. PMID- 28616604 TI - Percutaneous endoscopic intragastric surgery: an organ preserving approach to submucosal tumors at esophagogastric junction. AB - As an organ preserving option in the treatment of submucosal tumor found at the esophagogastric junction (EGJ), percutaneous endoscopic intragastric surgery (PEIGS) plays an important role, while it is not commonly performed and there have been very few reports on this unique operation. The current authors have been performing PEIGS since 1993 and have reported on its short- and long-term outcomes from one of the world largest series. Herein its confusing terminology is discussed and techniques of three different types of PEIGS (original PEIGS, single incision PEIGS, and needlescopic PEIGS) are precisely described. Although reports on clinical outcomes of PEIGS have been rarely published, both short-term and long-term outcomes seem acceptable, as far as we review our own experiences and the past literatures. PEIGS needs to be accessed by the data from larger series or RCT to be further justified and spread for the patients with submucosal tumors at EGJ to salvage their stomach. PMID- 28616605 TI - Splenic laceration after routine colonoscopy, a case report of a rare iatrogenic complication. AB - Colonoscopy is a common and routine procedure performed in the United States, most commonly performed for screening of colorectal cancer. Although colonoscopy is considered a safe procedure, it is associated with complications including intestinal hemorrhage and perforation. Splenic trauma, such as laceration or even complete rupture is a rarely reported, but potentially fatal complication if undetected. We present a case of splenic laceration with subcapsular hematoma status post routine colonoscopy. Fortunately, patient was able to be managed medically, without further operative intervention. We will also review the available literature related to this rare iatrogenic complication. PMID- 28616606 TI - Feasibility and safety of modified inverted T-shaped method using linear stapler with movable cartridge fork for esophagojejunostomy following laparoscopic total gastrectomy. AB - BACKGROUND: We previously reported the use of an inverted T-shaped method to obtain a suitable view for hand sewing to close the common entry hole when the linear stapler was fired for esophagojejunostomy after laparoscopic total gastrectomy (LTG). This conventional method involved insertion of the fixed cartridge fork to the Roux limb and the fine movable anvil fork to the esophagus to avoid perforation of the jejunum. However, insertion of the movable anvil fork to the esophagus during this procedure often requires us to strongly push down the main body of the stapler with the fixed cartridge fork to bring the direction of the anvil fork in line with the direction of the long axis of the esophagus while controlling the opening of the movable anvil fork. We therefore modified this complicated inverted T-shaped method using a linear stapler with a movable cartridge fork. This modified method involved insertion of the movable cartridge fork into the Roux limb followed by natural, easy insertion of the fixed anvil fork into the esophagus without controlling the opening of the movable cartridge fork. METHODS: We performed LTG in a total of 155 consecutive patients with gastric cancer from November 2007 to December 2015 in Kyushu University Hospital. After LTG, we performed the conventional inverted T-shaped method using a linear stapler with a fixed cartridge fork in 61 patients from November 2007 to July 2011 (fixed cartridge group). From August 2011, we used a linear stapler with a movable cartridge fork and performed the modified inverted T-shaped method in 94 patients (movable cartridge group). We herein compare the short-term outcomes in 94 cases of LTG using the modified method (movable cartridge fork) with those in 61 cases using the conventional method (fixed cartridge fork). RESULTS: We found no significant differences in the perioperative or postoperative events between the movable and fixed cartridge groups. One case of anastomotic leakage occurred in the fixed cartridge group, but no anastomotic leakage occurred in the movable cartridge group. CONCLUSIONS: Although there were no remarkable differences in the short-term outcomes between the movable and fixed cartridge groups, we believe that the modified inverted T-shaped method is technically more feasible and reliable than the conventional method and will contribute to the improved safety of LTG. PMID- 28616607 TI - A simple method for tension-free Billroth I anastomosis after gastrectomy for gastric cancer. AB - Billroth I anastomosis (B-I) is a popular reconstructive procedure performed after distal gastrectomy for the treatment of gastric cancer. Herein we introduce a new and simple technique to minimize tension after Billroth I for gastric cancer. PMID- 28616608 TI - Gastric cancer treatment in the world: Germany. AB - Epidemiologically, around 15,500 persons per year contract gastric cancer with continuously decreasing incidence and a 5-year survival rate of only 30% to 35%. Contrary to the Asian countries, there are no prevention programs for gastric cancer in Germany, which leads to the disease frequently being diagnosed in locally advanced stages and predominantly being treated with multimodal therapy concepts. Complete (R0) resection is the therapy of choice for resectable gastric cancer. Special forms of gastric cancer that are limited to the mucosa can be endoscopically resected with a curative intent. Systematic D2 lymphadenectomy (LAD) plays a decisive role in the management of local advanced tumors because it significantly contributes to the reduction of tumor-related death and both local and regional relapse rates. Perioperative chemotherapy improves prognosis in the advanced stages, whereas palliative chemotherapy is normally indicated for metastatic diseases. Standardized resection procedures and the use of individualized multimodal therapy concepts have led to improvement in the 5-year survival rate. PMID- 28616609 TI - Three-dimensional computed tomography simulation for laparoscopic lymph node dissection in the treatment of proximal gastric cancer. AB - Application of laparoscopic surgery (LS) has expanded worldwide in the various fields due to the potential advantage of being less invasive than open surgery; however difficulty in recognizing positional relationship of the organs is one of the disadvantages of this kind of surgery. In order to compensate this drawback, preoperative three-dimensional computed tomography (3D-CT) simulation is regarded as promising. In gastric cancer surgery, 3D-CT simulation seems particularly effective in the splenic hilar dissection, because this region is associated with remarkable anatomical variation with complexity. As effects from the use of 3D-CT simulation, reduction of blood loss or complication rate, shortening of operation time and enhancement of surgical quality are expected. In this article, we introduce our methodological protocol of 3D-CT simulation in gastric cancer surgery with clinical case examples, and also additionally review previous publications reporting this imaging technology. PMID- 28616610 TI - Current approaches to gastric cancer in Peru and Mexico. AB - In Peru, the incidence of gastric cancer is reported to be around 15.8 per 100,000 inhabitants and it is the second most common oncological disease in men and the third one in women. Additionally, a high mortality index was reported, especially among poor people. To address this issue, in 2008, Peru initiated several insurance treatment plans of oncological diseases with promising results. In Mexico, there is a high predominance of gastric cancer in male gender compared to female gender, even reaching a 2/1 ratio, and the detection rate of early gastric cancer is low (10% to 20%) which results in a mainly palliative treatment with an overall survival rate in 5 years about 10% to 15% only. In Peru, the average age at diagnosis is around 62.96+/-14.75 years old and the most frequent symptoms includes abdominal pain, indigestion, loss of appetite, weight loss and gastrointestinal bleeding, while in Mexico, some studies reported an average age at diagnosis around 60.3+/-4.1 years old (range, 23-78 years old) and the most frequent symptoms were postprandial fullness (74.4%), abdominal pain (37.2%), weight loss (18.6%), and melena (4.6%). The anemia rate was 65.1% with a mean Hb level of 6.14 g/dL. In Peru, the most common gastric cancer type is the intestinal-type adenocarcinoma (around 34%), followed by the diffuse-type adenocarcinoma (18.7%), whilst among Mexicans, the diffuse-type was reported in 55.2% of cases, the intestinal-type was reported in 28.2% and the undifferentiated-type corresponded to 6%. In both, Peru and Mexico, 90% of the associated factors includes tabaquismo, diets rich in salt, smoked foods, and a sedentary lifestyle. Family inheritance and advanced age and pharmacological resistant Helicobacter pylori infection are also important. Poverty has been heavily associated with a higher incidence of gastric cancer. The management of gastric cancer patients in Peru is carried out by general surgeons or general surgical oncologists. In recent years, efforts have been made by the Peruvian government to establish specialized surgical centers which resulted in an improvement in morbidity and mortality rates, as well as an increase in the retrieval of lymph nodes. In Mexico, during the last 5 years, D1+ has been reported to be the most predominant lymphadenectomy-type, particularly in specialized surgical services. There have been a decrease in mortality rate from 7.5 per 100,000 inhabitants in 2000 to 5.6 per 1,000,000 inhabitants in 2012. Additional steps in order to continue improving gastric cancer management in Peru and Mexico are needed. PMID- 28616611 TI - Technical success and short-term results of surgical treatment of gastrointestinal stromal tumors: an experience of three centers. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) comprise about 80% of gastrointestinal sarcomas. In patients with localized disease, surgery is considered as "Gold Standard" treatment. Organ-sparing radical en-block resection is widely accepted practice. Since lymph node dissection is not routinely indicated, minimally invasive approach is of particular interest. The aim of this study is to investigate the short-term outcomes of different surgical treatment of GISTs. METHODS: We analyzed data of 116 patients who received surgical treatment for localized forms of GIST. Tumors were located in the stomach in 87 (75%) cases, in the small intestine in 26 (22.4%) cases, and extragastrointestinal GISTs were found in 3 (2.6%) patients. Four different approaches were used-open surgery (OpS, n=48), laparoscopic surgery (LS, n=40), endoscopic procedures (EP, n=22) and hybrid rendezvous (HR, n=6). Patient demographics, clinical presentation of tumors, characteristics of operation procedures (duration, intraoperative blood loss, frequency of R0-resection and fragmentation of tumor), postoperative complications and length of hospital stay were examined in all these groups. RESULTS: Radical treatment (R0-resection) was performed in all patients. There were no cases of tumor ruptures during surgical procedure. Mean size of GIST in OpS was 9.1+/-2.0 [2-35] cm; in LS: 4.9+/-0.8 (1.5-15) cm; in HR: 3.5+/-0.8 (2-4.5) cm and in EP: 2.3+/-0.3 (0.4-3.5) cm. Intraoperative blood loss in OpS was 369.7+/-209.5 [0-4,000] mL; LS: 63.9+/-16.0 [0-150] mL; in HR: 96.7+/-44.3 [50-200] mL; in EP: 33.3+/-11.0 [0-150] mL. Duration of operation in OpS was 160+/-20.4 [50-310] min; in LS: 104.7+/-12.7 [50 185]; in HR: 176.7+/-44.0 [110-260] min and in EP: 89.8+/-15.5 [25-190] min. Complication rate in OpS was 5 (10.4%); in LS: 3 (7.5%); in HR: 0% and in EP: 3 (13.6%). Length of hospital stay in OpS was 13.8+/-2.2 [7-52] days; in LS: 11, 4+/-2.2 [4-21] days; in HR: 11+/-3.2 [7-15] days and in EP: 11, 9+/-2.1 [5-22] days. There were no postoperative deaths. CONCLUSIONS: There is a diversity of surgical approaches for GISTs treatment. From our point of view, the main selection criteria for certain procedure are size, localization, growth type of the tumor and status of overlying mucosa. Nevertheless, due to relative rarity and heterogeneity of this pathology, individualization is necessary in each specific case. Laparoscopic and endoscopic surgery is proved to be safe and feasible for resection of the gastric GISTs, with a reasonable operation time, low blood loss, and an acceptable complication rate. Immediate results indicate that all interventions were performed radically without mortality or serious morbidity. PMID- 28616613 TI - Comparison of the airway access skills of prehospital staff in moving and stationary ambulance simulation: A randomized crossover study. AB - OBJECTIVES: We aimed to compare the procedural success and intervention durations regarding various airway access skills in moving and stationary ambulance simulations. MATERIAL AND METHODS: An ambulance simulator was used to simulate the moving ambulance environment, and a standard manikin was used for airway simulation. The study included 38 paramedics and paramedic students. In stationary and moving environments, a classical endotracheal intubation with a stylet, an intubation with a gum elastic bougie (GEB), a laryngeal mask airway (LMA), and a laryngeal tube (LT) were applied randomly. The cuff inflation duration, the duration until the first ventilation, and the intubation success were assessed. RESULTS: There was no difference in terms of success and intubation durations of the four methods in moving and stationary environments. In both environments, the LT and LMA were inserted most rapidly (p < 0.001). There was no difference in the intubation duration and the success among the supraglottic methods. In moving and stationary environments, the intubation with a classic stylet was faster than the intubation with a GEB. The use of a GEB did not increase the intubation success. CONCLUSIONS: In this simulation study, the moving environment did not affect the duration or success of the endotracheal intubation. Supraglottic methods were applied more quickly in both moving and stationary environments. A GEB was used successfully by practioners with no previous experience; however, the duration of the intubation was longer. PMID- 28616612 TI - Robotic gastrectomy for gastric cancer. AB - The number of robotic gastrectomy (RG) performed per year has been increasing, particularly in East Asia where the incidence of gastric cancer is high and approximately half of the cases are diagnosed as early gastric cancer. With articulated devices of RG, surgeons are able to perform every procedure more meticulously, which can result in less bleeding and damage to organs. There are many single arm and comparative studies, and these study showed similar trends, which included relatively less estimated blood loss and longer operation time following RG than laparoscopic gastrectomy (LG), equivalent number of harvested lymph nodes and similar length of postoperative hospital stay between RG and LG. Considering the results of these retrospective comparative studies, RG seems to be as feasible as LG in terms of early surgical outcomes. However, medical expense of RG is approximately twice as much as that of LG. Lack of solid evidence in terms of long-term outcomes is another problem. Considering the higher medical expenses associated with RG, its superiority in terms of long-term survival outcomes needs to be confirmed in the future for it to be accepted more widely. PMID- 28616614 TI - An analysis of Emergency Medical Services demand: Time of day, day of the week, and location in the city. AB - OBJECTIVE: Effective planning of Emergency Medical Services (EMS), which is highly dependent on the analysis of past data trends, is important in reducing response time. Thus, we aimed to analyze demand for these services based on time and location trends to inform planning for an effective EMS. MATERIALS AND METHODS: Data for this retrospective study were obtained from the Izmir EMS 112 system. All calls reaching these services during first six months of 2013 were descriptively analyzed, based on time and location trends as a heat-map form. RESULTS: The analyses showed that demand for EMS varied within different time periods of day, and according to day of the week. For the night period, demand was higher at the weekend compared to weekdays, whereas for daytime hours, demand was higher during the week. For weekdays, a statistically significant relation was observed between the call distribution of morning and evening periods. It was also observed that the percentage of demand changed according to location. Among 30 locations, the five most frequent destinations for ambulances, which are also correlated with high population densities, accounted for 55.66% of the total. CONCLUSION: The results of this study shed valuable light on the areas of call center planning and optimal ambulance locations of Izmir, which can also be served as an archetype for other cities. PMID- 28616615 TI - The predictive value of biochemical parameters in evaluating patients with abdominal trauma: The new scoring system. AB - AIM: The aim of this study was to investigate the contribution of non-invasively and rapidly obtained biochemical parameter results to the diagnosis and follow-up of intraabdominal injuries in multitrauma patients. MATERIAL AND METHODS: A total of 2604 multitrauma patients who were treated following their referral to our emergency department between January 2009 and January 2012 were retrospectively reviewed. A logistic regression analysis was used in the risk assessment. RESULTS: Statistically significant associations between intraabdominal injury and certain biochemical variables measured at the time of the referral were determined. These variables were hemoglobin <=9.99 g/dL [odds ratio (OR): 6.25, 95% CI: 2.86-13.52, p < 0.0001], serum alanine amino transferase (ALT) >= 100 IU/L (OR: 34.45, 95% CI: 21.76-54.54, p < 0.0001), and serum lipase >= 61 U/L (OR: 10.44, 95% CI: 6.56-16.49, p < 0.0001). The pretest probability score was determined for each patient by adding the scores that were obtained from each factor. ROC curve analysis was performed to determine the diagnostic value of the pretest probability score for detecting intra-abdominal injury (area = 0.88; p < 0.0001). CONCLUSION: The results of our study demonstrated that biochemical parameters may contribute to the diagnosis and follow-up of intraabdominal injuries in multitrauma patients. In particular, ALT, AST, CK and myoglobin were found to have higher ORs than low hemoglobin. After these parameters are tested in larger scale studies in conjunction with the gold standard multislice abdominal CT, they may be used for establishing scores to evaluate the severity of abdominal injuries. PMID- 28616616 TI - Lipoprotein-associated phospholipase-A2 activity and its diagnostic potential in patients with acute coronary syndrome and acute ischemic stroke. AB - BACKGROUND: The study examined the Lp-PLA2 activity at the patients presented to the emergency department with acute coronary syndrome (ACS) or acute ischemic stroke (AIS), as well as its diagnostic value. METHODS: The prospective study included consecutive male and female patients aged >18 years that presented to the our emergency department with ACS or AIS between November 2009 and January 2010. Blood samples were obtained immediately following diagnosis in the ACS and AIS groups. The diagnostic value of Lp-PLA2 was determined based on receiver operating characteristic curves, sensitivity, specificity, predictive values, likelihood ratios and accuracy rates. RESULTS: In all, 34 ACS and 32 AIS patients were included in the study, and the control group included 35 patients. Lp-PLA2 enzyme activity was significantly lower in the ACS and AIS groups than in the control group (26.7 +/- 13.8, 31.4 +/- 13.6, and 41.4 +/- 8.1 nmol min-1.mL-1, respectively; p < 0.0001, p = 0.022). In the ACS group the area under the curve (AUC) was 0.825 (95%CI: 0.722-0.929), sensitivity was 71% for an optimal Lp-PLA2 cut-off value of 31.4 nmol min-1.mL-1, and specificity was 91%, whereas in the AIS group the AUC was 0.768 (95%CI: 0.652-0.884), sensitivity was 75% for an optimal Lp-PLA2 cut-off value of 38.1 nmol min-1.mL-1, and specificity was 74%. CONCLUSIONS: Lp-PLA2 enzyme activity was significantly lower during the early stage of both ACS and AIS. The obtained statistic data suggest that low Lp-PLA2 enzyme activity can be used for diagnostic purposes. PMID- 28616617 TI - Comparison of granisetron and metoclopramide in the treatment of pain and emesis in migraine patients: A randomized controlled trial study. AB - OBJECTIVES: One of the irritating features of migraine is emesis that can compromise taking oral medications. We designed this study to compare the effectiveness of granisetron and metoclopramide in reducing pain and treating emesis in migraine patients. METHODS: We included a total of 148 patients with migraine headache presenting to two referral hospitals in a prospective, double blinded randomized controlled trial. We compared the effect of granisetron (2 mg intravenous) with metoclopramide (10 mg intravenous). Pain intensity and emesis episodes were recorded before drug administration, one, two and four 4 h after drug administration. RESULTS: Of the 148 patients, 47 were male and 101 were female. 75 patients received granisetron and 73 metoclopramide. Mean pain intensity before the administration of the medications was 7.67 +/- 1.30 in granisetron group and 7.68 +/- 1.13 in metoclopramide group with an insignificant difference. Mean pain intensity at one, two, and 4 h after drug administration was 3.20 +/- 1.37, 2.39 +/- 1.28, and 1.31 +/- 0.52 in granisetron group and 5.04 +/- 1.77, 4.1 +/- 1.8, and 1.56 +/- 0.68 in metoclopramide group (P = 0.03). Mean emesis episodes before drug administration were 1.85 +/- 0.81 and 1.80 +/- 0.77 in granisetron and metoclopramide groups, respectively. These episodes were 1.33 +/- 0.66, 0.25 +/- 0.49, and 0.04 +/- 0.19 in granisetron group and 1.38 +/- 0.73, 0.21 +/- 0.47, and 0.41 +/- 0.19 in metoclopramide group at one, two, and 4 h after the drug administration (P = 0.7). CONCLUSION: To came in conclusion, compared to metoclopramide, granisetron is a better choice in acute migraine ATTACK because it decreases the patients' pain as well as their emesis. PMID- 28616618 TI - Flash pulmonary edema: A rare cause and possible mechanisms. AB - Flash pulmonary edema frequently develop in case of bilateral renal artery stenosis and unilateral renal artery stenosis with functional solitary kidney. In some rare cases, unilateral renal artery stenosis with bilaterally functional kidneys may also lead to flash pulmonary edema. Here, we present a case of flash pulmonary edema caused by accessory renal artery stenosis. To our knowledge, it is the first case reported in the literature. PMID- 28616619 TI - A case of late diagnosis of chronic subdural hematoma following spinal anesthesia. AB - Intracranial subdural hematoma developing following spinal anesthesia is a rare but serious complication. We describe a case of subdural hematoma developing following spinal anesthesia and diagnosed late. A female patient receiving spinal anesthesia for cesarean delivery 45 days prior to arrival at the emergency department presented to our hospital with non-severe headache persisting for 45 days after discharge. Computerized tomography (CT) of the brain performed due to long-term persisting headache resistant to medical treatment and a history of spinal intervention revealed a hypodense chronic subdural hematoma in the left frontoparietal area and a shift from left to right in midline structures. The patient was operated and discharged without sequelae on the 7th day postoperatively. Care must be taken over subdural hematoma in the presence of headache after spinal anesthesia persisting despite fluid intake and medical treatment and exceeding 48 h in duration, and diagnosis must not be delayed. PMID- 28616620 TI - Superior mesenteric artery syndrome: A rare but life threatening disease. AB - Superior mesenteric artery syndrome was observed in an adolescent patient. He had a 1-day history of nausea, vomiting, and abdominal pain, without chronic or recurrent symptoms. Diagnosis was established by abdominal plain x-ray, contrast enhanced abdominal computed tomography, and endoscopic examination. The patient was hospitalized, monitorized, and decompressed by nasogastric tube without oral feeding. The symptoms of the patient were gradually relieved by conservative treatment and he was discharged after one week. Clinicians should be careful when facing upper gastrointestinal symptoms that are resistant and non-responsive to treatment, and this syndrome should be kept in mind. This case is presented to draw attention to this disease because of its rare incidence. PMID- 28616621 TI - A rare cause of acute abdominal pain in children: Isolated tubal torsion; a case series. AB - Isolated tubal torsion -a rare cause of acute abdomen in children-is usually difficult to diagnose because of non-specific findings. Surgical salphingectomy is required in delayed diagnosis in most cases. Three sexual inactive adolescents diagnosed in isolated tubal torsion (ITT) were discussed for its diagnostic features and surgical management. Laboratory tests and radiological studies including ultrasonography (US), color doppler ultrasound were performed in all patients after evaluation for acute lower abdominal pain in emergency department and they underwent surgical intervention with laparotomy (n:2) and laparoscopy (n:1). One of the patients in this study had salpingectomy. Detorsion of the fallopian tube and cyst excision were performed in the remaining two patients who also had paratubal cysts. There was no recurrence in these patients during the follow-up for 3 and 2 years. The isolated tubal torsion should be kept in mind and early surgical management is essential in order to preserve fallopian tube because of its importance in fertility. PMID- 28616622 TI - A case of primary mediastinal Ewing's sarcoma/ primitive neuroectodermal tumor presenting with chest pain. PMID- 28616623 TI - Neglected facts in digoxin intoxication. PMID- 28616624 TI - Fatigue crack closure: a review of the physical phenomena. AB - Plasticity-induced, roughness-induced and oxide-induced crack closures are reviewed. Special attention is devoted to the physical origin, the consequences for the experimental determination and the prediction of the effective crack driving force for fatigue crack propagation. Plasticity-induced crack closure under plane stress and plane strain conditions require, in principle, a different explanation; however, both types are predictable. This is even the case in the transition region from the plane strain to the plane stress state and all types of loading conditions including constant and variable amplitude loading, the short crack case or the transition from small-scale to large-scale yielding. In contrast, the prediction of roughness-induced and oxide-induced closures is not as straightforward. PMID- 28616625 TI - Heterozygous eNOS Deficient Mice as a Model to Examine the Effects of eNOS Haploinsufficiency on the Cerebral Circulation. AB - Nitric oxide derived from endothelial nitric oxide synthase (eNOS) has been shown to be a major mediator of endothelium-dependent responses in cerebral blood vessels. Loss of a single eNOS gene is not associated with any apparent negative consequences on endothelial function in most blood vessels. In contrast, we have recently demonstrated that heterozygous eNOS gene deficiency in combination with a high fat diet is associated with marked impairment of endothelial function. These findings provide an important example of eNOS haploinsufficiency and one that directly impacts the cerebral vasculature. A major mechanism associated with the impairment of endothelial function with eNOS deficiency and a high fat diet appears to be related to increases in plasma IL-6 that serves to further reduce the bioavailability of NO either directly or indirectly via reductions in eNOS expression or activity and via increases in vascular superoxide. Taken together, these findings provide important insights into genetic and molecular mechanisms that promote endothelial dysfunction in response to a high fat diet in cerebral blood vessels with inherent reductions in eNOS gene expression, such as those due to eNOS gene polymorphisms. These findings also highlight the importance of eNOS+/- mice to study the effects of eNOS haploinsufficiency on cerebral blood vessels. PMID- 28616630 TI - Experimental and computational insights on the recognition mechanism between the estrogen receptor alpha with bisphenol compounds. AB - Certain bisphenols (BPs) have been regarded as endocrine-disrupting chemicals due to their structural similarities to bisphenol A (BPA), a well-known weak estrogenic chemical. However, very limited data are currently available on the relationship between estrogenic activity and the structure of BP analogs. Therefore, we systematically investigated the estrogenic potency of 14 selected BP analogs with typical structures using experimental and computational methods. Most of the tested BP analogs exhibited weak estrogenic activities in both cell proliferation and MVLN assays with the exception of TBBPA, TCBPA and TBBPS. Molecular modeling techniques have been performed to investigate the dynamic structural characteristics of recognition processes between BPs and estrogen receptor alpha (ERalpha) at the atomic level. Thr347 was identified as the key residue responsible for the recognition of TBBPA, TCBPA and TBBPS by means of induced-fit H-bonding interactions in the binding pocket of ERalpha, whereas other BPs, in turn, rely on the alternative formation of H-bonds with His524. Subsequent allosteric modulation interferes significantly with the stability of helix 12 that is crucial for the transcriptional activity of ERalpha. These structural perturbations that are induced by the three compounds were further confirmed to reduce the recruitment potency of co-activators more than other BPs based on calculations of binding free energies, which is in line with observed experimental transcriptional activities. Our findings may help to elucidate the estrogenic potency of BPs with different molecular structures. PMID- 28616631 TI - The effect of emodin on Staphylococcus aureus strains in planktonic form and biofilm formation in vitro. AB - Staphylococcus aureus (S. aureus) is a Gram-positive pathogen and forms biofilm easily. Bacteria inside biofilms display an increased resistance to antibiotics and disinfectants. The objective of the current study was to assess the antimicrobial activities of emodin, 1,2,8-trihydroxy-6-methylanthraquinone, an anthraquinone derivative isolated from Polygonum cuspidatum and Rheum palmatum, against S. aureus CMCC26003 grown in planktonic and biofilm cultures in vitro. In addition, a possible synergistic effect between emodin and berberine chloride was evaluated. As quantified by crystal violet method, emodin significantly decreased S. aureus biofilm growth in a dose-dependent manner. The above findings were further supported by scanning electron microscopy. Moreover, the present study demonstrated that sub-MICs emodin obviously intervened the release of extracellular DNA and inhibited expression of the biofilm-related genes (cidA, icaA, dltB, agrA, sortaseA and sarA) by real-time RT-PCR. These results revealed a promising application for emodin as a therapeutic agent and an effective strategy to prevent S. aureus biofilm-related infections. PMID- 28616633 TI - Xeromorphic traits help to maintain photosynthesis in the perhumid climate of a Taiwanese cloud forest. AB - Previous flux measurements in the perhumid cloud forest of northeastern Taiwan have shown efficient photosynthesis of the endemic tree species Chamaecyparis obtusa var. formosana even under foggy conditions in which leaf surface moisture would be expected. We hypothesized this to be the result of 'xeromorphic' traits of the Chamaecyparis leaves (hydrophobicity, stomatal crypts, stomatal clustering), which could prevent coverage of stomata by precipitation, fog, and condensation, thereby maintaining CO2 uptake. Here we studied the amount, distribution, and composition of moisture accumulated on Chamaecyparis leaf surfaces in situ in the cloud forest. We studied the effect of surface tension on gas penetration to stomata using optical O2 microelectrodes in the laboratory. We captured the dynamics of condensation to the leaf surfaces with an environmental scanning electron microscope (ESEM). In spite of substantial surface hydrophobicity, the mean water film thickness on branchlets under foggy conditions was 80 um (upper surface) and 40 um (lower surface). This amount of water could cover stomata and prevent CO2 uptake. This is avoided by the clustered arrangement of stomata within narrow clefts and the presence of Florin rings. These features keep stomatal pores free from water due to surface tension and provide efficient separation of plant and atmosphere in this perhumid environment. Air pollutants, particularly hygroscopic aerosol, may disturb this functionality by enhancing condensation and reducing the surface tension of leaf surface water. PMID- 28616632 TI - Dispensing of psychotropic medication among 400,000 immigrants in The Netherlands. AB - PURPOSE: Previously, a high prevalence of certain psychiatric disorders was shown among non-Western immigrants. This study explores whether this results in more prescriptions for psychotropic medication. METHODS: Data on dispensing of medication among adults living in the four largest Dutch cities in 2013 were linked to demographic data from Statistics Netherlands. Incident (i.e., following no dispensing in 2010-2012) and prevalent dispensing among immigrants was compared to that among native Dutch (N = 1,043,732) and analyzed using multivariable Poisson and logistic regression. RESULTS: High adjusted Odds Ratios (ORadj) of prevalent and high Incidence Rate Ratios (IRRadj) of incident dispensing of antipsychotics were found among Moroccan (N = 115,455) and Turkish individuals (N = 105,460), especially among young Moroccan males (ORadj = 3.22 [2.99-3.47]). Among Surinamese (N = 147,123) and Antillean individuals (N = 41,430), slightly higher rates of dispensed antipsychotics were found and the estimates decreased after adjustment. The estimates for antipsychotic dispensing among the Moroccan and Turkish increased, following adjustment for household composition. Rates for antidepressant dispensing among Turkish and Moroccan subjects were high (Moroccans: ORadj = 1.74 [1.70-1.78]). Among Surinamese and Antillean subjects, the rates for antidepressant dispensing were low and the ORadj lagged behind the IRRadj (Surinamese: 0.69 [0.67-0.71] vs. 1.06 [1.00 1.13]). Similar results were found for anxiolytics. For ADHD medication, lower dispensing rates were found among all migrant groups. CONCLUSIONS: The findings agree with earlier reports of more mental health problems among Moroccan and Turkish individuals. Surinamese/Antillean individuals did not use psychotropic drugs at excess and discontinued antidepressants and anxiolytics earlier. The data strongly suggest under-treatment for ADHD in all ethnic minority groups. PMID- 28616634 TI - Editorial. PMID- 28616635 TI - Angiostrongylus cantonensis: An optimized cultivation of this parasitic nematode under laboratory conditions. AB - Angiostrongylus cantonensis (A. cantonensis), a parasitic nematode, is the important neurotropic pathogen which causes human angiostrongyliasis. It has a complex life-cycle and severe parasite-host interaction in contrast to free living nematode. Establishment of a well-suited life-cycle and in vitro cultivation of A. cantonensis in the laboratory will be one of the key techniques to elucidate the mechanism of parasite-host interaction. However, the low survival and growth rate of worms is still to be the problem. We optimized the known life-cycle of A. cantonensis in the laboratory, showing that small in size, easy to breed, and high compatibility of Biomphalaria straminea precede the common snails as an intermediate host of A. cantonensis. Furthermore, the egg hatching rate in Ham's F-12 medium reached approximately 80% using the eggs of mature female adult worms. We also demonstrated that the survival of larvae could be sustained for more than 30 days by in vitro cultivation of L1 larvae in DMEM with mixed antibiotics (100 units/mL of penicillin G potassium, 50 MUg/mL of streptomycin sulfate, and 0.5 MUg/mL of amphotericin B) and L3, L4, and L5 larvae in Waymouth's medium with 20% fetal calf serum and mixed antibiotics. Infective L1 and L3 larvae kept high infective rate to the snail and rat after cultivation in these media, respectively. It will provide the basis for studying on genetic manipulations for functional genes, new drug screening, and the mechanism of parasite-host interaction of parasitic nematodes. PMID- 28616636 TI - A Semi-automated Approach to Improve the Efficiency of Medical Imaging Segmentation for Haptic Rendering. AB - The Sensimmer platform represents our ongoing research on simultaneous haptics and graphics rendering of 3D models. For simulation of medical and surgical procedures using Sensimmer, 3D models must be obtained from medical imaging data, such as magnetic resonance imaging (MRI) or computed tomography (CT). Image segmentation techniques are used to determine the anatomies of interest from the images. 3D models are obtained from segmentation and their triangle reduction is required for graphics and haptics rendering. This paper focuses on creating 3D models by automating the segmentation of CT images based on the pixel contrast for integrating the interface between Sensimmer and medical imaging devices, using the volumetric approach, Hough transform method, and manual centering method. Hence, automating the process has reduced the segmentation time by 56.35% while maintaining the same accuracy of the output at +/-2 voxels. PMID- 28616637 TI - Calcaneal cysts and lipomas: a common pathogenesis? AB - Calcaneal cysts and lipomas are relatively rare, benign bone lesions. They are similar in many ways, including in their location and radiological appearance, but their content differs. Cysts contain fluid whereas lipomas contain fat, although some lesions may exhibit a mixed content. The pathogenesis of the two entities is the subject of controversy. The theory that calcaneal cysts may result from lipomatous necrosis has been widely suggested in the literature, but no such progression has ever been shown. The contrary hypothesis has also been considered, i.e., that the content of regressing cysts may be replaced by fatty marrow, leading to a lipoma-like appearance. This second theory is based on indirect arguments, notably that lipomas have a similar location to intraosseous calcaneal ganglion cysts that arise from the subtalar joint and that patients are older in cases of calcaneus lipomas than in cases of calcaneus cysts. We offer an additional argument in favor of this hypothesis. We present an original observation of a calcaneal cyst incidentally discovered in a 15-year-old male whose spontaneous evolution 3 and 7 years later revealed progressive replacement of its fluid content by fat. PMID- 28616638 TI - Piriformis muscle syndrome with assessment of sciatic nerve using diffusion tensor imaging and tractography: a case report. AB - Piriformis muscle syndrome (PMS) is difficult to diagnose by objective evaluation of sciatic nerve injury. Here we report a case of PMS diagnosed by diffusion tensor imaging (DTI) and tractography of the sciatic nerve, which can assess and visualize the extent of nerve injury. The patient was a 53-year-old man with a 2 year history of continuous pain and numbness in the left leg. His symptoms worsened when sitting. Physical examination, including sensorimotor neurologic tests, the deep tendon reflex test, and the straight leg raise test, revealed no specific findings. The hip flexion adduction and internal rotation test and resisted contraction maneuvers for the piriformis muscle were positive. There were no abnormal findings on magnetic resonance imaging (MRI) of the lumbar spine. The transverse diameter of piriformis muscle was slightly thicker in affected side on MRI of the pelvis. A single DTI sequence was performed during MRI of the pelvis. Fractional anisotropy (FA) and the apparent diffusion coefficient (ADC) of the sciatic nerve were quantified at three levels using the fiber-tracking method. FA values were significantly lower and ADC values were significantly higher distal to the piriformis muscle. We performed endoscopic assisted resection of the piriformis tendon. Intraoperatively, the motor-evoked potentials in the left gastrocnemius were improved by resection of the piriformis tendon. The patient's symptoms improved immediately after surgery. There was no significant difference in FA or ADC at any level between the affected side and the unaffected side 3 months postoperatively. MRI-DTI may aid the diagnosis of PMS. PMID- 28616639 TI - [Assessment of physicians? : Results of a sample analysis for the selection of physicians for staff positions]. AB - As in aviation and other organizations requiring high levels of safety, medical complications and errors can in most cases be traced back to the human factor as a main cause. The correct selection of medical students and physicians is therefore very important, especially in leadership and key positions. This is not only a necessary safety aspect but also the prerequisite for the stipulated efficiency of modern medicine. PMID- 28616640 TI - [An open single-arm phase II monotherapy study of pembrolizumab (MK-3475) in locally advanced/metastatic renal cell carcinoma (mRCC) (Keynote 427) - AN 40/16 of the AUO]. PMID- 28616641 TI - [Are there any prognostic predictors for extracorporeal cardiopulmonary resuscitation (ECPR) in case of out-of-hospital cardiac arrest?] PMID- 28616642 TI - [Identification of common locations of out-of-hospital cardiac arrests in a German metropolis]. AB - BACKGROUND: Most patients who suffer a sudden cardiac arrest initially have a shockable rhythm. Fast defibrillation and correctly performed cardiopulmonary resuscitation (CPR) are key factors for patient survival. These can be carried out by bystanders if an automated external defibrillator (AED) is available even in the absence of emergency services. AIM: The place and time of CPRs in a German city were investigated and the strategic placement of emergency medical services and AEDs necessary were evaluated. METHODS: All prehospital resuscitation attempts by Bochum's emergency services in 2011 were retrospectively analyzed. The city was divided into a grid, according to the city map to describe the location of every resuscitation. The distribution of cases was correlated to the city grid and time of day. RESULTS: There were 299 cardiac arrests (mean age 74.2 +/- 12.47 years; 59% of patients were male). Most resuscitations happened in a home environment between 8 am and 8 pm. There was a higher proportion of resuscitation attempts in grid squares with a high population density. Of the resuscitations in public places 16 of 47 (34%) happened in city district centers. In 72% of all cases, only a nonshockable rhythm could be documented as primary arrhythmia on the arrival of the emergency services. Of the 299 attempted resuscitations, a return of spontaneous circulation was achieved in 41%. CONCLUSIONS: The knowledge about increased frequency of resuscitations in city centers provides insight for strategic placement of emergency devices and services in those areas. This can possibly minimize the time until first response and enables early defibrillation with AED in a first-responder program. In addition, bystanders should obtain clear instructions for resuscitation by the dispatcher of the emergency services. PMID- 28616643 TI - [Hypoxic hepatitis in cardiogenic shock : Incidence, laboratory detection and prognosis]. PMID- 28616644 TI - Synergistic hydrolysis of xylan using novel xylanases, beta-xylosidases, and an alpha-L-arabinofuranosidase from Geobacillus thermodenitrificans NG80-2. AB - Lignocellulosic biomass from various types of wood has become a renewable resource for production of biofuels and biobased chemicals. Because xylan is the major component of wood hemicelluloses, highly efficient enzymes to enhance xylan hydrolysis can improve the use of lignocellulosic biomass. In this study, a xylanolytic gene cluster was identified from the crude oil-degrading thermophilic strain Geobacillus thermodenitrificans NG80-2. The enzymes involved in xylan hydrolysis, which include two xylanases (XynA1, XynA2), three beta-xylosidases (XynB1, XynB2, XynB3), and one alpha-L-arabinofuranosidase (AbfA), have many unique features, such as high pH tolerance, high thermostability, and a broad substrate range. The three beta-xylosidases were highly resistant to inhibition by product (xylose) accumulation. Moreover, the combination of xylanase, beta xylosidase, and alpha-L-arabinofuranosidase exhibited the largest synergistic action on xylan degradation (XynA2, XynB1, and AbfA on oat spelt or beechwood xylan; XynA2, XynB3, and AbfA on birchwood xylan). We have demonstrated that the proposed enzymatic cocktail almost completely converts complex xylan to xylose and arabinofuranose and has great potential for use in the conversion of plant biomass into biofuels and biochemicals. PMID- 28616645 TI - Groundwater contamination with 2,6-dichlorobenzamide (BAM) and perspectives for its microbial removal. AB - The pesticide metabolite 2,6-dichlorobenzamide (BAM) is very persistent in both soil and groundwater and has become one of the most frequently detected groundwater micropollutants. BAM is not removed by the physico-chemical treatment techniques currently used in drinking water treatment plants (DWTP); therefore, if concentrations exceed the legal threshold limit, it represents a sizeable problem for the stability and quality of drinking water production, especially in places that depend on groundwater for drinking water. Bioremediation is suggested as a valuable strategy for removing BAM from groundwater by deploying dedicated BAM-degrading bacteria in DWTP sand filters. Only a few bacterial strains with the capability to degrade BAM have been isolated, and of these, only three isolates belonging to the Aminobacter genus are able to mineralise BAM. Considerable effort has been made to elucidate degradation pathways, kinetics and degrader genes, and research has recently been presented on the application of strain Aminobacter sp. MSH1 for the purification of BAM-contaminated water. The aim of the present review was to provide insight into the issue of BAM contamination and to report on the current status and knowledge with regard to the application of microorganisms for purification of BAM-contaminated water resources. This paper discusses the prospects and challenges for bioaugmentation of DWTP sand filters with specific BAM-degrading bacteria and identifies relevant perspectives for future research. PMID- 28616646 TI - Molecular genetic diagnostics for ventricular arrhythmias and sudden cardiac death syndromes. AB - Inherited forms of ventricular arrhythmias are rare diseases, but a major cause for severe cardiac events, sudden unexplained death syndromes, and death in young adults, infants, and children. Each disorder is genetically heterogeneous (5-20 genes per disease) and molecular testing may include both core genes and less common disease genes as well. Owing to the rapid development and feasibility of sequencing technologies enabling a parallel analysis of several hundred genes up to a whole exome, disease mutations can be identified very efficiently, but have to be seen in the complexity and natural variance of the human genome. Precise phenotypic knowledge and advanced gene variant interpretation are important to ensure adequate patient diagnostics and management. This article focuses on the genetic causes of inherited arrhythmia forms predisposing patients to sudden cardiac death and discusses practical issues and skills for molecular testing. PMID- 28616647 TI - Outcomes of direct stenting in patients with ST-elevated myocardial infarction. AB - BACKGROUND: We compared direct stenting (DS) with conventional stenting (CS) - i.e., stenting after predilation - during primary percutaneous coronary intervention (P-PCI) in terms of procedural results and long-term mortality in patients with ST-elevated myocardial infarction (STEMI). METHODS: We retrospectively analyzed 2306 patients (mean age 59 years, 22% female) who underwent P-PCI within 12 h of symptom onset. Patients were then followed up prospectively for clinical events. Patients were divided into a DS group (n = 597) and a CS group (n = 1709). The CS group was further divided into a CS-1 group (baseline thrombolysis in myocardial infarction [TIMI] flow grade >= 1) and a CS-2 group (baseline TIMI flow grade 0). Main outcome measures were postprocedural myocardial reperfusion and all-cause mortality in long-term follow up. RESULTS: Patients in the DS group had a higher percentage of final TIMI-3 flow, myocardial blush grade 3 and complete ST-segment resolution, better left ventricular ejection fraction, and a lower incidence of distal embolization compared with CS patients. In-hospital (1.5 vs. 4.6%, respectively, p = 0.001) and long-term all-cause mortality (8.8 vs. 17.0%, respectively, p < 0.001) were significantly lower in the DS group than in the CS group. Kaplan-Meier survival analysis showed similar survival rates in the DS and CS-1 groups (log-rank p = 0.40), but significantly worse survival in the CS-2 group than in the other groups (log-rank p < 0.001). After adjusting for risk factors, DS was not found to be a predictor of long-term mortality. CONCLUSION: DS in P-PCI was associated with better postprocedural angiographic results and long-term survival. However, the DS group had similar in-hospital and long-term mortality to matched patients in the CS group. PMID- 28616648 TI - Protective effect of dietary polyphenol caffeic acid on ethylene glycol-induced kidney stones in rats. AB - Dietary polyphenol caffeic acid (1) has been reported for various pharmacological activities. The aim of the current study was to investigate the effect of caffeic acid (1) on ethylene glycol-induced renal stones in rats. For the study, male Wistar rats were divided into seven groups; normal, pathological, and standard drug controls, and preventive and curative groups. Normal control group received drinking water for 8 weeks. Pathological, standard drug, preventive, and curative groups received 0.75% ethylene glycol in drinking water for the induction of calcium oxalate stone formation, along with the regular diet. Standard drug group received Urocit-K by gavage from day 1, while preventive and curative groups received caffeic acid (1) by gavage at doses of 20 and 40 mg/kg on day 1 and day 14, respectively. At the end of the experiment, urine analysis and kidney histopathology were performed. Real-time PCR was performed to evaluate the renal expression of the most important genes involved in urolithiasis, i.e., osteopontin, Tamm-Horsfall, prothrombin fragment 1, and bikunin genes. The results indicated that in both the preventive and curative groups, treatment of rats with caffeic acid (1) significantly regulated the altered biochemical parameters, along with the remarkable reduction of calcium oxalate deposits in the kidneys, as compared to the pathological group. Treatment with compound 1 also resulted in down-regulation of the osteopontin gene, and up-regulation of the prothrombin fragment 1, Tamm-Horsfall, and bikunin genes. These results suggest that caffeic acid (1) can be further investigated for the prevention, and treatment of kidney stones. PMID- 28616649 TI - Earlier Pulmonary Valve Replacement in Down Syndrome Patients Following Tetralogy of Fallot Repair. AB - The association between Down syndrome and pulmonary hypertension could contribute to more severe pulmonary regurgitation after tetralogy of Fallot repair and possibly earlier pulmonary valve replacement. We compared cardiac magnetic resonance measures of pulmonary regurgitation and right ventricular dilation as well as timing of pulmonary valve replacement between those with and without Down syndrome after tetralogy of Fallot repair. Review of our surgical database from 2000 to 2015 identified patients with tetralogy of Fallot with pulmonary stenosis. Those with Down syndrome were compared to those without. The primary outcome of interest was time from repair to pulmonary valve replacement. Secondary outcomes included pulmonary regurgitation and indexed right ventricular volume on cardiac magnetic resonance imaging. The cohort of 284 patients included 35 (12%) with Down syndrome. Transannular patch repair was performed in 210 (74%). Down syndrome showed greater degree of pulmonary regurgitation (55 +/- 14 vs. 37 +/- 16%, p = 0.01) without a significantly greater rate of right ventricular dilation (p = 0.09). In multivariable analysis, Down syndrome (HR 2.3, 95% CI 1.2-4.5, p = 0.02) and transannular patch repair (HR 5.5, 95% CI 1.7 17.6, p = 0.004) were significant risk factors for valve replacement. Those with Down syndrome had significantly lower freedom from valve replacement (p = 0.03). Down syndrome is associated with an increased degree of pulmonary regurgitation and earlier pulmonary valve replacement after tetralogy of Fallot repair. These patients require earlier assessment by cardiac magnetic resonance imaging to determine timing of pulmonary valve replacement and evaluation for and treatment of preventable causes of pulmonary hypertension. PMID- 28616650 TI - Erratum to: physiotherapy programme reduces fatigue in patients with advanced cancer receiving palliative care: randomized controlled trial. PMID- 28616651 TI - Comparison of efficacy of transversus abdominis plane block and iliohypogastric/ilioinguinal nerve block for postoperative pain management in patients undergoing inguinal herniorrhaphy with spinal anesthesia: a prospective randomized controlled open-label study. AB - PURPOSES: The purpose of this study was to compare the effects of lateral abdominal transversus abdominis plane block (TAP block) and iliohypogastric/ilioinguinal nerve block (IHINB) under ultrasound guidance for postoperative pain management of inguinal hernia repair. Secondary purposes were to compare the complication rates of the two techniques and to examine the effects of TAP block and IHINB on chronic postoperative pain. METHODS: This was a prospective randomized controlled open-label study. After approval of the Research Ethics Board, a total of 90 patients were allocated to three groups of 30 by simple randomized sampling as determined with a priori power analysis. Peripheral nerve blocks (TAP block or IHINB) were administered to patients following subarachnoid block according to their allocated group. Patient pain scores, additional analgesic requirements and complication rates were recorded periodically and compared. RESULTS: Pain scores were significantly lower in the study groups (p < 0.001, p < 0.001, p < 0.001, p = 0.002, p < 0.001, p < 0.001 for 1, 2, 4, 6, 24, and 48 h and at 1 and 6 months, respectively). First pain declaration times were significantly longer in the study groups (TAP block group [GT] 266.6 +/- 119.7 min; IHINB group [GI] 247.2 +/- 128.7 min; and control group [GC] 79.1 +/- 66.2 min; p < 0.001). At 24 h, the numeric rating scale scores of GT were significantly lower than GI (p = 0.048). Additional analgesic requirements of GT and GI patients were found to be significantly lower than GC patients (p = 0.001, p < 0.001, p = 0.006, p = 0.002, p = 0.001, p < 0.001 for 1, 2, 4, 6, 24, and 48 h, respectively). CONCLUSION: We conclude that administration of TAP block or IHINB for patients undergoing inguinal herniorrhaphy reduces the intensity of both acute and chronic postoperative pain and additional analgesic requirements. PMID- 28616652 TI - Effects of initial graft tension on femoral tunnel widening after anatomic anterior cruciate ligament reconstruction using a bone-patellar tendon-bone graft. AB - INTRODUCTION: The effects of initial graft tension upon tunnel widening (TW) following anatomic anterior cruciate ligament (ACL) reconstruction have not been elucidated. The purpose of this study was to retrospectively investigate the effect of two different graft-tensioning protocols upon femoral TW following anatomic ACL reconstruction using a bone-patellar tendon-bone (BPTB) graft and a three-dimensional (3D) computed tomography (CT) model. METHODS: Forty-three patients who underwent isolated ACL reconstruction using BPTB grafts were included in this study. In 18 out of the 43 patients, the graft was fixed at full knee extension with manual maximum pull (Group H). These patients were compared with 25 patients in whom the BPTB graft was fixed at full knee extension with 80 N pull (Group L). Tunnel aperture area was measured using 3D CT 1 week and 1 year postoperatively, thus enabling us to calculate the percentage change in the area of femoral tunnel aperture. Clinical assessment was performed 1 year postoperatively, corresponding to the time period of CT assessment, and involved the evaluation of Lysholm score, anterior knee stability using a KneeLax3 arthrometer, and the pivot-shift test. RESULTS: When measured at 1 year postoperatively, the mean area of the femoral tunnel aperture had increased by 78.6 +/- 36.8% in Group H when compared with at 1 week postoperatively, whereas that of Group L had increased by 27.7 +/- 32.3%. Furthermore, TW (%) in Group H was significantly greater than that of Group L (P < 0.001). No significant differences were detected between the two groups with regard to any of the clinical outcomes evaluated. CONCLUSION: High levels of initial graft tension resulted in greater TW of the femoral tunnel aperture following anatomical ACL reconstruction using BPTB grafts. However, such levels of graft tension did not affect clinical outcome. PMID- 28616653 TI - Bird migration. PMID- 28616655 TI - [Cognitive-perceptive approaches in the treatment of chronic pain]. AB - In the treatment of difficult chronic pain conditions, cognitive-perceptive approaches offer an alternative to conventional therapies. Especially phantom limb pain and complex regional pain syndrome (CRPS) are frequently treated with these promising modalities. This article provides an overview of the most important cognitive-perceptive therapies and the research results concerning their clinical efficacy. In addition, we discuss their neurobiological foundation and clinical perspectives. PMID- 28616656 TI - Accuracy of neutrophil gelatinase-associated lipocalin for acute kidney injury diagnosis in children: systematic review and meta-analysis. AB - OBJECTIVE: To estimate the accuracy of Neutrophil Gelatinase-Associated Lipocalin (NGAL) as a biomarker for acute kidney injury (AKI) in children. METHODS: A systematic review of the literature was performed. The review protocol was registered at PROSPERO (CRD 42015024153). We conducted searches in the following databases: Medline (PubMed), LILACS (BVS), SCOPUS (Elsevier), Embase (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Biomed Central, and ISI Web of Science, from January 1990 to October 2016. For inclusion, studies measured NGAL levels in plasma and urine for AKI in children. For each study, 2 * 2 contingency tables were developed. For statistical analysis we calculated the sensitivity, specificity and diagnostic odds ratio. For methodological assessment, we used Quality Assessment of Diagnostic Accuracy Studies-2. Software used for analysis was Stata 14, and RevMan 5.3. RESULTS: In total 13 studies were analyzed, which included 1629 children. For urinary NGAL, the pooled sensitivity was 0.76 (95% CI 0.62-0.85) and a pooled specificity 0.93 (95% CI 0.88-0.96). The diagnostic odds ratio (DOR) for the detection of AKI was 43 (95% CI 16-115) and the Area under the curve (AUC) was 0.94 (95% CI 0.92-0.96). For plasma NGAL the combined sensitivity was 0.80 (95% CI 0.64-0.90) and a combined specificity was 0.87 (95% CI 0.74-0.94). The DOR was 26 (95% CI 8.0-82) and AUC was 0.90 (95% CI 0.87-0.94) for the detection of AKI in children. CONCLUSION: The data suggest that NGAL levels can be an important biomarker for the early detection of AKI in children. PMID- 28616657 TI - Variant of classical high grade PTLD: post-transplant EBV-negative T cell lymphoblastic leukaemia after solid organ transplantation. PMID- 28616658 TI - High KIF2A expression predicts unfavorable prognosis in diffuse large B cell lymphoma. AB - Kinesin family member 2A (KIF2A), a conserved motor protein, plays a critical role in the pathogenesis and prognosis of several malignant tumors. The aim of the present study was to investigate KIF2A expression in diffuse large B cell lymphoma (DLBCL), evaluate the association between KIF2A expression and the clinical parameters of the disease, and determine its prognostic value. KIF2A expression was evaluated in 134 DLBCL and 57 reactive hyperplasia samples using immunohistochemistry on a tissue microarray. The correlations between KIF2A expression with clinical parameters and prognosis were estimated using univariate and multivariate analyses. The expression of KIF2A was significantly higher in DLBCL tissue samples compared with those from subjects with reactive hyperplasia (P=0.002). Furthermore, increased expression of KIF2A protein in DLBCL was related to Ann Arbor stage (P=0.027) and international prognostic index (IPI) score (P=0.01). The survival analysis showed that KIF2A expression (P=0.016), serum LDH level (P=0.049), and IPI score (P<0.001) were independent prognostic markers for DLBCL. Our findings also confirmed that downregulating KIF2A expression decreased tumor cell viability, accompanied by downregulation of pAKT levels. Taken together, these data provide the first evidence that increased KIF2A expression predicts poor prognosis in patients with DLBCL, and a rationale for treatment of DLBCL by targeting KIF2A. PMID- 28616659 TI - Isolation and functional characterization of a circadian-regulated CONSTANS homolog (GbCO) from Ginkgo biloba. AB - KEY MESSAGE: This is the first report to clone and functionally characterize a flowering time gene GbCO in perennial gymnosperm Ginkgo biloba. GbCO complements the co mutant of Arabidopsis, restoring normal early flowering. CONSTANS (CO) is a central regulator of photoperiod pathway, which channels inputs from light, day length, and circadian clock to promote the floral transition. In order to understand the role of CO in gymnosperm Ginkgo biloba, which has a long juvenile phase (15-20 years), a CO homolog (GbCO) was isolated and characterized from G. biloba. GbCO encodes a 1741-bp gene with a predicted protein of 400 amino acids with two zinc finger domains (B-box I and B-box II) and a CCT domain. Phylogenic analysis classified GbCO into the group 1a clade of CO families in accordance with the grouping scheme for Arabidopsis CO (AtCO). Southern blot analysis indicated that GbCO belongs to a multigene family in G. biloba. Real-time PCR analysis showed that GbCO was expressed in aerial parts of Ginkgo, with the highest transcript level of GbCO being observed in shoot apexes. GbCO transcript level exhibited a strong diurnal rhythm under flowering-inductive long days and peaked during early morning, suggesting that GbCO is tightly coupled to the floral inductive long-day signal. In addition, an increasing trend of GbCO transcript level was observed both in shoot tips and leaves as the shoot growth under long-day condition, whereas GbCO transcript level decreased in both tissues under short-day condition prior to growth cessation of shoot in G. biloba. GbCO complemented the Arabidopsis co-2 mutant, restoring normal early flowering. All the evidence being taken together, our findings suggested that GbCO served as a potential inducer of flowering in G. biloba. PMID- 28616660 TI - Arenavirus Dynamics in Experimentally and Naturally Infected Rodents. AB - Infectious diseases of wildlife are typically studied using data on antibody and pathogen levels. In order to interpret these data, it is necessary to know the course of antibodies and pathogen levels after infection. Such data are typically collected using experimental infection studies in which host individuals are inoculated in the laboratory and sampled over an extended period, but because laboratory conditions are controlled and much less variable than natural conditions, the immune response and pathogen dynamics may differ. Here, we compared Morogoro arenavirus infection patterns between naturally and experimentally infected multimammate mice (Mastomys natalensis). Longitudinal samples were collected during three months of bi-weekly trapping in Morogoro, Tanzania, and antibody titer and viral RNA presence were determined. The time of infection was estimated from these data using a recently developed Bayesian approach, which allowed us to assess whether the natural temporal patterns match the previously observed patterns in the laboratory. A good match was found for 52% of naturally infected individuals, while most of the mismatches can be explained by the presence of chronically infected individuals (35%), maternal antibodies (10%), and an antibody detection limit (25%). These results suggest that while laboratory data are useful for interpreting field samples, there can still be differences due to conditions that were not tested in the laboratory. PMID- 28616661 TI - Clinical relevance of P-glycoprotein activity on peripheral blood mononuclear cells and polymorphonuclear neutrophils to methotrexate in systemic lupus erythematosus patients. AB - To elucidate the relationship between P-glycoprotein activity on peripheral blood leukocytes of systemic lupus erythematosus (SLE) patients with lupus arthritis and the clinical response to methotrexate. An observational study was made in patients with SLE according to ACR criteria 1997 who had arthralgia and arthritis and received methotrexate for >=3 months. Methotrexate responders and non responders were compared according to the Clinical Disease Activity Index. Mononuclear cells and polymorphonuclear neutrophils were isolated from SLE patients and P-glycoprotein expression was measured using the relative fluorescence index and percentage of positive cells. The chi-square test was used to compare P-glycoprotein activity between responders and non-responders. Thirty two patients with a mean age of 45.4 +/- 10.7 years were included: 34.4% had a response to methotrexate and 65.6% did not. Mean relative fluorescence units of both mononuclear cells and polymorphonuclear neutrophils were significantly lower in patients with a good response (7.0 +/- 4.3 vs. 9.6 +/- 3.8; p = 0.041 and 4.2 +/- 3.5 vs. 7.6 +/- 4.0; p = 0.004). The prevalence of low fluorescence levels (<6 relative fluorescence units), signifying higher P-glycoprotein activity of both mononuclear cells and polymorphonuclear neutrophils, was higher in methotrexate responders than in non-responders (27.3 vs. 4.8%; p = 0.10 and 81.8 vs. 23.8%; p = 0.003, respectively). In SLE patients with joint involvement treated with methotrexate, P-glycoprotein activity was higher in responders to methotrexate than in non-responders. Further studies are required to determine the mechanisms behind this finding and whether P-glycoprotein activity mediates alterations in methotrexate efficacy. PMID- 28616662 TI - Perifosine enhances bevacizumab-induced apoptosis and therapeutic efficacy by targeting PI3K/AKT pathway in a glioblastoma heterotopic model. AB - Bevacizumab (BVZ) as an antiangiogenesis therapy leads to a transient therapeutic efficacy in high-grade glioma. However, the proapoptotic potential of BVZ has not been well elucidated, yet. There is also a tumor resistance to BVZ that is linked to post-treatment metalloproteinases and AKT activities. Herein, the association between therapeutic efficacy and putative proapoptotic activity of low-dose BVZ either alone or in combination with a specific inhibitor of AKT called perifosine (PRF), in a glioma model was investigated. BALB/c mice bearing C6 glioma tumor were treated with BVZ and PRF either alone or combined for 13 days (n = 11/group). At the end of treatments, apoptosis, proliferation and vascular density, in the xenografts (3/group) were detected by TUNEL staining, Ki67 and CD31 markers, respectively. Relative levels of cleaved-caspase3, phospho-AKT (Ser473) and matrix metalloproteinase2 (MMP2) were measured using western blotting. PRF and BVZ separately slowed down tumor growth along with the cell apoptosis induction associated with a profound increase in caspase3 activity through an AKT inhibition-related pathway for PRF but not BVZ. Unlike PRF, BVZ significantly increased the intratumor MMP2 and phospho-AKT (Ser473) levels coupled with the slight antiproliferative and significant antivascular effects. Co-administration of PRF and BVZ versus monotherapies potentiated the proapoptotic effects and reversed the BVZ-induced upregulation of phospho-AKT (Ser473) and MMP2 levels in C6 xenografts, leading to the optimal antiproliferative activity and tumor growth regression and longer survival. In conclusion, BVZ plus PRF renders a paramount proapoptotic effect, leading to a major therapeutic efficacy and might be a new substitute for GBM therapy in the clinic. PMID- 28616664 TI - Erratum to: The effects of multiphasic prepulses on automatic and attention modulated prepulse inhibition. PMID- 28616663 TI - The water soluble axially disubstituted silicon phthalocyanines: photophysicochemical properties and in vitro studies. AB - Two novel silicon(IV) phthalocyanines bearing 1,3 bis[3(dimethylamino)phenoxy]propan-2-ol or 1,3-bis[3(diethylamino)phenoxy]propan 2-ol groups at their axial positions were synthesized. These phthalocyanines were converted into their water soluble derivatives by the quaternization reaction with methyl iodide. The quaternized phthalocyanines show excellent solubility aqueous solutions without any aggregation which makes them potential photosensitizers for use in photodynamic therapy (PDT). For this reason, the photophysical and photochemical properties such as fluorescence quantum yields, lifetimes, singlet oxygen generation and photodegradation of both non-ionic (3 and 5) and quaternized cationic silicon(IV) phthalocyanines were investigated. Furthermore, the cytotoxicity of PDT was determined by colorimetric proliferation assay against to hepatocellular carcinoma (HuH-7) cancer cells. In this study, the cells were incubated with a novel water soluble silicon(IV) phthalocyanine derivatives and thereafter the cells were illuminated using broad-band incoherent light source. PMID- 28616665 TI - Psychoneurocutaneous medicine: past, present and future. AB - Psychoneurocutaneous medicine is an important and rapidly growing field. It is an integrative science created to address the interaction between the mind, nervous system and skin. Four major fields are involved: psychiatry, psychology, neurology and dermatology. The history of psychoneurocutaneous medicine is old and fascinating. Even though it is a young science only established in the last century, allusions to the nervous system and diseases of the skin can be traced back thousands of years in the literature. Characteristically, the last two centuries were of special importance for the development of this field in Europe, lately in America, with great effort placed on research and publications. More recently, the creation of associations, work groups and the merging of subspecialties dedicated exclusively to study the psychological impact of skin disorders in subpopulations of patients have helped to give momentum to psychoneurocutaneous medicine. Further development of this field will shed light on the appropriate diagnosis and treatment of psychodermatologic disorders, enhancing the functionality and quality of life of patients. This paper presents a summary of the most influential facts in the history of psychoneurocutaneous medicine, its present and future perspectives. PMID- 28616666 TI - The role of psychosomatic medicine in intensive care units. AB - Critically ill patients, their relatives, and intensive care staff are consistently exposed to stress. The principal elements of this exceptional burden are confrontation with a life-threatening disease, specific environmental conditions at the intensive care unit, and the social characteristics of intensive care medicine. The short- and long-term consequences of these stressors include a feeling of helplessness, distress, anxiety, depression, and even posttraumatic stress disorders. Not only the patients, but also their relatives and intensive care staff are at risk of developing such psychopathologies. The integration of psychosomatic medicine into the general concept of intensive care medicine is an essential step for the early identification of fear and anxiety and for understanding biopsychosocial coherence in critically ill patients. Preventive measures such as the improvement of individual coping strategies and enhancing the individual's resistance to stress are crucial aspects of improving wellbeing, as well as the overall outcome of disease. Additional stress-reducing measures reported in the published literature, such as hearing music, the use of earplugs and eye-masks, or basal stimulation, have been successful to a greater or lesser extent. PMID- 28616667 TI - Fluorescence turn-on detection of alkaline phosphatase activity based on controlled release of PEI-capped Cu nanoclusters from MnO2 nanosheets. AB - A fluorescence turn-on assay for alkaline phosphatase (ALP) activity is developed through the controlled release of polyethyleneimine-capped copper nanoclusters (PEI-capped CuNCs) from the MnO2 nanosheets. In an aqueous solution, the positively charged PEI-capped CuNCs could be adsorbed onto the surface of the negatively charged MnO2 nanosheets. Such adsorption through favorable electrostatic interactions could efficiently quench the nanocluster fluorescence emission via resonance energy transfer from the PEI-capped CuNCs to the MnO2 nanosheets. 2-Phospho-L-ascorbic acid (AAP) could be hydrolyzed to L-ascorbic acid (AA) in the presence of ALP. AA could reduce MnO2 into Mn2+ and trigger the disintegration of the MnO2 nanosheets. As a result, the CuNCs were released and the quenched fluorescence was recovered efficiently. The detection strategy is simple, inexpensive, sensitive, selective, with low toxicity, and has better biocompatibility. The newly fabricated biosensor for ALP activity will potentially make it a robust candidate for numerous biological and biomedical applications. PMID- 28616668 TI - Shunt age-related complications in adult patients with suspected shunt dysfunction. A recommended diagnostic workup. AB - BACKGROUND: Patients admitted for suspicion of shunt dysfunction (SD) often show unspecific symptoms and require time-consuming, expensive and even invasive diagnostics involving significant radiation exposure. The purpose of this retrospective study was to analyse the current diagnostic procedures and to propose a process optimisation. METHOD: As all patients admitted for suspicion of SD receive imaging studies, we searched for adult patients receiving neuroimaging in the period from January 2010 to July 2013, analysing referring diagnosis, clinical signs, products, diagnostic process and final diagnosis. Recursive partitioning was used to define time intervals for differentiating types of SD. RESULTS: A total of 148 patients, aged 18-89 (mean, 54) years, were studied. Forty-two percent were referred by a hospital or rehabilitation centre, 30% by general practitioners and 24% were self-referrals. The admission diagnosis was in the majority "shunt dysfunction" only. Further differentiations were rarely made. An SD was confirmed in 46% of the patients. In 17%, the symptoms were based on another cause and in 37% they could not be clearly attributed to any specific disorder. Abdominal dislocations (2%) and shunt infections (5%) were found within the first 6 months. Over- (3%) and under-drainage (14%) were the most frequent complications during the first 4 years. Disconnections (13%) occurred generally 4 years or more after implantation. Only shunt obstruction (9%) showed no temporal pattern. CONCLUSIONS: Symptoms of SD remain mostly unspecific. This study showed that the type of SD depends on the time interval from implantation. We propose a workup strategy for patients with SD based on the temporal profile. PMID- 28616669 TI - Awake craniotomy for vestibular schwannoma. PMID- 28616670 TI - Migration of a ventriculoperitoneal shunt catheter through the processus vaginalis in infants: how serious inguinal hernia and hydrocele might be. AB - Migration of the catheter tip of a ventriculoperitoneal shunt (VPS) through a patent processus vaginalis (PV) has seldom being reported. In this series, we analyzed all cases of inguinoscrotal migration of an VPS catheter at our center. Between 1975 and 2015, 295 VPS insertions were performed. In seven infants (2.3%), migration of the catheter through a patent PV was demonstrated. Cases with hydroceles had associated VPS malfunction, but cases with hernias were not associated with it. The current recommendation is to delay a PV closure until 2 years of age in cases of infants with hydrocele without further radiological examinations, but this might not be the case in infants with VPS. PMID- 28616671 TI - A novel bovine papillomavirus type in the genus Dyokappapapillomavirus. AB - Papillomaviruses are a diverse group of viruses that are known to infect a wide range of animal species. Bovine papillomaviruses (BPVs) are divided into at least 21 genotypes (BPV1 to BPV21), with most BPV isolates/strains described to date belonging to one of four genera, including Deltapapillomavirus, Xipapillomavirus, Epsilonpapillomavirus and Dyoxipapillomavirus. Here, we describe the identification and genetic characterization of a new BPV type in the genus Dyokappapapillomavirus. A farm in the state of New York, USA, reported chronic cases of vulvovaginitis in Holstein cows in 2016. Biopsies and/or swab samples collected from the vaginal mucosa were subjected to diagnostic investigation. Conventional diagnostic assays yielded negative results, and vaginal swab samples were subjected to viral metagenomic sequencing. Notably, BLAST searches revealed a papillomavirus genome with 7480 bp in length (67% nt sequence identity to BPV16). Additionally, phylogenetic analysis of the L1 gene of the papillomavirus identified here (tentatively named BPV22) revealed that it clusters with members of the genus Dyokappapapillomavirus. Interestingly, the recently identified BPV16, which was detected in fibropapilloma lesions in cattle also clusters within the Dyokappapapillomavirus group. Each virus, however, forms a separate branch in the phylogenetic tree. These results indicate that the putative BPV22 represents the second BPV within the genus Dyokappapapillomavirus. PMID- 28616672 TI - Biological effects of silk fibroin 3D scaffolds on stem cells from human exfoliated deciduous teeth (SHEDs). AB - The aim is to investigate in vitro biological effects of silk fibroin 3D scaffolds on stem cells from human exfoliated deciduous teeth (SHEDs) in terms of proliferation, morphological appearance, cell viability, and expression of mesenchymal stem cell markers. Silk fibroin 3D scaffolding materials may represent promising suitable scaffolds for their application in regenerative endodontic therapy approaches. SHEDs were cultured in silk fibroin 3D scaffolds. Then, cell numbers were counted and the Alamar blue colorimetric assay was used to analyse cell proliferation after 24, 48, 72, and 168 h of culture. The morphological features of SHEDs cultured on silk fibroin scaffolds were evaluated by scanning electron microscopy (SEM). Finally, cell viability and the expression of mesenchymal stem cell markers were analysed by flow cytometry. One-way analysis of variance (ANOVA) followed by a Bonferroni post-test was performed (P < 0.05). At 24 and 48 h of culture, SHED proliferation on scaffolds was modest compared to the control although still significant (p < 0.05). However, cell proliferation progressively increased from 72 to 168 h compared with the control (p < 0.001; p < 0.01). In addition, flow cytometry analysis showed that the culture of SHEDs on silk fibroin scaffolds did not significantly alter the level of expression of the mesenchymal markers CD73, CD90, or CD105 up to 168 h; in addition, cell viability in silk fibroin was similar to than obtained in plastic. Moreover, SEM studies revealed a suitable degree of proliferation, cell spreading, and attachment, especially after 168 h of culture. The findings from the current study suggest that silk fibroin 3D scaffolds had a favourable effect on the biological responses of SHEDs. Further in vivo investigations are required to confirm these results. PMID- 28616673 TI - Contribution of sellar dura integrity to symptom manifestation in pituitary adenomas with intratumoral hemorrhage. AB - PURPOSE: Although hemorrhage within pituitary adenomas frequently exacerbates the symptoms, there are many grades of severity. Moreover, the contributing factors for symptom severity are still controversial. METHODS: This retrospective study included 82 patients who underwent transsphenoidal surgery for pituitary adenomas with intratumoral hemorrhage. The grades of preoperative symptoms were classified into group A, asymptomatic or minor symptoms; group B, moderate symptoms sufficient for complain; and group C, severe symptoms disturbing daily life. RESULTS: The hemorrhage volume within an adenoma was significantly higher in group C (92.6%) than in groups A (48.6%) and B (58.7%). Both headache and diplopia were dominant in group C, occurring in 72.2% and 27.8% of the patients, respectively. In group C, there was no significant difference in frequency between adenoma extensions into the sphenoid sinus (0%) and involvement of the cavernous sinus of Knosp grade 4 (0%), and extensions into the suprasellar region were not common (38.9%). The most distinctive feature was that "no extrasellar extension" was found only in group C (41.2%), and "multidirectional extension" was not detected in this group (0%). Multiple regression analysis revealed that the most powerful determining factors were the high frequencies of intratumoral hemorrhage and lack of extrasellar and multidirectional extensions. CONCLUSION: Rapid volume expansion of a hematoma and lack of extension or unidirectional extension might lead to significant compression of the sellar and surrounding structures. Of note, the integrity of the sellar dura might contribute to the acute onset of symptom manifestations caused by hemorrhage in pituitary adenomas. PMID- 28616674 TI - Health-related quality of life of a very special population: monks of Holy Mountain Athos, Greece. AB - PURPOSE: The investigation of Health-Related Quality of Life (HRQOL) of Orthodox Christian monks who live at the Holy Mount Athos in Greece, and its correlation with demographic characteristics and Sense of Coherence (SOC-13). METHODS: A cross-sectional study was designed. The seven monasteries and five scetes with the largest number of monk population were invited to participate. Two monasteries and 1 scete gave their permission for the study. The final monks sample was formed by 166 monks from 215 who participated to the study. HRQOL was assessed using the SF-12 and Sense of Coherence the SOC-13 scales that were completed by monks from May to August 2012. MUultiple linear regression analyses were conducted to explore the association of the HRQOL subscales with the demographics and SOC-13. RESULTS: The mean age was 45.5 +/- 13.0 years; 83.7% lived in communal monasteries, and the mean number of years in monasticism was 18.4 +/- 12.1. The mean value of their Physical Component Summary (PCS) score was 47.3 +/- 5.3, which is lower than in the general Greek men population, while their Mental Component Summary (MCS) score was 56.4 +/- 5.8, which is higher than in the general Greek men population. The mean value of SOC-13 was 65.7 +/- 6.5. Positive association for PCS appeared for place of living (beta = 5.43, SE = 1.27, p < 0.001) and negative association for age (beta = -0.16, SE = 0.03, p < 0.001) while for MCS for number of years in monasticism (beta = 0.07, SE = 0.06, p = 0.023) and sense of coherence (beta = 0.47, SE = 0.06, p < 0.001). CONCLUSIONS: The results indicated that monks had better mental health but worse physical health compared to the general Greek male population. More studies are required to validate the above findings. PMID- 28616675 TI - Thank you to Carolyn Schwartz. PMID- 28616676 TI - [Liquid biopsy : A blood sample for early recognition and therapy control in lung cancer patients]. PMID- 28616677 TI - [Preoperative genetic diagnostics and imaging for pediatric pheochromocytoma and paraganglioma]. PMID- 28616678 TI - [The downside of transparency : On the devaluation of surgery by the dictate of transparency]. PMID- 28616680 TI - Melanization of Fusarium keratoplasticum (F. solani Species Complex) During Disseminated Fusariosis in a Patient with Acute Leukemia. AB - Fusarium spp. are recognized as the second most frequently filamentous fungi causing opportunistic infections and particularly important due to the increasing number of immunocompromised patients. F. keratoplasticum (a member of F. solani species complex) is one of the Fusarium species commonly associated with human infection, and therefore, studies on the virulence of this fungus are needed. This study aimed to confirm the presence of melanin in F. keratoplasticum from a patient with systemic fusariosis. Immunofluorescence labeling with anti-melanin monoclonal antibody (MAb) was used to examine an expression of melanin in F. keratoplasticum in vitro and during infection. Electron spin resonance identified the particles extracted from F. keratoplasticum as stable free radical consistent with melanin. Lesional skin from the sites with fusariosis contained hyphal structures that could be labeled by melanin-binding MAb, while digestion of the tissue yielded dark particles that were reactive. These findings suggest that F. keratoplasticum hyphae and chlamydospores can produce melanin in vitro and that hyphae can synthesize pigment in vivo. Given the potential role of melanin in virulence of other fungi, this pigment in F. keratoplasticum may play a role in the pathogenesis of fusariosis. PMID- 28616679 TI - Manganese superoxide dismutase (SOD2): is there a center in the universe of mitochondrial redox signaling? AB - It is becoming increasingly clear that mitochondria drive cellular functions and in vivo phenotypes by directing the production rate and abundance of metabolites that are proposed to function as signaling molecules (Chandel 2015; Selak et al. 2005; Etchegaray and Mostoslavsky 2016). Many of these metabolites are intermediates that make up cellular metabolism, part of which occur in mitochondria (i.e. the TCA and urea cycles), while others are produced "on demand" mainly in response to alterations in the microenvironment in order to participate in the activation of acute adaptive responses (Mills et al. 2016; Go et al. 2010). Reactive oxygen species (ROS) are well suited for the purpose of executing rapid and transient signaling due to their short lived nature (Bae et al. 2011). Hydrogen peroxide (H2O2), in particular, possesses important characteristics including diffusibility and faster reactivity with specific residues such as methionine, cysteine and selenocysteine (Bonini et al. 2014). Therefore, it is reasonable to propose that H2O2 functions as a relatively specific redox signaling molecule. Even though it is now established that mtH2O2 is indispensable, at least for hypoxic adaptation and energetic and/or metabolic homeostasis (Hamanaka et al. 2016; Guzy et al. 2005), the question of how H2O2 is produced and regulated in the mitochondria is only partially answered. In this review, some roles of this indispensable signaling molecule in driving cellular metabolism will be discussed. In addition, we will discuss how H2O2 formation in mitochondria depends on and is controlled by MnSOD. Finally, we will conclude this manuscript by highlighting why a better understanding of redox hubs in the mitochondria will likely lead to new and improved therapeutics of a number of diseases, including cancer. PMID- 28616682 TI - Evidence-Responsiveness and the Ongoing Autonomy of Treatment Preferences. AB - To be an autonomous agent is to determine one's own path in life. However, this cannot plausibly be seen as a one-off affair. An autonomous agent does not merely set herself on a particular course and then lock the steering wheel in place, so to speak, but must maintain some form of ongoing control over her direction in life-must keep her eyes on the road and her hands on the wheel. Circumstances often change in important and unexpected ways, after all, and it is reasonable to think that a crucial part of autonomy consists of the ability and disposition to recognize and properly respond to such changes. This implies, I contend, that a patient whose initial decision to undergo a given treatment satisfied plausible requirements of autonomy, but who is now unable to recognize that available evidence indicates the need to reconsider her medical situation and options has come to lack autonomy with respect to her desire to continue that treatment. However, and despite its importance with respect to both theoretical understandings of autonomy and applications of the concept to clinical ethics, this ongoing aspect of autonomy has received little attention. This paper aims to go some way toward remedying that. I first critically review two of the few theories of autonomy that do address "evidence-responsiveness" so as to identify and elaborate what I take to be the most promising way in which to account for this aspect of autonomy. After considering and responding to a possible objection to the evidence-responsiveness condition I propose, I conclude by discussing its clinical implications. That condition, I argue, is not merely theoretically sound, but can and should be applied to clinical practice. PMID- 28616681 TI - Frequency and anatomical features of the mandibular lingual foramina: systematic review and meta-analysis. AB - Lingual mandibular foramina are peculiar anatomical variations often present on the bone surface of the inferior jaw. These structures host vascular and nervous anastomosis deriving from the branches of the submental artery, lingual artery, and the mylohyoid nerve. Reports pointed out intra-operative massive bleeding accidents during implant interventions occurred in this area. The aim of this systematic review and meta-analysis was to summarize quantitatively the features of the lingual foramina on the midline of the inferior jaw. We performed a systematic review and meta-analysis complying the PRISMA statement and registering it in PROSPERO database. The frequency rate of the foramina resulted to have a point estimate of 0.965. The means of the diameters showed to have a point estimate of 0.840 with a standard error of 0.06. The results showed a significant high frequency reported in the literature of this variation, with a quite important diameter, sign of significant caliber of the related vessels. Even if this variation is underreported in modern textbooks of oral anatomy, we suggest an accurate screening via CT scan pre-operatively. In addition, a proper risk management is necessary to minimize injure hazard and properly managing the vascular plexus of the anterior floor of oral cavity. PMID- 28616683 TI - General practitioners' perceptions of the current status and pharmacists' contribution to primary care in Iceland. AB - Background For the past several years pharmacists' responsibilities have expanded globally from traditional tasks of dispensing medications to collaborating with other health care professionals in patient care. Similar developments have not occurred in outpatient settings in Iceland. Objective The aim of this study was to explore Icelandic general practitioners' views on the current status of primary care, their perceptions of pharmacists as a health care profession, and their attitudes towards future GP-pharmacist collaboration in primary care in Iceland. Setting Twelve primary care clinics in Iceland. Methods Semi-structured in-depth interviews were conducted with general practitioners from different primary care clinics in Iceland. A purposive and snowball sampling technique was used to select participants. All interviews were recorded and transcribed verbatim. The transcripts were categorized by themes and then analyzed using conventional content analysis. Main outcome measure General practitioners' attitudes towards pharmacists. Results Twenty general practitioners from twelve different primary care clinics in Iceland were interviewed. There are several unmet needs regarding medicines and patient monitoring in the Icelandic health care system. General practitioners suggested ways in which these gaps may be addressed and pharmacist-led clinical service was one of the suggestions. Currently, their communication with pharmacists in the primary sector solely surrounds practical non-clinical issues. Due to increasing polypharmacy and multimorbidity, they suggested that pharmacists should be more involved in patient care. Conclusions General practitioners believe that pharmacist-led clinical service can increase the quality of patient therapy. To improve communication between these health care providers, pharmacists must also re professionalize (strengthening the profession's status through new responsibilities and tasks), not having a conflict of interest and showing that they have expertise in patient care. PMID- 28616684 TI - Influence of Ethanol on Darunavir Hepatic Clearance and Intracellular PK/PD in HIV-Infected Monocytes, and CYP3A4-Darunavir Interactions Using Inhibition and in Silico Binding Studies. AB - PURPOSE: Although the prevalence of alcohol consumption is higher in HIV+ people than general public, limited information is available on how alcohol affects the metabolism and bioavailability of darunavir (DRV). METHODS: DRV was quantified by using LC-MS/MS method. All in vitro experiments were performed using human liver microsomes and HIV-infected monocytic cells. CYP3A4 and DRV/Ritonavir (RTV) docking was performed using GOLD suite 5.8. RESULTS: Ethanol (20 mM) significantly decreased apparent half-life and increased degradation rate constant of RTV-boosted DRV but not for DRV alone. Similarly, ethanol exposure increased hepatic intrinsic clearance for RTV-boosted DRV with no significant influence on DRV alone. Ethanol showed a limited influence on intracellular total DRV exposure in the presence of RTV without altering maximum concentration (Cmax) values in HIV-infected monocytic cells. Ethanol alone elevated HIV replication but this effect was nullified with the addition of DRV or DRV + RTV. Additionally, inhibitory potency of DRV was significantly reduced in the presence of ethanol. Our docking results projected that ethanol increases the average distance between DRV and CYP3A4 heme, and alter the orientation of DRV-CYP3A4 binding. CONCLUSIONS: Collectively these findings suggest that DRV metabolism is primarily influenced by ethanol in the liver, but has minor effect in HIV residing monocytes. PMID- 28616685 TI - Endocytic Uptake, Transport and Macromolecular Interactions of Anionic PAMAM Dendrimers within Lung Tissue. AB - PURPOSE: Polyamidoamine (PAMAM) dendrimers are a promising class of nanocarrier with applications in both small and large molecule drug delivery. Here we report a comprehensive evaluation of the uptake and transport pathways that contribute to the lung disposition of dendrimers. METHODS: Anionic PAMAM dendrimers and control dextran probes were applied to an isolated perfused rat lung (IPRL) model and lung epithelial monolayers. Endocytosis pathways were examined in primary alveolar epithelial cultures by confocal microscopy. Molecular interactions of dendrimers with protein and lipid lung fluid components were studied using small angle neutron scattering (SANS). RESULTS: Dendrimers were absorbed across the intact lung via a passive, size-dependent transport pathway at rates slower than dextrans of similar molecular sizes. SANS investigations of concentration dependent PAMAM transport in the IPRL confirmed no aggregation of PAMAMs with either albumin or dipalmitoylphosphatidylcholine lung lining fluid components. Distinct endocytic compartments were identified within primary alveolar epithelial cells and their functionality in the rapid uptake of fluorescent dendrimers and model macromolecular probes was confirmed by co-localisation studies. CONCLUSIONS: PAMAM dendrimers display favourable lung biocompatibility but modest lung to blood absorption kinetics. These data support the investigation of dendrimer-based carriers for controlled-release drug delivery to the deep lung. PMID- 28616686 TI - Mechanistic approach for fabrication of gold nanoparticles by Nitzschia diatom and their antibacterial activity. AB - The problem of chemically synthesized nanoproducts motivated scientific community to explore ecofriendly methods of nanosynthesis. Diatoms belong to a group of aquatic, unicellular, photosynthetic microalgae have been scarcely investigated as a source of reducing and capping agents for nanosynthesis of pesticides and antibiotics. The present study reports a novel ecofriendly method for the fabrication of bioactive gold nanoparticles using locally isolated Nitzschia diatoms. The diatom-fabricated gold nanoparticles show characteristic ruby red colored with sharp absorbance peak at 529 nm. Electron microscopy confirmed irregular shape of gold nanoparticles, with average size of 43 nm and zeta potential of -16.8 mV. The effects of gold nanoparticles on diatom viability were investigated using light and electron microscopy. The mechanistic approach to shed light on how diatoms reacted after exposure to gold metal salt revealed that exposure to gold chloride triggers elevated levels of catalase and peroxidase (12.76 and 14.43 unit/mg protein, respectively) to relieve reactive oxygen species (ROS) stress induced by gold salt exposure. Investigation studies on mechanisms behind Nitzschia-mediated gold nanoparticles fabrication outlined the role of diatom proteins, polysaccharides in reduction, and stabilization of nanoparticles as confirmed by FT-IR analysis. Bioactivity of gold nanoparticles was accessed by coupling them with antibiotics (penicillin and streptomycin), which increased their antibacterial activity compared to individual nanoparticles and antibiotics (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). Overall, the present novel phyco-nanotechnological approach is a promising tool to be used as sustainable strategy in green nanotechnology as well as to reduce use of antibiotics in microbial control. PMID- 28616687 TI - Controversies in the role of postmastectomy radiotherapy in breast cancer patients with one to three positive axillary nodes and safety of integrating radiotherapy and breast reconstruction. PMID- 28616690 TI - Anxiety Sensitivity Moderates the Relation Between Family Accommodation and Anxiety Symptom Severity in Clinically Anxious Children. AB - High levels of family accommodation (FA), or parental involvement in child symptoms, are associated with child anxiety symptom severity. The strength of associations has varied across studies, however, highlighting the need to identify moderating variables. We investigated whether anxiety sensitivity (AS) moderated the FA-anxiety symptom severity association in clinically anxious children (N = 103, ages 6-17; mean age 11.07 years). We collected child and mother ratings of FA, child anxiety symptom severity, and child AS ratings. AS significantly moderated the FA-child anxiety severity link. Specifically, this link was significant for low-AS but not high-AS children. Findings suggest that FA may operate in the typically observed fashion for low-AS children-alleviating immediate distress while inadvertently exacerbating longer-term anxiety-whereas high-AS children may experience distress following anxiety-provoking stimuli regardless of FA. Assessing AS in research and clinical settings may help identify subsets of children for whom FA is more closely tied to anxiety severity. PMID- 28616688 TI - Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas. AB - In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29-1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility. PMID- 28616691 TI - The influence of the counterfort while ballistic testing using gelatine blocks. AB - In wound ballistic research, gelatine blocks of various dimensions are used depending on the simulated anatomical region. When relatively small blocks are used as substitute for a head, problems with regard to the expansion of the gelatine block could arise. The study was conducted to analyse the influence of the material the gelatine block is placed upon. Thirty-six shots were performed on 12 cm gelatine cubes doped with thin foil bags containing acrylic paint. Eighteen blocks each were placed on a rigid table or on a synthetic sponge of 5 cm height. Deforming bullets with different kinetic energies were fired from distance and recorded by a high-speed video camera. Subsequently, the gelatine cubes were cut into 1 cm thick slices which were scanned using a flatbed scanner. Cracks in the gelatine were analysed by measuring the longest crack, Fackler's wound profile and the polygon (perimeter and area) outlining the ends of the cracks. The energy dissipated ranged from 153 to 707 J. For moderate energy transfer, no significant influence of the sustaining material was discerned. With increasing dissipated energy, the sponge was compressed correspondingly, and the cracks were longer than in gelatine blocks which had been placed on a table. High speed video revealed a loss of symmetry and a flattened inferior margin of the temporary cavity with energies superior to approx. Two hundred Joules when the blocks were placed on a rigid platform. However, 12 cm gelatine cubes showed material limits by a non-linear response when more than 400 J were dissipated for both rigid and elastic sustainment. In conclusion, the smaller the gelatine blocks and the greater the energy transfers, the more important it is to take into account the counterfort of the sustaining material. PMID- 28616692 TI - A minimally-invasive method for profiling volatile organic compounds within postmortem internal gas reservoirs. AB - In forensic casework, non-invasive and minimally-invasive methods for postmortem examinations are extremely valuable. Whole body postmortem computed tomography (PMCT) is often used to provide visualization of the internal characteristics of a body prior to more invasive procedures and has also been used to locate gas reservoirs inside the body to assist in determining cause of death. Preliminary studies have demonstrated that exploiting the volatile organic compounds (VOCs) located in these gas reservoirs by comprehensive two-dimensional gas chromatography-high-resolution time-of-flight mass spectrometry (GC*GC-HRTOF-MS) may assist in providing information regarding the postmortem interval. The aim of the current study was to further develop the procedures related to solid-phase microextraction (SPME) and GC*GC-HRTOF-MS analysis of gas reservoirs collected from deceased individuals. SPME fiber extraction parameters, internal standard approach, and sample stability were investigated. Altering the SPME parameters increased the selectivity and sensitivity for the VOC profile, and the use of a mixed deuterated internal standard contributed to data quality. Samples were found to be stable up to 6 weeks but were recommended to be analyzed within 4 weeks due to higher variation observed beyond this point. In addition, 29 VOC markers of interest were identified, and heart and/or abdominal cavity samples were suggested as a possible standardized sampling location for future studies. The data presented in this study will contribute to the long-term goal of producing a routine, accredited method for minimally-invasive VOC analysis in postmortem examinations. PMID- 28616693 TI - [Tinea barbae profunda due to Trichophyton mentagrophytes after journey to Thailand : Case report and review]. AB - Tinea barbae represents a very rare dermatophytosis. We report on a tinea barbae profunda following a journey to Southeast Asia. After travel to Thailand, a businessman was affected by a foudroyant proceeding abscessing infection of the upper lip and beard area. The initial therapy with oral acyclovir and oral ciprofloxacin, which later was changed to ampicillin plus sulbactam, intravenously, was unsuccessful. In a biopsy sample, histologically, with Grocott Gomori's methenamine silver stain, fungal mycelium was apparent in the tissue. Thereupon, terbinafine 250 mg was given for 4 weeks, topically, a 1% ciclopiroxolamine-containing cream. In fungal culture, T. mentagrophytes were found to grow. Meanwhile, the patient's German wife suffered from a tinea faciei. From skin scrapings from the cheek, T. mentagrophytes was also cultivated. This zoophilic dermatophyte was identical with other zoophilic strains of T. mentagrophytes currently found in Germany, which were also acquired in Thailand. The patient had contact with Thai female sex workers who must be considered as a source of infection of the dermatophytosis. There was no animal contact, neither in Thailand, nor in Germany. The infection chain of the dermatophytosis from Thailand probably reached from a female sex worker via the here described patient to his wife in Germany. This pathway of infection has been known for 1 or 2 years, but until now, in Germany, Switzerland, and Austria exclusively via pubogenital infections (tinea genitalis profunda) due to T. mentagrophytes after journeys to Southeast Asia. For treatment, oral antifungal agents should be used, first of all terbinafine, alternatively fluconazole or itraconazole. PMID- 28616694 TI - [Dermophytes and guinea pigs : An underestimated danger?] AB - BACKGROUND: For several years, an increasing number of human infections, mainly affecting children, with the zoophilic dermatophyte Trichophyton benhamiae has been observed. It is predominantly transmitted by pet guinea pigs. The prevalence of the dermatophyte on guinea pigs which are for sale in pet shops is unknown. OBJECTIVE: Therefore, the aim of this study was to analyze the frequency of T. benhamiae on symptomatic and asymptomatic guinea pigs from pet shops in Berlin. METHODS: We sampled 59 guinea pigs from 15 pet shops using toothbrushes (MacKenzie brush technique) and FLOQswabsTM and analyzed the material for the presence of T. benhamiae with polymerase chain reaction (PCR) and culture. RESULTS: We detected T. benhamiae on more than 90% of the guinea pigs; 9% of which showed visible tinea symptoms. The majority was identified as asymptomatic carriers of the dermatophyte. CONCLUSION: Pet shop guinea pigs have a high risk of being carriers of T. benhamiae, which can be transmitted to humans via physical contact, even though there is no visible infection in most cases. It is therefore recommended to have newly purchased animals examined by a veterinarian. PMID- 28616695 TI - Prediction of breast cancer recurrence using lymph node metabolic and volumetric parameters from 18F-FDG PET/CT in operable triple-negative breast cancer. AB - PURPOSE: Triple-negative breast cancer has a poor prognosis. We evaluated several metabolic and volumetric parameters from preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in the prognosis of triple-negative breast cancer and compared them with current clinicopathologic parameters. METHODS: A total of 228 patients with triple negative breast cancer (mean age 47.0 +/- 10.8 years, all women) who had undergone preoperative PET/CT were included. The PET/CT metabolic parameters evaluated included maximum, peak, and mean standardized uptake values (SUVmax, SUVpeak, and SUVmean, respectively). The volumetric parameters evaluated included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Metabolic and volumetric parameters were evaluated separately for tumor (T) and lymph nodes (N). The prognostic value of these parameters was compared with that of clinicopathologic parameters. RESULTS: All lymph node metabolic and volumetric parameters showed significant differences between patients with and without recurrence. However, tumor metabolic and volumetric parameters showed no significant differences. In a univariate survival analysis, all lymph node metabolic and volumetric parameters (SUVmax-N, SUVpeak-N, SUVmean-N, MTV-N, and TLG-N; all P < 0.001), T stage (P = 0.010), N stage (P < 0.001), and TNM stage (P < 0.001) were significant parameters. In a multivariate survival analysis, SUVmax N (P = 0.005), MTV (P = 0.008), and TLG (P = 0.006) with TNM stage (all P < 0.001) were significant parameters. CONCLUSIONS: Lymph node metabolic and volumetric parameters were significant predictors of recurrence in patients with triple-negative breast cancer after surgery. Lymph node metabolic and volumetric parameters were useful parameters for evaluating prognosis in patients with triple-negative breast cancer by 18F-FDG PET/CT, rather than tumor parameters. PMID- 28616696 TI - [Epileptic seizures and epilepsy after a stroke : Incidence, prevention and treatment]. AB - Following stroke, 3-6% of patients develop acute symptomatic seizures within the first 7 days. The rate is higher after cerebral haemorrhage compared to ischaemia. In 10-12% of patients, after more than 7 days unprovoked seizures occur. Due to these low incidence rates, primary prophylaxis with antiepileptic drugs is generally not necessary. Following one acute symptomatic seizure, recurrence risk within the first 7 days post-stroke is 10-20%, generally arguing against secondary prophylaxis with an antiepileptic drug. In clinical practice however, antiepileptic drug treatment in this constellation is often initiated. If this is done, the antiepileptic drug should be withdrawn soon after the acute phase, as the long-term risk for manifestation of an unprovoked seizure is approximately 30%. Following one post-stroke unprovoked seizure, recurrence risk within the next 10 years is more than 70%, this defines epilepsy. In this case, antiepileptic drug treatment is regularly recommended. PMID- 28616697 TI - Borders, Tensegrity and Development in Dialogue. AB - In this article we propose a development of the Dialogical Self Theory by introducing the notions of borders, cogenetic logic and tensegrity that we have elaborated during the last 5 years, in order to introduce a stronger developmental and dynamic perspective within the theory. We start from the discussion of some recent advancements of the model proposed by Hermans et al. (Integrative Psychological and Behavioural Science, 51(4), 2017), who refer to the metaphor of democratic society of the Self to understand the challenges and possible directions of adaptation that the persons can face in those border crossing processes characterizing contemporary western societies. We conceptualized the Self as a dynamic semiotic system in constant evolutive tension, rather than a system in equilibrium adapting to the environmental changing conditions. Then, we propose to replace the concept of stability and continuity of the Self with the more fruitful idea of tensional integrity. PMID- 28616698 TI - Costs of hematopoietic stem cell transplantation in a developing country. AB - Costs of HSCT in the United States have been widely reported, but complete information on costs in developing countries is lacking. We performed an analysis designed to assess the real, detailed costs of HSCT in Mexico. Using the database of the Current Accounts Department at our Institution, we performed a micro costing based analysis of patients from 2010 through 2015 to obtain the overall cost of HSCT during the in-patient procedure and 2-month follow-up. One hundred five transplantations (57% autologous) were performed. The most frequent indications for transplantation were lymphomas (32%), followed by acute leukemias (22%). The most frequently used conditioning regimen was reduced BUCY 2 (38%), followed by BEAM (28%). Among post-transplant complications, acute graft-versus host-disease was not associated with higher costs (p = 0.8). The median costs (in patient and 2-month outpatient follow-up) for auto and allo-HSCT were 12,155 and 18,260 USD, respectively. Advances in HSCT technology have improved outcomes and increased the availability of this technique; however, this procedure can also significantly influence the socioeconomic wellbeing of patients, especially in developing countries. Our study highlights the feasibility of performing HSCT in Mexico at lower costs than developed countries, while preserving quality of care. PMID- 28616699 TI - FLT3-ITD with DNMT3A R882 double mutation is a poor prognostic factor in Chinese patients with acute myeloid leukemia after chemotherapy or allogeneic hematopoietic stem cell transplantation. AB - To investigate clinical characteristics and outcomes of transplantation in AML patients with FLT3-ITD/DNMT3A double mutation, we retrospectively analyzed 206 Chinese patients with AML after Sanger sequencing. Our analysis showed that AML patients with FLT3-ITD and DNMT3A R882 mutations had a higher white blood cell count and a lower complete remission (CR) rate after first induction chemotherapy. All 206 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in status of CR. These results indicate that AML patients with FLT3-ITD and DNMT3A R882 double mutation show a higher 2-year cumulative incidence of relapse (CIR), lower 2-year overall survival (OS) rate, and lower 2-year leukocyte-free survival (LFS) after allo-HSCT. The univariate and multivariate analyses confirmed that disease status prior to transplantation, FLT3-ITD, FLT3-ITD, and DNMT3A R882 double mutation were independent factors for poor prognosis after allo-HSCT. In summary, the present cohort study demonstrated that FLT3-ITD and DNMT3A R882 double mutation predicts poor prognosis in Chinese AML patients receiving chemotherapy or allo-HSCT treatment. PMID- 28616700 TI - Evaluation of irradiation effects of near-infrared free-electron-laser of silver alloy for dental application. AB - In the application of lasers in dentistry, there is a delicate balance between the benefits gained from laser treatment and the heat-related damage arising from laser irradiation. Hence, it is necessary to understand the different processes associated with the irradiation of lasers on dental materials. To obtain insight for the development of a safe and general-purpose laser for dentistry, the present study examines the physical effects associated with the irradiation of a near-infrared free-electron laser (FEL) on the surface of a commonly used silver dental alloy. The irradiation experiments using a 2900-nm FEL confirmed the formation of a pit in the dental alloy. The pit was formed with one macro-pulse of FEL irradiation, therefore, suggesting the possibility of efficient material processing with an FEL. Additionally, there was only a slight increase in the silver alloy temperature (less than 0.9 degrees C) despite the long duration of FEL irradiation, thus inferring that fixed prostheses in the oral cavity can be processed by FEL without thermal damage to the surrounding tissue. These results indicate that dental hard tissues and dental materials in the oral cavity can be safely and efficiently processed by the irradiation of a laser, which has the high repetition rate of a femtosecond laser pulse with a wavelength around 2900 nm. PMID- 28616701 TI - Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab. AB - INTRODUCTION: PD-L1 is established as a predictive marker for therapy of non small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab. MATERIALS AND METHODS: Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings. RESULTS AND DISCUSSION: The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. PMID- 28616702 TI - The indication of completion lobectomy for lung adenocarcinoma <=3 cm after wedge resection during surgical operation. AB - PURPOSE: This retrospective study was designed to find out the potential indications of completion lobectomy (CL) during wedge resection (WR) operation among patients with lung adenocarcinoma (ADC) <=3 cm, by the use of Shanghai Chest Hospital Lung Cancer Database. PATIENTS AND METHODS: There were totally 1938 patients in this study, including 746 WRs and 1192 CLs. The propensity score matching (PSM) was performed to minimize the effect of confounders. Univariable and multivariable cox regressions were analyzed to discover the independent risk factors of recurrence-free survival (RFS) and overall survival (OS). Subgroup analysis and Kaplan-Meier survival curves were performed if necessary. RESULTS: The 5-year RFS (86.1 vs 91.5%, p = 0.001 for unmatched group; 84 v 92%, p < 0.001 for PSM group) and OS (83.6 vs 91.7%, p < 0.001 for unmatched group; 81.6 vs 88.2%, p < 0.001 for PSM group) all indicated a better prognosis when conducting CL. Subgroup analysis suggested that WR was appropriate for non-invasive ADC. Three prognostic factors (sex, surgical approach and pleural invasion) were correlated with RFS and two (sex and surgical approach) corresponded with OS in invasive ADC through multivariable analysis. Non-lepidic-predominant component showed a better RFS and OS when CL was operated after WR in the subgroup of invasive ADC. CONCLUSION: CL was an appropriate remediation to WR when the existence of invasive ADC, especially non-lepidic-predominant one. While WR could be applied if non-invasive ADC was confirmed. Whether lepidic-predominant adenocarcinoma was fit for WR needed further study. PMID- 28616703 TI - Preparation of a biphase composite scaffold and its application in tissue engineering for femoral osteochondral defects in rabbits. AB - PURPOSE: Three-dimensional bioactive scaffolds are useful tools for stem cell implant in tissue-engineering. For chondral and subchondral repair, the chondroinductive and osteoinductive property of a scaffold is a major challenge. The scaffolds that aim to osteogenic differentiation have been well studied. However, cartilage cells can hardly be induced for osteogenesis, and monophase scaffolds cannot ideally repair both cartilage and subchondral defects at the same time. METHODS: We developed a novel biphase composite scaffold and observe its application osteochondral defects. We combined the advantages of silk fibroin/chitosan (SF/CS) scaffold in chondrogenic differentiation and the silk fibroin/chitosan/nano-hydroxyapatite (SF/CS/nHA) scaffold in osteogenic differentiation and bone regeneration, and synthesized a SF/CS-SF/CS/nHA scaffold, which contained both the chondrocytic phase (SF/CS) and the osteoblastic phase (SF/CS/nHA). RESULTS: The biphase scaffold exhibited a porosity ratio around 90% and a water absorption ratio about 822%. A similar degradation property to traditional monophase scaffolds was observed. Bone mesenchymal stem cells (BMSCs) showed a good proliferation on this scaffold. Expression of two types of collagen was inducable for BMSCs on the scaffold. Neoformative extracellular matrix integrated with the scaffold was observed by the scanning electron microscope. When implanted in the lesion site in the rabbit femur with cartilage injury, mixing and filling function were exerted by the cell scaffold constructs (CSCs). Micro-CT scanning revealed both chondral and subchondral layers were repaired. Moreover, type I and II collagens were both expressed in the implanted CSCs. CONCLUSIONS: Chondral and subchondral repair can be achieved using the biphase scaffold implant that permits both chondrogenesis and osteogenesis from BMSCs. This approach has the potential to be clinically used for tissue engineering implantation. PMID- 28616704 TI - Metallic ion release after knee prosthesis implantation: a prospective study. AB - INTRODUCTION: Metal-on-metal (MoM) hip replacement bearings produce metallic ions that can cause health complications. Metallic release also occurs with other materials, but data on metallic ion levels after knee arthroplasty are sparse. We postulate that knee replacement generates elevating metallic ions (chromium (Cr), cobalt (Co) and titanium (Ti)) during the first year after implantation. PATIENTS AND METHODS: This ongoing prospective study included all patients who underwent the same type of knee arthroplasty between May and December 2013. Cr, Co and Ti levels were measured in whole blood at pre-operation and one-year follow-up (6 and 12 months). Clinical and radiographic data (range of motion, Oxford, International Knee Society (IKS) and satisfaction scores) were recorded. RESULTS: In 90 patients, preoperative Cr, Co and Ti metallic ion levels were respectively 0.45 MUg/l, 0.22 MUg/l, 2.94 MUg/l and increased to 1.27 MUg/l, 1.41 MUg/l, 4.08 MUg/l (p < 0.0001) at last one-year follow-up. Mean Oxford and IKS scores rose, respectively, from 45.9 (30-58) and 24.9 (12-52) to 88.3 (0-168) and 160.8 (93 200) (p < 0.001). CONCLUSION: After the implantation of knee arthroplasty, we found significant blood elevation of Cr, Co and Ti levels one year after implantation exceeding the normal values. This metallic ion release could lead to numerous effects: allergy, hypersensitivity, etc. PMID- 28616705 TI - Letter regarding article by Li AB et al.: intramedullary and extramedullary fixations for the treatment of unstable femoral intertrochanteric fractures: a meta-analysis of prospective randomized controlled trials. PMID- 28616706 TI - Surgical treatment of unstable pelvic fractures with concomitant acetabular fractures. AB - PURPOSE: To explore the diagnosis, treatment, and clinical prognosis of patients with both unstable pelvic fractures and concomitant acetabular fractures. MATERIAL AND METHODS: We retrospectively analyzed 21 cases of unstable pelvic fractures with concomitant acetabular fractures treated between January 2013 and December 2014. All 21 patients (18 males, 3 females), aged 43.5-55 years (range: 21-55 years), underwent surgery within four to 15 days (average = 6.5 days) after injury. We evaluated the pre-operative diagnoses, surgical approaches, types of fixation used, and prognoses. RESULTS: All 21 patients were followed-up for six to 18 months. The quality of post-operative pelvic fracture reduction (determined using the Matta scoring criteria) was excellent in five cases, good in 12, and fair in four. The clinical outcomes at the final follow-up (scored using the Majeed criteria) were excellent in ten cases, good in eight, and fair in three. The quality of post-operative acetabular fracture reduction (determined using the Matta scoring criteria) was excellent in five cases, good in 11, and poor in five. Hip joint function was evaluated at the final follow-up (using the D'Aubigne scoring system) and was excellent in eight cases, good in nine, and fair in four. The healing time was 12-18 weeks for pelvic fractures and 12-22 weeks for acetabular fractures. Post-operative wound infections in two patients were controlled after second operations featuring debridement and irrigation. We found no instance of heterotopic ossification, ischemic necrosis of the femoral head, or iatrogenic vascular or nerve injury. CONCLUSIONS: Good therapeutic outcomes in patients with unstable pelvic fractures and concomitant acetabular fractures can be achieved via accurate diagnosis, careful pre-operative planning, a well-performed operation, effective reduction and surgical fixation, and appropriate exercise to allow functional rehabilitation. PMID- 28616707 TI - Customer Characteristics and Shopping Patterns Associated with Healthy and Unhealthy Purchases at Small and Non-traditional Food Stores. AB - Small and non-traditional food stores (e.g., corner stores) are often the most accessible source of food for residents of lower income urban neighborhoods in the U.S. Although healthy options are often limited at these stores, little is known about customers who purchase healthy, versus less healthy, foods/beverages in these venues. We conducted 661 customer intercept interviews at 105 stores (corner stores, gas marts, pharmacies, dollar stores) in Minneapolis/St. Paul, Minnesota, assessing all food and beverage items purchased. We defined three categories of "healthy" and four categories of "unhealthy" purchases. Interviews assessed customer characteristics [e.g., demographics, body-mass index (BMI)]. We examined associations between healthy versus unhealthy purchases categories and customer characteristics. Overall, 11% of customers purchased >=1 serving of healthy foods/beverages in one or more of the three categories: 8% purchased fruits/vegetables, 2% whole grains, and 1% non-/low-fat dairy. Seventy-one percent of customers purchased >=1 serving of unhealthy foods/beverages in one or more of four categories: 46% purchased sugar-sweetened beverages, 17% savory snacks, 15% candy, and 13% sweet baked goods. Male (vs. female) customers, those with a lower education levels, and those who reported shopping at the store for convenience (vs. other reasons) were less likely to purchase fruits/vegetables. Unhealthy purchases were more common among customers with a BMI >=30 kg/m2 (vs. lower BMI). Results suggest intervention opportunities to increase healthy purchases at small and non-traditional food stores, particularly interventions aimed at male residents, those with lower education levels and residents living close to the store. PMID- 28616708 TI - Comparison of different definitions of acute kidney injury in extremely low birth weight infants. AB - BACKGROUND: The definition of acute kidney injury (AKI) has evolved over the years, and three definitions have been adapted including pediatric risk injury failure, loss of kidney function (pRIFLE), Acute Kidney Injury Network (AKIN), and Neonatal Modified Kidney Disease Improving Global Outcomes (KDIGO). We sought to report the prevalence and outcome of (AKI) according to the three existing definitions in extremely low birth weight (ELBW) infants. METHODS: In a retrospective cohort study, medical records of all ELBW infants (<1000 g) admitted to our neonatal intensive care unit (NICU) between Jan 2002 and Dec 2011 were reviewed. Infants' demographics, anthropometric measurements, and clinical characteristics were collected at the time of birth and at discharge from the NICU. Infants were staged according to the three different definitions. RESULTS: During the study period, 483 ELBW infants met our inclusion criteria. The incidence of AKI was 56, 59, and 60% according to pRIFLE, AKIN, and KDIGO, respectively. Mortality, NICU length of stay, and serum creatinine (SCr) at NICU discharge were higher in infants with advanced AKI stages regardless of the definition. In addition, discharge NICU weight and length z scores were lower in infants with advanced AKI stages. SCr at 72 h of life and SCr peak were predictable of NICU mortality [AUC 0.667 (95% CI 0.604-0.731), p < 0.001 and AUC 0.747 (95% CI 0.693-0.801), p < 0.001, respectively]. CONCLUSION: Regardless of the definition, advanced AKI is associated with increased mortality, prolonged NICU length of stay, and poor growth in ELBW infants. SCr at 72 h of life and SCr peak may be predictable of NICU mortality. PMID- 28616709 TI - A simplified surgical technique for recurrent inguinal hernia repair following total extraperitoneal patch plastic. AB - PURPOSE: To present a new and alternative method for surgical treatment of recurrent inguinal hernia after total extraperitoneal patch plastic (TEP). METHODS: From January 2005 to September 2015, 35 patients (34 male, 1 female; mean age 65 +/- 12.6 years) with recurrent inguinal hernia following TEP were operated at the Kliniken Essen-Mitte using a simplified method consisting of re fixation of the primary mesh to the inguinal ligament by an anterior approach. RESULTS: The mean operating time was 47 +/- 22 min. All complications were minor with an overall incidence of 6%. After a mean follow-up of 54 months one re recurrence was observed. CONCLUSIONS: This Simplified Hernia Repair is safe and avoids additional foreign body implantation. Therefore, it is our method of choice for recurrent inguinal hernias after TEP. PMID- 28616710 TI - Erratum to: Advances in systemic therapy for metastatic breast cancer: future perspectives. PMID- 28616711 TI - Integrating NOE and RDC using sum-of-squares relaxation for protein structure determination. AB - We revisit the problem of protein structure determination from geometrical restraints from NMR, using convex optimization. It is well-known that the NP-hard distance geometry problem of determining atomic positions from pairwise distance restraints can be relaxed into a convex semidefinite program (SDP). However, often the NOE distance restraints are too imprecise and sparse for accurate structure determination. Residual dipolar coupling (RDC) measurements provide additional geometric information on the angles between atom-pair directions and axes of the principal-axis-frame. The optimization problem involving RDC is highly non-convex and requires a good initialization even within the simulated annealing framework. In this paper, we model the protein backbone as an articulated structure composed of rigid units. Determining the rotation of each rigid unit gives the full protein structure. We propose solving the non-convex optimization problems using the sum-of-squares (SOS) hierarchy, a hierarchy of convex relaxations with increasing complexity and approximation power. Unlike classical global optimization approaches, SOS optimization returns a certificate of optimality if the global optimum is found. Based on the SOS method, we proposed two algorithms-RDC-SOS and RDC-NOE-SOS, that have polynomial time complexity in the number of amino-acid residues and run efficiently on a standard desktop. In many instances, the proposed methods exactly recover the solution to the original non-convex optimization problem. To the best of our knowledge this is the first time SOS relaxation is introduced to solve non-convex optimization problems in structural biology. We further introduce a statistical tool, the Cramer-Rao bound (CRB), to provide an information theoretic bound on the highest resolution one can hope to achieve when determining protein structure from noisy measurements using any unbiased estimator. Our simulation results show that when the RDC measurements are corrupted by Gaussian noise of realistic variance, both SOS based algorithms attain the CRB. We successfully apply our method in a divide and-conquer fashion to determine the structure of ubiquitin from experimental NOE and RDC measurements obtained in two alignment media, achieving more accurate and faster reconstructions compared to the current state of the art. PMID- 28616712 TI - Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling. AB - Vesicular storage of ATP is one of the processes initiating purinergic chemical transmission. Although an active transport mechanism was postulated to be involved in the processes, a transporter(s) responsible for the vesicular storage of ATP remained unidentified for some time. In 2008, SLC17A9, the last identified member of the solute carrier 17 type I inorganic phosphate transporter family, was found to encode the vesicular nucleotide transporter (VNUT) that is responsible for the vesicular storage of ATP. VNUT transports various nucleotides in a membrane potential-dependent fashion and is expressed in the various ATP secreting cells. Mice with knockout of the VNUT gene lose vesicular storage and release of ATP from neurons and neuroendocrine cells, resulting in blockage of the initiation of purinergic chemical transmission. Thus, VNUT plays an essential role in the vesicular storage and release of ATP. The VNUT knockout mice exhibit resistance for neuropathic pain and a therapeutic effect against diabetes by way of increased insulin sensitivity. Thus, VNUT inhibitors and suppression of VNUT gene expression may be used for therapeutic purposes through suppression of purinergic chemical transmission. This review summarizes the studies to date on VNUT and discusses what we have learned about the relevance of vesicular ATP release as a potential drug target. PMID- 28616713 TI - Modulation of the TGF-beta1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells. AB - Epithelial to mesenchymal transition (EMT) occurs during embryogenesis or under pathological conditions such as hypoxia, injury, chronic inflammation, or tissue fibrosis. In renal tubular epithelial cells (MDCK), TGF-beta1 induces EMT by reducing or increasing epithelial or mesenchymal marker expression, respectively. In this study, we confirmed that the cAMP analogues, 8-CPT-cAMP or N6-Ph-cAMP, inhibited the TGF-beta1-driven overexpression of the mesenchymal markers ZEB-1, Slug, Fibronectin, and alpha-SMA. Furthermore, we showed that A1, A2A, P2Y1, P2Y11, and P2X7 purine receptor agonists modulated the TGF-beta1-induced EMT through the involvement of PKA and/or MAPK/ERK signaling. The stimulation of A2A receptor reduced the overexpression of the EMT-related markers, mainly through the cAMP-dependent PKA pathway, as confirmed by cell pre-treatment with Myr-PKI. Both A1 and P2Y1 receptor stimulation exacerbated the TGF-beta1-driven effects, which were reduced by cell pre-treatment with the MAPK inhibitor PD98059, according to the increased ERK1/2 phosphorylation upon receptor activation. The effects induced by P2Y11 receptor activation were oppositely modulated by PKA or MAPK inhibition, in line with the dual nature of the Gs- and Gq-coupled receptor. Differently, P2X7 receptor induced, per se, similar and not additive effects compared to TGF-beta1, after prolonged cell exposure to BzATP. These results suggest a putative role of purine receptors as target for anti-fibrotic agents. PMID- 28616714 TI - Effect of fluid-air exchange on reducing residual silicone oil after silicone oil removal. AB - PURPOSE: Our purpose was to determine the effect of fluid-air exchange on the amount of silicone oil (SO) droplets remaining in the vitreous cavity after removal of the main body of the SO. METHODS: This was a retrospective comparative study of 56 eyes of 56 patients that had undergone vitrectomy with SO tamponade. Fluid-air exchange was performed during surgery in 30 eyes [Air Ex(+) group] and was not done in 26 eyes [Air Ex(-) group]. All of the eyes were examined by ultrasonography, and the images were converted to binarized image. The amount of residual SO droplets/vitreal area in the images was expressed as the, "silicone oil index (SOI)". The correlations between SOI and clinical findings were determined. RESULTS: The SOI was significantly correlated with the axial length (AL, R = 0.444, P = 0.023). The SOI in the Air Ex(+) group was significantly higher (7.4 +/- 2.6%) than in the Air Ex(-) group (4.9 +/- 3.4%; P = 0.004). Multiple linear regression analyses showed that the SOI was independently and significantly correlated with the AL and the Air Ex(+) group (P = 0.003, P = 0.006, respectively). CONCLUSIONS: Fluid-air exchange during vitrectomy to remove residual SO is not effective. Our findings indicate that it may increase the amount of residual SO droplets. PMID- 28616715 TI - Effects of intravitreal injection of bevacizumab with or without anterior chamber paracentesis on intraocular pressure and peripapillary retinal nerve fiber layer thickness: a prospective study. AB - PURPOSE: To investigate the effects of intravitreal injection of bevacizumab (IVB) with or without anterior chamber paracentesis on intraocular pressure (IOP) and peripapillary retinal nerve fiber layer (PRNFL) thickness. METHODS: In this prospective randomized clinical trial, 90 eyes with center involving diabetic macular edema or wet type age-related macular degeneration (AMD) were randomly assigned to receive IVB either without (group A) or with (group B) anterior chamber paracentesis. IOP was measured before and within 2 min, 30 min, 24 hours and 3 months after injections. Peripapillary spectral-domain optical coherence tomography (SD-OCT) was performed before and 3 months after injections. RESULTS: Mean IOP changes 2 minutes, 30 minutes, 24 hours, and 3 months after injections were 26.4 +/- 5.7 mmHg (P < 0.001), 6.5 +/- 6.3 mmHg (P < 0.001), 0.2 +/- 2.9 mmHg (P > 0.99) and 0.5 +/- 2.4 mmHg (P > 0.99) in group A and -1.3 +/- 2.4 mmHg (P < 0.001), -3.2 +/- 1.8 mmHg (P < 0.001), -3.1 +/- 1.8 mmHg (P < 0.001) and 1.8 +/- 2.2 mmHg (P < 0.001) in group B, respectively Mean baseline average PRNFL thickness was 85.3+/-5.6 MUm and 85.6 +/- 5 MUm in groups A and B respectively. Mean PRNFL thickness changes after 3 month was -2 +/- 2 MUm (P < 0.001) in group A and 0 +/- 2 MUm (P = 0.101) in group B. Mean PRNFL thickness in group A decreased more than group B (P < 0.001). CONCLUSION: Conventional method of IVB injection was associated with acute IOP rise and significant PRNFL loss 3 months after injection. Anterior chamber paracentesis prevents acute IOP rise and PRNFL loss. PMID- 28616716 TI - Retinal microstructures are altered in patients with idiopathic infantile nystagmus. AB - PURPOSE: To compare segmented retinal layer thicknesses between patients with idiopathic infantile nystagmus (IIN) and controls. METHODS: This retrospective case-control study included 66 patients with IIN and 66 age-matched controls. The retinal layers were examined using spectral domain optical coherence tomography with autosegmentation. Central foveal thickness (CFT), outer nuclear layer (ONL), and outer segment length (OSL) thickness were measured at the fovea center. Mean values for retinal nerve fiber layer, ganglion cell inner plexiform layer (GCIPL), inner nuclear layer, outer plexiform-outer nuclear layer (OPNL) thicknesses were calculated at two measurement points (nasal and temporal hump points at the macula area). RESULTS: There were no significant between-group differences in age, gender, or refraction error. The CFT was thicker in the IIN group compared with the control group (225.0 MUm vs. 217.8 MUm, P = 0.017) and OSL was shorter in IIN than in controls (40.0 MUm vs. 43.7 MUm., P < 0.001). The ONL thickness at the central fovea was not statistically different between the two groups. At the nasal and temporal position where the ganglion cell density was thickest, the GCIPL thickness was thinner in the IIN group compared to the controls (99.5 MUm vs. 102.8 MUm, P = 0.010). The GCIPL thickness was negatively correlated with logMAR visual acuity (Spearman's rho = -0.502, P < 0.001). CONCLUSIONS: The foveal pit was shallower, OSL was shorter, and the GCIPL thicknesses at macular humps were decreased in the patients with IIN compared with that of controls. The faulty development of the macula may be related to unknown pathophysiologic mechanism during fovea maturation in IIN or continuous eye movement itself interrupt fovea development. PMID- 28616717 TI - Patient and Public Outreach Initiatives in Chronic Rhinosinusitis from the Canadian Sinusitis Working Group: Support for Affected Patients and Extending an Understanding of CRS to the General Public. AB - Chronic rhinosinusitis is an important disease entity that affects patients worldwide, yet there is limited public awareness regarding the disease. The Canadian Rhinosinusitis Working Group, a group of diverse medical professionals, has made a multitude of efforts to help improve the health literacy of patients and important stakeholders, as well as the quality of life of patients with chronic rhinosinusitis. This review will aim to outline these initiatives. PMID- 28616718 TI - Effect of Intrastriatal 6-OHDA Lesions on Extrastriatal Brain Structures in the Mouse. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons, resulting in motor and non motor symptoms. The underlying pathology of non-motor symptoms is poorly understood. Discussed are pathological changes of extrastriatal brain structures. In this study, we characterized histopathological alterations of extrastriatal brain structures in the 6-hydroxydopamine (6-OHDA) PD animal model. Lesions were induced by unilateral stereotactic injections of 6-OHDA into the striatum or medial forebrain bundle of adult male mice. Loss of tyrosine hydroxylase positive (TH+) fibers as well as glia activation was quantified following stereological principles. Loss of dopaminergic innervation was further investigated by western blotting. As expected, 6-OHDA injection into the nigrostriatal route induced retrograde degeneration of dopaminergic neurons within the substantia nigra pars compacta (SNpc), less so within the ventral tegmental area. Furthermore, we observed a region-specific drop of TH+ projection fiber density in distinct cortical regions. This pathology was most pronounced in the cingulate- and motor cortex, whereas the piriform cortex was just modestly affected. Loss of cortical TH+ fibers was not paralleled by microglia or astrocyte activation. Our results demonstrate that the loss of dopaminergic neurons within the substantia nigra pars compacta is paralleled by a cortical dopaminergic denervation in the 6-OHDA model. This model serves as a valuable tool to investigate mechanisms operant during cortical pathology in PD patients. Further studies are needed to understand why cortical dopaminergic innervation is lost in this model, and what functional consequence is associated with the observed denervation. PMID- 28616719 TI - Are Partner Race and Intimate Partner Violence Associated with Incident and Newly Diagnosed HIV Infection in African-American Men Who Have Sex with Men? AB - Black gay, bisexual, and other men who have sex with men (BMSM) experience a disparate rate of HIV infections among MSM. Previous analyses have determined that STI coinfection and undiagnosed HIV infection partly explain the disparity. However, few studies have analyzed the impact of partner-level variables on HIV incidence among BMSM. Data were analyzed for BMSM who attended the Los Angeles LGBT Center from August 2011 to July 2015 (n = 1974) to identify risk factors for HIV infection. A multivariable logistic regression was used to analyze predictors for HIV prevalence among all individuals at first test (n = 1974; entire sample). A multivariable survival analysis was used to analyze predictors for HIV incidence (n = 936; repeat tester subset). Condomless receptive anal intercourse at last sex, number of sexual partners in the last 30 days, and intimate partner violence (IPV) were significant partner-level predictors of HIV prevalence and incidence. Individuals who reported IPV had 2.39 times higher odds (CI 1.35-4.23) and 3.33 times higher hazard (CI 1.47-7.55) of seroconverting in the prevalence and incidence models, respectively. Reporting Black partners only was associated with increased HIV prevalence, but a statistically significant association was not found with incidence. IPV is an important correlate of both HIV prevalence and incidence in BMSM. Further studies should explore how IPV affects HIV risk trajectories among BMSM. Given that individuals with IPV history may struggle to negotiate safer sex, IPV also warrants consideration as a qualifying criterion among BMSM for pre-exposure prophylaxis (PrEP). PMID- 28616720 TI - Quality of life after whole brain radiotherapy compared with radiosurgery of the tumor bed: results from a randomized trial. AB - BACKGROUND: A recent randomized trial (NCT01535209) demonstrated no difference in neurocognitive function between stereotactic radiotherapy of the tumor bed (SRT TB) and whole brain radiotherapy (WBRT) in patients with resected single brain metastasis. Patients treated with SRT-TB had lower overall survival compared with the WBRT arm. Here, we compared the health-related quality of life (HRQOL) in patients who received WBRT vs. SRT-TB. METHODS: A self-reported questionnaire was used to assess HRQOL (EORTC QLQ-C30 with the QLQ-BN20 module) before RT, 2 months after RT, and every 3 months thereafter. HRQOL results are presented as mean scores and compared between groups. RESULTS: Of 59 randomized patients, 37 (64%) were eligible for HRQOL analysis, 15 received SRT-TB, and 22 had WBRT. There were no differences between groups in global health status and main function scales/symptoms (except for drowsiness and appetite loss, which were worse with WBRT 2 months after RT). Global health status decreased 2 and 5 months after RT, but significantly only for SRT-TB (p = 0.025). Physical function decreased significantly 5 months after SRT-TB (p = 0.008). Future uncertainty worsened after RT, but significantly only for SRT-TB after 2 months (p = 0.036). Patients treated with WBRT had significant worsening of appetite, hair loss, and drowsiness after treatment. CONCLUSIONS: Despite higher symptom burden after WBRT attributed to the side effects of RT (such as appetite loss, drowsiness, and hair loss), global health status, physical functioning, and future uncertainty favored WBRT compared with SRT-TB. This may be related to the compromised brain tumor control with omission of WBRT. PMID- 28616721 TI - Biomarkers in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is currently the third most frequent form of malignancy. The role of biomarkers in the diagnostic and therapeutic strategy of cancer is constantly expanding. Translational research is already changing paradigms in tumours encompassing from early diagnosis to precision medicine in advanced disease. Nomenclature for molecular subtypes of tumours is gradually gaining acceptance and there are growing expectations it will further go from the bench to the bedside. However, the clinical relevance of biomarkers in PDAC is still far behind the relevance of biomarkers in other solid tumours. This article is part of a wider project (GALLgo) involving over forty specialists devoted to the multidisciplinary management of PDAC which concluded in recommendations based on scientific evidence. The aim of the present article is to review the diagnostic, prognostic and predictive biomarkers, either in localised or advanced disease, which have been lately subjected to study and analysis and others currently available for PDAC in order to give strength-graded recommendations linked to quality of evidence that can be used as guidelines in routine clinical practice. PMID- 28616722 TI - Duhamel operation for children with distal colonic dysmotility. AB - PURPOSE: To report outcomes of children with constipation refractory to medical management and manometrically proven distal colonic dysmotility, managed with rectosigmoidectomy followed by Duhamel operation (Duhamel). METHODS: Children who underwent a Duhamel from 2009 onwards for intractable constipation and left colonic dysmotility were retrospectively reviewed. The primary end point was resolution of constipation, and secondary end point was postoperative complications. Continuous data were median (range). RESULTS: 11 patients (4 males) had Duhamel at 11 years (5-16) with constipation started from 2 years (1 8). Hirschsprung's disease was excluded. All Duhamels were performed with a covering ileostomy: 9 following a Hartmann procedure, one following a previously failed reversal of Hartmann, and one Duhamel performed with a pre-existing ileostomy. All ileostomies were subsequently closed. Median resection length was 22 cm (11-31). Length of stay was 8 days (5-23). Follow-up was 5 years (0.5-7). Age at final review was 15 years (10-18). Resolution of constipation occurred in nine patients (4 required antegrade continence enemas (ACE), 5 with laxative); two had persistent constipation and faecal incontinence despite ACE, ultimately requiring an ileostomy. Two postoperative small bowel obstructions required laparotomy. CONCLUSION: Duhamel performed in children with manometrically proven distal colonic dysmotility yielded 82% resolution of refractory constipation; half of them subsequently needed ACE. PMID- 28616723 TI - Post-operative strictures in anorectal malformation: trends over 15 years. AB - AIM: For decades, paediatric surgeons have employed the standard posterior sagittal anorectoplasty (PSARP) approach to deal with patients with anorectal malformations (ARM). In recent years, we noted an apparent increase in the incidence of anal stricture after surgical repair of ARM following the introduction of laparoscopic pull-through and techniques aiming to preserve the internal sphincter-the internal sphincter sparing approach (ISSA). We decided to analyse our data to find out if these new trends had added to the problem of post operative strictures. METHODS: All patients with ARM at our institution from January 2000 to December 2015 were identified. A retrospective case note review was carried out. Data collected included patient demographics, type of ARM, operative details, and post-operative outcomes. RESULTS: 114 patients were identified. Ten patients were excluded. Of the remaining 104 children, 48 (46%) were female. Median age was 8.3 (range 1.2-16.8) years. Types of ARM were as follows: perineal fistula (15 patients), anterior stenotic anus (12), imperforate anus without fistula (10), vestibular fistula (32), rectourethral (bulbar) fistula (11), rectourethral (prostatic) fistula (14), rectovesical fistula (7), and cloaca (3). Twenty-seven patients with a perineal fistula or anterior stenotic anus underwent perineal procedures that were variably described by the different operating surgeons. The majority (15 patients) had an anoplasty, 5 had anal transposition, 5 had limited PSARP, and 2 patients had ISSA. Two patients with a cloacal anomaly underwent open cloacal reconstruction. Of the remaining 75 patients, 45 had a PSARP approach, 6 had a laparoscopic-assisted pull-through, and 18 had ISSA. Four girls with vestibular fistula had anal transposition and two boys with imperforate anus without fistula had anoplasty. 15 (14%) children developed anal stricture. Stricture incidence differed according to operation type. PSARP was the most commonly performed procedure, with only 6% developing a stricture. In contrast, 30% of ISSA patients and 50% of children who had laparoscopic pull-through developed a stricture. Strictures also occurred in 11 and 12% of children having anal transposition and anoplasty, respectively. CONCLUSION: The laparoscopic-assisted pull-through involves tunnelling the sphincter muscle complex. We found that often the tunnels were not wide enough, resulting in narrowing not just at the ano-cutaneous junction but also at the deeper level. 50% developed strictures. We have modified our technique by ensuring that the tunnels are generous enough to allow the rectum to be pulled through without any resistance. ISSA unfortunately resulted in 30% of our patients developing strictures. This approach, started in 2004, was, therefore, abandoned in 2013. The standard Pena's PSARP, with or without a laparotomy, has stood the test of time. Any modification of this approach must be carefully thought through and audited meticulously. Strictures can cause significant morbidity, which may need several revisions, and the resulting redo anoplasties run the risk of sphincter damage, ironically which the newer modifications of ISSA were trying to conserve. PMID- 28616724 TI - Nd:YAG laser therapy for rectal and vaginal venous malformations. AB - BACKGROUND: Limited therapeutic options exist for rectal and vaginal venous malformations (VM). We describe our center's experience using Nd:YAG laser for targeted ablation of abnormal veins to treat mucosally involved pelvic VM. METHODS: Records of patients undergoing non-contact Nd:YAG laser therapy of pelvic VM at a tertiary children's hospital were reviewed. Symptoms, operative findings and details, complications, and outcomes were evaluated. RESULTS: Nine patients (age 0-24) underwent Nd:YAG laser therapy of rectal and/or vaginal VM. Rectal bleeding was present in all patients and vaginal bleeding in all females (n = 5). 5/7 patients had extensive pelvic involvement on MRI. Typical settings were 30 (rectum) and 20-25 W (vagina), with 0.5-1.0 s pulse duration. Patients underwent the same-day discharge. Treatment intervals ranged from 14 to 180 (average = 56) weeks, with 6.1-year mean follow-up. Five patients experienced symptom relief with a single treatment. Serial treatments managed recurrent bleeding successfully in all patients, with complete resolution of vaginal lesions in 40% of cases. No complications occurred. CONCLUSIONS: Nd:YAG laser treatment of rectal and vaginal VM results in substantial improvement and symptom control, with low complication risk. Given the high morbidity of surgical resection, Nd:YAG laser treatment of pelvic VM should be considered as first line therapy. PMID- 28616726 TI - How to write an original radiological research manuscript. AB - : Many scientific manuscripts submitted for publication are limited by fundamental mistakes in their preparation, leading to rejection. We describe how to write a well-organized radiological research manuscript containing all of the important ingredients for effective communication of a hypothesis-driven scientific study in the context of medical imaging. KEY POINTS: * Mistakes in the preparation of scientific manuscripts lead to rejection. * Scientific writing, like any important skill, can be learned. * A well-developed approach will improve the quality of scientific writing. * High-quality scientific writing is essential to communicate research results. * A well-organized manuscript effectively communicates a hypothesis-driven scientific study. PMID- 28616725 TI - The role of T1 perfusion-based classification in magnetic resonance-guided high intensity focused ultrasound ablation of uterine fibroids. AB - OBJECTIVE: To comparatively evaluate the role of magnetic resonance (MR) T1 perfusion-based time-signal intensity (SI) curves of fibroid tissue and the myometrium in classification of fibroids for predicting treatment outcomes of high-intensity focused ultrasound (HIFU) treatment. METHODS: The fibroids of 74 women who underwent MR-HIFU treatment were classified into group A (time-SI curve of fibroid lower than that of the myometrium) and group B (time-SI curve of fibroid equal to or higher than that of the myometrium). Non-perfused volume (NPV) ratios immediately after treatment and fibroid volume reduction ratios and symptom severity scores (SSS) at the 6-month follow-up were retrospectively assessed. RESULTS: The immediate NPV ratios in groups A and B were 95.3 +/- 6.3% (n = 62) and 63.8 +/- 11% (n = 12), respectively. At the 6-month follow-up, the fibroid volume reduction ratios in groups A and B were 0.52 +/- 0.14 (n = 50) and 0.07 +/- 0.14 (n = 11), with the corresponding improvement in mean transformed SSS being 0.86 +/- 0.14 and 0.19 +/- 0.3, respectively. No serious adverse effects were reported. CONCLUSIONS: Our novel classification method could play an important role in classifying fibroids for predicting the immediate outcomes of HIFU treatment. KEY POINTS: * MRI is an important modality for outcome prediction in HIFU treatment * Patient selection is a significant factor for achieving high NPV ratio * NPV ratio is very strongly correlated with T1 perfusion-based classification * T1 perfusion-based classification is a strong predictor of treatment outcome. PMID- 28616727 TI - Preliminary study of diffusion kurtosis imaging in thyroid nodules and its histopathologic correlation. AB - OBJECTIVES: To evaluate the utility of diffusion kurtosis imaging (DKI) of patients with thyroid nodules and to assess the probable correlation with histopathological factors. METHODS: The study included 58 consecutive patients with thyroid nodules who underwent magnetic resonance imaging (MRI) examination, including DKI and diffusion-weighted imaging (DWI). Histopathological analysis of paraffin sections included cell density and immunohistochemical analysis of Ki-67 and vascular endothelial growth factor (VEGF). Statistical analyses were performed using Student's t-test, receiver operating characteristic (ROC) curves and Spearman's correlation. RESULTS: The diffusion parameters, cell density and immunohistochemistry analysis between malignant and benign lesions showed significant differences. The largest area under the ROC curve was acquired for the D value (AUC = 0.797). The highest sensitivity was shown with the use of K (threshold = 0.832, sensitivity = 0.917). The Ki-67 expression generally stayed low. A moderate correlation was found between ADC, D and cell density (r = 0.536, P = 0.000; r = -0.570, P = 0.000) and ADC, D and VEGF expression (r = 0.451, P = 0.000; r = -0.522, P = 0.000). CONCLUSION: The DKI-derived parameters D and K demonstrated an advantage compared to conventional DWI for thyroid lesion diagnosis. While the histopathological study indicated that the D value correlated better with extracellular change than the ADC value, the K value probably changed relative to the intracellular structure. KEY POINTS: * DWI and DKI parameters can identify PTC from benign thyroid nodules. * Correlations were found between diffusion parameters and histopathological analysis. * DKI obtains better diagnostic accuracy than conventional DWI. PMID- 28616728 TI - The relationship of cancer characteristics and patient outcome with time to lung cancer diagnosis after an abnormal screening CT. AB - PURPOSE: The National Lung Screening Trial (NLST) demonstrated a reduction in lung cancer and all-cause mortality with low-dose CT (LDCT) screening. The aim of our study was to examine the time to diagnosis (TTD) of lung cancer in the LDCT arm of the NLST and assess its relationship with cancer characteristics and survival. METHODS: The subjects (N = 462) with a positive baseline screen and subsequent lung cancer diagnosis within 3 years were evaluated by data and image review to confirm the baseline abnormality. The cases were analysed for the relationship between TTD and imaging features, cancer type, stage and survival for 7 years from baseline screen. RESULTS: Cancer was judged to be present at baseline in 397/462 cases. The factors that showed significant association (p value trend less than 0.05) with longer TTD included smaller nodule size, pure ground glass nodules (GGNs), smooth/lobulated margins, stages I/II, adenocarcinoma, and decreasing lung cancer mortality. The logistic regression model for lung cancer death showed significant inverse relationships with size less than 20 mm (OR = 0.32), pure GGNs (OR = 0.24), adenocarcinoma (OR = 0.57) and direct relationship with age (OR = 1.4). CONCLUSION: TTD after a positive LDCT screen in the NLST showed a strong association with imaging features, stage and mortality. KEY POINTS: * NLST observed variable time to lung cancer diagnosis from positive baseline screen. * Time to diagnosis was associated with imaging features, cancer type and stage. * In univariate but not multivariate analysis, longer TTD correlated with decreased mortality. PMID- 28616729 TI - Prediction of the estimated 5-year risk of sudden cardiac death and syncope or non-sustained ventricular tachycardia in patients with hypertrophic cardiomyopathy using late gadolinium enhancement and extracellular volume CMR. AB - OBJECTIVES: To evaluate the ability of late gadolinium enhancement (LGE) and mapping cardiac magnetic resonance (CMR) including native T1 and global extracellular volume (ECV) to identify hypertrophic cardiomyopathy (HCM) patients at risk for sudden cardiac death (SCD) and to predict syncope or non-sustained ventricular tachycardia (VT). METHODS: A 1.5-T CMR was performed in 73 HCM patients and 16 controls. LGE size was quantified using the 3SD, 5SD and full width at half maximum (FWHM) method. T1 and ECV maps were generated by a 3(3)5 modified Look-Locker inversion recovery sequence. Receiver-operating curve analysis evaluated the best parameter to identify patients with increased SCD risk >=4% and patients with syncope or non-sustained VT. RESULTS: Global ECV was the best predictor of SCD risk with an area under the curve (AUC) of 0.83. LGE size was significantly inferior to global ECV with an AUC of 0.68, 0.70 and 0.70 (all P < 0.05) for 3SD-, 5SD- and FWHM-LGE, respectively. Combined use of the SCD risk score and global ECV significantly improved the diagnostic accuracy to identify HCM patients with syncope or non-sustained VT. CONCLUSIONS: Combined use of the SCD risk score and global ECV has the potential to improve HCM patient selection, benefiting most implantable cardioverter defibrillators. KEY POINTS: * Global ECV identified the best HCM patients with increased SCD risk. * Global ECV performed equally well compared to a SCD risk score. * Combined use of the SCD risk score and global ECV improved test accuracy. * Combined use potentially improves selection of HCM patients for ICD implantation. PMID- 28616730 TI - Contrast-enhanced 3T MR Perfusion of Musculoskeletal Tumours: T1 Value Heterogeneity Assessment and Evaluation of the Influence of T1 Estimation Methods on Quantitative Parameters. AB - OBJECTIVE: To evaluate intra-tumour and striated muscle T1 value heterogeneity and the influence of different methods of T1 estimation on the variability of quantitative perfusion parameters. MATERIAL AND METHODS: Eighty-two patients with a histologically confirmed musculoskeletal tumour were prospectively included in this study and, with ethics committee approval, underwent contrast-enhanced MR perfusion and T1 mapping. T1 value variations in viable tumour areas and in normal-appearing striated muscle were assessed. In 20 cases, normal muscle perfusion parameters were calculated using three different methods: signal based and gadolinium concentration based on fixed and variable T1 values. RESULTS: Tumour and normal muscle T1 values were significantly different (p = 0.0008). T1 value heterogeneity was higher in tumours than in normal muscle (variation of 19.8% versus 13%). The T1 estimation method had a considerable influence on the variability of perfusion parameters. Fixed T1 values yielded higher coefficients of variation than variable T1 values (mean 109.6 +/- 41.8% and 58.3 +/- 14.1% respectively). Area under the curve was the least variable parameter (36%). CONCLUSION: T1 values in musculoskeletal tumours are significantly different and more heterogeneous than normal muscle. Patient-specific T1 estimation is needed for direct inter-patient comparison of perfusion parameters. KEY POINTS: * T1 value variation in musculoskeletal tumours is considerable. * T1 values in muscle and tumours are significantly different. * Patient-specific T1 estimation is needed for comparison of inter-patient perfusion parameters. * Technical variation is higher in permeability than semiquantitative perfusion parameters. PMID- 28616732 TI - Erratum to: Early gastric adenocarcinoma arising within foveolar-type dysplasia in a patient with Muir-Torre variant Lynch syndrome. PMID- 28616731 TI - Renal nerve stimulation for treatment of neurocardiogenic syncope: a review from perspective of commercialization potential. AB - A strong evidence of outcomes for vasovagal syncope is not easily identified. It would seem reasonable that the proposed Mayo Clinic technology would be reserved for cases with severe recurrent or refractory syncope. However, recurrence levels are relatively low, and while some predictive methods have been proposed, recurrence is also influenced by the interaction that occurs during screening and examinations, i.e. recurrence diminishes once an initial diagnosis has been made. Finally, a key factor in being able to identify suitable patients relates to understanding the relative significance of the vasodepression and cardioinhibitory components-the therapy is best suited to patients that have a significant level of both components. It is probably not needed in patients with mainly cardioinhibitory involvement-data from ISSUE 2 and ISSUE 3 studies suggest that this is a relatively large proportion, particularly with asystolic involvement. The challenge remains in having suitable screening tests to identify the best patients. Tilt table testing has questions concerning its ability to replicate clinical syncope-implantable loop recorders (ILRs) may provide more accurate data but their usage is not yet widely accepted given the costs and invasive nature of the monitor. PMID- 28616734 TI - Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), an anticancer agent, exerts an anti-inflammatory effect in activated human mast cells. AB - OBJECTIVE: Inflammation has been closely associated with the development and progression of cancer. Previously, we reported that mast cells play a critical role in tumor growth. The purpose of this study is to investigate the anti inflammatory effect of an anticancer agent, di-2-pyridylketone 4,4-dimethyl-3 thiosemicarbazone (Dp44mT), on an activated human mast cell line, in this case HMC-1 cells. METHODS: We evaluated the effect and specific molecular mechanism of Dp44mT on phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI) using HMC-1 cells. RESULTS: Here, we demonstrated that Dp44mT significantly decreased the protein levels of hypoxia-inducible factor-1alpha and vascular endothelial growth factor without exposing activated HMC-1 cells to any cytotoxicity. In activated mast cells, Dp44mT mitigated the strong production and mRNA expression of inflammatory cytokines, in this case, interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and thymic stromal lymphopoietin, through a blockade of caspase-1 and nuclear factor-kappaB activities. Furthermore, phosphorylations of the mitogen-activated protein kinase family included in inflammatory signaling cascades were significantly inhibited by a Dp44mT treatment. CONCLUSIONS: Overall, our results indicate that the anticancer agent Dp44mT has an anti-inflammatory effect and may be of therapeutic importance for the treatment of mast cell-mediated inflammatory diseases. PMID- 28616735 TI - Erratum to: Temporal trends of lipophilic persistent organic pollutants in serum from Danish nulliparous pregnant women 2011-2013. PMID- 28616736 TI - Geographic variations in female breast cancer incidence in relation to ambient air emissions of polycyclic aromatic hydrocarbons. AB - A significant geographic variation of breast cancer incidence exists, with incidence rates being much higher in industrialized regions. The objective of the current study was to assess the role of environmental factors such as exposure to ambient air pollution, specifically carcinogenic polycyclic aromatic hydrocarbons (PAHs) that may be playing in the geographic variations in breast cancer incidence. Female breast cancer incidence and ambient air emissions of PAHs were examined in the northeastern and southeastern regions of the USA by analyzing data from the Surveillance, Epidemiology, and End Results (SEER) Program and the State Cancer Profiles of the National Cancer Institute and from the Environmental Protection Agency. Linear regression analysis was conducted to evaluate the association between PAH emissions and breast cancer incidence in unadjusted and adjusted models. Significantly higher age-adjusted incidence rates of female breast cancer were seen in northeastern SEER regions, when compared to southeastern regions, during the years of 2000-2012. After adjusting for potential confounders, emission densities of total PAHs and four carcinogenic individual PAHs (benzo[a]pyrene, dibenz[a,h]anthracene, naphthalene, and benzo[b]fluoranthene) showed a significantly positive association with annual incidence rates of breast cancer, with a beta of 0.85 (p = 0.004), 58.37 (p = 0.010), 628.56 (p = 0.002), 0.44 (p = 0.041), and 77.68 (p = 0.002), respectively, among the northeastern and southeastern states. This study suggests a potential relationship between ambient air emissions of carcinogenic PAHs and geographic variations of female breast cancer incidence in the northeastern and southeastern US. Further investigations are needed to explore these interactions and elucidate the role of PAHs in regional variations of breast cancer incidence. PMID- 28616737 TI - Serum concentrations of selected organochlorine pesticides in a Lebanese population and their associations to sociodemographic, anthropometric and dietary factors: ENASB study. AB - Organochlorine pesticides (OCPs) were banned by the Stockholm Convention many years ago; however, they are still detected in the environment due to their high persistence, their current illegal use, and their import from countries where they have not been banned. We evaluated the serum concentrations of selected OCPs (hexachlorobenzene (HCB), beta-hexachlorocyclohexanes (beta-HCH), p,p' dichlorodiphenyltrichloroethane (DDT) and its metabolite p,p' dichlorodiphenyldichloroethylene (DDE) in a sample of Lebanese adults using gas chromatography coupled to an ion trap mass spectrometer detector. The mean concentrations of HCB, beta-HCH, DDT, and DDE were 7.1, 8.6, 2.1, and 18.9 ng/g of lipids, respectively, and the major contributor among the four OCPs was DDE. The OCP levels in the present study were in general lower than the values observed in several countries worldwide and their concentrations at the 95th percentile were lower than the biomonitoring equivalents (BEs) excluding any appreciable health risk. We observed an inverse association between HCB concentrations and body mass index (BMI) as well as HCB, beta-HCH, and DDE levels, and smoking habits. Milk consumption however was positively associated with an increased serum level of beta-HCH. This study, which was the first to investigate OCP serum levels in a Lebanese population, provides a baseline to which future measurements can be compared. PMID- 28616738 TI - Living in a Mediterranean city in 2050: broadleaf or evergreen 'citizens'? AB - The predicted effects of global change (GC) will be exacerbated in the more densely populated cities of the future, especially in the Mediterranean basin where some environmental cues, such as drought and tropospheric ozone (O3) pollution, already mine seriously plant survival. Physiological and biochemical responses of a Mediterranean, evergreen, isohydric plant species (Quercus ilex) were compared to those of a sympatric, deciduous, anisohydric species (Q. pubescens) under severe drought (20% of the effective daily evapotranspiration) and/or chronic O3 exposure (80 ppb for 5 h day-1 for 28 consecutive days) to test which one was more successful in those highly limiting conditions. Results show that (i) the lower reduction of total leaf biomass of Q. ilex as compared to Q. pubescens when subjected to drought and drought * O3 (on average -59 vs -70%, respectively); (ii) the steeper decline of photosynthesis found in Q. pubescens under drought (-87 vs -81%) and drought * O3 (-69 vs -59%, respectively); (iii) the increments of malondialdehyde (MDA) by-products found only in drought stressed Q. pubescens; (iv) the impact of O3, found only in Q. pubescens leaves and MDA, can be considered the best probes of the superiority of Q. ilex to counteract the effect of mild-severe drought and O3 stress. Also, an antagonistic effect was found when drought and O3 were applied simultaneously, as usually happens during typical Mediterranean summers. Our dataset suggests that on future, the urban greening should be wisely pondered on the ability of trees to cope the most impacting factors of GC, and in particular their simultaneity. PMID- 28616739 TI - Petrol filling workers as biomonitor of PAH exposure and functional health capacity in resource-limited settings of city Rawalpindi, Pakistan. AB - This is the first study from Pakistan to report the exposure of petrol filling workers (n = 120) to naphthalene (Nap) and pyrene (Pyr) in relation to their functional capacities and health outcome. A group of non-exposed subjects (controls n = 46) was also recruited for comparison. The perceived health risk of the exposed workers was monitored using a questionnaire based on the self reporting survey. The observed physical anomalies related to the health disorder included the acidity after meals, eye redness, appetite loss, skin lesions, and dryness of oral cavity, while those related to neurasthenic symptoms included the body aches, energy loss, twitching, fatigue, sleeplessness, fainting, and irritability. Mean Nap level observed in the exposed group (106 MUg L-1) was significantly correlated (r = 0.49; p < 0.01) with cigarette smoking, while the average Pyr concentration (19.18 MUg L-1) was associated with job duration. Workers exposed for 6 h per day or more had significantly high prevalence of physical disorders (OR = 2.79, 95% CI = 1.28-6.09). Neurasthenic symptoms were found in 65% of the subjects and were associated with years of involvement in job. Ten years or more work duration at petrol pumps could be associated with a substantial development of neurasthenic effects (OR = 2.80, 95% CI = 1.23-6.34). In conclusion, the subjects ascribed the disturbances in physical and neurological behavior to their occupation (petrol filling) and also rated their overall health and functional capacity as poor. To promote health of petrol pump workers, reduction in work hours and provision of masks and gloves could be introduced as occupational health interventions. PMID- 28616741 TI - Ecological risk assessment of an open dumping site at Mehmood Booti Lahore, Pakistan. AB - A robust risk assessment of Mehmood Booting Open Dumping (MBOD) site has been carried out by developing holistic risk assessment framework. Framework mainly comprises on baseline study, hazard identification, and risk quantification and evaluation. Physico-chemical analysis of groundwater and leachate, health risk assessment, and estimation of gas emissions from the site were carried out for risk evaluation. LandGEM 3.02 modelling software was used to measure the gas emissions. Analysis of leachate showed that all parameters were exceeding the WHO standard limit. Water samples were found polluted with heavy metals and total coliform contamination. Health survey inferred that problems which were faced by the majority of respondents were respiratory problems (80%). LandGEM model estimated that total landfill gas (TLG) emitted from the site for the year 2014 was 1.760E+05 Mg/year, CH4 emission was 5.445E+06 Mg/year, CO2 emission was 1.290E+05 Mg/year and for non-methane organic compound emission was 2.021E+03 Mg/year. It can be concluded that in the near future, almost all the water locations are possibly threatened with leachate contamination due to the continued accumulation of solid waste at MBOD site. The study recommends that new sanitary landfill sites should be designed to minimize the adverse effects associated with solid waste disposal and to preclude further pollution to surface water, groundwater, soil, and air. PMID- 28616740 TI - Different exposure levels of fine particulate matter and preterm birth: a meta analysis based on cohort studies. AB - The previous studies estimated the association between PM2.5 (particulate matter with aerodynamic diameter less than or equal to 2.5 MUm) exposure during pregnancy and preterm birth, only considered and highlighted the hazard effects of high levels of air pollutant exposure, and underestimated that low levels of pollutant exposure might also affect pregnancy outcome. We conducted a meta analysis of 11 cohort studies, a total of more than 1,500,000 subjects. The results of these studies were pooled by exposure levels and study periods. PM2.5 exposure during pregnancy was positively associated with preterm birth (OR = 1.15, 95% CI = 1.07-1.23), and during the first trimester of pregnancy, low levels of PM2.5 exposure were also positively associated with preterm birth (OR = 1.17, 95% CI = 1.04-1.30). It is important to protect pregnant women from PM2.5 exposures, especially during their first trimester of pregnancy even when the ambient PM2.5 concentration is relatively low. More relevant health policy should be carried out to prevent hazard effect of air pollutants. PMID- 28616742 TI - Wind-induced flow velocity effects on nutrient concentrations at Eastern Bay of Lake Taihu, China. AB - Shallow lakes are highly sensitive to respond internal nutrient loading due to wind-induced flow velocity effects. Wind-induced flow velocity effects on nutrient suspension were investigated at a long narrow bay of large shallow Lake Taihu, the third largest freshwater lake in China. Wind-induced reverse/compensation flow and consistent flow field probabilities at vertical column of the water were measured. The probabilities between the wind field and the flow velocities provided a strong correlation at the surface (80.6%) and the bottom (65.1%) layers of water profile. Vertical flow velocity profile analysis provided the evidence of delay response time to wind field at the bottom layer of lake water. Strong wind field generated by the west (W) and west-north-west (WNW) winds produced displaced water movements in opposite directions to the prevailing flow field. An exponential correlation was observed between the current velocities of the surface and the bottom layers while considering wind speed as a control factor. A linear model was developed to correlate the wind field-induced flow velocity impacts on nutrient concentration at the surface and bottom layers. Results showed that dominant wind directions (ENE, E, and ESE) had a maximum nutrient resuspension contribution (nutrient resuspension potential) of 34.7 and 43.6% at the surface and the bottom profile layers, respectively. Total suspended solids (TSS), total nitrogen (TN), and total phosphorus (TP) average concentrations were 6.38, 1.5, and 0.03 mg/L during our field experiment at Eastern Bay of Lake Taihu. Overall, wind-induced low-to-moderate hydrodynamic disturbances contributed more in nutrient resuspension at Eastern Bay of Lake Taihu. The present study can be used to understand the linkage between wind induced flow velocities and nutrient concentrations for shallow lakes (with uniform morphology and deep margins) water quality management and to develop further models. PMID- 28616744 TI - Demonstration that a Klebsiella pneumoniae subsp. pneumoniae isolated from an insect (Nezara viridula) harbors a plasmid-borne type IV secretion system. AB - Previously, we reported the isolation of Klebsiella pneumoniae subspecies pneumoniae strain Kp 5-1 from a southern green stink bug (Nezara viridula) that is a significant pest of numerous economically important crops. We subsequently sequenced the strains whole genome. Here, we report the presence of a functional plasmid-borne type IV secretion (TFSS) system that was identified using genomic mining of the annotated genome. Comparison of the Kp 5-1 resident 186 kb plasmid (pKp 5-1) with nine other Klebsiella with plasmids of comparable size from clinical and environmental strains revealed putative TFSS with identities ranging from 70 to 99%. A primer set was designed at the pKp 5-1 region that shared homology with traC of the conjugation capable F-plasmid. The 2.4 kb amplified PCR product was cloned, sequenced, and used in hybridization experiments verify that the predicted gene was extra-chromosomally located. Based on biparental mating experimental results, a K. pneumoniae Kp 5-1 derivative transformed with the non self-transmissible pMMB207alphabeta (an IncQ RSF1010 derivative) mobilized the vector into the parental strain with transfer frequencies of 10-3 transconjugants/donor. Identification of a TFSS in strain Kp 5-1 is significant since in other systems the mobilization capacity is involved in dissemination of plasmids that may confer antibiotic resistance and/or the delivery of virulence proteins into host cells, and thus may have an important role in the fitness of this strain as well. This is the first report that both compared and demonstrated functionality of a plasmid-harbored TFSS in a K. pneumoniae isolated from a N. viridula. PMID- 28616743 TI - The long-term survival of stage IV gastric cancer patients with conversion therapy. AB - PURPOSE: A retrospective study was performed to clarify the role of conversion therapy (surgery with a prospect of R0 resection performed in initially unresectable metastatic cancer that responded to the chemotherapy) in stage IV gastric cancer (GC). PATIENTS AND METHODS: We treated 259 stage IV GC patients with systemic chemotherapy at Gifu and Hiroshima University Hospitals between 2001-2013. Of these, 84 patients who were subsequently treated by surgery were classified into four categories according to our previously published classification of stage IV GC, and short- and long-term outcomes were analyzed. RESULTS: Surgery was performed in 84 patients, of which 7 were performed following the neoadjuvant chemotherapy, whereas the other 77 that excluded neoadjuvant chemotherapy cases were considered the conversion therapy. The postoperative mortality and morbidity were comparable with those reported clinical trials. The MSTs of the patients with/without surgery for each category were 28.3/5.8 months for category 1, 30.5/11.0 months for category 2, 31.0/18.5 months for category 3 and 24.7/10.0 months for category 4. The MST of the R0 resected patients (41.3 months) was far better than that of the R1-2 resected patients (21.2 months). The MSTs of the patients with R0/R1-2 resection were 56.2/16.3 months for category 2, 33.3/29.6 months for category 3 and 40.7/17.8 months for category 4. CONCLUSION: There were long-term survivors who underwent conversion therapy for stage IV GC. Adequate selection of stage IV GC patients for conversion therapy may be an important role for the surgical oncologist in the new era. PMID- 28616746 TI - Annual Convention SFCR 2017, (French Spine Society annual congress) Lille Grand Palais 1st-3rd June, 2017. PMID- 28616745 TI - Bacterial meningitis complicating the course of liver cirrhosis. AB - : Meningitis is rarely reported in studies investigating bacterial infections in patients affected by liver cirrhosis. We investigated the findings of bacterial meningitis in patients affected by liver cirrhosis referred to our department in a 16-year period. MATERIALS: Patients with cirrhosis and bacterial meningitis were enrolled. Cirrhosis was defined by liver histology or clinical, laboratory, and ultrasonographic and endoscopic findings. Bacterial meningitis was defined by cerebro-spinal fluid pleocytosis (>10/mcl) and characteristic clinical presentation. Fisher exact test and Wilcoxon rank-sum test were employed as appropriate for statistical analysis. RESULTS: Forty-four patients with bacterial meningitis and cirrhosis were enrolled in the study. Sex ratio (male:female) was 1.4:1 and median (IQR) age was 64 (55-72) years. Cirrhosis was viral in 40 patients. At admission, median (IQR) MELD score was 12 (9-14), and median (IQR) Child-Pugh score was 8 (6-10). Other conditions associated with immunodepression were present in 22 (50%) cases. Streptococcus pneumoniae and Listeria monocytogenes were the agents more frequently identified. An extra-meningeal focus of infection was identified in 17 (39%) cases. Main symptoms at admission were fever, nuchal rigidity, and an obtunded or comatose status, and at least 2 of these were reported in 37 (84%) episodes. Cerebro-spinal fluid showed high cells, low CSF/serum glucose ratio, and elevated protein. Seventeen patients (39%) died and 8 (18%) reported sequelae. High MELD and Child-Pugh scores were related to the mortality risk (p < 0.001). The findings of blood and cerebro spinal fluid analysis were not predictive of outcome. CONCLUSIONS: Bacterial meningitis should be considered in cirrhotics presenting with fever and altered conscience status. MELD and Child-Pugh scores predicted prognosis. PMID- 28616747 TI - Criteria for failure and worsening after surgery for lumbar disc herniation: a multicenter observational study based on data from the Norwegian Registry for Spine Surgery. AB - PURPOSE: In clinical decision-making, it is crucial to discuss the probability of adverse outcomes with the patient. A large proportion of the outcomes are difficult to classify as either failure or success. Consequently, cutoff values in patient-reported outcome measures (PROMs) for "failure" and "worsening" are likely to be different from those of "non-success". The aim of this study was to identify dichotomous cutoffs for failure and worsening, 12 months after surgical treatment for lumbar disc herniation, in a large registry cohort. METHODS: A total of 6840 patients with lumbar disc herniation were operated and followed for 12 months, according to the standard protocol of the Norwegian Registry for Spine Surgery (NORspine). Patients reporting to be unchanged or worse on the Global Perceived Effectiveness (GPE) scale at 12-month follow-up were classified as "failure", and those considering themselves "worse" or "worse than ever" after surgery were classified as "worsening". These two dichotomous outcomes were used as anchors in analyses of receiver operating characteristics (ROC) to define cutoffs for failure and worsening on commonly used PROMs, namely, the Oswestry Disability Index (ODI), the EuroQuol 5D (EQ-5D), and Numerical Rating Scales (NRS) for back pain and leg pain. RESULTS: "Failure" after 12 months for each PROM, as an insufficient improvement from baseline, was (sensitivity and specificity): ODI change <13 (0.82, 0.82), ODI% change <33% (0.86, 0.86), ODI final raw score >25 (0.89, 0.81), NRS back-pain change <1.5 (0.74, 0.86), NRS back-pain % change <24 (0.85, 0.81), NRS back-pain final raw score >5.5 (0.81, 0.87), NRS leg-pain change <1.5 (0.81, 0.76), NRS leg-pain % change <39 (0.86, 0.81), NRS leg-pain final raw score >4.5 (0.91, 0.85), EQ-5D change <0.10 (0.76, 0.83), and EQ-5D final raw score >0.63 (0.81, 0.85). Both a final raw score >48 for the ODI and an NRS >7.5 were indicators for "worsening" after 12 months, with acceptable accuracy. CONCLUSION: The criteria with the highest accuracy for defining failure and worsening after surgery for lumbar disc herniation were an ODI percentage change score <33% for failure and a 12-month ODI raw score >48. These cutoffs can facilitate shared decision-making among doctors and patients, and improve quality assessment and comparison of clinical outcomes across surgical units. In addition to clinically relevant improvements, we propose that rates of failure and worsening should be included in reporting from clinical trials. PMID- 28616748 TI - Intact Transition Epitope Mapping (ITEM). AB - Intact transition epitope mapping (ITEM) enables rapid and accurate determination of protein antigen-derived epitopes by either epitope extraction or epitope excision. Upon formation of the antigen peptide-containing immune complex in solution, the entire mixture is electrosprayed to translate all constituents as protonated ions into the gas phase. There, ions from antibody-peptide complexes are separated from unbound peptide ions according to their masses, charges, and shapes either by ion mobility drift or by quadrupole ion filtering. Subsequently, immune complexes are dissociated by collision induced fragmentation and the ion signals of the "complex-released peptides," which in effect are the epitope peptides, are recorded in the time-of-flight analyzer of the mass spectrometer. Mixing of an antibody solution with a solution in which antigens or antigen derived peptides are dissolved is, together with antigen proteolysis, the only required in-solution handling step. Simplicity of sample handling and speed of analysis together with very low sample consumption makes ITEM faster and easier to perform than other experimental epitope mapping methods. Graphical Abstract ?. PMID- 28616749 TI - miR-183 and miR-21 expression as biomarkers of progression and survival in tongue carcinoma patients. AB - OBJECTIVES: Micro RNAs (miRNAs) have a major role in human cancerogenesis.The current study investigated the prognostic significance of miR-183 and miR-21 expression in tongue carcinoma patients. MATERIAL AND METHOD: For qPCR of miR-183 and miR-21 expression, total RNA isolated from 60 fresh-frozen tissue of tongue carcinomas was converted into cDNA by TaqMan MicroRNA Reverse Transcription Kit and quantified by TaqMan MicroRNAs Expression Assays. Fold changes in the miRNAs expression, normalized to RNU6B, were determined using 2-DeltaDeltaCt method, and dichotomized into high and low according to cut-off values derived from ROC curve analysis. RESULTS: miR-183 emerged as promising discriminatory biomarker of poor outcome. Tissue over-expression of miR-183, observed in 68.3% of tongue carcinomas, was associated with clinical stage (p = 0.037), tumor size (p = 0.036), and high alcohol intake (p = 0.034).The patients with miR-183 over expression had significantly shorter overall survival (p = 0.006) and a 5.666 times higher risk of poor outcome (p = 0.005), while miR-21 over-expression carried a tendency towards poorer survival (p = 0.073). However, multivariate analysis revealed that the recurrences were independent adverse prognostic factors, while miR-183 over-expression lost its significance. CONCLUSION: Our results suggests that over-expression of miR-183 in tumor tissue could be a potential marker of clinical stage and a poor survival of tongue carcinoma patients and may be associated with high alcohol consumption. CLINICAL RELEVANCE: Oncogenic miRNAs, such as the investigated miR-183 and miR-21, could be novel prognostic biomarkers of tumor progression and adverse clinical outcome in oral cancer, as well as novel therapeutic targets in cancer. PMID- 28616751 TI - Roles of amino acids in preventing and treating intestinal diseases: recent studies with pig models. AB - Animal models are needed to study and understand a human complex disease. Because of their similarities in anatomy, structure, physiology, and pathophysiology, the pig has proven its usefulness in studying human gastrointestinal diseases, such as inflammatory bowel disease, ischemia/reperfusion injury, diarrhea, and cancer. To understand the pathogenesis of these diseases, a number of experimental models generated in pigs are available, for example, through surgical manipulation, chemical induction, microbial infection, and genetic engineering. Our interests have been using amino acids as therapeutics in pig and human disease models. Amino acids not only play an important role in protein biosynthesis, but also exert significant physiological effects in regulating immunity, anti-oxidation, redox regulation, energy metabolism, signal transduction, and animal behavior. Recent studies in pigs have shown that specific dietary amino acids can improve intestinal integrity and function under normal and pathological conditions that protect the host from different diseases. In this review, we summarize several pig models in intestinal diseases and how amino acids can be used as therapeutics in treating pig and human diseases. PMID- 28616752 TI - Effects of C-myc gene silencing on interleukin-1beta-induced rat chondrocyte cell proliferation, apoptosis and cytokine expression. AB - This study explores the effects of C-myc gene silencing on cell proliferation, apoptosis and cytokine expression in interleukin (IL)-1beta-induced rat chondrocytes. Primary chondrocytes were obtained from 40 Sprague-Dawley rats. For in vitro C-myc3-shRNA transfection, chondrocytes were assigned to a blank 1, model 1, IL-1beta + C-myc3-shRNA, C-myc3-shRNA, (IL-1beta + C-myc3-shRNA) + C-myc overexpression, C-myc3-shRNA + C-myc overexpression or IL-1beta + C-myc-Con group. Western blotting and quantitative real-time polymerase chain reaction (qRT PCR) were performed to detect C-myc, PCNA and cyclin D1 mRNA and protein expression. Cell proliferation was analyzed via CCK-8 assay and cell cycle while apoptosis was measured through flow cytometry. ELISA was utilized to assess the levels of metallopeptidase 13 (MMP-13), IL-6 and tumor necrosis factor-alpha (TNF alpha). Both the qRT-PCR and Western blotting results demonstrated that C-myc3 shRNA transfection inhibits C-myc expression and promotes PCNA and cyclin D1 expression. In comparison to the model 1 group, all groups except the (IL-1beta + C-myc3-shRNA) + C-myc overexpression and IL-1beta + C-myc-Con groups showed increases in cell proliferation and S phase cell count and decreases in G0/G1 phase cell count, cell apoptosis and MMP-13, IL-6 and TNF-alpha levels. The model 1, C-myc3-shRNA and C-myc3-shRNA + C-myc overexpression groups displayed higher cell proliferation and S phase cell count and reduced G0/G1 phase cell count, cell apoptosis and MMP-13, IL-6 and TNF-alpha levels than the IL-1beta + C-myc3 shRNA group. In comparison to the model 1 and C-myc3-shRNA + C-myc overexpression groups, the C-myc3-shRNA group promoted cell proliferation and S phase cell counts but suppressed G0/G1 phase cell count, cell apoptosis and MMP-13, IL-6 and TNF-alpha levels. In conclusion, the study demonstrates that C-myc gene silencing can promote cell proliferation and inhibit cell apoptosis and cytokine expression in IL-1beta-induced rat chondrocytes. PMID- 28616750 TI - Systematic review of oral manifestations related to hyperparathyroidism. AB - OBJECTIVES: We sought to identify oral symptoms found in hyperparathyroidism and compare their rate of occurrence, as well as potential variations in sequelae between primary, secondary, and tertiary hyperparathyroidism. MATERIALS AND METHODS: Database searches were performed through EMBASE and PubMed, with a continual handsearch for relevant articles. PRISMA guidelines were followed. RESULTS: Two hundred five articles including 245 patients were analyzed with data extraction. The average age was 34.02 years old (age range 1-83), with 91 male and 154 female patients (1:1.7 M/F ratio). Patients presented with symptoms including facial asymmetry or swelling (167/214 cases; 78.0%), oral pain (30/214; 14.0%), systemic symptoms (25/214; 11.7%), referrals or incidental findings (16/214; 7.5%), and neuropathy (6/214; 2.8%) independently and in combination together. Bony pathology occurred most often in the mandible (100/245 cases; 40.8%), while 72 cases were in the maxilla (29.4%) and 73 cases in both jaw bones (29.8%). CONCLUSIONS: Our data collection identifies a wide variation in the presentation of hyperparathyroidism. In order to be more certain of oral maladies from hyperparathyroidism, studies with large patient populations need to be conducted at healthcare centers to clarify the oral outcomes of hyperparathyroidism. CLINICAL RELEVANCE: What was thought to be a characteristic finding of HPT, mandibular radiolucency occurred in only a minor portion of cases. Furthermore, the pathognomonic sign of HPT on radiograph, loss of lamina dura, was only the third most common presentation. Bone pathology was most commonly reported in literature, but should not be assumed the only oral sequelae of hyperparathyroidism. PMID- 28616753 TI - Gemcitabine monotherapy in patients with heavily treated nasopharyngeal cancer: a case series. AB - BACKGROUND: Although gemcitabine is thought to play a critical role in the treatment of nasopharyngeal cancer, no research to evaluate the efficacy and toxicity of gemcitabine monotherapy has been conducted in Japan. METHODS: We retrospectively reviewed eight nasopharyngeal carcinoma patients treated with gemcitabine monotherapy at National Cancer Center Hospital East between May 2015 and August 2016. The main eligibility criteria were (1) histopathologically proven NPC; (2) tumor recurrence or an initial M1 TNM stage diagnosis; (3) at least two other types of systemic chemotherapy prior to gemcitabine; (4) no other active malignant tumor during treatment. RESULTS: All patients were administered gemcitabine 800-1000 mg/m2 on days 1, 8, and 15, repeated every 4 weeks. Gemcitabine was given as third-line systemic chemotherapy in six (74%) patients, as fourth-line in one (13%) and as fifth-line in one (13%). One patient had a complete response and one had a partial response, giving an overall response rate of 25%; four patients (50%) had stable disease and two (25%) experienced disease progression. The main toxicity was myelosuppression, with grade 3 leukopenia in three (38%) patients and neutropenia in four (50%). There were no treatment related deaths. Median dose intensity and relative dose intensity of gemcitabine were 620 mg/m2/week and 97.5%, respectively. CONCLUSION: Our findings suggest that GEM monotherapy is well tolerated and has potential as an active agent in Japanese patients with recurrent/metastatic NPC who have been heavily pretreated. PMID- 28616755 TI - CORR Insights(r): Does the FIFA 11+ Injury Prevention Program Reduce the Incidence of ACL Injury in Male Soccer Players? PMID- 28616754 TI - Sexually dimorphic distribution of Prokr2 neurons revealed by the Prokr2-Cre mouse model. AB - Prokineticin receptor 2 (PROKR2) is predominantly expressed in the mammalian central nervous system. Loss-of-function mutations of PROKR2 in humans are associated with Kallmann syndrome due to the disruption of gonadotropin releasing hormone neuronal migration and deficient olfactory bulb morphogenesis. PROKR2 has been also implicated in the neuroendocrine control of GnRH neurons post-migration and other physiological systems. However, the brain circuitry and mechanisms associated with these actions have been difficult to investigate mainly due to the widespread distribution of Prokr2-expressing cells, and the lack of animal models and molecular tools. Here, we describe the generation, validation and characterization of a new mouse model that expresses Cre recombinase driven by the Prokr2 promoter, using CRISPR-Cas9 technology. Cre expression was visualized using reporter genes, tdTomato and GFP, in males and females. Expression of Cre induced reporter genes was found in brain sites previously described to express Prokr2, e.g., the paraventricular and the suprachiasmatic nuclei, and the area postrema. The Prokr2-Cre mouse model was further validated by colocalization of Cre-induced GFP and Prokr2 mRNA. No disruption of Prokr2 expression, GnRH neuronal migration or fertility was observed. Comparative analysis of Prokr2-Cre expression in male and female brains revealed a sexually dimorphic distribution confirmed by in situ hybridization. In females, higher Cre activity was found in the medial preoptic area, ventromedial nucleus of the hypothalamus, arcuate nucleus, medial amygdala and lateral parabrachial nucleus. In males, Cre was higher in the amygdalo-hippocampal area. The sexually dimorphic pattern of Prokr2 expression indicates differential roles in reproductive function and, potentially, in other physiological systems. PMID- 28616756 TI - Editor's Spotlight/Take 5: Readability of Orthopaedic Patient-reported Outcome Measures: Is There a Fundamental Failure to Communicate? PMID- 28616757 TI - CORR Insights(r): Complete Circumferential Osseous Extension in the Acetabular Rim Occurs Regardless of Acetabular Coverage. PMID- 28616758 TI - Does Humeral Component Lateralization in Reverse Shoulder Arthroplasty Affect Rotator Cuff Torque? Evaluation in a Cadaver Model. AB - BACKGROUND: Humeral component lateralization in reverse total shoulder arthroplasty (RTSA) may improve the biomechanical advantage of the rotator cuff, which could improve the torque generated by the rotator cuff and increase internal and external rotation of the shoulder. PURPOSE: The purpose of this in vitro biomechanical study was to evaluate the effect of humeral component lateralization (or lateral offset) on the torque of the anterior and posterior rotator cuff. METHODS: Eight fresh-frozen cadaveric shoulders from eight separate donors (74 +/- 8 years; six males, two females) were tested using an in vitro simulator. All shoulders were prescreened for soft tissue deficit and/or deformity before testing. A custom RTSA prosthesis was implanted that allowed five levels of humeral component lateralization (15, 20, 25, 30, 35 mm), which avoided restrictions imposed by commercially available designs. The torques exerted by the anterior and posterior rotator cuff were measured three times and then averaged for varying humeral lateralization, abduction angle (0 degrees , 45 degrees , 90 degrees ), and internal and external rotation (-60 degrees , -30 degrees , 0 degrees , 30 degrees , 60 degrees ). A three-way repeated measures ANOVA (abduction angle, humeral lateralization, internal rotation and external rotation angles) with a significance level of alpha = 0.05 was used for statistical analysis. RESULTS: Humeral lateralization only affected posterior rotator cuff torque at 0 degrees abduction, where increasing humeral lateralization from 15 to 35 mm at 60 degrees internal rotation decreased external rotation torque by 1.6 +/- 0.4 Nm (95% CI, -0.07 -1.56 Nm; p = 0.06) from 4.0 +/- 0.3 Nm to 2.4 +/- 0.6 Nm, respectively, but at 60 degrees external rotation increased external rotation torque by 2.2 +/- 0.5 Nm (95% CI, -4.2 to 0.2 Nm; p = 0.029) from 6.2 +/- 0.5 Nm to 8.3 +/- 0.5 Nm, respectively. Anterior cuff torque was affected by humeral lateralization in more arm positions than the posterior cuff, where increasing humeral lateralization from 15 to 35 mm when at 60 degrees internal rotation increased internal rotation torque at 0 degrees , 45 degrees , and 90 degrees abduction by 3.2 +/- 0.5 Nm (95% CI, 1.1-5.2 Nm; p = 0.004) from 6.6 +/- 0.6 Nm to 9.7 +/- 0.6 Nm, 4.0 +/- 0.3 Nm (95% CI, 2.8-5.0 Nm; p < 0.001) from 1.7 +/- 1.0 Nm to 5.6 +/- 0.9 Nm, and 2.2 +/- 0.2 Nm (95% CI, 1.4 2.9 Nm; p < 0.001) from 0.6 +/- 0.6 Nm to 2.8 +/- 0.6 Nm, respectively. In neutral internal and external rotation, increasing humeral lateral offset from 15 to 35 mm increased the internal rotation torque at 45 and 90 abduction by 1.5 +/- 0.3 Nm (95% CI, 0.2-2.7 Nm; p = 0.02) and 1.3 +/- 0.2 Nm (95% CI, 0.4-2.3 Nm; p < 0.001), respectively. CONCLUSIONS: Humeral component lateralization improves rotator cuff torque. CLINICAL RELEVANCE: The results of this preliminary in vitro cadaveric study suggest that the lateral offset of the RTSA humeral component plays an important role in the torque generated by the anterior and posterior rotator cuff. However, further studies are needed before clinical application of these results. Increasing humeral offset may have adverse effects, such as the increased risk of implant modularity, increasing tension of the cuff and soft tissues, increased costs often associated with design modifications, and other possible as yet unforeseen negative consequences. PMID- 28616759 TI - Is Dual Semitendinosus Allograft Stronger Than Turndown for Achilles Tendon Reconstruction? An In Vitro Analysis. AB - BACKGROUND: Large Achilles tendon defects pose a treatment challenge. The standard treatment with a turndown flap requires a large extensile incision, puts the sural nerve at risk, and demands slow, careful rehabilitation. Dual allograft semitendinosus reconstruction is a new clinical alternative that has the theoretical advantages of a smaller incision, less dissection, and a stronger construct that may allow for faster rehabilitation. QUESTIONS/PURPOSES: In a cadaver biomechanical model, we compared the dual allograft semitendinosus reconstruction with the myofascial turndown in terms of (1) mechanical strength and resistance to deformation and (2) failure mechanisms in reconstruction of large segmental Achilles defects. METHODS: An 8-cm segmental Achilles defect was created in 18 cadaveric lower extremities, nine matched pairs without defect or previous surgery (mean age, 78.4 years; range, 60-97 years; three female and six male pairs). Femoral neck densitometry to determine bone mineral density found that all specimens except two were osteopenic or osteoporotic. Specimens in each pair were assigned to allograft or turndown reconstruction. The constructs were mounted on a load frame and differential variable reluctance transducers were applied to measure deformation. Specimens were preconditioned and then loaded axially. Tensile force and proximal and distal construct deformation were measured at clinical failure, defined as 10 mm of displacement, and at ultimate failure, defined as failure of the reconstruction. Failure mechanism was recorded. RESULTS: Tensile strength at time zero was higher in the allograft versus the turndown construct at clinical failure (156.9 +/- 29.7 N versus 107.2 +/- 20.0 N, respectively; mean difference, -49.7 N; 95% CI, -66.3 to -33.0 N; p < 0.001) and at ultimate failure (290.9 +/- 83.2 N versus 140.7 +/- 43.5 N, respectively; mean difference, -150.2 N; 95% CI, -202.9 to -97.6 N; p < 0.001). Distal construct deformation was lower in the turndown versus the allograft construct at clinical failure (1.6 +/- 1.0 mm versus 4.7 +/- 0.7 mm medially and 2.2 +/- 1.0 mm versus 4.8 +/- 1.1 mm laterally; p < 0.001). Semitendinosus allograft failure occurred via calcaneal bone bridge fracture in eight of nine specimens. All myofascial turndowns failed via suture pullout through the fascial tissue at its insertion. CONCLUSION: In this comparative biomechanical study, dual semitendinosus allograft reconstruction showed greater tensile strength and construct deformation compared with myofascial turndown in a cadaveric model of large Achilles tendon defects. CLINICAL RELEVANCE: Further study of dual semitendinosus allograft for treatment of severe Achilles tendon defects with cyclic loading and investigation of clinical results will better elucidate the clinical utility and indications for this technique. PMID- 28616761 TI - A Response to Predictors of Heart Disease Knowledge Among Older and Younger Asian Indian Adults. PMID- 28616760 TI - Liver segmentation: indications, techniques and future directions. AB - OBJECTIVES: Liver volumetry has emerged as an important tool in clinical practice. Liver volume is assessed primarily via organ segmentation of computed tomography (CT) and magnetic resonance imaging (MRI) images. The goal of this paper is to provide an accessible overview of liver segmentation targeted at radiologists and other healthcare professionals. METHODS: Using images from CT and MRI, this paper reviews the indications for liver segmentation, technical approaches used in segmentation software and the developing roles of liver segmentation in clinical practice. RESULTS: Liver segmentation for volumetric assessment is indicated prior to major hepatectomy, portal vein embolisation, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and transplant. Segmentation software can be categorised according to amount of user input involved: manual, semi-automated and fully automated. Manual segmentation is considered the "gold standard" in clinical practice and research, but is tedious and time-consuming. Increasingly automated segmentation approaches are more robust, but may suffer from certain segmentation pitfalls. Emerging applications of segmentation include surgical planning and integration with MRI based biomarkers. CONCLUSIONS: Liver segmentation has multiple clinical applications and is expanding in scope. Clinicians can employ semi-automated or fully automated segmentation options to more efficiently integrate volumetry into clinical practice. TEACHING POINTS: * Liver volume is assessed via organ segmentation on CT and MRI examinations. * Liver segmentation is used for volume assessment prior to major hepatic procedures. * Segmentation approaches may be categorised according to the amount of user input involved. * Emerging applications include surgical planning and integration with MRI-based biomarkers. PMID- 28616762 TI - A systematic comparison of cardiovascular magnetic resonance and high resolution histological fibrosis quantification in a chronic porcine infarct model. AB - The noninvasive reference standard for myocardial fibrosis detection on cardiovascular magnetic resonance imaging (CMR) is late gadolinium enhancement (LGE). Currently there is no consensus on the preferred method for LGE quantification. Moreover myocardial wall thickening (WT) and strain are measures of regional deformation and function. The aim of this research was to systematically compare in vivo CMR parameters, such as LGE, WT and strain, with histological fibrosis quantification. Eight weeks after 90 min ischemia/reperfusion of the LAD artery, 16 pigs underwent in vivo Cine and LGE CMR. Histological sections from transverse heart slices were digitally analysed for fibrosis quantification. Mean fibrosis percentage of analysed sections was related to the different CMR techniques (using segmentation or feature tracking software) for each slice using a linear mixed model analysis. The full width at half maximum (FWHM) technique for quantification of LGE yielded the highest R2 of 60%. Cine derived myocardial WT explained 16-36% of the histological myocardial fibrosis. The peak circumferential and radial strain measured by feature tracking could explain 15 and 10% of the variance of myocardial fibrosis, respectively. The used method to systematically compare CMR image data with digital histological images is novel and feasible. Myocardial WT and strain were only modestly related with the amount of fibrosis. The fully automatic FWHM analysis technique is the preferred method to detect myocardial fibrosis. PMID- 28616763 TI - Associations between fruit and vegetable variety and low-grade inflammation in Portuguese adolescents from LabMed Physical Activity Study. AB - PURPOSE: The dietary guidelines for the consumption of a variety of fruits and vegetables have been recognized as an important factor for achieving healthy eating patterns to reduce the risk of chronic disease throughout the lifespan. Our aim is to assess the association between fruit and vegetable variety and low grade inflammation in adolescents. METHODS: This cross-sectional analysis was conducted with 412 adolescents (ages 14.4 +/- 1.7 years; 52% girls). The consumption of a variety of fruits and vegetables was assessed with a food frequency questionnaire, considering the number of individual/category of fruit or vegetable intake at least once month, and categorized into tertiles. Blood samples were collected to determine C-reactive protein (CRP), interleukin-6 (IL 6), complement component 3 (C3), and 4 (C4). We created categories of lower or higher (inflammatory state) for each biomarker, considering sex- and age-adjusted median values. Then, we computed an overall inflammatory score, by adding all points awarded wherein one point was assigned if biomarker was higher or zero if lower, and created categories of 0-1 or 2-4 biomarkers above the median. The odds ratio (OR) and 95% interval confidence (95% CI) were calculated from binary logistic regression to estimate the magnitude of association between fruit and vegetable variety and inflammatory biomarkers. RESULTS: Adolescents with a greater variety of vegetable consumption (>=13 categories/month) had lower odds of having a higher CRP (OR 0.31, 95% CI 0.15-0.64, p trend = 0.004) when compared to those with lower variety consumption (<=6 categories/month), independent of vegetable quantity intake. However, a greater variety of fruit consumption (>=12 categories/month) had higher odds of having a higher IL-6 (OR 4.41, 95% CI 1.67 11.71, p trend = 0.012), C3 (OR 3.30, 95% CI 1.23-8.86, p trend = 0.047), and inflammatory score (OR 4.90, 95% CI 1.62-14.86, p trend = 0.017), when compared to those with lower variety consumption (<=9 categories/month), independent of fruit quantity intake, only for girls. CONCLUSIONS: The consumption of a variety of vegetables is inversely associated with lower CRP. This finding supports the current dietary guidelines regarding the consumption of a variety of vegetables. The role of fruit variety in low-grade inflammation should be further studied. PMID- 28616764 TI - Abrupt salinity stress induces oxidative stress via the Nrf2-Keap1 signaling pathway in large yellow croaker Pseudosciaena crocea. AB - The aim of the present study was to evaluate the effects of abrupt salinity stress (12, 26 (control), and 40) on lipid peroxidation, activities and mRNA levels of antioxidant enzymes (Cu/Zn-SOD, CAT, GPx, and GR), and gene expression of the Nrf2-Keap1 signaling molecules at different times (6, 12, 24, and 48 h) in the liver of large yellow croaker Pseudosciaena crocea. The results showed that lipid peroxidation was sharply reduced at 6 h and increased at 12 h before returning to control levels in the hypo-salinity group. Similarly, lipid peroxidation was significantly decreased at 6 h followed by a sharp increase towards the end of the exposure in the hyper-salinity group. Negative relationships between lipid peroxidation and antioxidant enzyme activities and positive relationships between activities and gene expression of antioxidant enzymes were observed, suggesting that the changes at molecular levels and enzyme activity levels may provide protective roles against damage from salinity stress. Obtained results also showed a coordinated transcriptional regulation of antioxidant genes, suggesting that Nrf2 is required for regulating these genes. Furthermore, there was a positive relationship between the mRNA levels of Nrf2 and Keap1, indicating that Keap1 plays an important role in switching off the Nrf2 response. In conclusion, this is the first study to elucidate effects of salinity stress on antioxidant responses in large yellow croaker through the Keap1-Nrf2 pathway. PMID- 28616765 TI - Effects of replacing fish meal with rubber seed meal on growth, nutrient utilization, and cholesterol metabolism of tilapia (Oreochromis niloticus * O. aureus). AB - A feeding trial was conducted to evaluate the effects of replacing fish meal with rubber seed meal (RSM) on growth, nutrient utilization, and cholesterol metabolism of tilapia (Oreochromis niloticus * Oreochromis aureus). Five experimental diets were formulated with 0, 150, 300, 450, and 600 g kg-1 RSM replacing graded levels of fish meal, respectively. Each diet was randomly assigned to triplicate groups of 25 fish (initial average weight 65.3 g) per aquarium in a rearing system maintained at 29 +/- 1 degrees C for 8 weeks. Dietary 150 g kg-1 RSM inclusion did not affect the weight gain and daily growth coefficient, whereas these were depressed by a further inclusion. Additionally, feed efficiency ratio and protein efficiency ratio were not affected by dietary RSM inclusion regardless of inclusion level. However, the inclusion of 450 and 600 g kg-1 RSM decreased the mid-intestinal trypsin, lipase, and amylase activities; the hepatic acyl-CoA/cholesterol acyl transferase; low-density lipoprotein receptor; and 3-hydroxy-3-methyl-glutaryl-CoA reductase activities. Similarly, dietary 600 g kg-1 RSM inclusion inhibited the plasma catalase and hepatic glutathione peroxidase activities. These results indicated that 150 g kg 1 RSM can be included in tilapia diets, whereas higher inclusion of RSM inhibited the growth rate, digestive enzyme activity, antioxidant capacity, and cholesterol metabolism. PMID- 28616766 TI - [Knowledge and information sources of parents of 3- to 6-year-old children concerning skin cancer risk factors]. AB - BACKGROUND: The dissemination of knowledge on risk factors and preventive strategies is a core element of skin cancer prevention. However, little is known about the information channels utilised by the population for this purpose. OBJECTIVES: Descriptive analysis of information sources used by parents of 3- to 6-year-old children as a particularly relevant target group and analysis of association patterns between socio-demographic factors, types of information sources and acquired knowledge. MATERIALS AND METHODS: A cross-sectional study was performed using a self-administered questionnaire with an online option between October 2011 and February 2012 with 3129 families who had at least one child visiting a kindergarten in the county of Erlangen-Hochstadt, the city of Erlangen or the city of Ansbach (Bavaria, Germany), with an 87.5% response rate on the level of kindergartens and 56.5% on the level of observational units (families). RESULTS: There were few structural differences between study regions. The internet was used by only 13.3% of participants. A positive association was found between the use of multiple information sources and relevant knowledge and, partly, protective behaviour. A negative association was identified between the use of the internet and knowledge. In contrast, the use of print media or audio visual or personal channels of information was positively associated with knowledge. CONCLUSIONS: Preventive efforts should be increased that target parts of the population with lower formal education. The internet does not seem to play an important role and may even adversely affect knowledge, possibly due to unvalidated and misleading information. PMID- 28616767 TI - Art and Science of Instrument Development for Stated-Preference Methods. PMID- 28616768 TI - Antitumor activity and safety profile of weekly carboplatin plus paclitaxel in metastatic breast cancer: a ten-year, monocentric, retrospective study. AB - BACKGROUND: Taxanes are a mainstay in the treatment of metastatic breast cancer (mBC). Combination chemotherapy, including platinum-taxens doublets, can improve tumor responses and progression-free survival (PFS), but is associated with more toxicities and an uncertain benefit in terms of overall survival (OS). METHODS: We performed a retrospective study on 274 consecutive patients with mBC treated at the Division of Medical Oncology of Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, during the decade 2007-2016 with the combination of carboplatin AUC 2 plus paclitaxel 80 mg/m2, both given on days 1 and 8 in every 21-day cycle. RESULTS: 264 patients were evaluable for treatment safety and activity. The objective response rate (ORR) was 44.7%. Median PFS and OS were 8.6 and 23.7 months, respectively. Triple-negative breast cancer (TNBC) patients had significantly lower PFS and OS times compared to other biology groups. At multivariable analysis, previous exposure to taxanes, HR-positive HER2-negative biology, a higher number of metastatic sites, and de novo metastatic disease at diagnosis were associated with reduced PFS, while receiving maintenance therapy correlated with improved PFS. Overall, the treatment was quite well tolerated, with 10.2% of patients discontinuing one or both drugs because of adverse events (AEs). G3-G4 neutropenia occurred in 16.8% of patients, while the incidence of febrile neutropenia was 2.3%. CONCLUSIONS: Weekly carboplatin-paclitaxel regimen is active and well tolerated in mBC treatment. Prospective studies should be conducted to compare its efficacy and tolerability with standard single-agent paclitaxel or docetaxel treatment schedules, as well as with more recent combination regimens. PMID- 28616769 TI - Prospective Associations Among Youth Religiosity and Religious Denomination and Youth Contraception Use. AB - This study prospectively investigates associations among youth religiosity, religious denomination, and contraception use. Associations between youth religiosity and religious denomination, and type of contraceptive used and consistent contraceptive use among sexually active youth (N = 757) were analyzed using multinomial and binomial logistic regression. Identifying with a religious denomination was a predictor of dual contraceptive use relative to using no method of contraception (AOR = 2.17). There was no association between youth religiosity and type of contraceptive use or contraceptive consistency. Religious leaders and public health practitioners should collaborate to develop strategies to engage in conversations with sexually active youth about contraceptive use. PMID- 28616770 TI - Protective Effect of Origanum Oil on Alterations of Some Trace Elements and Antioxidant Levels Induced by Mercuric Chloride in Male Rats. AB - In the current study, 48 male rats were classified into four groups (12 rats/group): 1-control group received 1 ml distilled water, 2-origanum oil group treated daily with oral dose of origanum oil (5 mg/kg) for 30 and 60 days, 3 mercuric chloride group treated daily with oral dose of mercuric chloride (4 mg/kg) for 30 and 60 days, and 4-origanum oil + mercuric chloride group treated with both origanum oil and mercuric chloride (5 and 4 mg/kg, respectively) for 30 and 60 days. All treatments were carried out by stomach tube. The results showed that administration of mercuric chloride induced significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in glutathione (GSH), catalase (CAT), and super oxide dismutase (SOD) in testis and spleen tissues. The data also showed significant increase in tumor necrossis factor-alpha (TNF alpha), 8-hydroxy deoxyguanosine (8-OHDG), acid phosphatase (ACP), urea, and creatinine. Furthermore, significant decreases in serum zinc (Zn), copper (Cu), magnesium (Mg), iron (Fe), and testosterone in mercuric chloride group were recorded. The histological examination of testis and spleen tissues showed some degenerative changes while significant improvement in the antioxidant levels, biochemical, trace elements, and histological changes were observed in mercuric chloride group treated with origanum oil. It could be concluded that origanum oil through its antioxidant potential may possess health promoting properties and could protect cells from oxidative damage induced by mercuric chloride. PMID- 28616771 TI - Androgen supplementation improves some but not all aspects of immune senescence in aged male macaques. AB - Aging leads to a progressive decline in immune function commonly referred to as immune senescence, which results in increased incidence and severity of infection. In addition, older males experience a significant disruption in their levels of circulating androgens, notably testosterone and dehydroepiandrosterone (DHEA), which has been linked to sarcopenia, osteoporosis, cardiovascular disease, and diabetes. Since sex steroid levels modulate immune function, it is possible that the age-related decline in androgen levels can also affect immune senescence. Therefore, in this study, we evaluated the pleiotropic effects of physiological androgen supplementation in aged male rhesus macaques (n = 7/group) on immune cell subset frequency and response to vaccination. As expected, frequency of naive CD4 and CD8 T cells declined in aged non-treated macaques, while that of memory T cells increased. In contrast, frequency of naive and memory T cells remained stable in androgen-supplemented males. In addition, levels of inflammatory cytokines increased less steeply in supplemented aged males compared to the aged controls. Despite these changes, androgen-supplemented animals only showed modest improvement in antibody responses following vaccination compared to age non-treated controls. These data indicate that short term physiological androgen supplementation can improve some but not all aspects of immune senescence. PMID- 28616772 TI - Evaluation of the cognitive behavioral smoking reduction program "Smoke_less": a randomized controlled trial. AB - : The vast majority of smokers are unable or unwilling to quit, but many are open to reducing smoking. No treatment options exist for these smokers besides medication-based therapies. Thus, this study investigated the efficacy of a cognitive behavioral therapy (CBT) smoking reduction program, Smoke_less. A sample of 155 outpatient smokers aged 18-70 years was recruited at the Tobacco Dependence Outpatient Clinic of the Medical Center of the University of Munich, Germany, and randomly assigned to the experimental group (Smoke_less: four weekly CBT group sessions and two telephone calls over 5 weeks, n = 51), active comparator group (one 15-minute counseling session, n = 49), or waiting control group (no intervention during the study, n = 55). The primary endpoint was a >=50% smoking reduction in the intention-to-treat group 1 week and 6 months after the intervention. We evaluated also abstinence rates at follow-up. Significantly more participants in the Smoke_less group had reduced smoking >=50% compared to the waiting group at 1 week [OR 7.59 (2.59-22.19)] and 6 months [OR 5.00 (1.68 14.84)] and compared to the active comparison group at 1 week [OR 8.58 (2.67 27.31)] but not at 6 months [OR 1.73 (0.71-4.20)]. We found no significant effects on abstinence rates. The CBT smoking reduction program Smoke_less is effective for smoking reduction but is superior to brief counseling only in the short term. Further research is required to improve its efficacy in long-term smoking reduction to provide a valid, non-medication-based alternative to smokers unable or unwilling to quit. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02337400. PMID- 28616773 TI - Intracochlear schwannoma : Tumor removal via subtotal cochleoectomy and partial cochlear reconstruction with preservation of semicircular canal function. AB - We report about a patient, who in 2005, as a 37-year-old, experienced a sudden, mild to moderate, mid-frequency sensorineural hearing loss in the right ear, along with tinnitus and mild dizziness. MRI of the temporal bone revealed a very small (1 mm) enhancing lesion in the second turn of the right cochlea after injection of contrast medium. Hearing gradually deteriorated, with complete hearing loss in 2015. At this time, an MRI scan showed a lesion completely filling the cochlea.The tumor was removed through a subtotal cochleoectomy. The cochlea was partially reconstructed with cartilage and fascia. A cochlea implant dummy electrode was inserted as a placeholder in order to try to preserve a channel within the most likely fibrosing "neocochlea" during follow-up MRI examinations.Vestibular function tests 2 months postoperatively showed preserved caloric excitability and a normal vestibulo-ocular reflex (video head impulse test, vHIT) in all three planes. The patient is free of vertigo.Intralabyrinthine schwannomas (ILS) are a rare differential diagnosis of sudden hearing loss. Surgical removal of an intracochlear ILS through partial or subtotal cochleoectomy with preservation of vestibular function is possible. PMID- 28616774 TI - [Molecular component-resolved allergy diagnostics in ENT]. AB - Molecular component-resolved diagnostics (CRD) are, in addition to its research applications, being increasingly used in daily allergological routine. CRD offers improved diagnostic accuracy via a better understanding of the underlying allergen causing symptoms and helps to distinguish between true sensitization and cross reactions in polysensitized patients, thereby providing an approach for individual personalized therapy. Particularly in food allergies and anaphylaxis, CRD can stratify risks for the recurrence of reactions and their severity. The education and extended vocational training of clinical allergologists has to keep pace with the tremendous increase of knowledge in the field of molecular allergology. PMID- 28616775 TI - Informing Reimbursement Decisions Using Cost-Effectiveness Modelling: A Guide to the Process of Generating Elicited Priors to Capture Model Uncertainties. AB - In informing decisions, utilising health technology assessment (HTA), expert elicitation can provide valuable information, particularly where there is a less developed evidence-base at the point of market access. In these circumstances, formal methods to elicit expert judgements are preferred to improve the accountability and transparency of the decision-making process, help reduce bias and the use of heuristics, and also provide a structure that allows uncertainty to be expressed. Expert elicitation is the process of transforming the subjective and implicit knowledge of experts into their quantifiable expressions. The use of expert elicitation in HTA is gaining momentum, and there is particular interest in its application to diagnostics, medical devices and complex interventions such as in public health or social care. Compared with the gathering of experimental evidence, elicitation constitutes a reasonably low-cost source of evidence. Given its inherent subject nature, the potential biases in elicited evidence cannot be ignored and, due to its infancy in HTA, there is little guidance to the analyst wishing to conduct a formal elicitation exercise. This article attempts to summarise the stages of designing and conducting an expert elicitation, drawing on key literature and examples, most of which are not in HTA. In addition, we critique their applicability to HTA, given its distinguishing features. There are a number of issues that the analyst should be mindful of, in particular the need to appropriately characterise the uncertainty associated with model inputs and the fact that there are often numerous parameters required, not all of which can be defined using the same quantities. This increases the need for the elicitation task to be as straightforward as possible for the expert to complete. PMID- 28616776 TI - Evidence towards RNA Binding Motif (RNP1, RRM) Protein 3 (RBM3) as a Potential Biomarker of Lithium Response in Bipolar Disorder Patients. AB - Lithium has been used for more than six decades for the management of bipolar disorder (BD). In a previous transcriptomic study, we showed that patients affected by either BD or cluster headache, both disorders characterized by circadian disturbances and response to lithium in a subgroup of patients, have higher expression of the RNA binding motif (RNP1, RRM) protein 3 (RBM3) gene compared to controls. To investigate whether RBM3 could represent a biomarker of lithium response, we screened raw microarray expression data from lymphoblastoid cell lines (LCLs) derived from 20 BD patients, responders or non-responders to lithium. RBM3 was the most significantly differentially expressed gene in the list, being overexpressed in responders compared to non-responders (fold change = 2.0; p = 1.5 * 10-16). We therefore sought to validate the microarray finding by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and explore whether RBM3 expression was modulated by lithium treatment in vitro in LCLs as well as in human-derived neural progenitor cells (NPCs). Our findings confirmed the higher expression of RBM3 in responders compared to non-responders (fold change = 3.78; p = 0.0002). Lithium did not change RBM3 expression in LCLs in any of the groups, but it increased its expression in NPCs. While preliminary, our data suggest that higher levels of RBM3 might be required for better lithium response and that the expression of this gene could be modulated by lithium in a tissue-specific manner. PMID- 28616777 TI - Differential Regulation of MeCP2 Phosphorylation by Laminin in Oligodendrocytes. AB - Oligodendrocytes (OLGs) are the myelinating cells of the central nervous system (CNS), and its proper differentiation is crucial for normal functioning of neurons. Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional methylated DNA binding protein; mutation of which causes Rett syndrome, a severe neurodevelopmental disorder. Previously, we reported that MeCP2 is expressed in all the stages of oligodendrocyte development, and also shown the role of MeCP2 as a transcription regulator of myelin genes in OLGs. The expression and function of MeCP2 phosphorylation at S80 (pS80MeCP2) has been well studied in neurons and astrocytes; however, there is no data so far available in OLGs regarding pS80MeCP2. Certain developmental stimuli such as growth factors and extracellular matrix (ECM) protein play important role in OLG development. In the present study, we have examined the effects of external stimuli (growth factors (GFs) and extracellular matrix (ECMs)) on S80 phosphorylation of MeCP2 in N19 oligodendroglial cells (N19 OLGs). This study provides the first evidence that laminin (LN) differentially regulates the expression of pS80MeCP2 in immature and mature N19 OLGs. Thus, MeCP2 is phosphorylated in a stimulus-dependent manner during oligodendrocyte development, and thereby, it may regulate the oligodendrocyte behavior. PMID- 28616778 TI - Auditory brainstem responses after electrolytic lesions in bilateral subdivisions of the medial geniculate body of tree shrews. AB - This study aimed to establish a tree shrew model of bilateral electrolytic lesions in the medial geniculate body (MGB) to determine the advantages of using a tree shrew model and to assess the pattern of sound processing in tree shrews after bilateral electrolytic damage in different parts of the MGB. The auditory brainstem responses (ABRs) of a normal control group (n = 30) and an electrical damage group (n = 30) were tested at 0 h, 24 h, 48 h, 72 h, 7 days, 15 days, and 30 days after surgery. (1) The bilateral ablations group exhibited a significant increase in the ABR threshold of the electrolytic damage group between pre- and post-operation. (2) There were significant increases in the I-VI latencies at 0 h after MGBd and MGBm lesions and at 24 h after MGBv lesion. (3) The amplitudes of wave VI were significantly decreased at 24 h and 48 h after MGBd lesion, at 72 h and 7 days after MGBm lesion, and at 24 h, 48 h, 72 h, and 7 days after MGBv lesion. (1) The electrolytic damage group suffered hearing loss that did not recover and appeared to be difficult to fully repair after bilateral ablation. (2) The latencies and amplitudes of responses in the MGB following bilateral electrolytic lesion were restored to pre-operation levels after 15-30 days, suggesting that a portion of the central nuclei lesion was reversible. (3) The tree shrew auditory animal model has many advantages compared to other animal models, such as greater complexity of brain structure and auditory nuclei fiber connections, which make the results of this experiment more useful for clinical diagnoses compared with studies using rats and guinea pigs. PMID- 28616779 TI - [Arthrodesis of the distal interphalangeal joint using the headless compression screw]. AB - OBJECTIVE: Arthrodesis of the distal interphalangeal joint of the fingers and interphalangeal joint of the thumb in order to gain reliable stability and function. INDICATIONS: Primary and secondary osteoarthritis, rheumatoid arthritis, defect lesions, septic joint destruction, posttraumatic joint deviation, fatal joint instability, fatal tendon lesions. CONTRAINDICATIONS: Persistent infections (empyema, osteomyelitis, phlegmon), deficient soft tissue mantle, bone/screw mismatch. SURGICAL TECHNIQUE: Using Beasley's approach the extensor tendon is identified and sectioned. Incision of the collateral ligaments enables good exposition. Precise resection of the joint surfaces. An orthograde guidewire is place into the distal phalanx. After adjustment of the arthrodesis which is controlled using x-ray, the guide wire is drilled into the middle phalanx in retrograde fashion. An adequate headless compression screw is introduced via a transverse incision at the fingertip using the guide wire, the former screw is placed until sufficient compression is generated. POSTOPERATIVE MANAGEMENT: Finger splint reaching to the proximal interphalangeal joint for 4 weeks after arthrodesis, full weight bearing after 6 weeks. RESULTS: Seventeen patients were examined after arthrodesis of the distal interphalangeal joint using the headless compression screw. The arthrodesis proved to be reliable and safe with a low complication rate and a good functional outcome. The modified Mayo Wrist Score (MMWS) was on average 89 (range 55-100); the outcome parameter DASH (disabilities of arm, shoulder and hand) score was on average 27 (range 1 60). PMID- 28616780 TI - [Is deferment of the time of administration to avoid an aspirin/metamizole interaction by chronic dosing sufficient?] PMID- 28616782 TI - Erratum to: Effect of high-fat diet on rat myometrium during pregnancy-isolated myometrial mitochondria are not affected. PMID- 28616781 TI - Impact of hyperglycemia on cystathionine-gamma-lyase expression during resuscitated murine septic shock. AB - BACKGROUND: Cystathionine-gamma-lyase (CSE) was shown to have a regulatory role in glucose metabolism. Circulatory shock can induce metabolic stress, thereby leading to hyperglycemia and mitochondrial dysfunction. In vitro data suggest an effect of high glucose on CSE expression. Therefore, the aim of this study was to investigate the effects of hyperglycemia on CSE expression in resuscitated murine septic shock. METHODS: Normo- (80-150 mg/dl) and hyperglycemic (>200 mg/dl) male C57/BL6J mice (n = 5-6 per group) underwent cecal ligation and puncture (CLP) induced polymicrobial sepsis or sham procedure (n = 6 per group) and, 15 h afterwards, were anesthetized again, surgically instrumented and received intensive care treatment, including antibiotics, lung protective mechanical ventilation, circulatory support, and intravenous (i.v.) glucose infusion (50% as stable-isotope labeled 1,2,3,4,5,6-13C6 glucose). Blood and breath gas were sampled hourly to quantify parameters of glucose metabolism. 5 h later, mice were sacrificed and organs were harvested. The liver mitochondrial respiratory activity was determined via high resolution respirometry; CSE, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha), and adipocyte differentiation-related protein (ADRP) expression was immunohistochemically investigated. RESULTS: In sepsis combined with hyperglycemia the least CSE and PGC1alpha expression could be detected, along with reduced mitochondrial respiratory activity, and enhanced ADRP expression, a marker of lipid droplet formation, in the liver. A novel in vivo finding is the CSE translocation from the cytosol to the nucleus triggered by metabolic stress. CONCLUSIONS: A relationship between CSE and glucose metabolism was established, which, when dysregulated, may contribute to fatty liver disease and hepatic steatosis. PMID- 28616783 TI - A search for glomuferrin: a potential siderophore of arbuscular mycorrhizal fungi of the genus Glomus. AB - Most fungi are known to synthesize siderophores under iron limitation. However, arbuscular mycorrhizal fungi (AM fungi) have so far not been reported to produce siderophores, although their metabolism is iron-dependent. In an approach to isolate siderophores from AM fungi, we have grown plants of Tagetes patula nana in the presence of spores from AM fungi of the genus Glomus (G. etunicatum, G. mossae & unidentified Glomus sp.) symbiotically under iron limitation and sterile conditions. A siderophore was isolated from infected roots after 2-3 weeks of growth in pots containing low-iron sand with Hoagland solution. HPLC analysis of the root cell lysate revealed a peak at a retention time of 6.7 min which showed iron-binding properties in a chrome azurol S test. The compound was isolated by preparative HPLC and the structure was determined by high resolution electrospray FTICR-MS and GC/MS analysis of the hydrolysis products. From an observed absolute mass to charge ratio (m/z) of 401.11925 [M+H]+ with a relative mass error of ? = 0.47 ppm an elemental composition of C16H21N2O10 [M+H]+ was derived, suggesting a molecular weight of 400 Da for glomuferrin. Corresponnding ion masses of m/z 423.10 and m/z 439.06 were asigned to the Na-adduct and K-adduct respectively. A mass of 455.03836 confirmed an Fe- complex with an elemental composition of C16H19N2O10Fe (? = 0.15 ppm). GC/MS analysis of the HCl lysate (6 N HCL, 12 h) revealed 1,4 butanediamine. Thus the proposed structure of the isolated siderophore from Glomus species consisted of 1,4 butanediamine amidically linked to two dehydrated citrate residues, similar to the previously identified bis amidorhizoferrin. Thus, the isolated siderophore (glomuferrin) is a member of the rhizoferrin family previously isolated from fungi of the Mucorales (Zygomycetes). PMID- 28616784 TI - Synthesis, X-ray crystal structure, DNA/BSA binding, DNA cleavage and cytotoxicity studies of phenanthroline based copper(II)/zinc(II) complexes. AB - Research on copperII 1,10-phenanththroline (phen) derivatives continues to attract interest in the context of structure and biological properties. In this paper, two metal complexes [Cu2(phen)2(MU-Cl)2]Cl2 (1), [Zn(phen)2(H2O)Cl]Cl.4H2O (2) were synthesized and characterized. The crystal structures of 1 and 2 were determined by X-ray diffraction. In order to investigate the biological properties of the prepared complexes, spectroscopic and biological studies were performed. Results of X-ray diffraction showed that 1 and 2 form two types of crystal structures in a given system: dinuclear and mono-nuclear complex. The preliminary study on the DNA cleavage activity has shown that 1 under study behaved as the chemical nucleases. The DNA binding interaction of 1 & 2 with CT DNA has been investigated by UV-Visible and fluorescence emission spectrometry and the apparent binding constant (K app) values are 5.1 * 104 and 1.2 * 104 M-1, respectively. In addition, fluorescence spectrometry of bovine serum albumin (BSA) with 1 & 2 showed that the quenching mechanism might be a static quenching procedure with one binding sites for BSA. In addition, the cytotoxicity of 1 in vitro on tumor cells lines (MCF-7, HepG2 and HT29) was examined by MTT and showed better antitumor effect on the tested cells. PMID- 28616785 TI - Usefulness of NKX2.2 Immunohistochemistry for Distinguishing Ewing Sarcoma from Other Sinonasal Small Round Blue Cell Tumors. AB - NKX2.2 is a new immunohistochemical marker that has been reported to be sensitive and specific for Ewing sarcoma (ES). It has not, however, been investigated specifically in the sinonasal small round blue cell tumor (SRBCT) differential diagnosis which includes many tumors specific to that site. It has also not been investigated in the newly recognized "adamantinoma-like" variant of ES. Immunohistochemistry for NKX2.2 was performed on 170 poorly differentiated sinonasal neoplasms: 73 squamous cell carcinomas (67 poorly differentiated, non keratinizing, or basaloid types and 6 nasopharyngeal carcinomas), 46 olfactory neuroblastomas, 8 sinonasal undifferentiated carcinomas (SNUCs), 6 melanomas, 7 Ewing sarcomas, 6 SMARCB1-deficient carcinomas, 6 teratocarcinosarcomas, 5 alveolar rhabdomyosarcomas, 4 solid adenoid cystic carcinomas, 4 NK/T cell lymphomas, 3 NUT carcinomas, and 2 small cell carcinomas. NKX2.2 was positive in 7 of 7 (100%) Ewing sarcomas, including 3 adamantinoma-like variant (all diffuse, 5 strong and 2 weak). It was also positive in 5 of 6 (83%) teratocarcinosarcomas (strong, but focal), 12 of 46 (26%) olfactory neuroblastomas (diffuse, 2 strong and 10 weak), 4 of 6 melanomas (2 diffuse, 2 focal, all weak), and 1 of 2 small cell carcinomas (diffuse and strong). All squamous cell carcinomas, NUT carcinomas, SMARCB1-deficient carcinomas, SNUCs, solid adenoid cystic carcinomas, NK/T cell lymphomas, and alveolar rhabdomyosarcomas were negative. In the sinonasal SRBCT differential diagnosis, NKX2.2 is a useful and very sensitive marker for Ewing sarcoma, including the treacherous adamantinoma-like variant. At the same time, it is not entirely specific, as it will be positive in a subset of other neuroendocrine/neuroectodermal tumors. As a result, NKX2.2 must be utilized as part of an immunohistochemical panel with other markers, especially cytokeratins, melanoma markers, and CD99. PMID- 28616786 TI - Laryngotracheal Involvement in Systemic Light Chain Amyloidosis. AB - Laryngotracheal amyloid deposition is an uncommon manifestation of systemic light chain amyloidosis. Diagnostic imaging, such as CT, is useful for suggesting the possibility of amyloidosis and delineating the extent of the lesions for surgical management; however, the diagnosis is confirmed with the histologic finding of amorphous eosinophilic material which stains positively for Congo red and may show apple green birefringence on polarization. These features are exemplified in this sine qua non radiology-pathology correlation article. PMID- 28616787 TI - Subtle radiographic signs of hamate body fracture: a diagnosis not to miss in the emergency department. AB - Hamate fractures are estimated to represent 1.7% of all carpal fractures and can occur at the hamulus (hook) or hamate body depending on mechanism of injury. Fractures of the hamate body can be exceedingly difficult to identify on standard wrist and hand radiographs in the emergency department. If the diagnosis is missed in the emergency department, orthopedic referral is often delayed. This can result in lasting functional disability for the patient, as these fractures have a propensity to destabilize the fourth and fifth carpometacarpal (CMC) joints. In this pictorial essay, we present six radiographic signs indicative of hamate body fracture with computed tomography (CT) imaging correlation. Injury mechanism and fracture classification schemes are portrayed to aid in the understanding of these injuries. Once radiographs raise suspicion for a hamate body fracture, further characterization with CT and orthopedic referral is paramount. Goals of orthopedic management include reestablishment of the fourth and fifth CMC articular surface, stabilization of the CMC joints, and appropriate treatment of concomitant soft tissue injury. PMID- 28616788 TI - Core curriculum case illustration: cardiac tamponade complicating proximal aortic dissection. AB - This is the 39th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at http://www.erad.org/page/CCIP_TOC . PMID- 28616789 TI - Core curriculum illustration: "Colles," dorsally angulated fracture of the distal radius. AB - This is the 41st installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.erad.org/page/CCIP_TOC . PMID- 28616790 TI - Serological survey for Brucella antibodies in donkeys of north-eastern Nigeria. AB - A cross-sectional epidemiological study was conducted to determine seroprevalence and risk factors influencing the presence of Brucella antibodies in donkeys of Borno State, north-eastern Nigeria. The study aimed at providing baseline information that may be used in planning a control policy against equine brucellosis. Blood samples were collected from 601 donkeys, comprised of 374 males and 227 females from the six agricultural zones of the state between March 2013 and September 2014. The sera obtained were tested for Brucella antibodies using Rose Bengal plate test (RBPT) and competitive enzyme-linked immunosorbent assay (cELISA). Of the 601 donkeys tested, 43 (7.2%) and 40 (6.7%) were seropositive by RBPT and cELISA, respectively. A seroprevalence of 8.6% was obtained in male and 3.5% in female donkeys. According to age, the highest seroprevalence of 9.6% was obtained from donkeys of age group 4-6 years. With respect to pregnancy status, a higher seroprevalence (6.8%) was obtained from pregnant donkeys compared to 3.8% obtained from the non-pregnant ones. There were statistically significant associations between the presence of antibodies and sex (p < 0.05) and the presence of antibodies and age (p < 0.05) of the studied donkeys. However, no statistically significant association (p > 0.05) was observed between the pregnancy status and presence of antibodies. The study concludes that Brucella infection is present in donkeys in all the agricultural zones of the state. The relatively high seroprevalence (7.2%) obtained is of public health concern because of the close interaction between donkeys, ruminants, and humans in the study area. PMID- 28616791 TI - The Delorme technique in colostomy prolapse. PMID- 28616792 TI - The use of carbon dioxide insufflation to facilitate identification of intestinal injuries in patients undergoing cytoreductive surgery and intraperitoneal chemotherapy. PMID- 28616793 TI - Pelvic exenteration with en bloc resection of the pelvic sidewall and intraoperative electron beam radiotherapy with Mobetron(r) for locally advanced rectal cancer. PMID- 28616794 TI - Long-term survival after multidisciplinary therapy for residual gallbladder cancer with peritoneal dissemination: a case report. AB - BACKGROUND: Although surgical resection is the only curative treatment for gallbladder cancer (GBC), concomitant peritoneal dissemination is considered far beyond the scope of resection. We report a long-term survivor with a residual GBC with multiple peritoneal disseminations who underwent an extended resection after effective chemotherapy. CASE PRESENTATION: A 59-year-old male underwent an open cholecystectomy for Mirizzi syndrome at a local hospital. Because of severe inflammation, the gallbladder was perforated during surgery, ending in a piecemeal resection. A pathological examination revealed GBC with positive margins, and the patient was referred to our hospital 1 month after surgery for further treatment. A multidetector-row computed tomography (MDCT) showed three hypoattenuated tumours: a tumour (3.9 cm) at the left medial segment corresponding to the gallbladder bed, a tumour (1.8 cm) around the hepatic flexure of the transverse colon, and a tumour (1.0 cm) at the stump of the cystic duct. Percutaneous needle biopsy was performed, which provided histologic evidence of adenocarcinoma. Thus, the patient had a rapidly progressive local relapse with limited peritoneal dissemination, labelled ycT3N0M1, stage IVB disease according to the UICC system. After the administration of 3 cycles of gemcitabine plus cisplatin combination chemotherapy, the size of all tumours and the CA19-9 level decreased significantly. Since the patient's general condition and liver function reserve were satisfactory, we decided the initial unresectable scenario to perform surgical therapy. After portal vein embolization, right hepatectomy, resection of the extrahepatic bile duct, partial duodenectomy, and partial colectomy were performed. Operative time was 555 min, and intraoperative blood loss was 1654 mL. Pathologic diagnosis of residual gallbladder carcinoma with peritoneal dissemination was confirmed, and the surgical margins were tumour free. The patient was discharged on postoperative day 29, with a Clavien-Dindo IIIa complication (abdominal wall abscess). Postoperative adjuvant chemotherapy with tegafur/gimeracil/oteracil was administered during 1 year after surgery. The patient is doing well 6 years after the second surgery without evidence of disease. CONCLUSIONS: Although specific clinical factors were associated with a favourable outcome in this patient, the present report suggests that multidisciplinary therapy may be a promising option in selected patients with distant metastatic GBC. PMID- 28616795 TI - Perspective. PMID- 28616796 TI - Comparison of surgeon comfort assessment during phacoemulsification using bilateral topical anesthesia versus ipsilateral topical anesthesia: a randomized controlled study. AB - AIM: To evaluate the effectiveness of bilateral use of topical anesthetic eye drops during phacoemulsification procedure as compared to use in one eye only. METHODS: This is a prospective double-blind randomized case study of 180 cases undergoing phacoemulsification under topical anesthesia using 0.5% proparacaine: Group 1 consisting of patients who had topical anesthetic eye drop instilled into the operating eye only and Group 2 consisting of patients who had both their eyes anesthetized using topical anesthetic eye drops. Phacoemulsification was done using standard surgical technique. Main parameters evaluated included number of intra-operative patient counseling score (IPCS), surgical comfort score (SCS), total phacoemulsification procedure time (TPPT) and total operation time (TOPT). RESULTS: A comparison of mean value of various variables between Group 1 (60; 33.3% cases) and Group 2 (120; 66.7% cases) using "t" test revealed that there was a statistically significant difference for mean SCS (78.38 +/- 10.31 vs. 85.05 +/- 8.70; p = 0.00), mean IPCS (12.60 +/- 3.11 vs. 6.63 +/- 1.74; p = 0.00) and mean TOPT (418.88 +/- 89.59 vs. 341.64 +/- 79.51; p = 0.00), respectively. However, no statistically significant difference existed for mean TPPT (143.57 +/ 87.96 vs. 152.96 +/- 78.99; p = 0.48). CONCLUSION: Simultaneous instillation of topical anesthetic eye drops in both the eyes, i.e., operating eye and the fellow eye as against practice of instilling topical anesthetic eye drop in the operating eye only, helps in decreasing the total surgical time by primarily shortening the durations of pre- and post-ultrasonic periods of surgery where effective globe stabilization is wanted. This is achieved by better patient compliance, which in turn enhances surgeon's comfort during phacoemulsification surgery. PMID- 28616797 TI - The efficacy and safety of bimatoprost/timolol maleate, latanoprost/timolol maleate, and travoprost/timolol maleate fixed combinations on 24-h IOP. AB - PURPOSE: To evaluate the effect of bimatoprost/timolol maleate fixed combination (BTFC), latanoprost/timolol maleate fixed combination (LTFC), and travoprost/timolol maleate fixed combination (TTFC) on 24-h intraocular pressure (IOP) in patients with open-angle glaucoma. METHODS: This prospective, observer masked, randomized study included 50 patients with primary open-angle glaucoma. All patients were using hypotensive lipids and timolol maleate fixed combination treatment for >=4 weeks and had an IOP <= 21 mmHg. Group 1 (n = 18) received BTFC, group 2 (n = 14) received LTFC, and group 3 (n = 18) received TTFC. All patients were hospitalized, and IOP was monitored for 24-h (10:00, 14:00, 18:00, 22:00, 02:00, and 06:00). Mean diurnal IOP variation measurements were taken between 06:00 and 18:00, and mean nocturnal IOP variation measurements were taken between 22:00 and 02:00. Mean IOP and IOP variation in the three groups were compared. RESULTS: Mean 24-h IOP did not differ significantly between the three groups (group 1: 14.6 +/- 2.9 mmHg; group 2: 14.1 +/- 3.7 mmHg and group 3: 15.8 +/- 2.0 mmHg; P > 0.05). Mean diurnal IOP variation was 4.6 +/- 2.3 mmHg in group 1, 5.8 +/- 2.4 mmHg in group 2, and 4.3 +/- 1.7 mmHg in group 3, and mean nocturnal IOP variation was 3.2 +/- 2.8 mmHg in group 1, 2.9 +/- 1.9 mmHg in group 2, and 3.0 +/- 1.6 mmHg group 3. There were not any significant differences in diurnal or nocturnal IOP variation between the three groups (P < 0.05). CONCLUSION: All three fixed combinations effectively controlled IOP for 24-h and had a similar effect on diurnal and nocturnal IOP variations. PMID- 28616798 TI - Postoperative diffuse opacification of a hydrophilic acrylic intraocular lens: analysis of an explant. AB - PURPOSE: We describe the clinicopathological and ultrastructural features of an opaque single-piece hydrophilic acrylic intraocular lens (IOL) explanted from a patient. METHOD: The main outcome of this report is the documentation of calcium deposits confirmed by surface analysis. The decrease in visual acuity was due to the opacification of the IOL. The opacification involved both the optic plate and the haptics. RESULTS: The analysis at the scansion electron microscope revealed that the opacity was caused by the deposition of calcium and phosphate within the lens optic and haptics. CONCLUSION: This is the first case about the opacification of an Oculentis L-313. The opacification was characterized by calcium and phosphate deposition probably due to a morphological alteration of the posterior surface of the IOL. PMID- 28616800 TI - Assessing LV remodeling in nuclear cardiology. PMID- 28616799 TI - Dolichol phosphate mannose synthase: a Glycosyltransferase with Unity in molecular diversities. AB - N-glycans provide structural and functional stability to asparagine-linked (N linked) glycoproteins, and add flexibility. Glycan biosynthesis is elaborative, multi-compartmental and involves many glycosyltransferases. Failure to assemble N glycans leads to phenotypic changes developing infection, cancer, congenital disorders of glycosylation (CDGs) among others. Biosynthesis of N-glycans begins at the endoplasmic reticulum (ER) with the assembly of dolichol-linked tetra decasaccharide (Glc3Man9GlcNAc2-PP-Dol) where dolichol phosphate mannose synthase (DPMS) plays a central role. DPMS is also essential for GPI anchor biosynthesis as well as for O- and C-mannosylation of proteins in yeast and in mammalian cells. DPMS has been purified from several sources and its gene has been cloned from 39 species (e.g., from protozoan parasite to human). It is an inverting GT-A folded enzyme and classified as GT2 by CAZy (carbohydrate active enZyme; http://www.cazy.org ). The sequence alignment detects the presence of a metal binding DAD signature in DPMS from all 39 species but finds cAMP-dependent protein phosphorylation motif (PKA motif) in only 38 species. DPMS also has hydrophobic region(s). Hydropathy analysis of amino acid sequences from bovine, human, S. crevisiae and A. thaliana DPMS show PKA motif is present between the hydrophobic domains. The location of PKA motif as well as the hydrophobic domain(s) in the DPMS sequence vary from species to species. For example, the domain(s) could be located at the center or more towards the C-terminus. Irrespective of their catalytic similarity, the DNA sequence, the amino acid identity, and the lack of a stretch of hydrophobic amino acid residues at the C terminus, DPMS is still classified as Type I and Type II enzyme. Because of an apparent bio-sensing ability, extracellular signaling and microenvironment regulate DPMS catalytic activity. In this review, we highlight some important features and the molecular diversities of DPMS. PMID- 28616801 TI - Life Course Perspectives on the Onset and Continuity of Preventive Healthcare Behaviors. AB - Preventive healthcare is considered a cornerstone of good health and well-being that can play a major role in reducing a country's healthcare costs and improving both the length and quality of people's lives. Previous research on preventive healthcare behaviors has been predominantly cross-sectional, ignoring the dynamic nature of people's health behaviors over a full life span. As a result, the reasons for the development, stability, and changes of individuals' preventive healthcare behaviors over time remain relatively unknown. Our article contends that to understand the degree of people's engagement in preventive healthcare behaviors, we must understand the origins, continuity, and discontinuity of such behaviors. We offer the life course paradigm as a viable framework for studying preventive healthcare behaviors at different stages in life. Based on theory and previous research, our article proposes that the onset, continuity, and changes in preventive healthcare behaviors are the outcomes of physical, social, and emotional demands triggered by life events that require adaptation through the mechanisms of socialization, stress and coping, and human development. These mechanisms are the underlying change processes of the three main life course theoretical perspectives-normative, stress, and human capital, respectively. Our paper discusses implications of adopting the life course approach for theory and practice, and offers a research agenda in the form of general propositions and conceptual directions for future research. PMID- 28616802 TI - Comparison of Two Amplitude-Integrated Electroencephalography (aEEG) Monitors in Term Neonates. PMID- 28616804 TI - Hypoglycemic Event Frequency and the Effect of Continuous Glucose Monitoring in Adults with Type 1 Diabetes Using Multiple Daily Insulin Injections. AB - INTRODUCTION: The benefits of continuous glucose monitoring (CGM) in type 1 diabetes have been established among adults using insulin pumps. The DIAMOND randomized clinical trial examined the effectiveness of using CGM in improving glycemic control in participants using insulin injections. The frequency of hypoglycemic events in this trial has not been previously examined. METHODS: Adults with type 1 diabetes using multiple daily insulin injections (MDI) with A1C values of 7.5% to 9.9% and not using CGM were randomized to adopt CGM (CGM group, n = 105) or continue with usual care (control group, n = 53). CGM data were collected from both groups at the beginning of the study and after 3 and 6 months. A hypoglycemic event was defined as a series of at least CGM values less than 3.0 mmol/L, separated by 20 min or more, with no intervening values of 3.0 mmol/L or more. Hypoglycemic event rates per 24 h were compared using a linear model adjusted for the baseline event rate per 24 h, baseline A1C, and site as a random effect. RESULTS: In the CGM group, the median hypoglycemic event rate fell by 30% (0.23 per 24 h at baseline and 0.16 per 24 h at follow-up) while in the control group the rate was nearly unchanged (0.31 per 24 h at baseline and 0.30 per 24 h at follow-up; p value = 0.03). CONCLUSION: In the DIAMOND randomized controlled trial, participants in the CGM group experienced a greater reduction in hypoglycemic event rate than participants receiving usual care in the control group. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02282397. PMID- 28616803 TI - Amitriptyline May Have Possibility to Induce Brugada Syndrome Rather than Long QT Syndrome. AB - Amitriptyline has been reported to induce long QT syndrome in addition to Brugada syndrome. We qualitatively and quantitatively analyzed the potential of amitriptyline to induce these lethal syndromes by using the halothane anesthetized dogs (n = 6). Amitriptyline was intravenously administered in doses of 0.1, 1 and 10 mg/kg over 10 min every 20 min, which would provide approximately 1, 10 and 100 times higher plasma concentrations than a therapeutic one, respectively. The low dose hardly altered any of the cardiovascular variables. The middle dose increased the heart rate, cardiac output and left ventricular contractility, but decreased the total peripheral vascular resistance and left ventricular end-diastolic pressure, whereas it did not alter any of the electrocardiographic variables. The high dose decreased the mean blood pressure and left ventricular contractility; suppressed atrioventricular nodal and intraventricular conduction; shortened the repolarization period without altering the J-T peak c and T peak-T end; and prolonged the effective refractory period, providing post-repolarization refractoriness in addition to the enhancement of the middle dose-induced cardiovascular effects. Thus, amitriptyline at up to 100 times its therapeutic concentration may not be associated with the onset of long QT syndrome, but may induce Brugada syndrome. PMID- 28616805 TI - Effects of Insulin Plus Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in Treating Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) has already been proven an efficient treatment option for type 2 diabetes. This combination can effectively improve glycated hemoglobin levels, cause weight loss and reduce the dosage of insulin. In addition, it can also reduce the risk of hypoglycemia. Several randomized controlled trials have confirmed that this treatment may be just as effective for type 1 diabetes mellitus (T1DM) patients. The objective of this meta-analysis was to assess the effects and efficacy of the treatment on glycemic changes, weight loss and insulin dosage in type 1 diabetes mellitus patients. METHODS: We searched Embase, PubMed and Cochrane for randomized controlled trials (no time restrictions) that investigated combined insulin and GLP-1 treatment. The main endpoints were measurements of glycated hemoglobin and changes in the weight and the dosage of insulin. RESULTS: In total, 1093 were studies identified, and 7 studies were included in our meta-analysis. GLP-1 agonist and insulin combination therapy led to greater reductions in HbA1c levels [P = 0.03; mean difference 0.21; 95% confidence intervals (CI) (-0.40, 0.02)] and weight [P < 0.05; -3.53 ( 4.86, 2.19)] compared to control treatments. The combination therapy did not significantly influence the daily weight-adjusted total insulin dose [P = 0.05; 0.11 (-0.23, 0)], but it did reduce the daily weight-adjusted bolus insulin dose [P = 0.001; -0.06 (-0.1, 0.02)]. CONCLUSION: Our meta-analysis supports the use of a combined therapeutic regimen of insulin and GLP-1RAs for treating patients with T1DM. Combination therapy with GLP-1 and insulin could achieve an ideal treatment effect on glycemic control, weight loss and bolus insulin dose in patients with T1DM. PMID- 28616807 TI - Skin Deep: Enhanced Variable May Help Explain Racial Disparities in Type 2 Diabetes and Prediabetes. AB - INTRODUCTION: The study refined definitions of type 2 diabetes and prediabetes (Pre-/T2D) via its four-category outcome variable. Respondents were identified as Pre-/T2D on the basis of (a) doctor's diagnosis only (i.e., managed Pre-/T2D); (b) biomarker only (i.e., undiagnosed Pre-/T2D); or (c) both diagnosis and biomarker (i.e., unmanaged Pre-/T2D). The reference was Pre-/T2D not indicated. We linked the outcome to social structural and social support factors, health care-related factors, mental disorder, and lifestyle variables, for each racial/ethnic group. METHODS: We used the 2011-2012 and 2013-2014 National Health and Nutrition Examination Surveys to measure the four-category outcome and examine race/ethnicity's role in explaining the outcome. RESULTS: We found Pre /T2D to be associated with age, BMI, physical activity, income, education, receiving health services, and other factors. A moderating role for race/ethnicity was also confirmed. CONCLUSION: The racial disparities observed in our three main categories generally resulted from high levels of undiagnosed Pre /T2D and high levels of diagnosed but unmanaged Pre-T2D. Race/ethnicity's moderating role generally indicated that, through the factors BMI, age, and receiving health services, minority status (with its attendant disadvantages) could facilitate undiagnosed Pre-/T2D as well as Pre-/T2D indicated concurrently by diagnosis and biomarker. PMID- 28616806 TI - Ipragliflozin Reduces Epicardial Fat Accumulation in Non-Obese Type 2 Diabetic Patients with Visceral Obesity: A Pilot Study. AB - INTRODUCTION: Epicardial fat (EF) was reported to be independently associated with cardiovascular disease regardless of obesity. We have previously reported that a sodium-glucose co-transporter-2 (SGLT2) inhibitor, luseogliflozin, reduces the EF volume (EFV) in parallel with the reduction of body weight in obese patients (BMI >=25 kg/m2) with type 2 diabetes. However, it is unknown whether SGLT2 inhibitors could reduce EFV in non-obese patients (BMI <25 kg/m2) with type 2 diabetes. Therefore, we evaluated the effect of SGLT2 inhibitors on the EFV in non-obese type 2 diabetic patients with visceral obesity in this pilot study. METHODS: Nine of type 2 diabetic patients (mean age 66 +/- 8 years; 33% female) with HbA1c 6.5-9.0%, body mass index (BMI, kg/m2) <25.0, and visceral fat area (VFA, cm2) >=100 were enrolled. Participants were administered ipragliflozin 50 mg daily. EFV [median (interquartile range), cm3] was measured by magnetic resonance imaging. Primary endpoint was the change in EFV at 12 weeks. VFA and liver attenuation index (LAI), skeletal muscle index (SMI), and body fat (%) were also assessed at baseline and at 12 weeks. RESULTS: The EFV was significantly reduced from 102 (79-126) cm3 to 89 (66-109) cm3 by ipraglifrozin (p = 0.008). The body weight, BMI, HbA1c, fasting plasma glucose, insulin, homeostasis model assessment-insulin resistance, triglycerides, leptin, body fat, android, gynoid, and VFA were significantly reduced and high-density lipoprotein cholesterol was significantly increased by ipraglifrozin at 12 weeks, whereas SFA and LAI were unchanged. The change in EFV was significantly correlated with the change in BMI. CONCLUSIONS: A12-week intervention of ipragliflozin reduced the EFV in non-obese type 2 diabetic patients with visceral adiposity. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trial Registry: UMIN000019071. FUNDING: Astellas Pharma Inc. and the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. PMID- 28616808 TI - Crop 3D-a LiDAR based platform for 3D high-throughput crop phenotyping. AB - With the growing population and the reducing arable land, breeding has been considered as an effective way to solve the food crisis. As an important part in breeding, high-throughput phenotyping can accelerate the breeding process effectively. Light detection and ranging (LiDAR) is an active remote sensing technology that is capable of acquiring three-dimensional (3D) data accurately, and has a great potential in crop phenotyping. Given that crop phenotyping based on LiDAR technology is not common in China, we developed a high-throughput crop phenotyping platform, named Crop 3D, which integrated LiDAR sensor, high resolution camera, thermal camera and hyperspectral imager. Compared with traditional crop phenotyping techniques, Crop 3D can acquire multi-source phenotypic data in the whole crop growing period and extract plant height, plant width, leaf length, leaf width, leaf area, leaf inclination angle and other parameters for plant biology and genomics analysis. In this paper, we described the designs, functions and testing results of the Crop 3D platform, and briefly discussed the potential applications and future development of the platform in phenotyping. We concluded that platforms integrating LiDAR and traditional remote sensing techniques might be the future trend of crop high-throughput phenotyping. PMID- 28616809 TI - Cooperative strategy for a dynamic ensemble of classification models in clinical applications: the case of MRI vertebral compression fractures. AB - PURPOSE: In clinical practice, the constructive consultation among experts improves the reliability of the diagnosis and leads to the definition of the treatment plan for the patient. Aggregation of the different opinions collected by many experts can be performed at the level of patient information, abnormality delineation, or final assessment. METHODS: In this study, we present a novel cooperative strategy that exploits the dynamic contribution of the classification models composing the ensemble to make the final class assignment. As a proof of concept, we applied the proposed approach to the assessment of malignant infiltration in 103 vertebral compression fractures in magnetic resonance images. RESULTS: The results obtained with repeated random subsampling and receiver operating characteristic analysis indicate that the cooperative system statistically improved ([Formula: see text]) the classification accuracy of individual modules as well as of that based on the manual segmentation of the fractures provided by the experts. CONCLUSIONS: The performances have been also compared with those obtained with those of standard ensemble classification algorithms showing superior results. PMID- 28616810 TI - Accuracy of non-contrast PMCT for determining cause of death. AB - The aim of this study was (1) to compare levels of accuracy regarding the categorization of causes of death between non-contrast post-mortem computed tomography (PMCT) and the final forensic report as well as between autopsy and the final forensic report, and (2) to assess levels of confidence regarding the categorization of causes of death after non-contrast PMCT and after autopsy. This prospective study was conducted over a 5 month period during which 221 cases were admitted to our institute for forensic investigations. Whole-body PMCT and forensic autopsy were performed in every case. Of these, 101 cases were included in the final study population. Inclusion criteria were: (1) age > 18 years, (2) presence of at least one of the two principal investigators at the time of admission. One radiologist and one forensic pathologist independently read all PMCT datasets using a report template. Cause of death category and confidence levels were determined by consensus. Forensic autopsy was performed by two forensic pathologists; both unblinded to imaging results. Both post-imaging and post-autopsy cause of death categorization were compared against the final cause of death, as stated in the forensic expert report, which included findings from histology and/or toxicology. Accuracy of post-imaging cause of death categorization in reference to the final cause of death category was substantial (82%, 83/101 cases, Kappa 0.752). Accuracy of post-autopsy cause of death categorization in reference to the final cause of death category was near perfect (89%, 90/101 cases, Kappa 0.852). Post-imaging sensitivity and specificity regarding the categorization of causes of death were 82% and 97%, respectively. Post-autopsy sensitivity and specificity regarding the categorization of causes of death were 89% and 98%, respectively. There was a high consistency between the accuracy of post-imaging cause of death categorization and post-imaging levels of confidence. There was less consistency between accuracy of post-autopsy cause of death categorization and post-autopsy levels of confidence. In this study categorization of causes of death based on non-contrast enhanced PMCT alone, and on PMCT and macroscopic autopsy together, proved to be consistent with the final cause of death-category as determined based on all available information including PMCT, autopsy, and (if available) histology and/or toxicology in more than 82% and 89% of all cases, respectively. There was higher consistency between levels of confidence and accuracy of causes of death categorization was higher post-imaging than post-autopsy. These results underline the fact that the diagnostic potential of PMCT goes beyond the assessment of trauma cases. PMID- 28616811 TI - Black cracks: staining of fracture lines. AB - During the investigation of fresh bone fractures, it might be difficult to visualize all the fracture lines that could contribute to the interpretation of the biomechanics behind a fracture. To optimize the examination of the fracture, the bones should first be defleshed to expose the osseous surface. To reveal small fracture lines more clearly, we developed two easy, fast, cheap and non destructive methods to enhance fracture lines and bone defects by coloring the fracture lines with ink. One method consists of cooking the bone in ink, and the second method uses capillary action for ink penetration. We strongly recommend the use of the latter method with Talens(r) Black Indian Ink for the clearest results. PMID- 28616812 TI - Biventricular noncompaction cardiomyopathy with malignant arrhythmia as a cause of sudden death. PMID- 28616813 TI - [Contributions to the thematic focal point from section III ( Social- and behavioural Gerontology) of the German Society of Gerontology and Geriatrics (DGGG) ]. PMID- 28616814 TI - [Considering diversity in nursing and palliative care - the example of migrants]. AB - Our society is characterized by increasing diversity. Immigrants greatly contribute to this diversification. Currently, one fifth of the population in Germany is considered to be of immigrant origin. Healthcare needs of immigrants are often not sufficiently taken into account by healthcare institutions. This may result in many barriers encountered by immigrants in the healthcare system, which may affect the utilization and quality of care. These barriers are particularly pronounced in nursing and palliative care. Current strategies aiming to reduce these barriers are limited as they often only focus on culture and religion, thereby neglecting the role of other diversity dimensions, such as sex and socioeconomic status. Diversity management is able to overcome these shortcomings by implementing conditions in healthcare institutions which promote awareness and openness towards the diversity of healthcare clients. This can improve the quality of care and can contribute to patient-oriented healthcare. PMID- 28616815 TI - [Prevention of nosocomial infections and antibiotic resistance in nursing homes]. AB - BACKGROUND: Nosocomial infections and multidrug-resistant organisms are an increasing problem in nursing homes worldwide; therefore, new approaches for infection control need to be developed. OBJECTIVES: This article gives an overview of infections in nursing homes, their medical treatment and previous measures for infection prevention. MATERIALS AND METHODS: The article is based on a selective literature search including the literature database PubMed. In particular, scientific studies on the prevalence of nosocomial infections in German nursing homes, publications for medical care in long-term care facilities in Europe and international studies for infection prevention were evaluated. RESULTS: The basis for an effective reduction of infections is the establishment of a surveillance system. All participating medical professionals provide feedback about local infections and resistance situations and the presence of risk factors, such as urinary catheters or chronic wounds. Only then can targeted antibiotic strategies be adapted and the effectiveness of preventive measures, such as hand disinfection is continuously reviewed. So far, in particular multimodal, multidisciplinary prevention projects were successful. These included frequent staff training, reduction of urinary catheters and a rational use of antibiotics. CONCLUSIONS: Most prevention models have been previously tested in hospitals. A possible applicability of the results to the infection prevention in long-term care facilities has so far hardly been studied. Accordingly, further studies on infection control in nursing homes are absolutely necessary. PMID- 28616817 TI - [The four dimensions for positive aging: the multifarious resources of elderly people]. PMID- 28616816 TI - Access to community care for people with dementia and their informal carers : Case vignettes for a European comparison of structures and common pathways to formal care. AB - BACKGROUND: People with dementia and their informal carers often do not receive appropriate professional support or it is not received at the right time. OBJECTIVES: Description and comparison of common pathways to formal community dementia care in eight European countries as a part of the transnational Actifcare project. MATERIALS AND METHODS: The German team was responsible for creating an individual case scenario as a starting point. The research teams in Ireland, Italy, the Netherlands, Norway, Portugal, Sweden, and the United Kingdom were then asked to describe a common pathway to formal dementia care by writing their own vignette using the provided individual case scenario. RESULTS: A transnational qualitative content analysis was used to identify the following categories as being the most important: involved professionals, dementia-specific and team-based approaches, proactive roles, and financial aspects. General practitioners (GPs) are described as being the most important profession supporting the access to formal care in all the involved countries. In some countries other professionals take over responsibility for the access procedure. Dementia-specific approaches are rarely part of standard care; team-based approaches have differing significances in each of the countries. Informal carers are mainly proactive in seeking formal care. The Nordic countries demonstrate how financial support enhances access to the professional system. CONCLUSION: Enhanced cooperation between GPs and other professions might optimize access to formal dementia care. Team-based approaches focusing on dementia care should be developed further. Informal carers should be supported and relieved in their role. Financial barriers remain which should be further investigated and reduced. PMID- 28616818 TI - Fosfomycin for the treatment of drug-resistant urinary tract infections: potential of an old drug not explored fully. AB - INTRODUCTION: Increased emergence of bacterial resistance and the limited options of novel antimicrobial agents have necessitated the reintroduction of some old antimicrobial agents. One such drug is fosfomycin, but its potential has not been explored fully, especially in India. AIMS AND OBJECTIVES: To analyze the in vitro activity of fosfomycin, against the urinary isolates and to compare it with in vitro activity of other orally administered antimicrobial agents. MATERIALS AND METHODS: This was a prospective observational study conducted between July 2014 and June 2016. All consecutive, non-duplicate and clinically significant urinary isolates obtained from patients of all ages and both genders, diagnosed to have UTI, were included. Patients already on antibiotic therapy were excluded. Urine culture was performed by semiquantitative method on cysteine lactose electrolyte deficient medium and the isolates obtained in significant count were subjected to antimicrobial sensitivity testing by the Kirby Bauer disk diffusion method as per CLSI guidelines. RESULTS: A total of 3947 non-repeating urinary isolates were included in the study, of which 2684 (68%) isolates originated from adult outpatients and remaining 1236 (32%) isolates from pediatric patients. Of these 2783 isolates were from enterobacteriaceae family. Out of these 2730 (98.1%) were sensitive to fosfomycin. Most [375 of 385 (97.4%)] Pseudomonas spp were also susceptible to fosfomycin. A majority of ESBL- (96.5%) and MBL (91.9%)-producing isolates were also susceptible to fosfomycin and so were of Gram-positive isolates [698/707 (96%)] and MRSA [61/69 (88.4%)] were susceptible to fosfomycin. CONCLUSIONS: Fosfomycin showed an excellent in vitro activity against all urinary pathogens, including the Gram-positive or Gram-negative, ESBL and MBL producers. Fosfomycin should be considered as a highly effective alternative in treatment UTIs in both adults and pediatric patients. PMID- 28616819 TI - "Safe Foods" or "Fear Foods": the implications of food avoidance in college students from low- and middle-income countries. AB - PURPOSE: The primary objective of this study was to explore if self-reported food avoidance (fats, carbohydrates and protein) exists among college students in low- and middle-income countries (LMICs) and its relationship with body mass index (BMI), dieting, mood/anxiety symptoms, physical activities and general health knowledge. METHODS: This study is a subset (N = 6096) of a larger 26 LMICs cross sectional survey, which consisted of 21,007 college students. We ascertained socio-demographic information, food avoidance, physical activities, dieting behaviours, depressive and PTSD symptoms, and recorded anthropometric measurements. Chi-square analyses assessed the relationship between predictor variables and food categories eliminated from participants' diet. Multiple logistic regression assessed if food avoidance predicts outcome variables such as binge drinking, high physical activity, being underweight, exhibiting significant depressive and PTSD symptoms. RESULTS: Food avoidance exists in as many as one third of college students in low- and middle-income countries, with this being more likely in persons who are trying to lose weight whether by dieting or otherwise. Food avoidance was associated with higher BMI, depressive symptoms, and high intensity exercises, as well as the level of health knowledge influencing the types of food avoided. A significant difference was noted between lower middle-income and upper middle-income countries with respect to the foods they avoided. CONCLUSION: Despite being knowledgeable about health-related behaviours, we found that college students in our sample were not that different from those in developed countries and may be influenced by a similar advice given by non-experts about macronutrients. These results hold implications for intervention programmes and policy makers. LEVEL OF EVIDENCE: Level V, descriptive cross-sectional survey. PMID- 28616820 TI - Possible involvement of central oxytocin in cisplatin-induced anorexia in rats. AB - During cancer chemotherapy, drugs such as 5-HT3 receptor antagonists have typically been used to control vomiting and anorexia. We examined the effects of oxytocin (OXT), which has been linked to appetite, on cisplatin-induced anorexia in rats. Fos-like immunoreactivity (Fos-LI) expressed in the supraoptic nucleus (SON), the paraventricular nucleus (PVN), the area postrema and the nucleus of the solitary tract (NTS) after intraperitoneal (ip) administration of cisplatin. We also examined the fluorescence intensity of OXT-mRFP1 after ip administration of cisplatin in OXT-mRFP1 transgenic rats. The mRFP1 fluorescence intensity was significantly increased in the SON, the PVN, and the NTS after administration of cisplatin. The cisplatin-induced anorexia was abolished by OXT receptor antagonist (OXTR-A) pretreatment. In the OXT-LI cells, cisplatin-induced Fos expression in the SON and the PVN was also suppressed by OXTR-A pretreatment. These results suggested that central OXT may be involved in cisplatin-induced anorexia in rats. PMID- 28616821 TI - Re-irradiation after gross total resection of recurrent glioblastoma : Spatial pattern of recurrence and a review of the literature as a basis for target volume definition. AB - BACKGROUND: Currently, patients with gross total resection (GTR) of recurrent glioblastoma (rGBM) undergo adjuvant chemotherapy or are followed up until progression. Re-irradiation, as one of the most effective treatments in macroscopic rGBM, is withheld in this situation, as uncertainties about the pattern of re-recurrence, the target volume, and also the efficacy of early re irradiation after GTR exist. METHODS: Imaging and clinical data from 26 consecutive patients with GTR of rGBM were analyzed. The spatial pattern of recurrences was analyzed according to the RANO-HGG criteria ("response assessment in neuro-oncology criteria for high-grade gliomas"). Progression-free (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Furthermore, a systematic review was performed in PubMed. RESULTS: All but 4 patients underwent adjuvant chemotherapy after GTR. Progression was diagnosed in 20 of 26 patients and 70% of recurrent tumors occurred adjacent to the resection cavity. The median extension beyond the edge of the resection cavity was 20 mm. Median PFS was 6 months; OS was 12.8 months. We propose a target volume containing the resection cavity and every contrast enhancing lesion as the gross tumor volume (GTV), a spherical margin of 5-10 mm to generate the clinical target volume (CTV), and a margin of 1-3 mm to generate the planning target volume (PTV). Re-irradiation of this volume is deemed to be safe and likely to prolong PFS. CONCLUSION: Re irradiation is worth considering also after GTR, as the volumes that need to be treated are limited and re-irradiation has already proven to be a safe treatment option in general. The strategy of early re-irradiation is currently being tested within the GlioCave/NOA 17/Aro 2016/03 trial. PMID- 28616823 TI - Population Pharmacokinetics of Combined Intravenous and Local Intrathecal Administration of Meropenem in Aneurysm Patients with Suspected Intracranial Infections After Craniotomy. AB - BACKGROUND AND OBJECTIVE: For patients with intracranial infection, local intrathecal administration of meropenem may be a useful method to obtain a sufficient drug concentration in the cerebral spinal fluid (CSF). However, a large inter-individual variability may pose treatment efficacy at risk. This study aimed to identify factors affecting drug concentration in the CSF using population pharmacokinetics method. METHODS: After craniotomy, aneurysm patients with an indwelling lumbar cistern drainage tube who received a combined intravenous and intrathecal administration of meropenem for the treatment of suspected intracranial infection were enrolled. Venous blood and CSF specimens were collected for determining meropenem concentrations. Nonlinear mixed-effects modeling method was used to fit blood and CSF concentrations simultaneously and to develop the population pharmacokinetic model. The proposed model was applied to simulate dosage regimens. RESULTS: A three-compartmental model was established to describe meropenem in vivo behavior. Lumbar CSF drainage resulted in a drug loss, and drug clearance in CSF (CLCSF) was employed to describe this. The covariate analysis found that the drainage volume (mL/day) was strongly associated with CLCSF, and the effect of creatinine clearance was significant on the clearance of meropenem in blood (CL). Visual predictive check suggested that the proposed pharmacokinetic model agreed well with the observations. Simulation showed that both intravenous and intrathecal doses should be increased with the increases of minimum inhibitory concentration and daily CSF drainage volume. CONCLUSION: This model incorporates covariates of the creatinine clearance and the drainage volume, and a simple to use dosage regimen table was created to guide clinicians with meropenem dosing. PMID- 28616822 TI - A comparison of swallowing dysfunction after three-dimensional conformal and intensity-modulated radiotherapy : A systematic review by the Italian Head and Neck Radiotherapy Study Group. AB - PURPOSE: Dysphagia is one of the most important treatment-related side effects in head and neck cancer (HNC), as it can lead to severe life-threating complications such as aspiration pneumonia and malnutrition. Intensity-modulated radiotherapy (IMRT) could reduce swallowing dysfunction by producing a concave dose distribution and reducing doses to the swallowing-related organs at risk (SWOARs). The aim of this study was to review the current literature in order to compare swallowing outcomes between IMRT and three-dimensional conformal radiotherapy (3DCRT). METHODS: A search was conducted in the PubMed and Embase databases to identify studies on swallowing outcomes, both clinically and/or instrumentally assessed, after 3DCRT and IMRT. Dysphagia-specific quality of life and objective instrumental data are summarized and discussed. RESULTS: A total of 262 papers were retrieved from the searched databases. An additional 23 papers were retrieved by hand-searching the reference lists. Ultimately, 22 papers were identified which discussed swallowing outcomes after 3DCRT and IMRT for HNC. No outcomes from randomized trials were identified. CONCLUSION: Despite several methodological limitations, reports from the current literature seem to suggest better swallowing outcomes with IMRT compared to 3DCRT. Further improvements are likely to result from the increased use of IMRT plans optimized for SWOAR sparing. PMID- 28616824 TI - Detecting and identifying offset gaze. AB - A number of experiments have demonstrated that observers can accurately identify stimuli that they fail to detect (Rollman and Nachmias, 1972; Harris and Fahle, 1995; Allik et al. 1982, 2014). Using a 2x2AFC double judgements procedure, we demonstrated an analogous pattern of performance in making judgements about the direction of eye gaze. Participants were shown two faces in succession: one with direct gaze and one with gaze offset to the left or right. We found that they could identify the direction of gaze offset (left/right) better than they could detect which face contained the offset gaze. A simple Thurstonian model, under which the detection judgement is shown to be more computationally complex, was found to explain the empirical data. A further experiment incorporated metacognitive ratings into the double judgements procedure to measure observers' metacognitive awareness (Meta-d') across the two judgements and to assess whether observers were aware of the evidence for offset gaze when detection performance was at and below threshold. Results suggest that metacognitive awareness is tied to performance, with approximately equal Meta-d' across the two judgements, when sensitivity is taken into account. These results show that both performance and metacognitive awareness rely not only on the strength of sensory evidence but also on the computational complexity of the decision, which determines the relative distance of that evidence from the decision axes. PMID- 28616825 TI - Correlation of cardio-metabolic parameters with vitamin D status in healthy premenopausal women. AB - PURPOSE: Vitamin D has been associated with metabolic disorders and increasing risk of cardiovascular diseases, with conflicting results. Aim of our study was to evaluate the relationship, if any, between cardio-metabolic risk factors and serum 25(OH)D concentrations in healthy women in premenopausal age. METHODS: We enrolled 200 healthy women, aged 19-50 years (mean age +/- SD, 38 +/- 11 years). In each subject, we measured serum 25(OH)D in relation to metabolic biomarkers and cardiovascular parameters. RESULTS: A status of vitamin D deficiency was found in 48% of the study population, while 38% showed levels higher than 30 ng/ml. Fasting glucose and insulin levels were significantly higher in subjects with vitamin D deficiency/insufficiency (P = 0.034 and P = 0.049, respectively) as well as HOMA-IR (P = 0.05). HDL cholesterol was significantly lower (P = 0.024) and intima-media thickness (IMT) higher (P = 0.014) in the vitamin D deficient/insufficient subjects. Moreover, serum 25(OH)D levels inversely correlated with insulin levels (P = 0.0001) and intima-media thickness (P = 0.015), and directly with serum HDL cholesterol (P = 0.010). At univariate regression analysis, the parameters that were significantly associated with vitamin D levels were insulin (P = 0.050), HDL cholesterol (P = 0.016), and intima-media thickness (P = 0.015). At multivariate analysis adjusted for age and BMI, vitamin D was still significantly associated with HDL cholesterol and intima media thickness. CONCLUSIONS: A positive association between vitamin D and HDL cholesterol was found in healthy women without any evidence of metabolic disorders, with a significant inverse correlation between vitamin D and IMT. These results suggest a possible protective role of 25(OH)D in cardiovascular disorders. PMID- 28616826 TI - Deposition of crystalline hydroxyapatite nano-particle on zirconia ceramic: a potential solution for the poor bonding characteristic of zirconia ceramics to resin cement. AB - The poor bonding strength of zirconia to different dental substrates is one of the challenging issues in restorative dentistry. Hydroxyapatite is an excellent biocompatible material with fine bonding properties. In this study, it was hypothesized that hydroxyapatite coating on zirconia would improve its bond strength. Forty-five zirconia blocks were prepared and randomly divided into three groups: hydroxyapatite coating, sandblasting, and no preparation (control). The blocks were bonded to cement and the micro-shear bond strength was measured following load application. The bond strength values were analyzed with the Kruskal-Wallis test in 3 groups and paired comparisons were made using the Mann Whitney U test. The failure patterns of the specimens were studied by a stereomicroscope and a scanning electron microscope and then analyzed by the chi square test (significance level = 0.05). Deposition of hydroxyapatite on the zirconia surface significantly improved its bond strength to the resin cement in comparison with the control specimens (p < 0.0001). Also, the bond strength was similar to the sandblasted group (p = 0.34). The sandblasted and control group only showed adhesive failure, but the hydroxyapatite coated group had mixed failures, indicating the better quality of bonding (p < 0.0001). As a final point, hydroxyapatite coating on the zirconia surface improved the bond strength quality and values. PMID- 28616828 TI - Perinatal and maternal outcomes at term in low-risk pregnancies according to NICE criteria: comparison between a tertiary obstetrical hospital and midwife-attended units. AB - PURPOSE: The aim of this study was to evaluate the perinatal and maternal outcomes at term at a single tertiary, university hospital in women with low-risk pregnancies. PATIENTS AND METHODS: We performed a retrospective cohort study of women with low-risk pregnancies, who delivered at University Women's Hospital Magdeburg between January 2010 and December 2014. Data were compared with data published by Brocklehurst et al. 2011. RESULTS: Of the 6052 women investigated, 2014 were classified as low risk according to the NICE criteria and were eligible for analysis. In 94.8%, a spontaneous vertex birth was observed. There were only 2 (0.1%) perinatal complications and 52 (2.5%) maternal complications. Ventouse delivery, forceps delivery, and caesarean sections were performed in 2.5, 1, and 3.1% of the cases, respectively. Episiotomy was performed in 37.7% of women. The third and fourth degree perineal trauma were observed in 0.3% of births investigated. Complications during the third stage of labour and blood transfusions were observed in 0.25 and 0.2%, respectively. In comparison with the births at home, we had lower rate of fetal complications for nulliparous women, but not for multiparous women, lower rate for blood transfusions, third and fourth degree perineal trauma and forceps delivery, and higher rate of spontaneous vertex birth, epidural analgesia, and episiotomy. The rate of vacuum extractions and caesarean sections were similar between both the places of birth. CONCLUSIONS: The tertiary-level obstetric unit is safe place of birth for women with low-risk pregnancies. PMID- 28616827 TI - Trastuzumab and survival of patients with metastatic breast cancer. AB - INTRODUCTION: Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. METHODS: All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. RESULTS: Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). CONCLUSION: Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2 negative breast cancer. The role of adjuvant chemotherapy with or without trastuzumab warrants further research. Survival is best in triple-positive metastatic breast cancer. This will effect counseling at the time of first diagnosis of metastatic breast cancer. PMID- 28616829 TI - Three studies in the focus of pelvic organ prolapse research. PMID- 28616830 TI - The Efficacy of Genetic Counseling for Psychiatric Disorders: a Meta-Analysis. AB - Psychiatric illnesses are complex, highly heritable disorders that have substantial implications for both affected individuals and their families. Though genetic testing is currently limited in its clinical usefulness in this area, interest in genetic counseling for psychiatric disorders has a relatively long history and many positive outcomes have been posited. Yet, empirical studies of genetic counseling outcomes have been emerging only more recently. The aim of the current meta-analysis was to analyze the efficacy of genetic counseling and explore potential moderators of its effect. An extensive electronic search was conducted investigating the literature published until July 2016. The initial search resulted in 2367 articles, four of which met the inclusion criteria and were included in the quantitative meta-analysis. Effect size parameters and sample sizes for all variables in each study were included. The efficacy has ben demonstrated both at post-intervention and at follow up, with an overall statistically significant effect size of moderate intensity. Implications of this study are discussed in detail. PMID- 28616831 TI - Invasive Prenatal Diagnostic Testing Recommendations are Influenced by Maternal Age, Statistical Misconception and Perceived Liability. AB - Funding policy and medico-legal climate are part of physicians' reality and might permeate clinical decisions. This study evaluates the influence of maternal age and government funding on obstetrician/gynecologist recommendation for invasive prenatal testing (i.e. amniocentesis) for Down syndrome (DS), and its association with the physician's assessment of the risk of liability for medical malpractice unless they recommend amniocentesis. Israeli physicians (N = 171) completed a questionnaire and provided amniocentesis recommendations for women at 18 weeks gestation with normal preliminary screening results, identical except aged 28 and 37. Amniocentesis recommendations were reversed for the younger ('yes' regardless of testing results: 6.4%; 'no' regardless of testing results: 31.6%) versus older woman ('yes' regardless of testing results: 40.9%; 'no' regardless of testing results: 7.0%; chi2 = 71.55, p < .01). About half of the physicians endorsed different recommendations per scenario; of these, 65.6% recommended amniocentesis regardless of testing results for the 37-year-old woman. Physicians routinely performing amniocentesis and those advocating for amniocentesis for all women >= age 35 were approximately twice as likely to vary their recommendations per scenario. Physicians who perceived risk of liability for malpractice as large were nearly one-and-a-half times more likely to vary recommendations. The results indicate physicians' recommendations are influenced by maternal age, though age is already incorporated in prenatal DS risk evaluations. The physician's assessment of the risk that they will be sued unless they recommend amniocentesis may contribute to this spurious influence. PMID- 28616832 TI - "If It Helps, It's Worth a Try": an Investigation of Perceptions and Attitudes about Genetic Counseling among Southern Manitoba Hutterites. AB - Few studies have explored the public's views of genetic counseling services, and even fewer focus on founder populations with high prevalence of genetic disease, such as Hutterites. The Hutterites are an Anabaptist religious group grounded in a strong Christian faith. The primary aim of this study was to assess Hutterites' views of genetic counseling services. A secondary aim was to compare their views to those obtained in a study of rural Midwestern U.S. residents (Riesgraf et al., Journal of Genetic Counseling, 24(4), 565-579, 2015). One-hundred eleven individuals from southern Manitoba Hutterite colonies completed an anonymous survey assessing familiarity with and attitudes about genetic counseling; perceptions of its purpose, scope and practice; and willingness to use genetic counseling services. Although many respondents were not familiar with genetic counseling, most had accurate perceptions and positive attitudes. For instance, mean ratings showed endorsement of trust in information provided by genetic counselors and agreement that genetic counseling aligns with their values. Logistic regression indicated reported willingness to use genetic counseling services increased if respondents: had a higher self-rated familiarity with genetic counseling; were younger; agreed with the statement: I would trust the information provided by a genetic counselor; and disagreed with the statements: Genetic counseling is only useful for a small group of people with rare diseases, and Genetic counselors help expectant parents choose the eye color of their child. Thematic analysis of comments regarding willingness to use genetic counseling services yielded themes of personal/family risk, pragmatism (genetic counseling is sensible and practical for managing health concerns), and desire to prevent genetic conditions in the Hutterite population. Comparison of the present findings to those of Riesgraf et al. suggests predictors of Hutterites' willingness to use genetic counseling are unique and culturally-based. Limited replication of Riesgraf et al. was achieved. Additional findings, practice implications and research recommendations are presented. PMID- 28616833 TI - Use of Preservative Agents and Antibiotics for Increased Poliovirus Survival on Positively Charged Filters. AB - Environmental surveillance of poliovirus (PV) and other non-enveloped viruses can help identify silent circulation and is necessary to certify eradication. The bag mediated filtration system is an efficient method to filter large volumes of environmental waters at field sites for monitoring the presence of viruses. As filters may require long transit times to off-site laboratories for processing, viral inactivation or overgrowth of bacteria and fungi can interfere with virus detection and quantification (Miki and Jacquet in Aquatic Microb Ecol 51(2):195 208, 2008). To evaluate virus survival over time on ViroCapTM filters, the filters were seeded with PV type 1 (PV1) and/or MS2 and then dosed with preservatives or antibiotics prior to storage and elution. These filters were stored at various temperatures and time periods, and then eluted for PV1 and MS2 recovery quantification. Filters dosed with the preservative combination of 2% sodium benzoate and 0.2% calcium propionate had increased virus survival over time when stored at 25 degrees C, compared to samples stored at 25 degrees C with no preservatives. While elution within 24 h of filtration is recommended, if storage or shipping is required then this preservative mixture can help preserve sample integrity. Addition of an antibiotic cocktail containing cephapirin, gentamicin, and ProclinTM 300 increased recovery after storage at 4 and 25 degrees C, when compared to storage with no antibiotics. The antibiotic cocktail can aid sample preservation if access to appropriate antibiotics storage is available and sample cold chain is unreliable. This study demonstrated that the use of preservatives or antibiotics is a simple, cost-effective method to improve virus detection from ViroCap cartridge filters over time. PMID- 28616834 TI - Minimizing Bias in Virally Seeded Water Treatment Studies: Evaluation of Optimal Bacteriophage and Mammalian Virus Preparation Methodologies. AB - One key assumption impacting data quality in viral inactivation studies is that reduction estimates are not altered by the virus seeding process. However, seeding viruses often involves the inadvertent addition of co-constituents such as cell culture components or additives used during preparation steps which can impact viral reduction estimates by inducing non-representative oxidant demand in disinfection studies and fouling in membrane assessments. The objective of this study was therefore to characterize a mammalian norovirus surrogate, murine norovirus (MNV), and bacteriophage MS2 at sequential stages of viral purification and to quantify their potential contribution to artificial oxidant demand and non representative membrane fouling. Our results demonstrate that seeding solvent extracted and 0.1 micron filtered MNV to ~105 PFU/mL in an experimental water matrix will result in additional total organic carbon (TOC) and 30 min chlorine demand of 39.2 mg/L and 53.5 mg/L as Cl2, respectively. Performing sucrose cushion purification on the MNV stock prior to seeding reduces the impacts of TOC and chlorine demand to 1.6 and 0.15 mg/L as Cl2, respectively. The findings for MNV are likely relevant for other mammalian viruses propagated in serum-based media. Thus, advanced purification of mammalian virus stocks by sucrose cushion purification (or equivalent density-based separation approach) is warranted prior to seeding in water treatment assessments. Studies employing bacteriophage MS2 as a surrogate virus may not need virus purification, since seeding MS2 at a concentration of ~106 PFU/mL will introduce only ~1 mg/L of TOC and ~1 mg/L as Cl2 of chlorine demand to experimental water matrices. PMID- 28616835 TI - Why does the acquired cholesteatoma trigger resorption of the temporal bone? PMID- 28616836 TI - Outpatient versus observation/inpatient parotidectomy: patient factors and perioperative complications. AB - The objective of this manuscript is to review a single institution's experience with superficial or total parotidectomy in outpatient and observation/inpatient groups. All patients who underwent superficial or total parotidectomy between 2009 and 2015 were identified. Patients were excluded if they had undergone concurrent surgery such as neck dissection, had prior radiation treatment or surgery at the operative site. Main outcomes were perioperative complications in both groups. 215 consecutive patients were included in the study, 116 (54%) patients in the inpatient group and 99 (46%) in the outpatient group. Aside from a higher observed rate of cardiac disease in the outpatient group (24.2 vs. 11.2%, p = 0.014) and larger mean body mass index (BMI) in the inpatient group (32.448 vs. 30.034, p = 0.017), there were no significant differences for age, sex or smoking status. Average operative time differed between groups with 2 h 42 min for inpatients and 2 h 18 min for outpatients (p < 0.001). There were 26 complications in the inpatient group (22.4%, including two hematomas) and 8 in the outpatient group (8.1%). The rate of seroma/sialocele formation was significantly higher in the inpatient group at 15.5% (n = 18) compared with the outpatient group at 3% (n = 3, p = 0.001). Our study shows that parotidectomy, superficial or total, was performed safely as an outpatient procedure without significant increase in complications when compared to patients observed for at least one night after surgery. PMID- 28616837 TI - A phase Ib study of everolimus combined with metformin for patients with advanced cancer. AB - Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides. PMID- 28616838 TI - Assessment of renal hemodynamic toxicity of fluid challenge with 0.9% NaCl compared to balanced crystalloid (PlasmaLyte(r)) in a rat model with severe sepsis. AB - BACKGROUND: According to international guidelines, volume expansion with crystalloids is the first-line treatment for hemodynamic management in patients with severe sepsis or septic shock. Compared to balanced crystalloids, 0.9% sodium chloride (0.9% NaCl) induces hyperchloremia and metabolic acidosis and may alter renal hemodynamics and function. We compared the effects of 0.9% NaCl to a less chloride-concentrated fluid, PlasmaLyte(r) (PL) in targeted fluid resuscitation in a randomized, double-blind controlled study in an experimental model of severe sepsis in rats. RESULTS: A sepsis with hypotension was induced by cecal ligature and puncture (CLP) in 40 male Wistar rats (20 for each crystalloid). Rats received fluid resuscitation over a period of 200 min for a targeted mean arterial pressure of 90 mm Hg. Animals received similar volumes of 0.9% NaCl or PL. Unlike PL-resuscitated rats, 0.9% NaCl-resuscitated rats experienced hyperchloremia and metabolic acidosis, whereas systemic hemodynamics, renal hemodynamics and renal function were not significantly different between both groups. CONCLUSION: In our model of rats with severe sepsis resuscitated with large amounts of crystalloids, 0.9% NaCl-induced hyperchloremic acidosis, but balanced crystalloid did not improve systemic and renal hemodynamics or renal function. PMID- 28616839 TI - Continuous Evaluation in Ethics Education: A Case Study. AB - A great need for systematic evaluation of ethics training programs exists. Those tasked with developing an ethics training program may be quick to dismiss the value of training evaluation in continuous process improvement. In the present effort, we use a case study approach to delineate how to leverage formative and summative evaluation measures to create a high-quality ethics education program. With regard to formative evaluation, information bearing on trainee reactions, qualitative data from the comments of trainees, in addition to empirical findings, can ensure that the training program operates smoothly. Regarding summative evaluation, measures examining trainee cognition, behavior, and organization-level results provide information about how much trainees have changed as a result of taking the ethics training. The implications of effective training program evaluation are discussed. PMID- 28616840 TI - End of 2016: Can We Save Research from Predators in 2017? AB - At the beginning of every year, we expect to see worthwhile improvements on the past. The end of 2016 showcased many important issues in the scientific world, ranging from criticisms of research misconduct and fraud to the introduction of new scientometrics. Despite the scientific community's continuing efforts, predatory journals and publishers are still on the rise, and the Beall's list calls attention to the need to take a firm action across the board. This short opinion piece highlights research conducted by the scholarly community on research publication predators during 2016, and offers suggestions as to how to bring about future improvements. PMID- 28616841 TI - Zebrafish prefer larger to smaller shoals: analysis of quantity estimation in a genetically tractable model organism. AB - Numerical abilities have been demonstrated in a variety of non-human vertebrates. However, underlying biological mechanisms have been difficult to study due to a paucity of experimental tools. Powerful genetic and neurobiological tools already exist for the zebrafish, but numerical abilities remain scarcely explored with this species. Here, we investigate the choice made by single experimental zebrafish between numerically different shoals of conspecifics presented concurrently on opposite sides of the experimental tank. We examined this choice using the AB strain and pet store zebrafish. We found zebrafish of both populations to generally prefer the numerically larger shoal to the smaller one. This preference was significant for contrasted ratios above or equalling 2:1 (i.e. 4 vs. 0, 4 vs. 1, 8 vs. 2, 6 vs. 2 and 6 vs. 3). Interestingly, zebrafish showed no significant preference when each of the two contrasted shoals had at least 4 members, e.g. in a contrast 8 versus 4. These results confirm that zebrafish possess the ability to distinguish larger numbers of items from smaller number of items, in a shoaling context, with a potential limit above 4. Our findings confirm the utility of the zebrafish for the exploration of both the behavioural and the biological mechanisms underlying numerical abilities in vertebrates. PMID- 28616842 TI - Characterization of Magneto-Endosymbionts as MRI Cell Labeling and Tracking Agents. AB - PURPOSE: Magneto-endosymbionts (MEs) show promise as living magnetic resonance imaging (MRI) contrast agents for in vivo cell tracking. Here we characterize the biomedical imaging properties of ME contrast agents, in vitro and in vivo. PROCEDURES: By adapting and engineering magnetotactic bacteria to the intracellular niche, we are creating magneto-endosymbionts (MEs) that offer advantages relative to passive iron-based contrast agents (superparamagnetic iron oxides, SPIOs) for cell tracking. This work presents a biomedical imaging characterization of MEs including: MRI transverse relaxivity (r 2) for MEs and ME labeled cells (compared to a commercially available iron oxide nanoparticle); microscopic validation of labeling efficiency and subcellular locations; and in vivo imaging of a MDA-MB-231BR (231BR) human breast cancer cells in a mouse brain. RESULTS: At 7T, r 2 relaxivity of bare MEs was higher (250 s-1 mM-1) than that of conventional SPIO (178 s-1 mM-1). Optimized in vitro loading of MEs into 231BR cells yielded 1-4 pg iron/cell (compared to 5-10 pg iron/cell for conventional SPIO). r 2 relaxivity dropped by a factor of ~3 upon loading into cells, and was on the same order of magnitude for ME-loaded cells compared to SPIO-loaded cells. In vivo, ME-labeled cells exhibited strong MR contrast, allowing as few as 100 cells to be detected in mice using an optimized 3D SPGR gradient-echo sequence. CONCLUSIONS: Our results demonstrate the potential of magneto-endosymbionts as living MR contrast agents. They have r 2 relaxivity values comparable to traditional iron oxide nanoparticle contrast agents, and provide strong MR contrast when loaded into cells and implanted in tissue. PMID- 28616843 TI - Intermittency in the Hodgkin-Huxley model. AB - We show that action potentials in the Hodgkin-Huxley neuron model result from a type I intermittency phenomenon that occurs in the proximity of a saddle-node bifurcation of limit cycles. For the Hodgkin-Huxley spatially extended model, describing propagation of action potential along axons, we show the existence of type I intermittency and a new type of chaotic intermittency, as well as space propagating regular and chaotic diffusion waves. Chaotic intermittency occurs in the transition from a turbulent regime to the resting regime of the transmembrane potential and is characterised by the existence of a sequence of action potential spikes occurring at irregular time intervals. PMID- 28616844 TI - Therapeutic Utility of Opioids for Restless Legs Syndrome. AB - Restless legs syndrome (RLS) is a sensorimotor neurologic disorder characterized by an unpleasant urge to move the legs, often accompanied by leg dysesthesias. Symptoms predominate in the evening or at night and often cause significant distress and disruption of sleep. Several non-opioid classes of drugs provide initial relief from the symptoms of RLS. Among these, however, the efficacy of dopamine agonists can wane over time or even paradoxically 'augment' the severity of symptoms during the course of long-term treatment. Opioids can alleviate RLS symptoms, even in patients who have become refractory to, or do not tolerate, other drugs. In a carefully selected group of patients with severe RLS that has not been effectively managed with other therapies, opioids may be an appropriate treatment. PMID- 28616846 TI - Characterizing user engagement with health app data: a data mining approach. AB - The use of mobile health applications (apps) especially in the area of lifestyle behaviors has increased, thus providing unprecedented opportunities to develop health programs that can engage people in real-time and in the real-world. Yet, relatively little is known about which factors relate to the engagement of commercially available apps for health behaviors. This exploratory study examined behavioral engagement with a weight loss app, Lose It! and characterized higher versus lower engaged groups. Cross-sectional, anonymized data from Lose It! were analyzed (n = 12,427,196). This dataset was randomly split into 24 subsamples and three were used for this study (total n = 1,011,008). Classification and regression tree methods were used to identify subgroups of user engagement with one subsample, and descriptive analyses were conducted to examine other group characteristics associated with engagement. Data mining validation methods were conducted with two separate subsamples. On average, users engaged with the app for 29 days. Six unique subgroups were identified, and engagement for each subgroup varied, ranging from 3.5 to 172 days. Highly engaged subgroups were primarily distinguished by the customization of diet and exercise. Those less engaged were distinguished by weigh-ins and the customization of diet. Results were replicated in further analyses. Commercially-developed apps can reach large segments of the population, and data from these apps can provide insights into important app features that may aid in user engagement. Getting users to engage with a mobile health app is critical to the success of apps and interventions that are focused on health behavior change. PMID- 28616847 TI - Interactive Voice Response Calls to Promote Smoking Cessation after Hospital Discharge: Pooled Analysis of Two Randomized Clinical Trials. AB - BACKGROUND: Hospitalization offers smokers an opportunity to quit smoking. Starting cessation treatment in hospital is effective, but sustaining treatment after discharge is a challenge. Automated telephone calls with interactive voice response (IVR) technology could support treatment continuance after discharge. OBJECTIVE: To assess smokers' use of and satisfaction with an IVR-facilitated intervention and to test the relationship between intervention dose and smoking cessation. DESIGN: Analysis of pooled quantitative and qualitative data from the intervention groups of two similar randomized controlled trials with 6-month follow-up. PARTICIPANTS: A total of 878 smokers admitted to three hospitals. All received cessation counseling in hospital and planned to stop smoking after discharge. INTERVENTION: After discharge, participants received free cessation medication and five automated IVR calls over 3 months. Calls delivered messages promoting smoking cessation and medication adherence, offered medication refills, and triaged smokers to additional telephone counseling. MAIN MEASURES: Number of IVR calls answered, patient satisfaction, biochemically validated tobacco abstinence 6 months after discharge. KEY RESULTS: Participants answered a median of three of five IVR calls; 70% rated the calls as helpful, citing the social support, access to counseling and medication, and reminders to quit as positive factors. Older smokers (OR 1.36, 95% CI 1.20-1.54 per decade) and smokers hospitalized for a smoking-related disease (OR 1.65, 95% CI 1.21-2.23) completed more calls. Smokers who completed more calls had higher quit rates at 6-month follow-up (OR 1.49, 95% CI 1.30-1.70, for each additional call) after multivariable adjustment for age, sex, education, discharge diagnosis, nicotine dependence, duration of medication use, and perceived importance of and confidence in quitting. CONCLUSIONS: Automated IVR calls to support smoking cessation after hospital discharge were viewed favorably by patients. Higher IVR utilization was associated with higher odds of tobacco abstinence at 6-month follow-up. IVR technology offers health care systems a potentially scalable means of sustaining tobacco cessation interventions after hospital discharge. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01177176, NCT01714323. PMID- 28616848 TI - Giant Cell Arteritis with Carotidynia. PMID- 28616845 TI - Neoadjuvant Therapy for Breast Cancer: Established Concepts and Emerging Strategies. AB - In the last decade, the systemic treatment approach for patients with early breast cancer has partly shifted from adjuvant treatment to neoadjuvant treatment. Systemic treatment administration started as a 'one size fits all' approach but is currently customized according to each breast cancer subtype. Systemic treatment in a neoadjuvant setting is at least as effective as in an adjuvant setting and has several additional advantages. First, it enables response monitoring and provides prognostic information; second, it downstages the tumor, allowing for less extensive surgery, improved cosmetic outcomes, and reduced postoperative complications such as lymphedema; and third, it enables early development of new treatment strategies by using pathological complete remission as a surrogate outcome of event-free and overall survival. In this review we give an overview of the current standard of neoadjuvant systemic treatment strategies for the three main subtypes of breast cancer: hormone receptor-positive, triple-negative, and human epidermal growth factor receptor 2 positive. Additionally, we summarize drugs that are under investigation for use in the neoadjuvant setting. PMID- 28616850 TI - The "broken chair" in patients with differentiated thyroid cancer. PMID- 28616851 TI - Effect of aerobic interval training on serum IL-10, TNFalpha, and adipokines levels in women with multiple sclerosis: possible relations with fatigue and quality of life. AB - PURPOSE: Multiple sclerosis is associated with immune system dysfunction and chronic inflammation; however, possible relations between immunologic and metabolic factors and some psychological indexes such as fatigue and quality of life, especially in relation to exercise training, have not yet been investigated. The present study was designed to investigate the effect of aerobic interval training on interleukin-10/tumor necrosis factor ratio and adipokine (leptin and adiponectin) concentrations in women with multiple sclerosis. Furthermore, the relationship between these factors with fatigue and quality of life were assessed. METHODS: Forty women with multiple sclerosis (Expanded Disability Status Scale <=3) were randomized into either a non-exercising control or training group. The training group performed 8-weeks of upper and lower limb aerobic interval training. Serum concentrations of tumor necrosis factoralpha, interleukin-10, leptin, and adiponectin were measured before and after the 8-week intervention. Moreover, antropometric measures and measures for fatigue and quality of life were determined at the onset of and after exercise training. RESULTS: The results revealed that leptin and tumor necrosis factoralpha levels significantly decreased subsequent to the aerobic interval training. Although blood adiponectin levels considerably increased in the training group, interleukin-10 and interleukin-10/tumor necrosis factoralpha ratio underwent no substantial change after the exercise training. In addition, the aerobic interval training was associated with improvement in fatigue, quality of life, and maximal oxygen consumption. CONCLUSIONS: Our findings suggested that aerobic interval training can be an effective strategy for managing the immune system at least by its significant impact on inflammatory cytokines and adipokines levels in women with multiple sclerosis. Additionally, this positive impact improved fatigue and adipose tissue indicators. PMID- 28616852 TI - Ultrasonographic prediction of highly aggressive telomerase reverse transcriptase (TERT) promoter-mutated papillary thyroid cancer. AB - PURPOSE: Telomerase reverse transcriptase promoter mutations are found in highly aggressive thyroid malignancies. Our aim was to define the ultrasonographic features of telomerase reverse transcriptase promoter-mutated papillary thyroid cancer and to evaluate their predictive performances. METHODS: Ultrasonographic findings were reviewed for 185 patients with surgically confirmed papillary thyroid cancer between 1994 and 2004. Genomic DNA to identify telomerase reverse transcriptase promoter mutations was extracted from archived surgical specimens. Logistic regression analysis was performed to compare clinical factors and ultrasonographic findings between telomerase reverse transcriptase promoter mutated and wild-type papillary thyroid cancers. RESULTS: A telomerase reverse transcriptase promoter mutation was detected in 8.1% (15 of 185) of specimens from papillary thyroid cancer patients with a strong trend toward increasing age. Nonparallel orientation and microlobulated margin were independent ultrasonographic findings for predicting telomerase reverse transcriptase promoter-mutated papillary thyroid cancer in patients over 50 years (odds ratio 5.898, 95% confidence interval 1.092-31.851, P = 0.039 for orientation; odds ratio 5.813, 95% confidence interval 1.320-25.602, P = 0.020 for margin). Prevalence of telomerase reverse transcriptase promoter mutations increased to 50.0% in papillary thyroid cancer patients older than 50 years with both ultrasonographic findings and was 0% in patients without either finding. For identifying telomerase reverse transcriptase promoter-mutated papillary thyroid cancer, ultrasonographic had 64.3% sensitivity, 80.8% specificity, 50.0% positive predictive value and 88.4% negative predictive value. CONCLUSIONS: Telomerase reverse transcriptase promoter-mutated papillary thyroid cancer could be suggested by the ultrasonographic features of nonparallel orientation and microlobulated margin in patients older than 50 years. Prebiopsy recognition of this unique ultrasonographic pattern would mandate the nodule fall into a "biopsy suggested" category. PMID- 28616853 TI - Comparison of the Simple Patient-Centric Atopic Dermatitis Scoring System PEST with SCORAD in Young Children Using a Ceramide Dominant Therapeutic Moisturizer. AB - INTRODUCTION: Patient eczema severity time (PEST) is a new atopic dermatitis (AD) scoring system based on patients' own perception of their disease. Conventional scales such as SCORing of atopic dermatitis (SCORAD) reflect the clinician's observations during the clinic visit. Instead, the PEST score captures eczema severity, relapse and recovery as experienced by the patient or caregiver on a daily basis, promoting patient engagement, compliance with treatment and improved outcomes. This study aims to determine the correlation between carer-assessed PEST and clinician-assessed SCORAD in paediatric AD patients after 12 weeks of treatment using a ceramide-dominant therapeutic moisturizer. METHODS: Prospective, open-label, observational, multi-centre study in which children with AD aged 6 months to 6 years were treated with a ceramide dominant therapeutic moisturizer twice daily for 12 weeks; 58 children with mild-to-moderate AD were included. Correlation between the 7-day averaged PEST and SCORAD scores for assessment of AD severity was measured within a general linear model. PEST and SCORAD were compared in week 4 and week 12. RESULTS: At week 12, a moderate correlation was found between the SCORAD and PEST scores (r = 0.51). The mean change in SCORAD and PEST scores from baseline to week 12 was -11.46 [95% confidence interval (CI) -14.99 to -7.92, p < 0.0001] and -1.33 (95% CI -0.71 to 0.10, p < 0.0001) respectively. PEST demonstrated greater responsiveness to change (33.3% of scale) compared to SCORAD (13.8% of scale). CONCLUSION: The PEST score correlates well with the SCORAD score and may have improved sensitivity when detecting changes in the severity of AD. The ceramide-dominant therapeutic moisturizer used was safe and effective in the management of AD in young children. FUNDING: Hyphens Pharma Pte Ltd. TRIAL REGISTRATION: clinicaltrials.gov identifier, NCT02073591. PMID- 28616854 TI - Ventricular-arterial coupling in centenarians without cardiovascular diseases. AB - BACKGROUND: Ventricular-arterial (VA) coupling is a central determinant of cardiovascular system performance and cardiac energetics. This index is expressed by the Ea/Ees ratio, where the effective arterial elastance (Ea) indicates the net arterial load exerted on the left ventricle and the left ventricular end systolic elastance (Ees) is a load-independent measure of left ventricular chamber performance. METHODS: Thirty-three centenarians (100.6 +/- 1.2 years, range 99-105 years, 10 M) without cardiovascular diseases underwent a complete echocardiographic evaluation and an instantaneous arterial blood pressure measurement, to characterize the Ea/Ees ratio and its two determinants indexed to body surface area. RESULTS: VA coupling was markedly reduced (Ea/Ees ratio 0.40 +/- 0.1), reflecting a disproportionate increase in Ees index (8.5 +/- 2.2 mmHg/ml/m2) compared with Ea index (3.2 +/- 0.8 mmHg/ml/m2). Notably, the coupling ratio was significantly lower in women (0.37 +/- 0.1) than in men (0.45 +/- 0.1, p = 0.0003), due to an increase in Ees index significantly greater in women (9.4 +/- 1.9 mmHg/ml/m2) than in men (6.5 +/- 1.5 mmHg/ml/m2, p = 0.0002). Using multivariate regression analysis, only female gender (beta coefficient 0.04, p = 0.01) and relative wall thickness (beta coefficient -0.49, p < 0.0001) showed a significant inverse correlation to VA coupling. CONCLUSIONS: Our analysis in a population of centenarians without overt cardiovascular disease revealed very low values of VA coupling, especially in women. Both a LV structural remodeling as well as a high aortic elastance might have contributed to a secondary disproportionate increase in myocardial stiffness. PMID- 28616855 TI - Respiratory Sinus Arrhythmia Predicts Restricted Repetitive Behavior Severity. AB - In addition to social communication deficits, restricted repetitive behaviors (RRBs) are a key diagnostic feature of autism spectrum disorder (ASD). Dysfunction of the autonomic nervous system (ANS) in ASD has been posited as a mechanism of RRBs; however, most studies investigating ANS activity in ASD have focused on its relation to social functioning. This study used respiratory sinus arrhythmia (RSA) patterns to measure ANS functioning and analyze its relation to RRBs in children with and without an ASD diagnosis. Baseline RSA and RSA reactivity predicted RRB severity and exploratory analyses revealed these measures may be associated with RRB subgroups. These results are discussed in regards to the behavioral literature on RRBs and the benefits of finding biomarkers for these behaviors. PMID- 28616856 TI - Social Media Use, Friendship Quality, and the Moderating Role of Anxiety in Adolescents with Autism Spectrum Disorder. AB - Social media holds promise as a technology to facilitate social engagement, but may displace offline social activities. Adolescents with ASD are well suited to capitalize on the unique features of social media, which requires less decoding of complex social information. In this cross-sectional study, we assessed social media use, anxiety and friendship quality in 44 adolescents with ASD, and 56 clinical comparison controls. Social media use was significantly associated with high friendship quality in adolescents with ASD, which was moderated by the adolescents' anxiety levels. No associations were founds between social media use, anxiety and friendship quality in the controls. Social media may be a way for adolescents with ASD without significant anxiety to improve the quality of their friendships. PMID- 28616857 TI - MR Imaging Features of Intestinal Phytobezoar. AB - PURPOSE: The aim of this study is to explore MR features and imaging mechanism of intestinal phytobezoar and to deepen the understanding of intestinal phytobezoar. METHODS: Eighteen cases of intestinal phytobezoar (including 15 cases in small intestine and 3 cases in colon) underwent MR examinations. Summing-up and analyzing MR features combinded with intraoperative findings. RESULTS: All 18 cases of intestinal phytobezoar showed irregular shape low signal on T2-weighted image, which was named coke sign in this study. And on T1-weighted image showed as follows: (i) 12 cases of intestinal phytobezoar (11 in small intestine and 1 in ascending colon) showed internal low signal and peripheral ring-like high signal, which was named empty shell sign in this study, (ii) 4 cases of intestinal phytobezoar (3 in jejunum and 1 in ileum) showed mixed slightly higher signal, and (iii) 2 cases of intestinal phytobezoar (both in colon) showed slightly low signal. CONCLUSIONS: Intestinal phytobezoar presented coke sign on T2-weighted image and complicated signal, more often empty shell sign on T1 weighted image. Correct diagnosis of an intestinal phytobezoar has an instructive value in selection of treatment strategy. PMID- 28616859 TI - ? PMID- 28616858 TI - Intensity dependence in high-level facial expression adaptation aftereffect. AB - Perception of a facial expression can be altered or biased by a prolonged viewing of other facial expressions, known as the facial expression adaptation aftereffect (FEAA). Recent studies using antiexpressions have demonstrated a monotonic relation between the magnitude of the FEAA and adaptor extremity, suggesting that facial expressions are opponent coded and represented continuously from one expression to its antiexpression. However, it is unclear whether the opponent-coding scheme can account for the FEAA between two facial expressions. In the current study, we demonstrated that the magnitude of the FEAA between two facial expressions increased monotonically as a function of the intensity of adapting facial expressions, consistent with the predictions based on the opponent-coding model. Further, the monotonic increase in the FEAA occurred even when the intensity of an adapting face was too weak for its expression to be recognized. These results together suggest that multiple facial expressions are encoded and represented by balanced activity of neural populations tuned to different facial expressions. PMID- 28616860 TI - Insomnia as a Precipitating Factor in New Onset Mental Illness: a Systematic Review of Recent Findings. AB - PURPOSE: We aimed to systematically review recent publications (01/2014-03/2017) with longitudinal designs allowing for the assessment of the prospective risk of insomnia on new onset mental illness in key conditions: anxiety, depression, bipolar disorder, posttraumatic stress disorder, substance use disorders, and suicide. RECENT FINDINGS: A literature yielded 1859 unique articles meeting search criteria were identified; 16 articles met all selection criteria and reviewed with some studies reporting on more than one mental health outcome. Overall, the review supports the hypothesis that insomnia is a predictor of subsequent mental illness. The evidence is strongest for an insomnia-depression relationship. The new studies identified and reviewed add to a modest number of publications supporting a prospective role of insomnia in new onset mental illness in three areas: anxiety disorders, bipolar disorder, and suicide. The few selected new studies focused on SUD were mixed, and no studies focused on PTSD were identified that met the selection criteria. Treatment of insomnia may also be a preventive mental health strategy. PMID- 28616861 TI - Medical Therapy and Recurrent Ischemic Events in High Risk Patients Surviving their Myocardial Infarction for at Least 12 Months: Comparison of Patients with ST Elevation Versus Non-ST Elevation Myocardial Infarction. AB - INTRODUCTION: Data about treatments and recurrent ischemic events in patients surviving their most recent myocardial infarction event-free for at least 12 months are scarce. METHODS: In a retrospective data analysis, charts of patients who had a myocardial infarction 1-3 years ago with an event-free period of at least 12 months after the index event and at least one high risk factor were centrally collected and analyzed. Here we compare patients with ST elevation myocardial infarction (STEMI) versus non-ST elevation myocardial infarction (NSTEMI). RESULTS: A total of 666 patients, 342 with STEMI and 324 with NSTEMI, were included. Revascularization procedures for the index event were performed in 89% of patients with STEMI and 72% of patients with NSTEMI. About 62% of patients were still on dual antiplatelet therapy after 12 months, predominantly with aspirin and clopidogrel. This rate declined to 30% after 18 months. Patients with STEMI had a higher mortality (19% versus 13%, p = 0.04) and major adverse cardiovascular and cerebrovascular event rate (MACCE; 33% versus 23%, p = 0.03) during follow-up up to 36 months, while there were no significant differences with respect to recurrent myocardial infarction or stroke. The number of high risk factors was closely linked to the rate of MACCE at follow up. CONCLUSIONS: Patients surviving their myocardial infarction without any further event during the first 12 months have a high rate of recurrent ischemic events in both STEMI and NSTEMI cases during subsequent follow-up. Therefore, secondary prevention therapies should be continued even one year after myocardial infarction, which might improve outcomes. PMID- 28616862 TI - Loops D, E and G in the Drosophila Dalpha1 subunit contribute to high neonicotinoid sensitivity of Dalpha1-chicken beta2 nicotinic acetylcholine receptor. AB - BACKGROUND AND PURPOSE: Neonicotinoid insecticides interact with the orthosteric site formed at subunit interfaces of insect nicotinic ACh (nACh) receptors. However, their interactions with the orthosteric sites at alpha-non alpha and alpha-alpha subunit interfaces remain poorly understood. The aim of this study was to elucidate the mechanism of neonicotinoid actions using the Drosophila Dalpha1-chicken beta2 hybrid nACh receptor. EXPERIMENTAL APPROACH: Computer models of the (Dalpha1)3 (beta2)2 nACh receptor in complex with imidacloprid and thiacloprid were generated. Amino acids in the Dalpha1 subunit were mutated to corresponding amino acids in the human alpha4 subunit to examine their effects on the agonist actions of neonicotinoids on (Dalpha1)3 (beta2)2 and (Dalpha1)2 (beta2)3 nACh receptors expressed in Xenopus laevis oocytes using voltage-clamp electrophysiology. KEY RESULTS: The (Dalpha1)3 (beta2)2 nACh receptor models indicated that amino acids in loops D, E and G probably determine the effects of neonicotinoids. The amino acid mutations tested had minimal effects on the EC50 for ACh. However, the R57S mutation in loop G, although having minimal effect on imidacloprid's actions, reduced the affinity of thiacloprid for the (Dalpha1)3 (beta2)2 nACh receptor, while scarcely affecting thiacloprid's action on the (Dalpha1)2 (beta2)3 nACh receptor. Both the K140T and the combined R57S;K140T mutations reduced neonicotinoid efficacy but only for the (Dalpha1)3 (beta2)2 nACh receptor. Combining the E78K mutation with the R57S;K140T mutations resulted in a selective reduction of thiacloprid's affinity for the (Dalpha1)3 (beta2)2 nACh receptor. CONCLUSIONS AND IMPLICATIONS: These findings suggest that a triangle of residues from loops D, E and G contribute to the selective actions of neonicotinoids on insect-vertebrate hybrid nACh receptors. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 28616864 TI - A phase I study of moxetumomab pasudotox in adults with relapsed or refractory B cell acute lymphoblastic leukaemia. PMID- 28616863 TI - Contrasting effects of phosphatidylinositol 4,5-bisphosphate on cloned TMEM16A and TMEM16B channels. AB - BACKGROUND AND PURPOSE: Ca2+ -activated Cl- channels (CaCCs) are gated open by a rise in intracellular Ca2+ concentration ([Ca2+ ]i ), typically provoked by activation of Gq -protein coupled receptors (Gq PCR). Gq PCR activation initiates depletion of plasmalemmal phosphatidylinositol 4,5-bisphosphate (PIP2 ). Here, we determined whether PIP2 acts as a signalling lipid for CaCCs coded by the TMEM16A and TMEM16B genes. EXPERIMENTAL APPROACH: Patch-clamp electrophysiology, in conjunction with genetically encoded systems to control cellular PIP2 content, was used to define the mechanism of action of PIP2 on TMEM16A and TMEM16B channels. KEY RESULTS: A water-soluble PIP2 analogue (diC8-PIP2 ) activated TMEM16A channels by up to fivefold and inhibited TMEM16B by ~0.2-fold. The effects of diC8-PIP2 on TMEM16A currents were especially pronounced at low [Ca2+ ]i . In contrast, diC8-PIP2 modulation of TMEM16B channels did not vary over a broad [Ca2+ ]i range but was only detectable at highly depolarized membrane potentials. Modulation of TMEM16A and TMEM16B currents was due to changes in channel gating, while single channel conductance was unaltered. Co-expression of TMEM16A or TMEM16B with a Danio rerio voltage-sensitive phosphatase (DrVSP), which degrades PIP2 , led to reduction and enhancement of TMEM16A and TMEM16B currents respectively. These effects were abolished by an inactivating mutation in DrVSP and antagonized by simultaneous co-expression of a phosphatidylinositol 4-phosphate 5-kinase that catalyses PIP2 formation. CONCLUSIONS AND IMPLICATIONS: PIP2 acts as a modifier of TMEM16A and TMEM16B channel gating. Drugs interacting with PIP2 signalling may affect TMEM16A and TMEM16B channel gating and have potential uses in basic science and implications for therapy. PMID- 28616866 TI - Vocal palsy increases the risk of lower respiratory tract infection in low-risk, low-morbidity patients undergoing thyroidectomy for benign disease: A big data analysis. AB - OBJECTIVES: Thyroidectomy is the commonest operation that places normally functioning laryngeal nerves at risk of injury. Vocal palsy is a major risk factor for dysphonia, dysphagia, and less commonly, airway obstruction. We investigated the association between post-thyroidectomy vocal palsy and long-term risks of pneumonia and laryngeal failure. DESIGN: An N=near-all analysis of the English administrative dataset using a previously validated informatics algorithm to identify young and otherwise low-risk patients undergoing first-time elective thyroidectomy for benign disease. Information about age, sex, morbidities, social deprivation and post-operative and late complications were derived. MAIN OUTCOME MEASURES: Between 2004 and 2012, 43 515 patients between the ages of 20 and 69 who had no history of cancer, neurological, or respiratory disease underwent elective total or hemithyroidectomy without concomitant or late neck dissection, parathyroidectomy or laryngotracheal surgery for benign thyroid disease for the first and only time. Information about age, sex, morbidities and in-hospital and late complications was recorded. RESULTS: Mean age at surgery was 46+/-12. There was a strong female preponderance (85%), and most patients (89%) had no recorded Charlson comorbidities Most patients (65%) underwent hemithyroidectomy. Late vocal palsy was recorded in 449 (1.03%) patients, and its occurrence was an independent risk factor for emergency hospital readmission (n=7113; Hazard Ratio 1.52; 95% confidence interval 1.21-1.91), hospitalisation for lower respiratory tract infection (n=944; HR 2.04; 95% CI 1.07-3.75), dysphagia (n=564; HR 3.47; 95% CI 1.57-7.65) and gastrostomy/tracheostomy placement (n=80; HR 20.8; 95% CI 2.5-171.2). Independent risk factors for late vocal palsy were age, burden of morbidities, total thyroidectomy, post operative bleeding, male sex, and annual surgeon volume <30. CONCLUSIONS: There is a significant association between post thyroidectomy vocal palsy and long-term risks of hospital readmission, dysphagia, hospitalisation for lower respiratory tract infection, and gastrostomy/tracheostomy tube placement. This adds weight to the need, from a thyroid surgical perspective, to undertake universal post-thyroidectomy laryngeal surveillance as a minimum standard of care, with a focus on post-operative dysphagia and aspiration, and from a medical/respiratory perspective, to initiate investigations to identify occult vocal palsy in patients who present with pneumonia, who have a history of thyroid surgery. PMID- 28616865 TI - Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization. AB - BACKGROUND AND PURPOSE: Isoacteoside (is a phenylethanoid isolated from Monochasma savatieri Franch. ex Maxim., which is an anti-inflammatory herb widely used in traditional Chinese medicine. However, the exact mechanism of the anti inflammatory activity of isoacteoside is not completely understood. In this study, its anti-inflammatory mechanism was elucidated in mouse macrophages. EXPERIMENTAL APPROACH: The expression of the NF-kappaB pathway, MAPK pathway, iNOS, TNF-alpha, IL-6 and IL-1beta was evaluated using Western blotting, quantitative real-time PCR or ELISA. TLR4 dimerization was determined by transfecting HEK293T cells with TLR4 plasmids. The in vivo anti-inflammatory effect of isoacteoside was determined using mouse models of xylene-induced ear oedema, LPS-induced endotoxic shock and LPS-induced endotoxaemia-associated acute kidney injury (AKI). KEY RESULTS: Isoacteoside suppressed COX-2, iNOS, TNF-alpha, IL-6 and IL-1beta expression. Furthermore, isoacteoside attenuated the LPS induced transcriptional activity of NF-kappaB by decreasing the levels of phosphorylated IkappaB-alpha and IKK and NF-kappaB/p65 nuclear translocation. In addition, isoacteoside inhibited LPS-induced transcriptional activity of AP-1 by reducing the levels of phosphorylated JNK1/2 and p38MAPK. Isoacteoside blocked LPS-induced TLR4 dimerization, resulting in a reduction in the recruitment of MyD88 and TIR-domain-containing adapter-inducing interferon-beta (TRIF) and the phosphorylation of TGF-beta-activated kinase-1 (TAK1). Pretreatment of mice with isoacteoside effectively inhibited xylene-induced ear oedema and LPS-induced endotoxic death and protected against LPS-induced AKI. CONCLUSIONS AND IMPLICATIONS: Isoacteoside blocked TLR4 dimerization, which activates the MyD88 TAK1-NF-kappaB/MAPK signalling cascades and TRIF pathway. Our data indicate that isoacteoside is a potential lead compound for the treatment of inflammatory diseases. PMID- 28616867 TI - Pelvic trauma mortality reduced by integrated trauma care. AB - OBJECTIVES: A multidisciplinary approach that emphasised improved triage, early pelvic binder application, early administration of blood and blood products, adherence to algorithmic pathways, screening with focused sonography (FAST), early computed tomography scanning with contrast angiography, angio-embolisation and early operative intervention by specialist pelvic surgeons was implemented in the last decade to improve outcomes after pelvic trauma. The manuscript evaluated the effect of this multi-faceted change over a 12-year period. METHODS: A retrospective cohort study was conducted comparing patients presenting with serious pelvic injury in 2002 to those presenting in 2013. The primary exposure and comparator variables were the year of presentation and the primary outcome variable was mortality at hospital discharge. Potential confounders were evaluated using multivariable logistic regression analysis. RESULTS: There were 1213 patients with a serious pelvic injury (Abbreviated Injury Scale >=3), increasing from 51 in 2002 to 156 in 2013. Demographics, injury severity and presenting clinical characteristics were similar between the two time periods. There was a statistically significant difference in mortality from 20% in 2002 to 7.7% in 2013 (P = 0.02). The association between the primary exposure variable of being injured in 2013 and mortality remained statistically significant (adjusted odds ratio 0.10; 95% confidence interval: 0.02-0.60) when adjusted for potential clinically important confounders. CONCLUSIONS: Multi-faceted interventions directed at the spectrum of trauma resuscitation from pre-hospital care to definitive surgical management were associated with significant reduction in mortality of patients with severe pelvic injury from 2002 to 2013. This demonstrates the effectiveness of an integrated, inclusive trauma system in achieving improved outcomes. PMID- 28616868 TI - Selection into Emergency Medicine specialist training: A commentary on the science of selection. PMID- 28616869 TI - A perfluorobutylpentane (F4H5)-based solution for the removal of residual emulsified silicone oil. AB - PURPOSE: The emulsification of silicone oil (SO) is associated with many complications. In this study, we investigate a new SO solvent, perfluorobutylpentane (F4H5) with 1% by volume of perfluorinated polyethers polyethylene glycol-perfluorinated polyethers (PFPE-PEG-PFPE) triblock copolymer, for removing emulsified droplets. METHODS: An in vitro 3D printed model eye chamber was used to evaluate the efficiency of the three test liquids in removing SO droplets, namely saline, F4H5 and F4H5 with surfactant PFPE-PEG-PFPE. The numbers of SO droplets were quantified using a Coulter Counter. The stability of double emulsion formed was tested with a fluidic device based on electro coalescence. Two retinal cell lines were used to test the biocompatibility of the liquids. RESULTS: The mean number of droplets remaining in the eye chamber after rinsing with a solution of F4H5 with surfactant was 13 315 +/- 4620/ml compared to saline (23 460 +/- 7595/ml; p < 0.05). The double emulsion was found to be highly stable. The biocompatibility of F4H5 and the surfactant was similar to that of the saline control. CONCLUSION: By adding a small amount of surfactant, the resultant F4H5 solution is able to promote double emulsification and remove more SO droplets. Although further in vivo safety studies are necessary before clinical trials, the result of our study suggests that F4H5 with surfactant is a promising Rinsing Solution for removing emulsified droplets. This work therefore translates a well-known phenomenon in emulsion science to tackle the emulsification problem observed in the routine vitreoretinal surgery. PMID- 28616870 TI - Hazard Experience, Geophysical Vulnerability, and Flood Risk Perceptions in a Postdisaster City, the Case of New Orleans. AB - This article investigates the determinants of flood risk perceptions in New Orleans, Louisiana (United States), a deltaic coastal city highly vulnerable to seasonal nuisance flooding and hurricane-induced deluges and storm surges. Few studies have investigated the influence of hazard experience, geophysical vulnerability (hazard proximity), and risk perceptions in cities undergoing postdisaster recovery and rebuilding. We use ordinal logistic regression techniques to analyze experiential, geophysical, and sociodemographic variables derived from a survey of 384 residents in seven neighborhoods. We find that residents living in neighborhoods that flooded during Hurricane Katrina exhibit higher levels of perceived risk than those residents living in neighborhoods that did not flood. In addition, findings suggest that flood risk perception is positively associated with female gender, lower income, and direct flood experiences. In conclusion, we discuss the implications of these findings for theoretical and empirical research on environmental risk, flood risk communication strategies, and flood hazards planning. PMID- 28616871 TI - From competition to facilitation: how tree species respond to neighbourhood diversity. AB - Studies on tree communities have demonstrated that species diversity can enhance forest productivity, but the driving mechanisms at the local neighbourhood level remain poorly understood. Here, we use data from a large-scale biodiversity experiment with 24 subtropical tree species to show that neighbourhood tree species richness generally promotes individual tree productivity. We found that the underlying mechanisms depend on a focal tree's functional traits: For species with a conservative resource-use strategy diversity effects were brought about by facilitation, and for species with acquisitive traits by competitive reduction. Moreover, positive diversity effects were strongest under low competition intensity (quantified as the total basal area of neighbours) for acquisitive species, and under high competition intensity for conservative species. Our findings demonstrate that net biodiversity effects in tree communities can vary over small spatial scales, emphasising the need to consider variation in local neighbourhood interactions to better understand effects at the community level. PMID- 28616872 TI - Culture and healthy lifestyles: a qualitative exploration of the role of food and physical activity in three urban Australian Indigenous communities. AB - OBJECTIVE: 1) To explore the links between Indigenous Australian children's perspectives on culture, and healthy lifestyle behaviours. 2) To provide insight into how to approach the development of a health intervention targeting lifestyle behaviours in Australian Indigenous children. METHODS: Seven semi-structured focus groups sessions were conducted with Australian Indigenous children aged 5 12 years living on the South Coast of New South Wales. Audio-recordings were transcribed and thematic analyses were conducted and related to principles of grounded theory. RESULTS: Participants had connections to aspects of Australian Indigenous culture that were embedded in their everyday lives. Healthy lifestyle behaviours (such as healthy eating and physical activity) were found to be interconnected with Australian Indigenous culture and positive emotional wellbeing was identified as an important outcome of connecting Australian Indigenous children to cultural practices. CONCLUSION: Understanding the importance of culture and its role in healthy lifestyles is critical in the development of health interventions for Indigenous populations. IMPLICATION: Health interventions embedded with Australian Indigenous culture may have potential to improve physical and emotional health within Australian Indigenous communities. However, it is unlikely that a 'one size fits all' approach to health interventions can be taken. PMID- 28616873 TI - Do childcare menus meet nutrition guidelines? Quantity, variety and quality of food provided in New Zealand Early Childhood Education services. AB - OBJECTIVE: To describe food provision and evaluate menus in New Zealand childcare services, determining associations with service characteristics and/or cost of menu. METHODS: Licensed services in three regions of New Zealand participated in an online survey, uploading a weekly menu where applicable. Menus were scored for compliance with guidelines on quantity, variety and quality of foods served. Bivariate and multivariate associations between menu score and service characteristics were analysed. RESULTS: A total of 257 services participated (30% of 847 services invited). Food was provided daily in 56%, with 34% providing lunch and snacks daily. Of the 57 full menus analysed, only three (5%) met all 10 scoring criteria (mean score of 6.8/10). Higher menu scores were statistically associated with employing a cook, high and low (not medium) neighbourhood deprivation, the Heart Foundation's Healthy Heart Award program; there was no association with food costs. The Healthy Heart Award remained statistically associated with higher menu score after adjustment for other service characteristics. CONCLUSION: Most menus did not meet current nutrition guidelines for quantity, variety, and limiting 'sometimes' and 'occasional' foods. Implications for public health: This study provides a baseline for monitoring menu compliance in New Zealand and evidence for nutrition promotion and menu improvement programmes in early education. PMID- 28616875 TI - Stakeholders' qualitative perspectives of effective telepractice pedagogy in speech-language pathology. AB - BACKGROUND: Academic programmes in speech-language pathology are increasingly providing telehealth/telepractice clinical education to students. Despite this growth, there is little information describing effective ways to teach it. AIMS: The current exploratory study analyzed the perceptions of speech-language pathology/therapy (SLP/SLT) faculty, student and SLP/SLT clinicians to ascertain effective pedagogical approaches for telepractice service delivery, rank the relative importance of telepractice skills and knowledge competencies, and define any pedagogical challenges to teaching them. METHODS & PROCEDURES: Qualitative data were collected from two sources: three open-ended questions within an online survey (SLP/SLT faculty n = 31, graduate students n = 16, telehealth ('telepractice') clinicians n = 16); and follow-up telephone interviews (n = 22). Data were analyzed with a grounded theory approach followed by a summative rank order analysis of themes. OUTCOMES & RESULTS: All three groups agreed the most effective telepractice instructional approach was telepractice demonstrations (such as students role playing or watching a supervisor). Professional development approaches such as workshops or training manuals were less effective and didactic approaches such as lecture-only were ineffective. Skills and knowledge competencies students needed before entering the workforce were, in order of implied importance: telepractice clinical skills, telepractice technology skills, legal knowledge pertinent to telepractice and knowledge of telepractice literature. The most important telepractice clinical skills students needed to acquire were appropriate selection of telepractice materials and engaging the client over the internet. Many participants said teaching and learning telepractice was more challenging than in-person service delivery because of the difficulties in selecting appropriate telepractice clinical materials, managing technology problems and engaging with clients over the internet. CONCLUSIONS & IMPLICATIONS: Despite substantial limitations to this investigation, findings imply that telepractice instruction, like other methods of SLP/SLT clinical education, may be most effective when students engage in critical thinking and problem-solving issues through intense practice. Because the skills and competencies associated with telepractice appear to vary in their perceived value, academic programmes may wish to consider prioritizing how they are taught, giving students additional instruction in the selection of telepractice clinical materials and development of online interpersonal communication skills. For some clinical educators, the challenges associated with telepractice may necessitate additional educator training. PMID- 28616874 TI - Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. AB - Romiplostim can improve platelet counts in about 50% of patients with low- or intermediate 1-risk (lower risk) myelodysplastic syndromes (MDS) and thrombocytopenia, but its long-term toxicity and efficacy are not known. This open-label extension study evaluated the long-term safety and efficacy of romiplostim in 60 patients with lower risk MDS and platelet counts <=50 * 109 /l. The primary endpoint was adverse event (AE) incidence. Secondary endpoints were efficacy parameters, including bleeding events and platelet response. Median (range) treatment time in the extension study and the median observation times thereafter were 25 (2-181) and 57 (11-209) weeks, respectively. Treatment-related AEs and serious AEs were reported in 14/60 (23%) and 4/60 (7%) patients, respectively. Progression to acute myeloid leukaemia (AML) occurred in two patients after 44 and 46 weeks. Patients (n = 34, 57%) with a platelet response were further evaluated for length of response. Median (range) response duration was 33 (7-174) weeks; 28/34 (82%) patients had a continuous response. Five of 34 patients (15%) had grade >=3 bleeding events; three when the platelet count was >50 * 109 /l. There were no new safety concerns and the rate of progression to AML was low; response to romiplostim was maintained for most patients. PMID- 28616876 TI - Erratum. PMID- 28616877 TI - Erratum. PMID- 28616878 TI - Lichen striatus following yellow fever vaccination in an adult woman. PMID- 28616879 TI - Risk factors associated with late entry to antenatal care visits in NSW in 2014. PMID- 28616880 TI - Imiquimod-induced cutaneous lupus erythematosus with antinuclear antibodies showing a homogenous pattern. PMID- 28616881 TI - Role of dietary modification in alleviating chronic fatigue syndrome symptoms: a systematic review. AB - OBJECTIVE: To review the evidence for the role of dietary modifications in alleviating chronic fatigue syndrome symptoms. METHODS: A systematic literature review was guided by PRISMA and conducted using Scopus, CINAHL Plus, Web of Science and PsycINFO scientific databases (1994-2016) to identify relevant studies. Twenty-two studies met the inclusion criteria, the quality of each paper was assessed and data extracted into a standardised tabular format. RESULTS: Positive outcomes were highlighted in some included studies for polyphenol intakes in animal studies, D-ribose supplementation in humans and aspects of symptom alleviation for one of three polynutrient supplement studies. Omega three fatty acid blood levels and supplementation with an omega three fatty acid supplement also displayed positive outcomes in relation to chronic fatigue syndrome symptom alleviation. CONCLUSIONS: Limited dietary modifications were found useful in alleviating chronic fatigue syndrome symptoms, with overall evidence narrow and inconsistent across studies. Implications for public health: Due to the individual and community impairment chronic fatigue syndrome causes the population, it is vital that awareness and further focused research on this topic is undertaken to clarify and consolidate recommendations and ensure accurate, useful distribution of information at a population level. PMID- 28616882 TI - Bullying among 18 to 23-year-old women in 2013. AB - OBJECTIVE: To identify the prevalence of bullying among women aged 18-23 in 2013, and to describe the demographic characteristics, health and risk factors of those who experienced bullying. METHODS: Cross-sectional analysis using data from the 1989-95 cohort of the Australian Longitudinal Study on Women's Health, a nationally representative cohort (n=16,801). RESULTS: More than one-quarter of women (28.4%) indicated they had never been bullied, 53.4% reported experiencing bullying in the past and 18.2% indicated that they were recently bullied. Women who had experienced bullying were more likely to have lower levels of education, less likely to be studying or employed, and had more difficulty managing on their income. Women who experienced bullying were more likely to use tobacco or illicit drugs, be overweight or obese and to be sedentary. Even after adjusting for these factors, women who had experienced bullying were at risk of poor physical health, psychological distress, suicidal thoughts and self-harm. CONCLUSIONS: This is the first nationally representative study to demonstrate the strong association between being a victim of bullying and health outcomes in a post-school-age population. Implications for public health: The findings highlight the need for interventions for women who have already experienced bullying and are past school age. PMID- 28616883 TI - Treatment for Thoracic Ossification of Posterior Longitudinal Ligament with Posterior Circumferential Decompression. AB - OBJECTIVE: To report the results of the posterior approach for thoracic ossification of posterior longitudinal ligament (TOPLL) by using a special "L" osteotome. METHODS: The present study enrolled 16 consecutive patients (9 men and 7 women) between May 2009 and September 2013. All patients underwent a posterior circumferential decompression osteotomy and segmental instrumentation with interbody fusion. The mean age at surgery was 57.3 years (range, 37-68 years). Patients' data, clinical manifestation, blood loss, length of surgery, complications, visual analog scale (VAS), Japanese Orthopedic Association (JOA), and Frankel grading system before and after surgery were collected and evaluated, retrospectively. RESULTS: The average follow-up period was 30 +/- 19 months (range, 12-50 months). All patients were successfully treated with posterior compression and segmental instrumentation with interbody fusion. The average operation time was 261.6 +/- 51.3 min (range, 190-310 min). The mean blood loss was 980.3 +/- 370.5 mL (range, 600-2100 mL). All patients had subjective improvement of motor power and gait. Average preoperative and postoperative JOA scores were 4.2 +/- 1.7 and 7.8 +/- 2.5 points, respectively. Differences in the overall JOA scores showed significant postoperative improvement. At the last follow-up, all patients improved either by one or two Frankel grades. There was a significant difference between preoperative VAS scores and those 3 months after surgery (P < 0.05). No significant difference was observed between the 3-month and 12-month results (P > 0.05). Cerebrospinal fluid (CSF) leakage occurred in 3 patients. Acute neurological deterioration was encountered postoperatively in 1 patient. CONCLUSION: Treatment with posterior transpedicular osteotomy and circumferential decompression was found to be safe, effective, reliable, and technically feasible, and keeping the thoracic cavity intact avoids many shortcomings of anterior surgery and results in a satisfactory spinal decompression. PMID- 28616885 TI - Non-fatal agricultural injury surveillance in the United States: A review of national-level survey-based systems. AB - BACKGROUND: Currently, surveillance of non-fatal agricultural injuries in the U.S. mainly relies on national surveys, and to date, none of these surveys were formally reviewed. Our objective was to review and evaluate these survey-based systems, to identify critical gaps in them and provide recommendations to improve them. METHODS: We used the updated Center for Disease Control and Prevention guidelines to describe each system and evaluate each system's attributes like simplicity, flexibility, data quality, timeliness, representativeness, etc. RESULTS: Four adult and two youth national surveys collected data for non-fatal agricultural injuries in the U.S. The evaluation identified three major gaps: 1) insufficient data quality attributed to non-response, measurement errors, and underreporting; 2) untimeliness of data; and 3) lack of flexibility to integrate with other existing systems. CONCLUSION: Improving data quality, timeliness and flexibility will provide reliable and valid injury estimates, and increase the usefulness of these surveys for surveillance and prevention of farm injuries. PMID- 28616886 TI - Cancer incidence among boat-building workers exposed to styrene. AB - BACKGROUND: A cancer incidence analysis was conducted on The National Institute for Occupational Safety and Health boat-builders cohort exposed to styrene, a possible carcinogen. METHODS: Standardized incidence ratios (SIR) and standardized rate ratios (SRR) were calculated using national and Washington State rates and a person-years analysis program. RESULTS: Among 3704 workers living in Washington State after 1991, when cancer registry case accrual began, 516 first primary diagnoses occurred through 2007. While overall cancer incidence was significantly reduced [SIR: 0.83 (0.76, 0.90)], internal comparisons suggest an association with exposure comparing high to low exposed person-time [SRR: 1.28 (1.05, 1.55)]. CONCLUSION: There is evidence of styrene exposure being linked to cancer incidence, which is notable since the cohort has not yet reached the median age of cancer diagnosis (65) in the United States. PMID- 28616887 TI - Computer-based training (CBT) intervention reduces workplace violence and harassment for homecare workers. AB - BACKGROUND: The study examines the effectiveness of a workplace violence and harassment prevention and response program with female homecare workers in a consumer driven model of care. METHODS: Homecare workers were randomized to either; computer based training (CBT only) or computer-based training with homecare worker peer facilitation (CBT + peer). Participants completed measures on confidence, incidents of violence, and harassment, health and work outcomes at baseline, 3, 6 months post-baseline. RESULTS: Homecare workers reported improved confidence to prevent and respond to workplace violence and harassment and a reduction in incidents of workplace violence and harassment in both groups at 6 month follow-up. A decrease in negative health and work outcomes associated with violence and harassment were not reported in the groups. CONCLUSION: CBT alone or with trained peer facilitation with homecare workers can increase confidence and reduce incidents of workplace violence and harassment in a consumer-driven model of care. PMID- 28616888 TI - Firefighter perceptions of cancer risk: Results of a qualitative study. AB - BACKGROUND: Recent epidemiological research on firefighters indicates an increased incidence of specific types of cancer. Intervention is needed in the fire service yet little is known about how firefighters perceive their cancer risk. METHODS: Participant observation (150 h, n = 100) and focus group (n = 17) data were collected from 15 fire stations in South Florida. Firefighters had at least 3 years of experience, ranks included drivers, captains, lieutenants, and specialty captains, with a median age of 51 years. RESULTS: From the qualitative analysis, two major categories (direct and indirect factors) for cancer risks emerged based on participant notions of cancer risk and cancer prevention behaviors as they relate to firefighting. CONCLUSIONS: Firefighters perceive cancer risks as the result of performing essential job tasks and from indirect job factors related to being a firefighter. The two categories of cancer risks suggest different points of entry for intervention. PMID- 28616889 TI - Risk Communication Emergency Response Preparedness: Contextual Assessment of the Protective Action Decision Model. AB - Studies are continuously performed to improve risk communication campaign designs to better prepare residents to act in the safest manner during an emergency. To that end, this article investigates the predictive ability of the protective action decision model (PADM), which links environmental and social cues, predecision processes (attention, exposure, and comprehension), and risk decision perceptions (threat, alternative protective actions, and stakeholder norms) with protective action decision making. This current quasi-longitudinal study of residents (N = 400 for each year) in a high-risk (chemical release) petrochemical manufacturing community investigated whether PADM core risk perceptions predict protective action decision making. Telephone survey data collected at four intervals (1995, 1998, 2002, 2012) reveal that perceptions of protective actions and stakeholder norms, but not of threat, currently predict protective action decision making (intention to shelter in place). Of significance, rather than threat perceptions, perception of Wally Wise Guy (a spokes-character who advocates shelter in place) correlates with perceptions of protective action, stakeholder norms, and protective action decision making. Wally's response efficacy advice predicts residents' behavioral intentions to shelter in place, thereby offering contextually sensitive support and refinement for PADM. PMID- 28616895 TI - Editorial 2016. PMID- 28616896 TI - High-resolution transbulbar ultrasonography helping differentiate intracranial hypertension in bilateral optic disc oedema patients. AB - PURPOSE: The enlargement of optic nerve sheath diameter (ONSD) has been proven to be related with raised intracranial pressure (ICP). No prospective study has been focused on utilizing retrobulbar ultrasonography in optic disc oedema patient presented to ophthalmologist. METHODS: High-resolution transbulbar ultrasonography was performed in a cohort of patient presented with bilateral optic disc oedema. The subarachnoid space of optic nerve (SAS), ONSD and optic nerve diameter (OND) was measured prior to other ancillaries including lumbar puncture. Subjects were classified into increased intracranial pressure (IIP) and normal intracranial pressure (NIP) group according to the open cerebrospinal fluid pressure more than 200 mm H2 0. The SAS, ONSD and OND were compared between groups and with normal control. The sensitivity of SAS or ONSD change for predicating intracranial hypertension was assessed. RESULTS: A total of 20 IIP, 25 NIP patients and 25 normal controls were evaluated. The mean SAS and ONSD measured in idiopathic intracranial hypertension group was significantly increased than that of NIP and controls (p < 0.001), whereas the OND showed no statistic difference between each group. The sensitivities using the SAS and ONSD for differentiating increased ICP in optic disc oedema patients were 0.99 and 0.97, respectively. CONCLUSIONS: The enlarged SAS and ONSD measured by high resolution transbulbar sonography are very sensitive parameters to predicate increased ICP in bilateral optic disc oedema patients. PMID- 28616897 TI - Alcohol and other substance use among a sample of young people in the Solomon Islands. AB - OBJECTIVE: Investigate alcohol and other substance use, with a focus on harmful alcohol use patterns, among young people in the Solomon Islands. METHODS: A structured, interviewer-administered questionnaire was administered to respondents aged 15-24 years across four of the country's provinces in late 2015. RESULTS: Four hundred young people completed the questionnaire across urban, peri urban and rural communities. The most common substances ever used by participants were betel nut (94%), licit/store-bought and/or illicit alcohol (79%) and tobacco (76%). Lifetime and recent substance use was particularly common among male respondents; e.g. 89% of male participants reported ever using any alcohol versus 54% of females (p<0.001). Harmful alcohol use patterns were common. CONCLUSIONS: Our sample generally reported higher levels of substance use compared to previous research in the Solomon Islands, including in relation to the country's relatively recent (2012/13) Household Income and Expenditure Survey. Implications for public health: Our study made considerable advances in addressing key knowledge gaps regarding alcohol and other substance use among young people in the Solomon Islands. Evidence-based initiatives to address early initiation of alcohol and other substance use and the progression to more problematic use patterns among young people in the Solomon Islands need to be explored. PMID- 28616898 TI - Smoking and the eye: what Quebec teenagers know and fear. AB - BACKGROUND: Although most people associate smoking with lung cancer and heart disease, few are aware of the impact of smoking on ocular health. Studies have suggested a better knowledge of this association might promote higher quit rates, particularly in teenagers. The purpose of our study was to determine the knowledge of teenagers about the effects of smoking on ocular health and the fear associated with several tobacco-related health conditions. METHODS: A self administered questionnaire was distributed to 180 high school students aged 14 to 17 years. Measured variables included socio-economic demographics, smoking status, knowledge of the effects of smoking on general and ocular health, and level of fear as well as level of motivation to quit smoking associated with the following tobacco-related conditions: lung cancer, cardiovascular disease, heart attack, blindness and deafness. RESULTS: Response rate was 100 per cent. Eleven per cent of responders were smokers. The proportion of smokers who thought smoking could cause blindness was 64.3 per cent while it was 13.5 per cent for non-smokers. The proportion of smokers fearing blindness was 30 per cent, as opposed to 69.8 per cent for non-smokers. The proportion of respondents who thought the presented conditions were 'extremely' or 'very good' reasons to quit were similarly high for all smoking-associated conditions. CONCLUSION: These findings suggest teenagers are unaware of the impact smoking can have on ocular health. Smokers did not seem more concerned about vision loss compared to other tobacco-related diseases, as opposed to non-smokers. Our findings suggest vision loss would be a strong motivator to prevent initiation, but not very effective regarding cessation in this group. However, optometrists should be aware teenagers seem receptive to the message that 'smoking can cause blindness' and use this strategy in order to prevent smoking initiation. PMID- 28616899 TI - Improving socially constructed cross-cultural communication in aged care homes: A critical perspective. AB - Cultural diversity between residents and staff is significant in aged care homes in many developed nations in the context of international migration. This diversity can be a challenge to achieving effective cross-cultural communication. The aim of this study was to critically examine how staff and residents initiated effective cross-cultural communication and social cohesion that enabled positive changes to occur. A critical hermeneutic analysis underpinned by Giddens' Structuration Theory was applied to the study. Data were collected by interviews with residents or their family and by focus groups with staff in four aged care homes in Australia. Findings reveal that residents and staff are capable of restructuring communication via a partnership approach. They can also work in collaboration to develop communication resources. When staff demonstrate cultural humility, they empower residents from culturally and linguistically diverse backgrounds to engage in effective communication. Findings also suggest that workforce interventions are required to improve residents' experiences in cross cultural care. This study challenges aged care homes to establish policies, criteria and procedures in cross-cultural communication. There is also the challenge to provide ongoing education and training for staff to improve their cross-cultural communication capabilities. PMID- 28616900 TI - What factors are associated with abstinence amongst socioeconomically disadvantaged smokers? A cross-sectional survey of use of cessation aids and quitting approach. AB - INTRODUCTION AND AIMS: This study aimed to compare current and ex-smokers' sociodemographic and psychosocial characteristics, use of cessation aids and abrupt versus gradual quitting approaches. DESIGN AND METHODS: A cross-sectional survey of financially disadvantaged adults attending a community service organisation was conducted in New South Wales, Australia, between February 2012 and December 2013. Sociodemographic and psychosocial factors, use of cessation aids and gradual versus abrupt quit approach were assessed. chi2 tests and logistic regression compared characteristics of current and ex-smokers. RESULTS: Of 905 individuals who completed the survey, 639 (71%) were current smokers and 107 (12%) were ex-smokers. Ex-smokers were older [odds ratio (OR) = 1.03, 95% confidence interval (CI) = 1.01, 1.05], had higher odds of being female (OR = 1.67, 95% CI = 1.06, 2.65), lower odds of being financially stressed (OR = 0.87, 95% CI = 0.76, 0.99), lower odds of anxiety and depression symptoms (OR = 0.91, 95% CI = 0.84, 0.98) and lower odds of having friends and family who were smokers (ORs ranged from 0.30-0.43). Ex-smokers had lower odds of using cessation aids and higher odds of reporting abrupt quitting during their last quit attempt (OR = 4.48, 95% CI = 2.66, 7.54). CONCLUSIONS: Lower levels of disadvantage, less smoking in social networks, less use of cessation aids and abrupt (vs. gradual) quitting approaches were associated with being an ex-smoker. Lower use of evidence based methods to quit by disadvantaged ex-smokers requires further exploration. [Twyman L, Bonevski B, Paul C, Bryant J, West R, Siahpush M, D'este C, Oldmeadow C, Palazzi K. What factors are associated with abstinence amongst socioeconomically disadvantaged smokers? A cross-sectional survey of use of cessation aids and quitting approach. Drug Alcohol Rev 2017;00:000-000]. PMID- 28616901 TI - [The Methods and Clinical Significance of Early Diagnosis of Lung Cancer]. AB - Lung cancer is the leading contributor to morbidity and mortality from cancer worldwide, with its 5-year overall survival being only about 15.6%. Due to the lack of specific early screening methods for lung cancer, about 75% patients are diagnosed late. Therefore, it remains the big challenge for the early diagnosis of lung cancer. We need to pay more attention to the screening of lung cancer, and more precise assessment and management to the pulmonary nodules screened out. Further study on liquid biopsy, optimization of new fiberoptic bronchoscopy and the sampling methods to harvest small volume of lung tissue, could be helpful to improve the early diagnosis of lung cancer. PMID- 28616902 TI - [Expression of TTF-1, NapsinA, P63, CK5/6 in Lung Cancer and Its Diagnostic Values for Histological Classification]. AB - OBJECTIVES: To investigate the expressions of thyroid transcription factor-1(TTF 1), NapsinA, P63 and CK5/6 in lung cancer tissues and their diagnostic value for histological classification. METHODS: The protein expression in a total of 964 lung cancer samples was detected by immunohistochemistry, of which 929 cases for TTF-1, 113 cases for NapsinA, 282 cases for P63, and 277 for CK5/6, respectively. The correlations between the protein expressions of the four markers and clinicopathological features in lung cancer patients were analyzed. The area under the curves (AUCs) of ROC curves, sensitivity and specificity were calculated to determine the diagnostic values for the four markers. RESULTS: There were 552 cases of lung adenocarcinoma (ADC), 146 cases of lung squamous cell carcinoma (SCC), 253 cases of small cell carcinoma (SCLC), and 13 cases of large cell carcinoma (LCC). The median age was 56 years old, and 63.4% was male. The positive expression rates of TTF-1, NapsinA, P63, and CK5/6 were 76.3% (709/929), 67.3% (76/113) , 47.2% (133/282) and 34.7% (96/277), respectively. The positive expression rates of TTF-1 and NapsinA were higher in lung ADC, and the sensitivity and specificity of TTF-1 in the diagnosis of ADC were 81.15% and 30.41% respectively, those of NapsinA were 82.05% and 65.71% respectively. The AUCs for TTF-1 and NapsinA were 0.557 8 (P=0.002 6, 95%CI:0.520 0-0.595 6) and 0.738 8 (P<0.000 1, 95%CI:0.633 4-0.844 2) respectively. The positive expression rates of P63 and CK5/6 were significantly higher in lung SCC, and their sensitivities to diagnose SCC were 80.68% and 81.25%, with specificity 68.04% and 84.26% respectively. TheAUCsfor P63 and CK5/6 were 0.743 6 (P<0.000 1, 95%CI:0.681 9-0.805 3) and 0.827 6 (P<0.000 1, 95%CI:0.770 0-0.885 2) respectively. Logistic regression model with small sample (44 cases, ADC or SCC) showed that NapsinA was an independent factor to distinguish ADC and SCC (partial regression coefficient=2.826, P=0.022), while the other three markers showed no statistical significance (P>0.05). CONCLUSIONS: TTF-1 and NapsinA can be used as prognositic markers for lung ADC. P63 and CK5/6 can be used as prognostic markers for lung SCC. NapsinA may be used to distinguish ADC and SCC. PMID- 28616903 TI - [Study on the Relationship Between Normalization of Tumor Microvessels and CA9 for Rh-Endostatin to Inhibit Lewis Lung Cancer]. AB - OBJECTIVES: To explore the relationship between normalization of tumor microvessels and CA9 for rh-Endostatin to inhibit Lewis lung cancer (LLC) and the expression level of CA9 in LLC. METHODS: Lewis cells of logarithmic growth phase were collected and made into 1*106 mL-1 cell suspensions were prepared. The transplanted tumor model of LLC was established on C57/BL6 mice by injected 0.2 mL cell suspensions/mice into 40 C57/BL6 mice. 40 LLC mice were randomly divided into control group and rh-ES group (20 mice per group). Control group experienced treatment of intraperitoneal injection (ip) for 0.2 mL NS/d, while rh-ES group was treated for 5 mg rh-ES/(kg.d) from the first to the ninth day. The samples of 5 mice were obtained from day 2, day 4, day 6 and day 9 after treatment in control group or rh-ES group, respectively. CA9 was tested by IHC in LLC and paracancerous tissues and estimated by RT-PCR and ELISA in the each time point of both rh-ES group and control group,respectively. RESULTS: The transplanted tumor model of LLC on C57/BL6 mice was established successfully. The expression of CA9 decreased on day 4 and day 6 in rh-ES group estimated by RT-PCR and ELISA, which indicated some great significance when compared with day 2, day 9 in rh-ES group and day 4, day 6 in control group (P<0.05), and the expression of CA9 in day 2, day 4, day 6, day 9 tested by IHC was higher in LLC than in paracancerous tissues in control group (P<0.05). CONCLUSIONS: The expression of CA9 was higher in LLC. Rh-ES could have positive effect on LLC model of C57/BL6 mice, in day 4-6 (a brief normalized time course) decreased the expression of CA9 and reversed the tumor hypoxia. PMID- 28616904 TI - [The Diagnostic Value of Endobronchial Ultrasound-guided Needle Aspiration Biopsy for Lung or Mediastinal Lymph Node Cancer and Tuberculosis]. AB - OBJECTIVES: To determine the value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in diagnosing lung or mediastinal lymph node cancer and tuberculosis. METHODS: Clinical and pathological data of 553 patients who underwent EBUS-TBNA from January 2013 to September 2016 in West China Hospital of Sichuan University were reviewed. The sensitivity, specificity and accuracy of EBUS-TBNA for diagnosing lymph node tumor and tuberculosis of hilar and mediastinal lymph nodes were calculated. RESULTS: The sensitivity, specificity and accuracy of EBUS-TBNA in diagnosing hilar and mediastinal lymph node cancer were 89.2% (263/295), 100% (247/247) and 94.1% (510/542), respectively, compared with 70% (76/117), 97.2% (385/396) and 89.9% (461/513), respectively, for diagnosing tuberculosis identified though granulomatous biopsy. In the 102 cases with acid fast staining and TB-PCR, 63.7% accuracy (58/91), 90.9% (10/11) sensitivity and 66.7% (68/102) specificity were found for any positive findings from acid fast bacilli or TB-DNA. CONCLUSIONS: EBUS-TBNA has high sensitivity and specificity for diagnosing hilar and mediastinal tumor, which can be used in combination with acid fast staining and TB-PCR for diagnosing tuberculosis. PMID- 28616905 TI - [Clinicopathological Features, Diagnoses and Treatments of 6 458 Lung Cancer Patients]. AB - OBJECTIVES: Lung cancer is the leading cause of cancer-related death on a global scale. This study aimed to review the clinicopathological featuresof primary lung cancer and the practice in diagnoses and treatments. METHODS: Medical record of patients diagnosed with primary lung cancer in West China Hospital of Sichuan University from 2008 to 2014 were retrospectively reviewed. Clinical characteristics of the patients, including pathological type, age, gender, and TNM stage were analyzed. RESULTS: A total of 6 458 patients were diagnosed with primary lung cancer, with male patients comprising the majority (male: 66.5%, n=4 291 vs. female: 33.5%, n=2 167). The patients had an average age of 59.22 yr., mostly (61.1%) between 50 and 70 yr. and 5.1% (n=335) under 40 yr. More than half (53.3%) of the patients were at stage IV at diagnosis, compared with 10.5% at stage I. The most common histological type was adenocarcinoma (ADC, n=3 523, 54.44%), followed by squamous cell carcinoma (SCC, n=1 637, 25.35%) and small cell lung cancer (SCLC, n=916, 14.18%). The majority of patients were confirmed with fibrobronchoscopy and surgery, and treated with surgery and chemotherapy. CONCLUSIONS: Patients diagnosed with primary lung cancer in West China Hospital of Sichuan University are primarily elderly men. Adenocarcinoma is the main type. Fibrobronchoscopyis the main method for diagnosis, and chemotherapy and surgery are the main treatments for lung cancer. PMID- 28616906 TI - [Diagnosis and Surgical Treatment of Lung Ground-glass Opacities:a Review of 663 Cases]. AB - OBJECTIVES: To retrospectively investigate the clinical characteristics, surgical treatments of the patients with lung ground-glass opacities (GGO). METHODS: All the patients, who underwent surgical resection of GGO in our department from Jan. 2013 to Dec. 2016 were retrospectively reviewed. The clinicpathological features were analyzed. RESULTS: A total of 663 patients were included in this study. The rate of malignancy was 92.6% (614/663). The diameter of GGO in benign group [(0.8+/-0.2) cm] was significant smaller than that in malignant group [ (1.5+/ 0.8) cm](P<0.001). The rate of irregular margin in malignant group was far higher than that in benign group (93.8% vs. 20.4%, P<0.001), but other CT signs such as vacuole sign, plural retraction, speculation and lobulation did not show significant difference between the two groups. A total of 652 (98.3%) cases were resected by video-assisted thoracoscopic surgery (VATS), and only 11 (1.7%) cases were resected by thoracotomy. A total of 336 (50.7%) patients underwent lobectomy, 226 (34.1%) underwent segmentectomy and 101 (15.2%) undewent wedge resection. The rate of surgery-related complications was 9.0% (60/663), and one (0.2%) patient died. CONCLUSIONS: With careful selection of GGO by experienced surgeons, the rate of malignancy is very high. Surgical resection may be recommended for highly suspected malignant cases. Sublobar resection or lobcotomy by VATS can achieve good treatment effect. PMID- 28616907 TI - [Differentiation of Cultivated CD45-/CD31+ Mouse Lung Side Population Cells into Vascular Smooth Muscle Cells in vitro]. AB - OBJECTIVES: To investigate the characteristics of differentiation of lung side population cells (LSP cells)in vitro. METHODS: CD45-/CD31+ LSP cells sorted by flow cytometry were taken from mouse lung tissues and cultured for 14 d. The cultured LSP cells were observed with colony formation assay and flow cytometryin vitro. The mRNA expressions of ATP-binding cassette transporter G2 (ABCG2), smooth muscle actin (SMA) and alpha-smooth muscle tropomyosin (alpha-SMT) in both freshly isolated LSP cells and cultured LSP cells were examined. The expressions of ABCG2 and stem cell antigen 1 (Sca1) in LSP cells were detected using immunofluorescence. RT-PCR tests were performed to detect the expressions of ABCG2, SMA and alpha-SMT in LSP cells. RESULTS: The isolated CD45-/CD31+ lung side population cells expressed ABCG2, SMA and Sca1, but not alpha-SMT. A large number of LSP in aggregated state were observed after 14 d of culture. Before induction of differentiation, the CD45-/CD31+ LSP cells expressed ABCG2 and SMA, but not alpha-SMT. After induction of differentiation, the CD45-/CD31+ lung side population cells expressed alpha-SMT and SMA, but not ABCG2. CONCLUSIONS: CD45 /CD31+ LSP cells might be progenitor cells of vascular smooth muscle cells, possessing the characteristics of stem cell differentiations. PMID- 28616908 TI - [The Correlation Between MicroRNAs in Serum and the Extent of Liver Injury]. AB - OBJECTIVES: To investigate the correlation between the absolute quantification of the microRNAs (miR-122, miR-451, miR-92a, miR-192) in serum during acute liver injury and the extent of liver injury on rat models of CCl4 induced acute liver injury and mice models of acetaminophen (APAP) induced acute liver injury. Furthermore, to investigate the correlation between the absolute quantification of microRNAs in serum and the drug induced liver injury pathological scoring system (DILI-PSS). METHODS: The acute liver injury model in rat by CCl4 (1.5 mL/kg), and the acute liver injury model in mice by APAP (160 mg/kg) were established. The serum at different time points on both models were collected respectively. The absolute quantification of microRNAs in serum were detected by using MiRbayTM SV miRNA Assay kit. Meanwhile, the pathological sections of liver tissue of the mice at each time point were collected to analyze the correlation between microRNAs and the degree of liver injury. RESULTS: In CCl4-induced rat acute liver injury model and APAP induced mouse acute liver injury, miR-122 and miR-192 appeared to be rising significantly, which remained the highest level at 24 h after treatment, and declined to the normal level after 72 h. In CCl4 induced rat acute liver injury model, the change of miR-92a was fluctuated and had no apparent rules, miR-451 declined gradually, but not obviously. In mice acute liver injury model induced by APAP, miR-92a and miR-451 in the progress of liver injury declined gradually, reached the lowest point at 48 h, and then recovered. The result of correlation analysis indicated that miR-122 and miR-192 presented a good positive correlation with the DILI-PSS ( r=0.741 3, P<0.05; r=0.788 3, P<0.01). CONCLUSIONS: The absolute quantification of miR-122 and miR 192 in serum has the highest level in 24 h, then decrease in 72 h, in both drug induced and chemical liver injury. In addition, both the two microRNAs have good correlation with DILI-PSS in APAP-induced liver injury models. PMID- 28616909 TI - [MIG7 Regulates the Vasculogenic Mimicry Formation in Hepatocellular Carcinoma then Effects the Metastasis Potential of HCC]. AB - OBJECTIVES: To investigate the expression of migration-inducing gene 7 (MIG7) in different HCC lines and its relationship with vasculogenic mimicry (VM) formation and metastatic potentiality. METHODS: Employing immunostaining to detect MIG7 protein expression and VM formation in 40 matched pairs of primary and metastatic HCC specimens from 40 patients, and investigating the correlation of VM formation with MIG7 protein expression. Detecting VM formation in HCC lines with different metastatic ability (MHCC-97H, MHCC-97L, Huh-7) and human normal hepatocyte line (L-02) through three-dimensional culture, and detecting MIG7 mRNA expression with RT-PCR, investigating the correlation of MIG7 protein expression with VM formation and HCC metastatic potentiality with Western blot assay; screening the HCC cell line with high MIG7 expression. RESULTS: In 40 matched pairs of HCC tissue, there was a significant positive correlation between MIG7 protein expression and VM formation ( rs=0.595, P<0.01). The capability of VM formation of MHCC-97H with high metastatic potentiality was stronger than that of MHCC-97L with low metastatic potentiality and Huh-7 with non-metastatic potentiality, and there was no VM formation in L-02. The result of RT-PCR and Western blot assay indicated the same. CONCLUSIONS: MIG7 expression in HCC tissue is high and correlated positively with VM formation. MIG7 expression in different HCC cell lines is coincident with theirs VM formation, invasion and metastasis. MIG7 is a potential target for inhibiting the invasion and metastasis of HCC. PMID- 28616910 TI - [Effects of Limb Ischemic Postconditioning on Behavioral Improvement and Proliferation of Neural Cells in Rats with Transient Cerebral Ischemia]. AB - OBJECTIVES: To determine the effects of non-invasive limb ischemic postconditioning (NLIP) on the behavioral performance and the expression and distribution of neural cells in rats with ischemic cortex. METHODS: Rats were randomly divided into 3 groups: sham group (n=10), ischemia/reperfusion (I/R) group (n=50), and NLIP group (n=50). Focal cerebral ischemia was induced by intraluminal MCAO in the rats in the I/R and NLIP groups, while no suture was inserted in the sham-operated rats. NLIP (reperfusion-10 min, ischemia-10 min, *3 cycles) was conducted immediately after reperfusion on bilateral femoral arteries by modified ischemicelastic bands. Body mass and behavioral performance of the rats were assessed at 3 d, 7 d, 14 d, 21 d and 28 d post-ischemia (n=5-10). Doublecortin (DCX) and glial fibrillary acidic protein (GFAP) in the ischemic cortex were detected by immunohistochemistry.The expression of microtubule associated protein 2 (MAP2) was detected by Western blot. RESULTS: The rats in the sham group showed mild body mass loss and minor neurological deficit 1-3 d post-ischemia and weakened muscle strength 1 d post-ischemia, which were alleviated gradually overtime. Compared with the sham group, neurological deficits were more obvious in the rats in the I/R and NLIP groups, which were alleviated 3-21 d post-ischemia and reached a level close to that of the sham group at 28 d post-ischemia. No significant difference was found betweenthe I/R and NLIP groups in neurologic deficit scores.NLIP significantly alleviated body mass loss 2-7 d post-ischemia (P<0.05) and improved muscle strength 14-28 d post ischemia (P<0.05).Compared with the sham group, rats in the I/R and NLP groups had increased numbers of DCX and GFAP-labeled cells in the ischemic penumbra over time, increased hypotrophic cell bodies and longer and thickened dendrites, and decreased expression of MAP2 (P>0.05) at 3 d post-ischemia prior to an up regulation.Higher expression of MAP2 was found 14-21 d post-ischemia (P<0.05) in the I/R group and 7-28 d post-ischemia in the NLIP group(P<0.05). Significant difference in MAP2 was found between the I/R and NLIP groups at 7 d post-ischemia (P<0.05). CONCLUSIONS: NLIP has the potential to improve neurological outcomes and promote increase of neural cells in penumbral cortex after cerebral ischemia. PMID- 28616911 TI - [Histone Deacetylation Down-regulates the Expression of BNIP3 in Renal Cell Carcinoma]. AB - OBJECTIVES: To investigate the down-regulation mechanism of (bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) expression in renal cell carcinoma (RCC). METHODS: RCC cell lines 786-O, ACHN and A498 were treated with different concentrations of histone deacetylase inhibitor TSA. Thereafter, the proliferation of RCC cells was determined with CCK-8 assay, cell apoptosis was observed by flow cytometry, and the expression levels of BNIP3 were determined by Q-PCR and Western blot, and the acetylation status of histone H3 in the promoter of BNIP3 was detected by ChIP. RESULTS: After the treatment with TSA, the proliferation of the three RCC cell lines was significantly inhibited (P<0.05), the early apoptosis of cells obviously increased, and the expression levels of BNIP3 mRNA (P<0.05) and protein were up-regulated. The histone H3 in BNIP3 promoter of both 786-O and ACHN was deacetylated, while the histone H3 in BNIP3 promoter of A498 was acetylated. CONCLUSIONS: Histone deacetylation may be the important mechanism of BNIP3 silencing in RCC. PMID- 28616912 TI - [The Roles of Glut5 in Imatinib Resistance in the Ph+ Acute Lymphoblastic Leukemia Cell]. AB - OBJECTIVES: To explore the possible roles of glucose transport 5 (Glut5) in imatinib resistance in the Ph+ acute lymphoblastic leukemia cell (Ph+ ALL). METHODS: The gene chip technique was used to detect different gene expression between Ph+ ALL cell line SUP-B15/R (imatinib resistant cell line) and SUP-B15/S (imatinib sensitive cell line), the gene of solute carrier family 2 member 5 (SLC2A5) and its coded protein Glut5 were screened out and were reconfirmed by qPCR and Western blot assay. The imatinib half maximal inhibitory concentration (IC50) to SUP-B15/S cells with or without fructose treatment was further detected by MTT assay, simultaneously signal pathway gene was detected by qPCR assay. RESULTS: Metabolism related gene SLC2A5 was screened out with gene chip technique and the Western blot assay and qPCR confirmed the high expression of SLC2A5 gene and its coded protein Glut5 in SUP-B15/R cells. IC50 values of imatinib to SUP B15/S cells after treatment with 25 MUmol/L fructose were increased from (44.50+/ 2.38) MUmol/L to (64.71+/-1.69) MUmol/L, in the meanwhile, PI3K and AKT mRNA level also increased in fructose treated SUP-B15/S cells compared to the control. CONCLUSIONS: High expression of SLC2A5 and Glut5 protein in SUP-B15/R cells leads to increased fructose absorption, and further activates PI3K/AKT pathway which cause the SUP-B15 cell resistance to imatinib. PMID- 28616913 TI - [The Effect of Exogenous Recombinant HMGB1 on Neural Stem Cells and Related Mechanism]. AB - OBJECTIVES: To explore the effect of exogenous recombinant high mobility group protein box1 (rHMGB1) on proliferation and differentiation of neural stem cells (NSCs) and the related mechanism. METHODS: SD rat cerebral cortex cells were cultured in serum-free medium, extending the culture and purification of neural stem cells. NSCs were identified by detecting nestin-label with immunofluorescence method.The NSCs proliferation activity after adding different concentrations of rHMGB1 was determined by CCK-8 assay and the optimal concentration of rHMGB1 for the follow-up experiments was selected.The effect of rHMGB1 on NSCs differentiation was detected by immunofluorescence assay. The mRNA and protein expression of involved factors were studied by real-time PCR and Western blot separately. RESULTS: The neural cells isolated from the cortex of rat embryos showed the expression of nestin antigen and the neural stem cells purity could reach more than 99% when cultured to the third generation. Under the stimulation of 10 ng/mL rHMGB1, neural stem cells proliferation activity were the highest, therefore, 10 ng/mL rHMGB1 was selected to treat the experimental group. The expression of TUJ1 in the experimental group was higher than that in the control group (P<0.05). Real-time PCR and Western blot confirmed rHMGB1 could improve the expression of receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), matrix metalloproteinase 9 (MMP-9) and nerve growth factor(NGF) respectively at the level of mRNA and protein expression. CONCLUSIONS: Exogenous rHMGB1 promoted rat NSCs proliferation and differentiation into neuronsin vitro by activating RAGE, TLRs, MMP-9 signaling. PMID- 28616914 TI - [Expressions and Significance of ALDH1, HIF-1alpha and VEGF in Laryngeal Squamous Cell Carcinoma]. AB - OBJECTIVES: To investigate the expressions of aldehyde dehydrogenase 1(ALDH1), hypoxia-inducible factor 1alpha(HIF-1alpha), vascular endothelial growth factor (VEGF) in laryngeal squamous cell carcinoma(LSCC) and their relationships with clinical significance. METHODS: In situ hybridization (ISH) method and immuohistochemical staining were used to detect the mRNA and protein expressions of ALDH1, HIF-1alpha and VEGF in 120 LSCC specimens and 60 cases of normal laryngeal tissue. Their relationships with clinical pathological parameters were analyzed. RESULTS: The positive rates of ALDH1, HIF-1alpha and VEGF mRNA in LSCC were 57.5% (69/120) , 73.3% (88/120) , 56.7% (68/120) , while the positive rates of proteins were 55.8% (67/120) , 70.8% (85/120) and 55.0% (66/120) , respectively. which were significantly higher than those in controls (P<0.05) . The expression of ALDH1 and VEGF proteins were significantly correlated with TNM stage and lymph node metastasis (P<0.05) . The expression of HIF-1alpha protein was significantly correlated with TNM stage, the degree of differentiation and lymph node metastasis (P<0.05). The positive expression of ALDH1 was positively associated with those of HIF-1alpha and VEGF (P<0.05). The lymph node metastasis rate increased with the positive factors. Kaplan-Meier survival analysis showed that the patients with positive expression of ALDH1, HIF-1alpha and VEGF had lower 5-year overall survival rate than those with negative expression (P<0.05) . CONCLUSIONS: The expressions of ALDH1, HIF-1alpha and VEGF are higher in LSCC, which may be used to determine the malignancy and prognosis of LSCC. PMID- 28616915 TI - [Association of Elevated Platelet Microparticles with Disease Activity in Rheumatoid Arthritis]. AB - OBJECTIVES: To explore the expression of platelets microparticles (PMPs) in peripheral blood (PB) and synovial fluid (SF) of rheumatoid arthritis (RA) patients and its correlation with clinical inflammatory parameters. METHODS: The levels of PMPs in PB were detected by flow cytometry in 26 active RA patients and 15 healthy control (HC). SF was collected from 16 patients. The percentages of CD62P+PMPs, CD154+PMPs and clinical parameters (including CRP, ESR, RF and ACPA) were also measured, then the correlations of PMPs with these parameters were analyzed. RESULTS: PMPs levels in PB of RA patients were higher than those in PB from HC and those in SF of RA patients (P< 0.01). CD62P+PMPs levels in PB of RA patients were higher than those in PB of HC and those in SF of RA patients (P< 0.05). CD154+PMPs levels in PB of RA patients were higher than those in PB of HC (P< 0.01) and those in SF of RA patients (P< 0.05). The levels of PB PMPs were positively correlated with disease activity score DAS28 ( r=0.462, P=0.018), but not with ESR, CRP, RF or ACPA. The levels of SF PMPs were not correlated with any of them (P>0.05). CONCLUSIONS: PMPs may be involved in immune regulation and systemic inflammation of RA. The elevated levels of PMPs could be a potential biomarker for RA. PMID- 28616916 TI - [Relationship Between LEP G2548A Polymorphism and Cholesterol Gallstone]. AB - OBJECTIVES: To determine the associations of single nucleotide polymorphism (SNP) in leptin (LEP) genes and environmental factors with cholesterol gallstone in southeast Han populations. METHODS: A 1:2 matched case-control study was conducted involving 200 patients with cholesterol gallstone. Genotyping of the SNP was examined on the LightCycler480 PCR platform using in-house high resolution melting (HRM) approaches. Detection correctness was validated through direct sequencing. Multifactor dimensionality reduction (MDR) analysis was applied to examine the effects of potential gene-environment interactions. RESULTS: Three genotypes of LEP G2548A were obtained by HRM genotyping, including 52 cases of GG wild type, 192 cases of GA mutant heterozygosity and 356 cases of AA mutation homozygous type. The genotype distribution of the SNP locus in the control group was in line with the Hardy-Weinberg genetic balance (P>0.05). The AA genotype carriers of LEP G2548A had significantly higher serum leptin than the GA/GG genotype carriers (H=6.83, P<0.05). The conditional logistic regression revealed that high serum leptin [odds ratio (OR)=5.012, 95% confidence interval (CI): 3.248-7.734], AA genotype of LEP G2548A site (OR=2.292, 95%CI: 1.012 5.193), family history of gallstones (OR=2.984, 95%CI: 1.329-6.700), high SBP (OR=1.927, 95%CI: 1.140-3.255) and smoking (OR=1.717, 95%CI: 1.006-2.928) were predictors of cholesterol gallstone. However, regular drinking of strong tea (OR=0.552, 95%CI: 0.336-0.907) and exercise (OR=0.591, 95%CI: 0.395-0.882) were protecting factors for cholesterol gallstone. The results of MDR analysis indicated that tea drinking, genotype of LEP G2548A site and serum leptin formed the optimal gene-environment interaction model. CONCLUSIONS: Individuals who drink less tea, carry AA genotype and have high serum leptin are more susceptible to cholesterol gallstone. PMID- 28616917 TI - [A Study on the Feasibility to Assay Minipig Insulin Through Human Insulin Radioimmunoassay Kit]. AB - OBJECTIVES: To investigate the feasibility of using human-specific insulin radioimmunoassay (Ins-RIA) kit to measure the concentrations of serum insulin in minipigs. METHODS: The Serum samples (219) of Bama minipigs were collected. The concentrations of serum insulin in Bama minipigs were measured by Ins-RIA kit and porcine-specific insulin enzyme linked immunosorbent assay (Ins-ELISA) kit, respectively. The linear regression analysis was undertaken in a randomly selected 175 samples (80% of total samples) to establish predictive equations between the concentrations of serum insulin measured by Ins-ELISA and the concentrations of serum insulin measured by Ins-RIA. The equations were then cross-validated in the remaining 44 samples (20% of total samples) that had not been included in the regression analysis. RESULTS: Measured insulin concentration was lower with the Ins-ELISA than that with the Ins-RIA [(15.32+/-15.50) MUIU/mL vs. (32.31+/-21.74) MUIU/mL, respectively, P<0.000 1]; The final predictive equation for the Ins-ELISA (MUIU/mL) was equal to -7.29+0.70 * Ins-RIA(MUIU/mL) ( R2=0.94). The differences between the predicted values and the actual measured values were 17.18%. CONCLUSIONS: Insulin values in Bama minipigs obtained from the Ins-ELISA and Ins-RIA are not equivalent and differ significantly. However, the insulin concentration by Ins-ELISA can be well estimated by Ins-RIA. PMID- 28616918 TI - [Value of Procalcitonin, High Sensitivity C-reactive Protein and Pancreatic Stone Protein in Predicting Prognosis of Children with Sepsis]. AB - OBJECTIVES: To determine the value of procalcitonin (PCT), high sensitivity C reactive protein (hs-CRP) and pancreatic stone protein(PSP) in predicting the prognosis of children with sepsis. METHODS: A total of 106 hospitalized children [(4.4+/-1.6) year-old] with sepsis were enrolled in this study. The expressions of PTC, hs-CRP and PSP in the serum samples of the children were detected on the first day of admission to hospital. Pearson correlation analyses were performed to test the correlations between pediatric critical illness score (PCIS) and PTC, hs-CRP and PSP. Logistic regression models were established to determine factors predicting death of children. The value of PTC, hs-CRP and PSP in predicting the prognosis of children with sepsis was determined using ROC curves. RESULTS: About 32% children (34 cases) died. Higher expressions of PTC, hs-CRP and PSP were found in those who died (P<0.001). Serum PTC, hs-CRP and PSP were negatively correlated with PCIS (P<0.001). The multivariate logistic regression showed that PTC, hs-CRP and PSP were independent predictors of death in patients with sepsis (P<0.001). PTC, hs-CRP and PSP had an area under the curve (AUC) value of 0.86[ (95% confidence interval (CI), 0.78-0.92], 0.70 (95%CI, 0.61-0.79) and 0.69 (95%CI, 0.60-0.78) , respectively.The AUC value increased (P<0.001) to 0.92 (95%CI, 0.85-0.96) when the three indicators were combined (0.481*PCT+0.392*hs CRP +0.314*PSP), with a value of less than 122.3 indicating good prognosis in 28 d. CONCLUSIONS: Serum PTC, hs-CRP and PSP can predict prognosis of children with sepsis. PMID- 28616919 TI - [Effects of Early Enteral Immunonutrition on Postoperative Immune Function and Rehabilitation of Patients with Gastric Cancer and Nutritional Risk]. AB - OBJECTIVES: To investigate the effects of early enteral immunonutrition on postoperative immune function and rehabilitation of gastric cancer patients with nutritional risk. METHODS: New hospitalized patients with gastric cancer were evaluated the nutrient status based on NRS 2002. The patients who scored between 3 to 5 points were randomized into two groups(30 cases for each group), and those in experimental group were given 7-d early postoperative enteral immune nutrition, those in control group were given normal nutrition. The immune indexes (CD3+, CD4+, CD8+ and CD4+/CD8+) and nutritional indexes(transferrin, pre albumin, albumin) were measured before operation and at the 3rd and 7th day postoperatively. In addition, the first flatus time, gastrointestinal adverse reactions and complications, length of hospital stays were compared between the two groups. RESULTS: The level of CD4+/CD8+ and transferrin, pre-albumin, albumin in experimental group were significantly higher than those in control group at the third and seventh day postoperatively (P<0.05).Compared with the control group, the experimental group had shorter first flatus time after surgery, which were (63.5+/-7.3) h vs. (72.8+/-8.6 ) h respectively (P<0.05).There were no statistically difference on pneumonia, anastomosis leakage, severe abdominal distension, inflammatory bowel obstruction and total postoperative hospitalization time between the two groups (P>0.05). CONCLUSIONS: Early enteral immunonutrition can effectively promote the recovery of nutritional status and immune function in gastric cancer patients with nutrition risk. PMID- 28616920 TI - [Association of GH and IGF-1 Burden with Cardiac Structural and Functional Changes in Acromegaly Patients]. AB - OBJECTIVES: To investigate the association of growth hormone (GH) and insulin like growth factor (IGF-1) burden with the cardiac structural and functional changes in acromegaly patients. METHODS: Ninety-nine acromegaly patients were enrolled in this study. According to the normal range of echocardiographic parameters of Peking Union Medical College Hospital, the patients were divided into parameter normal group and abnormal group. Correlation analyses were conducted between duration of disease, mean GH, mean IGF-1, GH burden, IGF-1 burden and echocardiography data retrospectively. RESULTS: Forty eight cases (48.5%) was diagnosed as abnormal echocardiography, including enlargement of the cardiac cambers (29.3%), valvular diseases (15.1%), dilation of aortic root (5.1%), functional abnormal of left ventricle (19.2%) and wall motion abnormalities (1.0%). The average GH and IGF-1 burdens in echocardiography abnormal group (n=48) were higher than those in the normal group (n=51), without statistical significant except for the left ventricle end-systolic diameter (LVESD) (P=0.018) in GH burden comparison and E/A (P=0.011) and left atrium longitudinal dimension (LALD) (P=0.017) in IGF-1 burden comparison. Abnormal diastolic function group (n=18) had similar GH burden with the normal group (n=81) (P=0.419), but had higher IGF-1 burden than the normal group did (P=0.018).The GH burden correlated with left ventricle end-diastolic diameter (LVEDD) and LVESD, and the IGF-1 burden correlated with left ventricular ejection fraction (LVEF) , LALD, right ventricle longitudinal dimension( RVLD), Left ventricular posterior wall thickness (LVPWT), LVEDD, LVESD, and E/A ratio statistical significantlly (P<0.05). CONCLUSIONS: There exist associations of GH and IGF-1 burden with echocardiography abnormalities and cardiac complications. PMID- 28616921 TI - [Prevalence of Anxiety and Depression in Hospitalized Patients with Heart Failure]. AB - OBJECTIVES: To determine the prevalence of anxiety and depression in hospitalized patients with heart failure. METHODS: From September 2015 to March 2016, 301 patients who were admitted to the cardiac ward of a tertiary hospital for heart failure were consecutively enrolled in this study. They were assessed with the Hospital Anxiety Depression Scale (HADs). Multivariate logistic regression analysis was performed to identify risk factors associated with anxiety and depression. RESULTS: Of the 301 participants, 124 (41.2%) were identified with anxiety and 177 (58.8%) with depression; 98 (32.6%) had both anxiety and depression. Higher prevalence of anxiety was found in female patients and those who resided in rural areas, had poor family support, had a class IV New York heart association (NYHA), and were admitted repeatedly (3 or more) for heart failure over the past year. Higher prevalence of depression was found in the patients with poor family support and those who had primary or lower education, had a class IV NYHA, and were in normal or under-weight range. The severity of the two conditions was positively correlated ( r=0.617, P<0.05). The multivariate logistic regression models identified female (OR=2.045), class IV NYHA (OR=1.955), 3 or more repeated admissions for heart failure (OR=2.288) as predictors for anxiety and/or depression. CONCLUSIONS: Anxiety and depression is prevalent in hospitalized patients with heart failure. Increased attention needs to be paid to the psychological health of those patients in high risk. PMID- 28616922 TI - [Clinical Characteristics of Patients with Type 2 Diabetes Mellitus and Obstructive Sleep Apnea Syndrome]. AB - OBJECTIVES: To compare the clinical characteristics and prevalence of chronic complications in type 2 diabetes mellitus (T2DM) patients with various degrees of obstructive sleep apnea syndrome (OSAS). METHODS: A total of 170 patients with T2DM and OSAS were enrolled in this study. These participants were divided into three groups with low, medium and high apnea-hypopnea index (AHI), respectively. The demographic characteristics, biochemical indicators and chronic complications of the patients in the three groups were compared. Multivariate Logistic regression analysis was performed to determine the associations between chronic complications and OSAS. RESULTS: The patients with severe OSAS had higher waist circumference (P=0.045), higher BMI (P=0.069), higher prevalence of diabetic peripheral neuropathy (DPN), and higher prevalence of diabetic retinopathy (DR) than the patients with mild-moderate OSAS. Similar levels of macrovascular complications were found in the three groups (P>0.05). The logistic regression analyses showed that DPN (OR=1.024, 95%CI 1.002-1.046) and chronic kidney disease (OR=1.026, 95%CI 1.004-1.049) were independent predictors of AHI, adjusting for the lowest oxygen saturation, gender, age, diabetic duration, family history of diabetes, BMI, and HbA1c. Other microvascular and macrovascular complications were not predictors of AHI. CONCLUSIONS: Patients with T2DM and severe OSAS have a higher risk of DPN and DR. Particular attention should be paid to T2DM patients with severe OSAS to prevent complications. PMID- 28616923 TI - [Effects of Tramadol on Insulin Resistance during Cesarean Section Complicated with Gestational Diabetes Mellitus]. AB - OBJECTIVES: To investigate the effects of tramadol on insulin resistance (IR) during cesarean section complicated with gestational diabetes mellitus (GDM). METHODS: 120 patients of elective caesarean sectioncomplicated with GDM (level A1) were collected from Dec.2015 to Oct.2016, randomly divided into the tramadol injection treated groups (0.5 mg/kg-TRM1, 1 mg/kg-TRM2 and 1.5 mg/kg-TRM3) and the control group (CON) (n=30). The patients of TRM groups were injected with tramadol after delivery of fetus during caesarean delivery under combined spinal epidural anaesthesia (CSEA) and the patients of CON group were treated with normal saline as control. The plasma were collected before CSEA (T0), after delivery of fetus (T1) and immediately after caesarean section (T2) for determination of the expression of blood glucose, insulin, HOMA-IR, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) by hexokinase, chemiluminescence method and ELISA. The activation of PI3K/Akt signaling pathway of epiploon were detected by RT-PCR and Western blot. RESULTS: Compared with T0, the concentration of blood glucose, insulin, HOMA-IR, IL-6 and TNF-alpha increased significantly in T1 and T2 (P<0.05). The factors of above decreased in T2 of TRM2 group and TRM3 group comparing with CON group, but of no significant differences between TRM1 group and CON group. Compared with CON group in T2, PI3K/Akt signaling pathway activated significantly in TRM2 group and TRM3 group (P<0.05). CONCLUSIONS: The tramadol can attenuate IR during cesarean section complicated with GDM and may regulate the secretion of IL-6, TNF-alpha and PI3K/Akt signaling pathway in the treatment of IR of GDM. PMID- 28616924 TI - [Reference Intervals of Thyroid Hormones in Normal Pregnant Women and Effects of Thyroid Autoantibodies on Thyroid Hormone Levels in Pregnant Women in Chengdu Area]. AB - OBJECTIVES: To establish the reference intervals of thyroid hormones in normal pregnant women in Chengdu area of China, and to investigate the effects of thyroid autoantibodies on thyroid function in pregnant women. METHODS: We included 696 pregnant women who had gestation data from June 2013 to March 2014 in Chengdu Women & Children's Central Hospital. Every subject under went questionnaire survey, physical examination, thyroid ultrasound and measurement of thyroid hormone and thyroid autoantibodies. The normal reference intervals were established according to the percentiles (P2.5-P97.5) of the healthy pregnant women in the same trimester. Another 50 non-pregnant women were selected as the control group. RESULTS: Of the 696 pregnant women, 579 subjects had negative thyroid autoantibodies and 117 subjects had positive thyroid autoantibodies. The positive rate of thyroid autoantibodies was 16.81%. Of the 579 subjects with negative thyroid autoantibodies, 257 were in the first trimester, 202 in the second trimester and 120 in the third trimester. In the first trimester of normal pregnancy, the reference intervals of serum thyrotropin (TSH) , free triiodothyronine (FT3) and free thyroxine (FT4) were 0.02-4.03 mIU/L, 3.85-6.27 pmol/L and 11.93-21.04 pmol/L respectively. In the second trimester, the reference intervals of serum TSH, FT3 and FT4 were 0.02-4.05 mIU/L, 3.51-5.82 pmol/L and 11.23-19.22 pmol/L respectively. In the thirdtrimester, the reference intervals for serum TSH, FT3 and FT4 were 0.24-5.41 mIU/L, 3.18-4.97 pmol/L and 11.10-17.00 pmol/L, respectively. When compared with non-pregnant women, the median TSH value was increasingly consisted with the progress of pregnancy period, while the median FT4 and FT3 values were decreasing accordingly. The similar tendencies of TSH, FT3, and FT4 were found in pregnant women with positive thyroid autoantibodies, but the trends were more remarkable when compared with those with negative thyroid autoantibodies. In pregnant women with positive thyroid autoantibodies, the incidences of clinical hypothyroidism, subclinical hypothyroidism and clinical hyperthyroidism were 0.85%, 15.38% and 0.85%, respectively. CONCLUSIONS: The thyroid hormone reference ranges of pregnant women is quite different from those of non-pregnant women. It is necessary to establish the reference intervals of thyroid hormones in normal pregnant women. Thyroid function of pregnant women with positive thyroid autoantibodies should be monitored during the pregnant period. PMID- 28616925 TI - [Perceptions and Attitudes of Chengdu Residents toward "Medical and Aged Care" Integrated Models]. AB - OBJECTIVES: To investigate the perceptions and attitudes of Chengdu residents toward "medical and aged care" integrated models and associated factors. METHODS: A cross-sectional questionnaire survey was conducted in 935 residents who were 45 years or older in 8 communities in Chengdu. Descriptive analyses and logistic binary regression analyses were performed. RESULTS: About 91.1% of respondents preferred self-care and family support, and only 8.9% preferred community and institutional care. About 84.9% of respondents reported no knowledge about the "medical and aged care" integrated models, and 15.1% had some basic understanding of the integrated care models. Middle-aged respondents were more likely to understand the integrated care models than their older counterparts, with 21.7% willing to endorse the integrated care models. The logistic regression analyses showed that age, educational attainment, marital status, chronic illness, available financial support, and knowledge and awareness were associated with the choice. CONCLUSIONS: Chengdu residents have low level of knowledge and awareness of the "medical and aged care" integrated models. Public education is needed to promote the new aged care models. PMID- 28616926 TI - [Clinical Application of Chromosomal Microarray Analysis in Karyotyping with Uncertain Genomic Rearrangement]. AB - OBJECTIVES: To apply chromosomal microarray analysis (CMA) in the diagnosis of karyotyping with uncertain genomic rearrangement. METHODS: We retrospectively reviewed 48 samples (34 samples of amniotic fluid, 14 samples of peripheral blood) of karyotype analyses with uncertain genomic rearrangement in patients admitted to our department from September 2014 to April 2016. The CMA results were compared with those of karyotyping. RESULTS: The 48 samples consisted of 13 samples with marker chromosomes, 19 samples with derivative chromosomes, and 16 samples with balanced translocation. Sixteen cases (33.33%) were detected with abnormalities by CMA. In the 32 samples with marker chromosomes or derivative chromosomes, 16 cases were detected with deletions or duplications (>5 Mb) by CMA, including 1 case 21-trisomy, 2 cases XYY syndrome and 3 cases microdeletion/ microduplication syndromes (22q11 duplication syndrome, Wolf-Hirschhorn syndrome and 15q26 overgrowth syndrome). In the 16 balanced translocation cases, all revealed negative results in CMA. CONCLUSIONS: CMA can confirm the karyotyping with uncertain genomic rearrangement and clarify its clinical significance. PMID- 28616927 TI - [Technology and MethodsSimultaneous Determination of 9 Natural Ingredientsin Functional Food for Anti-hangover and Hepatoprotection by High Performance Liquid Chromatography]. AB - OBJECTIVES: To develop a rapid method of high performance liquid chromatography coupled with variable wave length UV detection for simultaneous determination of 9 natural functional ingredients including puerarin, silymarin, quercetin hydrate, schisandrol A, curcumin, tanshinoneI, tanshinoneIIA, cryptotanshinone, and dihydrotanshinoneIin functional food for anti-hangover and hepatoprotection. METHODS: The samples were ultrasonically extracted with 90 % ethanol (V/V) and centrifuged at 10 000 r/min for 10 min prior to HPLC analysis. The nine target analytes were separated on a C18 column with gradient elution using methanol and water (The pH value was adjusted to 2.5 using H3PO4) as the mobile phase. Qualitative analysis was carried out using retention times of the chromatographic peaks, while the external standard curves were established for quantification. RESULTS: Under the optimal analytical conditions, the peak area of each analyte and its concentration had a good correlation within the linear range ( r>=0.998). The limits of detection and quantification of the method were 0.38-0.73 mg/kg (S/N=3) and 1.27-2.43 mg/kg (S/N=10), respectively. The spiked recoveries of the analytes were 88.9%-103.2%, and the relative standard deviations were 1.3%-3.7%. CONCLUSIONS: The method for the determination of 9 functional ingredients in functional food for anti-hangover and hepatoprotection was proposed for the first time in this study. The results showed that it could meet the requirement of routine analysis and quality control and evaluation. PMID- 28616928 TI - [Clinical Study of Rs-EPI DWI to Improve Imaging Quality and Assessment on Intracranial Mass Lesions]. AB - OBJECTIVES: To explore the clinical value of readout-segmented echo planar imaging (Rs-EPI) sequence in the assessment of intracranial mass lesions compared to the standard single-shot EPI (Ss-EPI) sequence. METHODS: We included 21 patients with intracranial mass lesions who underwent both Ss-EPI diffusion weighted imaging (DWI) and Rs-EPI DWI at 3.0T MR scanner with a twenty-channel head-neck coil. The quality of images was assessed by two experienced radiologists independently. The differences in image quality between two sequences were analyzed using Wilcoxon signed-rank test. Inter-observer agreements were analyzed using interclass correlation coefficient (ICC) and Kappa test. RESULTS: All objectives were completed on 3.0T MR. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in Rs-EPI DWI were higher than those in Ss-EPI DWI (130.46+/-49.10 vs. 71.58+/-30.43, P=0.000; 33.22+/-18.86 vs. 17.92+/-18.72, P=0.003). The scores of overall image quality, ghost artifact where next to the paranasal sinuses, mastoid air cells and frontal sinus of Rs EPI DWI were significantly higher than those of Ss-EPI DWI. Meanwhile, the geometric distortion of anatomical structures of Rs-EPI DWI were significantly lower compared to Ss-EPI DWI sequence (0.016+/-0.021 vs. 0.037+/-0.069, P=0.00). The inter-reader and intra-reader agreements for the assessment of qualitative parameters were good [0.74<=Kappa value or ICC<=0.92]. CONCLUSIONS: Rs-EPI DWI sequence is a potential technique to improve the imaging quality in the diagnosis of intracranial mass lesions. PMID- 28616929 TI - [Clinical MedicineThe Evaluation of He-Ne Laser Therapy Help Wound Healing of Nail Surgery]. AB - OBJECTIVES: To investigate the effect of He-Ne laser therapy on wound healing after nail surgery. METHODS: Patients who needed nail surgery were divided into treatment group (n=20) and control group (n=20) randomly.The He-Ne laser was applied to the wound after nail surgery in treatment group. The wound healing time, the inflammation duration, the pain rating, and the nail plate full-grown time were compared with control group. RESULTS: No significant differences in baseline of two groups were observed. The wound healing time was (16.00+/-2.51) d in control group and (11.35+/-1.73 ) d in treatment group, the inflammation duration was (9.10+/-2.10) d in control group and (7.20+/-1.44) d in treatment group (P<0.05), both above differences were significant (P<0.05).The nail plate full-grown time was (21.00+/-2.13) weeks in treatment group, whereas (21.40+/ 1.05) weeks in control group (P>0.05).The pain rating of the 2 groups was different from 25 h (after 3 times treatment)(P<0.05). Pain disappeared in 85.0% (17/20) patients of treatment group after 49 h (5 times treatment), and completely disappeared (20/20) after 54 h (6 times treatment), which were faster than those of control group at the same time points (pain disappeared only in 50.0% and 98.5% of patients respectively). CONCLUSIONS: He-Ne laser therapy can help wound healing after nail surgery. PMID- 28616930 TI - [A Study of Etiology Classification of Minor Stroke Based on TOAST and ASCO Systems]. AB - OBJECTIVES: To investigate the differences in the etiology between minor stroke and non-minor stroke based on TOAST and ASCO systems, and to guide the early intervention for minor stroke. METHODS: We retrospectively analyzed the patients with acute ischemic stroke admitted to our department from July 2012 to July 2014. We sub-typed minor stroke patients and non-minor stroke patients in etiology using Trial of Org 10172 in Acute Stroke Treatment (TOAST) and ASCO (A for atherosclerosis, S for small vessel disease, C for Cardiac source, O for other cause) systems respectively to investigate the difference of etiology between the two groups. RESULTS: We included a total of 406 patients with minor stroke and 651 patients with non-minor stroke. The constituent ratio of TOAST was different (P<0.001) between the two groups. small-artery occlusion (SAO) was the highest cause (40.4%, 164 cases) in minor stroke group, while stroke undertermined etiology (SUE) was the most common (30.9%, 201 cases)in non-minor stroke group. The A1+2 ratio and C1+2 ratio in minor stroke group were lower than those in non-minor stroke group (22.8% vs. 35.4%, P<0.001; 19.3% vs. 32.1%, P<0.001), and the ratio of S1+2 was higher than that in non-minor stroke group (49.8% vs. 27.3%, P<0.001). CONCLUSIONS: The etiology of minor stroke is different to non-minor stroke SAO is the most common cause in minor stroke, while CE and LAA are more common in non-minor stroke. PMID- 28616931 TI - Database for Rapid Dereplication of Known Natural Products Using Data from MS and Fast NMR Experiments. AB - The discovery of novel and/or new bioactive natural products from biota sources is often confounded by the reisolation of known natural products. Dereplication strategies that involve the analysis of NMR and MS spectroscopic data to infer structural features present in purified natural products in combination with database searches of these substructures provide an efficient method to rapidly identify known natural products. Unfortunately this strategy has been hampered by the lack of publically available and comprehensive natural product databases and open source cheminformatics tools. A new platform, DEREP-NP, has been developed to help solve this problem. DEREP-NP uses the open source cheminformatics program DataWarrior to generate a database containing counts of 65 structural fragments present in 229 358 natural product structures derived from plants, animals, and microorganisms, published before 2013 and freely available in the nonproprietary Universal Natural Products Database (UNPD). By counting the number of times one or more of these structural features occurs in an unknown compound, as deduced from the analysis of its NMR (1H, HSQC, and/or HMBC) and/or MS data, matching structures carrying the same numeric combination of searched structural features can be retrieved from the database. Confirmation that the matching structure is the same compound can then be verified through literature comparison of spectroscopic data. This methodology can be applied to both purified natural products and fractions containing a small number of individual compounds that are often generated as screening libraries. The utility of DEREP-NP has been verified through the analysis of spectra derived from compounds (and fractions containing two or three compounds) isolated from plant, marine invertebrate, and fungal sources. DEREP-NP is freely available at https://github.com/clzani/DEREP-NP and will help to streamline the natural product discovery process. PMID- 28616932 TI - Analysis of "Accuracy and User Performance Evaluation of a New, Wireless-Enabled Blood Glucose Monitoring System That Links to a Smart Mobile Device". AB - In the study published in Journal of Diabetes, Science and Technology, Timothy S. Bailey and coauthors evaluated system accuracy and user performance of a new, wireless-enabled blood glucose monitoring system, the Contour Plus ONE blood glucose monitoring system. The authors declare that the study protocol was performed according to ISO 15197:2013 guidelines, in particular to clauses 6.3 and 8. Results show a high level of accuracy of the product in a laboratory setting as well as in the hands of lay users. However, differences between both study parts emerge that stimulate discussion about the used comparison method. PMID- 28616933 TI - Split hand index and ulnar to median ratio in Hirayama disease and amyotrophic lateral sclerosis. AB - OBJECTIVE: We report the relative usefulness of split hand index (SHI) and ulnar to median (UM) ratio in Hirayama disease (HD) and amyotrophic lateral sclerosis (ALS). METHODS: The patients with HD, ALS and matched controls were subjected to evaluation of UM ratio and SHI. Compound muscle action potentials (CMAPs) were recorded from abductor digit minimi (ADM) and first dorsal interosseous (FDI) by stimulating ulnar nerve at the wrist, and abductor pollicis brevis (APB) by stimulating median nerve at the wrist. UM ratio (ADM/APB) and SHI (APB * FDI/ADM) were calculated, and compared. Sensitivity and specificity of SHI and UM ratio in HD and ALS were calculated. RESULTS: Twenty-six HD and 31 ALS patients were included. Twenty-six matched controls for HD and 20 for ALS were also evaluated. The APB amplitude was significantly lower in ALS compared to HD (6.89 +/- 2.0 mv vs. 2.13 +/- 1.27 mv, p = 0.01). UM ratio <0.86 had a sensitivity of 80.4% and specificity of 86.3% for HD. SH1 <= 5.2 had a sensitivity of 82% and specificity of 88.8% for ALS. UM ratio had a poor specificity for ALS (18.9%) and SHI for HD (34%). CONCLUSION: UM ratio is more sensitive and specific for HD and SHI for ALS patients. PMID- 28616934 TI - Temporal Trends in the Prevalence and Incidence of Diagnosed ADHD in Children and Young Adults between 1999 and 2012 in Canada: A Data Linkage Study. AB - OBJECTIVE: There is a need for the routine monitoring of treated attention deficit hyperactivity disorder (ADHD) for timely policy making. The objective is to report and assess over a decade the prevalence and incidence of diagnosed ADHD in Canada. METHODS: Administrative linked patient data from the provinces of Manitoba, Ontario, Quebec, and Nova Scotia were obtained from the same sources as the Canadian Chronic Diseases Surveillance Systems to assess the prevalence and incidence of a primary physician diagnosis of ADHD ( ICD-9 and ICD-10 codes: 314, F90.x) for consultations in outpatient and inpatient settings (Med-Echo in Quebec, the Canadian Institute of Health Information Discharge Abstract Database in the 3 other provinces, plus the Ontario Mental Health Reporting System). Dates of service, diagnosis, and physician specialty were retained. The estimates were presented in yearly brackets between 1999-2000 and 2011-2012 by age and sex groups. RESULTS: The prevalence of ADHD between 1999 and 2012 increased in all provinces and for all groups. The prevalence was approximately 3 times higher in boys than in girls, and the highest prevalence was observed in the 10- to 14-year age group. The incidence increased between 1999 and 2012 in Manitoba, Quebec, and Nova Scotia but remained stable in Ontario. Incident cases were more frequently diagnosed by general practitioners followed by either psychiatrists or paediatricians depending on the province. CONCLUSION: The prevalence and incidence of diagnosed ADHD did not increase similarly across all provinces in Canada between 1999 and 2012. Over half of cases were diagnosed by a general practitioner. PMID- 28616936 TI - Encephaloduroateriosynangiosis (EDAS) in the management of Moyamoya syndrome in children with sickle cell disease. AB - BACKGROUND: Encephalo-duro-arterio-synangiosis (EDAS) in Moyamoya syndrome (MMS) treatment has been well described in the literature, however in MMS caused by sickle cell anaemia (SCA), EDAS use remains controversial with poor long-term follow-up. We present a case-series of SCA patients who have undergone EDAS for SCA-related MMS and describe their post-operative course as well as provide a literature review of the role of EDAS in the treatment of sickle cell anaemia. METHODS: A retrospective review of all the paediatric EDAS procedures conducted in our institution for SCA from 2007 to 2015. Two patients underwent behavioural screening. RESULTS: A total of eight patients with MMS secondary to SCA underwent EDAS. Unilateral EDAS was performed without complication in seven patients. One patient underwent bilateral EDAS but with a two-year gap in between procedures. Follow-up magnetic resonance angiography demonstrated no progression of Moyamoya collaterals or further ischaemic events with regression of collaterals clearly visible in one patient. All patients have demonstrated a return to normal school activities. CONCLUSIONS: EDAS is a well-tolerated revascularisation procedure for children with MMS. The prevention of further infarcts in our group with sickle cell disease has allowed these children to resume normal school activities. PMID- 28616935 TI - Service Use and Unmet Needs for Substance Use and Mental Disorders in Canada. AB - OBJECTIVE: To investigate patterns and predictors of help seeking and met/unmet needs for mental health care in a national population health survey. METHOD: Participants were respondents to the 2012 Canadian Community Health Survey on Mental Health (CCHS-MH; n = 25,133). We used regression to identify the diagnostic and sociodemographic predictors of the use of informal supports, primary care, and specialist care, as well as perceived unmet needs. RESULTS: Eleven percent of Canadians reported using professionally led services for mental health or substance use in 2012, while another 9% received informal supports. Two thirds of people with substance use disorders did not receive any care, and among those who did, informal supports were most common. Seventy-four percent of people with mood/anxiety disorders and 88% of those with co-occurring disorders did access services, most commonly specialist mental health care. Men, older people, members of ethnocultural minorities, those not born in Canada, those with lower education, and those with higher incomes were less likely to receive care. Unmet needs were higher among people with substance use disorders. CONCLUSIONS: Gaps in services continue to exist for some potentially vulnerable population subgroups. Policy and practice solutions are needed to address these unmet needs. In particular, the convergence of research pointing to gaps in the availability and accessibility of high-quality services for substance use in Canada demands attention. PMID- 28616937 TI - Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study. AB - OBJECTIVE: To assess the prognostic influence of pre-morbid type 2 diabetes mellitus, arterial hypertension and cardiovascular (CV) risk profile on ALS phenotype and outcome in a population-based cohort of Italian patients. METHODS: A total of 650 ALS patients from the Piemonte/Valle d'Aosta Register for ALS, incident in the 2007-2011 period, were recruited. Information about premorbid presence of type 2 diabetes mellitus, arterial hypertension was collected at the time of diagnosis. Patients' CV risk profile was calculated according to the Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice (JBS2). RESULTS: At the univariate analysis, the presence of pre-morbid arterial hypertension was associated with a higher age at onset of ALS and a shorter survival, and patients with a high CV risk profile had a worse prognosis than those with a low CV risk profile. The Cox multivariable analysis did not confirm such findings. Type 2 diabetes mellitus did not modify either the phenotype or the prognosis of ALS patients. CONCLUSIONS: This study performed on a large population-based cohort of ALS patients has demonstrated that arterial hypertension, type 2 diabetes and CV risk factors, calculated using the Framingham equation, do not influence ALS phenotype and prognosis. PMID- 28616938 TI - Construction of an all-solid-state artificial Z-scheme system consisting of Bi2WO6/Au/CdS nanostructure for photocatalytic CO2 reduction into renewable hydrocarbon fuel. AB - An all-solid-state Bi2WO6/Au/CdS Z-scheme system was constructed for the photocatalytic reduction of CO2 into methane in the presence of water vapor. This Z-scheme consists of ultrathin Bi2WO6 nanoplates and CdS nanoparticles as photocatalysts, and a Au nanoparticle as a solid electron mediator offering a high speed charge transfer channel and leading to more efficient spatial separation of electron-hole pairs. The photo-generated electrons from the conduction band (CB) of Bi2WO6 transfer to the Au, and then release to the valence band (VB) of CdS to recombine with the holes of CdS. It allows the electrons remaining in the CB of CdS and holes in the VB of Bi2WO6 to possess strong reduction and oxidation powers, respectively, leading the Bi2WO6/Au/CdS to exhibit high photocatalytic reduction of CO2, relative to bare Bi2WO6, Bi2WO6/Au, and Bi2WO6/CdS. The depressed hole density on CdS also enhances the stability of the CdS against photocorrosion. PMID- 28616939 TI - Ultrafast growth of large-area monolayer MoS2 film via gold foil assistant CVD for a highly sensitive photodetector. AB - Two-dimensional molybdenum disulfide (MoS2) is a promising material for ultrasensitive photodetectors owing to its tunable band gap and high absorption coefficient. However, controlled synthesis of high-quality, large-area monolayer molybdenum disulfide (MoS2) is still a challenge in practical application. In this work, we report a gold foil assistant chemical vapor deposition method for the synthesis of large-size (>400 MUm) single-crystal MoS2 film on a silicon dioxide (SiO2) substrate. The influence of Au foil in enlarging the size of single-crystal MoS2 is investigated systemically using thermal simulation in Ansys workbench 16.0, including thermal conductivity, temperature difference and thermal relaxation time of the interface of SiO2 substrate and Au foil, which indicate that Au foil can increase the temperature of the SiO2 substrate rapidly and decrease the temperature difference between the oven and substrate. Finally, the properties of the monolayer MoS2 film are further confirmed using back-gated field-effect transistors: a high photoresponse of 15.6 A W-1 and a fast photoresponse time of 100 ms. The growth techniques described in this study could be beneficial for the development of other atomically thin two-dimensional transition metal dichalcogenide materials. PMID- 28616940 TI - Dirac node lines in two-dimensional Lieb lattices. AB - As a new type of quantum matter, Dirac node line (DNL) semimetals are currently attracting widespread interest in condensed matter physics and materials science. The DNL, featured by a closed line consisting of linear band crossings in the momentum space, was mostly predicted in three-dimensional materials. Here, we propose a tight-binding (TB) model of pz + px,y or pz + s orbitals defined on the two-dimensional (2D) Lieb lattice for the 2D version of DNL semimetals. The DNL states in these models are caused by the inversion of the bands with different symmetries and thus robust against spin-orbit interaction. By means of first principles calculations, we demonstrate two candidate materials: Be2C and BeH2 monolayers, which have Fermi circles centred at Gamma(0,0) and K(1/2,1/2) points, respectively. Their Fermi velocities are higher than that in graphene. The non zero Z2 topological invariant accompanied by the edge states is revealed in these materials. This work opens an avenue for the design of 2D DNL semimetals. PMID- 28616941 TI - Fluorescence correlation spectroscopy study of the complexation of DNA hybrids, IgG antibody, and a chimeric protein of IgG-binding ZZ domains fused with a carbohydrate binding module. AB - Fluorescence correlation spectroscopy (FCS) was used to characterize the molecular interactions between the four components of a DNA recognition system. A fluorescent DNA probe was used to assess: (i) the hybridization with a complementary biotin-labeled target, (ii) the complexation of the resulting hybrid and an anti-biotin antibody, and (iii) the binding of the latter complex to a ZZ-CBM fusion protein that combines small synthetic IgG Fc-binding Z domains with a carbohydrate binding module (CBM). These binding interactions were monitored by exposing the fluorescent DNA probe to different amounts and combinations of the other molecules in solution. Through the analysis of FCS autocorrelation curves, an association constant (Ka) of 2.9 * 107 M-1 was estimated for DNA.DNA hybridization, and the presence of (non-) complementary target DNA in solution could be discriminated. The specific capture of biotinylated DNA hybrids by anti-biotin IgG was verified, with an apparent Ka of 2.5 * 106 M-1. The increment in the diffusion time measured when the DNA.DNA:antibody complexes were in contact with the ZZ-CBM fusion protein suggested that the binding occurs at a stoichiometric ratio of DNA/antibody complex to fusion larger than 1 : 1. The FCS-derived information obtained is useful to gain insight into molecular interactions involved in diagnostic assays. PMID- 28616942 TI - Two tetraphenylethene-containing coordination polymers for reversible mechanochromism. AB - Two fluorescent coordination polymers have been designed and synthesized from a tetraphenylethene (TPE) derivative. These polymers, which can be potentially utilized as mechanical sensors, exhibit reversible mechanochromic luminescence with color changes visible to the naked-eye from blue to green-yellow by grinding or soaking in N,N-dimethylformamide (DMF) under UV irradiation. PMID- 28616943 TI - A colloidal quantum dot photonic crystal phosphor: nanostructural engineering of the phosphor for enhanced color conversion. AB - Phosphors, long-known color-converting photonic agents, are gaining increasing attention owing to the interest in white LEDs and related applications. Conventional material-based approaches to phosphors focus on obtaining the desired absorption/emission wavelengths and/or improving quantum efficiency. Here, we report a novel approach for enhancing the performance of phosphors: structural modification of phosphors. We incorporated inorganic colloidal quantum dots (CQDs) into a lateral one-dimensional (1D) photonic crystal (PhC) thin-film structure, with its photonic band-edge (PBE) modes matching the energy of 'excitation photons' (rather than 'emitted photons', as in most other PBE application devices). At resonance, we observed an approximately 4-fold enhancement of fluorescence over the reference bulk phosphor, which reflects an improved absorption of the excitation photons. This nano-structural engineering approach is a paradigm shift in the phosphor research area and may help to develop next-generation higher efficiency phosphors with novel characteristics. PMID- 28616944 TI - Acquiring multiple signals along with the reaction time: improving recognition capability of a multidimensional colorimetric sensor array for sensitive protein detection. AB - The development of sensitive and cheap sensor arrays for identification of proteins plays an important role in many bioanalytical and clinical investigations. Here, we introduce a multidimensional colorimetric sensor array for the detection of multiple proteins based on acquiring multiple signals along with the reaction time to enhance the discrimination ability. In a single experiment, the unique fingerprint for each protein against the sensor array is generated from a response absorbance signal at three reaction time points (at 10 min, 15 min, and 20 min). Our colorimetric sensing system is able to identify ten proteins not only in aqueous solution at 10 nM but also in human urine at the 50 nM level with an accuracy of 100%. Moreover, the identification of HSA in urine at the nanomolar level within a linear range of 0.05-1.0 MUM is achieved. Our sensing array system is sufficiently sensitive for the discrimination of pure HSA, binary mixtures of HSA and Lys at a total concentration of 50 nM in urine. This study indicates that the application of the real-time resolved response signals enables the enhancement of the discrimination ability for protein recognition. PMID- 28616945 TI - Assembling and ordering polymer-grafted nanoparticles in three dimensions. AB - Taking advantage of the aqueous biphasic behavior of polyethylene glycol (PEG)/salts, recent experiments have demonstrated self-assembly and crystallization of PEG-grafted gold nanoparticles (PEG-AuNPs) into tunable two dimensional (2D) supercrystals by adjusting salt concentration (for instance, K2CO3). In those studies, combined experimental evidence and theoretical analysis have pointed out the possibility that similar strategies can lead to three dimensional (3D) formation of ordered nanoparticle precipitates. Indeed, a detailed small-angle X-ray scattering (SAXS) study reported herein reveals the spontaneous formation of PEG-AuNPs assemblies in high-concentration salt solutions that exhibit short-range 3D order compatible with fcc symmetry. We argue that the assembly into fcc crystals is driven by partnering nearest neighbors to minimize an effective surface-tension gradient at the boundary between the polymer shell and the high-salt media. We report SAXS and other results on PEG-AuNPs of various Au core diameters in the range of 10 to 50 nm and analyze them in the framework of brush-polymer theory revealing a systematic prediction of the nearest-neighbor distance in the 3D assemblies. PMID- 28616946 TI - Glycocalyx scaffolding with synthetic nanoscale glycomaterials. AB - We report a method for programming complexity into the glycocalyx of live cells. Via a combination of glycomaterial synthesis and membrane remodeling, we have engineered cells to display native-like, mixed sialoglycan populations, while confining the activity of each glycan into a specific nanoscale presentation. PMID- 28616947 TI - The impact of metalation on adsorption geometry, electronic level alignment and UV-stability of organic macrocycles on TiO2(110). AB - Metal complexes of the tetradentate bipyridine based macrocycle pyrphyrin (Pyr) have recently shown promise as water reduction catalysts in homogeneous photochemical water splitting reactions. In this study, the adsorption and metalation of pyrphyrin on stoichiometric TiO2(110) is investigated in ultrahigh vacuum by means of scanning tunneling microscopy, photoelectron spectroscopy, low energy electron diffraction, and density functional theory. In a joint experimental and computational effort, the local adsorption geometry at low coverage, the long-range molecular ordering at higher coverage and the electronic structure have been determined for both the bare ligand and the cobalt-metalated Pyr molecule on TiO2. The energy level alignment of CoPyr/TiO2 supports electron injection into TiO2 upon photoexcitation of the CoPyr complex and thus renders it a potential sensitizer dye. Importantly, Co-incorporation is found to stabilize the Pyr molecule against photo-induced degradation, while the bare ligand is decomposed rapidly under continuous UV-irradiation. This interesting phenomenon is discussed in terms of additional de-excitation channels for electronically highly excited molecular states. PMID- 28616948 TI - Sub-diffraction-limit localization imaging of a plasmonic nanoparticle pair with wavelength-resolved dark-field microscopy. AB - In this work, with wavelength-resolved dark-field microscopy, the center-of-mass localization information from nanoparticle pairs (i.e., spherical (45 nm in diameter) and rod (45 * 70 nm) shaped gold nanoparticle pairs with different gap distances and orientations) was explored and compared with the results determined by scanning electron microscopy (SEM) measurements. When the gap distance was less than 20 nm, the scattering spectrum of the nanoparticle pair was seriously modulated by the plasmonic coupling effect. The measured coordinate information determined by the optical method (Gaussian fitting) was not consistent with the true results determined by SEM measurement. A good correlation between the optical and SEM measurements was achieved when the gap distance was further increased (e.g., 20, 40 and 60 nm). Under these conditions, well-defined scattering peaks assigned to the corresponding individual nanoparticles could be distinguished from the obtained scattering spectrum. These results would afford valuable information for the studies on single plasmonic nanoparticle imaging applications with the optical microscopy method such as super-localization imaging, high precision single particle tracking in a crowding environment and so on. PMID- 28616949 TI - Monitoring ATPase induced pH changes in single proteoliposomes with the lipid coupled fluorophore Oregon Green 488. AB - Monitoring the proton pumping activity of proteins such as ATPases in reconstituted single proteoliposomes is key to quantify the function of proteins as well as potential proton pump inhibitors. However, most pH-detecting assays available are either not quantitative, require well-adapted reconstitution protocols or are not appropriate for single vesicle studies. Here, we describe the quantitative and time-resolved detection of F-type ATPase-induced pH changes across vesicular membranes doped with the commercially available pH sensitive fluorophore Oregon Green 488 DHPE. This dye is shown to be well suited to monitor acidification of lipid vesicles not only in bulk but also at the single vesicle level. The pKa value of Oregon Green 488 DHPE embedded in a lipid environment was determined to be 6.1 making the fluorophore well suited for a variety of physiologically relevant proton pumps. The TFOF1-ATPase from a thermophilic bacterium was reconstituted into large unilamellar vesicles and the bulk acidification assay clearly reveals the overall activity of the F-type ATPase in the vesicle ensemble with an average pH change of 0.45. However, monitoring the pH changes in individual vesicles attached to a substrate demonstrates that the fraction of vesicles with a significant observable pH change is only about 5%, a number that cannot be gathered from bulk experiments and which is considerably lower than expected. PMID- 28616950 TI - Reliability of interacting quantum atoms (IQA) data computed from post-HF densities: impact of the approximation used. AB - The performance of BBC1, BBC2 and Muller approximations, in terms of reliability of IQA data, was investigated at the CCSD, CCSD(T) and MP2 levels using glycol, as a case study, in interpreting the relative stability of its conformers, one with H-bond type intramolecular interaction and the other with a steric clash between two O-atoms. The CCSD/BBC1 level appeared to be perfectly suited as a reference needed to evaluate all possible levels of theory/approximation combinations (LoT/LoA). We found the reliability trend LoT/BBC1 > LoT/BBC2 > LoT/Muller (as well as its origin) and concluded that the Muller approximation should not be used when the accuracy of IQA-defined energy terms is considered. Moreover, we have established that the requirement of reproducing, by IQA calculations, electronic energy is desirable but not a necessary requirement when a comparative approach is used, such as in FAMSEC-based analysis (FAMSEC = fragment attributed molecular system energy change). A new criterion is proposed to assess the quality of IQA data for comparative analyses, DeltaE(IQA) ~ DeltaE, where DeltaE(IQA) and DeltaE are the IQA and electronic energy differences, respectively, between the fin-state and ref-state of a molecular system. The closer DeltaE(IQA) approaches DeltaE, the closer the FAMSEC data approach values obtained at the exceptionally well performing CCSD/BBC1 level, regardless of the LoT/LoA combination used. Importantly, the MP2/BBC1 level performed nearly as well as the CCSD/BBC1 level in comparative studies. The origin of the MP2/BBC1 approximation's exceptional and the MP2/Muller approximations's acceptable performance in explaining the relative stability of glycol conformers has been uncovered and discussed in detail. PMID- 28616952 TI - Room-temperature discrete-charge-fluctuation dynamics of a single molecule adsorbed on a carbon nanotube. AB - Detection and use of physical noise fluctuations in a signal provides significant advantages in the development of bio- and neuro-sensing and functional mimicking devices. Low-dimensional carbon nanomaterials are a good candidate for use in noise generation due to the high surface sensitivity of these materials, which may themselves serve as the main building blocks of these devices. Here, we demonstrate that the addition of a molecule with high redox activity to a carbon nanotube (CNT) field-effect transistor provides tunable current fluctuation noise. A unique charge-trap state in the vicinity of the CNT surface due to the presence of the single molecule is the origin of the noise, which generates a prominent and unique slow discrete random telegraph signal in the device current. The power spectral density reveals the peculiar frequency limit of the fluctuation for different types of molecules depending on their redox activity and adsorption configuration. These results indicate that the detected noise will provide new opportunities to obtain electronic information for a single molecule combined with a nanotube surface, and that controllability of the noise may contribute to the expansion of noise utilization in future bio-inspired devices. PMID- 28616951 TI - Direct characterization of the native structure and mechanics of cyanobacterial carboxysomes. AB - Carboxysomes are proteinaceous organelles that play essential roles in enhancing carbon fixation in cyanobacteria and some proteobacteria. These self-assembling organelles encapsulate Ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and carbonic anhydrase using a protein shell structurally resembling an icosahedral viral capsid. The protein shell serves as a physical barrier to protect enzymes from the cytosol and a selectively permeable membrane to mediate transport of enzyme substrates and products. The structural and mechanical nature of native carboxysomes remain unclear. Here, we isolate functional beta carboxysomes from the cyanobacterium Synechococcus elongatus PCC7942 and perform the first characterization of the macromolecular architecture and inherent physical mechanics of single beta-carboxysomes using electron microscopy, atomic force microscopy (AFM) and proteomics. Our results illustrate that the intact beta-carboxysome comprises three structural domains, a single-layered icosahedral shell, an inner layer and paracrystalline arrays of interior Rubisco. We also observe the protein organization of the shell and partial beta-carboxysomes that likely serve as the beta-carboxysome assembly intermediates. Furthermore, the topography and intrinsic mechanics of functional beta-carboxysomes are determined in native conditions using AFM and AFM-based nanoindentation, revealing the flexible organization and soft mechanical properties of beta-carboxysomes compared to rigid viruses. Our study provides new insights into the natural characteristics of beta-carboxysome organization and nanomechanics, which can be extended to diverse bacterial microcompartments and are important considerations for the design and engineering of functional carboxysomes in other organisms to supercharge photosynthesis. It offers an approach for inspecting the structural and mechanical features of synthetic metabolic organelles and protein scaffolds in bioengineering. PMID- 28616953 TI - Universal liquid-phase laser fabrication of various nano-metals encapsulated by ultrathin carbon shells for deep-UV plasmonics. AB - The exploration of localized surface plasmon resonance (LSPR) beyond the usual visible waveband, for example within the ultraviolet (UV) or deep-ultraviolet (D UV) regions, is of great significance due to its unique applications in secret communications and optics. However, it is still challenging to universally synthesize the corresponding metal nanostructures due to their high activity. Herein, we report a universal, eco-friendly, facile and rapid synthesis of various nano-metals encapsulated by ultrathin carbon shells, significantly with a remarkable deep-UV LSPR characteristic, via a liquid-phase laser fabrication method. Firstly, a new generation of the laser ablation in liquid (LAL) method has been developed with an emphasis on the elaborate selection of solvents to generate ultrathin carbon shells, and hence to stabilize the formed metal nanocrystals. As a result, a series of metal@carbon nanoparticles (NPs), including Cr@C, Ti@C, Fe@C, V@C, Al@C, Sn@C, Mn@C and Pd@C, can be fabricated by this modified LAL method. Interestingly, these NPs exhibit LSPR peaks in the range of 200-330 nm, which are very rare for localized surface plasmon resonance. Consequently, the UV plasmonic effects of these metal@carbon NPs were demonstrated both by the observed enhancement in UV photoluminescence (PL) from the carbon nanoshells and by the improvement of the photo-responsivity of UV GaN photodetectors. This work could provide a universal method for carbon shelled metal NPs and expand plasmonics into the D-UV waveband. PMID- 28616954 TI - Surface charge and particle size determine the metabolic fate of dendritic polyglycerols. AB - Dendritic polyglycerols (dPG) are water soluble, polyether-based nanomaterials which hold great potential in diagnostic as well as therapeutic applications. In order to translate them for in vivo applications, a systematic assessment regarding their cell and tissue interactions as well as their metabolic fate in vivo is a crucial step. Herein, we explore the structure-activity relationship of three different sizes (ca. 3, 5, and 10 nm) of neutral dendritic polyglycerol (dPG) and their corresponding negatively charged sulfate analogs (dPGS) on their in vitro and in vivo characteristics. Cellular metabolic activity was studied in A431 and HEK293 cells. Biomolecular corona formation was determined using an electrophoretic mobility shift assay, which showed an increased protein binding of the dPGS even with serum concentrations as low as 20%. An in situ technique, microscale thermophoresis, was employed to address the binding affinities of these nanomaterials with serum proteins such as serum albumin, apo-transferrin, and fibrinogen. In addition, nanoparticle-cell interactions were studied in differentiated THP-1 cells which showed a charge dependent scavenger receptor mediated uptake. In line with this data, detailed biodistribution and small animal PET imaging studies in Wistar rats using 68Ga-labeled dPG-/dPGS-NOTA conjugates showed that the neutral dPG-NOTA conjugates were quantitatively excreted via the kidneys with a subsequent hepatobiliary excretion with an increase in their size, whereas the polysulfated analogs (dPGS-NOTA) were sequestered preferentially in the liver and kidneys irrespective of their size. Taken together, this systematic study accentuates that the pharmacokinetics of dPGs is critically dependent on the overall size and charge and can be, fine tuned for the intended requirements in nano-theranostics. PMID- 28616955 TI - Niacin for primary and secondary prevention of cardiovascular events. AB - BACKGROUND: Nicotinic acid (niacin) is known to decrease LDL-cholesterol, and triglycerides, and increase HDL-cholesterol levels. The evidence of benefits with niacin monotherapy or add-on to statin-based therapy is controversial. OBJECTIVES: To assess the effectiveness of niacin therapy versus placebo, administered as monotherapy or add-on to statin-based therapy in people with or at risk of cardiovascular disease (CVD) in terms of mortality, CVD events, and side effects. SEARCH METHODS: Two reviewers independently and in duplicate screened records and potentially eligible full texts identified through electronic searches of CENTRAL, MEDLINE, Embase, Web of Science, two trial registries, and reference lists of relevant articles (latest search in August 2016). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that either compared niacin monotherapy to placebo/usual care or niacin in combination with other component versus other component alone. We considered RCTs that administered niacin for at least six months, reported a clinical outcome, and included adults with or without established CVD. DATA COLLECTION AND ANALYSIS: Two reviewers used pre-piloted forms to independently and in duplicate extract trials characteristics, risk of bias items, and outcomes data. Disagreements were resolved by consensus or third party arbitration. We conducted random-effects meta-analyses, sensitivity analyses based on risk of bias and different assumptions for missing data, and used meta-regression analyses to investigate potential relationships between treatment effects and duration of treatment, proportion of participants with established coronary heart disease and proportion of participants receiving background statin therapy. We used GRADE to assess the quality of evidence. MAIN RESULTS: We included 23 RCTs that were published between 1968 and 2015 and included 39,195 participants in total. The mean age ranged from 33 to 71 years. The median duration of treatment was 11.5 months, and the median dose of niacin was 2 g/day. The proportion of participants with prior myocardial infarction ranged from 0% (4 trials) to 100% (2 trials, median proportion 48%); the proportion of participants taking statin ranged from 0% (4 trials) to 100% (12 trials, median proportion 100%).Using available cases, niacin did not reduce overall mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.97 to 1.12; participants = 35,543; studies = 12; I2 = 0%; high quality evidence), cardiovascular mortality (RR 1.02, 95% CI 0.93 to 1.12; participants = 32,966; studies = 5; I2 = 0%; moderate-quality evidence), non cardiovascular mortality (RR 1.12, 95% CI 0.98 to 1.28; participants = 32,966; studies = 5; I2 = 0%; high-quality evidence), the number of fatal or non-fatal myocardial infarctions (RR 0.93, 95% CI 0.87 to 1.00; participants = 34,829; studies = 9; I2 = 0%; moderate-quality evidence), nor the number of fatal or non fatal strokes (RR 0.95, 95% CI 0.74 to 1.22; participants = 33,661; studies = 7; I2 = 42%; low-quality evidence). Participants randomised to niacin were more likely to discontinue treatment due to side effects than participants randomised to control group (RR 2.17, 95% CI 1.70 to 2.77; participants = 33,539; studies = 17; I2 = 77%; moderate-quality evidence). The results were robust to sensitivity analyses using different assumptions for missing data. AUTHORS' CONCLUSIONS: Moderate- to high-quality evidence suggests that niacin does not reduce mortality, cardiovascular mortality, non-cardiovascular mortality, the number of fatal or non-fatal myocardial infarctions, nor the number of fatal or non-fatal strokes but is associated with side effects. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely. PMID- 28616956 TI - Tramadol for neuropathic pain in adults. AB - BACKGROUND: This review is an update of a review of tramadol for neuropathic pain, published in 2006; updating was to bring the review in line with current standards. Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Peripheral neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the peripheral nervous system. OBJECTIVES: To assess the analgesic efficacy of tramadol compared with placebo or other active interventions for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from inception to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing tramadol (any route of administration) with placebo or another active treatment for neuropathic pain, with subjective pain assessment by the participant. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH), using standard methods. We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: We identified six randomised, double-blind studies involving 438 participants with suitably characterised neuropathic pain. In each, tramadol was started at a dose of about 100 mg daily and increased over one to two weeks to a maximum of 400 mg daily or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months due to cancer, cancer treatment, postherpetic neuralgia, peripheral diabetic neuropathy, spinal cord injury, or polyneuropathy. The mean age was 50 to 67 years with approximately equal numbers of men and women. Exclusions were typically people with other significant comorbidity or pain from other causes. Study duration for treatments was four to six weeks, and two studies had a cross over design.Not all studies reported all the outcomes of interest, and there were limited data for pain outcomes. At least 50% pain intensity reduction was reported in three studies (265 participants, 110 events). Using a random-effects analysis, 70/132 (53%) had at least 50% pain relief with tramadol, and 40/133 (30%) with placebo; the risk ratio (RR) was 2.2 (95% confidence interval (CI) 1.02 to 4.6). The NNT calculated from these data was 4.4 (95% CI 2.9 to 8.8). We downgraded the evidence for this outcome by two levels to low quality because of the small size of studies and of the pooled data set, because there were only 110 actual events, the analysis included different types of neuropathic pain, the studies all had at least one high risk of potential bias, and because of the limited duration of the studies.Participants experienced more adverse events with tramadol than placebo. Report of any adverse event was higher with tramadol (58%) than placebo (34%) (4 studies, 266 participants, 123 events; RR 1.6 (95% CI 1.2 to 2.1); NNH 4.2 (95% CI 2.8 to 8.3)). Adverse event withdrawal was higher with tramadol (16%) than placebo (3%) (6 studies, 485 participants, 45 events; RR 4.1 (95% CI 2.0 to 8.4); NNH 8.2 (95% CI 5.8 to 14)). Only four serious adverse events were reported, without obvious attribution to treatment, and no deaths were reported. We downgraded the evidence for this outcome by two or three levels to low or very low quality because of small study size, because there were few actual events, and because of the limited duration of the studies. AUTHORS' CONCLUSIONS: There is only modest information about the use of tramadol in neuropathic pain, coming from small, largely inadequate studies with potential risk of bias. That bias would normally increase the apparent benefits of tramadol. The evidence of benefit from tramadol was of low or very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood is very high that the effect will be substantially different from the estimate in this systematic review. PMID- 28616957 TI - [What Are the Main Factors Assisting General Practitioners in the Development of Educational Strategies?] AB - General practitioners (GP) are in a special position to conduct educational strategies for their patients with chronic disease. Despite the GP's desire to be involved in patient education, this approach remains underdeveloped.Objective: To determine the factors required support the development of educational strategies in general practice from the GPs' perspective.Methods: Qualitative study based on a "modified nominal group technique" carried out among 21 GPs (not specifically trained in patient education) participating as investigators in an interventional study testing a structured educational strategy. The interventional study based on processes and tools specifically developed to suit general practice was held during their usual consultations. Thirty one patients with COPD were followed for 9 months.Results: GPs identified 23 specific factors restructured after the clarification-reformulation step in 6 main factors required for the development of educational strategies in general practice. The consensus revealed that reinforcement of initial and continuing medical training was the most frequently cited factor and was considered to be a priority. The development of inter- and intra-professional cooperation was the second leading factor to be taken into account.Conclusion: The improvement of GP training and the promotion of areas of cooperation could help GPs to develop educational strategies during their consultations. These results may provide insight to regional health agencies concerning the deployment of patient education in primary care. PMID- 28616958 TI - Interconnected Molybdenum Carbide-Based Nanoribbons for Highly Efficient and Ultrastable Hydrogen Evolution. AB - Electrocatalytic hydrogen evolution reaction (HER) is of great significance to produce clean, sustainable, and cost-effective hydrogen. However, the development of low-cost and high-efficiency non-noble-metal catalysts with a combination of superior catalytic activity and long-time stability still remains a challenge. Herein, we demonstrate a rationally designed three-dimensional architecture assembled from one-dimensional molybdenum carbide (MoC)-based nanoribbons where the MoC nanoparticles are embedded within the nitrogen-doped crystallized carbon nanolayers (MoC@NC nanoribbon). Such unique architecture of the MoC@NC nanoribbon not only provides abundant edge active sites and multielectron pathways for efficient mass/charge transportation but also greatly accelerates the hydrogen release from the reaction surface, thus boosting its electrocatalytic performances for HER either in an acid or in an alkaline aqueous solution. This advance provides a promising candidate toward the replacement of the noble-metal based catalysts for a highly stable and efficient HER electrocatalysis. PMID- 28616959 TI - Smelling, Seeing, Tasting-Old Senses for New Sensing. AB - The senses are the physiological mechanisms of perception that enable an organism to interact with the surrounding media. For centuries, humans have utilized these senses in science; vision and olfaction have been used the most extensively in laboratories followed by gustation and somatosensation, whereas audition has only rarely been employed. Most of these applications of senses were developed spontaneously based on the natural behavior of the chemistry of the reactants producing changes in scent, taste, or color. In recent years, by exploiting the outstanding properties of nanoparticles, many groups have demonstrated alternative sensing scenarios where the detection limits are remarkably improved, enabling the recognition of hazardous substances by mere sight, smell, or taste. Such alternative sensing approaches can be divided into two main groups: (i) methods that identify a single analyte by engineering a reaction that promotes a change in color or the generation of a characteristic scent, and (ii) methods that emulate or even improve mammalian senses, especially those related to taste and smell. In this Perspective, we discuss the context of each technology, present prominent examples, and evaluate the complexities, potential pitfalls, and opportunities presented by different re-engineering strategies. PMID- 28616960 TI - Functional Built-In Template Directed Siliceous Fluorescent Supramolecular Vesicles as Diagnostics. AB - Functional template directed synthesis of hybrid siliceous fluorescent vesicle (HSFV) is fabricated by using fluorescent vesicle as a built-in template. The template vesicle is the ionic self-assembly of an aggregation-induced emission (AIE) fluorogen. Upon depositing folic acid modified silica shell on its surface, the obtained HSFVs display low cytotoxicity, significant fluorescence, and targeted drug delivery toward cancer cells. Furthermore, the wall-thickness of the HSFVs can be controlled via altered concentration of silica source. This is the first report of HSFV employing the template vesicle as a built-in fluorescent agent, which represents a good example of rational design for an effective diagnostics, and may open up a new avenue for precision medicine. PMID- 28616961 TI - Na0.86Co0.95Fe0.05O2 Layered Oxide As Highly Efficient Water Oxidation Electrocatalyst in Alkaline Media. AB - Electrochemical energy storage and conversion technologies, such as water splitting devices, rechargeable metal-air batteries, and regenerative fuel cells, are promising alternatives to traditional nonrenewable energy systems. Given the sluggish oxygen evolution reaction (OER) in the above renewable-energy technologies, the development of efficient OER electrocatalysts with high performance is of great importance. Here, we demonstrate a layer-structured oxide Na0.86Co0.95Fe0.05O2 (NCF0.05) as a novel electrocatalyst for efficient water oxidation in alkaline media. NCF0.05 shows enhanced performance, including lower overpotential, lower Tafel slope and better stability than the parent Na0.86CoO2 (NC). Especially, the OER performance of NCF0.05 is comparable to the state-of the-art IrO2 catalyst. This enhanced catalytic activity of NCF0.05 may be ascribed to the unusual synergistic interplay between Fe and Co. A possible dual metal-site mechanism was also proposed for OER on NCF0.05. PMID- 28616962 TI - Size-Dependent Translocation of Nanoemulsions via Oral Delivery. AB - The in vivo translocation of nanoemulsions (NEs) was tracked by imaging tools with an emphasis on the size effect. To guarantee the accurate identification of NEs in vivo, water-quenching environment-responsive near-infrared fluorescent probes were used to label NEs. Imaging evidence confirmed prominent digestion in the gastrointestinal tract and oral absorption of integral NEs that survive digestion by enteric epithelia in a size-dependent way. In general, reducing particle size leads to slowed in vitro lipolysis and in vivo digestion, a prolonged lifetime in the small intestine, increased enteric epithelial uptake, and enhanced transportation to various organs. Histological examination revealed a pervasive distribution of smaller NEs (80 nm) into enterocytes and basolateral tissues, whereas bigger ones (550, 1000 nm) primarily adhered to villi surfaces. Following epithelial uptake, NEs are transported through the lymphatics with a fraction of approximately 3-6%, suggesting a considerable contribution of the lymphatic pathway to overall absorption. The majority of absorbed NEs were found 1 h post administration in the livers and lungs. A similar size dependency of cellular uptake and transmonolayer transport was confirmed in Caco-2 cell lines as well. In conclusion, the size-dependent translocation of integral NEs was confirmed with an absolute bioavailability of at least 6%, envisioning potential applications in oral delivery of labile entities. PMID- 28616963 TI - Novel Quaternary Chalcogenide/Reduced Graphene Oxide-Based Asymmetric Supercapacitor with High Energy Density. AB - In this work we have synthesized quaternary chalcogenide Cu2NiSnS4 (QC) nanoparticles grown in situ on 2D reduced graphene oxide (rGO) for application as anode material of solid-state asymmetric supercapacitors (ASCs). Thorough characterization of the synthesized composite validates the proper phase, stoichiometry, and morphology. Detailed electrochemical study of the electrode materials and ASCs has been performed. The as-fabricated device delivers an exceptionally high areal capacitance (655.1 mF cm-2), which is much superior to that of commercial micro-supercapacitors. Furthermore, a remarkable volumetric capacitance of 16.38 F cm-3 is obtained at a current density of 5 mA cm-2 combined with a very high energy density of 5.68 mW h cm-3, which is comparable to that of commercially available lithium thin film batteries. The device retains 89.2% of the initial capacitance after running for 2000 cycles, suggesting its long-term capability. Consequently, the enhanced areal and volumetric capacitances combined with decent cycle stability and impressive energy density endow the uniquely decorated QC/rGO composite material as a promising candidate in the arena of energy storage devices. Moreover, Cu2NiSnS4 being a narrow band gap photovoltaic material, this work offers a novel protocol for the development of self-charging supercapacitors in the days to come. PMID- 28616964 TI - Multiheteroatom-Doped Porous Carbon Catalyst for Oxygen Reduction Reaction Prepared using 3D Network of ZIF-8/Polymeric Nanofiber as a Facile-Doping Template. AB - We report a facile and versatile method for fabrication of multiheteroatom-doped hierarchically porous carbon with a large specific surface area, using the 3D network constructed by ZIF-8 coated wormlike micelles as template. The uniform and highly pure wormlike micelles developed in our laboratory is essential, because they not only are responsible for the formation of hierarchical porosity, but also play as a versatile platform for multiheteroatoms doping. In a primary experiment, S, N, B, and P heteroatoms were doped conveniently and the resultant porous carbons have the excellent oxygen reduction reaction performance comparable to the commercial 20% Pt/C. PMID- 28616965 TI - Inter-Sectoral Bisphenol A (BPA) Flows in the 2012 Chinese Economy. AB - Bisphenol A (BPA), a widely used petrochemical compound, has become an emerging global environmental management challenge because its leakage is associated with potential environmental and human health impacts. Until now, available BPA statistics have been limited to the products that directly use BPA. In this study, we delineate direct and indirect BPA flows for the 2012 Chinese economy. We find that construction, production of educational and recreational products, and automobile manufacturing are the most BPA-intensive sectors in terms of total BPA flows (300, 157, and 130 Gg total BPA flows, respectively). The public management and health sectors, however, incur significant indirect BPA flows, defined as embedded and inter-sectoral BPA placed into use, even though direct BPA use by these sectors is limited. By revealing the currently overlooked indirect BPA flows, this study reveals data gaps that are highly relevant to improving the accuracy of estimated BPA flows and losses. The method used herein is transferrable to other emerging and environmentally relevant materials, thereby providing the holistic understanding needed for cities, regions, or nations to design effective policy interventions. PMID- 28616966 TI - Magnetic Resonance Imaging-Guided Multi-Drug Chemotherapy and Photothermal Synergistic Therapy with pH and NIR-Stimulation Release. AB - The combination of multidrug chemotherapy and photothermal therapy (PTT) enhances cancer therapeutic efficacy. Herein, we develop a simple and smart pH/NIR dual stimulus-responsive degradable mesoporous CoFe2O4@PDA@ZIF-8 sandwich nanocomposite. The mesoporous CoFe2O4 core acts as T2-weighted magnetic resonance (MR) imaging probe, PTT agent, and loading platform of hydrophilic doxorubicin (DOX). A polydopamine (PDA) layer is used to avoid the premature leakage of DOX before arriving at tumor site, enhance PTT efficiency, and facilitate the integration of ZIF-8 (a kind of metal-organic framework). The ZIF-8 shell serves to encapsulate hydrophobic camptothecin (CPT) and as the switch for the pH and NIR stimulation-responsive release of the two drugs. Therefore, T2-weighted MR imaging-guided multidrug chemotherapy and PTT synergistic treatment is achieved. Two kinds of anticancer drugs, hydrophilic DOX and hydrophobic CPT, are successfully loaded in CoFe2O4 and ZIF-8, respectively, so no mutual interference between the two drugs exists. A unique two-stage stepwise release process is exhibited for CPT and DOX with an interval of 12 h to improve the anticancer efficacy under the acidic microenvironment of tumor tissue. NIR irradiation achieves the burst drug-release and PTT after laser stimulation, simultaneously. With this smart design, high drug concentration is achieved at the tumor site by quick release, especially for the therapeutic drugs that show nonlinear pharmacokinetics, and PTT is integrated efficiently. Furthermore, negligible biotoxicity and a remarkable synergic antitumor effect of the hybrid nanocomposites are validated by HepG2 cells and tumor-bearing mice as models. Our multidrug delivery-releasing composite improves tumor therapeutic efficiency significantly compared with a single-drug chemotherapy system. The simple multifunctional composite system can be applied as an effective platform for personal nanomedicine with diagnosis, smart drug delivery, and cancer treatment through its remarkable photothermal property and controllable multidrug release. PMID- 28616967 TI - Effects of Functional Groups of Materials on Nonspecific Adhesion and Chondrogenic Induction of Mesenchymal Stem Cells on Free and Micropatterned Surfaces. AB - Functional groups of materials are known to affect cell behaviors, yet the corresponding effect on stem cell differentiation is always coupled with that of cell spreading; it is thus unclear whether the chemical groups influence cell differentiation directly or via cell spreading indirectly. Herein we used a unique surface patterning technique to decouple the corresponding effects. Mesenchymal stem cells (MSCs) derived from bone marrow were seeded on surfaces coated with alkanethiols with one of four functional end groups (-CH3, -OH, COOH, and -NH2) and underwent 9 days of chondrogenic induction. The measurements of quartz crystal microbalance with dissipation confirmed less proteins adsorbed from the cell culture media on the neutral -CH3 and -OH surfaces than on the charged -COOH and -NH2 surfaces. The neutral surfaces exhibited less cell spreading and higher extents of chondrogenic differentiation than the charged surfaces, according to the characterizations of immunofluorescence staining and quantitative real-time polymerase chain reaction. We further used a transfer lithography technique to prepare patterned surfaces on nonfouling poly(ethylene glycol) hydrogels to localize single MSCs on microislands with self-assembly monolayers of different alkanethiols, under given microisland areas and thus well defined spreading areas of cells. While small microislands were always beneficial for chondrogenic induction, we found that the type of functional groups had no significant effect on chondrogenic induction under the given cell spreading areas, implying that the chemical groups influence cell differentiation only indirectly. Our results hence illustrate that functional groups regulate stem cell differentiation via tuning protein adsorption and then nonspecific cell adhesion and thus cell spreading. PMID- 28616968 TI - CRISPRi-sRNA: Transcriptional-Translational Regulation of Extracellular Electron Transfer in Shewanella oneidensis. AB - Extracellular electron transfer (EET) in Shewanella oneidensis MR-1, which is one of the most well-studied exoelectrogens, underlies many microbial electrocatalysis processes, including microbial fuel cells, microbial electrolysis cells, and microbial electrosynthesis. However, regulating the efficiency of EET remains challenging due to the lack of efficient genome regulation tools that regulate gene expression levels in S. oneidensis. Here, we systematically established a transcriptional regulation technology, i.e., clustered regularly interspaced short palindromic repeats interference (CRISPRi), in S. oneidensis MR-1 using green fluorescent protein (GFP) as a reporter. We used this CRISPRi technology to repress the expression levels of target genes, individually and in combination, in the EET pathways (e.g., the MtrCAB pathway and genes affecting the formation of electroactive biofilms in S. oneidensis), which in turn enabled the efficient regulation of EET efficiency. We then established a translational regulation technology, i.e., Hfq-dependent small regulatory RNA (sRNA), in S. oneidensis by repressing the GFP reporter and mtrA, which is a critical gene in the EET pathways in S. oneidensis. To achieve coordinated transcriptional and translational regulation at the genomic level, the CRISPRi and Hfq-dependent sRNA systems were incorporated into a single plasmid harbored in a recombinant S. oneidensis strain, which enabled an even higher efficiency of mtrA gene repression in the EET pathways than that achieved by the CRISPRi and Hfq-dependent sRNA system alone, as exhibited by the reduced electricity output. Overall, we developed a combined CRISPRi-sRNA method that enabled the synergistic transcriptional and translational regulation of target genes in S. oneidensis. This technology involving CRISPRi-sRNA transcriptional translational regulation of gene expression at the genomic level could be applied to other microorganisms. PMID- 28616969 TI - pH-Driven Actuation of DNA Origami via Parallel I-Motif Sequences in Solution and on Surfaces. AB - As bottom up DNA nanofabrication creates increasingly complex and dynamic mechanisms, the implementation of actuators within the DNA nanotechnology toolkit has grown increasingly important. One such actuator, the I-motif, is fairly simple in that it consists solely of standard DNA sequences and does not require any modification chemistry or special purification beyond that typical for DNA oligomer synthesis. This study presents a new implementation of parallel I-motif actuators, emphasizing their future potential as drivers of complex internal motion between substructures. Here we characterize internal motion between DNA origami substructures via AFM and image analysis. Such parallel I-motif design and quantification of actuation provide a useful step toward more complex and effective molecular machines. PMID- 28616970 TI - Structure and Biocompatibility of Bioabsorbable Nanocomposites of Aliphatic Aromatic Copolyester and Cellulose Nanocrystals. AB - Poly(butylene adipate-co-terephthalate) (PBAT) was first chemically modified via free radical grafting with maleic anhydride (MA) and the MA-g-PBAT graft copolymer was then used as a matrix material to obtain cellulose nanocrystal (CNC)-reinforced MA-g-PBAT bionanocomposites via reactive extrusion process to accelerate efforts to develop functional bioabsorbable polymer nanocomposites with improved properties. The molecular structure of the PBAT after chemical modification with maleic anhydride was confirmed by 1H NMR and FTIR spectroscopy. The morphological observation of the nanocomposites revealed that the CNCs were finely dispersed in the matrix. Thermal analysis of the hybrids showed an improvement of the thermal stability of the nanocomposites upon increasing the CNC content. In addition, it was found that the CNC nucleated crystallization of the PBAT in the nanocomposites. Extensive melt rheological characterization of the nanocomposite samples revealed a significant improvement of the viscoelastic properties of the matrix due to the strong interfacial adhesion of the CNC particles to the PBAT. Further, development of the nonterminal characteristics of the viscoelastic material functions and exhibition of yield stress were correlated with the evolution of a 3D-netowork nanostructure of CNCs in the matrix. This CNC nanostructure was interpreted in the framework of scaling theory of fractal elastic gels, and found to be consistent with the structure of open porous flocs. Tensile testing of the samples showed considerable improvement in the modulus and ultimate strength of the samples with increasing the CNC content. In addition, a positive shift of the glass transition temperature was found in dynamic mechanical analysis. Finally, in vitro biocompatibility using Thiazolyl blue tetrazolium bromide (MTT) assay and cell adhesion studies with L929 fibroblast cells revealed no cytotoxic effect of CNCs, confirming the biocompatibility of the nanocomposites and the associated significant improvement of cell adhesion, suggesting the potential applicability of this nanocomposite in biomedical and tissue engineering applications. PMID- 28616971 TI - Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid O-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-O-Methyltransferase. AB - In animal models, estrogens are complete carcinogens in certain target sites. 4 Hydroxyestradiol (4-OH-E2), an endogenous metabolite of 17beta-estradiol (E2), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E2 does not induce pituitary tumors in ACI female rats, whereas E2 produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E2 in several organs. We found that, whereas 4-OH-E2 had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E2 has similar efficacy as E2 in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E2. Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E2 (but not E2) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow Km value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E2 through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site. PMID- 28616973 TI - Vegetation Loss Decreases Salt Marsh Denitrification Capacity: Implications for Marsh Erosion. AB - Salt marshes play a key role in removing excess anthropogenic nitrogen (N) loads to nearshore marine ecosystems through sediment microbial processes such as denitrification. However, in the Gulf of Mexico, the loss of marsh vegetation because of human-driven disturbances such as sea level rise and oil spills can potentially reduce marsh capacity for N removal. To investigate the effect of vegetation loss on ecosystem N removal, we contrasted denitrification capacity in marsh and subtidal sediments impacted by the Deepwater Horizon oil spill using a combination of 29N2 and 30N2 production (isotope pairing), denitrification potential measurements (acetylene block), and quantitative polymerase chain reaction (qPCR) of functional genes in the denitrification pathway. We found that, on average, denitrification capacity was 4 times higher in vegetated sediments because of a combination of enhanced nitrification and higher organic carbon availability. The abundance of nirS-type denitrifers indicated that marsh vegetation regulates the activity, rather than the abundance, of denitrifier communities. We estimated that marsh sediments remove an average of 3.6 t N km-2 y-1 compared to 0.9 t N km-2 y-1 in unvegetated sediments. Overall, our findings indicate that marsh loss results in a substantial loss of N removal capacity in coastal ecosystems. PMID- 28616972 TI - Dss1 Regulates Association of Brh2 with Rad51. AB - Brh2, the BRCA2 ortholog in the fungus Ustilago maydis, mediates delivery of Rad51 to DNA during the course of homology-directed DNA repair. Rad51 interacts with Brh2 through the highly conserved BRC element and through a second region termed CRE located at the extreme carboxy terminus. Dss1, a small intrinsically unstructured protein that interacts with Brh2, is crucial for its activity in DNA repair, but the mechanism of this regulation is uncertain. In previous studies, we found that interaction of Brh2 with DNA was strongly modulated by association with Dss1. Here we report that CRE influences interaction of Dss1 with Brh2 and that Dss1 status markedly alters interaction of Brh2 with Rad51. While it appears that a single Rad51 protomer associates with Brh2 in complex with Dss1, loss of Dss1 is accompanied by a large increase in the number of Rad51 protomers that can associate with Brh2. Concomitant with this buildup of Rad51, Brh2 loses its ability to bind DNA. These observations suggest a feedback circuit in which release of Dss1 from Brh2 as it binds DNA triggers nucleation of a short Rad51 oligomer on Brh2, which in turn promotes dissociation of Brh2 from the DNA. PMID- 28616974 TI - Palladium-Catalyzed Desulfitative Cross-Coupling of Arylsulfonyl Hydrazides with Terminal Alkynes: A General Approach toward Functionalized Internal Alkynes. AB - A palladium-catalyzed Sonogashira-type coupling between arylsulfonyl hydrazides and terminal alkynes via Ar(C)-S bond cleavage is disclosed, which enables the general synthesis of functionalized internal alkynes, especially the Br substituted ones, in good to excellent yields under acid- and base-free conditions. PMID- 28616975 TI - Design, Synthesis, and Fungicidal Evaluation of Novel Pyrazole-furan and Pyrazole pyrrole Carboxamide as Succinate Dehydrogenase Inhibitors. AB - The identification of novel succinate dehydrogenase (SDH) inhibitors represents one of the most attractive directions in the field of fungicide research and development. During our continuous efforts to pursue inhibitors belonging to this class, some structurally novel pyrazole-furan carboxamide and pyrazole-pyrrole carboxamide derivatives have been discovered via the introduction of scaffold hopping and bioisosterism to compound 1, a remarkably potent lead obtained by pharmacophore-based virtual screening. As a result of the evaluation against three destructive fungi, including Sclerotinia sclerotiorum, Rhizoctonia solani, and Pyricularia grisea, a majority of them displayed potent fungicidal activities. In particular, compounds 12I-i, 12III-f, and 12III-o exhibited excellent fungicidal activity against S. sclerotiorum and R. solani comparable to that of commercial SDHI thifluzamide and 1. PMID- 28616976 TI - Synthesis and Herbicidal Activity of Pyrido[2,3-d]pyrimidine-2,4-dione Benzoxazinone Hybrids as Protoporphyrinogen Oxidase Inhibitors. AB - To search for new protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors with improved bioactivity, a series of novel pyrido[2,3-d]pyrimidine-2,4-dione benzoxazinone hybrids, 9-13, were designed and synthesized. Several compounds with improved tobacco PPO (mtPPO)-inhibiting and promising herbicidal activities were found. Among them, the most potent compound, 3-(7-fluoro-3-oxo-4-(prop-2-yn 1-yl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)-1-methylpyrido[2,3-d]pyrimidine 2,4(1H,3H)-dione, 11q, with a Ki value of 0.0074 MUM, showed six times more activity than flumioxazin (Ki = 0.046 MUM) against mtPPO. Compound 11q displayed a strong and broad spectrum of weed control at 37.5-150 g of active ingredient (ai)/ha by both post- and pre-emergence application, which was comparable to that of flumioxazin. 11q was safe to maize, soybean, peanut, and cotton at 150 g ai/ha, and selective to rice and wheat at 75 g ai/ha by pre-emergence application, indicating potential applicability in these fields. PMID- 28616977 TI - Gastrointestinal Simulation Model TWIN-SHIME Shows Differences between Human Urolithin-Metabotypes in Gut Microbiota Composition, Pomegranate Polyphenol Metabolism, and Transport along the Intestinal Tract. AB - A TWIN-SHIME system was used to compare the metabolism of pomegranate polyphenols by the gut microbiota from two individuals with different urolithin metabotypes. Gut microbiota, ellagitannin metabolism, short-chain fatty acids (SCFA), transport of metabolites, and phase II metabolism using Caco-2 cells were explored. The simulation reproduced the in vivo metabolic profiles for each metabotype. The study shows for the first time that microbial composition, metabolism of ellagitannins, and SCFA differ between metabotypes and along the large intestine. The assay also showed that pomegranate phenolics preserved intestinal cell integrity. Pomegranate polyphenols enhanced urolithin and propionate production, as well as Akkermansia and Gordonibacter prevalence with the highest effect in the descending colon. The system provides an insight into the mechanisms of pomegranate polyphenol gut microbiota metabolism and absorption through intestinal cells. The results obtained by the combined SHIME/Caco-2 cell system are consistent with previous human and animal studies and show that although urolithin metabolites are present along the gastrointestinal tract due to enterohepatic circulation, they are predominantly produced in the distal colon region. PMID- 28616978 TI - Synthesis and Preclinical Characterization of a Cationic Iodinated Imaging Contrast Agent (CA4+) and Its Use for Quantitative Computed Tomography of Ex Vivo Human Hip Cartilage. AB - Contrast agents that go beyond qualitative visualization and enable quantitative assessments of functional tissue performance represent the next generation of clinically useful imaging tools. An optimized and efficient large-scale synthesis of a cationic iodinated contrast agent (CA4+) is described for imaging articular cartilage. Contrast-enhanced CT (CECT) using CA4+ reveals significantly greater agent uptake of CA4+ in articular cartilage compared to that of similar anionic or nonionic agents, and CA4+ uptake follows Donnan equilibrium theory. The CA4+ CECT attenuation obtained from imaging ex vivo human hip cartilage correlates with the glycosaminoglycan content, equilibrium modulus, and coefficient of friction, which are key indicators of cartilage functional performance and osteoarthritis stage. Finally, preliminary toxicity studies in a rat model show no adverse events, and a pharmacokinetics study documents a peak plasma concentration 30 min after dosing, with the agent no longer present in vivo at 96 h via excretion in the urine. PMID- 28616979 TI - Proposed Biotransformation Pathways for New Metabolites of Paralytic Shellfish Toxins Based on Field and Experimental Mussel Samples. AB - A seafood poisoning event occurred in Qinhuangdao, China, in April 2016. Subsequently, the causative mussels (Mytilus galloprovincialis) were harvested and analyzed to reveal a high concentration [~10 758 MUg of saxitoxin (STX) equiv kg-1] of paralytic shellfish toxins (PSTs), including gonyautoxin (GTX)1/4 and GTX2/3, as well as new metabolites 11-hydroxy-STX (M2), 11,11-dihydroxy-STX (M4), open-ring 11,11-dihydroxy-STX (M6), 11-hydroxy-neosaxitoxin (NEO) (M8), and 11,11 dihydroxy-NEO (M10). To understand the origin and biotransformation pathways of these new metabolites, uncontaminated mussels (M. galloprovincialis) were fed with either of two Alexandrium tamarense strains (ATHK and TIO108) under laboratory conditions. Similar PST metabolites were also detected in mussels from both feeding experiments. Results supposed that 11-hydroxy-C2 toxin (M1) and 11,11-dihydroxy-C2 (M3) are transformed from C2, while 11-hydroxy-C4 toxin (M7) and 11,11-dihydroxy-C4 (M9) are converted from C4. In addition, the metabolites M2, M4, and M6 appear to be products of GTX2/3, and the metabolites M8 and M10 are likely derived from GTX1/4. PMID- 28616980 TI - Parallelization of Change Point Detection. AB - The change point detection method ( Watkins , L. P. ; Yang , H. J. Phys. Chem. B 2005 , 109 , 617 ) allows the objective identification and isolation of abrupt changes along a data series. Because this method is grounded in statistical tests, it is particularly powerful for probing complex and noisy signals without artificially imposing a kinetics model. The original algorithm, however, has a time complexity of [Formula: see text], where N is the size of the data and is, therefore, limited in its scalability. This paper puts forth a parallelization of change point detection to address these time and memory constraints. This parallelization method was evaluated by applying it to changes in the mean of Gaussian-distributed data and found that time decreases superlinearly with respect to the number of processes (i.e., parallelization with two processes takes less than half of the time of one process). Moreover, there was minimal reduction in detection power. These results suggest that our parallelization algorithm is a viable scheme that can be implemented for other change point detection methods. PMID- 28616981 TI - Bi(OTf)3-Mediated Intramolecular Olefinic Cyclization: Synthesis of Substituted Aryl-Dihydronaphthalenes and Indenes. AB - In this article, a facile two-step and one-pot synthetic route for the preparation of substituted aryl dihydronaphthalenes starting from 2 allylbenzaldehydes via Grignard 1,2-addition and Bi(OTf)3-catalyzed intramolecular olefinic cyclization has been developed. A five-membered ring indene skeleton is also prepared via olefin isomerization, 1,2-addition followed by cyclization. Some key structures are determined using single-crystal X-ray crystallography. A possible mechanism is presented herein. PMID- 28616982 TI - Destabilization of Titania Nanosheet Suspensions by Inorganic Salts: Hofmeister Series and Schulze-Hardy Rule. AB - Ion specific effects on colloidal stability of titania nanosheets (TNS) were investigated in aqueous suspensions. The charge of the particles was varied by the pH of the solutions, therefore, the influence of mono- and multivalent anions on the charging and aggregation behavior could be studied when they were present either as counter or co-ions in the systems. The aggregation processes in the presence of inorganic salts were mainly driven by interparticle forces of electrostatic origin, however, chemical interactions between more complex ions and the surface led to additional attractive forces. The adsorption of anions significantly changed the surface charge properties and hence, the resistance of the TNS against salt-induced aggregation. On the basis of their ability in destabilization of the dispersions, the monovalent ions could be ordered according to the Hofmeister series in acidic solutions, where they act as counterions. However, the behavior of the biphosphate anion was atypical and its adsorption induced charge reversal of the particles. The multivalent anions destabilized the oppositely charged TNS more effectively and the aggregation processes followed the Schulze-Hardy rule. Only weak or negligible interactions were observed between the anions and the particles in alkaline suspensions, where the TNS possessed negative charge. PMID- 28616983 TI - Absolute Rate Constants for Radical Additions to Alkenes in Solution. The Synergistic Effect of Perfluorination on the Reactivities of n-Alkyl Radicals1. AB - Laser flash photolysis has been used to determine the absolute rate constants for addition of several partially fluorinated n-alkyl radicals to three styrenes at 25 degrees C in Freon 113. Fluorination at the gamma-position (RCF2CH2CH2*) gives radicals with essentially the same reactivity as non-fluorinated n-alkyls. The RCH2CF2CH2* and RCH2CH2CHF* radicals are both about three times as reactive as RCF2CH2CH2*, but the RCH2CH2CF2* radical is ca. five to six times rather than ca. three times as reactive as RCH2CH2CHF*. Similarly, the perfluorinated radical CF3CF2CF2* is much more reactive than would be expected on the basis of the reactivities of the RCH2CF2CH2* and RCH2CH2CF2* radicals. Thus, perfluorinated n alkyl radicals are very considerably more reactive than would be predicted from the individual effects of alpha-, beta-, and gamma-fluorination. PMID- 28616984 TI - OH-Stretching Overtone Induced Dynamics in HSO3F from Reactive Molecular Dynamics Simulations. AB - The OH-stretch induced dynamics in fluorosulfonic acid (HSO3F) is characterized from a statistically significant number of trajectories using multisurface adiabatic reactive molecular dynamics (MS-ARMD) simulations. The global reactive potential energy surface, which describes H-transfer and HF-elimination, is parametrized at the MP2/6-311G++(2p,2d) level of theory with an accuracy of better than 1 kcal/mol. Excitation along the OH-local mode leads to H-transfer dynamics but elimination of HF is only observed for excitations with nu >= 6 for 1 out of 5000 trajectories. This finding differs fundamentally from the situation for vibrationally induced photodissociation of H2SO4 and HSO3Cl, for which, even with excitations of 4 quanta along the OH-stretch mode, elimination of H2O and HCl, respectively, is readily observed on the subnanosecond time scale. RRKM rates for HX-elimination in HSO3X (X = F, Cl) only differ by a factor of 5. The findings from the reactive molecular dynamics simulations together with the RRKM results thus indicate that the origin for a closed HF-production channel is dynamical. This is also consistent with experimental findings for hydrofluoroethanes in shock tubes, which found pronounced non-RRKM behavior. PMID- 28616985 TI - Transition-Metal-Free and Oxidant-Free Cross-Coupling of Arylhydrazines with Disulfides: Base-Promoted Synthesis of Unsymmetrical Aryl Sulfides. AB - A novel synthesis of unsymmetrical aryl sulfides, which requires no transition metal catalyst and no oxidant, was developed. This base-promoted cross-coupling reaction proceeded using arylhydrazines and 1 equiv amount of disulfides under inert gas conditions to afford the unsymmetrical aryl sulfides in good yields. PMID- 28616986 TI - On-a-chip Biosensing Based on All-Dielectric Nanoresonators. AB - Nanophotonics has become a key enabling technology in biomedicine with great promises in early diagnosis and less invasive therapies. In this context, the unique capability of plasmonic noble metal nanoparticles to concentrate light on the nanometer scale has widely contributed to biosensing and enhanced spectroscopy. Recently, high-refractive index dielectric nanostructures featuring low loss resonances have been proposed as a promising alternative to nanoplasmonics, potentially offering better sensing performances along with full compatibility with the microelectronics industry. In this letter we report the first demonstration of biosensing with silicon nanoresonators integrated in state of-the-art microfluidics. Our lab-on-a-chip platform enables detecting Prostate Specific Antigen (PSA) cancer marker in human serum with a sensitivity that meets clinical needs. These performances are directly compared with its plasmonic counterpart based on gold nanorods. Our work opens new opportunities in the development of future point-of-care devices toward a more personalized healthcare. PMID- 28616987 TI - Impact of Low-Intensity Pulsed Ultrasound on Transcript and Metabolite Abundance in Saccharomyces cerevisiae. AB - The interactions of ultrasound with biological materials are exploited for diagnostic, interventional, and therapeutic applications in humans and can improve productivity in industrial-scale generation of organic molecules such as biofuels, vaccines, and antibodies. Accordingly, there is great interest in better understanding the biological effects of ultrasound. We studied the impact of low-intensity pulsed ultrasound (LIPUS) on RNA expression and metabolism of S. cerevisiae. Although the transcript expression signature of LIPUS-treated cells does not differ significantly from that of untreated cells after 5 days, metabolomic profiling by chemical-isotopic-labeling-liquid-chromatography-mass spectrometry suggests that LIPUS has an impact on the pathways of pyrimidine, proline, alanine, aspartate, glutamate, and arginine metabolism. Therefore, LIPUS triggers metabolic effects beyond reprogramming of the core pathways of carbon metabolism. Further characterization of metabolism will likely be important for elucidation of the biological effects of LIPUS. PMID- 28616988 TI - Highly Diastereoselective alpha-Arylation of Cyclic Nitriles. AB - A highly diastereoselective alpha-arylation of cyclic nitriles has been developed via a Negishi cross-coupling of commercially available aryl, heteroaryl, and alkenyl halides with cyclobutyl nitriles in the presence of tetramethylpiperidinylzinc chloride lithium chloride (TMPZnCl*LiCl) and catalytic XPhos-Pd-G2. A variety of electronically diverse electrophiles were well tolerated, and this chemistry was further advanced with application of both cyclopropyl and cyclopentyl nitriles. PMID- 28616989 TI - Reconstructed Serine 288 in the Left Flipper Region of the Rat P2X7 Receptor Stabilizes Nonsensitized States. AB - Serine 275, a conserved residue of the left flipper region of ATP-gated P2X3 receptors, plays a key role in both agonist binding and receptor desensitization. It is conserved in most of the P2X receptors except P2X7 and P2X6. By combining experimental patch-clamp and modeling approaches, we explored the role of the corresponding residue in the rat P2X7 receptor (rP2X7) by replacing the phenylalanine at position 288 with serine and characterizing the membrane currents generated by either the wild-type (WT) or the mutated rP2X7 receptor. F288S, an rP2X7 mutation, slowed the deactivation subsequent to 2 and 20 s applications of 1 mM ATP. F288S also prevented sensitization (a progressive current growth) observed with the WT in response to a 20 s application of 1 mM ATP. Increasing the ATP concentration to 5 mM promoted sensitization also in the mutated rP2X7 receptor, accelerating the deactivation rate to typical WT values. YO-PRO1 uptake in cells expressing either the WT or the F288S P2X7 receptor was consistent with recorded membrane current data. Interestingly, in the human P2X7 (hP2X7) receptor, substitution Y288S did not change the deactivation rate, while the Y288F mutant generated a "rat-like" phenotype with a fast deactivation rate. Our combined experimental, kinetic, and molecular modeling data suggest that the rat F288S novel phenotype is due to a slower rate of ATP binding and/or unbinding and stabilization of nonsensitized receptor states. PMID- 28616990 TI - Modeling Binding with Large Conformational Changes: Key Points in Ensemble Docking Approaches. AB - Protein dynamics play a critical role in ligand binding, and different models have been proposed to explain the relationships between protein motion and molecular recognition. Here, we present a study of ligand-binding processes associated with large conformational changes of a protein to elucidate the critical choices in ensemble-docking approaches for effective prediction of the binding geometry. Two study cases were selected in which binding involves different protein motions and intermolecular interactions and, accordingly, conformational selection and induced-fit mechanisms play different roles: binding of multiple ligands to the acetylcholine binding protein and highly specific binding of D-allose to the allose binding protein. Our results indicated that the ensemble-docking technique can provide reliable predictions of the structure of ligand-protein complexes, starting from simulations of the apo systems, when suitable methodological choices are made according to the different mechanistic scenarios. In particular, accelerated molecular dynamics simulations are suitable for conformational sampling when the unbound and bound states are separated by high energy barriers, provided that the acceleration parameters are carefully set to extensively sample the relevant conformations. A strategy specifically developed for geometric clustering of the binding site proved to be effective for selecting a set of conformations relevant to binding from the MD trajectory. Specific strategies have to be selected to incorporate different degrees of ligand-induced protein flexibility into the docking or pose-refinement steps. PMID- 28616991 TI - Assessment of the Effects of Anisotropic Interactions among Hydrogen Molecules and Their Isotopologues: A Diffusion Monte Carlo Investigation of Gas Phase and Adsorbed Clusters. AB - Despite the fact that the para-hydrogen molecule (p-H2) and its isotopomers (o-D2 and p-T2) are commonly modeled as spherical objects due to the large separation between rotational states, there may be situations (e.g. adsorption in pores and on surfaces) in which such an approximation neglects important degrees of freedom (i.e. the rotational ones) and introduces uncontrolled biases in the predicted properties. To better understand when approximating such molecules as spheres introduces shortcomings in their representation, we employed diffusion Monte Carlo to simulate small/medium-sized molecular aggregates, either isolated in space or experiencing external model potentials, to compute energetic quantities and distribution functions. These were chosen to mimic situations possibly occurring in real systems, in which orientational isotropy is broken. The comparison between isolated clusters with molecules described as rigid rotors with a 4D potential or as spheres interacting via Adiabatic Hindered Rotor models shows that neither energetic nor structural quantities are affected by reducing the systems dimensionality. The orientational degrees of freedom of the rotors remains largely uncoupled from translational ones whatever the molecular mass. The same happens for rotors interacting with a frozen hydrogen molecule in the vicinity of a repulsive surface. Deviating from such behavior are molecular aggregates interacting with potentials mimicking the presence of ionic adsorption sites inside porous materials. Such difference is ascribable to the markedly anisotropic and longer ranged nature of those interactions, both features being relevant in defining the adsorption energy of the molecular species. PMID- 28616992 TI - Coherent Experimental and Simulation Approach To Explore the Underlying Mechanism of Denaturation of Stem Bromelain in Osmolytes. AB - Characterization of a protein in the context of its environment is of crucial importance for a complete understanding of its function. Although biophysical techniques provide powerful tools for studying the stability and activity of the enzyme in the presence of various cosolvents, an approach of combining both experimental techniques and molecular dynamic (MD) simulations may lead to the mechanistic insight into the interactions governing the stability of an enzyme. The knowledge of these interactions can be further utilized for range of modifications in the wild form of an enzyme for various pharmaceutical applications. Herein, we employed florescence, UV-visible, circular dichroism (CD), dynamic light scattering (DLS) study, and MD simulations for comprehensive understanding of stem bromelain (BM) in the presence of betaine, sarcosine, arginine, and proline. The thermal stability of BM in the presence of 1 M of osmolytes is found to be in order: proline > betaine > buffer > arginine > sarcosine. BM gets more preferentially hydrated in the presence of betaine and proline than in sarcosine and arginine. Nonetheless, MD simulations suggest that betaine, sarcosine, and arginine at 1 M interact with the active site of BM through H-bonding except proline which are responsible for more disruption of active site. The distances between the catalytic site residues are 1.6, 1.9, 4.3, 5.0, and 6.2 A for BM in proline, buffer, betaine, arginine, and sarcosine at 1 M, respectively. To the best of our knowledge, this is the first report on detailed unequivocal evidence of denaturation and deactivation of BM in the presence of methylamines and amino acids. PMID- 28616993 TI - Multimodal Characterization of the Morphology and Functional Interfaces in Composite Electrodes for Li-S Batteries by Li Ion and Electron Beams. AB - We report the characterization of multiscale 3D structural architectures of novel poly[sulfur-random-(1,3-diisopropenylbenzene)] copolymer-based cathodes for high energy-density Li-S batteries capable of realizing discharge capacities >1000 mAh/g and long cycling lifetimes >500 cycles. Hierarchical morphologies and interfacial structures have been investigated by a combination of focused Li ion beam (LiFIB) and analytical electron microscopy in relation to the electrochemical performance and physicomechanical stability of the cathodes. Charge-free surface topography and composition-sensitive imaging of the electrodes was performed using recently introduced low-energy scanning LiFIB with Li+ probe sizes of a few tens of nanometers at 5 keV energy and 1 pA probe current. Furthermore, we demonstrate that LiFIB has the ability to inject a certain number of Li cations into the material with nanoscale precision, potentially enabling control of the state of discharge in the selected area. We show that chemical modification of the cathodes by replacing the elemental sulfur with organosulfur copolymers significantly improves its structural integrity and compositional homogeneity down to the sub-5-nm length scale, resulting in the creation of (a) robust functional interfaces and percolated conductive pathways involving graphitic-like outer shells of aggregated nanocarbons and (b) extended micro- and mesoscale porosities required for effective ion transport. PMID- 28616994 TI - Direct training to improve educators' treatment integrity: A systematic review of single-case design studies. AB - In consultation, school psychologists may offer educators direct training to support the implementation of classroom interventions aimed to improve student outcomes. The purpose of this study was to conduct a systematic literature review of single-case design research studies during which educators received direct training to implement a classroom intervention, specifically instructions, modeling, practice, and feedback. Two doctoral students in school psychology screened 228 articles and evaluated 33 studies to determine if direct training is effective and an evidence-based practice per single-case design standards proposed by the What Works Clearinghouse. Results of the review indicate that there is support for the practice to be deemed evidence-based and associated with better intervention implementation than before its application. Implications include direct training being considered for intensive, complex interventions to promote educator success with implementation. (PsycINFO Database Record PMID- 28616995 TI - The hippocampus and the regulation of human food intake. AB - Human and animal data suggest that the hippocampus plays certain roles in regulating food intake. However, its actual role may be far broader than currently envisaged, a claim suggested by the centrality of the hippocampus to so many aspects of human/animal cognition. Understanding these ingestion-related functions is especially significant. This is because some degree of hippocampal impairment may be quite common, resulting for example from a Western-style diet, insomnia, diabetes, and depression-among many other causes. One potential consequence of hippocampal impairment could be a loosening of food intake regulation, leading in the longer-term to weight gain and its health-related impacts. Here we review known, suspected and newly hypothesized hippocampal dependent functions involved in regulating human food intake: (a) declarative memory processes, and their use in explicitly evaluating when, what and how much to eat; (b) interoception, as it relates to hunger, fullness and thirst; (c) inhibitory processes, especially as applied to physiological state, place, and time, and their role in modulating memory retrieval; (d) craving and imagery for food; (e) perception of time and its role in preparing the body for food intake and estimating meal length; (f) trace conditioning and nutrient-related learning; and (g) inhibition of the hypothalamic-pituitary-adrenal stress response and stress-related eating. For each we present evidence for hippocampal involvement, describe the putative regulatory role, and the hypothesized effects of hippocampal impairment. We conclude that the hippocampus is intimately involved in regulating human food intake via multiple interconnected pathways, many of which are unstudied and understudied. (PsycINFO Database Record PMID- 28616996 TI - Coping, emotion regulation, and psychopathology in childhood and adolescence: A meta-analysis and narrative review. AB - In this meta-analytic and narrative review, we examine several overarching issues related to the study of coping, emotion regulation, and internalizing and externalizing symptoms of psychopathology in childhood and adolescence, including the conceptualization and measurement of these constructs. We report a quantitative meta-analysis of 212 studies (N = 80,850 participants) that measured the associations between coping and emotion regulation with symptoms of internalizing and externalizing psychopathology. Within the meta-analysis we address the association of broad domains of coping and emotion regulation (e.g., total coping, emotion regulation), intermediate factors of coping and emotion regulation (e.g., primary control coping, secondary control coping), and specific coping and emotion regulation strategies (e.g., emotional expression, cognitive reappraisal) with internalizing and externalizing symptoms. For cross-sectional studies, which made up the majority of studies included, we examine 3 potential moderators: age, measure quality, and single versus multiple informants. Finally, we separately consider findings from longitudinal studies as these provide stronger tests of the effects. After accounting for publication bias, findings indicate that the broad domain of emotion regulation and adaptive coping and the factors of primary control coping and secondary control coping are related to lower levels of symptoms of psychopathology. Further, the domain of maladaptive coping, the factor of disengagement coping, and the strategies of emotional suppression, avoidance, and denial are related to higher levels of symptoms of psychopathology. Finally, we offer a critique of the current state of the field and outline an agenda for future research. (PsycINFO Database Record PMID- 28616997 TI - Emotion and the prefrontal cortex: An integrative review. AB - The prefrontal cortex (PFC) plays a critical role in the generation and regulation of emotion. However, we lack an integrative framework for understanding how different emotion-related functions are organized across the entire expanse of the PFC, as prior reviews have generally focused on specific emotional processes (e.g., decision making) or specific anatomical regions (e.g., orbitofrontal cortex). Additionally, psychological theories and neuroscientific investigations have proceeded largely independently because of the lack of a common framework. Here, we provide a comprehensive review of functional neuroimaging, electrophysiological, lesion, and structural connectivity studies on the emotion-related functions of 8 subregions spanning the entire PFC. We introduce the appraisal-by-content model, which provides a new framework for integrating the diverse range of empirical findings. Within this framework, appraisal serves as a unifying principle for understanding the PFC's role in emotion, while relative content-specialization serves as a differentiating principle for understanding the role of each subregion. A synthesis of data from affective, social, and cognitive neuroscience studies suggests that different PFC subregions are preferentially involved in assigning value to specific types of inputs: exteroceptive sensations, episodic memories and imagined future events, viscero-sensory signals, viscero-motor signals, actions, others' mental states (e.g., intentions), self-related information, and ongoing emotions. We discuss the implications of this integrative framework for understanding emotion regulation, value-based decision making, emotional salience, and refining theoretical models of emotion. This framework provides a unified understanding of how emotional processes are organized across PFC subregions and generates new hypotheses about the mechanisms underlying adaptive and maladaptive emotional functioning. (PsycINFO Database Record PMID- 28616998 TI - ExperienceSampler: An open-source scaffold for building smartphone apps for experience sampling. AB - Experience sampling methods allow researchers to examine phenomena in daily life and provide various advantages that complement traditional laboratory methods. However, existing experience sampling methods may be costly, require constant Internet connectivity, may not be designed specifically for experience sampling studies, or require a custom solution from a computer programming consultant. In this article, we present ExperienceSampler, an open-source scaffold for creating experience-sampling smartphone apps designed for Android and iOS devices. We designed ExperienceSampler to address the common barriers to using experience sampling methods. First, there is no cost to the user. Second, ExperienceSampler apps make use of local notifications to let participants know when to complete surveys and store the data locally until Internet connection is available. Third, our app scaffold was designed with experience sampling methodological issues in mind. We also demonstrate how researchers can easily customize ExperienceSampler even if they have no programming skills. Furthermore, we evaluate the utility of ExperienceSampler apps with results from one social psychological study conducted using ExperienceSampler (N = 168). Mean response rates averaged 84%, and the median response latency was 9 minutes. Taken together, ExperienceSampler creates cost-effective smartphone apps that can be easily customized by researchers to examine experiences in daily life. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28616999 TI - Investigating why and for whom management ethnic representativeness influences interpersonal mistreatment in the workplace. AB - Preliminary research suggests that employees use the demographic makeup of their organization to make sense of diversity-related incidents at work. The authors build on this work by examining the impact of management ethnic representativeness-the degree to which the ethnic composition of managers in an organization mirrors or is misaligned with the ethnic composition of employees in that organization. To do so, they integrate signaling theory and a sense-making perspective into a relational demography framework to investigate why and for whom management ethnic representativeness may have an impact on interpersonal mistreatment at work. Specifically, in three complementary studies, the authors examine the relationship between management ethnic representativeness and interpersonal mistreatment. First, they analyze the relationship between management ethnic representativeness and perceptions of harassment, bullying, and abuse the next year, as moderated by individuals' ethnic similarity to others in their organizations in a sample of 60,602 employees of Britain's National Health Service. Second, a constructive replication investigates perceived behavioral integrity as an explanatory mechanism that can account for the effects of representativeness using data from a nationally representative survey of working adults in the United States. Third and finally, online survey data collected at two time points replicated these patterns and further integrated the effects of representativeness and dissimilarity when they are measured using both objective and subjective strategies. Results support the authors' proposed moderated mediation model in which management ethnic representation is negatively related to interpersonal mistreatment through the mediator of perceived behavioral integrity, with effects being stronger for ethnically dissimilar employees. (PsycINFO Database Record PMID- 28617000 TI - How do leaders react when treated unfairly? Leader narcissism and self-interested behavior in response to unfair treatment. AB - In this article we employ a trait activation framework to examine how unfairness perceptions influence narcissistic leaders' self-interested behavior, and the downstream implications of these effects for employees' pro-social and voice behaviors. Specifically, we propose that narcissistic leaders are particularly likely to engage in self-interested behavior when they perceive that their organizations treat them unfairly, and that this self-interested behavior in turn decreases followers' pro-social behavior and voice. Data from a multisource, time lagged survey of 211 team leaders and 1,205 subordinates provided support for the hypothesized model. Implications for theory and practice are discussed. (PsycINFO Database Record PMID- 28617001 TI - Providing social services in a new immigrant settlement city: A qualitative inquiry. AB - Nationally, a new trend in migration has included the settlement of Latina/o immigrants in cities without an established community of Latinas/os. Social services become even more salient in this context in the absence of informal social networks of support. This study, guided by social ecological theory, advances our limited understanding of social services in new immigrant settlement destinations by elucidating contextual and structural factors endemic to the social service delivery process in these new immigrant destinations. Twenty-nine social service providers who work with Latina/o immigrants in Baltimore were interviewed and Consensual Qualitative Research (CQR; Hill, Thompson, & Nutt Williams, 1997) methods were used to analyze data through consensus and the use of multiple data "auditors." Findings extend our understanding of the context of social services in a new immigrant settlement city by identifying qualitative factors related to the new immigrant settlement, organization and work, community, and client level that impact access and quality of services. A theoretically driven conceptual framework adapted from the Structural Environmental conceptual framework (Organista, 2007) is also proposed to explain the transactional interconnectedness among structural-, environmental-, and client-level factors in the social service delivery process. (PsycINFO Database Record PMID- 28617002 TI - Understanding the mental health consequences of family separation for refugees: Implications for policy and practice. AB - Consistent evidence documents the negative impacts of family separation on refugee mental health and concerns for the welfare of distant family members and desire to reunite with family members as priorities for refugees postmigration. Less is known about refugees' emic perspectives on their experiences of family separation. Using mixed methods data from a community-based mental health intervention study, we found that family separation was a major source of distress for refugees and that it was experienced in a range of ways: as fear for family still in harm's way, as a feeling of helplessness, as cultural disruption, as the greatest source of distress since resettlement, and contributing to mixed emotions around resettlement. In addition to these qualitative findings, we used quantitative data to test the relative contribution of family separation to refugees' depression/anxiety symptoms, posttraumatic stress disorder (PTSD) symptoms, and psychological quality of life. Separation from a family member was significantly related to all 3 measures of mental health, and it explained significant additional variance in all 3 measures even after accounting for participants' overall level of trauma exposure. Relative to 26 other types of trauma exposure, family separation was 1 of only 2 traumatic experiences that explained additional variance in all 3 measures of mental health. Given the current global refugee crisis and the need for policies to address this large and growing issue, this research highlights the importance of considering the ways in which family separation impacts refugee mental health and policies and practices that could help ameliorate this ongoing stressor. (PsycINFO Database Record PMID- 28617003 TI - Sexual harassment victimization, school belonging, and depressive symptoms among LGBTQ adolescents: Temporal insights. AB - Peer victimization and the associated poor outcomes among lesbian, gay, bisexual, transgender, and questioning (LGBTQ) youth have been the focus of countless studies. School climate is a factor that has garnered significant attention. Perceptions of school contexts may even be mechanisms that define how victimization relates to poor outcomes. However, there is a lack of rigorous scholarship that could demonstrate directionality and therefore further augment our understanding of these relations. Specifically, it is not clear if victimization is strictly an antecedent to mental health issues like depressive symptoms. This longitudinal study examined the associations among sexual harassment victimization, school belonging, and depressive symptoms among LGBTQ high school students (n = 404). Self-report measures were completed at 3 time points across 3 school years in 6 Midwest high schools. Structural equation modeling indicated that peer victimization was an antecedent to depressive symptoms, and that school belonging mediated the association. Implications and future directions are discussed. (PsycINFO Database Record PMID- 28617004 TI - A critical-positive youth development model for intervening with minority youth at risk for delinquency. AB - Minority youths who experience adversity in the forms of concentrated poverty, neighborhood violence, and social marginalization are at increased risk for delinquency. Yet, traditional approaches to reducing delinquency do not typically account for these social-structural risk factors. This article proposes a model of intervening that was developed to address this limitation. The current model was informed by the findings of a 9-month ethnography of a leadership development program for African American youths as well as positive youth development and critical theory frameworks. It delineates the roles of key intervention features in enhancing important assets among minority youths that help them to better navigate adverse social-structural conditions, decrease problem behaviors, and increase prosocial behaviors. (PsycINFO Database Record PMID- 28617005 TI - Using adolescents' drawings to reveal stereotypes about ethnic groups in Guatemala. AB - It is important to identify stereotypes about indigenous people because those stereotypes influence prejudice and discrimination, both obstacles to social justice and universal human rights. The purpose of the current study was to document the stereotypes, as held by Guatemalan adolescents, of indigenous Maya people (e.g., Maya) and nonindigenous Ladinos in Guatemala (the 2 main ethnic groups in Guatemala). Guatemalan adolescents (N = 465; 38.3% female; Mage = 14.51 years; SDage = 1.81 years) provided drawings and written characteristics about indigenous Maya and nonindigenous Ladino people, which were then coded for patterns in the data. These patterns included negative stereotypes, such as the Maya being lazy and Ladina women being weak; and positive stereotypes, such as the Maya being caring and warm and Ladino men being successful. There were also interactions between the participants' own gender and ethnicity and how they depicted the target they were assigned. For example, male participants were unlikely to depict male targets of either ethnicity engaging in homemaking activities. Finally, there was evidence of in-group bias based both on gender and ethnicity. These findings suggest that perhaps because indigenous groups around the world share some common negative stereotypes, an understanding of these stereotypes will aid in decreasing prejudice and discrimination against indigenous people, could reduce intergroup conflict, and increase access to basic human rights. (PsycINFO Database Record PMID- 28617006 TI - Ethnographic case study of a community day center for asylum seekers as early stage mental health intervention. AB - Clinical guidelines in refugee mental health increasingly advocate phased approaches to intervention that foreground the provision of pragmatic and social support in contexts of ongoing instability. However, the impact of such interventions has rarely been explored from the perspective of refugees themselves. We conducted ethnographic research on the experiences and perceptions of users of an intervention embodying this approach: a community Day Center for asylum seekers in Montreal. Data comprising 15 interviews and field notes from 50 participant observation visits were analyzed using an established theoretical framework to identify mechanisms supporting self-perceived wellbeing among users in the domains of safety, social networks, justice, identity/roles, and existential meaning. Results shed light on how this nonspecific buffering intervention responds to the threats and pressures asylum seekers themselves identify as most salient in the immediate postflight context. These findings are discussed in relation to emerging theoretical frameworks in refugee mental health that emphasize agency, justice, and the role of local ecologies. We conclude that the Day Center shows significant promise as an innovative early stage mental health intervention for precarious status migrants and merits further research and evaluation. (PsycINFO Database Record PMID- 28617007 TI - Resilient family processes, personal reintegration, and subjective well-being outcomes for military personnel and their family members. AB - Deployment affects not just the service members, but also their family members back home. Accordingly, this study examined how resilient family processes during a deployment (i.e., frequency of communication and household management) were related to the personal reintegration of each family member (i.e., how well each family member begins to "feel like oneself again" after a deployment), as well as several indicators of subjective well-being. Drawing from the family attachment network model (Riggs & Riggs, 2011), the present study collected survey data from 273 service members, their partners, and their adolescent children. Resilient family processes during the deployment itself (i.e., frequency of communication, household management), postdeployment positive and negative personal reintegration, and several indicators of well-being were assessed. Frequency of communication was related to personal reintegration for service members, while household management was related to personal reintegration for nondeployed partners; both factors were related to personal reintegration for adolescents. Negative and positive personal reintegration related to a variety of subjective well-being outcomes for each individual family member. Interindividual (i.e., crossover) effects were also found, particularly between adolescents and nondeployed partners. (PsycINFO Database Record PMID- 28617009 TI - "The feasibility of implementing cognitive remediation for work in community based psychiatric rehabilitation programs": Correction to McGurk et al. (2017). AB - : Reports an error in "The feasibility of implementing cognitive remediation for work in community based psychiatric rehabilitation programs" by Susan R. McGurk, Kim T. Mueser, Melanie A. Watkins, Carline M. Dalton and Heather Deutsch (Psychiatric Rehabilitation Journal, 2017[Mar], Vol 40[1], 79-86). In the article, the author order was incorrect due to a printer error. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-13255-004.) Objective: Adding cognitive remediation to vocational rehabilitation services improves cognitive and work functioning in people with serious mental illness, but despite interest, the uptake of cognitive programs into community services has been slow. This study evaluated the feasibility of implementing an empirically supported cognitive remediation program in routine rehabilitation services at 2 sites. METHOD: The Thinking Skills for Work (TSW) program was adapted for implementation at 2 sites of a large psychiatric rehabilitation agency providing prevocational services, but not community-based vocational services, which were provided off-site. Agency staff were trained to deliver TSW to clients with work or educational goals. Cognitive assessments were conducted at baseline and posttreatment, with work and school activity tracked for 2 years. RESULTS: Eighty-three participants enrolled in TSW, of whom 79.5% completed at least 6 of the 24 computer cognitive exercise sessions (M = 16.7) over an average of 18 weeks. Participants improved significantly from baseline to posttreatment in verbal learning and memory, speed of processing, and overall cognitive functioning. Over the follow-up, 25.3% of participants worked and 47.0% were involved in work or school activity. Higher work rates were observed at the site where participants had easier access to vocational services. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The results support the feasibility of implementing the TSW program by frontline staff in agencies providing psychiatric rehabilitation, and suggest that ease of access to vocational services may influence work outcomes. (PsycINFO Database Record PMID- 28617008 TI - The application and importance of disability policy research to the mental health field. AB - This editorial provides an introduction to this unique special issue of the Psychiatric Rehabilitation Journal. Rather than focusing on a particular type of rehabilitative services, it more broadly addresses the subject, methods, and results of disability policy research. This special issue is meant to start a conversation about the role of psychiatric rehabilitation researchers, professionals, and consumers in shaping future policies affecting and affected by mental illness. In particular, this issue focuses on the application of rigorous research methodologies to answer policy-relevant questions to help ensure that decisions affecting our field are evidence-based and address the issues that matter most in the lives of consumers. (PsycINFO Database Record PMID- 28617010 TI - Value of psychiatric rehabilitation in a behavioral health medicaid managed care system. AB - OBJECTIVE: The present study was designed to describe individuals receiving psychiatric rehabilitation (PR) service and investigate program outcomes and factors associated with progress in a multisite, descriptive evaluation across Pennsylvania. METHOD: Through an outcomes-monitoring process integrated into routine service delivery, survey responses from 408 individuals participating in PR were summarized. Linear mixed models were used to examine change over time in self-reported progress ratings in rehabilitation domains and factors associated with progress. RESULTS: Significantly lower utilization of inpatient psychiatric service was observed in the 12 months after initiating PR versus the 12 months before service (15% vs. 24%; p = .002). Peer and case management service increased after initiation of PR. Specifying a domain as a goal in the service plan was associated with higher progress ratings in the learning (beta = .75, p < 0001), working (beta = 1.06, p < .0001), and physical wellness (beta = 1.27, p < .0001) domains. Average hopefulness rating was positively and significantly associated with self-reported progress in all domains. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The current investigation provides some evidence that individuals participating in PR decrease utilization of inpatient service. This finding and the goals and activities reported in domains over time support the added value of PR as a Medicaid-reimbursable service to managed care efforts to promote rehabilitation outcomes and recovery for individuals with psychiatric disabilities. (PsycINFO Database Record PMID- 28617011 TI - The long road from policy to practice. AB - TOPIC: As behavioral health care policies evolve, based on shifting paradigms and a developing base of evidence, day-to-day practices at the direct service level must change. Workforce development initiatives are a critical component to effect such change yet may be overlooked, underfunded, or implemented in ways that are ineffective. PURPOSE: This article highlights considerations for training focused on policy, for training issues relevant across recent policy initiatives, and components of effective workforce development initiatives. SOURCES USED: Sources include the personal experience of the authors and the available literature on education, training, and workforce development, as well as select references related to policy initiatives in psychiatric rehabilitation and behavioral health care. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Until policy initiatives include the necessary funding for and guidance on evidence-based workforce development, they are unlikely to achieve their full promise. (PsycINFO Database Record PMID- 28617012 TI - To clinician innovators: A special invitation. AB - Our vision for this special issue was simple: to inspire clinician innovators working in integrated care to not only consume the literature but also contribute to it. Growing the research capacity of clinician innovators in integrated care is vital for at least three reasons. First and foremost, real-world clinicians have an excellent vantage on the processes and outcomes that relate to the reach or the extent to which the given intervention or model of care engages its intended audience (Klesges, Estabrooks, Dzewaltowski, Bull, & Glasgow, 2005). Second, policy changes within the Affordable Care Act have facilitated the rapid uptake of integrated care in recent years (Beacham, Kinman, Harris, & Masters, 2012; Nash, Khatri, Cubic, & Baird, 2013), but the growth of the published evidence base has not kept pace. Third, clinician innovators in integrated care are well positioned to contribute to the evidence base because of the growing emphasis on demonstrating outcomes in health care. Many of the articles in this special issue highlight specific recommendations that clinician innovators can make to transform a local evaluation into one that produces generalizable findings worthy of publication. Our hope is that this special issue can help dismantle the "research" stereotype and inspire future clinician innovators to become more active participants. (PsycINFO Database Record PMID- 28617013 TI - The role of policy in supporting clinician-led research on behavioral health integration. AB - In Best Care at Lower Cost, the Institute of Medicine laid out a vision for continuously learning health systems (Institute of Medicine of the National Academies, 2016). This issue of Families, Systems, & Health represents a substantial step toward this vision, with on-the-ground clinicians and administrators testing empirically informed hypotheses about practice transformation and population health management, and using those results to produce shared learning within and across systems. While the studies in this issue demonstrate that producing generalizable knowledge from clinician-led initiatives is feasible, they also demonstrate that the current system does not adequately support clinicians in doing so. To achieve the triple aim of better care, lower costs, and healthier people, health care will need innovation at all levels of payment and delivery (Berwick, Nolan, & Whittington, 2008), and to pursue the suggested fourth aim - "improving the work life of those who deliver care" - clinicians on the ground who lead innovations will need to be supported (Bodenheimer & Sinsky, 2014). This issue of Families, Systems, & Health demonstrates that health policy will need to adapt to better support and foster emerging clinician-innovators, who can be crucial partners in producing the knowledge necessary to improve our nation's health care systems, bringing us closer to the triple aim. (PsycINFO Database Record PMID- 28617014 TI - Real-world program evaluation of integrated behavioral health care: Improving scientific rigor. AB - INTRODUCTION: Designing systematic, scientifically rigorous program evaluations (PE) is 1 way to contribute to the significant need to build best practices and a stronger evidence base for integrated behavioral health care. However, there are many potential pitfalls when conducting PE in real-world settings, and many clinicians and administrators may be hesitant to engage in PE due to lack of training or resources. Rigorous PE can be achieved feasibly and efficiently. METHOD: This article discusses common challenges that arise when conducting PE in integrated behavioral health care settings and illustrates ways to increase the methodological quality of PE efforts using lessons learned from 2 real-world case examples. The first example included a PE of a training program for brief alcohol interventions, and the second example included a PE of a depression medication monitoring service. RESULTS/DISCUSSION: The case examples demonstrate the need for strategic planning beforehand, including the use of a conceptual framework as well as appropriate study designs/methodology, measurement, and the need for consistency to achieve a well-designed PE. Using the recommendations within this article, it is hoped that the quality of PEs can be improved resulting in more generalizable data that can be used to inform organizations and policymakers to improve health care delivery. (PsycINFO Database Record PMID- 28617015 TI - Using implementation science to guide the integration of evidence-based family interventions into primary care. AB - This article is a demonstration of how an implementation-science (IS) framework can be coupled with the measurement of implementation outcomes to effectively integrate evidence-based family interventions in primary care. The primary care environment presents a number of challenges for successfully integrating such interventions. However, IS methods can improve the prospect of successfully implementing a new intervention while simultaneously and rigorously evaluating the impact on salient outcomes. We used our experiences across 2 pilot trials in which the family check-up (Smith, Montano, Mauricio, Berkel, & Dishion, 2016), an evidence-based family intervention, was integrated into primary care. In these pilot trials, the exploration, preparation, implementation, and sustainment (EPIS) framework and the Proctor et al. taxonomy of implementation outcomes were used to guide the implementation and evaluate its success. Grounding our presentation in our pilot work offers an illustration of applying the EPIS framework and outcomes measurement to real-world problems and contexts. When embarking on new efforts to integrate behavioral interventions into health-care settings, the application of IS frameworks and measurement strategies can create generalizable knowledge that substantively contributes to a sparse literature. Today, those "in the trenches" who are translating evidence-based interventions to their setting can contribute to the corpus of research in integrated care by using IS methods to plan a new program and evaluate its feasibility, adoption, and reach. (PsycINFO Database Record PMID- 28617016 TI - A systematic review of evaluation research in integrated behavioral health care: Operational and financial characteristics. AB - INTRODUCTION: Integrated behavioral health care (IBHC) is an emerging solution for the delivery of behavioral health in primary care contexts. Although IBHC has been implemented and studied for more than 2 decades, little seems to be known about how it is best evaluated. This article illustrates a framework for IBHC evaluation based on the Three World view (with a focus on the operational and financial worlds) and delivers results from a systematic review on the operational and financial characteristics of existing IBHC research. METHOD: This study identified original reports of research that included an evaluation or assessment of the operational or financial success or sustainability of IBHC sites or programs. RESULTS: A total of 3,386 articles were found through the selected databases and 46 articles were found to meet the inclusion criteria. From the 46 articles that contained an IBHC evaluation including operational or financial variables, 9 operational and 11 financial characteristics were identified as barriers or strengths to sustainability or success. The characteristics of the evaluation participants, IBHC settings, and method of evaluation were also coded and analyzed. DISCUSSION: As a result of this systematic review of articles, evaluation of the success and sustainability of the operational and financial worlds can now be conceptualized at provider and practice levels. Collaboration and communication between medical and behavioral health providers was a significant operational characteristic related to success and sustainability. Financial characteristics indicated that continuous financial evaluation throughout implementation was important to success and sustainability. (PsycINFO Database Record PMID- 28617018 TI - Integrated care in rural health: Seeking sustainability. AB - INTRODUCTION: The increased awareness of the financial impact associated with social determinants of health coincides with expectations of the Affordable Care Act (HR 3590) to improve care while reducing costs. The integration of behavioral health providers (BHPs) into primary care has demonstrated improved clinical outcomes. This study was designed with 2 aims, including the evaluation of the financial viability of an integrated care model in a rural setting and the demonstration of incorporating practice-based research into clinical work. METHOD: A rural health plan caring for 22,000 members funded a pilot project placing BHPs in 3 clinics to provide integrated care. Patient utilization of medical services for 6 months following BHP services was compared with baseline utilization. RESULTS: The BHPs treated 256 unique patients, with a total of 459 consultations. The percentage of patients receiving BHP services varied between clinics (Clinic A = 1.4%, Clinic B = 2.7%, and Clinic C = 3.9%). A between-clinic analysis showed differences in medical claims data between baseline and post-BH services. The overall effect sizes for reduced medical utilization for patients at clinics B and C were very large, Hedge's g = -2.31 and -4.79, respectively. Utilization of 4 of the services (emergency, lab, outpatient, and primary care) showed the large reductions in their costs. In contrast, the data for Clinic A showed no change. DISCUSSION: Patients receiving behavioral health services within the integrated care model may decrease utilization of medical services following treatment, resulting in cost offset. Potential reasons for variability between clinics are discussed. (PsycINFO Database Record PMID- 28617017 TI - Identifying trajectories of change to improve understanding of integrated health care outcomes on PTSD symptoms post disaster. AB - INTRODUCTION: Addressing life stressors is an important function for integrated care, especially for health care homes located in disaster prone environments. This study evaluated trajectories of change for patients with postdisaster posttraumatic stress disorder (PTSD) who were seen in integrated care. In addition to describing the results, this article provides the methods of subgroup analyses as this may be useful for others working in real-world practice. METHOD: Patients (N = 340) receiving services at 5 rural health clinics self-reported PTSD symptoms as part of an ongoing evaluation to study the effectiveness of integrated health. Analysis of variance was used to assess differences overtime and trajectories were identified with cluster analyses. Disaster and trauma related factors associated with these trajectories were assessed using logistic regression. RESULTS: Significant overall decreases in PTSD symptoms overtime were found; individual trajectories were identified and include stable low, steep declines, stable high symptoms, and increasing symptoms. Stress related to disaster and the number of other traumas patients experienced correctly classified trajectory membership. DISCUSSION: Trajectories indicate that patients have differing treatment needs and cluster analysis as an evaluation technique may be useful in identifying what treatment works and for whom. The present study addresses a major concern for health care providers serving disaster prone communities and emphasizes the importance of identifying pre incident and disaster related risk vulnerabilities that contribute to mental health outcomes. Subgroup analyses are a useful tool for developing more targeted treatment within integrated care and may be an accessible research strategy for others working in such settings. (PsycINFO Database Record PMID- 28617019 TI - Initial examination of characteristics of patients who are high utilizers of an established primary care behavioral health consultation service. AB - : Obective: Although much has been studied regarding high-utilizing patients of medical services, no studies have been published regarding high-utilizing patients of integrated primary care behavioral health (PCBH) services. The primary purpose of the current study was to examine characteristics of high utilizing patients of PCBH services and model adherence. The secondary purpose was to describe the process of conducting this research by clinicians in integrated care. METHOD: Data were obtained from electronic health records retrospectively for the study's time period, 2007-2013, for the sample of all patients who met with the behavioral health consultation team during that time. Variables include demographics, diagnoses, involvement in additional services, and scores on a patient-complexity scale for a subset of patients. Chi-square analyses, t tests and logistic regression analyses were performed. RESULTS: The results demonstrate significant associations between key demographic characteristics, use of population-based augmentation services (i.e., consulting psychiatry, care management, substance-abuse consulting), and high-utilizing status. Model adherence was maintained over time. Logistic regression analysis, controlling for high-utilizing status and number of visits, demonstrated a significant relationship between more complex diagnostic categories and behavioral health issues. DISCUSSION: There are differences between high utilizing patients and nonhigh-utilizing patients suggestive of increased clinical severity and appropriate use of services while maintaining PCBH model integrity. The use of the population-based augmentation services is associated with high-utilizer status, and reflects the ability of these services to target those patients who most need the clinical care. (PsycINFO Database Record PMID- 28617020 TI - Need, access, and the reach of integrated care: A typology of patients. AB - INTRODUCTION: This paper is a report on a study exploring a potential typology of primary care patients referred for integrated behavioral health care (IBHC) services. We considered whether primary care patients could be grouped into meaningful clusters based on perceived need for behavioral health services, barriers to accessing care, and past-year service utilization. We also described the development of a working partnership between our university-based research team and a federally qualified health center (FQHC). METHOD: A total of 105 adult primary care patients referred for same-day behavioral health appointments completed a brief self-report questionnaire assessing past-year behavioral health concerns, service utilization, and perceived barriers to utilization. RESULTS: Hierarchical and k-means cluster analyses revealed 3 groups: (a) Well-Served patients, characterized by high perceived need for services, high service use, and low barriers to service use (40%); (b) Underserved patients, characterized by high perceived need, low service utilization, and high barriers to service use (20%); and (c) Subclinical patients, characterized by low perceived need, low service use, and low barriers to service use (20%). Clusters were reliably differentiated by age, primary language, insurance status, and global functioning. DISCUSSION: We found primary care patients could be grouped into 3 categories and that 60% (Underserved and Subclinical) represented groups less commonly seen in traditional mental health (MH) settings. IBHC may be a promising approach for extending the reach of MH care, and partnerships between FQHCs and university-based research teams may be a promising approach for conducting research on the IBHC service-delivery model. (PsycINFO Database Record PMID- 28617021 TI - Development and implementation of a psychotherapy tracking database in primary care. AB - INTRODUCTION: Although there is a rapid increase in the integration of behavioral health services in primary care, few studies have evaluated the effectiveness of these services in real-world clinical settings, in part due to the difficulty of translating traditional mental health research designs to this setting. Accordingly, innovative approaches are needed to fit the unique challenges of conducting research in primary care. The development and implementation of one such approach is described in this article. METHOD: A continuously populating database for psychotherapy services was implemented across 5 primary care clinics in a large health system to assess several levels of patient care, including service utilization, symptomatic outcomes, and session-by-session use of psychotherapy principles by providers. RESULTS: Each phase of implementation revealed challenges, including clinician time, dissemination to clinics with different resources, and fidelity of data collection strategy across providers, as well as benefits, including the generation of useful data to inform clinical care, program development, and empirical research. DISCUSSION: The feasible and sustainable implementation of data collection for routine clinical practice in primary care has the potential to fuel the evidence base around integrated care. The current project describes the development of an innovative approach that, with further empirical study and refinement, could enable health care professionals and systems to understand their population and clinical process in a way that addresses essential gaps in the integrated care literature. (PsycINFO Database Record PMID- 28617022 TI - Reducing hospital readmission through team-based primary care: A 7-week pilot study integrating behavioral health and pharmacy. AB - INTRODUCTION: A team-based service delivery model was applied to provide patients with biopsychosocial care following hospital discharge to reduce hospital readmission. Most previous interventions focused on transitions of care occurred in the inpatient setting with attention to predischarge strategies. These interventions have not considered psychosocial stressors, and few have explored management in primary care settings. METHOD: A 7-week team-based service delivery model was implemented in a family medicine practice emphasizing a biopsychosocial approach. A physician, psychologist, pharmacist, care managers, and interdisciplinary trainees worked with 17 patients following hospital discharge. This comprehensive evaluation assessed patients' mood, cognitive abilities, and self-management of health behaviors. Modifications were made to improve ease of access to outpatient care and to improve patient understanding of the therapeutic plan. This pilot study was conducted to determine the utility of the model. RESULTS: Of 17 patients, 15 individuals avoided readmission at 30- and 90-day intervals. Other substantial benefits were noted, including reduced polypharmacy, engagement in specialty care, and reduction of environmental stressors to improve access to care. The clinic in which this was implemented is currently making efforts to maintain this model of care based on observed success. DISCUSSION: Although this work only represents a small sample, results are encouraging. This model can be replicated in other primary care settings with specialty clinicians on site. Specifically, approaches that promote a team-based delivery in a primary care setting may support improved patient outcomes and reduced overall systems' costs. Recommendations for research in a clinical setting are also offered. (PsycINFO Database Record PMID- 28617023 TI - Integrated behavioral health practice facilitation in patient centered medical homes: A promising application. AB - INTRODUCTION: The purpose of this study was to assess the degree of behavioral health (BH) integration change in patient-centered medical homes (PCMHs) when using a practice facilitator (PF) specially trained in implementing integrated care and how a quasi-experimental design assists in this process. METHOD: Twelve PCMHs, 8 Federally Qualified Health Centers and 4 private practices, with varying degrees of BH services participated in this study. The degree of BH integration was assessed with a quasi-experimental design using the Maine Health Access Foundation's Site Self Assessment (MeHAF SSA) at baseline and after implementing site-specific BH services. The sites tracked completion of unique objectively measured goals being implemented using the Goal Attainment Scale (GAS) score. RESULTS: At the conclusion of the study, sites saw a statistically significant increase in the level of BH integration from a baseline of 2.73 (SD = 0.44) to a postintervention score of 3.49 (SD = 0.22) with improvements from mild-moderate overall integration to moderate-advanced overall integration (p < .001). In addition, 10 out of the 12 sites achieved successful implementation of unique goals with assistance from the PF. DISCUSSION: This study provides the first quasi-experimental/pretest-posttest evidence utilizing real-world data that the practice facilitation method is an effective solution toward increasing the degree of BH integration. This paper describes the real-world efforts to evaluate the degree of BH integration change in PCMHs when using a PF with content expertise in BH integration within primary care. (PsycINFO Database Record PMID- 28617024 TI - Evaluating transformation with available resources: The influence of APEX on depression screening. AB - OBJECTIVE: The University of Colorado developed and piloted a team-based primary care delivery model called ambulatory process excellence (APEX) in a family medicine residency in 2015. We evaluated its impact on depression screening using found data and tools readily available to practice-based evaluators. METHOD: The APEX model calls for 5 medical assistants (MAs) supporting 2 providers. MAs have dedicated time to provide delegated care, including depression screening with 2 versions of the Patient Health Questionnaire: PHQ-2 and PHQ-9. Using an interrupted time-series-with-control design, we created longitudinal profiles of the pilot and a control practice using statistical process control charts. We obtained data from preexisting dashboards derived from the electronic medical record. Outcomes included PHQ-2 screening rates, patients screening positive, and the proportion of them completing a PHQ-9. Covariates included monthly visits and new-patient appointments. Using Microsoft Excel, we transformed all data into modified z scores, plotted them on a multivariate control chart for each practice, and assessed them for evidence of special cause variation. Key informants provided information about potentially confounding concurrent events. RESULTS: Compared with baseline, the intervention practice significantly increased primary care medical visits and new-patient appointments, increased positive PHQ-2 patients, and improved PHQ-9 completion. High screening rates remained stable. In the control practice, new-patient appointments increased and PHQ2 screening improved. DISCUSSION: APEX may contribute to better depression screening processes. We have provided a detailed description of a real-world, practice-based, quasi-experimental evaluation model using common spreadsheet software (Microsoft Excel) to transform and analyze found data with multivariate statistical process-control charts. (PsycINFO Database Record PMID- 28617025 TI - Confronting the new epidemic: Integrated care for opioid use disorders. AB - The inaugural Collaborative Family Health Care (CFHA) regional conference took place March 17, 2017, in St. Louis, Missouri. The conference theme was opioid use disorders and the potential of medication-assisted treatment using team-based care to address this epidemic. The conference ended with an emphasis on the importance of and strategies for self-care among caregivers working with this population and their families. This intensive meeting was crafted as a proof in concept for CFHA; however, the content was timely with regard to its importance in health care as well as compelling in the opportunity for collaborative care to offer an effective approach. In this article, the authors highlight five impotance topics: (1) opioid use disorders should be addressed in primary care; (2) a team is essential; (3) harm reduction; (4) sustaining self through mindful practice and self-compassion; and (5) medication-assisted treatment. (PsycINFO Database Record PMID- 28617026 TI - "The next Big Five Inventory (BFI-2): Developing and assessing a hierarchical model with 15 facets to enhance bandwidth, fidelity, and predictive power": Correction to Soto and John (2016). AB - Reports an error in "The Next Big Five Inventory (BFI-2): Developing and Assessing a Hierarchical Model With 15 Facets to Enhance Bandwidth, Fidelity, and Predictive Power" by Christopher J. Soto and Oliver P. John (Journal of Personality and Social Psychology, Advanced Online Publication, Apr 7, 2016, np). In the article, all citations to McCrae and Costa (2008), except for the instance in which it appears in the first paragraph of the introduction, should instead appear as McCrae and Costa (2010). The complete citation should read as follows: McCrae, R. R., & Costa, P. T. (2010). NEO Inventories professional manual. Lutz, FL: Psychological Assessment Resources. The attribution to the BFI-2 items that appears in the Table 6 note should read as follows: BFI-2 items adapted from "Conceptualization, Development, and Initial Validation of the Big Five Inventory 2," by C. J. Soto and O. P. John, 2015, Paper presented at the biennial meeting of the Association for Research in Personality. Copyright 2015 by Oliver P. John and Christopher J. Soto. The complete citation in the References list should appear as follows: Soto, C. J., & John, O. P. (2015, June). Conceptualization, development, and initial validation of the Big Five Inventory-2. Paper presented at the biennial meeting of the Association for Research in Personality, St. Louis, MO. Available from http://www.colby.edu/psych/personality-lab/ All versions of this article have been corrected. (The following abstract of the original article appeared in record 2016-17156-001.) Three studies were conducted to develop and validate the Big Five Inventory-2 (BFI-2), a major revision of the Big Five Inventory (BFI). Study 1 specified a hierarchical model of personality structure with 15 facet traits nested within the Big Five domains, and developed a preliminary item pool to measure this structure. Study 2 used conceptual and empirical criteria to construct the BFI-2 domain and facet scales from the preliminary item pool. Study 3 used data from 2 validation samples to evaluate the BFI-2's measurement properties and substantive relations with self-reported and peer-reported criteria. The results of these studies indicate that the BFI-2 is a reliable and valid personality measure, and an important advance over the original BFI. Specifically, the BFI-2 introduces a robust hierarchical structure, controls for individual differences in acquiescent responding, and provides greater bandwidth, fidelity, and predictive power than the original BFI, while still retaining the original measure's conceptual focus, brevity, and ease of understanding. The BFI-2 therefore offers valuable new opportunities for research examining the structure, assessment, development, and life outcomes of personality traits. (PsycINFO Database Record (c) 2017 APA, all rights reserved). PMID- 28617027 TI - Efficacy of peroral endoscopic myotomy compared with other invasive treatment options for the different esophageal motor disorders. AB - INTRODUCTION: Peroral endoscopic myotomy (POEM) has been performed since 2008 on more than 5,000 patients. It has proven to be highly effective in the treatment of achalasia and has shown promising outcomes for other esophageal motility spastic disorders. METHODS: A literature review of the efficacy of POEM compared to the previous invasive treatments for different esophageal motility disorders was performed. The application in the pediatric and elderly populations and its role as a rescue therapy after other procedures are also outlined. RESULTS: Short term outcomes are similar to laparoscopic Heller myotomy (LHM) and pneumatic endoscopic dilation (PD) (clinical success > 90%) for achalasia subtypes I and II. Mid-term outcomes are comparable to LHM and overcome the results obtained after PD (> 90% vs ~50%). With regard to type III achalasia, POEM efficacy is 98% compared to 80.8% for LHM and the PD success remains at 40%. With regard to spastic esophageal disorders (SED), POEM has an effectiveness of 88% and 70% for distal esophageal spasm (DES) and jackhammer esophagus (JE) respectively. A response of 95% in patients with sigmoid esophagus has been reported. POEM has been performed in pediatric and elderly populations and has obtained a higher efficacy than PD in pediatric series (100% vs 33%) without greater adverse events. Previous treatments do not seem to hinder POEM results with excellent response rates, including 97% in post LHM and 100% in a re-POEM series. Final considerations: POEM has shown excellent short and mid-term results for all subtypes of achalasia but long-term results are not yet available. The promising results in SED may make POEM the first-line treatment for SED. A high-safety profile and efficacy have been shown in elderly and pediatric populations. Previous treatments do not seem to diminish the success rate of POEM. Core tip: POEM has emerged as an efficient treatment option for all subtypes of achalasia and other scenarios (including previous treatments and elderly and pediatric populations). Short and mid-term results are comparable to LHM and are better than PD data. The clinical response rate of DES and JE may make POEM the first line treatment for SED. PMID- 28617028 TI - Laparoscopic transgastric ERCP in bariatric surgery patients: our experience. AB - Laparoscopic Roux-en-Y gastric bypass (LRYGB) is the surgical treatment of choice for morbid obesity. Several therapeutic options to remove common bile duct (CBD) stones have been proposed in these patients. Laparoscopy-assisted transgastric ERCP (LATERCP) has a high success rate. However, the procedure is not fully standardized and some technical variations have been proposed. We introduce two cases in which laparoscopic transgastric ERCP has been used to treat choledocholithiasis after LRYGB. PMID- 28617029 TI - Medium to long-term efficacy and safety of oral tacrolimus in moderate to severe steroid refractory ulcerative colitis. AB - BACKGROUND AND OBJECTIVE: Oral tacrolimus is an effective drug that induces clinical remission in patients with moderate to severe ulcerative colitis refractory to steroids. However, there is little data with regard to its medium to long-term efficacy and safety. The aim of this study was to assess the medium to long-term efficacy and safety of oral tacrolimus in this challenging clinical situation. METHODS: This was a retrospective observational review of the clinical charts of 34 patients with moderate to severe ulcerative colitis refractory to steroids treated with oral tacrolimus at our hospital (July 2001-July 2016). Remission was defined as a Lichtiger index score < 3 and response was defined as a score < 10 with a reduction of at least three points compared to the baseline score. RESULTS AND CONCLUSIONS: Seven patients (20.58%) required colectomy during the follow-up period (mean 65 months). Nine patients required rescue with infliximab (four patients during the first six months of follow-up and the other five after the first six months). The short to medium clinical efficacy combining both remission and clinical response was 82% at six months. Kaplan-Meier analysis showed that the percentage of patients free from colectomy and additional sequential rescue therapy was 75% at 54 months (median follow-up). The early introduction of thiopurines (< 2 months from start of tacrolimus) showed no significant improvement in prognosis (p = 0.72). Fifty-three per cent of patients experienced adverse effects, none of whom required treatment withdrawal. No severe infections were noted during the follow-up. PMID- 28617031 TI - Clinical manifestations and endoscopic presentations of gastric lymphoma: a multicenter seven year retrospective survey. AB - BACKGROUND AND AIM: To improve the diagnostic rate of gastric lymphoma by analyzing clinical and endoscopic features of patients with gastric lymphoma and suspected gastric lymphoma. METHODS: Clinical and endoscopic records of 35 patients with gastric lymphoma (positive group) and 133 patients with suspected gastric lymphoma but subsequent non-malignant pathology (negative group) were analyzed retrospectively. Data from another 99 gastric lymphoma patients with malignant pathology but nonspecific endoscopy (endoscopy non-suspect group) were analyzed. RESULTS: Abdominal pain was the predominant symptom reported in both the positive and negative lymphoma groups, representing 60.0 and 52.5%, respectively. No significant differences in age, sex and clinical manifestations in subjects from the two groups were found. In the positive group, 54.3% were ulcerative; 34.3%, infiltrative; 8.5%, polypoid; and 2.9%, granulonodular. In the negative group, 52.6% were infiltrative; 42.1%, ulcerative; 4.5%, granulonodular; and 0.75%, polypoid. The endoscopic results varied between the two groups (p < 0.05). In the non-suspect group, 66.7% were ulcerative; 17.2%, infiltrative; 14.1%, polypoid; and 2.0%, granulonodular. With regards to histology, diffuse large B cell lymphoma was the most common subtype. The sensitivity of endoscopy was 60% for detecting malignancy and 21% for gastric lymphoma. CONCLUSION: The present study suggests that gastric lymphoma and suspected gastric lymphoma have similar clinical features. Gastric lymphoma presented mainly as macroscopic ulcerative lesions, whereas suspected gastric lymphoma appeared mainly as infiltrative lesions. Although the diagnostic rate of gastric lymphoma was relatively low (21%), it can be identified by endoscopy (60%). To improve diagnosis, repetitive endoscopic biopsies should be performed and novel endoscopic techniques developed in the future. PMID- 28617030 TI - A real life study of Helicobacter pylori eradication with bismuth quadruple therapy in naive and previously treated patients. AB - OBJECTIVE: To evaluate the efficacy and safety of a quadruple regimen (BMTO) of the "3-in-1 capsule" (containing bismuth subcitrate potassium, metronidazole and tetracycline) plus omeprazole in naive and previously treated patients diagnosed with Helicobacter pylori (H. pylori) infection in the clinical setting in Seville (Spain). METHODS: This is a prospective study carried out on consecutive patients with a confirmed H. pylori infection and upper gastrointestinal symptoms. After providing their informed consent, the patients were treated for ten days with a 3 in-1 capsule containing bismuth subcitrate potassium (140 mg), metronidazole (125 mg) and tetracycline (125 mg: Pylera(r)), three capsules four times daily, plus omeprazole (20 or 40 mg) twice daily. Eradication of infection was determined by a negative urea breath test at least 28 days after the end of treatment. RESULTS: A total of 58 consecutive patients were enrolled into this study, two of whom withdrew early due to vomiting on days three and five, respectively. In this cohort, 17 patients (29.3%) had a prior history of medication to treat H. pylori. In the intent-to-treat population, eradication was achieved in 97.6% (40/41) and 82.4% (14/17) of cases in patients treated with BMTO as a first-line or rescue therapy, respectively. At least one adverse event was reported by 28 (48%) patients, mostly mild effects (86%). CONCLUSION: A ten day treatment with BMTO is an effective and safe strategy to combat confirmed H. pylori infection in patients. PMID- 28617032 TI - Intraductal papillary neoplasia of the bile duct with malignancy: a differentiated entity of cholangiocarcinoma with a better prognosis. A review of three new cases. AB - INTRODUCTION: Intraductal papillary neoplasms of the bile duct have been recognized as a differentiated entity to other biliary tumors since 2001. They are characterized by intraductal growth, with or without mucus production, and have malignant potential, although they have a better prognosis than other types of cholangiocarcinoma. CASE REPORTS: From January 2010 to August 2015, we included three patients with a confirmed diagnosis of bile duct intraductal papillary neoplasia with malignancy that were treated at our center. Two cases were male and one female with a mean age of 67.3 years. All three patients presented malignancy at the time of diagnosis. One patient was asymptomatic and the diagnosis was reported in the hepatectomy specimen after a liver transplant due to autoimmune hepatitis. The other two patients presented with cholestasis and acute cholangitis and the diagnosis was made based on imaging tests (computed tomography [CT] and magnetic resonance imaging [MRI]) and endoscopic retrograde cholangiopancreatography (ERCP) with brushing and a biopsy. The treatment in both cases was surgical with a left hepatectomy, and resection of the left bile duct and segment I. They did not receive adjuvant treatment. None of the cases had recurrence of the disease. DISCUSSION: Malignant intraductal papillary neoplasias of the biliary tract represent a different entity of cholangiocarcinoma with a better prognosis. Its diagnosis is based on imaging tests and histology by ERCP. The treatment is surgical, achieving a high rate of success with a low relapse rate. PMID- 28617034 TI - Fetal cells in maternal blood for prenatal diagnosis: a love story rekindled. PMID- 28617033 TI - A UPLC-MS/MS method for quantification of 5alpha-androst-3beta,5,6beta-triol in human plasma: development, validation and its application in clinical pharmacokinetic study. AB - AIM: 5alpha-androst-3beta,5,6beta-triol is a novel ischemic stroke drug under clinical development. The objective of this study was to develop and validate a simple ultraperformance liquid chromatography tandem mass spectrometry method for 5alpha-androst-3beta,5,6beta-triol in human plasma and its application in clinical pharmacokinetic study. Methodology & results: After being pretreated using an automatized solid-phase extraction procedure, plasma sample was separated on a Waters(r) AcquityTM BEH C18 column (2.1 * 50 mm id, 1.7 mm) by an Acquity UPLC system and detected by an API 5500 triple quadrupole mass spectrometer, which was validated following international guidelines. CONCLUSION: A simple method was successfully validated over a concentration range of 2.00-500 ng/ml for 5alpha-androst-3beta,5,6beta-triol and applied to investigate its plasma pharmacokinetic profiles in healthy Chinese subjects. PMID- 28617035 TI - Measuring Stress in Young Children Using Hair Cortisol: The State of the Science. AB - Extensive literature suggests that adverse experiences in early childhood may deleteriously impact later health. These effects are thought to be related to the impact of persistent or chronic stress on various biological processes, mediated by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and ultimately irregularities in cortisol levels. Ameliorating persistent stress in young children requires accurately measuring the chronicity of physiologic stress, which is difficult in young children because of unreliable self-report and the burden and inaccuracy associated with using invasive acute-stress biomeasures. A better way to approximate persistent stress in young children is measuring hair cortisol concentration (HCC), as it only requires one noninvasive collection to measure months of HPA-axis activity or experienced stress. However, few studies measure HCC in young children despite wide use in adult stress research. This article reviews and synthesizes research that uses HCC to approximate persistent stress in healthy children, 12-60 months of age. Reviewed studies indicate that HCC is elevated in young children who are experiencing forms of persistent stress such as low socioeconomic status and maternal distress. Hair cortisol is thus a promising measure of early childhood persistent stress, but due to the limited use of HCC in this population, much research is still needed. Specifically, nurse researchers may need to measure several factors associated with early childhood persistent stress and HCC to identify which children are at risk for stress related disease. PMID- 28617036 TI - An LC-MS/MS method to determine vancomycin in plasma (total and unbound), urine and renal replacement therapy effluent. AB - AIM: Critical illness and medical interventions, such as renal replacement therapy, can cause changes to vancomycin pharmacokinetics and lead to suboptimal dosing. To comprehensively characterize vancomycin pharmacokinetic a method must measure vancomycin in a range of clinical matrices. RESULTS: A LC-MS/MS method was developed using hydrophilic interaction liquid chromatography and microsample volumes, where possible. For all matrices, the linear concentration range was 1 100 MUg/ml, interassay accuracy and precision was within 15%, and recovery above 80%. No matrix effects were observed. Calibration equivalence may be applied for some matrix combinations. CONCLUSION: A method for the analysis of vancomycin in plasma (total, unbound), urine and renal replacement therapy effluent, suitable for use in any patient pharmacokinetic study, has been developed and validated. PMID- 28617037 TI - Quantitative determination of a siRNA (AD00370) in rat plasma using peptide nucleic acid probe and HPLC with fluorescence detection. AB - AIM: Toxicokinetic and pharmacokinetic studies of therapeutic oligonucleotides require validated bioanalytical methods for sensitive and specific quantification of oligonucleotide drug candidates in biological samples. RESULTS: A peptide nucleic acid (PNA) hybridization-based HPLC-fluorescence assay was developed and validated for quantification of Arrowhead Pharmaceuticals' proprietary siRNA in rat plasma samples via hybridization and anion-exchange-HPLC (AEX-HPLC) with fluorescence detection. CONCLUSION: The validated method provided a sensitive and selective approach for quantification of siRNA in biological samples at a linear quantitation range of 1-1000 ng/ml. The assay requires only 25 MUl of plasma sample and shows excellent accuracy and precision even without using an internal standard, providing a useful quantification method for siRNA determination in biological matrix with limited sample volume. PMID- 28617038 TI - Relation of subclinical serum creatinine elevation to adverse in-hospital outcomes among myocardial infarction patients. AB - BACKGROUND:: Acute kidney injury is associated with adverse outcomes after acute ST elevation myocardial infarction (STEMI). It remains unclear, however, whether subclinical increase in serum creatinine that does not reach the consensus criteria for acute kidney injury is also related to adverse outcomes in STEMI patients undergoing primary percutaneous coronary intervention. METHODS:: We conducted a retrospective study of 1897 consecutive STEMI patients between January 2008 and May 2016 who underwent primary percutaneous coronary intervention, and in whom acute kidney injury was not diagnosed throughout hospitalization. We investigated the incidence of subclinical acute kidney injury (defined as serum creatinine increase of >= 0.1 and < 0.3 mg/dl) and its relation to a composite end point of adverse in hospital outcomes. RESULTS:: Subclinical acute kidney injury was detected in 321 patients (17%). Patients with subclinical acute kidney injury had increased rate of the composite end point of adverse in hospital events (20.3% vs. 9.7%, p<0.001), a finding which was independent of baseline renal function. Individual components of this end point (occurrence of heart failure, atrial fibrillation, need for mechanical ventilation and in hospital mortality) were all significantly higher among patients with subclinical acute kidney injury ( p< 0.05 for all). In a multivariable regression model subclinical acute kidney injury was independently associated with higher risk for adverse in-hospital events (odds ratio 1.92.6, 95% confidence interval: 1.23 2.97, p=0.004). CONCLUSIONS:: Among STEMI patients treated with primary percutaneous coronary intervention, small, subclinical elevations of serum creatinine, while not fulfilling the consensus criteria for acute kidney injury, may serve as a significant biomarker for adverse outcomes. PMID- 28617039 TI - Raman and Energy Dispersive Spectroscopy (EDS) Analyses of a Microsubstance Adhering to a Fiber of the Turin Shroud. AB - The Raman spectrum of a microsubstance, smeared on a fiber coming from the Shroud of Turin, was compared with numerous spectra published for old or modern pigment dyes, whole bloods, dried bloods, red blood cells, albumin, very ancient blood stains, and various "degradation" products of heme. Within the wavenumber measure accuracy, it is shown that all Raman lines detected above background could correspond to vibration frequencies found in biliverdin-derived compounds except a weak line that we tentatively attributed to amide I. Biliverdin is known as an oxidative ring cleavage product of the heme of blood. Energy dispersive spectroscopy (EDS) analysis of the sample confirms an elemental composition fully compatible with this hypothesis. Therefore, it is very likely that this microsubstance contains products of heme including heme/biliverdin-derived compounds and protein traces (amide I). Nevertheless, other measures will be necessary to confirm it. This method of identification, adding EDS to Raman spectrometry can be applied to nondestructive testing (NDT) of many other microsamples. PMID- 28617040 TI - Complete atrioventricular block in acute coronary syndrome: prevalence, characterisation and implication on outcome. AB - PURPOSE: The aim was to characterise acute coronary syndrome patients with complete atrioventricular block and to assess the effect on outcome. METHODS: Patients admitted with acute coronary syndrome were divided according to the presence of complete atrioventricular block: group 1, with complete atrioventricular block; group 2, without complete atrioventricular block. Clinical, electrocardiographic and echocardiographic characteristics and prognosis during one year follow-up were compared between the groups. RESULTS: Among 4799 acute coronary syndrome patients admitted during the study period, 91 (1.9%) presented with complete atrioventricular block. At presentation, group 1 patients presented with lower systolic blood pressure, higher Killip class and incidence of syncope. In group 1, 86.8% presented with ST-segment elevation myocardial infarction (STEMI), and inferior STEMI was verified in 79.1% of patients in group 1 compared with 21.9% in group 2 ( P<0.001). Right ventricular myocardial infarction was more frequent in group 1 (3.3% vs. 0.2%; P<0.001). Among patients who underwent fibrinolysis complete atrioventricular block was observed in 7.3% in contrast to 2.5% in patients submitted to primary percutaneous coronary intervention ( P<0.001). During hospitalisation group 1 had worse outcomes, with a higher incidence of cardiogenic shock (33.0% vs. 4.5%; P<0.001), ventricular arrhythmias (17.6% vs. 3.6%; P<0.001) and the need for invasive mechanical ventilation (25.3% vs. 5.1%; P<0.001). After a propensity score analysis, in a multivariate regression model, complete atrioventricular block was an independent predictor of hospital mortality (odds ratio 3.671; P=0.045). There was no significant difference in mortality at one-year follow-up between the study groups. CONCLUSION: Complete atrioventricular block conferred a worse outcome during hospitalisation, including a higher incidence of cardiogenic shock, ventricular arrhythmias and death. PMID- 28617041 TI - A Fluorescence Quenching Analysis of the Binding of Fluoroquinolones to Humic Acid. AB - Fluorescence quenching was used to investigate the interaction of six fluoroquinolones with humic acid. Static quenching was observed for the binding of ciprofloxacin, enoxacin, fleroxacin, levofloxacin, norfloxacin, and ofloxacin to humic acid. The equilibrium binding constants were found from Stern-Volmer plots of the data. The quenching experiments were repeated over a temperature range of 25-45 C and van't Hoff plots were generated. From these linear plots, thermodynamic values were calculated for Delta H, Delta G, and Delta S for each of the fluoroquinolones. The equilibrium binding constants were found to be <1 for all the antibiotics studied. The calculated DeltaH values were all negative and ranged from -9.5 to -27.6 kJ/mol. The high water solubility of the antibiotics and low DeltaH of binding suggests that the antibiotics will be transported easily through the environment. Finally, whether the fluoroquinolones are in a protonated, deprotonated, or partially protonated state is found to correlate to the strength of binding to humic acid. PMID- 28617042 TI - Spectroscopic Analysis to Characterize Finishing Treatments of Ancient Bowed String Instruments. AB - Historical bowed string instruments exhibit acoustic features and aesthetic appeal that are still considered inimitable. These characteristics seem to be in large part determined by the materials used in the ground and varnishing treatments after the assembly of the instrument. These finishing processes were kept secret by the violinmakers and the traditional methods were handed down orally from master craftsmen to apprentices. Today, the methods of the past can represent a secret to be revealed through scientific investigations. The "Cremonese" methods used in the 17th and 18th centuries were lost as the last Great Masters from the Amati, Guarneri, and Stradivari families passed away. In this study, we had the chance of combining noninvasive and microinvasive techniques on six fragments of historical musical instruments. The fragments were detached from different instruments during extraordinary maintenance and restoration treatments, which involved the substitution of severely damaged structural parts like top plates, back plates, or ribs. Therefore, the fragments can offer to the scientists a valuable overview on the materials and techniques used by the violinmakers. The results obtained by portable X-ray fluorescence, optical microscopy, scanning electron microscopy coupled with energy dispersive X ray spectrometry, and Fourier transform infrared microscopy allowed us to: (1) determine the stratigraphy of six instruments; (2) obtain new information about the materials involved in the finishing processes employed in Cremona; and (3) elucidate the technological relationship among the procedures adopted in the violin making workshops during the considered period. PMID- 28617043 TI - Eveningness Is Associated With Greater Depressive Symptoms in Type 2 Diabetes Patients: A Study in Two Different Ethnic Cohorts. AB - BACKGROUND: Eveningness is associated with greater depressive symptoms in the general population. Depression and type 2 diabetes (T2D) commonly coexist. We aimed to explore the association between morningness-eveningness and depressive symptoms in T2D patients in the United States and in Thailand. PARTICIPANTS: T2D patients (n = 182) from an endocrinology clinic in Chicago, Illinois, and six hospitals in Thailand (n = 251) were enrolled. METHODS: Diabetes history was collected. Depressive symptoms were assessed by the Center for Epidemiologic Studies Depression scale (CES-D). The Chicago cohort completed the Morningness Eveningness Questionnaire (MEQ) and the Thai cohort completed the Composite Scale of Morningness (CSM). Sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). RESULTS: The mean (SD) CES-D score was 13.7 (9.1) in Chicago and 11.9 (6.4) in Thailand. In Chicago participants, after adjusting for age, sex, ethnicity, hemoglobin A1c, insulin use, and PSQI score, greater eveningness (lower MEQ scores) was associated with higher CESD scores (B = 0.117, p = 0.048). In Thai participants, after adjusting for age, sex, and PSQI score, eveningness (lower CSM score) was associated with higher CES-D score (B = 0.147, p = 0.016). In both cohorts, however, eveningness was not independently associated with the likelihood of being in the at-risk range for clinical depression (CES-D >= 16). CONCLUSIONS: Eveningness is independently associated with greater depressive symptoms in T2D in two different ethnic cohorts. The results support the association between individual differences in circadian rhythms and psychological functioning in T2D. PMID- 28617044 TI - Translation and validation of the Norwegian version of the Coronary Revascularisation Outcome Questionnaire. AB - BACKGROUND: Health-related quality of life (HRQOL) questionnaires are increasingly used as outcome measures in research and clinical practice to assess treatment effectiveness in coronary heart disease (CHD) alongside traditional outcome measures. The Coronary Revascularisation Outcome Questionnaire (CROQ) is a patient-reported outcome measure (PROM) to evaluate health outcomes and HRQOL before and after coronary artery bypass grafting surgery (CABG) and percutaneous coronary intervention (PCI). AIM: To translate the CROQ-PCI from English into Norwegian and test its psychometric properties. METHODS: Independent forward and backward translation was done following international guidelines. The CROQ was then pretested with both healthcare professionals and patients before the psychometric properties were field tested in a sample of patients who had undergone PCI. Psychometric testing included an evaluation of: acceptability; tests of scaling assumptions; reliability; content validity; construct validity based on within-scale analyses; and construct validity based on comparisons with external measures. RESULTS: 171 of 258 (66%) invited patients participated. The CROQ was acceptable to patients (low proportion of missing data and good response rate), reliable (good internal consistency and test-retest reliability for all scales), had good content validity (reported by both patients and healthcare professionals) and good construct validity (convergent validity with the SF-12 and Seattle Angina Questionnaire, known groups validity and factor analysis). CONCLUSION: The Norwegian version of CROQ-PCI is a reliable and valid PROM for assessing HRQOL in CHD patients. Further testing of its responsiveness and ability to detect change is needed before recommending its use in Norwegian clinical practice and research. PMID- 28617045 TI - Assessing attachment in school-aged children: Do the School-Age Assessment of Attachment and Family Drawings work together as complementary tools? AB - AIMS: Our goal was to identify an assessment package that could improve treatment planning for troubled children and their families. To assess the validity of our tools, we tested the relations among the School-Age Assessment of Attachment, the Family Drawing and children's risk status. We used the Dynamic-Maturational Model of Attachment and Adaptation to interpret the assessments in the hope of identifying a gradient of risk, and explore whether a new coding method improved the validity of Family Drawings and their utility as a tool to complement the School-Age Assessment of Attachment. METHOD: The participants were 89 children, aged between 5 and 12 years; 32 children were involved with mental health services or child protection. Each child completed a School-Age Assessment of Attachment and a Family Drawing. RESULTS: Both assessments differentiated between clinical and normative referrals with moderate effect sizes when dichotomizing risk versus non-risk attachment. When the analysis incorporated a gradient of six attachment classifications, the effect sizes decreased, but specificity of risk increased. CONCLUSIONS: The School-Age Assessment of Attachment had greater validity for discriminating risk, and type of risk, than the Family Drawings. With a School-Age Assessment of Attachment and family history, the Family Drawing can provide information about distress that some children do not provide verbally. Integration of the two assessment tools alongside information about parental and family functioning appears to be the key to formulating children's problems. PMID- 28617046 TI - Childhood maltreatment and its link to borderline personality disorder features in children: A systematic review approach. AB - BACKGROUND: Borderline personality disorder has repeatedly been associated with a history of maltreatment in childhood; however, research on maltreatment and its link to borderline features in children is limited. METHOD: The aim of this review is to synthesise the existing data on the association between maltreatment and borderline features in childhood. In total, 10 studies were included in this systematic review. RESULTS: Studies indicated that children with borderline features were more likely to have a history of maltreatment, and that children who had been maltreated were more likely to present with borderline features. Other risk factors such as cognitive and executive functioning deficits, parental dysfunction and genetic vulnerability were also identified across studies. CONCLUSION: This review adds to the literature by highlighting maltreatment as a risk factor for borderline features in childhood. Longitudinal research is required to establish the link between childhood borderline features and adult borderline features. Implications for early identification, prevention and intervention services are discussed. PMID- 28617047 TI - Interpersonal rejection sensitivity mediates the associations between peer victimization and two high-risk outcomes. AB - BACKGROUND: Previous research has demonstrated a strong link between peer victimization and suicidal ideation and aggression. This study examined interpersonal rejection sensitivity as a mediator of these associations. METHOD: Diagnostic interviews and assessments were administered to 80 psychiatrically hospitalized adolescents and their parents. RESULTS: Interpersonal rejection sensitivity mediated the association between peer victimization and suicidal ideation as well as aggression after controlling for participant sex and mood disorder diagnosis. CONCLUSION: Interpersonal rejection sensitivity influences the relation between peer victimization and mental health symptoms, including suicidal ideation and aggression. Assessing for and addressing heightened interpersonal rejection sensitivity among adolescents who have been victimized by peers may decrease the likelihood of negative mental health outcomes. Implications, especially for clinicians, are further discussed. PMID- 28617048 TI - Developmental Patterns of Child Emotion Dysregulation as Predicted by Serotonin Transporter Genotype and Parenting. AB - Individual differences in emotion regulation are central to social, academic, occupational, and psychological development, and emotion dysregulation (ED) in childhood is a risk factor for numerous developmental outcomes. The present study aimed to (a) describe the developmental trajectory of ED across early childhood (3-6 years) and (b) examine its sensitivity to youth serotonin transporter genotype, positive and negative parenting behaviors, and their interaction. Participants were 99 families in the Collaborative Family Study, a longitudinal study of children with or without developmental delays. Child ED and early parenting were coded from parent-child interactions. To examine serotonin transporter genotype as a moderator between parenting and child emotion dysregulation (ED), children with the homozygous short (SS) genotype were compared to children with the homozygous long (LL) or heterozygous (SL) genotype. We used latent growth curve modeling (LGCM) to model yearly change in ED from child age 3 to 6 years. LGCM revealed that ED decreased overall across early childhood. In addition, we observed separate Genotype * Positive and Genotype * Negative parenting behavior interactions in predictions of ED growth curves. Children with the SL/LL genotype had ED trajectories that were minimally related to positive and negative parenting behavior, whereas ED decreased more precipitously among children with the SS genotype when exposed to low negative parenting or high positive parenting. These findings provide evidence for Gene * Environment interactions (G*Es) in the development of ED in a manner that is conceptually consistent with vantage sensitivity, and they improve inferences afforded by prospective designs. PMID- 28617049 TI - Cytotoxic withanolides from Physalis angulata. AB - A new withanolide (1), physagulide P, together with five known withanolides (2 6), was isolated from the aerial parts of Physalis angulata L. The structure of new compound was elucidated on the basis of extensive spectroscopic techniques, including 1D, 2D NMR and HRESIMS. The activity screening indicated that compound 1 showed significant cytotoxicities against the human osteosarcoma cell line MG 63, HepG-2 hepatoma cells and breast cancer cells MDA-MB-231 with the IC50 value of 3.50, 4.22 and 15.74 MUM. PMID- 28617050 TI - Complications Following Operatively Treated Ankle Fractures in Insulin- and Non Insulin-Dependent Diabetic Patients. AB - BACKGROUND: Diabetics with ankle fractures experience more complications than the general population, but it is unclear whether complications differ between type 1 and 2 diabetics and between insulin- and non-insulin-dependent diabetics. This study aims to determine if there is a difference in postoperative complication rates between these groups. METHODS: An administrative health care database from a large commercial insurer was queried to identify operatively treated ankle fractures in patients with type 1 (T1D), type 2 (T2D), type 2 insulin-dependent (T2ID), and type 2 non-insulin-dependent (T2NID) diabetes. Postoperative complications were identified to include postoperative stiffness, posttraumatic arthritis, amputation, implant removal, and infection. Subgroup analysis was performed to control for comorbidities. RESULTS: A total of 20 703 closed and 2873 open operatively treated ankle fractures were identified. Patients with T1D experienced higher rates of amputation, postoperative infection, and total complications than patients with T2D (P < .05). Patients with T2ID experienced higher rates of amputation, infection, and total complications than those with T2NID (P < .0001). Subgroup analysis controlling for comorbidities showed a higher total complication rate for T1D compared with T2D in closed ankle fractures (P < .02) and for T2ID compared with T2NID in both open and closed ankle fractures (P < .0001). CONCLUSIONS: Patients with T1D and T2ID have higher complication rates than patients with T2D and T2NID, respectively. Foot and ankle surgeons should be cautioned not to classify diabetics as one cohort and should use these findings to stratify risk among this patient population. LEVELS OF EVIDENCE: Level III: Diagnostic. PMID- 28617051 TI - Radiographic Detection of Marginal Impaction in Supination-Adduction Ankle Fractures. AB - BACKGROUND: The purpose of this study was to describe the incidence of plafond impaction in supination-adduction type II (SAD-II) ankle fractures and assess the accuracy of plain radiographs in detecting plafond impaction and predicting planned operative management compared to computed tomography (CT). METHODS: Patients with SAD-II ankle fractures were retrospectively identified. All SAD-II plain radiographs were reviewed (120 fractures) and compared to CT images (55 fractures). For each plain radiograph or CT scan, 3 orthopedic surgeons were asked the following questions: (1) Is there impaction of the tibial plafond? (2) Does the impaction require direct visualization and articular reduction? The incidence of plafond impaction and the preoperative plan were calculated separately for plain radiographs and CT scans. The accuracy of plain radiographs was calculated using responses from corresponding CT imaging as the gold standard. Change in preoperative management decisions after reviewing CT images was also calculated. RESULTS: In 120 SAD-II ankle fracture plain radiographs, marginal impaction of the plafond was visualized in 61% of fractures. The diagnosis of impaction using plain radiographs was correct in 84% of fractures when compared to CT imaging, resulting in a 91% positive predictive value (PPV) and a 55% negative predictive value (NPV). Plain radiographs were able to predict planned operative management after review of CT imaging with an 87% PPV and 75% NPV. CONCLUSION: The majority of SAD-II ankle fractures involved marginal impaction of the tibial plafond. Plain radiographs were accurate in diagnosing impaction when it was present, but were not accurate in ruling out impaction. In the presence of impaction, CT likely will not change planned operative management. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 28617052 TI - Neotomodon alstoni mice present sex differences between lean and obese in daily hypothalamic leptin signaling. AB - This article compared the effects of spontaneous obesity on the daily profile in the relative amount of the leptin receptor (LepRb), and its output. That is the precursor Pro-opiomelanocortin (POMC) over a 24-hour period and compared with differences in locomotion and food intake in periods of artificial light. Differences between lean and obese mice were examined, as were sex differences. Body weight, food intake and locomotor activity were monitored in freely moving lean and obese mice. Hypothalamic tissue was collected at 5 h, 10 h, 15 h, 19 h and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein for LepRb, STAT3 phosphorylation (by pSTAT3/STAT3 ratio) and POMC. Obese mice were 60% less active in locomotion than lean mice during the night. While both locomotor activity and food intake were noticeably greater during the day in obese mice than in lean mice, the hypothalamus in obese mice showed a lower relative abundance of POMC and reduced pSTAT3/STAT3 ratio and leptin receptors. Behavioral and biochemical differences were more evident in obese females than in obese males. These results indicate that obesity in N. alstoni affects hypothalamic leptin signaling according to sex. PMID- 28617053 TI - Chemical constituents from Bletilla striata and their NO production suppression in RAW 264.7 macrophage cells. AB - A novel glucoside bletilloside A (1) was isolated from the tubers of Bletilla striata, together with seven known compounds (2-8). Their structures were determined on the basis of extensive spectroscopic analyses. All compounds were evaluated for the inhibition on NO production effects in RAW 264.7 macrophage cells, while militarine (4) and dactylorhin A (5) exhibited moderate inhibitory effects. PMID- 28617054 TI - In response to: "Loperamide metabolite-induced cardiomyopathy and QTc prolongation". PMID- 28617055 TI - New treatment strategies for ulcerative colitis. AB - INTRODUCTION: Therapeutic strategies in ulcerative colitis are evolving. A personalized and optimal use of available drugs and the integration of new drug classes are the cornerstones underpinning the new treatment paradigms. Areas covered: A structured literature search in Medline and PubMed, Cochrane meta analyses, and abstracts of international congresses has been performed to review therapeutic approaches to ulcerative colitis. The primary therapeutic objective of therapy is to achieve clinical remission since persistence of active disease, even if mild, leads to a significant reduction in quality of life. Current treatment paradigms of ulcerative colitis are based on the use of 5 aminosalycilates, corticosteroids, thiopurines, TNF-alpha inhibitors and alpha4beta7 integrin blockers. The main determinants for drug class selection are disease extension, disease severity, and previous drug history. New drug classes that will likely become available in the foreseeable future include inhibitors of Janus kinases, modulators of sphingosine-1-phosphate receptors, SMAD-7 antisense oligonucleotides, interleukin-12/23 blockers, and fecal microbiota transplantation. Expert commentary: Increasing therapeutic options for ulcerative colitis make predictors of response highly relevant. While these are not available, judicious use of therapies, avoidance of underdosing, or persistent therapy when criteria for drug failure are met are essential. PMID- 28617056 TI - An evaluation of quality of life in women with endometriosis who underwent primary surgery: a 6-month follow up in Sabah Women & Children Hospital, Sabah, Malaysia. AB - Endometriosis is a complex disease primarily affecting women of reproductive age worldwide. The management goals are to improve the quality of life (QoL), alleviate the symptoms and prevent severe disease. This prospective cohort study was to assess the QoL in women with endometriosis that underwent primary surgery. A pre- and post-operative questionnaire via ED-5Q and general VAS score used for the evaluation for endometrial-like pain such as dysmenorrhoea and dyspareunia. A total of 280 patients underwent intervention; 224 laparoscopically and 56 via laparotomy mostly with stage II disease with ovarian endometriomas. Improvements in dysmenorrhoea pain scores from 5.7 to 4.15 and dyspareunia from 4.05 to 2.17 (p <.001) were observed. The Self Rate Assessment was improved; 6.66-4.68 post operatively (p < .05). In EQ-5 D Index, the anxiety and activities outcomes showed a significant worsening post-intervention. There was no correlation between the stage of disease and endometrial pain; (p = .289), method of intervention (p = .290) and usage of post-operative hormonal therapy (p = .632). This study concluded that surgical treatment improved the QoL with added hormonal therapy post-intervention, despite not reaching statistical significance, showed a promising result. Impact statement Surgical intervention does improve the QoL for women with endometriosis however post interventional hormonal therapy is remain inconclusive. PMID- 28617058 TI - The Assessment of Skin Color and Iron Levels in Pediatric Patients with beta Thalassemia Major Using a Visual Skin Color Chart. AB - Patients with beta-thalassemia major (beta-TM), a disease that emerges due to disorder of hemoglobin (Hb) synthesis, require life-long erythrocyte transfusion. The purpose of this study was to evaluate skin color and iron levels of patients with beta-TM using a visual skin color chart. Each patient's skin color was matched on a skin color chart under a fluorescent lamp by the same physician on each occasion. Iron, iron binding capacity, ferritin and complete blood count (CBC) were studied for each patient enrolled. Colors marked on the visual skin color chart were compared with the laboratory results. Thirty-five patients being monitored at our hospital were included, 19 (54.3%) males and 16 (45.7%) females. The colors marked on the chart darkened as patients aged (p = 0.002, r = 0.49), the frequency of annual transfusions (p = 0.022, r = 0.385), ferritin levels (p < 0.001, r = 0.72) and iron levels increased (p = 0.001, r = 0.538) and as total iron binding capacity (TIBC) decreased (p < 0.001, r = -0.709). On the basis of this study, iron deposition in patients with beta-TM was correlated with the colors on the chart. PMID- 28617057 TI - Preliminary Evaluation of a Point-of-Care Testing Device (SickleSCANTM) in Screening for Sickle Cell Disease. AB - Sickle cell disease affects about 150,000 births annually in Nigeria. Early diagnosis is hampered by factors such as centralized and urban localization of laboratories, high cost of diagnostic equipment and inadequate skilled manpower to operate them. The need for a low-cost, portable, easy-to-use diagnostic test for sickle cell disease is critical, especially in resource-poor countries. In this study, we evaluated the performance characteristics of a novel point-of-care testing device (SickleSCANTM), and its acceptability and feasibility, as a possible screening tool for sickle cell disease. In the first phase, we assessed the performance characteristics of SickleSCANTM by evaluating 57 subjects comprising both children and adults attending a primary health center, for Hb SS (betaS/betaS; HBB: c.20A>T), Hb SC (betaS/betaC; HBB: c.19G>A) and Hb AS (betaA/betaS) using SickleSCANTM, cellulose acetate electrophoresis (CAE) and high performance liquid chromatography (HPLC). Performance characteristics such as diagnostic sensitivity and specificity were compared to HPLC as a standard method. We subsequently undertook a second phase wherein the acceptability and feasibility of the device for sickle cell disease screening, was evaluated using semi-structured and structured questionnaires among 197 healthcare personnel and 221 subjects, respectively. Sickle cell disease was carried by 3.4% of the subjects. The diagnostic sensitivity, specificity and test efficiency of SickleSCANTM for sickle cell disease (Hb SS and Hb SC), were 100.0, 98.2 and 98.2%, respectively. Findings from this study showed SickleSCANTM to be a viable screening tool that can easily be applied in community-based screening for early diagnosis of sickle cell disease with little expertise and low cost. PMID- 28617059 TI - Delayed ischaemia due to vasospasm after fenestration of a large arachnoid cyst. AB - An 18-year-old patient developed multiple infarcts, nine days after endoscopic fenestration of a large arachnoid cyst. We consider vasospasm to be the most likely cause, presumably triggered by a chemical meningitis. Although mostly seen after subarachnoid haemorrhage, vasospasm can also occur after traumatic brain injury, brain surgery or meningitis. PMID- 28617060 TI - Levonorgestrel-releasing intrauterine system (LNG-IUS 12) for prevention of pregnancy for up to five years. AB - INTRODUCTION: A new five-year low dose, smaller-framed, levonorgestrel-releasing intrauterine contraceptive system (LNG-IUS 12) has been introduced to complement the currently available systems. Areas Covered: This article will provide an overview of this new intrauterine system - its composition and its mechanisms of action as well as the results of the Phase II and III clinical trials of its efficacy, safety and tolerability. Expert Commentary: This new LNG-IUS 12 provides five-year contraceptive protection a pregnancy rate (less than 1%) in first year of use, which puts it into the top tier with the existing LNG-IUS 20 products; however, the LNG-IUS 12 does not have the high rates of amenorrhea often seen with the higher dose devices. On the other hand, this new IUD shares the smaller frame and narrower insertion tube with the lower dose LNG-IUS 8, but offers longer effective life. PMID- 28617061 TI - Cancer-Related Fatigue and Muscle Quality in Hodgkin's Lymphoma Survivors. AB - The purpose of this study was to compare fatigue, strength, body composition, muscle thickness, and muscle quality between Hodgkin's lymphoma survivors (HLS) and apparently healthy subjects matched by age, gender, and physical activity levels (CON). Twelve HLS (32.16 +/- 8.06) and 36 CON (32.42 +/- 7.64) were enrolled in the study. Fatigue was assessed using the 20-item Multidimensional Fatigue Inventory, muscle strength using an isokinetic dynamometer, body composition using dual-energy X-ray absorptiometry, and thickness and muscle quality using B-mode ultrasound. Differences between HLS and CON were analyzed using independent samples t tests. No significant differences were observed between groups for any demographic characteristics: age ( P = .922), weight ( P = .943), height ( P = .511), body mass index ( P = .796), fat mass ( P = .688), fat free mass ( P = .520), and percent body fat ( P = .446). No significant differences were observed for strength (peak torque; P = .552), relative peak torque ( P = .200), muscle thickness ( P > .05) and muscle quality ( P > .05). However, self-perceived fatigue was significantly higher in HLS than in CON ( P = .009). It appears that when HLS are matched by age and physical activity levels to CON, no significant difference in body composition, muscle thickness, muscle quality, or strength is observed. Self-perceived fatigue, as predicted, is higher in HLS, which may have implications and should be considered when prescribing exercise training to this cancer population. PMID- 28617062 TI - Novel approaches to targeting MYD88 in Waldenstrom macroglobulinemia. AB - INTRODUCTION: Waldenstrom macroglobulinemia (WM) is an incurable lymphoma characterized by the accumulation of IgM-producing lymphoplasmacytic cells in the bone marrow and other organs. Although WM patients can experience prolonged remissions, the disease invariably recurs advocating for the need of novel treatments in order to achieve higher response and survival rates. The discovery of a recurrent mutation in the MYD88 gene and an increased understanding behind the biology of MYD88 signaling have provided the opportunity to developing novel agents targeting the MYD88 pathway. Areas covered: The present review focuses on potential therapies that could change the landscape of treatment of patients with WM, specifically focusing on inhibitors of the Bruton tyrosine kinase (BTK), phosphatidylinositol-3 kinase, hematopoietic cell kinase, interleukin-1 receptor associated kinase and MYD88 assembly. Expert commentary: Novel agents such as the BTK inhibitor ibrutinib has shown to be safe and highly effective in the treatment of WM. Ibrutinib has been approved in Europe and the United States for its use in patients with symptomatic WM. Prospective studies are ongoing and/or planned to study many other novel agents alone and in combination with aims at improving response, survival and quality of life in patients with WM. PMID- 28617063 TI - Matrix metalloproteases-responsive nanomaterials for tumor targeting diagnosis and treatment. AB - Tumour poses tremendous challenges to mankind. In various tumours, matrix metalloproteases (MMPs) are ubiquitously over expressed and participate throughout the process of tumour development. MMPs are commonly used as internal stimuli, and MMPs-responsive nanomaterials are classified into three categories according to the drug delivery process: administration and distribution to tumour, intratumoural distribution and cell internalisation, and specific drug release. First, MMPs-sensitive polyethylene glycol (PEG) de-shielding and activatable cell penetrating peptides were developed to improve the blood circulation time of drug delivery systems, thereby, enhancing tumour or stroma cells recognition and penetration. Following tumour recognition, the MMPs sensitive and size- or morphology-changeable nanoparticles (NPs) could highly accumulate and penetrate into tumour. Lastly, several MMPs-sensitive drug release strategies were feasible for both small molecule drugs and macromolecule drugs. In conclusion, recent novel advances of MMPs-responsive nanomaterials in tumour targeting diagnosis and treatment were highlighted in this review. PMID- 28617064 TI - Corticosteroid Injection for the Treatment of Morton's Neuroma: A Prospective, Double-Blinded, Randomized, Placebo-Controlled Trial. AB - BACKGROUND: The effectiveness of corticosteroid injection for the treatment of Morton's neuroma is unclear. In addition, most of the studies related to it are case-control or retrospective case series. The purpose of this study was to compare the effectiveness between corticosteroid injection associated with local anesthetic and local anesthetic alone (placebo control group) for the treatment of Morton's neuroma. METHODS: Forty-one patients with a diagnosis of Morton's neuroma were randomized to receive 3 injections of either a corticosteroid plus a local anesthetic or a local anesthetic alone. The patients and the researcher who collected data were blinded to the treatment groups. The visual analog scale for pain and the American Orthopaedic Foot & Ankle Score (metatarsophalangeal/interphalangeal score) were obtained at baseline, after each injection, and at 3 and 6 months after the last injection. RESULTS: There were no significant between-group differences in terms of pain and function improvement at 3 and 6 months after treatment completion in comparison with baseline values. At the end of the study, 17 (48.5%) patients requested surgical excision of the neuroma: 7 (44%) in the experimental group and 10 (53%) in the control group ( P = 1.0). CONCLUSION: The injection of a corticosteroid plus a local anesthetic was not superior to a local anesthetic alone in terms of pain and function improvement in patients with Morton's neuroma. LEVEL OF EVIDENCE: Level I, randomized controlled trial. PMID- 28617065 TI - Unmet Needs for Family Caregivers of Elderly People With Dementia Living in Italy: What Do We Know So Far and What Should We Do Next? AB - Care of the elderly with dementia represents one of the major challenges for the modern society worldwide. The burden of dementia care often falls on the family members, entailing heavy psychosocial and economic consequences. The aim of this study was to evaluate the caregiver's perspective concerning the support for disease management on behalf of the physicians and the local Sicilian administrations (Italy), and the burden of care and effects on their lifestyle, to propose new prevention strategies and service for managing dementia and caregiver's burden. Fifty-nine caregivers of Italian elderly people with dementia (mean age, 73; age range: 63-83) were interviewed, and 55 of them completed an ad hoc self-report questionnaire composed of 54 multiple-choice questions. Our findings suggest that caregivers need more information on the disease's management, as well as on how to deal with the stress due to the disease burden. Moreover, a negative perception about the services offered from the local administration emerged. Assistive technology (AT) could be useful in promoting interaction between general practitioners and specialized centers for diagnosis, pharmacological and psychosocial treatments, and in saving costs. Moreover, case manager could follow patients and support family members within the care pathway, besides collecting and sharing information among the different health professionals involved. Further studies should be aimed at investigating whether AT and/or the use of specific educational strategies could be the right approach for meeting the needs of families living with dementia. PMID- 28617066 TI - Patient perceptions of treatment-free remission in chronic myeloid leukemia. AB - Around half of patients with chronic myeloid leukemia (CML) who achieve a stable deep molecular response would remain in treatment-free remission (TFR) if their tyrosine kinase inhibitors (TKIs) were stopped. TFR is increasingly becoming a goal of treatment. Eighty-seven patients answered a survey exploring patient perceptions of TFR, incorporating CML-specific factors (disease history, treatment toxicity, and adherence) and questions concerning health beliefs. 81% of participants (95% CI: 72%-89%) indicated that they would be willing to attempt TFR. No demographic or CML-related variable in the survey was significantly associated with willingness. In qualitative analysis, the commonest motivations for TFR included TKI toxicity (n = 26) and convenience (n = 18). The leading reason for reluctance was fear of consequences of stopping TKI (n = 16). Reluctance was often associated with needs for additional information or incomplete understanding of the current data. Understanding patient motivations and concerns is important if TFR is to become a part of CML management. PMID- 28617067 TI - Parametric model measurement: reframing traditional measurement ideas in neuropsychological practice and research. AB - OBJECTIVE: Neuropsychology is an applied measurement field with its psychometric work primarily built upon classical test theory (CTT). We describe a series of psychometric models to supplement the use of CTT in neuropsychological research and test development. METHOD: We introduce increasingly complex psychometric models as measurement algebras, which include model parameters that represent abilities and item properties. Within this framework of parametric model measurement (PMM), neuropsychological assessment involves the estimation of model parameters with ability parameter values assuming the role of test 'scores'. Moreover, the traditional notion of measurement error is replaced by the notion of parameter estimation error, and the definition of reliability becomes linked to notions of item and test information. The more complex PMM approaches incorporate into the assessment of neuropsychological performance formal parametric models of behavior validated in the experimental psychology literature, along with item parameters. These PMM approaches endorse the use of experimental manipulations of model parameters to assess a test's construct representation. Strengths and weaknesses of these models are evaluated by their implications for measurement error conditional upon ability level, sensitivity to sample characteristics, computational challenges to parameter estimation, and construct validity. CONCLUSION: A family of parametric psychometric models can be used to assess latent processes of interest to neuropsychologists. By modeling latent abilities at the item level, psychometric studies in neuropsychology can investigate construct validity and measurement precision within a single framework and contribute to a unification of statistical methods within the framework of generalized latent variable modeling. PMID- 28617068 TI - Nuclear factor-kappaB expression in the endometrium of normal and overweight women with polycystic ovary syndrome. AB - The aim of this study was to investigate whether the expression levels of endometrial NFkappaB p65 differ between normal weight and overweight PCOS women and to compare them with BMI-matched control subjects without PCOS. The study group comprised 20 normal weight (BMI: 18.5-24.9 kg/m2) and 15 overweight PCOS women (BMI: 25-29.9 kg/m2) with infertility. Healthy fertile women without PCOS were recruited as the control group. The patients in the normal weight PCOS group and control group were age and BMI-matched. Endometrial samples were obtained during the mid-luteal phase for immunohistochemical staining. The H-Score method was used to evaluate NF-kappaB p65 (Rel A) expression. Both normal and overweight PCOS women demonstrated significantly higher endometrial NF-kappaB p65 expression than the women without PCOS. The H-scores of endometrial NF-kappaB p65 expression were similar in both groups of PCOS women. NF-kappaB p65 was positively correlated with serum insulin, HOMA-IR and total testosterone levels in PCOS women. By leading to pathological inflammation, an increase in NF-kappaB p65 expression in the endometrium of normal and overweight PCOS women may contribute to PCOS-related subfertility. Impact statement What is already known on this subject: Although the pathogenesis of PCOS has not yet been clarified, low-grade chronic inflammation is gradually being established as an important pathogenetic factor. Increased levels of inflammatory cytokines such as IL-6 and TNF-alpha have been reported in women with PCOS. Causes of pathological endometrial inflammation may arise from either a local endometrial disease or linked to diseases which are located in a distant reproductive tissue. Nevertheless, possible role of endometrial NF-kappaB, basic cellular regulatory of inflammation, in the pathophysiology of PCOS related implantation defect has not been elucidated yet. What do the results of this study add: This study provides first and novel insights into the relationship between PCOS related infertility and pathological endometrial inflammation. We demonstrated that there is a close association between PCOS and pathological endometrial inflammation. Moreover, we clearly showed that pathological endometrial inflammation occurs in both normal and overweight women with PCOS. Further, endometrial NF-kappaB p65 (Rel A) expression were found to be positively correlated with serum insulin levels and hyperandrogenism in overweight PCOS women. What are the implications of these findings for clinical practice: If we can analyse pathological endometrial inflammation by measuring endometrial NF-kappaB p65 (Rel A) expression, treatment could be directed towards eliminating the source of pathological endometrial inflammation. PMID- 28617069 TI - Simultaneous determination of six tyrosine kinase inhibitors in human plasma using HPLC-Q-Orbitrap mass spectrometry. AB - AIM: Gefitinib, erlotinib, icotinib, crizotinib, lapatinib and apatinib are targeted cancer therapy agents acting through inhibition of tyrosine kinase. Method for quantifying these six drugs in human plasma of patients was required. MATERIALS & METHODS: An HPLC-Q-Orbitrap method (based on HPLC-MS/MS) was developed and validated for the simultaneous detection and quantitation of six tyrosine kinase inhibitors in human plasma. Sample was extracted by liquid-liquid extraction (ethyl acetate: tert-Butyl methyl ether, 1:1 v/v). The method shows a high level of accuracy and reproducibility. The lower limit of quantification was 0.02 ng/ml for apatinib, 0.1 ng/ml for crizotinib, 2.0 ng/ml for lapatinib and 0.05 ng/ml for erlotinib, gefitinib and icotinib. This method was successfully used for apatinib monitoring in plasma of patients with NSCLC. CONCLUSION: This simple and reproducible method has potential for monitoring of tyrosine kinase inhibitors in patients' plasma. PMID- 28617070 TI - Oral subchronic exposure to silver nanoparticles causes renal damage through apoptotic impairment and necrotic cell death. AB - Silver nanoparticles (AgNPs) are one of the most widely used nanomaterials. Following oral exposure, AgNPs can accumulate in various organs including kidneys where they show gender specific accumulation. There is limited information on their effect on renal system following long-term animal exposure especially at the ultramicroscopic and molecular level. In this study, we have assessed the effect of 60 days oral AgNPs treatment on kidneys of female Wistar rats at doses of 50 ppm and 200 ppm that are below previously reported lowest observed adverse effect level (LOAEL). AgNPs treatment led to decrease in kidney weight and some loss of renal function as seen by increased levels of serum creatinine and early toxicity markers such as KIM-1, clusterin and osteopontin. We also observed significant mitochondrial damage, loss of brush border membranes, pronounced swelling of podocytes and degeneration of their foot processes using transmission electron microscopy (TEM). These symptoms are similar to those seen in nephrotic syndrome and 'Minimal change disease' of kidney where few changes are visible under light microscopy but significant ultrastructural damage is observed. Prolonged treatment of AgNPs also led to the activation of cell proliferative, survival and proinflammatory factors (Akt/mTOR, JNK/Stat and Erk/NF-kappaB pathways and IL1beta, MIP2, IFN-gamma, TNF-alpha and RANTES) and dysfunction of normal apoptotic pathway. Our study shows how long term AgNPs exposure may promote ultrastructural damage to kidney causing inflammation and expression of cell survival factors. These changes, in the long term, could lead to inhibition of the beneficial apoptotic pathway and promotion of necrotic cell death in kidneys. PMID- 28617073 TI - Metabolomics of exhaled breath condensate: a means for phenotyping respiratory diseases? PMID- 28617072 TI - Evaluation of NinePoint Medical's Nvision VLE device for gastrointestinal applications. AB - INTRODUCTION: The incidence of esophageal adenocarcinoma (EAC) has increased over the last few decades. With a known precursor lesion, Barrett's esophagus, this remains a target for screening and surveillance with the goal of detecting and providing curative treatment for early neoplasia. Areas covered: Current surveillance techniques rely on white light endoscopy and random tissue sampling which is time consuming, costly and prone to sampling error. Volumetric laser endomicroscopy (VLE), a second-generation optical coherence technology, has emerged as an advanced imaging modality with the potential to improve dysplasia detection, surveillance and subsequently prevent esophageal adenocarcinoma. This review will focus on the use of VLE for advanced imaging of Barrett's esophagus and summarize its current and potential uses elsewhere in the GI tract. Expert commentary: NinePoint's VLE imaging device enables imaging of large segments of BE facilitating identification of luminal and subsurface abnormalities that may have otherwise been missed. Its diagnostic accuracy is improving and laser marking system adds the capacity for accurate VLE-histologic correlation. With the adoption of dysplasia scoring systems that utilize very few VLE imaging features, inexperienced endoscopists will likely be able to pick out areas concerning for dysplasia to target therapy. PMID- 28617071 TI - An endothelial link between the benefits of physical exercise in dementia. AB - The current absence of a disease-modifying treatment for Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) highlights the necessity for investigating the benefits of non-pharmacological approaches such as physical exercise (PE). Although evidence exists to support an association between regular PE and higher scores on cognitive function tests, and a slower rate of cognitive decline, there is no clear consensus on the underlying molecular mechanisms of the advantages of PE. This review seeks to summarize the positive effects of PE in human and animal studies while highlighting the vascular link between these benefits. Lifestyle factors such as cardiovascular diseases, metabolic syndrome, and sleep apnea will be addressed in relation to the risk they pose in developing AD and VCID, as will molecular factors known to have an impact on either the initiation or the progression of AD and/or VCID. This will include amyloid-beta clearance, oxidative stress, inflammatory responses, neurogenesis, angiogenesis, glucose metabolism, and white matter integrity. Particularly, this review will address how engaging in PE can counter factors that contribute to disease pathogenesis, and how these alterations are linked to endothelial cell function. PMID- 28617074 TI - Autism Symptoms in Fragile X Syndrome. AB - Fragile X syndrome (FXS) is recognized as the most common genetic cause of intellectual disability and autism spectrum disorder (ASD). Although symptoms of ASD are frequently observed in patients with FXS, researchers have not yet clearly determined whether the symptoms in patients with FXS differ from the symptoms in patients without ASD or nonsyndromic ASD. Behavioral similarities and differences between FXS and ASD are important to improve our understanding of the causes and correlations of ASD with FXS. Based on the evidence presented in this review, individuals with FXS and comorbid ASD have more severe behavioral problems than individuals with FXS alone. However, patients with FXS and comorbid ASD exhibit less severe impairments in the social and communication symptoms than patients with nonsyndromic ASD. Individuals with FXS also present with anxiety and seizures in addition to comorbid ASD symptoms, and differences in these conditions are noted in patients with FXS and ASD. This review also discusses the role of fragile X mental retardation 1 protein (FMRP) in FXS and ASD phenotypes. PMID- 28617075 TI - Follow-Up of Young Adults With ADHD in the MTA: Design and Methods for Qualitative Interviews. AB - OBJECTIVE: Qualitative interviews with 183 young adults (YA) in the follow-up of the Multimodal Treatment Study of Children With and Without ADHD (MTA) provide rich information on beliefs and expectations regarding ADHD, life's turning points, medication use, and substance use (SU). METHOD: Participants from four MTA sites were sampled to include those with persistent and atypically high SU, and a local normative comparison group (LNCG). Respondents were encouraged to "tell their story" about their lives, using a semistructured conversational interview format. RESULTS: Interviews were reliably coded for interview topics. ADHD youth more often desisted from SU because of seeing others going down wrong paths due to SU. Narratives revealed very diverse accounts and explanations for SU-ADHD influences. CONCLUSION: Qualitative methods captured the perspectives of YAs regarding using substances. This information is essential for improving resilience models in drug prevention and treatment programs and for treatment development for this at-risk population. PMID- 28617076 TI - Characterization of highly concentrated antibody solution - A toolbox for the description of protein long-term solution stability. AB - High protein titers are gaining importance in biopharmaceutical industry. A major challenge in the development of highly concentrated mAb solutions is their long term stability and often incalculable viscosity. The complexity of the molecule itself, as well as the various molecular interactions, make it difficult to describe their solution behavior. To study the formulation stability, long- and short-range interactions and the formation of complex network structures have to be taken into account. For a better understanding of highly concentrated solutions, we combined established and novel analytical tools to characterize the effect of solution properties on the stability of highly concentrated mAb formulations. In this study, monoclonal antibody solutions in a concentration range of 50-200 mg/ml at pH 5-9 with and without glycine, PEG4000, and Na2SO4 were analyzed. To determine the monomer content, analytical size-exclusion chromatography runs were performed. zeta-potential measurements were conducted to analyze the electrophoretic properties in different solutions. The melting and aggregation temperatures were determined with the help of fluorescence and static light scattering measurements. Additionally, rheological measurements were conducted to study the solution viscosity and viscoelastic behavior of the mAb solutions. The so-determined analytical parameters were scored and merged in an analytical toolbox. The resulting scoring was then successfully correlated with long-term storage (40 d of incubation) experiments. Our results indicate that the sensitivity of complex rheological measurements, in combination with the applied techniques, allows reliable statements to be made with respect to the effect of solution properties, such as protein concentration, ionic strength, and pH shift, on the strength of protein-protein interaction and solution colloidal stability. PMID- 28617078 TI - Interplay between Notch and p53 promotes neuronal cell death in ischemic stroke. AB - Stroke is the world's second leading cause of mortality, with a high incidence of morbidity. Numerous neuronal membrane receptors are activated by endogenous ligands and may contribute to infarct development. Notch is a well-characterized membrane receptor involved in cell differentiation and proliferation, and now shown to play a pivotal role in cell death during ischemic stroke. Blockade of Notch signaling by inhibition of gamma-secretase, an enzyme that generates the active form of Notch, is neuroprotective following stroke. We have also identified that Pin1, a peptidyl-prolyl isomerase that regulates p53 transactivation under stress, promotes the pathogenesis of ischemic stroke via Notch signaling. Moreover, Notch can also mediate cell death through a p53 dependent pathway, resulting in apoptosis of neural progenitor cells. The current study has investigated the interplay between Notch and p53 under ischemic stroke conditions. Using pharmacological inhibitors, we have demonstrated that a Notch intracellular domain (NICD)/p53 interaction is involved in transcriptional regulation of genes downstream of p53 and NICD to modify stroke severity. Furthermore, the NICD/p53 interaction confers stability to p53 by rescuing it from ubiquitination. Together, these results indicate that Notch contributes to the pathogenesis of ischemic stroke by promoting p53 stability and signaling. PMID- 28617077 TI - Factors affecting immune responses to the influenza vaccine. AB - Annual administration of the seasonal influenza vaccine is strongly recommended to reduce the burden of disease, particularly for persons at the highest risk for the viral infection. Even during years when there is a good match between the vaccine and circulating strains, host-related factors such as age, preexisting immunity, genetic polymorphisms, and the presence of chronic underlying conditions may compromise influenza vaccine responsiveness. The application of new methodologies and large-scale profiling technologies are improving the ability to measure vaccine immunogenicity and our understanding of the immune mechanisms by which vaccines induce protective immunity. This review attempts to summarize the general concepts of how host factors can contribute to the heterogeneity of immune responses induced by influenza vaccines. PMID- 28617079 TI - Particle Exposure and the Historical Loss of Native American Lives to Infections. PMID- 28617080 TI - Host-Microbial Interactions: Idiopathic Pulmonary Fibrosis in Technicolor. PMID- 28617081 TI - Pseudomonas aeruginosa Infection after CFTR Restoration. One Step Back, One Step Forward. PMID- 28617082 TI - Epstein-Barr Virus-induced Gene 2 and Leukocyte Airway Recruitment in Response to Allergen Challenge. PMID- 28617083 TI - Invasive Mediastinal Staging in Lung Cancer. Use a Prediction Model or Just Do It? PMID- 28617084 TI - Patients with Cystic Fibrosis and a G551D or Homozygous F508del Mutation: Similar Lung Function Decline. PMID- 28617085 TI - Kidney and Brain, an Unbroken Chain. PMID- 28617086 TI - Expiratory Diaphragmatic Recruitment in Acute Respiratory Distress Syndrome. A Happy Coincidence or Much More? PMID- 28617087 TI - When Innate Responses Matter: ILC2s Loom Large in Allergic Airway Inflammation. PMID- 28617088 TI - Clean Fuels to Reduce Household Air Pollution and Improve Health. Still Hoping to Answer Why and How. PMID- 28617089 TI - Pulmonary Hypertension and Precision Medicine through the "Omics" Looking Glass. PMID- 28617091 TI - Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads. AB - Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer's disease therapeutics. PMID- 28617092 TI - [Formula: see text]Determination of the smoking gun of intent: significance testing of forced choice results in social security claimants. AB - OBJECTIVE: Significantly below-chance findings on forced choice tests have been described as revealing "the smoking gun of intent" that proved malingering. The issues of probability levels, one-tailed vs. two-tailed tests, and the combining of PVT scores on significantly below-chance findings were addressed in a previous study, with a recommendation of a probability level of .20 to test the significance of below-chance results. The purpose of the present study was to determine the rate of below-chance findings in a Social Security Disability claimant sample using the previous recommendations. METHOD: We compared the frequency of below-chance results on forced choice performance validity tests (PVTs) at two levels of significance, .05 and .20, and when using significance testing on individual subtests of the PVTs compared with total scores in claimants for Social Security Disability in order to determine the rate of the expected increase. RESULTS: The frequency of significant results increased with the higher level of significance for each subtest of the PVT and when combining individual test sections to increase the number of test items, with up to 20% of claimants showing significantly below-chance results at the higher p-value. CONCLUSIONS: These findings are discussed in light of Social Security Administration policy, showing an impact on policy issues concerning child abuse and neglect, and the importance of using these techniques in evaluations for Social Security Disability. PMID- 28617090 TI - Left ventricular function in relation to chronic residential air pollution in a general population. AB - Background In view of the increasing heart failure epidemic and awareness of the adverse impact of environmental pollution on human health, we investigated the association of left ventricular structure and function with air pollutants in a general population. Methods In 671 randomly recruited Flemish (51.7% women; mean age, 50.4 years) we echocardiographically assessed left ventricular systolic strain and strain rate and the early and late peak velocities of transmitral blood flow and mitral annular movement (2005-2009). Using subject-level data, left ventricular function was cross-sectionally correlated with residential long term exposure to air pollutants, including black carbon, PM2.5, PM10 (particulate matter) and nitrogen dioxide (NO2), while accounting for clustering by residential address and confounders. Results Annual exposures to black carbon, PM2.5, PM10 and NO2 averaged 1.19, 13.0, 17.7, and 16.8 ug/m3. Systolic left ventricular function was worse ( p <= 0.027) with higher black carbon, PM2.5, PM10 and NO2 with association sizes per interquartile interval increment ranging from -0.339 to -0.458% for longitudinal strain and from -0.033 to -0.049 s-1 for longitudinal strain rate. Mitral E and a' peak velocities were lower ( p <= 0.021) with higher black carbon, PM2.5 and PM10 with association sizes ranging from -1.727 to -1.947 cm/s and from -0.175 to -0.235 cm/s, respectively. In the geographic analysis, the systolic longitudinal strain sided with gradients in air pollution. The path analysis identified systemic inflammation as a possible mediator of associations with black carbon. Conclusions Long-term low-level air pollution is associated with subclinical impairment of left ventricular performance and might be a risk factor for heart failure. PMID- 28617093 TI - Micro-SPE in pipette tips as a tool for analysis of small-molecule drugs in serum. AB - AIM: Micro-SPE in pipette tips (MU-SPE-PT) with particle sorbent has never been used in small-molecule drug analysis. Methodology & results: MU-SPE-PT was used for the extraction of statins from biological materials followed by UHPLC-MS/MS. The commercial and homemade MU-SPE-PT tips filled with particle sorbent were compared. While the homemade tips enabled direct serum sample loading into the sorbent, protein precipitation (PP) had to be implemented before MU-SPE-PT procedure using commercial tips. Three MU-SPE-PT methods were developed and validated: method A: MU-SPE-PT with homemade tips; method B: PP + MU-SPE-PT with homemade tips; and method C: PP + MU-SPE-PT with commercial tips. Method A enabled a simple high-throughput approach (48 samples in 90 min) compared with methods B and C that required three-times longer time. However, PP increased the recoveries of protein-bound analytes and extracts purity in methods B and C. The matrix effects without internal standards correction for method C were significantly higher than those for the methods A and B. CONCLUSION: Compared with commercial tips, homemade tips filled with particles were found to be more suitable for drug analysis. Commercial tips tested in this study were found challenging but the conditions under which they could be applicable were also defined. PMID- 28617094 TI - Connecting with healthcare providers at diagnosis: adolescent/young adult cancer survivors' perspectives. AB - Adolescents and young adults (AYAs) with cancer are a vulnerable and underserved population. AYAs' cancer survivorship is complicated by physical and psychosocial late effects which requires long-term follow-up. Connectedness with healthcare providers (HCPs) is a protective factor that may improve long-term follow-up behaviours of AYAs. However, little is known about AYAs' experiences connecting with HCPs. The purpose of this study was to describe AYA cancer survivors' experiences connecting with HCPs. This empirical phenomenological study interviewed nine AYA cancer survivors diagnosed during adolescence. Individual interviews were conducted and analysed using an adapted Colaizzi approach. The essential structure reveals that AYAs begin their experience of connectedness with a sense of disconnectedness prior to treatment. The diagnosis is a period of confusion and emotional turmoil that interfere with the AYAs' ability to connect. When AYAs come to accept their illness and gain familiarity with the environment, they then put forth an effort to connect with HCPs. Although it takes time for AYAs to reciprocate efforts to connect, HCPs should be aware that AYAs carefully assess and make judgments about whether or not HCPs can be trusted. Findings raise awareness of the actions and behaviours of HCPs that hinder connectedness, and targeted in future research. PMID- 28617095 TI - Association of Ankle Arthritis Score With Need for Revision Surgery. AB - BACKGROUND: The Ankle Arthritis Score (AAS) is a new patient-reported outcome derived from the Ankle Osteoarthritis Scale (AOS). This study analyzed longitudinally collected data from a cohort of patients in the Canadian Orthopaedic Foot and Ankle Society (COFAS) Ankle Arthritis Study in order to evaluate whether the postoperative AAS is associated with need for revision surgery. METHODS: A multicenter, prospective, ankle-reconstruction study enrolled 653 ankles undergoing total ankle replacement (TAR) or ankle arthrodesis (AA). The AAS was given at baseline and annually during postoperative follow-up. Time to revision surgery was modeled using a proportional hazards model. The final sample included 531 ankles in 509 patients. RESULTS: Sixty-two patients underwent metal-component revision and 8 underwent arthrodesis revision during the follow up time period. The remaining 461 unrevised ankles (300 TAR, 161 AA) had a minimum follow-up of 2 years (average of 3.4 years). Revision surgery after TAR was found to be associated with a higher postoperative AAS and a longer follow up. The hazard ratio for the AAS indicated that for every 1-point increase in the score, the rate of revision surgery after TAR was 1 percentage point higher. CONCLUSIONS: TAR patients who reported higher levels of postoperative functional impairment, as indicated by a higher AAS, were more likely to require metal component revision surgery. After adjustment for other patient factors, the risk of revision surgery increased with length of follow-up after TAR. This study provides further evidence for the utility of the AAS in the clinical setting. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 28617096 TI - Details matter: the role of genomic location and assay standardization in DNA methylation analyses. PMID- 28617097 TI - Involuntary Civil Commitment for Substance Use Disorder: Legal Precedents and Ethical Considerations for Social Workers. AB - Although each state in the United States legally authorizes involuntary civil commitment on the grounds of severe mental illness, a considerable number do not have comparable laws to mandate drug addiction treatment. This discrepancy is due, in part, to differing ethical positions regarding whether a substance use disorder diagnosis provides sufficient justification to suspend individual liberty rights. This article chronicles some of the legal and ethical thinking on the subject and applies them to a social work-specific context. PMID- 28617098 TI - Effects of chronic exposure to mercury and cadmium alone and in combination on the coagulation system of Sprague-Dawley rats. AB - Water contamination with heavy metals may adversely affect our health. High metal levels lead to changes in blood coagulation processes, increasing the risk for cardiovascular disease. Exposure is not limited to a single metal but usually involves a mixture of metals. In this study 24 male Sprague-Dawley rats were exposed to cadmium (Cd) and mercury (Hg), alone and in combination, for 28 days at dosages equivalent to 1000 times the World Health Organization water limits. Scanning electron microscopy analysis revealed that both metals caused platelet activation. Cd significantly increased fibrin fibers thickness and caused aggregation and formation of dense matted deposits (DMDs). Hg reduced fibrin network formation. In the combination group, Hg appeared to augment the effect of Cd, and the presence of extensive DMDs or aggregates between the fibers, with no changes to the actual fibrin thickness, was observed. PMID- 28617099 TI - Characterising omission errors in everyday task completion and cognitive correlates in individuals with mild cognitive impairment and dementia. AB - OBJECTIVE: Functional ability declines with age and cognitive impairment. This study investigated errors of omission made by community-dwelling older adults completing everyday tasks in a naturalistic setting. METHOD: Sixty-five cognitively healthy older adults (HOA), 19 individuals with single domain mild cognitive impairment (sdMCI), 33 individuals with multi-domain MCI (mdMCI), and 13 individuals with dementia completed measures of memory, processing speed, working memory, and executive functioning, as well as eight different activities of daily living in a naturalistic environment. Task steps were divided into preparatory, action-oriented, and concluding steps. RESULTS: For action-oriented steps, the number of omission errors increased with level of cognitive impairment beyond sdMCI (i.e., HOA = sdMCI < mdMCI < dementia). In contrast, for preparatory and concluding steps, the dementia group committed more omission errors than the HOA, sdMCI, and mdMCI groups, which did not differ. CONCLUSIONS: The results suggest that the more complex and integrative action-oriented steps may be the first type of everyday task step to be affected in the process of cognitive decline, with preparatory and concluding steps being preserved longer and only showing decline in later stages of impairment (i.e., dementia). Individuals with sdMCI may use other intact abilities to compensate for task omission errors. PMID- 28617100 TI - Discovery of potent and selective acetylcholinesterase (AChE) inhibitors: acacetin 7-O-methyl ether Mannich base derivatives synthesised from easy access natural product naringin. AB - Naringin, as a component universal existing in the peel of some fruits or medicinal plants, was usually selected as the material to synthesise bioactive derivates since it was easy to gain with low cost. In present investigation, eight new acacetin-7-O-methyl ether Mannich base derivatives (1-8) were synthesised from naringin. The bioactivity evaluation revealed that most of them exhibited moderate or potent acetylcholinesterase (AChE) inhibitory activity. Among them, compound 7 (IC50 for AChE = 0.82 +/- 0.08 MUmol*L-1, IC50 for BuChE = 46.30 +/- 3.26 MUmol*L-1) showed a potent activity and high selectivity compared with the positive control Rivastigmine (IC50 for AChE = 10.54 +/- 0.86 MUmol*L-1, IC50 for BuChE = 0.26 +/- 0.08 MUmol*L-1). The kinetic study suggested that compound 7 bind to AChE with mix-type inhibitory profile. Molecular docking study revealed that compound 7 could combine both catalytic active site (CAS) and peripheral active site (PAS) of AChE with four points (Trp84, Trp279, Tyr70 and Phe330), while it could bind with BuChE via only His 20. PMID- 28617101 TI - Facial emotion identification and sexual assault risk detection among college student sexual assault victims and nonvictims. AB - OBJECTIVE: High rates of sexual victimization among college students necessitate further study of factors associated with sexual assault risk detection. The present study examined how social information processing relates to sexual assault risk detection as a function of sexual assault victimization history. PARTICIPANTS: 225 undergraduates (Mage = 19.12, SD = 1.44; 66% women). METHODS: Participants completed an online questionnaire assessing victimization history, an emotion identification task, and a sexual assault risk detection task between June 2013 and May 2014. RESULTS: Emotion identification moderated the association between victimization history and risk detection such that sexual assault survivors with lower emotion identification accuracy also reported the least risk in a sexual assault vignette. CONCLUSIONS: Findings suggest that differences in social information processing, specifically recognition of others' emotions, are associated with sexual assault risk detection. College prevention programs could incorporate emotional awareness strategies, particularly for men and women who are sexual assault survivors. PMID- 28617102 TI - Predictors of well-being in the lives of student service members and veterans. AB - OBJECTIVE: The current study examined predictors of well-being, including quality of life and academic engagement, in a sample of student service members and veteran college students. METHODS: Eighty-seven student service members/veterans (SSM/V) completed an online survey containing questions about post-deployment social support, emotion regulation skills, psychological distress, academic engagement, quality of life, and demographics. Participants were recruited from September 2012 through May 2014. RESULTS: Results provided partial support for the proposed bi-directional mediational relations between post-deployment social support and emotion regulation predicting to quality of life and academic engagement. Path models indicated that both post-deployment social support and emotion regulation skills partially mediated the relation with quality of life while accounting for the effect of psychological distress, and that emotion regulation skills fully mediated the relation between social support and academic engagement. CONCLUSIONS: These findings suggest that both social support and emotion regulation skills may be useful targets for health promotion and intervention efforts for this population. Limitations and clinical implications for the development of on-campus SSM/V focused health promotion services are discussed. PMID- 28617103 TI - Effects of Mindfulness-Based Therapies for Female Sexual Dysfunction: A Meta Analytic Review. AB - Mindfulness-based therapy (MBT) represents a potentially efficacious treatment for female sexual dysfunction (FSD). A number of recent trials assessing MBT for FSD have been published, but we are aware of no existing meta-analysis synthesizing these results. We conducted a literature review to identify all published trials of MBT for FSD. References of retrieved studies were searched and key authors were contacted with requests for complete but unpublished trials. Eleven trials, including a total of 449 participants, were identified. Two of these studies were under review at the time of the current analyses. Four trials utilized wait-list controls. All aspects of sexual function and subjective sexual well-being exhibited significant improvement during MBT, with effect sizes generally moderate. Controlled effect sizes versus wait list were of similar magnitude in most cases; however, they did not reach statistical significance for multiple outcome measures. Results for some outcomes were consistent with possible publication bias. For some outcomes, larger effect sizes tended to be reported in studies requiring participants to be in a romantic relationship or studies providing individual (versus group) therapy. MBT may be an efficacious intervention for FSD. However, important limitations of the current literature and future directions for research are discussed. PMID- 28617104 TI - Progress on the clinical application of the SEPT9 gene methylation assay in the past 5 years. PMID- 28617105 TI - Freshman year alcohol and marijuana use prospectively predict time to college graduation and subsequent adult roles and independence. AB - OBJECTIVE: This study examined how freshman year substance use prospectively predicted time to college graduation, and whether delayed graduation predicted postponed adoption of adult roles and future substance use. PARTICIPANTS: Participants were part of a longitudinal study that began in 2004. The first analyses focused on freshman year (N = 2,050). The second analyses corresponded to a subset of participants at age 27 (N = 575). METHODS: Measures included self reported substance use, adult role adoption, and university reported graduation dates. RESULTS: Results indicated that frequent binge drinking and marijuana use during freshman year predicted delayed college graduation. Those who took longer to graduate were more likely to have lower incomes and were less likely to obtain a graduate degree. Taking 5-6 years to graduate was associated with greater likelihood of alcohol-related problems. CONCLUSIONS: Findings support the importance of interventions during freshman year of college to decrease substance use and promote timely graduation. PMID- 28617106 TI - An examination of ecological predictors of health literacy in black college students. AB - OBJECTIVE: Health literacy is a determinant of health, but disparities in health literacy persist. This study examined the influence of ecological factors on college students' health literacy. PARTICIPANTS: During January 2016 a nonrandom sample of black undergraduate students (n = 298) aged 18-24 were recruited from enrollment lists at two urban universities in the Southeastern United States. METHODS: Information on health literacy as well as numerous intrapersonal, social, and cultural-environment factors was obtained using an electronic questionnaire and then statistically modeled. RESULTS: Ecological factors accounted for 28.7% of the variance in health literacy. In particular, reappraisal (B = 0.323, p < .001), suppression (B = -0.289, p < .001), campus health education (B = 0.192, p < .05), campus tobacco culture (B = -0.174, p < .05), and perceived norms (B = -0.153, p < .05) directly predicted health literacy. CONCLUSIONS: Although intrapersonal factors influence health literacy, the sociocultural environment of college can also foster or hinder college students' health literacy. PMID- 28617107 TI - Thyroid cancer in adolescents and young adults. AB - Despite the increase in thyroid cancer incidence among adolescents and young adults (AYAs), this group has received limited attention. We reviewed the epidemiology and challenges of thyroid cancer care among AYAs, and proposed a research agenda to improve their care. Thyroid cancer is the most common cancer in American adults 16-33 years of age. AYAs with thyroid cancer face challenges including overdiagnosis reduced healthcare access and inconsistent care. Successful treatment of these patients results in additional challenges due to ongoing side effects of treatment as well as lasting impacts on their quality of life. These challenges should fuel a collaborative research agenda aimed at improving the quality of care for AYAs with thyroid cancer across the spectrum of diagnosis, treatment and survivorship. PMID- 28617108 TI - Prevention and management of skin tears in older people. AB - Skin tears are frequently encountered in emergency and unscheduled care, and are prevalent in older people. Patients may present soon after an acute skin tear, or at a later stage when the wound presentation is different and there are complications. This article describes evidence-based recommendations and strategies for the prevention, assessment and management of skin tears, discusses risk factors and explains when to refer patients for specialist management. PMID- 28617109 TI - Meet the new team players: physician associates. AB - Physician associates (PAs) were introduced into the NHS to add a new kind of team player to the medical workforce. The role originated in the US where they are known as physician assistants and have been practising since the mid-1960s ( Peate 2016 ).The PA competency and curriculum framework states that a newly qualified PA must be able to perform clinical work 'at the same standard as a newly qualified doctor', and trainees undergo a rigorous two-year postgraduate training ( Peate 2016 ). Before becoming eligible to practise, they must pass a Royal College of Physicians licensing exam and certified PAs are required to retake the examination every six years. PMID- 28617111 TI - The Drug Conversation: How to Talk to Your Child about Drugs Bowden-Jones Owen The Drug Conversation: How to Talk to Your Child about Drugs 180pp L12.99 Royal College of Psychiatrists 9781909726574 1909726575 [Formula: see text]. AB - Presented in a logical and easy-to follow format, this book is intended for parents, but could be a resource for GPs who want to talk to patients about drug use. PMID- 28617110 TI - Professionalism. AB - Essential facts Helping nurses provide the best care possible is at the heart of new guidance on professionalism from the Nursing and Midwifery Council and chief nursing officers from across the UK. PMID- 28617112 TI - Dying for a Drink: All You Need to Know to Beat the Booze Cantopher Tim Dying for a Drink: All You Need to Know to Beat the Booze 128pp L9.99 Sheldon Press 9781847094476 1847094473 [Formula: see text]. AB - This interesting and well-written book is now in its second edition. PMID- 28617113 TI - Change to healthcare is history repeating itself. AB - In my last Board's Eye View, I wrote about the US presidential candidates and uncertainty about healthcare reform. Six months later, the story is continuing. PMID- 28617114 TI - Significance of Chilaiditi sign and Chilaiditi syndrome. AB - Chilaiditi sign and syndrome are uncommon conditions and often misdiagnosed. They are clinically significant, however, because they can result in a range of complications, including bowel volvulus, perforation and obstruction. When patients are symptomatic, treatment is usually conservative and surgery is rarely indicated unless there is a suspicion of ischaemia, or if conservative management does not resolve other signs and symptoms. This article describes Chilaiditi sign and syndrome, and presents four case studies to illustrate the relevant signs and symptoms. PMID- 28617115 TI - From Twitter. AB - Nurses on Twitter. PMID- 28617116 TI - Peninsula Communications Skills. AB - This app from the Peninsula Schools of Medicine and Dentistry offers healthcare professionals learning opportunities to improve their communication skills. PMID- 28617117 TI - Congress debate can get lost in translation. AB - It has been suggested that RCN congress resolutions rarely spark debate and, with this in mind, the RCN Emergency Care Association (ECA) last month put forward a motion with the RCN mental health forum that emergency departments (EDs) should no longer be seen as designated places of safety for people in mental health crisis. PMID- 28617118 TI - Not enough is done to cut risk of death after cardiac arrest. AB - How much is being done to cut the number of people who die after cardiac arrests in public places? Not enough, says a group of cardiac experts and campaigners on the Out of Hospital Cardiac Arrest (OHCA) steering group. PMID- 28617120 TI - Queen leads tributes to nurses in wake of terrorist attacks. AB - The Queen and the prime minister led tributes to nurses and other NHS staff caring for people injured in the recent terrorist attacks in Manchester and London. Emergency services worked through the night to assist in the immediate aftermath of the explosion at the Manchester arena, which killed 22 people and left many more injured, who were treated at hospitals across the city. PMID- 28617121 TI - College launches new career pathway. AB - The RCN is launching its new credentialing programme for nurses working at an advanced level of practice, following a successful five-month trial. PMID- 28617122 TI - How to make a career in emergency nursing. AB - The Professional Framework for Emergency Care Nursing was officially launched at the Northern Ireland Practice and Education Council (NIPEC) annual conference in March. It was born from chief nursing officer Charlotte McArdle asking NIPEC to collaborate with the local RCN emergency care network to further the professional development of the emergency nursing workforce in Northern Ireland. PMID- 28617123 TI - ReSPECT - the emergency care planning tool. AB - Essential facts The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) creates recommendations for a person's clinical care in a future emergency in which they are unable to make or express choices. PMID- 28617124 TI - Noticeboard. AB - Courses, events, grants, and awards to progress your career. PMID- 28617125 TI - 'Emergency nursing is the best job you'll ever have'. AB - What is your job? I am a clinical development specialist at Hasbro Children's Hospital, the paediatric division of Rhode Island Hospital in Providence, US. I educate and mentor new graduate nurses from the paediatric emergency department (ED) and inpatient areas. PMID- 28617129 TI - Ability of parents to remember advice on head injury. AB - Parents are unsure when to return to emergency departments (EDs) after their child has been evaluated for head injury. PMID- 28617128 TI - A system for predicting admission and discharge. AB - A predictive model for admission developed at a healthcare campus in Israel identified 94% of hospitalisations and 90% of discharges within one hour of presentation to the emergency department (ED). PMID- 28617130 TI - Use of automated external defibrillators saves lives. AB - Ambulance services in England attempt the resuscitation of almost 30,000 people who have experienced out-of-hospital cardiac arrest (OHCA) each year. Outcomes can be much improved if automated external defibrillators (AEDs) are used immediately after cardiac arrest and before emergency services arrive on the scene. PMID- 28617132 TI - RCN congress discusses whether wearing helmets should be compulsory for cyclists. AB - Nurses at RCN congress debated whether cycle helmets should be made compulsory. PMID- 28617131 TI - Number of attacks on staff is rising. AB - Nurses shared personal stories during an RCN congress debate last month on whether sanctions against people who attack NHS staff should be made tougher. PMID- 28617133 TI - EDs unsuitable for mental health assessments. AB - The RCN will lobby to ensure emergency departments (EDs) are no longer used as designated places of safety for people experiencing mental health crises. PMID- 28617134 TI - Retraction Notice. PMID- 28617135 TI - Influence of Personalized Exercise Recommendations During Rehabilitation on the Sustainability of Objectively Measured Physical Activity Levels, Fatigue, and Fatigue-Related Biomarkers in Patients With Breast Cancer. AB - PURPOSE: Only one-third of patients with breast cancer reach the recommended activity level of 15 to 25 MET h/wk. The aim of this study was to determine the influence of personalized exercise recommendations during rehabilitation on patients' physical activity level, fatigue, and self-perceived cognitive function as well as on side effect-associated biomarkers. METHODS: Total metabolic rate, physical activity level, mean MET and steps, fatigue, self-perceived cognitive functioning , and biomarkers (C-reactive protein [CRP], interleukin 6, macrophage migration inhibiting factor [MIF], tumor necrosis factor [TNF]-alpha, brain derived neurotrophic factor [BDNF], insulin-like growth factor 1 [IGF1]) were assessed in 60 patients with breast cancer in the aftercare phase before ( t0) and 8 months after ( t1) the intervention. The rehabilitation program consisted of an initial 3-week period and a 1-week stay after 4 months. RESULTS: Paired t test indicated a statistically significant increase in all activity outcomes from t0 to t1. Patients' mean activity level significantly increased from 14.89 to 17.88 MET h/wk. Fatigue and self-perceived cognitive functioning significantly improved from t0 to t1. CRP levels significantly decreased, and BDNF as well as IGF1 levels significantly increased over time. Correlation analysis revealed statistically significant negative associations between fatigue, physical activity, and markers of inflammation (TNF-alpha and MIF). Furthermore, significant positive correlations between subjective cognitive functioning and all dimensions of fatigue were observed. CONCLUSIONS: The results support the importance of personalized exercise recommendations to increase physical activity levels in patients with breast cancer. Furthermore, the results highlighti an association between physical activity, fatigue, and inflammation. PMID- 28617136 TI - Essential oil extraction, chemical analysis and anti-Candida activity of Foeniculum vulgare Miller - new approaches. AB - A comprehensive study on essential oil samples of Foeniculum vulgare Miller from Tarquinia (Italy) is reported. A 24-h systematic steam distillation was performed on different harvested samples applying different extraction times. The GC-MS analysis of the residue outcome showed o-cymene, alpha-phellandrene, alpha-pinene and estragole as the major constituents. The predominance and continued presence of o-cymene makes this fennel oil a rather unique chemotype. An evident correlation between the antifungal activity and phenological stage is demonstrated. The most active fractions were particularly rich in estragole, as well as a significant amount of fenchone that possibly exerts some additive effect in the expression of overall antifungal potency. Pre-fruiting material produced oil particularly rich in o-cymene. With reference to the duration of the extraction, the maximum amount of oil was released within the first 3 h, whereas the reproductive phase material needed at least 6 h for the extraction. PMID- 28617137 TI - Drugs currently under investigation for the treatment of invasive candidiasis. AB - INTRODUCTION: The widespread implementation of immunosuppressants, immunomodulators, hematopoietic stem cell transplantation and solid organ transplantation in clinical practice has led to an expanding population of patients who are at risk for invasive candidiasis, which is the most common form of fungal disease among hospitalized patients in the developed world. The emergence of drug-resistant Candida spp. has added to the morbidity associated with invasive candidiasis and novel therapeutic strategies are urgently needed. Areas covered: In this paper, we explore investigational agents for the treatment of invasive candidiasis, with particular attention paid to compounds that have recently entered phase I or phase II clinical trials. Expert opinion: The antifungal drug development pipeline has been severely limited due to regulatory hurdles and a systemic lack of investment in novel compounds. However, several promising drug development strategies have recently emerged, including chemical screens involving Pathogen Box compounds, combination antifungal therapy, and repurposing of existing agents that were initially developed to treat other conditions, all of which have the potential to redefine the treatment of invasive candidiasis. PMID- 28617138 TI - Targeting transcription factor lysine acetylation in inflammatory airway diseases. AB - Asthma and chronic obstructive pulmonary disease are inflammatory airway diseases for which alternative therapeutic strategies are urgently needed. Interestingly, HDAC inhibitors show anti-inflammatory effects in mouse models for these diseases. Here we explore underlying mechanisms that may explain these effects. In previous studies, effects of HDAC inhibitors on histone acetylation are often correlated with their effects on gene expression. However, effects of HDAC inhibitors on transcription factors and their acetylation status may be particularly important in explaining these effects. These effects are also cell type-specific. Recent developments (including chemoproteomics and acetylomics) allow for a more detailed understanding of the selectivity of HDAC inhibitors, which will drive their further development into applications in inflammatory airway diseases. PMID- 28617139 TI - Human cytosolic glutathione-S-transferases: quantitative analysis of expression, comparative analysis of structures and inhibition strategies of isozymes involved in drug resistance. AB - Glutathione-S-transferase (GST) inhibition is a strategy to overcome drug resistance. Several isoforms of human GSTs are present and they are expressed in almost all the organs. Specific expression levels of GSTs in various organs are collected from the human transcriptome data and analysis of the organ-specific expression of GST isoforms is carried out. The variations in the level of expressions of GST isoforms are statistically significant. The GST expression differs in diseased conditions as reported by many investigators and some of the isoforms of GSTs are disease markers or drug targets. Structure analysis of various isoforms is carried out and literature mining has been performed to identify the differences in the active sites of the GSTs. The xenobiotic binding H site is classified into H1, H2, and H3 and the differences in the amino acid composition, the hydrophobicity and other structural features of H site of GSTs are discussed. The existing inhibition strategies are compared. The advent of rational drug design, mechanism-based inhibition strategies, availability of high throughput screening, target specific, and selective inhibition of GST isoforms involved in drug resistance could be achieved for the reversal of drug resistance and aid in the treatment of diseases. PMID- 28617140 TI - Introduction to the Special Section: Linking the MMPI-2-RF to Contemporary Models of Psychopathology. AB - This special section considers 9 independent articles that seek to link the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF; Ben Porath & Tellegen, 2008/ 2011 ) to contemporary models of psychopathology. Sellbom ( this issue ) maps the Specific Problems scales onto hierarchical psychopathology structures, whereas Romero, Toorabally, Burchett, Tarescavage, and Glassmire ( this issue ) and Shkalim, Almagor, and Ben-Porath ( this issue ) show evidence of linking the instruments' scales to diagnostic representations of common higher order psychopathology constructs. McCord, Achee, Cannon, Harrop, and Poynter ( this issue ) link the MMPI-2-RF scales to psychophysiological constructs inspired by the National Institute of Mental Health (NIMH) Research Domain Criteria. Sellbom and Smith ( this issue ) find support for MMPI-2-RF scale hypotheses in covering personality psychopathology in general, whereas Klein Haneveld, Kamphuis, Smid, and Forbey ( this issue ) and Kutchen et al. ( this issue ) demonstrate the utility of the MMPI-2-RF in capturing contemporary conceptualizations of the psychopathic personality. Finally, Franz, Harrop, and McCord ( this issue ) and Rogers et al. ( this issue ) mapped the MMPI-2-RF scales onto more specific transdiagnostic constructs reflecting interpersonal functioning and suicide behavior proneness, respectively. PMID- 28617142 TI - The Alternative Model for Personality Disorders. PMID- 28617141 TI - Therapeutic Assessment with Adults, by Stephen E. Finn. PMID- 28617143 TI - Does ethno-cultural betrayal in trauma affect Asian American/Pacific Islander college students' mental health outcomes? An exploratory study. AB - OBJECTIVES: Interpersonal trauma has deleterious effects on mental health, with college students experiencing relatively high rates of lifetime trauma. Asian American/Pacific Islanders (AAPIs) have the lowest rate of mental healthcare utilization. According to cultural betrayal trauma theory, societal inequality may impact within-group violence in minority populations, thus having implications for mental health. In the current exploratory study, between-group (interracial) and within-group (ethno-cultural betrayal) trauma and mental health outcomes were examined in AAPI college students. PARTICIPANTS: Participants (N = 108) were AAPI college students from a predominantly white university. Data collection concluded in December 2015. METHODS: Participants completed online self-report measures. RESULTS: A multivariate analysis of variance revealed that when controlling for interracial trauma, ethno-cultural betrayal trauma significantly impacted dissociation, hallucinations, posttraumatic stress symptoms, and hypervigilance. CONCLUSIONS: The results have implications for incorporating identity, discrimination, and ethno-cultural betrayal trauma victimization into assessments and case conceptualizations in therapy. PMID- 28617144 TI - The risk of stroke among acutely ill hospitalized medical patients: lessons from recent trials on extended-duration thromboprophylaxis. AB - Data from recent randomized controlled trials indicate that the incidence of stroke among acutely ill medical patients is unexpectedly high and approximates 1% at 90 days. Preliminary data suggest that betrixaban may reduce ischemic stroke in patients without atrial fibrillation. There is an unmet demand for stroke risk stratification schemes targeting hospitalized medical patients. The prognostic value of biomarkers such as natriuretic peptides and D-dimer in predicting short-term stroke remains uncertain. Future research should focus on identifying the high-risk subsets in which the benefit of anticoagulation significantly outweighs the associated hemorrhagic risk. Clinical trials: NCT00457002, NCT00571649, NCT01583218. PMID- 28617145 TI - Defining treatment success in rosacea as 'clear' may provide multiple patient benefits: results of a pooled analysis. AB - BACKGROUND: Rosacea treatment success is usually defined as a score of 1 ('almost clear') or 0 ('clear') on the 5-point Investigator Global Assessment (IGA) scale. OBJECTIVE: To evaluate whether, after successful treatment, 'clear' subjects had better outcomes than 'almost clear' subjects. METHODS: A pooled analysis was performed on 1366 rosacea subjects from four randomized controlled trials with IGA before and after treatment (ivermectin, metronidazole or vehicle). Assessments included the Dermatology Life Quality Index (DLQI) questionnaire and subject assessment of rosacea improvement. In one trial, patients were followed after the treatment period to measure time to relapse (IGA score >=2). RESULTS: At end of treatment, more 'clear' than 'almost clear' subjects had a clinically meaningful difference in DLQI (59% vs. 44%; p < .001) and a final DLQI score of 0 1 indicating no effect on quality of life (84% vs. 66%; p < .001). More 'clear' subjects reported an 'excellent' improvement in their rosacea (77% vs. 42%; p < .001). The median time to relapse was more than 8 months for 'clear' vs. 3 months for 'almost clear' subjects (p < .0001). CONCLUSIONS: Achieving an endpoint of 'clear' (IGA 0) vs. 'almost clear' (IGA 1) is associated with multiple positive patient outcomes, including delayed time to relapse. PMID- 28617146 TI - Diospyros rhodocalyx (Tako-Na), a Thai folk medicine, associated with hypokalemia and generalized muscle weakness: a case series. AB - INTRODUCTION: Diospyros rhodocalyx (Tako-Na) is a Thai folk medicine purported to promote longevity, treat impotence, etc. We present patients with hypokalemia, weakness and hypertension after consuming Tako-Na tea. CASE SERIES: Case 1: A 61 year-old man was brought in nine hours after drinking 400-500 mL of Tako-Na tea. One handful of Tako-Na bark was boiled in water to make tea. He had vomiting and watery diarrhea six hours after drinking it. He took no medications and had no history of hypertension. The only remarkable vital sign was BP 167/90 mmHg. Physical examination revealed generalized muscle weakness. Laboratory findings were potassium 2.7 mmol/L, bicarbonate 24 mmol/L, and transtubular potassium gradient (TTKG) 5.6. He was discharged the next day with a BP 140/90 mmHg and potassium 4.2 mmol/L. Case 2: A 78-year-old man, a friend of case 1, also drank Tako-Na tea from the same pot at the same time as case 1. He also had vomiting and diarrhea six hours later. He took no medications despite past history of hypertension (baseline SBP 140-160). Initial BP was 230/70 mmHg. He also had muscle weakness. Laboratory findings were potassium 3.3 mmol/L, bicarbonate 24 mmol/L, TTKG 7.37 and normal thyroid function. He was also discharged the next day with a BP 148/70 mmHg and potassium 4.2 mmol/L. Case 3-7: These were patients reported to a poison center and their potassium concentrations were 1.4, 1.4, 3.3, 1.3 and 1.2 mmol/L, respectively. Three of them were intubated and case 3 died. CONCLUSIONS: Tako-Na contains betulin, betulinic acid, taraxerone, lupeol, and lupenone. Their structures are similar to glycyrrhetic acid, the active metabolite of glycyrrhizic acid found in licorice which is well known to cause pseudoaldosteronism. Glycyrrhetic acid is potent in inhibiting 11-beta hydroxysteroid dehydrogenase, and causes pseudoaldosteronism. We hypothesize that the compounds in Tako-Na act in the same way as glycyrrhetic acid in producing pseudoaldosteronism. PMID- 28617147 TI - Therapy for wound infections after earthquakes requires inclusion of drugs targeting Gram-negative bacteria. PMID- 28617148 TI - Outcomes of IVF cycles coupled with PGS by aCGH of embryos from donor and autologous oocytes, transferred after vitrification to women of advanced maternal age. AB - It is well documented that aneuploidy rate in preimplantation embryos increases with the mother's age, and at the same time the number of oocytes diminishes. Consequently, for patients of advanced maternal age two options are available to overcome these limitations: use of oocytes from young donors, or use of own oocytes coupled with preimplantation genetic screening (PGS) for 24 chromosomes. However, it is not clear which strategy might be more effective. The aim of this retrospective study was to evaluate outcomes of IVF cycles coupled with transfer of vitrified embryos from donor or autologous oocytes, both with or without PGS. Our results demonstrate that while after PGS clinical pregnancy, twin pregnancy and spontaneous abortion rates are similar for embryos from donor and autologous oocytes, these rates are dramatically worse in all cycles without PGS. Therefore, PGS can be recommended as a screening method to all patients of advanced maternal age even when donor oocytes are used. PMID- 28617150 TI - Atorvastatin-loaded nanostructured lipid carriers (NLCs): strategy to overcome oral delivery drawbacks. AB - Atorvastatin (AT) is a widely used lipid-regulating drug to reduce cholesterol and triglycerides. Its poor aqueous solubility and hepatic metabolism require development of drug delivery systems able to improve its solubility and bypass hepatic effect. For this purpose, atorvastatin nanostructured lipid carriers (AT NLCs) were prepared and characterized. AT-NLCs were prepared by emulsification using high-speed homogenization followed by ultrasonication. The prepared NLCs showed particle size between 162.5 +/- 12 and 865.55 +/- 28 nm while zeta potential values varied between -34 +/- 0.29 and -23 +/- 0.36 mV. They also showed high encapsulation efficiency (>87%) and amorphous state of the drug in lipid matrix. Pharmacokinetic parameters of optimized formulation (NLC-1; composed of 2% Gelucire(r) 43/01, 8% Capryol(r) PGMC, 2% Pluronic(r)F68 and 0.5% lecithin) revealed 3.6- and 2.1-fold increase in bioavailability as compared to atorvastatin suspension and commercial product (Lipitor(r)), respectively. Administration of NLC-1 led to significant reduction (p < .05) in the rats' serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and significant increase in high-density lipoprotein (HDL). This improvement was confirmed histologically by minimizing the associated hepatic steatosis. These investigations demonstrated the superiority of NLCs for improvement of oral bioavailability and in vivo performance of AT. PMID- 28617149 TI - Comparison of airway deposition distributions of particles in healthy and diseased workers in an Egyptian industrial site. AB - The objective of this study is the prediction and comparison of airway deposition patterns of an industrial aerosol in healthy workers and workers suffering from silicosis. Mass concentrations and related size distributions of particulate matter were measured in the industrial area of Samalut in Minia, Egypt. A novel stochastic lung deposition model, simulating the symptoms of silicosis by chronic bronchial (Br) obstruction and emphysema in the acinar (Ac) region, was applied to compute mass deposition fractions, deposition density, deposition rate and deposition density rate distributions in healthy and diseased workers. In the case of healthy workers, both mass deposition fractions and deposition rates are highest in the first half of the Ac region of the lung, while the corresponding deposition density and deposition density rate distributions exhibit a maximum in the large Br airways. In the case of diseased lungs, bullous emphysema causes a large deposition peak in the region of the bronchioli respiratorii. Regional mass deposition fractions adopt maximum values in the extrathoracic region, except during mouth breathing for bullous emphysema, where Ac deposition can be the most prominent. In general, lung deposition is significantly higher in diseased than in healthy lungs. Indeed, workers suffering from silicosis receive significantly higher Ac doses than healthy workers exposed to the same aerosol. Thus, this illness may progress faster if a diseased worker remains in a strongly polluted area. PMID- 28617151 TI - Lithium exposure during pregnancy: outcomes for women who attended a specialist antenatal clinic. AB - INTRODUCTION: Lithium treatment in pregnancy represents a significant dilemma for women and treating health professionals alike. The complexity of risk-benefit analysis is impacted by limited information. METHODS: A cohort study of 33 women with severe mental illness, who were prescribed lithium at any time during the pregnancy, and gave birth between December 2007 and January 2015 at a specialist antenatal clinic in Western Australia. A descriptive comparison for women who continued lithium throughout pregnancy, and those who ceased on discovery of pregnancy was undertaken examining demographic, obstetric, neonatal and psychiatric variables. RESULTS: Women who were prescribed lithium, irrespective of whether they continued or discontinued the medication represented a high risk group obstetrically, with high rates of smoking overall (33%) medical comorbidities (54%) and antenatal complications (88%). Preconception counseling occurred in 33% of the cohort but increased the likelihood of continuing lithium in pregnancy (p = .007). Compared to those who ceased lithium, women who remained on lithium through the pregnancy had increased rates of fetal ultrasound abnormalities such as abdominal circumference >90th % (p = .005). Psychiatric relapses through the antenatal and immediate postpartum period appeared to be due to a combination of factors. DISCUSSION: Pregnant women with severe mood disorders treated with lithium are a vulnerable, high-risk obstetric population who would benefit from preconception counseling, regular antenatal care in a tertiary center, delivery with neonatal pediatric support and experienced psychiatric management. PMID- 28617152 TI - Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis. AB - BACKGROUND: Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration. OBJECTIVE: To model GM and WM volume changes after IA/aHSCT to further understand the effects seen on WB atrophy. METHODS: GM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with IA/aHSCT. A mixed-effects model with two predictors (total busulfan dose and baseline T1-weighted WM lesion volume "T1LV") characterized the time-courses after IA/aHSCT. RESULTS: Accelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were -0.18%/year (standard error (SE): 0.083) and -0.07%/year (SE: 0.14), respectively. CONCLUSION: Chemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging. PMID- 28617155 TI - Thirteen-Year Evaluation of the Management of Biliary Tract Complication After Deceased Donor Liver Transplantation. AB - INTRODUCTION: Although patient and graft survival rate has increased in recent years, biliary complications after liver transplantation are associated with significant morbidity and mortality. METHODS AND MATERIALS: We reviewed the database of 1930 patients who underwent deceased donor liver transplantation between 2000 and 2013. The patients had abnormal results in liver tests, as well as fever and jaundice. Abdominal sonography was performed, and if complication was identified, the patient underwent an interventional procedure by endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography. If the complication was not resolved by the mentioned procedures, exploration of common bile duct and Roux-en-Y choledochojejunostomy or revision of Roux-en-Y choledochojejunostomy was done. RESULTS: Our study group comprised 105 patients including 66 (63%) men and 39 (37.1%) women with a mean age of 36.7 +/- 12.5 years (range: 15-66 years). Among 1930 patients, 105 (5.4%) cases presented with biliary complication after liver transplantation, of which 97 (5%) and 8 (0.4%) cases presented with biliary stricture and bile leak/biloma, respectively. CONCLUSION: In our study, most patients with biliary complications after liver transplantation responded to interventional procedures, with 37.1% requiring surgical exploration. PMID- 28617153 TI - Pectin methylesterase is required for guard cell function in response to heat. AB - Pectin is an important cell wall polysaccharide required for cellular adhesion, extension, and plant growth. The pectic methylesterification status of guard cell walls influences the movement of stomata in response to different stimuli. Pectin methylesterase (PME) has a profound effect on cell wall modification, especially on the degree of pectic methylesterification during heat response. The Arabidopsis thaliana PME34 gene is highly expressed in guard cells and in response to the phytohormone abscisic acid. The genetic data highlighted the significant role of PME34 in heat tolerance through the regulation of stomatal movement. Thus, the opening and closure of stomata is mediated by changes in response to a given stimulus, could require a specific cell wall modifying enzyme to function properly. PMID- 28617156 TI - The Effect of Transplant Education on Nurses Attitudes Toward Organ Donation and Advocacy for Transplantation. AB - Nurses are the largest group of health-care professionals, yet they are not uniformly educated regarding transplantation and organ donation. The future of transplantation hinges on education of this group. Before meaningful studies can be conducted, an instrument to measure attitudes and commitment to organ transplantation is needed. The purpose of this study was to examine content and construct validity as well as establish internal reliability of an investigator developed online instrument to measure nurses' attitudes and commitment to organ transplantation by registered nurses. The online instrument was administered to registered nurses enrolled in transplantation electives at the University of Alabama in Huntsville and Vanderbilt University. Exploratory factor analysis revealed 4 components with eigenvalues over 1.0. The components were as follows: (1) desire to work in transplantation, (2) confidence in transplantation advocacy, (3) organ donation advocacy, and (4) procurement. Internal consistency of the revised instrument was established (alpha = .94). The Transplant Registered Nurse (TXP-RN) instrument is a new instrument with excellent reliability and validity that can be used to measure attitudes and knowledge of American nurses about organ donation and transplantation. This important step is necessary before educational interventions can be accurately assessed. PMID- 28617154 TI - Two-kidney one-clip is a pertinent approach to integrate arterial hypertension in animal models of stroke: Serial magnetic resonance imaging studies of brain lesions before and during cerebral ischemia. AB - Although chronic arterial hypertension (CAH) represents the major comorbid factor in stroke, it is rarely integrated in preclinical studies of stroke. The majority of those investigations employ spontaneously hypertensive rats (SHR) which display a susceptibility to ischemic damage independent of hypertension. Here, we used a renovascular model of hypertension (RH) to examine, with magnetic resonance imaging (MRI), brain alterations during the development of hypertension and after brain ischemia. We also examined whether MRI-derived parameters predict the extent of ischemia-induced brain damage. RH was induced according to the two kidney one-clip model and multiparametric MRI was performed at 3, 6, 9, and 12 weeks after hypertension and also at 10, 50, and 60 min following stroke. Blood pressure values increased progressively and reached a plateau at 6 weeks after RH induction. At 12 weeks, all hypertensive animals displayed spontaneous brain lesions (hemorrhages, deep and cortical lesions, ventricular dilatation), increased apparent diffusion coefficient (ADC) values in the corpus callosum and higher fractional anisotropy in the cortex. Following ischemia, these animals showed larger brain lesions (406 +/- 82 vs. 179 +/- 36 mm3, p < 0.002) which correlated with ADC values at chronic stage of hypertension. This model of hypertension displays many characteristics of the neuropathology of human CAH. The use of this model in stroke studies is relevant and desirable. PMID- 28617157 TI - Vesicoureteral Reflux in Kidney Transplantation. AB - BACKGROUND: Vesicoureteral reflux (VUR) is frequently found after transplantation, but its impact on graft function, urine tract infection, and graft loss remains uncertain. Therefore our objective was to evaluate the effects of VUR on the outcome of renal transplantation. MATERIAL AND METHODS: We included 1008 adult renal transplant recipients of whom a 1-week posttransplant voiding cystourethrogram was available. Study end points included occurrence of bacteriuria, renal function, and graft survival. RESULTS: In total, 106 (10.5%) of 1008 graft recipients had a diagnosis of VUR on voiding cystography. The incidence of bacteriuria was comparable in the reflux and nonreflux group (17% vs 17.4%, P = .91). There was no significant difference in renal function at 3 months and 1 year in patients with and without VUR. One- and 5-year graft survival in patients with VUR was 85.8% and 82.1% compared to 87.3% and 83.0% in patients without VUR ( P = .68 and P = .80). CONCLUSION: Posttransplant VUR has no correlations with early bacteriuria, renal function, and graft survival. PMID- 28617158 TI - Transcendental Spirituality and Acquaintance With the Activities of the Domestic National Transplant Center as Factors Shaping Attitudes Toward Organ Donation. AB - CONTEXT: Organ donation has been shown to be perceived as inappropriate by religiously observant individuals. The impact of spirituality level on attitudes toward organ donation has not been broadly explored. OBJECTIVE: To explore the contribution of ethnicity, spirituality, level of religious observance, and acquaintance with the activities of the Israel National Transplant Center (INTC) to forming attitudes toward organ donation among Jews and Muslim Arabs in Israel. DESIGN: A descriptive cross-sectional survey. PARTICIPANTS: Three hundred five (65.2%) Jewish and 163 (34.8%) Muslim Arab respondents living in Israel. RESULTS: Jewish respondents had more positive attitudes toward organ donation than Muslim Arabs. Muslim Arabs had a higher mean spirituality score than Jews. Gender, age, ethnicity, level of religious observance, education, 4 spirituality dimensions, and acquaintance with the activities of the INTC explained 41.5% of the variance in attitudes to organ donation. Transcendental spirituality, acquaintance with the activities of the INTC, and level of religious observance had the highest contribution to explaining attitudes to organ donation, while gender and age had a low contribution. Ethnicity, education, and the 3 other spirituality dimensions were not found to have a significant contribution. CONCLUSION: A multifaceted approach to improving attitudes toward organ donation among Jews and Muslim Arabs in Israel is important. PMID- 28617159 TI - Ambulatory Care Coordination Issues With Dual Use Veteran Organ Transplant Recipients. AB - The previous literature indicates that patients receiving ongoing care in both Veterans Affairs (VA) and non-VA setting (dual care) may have reduced health outcomes. The objective of this study was to assess the impact of dual care provided to a veteran solid organ transplant population. This was a retrospective cohort study of stable solid organ transplant recipients receiving care at both a Veterans Affairs Medical Center and transplant center. Forty-six veteran organ transplant recipients met inclusion criteria. At baseline, mean age at transplant was 57 +/- 10 years; 93% were male, 61% received kidney transplants. Thirty-nine percent of patients did not receive immunosuppressant concentrations at the recommended intervals. The incidence of veterans that had at least 2 providers caring for the same comorbidity was 63% for hypertension, 58% for diabetes, and 27% for dyslipidemia. Approximately one-third of veterans had documentation of care provided by the other institutions (30%-37%), and 93% of patients had medication regimen discrepancies between health-care systems, with 52% of patients having at least 1 medication discrepancy involving an immunosuppressant. Most veteran solid organ transplant recipients receive care across multiple health-care systems, with significant care coordination issues leading to gaps and duplications in their management. Improved communication between health systems is imperative to optimize outcomes in dual use veterans such as organ transplant recipients. PMID- 28617160 TI - Rising Need for Health Education Among Renal Transplant Patients and Caregiving Competence in Care Providers. AB - BACKGROUND: Health education positively affects the efficacy of self-management and should be carried out according to the status of patients' needs, knowledge, and the competence of the primary caregivers. OBJECTIVES: This study was to investigate the needs of health education knowledge in transplant patients and the competence of the primary caregivers. METHODS: This is a cross-sectional study using a convenient sampling approach. Self-report questionnaires were applied to 351 renal transplantation patients and their primary caregivers. RESULTS: Three-hundred nine valid questionnaires were included in the analysis. The intensive care unit environment, stress coping strategies, the operation procedure, anesthesia and adverse reactions, and hand hygiene were the 5 most poorly understood aspects in health education. Stress coping strategies, at-home self-monitoring of health, pulmonary infection prevention, dietary needs, and anesthesia and other adverse reactions were the top 5 health education needs. Decision and self-efficacy were the weakest caregiving competence. Significant positive correlations were observed between health education knowledge level and caregiving competence in the primary caregivers. Marriage, education level, career, expense reimbursement, and residence significantly contributed to the health education demand questionnaire model, whereas gender, age, ethnic group, education level, career, and expense reimbursement significantly contributed to health education knowledge questionnaire model ( P < .05). CONCLUSION: The renal transplant patients and their primary caregivers need health education on the intensive care unit environment, stress coping strategies, the operation procedure, and anesthesia and other adverse reactions. The primary caregivers need training in decision-making and self-efficacy. PMID- 28617161 TI - Insomnia and Relationship With Immunosuppressant Therapy After Lung Transplantation. AB - BACKGROUND: Lung transplant recipients are at high risk of developing sleep disorders such as insomnia, but the prevalence and features are currently poorly characterized within this population. Since these disorders are associated with increased morbidity and mortality, it is important to identify them to optimize the care of lung transplant recipients. We sought to evaluate the prevalence of insomnia within our university-based lung transplant clinic and determine whether a relationship exists between insomnia and exposure to immunosuppressant medications following transplantation. METHODS: Participants were recruited through the University of Wisconsin Hospital and Clinics Lung Transplant Clinic (N = 125). Participants (n = 92) completed the adult sleep history questionnaire, which included the Insomnia Severity Index (ISI) to assess for insomnia (defined as ISI score >10). Cumulative tacrolimus exposure was determined in 73 patients by performing an area under the curve calculation to assess for a potential relationship between tacrolimus exposure and insomnia. RESULTS: The prevalence of insomnia was 40% within this population. Although no difference in time since transplant was found, cumulative mean +/- standard error of the mean tacrolimus exposure was significantly higher in patients with insomnia versus those without insomnia (17 190 +/- 1673 ng.d/mL vs 12 130 +/- 1630 ng.d/mL, respectively; P = .04). Estimated tacrolimus exposure was not greater with increasing frequency of insomnia complaints (analysis of variance P = .54). CONCLUSION: In our population, insomnia is common after lung transplantation, with prevalence greater than the general population. Higher cumulative exposure to tacrolimus may contribute to insomnia in this group. Future research should investigate the relationship between immunosuppressant therapy and development of sleep disorders. PMID- 28617162 TI - The Use of Stroke Volume Variation to Guide Donor Management Is Associated With Increased Organs Transplanted per Donor. AB - BACKGROUND: There is a national shortage of organs available for transplantation, and utilization rates for thoracic organs are less than 40%. In addition, the optimal method of assessing cardiovascular status during donor management is uncertain. FloTrac is a noninvasive hemodynamic technique that measures cardiac output and fluid responsiveness. Our objective was to measure the impact of using this technique to guide management on fluid balance, vasopressor usage, thyroid hormone usage, and pulmonary function. We hypothesized that FloTrac guidance will increase thoracic organs transplanted per donor (OTPD). METHODS: Data were prospectively collected on a convenience sample of 38 donors after neurologic determination of death. Organs transplanted, net fluid balance, dosage of vasopressors, dosage of thyroid hormone, and Pao2:Fio2 were compared between treatment and control groups. RESULTS: The treatment group had greater thoracic OTPD (1.3 [1.0] vs 0.4 [0.6], P = .004) and overall OTPD (4.3 [1.5] vs 2.7 [1.5], P = .002). Donors in the treatment group maintained a neutral fluid balance, had more thyroid hormone used, and had an improvement in oxygenation. CONCLUSION: The implementation of this technology to aid providers may help ameliorate the shortage of thoracic and overall organs available for transplantation. PMID- 28617163 TI - Do Our Patients Trust Us to Do the Right Thing With Their Biomedical Information? PMID- 28617164 TI - Liver Transplantation Using Graft From a Donor With Aplastic Anemia. AB - Liver transplantation (LT) is a life-saving procedure in patients with end-stage liver disease. The number of patients in the waiting list for LT has steadily increased over time, so removing liver from deceased donors with unusual disorders could possibly be used for transplantation. We describe a case of LT from a donor with "aplastic anemia" to a patient with liver failure due to hepatitis C. Aplastic anemia is a syndrome of bone marrow failure. Aplastic anemia is one of the most common conditions linked to transfusion dependence, and long-term repeated transfusion inevitably results in iron overload. Also iron is a cofactor that influences the severity and progression of nonhemochromatic liver diseases, especially steatohepatitis and viral hepatitis. The aim of this report is to highlight the posttransplant findings of the recipient, with specific emphasis on the graft function. Our findings provide insights into the clinical implications of LT using graft with this rare disorder. PMID- 28617165 TI - Transplant Professionals' Perceptions of Long-Term Care Residents' Candidacy for Kidney Transplantation. AB - CONTEXT: Given the aging end-stage renal disease (ESRD) population, kidney transplant (KTx) centers may experience an increase in referrals of patients living in long-term care (LTC) settings (eg, skilled nursing facilities, assisted living facilities, group homes, and boarding homes). OBJECTIVE: To identify best practices among KTx professionals when considering individuals in LTC settings for transplantation. DESIGN AND SETTING: A cross-sectional survey administered online to US transplant professionals via e-mail LISTSERVs and other professional networks. PARTICIPANTS: One hundred twenty-six KTx professionals working in the United States. MAIN OUTCOME MEASURES: The survey was composed of demographic questions and 6 hypothetical scenarios. These scenarios asked participants to assess transplant candidacy of patients with ESRD living in LTC settings based on the information provided in the scenario. Each scenario presented a different variable that necessitated LTC placement, including lack of social support, moderate intellectual disability, stable neurological condition, mild dementia, a psychiatric condition controlled on medications, and limited mobility. RESULTS: The only scenario that elicited an overwhelmingly negative response was mild dementia with 73.9% of participants unwilling to consider such patients for KTx. By contrast, the proportion of KTx professionals reluctant to proceed with KTx in the remaining scenarios ranged between 40.0% and 50.6%. CONCLUSIONS: This survey of a large number of KTx professionals suggests that there is presently no best practice consensus regarding offering KTx to patients living in LTC settings. Further research should include a broader range of KTx professionals and should also include a study of outcomes with KTx in this particular patient population. PMID- 28617166 TI - Challenges in Providing Timely Physiotherapy and Opportunities to Influence Outcomes for Potential Lung Donors. AB - CONTEXT: There is a critical shortage of donor lungs however, considerable ethical considerations are associated with the conduct of research to optimize care of the potential organ donor. OBJECTIVE: To investigate pathways of consent, respiratory care by physiotherapists and donation rates to contextualize future research on physiotherapy effects on donor lung suitability for procurement. DESIGN: Retrospective audit. SETTING: Australian tertiary hospital. PATIENTS: Potential organ donors (defined as patients who may have been eligible to donate organs for transplantation via either brain death or circulatory death) 75 years or younger presenting to the emergency department or the intensive care unit (ICU) between September 2011 and December 2012. MAIN OUTCOME MEASURES: Donation rates, timing of organ procurement from initial hospital presentation, number of persons designated to make health-care decisions approached for and consenting to donation and clinical research, and number of patients assessed and/or treated by physiotherapists. RESULTS: Records of 65 potentially eligible donors were analyzed. Eighteen (28%) of the 65 became donors. Organ procurement occurred at a median of 48 hours (interquartile range: 34-72 hours) after ICU admission. All decision-makers approached regarding participation in clinical research (4 [6%] of the 65) consented. Physiotherapists assessed 48 (74%) of the 65 patients at least once and provided 28 respiratory treatments to 18 (28%) of the 65 patients, including lung hyperinflation and positioning. Limitations were the retrospective, single-center design and the "potential organ donor" definition. CONCLUSION: Organ procurement occurs early. There is potential for early intervention to improve lung donor rates. Randomized controlled trials investigating protocolized respiratory packages of care may increase the potential donor pool and transplantation rates. PMID- 28617167 TI - Patient-Reported Barriers to the Prekidney Transplant Evaluation in an At-Risk Population in the United States. AB - BACKGROUND: Despite our knowledge of barriers to the early stages of the transplant process, we have limited insight into patient-reported barriers to the prekidney transplant medical evaluation in populations largely at-risk for evaluation failure. METHODS: One-hundred consecutive adults were enrolled at an urban, Midwestern transplant center. Demographic, clinical, and quality of life data were collected prior to patients visit with a transplant surgeon/nephrologist (evaluation begins). Patient-reported barriers to evaluation completion were collected using the Subjective Barriers Questionnaire 90-days after the initial medical evaluation appointment (evaluation ends), our center targeted goal for transplant work-up completion. RESULTS: At 90 days, 40% of participants had not completed the transplant evaluation. Five barrier categories were created from the 85 responses to the Subjective Barriers Questionnaire. Patient-reported barriers included poor communication, physical health, socioeconomics, psychosocial influences, and access to care. In addition, determinants for successful evaluation completion included being of white race, higher income, free of dialysis, a lower comorbid burden, and reporting higher scores on the Kidney Disease Quality of Life subscale role-emotional. CONCLUSION: Poor communication between patients and providers, and among providers, was the most prominent patient-reported barrier identified. Barriers were more prominent in marginalized groups such as ethnic minorities and people with low income. Understanding the prevalence of patient-reported barriers may aid in the development of patient-centered interventions to improve completion rates. PMID- 28617168 TI - Renalase Assessment With Regard to Kidney Function, Lipid Disturbances, and Endothelial Dysfunction Parameters in Stable Renal Transplant Recipients. AB - BACKGROUND: Renal transplant dysfunction has been shown to be independent predictor for premature cardiovascular disease and mortality. Renalase, a flavoprotein secreted by several tissues, including the kidney, has been found to regulate sympathetic tone and blood pressure. The purpose of this secondary analysis was to explore relationships among parameters of endothelial dysfunction, lipids, glomerular filtration rate, and renalase in 2 groups: renal transplant patients with controlled hypertension and healthy volunteers. METHODS: In the parent study, 73 renal transplant recipients and 32 age- and gender matched controls were enrolled. A fasting sample for endothelial, lipid, and renalase values, along with other clinical parameters, was obtained. RESULTS: We found statistically significant inverse correlation between renalase and estimated glomerular filtration rate ( r = -0.552, P < .001), positive correlation between renalase and creatinine ( r = 0.364, P = .003), total cholesterol ( r = 0.578, P < .001), low-density lipoprotein cholesterol ( r = 0.261, P = .046), and non-high-density lipoprotein cholesterol ( r = 0.327, P = .01). Renalase inversely correlated with hemoglobin ( r = -0.232, P = .032) and positively with white blood cells ( r = 0.233, P = .032). There was a significant difference in plasma renalase with regard to chronic kidney disease stages ( F = 13.346, P < .001) but did not correlate with C-reactive protein. Renalase did not correlate with any of parameters of endothelial dysfunction, C-reactive protein, neither with some demographic data (gender, age, time or type of transplantation, risk factors). There were no differences in renalase concentration with regard to antihypertensive therapy. CONCLUSION: Renalase strongly and inversely correlated with kidney function, positively with creatinine and lipid disturbances. Due to that it is very likely that renalase levels are determined mostly by renal function. PMID- 28617169 TI - The Frequency and Associated Factors for BK Virus Infection in a Center Performing Mainly Living Kidney Transplantations. AB - PURPOSE: BK virus (BKV) nephropathy has increasingly become an important cause of morbidity in renal transplant recipients. We evaluated the frequency and associated factors for BKV infection in a center performing mainly living donor transplantations over a long time period. METHODS: One hundred consecutive renal transplant patients were included. Quarterly visits were planned to examine urine for decoy cells and to measure the BKV DNA in the blood and urine. Renal biopsy was performed in case of deteriorated allograft function. Serological examinations for BKV immunoglobulin G (IgG) were performed in donors. RESULTS: Throughout the entire follow-up period, the rates of viruria, viremia, and the positivity of decoy cells were 12%, 6%, and 13%, respectively. The negative and positive predictive values of decoy cells were 93.1% and 69.2%, respectively, for viruria, and 99.2% and 45.5%, respectively, for viremia. Biopsy-proven BKV nephropathy was observed in 1 patient. The BKV IgG was positive in all living donors. Viruria and viremia were associated with deceased donor transplantation, acute rejection, and pulse steroid therapy. In addition, viremia was associated with antithymocyte globulin therapy and a short duration of the posttransplant period. CONCLUSIONS: The frequency of BKV infection was lower in our transplant unit compared to previous reports. Reduced doses of immunosuppression seem to be the main factor that may explain the reduced frequency. However, an active screening strategy is still of importance for this patient group. PMID- 28617170 TI - Adherence of Heart Transplant Recipients to Prescribed Medication and Recommended Lifestyle Habits. AB - INTRODUCTION: Nonadherence may cause severe health problems in heart transplant (HTx) recipients. RESEARCH QUESTIONS: The present study aimed to investigate adherence to prescribed medication and recommended lifestyle habits in post-HTx patients and to assess associations between adherence, quality of life (QOL), and psychological well-being. DESIGN: A questionnaire package was sent to all HTx patients from our clinic (n = 858) to answer questions anonymously on medication adherence, dietary recommendations (avoidance of raw animal products and ice cream), pet keeping (risk of zoonosis), anxiety and depression, QOL, and posttraumatic stress disorders. RESULTS: Of the contacted patients, 524 (61%) responded and 505 fulfilled the inclusion criteria (age >=18 years and ability to understand German). Of the study participants, 72.4% reported taking their medications very correctly, 72.2% stated consuming alcohol less often than once a week, 58.3% performed physical exercise at least once a week, one-third reported eating nonrecommended foods, 22.1% stated pet keeping, and 4.3% reported smoking. Adherence to prescribed medication was positively associated with age ( P < .001) and mental QOL ( P = .015) but was unrelated to eating nonrecommended foods ( P > .05). Depressiveness correlated inversely with physical QOL ( r = -0.232; P < .01) and mental QOL ( r = -0.411; P < .01). Stress disorders and minor stressful events were reported by 7.8% and 46.6%, respectively. Stress disorders correlated inversely with mental QOL ( r = -0.282; P < .01) and physical QOL ( r = -0.422; P < .01). DISCUSSION: Many HTx patients adhere to prescribed medications and health advice. Nevertheless, nonadherence is a problem, especially in younger HTx patients, indicating the need for a nonadherence crisis intervention program for long-term HTx patients. PMID- 28617171 TI - Using Mobile Phone Technology to Support Young Liver Transplant Recipients Moving to Adult Services. AB - BACKGROUND: The process and preparation of moving from child to adult services (transition) is a challenging period of time for young people and represents significant changes in care and support systems. The proliferation of mobile phone applications for health purposes suggests that it is an area for further investigation. OBJECTIVE: The review explores the potential to use mobile phone technology to help support young liver transplant recipients moving to adult services. It represents the first review conducted in this specialism and considers a new model of support for young liver patients. METHODS: A systematic rapid review of the published peer-reviewed literature. RESULTS: Two searches were conducted: Search 1: the use of technology to support transition to adult services (6 studies) and Search 2: how best to support liver transplant recipients during transition (6 studies). DISCUSSION: Research shows that to achieve positive transition young people need information about their condition and transition. The process needs to be guided by transition readiness, rather than the young persons' age. Although parents and support networks should be in place and are valued, transition should build upon self-management and independence. Results suggest that there appears to be scope to use mobile phone technology to support transition. This is the first time a review has explored the types of issues or concerns facing liver transplant patients and how these can be addressed through mobile phone technology. PMID- 28617172 TI - Food supplements with red yeast rice: More regulations are needed. PMID- 28617173 TI - Premenstrual syndrome in university students: its correlation with their attitudes toward gender roles. AB - INTRODUCTION: Psychosocial factors causing premenstrual syndrome (PMS) are closely correlated with gender. Thus, this study's aim was to identify correlations between gender role attitudes (GRA) and PMS status of university students. METHODS: The participants of this descriptive study were 1515 female students from 13 departments of Hacettepe University using stratified sampling method. Data were collected between February and May 2014 using a semi-structured questionnaire, the Premenstrual Syndrome Scale (PMSS), and the Gender Roles Attitude Scale (GRAS). Correlations between PMSS and GRAS scores were analyzed using the Spearman correlation coefficient. The difference between PMSS and GRAS scores in terms of sociodemographic characteristics was analyzed using the t-test and one-way analysis of variance. RESULTS: The mean total PMSS score was 117.96 +/- 34.41, indicating moderate PMS levels. The total mean GRAS score was 162.71 +/- 17.50, indicating an egalitarian GRA. As the gender roles in marriage of the participants became traditional, depressive thoughts and swelling became more common (rs= -0.620, p < .05; rs= -0.560, p < .05). The educational level of the mothers and perceived economic status were sociodemographic factors affecting both GRA and PMS. DISCUSSION: GRA and sociodemographic characteristics should be considered in healthcare services for PMS. PMID- 28617174 TI - Selective catalytic reduction of nitric oxide with carbon monoxide over alumina pellet-supported catalysts in the presence of excess oxygen. AB - Selective catalytic reduction of nitrogen oxides with carbon monoxide (CO-SCR) is a promising technology to remove NOx and CO simultaneously from flue gas. The thermodynamic analyses of catalytic process were performed toward four kinds of active metal oxides (CuxOy, CoxOy, MnxOy and CexOy). According to the standard Gibbs free-energy changes calculated, Mn had better resistance to oxygen than Cu, Co and Ce, while Cu and Ce had better resistance to water vapor poisoning, as active metals. Then, a series of binary- and ternary-preformed catalysts with different metal ratios were prepared by the impregnation method using Al2O3 pellets as support and tested in excess oxygen (16 vol%) atmosphere with or without SO2. The results of experiment were analyzed based on thermodynamic analyses. Results indicated that the NO conversions of Cu-Co/Al2O3 catalysts increased with the rise of reaction temperature; however, the tendency changed at 160 degrees C for Cu-Mn/Al2O3. Besides, the NO conversions of Cu-Mn/Al2O3 were better than Cu-Co/Al2O3. The catalysts with the metal ratio of 1.5 had the best denitrification performance. Among various binary catalysts, Cu-Mn/Al2O3 with the metal ratio Cu:Mn of 1.5 showed promising activity for CO-SCR, giving nearly 90% NO conversion. Besides, the doping of Ce could inhibit the sulfur poisoning and promote the oxide of CO under experimental conditions. PMID- 28617175 TI - Operator models for delivering municipal solid waste management services in developing countries. Part A: The evidence base. AB - This article presents the evidence base for 'operator models' - that is, how to deliver a sustainable service through the interaction of the 'client', 'revenue collector' and 'operator' functions - for municipal solid waste management in emerging and developing countries. The companion article addresses a selection of locally appropriate operator models. The evidence shows that no 'standard' operator model is effective in all developing countries and circumstances. Each city uses a mix of different operator models; 134 cases showed on average 2.5 models per city, each applying to different elements of municipal solid waste management - that is, street sweeping, primary collection, secondary collection, transfer, recycling, resource recovery and disposal or a combination. Operator models were analysed in detail for 28 case studies; the article summarises evidence across all elements and in more detail for waste collection. Operators fall into three main groups: The public sector, formal private sector, and micro service providers including micro-, community-based and informal enterprises. Micro-service providers emerge as a common group; they are effective in expanding primary collection service coverage into poor- or peri-urban neighbourhoods and in delivering recycling. Both public and private sector operators can deliver effective services in the appropriate situation; what matters more is a strong client organisation responsible for municipal solid waste management within the municipality, with stable political and financial backing and capacity to manage service delivery. Revenue collection is also integral to operator models: Generally the municipality pays the operator from direct charges and/or indirect taxes, rather than the operator collecting fees directly from the service user. PMID- 28617176 TI - University student perceptions about the motives for and consequences of nonmedical use of prescription drugs (NMUPD). AB - OBJECTIVE: The purpose of the current study was to increase qualitative understanding of student motives for and consequences associated with nonmedical use of prescription drugs. PARTICIPANTS: Sixty-one students participated in eight focus groups between April and November 2013. METHODS: Students described prescription drugs commonly used for nonmedical reasons, as well as the motives for and consequences associated with their use. Data were analyzed using thematic content analysis. RESULTS: Students reported stimulants as the most commonly used prescription drug for nonmedical reasons, least expensive, and easiest to obtain on campus, followed by benzodiazepines. Opioids were less commonly used, more expensive, and difficult to acquire. Motives and consequences varied by prescription drug class. CONCLUSIONS: Our qualitative findings extend previous research by suggesting differences in students' perceived motives for using and consequences associated with the different classes of prescription drugs. These findings provide implications for the development of preventive interventions. PMID- 28617177 TI - Discordant Anomalies with Combined Features of Pentalogy of Cantrell and OEIS Complex: A Case Report in Monochorionic Twins. AB - INTRODUCTION: Ventral body wall defects have various manifestations. Among others, pentalogy of Cantrell (PC) and omphalocele exstrophy imperforate anus spinal abnormalities (OEIS) complex are defects that involve upper and lower anterior midline of body wall, respectively. Although both entities are in a spectrum of ventral body wall defects, the combination of PC and OEIS complex has not been described. CASE REPORT: In this report, we describe an unusual case of congenital ventral body wall defect with combined features of PC and OEIS complex, which discordantly occurred in monochorionic monoamniotic twins. CONCLUSION: PC and OEIS complex may be related regarding their embryologic origins. The combination may represent the most severe manifestation of ventral body wall defects. PMID- 28617178 TI - Concentrations of Pneumococcal IgA and IgM are compromised in some individuals with antibody deficiencies. AB - The response to pneumococcal vaccination is assessed by measurement of antigen specific IgG only and is compromised in a number of antibody deficiencies. We measured the concentrations of Pneumococcal IgA and IgM in individuals with both normal and abnormal pneumococcal capsular polysaccharide (PCP) IgG concentrations. A higher number of individuals had abnormal pre-vaccination IgA and IgM concentrations below the lower limit of the normal range compared to the control group. Post vaccination a lower number of individuals had IgA and IgM concentrations below the upper limit of the normal range compared to the control group. Non responders had a higher percentage of individuals with a prior history of infection. In addition, individuals with a history of prior infection had lower pre- and post-vaccination concentrations of PCP IgG, IgA, and IgM. Post vaccination IgA and IgM concentrations identified four groups of responses which correlated with prior history of infection. A higher percentage of individuals with abnormal PCP IgA and IgM concentrations had a history of prior infection compared to the percentage of individuals with normal concentrations. In individuals with an antibody deficiency, measurement of Pneumococcal IgA and IgM correlates with the number of individuals with prior history of infection. PMID- 28617179 TI - Predictive value of Pirani scoring system for tenotomy in the management of idiopathic clubfoot. AB - PURPOSE: To determine the predictive value of the Pirani scoring system in the need for tenotomy using the Ponseti method for management of idiopathic clubfoot. METHOD: This is a prospective observational study involving patients less than 2 years of age with idiopathic clubfoot. The consenting parents and institution ethical board approved the study. The relationship between Pirani scores and the need for tenotomy was evaluated using the independent t-test and the binary logistic regression to predict the need for tenotomy. Pearson's r and Cohen's kappa were used to measure correlation and agreement, respectively, between the predicted and observed values. A receiver operating characteristic curve was used to interpret sensitivity and specificity levels as well as to obtain a cutoff score for predicting the requirement for tenotomy. RESULTS: Eighty-four clubfeet from 50 patients were studied. Thirty-eight feet (45%) had percutaneous tenotomy. The initial total Pirani and hindfoot scores were found to predict the need for tenotomy with the model for prediction being able to predict correctly in 72.6% and 75% of the time, respectively. A higher Pirani score was associated with higher odds of requiring tenotomy (OR = 4.402, p < 0.001) and total Pirani score above the cutoff point of 4.75 predicted the need for tenotomy. CONCLUSION: The indication for tenotomy appears to be well predicted using the Pirani scoring system with the odds of requiring a tenotomy increasing by more than fourfold for every unit increase in Pirani score. PMID- 28617180 TI - Lumbar spondylolysis: A report of four cases from two generations of a family. AB - Spondylolysis is a major cause of back pain in children and adolescents. The prevalence of spondylolysis depends on the sex, race, and congenital abnormality. These biases suggest hereditary predisposition as an etiology of spondylolysis. However, no conclusive evidence still exists regarding the inheritance for spondylolysis. Herein, we report rare cases with familial occurrence of lumbar spondylolysis. In two generations of a Japanese family, three brothers including identical twins complained of back pain related to sports activities. Clinical, radiographic, and computed tomographic examinations identified spondylolysis at L4 and L5 in all these boys. The father experienced long-term back pain and had spondylolisthesis at L4-L5 and healed spondylolysis at L5. The daughter and mother did not show any lumbar spondylolysis. The frequent development of spondylolysis at L4, a rarely affected segment, in four of six family members (66.7%) support that lumbar spondylolysis has an underlying genetic etiology, primarily autosomal dominant inheritance. PMID- 28617181 TI - A novel surgical approach for treating distal radial extraarticular malunion: Oblique osteotomy with buttress plate stabilization. AB - PURPOSE: Distal radial extraarticular malunions are not uncommon. However, requirements of surgical correction depend on multiple conditions. Traditionally, surgical techniques include closing or opening wedge osteotomies. Each has unique advantages and disadvantages. An oblique osteotomy was developed to simplify the revision surgery. METHODS: Forty-eight consecutive adult patients with 48 malunions were surgically treated. An oblique osteotomy of 45 degrees vertical to the radial longitudinal axis was performed from medio-distally to latero proximally. Consequently, the osteotomized fragments were compressed with a bone clamp. The proximal part of the distal fragment was pushed backward to correct the dorsal tilt. A 7-hole buttress plate was inserted volarly and cancellous bone graft was packed. Postoperatively, a short-arm splint or brace without restriction of all five metacarpophalangeal joints was applied for 6 weeks. RESULTS: Forty-one patients were followed for an average of 2.8 years (range, 1.1 5.8 years). All malunions healed within 6 weeks. The union rate was 100% and no complications occurred. Radiographically, ulnar variance, volar tilt of radial articulation, and radial inclination restored to acceptable criteria in all patients. Patients with Modified Mayo Wrist Score (MMWS) improved from 17% to 80% ( p < 0.001) and Disability of Arm, Shoulder and Hand (DASH) Score improved from 0% to 80% ( p < 0.001). The relationship between MMWS and DASH Score was highly correlated (correlation coefficient = -0.90). CONCLUSION: The described approach may be an excellent alternative for treating distal radial extraarticular malunions. The technique is not difficult but the satisfactory rate is high. PMID- 28617182 TI - Simultaneous bilateral correction of genu varum with Smart frame. AB - PURPOSE: The aim of this study is to evaluate clinical and radiological results of simultaneous bilateral correction of genu varum with Smart frame. METHODS: Between 2011 and 2015, a total of 25 patients (10 females, 15 males) who had bilateral genu varum deformity were operated bilaterally with tibial and fibular osteotomy in the same session, using Smart frame. The mean follow-up period was 28.7 (range, 13-45) months. All patients had bilateral tibial varus deformity. Femoral deformity was corrected in an earlier session in nine patients. Mechanical axis deviation (MAD), mechanical lateral distal femoral angle, mechanical medial proximal tibial angle (mMPTA) and posterior proximal tibial angle (PPTA) were measured preoperatively and postoperatively. Short Form-36 questionnaire was filled by the patients preoperatively and during the last follow-up. RESULTS: The mean preoperative MAD was 37.6 mm (range, 9-98 mm), which improved to 8.4 mm (range, 3-44 mm) postoperatively ( p < 0.05). The mean preoperative mMPTA was 76 degrees , which improved to 89 degrees ( p < 0.05). The mean preoperative PPTA was 75.5 degrees , which improved to 80.3 ( p < 0.05). Ten problems (20%), two obstacles (4%) and no sequelae occurred in 50 legs of 25 patients. CONCLUSIONS: In conclusion, Smart frame is an accurate and reliable method for performing bilateral simultaneous deformity correction in patients with bilateral genu varum deformity. It can be applied for various childhood induced severe tibial deformities such as achondroplasia, rickets, skeletal dysplasia and Blount's disease. PMID- 28617183 TI - Hypermethylated CpG sites in the MTR gene promoter in preterm placenta. AB - AIM: Altered maternal one-carbon metabolism influences placental DNA methylation patterns and 'programs' the fetus for noncommunicable diseases in adult life. EXPERIMENTAL PROCEDURES: Levels of plasma folate, vitamin B12, homocysteine, mRNA and protein levels of MTHFR and MTR enzymes in placenta were compared among women delivering preterm (n = 83) and term (n = 75). MTR promoter CpG methylation was undertaken. RESULTS: MTHFR and MTR mRNA levels were higher while protein levels were lower, and MTR CpG sites were hypermethylated in the preterm group, as compared with the term group. Methylated CpG sites were negatively associated with maternal plasma vitamin B12 levels. CONCLUSION: Study suggests a dysregulation of enzyme genes in remethylation arm of the one-carbon metabolism in placenta of women delivering preterm. PMID- 28617184 TI - Patient perceptions of experience with cardiac rehabilitation after isolated heart valve surgery. AB - BACKGROUND: Little evidence exists on whether cardiac rehabilitation is effective for patients after heart valve surgery. Yet, accepted recommendations for patients with ischaemic heart disease continue to support it. To date, no studies have determined what heart valve surgery patients prefer in a cardiac rehabilitation programme, and none have analysed their experiences with it. AIMS: The purpose of this qualitative analysis was to gain insight into patients' experiences in cardiac rehabilitation, the CopenHeartVR trial. This trial specifically assesses patients undergoing isolated heart valve surgery. METHODS: Semi-structured interviews were conducted with nine patients recruited from the intervention arm of the trial. The intervention consisted of a physical training programme and a psycho-educational intervention. Participants were interviewed three times: 2-3 weeks, 3-4 months and 8-9 months after surgery between April 2013 and October 2014. Data were analysed using qualitative thematic analysis. RESULTS: Participants had diverse needs and preferences. Two overall themes emerged: cardiac rehabilitation played an important role in (i) reducing insecurity and (ii) helping participants to take active personal responsibility for their health. Despite these benefits, participants experienced existential and psychological challenges and musculoskeletal problems. Participants also sought additional advice from healthcare professionals both inside and outside the healthcare system. CONCLUSIONS: Even though the cardiac rehabilitation programme reduced insecurity and helped participants take active personal responsibility for their health, they experienced existential, psychological and physical challenges during recovery. The cardiac rehabilitation programme had several limitations, having implications for designing future programmes. PMID- 28617185 TI - Correction to: Syrpailyne Wankhar, et al., A versatile stretch sensor for measuring physiological movement using a centre loaded, end-supported load cell. PMID- 28617187 TI - Retrospective Analysis of Continuous Glucose Monitoring Data With the Surveillance Error Grid Supports Nonadjunctive Dosing Decisions. AB - OBJECTIVE: The objective was to assess clinical risks of inaccurate continuous glucose monitoring (CGM) system readings as estimated by the surveillance error grid (SEG). METHODS: Values from Dexcom G4 Platinum system with an advanced algorithm (Software 505) were plotted on the SEG with temporally matched reference venous (YSI) values collected during clinic visits on days 1, 4, and 7 of sensor wear. Data from a pediatric study (N = 79, age [mean +/- SD] 12.2 +/- 4.6 years, all with type 1 diabetes) and an adult study (N = 51, age 46.7 +/- 15.8 years, 44 with type 1 diabetes and 7 with type 2 diabetes) were used. RESULTS: Pediatric data included 2262 paired points, of which 1990 (88.0%) were in the "no risk" zone. Adult data included 2263 paired points, of which 2056 (90.9%) were in the "no risk" zone. Performance was best on Day 4, when 92.7% and 93.3% of points from the pediatric and adult studies, respectively, were in the "no risk" zone. Nine of the 4525 points (<0.2%) from 5 different sensors were in zones representing moderate risk, and none were in zones representing great or extreme risk. CONCLUSIONS: SEG analysis suggests that in pediatric and adult subjects with diabetes, using CGM values for diabetes management poses minimal risk to the user. CGM users also benefit from glucose trends and alerts. PMID- 28617189 TI - Stability of continuous and fed batch sequential anaerobic-anoxic-aerobic moving bed bioreactor systems at phenol shock load application. AB - The stability of two sequential moving bed bioreactor systems operated in anaerobic-anoxic-aerobic continuous moving bed bioreactor (CMBR: R1-R2-R3) and semi-continuous fed batch moving bed bioreactor (FMBR: B1-B2-B3) modes was assessed for phenol shock load (PSL) applications in the presence of thiocyanate and ammonia. Both the systems were exposed to 3000 mg phenol/L (PSL-I) and 3500 mg phenol/L (PSL-II) for 3 days each from initial 2500 mg phenol/L without any intermediate concentration at 6 days HRT (hydraulic retention time). The effect of PSL-I on R1 was reversible within 10-12 days. At PSL-II, R1 required 2 days stop of feed for stability and resumed removal efficiency of phenol (15%) and COD (3%). R2 remained robust to sustain both PSLs and recovered within 15 days from peak influent concentrations of 1727 mg phenol/L (removal: 67%) and 324 mg SCN- /L (removal: 68-70%). In B1, effluent COD increased by 2%, though effluent phenol decreased by 3% than the pre-shock condition after PSL-I exposure. B2 acted similar to R2 when exposed to PSLs. The effect of PSL-I on R3 and B3 was negligible. However, at PSL-II R3 became vulnerable for nitrification, whereas phenol, COD and SCN- removal remained unaffected. In B3, PSL-II caused a decrease in phenol, SCN- and NH+4-N removal. In B3, stop of feed for 4 days also did not improve nitrification. The performance of the CMBR system was better than that of the FMBR system for organic shock load exposure in the presence of multiple pollutants. PMID- 28617188 TI - Molecular Mechanisms Underlying the Inhibitory Effects of Qingzaojiufei Decoction on Tumor Growth in Lewis Lung Carcinoma. AB - OBJECTIVE: Qingzaojiufei decoction (QD) is an empirical herbal formula from traditional Chinese medicine that is used for the treatment of lung-related diseases. However, the effect of QD on the growth of lung tumor cells has not been investigated. The aim of this study was to examine the antitumor activity of QD in Lewis lung carcinomas (LLC) in vivo and in vitro, and to elucidate the underlying mechanisms. METHODS: The LLC cells were used to assess the antitumor activity of QD by Cell Counting Kit-8 assay in vitro. In vivo, mice were randomly assigned to 5 groups (n = 10/group): the model control (MC) group was intragastrically administered physiological saline (0.9% NaCl) twice daily from day 2 after tumor implantation for 2 weeks. The QD groups were intragastrically administered QD twice daily from 2 weeks before to 2 weeks after tumor implantation for 4 weeks. The mRNA levels were detected by quantitative polymerase chain reaction, the proteins expression was determined by immunohistochemistry or western blotting. RESULTS: Compared with the model group, QD showed inhibition of proliferation of LLC cells and reductions in tumor weight and proliferating cell nuclear antigen protein expression. Furthermore, QD up regulated p53 mRNA expression, and downregulated c-myc and Bcl-2 mRNA expression, while MMP-9, VEGF, and VEGFR protein expression was suppressed. Phosphorylated ERK1/2 levels were also reduced by QD in a dose-dependent manner. CONCLUSION: Our findings suggest that QD inhibited lung tumor growth and proliferation, by activation of tumor suppressor genes, inactivation of oncogenes, suppressing the potential for invasion and metastasis, and attenuating angiogenesis. The ERK/VEGF/MMPs signaling pathways may play an important role in QD-induced inhibition of malignant tumor cell proliferation. PMID- 28617190 TI - Experimental and theoretical studies of cadmium ions absorption by a new reduced recombinant defensin. AB - Heavy metal pollutants such as Cd, Hg, Pb, As, and Se are considered as both a global problem and a growing threat to the humanity. Being strongly poisonous to the metal-sensitive enzymes and leading to the growth inhibition and death of organisms, these metals have a toxic impact on the plants and animals. Inducing the metal-binding cysteine-rich peptides such as metallothioneins, phytochelatins, and defensins, higher organisms like plants and animals usually react to the heavy metal stress. In this study, a recombinant defensin protein was expressed in bean and its ability in the cadmium absorption was determined. Experimental studies revealed that this protein was able to absorb cadmium ions in reduced form more than oxide one. Molecular dynamics simulations were carried out in order to evaluation of experimental studies, using a model of Cd2+ or Na+ and Cl- ions enclosed in a fully hydrated simulation box with the recombinant defensin. The theoretical results also suggested that the reduced recombinant defensin was more powerful in the absorption of Cd2+ than its oxide form. The present study is the first report of Cd2+ absorption potential of this new reduced recombinant defensin. The results unraveled that this recombinant defensin can be adopted as a molecular switch in the cadmium pollution of the environment and also the important role of sulfur groups in the absorption of cadmium ions. PMID- 28617191 TI - Operator models for delivering municipal solid waste management services in developing countries: Part B: Decision support. AB - This is the second of two papers reporting the results of a major study considering 'operator models' for municipal solid waste management (MSWM) in emerging and developing countries. Part A documents the evidence base, while Part B presents a four-step decision support system for selecting an appropriate operator model in a particular local situation. Step 1 focuses on understanding local problems and framework conditions; Step 2 on formulating and prioritising local objectives; and Step 3 on assessing capacities and conditions, and thus identifying strengths and weaknesses, which underpin selection of the operator model. Step 4A addresses three generic questions, including public versus private operation, inter-municipal co-operation and integration of services. For steps 1 4A, checklists have been developed as decision support tools. Step 4B helps choose locally appropriate models from an evidence-based set of 42 common operator models ( coms); decision support tools here are a detailed catalogue of the coms, setting out advantages and disadvantages of each, and a decision-making flowchart. The decision-making process is iterative, repeating steps 2-4 as required. The advantages of a more formal process include avoiding pre-selection of a particular com known to and favoured by one decision maker, and also its assistance in identifying the possible weaknesses and aspects to consider in the selection and design of operator models. To make the best of whichever operator models are selected, key issues which need to be addressed include the capacity of the public authority as 'client', management in general and financial management in particular. PMID- 28617192 TI - Emerging biologic therapies for hypercholesterolaemia. AB - INTRODUCTION: LDL-cholesterol (LDL-C) is one of the most well-established risk factors for CV disease. Indeed, therapies that decrease LDL-C are proven to effectively reduce the risk of atherosclerotic CV disease. Monoclonal antibodies (mAbs) that target proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently gained traction as a promising therapeutic strategy. Areas covered: In this review, the authors discuss the effectiveness of mAbs against PCSK9 in lowering low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipid fractions. The discontinuation in the development of bococizumab due to efficacy and safety concerns, and the initial promising data about inclisiran, a long acting small inhibiting RNA molecule against PCSK9 synthesis, is also discussed. Expert opinion: Initial data about cardiovascular (CV) outcomes in large scale, long-term studies suggest a possible further therapeutic pathway for LDL-C reduction, and currently support the notion that further LDL-C reduction, obtained with PCSK9 inhibition on top of best available therapy, provides increased CV protection in subjects at very high CV risk. The development and marketing of mAbs against PCSK9 could help to redefine current therapeutic strategies aimed at reducing cardiovascular (CV) morbidity and risk, through the reduction of LDL-C concentrations. The cost-effectiveness of these emerging drugs is yet to be established. PMID- 28617193 TI - Are Contact Precautions ethically justifiable in contemporary hospital care? AB - : Hospital infection control practices known as Contact Precautions are recommended for the management of people with pathogens such as methicillin resistant Staphylococcus aureus or vancomycin-resistant Enterococci. BACKGROUND: The patient is isolated, and staff are required to wear gloves, and a gown or apron when providing care. A notice is displayed to remind staff of these requirements and an 'alert' message is placed in the patient's medical record. OBJECTIVE: The aim of this article is to discuss and explore whether practices used in hospitals to reduce the transmission of endemic antibiotic-resistant organisms are ethically justified in today's healthcare environment in the developed world. In order to do this, the history of the development of these practices is summarised, and the evidence base for their effectiveness is reviewed. Key bioethics principles are then discussed and contextualised from the perspective of hospital infection prevention and control, and an ethically superior model for the prevention and control of healthcare associated infection is proposed. PMID- 28617194 TI - Impact of online toxicology training on health professionals: the Global Educational Toxicology Uniting Project (GETUP). AB - OBJECTIVE: The Global Educational Toxicology Uniting Project (GETUP), supported by the American College of Medical Toxicology, links countries with and without toxicology services via distance education with the aim to improve education. Due to the lack of toxicology services in some countries there is a knowledge gap in the management of poisonings. We describe our experience with the worldwide delivery of an online introductory toxicology curriculum to emergency doctors and other health professionals treating poisoned patients. METHODS: We delivered a 15 module introductory Internet-based toxicology curriculum to emergency doctors and health professionals, conducted from August to December 2016. This Internet-based curriculum was adapted from one used to teach emergency residents toxicology in the United States. Modules covered themes such as pharmaceutical (n = 8), toxidromes (n = 2) and agrochemicals (n = 5) poisoning. Participants completed pre-test and post-test multiple choice questions (MCQs) before and after completing the online module, respectively, throughout the course. We collected information on participant demographics, education and training, and perception of relevance of the curriculum. Participants gave feedback on the course and how it affected their practice. RESULTS: One hundred and thirty-six health professionals from 33 countries participated in the course: 98 emergency doctors/medical officers, 25 physicians, eight pharmacists/poisons information specialists, two toxicologists, two medical students and one nurse. Median age of participants was 34 years. Median number of years postgraduate was seven. Ninety (65%) had access to either a poisons information centre over the phone or toxicologist and 48 (35%) did not. All participants expected the course to help improve their knowledge. Overall median pre-module MCQ scores were 56% (95%CI: 38, 75%) compared to post-module MCQ scores median 89% (95% CI: 67, 100%) (p < .0001). CONCLUSIONS: Our participants demonstrated an increase in medical knowledge based on performance on MCQs. An online toxicology curriculum is an effective way to deliver education to health professionals treating poisoned patients and can help to bridge the knowledge gap and change practice in developed and developing countries. PMID- 28617195 TI - Light- and clock-control of genes involved in detoxification. AB - Circadian regulation of hepatic detoxification seems to be amongst the key roles of the biological clock. The liver is the major site for biotransformation, and in mammals, it contains several clock-controlled transcription factors such as proline and acidic amino acid-rich basic leucine zipper proteins (PAR bZIP) and basic-helix-loop-helix Per-Arnt-Sim (bHLH-PAS) family that act as circadian regulators of detoxification genes. This investigation explored the existence of daily and circadian expression of transcription factors involved in detoxification, as well as the temporal profile of a set of their target genes in zebrafish liver. In our study, zebrafish were able to synchronize to a light-dark (LD) cycle and displayed a diurnal pattern of activity. In addition, the expression of clock genes presented daily and circadian rhythmicity in liver. Apart from hlfa, the expression of PAR bZIP transcription factors also displayed daily rhythms, which appeared to be both light-dependent and clock-controlled, as circadian rhythms free-ran under constant conditions (continuous darkness, DD). Under LD, tefb, dbpa and dbpb expression peaked at the end of the darkness period whereas tefa showed peak levels of expression at the onset of the photophase. In addition, these four genes exhibited circadian expression under DD, with higher expression levels at the end of the subjective night. The expression of the bHLH PAS transcription factor arh2 also showed circadian rhythmicity in zebrafish liver, peaking in the middle of the subjective night and approximately 3-4 h before peak expression of the PAR bZIP genes. Regarding the detoxification genes, the major target gene of AhR, cyp1a, showed daily and circadian expression with an acrophase 2 h after ahr2. Under LD, abcb4 also showed daily rhythmicity, with an acrophase 1-2 h after that of PAR bZIP factors during the transition between darkness and light phases, when zebrafish become active. However, the expression of six detoxification genes showed circadian rhythmicity under DD, including cyp1a and abcb4 as well as gstr1, mgst3a, abcg2 and sult2_st2. In all cases, the acrophases of these genes were found during the second half of the subjective night, in phase with the PAR bZIP transcription factors. This suggested that their expression is clock-controlled, either directly by core clock genes or through transcription factors. This study presents new data demonstrating that the process of detoxification is under circadian control in fish. Results showed that time of day should be considered when designing toxicological studies or administering drugs to fish. PMID- 28617196 TI - Factors Associated With Having a Physician, Nurse Practitioner, or Physician Assistant as Primary Care Provider for Veterans With Diabetes Mellitus. AB - Expanded use of nurse practitioners (NPs) and physician assistants (PAs) is a potential solution to workforce issues, but little is known about how NPs and PAs can best be used. Our study examines whether medical and social complexity of patients is associated with whether their primary care provider (PCP) type is a physician, NP, or PA. In this national retrospective cohort study, we use 2012 2013 national Veterans Administration (VA) electronic health record data from 374 223 veterans to examine whether PCP type is associated with patient, clinic, and state-level factors representing medical and social complexity, adjusting for all variables simultaneously using a generalized logit model. Results indicate that patients with physician PCPs are modestly more medically complex than those with NP or PA PCPs. For the group having a Diagnostic Cost Group (DCG) score >2.0 compared with the group having DCG <0.5, odds of having an NP or a PA were lower than for having a physician PCP (NP odds ratio [OR] = 0.83, 95% confidence interval [CI]: 0.79-0.88; PA OR = 0.85, CI: 0.80-0.89). Social complexity is not consistently associated with PCP type. Overall, we found minor differences in provider type assignment. This study improves on previous work by using a large national dataset that accurately ascribes the work of NPs and PAs, analyzing at the patient level, analyzing NPs and PAs separately, and addressing social as well as medical complexity. This is a requisite step toward studies that compare patient outcomes by provider type. PMID- 28617198 TI - Thinking about the environment and theorising change: how could Life History Strategy Theory inform mHealth interventions in low- and middle-income countries? AB - BACKGROUND: There is a growing body of literature outlining the promise of mobile information and communication technologies to improve healthcare in resource constrained contexts. METHODS: We reviewed the literature related to mobile information and communication technologies which aim to improve healthcare in resource-constrained contexts, in order to glean general observations regarding the state of mHealth in high-income countries (HIC) and low- and middle-income countries (LMIC). RESULTS: mHealth interventions in LMIC often differ substantively from those in HIC, with the former being simpler, delivered through a single digital component (an SMS as opposed to a mobile phone application, or 'app'), and, as a result, targeting only one of the many factors which impact on the activation (or deactivation) of the target behaviour. Almost as a rule, LMIC mHealth interventions lack an explicit theory of change. CONCLUSION: We highlight the necessity, when designing mHealth interventions, of having a theory of change that encompasses multiple salient perspectives pertaining to human behaviour. To address this need, we explore whether the concept of Life History Strategy could provide the mHealth field with a useful theory of change. Life History Strategy Theory may be particularly useful in understanding some of the problems, paradoxes, and limitations of mHealth interventions found in LMIC. Specifically, this theory illuminates questions regarding 'light-weight' programmes which solely provide information, reminders, and other virtual 'nudges' that may have limited impact on behaviours governed by extrinsic structural factors. PMID- 28617199 TI - An optimal ultrasonographic diagnostic test for early gout: A prospective controlled study. AB - Objective To identify the optimal sites for classification of early gout by ultrasonography. Methods Sixty patients with monosodium urate crystal-proven gout (25 with early gout [<=2-year symptom duration], 35 with late gout [>2-year symptom duration], and 36 normouricemic healthy controls) from one centre were prospectively evaluated. Standardized blinded ultrasound examination of 36 joints and the triceps and patellar tendons was performed to identify tophi and the double contour (DC) sign. Results Ultrasonographic sensitivity was lower in early than late gout. Binary logistic regression analysis showed that two ultrasonographic signs (tophi in the first metatarsophalangeal joint [odds ratio, 16.46] and the DC sign in the ankle [odds ratio, 25.18]) significantly contributed to the final model for early gout diagnosis (sensitivity and specificity of 84% and 81%, respectively). The inter-reader reliability kappa value for the DC sign and tophi was 0.712. Conclusions Four-joint investigation (both first metatarsophalangeal joints for tophi and both ankles for the DC sign) is feasible and reliable and could be proposed as a screening test for early ultrasonographic gout classification in daily practice. PMID- 28617200 TI - Exposure to PFOA and PFOS and fetal growth: a critical merging of toxicological and epidemiological data. AB - : Toxicological and epidemiological evidence on the association between perfluorooctanoic acid (PFOA) or perfluorooctane sulfonic acid (PFOS) and birth/fetal weight was assessed. An extensive search for toxicological information in rats and mice, and a systematic search for epidemiological evidence were conducted. The linear regression coefficient (LRC) of birth weight (BrthW) on PFOA/PFOS was considered, and separate random effects meta-analyses for untransformed (i.e. not mathematically transformed) and log-transformed values were performed. Toxicological evidence: PFOA: 12 studies (21 datasets) in mice showed statistically significant lower birth/fetal weights from 5 mg/kg body weight per day. PFOS: most of the 13 studies (19 datasets) showed lower birth/fetal weights following in utero exposure. Epidemiological evidence: Sixteen articles were considered. The pooled LRC for a 1 ng/mL increase in untransformed PFOA (12 studies) in maternal plasma/serum was -12.8 g (95% CI 23.2; 2.4), and -27.1 g (95% CI -50.6; -3.6) for an increase of 1 loge ng/mL PFOA (nine studies). The pooled LRC for untransformed PFOS (eight studies) was -0.92 g (95%CI -3.4; 1.6), and for an increase of 1 loge ng/mL was -46.1(95% CI -80.3; 11.9). No consistent pattern emerged for study location or timing of blood sampling. CONCLUSIONS: Epidemiological and toxicological evidence suggests that PFOA and PFOS elicit a decrease in BrthW both in humans and rodents. However, the effective animal extrapolated serum concentrations are 102-103 times higher than those in humans. Thus, there is no quantitative toxicological evidence to support the epidemiological association, thus reducing the biological plausibility of a causal relationship. PMID- 28617201 TI - A comprehensive review of regulatory test methods for endocrine adverse health effects. AB - Development of new endocrine disruption-relevant test methods has been the subject of intensive research efforts for the past several decades, prompted in part by mandates in the 1996 Food Quality Protection Act (FQPA). While scientific understanding and test methods have advanced, questions remain on whether current scientific methods are capable of adequately addressing the complexities of the endocrine system for regulatory health and ecological risk assessments. The specific objective of this article is to perform a comprehensive, detailed evaluation of the adequacy of current test methods to inform regulatory risk assessments of whether a substance has the potential to perturb endocrine-related pathways resulting in human adverse effects. To that end, approximately 42 existing test guidelines (TGs) were considered in the evaluation of coverage for endocrine-related adverse effects. In addition to evaluations of whether test methods are adequate to capture endocrine-related effects, considerations of further enhancements to current test methods, along with the need to develop novel test methods to address existing test method gaps are described. From this specific evaluation, up to 35 test methods are capable of informing whether a chemical substance perturbs known endocrine related biological pathways. Based on these findings, it can be concluded that current validated test methods are adequate to discern substances that may perturb the endocrine system, resulting in an adverse health effect. Together, these test methods predominantly form the core data requirements of a typical food-use pesticide registration submission. It is recognized, however, that the current state of science is rapidly advancing and there is a need to update current test methods to include added enhancements to ensure continued coverage and public health and environmental protection. PMID- 28617197 TI - Chronic early life stress induced by limited bedding and nesting (LBN) material in rodents: critical considerations of methodology, outcomes and translational potential. AB - The immediate and long-term effects of exposure to early life stress (ELS) have been documented in humans and animal models. Even relatively brief periods of stress during the first 10 days of life in rodents can impact later behavioral regulation and the vulnerability to develop adult pathologies, in particular an impairment of cognitive functions and neurogenesis, but also modified social, emotional, and conditioned fear responses. The development of preclinical models of ELS exposure allows the examination of mechanisms and testing of therapeutic approaches that are not possible in humans. Here, we describe limited bedding and nesting (LBN) procedures, with models that produce altered maternal behavior ranging from fragmentation of care to maltreatment of infants. The purpose of this paper is to discuss important issues related to the implementation of this chronic ELS procedure and to describe some of the most prominent endpoints and consequences, focusing on areas of convergence between laboratories. Effects on the hypothalamic-pituitary adrenal (HPA) axis, gut axis and metabolism are presented in addition to changes in cognitive and emotional functions. Interestingly, recent data have suggested a strong sex difference in some of the reported consequences of the LBN paradigm, with females being more resilient in general than males. As both the chronic and intermittent variants of the LBN procedure have profound consequences on the offspring with minimal external intervention from the investigator, this model is advantageous ecologically and has a large translational potential. In addition to the direct effect of ELS on neurodevelopmental outcomes, exposure to adverse early environments can also have intergenerational impacts on mental health and function in subsequent generation offspring. Thus, advancing our understanding of the effect of ELS on brain and behavioral development is of critical concern for the health and wellbeing of both the current population, and for generations to come. PMID- 28617202 TI - Hospital Capital Investment During the Great Recession. AB - Hospital capital investment is important for acquiring and maintaining technology and equipment needed to provide health care. Reduction in capital investment by a hospital has negative implications for patient outcomes. Most hospitals rely on debt and internal cash flow to fund capital investment. The great recession may have made it difficult for hospitals to borrow, thus reducing their capital investment. I investigated the impact of the great recession on capital investment made by California hospitals. Modeling how hospital capital investment may have been liquidity constrained during the recession is a novel contribution to the literature. I estimated the model with California Office of Statewide Health Planning and Development data and system generalized method of moments. Findings suggest that not-for-profit and public hospitals were liquidity constrained during the recession. Comparing the changes in hospital capital investment between 2006 and 2009 showed that hospitals used cash flow to increase capital investment by $2.45 million, other things equal. PMID- 28617203 TI - Effects of increased participation on veteran running performance. AB - Contrary to elite performance that is approaching an asymptote, recent analyses suggested a trend for improvement in veterans. This might be attributable to a disproportionate increase in older age-group participation. We extracted 26 years (1987-2012) of men's results of a running event in Switzerland, "La Course de l'Escalade" (7.25 km). We investigated trends in performance by five-year age groups, taking the 10, 20, 30, and 50 fastest in each group, and then the 1st, 5th, and 10th percentiles. Taking the 10, 20, 30 or 50 fastest runners there was a trend for improvement ranging from 0.07 to 0.22 min.year-1 (p < .0001; 95% CI 0.083 to -0.049 and p < .0001; 95% CI -0.250 to -0.196 respectively) in the elder age-groups. Taking the 1st, 5th, and 10th percentiles there were no trends for improvement, and actual deteriorations up to 0.13 (p < .0001; 95% CI +0.119 to +0.138) min.year-1. Mixed-effect models with repeated measures for runners, confirmed a global deteriorating trend with an estimate of +0.11 min.year-1 (p < .0001; 95% CI +0.107 to +0.116). The results suggest that increases in performance in older runners arise from modifications of sampling from a growing population. PMID- 28617204 TI - Is the Clinical High-Risk State a Valid Concept? Retrospective Examination in a First-Episode Psychosis Sample. AB - OBJECTIVE: One reason for worldwide interest in the clinical high-risk (CHR) state for psychosis is its potential as a target for prevention. However, the feasibility and utility of early intervention initiatives that are focused on this stage involve an untested assumption: that most patients with a first episode of psychosis (FEP) experience earlier CHR symptoms. The objective of this study was to identify and characterize the proportion of FEP patients who had experienced such symptoms prior to the onset of their psychosis. METHODS: Semistructured interviews of 351 patients and families with the Circumstances of Onset and Relapse Schedule were supplemented by chart reviews in a catchment area based sample of FEP patients. Information was extracted regarding pathways to care and psychiatric and behavioral changes over time. Experts (N=30) working in FEP and CHR settings identified which of 27 early signs and symptoms constitute attenuated positive or subthreshold psychotic symptoms (APSPS) if they appear prior to a syndromal-level psychotic episode. RESULTS: Nine early signs and symptoms were endorsed by the experts as representing APSPS. More than half of consenting patients, and two-thirds (68%) of those who completed all assessments, had experienced at least one such sign or symptom prior to their FEP. The groups with and without APSPS were similar in social, demographic, and clinical characteristics. CONCLUSIONS: Most consenting patients with an FEP had experienced previous signs and symptoms consistent with a CHR state prior to the onset of threshold-level psychotic symptoms, although a substantial minority had not. This finding validates the viability of the CHR construct as a potential target for early case identification and preventive and therapeutic interventions. PMID- 28617205 TI - Establishing a Research Agenda for Understanding the Role and Impact of Mental Health Peer Specialists. AB - Mental health peer specialists are individuals with serious mental illnesses who receive training to use their lived experiences to help others with serious mental illnesses in clinical settings. This Open Forum discusses the state of the research for mental health peer specialists and suggests a research agenda to advance the field. Studies have suggested that peer specialists vary widely in their roles, settings, and theoretical orientations. Theories of action have been proposed, but none have been tested. Outcome studies have shown benefits of peer specialists; however, many studies have methodological shortcomings. Qualitative descriptions of peer specialists are plentiful but lack grounding in implementation science frameworks. A research agenda advancing the field could include empirically testing theoretical mechanisms of peer specialists, developing a measure of peer specialist fidelity, conducting more rigorous outcomes studies, involving peer specialists in executing the research, and assessing various factors that influence implementing peer specialist services and testing strategies that could address those factors. PMID- 28617206 TI - Utilization Patterns at a Specialized Children's Comprehensive Psychiatric Emergency Program. AB - OBJECTIVE: Most youths experiencing a psychiatric crisis present to emergency departments (EDs) that lack the specialized staff to evaluate them, so youths are often discharged without appropriate mental health assessment or treatment. To better understand the needs of this population, this study described clinical details and disposition associated with visits for psychiatric emergencies to a specialized ED staffed 24/7 by child psychiatrists. METHODS: Through retrospective chart review, 1,180 visits to the ED during its first year of operation were reviewed for clinical characteristics, prior service utilization, and demographic characteristics. Bivariate analyses (chi-square test and Wilcoxon rank sum test) compared differences in disposition (evaluate and release, brief stabilization, and inpatient psychiatric admission) associated with characteristics of the children's first visit (N=885). Measures with bivariate association of p<.10 were further assessed by using multinomial logistic regression analyses. RESULTS: For most visits (59%), children were evaluated and released, 13% were briefly stabilized, and 28% were admitted for psychiatric treatment. Youths with mood or psychotic disorders were more likely to be admitted, as were those with current suicidality or aggression. Many youths who presented with aggression were also identified as having suicidality or self harm. CONCLUSIONS: Clinical factors, especially suicidality, predicted psychiatric admission. Admission rates for youths with suicidality were significantly higher in this study than previously reported, suggesting the availability of child psychiatrists in this ED allowed greater ascertainment of suicide risk (and thus hospitalization to mitigate that risk) than occurs in EDs without such staffing. PMID- 28617207 TI - Development and Validation of a Scale Assessing Mental Health Clinicians' Experiences of Associative Stigma. AB - OBJECTIVE: Mental health professionals who work with people with serious mental illnesses are believed to experience associative stigma. Evidence suggests that associative stigma could play an important role in the erosion of empathy among professionals; however, no validated measure of the construct currently exists. This study examined the convergent and discriminant validity and factor structure of a new scale assessing the associative stigma experiences of clinicians working with people with serious mental illnesses. METHODS: A total of 473 clinicians were recruited from professional associations in the United States and participated in an online study. Participants completed the Clinician Associative Stigma Scale (CASS) and measures of burnout, quality of care, expectations about recovery, and self-efficacy. RESULTS: Associative stigma experiences were commonly endorsed; eight items on the 18-item scale were endorsed as being experienced "sometimes" or "often" by over 50% of the sample. The new measure demonstrated a logical four-factor structure: "negative stereotypes about professional effectiveness," "discomfort with disclosure," "negative stereotypes about people with mental illness," and "stereotypes about professionals' mental health." The measure had good internal consistency. It was significantly related to measures of burnout and quality of care, but it was not related to measures of self-efficacy or expectations about recovery. CONCLUSIONS: Findings suggest that the CASS is internally consistent and shows evidence of convergent validity and that associative stigma is commonly experienced by mental health professionals who work with people with serious mental illnesses. PMID- 28617208 TI - Nurse Practitioner Independent Practice Authority and Mental Health Service Delivery in U.S. Community Health Centers. AB - OBJECTIVE: Little is known about how nurse practitioner independent practice authority (NP-IPA) influences patient care. This study examined the effect of NP IPA on patterns of mental health-related visits provided by NPs in U.S. community health centers (CHCs). METHODS: State NP regulatory information was linked to National Ambulatory Medical Care Survey data on NP- and physician-provided visits (N=61,457) in CHCs from 2006 through 2011. The proportion of NP-provided versus physician-provided mental health-related visits in states with NP-IPA was compared with the proportion in states without NP-IPA. The adjusted odds of mental health-related visits in CHCs provided by NPs in states with and without NP-IPA were compared by using multiple logistic regression models while accounting for the complex survey design. RESULTS: Between 2006 and 2011, the odds of NP- versus physician-provided mental health-related visits in CHCs were more than two times greater in states with NP-IPA than in states with no NP-IPA (adjusted odds ratio [OR]= 2.43, 95% confidence interval [CI]=1.12-4.60). In contrast, no significant difference between states with and without NP-IPA was noted in non-mental health-related CHC visits provided by NPs. Among all mental health-related visits, the odds of visits in which psychotropic medications were prescribed by an NP were more than three times higher in states with NP-IPA than in those without NP-IPA (adjusted OR=3.14, CI=1.50-6.54). CONCLUSIONS: Compared with physicians, NPs provided proportionally more CHC mental health-related visits in states with NP-IPA than in states without NP-IPA. PMID- 28617209 TI - Suicide Risk Assessment and Prevention: A Systematic Review Focusing on Veterans. AB - OBJECTIVE: Suicide rates in veteran and military populations in the United States are high. This article reviews studies of the accuracy of methods to identify individuals at increased risk of suicide and the effectiveness and adverse effects of health care interventions relevant to U.S. veteran and military populations in reducing suicide and suicide attempts. METHODS: Trials, observational studies, and systematic reviews relevant to U.S. veterans and military personnel were identified in searches of MEDLINE, PsycINFO, SocINDEX, and Cochrane databases (January 1, 2008, to September 11, 2015), on Web sites, and in reference lists. Investigators extracted and confirmed data and dual-rated risk of bias for included studies. RESULTS: Nineteen studies evaluated accuracy of risk assessment methods, including models using retrospective electronic records data and clinician- or patient-rated instruments. Most methods demonstrated sensitivity >=80% or area-under-the-curve values >=.70 in single studies, including two studies based on electronic records of veterans and military personnel, but specificity varied. Suicide rates were reduced in six of eight observational studies of population-level interventions. Only two of ten trials of individual-level psychotherapy reported statistically significant differences between treatment and usual care. CONCLUSIONS: Risk assessment methods have been shown to be sensitive predictors of suicide and suicide attempts, but the frequency of false positives limits their clinical utility. Research to refine these methods and examine clinical applications is needed. Studies of suicide prevention interventions are inconclusive; trials of population-level interventions and promising therapies are required to support their clinical use. PMID- 28617211 TI - "Docs vs. Glocks" and the Regulation of Physicians' Speech. AB - Physicians increasingly have recognized the importance of asking patients whether they own firearms and suggesting safe means of storage. Florida's legislature perceived these questions as threats to patients' rights to keep guns and passed a law restricting physicians from making such inquiries. When a number of physicians and their organizations challenged the law in 2011, a six-year odyssey through the courts ensued. In the end, the U.S. 11th Circuit Court of Appeals struck down the statute, recognizing that physicians' free speech rights extend to communications with patients, a decision that may influence other attempts to restrict clinicians' speech. PMID- 28617210 TI - Antipsychotic Medication Use Among Publicly Insured Pregnant Women in the United States. AB - OBJECTIVE: Given the increasing use and broadening of indications for use of antipsychotic medications in the general population, as well as the paucity of information on the safety of this drug class during pregnancy, the study documented patterns of antipsychotic medication use among pregnant women. METHODS: Medicaid Analytic eXtract data (2001-2010) from pregnant women who delivered live-born infants were used. Antipsychotic use at both the class and the individual drug level was defined based on dispensed outpatient prescriptions. Users' characteristics, including mental disorder diagnoses, were described. Temporal trends in use, as well as discontinuation patterns and psychotropic polytherapy, during pregnancy were evaluated. RESULTS: Among 1,522,247 pregnancies, the prevalence of use of second-generation antipsychotics at any time during pregnancy increased threefold, from .4% to 1.3%, over the ten year period, while the use of first-generation antipsychotics remained stable at around .1%. The increased use of second-generation antipsychotics was largely driven by more frequent use among patients with bipolar disorder. Quetiapine and aripiprazole were the most frequently dispensed drugs, and polytherapy with antipsychotics and antidepressants (65.2%), benzodiazepines (24.9%), and other mood stabilizers (22.0%) was common. More than 50% of women receiving an antipsychotic in the three months prior to pregnancy discontinued the drug during pregnancy. CONCLUSIONS: A growing number of pregnant women in Medicaid are exposed to second-generation antipsychotics, frequently in combination with other psychotropic medications. This study highlights the importance of documenting the use and safety of these drugs during pregnancy to inform therapeutic decision making for pregnant women with psychiatric disorders. PMID- 28617212 TI - Leveraging Technology to Address the Quality Chasm in Children's Evidence-Based Psychotherapy. AB - The quality of psychosocial treatment delivery is highly variable in community practice settings, even among well-trained providers. This column discusses the potential to improve patient outcomes by targeting two important quality-of-care indicators through technology: provider fidelity and children's engagement. A case example describes one provider's use of numerous tablet-based activities in the context of evidence-based psychotherapy. Providers and families responded favorably to this approach in a recent feasibility study funded by the National Institute of Mental Health. Further research is needed to determine whether this approach may improve outcomes, quality of care, provider fidelity, and patient engagement in community mental health service settings. PMID- 28617213 TI - Dermoscopy in differentiating palmar syphiloderm from palmar papular psoriasis. AB - Palmar syphiloderm is one of the most common presentations of secondary syphilis and its recognition is of utmost importance in order to promptly identify such a disease and initiate appropriate workup/management. However, the differential diagnosis with palmar papular psoriasis often poses some difficulties, with consequent possible diagnostic errors/delays and prescription of improper therapies. In this report, we underline the role of dermoscopy as a supportive tool to facilitate the non-invasive recognition of palmar syphiloderm and its distinction from palmar papular psoriasis. PMID- 28617214 TI - Clinical Q & A: Translating Therapeutic Temperature Management from Theory to Practice. PMID- 28617215 TI - Theoretical and applied issues regarding autobiographical belief and recollection. PMID- 28617216 TI - The effect of performance-based financing on maternal healthcare use in Burundi: a two-wave pooled cross-sectional analysis. AB - BACKGROUND: Several developing countries, especially in Africa, have implemented performance-based financing (PBF) schemes with the aim of improving healthcare provision. PBF was first implemented in Burundi in 2006 as a pilot programme in three provinces and was rolled out nationwide in 2010. OBJECTIVE: To enrich existing studies on Burundi in three ways. Firstly, by evaluating the effect of PBF on maternal care at primary and hospital levels; secondly, on the possession of maternity logbooks for maternal care records; and thirdly, how the amount of subsidies influences healthcare outputs. DESIGN: We used data from repeated cross sectional surveys in 500 households (intervention group: 225; control group: 275) conducted in 2006 and 2008. A total of 274 women, aged 15-49, who had recently given birth, were interviewed about the use of maternal healthcare and the possession of maternity logbooks. We performed a difference-in-differences analysis using pooled cross-sectional survey data from 2006 and 2008. RESULTS: We found that PBF is associated with an increased institutional deliveries probability of 39.5 percentage points (p < 0.01) - a relative improvement of 81.8%. Institutional deliveries probability increased significantly only at health centre level by 33.6 percentage points (p < 0.01), a relative rise of 80.6%. There is an indication of a positive spillover effect of PBF on the possession of maternity logbooks. We found no PBF effect on the number of antenatal care visits and anti-tetanus immunization. CONCLUSIONS: Our findings suggest that institutional delivery highly improved because it came from a low baseline and its unit payment was relatively high, leading health workers to promote its use. The fact that deliveries mainly increased in health centres and not in hospitals may be explained by the context of how health delivery is organized in Burundi. Health policymakers have to determine the appropriate financial incentives that best influence the improvement of each health service. PMID- 28617217 TI - Quantifying and filtering knowledge generated by literature based discovery. AB - BACKGROUND: Literature based discovery (LBD) automatically infers missed connections between concepts in literature. It is often assumed that LBD generates more information than can be reasonably examined. METHODS: We present a detailed analysis of the quantity of hidden knowledge produced by an LBD system and the effect of various filtering approaches upon this. The investigation of filtering combined with single or multi-step linking term chains is carried out on all articles in PubMed. RESULTS: The evaluation is carried out using both replication of existing discoveries, which provides justification for multi-step linking chain knowledge in specific cases, and using timeslicing, which gives a large scale measure of performance. CONCLUSIONS: While the quantity of hidden knowledge generated by LBD can be vast, we demonstrate that (a) intelligent filtering can greatly reduce the number of hidden knowledge pairs generated, (b) for a specific term, the number of single step connections can be manageable, and PMID- 28617218 TI - Multi-scale visual analysis of time-varying electrocorticography data via clustering of brain regions. AB - BACKGROUND: There exists a need for effective and easy-to-use software tools supporting the analysis of complex Electrocorticography (ECoG) data. Understanding how epileptic seizures develop or identifying diagnostic indicators for neurological diseases require the in-depth analysis of neural activity data from ECoG. Such data is multi-scale and is of high spatio-temporal resolution. Comprehensive analysis of this data should be supported by interactive visual analysis methods that allow a scientist to understand functional patterns at varying levels of granularity and comprehend its time-varying behavior. RESULTS: We introduce a novel multi-scale visual analysis system, ECoG ClusterFlow, for the detailed exploration of ECoG data. Our system detects and visualizes dynamic high-level structures, such as communities, derived from the time-varying connectivity network. The system supports two major views: 1) an overview summarizing the evolution of clusters over time and 2) an electrode view using hierarchical glyph-based design to visualize the propagation of clusters in their spatial, anatomical context. We present case studies that were performed in collaboration with neuroscientists and neurosurgeons using simulated and recorded epileptic seizure data to demonstrate our system's effectiveness. CONCLUSION: ECoG ClusterFlow supports the comparison of spatio-temporal patterns for specific time intervals and allows a user to utilize various clustering algorithms. Neuroscientists can identify the site of seizure genesis and its spatial progression during various the stages of a seizure. Our system serves as a fast and powerful means for the generation of preliminary hypotheses that can be used as a basis for subsequent application of rigorous statistical methods, with the ultimate goal being the clinical treatment of epileptogenic zones. PMID- 28617220 TI - A theorem proving approach for automatically synthesizing visualizations of flow cytometry data. AB - BACKGROUND: Polychromatic flow cytometry is a popular technique that has wide usage in the medical sciences, especially for studying phenotypic properties of cells. The high-dimensionality of data generated by flow cytometry usually makes it difficult to visualize. The naive solution of simply plotting two-dimensional graphs for every combination of observables becomes impractical as the number of dimensions increases. A natural solution is to project the data from the original high dimensional space to a lower dimensional space while approximately preserving the overall relationship between the data points. The expert can then easily visualize and analyze this low-dimensional embedding of the original dataset. RESULTS: This paper describes a new method, SANJAY, for visualizing high dimensional flow cytometry datasets. This technique uses a decision procedure to automatically synthesize two-dimensional and three-dimensional projections of the original high-dimensional data while trying to minimize distortion. We compare SANJAY to the popular multidimensional scaling (MDS) approach for visualization of small data sets drawn from a representative set of benchmarks, and our experiments show that SANJAY produces distortions that are 1.44 to 4.15 times smaller than those caused due to MDS. Our experimental results show that SANJAY also outperforms the Random Projections technique in terms of the distortions in the projections. CONCLUSIONS: We describe a new algorithmic technique that uses a symbolic decision procedure to automatically synthesize low-dimensional projections of flow cytometry data that typically have a high number of dimensions. Our algorithm is the first application, to our knowledge, of using automated theorem proving for automatically generating highly-accurate, low dimensional visualizations of high-dimensional data. PMID- 28617219 TI - Drug repositioning for enzyme modulator based on human metabolite-likeness. AB - BACKGROUND: Recently, the metabolite-likeness of the drug space has emerged and has opened a new possibility for exploring human metabolite-like candidates in drug discovery. However, the applicability of metabolite-likeness in drug discovery has been largely unexplored. Moreover, there are no reports on its applications for the repositioning of drugs to possible enzyme modulators, although enzyme-drug relations could be directly inferred from the similarity relationships between enzyme's metabolites and drugs. METHODS: We constructed a drug-metabolite structural similarity matrix, which contains 1,861 FDA-approved drugs and 1,110 human intermediary metabolites scored with the Tanimoto similarity. To verify the metabolite-likeness measure for drug repositioning, we analyzed 17 known antimetabolite drugs that resemble the innate metabolites of their eleven target enzymes as the gold standard positives. Highly scored drugs were selected as possible modulators of enzymes for their corresponding metabolites. Then, we assessed the performance of metabolite-likeness with a receiver operating characteristic analysis and compared it with other drug-target prediction methods. We set the similarity threshold for drug repositioning candidates of new enzyme modulators based on maximization of the Youden's index. We also carried out literature surveys for supporting the drug repositioning results based on the metabolite-likeness. RESULTS: In this paper, we applied metabolite-likeness to repurpose FDA-approved drugs to disease-associated enzyme modulators that resemble human innate metabolites. All antimetabolite drugs were mapped with their known 11 target enzymes with statistically significant similarity values to the corresponding metabolites. The comparison with other drug-target prediction methods showed the higher performance of metabolite likeness for predicting enzyme modulators. After that, the drugs scored higher than similarity score of 0.654 were selected as possible modulators of enzymes for their corresponding metabolites. In addition, we showed that drug repositioning results of 10 enzymes were concordant with the literature evidence. CONCLUSIONS: This study introduced a method to predict the repositioning of known drugs to possible modulators of disease associated enzymes using human metabolite likeness. We demonstrated that this approach works correctly with known antimetabolite drugs and showed that the proposed method has better performance compared to other drug target prediction methods in terms of enzyme modulators prediction. This study as a proof-of-concept showed how to apply metabolite likeness to drug repositioning as well as potential in further expansion as we acquire more disease associated metabolite-target protein relations. PMID- 28617221 TI - Identification of cancer-specific motifs in mimotope profiles of serum antibody repertoire. AB - BACKGROUND: For fighting cancer, earlier detection is crucial. Circulating auto antibodies produced by the patient's own immune system after exposure to cancer proteins are promising bio-markers for the early detection of cancer. Since an antibody recognizes not the whole antigen but 4-7 critical amino acids within the antigenic determinant (epitope), the whole proteome can be represented by a random peptide phage display library. This opens the possibility to develop an early cancer detection test based on a set of peptide sequences identified by comparing cancer patients' and healthy donors' global peptide profiles of antibody specificities. RESULTS: Due to the enormously large number of peptide sequences contained in global peptide profiles generated by next generation sequencing, the large number of cancer and control sera is required to identify cancer-specific peptides with high degree of statistical significance. To decrease the number of peptides in profiles generated by nextgen sequencing without losing cancer-specific sequences we used for generation of profiles the phage library enriched by panning on the pool of cancer sera. To further decrease the complexity of profiles we used computational methods for transforming a list of peptides constituting the mimotope profiles to the list motifs formed by similar peptide sequences. CONCLUSION: We have shown that the amino-acid order is meaningful in mimotope motifs since they contain significantly more peptides than motifs among peptides where amino-acids are randomly permuted. Also the single sample motifs significantly differ from motifs in peptides drawn from multiple samples. Finally, multiple cancer-specific motifs have been identified. PMID- 28617222 TI - An extensive assessment of network alignment algorithms for comparison of brain connectomes. AB - BACKGROUND: Recently the study of the complex system of connections in neural systems, i.e. the connectome, has gained a central role in neurosciences. The modeling and analysis of connectomes are therefore a growing area. Here we focus on the representation of connectomes by using graph theory formalisms. Macroscopic human brain connectomes are usually derived from neuroimages; the analyzed brains are co-registered in the image domain and brought to a common anatomical space. An atlas is then applied in order to define anatomically meaningful regions that will serve as the nodes of the network - this process is referred to as parcellation. The atlas-based parcellations present some known limitations in cases of early brain development and abnormal anatomy. Consequently, it has been recently proposed to perform atlas-free random brain parcellation into nodes and align brains in the network space instead of the anatomical image space, as a way to deal with the unknown correspondences of the parcels. Such process requires modeling of the brain using graph theory and the subsequent comparison of the structure of graphs. The latter step may be modeled as a network alignment (NA) problem. RESULTS: In this work, we first define the problem formally, then we test six existing state of the art of network aligners on diffusion MRI-derived brain networks. We compare the performances of algorithms by assessing six topological measures. We also evaluated the robustness of algorithms to alterations of the dataset. CONCLUSION: The results confirm that NA algorithms may be applied in cases of atlas-free parcellation for a fully network-driven comparison of connectomes. The analysis shows MAGNA++ is the best global alignment algorithm. The paper presented a new analysis methodology that uses network alignment for validating atlas-free parcellation brain connectomes. The methodology has been experimented on several brain datasets. PMID- 28617223 TI - Coupling effects on turning points of infectious diseases epidemics in scale-free networks. AB - BACKGROUND: Pandemic is a typical spreading phenomenon that can be observed in the human society and is dependent on the structure of the social network. The Susceptible-Infective-Recovered (SIR) model describes spreading phenomena using two spreading factors; contagiousness (beta) and recovery rate (gamma). Some network models are trying to reflect the social network, but the real structure is difficult to uncover. METHODS: We have developed a spreading phenomenon simulator that can input the epidemic parameters and network parameters and performed the experiment of disease propagation. The simulation result was analyzed to construct a new marker VRTP distribution. We also induced the VRTP formula for three of the network mathematical models. RESULTS: We suggest new marker VRTP (value of recovered on turning point) to describe the coupling between the SIR spreading and the Scale-free (SF) network and observe the aspects of the coupling effects with the various of spreading and network parameters. We also derive the analytic formulation of VRTP in the fully mixed model, the configuration model, and the degree-based model respectively in the mathematical function form for the insights on the relationship between experimental simulation and theoretical consideration. CONCLUSIONS: We discover the coupling effect between SIR spreading and SF network through devising novel marker VRTP which reflects the shifting effect and relates to entropy. PMID- 28617224 TI - ENIGMA-Viewer: interactive visualization strategies for conveying effect sizes in meta-analysis. AB - BACKGROUND: Global scale brain research collaborations such as the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium are beginning to collect data in large quantity and to conduct meta-analyses using uniformed protocols. It becomes strategically important that the results can be communicated among brain scientists effectively. Traditional graphs and charts failed to convey the complex shapes of brain structures which are essential to the understanding of the result statistics from the analyses. These problems could be addressed using interactive visualization strategies that can link those statistics with brain structures in order to provide a better interface to understand brain research results. RESULTS: We present ENIGMA-Viewer, an interactive web-based visualization tool for brain scientists to compare statistics such as effect sizes from meta-analysis results on standardized ROIs (regions-of-interest) across multiple studies. The tool incorporates visualization design principles such as focus+context and visual data fusion to enable users to better understand the statistics on brain structures. To demonstrate the usability of the tool, three examples using recent research data are discussed via case studies. CONCLUSIONS: ENIGMA-Viewer supports presentations and communications of brain research results through effective visualization designs. By linking visualizations of both statistics and structures, users can gain more insights into the presented data that are otherwise difficult to obtain. ENIGMA-Viewer is an open-source tool, the source code and sample data are publicly accessible through the NITRC website ( http://www.nitrc.org/projects/enigmaviewer_20 ). The tool can also be directly accessed online ( http://enigma-viewer.org ). PMID- 28617225 TI - A greedy alignment-free distance estimator for phylogenetic inference. AB - BACKGROUND: Alignment-free sequence comparison approaches have been garnering increasing interest in various data- and compute-intensive applications such as phylogenetic inference for large-scale sequences. While k-mer based methods are predominantly used in real applications, the average common substring (ACS) approach is emerging as one of the prominent alignment-free approaches. This ACS approach has been further generalized by some recent work, either greedily or exactly, by allowing a bounded number of mismatches in the common substrings. RESULTS: We present ALFRED-G, a greedy alignment-free distance estimator for phylogenetic tree reconstruction based on the concept of the generalized ACS approach. In this algorithm, we have investigated a new heuristic to efficiently compute the lengths of common strings with mismatches allowed, and have further applied this heuristic to phylogeny reconstruction. Performance evaluation using real sequence datasets shows that our heuristic is able to reconstruct comparable, or even more accurate, phylogenetic tree topologies than the kmacs heuristic algorithm at highly competitive speed. CONCLUSIONS: ALFRED-G is an alignment-free heuristic for evolutionary distance estimation between two biological sequences. This algorithm is implemented in C++ and has been incorporated into our open-source ALFRED software package ( http://alurulab.cc.gatech.edu/phylo ). PMID- 28617226 TI - Contextualization of drug-mediator relations using evidence networks. AB - BACKGROUND: Genomic analysis of drug response can provide unique insights into therapies that can be used to match the "right drug to the right patient." However, the process of discovering such therapeutic insights using genomic data is not straightforward and represents an area of active investigation. EDDY (Evaluation of Differential DependencY), a statistical test to detect differential statistical dependencies, is one method that leverages genomic data to identify differential genetic dependencies. EDDY has been used in conjunction with the Cancer Therapeutics Response Portal (CTRP), a dataset with drug-response measurements for more than 400 small molecules, and RNAseq data of cell lines in the Cancer Cell Line Encyclopedia (CCLE) to find potential drug-mediator pairs. Mediators were identified as genes that showed significant change in genetic statistical dependencies within annotated pathways between drug sensitive and drug non-sensitive cell lines, and the results are presented as a public web portal (EDDY-CTRP). However, the interpretability of drug-mediator pairs currently hinders further exploration of these potentially valuable results. METHODS: In this study, we address this challenge by constructing evidence networks built with protein and drug interactions from the STITCH and STRING interaction databases. STITCH and STRING are sister databases that catalog known and predicted drug-protein interactions and protein-protein interactions, respectively. Using these two databases, we have developed a method to construct evidence networks to "explain" the relation between a drug and a mediator. RESULTS: We applied this approach to drug-mediator relations discovered in EDDY CTRP analysis and identified evidence networks for ~70% of drug-mediator pairs where most mediators were not known direct targets for the drug. Constructed evidence networks enable researchers to contextualize the drug-mediator pair with current research and knowledge. Using evidence networks, we were able to improve the interpretability of the EDDY-CTRP results by linking the drugs and mediators with genes associated with both the drug and the mediator. CONCLUSION: We anticipate that these evidence networks will help inform EDDY-CTRP results and enhance the generation of important insights to drug sensitivity that will lead to improved precision medicine applications. PMID- 28617227 TI - In silico re-identification of properties of drug target proteins. AB - BACKGROUND: Computational approaches in the identification of drug targets are expected to reduce time and effort in drug development. Advances in genomics and proteomics provide the opportunity to uncover properties of druggable genomes. Although several studies have been conducted for distinguishing drug targets from non-drug targets, they mainly focus on the sequences and functional roles of proteins. Many other properties of proteins have not been fully investigated. METHODS: Using the DrugBank (version 3.0) database containing nearly 6,816 drug entries including 760 FDA-approved drugs and 1822 of their targets and human UniProt/Swiss-Prot databases, we defined 1578 non-redundant drug target and 17,575 non-drug target proteins. To select these non-redundant protein datasets, we built four datasets (A, B, C, and D) by considering clustering of paralogous proteins. RESULTS: We first reassessed the widely used properties of drug target proteins. We confirmed and extended that drug target proteins (1) are likely to have more hydrophobic, less polar, less PEST sequences, and more signal peptide sequences higher and (2) are more involved in enzyme catalysis, oxidation and reduction in cellular respiration, and operational genes. In this study, we proposed new properties (essentiality, expression pattern, PTMs, and solvent accessibility) for effectively identifying drug target proteins. We found that (1) drug targetability and protein essentiality are decoupled, (2) druggability of proteins has high expression level and tissue specificity, and (3) functional post-translational modification residues are enriched in drug target proteins. In addition, to predict the drug targetability of proteins, we exploited two machine learning methods (Support Vector Machine and Random Forest). When we predicted drug targets by combining previously known protein properties and proposed new properties, an F-score of 0.8307 was obtained. CONCLUSIONS: When the newly proposed properties are integrated, the prediction performance is improved and these properties are related to drug targets. We believe that our study will provide a new aspect in inferring drug-target interactions. PMID- 28617228 TI - Prediction models for drug-induced hepatotoxicity by using weighted molecular fingerprints. AB - BACKGROUND: Drug-induced liver injury (DILI) is a critical issue in drug development because DILI causes failures in clinical trials and the withdrawal of approved drugs from the market. There have been many attempts to predict the risk of DILI based on in vivo and in silico identification of hepatotoxic compounds. In the current study, we propose the in silico prediction model predicting DILI using weighted molecular fingerprints. RESULTS: In this study, we used 881 bits of molecular fingerprint and used as features describing presence or absence of each substructure of compounds. Then, the Bayesian probability of each substructure was calculated and labeled (positive or negative for DILI), and a weighted fingerprint was determined from the ratio of DILI-positive to DILI negative probability values. Using weighted fingerprint features, the prediction models were trained and evaluated with the Random Forest (RF) and Support Vector Machine (SVM) algorithms. The constructed models yielded accuracies of 73.8% and 72.6%, AUCs of 0.791 and 0.768 in cross-validation. In independent tests, models achieved accuracies of 60.1% and 61.1% for RF and SVM, respectively. The results validated that weighted features helped increase overall performance of prediction models. The constructed models were further applied to the prediction of natural compounds in herbs to identify DILI potential, and 13,996 unique herbal compounds were predicted as DILI-positive with the SVM model. CONCLUSIONS: The prediction models with weighted features increased the performance compared to non-weighted models. Moreover, we predicted the DILI potential of herbs with the best performed model, and the prediction results suggest that many herbal compounds could have potential to be DILI. We can thus infer that taking natural products without detailed references about the relevant pathways may be dangerous. Considering the frequency of use of compounds in natural herbs and their increased application in drug development, DILI labeling would be very important. PMID- 28617229 TI - Analyzing the field of bioinformatics with the multi-faceted topic modeling technique. AB - BACKGROUND: Bioinformatics is an interdisciplinary field at the intersection of molecular biology and computing technology. To characterize the field as convergent domain, researchers have used bibliometrics, augmented with text mining techniques for content analysis. In previous studies, Latent Dirichlet Allocation (LDA) was the most representative topic modeling technique for identifying topic structure of subject areas. However, as opposed to revealing the topic structure in relation to metadata such as authors, publication date, and journals, LDA only displays the simple topic structure. METHODS: In this paper, we adopt the Tang et al.'s Author-Conference-Topic (ACT) model to study the field of bioinformatics from the perspective of keyphrases, authors, and journals. The ACT model is capable of incorporating the paper, author, and conference into the topic distribution simultaneously. To obtain more meaningful results, we use journals and keyphrases instead of conferences and bag-of-words.. For analysis, we use PubMed to collected forty-six bioinformatics journals from the MEDLINE database. We conducted time series topic analysis over four periods from 1996 to 2015 to further examine the interdisciplinary nature of bioinformatics. RESULTS: We analyze the ACT Model results in each period. Additionally, for further integrated analysis, we conduct a time series analysis among the top-ranked keyphrases, journals, and authors according to their frequency. We also examine the patterns in the top journals by simultaneously identifying the topical probability in each period, as well as the top authors and keyphrases. The results indicate that in recent years diversified topics have become more prevalent and convergent topics have become more clearly represented. CONCLUSION: The results of our analysis implies that overtime the field of bioinformatics becomes more interdisciplinary where there is a steady increase in peripheral fields such as conceptual, mathematical, and system biology. These results are confirmed by integrated analysis of topic distribution as well as top ranked keyphrases, authors, and journals. PMID- 28617230 TI - Predicting anatomic therapeutic chemical classification codes using tiered learning. AB - BACKGROUND: The low success rate and high cost of drug discovery requires the development of new paradigms to identify molecules of therapeutic value. The Anatomical Therapeutic Chemical (ATC) Code System is a World Health Organization (WHO) proposed classification that assigns multi-level codes to compounds based on their therapeutic, pharmacological and chemical characteristics as well as the in-vivo sites(s) of activity. The ability to predict ATC codes of compounds can assist in creation of high-quality chemical libraries for drug screening and in applications such as drug repositioning. We propose a machine learning architecture called tiered learning for prediction of ATC codes that relies on the prediction results of the higher levels of the ATC code to simplify the predictions of the lower levels. RESULTS: The proposed approach was validated using a number of compounds in both cross-validation and test setting. The validation experiments compared chemical descriptors, initialization methods and classification algorithms. The prediction accuracy obtained with tiered learning was found to be either comparable or better than that of established methods. Additionally, the experiments demonstrated the generalizability of the tiered learning architecture, in that its use was found to improve prediction rates for a majority of machine learning algorithms when compared to their stand-alone application. CONCLUSION: The basis of our approach lies in the observation that anatomical-therapeutic biological activity of certain types typically precludes activities of many other types. Thus, there exists a characteristic distribution of the ATC codes, which can be leveraged to limit the search-space of possible codes that can be ascribed at a particular level once the codes at the preceding levels are known. Tiered learning utilizes this observation to constrain the learning space for ATC codes at a particular level based on the ATC code at higher levels. This simplifies the prediction and allows for improved accuracy. PMID- 28617231 TI - ATria: a novel centrality algorithm applied to biological networks. AB - BACKGROUND: The notion of centrality is used to identify "important" nodes in social networks. Importance of nodes is not well-defined, and many different notions exist in the literature. The challenge of defining centrality in meaningful ways when network edges can be positively or negatively weighted has not been adequately addressed in the literature. Existing centrality algorithms also have a second shortcoming, i.e., the list of the most central nodes are often clustered in a specific region of the network and are not well represented across the network. METHODS: We address both by proposing Ablatio Triadum (ATria), an iterative centrality algorithm that uses the concept of "payoffs" from economic theory. RESULTS: We compare our algorithm with other known centrality algorithms and demonstrate how ATria overcomes several of their shortcomings. We demonstrate the applicability of our algorithm to synthetic networks as well as biological networks including bacterial co-occurrence networks, sometimes referred to as microbial social networks. CONCLUSIONS: We show evidence that ATria identifies three different kinds of "important" nodes in microbial social networks with different potential roles in the community. PMID- 28617233 TI - Demystifying the Publication Process. PMID- 28617232 TI - TIGERi: modeling and visualizing the responses to perturbation of a transcription factor network. AB - BACKGROUND: Transcription factor (TF) networks play a key role in controlling the transfer of genetic information from gene to mRNA. Much progress has been made on understanding and reverse-engineering TF network topologies using a range of experimental and theoretical methodologies. Less work has focused on using these models to examine how TF networks respond to changes in the cellular environment. METHODS: In this paper, we have developed a simple, pragmatic methodology, TIGERi (Transcription-factor-activity Illustrator for Global Explanation of Regulatory interaction), to model the response of an inferred TF network to changes in cellular environment. The methodology was tested using publicly available data comparing gene expression profiles of a mouse p38alpha (Mapk14) knock-out line to the original wild-type. RESULTS: Using the model, we have examined changes in the TF network resulting from the presence or absence of p38alpha. A part of this network was confirmed by experimental work in the original paper. Additional relationships were identified by our analysis, for example between p38alpha and HNF3, and between p38alpha and SOX9, and these are strongly supported by published evidence. FXR and MYC were also discovered in our analysis as two novel links of p38alpha. To provide a computational methodology to the biomedical communities that has more user-friendly interface, we also developed a standalone GUI (graphical user interface) software for TIGERi and it is freely available at https://github.com/namshik/tigeri/ . CONCLUSIONS: We therefore believe that our computational approach can identify new members of networks and new interactions between members that are supported by published data but have not been integrated into the existing network models. Moreover, ones who want to analyze their own data with TIGERi could use the software without any command line experience. This work could therefore accelerate researches in transcriptional gene regulation in higher eukaryotes. PMID- 28617234 TI - The Sociopolitical Context of Canada's National Standard for Psychological Health and Safety in the Workplace: Navigating Policy Implementation. AB - In January 2013, Canada introduced the National Standard for Psychological Health and Safety in the Workplace. This paper describes how the standard, which is the first of its kind internationally, came to be the instrument of choice within the current Canadian sociopolitical climate. A key consideration was that the policy tool had to be packaged in a manner that would be accessible and relevant across all workplaces and across all provinces and territories. This paper explores possibilities for future regulation of the standard. PMID- 28617235 TI - What Do We Know and Not Know about the Professional Integration of International Medical Graduates (IMGs) in Canada? AB - BACKGROUND: The literature on international medical graduates (IMGs) in Canada is growing, but there is a lack of systematic analysis of the literature. OBJECTIVES: To examine (1) the major themes in academic and grey literature pertaining to professional integration of IMGs in Canada; and (2) the gaps in our knowledge on integration of IMGs. METHODS: This paper is based on the scoping review of academic and grey literature published during 2001-2013 about IMGs in Canada. RESULTS: The literature on IMGs focuses on (1) pre-immigration activities; (2) early-arrival activities; (3) credential recognition/professional recertification; (4) bridging and residency training; (5) workplace integration; and (6) alternative paths to integration. The gaps in the literature include pre immigration and early-arrival activities, and alternative paths for integration for those IMGs who do not pursue medical license. CONCLUSION: Pre-immigration and early-arrival activities and alternative career paths for IMGs should be addressed in academic and policy research. PMID- 28617236 TI - Retention Patterns of Canadians Who Studied Medicine Abroad and Other International Medical Graduates. AB - OBJECTIVES: Are Canadians who study abroad (CSAs) more likely to stay in Canada than other international medical graduates (IMGs)? We looked at retention patterns of CSAs and immigrant IMGs who completed post-graduate medical education (PGME) training in Canada to describe the proportion and predictors of those working in Canada and in rural communities in Canada in 2015. METHODS: We linked the National IMG Database to Scott's Medical Database to track the work locations of CSAs and immigrant IMGs in 2015. RESULTS: Of the 1,214 IMGs who entered PGME training in Canada between 2005 and 2011, most were working in Canada in 2015 (88.0%). Relatively few IMGs worked in rural communities (9.1%). There were no differences in work location patterns of CSAs and immigrant IMGs. CONCLUSION: Contrary to what CSA advocates suggest, CSAs have the same retention patterns as immigrant IMGs. PGME admission policies should treat all IMGs in the same manner, regardless of their citizenship or residency before medical school. PMID- 28617237 TI - Reforming Refugee Healthcare in Canada: Exploring the Use of Policy Tools. AB - Refugee healthcare in Canada has been a controversial and heavily debated topic over the past several years. In this paper, we present a policy analysis of the 2012 Canadian federal government decision to change the criteria and funding of the Interim Federal Health Program (IFHP). The IFHP provides federally funded healthcare coverage for refugees until they gain access to provincially funded health insurance. The paper offers a policy perspective on the changes to refugee health coverage over time. We draw on the policy concepts of agenda setting, framing, venues and causal stories to explore this topic. We suggest that these concepts represent a set of tools for both researchers and laypersons to critically appraise any issue on the policy agenda, and understand how certain topics become policy issues and why they are "solved" in particular ways. PMID- 28617238 TI - Public Health Policy in Support of Insurance Coverage for Smoking Cessation Treatments. AB - Insurance coverage for evidence-based smoking cessation treatments (SCTs) promotes uptake and reduces smoking rates. Published studies in this area are based in the US where employers are the primary source of health insurance. In Ontario, Canada, publicly funded healthcare does not cover SCTs, but it can be supplemented with employer-sponsored benefit plans. This study explores factors affecting the inclusion/exclusion of smoking cessation (SC) benefits. In total, 17 interviews were conducted with eight employers (auto, retail, banking, municipal and university industries), four health insurers, two government representatives and three advisors/consultants. Overall, SCT coverage varied among industries; it was inconsistently restrictive and SCT differed by coverage amount and length of use. Barriers impeding coverage included the lack of the following: Canadian-specific return on investment (ROI), SC cost information, employer demand, government regulations/incentives and employee awareness of and demand. A Canadian evidence-based calculation of ROI for SC coupled with government incentives and public education may be needed to promote uptake of SCT coverage by employers. PMID- 28617239 TI - Bifurcation of Health Policy Regimes: A Study of Sleep Apnea Care and Benefits Coverage in Saskatchewan. AB - BACKGROUND: A complex, poorly understood bifurcated health policy regime exists for Canada's First Nations people for extended health benefits coverage. This research adds to a small body of literature on the regime's impact on access and quality of care and its role in perpetuating health inequities in First Nations populations. METHODS: Using a case study of sleep apnea care in Saskatchewan, we identified issues of health service access and coverage through a literature review of extended benefits programs, legislation and policies and through 10 key informant interviews with federal and provincial extended benefit program administrators and sleep medicine physicians. RESULTS: Important access and coverage differences were found for First Nations populations, many of which were recognized by federal and provincial policy makers. Despite these, government respondents recommended few policy ameliorations, perhaps due to system complexities, constitutional constraints or political sensitivities. CONCLUSIONS: We suggest three policy options to ameliorate current hardships wrought by this policy bifurcation. PMID- 28617240 TI - What carcinoembryonic antigen level should trigger further investigation during colorectal cancer follow-up? A systematic review and secondary analysis of a randomised controlled trial. AB - BACKGROUND: Following primary surgical and adjuvant treatment for colorectal cancer, many patients are routinely followed up with blood carcinoembryonic antigen (CEA) testing. OBJECTIVE: To determine how the CEA test result should be interpreted to inform the decision to undertake further investigation to detect treatable recurrences. DESIGN: Two studies were conducted: (1) a Cochrane review of existing studies describing the diagnostic accuracy of blood CEA testing for detecting colorectal recurrence; and (2) a secondary analysis of data from the two arms of the FACS (Follow-up After Colorectal Surgery) trial in which CEA testing was carried out. SETTING AND PARTICIPANTS: The secondary analysis was based on data from 582 patients recruited into the FACS trial between 2003 and 2009 from 39 NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence and followed up for 5 years. CEA testing was undertaken in general practice. RESULTS: In the systematic review we identified 52 studies for meta-analysis, including in aggregate 9717 participants (median study sample size 139, interquartile range 72-247). Pooled sensitivity at the most commonly recommended threshold in national guidelines of 5 ug/l was 71% [95% confidence interval (CI) 64% to 76%] and specificity was 88% (95% CI 84% to 92%). In the secondary analysis of FACS data, the diagnostic accuracy of a single CEA test was less than was suggested by the review [area under the receiver operating characteristic curve (AUC) 0.74, 95% CI 0.68 to 0.80]. At the commonly recommended threshold of 5 ug/l, sensitivity was estimated as 50.0% (95% CI 40.1% to 59.9%) and lead time as about 3 months. About four in 10 patients without a recurrence will have at least one false alarm and six out of 10 tests will be false alarms (some patients will have multiple false alarms, particularly smokers). Making decisions to further investigate based on the trend in serial CEA measurements is better (AUC for positive trend 0.85, 95% CI 0.78 to 0.91), but to maintain approximately 70% sensitivity with 90% specificity it is necessary to increase the frequency of testing in year 1 and to apply a reducing threshold for investigation as measurements accrue. LIMITATIONS: The reference standards were imperfect and the main analysis was subject to work-up bias and had limited statistical precision and no external validation. CONCLUSIONS: The results suggest that (1) CEA testing should not be used alone as a triage test; (2) in year 1, testing frequency should be increased (to monthly for 3 months and then every 2 months); (3) the threshold for investigating a single test result should be raised to 10 ug/l; (4) after the second CEA test, decisions to investigate further should be made on the basis of the trend in CEA levels; (5) the optimal threshold for investigating the CEA trend falls over time; and (6) continuing smokers should not be monitored with CEA testing. Further research is needed to explore the operational feasibility of monitoring the trend in CEA levels and to externally validate the proposed thresholds for further investigation. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015019327 and Current Controlled Trials ISRCTN93652154. FUNDING: The main FACS trial and this substudy were funded by the National Institute for Health Research Health Technology Assessment programme. PMID- 28617241 TI - Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. AB - The turnover of endoplasmic reticulum (ER) ensures the correct biological activity of its distinct domains. In mammalian cells, the ER is degraded via a selective autophagy pathway (ER-phagy), mediated by two specific receptors: FAM134B, responsible for the turnover of ER sheets and SEC62 that regulates ER recovery following stress. Here, we identified reticulon 3 (RTN3) as a specific receptor for the degradation of ER tubules. Oligomerization of the long isoform of RTN3 is sufficient to trigger fragmentation of ER tubules. The long N-terminal region of RTN3 contains several newly identified LC3-interacting regions (LIR). Binding to LC3s/GABARAPs is essential for the fragmentation of ER tubules and their delivery to lysosomes. RTN3-mediated ER-phagy requires conventional autophagy components, but is independent of FAM134B. None of the other reticulon family members have the ability to induce fragmentation of ER tubules during starvation. Therefore, we assign a unique function to RTN3 during autophagy. PMID- 28617243 TI - Fingertip Capillary Malformation and Associated Disorders: Report of 9 Cases. AB - Although capillary malformations (CMs) are not usually serious health problems in themselves, they can occasionally be warning signs for syndromes with more serious or aggressive vascular malformations not readily apparent at birth or on initial examination. We describe a series of 9 patients with a common phenotype: (1) CM on the fingertips; (2) associated combined vascular (lymphatic-venous) malformations on the trunk and/or extremities; and (3) in some cases, partial overgrowth and asymmetry of the extremities. Data were collected retrospectively for patients with CM on the fingertips who were treated at 2 Vascular Anomalies Centers from January 2006 to January 2016. All the patients presented CM and other associated vascular abnormalities from birth. CMs were centripetal in their distribution. The greater the centripetal progression of the CM, the greater the associated vascular malformation observed. Some patients also presented varying degrees of overgrowth and asymmetry. At present, we have not found a patient with CM of the fingertip without associated anomalies. In conclusion, we present a series of patients with a particular morphology of CM located on the fingertips. All cases were associated with lymphatic-venous malformations at other sites. These data lead us to recommend these patients be referred from birth to a multidisciplinary unit of vascular anomalies. PMID- 28617242 TI - A subset of ipRGCs regulates both maturation of the circadian clock and segregation of retinogeniculate projections in mice. AB - The visual system consists of two major subsystems, image-forming circuits that drive conscious vision and non-image-forming circuits for behaviors such as circadian photoentrainment. While historically considered non-overlapping, recent evidence has uncovered crosstalk between these subsystems. Here, we investigated shared developmental mechanisms. We revealed an unprecedented role for light in the maturation of the circadian clock and discovered that intrinsically photosensitive retinal ganglion cells (ipRGCs) are critical for this refinement process. In addition, ipRGCs regulate retinal waves independent of light, and developmental ablation of a subset of ipRGCs disrupts eye-specific segregation of retinogeniculate projections. Specifically, a subset of ipRGCs, comprising ~200 cells and which project intraretinally and to circadian centers in the brain, are sufficient to mediate both of these developmental processes. Thus, this subset of ipRGCs constitute a shared node in the neural networks that mediate light dependent maturation of the circadian clock and light-independent refinement of retinogeniculate projections. PMID- 28617244 TI - Continuity of Care in Infancy and Early Childhood Health Outcomes. AB - BACKGROUND AND OBJECTIVES: Continuity of care is a key aspect of the patient centered medical home and improves pediatric outcomes. Health care reform requires high-quality data to demonstrate its continued value. We hypothesized that increased provider continuity in infancy will reduce urgent health care use and increase receipt of preventive services in early childhood. METHODS: Continuity, using the Usual Provider of Care measure, was calculated across all primary care encounters during the first year of life in a prospectively constructed cohort of 17 773 infants receiving primary care from birth through 3 years at 30 clinics. Health care utilization and preventive care outcomes were measured from ages 1 to 3 years. Confounders, including chronic conditions, number of sick visits in the first year, socioeconomic status, and site, were addressed by using multivariable regression models incorporating a propensity score. RESULTS: Demographics associated with the lowest continuity quartile included white race (adjusted odds ratio [aOR] 1.43; 95% confidence interval [CI] 1.25-1.64), Medicaid insurance (aOR 1.41; 95% CI 1.23-1.61), and asthma (aOR 1.59; 95% CI 1.30-1.93). Lower continuity was associated with more ambulatory care-sensitive hospitalizations (adjusted incidence rate ratio 2.74; 95% CI 1.49 5.03), ambulatory sick visits (adjusted incidence rate ratio 1.08; 95% CI 1.05 1.11), and lower odds of lead screening (aOR 0.61; 95% CI 0.46-0.79). These associations were stronger for children with chronic conditions. Continuity measured during well visits was not associated with outcomes. CONCLUSIONS: Continuity may improve care quality and prevent high-cost health encounters, especially for children with chronic conditions. Novel solutions are needed to improve continuity in the medical home. PMID- 28617245 TI - Efficient mixed-solvent exfoliation of few-quintuple layer Bi2S3 and its photoelectric response. AB - A scalable liquid exfoliation of layered Bi2S3 employing a mixed-solvent strategy was used for the fabrication of Bi2S3 nanosheets. We found that 10% deionized water in 90% isopropyl alcohol is the best mixed solvent for the efficient and effective exfoliation of layered Bi2S3. These results are consistent with the absorbance spectra and enthalpy of mixing theory. The obtained Bi2S3 nanosheets had few-quintuple layers and were investigated by transmission electron microscopy, atomic force microscopy, and Raman spectroscopy. These Bi2S3 nanosheets can be used to fabricate large-scale thin films by filtration method; the films demonstrated sensitive photoelectric response with the rise and decay response of photocurrent on the sub-second scale under visible light excitation. The electronic structures of bulk and one-quintuple layer Bi2S3 are calculated by first-principle calculation for better understanding of the photoelectric response. A green mixed-solvent processing of Bi2S3 opens up the potential application of Bi2S3 optoelectric films to photoelectric detection and solar energy conversion devices. PMID- 28617246 TI - Nanostructured as-deposited indium tin oxide thin films for broadband antireflection and light trapping. AB - Indium tin oxide (ITO) thin films were sputter-deposited at ambient temperature on a glass-like substrate that was periodically nanostructured by UV nanoimprint lithography. Cross gratings of the corrugated and conformal ITO, with different periods and modulation depths, were tailored to exhibit light trapping or antireflection properties at specific spectral windows by combined optical simulations and experiments. For dense gratings, the light transmission in the 450-850 nm range was enhanced by 8% (absolute) compared to flat ITO films, which is one of the largest performance improvements reported in the literature for nanostructured transparent electrodes. Increasing the grating period shifts the threshold for diffraction coupling to waveguide modes in the visible and near infrared part of the spectrum, resulting in broad light trapping behaviour at wavelengths below this threshold. This work demonstrates a simple processing route at ambient temperature for the fabrication of high-performance transparent electrodes in order to fulfil different device requirements. PMID- 28617247 TI - Uniquely confining Cu2S nanoparticles in graphitized carbon fibers for enhanced oxygen evolution reaction. AB - Up to now, the literature on Cu2S with specific morphology applied to oxygen evolution reaction (OER) in the electrocatalytic field has been limited. In this work, unique peapod-like Cu2S/C exhibiting superb electrocatalytic performance toward OER is successfully synthesized, by employing Cu(OH)2 nanorods as the template and nontoxic glucose as the carbon source and then annealing with sublimed sulfur. It can be seen that this work explores a new application area for Cu2S. More precisely, the novel morphology contributes to increasing the electrochemical active surface area effectively and promoting contact between the Cu2S nanoparticles and the electrolyte. During electrochemical measurements, the peapod-like Cu2S/C shows enhanced electrocatalytic activity with a low overpotential of 401 mV at the current density of 10 mA cm-2 and a Tafel slope of 52 mV dec-1. More importantly, our material is able to maintain stability for at least 8 h at constant potential and the current loss is negligible after 2000 cycles. Obviously, these striking properties fully demonstrate that the peapod like Cu2S/C as an efficient catalyst shows great promise for OER. PMID- 28617248 TI - Young's modulus and indirect morphological analysis of Bi2Se3 nanoribbons by resonance measurements. AB - An electrostatically induced resonance behaviour of individual topological insulator Bi2Se3 nanoribbons grown by a catalyst free vapour-solid synthesis was studied in situ by scanning electron microscopy. It was demonstrated that the relation between the resonant frequencies of vibrations in orthogonal planes can be applied to distinguish the nanoribbons with rectangular cross-sections from the nanoribbons having step-like morphology (terraces). The average Young's modulus of the Bi2Se3 nanoribbons with rectangular cross-sections was found to be 44 +/- 4 GPa. PMID- 28617249 TI - In situ biosynthesis of ultrafine metal nanoparticles within a metal-organic framework for efficient heterogeneous catalysis. AB - The synthesis of ultrafine, uniform, well-dispersed functional nanoparticles (NPs) under mild conditions in a controlled manner remains a great challenge. In biological systems, a well-defined biomineralization process is exploited, in which the control over NPs' size, shape and distribution is temporally and spatially regulated by a variety of biomolecules in a confined space. Inspired by this, we embedded proteins into metal-organic frameworks (MOFs) and explored a novel approach to synthesize metallic NPs by taking the synergy of protein induced biomineralization process and space-confined effect of MOFs. The generation and growth of ultrafine metal NPs (Ag or Au) was induced by the entrapped lysozyme molecules and confined by the ZIF-8 pores. Due to the narrow size distribution and homogeneous spatial distribution of metal NPs, the as synthesized NPs exhibit remarkably elevated catalytic activity. These findings demonstrate that MOFs can be loaded with specific proteins to selectively deposit inorganic NPs via biomimetic mineralization and these novel kinds of nanohybrid materials may find applications in catalysis, sensing and optics. PMID- 28617250 TI - Confinement of carbon nanotube enabled multi-strand helices of polyacetylenes. AB - Molecular dynamics simulations demonstrate that several polyacetylene (PA) chains can encapsulate and self-assemble into multi-stranded helical structures in confined inner space of carbon nanotubes (SWCNTs). The driving van der Waals force and curvature provided by the tube wall enable polymers to bend and spiral to maximize the pi-pi stacking area with the tube wall when filling the inside of the SWCNT. Structural forms and knitting patterns of multiple helices are influenced by the combined effect of the tube space, the number of PA chains and the temperature. The knitting pattern of a six-helix is unique and a knitted six helix can exist steadily after removing the SWCNT while a two- to five-helix will recover intrinsic straight configurations. PMID- 28617251 TI - On transparency in health care guidelines. Editorial. PMID- 28617252 TI - Patient-physician alliance: from Hippocrates to Post-Genomic Era. Commentary. AB - Patients need clinical competence, appropriate diagnosis and therapies in overcoming their disease. Yet this is insufficient. The illness experience tends to frighten people and the resulting emotional aspects could become relevant factors in coping with a sickness and disability. Hippocrates was the first to urge physicians to look beyond the physical features of diseases and to consider the patient as a unique psychosomatic entity. Additionally, the scientist spurred physicians to make the patient an active participant in combating the disease. According to Hippocrates, "the Medical Art has three actors: the physician, the patients and the disease. The physician and the patient must be allied against the disease in order to fight it". In the "Post-Genomic Era", an effective therapeutic approach merits a patient-physician participation, based on scientific understandings and human considerations. These recommendations are even more urgent for Rare Diseases. PMID- 28617253 TI - The emerging role of the human bone marrow as a privileged developmental niche for the transmission stages of the malaria parasite Plasmodium falciparum. Commentary. AB - The spread of malaria relies on the ability of the Plasmodium parasites to be transmitted from infected individuals to the Anopheles mosquito vectors. Recent work on the most lethal of the malaria parasites, Plasmodium falciparum, identified the infected human bone marrow as a preferential site for the localization and maturation of the parasite transmission stages, the gametocytes. These findings unveil a complex host parasite interplay and an unsuspected role of the bone marrow microenvironment in the successful transmission of the malaria parasite and have major implications in developing and targeting future interventions to block the transmission of P. falciparum. PMID- 28617254 TI - Pertussis in infants and the resurgence of a vaccine preventable disease: what to do? Commentary. AB - Pertussis or whooping cough remains one of the most poorly controlled vaccine preventable diseases across the world. Universal vaccination has dramatically reduced its incidence but has failed to bring it completely under control. In the last decades, changes in pertussis epidemiology have been noted, likely related to the introduction of acellular pertussis vaccines. Increasing incidence is recorded among adolescents and adults who have become a reservoir for transmission to unimmunized infants, who are at risk of severe disease and death. In Italy, experimental evidences suggest a sustained circulation of Bordetella pertussis in the adult population and a significant health burden of pertussis among infants less than six months of age. Public health systems are currently exploring new vaccination strategies, including a cocooning strategy to prevent the transmission of the disease from family members to the newborn and vaccination of pregnant mothers to transmit protective antibodies to the offspring, and neonatal vaccination. An integrated approach for pertussis control and prevention is needed to enhance the current surveillance system and provide an accurate estimate of the real burden of pertussis in our Country, particularly among infants. PMID- 28617255 TI - A harmonized and efficient clinical research environment would benefit patients and enhance European competitiveness. Commentary. AB - The forthcoming implementation of the European Clinical Trial Regulation (Regulation (EU) No. 536/2014), which is expected to facilitate the conduct of clinical trials across the European Union, will require National Authorities to create the best conditions for the implementation of the new Regulation through national guidelines, so that sponsors may reconsider Europe as a prime location for planning clinical trials. During a meeting titled "Innovation in Clinical Research", an expert panel discussed potential local advances fostering competitiveness of European clinical research with representatives of the pharmaceutical industry, patient organisations and Italian regulatory agency in view of the forthcoming implementation of (EU) No. 536/2014 on clinical trials of medicinal products. In this article we summarise the findings of the meeting, describe features characterising clinical research patterns and offer some suggestions on the possible involvement of all stakeholders in order to foster research innovation and allow the timely access to novel medicines for patients. PMID- 28617256 TI - Mortality of populations residing in geothermal areas of Tuscany during the period 2003-2012. AB - INTRODUCTION: The limited scientific knowledge on the relationship between exposure and health effects in relation to geothermal activity motivated an epidemiologic investigation of Tuscan geothermal area. AIM: This study aims at describing mortality of populations living in Tuscan municipalities in the period 2003-2012. METHOD: Sixteen municipalities were included in the study area: eight in the northern and eight in the southern area. Mortality data come from the Regional Mortality Registry of Tuscany. Fifty-four causes of death, considered of interest for population health status or consistent with "Project SENTIERI" criteria, are analyzed. RESULTS: Results show a worse mortality profile in the southern area, especially in males, for whom excesses of all cancers and some causes of cancer emerge, while in the northern area an excess of cerebrovascular diseases among females merits attention. Further and more appropriate studies are needed to clarify the etiology of some diseases and to better assess a potential cause-effect relationship. PMID- 28617257 TI - Do Italian pregnant women use periconceptional folate supplementation? AB - INTRODUCTION: Deficiency of folic acid (FA) has been identified as a risk factor for neural tube defects (NTDs) as well as other congenital anomalies. Thus, periconceptional folate supplementation is recommended for all women planning to get pregnant. METHODS: We conducted a KAP (knowledge, attitude, practice) survey to investigate the use of FA and its appropriateness. The survey included a sample of 562 women who delivered in the Lazio region between 2013 and 2014. Two logistic regression analyses were performed to evaluate the association between the characteristics of participating women and both the information received on FA intake and its use. RESULTS: The prevalence of periconceptional FA assumption was 19.4% although 82.2% of the interviewed women had planned their pregnancies. CONCLUSIONS: It shows that more periconceptional counseling is needed to increase women's awareness on the opportunity of FA supplementation. PMID- 28617258 TI - Micronized palmitoylethanolamide/trans-polydatin treatment of endometriosis related pain: a meta-analysis. AB - AIM: To demonstrate clinical effectiveness of micronized palmitoylethanolamide trans-polydatin combination in reducing endometriotic chronic pelvic pain. Other endometriotic-pains were also assessed. METHODS: Systematic reviews of PubMed, SCIELO, Scopus, and AJOL. Randomized trials and observational studies reporting a visual analogue scale for pain or similar in endometriotic patients were reviewed. A mean improvement of visual analogue scale (or visual analogue scale like) scores at enrollment and at a three-month follow-up was assessed and interpreted clinically. RESULTS: Four studies of poor quality were available. In a heterogeneous sample of endometriotic patients with pain, the administration of micronized palmitoylethanolamide/trans-polydatin (400 mg/40 mg) twice a day for three months provided a clinically relevant improvement of chronic pelvic pain and dysmenorrhea while improving deep dyspareunia to a limited degree. No clinically relevant improvement was found for dyschezia. CONCLUSION: More studies are warranted for assessing the drugs-related efficacy. PMID- 28617259 TI - Trend and variability in open and laparoscopic hysterectomies for patients with benign disease: a retrospective cohort study. AB - AIM: The aim of the present analysis on a regional hospital database was to ascertain the variability and 5-year trends of hysterectomy rates and the different surgical approaches used. METHODS: A retrospective cohort study was conducted in Veneto Region (North-East Italy), based on administrative data collected in 6 years, from 2009 to 2014. RESULTS: Our study showed an overall decline in the hospitalization rates for hysterectomy from 197.5 to 165.8/100 000 and shorter overall hospital stays for this procedure (from 5.5 to 4.5 days). During the six years analyzed, there was an overall increase in the use of laparoscopic surgery (from 28% to 35% of cases). There was also a marked variability within the region considered in terms of the hysterectomy rates and the type of procedure performed. CONCLUSIONS: The unwarranted variability in the rates of elective surgical procedures, and the techniques used to perform them, could be monitored by analyzing electronic hospital records. PMID- 28617260 TI - Pes planus and pes cavus in Southern Italy: a 5 years study. AB - INTRODUCTION: Baropodometrical digital techniques map the pressures exerted on the foot plant during both static and dynamic loadings. The study of the distribution of such pressures makes it possible to evaluate the postural and locomotory biomechanics together with its pathological variations. METHODS: From January 2011 to August 2016 we conducted a cross sectional study in order to diagnose flatfoot and hollowfoot through the baropodometric analysis, and collecting additional information such as gender and the age. 7816 static and dynamic baropodometric tests and radiological exams of the spine in different positions were performed in order to detect, evaluate and verify the presence of spine pathologies or postural disorders. 978 patients were screened for suspected foot deformities: 668 cases of hollow feet and 310 of flat feet were diagnosed. RESULTS: Dividing patients in "younger" and "older" (> 60 years) according to WHO, there is a statistically significant difference in the prevalence of hollow feet and flat feet (p < 0.01): the young age is a risk factor for flat feet (OR = 1.61 CI 95% 1.22-2.11) but protective for hollow feet (OR = 0.62 CI 95% 0.47 0.81). There is a statistically significant difference (p < 0.01) due to sex in the prevalence of hollow feet (OR = 0.44 CI 95% 0.33-0.59) and flat feet (OR = 2.23 CI 95% 1.68-2.98): to be a man is a preventive factor for hollow feet, but a risk factor for flat feet. CONCLUSIONS: Flatfoot and hollowfoot represent a serious public health problem which is related to working life because these deformities negatively influence the productivity of employees and the quality of life of affected patients. PMID- 28617261 TI - Health-promotion theories in nutritional interventions for community-dwelling older adults: a systematic review. AB - OBJECTIVE: To identify theories applied in interventions promoting healthy nutrition among community-dwelling older adults and determine the efficacy of theories in changing knowledge, attitudes, and behaviors. MATERIAL AND METHODS: The PubMed, PsycINFO, Embase, and ERIC databases were searched for English articles from January 1990 to December 2015. Mono or multicomponent randomized controlled trial studies were included, whereas research on nutritional interventions related to acute or chronic diseases were excluded. RESULTS: Eight articles satisfied the inclusion criteria. Only three articles referred explicitly to health promotion theories. Nutritional programs varied in terms of contents, outcomes, lengths of interventions and follow-up. Pooling the results and identifying the most effective theories were therefore impossible. CONCLUSIONS: Although researchers and practitioners recognize the significance of theoretical models in guiding the health-promoting interventions, referring to a theoretical model for such interventions is still relatively recent. PMID- 28617262 TI - MMR vaccine in the postpartum does not expose seronegative women to untoward effects. AB - BACKGROUND: The aim of this study was to assess whether rubella vaccination immediately after delivery could expose seronegative women to specific untoward effects. METHODS: 163 rubella-seronegative women received Measles-Mumps-Rubella (MMR) vaccine in the immediate postpartum period; they were evaluated at one month and at three months thereafter through telephone interviews. As controls, we matched 163 rubella-seropositive women, who might experience similar symptoms for any reason in the same timeframe. RESULTS: No relevant difference was still observed in the frequency of arthralgia and myalgia at one and three months. Instead, a statistically significant difference in the frequency of cervical lymphadenopathy and cutaneous rash at one month (p = 0.028 and p = 0.005, respectively), was observed between cases and controls. However, no statistical differences were reported at three months for the same symptoms. CONCLUSIONS: Postpartum rubella vaccination with MMR is safe and advisable to avoid congenital rubella syndrome. PMID- 28617263 TI - Vaccine hesitancy: parental, professional and public responsibility. AB - The opposition to vaccinations is a well-known phenomenon that dates back to the Victorian age when it was self-limited by the awareness of the importance to be protected against fearsome infectious diseases. In the XX century, the mass use of vaccination has - instead - consented to eradicate or drastically reduce the burden of diseases such as smallpox and polio. These positive effects of the vaccination campaigns have blurred out, if not erased, the memory of the tragic consequences of the past's widespread diseases, leading people to underestimate the severity of the harm that vaccinations prevent. In recent years, a complex mixture of contextual factors have promoted an amplification of that paradoxical situation, leading experts to study causes and consequences of the so called "vaccine hesitancy". Several studies have shown the impact for children and for the community of the refusal or hesitation towards vaccinations from different points of view, including epidemiological, clinical, social and economic evaluation. This article provides an analysis of vaccine hesitancy from an ethical perspective: parental, professional and public responsibilities are analysed and described according to the "responsibility of the fathers towards the children", as articulated by Hans Jonas in 1979. PMID- 28617264 TI - The professional quality criteria of Italian breast screening radiologists: results from a national survey comparing the programmes started in 2000-2012 versus the ones started in 1990-1999. AB - INTRODUCTION: In Italy, due to increasing healthcare budget and staff shortages, the recently created regional mammography screening programmes were established under worse radiology practice quality criteria than the previously created programmes. METHODS: Using available data from a national questionnaire survey conducted at the end of 2013 and involving 222 responder radiologists, we compared the main professional quality standards of radiologists working in the screening programmes established during the period 2000-2012 with those working in the screening programmes created from 1990 to 1999. RESULTS: The former reported more years of clinical experience in breast imaging and a greater clinical mammogram reading volume than the latter. Conversely, they dedicated less working time to breast imaging, were less likely to participate in the diagnostic assessment of screen-detected lesions, to work in large-staffed screening centres, and to have a screening and a total mammogram reading volume (SMRV and TMRV) >= 5000 per year. CONCLUSIONS: The level of most professional quality criteria of Italian mammography screening radiologists has decreased over time. As SMRV and TMRV are important predictors of diagnostic accuracy, we can expect a lower interpretation performance of radiologists working in the recently created screening programmes. PMID- 28617265 TI - A case of fulminant subacute sclerosing panencephalitis presenting with acute myoclonic-astatic epilepsy. AB - The neurologic sequelae post-measles are less common than other complications measles-related and can lead to severe disability or death: primary measles encephalitis (PME), acute post-infectious measles encephalomyelitis (APME), measles inclusion body encephalitis (MIBE), and subacute sclerosing panencephalitis (SSPE). SSPE syndrome can affect people years from the acute measles virus infection, as result of the persistence of defective viral particles in brain cells. Clinical onset typically manifests with progressive intellectual deterioration, behavioral changes, and myoclonic jerks. The course of SSPE in the majority of affected children is that of a progressive worsening with fatal outcome within two years. This report described an Italian case of fulminant SSPE syndrome that led to death within few months from the initial onset. PMID- 28617266 TI - Sustainable public health systems for rare diseases. AB - INTRODUCTION: In the framework of the Joint Action for Rare Diseases (RD-ACTION), a specific task was defined to identify mechanisms influencing sustainability, equity and resilience of health systems for rare diseases (RDs). METHOD: Literature narrative review on health systems sustainability and resilience for RDs. Years: 2000-2015. Databases: PubMed, Scopus, EBSCOHost, EMBAL, PASCAL, EMBASE, STN International and GoogleScholar. ANALYSIS: interpretive synthesis concept and thematic analysis (Dixon-Wood, et al.). RESULTS: 97 papers and 4 grey literature publications were identified. Two main topics stand out: economic evaluation and networks. The first topic did not identify widely accepted criterion to assign more weight to individuals with greater health needs. Healthcare network are identified as increasingly important for sustainability and resilience, in all of their aspects: professional "expertise", "experience" networks of users and carers; policy, learning, and interest networks. CONCLUSION: Possible mechanisms for ensuring sustainability can be identified in networking, patients' empowerment and reorienting healthcare towards integrated community and home care. PMID- 28617267 TI - Removal of cadmium and zinc from contaminated wastewater using Rhodobacter sphaeroides. AB - Rhodobacter sphaeroides was used for bioremediation of wastewater polluted with cadmium (Cd) and zinc (Zn). The tolerance of the microorganism to selected heavy metals (HMs), as well as the effects of pH, temperature and inoculum size on the removal rate, was investigated. The remediation effects of R. sphaeroides were analysed at different initial concentrations of HMs. Bioremediation mechanisms were thoroughly discussed based on the results from the cell characterisation analysis. Cd and Zn could inhibit the growth of R. sphaeroides. However, Cd was more toxic than Zn, with corresponding EC50 values of 5.34 and 69.79 mg L-1. Temperature and pH had greater influence on the removal rate of HMs than inoculum size. The optimal conditions for temperature and pH were 35 degrees C-40 degrees C and pH 7, respectively. Initial concentration of HMs and remediation time also affected the removal rate. Rhodobacter sphaeroides had a relatively higher remediation effect under the present experimental conditions. The removal rates for Cd and Zn reached 97.92% and 97.76%, respectively. Results showed that biosorption and HM precipitation were the main bioremediation mechanisms. This information is necessary to better understand the removal mechanism of R. sphaeroides, and is significant for its pilot test and future practical application. PMID- 28617268 TI - Hydrochemical characterization of a river affected by acid mine drainage in the Iberian Pyrite Belt. AB - This paper addresses the modelling of the processes associated with acid mine drainage affecting the Trimpancho River basin, chosen for this purpose because of its location and paradigmatic hydrological, geological, mining and environmental contexts. By using physical-chemical indicators it is possible to define the contamination degree of the system from the perspective of an entire river basin, due to its reduced dimension. This allows an exhaustive monitoring of the study area, considering the particularity that the stream flows directly into a water dam used for human supply. With such a perspective, and in order to find global solutions, the present study seeks to develop methodologies and tools for expeditious and accurate diagnosis of the pollution level of the affected stream that feeds the water reservoir. The implemented methodology can be applied to other water systems affected by similar problems, while the results will contribute to the development of the state of the art in a representative basin of the Iberian Pyrite Belt, whose pollutants' contributions are incorporated into the reservoir. PMID- 28617269 TI - Assessment of TiO2 photoactivity on the lead removal: kinetic and mechanistic processing. AB - Removal of lead ions from aqueous solutions, in the presence and in absence of commercial TiO2, under UV-light was studied. The influence of catalyst mass, concentration of Pb(II) ions and of citric acid in the starting solution as well as the impact of illumination conditions on the removal rate were also investigated. The results were fitted on the pseudo-first order, pseudo-second order and Elovich kinetic models, Weber-Morris intraparticle and liquid film diffusion models, in order to establish the photoreduction mechanism. The Pb removal rate increased in time by a combined linear-exponential mechanism. The catalyst had a positive influence on the removal rate at the start of the photoreduction. At a low concentration of Pb(II) ions (20 mg/L), the amount of photoreduced Pb(II) ions was proportional to the concentration of the citric acid solution, but at high concentrations (240 mg/L), the correlation was inversely proportional. The rate limiting steps in the removal of lead were both the photoreduction on the TiO2 surface and the diffusion through the film surrounding the catalyst particle. The lead removal was significantly influenced by the mobility and by the concentration of the species in solution. PMID- 28617270 TI - Flotation separation of strontium via phosphate precipitation. AB - Flotation separation of strontium (Sr) from wastewater via phosphate precipitation was investigated. While 37.33% of Sr precipitated at highly alkaline pH in the absence of PO43-, it completely precipitated as Sr3(PO4)2 at a molar ratio ([PO43-]:[Sr2+]) of 0.62 at a lower pH value. The presence of Ca2+ hindered Sr precipitation, yet it could be overcome by increasing the PO43- dose. Sodium dodecyl sulfate (SDS) was a better collector for dispersed air flotation of Sr3(PO4)2 than cetyl trimethyl ammonium bromide, or mixed collector systems of SDS and saponin. The highest separation efficiency of 97.5% was achieved at an SDS dose of 40 mg/L. The main mechanism in the precipitate flotation is adsorption of anionic SDS on the positively charged surface of colloidal Sr3(PO4)2 via electrostatic interaction. SDS enhanced the aggregation of Sr3(PO4)2 precipitates as the size increased from 1.65 to 28.0 MUm, which was beneficial to separation as well. PMID- 28617271 TI - Modelling and optimization of land use/land cover change in a developing urban catchment. AB - The impacts of land use/cover change (LUCC) on hydrological processes and water resources are mainly reflected in changes in runoff and pollutant variations. Low impact development (LID) technology is utilized as an effective strategy to control urban stormwater runoff and pollution in the urban catchment. In this study, the impact of LUCC on runoff and pollutants in an urbanizing catchment of Guang-Ming New District in Shenzhen, China, were quantified using a dynamic rainfall-runoff model with the EPA Storm Water Management Model (SWMM). Based on the simulations and observations, the main objectives of this study were: (1) to evaluate the catchment runoff and pollutant variations with LUCC, (2) to select and optimize the appropriate layout of LID in a planning scenario for reducing the growth of runoff and pollutants under LUCC, (3) to assess the optimal planning schemes for land use/cover. The results showed that compared to 2013, the runoff volume, peak flow and pollution load of suspended solids (SS), and chemical oxygen demand increased by 35.1%, 33.6% and 248.5%, and 54.5% respectively in a traditional planning scenario. The assessment result of optimal planning of land use showed that annual rainfall control of land use for an optimal planning scenario with LID technology was 65%, and SS pollutant load reduction efficiency 65.6%. PMID- 28617272 TI - Ammonia nitrogen removal and recovery from acetylene purification wastewater by air stripping. AB - Ammonia nitrogen (NH4-N) contaminated wastewater has posed a great threat to the safety of water resources. In this study, air stripping was employed to remove and recover NH4-N from acetylene purification wastewater (APW) in a polyvinylchloride manufacturing plant. Investigated parameters were initial APW pH, air flow rate, APW temperature and stripping time. The NH4-N removal by air stripping has been modeled and the overall volumetric mass transfer coefficient (KLa) of the stripping process has been calculated from the model equation obtained. In addition, the ability of H2SO4 solution to absorb the NH3 stripped was also investigated. The results indicated that under the experimental conditions, the APW temperature and its initial pH had significant effects on the NH4-N removal efficiency and the KLa, while the effects of other factors were relatively minor. The removal efficiency and residual concentration of NH4-N were about 91% and 12 mg/L, respectively, at the optimal operating conditions of initial APW pH of 12.0, air flow rate of 0.500 m3/(h.L), APW temperature of 60 degrees C and stripping time of 120 min. One volume of H2SO4 solution (0.2 mol/L) could absorb about 93% of the NH3 stripped from 54 volumes of the APW. PMID- 28617273 TI - Model-based methodology for the design of optimal control strategies in MBR plants. AB - This paper proposes a model-based methodology that allows synthesising the most appropriate strategies for optimising the operation of wastewater treatment plants (WWTPs). The methodology is applied with the aim of maximising the nitrogen removal in membrane bioreactors (MBRs). The proposed procedure is based on a systematic approach composed of four steps. First, a sensitivity analysis of the input variables is carried out in order to obtain a first assessment of the potential for operational improvements. Then, the optimum input variable values are calculated by a model-based optimisation algorithm that minimises a cost function associated with the effluent total nitrogen at different temperatures. Then, the optimum operational strategies are identified. Finally, these operational strategies form the conceptual knowledge base for designing automatic control laws. The obtained optimal control strategies have shown a significant improvement in performance in comparison with fixed operation for the studied case, reducing the total nitrogen by 40%. PMID- 28617274 TI - Supporting constructed wetlands in P removal efficiency from surface water. AB - The research investigated the implementation of suspended reactive filters to support the phosphorus (P) removal efficiency of constructed wetlands (CWs). The reactive material (RM) used in this study was autoclaved aerated concrete (AAC). The laboratory experiment consists of four plastic boxes filled with the volume of 10 L of artificial P solution with three variants of RM mass to volume ratio: 1:1 (g:L), 5:1 (g:L), 10:1 (g:L), and the blind probe 0:1 (g:L) as a reference. AAC of different weights (10, 50 and 100 g) was wrapped in a filter bag, put into boxes, and suspended. After 30 days of the laboratory experiment, AAC was able to reduce the P-PO4 concentration from 2.972 mg.L-1 to: 0.341 mgPO4-P.L-1, 0.006 mgPO4-P.L-1 and 0.004 mgPO4-P.L-1 for 10 g, 50 g and 100 g mass variant, respectively. This concentration reduction corresponds to unit sorption of: 2.53 mgP-PO4.g-1, 0.58 mgP-PO4.g-1 and 0.30 mgP-PO4.g-1 for 10 g, 50 g and 100 g, respectively. Based on the obtained data, the CW supporting filter was dimensioned to reduce the outflow P concentration to 0.01 mg.L-1. P removal efficiency prediction was calculated for Cetynia River, Poland. PMID- 28617275 TI - Cost comparison of full-scale water reclamation technologies with an emphasis on membrane bioreactors. AB - The paper assesses the costs of full-scale membrane bioreactors (MBRs). Capital expenditures (CAPEX) and operating expenses (OPEX) of Spanish MBR facilities have been verified and compared to activated sludge plants (CAS) using water reclamation treatment (both conventional and advanced). Spanish MBR facilities require a production of 0.6 to 1.2 kWh per m3, while extended aeration (EA) and advanced reclamation treatment require 1.2 kWh per m3. The energy represents around 40% of the OPEX in MBRs. In terms of CAPEX, the implementation costs of a CAS facility followed by conventional water reclamation treatment (physical chemical + sand filtration + disinfection) ranged from 730 to 850 ?.m-3d, and from 1,050 to 1,250 ?.m-3d in the case of advanced reclamation treatment facilities (membrane filtration) with a capacity of 8,000 to 15,000 m3d-1. The MBR cost for similar capacities ranges between 700 and 960 ?.m-3d. This study shows that MBRs that have been recently installed represent a cost competitive option for water reuse applications for medium and large capacities (over 10,000 m3d-1), with similar OPEX to EA and conventional water reclamation treatment. In terms of CAPEX, MBRs are cheaper than EA, followed by advanced water reclamation treatment. PMID- 28617276 TI - Removal of potentially toxic elements from aqueous solutions and industrial wastewater using activated carbon. AB - Water contamination with potentially toxic elements (PTEs) has become one of the key issues in recent years that threatens human health and ecological systems. The present study is aimed at removing PTEs like cadmium (Cd), chromium (Cr), copper (Cu) and lead (Pb) from aqueous solutions and industrial wastewater using activated carbon (AC) as an adsorbent through different batch and column experiments. Results demonstrated that the removal of PTEs from aqueous solutions was highly pH dependent, except for Cr, and the maximum removal (>78%) was recorded at pH 6.0. However, maximum Cr removal (82.8%) was observed at pH 3.0. The adsorption reached equilibrium after 60 min with 2 g of adsorbent. Coefficient (R2) values suggested by the Langmuir isotherm model were 0.97, 0.96, 0.93 and 0.95 for Cd, Cr, Cu and Pb, respectively, indicating the fit to this model. In column experiments, the maximum removal of PTEs was observed at an adsorbent bed height of 20 cm with the optimal flow rate of 3.56 mL/min. Furthermore, PTEs removal by AC was observed in the order of Cu > Cd > Pb > Cr. Findings from this study suggest that AC could be used as a promising adsorbent for simultaneously removing several PTEs from wastewaters. PMID- 28617277 TI - Promotion of partial nitritation-anammox process by improving granule proportion. AB - For enhancing the partial nitritation-anammox (PN/A) process, the effects of granule fraction on system performance were investigated in this study. Two sequencing batch reactors (SBRs) were inoculated with PN/A biomass with a floc mass fraction of 53%. In SBR1, when the nitrogen removal rate (NRR) was stable, flocculent sludge was gradually discharged from the reactor using a screen, and the granule fraction was therefore increased. However, nitrogen removal was not improved and finally deteriorated due to the loss of nitritation activity. In SBR2, most flocculent sludge was eliminated and granular proportion was maintained at over 90% by controlling a short settling and decanting time. NRR was low initially but gradually improved to 1.23 kg N/(m3.d), which was 54% higher than SBR1. Ammonium oxidation activities of flocs and granules were respectively measured. Results suggested that the increase of nitritation activity in the granules was the main reason for the improvement of nitrogen removal in SBR2. PMID- 28617278 TI - Performance assessment of a vertical flow constructed wetland treating unsettled combined sewer overflow. AB - The performance of a vertical flow constructed wetland for combined sewer overflow treatment (CSO CW) has been evaluated. The full-scale site has been monitored for 3 years for major pollutants and for two load events for a range of micropollutants (metals, metalloids and polycyclic aromatic hydrocarbons (PAHs)). Performance were predominantly high (97% for total suspended solids (TSS), 80% for chemical oxygen demand (COD), 72% for NH4-N), even if several loads were extremely voluminous, pushing the filter to its limits. Two different filter materials (a 4:1 mixture of sand and zeolite and natural pozzolana) showed similar treatment performance. Furthermore, environmental factors were correlated with COD removal efficiency. The greatest influencers of COD removal efficiency were the inlet dissolved COD concentrations and the duration and potential evapotranspiration during inter-event periods. Furthermore, sludge was analysed for quality and a sludge depth map was created. The map, and calculating the changes in sludge volume, helped to understand solid accumulation dynamics. PMID- 28617279 TI - Rotating belt sieves for primary treatment, chemically enhanced primary treatment and secondary solids separation. AB - Fine mesh rotating belt sieves (RBS) offer a very compact solution for removal of particles from wastewater. This paper shows examples from pilot-scale testing of primary treatment, chemically enhanced primary treatment (CEPT) and secondary solids separation of biofilm solids from moving bed biofilm reactors (MBBRs). Primary treatment using a 350 microns belt showed more than 40% removal of total suspended solids (TSS) and 30% removal of chemical oxygen demand (COD) at sieve rates as high as 160 m3/m2-h. Maximum sieve rate tested was 288 m3/m2-h and maximum particle load was 80 kg TSS/m2-h. When the filter mat on the belt increased from 10 to 55 g TSS/m2, the removal efficiency for TSS increased from about 35 to 60%. CEPT is a simple and effective way of increasing the removal efficiency of RBS. Adding about 1 mg/L of cationic polymer and about 2 min of flocculation time, the removal of TSS typically increased from 40-50% without polymer to 60-70% with polymer. Using coagulation and flocculation ahead of the RBS, separation of biofilm solids was successful. Removal efficiencies of 90% TSS, 83% total P and 84% total COD were achieved with a 90 microns belt at a sieve rate of 41 m3/m2-h. PMID- 28617280 TI - Two different purification systems at Istanbul-Tuzla and Adana-Kozan, their characterizations. AB - In most developed countries, wastewater treatment plants are presently utilizing efficient purification technology meeting the sufficiency requirements of quality and quantity. However, in developing countries, the number of wastewater treatment plants is limited. As a result, the establishment of a connection between the wastewater collection system and wastewater purification plants is increasingly becoming a top priority for researchers. The aim of this article is to analyze wastewater collection and purification systems and establish the links between these two processes. In the present study, the efficiency of the present purification system at the Istanbul-Tuzla and Adana-Kozan plants was investigated with the aim of enhancing their performance. The findings pertaining to the model sewage system revealed a decrease in NH3-N by 20-70%, total nitrogen (T-N) by 25 75%, biological oxygen demand (BOD5) by 50-60%, chemical oxygen demand (COD) by 35-55% and suspended solids (SS) by 55-85%. As a result of studies performed in the Tuzla sewage treatment system, we can confirm that T-N decreased by 50-75%, suspended solid particles by 24-57%, and BOD5 by 34-57%, while 35-55% of COD was removed. Similarly, in the canal exit at Kozan, BOD5 decreased by 40-55%, COD by 30-50%, SS by 25-45% and T-N by 5-40%. PMID- 28617281 TI - Comparison of culture-based, vital stain and PMA-qPCR methods for the quantitative detection of viable hookworm ova. AB - Accurate quantitative measurement of viable hookworm ova from environmental samples is the key to controlling hookworm re-infections in the endemic regions. In this study, the accuracy of three quantitative detection methods [culture based, vital stain and propidium monoazide-quantitative polymerase chain reaction (PMA-qPCR)] was evaluated by enumerating 1,000 +/- 50 Ancylostoma caninum ova in the laboratory. The culture-based method was able to quantify an average of 397 +/- 59 viable hookworm ova. Similarly, vital stain and PMA-qPCR methods quantified 644 +/- 87 and 587 +/- 91 viable ova, respectively. The numbers of viable ova estimated by the culture-based method were significantly (P < 0.05) lower than vital stain and PMA-qPCR methods. Therefore, both PMA-qPCR and vital stain methods appear to be suitable for the quantitative detection of viable hookworm ova. However, PMA-qPCR would be preferable over the vital stain method in scenarios where ova speciation is needed. PMID- 28617282 TI - Hg removal and the effects of coexisting metals in forward osmosis and membrane distillation. AB - In this study, we investigate the rejection of Hg, Cd, and Pb and the effect of coexisting metals on Hg removal through forward osmosis (FO) and membrane distillation (MD) in order to establish a more effective water treatment process. The results of our laboratory experiment indicate that more than 97% of the rejection for each metal is achieved through the FO system, and this rejection is the highest among previous studies using membrane filtrations. Moreover, we examine the matrix effect of the coexisting Cd and Pb on the rejection of Hg in the FO system. Hg2+ rejection increases with increase in the concentration of the coexisting metals. Furthermore, we study the effect of the Hg concentration and the water temperature on rejection of Hg2+. Indeed, the rejection of Hg2+ is achieved above 95% under any condition. However, approximately 1-10 ppb Hg from the feed solution remains in the draw solution due to permeation. Therefore, we use a FO-MD hybrid system. Approximately 100% rejection of Hg2+ and a stable water flux are achieved. Thus, the FO-MD hybrid system is considered an important alternative to previous studies using membrane filtration for heavy metals removal. PMID- 28617283 TI - Biosorption of six basic and acidic dyes on brown alga Sargassum ilicifolium: optimization, kinetic and isotherm studies. AB - Biosorption of Methyl Blue (MB), Fuchsin Acid (FA), Rhodamine B (RB), Methylene Blue (MEB), Bromocresol purple (BC) and Methyl Orange (MO) onto Sargassum ilicifolium was studied in a batch system. Effect of dye structure on biosorption by Sargassum ilicifolium was studied to define the correlation between chemical structure and biosorption capacity. Different dye groups such as triarylmethane (MB, FA and BC), monoazo (MO), thiazine (MEB) and xanthene (RB) were studied. At optimum experimental conditions for each dye, biosorption capacity was determined and compared. The results indicate that the chemical structure (triarylmethane, monoazo, thiazine, xanthene), number of sulfonic groups, basicity (element of chromophore group: S, N, O) and molecular weight of dye molecules influence their biosorption capacity. Experimental parameters such as biosorbent dose, pH, contact time, and initial dye concentration were optimized for each dye. The biosorption kinetic data were successfully described by the pseudo second-order model. The biosorption results were also analyzed by the Langmuir and Freundlich isotherms. Finally, biosorption capacities obtained using Sargassum ilicifolium were compared with the ones presented in the literature. PMID- 28617284 TI - Dynamic changes of bacterial community in activated sludge with pressurized aeration in a sequencing batch reactor. AB - This study aimed to investigate the organic removal efficiency and microbial population dynamics in activated sludge with pressurized aeration. The activated sludge was fed with synthetic wastewater composed of simple carbon source to avoid the effect of complex components on microbial communities. The pressurized acclimation process was conducted in a bench-scale sequencing batch reactor (SBR) under 0.3 MPa gage pressure. Another SBR was running in atmospheric environment as a control reactor, with the same operation parameters except for the pressure. Bacterial diversity was investigated by Illumina sequencing technology. The results showed that the total organic carbon removal efficiency of the pressurized reactor was significantly higher, while the mixed liquor suspended solids concentrations were much lower than those of the control reactor. Moderate pressure of 0.3 MPa had little effect on Alpha-diversity of bacterial communities due to the similar running conditions, e.g., feed water, solids retention time (SRT) and the cyclic change of dissolved oxygen (DO) concentrations. Although the relative percentage of the bacterial community changed among samples, there was no major change of predominant bacterial populations between the pressurized group and the control group. Pressurized aeration would have a far-reaching impact on microbial community in activated sludge when treating wastewaters being unfavorable to the dissolution of oxygen. PMID- 28617285 TI - Assessment of the technological reliability of a hybrid constructed wetland for wastewater treatment in a mountain eco-tourist farm in Poland. AB - The aim of the present study was to assess the technological reliability of a domestic hybrid wastewater treatment installation consisting of a classic three chambered (volume 6 m3) septic tank, a vertical flow trickling bed filled with granules of a calcinated clay material (KERAMZYT), a special wetland bed constructed on a slope, and a permeable pond used as a receiver. The test treatment plant was located at a mountain eco-tourist farm on the periphery of the spa municipality of Krynica-Zdroj, Poland. The plant's operational reliability in reducing the concentration of organic matter, measured as biochemical oxygen demand (BOD5) and chemical oxygen demand (COD), was 100% when modelled by both the Weibull and the lognormal distributions. The respective reliability values for total nitrogen removal were 76.8% and 77.0%, total suspended solids - 99.5% and 92.6%, and PO4-P - 98.2% and 95.2%, with the differences being negligible. The installation was characterized by a very high level of technological reliability when compared with other solutions of this type. The Weibull method employed for statistical evaluation of technological reliability can also be used for comparison purposes. From the ecological perspective, the facility presented in the study has proven to be an effective tool for protecting local aquifer areas. PMID- 28617286 TI - Improving the microbiological quality of the Ruhr River near Essen: comparing costs and effects for the reduction of Escherichia coli and intestinal enterococci. AB - After rain events in densely populated areas, combined sewer overflows (CSOs) can have severe health-related effects upon surface water quality, as well as diffuse overland runoff and wastewater treatment plants (WWTPs). All of these sources emit pathogens and fecal indicator bacteria into the surface water, which the EU Bathing Water Directive addresses by giving threshold values for the indicators Escherichia coli and intestinal enterococci. This study presents a comparison between 21 scenarios of costs for processes that reduce the load of Escherichia coli and intestinal enterococci into the Ruhr River during and shortly after rain events. The methods examined include UV irradiation for WWTPs, integrated sewer management and treatment of CSOs with vertical flow constructed wetlands or performic acid. For pollution by diffuse overland flow, we evaluated organizational measures. The treatment of only diffuse pollution shows merely a slight effect on intestinal enterococci, but none on Escherichia coli and hence, was not considered further. Combining all three CSO reduction methods with the irradiation of WWTP effluent provides the best simulation results in terms of reducing both indicator bacteria. PMID- 28617287 TI - Controlling the COD removal of an A-stage pilot study with instrumentation and automatic process control. AB - The pursuit of fully autotrophic nitrogen removal via the anaerobic ammonium oxidation (anammox) pathway has led to an increased interest in carbon removal technologies, particularly the A-stage of the adsorption/bio-oxidation (A/B) process. The high-rate operation of the A-stage and lack of automatic process control often results in wide variations of chemical oxygen demand (COD) removal that can ultimately impact nitrogen removal in the downstream B-stage process. This study evaluated the use dissolved oxygen (DO) and mixed liquor suspended solids (MLSS) based automatic control strategies through the use of in situ on line sensors in the A-stage of an A/B pilot study. The objective of using these control strategies was to reduce the variability of COD removal by the A-stage and thus the variability of the effluent C/N. The use of cascade DO control in the A-stage did not impact COD removal at the conditions tested in this study, likely because the bulk DO concentration (>0.5 mg/L) was maintained above the half saturation coefficient of heterotrophic organisms for DO. MLSS-based solids retention time (SRT) control, where MLSS was used as a surrogate for SRT, did not significantly reduce the effluent C/N variability but it was able to reduce COD removal variation in the A-stage by 90%. PMID- 28617289 TI - Study on method and mechanism of deep well circulation for the growth control of Microcystis in aquaculture pond. AB - In order to control the growth of Microcystis in aquaculture ponds and reduce its adverse effect on water quality and aquaculture, a production-scale experiment of deep well circulation treatment was carried out in an aquaculture pond with water surface area of 63,000 m2 and water depth of 1.6-2.0 m. Compared with the control pond, the experiment pond had better water quality as indicated by 64.2% reduction in chlorophyll a, and 81.1% reduction in algal cells. The chemical oxygen demand, total nitrogen, and total phosphorus concentration were reduced by 55.1%, 57.5%, and 50.8%, respectively. The treatment efficiency is mainly due to the growth control of Microcystis (i.e. cell reduction of 96.4%). The gas vesicles collapsing because of the water pressure was suggested to be the mechanism for Microcystis suppression by the deep well circulation treatment. The Microcystis lost its buoyancy after gas vesicles collapsed and it settled to the bottom of the aquaculture pond. As a result, the algae reproduction was suppressed because algae could only grow in the area with enough sunlight (i.e. water depth less than 1 m). PMID- 28617288 TI - Fate of selected pharmaceutically active compounds in the integrated fixed film activated sludge process. AB - The potential for integrated fixed film activated sludge (IFAS) processes to achieve enhanced transformation of pharmaceuticals relative to conventional activated sludge (CAS) processes was assessed. Previous studies have focused on direct comparisons of parallel reactors with and without fixed film carriers and little information is available on the impacts of how varying operating parameters impact the differences in observed pharmaceutical compound (PC) transformation capabilities between CAS reactors and those equipped with both an activated sludge (AS) and fixed film carriers. The testing was carried out using bench scale sequencing batch reactors fed with authentic municipal wastewater and operated at selected combinations of temperature and solids retention time (SRT). PC transformation efficiencies were assessed in a 22 factorial design that employed the IFAS and CAS processes, operated in parallel under identical process conditions. Nitrification rate testing that was conducted to obtain insight into the biomass activity demonstrated that IFAS consistently had improved nitrification kinetics despite lower mixed liquor volatile suspended solids levels thereby demonstrating the contribution of the biofilm to nitrification. Increased transformation of atenolol (ATEN; ranging from 10-60%) and trimethoprim (TRIM; ranging from 30-50%) in the IFAS equipped reactors relative to their respective activated sludge (AS) controls was observed under all experimental conditions. Negligible transformation of carbamazepine was observed in both reactors under all conditions investigated. More than 99% of acetaminophen was transformed in both configurations under all conditions. There was no correspondence between nitrification activity and TRIM removal in the control AS while conditions that stimulated nitrification in the control AS also resulted in enhanced removal of ATEN. The results of this study indicate that the integration of biofilms in AS processes enhances transformation of some PCs. PMID- 28617290 TI - Micro-zooplankton grazing as a means of fecal bacteria removal in stormwater BMPs. AB - A priority for environmental managers is control of stormwater runoff pollution, especially fecal microbial pollution. This research was designed to determine if fecal bacterial grazing by micro-zooplankton is a significant control on fecal bacteria in aquatic best management practices (BMPs); if grazing differs between a wet detention pond and a constructed wetland; and if environmental factors enhance grazing. Both 3-day grazing tests and 24-h dilution assays were used to determine grazing differences between the two types of BMP. Micro-zooplankton grazing was a stronger bacteria removal mechanism in stormwater wetlands rich in aquatic vegetation compared to a standard wet detention pond, although grazing was important in detention ponds as well. Our experiments indicated that the majority of grazers that fed on fecal bacteria were <20 MUm in size. Grazing rates were positively correlated with fecal coliform abundance and increased water temperatures. Enumeration of grazers demonstrated that protozoans were significantly more abundant among wetland vegetation than in open water, and open wetland waters contained more flagellates and dinoflagellates than open wet detention pond waters. Grazing on fecal bacteria in BMPs is enhanced by aquatic vegetation, and grazing in aquatic BMPs in warmer climates should be greater than in cooler climates. PMID- 28617291 TI - Optimizing external carbon source addition in domestics wastewater treatment based on online sensoring data and a numerical model. AB - The removal of total nitrogen in wastewater treatment plants (WWTPs) is often unsatisfactory for a variety of reasons. One possible measure to improve nitrogen removal is the addition of external carbon. However, the amount of carbon addition is directly related to WWTP operation costs, highlighting the importance of accurately determining the amount of external carbon required. The objective of this study was to obtain a low nitrate concentration in the anoxic zone of WWTPs efficiently and economically by optimizing the external carbon source dosage. Experiments were conducted using a pilot-scale pre-denitrification reactor at a Nanjing WWTP in China. External carbon source addition based on online monitoring of influent wastewater quality and a developed nitrification denitrification numerical model was investigated. Results showed that carbon addition was reduced by 47.7% and aeration costs were reduced by 8.0% compared with those using a fixed-dose addition mode in the pilot reactor. The obtained technology was applied to the full-scale Jiangxinzhou WWTP in Nanjing with promising results. PMID- 28617292 TI - Corrigendum: Water Science and Technology 75 (4), 987-997: Evaluation of the relative roles of a vegetative filter strip and a biofiltration swale in a treatment train for road runoff, Kelsey Flanagan, Philippe Branchu, David Ramier and Marie-Christine Gromaire, doi: 10.2166/wst.2016.578. PMID- 28617293 TI - Two publications. PMID- 28617294 TI - What is new in ACC/AHA 2017 focused update of valvular heart disease guidelines. PMID- 28617295 TI - Medicinal plants for management of diabetes: alternative or adjuvant? PMID- 28617296 TI - An adult case of single atrium diagnosed using three-dimensional echocardiography. PMID- 28617297 TI - Tp-e interval and Tp-e/QTc ratio: new choices for risk stratification of arrhythmic events in patients with hypertrophic cardiomyopathy. PMID- 28617298 TI - Author's Reply. PMID- 28617299 TI - A 31-year-old patient without the use of warfarin and with an aortic mechanical valve. PMID- 28617300 TI - Issues related to reliability of HRV analysis and effect of spontaneous saliva swallowing on HRV. PMID- 28617301 TI - Acute aortic regurgitation in a bicuspid aortic valve due to the rupture of an anomalous cord. PMID- 28617302 TI - A young girl presenting with cardiac thrombus: An unusual complication of inflammatory bowel disease. PMID- 28617303 TI - Prognostic value of coronary collaterals in patients with acute coronary syndromes. AB - BACKGROUND: The presence of good coronary collateral circulation (CCC) can protect and preserve myocardium from ischemia, increase myocardial contractility, and reduce adverse clinical events. However, its impact on mortality is still a topic of debate, particularly in acute coronary syndrome (ACS). The aim of this study was to investigate the association of CCC with cardiac risk factors and in hospital mortality in patients hospitalized with a diagnosis of ACS. METHODS: The study population included 2286 patients with ACS who underwent coronary angiography and were found to have at least 90% significant lesion in at least one major coronary artery. The CCC was graded according to the Rentrop classification. The patients were classified into a poor CCC group (Rentrop grades 0-1, n=1859) or a good CCC group (Rentrop grades 2-3, n=427). RESULTS: Patients with good CCC had more high-risk patient characteristics such as older age, higher rate of Killip class of at least 2 at admission, lower left ventricular ejection fraction, and impaired renal functions compared with the patients with poor CCC. In multivariate analysis, the presence of good CCC [odds ratio (OR): 2.000; 95% confidence interval: 1.116-3.585; P=0.020], left ventricular ejection fraction less than 40% (OR: 2.381; P=0.003), Killip class of at least 2 at admission (OR: 3.609; P<0.001), age of at least 65 years (OR: 2.975; P=0.003), and hemoglobin (OR: 0.797; P=0.003) were independent predictors of in-hospital mortality. CONCLUSION: In contrast to previous studies, our study did not confirm a beneficial role of good CCC in patients with ACS; the presence of good CCC was even independently associated with increased in-hospital mortality in the multivariate analysis. PMID- 28617304 TI - Human Herpesvirus 6 Reactivation in DRESS With Acute Liver Failure: A Missing Key Factor. PMID- 28617305 TI - Fibrotic Hypersensitivity Pneumonitis: Key Issues in Diagnosis and Management. AB - The diagnosis of hypersensitivity pneumonitis (HP) relies on the clinical evaluation of a number of features, including a history of significant exposure to potentially causative antigens, physical examination, chest CT scan appearances, bronchoalveolar lavage lymphocytosis, and, in selected cases, histology. The presence of fibrosis is associated with higher morbidity and mortality. Differentiating fibrotic HP from the idiopathic interstitial pneumonias can be a challenge. Furthermore, even in the context of a clear diagnosis of fibrotic HP, the disease behaviour can parallel that of idiopathic pulmonary fibrosis in a subgroup, with inexorable progression despite treatment. We review the current knowledge on the diagnosis, management, and prognosis of HP with particular focus on the fibrotic phenotype. PMID- 28617307 TI - Erratum: Michael A. Picker; et al.; H-NS, Its Family Members and Their Regulation of Virulence Genes in Shigella Species. Genes 2016, 7, 112. AB - n/a. PMID- 28617306 TI - Characterization of Hemagglutinin Negative Botulinum Progenitor Toxins. AB - Botulism is a disease involving intoxication with botulinum neurotoxins (BoNTs), toxic proteins produced by Clostridium botulinum and other clostridia. The 150 kDa neurotoxin is produced in conjunction with other proteins to form the botulinum progenitor toxin complex (PTC), alternating in size from 300 kDa to 500 kDa. These progenitor complexes can be classified into hemagglutinin positive or hemagglutinin negative, depending on the ability of some of the neurotoxin associated proteins (NAPs) to cause hemagglutination. The hemagglutinin positive progenitor toxin complex consists of BoNT, nontoxic non-hemagglutinin (NTNH), and three hemagglutinin proteins; HA-70, HA-33, and HA-17. Hemagglutinin negative progenitor toxin complexes contain BoNT and NTNH as the minimally functional PTC (M-PTC), but not the three hemagglutinin proteins. Interestingly, the genome of hemagglutinin negative progenitor toxin complexes comprises open reading frames (orfs) which encode for three proteins, but the existence of these proteins has not yet been extensively demonstrated. In this work, we demonstrate that these three proteins exist and form part of the PTC for hemagglutinin negative complexes. Several hemagglutinin negative strains producing BoNT/A, /E, and /F were found to contain the three open reading frame proteins. Additionally, several BoNT/A-containing bivalent strains were examined, and NAPs from both genes, including the open reading frame proteins, were associated with BoNT/A. The open reading frame encoded proteins are more easily removed from the botulinum complex than the hemagglutinin proteins, but are present in several BoNT/A and /F toxin preparations. These are not easily removed from the BoNT/E complex, however, and are present even in commercially-available purified BoNT/E complex. PMID- 28617308 TI - NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence. AB - Increases in reactive oxygen species (ROS) and decreases in nitric oxide (NO) have been linked to vascular dysfunction during diabetic retinopathy (DR). Diabetes can reduce NO by increasing ROS and by increasing activity of arginase, which competes with nitric oxide synthase (NOS) for their commons substrate l arginine. Increased ROS and decreased NO can cause premature endothelial cell (EC) senescence leading to defective vascular repair. We have previously demonstrated the involvement of NADPH oxidase 2 (NOX2)-derived ROS, decreased NO and overactive arginase in DR. Here, we investigated their impact on diabetes induced EC senescence. Studies using diabetic mice and retinal ECs treated with high glucose or H2O2 showed that increases in ROS formation, elevated arginase expression and activity, and decreased NO formation led to premature EC senescence. NOX2 blockade or arginase inhibition prevented these effects. EC senescence was also increased by inhibition of NOS activity and this was prevented by treatment with a NO donor. These results indicate that diabetes/high glucose-induced activation of arginase and decreases in NO bioavailability accelerate EC senescence. NOX2-generated ROS contribute importantly to this process. Blockade of NOX2 or arginase represents a strategy to prevent diabetes induced premature EC senescence by preserving NO bioavailability. PMID- 28617310 TI - Development of an Automatic Testing Platform for Aviator's Night Vision Goggle Honeycomb Defect Inspection. AB - Due to the direct influence of night vision equipment availability on the safety of night-time aerial reconnaissance, maintenance needs to be carried out regularly. Unfortunately, some defects are not easy to observe or are not even detectable by human eyes. As a consequence, this study proposed a novel automatic defect detection system for aviator's night vision imaging systems AN/AVS-6(V)1 and AN/AVS-6(V)2. An auto-focusing process consisting of a sharpness calculation and a gradient-based variable step search method is applied to achieve an automatic detection system for honeycomb defects. This work also developed a test platform for sharpness measurement. It demonstrates that the honeycomb defects can be precisely recognized and the number of the defects can also be determined automatically during the inspection. Most importantly, the proposed approach significantly reduces the time consumption, as well as human assessment error during the night vision goggle inspection procedures. PMID- 28617309 TI - Lipid Storage and Autophagy in Melanoma Cancer Cells. AB - Cancer stem cells (CSC) represent a key cellular subpopulation controlling biological features such as cancer progression in all cancer types. By using melanospheres established from human melanoma patients, we compared less differentiated melanosphere-derived CSC to differentiating melanosphere-derived cells. Increased lipid uptake was found in melanosphere-derived CSC vs. differentiating melanosphere-derived cells, paralleled by strong expression of lipogenic factors Sterol Regulatory Element-Binding Protein-1 (SREBP-1) and Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma). An inverse relation between lipid-storing phenotype and autophagy was also found, since microtubule-associated protein 1A/1B-Light Chain 3 (LC3) lipidation is reduced in melanosphere-derived CSC. To investigate upstream autophagy regulators, Phospho AMP activated Protein Kinase (P-AMPK) and Phospho-mammalian Target of Rapamycin (P-mTOR) were analyzed; lower P-AMPK and higher P-mTOR expression in melanosphere derived CSC were found, thus explaining, at least in part, their lower autophagic activity. In addition, co-localization of LC3-stained autophagosome spots and perilipin-stained lipid droplets was demonstrated mainly in differentiating melanosphere-derived cells, further supporting the role of autophagy in lipid droplets clearance. The present manuscript demonstrates an inverse relationship between lipid-storing phenotype and melanoma stem cells differentiation, providing novel indications involving autophagy in melanoma stem cells biology. PMID- 28617311 TI - Inducible Nitric Oxide Synthase Polymorphisms and Nitric Oxide Levels in Individuals with Chronic Periodontitis. AB - This study aimed to investigate whether the -1026(A>C)(rs2779249) and +2087(A>G)(2297518) polymorphisms in the NOS2 gene were associated with chronic periodontitis (CP) and with salivary levels of nitrite (NO2-) and/or nitrate + nitrite (NOx). A group of 113 mixed-race patients were subjected to periodontal, genetic, and biochemical evaluations (65 CP/48 periodontally healthy subjects). DNA was extracted from oral epithelial cells and used for genotyping by polymerase chain reaction (real-time). Salivary NOx concentrations were determined using an ozone-based chemiluminescence assay. Association of CP with alleles and genotypes of the -1026(A>C) polymorphism was found (X2 test, p = 0.0075; 0.0308), but this was not maintained after multiple logistic regression, performed to estimate the effect of covariates and polymorphisms in CP. This analysis demonstrated, after correction for multiple comparisons, that only the female gender was significantly associated with CP. Polymorphisms analyzed as haplotypes were not associated with CP. NOx levels were significantly higher in the control group of heterozygous individuals for both polymorphisms. In conclusion, the female gender was significantly associated with CP, and higher levels of salivary NOx were found in control subjects and associated with the heterozygous state of the NOS2 polymorphisms, reinforcing the potential of NO metabolites as markers of periodontitis status. PMID- 28617313 TI - TrackCC: A Practical Wireless Indoor Localization System Based on Less-Expensive Chips. AB - This paper aims at proposing a new wireless indoor localization system (ILS), called TrackCC, based on a commercial type of low-power system-on-chip (SoC), nRF24LE1. This type of chip has only l output power levels and acute fluctuation for a received minimum power level in operation, which give rise to many practical challenges for designing localization algorithms. In order to address these challenges, we exploit the Markov theory to construct a ( l + 1 ) * ( l + 1 ) -sized state transition matrix to remove the fluctuation, and then propose a priority-based pattern matching algorithm to search for the most similar match in the signal map to estimate the real position of unknown nodes. The experimental results show that, compared to two existing wireless ILSs, LANDMARC and SAIL, which have meter level positioning accuracy, the proposed TrackCC can achieve the decimeter level accuracy on average in both line-of-sight (LOS) and non-line-of sight (NLOS) senarios. PMID- 28617312 TI - Autocrine Human Growth Hormone Promotes Invasive and Cancer Stem Cell-Like Behavior of Hepatocellular Carcinoma Cells by STAT3 Dependent Inhibition of CLAUDIN-1 Expression. AB - Despite progress in diagnosis and treatment of hepatocellular carcinoma (HCC), the clinical outcome is still unsatisfactory. Increased expression of human growth hormone (hGH) in HCC has been reported and is associated with poor survival outcome in HCC patients. Herein, we investigated the mechanism of the oncogenic effects of hGH in HCC cell lines. In vitro functional assays demonstrated that forced expression of hGH in these HCC cell lines promoted cell proliferation, cell survival, anchorage-independent growth, cell migration, and invasion, as previously reported. In addition, forced expression of hGH promoted cancer stem cell (CSC)-like properties of HCC cells. The increased invasive and CSC-like properties of HCC cells with forced expression of hGH were mediated by inhibition of the expression of the tight junction component CLAUDIN-1. Consistently, depletion of CLAUDIN-1 expression increased the invasive and CSC like properties of HCC cell lines. Moreover, forced expression of CLAUDIN-1 abrogated the acquired invasive and CSC-like properties of HCC cell lines with forced expression of hGH. We further demonstrated that forced expression of hGH inhibited CLAUDIN-1 expression in HCC cell lines via signal transducer and activator of transcription 3 (STAT3) mediated inhibition of CLAUDIN-1 transcription. Hence, we have elucidated a novel hGH-STAT3-CLAUDIN-1 axis responsible for invasive and CSC-like properties in HCC. Inhibition of hGH should be considered as a therapeutic option to hinder progression and relapse of HCC. PMID- 28617314 TI - DNA Protection Protein, a Novel Mechanism of Radiation Tolerance: Lessons from Tardigrades. AB - Genomic DNA stores all genetic information and is indispensable for maintenance of normal cellular activity and propagation. Radiation causes severe DNA lesions, including double-strand breaks, and leads to genome instability and even lethality. Regardless of the toxicity of radiation, some organisms exhibit extraordinary tolerance against radiation. These organisms are supposed to possess special mechanisms to mitigate radiation-induced DNA damages. Extensive study using radiotolerant bacteria suggested that effective protection of proteins and enhanced DNA repair system play important roles in tolerability against high-dose radiation. Recent studies using an extremotolerant animal, the tardigrade, provides new evidence that a tardigrade-unique DNA-associating protein, termed Dsup, suppresses the occurrence of DNA breaks by radiation in human-cultured cells. In this review, we provide a brief summary of the current knowledge on extremely radiotolerant animals, and present novel insights from the tardigrade research, which expand our understanding on molecular mechanism of exceptional radio-tolerability. PMID- 28617315 TI - Study of a Compression-Molding Process for Ultraviolet Light-Emitting Diode Exposure Systems via Finite-Element Analysis. AB - Although wafer-level camera lenses are a very promising technology, problems such as warpage with time and non-uniform thickness of products still exist. In this study, finite element simulation was performed to simulate the compression molding process for acquiring the pressure distribution on the product on completion of the process and predicting the deformation with respect to the pressure distribution. Results show that the single-gate compression molding process significantly increases the pressure at the center of the product, whereas the multi-gate compressing molding process can effectively distribute the pressure. This study evaluated the non-uniform thickness of product and changes in the process parameters through computer simulations, which could help to improve the compression molding process. PMID- 28617316 TI - Globular Adiponectin Inhibits Lipopolysaccharide-Primed Inflammasomes Activation in Macrophages via Autophagy Induction: The Critical Role of AMPK Signaling. AB - The inflammasome acts as a key platform for the activation of pro-inflammatory cytokines. Adiponectin exhibits potent anti-inflammatory properties. However, the effect of adiponectin on the modulation of the inflammasome has not been explored. Herein, we show that globular adiponectin (gAcrp) suppressed lipopolysaccharide (LPS)-primed inflammasomes activation in murine peritoneal macrophages judged by prevention of interleukin-1beta (IL-1beta) maturation, caspase-1 activation, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, and pyroptotic cell death. Interestingly, pretreatment with 3-methyl adenine, a pharmacological inhibitor of autophagy, abrogated the suppressive effects of gAcrp on IL-1beta secretion and caspase-1 activation, indicating the crucial role of autophagy induction in gAcrp modulation of the inflammasome activation. In addition, inhibition of 5'Adenosine monophaspahate (AMP)-activated protein kinase (AMPK) signaling abolished suppressive effect of gAcrp on inflammasomes activation. Furthermore, autophagy induction or inhibition of the inflammasome activation by gAcrp was not observed in macrophages deficient in AMPK. Taken together, these results indicate that adiponectin inhibits LPS-primed inflammasomes activation in macrophages via autophagy induction and AMPK signaling-dependent mechanisms. PMID- 28617317 TI - Molecular Orientation of a Terbium(III)-Phthalocyaninato Double-Decker Complex for Effective Suppression of Quantum Tunneling of the Magnetization. AB - Single-molecule magnet (SMM) properties of crystals of a terbium(III) phthalocyaninato double-decker complex with different molecular packings (1: TbPc2, 2: TbPc2.CH2Cl2) were studied to elucidate the relationship between the molecular packing and SMM properties. From single crystal X-ray analyses, the high symmetry of the coordination environment of 2 suggested that the SMM properties were improved. Furthermore, the shorter intermolecular Tb-Tb distance and relative collinear alignment of the magnetic dipole in 2 indicated that the magnetic dipole-dipole interactions were stronger than those in 1. This was confirmed by using direct current magnetic measurements. From alternating current magnetic measurements, the activation energy for spin reversal for 1 and 2 were similar. However, the relaxation time for 2 is three orders of magnitude slower than that for 1 in the low-T region due to effective suppression of the quantum tunneling of the magnetization. These results suggest that the SMM properties of TbPc2 highly depend on the molecular packing. PMID- 28617318 TI - Occurrence of Penicillium brocae and Penicillium citreonigrum, which Produce a Mutagenic Metabolite and a Mycotoxin Citreoviridin, Respectively, in Selected Commercially Available Rice Grains in Thailand. AB - Commercially available rice grains in Thailand were examined to isolate the monoverticillate Penicillium species responsible for toxic yellowed rice. Penicillium species were obtained from seven out of 10 rice samples tested. Among them, one Penicillium citreonigrum isolate and six Penicillium brocae isolates were morphologically identified. The P. citreonigrum isolate produced the mycotoxin citreoviridin on a yeast extract sucrose broth medium. Mycotoxin surveys showed that citreoviridin was not detected in any samples, but one out of 10 rice samples tested was positive for aflatoxin B1 at a level of 5.9 MUg/kg. An Ames test revealed that methanol extracts from rice grains inoculated with selected P. brocae isolates were positive for strains TA100 and YG7108 of Salmonella typhimurium, suggesting the presence of base-pair substitution and DNA alkylation mutagens. Our data obtained here demonstrated that aflatoxin B1 and toxic P. citreonigrum were present on domestic rice grains in Thailand, although limited samples were tested. Penicillium brocae, which may produce mutagenic metabolites, was isolated for the first time from the surface of Thai rice grains. PMID- 28617320 TI - Crellasterones A and B: A-Norsterol Derivatives from the New Caledonian Sponge Crella incrustans. AB - Two new steroids, crellasterones A (1) and B (2), together with the previously reported compound chalinasterol (3) and several nucleosides (4-7), were isolated from the sponge Crella incrustans, collected in New Caledonia. The structures of the new compounds were established by extensive NMR and mass spectroscopic analysis and revealed unprecedented marine natural products with a ring contracted A-norsterone nucleus and 2-hydroxycyclopentenone chromophore. The absolute configurations were derived from electronic circular dichroism (ECD) measurements in conjunction with high-level density functional theory (DFT) calculations. PMID- 28617319 TI - PDE4 Inhibition and Inflammatory Bowel Disease: A Novel Therapeutic Avenue. AB - BACKGROUND: In the last few decades, a better knowledge of the inflammatory pathways involved in the pathogenesis of Inflammatory Bowel Disease (IBD) has promoted biological therapy as an important tool to treat IBD patients. However, in spite of a wider spectrum of biological drugs, a significant proportion of patients is unaffected by or lose their response to these compounds, along with increased risks of infections and malignancies. For these reasons there is an urgent need to look for new pharmacological targets. The novel Phosphodiesterase 4 (PDE4) inhibitors have been recently introduced as new modulators of intracellular signals and gene transcription for the treatment of IBD. AIM: To discuss and describe the state of the art of this new class of compounds in the IBD field, with particular attention to apremilast. METHODS: Published articles selected from PubMed were comprehensively reviewed, with key words including apremilast, inflammatory disease, IBD, psoriasis, psoriatic arthritis, pathogenesis, therapies, and treatment. RESULTS: PDE4 inhibitors generate elevated intracellular levels of cyclic Adenosine Monophosphate (cAMP), that consequently down-regulate the release of pro-inflammatory cytokines in the mucosa of IBD patients. The newly developed apremilast is one of these drugs and has already been approved for the treatment of dermatologic/rheumatologic inflammatory conditions; studies in psoriasis and psoriatic arthritis have in fact demonstrated its clinical activity. However, no clinical trials have yet been published on the use of apremilast in IBD. CONCLUSION: In light of the similarity of pro-inflammatory signaling pathways across the gut, the skin, and joints, apremilast is likely supposed to show its efficacy also in IBD. PMID- 28617321 TI - Evolving Identification of Blood Cells Associated with Clinically Isolated Syndrome: Importance of Time since Clinical Presentation and Diagnostic MRI. AB - It is not clear how the profile of immune cells in peripheral blood differs between patients with clinically isolated syndrome (CIS) and healthy controls (HC). This study aimed to identify a CIS peripheral blood signature that may provide clues for potential immunomodulatory approaches early in disease. Peripheral blood mononuclear cells (PBMCs) were collected from 18 people with CIS, 19 HC and 13 individuals with other demyelinating conditions (ODC) including multiple sclerosis (MS). Individuals with CIS separated into two groups, namely those with early (<=14 days post-diagnostic magnetic resonance imaging (MRI); n = 6) and late (>=27 days; n = 12) blood sampling. Transitional B cells were increased in the blood of CIS patients independently of when blood was taken. However, there were two time-dependent effects found in the late CIS group relative to HC, including decreased CD56bright NK cells, which correlated significantly with time since MRI, and increased CD141+ myeloid dendritic cell (mDC2) frequencies. Higher CD1c+ B cells and lower non-classical monocyte frequencies were characteristic of more recent demyelinating disease activity (ODC and early CIS). Analysing cell populations by time since symptoms (subjective) and diagnostic MRI (objective) may contribute to understanding CIS. PMID- 28617324 TI - A Sequential Optimization Calibration Algorithm for Near-Field Source Localization. AB - This paper considers the near-field source location problem for a nonuniform linear array (non-ULA) in the presence of sensor gain and phase errors. A sequential optimization calibration method is proposed to simultaneously estimate the gain and phase errors as well as the locations of calibration sources involving the ranges and the azimuths by exploiting some imprecise a-priori knowledge of calibration sources. At each iteration of the proposed method, the source locations, and the gain and phase errors are obtained iteratively. Finally, at the analysis stage, we evaluate the effectiveness of the proposed technique using some numerical simulations. Results show that the proposed algorithm shares the capability to jointly estimate the source locations and the errors. PMID- 28617322 TI - Chondroitin Sulfate-Rich Extract of Skate Cartilage Attenuates Lipopolysaccharide Induced Liver Damage in Mice. AB - The protective effects of a chondroitin sulfate-rich extract (CSE) from skate cartilage against lipopolysaccharide (LPS)-induced hepatic damage were investigated, and its mechanism of action was compared with that of chondroitin sulfate (CS) from shark cartilage. ICR mice were orally administrated 200 mg/kg body weight (BW) of CS or 400 mg/kg BW of CSE for 3 consecutive days, followed by a one-time intraperitoneal injection of LPS (20 mg/kg BW). The experimental groups were vehicle treatment without LPS injection (NC group), vehicle treatment with LPS injection (LPS group), CS pretreatment with LPS injection (CS group), and CSE pretreatment with LPS injection (CSE group). Hepatic antioxidant enzyme expression levels in the CS and CSE groups were increased relative to those in the LPS group. In LPS-insulted hepatic tissue, inflammatory factors were augmented relative to those in the NC group, but were significantly suppressed by pretreatment with CS or CSE. Moreover, CS and CSE alleviated the LPS-induced apoptotic factors and mitogen-activated protein kinase (MAPK). In addition, CS and CSE effectively decreased the serum lipid concentrations and downregulated hepatic sterol regulatory element-binding proteins expression. In conclusion, the skate CSE could protect against LPS-induced hepatic dyslipidemia, oxidative stress, inflammation, and apoptosis, probably through the regulation of MAPK signaling. PMID- 28617323 TI - Osteoblast Role in Rheumatic Diseases. AB - Alterations in osteoblast growth, differentiation and activity play a role in the pathogenesis of several rheumatic diseases, such as rheumatoid arthritis, spondyloarthritides, osteoarthritis, and osteoporosis. In fact, in these rheumatic diseases, abnormal activity of Wnt signaling, receptor activator of nuclear factor-kappaB (RANK)-RANK ligand (RANKL)-osteoprotegerin (OPG) signaling, bone morphogenetic proteins (BMPs) pathway and other mechanisms have been described in osteoblasts. This review article is focused on current knowledge on the role of osteoblast dysregulation occurring in rheumatic diseases. PMID- 28617326 TI - A Study on the Model of Detecting the Liquid Level of Sealed Containers Based on Kirchhoff Approximation Theory. AB - By simulating the sound field of a round piston transducer with the Kirchhoff integral theorem and analyzing the shape of ultrasound beams and propagation characteristics in a metal container wall, this study presents a model for calculating the echo sound pressure by using the Kirchhoff paraxial approximation theory, based on which and according to different ultrasonic impedance between gas and liquid media, a method for detecting the liquid level from outside of sealed containers is proposed. Then, the proposed method is evaluated through two groups of experiments. In the first group, three kinds of liquid media with different ultrasonic impedance are used as detected objects; the echo sound pressure is calculated by using the proposed model under conditions of four sets of different wall thicknesses. The changing characteristics of the echo sound pressure in the entire detection process are analyzed, and the effects of different ultrasonic impedance of liquids on the echo sound pressure are compared. In the second group, taking water as an example, two transducers with different radii are selected to measure the liquid level under four sets of wall thickness. Combining with sound field characteristics, the influence of different size transducers on the pressure calculation and detection resolution are discussed and analyzed. Finally, the experimental results indicate that measurement uncertainly is better than +/-5 mm, which meets the industrial inspection requirements. PMID- 28617325 TI - Development of Biopolymer Composite Films Using a Microfluidization Technique for Carboxymethylcellulose and Apple Skin Particles. AB - Biopolymer films based on apple skin powder (ASP) and carboxymethylcellulose (CMC) were developed with the addition of apple skin extract (ASE) and tartaric acid (TA). ASP/CMC composite films were prepared by mixing CMC with ASP solution using a microfluidization technique to reduce particle size. Then, various concentrations of ASE and TA were incorporated into the film solution as an antioxidant and an antimicrobial agent, respectively. Fourier transform infrared (FTIR), optical, mechanical, water barrier, and solubility properties of the developed films were then evaluated to determine the effects of ASE and TA on physicochemical properties. The films were also analyzed for antioxidant effect on 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity and antimicrobial activities against Listeria monocytogenes, Staphylococcus aureus, Salmonella enterica, and Shigella flexneri. From the results, the ASP/CMC film containing ASE and TA was revealed to enhance the mechanical, water barrier, and solubility properties. Moreover, it showed the additional antioxidant and antimicrobial properties for application as an active packaging film. PMID- 28617327 TI - Protein Hydrolysates as Promoters of Non-Haem Iron Absorption. AB - Iron (Fe) is an essential micronutrient for human growth and health. Organic iron is an excellent iron supplement due to its bioavailability. Both amino acids and peptides improve iron bioavailability and absorption and are therefore valuable components of iron supplements. This review focuses on protein hydrolysates as potential promoters of iron absorption. The ability of protein hydrolysates to chelate iron is thought to be a key attribute for the promotion of iron absorption. Iron-chelatable protein hydrolysates are categorized by their absorption forms: amino acids, di- and tri-peptides and polypeptides. Their structural characteristics, including their size and amino acid sequence, as well as the presence of special amino acids, influence their iron chelation abilities and bioavailabilities. Protein hydrolysates promote iron absorption by keeping iron soluble, reducing ferric iron to ferrous iron, and promoting transport across cell membranes into the gut. We also discuss the use and relative merits of protein hydrolysates as iron supplements. PMID- 28617328 TI - The Long-Term Consumption of Oats in Celiac Disease Patients Is Safe: A Large Cross-Sectional Study. AB - A strict gluten-free diet (GFD) can be diversified by non-contaminated oats, but there is a shortage of long-term studies concerning its safety. We compared long term treatment outcomes and factors associated with the introduction of oats between celiac patients on a GFD with or without oats. Eight hundred sixty-nine previously diagnosed celiac patients were interviewed. The validated Gastrointestinal Symptom Rating Scale (GSRS), Psychological General Well-Being (PGWB), and Short-Form 36 Health Survey (SF-36) questionnaires were used to assess symptoms and quality of life, serological tests were performed, and results of histology were confirmed from patient records. We found the median duration of GFD to be 10 years and 82% using oats. Factors predicting the consumption of oats were diagnosis after the year 2000, advice from a dietitian, detection by screening, and mild clinical presentation. Oat consumers and non consumers did not differ in dietary adherence (96.5% vs. 97.4%, p = 0.746), the prevalence of symptoms (22.9% vs. 22.5%, p = 0.931), positivity for endomysial antibodies (8.8% vs. 6.0%, p = 0.237), histological recovery after one year (63.1% vs. 60.0%, p = 0.773), malignancy (4.8% vs. 3.3%, p = 0.420), osteoporosis/osteopenia (9.2% vs. 11.0%, p = 0.489), or fractures (26.9% vs. 27.9%, p = 0.791). The oat consumers had better SF-36 physical role limitations and general health scores. Based on our results, the long-term consumption of oats in celiac disease patients is safe and may improve quality of life. PMID- 28617329 TI - Hepatoprotective Effect of Aqueous Extract from the Seeds of Orychophragmus violaceus against Liver Injury in Mice and HepG2 Cells. AB - Orychophragmus violaceus (O. violaceus) is a kind of edible wild herb in north China and its seeds have medical potential, however, the effect of O. violaceus seeds on liver injury and the mechanism of action remains poorly understood. Thus, the purpose of the present study is to investigate the effect of O. violaceus seeds on liver injury and further explore the molecular mechanism of the beneficial effects using aqueous extract from the seeds of O. violaceus (AEOV). Mice were orally administrated with saline, AEOV, and biphenyldicarboxylate for 4 days, and were then injected subcutaneously with 0.1% carbon tetrachloride (CCl4) dissolved in corn oil. Sixteen hours later, mice were sacrificed and blood samples were collected. Then, the serum was separated and used for biochemical assay. Livers were excised and were routinely processed for histological examinations. Enzyme activities and protein levels in liver homogenates were detected using commercial kits or by western blot analysis. Additionally, the hepatoprotective effect of AEOV in vitro was evaluated using epigoitrin, the major alkaloid compound isolated from AEOV. We found that AEOV attenuated liver injury induced by CCl4 as evidenced by decreased levels of alanine aminotransferase (ALT) and aminotransferase (AST) in serum, improvement of liver histopathological changes, and substantial attenuation of oxidative stress and inflammation via regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and nuclear factor kappaB (NFkappaB) pathways. These effects of AEOV were comparable to that of biphenyldicarboxylate which was commonly used as a hepatoprotective reference. Moreover, pretreatment of HepG2 cells with epigoitrin improved cell viability, decreased lactate dehydrogenase (LDH) and malondialdehyde (MDA) levels, increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, attenuated the NFkappaB pathway, and elevated the Nrf2 pathway after exposure to H2O2. These results suggest that AEOV could effectively prevent CCl4-induced liver injury in mice via regulating the Nrf2 and NFkappaB pathways, and reveal the cytoprotective effects of epigoitrin against H2O2-induced oxidative stress in HepG2 cells. PMID- 28617330 TI - Identification of Pathogenic Factors in Klebsiella pneumoniae Using Impedimetric Sensor Equipped with Biomimetic Surfaces. AB - K.pneumoniae is an opportunistic pathogen that causes nosocomial infections, such as, pneumonia, urinary tract infections, septic shock, and gastro intestinal disease. Lipopolysaccharide (LPS), capsular polysaccharide, and fimbriae are recognized major virulence factors of K.pneumoniae and play key roles during early stages of infections. In this study, we functionalized the surface of gold electrode with mannose and mucin to monitor the adhesion-associated virulence factors of K.pneumoniae. The binding characteristics of K.pneumoniae 2242 wild type and of its isogenic mutants lacking outer-core LPS (?wabG) or fimbriae (?fimA) were investigated using Faradaic impedance spectra. The results obtained showed fimbriae are responsible for K.pneumoniae adhesion to the mannose of glycoprotein on the surfaces of epithelial cells, whereas outer-core LPS and capsular polysaccharide are associated with specific binding to mucous. These results concurred with those of a conventional in vitro assay using human ileocecal epithelial cell (HCT-8 cells) and a human bladder epithelial cell (T 24), indicating that the devised method could be useful for investigating virulence-associated interactions of pathogenic bacteria with specific host cells and organs. PMID- 28617331 TI - Hormesis and Defense of Infectious Disease. AB - Infectious diseases are a global health burden and remain associated with high social and economic impact. Treatment of affected patients largely relies on antimicrobial agents that act by directly targeting microbial replication. Despite the utility of host specific therapies having been assessed in previous clinical trials, such as targeting the immune response via modulating the cytokine release in sepsis, results have largely been frustrating and did not lead to the introduction of new therapeutic tools. In this article, we will discuss current evidence arguing that, by applying the concept of hormesis, already approved pharmacological agents could be used therapeutically to increase survival of patients with infectious disease via improving disease tolerance, a defense mechanism that decreases the extent of infection-associated tissue damage without directly targeting pathogenic microorganisms. PMID- 28617332 TI - Dynamic Allostery Modulates Catalytic Activity by Modifying the Hydrogen Bonding Network in the Catalytic Site of Human Pin1. AB - Allosteric communication among domains in modular proteins consisting of flexibly linked domains with complimentary roles remains poorly understood. To understand how complementary domains communicate, we have studied human Pin1, a representative modular protein with two domains mutually tethered by a flexible linker: a WW domain for substrate recognition and a peptidyl-prolyl isomerase (PPIase) domain. Previous studies of Pin1 showed that physical contact between the domains causes dynamic allostery by reducing conformation dynamics in the catalytic domain, which compensates for the entropy costs of substrate binding to the catalytic site and thus increases catalytic activity. In this study, the S138A mutant PPIase domain, a mutation that mimics the structural impact of the interdomain contact, was demonstrated to display dynamic allostery by rigidification of the alpha2-alpha3 loop that harbors the key catalytic residue C113. The reduced dynamics of the alpha2-alpha3 loop stabilizes the C113-H59 hydrogen bond in the hydrogen-bonding network of the catalytic site. The stabilized hydrogen bond between C113 and H59 retards initiation of isomerization, which explains the reduced isomerization rate by ~20% caused by the S138A mutation. These results provide new insight into the interdomain allosteric communication of Pin1. PMID- 28617333 TI - An 'Aukward' Tale: A Genetic Approach to Discover the Whereabouts of the Last Great Auks. AB - One hundred and seventy-three years ago, the last two Great Auks, Pinguinusimpennis, ever reliably seen were killed. Their internal organs can be found in the collections of the Natural History Museum of Denmark, but the location of their skins has remained a mystery. In 1999, Great Auk expert Errol Fuller proposed a list of five potential candidate skins in museums around the world. Here we take a palaeogenomic approach to test which-if any-of Fuller's candidate skins likely belong to either of the two birds. Using mitochondrial genomes from the five candidate birds (housed in museums in Bremen, Brussels, Kiel, Los Angeles, and Oldenburg) and the organs of the last two known individuals, we partially solve the mystery that has been on Great Auk scholars' minds for generations and make new suggestions as to the whereabouts of the still missing skin from these two birds. PMID- 28617334 TI - The Molecular Effect of Diagnostic Absorbed Doses from 131I on Papillary Thyroid Cancer Cells In Vitro. AB - Diagnostic whole-body scan is a standard procedure in patients with thyroid cancer prior to the application of a therapeutic dose of 131I. Unfortunately, administration of the radioisotope in a diagnostic dose may decrease further radioiodine uptake-the phenomenon called "thyroid stunning". We estimated radiation absorbed dose-dependent changes in genetic material, in particular in the sodium iodide symporter (NIS) gene promoter, and the NIS protein level in a K1 cell line derived from the metastasis of a human papillary thyroid carcinoma exposed to 131I in culture. The different activities applied were calculated to result in absorbed doses of 5, 10 and 20 Gy. Radioiodine did not affect the expression of the NIS gene at the mRNA level, however, we observed significant changes in the NIS protein level in K1 cells. The decrease of the NIS protein level observed in the cells subjected to the lowest absorbed dose was paralleled by a significant increase in 8-oxo-dG concentrations (p < 0.01) and followed by late activation of the DNA repair pathways. Our findings suggest that the impact of 131I radiation on thyroid cells, in the range compared to doses absorbed during diagnostic procedures, is not linear and depends on various factors including the cellular components of thyroid pathology. PMID- 28617335 TI - ZnO Nano-Rod Devices for Intradermal Delivery and Immunization. AB - Intradermal delivery of antigens for vaccination is a very attractive approach since the skin provides a rich network of antigen presenting cells, which aid in stimulating an immune response. Numerous intradermal techniques have been developed to enhance penetration across the skin. However, these methods are invasive and/or affect the skin integrity. Hence, our group has devised zinc oxide (ZnO) nano-rods for non-destructive drug delivery. Chemical vapour deposition was used to fabricate aligned nano-rods on ZnO pre-coated silicon chips. The nano-rods' length and diameter were found to depend on the temperature, time, quality of sputtered silicon chips, etc. Vertically aligned ZnO nano-rods with lengths of 30-35 um and diameters of 200-300 nm were selected for in vitro human skin permeation studies using Franz cells with Albumin fluorescein isothiocyanate (FITC) absorbed on the nano-rods. Fluorescence and confocal studies on the skin samples showed FITC penetration through the skin along the channels formed by the nano-rods. Bradford protein assay on the collected fluid samples indicated a significant quantity of Albumin-FITC in the first 12 h. Low antibody titres were observed with immunisation on Balb/c mice with ovalbumin (OVA) antigen coated on the nano-rod chips. Nonetheless, due to the reduced dimensions of the nano-rods, our device offers the additional advantage of excluding the simultaneous entrance of microbial pathogens. Taken together, these results showed that ZnO nano-rods hold the potential for a safe, non-invasive, and painless intradermal drug delivery. PMID- 28617336 TI - Response Surface Optimized Infrared-Assisted Extraction and UHPLC Determination of Flavonoid Types from Flos Sophorae. AB - Single-factor experiment and Box-Behnken design were applied to optimize the infrared-assisted extraction (IRAE) of rutin, quercetin, kaempferol, and isorhamnetin from Flos sophorae. Four factors (extract solvent, solid-liquid ration, extraction time, infrared power) affecting the extraction yield of flavonoids were studied. Under optimized conditions the extraction yield was 33.199 +/- 0.24 mg/g, which substantially improved, compared with heating reflux extraction (HRE) and ultrasonic-assisted extraction (UAE), while extraction time was only 9 min. The eluents were rich in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azobis (2-methyl-propionamidine) dihydrochloride radical scavenging potential (IC50 of DPPH: 53.44 +/- 0.01 MUg/mL, oxygen radical absorbance capacity (ORAC): 3785.83 +/- 52 MUmol/g) than the extracts obtained by HRE and UAE. In addition, an ultra-high performance liquid chromatography method was optimized for the identification and quantification of the tested flavonoids, and the method was validated based on its correlation coefficient (r), reproducibility (RSD, n = 5), and recovery values, which were 0.9994-0.9998, 0.74 1.83%, and 97.78-102.94%, respectively. These results confirmed that high extraction yield of flavonoids results in stronger antioxidant values and response surface methodology optimization of IRAE is a promising alternative to traditional extraction techniques for flavonoids from medicinal plants. PMID- 28617337 TI - Tunable Temperature Response of a Thermochromic Photonic Gel Sensor Containing N Isopropylacrylamide and 4-Acryloyilmorpholine. AB - In this study, thermochromic photonic gels were fabricated using 2-hydroxyethyl methacrylate (HEMA) as a hydrogel building block, and 4-Acryloyl morpholine (ACMO) and N-isopropylacrylamide (NIPAAM) as thermoresponsive monomers with different critical solution temperature behaviors. Rapid photopolymerization of opal-templated monomer mixtures of varying ACMO contents formed five individual thermochromic inverse opal photonic gels integrated on a single substrate. With temperature variation from 10 degrees C to 80 degrees C, the changes in reflective colors and reflectance spectra of the respective thermochromic gels were noted, and lambdapeak changes were plotted. Because NIPAAM exhibits a lower critical solution temperature (LCST) at 33 degrees C, the NIPAAM-only gel showed a steep slope for dlambdapeak/dT below 40 degrees C, whereas the slope became flatter at high temperatures. As the ACMO content increased in the thermochromic gel, the curve of dlambdapeak/dT turned out to be gradual within the investigated temperature range, exhibiting the entire visible range of colors. The incorporation of ACMO in NIPAAM-based thermochromic gels therefore enabled a better control of color changes at a relatively high-temperature regime compared to a NIPAAM-only gel. In addition, ACMO-containing thermochromic gels exhibited a smaller hysteresis of lambdapeak for the heating and cooling cycle. PMID- 28617338 TI - Indoor Autonomous Control of a Two-Wheeled Inverted Pendulum Vehicle Using Ultra Wide Band Technology. AB - In this paper, we aimed to achieve the indoor tracking control of a two-wheeled inverted pendulum (TWIP) vehicle. The attitude data are acquired from a low cost micro inertial measurement unit (IMU), and the ultra-wideband (UWB) technology is utilized to obtain an accurate estimation of the TWIP's position. We propose a dual-loop control method to realize the simultaneous balance and trajectory tracking control for the TWIP vehicle. A robust adaptive second-order sliding mode control (2-RASMC) method based on an improved super-twisting (STW) algorithm is investigated to obtain the control laws, followed by several simulations to verify its robustness. The outer loop controller is designed using the idea of backstepping. Moreover, three typical trajectories, including a circle, a trifolium and a hexagon, have been designed to prove the adaptability of the control combinations. Six different combinations of inner and outer loop control algorithms have been compared, and the characteristics of inner and outer loop algorithm combinations have been analyzed. Simulation results demonstrate its tracking performance and thus verify the validity of the proposed control methods. Trajectory tracking experiments in a real indoor environment have been performed using our experimental vehicle to further validate the feasibility of the proposed algorithm in practice. PMID- 28617339 TI - Development of a Stereovision-Based Technique to Measure the Spread Patterns of Granular Fertilizer Spreaders. AB - Centrifugal fertilizer spreaders are by far the most commonly used granular fertilizer spreader type in Europe. Their spread pattern however is error-prone, potentially leading to an undesired distribution of particles in the field and losses out of the field, which is often caused by poor calibration of the spreader for the specific fertilizer used. Due to the large environmental impact of fertilizer use, it is important to optimize the spreading process and minimize these errors. Spreader calibrations can be performed by using collection trays to determine the (field) spread pattern, but this is very time-consuming and expensive for the farmer and hence not common practice. Therefore, we developed an innovative multi-camera system to predict the spread pattern in a fast and accurate way, independent of the spreader configuration. Using high-speed stereovision, ejection parameters of particles leaving the spreader vanes were determined relative to a coordinate system associated with the spreader. The landing positions and subsequent spread patterns were determined using a ballistic model incorporating the effect of tractor motion and wind. Experiments were conducted with a commercial spreader and showed a high repeatability. The results were transformed to one spatial dimension to enable comparison with transverse spread patterns determined in the field and showed similar results. PMID- 28617340 TI - Coumarin-Tetrapyrrolic Macrocycle Conjugates: Synthesis and Applications. AB - This review covers the synthesis of coumarin-porphyrin, coumarin-phthalocyanine and coumarin-corrole conjugates and their potential applications. While coumarin phthalocyanine conjugates were obtained almost exclusively by tetramerization of coumarin-functionalized phthalonitriles, coumarin-porphyrin and coumarin-corrole conjugates were prepared by complementary approaches: (a) direct synthesis of the tetrapyrrolic macrocycle using formylcoumarins and pyrrole or (b) by functionalization of the tetrapyrrolic macrocycle. In the last approach a range of reaction types were used, namely 1,3-dipolar cycloadditions, hetero-Diels Alder, Sonogashira, alkylation or acylation reactions. This is clearly a more versatile approach, leading to a larger diversity of conjugates and allowing the access to conjugates bearing one to up to 16 coumarin units. PMID- 28617342 TI - Dynamic Resource Allocation and Access Class Barring Scheme for Delay-Sensitive Devices in Machine to Machine (M2M) Communications. AB - Supporting simultaneous access of machine-type devices is a critical challenge in machine-to-machine (M2M) communications. In this paper, we propose an optimal scheme to dynamically adjust the Access Class Barring (ACB) factor and the number of random access channel (RACH) resources for clustered machine-to-machine (M2M) communications, in which Delay-Sensitive (DS) devices coexist with Delay-Tolerant (DT) ones. In M2M communications, since delay-sensitive devices share random access resources with delay-tolerant devices, reducing the resources consumed by delay-sensitive devices means that there will be more resources available to delay-tolerant ones. Our goal is to optimize the random access scheme, which can not only satisfy the requirements of delay-sensitive devices, but also take the communication quality of delay-tolerant ones into consideration. We discuss this problem from the perspective of delay-sensitive services by adjusting the resource allocation and ACB scheme for these devices dynamically. Simulation results show that our proposed scheme realizes good performance in satisfying the delay-sensitive services as well as increasing the utilization rate of the random access resources allocated to them. PMID- 28617341 TI - Microwave-Assisted Facile Synthesis, Anticancer Evaluation and Docking Study of N ((5-(Substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl) Benzamide Derivatives. AB - In the present work, 12 novel Schiff's bases containing a thiadiazole scaffold and benzamide groups coupled through appropriate pharmacophore were synthesized. These moieties are associated with important biological properties. A facile, solvent-free synthesis of a series of novel 7(a-l) N-((5-(substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl) benzamide was carried out under microwave irradiation. Structures of the synthesized compounds were confirmed by IR, NMR, mass spectral study and elemental analysis. All the synthesized hybrids were evaluated for their in vitro anticancer activity against a panel of four human cancer cell lines, viz. SK-MEL-2 (melanoma), HL-60 (leukemia), HeLa (cervical cancer), MCF-7 (breast cancer) and normal breast epithelial cell (MCF-10A) using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. Most of the synthesized compounds exhibited promising anticancer activity, showed comparable GI50 values comparable to that of the standard drug Adriamycin. The compounds 7k, 7l, 7b, and 7a were found to be the most promising anticancer agents in this study. A molecular docking study was performed to predict the probable mechanism of action and computational study of the synthesized compounds 7(a-l) was performed to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, by using QikProp v3.5 (Schrodinger LLC). The results showed the good oral drug-like behavior of the synthesized compounds 7(a l). PMID- 28617343 TI - Study of the Relation between the Resonance Behavior of Thickness Shear Mode (TSM) Sensors and the Mechanical Characteristics of Biofilms. AB - This work analyzes some key aspects of the behavior of sensors based on piezoelectric Thickness Shear Mode (TSM) resonators to study and monitor microbial biofilms. The operation of these sensors is based on the analysis of their resonance properties (both resonance frequency and dissipation factor) that vary in contact with the analyzed sample. This work shows that different variations during the microorganism growth can be detected by the sensors and highlights which of these changes are indicative of biofilm formation. TSM sensors have been used to monitor in real time the development of Staphylococcus epidermidis and Escherichia coli biofilms, formed on the gold electrode of the quartz crystal resonators, without any coating. Strains with different ability to produce biofilm have been tested. It was shown that, once a first homogeneous adhesion of bacteria was produced on the substrate, the biofilm can be considered as a semi-infinite layer and the quartz sensor reflects only the viscoelastic properties of the region immediately adjacent to the resonator, not being sensitive to upper layers of the biofilm. The experiments allow the microrheological evaluation of the complex shear modulus (G* = G' + jG") of the biofilm at 5 MHz and at 15 MHz, showing that the characteristic parameter that indicates the adhesion of a biofilm for the case of S. epidermidis and E. coli, is an increase in the resonance frequency shift of the quartz crystal sensor, which is connected with an increase of the real shear modulus, related to the elasticity or stiffness of the layer. In addition both the real and the imaginary shear modulus are frequency dependent at these high frequencies in biofilms. PMID- 28617344 TI - Synthesis and Biological Activity Evaluation of Novel Heterocyclic Pleuromutilin Derivatives. AB - A series of pleuromutilin derivatives were synthesized by two synthetic procedures under mild reaction conditions and characterized by Nuclear Magnetic Resonance (NMR), Infrared Spectroscopy (IR), and High Resolution Mass Spectrometer (HRMS). Most of the derivatives with heterocyclic groups at the C-14 side of pleuromutilin exhibited excellent in vitro antibacterial activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin resistant Enterococcus (VRE) in vitro antibacterial activity. The synthesized derivatives which contained pyrimidine rings, 3a, 3b, and 3f, displayed modest antibacterial activities. Compound 3a, the most active antibacterial agent, displayed rapid bactericidal activity and affected bacterial growth in the same manner as that of tiamulin fumarate. Moreover, molecular docking studies of 3a and lefamulin provided similar information about the interactions between the compounds and 50S ribosomal subunit. The results of the study show that pyrimidine rings should be considered in the drug design of pleuromutilin derivatives. PMID- 28617345 TI - Examining Associations of Environmental Characteristics with Recreational Cycling Behaviour by Street-Level Strava Data. AB - Policymakers pay much attention to effectively increasing frequency of people's cycling in the context of developing sustainable and green cities. Investigating associations of environmental characteristics and cycling behaviour could offer implications for changing urban infrastructure aiming at encouraging active travel. However, earlier examinations of associations between environmental characteristics and active travel behaviour are limited by low spatial granularity and coverage of traditional data. Crowdsourced geographic information offers an opportunity to determine the fine-grained travel patterns of people. Particularly, Strava Metro data offer a good opportunity for studies of recreational cycling behaviour as they can offer hourly, daily or annual cycling volumes with different purposes (commuting or recreational) in each street across a city. Therefore, in this study, we utilised Strava Metro data for investigating associations between environmental characteristics and recreational cycling behaviour at a large spatial scale (street level). In this study, we took account of population density, employment density, road length, road connectivity, proximity to public transit services, land use mix, proximity to green space, volume of motor vehicles and traffic accidents in an empirical investigation over Glasgow. Empirical results reveal that Strava cyclists are more likely to cycle for recreation on streets with short length, large connectivity or low volume of motor vehicles or on streets surrounded by residential land. PMID- 28617346 TI - LDMOS Channel Thermometer Based on a Thermal Resistance Sensor for Balancing Temperature in Monolithic Power ICs. AB - This paper presents a method of thermal balancing for monolithic power integrated circuits (ICs). An on-chip temperature monitoring sensor that consists of a poly resistor strip in each of multiple parallel MOSFET banks is developed. A temperature-to-frequency converter (TFC) is proposed to quantize on-chip temperature. A pulse-width-modulation (PWM) methodology is developed to balance the channel temperature based on the quantization. The modulated PWM pulses control the hottest of metal-oxide-semiconductor field-effect transistor (MOSFET) bank to reduce its power dissipation and heat generation. A test chip with eight parallel MOSFET banks is fabricated in TSMC 0.25 MUm HV BCD processes, and total area is 900 * 914 MUm2. The maximal temperature variation among the eight banks can reduce to 2.8 degrees C by the proposed thermal balancing system from 9.5 degrees C with 1.5 W dissipation. As a result, our proposed system improves the lifetime of a power MOSFET by 20%. PMID- 28617347 TI - Repetitive Behaviours and Restricted Interests in Individuals with Down Syndrome One Way of Managing Their World? AB - This paper argues that the repetitive behaviour and restrictive interests (RBRI) displayed by individuals with Down syndrome have mostly positive functions. However, as research has developed from interests in Obsessional Compulsive Disorder or Autistic Spectrum Disorder, unfortunately a view has arisen that RBRI in individuals with Down syndrome are also likely to be pathological. This is particularly the case in adults. The paper reviews: (a) measures employed and the perspectives that have been used; (b) the development in typically developing individuals, those with Down syndrome, and those with other conditions associated with intellectual disability; (c) positive and possible negative effects of RBRI; and (d) the need for more research. The conclusion is that, for their level of development, RBRI are helpful for most individuals with Down syndrome. PMID- 28617348 TI - Urban Ecological Security Simulation and Prediction Using an Improved Cellular Automata (CA) Approach-A Case Study for the City of Wuhan in China. AB - Ecological security is an important research topic, especially urban ecological security. As highly populated eco-systems, cities always have more fragile ecological environments. However, most of the research on urban ecological security in literature has focused on evaluating current or past status of the ecological environment. Very little literature has carried out simulation or prediction of future ecological security. In addition, there is even less literature exploring the urban ecological environment at a fine scale. To fill-in the literature gap, in this study we simulated and predicted urban ecological security at a fine scale (district level) using an improved Cellular Automata (CA) approach. First we used the pressure-state-response (PSR) method based on grid-scale data to evaluate urban ecological security. Then, based on the evaluation results, we imported the geographically weighted regression (GWR) concept into the CA model to simulate and predict urban ecological security. We applied the improved CA approach in a case study-simulating and predicting urban ecological security for the city of Wuhan in Central China. By comparing the simulated ecological security values from 2010 using the improved CA model to the actual ecological security values of 2010, we got a relatively high value of the kappa coefficient, which indicates that this CA model can simulate or predict well future development of ecological security in Wuhan. Based on the prediction results for 2020, we made some policy recommendations for each district in Wuhan. PMID- 28617349 TI - Investigation of Acute Pulmonary Deficits Associated with Biomass Fuel Cookstove Emissions in Rural Bangladesh. AB - The use of solid biomass fuels in cookstoves has been associated with chronic health impacts that disproportionately affect women worldwide. Solid fuel stoves that use wood, plant matter, and cow dung are commonly used for household cooking in rural Bangladesh. This study investigates the immediate effects of acute elevated cookstove emission exposures on pulmonary function. Pulmonary function was measured with spirometry before and during cooking to assess changes in respiratory function during exposure to cookstove emissions for 15 females ages 18-65. Cookstove emissions were characterized using continuous measurements of particulate matter (PM2.5-aerodynamic diameter <2.5 MUm) concentrations at a 1 s time resolution for each household. Several case studies were observed where women >=40 years who had been cooking for >=25 years suffered from severe pulmonary impairment. Forced expiratory volume in one second over forced vital capacity (FEV1/FVC) was found to moderately decline (p = 0.06) during cooking versus non-cooking in the study cohort. The study found a significant (alpha < 0.05) negative association between 3- and 10-min maximum PM2.5 emissions during cooking and lung function measurements of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and FEV1/FVC obtained during cooking intervals. This study found that exposure to biomass burning emissions from solid fuel stoves- associated with acute elevated PM2.5 concentrations- leads to a decrease in pulmonary function, although further research is needed to ascertain the prolonged (e.g., daily, for multiple years) impacts of acute PM2.5 exposure on immediate and sustained respiratory impairment. PMID- 28617350 TI - Public Perceptions of Service Dogs, Emotional Support Dogs, and Therapy Dogs. AB - As service dogs, emotional support dogs, and therapy dogs have become more prevalent in the USA, so too has the controversy surrounding their legitimacy. Yet, there is a lack of objective data regarding the public's understanding of the role played by each of these types of animals, as well as their perceptions regarding the legitimacy of their integration. An anonymous, online survey was distributed to examine the perceptions of US adults who do not own any type of assistance animal. A total of 505 individuals responded to the online survey, yielding 284 usable responses. Results suggest widespread misconceptions about definitions, rules, regulations, and rights associated with each type of assistance dog. In general, service dogs are more likely to be perceived as helping with a legitimate need, and their access to public spaces is viewed favorably. While there are some concerns about the legitimacy and necessary access rights for emotional support dogs, members of the public correctly identified the roles and rights of therapy dogs. Despite the media's focus on abuses and false representation of these dogs, most participants reported feeling the majority of people are not taking advantage of the system. PMID- 28617351 TI - An Extended Kriging Method to Interpolate Near-Surface Soil Moisture Data Measured by Wireless Sensor Networks. AB - In the practice of interpolating near-surface soil moisture measured by a wireless sensor network (WSN) grid, traditional Kriging methods with auxiliary variables, such as Co-kriging and Kriging with external drift (KED), cannot achieve satisfactory results because of the heterogeneity of soil moisture and its low correlation with the auxiliary variables. This study developed an Extended Kriging method to interpolate with the aid of remote sensing images. The underlying idea is to extend the traditional Kriging by introducing spectral variables, and operating on spatial and spectral combined space. The algorithm has been applied to WSN-measured soil moisture data in HiWATER campaign to generate daily maps from 10 June to 15 July 2012. For comparison, three traditional Kriging methods are applied: Ordinary Kriging (OK), which used WSN data only, Co-kriging and KED, both of which integrated remote sensing data as covariate. Visual inspections indicate that the result from Extended Kriging shows more spatial details than that of OK, Co-kriging, and KED. The Root Mean Square Error (RMSE) of Extended Kriging was found to be the smallest among the four interpolation results. This indicates that the proposed method has advantages in combining remote sensing information and ground measurements in soil moisture interpolation. PMID- 28617352 TI - Equivalent Circuit Model of Low-Frequency Magnetoelectric Effect in Disk-Type Terfenol-D/PZT Laminate Composites Considering a New Interface Coupling Factor. AB - This paper describes the modeling of magnetoelectric (ME) effects for disk-type Terfenol-D (Tb0.3Dy0.7Fe1.92)/PZT (Pb(Zr,Ti)O3) laminate composite at low frequency by combining the advantages of the static elastic model and the equivalent circuit model, aiming at providing a guidance for the design and fabrication of the sensors based on magnetoelectric laminate composite. Considering that the strains of the magnetostrictive and piezoelectric layers are not equal in actual operating due to the epoxy resin adhesive bonding condition, the magnetostrictive and piezoelectric layers were first modeled through the equation of motion separately, and then coupled together with a new interface coupling factor kc, which physically reflects the strain transfer between the phases. Furthermore, a theoretical expression containing kc for the transverse ME voltage coefficient alphav and the optimum thickness ratio noptim to which the maximum ME voltage coefficient corresponds were derived from the modified equivalent circuit of ME laminate, where the interface coupling factor acted as an ideal transformer. To explore the influence of mechanical load on the interface coupling factor kc, two sets of weights, i.e., 100 g and 500 g, were placed on the top of the ME laminates with the same thickness ratio n in the sample fabrication. A total of 22 T-T mode disk-type ME laminate samples with different configurations were fabricated. The interface coupling factors determined from the measured alphav and the DC bias magnetic field Hbias were 0.11 for 500 g pre-mechanical load and 0.08 for 100 g pre-mechanical load. Furthermore, the measured optimum thickness ratios were 0.61 for kc = 0.11 and 0.56 for kc = 0.08. Both the theoretical ME voltage coefficient alphav and optimum thickness ratio noptim containing kc agreed well with the measured data, verifying the reasonability and correctness for the introduction of kc in the modified equivalent circuit model. PMID- 28617353 TI - Torsional Ultrasound Sensor Optimization for Soft Tissue Characterization. AB - Torsion mechanical waves have the capability to characterize shear stiffness moduli of soft tissue. Under this hypothesis, a computational methodology is proposed to design and optimize a piezoelectrics-based transmitter and receiver to generate and measure the response of torsional ultrasonic waves. The procedure employed is divided into two steps: (i) a finite element method (FEM) is developed to obtain a transmitted and received waveform as well as a resonance frequency of a previous geometry validated with a semi-analytical simplified model and (ii) a probabilistic optimality criteria of the design based on inverse problem from the estimation of robust probability of detection (RPOD) to maximize the detection of the pathology defined in terms of changes of shear stiffness. This study collects different options of design in two separated models, in transmission and contact, respectively. The main contribution of this work describes a framework to establish such as forward, inverse and optimization procedures to choose a set of appropriate parameters of a transducer. This methodological framework may be generalizable for other different applications. PMID- 28617355 TI - [An analysis of the prevalence and risk factors of multiple sclerosis in the Republic of Ingushetia]. AB - AIM: To determine epidemiological characteristics and factors related to the development of multiple sclerosis (MS) in the population of the Republic of Ingushetia in 2013-2016. MATERIAL AND METHODS: A study was carried out in several clinical settings of the Republic of Ingushetia. A special medical form developed for the study was completed by patients. Medical examination of patients was performed as well. Statistical methods were used for data analysis. RESULTS AND CONCLUSION: A significant variation of MS prevalence was seen. The mean prevalence rate was low - 13.2 cases of MS per 100 000 of population. It was different in ethnic groups: 13.7 per 100 000 of population in Ingush, 15.2 in Chechen and 45 in the Slavonic population. The incidence of MS was 1.76 per 100 000 population in 2015. Different risk factors of MS, including adverse ecological factors and environmental risk predictors (contact with poisons), and their greater role compared to genetic factors were identified. PMID- 28617356 TI - [The association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk and rapid progression of multiple sclerosis]. AB - AIM: To evaluate the association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk of multiple sclerosis and its progression dynamics. MATERIAL AND METHODS: A case-control study included 100 patients with recurrent multiple sclerosis (MS), Russians from the Altai Territory, and 100 healthy volunteers. Real-time polymerase chain reaction was used to genotype the 1377G>A polymorphism in the promoter of the FAS/APO-1 (rs2234767) gene. Association of this polymorphism with the risk of multiple sclerosis and its progression was evaluated. RESULTS: The G/A genotype and the A-allele were associated with the increased risk of multiple sclerosis. The G/A genotype and the A-allele were associated with the risk of high progression rate of the disease. The G/G genotype and the G-allele had a protective effect. CONCLUSION: Predisposition to MS as well as to high progression rate are associated with the FAS/APO-1*G/A gene in Russians living in the Altai Territory. Further research is required to make the conclusion. PMID- 28617354 TI - Photoacoustic Drug Delivery. AB - Photoacoustic (PA) technology holds great potential in clinical translation as a new non-invasive bioimaging modality. In contrast to conventional optical imaging, PA imaging (PAI) enables higher resolution imaging with deeper imaging depth. Besides applications for diagnosis, PA has also been extended to theranostic applications. The guidance of PAI facilitates remotely controlled drug delivery. This review focuses on the recent development of PAI-mediated drug delivery systems. We provide an overview of the design of different PAI agents for drug delivery. The challenges and further opportunities regarding PA therapy are also discussed. PMID- 28617357 TI - [Polymorphic variants of the immune response genes as risk factors for primary progressive multiple sclerosis]. AB - AIM: To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS). MATERIAL AND METHODS: This multicenter study included 111 patients with PPMS from the Russian ethnic group. The association of PPMS with genes of immune system was analyzed by the study of polymorphic variants of genes of cytokines and genes of antigen-presenting cells. RESULTS AND CONCLUSION: The genotypes of IL-4 (rs2243250)*C/C and CLEC16A (rs6498169)*G/G were associated with PPMS in Russians. The association between the HLA-DRB1*15 and PPMS found out in other populations was confirmed in Russians. PMID- 28617358 TI - [Dendritic cells in multiple sclerosis]. AB - Main functions, structure and stages of development of dendritic cells (DCs) are reviewed. A role of DCs in the development of immune tolerance and autoimmune diseases as well as involvement of DCs in the immunopathogenesis of multiple sclerosis (MS and their therapeutic potential in the treatment of MS are discussed. PMID- 28617359 TI - [Clinical and molecular genetic analysis of a case of familial multiple sclerosis in the Republic of Bashkortostan]. AB - AIM: To investigate clinical manifestations of multiple sclerosis (MS) and the genetic makeup of six affected members of one family. MATERIAL AND METHODS: Six members of the family of Russian ethnic origin were examined. Pedigree analysis and genotyping of polymorphic markers of candidate genes for multiple sclerosis were performed. RESULTS AND CONCLUSION: The accumulation of alleles that were associated with autoimmune diseases according to the results of genome-wide association studies (rs1109670*C, rs3129934*T, rs9523762*G, rs1570538*T) was found in the family. The results confirm the contribution of several genetic variants to familial forms of MS. PMID- 28617360 TI - [The influence of solar and geomagnetic activity on the risk of multiple sclerosis (results of correlation and regression analysis)]. AB - AIM: Multiple sclerosis (MS) develops as a result of an interaction between genetic and environmental factors, among them solar (SA) and geomagnetic activity (GMA) attract the particular attention. An impact of SA and GMA on intrauterine and postnatal period in MS was studied. MATERIAL AND METHODS: The study included 358 patients with MS. Correlation (CA) and regression analysis (RA) were used to study the effects of SA and GMA during intrauterine period, the 1st year of life, a year of disease onset, a year before the onset. RESULTS AND CONCLUSIONS: CA revealed the association between the MS onset and mean values of kp-index in the onset year and the year before the onset year, number of days with kp>=4 and kp>=5 in the onset year and the year before the onset year, mean SFU in the onset year. RA revealed the association between the MS onset and mean kp in the year before the onset year and in the onset year, number of days with kp>=7 in the onset year and the year before the onset year, mean kp during pregnancy, number of days with kp>=7 in the 1st year of life and during pregnancy. The influence of high GMA during pregnancy and in the 1st year of life increases the MS risk in the future and the high GMA predisposes to the MS onset in adults. The practical value of the study is that predicting the GMA changes we can try to prevent the onset and relapses in the risk groups. PMID- 28617361 TI - [Atypical multiple sclerosis - Balo's concentric sclerosis: two case-reports and a review]. AB - This article presents two clinical cases of patients diagnosed with Balo's concentric sclerosis. Distinctive features of the pathogenesis in the aspect of differential diagnosis from other forms of multiple sclerosis and possible treatment are discussed. PMID- 28617362 TI - [Marburg's variant of multiple sclerosis: a case report]. AB - Marburg's variant of multiple sclerosis, first described by the Austrian neurologist Otto Marburg in 1906, is a rare demyelinating disease that usually leads to severe disability or death within weeks to months. Our case report describes a young 24-year old woman with Marburg's variant of multiple sclerosis who became totally disabled over a period of some months. Clinical features and MRI-characteristics of two demyelinating diseases: acute disseminated encephalomyelitis (ADEM) and Marburg's variant of multiple sclerosis are discussed. The use of intense immunosuppression in the case described is considered. PMID- 28617363 TI - [Diagnostic value of immunoglobulin free light chains at the debut of multiple sclerosis]. AB - AIM: To evaluate the diagnostic value of determination of free immunoglobulin light chains (IgG) in the debut of multiple sclerosis (MS). MATERIAL AND METHODS: Data from 226 patients, including 111 patients with clinically isolated syndrome with conversion to multiple sclerosis within the first 2 years of the disease (group 1), 49 patients with clinically isolated syndrome who did not develop multiple sclerosis within the first 2 years of the disease (group 2), 20 patients with other inflammatory diseases of the central nervous system (group 3) were analyzed. The control group consisted of 46 patients with non-inflammatory diseases of the central nervous system. The clonality of immunoglobulins in the CSF, concentration of kappa and lambda free light chains and their ratio were studied. RESULTS: Concentrations of free light chains were significantly higher in the first group in comparison with group 2 and the control group, but didn't differ from group 3. In group 3, concentrations of free light chains were significantly higher compared to group 2 and controls. In oligoclonal-positive patients with clinically isolated syndrome (groups 1 and 2), concentrations of kappa and lambda free light chains were significantly higher than in oligoclonal negative patients. The production of free light chains in patients from the first group was considerably higher than in group 2 regardless of the oligoclonal status. The concentration of kappa chains and quotient of kappa free light chains in the CSF had the best diagnostic characteristics. Their use, along with the evaluation of IgG clonality, reduced the risk of false-negative results by 50%. Regardless of other factors, elevated concentrations of kappa chains increase the likelihood of MS diagnosis by 9.718 times. CONCLUSION: The use of free light chains as a laboratory marker can increase the accuracy of MS diagnosis. These markers can help indirectly assess the risk of transformation of a clinically isolated syndrome into definite multiple sclerosis within the first 2 years of disease. PMID- 28617364 TI - [A current view on the MRI diagnosis of multiple sclerosis: an update of 2016 revised MRI criteria]. AB - Magnetic resonance imaging (MRI) is the primary method for confirming the clinical diagnosis of multiple sclerosis (MS). The article presents the current data on using MRI of the brain and spinal cord for diagnosis in suspected MS. Special attention is paid to the MRI criteria of McDonald and MAGNIMS for relapsing-remitting MS (RRMS) and primary-progressive MS (PPMS) in the latest revisions of 2010 and 2016. The information provided can help radiologists and neurologists to optimize the use of MRI in clinical practice for diagnosis of MS. PMID- 28617365 TI - [Immune reconstitution inflammatory syndrome and rebound syndrome in multiple sclerosis patients who stopped disease modification therapy: current understanding and a case report]. AB - More and more multiple sclerosis patients have been receiving treatment with new immunomodulatory drugs. Its discontinuation because of side-effects, lack of efficacy or pregnancy has been increasing as well. This paper reviews such severe complications of natalizumab and fingolimod cessation as immune reconstitution inflammatory syndrome (IRIS) and rebound. The short history, immunopathogenesis and diagnostic criteria of IRIS in individuals with human immunodeficiency virus infection are covered. Clinical and radiological presentations as well as possible pathogenic mechanisms of IRIS in patients treated with natalizumab and fingolimod are discussed. The authors also report the case of a woman with multiple sclerosis treated with fingolimod, who experienced a severe relapse when she stopped treatment. Diagnostic criteria and prognostic factors for IRIS and rebound are needed in patients with multiple sclerosis who discontinue the new disease modification therapy. PMID- 28617366 TI - [An effect of disease-modifying drugs on the development of children born to mothers with multiple sclerosis]. AB - AIM: To evaluate an effect of mother's treatment with disease-modifying drugs (DMD) on the mental and physical development of the child in the first year of life. MATERIAL AND METHODS: Thirty pregnancies resulted in birth of live babies in patients with multiple sclerosis (MS) were studied. The diagnosis of MS was made to the mother before conception of the child. Seven mothers did not receive DMD at the moment of conception (controls), 13 mother were treated with interferon-beta (IFN) and 10 with glatiramer acetate. A structure interview, examination of the child with the assessment of common anthropometric indices, the WHO scale for achievement of six milestones, medical history and statistical analysis were used. RESULTS AND CONCLUSION: The data on the negative effect of MS on the growth and development of the fetus and the positive impact of treatment of the mother with DMD in the early stages of pregnancy on anthropometric indices and development of the child in the first year of life were confirmed. It has been concluded that DMD positively influence the disease course of the female patient and potentially improve the prognosis for her future offspring. PMID- 28617367 TI - [Current algorithms of diagnosis and treatment of multiple sclerosis based on the individual assessment of the patient]. AB - This review presents the current knowledge on diagnosis, therapy of relapses of multiple Sclerosis (MS) and disease-modifying therapy (DMT) in MS. Algorithms of diagnosis and therapy of MS are presented. Special attention is paid to the analysis of efficacy, tolerability and safety of DMT in MS. PMID- 28617368 TI - [A comparative placebo-controlled clinical study on the efficacy and safety of interferon beta-1a for subcutaneous injections in patients with remitting multiple sclerosis: results of the first year of observations]. AB - AIM: To prove the equivalent efficacy of teberif (BCD-033, interferon beta-1) and rebif (interferon beta-1a) in patients with remitting multiple sclerosis (RMS). MATERIAL AND METHODS: A multicenter double blind placebo-controlled comparative randomized III phase study included 163 patients with RMS. Patients were randomized into three equal groups (teberif, rebif or placebo). RESULTS AND CONCLUSION: After 52 weeks, the equivalent efficacy of teberif and the brand drug rebif was shown. The result of assessment of the primary endpoint, which was combined unique active (CUA) lesion (the total of MRI T1-weighted lesions and new or newly enlarging T2-weighted lesions, without double counting of lesions with both activities), showed no significant differences (0.727+/-1.042 and 0.652+/ 1.059 (p=0.7354, t-Student test) in the teberif and rebif groups, respectively. No between-group differences were found for other MRI indices and clinical parameters related with relapses. Teberif was shown to have a favorable safety and tolerability profile comparable to that of rebif. The results suggest the therapeutic equivalency of the drugs and form the basis for using the bioanalogue of interferon-beta 1 in patients with RMS. PMID- 28617369 TI - [A.N. Boyko, O.V. Bykova, S.A. Sivertseva. Multiple sclerosis in children and adolescents. M; 2016]. PMID- 28617370 TI - [Clinical recommendations on the use of alemtuzumab (lemtrada)]. PMID- 28617371 TI - [Cognitive dysfunction and content of inflammatory markers in patients after coronary artery bypass graft]. AB - AIM: To study the relationship between the content of inflammatory biomarkers and cognitive function in patients after coronary artery bypass graft (CABG) performed in condition of artificial blood circulation (ABC) or open-heart surgery (OHS). MATERIAL AND METHODS: Twenty-nine patients with ischemic heart disease who survived CABG, mean age 62.4+/-6.2 years, were studied. The ABC group (n=18) and OHS group (n=11) were matched for age and sex. Patients underwent standard clinical examination as well as neurological examination and neuropsychological testing. Concentrations of pro- and anti-inflammatory cytokines (IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17, IL-1RA, IFN-gamma, IP 10; MCP-1, MIP-1alpha, MIP-1beta, RANTES, TNF) were determined in blood plasma obtained 24 h before and 2h after surgery using multiplex immunofluorescence assay. RESULTS: In both groups, an increase in concentrations of IL-6, IL-8, IL 10, IL-12, IP-10, MCP-1, MIP-1beta and RANTES was observed at point T1. Concentration of IL-1RA was significantly higher only in the ABC group but not in the OHS group. After CABG, an increase in concentrations of IL-8, IP-10, MIP 1beta, IL-1RA was significantly higher in the ABC group. The Montreal scale was the most sensitive test for assessment of cognitive functions in post CABG patients. A significant decrease in scores (>3) was noted in 8 out of 18 patients in the ABC group and in one patient of the OHS group. The correlations between the decrease in cognitive functioning in the 7th day after surgery and plasma cytokine concentration 2 h after surgery were identified for IL-6 (r=0.472; p=0.01); IL-8 (r=0.403; p=0.03); IP-10 (r=0.372; p=0.047); MCP-1 (r=0.470; p=0.01). CONCLUSION: CABG is accompanied by the systemic inflammatory reaction, with the more marked inflammatory effect in patients operated under condition of extracorporeal circulation. CABG with ABC causes an impairment of cognitive functions during the first week in many patients. Impaired cognitive status was associated with the increase in concentrations of proinflammatory cytokines in blood plasma. PMID- 28617372 TI - [Characteristics of psychopathological symptomatology in HIV-infection schizophrenic patients]. AB - AIM: To study the psychopathological structure of psychotic syndromes in HIV infected schizophrenic patients and in patients without HIV infection. MATERIAL AND METHODS: Forty HIV-infected patients, 23 women and 17 men, with confirmed diagnosis of schizophrenia were included in the study. The control group consisted of 40 patients without HIV infection, 23 women (48%) and 17 men (52%). The psychopathological state in all patients was assessed with the PANSS. Flow cytometry was used to measure immunological parameters in HIV-infected patients. Data analysis included principal component analysis. RESULTS AND CONCLUSION: There were independent positive, negative and affective symptoms in the structure of syndromes of schizophrenic patients without HIV. The structure of syndromes in HIV-infected schizophrenic patients included cognitive deficit as well. PMID- 28617373 TI - [A psychological content of social phobia syndrome]. AB - AIM: To perform a psychological analysis of social phobia syndrome. The subject area of research is the structure of mental activity and behavior in social activity. MATERIAL AND METHODS: The study included 32 patients with symptoms of social phobia (ICD-10 F40.1) and 29 healthy people (controls). A complex of psychological methods (questionnaires; pathopsychological experiment) was used. RESULTS AND CONCLUSION: Early maladaptive schemes and a tendency to mental rigidity can be a premorbid basis of the syndrome. Primary violation is in organizational target component by type of distortion of goal-setting regulation. The mechanism is a reduction in the mediation of emotions and behavior (an influence of emotions on the process of activity, excess metacognitive anxiety control leading to multi-task and exhaustion of resources of voluntary activity). Fear of negative evaluation leads to the fact that a wide class of situations is interpreted as threatening. Secondary are changes in the system of goals and motives of activity (technically performing components of social behavior act as a focus of attention, along with the target, the target replaces the suprasituational meaning). Along with a strong motivation to succeed, the motive of avoiding failure is formed, which leads to a decrease in social activity. Tertiary symptoms of syndrome dynamics (ways to cope with maladaptation) are destructive forms of decompensation (substance abuse, learned helplessness and hopelessness, suicidal behavior, etc.), repeatedly reinforcing the primary and secondary disturbances. PMID- 28617374 TI - [Positive changes in the severity of residual psychotic symptoms in schizophrenic patients switched to treatment with risperidone]. AB - AIM: To evaluate the effect of changing therapy from typical antipsychotics to the atypical antipsychotic risperidone in the treatment of difficult-to-treat residual psychotic symptoms. MATERIAL AND METHODS: The study included 15 patients, 8 men and 7 women, mean age 49.1+/-10.25 years, diagnosed with paranoid schizophrenia, partial remission (ICD-10 F20.04). At the beginning all participants received regular maintenance antipsychotic therapy with typical antipsychotics. The patient assessment with the PANSS, CGI scale and GAF scale was performed at the beginning (before the change of antipsychotics to risperidone) and in the end of the study. The primary efficacy endpoint was a reduction in scores on the PANSS items P1 'delusions' and P3 'hallucinatory behavior' to 1 (no such symptom) or 2 (minimal residual symptom). Secondary criteria were positive changes in the severity of other psychopathological symptoms and an increase in the social functioning level. The average dose of risperidone was 4.62+/-1.35 mg. The duration of treatment was 2 month. RESULTS: After switching from typical antipsychotics to risperidone and two months monotherapy, there were significant positive changes in the total PANSS score as well as in positive subscale score and CGI-S score. The small, but statistically significant, changes were detected in the overall functioning of the patients (the increase in the GAF score). The dynamics of residual psychotic symptoms was unequal: the severity of hallucinatory symptoms decreased significantly while the delusional symptoms remained unchanged. CONCLUSION: The authors suggest that excessive dopaminergic blockade might play a significant role in the pathogenesis of residual symptoms. This fact may explain the positive effect of treatment in the cases with the less degree of dopaminergic blockade. If it is true, the treatment strategy in the maintenance phase should not be a direct continuation of acute phase therapy and switching to other drugs and changing of the dose are needed. PMID- 28617375 TI - [Persistent postural-perceptual dizziness]. AB - AIM: To study persistent postural perceptual dizziness (PPPD) in outpatients with benign paroxysmal positional vertigo (BPPV) and patients with presbiataxia (PAt). MATERIAL AND METHODS: Eighty-four patients with PPPD, including 14 with Meniere's disease (MD), 19 with BPPV, 17 with a history of ischemic stroke (IS) in the vertebrobasilar system and 34 with Pat, were examined. For the diagnosis of anxiety, the original 15-point questionnaire with the Likert Scale structure was used. Patients received anvifen (aminophenylbutyric acid hydrochloride) in dose of 250 mg 3 times a day for 6 weeks. Results and sonclusion. The most common trigger of PPPD was sleep deprivation. The highest level of anxiety was identified in the PAt group (19,5+/-2,89). There was a good effect of the drug: it reduced anxiety in all patients studied. The quality of sleep was improved as well. The authors recommend anvifen as the drug of choice in patients with PPPD during vestibular rehabilitation and cognitive-behavioral therapy. PMID- 28617376 TI - [Postoperative cerebral dysfunction]. AB - AIM: To study the structure, risk factors and methods of prevention of postoperative brain dysfunction on the example of coronary artery bypass surgery with cardiopulmonary bypass. MATERIAL AND METHODS: The study included 77 patients who undergone elective coronary artery bypass surgery at the beating heart (22 patients) or with cardiopulmonary bypass (55 patients, including 24 patients, who received cerebroprotective treatment with cytoflavin in the preoperative period). All patients underwent dynamic (pre- and postoperative) neurological, neuropsychological, instrumental examinations. RESULTS: The postoperative cerebral dysfunction was diagnosed in 34 (44,2%) patients. The frequency of the clinical types of postoperative cerebral dysfunction significantly differed: perioperative stroke - 3 (3,9%) cases, symptomatic delirium of the early postoperative period - 11 (14,3%) cases, delayed cognitive impairment - 28 (36,4%) cases. The risk factors of postoperative cerebral dysfunction after the coronary artery bypass surgery with cardiopulmonary bypass were identified. Preventive preoperative use of the neuroprotective drug cytoflavin reduces the severity of delayed cognitive impairment after the coronary artery bypass surgery with cardiopulmonary bypass and has a good safety profile. CONCLUSION: An analysis of the literature data and the results of our own studies show that postoperative cerebral dysfunction is the nosological entity with various etiological factors, pathogenetic mechanisms and the characteristic clinical types, which has an effect on the outcome of surgical treatment. PMID- 28617377 TI - [Pharmacological treatment of patients with chronic fatigue syndrome]. AB - AIM: To evaluate the efficacy and safety of human placenta extract - laennec infusions in the treatment of patients with confirmed diagnosis of 'Chronic fatigue syndrome' (CFS). MATERIAL AND METHODS: The study included 38 patients with CFS, randomized into 2 groups: patients of the experimental group (EG, n=24) were treated with 10 intravenous laennec infusions, 4 ml each, 2 times/week, for 5 weeks. The control group (CG) consisted of 14 patients. Treatment efficacy evaluated by the severity of chronic fatigue ('The degree of chronic fatigue' questionnaire), state anxiety, depression and anger (Spilberger test) and quality of life (SF-36v2), exercise tolerance (cardiopulmonary exercise test with gas analysis), blood parameters were assessed before, after, and 5 weeks of follow up. RESULTS AND CONCLUSION: The EG patients showed a significant reduction in the index of chronic fatigue, which was accompanied by the significant decrease in state depression, anxiety, improvements in subjective assessment of quality of life, as well as a significant increase in physical performance indices (maximal oxygen consumption, anaerobic threshold, load time to failure, normalization of the lipid 'profile' immediately after course of infusions and in 5 weeks follow up). No changes in chronic fatigue index and other recorded indicators were identified in CG. Laennec did not cause side effects, was well tolerated by all patients. PMID- 28617378 TI - [The influence of growing seizure readiness on the autonomic regulation of the heart]. AB - AIM: To study the functional state of the heart in a progressive increase of seizure readiness (SR) due to pentylenetetrazole kindling. MATERIAL AND METHODS: The study was carried out on male rats of the Wistar line. Simultaneous telemetric monitoring of electrocardiogram and electroencephalogram on-line was used. Individual SR of animals in 7- and 27 day pentylenetetrazole kindling was determined. RESULTS: The decrease in the index of LF/HF after 7 days of kindling reflects a compensatory reaction of the autonomic nervous system. However, the increase in SI indicates that the result obtained at the price of considerable stress regulation mechanisms. The increase in QTc, Tpeak Tend and reduced SDNN and TP suggest that compensatory mechanisms cannot prevent the high risk of life threatening arrhythmias. High SR after 27 days of kindling is accompanied by a shift of autonomic balance towards the growth of tone of the sympathetic system which may lead to decompensation and prenosological state. CONCLUSION: The characteristics of autonomic regulation of the heart in progressive SR are important for fundamental and clinical cardioneurology. PMID- 28617379 TI - [Immunohistochemical characteristics of the substantia nigra neurons of the human]. AB - AIM: To determine the cytochemical characteristics of unchanged neurons of the human substantia nigra using a wide range of immunocytochemical markers some of which (glutamate decarboxylase-65, PGP 9.5, non-phosphorylated neurofilament proteins, alpa-tubulin) have never been used for study of human dopaminergic neurons. MATERIAL AND METHODS: Fragments of human midbrain (17 men and women, aged from 28 to 78 years) from the archives of the Department of General and Specific Morphology of the Institute of Experimental Medicine were used. The study was performed using classical neurohistological techniques and immunocytochemistry using antibodies to 15 different proteins. RESULTS: Most neurons in substantia nigra exhibited a reduced expression of common neuronal markers such as neuronal nuclear protein NeuN, PGP 9.5 protein, and neuron specific enolase. GABAergic (GAD65-immunopositive) neurons were not found in the substantia nigra. Single cholinergic neurons without neuromelanin were identified in the dorsal part of the substantia nigra. Calcium-binding proteins calbindin and calretinin were not found in the majority of nigral cells although calbindin was rarely seen in some neurons of the dorsal part and calretinin in the ventral one. Nitric oxide synthase (NOS) was present in the substantia nigra both in neuropil and neuronal bodies. CONCLUSION: The results suggest the unique cytochemical properties of the nigral neurons, which may be related to their increased susceptibility to lesion and degeneration. PMID- 28617380 TI - [Quality of life of patients with chronic cerebral ischemia]. AB - AIM: To evaluate the effectiveness of soft techniques of manual therapy and correction of main indices of quality-of-life in patients with chronic cerebral ischemia. MATERIAL AND METHODS: One hundred patients with chronic cerebral ischemia were examined. All patients received standard neurometabolic therapy. In the main group, patients had additional sessions of soft manual therapy techniques. Quality of life was assessed using the SF-36 questionnaire on 20th day, and 3 and 6 month after treatment. RESULTS AND CONCLUSION: A significant decrease in the quality-of-life of patients with chronic cerebral ischemia was identified. Quality-of-life has improved in patients who received neurometabolic therapy in the combination with soft techniques of manual therapy compared to the comparison group. PMID- 28617381 TI - [G.E. Sukhareva: a course of life and scientific/pedagogical heritage]. PMID- 28617382 TI - [Dimebon delays the onset of symptoms of FUS-proteinopathy in transgenic mice]. AB - AIM: To evaluate an effect of dimebon on the onset of symptomatic stage in FUS.1 513 transgenic mice - a new genetic model of neurodegeneration, and to study the dynamics of disease progression in the terminal stage. MATERIAL AND METHODS: The study was carried out on males of line FUS1-513 with the contribution of genes from CD1 strains. Mice of the experimental group (n=28) received dimebon with water in the concentration of 70 mcg/ml starting from the 35th day of life. The control group (n=25) did not receive the drug. Age, body mass of animals at the start of symptomatic stage and duration of symptomatic stage were assessed. RESULTS: Application of dimebon can delay the onset of the manifestation of clinical symptoms of the neurodegenerative process in the experimental group (127.6+/-4.6 days) compared to the control group (110.6+/-4.2 days). The body mass was similar in both groups. CONCLUSION: Dimebon leads to an increase in the duration of presymptomatic stage and delays the manifestation of clinical symptoms. The changes in the dynamics of the pathological process in the symptomatic stage are not detected. PMID- 28617383 TI - [Slinical and physiological characteristics and therapy asthenic disorders in adolescents girls]. AB - AIM: To study clinical and psychophysiological characteristics of asthenic disorders in adolescent girls in the aspect of treatment efficacy of cortexin. MATERIAL AND METHODS: Seventy-five women, aged 14-17 years, who were diagnosed with neurasthenia (ICD-10 F.48.0), were examined. Conventional neurological examination, a 10-point Visual Analogue Scale, the Multidimensional Fatigue Inventory (MFI-20), the A.M. Vein questionnaire, the Spielberger-Khanin questionnaire and EEG were used. RESULTS AND CONCLUSION: The high level of anxiety resulted in the development of autonomic symptoms and cephalgia. The EEG study showed that women with neurasthenia were characterized by lower alpha rhythm power in the occipital sites compared with healthy peers. Treatment with cortexin improved patient's condition in 80% of cases that was supported by the positive EG dynamics. PMID- 28617384 TI - [A comparative study of the effects of mexidolum and mildronatum on the physical performance of experimental animals]. AB - AIM: To evaluate the effects of mexidolum on physical performance using acute and subchronic administration in experimental animals. MATERIAL AND METHODS: The investigation was carried out using 123 male white outbred mice. The forced swim test was used to assess the effects of the drugs on the physical performance of mice. RESULTS AND CONCLUSION: A single intraperitoneal administration of 50 and 100 mg/kg mexidolum and subchronic intraperitoneal administration of 100 mg/kg mexidolum significantly enhances the physical performance of animals in the forced swim test. Subchronic intraperitoneal administration of 100 mg/kg of the comparison drug mildronatum enhances the physical performance of animals, while intraperitoneal administration at a lower dose (50 mg/kg) has no effect. The effect of mexidolum at a dose of 50 and 100 mg/kg is comparable with the effect of mildronatum in a dose of 100 mg/kg. PMID- 28617385 TI - [Differential diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy]. AB - Cerebral autosomal dominant arteriopathy with subcortical infarctions and leucoencephalopathy (CADASIL) is an inherited CNS disease, which is caused by mutations in the NOTCH3 gene. Selective disorders of small vessels underlie the disease pathogenesis. Clinically CADASIL is characterized by headaches, multiple stroke-like disorders (in most cases transient ischemic attacks and lacunar strokes), and different focal neurological symptoms and dementia. There are specific MRI signs of the disease: multiple lacunar infarctions located in the basal ganglia, brain steam and cerebellum, focal lesions of temporal poles, capsula externa, periventricular and subcortical areas; diffuse white matter changes and leukoaraiosis can be observed as well. The differential diagnosis of CADASIL is made with many diseases, which are manifested by multiple brain matter lesions, including demyelinating disorders. It should be taken into account that CADASIL is characterized by headaches as one of the initial symptoms, multiple lacunar and diffuse brain matter lesions based on MRI data with an absence of atherosclerosis and arterial hypertension. Family history and autosomal dominant mode of inheritance is also typical of CADASIL. Detection of the NOTCH3 gene mutation is necessary for the definite diagnosis of CADASIL. PMID- 28617386 TI - [L-2-hydroxyglutaric aciduria caused by a new mutation in the L2HGDH gene]. AB - The authors present a case-report of 13 year-old girl with L-2-hydroxyglutaric aciduria [MIM#236792], a rare autosomal/recessive metabolic disorder caused by mutations in the L-encoding 2-hydroxyglutarate dehydrogenase (L2HGDH, 14q21.3). Clinical signs of the disease are presented by predominantly neurological symptoms (epilepsy, cerebellar ataxia, cognitive impairment). The distinctive feature is the specific multifocal lesion of the white matter detected on MRI. The characteristic neuroimaging picture and positive results of biochemical and molecular genetic diagnosis were identified. PMID- 28617387 TI - [Pharmacological neuroprotection in stroke in clinical practice: new perspectives]. AB - Despite recent advances in acute stroke care, clinical armamentarium against stroke remains limited. Furthermore, highly effective approaches to stroke treatment, such as systemic reperfusion and mechanical thrombectomy, cannot be performed in the majority of patients. Neuroprotective strategies, i.e. prevention of irreversible cell damage due to the ischemia, may improve stroke outcomes. However, only few pharmacological agents demonstrated clinical efficacy. Citicoline is an endogenous mononucleotide with neuroprotective effect and established clinical safety and tolerability, which effectiveness in acute stroke was studied in several large, well-controlled trials. Recent meta-analysis confirmed benefit of citicoline treatment in terms of increase of chance for better recovery of functional independence compared to placebo. Maximal effect of citicoline is seen when it is administered as soon as possible after stroke onset in patients who are not eligible for reperfusion therapy. PMID- 28617388 TI - [Substance abuse: a relationship with childhood traumas]. AB - Childhood maltreatment contributes to poor mental and physical health and besides, in some cases, not only in early age but also throughout the life of the individual. Adverse effects of childhood trauma, along with depression, anxiety and other mental disorders, include predisposition to substance abuse. A reduction of child abuse may decrease the prevalence of mental disorders, including addictive disorders, and improve mental health. PMID- 28617389 TI - [Nosospecific anxiety and a spectrum of anxiolytic activity of psychotropic drugs]. AB - The article discusses the pathogenetic mechanisms of anxiety in different psychiatric disorders. The influence of anxiety on the course, pharmacotherapeutic treatment with respect to the pathogenesis and the possible neurochemical imbalance in the definite type of anxiety are discussed. An anti anxiety effect in the action of psychotropic drugs is described. It is proposed that neurochemical disturbances are not the same with the various types of anxiety, which requires using drugs from various groups to achieve treatment of the symptom on the pathogenetic level. The various roles of anxiety in the course of different mental disorders is suggested. PMID- 28617390 TI - [Pathopsychological aspects of low back pain]. AB - Low back pain is one of the most common causes of disability in the world. Discogenic process is the leading component of the disease. A significant part of these pain syndromes become chronic that leads to disability and social maladjustment. Chronic low back pain is hard to treat due to the several types of pathogenesis. The paper analyzes the etiology, mechanisms of development, clinical features, specific characteristics, pathomorphology of the formation of psychogenic component of pain. A role of comorbid psychogenic states involved in the chronization of low back pain is considered. Main approaches to treatment of the psychogenic component of pain are presented. PMID- 28617391 TI - [Cerebral markers of endothelial dysfunction in chronic brain ischemia]. AB - A review of the main markers of endothelial dysfunction in chronic cerebral ischemia is presented. The quantitative changes in the level of endothelial dysfunction markers in chronic cerebral ischemia help to evaluate the efficacy of preventive and therapeutic pharmacological activities. The results of clinical trials have demonstrated that the course use of divaza in patients with chronic cerebral ischemia leads to improvement of both clinical indicators and laboratory markers for normalization of cerebral ischemia and endothelial dysfunction. PMID- 28617392 TI - [Panic disorder: clinical phenomena and treatment options]. AB - Panic disorder is a common mental disease with high psychiatric comorbidity. It is considered that a combination of genetic predisposition and a special psychic vulnerability plays a key role in the occurrence of panic disorder. Clinically proven efficacy in the treatment of panic disorder have benzodiazepines, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors; antidepressants from other pharmaceutical groups are also used. Selective serotonin reuptake inhibitors are the first line medicines in the treatment of panic disorder. Atypical antipsychotics may be used for the therapy augmentation in addition to first line drugs. Psychotherapy is used along with medications, and a combination of pharmacotherapy and cognitive behavioral therapy is the best method of treatment. PMID- 28617393 TI - [V.A. Monich 'Biophotonics, sources of light, mechanisms, experimental and clinical medicine'. Nizhnii Novgorod State Medical Academy. 2016]. PMID- 28617395 TI - ['Actual issues of psychiatry and addiction medicine'. The jubilee conference devoted to 35-anniverssary of the Institute of Mental Health and 125-anniverssary of the Department of psychiatry, addiction medicine and psychotherapy of the Siberian State Medical University]. PMID- 28617394 TI - [L.A. Belova, V.V. Mashin 'Venous discirculation in chronic forms of cerebrovascular pathology'. Ulyanovsk State Univ. 2015]. PMID- 28617396 TI - [The II-nd All-Russian scientific-practical conference with international participation 'Modern problems of ethnocultural psychiatry and addiction medicine' held in the memory of academician of the RAS V.Ya. Semke]. PMID- 28617397 TI - [A.A. Scoromets (to the 80th anniversary of birth)]. PMID- 28617398 TI - [Ultrastructural changes of human dental hard tissues during orthodontic treatment with fixed appliances]. AB - The aim of the study was to evaluate ultrastructural changes of dental enamel after fixation of orthodontic appliances, initial influence of orthodontic forces and removal of braces. Five intact permanent tooth extracted for orthodontic reasons were included in the experimental study. Scanning probe microscopy was conducted in 4 random enamel points in each tooth (20 points overall) in semi contact mode with standard 10 nm probes. The study showed ultrastructural enamel changes such as nanofractures up to 1 mm along the braces locks. The changes correlated with surface morphological features and teeth anatomy and may play an important role in dental decay and non-carious lesions occurring in the course of orthodontic treatment. PMID- 28617399 TI - [Specific age-related and gender related features in oral status]. AB - The aim of the study was to assess age and gender related features of oral status and oral hygiene. The study included 234 patients (76 males and 158 females) aged 25 to 74 years. It is proved that females have more dental appointments than males mostly because of specific oral conditions associated with pregnancy and menopause as well as better compliance with prevention programs. Thus, females require more intense follow-up than males which should be taken into consideration in treatment and follow-up plans. PMID- 28617400 TI - [Teeth wedge-shaped defects in adults of different age groups: remark to prevention and treatment]. AB - The aim of the study was to assess the treatment of teeth wedge defects in different age groups. Records of 383 patients (125 males and 258 females aged 22 85 years) treated in outpatient dental facilities with different ownership forms. It is shown that the medical care of patients with wedge-shaped teeth defects routinely consists of remineralization therapy and restoration of anatomical teeth shape regardless of the form of ownership. The extensiveness of dental rehabilitation as well as the use of more modern technologies are typical for private clinics and 96-100% of patients finished their treatment there. In the state and departmental institutions complete rehabilitation of wedge-shaped defects was provided in 45.5-58.0% and 54.3-83.9, respectively. The paper also highlights the drawbacks of primary medical documentation identified in medical institutions of all forms of ownership. PMID- 28617401 TI - [The influence of teeth morphology on bioelectrical activity of masticatory muscles]. AB - The aim of the study was to reveal correlation of dental morphology and bioelectric activity of masticatory muscles. The study included 76 young adults (47.4% females and 52.6% males) divided in 3 groups according to dental morphology features: intact teeth (26 patients), dental decay in fissures with intact cusps (25 patients), pronounced dental decay with varying degree of crown destruction (25 patients). Electromyography (EMG) was used to document the bioelectric activity (BEA) of temporal and masticatory muscles. The study showed high level of correlation of destructive teeth changes with BEA of masticatory muscles. Intragroup correlation proved direct link of BEA to the number of decayed teeth. EMG activity differed significantly between groups 2 and 3. There was no statistically significant difference between groups 3 and 1 mostly because of high variability of BEA in group 3. Relative activity of temporal and masticatory muscles increased in groups 2 and 3 by 2 and 4% and 38 and 19%, correspondingly. There was no significant impact of gender or emotional status on masticatory muscles BEA. PMID- 28617402 TI - [Retrospective study on treatment results of patients with bone destruction in lower molars roots area]. AB - The paper presents retrospective study on the efficiency of tooth protecting operations in patients with odontogenic bone destruction in lower molars roots area. The study was based on the analysis of medical records of patients treated in Central Research Institute of Dentistry and Maxillofacial Surgery from 2011 to 2016. Tooth protecting procedures because of bone destruction in lower molars were carried out in 98 patients but only 59 of them were accessible to proper follow-up. Complications were seen in 15.2% of patients and teeth were extracted in 13.5% of cases. Thus, the efficacy of tooth protecting procedures in lower molars was 86.5%, which proves their feasibility despite of complicated surgical approach. PMID- 28617403 TI - [Local immune and oxidative status in exacerbated chronic apical periodontitis]. AB - The aim of the study was to define local immune and oxidative changes in patients with exacerbated chronic apical periodontitis. These changes were assessed in saliva of 67 patients with the mean age of 31+/-2.5 before and after treatment. The study revealed disturbances in cytokines and complement system balance and activation of lipids peroxidation. Combination of Gepon or Vobenzim with Essentiale forte H and Kaskatol proved to be the most effective for correction of this imbalance. PMID- 28617404 TI - [Reconstructive otoplasty: differentiated approach to rib cartilage processing and ear framework formation using carving technique]. AB - The aim of the research was to optimize surgical rehabilitation of patients with auricle defects and deformities by the developing of differentiated approach to the choice of reconstructive otoplasty method. The study involved 30 patients with auricle defects and deformities of congenital (20 patients) and acquired (10 patients) etiology. The defects were total in 25 patients and partial in 5 patients. All patients underwent ear reconstruction with rib cartilage using carving technique. Preoperative planning was based in Doppler ultrasound of temporal region vessels, laser Doppler flowmetry, temporal skin ultrasound and 3D ribcage CT. The surgical tactic was selected according to the possibility of mastoid region skin usage or necessity of the temporoparietal fascial flap. The approach proved to be highly efficient as otoplasty outcomes were good in 80% of cases, satisfactory in 10% and unsatisfactory in 10%. PMID- 28617405 TI - [Orthotopic bone implants for bone regeneration]. AB - Biotechnology industry is rapidly developing. The elaboration of new biomaterials for bone reconstruction is one of the most perspective directions in tissue engineering. There are millions of surgical operations associated with use of bone graft materials every year. In this article we tried to analyze and systematize data about advanced technologies and modern trends in the preparation of bio-composite bone graft materials. Special attention is given to 3D prototyping that allows making bone implants with individual form. Introduction of molecular biology technologies such as activating specific cytokines and growth factors at the right time makes it possible to optimize bone regeneration process. The article has also some suggestions on further improvement of the bone engineering technology. PMID- 28617406 TI - [Fibromyxoid sarcoma of maxilla]. AB - The paper presents literature review and clinical case of patient with fibromyxoid sarcoma of maxilla illustrating diagnostic difficulties and efficacy of multidisciplinary treatment approach. PMID- 28617407 TI - [Efficiency of cephalometry in orthodontic treatment planning: cephalometric parameters and their age-related changes]. AB - The aim of the study was to evaluate the efficiency of cephalometry in orthodontic treatment planning in patients with teeth crowding and Angle Class I molars relation. Cephalometric parameters were analyzed in 70 patients that completed orthodontic treatment in 'Orthodont' dental clinic (Samara). Cephalometric X-rays were taken at baseline examination and after treatment. In patients with crowding and Class I molars relationship treated with extraction of all four first premolars correlation between N-Se and mandibular and maxillary length was disturbed. These patients showed higher N-Se and reduced jaws length than patients with no extraction or extraction of 2 premolars. The observed increase of G angle with reduced mandibular length assumes compensatory changes of mandible position. These disproportions were aggravated by facial growth. In certain cases cephalometric assessment is inefficient for treatment strategy choice. PMID- 28617408 TI - [Gender-related differences in working practice and professional growth of dentists]. AB - The paper presents some aspects of professional growth, continuous education and working conditions of female dentists having impact on treatment quality and dental service state in general. Questionnaire survey was carried out in 124 dentists, both male and female, aged 22 to 60 years. The study revealed gender asymmetry influencing their competitive ability, physical and emotional well being. PMID- 28617409 TI - [Safe local anesthesia in patients with bronchial asthma]. AB - The paper presents the analysis of studies of local anesthesia in patients with bronchial asthma. It was found that the diagnosis of hypersensitivity to sodium metabisulfite in patients with bronchial asthma must be optimized for development of local anesthesia selection algorithm in outpatient dentistry. PMID- 28617410 TI - [Prof. V.A. Semkin and Prof. I.I. Babichenko 'Odontogenous cysts and tumors diagnosis and treatment' textbook review]. PMID- 28617411 TI - [Prof. A.I. Matveeva (on occasion of 80-t anniversary)]. PMID- 28617412 TI - [Abstracts of VIII Young Scientists Conference dedicated to 55th anniversary of Central Research Institute of Dentistry and Maxillofacial Surgery 'Modern scientific achievements in dentistry and maxillofacial surgery']. AB - Abstracts of VIII Young Scientists Conference dedicated to 55th anniversary of Central Research Institute of Dentistry and Maxillofacial Surgery 'Modern scientific achievements in dentistry and maxillofacial surgery'. Therapeutic stomatology. Surgical dentistry. Maxillofacial surgery. Orthopedic stomatology. Orthodontics. Organization of dental care. PMID- 28617414 TI - Obesity. AB - Excessive fat deposition in obesity has a multifactorial aetiology, but is widely considered the result of disequilibrium between energy intake and expenditure. Despite specific public health policies and individual treatment efforts to combat the obesity epidemic, >2 billion people worldwide are overweight or obese. The central nervous system circuitry, fuel turnover and metabolism as well as adipose tissue homeostasis are important to comprehend excessive weight gain and associated comorbidities. Obesity has a profound impact on quality of life, even in seemingly healthy individuals. Diet, physical activity or exercise and lifestyle changes are the cornerstones of obesity treatment, but medical treatment and bariatric surgery are becoming important. Family history, food environment, cultural preferences, adverse reactions to food, perinatal nutrition, previous or current diseases and physical activity patterns are relevant aspects for the health care professional to consider when treating the individual with obesity. Clinicians and other health care professionals are often ill-equipped to address the important environmental and socioeconomic drivers of the current obesity epidemic. Finally, understanding the epigenetic and genetic factors as well as metabolic pathways that take advantage of 'omics' technologies could play a very relevant part in combating obesity within a precision approach. PMID- 28617415 TI - Oral D-galactose supplementation in PGM1-CDG. AB - PurposePhosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous casereports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies have assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D gal in nine patients.MethodsD-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, and liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro.ResultsEight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (alanine transaminase, aspartate transaminase, activated partial thromboplastin time) improved or normalized already using 1 g/kg/day D-gal. Antithrombin-III levels and transferrin glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal lipid-linked oligosaccharide profile, and abnormal nucleotide sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment. D-gal increased both UDP-Glc and UDP-Gal levels and improved lipid-linked oligosaccharide fractions in concert with improved glycosylation in PGM1-CDG.ConclusionOral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer-duration trials are ongoing. PMID- 28617416 TI - Genome-wide cfDNA screening: clinical laboratory experience with the first 10,000 cases. AB - PurposeInvasive diagnostic prenatal testing can provide the most comprehensive information about the genetic status of a fetus. Noninvasive prenatal screening methods, especially when using cell-free DNA (cfDNA), are often limited to reporting only on trisomies 21, 18, and 13 and sex chromosome aneuploidies. This can leave a significant number of chromosomal and subchromosomal copy-number variations undetected. In 2015, we launched a new genome-wide cfDNA screening test that has the potential to narrow this detection gap.MethodsHere, we review the results from the first 10,000 cases submitted to the Sequenom clinical laboratory for genome-wide cfDNA screening.ResultsThe high-risk indication for this cohort differed compared with standard cfDNA screening. More samples were submitted with ultrasound indications (25% compared with 13% for standard cfDNA screening) and fewer for advanced maternal age (51% for genome-wide screening versus 68% for standard cfDNA screening). A total of 554 positive calls were made, of which 164 were detectable only via genome-wide analysis.ConclusionThis reports indicates a difference in utilization compared with standard cfDNA screening, where positivity rates are higher and a large subset of positive calls could not have been made using standard cfDNA screening. PMID- 28617418 TI - Medical genetics and genomics education: how do we define success? Where do we focus our resources? PMID- 28617417 TI - A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history. AB - PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER resident protein belonging to the family of FK506-binding peptidyl-prolyl cis trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS. PMID- 28617419 TI - Utilization of genomic sequencing for population screening of immunodeficiencies in the newborn. AB - PurposeImmunodeficiency screening has been added to many state-directed newborn screening programs. The current methodology is limited to screening for severe T cell lymphopenia disorders. We evaluated the potential of genomic sequencing to augment current newborn screening for immunodeficiency, including identification of non-T cell disorders.MethodsWe analyzed whole-genome sequencing (WGS) and clinical data from a cohort of 1,349 newborn-parent trios by genotype-first and phenotype-first approaches. For the genotype-first approach, we analyzed predicted protein-impacting variants in 329 immunodeficiency-related genes in the WGS data. As a phenotype-first approach, electronic health records were used to identify children with clinical features suggestive of immunodeficiency. Genomes of these children and their parents were analyzed using a separate pipeline for identification of candidate pathogenic variants for rare Mendelian disorders.ResultsWGS provides adequate coverage for most known immunodeficiency related genes. 13,476 distinct variants and 8,502 distinct predicted protein impacting variants were identified in this cohort; five individuals carried potentially pathogenic variants requiring expert clinical correlation. One clinically asymptomatic individual was found genomically to have complement component 9 deficiency. Of the symptomatic children, one was molecularly identified as having an immunodeficiency condition and two were found to have other molecular diagnoses.ConclusionNeonatal genomic sequencing can potentially augment newborn screening for immunodeficiency. PMID- 28617420 TI - miRNA-mediated post-transcriptional silencing of transgenes leads to increased adeno-associated viral vector yield and targeting specificity. AB - The production of high-titer recombinant adeno-associated virus (rAAV) vector is essential for treatment of genetic diseases affecting the retina and choroid, where anatomical constraints may limit injectable volumes. Problematically, cytotoxicity arising from overexpression of the transgene during vector production frequently leads to a reduction in vector yield. Herein, we evaluate the use of microRNA (miRNA)-mediated silencing to limit overexpression of cytotoxic transgenes during packaging as a method of increasing vector yield. We examined if post-transcriptional regulation of transgenes during packaging via miRNA technology would lead to increased rAAV yields. Our results demonstrate that silencing of cytotoxic transgenes during production resulted in up to a 22 fold increase in vector yield. The inclusion of organ-specific miRNA sequences improved biosafety by limiting off-target expression following systemic rAAV administration. The small size (22-23 bp) of the target site allows for the inclusion of multiple copies into the vector with minimal impact on coding capacity. Taken together, our results suggest that inclusion of miRNA target sites into the 3'-untranslated region of the AAV cassette allow for silencing of cytotoxic transgenes during vector production leading to improved vector yield, in addition to increasing targeting specificity without reliance on cell-specific promoters. PMID- 28617421 TI - A targeted noise reduction observational study for reducing noise in a neonatal intensive unit. AB - BACKGROUND: Excessive noise in neonatal intensive care units (NICUs) can interfere with infants' growth, development and healing.Local problem:Sound levels in our NICUs exceeded the recommended levels by the World Health Organization. METHODS: We implemented a noise reduction strategy in an urban, tertiary academic medical center NICU that included baseline noise measurements. We conducted a survey involving staff and visitors regarding their opinions and perceptions of noise levels in the NICU. Ongoing feedback to staff after each measurement cycle was provided to improve awareness, engagement and adherence with noise reduction strategies. After widespread discussion with active clinician involvement, consensus building and iterative testing, changes were implemented including: lowering of equipment alarm sounds, designated 'quiet times' and implementing a customized education program for staff. INTERVENTIONS: A multiphase noise reduction quality improvement (QI) intervention to reduce ambient sound levels in a patient care room in our NICUs by 3 dB (20%) over 18 months. RESULTS: The noise in the NICU was reduced by 3 dB from baseline. Mean (s.d.) baseline, phase 2, 3 and 4 noise levels in the two NICUs were: LAeq: 57.0 (0.84), 56.8 (1.6), 55.3 (1.9) and 54.5 (2.6) dB, respectively (P<0.01). Adherence with the planned process measure of 'quiet times' was >90%. CONCLUSIONS: Implementing a multipronged QI initiative resulted in significant noise level reduction in two multipod NICUs. It is feasible to reduce noise levels if QI interventions are coupled with active engagement of the clinical staff and following continuous process of improvement methods, measurements and protocols. PMID- 28617422 TI - Reduced narcotic and sedative utilization in a NICU after implementation of pain management guidelines. AB - OBJECTIVE: To assess the opioid and benzodiazepine usage in a level IV NICU after implementation of pain guidelines. STUDY DESIGN: Guidelines were developed for infants undergoing surgical procedures and infants on mechanical ventilation. Data collected for period 1 (July to December 2013) and period 2 (March to August 2014). RESULTS: Gestational age, birth weight and infants with hypoxic respiratory failure or requiring major procedures were comparable in two periods. Number of patients exposed to opioids decreased from 62.9% (129/205) in period 1 to 32.8% (82/250) in period 2, P=<0.001. Cumulative dose exposure decreased, opioids in morphine equivalent dose, mg kg-1 (1.64 (0.38 to 6.94) vs 0.51 (0.04 to 2.33), P=0.002), sedatives in midazolam equivalent, mg kg-1 (0.16 (0.03 to 7.39) vs 0.10 (0.00 to 4.00), P=0.03). Ten patients required treatment for iatrogenic opioid withdrawal versus only three in post guideline, P=0.02. CONCLUSIONS: Evidence-based guidelines led to significant reduction in opioids and sedatives exposure, and in the number of infants requiring methadone for iatrogenic narcotic dependence. PMID- 28617423 TI - Relationship between temperature variability and brain injury on magnetic resonance imaging in cooled newborn infants after perinatal asphyxia. AB - OBJECTIVE: The objective of the study was whether temperature management during therapeutic hypothermia correlates with the severity of brain injury assessed on magnetic resonance imaging in term infants with hypoxic-ischemic encephalopathy. STUDY DESIGN: Prospectively collected register data from the National Asphyxia and Cooling Register of Switzerland were analyzed. RESULT: Fifty-five newborn infants were cooled for 72 h with a target temperature range of 33 to 34 degrees C. Individual temperature variability (odds ratio (OR) 40.17 (95% confidence interval (CI) 1.37 to 1037.67)) and percentage of temperatures within the target range (OR 0.95 (95% CI 0.90 to 0.98)) were associated with the severity of brain injury seen on magnetic resonance imaging (MRI). Neither the percentage of measured temperatures above (OR 1.08 (95% CI 0.96 to 1.21)) nor below (OR 0.99 (95% CI 0.92 to 1.07) the target range was associated with the severity of brain injury seen on MRI. CONCLUSION: In a national perinatal asphyxia cohort, temperature variability and percentage of temperatures within the target temperature range were associated with the severity of brain injury. PMID- 28617424 TI - Outcomes following indomethacin prophylaxis in extremely preterm infants in an all-referral NICU. AB - OBJECTIVE: We examined data from a contemporary cohort of extreme prematurity (EP) infants admitted to an all-referral Children's Hospital neonatal intensive care unit (NICU) to determine whether prophylactic indomethacin (PI) may continue to benefit these patients. STUDY DESIGN: An observational study utilizing the small baby ICU data registry that was queried for all EP infants admitted between 2005 and 2014 with documentation of PI use (671 total EP infants; 141 (21%) did not receive PI (control); 530 (79%) received PI (PI). This cohort of EP infants was born at outside hospitals and transferred to our level IV NICU with a mean age on admission of 13 days, well after the PI would have been administered. RESULTS: No difference existed between the control and PI groups in gestational age, birth weight, severity of illness, other in-hospital outcomes or developmental delay. PI infants had a significantly lower mortality rate (P=0.0004), lower relative risk (RR) for mortality 0.52 (95% confidence interval (CI) 0.37 to 0.73, P=0.0001) and lower RR of developing the combined outcome of death or bronchopulmonary dysplasia (RR 0.91, 95% CI 0.85 to 0.98, P=0.012) when compared with the control group. Notably, there was no significant effect of PI on incidence of severe intraventricular hemorrhage or patent ductus arteriosus ligation. CONCLUSION: PI administration was associated with improved survival in EP infants referred to a level IV Children's Hospital NICU. PMID- 28617425 TI - Does preterm period sleep development predict early childhood growth trajectories? AB - OBJECTIVE: The current study examined the relationship between sleep state development across the preterm and early post-term periods and subsequent growth trajectories from 1 to 27 months corrected age. STUDY DESIGN: Retrospective analysis of data collected prospectively from 111 preterm infants (?34 weeks gestation) who participated in a multi-site longitudinal study. Separate longitudinal parallel process models were calculated for each sleep state (active and quiet sleep) and growth (weight, length and body mass index (BMI) Z-scores) variable to estimate the associations between their developmental trajectories. RESULTS: Significant associations were identified between the trajectories of quiet sleep and weight, active sleep and weight, quiet sleep and BMI, and active sleep and BMI. No statistically meaningful associations were identified between the trajectories of early childhood length and the preterm sleep states. CONCLUSION: Faster preterm period sleep development appears to predict more favorable early childhood growth trajectories, particularly for weight, indicating preterm sleep may be an important biomarker for subsequent growth outcomes. PMID- 28617426 TI - Prenatal (non)treatment decisions in extreme prematurity: evaluation of Decisional Conflict and Regret among parents. AB - OBJECTIVE: To evaluate Decisional Conflict and Regret among parents regarding the decision on initiating comfort or active care in extreme prematurity and to relate these to decision-making characteristics. STUDY DESIGN: A nationwide, multicenter, cross-sectional study using an online survey in the Netherlands. Data were collected from March 2015 to March 2016 among all parents with infants born at 24+0/7-24+6/7 weeks gestational age in 2010-2013. The survey contained a Decisional Conflict and Decision Regret Scale (potential scores range from 0 to 100) and decision-making characteristics. RESULTS: Sixty-one surveys were returned (response rate 27%). The median Decisional Conflict score was 28. From the subscores within Decisional Conflict, 'values clarity' revealed the highest median score of 42-revealing that parents felt unclear about personal values for benefits and risks of the decision on either comfort care or active care. The median Decision Regret score was 0. Regret scores were influenced by the actual decision made and by outcome: Decision Regret was lower in the active care group and in the survivor group. CONCLUSION: We found little Decisional Conflict and no Decision Regret among parents regarding decision-making at 24 weeks gestation. PMID- 28617427 TI - Mortality among infants with evolving bronchopulmonary dysplasia increases with major surgery and with pulmonary hypertension. AB - OBJECTIVE: To assess whether mortality in patients with evolving bronchopulmonary dysplasia (BPD, defined as ?28 days of oxygen exposure with lung disease) is independently associated with pulmonary arterial hypertension (PAH) and surgery. STUDY DESIGN: Single institution retrospective birth cohort of preterm infants with gestational age (GA) 230/7 to 366/7 weeks, and evolving BPD delivered between 2001 and 2014. Surgery was classified as minor or major using published criteria. Mortality was analyzed by stepwise logistic regression analysis. RESULTS: Among 577 patients with evolving BPD, 33 (6%) died prior to discharge. Mortality decreased with GA (adjusted odds ratio (aOR): 0.69; 95% confidence interval (CI): 0.55, 0.87), birth weight Z-score (aOR: 0.69, 95% CI: 0.47, 0.996) and increased with PAH (aOR: 30, 95% CI: 2.1, 415), major surgery (aOR; 2.8, 95% CI: 1.3, 6.3), and PAH and surgery (aOR: 10.3, 95% CI: 2.5, 42.1). CONCLUSION: Among preterm patients with evolving BPD, PAH and surgery are independently associated with mortality. PMID- 28617428 TI - Creation of interdisciplinary guidelines for care of women presenting to the emergency department with pregnancy loss. AB - A research trajectory is reported that created state-of-the-art interdisciplinary guidelines for care of women and their families who arrive in the emergency department with pregnancy loss. These guidelines include attention to mother and family bereavement as well as care of the fetus. Design was a triangulated non experimental exploratory action research for the purpose of changing practice. Included were: (1) A qualitative study of emergency room nurses and physicians to assess beliefs/barriers to providing optimal care for pregnancy loss patients. (2) A focus group of perinatal bereavement providers; (3) Another focus group in the form of a sponsored National Summit of professional and lay experts and (4) A Delphi Study to craft language for national position statement. Results allowed the creation of interdisciplinary guidelines from the National Perinatal Association. These guidelines are being adopted by organizations and facilities throughout the United States. Training programs for emergency department personnel have been created by pregnancy loss organizations and are available. PMID- 28617429 TI - Comparison between Bilistick System and transcutaneous bilirubin in assessing total bilirubin serum concentration in jaundiced newborns. AB - OBJECTIVE: To compare the performance and accuracy of the JM-103 transcutaneous bilirubinometer and Bilistick System in measuring total serum bilirubin for the early identification of neonatal hyperbilirubinemia. STUDY DESIGN: The study was performed on 126 consecutive term and near-term (?36 weeks' gestational age) jaundiced newborns in Cairo University Children Hospital NICU, Egypt. Total serum bilirubin was assayed concurrently by the clinical laboratory and Bilistick System and estimated using the JM-103 transcutaneous bilirubin instrument. Bland Altman analysis was used to evaluate the agreement between determinations. RESULT: The limits of agreement of the Bilistick System (-5.8 to 3.3 mg dl-1) and JM-103 system (-5.4 to 6.0 mg dl-1) versus the clinical laboratory results were similar. CONCLUSION: The Bilistick System is an accurate alternative to transcutaneous (TcB) determination for early diagnosis and proper management of the neonatal jaundice. PMID- 28617430 TI - Physician views regarding the benefits and burdens of prenatal surgery for myelomeningocele. AB - OBJECTIVE: Examine how pediatric and obstetrical subspecialists view benefits and burdens of prenatal myelomeningocele (MMC) closure. STUDY DESIGN: Mail survey of 1200 neonatologists, pediatric surgeons and maternal-fetal medicine specialists (MFMs). RESULTS: Of 1176 eligible physicians, 670 (57%) responded. Most respondents disagreed (68%, 11% strongly) that open fetal surgery places an unacceptable burden on women and their families. Most agreed (65%, 10% strongly) that denying the benefits of open maternal-fetal surgery is unfair to the future child. Most (94%) would recommend prenatal fetoscopic over open or postnatal MMC closure for a hypothetical fetoscopic technique that had similar shunt rates (40%) but decreased maternal morbidity. When the hypothetical shunt rate for fetoscopy was increased to 60%, physicians were split (49% fetoscopy versus 45% open). Views about burdens and fairness correlated with the likelihood of recommending postnatal or fetoscopic over open closure. CONCLUSION: Individual and specialty-specific values may influence recommendations about prenatal surgery. PMID- 28617431 TI - Nicotine protects rat hypoglossal motoneurons from excitotoxic death via downregulation of connexin 36. AB - Motoneuron disease including amyotrophic lateral sclerosis may be due, at an early stage, to deficit in the extracellular clearance of the excitatory transmitter glutamate. A model of glutamate-mediated excitotoxic cell death based on pharmacological inhibition of its uptake was used to investigate how activation of neuronal nicotinic receptors by nicotine may protect motoneurons. Hypoglossal motoneurons (HMs) in neonatal rat brainstem slices were exposed to the glutamate uptake blocker DL-threo-beta-benzyloxyaspartate (TBOA) that evoked large Ca2+ transients time locked among nearby HMs, whose number fell by about 30% 4 h later. As nicotine or the gap junction blocker carbenoxolone suppressed bursting, we studied connexin 36 (Cx36), which constitutes gap junctions in neurons and found it largely expressed by HMs. Cx36 was downregulated when nicotine or carbenoxolone was co-applied with TBOA. Expression of Cx36 was preferentially observed in cytosolic rather than membrane fractions after nicotine and TBOA, suggesting protein redistribution with no change in synthesis. Nicotine raised the expression of heat shock protein 70 (Hsp70), a protective factor that binds the apoptotic-inducing factor (AIF) whose nuclear translocation is a cause of cell death. TBOA increased intracellular AIF, an effect blocked by nicotine. These results indicate that activation of neuronal nicotinic receptors is an early tool for protecting motoneurons from excitotoxicity and that this process is carried out via the combined decrease in Cx36 activity, overexpression of Hsp70 and fall in AIF translocation. Thus, retarding or inhibiting HM death may be experimentally achieved by targeting one of these processes leading to motoneuron death. PMID- 28617432 TI - BST2 confers cisplatin resistance via NF-kappaB signaling in nasopharyngeal cancer. AB - Concurrent/adjuvant cisplatin-based chemoradiotherapy is regarded as the standard of treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, patients who do not respond to cisplatin suffer, rather than benefit, from chemotherapy treatment. The goal of this study was to identify molecules involved in cisplatin resistance and to clarify their molecular mechanisms, which would help in the discovery of potential therapeutic targets and in developing a personalized and precise treatment approach for NPC patients. We previously generated a cisplatin-sensitive NPC cell line, S16, from CNE2 cells and found that eIF3a, ASNS and MMP19 are upregulated in S16 cells, which contributes to their cisplatin sensitivity. In this study, we found that BST2 is downregulated in cisplatin-sensitive S16 cells compared with CNE2 cells. Knockdown of BST2 in NPC cells sensitized their response to cisplatin and promoted cisplatin-induced apoptosis, whereas exogenous overexpression of BST2 increased their cisplatin resistance and inhibited cisplatin-induced apoptosis. Further investigation demonstrated that BST2-mediated cisplatin resistance depended on the activation of the NF-kappaB signaling pathway and consequent upregulation of anti-apoptotic genes, such as Bcl-XL and livin. Moreover, an analysis of clinical data revealed that a high BST2 level might serve as an independent indicator of poor prognosis in patients with locally advanced NPC treated with platinum-based chemoradiotherapy. These findings suggest that BST2 likely mediates platinum resistance in NPC, offering guidance for personalized and precise treatment strategies for patients with NPC. PMID- 28617433 TI - Isodeoxyelephantopin induces protective autophagy in lung cancer cells via Nrf2 p62-keap1 feedback loop. AB - Isodeoxyelephantopin (ESI), isolated from Elephantopus scaber L. has been reported to exert anticancer effects. In this study, we aimed to investigate whether and how cancer cells exert protective responses against ESI treatment. Confocal fluorescence microscopy showed that ESI significantly induced autophagy flux in the lung cancer cells expressing mCherry-EGFP-LC3 reporter. Treatment of the cells with ESI increased the expression levels of the autophagy markers including LC3-II, ATG3 and Beclin1 in a dose-dependent manner. Pretreatment with autophagy inhibitor 3-methyladenine (3-MA) not only attenuated the effects of ESI on autophagy, but also enhanced the effects of ESI on cell viability and apoptosis. Mechanistically, the SILAC quantitative proteomics coupled with bioinformatics analysis revealed that the ESI-regulated proteins were mainly involved in Nrf2-mediated oxidative stress response. We found that ESI induced the nuclear translocation of Nrf2 for activating the downstream target genes including HO-1 and p62 (SQSTM1). More importantly, ESI-induced p62 could competitively bind with Keap1, and releases Nrf2 to activate downstream target gene p62 as a positive feedback loop, therefore promoting autophagy. Furthermore, knockdown of Nrf2 or p62 could abrogate the ESI-induced autophagy and significantly enhanced the anticancer effect of ESI. Taken together, we demonstrated that ESI can sustain cell survival by activating protective autophagy through Nrf2-p62-keap1 feedback loop, whereas targeting this regulatory axis combined with ESI treatment may be a promising strategy for anticancer therapy. PMID- 28617434 TI - LISPRO mitigates beta-amyloid and associated pathologies in Alzheimer's mice. AB - Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer's disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li2CO3). We found that LISPRO (8-week oral treatment) reduces beta-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3beta in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2 week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li2CO3. Oral administration of LISPRO for 28 weeks significantly reduced beta-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD. PMID- 28617436 TI - A hypoxia-inducible factor 1alpha null splice variant lacking exon 10. PMID- 28617435 TI - Interaction between autophagy and senescence is required for dihydroartemisinin to alleviate liver fibrosis. AB - Autophagy and cellular senescence are stress responses essential for homeostasis. Therefore, they may represent new pharmacologic targets for drug development to treat diseases. In this study, we sought to evaluate the effect of dihydroartemisinin (DHA) on senescence of activated hepatic stellate cells (HSCs), and to further elucidate the underlying mechanisms. We found that DHA treatment induced the accumulation of senescent activated HSCs in rat fibrotic liver, and promoted the expression of senescence markers p53, p16, p21 and Hmga1 in cell model. Importantly, our study identified the transcription factor GATA6 as an upstream molecule in the facilitation of DHA-induced HSC senescence. GATA6 accumulation promoted DHA-induced p53 and p16 upregulation, and contributed to HSC senescence. By contrast, siRNA-mediated knockdown of GATA6 dramatically abolished DHA-induced upregulation of p53 and p16, and in turn inhibited HSC senescence. Interestingly, DHA also appeared to increase autophagosome generation and autophagic flux in activated HSCs, which was underlying mechanism for DHA induced GATA6 accumulation. Autophagy depletion impaired GATA6 accumulation, while autophagy induction showed a synergistic effect with DHA. Attractively, p62 was found to act as a negative regulator of GATA6 accumulation. Treatment of cultured HSCs with various autophagy inhibitors, led to an inhibition of DHA induced p62 degradation, and in turn, prevented DHA-induced GATA6 accumulation and HSC senescence. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced senescence, by which points to the possibility of using DHA based proautophagic drugs for the treatment of liver fibrosis. PMID- 28617437 TI - EMT-Regulome: a database for EMT-related regulatory interactions, motifs and network. PMID- 28617438 TI - Connective tissue growth factor promotes temozolomide resistance in glioblastoma through TGF-beta1-dependent activation of Smad/ERK signaling. AB - Limited benefits and clinical utility of temozolomide (TMZ) for glioblastoma (GB) are frequently compromised by the development of acquired drug resistance. Overcoming TMZ resistance and uncovering the underlying mechanisms are challenges faced during GB chemotherapy. In this study, we reported that connective tissue growth factor (CTGF) was associated with GB chemoresistance and significantly upregulated in TMZ-treated GB cells. CTGF knockdown promoted TMZ-induced cell apoptosis and enhanced chemosensitivity, whereas its overexpression markedly conferred TMZ resistance in vitro and in vivo. Moreover, CTGF promoted TMZ resistance through stem-like properties acquisition and CD44 interference reversed the CTGF-induced TMZ resistance. Mechanistically, further investigation revealed that the TMZ-induced CTGF upregulation was tissue growth factor (TGF beta) dependent, and regulated by TGF-beta1 activation through Smad and ERK1/2 signaling. Together, our results suggest a pivotal role of CTGF-mediated TMZ resistance through TGF-beta1-dependent activation of Smad/ERK signaling pathways. These data provide us insights for identifying potential targets that are beneficial for overcoming TMZ resistance in GB. PMID- 28617439 TI - Cdc20 directs proteasome-mediated degradation of the tumor suppressor SMAR1 in higher grades of cancer through the anaphase promoting complex. AB - The Tumor suppressor SMAR1 (scaffold matrix attachment region binding protein 1) has a crucial role in maintaining genomic stability, cell cycle progression and apoptosis.Our previous finding showed that it is highly suppressed in higher grade of cancer. However, the underlying mechanism of this suppression was not well understood. In this study, we show that SMAR1 expression levels are controlled at the proteasomal level by five RING finger E3 ubiquitin ligases including, Cdc20, a substrate receptor of ubiquitin ligase APC/C complex. We found that Cdc20 binds and promotes proteasomal degradation of SMAR1 in a D-box motif dependent manner. Further, our results demonstrated that Cdc20 promotes proteasomal degradation of SMAR1 through K48-linked specific polyubiquitylation, and that short hairpin RNA mediated inactivation of Cdc20 leads to significant stabilization of SMAR1. These findings suggest that Cdc20 is responsible for maintaining the cellular levels of SMAR1. However, since Cdc20 fails to target SMAR1 upon exposure to genotoxic stresses, SMAR1 helps to maintain genomic stability under these conditions through its DNA damage repair activity. Interestingly, Cdc20-mediated degradation of SMAR1 promotes cell migration and invasion.The reciprocal relationship of the duo is evident in breast cancer cell lines as well as in patient samples, suggesting that Cdc20 functions as an important negative regulator of SMAR1 in higher grades of cancer. Our study reveals for the first time, the molecular mechanism associated with lower levels of expression of the important tumor suppressor SMAR1 in higher grades of breast cancer. PMID- 28617440 TI - The NF-kappaB1 is a key regulator of acute but not chronic renal injury. AB - The NF-kappaB family of transcription factors is important for many cellular functions, in particular initiation and propagation of inflammatory and immune responses. However, recent data has suggested that different subunits of the NF kappaB family can suppress the inflammatory response. NF-kappaB1, from the locus nfkappab1, can inhibit transcription, acting as a brake to the recognised pro inflammatory activity of other NF-kappaB subunits. We tested the function of NF kappaB1 in an acute (nephrotoxic serum (NTS) nephritis) and a chronic (unilateral ureteric obstruction (UUO)) model of renal injury using NF-kappaB1 (nfkappab1-/-) knockout mice. Deficiency in NF-kappaB1 increased the severity of glomerular injury in NTS-induced nephritis and was associated with greater proteinuria and persistent pro-inflammatory gene expression. Induction of disease in bone marrow chimeric mice demonstrated that the absence of NF-kappaB1 in either bone marrow or glomerular cells increased the severity of injury. Early after UUO (day 3) there was more severe histological injury in the nfkappab1-/- mice but by day 10, disease severity was equivalent in wild type and nfkappab1-/- mice. In conclusion, NF-kappaB1 modifies acute inflammatory renal injury but does not influence chronic fibrotic injury. PMID- 28617441 TI - Concomitant epigenetic targeting of LSD1 and HDAC synergistically induces mitochondrial apoptosis in rhabdomyosarcoma cells. AB - The lysine-specific demethylase 1 (LSD1) is overexpressed in several cancers including rhabdomyosarcoma (RMS). However, little is yet known about whether or not LSD1 may serve as therapeutic target in RMS. We therefore investigated the potential of LSD1 inhibitors alone or in combination with other epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Here, we identify a synergistic interaction of LSD1 inhibitors (i.e., GSK690, Ex917) and HDAC inhibitors (i.e., JNJ-26481585, SAHA) to induce cell death in RMS cells. By comparison, LSD1 inhibitors as single agents exhibit little cytotoxicity against RMS cells. Mechanistically, GSK690 acts in concert with JNJ-26481585 to upregulate mRNA levels of the proapoptotic BH3-only proteins BMF, PUMA, BIM and NOXA. This increase in mRNA levels is accompanied by a corresponding upregulation of BMF, PUMA, BIM and NOXA protein levels. Importantly, individual knockdown of either BMF, BIM or NOXA significantly reduces GSK690/JNJ-26481585-mediated cell death. Similarly, genetic silencing of BAK significantly rescues cell death upon GSK690/JNJ-26481585 cotreatment. Also, overexpression of antiapoptotic BCL-2 or MCL-1 significantly protects RMS cells from GSK690/JNJ-26481585-induced cell death. Furthermore, GSK690 acts in concert with JNJ-26481585 to increase activation of caspase-9 and -3. Consistently, addition of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) significantly reduces GSK690/JNJ-26481585-mediated cell death. In conclusion, concomitant LSD1 and HDAC inhibition synergistically induces cell death in RMS cells by shifting the ratio of pro- and antiapoptotic BCL-2 proteins in favor of apoptosis, thereby engaging the intrinsic apoptotic pathway. This indicates that combined treatment with LSD1 and HDAC inhibitors is a promising new therapeutic approach in RMS. PMID- 28617442 TI - Titanium particle-induced osteogenic inhibition and bone destruction are mediated by the GSK-3beta/beta-catenin signal pathway. AB - Wear debris-induced osteogenic inhibition and bone destruction are critical in the initiation of peri-prosthetic osteolysis. However, the molecular mechanism underlying this phenomenon is poorly understood. In this study, we analyzed the involvement of the GSK-3beta/beta-catenin signal pathway, which is important for bone formation in this pathological condition. We established a titanium (Ti) particle-stressed murine MC3T3-E1 cell culture system and calvariae osteolysis model to test the hypothesis that Ti particle-induced osteogenic inhibition and bone destruction are mediated by the GSK-3beta/beta-catenin signal pathway. Our findings showed that Ti particles reduced osteogenic differentiation induced by osteogenesis-related gene expression, alkaline phosphatase activity and matrix mineralization, as well as pSer9-GSK-3beta expression and beta-catenin signal activity. Downregulation of GSK-3beta activity attenuated Ti particle-induced osteogenic inhibition, whereas the beta-catenin inhibitor reversed this protective effect. Moreover, the GSK-3beta/beta-catenin signal pathway mediated the upregulation of RANKL and downregulation of OPG in Ti particle-stressed MC3T3 E1 cells. In addition, our in vivo results showed that Ti particles induced bone loss via regulating GSK-3beta and beta-catenin signals. Based on these results, we concluded that the GSK-3beta/beta-catenin signal pathway mediates the adverse effects of Ti particles on osteoblast differentiation and bone destruction, and can be used as a potential therapeutic target for the treatment of peri prosthetic osteolysis. PMID- 28617443 TI - Bilirubin neurotoxicity is associated with proteasome inhibition. AB - The molecular mechanism underlying bilirubin neurotoxicity remains obscure. Ubiquitin-proteasome system-mediated proteolysis is pivotal to virtually all cellular processes and cell survival. Here we report for the first time that bilirubin at a clinically relevant elevated level impairs proteasomal function via inhibiting both the 19S proteasome-associated deubiquitinases (USP14 and UCHL5) and the chymotrypsin-like (CT-like) peptidase activity of 20S proteasomes, thereby contributing to bilirubin neurotoxicity. This is supported by multiple lines of evidence. First, sera from patients with hyperbilirubinemia were able to inhibit the peptidase activity of purified 20S proteasome in vitro in a bilirubin concentration-dependent manner; meanwhile, the blood cells of these patients showed significantly increased levels of ubiquitinated proteins (Ub-prs), consistent with proteasome inhibition. Second, intracerebroventricular injection to adult rats or intraperitoneal injections to neonatal rats of bilirubin-induced neural accumulation of Ub-prs, concurrent with other neural pathology; and brain malfunction and pathology induced by neonatal exposure to hyperbilirubinemia were detectable in the rats during their adulthood. Third, in primary cultures of hippocampal neurons, bilirubin strikingly induced Ub-pr accumulation before the activation of cell death pathway becomes discernible. Finally, bilirubin in vitro directly inhibited both the deubiquitination activity of proteasome-associated USP14 and UCHL5 and the CT-like peptidase activity of purified 20S proteasomes, in a dose-dependent manner. Hence, this study has discovered that increased bilirubin at a clinically achievable level can act as a proteasome inhibitor via targeting the 19S proteasome-associated deubiquitinases (DUBs) and, perhaps to a less extent, the 20S proteasome, identifying a novel mechanism for bilirubin neurotoxicity. PMID- 28617444 TI - Heme oxygenase-1 derived carbon monoxide suppresses Abeta1-42 toxicity in astrocytes. AB - Neurodegeneration in Alzheimer's disease (AD) is extensively studied, and the involvement of astrocytes and other cell types in this process has been described. However, the responses of astrocytes themselves to amyloid beta peptides ((Abeta; the widely accepted major toxic factor in AD) is less well understood. Here, we show that Abeta(1-42) is toxic to primary cultures of astrocytes. Toxicity does not involve disruption of astrocyte Ca2+ homeostasis, but instead occurs via formation of the toxic reactive species, peroxynitrite. Thus, Abeta(1-42) raises peroxynitrite levels in astrocytes, and Abeta(1-42) toxicity can be inhibited by antioxidants, or by inhibition of nitric oxide (NO) formation (reactive oxygen species (ROS) and NO combine to form peroxynitrite), or by a scavenger of peroxynitrite. Increased ROS levels observed following Abeta(1-42) application were derived from NADPH oxidase. Induction of haem oxygenase-1 (HO-1) protected astrocytes from Abeta(1-42) toxicity, and this protective effect was mimicked by application of the carbon monoxide (CO) releasing molecule CORM-2, suggesting HO-1 protection was attributable to its formation of CO. CO suppressed the rise of NADPH oxidase-derived ROS caused by Abeta(1-42). Under hypoxic conditions (0.5% O2, 48 h) HO-1 was induced in astrocytes and Abeta(1-42) toxicity was significantly reduced, an effect which was reversed by the specific HO-1 inhibitor, QC-15. Our data suggest that Abeta(1 42) is toxic to astrocytes, but that induction of HO-1 affords protection against this toxicity due to formation of CO. HO-1 induction, or CO donors, would appear to present attractive possible approaches to provide protection of both neuronal and non-neuronal cell types from the degenerative effects of AD in the central nervous system. PMID- 28617445 TI - Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption. AB - BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2DeltaE5+7), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the 'BRCAness' profile. PMID- 28617446 TI - Cathepsin L and B as Potential Markers for Liver Fibrosis: Insights From Patients and Experimental Models. AB - OBJECTIVES: Cathepsin L (CTSL) and B (CTSB) have a crucial role in extracellular matrix (ECM) degradation and tissue remodeling, which is a prominent feature of fibrogenesis. The aim of this study was to determine the role and clinical significance of these cathepsins in liver fibrosis. METHODS: Hepatic histological CTSL and CTSB expression were assessed in experimental models of liver fibrosis, patients with liver cirrhosis, chronic viral hepatitis, and controls by real-time PCR and immunohistochemistry. Plasma levels of CTSL and CTSB were analyzed in 51 liver cirrhosis patients (Child-Pugh stages A, B and C) and 15 controls. RESULTS: Significantly enhanced CTSL mRNA (P=0.02) and protein (P=0.01) levels were observed in the liver of carbon tetrachloride-treated mice compared with controls. Similarly, hepatic CTSL and CTSB mRNA levels (P=0.02) were markedly increased in Abcb4-/- (ATP-binding cassette transporter knockout) mice compared with wild-type littermates. Elevated levels of CTSL and CTSB were also found in the liver (P=0.001) and plasma (P<0.0001) of patients with hepatic cirrhosis compared with healthy controls. Furthermore, CTSL and CTSB levels correlated well with the hepatic collagen (r=0.5, P=0.007; r=0.64, P=0.0001). CTSL and CTSB levels increased with the Child-Pugh stage of liver cirrhosis and correlated with total bilirubin content (r=0.4/0.2; P<=0.05). CTSL, CTSB, and their combination had a high diagnostic accuracy (area under the curve: 0.91, 0.89 and 0.96, respectively) for distinguishing patients from controls. CONCLUSIONS: Our data demonstrate the overexpression of CTSL and CTSB in patients and experimental mouse models, suggesting their potential as diagnostic biomarkers for chronic liver diseases. PMID- 28617448 TI - Diminishing Effectiveness of Long-Term Maintenance Topical Steroid Therapy in PPI Non-Responsive Eosinophilic Esophagitis. AB - OBJECTIVES: While topical corticosteroids are first-line therapy for eosinophilic esophagitis (EoE), the data regarding long-term effectiveness are lacking. We aimed to determine long-term histologic and endoscopic outcomes of maintenance therapy in EoE steroid responders. METHODS: We performed a retrospective study of adults with EoE at UNC Hospitals who had initial histologic response (<15 eos/hpf) after 8 weeks of topical steroids, and maintained on therapy. Endoscopic and the histologic data were recorded at baseline and follow-up endoscopies. Multivariable logistic regression was performed to assess loss of treatment response by steroid dose at recurrence, and Kaplan-Meier analysis to calculate durability of disease remission. RESULTS: Of 55 EoE patients with initial response to swallowed/topical fluticasone or budesonide over a median 11.7 months, 33 had at least two follow-up EGDs. Of these patients, 61% had histologic loss of response and worse endoscopic findings. There was no difference in baseline steroid dose (P=0.55) between the groups, but those maintained on their initial dose had lower odds (OR: 0.10; 95% CI: 0.01, 0.90) of loss of response compared to those who had subsequent dose reduction. On survival analysis, 50% had loss of response to steroids by 18.5 months and 75% by 29.6 months. CONCLUSIONS: In adult EoE steroid responders, loss of treatment response is common, and is associated with a steroid dose reduction. Routinely lowering doses for maintenance steroids may provide inferior outcomes. PMID- 28617447 TI - Targeting the vasculature in hepatocellular carcinoma treatment: Starving versus normalizing blood supply. AB - Traditional treatments for intermediate or advanced stage hepatocellular carcinoma (HCC) such as transarterial chemoembolization (TACE) and anti angiogenesis therapies were developed to starve tumor blood supply. A new approach of normalizing structurally and functionally abnormal tumor vasculature is emerging. While TACE improves survival in selected patients, the resulting tumor hypoxia stimulates proliferation, angiogenesis, treatment resistance and metastasis, which limits its overall efficacy. Vessel normalization decreases hypoxia and improves anti-tumor immune infiltrate and drug delivery. Several pre clinical agents aimed at normalizing tumor vasculature in HCC appear promising. Although anti-angiogenic agents with vessel normalizing potential have been trialed in advanced HCC with modest results, to date their primary intention had been to starve the tumor. Judicious use of anti-angiogenic therapies is required to achieve vessel normalization yet avoid excessive pruning of vessels. This balance, termed the normalization window, is yet uncharacterized in HCC. However, the optimal class, dose and schedule of vascular normalization agents, alone or in combination with other therapies needs to be explored further. PMID- 28617449 TI - Assessment of social transmission of threats in humans using observational fear conditioning. AB - Across the human life span, fear is often acquired indirectly by observation of the emotional expressions of others. The observational fear conditioning protocol was previously developed as a laboratory model for investigating socially acquired threat responses. This protocol serves as a suitable alternative to the widely used Pavlovian fear conditioning, in which threat responses are acquired through direct experiences. In the observational fear conditioning protocol, the participant (observer) watches a demonstrator being presented with a conditioned stimulus (CS) paired with an aversive unconditioned stimulus (US). The expression of threat learning is measured as the conditioned response (CR) expressed by the observer in the absence of the demonstrator. CRs are commonly measured as skin conductance responses, but behavioral and neural measures have also been implemented. The experimental procedure is suitable for divergent populations, can be administered by a graduate student and takes ~40 min. Similar protocols are used in animals, emphasizing its value as a translational tool for studying socioemotional learning. PMID- 28617450 TI - A human intestinal M-cell-like model for investigating particle, antigen and microorganism translocation. AB - The specialized microfold cells (M cells) in the follicle-associated epithelium (FAE) of intestinal Peyer's patches serve as antigen-sampling cells of the intestinal innate immune system. Unlike 'classical' enterocytes, they are able to translocate diverse particulates without digesting them. They act as pathways for microorganism invasion and mediate food tolerance by transcellular transport of intestinal microbiota and antigens. Their ability to transcytose intact particles can be used to develop oral drug delivery and oral immunization strategies. This protocol describes a reproducible and versatile human M-cell-like in vitro model. This model can be exploited to evaluate M-cell transport of microparticles and nanoparticles for protein, drug or vaccine delivery and to study bacterial adherence and translocation across M cells. The inverted in vitro M-cell model consists of three main steps. First, Caco-2 cells are seeded at the apical side of the inserts. Second, the inserts are inverted and B lymphocytes are seeded at the basolateral side of the inserts. Third, the conversion to M cells is assessed. Although various M-cell culture systems exist, this model provides several advantages over the rest: (i) it is based on coculture with well established differentiated human cell lines; (ii) it is reproducible under the conditions described herein; (iii) it can be easily mastered; and (iv) it does not require the isolation of primary cells or the use of animals. The protocol requires skills in cell culture and microscopy analysis. The model is obtained after 3 weeks, and transport experiments across the differentiated model can be carried out over periods of up to 10 h. PMID- 28617452 TI - Applied physics: Wireless power on the move. PMID- 28617451 TI - Biological and chemical strategies for exploring inter- and intra-kingdom communication mediated via bacterial volatile signals. AB - Airborne chemical signals emitted by bacteria influence the behavior of other bacteria and plants. We present an overview of in vitro methods for evaluating bacterial and plant responses to bacterial volatile compounds (BVCs). Three types of equipment have been used to physically separate the bacterial test strains from either other bacterial strains or plants (in our laboratory we use either Arabidopsis or tobacco plant seedlings): a Petri dish containing two compartments (BI Petri dish); two Petri dishes connected with tubing; and a microtiter-based assay. The optimized procedure for the BI Petri dish system is described in this protocol and can be widely used for elucidation of potential function in interactions between diverse microbes and those plant and chemical volatiles emitted by bacteria that are most likely to mediate bacterial or plant responses to BVCs. We also describe a procedure for metabolome-based BVC profiling via dynamic (i.e., continuous airflow) or static headspace sampling using solid-phase microextraction (SPME). Using both these procedures, bacteria-bacteria communications and bacteria-plant interactions mediated by BVCs can be rapidly investigated (within 1-4 weeks). PMID- 28617453 TI - Slush-like polar structures in single-crystal relaxors. AB - Despite more than 50 years of investigation, it is still unclear how the underlying structure of relaxor ferroelectrics gives rise to their defining properties, such as ultrahigh piezoelectric coefficients, high permittivity over a broad temperature range, diffuse phase transitions, strong frequency dependence in dielectric response, and phonon anomalies. The model of polar nanoregions inside a non-polar matrix has been widely used to describe the structure of relaxor ferroelectrics. However, the lack of precise knowledge about the shapes, growth and dipole patterns of polar nanoregions has led to the characterization of relaxors as "hopeless messes", and no predictive model for relaxor behaviour is currently available. Here we use molecular dynamics simulations of the prototypical Pb(Mg1/3,Nb2/3)O3-PbTiO3 relaxor material to examine its structure and the spatial and temporal polarization correlations. Our simulations show that the unusual properties of relaxors stem from the presence of a multi-domain state with extremely small domain sizes (2-10 nanometres), and no non-polar matrix, owing to the local dynamics. We find that polar structures in the multi-domain state in relaxors are analogous to those of the slush state of water. The multi domain structure of relaxors that is revealed by our molecular dynamics simulations is consistent with recent experimental diffuse scattering results and indicates that relaxors have a high density of low-angle domain walls. This insight explains the recently discovered classes of relaxors that cannot be described by the polar nanoregion model, and provides guidance for the design and synthesis of new relaxor materials. PMID- 28617454 TI - Corrigendum: MC4R-dependent suppression of appetite by bone-derived lipocalin 2. AB - This corrects the article DOI: 10.1038/nature21697. PMID- 28617458 TI - Materials science: How to suck like an octopus. PMID- 28617459 TI - Junior scientists: Senior scientists as allies for equity. PMID- 28617461 TI - Development: Sustainability and resilience differ. PMID- 28617462 TI - Conservation: Pay countries to stop whaling. PMID- 28617463 TI - Robust wireless power transfer using a nonlinear parity-time-symmetric circuit. AB - Considerable progress in wireless power transfer has been made in the realm of non-radiative transfer, which employs magnetic-field coupling in the near field. A combination of circuit resonance and impedance transformation is often used to help to achieve efficient transfer of power over a predetermined distance of about the size of the resonators. The development of non-radiative wireless power transfer has paved the way towards real-world applications such as wireless powering of implantable medical devices and wireless charging of stationary electric vehicles. However, it remains a fundamental challenge to create a wireless power transfer system in which the transfer efficiency is robust against the variation of operating conditions. Here we propose theoretically and demonstrate experimentally that a parity-time-symmetric circuit incorporating a nonlinear gain saturation element provides robust wireless power transfer. Our results show that the transfer efficiency remains near unity over a distance variation of approximately one metre, without the need for any tuning. This is in contrast with conventional methods where high transfer efficiency can only be maintained by constantly tuning the frequency or the internal coupling parameters as the transfer distance or the relative orientation of the source and receiver units is varied. The use of a nonlinear parity-time-symmetric circuit should enable robust wireless power transfer to moving devices or vehicles. PMID- 28617465 TI - Correction. PMID- 28617464 TI - Publishing: Journals could share peer-review data. PMID- 28617466 TI - Damming the rivers of the Amazon basin. AB - More than a hundred hydropower dams have already been built in the Amazon basin and numerous proposals for further dam constructions are under consideration. The accumulated negative environmental effects of existing dams and proposed dams, if constructed, will trigger massive hydrophysical and biotic disturbances that will affect the Amazon basin's floodplains, estuary and sediment plume. We introduce a Dam Environmental Vulnerability Index to quantify the current and potential impacts of dams in the basin. The scale of foreseeable environmental degradation indicates the need for collective action among nations and states to avoid cumulative, far-reaching impacts. We suggest institutional innovations to assess and avoid the likely impoverishment of Amazon rivers. PMID- 28617467 TI - A wet-tolerant adhesive patch inspired by protuberances in suction cups of octopi. AB - Adhesion strategies that rely on mechanical interlocking or molecular attractions between surfaces can suffer when coming into contact with liquids. Thus far, artificial wet and dry adhesives have included hierarchical mushroom-shaped or porous structures that allow suction or capillarity, supramolecular structures comprising nanoparticles, and chemistry-based attractants that use various protein polyelectrolytes. However, it is challenging to develop adhesives that are simple to make and also perform well-and repeatedly-under both wet and dry conditions, while avoiding non-chemical contamination on the adhered surfaces. Here we present an artificial, biologically inspired, reversible wet/dry adhesion system that is based on the dome-like protuberances found in the suction cups of octopi. To mimic the architecture of these protuberances, we use a simple, solution-based, air-trap technique that involves fabricating a patterned structure as a polymeric master, and using it to produce a reversed architecture, without any sophisticated chemical syntheses or surface modifications. The micrometre-scale domes in our artificial adhesive enhance the suction stress. This octopus-inspired system exhibits strong, reversible, highly repeatable adhesion to silicon wafers, glass, and rough skin surfaces under various conditions (dry, moist, under water and under oil). To demonstrate a potential application, we also used our adhesive to transport a large silicon wafer in air and under water without any resulting surface contamination. PMID- 28617468 TI - Tissue engineering: NIH competition to create 'eye in a dish'. PMID- 28617470 TI - Plutonium accident, ancient amber and a call to climate scientists. PMID- 28617469 TI - In Retrospect: A decade of shared genomic associations. PMID- 28617471 TI - Harmonize conflicting regulations for genetically engineered plants and animals. PMID- 28617472 TI - Eye-opening picture of fetal immune system emerges. PMID- 28617473 TI - United States revives space-policy council after 24-year absence. PMID- 28617474 TI - Empty rhetoric over data sharing slows science. PMID- 28617475 TI - UK scientists hope for softened Brexit after shock election result. PMID- 28617476 TI - Fight the silencing of gun research. PMID- 28617478 TI - Reassess dam building in the Amazon. PMID- 28617479 TI - Let Trump claim a better deal on climate. PMID- 28617480 TI - Bats are global reservoir for deadly coronaviruses. PMID- 28617481 TI - US mental-health agency's push for basic research has slashed support for clinical trials. PMID- 28617482 TI - The 'time machine' reconstructing ancient Venice's social networks. PMID- 28617483 TI - Epidemiology of chronic kidney disease: think (at least) twice! AB - The introduction of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines has substantially contributed to the early detection of different stages of chronic kidney disease (CKD). Several recent studies from different parts of the world mention a CKD prevalence of between 8 and 13%. There are several reasons the CKD prevalence found in a study of a particular population is clearly overestimated. The structure of the population pyramid (young or older age) of the study sample may result in high or low CKD prevalence. The absence of using an isotope dilution mass spectrometry creatinine assay can be the source of high bias in CKD prevalence. In addition, using an arbitrary single threshold of estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m2) for classifying CKD leads to a substantial 'overdiagnosis' (false positives) in the elderly (>65 years of age), particularly in those without albuminuria (or proteinuria), haematuria or hypertension. It also results in a significant 'underdiagnosis' (false negatives) in younger individuals with an eGFR >60 mL/min/1.73 m2 and below the third percentile for their age/gender category. The use of third percentile eGFR rates as a cut-off based on age/gender-specific reference values of eGFR allows the detection of these false positives and negatives. In the present article, we focus on an important and frequently omitted criterion in epidemiological studies: chronicity. Indeed, the two most important factors introducing a high number (up to 50%) of false positives are lack of confirming proteinuria and the absence of proof of chronicity of the eGFR found at first screening. There is an urgent need for quality studies of the prevalence of CKD using representative randomized samples of the population, applying the KDIGO guidelines correctly. PMID- 28617484 TI - Improved photocathodic performance in Pt catalyzed ferroelectric BiFeO3 films sandwiched by a porous carbon layer. AB - A porous carbon layer was inserted between a BiFeO3 film and a Pt catalyst for efficient solar water splitting. A photocathodic current density of -235.4 MUA cm 2 at 0 V versus RHE and an onset potential of 1.19 V versus RHE were obtained under 100 mW cm-2 Xe-lamp illumination. PMID- 28617485 TI - Non-trivial rheological exponents in sheared yield stress fluids. AB - In this work we discuss possible physical origins of non-trivial exponents in the athermal rheology of soft materials at low but finite driving rates. A key ingredient in our scenario is the presence of a self-consistent mechanical noise that stems from the spatial superposition of long-range elastic responses to localized plastically deforming regions. We study analytically a mean-field model, in which this mechanical noise is accounted for by a stress diffusion term coupled to the plastic activity. Within this description we show how a dependence of the shear modulus and/or the local relaxation time on the shear rate introduces corrections to the usual mean-field prediction, concerning the Herschel-Bulkley-type rheological response of exponent 1/2. This feature of the mean-field picture is then shown to be robust with respect to structural disorder and partial relaxation of the local stress. We test this prediction numerically on a mesoscopic lattice model that implements explicitly the long-range elastic response to localized shear transformations, and we conclude on how our scenario might be tested in rheological experiments. PMID- 28617486 TI - Ultra-high loading of sinoporphyrin sodium in ferritin for single-wave motivated photothermal and photodynamic co-therapy. AB - In this work, a potent photosensitizer, sinoporphyrin sodium (DVDMS), was loaded into RGD-modified ferritin (R-Fn) nanocages by a rapid, scalable and versatile approach for imaging guided photodynamic and photothermal (PTT/PDT) co-therapy. The resulting nanocomposite formed a well-defined nanocage with a photosensitizer loading capacity as high as 66.67 wt%, which far exceeds those reported previously. The bioengineered protein nanocage-based nanotheranostics exhibits a remarkably improved tumor treatment effect over DVDMS with good biocompatibility and the potential of clinical translation. PMID- 28617487 TI - Organ-on-a-chip devices advance to market. AB - To curb the high cost of drug development, there is an urgent need to develop more predictive tissue models using human cells to determine drug efficacy and safety in advance of clinical testing. Recent insights gained through fundamental biological studies have validated the importance of dynamic cell environments and cellular communication to the expression of high fidelity organ function. Building on this knowledge, emerging organ-on-a-chip technology is poised to fill the gaps in drug screening by offering predictive human tissue models with methods of sophisticated tissue assembly. Organ-on-a-chip start-ups have begun to spawn from academic research to fill this commercial space and are attracting investment to transform the drug discovery industry. This review traces the history, examines the scientific foundation and envisages the prospect of these renowned organ-on-a-chip technologies. It serves as a guide for new members of this dynamic field to navigate the existing scientific and market space. PMID- 28617488 TI - Potential use of the PRI and active fluorescence for the diagnosis of the physiological state of plants under ozone exposure and high atmospheric vapor pressure deficit. AB - Assessing photosynthesis rates with remote sensing is important for tracking the physiological state of plants. The photochemical reflectance index (PRI) is a good estimator of short-term light-use efficiency (LUE) at the leaf scale but its responses to environmental factors are poorly understood. In this study, we assessed changes in the responses of the PRI to ozone exposure and to an increase in atmospheric drought (separately and combined) in oak (Quercus robur) and holm oak (Quercus ilex) that were planted in climatic cells under controlled conditions. The aim was to evaluate the ability of the PRI as a relevant indicator to assess the impact of abiotic factors on photosynthesis. Leaf-scale measurements of biochemical, physiological and spectral properties, including the PRI in dim light on dark-adapted leaves (PRI0), kinetics of PRI responses to PAR variations (photosynthetically active radiation), and leaf chlorophyll fluorescence parameters were performed. The results show that PRI0 is a good proxy of the leaf chlorophyll content, and is correlated to chlorophyll fluorescence parameters on dark adapted leaves (Fo, Fm). The correction of the PRI from the leaf chlorophyll content variations (PRIc) significantly improves correlations between the PRI and NPQ (non-photochemical quenching). The variability of PARsat (estimated PAR value at PRI saturation using PRI vs. PAR relationships) depends on ozone exposure and on the increase in atmospheric vapor pressure deficit. For Quercus robur, results highlight that PARsat is linked to abiotic stress indicating that the PRI may be used as a relevant indicator of abiotic factors limiting the photosynthesis. Quercus ilex did not show significant variability in PRI0 and PARsat, which suggest that it is a more drought resistant species than Q. robur. PMID- 28617489 TI - Phase behaviour of hard board-like particles. AB - We examine the phase behaviour of colloidal suspensions of hard board-like particles (HBPs) as a function of their shape anisotropy, and observe a fascinating spectrum of nematic, smectic, and columnar liquid-crystalline phases, whose formation is entirely driven by excluded volume effects. We map out the phase diagram of short and long HBPs by gradually modifying their shape from prolate to oblate and investigate the long-range order of the resulting morphologies along the phase directors and perpendicularly to them. The intrinsic biaxial nature of these particles promotes the formation of translationally ordered biaxial phases, but does not show solid evidence that it would, per se, promote the formation of the biaxial nematic phase. Our simulations shed light on the controversial existence of the discotic smectic phase, whose layers are as thick as the minor particle dimension, which is stable in a relatively large portion of our phase diagrams. Additionally, we modify the Onsager theory to describe the isotropic-nematic phase transition of freely rotating biaxial particles as a function of the particle width, and find a relatively strong first order signature, in excellent agreement with our simulations. In an attempt to shed light on the elusive formation of the biaxial nematic phase, we apply this theory to predict the uniaxial-biaxial nematic phase transition and confirm, again in agreement with simulations, the prevailing stability of the translationally ordered smectic phase over the orientationally ordered biaxial nematic phase. PMID- 28617490 TI - Synthesis and bioactivity of fused- and spiro-beta-lactone-lactam systems. AB - An investigation of the formation of fused- and spiro-beta-lactone annulate to gamma-lactams has shown that the fused systems are formed preferentially, under standard conditions, but that spiro systems are accessible only when the formation of the fused system is blocked and require careful optimisation of reaction conditions. These systems display both weak antibacterial activity and proteasome inhibition. PMID- 28617491 TI - Deciphering the dynamics of star molecules in shear flow. AB - This work analyses the rotation of star polymers under shear flow, in melts, and in good solvent dilute solution. The latter is modeled by single molecule Brownian hydrodynamics, while melts are modeled using non-equilibrium molecular dynamics in closed (periodic) boxes and in open boundaries. A Dissipative Particle Dynamics (DPD) thermostat introduces pairwise monomer friction in melts at will, in directions normal and tangent to the monomer-monomer vectors. Although tangential friction is seldom modeled, we show that it is essential to control hydrodynamic effects in melts. We analyze the different sources of molecular angular momentum in solution and melts and distinguish three dynamic regimes as the shear rate [small gamma, Greek, dot above] is increased. These dynamic regimes are related with the disruption of the different relaxation mechanisms of the star in equilibrium. Although strong differences are found between harmonic springs and finitely extensible bonds, above a critical shear rate the star molecule has a "breathing" mode with successive elongations and contractions in the flow direction with frequency Omega. The force balance in the flow direction unveils a relation between Omega and the orientation angle. Using literature results for the tumbling of rings and linear chains, either in melt or in solution, we show that the relation is general. A different "tank-treading" dynamics determines the rotation of monomers around the center of mass of the molecule. We show that the tank-treading frequency does not saturate but keeps increasing with [small gamma, Greek, dot above]. This is at odds with previous studies which erroneously calculated the molecular angular frequency, used as a proxy for tank-treading. PMID- 28617492 TI - Heteroaryl bismuthines: a novel synthetic concept and metalpi heteroarene interactions. AB - The alkoxide Bi[OCMe2(2-C4H3S)]3 (1) is formed by the reaction of three equiv. of the alcohol HOCMe2(2-C4H3S) with Bi(OtBu)3 and subsequent hydrolysis provides the bismuth oxido cluster [Bi4O2{OCMe2(2-C4H3S)}8] (2). In contrast, the reaction of Bi(OtBu)3 and Bi[N(SiMe3)2]3 with the silanols HOSiMe2(2-C4H3X) (X = O, S, Se, and NMe), HOSiMe2(2-C4H2S-5-SiMe3) and HOSiMe2(3-C4H3S) leads to the formation of tris(heteroaryl)bismuthines Bi(2-C4H2X-5-R)3 [where X = O, R = H (3); X = S, R = H (4); X = S, R = SiMe3 (5); X = NMe, R = H (6); X = Se, R = H (7)] and Bi(3 C4H3S)3 (8). For the silanols, bismuth-carbon bond formation is observed rather than silanol-alcoholate or silanol-amide exchange. The structures of compounds 1, 2, and 4-7a in the solid state were established by single crystal X-ray diffraction and all compounds except 5 show London dispersion type bismuthpi heteroarene interactions. For the bismuthine Bi(2-C4H3Se)3 (7), two polymorphs were isolated depending on the conditions of crystallization. At 8 degrees C, polymorph I (7a) crystallizes from an n-hexane solution in the triclinic space group P1[combining macron], whereas polymorph II (7b) crystallizes at 20 degrees C from a CH2Cl2/n-pentane solution in the monoclinic space group P21/c. The heteroaryl bismuthines 3 and 4 exhibit 2D network structures as a result of bismuthpi heteroarene interactions, whereas for the pyrrole derivative 6 the dispersion type interactions provide separated dimers. PMID- 28617494 TI - Spectral and photochemical properties of hybrid organic-inorganic nanosystems based on CdS quantum dots and merocyanine ligands. AB - The spectral and photochemical properties of hybrid organic-inorganic nanosystems (HNSs) were investigated. HNS consisted of CdS quantum dots (QDs) functionalized with ligands containing the isothiouronium anchor group linked by a polymethylene chain with photochromic merocyanine (MC). The HNS synthesis was carried out via a microwave-assisted one-pot technique. Energy transfer from the QDs to MC in the HNS was observed and resulted in QD fluorescence quenching and MC sensitization. Compared to the free MC, trans-cis photoisomerization of MC in the HNS was suppressed and its photodestruction was accelerated. In addition, upon HNS photolysis by visible light with energy higher than the threshold, the photosensitized destruction of the QDs (which did not absorb the applied light) occurred. The observed effects were proposed to be caused by MC adsorption on QDs surface, which leads to the restriction of the MC photoisomerization and population of the surface electron trap states of the QDs. PMID- 28617493 TI - The formation of sesquiterpenoid presilphiperfolane and cameroonane metabolites in the Bcbot4 null mutant of Botrytis cinerea. AB - Botrytis cinerea is a polyphagous fungal parasite which causes serious damage to more than 200 plant species and consequent economic losses for commercial crops. This pathogen produces two families of phytotoxins, the botryanes and botcinins, which are involved in the infection mechanism. The B. cinerea genome has provided a complete picture of the genes involved in the biosynthesis of its secondary metabolites. The botrydial biosynthetic gene cluster has been identified. This cluster consists of seven genes, where the genes BcBOT1, BcBOT3 and BcBOT4 encode three mono-oxygenases. A study of the Bcbot4Delta null mutant revealed that this mono-oxygenase was involved in the hydroxylation at C-4 of the probotryane skeleton (C-11 of the presilphiperfolane skeleton). A detailed study of the Bcbot4Delta null mutant has been undertaken in order to study the metabolic fate of the presilphiperfolan-8-ol intermediate biosynthesized by this organism and in particular by this strain. As a result three new presilphiperfolanes and three new cameroonanes have been identified. The results suggest that the absence of the oxygen function at C-11 of the presilphiperfolane skeleton permits rearrangement to a cameroonane whilst hydroxylation at C-11 precludes this rearrangement. It is possible that the interactions of the C-11 hydroxylated derivatives perturb the stereo-electronic requirements for the migration of the C 11:C-7 sigma bond to C-8. PMID- 28617495 TI - Thiol-ene micropillar array electrospray ionization platform for zeptomole level bioanalysis. AB - A micropillar array electrospray ionization (MUPESI) platform fabricated from thiol-enes with 56 individual polyethylene glycol coated MUPESI chips for bioanalytical mass spectrometry is introduced. Bioanalysis capability is shown by measurement of a protein, a protein digest and a cell lysate sample. The thiol ene polyethylene glycol (PEG) coated MUPESI chip allows the use of a wide range of aqueous-organic solvent compositions and provides a detection limit at 60 zeptomole level (6 * 10-20 mol) for a peptide standard. PMID- 28617496 TI - A reconstructed anatase (001)-1 * 4 surface and its reactivity. AB - An anatase TiO2(001) surface has shown great potential as an ideal and powerful photocatalyst due to its chemical stability, nontoxicity, and high reactivity. However, the fundamental atomic structure of the reconstructed anatase (001)-(1 * 4) surface is still under debate, which greatly impedes further exploration of its chemical activity. Herein, the anatase (001)-(1 * 4) surface reconstruction and the photocatalytic reactivity have been extensively studied using an effective surface structure searching method in combination with the first principles calculations. Our study reveals that there exist two stable (1 * 4) reconstructed surfaces, i.e., the previously proposed "ad-molecule" (ADM) and oxidized ridge (OR) surface structures, and their simulated STM images are in good agreement with experimental observations. Moreover, we find that the ADM surface has superior photocatalytic reactivity to the OR surface and a small number of water can be dissociated at the terrace at one water monolayer coverage, which has never been found before. These findings can not only be applied to solve the experimental controversies about the atomic structure of the reconstructed anatase (001)-(1 * 4) surface but also provide a theoretical basis for exploring the intrinsic properties of the surface. PMID- 28617497 TI - Flexible hybrid graphene/a-Si:H multispectral photodetectors. AB - We report on the integration of large area CVD grown single- and bilayer graphene transparent conductive electrodes (TCEs) on amorphous silicon multispectral photodetectors. The broadband transmission of graphene results in 440% enhancement of the detectors' spectral response in the ultraviolet (UV) region at lambda = 320 nm compared to reference devices with conventional aluminum doped zinc oxide (ZnO:Al) electrodes. The maximum responsivity of the multispectral photodetectors can be tuned in their wavelength from 320 nm to 510 nm by an external bias voltage, allowing single pixel detection of UV to visible light. Graphene electrodes further enable fully flexible diodes on polyimide substrates. Here, an upgrade from single to bilayer graphene boosts the maximum photoresponsivity from 134 mA W-1 to 239 mA W-1. Interference patterns that are present in conventional TCE devices are suppressed as a result of the atomically thin graphene electrodes. The proposed detectors may be of interest in fields of UV/VIS spectroscopy or for biomedical and life science applications, where the extension to the UV range can be essential. PMID- 28617498 TI - Correction: A convenient, bio-inspired approach to the synthesis of multi functional, stable fluorescent silica nanoparticles using poly(ethylene-imine). AB - Correction for 'A convenient, bio-inspired approach to the synthesis of multi functional, stable fluorescent silica nanoparticles using poly(ethylene-imine)' by Christina A. Bauer, et al., Nanoscale, 2017, 9, 6509-6520. PMID- 28617499 TI - In vivo endoscopic mass spectrometry using a moving string sampling probe. AB - At present, endoscopy relies almost exclusively on optical microscopy and the accurate analysis such as MS interrogation is performed ex situ using biopsy. In this work, a novel probing system is developed to perform in situ and in vivo endoscopic mass spectrometry using a moving string for the sampling and transportation of material. A prototype of a mass spectrometric endoscope is constructed using an industrial endoscope and a commercial mass spectrometer. The sampling system consists of a moving cotton thread driven by motorized pulleys. When the target surface is touched by the sampling probe, the cotton thread "wipes" and transports the adhered sample to the ion source. Depending on the target analytes, desorption electrospray and atmospheric pressure chemical ionization sources are employed interchangeably for the desorption and ionization. The surface under analysis is not subjected to heat, organic solvents, high voltage or charged droplets. In situ endoscopic MS of a living mouse and surface analysis inside a volunteer subject's mouth are demonstrated. PMID- 28617500 TI - Decamethyltitanocene hydride intermediates in the hydrogenation of the corresponding titanocene-(eta2-ethene) or (eta2-alkyne) complexes and the effects of bulkier auxiliary ligands. AB - 1H NMR studies of reactions of titanocene [Cp*2Ti] (Cp* = eta5-C5Me5) and its derivatives [Cp*(eta5:eta1-C5Me4CH2)TiMe] and [Cp*2Ti(eta2-CH2[double bond, length as m-dash]CH2)] with excess dihydrogen at room temperature and pressures lower than 1 bar revealed the formation of dihydride [Cp*2TiH2] (1) and the concurrent liberation of either methane or ethane, depending on the organometallic reactant. The subsequent slow decay of 1 yielding [Cp*2TiH] (2) was mediated by titanocene formed in situ and controlled by hydrogen pressure. The crystalline products obtained by evaporating a hexane solution of fresh [Cp*2Ti] in the presence of hydrogen contained crystals having either two independent molecules of 1 in the asymmetric part of the unit cell or cocrystals consisting of 1 and [Cp*2Ti] in a 2 : 1 ratio. Hydrogenation of alkyne complexes [Cp*2Ti(eta2-R1C[triple bond, length as m-dash]CR2)] (R1 = R2 = Me or Et) performed at room temperature afforded alkanes R1CH2CH2R2, and after removing hydrogen, 2 was formed in quantitative yields. For alkyne complexes containing bulkier substituent(s) R1 = Me or Ph, R2 = SiMe3, and R1 = R2 = Ph or SiMe3, successful hydrogenation required the application of increased temperatures (70 80 degrees C) and prolonged reaction times, in particular for bis(trimethylsilyl)acetylene. Under these conditions, no transient 1 was detected during the formation of 2. The bulkier auxiliary ligands eta5-C5Me4tBu and eta5 C5Me4SiMe3 did not hinder the addition of dihydrogen to the corresponding titanocenes [(eta5-C5Me4tBu)2Ti] and [(eta5-C5Me4SiMe3)2Ti] yielding [(eta5 C5Me4tBu)2TiH2] (3) and [(eta5-C5Me4SiMe3)2TiH2] (4), respectively. In contrast to 1, the dihydride 4 did not decay with the formation of titanocene monohydride, but dissociated to titanocene upon dihydrogen removal. The monohydrides [(eta5 C5Me4tBu)2TiH] (5) and [(eta5-C5Me4SiMe3)2TiH] (6) were obtained by insertion of dihydrogen into the intramolecular titanium-methylene sigma-bond in compounds [(eta5-C5Me4tBu)(eta5:eta1-C5Me4CMe2CH2)Ti] and [(eta5-C5Me4SiMe3)(eta5:eta1 C5Me4SiMe2CH2)Ti], respectively. The steric influence of the auxiliary ligands became clear from the nature of the products obtained by reacting 5 and 6 with butadiene. They appeared to be the exclusively sigma-bonded eta1-but-2-enyl titanocenes (7) and (8), instead of the common pi-bonded derivatives formed for the sterically less congested titanocenes, including [Cp*2Ti(eta3-(1 methylallyl))] (9). The molecular structure optimized by DFT for compound 1 acquired a distinctly lower total energy than the analogously optimized complex with a coordinated dihydrogen [Cp*2Ti(eta2-H2)]. The stabilization energies of binding the hydride ligands to the bent titanocenes were estimated from counterpoise computations; they showed a decrease in the order 1 (-132.70 kJ mol 1), 3 (-121.11 kJ mol-1), and 4 (-112.35 kJ mol-1), in accordance with the more facile dihydrogen dissociation. PMID- 28617501 TI - Generation and characterisation of a stable nickel(ii)-aminoxyl radical complex. AB - A stable nickel(ii)-aminoxyl radical complex was generated by the reaction of a nickel(ii) complex supported by a tren ligand (tris(2-aminoethyl)amine) having bulky m-terphenyl substituents (TIPT: 3,5-bis(2,6-diisopropylphenyl)phenyl) and m CPBA (m-chloroperoxybenzoic acid). The formation mechanism of the nickel(ii) aminoxyl radical complex was examined. PMID- 28617502 TI - Bioelectrocatalytic NAD+/NADH inter-conversion: transformation of an enzymatic fuel cell into an enzymatic redox flow battery. AB - Diaphorase and a benzylpropylviologen redox polymer were combined to create a bioelectrode that can both oxidize NADH and reduce NAD+. We demonstrate how bioelectrocatalytic NAD+/NADH inter-conversion can transform a glucose/O2 enzymatic fuel cell (EFC) with an open circuit potential (OCP) of 1.1 V into an enzymatic redox flow battery (ERFB), which can be rapidly recharged by operation as an EFC. PMID- 28617503 TI - DNA intrastrand cross-links induced by the purine-type deoxyguanosine-8-yl radical: a DFT study. AB - Currently, all known DNA intrastrand cross-links are found to be induced by pyrimidine-type radicals; however, whether or not purine-type radicals are able to cause DNA intrastrand cross-links remains unclear. In the present study, probable additions of the highly reactive deoxyguanosine-8-yl radical to its 3'/5' neighboring pyrimidine nucleotides in four model compounds, 5'-GT-3', 5'-TG 3', 5'-GC-3', and 5'-CG-3', were studied using density functional theory (DFT) methods. In single-stranded DNA, the deoxyguanosine-8-yl radical is preferred to efficiently attack the C5 site of its 3' neighboring deoxythymidine or deoxycytidine, forming the G[8-5]T or G[8-5]C intrastrand cross-link rather than the C6 site forming the G[8-6]T or G[8-6]C intrastrand cross-link. The four corresponding sequence isomers, namely T[5-8]G, T[6-8]G, C[5-8]G, and C[6-8]G, formed by additions of deoxyguanosine-8-yl radical to its 5' neighboring pyrimidine nucleotides are predicted to be formed inefficiently. In double stranded DNA, considering the detrimental effects of stabilizing weak interactions on related structural adjustments required in each addition reaction path, relatively lower reaction yields are suggested for the G[8-5]T and G[8-5]C intrastrand cross-links, while the formation of the other six intrastrand cross links becomes quite difficult. All calculations definitely demonstrate that, in addition to pyrimidine-type radicals, the purine-type deoxyguanosine-8-yl radical is able to attack its 3'/5' neighboring pyrimidine nucleotides forming several DNA intrastrand cross-links. PMID- 28617504 TI - Biomimetic iterative method for polyketide synthesis. AB - An iterative method for synthesizing polyketides was demonstrated, in which the chain elongation of a carboxylic acid was performed by decarboxylative dehydration condensation with a malonic acid half thioester. After transforming the resulting beta-ketothioester into an appropriate form, the carboxylic acid functionality was regenerated for the next elongation step. PMID- 28617505 TI - Facile ring-opening of THF at a lithium center induced by a pendant Si-H bond and BPh3. AB - The macrocyclic polyamine 1,4,7-trimethyl-1,4,7,10-tetraazacyclododecane [LH = (Me3TACD)H] formed adducts with tetramethyl-silazides [M{N(SiHMe2)2}] (M = Li, Na, K) of light alkali metals. Upon heating, intramolecular dehydrocoupling occurred to give [M{(L)SiMe2N(SiHMe2)}]. BPh3 induced facile ring-opening of THF when reacted with [Li{(L)SiMe2N(SiHMe2)}]. PMID- 28617506 TI - A flexible 1,2-cis alpha-glycosylation strategy based on in situ adduct transformation. AB - A flexible 1,2-cis alpha-selective glycosylation strategy for a wide range of glycosyl donors and acceptors has been developed, which is based on an in situ adduct transformation protocol. Based on this strategy, both NFM-derived and iodide covalent adducts can be accessed for glycosylation. Using low temperature NMR spectroscopy, the aforementioned glycosyl adducts were detected. PMID- 28617507 TI - Silicene growth through island migration and coalescence. AB - We perform massively-parallel classical molecular dynamics (MD) simulations to study the long timescale monolayer silicene growth on an Ir (111) surface. We observe an intricate multi-stage growth process driven by atomic and cluster migration on the surface. Initial growth involves formation of sub-nanometer clusters via adatom surface diffusion. Subsequently, these clusters rearrange spontaneously with each additional Si atom, forming clusters containing 4-7 member rings. Growth of each cluster through adatom adhesion is accompanied by the formation of larger islands through cluster migration and coalescence. Coalescence of smaller, more mobile islands into larger clusters is aided by the internal rearrangement of rings within each cluster. This flexibility, both of clusters and their constituent atoms, allows the impinging clusters to reorient after first contact and form a more perfect union. We also report on the effect of temperature and flux on the growth process and the final nanostructure. Our study provides atomistic insights into the early stage growth mechanisms of silicene which can be significant for controlled synthesis of its 2D monolayers. PMID- 28617508 TI - Synthesis of functionalised azepanes and piperidines from bicyclic halogenated aminocyclopropane derivatives. AB - A series of 6,6-dihalo-2-azabicyclo[3.1.0]hexane and 7,7-dihalo-2 azabicyclo[4.1.0]heptane compounds were prepared by the reaction of dihalocarbene species with N-Boc-2,3-dihydro-1H-pyrroles or -1,2,3,4-tetrahydropyridines. Monochloro substrates were synthesised as well, using a chlorine-to-lithium exchange reaction. The behaviour of several aldehydes and ketones under reductive amination conditions with deprotected halogenated secondary cyclopropylamines was investigated, showing that this transformation typically triggers cyclopropane ring cleavage to give access to interesting nitrogen-containing ring-expanded products. PMID- 28617509 TI - Controlled rotation and translation of spherical particles or living cells by surface acoustic waves. AB - We show experimental evidence of the acoustically-assisted micromanipulation of small objects like solid particles or blood cells, combining rotation and translation, using high frequency surface acoustic waves. This was obtained from the leakage in a microfluidic channel of two standing waves arranged perpendicularly in a LiNbO3 piezoelectric substrate working at 36.3 MHz. By controlling the phase lag between the emitters, we could, in addition to translation, generate a swirling motion of the emitting surface which, in turn, led to the rapid rotation of spherical polystyrene Janus beads suspended in the channel and of human red and white blood cells up to several rounds per second. We show that these revolution velocities are compatible with a torque caused by the acoustic streaming that develops at the particles surface, like that first described by [F. Busse et al., J. Acoust. Soc. Am., 1981, 69(6), 1634-1638]. This device, based on standard interdigitated transducers (IDTs) adjusted to emit at equal frequencies, opens a way to a large range of applications since it allows the simultaneous control of the translation and rotation of hard objects, as well as the investigation of the response of cells to shear stress. PMID- 28617510 TI - A 1H-NMR based metabolomics study of the intervention effect of mangiferin on hyperlipidemia hamsters induced by a high-fat diet. AB - It has been demonstrated that mangiferin can ameliorate hypertriglyceridemia by modulating the expression levels of genes involved in lipid metabolism in animal experiments, but its effects on the serum metabolic fingerprinting of hyperlipidemia animal models have not been reported. Thus, a NMR-based metabolomics approach was conducted to explore the effects of mangiferin on hyperlipidemia hamsters and to gain a better understanding of the involved metabolic pathways. Hamsters fed with a high-fat diet were orally administered with mangiferin 150 mg per kg BW once a day for 8 weeks. Serum samples were analysed by 1H NMR, and multivariate statistical analysis was applied to the data to identify potential biomarkers. In total, 20 discriminating metabolites were identified. It turned out that mangiferin administration can partly reverse the metabolism disorders induced by a high-fat diet and exerted a good anti hypertriglyceridemia effect. Mangiferin ameliorated hyperlipidemia by intervening in some major metabolic pathways, involving glycolysis, the TCA cycle, synthesis of ketone bodies, and BCAAs as well as choline and lipid metabolism. These findings provided new essential information on the effects of mangiferin and demonstrated the great potential of this nutrimetabolomics approach. PMID- 28617511 TI - Correction: Unprecedented formation of 3-(tetrahydrofuran-2-yl)-4H-chromen-4-one in a reaction between 3,3a-dihydro-9H-furo[3,4-b]chromen-9-one and malononitrile. AB - Correction for 'Unprecedented formation of 3-(tetrahydrofuran-2-yl)-4H-chromen-4 one in a reaction between 3,3a-dihydro-9H-furo[3,4-b]chromen-9-one and malononitrile' by Jie-Jie Liu, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c7ob00904f. PMID- 28617512 TI - A concentration-independent micro/nanofluidic active diode using an asymmetric ion concentration polarization layer. AB - Over the past decade, nanofluidic diodes that rectify ionic currents (i.e. greater current in one direction than in the opposite direction) have drawn significant attention in biomolecular sensing, switching and energy harvesting devices. To obtain current rectification, conventional nanofluidic diodes have utilized complex nanoscale asymmetry such as nanochannel geometry, surface charge density, and reservoir concentration. Avoiding the use of sophisticated nano asymmetry, micro/nanofluidic diodes using microscale asymmetry have been recently introduced; however, their diodic performance is still impeded by (i) low (even absent) rectification effects at physiological concentrations over 100 mM and strong dependency on the bulk concentration, and (ii) the fact that they possess only passive predefined rectification factors. Here, we demonstrated a new class of micro/nanofluidic diode with an ideal perm-selective nanoporous membrane based on ion concentration polarization (ICP) phenomenon. Thin side-microchannels installed near a nanojunction served as mitigators of the amplified electrokinetic flows generated by ICP and induced convective salt transfer to the nanoporous membrane, leading to actively controlled micro-scale asymmetry. Using this device, current rectifications were successfully demonstrated in a wide range of electrolytic concentrations (10-5 M to 3 M) as a function of the fluidic resistance of the side-microchannels. Noteworthily, it was confirmed that the rectification factors were independent from the bulk concentration due to the ideal perm-selectivity. Moreover, the rectification of the presenting diode was actively controlled by adjusting the external convective flows, while that of the previous diode was passively determined by invariant nanoscale asymmetry. PMID- 28617513 TI - Reaction of S-geranyl-2-thiouracil modified oligonucleotides with alkyl amines leads to the N2-alkyl isocytosine derivatives. AB - S-Geranylated 2-thiouridines (geS2Us) are unique hydrophobic modified nucleosides identified very recently in bacterial tRNAs. Our study on the synthesis of geS2Ura-containing oligonucleotides (geS2U-RNA and geS2dU-DNA) revealed a fast substitution of the S-geranyl moiety by methylamine (frequently used in oligonucleotide deprotection procedures) or n-butylamine, providing the corresponding N2-alkyl isocytosine (R2isoCyt) derivatives. To retain the S geranyl moiety in the DNA or RNA chains, the optimized deprotection protocol with 8 M ethanolic ammonia should be applied. The oligomers bearing the R2isoCyt heterocycle (R2isoC-RNA and R2isodC-DNA) are less hydrophobic than the corresponding S2U- and geS2U-modified oligomers, whereas, contrary to the previously reported data, geS2dU-DNA and geS2U-RNA exhibit significantly higher lipophilicity than the parent S2Ura-containing oligonucleotides. Thermodynamic studies revealed that: (a) both geS2Ura- and R2isoCyt-modified oligomers exhibit similar hybridization properties towards DNA and RNA templates, and (b) the R2isoCyt nucleobase preferentially hybridizes to guanine moiety in the DNA/DNA and RNA/RNA duplexes. PMID- 28617514 TI - Enhancement of the antiproliferative activity of [RuCp(PPh3)2(dmoPTA 1kappaP)]+via its coordination to one {CoCl2} unit: synthesis, crystal structure and properties of [RuCp(PPh3)2-MU-dmoPTA-1kappaP:2kappa2N,N'-CoCl2](OTf).0.25H2O. AB - Synthesis, characterization and the antiproliferative activity of a new bimetallic complex [RuCp(PPh3)2-MU-dmoPTA-1kappaP:2k2N,N'-CoCl2]OTf.0.25H2O are described. The stability of the complex was studied under air and N2 atmospheres and in CDCl3, DMSO, water and the cell culture medium, at room temperature and 40 degrees C. The complex showed an enhanced antiproliferative activity (up to six fold) when compared with its parent complex [RuCp(PPh3)2(HdmoPTA)]2+ against human lung, cervix, breast, and colon solid tumor cell lines. PMID- 28617515 TI - Synthesis of N-acetoxy-N-arylamides via diacetoxyiodobenzene promoted double acylation reaction of hydroxylamines with aldehydes. AB - A facile and efficient synthesis of N-acetoxy-N-arylamides through double acylations of hydroxylamines with aldehydes and diacetoxyiodobenzene is reported. The yields of the products are good to excellent. PMID- 28617516 TI - Incorporation of native antibodies and Fc-fusion proteins on DNA nanostructures via a modular conjugation strategy. AB - A photocrosslinkable protein G variant was used as an adapter protein to covalently and site-specifically conjugate an antibody and an Fc-fusion protein to an oligonucleotide. This modular approach enables straightforward decoration of DNA nanostructures with complex native proteins while retaining their innate binding affinity, allowing precise control over the nanoscale spatial organization of such proteins for in vitro and in vivo biomedical applications. PMID- 28617517 TI - Selective Fasciotomy for Chronic Exertional Compartment Syndrome Detected With Exercise Magnetic Resonance Imaging. AB - Chronic exertional compartment syndrome that is refractory to conservative management should be treated with surgical fasciotomy. However, owing to the limitations of intracompartmental needle manometry in reaching a definite diagnosis, the appropriate timing for fasciotomy and on which compartment remain unclear. The authors report the case of a 22-year-old male military cadet who reported pain in his left calf when running or walking for long distances. The pain was located at the lateral aspect of the calf, from the mid-calf level to the ankle. At another hospital, nonenhanced magnetic resonance imaging had been performed, which showed no considerable abnormality. The authors used exercise magnetic resonance imaging to diagnose chronic exertional compartment syndrome. They performed selective fasciotomy on the compartment that showed a high signal intensity. As a military cadet, the patient was required to jog for more than an hour per day and perform strenuous muscle exercises. He reported that he did not have calf pain or discomfort during such activities 13 months postoperatively. The authors obtained a follow-up exercise magnetic resonance image. Compared with the preoperative magnetic resonance image, the follow-up exercise magnetic resonance image did not show high signal intensity at the lateral compartment. Exercise magnetic resonance imaging is useful in confirming the diagnosis of chronic exertional compartment syndrome and enables the performance of selective fasciotomy on the affected compartment. [Orthopedics. 2017; 40(6):e1099-e1102.]. PMID- 28617518 TI - Tibiofemoral Instability After Primary Total Knee Arthroplasty: Posterior Stabilized Implants for Obese Patients. AB - Tibiofemoral instability is a common complication after total knee arthroplasty (TKA), accounting for up to 22% of all revision procedures. Instability is the second most common cause of revision in the first 5 years after primary TKA. In this study, 13 knees with tibiofemoral instability after TKA were identified among 693 consecutive primary TKA procedures. Patient demographics, body mass index, clinical symptoms, previous deformity, previous knee surgery, complications, interval between index TKA and first tibiofemoral instability, causes of instability, and interval between index TKA and revision TKA were retrospectively reviewed. Clinical outcomes were assessed with the Lysholm Knee Scoring Scale. All patients were women, and mean body mass index was 37.7 kg/m2 (range, 27.2-52.6 kg/m2). Mean interval between index TKA and first tibiofemoral instability was 23.4 months (range, 9-45 months), and mean interval between index TKA and revision TKA was 25.6 months (range, 14-48 months). All patients had posterior cruciate ligament-retaining implants. Of the 13 knees, 11 had flexion instability and 2 had global instability. In all patients, instability was caused by incompetence of the posterior cruciate ligament; additionally, 1 patient had undersized and malpositioned implants. In 4 knees, the polyethylene insert was broken as well. All patients underwent revision TKA. Lysholm Knee Scoring Scale score had improved from a mean of 35.8 (range, 30-46) to a mean of 68.3 (range, 66-76). All patients included in this study were female and obese. The main cause of instability was secondary posterior cruciate ligament rupture and incompetence. The use of posterior-stabilized implants for primary TKA may prevent secondary instability in obese patients. [Orthopedics. 2017; 40(5):e812 e819.]. PMID- 28617519 TI - Pain and Opioid Use After Total Shoulder Arthroplasty With Injectable Liposomal Bupivacaine Versus Interscalene Block. AB - Postoperative pain control is a significant concern after total shoulder arthroplasty. Injectable periarticular liposomal bupivacaine, which has been found to decrease opioid use after orthopedic procedures, has been proposed as a viable alternative to regional anesthesia. This study compared the efficacy of liposomal bupivacaine vs interscalene block among patients undergoing total shoulder arthroplasty. A retrospective review was conducted of 79 patients who underwent anatomic total shoulder arthroplasty performed by a single surgeon between January 2013 and April 2015. Patient demographics, in-hospital Numeric Pain Rating Scale (NPRS) score obtained at 12-hour intervals, length of stay, and total in-hospital morphine equivalents in both the bupivacaine (n=25) and block (n=44) groups were recorded. Differences in length of stay, morphine equivalents, and age were assessed with Wilcoxon tests. Sex differences were assessed with the chi-square test. Repeated measures analysis with least square means was used to assess longitudinal changes in NPRS scores. No significant differences were found between groups for sex (P=.89), age (P=.81), American Society of Anesthesiologists classification (P=.50), preoperative opioid use (P=.41), length of stay (P=.32), or morphine equivalents (P=.71). The average NPRS score in the first 12 hours was 3.01 for the bupivacaine group and 4.41 for the interscalene block group (P=.25). By 48 hours postoperatively, average NPRS scores were similar (P=.93) for the 2 groups, 4.90 for the bupivacaine group and 4.19 for the interscalene block group. The findings for this cohort of patients undergoing anatomic total shoulder arthroplasty showed no significant difference for pain scores, postoperative narcotic use, or length of stay with injectable liposomal bupivacaine vs interscalene block. [Orthopedics. 2017; 40(5):e806-e811.]. PMID- 28617520 TI - Abnormal Spontaneous Brain Activity in Patients With Anisometropic Amblyopia Using Resting-State Functional Magnetic Resonance Imaging. AB - PURPOSE: To explore the abnormality of spontaneous activity in patients with anisometropic amblyopia under resting-state functional magnetic resonance imaging (Rs-fMRI). METHODS: Twenty-four participants were split into two groups. The anisometropic amblyopia group had 10 patients, all of whom had anisometropic amblyopia of the right eye, and the control group had 14 healthy subjects. All participants underwent Rs-fMRI scanning. Measurement of amplitude of low frequency fluctuations of the brain, which is a measure of the amplitudes of spontaneous brain activity, was used to investigate brain changes between the anisometropic amblyopia and control groups. RESULTS: Compared with an age- and gender-matched control group, the anisometropic amblyopia group showed increased amplitude of low frequency fluctuations of spontaneous brain activity in the left superior temporal gyrus, the left inferior parietal lobe, the left pons, and the right inferior semi-lunar lobe. The anisometropic amblyopia group also showed decreased amplitude of low frequency fluctuations in the bilateral medial frontal gyrus. CONCLUSIONS: This study demonstrated abnormal spontaneous brain activities in patients with anisometropic amblyopia under Rs-fMRI, and these abnormalities might contribute to the neuropathological mechanisms of anisometropic amblyopia. [J Pediatr Ophthalmol Strabismus. 2017;54(5):303-310.]. PMID- 28617521 TI - Regular Versus Releasable Sutures in Surgery for Primary Congenital Glaucoma. AB - PURPOSE: To compare releasable and regular sutures in combined angle and filtering surgery for primary congenital glaucoma. METHODS: A prospective study was conducted on 39 eyes (26 right eyes) of 39 children (20 boys; 19 girls) who had primary congenital glaucoma treated with combined trabeculotomy trabeculectomy with mitomycin C and scleral flap closure with regular or releasable sutures. Follow-up was 24 months. Success rates (defined as an intraocular pressure [IOP] < 16 mm Hg without hypotony-related complications and/or lack of IOP-related progression of the disease) were studied and complications were noted. RESULTS: The mean age of the study participants was 6.7 +/- 5.8 months (range: 1 to 24 months; median: 5 months) in the regular suture group (20 eyes) and 5.3 +/- 2.8 months (range: 1 to 13 months; median: 5 months) in the releasable suture group (19 eyes). The initial glaucoma surgery was successful in 13 (65%) and 13 (68.4%) eyes in the regular suture and releasable suture groups, respectively. The mean IOP was 17.4 +/- 7.3 and 16.0 +/- 5.4 mm Hg (P = .84) preoperatively and 8.0 +/- 9.7 and 5.8 +/- 3.6 mm Hg (P = .40) at the end of follow-up in the regular suture and releasable suture groups, respectively. There was no statistically significant difference in the clinical parameters between the two groups. Complications included rhegmatogenous retinal detachment, cataract, and superior lens subluxation, with each complication developing in one eye. CONCLUSIONS: Releasable sutures were not more advantageous than regular sutures in combined trabeculotomy-trabeculectomy with mitomycin C surgery for primary congenital glaucoma. [J Pediatr Ophthalmol Strabismus. 2017;54(5):295-301.]. PMID- 28617522 TI - Factors related to successful return to work following multidisciplinary rehabilitation. AB - OBJECTIVE: To examine factors associated with successful return to work among participants in a Social Security Organisation Return To Work programme. METHODS: Secondary data for 9,850 participants were obtained from the Social Security Organisation Return To Work database. The dependent variable was the Return To Work programme outcome, successful return to employment (same employer or different employer) or unsuccessful return. Logistic regression analysis with weighted sum contrasts was performed to assess the odds ratios with 95% confidence interval (95% CI) for successful return to employment across the various subgroups of participants. RESULTS: Overall, 65.5% of participants successfully returned to employment, either with their former employers or with new employers. Successful return to employment was found to be significantly higher than the overall proportion among those participants who had had commuting accidents, followed by those who had had workplace accidents. Successful return to employment was also associated with injuries of the upper and lower limbs, employers who were interested in hiring disabled workers, motivation to participate in the programme, an intervention period of 3 months or less, age 29 years or younger, and male participants. CONCLUSION: A structured multidisciplinary intervention programme provides a positive outcome in terms of returning to work. Related factors have various impacts on successful return to work. PMID- 28617523 TI - Electrochemical characterization of Geobacter lovleyi identifies limitations of microbial fuel cell performance in constructed wetlands. AB - Power generation in microbial fuel cells implemented in constructed wetlands (CW MFCs) is low despite the enrichment of anode electricigens most closely related to Geobacter lovleyi. Using the model representative G. lovleyi strain SZ, we show that acetate, but not formate or lactate, can be oxidized efficiently but growth is limited by the high sensitivity of the bacterium to oxygen. Acetate and highly reducing conditions also supported the growth of anode biofilms but only at optimal anode potentials (450 mV vs. standard hydrogen electrode). Still, electrode coverage was poor and current densities, low, consistent with the lack of key c-type cytochromes. The results suggest that the low oxygen tolerance of G. lovleyi and inability to efficiently colonize and form electroactive biofilms on the electrodes while oxidizing the range of electron donors available in constructed wetlands limits MFC performance. The implications of these findings for the optimization of CW-MFCs are discussed. [Int Microbiol 20(2):55-64 (2017)]. PMID- 28617524 TI - High prevalence of methicillin-resistant coagulase-negative staphylococci isolated from a university environment in Thailand. AB - The present study was conducted to isolate and characterize the molecular epidemiology of the methicillin-resistant staphylococci in the general university environment, where all five locations; the library, restrooms, canteens, computer rooms and outdoor surfaces, are in common use by a large population of students. We used Mannitol Salt Agar (MSA) supplemented with 4 MUg/ml of oxacillin to screen the methicillin-resistant staphylococci. The species level was identified by PCR of rdr (Staphylococcus epidermidis), groESL (Staphylococcus haemolyticus) and nuc (Staphylococcus aureus and Staphylococcus warneri) genes and DNA sequencing of tuf and dnaJ genes. The susceptibility patterns of the isolates were determined using the disk diffusion method. Antibiotic and disinfectant resistance genes, together with SCCmec types, were detected by the PCR method. The methicillin resistant-staphylococci were isolated from 41 of 200 samples (20.5%), and all of them were found to be methicillin-resistant coagulase negative staphylococci (MR-CoNS). The library had the highest percentage of contamination, with 43.3% of the samples found to be contaminated. All isolates belonged to 6 different species including S. haemolyticus, S. epidermidis, S. warneri, S. cohnii, S. saprophyticus and S. hominis. The antimicrobial resistance rates were highest against penicillin (100%), then cefoxitin (73.1%), erythromycin (73.1%) and oxacillin (68.3%). Altogether, the isolates were approximately 61.0% multidrug resistant (MDR), with the S. epidermidis isolates being the most multidrug resistant. The prevalence of the qacA/B gene was detected in 63.4% of the isolates, and SCCmec could be typed in 43.9% (18/41) of the isolates. The type range was: II (n = 1), IVd (n = 1), I (n = 2), V (n = 6), IVa (n = 8) and untypeable (n = 23). This result indicates that these university environments are contaminated with methicillin-resistant coagulase negative staphylococci that carry various SCCmec types and high rate of disinfectant resistance genes. [Int Microbiol 20(2):65-73 (2017)]. PMID- 28617525 TI - Characterization of high exopolysaccharide-producing Lactobacillus strains isolated from mustard pickles for potential probiotic applications. AB - The aim of this study was to characterize high exopolysaccharide (EPS)-producing lactic acid bacteria (LAB) isolated from mustard pickles in Taiwan for potential probiotic applications. Among 39 collected LAB strains, four most productive EPS producing strains were selected for further analysis. Comparative analyses of 16S rDNA genes rpoA and pheS sequences demonstrated that these strains were members of Lactobacillus plantarum-group (LPG). NCD 2, NLD 4, SLC 13, and NLD 16 showed survival rates of 95.83% +/- 0.49%, 95.07% +/- 0.64%, 105.84% +/- 0.82%, and 99.65% +/- 0.31% under simulated gastrointestinal conditions, respectively. No cytotoxic effects on macrophage RAW 264.7 cells were observed when they were treated with a low dose (1 MUg/ml) of stimulants extracted from the tested LAB strains. The production of nitric oxide in RAW 264.7 cells incubated with various LAB stimulants showed a dose-dependent increase. Among the four strains, SLC 13 showed higher inhibitory activity on growth of Enterococcus faecalis (BCRC 12302) and Yersinia enterocolitica (BCRC 10807). NLD 4 showed strong inhibitory activity against Escherichia coli O157:H7 (ATCC 43894) as compared with the other three strains. In summary, our results suggest that Lactobacillus pentosus SLC 13 may be a good candidate for probiotic applications and for development of antibacterial compounds. [Int Microbiol 20(2):75-84 (2017)]. PMID- 28617526 TI - Antimicrobial resistance gene expression associated with multidrug resistant Salmonella spp. isolated from retail meat in Hanoi, Vietnam. AB - The purpose of this study was to further characterize the multi-antimicrobial resistance and antibiotic resistance gene expression associated with multi-drug resistance (MDR) in Salmonella spp. isolates from retail meats in Hanoi, Vietnam. A total of 14 Salmonella spp. belonging to 9 serotypes (e.g., Warragul, London, Derby, Indiana, Meleagridis, Give, Rissen, Assine, and Typhimurium) were tested for sensitivity to 8 antibiotics. Resistance to at least one antibiotic was shown in 13 strains (92.85%). The multiple antimicrobial resistances accounted for 64.29% of isolates (9/14). One hundred percent of MDR isolates possessed antibiotic resistant genes, in which 17, 16 and 11 genes were found in Salmonella (Salm) Typhimurium S360, S384, S181 respectively; 12 genes in each strain as Indiana, Warragul, and Meleagridis; 11 genes in Give, 8 genes in Derby and 6 genes in Rissen. Three antibiotic resistance genes (ssaQ, aadA, and gyrB) were present in all isolates, whereas Cephalosporin-resistant gene (e.g., CTX-M3-like) was not detected in any isolates. The results suggest that retail meats could constitute a source of human exposure to multi-drug resistant Salmonella and future research should focus on the impact of these MDR source on the human genome. [Int Microbiol 20(2): 85-93 (2017)]. PMID- 28617527 TI - Impact of motility and chemotaxis features of the rhizobacterium Pseudomonas chlororaphis PCL1606 on its biocontrol of avocado white root rot. AB - The biocontrol rhizobacterium Pseudomonas chlororaphis PCL1606 has the ability to protect avocado plants against white root rot produced by the phytopathogenic fungus Rosellinia necatrix. Moreover, PCL1606 displayed direct interactions with avocado roots and the pathogenic fungus. Thus, nonmotile (flgK mutant) and non chemotactic (cheA mutant) derivatives of PCL1606 were constructed to emphasize the importance of motility and chemotaxis in the biological behaviour of PCL1606 during the biocontrol interaction. Plate chemotaxis assay showed that PCL1606 was attracted to the single compounds tested, such as glucose, glutamate, succinate, aspartate and malate, but no chemotaxis was observed to avocado or R. necatrix exudates. Using the more sensitive capillary assay, it was reported that smaller concentrations (1 mM) of single compounds elicited high chemotactic responses, and strong attraction was confirmed to avocado and R. necatrix exudates. Finally, biocontrol experiments revealed that the cheA and fglK derivative mutants reduced root protection against R. necatrix, suggesting an important role for these biological traits in biocontrol by P. chlororaphis PCL1606. [Int Microbiol 20(2):94-104 (2017)]. PMID- 28617528 TI - Influence of ablation therapy on the quality of life in children with supraventricular tachycardia. AB - OBJECTIVE: Numerous restrictions, which are imposed on children with arrhythmia, influence their quality of life (QoL) and may have a negative impact on their further development. Ablation is a highly successful treatment leaving patients free from arrhythmia and other related limitations. There are very few studies evaluating the influence of ablation on the QoL in children with arrhythmia, based on small groups of patients. The aim of this study was to evaluate the impact of ablation on the QoL in children with supraventricular tachycardia (SVT). PATIENTS AND METHODS: We included 122 children with SVT who underwent a successful ablation. The Qol was assessed before and after the ablation, using the WHOQOL-BREF and the Pediatric Arrhythmia Related Score (PARS) - a specific questionnaire developed by the authors. RESULTS: Six months after the ablation, WHOQOL-BREF showed a significant improvement in the QoL in the physical (Phd) (p < 0.0001), psychological (Psd) (p = 0.0014) and social relationships (SRD) (p = 0.0165) domains. PARS showed a significant improvement in the QoL in the Phd (p < 0.0001), Psd (p = 0.0307) and medical satisfaction domains (Msd) (p < 0.0001). No improvement in Psd was revealed in children who had been off medications before the ablation. In the youngest children, a significant improvement was observed in all the measured domains in both questionnaires (p < 0.05), while in older children the greatest improvement after the ablation was noted in the area of physical functioning. CONCLUSIONS: Ablation in children with SVT significantly improved general satisfaction with health and with the QoL and had a positive impact on QoL scores. The youngest patients and those on antiarrhythmic medication before the ablation, benefit most from the procedure. PMID- 28617529 TI - Effect of light deprivation on expression of extended vascular endothelial growth factor and neovascularization in retina of neonatal rats. AB - OBJECTIVE: The aim of this study is to analyze the effect of light deprivation on the expression of vascular endothelial growth factor (VEGF) and neovascularization in the retina of neonatal rats. MATERIALS AND METHODS: Thirty six neonatal SD rats (male and female) were used in this study. These rats were numbered randomly and assigned into 3 groups (12 rats in each group), ie. 10-day group (routine feeding after birth, eyeball enucleation on 10th day), 14-day group (routine feeding after birth, eyeball enucleation on 14th day) and light deprivation group (routine feeding within 1st week after birth, feeding with light deprivation within 2nd week after birth, eyeball enucleation on 14th day). The expression level of VEGF mRNA was measured by RT-PCR, and the percentage of the retinal vascular area was calculated by PAS staining, and the number of vascular endothelial cells was counted with a microscope in a double-blind manner. RESULTS: It was found that the expression levels of VEGF mRNA and the number of vascular endothelial cells in 10-day group and light deprivation group were significantly higher than 14-day group (p < 0.05), while the difference between the 10-day group and light deprivation group was not significant. The percentage of retinal vascular area in the 10-day group and light deprivation group was significantly lower than 14-day group (p < 0.05), while the difference between the 10-day group and the light deprivation group was not significant. CONCLUSIONS: The light deprivation delayed the growth of neovessels in the retina. PMID- 28617530 TI - Effects of folic acid combined with vitamin B12 on DVT in patients with homocysteine cerebral infarction. AB - OBJECTIVE: To investigate the effects of folic acid combined with vitamin B12 on deep vein thrombosis (DVT) in patients with homocysteine cerebral infarction. PATIENTS AND METHODS: 90 patients with homocysteine cerebral infarction with DVT that were admitted to our hospital from January to July 2015 were selected as study subjects. They were divided into 2 groups randomly, the treatment group (n=45) and the non-treatment group (n=45). The treatment group was administered folic acid and vitamin B12, while the non-treatment group wasn't administered folic acid and vitamin B12. We compared and analyzed the levels of Hcy, folic acid and vitamin B12 of both groups. We investigated the correlation between the groups of patients with Hcy and folic acid and vitamin B12 treatment. We performed a comparative analysis of both groups of patients with an anticoagulant international normalized ratio (INR). The INR was recorded in detail for the first time as standard time, stable value time, obtain stable INR value time, activated partial thromboplastin time (APTT) and Prothrombin Time (PT) by color Doppler ultrasound observation of both groups with recurrent thrombosis. RESULTS: We compared results of the intervention and treatment groups, and the prognosis of Hcy decreased significantly (p<0.05). While in the treatment group, folic acid and vitamin B12 levels increased significantly (p<0.05), the non-treatment difference of Hcy, folic acid, and vitamin B12 levels, before and after the patients in the intervention group, were not statistically significant (p>0.05). In the treatment group, Hcy was negatively correlated with folic acid (r=-0.376, p<0.05) while the Hcy of the treatment group was negatively correlated with vitamin B12 (r=-0.583, p<0.05). The intervention treatment group INR first standard time, stable value time and stable INR values were higher than those of non-treatment group (p<0.05). The treatment group APTT average was lower than in the non-treatment group (p<0.05). The average Pt in the treatment group was lower than non-treatment group (p<0.05). In the treatment group, lower limb deep static vein thrombosis recurrence rate was 4.4%, which was lower than the non-treatment group where the lower limb deep vein thrombosis recurrence rate was 28.9% (p<0.05). CONCLUSIONS: Hcy is negatively correlated to folic acid and vitamin B12. Folic acid and vitamin B12 can reduce the recurrence rate of thrombosis in patients with lower extremity deep venous thrombosis in patients with Hcy disease. The mechanism of action may be to prevent the recurrence of thrombosis by reducing the levels of Hcy. PMID- 28617531 TI - Controlled-release mitomycin C-polylactic acid film prevents epidural scar hyperplasia after laminectomy by inducing fibroblast autophagy and regulating the expression of miRNAs. AB - OBJECTIVE: To design a new controlled-release MMC-PLA film and explore whether and how this film could prevent epidural scar hyperplasia and adhesion in a post laminectomy rat model. MATERIALS AND METHODS: All procedures were performed under the approval and supervision of the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University. A total of 120 Sprague-Dawley (SD) rats were randomly placed into four groups after laminectomy (each group=30 rats). In Group I, the laminectomy area was flushed with saline as a control; in Group II, 25 mg of PLA film was applied to the dura mater in the laminectomy area; in Group III, a cotton pad soaked with 0.01% MMC solution was kept on the laminectomy area; and in Group IV, 25 mg of PLA film containing 0.01% MMC was implanted on the laminectomy area. Magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining and Masson staining were used to evaluate scar adhesion and collagen deposition one month after the operation. Autophagy-related proteins, including autophagy-related gene 5 (ATG5), beclin 1, light chain-3B-2/1 (LC3B-2/1) and protein 53 (p53), were detected by Western blotting. A microRNA microarray analysis was performed to screen for scar tissue miRNAs, especially those associated with autophagy, and changes in expression were confirmed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: A total of 112 rats recovered uneventfully from the surgery. MRI showed that the scar adhesion and scar area of the MMC-PLA group were significantly reduced compared with those of the PLA, MMC, and saline groups. Accordingly, scar adhesion and the deposition of collagen in the rats treated with MMC-PLA were also significantly reduced, as indicated by HE and Masson staining. In the scar tissue, the levels of autophagy related proteins (ATG5, beclin 1, LC3B-2/1 and p53) were significantly elevated in the MMC-PLA group. Additionally, in the MMC-PLA group, the expression levels of miR-34a, miR-146a and miR-200 were significantly increased, while the levels of miR-16, miR-221 and miR-378a were significantly decreased. CONCLUSIONS: The controlled-release MMC-PLA film could alleviate epidural scar hyperplasia after laminectomy; this outcome might be associated with increased autophagy and altered expression of miRNAs in the scar tissue. PMID- 28617532 TI - The effect of a natural, standardized bilberry extract (Mirtoselect(r)) in dry eye: a randomized, double blinded, placebo-controlled trial. AB - OBJECTIVE: Dry eye, a chronic disease of lachrymal fluid and corneo-conjunctival epithelium, could significantly impact visual function, affects quality of life and work productivity. Beside several conventional treatments, nutritional supplements based on bilberry extract have been identified as effective contributors to eye health. Here, we aim at investigating the bioavailability of a standardized bilberry extract, its ability to alleviate dry eye symptoms and its antioxidant potential. MATERIALS AND METHODS: Either bilberry dried standardized extract derived from Vaccinium myrtillus L. fresh frozen fruits (Mirtoselect(r)) or a highly purified anthocyanin-rich extract, devoid of the non anthocyanin component and supported on maltodextrins, were each orally administrated to 5 male rats. Blood samples were collected at 5, 10, 15, 20, 30, 45, 60, 90, 120 minutes after treatment, processed and analyzed by UV spectrophotometric method. In a parallel analysis, 22 otherwise healthy subjects suffering from dry eye symptoms were enrolled randomly assigned to receive the more bioavailable bilberry extract or placebo. Ophthalmological and clinical examinations including Schirmer's test, pupil constriction, diacron-reactive oxygen metabolites (d-ROMs) test and biological antioxidant potential (BAP) test were performed at inclusion and after the 4-week study period. RESULTS: The area under the curve of plasmatic levels of anthocyanosides in rats resulted 202.34+/ 24.23 ug.min/ml for Mirtoselect(r) and 130.93+/-4.93 ug.min/ml for the highly purified anthocyanin-rich bilberry extract, notwithstanding the fact that the highly purified anthocyanin-rich extract group received an anthocyanins dosage much higher than the Mirtoselect(r) group (354 mg/Kg in anthocyanosides vs. 136 mg/Kg in anthocyanosides). 21 subjects, 11 subjects in the bilberry extract (Mirtoselect(r)) group and 10 subjects in the placebo group completed the clinical study. Schirmer's test values indicating the volume of tear secretion were significantly improved in the bilberry extract group (p=0.019), whereas no significant changes were observed in the placebo group. A subset analysis revealed that Mirtoselect(r) could be more effective in subjects with higher tendency of dry eye. In terms of antioxidant potential, the bilberry extract produced significant improvement of BAP (p=0.003) and an increase of modified BAP/d-ROMs ratio, an indicator of overall balance between antioxidant potential and oxidative stress. CONCLUSIONS: Our results suggested that natural, standardized bilberry extract (Mirtoselect(r)) is a natural more bioavailable delivery form anthocyanins, suggesting a strong matrix effect exerted by the non anthocyanin component. Furthermore, it can improve tear secretion and plasmatic antioxidant potential in subjects suffering from DED symptoms. PMID- 28617534 TI - AFC vs. AMH: prediction of ovarian response in women with endometrioma undergoing controlled ovarian stimulation. AB - OBJECTIVE: To assess the clinical value of antral follicle count (AFC) and anti Mullerian hormone (AMH) for the prediction of ovarian response in women with endometrioma undergoing controlled ovarian stimulation for IVF using GnRH antagonist treatment. PATIENTS AND METHODS: Fifty patients with endometrioma who underwent their first IVF/ICSI cycle with GnRH antagonist treatment were included in the study. The average AMH values were recorded as 1.5-2 ng/mL. Fifty infertile women are not suffering from endometrioma were selected from those with male factor infertility as control. They were matched according to both serum AMH levels and age. Serum samples have been collected before the IVF treatment for determining AMH levels in both groups of subjects. Likewise, each group of subject underwent ultrasound scan for AFC on day 3. Total number of oocytes retrieved during OPU, the number of transferred embryo, implantation and clinical pregnancy rates, live birth and abortion rates, total dose of rhFSH were noted in both groups of subjects. RESULTS: Day 3 AFC was significantly higher in the control group compared to women with endometrioma. Both the number of retrieved oocytes during oocyte pick-up, MII oocytes and 2 PN embryo were significantly lower in the endometrioma. Likewise, the fertilization, implantation, clinical pregnancy and live birth rates of endometrioma group were significantly lower than those in the control group. The total rFSH dose was higher in the endometrioma group than those in control. The percentage of abortion in the endometrioma group was found to higher compared to those with controls. CONCLUSIONS: AFC is more sensitive than the AMH in detecting ovarian response in women with ovarian endometrioma. The individualization of GnRH antagonist protocols in subjects having endometrioma might be improved by using an AFC tailored approach instead of AMH. PMID- 28617533 TI - Cervical carcinogenesis, bacterial vaginosis, HPV-mRNA test and relapse of CIN2+ after loop electrosurgical excision procedure (LEEP). AB - OBJECTIVE: The aim of the study was to evaluate the relationship between bacterial vaginosis (BV) and relapse of cervical intraepithelial neoplasia grade 2 or more (CIN2+) after Loop electrosurgical excision procedure (LEEP). PATIENTS AND METHODS: One hundred four patients who underwent LEEP for CIN2+ were followed up every six months for three years. Fifty-three were negative for BV and fifty one were positive. Each clinical control included Pap test, colposcopy, Amsel criteria test, HPV-DNA, and HPV-mRNA test. RESULTS: Patients' age, presence of BV, positivity to HPV-DNA and HPV-mRNA tests were analyzed. The average age of patients was 42.5 +/- 8.92 years (median: 42.5; range from 27 to 58 years). The minimum follow-up was 6 months and maximum 36 months (average: 22.8 +/- 4.53; median: 24). The 10% of the patients with HPV-mRNA test negative had relapsed, compared to 45% of patients with HPV-mRNA test positive. Among the 53 patients without BV the 20% had relapsed compared with 23% of 51 patients with diagnosis of BV. CONCLUSIONS: There is no evidence for higher percentage of relapse in patients with BV, submitted to excisional procedure for CIN2+ associated to HPV-m RNA test positivity. There is only a correlation among BV and relapse of CIN2+ lesions after LEEP. PMID- 28617535 TI - Research on the protective effects of antioxidants on metabolic syndrome induced by thyroid dysfunction. AB - OBJECTIVE: This paper researches on the protective effects of antioxidants on metabolic syndrome induced by thyroid dysfunction. While the role of Lipoic acid (LA), Resveratrol (R) and Quercetin (Q) are recognized, the mechanisms for their ameliorative effects are partially understood. Therefore, the objective of this study was to determine the prevalence of MS among university workers and to examine the relationship with thyroid function and mechanisms for protective effects of LA, Resveratrol and Quercetin on the heart, kidneys and lungs. SUBJECTS AND METHODS: In the cross-sectional study, a total of 2273 university workers (1198 males and 1075 females) aged 22-60 participated. Anthropometric measurements (weight and height), blood pressure, fasting plasma glucose (FPG), lipids, liver and kidney function tests were carried out, thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total antioxidant capacity (T-AOC), lipid peroxidation products, malondialdehyde (MDA), advanced oxidation protein products (AOPP) and dityrosine levels were measured. RESULTS: A further evaluation of oxidative stress markers in subclinical hypothyroidism (SCH) compared with normal thyroid function showed the differences. Among middle-aged men with SCH (n = 467), MDA concentrations (8.11 +/- 1.39 nmol/ml) were significantly higher euthyroid controls (7.34 +/- 1.31 nmol/ml; n = 190) while AOPP, dityrosine and T-AOC levels were not different. CONCLUSIONS: It was demonstrated that prevalence of MS components was high. Targeting thyroid hormone restoration, inhibition of ACE and GSK3beta via PI3K/AKT signaling pathway using LA, Resveratrol and Quercetin are potential novel therapeutic approaches for developing pharmaceuticals that could make significance in MS treatment. PMID- 28617536 TI - Effects of mulberry leaf polysaccharide on oxidative stress in pancreatic beta cells of type 2 diabetic rats. AB - OBJECTIVE: To explore and discuss the effects and mechanisms of mulberry leaf polysaccharide (MLP) on oxidative stress in pancreatic beta-cells of type 2 diabetic rats. MATERIALS AND METHODS: The model of diabetic rats was established by inducing the Sprague-Dawley (SD) rats with high-sugar and high-fat diet for 6 weeks and then giving them streptozotocin (STZ) by single intraperitoneal injection. The mulberry leaf polysaccharide was administered via gavage daily for 8 weeks, and the tissue morphology was observed through electron microscopy. The levels of fasting blood glucose (FBG), free fatty acid (FFA), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were detected. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in the pancreas were tested. The activities of mitochondrial cytochrome C oxidase (CCO) and succinate dehydrogenase (SDH) in the pancreatic cell were examined. RESULTS: Compared with the normal control group, the level of FBG increased (p < 0.01), the levels of FFA, TG, LDL-C, IL-6, and TNF-alpha were higher (p < 0.05), the content of MDA increased (p < 0.05) and the activity of SOD, CCO and SDH declined (p < 0.05) in the model group. In comparison with the model group, the level of FBG in the group intervened by mulberry leaf polysaccharide decreased [(23.9 +/- 2.5) vs. (16.8 +/- 2.1) mmol*L-1]; the levels of FFA, TG and LDL-C dropped from (1.18 +/- 0.24), (2.95 +/- 0.65) and (2.18 +/- 0.46) mmol*L-1 to (0.65 +/- 0.14), (2.20 +/- 0.45) and (1.08 +/- 0.42) mmol*L-1, respectively; the levels of IL-6 and TNF alpha declined from (60.78 +/- 5.02) ng*L-1 and (2.34 +/- 0.42) MUg*L-1 to (30.94 +/- 3.02) ng*L-1 and (1.02 +/- 0.12) MUg*L-1, respectively; the content of MDA w as reduced from (1.38 +/- 0.21) MUmol*g-1 to (0.78 +/- 0.12) MUmol*g-1; the activities of SOD, CCO and SDH increased from (25.32 +/- 3.58) KU*g-1, (15.00 +/- 1.58) mmol*g-1 and (3.23 +/- 0.32) KU*g-1 to (32.87 +/- 2.62) KU*g-1, (18.30 +/- 1.78) mmol*g-1 and (5.62 +/- 0.38) KU*g-1, respectively; the electron microscopy results indicated that the intervention of mulberry leaf polysaccharide could improve the morphological structure of the pancreatic beta-cells. CONCLUSIONS: The mulberry leaf polysaccharide can lower down the levels of inflammatory mediators and free fatty acid in the diabetic rats, alleviate oxidative stress injury, improve the mitochondrial functions of islet cells and protect the pancreatic beta-cells. PMID- 28617537 TI - Spirulina maxima improves insulin sensitivity, lipid profile, and total antioxidant status in obese patients with well-treated hypertension: a randomized double-blind placebo-controlled study. AB - OBJECTIVE: Spirulina maxima consumption is known to be associated with enhanced cardiovascular and metabolic health. Human studies on this topic have recently been described in a few papers; however, potential protective cardiovascular properties of Spirulina in obese patients receiving standard pharmacological antihypertensive treatment remain to be elucidated. Putative beneficial cardiovascular effects of Spirulina supplementation in well treated, obesity related hypertension were studied in a double-blind placebo-controlled trial. PATIENTS AND METHODS: Total 50 obese subjects with treated hypertension, each randomized to receive 2 g of Spirulina or a placebo daily, for three months. At baseline and after treatment anthropometric parameters, plasma lipid levels, inflammation, and oxidative stress biomarkers along with insulin sensitivity estimated by euglycemic clamp were assessed. RESULTS: After three months of Spirulina supplementation significant decrease in body mass (p < 0.001), body mass index (BMI; p < 0.001) and waist circumference (WC; p = 0.002) were observed in Spirulina group. Spirulina had also significant, lowering effect on low density lipoprotein cholesterol (LDL-C; p < 0.001) and interleukin-6 (IL-6) concentration (p = 0.002) in supplemented patients compared to placebo group. Spirulina supplementation considerably improved total antioxidant status (TAS; p = 0.001) and insulin sensitivity ratio (M; p < 0.001) in Spirulina group compared to placebo-treated individuals. CONCLUSIONS: The favorable influence of Spirulina supplementation on insulin sensitivity, plasma lipid levels along with inflammation and oxidative stress biomarkers reported in this study creates the promise for new therapeutic approaches in obese patients with well-treated hypertension. PMID- 28617538 TI - Recent advances in management of tuberculosis in infants. AB - The global tuberculosis (TB) incidence estimated by WHO is found to be 8.6 million people. Moreover, the highest TB burden worldwide is found in Asian and African countries. The disease is more prevalent in infants due to their immature immune systems. Despite this, the available diagnostic tools pose a challenge due to paucibacillary nature of the disease and difficulty in obtaining specimens. The present review article discusses the important and upcoming advancements in the management of above pathological state. The article will enlighten the new vaccinations for TB in the pipeline. Moreover, new upcoming approaches involving system biology and gene expression profiling for efficient supervision of the disease will also be highlighted. PMID- 28617539 TI - Evaluation of cardiac troponin I stability in blood sample using the AccuTnI+3 assay. AB - OBJECTIVE: Troponins are considered as the biomarkers of choice to highlight cardiac injury in emergency departments, but are also valuable to detect cardiac injury in a non-emergency setting. In this latter case, transport of blood samples to laboratories often exceeds the manufacturer's recommendations (<2 h between vein puncture and analysis for the Beckman Coulter AccuTnI+3 assay). We aim to evaluate in vitro the stability of troponin Ic (cTnI) at two intervals (<2 h and at 4 h) over a wide range of concentrations using the Beckman Coulter AccuTnI+3 assay. PATIENTS AND METHODS: For each of the 95 patients included in this study, we analyzed the first blood sample with a time of transport <2 h, and the second sample after 4 h from vein puncture. We then calculated the correlation between the two periods of analysis and evaluated the bias by a Bland Altman test. RESULTS: Taking into account of our analytical reproducibility, we did not observe any significant differences in cTnI values between <2 h and 4 h. CONCLUSIONS: The time between vein puncture and analysis of cTnI can be extended to 4 h. PMID- 28617540 TI - Analysis of mechanism of PM2.5 and house dust mite antigen Der p1 in attack stage of child asthma. AB - OBJECTIVE: We analyzed the influence of PM2.5 and house dust mite antigen Der p1 on the treatment of child asthma attack. PATIENTS AND METHODS: A total of 96 children with asthma attack were included into the study. The patients were randomly divided into the PM2.5 group, the house dust mite antigen group, the synergistic group and the control group (n= 24 in each group). RESULTS: The PM2.5 concentration in the PM2.5 group was twice higher than standard level (<= the average value of PM2.5 in local air). All cases were given with same treatment, and the treatment effects were compared and analyzed. It was found that the asthma control rate in the control group was significantly higher than that in the PM2.5 group and the house dust mite antigen group, and the synergistic group was the lowest. The control time in the synergistic group was significantly longest, followed by the PM2.5 group and the house dust mite antigen group, and the control group was significantly short (p<0.05). After the intervention, the FVC, FEV1, and PEF levels were all increased. Those in control group were significantly higher than those of PM2.5 group and Dermatophagoides pteronyssinus group. Indicators in the collaborative group were the lowest. Differences were statistically significant (p<0.05). The differences in the PM2.5 group and Dermatophagoides pteronyssinus group were not statistically significant. The contents of serum IL-25, TSLP, and malondialdehyde after treatment of the control group significantly lowered while the other three groups showed a significant higher (p<0.05). CONCLUSIONS: The PM2.5 and house dust mite antigen Der p1 can influence the treating effects of child asthma attack by an inflammatory reaction and oxidative stress. PMID- 28617541 TI - Negative pressure wound therapy (NPWT) in duodenal breakdown fistulas: negative pressure fistula therapy (NPFT)? AB - OBJECTIVE: To describe for the first time in literature the specific methodology of use of negative pressure wound therapy (NPWT) for duodenal fistula through clinical cases. The constant increase of use of NPWT for complex surgical situations imposes tailored previously undescribed solutions for the technique. PATIENTS AND METHODS: Herein, three cases of high output duodenal fistula successfully treated with Negative Pressure Wound Therapy (NPWT) are reported. The technical details for the application of NPWT to these fistulas are discussed and described. RESULTS: All three patients recovered without the necessity of further surgical operations. CONCLUSIONS: When using NPWT, management of high output duodenal fistulas must rely on some degree of customization of the aspiration systems. The aim of the procedure is to put under depression the duodenal hole and surrounding tissues "all in one" and not to separate the complex wound in sectors as usually indicated. We suggest calling this technique Negative Pressure Fistula Therapy. PMID- 28617542 TI - Assessment of behavioral tasks performed by hemiplegic patients with impaired dexterity post stroke. AB - Disability continues to be one of the leading reasons individuals affected by stroke are left incapable of performing daily activities. Due to the staggering number of disabled adults suffering post-stroke neurological damage, there is a critical need for creating and monitoring effects of successful, intensive stroke therapies. Behavioral assessments are useful tools by which to examine the effectiveness of these stroke therapies as they allow for the investigation of multiple variables, including task performance time, performance quality, and degree of motor function. The purpose of this review is to discuss various behavioral assessments commonly administered during stroke rehabilitation. Developing a battery of standardized behavioral tests would create an instrument to assess therapies, and therefore, ensure the most successful therapies stay in practice to help the recovery of individuals suffering from impaired dexterity due to stroke. PMID- 28617543 TI - Study on the clinical application of the MRS in the cognitive assessment after stroke. AB - OBJECTIVE: To discuss the value of the application of the magnetic resonance spectroscopy (MRS) in the assessment of cognitive function impairment and the observation of therapeutic effect. PATIENTS AND METHODS: 30 patients with cognitive impairment after stroke (cognitive impairment group) and 30 patients with no apparent cognitive impairment (control group of the stroke) were selected through the screening of the mini-mental state examination (MMSE) scale, and another 30 healthy volunteers were selected (control group of the health). The general information of gender, age, education degree, disease duration and so on was matched among the 3 groups. MRS examined all the patients of the 3 groups at the time of enrollment, and the patients of both cognitive impairment and control groups received another assessment 2 months after treatment. RESULTS: The NAA/Cr (N-acetyl aspartate/creatine) of the bilateral hippocampus of the cognitive impairment group was lower than those of both control group of stroke and health (p < 0.05), while the Cho/Cr was higher (p < 0.05). After treatment, both patients of the cognitive impairment group and the control group of the stroke experienced an increase of NAA/Cr and a decrease of Cho/Cr (p < 0.05). CONCLUSIONS: MRS is applicative in the assessment of the cognitive impairment degree of the stroke patients and can also effectively identify the existence of the cognitive impairment, which makes it preferably valuable in the clinical application. PMID- 28617544 TI - The relationship between quality of life and clinical phenotype in patients with treatment resistant and non-treatment resistant depression. AB - OBJECTIVE: The purpose of this investigation is to determine the differences in quality of life (QOL) and clinical phenotype between patients with treatment resistant (TRD) and non-treatment resistant depression (NTRD). PATIENTS AND METHODS: The severity, QOL, and cognitive function of 107 TRD and 173 NTRD patients were evaluated and calculated by the Hamilton Depression Scale-17 (HAMD 17), the 36-Item Short Form Health Survey (SF-36), and the P300 component of event-related potentials (ERP), respectively. RESULTS: The scores of HAMD-17 showed no significant statistical differences between TRD (28.8+/-6.7) and NTRD patients (29.3+/-8.2). The scores of anxiety/somatization (t=4.535, p=0.002), core item (t=3.514, p=0.005) and sleep item (t=6.079, p=0.000) were statistically significantly higher in TRD patients than in NTRD patients. The scores of physiological function (75.46+/-20.1, 88.23+/-21.4), body pain (61.39+/-17.1, 77.19+/-21.2) and social functioning (40.27+/-20.6, 58.82+/-22.1) in SF-36 were statistically significantly lower in TRD patients than in NTRD patients. The P300 latency of ERP was statistically significantly longer in TRD patients than in NTRD patients. Each item in the quality of life was negatively related to the items in HAMD-17 in TRD patients, especially for anxiety/somatization, and sleep items. The QOL was negatively related to core item and retardation item in NTRD patients, and the QOL was negatively related to the P300 latency of ERP in both groups, p<0.05. The sleep disorder, anxiety/somatization and core items were more serious in TRD patients than in NTRD patients, when the severity of depression was not significantly different. The QOL was significantly lower in TRD patients than in NTRD patients, the anxiety/somatization and sleep disorder were the main symptomatic factors that caused decreased QOL in TRD patients. CONCLUSIONS: The abilities of abstract generalization, thinking transfer, and performing a function, were significantly lower in TRD patients than in NTRD patients, which were important factors which caused decreased QOL in TRD patients. PMID- 28617545 TI - Fluid status of patients during the early stages of continuous ambulatory peritoneal dialysis. AB - OBJECTIVE: The purpose of this paper is to investigate the fluid status of patients in the early stages of continuous ambulatory peritoneal dialysis (CAPD). PATIENTS AND METHODS: A total of 36 patients (13 males and 23 females), hospitalized in the Nephrology CAPD Center, Peking University Third Hospital, and undergoing intubation and CAPD treatment, were recruited in this study. By utilize a bioelectrical impedance analyzer, changes in extracellular fluid and intracellular fluid within the patients' cells, and overall fluid changes were monitored throughout six months following CAPD treatment. Blood pressure was taken before dialysis and during six months following dialysis. Dietary assessment was also performed by recording and analyzing the patients' dietary protein and caloric intake during this six months period. RESULTS: Over a six month period, following CAPD treatment, the fluid status of the patients displayed a rising trend, indicated by weight gain, increasing extracellular fluid (ECW), intracellular fluid (ICW), overall water (TBW) and standardized extracellular fluid (NECW). Peritoneal ultrafiltration volume, and residual urine volume, showed no significant difference before or after treatment. During the six-month period, the dietary caloric intake of patients increased. Prior to CAPD, the patients' systolic blood pressure level was higher than normal. Following treatment, it returned to normal, and, due to the patients' rising fluid status, no change occurred during the six-month monitoring period. CONCLUSIONS: During the early stages of CAPD treatment, patients' fluid status increased, as a result of dietary improvement and the increased intake of water and salt. However, weight gain, in the early stages of the CAPD, is more likely due to rising fluid status than nutritional improvement. Early control of water and salt intake is of crucial importance for CAPD patients. PMID- 28617546 TI - Down-expression of miR-373 predicts poor prognosis of glioma and could be a potential therapeutic target. AB - OBJECTIVE: MicroRNAs (miRNAs) are epigenetic regulators of gene expression, and their deregulation plays an important role in human cancer, including glioma. The main objective of this work was to investigate the expression level of miR-373 and its clinical significance in glioma. PATIENTS AND METHODS: The expression levels of miR-373 in glioma tissues and non-neoplastic brain tissues were measured by the qRT-PCR assay. Patients were divided into two groups based on the median miR-373 expression. The probability of differences in overall and progression-free survival as a function of time was ascertained by use of the Kaplan-Meier method. Cox regression analysis of factors potentially associated with survival was conducted to identify independent factors. RESULTS: In clinical gastric cancer samples, we found that miR-373 expression was significantly down regulated in glioma tissues compared with non-neoplastic brain tissues (p<0.01). Reduced expression of miR-373 was associated with serum WHO grade (p=0.015) and KPS score (p=0.001). Kaplan-Meier analysis indicated that patients with low level of miR-373 expression had poorer overall survival (OS) and progression-free survival (PFS). Multivariate survival analysis verified that miR-373 expression level was an independent predictor of both OS and PFS for glioma patients. CONCLUSIONS: Our study showed miR-373 was associated to progression in glioma, and suggested it as a potential predictive factor for the prognosis of glioma. PMID- 28617547 TI - MASTL is a potential poor prognostic indicator in ER+ breast cancer. AB - OBJECTIVE: In this study, we aimed to explore prognostic value of MASTL (microtubule-associated serine/threonine kinase-like) in breast cancer patients on the basis of ER status and molecular subtypes. MATERIALS AND METHODS: The raw microarray data (GDS5666) of 4T1 derived bone-aggressive explant and primary tumor explant were reanalyzed to identify the dysregulated genes. To pool previous annotated genomic data that assessed the association between MASTL expression and metastatic relapse (MR) risk, MR-free survival, any event (AE, defined as any relapse or death) risk, and AE-free survival in breast cancer patients, a meta-analysis was performed by bc-GenExMiner 4.0. RESULTS: MASTL is a significantly upregulated gene in 4T1 bone-aggressive explant compared to primary tumor explant. Univariate Cox analysis showed that high MASTL expression is associated with a higher risk of MR (HR: 1.43, 95%CI: 1.28-1.60; p<0.001) and a higher risk of AE (HR: 1.27, 95%CI: 1.18-1.37; p<0.001) in ER+ breast cancer. Also, high MASTL expression also predicts a worse MR-free survival (HR: 1.74, 95%CI: 1.40-2.17; p<0.001) and a worse AE-free survival (HR: 1.42, 95%CI: 1.23 1.63; p<0.001) in ER+ breast cancer. However, the associations were not observed in ER- patients. The following NPI adjusted analyses confirmed the results of univariate Cox analysis. In Single Sample Predictors (SSPs) and Subtype Clustering Models (SCMs) subtypes, high MASTL expression is associated with increased risk of AE and predicts a poor AE-free survival in ER+ subgroups. CONCLUSIONS: MASTL might be a valuable indicator of MR risk and AE risk in ER+ patients, but not in ER- patients. PMID- 28617548 TI - Bioinformatic analysis of prognostic value of ARAP3 in breast cancer and the associated signaling pathways. AB - OBJECTIVE: In this study, we tried to pool previous annotated genomic data to assess the association between ARAP3 expression and metastatic relapse (MR) risk in patients with breast cancer. Moreover, we also investigated the signaling pathways in which ARAP3 might be involved in breast cancer. MATERIALS AND METHODS: The raw microarray data (GDS5666) that compared gene transcriptional profiles of 4T1 derived lung-aggressive explant and primary tumor explant were reanalyzed to identify the dysregulated genes. ARAP3 mRNA expression, its association with MR-free survival and its co-upregulated genes in breast cancer, were studied by data mining in TCGA database and Breast Cancer Gene-Expression Miner Version 4.0 (bc-GenExMiner 4.0). RESULTS: ARAP3 is a significantly upregulated gene in the metastatic breast tumor cells. The ER- patients with high ARAP3 expression had significantly increased the risk of MR, regardless of the nodal status. Patients in ER-/Nm group with high ARAP3 expression had the highest risk of MR (HR: 1.25; 95%CI: 1.10-1.41, p<0.001). In patients with basal-like tumors, High ARAP3 level is associated with significantly worse MR-free survival (HR: 1.63, 95%CI: 1.22-2.19, p=0.001). ARAP3 might be closely related to the NOTCH4 and CDH5 signaling pathways in breast cancer. CONCLUSIONS: The expression level of ARAP3 might be a useful indicator of the metastatic likelihood of the basal-like breast tumors. ARAP3 might be involved in NOTCH4 and CDH5 related signaling pathways, but the underlying mechanism should be further studied. PMID- 28617549 TI - Identification of genes associated with lung cancer by bioinformatics analysis. AB - OBJECTIVE: This study was aimed to explore the underlying genes associated with lung cancer (LC) by bioinformatics analysis. DATA AND METHODS: Gene expression profile GSE2514 was downloaded from the Gene Expression Omnibus database. Twenty lung and nineteen para-carcinoma tissue samples were used to identify the differentially expressed genes (DEGs) by paired t-test. Pathway enrichment analysis of DEGs was performed, followed by the construction of protein-protein interaction (PPI) network. Functional enrichment analysis of the module identified from PPI network was performed, and the enriched term with the highest enrichment scores was selected for pathway enrichment analysis. RESULTS: Total 257 DEGs including 179 up-regulated DEGs such as monoamine oxidase A (MAOA) and intercellular adhesion molecule 2 (ICAM2), and 78 down-regulated DEGs such as thrombospondin-2 (THBS2) were identified. Up-regulated DEGs were enriched in 7 pathways, such as drug metabolism, tyrosine metabolism and cell adhesion molecules (CAMs). Down-regulated DEGs were enriched in extracellular cell matrix receptor interaction and focal adhesion pathways. In the PPI network, interleukin 6 (IL6) had the highest connectivity degree of 39. Module 1 with the highest functional enrichment scores of 5.457 containing 13 hub genes such as KIAA0101. CONCLUSIONS: DEGs of LC were mainly enriched in the pathways related to metabolism and cell adhesion. The DEGs such as MAOA, ICAM2, IL6, THBS2 and KIAA0101 may be the potential targets for LC diagnosis and treatment. PMID- 28617550 TI - Prognostic and diagnostic significance of long non-coding RNA AGAP2-AS1 levels in patients with non-small cell lung cancer. AB - OBJECTIVE: The purpose of this study was to explore whether long non-coding RNA AGAP2-AS1 (AGAP2-AS1) could serve as a novel biomarker for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Cancer and matched normal lung tissues were collected from 198 patients. AGAP2-AS1 levels were examined by RT-PCR, and the associations of AGAP2-AS1 levels with clinicopathological characteristics evaluated. Overall survival was evaluated using the Kaplan-Meier method. Cox proportional hazard modeling was performed for univariate and multivariate analysis to determine the effects of variables on survival. Receiver-operating characteristic. Besides, the receiver operating characteristic (ROC) curve analysis were applied to analyze its diagnostic value. RESULTS: Expression of AGAP2-AS1 was up-regulated in the NSCLC tissues compared with the adjacent normal tissues (p < 0.01). Furthermore, The level of AGAP2-AS19 in NSCLC was strongly correlated with tumor stage (p = 0.001) and lymph nodes metastasis (p = 0.005). Kaplan-Meier analysis demonstrated patients with higher AGAP2-AS1 expression had a shorter overall survival time than those with lower AGAP2-AS1 expression (p < 0.0001). The multivariate analysis showed that AGAP2-AS1 expression is an independent prognostic factor of overall survival in patients with NSCLC. The results of ROC curve analysis showed that AGAP2-AS1 might be a promising diagnostic marker of NSCLC with an AUC of 0.846. CONCLUSIONS: Our findings revealed that AGAP2-AS1 might be a potential biomarker for the diagnosis and prognosis of NSCLC. However, to completely elucidate its role as a biomarker, further studies are required. PMID- 28617551 TI - MiR-222 promotes proliferation, migration and invasion of lung adenocarcinoma cells by targeting ETS1. AB - OBJECTIVE: The lung adenocarcinoma is a type of lung cancer. This research is to investigate the effects of miR-222 on the proliferation, migration and invasion of the lung adenocarcinoma cells. MATERIALS AND METHODS: At the beginning, MiR 222 and the controls were transfected to the lung adenocarcinoma cell line A549 for CCK-8 proliferation, transwell migration and Matrigel invasion, and then observed the effect of miR-222 on the proliferation, migration and invasion of lung adenocarcinoma cells. The miR-222 target was regulated by ETS1 downwards to participate in the regulation of the process by using the luciferase reporter assay, the Real-time fluorescence quantitative polymerase chain reaction (RT qPCR) and the Western blotting. RESULTS: According to CCK-8 proliferation assay, the Transwell migration and the Matrigel invasion assay, it discovered that MiR 222 can promote the proliferation, migration and invasion of the lung adenocarcinoma cells. Luciferase reporter assay, RT-qPCR and Western blot assay showed that miR-222 could regulate the expression of ETS1 downwards and ETS1 participated in the regulation of the process CONCLUSIONS: ETS1 promotes proliferation, migration and invasion of lung adenocarcinoma cells by targeting the regulated miR-222 downwards. PMID- 28617552 TI - Long non-coding RNA TUG1 can promote proliferation and migration of pancreatic cancer via EMT pathway. AB - OBJECTIVE: This paper aimed to investigate the effect of long non-coding RNA TUG1 (lncRNA TUG1) on cell proliferation, as well as cell migration in pancreatic cancer. PATIENTS AND METHODS: The mRNA levels of Taurine-up-regulated gene 1 (TUG1) in three kinds of pancreatic cancer cells BxPC3, PaTu8988 and SW1990 was detected by RT-qPCR. Meantime, RT-qPCR was used to examine the mRNA levels of TUG1 in 20 cases of human pancreatic cancer tissues and its para-carcinoma tissues. pCDH-TUG1 plasmid and its empty plasmid pCDH were transfected into BxPC3 and PaTu8988 cells to up-regulate TUG1 expression. siRNA targeting TUG1 and the control siRNA were transfected into SW1990 cells to down-regulate TUG1 expression. Cell clone formation and CCK-8 assay were used to detect the cell proliferation capacity. Transwell assay was used to evaluate cell migration capacity. Western blot was applied to examine the protein expressions of MMP2, MMP9, E-cadherin, Smad 2, Smad 3, p-Smad 2, p-Smad 3, TGF-beta and TGF-betaR. RT qPCR was used to detect the levels of MMP2 and MMP9. RESULTS: The results showed that TUG1 was differentially expressed in the three kinds of pancreatic cancer cells, among which the expression level of SW1990 was relatively high, and the expression levels of BxPC3 and PaTu8988 were relatively low. TUG1 had more expression in pancreatic cancer tissues than that in para-carcinoma tissues. After the up-regulation of TUG1, cell proliferation and migration capacities were increased, protein levels of MMP2 and MMP9 were increased and protein level of E cadherin was declined. Conversely, after down-regulation of TUG1 expression, cell proliferation and migration capacities were weakened, protein levels of MMP2 and MMP9 were decreased and protein level of E-cadherin was increased. In addition, over-expressed TUG1 could promote Smad2 and Smad3 phosphorylation, but Smad2 and Smad3 phosphorylation were weakened after down-regulated expression of TUG1. The protein expression of TGF-beta and TGF-beta receptor were more in the TUG1 overexpression group than that in the control group, while the result was just opposite after TUG1 expression was down-regulated. CONCLUSIONS: These data suggest that lncRNA TUG1 may enhance the proliferation and migration of pancreatic cancer cells through EMT pathway. PMID- 28617553 TI - Higher RABEX-5 mRNA predicts unfavourable survival in patients with colorectal cancer. AB - OBJECTIVE: The aim of the present study was to clarify the expression pattern and prognostic role of RABEX-5 mRNA in colorectal cancer (CRC) patients. PATIENTS AND METHODS: RABEX-5 mRNA levels in 187 CRC were examined by Real-time polymerase chain reaction. Then, the association of RABEX-5 mRNA levels with clinicopathological features was analyzed. Survival curves were plotted using the Kaplan-Meier method and differences in survival rates were analyzed using the log rank test. The influence of each variable on survival was examined by the Cox multivariate regression analysis. RESULTS: RABEX-5 mRNA expression was significantly upregulated in CRC tissues compared with the adjacent noncancerous tissues (p < 0.01). By statistical analyses, high RABEX-5 mRNA expression was observed to be closely correlated with histology/differentiation (p = 0.010), N classification (p = 0.004), and TNM stage (p = 0.004). Kaplan-Meier curves showed that patients with high RABEX-5 mRNA expression showed unfavorable overall survival (OS) than the low RABEX-5 mRNA expression group (p < 0.001). Finally, univariate and multivariate analyses showed that RABEX-5 mRNA expression was an independent predictor of overall survival (p < 0.05). CONCLUSIONS: RABEX-5 mRNA may be a promising biomarker for the detection and prognosis evaluation of CRC. PMID- 28617554 TI - The study on specific umbilical blood Dc vaccine for Beige nude mice loaded human colorectal carcinoma to induce anti-tumor immunity. AB - OBJECTIVE: This study is to observe the immunosuppression of CD137L transfected umbilical blood Dcs (Dendritic cell) vaccine to tumor development of SCID/ Beige nude mice. MATERIALS AND METHODS: Samples of umbilical blood in the childbirth pregnant women were collected by density gradient centrifugation. Umbilical cord blood dendritic cells (Dcs) were transfected by specific CD137L via LipofectamineTM method and cells were harvested. Meanwhile, the peripheral blood of volunteers was collected to isolate Dcs, the Dcs were cultured for 5 days and hatched with SW-1116 cells antigen. The mature Dcs were harvested. The male SCID/Beige nude mice were subcutaneously injected with human SW-1116 cells in axillary to build colorectal carcinoma model as blank control (Blank). The naked peripheral blood Dc vaccine group (cPBMCs), the SW-1116 antigen-specific peripheral blood Dc vaccine group (pDcs) and the CD137L specific umbilical blood Dc vaccine group (tuDcs) were injected 24 h before tumor cells injection, respectively to recur the humanized immune reconstruction. The general life, living habits changes, tumor growing time and tumor size were observed. The nude mice were sacrificed 18 days after tumor formation. The tumor size, mice weight, in vitro tumor weight, liver weight and spleen weight of mice were recorded to evaluate the anti-tumor effect of the specific immune cells. RESULTS: The nude mice in pDcs group showed better general living condition, slower tumor growth, smaller tumor volume and no ulceration, necrosis, and death in nude mice. The tumor formation time in different groups was 4.71 +/- 0.18 ds (blank), 7.71 +/- 0.29 ds (cPBMCs), 7.86 +/- 0.26 ds (pDcs) and 8.14 +/- 0.69 ds (tuDcs) respectively. There were significant differences between blank and other three groups (F = 40.96, p < 0.01). Compared to mice in blank group, the tumor volume of cPBMCs group was significantly smaller (201.43 +/- 69.84 mm3 vs. 436.04 +/- 54.50 mm3, p < 0.01) and the tumor weight were significantly smaller (1.25 +/- 0.12 g vs. 2.83 +/- 0.24 g, p < 0.01). The tumor volume of tuDcs mice was significantly smaller than that of blank (92.11 +/- 11.55 mm3 vs. 436.04 +/- 54.50 mm3, p < 0.01) and cPBMCs mice (92.11 +/- 11.55 mm3 vs. 201.43 +/- 69.84 mm3, p < 0.01). Similarly, the tumor weight of tuDcs mice was significantly smaller than that of blank (0.66 +/- 0.07 g vs. 2.83 +/- 0.24 g, p < 0.01) and cPBMCs mice (0.66 +/- 0.07 g vs. 1.25 +/- 0.12 g, p < 0.01). There was no significant difference in tumor volume (92.11 +/- 11.55 mm3 vs. 85.61 +/- 11.59 mm3, p = 0.69) and tumor weight (0.66 +/- 0.07 g vs. 0.63 +/- 0.09 g, p = 0.75) between tuDcs group and pDcs group. CONCLUSIONS: The specific CD137L transfected umbilical blood Dc vaccine had significant anti-tumor effect against human colon cancer in nude mice via increasing the number of immune effector cell in tumor microenvironment. PMID- 28617555 TI - Correlation analysis of miR-200b, miR-200c, and miR-141 with liver metastases in colorectal cancer patients. AB - OBJECTIVE: To investigate correlation relationship between serum miR-200b, miR 200c, miR-141 levels with liver metastases in colorectal cancer patients. PATIENTS AND METHODS: A total of 85 colorectal cancer patients with liver metastases and 54 colorectal cancer patients without liver metastases were divided into experimental group and control. Serum sample was collected before surgery and tested by Real-time PCR to evaluate miR-200b, miR-200c, miR-141 expressions. RESULTS: The primary site of cancer of two groups was mostly derived from the colon cancer among the control and experimental group (there was no significant difference between the control group (61.1%) and experimental group (63.5%). Most of the invasive depth in the control group was T3 phase (50%), and most of the invasive depth in the experimental group was T4 phase (69.4%); therefore, the difference of the invasive depth between the control and experimental group is significant (p < 0.05). The majority of cases in experimental group were in stage IV, while they were in stage II in control. MiR 200b, miR-200c and miR-141 relate with tumor metastasis through epithelial mesenchymal transition (ETM) pathway, and target ZEB1 and ZEB2 genes. MiR-200b, miR-200c, and miR-141 have been confirmed to be related to tumor metastasis. miR 141 levels in serum from experimental group was higher significant compared to control group (p = 0.024). miR-200b levels in serum from experimental group was significantly increased compared to control group (p = 0.031). The miR-200c levels in serum from experimental group were significantly higher compared to control group (p = 0.015). Meanwhile, serum miR-141, miR-200b, miR-200c abnormal expressions in serum were related to tumor occurrence and development. Their levels were positively correlated with liver metastasis. CONCLUSIONS: The probability of liver metastases in colorectal cancer patients was positively correlated with serum miR-141, miR-200b, and miR-200c expressions, which could be treated as new biomarker for early diagnosis of liver metastases in colorectal cancer. PMID- 28617556 TI - Correlation between methylation of the p16 promoter and cervical cancer incidence. AB - OBJECTIVE: To study the methylation of the promoter of the p16 gene in cervical cancer patients and explore the correlation between methylation and the incidence of cervical cancer. PATIENTS AND METHODS: We recruited 78 patients with cervical cancer and 48 healthy individuals. The methylation-specific PCR was used to detect the methylation status in the promoter of the p16 gene. The mRNA expression of p16 was studied by quantitative fluorescence PCR. The protein expression of p16 was monitored by Enzyme-linked immunosorbent assay (ELISA) and Western blot. Immunohistochemistry was applied to detect the expression and distribution of p16 in cervical tissues. RESULTS: The methylation sequencing results showed that samples from cervical cancer patients had a methylation rate of 78.52% in the p16 gene promoter region compared with a much lower rate of 9.8% in the control group (9.8%). Quantitative fluorescence PCR indicated that the p16 mRNA expression was significantly reduced in cervical cancer patients compared with controls. ELISA and Western blot results showed that expression of the p16 protein in cancer tissue was 0.81 +/- 0.12 ug/l, whereas in the healthy controls it was 3.21 +/- 0.24 ug/l. Immunohistochemical results showed that the p16 protein was mainly present in the cytoplasm. The rate of p16 positive cells in the healthy cervical tissue 83.29% was higher than in cervical cancer 10.18%. CONCLUSIONS: The methylation of the p16 gene promoter could significantly reduce p16 expression, losing its tumor suppressor activity and promoting the development of cervical cancer. PMID- 28617557 TI - Expression of microRNA-142-3p in cervical cancer and its correlation with prognosis. AB - OBJECTIVE: The aim of current study was to assess the association between miR-142 3p expression and the prognosis of patients with cervical cancer. PATIENTS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to assess the expression level of miR-142-3p in cervical cancer tissues and matched normal tissues. Then, statistical analysis was performed to determine the associations of miR-142-3p expression with the clinical features and the prognosis of cervical cancer. RESULTS: Significantly lower levels of miR-142-3p was observed in the cervical cancer tissue, compared with the adjacent normal cervical tissue from the same patient (p < 0.05). Low miR-142-3p expression level was significantly associated with advanced FIGO stage (p = 0.002), lymph node metastasis (p = 0.005), and depth of cervical invasion (p = 0.006). Furthermore, Kaplan-Meier survival analysis demonstrated that patients with low miR-142-3 expression had poorer overall survival and progression-free survival (p < 0.001, respectively). The univariate proportional hazard model suggested that FIGO stage, lymph node metastasis, depth of cervical invasion and miR-142-3p expression level were prognostic predictors. Finally, Multivariate survival analysis also confirmed that miR-142-3p could be an independent prognostic marker for both overall survival and progression-free survival. CONCLUSIONS: MiR-142-3p may be a potential novel biomarker that predicts prognosis in cervical cancer. PMID- 28617558 TI - Up-regulation of miR-124 inhibits invasion and proliferation of prostate cancer cells through mediating JAK-STAT3 signaling pathway. AB - OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is an important protein in Janus kinase (JAK)-STAT signaling pathway, and can facilitate expression of Bcl-2 and Cyclin D1 gene, thus playing a role in tumor pathogenesis. Bioinformatics analysis revealed targeted binding sites between mircroRNA-124 (miR-124) and 3'-UTR of STAT3 mRNA. This study aims to investigate the role of miR-124 in regulating STAT3 expression and proliferation, cycle, apoptosis and invasion of prostate cancer cells. MATERIALS AND METHODS: Dual luciferase reporter gene assay demonstrated targeted correlation between miR-124 and STAT3. Expression of miR-124, STAT3, p-STAT3, Bcl-2 and Cyclin D1 was compared between normal human prostate epithelial cell RWPE-1 and prostate cancer cell DU145. In vitro cultured DU145 cells were treated with miR-124 mimic and/or si-STAT3, to compare expression of STAT3, phosphorylated STAT3 (p-STAT3), B-cell lymphoma-2 (Bcl-2) and Cyclin D1. Flow cytometry detected cell apoptosis and cycle, followed by clonal formation and transwell assay to test malignant proliferation and cell invasion. RESULTS: Targeted regulation existed between miR 124 and STAT3. Comparing to RWPE-1, DU145 cells had lower miR-124 expression, G0/G1 phase ratio, or cell apoptosis, plus higher expression of STAT3, p-STAT3, Bcl-2 and Cyclin D1, ratio of S or G2/M phase. Transfection of miR-124 mimic and/or si-STAT3 remarkably decreased gene expression, weakened clonal formation, cell invasion, ratio of S and G2/M phase, cell apoptosis and increased G0/G1 ratio. CONCLUSIONS: MiR-124 up-regulation significantly suppresses STAT3, pSTAT3 and downstream Bcl-2 and Cyclin D1 expression, weakens cell invasion or malignant proliferation potency, induces G0/G1 phase arrest, and facilitates cell apoptosis. PMID- 28617559 TI - Blockade of IL-17 alleviated inflammation in rat arthritis and MMP-13 expression. AB - OBJECTIVE: Rheumatoid arthritis (RA) is one systemic auto-immune disorder featured as chronic synovitis and can destruct joint cartilage. Fibroblast-like synoviocyte (FLS) secretes various factors affecting chondrocyte matrix and degradation. This study thus investigated the effect of interleukin-17A (IL-17A) on FLS and osteoclast. MATERIALS AND METHODS: Type II collagen-induced arthritis (CIA) rats were assigned to CIA model, CIA + IgG1 isotype, and CIA + Anti-Rat IL 17A groups. Tissue volume and arthritis index (AI) evaluated arthritis condition. ELISA and flow cytometry measured IL-17A content and Th17 cell percentage in joint cavity fluid. Matrix metallopeptidase 13 (MMP-13) and collagen type II alpha 1 (COL2A1) expression in synovial tissues were compared. FLS-osteoclast co culture system was treated with IL-17A + IgG1 Isotype or CIA + Anti-Rat IL-17A. MMP-13 and COL2A1 expression were compared. RESULTS: CIA model rats had significantly higher IL-17A and Th17 cell ratio in joint cavity fluid. Injection of Anti-Rat IL-17A decreased AI and tissue volume in model rats, decreased MMP-13 while increased COL2A1 expression in synovial or cartilage tissues. IL-17A treatment remarkably up-regulated MMP-13 mRNA or protein expression in chondrocytes. Anti-IL-17A weakened effects of IL-17A on FLS or chondrocytes. CONCLUSIONS: IL-17A inhibits COL2A1 mRNA and protein expression of chondrocyte in the co-culture system via inducing MMP-13 expression in FLS, thus enhancing collagen degradation and playing a role in RA-related cartilage injury. PMID- 28617560 TI - Influence of VEGF/BMP-2 on the proliferation and osteogenetic differentiation of rat bone mesenchymal stem cells on PLGA/gelatin composite scaffold. AB - OBJECTIVE: To investigate the influence of VEGF/BMP-2 on the proliferation and osteogenic differentiation of rat bone mesenchymal stem cells BMSCs) on PLGA/gelatin composite scaffold. MATERIALS AND METHODS: Randomly-oriented nanofibers with different ratios of Poly Lactic-co-Glycolic Acid (PLGA)/gelatin were produced through electrospinning. The mixture of nanofibers and BMSCs was pipetted onto the surface of the scaffolds, and BMSCs/PLGA/gelatin composite was obtained. The surface morphology, chemical structure, hydrophilicity and mechanical property of PLGA/gelatin nanofibers were revealed by scanning electron microscope. In vitro release kinetics of bone morphogenetic protein (BMP-2) and vascular endothelial growth factor (VEGF) were studied using ELISA kits. The cell adhesion, growth and proliferation of BMSCs on scaffolds were observed by scanning electron microscopy. The CCK-8 assay was used to evaluate the effects of VEGF/BMP-2 slow release system on the proliferation of BMSCs on scaffolds. RT-PCR was used to examine the activities of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX-2), and osteocalcin (OCN). RESULTS: In each group of cells in the in-vitro experiment, through electron microscope scanning, fiber scaffolds were interconnected three-dimensional reticular structure, BMSCs firmly attached to the fiber surface and internal stent, cells experienced a long spindle, polygon change, and branch-like protrusions on the cell surface were connected. Under the electron microscope, cell proliferation curve and osteogenesis markers (ALP, RUNX-2, OCN) expression in the dual factor group on cell adhesion, proliferation and differentiation were much better than those of blank control group and single factor groups. CONCLUSIONS: In the successfully constructed gelatin/PLGA nanofiber scaffold, VEGF and BMP-2 can be sequentially released, during which VEGF and BMP-2 can promote the adhesion, proliferation, and differentiation of BMSCs. PMID- 28617561 TI - Cervicovaginal bacteria and fungi in pregnant diabetic and non-diabetic women: a multicenter observational cohort study. AB - OBJECTIVE: We evaluated the prevalence of cervicovaginal Bacteria, group B Streptococcus (GBS), Gardnerella vaginalis (GV), Candida spp., Chlamydia trachomatis (CT), Mycoplasma hominis (MH) and Ureaplasma urealyticum (UU) in pregnant women with and without diabetes mellitus (DM). PATIENTS AND METHODS: Cervicovaginal swabs were gathered from 473 pregnant patients divided into 127 diabetic and 346 non-diabetic. The results were correlated to gestational age, parity and glycemic control. RESULTS: A higher prevalence of MH/UU (p=0.012) was found in the diabetic patients. After the 28th week of pregnancy, the prevalence for all investigated microorganisms appeared similar except for MH/UU (p=0.014). In multigravida, there were statistical differences between two groups in testing for Bacteria (p=0.015) and for MH/UU (p=0.037). The diabetic condition correlated to the state of multigravida in cases positive for Candida spp. (p=0.049) and in those testing positive for at least one microorganism (p=0.043). Pregnant with a blood glucose > 92 have twice the risk of being positive to a single microbiological test than those with better glycemic control. CONCLUSIONS: The higher prevalence of MH/UU after the 28th weeks can be explained with the physiologically reduced insulin tolerance characteristic of this gestational period. Among the diabetic testing positive to Candida spp. the statistically significant association was observed only in multigravida condition. These data suggest that diabetic multigravida women are at increased risk for Candida spp. infection in relation to the improper glycemic control. PMID- 28617562 TI - 5-Aminolevulinic acid photodynamic therapy stimulates local immunity in patients with condylomata acuminata via activation of T lymphocytes. AB - The article "5-Aminolevulinic acid photodynamic therapy stimulates local immunity in patients with condylomata acuminata via activation of T lymphocytes" by J. Du, Q. Cheng, Z. Zhang, J.-F. Wu, F. Li, S.-Y. Chen, Y.-L. Wang, X.-N. Lu, J.-H. Xu, published in Eur Rev Med Pharmacol Sci 2017; 21 (5): 1125-1135 has been withdrawn. PMID- 28617563 TI - Regulatory mechanism of miR-29 over TGF-beta1 and COL1 in scar cells. AB - OBJECTIVE: To study the regulatory mechanism of miR-29 over TGF-beta1 and COL1 in scar cells. PATIENTS AND METHODS: 5 clinical cases of hypertrophic scar (HS) skin and adjacent normal skin tissues were separated into fibroblast for primary culture and subculture before being observed morphologically and standard HE staining under an ordinary optical microscope. RT-PCR method was applied to test the expression level of miR-29, TGF-beta1, and COL1 mRNA. ELISA method was applied to test the expression level of extracellular matrix COL1, fibronectin (FN) and alpha-SMA. The miR-29 overexpression vector was built and transfected in vitro. RT-PCR method was applied to test related genes and ELISA method was applied to test the expression level of the extracellular matrix. RESULTS: The color of karyon and cytoplasm of normal fibroblast were both light red, with little ECM. The color of karyon of scar fibroblast was blue. The cytoplasm was red of different degrees, with relatively much ECM, in deep blue color. Compared with that in the normal fibroblast group, the miR-29 mRNA in fibroblast in the scar group significantly decreased (p<0.05). The TGF-beta1 and COL1 mRNA significantly increased (p<0.05). The COL1, FN and alpha-SMA level were significantly higher (p<0.05) than that in the normal group. These mRNAs levels in miR-29 overexpression group were lower than scar group but higher than the normal group. CONCLUSIONS: The expression of miR-29 which regulates the expression of TGF-beta1 and COL1 and increases the level of ECM significantly decreases in scar cells. This one suggests a mechanism of the formation of the scars through TGF-beta1 and COL1. PMID- 28617564 TI - A Peep Into "Peeping Tom": Successful Management of Cyclothymia Presenting as Voyeuristic Disorder. PMID- 28617565 TI - Psychotropic Medications in Swedish Homicide Victims and Offenders: A Forensic Toxicological Case-Control Study of Adherence and Recreational Use. AB - OBJECTIVE: We aimed to assess the extent to which adherence to, and recreational use of, psychotropic medications influence the risk of homicide offending and victimization. METHODS: We conducted a population-based case-control study by way of linking a nationwide registry of dispensed prescriptions with a forensic toxicological database. Homicide victims (n = 200) and offenders (n = 105) were identified for the years 2007-2009 and vehicle-accident controls (n = 1,643) for the years 2006-2013. The occurrence of congruence and incongruence between dispensed prescriptions and toxicology was used as a measure of adherence and recreational use. RESULTS: For antidepressants, incongruence-but not congruence between dispensed prescriptions and toxicology was associated with a significantly increased risk of homicide offending (odds ratio adjusted for age and sex [aOR] = 6.2; 95% confidence interval [CI], 3.3-11.6) but not homicide victimization (aOR = 0.8; 95% CI, 0.3-2.0). For antipsychotics and mood stabilizers, a significantly increased risk of homicide offending was associated with incongruence between prescriptions and toxicology (aOR = 7.0; 95% CI, 2.8 17.7), whereas risk estimates for congruence were not significantly elevated for either homicide offending or victimization. For GABAergic hypnotics, congruence and incongruence were significantly associated with increased risks of both homicide offending (aOR = 5.4; 95% CI, 2.6-11.0 and aOR = 4.9; 95% CI, 2.6-9.3, respectively) and homicide victimization (aOR = 2.1; 95% CI, 1.1-4.2 and aOR = 3.2; 95% CI, 1.7-6.1, respectively). Sensitivity analyses with a subset of controls yielded similar estimates. CONCLUSIONS: Nonadherence to medications used to treat affective and psychotic disorders appears to elevate the risk of homicide offending. Both medicinal and recreational use of GABAergic hypnotics appears to elevate the risk of homicide offending and victimization. In summary, vigilance regarding adherence to medications prescribed for mood disorders and psychosis, as well as restrictiveness regarding licit and illicit access to addictive hypnotics, might contribute to a reduction of homicidal violence. PMID- 28617566 TI - Randomized, Double-Blind, Placebo-Controlled Trial of N-Acetylcysteine Augmentation for Treatment-Resistant Obsessive-Compulsive Disorder. AB - OBJECTIVE: To evaluate the efficacy of serotonin reuptake inhibitor (SRI) augmentation with N-acetylcysteine (NAC), a glutamate modulator and antioxidant medication, for treatment-resistant obsessive-compulsive disorder (OCD). METHODS: We conducted a randomized, double-blind, placebo-controlled, 16-week trial of NAC (3,000 mg daily) in adults (aged 18-65 years) with treatment-resistant OCD, established according to DSM-IV criteria. Forty subjects were recruited at an OCD specialized outpatient clinic at a tertiary hospital (May 2012-October 2014). The primary outcome measure was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores. To evaluate the variables group, time, and interaction effects for Y-BOCS scores at all time points, we used nonparametric analysis of variance with repeated measures. Secondary outcomes were the severity scores for anxiety, depression, specific OCD symptom dimensions, and insight. RESULTS: Both groups showed a significant reduction of baseline Y-BOCS scores at week 16: the NAC group had a reduction of 4.3 points (25.6 to 21.3), compared with 3.0 points (24.8 to 21.8) for the placebo group. However, there were no significant differences between groups (P = .92). Adding NAC was superior to placebo in reducing anxiety symptoms (P = .02), but not depression severity or specific OCD symptom dimensions. In general, NAC was well tolerated, despite abdominal pain being more frequently reported in the NAC group (n [%]: NAC = 9 [60.0], placebo = 2 [13.3]; P < .01). CONCLUSIONS: Our trial did not demonstrate a significant benefit of NAC in reducing OCD severity in treatment-resistant OCD adults. Secondary analysis suggested that NAC might have some benefit in reducing anxiety symptoms in treatment-resistant OCD patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01555970. PMID- 28617570 TI - Trial of Pregabalin for Acute and Chronic Sciatica. PMID- 28617571 TI - Trial of Pregabalin for Acute and Chronic Sciatica PMID- 28617572 TI - Treatment of Benzodiazepine Dependence. PMID- 28617573 TI - Case 8-2017: A Zimbabwean Man with a Severe Headache. PMID- 28617574 TI - Synergistic Suppression of Tumor Angiogenesis by the Co-delivering of Vascular Endothelial Growth Factor Targeted siRNA and Candesartan Mediated by Functionalized Carbon Nanovectors. AB - Single-walled carbon nanotubes (SWNTs) with unique physicochemical properties have exhibited promising biomedical applications as drug and gene carriers. In this study, polyethylenimine (PEI)-modified SWNT conjugates linked with candesartan (CD) were developed to deliver vascular endothelial growth factor (VEGF)-targeted siRNA (siVEGF) for the synergistic and targeted treatment of tumor angiogenesis. The characterization results revealed that SWNT-PEI-CD conjugates were successfully synthesized and exhibited desirable dispersibility and superior stability. Confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) results showed that SWNT-PEI-CD/siVEGF complexes could achieve high cellular uptake and specific intracellular distribution of siRNA in AT1R overexpressed PANC-1 cells. Strong down-regulation of VEGF was also verified by qualitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot in complex-treated PANC-1 cells. The in vitro angiogenesis assay showed that SWNT-PEI-CD/siVEGF complexes highly inhibited tube formation of human umbilical vein endothelial cells. Furthermore, in vivo observation in PANC-1 xenografted nude mice demonstrated that SWNT-PEI-CD/siVEGF complexes exhibited significant distribution at tumor sites and caused obvious inhibition of tumor growth and tumor-associated angiogenesis repression induced by the drug combination of CD and siVEGF. Finally, a WST-1 assay indicated that SWNT-PEI-CD possessed low cytotoxicity, and a hemolysis test showed good biocompatibility of SWNT-PEI-CD. Hematological and histological analyses confirmed that SWNT-PEI-CD/siVEGF complexes did not cause any obvious toxic effects to blood and major organs. These findings suggested that the SWNT-PEI CD/siVEGF co-delivery system with tumor-targeting specificity, improved endosomal escaping properties, and collaboration of angiogenesis inhibition could be a prospective method for efficient tumor antiangiogenic therapy. PMID- 28617575 TI - External Influences on Invertebrate Brain Histamine and Related Compounds via an Automated Derivatization Method for Capillary Electrophoresis. AB - Histamine has been shown to modulate visual system and photic behavior in arthropods. However, few methods are available for the direct quantification of histamine and its precursor and metabolites in arthropod brain. In this work, a method for the separation of histamine, its precursor histidine, and its metabolite N-methyl-histamine from brain extracts of a freshwater crustacean has been developed using capillary electrophoresis with laser-induced fluorescence detection. Molecules were tagged on their primary amine function with naphthalene 2,3-dicarboxaldehyde, but derivatized histamine and N-methyl-histamine exhibited poor stability in contrast to derivatized histidine. To overcome this limitation, an automated derivatization performed within the capillary electrophoresis instrument was optimized and quantitatively validated. The limits of detection were 50, 30, and 60 nmol/L for histidine, histamine, and N-methyl-histamine, respectively. This study reports, for the first time, the amounts of histamine and its related compounds in brain extracts from populations of the freshwater amphipod Gammarus fossarum, and shows that these amounts vary mainly according to population and season, but are not affected by an experimental electrical shock. PMID- 28617577 TI - Imaging with Mass Spectrometry of Bacteria on the Exoskeleton of Fungus-Growing Ants. AB - Mass spectrometry imaging is a powerful analytical technique for detecting and determining spatial distributions of molecules within a sample. Typically, mass spectrometry imaging is limited to the analysis of thin tissue sections taken from the middle of a sample. In this work, we present a mass spectrometry imaging method for the detection of compounds produced by bacteria on the outside surface of ant exoskeletons in response to pathogen exposure. Fungus-growing ants have a specialized mutualism with Pseudonocardia, a bacterium that lives on the ants' exoskeletons and helps protect their fungal garden food source from harmful pathogens. The developed method allows for visualization of bacterial-derived compounds on the ant exoskeleton. This method demonstrates the capability to detect compounds that are specifically localized to the bacterial patch on ant exoskeletons, shows good reproducibility across individual ants, and achieves accurate mass measurements within 5 ppm error when using a high-resolution, accurate-mass mass spectrometer. PMID- 28617576 TI - Ex Vivo Measurement of Electrically Evoked Dopamine Release in Zebrafish Whole Brain. AB - Zebrafish (Danio rerio) have recently emerged as useful model organism for the study of neuronal function. Here, fast-scan cyclic voltammetry (FSCV) at carbon fiber microelectrodes was used to measure locally evoked dopamine release and uptake in zebrafish whole brain preparations and results were compared with those obtained from brain slices. Evoked dopamine release ([DA]max) was similar in whole brain and sagittal brain slice preparations (0.49 +/- 0.13 MUM in whole brain and 0.59 +/- 0.28 MUM in brain slices). Treatment with alpha-methyl-p tyrosine methyl ester (alphaMPT), an inhibitor of tyrosine hydroxylase, diminished release and the electrochemical signal reappeared after subsequent drug washout. No observed change in stimulated release current occurred after treatment with desipramine or fluoxetine in the whole brain. Treatment with the uptake inhibitors, nomifensine or GBR 12909 increased [DA]max, while treatment with sulpiride, a D2 dopamine autoreceptor antagonist, resulted in increased stimulated dopamine release in whole brain, but had no effect on release in slices. Dopamine release in whole brains increased progressively up to an electrical stimulation frequency of 25 Hz, while release in slices increased up to a frequency of only 10 Hz and then plateaued, highlighting another key difference between these preparations. We observed a lag in peak dopamine release following stimulation, which we address using diffusion models and pharmacological treatments. Collectively, these results demonstrate the electrochemical determination of dopamine release in the whole, intact brain of a vertebrate species ex vivo and are an important step for carrying out further experiments in zebrafish. PMID- 28617578 TI - Antibodies Against Specific MUC16 Glycosylation Sites Inhibit Ovarian Cancer Growth. AB - Expression of the retained C-terminal extracellular portion of the ovarian cancer glycoprotein MUC16 induces transformation and tumor growth. However, the mechanisms of MUC16 oncogenesis related to glycosylation are not clearly defined. We establish that MUC16 oncogenic effects are mediated through MGAT5-dependent N glycosylation of two specific asparagine sites within its 58 amino acid ectodomain. Oncogenic signaling from the C-terminal portion of MUC16 requires the presence of Galectin-3 and growth factor receptors colocalized on lipid rafts. These effects are blocked upon loss of either Galectin-3 expression or activity MGAT5. Using synthetic MUC16 glycopeptides, we developed novel N-glycosylation site directed monoclonal antibodies that block Galectin-3-mediated MUC16 interactions with cell surface signaling molecules. These antibodies inhibit invasion of ovarian cancer cells, directly blocking the in vivo growth of MUC16 bearing ovarian cancer xenografts, elucidating new therapeutic modalities. PMID- 28617579 TI - Programming Feature Size in the Thermal Wrinkling of Metal Polymer Bilayer by Modulating Substrate Viscoelasticity. AB - We report a novel strategy for creating stress-induced self-organized wrinkles in a metal polymer bilayer with programmable periodicity (lambdaS) varying over a wide range, from ~20 MUm down to ~800 nm by modulating the viscoelasticity of the bottom polymer layer. Substrates with different viscoelasticity are prepared by precuring thin films of a thermo-curable poly dimethylsiloxane (PDMS) elastomer (Sylgard 184) for different durations (tP) prior to deposition of the top aluminum layer by thermal evaporation. Precuring of the Sylgard 184 film for different durations leads to films with different degrees of viscoelasticity due to variation in the extent of cross-linking of the polymer matrix. The lambdaS as well as the amplitude (aS) of the wrinkles progressively decrease with an increase in the extent of elasticity of the film, manifested as an increase in the storage modulus (G'). Based on the variation in the rate of decay of lambdaS with G', we identify three clearly distinguishable regimes over predominantly viscous, viscoelastic, and elastic bottom layers. While lambdaS and aS drop with an increase in G' for both the first and the third regimes, it remains nearly independent of G' for the intermediate regime. This is attributed to the difference in the mechanisms of wrinkle formation in the different regimes. We finally show that simultaneous modulation of lambdaS and aS can be used to engineer surfaces with different wettability as well as anti-reflection properties. PMID- 28617582 TI - Liquid-Crystal-Based Immunosensor for Diagnosis of Tuberculosis in Clinical Specimens. AB - Tuberculosis (TB) is a serious global health problem, although it is easily preventable and curable. The prevalence of TB is caused by a lack of simple, rapid, cheap, and effective TB diagnostic tests. In this study, we have established a novel liquid crystal (LC)-based immunosensor to diagnose TB in clinical specimens. The clinical serum samples were incubated on a TB antigen immobilized substrate, and their optical LC responses were observed using a polarized light microscope. Specific binding of anti-TB antibodies to the TB antigen-immobilized surface only occurred in clinical specimens from TB patients, inducing the disruption of the orientation of LCs. This was followed by the distinctive change in the optical appearance of LCs from uniform to random. However, when clinical serum samples from healthy people or latent TB patients were incubated, the orientation of LCs remained uniform. Through the change of optical LC images, in 76% of TB patients, this essay correctly identified the patients as having antibodies to TB in their serums. 91% of healthy people free of TB were correctly identified as not having antibodies to TB. Thus, this LC based immunosensor is a promising platform, particularly in clinical TB diagnostics, which does not require complicated preparation of clinical specimens or complex instrumentation. PMID- 28617581 TI - Creating an Optimal Microenvironment within Mesoporous Silica MCM-41 for Capture of Tobacco-Specific Nitrosamines in Solution. AB - To meet the requirement of capturing tobacco-specific nitrosamines (TSNA) for environment protection, a unique microenvironment was carefully created inside the channels of mesoporous silica MCM-41. In situ carbonization of template micelles at 923 K, combined with the excess aluminum used in one-pot synthesis of MCM-41, is adopted to tailor the tortuosity of mecsoporous channels, while loaded metal oxides (5 wt %) and the Al component in the framework are employed to exert the necessary electrostatic interaction toward the target carcinogens TSNA in solution. The elaborated microenvironment created in mesoporous sorbents was characterized with XRD, N2 adsorption-desorption, TEM, XPS, and TG-DSC methods. Various solutions of Burley- and Virginia-type tobaccos were used to assess the adsorption performance of new mesoporous sorbents, and the influence of the solid to-liquid ratio, adsorption time, and loading amount of CuO on the adsorption was carefully examined. The representative sample 5%Cu/AM-10c could capture 27.2% of TSNA in Burley tobacco solution, and its capacity reached 0.3 mg g-1 in Snus tobacco extract solution, offering a promising candidate for the protection of the environment and public health. PMID- 28617580 TI - Progressive Stereo Locking (PSL): A Residual Dipolar Coupling Based Force Field Method for Determining the Relative Configuration of Natural Products and Other Small Molecules. AB - Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to allow free sampling of both R and S configurations of the stereocenters of interest. The algorithm uses a floating alignment tensor in a simulated annealing protocol to identify the conformations and configurations that best fit experimental RDC and distance restraints (from NOE and J-coupling data). A unique configuration (for rigid molecules) or a very small number of configurations (for less rigid molecules) of the structural models having the lowest chiral angle energies and reasonable magnitudes of the alignment tensor are provided as the best predictions of the unknown configuration. For highly flexible molecules, the progressive locking of their stereocenters into their statistically dominant R or S state dramatically reduces the number of possible relative configurations. The result is verified by checking that the same configuration is obtained by initiating the locking from different regions of the molecule. For all molecules tested having known configurations (with conformations ranging from mostly rigid to highly flexible), the method accurately determined the correct configuration. PMID- 28617583 TI - ToF-SIMS Depth Profiling of PS-b-PMMA Block Copolymers Using Arn+, C60++, and Cs+ Sputtering Ions. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a high performance tool for molecular depth profiling of polymer films, in particular when they are structured in microphases. However, a major issue is the degradation of polymer materials under ion irradiation in reactions such as cross-linking, chain breaking, or reorganization processes of polymers which have been demonstrated for materials such as polystyrene (PS) and poly(methyl methacrylate) (PMMA). This work aims at comparing ToF-SIMS molecular depth profiling of structured polymers (polystyrene (PS)-b-polymethyl methacrylate (PMMA) block copolymers (BCP)) using either ultralow energy cesium or the more recently introduced C60++ (under NO dosing and with sample cooling) and argon cluster ion beams (using Ar1500+ ions at 5 keV). The latter improved the quality of the depth profiles, especially the argon cluster ion beam, as it is characterized by a greater homogeneity for the sputter yields of PS and PMMA. No significant artifacts were observed, and this was confirmed by the comparison of depth profiles obtained from films with variable thickness, annealing time, and morphology (cylindrical blocks vs spherical blocks). Comparison to a theoretical model (hexagonal centered pattern) ensured that the ToF-SIMS depth profiles described the real morphology and may thus be a relevant characterization tool to verify the morphology of the films as a function of the deposition parameters. PMID- 28617584 TI - Tunability of the Quantum Spin Hall Effect in Bi(110) Films: Effects of Electric Field and Strain Engineering. AB - The quantum spin Hall (QSH) effect is promising for achieving dissipationless transport devices due to their robust gapless edge states inside insulating bulk gap. However, the currently discussed QSH insulators usually suffer from ultrahigh vacuum or low temperature due to the small bulk gap, which limits their practical applications. Searching for large-gap QSH insulators is highly desirable. Here, the tunable QSH state of a Bi(110) films with a black phosphorus (BP) structure, which is robust against structural deformation and electric field, is explored by first-principles calculations. It is found that the two monolayer BP-Bi(110) film obtains a tunable large bulk gap by strain engineering and its QSH effect shows a favorable robustness within a wide range of combinations of in-plane and out-of-plane strains, although a single in-plane compression or out-of-plane extension may restrict the topological phase due to the self-doping effect. More interestingly, in view of biaxial strain, two competing physics on band topology induced by bonding-antibonding and px,y-pz band inversions are obtained. Meanwhile, the QSH effect can be persevered under an electric field of up to 0.9 V/A. Moreover, with appropriate in-plane strain engineering, a nontrivial topological phase in a four-monolayer BP-Bi(110) film is identified. Our findings suggest that these two-dimensional BP-Bi(110) films are ideal platforms of the QSH effect for low-power dissipation devices. PMID- 28617585 TI - Solution-Phase Photochemical Nanopatterning Enabled by High-Refractive-Index Beam Pen Arrays. AB - A high-throughput, solution-based, scanning-probe photochemical nanopatterning approach, which does not require the use of probes with subwavelength apertures, is reported. Specifically, pyramid arrays made from high-refractive-index polymeric materials were constructed and studied as patterning tools in a conventional liquid-phase beam pen lithography experiment. Two versions of the arrays were explored with either metal-coated or metal-free tips. Importantly, light can be channeled through both types of tips and the appropriate solution phase (e.g., H2O or CH3OH) and focused on subwavelength regions of a substrate to effect a photoreaction in solution that results in localized patterning of a self assembled monolayer (SAM)-coated Au thin film substrate. Arrays with as many as 4500 pyramid-shaped probes were used to simultaneously initiate thousands of localized free-radical photoreactions (decomposition of a lithium acylphosphinate photoinitiator in an aqueous solution) that result in oxidative removal of the SAM. The technique is attractive since it allows one to rapidly generate features less than 200 nm in diameter, and the metal-free tips afford more than 10-fold higher intensity than the tips with nanoapertures over a micrometer propagation length. In principle, this mask-free method can be utilized as a versatile tool for performing a wide variety of photochemistries across multiple scales that may be important in high-throughput combinatorial screening applications related to chemistry, biology, and materials science. PMID- 28617586 TI - Research Progress toward the Practical Applications of Lithium-Sulfur Batteries. AB - The renaissance of Li-S battery technology is evidenced by the intensive R&D efforts in recent years. Although the theoretical capacity and energy of a Li-S battery is theoretically very high, the projected usable energy is expected to be no more than twice that of state-of-the-art Li-ion batteries, or 500 Wh/kg. The recent "sulfur fever" has certainly gathered new knowledge on sulfur chemistry and electrochemistry, electrolytes, lithium metal, and their interactions in this "new" system; however, a real advance toward a practical Li-S battery is still missing. One of the main reasons behind this is the sensitivity of Li-S batteries to the experimental testing parameters. Sophisticated nanostructures are usually employed, while the practicality of these nanomaterials for batteries is rarely discussed. The sulfur electrode, usually engineered in a thin-film configuration, further poses uncertainties in the knowledge transfer from the lab to industry. This review article briefly overviews the recent research progress on Li-S batteries, followed by a discussion of the Li-S battery system from the authors' own understandings collected from their past few years of research. The critical findings, the unresolved issues, and the scientific gap between lab research and industrial application are discussed. The future work in Li-S battery research is also explored to propel relevant research efforts toward industrial applications. PMID- 28617587 TI - Variable Regions of Antibodies and T-Cell Receptors May Not Be Sufficient in Molecular Simulations Investigating Binding. AB - Antibodies and T-cell receptors are important proteins of the immune system that share similar structures. Both contain variable and constant regions. Insight into the dynamics of their binding can be provided by computational simulations. For these simulations the constant regions are often removed to save runtime as binding occurs in the variable regions. Here we present the first study to investigate the effect of removing the constant regions from antibodies and T cell receptors on such simulations. We performed simulations of an antibody/antigen and T-cell receptor/MHC system with and without constant regions using 10 replicas of 100 ns of each of the four setups. We found that simulations without constant regions show significantly different behavior compared to simulations with constant regions. If the constant regions are not included in the simulations alterations in the binding interface hydrogen bonds and even partial unbinding can occur. These results indicate that constant regions should be included in antibody and T-cell receptor simulations for reliable conclusions to be drawn. PMID- 28617588 TI - Biosynthesis of Single Thioether c-Type Cytochromes Provides Insight into Mechanisms Intrinsic to Holocytochrome c Synthase (HCCS). AB - C-type cytochromes (cyts c) are generally characterized by the presence of two thioether attachments between heme and two cysteine residues within a highly conserved CXXCH motif. Most eukaryotes use the System III cyt c biogenesis pathway composed of holocytochrome c synthase (HCCS) to catalyze thioether formation. Some protozoan organisms express a functionally equivalent, natural variant of cyt c with an XXXCH heme-attachment motif, resulting in a single covalent attachment. Previous studies have shown that recombinant HCCS can produce low levels of the XXXCH single thioether variant. However, cyt c variants containing substitutions at the C-terminal cysteine of the heme-attachment site (i.e., resulting in CXXXH) have never been observed in nature, and attempts to biosynthesize a recombinant version of this cyt c variant have been largely unsuccessful. In this study, we report the biochemical analyses of an HCCS matured CXXXH cyt c variant, comparing its biosynthesis and properties to those of the XXXCH variant. The results indicate that although HCCS mediates heme attachment to the N-terminal cysteine in CXXXH cyt c variants, up to 50% of the cyt c produced is modified in an oxygen-dependent manner, resulting in a mixed population of cyt c. Since this aerobic modification occurs only in the context of CXXXH, we also propose that natural HCCS-mediated heme attachment to CXXCH likely initiates at the C-terminal cysteine. PMID- 28617589 TI - rRNA C-Loops: Mechanical Properties of a Recurrent Structural Motif. AB - C-loop is an internal loop motif found in the ribosome and used in artificial nanostructures. While its geometry has been partially characterized, its mechanical properties remain elusive. Here we propose a method to evaluate global shape and stiffness of an internal loop. The loop is flanked by short A-RNA helices modeled as rigid bodies. Their relative rotation and displacement are fully described by six interhelical coordinates. The deformation energy of the loop is assumed to be a general quadratic function of the interhelical coordinates. The model parameters for isolated C-loops are inferred from unrestrained all-atom molecular dynamics simulations. C-loops exhibit high twist as reported earlier, but also a bend and a lateral displacement of the flanking helices. Their bending stiffness and lateral displacement stiffness are nearly isotropic and similar to the control A-RNA duplexes. Nevertheless, we found systematic variations with the C-loop position in the ribosome and the organism of origin. The results characterize global properties of C-loops in the full six dimensional interhelical space and enable one to choose an optimally stiff C-loop for use in a nanostructure. Our approach can be readily applied to other internal loops and extended to more complex structural motifs. PMID- 28617591 TI - Control of Interchain Antiferromagnetic Coupling in Porous Co(II)-Based Metal Organic Frameworks by Tuning the Aromatic Linker Length: How Far Does Magnetic Interaction Propagate? AB - Three MOF-74-type Co(II) frameworks with one-dimensional hexagonal channels have been prepared. Co(II) spins in a chain are ferromagnetically coupled through carboxylate and phenoxide bridges. Interchain antiferromagnetic couplings via aromatic ring pathways operate over a Co-Co length shorter than ~10.9 A, resulting in a field-induced metamagnetic transition, while being absent over lengths longer than ~14.7 A. PMID- 28617590 TI - Structure and Dynamics of RNA Repeat Expansions That Cause Huntington's Disease and Myotonic Dystrophy Type 1. AB - RNA repeat expansions cause a host of incurable, genetically defined diseases. The most common class of RNA repeats consists of trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 * 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Huntington's disease and myotonic dystrophy type 1, which are caused by r(CAG) and r(CUG) repeats, respectively. We report the structures of two RNA constructs containing three copies of a r(CAG) [r(3*CAG)] or r(CUG) [r(3*CUG)] motif that were modeled with nuclear magnetic resonance spectroscopy and simulated annealing with restrained molecular dynamics. The 1 * 1 internal loops of r(3*CAG) are stabilized by one-hydrogen bond (cis Watson-Crick/Watson-Crick) AA pairs, while those of r(3*CUG) prefer one or two-hydrogen bond (cis Watson-Crick/Watson-Crick) UU pairs. Assigned chemical shifts for the residues depended on the identity of neighbors or next nearest neighbors. Additional insights into the dynamics of these RNA constructs were gained by molecular dynamics simulations and a discrete path sampling method. Results indicate that the global structures of the RNA are A-form and that the loop regions are dynamic. The results will be useful for understanding the dynamic trajectory of these RNA repeats but also may aid in the development of therapeutics. PMID- 28617592 TI - Kinetic and Thermodynamic Analysis of Acetyl-CoA Activation of Staphylococcus aureus Pyruvate Carboxylase. AB - Allosteric regulation of pyruvate carboxylase (PC) activity is pivotal to maintaining metabolic homeostasis. In contrast, dysregulated PC activity contributes to the pathogenesis of numerous diseases, rendering PC a possible target for allosteric therapeutic development. Recent research efforts have focused on demarcating the role of acetyl-CoA, one of the most potent activators of PC, in coordinating catalytic events within the multifunctional enzyme. Herein, we report a kinetic and thermodynamic analysis of acetyl-CoA activation of the Staphylococcus aureus PC (SaPC)-catalyzed carboxylation of pyruvate to identify novel means by which acetyl-CoA synchronizes catalytic events within the PC tetramer. Kinetic and linked-function analysis, or thermodynamic linkage analysis, indicates that the substrates of the biotin carboxylase and carboxyl transferase domain are energetically coupled in the presence of acetyl-CoA. In contrast, both kinetic and energetic coupling between the two domains is lost in the absence of acetyl-CoA, suggesting a functional role for acetyl-CoA in facilitating the long-range transmission of substrate-induced conformational changes within the PC tetramer. Interestingly, thermodynamic activation parameters for the SaPC-catalyzed carboxylation of pyruvate are largely independent of acetyl-CoA. Our results also reveal the possibility that global conformational changes give rise to observed species-specific thermodynamic activation parameters. Taken together, our kinetic and thermodynamic results provide a possible allosteric mechanism by which acetyl-CoA coordinates catalysis within the PC tetramer. PMID- 28617593 TI - Solid-Phase Fe Speciation along the Vertical Redox Gradients in Floodplains using XAS and Mossbauer Spectroscopies. AB - Properties of Fe minerals are poorly understood in natural soils and sediments with variable redox conditions. In this study, we combined 57Fe Mossbauer and Fe K-edge X-ray absorption spectroscopic (XAS) techniques to assess solid-phase Fe speciation along the vertical redox gradients of floodplains, which exhibited a succession of oxic, anoxic, and suboxic-oxic zones with increasing depth along the vertical profiles. The incised stream channel is bounded on the east by a narrow floodplain and a steep hillslope, and on the west by a broad floodplain. In the eastern floodplain, the anoxic conditions at the intermediate horizon (55 80 cm) coincided with lower Fe(III)-oxides (particularly ferrihydrite), in concurrence with a greater reduction of phyllosilicates(PS)-Fe(III) to PS-Fe(II), relative to the oxic near-surface and sandy gravel layers. In addition, the anoxic conditions in the eastern floodplain coincided with increased crystallinity of goethite, relative to the oxic layers. In the most reduced intermediate sediments at 80-120 cm of the western floodplain, no Fe(III)-oxides were detected, concurrent with the greatest PS-Fe(III) reduction (PS Fe(II)/Fe(III) ratio ~ 1.2 (Mossbauer) or 0.8 (XAS)). In both oxic near-surface horizon and oxic-suboxic gravel aquifers beneath the soil horizons, Fe(III) oxides were mainly present as ferrihydrite with a much less amount of goethite, which preferentially occurred as nanogoethite or Al/Si-substituted goethite. Ferrihydrite with varying crystallinity or impurities such as organic matter, Al or Si, persisted under suboxic-oxic conditions in the floodplain. This study indicates that vertical redox gradients exert a major control on the quantity and speciation of Fe(III) oxides as well as the oxidation state of structural Fe in PS, which could significantly affect nutrient cycling and carbon (de)stabilization. PMID- 28617594 TI - Formation of Polyrotaxane Particles via Template Assembly. AB - In this study, we report a versatile method to assemble tunable poly(ethylene glycol) (PEG)-based polyrotaxane (PRX) particles and capsules. By threading alpha cyclodextrins (alphaCDs) onto PEG chains physically adsorbed onto template particles and subsequently dissolving the templates, PRX replica particles and hollow capsules are formed. This approach overcomes issues related to CD steric hindrance, and also reduces the multiple processing steps often associated with PRX-based particle formation. By simple variation of the molecular weight and end group functionality of the PEG, we show that the rate of particle degradation as well as the stability of the particles can be tuned. We also demonstrate the loading and release of model (drug) compounds, achieving burst and controlled release of the compounds. It is envisaged that this approach will provide a flexible platform for the engineering of a diverse range of PRX-based particles, enabling PRX materials to be further explored in various applications. PMID- 28617595 TI - An Ab Initio Exciton Model Including Charge-Transfer Excited States. AB - The Frenkel exciton model is a useful tool for theoretical studies of multichromophore systems. We recently showed that the exciton model could be used to coarse-grain electronic structure in multichromophoric systems, focusing on singly excited exciton states [ Acc. Chem. Res. 2014 , 47 , 2857 - 2866 ]. However, our previous implementation excluded charge-transfer excited states, which can play an important role in light-harvesting systems and near-infrared optoelectronic materials. Recent studies have also emphasized the significance of charge-transfer in singlet fission, which mediates the coupling between the locally excited states and the multiexcitonic states. In this work, we report on an ab initio exciton model that incorporates charge-transfer excited states and demonstrate that the model provides correct charge-transfer excitation energies and asymptotic behavior. Comparison with TDDFT and EOM-CC2 calculations shows that our exciton model is robust with respect to system size, screening parameter, and different density functionals. Inclusion of charge-transfer excited states makes the exciton model more useful for studies of singly excited states and provides a starting point for future construction of a model that also includes double-exciton states. PMID- 28617596 TI - Review of Organic Wastewater Compound Concentrations and Removal in Onsite Wastewater Treatment Systems. AB - Onsite wastewater treatment systems, such as septic systems, serve 20% of U.S. households and are common in areas not served by wastewater treatment plants (WWTPs) globally. They can be sources of nutrients and pathogen pollution and have been linked to health effects in communities where they contaminate drinking water. However, few studies have evaluated their ability to remove organic wastewater compounds (OWCs) such as pharmaceuticals, hormones, and detergents. We synthesized results from 20 studies of 45 OWCs in conventional drainfield-based and alternative onsite wastewater treatment systems to characterize concentrations and removal. For comparison, we synthesized 31 studies of these same OWCs in activated sludge WWTPs. OWC concentrations and removal in drainfields varied widely and depended on wastewater sources and compound specific removal processes, primarily sorption and biotransformation. Compared to drainfields, alternative systems had similar median and higher maximum concentrations, reflecting a wider range of system designs and redox conditions. OWC concentrations and removal in drainfields were generally similar to those in conventional WWTPs. Persistent OWCs in groundwater and surface water can indicate the overall extent of septic system impact, while the presence of well-removed OWCs, such as caffeine and acetaminophen, may indicate discharges of poorly treated wastewater from failing or outdated septic systems. PMID- 28617597 TI - Ruthenium-Catalyzed Carbonylation of Oxalyl Amide-Protected Benzylamines with Isocyanate as the Carbonyl Source. AB - An efficient synthesis of isoindolin-1-ones from oxalyl amide-protected benzylamines, through ruthenium-catalyzed intramolecular C(sp2)-H carbonylation, has been developed. Variously substituted benzylamines could be well tolerated in this new protocol, affording the corresponding products in moderate to excellent yields. This approach constitutes the first example of Ru(II)-catalyzed C(sp2)-H carbonylation with isocyanate as a novel commercially available carbonyl source. PMID- 28617598 TI - Withanolides from Aeroponically Grown Physalis peruviana and Their Selective Cytotoxicity to Prostate Cancer and Renal Carcinoma Cells. AB - Investigation of aeroponically grown Physalis peruviana resulted in the isolation of 11 new withanolides, including perulactones I-L (1-4), 17-deoxy-23beta hydroxywithanolide E (5), 23beta-hydroxywithanolide E (6), 4-deoxyphyperunolide A (7), 7beta-hydroxywithanolide F (8), 7beta-hydroxy-17-epi-withanolide K (9), 24,25-dihydro-23beta,28-dihydroxywithanolide G (10), and 24,25-dihydrowithanolide E (11), together with 14 known withanolides (12-25). The structures of 1-11 were elucidated by the analysis of their spectroscopic data, and 12-25 were identified by comparison of their spectroscopic data with those reported. All withanolides were evaluated for their cytotoxic activity against a panel of tumor cell lines including LNCaP (androgen-sensitive human prostate adenocarcinoma), 22Rv1 (androgen-resistant human prostate adenocarcinoma), ACHN (human renal adenocarcinoma), M14 (human melanoma), SK-MEL-28 (human melanoma), and normal human foreskin fibroblast cells. Of these, the 17beta-hydroxywithanolides (17 BHWs) 6, 8, 9, 11-13, 15, and 19-22 showed selective cytotoxic activity against the two prostate cancer cell lines LNCaP and 22Rv1, whereas 13 and 20 exhibited selective toxicity for the ACHN renal carcinoma cell line. These cytotoxicity data provide additional structure-activity relationship information for the 17 BHWs. PMID- 28617600 TI - First-Principles Interaction Analysis Assessment of the Manganese Cation in the Catalytic Activity of Glycosyltransferases. AB - The energetic effect of water substitution reactions in hexacoordinated [Mn(H2O)6 nLzn]2+nz complexes with L = methanol, formic acid, formamide, formate, imidazole, and diphosphate is quantitatively analyzed at the MP2/triple-zeta level of theory. Subsequently, the state-of-the-art open shell symmetry-adapted perturbation theory (SAPT) analysis of the interaction energies of Mn2+...ligand dimers with selected O-, S-, and N-binding ligands is presented and compared to similar interactions of Mg2+ and Zn2+ ions. We find that the induction energies in the dimers with manganese are almost twice as large as in dimers with magnesium. The total interaction energies rise in the order Mn2+ < Mg2+ < Zn2+. The calculations of the Mn2+ -> Mg2+ replacement reaction suggest that metal dependent glycosyltransferases influence the binding preference of Mn2+ over Mg2+ by inserting amino acids that coordinate the metal via nitrogen or sulfur into their active site. PMID- 28617599 TI - Effects of the Adulteration Technique on the Near-Infrared Detection of Melamine in Milk Powder. AB - The United States Pharmacopeial Convention has led an international collaborative project to develop a toolbox of screening methods and reference standards for the detection of milk powder adulteration. During the development of adulterated milk powder reference standards, blending methods used to combine melamine and milk had unanticipated strong effects on the near-infrared (NIR) spectrum of melamine. The prominent absorbance band at 1468 nm of melamine was retained when it was dry blended with skim milk powder but disappeared in wet-blended mixtures, where spray-dried milk powder samples were prepared from solution. Analyses using polarized light microscopy, Raman spectroscopy, dielectric relaxation spectroscopy, X-ray diffraction, and mass spectrometry indicated that wet blending promoted reversible and early Maillard reactions with lactose that are responsible for differences in melamine NIR spectra between wet- and dry-blended samples. Targeted detection estimates based solely on dry-blended reference standards are likely to overestimate NIR detection capabilities in wet-blended samples as a result of previously overlooked matrix effects arising from changes in melamine hydrogen-bonding status, covalent complexation with lactose, and the lower but more homogeneous melamine local concentration distribution produced in wet-blended samples. Techniques used to incorporate potential adulterants can determine the suitability of milk reference standards for use with rapid detection methods. PMID- 28617601 TI - Effects of the Surface Morphology and Conformations of Lignocellulosic Biomass Biopolymers on Their Nanoscale Interactions with Hydrophobic Self-Assembled Monolayers. AB - The effects of the morphology and conformations of the surface biopolymers present on lignocellulosic biomass as well as their steric hindrance on enzymatic adsorption to biomass surfaces remain elusive. In a step to better understand these effects, nanoscale steric forces between a model surface that represents the hydrophobic residues of a cellulase enzyme and a set of reference lignocellulosic substrates were measured using atomic force microscopy (AFM) in liquid media. The reference substrates investigated were prepared by kraft, sulfite, and organosolv pulping pretreatment methods and varied in their surface lignin, xylan, and acetone extractives' contents. Measured steric forces were quantified through fitting to a model developed to describe polyelectrolytes brushes in terms of a brush thickness and a brush grafting density. Our data indicated that cellulose microfibrils extend from the microfibril matrix leading to a long-range steric repulsion and low attractive forces to the hydrophobic model of the enzyme, suggesting that steric hindering can be a possible mechanism for nonproductive binding of enzymes to cellulose. When the amount of xylan increased in the absence of lignin, steric repulsions between the hydrophobic model of the enzyme, and biomass biopolymers decreased as a result of collapsed cellulose microfibrils and adhesion forces increased. This suggests that leaving a small amount of xylan after biomass pretreatment can help improve enzymatic binding to cellulose. Irrespective of the type of lignin present on biomass, grafting densities increased and brush thicknesses decreased compared to those of lignin-free substrates. When compared to lignin-free substrates, lignin containing substrates had higher attractive forces and lower steric repulsive forces. In addition, AFM images of the reference substrates in the wet and dry states showed that lignin precipitates on the biomass surface where kraft lignin had the highest particle size leading to a limited accessibility of the enzyme to the cellulose in biomass. When the effects of lignin precipitate size, the adhesion force, and steric forces on nonproductive enzymatic binding were all considered, our results indicate that organosolv pretreatment should be the treatment of choice to minimize enzymatic nonproductive binding to lignin. PMID- 28617602 TI - Rewriting Electron-Transfer Kinetics at Pyrolytic Carbon Electrodes Decorated with Nanometric Ruthenium Oxide. AB - Platinum is state-of-the-art for fast electron transfer whereas carbon electrodes, which have semimetal electronic character, typically exhibit slow electron-transfer kinetics. But when we turn to practical electrochemical devices, we turn to carbon. To move energy devices and electro(bio)analytical measurements to a new performance curve requires improved electron-transfer rates at carbon. We approach this challenge with electroless deposition of disordered, nanoscopic anhydrous ruthenium oxide at pyrolytic carbon prepared by thermal decomposition of benzene (RuOx@CVD-C). We assessed traditionally fast, chloride assisted ([Fe(CN)6]3-/4-) and notoriously slow ([Fe(H2O)6]3+/2+) electron transfer redox probes at CVD-C and RuOx@CVD-C electrodes and calculated standard heterogeneous rate constants as a function of heat treatment to crystallize the disordered RuOx domains to their rutile form. For the fast electron-transfer probe, [Fe(CN)6]3-/4-, the rate increases by 34* over CVD-C once the RuOx is calcined to form crystalline rutile RuO2. For the classically outer-sphere [Fe(H2O)6]3+/2+, electron-transfer rates increase by an even greater degree over CVD-C (55*). The standard heterogeneous rate constant for each probe approaches that observed at Pt but does so using only minimal loadings of RuOx. PMID- 28617603 TI - Antifouling Stripes Prepared from Clickable Zwitterionic Copolymers. AB - In this study, we have fabricated robust patterned surfaces that contain biocompatible and antifouling stripes, which cause microorganisms to consolidate into bare silicon spaces. Copolymers of methacryloyloxyethyl phosphorylcholine (MPC) and a methacrylate-substituted dihydrolipoic acid (DHLA) were spin-coated onto silicon substrates. The MPC units contributed biocompatibility and antifouling properties, and the DHLA units enabled cross-linking and the formation of robust thin films. Photolithography enabled the formation of 200-MUm wide poly(MPC-DHLA) stripped patterns that were characterized using atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and rhodamine 6G staining. Regardless of the spacing between poly(MPC-DHLA) stripes (10, 50, or 100 MUm), Escherichia coli rapidly adhered to the bare silicon gaps that lacked the copolymer, confirming the antifouling nature of MPC. Overall, this work provides a surface modification strategy for generating alternating biofouling and nonfouling surface structures that are potentially applicable for researchers studying cell biology, drug screening, and biosensor technology. PMID- 28617604 TI - Directional Emission from Dielectric Leaky-Wave Nanoantennas. AB - An important source of innovation in nanophotonics is the idea to scale down known radio wave technologies to the optical regime. One thoroughly investigated example of this approach are metallic nanoantennas which employ plasmonic resonances to couple localized emitters to selected far-field modes. While metals can be treated as perfect conductors in the microwave regime, their response becomes Drude-like at optical frequencies. Thus, plasmonic nanoantennas are inherently lossy. Moreover, their resonant nature requires precise control of the antenna geometry. A promising way to circumvent these problems is the use of broadband nanoantennas made from low-loss dielectric materials. Here, we report on highly directional emission from hybrid dielectric leaky-wave nanoantennas made of Hafnium dioxide nanostructures deposited on a glass substrate. Colloidal semiconductor quantum dots deposited in the nanoantenna feed gap serve as a local light source. The emission patterns of hybrid nanoantennas with different sizes are measured by Fourier imaging. We find for all antenna sizes a highly directional emission, underlining the broadband operation of our design. PMID- 28617605 TI - Arginine-Based Polymer Brush Coatings with Hydrolysis-Triggered Switchable Functionalities from Antimicrobial (Cationic) to Antifouling (Zwitterionic). AB - Arginine polymer based coatings with switchable properties were developed on glass slides (GS) to demonstrate the smart transition from antimicrobial (cationic) to fouling-resistant (zwitterionic) surfaces. l-Arginine methyl ester methacryloylamide (Arg-Est) and l-arginine-methacryloylamide (Arg-Me) polymer brushes were grafted from the GS surface via surface-initiated reversible addition-fragmentation chain-transfer (SI-RAFT) polymerization. In comparison to the pristine GS and Arg-Me graft polymerized GS (GS-Arg-Me) surfaces, the Arg-Est polymer brushes-functionalized GS surfaces exhibit a superior antimicrobial activity. Upon hydrolysis treatment, the strong bactericidal efficacy switches to good resistance to adsorption of bovine serum albumin (BSA), the adhesion of Gram positive bacteria Staphylococcus aureus and Gram-negative bacteria Escherichia coli, as well as the attachment of Amphora coffeaeformis. In addition, the switchable coatings are proven to be biocompatible. The stability and durability of the switchable coatings are also ascertained after exposure to filtered seawater for 30 days. Therefore, deposition of the proposed "smart coatings" offers another environmentally friendly alternative for combating biofouling. PMID- 28617606 TI - Rapid Three-Dimensional Printing in Water Using Semiconductor-Metal Hybrid Nanoparticles as Photoinitiators. AB - Additive manufacturing processes enable fabrication of complex and functional three-dimensional (3D) objects ranging from engine parts to artificial organs. Photopolymerization, which is the most versatile technology enabling such processes through 3D printing, utilizes photoinitiators that break into radicals upon light absorption. We report on a new family of photoinitiators for 3D printing based on hybrid semiconductor-metal nanoparticles. Unlike conventional photoinitiators that are consumed upon irradiation, these particles form radicals through a photocatalytic process. Light absorption by the semiconductor nanorod is followed by charge separation and electron transfer to the metal tip, enabling redox reactions to form radicals in aerobic conditions. In particular, we demonstrate their use in 3D printing in water, where they simultaneously form hydroxyl radicals for the polymerization and consume dissolved oxygen that is a known inhibitor. We also demonstrate their potential for two-photon polymerization due to their giant two-photon absorption cross section. PMID- 28617607 TI - Structural Transformations in Two-Dimensional Transition-Metal Dichalcogenide MoS2 under an Electron Beam: Insights from First-Principles Calculations. AB - The polymorphism of two-dimensional (2D) transition-metal dichalcogenides (TMDs) and different electronic properties of the polymorphs make TMDs particularly promising materials in the context of applications in electronics. Recently, local transformations from the semiconducting trigonal prismatic H phase to the metallic octahedral T phase in 2D MoS2 have been induced by electron irradiation [ Nat. Nanotech. 2014 , 9 , 391 ], but the mechanism of the transformations remains elusive. Using density functional theory calculations, we study the energetics of the stable and metastable phases of 2D MoS2 when additional charge, mechanical strain, and vacancies are present. We also investigate the role of finite temperatures, which appear to be critical for the transformations. On the basis of the results of our calculations, we propose an explanation for the beam induced transformations, which are likely promoted by charge redistribution in the monolayer due to electronic excitations combined with formation of vacancies under electron beam and buildup of the associated mechanical strain in the sample. As this mechanism should be relevant to other 2D TMDs, our results provide hints for further development and optimization of electron-beam-mediated engineering of the atomic structure and electronic properties of 2D TMDs with subnanometer resolution. PMID- 28617608 TI - Anti-Ice Nucleating Activity of Surfactants against Silver Iodide in Water-in-Oil Emulsions. AB - Various water-soluble substances are known as anti-ice nucleating agents (anti INAs), which inhibit heterogeneous ice nucleation initiated by ice nucleating agents (INAs). Among them, several surfactants are reportedly effective as anti INAs especially against silver iodide (AgI), which is a typical inorganic INA that induces heterogeneous ice nucleation at relatively high temperatures. In this study, the anti-ice nucleating activities of seven surfactants were examined in emulsified surfactant solutions containing AgI particles. Among previously reported anti-INAs (e.g., antifreeze proteins (AFPs), polyphenol compounds and synthetic polymers), a cationic surfactant used in this study, hexadecyltrimethylammonium bromide (C16TAB), showed the highest anti-ice nucleating activity against AgI. Based on the unique concentration-dependent dispersibility of AgI particles in C16TAB solution, the anti-ice nucleating activity of C16TAB must be caused by the adsorption of C16TAB molecules on AgI surfaces either as a monolayer or a bilayer depending on the C16TAB concentration. PMID- 28617609 TI - Transition-Metal-Free Photoinduced Intramolecular Annulation of 2,3 Di(hetero)arylchromen-4-one. AB - An efficient transition-metal-free photoinduced intracyclization of 4H-chromen-4 ones in EtOH-H2O (7:1, v/v) at ambient temperature for the construction of complicated fused-ring heteroaromatics is established. The reaction proceeds smoothly without requiring any catalysts/additives. PMID- 28617610 TI - Total Synthesis of the Cyclic Dodecapeptides Wewakazole and Wewakazole B. AB - The cyclic dodecapeptides wewakazole and wewakazole B have been synthesized by a divergent strategy via a common tris-proline containing oxazole octapeptide and two separate bis-oxazole containing tetrapeptide units, followed by peptide coupling and macrocyclization. The three oxazole amino acid fragments are readily accessible by rhodium(II)-catalyzed amide N-H insertion of diazocarbonyl compounds, or by the cycloaddition of rhodium carbenoids with nitriles. PMID- 28617611 TI - Palladium Catalyzed Arylation and Benzylation of Nitroarenes Using Aryl Sulfonates and Benzyl Acetates. AB - Pd-catalyzed arylation or benzylation of nitroazoles using aryl sulfonates or benzyl acetates is described. Electronically varied aryl tosylates and mesylates, as well as benzyl acetates, afford the arylated and benzylated products. Arylation of nitrobenzene is also reported. The relative rate for the arylation of halides is greater than that of tosylates using the reported reaction parameters. These studies enhance the scope of electrophiles for nitroarene arylations and benzylations, which was hitherto limited to the use of halide electrophiles. PMID- 28617612 TI - Effect of Urea on G-Quadruplex Stability. AB - G-quadruplexes represent a class of noncanonical nucleic acid structures implicated in transcriptional regulation, cellular function, and disease. An understanding of the forces involved in stabilization and destabilization of the G-quadruplex conformation relative to the duplex or single-stranded conformation is a key to elucidating the biological role of G-quadruplex-based genomic switches and the quest for therapeutic means for controlled induction or suppression of a G-quadruplex at selected genomic loci. Solute-solvent interactions provide a ubiquitous and, in many cases, the determining thermodynamic force in maintaining and modulating the stability of nucleic acids. These interactions involve water as well as water-soluble cosolvents that may be present in the solution or in the crowded environment in the cell. We present here the first quantitative investigation of the effect of urea, a destabilizing cosolvent, on the conformational preferences of a G-quadruplex formed by the telomeric d[A(G3T2A)3G3] sequence (Tel22). At 20 mM NaCl and room temperature, Tel22 undergoes a two-state urea-induced unfolding transition. An increase in salt mitigates the deleterious effect of urea on Tel22. The urea m-value of Tel22 normalized per change in solvent-accessible surface area, DeltaSA, is similar to those for other DNA and RNA structures while being several-fold larger than that of proteins. Our results suggest that urea can be employed as an analytical tool in thermodynamic characterizations of G-quadruplexes in a manner similar to the use of urea in protein studies. We emphasize the need for further studies involving a larger selection of G-quadruplexes varying in sequence, topology (parallel, antiparallel, hybrid), and molecularity (monomolecular, bimolecular, tetramolecular) to outline the advantages and the limits of the use of urea in G quadruplex studies. A deeper understanding of the effect of solvent and cosolvents on the differential stability of the G-quadruplex and duplex conformations is a step toward elucidation of the modulating influence of different types of cosolvents on duplex-G-quadruplex molecular switches triggering genomic events. PMID- 28617613 TI - Additions of Organomagnesium Halides to alpha-Alkoxy Ketones: Revision of the Chelation-Control Model. AB - The chelation-control model explains the high diastereoselectivity obtained in additions of organometallic nucleophiles to alpha-alkoxy ketones but fails for reactions of allylmagnesium halides. Low diastereoselectivity in ethereal solvents results from no chelation-induced rate acceleration. Additions of allylmagnesium bromide to carbonyl compounds are diastereoselective using CH2Cl2 as the solvent even though rate acceleration is still absent. Stereoselectivity likely arises from the predominance of the chelated form in solution. Therefore, a revised chelation-control model is proposed. PMID- 28617614 TI - Effects of background color and symbol arrangement cues on construction of multi symbol messages by young children without disabilities: implications for aided AAC design. AB - Children whose speech does not meet their communication needs often benefit from augmentative and alternative communication (AAC). The design of an AAC display may influence the child's ability to communicate effectively. The current study examined how symbol background color cues and symbol arrangement affected construction of multi-symbol messages using line-drawing symbols, by young children with typical development. Participants (N = 52) heard a spoken phrase matching a photograph and selected line drawings within a 4 * 4 array. Friedman two-way ANOVAs evaluated speed and accuracy of multi-symbol message construction under four conditions in which the background color and arrangement of symbols was manipulated. Participants demonstrated significantly faster response times when symbols were arranged by word-class category compared to no symbol arrangement. The majority of children responded faster when symbols had white backgrounds, but this effect failed to reach statistical significance. This study provides preliminary evidence suggesting the importance of symbol arrangement for young children. The findings highlight the need for caution when incorporating background color on displays for young children. Future research is needed to examine the effect of visual cues on children who use AAC and consider additional factors that could influence efficacy of symbol arrangement and background color use. PMID- 28617615 TI - Association between PNPLA3 gene polymorphisms and risk of hepatitis B virus related hepatocellular carcinoma in Han population in China:a case-control study. AB - BACKGROUND AND AIM: Several recent studies showed that the genetic polymorphisms in the PNPLA3 region (rs738408, rs738409, rs2294918, rs2294919 and rs2281135) were with related to various kinds of liver diseases. We analyzed the five single nucleotide polymorphisms (SNPs) for major HBV outcomes in Han Chinese. METHODS: A total of 2410 samples were involved and peripheral blood samples were collected in this study. The SNPs in the PNPLA3 region were genotyped by using Matrix assisted laser desorption/ionization time of flight mass spectrometry. RESULTS: Our study indicated the clear relationship between the PNPLA3 rs2294918, rs2294919 and HBV-related HCC after control for the effects of sex, drinking and smoking. Health subjects with the PNPLA3 rs2294919 TC genotype would have a 0.605 (95% CI: 0.413, 0.886; p = .010) times lower odds of having HCC, and those with the rs2294918 AG genotype would have a 1.872 (95% CI: 1.256, 2.792; p = .002) times higher odds of having HCC, whereas the values of sex, age, drinking and smoking were fixed. In addition, CA haplotype of the haplotype block of rs738409 and rs2281135 was also associated with HBV-related HCC. CONCLUSIONS: Our study suggested that PNPLA3 loci (rs2294918, rs2294919) were associated with HBV related HCC in Han Chinese. PMID- 28617616 TI - The Role of NrF2 in the Regulation of Periodontal Health and Disease. AB - Immune-related disease tolerance is an important defense strategy that facilitates the maintenance of health in organs and tissues that are commonly colonized by bacteria. Immune tolerance to dysbiotic, tooth-borne biofilms is a poorly understood yet clinically relevant concept in the immunopathological mechanisms that are involved in the pathogenesis of periodontitis, particularly those related to neutrophil and macrophage responses. In periodontal health, neutrophils and macrophages respond to the formation of pathogenic bacterial biofilms by the production of bactericidal reactive oxygen species (ROS). However, when released in excess, ROS cause tissue damage and exacerbate inflammation. To counter these destructive responses, many cell types, including neutrophils and macrophages, launch a dedicated antioxidant system that limits the cell and tissue-damaging effects of ROS. The expression of antioxidants is primarily regulated by genetic response elements in their promoters. Here we consider the roles of nuclear factor erythroid 2-related factor (NrF2), a transcription factor, and other key regulators of antioxidants. The concept of disease tolerance, neutrophil and macrophage-generated oxidative stress, and their relationship to the pathogenesis of periodontitis is reviewed. We focus on the regulation of NrF2 and recent evidence suggesting that NrF2 plays a central role in host protection against tissue destruction in periodontitis. PMID- 28617617 TI - Accuracy and User Performance Evaluation of a New, Wireless-enabled Blood Glucose Monitoring System That Links to a Smart Mobile Device. AB - BACKGROUND: The new Contour(r)Plus ONE blood glucose monitoring system (BGMS) features an easy-to-use, wireless-enabled blood glucose meter that links to a smart mobile device via Bluetooth(r) connectivity and can sync with the ContourTM Diabetes app on a smartphone or tablet. METHODS: The accuracy of the new BGMS was assessed in 2 studies according to ISO 15197:2013 criteria. In Study 1 (laboratory study), fingertip capillary blood samples from 100 subjects were tested in duplicate using 3 test strip lots. In Study 2 (clinical study), 134 subjects with type 1 or type 2 diabetes enrolled at 2 clinical sites. BGMS results and YSI analyzer (YSI) reference results were compared for fingertip blood obtained by untrained subjects' self-testing and for study staff-obtained fingertip, subject palm, and venous results. RESULTS: In Study 1, 99.0% (594/600) of combined results for all 3 test strip lots fulfilled ISO 15197:2013 Section 6.3 accuracy criteria. In Study 2, 99.2% (133/134) of subject-obtained capillary fingertip results, 99.2% (133/134) of study staff-obtained fingertip results, 99.2% (125/126) of subject-obtained palm results, and 100% (132/132) of study staff-obtained venous results met ISO 15197:2013 Section 8 accuracy criteria. Moreover, 95.5% (128/134) of subject-obtained fingertip self-test results were within +/-10 mg/dl (+/-0.6 mmol/L) or +/-10% of the YSI reference result. Questionnaire results showed that most subjects found the BGMS easy to use. CONCLUSIONS: The BGMS exceeded ISO 15197:2013 accuracy criteria both in the laboratory and in a clinical setting when used by untrained subjects with diabetes. PMID- 28617618 TI - Value-Based Calculators in Cancer: Current State and Challenges. AB - The ASCO Value Framework, National Comprehensive Cancer Network Evidence Blocks, Memorial Sloan Kettering's DrugAbacus, and Institute for Clinical and Economic Review incremental cost-effectiveness ratio calculator are value-based methodologies that attempt to address the disproportionate increase in cancer care spending. These calculators can be used as an initial step for discussing cost versus value, but they fall short in recognizing the importance of the cancer journey because they do not fully factor the patient's perspective or the global cost of care. This timely review highlights both the limitations and the advantages of each value calculator and suggests opportunities for refinement. Practicing oncologists, payers, and manufacturers should be familiar with value based calculators because the role these tools play in cost containment is likely to be hotly debated. PMID- 28617619 TI - Early Functional Outcomes of Periacetabular Osteotomy After Failed Hip Arthroscopic Surgery for Symptomatic Acetabular Dysplasia. AB - BACKGROUND: Persistent acetabular dysplasia is a common reason for the failure of hip arthroscopic surgery; however, the effect of prior hip arthroscopic surgery on functional outcomes after subsequent periacetabular osteotomy (PAO) is unknown. Hypothesis/Purpose: The purpose of this study was to (1) compare demographic and radiological findings in patients who had and had not undergone previous hip arthroscopic surgery before PAO for symptomatic acetabular dysplasia and (2) compare the short-term, hip-specific patient-reported outcomes in these same patient populations. It was hypothesized that prior hip arthroscopic surgery is associated with worse early functional outcomes in PAO. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective cohort study design was utilized. Patients undergoing PAO were enrolled from a single-center, prospective hip preservation registry from March 2011 to April 2015. Patients with a minimum of 1-year clinical follow-up with preoperative and postoperative outcome scores undergoing PAO were eligible for inclusion (n = 93 patients; mean clinical follow up, 24 months [range, 11-58 months]). The study group consisted of patients undergoing PAO for symptomatic hip dysplasia after prior hip arthroscopic surgery (PREVSCOPE group; 22 patients, 25 hips). Patients undergoing PAO without prior hip arthroscopic surgery (PAOALONE group; 71 patients, 85 hips) were included as a comparison group. Demographic and radiological variables were recorded. Postoperative functional outcome scores (modified Harris Hip Score [mHHS], Hip Outcome Score [HOS], and International Hip Outcome Tool [iHOT-33]) were recorded at 6 months and annually postoperatively. RESULTS: There were no demographic differences between the 2 groups at baseline. Acetabular version, femoral version, Tonnis grade, preoperative lateral center edge angle, and intraoperative procedures were not different between the 2 groups. At 1-year follow-up from the last hip surgical procedure, the mean (+/-SD) mHHS (73 +/- 14 vs 86 +/- 14, respectively; P < .001), HOS-Activities of Daily Living (84 +/- 12 vs 93 +/- 11, respectively; P = .007), HOS-Sport (62 +/- 25 vs 85 +/- 18, respectively; P < .001), and iHOT-33 (62 +/- 21 vs 79 +/- 20, respectively; P = .004) were decreased in the PREVSCOPE group versus the PAOALONE group. At last follow-up (mean, 18 months from the last hip surgical procedure), the mHHS and HOS-Sport were lower in the PREVSCOPE group versus the PAOALONE group. There was no difference in complication or reoperation rates between the 2 groups. CONCLUSION: Failed hip arthroscopic surgery before PAO for symptomatic hip dysplasia is associated with lower hip-specific functional outcomes within the first 1 year of follow-up despite similar baseline demographic and radiological characteristics. These differences persisted in certain outcome scores (mHHS, HOS-Sport) at last follow-up but were less pronounced than at 1 year. PMID- 28617620 TI - Atrial fibrillation and the risk for myocardial infarction, all-cause mortality and heart failure: A systematic review and meta-analysis. AB - Background In contemporary atrial fibrillation trials most deaths are cardiac related, whereas stroke and bleeding represent only a small subset of deaths. We aimed to evaluate the long-term risk of cardiac events and all-cause mortality in individuals with atrial fibrillation compared to no atrial fibrillation. Design A systematic review and meta-analysis of studies published between 1 January 2006 and 21 October 2016. Methods Four databases were searched. Studies had follow-up of at least 500 stable patients for either cardiac endpoints or all-cause mortality for 12 months or longer. Publication bias was evaluated and random effects models were used to synthesise the results. Heterogeneity between studies was examined by subgroup and meta-regression analyses. Results A total of 15 cohort studies was included. Analyses indicated that atrial fibrillation was associated with an increased risk of myocardial infarction (relative risk (RR) 1.54, 95% confidence interval (CI) 1.26-1.85), all-cause mortality (RR 1.95, 95% CI 1.50-2.54) and heart failure (RR 4.62, 95% CI 3.13-6.83). Coronary heart disease at baseline was associated with a reduced risk of myocardial infarction and explained 57% of the heterogeneity. A prospective cohort design accounted for 25% of all-cause mortality heterogeneity. Due to there being fewer than 10 studies, sources of heterogeneity were inconclusive for heart failure. Conclusions Atrial fibrillation seems to be associated with an increased risk of subsequent myocardial infarction in patients without coronary heart disease and an increased risk of, all-cause mortality and heart failure in patients with and without coronary heart disease. PMID- 28617621 TI - The ESMO-Magnitude of Clinical Benefit Scale for novel oncology drugs: correspondence with three years of reimbursement decisions in Israel. AB - BACKGROUND: The European Society for Medical Oncology published in 2015 its Magnitude of Clinical Benefit Scale (ESMO-MCBS) for cancer medicines. Our objective was to evaluate the association between Israel's national reimbursement decisions regarding novel cancer drugs, prior to the availability of ESMO-MCBS, and the later published ESMO-MCBS scores. RESEARCH DESIGN AND METHODS: ESMO-MCBS scores were obtained retrospectively for the cancer drugs that were candidates for reimbursement in Israel in 2013-2015 and were categorized to 'highest benefit' (ESMO-MCBS 4-5 or A) 'medium benefit' (3 or B) and 'lowest benefit' (0-2 or C). The reimbursement decisions were accessed and compared with the categorized ESMO scores. RESULTS: ESMO-MCBS score was available for 19/22 drugs approved for reimbursement and 15/16 non-approved drugs. 58% of the approved drugs gained a 'highest benefit' score and 37% were 'medium benefit'. 87% of the non-approved drugs had 'lowest benefit' scores. Median score for approved drugs was 4 vs. 1 for the non-approved (p < 0.05). CONCLUSIONS: The Israeli decisions regarding reimbursement of novel cancer drugs, demonstrated concordance with ESMO MCBS scores. Incorporation of ESMO-MCBS data in reimbursement deliberations could assist in framing the appropriate use of the limited resources to deliver effective and affordable cancer care. PMID- 28617622 TI - Treatment and Communication-That Is What Matters: An Analysis of Complaints Regarding End-of-Life Care. AB - BACKGROUND: Investigating complaints concerning end-of-life (EoL) care is a necessary step for improving the quality of life at its final stage. OBJECTIVE: We aimed to classify and quantify the aspects of EoL care that require improvement by analyzing caregivers' feedback on the care their relatives received before death. DESIGN: A survey of primary family caregivers of deceased patients. SETTING/SUBJECTS: Relatives of decedents were recruited through two geriatric medical centers and from persons contacted for other studies, who reported losing a relative. Face-to-face interviews of 70 relatives of the deceased were conducted. The participants' mean age was 64, 68.6% were female, and most (57%) were born in Israel. Regarding relationship to the deceased, 74.3% were sons/daughters, 24.3% were spouses, and one (1.4%) was a cousin. MEASURES: Responses to the question "Is there something in the health system or the behavior of the doctors/nurses that you would recommend changing?" were analyzed qualitatively. RESULTS: 82.9% of participants had complaints about the care received. Within this, 62.9% related to provision of services, 51.4% to communication, 27.1% to system issues, 15.7% to institutional issues, and 10.0% to staffing issues. Qualitative analysis revealed potential causal relationships between these EoL issues. We therefore propose a theoretical model involving the distal factors of system, institution, and staff that impact the proximal factors of provision of services and communication. CONCLUSION: The new model has the potential to clarify directions in research, quality assessment, and intervention regarding end-of-life care. PMID- 28617623 TI - Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival. AB - Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors. PMID- 28617624 TI - How Satisfied Are Patients When Their Choice of Funded Glucose Meter Is Restricted to a Single Brand? AB - BACKGROUND: Many governments and insurers are driving down the cost of medical devices, including glucose meters, by the central management of purchasing decisions. We report patients' responses to an "enforced" change in brand of glucose meter, one year after the introduction of a national sole supplier arrangement for funded glucose meters and strips. METHOD: Specialist diabetes clinic attendees from two geographical locations completed a questionnaire one year after the final meter changeover date. In the first location, consecutive patients were asked to complete a glucose meter satisfaction questionnaire during their clinic visit. In the second location, this questionnaire was mailed to clinic attendees. Responses to open questions were analyzed thematically. RESULTS: Response rates were 85% and 31% from the first and second locations, respectively and 378 questionnaires were suitable for analysis, 309 from the first and 69 from the second location. Insulin users composed 90% of participants. Results from the two locations were broadly similar. Most participants adapted well to the changeover, however 36% reported ongoing dissatisfaction with their "new" meter. The commonest concern, expressed by 23% of participants, related to meter accuracy and precision. CONCLUSIONS: One year after glucose meter changeover, a third of participants expressed dissatisfaction with their meter, with many participants describing a failure to adapt to the sole supplier arrangement. Providing a choice of meters and strips, ideally from two or more brands that have demonstrable differences in technical and ergonomic features, is likely to produce higher overall patient satisfaction than is a sole supplier arrangement. PMID- 28617626 TI - Understanding the rules governing NCX1 palmitoylation. PMID- 28617627 TI - Effect of position, time in the season, and playing surface on Achilles tendon ruptures in NFL games: a 2009-10 to 2016-17 review. AB - OBJECTIVES: Achilles tendon (AT) ruptures are a potentially career-altering and ending injury. Achilles tendon ruptures have a below average return-to-play rate compared to other common orthopaedic procedures for National Football League (NFL) players. The objective of this study was to monitor the incidence and injury rates (IR) of AT ruptures that occurred during the regular season in order to evaluate the influence of player position, time of injury, and playing surface on rupture rates. METHODS: A thorough online review was completed to identify published injury reports and public information regarding AT ruptures sustained during regular season and post-season games in the National Football League (NFL) during the 2009-10 to 2016-17 seasons. Team schedules, player position details and stadium information was used to determine period of the season of injury and playing surface. IRs were calculated per 100 team games (TG). Injury rate ratios (IRR) were utilized to compare IRs. RESULTS: During eight monitored seasons, there were 44 AT ruptures in NFL games. A majority of AT ruptures were sustained in the first eight games of the regular season (n = 32, 72.7%). There was a significant rate difference for the first and second four-game segments of the regular season compared to the last two four-game segments of the regular season. Defensive players suffered a majority of AT ruptures (n = 32, 72.7%). The IR on grass was 1.00 per 100 TG compared to 1.08 per 100 TG on artificial turf (IRR: 0.93, p = .80). CONCLUSION: A significant increase in AT ruptures occurred in the first and second four game segments of the regular season compared to the last two-four game segments of the regular season. Defensive players suffered a majority of AT ruptures compared to offensive or specialist players. There was no difference between AT rupture rates and playing surface in games. PMID- 28617628 TI - Pilot Study of a Novel Application for Data Visualization in Type 1 Diabetes. AB - BACKGROUND: A novel software application, Blip, was created to combine and display diabetes data from multiple devices in a uniform, user-friendly manner. The objective of this study was to test the usability of this application by adults and caregivers of children with type 1 diabetes (T1D). METHODS: Patients (n = 35) and caregivers of children with T1D (n = 30) using an insulin pump for >1 year +/- CGM were given access to the software for 3 months. Diabetes management practices and the use of diabetes data were assessed at baseline and at study end, and feedback was gathered in a concluding questionnaire. RESULTS: At baseline, 97% of participants agreed it was important for patients to know how to interpret glucose data. Most felt that clinicians and patients should share the tasks of reviewing data, finding patterns, and making changes to their insulin plans. However, despite valuing shared responsibility, at baseline, 43% of participants never downloaded pump data, and only 9% did so at least once per month. At study end, 72% downloaded data at least once during the 3-month study, and 38% downloaded at least once per month. Regarding the software application, participants liked the central repository of data and the user interface. Suggestions included providing tools for understanding and interpreting glucose patterns, an easier uploading process, and access with mobile devices. CONCLUSIONS: Collaboration between developers and researchers prompted iterative, rapid development of data visualization software and improvements in the uploading process and user interface, which facilitates clinical integration and future clinical studies. PMID- 28617629 TI - Bio-extract-mediated ZnO nanoparticles: microwave-assisted synthesis, characterization and antidiabetic activity evaluation. AB - Herein, ZnO nanoparticles were synthesized using microwave-assisted method in the presence of Vaccinium arctostaphylos L, fruits extract. The structure, size, morphology and optical properties of the samples were characterized by XRD, SEM, TEM, EDX, FT-IR, UV-vis DRS and TGA analysis. A decrease in crystallite size was observed for the biologically synthesized ZnO compared to the chemically synthesized sample. Furthermore, the existence of organic moieties over the biologically synthesized ZnO NPs was approved using characterizing methods. Then, the alloxan-induced diabetic rats were divided into not treated (diabetic control group), and the groups received: insulin, chemically synthesized ZnO, plant extract, biologically synthesized ZnO with a normal healthy control group. After treatment, fasting blood glucose (FBS), high-density lipoprotein (HDL), total triglyceride (TG), total cholesterol (TC) and insulin were measured. Analysis showed a significant decrease in FBS and increase in HDL levels in all groups under treatment. However, the results for cholesterol reduction were only significant for the group treated by biologically synthesized ZnO. Despite the changes in the triglyceride and insulin levels, the results were not significant. For all the studied parameters, bio-mediated ZnO NPs were found the most effective in treating the alloxan-diabetic rats compared to the other studied treatment agents. PMID- 28617630 TI - The cutting edge of platelets. PMID- 28617631 TI - Sixty-Five Million Years of Change in Temperature and Topography Explain Evolutionary History in Eastern North American Plethodontid Salamanders. AB - For many taxa and systems, species richness peaks at midelevations. One potential explanation for this pattern is that large-scale changes in climate and geography have, over evolutionary time, selected for traits that are favored under conditions found in contemporary midelevation regions. To test this hypothesis, we use records of historical temperature and topographic changes over the past 65 Myr to construct a general simulation model of plethodontid salamander evolution in eastern North America. We then explore possible mechanisms constraining species to midelevation bands by using the model to predict plethodontid evolutionary history and contemporary geographic distributions. Our results show that models that incorporate both temperature and topographic changes are better able to predict these patterns, suggesting that both processes may have played an important role in driving plethodontid evolution in the region. Additionally, our model (whose annotated source code is included as a supplement) represents a proof of concept to encourage future work that takes advantage of recent advances in computing power to combine models of ecology, evolution, and earth history to better explain the abundance and distribution of species over time. PMID- 28617632 TI - Evolutionary Determinants of Morphological Polymorphism in Colonial Animals. AB - Colonial animals commonly exhibit morphologically polymorphic modular units that are phenotypically distinct and specialize in specific functional tasks. But how and why these polymorphic modules have evolved is poorly understood. Across colonial invertebrates, there is wide variation in the degree of polymorphism, from none in colonial ascidians to extreme polymorphism in siphonophores, such as the Portuguese man-of-war. Bryozoa are a phylum of exclusively colonial invertebrates that uniquely exhibit almost the entire range of polymorphism, from monomorphic species to others that rival siphonophores in their polymorphic complexity. Previous approaches to understanding the evolution of polymorphism have been based on analyses of (1) the functional role of polymorphs or (2) presumed evolutionary costs and benefits based on evolutionary theory that postulates polymorphism should be evolutionarily sustainable only in more stable environments because polymorphism commonly leads to the loss of feeding and sexual competence. Here we use bryozoans from opposite shores of the Isthmus of Panama to revisit the environmental hypothesis by comparison of faunas from distinct oceanographic provinces that differ greatly in environmental variability, and we then examine the correlations between the extent of polymorphism in relation to patterns of ecological succession and variation in life histories. We find no support for the environmental hypothesis. Distributions of the incidence of polymorphism in the oceanographically unstable Eastern Pacific are indistinguishable from those in the more stable Caribbean. In contrast, the temporal position of species in a successional sequence is collinear with the degree of polymorphism because species with fewer types of polymorphs are competitively replaced by species with higher numbers of polymorphs on the same substrata. Competitively dominant species also exhibit patterns of growth that increase their competitive ability. The association between degrees of polymorphism and variations in life histories is fundamental to understanding of the macroevolution of polymorphism. PMID- 28617633 TI - When Predators Help Prey Adapt and Persist in a Changing Environment. AB - To persist in a changing world, populations must adapt. The ability to adapt is influenced by interactions with other species, such as predators. Recent experiments and theory suggest that selective pressures arising from predation may help prey adapt phenotypically to changing environments, but how this influences persistence remains unclear. In particular, it has not yet been shown whether predator-induced adaptation can outweigh predator-imposed reductions in population size, allowing prey to persist when they would otherwise go extinct. Here we examine if (and if so, how) predation can enhance the ability of prey to persist in a directionally changing environment. To do so, we extend a single species quantitative-genetics framework that predicts rates of environmental change beyond which populations go extinct. While we assume predation decreases prey density, we find that predators can indeed help prey persist if they sufficiently increase prey adaptedness (decrease phenotypic lag). We show two ways this can occur: (1) the selective push, in which predators consume maladapted individuals and thus add selection that pushes the mean prey trait toward its optimum; and (2) the evolutionary hydra effect, when predation reduces prey density and thereby increases prey birthrate, allowing more selective events per unit time and effectively reducing generation time. We also discuss how our results apply more broadly to sources of mortality beyond predation. PMID- 28617634 TI - Dramatic Fighting by Male Cuttlefish for a Female Mate. AB - Male cuttlefish compete for females with a repertoire of visually dramatic behaviors. Laboratory experiments have explored this system in Sepia officinalis, but corroborative field data have eluded collection attempts by many researchers. While scuba diving in Turkey, we fortuitously filmed an intense sequence of consort/intruder behaviors in which the consort lost and then regained his female mate from the intruder. These agonistic bouts escalated in stages, leading to fast dramatic expression of the elaborate intense zebra display and culminating in biting and inking as the intruder male attempted a forced copulation of the female. When analyzed in the context of game theory, the patterns of fighting behavior were more consistent with mutual assessment than self-assessment of fighting ability. Additional observations of these behaviors in nature are needed to conclusively determine which models best represent conflict resolution, but our field observations agree with laboratory findings and provide a valuable perspective. PMID- 28617635 TI - Unexpected Nongenetic Individual Heterogeneity and Trait Covariance in Daphnia and Its Consequences for Ecological and Evolutionary Dynamics. AB - Individual differences in genetics, age, or environment can cause tremendous differences in individual life-history traits. This individual heterogeneity generates demographic heterogeneity at the population level, which is predicted to have a strong impact on both ecological and evolutionary dynamics. However, we know surprisingly little about the sources of individual heterogeneity for particular taxa or how different sources scale up to impact ecological and evolutionary dynamics. Here we experimentally study the individual heterogeneity that emerges from both genetic and nongenetic sources in a species of freshwater zooplankton across a large gradient of food quality. Despite the tight control of environment, we still find that the variation from nongenetic sources is greater than that from genetic sources over a wide range of food quality and that this variation has strong positive covariance between growth and reproduction. We evaluate the general consequences of genetic and nongenetic covariance for ecological and evolutionary dynamics theoretically and find that increasing nongenetic variation slows evolution independent of the correlation in heritable life-history traits but that the impact on ecological dynamics depends on both nongenetic and genetic covariance. Our results demonstrate that variation in the relative magnitude of nongenetic versus genetic sources of variation impacts the predicted ecological and evolutionary dynamics. PMID- 28617636 TI - A Sea Scorpion's Strike: New Evidence of Extreme Lateral Flexibility in the Opisthosoma of Eurypterids. AB - Among the largest and most abundant aquatic predators during much of the early evolution of vertebrates, eurypterids have long been an iconic and intensely studied group of Paleozoic arthropods. We report a new specimen of the eurypterid Slimonia acuminata, which includes a fully articulated series of tail (postabdominal and telsonal) segments preserved in a tight lateral curve. Such a high degree of apparent lateral tail flexibility has not been previously recognized in eurypterids. From the perspective of hydrodynamics, the dorsoventrally flattened body plan of eurypterids would have limited the effectiveness of lateral tail motion as a means of propulsion. However, the long and serrated terminal tail spine of S. acuminata (and other eurypterids) would have made lateral tail strikes-which would have met a minimum of hydraulic resistance-an effective means of predatory attack and self-defense. Thus, many eurypterids are reinterpreted as substantially better-armed predators than previously supposed. PMID- 28617637 TI - How Parallel Is Parallel Evolution? A Comparative Analysis in Fishes. AB - Evidence of phenotypic parallelism is often used to infer the deterministic role played by natural selection. However, variation in the extent or direction of divergence is often evident among independent evolutionary replicates, raising the following question: just how parallel, overall, is parallel evolution? We answer this question through a comparative analysis of studies of fishes, a taxon where parallel evolution has been much discussed. We first ask how much of the among-population variance in phenotypic traits can be explained by different "environment" types, such as high predation versus low predation or benthic versus limnetic. We then use phenotypic change vector analysis to quantify variation in the direction (vector angles) and magnitude (vector lengths) of environment-associated divergence. All analyses show high variation in the extent of parallelism-from very high to very low, along with everything in between highlighting the importance of quantifying parallelism rather than just asserting its presence. Interestingly, instances of low extents of parallelism represent important components of divergence in many cases, promising considerable opportunities for inferences about the factors shaping phenotypic divergence. PMID- 28617638 TI - Frontispiece (1929). PMID- 28617639 TI - Genetic Correlations among Developmental and Contextual Behavioral Plasticity in Drosophila melanogaster. AB - Correlations among traits, including behaviors, are important because traits that are genetically correlated may not evolve independently. Recently, behavioral correlations research has expanded to include correlations not only in mean-level behaviors but also in behavioral plasticity, that is, the degree to which individuals change their behavior in response to environmental stimuli. Positive correlations among behavioral plasticities would imply that individuals or genotypes that are behaviorally plastic in one way may also be plastic in other ways; negative correlations could imply trade-offs. Here, we examine aversive odor conditioning (learning) at two time points and plasticity in pupation site selection behavior across substrates in a panel of Drosophila genotypes. These behaviors represent different types of behavioral plasticity: contextual plasticity describes behavioral responses to stimuli that are currently present, while developmental plasticity describes behavioral responses to remembered experiences with stimuli in the recent past. We find that learning scores and plasticity in pupation site selection behavior are positively genetically correlated, representing the first example of a genetic correlation between developmental and contextual plasticity. These findings imply that ecological and evolutionary theories focusing on variation in a single dimension of behavioral plasticity may be incomplete. PMID- 28617640 TI - Microhabitat and Climatic Niche Change Explain Patterns of Diversification among Frog Families. AB - A major goal of ecology and evolutionary biology is to explain patterns of species richness among clades. Differences in rates of net diversification (speciation minus extinction over time) may often explain these patterns, but the factors that drive variation in diversification rates remain uncertain. Three important candidates are climatic niche position (e.g., whether clades are primarily temperate or tropical), rates of climatic niche change among species within clades, and microhabitat (e.g., aquatic, terrestrial, arboreal). The first two factors have been tested separately in several studies, but the relative importance of all three is largely unknown. Here we explore the correlates of diversification among families of frogs, which collectively represent ~88% of amphibian species. We assemble and analyze data on phylogeny, climate, and microhabitat for thousands of species. We find that the best-fitting phylogenetic multiple regression model includes all three types of variables: microhabitat, rates of climatic niche change, and climatic niche position. This model explains 67% of the variation in diversification rates among frog families, with arboreal microhabitat explaining ~31%, niche rates ~25%, and climatic niche position ~11%. Surprisingly, we show that microhabitat can have a much stronger influence on diversification than climatic niche position or rates of climatic niche change. PMID- 28617641 TI - Decreasing Stoichiometric Resource Quality Drives Compensatory Feeding across Trophic Levels in Tropical Litter Invertebrate Communities. AB - Living organisms are constrained by both resource quantity and quality. Ecological stoichiometry offers important insights into how the elemental composition of resources affects their consumers. If resource quality decreases, consumers can respond by shifting their body stoichiometry, avoiding low-quality resources, or up-regulating feeding rates to maintain the supply of required elements while excreting excess carbon (i.e., compensatory feeding). We analyzed multitrophic consumer body stoichiometry, biomass, and feeding rates along a resource-quality gradient in the litter of tropical forest and rubber and oil palm plantations. Specifically, we calculated macroinvertebrate feeding rates based on consumer metabolic demand and assimilation efficiency. Using linear mixed effects models, we assessed resource-quality effects on macroinvertebrate detritivore and predator communities. We did not detect shifts in consumer body stoichiometry or decreases in consumer biomass in response to declining resource quality, as indicated by increasing carbon-to-nitrogen ratios. However, across trophic levels, we found a strong indication of decreasing resource quality leading to increased consumer feeding rates through altered assimilation efficiency and community body size structure. Our study reveals the influence of resource quality on multitrophic consumer feeding rates and suggests compensatory feeding to be more common across consumer trophic levels than was formerly known. PMID- 28617642 TI - Extinction Risk and Lack of Evolutionary Rescue under Resource Depletion or Area Reduction. AB - Evolutionary adaptations following environmental deterioration can sometimes rescue populations from extinction. Here we provide a scenario in which such evolutionary rescue will be difficult. Using a rather general model for fluctuating r- and K-selection in a density-dependent population, we show that reduction of available resources will not necessarily induce evolution of adaptations to counteract such changes provided that density regulation acts through available resources per individual. In large populations, resource depletion may induce a change in stationary distribution of population size while the optimal phenotype remains unchanged. Under a period of continuous reduction in available resources, increased strength of K-selection will occur in the sense that individuals are able to live and reproduce under less favorable conditions. Smaller growth rates as a consequence of K-selection and trade-offs between intrinsic growth rate r and carrying capacity K may then have a considerable negative effect on the persistence of the population even after the reduction of available resources is stopped. This negative effect comes in addition to the purely ecological effect of reduced time to extinction because of a reduction in K and increased demographic stochasticity. Continuous reduction in the available area or in available resources per individual may result in long-run maladaptation even if demographic noise increases and, finally but too late, induces r-selection. PMID- 28617643 TI - Network Structure and Selection Asymmetry Drive Coevolution in Species-Rich Antagonistic Interactions. AB - Ecological interactions shape and are shaped by the evolution of interacting species. Mathematical models and empirical work have explored the multiple ways coevolution could occur in small sets of species, revealing that the addition of even one species can change the coevolutionary dynamics of a pairwise interaction. As a consequence, one of the current challenges in evolutionary biology is to understand how species-rich assemblages evolve and coevolve as networks of interacting species. We combined an adaptive network framework, a trait evolutionary model, and data on network structure to study how network organization affects and is affected by selection in antagonistic interactions such as parasitism, predation, and herbivory. We explored how selection imposed by interactions shapes the evolution of attack and defense traits, parameterizing our models with structural information from 31 empirical assemblages of antagonistic species. In the simulations, the form of coevolution in antagonistic interactions is affected by the intensity and asymmetry of the selection imposed by the interacting partners. Transient escalation in attack and defensive traits was the most prevalent form of coevolutionary dynamics, especially in networks formed by modules of highly interacting species. Fluctuating evolution of traits was observed when the intensity of selection was higher in exploiters than in victims and was especially favored in nested networks. At the species level, highly connected species experienced higher temporal variation in selection regardless of the network structure, resulting in high trait mismatching with their partners. The mismatched patterns of highly connected species, in turn, may explain the emergence of modularity in antagonistic interactions in which selection is stronger on exploiters than on their victims. Our results highlight the roles of different aspects of network structure on antagonistic coevolution: nestedness shapes coevolutionary dynamics, whereas modularity emerges as one outcome of coevolutionary dynamics. PMID- 28617644 TI - A Parent-Offspring Trade-Off Limits the Evolution of an Ontogenetic Niche Shift. AB - Many free-living animal species, including the majority of fish, insects, and amphibians, change their food and habitat during their life. Even though these ontogenetic changes in niche are common, it is not well understood which ecological conditions have favored the evolution of these shifts. Using an adaptive dynamics approach, we show that it is evolutionarily advantageous to switch to an alternative food source in the course of ontogeny when this results in a higher intake rate for the switching consumers. Individuals are, however, not able to specialize on this new food source when this negatively affects the performance early in life on the original food source. Selection on these early life stages is so strong that in species with a complete diet shift, evolution results in large juveniles and adults that are maladapted to the alternative food source while their offspring are specialized on the original food source when young. These outcomes suggest strong selection to decouple the different life stages, such that they can maximize their performance on different food sources independently from each other. Metamorphosis could be a way to decouple the different life stages and therefore evolve in species that feed on multiple food sources during their life. PMID- 28617645 TI - The Implications of Eco-Evolutionary Processes for the Emergence of Marine Plankton Community Biogeography. AB - Models of community assembly have been used to illustrate how the many functionally diverse species that compose plankton food webs can coexist. However, the evolutionary processes leading to the emergence of plankton food webs and their interplay with migratory processes and spatial heterogeneity are yet to be explored. We study the eco-evolutionary dynamics of a modeled plankton community structured in both size and space and physiologically constrained by empirical data. We demonstrate that a complex yet ecologically and evolutionarily stable size-structured food web can emerge from an initial set of two monomorphic phytoplankton and zooplankton populations. We also show that the coupling of spatial heterogeneity and migration results in the emergence of specific biogeographic patterns: (i) the emergence of a source-sink structure of the plankton metacommunities, (ii) changes in size diversity dependent on migratory intensity and on the scale at which diversity is considered (local vs. global), and (iii) the emergence of eco-evolutionary provinces (i.e., a spatial unit characterized by some level of abiotic heterogeneity but of homogenous size composition due to horizontal movements) at spatial scales that increase with the strength of the migratory processes. PMID- 28617647 TI - Lymphatic Endothelial Cells: Mechanical Stress, Cytokines, Fibrosis, and Age. PMID- 28617648 TI - Increasing Morbidity with Extent of Lymphadenectomy for Primary Malignant Melanoma. AB - BACKGROUND: According to current guidelines, complete lymphadenectomy (LAD) is indicated in melanoma patients with a positive sentinel lymph node. Whereas there is little evidence from randomized trials for a survival benefit of this procedure, its morbidity is not trivial. We aimed to assess clinical associations between risk factors and complications of LAD to guide decision making about this aspect of melanoma management. METHODS AND RESULTS: A cohort of 174 patients who had undergone LAD for primary melanoma was retrospectively analyzed, and multivariable logistic regression models were used to correlate patient risk factors, tumor characteristics, number of excised lymph nodes, and procedural details with the incidence of complications. The overall rate of LAD-associated complications was 41.4%, 33.9% being lymphatic complications. The number of excised lymph nodes was independently associated with development of lymphatic complications (odds ratio 3.90/12.78 if more than 10/20 lymph nodes had been removed, p = 0.01/<0.001, respectively). However, the number of excised lymph nodes had no influence on overall survival using a multivariable Cox proportional hazards regression analysis. CONCLUSIONS: In this retrospective cohort study, an important association was found between the extent of LAD and lymphatic complications. Further studies should evaluate the necessity and extent of aggressive LAD to balance survival benefit with morbidity of LAD procedures. PMID- 28617649 TI - Correlation Between the Severity of Subcutaneous Echo-Free Space and the Amount of Extracellular Fluid Determined by Bioelectrical Impedance Analysis of Leg Edema. AB - BACKGROUND: Both subcutaneous echo-free space (SEFS) observed by ultrasonography and the ratio of intracellular fluid resistance to extracellular fluid resistance (Ri/Re) calculated from bioelectrical impedance analysis (BIA) represent extracellular edema status in the extremities. We tried to correlate these parameters. METHODS AND RESULTS: In 70 legs with venous edema (VE) and 68 legs with lymphedema (LE), subcutaneous tissue ultrasonography to determine SEFS severity (range, 0-2) and BIA to calculate Ri/Re were performed. In the calf, SEFS severity showed good linear correlation with Ri/Re, particularly in the lower lateral calf where the mean Ri/Re for LE (SEFS grade 0: 3.2 +/- 0.8; SEFS grade 1: 4.0 +/- 0.9; SEFS grade 2: 6.3 +/- 3.6) and VE (SEFS grade 0: 3.6 +/- 0.6; SEFS grade 1: 4.4 +/- 1.6; SEFS grade 2: 5.3 +/- 2.0) was similar. In the thigh, a mild correlation was confirmed only in LE. CONCLUSIONS: It may be concluded that SEFS in the lower calf area well represents the local fluid status regardless of the type of edema, but not so in the thigh. PMID- 28617651 TI - Microbiota-Based Therapies for Clostridium difficile and Antibiotic-Resistant Enteric Infections. AB - Bacterial pathogens are increasingly antibiotic resistant, and development of clinically effective antibiotics is lagging. Curing infections increasingly requires antimicrobials that are broader spectrum, more toxic, and more expensive, and mortality attributable to antibiotic-resistant pathogens is rising. The commensal microbiota, comprising microbes that colonize the mammalian gastrointestinal tract, can provide high levels of resistance to infection, and the contributions of specific bacterial species to resistance are being discovered and characterized. Microbiota-mediated mechanisms of colonization resistance and pathogen clearance include bactericidal activity, nutrient depletion, immune activation, and manipulation of the gut's chemical environment. Current research is focusing on development of microbiota-based therapies to reduce intestinal colonization with antibiotic-resistant pathogens, with the goal of reducing pathogen transmission and systemic dissemination. PMID- 28617652 TI - A comparative evaluation of in-vehicle side view displays layouts in critical lane changing situation. AB - This study conducted a driving simulator experiment to comparatively evaluate three in-vehicle side view displays layouts for camera monitor systems (CMS) and the traditional side view mirror arrangement. The three layouts placed two electronic side view displays near the traditional mirrors positions, on the dashboard at each side of the steering wheel and on the centre fascia with the two displays joined side-by-side, respectively. Twenty-two participants performed a time- and safety-critical driving task that required rapidly gaining situation awareness through the side view displays/mirrors and making a lane change to avoid collision. The dependent variables were eye-off-the-road time, response time, and, ratings of perceived workload, preference and perceived safety. Overall, the layout placing the side view displays on the dashboard at each side of the steering wheel was found to be the best. The results indicated that reducing eye gaze travel distance and maintaining compatibility were both important for the design of CMS displays layout. Practitioner Summary: A driving simulator study was conducted to comparatively evaluate three in-vehicle side view displays layouts for camera monitor systems (CMS) and the traditional side view mirror arrangement in critical lane changing situation. Reducing eye movement and maintaining compatibility were found to be both important for the ergonomics design of CMS displays layout. PMID- 28617653 TI - Systematic Review of the Effect of Taping Techniques on Patellofemoral Pain Syndrome. AB - CONTEXT: Taping is commonly used in the management of several musculoskeletal conditions, including patellofemoral pain syndrome (PFPS). Specific guidelines for taping are unknown. OBJECTIVE: To investigate the efficacy of knee taping in the management of PFPS. Our hypothesis was that tension taping and exercise would be superior to placebo taping and exercise as well as to exercise or taping alone. DATA SOURCES: The PubMed/MEDLINE, Cochrane, Rehabilitation and Sports Medicine Source, and CINAHL databases were reviewed for English-language randomized controlled trials (RCTs) evaluating the efficacy of various taping techniques that were published between 1995 and April 2015. Keywords utilized included taping, McConnell, kinesio-taping, kinesiotaping, patellofemoral pain, and knee. STUDY SELECTION: Studies included consisted of RCTs (level 1 or 2) with participants of all ages who had anterior knee or patellofemoral pain symptoms and had received nonsurgical management using any taping technique. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 2. DATA EXTRACTION: A checklist method was used to determine selection, performance, detection, and attrition bias for each article. A quality of evidence grading was then referenced using the validated PEDro database for RCTs. Three difference comparison groups were compared: tension taping and exercise versus placebo taping and exercise (group 1), placebo taping and exercise versus exercise alone (group 2), and tension taping and exercise versus taping alone (group 3). RESULTS: Five RCTs with 235 total patients with multiple intervention arms were included. Taping strategies included McConnell and Kinesiotaping. Visual analog scale (VAS) scores indicated improvement in all 3 comparison groups (group 1: 91 patients, 39% of total, mean VAS improvement 44.9 [tension taping + exercise] vs 66 [placebo taping + exercise]; group 2: 56 patients, 24% of total, mean VAS improvement 66 [placebo taping + exercise] vs 47.6 [exercise alone]; and group 3: 112 patients, 48% of total, mean VAS improvement 44.9 [tension taping + exercise] vs 14.1 [taping alone]). CONCLUSION: This systematic review supports knee taping only as an adjunct to traditional exercise therapy for PFPS; however, it does not support taping in isolation. PMID- 28617654 TI - Function, Discovery, and Exploitation of Plant Pattern Recognition Receptors for Broad-Spectrum Disease Resistance. AB - Plants are constantly exposed to would-be pathogens and pests, and thus have a sophisticated immune system to ward off these threats, which otherwise can have devastating ecological and economic consequences on ecosystems and agriculture. Plants employ receptor kinases (RKs) and receptor-like proteins (RLPs) as pattern recognition receptors (PRRs) to monitor their apoplastic environment and detect non-self and damaged-self patterns as signs of potential danger. Plant PRRs contribute to both basal and non-host resistances, and treatment with pathogen /microbe-associated molecular patterns (PAMPs/MAMPs) or damage-associated molecular patterns (DAMPs) recognized by plant PRRs induces both local and systemic immunity. Here, we comprehensively review known PAMPs/DAMPs recognized by plants as well as the plant PRRs described to date. In particular, we describe the different methods that can be used to identify PAMPs/DAMPs and PRRs. Finally, we emphasize the emerging biotechnological potential use of PRRs to improve broad spectrum, and potentially durable, disease resistance in crops. PMID- 28617655 TI - Adapted Biotroph Manipulation of Plant Cell Ploidy. AB - Diverse plant biotrophs that establish a sustained site of nutrient acquisition induce localized host endoreduplication. Endoreduplication is a process by which cells successively replicate their genomes without mitosis, resulting in an increase in nuclear DNA ploidy. Elevated ploidy is associated with enhanced cell size, metabolic capacity, and the capacity to differentiate. Localized host endoreduplication induced by adapted plant biotrophs promotes biotroph colonization, development, and/or proliferation. When induced host endoreduplication is limited, biotroph growth and/or development are compromised. Herein, we examine a diverse set of plant-biotroph interactions to identify (a) common host components manipulated to promote induced host endoreduplication and (b) biotroph effectors that facilitate this induced host process. Shared mechanisms to promote host endoreduplication and development of nutrient exchange/feeding sites include manipulation centered on endocycle entry at the G2 M transition as well as yet undefined roles for differentiation regulators (e.g., CLE peptides) and pectin/cell wall modification. PMID- 28617657 TI - National Institutes of Health research plan on rehabilitation. AB - One in five Americans experiences disability that affects their daily function because of impairments in mobility, cognitive function, sensory impairment, or communication impairment. The need for rehabilitation strategies to optimize function and reduce disability is a clear priority for research to address this public health challenge. The National Institutes of Health (NIH) recently published a Research Plan on Rehabilitation that provides a set of priorities to guide the field over the next 5 years. The plan was developed with input from multiple Institutes and Centers within the NIH, the National Advisory Board for Medical Rehabilitation Research, and the public. This article provides an overview of the need for this research plan, an outline of its development, and a listing of six priority areas for research. The NIH is committed to working with all stakeholder communities engaged in rehabilitation research to track progress made on these priorities and to work to advance the science of medical rehabilitation. PMID- 28617656 TI - Sarcocystis pantherophisi n. sp., from Eastern Rat Snakes (Pantherophis alleghaniensis) as Definitive Hosts and Interferon Gamma Gene Knockout Mice as Experimental Intermediate Hosts. AB - Here, we report a new species, Sarcocystis pantherophisi n. sp., with the Eastern rat snake (Pantherophis alleghaniensis) as natural definitive host and the interferon gamma gene knockout (KO) mouse as the experimental intermediate host. Sporocysts (n = 15) from intestinal contents of the snake were 10.8 * 8.9 MUm. Sporocysts were orally infective to KO mice but not to laboratory-raised albino outbred house mice (Mus musculus). The interferon gamma KO mice developed schizont-associated neurological signs, and schizonts were cultivated in vitro from the brain. Mature sarcocysts were found in skeletal muscles of KO mice examined 41 days postinoculation (PI). Sarcocysts were slender, up to 70 MUm wide and up to 3.5 mm long. By light microscopy, sarcocysts appeared thin-walled (<1 MUm) without projections. By transmission electron microscopy, the sarcocyst wall was a variant of "type 1" (type 1i, new designation). The parasitophorous vacuolar membrane (pvm) had approximately 100-nm-wide * 100-nm-long bleb-like evaginations interspersed with 100-nm-wide * 650-nm-long elongated protrusions at irregular distances, and invaginations into the ground substance layer (gs) for a very short distance (6 nm). The gs was smooth, up to 500 nm thick, without tubules, and contained a few vesicles. Longitudinally cut bradyzoites at 54 days PI were banana-shaped, 7.8 * 2.2 MUm (n = 5). Molecular characterization using 18S rRNA, 28S rRNA, ITS-1, and cox1 genes indicated a close relationship with other Sarcocystis parasites that have snake-rodent life cycles. The parasite in the present study was molecularly and biologically similar to a previously reported isolate (designated earlier as Sarcocystis sp. ex Pantherophis alleghaniensis) from P. alleghaniensis, and it was structurally different from other Sarcocystis species so far described. PMID- 28617658 TI - Rehabilitation research at the National Institutes of Health: Moving the field forward (Executive Summary). PMID- 28617659 TI - Inhibitory Interneurons in the Retina: Types, Circuitry, and Function. AB - Visual signals in the vertebrate retina are shaped by feedback and feedforward inhibition in two synaptic layers. In one, horizontal cells establish fundamental center-surround receptive-field properties via morphologically and physiologically complex synapses with photoreceptors and bipolar cells. In the other, a panoply of amacrine cells imbue ganglion cell responses with spatiotemporally complex information about the visual world. Here, I review current ideas about horizontal cell signaling, considering the evidence for and against the leading, competing theories. I also discuss recent work that has begun to make sense of the remarkable morphological and physiological diversity of amacrine cells. These latter efforts have been aided tremendously by increasingly complete connectivity maps of inner retinal circuitry and new genetic tools that enable study of individual, sparsely expressed amacrine cell types. PMID- 28617661 TI - Molecular dynamics approach to probe the antigenicity of PagN - an outer membrane protein of Salmonella Typhi. AB - PagN is a highly immunogenic 27-kDa outer membrane adhesin present in Salmonella Typhi. It plays a major role in the pathogenesis of typhoid fever and has emerged as a strong vaccine candidate. In this report, we predict the three-dimensional structure of PagN and describe the conformational dynamics associated with its four extracellular loops based on two 100-ns molecular dynamics simulations at 300 and 310 K. The formation and deformation of the secondary structures on these loops were also investigated during the simulations which revealed loops L1 and L2 to be highly flexible, whereas the relative flexibility of loops L3 and L4 was minimal. Essential dynamics and principal component analysis deciphered more realistic dynamic behaviours of the loops, particularly at 310 K. Moreover, our epitope predictions suggest that the antigenic peptides for B-cell recognition are located within the loops L1 and L2, while those for T-cell recognition are located within the loops L3 and L4. The binding specificities of the antigenic peptides towards specific human MHC-I and MHC-II HLA alleles closely resembled the stability of the loops L3 and L4 inferred from the simulations. Finally, we identified potential antigenic peptides in the flexible (L1 and L2) as well as stable (L3 and L4) regions of PagN for both B- and T-cell recognitions, which can help in developing effective sub-unit vaccines. PMID- 28617662 TI - Telomere Length and Accelerated Biological Aging in the China Suboptimal Health Cohort: A Case-Control Study. AB - Suboptimal health status (SHS) has been linked to cardiovascular risk factors, psychosocial stress, and unhealthy lifestyle. These factors also contribute to the shortening of telomere length (TL). A case-control study was conducted to examine the association between subjective health measures of SHS from the behavior perspective and also objective measures of TL at molecular level. SHS (cases = 294) was matched by age, sex, and body mass index with ideal health (controls = 294) using a propensity score matching method. Suboptimal health status questionnaire-25 (SHSQ-25) was used in the community-based health survey. A quantitative polymerase chain reaction was used to measure relative telomere length (RTL). Shorter RTL was found among the SHS group compared to the ideal health group (p < 0.05). SHS was almost four times likely to be in the first quartile (odds ratio [OR] = 3.81; 95% confidence interval [CI] 2.21-6.56), almost thrice in second quartile (OR = 2.84; 95% CI 1.65-4.90), and almost twice likely to be in the third quartile (OR = 1.71; 95% CI 1.00-2.94) compared to the fourth quartile (the longest) of RTL after adjusting for socioeconomic, dietary intake, anthropometric, blood pressure, and biochemistry variables (p < 0.05). Notably, SHS score was negatively correlated with RTL (r = -0.218, p < 0.05). Our study confirms an association between SHS and short RTL. Combination of subjective (SHS) and objective (RTL) measures is a novel tool for health aging investigation. Therefore, SHSQ-25 could be used as a screening tool for measuring biological aging in low-income countries at community level where the expensive technique for RTL measurement is not applicable. PMID- 28617663 TI - An Updated Systematic Review and Meta-analysis of Association Between Adiponectin Gene Polymorphisms and Coronary Artery Disease. AB - Coronary artery disease (CAD) is a significant contributor to global health burden. Adiponectin gene single nucleotide polymorphisms (SNPs) have been associated with CAD susceptibility, but with inconsistent results across the studies. We present, in this study, an updated meta-analysis to discern the genetic susceptibility of adiponectin SNPs in relation to CAD. PubMed and EMBASE databases were used to identify the relevant published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Pooled odds ratios and 95% confidence intervals were generated to assess the strength of the associations. Thirty-five articles with a total of 28,947 participants (mean age 55.3 years, 11,632 cases/17,315 controls, 19,443 males/8353 females, and 1151 persons with unspecified gender data) were included. The dominant, recessive, and additive models were applied. We found that the SNPs +45T>G (rs2241766), -4034A>C (rs822395), and -11391G>A (rs17300539) were linked to CAD development. In addition, +276G>T (rs1501299) SNP was associated with a decreased susceptibility to CAD among Caucasians. We did not find an association between the CAD susceptibility and the -11377C>G (rs266729) SNP. These observations offer new potential genetic biomarker candidates in relation to CAD, and warrant further research in independent world populations. PMID- 28617664 TI - Beyond Body Mass Index: Are Weight-loss Programs the Best Way to Improve the Health of African American Women? AB - African American women have higher prevalence (82%) of overweight (body mass index [BMI] 25-29) and obesity (BMI >=30) than white women (63.2%) or Hispanic women (77.2%), and weight-loss programs yield minimal results in this population. We examine the concept of BMI as a measure of health for African American women and suggests a more holistic, multifaceted approach to preventing chronic disease. PMID- 28617660 TI - Circuits for Action and Cognition: A View from the Superior Colliculus. AB - The superior colliculus is one of the most well-studied structures in the brain, and with each new report, its proposed role in behavior seems to increase in complexity. Forty years of evidence show that the colliculus is critical for reorienting an organism toward objects of interest. In monkeys, this involves saccadic eye movements. Recent work in the monkey colliculus and in the homologous optic tectum of the bird extends our understanding of the role of the colliculus in higher mental functions, such as attention and decision making. In this review, we highlight some of these recent results, as well as those capitalizing on circuit-based methodologies using transgenic mice models, to understand the contribution of the colliculus to attention and decision making. The wealth of information we have about the colliculus, together with new tools, provides a unique opportunity to obtain a detailed accounting of the neurons, circuits, and computations that underlie complex behavior. PMID- 28617665 TI - Prevalence and Correlates of Sleep Apnea Among US Male Veterans, 2005-2014. AB - The objective of this study was to assess the prevalence of and factors associated with sleep apnea among US male veterans. We used data from the 2005 2014 National Survey on Drug Use and Health to conduct survey-weighted descriptive, bivariate, and regression analyses. The prevalence of sleep apnea increased from 3.7% to 8.1% (P for trend <.001 for adjusted model) from 2005 through 2014. Increasing severity of psychological distress and unmet mental health care need were associated with increased odds of sleep apnea, as was a diagnosis of asthma. Increased screening of sleep health is critical to improve the health outcomes of veterans. PMID- 28617667 TI - A heuristic computational model of basic cellular processes and oxygenation during spheroid-dependent biofabrication. AB - An emerging approach in biofabrication is the creation of 3D tissue constructs through scaffold-free, cell spheroid-only methods. The basic mechanism in this technology is spheroid fusion, which is driven by the minimization of energy, the same biophysical mechanism that governs spheroid formation. However, other factors such as oxygen and metabolite accessibility within spheroids impact on spheroid properties and their ability to form larger-scale structures. The goal of our work is to develop a simulation platform eventually capable of predicting the conditions that minimize metabolism-related cell loss within spheroids. To describe the behavior and dynamic properties of the cells in response to their neighbors and to transient nutrient concentration fields, we developed a hybrid discrete-continuous heuristic model, combining a cellular Potts-type approach with field equations applied to a randomly populated spheroid cross-section of prescribed cell-type constituency. This model allows for the description of: (i) cellular adhesiveness and motility; (ii) interactions with concentration fields, including diffusivity and oxygen consumption; and (iii) concentration-dependent, stochastic cell dynamics, driven by metabolite-dependent cell death. Our model readily captured the basic steps of spheroid-based biofabrication (as specifically dedicated to scaffold-free bioprinting), including intra-spheroid cell sorting (both in 2D and 3D implementations), spheroid defect closure, and inter-spheroid fusion. Moreover, we found that when hypoxia occurring at the core of the spheroid was set to trigger cell death, this was amplified upon spheroid fusion, but could be mitigated by external oxygen supplementation. In conclusion, optimization and further development of scaffold-free bioprinting techniques could benefit from our computational model which is able to simultaneously account for both cellular dynamics and metabolism in constructs obtained by scaffold-free biofabrication. PMID- 28617666 TI - Parasitic diseases of camels in Iran (1931-2017) - a literature review. AB - Parasitic diseases of camels are major causes of impaired milk and meat production, decreases in performance or even death. Some camel parasites also represent a threat to human health. About 171,500 one-humped camels (Camelus dromedarius) and 100-300 two-humped camels (Camelus bactrianus) live in Iran. Knowledge of the biodiversity of their parasites is still limited. The present review covers all information about camel parasitic diseases in Iran published as dissertations and in both Iranian and international journals from 1931 to February 2017. Ten genera of Protozoa (Trypanosoma, Eimeria, Cryptosporidium, Toxoplasma, Neospora, Sarcocystis, Besnoitia, Theileria, Babesia and Balantidium), 48 helminth species detected in the digestive system, including three species of Trematoda, four species of Cestoda, and 41 species of Nematoda, as well as helminths from other organs - Echinococcus spp., Dictyocaulus filaria, Thelazia leesei, Dipetalonema evansi and Onchocerca fasciata - have so far been described in Iranian camels. Furthermore, 13 species of hard ticks, mange mites, the myiasis flies Cephalopina titillator and Wohlfahrtia magnifica, and immature stages of the Pentastomida Linguatula serrata have also been reported from camels of Iran. Camel parasitic diseases are a major issue in Iran in terms of economics and public health. The present review offers information for an integrated control programme against economically relevant parasites of camels. PMID- 28617668 TI - Flexible room-temperature formaldehyde sensors based on rGO film and rGo/MoS2 hybrid film. AB - Gas sensors based on reduced graphene oxide (rGO) films and rGO/MoS2 hybrid films were fabricated on polyethylene naphthalate substrates by a simple self-assembly method, which yielded flexible devices for detection of formaldehyde (HCHO) at room temperature. The sensing test results indicated that the rGO and rGO/MoS2 sensors were highly sensitive and fully recoverable to a ppm-level of HCHO. The bending and fatigue test results revealed that the sensors were also mechanically robust, durable and effective for long-term use. The rGO/MoS2 sensors showed higher sensitivities than rGO sensors, which was attributed to the enhanced HCHO adsorption and electron transfer mediated by MoS2. Furthermore, two kinds of MoS2 nanosheets were prepared by either hydrothermal synthesis or chemical exfoliation and were compared for their detection of HCHO, which revealed that the hydrothermally produced MoS2 nanosheets with rich defects led to enhanced sensitivity of the rGO/MoS2 sensors. Moreover, these fabricated flexible sensors can be applied for the HCHO detection in food packaging. PMID- 28617669 TI - Representativeness of individual external doses estimated for one quarter of residents in the Fukushima Prefecture after the nuclear disaster: the Fukushima Health Management Survey. AB - After the Fukushima Dai-ichi Nuclear Power Plant accident, the Fukushima Health Management Survey (FHMS) was launched. The Basic Survey, a component of FHMS, is a questionnaire used to survey residents across the Fukushima Prefecture about their behaviour in the first 4 months after the accident. The questionnaire findings are used to determine individual external doses by linking behaviour data to a computer programme with daily gamma ray dose rate maps, drawn after the accident. Through 30 June 2015, the response rate was only 27.2% (558 550 population), indicating that the findings might not be generalisable because of poor representativeness of the population. The objective of this study was to clarify if the data from the FHMS Basic Survey were representative of the entire population, by conducting a new survey to compare the external doses between non respondents and respondents in the previous survey. A total of 5350 subjects were randomly selected from 7 local regions of Fukushima Prefecture. An interview survey was conducted with the non-respondents to the FHMS Basic Survey. A total of 990 responses were obtained from the previous non-responders by interview survey. For the regions Kempoku, Kenchu, Kennan, Aizu, Minami-Aizu, Soso, and Iwaki, differences in mean effective dose (95% confidence interval) in mSv between the non-responders and previous responders were 0.12 (0.01-0.23), -0.09 ( 0.21-0.03), -0.06 (-0.18-0.07), 0.05 (-0.04-0.14), 0.01 (-0.01-0.02), 0.09 (0.01 0.17), 0.09 (0.00-0.17), respectively. The differences fall neither within the interval (-infinity, -0.25) nor within the interval (0.25, infinity). These findings imply that mean effective doses between the previous and new respondents were not different, with a significantly indifferent region of 0.25 mSv according to equivalence tests. The present study indicates that the dose distribution obtained from about one-quarter of Fukushima residents represents the dose distribution for the entire Fukushima Prefecture. PMID- 28617670 TI - Synthetically simple, click-generated quinoline-based Fe3+ sensors. AB - Simple quinoline-based fluorescent probes for Fe3+ have been efficiently synthesized through 'click' reaction. Both probes gave intense fluorescence compared to 8-hydroquinoline in various organic solvents due to the inhibition of the excited state intramolecular photon transfer process, while showing dramatically quenched and red-shifted fluorescence in an aqueous solution, which can be attributed to the hydrogen bond-induced intermolecular excited state proton transfer process. In the presence of Fe3+ or in an acidic condition (pH less than 4.0), both probes showed similar quenching of the emission and over 100 nm red-shifts of their emission maxima. The binding mode between the probes and Fe3+ has been found to be 1:1 based on Job's plot. A highly sensitive and selective response in their absorption and emission towards Fe3+ over many other metal ions, including Cr3+ and Cu2+, was observed and may be the result of the ground state metal to ligand charge transfer effect from Fe3+ to quinoline ligands. PMID- 28617671 TI - Nickel skeleton three-dimensional nitrogen doped graphene nanosheets/nanoscrolls as promising supercapacitor electrodes. AB - A novel nickel skeleton 3D nitrogen doped graphene (N-GR/NF) superstructure with interconnected graphene nanosheets and nanoscrolls was synthesized using a facile two-step method. By varying the precursor concentration, the assembly of a graphene aerogel can be easily regulated, yielding different micro-structures and morphologies which accelerate the fast electron/ion transportation. The N-GR/NF composites demonstrate enhanced capacitance of 250 F g-1 at 5 A g-1, good rate performance (237 F g-1 at the current density of 12 A g-1) and cycle stability (90.9% retention after 5000 cycles) in 1 M KOH electrolyte. This study provides a new strategy for the microporous engineering of graphene gel, promising for further exploitation in various other applications. PMID- 28617672 TI - Comparison of Pd electron beam induced deposition using two precursors and an oxygen purification strategy. AB - Focused electron beam induced deposition (FEBID) allows the creation of nanoscale structures through dissociation of an organo-metallic precursor by electrons at the beam impact point. The deposition of Pd can be interesting for its catalytic behavior and ability to contact carbon based materials. Two precursors were investigated-Pd(hfac)2 and (Cp)Pd(allyl)-and two deposition methods: with and without an in situ oxygen purification process. The deposition parameters can be tuned for the Pd(hfac)2 precursor to provide a deposition with 23 +/- 2 at.% of Pd and a main component of C at 51 +/- 3 at.% and minor components of O and F. An in situ purification process using O2 was much faster than expected and improved the Pd content to up to >65 at.% while reducing the C to ~20 at.%, and avoiding the oxidation of Pd. The resistivity was ~100 MUOhm . cm and compares favorably with a bulk value of 10 MUOhm . cm. The (Cp)Pd(allyl) precursor is interesting because it does not release fluorine during the deposition and hence it does not etch a possible substrate. Its FEBID deposition had a composition of 26 +/- 5 at.% of Pd with 74 +/- 5 at.% of C. The O2 purification process can improve the Pd content up to ~60 at.% while reducing C to <20 at.%, but also increasing the O content to 18 at%, which was released afterwards. The best resistivity was measured at ~1000 MUOhm . cm, although better values can be anticipated for longer post treatment times. PMID- 28617673 TI - Investigating the impact of SEM chamber conditions and imaging parameters on contact resistance of in situ nanoprobing. AB - In this paper, we investigate the impact of vacuum chamber conditions (cleanliness level and vacuum pressure) and imaging parameters (magnification and acceleration voltage) of scanning electron microscopy (SEM) on the contact resistance of two-point in situ nanoprobing of nanomaterials. Using two typical types of conductive nanoprobe, two-point nanoprobing is performed on silicon nanowires, during which changing trends of the nanoprobing contact resistance with the SEM chamber conditions and imaging parameters are quantified. The mechanisms underlying the experimental observations are also explained. Through systematically adjusting the experimental parameters, the probe-sample contact resistance is significantly reduced from the mega-ohm level to the kilo-ohm level. The experimental results can serve as a guideline to evaluate electrical contacts of nanoprobing and instruct how to reduce the contact resistance in SEM based, two-point nanoprobing. PMID- 28617674 TI - Ultrasensitive, highly selective, and real-time detection of protein using functionalized CNTs as MIP platform for FOSPR-based biosensor. AB - A facile approach is presented for the detection of bovine serum albumin (BSA), based on fiber optic surface plasmon resonance (FOSPR) combined with molecular imprinting (MI). The probe is fabricated by exploiting the plasmonic property of silver thin film and vinyl-functionalised carbon nanotube-based MIP platform. BSA template molecules are imprinted on the MIP layer coated over multi-walled carbon nanotubes to ensure high specificity of the probe in the interfering environments. In addition, FOSPR endorses the sensor capability of real-time and remote sensing along with very high sensitivity due to the use of nanostructured MI platform. The response of the probe is considered in terms of the absorbance spectrum recorded for various concentrations of BSA. The sensor shows a wide dynamic range of 0-350 ng l-1 with a considerably linear response up to 100 ng l 1 in the peak absorbance wavelength with BSA concentration. A highest sensitivity of 0.862 nm per ng l-1 is achieved for the lowest concentration of BSA and it decreases with the increase in BSA concentration. The performance of the present sensor is compared with those reported in the literature in terms of the limit of detection. It is found that the probe possesses a lowest LOD of 0.386 ng l-1 in addition to other advantages such as real-time online monitoring, high sensitivity, high specificity, and remote sensing. PMID- 28617675 TI - Application of rodes software to experimental biokinetic data for dose assessment in mice and rats. AB - H Miloudi, M Locatelli, G Autret, D Balvay, A Desbree, E Blanchardon, J M Bertho: application of RODES software to experimental biokinetic data for dose assessment in mice and rats. In support of experimental studies of chronic, long-term contamination in rodents, voxel-based computer models were built representing adult mice and juvenile, adult and elderly rats of both sexes. RODES software was created to calculate absorbed radiation doses to organs with these specific anatomical models. Absorbed doses were then calculated starting from previously published biokinetic data. Whole body doses showed less than 5% differences between calculation with RODES and calculation with the ICRP Publication 108 model for long term exposure to 90Sr of mice. Similar results were obtained for long term exposure to 137Cs. Dose distribution for 90Sr internal contamination also showed that the dose to the skeleton is six fold more as compared to the whole body dose while radiation dose to other organs is less than the mean whole body dose. These results underline the importance of using specific anatomical models according to the age and the sex of experimental animals. PMID- 28617676 TI - Interactions between low energy electrons and DNA: a perspective from first principles simulations. AB - DNA damage caused by irradiation has been studied for many decades. Such studies allow us to better assess the dangers posed by radiation, and to increase the efficiency of the radiotherapies that are used to combat cancer. A full description of the irradiation process involves multiple size and time scales. It starts with the interaction of radiation-either photons or swift ions-and the biological medium, which causes electronic excitation and ionisation. The two main products of ionising radiation are thus electrons and radicals. Both of these species can cause damage to biological molecules, in particular DNA. In the long run, this molecular level damage can prevent cells from replicating and can hence lead to cell death. For a long time it was assumed that the main actors in the damage process were the radicals. However, experiments in a seminal paper by the group of Leon Sanche in 2000 showed that low-energy electrons (LEE), such as those generated when ionising biological targets, can also cause bond breaks in biomolecules, and strand breaks in plasmid DNA in particular (Boudaiffa et al 2000 Science 287 1658-60). These results prompted a significant amount of experimental and theoretical work aimed at elucidating the role played by LEE in DNA damage. In this Topical Review we provide a general overview of the problem. We discuss experimental findings and theoretical results hand in hand with the aim of describing the physics and chemistry that occurs during the process of radiation damage, from the initial stages of electronic excitation, through the inelastic propagation of electrons in the medium, the interaction of electrons with DNA, and the chemical end-point effects on DNA. A very important aspect of this discussion is the consideration of a realistic, physiological environment. The role played by the aqueous solution and the amino acids from the histones in chromatin must be considered. Moreover, thermal fluctuations must be incorporated when studying these phenomena. Hence, a special place in this Topical Review is occupied by our recent first-principles molecular dynamics simulations that address the issue of how the environment favours or prevents LEEs from causing damage to DNA. We finish by summarising the conclusions achieved so far, and by suggesting a number of possible directions for further study. PMID- 28617677 TI - Ferroelectric switching of band alignments in LSMO/PZT/Co multiferroic tunnel junctions: an ab initio study. AB - Band alignments in ferroelectric tunnel junctions (FTJs) are expected to play a critical role in determining the charge transport across the tunneling barrier. In general, however, the interface band discontinuities and their polarization dependence are not well known in these systems. Using a first-principles density functional-theory approach, we explore the ferroelectric (FE) polarization dependence of the band alignments in [Formula: see text] (LSMO/PZT/Co) multiferroic tunnel junctions, for which recent experiments indicated an ON/OFF conductivity behavior upon switching the PZT FE polarization. Our results on the pseudomorphic defect-free LSMO/PZT/Co FTJs evidence a major FE switching effect on the band discontinuities at both interfaces. Based on the changes in the band alignments, we provide a possible explanation for the observed trends in the resistive switching. PMID- 28617678 TI - Single variant bottleneck in the early dynamics of H. influenzae bacteremia in neonatal rats questions the theory of independent action. AB - There is an abundance of information about the genetic basis, physiological and molecular mechanisms of bacterial pathogenesis. In contrast, relatively little is known about population dynamic processes, by which bacteria colonize hosts and invade tissues and cells and thereby cause disease. In an article published in 1978, Moxon and Murphy presented evidence that, when inoculated intranasally with a mixture streptomycin sensitive and resistant (Sm S and Sm R ) and otherwise isogenic strains of Haemophilus influenzae type b (Hib), neonatal rats develop a bacteremic infection that often is dominated by only one strain, Sm S or Sm R . After ruling out other possibilities through years of related experiments, the field seems to have settled on a plausible explanation for this phenomenon: the first bacterium to invade the host activates the host immune response that 'shuts the door' on the second invading strain. To explore this hypothesis in a necessarily quantitative way, we modeled this process with a set of mixed stochastic and deterministic differential equations. Our analysis of the properties of this model with realistic parameters suggests that this hypothesis cannot explain the experimental results of Moxon and Murphy, and in particular the observed relationship between the frequency of different types of blood infections (bacteremias) and the inoculum size. We propose modifications to the model that come closer to explaining these data. However, the modified and better fitting model contradicts the common theory of independent action of individual bacteria in establishing infections. We suggest possible experiments that would be able to confirm or reject our proposed modification of the early infection model. PMID- 28617679 TI - Bendamustine-Induced Acute Generalized Exanthematous Pustulosis Confirmed by Patch Testing. PMID- 28617680 TI - Pulse photoplethysmographic amplitude and heart rate variability during laparoscopic cholecystectomy: A prospective observational study. AB - BACKGROUND: Surgical stress affects the autonomic nervous system by increasing sympathetic outflow. One method of monitoring sympathetic activity is pulse photoplethysmographic analysis. From this two indices can be derived - autonomic nervous system state (ANSS) and ANSS index (ANSSi). It has recently been claimed that these indices can be used to measure sympathetic activity in anaesthetised patients, but their validity has not yet been demonstrated. OBJECTIVE: To measure changes in pulse photoplethysmographic indices and determine any agreement with autonomic nervous system modulation of the cardiovascular system in healthy study participants during surgery under general anaesthesia. DESIGN: Prospective observational study. SETTING: Single-centre study based at a tertiary care centre in Milan, Italy. PATIENTS: Healthy patients undergoing general anaesthesia for elective laparoscopic cholecystectomy. INTERVENTIONS: ANSS, ANSSi, and heart rate variability (HRV) were analysed at three main times: baseline, after induction of general anaesthesia, and after pneumoperitoneum insufflation. MAIN OUTCOME MEASURES: The magnitude of changes in photoplethysmographic and HRV indices was measured. The agreement between pulse photoplethysmographic and HRV-derived indices was assessed by Bland-Altman plots. RESULTS: In total, 52 patients were enrolled and their data analysed. Both pulse photoplethysmographic and HRV indices changed during the study phases. An agreement was found between ANSSi and low frequency spectral components of HRV [bias 10.2nu, 95% confidence interval (CI) -13 to 33.4], high frequency spectral components of HRV (bias 6.1 nu, 95% CI -16.3 to 28.6), and low frequency/high frequency ratio (bias 16.1nu, 95% CI -1.4 to 33.5). The agreement was weaker between ANSSI and HRV indices. CONCLUSION: The study endorses the use of pulse photoplethysmographic indices ANSS and ANSSi as surrogates to estimate changes of autonomic modulation of the cardiovascular system in healthy adults during surgery under general anaesthesia.Orcid ID: orcid.org/0000-0002-9616-803X. PMID- 28617681 TI - Psychotropic drugs prescription in undocumented migrants and indigent natives in Italy. AB - To evaluate psychotropic drug use in undocumented migrants and natives in the same conditions of poverty. We studied drug dispensation by a nongovernmental organization during the year 2014. Drugs were identified according to the Anatomical Chemical Therapeutic classification and their quantity was measured in defined daily doses (DDD). We determined the percentage of patients taking at least one medicine with psychotropic activity in relation to the total number of patients receiving medicines of any class. We also calculated the individual DDD for psychoactive drugs. The percentage of natives receiving this type of medicine is significantly higher than that of undocumented migrants. Individual DDDs for each class of psychotropic drug are comparable in Italians and undocumented migrants and, among the latter, no difference was found in relation to ethnicity. Our findings describe for the first time the use of psychotropic medicines by undocumented migrants. On this basis, we hypothesize that poverty is more important than migration and ethnicity in generating the need for this type of pharmacological treatment. Both natives and undocumented migrants show poor adherence to treatment. This situation should be considered when programming health interventions in this field for the very poor and undocumented migrants. PMID- 28617682 TI - Carers and breathlessness. AB - PURPOSE OF REVIEW: Informal carers play a key role in supporting patients living with breathlessness in advanced disease, but with considerable impacts on their own well being. The purpose was to review recent advances in our understanding of the caring role in refractory breathlessness, its impacts on carers, and interventions to support them. RECENT FINDINGS: A systematic literature search resulted in 28 included articles that could be mapped to four broad areas of carer enquiry: the carer role (n = 6), role impact (n = 7), carer support (n = 11) and carer views (n = 4). Search terms focused on breathlessness, but few of the included articles were exclusively on breathlessness: most were disease related, predominantly chronic obstructive pulmonary disease (COPD). There were a range of methodologies, including four systematic reviews; UK studies were most common. SUMMARY: Carers of patients with breathlessness take on a role characterized by uncertainty, largely unsupported by healthcare professionals (HCPs). HCP acknowledgement of these carers, their contribution and the impact of the caring role, is lacking. The patient-carer dyad should be considered the unit of care. Carer intervention should be individualized, supporting carers as clients and coworkers. There was a dearth of studies recruiting via primary care, focusing on conditions other than COPD and longitudinal work. PMID- 28617683 TI - Estimation of population-based cancer-specific potential years of life lost in Belgium. AB - The potential years of life lost (PYLL) observed in a cohort of cancer patients cannot be fully assigned to the cancer as both cancer-related and non-cancer related deaths contribute. A method is presented to decompose the observed all cause PYLL into cancer mortality and population background mortality fractions when cause of death information is not available. Furthermore, the association of cancer-specific PYLL with cancer-specific mortality and mean age at diagnosis is explored and the impact of the follow-up window length is examined. The framework of the actuarial relative survival and the Ederer II method is applied to estimate the population background mortality contribution, PYLL*. The fraction (PYLL-PYLL*)/PYLL is then attributed to the cancer. The method is applied to cancer incidence in Belgium 2004-2014, about 631 300 cancer patients. The cancer specific PYLL divided by the number of cancer patients, mean PYLL, in the Belgian cancer population ranges from 0.4 years for prostate cancer to 15 years for tumours of the central nervous system. The cancer-specific mean PYLL increases with both increasing cancer-specific mortality and decreasing age at diagnosis. Longer follow-up periods yield larger cancer-specific mean PYLL until statistical cure of cancer is achieved. The mean PYLL results, obtained by dividing the PYLL by the number of cancer patients, are visualized in combination with cancer incidence and mean age and mean life expectancy at diagnosis, providing an elegant summary to rank and compare cancer sites in terms of incidence, relative survival and PYLL. PMID- 28617684 TI - Non-infarct related artery revascularization in ST-segment elevation myocardial infarction patients with multivessel disease. AB - PURPOSE OF REVIEW: Multivessel disease (MVD) is common in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) and is associated with significant risk of future cardiovascular (CV) events including short and longer-term mortality. In this review, we examine the pathophysiologic construct contributing to adverse prognosis of MVD in STEMI, relevant available evidence that currently guides the management of the noninfarct-related artery (IRA) stenosis and define the remaining knowledge gaps for future studies. RECENT FINDINGS: Results of recent small sized randomized trials, when pooled, suggest improvement in CV outcomes including CV mortality and repeat revascularization with revascularization of the non-IRA stenosis compared with medical management alone. In addition, there does not appear to be an increase in bleeding, contrast-induced nephropathy or stroke, as suggested by earlier observational data. SUMMARY: These recent data have led to a Class IIb recommendation in the American College of Cardiology/American Heart Association guidelines stating that non-IRA revascularization may be considered in selected patients with STEMI and MVD who are hemodynamically stable, either at the time of primary PCI or as a planned staged procedure. The ongoing COMPLETE and CULPRIT-SHOCK studies will provide additional data to further inform the role of non-IRA revascularization and its timing in the management of these patients. PMID- 28617685 TI - Adult congenital heart disease: magnitude of the problem. AB - PURPOSE OF REVIEW: To define the magnitude of problems faced by patients with adult congenital heart disease (ACHD) and to identify unmet needs for this population. RECENT FINDINGS: The ACHD population is estimated to include more than 1 million people in the United States and continues to grow at a steady rate. Owing to the decline in early mortality in this group, modern medicine is now faced by the long-term complications associated with congenital heart disease such as chronic heart failure, increased endocarditis risk, elevated burden of arrhythmias, pulmonary hypertension, valvular dysfunction, and pregnancy. SUMMARY: Increasing access to ACHD care, evolution of imaging techniques and transcatheter technology and continued efforts at quality improvement will be key to successfully facing the challenges that are a product of the astounding success of pediatric cardiac surgery. PMID- 28617686 TI - Imaging adult patients with coarctation of the aorta. AB - PURPOSE OF REVIEW: To provide an overview of current recommendations and techniques used to image coarctations of the aorta. RECENT FINDINGS: Imaging of coarctation of the aorta in adults is moving away from conventional techniques such as echocardiography and invasive angiography. Echocardiography may assist in making the diagnosis but is limited in its ability to quantify the severity of coarctations. Current guidelines recommend that every patient with a coarctation must undergo a computed tomography (CT) or MRI scan for accurate delineation of morphology. MRIs provide important hemodynamic data and this is rapidly evolving to include techniques such as 4D flow cardiac MRI which can provide time-resolved data; research on using MRIs in the interventional suite is underway. CT is important for surveillance and provides detailed information about repair-site anatomy. Additionally, the use of CT-based technology to guide transcatheter interventions may improve the safety and efficiency of angioplasty and stent deployment. SUMMARY: Although echocardiography is an important first line means to establish the diagnosis of aortic coarctations, CT and MRI-based techniques enable the provision of patient-specific management options, can guide transcatheter interventions and detect long-term post-intervention complications. PMID- 28617687 TI - Preoperatively Assessable Clinical and Pathological Risk Factors for Parametrial Involvement in Surgically Treated FIGO Stage IB-IIA Cervical Cancer. AB - OBJECTIVE: Determining the risk factors associated with parametrial involvement (PMI) is of paramount importance to decrease the multimodality treatment in early stage cervical cancer. We investigated the preoperatively assessable clinical and pathological risk factors associated with PMI in surgically treated stage IB1 IIA2 cervical cancer. METHODS: A retrospective cohort study of women underwent Querleu-Morrow type C hysterectomy for cervical cancer stage IB1-IIA2 from 2001 to 2015. All patients underwent clinical staging examination under anesthesia by the same gynecological oncologists during the study period. Evaluated variables were age, menopausal status, body mass index, smoking status, FIGO (International Federation of Obstetrics and Gynecology) stage, clinically measured maximal tumor diameter, clinical presentation (exophytic or endophytic tumor), histological type, tumor grade, lymphovascular space invasion, clinical and pathological vaginal invasion, and uterine body involvement. Endophytic clinical presentation was defined for ulcerative tumors and barrel-shaped morphology. Two-dimensional transvaginal ultrasonography was used to measure tumor dimensions. RESULTS: Of 127 eligible women, 37 (29.1%) had PMI. On univariate analysis, endophytic clinical presentation (P = 0.01), larger tumor size (P < 0.001), lymphovascular space invasion (P < 0.001), pathological vaginal invasion (P = 0.001), and uterine body involvement (P < 0.001) were significantly different among the groups with and without PMI. In multivariate analysis endophytic clinical presentation (odds ratio, 11.34; 95% confidence interval, 1.34-95.85; P = 0.02) and larger tumor size (odds ratio, 32.31; 95% confidence interval, 2.46-423.83; P = 0.008) were the independent risk factors for PMI. Threshold of 31 mm in tumor size predicted PMI with 71% sensitivity and 75% specificity. We identified 18 patients with tumor size of more than 30 mm and endophytic presentation; 14 (77.7%) of these had PMI. CONCLUSIONS: Endophytic clinical presentation and larger clinical tumor size (>3 cm) are independent risk factors for PMI in stage IB-IIA cervical cancer. Approximately 78% of the patients with a tumor size of more than 3 cm and endophytic presentation will require adjuvant chemoradiation for PMI following radical surgery. Considering clinical tumor presentation along with tumor size can enhance the physician's prediction of PMI in early-stage cervical cancer. PMID- 28617688 TI - Compliance with the prescribed occlusion treatment for amblyopia. AB - PURPOSE OF REVIEW: The present review article is an update on the current evidence about compliance to the prescribed occlusion treatment for amblyopia. In particular, the authors focus on the predictors and causes of noncompliance and possible interventions to increase it. RECENT FINDINGS: Compliance with prescribed occlusion treatment is often challenging. Reported rates of compliance range widely from 49% to 87%. Objective monitoring of occlusion has opened up new research opportunities and allow the design of effective therapeutic regimens. Also, predictors and causes of noncompliance have been investigated and their knowledge may help the clinician to improved compliance with prescribed occlusion treatment for amblyopia. SUMMARY: Although many of the studies assessing the effectiveness of interventions to increase compliance to patching treatment for amblyopia have many limitations, evidences support that use of educational supports, parents, and patient understanding on the importance of patching and written information should be considered to increase compliance with patching. PMID- 28617689 TI - Paracellular transport and energy utilization in the renal tubule. AB - PURPOSE OF REVIEW: Paracellular transport across the tight junction is a general mechanism for transepithelial transport of solutes in epithelia, including the renal tubule. However, why paracellular transport evolved, given the existence of a highly versatile system for transcellular transport, is unknown. RECENT FINDINGS: Recent studies have identified the paracellular channel, claudin-2, that is responsible for paracellular reabsorption of sodium in the proximal renal tubule. Knockout of claudin-2 in mice impairs proximal sodium and fluid reabsorption but is compensated by upregulation of sodium reabsorption in the loop of Henle. This occurs at the expense of increased renal oxygen consumption, hypoxia of the outer medulla and increased susceptibility to ischemic kidney injury. SUMMARY: Paracellular transport can be viewed as a mechanism to exploit the potential energy in existing electrochemical gradients to drive passive transepithelial transport without consuming additional energy. In this way, it enhances the efficiency of energy utilization by transporting epithelia. PMID- 28617690 TI - Short- and Long-term Cognitive Outcomes in Patients With Major Depression Treated With Electroconvulsive Therapy. AB - OBJECTIVES: The risk of cognitive impairment is a concern for patients with major depressive disorder receiving electroconvulsive therapy (ECT). Here, we evaluate the acute, short-term and long-term effects of ECT on tests of processing speed, executive function, memory, and attention. METHODS: Forty-four patients with major depressive disorder receiving ECT (61% right unilateral, 39% mixed right unilateral-bitemporal, left unilateral, and/or bitemporal lead placement) underwent a cognitive battery prior to ECT (T1), after 2 sessions (T2), and at the end of the index (T3). Thirty-two patients returned for a 6-month follow-up (T4). Thirty-three control subjects were assessed at 2 times approximately 4 weeks apart (C1 and C2). RESULTS: At baseline, patients showed deficits in processing speed, executive function, and memory compared with control subjects. Including depression severity and lead placement covariates, linear mixed-model analysis showed significant improvement in only processing speed between T1 and T3 and between T1 and T4 in patients. An acute decline in attention and verbal memory was observed at T2, but performance returned to baseline levels at T3. Longitudinal cognitive outcomes did not differ in patients defined as ECT responders/nonresponders. LIMITATIONS: Episodic memory was not measured, and medications were not controlled between T3 and T4. Control subjects also showed improvements in processing speed, suggesting practice effects for some measures. CONCLUSIONS: In this naturalistic ECT treatment study, results show that the initiation of ECT may transiently affect memory and executive function, but cognition is largely unaffected during and after ECT. Whereas some functions might improve, others will at least remain stable up to 6 months following the ECT index. PMID- 28617691 TI - The PRIDE Study and the Conduct of Electroconvulsive Therapy: Questions Answered and Unanswered. AB - The recently published PRIDE study (prolonging remission in the depressed elderly) constitutes an important contribution to electroconvulsive therapy (ECT) technique, from the standpoint of both the index course to treat depressive symptoms and the post-remission continuation period to prevent relapse. This study was probably the last large, National Institute of Mental Health-funded, multisite ECT technical study for some time to come, so extracting clinically relevant recommendations is worthwhile. In this commentary, the author discusses evidence from this trial relevant to several important clinical index and continuation ECT technical issues and elaborates several unanswered questions deserving further consideration. PMID- 28617692 TI - Update on the supraclavicular flap. AB - PURPOSE OF REVIEW: The purpose of this study is to describe the supraclavicular flap and its utility in head and neck reconstruction in the context of recent studies. RECENT FINDINGS: Current literature regarding the supraclavicular flap has described its expanded uses in a variety of head and neck reconstructive settings. Its reliability and limited morbidity have been well demonstrated, and it has been cited as a reasonable alternative to other reconstructive options including, in some situations, free tissue transfer. SUMMARY: The supraclavicular flap has shown dependability in reconstruction of defects in the head and neck, and it warrants consideration among reconstructive surgeons, especially for circumstances in which free tissue or other pedicled flaps are less than ideal. PMID- 28617693 TI - Bryukhonenko's Autojector: The First Apparatus for Cardiopulmonary Bypass and Extracorporeal Life Support. AB - Sergey Bryukhonenko was a prominent Soviet physician-scientist who from 1922 to 1924 developed a methodology for perfusing a canine head and keeping it alive using the first extracorporeal life support device he created called "Autojector." From 1926 to 1927, in collaboration with surgeon Nikolay Terebinsky, he performed a series of perfusion experiments of the entire canine body using a more advanced model of Autojector. Subsequently, Bryukhonenko concluded the possibility of extending this methodology to heart surgery. Although Bryukhonenko never applied his device in clinical practice, Terebinsky used the concept from 1929 to 1940 on open heart experiments. Although he never received sufficient acknowledgement for his pioneering work, it must be recognized that Bryukhonenko, along with Terebinsky, laid the groundwork for developing cardiac surgery in the Soviet Union. PMID- 28617694 TI - The Spectrum of General Surgery Interventions in Pediatric Patients with Ventricular Assist Devices. AB - Ventricular assist devices (VADs) have positively impacted the management of heart failure. However, they come with a range of complications. Although general surgical complications have been assessed in adults with VADs, there is no study to date that has assessed general surgery intervention in the pediatric population. Fifty-two patients who received VADs from 2005 to 2015 at the Stollery Children's Hospital were assessed for general surgery intervention and anticoagulation status at the time of intervention. Eighteen patients (35%) had general surgery intervention; there were 21 nonemergency procedures and six emergency procedures performed. For nonemergency procedures, 89% of patients had anticoagulation held within 24 hours of surgery and 84% had anticoagulation resumed within 4 hours postoperatively. Antiplatelet therapy was not held perioperatively. In both emergency and nonemergency procedures, anticoagulation status was not a factor in the success of the procedure. This study shows that it is safe to have general surgery intervention on the same admission as a VAD implant provided an appropriate interdisciplinary healthcare team is involved with the perioperative management of the patient. PMID- 28617695 TI - An Alternative Consent Process for Minimal Risk Research in the ICU. AB - OBJECTIVES: Seeking consent for minimal risk research in the ICU poses challenges, especially when the research is time-sensitive. Our aim was to determine the extent to which ICU patients or surrogates support a deferred consent process for a minimal risk study without the potential for direct benefit. DESIGN: Prospective cohort study. SETTING: Five ICUs within a tertiary care hospital. PATIENTS: Newly admitted ICU patients 18 years old or older. INTERVENTIONS: We administered an eight-item verbal survey to patients or surrogates approached for consent to participate in a minimal risk, ICU-based study. The parent study involved noninvasive collection of biosamples and clinical data at the time of ICU admission and again 3 days later. If patients had capacity at the time of ICU admission, or if a surrogate was readily available, consent was sought prior to initial sample collection; otherwise, a waiver of consent was granted, and deferred consent was sought 3 days later. Quantitative and qualitative data were analyzed. MEASUREMENTS AND MAIN RESULTS: One hundred fifty-seven individuals were approached for consent to participate in the parent study; none objected to the consent process. One hundred thirty-five of 157 (86%) competed the survey, including 94 who consented to the parent study and 41 who declined. Forty-four of 60 individuals (73%) approached for deferred consent responded positively to the question "Did we make the right choice in waiting until now to ask your consent?" three of 60 (5%) responded negatively, and 13 of 60 (22%) made a neutral or unrelated response. The most common reason given for endorsing the deferred consent process was the stress of the early ICU experience 25 of 44 (61%). CONCLUSIONS: Most patients and surrogates accept a deferred consent process for minimal risk research in the ICU. For appropriate ICU-based research, investigators and Institutional Review Boards should consider a deferred consent process if the subject lacks capacity and an appropriate surrogate is not readily available. PMID- 28617696 TI - Should Hyperoxia Be Avoided During Sepsis? An Experimental Study in Ovine Peritonitis. AB - OBJECTIVES: Optimizing oxygen delivery is an important part of the hemodynamic resuscitation of septic shock, but concerns have been raised over the potentially deleterious effects of hyperoxia. We evaluated the impact of hyperoxia on hemodynamics, the microcirculation, and cerebral and renal metabolism in an ovine model of septic shock. DESIGN: Randomized animal study. SETTING: University hospital animal research laboratory. SUBJECTS: Fourteen adult female sheep. INTERVENTIONS: After induction of fecal peritonitis, sheep were randomized to ventilation with an FIO2 of 100% (n = 7) or an FIO2 adjusted to maintain PaO2 between 90 and 120 mm Hg (n = 7, control). All animals were fluid resuscitated and observed until death. MEASUREMENTS AND MAIN RESULTS: In addition to hemodynamic measurements, we assessed the sublingual microcirculation, renal and cerebral microdialysis and microvascular perfusion, and brain tissue oxygen pressure. Hyperoxic animals initially had a higher mean arterial pressure than control animals. After onset of shock, hyperoxia blunted the decrease in stroke volume index observed in the control group. Hyperoxia was associated with a higher sublingual microcirculatory flow over time, with higher cerebral perfusion and brain tissue oxygen pressure and with a lower cerebral lactate-to-pyruvate ratio than in control animals. Hyperoxia was also associated with preserved renal microvascular perfusion, lower renal lactate-to-pyruvate ratio, and higher PaO2/FIO2 ratio. CONCLUSIONS: In this acute peritonitis model, hyperoxia induced during resuscitation provided better hemodynamics and peripheral microvascular flow and better preserved cerebral metabolism, renal function, and gas exchange. These observations are reassuring with recent concerns about excessive oxygen therapy in acute diseases. PMID- 28617697 TI - Evaluation of the Temple Touch Pro, a Novel Noninvasive Core-Temperature Monitoring System. AB - BACKGROUND: The Temple Touch Pro (TTP) is a novel system that estimates core temperature from skin over the temporal artery. We tested the hypothesis that this noninvasive system estimates core temperature to an accuracy within 0.5 degrees C. METHODS: Core temperature was continuously monitored in 50 adult and pediatric surgical patients by positioning the sensor patch of a TTP over one temporal artery. The sensor consists of a thermistor array near the skin surface, another set of thermistors above an insulator, and a second insulator between the upper unit and the environment. The sensor measures skin temperature and heat flux, from which the monitor unit estimates core temperature from a proprietary algorithm. Reference core temperature was measured from the esophagus or nasopharynx. We conducted agreement analysis between the TTP and the reference core temperature measurements using the 95% Bland-Altman limits of agreement for repeated measurement data. The proportion of all differences that were within 0.5 degrees C and repeat measures concordance correlation coefficient (CCC) were estimated as well. RESULTS: TTP and the reference core temperature measurements agreed well in both adults and pediatric patients. Bland-Altman plots showed no evidence of systematic bias or variability over the temperature from 35.2 degrees C to 37.8 degrees C. The estimated 95% lower and upper limits of agreement were 0.57 degrees C (95% confidence interval [CI], -0.76 to -0.41) and 0.57 degrees C (95% CI, 0.44 to 0.71), indicating good agreement between the 2 methods. Ninety four percentage (95% CI, 87% to 99%) of the TTP temperatures were within 0.5 degrees C of the reference temperature. Good agreement was also supported by an estimated repeated measures CCC of 0.82 (95% CI, 0.66 to 0.91). The TTP core temperature measurements also agreed well with nasopharyngeal reference temperatures. CONCLUSIONS: The noninvasive TTP system is sufficiently accurate and reliable for routine intraoperative core temperature monitoring. PMID- 28617698 TI - In Response. PMID- 28617699 TI - Wind of Change or Siren Song? PMID- 28617700 TI - In Response. PMID- 28617701 TI - In Response. PMID- 28617702 TI - Intraperitoneal Instillation of Local Anesthetics: Is This a Suitable Alternative for Postcesarean Pain Relief Without Toxicity Profiling? PMID- 28617703 TI - Using Self-reports or Claims to Assess Disease Prevalence: It's Complicated. AB - BACKGROUND: Two common ways of measuring disease prevalence include: (1) using self-reported disease diagnosis from survey responses; and (2) using disease specific diagnosis codes found in administrative data. Because they do not suffer from self-report biases, claims are often assumed to be more objective. However, it is not clear that claims always produce better prevalence estimates. OBJECTIVE: Conduct an assessment of discrepancies between self-report and claims based measures for 2 diseases in the US elderly to investigate definition, selection, and measurement error issues which may help explain divergence between claims and self-report estimates of prevalence. DATA: Self-reported data from 3 sources are included: the Health and Retirement Study, the Medicare Current Beneficiary Survey, and the National Health and Nutrition Examination Survey. Claims-based disease measurements are provided from Medicare claims linked to Health and Retirement Study and Medicare Current Beneficiary Survey participants, comprehensive claims data from a 20% random sample of Medicare enrollees, and private health insurance claims from Humana Inc. METHODS: Prevalence of diagnosed disease in the US elderly are computed and compared across sources. Two medical conditions are considered: diabetes and heart attack. RESULTS: Comparisons of diagnosed diabetes and heart attack prevalence show similar trends by source, but claims differ from self-reports with regard to levels. Selection into insurance plans, disease definitions, and the reference period used by algorithms are identified as sources contributing to differences. CONCLUSIONS: Claims and self reports both have strengths and weaknesses, which researchers need to consider when interpreting estimates of prevalence from these 2 sources. PMID- 28617704 TI - Greater Oxidative Capacity in Primary Myotubes from Endurance-trained Women. AB - PURPOSE: Exercise training promotes skeletal muscle mitochondrial biogenesis and an increase in maximal oxygen consumption. Primary myotubes retain some metabolic properties observed in vivo but it is unknown whether this includes exercise induced mitochondrial adaptations. The goal of this study was to test if primary myotubes from exercise-trained women have higher mitochondrial content and maximal oxygen consumption compared with untrained women. METHODS: Six trained and nine untrained white women participated in this study. Muscle biopsies from the vastus lateralis muscle of the right leg were obtained and primary muscle cells were isolated. Maximal respiration rates, mitochondrial mRNA and protein content, and succinate dehydrogenase activity were measured in skeletal muscle and primary myotubes from trained and untrained women. RESULTS: Trained women, compared with untrained women, had higher maximal whole-body oxygen consumption (+18%, P = 0.03), in vivo maximal skeletal muscle oxidative capacity measured with near infrared spectroscopy (+48%, P < 0.01), and maximal oxygen consumption in permeabilized muscle fibers (+38%, P = 0.02), which coincided with higher protein levels of muscle mitochondrial enzymes. Primary myotubes from trained women had higher maximal oxygen consumption (+38%, P = 0.03), suggesting that some elements of exercise-induced metabolic programming persists ex vivo. Consistent with this idea, myotubes from trained women had higher mRNA levels of transcriptional regulators of mitochondrial biogenesis in addition to higher protein levels of mitochondrial enzymes. CONCLUSIONS: These data suggest the existence of an "exercise metabolic program," where primary myotubes isolated from exercise-trained individuals exhibit greater mitochondrial content and oxidative capacity compared with untrained individuals. These myotubes may be a useful model to study molecular mechanisms relevant to exercise adaptations in human skeletal muscle. PMID- 28617705 TI - Liver X Receptor alpha Is Involved in Counteracting Mechanical Allodynia by Inhibiting Neuroinflammation in the Spinal Dorsal Horn. AB - BACKGROUND: Liver X receptors, including alpha and beta isoforms, are ligand activated transcription factors. Whether liver X receptor alpha plays a role in neuropathic pain is unknown. METHODS: A spared nerve injury model was established in adult male rats and mice. Von Frey tests were performed to evaluate the neuropathic pain behavior; Western blot and immunohistochemistry were performed to understand the underlying mechanisms. RESULTS: Intrathecal injection of a specific liver X receptor agonist T0901317 or GW3965 could either prevent the development of mechanical allodynia or alleviate the established mechanical allodynia, both in rats and wild-type mice. GW3965 could inhibit the activation of glial cells and the expression of tumor necrosis factor-alpha (mean +/- SD: 196 +/- 48 vs. 119 +/- 57; n = 6; P < 0.01) and interleukin 1beta (mean +/- SD: 215 +/- 69 vs. 158 +/- 74; n = 6; P < 0.01) and increase the expression of interleukin 10 in the spinal dorsal horn. All of the above effects of GW3965 could be abolished by liver X receptor alpha mutation. Moreover, more glial cells were activated, and more interleukin 1beta was released in the spinal dorsal horn in liver X receptor alpha knockout mice than in wild-type mice after spared nerve injury. Aminoglutethimide, a neurosteroid synthesis inhibitor, blocked the inhibitory effect of T0901317 on mechanical allodynia, on the activation of glial cells, and on the expression of cytokines. CONCLUSIONS: Activation of liver X receptor alpha inhibits mechanical allodynia by inhibiting the activation of glial cells and rebalancing cytokines in the spinal dorsal horn via neurosteroids. PMID- 28617706 TI - Fulminant Hyperfibrinolysis Diagnosed by Rotational Thromboelastometry. PMID- 28617707 TI - Lingual Thyroid. PMID- 28617709 TI - Editorial. PMID- 28617708 TI - The impact of nutrition on quality of life of patients with hepatitis C. AB - PURPOSE OF REVIEW: The aim of this study was to review the most recent aspects of nutrition and its impact on health-related quality of life (HRQOL) in patients with chronic hepatitis C (CHC). RECENT FINDINGS: Low HRQOL scores have been found in all stages of hepatitis C virus (HCV) infection. Of the factors linked to HRQOL, three aspects should be emphasized, nutritional status, physical activity and mental health status. Regarding the nutrition and metabolic conditions, a broad spectrum of nutritional disorders may impact on HRQOL of patients with CHC. SUMMARY: Malnutrition, which is a significant comorbidity in end-stage of all chronic liver diseases, has been recognized as a significant factor related to poor HRQOL. Of note, in individuals chronically infected with HCV, low muscle skeletal mass, an early indicator of undernourishment, precedes the development of cirrhosis. Because of the strict linkage between HRQOL, nutrition and physical activity, the assessment of the musculoskeletal system abnormalities in every patient with CHC, independently of the stage of the liver disease, is of utmost relevance. Maintenance of healthy skeletal muscle is essential to reduce the negative effects of sarcopenia on HRQOL. Otherwise, overweight/obesity and chronic HCV infection can cause insulin resistance, which has been associated with HRQOL impairment. PMID- 28617710 TI - The low FODMAP diet: fundamental therapy in the management of irritable bowel syndrome. AB - PURPOSE OF REVIEW: The low FODMAP diet is now recognized as first-line therapy for treatment of irritable bowel syndrome (IBS) symptoms including abdominal pain, gas, bloating, diarrhea and or constipation. This information must be disseminated for application to clinical practice. RECENT FINDINGS: There are many people with IBS worldwide who can benefit from following the low FODMAP diet to alleviate or minimize symptoms. Clinical studies and trials demonstrating the positive outcomes of the low FODMAP diet have been based on diet education provided by dietitians. Understanding the types of carbohydrates that are high in FODMAPs and the associated symptoms, nutrition intervention can be targeted using the low FODMAP diet. The nutrition intervention is relatively in expensive, noninvasive and basically without side-effects if monitored by a dietitian and clinical team. SUMMARY: Applying the low FODMAP diet in IBS can greatly improve health and quality of life outcomes by alleviating or significantly improves symptoms. PMID- 28617711 TI - Addressing engagement in technology-based behavioural HIV interventions through paradata metrics. AB - PURPOSE OF REVIEW: The goal of this review was to examine how often researchers report participants' online engagement using paradata (i.e. intervention usage metrics) when describing the outcomes of online behavioural HIV prevention and care interventions. We also highlight the utility of paradata collection and analysis in future technology-based trials. RECENT FINDINGS: We focused on studies indexed on PubMed and published between 1 January 2016 and 31 March 2017 that reported the development and testing of online behavioural interventions for HIV prevention and/or care. Of the 705 extracted citations, six met study criteria. SUMMARY: Only one study reported paradata reflecting participants' engagement with a technology-based intervention. Researchers should systematically collect and analyse paradata to strengthen the evidence base for technology-based interventions (do they work?), advance the use of behaviour change theory across modalities and platforms (how/why do they work?) and inform reach and scale-up efforts (for whom do they work?). Researchers may also rely on paradata to examine dose-response relationships due to user engagement, to identify replicable core components linked to behaviour change outcomes, to allocate resources judiciously and drive down development costs, and to pool these metrics for use in future meta-analyses. PMID- 28617713 TI - Gastric Emphysema: A Cannot-Miss Emergency Medicine Diagnosis. AB - The radiographic finding of gastric emphysema with portal venous gas is classically an ominous finding, associated with a high rate of mortality. Although classically the case, this imaging finding must be quickly correlated with the overall clinical picture, allowing for the essential differentiation between the highly lethal emphysematous gastritis and the much more benign gastric emphysema, each of which has drastically different management strategies. We report a case of gastric emphysema with portal venous gas likely attributable to a gastric outlet obstruction and gastric mucosal defect in a 17-year-old girl with a chief complaint of syncope that was diagnosed in the emergency department and treated conservatively. PMID- 28617712 TI - Using technology to support HIV self-testing among MSM. AB - PURPOSE OF REVIEW: Technology-based HIV self-testing (HST) interventions have the potential to improve access to HIV testing among gay, bisexual, and other MSM, as well as address concerns about HST use, including challenges with linkage to appropriate follow-up services. This review examines studies that use technology based platforms to increase or improve the experience of HST among MSM. RECENT FINDINGS: Seven published studies and eight funded studies were included in this review. Comprehensive prevention interventions with free HST kit distribution and interventions that provide free HST kits and support the HST process address a greater number of barriers (e.g., access, correct use of testing kits, and correct interpretation of results) than studies that only distribute free HST kits through technology-based platforms. SUMMARY: By addressing HIV-testing barriers and specific HST concerns, these interventions address a critical need to improve first time and repeat testing rates among MSM. Additional research is needed to determine the efficacy of recent formative HST interventions. If proven efficacious, scale-up of these strategies have the potential to increase HIV testing among MSM via expanded HST uptake. PMID- 28617714 TI - Perioperative chemotherapy with and without high-dose methotrexate in adult osteosarcoma. AB - Treatment of adult osteosarcoma (AOS) includes perioperative chemotherapy and surgery. Standard chemotherapy consists of cisplatin (CP) and doxorubicin (DOX). Although considered the standard of care for pediatric patients, high-dose methotrexate (HDM) remains controversial in adults. We aimed to evaluate the role of HDM in AOS treated with curative intent. This study included patients with AOS who received perioperative chemotherapy with DOX and CP (group 1; N=16) and DOX, CP, and HDM (group 2; N=10). The primary endpoint was grade 3 or superior toxicities. The secondary endpoints included overall survival (OS) and disease free survival. Despite lower average age (35.0+/-12.1 vs. 18.9+/-2.1 years), group 2 presented more grade 3-4 thrombocytopenia (0 vs 50%) and mucositis (0 vs 40%), whereas group 1 presented more grade 3-4 neutropenia (43.75 vs 40%). No grade 3-4 renal toxicities occurred. Two grade 5 toxicities occurred in group 2, both after the first HDM cycle. Disease-free survival (4.38+/-0.61 vs. 2.3+/-0.54 years, P=0.228) and OS (4.70+/-0.56 vs 2.52+/-0.57 years, P=0.107) were not statistically different, but presented a trend toward better outcomes in group 1. The 4-year OS was 65.6 and 32.8% for groups 1 and 2, respectively. In conclusion, HDM was associated with greater severe and lethal toxicity when added to CP and DOX in AOS. Also, it does not seem to impact on treatment efficacy. These data do not support the use of HDM for the perioperative treatment of AOS. PMID- 28617715 TI - Strength And Muscular Adaptations Following 6 Weeks Of Rest-Pause Versus Traditional Multiple-Sets Resistance Training In Trained Subjects. AB - The purpose of the present study was to compare the longitudinal effects of six weeks of rest-pause versus traditional multiple-set RT on muscle strength, hypertrophy, localized muscular endurance, and body composition in trained subjects. Eighteen trained subjects (mean +/- SD; age = 30.2 +/- 6.6 years; weight = 74.8 +/- 17.2 kg; height = 171.4 +/- 10.3 cm) were randomly assigned to either a traditional multiple-set group (n = 9; 7 males and 2 females; 3 sets of 6 repetitions with 80% of 1-RM and 2 min rest intervals between sets) or a rest pause group (n = 9; 7 males and 2 females). The results showed no significant differences (p > 0.05) between groups in 1RM strength (rest-pause: 16 +/- 11% for BP, 25 +/- 17% for LP, and 16 +/- 10% for BC versus traditional multiple-set: 10 +/- 21% for BP, 30 +/- 20% for LP and 21 +/- 20% for BC). In localized muscular endurance, the rest-pause group displayed significantly greater (p < 0.05) repetitions, only for the LP exercise (rest pause: 27 +/- 8% versus traditional multiple set: 8 +/- 2%). In muscle hypertrophy, the rest-pause group displayed significantly greater (p < 0.05) thickness, only for the thigh (rest-pause: 11 +/ 14% versus traditional multiple-set: 1 +/- 7%). In conclusion, resistance training performed with the rest-pause method resulted in similar gains in muscle strength as traditional multiple-set training. However, the rest-pause method resulted in greater gains in localized muscular endurance and hypertrophy for the thigh musculature. PMID- 28617716 TI - Hybrid Blocks for Total Knee Arthroplasty: A Technical Description. AB - INTRODUCTION: This narrative review article aims to examine current evidence of knee innervation in order to develop a technique of targeting pure sensory innervation of the knee joint without compromising motor function. METHODS: A literature review of knee innervation was performed to gain an anatomic understanding of terminal sensory branches of the relevant target nerves (femoral, obturator, sciatic, and lateral femoral cutaneous). RESULTS: Pure sensory block of the knee joint is challenging due to important contributions from themuscular innervation close to the joint and the variability of nerves afferents contained within and around the adductor canal. CONCLUSION: On the basis of this anatomic knowledge we describe an ultrasound-guided 3-injection hybrid technique that represents a balance between preserving adequate motor power while still providing analgesia in a simple method. PMID- 28617717 TI - Validation of the YuWell YE690A upper-arm blood pressure monitor, for clinic use and self-measurement, according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: The present study aimed to evaluate the accuracy of the automated oscillometric upper-arm blood pressure monitor YuWell YE690A for blood pressure measurement according to the International Protocol of the European Society of Hypertension revision 2010. PARTICIPANTS AND METHODS: Systolic and diastolic blood pressures were measured sequentially in 33 adult Chinese (12 women, 44.2 years of mean age) using a mercury sphygmomanometer (two observers) and the YE690A device (one supervisor). A total of 99 pairs of comparisons were obtained from 33 participants for judgments in two parts with three grading phases. RESULTS: All the blood pressure requirements were fulfilled. The YuWell YE690A device achieved the targets in part 1 of the validation study. The number of absolute differences between device and observers within 5, 10, and 15 mmHg was 79/99, 96/99, and 97/99, respectively, for systolic blood pressure and 72/99, 95/99, and 98/99, respectively, for diastolic blood pressure. The device also fulfilled the criteria in part 2 of the validation study. Thirty-one and 25 participants for systolic and diastolic blood pressure, respectively, had at least two of the three device-observer differences within 5 mmHg (required >=24). No participant for systolic and two participants for diastolic blood pressure had all the three device-observer comparisons greater than 5 mmHg. CONCLUSION: The YuWell blood pressure monitor YE690A has passed the requirements of the International Protocol revision 2010 and hence can be recommended for blood pressure measurement in adults. PMID- 28617718 TI - Self-monitoring of blood pressure during pregnancy: an observational study in the obstetrical waiting room. AB - OBJECTIVE: The aim of this study was to assess the feasibility of self-monitoring of blood pressure with a semiautomatic device in pregnant women. PARTICIPANTS AND METHODS: Women attending routine obstetrical ultrasound scanning were invited to participate. The hospital staff initially demonstrated and instructed each participant in correct measurement and then took three measurements on both arms. The participant then repeated the measurements and filled an evaluation questionnaire. We used a validated semiautomatic device for all measurements. Mean values were calculated for systolic, diastolic and mean arterial blood pressure (MAP) and were compared using the paired sample t-test. Mean values and differences of systolic and diastolic pressure were plotted in Bland-Altman plots to test the agreement of the measurements. Finally, a mean evaluation score was calculated. RESULTS: One hundred pregnant women were included in the study. Mean values of systolic, diastolic and MAP were 110.6, 69.7 and 83.3 mmHg, respectively, as assessed by the hospital staff. The corresponding self measurements were 111.4, 70.2 and 83.9 mmHg, respectively. Mean differences between hospital and self-measurements were 0.79 mmHg for systolic [P=0.052, 95% confidence interval (CI)=-0.008 to 1.58], 0.49 mmHg for diastolic (P=0.056, 95% CI=-0.01 to 0.99) and 0.59 mmHg for MAP (P=0.019, 95% CI=0.099-1.08). The mean evaluation score was 9.2 of 10. CONCLUSION: Differences between hospital staff and self-measurements in systolic, diastolic and MAP are within acceptable international standards. The semiautomatic device Microlife-VSA is well suited for self-measurement; however, safety studies on the use of home measurements in hypertensive pregnancies are still warranted. PMID- 28617719 TI - Guillain-Barre syndrome and Zika virus outbreaks. AB - PURPOSE OF REVIEW: Arboviruses have been associated with central and peripheral nervous system injuries, in special the flaviviruses. Guillain-Barre syndrome (GBS), transverse myelitis, meningoencephalitis, ophthalmological manifestations, and other neurological complications have been recently associated to Zika virus (ZIKV) infection. In this review, we aim to analyze the epidemiological aspects, possible pathophysiology, and what we have learned about the clinical and laboratory findings, as well as treatment of patients with ZIKV-associated neurological complications. RECENT FINDINGS: In the last decades, case series have suggested a possible link between flaviviruses and development of GBS. Recently, large outbreaks of ZIKV infection in Asia and the Americas have led to an increased incidence of GBS in these territories. Rapidly, several case reports and case series have reported an increase of all clinical forms and electrophysiological patterns of GBS, also including cases with associated central nervous system involvement. Finally, cases suggestive of acute transient polyneuritis, as well as acute and progressive postinfectious neuropathies associated to ZIKV infection have been reported, questioning the usually implicated mechanisms of neuronal injury. SUMMARY: The recent ZIKV outbreaks have triggered the occurrence of a myriad of neurological manifestations likely associated to this arbovirosis, in special GBS and its variants. PMID- 28617720 TI - Development of a Trigger Tool to Identify Adverse Drug Events in Elderly Patients With Multimorbidity. AB - PURPOSE: Elderly patients with multimorbidity are especially vulnerable to adverse drug events (ADEs) and had high prevalence rates. Identifying ADEs is essential for enabling timely interventions that can mitigate the adverse events detected and for developing targeted strategies to prevent their occurrence as well as to monitor implementation. The aim of this study was to develop a set with appropriate triggers for detecting potential ADEs in elderly patients with multimorbidity. METHODS: A modified Delphi methodology was used to reach consensus. Existing triggers for detecting ADEs in adult patients were identified from a literature search in several databases (EMBASE, MEDLINE, Web of Science, Centre for Reviews and Dissemination, and Cochrane Library) and from Institute for Healthcare Improvement published lists. Twelve experts in patient/medication safety or in chronic diseases scored candidate triggers for appropriateness according to 3 criteria (evidence, usefulness for elderly patients, and feasibility of implementation in clinical practice). RESULTS: Seventy-two triggers were initially selected to be evaluated. The final set includes a total of 51 triggers for which the panelists who completed the 2 rounds of evaluation reached agreement. These triggers were organized into 5 modules: 11 as care module triggers, 10 as antidotes/treatment, 11 medication concentrations, 18 abnormal laboratory values, and 1 as emergency department trigger. CONCLUSIONS: A set of triggers for detecting ADEs in elderly patients with multimorbidity have been developed, following the consensus of a panel of experts. Subsequent validation in clinical practice is needed to confirm the accuracy and efficiency of these triggers for this population. PMID- 28617721 TI - Analysis of a Physician-led, Team-based Care Model for the Treatment of Glaucoma. AB - PURPOSE: To determine the effect of a protocol for a new physician-led, team based glaucoma care model implemented in 2008 at Mayo Clinic's campus in Rochester, Minnesota (MCR), to increase conformance with the American Academy of Ophthalmology (AAO) Preferred Practice Pattern guidelines for treatment of primary open-angle glaucoma. METHODS: Records of 591 patients with newly diagnosed glaucoma were assessed retrospectively for the completion of 9 AAO Preferred Practice Pattern recommended metrics including measured corneal thickness, intraocular pressure (IOP), cup to disk ratio, visual acuity, recorded IOP target, gonioscopy, fundus photos, ocular coherence tomography, and visual field in the 3 years before and 3 years after protocol implementation. Treatment by the glaucoma care team at MCR was compared with treatment at a community-based general ophthalmology practice and with a group of comprehensive ophthalmologists at MCR without team care, which served as controls. RESULTS: Adherence to AAO recommendations increased for the documentation of target IOP (+24%, 42.6% to 66.7%; P=0.007), gonioscopy (+27%, 66.7% to 93.3%; P<=0.001), fundus photos (+29%, 44.4% to 73.3%; P<=0.001), and ocular coherence tomography (+20%, 48.1% to 68.0%; P=0.02) after protocol initiation. No change in pattern of testing occurred in the control groups without team care during the same time period. Type and severity of glaucoma were similar between MCR and community practice. CONCLUSIONS: An increase in compliance with AAO guidelines was found after implementation of our protocol for a physician-led, team-based care model to standardize glaucoma care among providers. PMID- 28617722 TI - Prevalence of Pseudoexfoliation Syndrome in an Isolated Island Population of Korea: The Woodo Study. AB - PURPOSE: To determine the prevalence and clinical characteristics of pseudoexfoliation syndrome (PXS) within Korean population living in Woodo Island. METHODS: Among the 625 residents aged 50 years or older, 305 residents (197 women and 108 men) participated in the study; a response rate of 48.8%. Participants filled out questionnaires on life style. Intraocular pressure and corneal endothelial cell function was measured. Both pupils were dilated. Fundus photographs and stereo disc photographs were taken. Vertical cup-to-disc ratio was determined. Pure tone audiometry threshold was measured at 0.5, 1, 2, 4, and 6 kHz of frequencies for each ear. RESULTS: The prevalence rate of PXS among Woodo Island residents older than 50 years significantly increased with age, from 1.0% [95% confidence interval (CI), 0%-2.8%] in participants aged 50 to 59 years to 23.3% (95% CI, 8.2%-38.5%) in those aged over 80 years (P<0.001). The prevalence of PXS showed no significant difference between men and women in all age groups. The age-standardized prevalence rate of PXS was 10.4% (95% CI, 8.0% 12.8%), with a rate of 9.4% (95% CI, 5.8%-13.1%) in men and 14.9% (95% CI, 11.3% 18.4%) in women. PXS did not show significant association with smoking, outdoor activity, and occupation, except alcohol consumption. PXS showed significant decrease in endothelial cell density. Pure tone audiometry test of PXS group revealed statistically significant decrease in 1, 2 kHz. CONCLUSIONS: The prevalence of PXS was 10.4% in the 50 years and older age group, and tended to increase with age. Decrease in corneal endothelial function and selective hearing loss was correlated in PXE patients, supporting impairment of systemic endothelial function in PXE syndrome. PMID- 28617723 TI - Effect of Uterine Fundal Pressure on Maternal Intraocular Pressure in Cesarean Delivery: Comparison of Regional and General Anesthesia. AB - PURPOSE: To evaluate the intraocular pressure (IOP) changes accompanying fundal pressure during a cesarean-section procedure under both regional and general anesthesia. METHODS: In total, 60 women scheduled for elective cesarean section, none of them diagnosed with ocular problems, were enrolled in the study. Patients underwent cesarean section under either general (group G, n=30) or regional anesthesia (group S, n=30) according to their choice. IOP was measured with a Tono-Pen before (T1) and after (T2) application of anesthesia, during fundal pressure (T3), and after the birth of the baby (T4). Heart rate as well as systolic, diastolic, and mean arterial pressure were recorded during the procedure. RESULTS: There was no significant difference in IOP between the groups (P>0.05). In group S, IOP at T3 was significantly higher than at all other timepoints (P<0.001). In group G, IOP at T3 was significantly higher than at T2 and T4. Mean arterial pressure was significantly lower in group S at all timepoints except T1. CONCLUSIONS: In conclusion, fundal pressure may significantly increase the IOP, but the choice of anesthetic technique may not have any effect on IOP. PMID- 28617724 TI - Intracorneal Inlays for the Correction of Presbyopia. AB - The current nonsurgical approaches for the correction of presbyopia are spectacles or contact lenses or the use of pharmaceuticals to create an artificial pupil and/or to stimulate residual accommodation. Refractive surgical procedures use a monovision approach and/or a multifocal corneal laser ablation with or without the induction of negative spherical aberration to improve near vision. More recently, new surgical approaches include intracorneal inlays. Inlay approaches include increasing corneal curvature alone, implanting a multifocal inlay, or by implanting a small aperture device that functions as a pinhole to restore unaided near and intermediate visual acuity. This review presents an analysis of the history and development of the various inlay approaches designed to improve presbyopia. Unlike other refractive surgical approaches, these newer techniques are removable. Each has its advantages and disadvantages. PMID- 28617725 TI - Depth Profile Assessment of the Early Phase Deposition of Lysozyme on Soft Contact Lens Materials Using a Novel In Vitro Eye Model. AB - OBJECTIVE: To characterize the location of fluorescently labeled lysozyme on commercial contact lenses (CLs) using an in vitro eye model that simulates tear volume, tear flow, air exposure, and mechanical wear. METHODS: One commercially available conventional hydrogel CL material (etafilcon A) and three silicone hydrogel CL materials (balafilcon A, lotrafilcon B, and senofilcon A) were evaluated in this study. The CLs were mounted on the in vitro eye model and exposed to artificial tear fluid containing fluorescein isothiocyanate (FITC) labeled lysozyme for 2 and 10 hrs. After these short incubation periods, circular discs were punched from the CLs at the center and periphery and were prepared for confocal laser scanning microscopy (CLSM). The CLSM captured a series of consecutive images spaced 5 MUm apart, and the resulting images were rendered into two dimensional cross-sectional views of the CL. The mean fluorescence at each 5 MUm slice was used to generate a histogram depicting the penetration of FITC-lysozyme into CLs. RESULTS: For both incubation periods, the CLSM images and histogram of etafilcon A showed that FITC-lysozyme is more concentrated at the lens surface, with a moderate amount of deposition in the lens matrix. For balafilcon A, FITC-lysozyme was evenly distributed throughout the lens. For lotrafilcon B, there was a greater amount of FITC-lysozyme deposition on the surfaces of the lens versus the matrix. Senofilcon A had differential FITC lysozyme distribution profiles depending on the location of the lens. At the lens periphery, FITC-lysozyme primarily deposited on the surface, whereas FITC lysozyme was uniformly distributed at the center of the lens. CONCLUSIONS: With the use of a sophisticated in vitro eye model, the study revealed a complex deposition pattern of FITC-labeled lysozyme on various CL materials after short periods of exposure. An understanding of the early deposition pattern of lysozyme on different CL material may elucidate new insights into the processes behind CL discomfort. PMID- 28617726 TI - Comparative Analysis of Peripheral Corneal Geometry in Health and Keratoconus. AB - OBJECTIVES: To describe and compare corneal peripheral angles in normal and keratoconic eyes, to gain a better understanding of the topography of the periphery of the cornea in keratoconus and assist practitioners in the selection and fitting of large diameter contact lenses. METHODS: Eighty-eight eyes were included in the study, divided into three groups: healthy (A0, 28 eyes), keratoconus at stage I according to the Amsler-Krumeich classification (AI, 33 eyes) and keratoconus at stages II to IV (AII, 27 eyes). The Pentacam Scheimpflug system was used to manually measure the corneal peripheral angles corresponding to a chord length range between 8.6 and 12.6 mm at 8 different peripheral locations. RESULTS: The peripheral angle was influenced by ocular condition and by the peripheral location, with no interaction effect between both factors. Statistically significant differences were found in mean corneal peripheral angles between groups A0 (30.84 degrees +/-2.33 degrees ) and AI (31.63 degrees +/-2.02 degrees ) (P=0.001) and between A0 and AII (31.37 degrees +/-2.11 degrees ) (P=0.030). The differences between AI and AII were not significant. In all eyes, the largest and smallest peripheral angles were found at the temporal inferior and temporal superior locations, respectively, with a mean difference between largest and smallest of 3.37 degrees +/-1.42 degrees in healthy eyes and 2.96 degrees +/-1.54 degrees in keratoconus (AI+AII). CONCLUSION: Clinically insignificant differences were found in peripheral angles between keratoconus and healthy eyes, giving support to the use of large diameter, intralimbal contact lenses with peripheral designs, and resting on the same corneal region, as those fitted on normal corneas. PMID- 28617727 TI - Descemet's Membrane Dehiscence Resulting From Misdirected Viscoelastic During Anterior Chamber Reformation. AB - We report a case of Descemet's membrane detachment after inadvertent intrastromal injection of hyaluronic acid. Surgical removal was attempted with minimal but slow improvement. Near-complete resolution occurred with subsequent conservative management within 6 weeks. PMID- 28617728 TI - A Comparison of the Effects of Orthokeratology Lens, Medcall Lens, and Ordinary Frame Glasses on the Accommodative Response in Myopic Children. AB - OBJECTIVE: To observe and compare changes in accommodative response between myopic children wearing ordinary frame glasses (OFG), Mouldway orthokeratology lenses (M-OK), and medcall lenses (ML). METHODS: A total of 240 myopic children were divided into three groups: OFG [n=90]; M-OK [n=90]; and ML [n=60]). The diopter, accommodative lag, and binocular accommodative facility before wearing glasses (T0) and 1-year after wearing glasses (T1) were compared among the three groups. RESULTS: Commercially available software was used to perform statistical analysis, and the data were expressed as mean+/-SD. There were no significant differences among the three groups at T0. The accommodative lags in M-OK and ML at T1 were significantly lower than those at T0; this finding was most evident in M-OK. Although accommodative facility increased in all three groups, the increase was most evident in M-OK and ML. CONCLUSION: Mouldway orthokeratology lenses and ML can reduce the accommodative lag and increase the accommodative facility in myopic children. Compared with ML, M-OK showed considerably more marked effects to myopia progression in children. PMID- 28617729 TI - Demographic Characteristics and Prescribing Patterns of Scleral Lens Fitters: The SCOPE Study. AB - OBJECTIVES: This study reports demographic characteristics of scleral lens providers and indications for scleral lens prescription as assessed by a worldwide online survey. METHODS: The Scleral Lenses in Current Ophthalmic Practice: an Evaluation (SCOPE) study group designed the online survey regarding current scleral lens prescription and management practices. The Mayo Clinic Survey Research Center administered the survey, which was open from January 15 to March 31, 2015. Data from 989 responses were collated by the Survey Research Center and deidentified before analysis. Responses of individuals who had fit at least five patients with scleral lenses were analyzed in detail. RESULTS: Most lens fitters were men (61%, n=800). Of survey respondents, 29% were 25 to 34 years; 22%, 35 to 44 years; 22%, 45 to 54 years; and 26%, more than 55 years (n=806). For 29% of all respondents, professional training was completed between 2009 and 2014 (n=804). Most (54%) fit their first patient between 2010 and 2015, with the earliest lens fit reported in 1956 (n=634). Most respondents (63%) worked primarily in private, group, or retail practice (n=811). Scleral lenses were most often prescribed for corneal irregularity (74%), followed by ocular surface disease (16%) and uncomplicated refractive error (10%) (n=673). CONCLUSIONS: Eye care providers of all ages are fitting scleral lenses. The number of individuals who fit this lens modality has increased during the past decade. Scleral lenses are being fit by providers in a wide range of practice settings. Most scleral lenses are prescribed for corneal irregularity. PMID- 28617730 TI - Eye Symptom Questionnaire to Evaluate Anterior Eye Health. AB - OBJECTIVES: Ophthalmologists assess eye complaints with a careful history and eye examination; however, other types of physicians have limited tools to evaluate anterior segment (AS) eye diseases. We identified the eye symptom questions that providers should ask to help determine the presence and urgency of AS eye diseases. METHODS: Persons with and without AS disease completed a self-report eye symptom questionnaire (ESQ) based on the National Institutes of Health Toolbox symptom items in an academic center's corneal and comprehensive eye clinics. Gold standard ophthalmic examination determined the presence and urgency of AS disease. The association between reported symptom severity and the probability of AS disease, or urgent AS disease, was evaluated using logistic regression models, and sensitivity and specificity of the ESQ were also calculated. RESULTS: A total of 324 eyes of 162 subjects were included in the study. Of these, AS disease was present in 255 eyes (79%); of which, 111 eyes showed urgent disease. Increasing symptom severity for eye pain (odds ratio [OR]=2.58; P<0.001), glare (OR=2.61; P=0.001), and blurry vision (OR=1.98; P<0.001) were associated with increased odds of AS disease. Increasing symptom severity for eye pain (OR=2.02; P<0.001), eye redness (OR=1.69; P=0.02), and blurry vision (OR=1.41, P=0.01) were associated with increased odds of urgent AS disease. For the primary analysis with mild symptoms considered relevant, the sensitivity of the ESQ to detect AS disease was 83% and to detect urgent AS disease was 92%. CONCLUSION: Symptoms of eye pain, glare, redness, and blurry vision indicate the presence and urgency of AS disease. PMID- 28617731 TI - Retention Rates in New Contact Lens Wearers. AB - PURPOSE: To determine the retention rate (RR) for neophyte patients fitted with contact lenses (CLs) and to identify factors associated with retention and dropout. METHOD: This multisite, sponsor-masked registry study evaluated the 1 year status of neophyte CL wearers fitted in a representative range of UK practices. A total of 26 UK investigational sites each recruited up to 89 neophyte patients. The participants were requested to complete surveys at 1 month (+/-1 week from date of fitting), 3 months (+/-2 weeks), and 12 months (+/-3 weeks) online or through phone. Participants were contacted by email (or phone) and invited to complete an online survey that asked a range of questions regarding their CL wearing experience. RESULTS: Of the 531 participants recruited, 65.3% (347/531) responded to at least one follow-up survey and 42.3% (225/531) responded to all three surveys. One in four patients showed discontinued CL wear by 12 months. Based on evaluable subjects at 12 months, the RR was 77.6% (194/250, 95% confidence interval: 72.0-82.3). The most common reason for discontinuation was problems with vision (41%), followed by discomfort (36%) and handling problems (25%). The factors affecting first-year RRs: sex, spherical refraction, lens usage (full time or part time), and supply method (collected or posted). CONCLUSIONS: In this prospective study, the first-year RR for neophyte CL wearers was 77.6%. This was consistent with that noted in a retrospective study: 74.0%. As with the previous study, the commonly cited reason for discontinuation was visual problems. PMID- 28617732 TI - The Effects of Latanoprost With Benzalkonium Chloride Versus Travoprost With SofZia on the Ocular Surface. AB - PURPOSE: To assess ocular surface changes in participants using latanoprost with benzalkonium chloride (Xalatan) and travoprost with SofZia (Travatan Z). METHODS: In this prospective, open-label, nonrandomized cohort study, participants were classified into two groups: group 1 (n=28) naive to glaucoma therapy, group 2 (n=27) on previous Xalatan monotherapy in both eyes. Both groups started (or continued) Xalatan in the right eye and Travatan Z in the left eye. Baseline, 1-, and 2-month measurements of tear breakup time (TBUT), corneal staining score, conjunctival staining score, conjunctival hyperemia score, tear production, and intraocular pressure were obtained. The Ocular Surface Disease Index questionnaire measured participants' comfort and dryness symptoms. Medication preference was recorded. RESULTS: Data were collected from 55 participants. Tear breakup time at baseline and 1-month follow-up in group 1 was significantly longer than that of group 2 (P=0.005). At 2 months, there was no significant difference in TBUT between the two groups (P=0.779). Tear production in group 1 at all three time points was significantly higher than group 2 (P<0.05). Conjunctival staining score at 2 months in group 1 was significantly higher than group 2 (P=0.031). There was no significant difference in other parameters between the groups at any other time point. No significant difference in any parameter was found between Xalatan and Travatan Z (intragroup comparison). CONCLUSIONS: Significant differences in ocular surface characteristics were detected between groups, but no significant difference was detected between participants treated with Xalatan and Travatan Z. PMID- 28617733 TI - Economic Costs and Health-Related Quality of Life Outcomes of HIV Treatment After Self- and Facility-Based HIV Testing in a Cluster Randomized Trial. AB - BACKGROUND: The scale-up of HIV self-testing (HIVST) in Africa is recommended, but little is known about how this novel approach influences economic outcomes following subsequent antiretroviral treatment (ART) compared with established facility-based HIV testing and counseling (HTC) approaches. SETTING: HIV clinics in Blantyre, Malawi. METHODS: Consecutive HIV-positive participants, diagnosed by HIVST or facility-based HTC as part of a community cluster-randomized trial (ISRCTN02004005), were followed from initial assessment for ART until 1-year postinitiation. Healthcare resource use was prospectively measured, and primary costing studies undertaken to estimate total health provider costs. Participants were interviewed to establish direct nonmedical and indirect costs over the first year of ART. Costs were adjusted to 2014 US$ and INT$. Health-related quality of life was measured using the EuroQol EQ-5D at each clinic visit. Multivariable analyses estimated predictors of economic outcomes. RESULTS: Of 325 participants attending HIV clinics for assessment for ART, 265 were identified through facility-based HTC, and 60 through HIVST; 168/265 (69.2%) and 36/60 (60.0%), respectively, met national ART eligibility criteria and initiated treatment. The mean total health provider assessment costs for ART initiation were US$22.79 (SE: 0.56) and US$19.92 (SE: 0.77) for facility-based HTC and HIVST participants, respectively, and was US$2.87 (bootstrap 95% CI: US$1.01 to US$4.73) lower for the HIVST group. The mean total health provider costs for the first year of ART were US$168.65 (SE: 2.02) and US$164.66 (SE: 4.21) for facility-based HTC and HIVST participants, respectively, and comparable between the 2 groups (bootstrap 95% CI: -US$12.38 to US$4.39). EQ-5D utility scores immediately before and one year after ART initiation were comparable between the 2 groups. EQ-5D utility scores 1 year after ART initiation had increased by 0.129 (SE: 0.011) and 0.139 (SE: 0.027) for facility-based HTC and HIVST participants, respectively. CONCLUSIONS: Once HIV self-testers are linked into HIV services, their economic outcomes are comparable to those linking to services after facility-based HTC. PMID- 28617734 TI - Is PrEP Needed for MSM in West Africa? HIV Incidence in a Prospective Multicountry Cohort. PMID- 28617736 TI - Symmetry Restoration at Rest after Masseter-to-Facial Nerve Transfer: Is It as Efficient as Smile Reanimation? AB - BACKGROUND: Masseter-to-facial nerve transfer is a highly efficient technique for reanimating paralyzed muscle and has been reported to restore facial symmetry at rest. However, no systematic studies have been performed, and the effects of preoperative droop of the oral commissure on postoperative symmetry at rest have rarely been reported. METHODS: The authors retrospectively analyzed 35 patients with masseteric-to-facial nerve anastomosis and assessed the quality and quantity of the dynamic recovery and the oral commissure symmetry at rest. The dynamic and static effects were then compared. RESULTS: All of the patients' Terzis scores were increased postoperatively, and over half of the patients presented restored symmetric smiles (Terzis scores of 4 or 5). The postoperative symmetry scale of the oral commissure at rest improved in 18 of 35 patients. Both the mean postoperative altitude difference of oral commissure excursion and the postoperative altitude difference of bilateral oral commissure position were decreased compared with preoperative values. The preoperative symmetry had a significant effect on the postoperative altitude difference of the bilateral oral commissure position. The effects of the dynamic and static symmetry improvements were transformed to a comparable factor alpha. The dynamic alpha was significantly greater than the static alpha. CONCLUSIONS: Masseter-to-facial nerve transfer is a reliable technique for smile reanimation. However, it has only a limited effect on the improvement of symmetry at rest. Assessing the preoperative symmetry of the oral commissure at rest can be used to predict postoperative outcomes, and patients with severe droop of the oral commissure (symmetry scale grade III or IV) should receive static suspension. PMID- 28617738 TI - The Whitaker Classification of Craniosynostosis Outcomes: An Assessment of Interrater Reliability. AB - BACKGROUND: The Whitaker classification is a simple and widely used system for describing aesthetic outcomes after craniosynostosis surgery. The purpose of this study is to evaluate its interrater reliability for patients who have undergone fronto-orbital surgery. METHODS: A retrospective review of patients with craniosynostosis who underwent surgical intervention at a tertiary referral center was conducted. Inclusion criteria were as follows: single-suture craniosynostosis, surgical intervention before age 2 years, and photographs taken before revisions between 5 and 20 years of age. Thirteen craniofacial surgeons independently reviewed the subjects' photographs and assigned Whitaker classifications. Interrater reliability was assessed with the Cohen kappa statistic. RESULTS: Twenty-nine subjects were included. Average ages at surgery and at the time of postoperative photography were 0.8 year and 12.8 years, respectively. The kappa value for all 13 raters was 0.1567 (p < 0.0001), indicating "slight agreement." Pairwise comparisons demonstrated kappa values ranging from 0.0384 to 0.5492. The average rating for the set of 29 photographs differed significantly across the 13 raters (p = 0.0020) and ranged from 1.79 +/- 0.68 to 2.79 +/- 0.77. Finally, we found that average Whitaker classification did not differ significantly between subjects who subsequently underwent cranioplasty and/or fronto-orbital advancement and those who did not (subsequent procedures, 2.45 +/- 0.55; no subsequent procedures, 1.88 +/- 0.78; p = 0.1087). CONCLUSIONS: The Whitaker classification exhibits low interrater reliability and does not predict future treatment. It may benefit craniofacial surgeons to create new evaluation tools with greater precision, to improve the quality of patient care and craniofacial outcomes research. PMID- 28617739 TI - Gynecomastia Classification for Surgical Management: A Systematic Review and Novel Classification System. PMID- 28617740 TI - Academic Productivity, Knowledge, and Education in Plastic Surgery: The Benefit of the Clinical Research Fellow. AB - BACKGROUND: Academic research productivity is limited by strenuous resident and faculty schedules but nevertheless is imperative to the growth and success of our discipline. The authors report institutional experience with their clinical research fellowship model, providing two positions per year. METHODS: A critical analysis of research productivity was performed for all trainees, faculty, and research fellows from 2000 to 2015. Academic productivity was determined by the number of peer-reviewed publications, podium presentations, and h-index. Academic fate of previous research fellows was also noted. During the 16-year timeframe, 484 articles were published in print. Notably, 92 articles were published from 2000 to 2007 and 392 articles were published from 2008 to 2015 (p = 0.0066), demonstrating linear growth after instituting the research fellowship. In addition, 33 articles were published from 2002 to 2004 before leadership change, 47 from 2005 to 2007 after leadership change but before fellowship, and 58 from 2008 to 2010 in the first few years of the fellowship (p = 0.0204). RESULTS: Overall, 39.9 percent of publications appeared in Plastic and Reconstructive Surgery, with a total of 77 different peer-reviewed journal inclusions. American Association of Plastic Surgeons, American Society of Plastic Surgeons, and Northeastern Society of Plastic Surgeons podium presentations totaled 143 between 2005 and 2015. Of the eight previous fellows who applied into integrated and independent programs, 100 percent have matched. CONCLUSION: Incorporation of a formalized research fellowship into a plastic surgery program can drastically increase clinical research contribution in a reproducible fashion. PMID- 28617741 TI - Soft-Tissue Reconstruction of Large Spinal Defects: A 12-Year Institutional Experience. AB - BACKGROUND: Spinal resections can lead to defects requiring soft-tissue reconstruction. The purpose of this study was to review the authors' institutional experience with reconstruction of spinal defects and identify risk factors predictive of wound complications, focusing on timing of reconstruction with ablative surgery. METHODS: The authors retrospectively reviewed patients who underwent spinal resection and required soft-tissue reconstruction from 2002 to 2014. Logistic regression was performed to identify risk factors for complications. RESULTS: Of 289 reconstructions performed in 259 patients, 64 cases (22.1 percent) had major wound complications requiring reoperation. Lumbosacral defects were the most common location (43.6 percent) and paraspinous muscle flaps were the preferred reconstructive method used for all defect regions. A total of 224 reconstructions (77.5 percent) were performed immediately at the time of spinal surgery, and 65 (22.5 percent) were performed in delayed fashion as a result of wound complications from previous spinal surgery. Patients undergoing immediate reconstruction had significantly lower rates of instrumentation removal (0.9 percent versus 4.6 percent; p = 0.043), unplanned reoperations (0.5 versus 1.3; p < 0.001), and mortality (0.9 percent versus 9.2 percent; p < 0.001) compared with those undergoing delayed reconstruction. On logistic regression analysis, presence of instrumentation (OR, 3.2; p = 0.012), requirement for a free flap (OR, 9.0; p = 0.016), and spinal cord exposure (OR, 2.6; p = 0.036) were associated with increased odds of a major wound complication. CONCLUSION: Spinal resections carry significant surgical-site morbidity, and selection of high-risk patients for immediate reconstruction with locoregional muscle flaps may be beneficial for improving wound-related outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28617742 TI - Facial Contouring by Targeted Restoration of Facial Fat Compartment Volume: The Midface. PMID- 28617743 TI - Reply: Gynecomastia Classification for Surgical Management: A Systematic Review and Novel Classification System. PMID- 28617744 TI - Evidence-Based Medicine: A FINER PICO Analysis. PMID- 28617745 TI - Grafting Techniques Discussed. PMID- 28617749 TI - Are You Correctly Using ABNs? PMID- 28617750 TI - Skin and Wound Care in Lymphedema Patients: A Taxonomy, Primer, and Literature Review. AB - BACKGROUND: Lymphedema is a condition of localized protein-rich swelling from damaged or malfunctioning lymphatics. Because the immune system is compromised, there is a high risk of infection. Infection in patients with lymphedema may present in a variety of ways. OBJECTIVE: The goals of this review were to standardize the terminology of skin breakdown in the context of lymphedema, synthesize the available information to create best practice recommendations in support of the American Lymphedema Framework Project update to its Best Practices document, and create recommendations for further research. DATA SOURCES: Publications on skin care and wounds were retrieved, summarized, and evaluated by a team of investigators and clinical experts. STUDY SELECTION AND DATA EXTRACTION: Terms for lymphedema-associated skin breakdown were compiled and paired with photographs of commonly noted skin changes among patients with lymphedema. A list of standard dermatological terms was created. A more extensive literature search was then conducted by all authors. DATA SYNTHESIS: Skin disorders associated with lymphedema have been classified into 5 categories. Descriptions, photographs, and recommendations for treatment are presented. CONCLUSIONS: Skin care is an important defense against infection. Because of the lack of research, a consensus of thought and content leaders' opinion should guide the best practices for wound care in lymphedema. PMID- 28617752 TI - Quality Payment Program: Engaging in Improvement Activity for the Merit-based Incentive Payment System. PMID- 28617751 TI - Economic Evaluations of Strategies to Prevent Hospital-Acquired Pressure Injuries. AB - GENERAL PURPOSE: To provide information from a review of literature about economic evaluations of preventive strategies for pressure injuries (PIs). TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Identify the purpose and methods used for this study.2. Compare costs and effectiveness related to preventative strategies for PIs. ABSTRACT: BACKGROUND: Pressure injuries (PIs) are a common and resource-intensive challenge for acute care hospitals worldwide. While a number of preventive strategies have the potential to reduce the cost of hospital-acquired PIs, it is unclear what approach is the most effective. OBJECTIVE: The authors performed a narrative review of the literature on economic evaluations of preventive strategies to survey current findings and identify important factors in economic assessments. DATA SOURCES: Ovid, MEDLINE, NHS Economic Evaluation Databases, and the Cochrane Database of Systematic ReviewsSELECTION CRITERIA: Potentially relevant original research articles and systematic reviews were considered. DATA EXTRACTION: Selection criteria included articles that were written in English, provided data on cost or economic evaluations of preventive strategies of PIs in acute care, and published between January 2004 and September 2015. Data were abstracted from the articles using a standardized approach to evaluate how the items on the Consolidated Health Economic Evaluation Reporting Standards checklist were addressed. DATA SYNTHESIS: The searches identified 192 references. Thirty-three original articles were chosen for full-text reviews. Nineteen of these articles provided clear descriptions of interventions, study methods, and outcomes considered. CONCLUSIONS: Limitations in the available literature prevent firm conclusions from being reached about the relative economic merits of the various approaches to the prevention of PIs. The authors' review revealed a need for additional high quality studies that adhere to commonly used standards of both currently utilized and emerging ways to prevent hospital-acquired PIs. PMID- 28617755 TI - Prevalence and Phenotype of Concurrent Psoriasis and Inflammatory Bowel Disease. AB - BACKGROUND: Psoriasis, psoriatic arthritis (PsA), and inflammatory bowel disease (IBD) are related inflammatory immune-mediated diseases, with considerable overlap. However, it is as yet unclear whether co-occurrence of these diseases affects disease course and characteristics of the individual complaints. The objective of this study was to identify the prevalence of IBD and PsA in a psoriasis cohort and to examine whether patients with concurrent psoriasis and IBD carry a distinct phenotype. METHODS: Data of all patients with psoriasis visiting a general hospital in the Netherlands between 2009 and 2014 were retrospectively retrieved from electronic patient files. In addition, clinical characteristics of patients with concurrent psoriasis and IBD (n = 40) were compared with psoriasis-only (n = 1643) and IBD-only (n = 385) cohorts. RESULTS: Among 1669 hospital-based patients with psoriasis, prevalence of PsA was 12.2% (n = 203, 95% confidence interval, 10.5-13.7) and of IBD 1.6% (n = 26, 95% confidence interval, 1.0-2.2), including 12 Crohn's disease (CD) and 14 ulcerative colitis. Psoriasis-PsA patients were more likely to have IBD than psoriasis-only patients (3.0 versus 1.4%).Psoriasis-CD patients were younger at CD diagnosis (20.0 versus 32.0 yr, P = 0.001), and psoriasis diagnosis (28.0 versus 43.5 yr, P = 0.004) than psoriasis-only patients. Psoriasis-IBD patients had a mild psoriasis phenotype similar to psoriasis-only patients, but the CD phenotype was significantly more severe than in CD-only patients. CONCLUSIONS: The prevalence of IBD in psoriasis was approximately 4 times higher than that in the general population, with the highest risk for psoriasis-PsA patients. Psoriasis-CD patients have a mild (early-onset) psoriasis but an earlier-onset and severe CD-phenotype. PMID- 28617754 TI - Longitudinal Patterns of Medication Nonadherence and Associated Health Care Costs. AB - BACKGROUND: Nonadherence to treatment recommendations is associated with poorer outcomes in inflammatory bowel disease and may increase the cost of care. We examined the longitudinal relationship between nonadherence and health care costs and hypothesized that at least 3 distinct trajectories of nonadherence would be observed and that increasing nonadherence would account for significantly greater health care costs after controlling for disease activity. METHODS: Ninety-nine patients aged 2 to 21 years with inflammatory bowel disease were recruited into this 2-year longitudinal study. Medication possession ratios were calculated from pharmacy refill data, disease activity ratings were obtained from medical charts, and hospital and physician charges associated with an International Classification of Diseases, Ninth Revision code for ulcerative colitis or Crohn's disease were obtained from the hospital's accounting database. RESULTS: An average total cost effect size of d = 0.68 was observed between the increasing severity and stable low severity groups, but the confidence intervals overlap. Conversely, patients with increasing nonadherence demonstrated significantly higher health care costs than patients with stable <=10%, stable 11% to 20%, or decreasing nonadherence. CONCLUSIONS: Medication nonadherence is related to increased health care costs after controlling for disease severity. Patients with increasing nonadherence over time demonstrate more than a 3-fold increase in costs compared with adherent patients. In addition, patients whose adherence improves over time incur approximately the same costs as those who are consistently adherent. This suggests that, in addition to leveraging prevention efforts to keep patients from becoming more nonadherent as treatment continues, efforts aimed at modifying adherence behavior may result in significant cost savings over time. PMID- 28617756 TI - Optimizing Thiopurine Therapy in Inflammatory Bowel Disease Among 2 Real-life Intercept Cohorts: Effect of Allopurinol Comedication? AB - BACKGROUND: Thiopurines (azathioprine and mercaptopurine) are frequently used immunosuppressive drugs to maintain remission in patients with inflammatory bowel disease. Half of the conventional thiopurine-derivative users have to discontinue treatment within 5 years, mainly because of intolerable adverse events. Over recent years, different strategies to optimize thiopurine treatment were suggested, yet, studies describing the clinical effectiveness of these strategies remain scarce. The aims of this study were to compare tolerability and sustained clinical benefit of conventional thiopurine derivatives therapy among two 5-year real-life intercept cohorts and to assess the clinical value of specifically allopurinol cotherapy. METHODS: In this retrospective single-center cohort study, we analyzed data from patients in whom weight-based thiopurine monotherapy was initiated between 2005 and 2009 (cohort 1) or between 2010 and 2014 (cohort 2). The initiation of the second cohort was synchronic to the start of allopurinol based optimization in our center. Optimization strategies were extracted from patient charts. RESULTS: In total, 105 patients were included (60 in cohort 1, and 45 in cohort 2). Metabolite measurement was performed in 37% versus 84% of the patients (P < 0.001). Subsequent optimization strategies were applied in 33% versus 58% of the patients because of inadequate metabolite concentrations, intolerance, or ineffectiveness (P = 0.01). Allopurinol was coadministered to therapy in 18 patients (40%) in the second cohort. Therapy was switched to thioguanine in 11 versus 6 patients (P > 0.05). Overall, total duration was longer in the second cohort (10.8 versus 34.1 months, P < 0.001). The number of ongoing thiopurine users (20% versus 49%) and sustained clinical benefit (13% versus 38%) were higher in the second cohort (both P < 0.05). This was mainly because of a decrease in hepatotoxicity after optimization (P < 0.01). CONCLUSIONS: Optimization of thiopurine therapy by the use of therapeutic drug monitoring with subsequent administration of allopurinol cotherapy successfully enhanced sustained clinical benefit and tolerability in patients with inflammatory bowel disease. PMID- 28617757 TI - Looking into Enteric Virome in Patients with IBD: Defining Guilty or Innocence? AB - BACKGROUND: Although there is some evidence suggesting that certain viruses may be involved in the onset of inflammatory bowel disease (IBD), data regarding viral prevalence and viral load in blood and mucosa of patients with IBD are scarce. The main aim of this study is to evaluate the prevalence and viral load of common Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus 6 in blood and mucosa of adult patients with endoscopic active IBD. METHODS: From January to December 2014, ulcerative colitis and Crohn's disease patients with active endoscopic disease were consecutively enrolled. Subjects undergoing colonoscopy for colorectal cancer screening served as healthy controls (HCs). Paired blood and mucosal samples from each patient and HC were collected for EBV, CMV, and human herpes virus 6 quantitative real time polymerase chain reaction assessment of the viral load. RESULTS: One hundred forty-five subjects were included; 95 IBD patients with active endoscopic disease (43 ulcerative colitis and 52 Crohn's disease) and 50 healthy subjects. CMV and EBV DNA were detected more frequently in the mucosa of patients with IBD compared with HCs (CMV P = 0.017; EBV P < 0.001), irrespective of IBD type. The frequency of human herpes virus 6 DNA detection both in the blood and in the mucosa did not differ between patients with IBD and HCs. EBV median viral load was similar in the inflamed and noninflamed mucosa was not affected by the use of immunomodulators and/or anti tumor necrosis factor alpha agents, and did not correlate with endoscopic disease activity. CONCLUSIONS: EBV, and to a lesser extent CMV, were more prevalent in patients with IBD than in HCs. Mucosal viral load was not influenced by the therapeutic regimen, did not differ between inflamed and noninflamed mucosa, and did not seem to be influenced by the endoscopic activity of the disease, suggesting that EBV may be more involved in the onset of IBD than in its severity and clinical evolution. PMID- 28617758 TI - Individualized Infliximab Treatment Guided by Patient-managed eHealth in Children and Adolescents with Inflammatory Bowel Disease. AB - BACKGROUND: To individualize timing of infliximab (IFX) treatment in children and adolescents with inflammatory bowel disease (IBD) using a patient-managed eHealth program. METHODS: Patients with IBD, 10 to 17 years old, treated with IFX were prospectively included. Starting 4 weeks after their last infusion, patients reported a weekly symptom score and provided a stool sample for fecal calprotectin analysis. Based on symptom scores and fecal calprotectin results, the eHealth program calculated a total inflammation burden score that determined the timing of the next IFX infusion (4-12 wk after the previous infusion). Quality of Life was scored by IMPACT III. A control group was included to compare trough levels of IFX antibodies and concentrations and treatment intervals. Patients and their parents evaluated the eHealth program. RESULTS: There were 29 patients with IBD in the eHealth group and 21 patients with IBD in the control group. During the control period, 94 infusions were provided in the eHealth group (mean interval 9.5 wk; SD 2.3) versus 105 infusions in the control group (mean interval 6.9 wk; SD 1.4). Treatment intervals were longer in the eHealth group (P < 0.001). Quality of Life did not change during the study. Appearance of IFX antibodies did not differ between the 2 groups. Eighty percent of patients reported increased disease control and 63% (86% of parents) reported an improved knowledge of the disease. CONCLUSIONS: Self-managed, eHealth-individualized timing of IFX treatments, with treatment intervals of 4 to 12 weeks, was accompanied by no significant development of IFX antibodies. Patients reported better control and improved knowledge of their IBD. PMID- 28617759 TI - Functional topography of the primary motor cortex during motor execution and motor imagery as revealed by functional MRI. AB - Controversy exists regarding the involvement of the primary motor cortex (M1) during motor imagery (MI) and also regarding the differential somatotopic representation of motor execution (ME) and mental simulation of movement, that is, MI within M1. Although some research reported clear M1 involvement during MI without overt motor output, others did not. However, possible somatotopic representation between execution and imagery has not been clearly investigated to date. The aim of the present study was to aid in the resolution of this controversy by investigating the possible involvement of M1 during MI, and the differential, within M1, somatotopic representation between execution and imagery by quantitatively assessing different location markers such as activation peak and center of mass as well as intensity differences between the two tasks in case of with and without the overlap between the two representations. Forty-one healthy volunteers participated in two functional MRI runs of mouth-stretching ME and MI tasks. Our findings suggest the clear involvement of M1 (BA 4) during MI with lower signal intensity compared with ME, and further showed distinct centers for each representation along the y-axis (anteroposterior plane), with MI showing more involvement of the anterior sector of M1 (BA 4a), whereas ME recruited more of the posterior sector (BA 4p). These results parallel the pioneering findings of a functional distinction between BA 4a and BA 4p, where BA 4a is more involved in the cognitive aspects of MI, whereas BA 4p is more related to executive function, promoting the idea of distinctive somatotopic mapping between execution and imagery within M1 sectors. PMID- 28617760 TI - Nonisolated Small Bowel Gastrointestinal Angiodysplasias are Associated With Higher Rebleeding Rates When Compared With Isolated Small Bowel Gastrointestinal Angiodysplasia on Video Capsule Endoscopy. AB - BACKGROUND: Gastrointestinal angiodysplasias (GIAD) are commonly diagnosed in the small bowel but can be located in other areas of the gastrointestinal tract. About half of patients diagnosed with GIAD have more than 1 lesion and 20% of patients have GIAD in both the small bowel and a source outside of the small bowel (nonisolated to small bowel GIAD or NISGIAD). The remaining patients with GIAD have lesions isolated to the small bowel (ISGIAD). Complications including rebleeding, hospitalization and mortality rates have not been previously analyzed between these 2 groups. AIM: To compare rebleeding, hospitalization and mortality rates between ISGIAD and NISGIAD. The secondary goals were to evaluate comorbidities that may be associated with ISGIAD and/or NISGIAD, and to determine if any of these comorbidities are associated with a higher risk of rebleeding from GIAD. MATERIALS AND METHODS: This was a retrospective study that included 425 patients who underwent video capsule endoscopy between 2006 and 2013. Patients underwent esophagogastroduodenoscopy and colonoscopy before video capsule endoscopy. The primary indications for workup included obscure gastrointestinal bleeding. After exclusion criteria, 87 patients diagnosed with GIAD remained, 57 patients with ISGIAD and 30 with NISGIAD. Categorical variables were compared by the Fisher exact test or chi test and continuous data were compared using the Student T test. RESULTS: Risk factors associated with rebleeding rates included coronary artery disease, chronic kidney disease, and congestive heart failure on multivariate analysis. Odds ratios for rebleeding was found in patients with NISGIAD (odds ratio, 4.222; P=0.036). There was no difference in hospitalization rates between patients with ISGIAD and NISGIAD. There was no statistically significant difference in mortality from any cause at 30, 60, and 90 days in patients with ISGIAD and NISGIAD. CONCLUSIONS: In this retrospective analysis of GIAD at a single institution, patients with NISGIAD compared with ISGIAD had a 4 times odds of rebleeding within 1 year after capsule endoscopy. This is a novel study, as the distribution of GIAD has not been previously described as being a risk factor for rebleeding. PMID- 28617761 TI - Hepatitis C Virus Prevalence in Egyptian Americans in Southern California. AB - BACKGROUND: Hepatitis C virus (HCV) is a global medical health concern. Egypt has the highest HCV prevalence. Few studies have assessed the HCV prevalence rates among Egyptian-born expatriates. We sought to define the HCV prevalence Egyptian born individuals residing in the Southern California area. PATIENTS AND METHODS: We screened Egyptian-born individuals in houses of worship in the Southern California area using a point of care test HCV antibody test. Results were confirmed by testing the blood for viral load. Demographic information including risk factors were also collected. Individuals were contacted with their results, and those found to be detectable HCV antibodies were referred for further testing and additional care. RESULTS: Three hundred twenty-six Egyptian expatriates from 7 houses of worship in Southern California were screened for the HCV infection. Most of the participants were screened at Coptic Churches. Nine of these individuals were found to be HCV infected (2.8%). We found an increased HCV seroprevalence in subjects were male and born in Egyptian urban areas. Five of the 9 subjects (56%) who tested positive were not baby boomers and only 2 of these 9 subjects (22%) had recognized Center for Disease Control risk factors. CONCLUSIONS: The HCV prevalence rate of Egyptian-born individuals living in the Southern California area was lower compared with the prevalence rate in the general Egyptian population, but higher than that seen in the general US population. The utility of using Center for Disease Control risk factors to define individuals at risk of HCV among Egyptian expatriates is not applicable. PMID- 28617762 TI - Racial Disparities and Sociodemographic Differences in Incidence and Survival Among Pediatric Patients in the United States With Primary Liver Cancer: A Surveillance, Epidemiology, and End Results (SEER) Population Study. AB - BACKGROUND: Primary liver cancer, including Hepatoblastoma (HB) and hepatocellular carcinoma (HCC), in pediatric populations is often fatal. The outcomes are poor despite universal health care access in pediatric patients. AIM: We investigated the sociodemographic factors affecting outcomes in pediatric patients with primary liver cancer. MATERIALS AND METHODS: This is a large population database study of Surveillance, Epidemiology, and End Results cancer registry data from 1973 to 2011. HB and HCC were analyzed regarding age, sex, race, geographic area, and treatment-related information including survival. RESULTS: In total, 998 patients, the median age at time of diagnosis was 1 year for HB [0-19; 95% confidence interval (CI), 1.5-1.9] and 14 years for HCC (0-19; 95% CI, 12.1-13.3) (P<0.001). Overall Survival (OS) in HB was 374 months (25% failures 19) versus HCC 21 months (25% failures 5; P<0.0001). In HCC, the fibrolamellar subgroup OS was 41 months (32-.) versus 16 months (11-21) in all others [hazard ratio (HR) 2.0; P=0.005]. Diagnosis between 2000 and 2011 (HB: 25% failures not reached; HCC: 38) versus diagnosis 1973 to 1999 (HB: 374; HCC: 12) had different survival (P=0.01; HR 1.9). For HB, OS in patients with age of diagnosis under 2, 25% failures was not reached versus 374 months over the age of 2 (HR 1.7; P<0.0007). African American children with HB had OS of 67 (17-.) versus all others (25% failures 21) and 48% of African American children were diagnosed after the age of 2 versus 34% of whites (HR 1.9; P=0.01). CONCLUSIONS: Later diagnosis and decreased survival in African American children with HB warrants further research. PMID- 28617763 TI - Short-Term Peripheral Vasoactive Infusions in Pediatrics: Where Is the Harm? AB - OBJECTIVE: Pediatric shock represents a major cause of morbidity and mortality in the United States. Standardization of treatment such as volume resuscitation and vasoactive administration has resulted in improved patient outcomes. Vasoactives have been anecdotally associated with peripheral IV infiltration and extravasation. There is a paucity of evidence in pediatrics to determine the ideal route of vasoactive infusions and what, if any, risk factors and harm are associated with peripheral IV infiltration and extravasation. We aim to assess the frequency of and risk factors for peripheral IV infiltration and extravasation during peripheral IV vasoactive infusions in children admitted to the PICU. DESIGN: A retrospective, cohort study of all children admitted to a PICU from January 2012 to June 2014. SETTING: Forty-four-bed PICU at Children's National Health System. PATIENTS: All children 0-18 years old receiving a vasoactive infusion through a peripheral IV for a minimum of 1 hour. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcomes of this study were incidence of peripheral IV infiltration and extravasation and resultant tissue injury. Secondary outcomes were peripheral IV characteristics and vasoactive infusion data. One hundred two patients met inclusion criteria. Sixty-two percent (63/102) were admitted with the diagnosis of septic shock. The most commonly used vasoactive agent was dopamine. The median peak Vasoactive Infusion Score was 10 (6-14). Peripheral IV infiltration and extravasation incidence was 2% (2/102) and neither event resulted in injury requiring medical or surgical intervention. CONCLUSIONS: Vasoactive infusions through peripheral IV in children admitted to the PICU with shock were observed to have a low incidence of peripheral IV infiltration and extravasation and resultant tissue injury. Short-term delivery of vasoactives via peripheral IV catheter in a highly monitored PICU setting appears to be safe. PMID- 28617764 TI - Oropharyngeal Colostrum Administration in Very Low Birth Weight Infants: A Randomized Controlled Trial. AB - OBJECTIVES: Studies have confirmed the safety of oropharyngeal administration of colostrum in very low birth weight infants. However, the effect of oropharyngeal administration of colostrum on immune system is inconclusive. This study aims to evaluate the effect of oropharyngeal administration of colostrum on secretory immunoglobulin A and lactoferrin in very low birth weight infants. DESIGN: Randomized controlled trial. SETTING: Forty-bedded neonatal ICU in a university children's hospital in the People's Republic of China. PATIENTS: Very low birth weight infants were allocated to the study group (n = 32) and control group (n = 32). INTERVENTION: The intervention was oropharyngeal administration of 0.2 mL of their mother's colostrum every 4 hours for 7 days. The control group received saline solution. MEASUREMENTS AND MAIN RESULTS: Secretory immunoglobulin A and lactoferrin in urine and saliva were measured within 24 hours of life (baseline) and at 7 and 21 days. Primary outcomes were changes of secretory immunoglobulin A and lactoferrin in urine and saliva between baseline and at 7 and 21 days. Infant's clinical data were also collected during hospitalization. Change from baseline in lactoferrin in saliva at 7 days (5.18 +/- 7.07 vs -1.74 +/- 4.67 ug/mL; p < 0.001) and 21 days (5.31 +/- 9.74 vs -1.17 +/- 10.38 ug/mL; p = 0.02) shows statistic difference. No differences were found of lactoferrin in urine and also no differences of secretory immunoglobulin A in urine and saliva. There were also no differences between days to full enteral feeding, occurrence rate of clinical sepsis, proven sepsis, and necrotizing enterocolitis. CONCLUSIONS: Oropharyngeal administration of colostrum can increases the level of lactoferrin in saliva in very low birth weight infants. No effect could be documented of secretory immunoglobulin A and lactoferrin in urine. Larger trials are needed to better describe the benefit of oropharyngeal administration of colostrum, if any, in very low birth weight infants. PMID- 28617766 TI - Notes from the Field: Evaluation of a Perceived Cluster of Plasma Cell Dyscrasias Among Workers at a Natural Gas Company - Illinois, 2014. PMID- 28617767 TI - QuickStats: Percentage* of Children and Teens Aged 4-17 Years Ever Diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD),? by Sex and UrbanizationS of County of Residence - National Health Interview Survey, 2013-2015. AB - During 2013-2015, the percentage of children and teens aged 4-17 years who had ever received a diagnosis of ADHD was significantly higher among boys than among girls within all urbanization levels. Among boys, those living in small metro and nonmetro micropolitan areas were more likely to have received a diagnosis of ADHD (17.4% and 16.4%, respectively) than were those living in large central (11.4%) and large fringe (12.7%) metropolitan areas. Among girls, those living in large central areas were less likely to have received a diagnosis of ADHD (4.4%) than those living in each of the other five types of urban/rural areas. PMID- 28617765 TI - Cardioprotective Effects of Nicorandil on Coronary Heart Disease Patients Undergoing Elective Percutaneous Coronary Intervention. AB - BACKGROUND Nicorandil is a nicotinamide ester commonly prescribed for treatment of patients with coronary heart disease (CHD). In the present study, we aimed to explore the cardioprotective effects of nicorandil on CHD patients undergoing elective percutaneous coronary intervention (PCI). MATERIAL AND METHODS One hundred patients with CHD undergoing PCI were randomly divided into a control group (n=48) and a nicorandil group (n=52). Patients in the control group received traditional therapy, and while patients in the nicorandil group received nicorandil before PCI in addition to the traditional therapy. After PCI, all patients underwent coronary angiogram, and TIMI frame count (TFC) was calculated. Plasma levels of cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), myeloperoxidase (MPO), and malondialdehyde (MDA) were determined before and at 6, 18, and 24 h after PCI. Moreover, systolic blood pressure (SBP), mean blood pressure (DBP), heart rate (HR), and left ventricular ejection fractions (LVEF) were recorded before and 3 months after PCI. RESULTS There was a significant difference in the rate of no-reflow (P=0.036) between the 2 groups. The blood frames and levels of cTnI, CK-MB, MPO, and MDA in the nicorandil group were significantly decreased compared to the control group (all P<0.05). Moreover, administration of nicorandil markedly decreased SBP, MBP, and HR, but obviously increased LVEF at 3 months after PCI (P<0.05 or P<0.01). CONCLUSIONS Nicorandil exerts cardioprotective effects on CHD patients undergoing elective PCI by decreasing PCI-related myocardial injury and rate of no-reflow and improvement of LVEF. PMID- 28617768 TI - Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease - United States. AB - The term "chronic Lyme disease" is used by some health care providers as a diagnosis for various constitutional, musculoskeletal, and neuropsychiatric symptoms (1,2). Patients with a diagnosis of chronic Lyme disease have been provided a wide range of medications as treatment, including long courses of intravenous (IV) antibiotics (3,4). Studies have not shown that such treatments lead to substantial long-term improvement for patients, and they can be harmful (1,5). This report describes cases of septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess resulting from treatments for chronic Lyme disease. Patients, clinicians, and public health practitioners should be aware that treatments for chronic Lyme disease can carry serious risks. PMID- 28617769 TI - Trends in Breastfeeding Among Infants Enrolled in the Special Supplemental Nutrition Program for Women, Infants and Children - New York, 2002-2015. AB - Breastfeeding is widely accepted as the optimal method of infant feeding (1,2). New York Special Supplemental Nutrition Program for Women, Infants and Children (WIC) has prioritized the promotion of breastfeeding. To assess breastfeeding trends among New York WIC infants, indicators for measuring breastfeeding practices reported by the New York Pediatric Nutrition Surveillance System (PedNSS) during 2002-2015 were examined. The prevalence of breastfeeding initiation increased from 62.0% (2002) to 83.4% (2015), exceeding the Healthy People 2020 (HP2020)* objective of 81.9% in 2014, with improvements among all racial/ethnic groups. The percentage of New York WIC infants who breastfed for >=6 and >=12 months increased from 30.2% and 15.0% (2002) to 39.5% and 22.8% (2015), respectively. The prevalence of exclusive breastfeeding for >=3 and >=6 months increased from 8.9% and 2.9% (2006) to 14.3% and 8.0% (2015), respectively. Despite improvements in breastfeeding initiation, increasing the duration of breastfeeding and of exclusive breastfeeding among infants enrolled in the New York WIC program remains challenging. Identifying targeted strategies to support continued and exclusive breastfeeding should remain priorities for the New York WIC program. PMID- 28617770 TI - Announcement: Community Preventive Services Task Force Recommendation for Team Based Care for Patients with Type 2 Diabetes. AB - The Community Preventive Services Task Force recently posted new information on its website: "Diabetes Management: Team-Based Care for Patients with Type 2 Diabetes." The information is available at https://www.thecommunityguide.org/findings/diabetes-management-team-based-care patients-type-2-diabetes. PMID- 28617771 TI - Tobacco Use Among Middle and High School Students - United States, 2011-2016. AB - Tobacco use is the leading cause of preventable disease and death in the United States; nearly all tobacco use begins during youth and young adulthood (1,2). Among youths, use of tobacco products in any form is unsafe (1,3). CDC and the Food and Drug Administration (FDA) analyzed data from the 2011-2016 National Youth Tobacco Surveys (NYTS) to determine recent patterns of current (past 30 day) use of seven tobacco product types among U.S. middle (grades 6-8) and high (grades 9-12) school students. In 2016, 20.2% of surveyed high school students and 7.2% of middle school students reported current tobacco product use. In 2016, among current tobacco product users, 47.2% of high school students and 42.4% of middle school students used >=2 tobacco products, and electronic cigarettes (e cigarettes) were the most commonly used tobacco product among high (11.3%) and middle (4.3%) school students. Current use of any tobacco product did not change significantly during 2011-2016 among high or middle school students, although combustible tobacco product use declined. However, during 2015-2016, among high school students, decreases were observed in current use of any tobacco product, any combustible product, >=2 tobacco products, e-cigarettes, and hookahs. Among middle school students, current use of e-cigarettes decreased. Comprehensive and sustained strategies can help prevent and reduce the use of all forms of tobacco products among U.S. youths (1-3). PMID- 28617772 TI - Electronic Cigarettes as an Introductory Tobacco Product Among Eighth and 11th Grade Tobacco Users - Oregon, 2015. AB - During 2011-2015, increased electronic cigarette (e-cigarette) and hookah use offset declines in cigarette and other tobacco product use among youths (persons aged <18 years) (1). Limited information exists about which tobacco product introduced youths to tobacco product use. Patterns of first use of e-cigarettes among Oregon youths who were tobacco users were assessed in the Oregon Healthy Teens 2015 survey, a cross-sectional survey of eighth and 11th grade students in Oregon. Respondents were asked, "The very first time you used any tobacco or vaping product, which type of product did you use?" Among students who had ever used any tobacco product (ever users), e-cigarettes were the most common introductory tobacco product reported by both eighth (43.5%) and 11th (34.4%) grade students. Among students who used a tobacco product for >=1 day during the past 30 days (current users), e-cigarettes were the most common introductory tobacco product reported by eighth grade students (44.4%) and the second most common introductory tobacco product reported by 11th grade students (31.0%). Introductory use of e-cigarettes was commonly reported among youths in Oregon who were ever or current tobacco users, underscoring the importance of proven interventions to prevent all forms of tobacco use among youths (2,3). PMID- 28617774 TI - ? PMID- 28617775 TI - [Doctors' and nurses' perceptions of the spending review in the autonomous province of Trento (Italy)]. AB - The national expenditure limits set by the spending review has required reorganization and streamlining measures. The present study was conducted in 2015, among 2,020 nurses and 861 doctors in the autonomous province of Trento (Italy), to describe their perceptions of the containment measures introduced in healthcare spending, following the spending review. Results show that nurses and doctors were most affected by the measures regarding staff management (staff turnover rate, reducing overtime and changes in training). These measures, however, cannot be adopted for a long period of time without leading to negative effects on organization and quality of care. PMID- 28617773 TI - Pregnancy Outcomes After Maternal Zika Virus Infection During Pregnancy - U.S. Territories, January 1, 2016-April 25, 2017. AB - Pregnant women living in or traveling to areas with local mosquito-borne Zika virus transmission are at risk for Zika virus infection, which can lead to severe fetal and infant brain abnormalities and microcephaly (1). In February 2016, CDC recommended 1) routine testing for Zika virus infection of asymptomatic pregnant women living in areas with ongoing local Zika virus transmission at the first prenatal care visit, 2) retesting during the second trimester for women who initially test negative, and 3) testing of pregnant women with signs or symptoms consistent with Zika virus disease (e.g., fever, rash, arthralgia, or conjunctivitis) at any time during pregnancy (2). To collect information about pregnant women with laboratory evidence of recent possible Zika virus infection* and outcomes in their fetuses and infants, CDC established pregnancy and infant registries (3). During January 1, 2016-April 25, 2017, U.S. territories? with local transmission of Zika virus reported 2,549 completed pregnanciesS (live births and pregnancy losses at any gestational age) with laboratory evidence of recent possible Zika virus infection; 5% of fetuses or infants resulting from these pregnancies had birth defects potentially associated with Zika virus infection (4,5). Among completed pregnancies with positive nucleic acid tests confirming Zika infection identified in the first, second, and third trimesters, the percentage of fetuses or infants with possible Zika-associated birth defects was 8%, 5%, and 4%, respectively. Among liveborn infants, 59% had Zika laboratory testing results reported to the pregnancy and infant registries. Identification and follow-up of infants born to women with laboratory evidence of recent possible Zika virus infection during pregnancy permits timely and appropriate clinical intervention services (6). PMID- 28617776 TI - [Employment status and perceived health in Italy: data from the European Union Statistics on Income and Living Conditions (EU-SILC) longitudinal study]. AB - The aim of this study was to investigate the relationship between employment status (permanent employment, fixed-term employment, unemployment, other) and perceived health status in a sample of the Italian population. Data was obtained from the European Union Statistics on Income and Living Condition (EU-SILC) study during the period 2009 - 2012. The sample consists of 4,848 individuals, each with a complete record of observations during four years for a total of 19,392 observations. The causal relationship between perceived/self-reported health status and employment status was tested using a global logit model (STATA). Our results confirm a significant association between employment status and perceived health, as well as between perceived health status and economic status. Unemployment that was dependent on an actual lack of work opportunities and not from individual disability was found to be the most significant determinant of perceived health status; a higher educational level produces a better perceived health status. PMID- 28617777 TI - [Healthcare associated infections: patient mobility in Italy and costs for Italian healthcare organizations]. AB - Healthcare-associated infections (HCI) are an obstacle to assuring safe hospital treatments. This study evaluates awareness of HCIs among the Italian population, readiness to file a complaint against the hospital in the event of an HCI, and the distance patients would be willing to travel to be treated in hospitals with lower HCI rates. Furthermore, the report highlights the importance of this issue in the context of hospital management. PMID- 28617778 TI - [Inequalities in oral health in Italy: what role for dentists?] AB - Due to the lack of both available data and political attention, the oral health of the popula-tion seems to be neglected at a scientific level. Actually, however, the dental sector shows strong ine-qualities in access, especially because of the economic crisis that hit most European countries, particu-larly Italy. In order to understand the impact of the organizational variables related to the supply of dental services on the inequalities, an empirical research was carried out in 2013, involving representatives of the dental profession within the 105 Italian provincial orders of physicians and dentists. Both qualitative and quantitative methodological tools have been used. The main results seem to give us back the image of a profession that is going through a very difficult period; problems, which occur on multiple levels, cannot be attributed solely to the economic crisis that started in 2008. Problems appear structural and require a process of change that has to involve, on the one hand, citizens and government institutions and, on the other, the latter and the dental profession. PMID- 28617779 TI - [Physical activity and its importance in the workplace]. AB - The present study aims to highlight the importance of physical activity in the workplace and its fundamental role for the wellness of an individual. The relationship between sedentary lifestyle and health is supported by several epidemiological studies and inactivity is one of the main risk factors for cardiovascular disease, chronic conditions and cancer. According to the World Health Organization, physical activity represents: "any bodily movement produced by skeletal muscles that requires energy expenditure". The promotion of regular physical activity, including its promotion in the workplace is of fundamental importance since a close correlation exists between good health and physical activity. Moreover, regular physical activity improves psycho-physical performance, social relationships, work performance and reduces sickness, absenteeism from work and work injuries. PMID- 28617780 TI - [The burden of disability in Cameroon]. AB - AIM: Rehabilitation services for disabled persons are lacking in countries with limited economic resources. Reliable and objective data are needed to plan for their implementation and to determine the burden of disability in these countries. METHODS: A descriptive cross-sectional study conducted in June 2013 among people living in Dschang Health District, in the West region of Cameroon, to collect information about socio-demographic aspects of physically disabled subjects and health determinants of disabilities. Data was collected using a standard questionnaire in French. RESULTS: In total, 159 physically disabled subjects were enrolled in the study. Mean age was 36 years [+/- SD 17.26], 55.9% of subjects were female, and 33.8% had a low educational-level. The most frequently reported disabilities were orthopaedic problems (mainly fractures) [45.8%], infectious diseases [29.1%]), and neurological disabilities (mainly hemiplegia [33.3%], hemiparesis [23.8%], and monoplegia [23.8%]). The main causes of disability were trauma due to traffic accidents (17.8%) and inappropriate medical interventions (14.5%). Disability was related to age and 50% of participants experienced social discrimination. Disabled subjects with low incomes (from 50.000 to 200.000 XAF) were required to pay for rehabilitative care (XAF 10.000 to 100.000), and up to 83% had appealed for improved quality of Rehabilitation Medicine. CONCLUSION: Although Law n. 83/013 for the protection of persons with disabilities in Cameroon dates back to 1983, the results of this study show that disabled people, and children in particular, are still marginalized, vulnerable and have little chance of recovery. Therefore, there is a clear need to improve the quality and availability of rehabilitative care services , with programmatic interventions that ensure implementation of existing laws, improve access to rehabilitative services, provide disabled persons with the necessary specialty medical products, and eliminate barriers to their social participation. PMID- 28617781 TI - [The Italian Immunization Plan 2017: analysis and starting point for the Regional Plans]. AB - The National Immunization Plan 2017-2019 has been approved on January 2017. This official document contains the new Italian guidelines to improve vaccination coverage in the country. We conducted an accurate and critical analysis of the document, highlighting its key points and critical issues, in order to offer an practical tool for writing the Regional Plans. The new immunization schedule and the establishment of a restricted panel for the vaccine vigilance are the most significant innovations of the Plan. The Plan addresses also the issues of mandatory vaccination and of penalties for physicians who advise against vaccinations. Together with the presence of qualifying aspects as information about the ethical value and the benefits of vaccination, the Plan contains other interesting proposals, such as the introduction of a computerized vaccination register and the targeted use of new technologies to reach the population extensively. The Plan is set up as a conceptually rich tool, suitable for the development of regional operational plans. PMID- 28617782 TI - Data sharing statements for clinical trials: a requirement of the International Committee of Medical Journal Editors. PMID- 28617783 TI - Progress in public reporting in New Zealand since the Ombudsman's ruling, and an invitation. PMID- 28617784 TI - Rising medical student debt: should we be alarmed? PMID- 28617785 TI - Haemochromatosis: evaluating the effectiveness of a novel patient self-management approach to venesection as blood donation. AB - AIM: We set out to evaluate the effectiveness of a new model of self management of haemochromatosis, whereby patients with stable ferritin control were discharged from the New Zealand Blood Service (NZBS) therapeutic venesection clinic and educated to manage their own venesection by regular blood donation and annual serum ferritin check by their general practitioner. METHOD: Data regarding the frequency of blood donation and serum ferritin level were collected from the NZBS and Concerto records of haemochromatosis patients in the Wellington region who had been discharged back to the care of their general practitioner between January 2014 and June 2015. RESULTS: Of the 107 patients, 93% continued to donate blood after discharge. A serum ferritin level was checked in 78% of patients by their general practitioner. The mean number of blood donations per year decreased after discharge, with a corresponding rise in the average ferritin level (difference 28 mcg/L; range 13-43 mcg/L; p<0.005). CONCLUSION: The new model of self management was effective for the majority of patients who were discharged from the therapeutic venesection clinic. Longer follow up is required to assess the overall pattern of ferritin control in patients who self manage their haemochromatosis by regular blood donation. PMID- 28617786 TI - Audit of Trichomonas vaginalis test requesting by community referrers after a change from culture to molecular testing, including a cost analysis. AB - AIMS: Trichomonas vaginalis (TV) prevalence varies among different communities and peoples. The availability of robust molecular platforms for the detection of TV has advanced diagnosis; however, molecular tests are more costly than phenotypic methodologies, and testing all urogenital samples is costly. We recently replaced culture methods with the Aptima Trichomonas vaginalis nucleic acid amplification test on specific request and as reflex testing by the laboratory, and have audited this change. METHODS: Data were collected from August 2015 (microbroth culture and microscopy) and August 2016 (Aptima TV assay) including referrer, testing volumes, results and test cost estimates. RESULTS: In August 2015, 10,299 vaginal swabs, and in August 2016, 2,189 specimens (urogenital swabs and urines), were tested. The positivity rate went from 0.9% to 5.3%, and overall more TV infections were detected in 2016. The number needed to test and cost for one positive TV result respectively was 111 and $902.55 in 2015, and 19 and $368.92 in 2016. Request volumes and positivity rates differed among referrers. CONCLUSIONS: The methodology change was associated with higher overall detection of TV, and reductions in the numbers needed to test/cost for one TV diagnosis. Our audit suggests that there is room for improvement with TV test requesting in our community. PMID- 28617787 TI - Rising levels of New Zealand medical student debt. AB - AIM: There is little recent data on the debt levels accrued by New Zealand medical graduates. We aimed to quantify the level of student loan debt accrued by medical graduates upon completion of their medical degree, and to investigate the association of New Zealand Government Student Loan (GSL) debt with gender and age. METHODS: At graduation each year from 2006-2015, students from one New Zealand medical programme were invited to complete a career intention survey that included information on levels of GSL debt and the number of income sources used. RESULTS: The overall response rate was 83.8%. On average, 92% of domestic students reported having some student loan debt, with 28% a debt of $90,000 or more. The proportion of students reporting a student loan debt of $90,000 or more increased over the period of the study (P<0.0001). While older students were more likely to have a larger student loan debt than younger students, there was no difference in debt levels by gender. Students with larger student loans were more likely to rely on a larger number of financial sources to fund their studies. CONCLUSIONS: New Zealand medical students are carrying higher levels of student loan debt year on year. The effect of this on the future medical workforce is not certain; however, this could be negative if graduates choose to enter careers that are more highly paid over areas of high need. The full impact of large loans on individuals and the health system will take years to determine. PMID- 28617788 TI - Age at referral for undescended testes: has anything changed in a decade? AB - AIM: Undescended testis (UDT) affects 1-6% of males and is one of the most common disorders in paediatric surgery.Updated consensus guidelines now recommend surgical management of UDT by 18 months. We compare the age at referral and subsequent timing of orchiopexy with data published from 1996-1998 at our institution, prior to the advent of updated guidelines. METHODS: A retrospective review of all patients undergoing an orchiopexy for UDT from 2014 to 2016 was conducted. The age at time of first referral, first outpatient review and age at date of surgery were recorded. Calculations were made for time between referral and clinic visit (T-1) and between clinic visit and surgery (T-2). Data are reported as median (range). RESULTS: In the 2014-2016 group (n=216), the median age at time of referral was 5.3 (range 0-182) months. Following referral, children were seen in the clinic at a median interval 1.84 (T-1: range 0.16-17) months. The median interval between the clinic visit and operation was 2.95 (T-2: range 0-30.7) months. The median age at time of surgery was 12.6 (range 4.6 191.3) months. Compared to the data from 1996-1998 (n=325), there was a drop in the median ages both at time of referral (23 months vs 5.3) and at time of operation (38.8 months vs 12.6). In this cohort, 66% (n=143) of boys had surgery before eighteen months of age. The median times between referral and clinic visit (T-1: 1.7 months vs 1.84) and between clinic and operation (T-2: 3.3 months vs 2.95) were essentially unchanged. CONCLUSION: Our second snapshot in time (2014 2016) shows improvements in median age at referral (under six months) and age at time of operation (at 12.6 months) when compared to the older snapshot (1996 1998). These timings are more in keeping with recommendations for orchiopexy. PMID- 28617789 TI - Adequate adherence to benzathine penicillin secondary prophylaxis following the diagnosis of rheumatic heart disease by echocardiographic screening. AB - AIMS: The primary aim of this study was to determine adherence to benzathine penicillin (BPG) for individuals diagnosed with rheumatic heart disease (RHD) by echocardiographic screening between 2007-2012. METHODS: BPG records were obtained for 57 patients, median age 12 at time of diagnosis. A 'days at risk' analysis was undertaken. Annual adherence was calculated for each individual. A comparison with the Wellington region's Rheumatic Fever 2013 adherence data was undertaken. RESULTS: Adherence to BPG was good with a median follow-up time of 5.8 years. Days at risk analysis: median 0% at year one and 2.7% at year five. The median adherence for the entire cohort over the entire follow-up period was 92%, range 0 100%. There was no difference of proportions of late doses compared to the Wellington region. Median adherence was higher for register based (94%, n=48) compared to primary health care penicillin delivery (37%, n=7), p<0.005. During follow-up, 30% of the cohort moved between regions or overseas. CONCLUSIONS: Good adherence rates are achievable for secondary prophylaxis when RHD is diagnosed by echocardiographic screening. This likely reflects the benefit of rheumatic fever registers and community nursing services rather than the pathway of the diagnosis for RHD. PMID- 28617790 TI - Clinical management and patient persistence with antibiotic course in suspected group A streptococcal pharyngitis for primary prevention of rheumatic fever: the perspective from a New Zealand emergency department. AB - AIM: Rates of acute rheumatic fever in the Northland region are historically among the highest in New Zealand, impacting disproportionately on Maori children and youth. The primary aim of this study was to determine patient persistence to antibiotic treatment for group A streptococcus (GAS) pharyngitis in patients presenting with sore throat to the Whangarei Hospital Emergency Department. Secondarily, this study sought to determine prescriber adherence to the national antibiotic guideline for sore throat management. METHOD: A retrospective audit of patients presenting to ED with presumed GAS pharyngitis between 1 May 2016 and 31 August 2016 was carried out. Data on patient demographics, clinical examination findings, investigations and antibiotic prescription were extracted from electronic medical records. Patients were contacted and after obtaining consent, were asked about their antibiotic treatment using a standardised telephone interview script. RESULTS: The patient population audited reflects those at high risk for acute rheumatic fever. All patients were discharged on the recommended medication, but only 82.7% (62/75) received the correct length (10 days) of oral antibiotics. Of the total of 75 patients audited, 61 (81%) had a swab taken and 41% (25/61) of these were confirmed positive for GAS. Patients were either advised to commence medication without waiting for a swab result (96%, 72/75) or delay treatment and commence only if no improvement in symptoms (4%, 3/75). Of those advised to commence medication immediately, 94% (67/72) obtained their medication from a community pharmacy. Three patients were advised to stop treatment after confirmation of a negative result. Of those patients assessable for medication persistence (n=65), 73.8% (48/65) of patients were compliant in completing the full course of antibiotic therapy. CONCLUSION: This is the first study to assess patient persistence to an antibiotic course for GAS after presentation at an emergency department in Northland and possibly New Zealand. The results indicate a relatively high persistence rate with oral antibiotic treatment by patients treated for suspected GAS pharyngitis. An important finding is that community pharmacy dispensing does not appear to be a major barrier to patients acquiring medications. Additionally, the study shows low levels of follow up of patients with negative throat swab results, resulting in these patients completing the course of antibiotics unnecessarily. PMID- 28617791 TI - Mapping housing for the disabled in New Zealand. PMID- 28617793 TI - Survival of Legionella in earthquake-induced soil disturbance (liquefaction). PMID- 28617792 TI - Simultaneous bilateral snowboarder's fractures in a young woman: a rare entity. AB - BACKGROUND: Talus is a well-supported bone in the foot. A fracture of talus requires a high-impact injury. A wedge-shaped inferolateral component is the lateral process of the talus (LPT). A fracture of LPT is also known as a 'snowboarder's fracture'. Simultaneous bilateral snowboarder's fracture is rarely reported in English literature. CASE: We present here a case of simultaneous bilateral snowboarder's fractures in a slow-moving motor vehicle accident in the icy conditions. The injuries were unique because the snowboarder's fractures were accompanied by fractures of the inferior aspect of talus bilaterally and a fracture of the anterior process of the calcaneus in the right foot. To our knowledge, no such case has been reported in the past. Our patient underwent successful open reduction and internal fixation with plate and screws. CONCLUSION: Snowboarder's fractures are frequently missed by the clinicians, which causes significant morbidity of the patients. Adequate knowledge and awareness among the physicians about this type of injury may improve the patient care. PMID- 28617794 TI - New Zealand infants weaned onto a high sugar diet from four months old: better health or better business? Part II. PMID- 28617795 TI - The consequences of courage: the US Surgeon General, the National Rifle Association (NRA) and the Trump regime. PMID- 28617796 TI - Egocentric and allocentric representations in auditory cortex. AB - A key function of the brain is to provide a stable representation of an object's location in the world. In hearing, sound azimuth and elevation are encoded by neurons throughout the auditory system, and auditory cortex is necessary for sound localization. However, the coordinate frame in which neurons represent sound space remains undefined: classical spatial receptive fields in head-fixed subjects can be explained either by sensitivity to sound source location relative to the head (egocentric) or relative to the world (allocentric encoding). This coordinate frame ambiguity can be resolved by studying freely moving subjects; here we recorded spatial receptive fields in the auditory cortex of freely moving ferrets. We found that most spatially tuned neurons represented sound source location relative to the head across changes in head position and direction. In addition, we also recorded a small number of neurons in which sound location was represented in a world-centered coordinate frame. We used measurements of spatial tuning across changes in head position and direction to explore the influence of sound source distance and speed of head movement on auditory cortical activity and spatial tuning. Modulation depth of spatial tuning increased with distance for egocentric but not allocentric units, whereas, for both populations, modulation was stronger at faster movement speeds. Our findings suggest that early auditory cortex primarily represents sound source location relative to ourselves but that a minority of cells can represent sound location in the world independent of our own position. PMID- 28617797 TI - GINOM: A statistical framework for assessing interval overlap of multiple genomic features. AB - A common problem in genomics is to test for associations between two or more genomic features, typically represented as intervals interspersed across the genome. Existing methodologies can test for significant pairwise associations between two genomic intervals; however, they cannot test for associations involving multiple sets of intervals. This limits our ability to uncover more complex, yet biologically important associations between multiple sets of genomic features. We introduce GINOM (Genomic INterval Overlap Model), a new method that enables testing of significant associations between multiple genomic features. We demonstrate GINOM's ability to identify higher-order associations with both simulated and real data. In particular, we used GINOM to explore L1 retrotransposable element insertion bias in lung cancer and found a significant pairwise association between L1 insertions and heterochromatic marks. Unlike other methods, GINOM also detected an association between L1 insertions and gene bodies marked by a facultative heterochromatic mark, which could explain the observed bias for L1 insertions towards cancer-associated genes. PMID- 28617798 TI - Robust transmission of rate coding in the inhibitory Purkinje cell to cerebellar nuclei pathway in awake mice. AB - Neural coding through inhibitory projection pathways remains poorly understood. We analyze the transmission properties of the Purkinje cell (PC) to cerebellar nucleus (CN) pathway in a modeling study using a data set recorded in awake mice containing respiratory rate modulation. We find that inhibitory transmission from tonically active PCs can transmit a behavioral rate code with high fidelity. We parameterized the required population code in PC activity and determined that 20% of PC inputs to a full compartmental CN neuron model need to be rate-comodulated for transmission of a rate code. Rate covariance in PC inputs also accounts for the high coefficient of variation in CN spike trains, while the balance between excitation and inhibition determines spike rate and local spike train variability. Overall, our modeling study can fully account for observed spike train properties of cerebellar output in awake mice, and strongly supports rate coding in the cerebellum. PMID- 28617799 TI - p53 and TAp63 participate in the recombination-dependent pachytene arrest in mouse spermatocytes. AB - To protect germ cells from genomic instability, surveillance mechanisms ensure meiosis occurs properly. In mammals, spermatocytes that display recombination defects experience a so-called recombination-dependent arrest at the pachytene stage, which relies on the MRE11 complex-ATM-CHK2 pathway responding to unrepaired DNA double-strand breaks (DSBs). Here, we asked if p53 family members targets of ATM and CHK2-participate in this arrest. We bred double-mutant mice combining a mutation of a member of the p53 family (p53, TAp63, or p73) with a Trip13 mutation. Trip13 deficiency triggers a recombination-dependent response that arrests spermatocytes in pachynema before they have incorporated the testis specific histone variant H1t into their chromatin. We find that deficiency for either p53 or TAp63, but not p73, allowed spermatocytes to progress further into meiotic prophase despite the presence of numerous unrepaired DSBs. Even so, the double mutant spermatocytes apoptosed at late pachynema because of sex body deficiency; thus p53 and TAp63 are dispensable for arrest caused by sex body defects. These data affirm that recombination-dependent and sex body-deficient arrests occur via genetically separable mechanisms. PMID- 28617800 TI - Whole genome sequencing distinguishes between relapse and reinfection in recurrent leprosy cases. AB - BACKGROUND: Since leprosy is both treated and controlled by multidrug therapy (MDT) it is important to monitor recurrent cases for drug resistance and to distinguish between relapse and reinfection as a means of assessing therapeutic efficacy. All three objectives can be reached with single nucleotide resolution using next generation sequencing and bioinformatics analysis of Mycobacterium leprae DNA present in human skin. METHODOLOGY: DNA was isolated by means of optimized extraction and enrichment methods from samples from three recurrent cases in leprosy patients participating in an open-label, randomized, controlled clinical trial of uniform MDT in Brazil (U-MDT/CT-BR). Genome-wide sequencing of M. leprae was performed and the resultant sequence assemblies analyzed in silico. PRINCIPAL FINDINGS: In all three cases, no mutations responsible for resistance to rifampicin, dapsone and ofloxacin were found, thus eliminating drug resistance as a possible cause of disease recurrence. However, sequence differences were detected between the strains from the first and second disease episodes in all three patients. In one case, clear evidence was obtained for reinfection with an unrelated strain whereas in the other two cases, relapse appeared more probable. CONCLUSIONS/SIGNIFICANCE: This is the first report of using M. leprae whole genome sequencing to reveal that treated and cured leprosy patients who remain in endemic areas can be reinfected by another strain. Next generation sequencing can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission. PMID- 28617801 TI - Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials. AB - OBJECTIVES: To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. METHODS AND FINDINGS: We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23) and weight (RR 3.89, 95% CI 1.43 to 10.59). In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04). We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. CONCLUSION: Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found. PMID- 28617802 TI - Oxidative stress affects processing of amyloid precursor protein in vascular endothelial cells. AB - BACKGROUND: Oxidative stress is thought to be a key player in the pathogenesis of neurodegenerative dementia, including Alzheimer's disease (AD). It has been assumed that oxidative stress contributes to the beta-amyloid deposition in cerebral blood vessels. METHODS: In order to prove this hypothesis, we examined the effect of oxidative stress on the processing of amyloid precursor protein (APP) in primary endothelial cells (EC) derived from cerebral cortical tissue of transgenic Tg2576 mice. Following exposure of EC by 1 MUM hydrogen peroxide for up to 48 hours, formation and secretion of APP cleavage products sAPPalpha and sAPPbeta into the culture medium as well as the expression of endothelial APP were assessed. RESULTS: Oxidative stress resulted in enhanced secretion of sAPPbeta into the culture medium as compared to controls (absence of hydrogen peroxide), which was accompanied by an increased APP expression, induction of VEGF synthesis, nitric oxide and oxygen free radicals productions, and differential changes of endothelial phospo-p42/44 MAPK expression. CONCLUSION: The data suggest that oxidative stress may represent a major risk factor in causing Abeta deposition in the brain vascular system by initiating the amyloidogenic route of endothelial APP processing. The enhanced beta-secretase activity following oxidative stress exposure, possibly promoted by phosphorylation of p42/44 MAPK. PMID- 28617803 TI - Dengue seroprevalence and force of primary infection in a representative population of urban dwelling Indonesian children. AB - BACKGROUND: Indonesia reports the second highest dengue disease burden in the world; these data are from passive surveillance reports and are likely to be significant underestimates. Age-stratified seroprevalence data are relatively unbiased indicators of past exposure and allow understanding of transmission dynamics. METHODOLOGY/PRINCIPAL FINDINGS: To better understand dengue infection history and associated risk factors in Indonesia, a representative population based cross-sectional dengue seroprevalence study was conducted in 1-18-year-old urban children. From October to November 2014, 3,210 children were enrolled from 30 geographically dispersed clusters. Serum samples were tested for anti-dengue IgG antibodies by indirect ELISA. A questionnaire investigated associations between dengue serologic status and household socio-demographic and behavioural factors. Overall, 3,194 samples were tested, giving an adjusted national seroprevalence in this urban population of 69.4% [95% CI: 64.4-74.3] (33.8% [95% CI: 26.4-41.2] in the 1-4-year-olds, 65.4% [95% CI: 69.1-71.7] in the 5-9-year olds, 83.1% [95% CI: 77.1-89.0] in the 10-14-year-olds, and 89.0% [95% CI: 83.9 94.1] in the 15-18-year-olds). The median age of seroconversion estimated through a linear model was 4.8 years. Using a catalytic model and considering a constant force of infection we estimated 13.1% of children experience a primary infection per year. Through a hierarchical logistic multivariate model, the subject's age group (1-4 vs 5-9 OR = 4.25; 1-4 vs. 10-14 OR = 12.60; and 1-4 vs 15-18 OR = 21.87; p<0.0001) and the number of cases diagnosed in the household since the subject was born (p = 0.0004) remained associated with dengue serological status. CONCLUSIONS/SIGNIFICANCE: This is the first dengue seroprevalence study in Indonesia that is targeting a representative sample of the urban paediatric population. This study revealed that more than 80% of children aged 10 years or over have experienced dengue infection at least once. Prospective incidence studies would likely reveal dengue burdens far in excess of reported incidence rates. PMID- 28617804 TI - Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification. AB - PURPOSE: Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. EXPERIMENTAL DESIGN: This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. RESULTS: Among complete cases with 5-year median follow up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group. CONCLUSION: Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma. PMID- 28617805 TI - Effect of eliminating CD4-count thresholds on HIV treatment initiation in South Africa: An empirical modeling study. AB - BACKGROUND: The World Health Organization recommends initiating antiretroviral therapy (ART) regardless of CD4 count. We assessed the effect of ART eligibility on treatment uptake and simulated the impact of WHO's recommendations in South Africa. METHODS: We conducted an empirical analysis of cohort data using a regression discontinuity design, and then used this model for policy simulation. We enrolled all patients (n = 19,279) diagnosed with HIV between August 2011 and December 2013 in the Hlabisa HIV Treatment and Care Programme in rural South Africa. Patients were ART-eligible with CD4<350 cells/mm3 or Stage III/IV illness. We estimated: (1) distribution of first CD4 counts in 2013; (2) probability of initiating ART <=6 months of HIV diagnosis under existing criteria at each CD4 count; (3) probability of initiating ART by CD4 count if thresholds were eliminated; and (4) number of expected new initiators if South Africa eliminates thresholds. FINDINGS: In 2013, 38.9% of patients diagnosed had a CD4 count >=500. 8.0% of these patients initiated even without eligible CD4 counts. If CD4 criteria were eliminated, we project that an additional 19.2% of patients with CD4 >=500 would initiate ART; 72.8% would not initiate ART despite being eligible. Eliminating CD4 criteria would increase the number starting ART by 26.7%. If these numbers hold nationally, this would represent an additional 164,000 initiators per year, a 5.2% increase in patients receiving ART and 5.3% increase in programme costs. CONCLUSIONS: Removing CD4 criteria alone will modestly increase timely uptake of ART. However, our results suggest the majority of newly-eligible patients will not initiate. Improved testing, linkage, and initiation procedures are needed to achieve 90-90-90 targets. PMID- 28617806 TI - A misdiagnosed infection mimicking "tree man disease". PMID- 28617808 TI - Lessons learned on Zika virus vectors. PMID- 28617807 TI - Treatment with macrolides and glucocorticosteroids in severe community-acquired pneumonia: A post-hoc exploratory analysis of a randomized controlled trial. AB - BACKGROUND: Systemic corticosteroids have anti-inflammatory effects, whereas macrolides also have immunomodulatory activity in addition to their primary antimicrobial actions. We aimed to evaluate the potential interaction effect between corticosteroids and macrolides on the systemic inflammatory response in patients with severe community-acquired pneumonia to determine if combining these two immunomodulating agents was harmful, or possibly beneficial. METHODS: We performed a post-hoc exploratory analysis of a randomized clinical trial conducted in three tertiary hospitals in Spain. This trial included patients with severe community-acquired pneumonia with high inflammatory response (C-reactive protein [CRP] >15 mg/dL) who were randomized to receive methylprednisolone 0.5 mg/kg/tpd or placebo. The choice of antibiotic treatment was at the physician's discretion. One hundred and six patients were classified into four groups according to antimicrobial therapy combination (beta-lactam plus macrolide or beta-lactam plus fluoroquinolone) and corticosteroid arm (placebo or corticosteroids). The primary outcome was treatment failure (composite outcome of early treatment failure, or of late treatment failure, or of both early and late treatment failure). RESULTS: The methylprednisolone with beta-lactam plus macrolide group had more elderly patients, with comorbidities, and higher pneumonia severity index (PSI) risk class V, but a lower proportion of intensive care unit admission, compared to the other groups. We found non differences in treatment failure between groups (overall p = 0.374); however, a significant difference in late treatment failure was observed (4 patients in the placebo with beta-lactam plus macrolide group (31%) vs. 9 patients in the placebo with beta lactam plus fluoroquinolone group (24%) vs. 0 patients in the methylprednisolone with beta-lactam plus macrolide group (0%) vs. 2 patients [5%] in the methylprednisolone with beta-lactam plus fluoroquinolone group overall p = 0.009). We found a significant difference for In-hospital mortality in the per protocol population (overall p = 0.01). We did not find significant differences in treatment failure, early or late; or In-hospital mortality after adjusting for severity (PSI), year and centre of enrolment. CONCLUSIONS: In this exploratory analysis, we observed that the glucocorticosteroids and macrolides combination had no statistically significant association with main clinical outcomes compared with other combinations in patients with severe community acquired pneumonia and a high inflammatory response after taking account potential confounders. TRIAL REGISTRATION: Clinicaltrials.gov NCT00908713. PMID- 28617809 TI - Giant elephantiasis and inguino-scrotal hernia. PMID- 28617810 TI - Population-level impact of an accelerated HIV response plan to reach the UNAIDS 90-90-90 target in Cote d'Ivoire: Insights from mathematical modeling. AB - BACKGROUND: National responses will need to be markedly accelerated to achieve the ambitious target of the Joint United Nations Programme on HIV/AIDS (UNAIDS). This target aims for 90% of HIV-positive individuals to be aware of their status, for 90% of those aware to receive antiretroviral therapy (ART), and for 90% of those on treatment to have a suppressed viral load by 2020, with each individual target reaching 95% by 2030. We aimed to estimate the impact of various treatment as-prevention scenarios in Cote d'Ivoire, one of the countries with the highest HIV incidence in West Africa, with unmet HIV prevention and treatment needs, and where key populations are important to the broader HIV epidemic. METHODS AND FINDINGS: An age-stratified dynamic model was developed and calibrated to epidemiological and programmatic data using a Bayesian framework. The model represents sexual and vertical HIV transmission in the general population, female sex workers (FSW), and men who have sex with men (MSM). We estimated the impact of scaling up interventions to reach the UNAIDS targets, as well as the impact of 8 other scenarios, on HIV transmission in adults and children, compared to our baseline scenario that maintains 2015 rates of testing, ART initiation, ART discontinuation, treatment failure, and levels of condom use. In 2015, we estimated that 52% (95% credible intervals: 46%-58%) of HIV-positive individuals were aware of their status, 72% (57%-82%) of those aware were on ART, and 77% (74%-79%) of those on ART were virologically suppressed. Reaching the UNAIDS targets on time would avert 50% (42%-60%) of new HIV infections over 2015-2030 compared to 30% (25%-36%) if the 90-90-90 target is reached in 2025. Attaining the UNAIDS targets in FSW, their clients, and MSM (but not in the rest of the population) would avert a similar fraction of new infections (30%; 21%-39%). A 25 percentage-point drop in condom use from the 2015 levels among FSW and MSM would reduce the impact of reaching the UNAIDS targets, with 38% (26%-51%) of infections averted. The study's main limitation is that homogenous spatial coverage of interventions was assumed, and future lines of inquiry should examine how geographical prioritization could affect HIV transmission. CONCLUSIONS: Maximizing the impact of the UNAIDS targets will require rapid scale-up of interventions, particularly testing, ART initiation, and limiting ART discontinuation. Reaching clients of FSW, as well as key populations, can efficiently reduce transmission. Sustaining the high condom-use levels among key populations should remain an important prevention pillar. PMID- 28617811 TI - Genetic, structural, and chemical insights into the dual function of GRASP55 in germ cell Golgi remodeling and JAM-C polarized localization during spermatogenesis. AB - Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects. Acrosome formation and polarized localization of JAM-C in spermatids were altered in Gorasp2-/- mice. In addition, Golgi morphology of spermatocytes was disturbed in Gorasp2-/- mice. Crystal structures of GRASP55 in complex with JAM-C or JAM-B revealed that GRASP55 interacted via PDZ-mediated interactions with JAMs and induced a conformational change in GRASP55 with respect of its free conformation. An in silico pharmacophore approach identified a chemical compound called Graspin that inhibited PDZ-mediated interactions of GRASP55 with JAMs. Treatment of mice with Graspin hampered the polarized localization of JAM-C in spermatids, induced the premature release of spermatids and affected the Golgi morphology of meiotic spermatocytes. PMID- 28617812 TI - Inferring repeat-protein energetics from evolutionary information. AB - Natural protein sequences contain a record of their history. A common constraint in a given protein family is the ability to fold to specific structures, and it has been shown possible to infer the main native ensemble by analyzing covariations in extant sequences. Still, many natural proteins that fold into the same structural topology show different stabilization energies, and these are often related to their physiological behavior. We propose a description for the energetic variation given by sequence modifications in repeat proteins, systems for which the overall problem is simplified by their inherent symmetry. We explicitly account for single amino acid and pair-wise interactions and treat higher order correlations with a single term. We show that the resulting evolutionary field can be interpreted with structural detail. We trace the variations in the energetic scores of natural proteins and relate them to their experimental characterization. The resulting energetic evolutionary field allows the prediction of the folding free energy change for several mutants, and can be used to generate synthetic sequences that are statistically indistinguishable from the natural counterparts. PMID- 28617813 TI - Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice. AB - Recent findings indicate that growth factor-driven angiogenesis is markedly influenced by genetic variation. This variation in angiogenic responsiveness may alter the susceptibility to a number of angiogenesis-dependent diseases. Here, we utilized the genetic diversity available in common inbred mouse strains to identify the loci and candidate genes responsible for differences in angiogenic response. The corneal micropocket neovascularization assay was performed on 42 different inbred mouse strains using basic fibroblast growth factor (bFGF) pellets. We performed a genome-wide association study utilizing efficient mixed model association (EMMA) mapping using the induced vessel area from all strains. Our analysis yielded five loci with genome-wide significance on chromosomes 4, 8, 11, 15 and 16. We further refined the mapping on chromosome 4 within a haplotype block containing multiple candidate genes. These genes were evaluated by expression analysis in corneas of various inbred strains and in vitro functional assays in human microvascular endothelial cells (HMVECs). Of these, we found the expression of peptidyl arginine deiminase type II (Padi2), known to be involved in metabolic pathways, to have a strong correlation with a haplotype shared by multiple high angiogenic strains. In addition, inhibition of Padi2 demonstrated a dosage-dependent effect in HMVECs. To investigate its role in vivo, we knocked down Padi2 in transgenic kdrl:zsGreen zebrafish embryos using morpholinos. These embryos had disrupted vessel formation compared to control siblings. The impaired vascular pattern was partially rescued by human PADI2 mRNA, providing evidence for the specificity of the morphant phenotype. Taken together, our study is the first to indicate the potential role of Padi2 as an angiogenesis-regulating gene. The characterization of Padi2 and other genes in associated pathways may provide new understanding of angiogenesis regulation and novel targets for diagnosis and treatment of a wide variety of angiogenesis-dependent diseases. PMID- 28617814 TI - Risk of pneumonia in obstructive lung disease: A real-life study comparing extra fine and fine-particle inhaled corticosteroids. AB - BACKGROUND: Regular use of inhaled corticosteroids (ICS) in patients with obstructive lung diseases has been associated with a higher risk of pneumonia, particularly in COPD. The risk of pneumonia has not been previously evaluated in relation to ICS particle size and dose used. METHODS: Historical cohort, UK database study of 23,013 patients with obstructive lung disease aged 12-80 years prescribed extra-fine or fine-particle ICS. The endpoints assessed during the outcome year were diagnosis of pneumonia, acute exacerbations and acute respiratory events in relation to ICS dose. To determine the association between ICS particle size, dose and risk of pneumonia in unmatched and matched treatment groups, logistic and conditional logistic regression models were used. RESULTS: 14788 patients were stepped-up to fine-particle ICS and 8225 to extra-fine ICS. On unmatched analysis, patients stepping-up to extra-fine ICS were significantly less likely to be coded for pneumonia (adjusted odds ratio [aOR] 0.60; 95% CI 0.37, 0.97]); experience acute exacerbations (adjusted risk ratio [aRR] 0.91; 95%CI 0.85, 0.97); and acute respiratory events (aRR 0.90; 95%CI 0.86, 0.94) compared with patients stepping-up to fine-particle ICS. Patients prescribed daily ICS doses in excess of 700 mcg (fluticasone propionate equivalent) had a significantly higher risk of pneumonia (OR [95%CI] 2.38 [1.17, 4.83]) compared with patients prescribed lower doses, irrespective of particle size. CONCLUSIONS: These findings suggest that patients with obstructive lung disease on extra-fine particle ICS have a lower risk of pneumonia than those on fine-particle ICS, with those receiving higher ICS doses being at a greater risk. PMID- 28617815 TI - Impressive predictive value of ankle-brachial index for very long-term outcomes in patients with cardiovascular disease: IMPACT-ABI study. AB - BACKGROUND: The ankle-brachial index (ABI) is a marker of generalized atherosclerosis and is predictive of future cardiovascular events. However, few studies have assessed its relation to long-term future cardiovascular events, especially in patients with borderline ABI. We therefore evaluated the relationship between long-term future cardiovascular events and ABI. METHODS: In the IMPACT-ABI study, a single-center, retrospective cohort study, we enrolled 3131 consecutive patients (67 +/- 13 years; 82% male) hospitalized for cardiovascular disease and measured ABI between January 2005 and December 2012. After excluding patients with an ABI > 1.4, the remaining 3056 patients were categorized as having low ABI (<= 0.9), borderline ABI (0.91-0.99), or normal ABI (1.00-1.40). The primary endpoint was MACE (cardiovascular death, myocardial infarction [MI] and stroke). The secondary endpoints were cardiovascular death, MI, stroke, admission due to heart failure, and major bleeding. RESULTS: During a 4.8-year mean follow-up period, the incidences of MACE (low vs. borderline vs. normal: 32.9% vs. 25.0% vs. 14.6%, P<0.0001) and cardiovascular death (26.2% vs. 18.7% vs. 8.9%, P<0.0001) differed significantly across ABIs. The incidences of stroke (9.1% vs. 8.6% vs. 4.8%, P<0.0001) and heart failure (25.7% vs. 20.8% vs. 8.9%, P<0.0001) were significantly higher in the low and borderline ABI groups than in the normal ABI group. But the incidences of MI and major bleeding were similar in the borderline and normal ABI groups. The hazard ratios for MACE adjusted for traditional atherosclerosis risk factors were significantly higher in patients with low and borderline ABI than those with normal ABI (HR, 1.93; 95%CI: 1.44-2.59, P < 0.0001, HR, 1.54; 95% CI: 1.03-2.29, P = 0.035). CONCLUSIONS: The incidence of long-term adverse events was markedly higher among patients with low or borderline ABI than among those with normal ABI. This suggests that more attention should be paid to patients with borderline ABIs, especially with regard to cardiovascular death, stroke, and heart failure. PMID- 28617816 TI - Testing the arousal hypothesis of neonatal imitation in infant rhesus macaques. AB - Neonatal imitation is the matching of (often facial) gestures by newborn infants. Some studies suggest that performance of facial gestures is due to general arousal, which may produce false positives on neonatal imitation assessments. Here we examine whether arousal is linked to facial gesturing in newborn infant rhesus macaques (Macaca mulatta). We tested 163 infants in a neonatal imitation paradigm in their first postnatal week and analyzed their lipsmacking gestures (a rapid opening and closing of the mouth), tongue protrusion gestures, and yawn responses (a measure of arousal). Arousal increased during dynamic stimulus presentation compared to the static baseline across all conditions, and arousal was higher in the facial gestures conditions than the nonsocial control condition. However, even after controlling for arousal, we found a condition specific increase in facial gestures in infants who matched lipsmacking and tongue protrusion gestures. Thus, we found no support for the arousal hypothesis. Consistent with reports in human newborns, imitators' propensity to match facial gestures is based on abilities that go beyond mere arousal. We discuss optimal testing conditions to minimize potentially confounding effects of arousal on measurements of neonatal imitation. PMID- 28617817 TI - Prevalence of cryptococcal infection among advanced HIV patients in Argentina using lateral flow immunoassay. AB - BACKGROUND: Globally, Latin America ranks third among regions with most cases of AIDS related cryptococcal meningitis. In 2009, a lateral flow immunoassay (LFA) for the detection of cryptococcal antigen (CrAg) was developed as a potential point-of-care test for diagnosis of cryptococcal infection. In 2011 World Health Organizations recommended on CrAg screening for HIV positive persons with CD4 below 100 cells/MUL, followed by preemptive fluconazole treatment. However, in Argentina no formal recommendations for CrAg screening have been issued. METHODS: HIV positive patients > = 18 years with advanced immunosuppression (CD4 counts <=100 cells/MUL within 3 months or WHO stage III/IV), who visited the hospital between April 1, 2014 and January 31, 2015, were included. The LFA was performed according to the manufacturer's instructions on all serum samples. When CrAg detection was positive, a lumbar puncture was performed to rule out cryptococcal meningitis. Patients without evidence of meningeal involvement were treated with preemptive oral fluconazole in ambulatory care. RESULTS: We included 123 patients. Prevalence of CrAg-positivity was 8.1%. Among the 10 CrAg-positive patients, 6 had meningeal involvement detected through the CSF analysis (CSF India-ink testing, CSF CrAg and culture). The remaining 4 patients with positive CrAg received targeted preemptive treatment with oral fluconazole and were free of cryptococcal disease during the follow-up period. None of the 113 patients with a negative CrAg test result developed cryptococcal disease. CONCLUSIONS: This is the first study in Argentina, to our knowledge, describing the prevalence of cryptococcosis and usefulness of CrAg screening. LFA provided early diagnosis to determine a high prevalence of CrAg in our hospital, and that screening for subclinical infection with preemptive antifungal treatment, prevented a substantial proportion of meningeal disease. PMID- 28617819 TI - Between simplicity and accuracy: Effect of adding modeling details on quarter vehicle model accuracy. AB - Quarter vehicle model is the simplest representation of a vehicle that belongs to lumped-mass vehicle models. It is widely used in vehicle and suspension analyses, particularly those related to ride dynamics. However, as much as its common adoption, it is also commonly accepted without quantification that this model is not as accurate as many higher-degree-of-freedom models due to its simplicity and limited degrees of freedom. This study investigates the trade-off between simplicity and accuracy within the context of quarter vehicle model by determining the effect of adding various modeling details on model accuracy. In the study, road input detail, tire detail, suspension stiffness detail and suspension damping detail were factored in, and several enhanced models were compared to the base model to assess the significance of these details. The results clearly indicated that these details do have effect on simulated vehicle response, but to various extents. In particular, road input detail and suspension damping detail have the most significance and are worth being added to quarter vehicle model, as the inclusion of these details changed the response quite fundamentally. Overall, when it comes to lumped-mass vehicle modeling, it is reasonable to say that model accuracy depends not just on the number of degrees of freedom employed, but also on the contributions from various modeling details. PMID- 28617818 TI - Proteome profiling in IL-1beta and VEGF-activated human umbilical vein endothelial cells delineates the interlink between inflammation and angiogenesis. AB - Endothelial cells represent major effectors in inflammation and angiogenesis, processes that drive a multitude of pathological states such as atherosclerosis and cancer. Both inflammation and angiogenesis are interconnected with each other in the sense that many pro-inflammatory proteins possess proangiogenic properties and vice versa. To elucidate this interplay further, we present a comparative proteome study of inflammatory and angiogenic activated endothelial cells. HUVEC were stimulated with interleukin 1-beta and VEGF, respectively. Cultured primary cells were fractionated into secreted, cytoplasmic and nuclear protein fractions and processed for subsequent LC-MS/MS analysis. Obtained protein profiles were filtered for fraction-specific proteins to address potential cross fractional contamination, subjected to comparative computational biology analysis (GO-Term enrichment analysis, weighted gene co-expression analysis) and compared to published mRNA profiles of IL-1beta respectively VEGF stimulated HUVEC. GO Term enrichment analysis and comparative pathway analysis revealed features such as NOD and NfkB signaling for inflammatory activated HUVEC and VEGF and ErB signaling for VEGF-activated HUVEC with potential crosstalk via map kinases MAP2K2. Weighted protein co-expression network analysis revealed several potential hub genes so far not associated with driver function in inflammation or angiogenesis such as HSPG2, ANXA3, and GPI. "Classical" inflammation or angiogenesis markers such as IL6, CXCL8 or CST1 were found in a less central position within the co-expression networks. In conclusion, this study reports a framework for the computational biology based analysis of proteomics data applied to cytoplasmic, nucleic and extracellular fractions of quiescent, inflammatory and angiogenic activated HUVEC. Novel potential hub genes relevant for these processes were successfully identified. PMID- 28617820 TI - Defining health-related quality of life for young wheelchair users: A qualitative health economics study. AB - BACKGROUND: Wheelchairs for children with impaired mobility provide health, developmental and psychosocial benefits, however there is limited understanding of how mobility aids affect the health-related quality of life of children with impaired mobility. Preference-based health-related quality of life outcome measures are used to calculate quality-adjusted life years; an important concept in health economics. The aim of this research was to understand how young wheelchair users and their parents define health-related quality of life in relation to mobility impairment and wheelchair use. METHODS: The sampling frame was children with impaired mobility (<=18 years) who use a wheelchair and their parents. Data were collected through semi-structured face-to-face interviews conducted in participants' homes. Qualitative framework analysis was used to analyse the interview transcripts. An a priori thematic coding framework was developed. Emerging codes were grouped into categories, and refined into analytical themes. The data were used to build an understanding of how children with impaired mobility define health-related quality of life in relation to mobility impairment, and to assess the applicability of two standard measures of health-related quality of life. RESULTS: Eleven children with impaired mobility and 24 parents were interviewed across 27 interviews. Participants defined mobility-related quality of life through three distinct but interrelated concepts: 1) participation and positive experiences; 2) self-worth and feeling fulfilled; 3) health and functioning. A good degree of consensus was found between child and parent responses, although there was some evidence to suggest a shift in perception of mobility-related quality of life with child age. CONCLUSIONS: Young wheelchair users define health-related quality of life in a distinct way as a result of their mobility impairment and adaptation use. Generic, preference-based measures of health-related quality of life lack sensitivity in this population. Development of a mobility-related quality of life outcome measure for children is recommended. PMID- 28617821 TI - Supplementation with small-extracellular vesicles from ovarian follicular fluid during in vitro production modulates bovine embryo development. AB - Pregnancy success results from the interaction of multiple factors, among them are folliculogenesis and early embryonic development. Failure during these different processes can lead to difficulties in conception. Alternatives to overcome these problems are based on assisted reproductive techniques. Extracellular vesicles are cell-secreted vesicles present in different body fluids and contain bioactive materials, such as messenger RNA, microRNAs (miRNAs), and proteins. Thus, our hypothesis is that extracellular vesicles from follicular fluid from 3-6 mm ovarian follicles can modulate bovine embryo development in vitro. To test our hypothesis follicular fluid from bovine ovaries was aspirated and small-extracellular vesicles (<200 nm) were isolated for further analysis. Additionally, small-extracellular vesicles (EVs) were utilized for functional experiments investigating their role in modulating messenger RNA, microRNA as well as global DNA methylation and hydroxymethylation levels of bovine blastocysts. EVs from 3-6 mm follicles were used for RNA-seq and miRNA analysis. Functional annotation analysis of the EVs transcripts revealed messages related to chromatin remodeling and transcriptional regulation. EVs treatment during oocyte maturation and embryo development causes changes in blastocyst rates, as well as changes in the transcription levels of genes related to embryonic metabolism and development. Supplementation with EVs from 3-6 mm follicles during oocyte maturation and early embryo development (until the 4-cell stage) increased the levels of bta-miR-631 (enriched in EVs from 3-6 mm follicles) in embryos. Interestingly, the addition of EVs from 3-6 mm follicles induced changes in global DNA methylation and hydroxymethylation levels compared to embryos produced by the standard in vitro production system. Our results indicate that the supplementation of culture media with EVs isolated from the follicular fluid of 3-6 mm follicles during oocyte maturation and early embryo development can partially modify metabolic and developmental related genes as well as miRNA and global DNA methylation and hydroxymethylation, suggesting that EVs play an important role during oocyte maturation and early embryo development in vitro. PMID- 28617822 TI - Intronic SNP in ESR1 encoding human estrogen receptor alpha is associated with brain ESR1 mRNA isoform expression and behavioral traits. AB - Genetic variants of ESR1 have been implicated in multiple diseases, including behavioral disorders, but causative variants remain uncertain. We have searched for regulatory variants affecting ESR1 expression in human brain, measuring allelic ESR1 mRNA expression in human brain tissues with marker SNPs in exon4 representing ESR1-008 (or ESRalpha-36), and in the 3'UTR of ESR1-203, two main ESR1 isoforms in brain. In prefrontal cortex from subjects with bipolar disorder, schizophrenia, and controls (n = 35 each; Stanley Foundation brain bank), allelic ESR1 mRNA ratios deviated from unity up to tenfold at the exon4 marker SNP, with large allelic ratios observed primarily in bipolar and schizophrenic subjects. SNP scanning and targeted sequencing identified rs2144025, associated with large allelic mRNA ratios (p = 1.6E10-6). Moreover, rs2144025 was significantly associated with ESR1 mRNA levels in the Brain eQTL Almanac and in brain regions in the Genotype-Tissue Expression project. In four GWAS cohorts, rs2104425 was significantly associated with behavioral traits, including: hypomanic episodes in female bipolar disorder subjects (GAIN bipolar disorder study; p = 0.0004), comorbid psychological symptoms in both males and females with attention deficit hyperactivity disorder (GAIN ADHD, p = 0.00002), psychological diagnoses in female children (eMERGE study of childhood health, subject age >=9, p = 0.0009), and traits in schizophrenia (e.g., grandiose delusions, GAIN schizophrenia, p = 0.0004). The first common ESR1 variant (MAF 12-33% across races) linked to regulatory functions, rs2144025 appears conditionally to affect ESR1 mRNA expression in the brain and modulate traits in behavioral disorders. PMID- 28617823 TI - Resource capture and competitive ability of non-pathogenic Pseudogymnoascus spp. and P. destructans, the cause of white-nose syndrome in bats. AB - White-nose syndrome (WNS) is a devastating fungal disease that has been causing the mass mortality of hibernating bats in North America since 2006 and is caused by the psychrophilic dermatophyte Pseudogymnoascus destructans. Infected bats shed conidia into hibernaculum sediments and surfaces, but it is unknown if P. destructans can form stable, reproductive populations outside its bat hosts. Previous studies have found non-pathogenic Pseudogymnoascus in bat hibernacula, and these fungi may provide insight into the natural history of P. destructans. We compared the relatedness, resource capture, and competitive ability of non pathogenic Pseudogymnoascus isolates with P. destructans to determine if they have similar adaptations for survival in hibernacula sediment. All non-pathogenic Pseudogymnoascus isolates grew faster, utilized a broader range of substrates with higher efficiency, and were generally more resistant to antifungals compared to P. destructans. All isolates also showed the ability to displace P. destructans in co-culture assays, but only some produced extractible antifungal metabolites. These results suggest that P. destructans would perform poorly in the same environmental niche as non-pathogenic Pseudogymnoascus, and must have an alternative saprophytic survival strategy if it establishes active populations in hibernaculum sediment and non-host surfaces. PMID- 28617824 TI - Regulation of type 1 iodothyronine deiodinase by LXRalpha. AB - The iodothyronine deiodinases are selenoenzymes that regulate the activity of thyroid hormone via specific inner- or outer-ring deiodination. In humans, type 1 deiodinase (D1) is highly expressed in the liver, but the mechanism by which its gene expression is regulated remains to be elucidated. Liver X receptor alpha (LXRalpha), a transcription factor of the nuclear receptor superfamily, is highly expressed in the liver, where it functions as a sensor for excess intracellular oxysterols. LXRalpha interacts with other nuclear receptors on promoters of genes that contain a binding core sequence for nuclear receptors. In addition, it is reported that the promoter of the gene encoding human D1 (hDIO1) contains the core sequence for one of nuclear receptors, thyroid hormone receptor (TR). We investigated the involvement of LXRalpha in the regulation of hDIO1, in the liver. We performed hDIO1 promoter-reporter assays using a synthetic LXR agonist, T0901317, and compared promoter activity between a human liver carcinoma cell line, HepG2, and a clone of human embryonic kidney cells, TSA201. We defined the region between nucleotides -131 and -114, especially nucleotides -126 and -125, of the hDIO1 promoter as critical for basal and LXRalpha-mediated specific transcriptional activation in HepG2 cells. An increase in hDIO1 expression was observed in LXRalpha-stimulated cells, but absent in cycloheximide-treated cells, indicating that new protein synthesis is required for LXRalpha-mediated regulation of hDIO1. On the other hand, electrophoretic mobility shift assays revealed that LXRalpha and RXRalpha bound to the hDIO1 promoter. We also demonstrated that LXRalpha and TRbeta compete with each other on this specific region of the promoter. In conclusion, our results indicated that LXRalpha plays a specific and important role in activation of TH by regulating D1, and that LXRalpha binds to and regulates the hDIO1 promoter, competing with TRbeta on specific sequences within the promoter. PMID- 28617825 TI - Concurrent development of facial identity and expression discrimination. AB - Facial identity and facial expression processing both appear to follow a protracted developmental trajectory, yet these trajectories have been studied independently and have not been directly compared. Here we investigated whether these processes develop at the same or different rates using matched identity and expression discrimination tasks. The Identity task begins with a target face that is a morph between two identities (Identity A/Identity B). After a brief delay, the target face is replaced by two choice faces: 100% Identity A and 100% Identity B. Children 5-12-years-old were asked to pick the choice face that is most similar to the target identity. The Expression task is matched in format and difficulty to the Identity task, except the targets are morphs between two expressions (Angry/Happy, or Disgust/Surprise). The same children were asked to pick the choice face with the expression that is most similar to the target expression. There were significant effects of age, with performance improving (becoming more accurate and faster) on both tasks with increasing age. Accuracy and reaction times were not significantly different across tasks and there was no significant Age x Task interaction. Thus, facial identity and facial expression discrimination appear to develop at a similar rate, with comparable improvement on both tasks from age five to twelve. Because our tasks are so closely matched in format and difficulty, they may prove useful for testing face identity and face expression processing in special populations, such as autism or prosopagnosia, where one of these abilities might be impaired. PMID- 28617826 TI - CF2 transcription factor is involved in the regulation of Mef2 RNA levels, nuclei number and muscle fiber size. AB - CF2 and Mef2 influence a variety of developmental muscle processes at distinct stages of development. Nevertheless, the exact nature of the CF2-Mef2 relationship and its effects on muscle building remain yet to be resolved. Here, we explored the regulatory role of CF2 in the Drosophila embryo muscle formation. To address this question and not having proper null CF2 mutants we exploited loss or gain of function strategies to study the contribution of CF2 to Mef2 transcription regulation and to muscle formation. Our data point to CF2 as a factor involved in the regulation of muscle final size and/or the number of nuclei present in each muscle. This function is independent of its role as a Mef2 collaborative factor in the transcriptional regulation of muscle-structural genes. Although Mef2 expression patterns do not change, reductions or increases in parallel in CF2 and Mef2 transcript abundance were observed in interfered and overexpressed CF2 embryos. Since CF2 expression variations yield altered Mef2 expression levels but with correct spatio-temporal Mef2 expression patterns, it can be concluded that only the mechanism controlling expression levels is de regulated. Here, it is proposed that CF2 regulates Mef2 expression through a Feedforward Loop circuit. PMID- 28617827 TI - NOG-hIL-4-Tg, a new humanized mouse model for producing tumor antigen-specific IgG antibody by peptide vaccination. AB - Immunodeficient mice transplanted with human peripheral blood mononuclear cells (PBMCs) are promising tools to evaluate human immune responses to vaccines. However, these mice usually develop severe graft-versus-host disease (GVHD), which makes estimation of antigen-specific IgG production after antigen immunization difficult. To evaluate antigen-specific IgG responses in PBMC transplanted immunodeficient mice, we developed a novel NOD/Shi-scid IL2rgammanull (NOG) mouse strain that systemically expresses the human IL-4 gene (NOG-hIL-4-Tg). After human PBMC transplantation, GVHD symptoms were significantly suppressed in NOG-hIL-4-Tg compared to conventional NOG mice. In kinetic analyses of human leukocytes, long-term engraftment of human T cells has been observed in peripheral blood of NOG-hIL-4-Tg, followed by dominant CD4+ T rather than CD8+ T cell proliferation. Furthermore, these CD4+ T cells shifted to type 2 helper (Th2) cells, resulting in long-term suppression of GVHD. Most of the human B cells detected in the transplanted mice had a plasmablast phenotype. Vaccination with HER2 multiple antigen peptide (CH401MAP) or keyhole limpet hemocyanin (KLH) successfully induced antigen-specific IgG production in PBMC transplanted NOG-hIL-4-Tg. The HLA haplotype of donor PBMCs might not be relevant to the antibody secretion ability after immunization. These results suggest that the human PBMC-transplanted NOG-hIL-4-Tg mouse is an effective tool to evaluate the production of antigen-specific IgG antibodies. PMID- 28617828 TI - ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency. AB - BACKGROUND: The most common and severe disease causing allele of Alpha 1 Antitrypsin Deficiency (1ATD) is Z-1AT. This protein aggregates in the endoplasmic reticulum, which is the main cause of liver disease in childhood. Based on recent evidences and on the frequency of liver disease occurrence in Z 1AT patients, it seems that liver disease progression is linked to still unknown genetic factors. METHODS: We used an innovative approach combining yeast genetic screens with next generation exome sequencing to identify and functionally characterize the genes involved in 1ATD associated liver disease. RESULTS: Using yeast genetic screens, we identified HRD1, an Endoplasmic Reticulum Associated Degradation (ERAD) associated protein, as an inducer of Z-mediated toxicity. Whole exome sequencing of 1ATD patients resulted in the identification of two variants associated with liver damages in Z-1AT homozygous cases: HFE H63D and HERPUD1 R50H. Functional characterization in Z-1AT model cell lines demonstrated that impairment of the ERAD machinery combined with the HFE H63D variant expression decreased both cell proliferation and cell viability, while Unfolded Protein Response (UPR)-mediated cell death was hyperstimulated. CONCLUSION: This powerful experimental pipeline allowed us to identify and functionally validate two genes involved in Z-1AT-mediated severe liver toxicity. This pilot study moves forward our understanding on genetic modifiers involved in 1ATD and highlights the UPR pathway as a target for the treatment of liver diseases associated with 1ATD. Finally, these findings support a larger scale screening for HERPUD1 R50H and HFE H63D variants in the sub-group of 1ATD patients developing significant chronic hepatic injuries (hepatomegaly, chronic cholestasis, elevated liver enzymes) and at risk developing liver cirrhosis. PMID- 28617829 TI - Rhythmic syllable-related activity in a songbird motor thalamic nucleus necessary for learned vocalizations. AB - Birdsong is a complex behavior that exhibits hierarchical organization. While the representation of singing behavior and its hierarchical organization has been studied in some detail in avian cortical premotor circuits, our understanding of the role of the thalamus in adult birdsong is incomplete. Using a combination of behavioral and electrophysiological studies, we seek to expand on earlier work showing that the thalamic nucleus Uvaeformis (Uva) is necessary for the production of stereotyped, adult song in zebra finch (Taeniopygia guttata). We confirm that complete bilateral lesions of Uva abolish singing in the 'directed' social context, but find that in the 'undirected' social context, such lesions result in highly variable vocalizations similar to early babbling song in juvenile birds. Recordings of neural activity in Uva reveal strong syllable related modulation, maximally active prior to syllable onsets and minimally active prior to syllable offsets. Furthermore, both song and Uva activity exhibit a pronounced coherent modulation at 10Hz-a pattern observed in downstream premotor areas in adult and, even more prominently, in juvenile birds. These findings are broadly consistent with the idea that Uva is critical in the sequential activation of behavioral modules in HVC. PMID- 28617831 TI - Depression in dementia with Lewy bodies: A comparison with Alzheimer's disease. AB - BACKGROUND: Depression is highly associated with dementia, and this study will compare the frequencies, severity, and symptoms of depression between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: Frequency of depression was determined according to the DSM-IV criteria for major depression or the National Institute of Mental Health criteria for depression in AD (NIMH dAD). Severity of depression were assessed using the Hamilton Depression Rating Scale, the Cornell Scale for Depression in Dementia, and the depression subscale in Neuropsychiatric Inventory. The rates of depressive symptoms were compared between AD and DLB. RESULTS: A total of 312 patients were investigated (AD/DLB = 241/71). The frequency of major depression was significantly higher (p = 0.017) in DLB (19.7%) than in AD (8.7%). The higher frequency of depression in DLB was not reproduced by using the NIMH-dAD criteria (DLB: AD = 43.7%: 33.2%; p = 0.105). The severity of depression was higher in DLB than in AD according to the Hamilton Depression Rating Scale (p < 0.001) and the Cornell Scale for Depression in Dementia (p < 0.001). Among depressive symptoms, pervasive anhedonia had the highest odds ratio in DLB compared with AD. CONCLUSION: This is the first study using the NIMH-dAD criteria to investigate the frequency of depression in DLB. Our study shows that co-morbid major depression is more frequent in DLB than in AD. Pervasive anhedonia had the greatest value for the differential diagnosis of depression between DLB and AD. PMID- 28617830 TI - On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C. AB - BACKGROUND AND AIMS: Interferon (IFN)- free direct antiviral agents (DAAs) with rapid HCV eradication might evoke immunological reconstitutions, and some early recurrences of HCC after IFN-free DAAs have been reported. This study aimed to investigate whether natural killer group 2, member D (NKG2D) predicts early emergence of HCC after IFN-free DAAs. METHODS: We conducted a clinical practice based observational study of 101 patients infected with genotype 1 HCV who received IFN-free (DAAs), and stratified them into those who did or did not develop early (i.e., during the 6-month surveillance period following treatment.) recurrence or occurrence of clinically evident HCC. We also analyzed the peripheral blood mononuclear cells, both before treatment and at end of treatment (EOT), of 24 of the patients who received IFN-free DAAs, and 16 who received IFN combined protease inhibitor. RESULTS: We found early emergence of clinically evident HCC after IFN-free DAAs in 12 (12%) patients. Higher pre-treatment NKG2D expression, higher FIB-4 score, previous HCC history and failure to achieve sustained viral response were significant factors correlating to early HCC emergence. After IFN-free DAAs, a rapid decrease of NKG2D at EOT correlated with early HCC emergence in the IFN-free DAA-treated patients, but not in patients treated with the IFN-combined regimen. The decrease of NKG2D until EOT was predictive of early HCC emergence at a cut-off of -52% (AUC = 0.92). CONCLUSIONS: On-treatment decrease of NKG2D may be a useful predictor of early emerging HCC in patients treated with IFN-free DAAs. PMID- 28617832 TI - A TALE-inspired computational screen for proteins that contain approximate tandem repeats. AB - TAL (transcription activator-like) effectors (TALEs) are bacterial proteins that are secreted from bacteria to plant cells to act as transcriptional activators. TALEs and related proteins (RipTALs, BurrH, MOrTL1 and MOrTL2) contain approximate tandem repeats that differ in conserved positions that define specificity. Using PERL, we screened ~47 million protein sequences for TALE-like architecture characterized by approximate tandem repeats (between 30 and 43 amino acids in length) and sequence variability in conserved positions, without requiring sequence similarity to TALEs. Candidate proteins were scored according to their propensity for nuclear localization, secondary structure, repeat sequence complexity, as well as covariation and predicted structural proximity of variable residues. Biological context was tentatively inferred from co-occurrence of other domains and interactome predictions. Approximate repeats with TALE-like features that merit experimental characterization were found in a protein of chestnut blight fungus, a eukaryotic plant pathogen. PMID- 28617833 TI - Clinical performance validation of PITX2 DNA methylation as prognostic biomarker in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: Despite advances in combined modality therapy, outcomes in head and neck squamous cell cancer (HNSCC) remain dismal with five-year overall survival rates of less than 50%. Prognostic biomarkers are urgently needed to identify patients with a high risk of death after initial curative treatment. Methylation status of the paired-like homeodomain transcription factor 2 (PITX2) has recently emerged as a powerful prognostic biomarker in various cancers. In the present study, the clinical performance of PITX2 methylation was validated in a HNSCC cohort by means of an independent analytical platform (Infinium HumanMethylation450 BeadChip, Illumina, Inc.). METHODS: A total of 528 HNSCC patients from The Cancer Genome Atlas (TCGA) were included in the study. Death was defined as primary endpoint. PITX2 methylation was correlated with overall survival and clinicopathological parameters. RESULTS: PITX2 methylation was significantly associated with sex, tumor site, p16 status, and grade. In univariate Cox proportional hazards analysis, PITX2 hypermethylation analyzed as continuous and dichotomized variable was significantly associated with prolonged overall survival of HNSCC patients (continuous: hazard ratio (HR) = 0.19 [95%CI: 0.04-0.88], p = 0.034; dichotomized: HR = 0.52 [95%CI: 0.33-0.84], p = 0.007). In multivariate Cox analysis including established clinicopathological parameters, PITX2 promoter methylation was confirmed as prognostic factor (HR = 0.28 [95%CI: 0.09-0.84], p = 0.023). CONCLUSION: Using an independent analytical platform, PITX2 methylation was validated as a prognostic biomarker in HNSCC patients, identifying patients that potentially benefit from intensified surveillance and/or administration of adjuvant/neodjuvant treatment, i.e. immunotherapy. PMID- 28617834 TI - Community pharmacists' interest in and attitude to pharmacy practice research in Ethiopia: A cross-sectional study. AB - Pharmacy practice-research became an important component in the pharmacy practice. However, limited studies were conducted in sub-Saharan Africa to understand the pharmacists' interest and attitude towards pharmacy practice research. We aimed to assess the community pharmacists' interest and attitude towards pharmacy practice-research in Ethiopia. A cross-sectional survey was conducted among community pharmacists in eight major cities in Ethiopia. A validated 25-item self-administered questionnaire covering interest and attitude related to pharmacy practice-research was distributed. Responses were analysed using descriptive and inferential statistics. A total of 389 community pharmacists responded to the survey (response rate- 88.4%). Most of community pharmacists showed a high level of interest and positive attitude in being involved in all aspects of pharmacy practice-research. The median summary score for interest and attitude were 38 (IQR 20-40) (range possible 10-50) and 30 (IQR 18-39), respectively. Sixty-seven percent of the respondents thought about being involved in research, felt research is important for their career (57.6%), confident to conduct the research (56.2%), and agreed that research is a part of pharmacy practice (48.5%). However, only forty-six percent agreed that they underwent research training. A multivariate analysis showed that females were more interested in pharmacy practice research than males [AOR: 1.50, 95% CI: 0.99 2.27; p<0.05]. Community pharmacists showed high interest towards several areas of research competencies and demonstrated positive attitude towards pharmacy practice-research. Our findings suggest that providing research training to community pharmacists may contribute in undertaking research activities and build the research capacity in Ethiopia. PMID- 28617835 TI - Autopsy rates in the Netherlands: 35 years of decline. AB - OBJECTIVE: Although the autopsy still is a valuable tool in health statistics, health care quality control, medical education, and biomedical research, autopsy rates have been declining worldwide. The aim of this study was to examine trends of overall, clinical and forensic autopsy rates among adults in the Netherlands over the last four decades, and trends per sex, age (groups), and hospital type. METHODS: We performed a retrospective study covering 35 years of Dutch national death counts (1977-2011), the number of in-hospital deceased patients, the number of deaths due to external causes, and the proportion of autopsies performed in these populations. The effects of sex, age and hospital category were analysed by linear and logistic regression and differences were evaluated by chi-square tests. RESULTS: Overall autopsy rates declined by 0.3% per calendar year, clinical autopsy rates by 0.7% per calendar year (from 31.4% to 7.7%), and forensic autopsy rates did not decline. Per calendar year the fraction of in hospital deceased patients decreased by 0.2%. Autopsy rates were highest among men and younger patients; clinical autopsy rates were highest for patients dying in academic hospitals. CONCLUSIONS: In the Netherlands clinical autopsy rates have rapidly declined while at the same time the fraction of in-hospital deaths decreased, both contributing to the overall reduced absolute number of autopsies performed. It is important to improve awareness among both clinicians and general practitioners of the significance of the clinical autopsy. PMID- 28617836 TI - Molecular diversity and frequency of the diarrheagenic enteric protozoan Giardia duodenalis and Cryptosporidium spp. in a hospital setting in Northern Spain. AB - BACKGROUND: Human giardiosis and cryptosporidiosis are caused by the enteric protozoan parasites Giardia duodenalis and Cryptosporidium spp. Both pathogens are major contributors to the global burden of diarrhoeal disease, affecting primarily children and immunodebilitated individuals in resource-poor settings. Giardiosis and cryptosporidiosis also represent an important, often underestimate, public health threat in developed countries. In Spain only limited information is currently available on the epidemiology of these infections. Molecular data on the diversity, frequency, geographical distribution, and seasonality of G. duodenalis assemblages/sub-assemblages and Cryptosporidium species/sub-genotypes are particularly scarce. METHODS: A longitudinal molecular epidemiological survey was conducted between July 2015 to September 2016 in patients referred to or attended at the Hospital San Pedro (La Rioja, Northern Spain) that tested positive for G. duodenalis (N = 106) or Cryptosporidium spp. (N = 103) by direct microscopy and/or a rapid lateral flow immunochromatographic assay. G. duodenalis infections were subsequently confirmed by real-time PCR and positive isolates assessed by multi-locus sequence genotyping of the glutamate dehydrogenase and beta-giardin genes of the parasite. Cryptosporidium species and sub-genotypes were investigated at the 60 kDa glycoprotein or the small subunit ribosomal RNA genes of the parasite. Sociodemographic and clinical parameters of infected patients were also gathered and analysed. PRINCIPAL FINDINGS: Out of 90 G. duodenalis-positive isolates by real-time PCR a total of 16 isolates were successfully typed. AII (44%, 7/16) was the most prevalent sub-assemblage found, followed by BIV (31%, 5/16) and BIII (19%, 3/16). A discordant genotype result AII/AIII was identified in an additional (6%, 1/16) isolate. No mixed infections A+B were detected. Similarly, a total of 81 Cryptosporidium spp. isolates were successfully typed, revealing the presence of C. hominis (81%, 66/81) and C. parvum (19%, 15/81). Obtained GP60 sequences were assigned to sub-type families Ib (73%, 59/81) within C. hominis, and IIa (7%, 6/81) and IId (2%, 2/81) within C. parvum. A marked inter-annual variation in Cryptosporidium cases was observed. CONCLUSIONS: Human giardiasis and cryptosporidiosis are commonly identified in patients seeking medical care in Northern Spain and represent a more important health concern than initially thought. Assemblage A within G. duodenalis and sub genotype IbA10G2 within C. hominis were the genetic variants of these parasite species more frequently found circulating in the population under study. Molecular data presented here seem to suggest that G. duodenalis and Cryptosporidium infections arise through anthroponotic rather than zoonotic transmission in this Spanish region. PMID- 28617837 TI - Risk factors and protective factors associated with incident or increase of frailty among community-dwelling older adults: A systematic review of longitudinal studies. AB - INTRODUCTION: Frailty is one of the greatest challenges facing our aging population, as it can lead to adverse outcomes such as institutionalization, hospitalization, and mortality. However, the factors that are associated with frailty are poorly understood. We performed a systematic review of longitudinal studies in order to identify the sociodemographic, physical, biological, lifestyle-related, and psychological risk or protective factors that are associated with frailty among community-dwelling older adults. METHODS: A systematic literature search was conducted in the following databases in order to identify studies that assessed the factors associated with of frailty among community-dwelling older adults: Embase, Medline Ovid, Web of Science, Cochrane, PsychINFO Ovid, CINAHL EBSCOhost, and Google Scholar. Studies were selected if they included a longitudinal design, focused on community-dwelling older adults aged 60 years and older, and used a tool to assess frailty. The methodological quality of each study was assessed using the Quality of Reporting of Observational Longitudinal Research checklist. RESULTS: Twenty-three studies were included. Significant associations were reported between the following types of factors and frailty: sociodemographic factors (7/7 studies), physical factors (5/6 studies), biological factors (5/7 studies), lifestyle factors (11/13 studies), and psychological factors (7/8 studies). Significant sociodemographic factors included older age, ethnic background, neighborhood, and access to private insurance or Medicare; significant physical factors included obesity and activities of daily living (ADL) functional status; significant biological factors included serum uric acid; significant lifestyle factors included a higher Diet Quality Index International (DQI) score, higher fruit/vegetable consumption and higher tertile of all measures of habitual dietary resveratrol exposure; significant psychological factors included depressive symptoms. CONCLUSIONS: A broad range of sociodemographic, physical, biological, lifestyle, and psychological factors show a longitudinal association with frailty. These factors should be considered when developing interventions aimed at preventing and/or reducing the burden associated with frailty among community-dwelling older adults. PMID- 28617838 TI - Safety and metabolic effects of tesamorelin, a growth hormone-releasing factor analogue, in patients with type 2 diabetes: A randomized, placebo-controlled trial. AB - OBJECTIVE: Use of growth hormone is associated with side effects, including insulin resistance. The objective of this study was to determine whether tesamorelin, a stabilized growth hormone-releasing hormone analogue, would alter insulin sensitivity or control of diabetes. DESIGN: A 12-week randomized, placebo controlled study of 53 patients with type 2 diabetes. Three treatment groups: placebo, 1 and 2 mg tesamorelin. MEASUREMENTS: Fasting glucose, glucose and insulin from oral glucose tolerance test, glycosylated hemoglobin (HbA1c), home blood glucose, insulin-like growth factor-1, and lipids. MAIN OUTCOME MEASURE: Relative insulin response following oral ingestion of glucose. RESULTS: No significant differences were observed between groups in relative insulin response over the 12-week treatment period. At Week 12, fasting glucose, HbA1c and overall diabetes control were not significantly different between groups. In addition, relevant modifications in diabetes medications were similar between groups. Total cholesterol (-0.3+/-0.6 mmol/L) and non-HDL cholesterol (-0.3+/-0.5 mmol/L) significantly decreased from baseline to Week 12 in the tesamorelin 2 mg group (p<0.05 vs. placebo). No patient discontinued the study due to loss of diabetes control. CONCLUSIONS: Treatment of type 2 diabetic patients with tesamorelin for 12 weeks did not alter insulin response or glycemic control. TRIAL REGISTRATION: ClinicalTrials.gov NCT01264497. PMID- 28617839 TI - Comparative transcriptomes analysis of the wing disc between two silkworm strains with different size of wings. AB - Wings of Bombyx mori (B. mori) develop from the primordium, and different B. mori strains have different wing types. In order to identify the key factors influencing B. mori wing development, we chose strains P50 and U11, which are typical for normal wing and minute wing phenotypes, respectively. We dissected the wing disc on the 1st-day of wandering stage (P50D1 and U11D1), 2nd-day of wandering stage (P50D2 and U11D2), and 3rd-day of wandering stage (P50D3 and U11D3). Subsequently, RNA-sequencing (RNA-Seq) was performed on both strains in order to construct their gene expression profiles. P50 exhibited 628 genes differentially expressed to U11, 324 up-regulated genes, and 304 down-regulated genes. Five enriched gene ontology (GO) terms were identified by GO enrichment analysis based on these differentially expressed genes (DEGs). KEGG enrichment analysis results showed that the DEGs were enriched in five pathways; of these, we identified three pathways related to the development of wings. The three pathways include amino sugar and nucleotide sugar metabolism pathway, proteasome signaling pathway, and the Hippo signaling pathway. The representative genes in the enrichment pathways were further verified by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The RNA-Seq and qRT-PCR results were largely consistent with each other. Our results also revealed that the significantly different genes obtained in our study might be involved in the development of the size of B. mori wings. In addition, several KEGG enriched pathways might be involved in the regulation of the pathways of wing formation. These results provide a basis for further research of wing development in B. mori. PMID- 28617840 TI - A new test for diagnosing vasovagal syncope: Standing after treadmill test with sublingual nitrate administration. AB - INTRODUCTION: Increased adrenergic tone might be an additional trigger of orthostatic stress of vasovagal syncope (VVS). Exercise before standing might provide increased sensitivity compared to standing using a sublingual nitroglycerines protocol during tilt table testing. The aim of this study was to evaluate the diagnostic value of treadmill testing before standing with nitroglycerin administration. METHODS AND RESULTS: A total of 36 patients with syncope or presyncope were enrolled for the test. VVS was confirmed in 29 patients according to the Calgary Score (>= -2), including 20 patients who were likely to have typical (classical) VVS. All 36 subjects were subjected to a novel provocation test consisting of treadmill test using the Bruce protocol followed by standing with administration of 300 MUg sublingual nitroglycerin. Consequently, syncope or presyncope occurred in 22 patients of the 36 patients. The sensitivity and a specificity of the test for Calgary score based VVS was 82.7% and 85.75%, respectively. Reproducibility rate for typical VVS was 90% (18 of 20). In all symptomatic patients, systolic blood pressure dropped to < 90 mmHg and symptom occurred a mean of 6.7 +/- 2.3 minutes after the nitroglycerine administration. No patient required anticholinergics injection to restore vital signs. CONCLUSIONS: Treadmill test with administration of sublingual nitroglycerines might be safely used to reproduce syncope in patients with VVS. More clinical experience and confirmation are needed to validate this protocol. PMID- 28617841 TI - Height-diameter allometry and above ground biomass in tropical montane forests: Insights from the Albertine Rift in Africa. AB - Tropical montane forests provide an important natural laboratory to test ecological theory. While it is well-known that some aspects of forest structure change with altitude, little is known on the effects of altitude on above ground biomass (AGB), particularly with regard to changing height-diameter allometry. To address this we investigate (1) the effects of altitude on height-diameter allometry, (2) how different height-diameter allometric models affect above ground biomass estimates; and (3) how other forest structural, taxonomic and environmental attributes affect above ground biomass using 30 permanent sample plots (1-ha; all trees >= 10 cm diameter measured) established between 1250 and 2600 m asl in Kahuzi Biega National Park in eastern Democratic Republic of Congo. Forest structure and species composition differed with increasing altitude, with four forest types identified. Different height-diameter allometric models performed better with the different forest types, as trees got smaller with increasing altitude. Above ground biomass ranged from 168 to 290 Mg ha-1, but there were no significant differences in AGB between forests types, as tree size decreased but stem density increased with increasing altitude. Forest structure had greater effects on above ground biomass than forest diversity. Soil attributes (K and acidity, pH) also significantly affected above ground biomass. Results show how forest structural, taxonomic and environmental attributes affect above ground biomass in African tropical montane forests. They particularly highlight that the use of regional height-diameter models introduces significant biases in above ground biomass estimates, and that different height-diameter models might be preferred for different forest types, and these should be considered in future studies. PMID- 28617842 TI - Intra-individual gait patterns across different time-scales as revealed by means of a supervised learning model using kernel-based discriminant regression. AB - OBJECTIVE: Traditionally, gait analysis has been centered on the idea of average behavior and normality. On one hand, clinical diagnoses and therapeutic interventions typically assume that average gait patterns remain constant over time. On the other hand, it is well known that all our movements are accompanied by a certain amount of variability, which does not allow us to make two identical steps. The purpose of this study was to examine changes in the intra-individual gait patterns across different time-scales (i.e., tens-of-mins, tens-of-hours). METHODS: Nine healthy subjects performed 15 gait trials at a self-selected speed on 6 sessions within one day (duration between two subsequent sessions from 10 to 90 mins). For each trial, time-continuous ground reaction forces and lower body joint angles were measured. A supervised learning model using a kernel-based discriminant regression was applied for classifying sessions within individual gait patterns. RESULTS AND DISCUSSION: Discernable characteristics of intra individual gait patterns could be distinguished between repeated sessions by classification rates of 67.8 +/- 8.8% and 86.3 +/- 7.9% for the six-session classification of ground reaction forces and lower body joint angles, respectively. Furthermore, the one-on-one-classification showed that increasing classification rates go along with increasing time durations between two sessions and indicate that changes of gait patterns appear at different time-scales. CONCLUSION: Discernable characteristics between repeated sessions indicate continuous intrinsic changes in intra-individual gait patterns and suggest a predominant role of deterministic processes in human motor control and learning. Natural changes of gait patterns without any externally induced injury or intervention may reflect continuous adaptations of the motor system over several time-scales. Accordingly, the modelling of walking by means of average gait patterns that are assumed to be near constant over time needs to be reconsidered in the context of these findings, especially towards more individualized and situational diagnoses and therapy. PMID- 28617843 TI - Characterization of the regulation of a plant polysaccharide utilization operon and its role in biofilm formation in Bacillus subtilis. AB - The soil bacterium Bacillus subtilis is often found in association with plants in the rhizosphere. Previously, plant polysaccharides have been shown to stimulate formation of root-associated multicellular communities, or biofilms, in this bacterium, yet the underlying mechanism is not fully understood. A five-gene gan operon (ganSPQAB) in B. subtilis has recently been shown to be involved in utilization of the plant-derived polysaccharide galactan. Despite these findings, molecular details about the regulation of the operon and the role of the operon in biofilm formation remain elusive. In this study, we performed comprehensive genetic analyses on the regulation of the gan operon. We show that this operon is regulated both by a LacI-like transcription repressor (GanR), which directly binds to pairs of inverted DNA repeats in the promoter region of the operon, and by the catabolite control protein A (CcpA). Derepression can be triggered by the presence of the inducer beta-1,4-galactobiose, a hydrolysis product of galactan, or in situ when B. subtilis cells are associated with plant roots. In addition to the transcriptional regulation, the encoded beta-galactosidase GanA (by ganA), which hydrolyzes beta-1,4-galactobiose into galactose, is inhibited at the enzymatic level by the catalytic product galactose. Thus, the galactan utilization pathway is under complex regulation involving both positive and negative feedback mechanisms in B. subtilis. We discuss about the biological significance of such complex regulation as well as a hypothesis of biofilm induction by galactan via multiple mechanisms. PMID- 28617844 TI - Wolbachia elevates host methyltransferase expression to block an RNA virus early during infection. AB - Wolbachia pipientis is an intracellular endosymbiont known to confer host resistance against RNA viruses in insects. However, the causal mechanism underlying this antiviral defense remains poorly understood. To this end, we have established a robust arthropod model system to study the tripartite interaction involving Sindbis virus and Wolbachia strain wMel within its native host, Drosophila melanogaster. By leveraging the power of Drosophila genetics and a parallel, highly tractable D. melanogaster derived JW18 cell culture system, we determined that in addition to reducing infectious virus production, Wolbachia negatively influences Sindbis virus particle infectivity. This is further accompanied by reductions in viral transcript and protein levels. Interestingly, unchanged ratio of proteins to viral RNA copies suggest that Wolbachia likely does not influence the translational efficiency of viral transcripts. Additionally, expression analyses of candidate host genes revealed D. melanogaster methyltransferase gene Mt2 as an induced host factor in the presence of Wolbachia. Further characterization of viral resistance in Wolbachia-infected flies lacking functional Mt2 revealed partial recovery of virus titer relative to wild-type, accompanied by complete restoration of viral RNA and protein levels, suggesting that Mt2 acts at the stage of viral genome replication. Finally, knockdown of Mt2 in Wolbachia uninfected JW18 cells resulted in increased virus infectivity, thus demonstrating its previously unknown role as an antiviral factor against Sindbis virus. In conclusion, our findings provide evidence supporting the role of Wolbachia-modulated host factors towards RNA virus resistance in arthropods, alongside establishing Mt2's novel antiviral function against Sindbis virus in D. melanogaster. PMID- 28617845 TI - Frequency and significance of rare RNF213 variants in patients with adult moyamoya disease. AB - PURPOSE: Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by stenosis of the internal carotid arteries with compensatory development of collateral vessels. Although a founder variant of RNF213, p.Arg4810Lys (c.14429G>A, rs112735431), is a major genetic risk factor for MMD in East Asians, the frequency and disease susceptibility of other variants in this gene remain largely unknown. In the present study, we investigated the association of RNF213 variants with MMD in Korean patients and population controls. METHODS: For all RNF213 variants listed in the Human Gene Mutation Database (HGMD) as disease causing or likely disease-causing mutations for MMD, genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genetic data from 264 adult patients with MMD were analyzed and compared with two control populations comprised of 622 and 1,100 Korean individuals, respectively. RESULTS: Among the 30 RNF213 variants that were listed in the HGMD, p.Arg4810Lys was identified in 67.4% (178/264) of patients with MMD and showed a significantly higher allele frequency than in the controls, giving an odds ratio of 63.29 (95% confidence interval, 33.11-120.98) for the 622 controls and 48.55 (95% confidence interval, 31.00-76.03) for the 1100 controls. One additional variant, p.Ala5021Val (c.15062C>T, rs138130613), was identified in 0.8% (2/264) of patients; however, the allele frequencies were not significantly different from those in the controls. CONCLUSIONS: These results suggest that, in our cohort of Korean patients, the p.Arg4810Lys is the only variant that is strongly associated with MMD among the 30 RNF213 variants listed in the HGMD. PMID- 28617846 TI - A metabolite of leucine (beta-hydroxy-beta-methylbutyrate) given to sows during pregnancy alters bone development of their newborn offspring by hormonal modulation. AB - The effects of dietary beta-hydroxy-beta-methylbutyrate (HMB) supplementation during gestation on bone, growth plate, and articular cartilage in newborns were determined. Thermal analysis of articular cartilage was performed to examine the structural changes in collagen. At day 70 of gestation, a total of 12 sows (Large White Polish breed, at the second parity) were randomly assigned to two groups, with each group receiving either a basal diet or the same diet supplemented with 0.2 g/day HMB until the 90th day. Maternal HMB supplementation enhanced body weight, bone length, and diameter in males. It also improved geometric and mechanical properties contributing to increased bone morphology and endurance. In turn, alteration of the length was only observed in females. The positive effects were mediated by increased serum concentrations of insulin-like growth factor-1 and leptin. HMB-treatment enhanced the concentration of FSH, LH, estradiol, and testosterone. Serum TAP was enhanced by the HMB-treatment by 34% in females and 138% in males. Beneficial effects of the HMB-treatment on trabecular bone and content of proteoglycans in articular cartilage were shown. The HMB-treatment significantly changed the collagen structure in cartilages, especially in the females, which was demonstrated by the PSR analysis. Differences between the HMB supplemented and the control females in the calorimetric peak temperatures were presumably related to different collagen fibril density in the articular cartilage structure. In summary, maternal HMB supplementation in the mid gestation period significantly improved general growth and mechanical endurance of long bones by the influence on the somatotropic and pituitary-gonadal axes in the offspring. PMID- 28617847 TI - The association between 38 previously reported polymorphisms and psoriasis in a Polish population: High predicative accuracy of a genetic risk score combining 16 loci. AB - OBJECTIVES: To confirm the association of previously discovered psoriasis (Ps) risk loci with the disease in a Polish population and to create predictive models based on the combination of these single nucleotide polymorphisms (SNPs). MATERIAL AND METHODS: Thirty-eight SNPs were genotyped in 480 Ps patients and 490 controls. Alleles distributions were compared between patients and controls, as well as between different Ps sub-phenotypes. The genetic risk score (GRS) was calculated to assess the cumulative risk conferred by multiple loci. RESULTS: We confirmed associations of several loci with Ps: HLA-C, REL, IL12B, TRIM39/RPP21, POU5F1, MICA. The analysis of ROC curves showed that GRS combining 16 SNPs at least nominally (uncorrected P<0.05) associated with Ps (GRS-N) had significantly better discriminative power than GRS combining SNPs associated with Ps after the Bonferroni correction (AUC 0.776 vs. 0.750, P = 1 x 10-4) or HLA-C (AUC 0.776 vs. 0.694, P<1 x 10-5). On the other hand, adding additional SNPs to the model did not improve its discriminatory ability (AUC 0.782 for GRS combining all SNPs, P>0.05). In order to assess the total risk conferred by GRS-N, we calculated ORs according to GRS-N quartile - the Ps OR for top vs. bottom GRS-N quartiles was 12.29 (P<1 x 10-6). The analysis of different Ps sub-phenotypes showed an association of GRS-N with age of onset and family history of Ps. CONCLUSIONS: We confirmed the association of Ps with several previously identified genetic risk factors in a Polish population. We found that a GRS combining 16 SNPs at least nominally associated with Ps had a significantly better discriminatory ability than HLA-C or GRS combining SNPs associated with Ps after the Bonferroni correction. In contrast, adding additional SNPs to GRS did not increase significantly the discriminative power. PMID- 28617848 TI - Effect of caffeine ingestion on anaerobic capacity quantified by different methods. AB - We investigated whether caffeine ingestion before submaximal exercise bouts would affect supramaximal oxygen demand and maximal accumulated oxygen deficit (MAOD), and if caffeine-induced improvement on the anaerobic capacity (AC) could be detected by different methods. Nine men took part in several submaximal and supramaximal exercise bouts one hour after ingesting caffeine (5 mg.kg-1) or placebo. The AC was estimated by MAOD, alternative MAOD, critical power, and gross efficiency methods. Caffeine had no effect on exercise endurance during the supramaximal bout (caffeine: 131.3 +/- 21.9 and placebo: 130.8 +/- 20.8 s, P = 0.80). Caffeine ingestion before submaximal trials did not affect supramaximal oxygen demand and MAOD compared to placebo (7.88 +/- 1.56 L and 65.80 +/- 16.06 kJ vs. 7.89 +/- 1.30 L and 62.85 +/- 13.67 kJ, P = 0.99). Additionally, MAOD was similar between caffeine and placebo when supramaximal oxygen demand was estimated without caffeine effects during submaximal bouts (67.02 +/- 16.36 and 62.85 +/- 13.67 kJ, P = 0.41) or when estimated by alternative MAOD (56.61 +/- 8.49 and 56.87 +/- 9.76 kJ, P = 0.91). The AC estimated by gross efficiency was also similar between caffeine and placebo (21.80 +/- 3.09 and 20.94 +/- 2.67 kJ, P = 0.15), but was lower in caffeine when estimated by critical power method (16.2 +/- 2.6 vs. 19.3 +/- 3.5 kJ, P = 0.03). In conclusion, caffeine ingestion before submaximal bouts did not affect supramaximal oxygen demand and consequently MAOD. Otherwise, caffeine seems to have no clear positive effect on AC. PMID- 28617849 TI - Protective effect of HDL on NADPH oxidase-derived super oxide anion mediates hypoxia-induced cardiomyocyte apoptosis. AB - Cardiovascular diseases are the leading cause of death of death in Taiwan. Atherosclerosis can lead to serious problems, including heart attack, stroke, or even death. Coronary heart disease (CHD) occurs when plaque builds up in the coronary arteries to cause the ischemic heart disease which will enhance myocardial remodeling and also induce myocardial hypoxia. High density lipoprotein (HDL) has been proposed to have cardio-protective effects. Under hypoxic conditions (1%O2 for 24hr), in H9c2 cells, reactive oxygen species (ROS) is induced which leads to cardiomyocyte apoptosis and cardiac dysfunction. Therefore, the present study described the protective effect of HDL on hypoxia induced cardiomyocyte damage. We investigated the NADPH oxidase-produced ROS related signaling pathways and apoptosis in cardiomyocytes under hypoxia conditions. Results showed that the ROS mediated cardiac damage might occur via AT1 and PKC activation. Furthermore, hypoxia downregulated the survival protein (p-AKTser473) and anti-apoptotic protein (BCL2), whereas pro-apoptotic protein, Bax and caspase 3 were upregulated. These detrimental effects by ROS and apoptosis were prevented by HDL pretreatment. Our findings revealed the underlying molecular mechanism by which HDL suppresses the hypoxia-induced cardiomyocyte dysfunction. Further, we elucidated the role of HDL on preventing hypoxia induced cardiomyocyte apoptosis is mediated through the inhibition of NADPH oxidase-derived ROS. PMID- 28617850 TI - Molecular determinants for the thermodynamic and functional divergence of uniporter GLUT1 and proton symporter XylE. AB - GLUT1 facilitates the down-gradient translocation of D-glucose across cell membrane in mammals. XylE, an Escherichia coli homolog of GLUT1, utilizes proton gradient as an energy source to drive uphill D-xylose transport. Previous studies of XylE and GLUT1 suggest that the variation between an acidic residue (Asp27 in XylE) and a neutral one (Asn29 in GLUT1) is a key element for their mechanistic divergence. In this work, we combined computational and biochemical approaches to investigate the mechanism of proton coupling by XylE and the functional divergence between GLUT1 and XylE. Using molecular dynamics simulations, we evaluated the free energy profiles of the transition between inward- and outward facing conformations for the apo proteins. Our results revealed the correlation between the protonation state and conformational preference in XylE, which is supported by the crystal structures. In addition, our simulations suggested a thermodynamic difference between XylE and GLUT1 that cannot be explained by the single residue variation at the protonation site. To understand the molecular basis, we applied Bayesian network models to analyze the alteration in the architecture of the hydrogen bond networks during conformational transition. The models and subsequent experimental validation suggest that multiple residue substitutions are required to produce the thermodynamic and functional distinction between XylE and GLUT1. Despite the lack of simulation studies with substrates, these computational and biochemical characterizations provide unprecedented insight into the mechanistic difference between proton symporters and uniporters. PMID- 28617851 TI - Severity classification of repeated isoflurane anesthesia in C57BL/6JRj mice Assessing the degree of distress. AB - According to the EU Directive 2010/63, the severity of a procedure has to be classified as mild, moderate or severe. General anesthesia is thought to be mild, but the Directive does not differentiate between single and repeated anesthesia. Therefore, we investigated the impact of repeated administration of isoflurane, the most commonly used inhalation anesthetic, on the well-being of adult C57BL/6JRj mice, in comparison to single administrations and to untreated animals, when applied six times for 45 min at an interval of 3-4 days. For the animals anesthetized, excitations, phases of anesthesia, and vital parameters were monitored. Well-being after anesthesia was assessed using a behavioral test battery including luxury behavior like burrowing and nest building behavior, the Mouse Grimace Scale (MGS), the free exploratory paradigm for anxiety-related behavior, home cage activity and the rotarod test for activity, as well as food intake and body weight. Additionally, hair corticosterone and fecal corticosterone metabolites were measured. Our results show that nest building behavior, home cage activity, body weight, and corticosterone concentrations were not influenced by anesthesia, whereas changes in burrowing behavior, the MGS, food intake, and the free exploratory behavior indicated that the well-being of the mice was more affected by repeated than single isoflurane anesthesia. This effect depended on the sex of the animals, with female mice being more susceptible than male mice. However, repeated isoflurane anesthesia caused only short-term mild distress and impairment of well-being, mainly in the immediate postanesthetic period. Well-being stabilized at 8 days after the last anesthesia, at the latest. Therefore, we conclude that when using our anesthesia protocol, the severity of both single and repeated isoflurane anesthesia in C57BL/6JRj mice can be classified as mild. However, within the mild severity category, repeated isoflurane anesthesia ranks higher than single isoflurane anesthesia. Additionally, our results imply that male and female mice can differently perceive the severity of a procedure. PMID- 28617853 TI - Co-occurrence of viruses and mosquitoes at the vectors' optimal climate range: An underestimated risk to temperate regions? AB - Mosquito-borne viruses have been estimated to cause over 100 million cases of human disease annually. Many methodologies have been developed to help identify areas most at risk from transmission of these viruses. However, generally, these methodologies focus predominantly on the effects of climate on either the vectors or the pathogens they spread, and do not consider the dynamic interaction between the optimal conditions for both vector and virus. Here, we use a new approach that considers the complex interplay between the optimal temperature for virus transmission, and the optimal climate for the mosquito vectors. Using published geolocated data we identified temperature and rainfall ranges in which a number of mosquito vectors have been observed to co-occur with West Nile virus, dengue virus or chikungunya virus. We then investigated whether the optimal climate for co-occurrence of vector and virus varies between "warmer" and "cooler" adapted vectors for the same virus. We found that different mosquito vectors co-occur with the same virus at different temperatures, despite significant overlap in vector temperature ranges. Specifically, we found that co-occurrence correlates with the optimal climatic conditions for the respective vector; cooler-adapted mosquitoes tend to co-occur with the same virus in cooler conditions than their warmer-adapted counterparts. We conclude that mosquitoes appear to be most able to transmit virus in the mosquitoes' optimal climate range, and hypothesise that this may be due to proportionally over-extended vector longevity, and other increased fitness attributes, within this optimal range. These results suggest that the threat posed by vector-competent mosquito species indigenous to temperate regions may have been underestimated, whilst the threat arising from invasive tropical vectors moving to cooler temperate regions may be overestimated. PMID- 28617852 TI - Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells. AB - Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in ovarian cancer and thus is a promising anticancer therapeutic target. Our previous work suggests that coumarin compounds are potential inhibitors of PDKs. In this study, we used the ovarian cancer cell line SKOV3 as the model system and examined whether dicumarol (DIC), a coumarin compound, could inhibit ovarian cancer through targeting PDK1. We showed that DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. The same phenotypes induced by DIC also were translated in vivo, leading to significant suppression of xenograft growth. This study not only identifies a novel inhibitor for PDK1, but it also reveals novel anticancer mechanisms of DIC and provides a promising anticancer therapy that targets the Warburg effect. PMID- 28617854 TI - Choroidal thickness in school children: The Gobi Desert Children Eye Study. AB - PURPOSE: To investigate choroidal thickness (CT) and its associations in children in a school-based study. METHODS: The cross-sectional school-based Gobi Desert Children Eye Study included 1565 out of 1911 (81.9%) eligible children from all schools in the oasis region of Ejina in the Gobi Desert. A detailed ophthalmic examination was performed, including spectral-domain optical coherence tomography with enhanced depth imaging for CT measurement. RESULTS: CT measurements were available for 1463 (93.5%) students (mean age: 11.8+/-3.5 years; range:7-21 years). Mean subfoveal choroidal thickness (SFCT) was 282+/-49MUm. CT was thickest at 1000MUm temporal to the fovea (286+/-49MUm), followed by the subfoveal region (282+/-49 MUm; P<0.001), the region at 2500MUm temporal to the fovea (278+/-49MUm), the region at 1000MUm nasal to the fovea (254+/ 49MUm;P<0.001), and the region at 2500MUm nasal to the fovea (197+/ 50MUm;P<0.001). In cross-sectional analysis, the mean SFCT increased with age from 288MUm at 7 years of age to 304MUm at 11 years, and then decreased to 258 MUm at 18 years. In multivariate analysis, thicker SFCT was associated (regression coefficient r:0.38) with higher hyperopic refractive error (P<0.001;standardized regression coefficient beta:0.31;non-standardized regression coefficient B:7.61;95% confidence intervals (CI):6.29,8.93), younger age (P<0.001;beta:-0.10;B:-1.39;95%CI:-2.14,-0.64), male gender (P = 0.03;beta: 0.05;B:-5.33;95%CI:-10.1,-0.53), higher corneal refractive power (P<0.001;beta:0.12;B:3.68;95%CI:2.12,5.24), and non-Han Chinese ethnicity (P = 0.03;beta:0.05;B:6.16;95%CI:0.50,11.8). Ratio of CT(1000MUm nasal to fovea)/SFCT (0.90+/-0.06;range:0.66,1.23) and ratio of CT(2500MUm nasal to fovea)/SFCT (0.70+/-0.13;range:0.28,1.23) decreased with older age (P = 0.01;and P = 0.001, respectively), while ratio of CT(1000MUm temporal to fovea)/SFCT (1.02+/ 0.06;range:0.56,1.37) and ratio of CT(2500MUm temporal to fovea)/SFCT (0.99+/ 0.11;range:0.54,1.84) increased with older age (both P<0.001). Time spent outdoors or indoors was not significantly associated with CT-related parameter in multivariate analysis. CONCLUSIONS: In contrast to SFCT in adults and despite elongating axial length, SFCT in children increased in cross-sectional analysis with older age (up to 11 years of age) and then started to decrease with further ageing. It suggests an increase in choroidal volume up to the age of 11 years. In children, the choroid was thickest at 1000MUm temporal to the fovea, followed by the subfoveal region, and this difference significantly increased with older age. In contrast, CT nasal to the fovea in relationship to SFCT decreased with older age. CT was independent of lifestyle-associated parameters. PMID- 28617855 TI - Stroke in HIV-infected individuals with and without HCV coinfection in Spain in the combination antiretroviral therapy era. AB - The incidence of stroke in human immunodeficiency virus (HIV)-infected individuals has been well analyzed in recent epidemiological studies. However, little is known about the specific contribution of hepatitis C virus (HCV) infection to stroke among HIV-infected individuals. The aims of this study were to analyze trends in the incidence rates of stroke in HIV-infected individuals during the combination antiretroviral (cART) era in Spain and to categorize them by the presence or absence of HCV coinfection. We analyzed hospital discharges with a diagnosis of stroke in Spain according to ICD-9-CM during 1997-2013. The study period was divided into four calendar periods (1997-1999, 2000-2003, 2004 2007, and 2008-2013). Patients were classified according to HCV serology. The number of HIV-infected patients was estimated based on data from the National Centre of Epidemiology. We calculated incidence rates (events per 10,000 patient years) and in-hospital case fatality rates (CFR). The incidence of hemorrhagic stroke (HS) decreased in HIV-monoinfected patients (15.8 [1997-1999] to 6.5 [2008 2013]; P<0.001) and increased in HIV/HCV-coinfected patients (1.3 [1997-1999] to 5.5 [2008-2013]; P<0.001). The incidence of ischemic stroke (IS) decreased in HIV monoinfected patients (27.4 [1997-1999] to 21.7 [2008-2013]; P = 0.005) and increased in HIV/HCV-coinfected patients (1.8 [1997-1999] to 11.9 [2008-2013]; P<0.001). The CFR was 3.3 times higher for HS than for IS for the whole study period. The CFR of HS in HIV-monoinfected patients decreased significantly (47.4% [1997-1999] to 30.6% [2008-2013]; P = 0.010) but did not change significantly among HIV/HCV-coinfected patients (41.4% [1997-1999] to 44.7% [2008-2013]; P = 0.784). The CFR of IS in the whole HIV-infected population decreased significantly (14.6% [1997-1999] to 10.9% [2008-2013]; P = 0.034), although no significant differences were found when each group was analyzed separately. In conclusion, after the introduction of cART, HS and IS rates decreased in HIV monoinfected individuals, but increased steadily in HIV/HCV-coinfected individuals. PMID- 28617856 TI - The associations between VDR BsmI polymorphisms and risk of vitamin D deficiency, obesity and insulin resistance in adolescents residing in a tropical country. AB - BACKGROUND: The vitamin D receptor (VDR) gene is expressed abundantly in different tissues; including adipocytes and pancreatic beta cells. The rs1544410 or BsmI single nucleotide polymorphism (SNP) in the intronic region of the VDR gene has been previously associated with vitamin D levels, obesity and insulin resistance. AIMS: This study was aimed to examine the association between BsmI polymorphism and risk of vitamin D deficiency, obesity and insulin resistance in adolescents living in a tropical country. METHODS: Thirteen-year-old adolescents were recruited via multistage sampling from twenty-three randomly selected schools across the city of Kuala Lumpur, Malaysia (n = 941). Anthropometric measurements were obtained. Obesity was defined as body mass index higher than the 95th percentile of the WHO chart. Levels of fasting serum vitamin D (25 hydroxyvitamin D (25(OH)D)), glucose and insulin were measured. HOMA-IR was calculated as an indicator for insulin resistance. Genotyping was performed using the Sequenom MassARRAY platform (n = 807). The associations between BsmI and vitamin D, anthropometric parameters and HOMA-IR were examined using analysis of covariance and logistic regression. RESULT: Those with AA genotype of BsmI had significantly lower levels of 25(OH)D (p = 0.001) compared to other genotypes. No significant differences was found across genotypes for obesity parameters. The AA genotype was associated with higher risk of vitamin D deficiency (p = 0.03) and insulin resistance (p = 0.03) compared to GG. The A allele was significantly associated with increased risk of vitamin D deficiency compared to G allele (adjusted odds ratio (OR) = 1.63 (95% Confidence Interval (CI) 1.03-2.59, p = 0.04). In those with concurrent vitamin D deficiency, having an A allele significantly increased their risk of having insulin resistance compared to G allele (adjusted OR = 2.66 (95% CI 1.36-5.19, p = 0.004). CONCLUSION: VDR BsmI polymorphism was significantly associated with vitamin D deficiency and insulin resistance, but not with obesity in this population. PMID- 28617857 TI - Variability in CitXET expression and XET activity in Citrus cultivar Huangguogan seedlings with differed degrees of etiolation. AB - Considering the known effects of xyloglucan endotransglycosylase (XET) on plant growth and development, we aimed to determine whether XETs help to regulate the growth and elongation of Huangguogan shoots and roots. We confirmed a possible role for XET during seedling etiolation. Our results revealed that the roots of etiolated seedlings (H-E) were longer than those of green seedlings (H-G). However, shoot length exhibited the opposite pattern. We also observed positive and negative effects on the xyloglucan-degrading activity of XET in the root sub apical region and shoots of etiolated Huangguogan seedling, respectively. There was a significant down-regulation in CitXET expression in the etiolated shoots at 15 days after seed germination. On the contrary, it was significantly increased in the root sub-apical region of etiolated and multicolored seedlings at 15 days after seed germination. The XET coding sequence (i.e., CitXET) was cloned from Huangguogan seedlings using gene-specific primers. The encoded amino acid sequence was predicted by using bioinformatics-based methods. The 990-bp CitXET gene was highly homologous to other XET genes. The CitXET protein was predicted to contain 319 amino acids, with a molecular mass of 37.45 kDa and an isoelectric point of 9.05. The predicted molecular formula was C1724H2548N448O466S14, and the resulting protein included only one transmembrane structure. The CitXET secondary structure consisted of four main structures (i.e., 21% alpha-helix, 30.72% extended strand, 9.09% beta-turn, and 39.18% random coil). Analyses involving the NCBI Conserved Domains Database (NCBI-CDD), InterPro, and ScanProsite revealed that CitXET was a member of the glycosyl hydrolase family 16 (GH16), and included the DEIDFEFLG motif. Our results indicate that the differed degrees of etiolation influenced the CitXET expression pattern and XET activity in Huangguogan seedlings. The differential changes in XET activity and CitXET expression levels in Huangguogan seedlings may influence the regulation of root and shoot development, and may be important for seedling etiolation. PMID- 28617858 TI - Effect of three edible oils on the intestinal absorption of caffeic acid: An in vivo and in vitro study. AB - Polyphenolic antioxidants are mainly absorbed through passive paracellular permeation regulated by tight junctions. Some fatty acids are known to modulate tight junctions. Fatty acids resulting from the digestion of edible oils may improve the absorption of polyphenolic antioxidants. Therefore, we explored the effect of three edible oils on the intestinal absorption of caffeic acid. Rats were fed with soybean oil and caffeic acid dissolved in distilled water. Caffeic acid contents in the plasma collected up to 1 hr were quantified. The experiment was repeated with coconut oil and olive oil. Component fatty acids of the oils were individually tested in vitro for their effect on permeability of caffeic acid using Caco-2 cell monolayers. Highest absorption of caffeic acid was observed in animals fed with coconut oil. In vitro transport percentages of caffeic acid in 2.5 mmol/L solutions of fatty acids were 22.01+/-0.12 (lauric), 15.30 +/- 0.25 (myristic acid), 13.59 +/- 0.35 (linoleic acid), 3.70 +/- 0.09 (oleic acid) and 0.10-2.0 (all other fatty acids). Lauric acid and myristic acid are the two major fatty acids present in coconut oil. Therefore, these fatty acids may contribute to the higher absorption of caffeic acid in the presence of coconut oil. PMID- 28617859 TI - Co-localization of acinar markers and insulin in pancreatic cells of subjects with type 2 diabetes. AB - To search for clues suggesting that beta cells may generate by transdifferentiation in humans, we assessed the presence of cells double positive for exocrine (amylase, carboxypeptidase A) and endocrine (insulin) markers in the pancreas of non-diabetic individuals (ND) and patients with type 2 diabetes (T2D). Samples from twelve ND and twelve matched T2D multiorgan donors were studied by electron microscopy, including amylase and insulin immunogold labeling; carboxypeptidase A immunofluorescence light microscopy assessment was also performed. In the pancreas from four T2D donors, cells containing both zymogen-like and insulin-like granules were observed, scattered in the exocrine compartment. Nature of granules was confirmed by immunogold labeling for amylase and insulin. Double positive cells ranged from 0.82 to 1.74 per mm2, corresponding to 0.26+/-0.045% of the counted exocrine cells. Intriguingly, cells of the innate immune systems (mast cells and/or macrophages) were adjacent to 33.3+/-13.6% of these hybrid cells. No cells showing co-localization of amylase and insulin were found in ND samples by electron microscopy. Similarly, cells containing both carboxypeptidase A and insulin were more frequently observed in the diabetic pancreata. These results demonstrate more abundant presence of cells containing both acinar markers and insulin in the pancreas of T2D subjects, which suggests possible conversion from one cellular type to the other and specific association with the diseased condition. PMID- 28617860 TI - Increasing prevalence of infectious diseases in asylum seekers at a tertiary care hospital in Switzerland. AB - OBJECTIVE: The increasing number of refugees seeking asylum in Europe in recent years poses new challenges for the healthcare systems in the destination countries. The goal of the study was to describe the evolution of medical problems of asylum seekers at a tertiary care centre in Switzerland. METHODS: At the University Hospital Basel, we compared all asylum seekers during two 1-year time periods in 2004/05 and 2014/15 concerning demographic characteristics and reasons for referrals and hospitalizations. RESULTS: Hundred ninety five of 2'544 and 516 of 6'243 asylum seekers registered at the national asylum reception and procedure centre Basel were referred to the University Hospital Basel in 2004/05 and 2014/15, and originated mainly from Europe (62.3%, mainly Turkey) and Africa (49.1%, mainly Eritrea), respectively. Median age was similar in both study periods (26.9 and 26.2 years). Infectious diseases in asylum seekers increased from 22.6% to 36.6% (p<0.001) and were the main reasons for hospitalizations (33.3% of 45 and 55.6% of 81 hospitalized patients, p = 0.017) in 2004/05 compared to 2014/15. The leading infectious diseases in hospitalized patients were tuberculosis (n = 4) and bacterial skin infections (n = 2) in 2004/05; Malaria (n = 9), pneumonia (n = 6), Chickenpox (n = 5), other viral infections (n = 5) and bacterial skin infections (n = 5) in 2014/15. Infectious diseases like malaria, cutaneous diphtheria, louseborne-relapsing fever or scabies were only found in the second study period. Almost one third of the admitted asylum seekers required isolation precautions with median duration of 6-9.5 days in both study periods. CONCLUSIONS: The changing demography of asylum seekers arriving in Switzerland in the current refugee crisis has led to a shift in disease patterns with an increase of infectious diseases and the re-emergence of migration associated neglected infections. Physicians should be aware of these new challenges. PMID- 28617861 TI - Unconscious improvement in foreign language learning using mismatch negativity neurofeedback: A preliminary study. AB - When people learn foreign languages, they find it difficult to perceive speech sounds that are nonexistent in their native language, and extensive training is consequently necessary. Our previous studies have shown that by using neurofeedback based on the mismatch negativity event-related brain potential, participants could unconsciously achieve learning in the auditory discrimination of pure tones that could not be consciously discriminated without the neurofeedback. Here, we examined whether mismatch negativity neurofeedback is effective for helping someone to perceive new speech sounds in foreign language learning. We developed a task for training native Japanese speakers to discriminate between 'l' and 'r' sounds in English, as they usually cannot discriminate between these two sounds. Without participants attending to auditory stimuli or being aware of the nature of the experiment, neurofeedback training helped them to achieve significant improvement in unconscious auditory discrimination and recognition of the target words 'light' and 'right'. There was also improvement in the recognition of other words containing 'l' and 'r' (e.g., 'blight' and 'bright'), even though these words had not been presented during training. This method could be used to facilitate foreign language learning and can be extended to other fields of auditory and clinical research and even other senses. PMID- 28617862 TI - Evaluating age-related change in lip somatosensation using somatosensory evoked magnetic fields. AB - Somatosensory evoked fields (SEFs) to electrical stimulation on the right and left sides of the lower lip were measured using magnetoencephalography and compared in the bilateral hemispheres of 31 healthy normal young and 29 healthy normal elderly subjects to evaluate age-related change in lip somatosensation. The initial peak of the response around 13 ms, designated as N13m, and the second peak of the response, designated as P21m, were investigated. The N13m response, which was detected in 22 of 62 hemispheres in young adults and 37 of 58 hemispheres in elderly adults, showed significantly prolonged latency and increased equivalent current dipole (ECD) moment in the elderly adults. The P21m response, which was detected in 56 of 62 hemispheres in young adults and in 52 of 58 hemispheres in elderly adults, showed longer peak latency in the elderly adults. No significant difference was found in the ECD moment for P21m, which suggests that aging affected the SEFs of the lip somatosensation, but the effects of aging on N13m and P21m differed. Prolonged latency and increased ECD moment of N13m might result from decreased peripheral conduction and increased cortical excitation system associated with aging. Therefore, the initial response component might be an objective parameter for investigating change in lip function with age. PMID- 28617863 TI - The use of metabolic profiling to identify insulin resistance in veal calves. AB - Heavy veal calves (4-6 months old) are at risk of developing insulin resistance and disturbed glucose homeostasis. Prolonged insulin resistance could lead to metabolic disorders and impaired growth performance. Recently, we discovered that heavy Holstein-Friesian calves raised on a high-lactose or high-fat diet did not differ in insulin sensitivity, that insulin sensitivity was low and 50% of the calves could be considered insulin resistant. Understanding the patho physiological mechanisms underlying insulin resistance and discovering biomarkers for early diagnosis would be useful for developing prevention strategies. Therefore, we explored plasma metabolic profiling techniques to build models and discover potential biomarkers and pathways that can distinguish between insulin resistant and moderately insulin sensitive veal calves. The calves (n = 14) were classified as insulin resistant (IR) or moderately insulin sensitive (MIS) based on results from a euglycemic-hyperinsulinemic clamp, using a cut-off value (M/I value <4.4) to identify insulin resistance. Metabolic profiles of fasting plasma samples were analyzed using reversed phase (RP) and hydrophilic interaction (HILIC) liquid chromatography-mass spectrometry (LC-MS). Orthogonal partial least square discriminant analysis was performed to compare metabolic profiles. Insulin sensitivity was on average 2.3x higher (P <0.001) in MIS than IR group. For both RP-LC-MS and HILIC-LC-MS satisfactory models were build (R2Y >90% and Q2Y >66%), which allowed discrimination between MIS and IR calves. A total of 7 and 20 metabolic features (for RP-LC-MS and HILIC-LC-MS respectively) were most responsible for group separation. Of these, 7 metabolites could putatively be identified that differed (P <0.05) between groups (potential biomarkers). Pathway analysis indicated disturbances in glycerophospholipid and sphingolipid metabolism, the glycine, serine and threonine metabolism, and primary bile acid biosynthesis. These results demonstrate that plasma metabolic profiling can be used to identify insulin resistance in veal calves and can lead to underlying mechanisms. PMID- 28617864 TI - Pitch contour impairment in congenital amusia: New insights from the Self-paced Audio-visual Contour Task (SACT). AB - Individuals with congenital amusia usually exhibit impairments in melodic contour processing when asked to compare pairs of melodies that may or may not be identical to one another. However, it is unclear whether the impairment observed in contour processing is caused by an impairment of pitch discrimination, or is a consequence of poor pitch memory. To help resolve this ambiguity, we designed a novel Self-paced Audio-visual Contour Task (SACT) that evaluates sensitivity to contour while placing minimal burden on memory. In this task, participants control the pace of an auditory contour that is simultaneously accompanied by a visual contour, and they are asked to judge whether the two contours are congruent or incongruent. In Experiment 1, melodic contours varying in pitch were presented with a series of dots that varied in spatial height. Amusics exhibited reduced sensitivity to audio-visual congruency in comparison to control participants. To exclude the possibility that the impairment arises from a general deficit in cross-modal mapping, Experiment 2 examined sensitivity to cross-modal mapping for two other auditory dimensions: timbral brightness and loudness. Amusics and controls were significantly more sensitive to large than small contour changes, and to changes in loudness than changes in timbre. However, there were no group differences in cross-modal mapping, suggesting that individuals with congenital amusia can comprehend spatial representations of acoustic information. Taken together, the findings indicate that pitch contour processing in congenital amusia remains impaired even when pitch memory is relatively unburdened. PMID- 28617865 TI - A human genotyping trial to estimate the post-feeding time from mosquito blood meals. AB - Mosquitoes occur almost worldwide, and females of some species feed on blood from humans and other animals to support ovum maturation. In warm and hot seasons, such as the summer in Japan, fed mosquitoes are often observed at crime scenes. The current study attempted to estimate the time that elapsed since feeding from the degree of human DNA digestion in mosquito blood meals and also to identify the individual human sources of the DNA using genotyping in two species of mosquito: Culex pipiens pallens and Aedes albopictus. After stereomicroscopic observation, the extracted DNA samples were quantified using a human DNA quantification and quality control kit and were genotyped for 15 short tandem repeats using a commercial multiplexing kit. It took about 3 days for the complete digestion of a blood meal, and genotyping was possible until 2 days post feeding. The relative peak heights of the 15 STRs and DNA concentrations were useful for estimating the post-feeding time to approximately half a day between 0 and 2 days. Furthermore, the quantitative ratios derived from STR peak heights and the quality control kit (Q129/Q41, Q305/Q41, and Q305/Q129) were reasonably effective for estimating the approximate post-feeding time after 2-3 days. We suggest that this study may be very useful for estimating the time since a mosquito fed from blood meal DNA, although further refinements are necessary to estimate the times more accurately. PMID- 28617866 TI - Characterization of trace metal content in the developing zebrafish embryo. AB - Trace metals are essential for health but toxic when present in excess. The maintenance of trace metals at physiologic levels reflects both import and export by cells and absorption and excretion by organs. The mechanism by which this maintenance is achieved in vertebrate organisms is incompletely understood. To explore this, we chose zebrafish as our model organism, as they are amenable to both pharmacologic and genetic manipulation and comprise an ideal system for genetic screens and toxicological studies. To characterize trace metal content in developing zebrafish, we measured levels of three trace elements, copper, zinc, and manganese, from the oocyte stage to 30 days post-fertilization using inductively coupled plasma mass spectrometry. Our results indicate that metal levels are stable until zebrafish can acquire metals from the environment and imply that the early embryo relies on maternal contribution of metals to the oocyte. We also measured metal levels in bodies and yolks of embryos reared in presence and absence of the copper chelator neocuproine. All three metals exhibited different relative abundances between yolks and bodies of embryos. While neocuproine treatment led to an expected phenotype of copper deficiency, total copper levels were unaffected, indicating that measurement of total metal levels does not equate with measurement of biologically active metal levels. Overall, our data not only can be used in the design and execution of genetic, physiologic, and toxicologic studies but also has implications for the understanding of vertebrate metal homeostasis. PMID- 28617867 TI - Complete chloroplast genome sequence of common bermudagrass (Cynodon dactylon (L.) Pers.) and comparative analysis within the family Poaceae. AB - Common bermudagrass (Cynodon dactylon (L.) Pers.) belongs to the subfamily Chloridoideae of the Poaceae family, one of the most important plant families ecologically and economically. This grass has a long connection with human culture but its systematics is relatively understudied. In this study, we sequenced and investigated the chloroplast genome of common bermudagrass, which is 134,297 bp in length with two single copy regions (LSC: 79,732 bp; SSC: 12,521 bp) and a pair of inverted repeat (IR) regions (21,022 bp). The annotation contains a total of 128 predicted genes, including 82 protein-coding, 38 tRNA, and 8 rRNA genes. Additionally, our in silico analyses identified 10 sets of repeats longer than 20 bp and predicted the presence of 36 RNA editing sites. Overall, the chloroplast genome of common bermudagrass resembles those from other Poaceae lineages. Compared to most angiosperms, the accD gene and the introns of both clpP and rpoC1 genes are missing. Additionally, the ycf1, ycf2, ycf15, and ycf68 genes are pseudogenized and two genome rearrangements exist. Our phylogenetic analysis based on 47 chloroplast protein-coding genes supported the placement of common bermudagrass within Chloridoideae. Our phylogenetic character mapping based on the parsimony principle further indicated that the loss of the accD gene and clpP introns, the pseudogenization of four ycf genes, and the two rearrangements occurred only once after the most recent common ancestor of the Poaceae diverged from other monocots, which could explain the unusual long branch leading to the Poaceae when phylogeny is inferred based on chloroplast sequences. PMID- 28617868 TI - Three mutations switch H7N9 influenza to human-type receptor specificity. AB - The avian H7N9 influenza outbreak in 2013 resulted from an unprecedented incidence of influenza transmission to humans from infected poultry. The majority of human H7N9 isolates contained a hemagglutinin (HA) mutation (Q226L) that has previously been associated with a switch in receptor specificity from avian-type (NeuAcalpha2-3Gal) to human-type (NeuAcalpha2-6Gal), as documented for the avian progenitors of the 1957 (H2N2) and 1968 (H3N2) human influenza pandemic viruses. While this raised concern that the H7N9 virus was adapting to humans, the mutation was not sufficient to switch the receptor specificity of H7N9, and has not resulted in sustained transmission in humans. To determine if the H7 HA was capable of acquiring human-type receptor specificity, we conducted mutation analyses. Remarkably, three amino acid mutations conferred a switch in specificity for human-type receptors that resembled the specificity of the 2009 human H1 pandemic virus, and promoted binding to human trachea epithelial cells. PMID- 28617869 TI - Statins are related to impaired exercise capacity in males but not females. AB - BACKGROUND: Exercise and statins reduce cardiovascular disease (CVD). Exercise capacity may be assessed using cardiopulmonary exercise testing (CPET). Whether statin medication is associated with CPET parameters is unclear. We investigated if statins are related with exercise capacity during CPET in the general population. METHODS: Cross-sectional data of two independent cohorts of the Study of Health in Pomerania (SHIP) were merged (n = 3,500; 50% males). Oxygen consumption (VO2) at peak exercise (VO2peak) and anaerobic threshold (VO2@AT) was assessed during symptom-limited CPET. Two linear regression models related VO2peak with statin usage were calculated. Model 1 adjusted for age, sex, previous myocardial infarction, and physical inactivity and model 2 additionally for body mass index, smoking, hypertension, diabetes and estimated glomerular filtration rate. Propensity score matching was used for validation. RESULTS: Statin usage was associated with lower VO2peak (no statin: 2336; 95%-confidence interval [CI]: 2287-2,385 vs. statin 2090; 95%-CI: 2,031-2149 ml/min; P < .0001) and VO2@AT (no statin: 1,172; 95%-CI: 1,142-1,202 vs. statin: 1,111; 95%-CI: 1,075-1,147 ml/min; P = .0061) in males but not females (VO2peak: no statin: 1,467; 95%-CI: 1,417-1,517 vs. statin: 1,503; 95%-CI: 1,426-1,579 ml/min; P = 1.00 and VO2@AT: no statin: 854; 95%-CI: 824-885 vs. statin 864; 95%-CI: 817-911 ml/min; P = 1.00). Model 2 revealed similar results. Propensity scores analysis confirmed the results. CONCLUSION: In the general population present statin medication was related with impaired exercise capacity in males but not females. Sex specific effects of statins on cardiopulmonary exercise capacity deserve further research. PMID- 28617870 TI - A novel genetic technique in Plasmodium berghei allows liver stage analysis of genes required for mosquito stage development and demonstrates that de novo heme synthesis is essential for liver stage development in the malaria parasite. AB - The combination of drug resistance, lack of an effective vaccine, and ongoing conflict and poverty means that malaria remains a major global health crisis. Understanding metabolic pathways at all parasite life stages is important in prioritising and targeting novel anti-parasitic compounds. The unusual heme synthesis pathway of the rodent malaria parasite, Plasmodium berghei, requires eight enzymes distributed across the mitochondrion, apicoplast and cytoplasm. Deletion of the ferrochelatase (FC) gene, the final enzyme in the pathway, confirms that heme synthesis is not essential in the red blood cell stages of the life cycle but is required to complete oocyst development in mosquitoes. The lethality of FC deletions in the mosquito stage makes it difficult to study the impact of these mutations in the subsequent liver stage. To overcome this, we combined locus-specific fluorophore expression with a genetic complementation approach to generate viable, heterozygous oocysts able to produce a mix of FC expressing and FC deficient sporozoites. These sporozoites show normal motility and can invade liver cells, where FC deficient parasites can be distinguished by fluorescence and phenotyped. Parasites lacking FC exhibit a severe growth defect within liver cells, with development failure detectable in the early to mid stages of liver development in vitro. FC deficient parasites could not complete liver stage development in vitro nor infect naive mice, confirming liver stage arrest. These results validate the heme pathway as a potential target for prophylactic drugs targeting liver stage parasites. In addition, we demonstrate that our simple genetic approach can extend the phenotyping window beyond the insect stages, opening considerable scope for straightforward reverse genetic analysis of genes that are dispensable in blood stages but essential for completing mosquito development. PMID- 28617872 TI - Growing up with a single mother and life satisfaction in adulthood: A test of mediating and moderating factors. AB - Single parenthood is increasingly common in Western societies but only little is known about its long-term effects. We therefore studied life satisfaction among 641 individuals (ages 18-66 years) who spent their entire childhood with a single mother, 1539 individuals who spent part of their childhood with both parents but then experienced parental separation, and 21,943 individuals who grew up with both parents. Individuals who grew up with a single mother for their entire childhood and to a lesser degree also individuals who experienced parental separation showed a small but persistent decrease in life satisfaction into old age controlling childhood socio-economic status. This decrease was partly mediated by worse adulthood living conditions related to socio-economic and educational success, physical health, social integration, and romantic relationship outcomes. No moderation by age, gender, and societal system where the childhood was spent (i.e. western oriented FRG or socialist GDR) was found. PMID- 28617871 TI - Hypoxia-inducible factor-1alpha plays roles in Epstein-Barr virus's natural life cycle and tumorigenesis by inducing lytic infection through direct binding to the immediate-early BZLF1 gene promoter. AB - When confronted with poor oxygenation, cells adapt by activating survival signaling pathways, including the oxygen-sensitive transcriptional regulators called hypoxia-inducible factor alphas (HIF-alphas). We report here that HIF 1alpha also regulates the life cycle of Epstein-Barr virus (EBV). Incubation of EBV-positive gastric carcinoma AGS-Akata and SNU-719 and Burkitt lymphoma Sal and KemIII cell lines with a prolyl hydroxylase inhibitor, L-mimosine or deferoxamine, or the NEDDylation inhibitor MLN4924 promoted rapid and sustained accumulation of both HIF-1alpha and lytic EBV antigens. ShRNA knockdown of HIF 1alpha significantly reduced deferoxamine-mediated lytic reactivation. HIF-1alpha directly bound the promoter of the EBV primary latent-lytic switch BZLF1 gene, Zp, activating transcription via a consensus hypoxia-response element (HRE) located at nt -83 through -76 relative to the transcription initiation site. HIF 1alpha did not activate transcription from the other EBV immediate-early gene, BRLF1. Importantly, expression of HIF-1alpha induced EBV lytic-gene expression in cells harboring wild-type EBV, but not in cells infected with variants containing base-pair substitution mutations within this HRE. Human oral keratinocyte (NOK) and gingival epithelial (hGET) cells induced to differentiate by incubation with either methyl cellulose or growth in organotypic culture accumulated both HIF 1alpha and Blimp-1alpha, another cellular factor implicated in lytic reactivation. HIF-1alpha activity also accumulated along with Blimp-1alpha during B-cell differentiation into plasma cells. Furthermore, most BZLF1-expressing cells observed in lymphomas induced by EBV in NSG mice with a humanized immune system were located distal to blood vessels in hypoxic regions of the tumors. Thus, we conclude that HIF-1alpha plays central roles in both EBV's natural life cycle and EBV-associated tumorigenesis. We propose that drugs that induce HIF 1alpha protein accumulation are good candidates for development of a lytic induction therapy for treating some EBV-associated malignancies. PMID- 28617873 TI - Fungal manipulation of hormone-regulated plant defense. PMID- 28617875 TI - Cholangioscopy using the SpyGlass system for a rare cause of obstruction: inflammatory polyp of the common bile duct. PMID- 28617876 TI - Cholecysto-cutaneous fistula in a patient with biliary lithiasis. PMID- 28617874 TI - Candida albicans mannans mediate Streptococcus mutans exoenzyme GtfB binding to modulate cross-kingdom biofilm development in vivo. AB - Candida albicans is frequently detected with heavy infection by Streptococcus mutans in plaque-biofilms from children with early-childhood caries (ECC). This cross-kingdom biofilm contains an extensive matrix of extracellular alpha-glucans that is produced by an exoenzyme (GtfB) secreted by S. mutans. Here, we report that mannans located on the outer surface of C. albicans cell-wall mediates GtfB binding, enhancing glucan-matrix production and modulating bacterial-fungal association within biofilms formed in vivo. Using single-molecule atomic force microscopy, we determined that GtfB binds with remarkable affinity to mannans and to the C. albicans surface, forming a highly stable and strong bond (1-2 nN). However, GtfB binding properties to C. albicans was compromised in strains defective in O-mannan (pmt4DeltaDelta) or N-mannan outer chain (och1DeltaDelta). In particular, the binding strength of GtfB on och1DeltaDelta strain was severely disrupted (>3-fold reduction vs. parental strain). In turn, the GtfB amount on the fungal surface was significantly reduced, and the ability of C. albicans mutant strains to develop mixed-species biofilms with S. mutans was impaired. This phenotype was independent of hyphae or established fungal-biofilm regulators (EFG1, BCR1). Notably, the mechanical stability of the defective biofilms was weakened, resulting in near complete biomass removal by shear forces. In addition, these in vitro findings were confirmed in vivo using a rodent biofilm model. Specifically, we observed that C. albicans och1DeltaDelta was unable to form cross-kingdom biofilms on the tooth surface of rats co-infected with S. mutans. Likewise, co-infection with S. mutans defective in GtfB was also incapable of forming mixed-species biofilms. Taken together, the data support a mechanism whereby S. mutans-secreted GtfB binds to the mannan layer of C. albicans to promote extracellular matrix formation and their co-existence within biofilms. Enhanced understanding of GtfB-Candida interactions may provide new perspectives for devising effective therapies to disrupt this cross-kingdom relationship associated with an important childhood oral disease. PMID- 28617877 TI - Degenerate intraductal papillary mucinous carcinoma with fish-mouth appearance of the papilla. PMID- 28617879 TI - It is time to rethink H. pylori therapy. PMID- 28617878 TI - Granulomatous hepatitis: a rare primary manifestation of disseminated histoplasmosis in a renal transplant recipient. PMID- 28617880 TI - How to increase the efficiency in research on non-surgical interventions during cancer surgery? PMID- 28617881 TI - Is Heller myotomy better than balloon dilation? A meta-analysis. AB - BACKGROUND AND AIM: Endoscopic balloon dilation (EBD) and laparoscopic Heller myotomy (LHM) are the most commonly performed treatment options for achalasia. Decision between these treatment options is difficult. The aim of this meta analysis was to evaluate the efficacy of EBD compared to LHM. METHODS: The electronic databases PubMed, Embase and Cochrane Controlled Trials Registry were systematically searched for the period between January 1, 1976 and December 31, 2015. Meta-analysis was performed using the PICOS (problem, intervention, comparison, outcome, study design) format. Efficacy and safety of EBD were compared to LHM. Forest plot analyses were used to illustrate the success rate, perforation rate and post-procedural gastroesophageal reflux. RESULTS: Using the search strategy, eight studies met the selection criteria and were included in the meta-analysis. The total number of patients included was 749 (360 in the EBD group and 389 in the LHM group). The success rate was lower in the EBD group than in the LHM group (OR=0.486; CI: 0.304-0.779; p=0.003). The rate of perforation did not differ significantly between the EBD and LHM group (RR= 0.635, CI: 0.340 1.186, p=0.154). The incidence of post-procedural symptomatic gastroesophageal reflux did not differ between the two treatment groups (RR=0.663, CI: 0.328 1.343, p=0.254). CONCLUSION: Our data suggest that the efficacy of LHM is superior to that of EBD, while there is no difference in safety between the two treatment groups. PMID- 28617882 TI - Eradication rates in Italian subjects heterogeneously managed for Helicobacter pylori infection. Time to abandon empiric treatments in Southern Europe. AB - BACKGROUND AND AIMS: H. pylori eradication is strongly affected by various factors, including the ongoing antibiotic resistance. We describe a "real life" scenario in patients managed for H. pylori-related conditions, living in a southern Italian region (Apulia), an area with clarithromycin resistance >15%. METHODS: 2,224 subjects were studied in two tertiary referral centers in Apulia. Analyses included: reason for referral, H. pylori infection rates (13C-urea breath test - UBT or upper endoscopy), and eradication rates following distinct regimens previously prescribed or prospectively prescribed (such as the bismuth based quadruple therapy Pylera(r), recently marketed in Italy). RESULTS: Over 80% of the patients were referred by family physicians (60% naive subjects). The overall infection rate was 32.5% and it was similar in asymptomatic patients (31.1%) or with H. pylori-related symptoms/clinical conditions (34.3%). In the 987 H. pylori+ve patients receiving therapy, the overall eradication rate was 80.2% (ITT). Observed eradication rate varied greatly across different regimens: 57.1% (2nd line levofloxacin), 59.6% (unconventional), 70.7% (7-day triple), 73.2% (7-day undefined), 89% (10-day sequential) and 96.9% (ITT, 10 day Pylera(r), 1st to 5th line regimens given to 227 patients). CONCLUSIONS: A heterogeneous "real life" scenario in Southern Europe shows that H. pylori+ve patients are put at risk of poor outcomes and points to the need of a susceptibility-based therapy according to guidelines and local microbial resistance. In the present setting (i.e. high clarithromycin resistance), despite the high observed eradication rate, sequential therapy should not be recommended (absent in guidelines, unneeded antibiotic). Bismuth-based quadruple treatment (1st, 2nd or subsequent lines) yields the highest eradication rates. PMID- 28617883 TI - Ruling-in and Ruling-out Significant Fibrosis and Cirrhosis in Patients with Chronic Hepatitis C Using a Shear Wave Measurement Method. AB - AIMS: To prospectively assess the cutoff values of a point shear wave measurement (SWM) method for ruling-in and ruling-out significant fibrosis and cirrhosis using transient elastography (TE) as the reference standard. METHOD: Consecutive patients with chronic hepatitis C were enrolled. Liver stiffness was assessed with the SWM method implemented on the HI VISION Ascendus ultrasound system (Hitachi Ltd, Japan) and with the TE method of the FibroScan(r) device (Echosens, France). For staging significant fibrosis (F>/=2) and cirrhosis (F=4) we used the TE cutoffs of 7.0 and 12.0 kiloPascal (kPa), respectively. The diagnostic performance of SWM was assessed by calculating the area under the receiver operating characteristic (AUROC) curve. Cutoffs with specificity or sensitivity > 90% were chosen to rule-in or rule-out F>/=2 and F=4. RESULTS: 445 individuals [235 males, 210 females; mean age, 61.1 (13.3) years] were studied: 190 (42.7%) individuals had F0-F1 fibrosis stage, 82 (18.4%) F2, 46 (10.3%) F3, and 127 (28.6%) F4 fibrosis stage. For ruling-in F>/=2 the SWM cutoff was 6.78 kPa [sensitivity, 76.9%(70.6-82.4); specificity, 90.3% (85.0-94.3)] and for ruling out it was 5.55 kPa [sensitivity, 90.6% (85.8-94.1); specificity, 72.2% (64.9 78.6)]. For ruling-in F=4 the SWM cutoff was 9.15 kPa [sensitivity, 83.3% (74.4 90.2); specificity, 90.1% (86.0-93.2)] and for ruling-out it was 8.41 kPa [sensitivity, 90.6% (82.9-95.6); specificity, 82.2% (77.3-86.4)]. AUROCs were 0.92 (0.89-0.94) for F>/=2 and 0.94 (0.91-0.96) for F=4. CONCLUSIONS: In clinical practice, the use of a dual cutoff of SWM may increase the confidence in staging liver fibrosis with a non-invasive shear wave elastography technique. PMID- 28617884 TI - Dynamics of liver stiffness values by means of transient elastography in patients with HCV liver cirrhosis undergoing interferon free treatment. AB - BACKGROUND AND AIMS: Liver stiffness (LS) measurement by Transient Elastography (TE) has been widely accepted as a tool for fibrosis assessment. The aim of this study was to assess LS dynamics in a group of patients with HCV liver cirrhosis after interferon free treatment (IFT). METHODS: This two-center clinical trial included 225 patients with compensated HCV cirrhosis (all genotype 1b), who received IFT for 12 weeks. All patients were evaluated by means of TE at the beginning and at the end of treatment (EOT), and a subgroup (170 patients) also 12 weeks after EOT; all of them had sustained viral response (SVR). Reliable LS measurements (LSM) were defined as a median value of 10 valid LSM, with IQR <30% and SR >/=60%. Both M and XL probes were used. For diagnosing cirrhosis we used a cut-off value of 12kPa as proposed by the Tsochatzis meta-analysis. We considered a decrease or increase of more than 10% in LSM as being significant. RESULTS: Out of 225 subjects, reliable measurements were obtained in 93.7%, so that the final analysis included 211 patients. The mean LS values decreased significantly after IFT: 26.4+/-11.7 vs. 23.5+/-13.3 kPa (p=0.01). Most patients, 59.2% (125/211) presented more than 10% decrease in LS values, 24.1% (51/211) had stable LS values, while in 16.4% (35/211) cases, the LS values increased. In the subgroup of 170 patients with LSM also performed 12 weeks after EOT (SVR), the mean LS values were significantly lower as compared to baseline: 21.3+/-11 kPa vs. 27.4+/ 11.9 kPa (p<0.0001) and also as compared to EOT: 21.3+/-11 kPa vs. 23.7+/-13.3 kPa (p<0.0001). CONCLUSION: In our patients with HCV liver cirrhosis, the mean LS values evaluated by TE significantly decreased after antiviral treatment at EOT and also 12 weeks after EOT as compared to baseline. Overall, about 60% of patients had LS values at EOT lower than at baseline, while 12 weeks after EOT about 75% of patients had LS values lower than at baseline. PMID- 28617885 TI - The role of wireless capsule endoscopy (WCE) in the detection of occult primary neuroendocrine tumors. AB - BACKGROUND AND AIMS: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with unclear etiology that may show functioning or non-functioning features. Primary tumor localization often requires integrated imaging. The European Neuroendocrine Tumors Society (ENETS) guidelines proposed wireless capsule endoscopy (WCE) as a possible diagnostic tool for NETs, if intestinal origin is suspected. However, its impact on therapeutic management is debated. We aimed to evaluate the yield of WCE in detecting intestinal primary tumors in patients showing liver NET metastases when first-line investigations are inconclusive. METHOD: Twenty-four patients with a histological diagnosis of metastatic NET from liver biopsy and no evidence of primary lesions at first-line investigations were prospectively studied in an ENETS-certified tertiary care center. Wireless-capsule endoscopy was requested before explorative laparotomy and intra-operative ultrasound. The diagnostic yield of WCE was compared to the surgical exploration. RESULTS: Sixteen subjects underwent surgery; 11/16 had positive WCE identifying 16 bulging lesions. Mini-laparotomy found 13 NETs in 11/16 patients (9 small bowel, 3 pancreas, 1 bile ducts). Agreement between WCE and laparotomy was recorded in 9 patients (Sensitivity=75%; Specificity=37.5%; PPV=55%; NPV=60%). Correspondence assessed per-lesions produced similar results (Sensitivity=70%; Specificity=25%; PPV=44%; NPV=50%). No capsule retentions were recorded. CONCLUSIONS: Wireless-capsule endoscopy is not indicated as second-line investigation for patients with gastro-entero-pancreatic NETs. In the setting of a referral center, it might provide additional information when conventional investigations are inconclusive about the primary site. PMID- 28617886 TI - Major hereditary gastrointestinal cancer syndromes: a narrative review. AB - Gastrointestinal cancer is one of the major causes of death worldwide. Hereditary gastrointestinal cancer syndromes constitute about 5-10% of all cancers. About 20 25% of undiagnosed cases have a possible hereditary component, which is not yet established. In the last few decades, the advance in genomics has led to the discovery of multiple cancer predisposition genes in gastrointestinal cancer. Physicians should be aware of these syndromes to identify high-risk patients and offer genetic testing to prevent cancer death. In this review, we describe clinical manifestations, genetic testing and its challenges, diagnosis and management of the major hereditary gastrointestinal cancer syndromes. PMID- 28617887 TI - Peroral cholangiopancreatoscopy with the SpyGlass(r) system: what do we know 10 years later. AB - Smaller endoscopes and catheters have been developed that permit direct visualization of the bile and pancreatic ducts (cholangioscopy and pancreatoscopy, respectively). These endoscopes and catheters are passed through the working channel of a standard therapeutic duodenoscope during endoscopic retrograde cholangiopancreatography (ERCP). The SpyGlass Direct Visualization System (Boston Scientific Corp, Natick, MA, USA) is currently the most widely used and studied device. Cholangioscopy with intraductal lithotripsy has become an established modality in the treatment of difficult biliary lithiasis. When used in the evaluation of indeterminate biliary strictures by experienced endoscopists in recognizing intraductal pathology, it increases the diagnostic yield of tissue sampling. Pancreatoscopy is complementary to other imaging modalities in the evaluation of intraductal papillary mucinous neoplasms of the pancreas and is emerging as a sole or adjunctive therapy to extracorporeal shock wave lithotripsy for the treatment of main pancreatic duct stones. It remains investigational in the diagnosis of pancreatic adenocarcinoma. Complications specific to the performance of cholangiopancreatoscopy include cholangitis, which is related to intraductal fluid irrigation. PMID- 28617888 TI - Position paper on treatment of hepatitis C in Romania, 2017. Part one. AB - BACKGROUND AND AIMS: Hepatitis C Virus (HCV) infection is a common condition with endemic prevalence in some areas of the world. In Romania the mean prevalence is about 3%. New treatments became available on the market in recent years and new drugs are in the pipeline. A re-evaluation of HCV therapy was considered mandatory. The Romanian Society of Gastroenterology and Hepatology undertook this task for the practitioners of this country. METHODOLOGY: A group of recognized experts was created who screened the available literature and the major available guidelines. A list of items requiring attention has been created. These items were discussed and rated. Decisions were taken by consensus. RECOMMENDATIONS: We present here the first of the two parts of our Society's recommendations for chronic HCV infection treatment. An agreement was reached regarding the diagnostic tools, the assessment of severity and the up-dated therapy schedules. CONCLUSIONS: This Position Paper represents a guide for the assessment and the therapy of HCV infection. The recommendations are in concordance with other guidelines but are applied to the real-life conditions in this country. PMID- 28617889 TI - Erdheim-Chester Disease presenting with histiocytic colitis and cytokine storm. AB - BACKGROUND: Non-Langerhans histiocytosis is a group of inflammatory lymphoproliferative disorders originating from non-clonal expansion of hematopoietic stem cells into cytokine-secreting dendritic cells or macrophages. Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans cell histiocytosis characterized by tissue inflammation and injury caused by macrophage infiltration and histologic findings of foamy histiocytes. Often ECD involves the skeleton, retroperitoneum and the orbits. This is the first report documenting ECD manifesting as segmental colitis and causing cytokine-release syndrome. CASE PRESENTATION: A 68-year old woman presented with persistent fever without infectious etiology and hematochezia. Endoscopy showed segmental colitis and pathology revealed infiltration of large foamy histiocytes CD3-/CD20 /CD68+/CD163+/S100- consistent with ECD. The patient was empirically treated with steroids but continued to have fever and developed progressive distributive shock. CONCLUSION: This case report describes the differential diagnosis of infectious and immune-mediated inflammatory and rheumatologic segmental colitis. Non-Langerhans histiocytosis and ECD are rare causes of gastrointestinal inflammation. Prompt diagnosis is imperative for the appropriate treatment to prevent hemodynamic compromise due to distributive shock or gastrointestinal bleeding. Importantly, gastrointestinal ECD might exhibit poor response to steroid treatment and other potential treatments including chemotherapy, and biologic treatments targeting IL-1 and TNF-alpha signalling should be considered. PMID- 28617890 TI - Peroral endoscopic myotomy for the treatment of achalasia in a patient with esophageal varices. A case report. AB - Achalasia is very uncommon, and rarely does achalasia co-exist with esophageal varices. We present a 62-year-old woman who was diagnosed with both achalasia and esophageal varices in December 2014 and had a past history of hematemesis. The patient's achalasia symptoms' Eckardt score was 9, and her hepatic function was Child-Pugh grade A6. After comprehensive assessment of the patient's health and discussion of the pros and cons of various therapies for achalasia, the patient underwent a peroral endoscopic myotomy. She was symptom-free after the operation and had no recurrence of achalasia symptoms at 20-month follow-up. No adverse events were reported. Peroral endoscopic myotomy for achalasia with esophageal varices has not been previously reported in the English literature. PMID- 28617891 TI - Esophageal adenocarcinoma with enteroblastic differentiation arising in ectopic gastric mucosa in the cervical esophagus: a case report and literature review. AB - BACKGROUND: Adenocarcinoma with enteroblastic differentiation is a subtype of alpha-fetoprotein (AFP) producing adenocarcinoma. This type of tumor is associated with a poor prognosis and is prone to metastasize. Esophageal adenocarcinoma with enteroblastic differentiation is extremely rare. CASE PRESENTATION: The patient was a 65-year-old woman who was referred to our hospital with dysphagia. Endoscopic examination revealed an elevated lesion 20mm in diameter at 17cm from the upper incisors. Endoscopic submucosa dissection (ESD) was performed and histopathological examination revealed tubular adenocarcinoma composed of cuboidal cells with clear cell cytoplasm. Immunohistochemical stain was diffusely positive for Sall-like protein 4 (SALL4) and weakly positive for AFP and glypican 3. From this result, we diagnosed esophageal adenocarcinoma with enteroblastic differentiation. The patient is still alive without recurrence of cancer 40 months after ESD. CONCLUSION: To our knowledge, this is the first report to undergo ESD for esophageal adenocarcinoma with enteroblastic differentiation arising from ectopic gastric mucosa in the esophagus. PMID- 28617892 TI - Intestinal heterotopic pancreas involved by simultaneous PanIN-2 lesion and endocrine microadenoma: a unique case. AB - We hereby present the case of a 58-year-old male who underwent a total gastrectomy for gastric neoplasm. During the surgery, a tumor mass in the jejunum was identified, considered as metastasis, and resected. The histopathological examination of the jejunal lesion showed ectopic pancreas. In this area, two pathological distinct lesions were identified, one histologically compatible with pancreatic intraepithelial neoplasia (PanIN) type 2 lesion and the other with morphologic criteria for endocrine microadenoma. To our knowledge, this is the first case that evidences the presence of a concomitant premalignant exocrine lesion and benign endocrine lesion in a heterotopic pancreas. PMID- 28617893 TI - The "report card" to grade H. Pylori treatment regimens: is it achievable in real world in areas with high clarithromycin resistance? PMID- 28617894 TI - The "two-devices-in-one-channel technique" for biliary through-the-scope stent removal. PMID- 28617895 TI - Oral Direct Acting Antivirals treatment failed to cure a patient with chronic hepatitis C due to shifts of viral genotype. PMID- 28617896 TI - Retraction. AB - The authors of the case report "One-shot Balloon Dilation of Esophageal Stricture due to Unusual Lichen Planus Localization" published as an Image of the Issue in December 2016 in the Journal of Gastrointestinal and Liver Diseases (volume 25, number 4) have communicated to us they wish to retract this article from the journal. The Editors accept the retraction of this article from the Journal at the request of the author and will proceed accordingly. PMID- 28617898 TI - Mutation in BRAF V600E: A Poor Prognostic Marker in Stage III Colon Cancers With Deficient MMR? PMID- 28617897 TI - Recreational Activity and Facial Trauma Among Older Adults. AB - Importance: As the US population ages, public health agencies have released guidelines encouraging aerobic activity and muscle-strengthening exercises among older individuals. Facial trauma from such activities among elderly individuals has long been underappreciated. Objectives: To evaluate the incidence of recreational activity-associated facial fractures among older adults and to further delineate injury characteristics including demographics, fracture location, and specific activities. Design, Setting, and Participants: The National Electronic Injury Surveillance System was used to collect data on emergency department visits from January 1, 2011, to December 31, 2015, for individuals 55 years of age or older who sustained facial fractures from recreational activities. Individual entries were evaluated for activity code, fracture site, and demographics. Weighting data were used to extrapolate national incidence. Main Outcomes and Measures: Incidence and location of facial fractures and associated recreational activity. Results: During the study period, there were 20 519 emergency department visits for recreational activity-associated facial fractures among adults 55 years of age or older (8107 women and 12 412 men; mean [SD] age, 66.5 [9.1] years). The annual incidence of facial fractures increased by 45.3% from 2011 (n = 3174) through 2015 (n = 4612). Bicycling (26.6%), team sports (15.4%), outdoor activities (10.1%), and gardening (9.5%) were the most common causes of facial fractures. Walking and jogging caused 5.5% of fractures. In cases specifying site of fracture, nasal (65.4%) and orbital (14.1%) fractures were the most common. A greater proportion of men than women sustained bicycle-associated fractures (35.7% vs 14.9%; P = 3.1056 * 10-170), while more women than men sustained fractures associated with gardening (15.5% vs 6.1%; P = 2.1029 * 10-97), outdoor activities (14.6% vs 7.7%; P = 4.3156 * 10 50), and gym exercise (7.7% vs 1.3%; P = 3.0281 * 10-114). Men harbored a greater likelihood than women of orbital (14.9% vs 12.8%; P = 6.1468 * 10-5) and mandible fractures (9.3% vs 2.0%; P = 9.3760 * 10-64). Walking and jogging and gardening comprised a greater proportion of injuries in older cohorts. Conclusions and Relevance: Facial fractures sustained from recreational activity increased by 45.3% during a 5-year period among older adults. Although bicycling was the most common activity facilitating these injuries, many other pursuits represent areas of concern. Nasal fractures predominated, although orbital fractures increased with age. These findings offer areas for targeted prevention and provide valuable information for patient counseling. Furthermore, initiatives encouraging greater activity among this population may need to be accompanied by guidelines for injury prevention. Level of Evidence: NA. PMID- 28617899 TI - When Somatic Mutations Are Associated With a Higher Aggressive Behavior-A Story of Announced Evidence. PMID- 28617900 TI - Importance of Reporting Duration of Facial Paralysis in Studies of Emotion and Well-being. PMID- 28617901 TI - Importance of Reporting Duration of Facial Paralysis in Studies of Emotion and Well-Being-Reply. PMID- 28617902 TI - Mother Tongue. PMID- 28617903 TI - Association Between Patient Review of Systems Score and Somatization. AB - Importance: Somatization is a condition in which psychological distress is manifested by medically unexplained symptoms, and it is prevalent in all medical specialties, including otolaryngology. Recognition of somatization can be difficult, and there are limited methods available. Objectives: To determine whether patients with somatization respond differently to the review of systems (ROS) portion of the patient interview and whether the ROS can be used to identify patients with somatization. Design, Setting, and Participants: A retrospective review of medical records of 2120 consecutive consultations of English- or Spanish-speaking patients aged 18 to 89 years who presented to the otolaryngology clinic from January 1, 2014, to November 10, 2015, was conducted to compare how the ROS of patients with chief complaints associated with somatization (group B: globus sensation, dizziness, and tinnitus) differs from those with symptoms more often associated with objective findings (group A: nasal obstruction, hoarseness, and hearing loss); a total of 605 patients were included. Objective clinical findings after physical examination and related testing were reviewed and classified as either significant, marginal, or absent. Current or past psychiatric comorbidities were also examined. Main Outcomes and Measures: Number of affirmative responses on a standardized, 69-point ROS was recorded as a ROS score (ROSS). Objective clinical findings, symptoms, and psychiatric comorbidities were recorded. Results: Of the 605 patients included in the analysis, 346 (57.2%) were women, and the mean (SD) age was 51.6 (15.7) years. Among patients with medically unexplained symptoms (median, 11; range, 0 39), the ROSS was higher compared with those with objective clinical findings (median, 6; range, 0-31) (median difference, 4; 95% CI, 3 to 6). Group A (hoarseness, nasal obstruction, and hearing loss: median ROSS, 6, range, 0-41) exhibited lower ROSS than group B (dizziness, globus sensation, and tinnitus: median ROSS, 9; range, 0-39) (median difference, -2; 95% CI -3 to -1). Psychiatric comorbidity (median, 10; range, 0-41) was associated with higher ROSS than patients without psychiatric comorbidity (median, 5.5; range, 0 to 36) (median difference, 5; 95% CI, 3 to 6). Conclusions and Relevance: The manner in which patients respond to a standardized ROS differs in those with medically unexplained symptoms and in those with psychiatric disease. The ROS offers information beyond the actual systems review, and may be useful in the identification of somatization. PMID- 28617904 TI - Airway Foreign Body in a Premature Neonate. PMID- 28617905 TI - Incidence of Presumed Silicone Oil Droplets in the Vitreous Cavity After Intravitreal Bevacizumab Injection With Insulin Syringes. AB - Importance: Intravitreal bevacizumab is a frequently used antivascular endothelial growth factor medication in the United States, but its off-label use is associated with risks associated with the compounding preparation. Objective: To determine the incidence of presumed silicone oil droplets after intravitreal bevacizumab was prepared in insulin syringes by a compounding pharmacy. Design, Setting, and Participants: A retrospective review was conducted of 60 patients who experienced intravitreal silicone oil droplets in the eye after intravitreal bevacizumab injections from a single specialist practice from October 1, 2015, to November 30, 2016. Bevacizumab, 1.25 mg/0.05 mL, was delivered in insulin syringes with a 31-gauge needle. Main Outcomes and Measures: Small, round clear spheres in vitreous on dilated biomicroscopic retinal examination. Results: Over a 14-month period involving 6632 intravitreal bevacizumab injections, 60 cases (35 [58%] women) of intravitreal silicone droplets were identified. Mean [SD] age of the patients was 80 [12] years; the population comprised 48 white, 9 Asian, and 3 Hispanic patients. The incidence of silicone oil droplet injections was 0.03% (1 of 3230) from October 2015 to April 2016 and 1.7% (59 of 3402) from May to November 2016 (Fisher exact test, P < .001; odds ratio [OR], 57; 95% CI, 9.8 2260). From May to November 2016, nonpriming the syringe before the intravitreal injection had a higher risk of intravitreal silicone oil droplets compared with priming the syringe (6.4% [47 of 739] vs 0.5% [12 of 2627]; Fisher exact test, P < .001; OR, 15.1; 95% CI, 7.9-33.4). Among the 60 cases, 41 patients (68%) were symptomatic, and the main symptom was floaters with spots of light. Among the patients with floaters, 36 (88%) improved over time (range, 2-8 months) despite the silicone droplets still being present on ophthalmoscopic examination. Conclusions and Relevance: An increase in intravitreal silicone oil associated with bevacizumab prepared with insulin syringes was documented. Priming the syringe before injection was associated with a lower frequency of this complication. These findings suggest that physicians should counsel their patients on the risk of floaters with intravitreal bevacizumab preloaded in insulin syringes. PMID- 28617906 TI - Comprehensive Hearing Aid Intervention at a Free Subspecialty Clinic. AB - Importance: Providing a model of a comprehensive free audiologic program may assist other health care professionals in developing their own similar program. Objective: To describe the structure, feasibility, and outcomes of a free subspecialty clinic providing hearing aids to develop a paradigm for other programs interested in implementing similar projects. Design, Setting, and Participants: A retrospective case series was conducted from September 1, 2013, through March 31, 2016. In a partnership between a free independent clinic for indigent patients and an academic medical center, 54 indigent patients were referred to the clinic for audiograms. A total of 50 of these patients had results of audiograms available for review and were therefore included in the study; 34 of these 50 patients were determined to be eligible for hearing aid fitting based on audiometric results. Exposures: Free audiometric testing, hearing aid fitting, and hearing aid donation. Main Outcomes and Measures: The number of hearing aids donated, number of eligible patients identified, number of patients fitted with hearing aids, and work effort (hours) and start-up costs associated with implementation of this program were quantified. Results: A total of 54 patients (31 women [57.4%] and 23 men [42.6%]; median age, 61 years; range, 33-85 years) had audiograms performed, and 84 hearing aids were donated to the program. The patients were provided with free audiograms, hearing aid molds, and hearing aid programming, as well as follow-up appointments to ensure continued proper functioning of their hearing aids. Since 2013, a total of 34 patients have been determined to be eligible for the free program and were offered hearing aid services. Of these, 20 patients (59%) have been fitted or are being fitted with free hearing aids. The value of services provided is estimated to be $2260 per patient. Conclusions and Relevance: It is feasible to provide free, comprehensive audiologic care, including hearing aids and fitting, in a well-established, free clinic model. The opportunity for indigent patients to use hearing aids at minimal personal cost is a major step forward in improving access to high-quality care. PMID- 28617907 TI - Reducing Excessive Use of Antipsychotic Agents in Nursing Homes. PMID- 28617908 TI - Validation of Single C-Arm Fluoroscopic Technique for Measuring In Vivo Abdominal Wall Deformation. AB - Hernia meshes significantly reduce the recurrence rates in hernia repair. It is known that they affect the abdominal wall postimplantation, yet the understanding of in vivo mechanics in the mesh placement area is lacking. We established a single C-arm biplane fluoroscopic system to study strains at the interface between the mesh and repaired abdominal tissues. We aimed to validate this system for future porcine hernia repair studies. Custom matlab programs were written to correct for pincushion distortion, and direct linear transformation (DLT) reconstructed objects in 3D. Using a custom biplane-trough setup, image sets were acquired throughout the calibrated volume to evaluate a radio-opaque test piece with known distances between adjacent beads. Distances were measured postprocessing and compared to known measurements. Repeatability testing was conducted by taking image sets of the test piece in a fixed location to determine system movement. The error in areal stretch tracking was evaluated by imaging a square plate with fixed radio-opaque beads and using matlab programs to compare the measured areal stretch to known bead positions. Minor differences between measured and known distances in the test piece were not statistically different, and the system yielded a 0.01 mm bias in the XY plane and a precision of 0.61 mm. The measured areal stretch was 0.996, which was not significantly different than the expected value of 1. In addition, preliminary stretch data for a hernia mesh in a porcine model demonstrated technique feasibility to measure in vivo porcine abdominal mechanics. PMID- 28617910 TI - Error in Author Degree. PMID- 28617909 TI - Development of a Flow Evolution Network Model for the Stress-Strain Behavior of Poly(L-lactide). AB - Computational modeling is critical to medical device development and has grown in its utility for predicting device performance. Additionally, there is an increasing trend to use absorbable polymers for the manufacturing of medical devices. However, computational modeling of absorbable devices is hampered by a lack of appropriate constitutive models that capture their viscoelasticity and postyield behavior. The objective of this study was to develop a constitutive model that incorporated viscoplasticity for a common medical absorbable polymer. Microtensile bars of poly(L-lactide) (PLLA) were studied experimentally to evaluate their monotonic, cyclic, unloading, and relaxation behavior as well as rate dependencies under physiological conditions. The data were then fit to a viscoplastic flow evolution network (FEN) constitutive model. PLLA exhibited rate dependent stress-strain behavior with significant postyield softening and stress relaxation. The FEN model was able to capture these relevant mechanical behaviors well with high accuracy. In addition, the suitability of the FEN model for predicting the stress-strain behavior of PLLA medical devices was investigated using finite element (FE) simulations of nonstandard geometries. The nonstandard geometries chosen were representative of generic PLLA cardiovascular stent subunits. These finite element simulations demonstrated that modeling PLLA using the FEN constitutive relationship accurately reproduced the specimen's force displacement curve, and therefore, is a suitable relationship to use when simulating stress distribution in PLLA medical devices. This study demonstrates the utility of an advanced constitutive model that incorporates viscoplasticity for simulating PLLA mechanical behavior. PMID- 28617911 TI - A Supraclavicular Mass. PMID- 28617912 TI - Mutation in BRAF V600E-Reply. PMID- 28617913 TI - A Woman With a Spot in Her Vision. PMID- 28617914 TI - Trends in Fluoroquinolone Nonsusceptibility Among Coagulase-Negative Staphylococcus Isolates Causing Endophthalmitis, 1995-2016. PMID- 28617915 TI - The Reduction in the Age-Adjusted Prevalence of Hearing Impairment in the United States-Reply. PMID- 28617916 TI - When Somatic Mutations Are Associated With a Higher Aggressive Behavior-Reply. PMID- 28617918 TI - Intravitreal Melphalan for Treatment of Primary Vitreoretinal Lymphoma: A New Indication for an Old Drug. PMID- 28617917 TI - Genomic Profiling of Small-Bowel Adenocarcinoma. AB - Importance: Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking. Objective: To perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations. Design, Setting, and Participants: Prospective analysis was performed of clinical samples from patients with SBA (n = 317), colorectal cancer (n = 6353), and gastric carcinoma (n = 889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture-based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. Results: Of the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% [85 of 317] vs 75.9% [4823 of 6353], P < .001; and CDKN2A: 14.5% [46 of 317] vs 2.6% [165 of 6353], P < .001) or gastric carcinoma (KRAS: 53.6% [170 of 317] vs 14.2% [126 of 889], P < .001; APC: 26.8% [85 of 317] vs 7.8% [69 of 889], P < .001; and SMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889], P < .001). BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF-mutated cases. The ERBB2/HER2 point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease-associated SBAs. Targetable alterations in several additional genes, including PIK3CA and MEK1, and receptor tyrosine kinase fusions, were also identified in all 3 series. Conclusions and Relevance: This study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy. PMID- 28617919 TI - The Persistence and Functional Impact of English Language Difficulties Experienced by Children Learning English as an Additional Language and Monolingual Peers. AB - Purpose: This study explored whether a monolingual-normed English language battery could identify children with English as an additional language (EAL) who have persistent English language learning difficulties that affect functional academic attainment. Method: Children with EAL (n = 43) and monolingual English speaking children (n = 46) completed a comprehensive monolingual-normed English language battery in Year 1 (ages 5-6 years) and Year 3 (ages 7-8 years). Children with EAL and monolingual peers, who either met monolingual criteria for language impairment or typical development on the language battery in Year 1, were compared on language growth between Year 1 and Year 3 and on attainment in national curriculum assessments in Year 2 (ages 6-7 years). Results: Children with EAL and monolingual peers who met monolingual criteria for language impairment in Year 1 continued to display comparably impaired overall language ability 2 years later in Year 3. Moreover, these groups displayed comparably low levels of academic attainment in Year 2, demonstrating comparable functional impact of their language difficulties. Conclusion: Monolingual-normed language batteries in the majority language may have some practical value for identifying bilingual children who need support with language learning, regardless of the origin of their language difficulties. PMID- 28617920 TI - Milestone Analyses of Immune Checkpoint Inhibitors, Targeted Therapy, and Conventional Therapy in Metastatic Non-Small Cell Lung Cancer Trials: A Meta analysis. AB - Importance: Novel intermediate end points may be useful to detect signals of early activity and prioritize new therapies to treat patients with advanced malignant neoplasms, including metastatic non-small cell lung cancer (mNSCLC). Objective: To explore milestone rate, a proposed intermediate end point for immunotherapy trials. Data Sources: Trials submitted to the US Food and Drug Administration with more than 150 patients and in which the intention-to-treat population was assessed were identified. Study Selection: An initial meta analysis identified 14 randomized clinical trials for treatment of mNSCLC with active controls submitted to the US Food and Drug Administration from January 1, 2003, through December 31, 2013. An additional 11 randomized clinical trials submitted from January 1, 2014, through December 31, 2016 were included. Data Extraction and Synthesis: Two investigators abstracted data and pooled data to compare trial-level milestone ratios with conventional end points. Main Outcomes and Measures: Trial-level milestone ratios for milestone rates were calculated for overall response rate (ORR) within 6 months, 9-month progression-free survival (PFS), 9-month overall survival (OS), and 12-month OS. A weighted linear regression model evaluated associations between milestone ratios and hazard ratios (HRs). Experimental and control arms of trials testing immunotherapy, targeted therapy, and other trials were pooled to compare Kaplan-Meier survival estimates in the 3 therapeutic classes. Results: A total of 20 013 unique patients (65.4% male and 34.6% female; mean age, 60 [range, 18-92] years) with advanced lung cancer were identified in 25 unique trials. A moderate association was observed between 12-month OS milestone ratio and OS HR (R2 = 0.80; 95% CI, 0.63-0.91) and 9-month OS milestone ratio and OS HR (R2 = 0.67; 95% CI, 0.49 0.82). No associations were observed between 9-month PFS milestone ratio and OS HR (R2 = 0.19; 95% CI, 0.03-0.49) or 6-month ORR and OS HR (R2 = 0.05; 95% CI, 0.0001-0.31). The aggregated Kaplan-Meier analysis of immunotherapy trials vs chemotherapy revealed an OS HR of 0.69 (95% CI, 0.63-0.75) and PFS HR of 0.82 (95% CI, 0.76-0.89). Targeted therapy trials vs chemotherapy had an OS HR of 0.98 (95% CI, 0.80-1.19) and PFS HR of 0.48 (95% CI, 0.42-0.56). Conclusions and Relevance: This analysis of milestone rates suggests a moderate association between OS milestones at 12 or 9 months and OS HR but not 9-month PFS or 6-month ORR milestones and OS HR. Although OS at 12 months had the strongest association with OS HR, it may not be the optimal time for future trials, which will increasingly have immunotherapy as the control, deploy new biomarker-enrichment strategies, and likely enroll patients with longer survival. Milestone rates may be useful as a complementary tool to summarize or interpret trial results or as a secondary end point in exploratory studies. PMID- 28617921 TI - Optical coherence tomography angiography-based capillary velocimetry. AB - Challenge persists in the field of optical coherence tomography (OCT) when it is required to quantify capillary blood flow within tissue beds in vivo. We propose a useful approach to statistically estimate the mean capillary flow velocity using a model-based statistical method of eigendecomposition (ED) analysis of the complex OCT signals obtained with the OCT angiography (OCTA) scanning protocol. ED-based analysis is achieved by the covariance matrix of the ensemble complex OCT signals, upon which the eigenvalues and eigenvectors that represent the subsets of the signal makeup are calculated. From this analysis, the signals due to moving particles can be isolated by employing an adaptive regression filter to remove the eigencomponents that represent static tissue signals. The mean frequency (MF) of moving particles can be estimated by the first lag-one autocorrelation of the corresponding eigenvectors. Three important parameters are introduced, including the blood flow signal power representing the presence of blood flow (i.e., OCTA signals), the MF indicating the mean velocity of blood flow, and the frequency bandwidth describing the temporal flow heterogeneity within a scanned tissue volume. The proposed approach is tested using scattering phantoms, in which microfluidic channels are used to simulate the functional capillary vessels that are perfused with the scattering intralipid solution. The results indicate a linear relationship between the MF and mean flow velocity. In vivo animal experiments are also conducted by imaging mouse brain with distal middle cerebral artery ligation to test the capability of the method to image the changes in capillary flows in response to an ischemic insult, demonstrating the practical usefulness of the proposed method for providing important quantifiable information about capillary tissue beds in the investigations of neurological conditions in vivo. PMID- 28617922 TI - Automated circumferential construction of first-order aqueous humor outflow pathways using spectral-domain optical coherence tomography. AB - The purpose was to create a three-dimensional (3-D) model of circumferential aqueous humor outflow (AHO) in a living human eye with an automated detection algorithm for Schlemm's canal (SC) and first-order collector channels (CC) applied to spectral-domain optical coherence tomography (SD-OCT). Anterior segment SD-OCT scans from a subject were acquired circumferentially around the limbus. A Bayesian Ridge method was used to approximate the location of the SC on infrared confocal laser scanning ophthalmoscopic images with a cross multiplication tool developed to initiate SC/CC detection automated through a fuzzy hidden Markov Chain approach. Automatic segmentation of SC and initial CC's was manually confirmed by two masked graders. Outflow pathways detected by the segmentation algorithm were reconstructed into a 3-D representation of AHO. Overall, only <1% of images (5114 total B-scans) were ungradable. Automatic segmentation algorithm performed well with SC detection 98.3% of the time and <0.1% false positive detection compared to expert grader consensus. CC was detected 84.2% of the time with 1.4% false positive detection. 3-D representation of AHO pathways demonstrated variably thicker and thinner SC with some clear CC roots. Circumferential (360 deg), automated, and validated AHO detection of angle structures in the living human eye with reconstruction was possible. PMID- 28617923 TI - Mapping absolute tissue endogenous fluorophore concentrations with chemometric wide-field fluorescence microscopy. AB - We report chemometric wide-field fluorescence microscopy for imaging the spatial distribution and concentration of endogenous fluorophores in thin tissue sections. Nonnegative factorization aided by spatial diversity is used to learn both the spectral signature and the spatial distribution of endogenous fluorophores from microscopic fluorescence color images obtained under broadband excitation and detection. The absolute concentration map of individual fluorophores is derived by comparing the fluorescence from "pure" fluorophores under the identical imaging condition following the identification of the fluorescence species by its spectral signature. This method is then demonstrated by characterizing the concentration map of endogenous fluorophores (including tryptophan, elastin, nicotinamide adenine dinucleotide, and flavin adenine dinucleotide) for lung tissue specimens. The absolute concentrations of these fluorophores are all found to decrease significantly from normal, perilesional, to cancerous (squamous cell carcinoma) tissue. Discriminating tissue types using the absolute fluorophore concentration is found to be significantly more accurate than that achievable with the relative fluorescence strength. Quantification of fluorophores in terms of the absolute concentration map is also advantageous in eliminating the uncertainties due to system responses or measurement details, yielding more biologically relevant data, and simplifying the assessment of competing imaging approaches. PMID- 28617924 TI - The Reduction in the Age-Adjusted Prevalence of Hearing Impairment in the United States: An Unexpected Dividend of Phasing Out Leaded Gasoline? PMID- 28617925 TI - Gap in Capillary Perfusion on Optical Coherence Tomography Angiography. PMID- 28617926 TI - Author Response: Gap in Capillary Perfusion on Optical Coherence Tomography Angiography. PMID- 28617927 TI - Biomechanical Evaluations of Ocular Injury Risk for Blast Loading. AB - Ocular trauma is one of the most common types of combat injuries resulting from the exposure of military personnel with improvised explosive devices. The injury mechanism associated with the primary blast wave is poorly understood. We employed a three-dimensional computational model, which included the main internal ocular structures of the eye, spatially varying thickness of the cornea scleral shell, and nonlinear tissue properties, to calculate the intraocular pressure and stress state of the eye wall and internal ocular structure caused by the blast. The intraocular pressure and stress magnitudes were applied to estimate the injury risk using existing models for blunt impact and blast loading. The simulation results demonstrated that blast loading can induce significant stresses in the different components of the eyes that correlate with observed primary blast injuries in animal studies. Different injury models produced widely different injury risk predictions, which highlights the need for experimental studies evaluating mechanical and functional damage to the ocular structures caused by the blast loading. PMID- 28617928 TI - Expectation modulates repetition priming under high stimulus variability. AB - Neural responses to stimuli are often attenuated by repeated presentation. When observed in blood oxygen level-dependent signals, this attenuation is known as fMRI adaptation (fMRIa) or fMRI repetition suppression. According to a prominent account, fMRIa reflects the fulfillment of perceptual expectations during recognition of repeated items (Summerfield, Trittschuh, Monti, Mesulam, & Egner, 2008). Supporting this idea, expectation has been shown to modulate fMRIa under some circumstances; however, it is not currently known whether expectation similarly modulates recognition performance. To address this lacuna, we measured behavioral and fMRI responses to faces while varying the extent to which each stimulus was informative about its successor. Behavioral priming was greater when repetitions were more likely, suggesting that recognition was facilitated by the expectation than an item would repeat. Notably, this effect was only observed when stimuli were drawn from a broad set of faces including many ethnicities and both genders, but not when stimuli were drawn from a narrower face set, thus making repetitions less informative. Moreover, expectation did not modulate fMRIa in face-selective cortex, contrary to previous studies, although an exploratory analysis indicated that it did so in a medial frontal region. These results support the idea that expectation modulates recognition efficiency, but insofar as behavioral effects of expectation were not accompanied by fMRI effects in visual cortex, they suggest that fMRIa cannot be entirely explained in terms of fulfilled expectations. PMID- 28617929 TI - Age effects on saccadic adaptation: Evidence from different paradigms reveals specific vulnerabilities. AB - Saccadic eye movements provide an opportunity to study closely interwoven perceptual, motor, and cognitive changes during aging. Here, we investigated age effects on different mechanisms of saccadic plasticity. We compared age effects in two different adaptation paradigms that tap into low- and high-level adaptation processes. A total of 27 senior adults and 25 young adults participated in our experiments. In our first experiment, we elicited adaptation by a double-step paradigm, which is designed to trigger primarily low-level, gradual motor adaptation. Age groups showed equivalent adaptation of saccadic gain. In our second experiment, adaptation was induced by a perceptual task that emphasizes high-level, fast processes. We consistently found no evidence for age related differences in low-level adaptation; however, the fast adaptation response was significantly more pronounced in the young adult group. We conclude that low-level motor adaptation is robust during healthy aging but that high level contributions, presumably involving executive strategies, are subject to age-related decline. Our findings emphasize the need to differentiate between specific aging processes in order to understand functional decline and stability across the adult life span. PMID- 28617932 TI - Effect of the treatment of Type 2 diabetes mellitus on the development of cognitive impairment and dementia. AB - BACKGROUND: Prevention of cognitive impairment and dementia is an important public health goal. Epidemiological evidence shows a relationship between cognitive impairment and Type 2 diabetes mellitus. The risk of dementia increases with duration of disease. This updated systematic review investigated the effect on cognitive function of the type of treatment and level of metabolic control in people with Type 2 diabetes. OBJECTIVES: To assess the effects of different strategies for managing Type 2 diabetes mellitus on cognitive function and the incidence of dementia. SEARCH METHODS: We searched ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG)), the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL and LILACS on 15 October 2016. ALOIS contains records from all major health care databases, (CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many trials' registers and grey literature sources. SELECTION CRITERIA: We included randomised controlled trials (RCTs) which compared two or more different treatments for Type 2 diabetes mellitus and in which cognitive function was measured at baseline and after treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of the included RCTs. We pooled data for comparable trials and estimated the effects of treatment by using risk ratios (RRs) and mean differences (MDs), according to the nature of the outcome. We assessed the quality of the evidence using GRADE methods. MAIN RESULTS: We identified seven eligible studies but only four provided data we could include in efficacy analyses. Two of these studies compared intensive versus standard glycaemic control and two compared different pharmacological treatments. All studies were at unclear risk of bias in at least two domains and one large study was at high risk of performance and detection bias.(a) Two studies with 13,934 participants at high cardiovascular risk provided efficacy data on intensive versus standard glycaemic control. A third study with 1791 participants provided additional data on hypoglycaemic episodes and mortality. There is probably no difference between treatment groups in the number of participants who decline by at least 3 points on the Mini-Mental State Examination (MMSE) over five years (RR 0.98, 95% CI 0.88 to 1.08; 1 study; n = 11,140; moderate-quality evidence); and there may also be little or no difference in the incidence of dementia (RR 1.27, 95% CI 0.87 to 1.85; 1 study; n = 11,140; low-quality evidence). From another study, there was probably little or no difference in MMSE score after 40 months (MD -0.01, 95% CI -0.18 to 0.16; 1 study; n = 2794; moderate quality evidence). Participants exposed to the intensive glycaemic control strategy probably experience more episodes of severe hypoglycaemia than those who have standard treatment (RR 2.18, 95% CI 1.52 to 3.14; 2 studies; n = 12,827; moderate-quality evidence). The evidence from these trials suggests that the intensity of glycaemic control may have little or no effect on all-cause mortality (RR 0.99, 95% CI 0.87 to 1.13; 3 studies; n = 15,888; low-quality evidence).(b) One study with 156 participants compared glibenclamide (glyburide) with repaglinide. There may be a small advantage of glibenclamide on global cognitive function measured with the MMSE after 12 months (MD -0.90, 95% CI -1.68 to -0.12; low-quality evidence). No data were reported on the incidence of dementia, hypoglycaemic events or all-cause mortality.(c) One study with 145 participants compared rosiglitazone plus metformin to glibenclamide (glyburide) plus metformin over 24 weeks. It reported only on cognitive subdomains and not on global cognitive function, incidence of MCI or dementia, hypoglycaemic events or all causes of mortality. AUTHORS' CONCLUSIONS: We found no good evidence that any specific treatment or treatment strategy for Type 2 diabetes can prevent or delay cognitive impairment. The best available evidence related to the comparison of intensive with standard glycaemic control strategies. Here there was moderate quality evidence that the strategies do not differ in their effect on global cognitive functioning over 40 to 60 months. PMID- 28617933 TI - Outcomes of radiation therapy for advanced T3/T4 nonmelanoma cutaneous squamous cell and basal cell carcinoma. PMID- 28617934 TI - The anaerobic biosynthesis of plasmalogens. AB - The biosynthesis of plasmalogens in anaerobic bacteria differs fundamentally from that in animal cells. Firstly, the formation of the alk-1'-enyl ether bond in animal cells is oxygen dependent. Secondly, the first step in plasmalogen formation in animal cells is an acylation of dihydroxyacetone phosphate, which has been ruled out as a precursor in anaerobes. In bacteria the alk-1'-enyl ether bond is formed after the fully formed acyl glycerolipids are synthesized. Evidence will be presented for the conversion of the sn-1 acyl-linked chain to an O-alk-1'-enyl ether by an as yet unknown mechanism. PMID- 28617935 TI - Patch testing in patients with psoriasis: results of a 30-year retrospective study. PMID- 28617936 TI - T follicular regulatory cells in mice and men. AB - It has long been known that CD4 T cells are necessary to provide help to B cells, triggering a germinal centre (GC) reaction where affinity maturation and isotype switching occur. However, the nature of the dedicated CD4 helper T cells, known as T follicular helper (Tfh), was only recently described. Here, we review the biology and function of the recently described T follicular regulatory (Tfr) cells, another CD4 T-cell population also found within GCs but with regulatory function and characteristics. Tfr cells have been identified in mice and humans as simultaneously presenting characteristics of T follicular cells (namely CXCR5 expression) and regulatory T cells (including Foxp3 expression). These Tfr cells have been implicated in the regulation of the magnitude of the GC reaction, as well as in protection from immune-mediated pathology. PMID- 28617937 TI - Resilience in Context: A Brief and Culturally Grounded Measure for Syrian Refugee and Jordanian Host-Community Adolescents. AB - Validated measures are needed for assessing resilience in conflict settings. An Arabic version of the Child and Youth Resilience Measure (CYRM) was developed and tested in Jordan. Following qualitative work, surveys were implemented with male/female, refugee/nonrefugee samples (N = 603, 11-18 years). Confirmatory factor analyses tested three-factor structures for 28- and 12-item CYRMs and measurement equivalence across groups. CYRM-12 showed measurement reliability and face, content, construct (comparative fit index = .92-.98), and convergent validity. Gender-differentiated item loadings reflected resource access and social responsibilities. Resilience scores were inversely associated with mental health symptoms, and for Syrian refugees were unrelated to lifetime trauma exposure. In assessing individual, family, and community-level dimensions of resilience, the CYRM is a useful measure for research and practice with refugee and host-community youth. PMID- 28617938 TI - Fragile X syndrome: An overview and update of the FMR1 gene. AB - Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene premutation is the first single-gene cause of primary ovarian failure (Fragile X-associated primary ovarian insufficiency [FXPOI]) and one of the most common causes of ataxia (fragile X-associated tremor/ataxia syndrome [FXTAS]), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss-of-function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene. PMID- 28617939 TI - Commentary on Cross-Cultural Perspectives on Positive Youth Development With Implications for Intervention Research. AB - There is a growing focus on youth positive development issues among researchers and practitioners around the world. In this special issue of Child Development, each of the international authors provides new perspectives and understanding about youth developmental assets in different cultural settings. The present commentary (a) examines some of the cross-cultural themes that emerge from the four articles by international authors in this issue with implications for positive youth development (PYD) and (b) how intervention science can benefit by incorporating a PYD approach. As evident, youth involved in contexts that provide positive resources from significant others not only were less likely to exhibit negative outcomes, but also were more likely to show evidence of positive development. PMID- 28617940 TI - Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. AB - Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 +/- 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo controlled, double-blind trials are necessary to confirm this finding. PMID- 28617941 TI - Association of immunoglobulin G4 and free light chain with idiopathic pleural effusion. AB - The cause of pleural effusion remains uncertain in approximately 15% of patients despite exhaustive evaluation. As recently described immunoglobulin (Ig)G4 related disease is a fibroinflammatory disorder that can affect various organs, including the lungs, we investigate whether idiopathic pleural effusion includes IgG4-associated etiology. Between 2000 and 2012, we collected 830 pleural fluid samples and reviewed 35 patients with pleural effusions undiagnosed after pleural biopsy at Yamaguchi-Ube Medical Center. Importantly, IgG4 immunostaining revealed infiltration of IgG4-positive plasma cells in the pleura of 12 patients (34%, IgG4+ group). The median effusion IgG4 level was 41 mg/dl in the IgG4+ group and 27 mg/dl in the IgG4- group (P < 0.01). The light and heavy chains of effusion IgG4 antibodies of patients in the IgG4+ group were heterogeneous by two dimensional electrophoresis, indicating the absence of clonality of the IgG4 antibodies. Interestingly, the kappa light chains were more heterogeneous than the lambda light chains. The measurement of the kappa and lambda free light chain (FLC) levels in the pleural fluids showed significantly different kappa FLC levels (median: 28.0 versus 9.1 mg/dl, P < 0.01) and kappa/lambda ratios (median: 2.0 versus 1.2, P < 0.001) between the IgG4+ and IgG4- groups. Furthermore, the kappa/lambda ratios were correlated with the IgG4+ /IgG+ plasma cell ratios in the pleura of the IgG4+ group. Taken together, these results demonstrate the involvement of IgG4 in certain idiopathic pleural effusions and provide insights into the diagnosis, pathogenesis and therapeutic opportunities of IgG4-associated pleural effusion. PMID- 28617942 TI - Withasteroid B from D. metel L. regulates immune responses by modulating the JAK/STAT pathway and the IL-17+ RORgammat+ /IL-10+ FoxP3+ ratio. AB - Datura metel L. is a medicinal herb that contains withasteroids and has a wide range of biological activities. We isolated seven withasteroids from the flowers of D. metel L and examined their ability to inhibit immune responses in vitro and in vivo. Among the withasteroids, withasteroid B2 exhibited the strongest inhibitory effect on immune responses comparing B2 with other isolated compounds from D. metel L., including suppressing the differentiation of CD4+ T cells by inhibiting the expression and production of T cell lineage-specific master regulators and cytokines and directly suppressing the cytokine-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathways. In the interleukin (IL)-23-induced mouse ear model of skin disease, B2 repressed disease development by inhibiting the expression of proinflammatory mediators in murine ear skin. Moreover, B2 affected the maturation of dendritic cells (DCs) in vitro which, in turn, induced T cell differentiation with an increased regulatory T cell (Treg ) phenotype and decreased T helper type 17 (Th17) phenotype. This study provides new evidence that B2 might ameliorate chronic inflammatory skin diseases by suppressing pathogenic CD4+ T cell differentiation and the IL-17+ retinoic-acid-receptor-related orphan receptor gamma t (RORgammat)+ /IL-10+ forkhead box protein 3 (FoxP3)+ ratio. These findings suggest that B2 might mediate the therapeutic effects observed in psoriasis patients following treatment with D. metel L. PMID- 28617943 TI - Long-term impact of childhood selective dorsal rhizotomy on pain, fatigue, and function: a case-control study. AB - AIM: Selective dorsal rhizotomy (SDR) is a surgical treatment for spasticity in children with cerebral palsy (CP). Studies suggest long-lasting effects of SDR on spasticity; long-term effects on symptoms and function are not clear. This study tested whether adults with CP (average 22y after SDR) report less pain, fatigue, and functional decline than a retrospectively assessed non-surgical comparison group. METHOD: This was a case-control study. Eighty-eight adults with CP (mean age 27y; SDR=38 male/female/missing=20/16/2; non-surgical [comparison]=50, male/female=19/31) recruited from a tertiary care center and the community completed a battery of self-reported outcome measures. Regression models were used to test whether SDR status predicted pain, fatigue, functional change, and hours of assistance (controlling for Gross Motor Function Classification System level). RESULTS: SDR status did not significantly predict pain interference (p=0.965), pain intensity (p=0.512), or fatigue (p=0.404). SDR related to lower decline in gross motor functioning (p=0.010) and approximately 6 fewer hours of daily assistance than for those in the comparison group (p=0.001). INTERPRETATION: Adults with CP who had SDR in childhood reported less gross motor decline and fewer daily assistance needs than non-surgically treated peers, suggesting the functional impact of SDR persists long after surgery. PMID- 28617944 TI - Inequity in timing of prenatal screening in New Zealand: Who are our most vulnerable? AB - BACKGROUND: In New Zealand (NZ), Maori and Pacific women are less likely to complete prenatal screening for Down syndrome and other aneuploidies than other ethnic groups. Young women <20 have low rates of completed screening compared with women >20 years. Women living in deprived areas have lower completed screen rates than women living in more affluent areas. Combined first trimester screening has a superior sensitivity (85%) compared with second trimester screening (75%) for trisomy 21. The relative contribution of demographic factors to timing of screening uptake (first vs second trimester) has not previously been examined. AIM: To evaluate the association of ethnicity, deprivation, District Health Board (DHB) of domicile and maternal age with timing of prenatal screening (first vs second trimester) in pregnant women screened in NZ from 2010 to 2013. METHODS AND MATERIALS: Univariate logistic regression analyses were used to explore the association between timing of completed screening and each of ethnicity, deprivation index, DHB of domicile and maternal age. Multivariate logistic regression models were developed to calculate odds ratios (OR) and 95% confidence intervals (CI). Statistical analyses were performed using SAS v9.3 RESULTS: Of completed prenatal screens, 88% were completed in the first trimester. Ethnicity, age, deprivation and DHB were all significant predictors of completed first versus second trimester screening. Maori women were almost 60% less likely (adjusted OR 0.37, CI 0.35-0.39) and Pacific women almost 80% less likely (adjusted OR 0.23, CI 0.21-0.24) than NZ European women to have completed first versus second trimester screening. Women <30 years were less likely to have completed first trimester screening, as were more deprived women. Variation was also seen by DHB with women living in Whanganui DHB less likely to have completed first versus second trimester screening than women living in Auckland (adjusted OR 0.76, CI 0.71-0.81). Women living in Bay of Plenty DHB were more likely to be screened in the first versus second trimester compared with women living in Auckland (adjusted OR 1.55, CI 1.38-1.74). Within Auckland itself, women living in Counties Manukau DHB were less likely to be screened in the first versus second trimester than women living in Auckland DHB even after adjusting for ethnicity, deprivation and maternal age. CONCLUSION: Maori and Pacific women have the lowest uptake of completed first versus second trimester screening after adjusting for age, deprivation and DHB. Research is required to understand if this relates to characteristics of the carer making the offer of screening, language and/or cultural barriers to care or specific collective cultural or religious views held by women from these ethnicities. The lower completed first trimester versus second trimester prenatal screening in deprived areas, as well as variation by DHB, may relate to the availability of ultrasound and/or laboratory services in specific regions. Cost may be a contributing factor to inequity in timing of completed prenatal screening uptake, as first trimester screening incurs a part-charge to the individual, while second trimester screening is fully funded. Systemic factors within the NZ maternity model of care may also be contributory with a potential disconnect occurring for the woman between primary medical care and later registration with a Lead Maternity Carer in the first trimester. PMID- 28617946 TI - Heterogeneity in Perceptions of Parenting Among Arab Refugee Adolescents in Jordan. AB - Heterogeneity in parenting was examined in 883 Arab refugee adolescents in Jordan (Mage = 15.01 years, SD = 1.60). Latent profile analyses of five parenting dimensions rated separately for mothers and fathers yielded authoritative, authoritarian, indifferent, punitive, and for mothers, permissive profiles, with most mothers (60%) and fathers (66%) classified as authoritative. Parenting was more often authoritative for women than men and punitive (for fathers) or permissive (for mothers) of boys than girls. Authoritative fathers and authoritarian mothers were better educated than punitive parents, whose offspring reported more norm breaking and internalizing symptoms and lower academic achievement than other youth. Adjustment was better when adolescents had at least one authoritative parent than when parents were either consistent or discrepant but nonauthoritative. PMID- 28617945 TI - microRNA cluster 106a~363 is involved in T helper 17 cell differentiation. AB - T-helper cell type 17 (Th17) mediated inflammation is associated with various diseases including autoimmune encephalitis, inflammatory bowel disease and lung diseases such as chronic obstructive pulmonary disease and asthma. Differentiation into distinct T helper subtypes needs to be tightly regulated to ensure an immunological balance. As microRNAs (miRNAs) are critical regulators of signalling pathways, we aimed to identify specific miRNAs implicated in controlling Th17 differentiation. We were able to create a regulatory network model of murine T helper cell differentiation by combining Affymetrix mRNA and miRNA arrays and in silico analysis. In this model, the miR-212~132 and miR 182~183 clusters were significantly up-regulated upon Th17 differentiation, whereas the entire miR-106~363 cluster was down-regulated and predicted to target well-known Th17 cell differentiation pathways. In vitro transfection of miR-18b, miR-106a and miR-363-3p into primary murine Cd4+ lymphocytes decreased expression of retinoid-related orphan receptor c (Rorc), Rora, Il17a and Il17f, and abolished secretion of Th17-mediated interleukin-17a (Il17a). Moreover, we demonstrated target site-specific regulation of the Th17 transcription factors Rora and nuclear factor of activated T cells (Nfat) 5 by miR-18b, miR-106a and miR-363-3p through luciferase reporter assays. Here, we provide evidence that miRNAs are involved in controlling the differentiation and function of T helper cells, offering useful tools to study and modify Th17-mediated inflammation. PMID- 28617948 TI - Clinical Abstracts of the British Small Animal Veterinary Association Congress 2017, Birmingham, UK, April 6-9, 2017. PMID- 28617947 TI - Poly r(C) binding protein 1-mediated regulation of microRNA expression underlies post-sevoflurane amelioration of acute lung injury in rats. AB - Acute lung injury (ALI) presents a pervasive health burden due to the high morbidity and mortality associated with it. Volatile anesthetics like sevoflurane has been previously shown to have organ-protective effect, both in the context of normal physiological function in liver, and during LPS-induced ALI. Sevoflurane was shown to exert lung protective effect during LPS-induced ALI by modulating expression level of microRNAs (miRNAs), specifically miR-155. The objective of the current study was to define the underlying mechanism by which sevoflurane alters miRNA expression levels. Lung injury caused by LPS and its amelioration post sevoflurane administration was first confirmed. Expression levels of different miRNA and messenger RNAs (mRNAs) encoding inflammatory cytokines were measured in a rat model of lipopolysaccharide (LPS)-induced ALI, which were subsequently treated with either sevoflurane or vehicle control. Host of miRNAs and messenger RNAs encoding pro-inflammatory cytokines are overexpressed during LPS-induced ALI, which are reversed following sevoflurane administration. Mass spectrometry analysis revealed that the RNA-binding protein, poly r(C) binding protein 1 (PCBP1) expression is induced in ALI and is repressed following sevoflurane treatment. RNA immunoprecipitation experiments revealed that PCBP1 expression dictates the altered miRNA expression and sevoflurane altered miRNA expression by suppressing PCBP1 expression. Our study thus elucidates a unique mechanism of lung protective effect of sevoflurane mediated by suppression of expression of a RNA-binding protein that potentiates expression of pro inflammatory miRNAs. PMID- 28617949 TI - Anxiety and depression among school students in Jordan: Prevalence, risk factors, and predictors. AB - PURPOSE: This study aimed to assess the prevalence of anxiety and depression, examine their relationships with sociodemographic factors and Internet addiction, and identify their main predictors among Jordanian school students aged 12-18 years. DESIGN AND METHODS: A descriptive correlational study was conducted on a random sample of 800 students from 10 public schools in Amman. Symptom Checklist anxiety, Center for Epidemiological Studies Depression Scale for Children, and Young's Internet Addiction Tool were used for the purpose. FINDINGS: Overall, 42.1 and 73.8% of the students were experiencing anxiety and depression. Risk factors for both problems were school class and Internet addiction, with the latter being the main predictor. PRACTICE IMPLICATIONS: Increasing students' and stakeholders' awareness of mental illnesses and health programs and developing counseling centers to meet the students' needs are necessary. PMID- 28617950 TI - Effect of cross-linked vs non-cross-linked collagen membranes on bone: A systematic review. AB - The aim of this study was to conduct a systematic review to compare the clinical outcomes of two different resorbable collagen membranes in terms of regenerated bone volume, postoperative complications and membrane degradation during bone regeneration procedures. Randomized controlled trials (RCT) or controlled trials (CT) that compared both techniques were reviewed on four electronic databases up to December 2015, a manual search was performed on the bibliography of the collected articles and the authors were contacted for additional references if undetected on the electronic and manual search. Membrane exposure was evaluated as a dichotomous outcome and the statistical unit was the membrane. The results were presented as relative risk (RR) with a 95% confidence interval. Eight RCTs and one CT were included in this study. The majority of the studies depicted a bone augmentation area, which ranged from 46.15% to 94.6% for the non-cross-link membranes and from 44% to 92.6% for the cross-link membranes at the 4-6 month re entry surgery. From a total of 289 patients, a forest plot concerning the membrane exposure was constructed using the obtained RR of the included studies. The overall RR was 1.43 (95% CI: 0.85-2.39) with no statistically significant differences between the two groups, although with a marginal tendency towards higher exposure in the cross-link membrane group. This systematic review suggests the different membranes present themselves as appropriate for bone regeneration procedures, although cross-link membranes present higher rates of postoperative complications. However, more RCT with higher sample sizes are needed to evaluate the different membranes. The suggested lack of clinical differences between the compared membranes suggest that further cost-benefit ratio, tissue integration and postoperative complication oriented studies should be performed so that clinicians can take a patient-centred, evidence-based decision. PMID- 28617951 TI - Altered expression of IGF-I system in neurons of the inflamed spinal cord during acute experimental autoimmune encephalomyelitis. AB - There is growing evidence that the impaired IGF-I system contributes to neurodegeneration. In this study, we examined the spinal cords of the EAE, the animal model of multiple sclerosis, to see if the expression of the IGF-I system is altered. To induce EAE, C57/BL6 mice were immunized with the Hooke lab MOG kit, sacrificed at the peak of the disease and their spinal cords were examined for the immunoreactivities (ir) of the IGF-I, IGF binding protein-1 (IGFBP-1) and glycogen synthase kinase 3beta (GSK3beta), as one major downstream molecule in the IGF-I signaling. Although neurons in the non EAE spinal cords did not show the IGF-I immunoreactivity, they were numerously positive for the IGFBP-1. In the inflamed EAE spinal cord however, the patterns of expressions were reversed, that is, a significant increased number of IGF-I expressing neurons versus a reduced number of IGFBP-1 positive neurons. Moreover, while nearly all IGF-I-ir neurons expressed GSK3beta, some expressed it more intensely. Considering our previous finding where we showed a significant reduced number of the inactive (phosphorylated) but not that of the total GSK3beta expressing neurons in the EAE spinal cord, it is conceivable that the intense total GSK3beta expression in the IGF-I-ir neurons belongs to the active form of GSK3beta known to exert neuroinflammatory effects. We therefore suggest that the altered expression of the IGF-I system including GSK3beta in spinal cord neurons might involve in pathophysiological events during the EAE. PMID- 28617953 TI - The gingival biotype in a cohort of Chinese subjects with and without history of periodontal disease. AB - OBJECTIVE: The present study aimed to determine the gingival biotype in Chinese subjects with and without a history of periodontal disease. MATERIAL AND METHODS: Thirty periodontally healthy subjects and 20 subjects with treated chronic periodontitis were recruited. The mid-buccal gingival thickness of upper central and lateral incisors was measured by a customized caliper in all subjects. The crown length and crown width of these teeth were recorded in the healthy group, while gingival recession was measured in the periodontitis group. These outcome measures were compared among the groups and sub-groups, and the correlation of gingival biotypes with clinical parameters was analyzed. RESULTS: The mean thickness of gingiva in the 30 periodontally healthy subjects was 1.05+/-0.31 mm (0.47-1.57 mm). The males exhibited a greater crown length than the females (P<.05). No significant correlation was found between gingival thickness and the crown width to crown length ratio. The mean gingival thickness at the 80 sites measured in the 20 periodontitis subjects was 0.89+/-0.29 mm (0.33-1.56 mm). Overall, gingival biotype as measured by gingival thickness was significantly correlated with gingival recession (r=-.240, P=.032), while a stronger correlation was found among the 42 sites with bleeding on probing prior to periodontal treatment (r=-.382, P=.013). CONCLUSION: This study shows that gingival biotype measured by gingival thickness in subjects with treated periodontitis is significantly correlated with gingival recession. Further study could clarify the clinical implications of gingival biotype in the management of periodontal patients. PMID- 28617952 TI - Systolic [Ca2+ ]i regulates diastolic levels in rat ventricular myocytes. AB - KEY POINTS: For the heart to function as a pump, intracellular calcium concentration ([Ca2+ ]i ) must increase during systole to activate contraction and then fall, during diastole, to allow the myofilaments to relax and the heart to refill with blood. The present study investigates the control of diastolic [Ca2+ ]i in rat ventricular myocytes. We show that diastolic [Ca2+ ]i is increased by manoeuvres that decrease sarcoplasmic reticulum function. This is accompanied by a decrease of systolic [Ca2+ ]i such that the time-averaged [Ca2+ ]i remains constant. We report that diastolic [Ca2+ ]i is controlled by the balance between Ca2+ entry and Ca2+ efflux during systole. The results of the present study identify a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i . ABSTRACT: The intracellular Ca concentration ([Ca2+ ]i ) must be sufficently low in diastole so that the ventricle is relaxed and can refill with blood. Interference with this will impair relaxation. The factors responsible for regulation of diastolic [Ca2+ ]i , in particular the relative roles of the sarcoplasmic reticulum (SR) and surface membrane, are unclear. We investigated the effects on diastolic [Ca2+ ]i that result from the changes of Ca cycling known to occur in heart failure. Experiments were performed using Fluo-3 in voltage clamped rat ventricular myocytes. Increasing stimulation frequency increased diastolic [Ca2+ ]i . This increase of [Ca2+ ]i was larger when SR function was impaired either by making the ryanodine receptor leaky (with caffeine or ryanodine) or by decreasing sarco/endoplasmic reticulum Ca-ATPase activity with thapsigargin. The increase of diastolic [Ca2+ ]i produced by interfering with the SR was accompanied by a decrease of the amplitude of the systolic Ca transient, such that there was no change of time-averaged [Ca2+ ]i . Time-averaged [Ca2+ ]i was increased by beta adrenergic stimulation with isoprenaline and increased in a saturating manner with increased stimulation frequency; average [Ca2+ ]i was a linear function of Ca entry per unit time. Diastolic and time-averaged [Ca2+ ]i were decreased by decreasing the L-type Ca current (with 50 MUm cadmium chloride). We conclude that diastolic [Ca2+ ]i is controlled by the balance between Ca entry and efflux during systole. Furthermore, manoeuvres that decrease the amplitude of the Ca transient (without decreasing Ca influx) will therefore increase diastolic [Ca2+ ]i . This identifies a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i . PMID- 28617954 TI - Mind the movement: Frontal asymmetry stands for behavioral motivation, bilateral frontal activation for behavior. AB - Frontal asymmetry has been investigated over the past 30 years, and several theories have been developed about its meaning. The original theory of Davidson and its diversification by Harmon-Jones & Allen allocated approach motivation to relative left frontal brain activity and withdrawal motivation to relative right frontal brain activity. Hewig and colleagues extended this theory by adding bilateral frontal activation representing a biological correlate of the behavioral activation system if actual behavior is shown. Wacker and colleagues formulated a theory related to the revised reinforcement sensitivity theory by Gray & McNaughton. Here, relative left frontal brain activation represents the revised behavioral activation system and behavior, while relative right frontal brain activation represents the revised behavioral inhibition system, representing the experience of conflict. These theories were investigated with a newly developed paradigm where participants were able to move around freely in a virtual T maze via joystick while having their EEG recorded. Analyzing the influence of frontal brain activation during this virtual reality task on observable behavior for 30 participants, we found more relative left frontal brain activation during approach behavior and more relative right brain activation for withdrawal behavior of any kind. Additionally, there was more bilateral frontal brain activation when participants were engaged in behavior compared to doing nothing. Hence, this study provides evidence for the idea that frontal asymmetry stands for behavioral approach or avoidance motivation, and bilateral frontal activation stands for behavior. Additionally, observable behavior is not only determined by frontal asymmetry, but also by relevant traits. PMID- 28617955 TI - Expression atlas and comparative coexpression network analyses reveal important genes involved in the formation of lignified cell wall in Brachypodium distachyon. AB - While Brachypodium distachyon (Brachypodium) is an emerging model for grasses, no expression atlas or gene coexpression network is available. Such tools are of high importance to provide insights into the function of Brachypodium genes. We present a detailed Brachypodium expression atlas, capturing gene expression in its major organs at different developmental stages. The data were integrated into a large-scale coexpression database ( www.gene2function.de), enabling identification of duplicated pathways and conserved processes across 10 plant species, thus allowing genome-wide inference of gene function. We highlight the importance of the atlas and the platform through the identification of duplicated cell wall modules, and show that a lignin biosynthesis module is conserved across angiosperms. We identified and functionally characterised a putative ferulate 5 hydroxylase gene through overexpression of it in Brachypodium, which resulted in an increase in lignin syringyl units and reduced lignin content of mature stems, and led to improved saccharification of the stem biomass. Our Brachypodium expression atlas thus provides a powerful resource to reveal functionally related genes, which may advance our understanding of important biological processes in grasses. PMID- 28617956 TI - Apigenin induces ROS-dependent apoptosis and ER stress in human endometriosis cells. AB - Apigenin is a plant-derived flavonoid having antiproliferative, anti inflammatory, and anti-angiogenic properties in chronic and metabolic diseases, and cancers. However, the functional role of apigenin remains to be identified in human endometriosis that is a benign inflammatory disease causing infertility, dysmenorrhea, dyspareunia, and chronic abdominal or pelvic pain. In the present study, we determined the effects of apigenin on two well-established human endometriosis cell lines (VK2/E6E7 and End1/E6E7). Apigenin reduced proliferation and induced cell cycle arrest and apoptosis in the both endometriosis cell lines. In addition, it disrupted mitochondrial membrane potential (MMP) which was accompanied by an increase in concentration of calcium ions in the cytosol and in pro-apoptotic proteins including Bax and cytochrome c in the VK2/E6E7 and End1/E6E7 cells. Moreover, apigenin treated cells accumulated excessive reactive oxygen species (ROS), and experienced lipid peroxidation and endoplasmic reticulum (ER) stress with activation of the unfolded protein response (UPR) regulatory proteins. Furthermore, the apigenin-induced apoptosis in endometriosis cells was regulated via the ERK1/2, JNK, and AKT cell signaling pathways. Taken together, apigenin is a potential novel therapeutic agent to overcome current limitations in the treatment to endometriosis. PMID- 28617957 TI - MicroRNA: A novel target of curcumin in cancer therapy. AB - Curcumin is known as a natural dietary polyphenol which is extracted from Curcuma longa L. It has been shown that curcumin has a variety of pharmacological effects such as antioxidant, anti-cancer, anti-inflammatory, and anti-microbial activities. Anti-cancer effects of curcumin are due to targeting of a wide range of cellular and molecular pathways involved in cancer pathogenesis including NF kB, MAPK, PTEN, P53, and microRNAs (miRNA) network. Multiple lines of evidence have indicated that curcumin exerts its therapeutic effects via regulating miRNA expression (e.g., miR-1, miR-7, miR-9, miR-34a, miR-181, miR-21, and miR-19) which could lead to the regulation of underlying cellular and molecular pathways involved in cancer pathogenesis. Exosomes are one of the important classes of biological vehicles which could be released from various types of cells such as cancer cells and stem cells and could change the behavior of recipient cells. It has been shown that treatment of cancer cells with different dose of curcumin leads to the release of exosomes containing curcumin. These exosomes could induce anti-cancer properties in recipient cells and reduce tumor growth. Hence, exosomes containing curcumin could be applied as powerful tools for cancer treatment. Here, we highlighted various miRNAs which could be affected by curcumin in various types of cancer. Moreover, we highlight exosomes containing curcumin as suitable therapeutic tools in cancer therapy. PMID- 28617958 TI - Alcohol Consumption Decreases Oxytocin Neurons in the Anterior Paraventricular Nucleus of the Hypothalamus in Prairie Voles. AB - BACKGROUND: Alcohol use disorders are associated with dysfunctional social relationships and stress responses. The neuropeptides oxytocin (OT) and vasopressin (AVP) are known to orchestrate or mediate many aspects of social behavior, stress responses, and ingestive behaviors. Because of the overlap between the effects of alcohol and the roles of OT and AVP, we sought to determine whether alcohol consumption altered expression of OT and AVP in the paraventricular nucleus (PVN) of the hypothalamus, one of the key sites for OT and AVP synthesis. METHODS: Pair-housed adult male prairie voles were allowed to consume 15% ethanol versus water in the home cage continuously (Continuous-Access [CA] group) or every other day for 4 hours (Intermittent-Access [IA] group). Control animals never had access to alcohol. After 7 weeks, animals were sacrificed and their brains were removed and immunohistochemical analysis of OT- and AVP-immunopositive neurons was performed. RESULTS: OT-immunopositive neurons were significantly decreased in the anterior PVN in the CA but not IA group, relative to Control animals, suggesting that continuous alcohol consumption decreases the number of OT neurons. There was no effect of alcohol consumption on posterior PVN OT neurons, and no effect on PVN AVP neurons. CONCLUSIONS: These data show that continuous-access voluntary alcohol consumption is associated with decreased OT neurons in the anterior PVN, suggesting that alcohol-induced alterations in the OT system should be investigated as a mechanism for alcohol related changes in social behavior, stress responses, and exacerbation of alcohol use disorders. PMID- 28617959 TI - Varenicline Reduces Alcohol Intake During Repeated Cycles of Alcohol Reaccess Following Deprivation in Alcohol-Preferring (P) Rats. AB - BACKGROUND: Most alcoholics experience periods of voluntary alcohol abstinence or imposed alcohol deprivation followed by a return to alcohol drinking. This study examined whether varenicline (VAR) reduces alcohol intake during a return to drinking after periods of alcohol deprivation in rats selectively bred for high alcohol drinking (the alcohol preferring or "P" rats). METHODS: Alcohol experienced P rats were given 24-hour access to food and water and scheduled access to alcohol (15% and 30% v/v) for 2 h/d. After 4 weeks, rats were deprived of alcohol for 2 weeks, followed by reaccess to alcohol for 2 weeks, and this pattern was repeated for a total of 3 cycles. Rats were fed either vehicle (VEH) or VAR, in doses of 0.5, 1.0, or 2.0 mg/kg BW, at 1 hour prior to onset of the daily alcohol reaccess period for the first 5 days of each of the 3 alcohol reaccess cycles. RESULTS: Low-dose VAR (0.5 mg/kg BW) reduced alcohol intake during the 5 days of drug treatment in alcohol reaccess cycles 1 and 2. Higher doses of VAR (1.0 mg/kg BW and 2.0 mg/kg BW) reduced alcohol intake during the 5 days of treatment in all 3 alcohol reaccess cycles. The decrease in alcohol intake disappeared with termination of VAR treatment in all alcohol reaccess cycles. CONCLUSIONS: The results demonstrate that VAR decreases alcohol intake during multiple cycles of alcohol reaccess following alcohol deprivation in rats and suggests that it may prevent a return to heavy alcohol drinking during a lapse from alcohol abstinence in humans with alcohol use disorder. PMID- 28617960 TI - Low prevalence of IgG antibodies against antigens of HEV genotypes 1 and 3 in women with a high-risk pregnancy. AB - The aim of the study was to assess whether high-risk pregnant women have a higher prevalence of HEV during the perinatal period. This was a cross-sectional study of 428 patients: Group 1, 127 women with a high-risk pregnancy; Group 2, 97 asymptomatic people with reactivity to HCV or HBV; Group 3, 94 patients with clinical symptoms suggestive of HEV infection; and Group 4, 110 healthy blood donors from an urban area of Mexico City. ELISA was used to measure antibody to HEV genotypes 1 and 3. The prevalence rates of anti-HEV IgG antibodies were 0.79% in Group 1, 2.1% in Group 2, 7.4% in Group 3, and 0% in Group 4. Women with a high-risk pregnancy did not have a higher prevalence of HEV infection in this clinical setting. PMID- 28617961 TI - Interlaboratory quality control of total HIV-1 DNA load measurement for multicenter reservoir studies. AB - BACKGROUND: Viral reservoirs represent an important barrier to HIV cure. Accurate markers of HIV reservoirs are needed to develop multicenter studies. The aim of this multicenter quality control (QC) was to evaluate the inter-laboratory reproducibility of total HIV-1-DNA quantification. METHODS: Ten laboratories of the ANRS-AC11 working group participated by quantifying HIV-DNA with a real-time qPCR assay (Biocentric) in four samples (QCMD). RESULTS: Good reproducibility was found between laboratories (standard deviation <= 0.2 log10 copies/106 PBMC) for the three positive QC that were correctly classified by each laboratory (QC180% for both enantiomers. A variety of stability tests were executed in plasma and in neat samples, which complies with the FDA guidelines. After complete validation, the method was successfully applied to a pharmacokinetic study of a manidipine 20 mg oral dose in 10 healthy South India subjects under fasting conditions. The assay reproducibility is shown through incurred samples reanalysis of 20 subject plasma samples. PMID- 28617979 TI - The Turner syndrome life course project: Karyotype-phenotype analyses across the lifespan. AB - INTRODUCTION: Turner syndrome (TS) is associated with a variety of morbidities affecting nearly every body system, some of which increase in prevalence in adult life. The severity of clinical features in TS is roughly in parallel with the magnitude of the deficit of X-chromosome material. The aim of this study was to extend the established karyotype-phenotype relationships using data from a large adult cohort. MATERIALS AND METHODS: Karyotypes were available in 656 women with TS. 611 of whom could be classified into five major groups within the cohort: 45,X; 45,X mosaicism (45,X/46,XX); isochromosome X (isochromosome Xq); mosaicism 45,X/46,XY and ring X. Continuous variables such as blood pressure and biochemical markers from clinic data were binarised allocating those in the upper quartile to represent at-risk individuals. With the exception of bone mineral density T-score for which the lower quartile was allocated as at risk. For comorbidities, initiation of formal treatment was recorded. RESULTS: 45,X/46,XX had considerably lower frequency of comorbidities compared to 45,X. The isochromosome group experienced similar outcomes to 45,X. Novel associations were found between the XY mosaic karyotype group and a decreased prevalence of thyroid disease and severe hearing loss. A previously unreported increased incidence of metabolic syndrome was noted within the ring chromosome subgroup. CONCLUSIONS: Karyotype may play an important factor against stratifying risk of comorbidity in TS and should be taken into consideration when managing adults with TS. Further investigations of the isochromosome (Xq) and ring groups are necessary to further clarify their associations with comorbidities. PMID- 28617980 TI - Instruments to assess self-care among healthy children: A systematic review of measurement properties. AB - AIM: To identify, critically appraise and summarize the measurement properties of instruments to assess self-care in healthy children. BACKGROUND: Assessing self care is a proper consideration for nursing practice and nursing research. No systematic review summarizes instruments of measurement validated in healthy children. DESIGN: Psychometric review in accordance with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) panel. DATA SOURCES: MEDLINE, CINAHL, PsycINFO, Web of Science and Open Grey were searched from their inception to December 2016. REVIEW METHODS: Validation studies with a healthy child population were included. Search was not restricted by language. Two reviewers independently assessed the methodological quality of included studies using the COSMIN checklist. RESULTS: Eleven studies were included in the review assessing the measurement properties of ten instruments. There was a maximum of two studies per instrument. None of the studies evaluated the properties of test-retest reliability, measurement error, criterion validity and responsiveness. Internal consistency and structural validity were rated as "excellent" or "good" in four studies. Four studies were rated as "excellent" in content validity. Cross-cultural validity was rated as "poor" in the two studies (three instruments) which cultural adaptation was carried out. CONCLUSION: The evidence available does not allow firm conclusions about the instruments identified in terms of reliability and validity. Future research should focus on generate evidence about a wider range of measurement properties of these instruments using a rigorous methodology, as well as instrument testing on different countries and child population. PMID- 28617981 TI - What is the variability in shoulder, axillae and waist position in a group of adolescents? AB - The clinical assessment of scoliosis is based on the recognition of asymmetry. It is not clear what the degree of asymmetry is in a population without scoliosis, which could make the differentiation between abnormal and normal uncertain. This study defines the range of normality in certain parameters of torso shape that are also associated with the clinical assessment of scoliosis. This was done by analysing the surface topography of a group of 195 children serially measured over a 5-year period. The analysis considered both the spinal curvature and the relative position of shoulders, axillae and waist on each side. The bivariate relationships were examined using 95% confidence interval data ellipses. Our results showed that a degree of spinal curvature was seen, either as a main thoracic or main thoracolumbar curve. The distribution of the data about a mean point is illustrated by 95% confidence interval (CI) data ellipses with shoulder, axilla and waist data plotted against spinal curvature. The mean values were close to zero (exact symmetry) for all of the measured parameters, with the ellipses showing little differences in the distributions. We conclude that mild asymmetry of the measured torso parameters is normal. These results define what is normal and beyond what point asymmetry becomes abnormal. This information is of use for those managing and counselling patients with scoliosis both before and after surgery. PMID- 28617982 TI - Issue Information - Info for Authors. PMID- 28617986 TI - A novel HSD17B3 gene mutation in a 46,XY female-phenotype newborn identified by whole-exome sequencing. PMID- 28617987 TI - The sex-selective impact of the Black Death and recurring plagues in the Southern Netherlands, 1349-1450. AB - : Although recent work has begun to establish that early modern plagues had selective mortality effects, it was generally accepted that the initial outbreak of Black Death in 1347-52 was a "universal killer." Recent bioarchaeological work, however, has argued that the Black Death was also selective with regard to age and pre-plague health status. The issue of the Black Death's potential sex selectivity is less clear. Bioarchaeological research hypothesizes that sex selection in mortality was possible during the initial Black Death outbreak, and we present evidence from historical sources to test this notion. OBJECTIVE: To determine whether the Black Death and recurring plagues in the period 1349-1450 had a sex-selective mortality effect. MATERIALS AND METHODS: We present a newly compiled database of mortality information taken from mortmain records in Hainaut, Belgium, in the period 1349-1450, which not only is an important new source of information on medieval mortality, but also allows for sex disaggregation. RESULTS: We find that the Black Death period of 1349-51, as well as recurring plagues in the 100 years up to 1450, often had a sex-selective effect-killing more women than in "non-plague years." DISCUSSION: Although much research tends to suggest that men are more susceptible to a variety of diseases caused by bacteria, viruses and parasites, we cannot assume that the same direction of sex-selection in mortality applied to diseases in the distant past such as Second Pandemic plagues. While the exact reasons for the sex-selective effect of late-medieval plague are unclear in the absence of further data, we suggest that simple inequities between the sexes in exposure to the disease may not have been a key driver. PMID- 28617988 TI - MiR-145 detection in urinary extracellular vesicles increase diagnostic efficiency of prostate cancer based on hydrostatic filtration dialysis method. AB - BACKGROUND: Extracellular vesicles (EVs) can be detected in body fluids and may serve as disease biomarkers. Increasing evidence suggests that circulating miRNAs in serum and urine may be potential non-invasive biomarkers for prostate cancer (PCa). In the present study, we aimed to investigate whether hydrostatic filtration dialysis (HFD) is suitable for urinary EVs (UEVs) isolation and whether such reported PCa-related miRNAs can be detected in UEVs as PCa biomarkers. METHODS: To analyze EVs miRNAs, we searched for an easy and economic method to enrich EVs from urine samples. We compared the efficiency of HFD method and conventional ultracentrifugation (UC) in isolating UEVs. Subsequently, UEVs were isolated from patients with PCa, patients with benign prostate hyperplasia (BPH) and healthy individuals. Differential expression of four PCa-related miRNAs (miR-572, miR-1290, miR-141, and miR-145) were measured in UEVs and paired serum EVs using SYBR Green-based quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: The overall performance of HFD was similar to UC. In miRNA yield, both HFD and UC can meet the needs of further analysis. The level of miR-145 in UEVs was significantly increased in patients with PCa compared with the patients with BPH (P = 0.018). In addition, significant increase was observed in miR-145 levels when patients with Gleason score >=8 tumors compared with Gleason score <=7 (P = 0.020). Receiver-operating characteristic curve (ROC) revealed that miR-145 in UEVs combined with serum PSA could differentiate PCa from BPH better than PSA alone (AUC 0.863 and AUC 0.805, respectively). In serum EVs, four miRNAs were significantly higher in patients with PCa than with BPH. CONCLUSION: HFD is appropriate for UEVs isolation and miRNA analysis when compared with conventional UC. miR-145 in UEVs is upregulated from PCa patients compared BPH patients and healthy controls. We suggest the potential use of UEVs miR-145 as a biomarker of PCa. PMID- 28617990 TI - Cell-specific diversity in the expression and organization of cytoplasmic plaque proteins of apical junctions. AB - Tight and adherens junctions play critical roles in the barrier, adhesion, and signaling functions of epithelial and endothelial cells. How the molecular organization of these junctions is tuned to the widely diverse physiological requirements of each tissue type is not well understood. Here, we address this question by examining the expression, localization, and interactions of major cytoplasmic plaque proteins of tight and adherens junctions in different cultured epithelial and endothelial cell lines. Immunoblotting and immunofluorescence analyses show that the expression profiles of cingulin, paracingulin, ZO-1, ZO-2, ZO-3, PLEKHA7, afadin, PDZD11, p120-catenin, and alpha-catenin, as well as the transmembrane junctional proteins occludin, E-cadherin, and VE-cadherin, are significantly diverse when comparing kidney cells (MDCK, mCCD), keratinocytes (HaCaT), lung carcinoma (A427, A549), and endothelium-derived cells (bEnd.3, meEC, H5V). Proximity ligation and co-immunoprecipitation assays show that PLEKHA7 and PDZD11 are significantly more associated with the tight junction proteins cingulin and ZO-1 in aortic endothelium-derived (meEC) cells but not kidney collecting duct epithelial (mCCD) cells. These results provide evidence that the cytoplasmic plaques of tight and adherens junctions are diverse in their composition and molecular architecture and establish a conceptual framework by which we can rationally address the mechanisms of tissue-dependent junction physiology and signaling by cytoplasmic junctional proteins. PMID- 28617989 TI - 1,25-dihydroxyvitamin D3 -induced dendritic cells suppress experimental autoimmune encephalomyelitis by increasing proportions of the regulatory lymphocytes and reducing T helper type 1 and type 17 cells. AB - Dendritic cells (DCs), a bridge for innate and adaptive immune responses, play a key role in the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Administration of tolerogenic DCs has been used as an immunotherapy in autoimmune diseases. Deficiency of vitamin D is an environmental risk factor of MS. In this study, we induced tolerogenic DCs by 1,25-dihydroxyvitamin D3 and transferred the tolerogenic DCs (VD3 -DCs) into EAE mice by adoptive transfer. We found that VD3 DCs inhibited the infiltrations of T helper type 1 (Th1) and Th17 cells into spinal cord and increased the proportions of regulatory T cells (CD4+ CD25+ Foxp3+ ), CD4+ IL-10+ T cells and regulatory B cells (CD19+ CD5+ CD1d+ ) in peripheral immune organs, which resulted in attenuated EAE. However, the proportions of T helper type 1 (Th1) and Th17 cells in spleen and lymph nodes and the levels of pro-inflammatory cytokines and IgG in serum also increased after transfer of VD3 -DCs. We conclude that transfer of VD3 -DCs suppressed EAE by increasing proportions of regulatory T cells, CD4+ IL-10+ T cells and regulatory B cells in spleen and reducing infiltration of Th1 and Th17 cells into spinal cord, which suggests a possible immunotherapy method using VD3 -DCs in MS. PMID- 28617991 TI - Interferon-beta regulates the production of IL-10 by toll-like receptor-activated microglia. AB - Pattern recognition receptors, such as toll-like receptors (TLRs), perceive tissue alterations and initiate local innate immune responses. Microglia, the resident macrophages of the brain, encode TLRs which primary role is to protect the tissue integrity. However, deregulated activation of TLRs in microglia may lead to chronic neurodegeneration. This double role of microglial responses is often reported in immune-driven neurologic diseases, as in multiple sclerosis (MS). Consequently, strategies to manipulate microglia inflammatory responses may help to ameliorate disease progression. In this context, the anti-inflammatory cytokine interleukin (IL)-10 appears as an attractive target. In this study, we investigated how activation of microglia by TLRs with distinct roles in MS impacts on IL-10 production. We found that activation of TLR2, TLR4, and TLR9 induced the production of IL-10 to a greater extent than activation of TLR3. This was surprising as both TLR3 and IL-10 play protective roles in animal models of MS. Interestingly, combination of TLR3 triggering with the other TLRs, enhanced IL-10 through the modulation of its transcription, via interferon (IFN)-beta, but independently of IL-27. Thus, in addition to the modulation of inflammatory responses of the periphery described for the axis TLR3/IFN-beta, we now report a direct modulation of microglial responses. We further show that the presence of IFN-gamma in the microenvironment abrogated the modulation of IL-10 by TLR3, whereas that of IL-17 had no effect. Considering the therapeutic application of IFN-beta in MS, our study bears important implications for the understanding of the cytokine network regulating microglia responses in this setting. PMID- 28617992 TI - Antiplatelet therapy and the risk of hepatocellular carcinoma in chronic hepatitis B patients on antiviral treatment. AB - : Antiplatelet therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether antiplatelet therapy lowers the risk of HCC in patients with chronic hepatitis B. A retrospective analysis was conducted of data from 1,674 chronic hepatitis B patients, enrolled between January 2002 and May 2015, whose serum hepatitis B virus DNA levels were suppressed by antivirals to <2,000 IU/mL. The primary and secondary outcomes were development of HCC and bleeding events, respectively. Risk was compared between patients with antiplatelet treatment (aspirin, clopidogrel, or both; antiplatelet group) and patients who were not treated (non antiplatelet group) using a time-varying Cox proportional hazards model for total population and propensity score-matching analysis. The antiplatelet group included 558 patients, and the non-antiplatelet group had 1,116 patients. During the study period, 63 patients (3.8%) developed HCC. In time-varying Cox proportional analyses, the antiplatelet group showed a significantly lower risk of HCC (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23-0.85; P = 0.01), regardless of antiplatelet agent. In propensity score-matched pairs, antiplatelet therapy significantly reduced the risk of HCC (HR, 0.34; 95% CI, 0.15-0.77; P = 0.01). However, the overall risk of bleeding was higher in the antiplatelet group (HR, 3.28; 95% CI, 1.98-5.42; P < 0.001), particularly for clopidogrel with or without aspirin. Treatment with aspirin alone was not associated with a higher bleeding risk (HR, 1.11; 95% CI, 0.48-2.54; P = 0.81). CONCLUSION: Antiplatelet therapy reduces the risk of HCC in chronic hepatitis B patients whose hepatitis B virus is effectively suppressed. However, antiplatelet therapy containing clopidogrel may increase the risk of bleeding. (Hepatology 2017;66:1556-1569). PMID- 28617993 TI - Rigid-body motion correction of the liver in image reconstruction for golden angle stack-of-stars DCE MRI. AB - PURPOSE: Respiratory motion can affect pharmacokinetic perfusion parameters quantified from liver dynamic contrast-enhanced MRI. Image registration can be used to align dynamic images after reconstruction. However, intra-image motion blur remains after alignment and can alter the shape of contrast-agent uptake curves. We introduce a method to correct for inter- and intra-image motion during image reconstruction. METHODS: Sixteen liver dynamic contrast-enhanced MRI examinations of nine subjects were performed using a golden-angle stack-of-stars sequence. For each examination, an image time series with high temporal resolution but severe streak artifacts was reconstructed. Images were aligned using region-limited rigid image registration within a region of interest covering the liver. The transformations resulting from alignment were used to correct raw data for motion by modulating and rotating acquired lines in k-space. The corrected data were then reconstructed using view sharing. RESULTS: Portal venous input functions extracted from motion-corrected images had significantly greater peak signal enhancements (mean increase: 16%, t-test, P < 0.001) than those from images aligned using image registration after reconstruction. In addition, portal-venous perfusion maps estimated from motion-corrected images showed fewer artifacts close to the edge of the liver. CONCLUSIONS: Motion corrected image reconstruction restores uptake curves distorted by motion. Motion correction also reduces motion artifacts in estimated perfusion parameter maps. Magn Reson Med 79:1345-1353, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28617994 TI - Photooxidation of phytochemicals in food and control: a review. AB - Phytochemicals are widely present in food and have been confirmed to be bioactive, thereby contributing to human health. However, some phytochemicals are sensitive to light owing to their structures and may suffer from photodegradation, especially when sensitizers exist, resulting in sensory quality change, nutrient loss in food, and even the formation of toxic compounds. The photooxidation of phytochemicals occurs through three different mechanisms: (1) by directly absorbing luminous energy, (2) with triplet-excited state sensitizers through electron transfer or proton transfer (type I photooxidation), and (3) with singlet oxygen produced by O2 (type II photooxidation). On the basis of these mechanisms, adequate antioxidants can be added to quench the triple-excited state sensitizers or singlet oxygen to protect against the photooxidation of phytochemicals in food. Here, we summarize and discuss the possible pathways and products of the photooxidation of phytochemicals that have been reported and the relationships between structures and photooxidation. We also propose some control measures, with special attention paid to the potential abilities of phytochemicals in the prevention of food photooxidation. PMID- 28617995 TI - Investigation of an N-Terminal Prohormone of Brain Natriuretic Peptide Point-of Care ELISA in Clinically Normal Cats and Cats With Cardiac Disease. AB - BACKGROUND: N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations may be increased in cats with various cardiac disorders. The point of-care (POC) ELISA assay uses the same biologic reagents as the quantitative NT proBNP ELISA. Previous studies have evaluated the sensitivity and specificity of the POC ELISA in cats with cardiac disease. OBJECTIVES: To prospectively evaluate the diagnostic utility of the POC ELISA in a select population of cats. ANIMALS: Thirty-eight client-owned cats presented to the University of Florida Cardiology Service for cardiac evaluation. Fifteen apparently healthy cats recruited as part of another study. METHODS: Physical examination and echocardiography were performed in all cats. The POC ELISA was assessed visually as either positive or negative by a reader blinded to the echocardiographic findings, and results were analyzed relative to quantitative assay results. RESULTS: Twenty-six cats were diagnosed with underlying cardiac disease, and 27 cats were considered free of cardiac disease. Cats with cardiac disease included: 21 with hypertrophic cardiomyopathy, 2 with unclassified cardiomyopathy, 2 with restrictive cardiomyopathy, and 1 with 3rd degree atrioventricular (AV) block. The POC ELISA differentiated cats with cardiac disease with a sensitivity of 65.4% and specificity of 100%. CONCLUSIONS AND CLINICAL IMPORTANCE: The POC NT-proBNP ELISA performed moderately well in a selected population of cats. A negative test result cannot exclude the presence of underlying cardiac disease, and a positive test result indicates that cardiac disease likely is present, but further diagnostic investigation would be indicated for a definitive diagnosis. PMID- 28617996 TI - Gradient nonlinearity effects on upper cervical spinal cord area measurement from 3D T1 -weighted brain MRI acquisitions. AB - PURPOSE: To explore (i) the variability of upper cervical cord area (UCCA) measurements from volumetric brain 3D T1 -weighted scans related to gradient nonlinearity (GNL) and subject positioning; (ii) the effect of vendor-implemented GNL corrections; and (iii) easily applicable methods that can be used to retrospectively correct data. METHODS: A multiple sclerosis patient was scanned at seven sites using 3T MRI scanners with the same 3D T1 -weighted protocol without GNL-distortion correction. Two healthy subjects and a phantom were additionally scanned at a single site with varying table positions. The 2D and 3D vendor-implemented GNL-correction algorithms and retrospective methods based on (i) phantom data fit, (ii) normalization with C2 vertebral body diameters, and (iii) the Jacobian determinant of nonlinear registrations to a template were tested. RESULTS: Depending on the positioning of the subject, GNL introduced up to 15% variability in UCCA measurements from volumetric brain T1 -weighted scans when no distortion corrections were used. The 3D vendor-implemented correction methods and the three proposed methods reduced this variability to less than 3%. CONCLUSIONS: Our results raise awareness of the significant impact that GNL can have on quantitative UCCA studies, and point the way to prospectively and retrospectively managing GNL distortions in a variety of settings, including clinical environments. Magn Reson Med 79:1595-1601, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28617997 TI - A market on both "sides" of the law: The use of the hidden web for the sale of new psychoactive substances. AB - OBJECTIVE: The hidden Web is used for the anonymous sale of drugs, and with the UK Psychoactive Substances Act, 2016, implemented on May 26th 2016; it could increase as a platform for obtaining new psychoactive substances (NPS). This study aims to describe the NPS market on the visible and hidden Web preban, and assess whether the hidden Web is a likely place for the sale of NPS postban. METHODS: Data collection of 113 online shops took place in October 2015. Data collection of 22 cryptomarkets took place every 2 months from October 2015 to 2016 as part of the CASSANDRA project. RESULTS: All online shops with a UK domain location sold NPS that were uncontrolled by the UK Misuse of Drugs Act, 1971, and closed after the ban. Of the cryptomarkets analysed, the total number of vendors selling NPS, number of substances, and listings advertised, all increased over the year. The majority of the NPS advertised on the hidden Web were phenethylamines and cathinones, yet the majority of uncontrolled NPS were synthetic cannabinoids. CONCLUSIONS: Vendors selling and availability of NPS increased over the 12 months of data collection. Potential displacement from the visible Web to hidden Web should be taken into consideration. PMID- 28617999 TI - Adenosine: An endogenous mediator in the pathogenesis of gynecological cancer. AB - Extracellular concentration of adenosine increases in the hypoxic tumor microenvironment. Adenosine signaling regulates apoptosis, angiogenesis, metastasis, and immune suppression in cancer cells. Adenosine-induced cell responses depend upon different subtypes of adenosine receptors activation and type of cancer. Suppression of adenosine signaling via inhibition of adenosine receptors or adenosine generating enzymes including CD39 and CD73 on ovarian or cervical cancer cells is a potentially novel therapeutic approach for gynecological cancer patients. This review summarizes the role of adenosine in the pathogenesis of gynecological cancer for a better understanding and hence a better management of this disease. PMID- 28617998 TI - Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling. AB - The PI 3-kinase Vps34 (Pik3c3) synthesizes phosphatidylinositol 3-phosphate (PI3P), a lipid critical for both endosomal membrane traffic and macroautophagy. Human genetics have implicated PI3P dysregulation, and endosomal trafficking in general, as a recurring cause of demyelinating Charcot-Marie-Tooth (CMT) peripheral neuropathy. Here, we investigated the role of Vps34, and PI3P, in mouse Schwann cells by selectively deleting Vps34 in this cell type. Vps34 Schwann cell knockout (Vps34SCKO ) mice show severe hypomyelination in peripheral nerves. Vps34-/- Schwann cells interact abnormally with axons, and there is a delay in radial sorting, a process by which large axons are selected for myelination. Upon reaching the promyelinating stage, Vps34-/- Schwann cells are significantly impaired in the elaboration of myelin. Nerves from Vps34SCKO mice contain elevated levels of the LC3 and p62 proteins, indicating impaired autophagy. However, in the light of recent demonstrations that autophagy is dispensable for myelination, it is unlikely that hypomyelination in Vps34SCKO mice is caused by impaired autophagy. Endosomal trafficking is also disturbed in Vps34-/- Schwann cells. We investigated the activation of the ErbB2/3 receptor tyrosine kinases in Vps34SCKO nerves, as these proteins, which play essential roles in Schwann cell myelination, are known to traffic through endosomes. In Vps34SCKO nerves, ErbB3 was hyperphosphorylated on a tyrosine known to be phosphorylated in response to neuregulin 1 exposure. ErbB2 protein levels were also decreased during myelination. Our findings suggest that the loss of Vps34 alters the trafficking of ErbB2/3 through endosomes. Abnormal ErbB2/3 signaling to downstream targets may contribute to the hypomyelination observed in Vps34SCKO mice. PMID- 28618000 TI - In vivo analysis of synaptic activity in cerebellar nuclei neurons unravels the efficacy of excitatory inputs. AB - KEY POINTS: Cerebellar nuclei (CN) neurons can be classified into four groups according to their action potential (AP) waveform, corresponding to four types of neurons previously characterized. Half of the APs are generated by excitatory events, suggesting that excitatory inputs play a key role in generating CN outputs. Analysis of post-synaptic potentials reveals that the probability of excitatory inputs generating an AP is 0.1. The input from climbing fibre collaterals is characterized by a pair of synaptic potentials with a distinct interpair interval of 4.5 ms. The probability of climbing fibre collaterals initiating an AP in CN neurons is 0.15. ABSTRACT: It is commonly agreed that the main function of the cerebellar system is to provide well-timed signals used for the execution of motor commands or prediction of sensory inputs. This function is manifested as a temporal sequence of spiking that should be expressed in the cerebellar nuclei (CN) projection neurons. Whether spiking activity is generated by excitation or release from inhibition is still a hotly debated issue. In an attempt to resolve this debate, we recorded intracellularly from CN neurons in anaesthetized mice and performed an analysis of synaptic activity that yielded a number of important observations. First, we demonstrate that CN neurons can be classified into four groups. Second, shape-index plots of the excitatory events suggest that they are distributed over the entire dendritic tree. Third, the rise time of excitatory events is linearly related to amplitude, suggesting that all excitatory events contribute equally to the generation of action potentials (APs). Fourth, we identified a temporal pattern of spontaneous excitatory events that represent climbing fibre inputs and confirm the results by direct stimulation and analysis on harmaline-evoked activity. Finally, we demonstrate that the probability of excitatory inputs generating an AP is 0.1 yet half of the APs are generated by excitatory events. Moreover, the probability of a presumably spontaneous climbing fibre input generating an AP is higher, reaching a mean population value of 0.15. In view of these results, the mode of synaptic integration at the level of the CN should be re-considered. PMID- 28618001 TI - Three-dimensional cell culture models for anticancer drug screening: Worth the effort? AB - High attrition of new oncology drug candidates in clinical trials is partially caused by the poor predictive capacity of artificial monolayer cell culture assays early in drug discovery. Monolayer assays do not take the natural three dimensional (3D) microenvironment of cells into account. As a result, false positive compounds often enter clinical trials, leading to high dropout rates and a waste of time and money. Over the past 2 decades, tissue engineers and cell biologists have developed a broad range of 3D in vitro culturing tools that better represent in vivo cell biology. These tools preserve the 3D architecture of cells and can be used to predict toxicity of and resistance against antitumor agents. Recent progress in tissue engineering further improves 3D models by taking into account the tumor microenvironment, which is important for metastatic progression and vascularization. However, the widespread implementation of 3D cell cultures into cell-based research programs has been limited by various factors, including their cost and reproducibility. In addition, different 3D cell culture techniques often produce spheroids of different size and shape, which can strongly influence drug efficacy and toxicity. Hence, it is imperative to morphometrically characterize multicellular spheroids to avoid generalizations among different spheroid types. Standardized 3D culturing procedures could further reduce data variability and enhance biological relevance. Here, we critically evaluate the benefits and challenges inherent to growing cells in 3D, along with an overview of the techniques used to form spheroids. This is done with a specific focus on antitumor drug screening. PMID- 28618002 TI - Novel psychoactive substance use among treatment-seeking opiate users: The role of life events and psychiatric symptoms. AB - OBJECTIVE: Over the past 5 years, a shift to the use of novel psychoactive substances (NPS) has been observed among opioid users. The aim of this study was to assess the potential reasons for NPS use among treatment-seeking patients receiving opiate substitution therapy. METHOD: A structured questionnaire was filled out by a sample of 198 opiate dependent patients of Hungary's National Institute of Psychiatry and Addiction. This questionnaire assessed demographics, treatment characteristics, lifetime substance use, potential reasons for NPS use, negative life events (Life Events Scale), and psychiatric symptoms (Brief Symptom Inventory). RESULTS: The most frequent reasons for NPS use were curiosity, replacing other drugs, and easy availability. The majority of the respondents used synthetic cathinones and chose practical reasons, not psychopharmacological preferences. A series of binary logistic regressions indicated that lifetime amphetamine use (OR = 4.64, 95% CI [2.16, 9.96]) and more severe psychiatric symptoms (OR = 1.89, 95% CI [1.18, 3.04]) may predict NPS use. Time spent in treatment was a minor protective factor (OR = 0.92, 95% CI [0.86, 0.99]). CONCLUSION: Synthetic cathinones might still substitute amphetamine-derivatives, although these NPS are no longer legal. There is a need for the regular screening of psychiatric symptoms and the use of family therapy among participants on opioid substitution programs. PMID- 28618003 TI - A multi-template multiplex PCR assay for hepatitis B virus and human beta-globin. AB - The Hepatitis B surface antigen (HBsAg) is the hallmark of HBV infection. Detection of antibodies to HBs and the core (ie, HBsAg and HBcAb) are primary serological algorithms in the laboratory diagnosis of HBV. Detection of HBsAg DNA is an important supplement to serological diagnosis especially in clinical cases. Simultaneous amplification of internal cellular controls is a good indicator of sample quality. Human beta-globin is a well characterized housekeeping gene (HKG) that is often applied as internal controls (IC) in molecular diagnosis. In this study, individual plasmid clones of the human beta-globin and HBs genes were constructed. These plasmid constructs have been applied to characterize a multiplex PCR assays for HBs and beta-globin genes. The findings suggest detection limits of less than 10 genome copies of either template In vitro using conventional and multiplex PCR conditions. Under the multiplex conditions, co amplification of beta-globin and HBsAg DNA had a resultant effect on assay sensitivity. This study further highlights the importance of molecular diagnosis in HBV infectious individuals. If fully optimized, this assay could provide a possible diagnostic complement to serological detection in developing countries. PMID- 28618004 TI - Silencing of a lipase maturation factor 2-like gene by wheat-mediated RNAi reduces the survivability and reproductive capacity of the grain aphid, Sitobion avenae. AB - Lipase maturation factor (LMF) family proteins are required for the maturation and transport of active lipoprotein lipases. However, the specific roles of LMF2 remain unknown. In this study, a grain aphid lmf2-like gene fragment was cloned and was highly similar in sequence to a homologous gene in the pea aphid, Acyrthosiphon pisum. An RNAi vector was constructed with this fragment and used for wheat transformation. The expression of the lmf2-like gene in aphid, as well as the growth and reproduction of the aphids, was analyzed after feeding on the transgenic wheat. There were no significant differences in the expression of the lmf2-like gene over development. The expression of the lmf2-like gene was significantly reduced by 27.6% on the fifth day, and 57.6% on the 10th day after feeding. The total number of aphids produced on the transgenic plants was less than the number produced on control plants, and the difference became significant or after 2 weeks. The molting numbers were also reduced in the aphids reared on the transgenic plants. Our findings indicate that lmf2-like genes may have potential as a target gene for the control of grain aphids and show that feeding aphids with wheat expressing lmf2-like RNAi resulted in significant reductions in survival and reproduction. PMID- 28618005 TI - BACE1 Inhibitor Lanabecestat (AZD3293) in a Phase 1 Study of Healthy Japanese Subjects: Pharmacokinetics and Effects on Plasma and Cerebrospinal Fluid Abeta Peptides. AB - Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human beta-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-beta (Abeta) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Abeta peptide reductions were also seen at all doses, with CSF Abeta42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-beta precursor protein beta also decreased following lanabecestat treatment. Suppression of CSF Abeta peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease. PMID- 28618006 TI - Lucerastat, an Iminosugar for Substrate Reduction Therapy: Pharmacokinetics, Tolerability, and Safety in Subjects With Mild, Moderate, and Severe Renal Function Impairment. AB - Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for substrate reduction therapy in glycosphingolipid storage disorders such as Fabry disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main route of elimination was renal. The pharmacokinetics, tolerability, and safety of lucerastat were evaluated in subjects with mild (group A), moderate (group B), and severe (group C) renal impairment. Group D included healthy subjects. Thirty two subjects (8 per group) were included in this single-center, open-label study and received a single oral dose of 1000 mg lucerastat in groups A and B and 500 mg in groups C and D. The degree of renal impairment of the subjects was based on estimated glomerular filtration rate. Plasma lucerastat concentrations (dose corrected) were higher in groups B and C compared to group D. The elimination phase half-life was slower in groups B (9.6 hours) and C (16.1 hours) compared to group D (7.0 hours). Increased exposure to lucerastat was observed in subjects from groups B and C with ratio of geometric means (90%CI) of 1.60 (1.29, 1.98) for group B vs D and 3.17 (2.76, 3.65) for group C vs D. There were no clinically relevant abnormalities in vital signs, 12-lead electrocardiograms, and clinical laboratory values. Four nonserious adverse events were reported by 4 subjects (1 in group A, 3 in group D). Lucerastat was well tolerated in all dose groups. Dose adjustment is warranted in subjects with moderate and severe renal impairment. PMID- 28618007 TI - An Exploratory Study in Healthy Male Subjects of the Mechanism of Mirabegron Induced Cardiovascular Effects. AB - To explore the role of beta1 -adrenoceptors (ARs) in the heart rate response to the selective beta3 -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective beta1/2 -AR antagonist propranolol (160 mg), the selective beta1 -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected. Mirabegron increased heart rate and systolic blood pressure and reduced stroke volume, whereas cardiac output and diastolic blood pressure were unaffected. Mirabegron induced changes were attenuated by propranolol and bisoprolol. The data indicate that mirabegron has a positive chronotropic effect at supratherapeutic concentrations, which is at least partly mediated by stimulation of beta1 -AR. PMID- 28618008 TI - NEEDS AND CHALLENGES OF HOME VISITORS CONDUCTING PERINATAL DEPRESSION SCREENING. AB - This article describes the needs and challenges faced by home visitors, supervisors, and clients when conducting perinatal depression screening. Home visitors (n = 11), supervisors (n = 5), and clients (n = 9) representing rural and urban practice settings in Wisconsin were recruited into three separate focus groups. Themes were identified from the transcribed audio-recorded interviews using content analysis. Results indicate that a trusting relationship was leveraged to facilitate depression screening and referral. Home visitors personalized care to a client's context and to protect confidentiality. Home visiting practice demanded flexibility and negotiation in decision-making with clients and families. Coordinating access to mental health evaluation in areas of limited access was a common challenge. Participants reported a need for further training on safety management. With adequate training and support, home visitors are well-positioned to promote access to mental health services in vulnerable families to support infant mental health. PMID- 28618009 TI - Evidence of an evolutionary hourglass pattern in herbivory-induced transcriptomic responses. AB - Herbivory-induced defenses are specific and activated in plants when elicitors, frequently found in the herbivores' oral secretions, are introduced into wounds during attack. While complex signaling cascades are known to be involved, it remains largely unclear how natural selection has shaped the evolution of these induced defenses. We analyzed herbivory-induced transcriptomic responses in wild tobacco, Nicotiana attenuata, using a phylotranscriptomic approach that measures the origin and sequence divergence of herbivory-induced genes. Highly conserved and evolutionarily ancient genes of primary metabolism were activated at intermediate time points (2-6 h) after elicitation, while less constrained and young genes associated with defense signaling and biosynthesis of specialized metabolites were activated at early (before 2 h) and late (after 6 h) stages of the induced response, respectively - a pattern resembling the evolutionary hourglass pattern observed during embryogenesis in animals and the developmental process in plants and fungi. The hourglass patterns found in herbivory-induced defense responses and developmental process are both likely to be a result of signaling modularization and differential evolutionary constraints on the modules involved in the signaling cascade. PMID- 28618010 TI - THE TRANSITION FROM MOTHER-OF-ONE TO MOTHER-OF-TWO: MOTHERS' PERCEPTIONS OF THEMSELVES AND THEIR RELATIONSHIPS WITH THEIR FIRSTBORN CHILDREN. AB - This qualitative study aimed to explore mothers' perceptions of the transition to second-time motherhood, and advance methodology for supporting mothers during this transition. Fifty-seven pregnant mothers and their firstborn children (M age = 30.3 months) participated in a laboratory procedure in which the mother exposed her child to a brief episode of differential treatment. The episode was designed to simulate an expected experience of caregiving that would occur after the birth of a second child. During a postnatal visit (M=5.72 weeks following childbirth), mothers provided written feedback on their perceptions of the transition and the contribution of the laboratory experience to that transition. Qualitative content analysis revealed that mothers approached the birth of a second child with apprehension. Intrapersonal themes revealed that participation in the procedure shaped mothers' understanding of their expanded maternal roles by enhancing their sense of preparedness and confidence in their abilities to support their children. Interpersonal themes revealed that participation helped mothers appreciate the magnitude of the challenge that their children would face and gave mothers reason to believe that their children would adjust successfully. Findings are discussed in terms of their potential contribution toward developing methodology for helping mothers prepare for the addition of a second child. PMID- 28618011 TI - The healthy effects of strawberry bioactive compounds on molecular pathways related to chronic diseases. AB - It is generally accepted that a fruit and vegetable-enriched diet is favorable for human health. The consumption of strawberries, in particular, has been related to the maintenance of well-being and the prevention of several chronic diseases, owing to the high contents of antioxidants and phytochemicals present in the fruit. Several biological effects have been explained through the total antioxidant capacity exerted by these bioactive compounds, but recently more intricate mechanisms have begun to be examined. In this context, it has been reported that strawberry phenolics are able to exert anti-inflammatory, anticarcinogenic, antiproliferative, and antiatherosclerotic activities, acting on specific molecular pathways related to antioxidant defenses, metabolism, survival, and proliferation. The overall aim of this work is to discuss and update the cellular and molecular mechanisms recently proposed to clarify the effects of strawberry phenolics on human health, with particular attention to the most common chronic diseases, such as metabolic syndrome, cardiovascular disease, and cancer. PMID- 28618013 TI - Not a barrier but a key: How bacteriophages exploit host's O-antigen as an essential receptor to initiate infection. AB - Tailed bacteriophages specific for Gram-negative bacteria encounter lipopolysaccharide (LPS) during the first infection steps. Yet, it is not well understood how biochemistry of these initial interactions relates to subsequent events that orchestrate phage adsorption and tail rearrangements to initiate cell entry. For many phages, long O-antigen chains found on the LPS of smooth bacterial strains serve as essential receptor recognized by their tailspike proteins (TSP). Many TSP are depolymerases and O-antigen cleavage was described as necessary step for subsequent orientation towards a secondary receptor. However, O-antigen specific host attachment must not always come along with O antigen degradation. In this issue of Molecular Microbiology Prokhorov et al. report that coliphage G7C carries a TSP that deacetylates O-antigen but does not degrade it, whereas rough strains or strains lacking O-antigen acetylation remain unaffected. Bacteriophage G7C specifically functionalizes its tail by attaching the deacetylase TSP directly to a second TSP that is nonfunctional on the host's O-antigen. This challenges the view that bacteriophages use their TSP only to clear their way to a secondary receptor. Rather, O-antigen specific phages may employ enzymatically active TSP as a tool for irreversible LPS membrane binding to initiate subsequent infection steps. PMID- 28618014 TI - Dual-Mode Optical Sensing of Histamine at Nanomolar Concentrations in Complex Biological Fluids and Living Cells. AB - An easily synthesized fluorescein-based luminescent dye has been utilized for the dual-mode detection of histamine at nanomolar concentrations at pH 7.0 in water. The specific response to histamine was achieved by imidazole-catalyzed 'imine formation' reaction. The protocol was subsequently applied for the estimation of histamine in complex biological milieu such as human blood serum and urine samples. Furthermore, the dose-dependent cellular uptake of histamine and de novo synthesis (by thapsigargin treatment) was visualized in RAW 264.7, a mouse macrophage cell line. We have also developed portable paper strips for rapid, on site detection of histamine without involving costly instruments. PMID- 28618015 TI - Soluble CD163 and mannose receptor associate with chronic hepatitis B activity and fibrosis and decline with treatment. AB - BACKGROUND AND AIM: Liver macrophages are activated in chronic hepatitis B virus (CHB) infection and play a pivotal role in hepatic inflammation and fibrosis. However, their role during antiviral treatment is unclear. The soluble (s) macrophage activation markers, sCD163 and mannose receptor (sMR), are released during liver damage, and their serum levels reflect liver disease severity and portal hypertension. We aimed to investigate associations between sCD163 and sMR and histopathological activity and fibrosis and changes in sCD163, sMR, and hepatic CD163-expression following antiviral treatment in CHB patients. METHODS: We assessed Ishak histological necroinflammatory activity and fibrosis scores in liver biopsies from 254 CHB patients and serially in 71 patients before and after nucleoside-analogue treatment. Liver CD163-expression was semi-quantitatively determined by immunohistochemistry and serum sCD163 and sMR measured by enzyme linked immunosorbent assays. RESULTS: Before treatment, the mean levels of sCD163 and sMR were 3.57 (SD 1.72) mg/L and 0.35 (0.12) mg/L. sCD163 and sMR increased with histological inflammatory activity (sCD163: r = 0.46, P < 0.00001; sMR: r = 0.48, P < 0.00001) and correlated positively with fibrosis (sCD163: OR 1.16, 95% CI:1.03-1.31; sMR: OR 1.34, 95% CI:1.13-1.59); both were markers of fibrosis independent of other biochemical parameters and risk factors. Antiviral treatment significantly reduced sCD163 (3.76 [1.46] vs 2.31 [0.95], P < 0.00001), sMR (0.37 [0.1] vs 0.29 [0.07], P < 0.00001) and hepatic CD163-expression (P = 0.0002). CONCLUSION: The macrophage activation markers sCD163 and sMR were associated with activity and fibrosis in liver biopsies from CHB patients. Both serum markers decreased with antiviral treatment, along with decreased hepatic CD163 expression. PMID- 28618012 TI - Metabolomic signature of brain cancer. AB - Despite advances in surgery and adjuvant therapy, brain tumors represent one of the leading causes of cancer-related mortality and morbidity in both adults and children. Gliomas constitute about 60% of all cerebral tumors, showing varying degrees of malignancy. They are difficult to treat due to dismal prognosis and limited therapeutics. Metabolomics is the untargeted and targeted analyses of endogenous and exogenous small molecules, which charact erizes the phenotype of an individual. This emerging "omics" science provides functional readouts of cellular activity that contribute greatly to the understanding of cancer biology including brain tumor biology. Metabolites are highly informative as a direct signature of biochemical activity; therefore, metabolite profiling has become a promising approach for clinical diagnostics and prognostics. The metabolic alterations are well-recognized as one of the key hallmarks in monitoring disease progression, therapy, and revealing new molecular targets for effective therapeutic intervention. Taking advantage of the latest high-throughput analytical technologies, that is, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), metabolomics is now a promising field for precision medicine and drug discovery. In the present report, we review the application of metabolomics and in vivo metabolic profiling in the context of adult gliomas and paediatric brain tumors. Analytical platforms such as high-resolution (HR) NMR, in vivo magnetic resonance spectroscopic imaging and high- and low-resolution MS are discussed. Moreover, the relevance of metabolic studies in the development of new therapeutic strategies for treatment of gliomas are reviewed. PMID- 28618016 TI - ABCG2 and CD200 define patients at high risk of relapse in ELN favorable subgroup of AML. AB - OBJECTIVE: Overexpression of ABCG2 and CD200 has been independently associated with poor outcome in acute myeloid leukemia (AML). However, no data are available on the role of these two factors in patients with core-binding factor (CBF) positive or FLT3-negative/NPM1-mutated cytogenetically normal (CN) AML. METHODS: We analyzed 65 adult AML patients with CBF+ (n=16) or FLT3-/NPM1+ CN (n=49), evaluating clinical and biological factors associated with complete remission attainment, leukemia-free survival (LFS) and overall survival (OS). RESULTS: ABCG2 was expressed in 36 (55%) cases, and CD200 was positive in 33 (51%) cases, six at high levels. Both ABCG2 and CD200 positivity have a negative impact on relapse risk: 3-year LFS was 51% vs 82% in ABCG2+ cases (RR 3.3), 49% vs 82% in CD200+ patients (RR=4.4), and 25% in CD200- high cases (RR=17.1). ABCG2 and CD200 affected also OS with 3-year OS of 39% in ABCG2+ (compared to 71% in ABCG2-; RR=2.6) and CD200+ (compared to 68% in CD200-; RR=2.5) patients. CONCLUSIONS: Our data confirm a negative impact of ABCG2 and CD200 overexpression also in AML patients considered at favorable risk according to ELN cytogenetic/molecular classification. PMID- 28618017 TI - Curcumin and metformin-mediated chemoprevention of oral cancer is associated with inhibition of cancer stem cells. AB - Effective chemoprevention is critical for improving outcomes of oral cancer. As single agents, curcumin and metformin are reported to exhibit chemopreventive properties, in vitro as well as in patients with oral cancer. In this study, the chemopreventive efficacy of this drug combination was tested in a 4-nitro quinoline-1-oxide (4NQO) induced mice oral carcinogenesis model. Molecular analysis revealed a cancer stem cell (CSC)-driven oral carcinogenic progression in this model, wherein a progressive increase in the expression of CSC-specific markers (CD44 and CD133) was observed from 8th to 25th week, at transcript (40 100-fold) and protein levels (P <= 0.0001). Chemopreventive treatment of the animals at 17th week with curcumin and metformin indicated that the combination regimen decreased tumor volume when compared to the control arm (0.69+0.03 vs 6.66+2.4 mm3 ; P = 0.04) and improved overall survival of the animals (P = 0.03). Assessment of the molecular status showed an overall downregulation of CSC markers in the treatment arms as compared to the untreated control. Further, in vitro assessment of the treatment on the primary cells generated from progressive stages of 4NQO-induced mice tissue showed a concordant and consistent downregulation of the CSC markers following combination treatment (P < 0.05). The treatment also inhibited the migratory and self-renewal properties of these cells; the effect of which was prominent in the cultures of early dysplastic tissue (P < 0.002). Collectively, our observations suggest that the combination of curcumin and metformin may improve chemopreventive efficacy against oral squamous cell carcinoma through a CSC-associated mechanism. PMID- 28618019 TI - Predictors of histological indication for treatment in HBeAg negative chronic HBV infection. AB - In this study, we evaluated the relationship of hepatitis B virus (HBV) DNA levels with liver histology and various other liver related parameters and the predictors of histologically active liver disease requiring treatment (Histological activity >=6 and/or grade >=2 by Ishak's classification) in patients with HBeAg negative chronic HBV infection. Demographic data, laboratory findings and liver histology findings of patients with no clinical cirrhosis who underwent liver biopsy considering HBeAg negative chronic hepatitis (HBV DNA >2000 IU/mL) were analyzed. Two hundred and fifteen patients were included in this retrospective study. Treatment indication by histologic findings were 85.7%, 61.2%, and 64%, respectively, in group 1 (HBV DNA >=200 000), group 2 (HBV DNA 20 000-200 000), and group 3 (HBV DNA 2000-20 000 IU/mL) (P = 0.001). Group 1 was different from other groups in terms of aspartate aminotransferase (AST), alanine aminotransferase (ALT), fibrosis stage, necroinflammatory activity, and platelet count. Multiple logistic regression analysis revealed that, advanced age (cut-off was 46 years), higher than normal AST and HBV DNA >=200 000 IU/mL (compared to group 3) were found to be the predictors of histologically active disease with treatment indication. Conclusively, most of the patients with HBV DNA >=200 000 IU/mL showed treatment requiring liver injury, but also a significant portion of the patients with HBV DNA 2000-200 000 IU/mL carried an indication for treatment. Although age (>46 years) and AST (>40 IU/L) can be helpful to predict treatment requirement in patients with HBV DNA 2000-200 000 IU/mL, sufficient effort should be made to find out the significant liver damage. PMID- 28618021 TI - Calculation of photoionization differential cross sections using complex Gauss type orbitals. AB - Accurate theoretical calculation of photoelectron angular distributions for general molecules is becoming an important tool to image various chemical reactions in real time. We show in this article that not only photoionization total cross sections but also photoelectron angular distributions can be accurately calculated using complex Gauss-type orbital (cGTO) basis functions. Our method can be easily combined with existing quantum chemistry techniques including electron correlation effects, and applied to various molecules. The so called two-potential formula is applied to represent the transition dipole moment from an initial bound state to a final continuum state in the molecular coordinate frame. The two required continuum functions, the zeroth-order final continuum state and the first-order wave function induced by the photon field, have been variationally obtained using the complex basis function method with a mixture of appropriate cGTOs and conventional real Gauss-type orbitals (GTOs) to represent the continuum orbitals as well as the remaining bound orbitals. The complex orbital exponents of the cGTOs are optimized by fitting to the outgoing Coulomb functions. The efficiency of the current method is demonstrated through the calculations of the asymmetry parameters and molecular-frame photoelectron angular distributions of H2+ and H2 . In the calculations of H2 , the static exchange and random phase approximations are employed, and the dependence of the results on the basis functions is discussed. (c) 2017 Wiley Periodicals, Inc. PMID- 28618020 TI - Bacterial colonization of resin composite cements: influence of material composition and surface roughness. AB - So-called secondary caries may develop in the cement gap between the tooth and the bonded restoration. Cement materials with a low susceptibility to biofilm formation are therefore desirable. In the present study, the adhesion of Strepococcus mutans onto three adhesive (Multilink Automix, RelyX Ultimate, and Panavia V5) and three self-adhesive (Multilink Speed Cem, RelyX Unicem 2 Automix, and Panavia SA plus) resin composite cements was evaluated. Previous studies have failed to evaluate concomitantly the effect of both the composition of the cements and their surface roughness on biofilm formation. The presence of S. mutans on cement surfaces with differing degrees of roughness was therefore recorded using fluorescence microscopy and crystal violet staining, and the composition of the cements was analyzed using energy-dispersive X-ray spectroscopy mapping. Biofilm formation on resin composite cements was found to be higher on rougher surfaces, implying that adequate polishing of the cement gap is essential. The use of copper-containing cements (Multilink Automix, Panavia V5, and Panavia SA plus) significantly reduced biofilm formation. PMID- 28618018 TI - Executive Functions, Memory, and Social Cognitive Deficits and Recovery in Chronic Alcoholism: A Critical Review to Inform Future Research. AB - Alcoholism is a complex and dynamic disease, punctuated by periods of abstinence and relapse, and influenced by a multitude of vulnerability factors. Chronic excessive alcohol consumption is associated with cognitive deficits, ranging from mild to severe, in executive functions, memory, and metacognitive abilities, with associated impairment in emotional processes and social cognition. These deficits can compromise efforts in initiating and sustaining abstinence by hampering efficacy of clinical treatment and can obstruct efforts in enabling good decision making success in interpersonal/social interactions, and awareness of cognitive and behavioral dysfunctions. Despite evidence for differences in recovery levels of selective cognitive processes, certain deficits can persist even with prolonged sobriety. Herein is presented a review of alcohol-related cognitive impairments affecting component processes of executive functioning, memory, and the recently investigated cognitive domains of metamemory, social cognition, and emotional processing; also considered are trajectories of cognitive recovery with abstinence. Finally, in the spirit of critical review, limitations of current knowledge are noted and avenues for new research efforts are proposed that focus on (i) the interaction among emotion-cognition processes and identification of vulnerability factors contributing to the development of emotional and social processing deficits and (ii) the time line of cognitive recovery by tracking alcoholism's dynamic course of sobriety and relapse. Knowledge about the heterochronicity of cognitive recovery in alcoholism has the potential of indicating at which points during recovery intervention may be most beneficial. PMID- 28618022 TI - Utility of a formatted pathologic reporting system in thyroid core needle biopsy: A validation study of 1998 consecutive cases. AB - OBJECTIVE: Thyroid core needle biopsy (CNB) is increasingly being used as a tool for evaluating thyroid nodules; thus, standardization of its diagnostic terminology is called for. We aimed to analyse the pathologic reporting system of thyroid CNB based on the recently proposed protocol by the Korean Endocrine Pathology Thyroid Core Needle Biopsy Study Group and evaluate its usefulness. DESIGN/METHODS: A total of 1998 consecutive cases of thyroid CNBs were reviewed and divided into six categories according to the protocol. Malignancy rate in each category and the diagnostic performance of thyroid CNB were calculated using 705 resected cases. RESULTS: Thyroid CNB yielded 132 nondiagnostic (6.6%), 791 benign (39.6%), 328 indeterminate (16.4%), 227 follicular neoplasm (11.4%), 69 suspicious for malignancy (3.5%) and 451 malignant lesions (22.6%). In resected specimens, all of the cases designated as suspicious for malignancy and malignant categories in CNB were proven to be true malignant lesions. Lesions diagnosed with follicular neoplasm in CNB were identified as malignant lesions in 57.0%. Malignancy rate was significantly higher in indeterminate lesions with nuclear atypia compared to those with architectural atypia (80.0% vs 28.2%). When CNB diagnoses of indeterminate lesions or higher categories were considered positive, the sensitivity and positive predictive value for final malignant diagnoses were 99.2% and 81.3%, respectively. CONCLUSIONS: CNB is an accurate method of evaluating thyroid nodules and can serve as an alternative to fine needle aspiration when it is used and reported according to standardized diagnostic categories. PMID- 28618023 TI - Is the atopic march related to confounding by genetics and early-life environment? A systematic review of sibship and twin data. AB - A popular hypothesis known as the atopic march proposes a set of sequential allergy and respiratory disorders in early childhood contributes enormously to the burden of disease in developed countries. Although the concept of the atopic march has been refined and strengthened by many cross-sectional and longitudinal studies linking eczema as the initial manifestation with progression to hay fever and then asthma, there is yet no definitive proof that the atopic march is the primary causal factor in childhood allergic disease. This debate is mainly related to the controversy around potential confounding of these associations by genetic and environmental factors. Family studies are ideally suited to unravelling the role of these factors. While multiple reviews have synthesized evidence from studies investigating this question, no review to date has explored specific evidence generated by twin and sibling studies to understand the aetiology of atopic march diseases. Our aim was to conduct a systematic review of twin and sibling studies that examine the allergic phenotypes that form the atopic march, to determine whether such analyses of data from these studies attempt to control for the effect confounding by shared factors, and to report estimates of the magnitude of associations between multiple phenotypes. Our review suggests that (1) genetics play a bigger role predisposing eczema to hay fever and eczema to asthma than environmental factors, and (2) the link between eczema and asthma and hay fever is independent of shared early-life environmental factors. PMID- 28618024 TI - First-principles modeling of hafnia-based nanotubes. AB - Hybrid density functional theory calculations were performed for the first time on structure, stability, phonon frequencies, and thermodynamic functions of hafnia-based single-wall nanotubes. The nanotubes were rolled up from the thin free layers of cubic and tetragonal phases of HfO2 . It was shown that the most stable HfO2 single-wall nanotubes can be obtained from hexagonal (111) layer of the cubic phase. Phonon frequencies have been calculated for different HfO2 nanolayers and nanotubes to prove the local stability and to find the thermal contributions to their thermodynamic functions. The role of phonons in stability of nanotubes seems to be negligible for the internal energy and noticeable for the Helmholtz free energy. Zone folding approach has been applied to estimate the connection between phonon modes of the layer and nanotubes and to approximate the nanotube thermodynamic properties. It is found that the zone-folding approximation is sufficiently accurate for heat capacity, but less accurate for entropy. The comparison has been done between the properties of TiO2 , ZrO2 , and HfO2 . (c) 2017 Wiley Periodicals, Inc. PMID- 28618025 TI - CHEMICAL, PHYSICOCHEMICAL AND IMMUNOLOGICAL CHARACTERISATION OF beta-TRACE PROTEIN AND gamma-TRACE PROTEIN. PMID- 28618026 TI - CHEMICAL AND IMMUNOLOGICAL CHARACTERISATION OF IMMUNOGLOBULIN G FROM CEREBROSPINAL FLUID. PMID- 28618027 TI - THE MOBILITY OF beta-TRACE PROTEIN gamma-TRACE PROTEIN AND IMMUNOGLOBULIN G FROM CEREBROSPINAL FLUID ON AGAR GEL ELECTROPHORESIS. PMID- 28618029 TI - CONCLUDING REMARKS. PMID- 28618030 TI - GENERAL SUMMARY. PMID- 28618032 TI - QUANTITATION OF beta-TRACE PROTEIN IN CEREBROSPINAL FLUID IN ANTIBODY-AGAR PLATES. PMID- 28618031 TI - ISOLATION OF beta-TRACE PROTEIN, gamma-TRACE PROTEIN AND IMMUNOGLOBULIN G FROM CEREBROSPINAL FLUID. PMID- 28618033 TI - INTRODUCTION. PMID- 28618034 TI - Computer-Mediated Communication in Intimate Relationships: Associations of Boundary Crossing, Intrusion, Relationship Satisfaction, and Partner Responsiveness. AB - This study examined the impact of technology on couples in committed relationships through the lens of the couple and technology framework. Specifically, we used data from 6,756 European couples to examine associations between online boundary crossing, online intrusion, relationship satisfaction, and partner responsiveness. The results suggest that participants' reports of online boundary crossing were linked with lower relationship satisfaction and partner responsiveness. Also, lower relationship satisfaction and partner responsiveness were associated with increased online boundary crossing. The results suggest that men, but not women, who reported greater acceptability for online boundary crossing were more likely to have partners who reported lower relationship satisfaction in their relationships. Implications for clinicians, relationship educators, and researchers are discussed. PMID- 28618035 TI - Population Pharmacokinetics of Imatinib in Nigerians With Chronic Myeloid Leukemia: Clinical Implications for Dosing and Resistance. AB - Imatinib, a tyrosine kinase inhibitor, is the drug of choice for the treatment of chronic myeloid leukemia in Nigeria. Several studies have established interindividual and interpopulation variations in imatinib disposition although no pharmacokinetic study have been conducted in an African population since the introduction of the drug. This study explored a population pharmacokinetic approach to investigate the disposition of imatinib in Nigerians and examined the involvement of some covariates including genetic factors in the variability of the drug disposition with a view to optimize the use of the drug in this population. A total of 250 plasma concentrations from 126 chronic myeloid leukemia patients were quantified using a validated method. A population pharmacokinetic model was fitted to the data using NONMEM VII software, and the influences of 12 covariates were investigated. The mean population-derived apparent steady-state clearance, elimination half-life, area under the concentration-time curve over 24 hours, and volume of distribution were 17.2 +/- 1.8 L/h., 12.05 +/- 2.1 hours, 23.26 +/- 0.6 MUg.h/mL, and 299 +/- 20.4 L, respectively. Whole blood count, ethnicity, CYP3A5*3, and ABCB1 C3435T were found to have significant influence on the apparent clearance, while the interindividual variability in clearance and interoccasion variability in bioavailability were 17.4% and 20.4%, respectively. There was a wide variability in apparent clearance and area under the curve compared to those reported in other populations. Thus, treatment with a standard dose of imatinib in this population may not produce the desired effect in most of the patients, whereas continuous exposure to a low drug concentration could lead to pharmacokinetic derived resistance. The authors suggest the need for therapeutic drug monitoring guided dose individualization in this population. PMID- 28618036 TI - Ultra-low radiation dose during electrophysiology procedures using optimized new generation fluoroscopy technology. AB - BACKGROUND: Electrophysiology procedures require fluoroscopic guidance, with the associated potentially adverse effects of ionizing radiation. Newer fluoroscopy systems have more features that enable dose-reduction strategies. This study aimed to investigate any reduction in radiation dose between an older fluoroscopy system (Philips Integris H5000, Philips Healthcare, Einhoven, Netherlands) and one of the latest systems (Siemens Artis Q, Siemens Healthcare, Erlangen, Germany), optimized with dose-reduction strategies. METHODS: Radiation dose measures were collected over a 2-year period in a single electrophysiology laboratory. Procedures were separated into seven groups: devices, biventricular devices, electrophysiology studies, standard radiofrequency ablation, complex atrial ablation, ablation for ventricular arrhythmias, and pulmonary vein isolation. In the first year, an older fluoroscopy system was used, and in the second year, a new system, with dose reduction strategies. Comparisons were also made to the literature with regard to radiation dose levels. RESULTS: Patient characteristics, fluoroscopy times, number of digital acquisitions, procedural times, and procedural success were largely similar between the old and new system across procedure groups. Overall dose area product (DAP) was reduced by 91% (5.0 [2.0-17.0] to 0.45 [0.16-2.61] Gycm2 [P > 0.001]) with the new system and was lower across all groups. DAP readings with the new system are some of the lowest published in the literature in all groups. CONCLUSION: An optimized contemporary digital fluoroscopy system, with low radiation dose configuration and continued good procedural practice, can result in ultra-low radiation levels for all electrophysiology procedures, without compromising procedural time or procedural success. PMID- 28618037 TI - Hydrogen Peroxide Stimulates Exosomal Cathepsin B Regulation of the Receptor for Advanced Glycation End-Products (RAGE). AB - Exosomes are nano-sized vesicles that are secreted into the extracellular environment. These vesicles contain various biological effector molecules that can regulate intracellular signaling pathways in recipient cells. The aim of this study was to examine a correlation between exosomal cathepsin B activity and the receptor for advanced glycation end-products (RAGE). Type 1 alveolar epithelial (R3/1) cells were treated with or without hydrogen peroxide and exosomes isolated from the cell conditioned media were characterized by NanoSight analysis. Lipidomic and proteomic analysis showed exosomes released from R3/1 cells exposed to oxidative stress induced by hydrogen peroxide or vehicle differ in their lipid and protein content, respectively. Cathepsin B activity was detected in exosomes isolated from hydrogen peroxide treated cells. The mRNA and protein expression of RAGE increased in cultured R3/1 cells treated with exosomes containing active cathepsin B while depletion of exosomal cathepsin B attenuated RAGE mRNA and protein expression. These results suggest exosomal cathepsin B regulates RAGE in type 1 alveolar cells under conditions of oxidative stress. J. Cell. Biochem. 119: 599-606, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28618038 TI - Open visitation and nurse job satisfaction: An integrative review. AB - AIMS AND OBJECTIVES: To explore the effect of open visitation on critical care nurse job satisfaction. BACKGROUND: Open visitation has many benefits for ICU patients and families. However, ICU open visitation also affects nurses' work environment. Because nurse satisfaction is crucial to overall patient satisfaction, nurses' perceptions, experiences and opinions about open visitation should be considered. DESIGN: A literature search was performed through CINAHL Complete, MEDLINE Complete, PubMed, ScienceDirect, Academic Search Premier and PsychINFO. METHODS: Key terms, inclusion criteria and exclusion criteria were applied. Duplicates and articles focusing on family presence during end of life care were excluded. Articles were evaluated for data quality, resulting in 14 articles. RESULTS: Family presence can negatively affect nurses' workflow and environment. Nurses report a loss of control, interruptions in care and increased workloads with open visitation. Therefore, nurses prefer restricted visitation. CONCLUSIONS: The literature evidence encourages visitation policies that support nurses in managing the additional work and stress of meeting patient and family needs. Implementation of evidence-based strategies to support nursing staff in stressful ICU environments can improve job satisfaction. RELEVANCE TO CLINICAL PRACTICE: The conclusions of this integrative review can be utilized by hospitals considering or implementing ICU open visitation. PMID- 28618039 TI - Correlation between serum galectin-9 levels and liver fibrosis. AB - BACKGROUND AND AIM: Chronic liver diseases progress from chronic inflammation to fibrosis to tumorigenesis. Galectin-9, a beta-galactoside-specific animal lectin, is indicated to contribute to all three steps of progression. The aim of this study was to determine which of the three steps was most dominant in elevating the serum galectin-9 concentration and to test the possibility of galectin-9 as a serum biomarker. METHODS: Japanese patients with chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease, or alcoholic liver disease who provided informed consent were enrolled in this study. Serum galectin-9 levels were measured using a sandwich ELISA. Multiple regression analyses were performed using ezr to identify factors that determined serum galectin-9 concentration. RESULTS: One hundred one patients with 50 of chronic hepatitis and 51 of liver cirrhosis were enrolled; the cohort included 45 cases of hepatitis C virus infection, 13 cases of hepatitis B virus infection, and 46 cases with HCC-related complications. The median serum galectin-9 concentration was 77.54 pg/mL (interquartile range: 18.89-241.9 pg/mL). Multiple linear regression analyses proved Fibrosis-4 index and aspartate aminotransferase to platelet ratio index, indexes of liver fibrosis, were able to predict the serum galectin-9 levels with statistical significance. A multiple logistic regression analysis determined 10 pg/mL increase in the serum galectin-9 concentration presented an odds ratio of 3.90 for liver fibrosis progression. CONCLUSIONS: The serum galectin-9 concentration represents a potential biomarker of liver fibrosis in patients with chronic liver diseases, regardless of chronic inflammation or the presence of HCC complications. Furthermore, higher serum galectin-9 levels are a predictor for liver fibrosis progression. PMID- 28618040 TI - Optimising implementation of a patient-assessment framework for emergency nurses: A mixed-method study. AB - AIMS AND OBJECTIVES: To determine potential facilitators and barriers and tailor interventions to optimise future implementation of a patient-assessment framework into emergency nursing practice. BACKGROUND: An evidence-informed patient assessment framework HIRAID (History, Identify Red flags, Assessment, Interventions, Diagnostics, communication and reassessment) improves the quality of patient assessments performed by emergency nurses. Facilitators and barriers must be understood and tailored interventions selected to optimise implementation. DESIGN: A mixed-method convergent study design was used. METHODS: Thirty eight early career emergency nurses from five Australian hospitals participated in an education workshop on the HIRAID assessment framework. Simulated clinical scenarios enabled participants to experience conducting a patient assessment with and without using the framework. All participants completed surveys, interviews and focus groups to identify potential facilitators and barriers. Twenty three participants completed follow-up telephone surveys 4-6 months later. Quantitative and qualitative data were analysed separately using descriptive statistics and inductive content analysis, prior to integration. Implementation interventions were selected using the Behaviour Change Wheel. RESULTS: Nine facilitators and nine barriers were identified to potentially effect implementation of the HIRAID assessment framework. Twelve of the 23 participants (52.2%) who completed follow-up surveys reported using the framework in the clinical setting. To optimise future implementation, the education workshop needs refinement, and environmental restructuring, modelling and social support are required. CONCLUSION: A multimodal strategy is needed to promote future successful implementation of the HIRAID assessment framework into emergency nursing practice. RELEVANCE FOR CLINICAL PRACTICE: The successful implementation of the HIRAID assessment framework has the potential to improve nursing assessments of patients in emergency and other acute care settings. This study demonstrates how to systematically identify facilitators and barriers to behaviour change and select interventions to optimise implementation of evidence informed nursing practices. PMID- 28618041 TI - Effect of Various Ratios of Co-Cultured ATDC5 Cells and Chondrocytes on the Expression of Cartilaginous Phenotype in Microcavitary Alginate Hydrogel. AB - The present study introduced a direct co-culture of mouse ATDC5 cells and primary porcine chondrocytes into a microcavitary hydrogel, which possessed advantages in promoting the growth of chondrocytes and retaining the phenotype. These two types of cells were encapsulated with gelatin microspheres in alginate hydrogels in either of the three ratios (3:1, 1:1, or 1:3 of ATDC5 cells to chondrocytes) and cultured in chondrogenic medium for 28 days. Simultaneously, the single encapsulation of ATDC5 cells or chondrocytes was set as a control. Cell Counting Kit-8 (CCK-8), real-time PCR, and immunohistochemistry staining were used to evaluate the effect of various ratios of co-cultured ATDC5 cells and chondrocytes on the expression of the cartilaginous phenotype. The CCK-8 data indicated that the ratio of 3:1 group had an outstanding ability of cell growth. The other results demonstrated that higher the ATDC5 ratios and longer the culture duration, greater the expression of cartilage-specific genes (including type II collagen and aggrecan) and more the synthesized cartilaginous extracellular matrix. Also, the Western blot analysis suggested that p44/42 MAP Kinase was involved in cell proliferation. However, due to the direct co-culture of the two cell types, the underlying mechanism necessitates further investigation. Overall, the co-culture system in microcavitary hydrogel improved the effect of chondrogenesis and exhibited promising strategy for cartilage tissue engineering therapies. J. Cell. Biochem. 118: 3607-3615, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28618042 TI - Farmers' knowledge of Q fever and prevention approaches in New South Wales. AB - OBJECTIVE: To identify what New South Wales (NSW) farmers know about Q fever to inform preventive approaches. DESIGN: Thematic analysis of qualitative data gathered through semi-structured individual interviews, focus groups and a community meeting. SETTING: Rural communities in NSW, Australia. PARTICIPANTS: A total of 25 farmers participated in individual interviews (n = 4) or three focus groups, each with seven participants (n = 21). A further 27 persons, were involved in a community meeting. MAIN OUTCOME MEASURES: Themes derived from the interviews, focus groups and community meeting. RESULTS: Knowledge variations regarding Q fever risk and transmission highlight a need for improved risk communication. Vaccination was viewed as the preferred prevention approach; barriers were raised including time, costs, access to screening/vaccination and General Practitioner (GP) knowledge about Q fever. Local vaccination initiatives were supported. CONCLUSIONS: Strengthening existing GP knowledge and services leading to expanded provision of screening/vaccination could improve the coverage of Q fever vaccine in endemic NSW farming and rural communities. PMID- 28618043 TI - Nurses' knowledge on diabetic foot ulcer disease and their attitudes towards patients affected: A cross-sectional institution-based study. AB - AIMS AND OBJECTIVES: To assess nurses' knowledge on diabetic ulcer disease and their attitudes towards patients suffering from it and to identify factors which influence them. BACKGROUND: Diabetic wound care is an evolving specialty with the rising prevalence of diabetes foot complications. As nurses play a key role in wound care, their knowledge and attitudes are important in providing optimum care to patients. DESIGN: Descriptive cross-sectional survey design. METHODS: The study was conducted in three teaching hospitals. Data were collected using a pretested, validated, self-administered questionnaire from purposively recruited, voluntarily participating nurses (n = 200) who were in diabetic wound care practice for >=1 year. RESULTS: Lack of formal wound care training was reported by 91.2%. Mean knowledge score was 77.9 (range 53.3-100 on a scale from 0-100) with 57.8% of nurses obtaining >=80%. Nurses demonstrated an overall positive attitude towards caring for diabetic ulcer patients (median = 41, range 23-50 on a scale from 10-50). However, the study identified deficits in core knowledge and some negative attitudes such as insensitivity to pain. Statistically significant associations were seen between nurses' knowledge and duration of nursing, wound care experience and the type of unit they are attached to. In-service education (77.2%) and knowledge sharing with peers (77.9%) were the most popular knowledge updating sources. Although 98.6% of nurses were interested in wound care, only 8.3% wished to engage in research. No correlation was observed between nurses' knowledge and attitudes. CONCLUSION: Gaps in core knowledge and negative attitudes may be attributed to inadequate training, suboptimal update of knowledge and lack of interest in wound care research. RELEVANCE TO CLINICAL PRACTICE: Wound care training should be made mandatory to improve quality of care given by nurses to patients with diabetic ulcers. Continuous professional development, evidence-based practices and wound care research should be encouraged. PMID- 28618044 TI - Rising Trend in Non-Indicated Caesarean Deliveries: Can the Trend be Reversed? PMID- 28618045 TI - Clean catch urine collection: Time taken and diagnostic implication. A prospective observational study. AB - AIM: Clean catch urine (CCU) collection is commonly used in pre-continent children. CCU can be time-consuming and specimens may be contaminated. Our aim was to determine the time taken for CCU attempts and to describe the success of this method in diagnosing or excluding urinary tract infection. METHODS: Prospective observational study of CCU in pre-continent children aged 2-48 months in the emergency department. Time taken until urine collection, 'successful' (voided and caught), 'missed' (voided not caught) or the procedure 'stopped', were recorded and urine culture results analysed. RESULTS: Two hundred and seventeen children (131 (60%) male) were enrolled. There were a total of 247 attempts at CCU. For the first attempt, the median collecting time was 30.5 min (interquartile range (IQR) 11-66). Outcome was 'successful' in 64% (95% confidence intervals (CI) 58-70%), 'missed' in 16% (95% CI 11-20%) and 'stopped' in 20% (95% CI 15-26%). Median time if 'successful' was 25 min (IQR 7-46.5), 'missed' 27 min (IQR 11.6-59) and 71 min (IQR 42.5-93) when 'stopped'. One hundred and sixty children had successful CCU collection, 129 were sent for culture. Fifty of 129 (39%) cultures were contaminated. If all urine specimens caught were sent for culture, the estimated yield of an uncontaminated urine specimen was 45%. Contamination was not related to time taken for CCU. CONCLUSIONS: CCU is time-consuming, frequently unsuccessful and contaminated, resulting in a low overall diagnostic yield. Clinicians could expect a 45% chance of obtaining a definitive urine sample from this method overall. PMID- 28618046 TI - Open-label randomised controlled trial about application of bundle care in prevention of unplanned extubation of nasobiliary drainage catheter after endoscopic retrograde cholangiopancreatography. AB - AIMS AND OBJECTIVES: To observe the effects of bundle care on preventing unplanned extubation of nasobiliary drainage catheter after endoscopic retrograde cholangiopancreatography. BACKGROUND: Preventing unplanned extubation has become a difficult problem for nursing staff because the catheter is stiff, fine and long. DESIGN: A total of 114 cases that experienced nasobiliary drainage after endoscopic retrograde cholangiopancreatography for the first time in our hospital from April 2015-July 2016 were enrolled in this study. According to receiving routine nurse or bundle nurse, these cases were randomly divided into control (n = 56) and intervention (n = 58) group. METHOD: The unplanned extubation incidence, contact area between tape and catheter and tensile resistance were compared between the two groups. RESULTS: The contact area was one square centimetre in the control group and 5 cm2 in the intervention group. Tensile resistance was significantly higher in the intervention group than in the control (all p < .05). Unplanned extubation incidence was significantly lower in the intervention group (1.72%, 1/58) than in the control (12.5%, 7/56) (p = .0305). CONCLUSION: Bundle care can effectively decrease unplanned extubation incidence after endoscopic retrograde cholangiopancreatography. RELEVANCE TO CLINICAL PRACTICE: This study provides a basis for decreasing unplanned extubation incidence. PMID- 28618047 TI - Focal beta-catenin mutation identified on formalin-fixed and paraffin-embedded inflammatory hepatocellular adenomas. AB - The identification of hepatocellular adenoma (HCA) with mutation in exon 3 of the CTNNB1 gene encoding for beta-catenin is clinically relevant due to a higher risk of malignant transformation. Inflammatory HCA (IHCA) can exhibit beta-catenin activation (beta-IHCA). We report two cases with multiple IHCA in which focal beta-catenin activation has been found in one of the IHCA. In both cases, the diagnosis of IHCA was confirmed on the resected nodules by routine stains, immunohistochemical detection of C-reactive protein (CRP) and molecular biology on frozen material. An additional molecular analysis was performed on formalin fixed paraffin-embedded (FFPE) material that showed focal glutamine synthetase (GS) staining, the surrogate marker of beta-catenin activation. In case 1, it was a 1.8-cm area within the 7.5 cm IHCA, and in case 2 a small 0.3-cm area within a 1.8 cm resected IHCA located close to a larger IHCA, negative for GS. In both cases, nuclear beta-catenin expression and decreased reticulin network were observed in the GS expressing foci, together with cholestasis and diffuse CD34 expression in case 1. Molecular analysis by pyrosequencing on FFPE material using the GS-stained slides as reference to select areas with/without positive staining revealed a CTNNB1 exon 3 mutation restricted to the areas exhibiting both positive GS and CRP expression, whereas wild-type CTNNB1 was found in areas showing only CRP staining. These two cases illustrate focal beta-catenin activation that can occur within IHCAs. Additional data are needed to determine if beta-catenin mutation is a secondary event in IHCA. PMID- 28618048 TI - Transcriptomic Profiling in Human Decidua of Severe Preeclampsia Detected by RNA Sequencing. AB - Maternal decidua plays a critical role in implantation and placentation. Impaired decidualization causes failed intravascular trophoblast invasion and inadequate placentation and then increases the risk of preeclampsia (PE). RNA sequencing (RNA-Seq) has achieved great advances in the characterization and quantification of transcriptomes; is a powerful tool for new transcript discovery, genome annotation, and expression profiling. In the present study, we conducted a RNA Seq analysis to compare gene expression between decidua of PE (n = 3, early-onset severe PE, EOSPE; n = 3, late-onset severe PE, LOSPE) and normal pregnancies (n = 3). We revealed that decidual gene transcription profile was altered in severe PE and identified 293 key PE-related genes involved in 19 differentially regulated pathways relevant for the pathogenesis of PE, among which ENO2, PGK1, and HK2 involved in glycolysis/gluconeogenesis and HIF-1 signaling pathway which are all highly related with tumorigenesis and are significantly upregulated in cancer cells were severely inhibited in the decidua of PE. Moreover, we identified 22 core regulatory genes, including the newly identified pseudogenes BNIP3P1, HK2P1, and PGK1P1 that encode long non-coding RNA (lncRNA); interestingly, BNIP3/BNIP3P1, HK2/HK2P1, and PGK1/PGK1P1 appear in pairs in core genes. Subsequent analyses using quantitative PCR validated a portion of these results. This study may provide further insight into the mechanisms of PE and function as preventive, predictive, and therapeutic measures. Future functional studies are needed in order to accomplish a greater understanding of the mechanisms involved. J. Cell. Biochem. 119: 607-615, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28618049 TI - Study of gliquidone degradation behavior by high-performance thin-layer chromatography and ultra-performance liquid chromatography methods. AB - Gliquidone (GQ) is an oral hypoglycemic agent, belonging to second-generation sulfonylurea derivatives. New high-performance thin-layer chromatography (HPTLC) and ultra-performance liquid chromatography (UPLC) methods have been developed and validated and used for complete stability study of GQ following International Conference on Harmonization guidelines. GQ was subjected to stress and forced degradation under hydrolytic, oxidative and photolytic conditions. The drug was found to be unstable under acidic, alkaline and oxidative conditions with the formation of gliquidone sulfonamide (GQS), while a marked stability was confirmed under thermal and photolytic stress conditions. GQS is the British pharmacopeial impurity A of GQ and also considered as its synthesis intermediate. The developed chromatographic methods have been utilized for anticipating the degradation behavior of GQ under the studied conditions and then used for quantitation of GQ and GQS either in their pure forms or in laboratory prepared mixtures. The methods were successfully applied to GQ in pharmaceutical formulation. The methods have the advantages of being sensitive and less time consuming compared with the reported methods. The obtained results were statistically compared with a reported HPLC method showing no significant difference regarding both accuracy and precision. PMID- 28618050 TI - Different Porosities of Chitosan Can Influence the Osteogenic Differentiation Potential of Stem Cells. AB - Scaffolds porosity has an important role in in vitro and in vivo differentiation process of stem cells with given the amount of space available to the cells to proliferate and differentiate. In the present study, chitosan with three porosities including 10%, 15%, and 20% that created by gelatin were used for investigation of the proliferation and osteogenic differentiation potential of adipose-derived stem cells (ADSCs). In order to be more like the scaffold to natural bone tissue, freeze-drying method was used in the scaffold preparation. Scaffold morphology, cell attachment, and toxicity were evaluated using scanning electron microscopy and MTT assay. Then, osteogenic differentiation potential of ADSCs cultured on chitosan with different porosities was evaluated by common osteogenic markers such as Alizarin red staining, ALP activity, calcium content, and osteogenic-related genes expression via real-time RT-PCR. Although all scaffolds supported the proliferation and differentiation of ADSCs, but 10% scaffold demonstrated higher amount of osteogenic markers in comparison with the other porosities and control groups. Taking together, it can be concluded that osteogenic differentiation well done in the scaffolds with lower porosity because density of the cells will increase by forcing resulted from the scaffold, so osteogenic differentiation of the stem cells have an inverse association with scaffold porosity. J. Cell. Biochem. 119: 625-633, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28618051 TI - Quantitative bioanalysis of bavachalcone in rat plasma by LC-MS/MS and its application in a pharmacokinetics study. AB - This study aims to develop and validate a simple and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for investigating the pharmacokinetic characteristics of bavachalcone. Liquid-liquid extraction was used to prepare plasma sample. Chromatographic separation of bavachalcone and IS was achieved using a Venusil ASB C18 (2.1 * 50 mm, 5 MUm) column with a mobile phase of methanol (A)-water (B) (70:30, v/v). The detection and quantification of analytes was performed in selected-reaction monitoring mode using precursor -> product ion combinations of m/z 323.1 -> 203.2 for bavachalcone, and m/z 373.0 -> 179.0 for IS. Linear calibration plots were achieved in the range of 1-1000 ng/mL for bavachalcone (r2 > 0.99) in rat plasma. The recovery of bavachalcone ranged from 84.1 to 87.0%. The method was precise, accurate and reliable. It was fully validated and successfully applied to pharmacokinetic study of bavachalcone. PMID- 28618052 TI - Comparison between swinging and playing of white noise among colicky babies: A paired randomised controlled trial. AB - AIMS AND OBJECTIVE: This study aimed to compare the effects of swinging and playing of white noise on the crying and sleeping durations of colicky babies. BACKGROUND: Infantile colic (IC) is one of the most common reasons for doctor visits among babies younger than 3 months. One of five babies older than 3 months also experiences IC. IC, unlike gastrointestinal problems, is regarded as an individual differentiation and maturation of the central nervous system. Providing a warm bath, breastfeeding, swinging and playing of white noise are nonpharmacological methods. The efficiency of these methods has been proven by various studies independently of one another. DESIGN: The study is a prospective, multicentre, paired randomised controlled trial. METHODS: The study was conducted between April-December 2016. The study sample consisted of 40 1-month-old babies with gas pains who passed a hearing screening and their mothers. The total daily crying and sleeping durations of the babies were determined without any intervention on the first week. On the second week, 20 randomly selected babies (first group) were swung each time they cried, and on the third week, they were made to listen to white noise. The other 20 babies (second group) were made to listen to white noise on the second week and were swung on the third week. Swinging and playing of white noise were performed until the babies stopped crying. After every intervention, the total crying and sleeping durations of the babies were evaluated using a "Colicky Baby's Diary." RESULTS: Playing of white noise significantly decreased the daily crying durations (p < .05) and increased the sleeping durations of the colicky babies (p < .05) compared to swinging in both groups. CONCLUSION: Playing of white noise was found to be a more effective nonpharmacological method on crying and sleeping durations of colicky babies than swinging. RELEVANCE TO CLINICAL PRACTICE: Playing of white noise may be helpful for parents and healthcare personnel in reducing the gas pains of babies. PMID- 28618053 TI - Association of aberrant right subclavian artery with abnormal karyotype and microarray results. AB - OBJECTIVES: The objective of this study is to evaluate the incidence of chromosomal aberration (both microscopic and sub-microscopic) in fetuses with an aberrant right subclavian artery (ARSA) detected by ultrasonographic anomaly scan. METHODS: The study included 62 pregnant women whose fetuses were diagnosed with ARSA who were referred for genetic counseling. Of these, 55 patients underwent amniocentesis and 7 declined invasive testing. All 55 amniocentesis samples were tested by standard G-banding and chromosomal microarray, except for 2 samples for which only karyotype and fluorescence in situ hybridization for 22q11.2 deletions were performed. RESULTS: Of the 55 women who underwent amniocentesis, 5 were detected with trisomy 21 (9.1%), all of whom had additional ultrasound findings. Among the 14 fetuses with ARSA and additional ultrasound findings, the incidence of trisomy 21 was 35.7%. In fetuses with isolated ARSA, no chromosomal aberrations were detected by standard cytogenetic analysis and only one (1.9%) deleterious copy number variants (CNV) was detected by chromosomal microarray. CONCLUSION: Aberrant right subclavian artery with additional ultrasound findings constitute a strong predictor for aneuploidy. However, when ARSA is found in isolation, it confers no increased risk for aneuploidy or pathogenic CNVs. (c) 2017 John Wiley & Sons, Ltd. PMID- 28618054 TI - Ethics, intimacy and sexuality in aged care. AB - AIM: To analyse the accounts of staff, family and residents to advance ethical insights into intimacy and sexuality in residential care. BACKGROUND: Discourses of ageing readily construct people in residential aged care as postsexual, vulnerable and at risk of sexual exploitation, and therefore, expressions of intimacy and sexuality may be responded to as deviant and inherently risky. Staff may manage decision-making tacitly, without recourse to policies and education. DESIGN: The proof-of-concept study used a discursive methodology, identifying discourses that shape diverse meanings of intimacy, sexuality and ageing. Data analysis involved thematic analysis. METHODS: Semi-structured interviews were conducted with four participants in 2015 as part of a mixed-methods study. This article reports on the qualitative data. RESULTS: Four themes were identified in the data analysis: mediated intimate relationships and everyday ethics; self referential morality; knowing the person then and now; and juggling ethical priorities. Data indicated that participants used their personal moral compass to inform their decision-making, without any related policies and applied ethics and communication education. As a result, staff described moral uncertainty and moral distress. Staff indicated that there were tensions in terms of the role of proxy decision-makers, as there were situations where staff believed they were more aware of residents' current wishes and cognitive capabilities than family members. CONCLUSIONS: Staff, families and residents routinely address intimacy and sexuality in aged care. Ethically informed education and policies may enhance the role of staff as advocates, ensuring older people living in RAC are as at home and autonomous as possible. PMID- 28618055 TI - Pericardial-esophageal fistula after catheter ablation of atrial fibrillation. PMID- 28618056 TI - Improving substance information in USEtox(r) , part 1: Discussion on data and approaches for estimating freshwater ecotoxicity effect factors. AB - The scientific consensus model USEtox(r) is recommended by the European Commission as the reference model to characterize life cycle chemical emissions in terms of their potential human toxicity and freshwater aquatic ecotoxicity impacts in the context of the International Reference Life Cycle Data System Handbook and the Environmental Footprint pilot phase looking at products (PEF) and organizations (OEF). Consequently, this model has been systematically used within the PEF/OEF pilot phase by 25 European Union industry sectors, which manufacture a wide variety of consumer products. This testing phase has raised some questions regarding the derivation of and the data used for the chemical specific freshwater ecotoxicity effect factor in USEtox. For calculating the potential freshwater aquatic ecotoxicity impacts, USEtox bases the effect factor on the chronic hazard concentration (HC50) value for a chemical calculated as the arithmetic mean of all logarithmized geometric means of species-specific chronic median lethal (or effect) concentrations (L[E]C50). We investigated the dependency of the USEtox effect factor on the selection of ecotoxicological data source and toxicological endpoints, and we found that both influence the ecotoxicity ranking of chemicals and may hence influence the conclusions of a PEF/OEF study. We furthermore compared the average measure (HC50) with other types of ecotoxicity effect indicators, such as the lowest species EC50 or no observable-effect concentration, frequently used in regulatory risk assessment, and demonstrated how they may also influence the ecotoxicity ranking of chemicals. We acknowledge that these indicators represent different aspects of a chemical's ecotoxicity potential and discuss their pros and cons for a comparative chemical assessment as performed in life cycle assessment and in particular within the PEF/OEF context. Environ Toxicol Chem 2017;36:3450-3462. (c) 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28618057 TI - The Role of Serum High Mobility Group Box 1 and Interleukin-6 Levels in Acute Pancreatitis: A Meta-Analysis. AB - The purpose of this meta-analysis was to comprehensively investigate the correlation between high mobility group box 1 (HMGB1) and interleukin-6 (IL-6) in relation to acute pancreatitis. A highly regulated exploration of various electronic databases, supplemented by manual searching methods, was performed in an attempt to identify pertinent articles of a useful nature. Subsequently, high quality cohort studies that were deemed to comply with the arduous inclusion and exclusion criteria were selected for our meta-analysis. The extensive data analyses reported in our meta-analysis were conducted in connection with the Comprehensive Meta-analysis 2.0 (CMA 2.0). A total of 395 studies (135 Chinese studies and 260 English studies) were initially retrieved. 27 of those studies were selected for our meta-analysis, comprising of 896 cases of mild acute pancreatitis (MAP), 700 cases of severe acute pancreatitis (SAP) as well as 312 healthy controls. Pooled data suggested that serum HMGB1 and IL-6 levels of SAP and MAP patients were higher than in healthy controls. Moreover, serum HMGB1 and IL-6 levels of SAP patients exhibited significantly higher levels than in that of MAP patients. Based on the rigorous investigation of our meta-analysis, it was concluded that serum HMGB1 and IL-6 levels might be used as effective indicators for pancreatic lesions as well as the degree of inflammatory response, owing ultimately to the observations and data analyses, suggesting that serum HMGB1 and IL-6 levels share a close correlation with the severity of pancreatitis. J. Cell. Biochem. 119: 616-624, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28618058 TI - Detection of iron restriction in anaemic and non-anaemic patients: New diagnostic approaches. AB - OBJECTIVE: The aim of this study was to detect iron restriction in non-anaemic patients and iron-restricted erythropoiesis (IRE) in patients with anaemia. METHOD: Haematologic indices and biochemical markers of iron deficiency (ID) were determined using the clinically accepted cut-off level for serum ferritin of <=30 MUg/L as reference of ID. To evaluate the prevalence of iron restriction and IRE in patients with higher ferritin levels, we used the thresholds of the markers of ID as reference. RESULTS: In the anaemic group, 17.1% of patients with ferritin levels >30 MUg/L had IRE. The number of patients with IRE declined with increasing ferritin concentration. Approximately 14% of patients without anaemia and ferritin levels >30 MUg/L had iron restriction because of iron-sequestration syndromes. About 30% of the anaemic patients with IRE had ferritin concentrations in the range >300 MUg/L, but no patient of the non-anaemic group. CONCLUSIONS: Detection of iron restriction and IRE in patients with ferritin levels >30 MUg/L is not possible with a single test used in isolation. Based on the results, we have developed a scoring system to provide optimal guidance for the evaluation of iron restriction in non-anaemic patients and iron-restricted erythropoiesis (IRE) in patients with anaemia. PMID- 28618059 TI - Cells from subcutaneous tissues contribute to scarless skin regeneration in Xenopus laevis froglets. AB - BACKGROUND: Mammals cannot regenerate the dermis and other skin structures after an injury and instead form a scar. However, a Xenopus laevis froglet can regenerate scarless skin, including the dermis and secretion glands, on the limbs and trunk after skin excision. Subcutaneous tissues in the limbs and trunk consist mostly of muscles. Although subcutaneous tissues beneath a skin injury appear disorganized, the cellular contribution of these underlying tissues to skin regeneration remains unclear. RESULTS: We crossed the inbred J strain with a green fluorescent protein (GFP)-labeled transgenic Xenopus line to obtain chimeric froglets that have GFP-negative skin and GFP-labeled subcutaneous tissues and are not affected by immune rejection after metamorphosis. We found that GFP-positive cells from subcutaneous tissues contributed to regenerating the skin, especially the dermis, after an excision injury. We also showed that the skin on the head, which is over bone rather than muscle, can also completely regenerate skin structures. CONCLUSIONS: Cells derived from subcutaneous tissues, at least in the trunk region, contribute to and may be essential for skin regeneration. Characterizing the subcutaneous tissue-derived cells that contribute to skin regeneration in amphibians may lead to the induction of cells that can regenerate complete skin structures without scarring in mammals. Developmental Dynamics 246:585-597, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28618060 TI - Clinical validation of the nursing diagnosis of ineffective protection in haemodialysis patients. AB - AIMS AND OBJECTIVES: To evaluate the clinical validity of indicators of the nursing diagnosis of "ineffective protection" in haemodialysis patients. BACKGROUND: Haemodialysis patients have reduced protection. Studies on the nursing diagnosis of "ineffective protection" are scarce in the literature. The use of indicators to diagnose "ineffective protection" could improve the care of haemodialysis patients. The clinical usefulness of the indicators requires clinical validation. DESIGN: This was a diagnostic accuracy study. METHOD: This study assessed a sample of 200 patients undergoing haemodialysis in a reference clinic for nephrology during the first half of 2015. Operational definitions were created for each clinical indicator based on concept analysis and content validation by experts for these indicators. Diagnostic accuracy measurement was performed with latent class analysis with randomised effects. RESULTS: The clinical indicator of "fatigue" had high sensitivity (p = .999) and specificity (p = 1.000) for the identification of "ineffective protection." Additionally, "maladaptive response to stress" (p = .711) and "coagulation change" (p = .653) were sensitive indicators. The main indicators that showed high specificity were "fever" (p = .987), "increased number of hospitalisations" (p = .911), "weakness" (p = .937), "infected vascular access" (p = .962) and "vascular access dysfunction" (p = .722). CONCLUSION: A set of nine clinical indicators of "ineffective protection" were accurate and statistically significant for haemodialysis patients. Three clinical indicators showed sensitivity, and six indicators showed specificity. RELEVANCE TO CLINICAL PRACTICE: Accurate measures for nursing diagnoses can help nurses confirm or rule out the probability of the occurrence of "ineffective protection" in patients undergoing haemodialysis. PMID- 28618061 TI - Electrical storm in a patient with Duchenne muscular dystrophy cardiomyopathy triggered by abrupt beta-blocker interruption. AB - We present a case of a young man with Duchenne muscular dystrophy cardiomyopathy (DMDC) having an implantable cardioverter defibrillator for secondary prevention, who presented with electrical storm shortly after beta-blocker interruption. The patient was stabilized and remained free of ventricular arrhythmias soon after reinitiating b-adrenoreceptor antagonists. The present case highlights the importance of sympathetic blockage in patients with DMDC due to existing pathophysiology of excess diastolic Ca2+ leak from sarcoplasmic reticulum as a result of ryanodine receptor dysfunction. PMID- 28618062 TI - Examining maintenance care following infliximab salvage therapy for acute severe ulcerative colitis. AB - BACKGROUND AND AIM: Data supporting the optimal maintenance drug therapy and strategy to monitor ongoing response following successful infliximab (IFX) induction, for acute severe ulcerative colitis (ASUC), are limited. We aimed to evaluate maintenance and monitoring strategies employed in patients post-IFX induction therapy. METHODS: Patients in six Australian tertiary centers treated with IFX for steroid-refractory ASUC between April 2014 and May 2015 were identified via hospital IBD and pharmacy databases. Patients were followed up for 1 year with clinical data over 12 months recorded. Analysis was limited to patient outcomes beyond 3 months. RESULTS: Forty one patients were identified. Five of the 41 (12%) patients underwent colectomy within 3 months, and one patient was lost to follow-up. Six of 35 (17%) of the remaining patients progressed to colectomy by 12 months. Maintenance therapy: Patients maintained on thiopurine monotherapy (14/35) versus IFX/thiopurine therapy (15/35) were followed up. Two of 15 (13%) patients who received combination maintenance therapy underwent a colectomy at 12 months, compared with 1/14 (7%) patients receiving thiopurine monotherapy (P = 0.610). Monitoring during maintenance: Post discharge, thiopurine metabolites were monitored in 15/27 (56%); fecal calprotectin in 11/32 (34%); and serum IFX levels in 4/20 (20%). Twenty of 32 (63%) patients had an endoscopic evaluation after IFX salvage with median time to first endoscopy of 109 days (interquartile range 113-230). CONCLUSION: Following IFX induction therapy for ASUC, the uptake of maintenance therapy in this cohort and strategies to monitor ongoing response were variable. These data suggest that the optimal maintenance and monitoring strategy post-IFX salvage therapy remains to be defined. PMID- 28618063 TI - Papillary thyroid carcinoma expressing CD20. AB - We identified a case of lymphadenopathy of metastatic papillary thyroid carcinoma (PTC) with CD20 expression, which was also expressed by the primary tumor. CD20 expression was identified using immunohistochemistry (IHC) in metastatic PTC biopsy samples from a 58-year-old woman. CD20 expression was initially determined using a CD20-recognizing L26 clone. To validate this phenomenon, we performed IHC with another antibody that recognizes the N-terminus of CD20 and fluorescent double staining using anti-TTF-1 and anti-CD20 antibodies. Taken together, we concluded metastatic PTC expressed CD20. We also examined 21 additional PTC cases and found four more cases that were CD20 positive. Therefore, five of the 22 (23%) cases were positive for CD20. In the positive cases, four cases were classical papillary thyroid carcinoma and one case was a follicular variant of papillary thyroid carcinoma. CD20 is an important target for molecularly targeted therapy for a subset of B-cell lymphomas. Complement-dependent and antibody dependent cellular cytotoxicities are important effector mechanisms of anti-CD20 therapy. Here, for the first time, we report PTC with expression of CD20. Our findings provide a rationale for treating CD20-positive PTC patients with anti CD20 therapy. PMID- 28618064 TI - Technetium-99m radiochemistry for pharmaceutical applications. AB - Technetium-99m (99m Tc) is a widely used radionuclide, and the development of 99m Tc imaging agents continues to be in demand. This overview discusses basic principles of 99m Tc radiopharmaceutical preparation and design and focuses on the 99m Tc radiochemistry relevant to its pharmaceutical applications. The 99m Tc complexes are described based on the most typical examples in each category, keeping up with the state-of-the-art in the field. In addition, the main current strategies to develop targeted 99m Tc radiopharmaceuticals are summarized. PMID- 28618065 TI - Cold interferes with male meiotic cytokinesis in Arabidopsis thaliana independently of the AHK2/3-AHP2/3/5 cytokinin signaling module. AB - Previously we have shown that low temperature stress in Arabidopsis causes defects in microtubule organization and cytokinesis in male meiocytes, which leads to the formation of diploid pollen. Because cytokinin (CK) mediates multiple physiological responses to cold stress, we investigated whether CK signaling is involved in cold-induced diploid pollen formation. To this end, we monitored male sporogenesis in a series of mutants defective in CK metabolism and signalling. Arabidopsis plants with altered CK homeostasis, that is, the ahk2-2 ahk3-3 double and the ahp2-1 ahp3 ahp5-2 triple mutant, were cold sensitive and displayed similar defective male meiotic cytokinesis as wild type plants upon cold stress. These findings demonstrate that the AHK2/3-AHP2/3/5 CK-signaling module is not required for cold-induced ploidy stability of male gamete in Arabidopsis. Cytological analysis further revealed that the cold-induced cytokinesis defects in the ahk2-2 ahk3-3 mutant correlated with irregular organization of the radial microtubule array (RMA) in tetrad microspores at the end of male meiosis. Contrary to the ahk and ahp mutants, Arabidopsis plants defective for ARR1, a downstream target of ahk and ahp mediated CK signalling, displayed higher cold-tolerance of male meiotic cytokinesis program. We here suggest that the transcription regulator ARR1 may act independently from the CK AHK2/3-AHP2/3/5 signaling module in conveying the cold response to male meiocytes. PMID- 28618066 TI - Assessment of ferritin content in multiple sclerosis brains using temperature induced R*2 changes. AB - PURPOSE: Current MRI techniques cannot reliably assess iron content in white matter due to the confounding diamagnetic effect of myelin. The purpose of this study was to validate with histology a novel iron mapping technique that uses the temperature dependency of the paramagnetic susceptibility in multiple sclerosis (MS) brains, where white matter has been reported to show significant variations in iron content. METHODS: We investigated post mortem brain tissue from three MS patients and one control subject. Temperature-dependent R2* relaxometry was performed between 4 degrees C and 37 degrees C. The resulting temperature coefficient ( TcR2*) maps were compared with immunohistochemical stains for ferritin light chain. RESULTS: Good agreement between TcR2* maps and ferritin staining was found by way of visual comparison and quantitative analysis. The highest iron concentrations were detected at the edge of MS lesions and in the basal ganglia. For all regions, except the subcortical U-fibers, there was a significant negative correlation between the TcR2* values and the ferritin count. CONCLUSION: This study provides further evidence that TcR2* may be a reliable measure of white matter iron content due to the elimination of myelin-induced susceptibility changes and is well suited for further research into neurological diseases with distortions of the iron homeostasis. Magn Reson Med 79:1609-1615, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28618067 TI - Prospects for stakeholder coordination by protected-area managers in Europe. AB - Growing resource demands by humans, invasive species, natural hazards, and a changing climate have created broad-scale impacts and the need for broader-extent conservation activities that span ownerships and even political borders. Implementing regional-scale conservation brings great challenges, and learning how to overcome these challenges is essential for maintaining biodiversity (i.e., richness and evenness of biological communities) and ecosystem functions and services across scales and borders in the face of system change. We administered an online survey to examine factors potentially driving perspectives of protected area (PA) managers regarding coordination with neighboring PAs and other stakeholders (i.e., stakeholder coordination) for conserving biodiversity and ecosystem services during the next decade within diverse regions across Europe. Although >70% (n = 58) of responding PA managers indicated that climate change and invasive species are relevant for their PAs, they gave <50% probability that these threats could be mitigated through stakeholder coordination. They thought there was a >60% probability (n = 85) that stakeholder coordination would take place with the aim to improve conservation outcomes. Consistent with the foundation on which many European PAs were established, managers viewed maintaining or enhancing biodiversity as the most important (>70%; n = 61) expected benefit. Other benefits included maintaining or enhancing human resources and environmental education (range of Bayesian credibility intervals [CIs] 57-93%). They thought the main barriers to stakeholder coordination were the lack of human and economic resources (CI 59-67% chance of hindering; n = 64) followed by communication and interstakeholder differences in political structures and laws (CI 51-64% probability of hindering). European policies and strategies that address these hindering factors could be particularly effective means of enabling implementation of green infrastructure networks in which PAs are the nodes. PMID- 28618068 TI - Molecular cloning and analysis of a C-type lectin from silkworm Bombyx mori. AB - C-type lectins (CTLs) play a variety of roles in plants and animals. They are involved in animal development, pathogen recognition, and the activation of immune responses. CTLs carry one or more non-catalytic carbohydrate-recognition domains (CRDs) to bind specific carbohydrates reversibly. Here, we report the molecular cloning and functional analysis of a single-CRD CTL, named C-type lectin-S2 (BmCTL-S2) from the domesticated silkmoth Bombyx mori (Lepidoptera: Bombycidae). The ORF of CTL-S2 is 666 bp, which encodes a putative protein of 221 amino acids. BmCTL-S2 is expressed in a variety of immune-related tissues, including hemocytes and fat body among others. BmCTL-S2 mRNA level in the midgut and the fat body was significantly increased by bacterial challenges. The recombinant protein (rBmCTL-S2) bound different bacterial cell wall components and bacterial cells. rBmCTL-S2 also inhibited the growth of Bacillus subtilis and Staphylococcus aureus. Taken together, we infer that BmCTL-S2 is a pattern recognition receptor with antibacterial activities. PMID- 28618069 TI - Optimization of acoustic radiation force imaging: Influence of timing parameters on sensitivity. AB - PURPOSE: Optimization of timing parameters for MR-guided ARFI to achieve the highest displacement signal-to-noise ratio (SNRd ). THEORY AND METHODS: In MR guided ARFI the phase change induced by motion encoding gradients (MEGs) is measured to assess tissue displacement. The sensitivity of this encoding procedure depends on several timing parameters, such as the MEG duration and the offset time between ultrasound (US) and MEG. Furthermore, mechanical and MR tissue constants and MEG schemes (bipolar or three-lobed) influence SNRd . Optimal timing parameters were determined in simulations for bipolar and three lobed MEGs, and the results were compared with measurements. To provide clinically usable timing parameters, physiologically relevant ranges of tissue constants were considered. RESULTS: For the considered ranges of tissue constants, optimal timing parameters provide only 6% higher SNRd for bipolar than for three-lobed MEG. Three-lobed MEG is less sensitive to motion as confirmed in phantom experiments. Bipolar MEG can use approximately 1.5-fold shorter MEG durations. CONCLUSION: Both bipolar and three-lobed MEGs can yield approximately the same SNRd if the optimal timing parameters are chosen. Bipolar MEG allows for shorter durations, which is preferable if deposition of US energy needs to be minimized, and three-lobed MEG is more suitable when residual motion compensation is necessary. Magn Reson Med 79:981-986, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28618070 TI - Morin Suppresses Astrocyte Activation and Regulates Cytokine Release in Bone Cancer Pain Rat Models. AB - As inflammatory and immune responses are involved in pathophysiology of debilitating neuropathic pain, reagents that can modulate these two responses may have therapeutic potential. Morin, derived from the moraceae family of plants, benefits inflammation-related diseases, but its antinociceptive effects on cancer pain remain elusive. In the present study, we investigated antinociceptive effects of morin on bone cancer pain using a rat model, where rats were subject to implantation of Walker 256 mammary gland carcinoma cells into the tibia. Morin (5-20 mg/kg) dose-dependently attenuated behavioral hypersensitivities, including mechanical allodynia and free movement pain, which was accompanied by downregulation of astrocyte marker glial fibrillary acidic protein in the spinal cord in cancer-bearing rats. Treatment with morin also induced reduction of pro inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 and upregulation of an antiinflammatory cytokine IL-10. Furthermore, intrathecal injection of AM630 (an antagonist of cannabinoid receptor 2, CB2 ), but not naloxone (an antagonist of opioid receptors), significantly blocked morin attenuation of behavioral hypersensitivities. Taken together, these results suggest that morin suppresses astrocyte activation and neuro-inflammation induced by bone cancer pain and its antinociceptive effects on bone cancer pain may be associated with activation of CB2 receptors in the spinal cord. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28618071 TI - Histamine receptor 2 modifies iNKT cell activity within the inflamed lung. AB - BACKGROUND: Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H2 R). The aim of this study was to determine the role of H2 R in modulating lung inflammatory responses. METHODS: H2 R was blocked using famotidine or activated using dimaprit in both the ovalbumin (OVA) and house dust mite extract (HDM) murine models of respiratory inflammation. H2 R-deficient animals and CD1d/H2 R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (alphaGalCer or OCH) to invariant natural killer T (iNKT) cells. RESULTS: Famotidine treatment resulted in more severe airway disease in the OVA model, while dimaprit treatment significantly reduced disease severity. Both OVA and HDM-induced airway diseases were more severe in H2 R-deficient animals. Flow cytometric analysis of lung tissue from H2 R-deficient animals revealed increased numbers of CD1d+ dendritic cells and increased numbers of iNKT cells. In vitro, alphaGalCer-stimulated iNKT cells from H2 R-deficient mice secreted higher levels of IL-4, IL-5, and GM-CSF. In vivo, alphaGalCer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment, and cytokine production in H2 R deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to alphaGalCer. Removal of iNKT cells in H2 R-deficient (CD1d-/- H2 R-/- ) animals normalized the lung response to HDM. CONCLUSION: The deliberate activation of H2 R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d mediated presentation of lipid antigens to iNKT cells is contributing to the pathology. PMID- 28618072 TI - To break the weight gain-A qualitative study on the experience of school nurses working with overweight children in elementary school. AB - AIMS AND OBJECTIVES: To describe the experiences of school nurses working with overweight schoolchildren. BACKGROUND: School nurses play an important role in health promotion of overweight children. Lifestyle changes and interventions to address being overweight can improve health outcomes and decrease the risk for future health problems. DESIGN: A descriptive and qualitative design with a phenomenological approach was used. Data were gathered through interviews with school nurses working with overweight schoolchildren in Swedish elementary school; the data were subsequently analysed for meanings. RESULTS: Working with overweight children was perceived as demanding and challenging by the school nurses who found conversations on this topic emotionally loaded and complex. In addition, the school nurses needed to be sensitive and supportive to succeed in their support for a healthier everyday life for the schoolchildren. It was stated as important to find ways to break the child's weight gain and to cooperate with the parents in this work. The children's decrease in weight was experienced to be more successful when making small, step-by-step changes together with the child and his or her parents. CONCLUSIONS: This study concludes that health talks about being overweight may be a challenge for school nurses. Strategies used to manage and succeed in this work included engaging in motivational conversations, working step by step and cooperating with the child's parents. Furthermore, the nurses experienced that they needed to provide emotional support for overweight children during school time. RELEVANCE TO CLINICAL PRACTICE: The school nurses' health promotion needs to focus on how to break weight gain in overweight children. In this work, the nurses' sensitiveness seems pivotal. Further research is needed on school nurses' work with health promotion and support of overweight children concerning how to perform efficient communication and cooperation with the children and their parents. PMID- 28618073 TI - Drug discovery for remyelination and treatment of MS. AB - Glia constitute the majority of the cells in our nervous system, yet there are currently no drugs that target glia for the treatment of disease. Given ongoing discoveries of the many roles of glia in numerous diseases of the nervous system, this is likely to change in years to come. Here we focus on the possibility that targeting the oligodendrocyte lineage to promote regeneration of myelin (remyelination) represents a therapeutic strategy for the treatment of the demyelinating disease multiple sclerosis, MS. We discuss how hypothesis driven studies have identified multiple targets and pathways that can be manipulated to promote remyelination in vivo, and how this work has led to the first ever remyelination clinical trials. We also highlight how recent chemical discovery screens have identified a host of small molecule compounds that promote oligodendrocyte differentiation in vitro. Some of these compounds have also been shown to promote myelin regeneration in vivo, with one already being trialled in humans. Promoting oligodendrocyte differentiation and remyelination represents just one potential strategy for the treatment of MS. The pathology of MS is complex, and its complete amelioration may require targeting multiple biological processes in parallel. Therefore, we present an overview of new technologies and models for phenotypic analyses and screening that can be exploited to study complex cell-cell interactions in in vitro and in vivo systems. Such technological platforms will provide insight into fundamental mechanisms and increase capacities for drug-discovery of relevance to glia and currently intractable disorders of the CNS. PMID- 28618074 TI - BCRP mRNA and FLT3-ITD are independent poor risk factors in adult patients with acute myeloid leukemia and intermediate or normal karyotype. AB - PURPOSE: FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is aberration associated with poor prognosis in AML. We have analyzed the expression of MDR-1, MRP-1, and BCRP mRNA in relation to FLT3-ITD in 100 AML adult patients with normal and intermediate karyotype. METHODS: The RQ-PCR method was performed to assess the expression of MDR-1, MRP-1, and BCRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule. RESULTS: According to univariate analysis, the following pretreatment variables negatively influenced disease-free survival (DFS): WBC count >=25*109 /L (P=.037), MRP-1 mRNA >=1.6818 (P=.028), BCRP mRNA >=1.1892 (P=.004), FLT3-ITD (P=.005) and overall survival (OS): WBC count >=25*109 /L (P=.031), MRP-1 mRNA >=1.6818 (P=.01), BCRP mRNA >=1.1892 (P=.01), FLT3-ITD (P=.001). When all prognostic variables were pooled into a multivariate model, we found that WBC count >=25*109 /L (P=.026) and BCRP mRNA >=1.1892 (P=.011). We observed trend in negative influence of FLT3-ITD on DFS (P=.057). BCRP mRNA >=1.1892 (P=.035) and FLT3-ITD (P=.006) negatively, independently influenced the OS. CONCLUSIONS: The high expressions of BCRP mRNA calculated with Pfaffl's rule and FLT3-ITD are independent poor risk factors in adult patients with AML and intermediate or normal karyotype. PMID- 28618075 TI - Surgical treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus. AB - The Barcelona Clinic Liver Cancer staging system recommends a tyrosine kinase inhibitor (sorafenib) as standard therapy in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). Sorafenib has been shown to prolong median overall survival (OS) by approximately 3 months in advanced HCC patients with PVTT (8.1 vs. 4.9 months). However, its clinical effectiveness is still controversial and standard treatment with sorafenib is not established in Japan. Surgical resection is considered a potentially curative treatment and provides an acceptable outcome for carefully selected patients. The surgical mortality rate in patients with PVTT who receive surgical resection ranges from 0% to 10%. The median survival time and 1-year OS rate in HCC patients with PVTT who undergo surgical resection have been found to range from 8 to 22 months and 21.7% to 69.6%, respectively. But improvement in therapeutic outcome is difficult with surgical treatment alone. Combination treatment in conjunction with such methods as transarterial chemoembolization, hepatic artery infusion chemotherapy, and radiotherapy has been found to improve the prognosis (median survival time, 11.5-37 months; 1-year OS rate, 46.8-100%). Yet, many problems remain, such as surgical indications and surgical techniques. After resolving these points, a multidisciplinary strategy based on surgical treatment should be established for advanced HCC with PVTT. PMID- 28618076 TI - Priorities for methodological research on patient and public involvement in clinical trials: A modified Delphi process. AB - BACKGROUND: Despite increasing international interest, there is a lack of evidence about the most efficient, effective and acceptable ways to implement patient and public involvement (PPI) in clinical trials. OBJECTIVE: To identify the priorities of UK PPI stakeholders for methodological research to help resolve uncertainties about PPI in clinical trials. DESIGN: A modified Delphi process including a two round online survey and a stakeholder consensus meeting. PARTICIPANTS: In total, 237 people registered of whom 219 (92%) completed the first round. One hundred and eighty-seven of 219 (85%) completed the second; 25 stakeholders attended the consensus meeting. RESULTS: Round 1 of the survey comprised 36 topics; 42 topics were considered in round 2 and at the consensus meeting. Approximately 96% of meeting participants rated the top three topics as equally important. These were as follows: developing strong and productive working relationships between researchers and PPI contributors; exploring PPI practices in selecting trial outcomes of importance to patients; and a systematic review of PPI activity to improve the accessibility and usefulness of trial information (eg participant information sheets) for participants. CONCLUSIONS: The prioritized methodological research topics indicate important areas of uncertainty about PPI in trials. Addressing these uncertainties will be critical to enhancing PPI. Our findings should be used in the planning and funding of PPI in clinical trials to help focus research efforts and minimize waste. PMID- 28618077 TI - Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. AB - Evidence suggests many neurological disorders emerge when normal neurodevelopmental trajectories are disrupted, i.e., when circuits or cells do not reach their fully mature state. Microglia play a critical role in normal neurodevelopment and are hypothesized to contribute to brain disease. We used whole transcriptome profiling with Next Generation sequencing of purified developing microglia to identify a microglial developmental gene expression program involving thousands of genes whose expression levels change monotonically (up or down) across development. Importantly, the gene expression program was delayed in males relative to females and exposure of adult male mice to LPS, a potent immune activator, accelerated microglial development in males. Next, a microglial developmental index (MDI) generated from gene expression patterns obtained from purified mouse microglia, was applied to human brain transcriptome datasets to test the hypothesis that variability in microglial development is associated with human diseases such as Alzheimer's and autism where microglia have been suggested to play a role. MDI was significantly increased in both Alzheimer's Disease and in autism, suggesting that accelerated microglial development may contribute to neuropathology. In conclusion, we identified a microglia-specific gene expression program in mice that was used to create a microglia developmental index, which was applied to human datasets containing heterogeneous cell types to reveal differences between healthy and diseased brain samples, and between males and females. This powerful tool has wide ranging applicability to examine microglial development within the context of disease and in response to other variables such as stress and pharmacological treatments. PMID- 28618079 TI - Protected areas as social-ecological systems: perspectives from resilience and social-ecological systems theory. AB - Conservation biology and applied ecology increasingly recognize that natural resource management is both an outcome and a driver of social, economic, and ecological dynamics. Protected areas offer a fundamental approach to conserving ecosystems, but they are also social-ecological systems whose ecological management and sustainability are heavily influenced by people. This editorial, and the papers in the invited feature that it introduces, discuss three emerging themes in social-ecological systems approaches to understanding protected areas: (1) the resilience and sustainability of protected areas, including analyses of their internal dynamics, their effectiveness, and the resilience of the landscapes within which they occur; (2) the relevance of spatial context and scale for protected areas, including such factors as geographic connectivity, context, exchanges between protected areas and their surrounding landscapes, and scale dependency in the provision of ecosystem services; and (3) efforts to reframe what protected areas are and how they both define and are defined by the relationships of people and nature. These emerging themes have the potential to transform management and policy approaches for protected areas and have important implications for conservation, in both theory and practice. PMID- 28618080 TI - Electrocatalytic Mechanism Involving Michaelis-Menten Kinetics at the Preparative Scale: Theory and Applicability to Photocurrents from a Photosynthetic Algae Suspension With Quinones. AB - In the past years, many strategies have been implemented to benefit from oxygenic photosynthesis to harvest photosynthetic electrons and produce a significant photocurrent. Therefore, electrochemical tools were considered and have globally relied on the electron transfer(s) between the photosynthetic chain and a collecting electrode. In this context, we recently reported the implementation of an electrochemical set-up at the preparative scale to produce photocurrents from a Chlamydomonas reinhardtii algae suspension with an appropriate mediator (2,6 DCBQ) and a carbon gauze as the working electrode. In the present work, we wish to describe a mathematical modeling of the recorded photocurrents to better understand the effects of the experimental conditions on the photosynthetic extraction of electrons. In that way, we established a general model of an electrocatalytic mechanism at the preparative scale (that is, assuming a homogenous bulk solution at any time and a constant diffusion layer, both assumptions being valid under forced convection) in which the chemical step involves a Michaelis-Menten-like behaviour. Dependences of transient and steady state corresponding currents were analysed as a function of different parameters by means of zone diagrams. This model was tested to our experimental data related to photosynthesis. The corresponding results suggest that competitive pathways beyond photosynthetic harvesting alone should be taken into account. PMID- 28618078 TI - The perceptions of key stakeholders of the roles of specialist and advanced nursing and midwifery practitioners. AB - AIM: To explore the perceptions of key stakeholders of the roles of specialist and advanced nursing and midwifery practitioners. BACKGROUND: There is evidence that the contribution of these roles to patient care is poorly understood. DESIGN: This research took place over 2 months in 2015 and is part of a larger study involving a rapid review to inform policy development on the specialist and advanced nursing and midwifery practice in Ireland. As an added value, a qualitative element involving thematic analysis was undertaken with key stakeholders. METHODS: A phenomenological qualitative study was conducted incorporating semi-structured interviews with key stakeholders (n = 15). Purposive sampling with maximum diversity was used to recruit a wide range of perspectives. FINDINGS: Participant's perspectives led to seven themes: Impact of these roles; role preparation, experience and organizational support; specialist and advanced practice roles in an interdisciplinary context; different folks but not such different roles; impact of specialist and advanced practice roles on patient outcomes; barriers and facilitators to enacting specialist and advanced practice roles; future development of these roles. CONCLUSION: There is acknowledgement of the positive impact of specialist and advanced practitioners; however, the evidence is currently not conclusive. Preparation for these roles needs to reflect changes in the calibre of today's professional applicants, and organizational support is paramount to their successful execution. The contribution of their activity to patient outcome needs to be made visible to enhance these roles and to justify the development of new roles across a variety of healthcare areas. PMID- 28618082 TI - Slow Magnetic Relaxation in a Mononuclear Ruthenium(III) Complex. AB - The development of magnetic molecules with long spin reversal/decoherence times highly depends on the understanding of relaxation behavior under different external conditions. Herein, a magnetic study on a RuIII complex (1) is presented. Detailed analysis of the relaxation time and the magneto-heat capacity data suggests that the resonant phonon trapping process dominates the magnetic relaxation in the crystalline sample of 1, slowing down the spin relaxation rate, as further confirmed by the measurements on a ground sample and frozen solution. Thus, it provides a rare example showing that 4d metal-centered mononuclear compounds without second-order anisotropy can display slow magnetic relaxation. PMID- 28618081 TI - Loss of the ssrA genome island led to partial debromination in the PBDE respiring Dehalococcoides mccartyi strain GY50. AB - Polybrominated diphenyl ethers (PBDEs), chemicals commonly used as flame retardants in consumer products, are emerging persistent organic pollutants that are ubiquitous in the environment. In this study, we report a PBDE-respiring isolate - Dehalococcoides mccartyi strain GY50, which debrominates the most toxic tetra- and penta-BDE congeners (~1.4 uM) to diphenyl ether within 12 days with hydrogen as the electron donor. The complete genome sequence revealed 26 reductive dehalogenase homologous genes (rdhAs), among which three genes (pbrA1, pbrA2 and pbrA3) were highly expressed during PBDE debromination. After 10 transfers of GY50 with trichloroethene or 2,4,6-trichlorophenol as the electron acceptor instead of PBDEs, the ssrA-specific genome island (ssrA-GI) containing pbrA1 and pbrA2 was deleted from the genome of strain GY50, leading to two variants (strain GY52 with trichloroethene, strain GY55 with 2,4,6 trichlorophenol) with identically impaired debromination capabilities (debromination of penta-/tetra-BDEs ceased at di-BDE 15). Through analysis of Illumina paired-end sequencing data, we identified read pairs that probably came from variants that contain ssrA-GI deletions, indicating their possible presence in the original strain GY50 culture. The two variant strains provide real-time examples on rapid evolution of organohalide-respiring organisms. As PBDE respiring organisms, GY50-like strains may serve as key players in detoxifying PBDEs in contaminated environments. PMID- 28618083 TI - Low-abundant species facilitates specific spatial organization that promotes multispecies biofilm formation. AB - Microorganisms frequently co-exist in matrix-embedded multispecies biofilms. Within biofilms, interspecies interactions influence the spatial organization of member species, which likely play an important role in shaping the development, structure and function of these communities. Here, a reproducible four-species biofilm, composed of Stenotrophomonas rhizophila, Xanthomonas retroflexus, Microbacterium oxydans and Paenibacillus amylolyticus, was established to study the importance of individual species spatial organization during multispecies biofilm development. We found that the growth of species that are poor biofilm formers, M. oxydans and P. amylolyticus, were highly enhanced when residing in the four-species biofilm. Interestingly, the presence of the low-abundant M. oxydans (0.5% of biomass volume) was observed to trigger changes in the composition of the four-species community. The other three species were crucially needed for the successful inclusion of M. oxydans in the four-species biofilm, where X. retroflexus was consistently positioned in the top layer of the mature four-species biofilm. These findings suggest that low abundance key species can significantly impact the spatial organization and hereby stabilize the function and composition of complex microbiomes. PMID- 28618084 TI - CCL20 promotes migration and invasiveness of human cancerous breast epithelial cells in primary culture. AB - The relation between the tumor and its microenvironment is one of the most interesting and less understood issues. Recently, we showed a role of CCL20 chemokine in proning the healthy tissue neighboring the tumor to carcinogenesis. Besides, tumor-secreted CCL20 induced proliferation, migration, and EMT of healthy cells. In this context, we have studied here if CCL20 had effects on the migration of cancer cells and the intracellular pathways used in breast epithelial cells in primary culture. Using molecular (siRNA) and pharmacological (inhibitors) techniques, we found multiple signaling kinases to be activated and involved in CCL20-induced tumor breast cell migration. CCL20 provoked a 2.5-fold increase of cell migration and invasion; CCL20 also enhanced MMP- 2 and MMP-9 mRNAs/protein expression and activities. Cell migration and invasiveness due to CCL20 significantly decreased when MMP-2 and MMP-9 were inhibited in CCL20 stimulated cells. CCL20 controlled MMP-2 expression through the JAK2/STAT3 pathway, while the expression of MMP-9 occurred by PKC-alpha that activated, consequently, c-Src, Akt, and finally NF-kB. These results reveal a role for CCL20 also in tumor breast cell and point to CCL20 as a novel therapeutic target in cancer. PMID- 28618085 TI - Improved localization, spectral quality, and repeatability with advanced MRS methodology in the clinical setting. AB - PURPOSE: To investigate the utility of an advanced magnetic resonance spectroscopy (MRS) protocol in the clinical setting, and to compare the localization accuracy, spectral quality, and quantification repeatability between this advanced and the conventional vendor-provided MRS protocol on a clinical 3T platform. METHODS: Proton spectra were measured from the posterior cingulate cortices in 30 healthy elderly subjects by clinical MR technologists using a vendor-provided (point resolved spectroscopy with advanced 3D gradient-echo B0 shimming) and an advanced (semi-LASER with FAST(EST)MAP shimming) protocol, in random order. Spectra were quantified with LCModel using standard pipelines for the clinical and research settings, respectively. RESULTS: The advanced protocol outperformed the vendor-provided protocol in localization accuracy (chemical shift-displacement error: 2.0%/ppm, semi-LASER versus 11.6%/ppm, point resolved spectroscopy), spectral quality (water linewidth: 6.1 +/- 1.8 Hz, FAST(EST)MAP versus 10.5 +/- 3.7 Hz, 3D gradient echo; P < 7e-6; residual water: 0.08 +/- 0.12%, VAPOR versus 0.45 +/- 0.50%, WET; P < 2e-5) and within-session repeatability of metabolite concentrations, particularly of low signal-to-noise ratio data with two to eight averages (test-retest coefficients of variance of metabolite concentrations, P < 0.01). Concentrations of J-coupled metabolites such as gamma-aminobutyric acid and glutamate were biased when using the default pipeline with simulated macromolecules. CONCLUSIONS: The quality of MRS data can be improved using advanced acquisition and analysis protocols on standard 3T hardware in the clinical setting, which can facilitate robust applications in central nervous system diseases. Magn Reson Med 79:1241-1250, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28618086 TI - Jordanian nurses' perception and interventions related to promoting smoking cessation. AB - AIMS AND OBJECTIVES: To determine nurses' perceptions related to smoking cessation, health promotion and interventions provided to hospitalised patients. BACKGROUND: Smoking is a major health problem in Jordan. The cost for treating smoking-related health conditions is a significant strain on the healthcare system. Nurses are in an ideal position to encourage smoking cessation. Little is known about Jordanian nurses' perceptions related to smoking cessation issues. METHODS: A qualitative design was used to collect data from 22 Jordanian nurses using focus groups. Purposive sampling was used to select the study participants. Content analysis was conducted, to determine themes related to the research questions. RESULTS: Nurses indicated that smoking cessation counselling is important. However, they did not feel that their counselling was very effective. Nurses indicated that the presence of a well-defined hospital policy regarding smoking was a facilitator to smoking cessation and antismoking clinics would also help to decrease smoking. Challenges to nurses' interventions included lack of hospital policy, lack of time and nurses who smoke could not be role models or provide effective counselling. Regarding decreasing smoking in Jordan, nurses had suggestions that included scare techniques and increasing taxes on cigarettes as well as enforcing policies that prevent cigarette sales to children under 16. CONCLUSIONS: Nurses are well aware of the hazards of smoking and indicate a belief that encouraging smoking cessation is an appropriate activity. Changes in smoking rules and the enforcement of rules, as well as increased public health efforts related to smoking cessation, are necessary to decrease smoking prevalence in Jordan. RELEVANCE TO CLINICAL PRACTICE: Training in smoking cessation counselling and increased awareness of the resources may increase nurses' ability to have an impact on decreasing the smoking prevalence in Jordan. PMID- 28618087 TI - Telephone nursing in Sweden: A narrative literature review. AB - Telephone nursing services are expanding globally. Swedish Healthcare Direct is the largest healthcare provider in Sweden. This paper provides a comprehensive understanding of telephone nursing, as reflected by research on Swedish national telephone nursing, and discusses the findings in relation to international literature. A descriptive, mixed-studies literature review was conducted. Twenty four articles from January 2003 to April 2015 were identified from PubMed, Scopus, and CINAHL, and included. The issues explored in this study are how telephone nursing is perceived by callers, telephone nurses, and managers, and what characterizes such calls. Callers value reassurance, support, respect and satisfaction and involvement in decisions can increase their adherence. The telephone nurses' perspective focused on problems and ethical dilemmas, communication, the decision support tool, and working tasks. The managers' perspective focused on nursing work goals and malpractice claims. Concerning call characteristics, authentic calls, incident reports, and threats to patient safety were considered. Telephone nursing seems safe, but gender can play a role in calls. Future research on caller access, equity, and efficiency, healthcare cost effectiveness, distribution, and patient safety is needed. PMID- 28618088 TI - A comparison of barriers to mental health support-seeking among farming and non farming adults in rural South Australia. AB - OBJECTIVE: To assess the differences between farming and non-farming rural adults in perceived barriers to mental health service use. DESIGN: A cross-sectional survey, modified from the Barriers to Help-Seeking Scale (BHSS), was conducted using a computer-assisted telephone interview. SETTING: Respondents (age 52.6 +/- 11.6 years) were recruited from three rural regions of South Australia. PARTICIPANTS: Approximately, 78 non-farmers and 45 farmers were included in analyses. 78 retired and two unemployed participants were excluded from the analyses. MAIN OUTCOME MEASURE: Farmers and non-farmers were compared on domain scores and individual item responses from the adapted BHSS that represent 'agrarian' attitudes to support-seeking for mental health: stoicism, self reliance, minimisation of the problem, stigma and distrust of health professionals. RESULTS: In the analysis of domain scores, 'Need for Control and Self-Reliance' was a stronger barrier for farmers than non-farmers (P = 0.009) with a trend (P = 0.07) towards stronger barriers among farmers in the 'Minimising Problem and Resignation' domain. In the analysis of item-level responses, there was a difference (P = 0.03) between farmers and non-farmers in responses to 'I find it difficult to understand my doctor/health professional', with 24.4% of the farmers agreeing that this is a barrier compared with 15.3% of the non-farmers. CONCLUSION: Long-held stereotypes of stoicism and self-reliance among farmers were somewhat supported, in the context of mental health. Mental health services and professionals in rural Australia might need to adapt their practices to successfully engage this population. PMID- 28618089 TI - CRH promotes human colon cancer cell proliferation via IL-6/JAK2/STAT3 signaling pathway and VEGF-induced tumor angiogenesis. AB - Corticotrophin-releasing hormone (CRH) has been demonstrated to participate in various diseases. Our previous study showed that its receptor CRHR1 mediated the development of colitis-associated cancer in mouse model. However, the detailed mechanisms remain unclear. In this study, we explored the oncogenetic role of CRH/CRHR1 signaling in colon cancer cells. Cell proliferation and colony formation assays revealed that CRH contributed to cell proliferation. Moreover, tube formation assay showed that CRH-treated colon cancer cell supernatant significantly promoted tube formation of human umbilical vein endothelial cells (HUVECs). And these effects could be reversed by the CRHR1 specific antagonist Antalarmin. Further investigation showed that CRH significantly upregulated the expressions of interlukin-6 (IL-6) and vascular endothelial growth factor (VEGF) through activating nuclear factor-kappa B (NF-kappaB). The CRH-induced IL-6 promoted phosphorylation of janus kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3). STAT3 inhibition by Stattic significantly inhibited the CRH-induced cell proliferation. In addition, silence of VEGF resulted in declined tube formation induced by CRH. Taken together, CRH/CRHR1 signaling promoted human colon cancer cell proliferation via NF-kappaB/IL 6/JAK2/STAT3 signaling pathway and tumor angiogenesis via NF-kappaB/VEGF signaling pathway. Our results provide evidence to support a critical role for the CRH/CRHR1 signaling in colon cancer progression and suggest its potential utility as a new therapeutic target for colon cancer. PMID- 28618091 TI - Bacterial transformation: ComFA is a DNA-dependent ATPase that forms complexes with ComFC and DprA. AB - Pneumococcal natural transformation contributes to genomic plasticity, antibiotic resistance development and vaccine escape. Streptococcus pneumoniae, like many other naturally transformable species, has evolved sophisticated protein machinery for the binding and uptake of DNA. Two proteins encoded by the comF operon, ComFA and ComFC, are involved in transformation but their exact molecular roles remain unknown. In this study, we provide experimental evidence that ComFA binds to single stranded DNA (ssDNA) and has ssDNA-dependent ATPase activity. We show that both ComFA and ComFC are essential for the transformation process in pneumococci. Moreover, we show that these proteins interact with each other and with other proteins involved in homologous recombination, such as DprA, thus placing the ComFA-ComFC duo at the interface between DNA uptake and DNA recombination during transformation. PMID- 28618090 TI - Road map for the clinical application of the basophil activation test in food allergy. AB - The diagnosis of IgE-mediated food allergy based solely on the clinical history and the documentation of specific IgE to whole allergen extract or single allergens is often ambiguous, requiring oral food challenges (OFCs), with the attendant risk and inconvenience to the patient, to confirm the diagnosis of food allergy. This is a considerable proportion of patients assessed in allergy clinics. The basophil activation test (BAT) has emerged as having superior specificity and comparable sensitivity to diagnose food allergy, when compared with skin prick test and specific IgE. BAT, therefore, may reduce the number of OFC required for accurate diagnosis, particularly positive OFC. BAT can also be used to monitor resolution of food allergy and the clinical response to immunomodulatory treatments. Given the practicalities involved in the performance of BAT, we propose that it can be applied for selected cases where the history, skin prick test and/or specific IgE are not definitive for the diagnosis of food allergy. In the cases that the BAT is positive, food allergy is sufficiently confirmed without OFC; in the cases that BAT is negative or the patient has non responder basophils, OFC may still be indicated. However, broad clinical application of BAT demands further standardization of the laboratory procedure and of the flow cytometry data analyses, as well as clinical validation of BAT as a diagnostic test for multiple target allergens and confirmation of its feasibility and cost-effectiveness in multiple settings. PMID- 28618092 TI - A platinized stainless steel fiber with in-situ coated polyaniline/polypyrrole/graphene oxide nanocomposite sorbent for headspace solid phase microextraction of aliphatic aldehydes in rice samples. AB - The surface of a stainless steel fiber was made larger, porous and cohesive by platinizing for tight attachment of its coating. Then it was coated by a polyaniline/polypyrrole/graphene oxide (PANI/PP/GO) nanocomposite film using electrochemical polymerization. The prepared PANI/PP/GO fiber was used for headspace solid-phase microextraction (HS-SPME) of linear aliphatic aldehydes in rice samples followed by GC-FID determination. To achieve the highest extraction efficiency, various experimental parameters including extraction time and temperature, matrix modifier and desorption condition were studied. The linear calibration curves were obtained over the range of 0.05-20 MUg g-1 (R2 > 0.99) for C4 -C11 aldehydes. The limits of detection were found to be in the range of 0.01-0.04 MUg g-1 . RSD values were calculated to be <7.4 and 10.7% for intra- and inter-day, respectively. The superiority of the prepared nanocomposite SPME fiber was established by comparison of its results with those obtained by polydimethylsiloxane, carbowax-divinylbenzene, divinylbenzene-carboxen polydimethylsiloxane and polyacrylate commercial ones. Finally, the nanocomposite fiber was used to extract and determine linear aliphatic aldehydes in 18 rice samples. PMID- 28618093 TI - Influence of gender, BMI and body shape on theoretical injection outcome at the ventrogluteal and dorsogluteal sites. AB - AIMS AND OBJECTIVES: This study aimed to determine the influences of gender, BMI and observed body shape on subcutaneous fat and muscle thicknesses, and theoretical injection outcome, at the ventrogluteal and dorsogluteal intramuscular injection sites. BACKGROUND: Debate continues as to whether the dorsogluteal or ventrogluteal injection site is more reliable for a successful intramuscular injection outcome. Subcutaneous fat and muscle thicknesses at the injection site are direct determinants of intramuscular injection outcome. BMI and observed body shape influence gluteal subcutaneous fat and muscle thicknesses, and therefore injection outcome, with potentially distinct effects at the ventrogluteal and dorsogluteal sites. DESIGN: This was a cross-sectional study. METHODS: Demographic data were collected, and subcutaneous fat and muscle thicknesses were quantified bilaterally at the dorsogluteal and ventrogluteal injection sites using ultrasound, for 145 participants (57% female). RESULTS: Subcutaneous fat and muscle were significantly thicker at the dorsogluteal than the ventrogluteal site, and 75% and 86% of participants would receive a successful intramuscular injection at these sites, respectively. There were significant effects of gender, BMI and observed body shape on subcutaneous fat thickness and theoretical injection outcome at both sites. Females, obese individuals and endomorph individuals had thicker subcutaneous fat and were more likely to have a subcutaneous injection outcome. CONCLUSIONS: Gender, BMI and observed body shape could be used to guide site and needle length selection when administering gluteal intramuscular injections to increase the likelihood of a successful intramuscular injection outcome. RELEVANCE TO CLINICAL PRACTICE: Both gluteal injection sites should be avoided in obese individuals and endomorph individuals. An intramuscular injection will be successful: using a 32-mm needle at the ventrogluteal site for all males and normal-weight females and using a 38 mm needle for all females at the ventrogluteal site, and for all males and at least 98% of females at the dorsogluteal site. PMID- 28618096 TI - Perioperative use of terlipressin in adult liver transplant. PMID- 28618095 TI - A qualitative formative evaluation of a patient-centred patient safety intervention delivered in collaboration with hospital volunteers. AB - BACKGROUND: Evidence suggests that patients can meaningfully feed back to healthcare providers about the safety of their care. The PRASE (Patient Reporting and Action for a Safe Environment) intervention provides a way to systematically collect feedback from patients to support service improvement. The intervention is being implemented in acute care settings with patient feedback collected by hospital volunteers for the first time. OBJECTIVE: To undertake a formative evaluation which explores the feasibility and acceptability of the PRASE intervention delivered in collaboration with hospital volunteers from the perspectives of key stakeholders. DESIGN: A qualitative evaluation design was adopted across two acute NHS trusts in the UK between July 2014 and November 2015. We conducted five focus groups with hospital volunteers (n=15), voluntary services and patient experience staff (n=3) and semi-structured interviews with ward staff (n=5). Data were interpreted using framework analysis. RESULTS: All stakeholders were positive about the PRASE intervention as a way to support service improvement, and the benefits of involving volunteers. Volunteers felt adequate training and support would be essential for retention. Staff concentrated on the infrastructure needed for implementation and raised concerns around sustainability. Findings were fed back to the implementation team to support revisions to the intervention moving into the subsequent summative evaluation phase. CONCLUSION: Although there are concerns regarding sustainability in practice, the PRASE intervention delivered in collaboration with hospital volunteers is a promising approach to collect patient feedback for service improvement. PMID- 28618097 TI - Accuracy of navigated cam resection in femoroacetabular impingement: A randomised controlled trial. AB - BACKGROUND: The main cause for revision hip arthroscopy surgery is incomplete bony resection of femoroacetabular impingement (FAI). This study aimed to compare the cam resection accuracy via the conventional hip arthroscopy technique with the navigation technique. METHODS: Two prospectively randomized groups were recruited: navigated (n = 15) and conventional (n = 14). A pre-operative CT and post-operative MRI scan were obtained in all cases to compare alpha angle, range of motion simulation and determine a pre-operative 3D surgical resection plan. RESULTS: Post-operatively, the mean maximal alpha angle improved significantly in the navigated group compared with the conventional group (55 degrees vs.66 degrees ; P = 0.023), especially in the 12 o' clock position (45 degrees vs.60 degrees ; P = 0.041). However, positioning time and radiation exposure were significantly longer in the navigated group. CONCLUSION: Navigated surgery is effective for patients with cam type FAI in helping restore normal anatomy, however, not without drawbacks. Larger studies will be required to validate our results. PMID- 28618098 TI - Relationship of prelabor fetal cardiac function with intrapartum fetal compromise and neonatal status at term. AB - OBJECTIVES: To investigate prospectively the relationship of fetal cardiac function and Doppler ultrasound parameters with intrapartum fetal compromise (IFC) in appropriately grown term fetuses. Secondary aims were to correlate prenatal cardiac function with neonatal acid-base status, intrapartum fetal heart rate (FHR) abnormalities and adverse neonatal outcomes. METHODS: This was a blinded, prospective, observational, cohort study of 270 women with an uncomplicated singleton pregnancy who underwent fortnightly ultrasound assessment from 36 weeks' gestation until delivery at the Mater Mother's Hospital, Brisbane, Australia. Fetal cardiac output and blood flow parameters were assessed and correlated with intrapartum and neonatal outcomes. The primary outcome was need for operative (either Cesarean or instrumental vaginal) delivery for IFC. Secondary outcome measures were acidosis at birth, 5-min Apgar score <= 7, suspicious or pathological FHR abnormalities and admission to the neonatal intensive care unit. RESULTS: Two hundred and seventy women were included in the analysis, of whom 51 (18.9%) had an emergency operative delivery for IFC. Fetuses that had emergency delivery for IFC showed lower mean left ventricular cardiac output (LVCO) (560 +/- 44 mL/min vs 617 +/- 73 mL/min; P < 0.001), lower mean LVCO/right ventricular cardiac output (RVCO) ratio (0.55 +/- 0.07 vs 0.64 +/- 0.11; P < 0.001), lower mean cerebroplacental ratio (CPR) (1.62 +/- 0.3 vs 1.90 +/- 0.5; P < 0.001) and higher mean RVCO (1026 +/- 105 mL/min vs 978 +/- 110 mL/min; P = 0.003) compared with those that did not develop IFC. Additionally, LVCO and CPR were lower in fetuses with adverse neonatal outcome. CONCLUSION: Term fetuses with estimated fetal weight > 10th centile that develop IFC have evidence of lower LVCO and higher RVCO, which are in turn associated with poorer condition of the newborn. Fetal CPR is positively correlated with LVCO. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28618100 TI - Characteristics of an effective nursing clinical instructor: The state of the science. AB - AIMS AND OBJECTIVES: To analyse the perceived characteristics of an effective nursing clinical instructor and methods for measure instructor effectiveness. This review also examined importance of characteristics based on student age. BACKGROUND: The clinical instructor has a vital role in clinical education. While the role may be well defined, the characteristics these instructors need to do their jobs effectively are not. DESIGN: An integrative review from 1985 to present using four key terms: nursing, clinical, teaching and effectiveness. This review revealed 37 articles that met the inclusion criteria for analysis. METHODS: Inclusion criteria included studies related to nursing clinical teaching effectiveness of the clinical instructor in a direct patient care setting. An integrative review table of the studies was made by the author. Keywords were analyzed in the results column, and same concepts were grouped together. RESULTS: A synthesis of current research revealed three dominant themes: competency, the ability to develop interpersonal relationships and certain personality traits. The analysis of the literature suggests the ability to develop interpersonal relationships is the most valued skill. Overall, approachability emerged as the most important personality trait needed to be an effective clinical instructor. The analysis also revealed a difference regarding the priority of characteristics based on age of the student. CONCLUSION: The analysis of the literature suggests the ability to develop interpersonal relationships is the most valued skill for clinical instructors. Overall, approachability emerged as the most important personality trait needed to be an effective clinical instructor. RELEVANCE TO CLINICAL PRACTICE: Future studies should continue to evaluate the extent of the dominant themes especially considering the rise of the millennial student generation. PMID- 28618101 TI - Understanding nurses' concerns when caring for patients from diverse cultural and ethnic backgrounds. AB - AIMS AND OBJECTIVES: To explore the experiences of both student and qualified nurses of caring for patients from diverse cultural, ethnic and linguistic backgrounds, in one region of Ireland. Hearing the stories, experiences and attitudes of nurses has the potential to influence future clinical practice and has implication for nurses, nurse educators and nurse managers and leaders. BACKGROUND: There is a wealth of international literature highlighting the importance of providing culturally sensitive care. However, global reports of culturally insensitive care continue. There is a paucity of in-depth research exploring the actual concerns and challenges nurses experience when caring for patients from diverse cultural and ethnic backgrounds, as well as what influences their actions and omissions of care in practice. DESIGN: A qualitative exploratory descriptive design adopting the principles of a classic grounded theory approach was used. METHODS: Focus groups (n - 10) and individual face-to face interviews (n - 30) were conducted with student and qualified nurses studying and working in one region of Ireland. As data were collected, it was simultaneously analysed using the classic grounded theory methodological principles of coding, constant comparison and theoretical sampling. FINDINGS: Uncertainty was the consistent main concern that emerged. Feelings of ambiguity of how to act were further influenced by a lack of knowledge, an awareness of ethnocentric beliefs and the culture of the organisation in which participants learn and work in. Instead of finding answers to uncertainties, participants demonstrated a lack of commitment to meeting patients' needs in a culturally appropriate way. CONCLUSIONS: This study adds new perspectives to our understanding of enablers and barriers to culturally sensitive care. It explains the poignant effect of uncertainty and describes how nurses were unable (or unwilling) to find answers when in doubt. It raises questions that remain unanswered in the existing literature, as to why nurses feel it is acceptable to choose to do nothing about their lack of cultural knowledge and the uncertainties which follow. RELEVANCE TO CLINICAL PRACTICE: Identifying the nature and implications of the uncertainty experienced when providing care for patients from diverse cultural and ethnic backgrounds is an important contributing factor to improving cultural sensitivity and quality care. PMID- 28618102 TI - Factors contributing to serious adverse events in nursing homes. AB - AIMS AND OBJECTIVES: To identify the most common serious adverse events that occurred in nursing homes and their most frequent contributing factors to the improvement of safe nursing care. BACKGROUND: There is a need to improve safe nursing care in nursing homes. Residents are often frail and vulnerable with extensive needs for nursing care. A relatively minor adverse event in nursing care can cause serious injury that could have been preventable. DESIGN: This was a retrospective study, with a total sample of data regarding adverse events (n = 173) in nursing homes, concerning nursing care reported by healthcare providers in Sweden to the Health and Social Care Inspectorate. The reports were analysed with content analysis, and the frequencies of the adverse events, and their contributing factors, were described with descriptive statistics. RESULTS: Medication errors, falls, delayed or inappropriate intervention and missed nursing care contributed to the vast majority (89%) of the serious adverse events. A total of 693 possible contributing factors were identified. The most common contributing factors were (i) lack of competence, (ii) incomplete or lack of documentation, (iii) teamwork failure and (iv) inadequate communication. CONCLUSIONS: The contributing factors frequently interacted yet they varied between different groups of serious adverse events. The resident's safety depends on the availability of staff's competence as well as adequate documentation about the resident's condition. Lack of competence was underestimated by healthcare providers. RELEVANCE TO CLINICAL PRACTICE: Registered nurses and assistant nurses need to have awareness of contributing factors to adverse events in nursing care. A holistic approach to improve patient safety in nursing homes requires competence of the staff, safe environments as well as resident's and relative's participation. PMID- 28618099 TI - EPEC effector EspF promotes Crumbs3 endocytosis and disrupts epithelial cell polarity. AB - Enteropathogenic Escherichia coli (EPEC) uses a type III secretion system to inject effector proteins into host intestinal epithelial cells causing diarrhoea. EPEC infection redistributes basolateral proteins beta1-integrin and Na+ /K+ ATPase to the apical membrane of host cells. The Crumbs (Crb) polarity complex (Crb3/Pals1/Patj) is essential for epithelial cell polarisation and tight junction (TJ) assembly. Here, we demonstrate that EPEC displaces Crb3 and Pals1 from the apical membrane to the cytoplasm of cultured intestinal epithelial cells and colonocytes of infected mice. In vitro studies show that EspF, but not Map, alters Crb3, whereas both effectors modulate Pals1. EspF perturbs polarity formation in cyst morphogenesis assays and induces endocytosis and apical redistribution of Na+ /K+ ATPase. EspF binds to sorting nexin 9 (SNX9) causing membrane remodelling in host cells. Infection with DeltaespF/pespFD3, a mutant strain that ablates EspF binding to SNX9, or inhibition of dynamin, attenuates Crb3 endocytosis caused by EPEC. In addition, infection with DeltaespF/pespFD3 has no impact on Na+ /K+ ATPase endocytosis. These data support the hypothesis that EPEC perturbs apical-basal polarity in an EspF-dependent manner, which would contribute to EPEC-associated diarrhoea by disruption of TJ and altering the crucial positioning of membrane transporters involved in the absorption of ions and solutes. PMID- 28618104 TI - Effect of two different polishing systems on fluoride release, surface roughness and bacterial adhesion of newly developed restorative materials. AB - OBJECTIVES: To evaluate the effects of two different polishing systems on fluoride release, surface roughness and bacterial adhesion of five restorative materials MATERIALS AND METHODS: The study groups were comprised of five different restorative materials, Beautifil II (B); GCP Glass Fill (G); Amalgomer CR (A); Dyract XP (D); Fuji IX GP (F) and 21 specimens were prepared from each material. Each group was divided into three subgroups according to the polishing system: Mylar (control) (C), Sof-lex (S), and Enhance-Pogo (EP). The amount of fluoride release was measured using a fluoride ion-selective electrode and surface roughness was investigated with a profilometer. Bacterial adhesion on the materials was evaluated by optical density readouts for S.mutans on a spectrophotometer. RESULTS: The highest amount of fluoride was released from specimens in the S subgroup of group G during all measurement days. Surface roughness values were significantly lower in subgroup C than the other polishing systems in all study groups except group G (P < .05). Group A displayed significantly higher surface roughness values than the other material groups in both subgroups (S and EP) (P < .01). Highest bacterial adhesion was observed in the EP subgroup of group A. CONCLUSIONS: Polishing promoted a significant increase of fluoride release on restorative materials especially in glass ionomer based materials. CLINICAL SIGNIFICANCE: This article stated that polishing promoted a significant increase of fluoride release on restorative materials especially in glass ionomer-based materials. Further, proper polishing systems must be chosen according to the structure and composition of materials to provide the best clinical benefits in terms of fluoride release, surface roughness and bacterial adhesion. PMID- 28618103 TI - Secretory pathway Ca2+ -ATPases promote in vitro microcalcifications in breast cancer cells. AB - Calcification of the breast is often an outward manifestation of underlying molecular changes that drive carcinogenesis. Up to 50% of all non-palpable breast tumors and 90% of ductal carcinoma in situ present with radiographically dense mineralization in mammographic scans. However, surprisingly little is known about the molecular pathways that lead to microcalcifications in the breast. Here, we report on a rapid and quantitative in vitro assay to monitor microcalcifications in breast cancer cell lines, including MCF7, MDA-MB-231, and Hs578T. We show that the Secretory Pathway Ca2+ -ATPases SPCA1 and SPCA2 are strongly induced under osteogenic conditions that elicit microcalcifications. SPCA gene expression is significantly elevated in breast cancer subtypes that are associated with microcalcifications. Ectopic expression of SPCA genes drives microcalcifications and is dependent on pumping activity. Conversely, knockdown of SPCA expression significantly attenuates formation of microcalcifications. We propose that high levels of SPCA pumps may initiate mineralization in the secretory pathway by elevating luminal Ca2+ . Our new findings offer mechanistic insight and functional implications on a widely observed, yet poorly understood radiographic signature of breast cancer. PMID- 28618105 TI - Factors influencing medication adherence in patients with gout: A descriptive correlational study. AB - AIMS AND OBJECTIVES: To examine the factors influencing adherence to urate lowering therapy in patients with gout in Singapore. BACKGROUND: Gout is the most common type of chronic inflammatory arthritis. Urate-lowering therapy is used to treat gout by reducing serum uric acid levels. However, adherence to urate lowering therapy among patients remains poor. To date, there have been no available studies based on a conceptual framework that examined factors influencing medication adherence in patients with gout. DESIGN: Cross-sectional, descriptive correlational study. METHODS: A convenience sample of outpatients (n = 108) was recruited between October 2014-January 2015 from a tertiary hospital in Singapore. Outcomes were measured by relevant valid and reliable instruments. Descriptive statistics and parametric tests including multiple linear regression were used to analyse the data. RESULTS: Although 44.4% of the participants were high adherers to urate-lowering therapy, the mean adherence level was moderate. Significant differences in medication adherence scores were found among the subgroups of gender, ethnicity, marital status, employment status and presence of comorbidity. Medication adherence was positively significantly correlated with age, number of comorbidities and beliefs about medicines. Linear regression showed that higher level of beliefs about medicines, presence of comorbidity and being married were factors positively influencing medication adherence. CONCLUSIONS: This study revealed moderate adherence to urate-lowering therapy in patients with gout in Singapore, indicating the need for strategies to improve adherence by considering its main influencing factors. Future research should be conducted to develop interventions targeted at modifying patients' beliefs about medicines in order to improve medication adherence. RELEVANCE TO CLINICAL PRACTICE: Findings from this study allow healthcare providers to quickly and easily identify patients who may have low adherence. Nurses should take the lead in educating patients on the mechanism of urate-lowering therapy and highlight the importance of adhering to it. PMID- 28618106 TI - Authors' response. PMID- 28618107 TI - Blood pressure and psychological distress among North Africans in France: The role of perceived personal/group discrimination and gender. AB - OBJECTIVES: The purpose of this study was to examine the associations between perceived ethnic discrimination and (physical and mental) health indicators among North African women and men living in France. METHODS: This study included 82 North Africans, aged 18-64 years. Perceived discrimination was measured at both group level (PGD) and personal level (PPD). The physical health indicator was blood pressure. The mental health indicator was self-reported psychological distress. RESULTS: Multiple regression analyses showed that higher levels of PGD predicted higher blood pressure. PPD was not related to blood pressure. PPD was positively related to psychological distress among women, but not among men. CONCLUSION: PPD and PGD are associated with physical and mental health indicators in different ways among North African women and men in France. PMID- 28618108 TI - Chronic respiratory disease in the regional and remote population of the Northern Territory Top End: A perspective from the specialist respiratory outreach service. AB - OBJECTIVE: To study the demographic, rates and types of chronic respiratory conditions in Indigenous and non-Indigenous patients in regional and remote communities of Northern Territory Top End, who were referred to the specialist respiratory outreach service. DESIGN: A retrospective, observational study over a 2 years period. SETTING: Remote community health clinics within the Northern Territory Top End visited by the specialist respiratory outreach team. PARTICIPANTS: Only patients referred to respiratory specialist outreach team were included. There were 444 participants, with 210 males and 234 females. In total, 79.3% were Indigenous. MAIN OUTCOME MEASURES: The rates of chronic respiratory disease diagnoses and smoking status within the different communities and health district regions. RESULTS: Chronic obstructive pulmonary disease (COPD) was the most common primary respiratory condition in our cohort of patients (50.5%) followed by sleep apnoea in (14.2%), bronchiectasis in (11.6%), asthma (11%), interstitial lung disease (2.5%), nodule/cancer (1.8%) sarcoidosis (0.2%) and others (9.2%). COPD, smoking status and bronchiectasis was more frequently noted among the Indigenous patients compared to non-Indigenous patients (56.3% versus 28.3%, P < 0.001), (52.6% versus 25.0%, P < 0.001), and (12.5% versus 3.3%, P = 0.01) respectively. Obstructive sleep apnoea was more commonly diagnosed in non Indigenous patients. CONCLUSION: Indigenous patients of the remote and rural communities of the Top End have significantly higher rates of smoking and COPD compared to non-Indigenous patients. Bronchiectasis is also more common among Indigenous patients. Further efforts are warranted to develop strategies to address the disparity and optimise the respiratory outreach service to this population. PMID- 28618109 TI - Vaccination timeliness in preterm infants: An integrative review of the literature. AB - AIMS AND OBJECTIVES: To take a systematic approach to reviewing the scientific literature examining the timeliness of vaccination in preterm infants and to identify any factors associated with timeliness. BACKGROUND: Preterm infants are vulnerable to infection and guidance advocates they are vaccinated in accordance with their full-term peers. Vaccination is well tolerated and protective immune responses are observed, yet some early enquiries suggest that preterm infants experience unwarranted delays. The recent surge in pertussis cases and the increase in vaccinations administered make this a topic requiring further exploration. DESIGN: An integrative review of the empirical literature. METHODS: Studies were identified following a search of Medline, Academic Search Premier, Cochrane Database of Systematic Reviews and the Cumulative Index to Nursing and Allied Health Literature. The review methods used were influenced by a narrative synthesis approach. The retrieval of papers adhered to recognised reporting standards. RESULTS: Fourteen studies were identified, which indicated that infants with the lowest gestational ages and birthweights experience the greatest delays. Vaccination timeliness is influenced by hospitalisation and increased postdischarge follow-up. There was a lack of consensus to indicate that parental socio-economic status and level of education were indicators for a delay. The studies propose that many delays are unjustified and not according to genuine contraindications. CONCLUSION: This review indicates that preterm infants are not vaccinated in a timely manner. Those involved in vaccinating preterm infants must be informed of the genuine contraindications to avoid unnecessary delays putting preterm infants at an increased risk of infection. RELEVANCE TO CLINICAL PRACTICE: Care providers should acknowledge the risk of a delay in preterm infants and actively promote vaccination in this population. Regular training should help to negate the occurrence of inappropriate delays, and careful discharge planning is needed to ensure that preterm infants are vaccinated on time. PMID- 28618111 TI - Iron-Catalyzed Olefin Metathesis with Low-Valent Iron Alkylidenes. AB - Inspired by recent reports of low-valent iron-complex-catalyzed formal [2+2] cycloaddition of olefins, we demonstrate computationally that with such low valent iron complexes and with "strong" ligands, the olefin metathesis is also preferred over the undesired cyclopropanation side-reaction, competition already studied by Hoffmann and co-workers almost 40 years ago (J. Am. Chem. Soc. 1981, 103, 5582). The [2+2] cycloaddition step in metathesis propagation, which gives a Chauvin-type metallacyclobutane intermediate, is proposed to proceed either via a planar four-electron Craig-Mobius aromatic [pi2s +pi2s ] transition-state structure with a low barrier of 4.7 kcal mol-1 or, alternatively, via a twisted Zimmerman-Mobius aromatic [pi2s +pi2a ] transition state with a 5.5 kcal mol-1 activation-energy barrier, with respect to an "encounter" pi-complex minimum obtained from an FeII alkylidene and the entering olefin, while the corresponding triplet pathways are all disfavored. PMID- 28618110 TI - Intravesical vanilloids for treating neurogenic lower urinary tract dysfunction in patients with multiple sclerosis: A systematic review and meta-analysis. A report from the Neuro-Urology Promotion Committee of the International Continence Society (ICS). AB - AIMS: To systematically assess all available evidence on efficacy and safety of vanilloids for treating neurogenic lower urinary tract dysfunction (NLUTD) in patients with multiple sclerosis (MS). METHODS: This systematic review and meta analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were identified by electronic search of Cochrane register, Embase, Medline, Scopus, (last search January 8, 2016). RESULTS: After screening of 7848 abstracts, 4 randomized controlled trials (RCTs) and 3 prospective cohort studies were included. Pooled data from three RCTs evaluating intravesical capsaicin showed the standardized mean difference to be -2.16 (95% confidence interval [CI] -2.87 to -1.45) in incontinence episodes per 24 h and -0.54 (95%CI -1.03 to -0.05) in voids per 24 h. There was no statistically significant effect on maximum cystometric capacity and maximum storage detrusor pressure. Overall, adverse events were reported by >50% of the patients, most commonly were pelvic pain, facial flush, worsening of incontinence, autonomic dysreflexia, urinary tract infection and haematuria. Risk of bias and confounding was relevant in both RCTs and non-RCTs. CONCLUSIONS: Preliminary data suggest that intravesical vanilloids might be effective for treating NLUTD in patients with MS. However, the safety profile seems unfavorable, the overall quality of evidence is low and no licensed substance is currently available warranting well-designed, adequately sampled and properly powered RCTs. PMID- 28618112 TI - Older patients with late-stage COPD: Their illness experiences and involvement in decision-making regarding mechanical ventilation and noninvasive ventilation. AB - AIMS AND OBJECTIVES: To explore the illness experiences of older patients with late-stage chronic obstructive pulmonary disease and to develop knowledge about how patients perceive their preferences to be taken into account in decision making processes concerning mechanical ventilation and/or noninvasive ventilation. BACKGROUND: Decisions about whether older patients with late-stage chronic obstructive pulmonary disease will benefit from noninvasive ventilation treatment or whether the time has come for palliative treatment are complicated, both medically and ethically. Knowledge regarding patients' values and preferences concerning ventilation support is crucial yet often lacking. DESIGN: Qualitative design with a hermeneutic-phenomenological approach. METHODS: The data consist of qualitative in-depth interviews with 12 patients from Norway diagnosed with late-stage chronic obstructive pulmonary disease. The data were analysed within the three interpretative contexts described by Kvale and Brinkmann. RESULTS: The participants described their lives as fragile and burdensome, frequently interrupted by unpredictable and frightening exacerbations. They lacked information about their diagnosis and prognosis and were often not included in decisions about noninvasive ventilation or mechanical ventilation. CONCLUSION: Findings indicate that these patients are highly vulnerable and have complex needs in terms of nursing care and medical treatment. Moreover, they need access to proactive advanced care planning and an opportunity to discuss their wishes for treatment and care. RELEVANCE TO CLINICAL PRACTICE: To provide competent care for these patients, healthcare personnel must be aware of how patients experience being seriously ill. Advanced care planning and shared decision-making should be initiated alongside the curative treatment. PMID- 28618113 TI - The mechanism of interactions between tea polyphenols and porcine pancreatic alpha-amylase: Analysis by inhibition kinetics, fluorescence quenching, differential scanning calorimetry and isothermal titration calorimetry. AB - SCOPE: This study aims to use a combination of biochemical and biophysical methods to derive greater mechanistic understanding of the interactions between tea polyphenols and porcine pancreatic alpha-amylase (PPA). METHODS AND RESULTS: The interaction mechanism was studied through fluorescence quenching (FQ), differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC) and compared with inhibition kinetics. The results showed that a higher quenching effect of polyphenols corresponded to a stronger inhibitory activity against PPA. The red-shift of maximum emission wavelength of PPA bound with some polyphenols indicated a potential structural unfolding of PPA. This was also suggested by the decreased thermostability of PPA with these polyphenols in DSC thermograms. Through thermodynamic binding analysis of ITC and inhibition kinetics, the equilibrium of competitive inhibition was shown to result from the binding of particularly galloylated polyphenols with specific sites on PPA. There were positive linear correlations between the reciprocal of competitive inhibition constant (1/Kic ), quenching constant (KFQ ) and binding constant (Kitc ). CONCLUSION: The combination of inhibition kinetics, FQ, DSC and ITC can reasonably characterize the interactions between tea polyphenols and PPA. The galloyl moiety is an important group in catechins and theaflavins in terms of binding with and inhibiting the activity of PPA. PMID- 28618114 TI - Subjective insomnia symptoms and sleep duration are not related to hypothalamic pituitary-adrenal axis activity in older adults. AB - Insomnia symptoms are highly prevalent in depressed older adults. This study investigates the association between hypothalamic-pituitary-adrenal (HPA) axis activity and symptoms of insomnia, respectively, sleep duration among 294 depressed and 123 non-depressed older adults of the Netherlands Study of Depression in Older people (NESDO) study. Insomnia symptoms were defined as clinically relevant when having a score >= 10 points on the Women's Health Initiative Insomnia Rating Scale (WHIIRS). Sleep duration was categorized in short (<= 6 h per night), normal (7-8 h per night) and long (>= 9 h per night) duration. Salivary cortisol levels were used to assess the following cortisol parameters for HPA axis activity: area under the curve with respect to the increase (AUCi) and to the ground (AUCg), diurnal slope, evening cortisol level and dexamethasone suppression ratio. Clinically relevant insomnia symptoms were present in 46% of the participants. Thirty-two per cent of the participants were short sleepers, whereas 16% were long sleepers. However, univariate analyses showed no differences in any of the HPA axis parameters between people with and without insomnia symptoms or between the three groups with different sleep duration. In addition, no significant interaction was found between a diagnosis of depression or the severity of depressive symptoms and any of the cortisol parameters in relation to insomnia symptoms or sleep duration. PMID- 28618115 TI - Iron-sulfur glutaredoxin 2 protects oligodendrocytes against damage induced by nitric oxide release from activated microglia. AB - Demyelinated brain lesions, a hallmark of autoimmune neuroinflammatory diseases like multiple sclerosis, result from oligodendroglial cell damage. Activated microglia are considered a major source of nitric oxide and subsequent peroxynitrite-mediated damage of myelin. Here, we provide biochemical and biophysical evidence that the oxidoreductase glutaredoxin 2 inhibits peroxynitrite formation by transforming nitric oxide into dinitrosyl diglutathionyl-iron-complexes. Glutaredoxin 2 levels influence both survival rates of primary oligodendrocyte progenitor cells and preservation of myelin structure in cerebellar organotypic slice cultures challenged with activated microglia or nitric oxide donors. Of note, glutaredoxin 2-mediated protection is not linked to its enzymatic activity as oxidoreductase, but to the disassembly of its uniquely coordinated iron-sulfur cluster using glutathione as non-protein ligand. The protective effect of glutaredoxin 2 is connected to decreased protein carbonylation and nitration. In line, brain lesions of mice suffering from experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, show decreased glutaredoxin 2 expression and increased nitrotyrosine formation indicating that this type of protection is missing in the inflamed central nervous system. Our findings link inorganic biochemistry to neuroinflammation and identify glutaredoxin 2 as a protective factor against neuroinflammation-mediated myelin damage. Thus, improved availability of glutathione-coordinated iron-sulfur clusters emerges as a potential therapeutic approach in inflammatory demyelination. PMID- 28618116 TI - Differences in p53 status significantly influence the cellular response and cell survival to 1,25-dihydroxyvitamin D3-metformin cotreatment in colorectal cancer cells. AB - Mutations in the tumor suppressor p53 are highly prevalent in cancers and are known to influence the sensitivity of cells to various chemotherapeutics including the anti-cancer candidates 1,25-dihydrovitamin D3 [1,25D3] and metformin. Previous studies have demonstrated additive/synergistic anti-cancer effects of the 1,25D3-metformin combination in different models, however, the influence of p53 status on the efficacy of this regimen has not been investigated. The CRC colorectal cancer (CRC) cell lines HCT116 wild-type (wt), HCT116 p53-/-, and HT-29 (mutant; R273H) were employed, covering three different p53 variations. Synergistic effects of the combination were confirmed in all cell lines using MTT assay. Detailed evaluation of the combination's effects was performed, including on-line measurements of cellular metabolism (glycolysis/respiration) using a biosensor chip system, analyses of mitochondrial activity (membrane potential and ATP/ROS production), mRNA expression analysis of WNT/beta-catenin pathway players, and a comprehensive proteomic screen using immunoblotting and ELISA microarrays. AMPK signaling was found to be more strongly induced in response to all treatments in HCT116 wt cells compared to other cell lines, an observation that was coupled to a stronger accumulation of intracellular ROS in response to metformin/combination, and finally an induction in autophagy, depicted by an increase in LC3II:LC3I ratio in combination-treated cells compared to mono-treatments. An induction in apoptotic signaling was observed in the other cell lines in response to the combination, illustrated by a decrease in expression of pro-survival Bcl2 family members. P53 status impacts cellular responses to the combination but does not hamper its anti-proliferative synergy. PMID- 28618117 TI - iTRAQ-based proteomics of sunflower cultivars differing in resistance to parasitic weed Orobanche cumana. AB - Orobanche cumana is an obligate root parasite causing severe damage to many economically important crops, including sunflowers worldwide. For efficient control measures, it is necessary to understand the resistant mechanism during interaction at molecular level. The present study emphasizes on comparative proteomics to investigate the mechanistic basis of compatible and incompatible interaction of O. cumana with resistant (JY207) and susceptible (TK0409) sunflowers. More than 3500 proteins were identified from two cultivars by iTRAQ analysis. Identified proteins associated with general functions, posttranslational modification, energy production and conversion, carbohydrate transport and metabolism, and signal transduction mechanisms were the most represented category of induced proteins in both cultivars. The resistant interaction was characterized by alteration of defense-related proteins involved in recognition of parasites, accumulation of pathogenesis-related proteins, biosynthesis of lignin, and detoxification of toxic metabolites in JY207 after inoculation. The susceptible interaction was characterized by decreased abundance of proteins involved in biosynthesis and signaling of plant growth regulators including auxin, gibberellin, brassinosteroid, and ethylene in TK0409 after inoculation. The present study provides comprehensive details of proteins and differential modulation of pathways regulated under compatible and incompatible interaction, allowing the identification of important molecular components for development of sustainable resistance against this parasite. PMID- 28618118 TI - Response to "Rebutting the inclined analyses on the cost-effectiveness and feasibility of coral reef restoration". PMID- 28618119 TI - KH-type splicing regulatory protein mediate inflammatory response in gastric epithelial cells induced by lipopolysaccharide. AB - To study differential expressions of KH-type splicing regulatory protein (KSRP) and inflammatory factors and to explore the relationship between them in Lipopolysaccharide (LPS)-induced gastric epithelial cells (GES-1), cells were exposed to LPS for 24 h in the presence or absence of SC-514. Western blot and real-time PCR (RT-PCR) were used to analysis the contents of KSRP, inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). The results showed that LPS decreased the expression of KSRP protein in GES-1 cells, but not KSRP mRNA, while increasing the levels of iNOS and COX-2 proteins and mRNAs in GES-1cells. High expression of KSRP induced low expressions and stabilities of iNOS and COX-2 in GES-1 cells, indicated that KSRP protein presented negative correlation with iNOS and COX-2 with LPS stimulation. In conclusion, the regulation of expression of KSRP was mainly achieved through post-translational modification. KSRP protein participated in regulating the expression of iNOS and COX-2 in their transcription and translation levels. In response to LPS or gram negative pathogenic microorganism, KSRP could regulate Toll-like receptor (TLR)/ Nuclear factor-kappa B (NF-kappaB) signal pathway in GES-1 cells. PMID- 28618120 TI - Supportive periodontal treatment: Pocket depth changes and tooth loss. AB - AIM: The purpose of this retrospective study was to determine the results of 10 years of supportive periodontal treatment(SPT) following active periodontal therapy(APT). Probing pocket depth(PPD), bleeding on probing(BOP), tooth loss(TL)and the effects of two patient-related factors, smoking and gender were evaluated. METHODS: This retrospective study examined patients who underwent APT and SPT for adult periodontitis. Analyses were conducted using site-, tooth- and patient-level information. Mean values were calculated, and parametric and nonparametric analyses were conducted as appropriate to assess the results of APT and SPT. RESULTS: There was a significant improvement in BOP and PPD after APT. After 10 years, 9.3% of the patients adhered to the SPT protocol. The improvement in BOP and PPD was maintained, with no additional improvement in the clinical parameters at the 10-year follow-up. Furthermore, differences between non-smokers and smokers were found. After the 10-year follow-up, smokers had a significantly higher percentage of sites with a PPD of 4 mm or higher; the mean PPD was also significantly higher in smokers. A significant difference was also found between males and females during SPT for the percentage of sites with BOP and the percentage of sites with a PPD>=6 mm. A minority of patients(18.5%) did not lose teeth, and it was found that molars are the teeth most likely to be lost. The mean number of teeth lost was 2.6 during 10-year follow-up. CONCLUSION: This study indicates that with regard to bleeding on probing and probing pocket depth, patients receiving supportive periodontal treatment maintain their periodontal condition. However, in this group of adherent maintenance patients, tooth loss was most prevalent for molar teeth. PMID- 28618121 TI - Specificity traits consistent with legume-rhizobia coevolution displayed by Ensifer meliloti rhizosphere colonization. AB - Rhizobia are alpha- and beta-proteobacteria that associate with legumes in symbiosis to fix atmospheric nitrogen. The chemical communication between roots and rhizobia begins in the rhizosphere. Using signature-tagged-Tn5 mutagenesis (STM) we performed a genome-wide screening for Ensifer meliloti genes that participate in colonizing the rhizospheres of alfalfa and other legumes. The analysis of ca. 6,000 mutants indicated that genes relevant for rhizosphere colonization account for nearly 2% of the rhizobial genome and that most (ca. 80%) are chromosomally located, pointing to the relevance and ancestral origin of the bacterial ability to colonize plant roots. The identified genes were related to metabolic functions, transcription, signal transduction, and motility/chemotaxis among other categories; with several ORFs of yet-unknown function. Most remarkably, we identified a subset of genes that impacted more severely the colonization of the roots of alfalfa than of pea. Further analyses using other plant species revealed that such early differential phenotype could be extended to other members of the Trifoliae tribe (Trigonella, Trifolium), but not the Fabeae and Phaseoleae tribes. The results suggest that consolidation of E. meliloti into its current symbiotic state should have occurred in a rhizobacterium that had already been adapted to rhizospheres of the Trifoliae tribe. PMID- 28618122 TI - Purification of lignans from Fructus Arctii using off-line two-dimensional supercritical fluid chromatography/reversed-phase liquid chromatography. AB - As a common traditional Chinese medicine, Fructus Arctii has important clinical medical values. Its main components are lignans, which are difficult to separate and analyze because of the complex composition, similar chemical structures, and close properties. In this study, an off-line two-dimensional supercritical fluid chromatography/reversed-phase liquid chromatography method, as well as an effective sample pretreatment method based on hydrophilic interaction chromatography material, was developed to enrich the minor lignan fractions and obtain high-purity compounds. In total, 12 high-purity compounds were isolated from Fructus Arctii. Their structures were identified by using high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy, which showed that all were lignans and that most of them were isomers. The results demonstrated the effective off-line two-dimensional supercritical fluid chromatography/reversed phase liquid chromatography method for the purification of lignans from Fructus Arctii. The separation protocol established here will be beneficial for the separation of complex samples from other kinds of natural products. PMID- 28618123 TI - "Pain relieved, but still struggling"-Critically ill patients experiences of pain and other discomforts during analgosedation. AB - AIMS AND OBJECTIVES: To explore how critically ill patients treated according to a strategy of analgosedation experience and handle pain, other discomforts and wakefulness. BACKGROUND: Patients experience both pain and discomfort while in the intensive care unit. International guidelines recommend focused pain treatment and light sedation. An analgosedation protocol favouring pain management, light sedation and early mobilisation was implemented in our university hospital medical and surgical intensive care unit in Norway in 2014. The analgosedation approach may affect patients' experiences of the intensive care unit stay. DESIGN: Exploratory, descriptive design using semi-structured interviews. METHOD: Eighteen adult patients treated in intensive care unit >24 hr and receiving mechanical ventilation were interviewed 1-9 days after intensive care unit discharge. Ten patients were re-interviewed after 3 months. Data were analysed using the "systematic text condensation" approach. FINDINGS: Four main categories emerged from the analysis: "In discomfort, but rarely in pain," "Struggling to get a grip on reality," "Holding on" and "Handling emotionally trapped experiences." "Pain relieved, but still struggling" was the overarching theme. Analgosedation provided good pain relief, but patients still described frequent physical and psychological discomforts, in particular related to mechanical ventilation, not understanding what was going on, and experiences of delusions. To come to terms with their intensive care unit stay, patients needed to participate, trust in others and endure suffering. After hospital discharge, patients described both repression of experiences and searching for recognition of what they had gone through. RELEVANCE TO CLINICAL PRACTICE: Despite good pain relief during analgosedation, other discomforts were commonly described. Critically ill patients still experience an intensive care unit stay as a traumatic part of their illness trajectory. Nurses need to attend carefully also to discomforts other than pain. PMID- 28618124 TI - piR-823 contributes to colorectal tumorigenesis by enhancing the transcriptional activity of HSF1. AB - Piwi-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, were first discovered in germline cells and are thought to silence transposons in spermatogenesis. Recently, piRNAs have also been identified in somatic tissues, and aberrant expression of piRNAs in tumor tissues may be implicated in carcinogenesis. However, the function of piR-823 in colorectal cancer (CRC) remains unclear. Here, we first found that piR-823 was significantly upregulated in CRC tissues compared with its expression in the adjacent tissues. Inhibition of piR-823 suppressed cell proliferation, arrested the cell cycle in the G1 phase and induced cell apoptosis in CRC cell lines HCT116 and DLD-1, whereas overexpression of piR-823 promoted cell proliferation in normal colonic epithelial cell line FHC. Interestingly, Inhibition of piR-823 repressed the expression of heat shock protein (HSP) 27, 60, 70. Furthermore, elevated HSPs expression partially abolished the effect of piR-823 on cell proliferation and apoptosis. In addition, we further demonstrated that piR-823 increased the transcriptional activity of HSF1, the common transcription factor of HSPs, by binding to HSF1 and promoting its phosphorylation at Ser326. Our study reveals that piR-823 plays a tumor-promoting role by upregulating phosphorylation and transcriptional activity of HSF1 and suggests piR-823 as a potential therapeutic target for CRC. PMID- 28618127 TI - Regional citrate anticoagulation in membrane based plasma exchange: safety, efficacy and effect on calcium balance. AB - AIM: To assess the efficacy, safety and calcium balance of a membrane based regional citrate anticoagulation plasma exchange protocol METHODS: This was an observational, prospective, single center study of membrane separation plasma exchange using regional citrate anticoagulation. It was performed using a fixed dose pre-filter citrate infusion that was based on the plasma flow rate. Patients received a post filter calcium infusion which was modified during treatment based on systemic ionized calcium monitoring. Post filter ionized calcium was not assessed. Safety and efficacy were assessed by extraction of clinical events and laboratory data contemporaneously recorded in electronic health records. RESULTS: 36 sessions in 5 patients were performed. No patients developed symptomatic hypocalcaemia and no patient had a recorded ionized calcium below 0.81 mmol/L. Filter clotting occurred in 2 sessions. The mean net calcium gained was 9.6+/-1.8 mmol per session CONCLUSION: Regional citrate anticoagulated membrane separation plasma exchange can be performed safely and effectively without the need for post filter ionized calcium monitoring. The algorithm employed resulted in a net calcium gain. PMID- 28618126 TI - Temporal scale dependent interactions between multiple environmental disturbances in microcosm ecosystems. AB - Global environmental change has negative impacts on ecological systems, impacting the stable provision of functions, goods, and services. Whereas effects of individual environmental changes (e.g. temperature change or change in resource availability) are reasonably well understood, we lack information about if and how multiple changes interact. We examined interactions among four types of environmental disturbance (temperature, nutrient ratio, carbon enrichment, and light) in a fully factorial design using a microbial aquatic ecosystem and observed responses of dissolved oxygen saturation at three temporal scales (resistance, resilience, and return time). We tested whether multiple disturbances combine in a dominant, additive, or interactive fashion, and compared the predictability of dissolved oxygen across scales. Carbon enrichment and shading reduced oxygen concentration in the short term (i.e. resistance); although no other effects or interactions were statistically significant, resistance decreased as the number of disturbances increased. In the medium term, only enrichment accelerated recovery, but none of the other effects (including interactions) were significant. In the long term, enrichment and shading lengthened return times, and we found significant two-way synergistic interactions between disturbances. The best performing model (dominant, additive, or interactive) depended on the temporal scale of response. In the short term (i.e. for resistance), the dominance model predicted resistance of dissolved oxygen best, due to a large effect of carbon enrichment, whereas none of the models could predict the medium term (i.e. resilience). The long-term response was best predicted by models including interactions among disturbances. Our results indicate the importance of accounting for the temporal scale of responses when researching the effects of environmental disturbances on ecosystems. PMID- 28618128 TI - Sexual life after mastectomy in breast cancer survivors: A qualitative study. AB - OBJECTIVE: Mastectomy is a highly frequent form of breast cancer treatment in Iran, and sexual dysfunction after mastectomy has been reported in the majority of breast cancer survivors in Iran. In this qualitative study, an attempt was made to examine the stages that patients go through in their sexual lives after mastectomy. METHOD AND MATERIALS: Using purposeful sampling, 30 married women, who had undergone surgery and had completed an adjuvant treatment period, participated in the study. Data collection was done using in-depth, open, and semistructured interviews. Content analysis was used. RESULTS: Two main categories were identified in the stages the patients go through following mastectomy: sexual function breakdown and restoration of sexual function, each of which involved 3 subcategories, in turn. Subcategories of the first category were perceived physical changes by the survivor and altered sexual behaviors. These 2 factors lead to sexual function breakdown. The third subcategory includes the factors exacerbating the sexual function breakdown. The subcategories of the second category were modification in sexual behaviors, effort for physical restoration, and striving to gain support. CONCLUSION: It was found that in Iranian society, due to cultural context, some taboos, and patriarchal structure, the patients are placed under added pressure following mastectomy. As a consequence, they suffer emotional problems, in addition to physical complications of the disease and its treatments. PMID- 28618129 TI - Alkynyl Moiety for Triggering 1,2-Metallate Shifts: Enantiospecific sp2 -sp3 Coupling of Boronic Esters with p-Arylacetylenes. AB - The enantiospecific coupling of secondary and tertiary boronic esters to aromatics has been investigated. Using p-lithiated phenylacetylenes and a range of boronic esters coupling has been achieved by the addition of N bromosuccinimide (NBS). The alkyne functionality of the intermediate boronate complex reacts with NBS triggering the 1,2-migration of the group on boron to carbon giving a dearomatized bromoallene intermediate. At this point elimination and rearomatization occurs with neopentyl boronic esters, giving the coupled products. However, using pinacol boronic esters, the boron moiety migrates to the adjacent carbon resulting in formation of ortho boron-incorporated coupled products. The synthetic utility of the boron incorporated product has been demonstrated by orthogonal transformation of both the alkyne and boronic ester functionalities. PMID- 28618130 TI - Benefits of an individualized perioperative plan for children with autism spectrum disorder. AB - BACKGROUND: Perioperative care for children with autism spectrum disorder may be challenging. Previous investigators recommend development of an individualized perioperative management plan with caregiver involvement. AIM: The primary goal was to determine the usefulness of an individualized plan based on the decision to provide preoperative sedation stratified by autism spectrum severity level. Secondary goals were to assess the effectiveness of the plan based on subjective assessment of patient behavior at induction of anesthesia and caregiver satisfaction. METHODS: We developed an individualized plan for each child with autism spectrum disorder scheduled for anesthesia. Children were categorized by autism spectrum disorder severity level. With institutional ethics approval, we conducted a retrospective chart review to document need for preoperative sedation, sedation stratified by autism spectrum disorder severity level, behavior at induction, and caregiver satisfaction. RESULTS: Between 2012 and 2014, we successfully prepared a plan for 246 (98%) of 251 surgical or diagnostic procedures in 224 patients. Severity level was distributed as 45% Severity Level 1 and Asperger's, 25% Severity Level 2, and 30% Severity Level 3. The majority (90%) of cases were scheduled as day surgery. Preoperative sedation increased with increasing severity level: Severity Level 1 (21%) or Asperger's (31%), Severity Level 2 (44%), and Severity Level 3 (56%). The odds ratio for sedation use was 5.5 [CI: 2.6-11.5, P<.001] with Severity Level 3 vs Severity Level 1 patients. Cooperation at induction of anesthesia was 90% overall with preoperative sedation administered to 94 (38%) of the entire cohort. Cooperation was greatest in Severity Level 1 (98%) and Asperger's patients (93%) and somewhat less (85%) in patients in Severity Levels 2 and 3. The plan was helpful to guide sedation choices as cooperation did not differ between sedated and unsedated children at any severity level (overall chi2 =2.87 P=.09). Satisfaction among caregivers contacted was 98%. CONCLUSION: The results suggest that an individualized plan is helpful in the perioperative management of children with autism spectrum disorder and that knowledge of autism spectrum disorder severity level may be helpful in determining the need for preoperative sedation. PMID- 28618131 TI - Pharmacognosy, Phytochemistry and Pharmacological Properties of Achillea millefolium L.: A Review. AB - Achillea millefoilum L. (Yarrow) is an important species of Asteraceae family with common utilization in traditional medicine of several cultures from Europe to Asia for the treatment of spasmodic gastrointestinal disorders, hepatobiliary, gynecological disorders, against inflammation and for wound healing. An extensive review of literature was made on A. millefoilum L. using ethno botanical text books, published articles in peer-reviewed journals, unpublished materials and scientific databases. The Plant List, International Plant Name Index and Kew Botanical Garden databases were used to authenticate the scientific names. Monoterpenes are the most representative metabolites constituting 90% of the essential oils in relation to the sesquiterpenes, and a wide range of chemical compounds have also been reported. Different pharmacological experiments in many in-vitro and in-vivo models have proved the potential of A. millefoilum with antiinflammatory, antiulcer, anticancer activities etc. lending support to the rationale behind numerous of its traditional uses. Due to the noteworthy pharmacological activities, A. millefoilum will be a better option for new drug discovery. The present review will comprehensively summarize the pharmacognosy, phytochemistry and ethnopharmacology of A. millefoilum reported to date, with emphasis on more in vitro, clinical and pathological studies needed to investigate the unexploited potential of this plant. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28618132 TI - Mugs of the bugs: The most wanted ones. PMID- 28618133 TI - Effects of hispolon on glioblastoma cell growth. AB - Hispolon is a polyphenolic compound isolated from Phellinus linteus which exhibits antitumor activity. Here, we explored the effects of hispolon on human glioblastoma cells U87MG. Cell viability was examined by MTT assay. Growth was investigated by incubating cells with various concentrations of hispolon (25 and 50 uM) for 24, 48 or 72 h and daily cell count. Cell cycle and apoptosis assay were assessed by flow cytometry. Hispolon decreased cell viability in a dose- and time-dependent manner. The cell cycle distribution showed that hispolon enhanced the accumulation of the cells in G2/M phase. Hispolon decreased the expression of G1-S transition-related protein cyclin D4 but increased the expression of CDK inhibitor p21. Additionally, hispolon enhanced the expression of p53. Moreover, hispolon treatment was effective on U87MG cells in inhibiting cell viability and inducing cell apoptosis. Our results indicate that hispolon inhibits the cell viability, induces G2/M cell cycle arrest and apoptosis in glioblastoma U87MG cells, and p53 should play a role in hispolon-mediated antitumor activity. PMID- 28618134 TI - Potentially inappropriate use of furosemide in a very elderly population: An observational study. AB - OBJECTIVE: Little is known about furosemide prescription modalities in elderly people. We describe furosemide prescription in ambulatory elderly patients. METHODS: All patients aged over 80 years, affiliated to Mutualite Sociale Agricole de Bourgogne, a French regional health insurance plan, with a medical prescription delivered in March 2015, were retrospectively included. RESULTS: Among 15 141 patients with a median age of 86 years, comprising 61.3% of women, 3937 patients (26%) had a prescription for furosemide. Severe heart failure was the most common chronic comorbidity (27.7%). Furosemide was considered a long term therapy for almost all patients (98.7% with prescriptions for 3 months or more). Recommended indications for long-term furosemide therapy included severe heart failure (50.9%), chronic nephropathy (3%) and cirrhosis (0.1%). The furosemide prescription rate increased with age (81-85: 20.4%, 86-90: 28.5%, 91 95: 35.6%, >95: 42.7%, P<.001), and the increase was associated with a decrease in recommended heart failure therapeutics (beta-blockers, angiotensin-conversion enzyme-inhibitors or angiotensin-receptor-blockers). Prescribers were mostly general practitioners (81.3%). Plasma electrolytes were controlled in less than a half of the patients with furosemide. CONCLUSIONS: In this large study, long course furosemide was prescribed in a quarter of ambulatory patients. Half of those taking furosemide suffered from severe heart failure. Age was associated with a linear increase in furosemide use and a decrease in recommended heart failure therapeutic prescriptions. A large part of these prescriptions do not seem to be in accordance with recommendations. PMID- 28618135 TI - Self-Assembled Nano-Immunostimulant for Synergistic Immune Activation. AB - Immunotherapy has become one of the most promising therapies for the treatment of diseases. Synthetic immunostimulants and nanomaterial immunostimulant systems are indispensable for the activation of the immune system in cancer immunotherapy. Herein, a strategy for preparing self-assembled nano-immunostimulants (SANIs) for synergistic immune activation is reported. Three immunostimulants self-assemble into nanoparticles through electrostatic interactions. SANIs showed strong synergistic immunostimulation in macrophages. SANIs could also induce a strong antitumor immune response to inhibit tumor growth in mice and act as an efficient adjuvant of antitumor vaccines. Therefore, SANIs may be generally applied in cancer immunotherapy. This novel SANI strategy provides a new way for the development of both immunostimulants and -suppressants. PMID- 28618136 TI - Amphiphilic Cargo-Loaded Nanocarrier Enhances Antibiotic Uptake and Perturbs Efflux: Effective Synergy for Mitigation of Methicillin-Resistant Staphylococcus aureus. AB - A pyridinium-amphiphile-loaded poly(lactic-co-glycolic acid) (PLGA) nanocarrier (C1-PNC) was developed as an adjuvant in order to break the resistance and restore the susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) cells to therapeutic antibiotics. Notably, against a clinical MRSA strain, C1-PNC was found to render 8- and 6-fold decreases in the minimum biofilm eradication concentration (MBEC90 ) of gentamicin and ciprofloxacin, respectively. Mechanistic studies on MRSA planktonic cells revealed that in the case of gentamicin, C1-PNC promotes enhanced cellular uptake of the antibiotic, whereas the propensity of C1-PNC to inhibit efflux pump activity could be leveraged to enhance cellular accumulation of ciprofloxacin, leading to effective killing of MRSA cells. Interestingly, the combinatorial dosing regimen of C1-PNC and the antibiotics was nontoxic to cultured HEK293 cells. This nontoxic amphiphile loaded nanomaterial holds considerable promise as an adjuvant for antibiotic mediated alleviation of MRSA biofilms. PMID- 28618137 TI - The impact of aspiration pneumonia and nasogastric feeding on clinical outcomes in stroke patients: A retrospective cohort study. AB - AIMS AND OBJECTIVES: To determine presence of clinical complications related to dysphagia and to explore their operational outcomes. BACKGROUND: Dysphagia is a common complication of stroke. The management of poststroke dysphagia is multidisciplinary with nurses playing a key role in screening for dysphagia risk, monitoring tolerance of food and fluids and checking for the development of complications such as fever, dehydration and change in medical status. Dysphagia often results in further complications including aspiration pneumonia and the need for nasogastric feeding. Dysphagia-related complications have been shown to have a significant impact on morbidity and mortality, length of stay and cost of admission. DESIGN: Retrospective cohort study. METHODS: A total of 110 patients presenting with an ischaemic stroke were chart-audited. RESULTS: Aspiration pneumonia poststroke was found to be significantly associated with increased overall length of stay, poorer functional outcomes poststroke as well as being associated with a high risk of mortality. The presence of a nasogastric tube was also associated with reduced functional outcomes poststroke and increased risk of death. CONCLUSION: High prevalence and cost of complications associated with stroke highlight the complexity of providing nursing and allied health care to this patient population. This provides a snapshot of dysphagia-related complications experienced by stroke patients. RELEVANCE TO CLINICAL PRACTICE: This paper highlights that poststroke complications can significantly impact on patient outcomes and operational factors such as cost of admission; therefore, poststroke care requires a multidisciplinary approach to management. Furthermore, preventing and managing complications poststroke is a key element of nursing care and has the potential to significantly reduce incidence of mortality, length of stay and cost of hospital admission. PMID- 28618138 TI - Expansion of Umbilical Cord Blood Aldehyde Dehydrogenase Expressing Cells Generates Myeloid Progenitor Cells that Stimulate Limb Revascularization. AB - Uncompromised by chronic disease-related comorbidities, human umbilical cord blood (UCB) progenitor cells with high aldehyde dehydrogenase activity (ALDHhi cells) stimulate blood vessel regeneration after intra-muscular transplantation. However, implementation of cellular therapies using UCB ALDHhi cells for critical limb ischemia, the most severe form of severe peripheral artery disease, is limited by the rarity (<0.5%) of these cells. Our goal was to generate a clinically-translatable, allogeneic cell population for vessel regenerative therapies, via ex vivo expansion of UCB ALDHhi cells without loss of pro angiogenic potency. Purified UCB ALDHhi cells were expanded >18-fold over 6-days under serum-free conditions. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, only 15.1% +/- 1.3% of progeny maintained high ALDH-activity after culture. However, compared to fresh UCB cells, expansion increased the total number of ALDHhi cells (2.7-fold), CD34+ /CD133+ cells (2.8-fold), and hematopoietic colony forming cells (7.7-fold). Remarkably, injection of expanded progeny accelerated recovery of perfusion and improved limb usage in immunodeficient mice with femoral artery ligation-induced limb ischemia. At 7 or 28 days post-transplantation, mice transplanted with expanded ALDHhi cells showed augmented endothelial cell proliferation and increased capillary density compared to controls. Expanded cells maintained pro angiogenic mRNA expression and secreted angiogenesis-associated growth factors, chemokines, and matrix modifying proteins. Coculture with expanded cells augmented human microvascular endothelial cell survival and tubule formation under serum-starved, growth factor-reduced conditions. Expanded UCB-derived ALDHhi cells represent an alternative to autologous bone marrow as an accessible source of pro-angiogenic hematopoietic progenitor cells for the refinement of vascular regeneration-inductive therapies. Stem Cells Translational Medicine 2017;6:1607-1619. PMID- 28618139 TI - Large-Scale Ex Vivo Generation of Human Red Blood Cells from Cord Blood CD34+ Cells. AB - The ex vivo generation of human red blood cells on a large scale from hematopoietic stem and progenitor cells has been considered as a potential method to overcome blood supply shortages. Here, we report that functional human erythrocytes can be efficiently produced from cord blood (CB) CD34+ cells using a bottle turning device culture system. Safety and efficiency studies were performed in murine and nonhuman primate (NHP) models. With the selected optimized culture conditions, one human CB CD34+ cell could be induced ex vivo to produce up to 200 million erythrocytes with a purity of 90.1% +/- 6.2% and 50% +/ 5.7% (mean +/- SD) for CD235a+ cells and enucleated cells, respectively. The yield of erythrocytes from one CB unit (5 million CD34+ cells) could be, in theory, equivalent to 500 blood transfusion units in clinical application. Moreover, induced human erythrocytes had normal hemoglobin content and could continue to undergo terminal maturation in the murine xenotransplantation model. In NHP model, xenotransplantation of induced human erythrocytes enhanced hematological recovery and ameliorated the hypoxia situation in the primates with hemorrhagic anemia. These findings suggested that the ex vivo-generated erythrocytes could be an alternative blood source for traditional transfusion products in the clinic. Stem Cells Translational Medicine 2017;6:1698-1709. PMID- 28618141 TI - Mortality caused by intracranial bleeding in non-severe hemophilia A patients: reply. PMID- 28618140 TI - How does the side-effect information in patient information leaflets influence peoples' side-effect expectations? A cross-sectional national survey of 18- to 65 year-olds in England. AB - OBJECTIVES: To establish how the terms recommended by the European Commission to describe side-effect risk in patient information leaflets (PILs) influences expectations of side-effects and to identify factors associated with these side effect expectations. DESIGN: A cross-sectional online survey was carried out by a market research company. SETTING: Data were collected in England between 18th March and 1st April 2016. PARTICIPANTS: A total of 1003 adults aged between 18 and 65. MAIN OUTCOME MEASURES: Self-reported expectation that the described side effects would affect participants if they took the medicine, measured on a likelihood scale from 1 (very unlikely) to 5 (very likely). RESULTS: Participants formed high expectations of side-effects for "very common" and "common" side effects, with 51.9% and 45.0% of participants rating these as "very likely" or "likely" to happen to them, respectively. This fell to 8.1% for "uncommon," 5.8% for "rare" and 4.1% for "very rare." For each descriptor, higher expectations of side-effects were more associated with women or being from an ethnic minority, or having less education, a household illness, high perceived sensitivity to medicines or negative beliefs about medicines. DISCUSSION: The current use of verbal descriptors to communicate side-effect risk in PILs leads to high side effect expectations. These expectations could contribute to nocebo-induced medication side-effects experienced by patients. Additional work is required to identify ways to improve the way risk information is conveyed in PILs. PMID- 28618142 TI - Functional diversity and redundancy across fish gut, sediment and water bacterial communities. AB - This article explores the functional diversity and redundancy in a bacterial metacommunity constituted of three habitats (sediment, water column and fish gut) in a coastal lagoon under anthropogenic pressure. Comprehensive functional gene arrays covering a wide range of ecological processes and stress resistance genes to estimate the functional potential of bacterial communities were used. Then, diversity partitioning was used to characterize functional diversity and redundancy within (alpha), between (beta) and across (gamma) habitats. It was showed that all local communities exhibit a highly diversified potential for the realization of key ecological processes and resistance to various environmental conditions, supporting the growing evidence that macro-organisms microbiomes harbour a high functional potential and are integral components of functional gene dynamics in aquatic bacterial metacommunities. Several levels of functional redundancy at different scales of the bacterial metacommunity were observed (within local communities, within habitats and at the metacommunity level). The results suggested a high potential for the realization of spatial ecological insurance within this ecosystem, that is, the functional compensation among microorganisms for the realization and maintenance of key ecological processes, within and across habitats. Finally, the role of macro-organisms as dispersal vectors of microbes and their potential influence on marine metacommunity dynamics were discussed. PMID- 28618143 TI - Cedratvirus lausannensis - digging into Pithoviridae diversity. AB - Amoeba-infecting viruses have raised scientists' interest due to their novel particle morphologies, their large genome size and their genomic content challenging previously established dogma. We report here the discovery and the characterization of Cedratvirus lausannensis, a novel member of the Megavirales, with a 0.75-1 um long amphora-shaped particle closed by two striped plugs. Among numerous host cell types tested, the virus replicates only in Acanthamoeba castellanii leading to host cell lysis within 24 h. C. lausannensis was resistant to ethanol, hydrogen peroxide and heating treatments. Like 30 000-year-old Pithovirus sibericum, C. lausannensis enters by phagocytosis, releases its genetic content by fusion of the internal membrane with the inclusion membrane and replicates in intracytoplasmic viral factories. The genome encodes 643 proteins that confirmed the grouping of C. lausannensis with Cedratvirus A11 as phylogenetically distant members of the family Pithoviridae. The 575,161 bp AT rich genome is essentially devoid of the numerous repeats harbored by Pithovirus, suggesting that these non-coding repetitions might be due to a selfish element rather than particular characteristics of the Pithoviridae family. The discovery of C. lausannensis confirms the contemporary worldwide distribution of Pithoviridae members and the characterization of its genome paves the way to better understand their evolution. PMID- 28618144 TI - Thermal barriers constrain microbial elevational range size via climate variability. AB - Range size is invariably limited and understanding range size variation is an important objective in ecology. However, microbial range size across geographical gradients remains understudied, especially on mountainsides. Here, the patterns of range size of stream microbes (i.e., bacteria and diatoms) and macroorganisms (i.e., macroinvertebrates) along elevational gradients in Asia and Europe were examined. In bacteria, elevational range size showed non-significant phylogenetic signals. In all taxa, there was a positive relationship between niche breadth and species elevational range size, driven by local environmental and climatic variables. No taxa followed the elevational Rapoport's rule. Climate variability explained the most variation in microbial mean elevational range size, whereas local environmental variables were more important for macroinvertebrates. Seasonal and annual climate variation showed negative effects, while daily climate variation had positive effects on community mean elevational range size for all taxa. The negative correlation between range size and species richness suggests that understanding the drivers of range is key for revealing the processes underlying diversity. The results advance the understanding of microbial species thermal barriers by revealing the importance of seasonal and diurnal climate variation, and highlight that aquatic and terrestrial biota may differ in their response to short- and long-term climate variability. PMID- 28618145 TI - Solid-State Lithium Conductors for Lithium Metal Batteries Based on Electrospun Nanofiber/Plastic Crystal Composites. AB - Organic ionic plastic crystals (OIPCs) are a class of solid-state electrolytes with good thermal stability, non-flammability, non-volatility, and good electrochemical stability. When prepared in a composite with electrospun polyvinylidene fluoride (PVdF) nanofibers, a 1:1 mixture of the OIPC N-ethyl-N methylpyrrolidinium bis(fluorosulfonyl)imide ([C2 mpyr][FSI]) and lithium bis(fluorosulfonyl)imide (LiFSI) produced a free-standing, robust solid-state electrolyte. These high-concentration Li-containing electrolyte membranes had a transference number of 0.37(+/-0.02) and supported stable lithium symmetric-cell cycling at a current density of 0.13 mA cm-2 . The effect of incorporating PVdF in the Li-containing plastic crystal was investigated for different ratios of PVdF and [Li][FSI]/[C2 mpyr][FSI]. In addition, Li|LiNi1/3 Co1/3 Mn1/3 O2 cells were prepared and cycled at ambient temperature and displayed a good rate performance and stability. PMID- 28618146 TI - Green alder (Alnus viridis) encroachment shapes microbial communities in subalpine soils and impacts its bacterial or fungal symbionts differently. AB - Since the mid-twentieth century, subalpine grasslands undergo a progressive encroachment by Alnus viridis shrubs. Thanks to its rapid vegetative reproduction, its nitrogen fixing symbiosis with Frankia and its ectomycorrhizal cohorts, green alders are vigorous colonizers that quickly form mosaic of alder patches that evolves into a close canopy shrub community. To better understand how alder encroachment might influence microbial communities in this successional sequence, symbiont distribution, microbial richness and community structure in both soils and nodules were analyzed at three successional stages: grassland, mosaic and forest. Soil analyses were performed in association with measures of nitrification and denitrification, as well as DNA metabarcoding of three bacterial genes (16S rDNA, nifH and amoA) and one fungal gene (ITS1). Our results show that (i) A. viridis encroachment is associated with soil microbial community changes that are in turn, linked to certain soil properties (i.e., pH, C/N ratio and organic matter content), (ii) both taxonomic and N related functional gene structures of bacteria are modified by alder encroachment and (iii) the distribution in soils of its bacterial symbionts (Frankia) is apparently weakly influenced by alder establishment while Alnus-specific ectomyccorrhizae increase with the increase in alder shrub density. PMID- 28618147 TI - Feedback preferences of patients, professionals and health insurers in integrated head and neck cancer care. AB - BACKGROUND: Audit and feedback on professional practice and health care outcomes are the most often used interventions to change behaviour of professionals and improve quality of health care. However, limited information is available regarding preferred feedback for patients, professionals and health insurers. OBJECTIVE: Investigate the (differences in) preferences of receiving feedback between stakeholders, using the Dutch Head and Neck Audit as an example. METHODS: A total of 37 patients, medical specialists, allied health professionals and health insurers were interviewed using semi-structured interviews. Questions focussed on: "Why," "On what aspects" and "How" do you prefer to receive feedback on professional practice and health care outcomes? RESULTS: All stakeholders mentioned that feedback can improve health care by creating awareness, enabling self-reflection and reflection on peers or colleagues, and by benchmarking to others. Patients prefer feedback on the actual professional practice that matches the health care received, whereas medical specialists and health insurers are interested mainly in health care outcomes. All stakeholders largely prefer a bar graph. Patients prefer a pie chart for patient-reported outcomes and experiences, while Kaplan-Meier survival curves are preferred by medical specialists. Feedback should be simple with firstly an overview, and 1-4 times a year sent by e-mail. Finally, patients and health professionals are cautious with regard to transparency of audit data. CONCLUSIONS: This exploratory study shows how feedback preferences differ between stakeholders. Therefore, tailored reports are recommended. Using this information, effects of audit and feedback can be improved by adapting the feedback format and contents to the preferences of stakeholders. PMID- 28618149 TI - Sudden cardiac death in the young: Epidemiology and overview. AB - Sudden cardiac death (SCD), particularly in the young athlete, is a rare though devastating event for families, institutions, and communities at large. It can also affect the nonathlete and occur at rest, although most commonly associated with exercise activities and/or sports participation. Common causes of SCD include cardiomyopathies, particularly hypertrophic cardiomyopathy in the United States, congenital coronary artery anomalies, channelopathies, among others. This report will explore an overview of the prevalence and causes of SCD in the young. PMID- 28618150 TI - Impact of family characteristics by marital status of cohabitating adult children on depression among Korean older adults. AB - AIM: To identify the association between different living arrangements of intergenerational household composition and depression in older adults. METHODS: Data from the Korea Longitudinal Study of Aging, the first to fourth waves, were used. Using the first wave as baseline, our analysis included 5046 participants aged >=60 years with at least one living child. Depression was measured using the 10-item Center for Epidemiological Studies Depression scale. Factors investigated included living arrangements according to household composition and the marital status of a cohabiting adult child. A generalized estimating equation with the logit link for binary outcomes was used to examine the association between living arrangements and depression. RESULTS: Compared with the older adults living with a married child and grandchildren, those living alone, those living with an unmarried child, and those living with an unmarried child and grandchildren were more likely to have depression (OR 1.41, 95% CI 1.13-1.75; OR 1.40, 95% CI 1.18 1.66; OR 1.60, 95% CI 1.27-2.01). In particular, women were more likely to have depression than men in the association between living arrangements and depression. CONCLUSIONS: Efforts should be made to provide social services for older adults living alone and those living with an unmarried child in a two /three-generation family, in particular, for those who are female. Geriatr Gerontol Int 2017; 17: 2527-2536. PMID- 28618148 TI - Mechanisms underlying induction of allergic sensitization by Pru p 3. AB - BACKGROUND: Recently, the nature of the lipid-ligand of Pru p 3, one of the most common plant food allergens in southern Europe, has been identified as a derivative of the alkaloid camptothecin bound to phytosphingosine. However, the origin of its immunological activity is still unknown. OBJECTIVE: We sought to evaluate the role of the Pru p 3 lipid-ligand in the immunogenic activity of Pru p 3. METHODS: In vitro cultures of different cell types (monocyte-derived dendritic cells [moDCs], PBMCs [peripheral blood mononuclear cells] and epithelial and iNKT-hybridoma cell lines) have been used to determine the immunological capacity of the ligand, by measuring cell proliferation, maturation markers and cytokine production. To study the capacity of the lipid-ligand to promote sensitization to Pru p 3 in vivo, a mouse model of anaphylaxis to peach has been produced and changes in the humoral and basophil responses have been analysed. RESULTS: The lipid-ligand of Pru p 3 induced maturation of moDCsc and proliferation of PBMCs. Its immunological activity resided in the phytosphingosine tail of the ligand. The adjuvant activity of the ligand was also confirmed in vivo, where the complex of Pru p 3-ligand induced higher levels of IgE than Pru p 3 alone. The immunological capacity of the Pru p 3 ligand was mediated by CD1d, as maturation of moDCs was inhibited by anti-CD1d antibodies and Pru p 3-ligand co-localized with CD1d on epithelial cells. Finally, Pru p 3 ligand presented by CD1d was able to interact with iNKTs. CONCLUSIONS AND CLINICAL RELEVANCE: The Pru p 3 lipid-ligand could act as an adjuvant to promote sensitization to Pru p 3, through its recognition by CD1d receptors. This intrinsic adjuvant activity of the accompanying lipid cargo could be a general essential feature of the mechanism underlying the phenomenon of allergenicity. PMID- 28618151 TI - Development and evaluation of a multimedia child development resource for rural clinicians. PMID- 28618153 TI - Cascading influence of inorganic nitrogen sources on DOM production, composition, lability and microbial community structure in the open ocean. AB - Nitrogen frequently limits oceanic photosynthesis and the availability of inorganic nitrogen sources in the surface oceans is shifting with global change. We evaluated the potential for abrupt increases in inorganic N sources to induce cascading effects on dissolved organic matter (DOM) and microbial communities in the surface ocean. We collected water from 5 m depth in the central North Pacific and amended duplicate 20 liter polycarbonate carboys with nitrate or ammonium, tracking planktonic carbon fixation, DOM production, DOM composition and microbial community structure responses over 1 week relative to controls. Both nitrogen sources stimulated bulk phytoplankton, bacterial and DOM production and enriched Synechococcus and Flavobacteriaceae; ammonium enriched for oligotrophic Actinobacteria OM1 and Gammaproteobacteria KI89A clades while nitrate enriched Gammaproteobacteria SAR86, SAR92 and OM60 clades. DOM resulting from both N enrichments was more labile and stimulated growth of copiotrophic Gammaproteobacteria (Alteromonadaceae and Oceanospirillaceae) and Alphaproteobacteria (Rhodobacteraceae and Hyphomonadaceae) in weeklong dark incubations relative to controls. Our study illustrates how nitrogen pulses may have direct and cascading effects on DOM composition and microbial community dynamics in the open ocean. PMID- 28618152 TI - Potential risk of HBV reactivation in patients with resolved HBV infection undergoing direct-acting antiviral treatment for HCV. AB - BACKGROUND & AIMS: Despite a known risk of hepatitis B virus (HBV) reactivation during direct-acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV)-HBV coinfection, it remains unclear whether patients with past HBV infection are at risk for reactivation. This study evaluated the risk of HBV reactivation during treatment with sofosbuvir (SOF)-based regimens, focusing on patients with resolved HBV infection. METHODS: This study analyzes the data of 183 consecutive patients treated with SOF-based regimens. From these patients, 63 with resolved HBV infection (negative for hepatitis B surface antigen [HBsAg] and undetectable HBV DNA but positive for hepatitis B core antibody) were eligible for this study. HBV reactivation was defined as a quantifiable HBV DNA level >20 IU/mL. RESULTS: Among the patients antibody to HBsAg (anti-HBs) positive (10-500 mIU/mL) (n = 30), the titre of anti-HBs was significantly decreased with time, as shown by the results of repeated-measures analysis of variance (P = .0029). Overall, four patients (6.3%) with resolved HBV infection came to have detectable HBV DNA during treatment, including one who had HBV reactivation at week 4 (HBV DNA 80 IU/mL). However, none developed hepatic failure. Among four patients who had detectable HBV DNA during treatment, all were negative or had very low-titre (<20 mIU/mL) anti-HBs at baseline. CONCLUSIONS: The titre of anti-HBs was significantly decreased from the early stage of DAA treatment. Chronic hepatitis C patients with resolved HBV infection and negative or very low-titre anti-HBs at baseline are at risk for having detectable HBV DNA transiently during treatment. PMID- 28618154 TI - Catalytic Enantioselective Aza-pinacol Rearrangement. AB - The first catalytic enantioselective asymmetric aza-pinacol rearrangement is reported. The reactions are catalyzed by a chiral phosphoric acid and proceed via a highly organized transition state involving a cyclic aza-ortho-xylylene intermediate to afford the indoline structures with good to excellent enantioselectivity. The synthetic utility of this method is demonstrated by the asymmetric synthesis of a key intermediate to the natural product minfiensine and the identification of a chiral lead compound to repress antibiotic resistance. PMID- 28618155 TI - Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience. AB - BACKGROUND: Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT. METHODS: Here, we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period. RESULTS: During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive. CONCLUSIONS: It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed. PMID- 28618156 TI - The Gelpoint(r) Path Mini for transanal resection of rectal polyps - a video vignette. PMID- 28618157 TI - Liver microsomal lipid enhances the activity and redox coupling of colocalized cytochrome P450 reductase-cytochrome P450 3A4 in nanodiscs. AB - The haem-containing mono-oxygenase cytochrome P450 3A4 (CYP3A4) and its redox partner NADPH-dependent cytochrome P450 oxidoreductase (CPR) are among the most important enzymes in human liver for metabolizing drugs and xenobiotic compounds. They are membrane-bound in the endoplasmic reticulum (ER). How ER colocalization and the complex ER phospholipid composition influence enzyme activity are not well understood. CPR and CYP3A4 were incorporated into phospholipid bilayer nanodiscs, both singly, and together in a 1 : 1 ratio, to investigate the significance of membrane insertion and the influence of varying membrane composition on steady-state reaction kinetics. Reaction kinetics were analysed using a fluorimetric assay with 7-benzyloxyquinoline as substrate for CYP3A4. Full activity of the mono-oxygenase system, with electron transfer from NADPH via CPR, could only be reconstituted when CPR and CYP3A4 were colocalized within the same nanodiscs. No activity was observed when CPR and CYP3A4 were each incorporated separately into nanodiscs then mixed together, or when soluble forms of CPR were mixed with preassembled CYP3A4-nanodiscs. Membrane integration and colocalization are therefore essential for electron transfer. Liver microsomal lipid had an enhancing effect compared with phosphatidylcholine on the activity of CPR alone in nanodiscs, and a greater enhancing effect on the activity of CPR CYP3A4 nanodisc complexes, which was not matched by a phospholipid mixture designed to mimic the ER composition. Furthermore, liver lipid enhanced redox coupling within the system. Thus, natural ER lipids possess properties or include components important for enhanced catalysis by CPR-CYP3A4 nanodisc complexes. Our findings demonstrate the importance of using natural lipid preparations for the detailed analysis of membrane protein activity. PMID- 28618158 TI - A Fitbit and Facebook mHealth intervention for promoting physical activity among adolescent and young adult childhood cancer survivors: A pilot study. AB - BACKGROUND: Physical activity (PA) may be important for preventing chronic diseases for adolescent and young adult (AYA) childhood cancer survivors. Randomized controlled trials (RCTs) of PA interventions for AYA survivors are sparse, but necessary to determine effective programs for increasing PA among this population. Thus, we conducted a pilot RCT, testing the feasibility of a mobile health (mHealth) intervention to promote PA among AYA survivors. PROCEDURE: We recruited 14- to 18-year-olds who were >=1-year post cancer therapy from Seattle Children's Hospital. The 10-week intervention consisted of a wearable PA-tracking device (Fitbit Flex) and a peer-based virtual support group (Facebook group). Research staff helped set step goals and awarded badges weekly. Controls received usual care. Baseline assessments occurred before randomization and follow-up assessments occurred during weeks 8-10 of the intervention period. Feasibility criteria are defined below. Qualitative interviews assessed acceptability. Exploratory outcomes included PA, quality of life, and motivation for PA. RESULTS: All feasibility criteria were met: we recruited 60 survivors, intervention participants wore the Fitbit on the majority (71.5%) of intervention days, and >=90% of all participants completed questionnaires. Qualitative data confirmed intervention acceptability. Exploratory analyses found no significant adjusted group differences for change in moderate-to-vigorous PA (4.4 vs. 5.0 min/day; P = 0.92) or sedentary time (-4.5 vs. 1.0 min/day; P = 0.73), comparing intervention subjects to controls. Some modest differences were found for select subscales of quality of life and motivation for PA. CONCLUSIONS: This mHealth PA intervention was feasible and acceptable to AYA childhood cancer survivors and warrants a fully powered RCT. PMID- 28618159 TI - Are herbicides a once in a century method of weed control? AB - The efficacy of any pesticide is an exhaustible resource that can be depleted over time. For decades, the dominant paradigm - that weed mobility is low relative to insect pests and pathogens, that there is an ample stream of new weed control technologies in the commercial pipeline, and that technology suppliers have sufficient economic incentives and market power to delay resistance - supported a laissez faire approach to herbicide resistance management. Earlier market data bolstered the belief that private incentives and voluntary actions were sufficient to manage resistance. Yet, there has been a steady growth in resistant weeds, while no new commercial herbicide modes of action (MOAs) have been discovered in 30 years. Industry has introduced new herbicide tolerant crops to increase the applicability of older MOAs. Yet, many weed species are already resistant to these compounds. Recent trends suggest a paradigm shift whereby herbicide resistance may impose greater costs to farmers, the environment, and taxpayers than earlier believed. In developed countries, herbicides have been the dominant method of weed control for half a century. Over the next half-century, will widespread resistance to multiple MOAs render herbicides obsolete for many major cropping systems? We suggest it would be prudent to consider the implications of such a low-probability, but high-cost development. (c) 2017 Society of Chemical Industry. PMID- 28618160 TI - Vaccinia virus A11 is required for membrane rupture and viral membrane assembly. AB - Although most enveloped viruses acquire their membrane from the host by budding or by a wrapping process, collective data argue that nucleocytoplasmic large DNA viruses (NCLDVs) may be an exception. The prototype member of NCLDVs, vaccinia virus (VACV) may induce rupture of endoplasmic-reticulum-derived membranes to build an open-membrane sphere that closes after DNA uptake. This unconventional membrane assembly pathway is also used by at least 3 other members of the NCLDVs. In this study, we identify the VACV gene product of A11, as required for membrane rupture, hence for VACV membrane assembly and virion formation. By electron tomography, in the absence of A11, the site of assembly formed by the viral scaffold protein D13 is surrounded by endoplasmic reticulum cisternae that are closed. We use scanning transmission electron microscopy-electron tomography to analyse large volumes of cells and demonstrate that in the absence of A11, no open membranes are detected. Given the pivotal role of D13 in initiating VACV membrane assembly, we also analyse viral membranes in the absence of D13 synthesis and show that this protein is not required for rupture. Finally, consistent with a role in rupture, we show that during wild-type infection, A11 localises predominantly to the small ruptured membranes, the precursors of VACV membrane assembly. These data provide strong evidence in favour of the unusual membrane biogenesis of VACV and are an important step towards understanding its molecular mechanism. PMID- 28618161 TI - Prevention of osteoporotic refractures in regional Australia. AB - OBJECTIVE: Clinical guidelines recommend that patients who sustain a minimal trauma fracture (MTF) should receive a bone mineral density (BMD) scan and bisphosphonate (or equivalent) therapy if diagnosed with osteoporosis. A pilot fracture liaison service (FLS) was implemented in regional NSW to improve adherence to the guidelines. DESIGN: Prospective cohort study with an historical control. SETTING: Primary care. PARTICIPANTS: Control (n = 47) and cohort (n = 93) groups comprised patients consenting to interview who presented with a MTF to the major referral hospital 4 months before and 12 months after FLS implementation respectively. MAIN OUTCOME MEASURES: Primary outcome measures were the rates of BMD scans and anti-osteoporotic medication initiation/review after MTF. Hospital admission data were also examined to determine death and refracture rates for all patients presenting during the study period with a primary diagnosis of MTF within 3 years of their initial fracture. RESULTS: Although there was no improvement in BMD scanning rates, the reported rate of medication initiation/review after fracture was significantly higher (P < 0.05) in the FLS cohort. However, once adjusted for age, this association was not significant (P = 0.086). There was a lower refracture rate during the cohort period (P = 0.013), however, there were significantly more deaths (P = 0.035) within 3 years of initial fracture. When deaths were taken into account via competing risk regression, patients in the cohort period were significantly less likely to refracture than those in the control period (Hazard ratio = 0.576, P = 0.032). CONCLUSIONS: A rurally based nurse-led FLS was associated with modest improvement after MTF. Consideration should be given to ways to strengthen the model of care to improve outcomes. PMID- 28618163 TI - The communication of health information through the media: public health opportunity. PMID- 28618164 TI - Is liver transplant education patient-centered? PMID- 28618162 TI - ZEB1-regulated inflammatory phenotype in breast cancer cells. AB - Zinc finger E-box binding protein 1 (ZEB1) and ZEB2 induce epithelial-mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1-regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1-bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL-6 and IL-8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid-derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT. PMID- 28618165 TI - Herpes simplex virus-2 transmission following solid organ transplantation: Donor derived infection and transplantation from prior organ recipients. AB - BACKGROUND: Owing to limited availability of donor organs, previous solid organ transplant (SOT) recipients are increasingly considered as potential organ donors. We report donor-derived transmission of herpes simplex virus type-2 (HSV 2) to two clusters of SOT recipients with transmission from the original donor and an HSV-2-infected recipient who subsequently became a donor. METHODS: We reviewed medical records of the donors and recipients in both clusters. Pre transplant serology and virological features of HSV-2 were characterized. Genotyping of HSV-2 isolates to determine potential for donor transmission of HSV 2 through transplantation of organs from prior organ recipients was performed. RESULTS: A kidney-pancreas recipient died day 9 post transplant. Following confirmation of brain death, the lungs and recently transplanted kidney were donated to two further recipients. The liver was not retrieved, but biopsy confirmed HSV-2 infection. Testing on the original donor showed negative HSV-2 polymerase chain reaction and HSV immunoglobulin (Ig)M, but positive HSV-2 IgG. The liver recipient from the original donor developed HSV-2 hepatitis and cutaneous infection that responded to treatment with intravenous acyclovir. In the second cluster, lung and kidney recipients both developed HSV-2 viremia that was successfully treated with antiviral therapy. Genotyping of all HSV-2-positive samples showed 100% sequence homology for three recipients. CONCLUSIONS: Donor derived HSV infection affected two clusters of recipients because of transplantation of organs from a prior organ recipient. HSV should be considered as a possible cause of illness in febrile SOT recipients in the immediate post transplant period and may cause disseminated disease and re-infection in HSV-2 seropositive recipients. Testing of HSV serology and prophylaxis may be considered in SOT recipients not receiving cytomegalovirus prophylaxis. PMID- 28618166 TI - Abundance, genetic diversity and sensitivity to demethylation inhibitor fungicides of Aspergillus fumigatus isolates from organic substrates with special emphasis on compost. AB - BACKGROUND: Aspergillus fumigatus is a widespread fungus that colonizes dead organic substrates but it can also cause fatal human diseases. Aspergilloses are treated with demethylation inhibitor (DMI) fungicides; however, resistant isolates appeared recently in the medical and also environmental area. The present study aims at molecular characterizing and quantifying A. fumigatus in major environmental habitats and determining its sensitivity to medical and agricultural DMI fungicides. RESULTS: A. fumigatus was isolated only rarely from soil and meadow/forest organic matter but high concentrations (103 to 107 cfu/g) were detected in substrates subjected to elevated temperatures, such as compost and silage. High genetic diversity of A. fumigatus from compost was found based on SSR markers, distinguishing among fungal isolates even when coming from the same substrate sample, while subclustering was observed based on mutations in cyp51A gene. Several cyp51A amino acid substitutions were found in 15 isolates, although all isolates were fully sensitive to the tested DMI fungicides, with exception of one isolate in combination with one fungicide. CONCLUSION: This study suggests that the tested A. fumigatus isolates collected in Italy, Spain and Hungary from the fungus' major living habitats (compost) and commercial growing substrates are not potential carriers for DMI resistance in the environment. (c) 2017 Society of Chemical Industry. PMID- 28618167 TI - Neuropilin-1 regulated by miR-320 contributes to the growth and metastasis of cholangiocarcinoma cells. AB - BACKGROUND & AIMS: Neuropilin-1 (NRP-1) activates signalling pathways as multifunctional co-receptors in cancer cells. However, its role and how it is regulated by miRNAs in cholangiocarcinoma (CCA) have not yet been investigated. METHODS: The expression of NRP-1, miR-320 and key molecules involved in cell proliferation, migration and related signalling pathways were detected by immunohistochemistry, immunoblotting and qRT-PCR. Stable transfectants depleted of NRP-1 were generated. The regulatory effect of miR-320 on NRP-1 was evaluated by luciferase reporter assays. Cell proliferation, cell cycle distribution and migration were examined. Xenograft tumour models were established to assess tumourigenesis, tumour growth and lung metastasis. RESULTS: Cholangiocarcinoma tissues expressed higher levels of NRP-1 than adjacent normal biliary tissues, and its expression negatively correlated with miR-320. NRP-1 depletion inhibited cell proliferation and induced cell cycle arrest in the G1/S phase by upregulating p27, and downregulating cyclin E and cyclin-dependent kinase 2; and reduced cell migration by inhibiting the phosphorylation of focal adhesion kinase. NRP-1 depletion suppressed tumourigenesis, tumour growth and lung metastasis by inhibiting cell proliferation and tumour angiogenesis in experimental animals. Depletion of NRP-1 inhibited the activation of VEGF/VEGFR2, EGF/EGFR and HGF/c-Met pathways stimulated by respective ligands. MiR-320 negatively regulated the expression of NRP-1 by binding to the 3'-UTR of NRP-1 promoter, and miR-320 mimics inhibited cell proliferation and migration, and the growth of established tumours in animals by downregulating NRP-1. CONCLUSIONS: The present results indicate that NRP-1 is negatively regulated by miR-320, and both of them may be potentially therapeutic targets for CCA. PMID- 28618168 TI - Streptococcus pyogenes quinolinate-salvage pathway-structural and functional studies of quinolinate phosphoribosyl transferase and NH3 -dependent NAD+ synthetase. AB - : Streptococcus pyogenes, also known as Group A Strep (GAS), is an obligate human pathogen that is responsible for millions of infections and numerous deaths per year. Infection manifestations can range from simple, acute pharyngitis to more complex, necrotizing fasciitis. To date, most treatments for GAS infections involve the use of common antibiotics including tetracycline and clindamycin. Unfortunately, new strains have been identified that are resistant to these drugs, therefore, new targets must be identified to treat drug-resistant strains. This work is focused on the structural and functional characterization of three proteins: spNadC, spNadD, and spNadE. These enzymes are involved in the biosynthesis of nicotinamide adenine dinucleotide (NAD+ ). The structures of spNadC and spNadE were determined. SpNadC is suggested to play a role in GAS virulence, while spNadE, functions as an NAD synthetase and is considered to be a new drug target. Determination of the spNadE structure uncovered a putative, NH3 channel, which may provide insight into the mechanistic details of NH3 -dependent NAD+ synthetases in prokaryotes. ENZYMES: Quinolinate phosphoribosyltransferase: EC2.4.2.19 and NAD synthetase: EC6.3.1.5. DATABASE: Protein structures for spNadC, spNadCDelta69A , and spNadE are deposited into Protein Data Bank under the accession codes 5HUL, 5HUO & 5HUP, and 5HUH & 5HUJ, respectively. PMID- 28618169 TI - ECG-derived Cheyne-Stokes respiration and periodic breathing in healthy and hospitalized populations. AB - BACKGROUND: Cheyne-Stokes respiration (CSR) has been investigated primarily in outpatients with heart failure. In this study we compare CSR and periodic breathing (PB) between healthy and cardiac groups. METHODS: We compared CSR and PB, measured during 24 hr of continuous 12-lead electrocardiographic (ECG) Holter recording, in a group of 90 hospitalized patients presenting to the emergency department with symptoms suggestive of acute coronary syndrome (ACS) to a group of 100 healthy ambulatory participants. We also examined CSR and PB in the 90 patients presenting with ACS symptoms, divided into a group of 39 (43%) with confirmed ACS, and 51 (57%) with a cardiac diagnosis but non-ACS. SuperECG software was used to derive respiration and then calculate CSR and PB episodes from the ECG Holter data. Regression analyses were used to analyze the data. We hypothesized SuperECG software would differentiate between the groups by detecting less CSR and PB in the healthy group than the group of patients presenting to the emergency department with ACS symptoms. RESULTS: Hospitalized patients with suspected ACS had 7.3 times more CSR episodes and 1.6 times more PB episodes than healthy ambulatory participants. Patients with confirmed ACS had 6.0 times more CSR episodes and 1.3 times more PB episodes than cardiac non-ACS patients. CONCLUSION: Continuous 12-lead ECG derived CSR and PB appear to differentiate between healthy participants and hospitalized patients. PMID- 28618171 TI - Highly fluorinated polymers with sulfonate, sulfamide and N,N-diethylamino groups for the capillary electromigration separation of proteins and steroid hormones. AB - Highly fluorinated polymers are promising materials in separation methods due to their combination of high chemical and thermally stability, hydro- and oleophobicity, and weak intermolecular forces. However, application of these polymers in chromatography is limited because of their low solubility in aqueous organic solvents. In our research, the highly fluorinated water soluble polymers with -SO3- N(Et)4+ , -SO2 NH2 , and -N(Et)2 terminal groups were synthesized and applied as additives to the background electrolyte for the separation of steroid hormones and proteins by capillary electromigration methods. It is shown that highly fluorinated polymers can be used both as pseudo-stationary phases in electrokinetic chromatography for high separation efficiency (N ~ 200 * 103 ) and selectivity (alpha ~ 1.1) of uncharged analytes (e.g., steroid hormones), and as dynamic modifiers of fused silica capillary walls. The highest separation efficiency (N ~ 1 * 106 ) and selectivity (alpha ~ 1.3) of steroid hormones was achieved by combination of sodium dodecyl sulfate and fluoropolymer with sulfonate groups in background electrolyte with pH 2. Dynamic wall coatings based on fluoropolymer with -SO2 NH2 (which are easier and faster to create and wash off) exhibit significantly higher separation efficiency and selectivity compared to capillary electrochromatography on capillary columns based on polymethacrylate polymers. PMID- 28618170 TI - Frequency of Consuming Foods Predicts Changes in Cravings for Those Foods During Weight Loss: The POUNDS Lost Study. AB - OBJECTIVE: Food cravings are thought to be the result of conditioning or pairing hunger with consumption of certain foods. METHODS: In a 2-year weight loss trial, subjects were randomized to one of four diets that varied in macronutrient content. The Food Craving Inventory (FCI) was used to measure cravings at baseline and at 6 and 24 months. Food intake was also measured at those time points. To measure free-living consumption of food items measured in the FCI, items on the FCI were matched to the foods consumed from the food intake assessments. Secondarily, the amount of food consumed on food intake assessments from foods on the FCI was analyzed. RESULTS: Three hundred and sixty-seven subjects with overweight and obesity were included. There was an association between change from baseline FCI item consumption and change in cravings at months 6 (P < 0.001) and 24 (P < 0.05). There was no association between change from baseline amount of energy consumed per FCI item and change in cravings. CONCLUSIONS: Altering frequency of consuming craved foods is positively associated with cravings; however, changing the amount of foods consumed does not appear to alter cravings. These results support the conditioning model of food cravings and provide guidance on how to reduce food cravings. PMID- 28618172 TI - Dominance of Sulfuritalea species in nitrate-depleted water of a stratified freshwater lake and arsenate respiration ability within the genus. AB - Facultative autotrophs of the genus Sulfuritalea within the class Betaproteobacteria have been predicted to be an important bacterial population in stratified freshwater lakes based on previous PCR-based studies. Here, we designed a new probe specific for the genus Sulfuritalea and performed catalysed reporter deposition-fluorescence in situ hybridisation to enumerate cells of Sulfuritalea species throughout the water column in a stratified freshwater lake. The cells stained with the Sulfuritalea-specific probe were detected in all hypoxic water samples collected in different seasons and years. Their abundance ranged from 1.4 * 104 to 2.1 * 105 cells ml-1 , corresponding to 0.5-5.5% of the total DAPI-stained cells and 2.3-15% of the total bacterial cells. A high abundance of Sulfuritalea species was recorded in hypoxic water samples without nitrate, which is the only known anaerobic electron acceptor for Sulfuritalea. Nitrate-independent anaerobic respiration was further investigated using a single cultured representative of this genus, and its growth via arsenate respiration was experimentally demonstrated. In conclusion, Sulfuritalea species were found to be a major component of the planktonic bacterial community in nitrate-depleted hypoxic water, where arsenate respiration is one of the possible energy metabolisms of Sulfuritalea. PMID- 28618173 TI - Inter-individual differences determine the outcome of wheat bran colonization by the human gut microbiome. AB - Gut microbiota research reveals a vital role for the luminal and mucosal gut microbiota in human health. Fewer studies, however, have characterized the microbiome associated with undigested, insoluble dietary particles in the gut. These particles can act as a food source for bacteria and offer a physical platform to which they can attach. In this study, the microbiome colonizing wheat bran particles was analyzed. In a batch experiment, wheat bran particles were separately incubated with the faecal microbiota derived from 10 donors and washed after 48 h to remove loosely attached bacteria. The response of the luminal community to wheat bran and inulin, acting as a well-characterized control, was largely donor-dependent, both functionally, and with respect to the microbiome composition. Depending on the donor, wheat bran and inulin fermentation yielded proportionally higher propionate or butyrate production. Clostridium cluster XIVa and, depending on the donor, Prevotella, Roseburia, Megamonas, Bifidobacterium and Bacteroides species were enriched on the wheat bran particles. These genera include species with the documented ability to serve as primary degraders of wheat bran components and other species depending on cross-feeding to obtain their energy. Both functional groups were present in all donors, despite the large inter-individual differences. PMID- 28618174 TI - Intraspecific maternal competition induces summer diapause in insect parasitoids. AB - Organisms often live in unpredictable environments and have to adopt life history strategies that optimize their fitness under these conditions. According to bet hedging theory, individuals can reduce variation in fitness outcomes by investing in different strategies at the same time. For arthropods, facultative summer diapause enables survival during dry and hot periods of the year, and can be triggered by a decrease in resource abundance. However, the effect of resource depletion on diapause induction has never been disentangled from the effect of the perception of the presence of competitors. Using two solitary parasitoid species of cereal aphids as a model system, Aphidius avenae (Haliday) and Aphidius rhopalosiphi (De Stefani-Perez) (Hymenoptera: Braconidae), we tested whether (i) low absolute host density and/or (ii) high levels of parasitoid females' competition lead to maternal-induced summer diapause in parasitoid offspring. Under summer-like climatic conditions, emerging parasitoid females were (i) reared alone and exposed to different host densities (from 5 to 130 aphids), or (ii) reared together with competing females (from 2 to 20 females) and then exposed individually to 50 aphids. For both parasitoid species, low aphid densities did not induce summer diapause. However, the incidence of summer diapause increased up to a maximum of 11% with increasing levels of competition experienced by female parasitoids. More than 60% of the females produced both diapausing and nondiapausing offspring after being kept at the two highest competition densities. Such a "spreading-the-risk" strategy has likely evolved to optimize parasitoid fitness by preventing the following generation from exposure to low populations of suitable hosts and high mortality from superparasitism. These results provide the first experimental evidence of direct maternal competition-induced diapause in insects, and may change the way we apprehend the evolution of arthropod seasonal ecology, by considering intraspecific competition. PMID- 28618175 TI - The ominous association between severe endometriosis, in vitro fertilisation, and placenta previa: raising awareness, limiting risks, informing women. PMID- 28618176 TI - Bis(trifluoromethylsulfonyl)imide-based frozen ionic liquid for the hollow-fiber solid-phase microextraction of dichlorodiphenyltrichloroethane and its main metabolites. AB - 1-Hexadecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide is a solid phase ionic organic material under ambient temperature and is considered as a kind of "frozen" ionic liquid. Because of their solid-state and ultra hydrophobicity, "frozen" ionic liquids are able to be confined in the pores of hollow fiber, based on which a simple method was developed for the hollow-fiber solid-phase microextraction of dichlorodiphenyltrichloroethane and its main metabolites. Under optimized conditions, the proposed method results in good linearity (R2 > 0.9965) over the range of 0.5-50 MUg/L, with low limits of detection and quantification in the range of 0.33-0.38 and 1.00-1.25 MUg/L, respectively. Intra- and interday precisions evaluated by relative standard deviation were 3-6 and 1-6%, respectively. The spiked recoveries of dichlorodiphenyltrichloroethane and its main metabolites from real water samples were in the range of 64-113 and 79-112%, respectively, at two different concentration levels. The results suggest that "frozen" ionic liquids are promising for use as a class of novel sorbents. PMID- 28618178 TI - Decarboxylation of Lactones over Zn/ZSM-5: Elucidation of the Structure of the Active Site and Molecular Interactions. AB - Herein, we report the catalytic decarboxylation of gamma-valerolactone (GVL) over Zn/ZSM-5 to butene, followed by aromatization at high yield with co-feeding of water. An evaluation of the catalytic performance after prolonged periods of time showed that a water molecule is essential to maintain the decarboxylation and aromatization activities and avoid rapid catalyst deactivation. Synchrotron X-ray powder diffraction and Rietveld refinement were then used to elucidate the structures of adsorbed GVL and immobilized Zn species in combination with EXAFS and NMR spectroscopy. A new route for the cooperative hydrolysis of GVL by framework Zn-OH and Bronsted acidic sites to butene and then to aromatic compounds has thus been demonstrated. The structures and fundamental pathways for the nucleophilic attack of terminal Zn-OH sites are comparable to those of Zn containing enzymes in biological systems. PMID- 28618177 TI - Assessing the quality of primary care referrals to surgery of patients with diabetes in the East of England: A multi-centre cross-sectional cohort study. AB - AIM: Peri-operative hyperglycaemia is associated with an increased incidence of adverse outcomes. Communication between primary and secondary care is paramount to minimise these harms. National guidance in the UK recommends that the glycated haemoglobin (HbA1c) should be measured within 3 months prior to surgery and that the concentration should be less that 69 mmol/mol (8.5%). In addition, national guidance outlines the minimum dataset that should be included in any letter at the time of referral to the surgeons. Currently, it is unclear how well this process is being carried out. This study investigated the quality of information being handed over during the referral from primary care to surgical outpatients within the East of England. METHODS: Primary care referrals to nine different NHS hospital Trusts were gathered over a 1-week period. All age groups were included from 11 different surgical specialties. Referral letters were analysed using a standardised data collection tool based on the national guidelines. RESULTS: A total of 1919 referrals were received, of whom 169 (8.8%) had previously diagnosed diabetes mellitus (DM). However, of these, 38 made no mention of DM in the referral letter but were on glucose-lowering agents. Only 13 (7.7%) referrals for patients with DM contained a recent HbA1c, and 20 (11.8%) contained no documentation of glucose-lowering medication. CONCLUSION: This study has shown that the quality of referral letters to surgical specialties for patients with DM in the East of England remain inadequate. There is a clear need for improving the quality of clinical data contained within referral letters from primary care. In addition, we have shown that the rate of referral for surgery for people with diabetes is almost 50% higher than the background population with diabetes. PMID- 28618179 TI - Critical Evaluation of Native Electrospray Ionization Mass Spectrometry for Fragment-Based Screening. AB - Fragment-based screening presents a promising alternative to high-throughput screening and has gained great attention in recent years. So far, only a few studies have discussed mass spectrometry as a screening technology for fragments. Herein, we report the application of native electrospray ionization mass spectrometry (MS) for screening defined sets of fragments against four different target proteins. Fragments were selected from a primary screening conducted with a thermal shift assay (TSA) and represented different binding categories. Our data indicated that, beside specific complex formation, many fragments show extensive multiple binding and also charge-state shifts. Both of these factors complicate automated data analysis and decrease the attractiveness of native MS as a primary screening tool for fragments. A comparison of the hits identified by native MS and TSA showed good agreement for two of the proteins. Furthermore, we discuss general challenges, including the determination of an optimal fragment concentration and the question of how to rank fragment hits according to their affinity. In conclusion, we consider native MS to be a highly valuable tool for the validation and deeper investigation of promising fragment hits rather than a method for primary screening. PMID- 28618180 TI - Neutrophil-lymphocyte ratio and a dosimetric factor for predicting symptomatic radiation pneumonitis in non-small-cell lung cancer patients treated with concurrent chemoradiotherapy. AB - OBJECTIVES: To identify the factors that predict the progression of radiological radiation pneumonitis (RP) to symptomatic RP, and to evaluate the usefulness of the neutrophil-lymphocyte ratio (NLR) as a marker of RP severity and prognosis in stage III non-small cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: We retrospectively reviewed 61 patients treated between January 2010 and December 2015. Patients' demographic characteristics, clinical data, laboratory findings and treatment parameters were analyzed to determine the predictive factors associated with progression from radiological RP to symptomatic RP. RESULTS: Forty-seven patients (77%) exhibited radiological RP at a median of 78 days after radiation therapy (RT) completion, and 15 (32%) of these patients developed symptomatic RP. The interval between RT completion and radiological RP presentation was shorter in patients who progressed to symptomatic RP (P = .001); progression was highly probable if this latency period was <=2 months (P = .002). Stage and RT technique correlated with symptomatic RP development (P = .046 and P = .046, respectively). Among dosimetric factors, a V20 (defined as the lung volume receiving >=20 Gy) of >30% was the most significant predictor of symptomatic RP (P = .001). The NLR and C-reactive protein level at radiological RP were higher in patients who developed symptomatic RP (P = .067 and P = .012, respectively). On multivariate analysis, a V20 >30% and an NLR at radiological RP >6 were associated with symptomatic RP development. CONCLUSION: The NLR at radiological RP is a useful biomarker for predicting symptomatic RP development after CCRT in stage III NSCLC patients. PMID- 28618181 TI - Ineffective Protection in Hemodialysis Patients: Sociodemographic and Clinical Context. AB - PURPOSE: To analyze the association between components of the nursing diagnosis ineffective protection (00043) and sociodemographic and clinical data of hemodialysis patients. METHOD: Cross-sectional study was conducted during the first half of 2015 with a sample of 200 patients from a reference clinic of nephrology. A structured instrument containing operational definitions was used to collect data. FINDINGS: Hemodialysis patients presented defining characteristics of ineffective protection (00043) associated with sociodemographic and clinical context variables. CONCLUSION: Components of this diagnosis may be influenced by sociodemographic and clinical context of hemodialysis patients. PMID- 28618182 TI - Mechanism and regulation of sorbicillin biosynthesis by Penicillium chrysogenum. AB - Penicillium chrysogenum is a filamentous fungus that is used to produce beta lactams at an industrial scale. At an early stage of classical strain improvement, the ability to produce the yellow-coloured sorbicillinoids was lost through mutation. Sorbicillinoids are highly bioactive of great pharmaceutical interest. By repair of a critical mutation in one of the two polyketide synthases in an industrial P. chrysogenum strain, sorbicillinoid production was restored at high levels. Using this strain, the sorbicillin biosynthesis pathway was elucidated through gene deletion, overexpression and metabolite profiling. The polyketide synthase enzymes SorA and SorB are required to generate the key intermediates sorbicillin and dihydrosorbicillin, which are subsequently converted to (dihydro)sorbillinol by the FAD-dependent monooxygenase SorC and into the final product oxosorbicillinol by the oxidoreductase SorD. Deletion of either of the two pks genes not only impacted the overall production but also strongly reduce the expression of the pathway genes. Expression is regulated through the interplay of two transcriptional regulators: SorR1 and SorR2. SorR1 acts as a transcriptional activator, while SorR2 controls the expression of sorR1. Furthermore, the sorbicillinoid pathway is regulated through a novel autoinduction mechanism where sorbicillinoids activate transcription. PMID- 28618184 TI - Big improvements for the smallest recipients. PMID- 28618183 TI - Effects of different temperature regimes on survival of Diaphorina citri and its endosymbiotic bacterial communities. AB - The Asian citrus psyllid, Diaphorina citri, is a major pest of citrus and vector of citrus greening (huanglongbing) in Asian. In our field-collected psyllid samples, we discovered that Fuzhou (China) and Faisalabad (Pakistan), populations harbored an obligate primary endosymbiont Candidatus Carsonella (gen. nov.) with a single species, Candidatus Carsonella ruddii (sp. nov.) and a secondary endosymbiont, Wolbachia surface proteins (WSP) which are intracellular endosymbionts residing in the bacteriomes. Responses of these symbionts to different temperatures were examined and their host survival assessed. Diagnostic PCR assays showed that the endosymbionts infection rates were not significantly reduced in both D. citri populations after 24 h exposure to cold or heat treatments. Although quantitative PCR assays showed significant reduction of WSP relative densities at 40 degrees C for 24 h, a substantial decrease occurred as the exposure duration increased beyond 3 days. Under the same temperature regimes, Ca. C. ruddii density was initially less affected during the first exposure day, but rapidly reduced at 3-5 days compared to WSP. However, the mortality of the psyllids increased rapidly as exposure time to heat treatment increased. The responses of the two symbionts to unfavorable temperature regimes highlight the complex host-symbionts interactions between D. citri and its associated endosymbionts. PMID- 28618185 TI - Let's talk about sleep: a systematic review of psychological interventions to improve sleep in college students. AB - Sleep problems are a common occurrence in college students. Insomnia, nightmares and impaired sleep quality lead to several mental health issues, as well as impaired academic performance. Although different sleep programmes exist, a systematic overview comparing their effectiveness is still missing. This systematic review aims to provide an overview of psychological interventions to improve sleep in college students. Seven databases were searched from November to December 2016 (MEDLINE, EMBASE, PsycINFO, Cinahl, Cochrane Library, PubMed, OpenSigle). The search string included search terms from three different topics: sleep, intervention and college students. Outcome measures included subjective as well as objective measures and focused on sleep, sleep-related and mental health variables. Twenty-seven studies met the inclusion criteria. They were assigned to four intervention categories: (1) sleep hygiene, (2) cognitive-behavioural therapy (CBT), (3) relaxation, mindfulness and hypnotherapy and (4) other psychotherapeutic interventions. Fifteen studies were randomized controlled trials. While sleep hygiene interventions provided small to medium effects, the CBTs showed large effects. The variability of the effect sizes was especially large in the relaxation category, ranging from very small to very large effect sizes. Other psychotherapeutic interventions showed medium effects. CBT approaches provided the best effects for the improvement of different sleep variables in college students. Five studies included insomnia patients. The other three intervention categories also showed promising results with overall medium effects. In the future, CBT should be combined with relaxation techniques, mindfulness and hypnotherapy. Furthermore, the interventions should broaden their target group and include more sleep disorders. PMID- 28618187 TI - Physically consistent data assimilation method based on feedback control for patient-specific blood flow analysis. AB - This paper presents a novel data assimilation method for patient-specific blood flow analysis based on feedback control theory called the physically consistent feedback control-based data assimilation (PFC-DA) method. In the PFC-DA method, the signal, which is the residual error term of the velocity when comparing the numerical and reference measurement data, is cast as a source term in a Poisson equation for the scalar potential field that induces flow in a closed system. The pressure values at the inlet and outlet boundaries are recursively calculated by this scalar potential field. Hence, the flow field is physically consistent because it is driven by the calculated inlet and outlet pressures, without any artificial body forces. As compared with existing variational approaches, although this PFC-DA method does not guarantee the optimal solution, only one additional Poisson equation for the scalar potential field is required, providing a remarkable improvement for such a small additional computational cost at every iteration. Through numerical examples for 2D and 3D exact flow fields, with both noise-free and noisy reference data as well as a blood flow analysis on a cerebral aneurysm using actual patient data, the robustness and accuracy of this approach is shown. Moreover, the feasibility of a patient-specific practical blood flow analysis is demonstrated. PMID- 28618186 TI - Therapeutic Efficacy of Fresh, Allogeneic Mesenchymal Stem Cells for Severe Refractory Feline Chronic Gingivostomatitis. AB - Mesenchymal stem cells (MSCs) have potent immunomodulatory functions and are a promising therapy for immune-mediated inflammatory disorders. We previously demonstrated the efficacy of fresh, autologous, adipose-derived MSCs (ASCs) to treat feline chronic gingivostomatitis (FCGS), a chronic oral mucosal inflammatory disease similar to human oral lichen planus. Here, we investigate the use of fresh allogeneic ASCs for treatment of FCGS in seven cats. Radiolabeled ASCs were also tracked systemically. Each cat received two intravenous injections of 20 million ASCs, 1 month apart. Oral inflammation, blood lymphocyte subsets, anti-fetal bovine serum antibody levels, ASC crossmatching and serum proteins and cytokine concentrations were determined. Four of the 7 cats (57%) responded to treatment [complete clinical remission (n = 2) or substantial clinical improvement (n = 2)]. Three cats were nonresponders. Prior to therapy, most cats had increased circulating CD8+ T cells, decreased CD8lo cells, and a decreased CD4/CD8 ratio, however clinical resolution was not associated with normalization of these parameters. Nonresponders showed more severe systemic inflammation (neutrophilia, hyperglobulinemia and increased interferon gamma and tumor necrosis factor alpha concentration) prior to ASC therapy. Clinical remission took up to 20 months and no clinical relapse has occurred. A higher fraction of radiolabeled ASCs were identified in the oral cavity of FCGS affected cats than the control cat. The administration of fresh, allogenic ASCs appeared to have lower clinical efficacy with a delayed response as compared to the fresh, autologous ASCs. In addition, the mechanism(s) of action for autologous and allogenic ASCs may differ in this model of oral inflammation. Stem Cells Translational Medicine 2017;6:1710-1722. PMID- 28618188 TI - Real-time viability and apoptosis kinetic detection method of 3D multicellular tumor spheroids using the Celigo Image Cytometer. AB - The development of three-dimensional (3D) multicellular tumor spheroid models for cancer drug discovery research has increased in the recent years. The use of 3D tumor spheroid models may be more representative of the complex in vivo tumor microenvironments in comparison to two-dimensional (2D) assays. Currently, viability of 3D multicellular tumor spheroids has been commonly measured on standard plate-readers using metabolic reagents such as CellTiter-Glo(r) for end point analysis. Alternatively, high content image cytometers have been used to measure drug effects on spheroid size and viability. Previously, we have demonstrated a novel end point drug screening method for 3D multicellular tumor spheroids using the Celigo Image Cytometer. To better characterize the cancer drug effects, it is important to also measure the kinetic cytotoxic and apoptotic effects on 3D multicellular tumor spheroids. In this work, we demonstrate the use of PI and caspase 3/7 stains to measure viability and apoptosis for 3D multicellular tumor spheroids in real-time. The method was first validated by staining different types of tumor spheroids with PI and caspase 3/7 and monitoring the fluorescent intensities for 16 and 21 days. Next, PI-stained and nonstained control tumor spheroids were digested into single cell suspension to directly measure viability in a 2D assay to determine the potential toxicity of PI. Finally, extensive data analysis was performed on correlating the time dependent PI and caspase 3/7 fluorescent intensities to the spheroid size and necrotic core formation to determine an optimal starting time point for cancer drug testing. The ability to measure real-time viability and apoptosis is highly important for developing a proper 3D model for screening tumor spheroids, which can allow researchers to determine time-dependent drug effects that usually are not captured by end point assays. This would improve the current tumor spheroid analysis method to potentially better identify more qualified cancer drug candidates for drug discovery research. (c) 2017 International Society for Advancement of Cytometry. PMID- 28618189 TI - Comparative genomics of the DNA damage-inducible network in the Patescibacteria. AB - Metagenomics provide unprecedented insights into the genetic diversity of uncultivated bacteria inhabiting natural environments. Recent surveys have uncovered a major radiation of candidate phyla encompassing the Patescibacteria superphylum. Patescibacteria have small genomes and a presumed symbiotic or parasitic lifestyle, but the difficulty in culturing representative members constrains the characterization of behavioural and adaptive traits. Here we combine in silico and in vitro approaches to characterize the SOS transcriptional response to DNA damage in the Patescibacteria superphylum. Leveraging comparative genomics methods, we identify and experimentally define a novel binding motif for the SOS transcriptional repressor LexA, and we use this motif to characterize the conserved elements of the SOS regulatory network in Patescibacteria. The Patescibacteria LexA-binding motif has unusual direct-repeat structure, and comparative analyses reveal sequence and structural similarities with the distant Acidobacteria LexA protein. Our results reveal a shared core SOS network, complemented by varying degrees of LexA regulation of other core SOS functions. This work illustrates how the combination of computational and experimental methods can leverage metagenomic data to characterize transcriptional responses in uncultivated bacteria. The report of an operational SOS response in presumed symbiotic and parasitic bacteria hints at an intermediate step in the process of genome reduction. PMID- 28618190 TI - Relation between upper-limb muscle strength with exercise capacity, quality of life and dyspnea in patients with severe chronic obstructive pulmonary disease. AB - INTRODUCTION: In chronic obstructive pulmonary disease (COPD), skeletal muscle weakness is characterized by reduced muscle strength, reduced muscle endurance and the presence of muscle fatigue especially in lower limbs. There has been little research into the upper limb skeletal muscles. OBJECTIVES: In this study, we aimed to investigate the relation of upper limb muscle strength with pulmonary function, exercise capacity, quality of life (QoL) and dyspnea sensation. METHODS: Eigthy-eight patients (89.8% male; age: 64.2 +/- 8.7 years) with COPD (FEV1 = 34.2% +/- 15.2%) were evaluated. Tests included hand grip strength and actual 1-repetition maximum (1RM) test for upper limb strength. Dyspnea sensation was assessed with medical research council (MRC) scale. St. George Respiratory Questionary (SGRQ) was used to evaluate patients health related QoL. Exercise capacity was evaluated with incremental shuttle walk test and endurance shuttle walk test. RESULTS: Upper limb muscle strength correlated with exercise capacity but no correlations were found with pulmonary functions.There were negative correlations with all the domains of SGRQ both actual 1RM and handgrip strength. MRC scores revealed a negative correlation with upper limb muscle strength. CONCLUSION: In our study, we showed that upper limb muscle strength correlated with exercise capacity, QoL, dyspnea sensation. Identifying patients who have greater reductions in strength will allow early interventions with a multidisciplinary manner. PMID- 28618193 TI - Introduction of color-flow injection test to confirm intravascular location of peripherally placed intravenous catheters. AB - BACKGROUND: The incidence of infiltration and extravasation when using peripheral intravenous catheters is high in pediatric patients. Due to the lack of a gold standard test to confirm intravascular location of a peripherally placed intravenous catheter, we introduce a novel method, the color-flow injection test to assess the intravascular location of these catheters. For the color-flow injection test, 1 mL of normal saline was injected within 2 seconds in the distal intravenous catheter and changes in color-flow via ultrasonography were observed at the proximal draining veins. The primary objective of the study was to demonstrate feasibility of the color-flow injection test. METHODS: A prospective study was conducted on children <18 years old undergoing general anesthesia. All peripheral intravenous catheters were subject to the color-flow injection test and standard confirmation tests. RESULTS: Out of the 100 patients enrolled, 22 patients came to the operating room with preexisting peripheral intravenous catheters. Intraoperatively, 105 attempts were made on 78 patients of which 27 catheters were considered as infiltrated during their placement. A final set of 100 catheters were considered for intraoperative usage after they had passed at least one of the standard confirmatory tests. For the color-flow injection test, the ideal sites for ultrasound evaluation of proximal draining veins were the axillary veins and femoral veins. The color-flow injection test was positive in 93 of the 100 catheters with color-flow changes noticed in the proximal veins during the saline injection. Of the 100 catheters, infiltration around seven catheter sites were observed within 2 hours of intraoperative usage and the color flow injection test was negative in these seven catheters. The color-flow injection test was also negative in the 27 catheters that had infiltrated during their placement. The color-flow injection test was sensitive at 100% [95% confidence interval (CI)=95-100] and specific at 100% (95% CI=56-100) to indicate intravascular location. CONCLUSION: We were able to confirm intravascular location of peripheral intravenous catheters using the color-flow injection test in pediatric patients. The test can lead to early recognition of malfunctioning peripheral intravenous catheters and decrease rate of infiltration-extravasation injuries associated with their use. PMID- 28618191 TI - A Proton Pump Inhibitor in the Reformulation Setting: Bioequivalence and Potential Implications for Long-Term Safety. AB - Proton pump inhibitors (PPIs) have become known for both their therapeutic effect and good safety profile. An application was submitted to the US Food and Drug Administration for approval of a reformulated PPI product that failed bioequivalence testing, but was submitted on the basis of the long history of PPI use as a "surrogate" for equivalence. This review evaluates the safety data for PPIs, discuss variability of pharmacokinetic parameters of PPIs in the reformulation setting, and potential implications of those changes for long-term safety. PMID- 28618192 TI - The patient buddy app can potentially prevent hepatic encephalopathy-related readmissions. AB - BACKGROUND & AIMS: Readmissions are a major burden in cirrhosis. A proportion of readmissions in cirrhosis, especially because of hepatic encephalopathy (HE) could be avoided through patient and caregiver engagement. We aimed to define the feasibility of using the Patient Buddy App and its impact on 30-day readmissions by engaging and educating cirrhotic inpatients and caregivers in a pilot study. METHODS: Cirrhotic inpatients with caregivers were enrolled and followed for 30 days post-discharge. On separately assigned devices loaded with Patient Buddy, they were trained on entering medication adherence, daily sodium intake and weights, and weekly cognitive (EncephalApp_Stroop) and fall-risk assessment and were educated regarding cirrhosis-related symptoms. These were monitored daily through a Patient Buddy loaded iPad by the clinical team. The App sent automatic alerts between patient/caregivers and clinical team regarding adherence and critical values. At 30 days, total, and HE-related admissions were analysed as well as the feasibility and feedback regarding educational values. RESULTS: Forty patients and 40 caregivers were enrolled. Seventeen patients were readmitted within 30-days but none for HE. Eight potential HE-related readmissions were prevented through App-generated alerts that encouraged early outpatient interventions. Caregivers and patients were concordant in data entry but six did not complete data entries. Most respondents rated the App favourably for its educational value. CONCLUSIONS: In this proof-of-concept trial, the use of Patient Buddy is feasible in recently discharged patients with cirrhosis and their caregivers. Eight HE-related readmissions were potentially avoided after the use of the App. PMID- 28618194 TI - Sexual dimorphism in the alpine butterflies Boloria pales and Boloria napaea: differences in movement and foraging behavior (Lepidoptera: Nymphalidae). AB - Sexual dimorphism is a widespread phenomenon in Lepidoptera. It is reflected in differences in life history, behavior and morphology. Analyses of differences in behavior are mostly difficult and time-consuming, especially in high mountain ecosystems. To enhance our knowledge on sexual dimorphisms of alpine butterflies, we performed a mark-release-recapture study on 2 species common in the Alps: Boloria pales and Boloria napaea. We analysed movement and foraging behavior to investigate differences between sexes. Both sexes were mostly sedentary and the movement distances of males and females similar. However, obvious differences in dispersal behavior between the sexes were found in the movement patterns. Three different patterns were distinguished. Most males showed intensive flight activity, but mostly flew only in a limited part of the entire habitat (i.e., their individual home range) searching for females, whereas females were less flight active and flew only to find places for oviposition or feeding. The third pattern, where individuals flew larger distances, was only observed in a small number of males, which always returned to their home range. Nearly all feeding was observed on Asteraceae. However, males preferred the genera Leontodon and Crepis, while females preferred Leontodon and Carduus. Apart from this sexual difference in foraging, individuals of both sexes were found to be more or less specialised on nectar sources. Flight activity was generally greater in males than females. Therefore, we think that sex-specific requirements in nectar ingredients exist, that is, sugar for the intensive flight activity of males and amino acids for egg production of females. PMID- 28618195 TI - Novel reductive dehalogenases from the marine sponge associated bacterium Desulfoluna spongiiphila. AB - Desulfoluna spongiiphila strain AA1 is an organohalide respiring bacterium, isolated from the marine sponge Aplysina aerophoba, that can use brominated and iodinated phenols, in addition to sulfate and thiosulfate as terminal electron acceptors. The genome of Desulfoluna spongiiphila strain AA1 is approximately 6.5 Mb. Three putative reductive dehalogenase (rdhA) genes involved in respiratory metabolism of organohalides were identified within the sequence. Conserved motifs found in respiratory reductive dehalogenases (a twin arginine translocation signal sequence and two iron-sulfur clusters) were present in all three putative AA1 rdhA genes. Transcription of one of the three rdhA genes was significantly upregulated during respiration of 2,6-dibromophenol and sponge extracts. Strain AA1 appears to have the ability to synthesize cobalamin, the key cofactor of most characterized reductive dehalogenase enzymes. The genome contains genes involved in cobalamin synthesis and uptake and can grow without cobalamin supplementation. Identification of this target gene associated with debromination lays the foundation for understanding how dehalogenating bacteria control the fate of organohalide compounds in sponges and their role in a symbiotic organobromine cycle. In the sponge environment, D. spongiiphila strain AA1 may thus take advantage of both brominated compounds and sulfate as electron acceptors for respiration. PMID- 28618196 TI - Integrating chytrid fungal parasites into plankton ecology: research gaps and needs. AB - Chytridiomycota, often referred to as chytrids, can be virulent parasites with the potential to inflict mass mortalities on hosts, causing e.g. changes in phytoplankton size distributions and succession, and the delay or suppression of bloom events. Molecular environmental surveys have revealed an unexpectedly large diversity of chytrids across a wide range of aquatic ecosystems worldwide. As a result, scientific interest towards fungal parasites of phytoplankton has been gaining momentum in the past few years. Yet, we still know little about the ecology of chytrids, their life cycles, phylogeny, host specificity and range. Information on the contribution of chytrids to trophic interactions, as well as co-evolutionary feedbacks of fungal parasitism on host populations is also limited. This paper synthesizes ideas stressing the multifaceted biological relevance of phytoplankton chytridiomycosis, resulting from discussions among an international team of chytrid researchers. It presents our view on the most pressing research needs for promoting the integration of chytrid fungi into aquatic ecology. PMID- 28618197 TI - Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights. AB - Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAFV600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAFV600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting. PMID- 28618198 TI - Effect of intravenous paracetamol as pre-emptive compared to preventive analgesia in a pediatric dental setting: a prospective randomized study. AB - BACKGROUND: Efficacy of pre-emptive analgesia compared to preventive regimen, managing postoperative pain is still controversial. AIM: Evaluating the efficacy of intravenous (IV) paracetamol as pre-emptive analgesia compared to preventive post-treatment administration in pediatric dental setting. DESIGN: In a prospective trial, 60 noncooperative children of ASA I, II aged 3-10 years who underwent dental rehabilitation under general anesthesia were randomly divided into two groups. Pre-emptive group (n = 30) received 15 mg/kg of IV paracetamol before the start of treatment. Preventive group (n = 30) received 15 mg/kg of paracetamol at the end of treatment. Analgesic efficacy was measured by visual analog scale of faces (VASOF), percentage of children received postoperative analgesia. RESULTS: The VASOF results in the pre-emptive group were significantly lower compared to the preventive group at 4, 8, 12, and 24 h (0.0146, 0.0188, 0.0085, and 0.0001, respectively). Less children in the pre-emptive group received supplemental fentanyl postoperatively compared to the preventive group (27.6%, 58.6%, respectively, P = 0.0170). Time to first rescue dose of fentanyl postoperatively in the pre-emptive group was later than in the preventive group (P = 0.0432). CONCLUSIONS: Administration of IV paracetamol pre-emptively provides lower pain scores, and a decreased percentage of children required pain relief and less amount of postoperative opioids, compared to preventive administration. PMID- 28618199 TI - Lipid interactions modulate the structural and antigenic properties of the C terminal domain of the malaria antigen merozoite surface protein 2. AB - : Merozoite surface protein 2 (MSP2) is a highly abundant, GPI-anchored antigen on the malaria parasite Plasmodium falciparum. MSP2 induces an immune response in the context of natural infections and vaccine trials, and these responses are associated with protection from parasite infection. Recombinant MSP2 is highly disordered in solution but antigenic analyses suggest that it is more ordered on the merozoite surface. We have shown previously that the interaction of recombinant full-length MSP2 with lipid surfaces induces a conformational change in the conserved N-terminal region of MSP2, which contributes to epitope masking in this region. To explore the impacts of lipid interactions on the conformation and antigenicity of the conserved C-terminal region of MSP2, a construct corresponding to this domain, MSP2172-221 , was designed. NMR studies indicate that many residues in MSP2172-221 interact with DPC micelles, including some in epitopes recognised by C-terminal-specific monoclonal antibodies, but, in contrast to the MSP2 N-terminus, there is no indication of stable helical conformation. The binding affinities of a panel of monoclonal antibodies indicate that MSP2172-221 is antigenically similar to full-length MSP2 and show that liposome conjugation alters the antigenicity in a manner that may mimic native MSP2 on the merozoite surface. These findings highlight the impact of lipid interactions on the conformation and antigenicity of MSP2172-221 and will assist in the design of recombinant MSP2 immunogens for use as malaria vaccine candidates. DATABASES: Resonance assignments are available in the BioMagResBank (BMRB) database under the accession number 27134. PMID- 28618200 TI - Ambient and Dosed Exposure to Quaternary Ammonium Disinfectants Causes Neural Tube Defects in Rodents. AB - BACKGROUND: Quaternary ammonium compounds are a large class of chemicals used for their antimicrobial and antistatic properties. Two common quaternary ammonium compounds, alkyldimethylbenzyl ammonium chloride (ADBAC) and didecyldimethyl ammonium chloride (DDAC), are combined in common cleaners and disinfectants. Introduction of a cleaner containing ADBAC+DDAC in the vivarium caused neural tube defects (NTDs) in mice and rats. METHODS: To further evaluate this finding, male and female mice were dosed in the feed at 60 or 120 mg/kg/day, or by oral gavage at 7.5, 15, or 30 mg/kg ADBAC+DDAC. Mice also received ambient exposure to ADBAC+DDAC from the disinfectant used in the mouse room. Embryos were evaluated on gestational day 10 for NTDs, and fetuses were evaluated on gestational day 18 for gross and skeletal malformations. RESULTS: We found increased NTDs with exposure to ADBAC+DDAC in both rats and mice. The NTDs persisted for two generations after cessation of exposure. Notably, male exposure alone was sufficient to cause NTDs. Equally significant, ambient exposure from disinfectant use in the vivarium, influenced the levels of NTDs to a greater extent than oral dosing. No gross or significant axial skeletal malformations were observed in late gestation fetuses. Placental abnormalities and late gestation fetal deaths were increased at 120 mg/kg/day, which might explain the lack of malformations observed in late gestation fetuses. CONCLUSION: These results demonstrate that ADBAC+DDAC in combination are teratogenic to rodents. Given the increased use of these disinfectants, further evaluation of their safety in humans and their contribution to health and disease is essential. Birth Defects Research 109:1166 1178, 2017. (c) 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc. PMID- 28618202 TI - Effects of persistent Fontan fenestration patency on cardiopulmonary exercise testing variables. AB - Cardiopulmonary exercise testing (CPET) aids in clinical assessment of patients with Fontan circulation. Effects of persistent fenestration on CPET variables have not been clearly defined. Associations between fenestration and CPET variables at anaerobic threshold (AT) and peak exercise were explored in the Pediatric Heart Network Fontan Cross-Sectional Study cohort. Fenestration patency was associated with a greater decrease in oxygen saturation from rest to peak exercise (fenestration -4.9 +/- 3.8 v. nonfenestration -3 +/- 3.5; P < .001). Physiological dead space at peak exercise was higher in fenestrated v. nonfenestrated (25.2 +/- 16.1 v. 21.4 +/- 15.2; P = .03). There was a weak association between fenestration patency and maximal work and heart rate. Fenestration patency was also weakly correlated with oxygen pulse, work and VE/VCO2 at AT. The effect of persistent fenestration on CPET measurements was minimal in this study, likely due to the cross-sectional design. PMID- 28618201 TI - Targeted quantification of functional enzyme dynamics in environmental samples for microbially mediated biogeochemical processes. AB - Microbial enzymes catalytically drive biogeochemical processes in environments. The dynamic linkage between functional enzymes and biogeochemical species transformation has, however, rarely been investigated for decades because of the challenges to directly quantify enzymes in environmental samples. The diversity of microorganisms, the low amount of available biomass and the complexity of chemical composition in environmental samples represent the main challenges. To address the diversity challenge, we first identify several signature peptides that are conserved in the targeted enzymes with the same functionality across many phylogenetically diverse microorganisms using metagenome-based protein sequence data. Quantification of the signature peptides then allows estimation of the targeted enzyme abundance. To achieve analyses of the requisite sensitivity for complex environmental samples with low available biomass, we adapted a recently developed ultrasensitive targeted quantification technology, termed high pressure high-resolution separations with intelligent selection and multiplexing (PRISM) by improving peptide separation efficiency and method detection sensitivity. Nitrate reduction dynamics catalyzed by dissimilatory and assimilatory enzymes in a hyporheic zone sediment was used as an example to demonstrate the application of the enzyme quantification approach. Together with the measurements of biogeochemical species, the approach enables investigating the dynamic linkage between functional enzymes and biogeochemical processes. PMID- 28618203 TI - Modelling the dynamic physical protection of soil organic carbon: Insights into carbon predictions and explanation of the priming effect. AB - The role and significance of physically protected soil organic carbon (SOC) in regulating SOC dynamics remains unclear. Here, we developed a simple theoretical model (DP model) considering dynamic physical protection to simulate the dynamics of protected (Cp ) and unprotected SOC (Cu ), and compared the modelling results with a conventional two-pool (fast vs. slow) model considering chemical recalcitrance. The two models were first constrained using extensive SOC data collected from soils with and without fresh carbon (C) inputs under incubation conditions, and then applied to project SOC dynamics and explore mechanisms underpinning the priming effect (PE). Overall, both models explained more than 99% of the variances in observed SOC dynamics. The DP model predicted that Cp accounted for the majority of total SOC. As decomposition proceeds, the proportion of Cp reached >90% and kept relatively constant. Although the similar performance of the two models in simulating observed total SOC dynamics, their predictions of future SOC dynamics were divergent, challenging the predictions of widely used pool-based models. The DP model also suggested alternative mechanisms underpinning the priming of SOC decomposition by fresh C inputs. The two-pool model suggested that the PE was caused by the stimulated decomposition rates, especially for the slow recalcitrant pool, while the DP model suggested that the PE might be the combined consequence of stimulated Cu decomposition, the liberation of Cp to decomposition and the inhibition of the protection of unprotected SOC. The model-data integration provided a new explanation for the PE, highlighting the importance of liberation of initially physically protected SOC to decomposition by new C inputs. Our model-data integration demonstrated the importance of simulating physical protection processes for reliable SOC predictions, and provided new insights into mechanistic understanding of the priming effect. PMID- 28618204 TI - Bacterial weathering of fossil organic matter and organic carbon mobilization from subterrestrial Kupferschiefer black shale: long-term laboratory studies. AB - A large part of the organic carbon present in the lithosphere is trapped in fossil organic matter deposited in sedimentary rocks. Only specialized microorganisms are able to degrade it contributing to the return of the carbon to the global cycle. The role of bacteria in this process is not yet completely understood. In the present laboratory studies, subterrestrial organic-rich ~256 million-year-old Kupferschiefer black shale was exposed to the activity of an indigenous consortium of lithobiontic bacteria for 365 days under aerobic conditions. An interdisciplinary research approach was applied, consisting of a detailed comparison of the chemical composition of extractable bitumens as well as resistant to extraction kerogen of the unweathered black shale to that of the bioweathered and chemically weathered, identification of mobilized organic compounds and spectrometry-based determination of proteomic composition of the bacterial biofilm. The oxidative bioweathering of bitumens and kerogen was confirmed. The mobilization of organic carbon in the form of oxidized organic compounds, such as monohydroxy and dihydroxy alcohols, aldehydes, monocarboxylic and dicarboxylic acids and esters due to the microbial activity, was documented. The enzymes crucial for the aerobic metabolism of aliphatic and aromatic hydrocarbons such as monooxygenases and dehydrogenases were identified in the epilithic biofilm inhabiting the black shale. PMID- 28618205 TI - Reduced expression of circRNA hsa_circ_0003159 in gastric cancer and its clinical significance. AB - BACKGROUND: Circular RNAs (circRNAs) play a crucial role in the occurrence of several diseases including cancers. However, little is known about circRNAs' diagnostic values for gastric cancer, one of the worldwide most common diseases of mortality. METHODS: The hsa_circ_0003159 levels in 108 paired gastric cancer tissues and adjacent non-tumorous tissues from surgical patients with gastric cancer were first detected by real-time quantitative reverse transcription polymerase chain reaction. Then, the relationships between hsa_circ_0003159 expression levels in gastric cancer tissues and the clinicopathological factors of patients with gastric cancer were analyzed. Finally, its diagnostic value was evaluated through the receiver operating characteristic curve. RESULTS: Compared with paired adjacent non-tumorous tissues, hsa_circ_0003159 expression was significantly down-regulated in gastric cancer tissues. What is more, we found that hsa_circ_0003159 expression levels were significantly negatively associated with gender, distal metastasis, and tumor-node-metastasis stage. CONCLUSIONS: All of the results suggest that hsa_circ_0003159 may be a potential cancer marker of patients with gastric cancer. PMID- 28618206 TI - Grazing of leaf-associated Cercomonads (Protists: Rhizaria: Cercozoa) structures bacterial community composition and function. AB - Preferential food selection in protists is well documented, but we still lack basic understanding on how protist predation modifies the taxonomic and functional composition of bacterial communities. We conducted feeding trials using leaf-associated cercomonad Cercozoa by incubating them on a standardized, diverse bacterial community washed from plant leaves. We used a shotgun metagenomics approach to investigate the taxonomic and functional changes of the bacterial community after five days protist predation on bacteria. Predation induced shifts in bacterial community composition could be linked to phenotypic protist traits. Protist reproduction rate, morphological plasticity and cell speed were most important in determining bacterial community composition. Analyses of co-occurrence patterns showed less complex correlations between bacterial taxa in the protist-grazed treatments with a higher proportion of positive correlations than in non-grazed controls, suggesting that predation reduced the influence of strong competitors. Protist predation influenced 14 metabolic core functions including membrane transport from which type VI secretion systems were in particular upregulated. In view of the functional importance of bacterial communities in the phyllosphere and rhizosphere of plants, a more detailed understanding of predator-prey interactions, changes in microbial composition and function, and subsequent repercussions on plant performance are clearly required. PMID- 28618207 TI - Effect of dioxin and 17beta-estradiol on the expression of cytochrome P450 1A1 gene via an estrogen receptor dependent pathway in cellular and xenografted models. AB - Cytochrome P450 (CYP) 1A1 plays a major role in the metabolic activation of procarcinogens to carcinogens via aryl hydrocarbon receptor (AhR) pathway. Especially, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known as an agonist of AhR. In estrogen responsive cancers, 17beta-estradiol (E2) may influence on AhR dependent expression of CYP1 family via the interaction between estrogen receptor (ER) and AhR. In the present study, the effect of E2/ER on the expression of AhR and CYP1A1 genes was investigated for MCF-7 clonal variant (MCF-7 CV) breast cancer cells expressing ER. In reverse transcription-PCR and Western blot analysis, mRNA expression level of AhR was not altered, but its protein expression level was increased by TCDD or E2. The transcriptional and translational levels of CYP1A1 appeared to be increased by TCDD or E2. The increased expression of AhR and CYP1A1 induced by E2 was restored to the control level by the co-treatment of ICI 182,780, indicating that E2 induced the protein expression levels of AhR and CYP1A1 like TCDD via an ER dependent pathway. In an in vivo xenograft mouse model transplanted with MCF-7 CV cells, the protein expression levels of AhR and CYP1A1 of tumor masses were also increased by E2 or TCDD. Taken together, these results indicate that E2 may promote AhR dependent expression of CYP1A1 via ER dependent pathway in MCF-7 CV cells expressing ER in the absence of TCDD, an agonist of AhR. The relevance of E2 and ER in CYP1A1 activation of estrogen responsive cancers may be targeted for developing more effective cancer treatments. PMID- 28618208 TI - Experiences of registered nurses transitioning from employment in acute care to primary health care-quantitative findings from a mixed-methods study. AB - AIMS AND OBJECTIVES: To describe the experiences of registered nurses who transition from acute to primary health care (PHC) employment. BACKGROUND: Internationally the provision of health care in PHC settings is increasing. Nurses are moving from acute care employment to meet the growing demand for a PHC workforce. However, little is known about the transition experiences of these nurses. DESIGN: A sequential mixed-methods study comprising a survey, and semi structured interviews. This study reports on survey findings relating to the transition experience. METHODS: Convenience and snowballing techniques were used to recruit 111 registered nurses who had transitioned from Australian acute settings to PHC employment within the last 5 years. An online survey gathered data relating to personal and professional demographics, type of PHC setting and transition experiences. RESULTS: Most respondents (n = 90, 81.1%) reported receiving some orientation, although the length and content varied considerably. Those working in metropolitan locations were more likely to report concerns associated with their orientation, with respondents from rural or remote locations more likely to have access to a preceptor than city/metropolitan respondents. Just under half of respondents found prioritising workload (n = 47; 42.7%) or organisational knowledge (n = 45; 40.9%) difficult or very difficult, and 47.7% (n = 53) felt isolated or unsupported. 49.5% (n = 55) reported being overwhelmed with the new role either sometimes or regularly. Barriers to transitioning successfully included limited employer support to attend professional development activities. CONCLUSIONS: Availability of specific support measures may assist in the transition process. Findings from our study should be considered by employers when recruiting nurses new to PHC, and when designing orientation and ongoing education programmes. RELEVANCE TO CLINICAL PRACTICE: This study highlights the challenges faced by nurses who transition from acute care into PHC employment. Understanding the barriers and facilitators to successful transitions enhances the process for future recruitment and retention of PHC nurses. This evidence can inform managers, educators and policymakers in developing support programmes for nurses moving into PHC. PMID- 28618209 TI - Chemical Compositions, Antioxidant and Antimicrobial Activities of Essential Oils of Psidium guajava L. Leaves from Different Geographic Regions in China. AB - Hydrodistilled essential oils (EO) of Psidium guajava L. leaves from different regions in China were analyzed by GC and GC/MS. The samples from Guangdong Province displayed high EO yields (0.61 - 0.75%, v/w). A total of 50 components, representing over 98.00% of the EOs, were identified and semi-quantitatived. The major constituents of EOs included beta-caryophyllene (17.17 - 31.38%), gamma gurjunene (9.17 - 15.22%), tau-cadinol (1.35 - 10.02%) and calamenene (2.13 - 7.80%). The terpenoids in all sample oils were dominated by sesquiterpenes hydrocarbons (70.18 - 84.35%), followed by oxygenated sesquiterpenes (9.89 - 22.19%). The similarities and differences among EOs from different samples were evaluated by hierarchical cluster analysis and principal component analysis methods. The IC50 values of EOs from different regions were between 18.52 - 33.72 mg/ml (DPPH) and 13.12 - 25.15 mg/ml (ABTS+ ). The FRAP value of EO from Guangdong Province was 7.34 - 9.13 mmol Vc/g DM, while the FRAP value of EO from Taiwan Province was 2.29 - 2.36 mmol Vc/g DM. The antimicrobial tests revealed that EO had a higher antimicrobial activity against all Gram-positive bacteria and two fungi. Moreover, EO from P. guajava leaves of Guangdong Province showed the highest antimicrobial activity. These properties can be considered in the design of industrial products and for further application in the food, pharmaceutical and cosmetic industries. PMID- 28618210 TI - The Non-Canonical Substrates of Trypanosoma cruzi Tyrosine and Aspartate Aminotransferases: Branched-Chain Amino Acids. AB - Trypanosoma cruzi, the etiological agent of Chagas disease, lacks genes that encode canonical branched-chain aminotransferases. However, early studies showed that when epimastigotes were grown in the presence of 14 C1 -DL-leucine, the label was incorporated into various intermediates. More recently, our studies provided evidence that T. cruzi epimastigotes display a single ATP-dependent and saturable transport system that enables epimastigotes to uptake branched-chain amino acids (BCAAs) from the culture media. To extend our knowledge of the first step of BCAA catabolism, the ability of this parasite's noncanonical broad specificity aminotransferases, such as tyrosine aminotransferase (TAT) and aspartate aminotransferase (ASAT), to transaminate these amino acids was investigated. Indeed, our results show that TAT and ASAT utilize BCAAs as substrates; however, both enzymes differ in their catalytic competence in utilizing these amino donors. For instance, ASAT transaminates isoleucine nearly 10-fold more efficiently than does TAT. This unique characteristic of TAT and ASAT allows to explain how BCAAs can be oxidized in the absence of a BCAA transaminase in T. cruzi. PMID- 28618211 TI - Tribute to Fumio Oosawa the pioneer in actin biophysics. AB - Fumio Oosawa and his colleagues at Nagoya University laid the foundation for mechanistic studies of actin. Using relatively primitive tools they discovered that actin monomers assemble in a two-step mechanism: highly unfavorable formation of small oligomeric nuclei followed by rapid elongation. Oosawa and his student Sadashi Hatano were the first to purify actin from a nonmuscle cell, Physarum polycephalum, initiating studies of the molecular mechanism of cellular movements. PMID- 28618212 TI - Quantum chemistry in environmental pesticide risk assessment. AB - The scientific community and regulatory bodies worldwide, currently promote the development of non-experimental tests that produce reliable data for pesticide risk assessment. The use of standard quantum chemistry methods could allow the development of tools to perform a first screening of compounds to be considered for the experimental studies, improving the risk assessment. This fact results in a better distribution of resources and in better planning, allowing a more exhaustive study of the pesticides and their metabolic products. The current paper explores the potential of quantum chemistry in modelling toxicity and environmental behaviour of pesticides and their by-products by using electronic descriptors obtained computationally. Quantum chemistry has potential to estimate the physico-chemical properties of pesticides, including certain chemical reaction mechanisms and their degradation pathways, allowing modelling of the environmental behaviour of both pesticides and their by-products. In this sense, theoretical methods can contribute to performing a more focused risk assessment of pesticides used in the market, and may lead to higher quality and safer agricultural products. (c) 2017 Society of Chemical Industry. PMID- 28618213 TI - Solid-phase extraction assisted dispersive liquid-liquid microextraction based on solidification of floating organic droplet to determine sildenafil and its analogues in dietary supplements. AB - A novel analytical method for the simultaneous determination of the concentration of sildenafil and its five analogues in dietary supplements using solid-phase extraction assisted reversed-phase dispersive liquid-liquid microextraction based on solidification of floating organic droplet combined with ion-pairing liquid chromatography with an ultraviolet detector was developed. Parameters that affect extraction efficiency were systematically investigated, including the type of solid-phase extraction cartridge, pH of the extraction environment, and the type and volume of extraction and dispersive solvent. The method linearity was in the range of 5.0-100 ng/mL for sildenafil, homosildenafil, udenafil, benzylsildenafil, and thiosildenafil and 10-100 ng/mL for acetildenafil. The coefficients of determination were >=0.996 for all regression curves. The sensitivity values expressed as limit of detection were between 2.5 and 7.5 ng/mL. Furthermore, intraday and interday precisions expressed as relative standard deviations were less than 5.7 and 9.9%, respectively. The proposed method was successfully applied to the analysis of sildenafil and its five analogues in complex dietary supplements. PMID- 28618214 TI - How to Stop Smoking. AB - Despite the known dangers of cigarette smoking, many smokers do not use effective means for cessation. Smoking-cessation guidelines recommend a variety of psychological and medicinal options that include nicotine-replacement products, pharmaceuticals, and electronic cigarettes. This article describes these smoking cessation options and provides guidance for physicians. PMID- 28618215 TI - Low-Density, Mechanical Compressible, Water-Induced Self-Recoverable Graphene Aerogels for Water Treatment. AB - Graphene aerogels (GAs) have demonstrated great promise in water treatment, acting as separation and sorbent materials, because of their high porosity, large surface area, and high hydrophobicity. In this work, we have fabricated a new series of compressible, lightweight (3.3 mg cm-3) GAs through simple cross linking of graphene oxide (GO) and poly(vinyl alcohol) (PVA) with glutaraldehyde. It is found that the cross-linked GAs (xGAs) show an interesting water-induced self-recovery ability, which can recover to their original volume even under extremely high compression strain or after vacuum-/air drying. Importantly, the amphiphilicity of xGAs can be adjusted facilely by changing the feeding ratio of GO and PVA and it exhibits affinity from polar water to nonpolar organic liquids depended on its amphiphilicity. The hydrophobic xGAs with low feeding ratio of PVA and GO can be used as adsorbent for organic liquid, while the hydrophilic xGAs with high feeding ratio of PVA and GO can be used as the filter material to remove some water-soluble dye in the wastewater. Because of the convenience of our approach in adjusting the amphiphilicity by simply changing the PVA/GO ratio and excellent properties of the resulting xGAs, such as low density, compressive, and water-induced self-recovery, this work suggests a promising technique to prepare GAs-based materials for the water treatment in different environment with high recyclability and long life. PMID- 28618216 TI - Competitive Coordination Strategy to Finely Tune Pore Environment of Zirconium Based Metal-Organic Frameworks. AB - Metal-organic frameworks (MOFs) are a class of crystalline porous materials with reticular architectures. Precisely tuning pore environment of MOFs has drawn tremendous attention but remains a great challenge. In this work, we demonstrate a competitive coordination approach to synthesize a series of zirconium metalloporphyrinic MOFs through introducing H2O and monocarboxylic acid as modulating reagents, in which well-ordered mesoporous channels could be observed clearly under conventional transmission electron microscopy. Owing to plenty of unsaturated Lewis acid catalytic sites exposed in the visualized mesoporous channels, these structures exhibit outstanding catalytic activity and excellent stability in the chemical fixation of carbon dioxide to cyclic carbonates. The zirconium-based MOFs with ordered channel structures are expected to pave the way to expand the potential applications of MOFs. PMID- 28618217 TI - Transparent Electrochemical Gratings from a Patterned Bistable Silver Mirror. AB - Silver mirror patterns were formed reversibly on a polystyrene (PS)-patterned electrode to produce gratings through the electrochemical reduction of silver ions. The electrochemical gratings exhibited high transparency (T > 95%), similar to a see-through window, by matching the refractive index of the grating pattern with the surrounding medium. The gratings switch to a diffractive state upon the formation of a mirror pattern (T < 5%) with a high diffraction efficiency up to 40%, providing reversible diffractive gratings. The diffraction state was maintained in the voltage-off state (V-off) for 40 min, which demonstrated bistable reversible electrochemical grating (BREG) behavior. By carefully combining the BREGs through period matching, dual-color switching was achieved within the full color region, which exhibited three distinct optical switching states between -2.5, 0, and +2.5 V. The wide range of light tenability using the metallic BREGs developed herein enabled IR modulation, NIR light reflection, and on-demand heat transfer. PMID- 28618218 TI - Citrate-Coated Silver Nanoparticles Growth-Independently Inhibit Aflatoxin Synthesis in Aspergillus parasiticus. AB - Manufactured silver nanoparticles (Ag NPs) have long been used as antimicrobials. However, little is known about how these NPs affect fungal cell functions. While multiple previous studies reveal that Ag NPs inhibit secondary metabolite syntheses in several mycotoxin producing filamentous fungi, these effects are associated with growth repression and hence need sublethal to lethal NP doses, which besides stopping fungal growth, can potentially accumulate in the environment. Here we demonstrate that citrate-coated Ag NPs of size 20 nm, when applied at a selected nonlethal dose, can result in a >2 fold inhibition of biosynthesis of the carcinogenic mycotoxin and secondary metabolite, aflatoxin B1 in the filamentous fungus and an important plant pathogen, Aspergillus parasiticus, without inhibiting fungal growth. We also show that the observed inhibition was not due to Ag ions, but was specifically associated with the mycelial uptake of Ag NPs. The NP exposure resulted in a significant decrease in transcript levels of five aflatoxin genes and at least two key global regulators of secondary metabolism, laeA and veA, with a concomitant reduction of total reactive oxygen species (ROS). Finally, the depletion of Ag NPs in the growth medium allowed the fungus to regain completely its ability of aflatoxin biosynthesis. Our results therefore demonstrate the feasibility of Ag NPs to inhibit fungal secondary metabolism at nonlethal concentrations, hence providing a novel starting point for discovery of custom designed engineered nanoparticles that can efficiently prevent mycotoxins with minimal risk to health and environment. PMID- 28618219 TI - Hierarchical Microspheres Constructed from Chitin Nanofibers Penetrated Hydroxyapatite Crystals for Bone Regeneration. AB - Chitin exists abundantly in crab and shrimp shells as the template of the minerals, which inspired us to mineralize it for fabricating bone grafting materials. In the present work, chitin nanofibrous microspheres were used as the matrix for in situ synthesis of hydroxyapatite (HA) crystals including microflakes, submicron-needles, and submicron-spheres, which were penetrated by long chitin nanofibers, leading to the hierarchical structure. The shape and size of the HA crystals could be controlled by changing the HA synthesis process. The tight interface adhesion between chitin and HA through the noncovanlent bonds occurred in the composite microspheres, and HAs were homogeneously dispersed and bounded to the chitin nanofibers. In our findings, the inherent biocompatibilities of the both chitin and HA contributed the bone cell adhesion and osteoconduction. Moreover, the chitin microsphere with submicron-needle and submicron-sphere HA crystals remarkably promoted in vitro cell adhesion and in vivo bone healing. It was demonstrated that rabbits with 1.5 cm radius defect were almost cured completely within three months in a growth factor- and cell free state, as a result of the unique surface microstructure and biocompatibilities of the composite microspheres. The microsphere scaffold displayed excellent biofunctions and an appropriate biodegradability. This work opened up a new avenue to construct natural polymer-based organic-inorganic hybrid microspheres for bone regeneration. PMID- 28618220 TI - Au@Void@Ag Yolk-Shell Nanoclusters Visited by Molecular Dynamics Simulation: The Effects of Structural Factors on Thermodynamic Stability. AB - Au@void@Ag yolk-shell nanoclusters were studied by molecular dynamics simulation in order to study the effects of core and shell sizes on their thermodynamic stability and structural transformation. The results demonstrated that all of simulated nanoclusters with different core and shell sizes are unstable at temperatures lower than 350 K in such a way that Ag atoms are collapsed into the void space and fill it, which leads to creation of a more stable core-shell morphology, and at the melting point, only core-shell structures with altered thickness of the shell exist. Also, at higher temperatures, Au atoms tend to migrate toward the surface, and an increase of both the core and shell sizes leads to an increase of the thermodynamic stability. Moreover, a Au147@void@Ag252 nanocluster with the largest core and shell and minimum void space exhibited the most thermodynamic stability and highest melting point. Generally, the core and shell sizes affect the stability and thermal behavior of yolk-shell nanoclusters cooperatively. PMID- 28618221 TI - Constructing 3D Polyphosphazene Nanotube@Mesoporous Silica@Bimetallic Phosphide Ternary Nanostructures via Layer-by-Layer Method: Synthesis and Applications. AB - A novel ternary nanostructure polyphosphazene nanotube (PZS)@ mesoporous silica (M-SiO2)@bimetallic phosphide (CoCuP) was facilely fabricated, using PZS as the template, where large amount of cetyltrimethylammonium bromide molecules were anchored to PZS via a similar layer-by-layer assembly strategy, and then uniform M-SiO2 shells can be formed successfully by Hyeon's coating method. Subsequently, the three-dimensional (3D) nanostructure on the basis of bimetallic phosphide (CoCuP) interconnected with PZS@M-SiO2 was synthesized via a convenient, mild hydrothermal route. It is noted that incorporating well-designed PZS@M-SiO2@CoCuP led to significant decrease on fire hazard of thermoplastic polyurethane (TPU), that is, 58.2% and 19.4% reductions in peak heat release rate and total heat release, respectively, as well as lower toxic hydrogen cyanide and carbon monoxide yield accompanied by higher graphitized char layer. In the case of TPU/PZS@M-SiO2@CoCuP system, the storage modulus at -97 degrees C was dramatically improved by 62.6%, and glass transition temperature was shifted to higher value, compared to those of pure TPU. The enhanced fire safety and mechanical property for TPU composites can be ascribed to tripartite cooperative effect from respective parts (CoCuP and M-SiO2) plus the PZS. PMID- 28618222 TI - De Novo Biosynthesis of Glutarate via alpha-Keto Acid Carbon Chain Extension and Decarboxylation Pathway in Escherichia coli. AB - Microbial based bioplastics are promising alternatives to petroleum based synthetic plastics due to their renewability and economic feasibility. Glutarate is one of the most potential building blocks for bioplastics. The recent biosynthetic routes for glutarate were mostly based on the l-lysine degradation pathway from Pseudomonas putida that required lysine either by feeding or lysine overproduction via genetic manipulations. Herein, we established a novel glutarate biosynthetic pathway by incorporation of a "+1" carbon chain extension pathway from alpha-ketoglutarate (alpha-KG) in combination with alpha-keto acid decarboxylation pathway in Escherichia coli. Introduction of homocitrate synthase (HCS), homoaconitase (HA) and homoisocitrate dehydrogenase (HICDH) from Saccharomyces cerevisiae into E. coli enabled "+1" carbon extension from alpha-KG to alpha-ketoadipate (alpha-KA), which was subsequently converted into glutarate by a promiscuous alpha-keto acid decarboxylase (KivD) and a succinate semialdehyde dehydrogenase (GabD). The recombinant E. coli coexpressing all five genes produced 0.3 g/L glutarate from glucose. To further improve the titers, alpha-KG was rechanneled into carbon chain extension pathway via the clustered regularly interspersed palindromic repeats system mediated interference (CRISPRi) of essential genes sucA and sucB in tricarboxylic acid (TCA) cycle. The final strain could produce 0.42 g/L glutarate, which was increased by 40% compared with the parental strain. PMID- 28618223 TI - Covalent Protein Labeling and Improved Single-Molecule Optical Properties of Aqueous CdSe/CdS Quantum Dots. AB - Semiconductor quantum dots (QDs) have proven to be superior probes for single molecule imaging compared to organic or genetically encoded fluorophores, but they are limited by difficulties in protein targeting, their larger size, and on off blinking. Here, we report compact aqueous CdSe/CdS QDs with significantly improved bioconjugation efficiency and superior single-molecule optical properties. We have synthesized covalent protein labeling ligands (i.e., SNAP tags) that are optimized for nanoparticle use, and QDs functionalized with these ligands label SNAP-tagged proteins ~10-fold more efficiently than existing SNAP ligands. Single-molecule analysis of these QDs shows 99% of time spent in the fluorescent on-state, ~4-fold higher quantum efficiency than standard CdSe/ZnS QDs, and 350 million photons detected before photobleaching. Bright signals of these QDs enable us to track the stepping movement of a kinesin motor in vitro, and the improved labeling efficiency enables tracking of single kinesins in live cells. PMID- 28618225 TI - Role of Grafting Mechanism on the Polymer Coverage and Self-Assembly of Hairy Nanoparticles. AB - It is now well-accepted that controlling the spatial dispersion of nanoparticles (NPs), which can be achieved by grafting them with polymers of different chain lengths and grafting densities, is central to optimizing the thermomechanical properties of the resulting polymer nanocomposites. In general, there are two methods for creating such polymer-grafted NPs: "grafting to" and "grafting from". The conventional wisdom is that the "grafting from" mechanism, where monomer sized initiator/functional groups are attached to the surface followed by growing the chains, allows for higher polymer grafting densities and hence a more uniform polymer coverage of the NP surface. Here, we perform calculations and instead show that the "grafting to" strategy surprisingly leads to a more uniform polymer coverage of the NP surface at a given grafting density since the brush is formed while respecting the excluded volume constraints of the previously grafted chains. This conclusion is especially clear in the limit of low-to-moderate grafting density. Thus, at a given grafting density, the "grafting to" mechanism leads to an enhanced miscibility of the NPs in the matrix (which has the same chemistry as the grafts) and lower propensity to create self-assembled structures. Another important factor is that the dispersity in the number of grafted chains on the NPs is also smaller in the case of "grafting to" systems, thus leading to better defined materials. These two conclusions imply that the "grafting to" mechanism may provide better control over the NP dispersion state and hence the thermomechanical properties of polymer nanocomposites. PMID- 28618224 TI - Design, Synthesis, and Structure-Activity Relationship of Tetrahydropyrido[4,3 d]pyrimidine Derivatives as Potent Smoothened Antagonists with in Vivo Activity. AB - Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its nonlinear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility. Many patients experience adverse events such as muscle spasms and weight loss. In addition, drug resistance often arises among tumor cells during treatment with vismodegib. There is clearly an urgent need to explore novel Smo antagonists with improved potency and efficacy. Through a scaffold hopping strategy, we have identified a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives, which exhibited effective inhibition of Hh signaling. Among them, compound 24 is three times more potent than vismodegib in the NIH3T3-GRE-Luc reporter gene assay. Compound 24 has a lower melting point and much greater solubility compared with vismodegib, resulting in linear PK profiles when dosed orally at 10, 30, and 100 mg/kg in rats. Furthermore, compound 24 showed excellent PK profiles with a 72% oral bioavailability in beagle dogs. Compound 24 demonstrated overall favorable in vitro safety profiles with respect to CYP isoform and hERG inhibition. Finally, compound 24 led to significant regression of subcutaneous tumor generated by primary Ptch1-deficient medulloblastoma cells in SCID mouse. In conclusion, tetrahydropyrido[4,3-d]pyrimidine derivatives represent a novel set of Smo inhibitors that could potentially be utilized to treat medulloblastoma and other Hh pathway related malignancies. PMID- 28618226 TI - Nanotexturing of Conjugated Polymers via One-Step Maskless Oxygen Plasma Etching for Enhanced Tunable Wettability. AB - A one-step maskless oxygen plasma etching process is investigated to nanopattern conjugated polymer dodecylbenzenesulfonate doped polypyrrole (PPy(DBS)) and to examine the effects of nanostructures on the inherent tunable wettability of the surface and the droplet mobility. Etching characteristics such as the geometry and dimensions of the nanostructures are systematically examined for the etching power and duration. The mechanism of self-formation of vertically aligned dense array pillared nanostructures in the one-step maskless oxygen plasma etching process is also investigated. Results show that lateral dimensions such as the periodicity and diameter of the pillared nanostructures are insensitive to the etching power and duration, whereas the length and aspect ratio of the nanostructures increase with them. X-ray photoelectron spectroscopy analysis and thermal treatment of the polymer reveal that the codeposition of impurities on the surface resulting from the holding substrate is the primary reason for the self-formation of nanostructures during the oxygen plasma etching, whereas the local crystallinity subject to thermal treatment has a minor effect on the lateral dimensions. Retaining the tunable wettability (oleophobicity) for organic droplets during the electrochemical redox (i.e., reduction and oxidization) process, the nanotextured PPy(DBS) surface shows significant enhancement of droplet mobility compared to that of the flat PPy(DBS) surface with no nanotexture by making the surface superoleophobic (i.e., in a Cassie-Baxter wetting state). Such enhancement of the tunable oleophobicity and droplet mobility of the conjugated polymer will be of great significance in many applications such as microfluidics, lab-on-a-chip devices, and water/oil treatment. PMID- 28618227 TI - Nanocomposite Microgels for the Selective Separation of Halogen Compounds from Aqueous Solution. AB - Nanocomposite microgels that selectively adsorb and release halogen compounds were developed. These nanocomposite microgels consist of poly(2-methoxyethyl acrylate) (pMEA) and a poly(oligo ethylene glycol methacrylate) hydrogel matrix. Therefore, the methoxy groups of the former are crucial for the halogen bonding, while the presence of the latter adds colloidal stability and allows controlled uptake/release of the halogen compounds. Such nanocomposite microgels may not only be used as dispersed carriers, but also in films and columnar formations. Thus, these unprecedented polymer/polymer nanocomposite microgels resolve a variety of problems associated with, e.g., the removal of halogen compounds from wastewater, or with the delivery of halogen-containing drugs. PMID- 28618228 TI - Mechanical Properties and Cell Compatibility of Agarose Hydrogels Containing Proteoglycan Mimetic Graft Copolymers. AB - Proteoglycans have vital biochemical and biomechanical functions. Their proteolytic degradation results in loss of these functions. We have previously reported nonprotein proteoglycan-mimetic graft copolymers that stabilize and deliver growth factors and are not subject to proteases. Here we expand our investigation of these proteoglycan mimics by also investigating their effects on hydrogel mechanical properties. Four polysaccharide side chains, chondroitin sulfate, heparin, dextran, and dextran sulfate, are each grafted to a hyaluronan backbone. The polysaccharides and graft copolymers are added to agarose hydrogels. Cyclic compression and stress relaxation tests reveal how the addition of the polysaccharides and graft copolymers influence hydrogel modulus. Cells encapsulated in agarose hydrogels containing chondroitin sulfate and the chondroitin sulfate graft copolymer have decreased cell viability and metabolic activity compared to cells in unmodified agarose hydrogels. These multifunctional additives can be used to improve both the biochemistry and biomechanics of materials, warranting further optimization to overcome the potentially negative effects these may have on cell viability and activity. PMID- 28618229 TI - Staggered Linear Assembly of Spherical-Cap Colloids. AB - Linear assembly of colloidal particles is of fundamental interest in visualizing polymer dynamics and living organisms. We have developed a fluid-fluid interface based method to synthesize spherical-cap polymeric latex particles. These particles are shown to spontaneously self-assemble in zigzag arrangement. The linear assembly is induced due to the shape anisotropy (one side is curved and the other side is nearly flat) and heterogeneous charge distribution on the particle surfaces. The necessities of these conditions are justified within the framework of DLVO theory. Spherical-cap particles of various size and aspect ratio reproduced the observed linear assembly, thus demonstrating the robustness of the self-assembly mechanism. While these types of assemblies are observed in spherical particles using microfluidic devices or electric field, the proposed approach is rather facile and does not require any external field. These novel assemblies could be potentially useful to understand kinetics of nucleation and growth of amyloidogenic proteins and to prepare artificial swimming microorganisms. PMID- 28618230 TI - Antimosquito Activity of a Titanium-Organic Framework Supported on Fabrics. AB - Waste swamps, stagnant water, and poor hygiene practices result in the proliferation of mosquitoes that may cause transmissible and infectious diseases such as malaria, typhoid, cholera, and Zika virus sickness. It has been shown that composites of the traditional natural fibers cotton, viscose, and linen and a Ti-bearing metal-organic framework, NH2-MIL-125, are very effective against mosquitoes in the absence of any conventional insecticides. In our study, prior to coating with NH2-MIL-125 crystals, the fabrics were modified with 3 glycidyloxypropyltrimethoxysilane. The composite materials were characterized by powder X-ray diffraction, UV-vis spectroscopy, Fourier transform infrared spectroscopy, and scanning electron microscopy with energy-dispersive X-ray spectroscopy analysis. The latter, in particular, has shown the uniform coating of the fabrics with NH2-MIL-125 crystals. The modified fabrics have excellent antimosquito properties, attracting and killing them. PMID- 28618231 TI - A High Resolution Study of Dynamic Changes of Ce2O3 and CeO2 Nanoparticles in Complex Environmental Media. AB - Ceria nanoparticles (NPs) rapidly and easily cycle between Ce(III) and Ce(IV) oxidation states, making them prime candidates for commercial and other applications. Increased commercial use has resulted in increased discharge to the environment and increased associated risk. Once in complex media such as environmental waters or toxicology exposure media, the same redox transformations can occur, causing altered behavior and effects compared to the pristine NPs. This study used high resolution scanning transmission electron microscopy and electron energy loss spectroscopy to investigate changes in structure and oxidation state of small, polymer-coated ceria suspensions in complex media. NPs initially in either the III or IV oxidation states, but otherwise identical, were used. Ce(IV) NPs were changed to mixed (III, IV) NPs at high ionic strengths, while the presence of natural organic macromolecules (NOM) stabilized the oxidation state and increased crystallinity. The Ce(III) NPs remained as Ce(III) at high ionic strengths, but were modified by the presence of NOM, causing reduced crystallinity and degradation of the NPs. Subtle changes to NP properties upon addition to environmental or ecotoxicology media suggest that there may be small but important effects on fate and effects of NPs compared to their pristine form. PMID- 28618232 TI - Toward Fast and Accurate Binding Affinity Prediction with pmemdGTI: An Efficient Implementation of GPU-Accelerated Thermodynamic Integration. AB - We report the implementation of the thermodynamic integration method on the pmemd module of the AMBER 16 package on GPUs (pmemdGTI). The pmemdGTI code typically delivers over 2 orders of magnitude of speed-up relative to a single CPU core for the calculation of ligand-protein binding affinities with no statistically significant numerical differences and thus provides a powerful new tool for drug discovery applications. PMID- 28618233 TI - Simple and Consecutive Melt Extrusion Method to Fabricate Thermally Conductive Composites with Highly Oriented Boron Nitrides. AB - In the region of thermally conductive polymer composites, forcing anisotropic fillers into the highly oriented structure is the most effective method to improve thermal conductivity and mechanical properties simultaneously. However, up to now, such highly oriented structure was mainly achieved in low viscosity polymer matrix or solutions. For the purpose of expanding the range of applications, in the present work, a new strategy, the consecutive and powerful shear flow field, was applied to introduce highly oriented boron nitride (BN) into high viscosity polymer matrix. Results indicated that BN was almost totally oriented along the extrusion plane; as a result, the anisotropic index and thermal conductivity of the composite filled with 40 wt % BN reached as high as 480% and 3.57 W/(m K), respectively. Furthermore, compared with the samples with randomly oriented BN, elongations at break were improved more than 50-fold at the same filler content. Finite element analysis was also applied to systematically investigate the effect of the orientation direction of BN on heat dissipation property of the composites, and results indicated that orienting the longitudinal direction of BN parallel to the heat source is the best way to reduce the heat source temperature to a low level. Therefore, the simple, consecutive, and environmentally friendly melt extrusion with powerful shear flow field is an outstanding method to fabricate high efficiency thermally conductive composites, and the simulative results also have important significance on designing such composites for different applications. PMID- 28618234 TI - Successful Treatment of Acute Radiation Proctitis with Aloe Vera: A Preliminary Randomized Controlled Clinical Trial. AB - BACKGROUND: Acute radiation proctitis (ARP) is a common side-effect that affects up to 50% of patients receiving radiotherapy. The aim of this study was to evaluate the role of a topical preparation of Aloe vera in the treatment of ARP induced by radiotherapy of pelvic area. SUBJECTS AND INTERVENTIONS: In this double-blind placebo-controlled trial, 20 consecutive patients with ARP after external-beam radiation therapy (46-72 Gy) of pelvic malignancies were randomized to receive either Aloe vera 3% or placebo ointment, 1 g twice daily for 4 weeks. These patients presented with at least two of the following symptoms: rectal bleeding, abdominal/rectal pain, diarrhea, or fecal urgency. These symptoms were rated by the patients in terms of their severity (grade 0-4) for each of the symptoms mentioned earlier at baseline and then weekly for 4 weeks. A symptom index was calculated by the addition of the scores (16 most symptomatic). Radiation Therapy Oncology Group (RTOG) acute toxicity criteria and psychosocial status of the patients were also recorded weekly. The lifestyle impact of the symptoms was assessed by questionnaire grading from 0 (no effect on daily activity) to 4 (afraid to leave home). RESULTS: There was a significant (p < 0.05) improvement in the symptom index (before treatment vs. after treatment with Aloe vera) for diarrhea (median score: 0.67 vs. 0.11), fecal urgency (median score: 0.89 vs. 0.11), clinical presentation total (median score: 4.33 vs. 1.22), RTOG total (median score: 2.89 vs. 0.89), and lifestyle (median score: 1.1 vs. 0.33). Hemorrhage and abdominal/rectal pain did not improve significantly. The odds ratios for advantage of Aloe vera over placebo for "clinical presentation total" and "RTOG total" were 3.97 (1.3-11.9) and 5.9 (1.6-21.6), respectively. CONCLUSION: A substantial number of patients with radiation proctitis seem to benefit from therapy with Aloe vera 3% ointment. PMID- 28618235 TI - The Many Ways to Celebrate World Breastfeeding Week 2017. PMID- 28618236 TI - Eyes on New Product Development. PMID- 28618237 TI - Effect of Sweetened Dried Cranberry Consumption on Urinary Proteome and Fecal Microbiome in Healthy Human Subjects. AB - The relationship among diet, human health, and disease is an area of growing interest in biomarker research. Previous studies suggest that the consumption of cranberries (Vaccinium macrocarpon) could beneficially influence urinary and digestive health. The present study sought to determine if daily consumption of sweetened dried cranberries (SDC) changes the urinary proteome and fecal microbiome, as determined in a prospective sample of 10 healthy individuals. Baseline urine and fecal samples were collected from the subjects in the fasted (8-12 h) state. The subjects then consumed one serving (42 g) of SDC daily with lunch for 2 weeks. Urine and fecal samples were collected again the day after 2 weeks of SDC consumption. Orbitrap Q-Exactive mass spectrometry of urinary proteins showed that consumption of SDC resulted in changes to 22 urinary proteins. Multiplex sequencing of 16S ribosomal RNA genes in fecal samples indicated changes in relative abundance of several bacterial taxonomic units after consumption of SDC. There was a shift in the Firmicutes:Bacteroidetes ratio, increases in commensal bacteria, and decreases or the absence of bacteria associated with negative health effects. A decrease in uromodulin in all subjects and an increase in Akkermansia bacteria in most subjects were observed and warrant further investigation. Future larger clinical studies with multiomics and multitissue sampling designs are required to determine the effects of SDC consumption on nutrition and health. PMID- 28618238 TI - Antiglycating potential of acesulfame potassium: an artificial sweetener. AB - Sweeteners have replaced the natural sugars in the food and beverage industry because of many reasons, such as hyperglycemia and cost. Saccharin, sucralose, aspartame and acesulfame-K are the most commonly used sweeteners. In the present study, the abovementioned artificial sweeteners were used to assess their glycating properties by established methods such as browning, fructosamine assay, determination of carbonyl content, protein aggregation, and measurement of fluorescence. Amadori and advanced glycation end products (AGEs) are formed as a result of the interaction between carbonyl groups of reducing sugars and amino groups of proteins and other macromolecules during glycation. The objective of this study was to investigate the influence of artificial sweeteners on the formation of AGEs and protein oxidation in an in vitro model of glucose-mediated protein glycation. The results indicated that the abovementioned artificial sweeteners do not enhance the process of glycation. On the other hand, acesulfame K was found to have antiglycating potential as it caused decreased formation of Amadori products and AGEs. Further studies are essential in the characterization of Amadori products and AGEs produced as a result of interaction between sweeteners and proteins, which are interfered with by sweeteners. This study is significant in understanding the probable role of artificial sweeteners in the process of glycation and the subsequent effect on macromolecular alteration. PMID- 28618239 TI - Extent and Risks of Antipsychotic Off-Label Use in Children and Adolescents in Germany Between 2004 and 2011. AB - OBJECTIVE: Only little is known about antipsychotic (AP) off-label use (OLU) in pediatric populations. It was the aim of this study to examine the frequency as well as the risks of off-label AP use in underaged patients. METHODS: To calculate the frequency of off-label AP prescriptions for the years 2004-2011, we used claims data of more than two million minors aged 0-17 years. Off-label prescriptions were analyzed with regard to type of OLU, physician specialty, and underlying diagnoses. Incidence rates of selected adverse events were calculated for on-label as well as for OLU. The risk of poisoning associated with on- or OLU was assessed in a nested case-control study. RESULTS: The annual share of pediatric AP users with off-label prescriptions varied between 52.3% and 71.1%. OLU by indication (42.8%-66.5%) was the most common type of OLU. Of the subjects with OLU by indication, 52.5% had a diagnosis of hyperkinetic disorder. Adverse events were scarce (incidence rates between 0.8 and 8.6 per 10,000 person-years), and no significant difference was observed between on- and OLU. CONCLUSION: Because of their frequent use in hyperkinetic disorder patients, APs are commonly prescribed off-label for minors. Since OLU by contraindication was rare and the risk of the adverse events under study was similarly small for on- and OLU, this is not necessarily an indication for inappropriate treatment. It rather indicates that further randomized studies are needed to examine efficacy and safety of pediatric AP use in this indication. PMID- 28618240 TI - Omics for Precious Rare Biosamples: Characterization of Ancient Human Hair by a Proteomic Approach. AB - Omics technologies have far-reaching applications beyond clinical medicine. A case in point is the analysis of ancient hair samples. Indeed, hair is an important biological indicator that has become a material of choice in archeometry to study the ancient civilizations and their environment. Current characterization of ancient hair is based on elemental and structural analyses, but only few studies have focused on the molecular aspects of ancient hair proteins-keratins-and their conservation state. In such cases, applied extraction protocols require large amounts of raw hair, from 30 to 100 mg. In the present study, we report an optimized new proteomic approach to accurately identify archeological hair proteins, and assess their preservation state, while using a minimum of raw material. Testing and adaptation of three protocols and of nano liquid chromatography-tandem mass spectrometry (nanoLC-MS/MS) parameters were performed on modern hair. On the basis of mass spectrometry data quality, and of the required initial sample amount, the most promising workflow was selected and applied to an ancient archeological sample, dated to about 3880 years before present. Finally, and importantly, we were able to identify 11 ancient hair proteins and to visualize the preservation state of mummy's hair from only 500 MUg of raw material. The results presented here pave the way for new insights into the understanding of hair protein alteration processes such as those due to aging and ecological exposures. This work could enable omics scientists to apply a proteomic approach to precious and rare samples, not only in the context of archeometrical studies but also for future applications that would require the use of very small amounts of sample. PMID- 28618242 TI - Errata. PMID- 28618243 TI - Errata. PMID- 28618241 TI - Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. AB - Purpose To make recommendations regarding the use of bisphosphonates and other bone-modifying agents as adjuvant therapy for patients with breast cancer. Methods Cancer Care Ontario and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature. Results Adjuvant bisphosphonates were found to reduce bone recurrence and improve survival in postmenopausal patients with nonmetastatic breast cancer. In this guideline, postmenopausal includes patients with natural menopause or that induced by ovarian suppression or ablation. Absolute benefit is greater in patients who are at higher risk of recurrence, and almost all trials were conducted in patients who also received systemic therapy. Most studies evaluated zoledronic acid or clodronate, and data are extremely limited for other bisphosphonates. While denosumab was found to reduce fractures, long-term survival data are still required. Recommendations It is recommended that, if available, zoledronic acid (4 mg intravenously every 6 months) or clodronate (1,600 mg/d orally) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy. Further research comparing different bone-modifying agents, doses, dosing intervals, and durations is required. Risk factors for osteonecrosis of the jaw and renal impairment should be assessed, and any pending dental or oral health problems should be dealt with prior to starting treatment. Data for adjuvant denosumab look promising but are currently insufficient to make any recommendation. Use of these agents to reduce fragility fractures in patients with low bone mineral density is beyond the scope of the guideline. Recommendations are not meant to restrict such use of bone-modifying agents in these situations. Additional information at www.asco.org/breast-cancer-adjuvant bisphosphonates-guideline , www.asco.org/guidelineswiki , https://www.cancercareontario.ca/guidelines-advice/types-of-cancer/breast . PMID- 28618244 TI - Errata. PMID- 28618245 TI - Multi-omics Integrative Investigation of Fatty Acid Metabolism in Obese and Lean Subcutaneous Tissue. AB - White adipose tissue (WAT) plays a central role in whole-body energy homeostasis through storage and release of fatty acids. A deeper understanding of the complex and highly integrated pathways regulating WAT fatty acid metabolism, and how they are altered with obesity, is necessary for diagnostic and therapeutic innovations in nutritional disorders. In this multi-omics study, we investigated the influence of obesity on fatty acid metabolism in human subcutaneous adipose tissue (SAT) using an approach that integrated transcriptomic, peptidomic, and fatty acid analyses. Notably, all analyses were conducted in the same adipose tissue sample from each participant, thus minimizing the chance of spurious results. In a sample of SAT from the periumbilical abdominal region of obese (n = 11, mean body mass index [BMI] = 35.0 +/- 1.2 kg/m2) and lean subjects (n = 9, mean BMI = 22.1 +/- 0.5 kg/m2), we found that obese SAT tended to have higher relative amounts of specific monounsaturated fatty acids and n-6 polyunsaturated fatty acids, and lower amounts of saturated fatty acids (p < 0.05). These changes were associated with differential regulation of lipogenic and lipolytic pathways in obese SAT. Fatty acid analysis showed changes in estimated fatty acid desaturase and elongase activities between lean and obese SAT (p < 0.05). Biomarkers of lipogenesis (e.g., fatty acid synthase protein) were differentially regulated between lean and obese SAT. These changes were noted in conjunction with increases in extracellular matrix remodeling proteins. Transcriptomic data revealed that the key regulators of lipolysis were reduced in obese SAT. This integrative multi-omics analysis collectively shows that obese SAT has a distinct fatty acid signature compared to lean SAT and the pathways underlying fatty acid metabolism are broadly regulated at the level of gene expression and protein abundance. PMID- 28618246 TI - Adjuvants for Animal Vaccines. AB - Vaccines are essential tools for the prevention and control of infectious diseases in animals. One of the most important steps in vaccine development is the selection of a suitable adjuvant. The focus of this review is the adjuvants used in vaccines for animals. We will discuss current commercial adjuvants and experimental formulations with attention to mineral salts, emulsions, bacterial derived components, saponins, and several other immunoactive compounds. In addition, we will also examine the mechanisms of action for different adjuvants, examples of adjuvant combinations in one vaccine formulation, and challenges in the research and development of veterinary vaccine adjuvants. PMID- 28618247 TI - Contraception - what about the men? Experience, knowledge and attitudes: a survey of 2438 heterosexual men using an online dating service. AB - : Background There is little research on men's contraceptive knowledge, attitudes and beliefs, yet the male partner is known to influence contraceptive choices. This study investigates contraceptive experiences, knowledge, attitudes and beliefs of a sample of sexually active, heterosexual men via an online dating site. METHODS: An anonymous online survey was sent to men who had logged onto an online dating site within the previous year. RESULTS: We analysed 2438 survey responses. A contraceptive method was used at last intercourse for 82% of men <50 years old versus 69% of men >=50 (P<0.0001). Condoms (35%), vasectomy (22%) and the contraceptive pill (21%) were the most commonly used methods. Older men were less likely to use condoms than younger men (P<0.0001). More than 80% of participants had heard of each method. The greatest perceived harm was with the emergency contraceptive pill, with 32% responding that it was 'harmful to the health of the user' and 37% not sure. Belief that contraception decision-making should be shared between partners increased from 57% in a 'one-night stand' to 75% in a casual relationship, to 92% in a long-term relationship. CONCLUSION: Among this sample there is high contraceptive use, especially vasectomy in older men and a desire to share contraceptive decision-making with their partners, especially in long-term relationships. However, low awareness of some methods and misperceptions about hormonal contraceptive method safety, especially the emergency contraceptive pill, highlight the need for education for men. PMID- 28618248 TI - Effect of attitudes towards patients on sexual history taking: a survey of Iranian-American physicians in California, USA. AB - BACKGROUND: Although obtaining sexual history from patients is essential, the attitudes of physicians can become a barrier to sexual health care. Iranian American physicians may face particular challenges because talking about sexuality is considered a taboo within their culture. Our study examined these physicians' attitudes when taking a sexual history from their patients. METHODS: In 2013, a self-administrated questionnaire was sent to 1550 Iranian-American physicians in California, USA. Using factor analysis, the principal components approach with a Varimax rotation was used on a set of 12-item questions (five point Likert scales) to detect latent factors that explain attitudes affecting sexual history taking. Scores are generated to determine physicians' attitudes towards sexual history taking. RESULTS: In total, 354 questionnaires were returned (23% response rate). Three factors were identified as internally consistent (Cronbach's alpha=0.84 - 0.94): (1) attitude towards various patients; (2) female sexuality; and (3) age and marriage. Significant association were found between these three factors and some variables such as physicians' gender, country of medical graduation, religion, birthplace and age. CONCLUSIONS: Results revealed that cultural attitudes are important factors affecting physicians' involvement in sexual history taking. Additional studies from this population and other subpopulations of US physicians are needed. New strategies that reflect on physicians' attitude on sexual healthcare delivery is needed. If confirmed in other studies, our findings could have implications for the training of medical graduates globally. PMID- 28618249 TI - An integrative study of motivation and goal regulation processes in subclinical anxiety, depression and hypomania. AB - Research has implicated motivation and goal regulation in susceptibility to mood disorders. We studied for the first time key facets of motivation and goal regulation concurrently in relation to affective symptoms. The cross-national sample comprised 510 university students from the United States (n = 279) and United Kingdom (n = 231). Participants completed self-report measures of motivation, conditional goal setting, urgency, depression, anxiety, and mania risk. Structural Equation Modeling results found that behavioral activation system scores correlated negatively with depression and positively with mania risk, but were unrelated to anxiety. High conditional goal setting correlated uniquely with higher depression but not to anxiety or mania risk. Urgency correlated with higher anxiety, depression, and mania risk. Behavioral inhibition system scores correlated negatively with mania risk but unexpectedly did not correlate with anxiety in the multivariate model. The behavioral activation, behavioral inhibition, conditional goal setting, and urgency results showed shared and distinct patterns of relationships with depression, anxiety and mania risk. Our findings indicate unique and common risk vulnerabilities in depressive, anxious, and manic syndromes and extend an integrative knowledge of these syndromes in relation to goal regulation. PMID- 28618250 TI - Backward design toward a meaningful legacy. PMID- 28618251 TI - Overexpression of FADD and Caspase-8 inhibits proliferation and promotes apoptosis of human glioblastoma cells. AB - INTRODUCTION: The study aimed at exploring the effects involved in Fas-Associated protein with Death Domain (FADD) expression and cysteine-aspartic acid specific protease-8 (Caspase-8) in relation to the proliferation and apoptosis of human glioblastoma (GBM) cells. MATERIAL AND METHODS: 93 GBM tissues and 64 normal brain tissues were the central mediums used for the investigation of the study. Cultured human GBM SC189 cells were divided into separate groups including the blank negative control (NC), FADD and Caspase-8 groups. The mRNA and protein expressions of FADD and Caspase-8 in tissues and human glioblastoma (GBM) cells were detected using qRT-PCR and Western blotting techniques. Cell proliferation was tested by CCK-8. Flow cytometry was used for the measure of cell cycle and apoptosis rates. RESULTS: The mRNA and protein expressions of FADD and Caspase-8 in GBM tissues were less than the levels of expression displayed in normal brain tissues. Correlations between the expressions of FADD and Caspase-8 in GBM tissues were analyzed as being linked with the clinical grades of GBM patients. Patients in stage III+IV displayed lower expressions of FADD and Caspase-8 than patients in stage I+II. In comparison with the blank group, the FADD and Caspase 8 groups showed decreased proliferation rates of SHG44 cells and lower ratios of cells in the S phase and Bcl-2 expression. Greater ratios of cells in the G0/G1 stage as well as increased cell apoptosis and expressions of Caspase-8 and Bax were exhibited. The expression of FADD in the FADD group was higher than the blank group, however no significant differences in FADD expression was observed between the blank and Caspase-8 groups. CONCLUSION: The data obtained during the study demonstrated that overexpression of FADD and Caspase-8 suppresses proliferation whilst promoting the apoptosis of human GBM cells. PMID- 28618252 TI - Epidemiological Trends of Head and Neck Cancer in the United States: A SEER Population Study. AB - PURPOSE: This study represents the most recent epidemiologic trends of head and neck cancer (HNC) in the United States. It provides an important discussion on oropharyngeal cancer and cancers related to the human papillomavirus. The objective was to identify trends in HNC (2002 to 2012) within the United States. MATERIALS AND METHODS: This study is a retrospective analysis of the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) submission. Using the November 2014 submission of the SEER database and SEER-18 data files, data from 2002 to 2012 were analyzed to determine the most recent epidemiologic trends. HNCs of all subtypes were analyzed together. Laryngeal cancers were further analyzed separately. Oropharyngeal cancers of the base of tongue and tonsil were analyzed independently to attempt to trend HPV-related cancers. RESULTS: From 2002 to 2012, there were 149,301 cases of HNC recorded in the SEER database. The HNC rate decreased by 0.22% per year (P = .0549) and the rate of laryngeal cancer decreased by 1.9% per year (P < .0001). The rate of oropharyngeal (HPV-related) cancer increased by 2.5% per year (P < .0001). HNC rates increased significantly in Kentucky and Connecticut and decreased in California (P < .05). HPV-related cancers increased significantly in all states except Georgia, Hawaii, and Michigan (P < .05). Laryngeal cancer rates decreased in California, Georgia, New Jersey, and New Mexico (P < .05). CONCLUSIONS: The overall incidence of HNC is decreasing in the United States. There is an increasing incidence of HPV-related cancers of the oropharynx. Meaningful differences in cancer incidence and rate of change exist between men and women. Furthermore, younger groups have a greater decrease of overall HNC, with an overall increase in HPV-related cancer in patients older than 50 years. PMID- 28618254 TI - Platelet-Derived Growth Factor BB Influences Muscle Regeneration in Duchenne Muscle Dystrophy. AB - Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle biopsy samples from controls and patients with DMD. We performed in vitro experiments to understand the effects of PDGF-BB on myoblasts involved in the pathophysiology of muscular dystrophies and confirmed our results in vivo by treating the mdx murine model of DMD with repeated i.m. injections of PDGF-BB. We observed that regenerating and necrotic muscle fibers in muscle biopsy samples from DMD patients expressed PDGF-BB. In vitro, PDGF-BB attracted myoblasts and activated their proliferation. Analysis of muscles from the animals treated with PDGF-BB showed an increased population of satellite cells and an increase in the number of regenerative fibers, with a reduction in inflammatory infiltrates, compared with those in vehicle-treated mice. Based on our results, PDGF-BB may play a protective role in muscular dystrophies by enhancing muscle regeneration through activation of satellite cell proliferation and migration. PMID- 28618253 TI - Hypoxia-Inducible Factor 1alpha Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury. AB - During the acute respiratory distress syndrome, epithelial cells, primarily alveolar type (AT) I cells, die and slough off, resulting in enhanced permeability. ATII cells proliferate and spread onto the denuded basement membrane to reseal the barrier. Repair of the alveolar epithelium is critical for clinical recovery; however, mechanisms underlying ATII cell proliferation and spreading are not well understood. We hypothesized that hypoxia-inducible factor (HIF)1alpha promotes proliferation and spreading of ATII cells during repair after lung injury. Mice were treated with lipopolysaccharide or hydrochloric acid. HIF activation in ATII cells after injury was demonstrated by increased luciferase activity in oxygen degradation domain-Luc (HIF reporter) mice and expression of the HIF1alpha target gene GLUT1. ATII cell proliferation during repair was attenuated in ATII cell-specific HIF1alpha knockout (SftpcCreERT2+/ ;HIF1alphaf/f) mice. The HIF target vascular endothelial growth factor promoted ATII cell proliferation in vitro and after lung injury in vivo. In the scratch wound assay of cell spreading, HIF stabilization accelerated, whereas HIF1alpha shRNA delayed wound closure. SDF1 and its receptor, CXCR4, were found to be HIF1alpha-regulated genes in ATII cells and were up-regulated during lung injury. Stromal cell-derived factor 1/CXCR4 inhibition impaired cell spreading and delayed the resolution of permeability after lung injury. We conclude that HIF1alpha is activated in ATII cells after lung injury and promotes proliferation and spreading during repair. PMID- 28618255 TI - Osteocyte Regulation of Receptor Activator of NF-kappaB Ligand/Osteoprotegerin in a Sheep Model of Osteoporosis. AB - Osteoporosis induction in a sheep model by steroid administration combined with ovariectomy recapitulates decreased bone formation and substandard matrix mineralization in patients. Recently, the role of osteocytes has been frequently addressed, with focus on their role in osteoclastogenesis. However, the quantification of receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) signaling in osteocytes was not studied in sheep. The current study reproduced the sheep model of osteoporosis to study the RANKL/OPG ratio correlation to the method of osteoporosis induction. We investigated the induction of osteoporosis after 8 months using 31 female merino land sheep divided into four groups: control, ovariectomy, ovariectomy with dietary limitation, and ovariectomy with dietary limitation and steroid injection. In accordance to previous reports, the present study showed trabecular thinning, higher numbers of apoptotic osteocytes, and imbalanced metabolism, leading to defective mineralization. The global RANKL/OPG ratio in the spine after 8 months of steroid and dietary treatment was not different from that of the control. Interestingly, assessment of the osteocyte-specific RANKL/OPG ratio showed that the steroid-induced osteoporosis in its late progressive phase stimulates RANKL expression in osteocytes. Sclerostin is suggested to induce RANKL expression in osteocytes. The findings of this study can contribute to further explain the success of sclerostin antibodies in treating osteoporotic patients despite increased osteocyte-expressed RANKL. PMID- 28618256 TI - Cigarette Smoke Regulates Calcium-Independent Phospholipase A2 Metabolic Pathways in Breast Cancer. AB - Phospholipase A2 (PLA2)-dependent pathways are important in the regulation of cell proliferation, differentiation, motility, and immune responses, and can be dysregulated during tumor development and progression. We show herein, for the first time, that cigarette smoking leads to an increase in platelet-activating factor (PAF) content and PAF receptor expression in human breast cancer cells and tissue. PAF production could be abrogated in triple-negative breast cancer cells by inhibition of calcium-independent PLA2 (iPLA2). We also demonstrate that cigarette smoke induces the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 and reduces 15-hydroxyprostaglandin dehydrogenase, resulting in prostaglandin E2 release in human breast cancer. Increased cyclooxygenase-2 expression and prostaglandin E2 release could be abrogated in metastatic breast cancer cells by inhibition of iPLA2. These studies indicate that iPLA2-dependent metabolic pathways play an important role in tumor initiation or progression in smokers, representing novel therapeutic targets for breast cancer patients who smoke. PMID- 28618257 TI - Is a therapeutic anticoagulation window needed for delivery when using prophylactic low molecular weight heparin during pregnancy? A retrospective monocentric study. AB - OBJECTIVES: The aim of the study was to evaluate the usefulness of therapeutic window for delivery for patients under prophylactic anticoagulation by low molecular weight heparin (LMWH) by comparing those who had a planned delivery versus those who delivered spontaneously. STUDY DESIGN: This retrospective monocentric study included pregnant patients with prophylactic anticoagulation (one injection per day of enoxaparin 4000UI), who delivered after 24 weeks of gestation. We collected data on pregnancy characteristics and on the delivery. We divided patients in two groups: GROUP S were patients who delivered spontaneously and GROUP P were patients who had a planned delivery for a therapeutic anticoagulant window. Our primary endpoint was the neuraxial anaesthesia rate. We compared the two groups with the student test for quantitative data and the Chi-2 test or the exact test of Fisher for qualitative data. RESULTS: Over a 3.5 years period, we included 100 pregnant patients with prophylactic anticoagulation. Indications of prophylactic LMWH were patients with a low risk of thrombosis, mostly personal history of cured deep venous thrombosis (36%) prior to pregnancy or non-thrombotic antiphospholid syndrome (37%). The overall rate of neuraxial anaesthesia during delivery was 86%. Twenty-six patients were included in GROUP S and 74 in GROUP P. In GROUP P, all patients had access to neuraxial anaesthesia versus 88.4% (23/26) in the GROUP S (p<0.0001). For the three remaining patients, the contraindication was a short delay between the last injection of LMWH and the need for anaesthesia. The mean delay between the last injection of LMWH and neuraxial anaesthesia was 42.6+/-24.1 (13-123)h in the GROUP P and 22.7+/-9.9 (11 42)h in the GROUP S (p<0.0001). One patient had deep venous thrombosis in the 6 weeks postpartum, in the GROUP P. CONCLUSION: With a planned induced delivery between 38 and 39 weeks of gestation, 11.5% of patients who went into spontaneous labour before induction would not have a neuraxial anaesthesia when respecting the 12h delay between the last injection of low molecular weight heparin and the need for anaesthesia. PMID- 28618258 TI - Differential physiological and genetic responses of five European Scots pine provenances to induced water stress. AB - Pinus sylvestris L. (Scots pine) is the conifer with widest natural distribution area. Portugal constitutes its westernmost limit of distribution. Most of the Portuguese populations were planted but two autochthonous populations were recently ascribed to 'Serra do Geres' (NW Portugal), and seem to be well adapted to the temperate climate. However, the ongoing climate changes may compromise their survival. With this study we intend to evaluate the anatomic-physiological and genetic responses of Scots pine from five European provenances ('Geres', 'Puebla de Lillo', 'Montes Universales', Germany and Sweden) to three water availability regimes, in order to determine which one(s) present higher resistance to drought. Individuals from 'Geres' presented the highest stability in photosynthetic reactions as well as the better photochemical and metabolic behaviours under drought (T3). Hence, the relative expression ratio of three water stress-responsive genes during drought was lower and gradual in 'Geres', compared to all other provenances, followed by Germany. The results achieved in 'Geres' and Germany provenances are very interesting since they reflected that the native populations of 'Geres' along with the Portuguese Scots pine planted populations with a probable German provenance, have ability and high adaptive potential to respond to situations of water deficit. Moreover, the present genetic and physiological data demonstrated the urgent demand for the conservation of Portuguese Scots pine genetic resources as well as its use in plantation/afforestation of areas where the warming and drought has been affecting the survival of this species. PMID- 28618259 TI - Synthesis of tricyclic butenolides and comparison their effects with known smoke butenolide, KAR1. AB - Plant-derived smoke - butenolide, called at present karrikin 1 (KAR1) is known as an important inductor of seed germination and seedling growth. In this study, tricyclic butenolides were synthesized and their effects on germination of dormant and non-dormant Avena fatua caryopses were compared, as were also their effects versus those of KAR1 on seedling growth. KAR1 was found to be most effective and to completely remove dormancy. Butenolides, rac-8 and (S)-8a, showed a low stimulatory effect on germination of dormant caryopses, visible only when applied at very high concentrations. These compounds used at concentrations 100 times those of KAR1 similarly increased the speed of germination and vigor of non-dormant caryopses. Likewise, growth of coleoptiles and their fresh weight were increased by KAR1 as well as by rac-8 and (S)-8a to a similar value. KAR1 and rac-8 were more effective than (S)-8a in increasing root growth. The results shown indicate that the presence of an aromatic ring in the absence of methyl group at C3 induced a much lower, or a similar, effect on germination of dormant and non-dormant Avena fatua caryopses and seedling growth compared to KAR1, but only when used at much higher concentrations. The simultaneous presence of a methyl group at C3 and an aromatic ring in the compound rac-7 exerted only a slight effect on the root growth. PMID- 28618260 TI - Protectors of the Neonatal Gut: Clostridia Send Pathogens Packing. AB - Commensal bacteria are known to provide colonization resistance in the gut. But exactly which ones provide this function? In a recent paper in Science, Kim et al. (2017) revealed that Clostridia added to mouse infant gut microbiota are sufficient to limit colonization of pathogenic Enterobacteriaceae. PMID- 28618261 TI - The Making of a Pathogen. AB - Enterococci are opportunistic pathogens, hard to eradicate because of their unusually robust resistance to antibiotics, disinfectants, and desiccation. In recent work, Lebreton et al. (2017) show that traits promoting survival in hospitals were acquired upon adaptation to terrestrial life when Enterococci split from marine ancestors 400 million years ago. PMID- 28618262 TI - The Helper T Cell's Dilemma in Tuberculosis. AB - Vaccination approaches eliciting strong CD4 T cell responses provide only weak protection from tuberculosis. In this issue of Cell Host & Microbe, Moguche et al. (2017) show that T cells specific for different immunodominant vaccine antigens can fail to protect for opposite reasons, highlighting a major challenge in tuberculosis vaccine design. PMID- 28618263 TI - Relish the Thought and Channel Your Chloride, for Bacterial Clearance Depends on It. AB - Macrophage-mediated bacterial clearance relies on phagocytic uptake of the pathogen, subsequent phagolysosomal maturation, and microbial degradation. In this issue of Cell Host & Microbe, Wong et al. (2017) report that a chloride transporter couples phagocytosis and bacterial clearance in an NF-kappaB-mediated feedforward loop, which is required for sustained pathogen uptake. PMID- 28618264 TI - Unconventional Interrogation Yields HIV's Escape Plan. AB - Chasing HIV-1 across the genotype landscape, unequipped to anticipate its maneuvers, the antibody variable-region genes pursue the virus in futility. In this issue of Cell Host & Microbe, Dingens et al. (2017) exhibit a powerful technology that reveals the escape pathways of HIV-1 and may enable its capture. PMID- 28618265 TI - Making the Mark: The Role of Adenosine Modifications in the Life Cycle of RNA Viruses. AB - Viral epitranscriptomics is a newly emerging field that has identified unique roles for RNA modifications in modulating life cycles of RNA viruses. Despite the observation of a handful of modified viral RNAs five decades ago, very little was known about how these modifications regulate viral life cycles, until recently. Here we review the pro- and anti-viral effects of methyl-6-adenosine in distinct viral life cycles, the role of 2' O-methyl modifications in RNA stability and innate immune sensing, and functions of adenosine to inosine modifications in retroviral life cycles. With roles for over 100 modifications in RNA still unknown, this is a rapidly emerging field that is destined to suggest novel antiviral therapies. PMID- 28618266 TI - IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance. AB - Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na+ channel formed by claudin-2. Relative to wild-type, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2-deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance. PMID- 28618267 TI - Enhancement of IFNgamma Production by Distinct Commensals Ameliorates Salmonella Induced Disease. AB - The microbiota contributes to colonization resistance against invading pathogens by competing for metabolites, producing inhibitory substances, and priming protective immune responses. However, the specific commensal bacteria that promote host resistance and immune-mediated protection remain largely elusive. Using isogenic mouse lines with distinct microbiota profiles, we demonstrate that severity of disease induced by enteric Salmonella Typhimurium infection is strongly modulated by microbiota composition in individual lines. Transferring a restricted community of cultivable intestinal commensals from protected into susceptible mice decreases S. Typhimurium tissue colonization and consequently disease severity. This reduced tissue colonization, along with ameliorated weight loss and prolonged survival, depends on microbiota-enhanced IFNgamma production, as IFNgamma-deficient mice do not exhibit protective effects. Innate cells and CD4+ T cells increase in number and show high levels of IFNgamma after transfer of the commensal community. Thus, distinct microbiota members prevent intestinal Salmonella infection by enhancing antibacterial IFNgamma responses. PMID- 28618268 TI - Antigen Availability Shapes T Cell Differentiation and Function during Tuberculosis. AB - CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet to date, TB vaccine candidates that boost antigen-specific CD4 T cells have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb-infected mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6 specific T cells to be more differentiated than Ag85B-specific T cells. The ability of each T cell population to control Mtb in the lungs of mice was restricted for opposite reasons: Ag85B-specific T cells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific T cells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required to optimize protection mediated by T cells recognizing antigens expressed at distinct stages of Mtb infection. PMID- 28618269 TI - Red Blood Cell Invasion by the Malaria Parasite Is Coordinated by the PfAP2-I Transcription Factor. AB - Obligate intracellular parasites must efficiently invade host cells in order to mature and be transmitted. For the malaria parasite Plasmodium falciparum, invasion of host red blood cells (RBCs) is essential. Here we describe a parasite specific transcription factor PfAP2-I, belonging to the Apicomplexan AP2 (ApiAP2) family, that is responsible for regulating the expression of genes involved in RBC invasion. Our genome-wide analysis by ChIP-seq shows that PfAP2-I interacts with a specific DNA motif in the promoters of target genes. Although PfAP2-I contains three AP2 DNA-binding domains, only one is required for binding of the target genes during blood stage development. Furthermore, we find that PfAP2-I associates with several chromatin-associated proteins, including the Plasmodium bromodomain protein PfBDP1 and that complex formation is associated with transcriptional regulation. As a key regulator of red blood cell invasion, PfAP2 I represents a potential new antimalarial therapeutic target. PMID- 28618270 TI - Diversity of Functionally Permissive Sequences in the Receptor-Binding Site of Influenza Hemagglutinin. AB - Influenza A virus hemagglutinin (HA) initiates viral entry by engaging host receptor sialylated glycans via its receptor-binding site (RBS). The amino acid sequence of the RBS naturally varies across avian and human influenza virus subtypes and is also evolvable. However, functional sequence diversity in the RBS has not been fully explored. Here, we performed a large-scale mutational analysis of the RBS of A/WSN/33 (H1N1) and A/Hong Kong/1/1968 (H3N2) HAs. Many replication competent mutants not yet observed in nature were identified, including some that could escape from an RBS-targeted broadly neutralizing antibody. This functional sequence diversity is made possible by pervasive epistasis in the RBS 220-loop and can be buffered by avidity in viral receptor binding. Overall, our study reveals that the HA RBS can accommodate a much greater range of sequence diversity than previously thought, which has significant implications for the complex evolutionary interrelationships between receptor specificity and immune escape. PMID- 28618271 TI - Lck/Hck/Fgr-Mediated Tyrosine Phosphorylation Negatively Regulates TBK1 to Restrain Innate Antiviral Responses. AB - Cytosolic nucleic acid sensing elicits interferon production for primary antiviral defense through cascades controlled by protein ubiquitination and Ser/Thr phosphorylation. Here we show that TBK1, a core kinase of antiviral pathways, is inhibited by tyrosine phosphorylation. The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation. Accordingly, antiviral sensing and resistance were substantially enhanced in Lck/Hck/Fgr triple knockout cells and ectopic expression of Lck/Hck/Fgr dampened the antiviral defense in cells and zebrafish. Small-molecule inhibitors of SFKs, which are conventional anti-tumor therapeutics, enhanced antiviral responses and protected zebrafish and mice from viral attack. Viral infection induced the expression of Lck/Hck/Fgr through TBK1 mediated mobilization of IRF3, thus constituting a negative feedback loop. These findings unveil the negative regulation of TBK1 via tyrosine phosphorylation and the functional integration of SFKs into innate antiviral immunity. PMID- 28618272 TI - Shigella sonnei Encodes a Functional T6SS Used for Interbacterial Competition and Niche Occupancy. AB - Shigella is a leading cause of dysentery worldwide, with the majority of infections caused by two subgroups, S. flexneri and S. sonnei. Although S. flexneri has been highly prevalent in low-income countries, global development has brought an increase in S. sonnei at the expense of S. flexneri. However, the mechanisms behind this shift are not understood. Here we report that S. sonnei, but not S. flexneri, encodes a type VI secretion system (T6SS) that provides a competitive advantage in the gut. S. sonnei competes against E. coli and S. flexneri in mixed cultures, but this advantage is reduced in T6SS mutant strains. In addition, S. sonnei can persist as well as outcompete E. coli and S. flexneri in mice in a T6SS-dependent manner. These findings suggest that S. sonnei has a competitive advantage over S. flexneri and potentially explain the increasing global prevalence of S. sonnei. PMID- 28618273 TI - STING Requires the Adaptor TRIF to Trigger Innate Immune Responses to Microbial Infection. PMID- 28618274 TI - The relationship between birth and placental weights changes with placental size. PMID- 28618275 TI - Adsorptive removal of sulfate from acid mine drainage by polypyrrole modified activated carbons: Effects of polypyrrole deposition protocols and activated carbon source. AB - Polypyrrole modified activated carbon was used to remove sulfate from acid mine drainage water. The polypyrrole modified activated carbon created positively charged functionality that offered elevated sorption capacity for sulfate. The effects of the activated carbon type, approach of polymerization, preparation temperature, solvent, and concentration of oxidant solution over the sulfate adsorption capacity were studied at an array of initial sulfate concentrations. A hardwood based activated carbon was the more favorable activated carbon template, and this offered better sulfate removal than when using bituminous based activated carbon or oak wood activated carbon as the template. The hardwood-based activated carbon modified with polypyrrole removed 44.7 mg/g sulfate, and this was five times higher than for the pristine hardwood-based activated carbon. Various protocols for depositing the polypyrrole onto the activated carbon were investigated. When ferric chloride was used as an oxidant, the deposition protocol that achieved the most N+ atomic percent (3.35%) while also maintaining the least oxygen atomic percent (6.22%) offered the most favorable sulfate removal. For the rapid small scale column tests, when processing the AMD water, hardwood-based activated carbon modified with poly pyrrole exhibited 33 bed volume compared to the 5 bed volume of pristine activated carbons. PMID- 28618276 TI - Common explosives (TNT, RDX, HMX) and their fate in the environment: Emphasizing bioremediation. AB - Explosive materials are energetic substances, when released into the environment, contaminate by posing toxic hazards to environment and biota. Throughout the world, soils are contaminated by such contaminants either due to manufacturing operations, military activities, conflicts of different levels, open burning/open detonation (OB/OD), dumping of munitions etc. Among different forms of chemical explosives, 2,4,6-trinitrotoluene (TNT), hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), and octahydro-1,3,5,7-tetranitro- 1,3,5,7-tetrazocine (HMX) are most common. These explosives are highly toxic as USEPA has recommended restrictions for lifetime contact through drinking water. Although, there are several utilitarian aspects in anthropogenic activities, however, effective remediation of explosives is very important. This review article emphasizes the details of appropriate practices to ameliorate the contamination. Critical evaluation has also been made to encompass the recent knowledge and advancement about bioremediation and phytoremediation of explosives (especially TNT, RDX and HMX) along with the molecular mechanisms of biodegradation. PMID- 28618277 TI - Fate and adverse effects of hexabromocyclododecane diastereoisomers (HBCDDs) in a soil-ryegrass pot system. AB - This study explored the fate and adverse effects of 3 main hexabromocyclododecane diastereoisomers (alpha-, beta-, and gamma-HBCDDs) in a soil pot system planted with ryegrass (Lolium perenne L.) using a short-term (8 weeks) experiment. At the end of the experiment, soil urease activity in planted spiked soil increased and catalase activity decreased; while there was no obvious change in sucrase and peroxidase activities. HBCDDs mainly accumulated in the root of ryegrass, with root concentration factors (RCF) in the range of 1.46-4.43 and only a small part was transferred to the stem (SCF: 0.198-0.305) and leaf (LCF: 0.042-0.062). The concentration factors varied for different HBCDD diastereoisomers, being in the order of alpha- > beta- > gamma-HBCDD for all tissues, indicating preferential accumulation of alpha-HBCDD in ryegrass tissues. Moreover, the enantiomeric analysis revealed an enrichment of (+)-alpha-, (-)-beta- and (+)-gamma-HBCDD enantiomers in ryegrass tissues. beta- and gamma-HBCDDs (up to 1.90% and 4.11%, respectively) were transformed to aalpha-HBCDD in ryegrass, while no isomerization product from alpha-HBCDD was found. Hydroxylated HBCDDs metabolites, such as monoOHHBCDDs and diOHHBCDDs were found in ryegrass tissues for the first time. PMID- 28618278 TI - Interindividual variability of soil arsenic metabolism by human gut microbiota using SHIME model. AB - Arsenic (As) metabolism by human gut microbiota has been evidenced with in vitro experiments from contaminated soils. In this study, the variability in the metabolic potency toward As-contaminated soils and gut microbial diversity were investigated between healthy individuals (Adult versus Child). Arsenic bioaccessibility in the colon phase increased by 1.4-6.8 and 1.2-8.7 folds for adult and child, respectively. We found a high degree of As methylation for the colon digests of the adult (mean 2 MUg methylarsenicals/hr/g biomass), 3-folds higher than that of the child. Besides, arsenite [As(III)] concentration (1.5 391.3 MUg/L) for the child was 2-18 times for the adult. 16S rRNA gene sequencing revealed that human gut microbiota from 20 various genera potentially had resistance genes to reduce and methylate As under conservative statistics. Our results indicated that As metabolism by gut microbiota from adult and child was significantly different. The adult gut microbiota had a great ability of As methylation; the child gut microbiota exhibited high As(III) level, which could encounter high health risk. The identity and activity of arsenic-metabolizing bacteria isolated from human gut and its homologous role in As metabolism need be further explored. This study provides a better understanding of health risk assessment to adults and children upon soil As exposures. PMID- 28618279 TI - Analyzing the impacts of three types of biochar on soil carbon fractions and physiochemical properties in a corn-soybean rotation. AB - Biochar is a solid material obtained when biomass is thermochemically converted in an oxygen-limited environment. In most previous studies, the impacts of biochar on soil properties and organic carbon (C) were investigated under controlled conditions, mainly laboratory incubation or greenhouse studies. This 2 year field study was conducted to evaluate the influence of biochar on selected soil physical and chemical properties and carbon and nitrogen fractions for two selected soil types (clay loam and a sandy loam soil) under a corn (Zea mays L.) soybean (Glycine max L.) rotation. The three plant based biochar materials used for this study were corn stover (CS), ponderosa pine (Pinus ponderosa Lawson and C. Lawson) wood residue (PW), and switchgrass (Panicum virgatum L.) (SG). Data showed that CS and SG significantly increased the pH of acidic soil at the eroded landscape position but produced no significant change in soil pH at the depositional landscape position. The effects of biochar treatments on cold water extractable C (WSC) and nitrogen (WSN) fractions for the 0-7.5 cm depth were depended on biochar and soil type. Results suggested that alkaline biochars applied at 10 Mg ha-1 can increase the pH and WSC fraction of acidic sandy loam soil, but the 10 Mg ha-1 rate might be low to substantially improve physical properties and hot water extractable C and N fractions of soil. Application of higher rates of biochar and long-term monitoring is needed to quantify the benefits of biochar under field conditions on soils in different environmental conditions. PMID- 28618280 TI - Evaluation of bacterial biodegradation and accumulation of phenanthrene in the presence of humic acid. AB - This study evaluated the effect of humic acid (HA) on physicochemical properties of bacterial surfaces and on mass transfer of polycyclic aromatic hydrocarbons (PAHs) from aqueous phase into intracellular bacteria. Due to this process' potential for bacterial degradation, using Sphingobium sp. PHE3, degradation of phenanthrene (PHE) was compared in HA and non-HA sets. The results showed that approximately 51.1% of PHE at a concentration of 102.0 mg L-1 was biodegraded in the non-HA sets, whereas almost all PHE was biodegraded with HA after 72 h. Interestingly, PHE that accumulated in the intracellular bacteria reached 3.80 mg L-1 for the HA sets, which was significantly higher than that of non-HA. Lipid inclusion bodies appeared when Sphingobium sp. PHE3 was treated with HA. The results were further confirmed by the enhanced bacterial surface sorption capacity for the HA sets. Therefore, we concluded that added HA not only act as carriers and biosurfactants facilitating PHE uptake but also adjust bacteria cell wall properties for internalizing PHE, which ultimately overcame the PHE bioavailability resulting in enhanced biodegradation. PMID- 28618281 TI - Chlor(am)ination of iopamidol: Kinetics, pathways and disinfection by-products formation. AB - The degradation kinetics, pathways and disinfection by-products (DBPs) formation of iopamidol by chlorine and chloramines were investigated in this paper. The chlorination kinetics can be well described by a second-order model. The apparent second-order rate constants of iopamidol chlorination significantly increased with solution pH. The rate constants of iopamidol with HOCl and OCl- were calculated as (1.66 +/- 0.09) * 10-3 M-1 s-1 and (0.45+/- 0.02) M-1 s-1, respectively. However, the chloramination of iopamidol fitted well with third order kinetics and the maximum of the apparent rate constant occurred at pH 7. It was inferred that the free chlorine (i.e., HOCl and OCl-) can react with iopamidol while the combined chlorine species (i.e., NH2Cl and NHCl2) were not reactive with iopamidol. The main intermediates during chlorination or chloramination of iopamidol were identified using ultra performance liquid chromatography - electrospray ionization-mass spectrometry (UPLC-ESI-MS), and the destruction pathways including stepwise deiodination, hydroxylation as well as chlorination were then proposed. The regular and iodinated DBPs formed during chlorination and chloramination of iopamidol were measured. It was found that iodine conversion from iopamidol to toxic iodinated DBPs distinctly increased during chloramination. The results also indicated that although chloramines were much less reactive than chlorine toward iopamidol, they led to the formation of much more toxic iodinated DBPs, especially CHI3. PMID- 28618282 TI - Global shape integration and illusory form perception in the absence of awareness. AB - Previous research on perceptual organization operations still provides contradictory evidence on whether the integration of sparse local elements into coherently unified shapes and the construction of the illusory form are accomplished without the need of awareness. In the present study, three experiments were conducted in which participants were presented with masked (Experiment 1, SOA=27ms; Experiment 2; SOA=53ms) and unmasked (Experiment 3) primes consisting of geometric shapes (a square or a diamond) that could be congruent or incongruent with subsequent probe stimuli (square vs. diamond). Furthermore, the primes were divided into: a grouping condition (where local elements may group together into global shapes), an illusory condition (where the arrangement of local elements produced illusory shapes) and a hybrid condition (where both operations were presented simultaneously). While no priming effects were found for the shortest SOA (27ms), both grouping and illusory primes produced significant priming effects in the longer SOA (53ms). On the other hand, results in Experiment 3 (unmasked) showed strong priming effects for the grouping of the inducers in both the grouping and the hybrid conditions, and also a significant but weaker priming effect for the illusory condition. Overall, our results support the possibility of the integration of local visual features into a global shape in the absence of awareness and, likewise, they suggest an early subliminal- construction of the illusory shape, implying that feedback projections from higher to lower visual areas are not crucial in the construction of the illusory form. PMID- 28618283 TI - Vocational education paths, youth activities, and underage drinking in Russia: How early does the trouble start? AB - Working-class educational paths tend to be associated with elevated drinking. Little research has examined whether disproportionate alcohol use among vocationally oriented youth begins before or after the start of their vocational education. The present study analyzes a large sample of Russian middle-school students (N=1269; mean age=14.9), comparing the patterns of drinking among middle schoolers oriented towards vocational educational, and their peers who do not plan a vocational education path. Results suggest that the orientation towards vocational education is associated with disproportionately high alcohol involvement among Russian middle-school students, even before they enter vocational schools. We studied if such difference could be partially explained by how youth orient towards extracurricular activities: discretionary peer time in risky contexts, reading for pleasure, working for pay, and religious activities. Reading demonstrated the strongest (negative) association with alcohol use, while religious activity unexpectedly revealed a positive (though weak) association with drinking. Research and policy implications are discussed. PMID- 28618284 TI - Differences in biomarkers of crack-cocaine adolescent users before/after abstinence. AB - AIMS: To measure the variation in Brain-Derived Neurotrophic Factor (BDNF), Thiobarbituric Acid Reactive Substances (TBARS) and interleukin (IL) levels in crack-cocaine dependent adolescents after 21days of abstinence, comparing to levels found in a group of healthy controls. DESIGN: Cross-sectional nested on a short follow-up study. SETTING: Two inpatient treatment units for adolescents, and a low-income neighborhood. PARTICIPANTS: 90 adolescents, of both genders, with diagnosis of crack cocaine dependence, and 81 healthy adolescents. MEASUREMENTS: Serum levels of IL-6, IL-10, TBARS and BDNF were assessed on admission and discharge. Drug addiction severity was assessed by the Addiction Severity Index - Teen Version (T-ASI) and Cocaine Craving Questionnaire - Brief version (CCQ-b). Psychiatric comorbidities were assessed by the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version (K-SADS-PL). Generalized Estimating Equations (GEE) were used to estimate the IL-6, IL-10, TBARS and BDNF levels, adjusted for confounders. Hedges' g was used to estimate effect size. FINDINGS: TBARS (p=0.005, d=0.04), IL 6 (p=0.027, d=0.40) and IL-10 (p=0.025, d=0.41) were elevated and BDNF (p<0.001, d=0.62) was reduced (p<0.001), in patients, in comparison to controls, at admission time. Variation in those levels between admission and discharge were not significant. CONCLUSIONS: Crack-cocaine use seems to be associated with inflammatory and oxidative imbalances in adolescents. PMID- 28618285 TI - Belgian experience with direct acting antivirals in people who inject drugs. AB - BACKGROUND AND AIM: Hepatitis C viral infection (HCV) has become a curable disease due to the development of direct acting antivirals (DAA). The WHO has set a target to eliminate HCV completely. Therefore, people who inject drugs (PWID) also need to be treated. In this study, we compared the real-life uptake and outcome of DAA treatment for HCV in PWID and non-PWID. METHODS: We performed a nation-wide, retrospective cohort study in 15 hospitals. All patients who were treated with simeprevir-sofosbuvir, daclatasvir-sofosbuvir, or ombitasvir/paritaprevir ritonavir-dasabuvir between December 2013 and November 2015 were included. RESULTS: The study population consisted of 579 patients: 115 PWID (19.9%) and 464 non-PWID (80.1%). Of the PWID 18 were active PWID (15.6%), 35 still received opiate substitution therapy (OST) (30.4%) and 62 were former PWID without OST (53.9%). PWID were more infected with genotype 1a and 3 (p=0.001). There were equal rates of side-effects (44.7% vs. 46.6%; p=0.847), similar rates of treatment completion (95.7% vs 98.1%; p=0.244) and SVR (93.0% vs 94.8%; p=0.430) between PWID and non-PWID, respectively. CONCLUSION: PWID, especially active users, are underserved for DAA treatment in real life in Belgium. Reimbursement criteria based on fibrosis stage make it difficult to treat PWID. Treatment adherence is similar in PWID and the general population, even in patients with active abuse. DAA were safe and effective in PWID despite the higher prevalence of difficult-to-treat genotypes. Based on these data more efforts to treat PWID are needed and policy changes are necessary to reach the WHO targets. PMID- 28618287 TI - Age-related changes in the carcass yield and meat quality of male and female nutrias (Myocastor coypus) under intensive production system. AB - The age at which final nutria weight is achieved varies in literature between six and 14months. The aim of this study was to evaluate the growth, carcass composition and meat quality of male and female nutrias between the ages of six and eight months in intensive production system. Sexual dimorphism in growth was observed from three months of age, and in females, growth considerably decreased after six months of age. The dressing-out percentage and the meat color were not affected by the age or sex of nutrias. Dry matter, ether extract and energetic values were significantly higher in females and in older nutrias. The decreasing frequency of type IIA fibers in older nutrias was presumably associated with a conversion of type IIA fibers to type IIB fibers. Nutrias under intensive production system can be slaughtered at six months of age when they reach a high carcass yield and meat quality. PMID- 28618286 TI - Insomnia severity as a mediator of the association between mental health symptoms and alcohol use in young adult veterans. AB - PURPOSE: Prior research has documented associations between mental health and alcohol use, mental health and insomnia, and insomnia and alcohol use. This study examined insomnia severity as a mediator of the association between mental health and alcohol-related outcomes in young adult veterans. PROCEDURES: Veterans aged 18-34 years (N=622, 83% male) who reported drinking in the past year completed assessments at baseline and one-month follow-up as part of a larger intervention trial. Participants reported symptoms of depression and posttraumatic stress disorder (PTSD) at baseline, insomnia severity at one month, and alcohol use and related consequences at baseline and one month. Mediation analyses using bootstrapped confidence intervals were used to examine the indirect effects of baseline mental health symptoms on alcohol-related outcomes at one month via insomnia severity. MAIN FINDINGS: Insomnia severity was associated with both drinking quantity and alcohol-related consequences. Greater depressive (but not PTSD) symptoms were associated directly with more alcohol-related consequences. Neither depressive nor PTSD symptoms had direct effects on drinking quantity when controlling for the other mental health symptoms (e.g., depressive symptoms did not predict drinking quantity when controlling for symptoms of PTSD). However, symptoms of depression and PTSD predicted drinks per week and alcohol-related consequences indirectly through insomnia severity. CONCLUSIONS: Symptoms of depression and PTSD increase risk for alcohol use and related consequences in part by increasing symptoms of insomnia. Findings suggest that insomnia may be an appropriate target for prevention and intervention efforts among heavy-drinking Veterans reporting symptoms of depression or PTSD. PMID- 28618289 TI - Erratum to "Comparison of turnaround time and total cost of HIV testing before and after implementation of the 2014 CDC/APHL laboratory testing algorithm for diagnosis of HIV infection" [J. Clin. Virol. 91 (2017) 69-72]. PMID- 28618288 TI - An enhanced Enterovirus surveillance system allows identification and characterization of rare and emerging respiratory enteroviruses in Denmark, 2015 16. AB - BACKGROUND: The potential for outbreaks due to Enteroviruses (EV) with respiratory tropism, such as EV-D68, and the detection of new and rare EV species C is a concern. These EVs are typically not detected in stool specimens and may therefore be missed by standard EV surveillance systems. Following the North American outbreak of EV-D68 in 2014, Denmark piloted an enhanced EV surveillance system that included the screening of respiratory samples. OBJECTIVES: We aim to report clinical manifestations and phylogenetic descriptions from the rare and emerging EVs identified thereby demonstrating the usefulness of this system. STUDY DESIGN: Positive EV samples received through the enhanced non-polio EV pilot surveillance system were characterized by sequencing fragments of VP1, VP2 and VP4 capsid proteins and clinical observations were compiled. RESULTS: Between January 2015 and October 2016, six cases of rare genotypes EV-C104, C105 and C109 and nine cases of EV-D68 were identified. Patients presented with mild to moderately severe respiratory illness; no paralysis occurred. Distinct EV-C104, EV-C109 and EV-D68 sequences argue against a common source of introduction of these genotypes in the Danish population. CONCLUSIONS: The enhanced EV surveillance system enabled detection and characterization of rare EVs in Denmark. In order to improve our knowledge of and our preparedness against emerging EVs, public health laboratories should consider expanding their EV surveillance system to include respiratory specimens. PMID- 28618291 TI - Immune-mediated neuropathies: Role of single-fiber conduction velocity. PMID- 28618290 TI - Defining trauma in complex care management: Safety-net providers' perspectives on structural vulnerability and time. AB - In this paper, we delineate how staff of two complex care management (CCM) programs in urban safety net hospitals in the United States understand trauma. We seek to (1) describe how staff in CCM programs talk about trauma in their patients' lives; (2) discuss how trauma concepts allow staff to understand patients' symptoms, health-related behaviors, and responses to care as results of structural conditions; and (3) delineate the mismatch between long-term needs of patients with histories of trauma and the short-term interventions that CCM programs provide. Observation and interview data gathered between February 2015 and August 2016 indicate that CCM providers define trauma expansively to include individual experiences of violence such as childhood abuse and neglect or recent assault, traumatization in the course of accessing health care and structural violence. Though CCM staff implement elements of trauma-informed care, the short term design of CCM programs puts pressure on the staff to titrate their efforts, moving patients towards graduation or discharge. Trauma concepts enable clinicians to name structural violence in clinically legitimate language. As such, trauma-informed care and structural competency approaches can complement each other. PMID- 28618292 TI - Influence of transcutaneous spinal stimulation on human LTP-like pain amplification. A randomized, double-blind study in volunteers. AB - OBJECTIVE: Transcutaneous spinal direct current stimulation (tsDCS) has been proven to affect nociceptive signal processing. We designed a randomized, double blind, cross-over study to investigate whether tsDCS applied before or after inducing long-term potentiation-(LTP)-like hyperalgesia may decrease nociceptive sensitivity. METHODS: In healthy volunteers, tsDCS (2.5mA, 15min) was applied to the thoracic spine prior (n=14) or immediately following (n=12) electrical high frequency stimulation (HFS) to the thigh, inducing hyperalgesia. Mechanical and electrical perception were assessed before HFS stimulation and at three time points following HFS stimulation (all within 90min of HFS). Subjects took part in three separate sessions to test effects of anodal, cathodal, or sham tsDCS. RESULTS: Within 60minHFS led to unilateral changes on the conditioned side: mechanical pain thresholds tended to decrease and electrical detection thresholds significantly decreased (p<0.001); pain ratings measured using the numerical rating scale (NRS) increased for electrical stimuli (p<0.01) and two categories of mechanical stimuli ("Light(8-64mN)": p=ns; "Heavy(128-512mN)": p<0.01). Irrespective of stimulation order or polarity, tsDCS could not influence nociceptive sensitivity. CONCLUSION: Hyperalgesia was adequately induced, but tsDCS had no effect on HFS-induced sensitization. SIGNIFICANCE: While tsDCS has been shown to affect pain measures, our results suggest irrespective of time of stimulation or polarity that tsDCS may be less effective in modulating pain in a sensitized state in healthy subjects. PMID- 28618293 TI - Pilot prospective study of post-surgery sleep and EEG predictors of post operative delirium. AB - OBJECTIVE: Delirium is a common post-operative complication associated with significant costs, morbidity, and mortality. We sought sleep/EEG predictors of delirium present prior to delirium symptoms to facilitate developing and targeting therapies. METHODS: Continuous EEG data were obtained in 12 patients post-orthopedic surgery from the day of surgery until delirium assessment on post operative day 2 (POD2). RESULTS: Diminished total sleep time (r=-0.68; p<0.05) and longer latency to sleep onset (r=0.67; p<0.05) on the first night in the hospital were associated with greater POD2 delirium severity. Patients experiencing delirium slept 2.4h less and took 2h longer to fall asleep. Greater waking EEG delta power (r=0.84; p<0.05) on POD1 and less non-REM sleep EEG delta power (r=-0.72; p<0.05) on night 2 also predicted POD2 delirium severity. CONCLUSIONS: Loss of sleep on night1 post-surgery is an early predictor of subsequent delirium. EEG Delta Power alterations in waking and sleep appear to be later indicators of impending delirium. Further work is needed to evaluate reproducibility/generalizability and assess whether sleep loss contributes to causing delirium. SIGNIFICANCE: This first study to prospectively collect continuous EEG data for an extended period prior to delirium onset identified EEG derived indices that predict subsequent delirium that could aid in developing and targeting therapies. PMID- 28618294 TI - Focused high-resolution sonography of the suprascapular nerve: A simple surrogate marker for neuralgic amyotrophy? AB - OBJECTIVES: To define the diagnostic value of high-resolution ultrasound (HRUS) of the suprascapular nerve (SSN) in the diagnosis of neuralgic amyotrophy (NA). METHODS: The cross-section areas (CSA) of the SSN at the C5 root (CSA1) and the omohyoid muscle in the midclavicular line (CSA2) were assessed bilaterally in 15 healthy volunteers and 14 patients with clinically and electrophysiologically verified NA. Receiver-operator-characteristics (ROC) curves were generated and cut-off values, sensitivity, specificity, positive (PPV) and negative predictive values (NPV), likelihood (LR) and odds ratios (OR) were calculated. RESULTS: Patients with NA had significantly higher CSA2-values than controls (6.36+/ 2.75vs. 2.79+/-0.83mm2, p<0.0001) and significantly higher ratios of SSN CSA2 values of the affected vs. contralateral side (224.6+/-78.5% vs. 127.7+/-51.1%, p<0.0001). The ratios of SSN CSA2-values vs. CSA1-values (146.7+/-74.5% vs. 99.9+/-28.3%, p=0.008) and CSA1-values were also significantly higher (4.70+/ 2.00vs. 2.90+/-0.90mm2, p=0.0028) than in controls. Beyond a CSA2 cut-off value of 4.2mm2, the ROC-AUC was 0.939 [0.861-1.00] when compared against healthy volunteers and 0.971 [0.901-1.00] when compared to patients with degenerative shoulder pain. Sensitivity was 85.7% [57.2-98.2%], specificity 96.7% [82.8 99.9%], PPV 92.3% [64.0-99.8%], NPV 93.5% [78.6-99.2%], OR 174.0 [14.4-2106.0] and LR 25.7 (95% confidence intervals in brackets). CONCLUSION: SSN swelling in the lateral cervical region could be a supportive finding to identify NA patients. SIGNIFICANCE: This method allows for the rapid sonographic identification of NA. PMID- 28618295 TI - Phase-locked and non-phase-locked EEG responses to pinprick stimulation before and after experimentally-induced secondary hyperalgesia. AB - OBJECTIVE: Pinprick-evoked brain potentials (PEPs) have been proposed as a technique to investigate secondary hyperalgesia and central sensitization in humans. However, the signal-to-noise (SNR) of PEPs is low. Here, using time frequency analysis, we characterize the phase-locked and non-phase-locked EEG responses to pinprick stimulation, before and after secondary hyperalgesia. METHODS: Secondary hyperalgesia was induced using high-frequency electrical stimulation (HFS) of the left/right forearm skin in 16 volunteers. EEG responses to 64 and 96mN pinprick stimuli were elicited from both arms, before and 20min after HFS. RESULTS: Pinprick stimulation applied to normal skin elicited a phase locked low-frequency (<5Hz) response followed by a reduction of alpha-band oscillations (7-10Hz). The low-frequency response was significantly increased when pinprick stimuli were delivered to the area of secondary hyperalgesia. There was no change in the reduction of alpha-band oscillations. Whereas the low frequency response was enhanced for both 64 and 96mN intensities, PEPs analyzed in the time domain were only significantly enhanced for the 64mN intensity. CONCLUSIONS: Time-frequency analysis may be more sensitive than conventional time domain analysis in revealing EEG changes associated to secondary hyperalgesia. SIGNIFICANCE: Time-frequency analysis of PEPs can be used to investigate central sensitization in humans. PMID- 28618296 TI - Impaired body perception in developmental prosopagnosia. AB - Developmental prosopagnosia (DP) is a lifelong neurodevelopmental disorder associated with difficulties recognising and discriminating faces. In some cases, the perceptual deficits seen in DP appear to be face-specific. However, DP is known to be a heterogeneous condition, and many cases undoubtedly exhibit impaired perception of other complex objects. There are several well-documented parallels between body and face perception; for example, faces and bodies are both thought to recruit holistic analysis and engage similar regions of visual cortex. In light of these similarities, individuals who exhibit face perception deficits, possibly due to impaired holistic processing or aberrant white matter connectivity, might also show co-occurring deficits of body perception. The present study therefore sought to investigate body perception in DP using a sensitive delayed match-to-sample task and a sizeable group of DPs. To determine whether body perception deficits, where observed, co-vary with wider object recognition deficits, observers' face and body matching ability was compared with performance in a car matching condition. Relative to age-matched controls, the DP sample exhibited impaired body matching accuracy at the group level, and several members of the sample were impaired at the single-case level. Consistent with previous reports of wider object recognition difficulties, a number of the DPs also showed evidence of impaired car recognition. PMID- 28618297 TI - Does communication partner training improve the conversation skills of speech language pathology students when interacting with people with aphasia? AB - BACKGROUND: Aphasia is a common consequence of stroke. Despite receiving specialised training in communication, speech-language pathology students may lack confidence when communicating with People with Aphasia (PWA). This paper reports data from secondary outcome measures from a randomised controlled trial. OBJECTIVE: The aim of the current study was to examine the effects of communication partner training on the communication skills of speech-language pathology students during conversations with PWA. METHOD: Thirty-eight speech language pathology students were randomly allocated to trained and untrained groups. The first group received a lecture about communication strategies for communicating with PWA then participated in a conversation with PWA (Trained group), while the second group of students participated in a conversation with the PWA without receiving the lecture (Untrained group). The conversations between the groups were analysed according to the Measure of skill in Supported Conversation (MSC) scales, Measure of Participation in Conversation (MPC) scales, types of strategies used in conversation, and the occurrence and repair of conversation breakdowns. RESULTS: The trained group received significantly higher MSC Revealing Competence scores, used significantly more props, and introduced significantly more new ideas into the conversation than the untrained group. The trained group also used more gesture and writing to facilitate the conversation, however, the difference was not significant. There was no significant difference between the groups according to MSC Acknowledging Competence scores, MPC Interaction or Transaction scores, or in the number of interruptions, minor or major conversation breakdowns, or in the success of strategies initiated to repair the conversation breakdowns. CONCLUSION: Speech-language pathology students may benefit from participation in communication partner training programs. PMID- 28618298 TI - Shape of change in internet based behavioral activation treatment for depression. AB - : Shape of change, sudden gains and depression spikes were examined in an online 12-session Behavioral Activation (BA) treatment for depression. Client and therapist factors related to sudden gains were examined to investigate processes associated with outcome. METHODS: Participants were postpartum Women with Major Depressive Disorder (n=42) who received online BA supported in 30-minute telephone sessions by a mental health worker. Depression symptoms were assessed at each session and number of sessions completed were recorded by the online program. Therapist records were rated for client stressful life event and therapist concrete focus. A quadratic pattern provided the best fit with the data; a cubic pattern was a poor fit. Sudden gains, but not depression spikes, predicted lower depression scores at 17-week outcome. Women who had higher baseline social functioning, did not experience a stressful life event during therapy, and completed more online modules, but not more telephone sessions, were more likely to have a sudden gain. A concrete therapist focus was associated with sudden gains. These results extend research on trajectories of change and sudden gains to an online BA treatment and to postpartum depression, and suggest important client and therapist factors associated with sudden gains. PMID- 28618299 TI - Is the devil in the detail? A randomised controlled trial of guided internet based CBT for perfectionism. AB - An internet guided self-help cognitive-behavioural treatment (ICBT) for perfectionism was recently found to be effective (see this issue). Such studies stand in need of replication. The aim of this study was to report the outcomes and predictors of change when the treatment is delivered in a UK setting. A total of 120 people (Mean = 28.9 years; 79% female) were randomised to receive ICBT or wait-list control over 12 weeks (trial registration: NCT02756871). While there were strong similarities between the current study and its Swedish counterpart, there were also important differences in procedural details. There was a significant impact of the intervention on the primary outcome measure (Frost Multidimensional Perfectionism Scale, Concern over Mistakes subscale) and also on the Clinical Perfectionism Questionnaire (between group effect sizes d = 0.98 (95% CI: 0.60-1.36) and d = 1.04 (95% CI: 0.66-1.43) respectively using intent-to treat analyses). Unlike the Swedish study, there was significant non-engagement and non-completion of modules with 71% of participants completing fewer than half the modules. The number of modules completed moderated the rate of change in clinical perfectionism over time. In conclusion, the study indicates the intervention is effective in a UK setting but highlighted the importance of procedural details to optimise retention. PMID- 28618300 TI - Effects of context and individual differences on the processing of taboo words. AB - Previous studies suggest that taboo words are special in regards to language processing. Findings from the studies have led to the formation of two theories, global resource theory and binding theory, of taboo word processing. The current study investigates how readers process taboo words embedded in sentences during silent reading. In two experiments, measures collected include eye movement data, accuracy and reaction time measures for recalling probe words within the sentences, and individual differences in likelihood of being offended by taboo words. Although certain aspects of the results support both theories, as the likelihood of a person being offended by a taboo word influenced some measures, neither theory sufficiently predicts or describes the effects observed. The results are interpreted as evidence that processing effects ascribed to taboo words are largely, but not completely, attributable to the context in which they are used and the individual attitudes of the people who hear/read them. The results also demonstrate the importance of investigating taboo words in naturalistic language processing paradigms. A revised theory of taboo word processing is proposed that incorporates both global resource theory and binding theory along with the sociolinguistic factors and individual differences that largely drive the effects observed here. PMID- 28618301 TI - Noninvasive measurement of wave speed of porcine cornea in ex vivo porcine eyes for various intraocular pressures. AB - The objective of this study was to extend an ultrasound surface wave elastography (USWE) technique for noninvasive measurement of ocular tissue elastic properties. In particular, we aim to establish the relationship between the wave speed of cornea and the intraocular pressure (IOP). Normal ranges of IOP are between 12 and 22mmHg. Ex vivo porcine eye balls were used in this research. The porcine eye ball was supported by the gelatin phantom in a testing container. Some water was pour into the container for the ultrasound measurement. A local harmonic vibration was generated on the side of the eye ball. An ultrasound probe was used to measure the wave propagation in the cornea noninvasively. A 25 gauge butterfly needle was inserted into the vitreous humor of the eye ball under the ultrasound imaging guidance. The needle was connected to a syringe. The IOP was obtained by the water height difference between the water level in the syringe and the water level in the testing container. The IOP was adjusted between 5mmHg and 30mmHg with a 5mmHg interval. The wave speed was measured at each IOP for three frequencies of 100, 150 and 200Hz. Finite element method (FEM) was used to simulate the wave propagation in the corneal according to our experimental setup. A linear viscoelastic FEM model was used to compare the experimental data. Both the experiments and the FEM analyses showed that the wave speed of cornea increased with IOP. PMID- 28618302 TI - Growth and physiological responses of a marine diatom (Phaeodactylum tricornutum) against two imidazolium-based ionic liquids ([C4mim]BF4 and [C8mim]BF4). AB - Ionic liquids (ILs) have been considered as "green" substitutes for traditional organic solvents in many existing biological and chemical areas. However, they have high solubility and poor biodegradability in water, suggesting that they could become persistent chemical pollutants in aquatic environment. The ability of two widely used imidazolium-based ILs to affect the growth and physiological characteristics of a marine diatom (Phaeodactylum tricornutum) was investigated in this study. The diatom was exposed to different concentrations of 1-butyl-3 methylimidazolium tetrafluoroborate ([C4mim]BF4) and 1-octyl-3-methylimidazolium tetrafluoroborate ([C8mim]BF4) for 96h within a batch-culture system. Results showed that [C4mim]BF4 and [C8mim]BF4 were very stable in seawater during 96h of exposure, and the compounds significantly inhibited the growth of P. tricornutum with 24, 48, 72 and 96h EC50 values of 30.81, 28.53, 39.92, 45.88mgL-1 and 30.17, 23.36, 28.62, 31.37mgL-1, respectively. In addition, the photosynthetic activity and chlorophyll a synthesis of P. tricornutum were inhibited by [C4mim]BF4 and [C8mim]BF4, indicating that the structural integrity of chloroplasts of the diatom may be disrupted or damaged by the two ILs. Compared with that of the controls, reactive oxygen species (ROS) level was increased by 0.65, 1.17, 1.85, 3.13, 2.94 times and 0.55, 1.77, 2.42, 3.45, 3.47 times in 5, 10, 20, 40 and 60mgL-1 [C4mim]BF4 and [C8mim]BF4 treatments, respectively. The excessive ROS may cause lipid peroxidation, shortage of metabolic energy and decline of photosynthetic efficiency, which may be the main reason for toxicity of the two ILs to marine diatoms. To withstand the damaging effects of excessive ROS, remarkable physiological and biochemical responses occurred in treatments with the two ILs to protect the cells of P. tricornutum. Parameters such as soluble protein content, soluble sugar content, and superoxide dismutase (SOD) and peroxidase (POD) activities of the diatom increased significantly with increasing concentrations of the two ILs at 96h of exposure relative to the controls. These findings not only provide strong background for evaluating the ecological risks and toxicity of ILs in marine environment, but also help to unravel the toxic mechanism of the two ILs to marine diatoms. PMID- 28618303 TI - Transcriptomic response of the insect vector, Peregrinus maidis, to Maize mosaic rhabdovirus and identification of conserved responses to propagative viruses in hopper vectors. AB - Maize mosaic virus (MMV) is a plant-pathogenic rhabdovirus that is transmitted by the corn planthopper, Peregrinus maidis, in a propagative manner. P. maidis supports long-term MMV infections with no negative effects on insect performance. To elucidate whole-body transcriptome responses to virus infection, RNA-Seq was used to examine differential gene expression of virus-infected adult insects, and libraries were prepared from replicated groups of virus-exposed insects and non exposed insects. From the 68,003 de novo-assembled transcripts, 144 were differentially-expressed (DE) during viral infection with comparable numbers up- and down-regulated. DE transcripts with similarity to genes associated with transposable elements (i.e., RNA-directed DNA polymerases) were enriched and may represent a mechanisim for modulating virus infection. Comparison of the P. maidis DE transcripts to published propagative virus-responsive transcript databases for two other hopper vectors revealed that 16% of the DE transcripts were shared across the three systems and may represent conserved responses to propagative viruses. PMID- 28618304 TI - Breast magnetic resonance imaging use in patients undergoing neoadjuvant chemotherapy is associated with less mastectomies in large ductal cancers but not in lobular cancers. AB - BACKGROUND: To assess the impact of breast magnetic resonance imaging (MRI) use on surgical outcome per histological breast cancer subtype in patients treated with neoadjuvant chemotherapy. PATIENTS AND METHODS: All patients aged 18-70 years who underwent neoadjuvant chemotherapy for stage I-III invasive breast cancer in the Netherlands in the years 2011-2013 were identified from the Netherlands Cancer Registry. Patients with cT4 tumours were excluded from the analysis. Use of breast MRI and impact on surgical treatment, resection margins and detection of contralateral breast cancer were analysed by multivariable analyses. RESULTS: Breast MRI was performed in 2879 (83.9%) out of 3433 patients treated with neoadjuvant chemotherapy. Younger age (odds ratio [OR] 1.42; 95% confidence interval [CI] 1.17-1.71 for 18-50 years compared with 50-70 years), larger tumour stage (OR 1.46 [95% CI 1.15-1.86] for cT3, compared to cT1-2 tumours) and multifocality (OR 1.30; 95% CI 1.04-1.61, versus unifocality) were associated with increased breast MRI use. In ductal breast cancer, after stratification for cT-status, breast MRI use is associated with a significant lower OR for mastectomy as final surgery in cT3 tumours (OR 0.45, 95% CI 0.21 0.99). Resection margin involvement and detection of contralateral breast cancer were not associated with breast MRI use. CONCLUSION: In patients treated with neoadjuvant chemotherapy, the use of breast MRI was associated with a reduced mastectomy rate, particularly in patients with large invasive ductal breast tumours but not in patients with lobular breast cancer. PMID- 28618305 TI - Phase I study of temsirolimus in combination with cetuximab in patients with advanced solid tumours. AB - BACKGROUND: Preclinical studies suggest synergistic antitumour effects of mammalian target of rapamycin (mTOR) inhibitor such as temsirolimus combined with anti-EGFR monoclonal antibody such as cetuximab. METHODS: Temsirolimus (T) and cetuximab (C) were combined and escalated in cohorts of patients with advanced or metastatic solid tumours, respectively from 15 to 25 mg and 150-250 mg/m2, until the maximum tolerated dose (MTD) was determined. Effort was made in the expansion cohort to enrol patients harbouring a molecular aberration in the human epidermal growth factor receptor (EGFR) and/or phosphoinositide 3-kinase (PI3K) pathways. Paired biopsies were optional to evaluate pathway modulation. RESULTS: Among 39 patients enrolled, three experienced dose-limiting toxicities (DLTs): pulmonary embolism (C200 + T20), stomatitis (C250 + T20) and acneiform rash (C250 + T25). The weekly C 250 mg/m2 and T 25 mg dose level was selected as the MTD. The most common treatment-related adverse events were: acneiform rash (97%), oral mucositis (82%), fatigue (59%), nausea (41%) and diarrhoea (36%). The median progression-free survival (PFS) and overall survival (OS) were respectively 2.0 months [95% CI: 1.8, 3.5] and 7.5 months [95% CI: 5.5, 11.9]. Among all patients, partial responses (PRs) and stable diseases (SDs) were observed in 2 (5.1%) and 18 patients (46.2%), respectively. The objective response rate (ORR) in patients with a molecular aberration was 2/14 (14%), versus 0/24 in those without molecular aberration. CONCLUSIONS: Combination of T + C showed significant but manageable toxicities. Due to modest clinical activity, further evaluation is not recommended. Molecular selection could potentially increase the objective response rate and should be implemented during drug development. PMID- 28618306 TI - Effects of acute exercise on fear extinction in rats and exposure therapy in humans: Null findings from five experiments. AB - BACKGROUND: Exposure therapy is an established learning-based intervention for the treatment of anxiety disorders with an average response rate of nearly 50%, leaving room for improvement. Emerging strategies to enhance exposure therapy in humans and fear extinction retention in animal models are primarily pharmacological. These approaches are limited as many patients report preferring non-pharmacological approaches in therapy. With general cognitive enhancement effects, exercise has emerged as a plausible non-pharmacological augmentation strategy. The present study tested the hypothesis that fear extinction and exposure therapy would be enhanced by a pre-training bout of exercise. METHODS: We conducted four experiments with rats that involved a standardized conditioning and extinction paradigm and a manipulation of exercise. In a fifth experiment, we manipulated vigorous-intensity exercise prior to a standardized virtual reality exposure therapy session among adults with fear of heights. RESULTS: In experiments 1-4, exercise did not facilitate fear extinction, long-term memory, or fear relapse tests. In experiment 5, human participants showed an overall reduction in fear of heights but exercise did not enhance symptom improvement. CONCLUSIONS: Although acute exercise prior to fear extinction or exposure therapy, as operationalized in the present 5 studies, did not enhance outcomes, these results must be interpreted within the context of a broader literature that includes positive findings. Taken all together, this suggests that more research is necessary to identify optimal parameters and key individual differences so that exercise can be implemented successfully to treat anxiety disorders. PMID- 28618307 TI - Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: Palbociclib and ribociclib. AB - PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors such as palbociclib and ribociclib are associated with distinct adverse effects (AEs) compared to other targeted therapies. This meta-analysis of clinical trials summarizes these agents' toxicity profile. METHODS: A librarian-guided literature search was conducted in March of 2017. The trials needed to have at least one of the study arms consisting of palbociclib or ribociclib monotherapy at currently FDA approved dose regimens. Heterogeneity across studies was analyzed using I2 statistics. Data were analyzed using random effects meta-analysis for absolute risks. RESULTS: Seven randomized trials and 1,332 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies for serious AEs but not for death. The pooled absolute risk (AR) for all causality serious AEs and treatment-related death were 16% and 0%, respectively. Patients treated with CDK 4/6 inhibitors had an AR of grade 3/4 neutropenia of 61%; neutropenic fever and infections were rare (1% and 3%, respectively). Grade 3/4 nausea, vomiting, and rash were rare. There was no significant correlation between age of patients at study entry and the risk of grade 3/4 neutropenia. CONCLUSION: Treatment with CDK 4/6 inhibitors is well tolerated and associated with a low risk of treatment-related deaths. There is an increased AR of grade 3/4 neutropenia but a low AR of associated infections. PMID- 28618308 TI - Supplementary medial locking plate fixation of Ludloff osteotomy versus sole lag screw fixation: A biomechanical evaluation. AB - BACKGROUND: The Ludloff oblique osteotomy is inherently unstable, which might lead to delayed union and loss of correction. Supplementary fixation to two lag screw fixation has been proposed. The hypothesis is that the osteotomy fixation constructs supplemented by a mini locking plate provide greater resistance to osteotomy gaping and loss of angular correction in response to cyclic loading. METHODS: Twenty fourth generation composite 1st metatarsals were used and underwent a Ludloff osteotomy. They were divided in two fixation groups: two lag screws (Group A), and with a supplementary mini locking plate (Group B). Specimens were subjected to either monotonic loading up to failure or to fatigue (cyclic) tests and tracked using an optical system for 3D Digital Image Correlation. FINDINGS: The osteotomy gap increased in size under maximum loading and was significantly greater in Group A throughout the test. This increase was observed very early in the loading process (within the first 1000cycles). The most important finding though, was that with the specimens completely unloaded the residual gap increase was significantly greater in Group A after only 5000cycles of loading up to the completion of the test. The lateral angle change under maximum loading was also significantly greater in Group A throughout the test, with that increase observed early in the loading process (5000cycles). With the specimens completely unloaded the residual lateral angle change was also significantly greater in Group A at the completion of the test. INTERPRETATION: Supplementary fixation with a mini locking plate of the Ludloff osteotomy provided greater resistance to osteotomy gaping and loss of angular correction compared to sole lag screws, in response to cyclic loading. PMID- 28618309 TI - Exertion and pain do not alter coordination variability in runners with iliotibial band syndrome. AB - BACKGROUND: Iliotibial band syndrome is a common overuse running injury which results in altered mechanics. While injuries alter discrete mechanics, they may also cause a change in coordination variability, the stride-to-stride organization of runners' movement patterns. Uninjured and injured runners may experience a change in coordination variability during a run to exertion due to fatigue, pain, or a combination of these factors. The aim of the current study was to determine if runners with iliotibial band syndrome and uninjured runners display different segment coordination variability across the course of a run to exertion. METHODS: 3D kinematics were collected as 13 uninjured runners and 12 runners with iliotibial band syndrome ran on a treadmill. A modified vector coding technique was used to calculate coordination variability during stance for segment couples of interest. Coordination variability was compared between uninjured and injured runners at the beginning and end of the run. The influence of pain on coordination variability was also examined. FINDINGS: There were no differences in coordination variability at the beginning or end of the run between uninjured runners and those with iliotibial band syndrome. The change in coordination variability due to the run was not different between uninjured runners, injured runners who experienced no change in pain, and injured runners who did experience a change in pain. INTERPRETATION: Runners do not constrain the patterns of segment motion they use in response to exertion nor does it appear that occurrence of pain during running results in a differential change in coordination variability. PMID- 28618310 TI - Bilateral changes in 3-D scapular kinematics in individuals with chronic stroke. AB - BACKGROUND: Stroke can lead to altered scapular motion that may limit the ability to perform activities of daily living. The aims were to evaluate scapular kinematics of individuals with chronic stroke and the correlation with paretic arm function. METHODS: Scapular kinematics was assessed in thirty-four individuals (Chronic stroke=17; controls=17) during arm elevation and lowering in scapular and self-selected planes, and during hair combing. The use of the paretic arm to perform activities of daily living was assessed by the Motor Activity Log (MAL-30). Scapular kinematics was compared among paretic and non paretic arms, and controls. Correlation between scapular kinematics and MAL-30 was also verified. FINDINGS: Paretic and non-paretic arms showed increased scapular internal rotation (p<0.05) during arm lowering in the scapular plane, and during arm elevation and lowering in the self-selected plane compared to controls. Increased internal rotation (p<0.05) was also found in the paretic arm during hair combing compared to controls. Increased scapular anterior tilt (p<0.05) was observed in the paretic arm during arm elevation while performing the activity of hair combing and during arm elevation and lowering in the scapular and self-selected planes compared to controls. The non-paretic arm showed increased anterior tilt (p<0.05) during arm elevation and lowering in self selected plane compared to controls. No difference in scapular upward rotation among neither arms, nor correlation between scapular kinematics and MAL-30 were found (p>0.05). INTERPRETATION: Individuals with chronic stroke showed bilateral scapular kinematics alterations. However, these alterations are not correlated with paretic arm function. PMID- 28618311 TI - Predicting knee osteoarthritis risk in injured populations. AB - BACKGROUND: Individuals who suffered a lower limb injury have an increased risk of developing knee osteoarthritis. Early diagnosis of osteoarthritis and the ability to track its progression is challenging. This study aimed to explore links between self-reported knee osteoarthritis outcome scores and biomechanical gait parameters, whether self-reported outcome scores could predict gait abnormalities characteristic of knee osteoarthritis in injured populations and, whether scores and biomechanical outcomes were related to osteoarthritis severity via Spearman's correlation coefficient. METHODS: A cross-sectional study was conducted with asymptomatic participants, participants with lower-limb injury and those with medial knee osteoarthritis. Spearman rank determined relationships between knee injury and outcome scores and hip and knee kinetic/kinematic gait parameters. K-Nearest Neighbour algorithm was used to determine which of the evaluated parameters created the strongest classifier model. FINDINGS: Differences in outcome scores were evident between groups, with knee quality of life correlated to first and second peak external knee adduction moment (0.47, 0.55). Combining hip and knee kinetics with quality of life outcome produced the strongest classifier (1.00) with the least prediction error (0.02), enabling classification of injured subjects gait as characteristic of either asymptomatic or knee osteoarthritis subjects. When correlating outcome scores and biomechanical outcomes with osteoarthritis severity only maximum external hip and knee abduction moment (0.62, 0.62) in addition to first peak hip adduction moment (0.47) displayed significant correlations. INTERPRETATION: The use of predictive models could enable clinicians to identify individuals at risk of knee osteoarthritis and be a cost-effective method for osteoarthritis screening. PMID- 28618312 TI - The effects of brief individual cognitive behavioural therapy for depression and homesickness among international students in Malaysia. AB - BACKGROUND: Students who go to other countries for higher education face various psychological problems, particularly homesickness and depression. The objectives of this study were to: (a) identify differences between students who did and did not receive brief individual cognitive behavioural therapy (CBT) for depression to reduce homesickness; (b) identify whether brief individual CBT for depression reduces the level of homesickness in students between pre-, post- and follow-up assessment; and (c) compare the scores of students experiencing only homesickness and those experiencing both homesickness and depression. METHOD: The sample consisted of 520 first-year undergraduate international students. The experimental group contained students who were diagnosed with depression and homesickness and received seven sessions of brief individual CBT for depression to reduce homesickness. The control group contained students who were diagnosed with depression and homesickness and received one session of advice and suggestions. The comparison group contained students who experienced only homesickness and did not receive any interventions. The study used the comparison group to determine if an interaction effect existed between students experiencing only homesickness and students experiencing both homesickness and depression. RESULTS: Students who received brief individual CBT displayed a significant reduction in their homesickness and depression scores compared to the scores of students in the control group. Students who experienced only homesickness exhibited a significant reduction in the scores on homesickness in the post assessment compared to the control group's post-assessment homesickness scores. LIMITATION: The results of this study cannot be generalized as data were collected from three universities in Malaysia. The follow-up assessment was conducted six months after the post-assessment, which also limits generalizability beyond six months. CONCLUSION: Overall, homesickness is considered a normal reaction. Brief individual CBT for depression is effective in reducing homesickness and depression among international students. PMID- 28618313 TI - A MIR4646 associated methylation locus is hypomethylated in adolescent depression. AB - BACKGROUND: Studies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression. METHODS: We present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n=93) and validation data set 1 (n=78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n=58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers. RESULTS: The methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p<10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p<0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p<0.05). LIMITATIONS: MIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements. CONCLUSION: We identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression. PMID- 28618314 TI - The metacognitions about self-critical rumination questionnaire. AB - BACKGROUND: Self-criticism refers to a series of persistent and negative self judgements, often involuntary, that an individual makes about themselves. Recent research has explored the possibility that self-criticism can lead to a more perseverative style of thinking called self-critical rumination. There is evidence that self-critical rumination may be a separate construct from other forms of rumination, such as depressive rumination and post-event processing. Research has indicated that metacognitions, beliefs that individuals have about their internal experiences and how to control them, may play a role in self critical rumination. The aim of our work was to develop a measure to assess metacognitions related to self-critical rumination. METHOD: In Study 1, a community sample of 178 participants completed the newly developed Metacognitions about Self-Critical Rumination Questionnaire (MSCRQ) and results were subjected to a Principal Components Analysis. In Study 2, a community sample of 247 participants completed a battery of questionnaires including the MSCRQ. A Confirmatory Factors Analysis was performed on the MSCRQ and validity was ascertained by correlating with other measures. RESULTS: In Study 1, a 15-item two-factor structure was identified. A 10-item two-factor structure was confirmed in Study 2. Results also indicated that the MSCRQ has acceptable levels of reliability, and good concurrent and incremental validity. CONCLUSIONS: The MSCRQ appears to be a reliable and valid measure of metacognitions about self-critical rumination whilst the MCQ-30 is a better predictor of general emotional distress. PMID- 28618315 TI - Simulation of green roof runoff under different substrate depths and vegetation covers by coupling a simple conceptual and a physically based hydrological model. AB - In spite of the well-known green roof benefits, their widespread adoption in the management practices of urban drainage systems requires the use of adequate analytical and modelling tools. In the current study, green roof runoff modeling was accomplished by developing, testing, and jointly using a simple conceptual model and a physically based numerical simulation model utilizing HYDRUS-1D software. The use of such an approach combines the advantages of the conceptual model, namely simplicity, low computational requirements, and ability to be easily integrated in decision support tools with the capacity of the physically based simulation model to be easily transferred in conditions and locations other than those used for calibrating and validating it. The proposed approach was evaluated with an experimental dataset that included various green roof covers (either succulent plants - Sedum sediforme, or xerophytic plants - Origanum onites, or bare substrate without any vegetation) and two substrate depths (either 8 cm or 16 cm). Both the physically based and the conceptual models matched very closely the observed hydrographs. In general, the conceptual model performed better than the physically based simulation model but the overall performance of both models was sufficient in most cases as it is revealed by the Nash-Sutcliffe Efficiency index which was generally greater than 0.70. Finally, it was showcased how a physically based and a simple conceptual model can be jointly used to allow the use of the simple conceptual model for a wider set of conditions than the available experimental data and in order to support green roof design. PMID- 28618316 TI - Change detection using Landsat images and an analysis of the linkages between the change and property tax values in the Istanbul Province of Turkey. AB - In this study, the Istanbul Province was monitored using Landsat 5 TM, MSS, Landsat 7 ETM+, and Landsat 8 OLI imagery from the years 1986, 2000, 2009, 2011, 2013, and 2015 in order to assess land cover changes in the province. The aim of the study was to classify manmade structures, land, green, and water areas, and to observe the changes in the province using satellite images. After classification, the images were compared in selected years to observe land cover. Moreover, these changes were correlated with the property tax values of Istanbul by years. The findings of the study showed that manmade structure areas increased while vegetation areas decreased due to rapid population growth, urbanization, and industrial and commercial development in Istanbul. These changes also explain the transformation of land from rural and natural areas to residential use, and serve as a tool with which to assess land value increments. Land value capturing is critical for the analysis of the linkages between the changes in land cover, and for assessing land transformation and urban growth. Due to inadequate market data, real estate tax values were used to analyze the linkages between detection changes, land cover, and taxation. In fact, the declared tax values of land owners are generally lower than the actual market values and therefore it is not possible to transfer the value increasing of land in urban areas by using property taxation from the owner to local and central governments. The research results also show that the integration of remote sensing results with real estate market data give us to determine the tax base values of real estate more realistically. PMID- 28618317 TI - Citizen science for water quality monitoring: Data implications of citizen perspectives. AB - Citizen science, where citizens play an active role in the scientific process, is increasingly used to expand the reach and scope of scientific research while also achieving engagement and educational goals. Despite the emergence of studies exploring data outcomes of citizen science, the process and experience of engaging with citizens and citizen-lead groups through participatory science is less explored. This includes how citizen perspectives alter data outcomes, a critical upshot given prevalent mistrust of citizen versus scientist data. This study uses a citizen science campaign investigating watershed impacts on water quality to interrogate the nature and implications of citizen involvement in producing scientifically and societally relevant data. Data representing scientific outcomes are presented alongside a series of vignettes that offer context regarding how, why, and where citizens engaged with the project. From these vignettes, six specific lessons are examined towards understanding how integration of citizen participation alters data outcomes relative to 'professional' science. In particular, elements of participant social identity (e.g., their motivation for participation), and contextual knowledge (e.g., of the research program itself) can shape participation and resulting data outcomes. Such scientific outcomes are particularly relevant given continued concerns regarding the quality of citizen data, which could hinder scientific acceptance of citizen sciences. Importantly, the potential for meaningful engagement with citizen and participants within citizen groups - given significant capacity within the community - represents a substantial and under-realized opportunity. PMID- 28618318 TI - Effect of differential forest management on land-use change (LUC) in a tropical hill forest of Malaysia. AB - Forest ownership is considered as a vital aspect for sustainable management of forest and its associated biodiversity. The Global Forest Resources Assessment 2015 reported that privately owned forest area are increasing on a global scale, but deforestation was found very active in privately owned hill forest areas of Malaysia. Penang State was purposively chosen as it has been experiencing rapid and radical changes due to urban expansion over the last three decades. In this study, analyses of land-use changes were done by PCI Geomatica using Landsat images from 1991 to 2015, future trends of land-use change were assessed using EXCEL forecast function, and its impact on the surrounding environment were conducted by reviewing already published articles on changing environment of the study area. This study revealed an annual deforestation rate of 1.4% in Penang Island since 1991. Trend analysis forecasted a forest area smaller than the current forest reserves by the year 2039. Impact analysis revealed a rapid biodiversity loss with increasing landslides, mudflows, water pollution, flash flood, and health hazard. An immediate ban over hill-land development is crucial for overall environmental safety. PMID- 28618319 TI - Distress and everyday problems in Dutch mothers and fathers of young adolescents with Down syndrome. AB - BACKGROUND: To provide targeted support to parents of children with DS, knowledge of their distress and everyday problems is crucial. For this purpose, psychosocial screening instruments can be a valuable addition to routine clinical practice. AIMS: To determine differences on a psychosocial screener concerning distress and everyday problems in parents of young adolescents (YAs) with DS versus control parents and in mothers of YAs with DS versus fathers. METHODS AND PROCEDURES: We compared outcomes of the Distress Thermometer for Parents in 76 mothers and 44 fathers of 11-13-year-olds with DS versus 64 mothers and 52 fathers of age-matched children without DS (comparing mothers and fathers separately). Additionally, we compared mothers and fathers within 34 parent couples of YAs with DS. OUTCOMES AND RESULTS: Clinical distress was not more frequent than in control parents. Mothers further did not report more everyday problems and only differed from their controls on one problem domain and some problem items. Fathers, however, reported more problems than their controls across most domains and wished to talk to a professional about their situation more frequently. Outcomes in mothers and fathers within parent couples did not differ significantly. CONCLUSIONS AND IMPLICATIONS: This is one of few studies to report on the use of psychosocial screening instruments in parents of children with DS. Our results suggested that attention for fathers of YAs with DS is required. Psychosocial screening instruments that inquire about specific problems and the wish for referral can play an important role in achieving this. PMID- 28618320 TI - Screening for potential child maltreatment in parents of a newborn baby: The predictive validity of an Instrument for early identification of Parents At Risk for child Abuse and Neglect (IPARAN). AB - For preventive purposes it is important to be able to identify families with a high risk of child maltreatment at an early stage. Therefore we developed an actuarial instrument for screening families with a newborn baby, the Instrument for identification of Parents At Risk for child Abuse and Neglect (IPARAN). The aim of this study was to assess the predictive validity of the IPARAN and to examine whether combining actuarial and clinical methods leads to an improvement of the predictive validity. We examined the predictive validity by calculating several performance indicators (i.e., sensitivity, specificity and the Area Under the receiver operating characteristic Curve [AUC]) in a sample of 4692 Dutch families with newborns. The outcome measure was a report of child maltreatment at Child Protection Services during a follow-up of 3 years. For 17 children (.4%) a report of maltreatment was registered. The predictive validity of the IPARAN was significantly better than chance (AUC=.700, 95% CI [.567-.832]), in contrast to a low value for clinical judgement of nurses of the Youth Health Care Centers (AUC=.591, 95% CI [.422-.759]). The combination of the IPARAN and clinical judgement resulted in the highest predictive validity (AUC=.720, 95% CI [.593 .847]), however, the difference between the methods did not reach statistical significance. The good predictive validity of the IPARAN in combination with clinical judgment of the nurse enables professionals to assess risks at an early stage and to make referrals to early intervention programs. PMID- 28618321 TI - The crucial role of the micro caregiving environment: Factors associated with attachment styles in alternative care in Chile. AB - The distribution of attachment styles has been shown to differ between groups of children living with their parents and children placed in alternative care (AC), defined as residential or foster. However, this is the first study in Latin America to explore possible factors affecting the quality of attachment in children living in both residential and foster care. Two groups of children (N=57) were compared: one group living in Residential Homes (RC) and the other in Foster Care (FC) in Chile. Children's, caregivers' and structural factors (e.g., child: caregiver ratios) and their links with attachment styles were investigated. The micro caregiving environment (i.e., the specific individual child caregiver relationship), especially the caregivers' engagement, sensitivity, disciplinary control and affection, as well as some structural factors (i.e., child: caregiver ratios), were linked to attachment security in children. Specifically, better emotional caregiving and lower child-caregiver ratios were associated with higher rates of secure attachment. The association between quality of care (as measured by the HOME inventory) and attachment styles seems to be influenced by caregiver relationships (as measured by CCSERSS). Caregiver relationship factors (i.e., affection, engagement and sensitivity) directly impact the quality of the attachment children establish with them while living in AC. However, the relationships that caregivers establish with children under their care can be facilitated by good quality structural factors, particularly child-caregiver ratios. PMID- 28618322 TI - Multiple inflammatory markers and 15-year incident ADL disability in admixed older adults: The Bambui-Epigen Study. AB - BACKGROUND: The ability of inflammatory markers to predict disability in later life has received growing attention. However, the current evidence came predominantly from Caucasians and the role of genomic ancestry has not been investigated. OBJECTIVE: We investigated the prognostic value of multiple citokynes and chemokines for incident disability in admixed older Brazilians and whether genomic African and Native American ancestry affects the association. DESIGN: Population-based longitudinal study. SETTING: The Bambui-Epigen (Brazil) Cohort Study of Aging. SUBJECTS: 1171 males and females aged >=60 years over 15 year of follow-up. METHODS: Outcome examined was incident activity of daily living (ADL) disability assessed annually (10,039 measures were performed). Serum levels of citokynes (IL6, IL12, TNF, IL10, and IL1beta) and chemokines (CCL2, CCL5, CXCL8, CXCL9 and CXCL10) were measured at baseline. We used 370,539 Single Nucleotide Polymorphisms (SNPs) to estimate each individual genomic ancestry proportions. Potential confounding variables included a wide range of socio demographic variables and health indicators. Statistical analyses were based on competing risk framework. RESULTS: The incidence rate of disability was 57.9 per 1000 person-years. IL6 level at the highest quartile showed an independent association with ADL disability (SRH=1.32; 95% CI: 1.03, 1.70). Other inflammatory markers showed no statistically significant associations with the outcome. Neither genomic African nor Native American ancestry had an effect modifier on the associations (P for interaction >0.05 for all). CONCLUSION: Among multi-inflammatory markers, only IL6 had the potential to identify people at increased risk of ADL disability, independently of ethno-racial background. PMID- 28618323 TI - A systematic review of trends in the selective exclusion of older participant from randomised clinical trials. AB - INTRODUCTION: The unjustified exclusion of older participants from clinical trials creates research populations that are non-representative, in turn creating difficulties applying research to the target populations. The aim of this study was to assess the proportion of randomised control trials (RCTs) that have unexplained upper age limits and review whether this proportion is reducing over time. METHODS: All RCTs in BMJ, Lancet, JAMA and NEJM from 1998 to 2015 were reviewed to identify any specified upper-age cut off and, if so, whether this exclusion criterion had an explanation in the text. The proportion of RCTs with an unexplained cut off was then correlated over time to look for any changes. RESULTS: 5680 papers were identified and 1339 excluded as they did not meet the search criteria. Of the remaining 4341 RCTs, 1258 (29%) had upper age limits specified, 1168 (92.8%) of which did not have any explanation for this cut off, a total of 26.9% of the RCTs reviewed. Over the 18-year period there was limited but statistically significant decrease in the proportion of RCTs with unexplained upper age limits (Pearson Correlation -0.609, P valve 0.007). CONCLUSION: Despite being the highest consumers of medical interventions and medications, this review highlights that older patients remain under-represented in clinical trial with only modest improvements despite increasing awareness of the problem. Future research must continue to adapt to provide insight into the differential effects of medical treatments in older patients by ensuring that trial participants are representative of the patient population receiving the intended therapy. PMID- 28618324 TI - Stem cells: An emerging novel therapeutic for type-1 diabetes mellitus. AB - Stem cell based strategies are therapeutically potent for treating type-1 diabetes mellitus owing to their intrinsic regenerative capacity and immunomodulatory properties to arrest autoimmune beta-cell destruction, preserve residual beta-cell mass, facilitate endogenous regeneration, ameliorate innate/ alloimmune graft rejection, restore beta-cell-specific unresponsiveness in absence of chronic immunosuppression and to reverse hyperglycemia. PMID- 28618325 TI - Early short-term intensive multidisciplinary diabetes care: A ten-year follow-up of outcomes. AB - OBJECTIVES: To evaluate the outcome of an early short-term intensive diabetic care program followed by a regular out-patient shared-care education program. METHODS: We retrospectively reviewed the medical charts of 196 patients newly diagnosed with type 2 diabetes mellitus (DM) who were admitted to the hospital for intensive multidisciplinary interventions. For comparison, we also enrolled 206 patients with type 2 DM newly diagnosed but not receiving short-term intensive program. Both groups all attended an out-patient shared-care education program for more than one year. Outcome measure included average and standard deviation (SD) of glycated hemoglobin (HbA1c) over ten years, serum creatinine (Cr), lipid profile, urine albumin/Cr (UACR), and chronic diabetic complications after 10years later. The Kaplan-Meier event happening rates were used to compare the event rate of two samples. Multivariate Cox proportional-hazards models were used to investigate the influence of different variables on chronic complications. RESULTS: Patients who received short-term intensive diabetic education had less SD of HbA1cs: (0.7+/-0.7% vs. 1.0+/-0.8% (5.3+/-5.3mmol/mol vs 9.2+/-6.4mmol/mol), p<0.001), less new-onset coronary heart disease (CHD) (8.2% vs. 13.7%, p=0.005), lower serum Cr (1.4+/-0.7mg/dL vs. 1.5+/-0.9mg/dL, p=0.005), less progression of nephropathy was also revealed (13.5% vs. 21.2%, p=0.009) and lower UACR (4.7+/-1.4mg/g vs. 5.3+/-1.0mg/g, p<0.001). There were no group differences in age, gender distribution, average HbA1c, lipid profile, and new onset of neuropathy and retinopathy. The independent predictors of CHD and nephropathy were short-term intensive diabetic education and SD of HbA1cs. CONCLUSION: Initiation of earlier intensive short-term multidisciplinary interventions in patients with newly diagnosed DM may decrease coronary heart disease and nephropathy. These better outcomes may be related to less fluctuation in blood glucose levels. PMID- 28618326 TI - Inflammation as target in cancer therapy. AB - Cells of the innate immunity infiltrating tumour tissues promote, rather than halt, cancer cell proliferation and distant spreading. Tumour-Associated Macrophages (TAMs) are abundantly present in the tumour milieu and here trigger and perpetrate a state of chronic inflammation which ultimately supports disease development and contributes to an immune-suppressive environment. Therapeutic strategies to limit inflammatory cells and their products have been successful in pre-clinical tumour models. Early clinical trials with specific cytokine and chemokine inhibitors, or with strategies designed to target TAMs, are on their way in different solid malignancies. Partial clinical responses and stabilization of diseases were observed in some patients, in the absence of significant toxicity. These encouraging results open new perspectives of combination treatments aimed at reducing cancer-promoting inflammation to maximize the anti tumour efficacy. PMID- 28618327 TI - Long-term antipsychotic and benzodiazepine use and brain volume changes in schizophrenia: The Northern Finland Birth Cohort 1966 study. AB - High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning. PMID- 28618328 TI - Preparation of a polylactic acid knitting mesh for pelvic floor repair and in vivo evaluation. AB - The health warning report by the Food and Drug Administration (FDA) in 2011 has drawn attention to the need for developing a suitable bio-scaffold for repairing female pelvic from disease. This work prepared a pure polylactic acid knitting mesh (PPA) and compared its structure and properties with a commercial mesh - Surgimesh(r) Prolapse (SP; Aspide Medical, France). Mechanical tests showed that the PPA mesh was stronger than SP with higher breaking strength and bursting strength. The in vivo property of PPA was evaluated with an animal model. Both PPA-tissue and SP-tissue were tested to have lower strength and initial elastic modulus; tissue layer played a vital role in the bio-mechanics, especially after 3 months of implantation. New tissues on the surface of PPA grew faster and thicker than that on SP at each observation period. The final shrinkage rate of PPA (2.13 +/- 0.41%) was much lower than that of SP (30.35 +/- 1.7%). Obvious adhesion phenomenon was observed on both PPA and SP meshes at each test point. Two meshes showed different adhesion level, that PPA was assessed of severe adhesion, even causing host tissue rupture. By histological evaluation, both PPA and SP groups showed obvious tissue inflammation reaction evidenced by rich lymphocytes. However the surrounding tissues on the PPA recovered better, with higher inflammation response scores and presence of significant vascularization and adipogenesis after six months of implantation. PMID- 28618329 TI - Therapy of older persons with acute myeloid leukaemia. AB - Most persons age>=60 y with acute myeloid leukaemia (AML) die from their disease. When interpreting clinical trials data from these persons one must be aware of substantial selection biases. Randomized trials of post-remission treatments can be performed upfront or after achieving defined landmarks. Both strategies have important limitations. Selection of the appropriate treatment is critical. Age, performance score, co-morbidities and frailty provide useful data to treatment selection. If an intensive remission induction therapy is appropriate, therapy with cytarabine and an anthracycline is the most common regimen. Non-intensive therapies consist of the hypo-methylating drugs azacitidine and decitabine, low dose cytarabine and supportive care. Feasibility of doing an allotransplant in older persons with AML is increasing. However, only very few qualify. Results of cytogenetic testing are risk factor in young and old persons with AML. Adverse abnormalities are more frequent in older persons. Although data about the frequency of mutations in older persons with AML is increasing their prognostic impact is less clear than in younger subjects. Neither differences in the distribution of cytogenetic risk, mutations, nor differences in clinical risk factors between younger and older persons with AML completely explain the age dependent outcome. Many drugs are in clinical development in older persons with AML. Their potential role in the treatment of older persons with AML remains to be defined. PMID- 28618330 TI - Improvements in self-curing composites. AB - PURPOSE: The purpose of this study was to test the influence of a barbituric acid derivative acting as a catalyst and small amounts of pyrolytic silica in acrylic resins on color stability, solubility and sorption of a composite. MATERIALS AND METHODS: A series of two-component powder/liquid resin systems were prepared. Monomer-like mixtures (bis-GMA, TEGDMA, tertiary amine 60/40) and a quartz powder with additions of various silica and barbituric acid derivatives were used. Temperature of the material during polymerization was measured with the use of a thermometer. In addition, the material's flexural and compressive strength, sorption and solubility were tested pursuant to ISO4049:2009. RESULTS: The powder based acrylic composition in a liquid mixed immediately before use, after an addition of a 0.5% barbituric acid derivative, has a lower temperature during the polymerization process (a reduction from 43 degrees C to 37 degrees C), whereas color stability over time is improved, with DeltaE=1.81 for samples of powder mixtures containing between 0.45% of BPO and 0.15% of barbituric acid derivatives. For silanized quartz powder with 0.55% BPO and 0.1% BA+0.5% Aerosil R711, the obtained sorption value was 4.57+/-0.22MUg/mm3, whereas solubility was 1.60+/-0.32MUg/mm3. CONCLUSIONS: New catalytic system with barbituric acid derivative, improves color stability for samples stored at room condition and under light of high intensity. A two-phase composite (bis GMA TEGDMA/Quartz), with a new catalytic system with barbituric acid derivatives, has a lower self cured temperature. Adding a small quantity of hydrophobic silica (0.5%) has a significant influence, with reduced sorption and solubility of the material. PMID- 28618331 TI - Psychogenic nonepileptic seizures: Namibian healthcare providers' perceptions and frustrations. AB - PURPOSE: Most studies conducted on the diagnosis and treatment of psychogenic nonepileptic seizures (PNES) have been performed in developed countries with developing countries, such as Namibia, receiving less attention. This study aimed to contribute to the aims of The International League against Epilepsy Psychogenic Nonepileptic Seizure Task Force by investigating the perceptions and frustrations of healthcare providers (HCPs) in Namibia regarding the diagnosis and treatment of psychogenic nonepileptic seizures. METHODS: Semi-structured interviews were conducted with fifteen HCPs from the private healthcare sector in Namibia. Thematic analysis was used to analyse the semi-structured interviews in order to identify themes and subthemes within the data. RESULTS: Main themes centred on the areas of diagnosis, treatment, patients and awareness. It was found that HCPs' perceptions and frustrations were often related to the lack of knowledge and awareness regarding the disorder. Furthermore, the lack of access to specialized services and equipment contributed to HCPs' frustrations. Delays in the diagnosis of PNES added to HCPs' concerns regarding ineffective referral practices and the subsequent increase in healthcare costs. Although HCPs expressed the need for adequate training opportunities and increased awareness concerning the disorder, the lack of such opportunities and awareness campaigns were identified as possible problem areas. CONCLUSIONS: It was evident from the findings that there are several gaps in how PNES are diagnosed and treated in Namibia. The unique challenges faced by a developing country such as Namibia were evident in some of the subthemes that highlighted the cultural differences in how PNES are conceptualized and treated. PMID- 28618332 TI - Brief report: Trait emotional intelligence, peer nominations, and scholastic achievement in adolescence. AB - Current research on trait EI in adolescents suggests that the construct impacts on several important domains of youths' psychological functioning, including school adjustment and achievement. The purpose of this study is to explore the role of trait EI and of its subcomponents, on adolescent's academic achievement. Data were collected from 321 Italian adolescents (162 female; Mage = 15.5, SD = 1.86; aged 13-18 years) recruited from secondary schools. The effects of perceived and actual peer nominations, gender, personality dimensions, and non verbal cognitive abilities were also controlled. Results highlight that trait EI as assessed by means of the TEIQue impacts Italian but not math's grades, while trait EI's factors predicted both academic subjects, with significant contributions of Self-Control and Sociability. Limitations and implications are discussed. PMID- 28618333 TI - DNA polymerases and biotechnological applications. AB - A multitude of biotechnological techniques used in basic research as well as in clinical diagnostics on an everyday basis depend on DNA polymerases and their intrinsic capability to replicate DNA strands with astoundingly high fidelity. Applications with fundamental importance to modern molecular biology, including the polymerase chain reaction and DNA sequencing, would not be feasible without the advances made in characterizing these enzymes over the course of the last 60 years. Nonetheless, the still growing application scope of DNA polymerases necessitates the identification of novel enzymes with tailor-made properties. In the recent past, DNA polymerases optimized for diverse PCR and sequencing applications as well as enzymes that accept a variety of unnatural substrates for the synthesis and reverse transcription of modified nucleic acids have been developed. PMID- 28618334 TI - Comprehensive modelling and simulation of cylindrical nanoparticles manipulation by using a virtual reality environment. AB - With the expansion of nanotechnology, robots based on atomic force microscope (AFM) have been widely used as effective tools for displacing nanoparticles and constructing nanostructures. One of the most limiting factors in AFM-based manipulation procedures is the inability of simultaneously observing the controlled pushing and displacing of nanoparticles while performing the operation. To deal with this limitation, a virtual reality environment has been used in this paper for observing the manipulation operation. In the simulations performed in this paper, first, the images acquired by the atomic force microscope have been processed and the positions and dimensions of nanoparticles have been determined. Then, by dynamically modelling the transfer of nanoparticles and simulating the critical force-time diagrams, a controlled displacement of nanoparticles has been accomplished. The simulations have been further developed for the use of rectangular, V-shape and dagger-shape cantilevers. The established virtual reality environment has made it possible to simulate the manipulation of biological particles in a liquid medium. PMID- 28618335 TI - Specific interactions between zinc metalloproteinase and its inhibitors: Ab initio fragment molecular orbital calculations. AB - Bacteria secrete the enzyme pseudolysin (PLN) to degrade exocellular proteins, and the produced peptides are used as a nutrient for the bacteria. It is thus expected that inhibition of PLN can suppress bacterial growth. Since such inhibitors do not attack to bacteria directly, the risk of producing drug resistance bacteria is less. However, endogenous proteinases such as the matrix metalloproteinases (MMPs) have active site similar to that of PLN, and there is a possibility that PLN inhibitors also inhibit the activity of MMPs, resulting in a loss of substrate degradation by these proteinases. Therefore, agents that inhibit the activity of only PLN and not MMPs are required. In the present study, we select two compounds (ARP101 and LM2) and investigate their specific interactions with PLN and MMPs by use of ab initio molecular simulations. Based on the results, we propose several novel compounds as candidates for potent PLN inhibition and investigate their binding properties with PLN, elucidating that the compound, in which a toluene group is introduced into LM2, has larger binding energy with PLN compared with the pristine LM2. Therefore, this compound is suggested to be a potent PLN inhibitor. PMID- 28618336 TI - Left ventricle Hermite-based segmentation. AB - In recent years, computed tomography (CT) has become a standard technique in cardiac imaging because it provides detailed information that may facilitate the diagnosis of the conditions that interfere with correct heart function. However, CT-based cardiac diagnosis requires manual segmentation of heart cavities, which is a difficult and time-consuming task. Thus, in this paper, we propose a novel technique to segment endocardium and epicardium boundaries based on a 2D approach. The proposal computes relevant information of the left ventricle and its adjacent structures using the Hermite transform. The novelty of the work is that the information is combined with active shape models and level sets to improve the segmentation. Our database consists of mid-third slices selected from 28 volumes manually segmented by expert physicians. The segmentation is assessed using Dice coefficient and Hausdorff distance. In addition, we introduce a novel metric called Ray Feature error to evaluate our method. The results show that the proposal accurately discriminates cardiac tissue. Thus, it may be a useful tool for supporting heart disease diagnosis and tailoring treatments. PMID- 28618337 TI - Biomechanical study of different fixation techniques for the treatment of sacroiliac joint injuries using finite element analyses and biomechanical tests. AB - The pelvis is one of the most stressed areas of the human musculoskeletal system due to the transfer of truncal loads to the lower extremities. Sacroiliac joint injury may lead to abnormal joint mechanics and an unstable pelvis. Various fixation techniques have been evaluated and discussed. However, it may be difficult to investigate each technique due to variations in bone quality, bone anatomy, fracture pattern, and fixation location. Additionally, the finite element method is one useful technology that avoids these variations. Unfortunately, most previous studies neglected the effects of the lumbar spine and femurs when they investigated the biomechanics of pelvises. Thus, the aim of this study was to investigate the biomechanical performance of intact, injured, and treated pelvises using numerical and experimental approaches. Three dimensional finite element models of the spine-pelvis-femur complex with and without muscles and ligaments were developed. The intact pelvis, the pelvis with sacroiliac joint injury, and three types of pelvic fixation techniques were analyzed. Concurrently, biomechanical tests were conducted to validate the numerical outcomes using artificial pelvises. Posterior iliosacral screw fixation showed relatively better fixation stability and lower risks of implant failure and pelvic breakage than sacral bar fixation and a locking compression plate fixation. The present study can help surgeons and engineers understand the biomechanics of intact, injured, and treated pelvises. Both the simulation technique and the experimental setup can be applied to investigate different pelvic injuries. PMID- 28618338 TI - MarkoLAB: A simulator to study ionic channel's stochastic behavior. AB - : Mathematical models of the cardiac cell have started to include markovian representations of the ionic channels instead of the traditional Hodgkin & Huxley formulations. There are many reasons for this: Markov models are not restricted to the idea of independent gates defining the channel, they allow more complex description with specific transitions between open, closed or inactivated states, and more importantly those states can be closely related to the underlying channel structure and conformational changes. METHODS: We used the LabVIEW(r) and MATLAB(r) programs to implement the simulator MarkoLAB that allow a dynamical 3D representation of the markovian model of the channel. The Monte Carlo simulation was used to implement the stochastic transitions among states. The user can specify the voltage protocol by setting the holding potential, the step-to voltage and the duration of the stimuli. RESULTS: The most studied feature of a channel is the current flowing through it. This happens when the channel stays in the open state, but most of the time, as revealed by the low open probability values, the channel remains on the inactive or closed states. By focusing only when the channel enters or leaves the open state we are missing most of its activity. MarkoLAB proved to be quite useful to visualize the whole behavior of the channel and not only when the channel produces a current. Such dynamic representation provides more complete information about channel kinetics and will be a powerful tool to demonstrate the effect of gene mutations or drugs on the channel function. CONCLUSIONS: MarkoLAB provides an original way of visualizing the stochastic behavior of a channel. It clarifies concepts, such as recovery from inactivation, calcium- versus voltage-dependent inactivation, and tail currents. It is not restricted to ionic channels only but it can be extended to other transporters, such as exchangers and pumps. This program is intended as a didactical tool to illustrate the dynamical behavior of a channel. It has been implemented in two platforms MATLAB(r) and LabVIEW(r) to enhance the target users of this new didactical tool. The computational cost of implementing a stochastic simulation is within the range of a personal computer performance; making MarkoLAB suitable to be run during a lecture or presentation. PMID- 28618339 TI - HPLC-MS/MS method for troventol determination in human plasma and its application to biological samples. AB - For the first time, an HPLC-MS/MS method for the determination pmol/l levels of troventol (TRV) and clenbuterol as an internal standard (IS) in human plasma was developed, validated and tested on biological samples. The method included solid phase extraction by Waters Oasis WCX cartridges and chromatographic separation on a YMC-Pack SIL (100mm*2.1mm, 5MUm, 12nm) analytical column with acetonitrile water-formic acid (50:50:0.1, v/v/v) as the mobile phase; the selected ion transitions were m/z 332.2->138.2 and m/z 277.0->203.1 for TRV and IS, respectively, in positive ionization mode. The calibration curve for TRV showed good linearity in the concentration range of 35-500pg/ml. The method was applied to real samples taken from healthy subjects after inhalation of an aerosol containing 640MUg of TRV. PMID- 28618340 TI - Fast and efficient zirconia-based reversed phase chromatography for selective determination of triptans in rat plasma. AB - Selective and fast chromatographic method was essential for the determination of triptans, selective serotonin receptor (5-HT1) agonists, in biological specimens. However, selective chromatographic separation of these highly basic drugs is a challenging problem on silica-based stationary phases. Zirconia-based stationary phases have been introduced as an efficient alternative for silica-based columns offering unique stability, selectivity, and retention ability for various classes of drugs. Herein, a new selective, fast and reproducible high performance liquid chromatographic method (HPLC) was developed and validated for the determination of four triptans in plasma samples namely; Sumatriptan (SMT), Zolmitriptan (ZLT), Eletriptan (ELT) and Rizatriptan (RZT). Zirconia-based polybutadiene (PBD) column was used for the separation and quantitation of the studied triptans in rat plasma based on mixed mode ion exchange and reversed phase chromatography. Zirconia-PBD column (ZirChrom-PBD) has enhanced chemical and thermal stability, selectivity and provides high resolution for the investigated triptans in short analysis time compared with the commonly used C18 columns. A simple isocratic separation mode was used with a mobile phase consisted of acetonitrile and 10mM phosphate buffer adjusted to pH 3.0 (20:80; v/v) at flow rate 1.0mLmin-1. The column was maintained at 50 degrees C and effluent was monitored by photodiode array detector (PDA). The developed method was validated in agreement with US-FDA guidelines and was appropriate for analysis of triptans in plasma samples. The linearity range obtained for the developed HPLC method was 15-2000ngmL-1 with detection limits of 4.8- 6.2ngmL-1 for all the studied triptans. The developed zirchonia-PBD-HPLC method was applied successfully to study the pharmacokinetics of ZLT in rats after a single oral dose. The method was proved to be valuable for therapeutic drug monitoring and bioavailability studies of the studied triptans. PMID- 28618341 TI - Analytical profiling of selected antioxidants and total antioxidant capacity of goji (Lycium spp.) berries. AB - Goji berries and derived products represent a relevant source of micronutrients, most of which are natural antioxidants and contribute to the high nutritional quality of these fruits. Three brands of dried goji berries have been analysed by a multidisciplinary approach to get an insight into both their content of selected antioxidants and their antioxidant capacity (AC). The former goal has been achieved by developing a liquid chromatographic method coupled to mass spectrometry and combined to a fast solid phase extraction. Several significant representative antioxidant compounds belonging to the following classes: flavonoids, flavan-3-ols, phenolic acids, amino acids and derivatives, and carotenoids have been taken into account. Quercetin and rutin were found to be the predominant flavonoids, chlorogenic acid was the most abundant phenolic acid and zeaxanthin was the major carotenoid. The AC of the goji berries has been evaluated by four analytical methods in order to estimate the contributions of different reactions involved in radicals scavenging. In particular, AC has been determined using 3 standardised methods (DPPH, ABTS, ORAC) and a recently proposed electrochemical method, which measures the scavenging activity of antioxidants towards OH radicals generated both by hydrogen peroxide photolysis and the Fenton reaction. The results obtained from chemical composition and antioxidant capacity assays confirm the high nutritional and commercial value of goji berries and highlight that the three brands do not exhibit significant differences. PMID- 28618342 TI - Monitoring breast cancer treatment using a Fourier transform infrared spectroscopy-based computational model. AB - Breast cancer affects one in four women, therefore, the search for new diagnostic technologies and therapeutic approaches is of critical importance. This involves the development of diagnostic tools to facilitate the detection of cancer cells, which is useful for assessing the efficacy of cancer therapies. One of the major challenges for chemotherapy is the lack of tools to monitor efficacy during the course of treatment. Vibrational spectroscopy appears to be a promising tool for such a purpose, as it yields Fourier transformation infrared (FTIR) spectra which can be used to provide information on the chemical composition of the tissue. Previous research by our group has demonstrated significant differences between the infrared spectra of healthy, cancerous and post-chemotherapy breast tissue. Furthermore, the results obtained for three extreme patient cases revealed that the infrared spectra of post-chemotherapy breast tissue closely resembles that of healthy breast tissue when chemotherapy is effective (i.e., a good therapeutic response is achieved), or that of cancerous breast tissue when chemotherapy is ineffective. In the current study, we compared the infrared spectra of healthy, cancerous and post-chemotherapy breast tissue. Characteristic parameters were designated for the obtained spectra, spreading the function of absorbance using the Kramers-Kronig transformation and the best fit procedure to obtain Lorentz functions, which represent components of the bands. The Lorentz function parameters were used to develop a physics-based computational model to verify the efficacy of a given chemotherapy protocol in a given case. The results obtained using this model reflected the actual patient data retrieved from medical records (health improvement or no improvement). Therefore, we propose this model as a useful tool for monitoring the efficacy of chemotherapy in patients with breast cancer. PMID- 28618343 TI - Design, synthesis, immunocytochemistry evaluation, and molecular docking investigation of several 4-aminopyridine derivatives as potential neuroprotective agents for treating Parkinson's disease. AB - Neuroprotection refers to the relative preservation of neuronal structure and function. Neuroprotective agents refer to substances that are capable of preserving brain function and structure. Currently, there are no neuroprotective agents available that can effectively relieve the progression of Parkinson's disease. In this work, five novel 4-aminopyridine derivatives, including three amides and two ureas, were designed, synthesized, and evaluated using the rat PC12 mice pheochromocytoma cell line as an in vitro model. As well as human Rho kinase inhibitory experiment was performed. Among them, compound 3, which exhibited high cell viability, low cytotoxicity and good efficacy of inhibition on alpha-synuclein, oxidation, inflammation and Rho kinase, was profound as potential agents for Parkinson's disease (PD). PMID- 28618344 TI - Developmental mechanism of muscle-tendon-bone complex in the fetal soft palate. AB - OBJECTIVE: This study was performed to investigate how the palatine aponeurosis, medial pterygoid process (MPP) of the sphenoid bone, and tensor veli palatini (TVP) muscle form the pulley: muscle-tendon-bone complex. DESIGN: Mice at embryonic day (ED) 14-17 were used as sample in this study. Azan staining was performed to observe the morphology, and immunohistochemical staining of desmin was performed to closely observe the development of the myotendinous junction. To confirm the bone formation process, immunohistochemical staining of type II collagen (col II), tartrate-resistant acid phosphatase (TRAP), and alkaline phosphatase (ALP) staining were performed. Furthermore, to objectively evaluate bone formation, the major axis and width of the MPP were measured, and osteoclasts that appeared in the MPP were counted. RESULTS: At ED 14 and 14.5, ALP showed a reaction throughout the MPP. The col II-positive area expanded until ED 16.5, but it was markedly reduced at ED 17. The TVP initially contacted with the palatine aponeurosis at ED 16.5. The major axis and width of the MPP and the number of TRAP-positive osteoclasts were significantly increased as the TVP and palatine aponeurosis joined. CONCLUSIONS: Therefore, in addition to the tissue units: muscle, tendon, and bone, the interaction in organogenesis promotes rapid growth of the pulley: muscle-tendon-bone complex. PMID- 28618345 TI - A NIR-controlled cage mimicking system for hydrophobic drug mediated cancer therapy. AB - Most chemotherapeutic drugs commonly suffer from several shortcomings, including the lack of aqueous solubility, limited stability and adverse side effects. Although caging strategy has recently been employed as an effective approach to conceal and stabilize these drugs to achieve light-activated cancer therapy, it is plagued by the sophisticated drug modification process and deleterious solvent usage. In addition, using UV or Visible light to remove photocaged group is restricted to its limited tissue penetration ability in and phototoxicity. In this paper, by anchoring photochromic spiropyran on the mesoporous silica coated upconversion nanoparticles (UCNP-SP), we design a NIR-controlled cage mimicking system. Our results indicate that hydrophobic drug can be concealed inside the channels of the nanocarrier with high stability and "uncaged" via NIR irradiation triggered hydrophobicity-hydrophilicity switch of the spiropyran molecules, finally inducing drug release and recovering their bioactivity. Moreover, under NIR illumination, the UV/Visible emissions from UCNP can also efficaciously initiate the generation of reactive oxygen species (ROS) by Curcumin, further improving the therapeutic efficiency. Both in vitro and in vivo experimental results validate that NIR irradiated nanosystem can produce remarkably enhanced antitumor efficiency. PMID- 28618347 TI - Biodegradation and biocompatibility of haloarchaea-produced poly(3 hydroxybutyrate-co-3-hydroxyvalerate) copolymers. AB - We previously reported that the tailor-made random poly(3-hydroxybutyrate-co-3 hydroxyvalerate) (R-PHBHV) and higher-order PHBHV (O-PHBHV) produced by haloarchaea possessed unique material properties to meet biomedical application specific requirements. Here, we further investigated the biocompatibility and biodegradation of these novel materials. Cell biocompatibility of solution-cast films, assessed using rat fibroblast and osteoblast cells, revealed that R-PHBHV and O-PHBHV exhibited better support for cell attachment and proliferation compared with the bacteria-produced poly-3-hydroxybutyrate (PHB) and PHBHV or polylactic acid (PLA). In vitro and in vivo biodegradation of these materials were evaluated in lipase-containing phosphate buffered solution (LPBS) at pH 7.4 and by implantation in the rabbit dorsal subcutis, respectively. As expected, the R-PHBHV and O-PHBHV films degraded much faster in vivo than those observed in vitro, as demonstrated by obvious weight loss, heavy surface erosion, and fast molecular weight drop under implantation condition. These films showed diverse in vivo degradation rates. Among them, the O-PHBHV-1 film degraded fastest and even faster than PLA. Generally, the tissue response was mild for R-PHBHV and O-PHBHV compared with the controls during the implantation period. Taken together, these data revealed that R-PHBHV and O-PHBHV copolyesters had a wild range of biodegradation profiles and excellent biocompatibility. Thus, haloarchaea produced PHBHV materials would have great potential for use in different biomedical applications. PMID- 28618348 TI - Ultrasound-sensitive nanoparticle aggregates for targeted drug delivery. AB - Here we describe injectable, ultrasound (US)-responsive, nanoparticle aggregates (NPAs) that disintegrate into slow-release, nanoscale, drug delivery systems, which can be targeted to selective sites by applying low-energy US locally. We show that, unlike microbubble based drug carriers which may suffer from stability problems, the properties of mechanical activated NPAs, composed of polymer nanoparticles, can be tuned by properly adjusting the polymer molecular weight, the size of the nanoparticle precursors as well as the percentage of excipient utilized to hold the NPA together. We then apply this concept to practice by fabricating NPAs composed of nanoparticles loaded with Doxorubicin (Dox) and tested their ability to treat tumors via ultrasound activation. Mouse studies demonstrated significantly increased efficiency of tumor targeting of the US activated NPAs compared to PLGA nanoparticle controls (with or without US applied) or intact NPAs. Importantly, when the Dox-loaded NPAs were injected and exposed to US energy locally, this increased ability to concentrate nanoparticles at the tumor site resulted in a significantly greater reduction in tumor volume compared to tumors treated with a 20-fold higher dose of the free drug. PMID- 28618346 TI - Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. AB - Biochemically modified proteins have attracted significant attention due to their widespread applications as biomaterials. For instance, chemically modified gelatin derivatives have been widely explored to develop hydrogels for tissue engineering and regenerative medicine applications. Among the reported methods, modification of gelatin with methacrylic anhydride (MA) stands out as a convenient and efficient strategy to introduce functional groups and form hydrogels via photopolymerization. Combining light-activation of modified gelatin with soft lithography has enabled the materialization of microfabricated hydrogels. So far, this gelatin derivative has been referred to in the literature as gelatin methacrylate, gelatin methacrylamide, or gelatin methacryloyl, with the same abbreviation of GelMA. Considering the complex composition of gelatin and the presence of different functional groups on the amino acid residues, both hydroxyl groups and amine groups can possibly react with methacrylic anhydride during functionalization of the protein. This can also apply to the modification of other proteins, such as recombinant human tropoelastin to form MA-modified tropoelastin (MeTro). Here, we employed analytical methods to quantitatively determine the amounts of methacrylate and methacrylamide groups in MA-modified gelatin and tropoelastin to better understand the reaction mechanism. By combining two chemical assays with instrumental techniques, such as proton nuclear magnetic resonance (1H NMR) and liquid chromatography tandem-mass spectrometry (LC-MS/MS), our results indicated that while amine groups had higher reactivity than hydroxyl groups and resulted in a majority of methacrylamide groups, modification of proteins by MA could lead to the formation of both methacrylamide and methacrylate groups. It is therefore suggested that the standard terms for GelMA and MeTro should be defined as gelatin methacryloyl and methacryloyl-substituted tropoelastin, respectively, to remain consistent with the widespread abbreviations used in literature. PMID- 28618349 TI - Management of parotid duct injury secondary to cow horn in a developing country. AB - Stensen duct injury has been reported in the medical literature following penetrating injuries of the cheek or by exeresis of tumors of the cheek or of the oral mucosa. This type of physical trauma often arises from injuries as a result being assaulted (e.g. with knife) or from road accidents. The complexity of the damage to the anatomical structures and the causative agent sometimes makes the diagnosis difficult. We report on a clinical case of managemenent Stensen duct injury secondary of goring by a cow horn. PMID- 28618350 TI - Minimally invasive appendectomy for resection of appendiceal mucocele: Case series and review of the literature. AB - INTRODUCTION: Appendiceal mucoceles encompass neoplastic and non-neoplastic causes of a distended Appendix filled with mucus. Appendectomy is recommended when an appendiceal mucocele is identified, incidentally or otherwise, in the event it is secondary to a malignancy. For an intact mucocele, it is critically important to avoid rupturing the mucocele during resection, as rupture of a neoplastic mucocele can result in pseudomyxoma peritonei, or mucin deposits in the peritoneum, which is associated with long-term morbidity and mortality. For this reason, laparotomy is the traditionally recommended surgical approach for treatment. PRESENTATION OF CASES: In our case series, we describe two patients, a 49-year-old woman and a 79-year-old man, with incidentally identified appendiceal mucoceles. These patients were successfully treated with minimally invasive approaches to appendectomy, one with a robotic approach and one with a hand assisted laparoscopic approach. The mucoceles were removed without rupture, and both patients recovered well postoperatively without complication. DISCUSSION: While laparotomy is the traditionally recommended surgical approach for resection of appendiceal mucoceles, certain minimally invasive techniques allow for safe removal of the mucoceles while minimizing the morbidity of laparotomy. CONCLUSION: Minimally invasive approaches to appendenctomy, specifically the robotic-assisted approach and the hand-assisted laparoscopic approach, can be considered for safe resection of appendiceal mucoceles. PMID- 28618352 TI - Spectrum average cross section measurement of 183W (n, p)183Ta and 184W (n, p)184Ta reaction cross section in 252Cf(sf) neutron field. AB - Neutron induced nuclear reactions are of prime importance for both fusion and fission nuclear reactor technology. Present work describes the first time measurement of spectrum average cross section of nuclear reactions 183W(n,p)183Ta and 184W(n,p)184Ta using 252Cf spontaneous fission neutron source. Standard neutron activation analysis (NAA) technique was used. The neutron spectra were calculated using Monte Carlo N Particle Code (MCNP). The effects of self shielding and back scattering were taken into account by optimizing the detector modeling. These effects along with efficiency of detector were corrected for volume sample in the actual source-detector geometry. The measured data were compared with the previously measured data available in Exchange Format (EXFOR) data base and evaluated data using EMPIRE - 3.2.2. PMID- 28618351 TI - Structure of IP3R channel: high-resolution insights from cryo-EM. AB - Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ubiquitously expressed intracellular Ca2+ channels and the major mediators of cellular Ca2+ signals generated by the release of Ca2+ ions from intracellular stores in response to a variety of extracellular stimuli. Despite established physiological significance and proven involvements of IP3R channels in many human diseases, detailed structural basis for signal detection by these ion channels and their gating remain obscure. Recently, single particle electron cryomicroscopy (cryo-EM) has yielded a long-awaited near-atomic resolution structure of the entire full-length type 1 IP3R. This structure provided exciting mechanistic insights into the molecular assembly of IP3R, revealing the pronounced structural conservation of Ca2+ release channels and raising many fundamental and controversial questions on their activation and gating. Here we summarize the major technological advances that propelled our cryo-EM analysis of IP3R to near-atomic resolution and discuss what the future holds for structural biology of Ca2+ release channels. PMID- 28618353 TI - Another look at the safety effects of horizontal curvature on rural two-lane highways. AB - Crash Modification Factors (CMFs) are used to represent the effects on crashes of changes to highway design elements and are usually obtained from observational studies based on reported crashes. The design element of interest for this paper is horizontal curvature on rural 2-lane highways. The data for this study came from the Washington State database in the Highway Safety Information System (HSIS). Crash prediction models are developed for curve sections on rural 2-lane highway and the tangent sections up- and down-stream of the curve sections. Different negative binomial models were developed for segments on level grades (<3%), moderate grades (3-6%), and steep grades (>6%) to account for the confounding effects of gradient. The relationships between crashes at different traffic volumes and deflection angles are explored to illustrate how to get estimates of CMFs for increases in the minimum radius, considering the effect of increased tangent length for sharper curves, an effect that is overlooked in the Highway Safety Manual CMF, in addition to the effect of gradient. The results of that exploration indicated that even at different design speeds and deflection angles, the CMF estimates for incremental increases in radius lie within the same range, and that the crash reduction rate (CRR) is higher at segments on higher grades compared to the ones on lower grades. PMID- 28618354 TI - Canadian drivers' attitudes regarding preventative responses to driving while impaired by alcohol. AB - BACKGROUND: In many jurisdictions, a risk assessment following a first driving while impaired (DWI) offence is used to guide administrative decision making regarding driver relicensing. Decision error in this process has important consequences for public security on one hand, and the social and economic well being of drivers on the other. Decision theory posits that consideration of the costs and benefits of decision error is needed, and in the public health context, this should include community attitudes. The objective of the present study was to clarify whether Canadians prefer decision error that: i) better protects the public (i.e., false positives); or ii) better protects the offender (i.e., false negatives). METHODS: A random sample of male and female adult drivers (N=1213) from the five most populated regions of Canada was surveyed on drivers' preference for a protection of the public approach versus a protection of DWI drivers approach in resolving assessment decision error, and the relative value (i.e., value ratio) they imparted to both approaches. The role of region, sex and age on drivers' value ratio were also appraised. RESULTS: Seventy percent of Canadian drivers preferred a protection of the public from DWI approach, with the overall relative ratio given to this preference, compared to the alternative protection of the driver approach, being 3:1. Females expressed a significantly higher value ratio (M=3.4, SD=3.5) than males (M=3.0, SD=3.4), p<0.05. Regression analysis showed that both days of alcohol use in the past 30days (CI for B: 0.07, -0.02) and frequency of driving over legal BAC limits in the past year (CI for B=-0.19, -0.01) were significantly but modestly related to lower value ratios, R2(adj.)=0.014, p<0.001. Regional differences were also detected. CONCLUSIONS: Canadian drivers strongly favour a protection of the public approach to dealing with uncertainty in assessment, even at the risk of false positives. Accounting for community attitudes concerning DWI prevention and the individual differences that influence them could contribute to more informed, coherent and effective regional policies and prevention program development. PMID- 28618355 TI - Chemical constituents from the fruits of Ligustrum japonicum and their inhibitory effects on T cell activation. AB - A previously undescribed nor-dammarane, 3beta,20,23-trihydroxy-24,25,26,27 tetranordammarane; three previously undescribed secoiridoid glycosides, ligujaponosides A-B, and iso-oleonuzhenide; and twenty three known compounds, were isolated from the fruits of Ligustrum japonicum Thunb. Their chemical structures were elucidated by extensive spectroscopic analyses, including 1D and 2D NMR, and HRMS. The isolated compounds were screened for immunosuppressive effects on T activated cells by evaluating interleukin-2 (IL-2) production. Among them, sesamin inhibited IL-2 production in Jurkat T cells with an IC50 value of 38 +/- 2 MUM. In addition, sesamin inhibited the phosphorylation of extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) family, in phorbol 12-myristate 13-acetate (PMA)/A23187-stimulated T cells. Therefore, sesamin was demonstrated to inhibit T cell activation via regulation of MAPK phosphorylation pathway. PMID- 28618356 TI - Developmental neurotoxic effects of graphene oxide exposure in zebrafish larvae (Danio rerio). AB - Although graphene oxide (GO), a nanomaterial with hexagonal planar layer, has been widely studied due to its applications in neurobiology that include drug delivery and tissue engineering, additional studies to assess its potential toxic effects are still needed. Thus, this study evaluated the effects of GO exposure (at 5, 10, 50 or 100mg/L) during six consecutive days on mortality, hatching, spontaneous movement, heart rate, morphology, locomotion behavior, acetylcholinesterase (AChE) activity, dopamine levels and relative gene expression of developmental neurology-related genes using zebrafish larvae. In the 5mg/L dose, synapsin IIa expression up-regulation was seen concomitantly with down-regulation of dat expression, showing a potential compensatory mechanism. Moreover, the 10mg/L exposure caused an increase in heart rate, in absolute turn angle, brain cell damage and a decrease in dopamine levels. These alterations may be associated with autophagosome formation found in GO-exposed larval brain. No changes were observed on higher doses of GO exposure, probably due to nanomaterial agglomeration. Taken together, these results show that toxic effects of GO exposure are not dose-dependent, and are preeminent in lower concentrations. Additional studies are needed to deepen the specific mechanisms of GO neurotoxicity and are required to elucidate its potential biomedical use. PMID- 28618357 TI - Visualisation study on Pseudomonas migulae AN-1 transport in saturated porous media. AB - Influence of granular size and groundwater flow rate on transport of Pseudomonas migulae AN-1 in saturated porous media was non-invasively and visually investigated with a novel imaging technique based on our previously established green fluorescent protein-tagging approach. AN-1 was transported faster than water was. The finer the media were, the greater the enhancement of bacterial velocity was. Mass recovery (MR) increased, while deposition rate coefficient (Kc) decreased, with increasing granular size. Similar and linear trends of MR and Kc, respectively, were quantitatively observed with increasing water flow rate. The images revealed that the initial shape of bacterial plume after injection was a narrow strip along the injection well and an ellipsoid in the lower part of the injection well in medium and coarse sand, respectively. Bacterial plume migrated horizontally in medium sand, but shifted slightly downward in coarse sand. Under similar conditions, the fluorescent area carrying AN-1 in medium sand was larger than that carrying AN-1 in coarse sand during the same period. The visualisation method of this study captured both the movement of free-state and retained bacteria that adhered to sediments. A continuous biological zone composed of planktonic and retained AN-1 was observed. These findings are significant for actual bioremediation. PMID- 28618358 TI - Identifying structural characteristics of humic acid to static and dynamic fluorescence quenching of phenanthrene, 9-phenanthrol, and naphthalene. AB - Fluorescence quenching is a sensitive and fast method to quantify the interactions between a fluorescent organic contaminant and a quencher, such as dissolved organic matter (DOM). Dynamic fluorescence quenching is resulted from molecular collision, not the real binding, and thus it complicates the binding data interpretation. On the other hand, static fluorescence quenching occurs for fluorescent contaminants of ground states, which decreases the concentration of freely dissolved contaminants. However, how a particular structure in DOM contributes to the static and dynamic fluorescence quenching of a fluorescent contaminant is still unclear, which has greatly hindered the application of fluorescence quenching technique. A humic acid (HA) extracted from sediment was chemically modified, i.e., bleaching, acid hydrolysis, and decarboxylation. HAs before and after these modifications were used in fluorescence quenching experiments for phenanthrene (PHE), 9-phenanthrol (PTR) and naphthalene (NAP). Different quenching mechanisms were observed for these chemicals depending on HA properties. For PHE and NAP, aromatic components showed static quenching, while carboxyl groups primarily showed dynamic quenching. Aromatic components and carbohydrates in HAs primarily bound (static quenching) rather than collided (dynamic quenching) with PTR. Carboxyl groups showed interactions with PTR through dynamic quenching only when carboxyl groups were on the benzene ring. Based on the results, we emphasized that dynamic quenching should be carefully excluded in fluorescence quenching studies. This line of study is important to establish a general relationship between DOM properties and static/dynamic quenching contributions. PMID- 28618359 TI - Removal of phosphonates from industrial wastewater with UV/FeII, Fenton and UV/Fenton treatment. AB - Phosphonates are an important group of phosphorus-containing compounds due to their increasing industrial use and possible eutrophication potential. This study involves investigations into the methods UV/FeII, Fenton and UV/Fenton for their removal from a pure water matrix and industrial wastewaters. It could be shown that the degradability of phosphonates by UV/FeII (6 kWh/m3) in pure water crucially depended on the pH and was higher the less phosphonate groups a phosphonate contains. The UV/FeII method is recommended in particular for the treatment of concentrates with nitrogen-free phosphonates, only little turbidity and a low content of organic compounds. Using Fenton reagent, the degradation of polyphosphonates was relatively weak in a pure water matrix (<20% transformation to o-PO43-). By means of the Photo-Fenton method (6 kWh/m3), those phosphonates with the smallest numbers of phosphonate groups were easier degraded as well at pH 3.5 in a pure water matrix (o-PO43- formation rates of up to 80%). Despite an incomplete transformation of organically bound phosphorus to o-PO43- with Fenton reagent in an organically highly polluted wastewater (max. 15%), an almost total removal of the total P occurred. The most efficient total P elimination rates were achieved in accordance with the following Fenton implementation: reaction -> sludge separation (acidic) -> neutralization of the supernatant -> sludge separation (neutral). Accordingly, a neutralization directly after the reaction phase led to a lower total P removal extent. PMID- 28618360 TI - The distribution of phosphorus and its transformations during batch growth of Synechocystis. AB - Phosphorus (P) is an essential nutrient that affects the growth and metabolism of microalgal biomass. Despite the obvious importance of P, the dynamics of how it is taken up and distributed in microalgae are largely undefined. In this study, we tracked the fate of P during batch growth of the cyanobacterium Synechocystis sp. PCC 6803. We determined the distribution of P in intracellular polymeric substances (IPS), extracellular polymeric substances (EPS), and soluble microbial products (SMP) for three initial ortho-phosphate concentrations. Results show that the initial P concentration had no impact on the production of biomass, SMP, and EPS. While the initial P concentration affected the rate and the timing of how P was transformed among internal and external forms of inorganic P (IP) and organic P (OP), the trends were the same no matter the starting P concentration. Initially, IP in the bulk solution was rapidly and simultaneously adsorbed by EPS (IPEPS) and taken up as internal IP (IPint). As the bulk-solution's IP was depleted, desorption of IPEPS became the predominant source for IP that was taken up by the growing cells and converted into OPint. At the end of the 9-d batch experiments, almost all P was OP, and most of the OP was intracellular. Based on all of the results, we propose a set of transformation pathways for P during the growth of Synechocystis. Key is that EPS and intracellular P pool play important and distinct roles in the uptake and storage of P. PMID- 28618361 TI - Diffusion tensor MRI tractography reveals increased fractional anisotropy (FA) in arcuate fasciculus following music-cued motor training. AB - Auditory cues are frequently used to support movement learning and rehabilitation, but the neural basis of this behavioural effect is not yet clear. We investigated the microstructural neuroplasticity effects of adding musical cues to a motor learning task. We hypothesised that music-cued, left-handed motor training would increase fractional anisotropy (FA) in the contralateral arcuate fasciculus, a fibre tract connecting auditory, pre-motor and motor regions. Thirty right-handed participants were assigned to a motor learning condition either with (Music Group) or without (Control Group) musical cues. Participants completed 20minutes of training three times per week over four weeks. Diffusion tensor MRI and probabilistic neighbourhood tractography identified FA, axial (AD) and radial (RD) diffusivity before and after training. Results revealed that FA increased significantly in the right arcuate fasciculus of the Music group only, as hypothesised, with trends for AD to increase and RD to decrease, a pattern of results consistent with activity-dependent increases in myelination. No significant changes were found in the left ipsilateral arcuate fasciculus of either group. This is the first evidence that adding musical cues to movement learning can induce rapid microstructural change in white matter pathways in adults, with potential implications for therapeutic clinical practice. PMID- 28618362 TI - Exposure of larvae to thiamethoxam affects the survival and physiology of the honey bee at post-embryonic stages. AB - Under laboratory conditions, the effects of thiamethoxam were investigated in larvae, pupae and emerging honey bees after exposure at larval stages with different concentrations in the food (0.00001 ng/MUL, 0.001 ng/MUL and 1.44 ng/MUL). Thiamethoxam reduced the survival of larvae and pupae and consequently decreased the percentage of emerging honey bees. Thiamethoxam induced important physiological disturbances. It increased acetylcholinesterase (AChE) activity at all developmental stages and increased glutathione-S-transferase (GST) and carboxylesterase para (CaEp) activities at the pupal stages. For midgut alkaline phosphatase (ALP), no activity was detected in pupae stages, and no effect was observed in larvae and emerging bees. We assume that the effects of thiamethoxam on the survival, emergence and physiology of honey bees may affect the development of the colony. These results showed that attention should be paid to the exposure to pesticides during the developmental stages of the honey bee. This study represents the first investigation of the effects of thiamethoxam on the development of A. mellifera following larval exposure. PMID- 28618363 TI - Simultaneous sorption and catalytic oxidation of trivalent antimony by Canna indica derived biochars. AB - The simultaneous sorption and oxidation of Sb(III) on biochars were investigated using batch experiments. The biochars were derived from Canna indica at different pyrolysis temperatures (300-600 degrees C, referred as CIB300-CIB600), and characterized by FTIR, BET, XRD, SEM-EDS, EPR and Boehm titration. The Sb(III) sorption data could be well fitted by both the Langmuir and Freundlich models, and the pseudo-second order model is best for describing the kinetic data. The maximum Sb(III) sorption capacity of CIB300 was 16.1 mg g-1, which was greater than that of other biochars. Inner-sphere complexation with oxygen-containing functional groups and coordination with pi electrons are the possible sorption mechanisms. It is worthwhile to note that 4.7-32.3% of Sb(III) was oxidized to Sb(V) after sorption equilibration, demonstrating the occurrence of Sb(III) oxidation during the sorption process. Further study of oxidation under anoxic condition confirmed the catalytic role of biochar for Sb(III) oxidation, and free radicals in biochars were crucial for electron transfer. CIB400 exhibited the highest catalytic oxidative ability for Sb(III), which could be ascribe to its reserve of more electroactive polyphenolic macromolecule and less electroinactive cellulose. These results imply that biochars have good potential as a green effective sorbent for remediation of Sb(III) contaminated water, and simultaneously reduce the toxicity of Sb(III) by catalytic oxidation. PMID- 28618364 TI - Amyloid-like protein nanofibrous membranes as a sensing layer infrastructure for the design of mass-sensitive biosensors. AB - Quartz crystal microbalances (QCMs) have been used in the literature for mass sensitive biosensor applications. However, their performance, reliability and stability have been limited by the chemical treatment steps required for the functionalization and activation of the QCM surface, prior to antibody immobilization. Specifically, these steps cause increased film thickness, which diminishes performance by mass overload, and create a harsh environment, which reduces biological activity. In this work, we eliminated this chemical step by introducing a sensing layer modification using electrospun amyloid like-bovine serum albumin (AL-BSA) nanofibers on QCM surfaces. Owing to the self functionality of AL-BSA nanofibers, these modified QCM surfaces were directly activated by glutaraldehyde (GA). To assess the performance of these modified electrodes, a model protein, lysozyme (Lys), was selected as the biological agent to be immobilized. Frequency measurements were performed in batch (dip-and-dry) and continuous (flow-cell) processes, and binding performances were compared. AL BSA modified surfaces were characterized by X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), quartz crystal microbalance (QCM), contact angle (CA) and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). Protein detection was measured based on the frequency shift before and after the covalent bonding of Lys. Under optimized conditions, the proposed immobilization platforms could bind 335ng/mL and 250ng/mL of Lys for batch and continuous processes, respectively. Our results demonstrate the potential usage of these self-functional electrospun AL-BSA infrastructure sensing layers on QCM surfaces. This modification enables the direct immobilization of bioactive agents by eliminating any surface functionalization process for further mass-sensitive biosensor applications. PMID- 28618365 TI - A highly sensitive and widely adaptable plasmonic aptasensor using berberine for small-molecule detection. AB - Localized surface plasmon resonance (LSPR) biosensors allow label-free detection of small molecules in molecular binding events; however, they are limited by a relatively low sensitivity and narrow dynamic range. Here, we report highly sensitive small-molecule detection by LSPR peak shift exploiting the G-quadruplex (GQx) structure-binding characteristic of known GQx binders to enhance the LSPR signal of a plasmonic aptasensor. Six known GQx binders (thiazole orange, malachite green, crystal violet, zinc protoporphyrin IX, thioflavin T, and berberine) were tested for their ability to enhance the LSPR signal. Among these, berberine (BER) induced the largest LSPR peak shift by interacting with the GQx structure formed by the aptamer/target binding event on a gold nanorod surface. This specific binding performance was confirmed by the fluorescence signal of BER and through repeated cycles of BER addition and washing on the plasmonic sensing chip. The proposed plasmonic aptasensor respectively showed limit of detection (LOD) of 0.56, 0.63, 0.87 and 1.05 pM for ochratoxin A, aflatoxin B1, adenosine triphosphate and potassium ions, which was 1000-fold higher than that in BER-free condition, and a wide dynamic range from 10 pM to 10MUM. In addition, the proposed LSPR aptasensor could effectively be used to quantitatively analyze small molecules in real samples. PMID- 28618366 TI - Eu3+ functionalized Sc-MOFs: Turn-on fluorescent switch for ppb-level biomarker of plastic pollutant polystyrene in serum and urine and on-site detection by smartphone. AB - The harm of plastic pollutants for human and environment is being paid more and more attention. Polystyrene (PS) and styrene are toxic compounds used in large quantities in the production of fiberglass reinforced polyesters. In this work, a simple method was designed for independent detecting polystyrene and styrene biomarker (phenylglyoxylic acid, PGA) in serum and urine. We prepared Eu3+ functionalized Sc-based metal-organic frameworks as turn-on fluorescent switch for PGA. The distinct enhanced luminescence is observed from the Eu@MOFs with addition of PGA. The fabricated fluorescent switch has several appealing features including high sensitivity (LOD = 4.16 ppb), quick response time (less than 5s) and broad linear range (0.02mg/mL to 0.5mg/mL). Furthermore, Eu@MOFs exhibits excellent selectivity that it is not affected by congeneric biomarkers. More interestingly, a paper-based probe has been devised. The paper-based fluorescence probe would perform an obvious fluorescence change from navy to red with the variety of PGA content. The practicability of the on-site detection platform for quantitative analysis using a colour scanning APP in smartphone has been also demonstrated by coupled with our proposed paper based fluorescence probe. This work first provides a fast, accurate and sensitive method for independent monitoring PS biomarker PGA, and the paper-based probe exhibit a new idea for design portable and easy to operate sensing devices combine with smartphone. PMID- 28618367 TI - Recent advances in transition-metal dichalcogenides based electrochemical biosensors: A review. AB - Layered transition metal dichalcogenides (TMDCs) comprise a category of two dimensional (2D) materials that offer exciting properties, including large surface area, metallic and semi-conducting electrical capabilities, and intercalatable morphologies. Biosensors employ biological molecules to recognize the target and utilize output elements which can translate the biorecognition event into electrical, optical or mass-sensitive signals to determine the quantities of the target. TMDCs nanomaterials have been widely applied in various electrochemical biosensors with high sensitivity and selectivity. The marriage of TMDCs and electrochemical biosensors has created many productive sensing strategies for applications in the areas of clinical diagnosis, environmental monitoring and food safety. In recent years, an increasing number of TMDCs-based electrochemical biosensors are reported, suggesting TMDCs offers new possibilities of improving the performance of electrochemical biosensors. This review summarizes recent advances in electrochemical biosensors based on TMDCs for detection of various inorganic and organic analytes in the last five years, including glucose, proteins, DNA, heavy metal, etc. In addition, we also point out the challenges and future perspectives related to the material design and development of TMDCs-based electrochemical biosensors. PMID- 28618368 TI - The scales of the zebrafish: host-microbiota interactions from proteins to populations. AB - The interactions between animal hosts and their associated microbiota can be studied at multiple spatial and conceptual scales, with each providing unique perspectives on the processes structuring host-microbe systems. Recently, zebrafish, Danio rerio, has emerged as a powerful model in which to study these interactions at many different scales. Controlled but simplified gnotobiotic experiments enable discovery of the molecules and cellular dynamics that shape host-microbe system development, whereas population level investigations of bacterial dispersal and transmission are beginning to reveal the processes shaping microbiota assembly across hosts. Here we review recent examples of these studies and discuss how the results can be integrated to better understand host microbiota systems. PMID- 28618369 TI - Characterization and quantification of chromate adsorption by layered porous iron oxyhydroxide: An experimental and theoretical study. AB - The inner structure of iron oxyhydroxide agglomerates (IOAs) prepared from hydrolysis of ferric chloride was characterized and correlated to surface complexation of hexavalent chromium, Cr(VI), in a broad range of pH (3-12) and ionic strengths (0.0-5.0M). Evolution of particle size, morphology, and surface activity, combined with density functional theory (DFT) calculations, support the condensation reaction initiated formation of IOAs in three levels: iron nanoparticles to nanolayers to agglomerates. This agglomeration process led to a layered porous structure for aqueous-phase IOAs resulting in a rapid and high removal of Cr(VI) in batch tests. By integrating adsorption results, thermodynamic modeling, and quantum chemical calculations for the adsorption reactions, a quantitative distribution profile for each surface coordination of Cr(VI) ions (i.e., monodentate, bidentate, and hydrogen-bonding) was established. Results of this study are important to understand the fundamental mechanism of IOAs formation in aqueous phase and the intrinsic nature of surface complexations at the mineral-water interface for optimal Cr(VI) removal in hypersaline waste streams. PMID- 28618370 TI - Preferential adsorption and surface precipitation of lead(II) ions onto anatase in artificially contaminated Dixie clay. AB - During TEM-EDS (transmission electron microscopy coupled with an X-ray energy dispersive spectrometer) analysis of Dixie clay artificially contaminated with Pb(II), we observed that Pb(II) was preferentially adsorbed and precipitated on the surface of TiO2. To deepen the understanding of the mechanism and importance of this phenomenon, batch sorption experiments, XANES (X-ray absorption near edge spectroscopy) analysis, and sequential extraction analysis were performed. The TiO2 in Dixie clay was found to be anatase, and anatase showed a higher Pb(II) sorption propensity than rutile, alpha-FeOOH, and one of two MnO2 investigated in this study. Our experimental results indicated that the Pb precipitates preferentially formed on the surface of anatase was Pb(II) hydroxide or Pb(II) oxide. Additionally, sequential extraction analysis showed that at least 32% and 42% of Pb(II) was sorbed onto anatase in the Dixie clay contaminated with a Pb content of 736mg Pb/kg and 1,958mg Pb/kg, respectively. These results demonstrated that in addition to Fe and Mn oxides that are well-known metal oxides that serve as sinks for Pb(II) in the soil environment, TiO2 is also a metal oxide that controls the behavior and fate of Pb(II) in soils. PMID- 28618371 TI - Photodegradation of 4-chlorophenoxyacetic acid under visible LED activated N doped TiO2 and the mechanism of stepwise rate increment of the reused catalyst. AB - Photodegradation of 4-chlorophenoxyacetic acid (4-CPA) was systematically investigated using N-doped TiO2 (N-TiO2) under commercially available visible light emitting diode (Vis LED) as a novel Vis LED illumination in photocatalysis applications. The synergetic effect of Vis LED/N-TiO2 process was studied in detail by varying reaction conditions including the initial concentration of 4 CPA, catalyst dosage, light intensity, and initial pH. Additionally, the influence of inorganic anions and radical scavengers on the performance of the Vis LED/N-TiO2 process was also evaluated. The Vis LED/N-TiO2 was found to be a promising process in terms of mineralization of 4-CPA. It is interesting to note that the performance of this process was not reduced after successive usage of the recycled catalyst; instead, the reaction rate of 4-CPA decay actually increased by using the spent catalyst. The mechanism behind rate enhancement after/during reuse was explored by XPS and FT-IR analyses and it was proven that hydroxyl groups can be incorporated into the catalyst surface by the repeated wetting of N-TiO2 after each reuse. This facilitates the formation of hydrogen bonds between the 4-CPA molecules and N-TiO2, thereby allowing more collisions between the trapped 4-CPA and radicals at the interface of bulk solution and catalyst, respectively. PMID- 28618372 TI - Experimental research of heat-mass coupling response of liquid storage tanks. AB - In order to study the coupling response process of the liquid tank under the external thermal attack, experiments were carried out on a vertical cylindrical storage tank by electric heating. The response processes of the tank pressure, the medium temperatures, and the wet and dry tank wall temperatures were monitored in the experiments. The coupling responding process between the evolving characters of the medium temperature and the tank wall temperature, as well as the resulting rising features of the tank pressure were analyzed comprehensively. The results indicated that, on the one side the heat transfers process across and through the tank wall were influenced obviously by the thermal flow fields of the two phase mediums which differ a lot in the thermal physical properties. On the other side, affected by the temperature rise in the wall, the vapor medium became thermal stratified and overheated with respect to the tank pressure, and the flow regime in the liquid medium would transform from causing stratification to promoting de-stratification affected by the wall boiling phenomenon. PMID- 28618373 TI - Structural changes in cell wall pectins during strawberry fruit development. AB - Strawberry (Fragaria * anannasa Duch.) is one of the most important soft fruit. Rapid loss of firmness occurs during the ripening process, resulting in a short shelf life and high economic losses. To get insight into the role of pectin matrix in the softening process, cell walls from strawberry fruit at two developmental stages, unripe-green and ripe-red, were extracted and sequentially fractionated with different solvents to obtain fractions enriched in a specific component. The yield of cell wall material as well as the per fresh weight contents of the different fractions decreased in ripe fruit. The largest reduction was observed in the pectic fractions extracted with a chelating agent (trans-1,2- diaminocyclohexane-N,N,N'N'-tetraacetic acid, CDTA fraction) and those covalently bound to the wall (extracted with Na2CO3). Uronic acid content of these two fractions also decreased significantly during ripening, but the amount of soluble pectins extracted with phenol:acetic acid:water (PAW) and water increased in ripe fruit. Fourier transform infrared spectroscopy of the different fractions showed that the degree of esterification decreased in CDTA pectins but increased in soluble fractions at ripen stage. The chromatographic analysis of pectin fractions by gel filtration revealed that CDTA, water and, mainly PAW polyuronides were depolymerised in ripe fruit. By contrast, the size of Na2CO3 pectins was not modified. The nanostructural characteristics of CDTA and Na2CO3 pectins were analysed by atomic force microscopy (AFM). Isolated pectic chains present in the CDTA fractions were significantly longer and more branched in samples from green fruit than those from red fruit. No differences in contour length were observed in Na2CO3 strands between samples of both stages. However, the percentage of branched chains decreased from 19.7% in unripe samples to 3.4% in ripe fruit. The number of pectin aggregates was higher in green fruit samples of both fractions. These results show that the nanostructural complexity of pectins present in CDTA and Na2CO3 fractions diminishes during fruit development, and this correlates with the solubilisation of pectins and the softening of the fruit. PMID- 28618374 TI - Proteomic profiling of German Dornfelder grape berries using data-independent acquisition. AB - Grapevine is one of the most important fruit plants throughout the world. Sequencing of the grape genome in 2007 enabled in-depth analyses of the grape proteome. Whereas many studies addressed changes in proteomic composition of grapes during ripening, we focused on the proteome of mature grape berries from Dornfelder, a characteristic red wine grape for Germany. Current data-independent acquisition proteomics technology enables the analysis of proteomic compositions in a degree of accuracy that was unreachable only a few years ago. Using a label free proteomics approach, we quantified 712 proteins in mature Dornfelder grape berries, of which 650 could be annotated by the Blast2GO software. Besides identification of proteins, our analysis provides protein amounts using the TOP3 absolute quantification approach. Most of the proteins (200) in mature Dornfelder grape berries are involved in stress response. In addition, all glycolytic key enzymes were detected in mature grape berries suggesting that glycolysis is still active, whereas sugar accumulation through gluconeogenesis utilizing malate as substrate seems to play a minor role. PMID- 28618375 TI - Effects of a training program for home health care workers on the provision of preventive activities and on the health-related behavior of their clients: A quasi-experimental study. AB - BACKGROUND: Because home health care workers repeatedly visit the same older adults, they are in an excellent position to improve the health-related behavior of older adults, their clients, by providing preventive activities. OBJECTIVES: The objective of this study was to determine the short- and medium term effects of an intervention to support workers in providing preventive activities for older adults. To do this, the number of activities undertaken by workers and the health-related behavior of their clients were assessed. DESIGN: A quasi experimental study was performed with a pre-post design and inclusion of one control group. SETTINGS: The study took place in a deprived, semi-rural area in The Netherlands (2011-2013). Data in three districts served by one home health care organization were gathered. PARTICIPANTS: The participants were home health care workers (registered nurses and nurse aides) and home health care clients aged 55 and over (community-dwelling, dependent older adults receiving home health care). 205 home health care workers participated in the study, 97 of them in the first effect measurement; and 83 of them in the second effect measurement. A total of 304 home health care clients participated, 214 of them in the first effect measurement; and 186 of them in the second effect measurement. METHODS: Differences in change were determined in health-related behavior between groups of older adults as a result of training home health care workers in preventive activities RESULTS: In the control group of home health care professionals a significant increase was found regarding the provision of preventive activities for the domain 'weight' (partial eta squared: 0.05 and 0.08 at first and second effect measurements, respectively). We found preventive activities performed by home health care professionals to have no significant effects on older adult reported health-related behavior, but observed in the intervention group a non significant trend in improvement of physical activity of, respectively, 85 and 207min for the first and second effect-measurements. CONCLUSION: This training program had hardly any effect on preventive activities performed by home health care workers and on the health-related behavior of older adults. Offering health promotion via home health care workers may be promising but its delivery should be enhanced. PMID- 28618376 TI - Association between the HLA-B alleles and carbamazepine-induced SJS/TEN: A meta analysis. AB - PURPOSE: From our current understanding, the association between the human leukocyte antigen (HLA), HLA-B*1502, and carbamazepine(CBZ)-induced Stevens Jonson syndrome and toxic epidermal necrolysis (SJS/TEN) in the Asian population is quite clear. However the relationship between other HLA-B alleles and CBZ induced severe cutaneous adverse drug reactions (SCADRs) remains unclear. We aimed to identify other non-HLA-B*1502 alleles in patients with CBZ-induced SCADRs through a meta-analysis. MATERIALS AND METHODS: A thorough literature search was performed using Embase, PubMed, Web of Knowledge and Cochrane databases. A meta-analysis was performed from their inceptions to May 31, 2016. Studies investigating the association of HLA-B alleles and CBZ-induced SJS/TEN were retrieved. Two reviewers independently extracted the data. Overall odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using the RevMan 5.3 software. RESULTS: A total of 11 studies met the inclusion criteria, totaling 343 CBZ-induced SJS/TEN cases, 838 CBZ tolerant controls, and 978 population controls. We observed HLA-B*1511 as a risk marker, and HLA-B*4001 and HLA-B*4601 as protective markers for the development of SJS/TEN in patients taking CBZ. SJS/TEN cases were found to be significantly associated with HLA B*1511 in both the tolerant group (OR=17.43;95%CI=3.12-97.41;P=0.001) and the population-control group (OR=11.11; 95%CI=2.62-47.09; P=0.001). The sensitivity analysis found that HLA-B*5801 was a protective marker in the Southeast Asian population (OR=0.23; 95%CI=0.09-0.58; P=0.002). CONCLUSION: Our study demonstrated that in the Asian population, HLA-B*4001, HLA-B*4601, HLA-B*5801 were strong protective factors in the development of CBZ-induced SJS/TEN whereas HLA-B*1511 was a risk factor. While more studies may be needed in order to confirm these findings, consideration should be taken into testing Asian patients for at-risk alleles prior to CBZ therapy initiation. PMID- 28618377 TI - Ring and peg electrodes for minimally-Invasive and long-term sub-scalp EEG recordings. AB - OBJECTIVE: Minimally-invasive approaches are needed for long-term reliable Electroencephalography (EEG) recordings to assist with epilepsy diagnosis, investigation and more naturalistic monitoring. This study compared three methods for long-term implantation of sub-scalp EEG electrodes. METHODS: Three types of electrodes (disk, ring, and peg) were fabricated from biocompatible materials and implanted under the scalp in five ambulatory ewes for 3months. Disk electrodes were inserted into sub-pericranial pockets. Ring electrodes were tunneled under the scalp. Peg electrodes were inserted into the skull, close to the dura. EEG was continuously monitored wirelessly. High resolution CT imaging, histopathology, and impedance measurements were used to assess the status of the electrodes at the end of the study. RESULTS: EEG amplitude was larger in the peg compared with the disk and ring electrodes (p<0.05). Similarly, chewing artifacts were lower in the peg electrodes (p<0.05). Electrode impedance increased after long-term implantation particularly for those within the bone (p<0.01). Micro-CT scans indicated that all electrodes stayed within the sub-scalp layers. All pegs remained within the burr holes as implanted with no evidence of extrusion. Eight of 10 disks partially eroded into the bone by 1.0mm from the surface of the skull. The ring arrays remained within the sub-scalp layers close to implantation site. Histology revealed that the electrodes were encapsulated in a thin fibrous tissue adjacent to the pericranium. Overlying this was a loose connective layer and scalp. Erosion into the bone occurred under the rim of the sub-pericranial disk electrodes. CONCLUSIONS: The results indicate that the peg electrodes provided high quality EEG, mechanical stability, and lower chewing artifact. Whereas, ring electrode arrays tunneled under the scalp enable minimal surgical techniques to be used for implantation and removal. PMID- 28618378 TI - Simultaneously upgrading biogas and purifying biogas slurry using cocultivation of Chlorella vulgaris and three different fungi under various mixed light wavelength and photoperiods. AB - In order to purify biogas slurry and biogas simultaneously, three different fungi, Pleurotus geesteranus (P. geesteranus), Ganoderma lucidum (G. lucidum), and Pleurotus ostreatus (P. ostreatus) were pelletized with Chlorella vulgaris (C. vulgaris). The results showed that the optimal light wavelength ratio for red:blue was 5:5 for these three different fungi-assisted C. vulgaris, resulting in higher specific growth rate as well as nutrient and CO2 removal efficiency compared with other ratios. G. lucidum/C. vulgaris was screened as the best fungi mialgae for biogas slurry purification and biogas upgrading with light/dark ratio of 14h:10h, which was also confirmed by the economic efficiency analysis of the energy consumptions. These results will provide a theoretical foundation for large-scale biogas slurry purifying and biogas upgrading using microalgae. PMID- 28618379 TI - Well encapsulated Mn3O4 octahedra in graphene nanosheets with much enhanced Li storage performances. AB - Mn3O4@graphene (Mn3O4@G) nanocomposite is easily fabricated through a facile preparation of Mn3O4 octahedra by dealloying MnAl alloy and a following reduction of coassembled aggregates of Mn3O4 octahedra and graphene oxide. Benefitting from the distinctive nanostructure and the hybridization with well-conductive graphene, the capacity retentions of Mn3O4@G are dramatically improved from 25.5 to 58.0% after 100 cycles at 300mAg-1 and from 15.8 to 43.8% after 200 cycles at 1000mAg-1, respectively. Even the current rates reach up to 2000 and 3000mAg-1, Mn3O4@G electrode could still hold the highly stable capacities around 520 and 430mAhg-1, respectively. On account of the superiorities of high electrochemical performances and easy preparation, the Mn3O4@G composite shows encouraging application potential to be an advanced anode material for lithium storage. PMID- 28618380 TI - Magnetite/Fe-Al-montmorillonite as a Fenton catalyst with efficient degradation of phenol. AB - A Fe-Al-MPM material assembled from nanosized magnetite and Fe-Al-pillared montmorillonite (Fe-Al-Mt) was characterized by XRD, XPS, BET, SEM and TEM. Fe-Al Mt was proven to be capable of facilitating the dispersion of magnetite nanoparticles and inhibiting their aggregation. The coupling of Fe-Al-Mt with magnetite in Fe-Al-MPM improved its Fenton catalytic activity. Complete conversion of phenol within 80min with a high TOC removal rate (>78%) was achieved using Fe-Al-MPM as a heterogeneous Fenton catalyst under optimized conditions. The Fenton process first underwent a slow induction reaction, followed by the rapid oxidative decomposition of phenol. The existence of the induction reaction period was attributed to the need for activation of the iron species on the catalyst surfaces, and the duration depended on the solution temperature, pH and catalyst's nature. More importantly, Fe-Al-MPM showed high stability, with a low iron-release even after it was recycled 5 times. The minimal iron-leaching from Fe-Al-MPM was ascribed to the competitive adsorption of the incorporated aluminum and all the iron species for the residual (low ecotoxicity) organic ligands. These organic acids were among the main products that remained at the end of the Fenton process. Also important was the ease of separation of Fe-Al-MPM under a magnetic field. PMID- 28618381 TI - Magnetic recyclable bismuth oxyiodide/polyacrylic anion exchange resin composites with enhanced photocatalytic activity under visible light. AB - A series of magnetic recyclable bismuth oxyiodide (BiOI)/polyacrylic anion exchange resin (PAER) composites with visible light responses have been synthesized for the first time through a facile and low-cost method at normal temperature. The photocatalytic performances of BiOI/PAER composites were evaluated by photodegrading 1-amino-8-naphthol-3,6-disulfonic acid under visible light. It was found that 1-amino-8-naphthol-3,6-disulfonic acid (H-acid) removal rate reached to 90.1% (BiOI/PAER-2), which was higher than the pure BiOI (50.3%) in 60min. The enhanced photocatalytic performance of BiOI/PAER composites should be attributed to the improved separation efficiency of the charge carriers. Furthermore, the BiOI/PAER composites exhibited excellent cyclinic utilization stability, which is a key factor for their potential practical applications. PMID- 28618382 TI - Electrochemical determination of morin in Kiwi and Strawberry fruit samples using vanadium pentoxide nano-flakes. AB - Herein, we report the synthesis of Vanadium Pentoxide Nanoflakes (V2O5 NF) using ionic liquid and employed the V2O5 NF in electrochemical determination of Morin (MR) in fruit samples. The V2O5 NF were characterized by Powder X-ray diffraction (PXRD), scanning electron microscope (SEM), energy-dispersive X-ray analyzer (EDX), differential pulse voltammetry (DPV), and cyclic voltammetry (CV). Remarkably, the as-synthesized V2O5 NF exhibited excellent electrochemical behavior and electrochemical ability towards MR. The CV and DPV studies were recognized that the electrochemical performance of V2O5 NF film modified glassy carbon electrode (V2O5 NF/GCE) towards detection of MR is outstanding in comparison with unmodified GCE. The proposed MR sensor shows a wide linear range, high sensitivity, and low limit of detection are 0.05-10.93MUm, 1.130MUAMUM-1cm 2, and 9nM respectively. The fabulous analytical parameters of the developed sensor surpassed the previously reported modified electrodes, rendering the potential application of V2O5 NF in environmental, biomedical, and pharmaceutical samples. PMID- 28618383 TI - Disassembly of micelle-like polyethylenimine nanocomplexes for siRNA delivery: High transfection efficiency and reduced toxicity achieved by simple reducible lipid modification. AB - Amphiphilic compounds consisting of polycations and lipid segments are well established as building blocks for the construction of siRNA carriers. They are capable of forming nanoparticles with high-affinity positive charges for siRNA in aqueous media due to their intra- and/or intermolecular hydrophobic and electrostatic interactions. Unfortunately, safety and efficiency of lipid modified polycations as the two great challenges to the clinical application need to be improved. Beyond that, the role of the hydrophobic segment in the process of siRNA delivery is elusive. Herein, in this study, branched polyethylenimine with a molecular weight of 600 (bPEI600) was grafted with reducible lipids via Michael addition reaction between amines and alkyl acrylates. Reducible amphiphilic polyethylenimines (PEIs) were able to condense siRNA into nanoparticles and disassemble under the reductive environment. Investigations with these materials in vitro revealed that the polymers with higher grafting degree provided high luciferase knockdown efficacies even at lower N/P ratios and the polymers with longer lipid chain displayed greater cellular uptake rate. Interestingly, the polymers with lower grafting degree had efficient cellular uptake than native bPEI600, although their in luciferase knockdown assays were most likely inefficient. The inconsistency between the cellular uptake profile and silencing efficacy proved that the intracellular trafficking of siRNA was a bottleneck for siRNA delivery with some polymers prepared in this study. As expected, reducible lipid-modified PEIs were equally efficient and much less toxic compared to non-reducible counterparts and might provide broader therapeutic windows. These findings showed the feasibility of reducible lipid modified PEIs as carriers for therapeutic siRNA. PMID- 28618384 TI - A fatty acid solvent of switchable miscibility. AB - Ion pair interactions were explored to design a fatty acid solvent of switchable miscibility with water. Fatty acids of medium length chains are immiscible with water but become miscible with water when ion pairs are formed with amines. The ion pairs become phase separated after bubbling CO2 into the solution due to the dissociation of the fatty acid-amine complexes. Ion pairs of caprylic acid (C8) and low toxic poly(oxypropylene) diamine (Jeffamine D-230) were characterized by FT-IR and 1H NMR. Log Kow values and surface activity were used to understand the switchable solvent mechanism in removing and recovering oily contaminants. More importantly, the ion pairs show a negligible adsorption on solid surfaces. Furthermore, both C8 and D-230 were recycled during the washing process. Thus the fatty acid as switchable solvent could be applied for oily contaminant removal from oily solid wastes. PMID- 28618385 TI - Enhanced hydrogen production of PbTe-PbS/TNAs electrodes modified with ordered mesoporous carbon. AB - PbTe-PbS/TiO2 nanotube arrays (PbTe-PbS/TNAs) were synthesized by the successive ionic layer adsorption and reaction (SILAR) followed by linear sweep voltammetry (LSV). Using Nafion as a binder, ordered mesoporous carbon was cast on these materials to generate the modified electrodes OMC/PbTe-PbS/TNAs. It was demonstrated that the electrode modification with OMC could enhance the charge transfer between the electrode surface and the electrolyte solution, improve the energy band bending of the electrode/electrolyte interface, increase the active electrochemical surface area of the electrode, and reduce the overpotential of the electrode reactions. Under ambient conditions, the short circuit current density (37.84mAcm-2) and the active electrochemical surface area (29mFcm-2) of the OMC/PbTe-PbS/TNAs electrode were 27.49% and 36.79% higher than that of PbTe PbS/TNAs (29.68mAcm-2 and 21.2mFcm-2), respectively. A particularly important feature of the OMC modification is that the hot electron extraction capability of the PbTe-PbS/TNAs electrode remained in the new system to provide rapid enhancement of short circuit current density upon increasing temperature. The OMC/PbTe-PbS/TNAs electrode registered a hydrogen generation rate of 11mLcm2h-1, with an energy efficiency of 98.79% and a heat efficiency of 43.03% under cell voltage of 1.0V at 55 degrees C. PMID- 28618386 TI - A novel method for synthesizing well-defined boehmite hollow microspheres. AB - A novel and effective synthesis route has been developed to fabricate gamma-AlOOH (boehmite) hollow microspheres (diameter in 1-2MUm) with urchin-like shell structures. The external surface of the hollow microspheres was constructed by randomly aggregated and interconnecting nanoplatelets (length in 50nm). The method involves two processes: (1) solid spherical particles can be obtained by an epoxide-driven sol-gel process in several seconds, (2) solid spheres particles transform into urchin-like hollow spheres through chemically induced self transformation process. Formation of the gamma-AlOOH hollow microspheres was strongly dependent on the amount of propylene oxide, the volume ratio of solvents, as well as the kinds of anion. gamma-AlOOH hollow microspheres could only be obtained in a particular situation that AlCl3.6H2O acts as salt precursor and the volume between H2O and ethanol were defined as 4ml, 6ml and 6ml, 4ml. In general, the described method is efficient and environmentally benign, and has significant advantages over traditional template approaches to the large-scale production of hollow inorganic materials. PMID- 28618387 TI - Two pulse recoupling. AB - The paper describes a family of novel recoupling pulse sequences in magic angle spinning (MAS) solid state NMR, called two pulse recoupling. These pulse sequences can be employed for both homonuclear and heteronuclear recoupling experiments and are robust to dispersion in chemical shifts and rf-inhomogeneity. The homonuclear pulse sequence consists of a building block (pi)phi(pi)-phi where phi=pi4n, and n is number of blocks in a rotor period. The recoupling block is made robust to rf-inhomogeneity by extending it to (pi)phi(pi) phi(pi)pi+phi(pi)pi-phi. The heteronuclear recoupling pulse sequence consists of a building block [Formula: see text] and [Formula: see text] on channel I and S, where phi1=3pi8n,phi2=pi8n and n is number of blocks in a rotor period. The recoupling block is made robust to rf-inhomogeneity by extending it to [Formula: see text] and [Formula: see text] on two channels respectively. The recoupling pulse sequences mix the z magnetization. Experimental quantification of this method is shown for13Calpha-13CO homonuclear recoupling in a sample of Glycine and 15N-13Calpha heteronuclear recoupling in Alanine. Application of this method is demonstrated on a sample of tripeptide N-formyl-[U-13C,15N]-Met-Leu-Phe-OH (MLF). Compared to R-sequences (Levitt, 2002), these sequences are more robust to rf-inhomogeneity and give better sensitivity, as shown in Fig. 3. PMID- 28618388 TI - Simultaneous determination of nine beta-lactam antibiotics in human plasma by an ultrafast hydrophilic-interaction chromatography-tandem mass spectrometry. AB - Contemporary beta-lactam antibiotic dosing is debatable in severely ill patients, since the occurrence of pathophysiological changes in critical illness can result in great inter-individual variability. Therapeutic drug monitoring (TDM) is a commonly used dosing strategy to optimize exposure and thereby minimize toxicity and maximize the efficacy. Currently, TDM of beta-lactam antibiotics is rarely performed, due to poor availability in clinical practice. We describe an ultrafast Hydrophilic-Interaction Chromatography (HILIC) based UPLC-MS/MS method for the determination of amoxicillin, benzylpenicillin, cefotaxime, cefuroxime, ceftazidime, flucloxacillin, imipenem, meropenem and piperacillin in human plasma. This method involves simple sample preparation steps and was comprehensively validated according to standard FDA guidelines. For all analytes, mean accuracy and precision values were within the acceptance value. The lower and upper limits of quantification were found to be sufficient to cover the therapeutic range for all antibiotics. Finally, the method was successfully applied in a large pharmacokinetic study performed in the intensive care setting, and the feasibility of the analytical procedure was demonstrated in routine clinical practice. To the best of our knowledge, we report here the first HILIC based UPLC-MS/MS assay for the determination of beta-lactam antibiotics in human plasma. This simple, sensitive and ultrafast assay requires small-volume samples and can easily be implemented in clinical laboratories to promote the TDM of beta lactam antibiotics. PMID- 28618389 TI - Involvement of p38 MAPK and ATF-2 signaling pathway in anti-inflammatory effect of a novel compound bis[(5-methyl)2-furyl](4-nitrophenyl)methane on lipopolysaccharide-stimulated macrophages. AB - Activated macrophages produce various pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) and cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) during inflammatory response. However, overproduction of NO and PGE2 appears to be involved in pathogenesis of various inflammatory diseases. Therefore, inhibition of NO and PGE2 production might be useful for the treatment of inflammatory-related diseases. In this study, the bis[(5-methyl)2-furyl](4-nitrophenyl)methane or BFNM was evaluated for the anti-inflammatory activity and mechanism of action in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage. BFNM inhibited NO and PGE2 production in a concentration-dependent manner and down-regulated the expression of iNOS and COX-2 at mRNA and protein levels. BFNM suppressed nuclear translocation of NF-kappaB p65 subunit only very slightly, and failed to decrease NF-kappaB DNA binding activity. In contrast, the compound significantly reduced phosphorylation of p38 MAPK and ATF-2, a component of AP-1 known to be involved in the transcriptional regulation of iNOS and COX-2, in a dose-dependent manner in LPS-induced cells. Collectively, these results suggest that BFNM has an anti inflammatory effect in RAW 264.7 macrophages, at least in part, by suppression of NO and PGE2 production. The inhibitory effect of BFNM is mediated mainly via the p38 MAPK/ATF-2 signaling pathway. Thus, BFNM would be a lead compound for the development of novel anti-inflammatory agents. PMID- 28618390 TI - Thirty-day non-seizure outcomes following temporal lobectomy for adult epilepsy. AB - OBJECTIVE: Multi-institutional rates of acute adverse outcomes other than seizures after temporal lobectomy (TL) are not well understood. Here we analyzed short-term morbidity and mortality following TL using a validated national database. PATIENTS AND METHODS: The multi-institutional American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was queried by Current Procedural Terminology (CPT) code for TL procedures performed for adult patients with diagnoses related to epilepsy from 2008 to 2014. Patient demographics, operative variables, hospital variables, preoperative laboratory values, and preexisting comorbidities were analyzed using univariate and multivariate techniques to determine associations with 30-day postoperative morbidity and mortality. RESULTS: A total of 202 TL procedures were analyzed, 80 (39.6%) with intraoperative electrocorticography (ECOG) and 122 (60.4%) without ECOG. Mean age was 40.4+/-13.7years, and 47.5% of patients were male. Overall morbidity and mortality were 11.4% and 2.0%, respectively. The most common adverse outcomes were reoperation (5.4%), stroke with residual deficit (2.5%), failure to wean from ventilator (2.0%), and surgical site infection (2.0%). Adverse event rates were not significantly different between TLs with and without ECOG (13.1% vs. 8.8%, p=0.375). Independent predictors of adverse events included prior stroke (OR 7.60, 95% CI 1.22-47.17, p=0.029) and chronic steroid use (OR 10.90, 95% CI 1.03-115.79, p=0.048). Diabetes mellitus (p=0.078) and older age (p=0.145) approached but did not reach significance in the multivariate model. CONCLUSIONS: We report rates of acute morbidity and mortality following TL procedures using a national database. These findings can be used both to assist with patient selection as well as patient counseling prior to surgery. PMID- 28618392 TI - Radiocesium decontamination of a riverside in Fukushima, Japan. AB - Extensive decontamination measures have been implemented in the area affected by the Fukushima Dai-ichi nuclear disaster. Typical decontamination measures, such as removing topsoil of several centimeters in depth, are not suitable for rivers where contaminated sediments have been deposited. A decontamination measure was tested that considered the spatial distribution of radiocesium at the lower part of a tributary of the Abukuma River in Fukushima. The radiocesium distribution in the flood channel was vertically and horizontally highly heterogeneous. In some parts, the activity concentration was high (>10 kBq/kg for 137Cs) even at depths of 25 cm in the sediment. This may be due to plant growth in the flood channel favoring the deposition of sediment with high activity concentration. On the basis of the radiocesium distribution, the flood channel sediment was removed to a depth of 15-35 cm, which accumulated the most radiocesium (>3.0 kBq/kg for the sum of 134Cs and 137Cs). The upper 5 cm of soil was removed from the dike slopes. The river bed was not decontaminated because the activity concentration was low (<1 kBq/kg) in the river bed sediment and because the water shields gamma rays emitted from the sediment. The test decontamination measure reduced the air dose rate by a factor of approximately two, demonstrating the effectiveness of our measures. Annual external doses were calculated for when this part of the dike and the flood channel is used for commuting to school and outdoor education. The doses during the activities at the test site accounted for only 1-2% of the value during daily life in the surrounding area, indicating that radiation exposure during riverside activities is limited. PMID- 28618391 TI - Daily-level associations between PTSD and cannabis use among young sexual minority women. AB - INTRODUCTION: Sexual minority women have elevated trauma exposure and prevalence of posttraumatic stress disorder (PTSD) compared to heterosexual women and they are also more likely to use cannabis, although no research has examined relationships between PTSD and cannabis use in this population. Daily-level methodologies are necessary to examine proximal associations between PTSD and use. METHODS: This study included 90 trauma-exposed young adult women who identified as sexual minorities (34.4% identified as lesbian and 48.9% identified as bisexual) and evaluated daily-level associations between their PTSD symptoms and cannabis use. Participants were assessed at two measurement waves, one year apart, each consisting of 14 consecutive daily assessments. RESULTS: Cannabis use occurred on 22.8% of the days. Results from generalized linear mixed effects models showed that a person's mean level of PTSD symptom severity across days was strongly associated with same-day likelihood of cannabis use (OR=2.67 for 1 SD increase in PTSD score; p<0.001). However, daily deviation from one's average PTSD score was not associated with cannabis use on the same day. CONCLUSIONS: Findings suggest that PTSD severity may confer general risk for cannabis use, rather than being a state-dependent risk factor. PMID- 28618393 TI - Young infants' visual fixation patterns in addition and subtraction tasks support an object tracking account. AB - Investigating infants' numerical ability is crucial to identifying the developmental origins of numeracy. Wynn (1992) claimed that 5-month-old infants understand addition and subtraction as indicated by longer looking at outcomes that violate numerical operations (i.e., 1+1=1 and 2-1=2). However, Wynn's claim was contentious, with others suggesting that her results might reflect a familiarity preference for the initial array or that they could be explained in terms of object tracking. To cast light on this controversy, Wynn's conditions were replicated with conventional looking time supplemented with eye-tracker data. In the incorrect outcome of 2 in a subtraction event (2-1=2), infants looked selectively at the incorrectly present object, a finding that is not predicted by an initial array preference account or a symbolic numerical account but that is consistent with a perceptual object tracking account. It appears that young infants can track at least one object over occlusion, and this may form the precursor of numerical ability. PMID- 28618404 TI - Prevalence of Hyponatremia and Its Associated Morbimortality in Hospitalized Patients Receiving Parenteral Nutrition. AB - BACKGROUND: The objective of the study was to determine the prevalence of hyponatremia (HN) and its associated morbimortality in hospitalized patients receiving parenteral nutrition (PN). METHODS: A retrospective study including 222 patients receiving total PN (parenteral nutrition group [PNG]) over a 7-month period in a tertiary hospital and 176 matched to 179 control subjects without PN (control subjects group [CSG]). Demographic data, Charlson Comorbidity Index (CCI), date of HN detection-(serum sodium or SNa <135 mmol/L)-intrahospital mortality, and hospital length-of-stay (LOS) were registered. In the PNG, body mass index (BMI) and SNa before, during, and after PN were recorded. RESULTS: HN was more prevalent in the PNG: 52.8 vs. 35.8% (p = 0.001), and independent of age, gender, or CCI (OR 1.8 [95% CI 1.1-2.8], p = 0.006). In patients on PN, sustained HN (75% of all intraindividual SNa <135 mmol/L) was associated with a higher mortality rate independent of age, gender, CCI, or BMI (OR 7.38 [95% CI 1.07-50.8], p = 0.042). The absence of HN in PN patients was associated with a shorter hospital LOS (<30 days) and was independent of other comorbidities (OR 3.89 [95% CI 2.11-7.18], p = 0.001). CONCLUSIONS: HN is more prevalent in patients on PN. Sustained HN is associated with a higher intrahospital mortality rate. Absence of HN is associated with a shorter hospital LOS. PMID- 28618405 TI - Upregulation of Circulating miR-195-3p in Heart Failure. AB - OBJECTIVES: Many circulating microRNAs (miRs) have been shown to have potential biomarker effects in cardiovascular disease. We studied the dysregulation of circulating miR-195-3p in patients with heart failure (HF) to elucidate its value as a potential biomarker for HF. METHODS: Eight ischemic HF (IHF) patients, 8 nonischemic HF patients (NIHF), and 8 healthy volunteers (matched by age and sex normal controls [NCs]) were chosen for miR sequencing. The plasma RNA was extracted, and a small RNA library of HF was established and then sequenced using next-generation sequencing (NGS) technology. The miR-195-3p was selected for a second clinical study in 60 IHF, 48 NIHF patients, and 35 NCs for qRT-PCR validation. RESULTS: The expression of circulating miR-195-3p in the IHF group was increased 69.5-fold compared with the NC group using NGS technique, and it was the most elevated in all upregulated miRs. MiR-195-3p was ranked in the top 1 of all upregulated miRs in contribution to HF based on a random forest model analysis. The upregulation of circulating miR-195-3p was also validated with the qRT-PCR method, and receiver operating characteristic curve analysis showed that the area under the curve (AUC) was 0.831. CONCLUSIONS: The circulating miR-195-3p was upregulated in IHF and NIHF patients and could be a potential biomarker for HF. PMID- 28618406 TI - An Analysis of Outcome of Endoscopic Fenestration of Cavum Septum Pellucidum Cyst - More Grey than Black and White? AB - BACKGROUND: Cavum septum pellucidum (CSP) and cavum vergae are actually fluid filled, generally communicating midline cavities located between the third ventricle and corpus callosum. There have been various reports of their association with many behavioral and psychiatric disorders. Infrequently, they have been associated with an obstructive hydrocephalus-like picture. Although the structure and management of CSP has long been known, it has been an enigma as far as functional significance and management indications are concerned. The authors of this article try to analyze the significance of a persistent cavum and involvement of the same entity in varied presentations ranging from an incidental imaging finding to acute hydrocephalus, and propose a possible implication on the present surgical intervention paradigm. PURPOSE: To assess the surgical outcome of fenestration of a CSP cyst. METHODS: Retrospective analysis of 3 patients who underwent endoscopic fenestration for CSP with obstructive hydrocephalus between 2012 and 2014 was done, and data were analyzed for symptomatic clinical improvement in particular behavior. RESULTS: Pre- and postoperative brain MRI showed a significant decrease in the size of the cyst as well as the ventricles. There were no recurrences during follow-up. All of the patients improved. CONCLUSIONS: (1) Endoscopic fenestration of symptomatic CSP cysts is a safe treatment option. (2) Neurocognitive assessment is essential in the evaluation and outcome assessment of CSP. PMID- 28618407 TI - Association between Thyroid Function and Body Mass Index: A 10-Year Follow-Up. AB - BACKGROUND/AIMS: We aimed to evaluate the association between change in thyroid function tests within the euthyroid range and body mass index (BMI) in persons with normal weight at baseline. METHODS: This study investigated 1,100 normal weight euthyroid persons in a population-based cohort study, Tehran Thyroid Study. BMI was calculated and serum concentrations of thyrotropin (TSH) and free T4 (FT4) were assayed at baseline and after 10 years of follow-up. We evaluated the relationship between thyroid and obesity based on 2 definitions for outcome: (1) a binary outcome as BMI <25 or >=25 kg/m2, and (2) a multinomial outcome as normal BMI, overweight, and obese. RESULTS: A total of 569 women and 531 men, aged 36.3 +/- 13.5 years, were included. Modified Poisson regression analysis for binary outcome, after adjustment for age, sex, smoking, and anti-thyroid peroxidase antibody status, revealed a negative association between delta serum FT4 and follow-up BMI (relative risk 0.55 [95% CI 0.37-0.80]) without any significant association between change in serum TSH and follow-up BMI. However, in multinomial logistic regression analysis, we found no relationship between delta serum FT4 or TSH and follow-up BMI categories, for either overweight or obese vs. normal-weight participants. CONCLUSIONS: In normal-weight euthyroid individuals, changes in serum concentrations of FT4, but not TSH, may contribute to change in body weight. PMID- 28618408 TI - Inflammatory Pathways in Acute Myocardial Infarction: A Matter of Prime Importance. PMID- 28618409 TI - Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis. AB - BACKGROUND: Few genetic studies have focused on unilateral renal agenesis (URA), which is a disorder with insidious clinical manifestations and a tendency to result in renal failure. We aimed to detect pathogenic mutations in nephrogenesis related genes, which were identified by a literature review conducted among a large cohort of Chinese Han patients with URA. METHODS: Totally, 86 unrelated URA patients were included. All URA patients were diagnosed by employing radiological methods. Patients with a solitary kidney owing to nephrectomy or renal atrophy due to secondary factors were excluded. Nine (10.5%) patients had a family history of abnormal nephrogenesis. Fifteen (17.4%) had other malformations in the urogenital system. All coding exons and adjacent intron regions of 25 genes were analyzed using next-generation sequencing and validated by Sanger sequencing and 100 ethnically matched healthy controls. RESULTS: Ten conserved mutations (9 missense mutations and 1 deletion mutation) were identified in SALL1, EYA1, RET, HNF1B, DSTYK, WNT4, and SIX5. All mutations were novel or rare (frequency <0.1%) in the public databases and absent from the 100 healthy controls. Nine patients carried mutations in candidate genes. Most of the patients carried one single heterozygous mutation, except for 2, who respectively carried compound heterozygous mutations and 2 single heterozygous mutations. In addition, 2 patients shared the same mutation in DSTYK. CONCLUSION: A total of 10.5% of our URA cases could be explained by mutations in our candidate genes. The mutations in nephrogenesis-related genes in the Chinese Han patients with URA had a decentralized distribution without any hotspot mutations. PMID- 28618410 TI - Deletion of the Inflammasome Sensor Aim2 Mitigates Abeta Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model. AB - OBJECTIVE: Inflammation is clearly associated with Alzheimer disease (AD). Knockout of Nlrp3, a gene encoding an inflammasome sensor, has been shown to ameliorate AD pathology in a mouse model. Because AIM2 is the most dominant inflammasome sensor expressed in mouse brains, here we investigate whether Aim2 deletion also influences the phenotype of a 5XFAD AD mouse model. METHODS: Quantitative RT-PCR, immunostaining, immunoblotting, and behavioral analyses were applied to compare wild-type, Aim2-/-, 5XFAD, and Aim2-/-;5XFAD mice. RESULTS: We found that Aim2 knockout mitigates Abeta deposition in the cerebral cortex and hippocampus of 5XFAD mice. The activation of microglial cells is also reduced in Aim2-/-;5XFAD brains compared with 5XFAD brains. However, Aim2 knockout does not improve memory and anxiety phenotypes of 5XFAD mice in an open field, cued Y maze, or Barnes maze. Compared with 5XFAD mice, Il-1 expression levels are not reduced in Aim2-/-;5XFAD mice. Unexpectedly, Il-6 and Il-18 expression levels in 5XFAD brains were further increased when Aim2 was deleted. Thus, inflammatory cytokine expression in 5XFAD brains is upregulated by Aim2 deletion through an unknown mechanism. CONCLUSION: Although Aim2 knockout mitigates Abeta deposition and microglial activation, Aim2 deletion does not have a beneficial effect on the spatial memory or cytokine expression of 5XFAD mice. Our findings suggest that Abeta aggregation and microglial activation may not always be correlated with the expression of inflammatory cytokines or cognitive function of 5XFAD mice. Our study also implies that different inflammasomes likely perform distinct roles in different physiological and/or pathological events. PMID- 28618411 TI - Prevalence and Physical Distribution of SRY in the Gonads of a Woman with Turner Syndrome: Phenotypic Presentation, Tubal Formation, and Malignancy Risk. AB - Although monosomy X is the most common karyotype in patients with Turner syndrome, the presence of Y chromosome material has been observed in about 10% of patients. Y chromosome material in patients with Turner syndrome poses an increased risk of gonadoblastoma and malignant transformation. We report a woman with a diagnosis of Turner syndrome at 12 years of age, without signs of virilization, and karyotype reported as 46,X,del(X)(q13). At 26 years, cytogenetic studies indicated the patient to be mosaic for monosomy X and a cell line that contained a du-plicated Yq chromosome. Bilateral gonadectomy was performed and revealed streak gonads, without evidence of gonadoblastoma. Histological analysis showed ovarian stromal cells with few primordial tubal structures. FISH performed on streak gonadal tissue showed a heterogeneous distribution of SRY, with exclusive localization to the primordial tubal structures. DNA extraction from the gonadal tissue showed a 6.5% prevalence of SRY by microarray analysis, contrasting the 86% prevalence in the peripheral blood sample. This indicates that the overall gonadal sex appears to be determined by the majority gonosome complement in gonadal tissue in cases of sex chromosome mosaicism. This case also raises questions regarding malignancy risk associated with Y prevalence and tubal structures in gonadal tissue. PMID- 28618412 TI - Failed Downregulation of Circulating MicroRNA-155 in the Early Phase after ST Elevation Myocardial Infarction Is Associated with Adverse Left Ventricular Remodeling. AB - BACKGROUND: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases. AIMS: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI). METHODS: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls. RESULTS: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (rho = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA 155 and the amount of monocytes (day 5, rho = 0.463, p = 0.046). CONCLUSION: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling. PMID- 28618413 TI - Induction of Apoptosis in HepaRG Cell Line by Aloe-Emodin through Generation of Reactive Oxygen Species and the Mitochondrial Pathway. AB - BACKGROUND/AIMS: Aloe-emodin (1,8-dihydroxy-3-hydroxymethyl-anthraquinone), an anthraquinone active compounds, is isolated from some traditional medicinal plants such as Rheum palmatum L. and Cassia occidentalis, which induce hepatotoxicity in rats. The aim of this study was to determine potential cytotoxic effects of aloe-emodin on HepaRG cells and to define the underlying mechanism. METHODS: MTT was used to evaluate cell viability. Apoptotic cell death was analyzed via Annexin V-FITC/PI double staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were determined by flow cytometry, while the expression of apoptosis-related proteins was determined by Western blot analysis. RESULTS: Treatment with aloe-emodin significantly reduced cell viability and induced apoptosis in HepaRG cells in a dose- and time dependent manner. It provoked ROS generation and depolarization of MMP in HepaRG cells when compared with controls. Aloe-emodin dose-dependently increased release of mitochondrial cytochrome c, and levels of Fas, p53, p21, Bax/Bcl-2 ratio, as well as activation of caspase-3, caspase-8, caspase-9, and subsequent cleavage of poly(ADP-ribose)polymerase (PARP). It also induced S-phase cell cycle arrest by increasing the expression of p21 and cyclin E proteins while significantly decreasing the expression of cyclin A and CDK2. CONCLUSION: These results suggest that aloe-emodin inhibits cell proliferation and induces apoptosis in HepaRG cells, most probably through a mechanism involving both Fas death pathway and the mitochondrial pathway by generation of ROS. These findings underscore the need for risk assessment of human exposure to aloe-emodin. PMID- 28618414 TI - Failed Downregulation of Circulating MicroRNA-155 as a Marker of Adverse Left Ventricular Remodeling: A New Useful Tool for Cardiologists? PMID- 28618415 TI - Disconnections of Cortico-Subcortical Pathways Related to Cognitive Impairment in Patients with Leukoaraiosis: A Preliminary Diffusion Tensor Imaging Study. AB - BACKGROUND: We aimed to explore the relation between the microstructural integrity of white matter using the technique of diffusion tensor imaging (DTI) and changes of cognition in leukoaraiosis (LA). METHODS: Fifty patients with LA and 50 age- and gender-matched controls were recruited consecutively. The average values of mean diffusivity (MD) and fractional anisotropy (FA) were quantified both within white matter lesions (WMLs) and normal-appearing white matter (NAWM) from the regions of interest (ROIs). RESULTS: We found significantly decreased FA and increased MD in WMLs at the 5 ROIs than that in NAWM and controls (p < 0.05). The values of FA in NAWM were significantly lower at centrum semiovale and posterior periventricular white matter than those of controls (p < 0.05). The values of MD in NAWM were significantly higher at the anterior periventricular white matter and corpus callosum than those of controls (p < 0.05). The values of FA in NAWM located at anterior periventricular white matter correlated inversely with the Z scores of executive function (r = -0.420, p = 0.028). CONCLUSIONS: DTI may provide some important information about the cognitive dysfunction in patients with LA, which may largely attribute to the "disconnection" of cortico subcortical pathways, with the evidence of reduced FA and increased MD. PMID- 28618416 TI - Shock Wave Therapy Promotes Cardiomyocyte Autophagy and Survival during Hypoxia. AB - BACKGROUND: Autophagy plays an important role in cardiovascular disease. Controversy still exists regarding the effect of autophagy on ischemic/hypoxic myocardium. Cardiac shock wave therapy (CSWT) is an effective alternative treatment for refractory ischemic heart disease. Whether CSWT can regulate cardiomyocyte autophagy under hypoxic conditions is not clear. We established a myocardial hypoxia model using the H9c2 cell line and performed shock waves (SWs) treatment to evaluate the effect of SW on autophagy. METHODS: The H9c2 cells were incubated under hypoxic conditions, and SW treatment was then performed at energies of 0.02, 0.05, or 0.10 mJ/mm2. The cell viability and intracellular ATP level were examined. Western blot analysis was used to assess the expression of LC3B, AMPK, mTOR, Beclin-1, Sirt1, and HIF-1alpha. Autophagic vacuoles were visualized by monodansylcadaverine staining. RESULTS: After the 24-hour hypoxic period, cardiomyocyte viability and ATP levels were decreased and autophagy was significantly increased in H9c2 cells. SW treatment with an energy of 0.05 mJ/mm2 significantly increased the cellular viability, ATP level, LC3B-II/I, and number of autophagic vacuoles. In addition, phosphorylated AMPK and Sirt1 were increased and phosphorylated mTOR and HIF-1alpha were decreased after SW treatment. CONCLUSION: SW treatment can potentially promote cardiomyocyte autophagy during hypoxia and protect cardiomyocyte function by regulating the AMPK/mTOR pathway. PMID- 28618417 TI - Cholesterol Enhances Colorectal Cancer Progression via ROS Elevation and MAPK Signaling Pathway Activation. AB - BACKGROUND/AIMS: Elevated serum cholesterol levels were linked to a higher risk of colorectal adenoma and colorectal cancer (CRC), while the effect of cholesterol on CRC metastasis has not been widely studied. METHODS: CRC patients were enrolled to evaluate the association between low-density lipoprotein cholesterol (LDL) and CRC metastases, and LDL receptor (LDLR) level of the CRC tissue was assessed by immunohistochemistry. The effects of LDL on cell proliferation, migration and stemness were assessed in CRC cells in vitro, and the effects of high fat diet (HFD) on tumor growth and intestinal tumorigenicity were investigated in vivo. ROS assays, gene expression array analysis and western blot were used to explore the mechanisms of LDL in CRC progression. RESULTS: The level of LDL was positively correlated with liver metastases, and a higher level of LDL receptor (LDLR) expression was associated with advanced N and M stages of CRC. In vitro, LDL promoted the migration and sphere formation of CRC cells and induced upregulated expression of "stemness" genes including Sox2, Oct4, Nanog and Bmi 1. High-fat diet (HFD) significantly enhanced tumor growth in vivo, and was associated with a shorter intestinal length in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice. Furthermore, LDL significantly elevated reactive oxygen species (ROS) levels and Whole Human Genome Microarray found 87 differentially expressed genes between LDL-treated CRC cells and controls, which were largely clustered in the MAP kinase (MAPK) signaling pathway. CONCLUSIONS: LDL enhances intestinal inflammation and CRC progression via activation of ROS and signaling pathways including the MAPK pathway. Inflammation is strongly associated with cancer initiation, and the role of LDL in intestinal tumorigenicity should be further explored. PMID- 28618418 TI - Prognostic Significance of microRNA-7 and its Roles in the Regulation of Cisplatin Resistance in Lung Adenocarcinoma. AB - BACKGROUND: Previously, microRNA (miR)-7 has been reported to function as a tumor suppressor in human cancers, but the correlations of miR-7 expression with prognosis and cisplatin (CDDP) resistance in lung adenocarcinoma (LA) are unclear. Here, our aim is to determine the prognostic significance of miR-7 and its roles in the regulation of CDDP resistance in LA. METHODS: Quantitative real time PCR (qRT-PCR) assay was performed to determine miR-7 expression in 108 paired of LA tissues and analyze its correlations with clinicopathological factors of patients. The patient survival data were collected retrospectively by Kaplan-Meier analyses, and multivariate analysis was performed using the Cox proportional hazards model to determine the prognostic significance of miR-7 expression. The effects of miR-7 expression on the chemosensitivity of LA cells to CDDP and its possible mechanisms were evaluated by MTT, flow cytometry, Western blot and luciferase assays. RESULTS: It was observed that the relative expression level of miR-7 in LA tissues was significantly lower than that in the adjacent normal tissues and low miR-7 expression level was closely associated with poorer tumor differentiation, advanced pathological T-factor, higher incidence of lymph node metastasis and advanced p-TNM stage. Also, patients with low miR-7 expression showed a shorter overall survival than those with high miR-7 expression, and multivariate analysis indicated that status of miR-7 expression was an independent molecular biomarker for predicting the overall survival (OS) of LA patients. In addition, upregulation of miR-7 increases the sensitivity of LA cells to CDDP via induction of apoptosis by targeting Bcl-2. CONCLUSIONS: Our finding for the first time demonstrates that low miR-7 expression may be an independent poor prognostic factor and targeting miR-7 may be a potential strategy for the reversal of CDDP resistance in LA. PMID- 28618419 TI - Addictive Potential of Internet Applications and Differential Correlates of Problematic Use in Internet Gamers versus Generalized Internet Users in a Representative Sample of Adolescents. AB - AIMS: This paper examines the addictive potential of 8 different Internet applications, distinguishing male and female users. Moreover, differential correlates of problematic use are investigated in Internet gamers (IG) and generalized Internet users (GIU). METHOD: In a representative sample of 5,667 adolescents aged 12-19 years, use of Internet applications, problematic Internet use, psychopathologic symptoms (emotional problems, hyperactivity/inattention, and psychosomatic complaints), personality (conscientiousness and extraversion), psychosocial correlates (perceived stress and self-efficacy), and coping strategies were assessed. The addictive potential of Internet applications was examined in boys and girls using regression analysis. MANOVAs were conducted to examine differential correlates of problematic Internet use between IG and GIU. RESULTS: Chatting and social networking most strongly predicted problematic Internet use in girls, while gaming was the strongest predictor in boys. Problematic IG exhibited multiple psychosocial problems compared to non problematic IG. In problematic Internet users, GIU reported even higher psychosocial burden and displayed dysfunctional coping strategies more frequently than gamers. CONCLUSION: The results extend previous findings on the addictive potential of Internet applications and validate the proposed distinction between specific and generalized problematic Internet use. In addition to Internet gaming disorder, future studies should also focus on other highly addictive Internet applications, that is, chatting or social networking, regarding differential correlates of problematic use. PMID- 28618420 TI - Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications. AB - Gastric cancer (GC) represents a global health concern. Despite advances in prevention, diagnosis, and therapy, GC is still the third leading cause of cancer mortality worldwide, with more than 720,000 estimated deaths in 2012. Overall survival for advanced disease is about 1 year, a dismal prognosis that is partly due to the high levels of biological heterogeneity found in GC. Indeed, GC is a highly heterogeneous disease from morphological and molecular standpoints. The numerous histological and molecular classifications currently available reflect such heterogeneity. Although recent high-throughput studies cluster the molecular data obtained into subgroups with clinical relevance, we still need a practical, prognostic, and predictive classification system, integrating morphological and molecular features, towards the identification of novel therapeutic targets. It is noteworthy that GC heterogeneity encompasses not only interpatient variability (intertumour heterogeneity), but also variations within the same tumour (intratumour heterogeneity). The latter encompasses spatial heterogeneity (in different tumour areas) and temporal heterogeneity (along progression from primary to recurrent and/or metastatic disease). In this review, we analyse the morphological, immunophenotypic, and molecular heterogeneity in GC as the basis for a better understanding of the disease, and discuss the practical implications for diagnostic pathology, prognostic evaluation, and precision therapy. PMID- 28618421 TI - Identification of Tisp40 as an Essential Regulator of Renal Tubulointerstitial Fibrosis via TGF-beta/Smads Pathway. AB - BACKGROUND: Tisp40, a transcription factor of the CREB/CREM family, is involved in cell proliferation, differentiation and other biological functions, but its role in renal tubulointerstitial fibrosis is unknown. METHODS: In our study, we investigated the effects of Tisp40 on extracellular matrix (ECM) accumulation, epithelial-mesenchymal transition (EMT) and the underlying molecular mechanisms in transforming growth factor-beta (TGF-beta)-stimulated TCMK-1 cells by quantitative real-time polymerase chain reaction (qPCR), Western blot analysis and immunofluorescence in vitro, and further explored the role of Tisp40 on renal fibrosis induced by ischemia-reperfusion (I/R) by qPCR, Western blot analysis, hydroxyproline analysis, Masson trichrome staining and immunohistochemistry staining in vivo. RESULTS: The data showed that Tisp40 was upregulated in a model of renal fibrosis induced by I/R injury (IRI). Upon IRI, Tisp40-deficient mice showed attenuated renal fibrosis compared with wild-type mice. Furthermore, the expression of alpha-smooth muscle actin, E-cadherin, fibronectin, and collagen I was suppressed. Tisp40 overexpression aggravated ECM accumulation and EMT in the TGF-beta-stimulated TCMK-1 cell line, whereas the opposite occurred in cells treated with small interfering RNA (siRNA) targeting Tisp40. Importantly, it is changes in the Smad pathway that attenuate renal fibrosis. CONCLUSION: These findings suggest that Tisp40 plays a critical role in the TGF-beta/ Smads pathway involved in this process. Hence, Tisp40 could be a useful therapeutic target in the fight against renal tubulointerstitial fibrosis. PMID- 28618422 TI - Measurement of Aortic Cell Fluid-Phase Pinocytosis in vivo by Flow Cytometry. AB - OBJECTIVE: Fluid-phase pinocytosis is a receptor-independent mechanism of endocytosis that occurs in all mammalian cells and may be a mechanism for the uptake of LDL by macrophages. As there are currently no methods for the measurement of fluid-phase pinocytosis by individual aortic cells in vivo, we sought to identify a suitable method. METHODS: ApoE-/- mice were retro-orbitally injected with AngioSPARK fluorescent nanoparticles specifically designed to not interact with cells. After 24 h, mice were sacrificed, and the aortas were isolated and then digested to analyze aortic cell uptake of AngioSPARK by flow cytometry. RESULTS: CD11b-expressing aortic macrophages from mice injected with AngioSPARK showed high levels of fluid-phase pinocytosis compared to aortic cells not expressing CD11b (4,393.7 vs. 408.3 mean fluorescence intensity [MFI], respectively). CONCLUSION: This new technique allows for the measurement of fluid phase pinocytosis by aortic cells in vivo, making it possible to examine the cell signaling molecules and drugs that affect this process. Published by S. Karger AG, Basel. PMID- 28618423 TI - Long-Term Clinical Outcomes of the Carpentier-Edwards Perimount Pericardial Bioprosthesis in Chinese Patients with Single or Multiple Valve Replacement in Aortic, Mitral, or Tricuspid Positions. AB - OBJECTIVES: To report the safety and efficacy results of a 9- to 15-year follow up investigation among patients who had received Carpentier-Edwards Perimount (CE P) bovine pericardial bioprostheses (Edwards Lifesciences, Irvine, CA, USA) for valve replacement. METHODS: This retrospective study investigated freedom from structural valve deterioration (SVD) as well as survival and reoperation among different age and etiology groups in patients who were implanted with a CE-P bioprosthesis at Guangdong General Hospital between 2001 and 2007. Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression were performed. RESULTS: The mean age of the patients (N = 225) was only 61.2 +/- 11.5 years at valve replacement. More than half of the patients (55.1%) had rheumatic heart disease. The survival rates were 86.46, 81.58, and 74.42% at 5 years, 64.39, 66.19, and 55.85% at 10 years, and 48.37, 57.33, and 46.54% at 15 years for the groups with mitral valve replacement (MVR), aortic valve replacement (AVR), and double valve replacement (DVR), respectively. The median time to freedom from SVD was 12.5, 13.2, and 11.2 years, respectively, for patients with MVR, AVR, and DVR. A higher age at valve replacement was a significant risk factor for SVD in all patients (p < 0.01). CONCLUSIONS: Good long-term clinical results of CE-P valves have been demonstrated in Chinese patients >60 years. PMID- 28618424 TI - Preventive and Therapeutic Proximal Sealing: A 3.5-Year Randomized Controlled Clinical Trial Follow-Up. AB - OBJECTIVE: The aim of this split-mouth, randomized controlled clinical trial was to evaluate the efficacy of proximal sealing for avoiding the development of new caries lesions or arresting incipient caries lesions on the mesial surface of first permanent molars (6m) abutting lesions on the distal surface of second primary molars (05d) in children at high caries risk. METHODS: A total of 61 children 8-10 years old were selected based on the caries status of the proximal sites of 05d and 6m. Children with caries on 05d and caries-free 6m were placed in the preventive sealing group and children with caries on both 05d and 6m in the therapeutic group. The children in each group had one 6m surface pair and in each pair one 6m surface was randomly allocated to receive a preventive or therapeutic sealing. Using a split-mouth design, the other 6m surface in the pair served as control. RESULTS: After 3.5 years, standardized follow-up radiographs were obtained for the 45 children who remained. In the preventive sealing group, 4 out of 30 (13.3%) sealed and 16 out of 30 (53.3%) unsealed sound 6m surfaces had developed new caries lesions (p = 0.004, McNemar test). In the therapeutic sealing group, the progression of the carious lesions on 6m was observed in 3 out of 15 sealed (20.0%) and 8 out of 15 (53.3%) unsealed caries control surfaces (p = 0.06). CONCLUSIONS: Preventive sealing on sound 6m surfaces abutting 05d lesions in children at high caries risk efficaciously prevents the development of caries lesions. Therapeutically sealing active non-cavitated caries lesions reduces the progression. PMID- 28618425 TI - Electronic Cigarettes in Germany: Patterns of Use and Perceived Health Improvement. AB - AIMS: The aim of the study was to characterize e-cigarette users in terms of their consumption patterns, motives, and the perceived health benefits they experience from using e-cigarettes. DESIGN: The study was a cross-sectional online survey in 2015. A total of 3,320 German e-cigarette users were enrolled. A total of 91.5% were former tobacco smokers, 7.5% used both e-cigarettes and tobacco products, 1.0% were never-smokers. RESULTS: No differences were found between ex-smokers and dual users with regard to sociodemographic and smoking history (mean age 40.8 years, 81% men, 45% with a high school degree or above). Both groups had smoked 26.4 tobacco cigarettes a day for 22 years, had unsuccessfully tried to quit smoking using various other nicotine replacement products, and had used e-cigarettes for an average of 2 years. Ex-smokers consumed lower nicotine strength and more liquid per month, experienced more positive health changes, and had made vaping their hobby. Never-smokers were about 5 years younger, used liquid without nicotine and without tobacco flavor, and had no physical dependency. CONCLUSIONS: E-cigarettes were primarily used as an alternative to smoking and a substitute for nicotine. More dual users than ex smokers used e-cigarettes in places where smoking is forbidden. Positive health changes were more pronounced in ex-smokers than dual users. PMID- 28618426 TI - Renoprotective Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Diabetic Patients with Proteinuria. AB - BACKGROUND/AIMS: Limited evidence exists on the choice of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in diabetic patients with nephropathy. We aim to assess the renal effectiveness and safety of these drugs among diabetic nephropathy patients. METHODS: This retrospective cohort study was conducted with diabetic nephropathy patients who initiated ACEI or ARB monotherapy. The primary outcome was a composite of end stage of renal disease and renal transplantation, and the secondary outcome was all-cause mortality. The safety endpoint was hyperkalemia. RESULTS: Three thousand seven hundred and thirty-nine ACEI users and 3,316 ARB users were identified. ARBs seemed to be inferior to ACEIs given their poorer renal outcome (HR 1.31; 95% CI, 1.15-1.50) and higher risk of hyperkalemia (HR 1.17; 95% CI, 1.04-1.32). Among the four ACEIs compared, captopril was an inferior treatment choice given its poorer renal outcomes (HR 1.42; 95% CI, 1.05-1.93) and higher mortality rate (HR 1.25; 95% CI, 1.01-1.55). Irbesartan appeared to be a poorer treatment choice among the three ARBs compared, given its inferior renal protective effect (HR 1.35; 95% CI, 1.03-1.78). CONCLUSIONS: Our findings suggest ACEIs as a relatively more renoprotective and safer treatment as compared to ARBs. Captopril and irbesartan may be inferior to the other ACEIs and ARBs respectively. PMID- 28618427 TI - Matrix Metalloproteases in Arterial Hypertension and their Trend after Antihypertensive Treatment. AB - BACKGROUND/AIMS: Arterial hypertension is characterized by vascular remodelling, atherosclerosis and cardiovascular complications. Matrix metalloproteases (MPPs) are endopeptidases produced by all the cells present in the vascular wall and are involved in the regulation of the extracellular matrix protein turnover. MMPs contribute to blood vessel formation, remodelling, angiogenesis; whereas an altered expression or activity of MMPs or their tissue inhibitors (TIMPs) results correlated with the development and progression of cardiovascular complications. METHODS: We examined the literature data regarding the role of MMPs in human hypertension, including their involvement in vascular remodelling, and the effects of some antihypertensive molecules on these MMP/TIMP profile. RESULTS: The expression and the activity of some MMPs and TIMPs are impaired in human hypertension. An altered MMPs/TIMPs balance plays an important role in the vascular wall rearrangement, in response to hemodynamic changes which may induce myocardial hypertrophy and fibrosis leading to ventricular remodelling. Several studies have examined the effects of some antihypertensive molecules, such as ACE inhibitors, angiotensin receptor blockers, calcium-channel blockers, and aldosterone antagonists, on the MMPs/TIMPs profile by obtaining positive results. CONCLUSION: Considering the data taken into consideration, the authors believe that in clinical practice a strategic antihypertensive therapy directed to the MMPs profile, may be useful to decrease the risk of cardiovascular complications. PMID- 28618428 TI - The Impact of Circulating Mitochondrial DNA on Cardiomyocyte Apoptosis and Myocardial Injury After TLR4 Activation in Experimental Autoimmune Myocarditis. AB - BACKGROUND/AIMS: Mitochondrial DNA (mtDNA), acting as a newly found 'danger associated molecular patterns' (DAMPs), is released into circulation upon tissue injury and performs as a considerable activator of inflammation and immune response. However, the role of circulating mtDNA in experimental autoimmune myocarditis (EAM) as well as Toll like receptor4 (TLR4) mediated cardiac inflammation and injury remains unknown. METHODS: A model of EAM was established in BALB/c mice by immunization with porcine cardiac myosin. Lipopolysaccharide (LPS) was used to stimulate TLR4 activation in EAM mice and H9C2 cells. RESULTS: LPS stimulation significantly aggravated cardiac inflammation and tissue injury in EAM, as demonstrated by increased myocardium inflammatory cell infiltration, and up-regulated inflammatory cytokines and troponin I(TnI) level in serum. Circulating mtDNA level was increased in EAM and TLR4 activation led to a greater elevation, which may be related to Reactive oxygen species (ROS) stress involved mtDNA damage characterized by reduced mtDNA copy number in myocardium tissue. In addition, the expression of Toll like receptor9 (TLR9), a ligand of mtDNA, was significantly up-regulated in the myocardium of EAM and EAM LPS group; meanwhile, TLR9 inhibition by ODN 2088 caused an inhibited apoptosis in LPS treated H9C2 cells. Moreover, in EAM and EAM LPS group, simultaneously giving ODN 2088 treatment significantly ameliorated cardiac inflammation and tissue injury compared with untreated group. CONCLUSION: Increased circulating mtDNA combined with upregulated TLR9 expression may corporately play a role in EAM as well as TLR4 activation mediated cardiac inflammation and injury. PMID- 28618429 TI - Microarray Expression Profile of Circular RNAs in Peripheral Blood Mononuclear Cells from Rheumatoid Arthritis Patients. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs) compose a large class of RNAs that can be used as biomarkers in clinical blood samples. This study aimed to determine the expression of circRNAs in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis (RA) patients to identify novel biomarkers for RA screening. METHODS: We started with a microarray screening of circRNA changes in PBMCs from 5 RA patients and 5 healthy controls. We then confirmed the selected circRNA changes in PBMCs from 30 RA patients and 25 age- and sex-matched controls using the real-time quantitative reverse transcription-polymerase chain reaction (qRT PCR). Spearman correlation test was performed to assess the correlation of circRNAs and clinical variables. Receiver operating characteristic (ROC) curve was calculated to evaluate the diagnostic value. RESULTS: We identified and verified five circRNAs (092516, 003524, 103047, 104871, 101873) that were significantly elevated in PBMCs from RA patients. Among these RA patients, we detected no significant correlation between the five circRNAs and the disease severity, including disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and health assessment questionnaire (HAQ). Yet, ROC curve analysis suggested that circRNA_104871 has significant value of RA diagnosis (AUC=0.833, P<0.001), followed by circRNA_003524 (AUC = 0.683, P = 0.020), circRNA_101873 (AUC = 0.676, P = 0.026), and circRNA_103047 (AUC = 0.671, P = 0.030). CONCLUSIONS: This study suggests that increased expression of circRNAs circRNA_104871, circRNA_003524, circRNA_101873 and circRNA_103047 in PBMC from RA patients may serve as potential biomarkers for RA patient diagnosis. PMID- 28618430 TI - Extreme assay sensitivity in molecular diagnostics further unveils intratumour heterogeneity in metastatic colorectal cancer as well as artifactual low frequency mutations in the KRAS gene. AB - BACKGROUND: Gene mutations in the RAS family rule out metastatic colorectal carcinomas (mCRCs) from anti-EGFR therapies. METHODS: We report a retrospective analysis by Sequenom Massarray and fast COLD-PCR followed by Sanger sequencing on 240 mCRCs. RESULTS: By Sequenom, KRAS and NRAS exons 2-3-4 were mutated in 52.9% (127/240) of tumours, while BRAF codon 600 mutations reached 5% (12/240). Fast COLD-PCR found extra mutations at KRAS exon 2 in 15/166 (9%) of samples, previously diagnosed by Sequenom as wild-type or mutated at RAS (exons 3-4) or BRAF genes. After UDG digestion results were reproduced in 2/12 analysable subclonally mutated samples leading to a frequency of true subclonal KRAS mutations of 1.2% (2.1% of the previous Sequenom wild-type subgroup). In 10 out of 12 samples, the subclonal KRAS mutations disappeared (9 out of 12) or turned to a different sequence variant (1 out of 12). CONCLUSIONS: mCRC can harbour coexisting multiple gene mutations. High sensitivity assays allow the detection of a small subset of patients harbouring true subclonal KRAS mutations. However, DNA changes with mutant allele frequencies <3% detected in formalin-fixed paraffin-embedded samples may be artifactual in a non-negligible fraction of cases. UDG pre-treatment of DNA is mandatory to identify true DNA changes in archival samples and avoid misinterpretation due to artifacts. PMID- 28618432 TI - Accuracy of Digital vs Conventional Implant Impression Approach: A Three Dimensional Comparative In Vitro Analysis. AB - PURPOSE: To assess the three-dimensional (3D) accuracy and clinical acceptability of implant definitive casts fabricated using a digital impression approach and to compare the results with those of a conventional impression method in a partially edentulous condition. MATERIALS AND METHODS: A mandibular reference model was fabricated with implants in the first premolar and molar positions to simulate a patient with bilateral posterior edentulism. Ten implant-level impressions per method were made using either an intraoral scanner with scanning abutments for the digital approach or an open-tray technique and polyvinylsiloxane material for the conventional approach. 3D analysis and comparison of implant location on resultant definitive casts were performed using laser scanner and quality control software. The inter-implant distances and interimplant angulations for each implant pair were measured for the reference model and for each definitive cast (n = 20 per group); these measurements were compared to calculate the magnitude of error in 3D for each definitive cast. The influence of implant angulation on definitive cast accuracy was evaluated for both digital and conventional approaches. Statistical analysis was performed using t test (alpha = .05) for implant position and angulation. Clinical qualitative assessment of accuracy was done via the assessment of the passivity of a master verification stent for each implant pair, and significance was analyzed using chi-square test (alpha = .05). RESULTS: A 3D error of implant positioning was observed for the two impression techniques vs the reference model, with mean +/- standard deviation (SD) error of 116 +/- 94 MUm and 56 +/- 29 MUm for the digital and conventional approaches, respectively (P = .01). In contrast, the inter-implant angulation errors were not significantly different between the two techniques (P = .83). Implant angulation did not have a significant influence on definitive cast accuracy within either technique (P = .64). The verification stent demonstrated acceptable passive fit for 11 out of 20 casts and 18 out of 20 casts for the digital and conventional methods, respectively (P = .01). CONCLUSION: Definitive casts fabricated using the digital impression approach were less accurate than those fabricated from the conventional impression approach for this simulated clinical scenario. A significant number of definitive casts generated by the digital technique did not meet clinically acceptable accuracy for the fabrication of a multiple implant supported restoration. PMID- 28618431 TI - Tumour heterogeneity poses a significant challenge to cancer biomarker research. AB - BACKGROUND: The high degree of genomic diversity in cancer represents a challenge for identifying objective prognostic markers. We aimed to examine the extent of tumour heterogeneity and its effect on the evaluation of a selected prognostic marker using prostate cancer as a model. METHODS: We assessed Gleason Score (GS), DNA ploidy status and phosphatase and tensin homologue (PTEN) expression in radical prostatectomy specimens (RP) from 304 patients followed for a median of 10 years (interquartile range 6-12). GS was assessed for every tumour-containing block and DNA ploidy for a median of four samples for each RP. In a subgroup of 40 patients we assessed DNA ploidy and PTEN status in every tumour-containing block. In 102 patients assigned to active surveillance (AS), GS and DNA ploidy were studied in needle biopsies. RESULTS: Extensive heterogeneity was observed for GS (89% of the patients) and DNA ploidy (40% of the patients) in the cohort, and DNA ploidy (60% of the patients) and PTEN expression (75% of the patients) in the subgroup. DNA ploidy was a significant prognostic marker when heterogeneity was taken into consideration. In the AS cohort we found heterogeneity in GS (24%) and in DNA ploidy (25%) specimens. CONCLUSIONS: Multi-sample analysis should be performed to support clinical treatment decisions. PMID- 28618433 TI - Crestal Sinus Augmentation with Recombinant Human Bone Morphogenetic Protein 2: Clinical and Radiographic Outcomes of 2-Year Pilot Trial. AB - PURPOSE: Recombinant human bone morphogenetic protein 2 (rhBMP-2) together with an absorbable collagen carrier (ACS) was approved for augmentation of the maxillary sinus prior to implant placement. The original registration trial was based on a lateral window approach. Clinical outcomes of crestal sinus augmentation with rhBMP-2 have not been reported so far. MATERIALS AND METHODS: An uncontrolled pilot trial in which seven patients with a residual maxillary height below 5 mm were enrolled to receive crestal sinus augmentation with rhBMP 2/ACS was conducted. Elevation of the sinus mucosa was performed by gel pressure. Primary endpoints were the gain in augmentation height and volume measured by computed tomography after 6 months. Evaluation of bone quality at the time of implant placement was based on histology. Secondary endpoints were the clinical and radiologic evaluation of the implants and patient satisfaction by visual analog scale (VAS) at the 2-year follow-up. RESULTS: Median gain in augmentation height was 7.2 mm (range 0.0 to 17.5 mm). Five patients gained at least 5 mm of bone height. Two patients with a perforation of the sinus mucosa failed to respond to rhBMP-2/ACS and underwent lateral window augmentation. The median gain in augmentation volume of the five patients was 781.3 mm3 (range 426.9 to 1,242.8 mm3). Biopsy specimens showed a cancellous network consisting of primary plexiform bone with little secondary lamellar bone. After 2 years, implants were in function with no signs of inflammation or peri-implant bone loss. Patients were satisfied with the esthetic outcomes and chewing function. CONCLUSION: This pilot clinical trial supports the original concept that rhBMP-2/ACS supports bone formation, also in crestal sinus augmentation, and emphasizes the relevance of the integrity of the sinus mucosa to predict the bone gain. PMID- 28618434 TI - Alveolar Ridge Augmentation Using Dystopic Autogenous Tooth: 2-Year Results of an Open Prospective Study. AB - PURPOSE: To evaluate the use of chemically unchanged tooth material in lateral alveolar ridge augmentation or for the filling of jaw defects. MATERIALS AND METHODS: A total of 20 patients underwent either lateral augmentation of the alveolar process (11 patients) or filling of jaw defects (6 patients) with autogenous unaltered tooth material in a longitudinal 2-year study. In three patients, the jaw defect was so marked that a bone block graft had to be used for augmentation in addition to particulate dental material. In four patients, an autogenous tooth block was exclusively used; in seven, crushed tooth material was exclusively used; and in the remaining six, dystopic teeth that had been extracted were removed, crushed, and reinserted into the defect in particulate form. Fully impacted teeth served as autogenous donor teeth. RESULTS: After a healing time of 3 to 6 months, 28 implants could be placed (10 immediate implants, 18 delayed implants). At 6, 12, and 24 months postrestoration, peri implant bone loss as assessed by x-ray was 0 mm, 0.4 mm, and 0.6 mm, respectively. Peri-implant probing depth was 1 mm after 1 year and 2 mm after 2 years. Bleeding on probing was not seen in any of the implants after 2 years. CONCLUSION: Autogenous tooth material appears to be suitable for the restoration of lateral and intraosseous defects of the alveolar ridge with both complete blocks and in particulate form. However, additional long-term studies with higher case numbers will be required for substantiating these results. PMID- 28618435 TI - Anteromedializing Tibial Tubercle Osteotomy for Patellofemoral Instability: Occupational and Functional Outcomes in U.S. Military Service Members. AB - This article sought to determine rates for return to work, pain relief, and recurrent patellofemoral instability for military service members undergoing tibial tubercle osteotomy (TTO) for persistent lateral patellar subluxation or dislocation. Patient demographic and surgical variables were isolated from the medical records of active duty service members with at least 2 years of postoperative follow-up, and correlated with return to work, pain improvement, recurrent patellofemoral instability, and perioperative complications. There were 51 service members (58 primary TTOs) with an average follow-up of 3.3 (range, 2.0 6.7) years. Service members had an average of 2.8 (1-12) instability events preoperatively. At a minimum of 2 years postoperatively, 41 (80%) military service members returned to full active duty service. Among the 58 TTOs, there was a 46% improvement in the patient-reported visual analog score from 4.1 to 2.2 (p < 0001). The postoperative recurrent instability rates were patellar dislocation (5.1%) and patellar subluxation (15.5%). Concomitant proximal realignment was performed in 48% of cases, which did not affect return to service, postoperative patellar instability events, or pain improvement (p > 0.05). The overall complication rate was 10%. Postoperative tibial fractures occurred in 6.9% of TTOs. At short- to mid-term follow-up, 80% of service members undergoing TTO for patellofemoral instability returned to military duty with significant improvement in pain scores and a moderate perioperative complication and postoperative instability rate. This study is a level IV therapeutic case series. PMID- 28618437 TI - The Importance of Facts and the Role of Academic Publishers in Today's World-A Publisher's View. PMID- 28618436 TI - More on the Limitations of the Activated Partial Thromboplastin Time for Monitoring Argatroban Therapy. PMID- 28618438 TI - Innovations in Dysarthria Management. PMID- 28618439 TI - Dysarthria of Spinal Cord Injury and Its Management. PMID- 28618440 TI - Perspectives on the Psychosocial Management of Oromandibular Dystonia. PMID- 28618441 TI - Toward a Measure of Communicative Participation for Children with Developmental Speech Disorders. PMID- 28618442 TI - Examining Variation in Treatment Outcomes among Speakers with Dysarthria. PMID- 28618443 TI - Longitudinal Changes in Speech Breathing in Older Adults with and without Parkinson's Disease. PMID- 28618444 TI - Incorporating the Principles of Self-Management into Treatment of Dysarthria Associated with Parkinson's Disease. PMID- 28618445 TI - Speech Recognition as a Practice Tool for Dysarthria. PMID- 28618446 TI - Patient-Provider Communication Training for Dysarthria: Lessons Learned from Student Trainees. PMID- 28618447 TI - Patient-Provider Communication for People with Severe Dysarthria: Referral Policies that Lead to Systems Change. PMID- 28618448 TI - Out of sight but not out of mind: Home countries' macroeconomic volatilities and immigrants' mental health. AB - We provide the first empirical evidence that better economic performances by immigrants' countries of origin, as measured by lower consumer price index (CPI) or higher gross domestic product, improve immigrants' mental health. We use an econometrically-robust approach that exploits exogenous changes in macroeconomic conditions across immigrants' home countries over time and controls for immigrants' observable and unobservable characteristics. The CPI effect is statistically significant and sizeable. Furthermore, the CPI effect diminishes as the time since emigrating increases. By contrast, home countries' unemployment rates and exchange rate fluctuations have no impact on immigrants' mental health. PMID- 28618449 TI - Groundwater Quality: Analysis of Its Temporal and Spatial Variability in a Karst Aquifer. AB - This study develops an approach based on hierarchical cluster analysis for investigating the spatial and temporal variation of water quality governing processes. The water quality data used in this study were collected in the karst aquifer of Yucatan, Mexico, the only source of drinking water for a population of nearly two million people. Hierarchical cluster analysis was applied to the quality data of all the sampling periods lumped together. This was motivated by the observation that, if water quality does not vary significantly in time, two samples from the same sampling site will belong to the same cluster. The resulting distribution maps of clusters and box-plots of the major chemical components reveal the spatial and temporal variability of groundwater quality. Principal component analysis was used to verify the results of cluster analysis and to derive the variables that explained most of the variation of the groundwater quality data. Results of this work increase the knowledge about how precipitation and human contamination impact groundwater quality in Yucatan. Spatial variability of groundwater quality in the study area is caused by: a) seawater intrusion and groundwater rich in sulfates at the west and in the coast, b) water rock interactions and the average annual precipitation at the middle and east zones respectively, and c) human contamination present in two localized zones. Changes in the amount and distribution of precipitation cause temporal variation by diluting groundwater in the aquifer. This approach allows to analyze the variation of groundwater quality controlling processes efficiently and simultaneously. PMID- 28618450 TI - SAV1 represses the development of human colorectal cancer by regulating the Akt mTOR pathway in a YAP-dependent manner. AB - OBJECTIVES: SAV1 is a human homologue of Salvador that contains two protein protein interaction modules known as WW domains and acts as a scaffolding protein. SAV1 participates in the development of diverse types of cancer. We aimed to investigate the role of SAV1 in human colorectal cancer. MATERIALS AND METHODS: Human colorectal cancer samples were used to study the expression of SAV1 and YAP. Loss-of-function and gain-of-function strategies were used to study the effects of SAV1 on colorectal cancer cell growth. Rapamycin was used to treat cells and mice to investigate the effect of mTOR signalling. RESULTS: SAV1 represses the development of colorectal cancer by inhibiting the Akt-mTOR signalling in a YAP-dependent manner. The mRNA and protein levels of SAV1 are down-regulated in human colorectal cancer tissues compared with adjacent non cancer tissues. SAV1 knockdown promotes the growth of colorectal cancer cells in vitro and in vivo, whereas SAV1 overexpression leads to opposing results. SAV1 represses the activation of the Akt-mTOR signalling, and rapamycin treatment blunts the effects of SAV1 on in vitro and in vivo growth of colorectal cancer cells. Finally, we show that SAV1 promotes the phosphorylation and inactivation of YAP, which contributes to the effect of SAV1 on Akt-mTOR signalling pathway. CONCLUSIONS: SAV1 is a repressor during the development of human colorectal cancer by inhibiting the YAP-Akt-mTOR signalling pathway. PMID- 28618451 TI - Multicenter comparison of CD34+ myeloid cell count by flow cytometry in low-risk myelodysplastic syndrome. Is it feasible? AB - BACKGROUND: Accuracy of bone marrow (BM) blast count in low-risk myelodysplastic syndromes (MDS) still remains a challenge though it is essential for prognosis. We investigated whether the enumeration of CD34+ myeloid cells by flow cytometry immunophenotyping (FCI) could be used as a consistent parameter for clinical MDS studies. METHODS: Six clinical centers entered the study and information on their FCI protocols was recorded. Sixty-seven flow cytometry listmodes from BM samples of patients with low-risk MDS with <5% BM blasts were exchanged among participants in two different rounds. Interlaboratory variations on the quantification of CD34+ myeloid cells were calculated and strategies to solve differences were evaluated. RESULTS: An overall "very good" agreement on CD34+ cell count among participants (intraclass correlation coefficient = 0.720) was observed, but agreement was "low" in 22 files. No single parameter could fully explain all discrepancies, but 3 technical issues were identified as relevant: the use of the CD34/CD45/CD117/HLA-DR mAb combination, acquisition of >=50,000 events and a low percentage of debris/aggregates. The frequency of discordant results increased with the accumulation of pitfalls (none, 16%; 1 pitfall, 40%; 2 pitfalls, 83%; P = 0.006). Finally, the use of a common gating strategy for analysis increased the percentage of files with "very good" agreement to 100%. CONCLUSIONS: Prevention of specific technical pitfalls is mandatory to reach a good reproducibility of CD34+ cell count among centers. These recommendations set the basis for laboratory standardization and enable the use of CD34+ cell enumeration as additional information in low-risk MDS patients. (c) 2017 International Clinical Cytometry Society. PMID- 28618452 TI - Murine melanoma cells incomplete reprogramming using non-viral vector. AB - OBJECTIVES: The reprogramming of cancer cells into induced pluripotent stem cells or less aggressive cancer cells can provide a modern platform to study cancer related genes and their interactions with cell environment before and after reprogramming. Herein, we aimed to investigate the reprogramming capacity of murine melanoma B16F10 cells. MATERIALS AND METHODS: The B16F10 was transfected using non-viral circular DNA plasmid containing the genes Sox-2, Oct4, Nanog, Lin28 and green fluorescent protein (GFP). These cells were characterized by immunofluorescence, analysis RT-PCR and cell cycle. RESULTS: Our results demonstrated for the first time that reprogramming of B16F10 may be induced using non-viral minicircle DNA containing the four reprogramming factors Oct4, Sox2, Lin 28, Nanog (OSLN) and the GFP reporter gene. The resulting clones are composed by epithelioid cells. These cells display characteristics of cancer stem cells, thus expressing pluripotent stem cell markers and dividing asymmetrically and symmetrically. Reprogrammed B16F10 cells did not form teratomas; however, they showed the suppression of tumourigenic abilities characterized by a reduced tumour size, when compared with parental B16F10 cell line. In contrast to parental cell line that showed accumulation of the cells in S phase of cell cycle, the cells of reprogrammed clones are accumulated in G1 phase. Long-term cultivation of reprogrammed B16F10 cells induces regression of their reprogramming. CONCLUSIONS: Our data imply that in result of reprogramming of B16F10 cells less aggressive Murine Melanoma Reprogrammed Cancer Cells may be obtained. These cells represent an interesting model to study mechanism of cells malignancy as well as provide a novel tool for anti-cancer drugs screening. PMID- 28618453 TI - Data-driven programmatic approach to analysis of basophil activation tests. AB - BACKGROUND: Conventional data analysis of flow cytometry-based basophil activation testing requires repetitive, labor-intensive analysis that hampers efforts to standardize testing for clinical applications. Using an open-source platform, we developed and implemented a programmatic approach to the analysis of the basophil activation test (BAT) by flow cytometry. METHODS: Using the BUHLMANN FlowCAST(r) assay, peripheral blood from peanut allergic patients undergoing oral immunotherapy was incubated with peanut allergens (Arah1, Arah2, Arah6, whole peanut extract) and stained with fluorescent antibodies to CCR3 and CD63 for the development of a data-driven programmatic analysis using Bioconductor and R. Basophil identification using clustering and classification was validated using manually gated comparisons in an experimental subset. Reproducibility of CD63 upregulation set on unstimulated or anti-FcERI stimulated basophils was compared. RESULTS: BAT analysis of 294 experiments was successful in 91.5% using the above approach, with a total of 7,166 individual basophil activation tests from 269 experiments. We estimate this represents a net saving of 1340 min of labor by a skilled operator. Medium-based gating correlated to respective manual gating more closely than anti-FcERI based gating (R = 0.96 vs. R = 0.84, P < 0.001). Only 2% of the basophil activation results were significantly different from manual gating. Quality measures of the experiments and other measures of basophil activation were also provided by the analysis. CONCLUSIONS: We present a novel data-driven flow cytometric platform for the analysis of clinical basophil activation testing, providing a high throughput objective approach to basophil activation analysis. (c) 2017 International Clinical Cytometry Society. PMID- 28618454 TI - The enacted unconscious: a neuropsychological model of unconscious processes. AB - Integrating neuropsychology with psychoanalytic thinking and experience, this paper offers a new view of the unconscious that veers away from more traditional conceptualizations. Rather, it emphasizes the ever-present influence of ongoing unconscious processes on much of our behaviors and mental states. Importantly, this new understanding is based on the functional unity of the brain/mind. PMID- 28618455 TI - Anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration: Comparison of Age-related Macular Degeneration Treatments Trials 5 year outcomes and implication for clinical practice. PMID- 28618457 TI - Continuing Professional Development. PMID- 28618456 TI - Mechanisms underlying acute angle closure. PMID- 28618458 TI - Dreaming: a gateway to the unconscious? AB - Where do our dreams originate from, and what do they tell us? Is there a universal set of symbols that are common to all dreams, regardless of a person's ethnicity or culture? What does dreaming reveal about the unconscious? Why do some dreams remain etched in our memories, whereas others are almost instantly forgotten? Some scientists have adopted the position that dreams are little more than noise in the brain, without any substantive purpose or function. Yet, such a stance seemingly runs counter to the experience of many people who reflect upon and even analyze their dreams, often in search of clues to their daily lives or insights into their deeper selves. Similarly, in virtually all wisdom traditions, dreams are invoked as an important source of revelation or prophecy. Steve Paulson, executive producer and host of To the Best of Our Knowledge, moderated a discussion that included psychologist Deirdre Barrett, dream researcher Kelly Bulkeley, and psychologist and sleep/dream medicine specialist Rubin Naiman; they examined dreams from a variety of perspectives to answer these questions. PMID- 28618459 TI - Colored percolation. AB - A model called "colored percolation" has been introduced with its infinite number of versions in two dimensions. The sites of a regular lattice are randomly occupied with probability p and are then colored by one of the n distinct colors using uniform probability q=1/n. Denoting different colors by the letters of the Roman alphabet, we have studied different versions of the model like AB,ABC,ABCD,ABCDE,... etc. Here, only those lattice bonds having two different colored atoms at the ends are defined as connected. The percolation threshold p_{c}(n) asymptotically converges to its limiting value of p_{c} as 1/n. The model has been generalized by introducing a preference towards a subset of colors when m out of n colors are selected with probability q/m each and the rest of the colors are selected with probability (1-q)/(n-m). It has been observed that p_{c}(q,m) depends nontrivially on q and has a minimum at q_{min}=m/n. In another generalization the fractions of bonds between similarly and dissimilarly colored atoms have been treated as independent parameters. Phase diagrams in this parameter space have been drawn exhibiting percolating and nonpercolating phases. PMID- 28618460 TI - Surprising convergence of the Monte Carlo renormalization group for the three dimensional Ising model. AB - We present a surprisingly simple approach to high-accuracy calculations of the critical properties of the three-dimensional Ising model. The method uses a modified block-spin transformation with a tunable parameter to improve convergence in the Monte Carlo renormalization group. The block-spin parameter must be tuned differently for different exponents to produce optimal convergence. PMID- 28618461 TI - Noise-induced transitions in a double-well excitable oscillator. AB - The model of a double-well oscillator with nonlinear dissipation is studied. The self-sustained oscillation regime and the excitable one are described. The first regime consists of the coexistence of two stable limit cycles in the phase space, which correspond to self-sustained oscillations of the point mass in either potential well. The self-sustained oscillations do not occur in a noise-free system in the excitable regime, but appropriate conditions for coherence resonance in either potential well can be achieved. The stochastic dynamics in both regimes is researched by using numerical simulation and electronic circuit implementation of the considered system. Multiple qualitative changes of the probability density function caused by noise intensity varying are explained by using the phase-space structure of the deterministic system. PMID- 28618462 TI - Quantum-to-classical transition in the work distribution for chaotic systems. AB - The work distribution is a fundamental quantity in nonequilibrium thermodynamics mainly due to its connection with fluctuation theorems. Here, we develop a semiclassical approximation to the work distribution for a quench process in chaotic systems that provides a link between the quantum and classical work distributions. The approach is based on the dephasing representation of the quantum Loschmidt echo and on the quantum ergodic conjecture, which states that the Wigner function of a typical eigenstate of a classically chaotic Hamiltonian is equidistributed on the energy shell. Using numerical simulations, we show that our semiclassical approximation accurately describes the quantum distribution as the temperature is increased. PMID- 28618463 TI - Diffusion-driven self-assembly of rodlike particles: Monte Carlo simulation on a square lattice. AB - The diffusion-driven self-assembly of rodlike particles was studied by means of Monte Carlo simulation. The rods were represented as linear k-mers (i.e., particles occupying k adjacent sites). In the initial state, they were deposited onto a two-dimensional square lattice of size L*L up to the jamming concentration using a random sequential adsorption algorithm. The size of the lattice, L, was varied from 128 to 2048, and periodic boundary conditions were applied along both x and y axes, while the length of the k-mers (determining the aspect ratio) was varied from 2 to 12. The k-mers oriented along the x and y directions (k_{x}-mers and k_{y}-mers, respectively) were deposited equiprobably. In the course of the simulation, the numbers of intraspecific and interspecific contacts between the same sort and between different sorts of k-mers, respectively, were calculated. Both the shift ratio of the actual number of shifts along the longitudinal or transverse axes of the k-mers and the electrical conductivity of the system were also examined. For the initial random configuration, quite different self organization behavior was observed for short and long k-mers. For long k-mers (k>=6), three main stages of diffusion-driven spatial segregation (self-assembly) were identified: the initial stage, reflecting destruction of the jamming state; the intermediate stage, reflecting continuous cluster coarsening and labyrinth pattern formation; and the final stage, reflecting the formation of diagonal stripe domains. Additional examination of two artificially constructed initial configurations showed that this pattern of diagonal stripe domains is an attractor, i.e., any spatial distribution of k-mers tends to transform into diagonal stripes. Nevertheless, the time for relaxation to the steady state essentially increases as the lattice size growth. PMID- 28618464 TI - Experimental investigations and phase-field simulations of triple-phase separation kinetics within liquid ternary Co-Cu-Pb immiscible alloys. AB - The phase-separation kinetics and microstructure evolution mechanisms of liquid ternary Co_{43}Cu_{40}Pb_{17} immiscible alloys are investigated by both the drop tube technique and phase-field method. Two successive phase separations take place during droplet falling and lead to the formation of a three-phase three layer core-shell structure composed of a Co-rich core, a Cu-rich middle layer, and a Pb-rich shell. The Pb-rich shell becomes more and more conspicuous as droplet diameter decreases. Meanwhile, the Co-rich core center gradually moves away from the core-shell center. Theoretical analyses show that a larger temperature gradient inside a smaller alloy droplet induces the accelerated growth of the surface segregation shell during triple-phase separation. The residual Stokes motion and the asymmetric Marangoni convection result in the appearance of an eccentric Co-rich core and the core deviation degree is closely related to the droplet size and initial velocity. A three-dimensional phase-field model of ternary immiscible alloys, which considers the successive phase separations under the combined effects of Marangoni convection and surface segregation, is proposed to explore the formation mechanisms of three-phase core shell structures. The simulated core-shell morphologies are consistent with the experimental observations, which verifies the model's validity in reproducing the core-shell dynamic evolution. Numerical results reveal that the development of three-phase three-layer core-shell structures can be attributed to the primary and then secondary phase separations dominated simultaneously by Marangoni convection and surface segregation. Furthermore, the effects of droplet temperature gradient on the growth kinetics of the surface segregation shell are analyzed in the light of phase-field theory. PMID- 28618465 TI - Two-dimensional localized chaotic patterns in parametrically driven systems. AB - We study two-dimensional localized patterns in weakly dissipative systems that are driven parametrically. As a generic model for many different physical situations we use a generalized nonlinear Schrodinger equation that contains parametric forcing, damping, and spatial coupling. The latter allows for the existence of localized pattern states, where a finite-amplitude uniform state coexists with an inhomogeneous one. In particular, we study numerically two dimensional patterns. Increasing the driving forces, first the localized pattern dynamics is regular, becomes chaotic for stronger driving, and finally extends in area to cover almost the whole system. In parallel, the spatial structure of the localized states becomes more and more irregular, ending up as a full spatiotemporal chaotic structure. PMID- 28618466 TI - Compressive response and helix formation of a semiflexible polymer confined in a nanochannel. AB - Configurations of a single semiflexible polymer is studied when it is pushed into a nanochannel in the case where the polymer persistence length l_{p} is much longer than the channel diameter D:l_{p}/D?1. Using numerical simulations, we show that the polymer undergoes a sequence of recurring structural transitions upon longitudinal compression: random deflection along the channel, a helix going around the channel wall, double-fold random deflection, double-fold helix, etc. We find that the helix transition can be understood as buckling of deflection segments, and the initial helix formation takes place at very small compression with no appreciable weak compression regime of the random deflection polymer. PMID- 28618467 TI - Effect of axial electric field on the Rayleigh instability at small length scales. AB - The effect of an electric field along the longitudinal axis of a nanoscale liquid thread is studied to understand the mechanism of breakup. The Rayleigh instability (commonly known as the Plateau-Rayleigh instability) of a nanosized liquid water thread is investigated by using molecular dynamics simulations. The breakup mechanism of the liquid nanothread is studied by analyzing the temporal evolution of the thread radius. The influence of the temperature of the liquid nanothread and the electric-field strength on the stability and breakup is the major focus of the study. The results show that the axial electric field has a stabilizing effect even at nanoscale. The results from the simulations are in good agreement with the solutions obtained from the dispersion relation developed by Hohman et al. for the liquid thread. The critical electric-field strength necessary to avoid the breakup of the liquid thread is calculated and other effects such as the splaying and whipping instability are also discussed. PMID- 28618468 TI - Optimization of plasma amplifiers. AB - Plasma amplifiers offer a route to side-step limitations on chirped pulse amplification and generate laser pulses at the power frontier. They compress long pulses by transferring energy to a shorter pulse via the Raman or Brillouin instabilities. We present an extensive kinetic numerical study of the three dimensional parameter space for the Raman case. Further particle-in-cell simulations find the optimal seed pulse parameters for experimentally relevant constraints. The high-efficiency self-similar behavior is observed only for seeds shorter than the linear Raman growth time. A test case similar to an upcoming experiment at the Laboratory for Laser Energetics is found to maintain good transverse coherence and high-energy efficiency. Effective compression of a 10kJ, nanosecond-long driver pulse is also demonstrated in a 15-cm-long amplifier. PMID- 28618469 TI - Collisional dissipation rate in shearing flows of granular liquid crystals. AB - We make use of discrete-element-method numerical simulations of inelastic frictionless cylinders in simple shearing at different length-to-diameter ratios and solid volume fractions to analyze the rate of collisional dissipation of the fluctuation kinetic energy. We show that the nonspherical geometry of the particles is responsible, by inducing rotation, for increasing the dissipation rate of the fluctuation kinetic energy with respect to that for frictionless spheres. We also suggest that the partial alignment of the cylinders induced by shearing concurs with the particle inelasticity in generating correlation in the velocity fluctuations and thus affecting the collisional dissipation rate as the solid volume fraction increases. Finally, we propose simple phenomenological modifications to the expression of the collisional dissipation rate of kinetic theory of granular gases to take into account our findings. PMID- 28618470 TI - Fluidization and wall slip of soft glassy materials by controlled surface roughness. AB - We present a comprehensive study of concentrated emulsions flowing in microfluidic channels, one wall of which is patterned with micron-size equally spaced grooves oriented perpendicularly to the flow direction. We find a scaling law describing the roughness-induced fluidization as a function of the density of the grooves, thus fluidization can be predicted and quantitatively regulated. This suggests common scenarios for droplet trapping and release, potentially applicable for other jammed systems as well. Numerical simulations confirm these views and provide a direct link between fluidization and the spatial distribution of plastic rearrangements. PMID- 28618471 TI - Energy-dissipation anomaly in systems of localized waves. AB - We study the statistics of the power P dissipated by waves propagating in a one dimensional disordered medium with damping coefficient nu. An operator imposes the wave amplitude at one end, therefore injecting a power P that balances dissipation. The typical realization of P vanishes for nu->0: Disorder leads to localization and total reflection of the wave energy back to the emitter, with negligible losses. More surprisingly, the mean dissipated power

averaged over the disorder reaches a finite limit for nu->0. We show that this "anomalous dissipation" lim_{nu->0}

is directly given by the integrated density of states of the undamped system. In some cases, this allows us to compute the anomalous dissipation exactly, using properties of the undamped system only. As an example, we compute the anomalous dissipation for weak correlated disorder and for Gaussian white noise of arbitrary strength. Although the focus is on the singular limit nu->0, we finally show that this approach is easily extended to arbitrary nu. PMID- 28618472 TI - Cyclic public goods games: Compensated coexistence among mutual cheaters stabilized by optimized penalty taxation. AB - We study the problem of stabilized coexistence in a three-species public goods game in which each species simultaneously contributes to one public good while freeloading off another public good ("cheating"). The proportional population growth is governed by an appropriately modified replicator equation, depending on the returns from the public goods and the cost. We show that the replicator dynamic has at most one interior unstable fixed point and that the population becomes dominated by a single species. We then show that by applying an externally imposed penalty, or "tax" on success can stabilize the interior fixed point, allowing for the symbiotic coexistence of all species. We show that the interior fixed point is the point of globally minimal total population growth in both the taxed and untaxed cases. We then formulate an optimal taxation problem and show that it admits a quasilinearization, resulting in novel necessary conditions for the optimal control. In particular, the optimal control problem governing the tax rate must solve a certain second-order ordinary differential equation. PMID- 28618473 TI - Approximate probabilistic cellular automata for the dynamics of single-species populations under discrete logisticlike growth with and without weak Allee effects. AB - We investigate one-dimensional elementary probabilistic cellular automata (PCA) whose dynamics in first-order mean-field approximation yields discrete logisticlike growth models for a single-species unstructured population with nonoverlapping generations. Beginning with a general six-parameter model, we find constraints on the transition probabilities of the PCA that guarantee that the ensuing approximations make sense in terms of population dynamics and classify the valid combinations thereof. Several possible models display a negative cubic term that can be interpreted as a weak Allee factor. We also investigate the conditions under which a one-parameter PCA derived from the more general six parameter model can generate valid population growth dynamics. Numerical simulations illustrate the behavior of some of the PCA found. PMID- 28618474 TI - Variance of permutation entropy and the influence of ordinal pattern selection. AB - Permutation entropy (PE) is a widely used measure for complexity, often used to distinguish between complex systems (or complex systems in different states). Here, the PE variance for a stationary time series is derived, and the influence of ordinal pattern selection, specifically whether the ordinal patterns are permitted to overlap or not, is examined. It was found that permitting ordinal patterns to overlap reduces the PE variance, improving the ability of this statistic to distinguish between complex system states for both numeric (fractional Gaussian noise) and experimental (semiconductor laser with optical feedback) systems. However, with overlapping ordinal patterns, the precision to which the PE variance can be estimated becomes diminished, which can manifest as increased incidences of false positive and false negative errors when applying PE to statistical inference problems. PMID- 28618475 TI - Stationary engines in and beyond the linear response regime at the Carnot efficiency. AB - The condition for stationary engines to attain the Carnot efficiency in and beyond the linear response regime is investigated. We find that this condition for finite-size engines is significantly different from that for macroscopic engines in the thermodynamic limit. For the case of finite-size engines, the tight-coupling condition in the linear response regime directly implies the attainability of the Carnot efficiency beyond the linear response regime. As opposed to this, for the case of macroscopic engines in the thermodynamic limit, there are three types of mechanisms to attain the Carnot efficiency. One mechanism allows engines to attain the Carnot efficiency only in the linear response limit, while the other two mechanisms enable engines to attain the Carnot efficiency beyond the linear response regime. These three mechanisms are classified by introducing a tight-coupling window. PMID- 28618476 TI - Bremsstrahlung from the interaction of short laser pulses with dielectrics. AB - An intense, short laser pulse incident on a transparent dielectric can excite electrons from the valence to the conduction band. As these electrons undergo scattering, both from phonons and ions, they emit bremsstrahlung. Here we present a theory of bremsstrahlung emission appropriate for the interaction of laser pulses with dielectrics. Simulations of the interaction, incorporating this theory, illustrate characteristics of the radiation (power, energy, and spectra) for arbitrary ratios of electron collision frequency to radiation frequency. The conversion efficiency of laser pulse energy into bremsstrahlung depends strongly on both the intensity and duration of the pulse, saturating at values of about 10^{-5}. Depending on whether the intensity is above or below the damage threshold of the material, the emission can originate either from the surface or the bulk of the dielectric, respectively. The bremsstrahlung emission may provide a broadband light source for diagnostics. PMID- 28618477 TI - Stability of viscous film flow coating the interior of a vertical tube with a porous wall. AB - The stability of the gravity-driven flow of a viscous film coating the inside of a tube with a porous wall is studied theoretically. We used Darcy's law to describe the motion of fluids in a porous medium. The Beaver-Joseph condition is used to describe the discontinuity of velocity at the porous-fluid interface. We derived an evolution equation for the film thickness using a long-wave approximation. The effect of velocity slip at the porous wall is identified by a parameter beta. We examine the effect of beta on the temporal stability, the absolute-convective instability (AI-CI), and the nonlinear evolution of the interface deformation. The results of the temporal stability reveal that the effect of velocity slip at the porous wall is destabilizing. The parameter beta plays an important role in determining the AI-CI behavior and the nonlinear evolution of the interface. The presence of the porous wall promotes the absolute instability and the formation of the plug in the tube. PMID- 28618478 TI - Exact solution for the force-extension relation of a semiflexible polymer under compression. AB - Exact solutions for the elastic and thermodynamic properties for the wormlike chain model are elaborated in terms of Mathieu functions. The smearing of the classical Euler buckling instability for clamped polymers is analyzed for the force-extension relation. Interestingly, at strong compression forces the thermal fluctuations lead to larger elongations than for the elastic rod. The susceptibility defined as the derivative of the force-extension relation displays a prominent maximum at a force that approaches the critical Euler buckling force as the persistence length is increased. We also evaluate the excess entropy and heat capacity induced by the compression and find that they vary nonmonotonically with the load. These findings are corroborated by pseudo-Brownian simulations. PMID- 28618479 TI - Measurements and simulations of microscopic damage to DNA in water by 30 keV electrons: A general approach applicable to other radiation sources and biological targets. AB - The determination of the microscopic dose-damage relationship for DNA in an aqueous environment is of a fundamental interest for dosimetry and applications in radiation therapy and protection. We combine geant4 particle-scattering simulations in water with calculations concerning the movement of biomolecules to obtain the energy deposit in the biologically relevant nanoscopic volume. We juxtaposition these results to the experimentally determined damage to obtain the dose-damage relationship at a molecular level. This approach is tested for an experimentally challenging system concerning the direct irradiation of plasmid DNA (pUC19) in water with electrons as primary particles. Here a microscopic target model for the plasmid DNA based on the relation of lineal energy and radiation quality is used to calculate the effective target volume. It was found that on average fewer than two ionizations within a 7.5-nm radius around the sugar-phosphate backbone are sufficient to cause a single strand break, with a corresponding median lethal energy deposit being E_{1/2}=6+/-4 eV. The presented method is applicable for ionizing radiation (e.g., gamma rays, x rays, and electrons) and a variety of targets, such as DNA, proteins, or cells. PMID- 28618480 TI - Coherent oscillations of driven rf SQUID metamaterials. AB - Through experiments and numerical simulations we explore the behavior of rf SQUID (radio frequency superconducting quantum interference device) metamaterials, which show extreme tunability and nonlinearity. The emergent electromagnetic properties of this metamaterial are sensitive to the degree of coherent response of the driven interacting SQUIDs. Coherence suffers in the presence of disorder, which is experimentally found to be mainly due to a dc flux gradient. We demonstrate methods to recover the coherence, specifically by varying the coupling between the SQUID meta-atoms and increasing the temperature or the amplitude of the applied rf flux. PMID- 28618481 TI - Crack propagation through disordered materials as a depinning transition: A critical test of the theory. AB - The dynamics of a planar crack propagating within a brittle disordered material is investigated numerically. The fracture front evolution is described as the depinning of an elastic line in a random field of toughness. The relevance of this approach is critically tested through the comparison of the roughness front properties, the statistics of avalanches, and the local crack velocity distribution with experimental results. Our simulations capture the main features of the fracture front evolution as measured experimentally. However, some experimental observations such as the velocity distribution are not consistent with the behavior of an elastic line close to the depinning transition. This discrepancy suggests the presence of another failure mechanism not included in our model of brittle failure. PMID- 28618482 TI - Quantum Monte Carlo study of the spin-1/2 honeycomb Heisenberg model with mixed antiferromagnetic and ferromagnetic interactions in external magnetic fields. AB - The continuous imaginary-time quantum Monte Carlo method with the worm update algorithm is applied to explore the ground-state properties of the spin-1/2 Heisenberg model with antiferromagnetic (AF) coupling J>0 and ferromagnetic (F) coupling J^{'}<0 along zigzag and armchair directions, respectively, on honeycomb lattice. It is found that by enhancing the F coupling J^{'} between zigzag AF chains, the system is smoothly crossover from one-dimensional zigzag spin chains to a two-dimensional magnetic ordered state. In absence of an external field, the system is in a stripe-ordered phase. In the presence of uniform and staggered fields, the uniform and staggered out-of-plane magnetizations appear while the stripe order remains in the xy plane, and a second-order quantum phase transition (QPT) at a critical staggered field is observed. The critical exponents of correlation length for QPTs induced by a staggered field for the cases with J>0, J^{'}<0 and J<0, J^{'}>0 are obtained to be nu=0.70046(1) and 0.7086(3), respectively, indicating that both cases belong to O(3) universality. The corresponding dynamic and susceptibility exponent z and gamma/nu are fitted to be 1.006572(9), 1.9412(2) and 1.004615(8), 1.96121(9) for the two cases, respectively. The scaling behavior in a staggered field is analyzed, and the ground-state phase diagrams in the plane of coupling ratio and staggered field are presented for two cases. The temperature dependence of susceptibility and specific heat of both systems in external magnetic fields is also discussed. A Kosterlitz-Thouless phase transition is found for the present system in a uniform field. PMID- 28618483 TI - Heterogeneous colloidal particles immersed in a liquid crystal. AB - In this paper, we explore anisotropic interactions between particles with heterogeneous boundary conditions inside both nematic and cholesteric liquid crystals. The results show that when particles are put at different distances and angles with respect to each other, new types of defect structures are produced, depending on the relative distances and directions. In a cholesteric liquid crystal, the value of the pitch affects the defect structures and induced forces. Moreover, it was observed that it is energetically favorable for the particles to remain in a plane parallel to the far-field director in a nematic liquid crystal, while for particles immersed in a cholesteric there are multiple energy minima not all located in the same plane. PMID- 28618484 TI - Nondivergent and negative susceptibilities around critical points of a long-range Hamiltonian system with two order parameters. AB - The linear response is investigated in a long-range Hamiltonian system from the viewpoint of dynamics, which is described by the Vlasov equation in the large population limit. Because of the existence of the Casimir invariants of the Vlasov dynamics, an external field does not drive the system to the forced thermal equilibrium in general, and the linear response is suppressed. With the aid of a linear response theory based on the Vlasov dynamics, we compute the suppressed linear response in a system having two order parameters, which introduce the conjugate two external fields and the susceptibility matrix of size 2 accordingly. Moreover, the two order parameters bring three phases and there are three types of second-order phase transitions between them. For each type of phase transition, all the critical exponents for elements of the susceptibility matrix are computed. The critical exponents reveal that some elements of the matrices do not diverge even at critical points, while the mean-field theory predicts divergences. The linear response theory also suggests the appearance of negative off-diagonal elements; in other words, an applied external field decreases the value of an order parameter. These theoretical predictions are confirmed by direct numerical simulations of the Vlasov equation. PMID- 28618485 TI - Numerical solution of the time-dependent Schrodinger equation for H_{2}^{+} ion with application to high-harmonic generation and above-threshold ionization. AB - Time evolution of the bound state of a molecular hydrogen cation in an intense, linearly polarized laser field is investigated by solving the full three dimensional time-dependent Schrodinger equation. Our method is based on the Born Oppenheimer and dipole approximations, and the wave function is expanded in finite series using B-spline functions and spherical harmonics in prolate spheroidal coordinates. After solving the stationary Schrodinger equation, the initial state is propagated under the influence of the laser field employing the Crank-Nicolson propagator. Using this method we calculate and present high harmonic photon spectra and above-threshold ionization angle-resolved electron spectra. PMID- 28618486 TI - Role of particle size in the kinematic properties of silo flow. AB - We experimentally analyze the effect that particle size has on the mass flow rate of a quasi two-dimensional silo discharged by gravity. In a previous work, Janda et al. [Phys. Rev. Lett. 108, 248001 (2012)PRLTAO0031 900710.1103/PhysRevLett.108.248001] introduced a new expression for the mass flow rate based on a detailed experimental analysis of the flow for 1-mm diameter beads. Here, we aim to extend these results by using particles of larger sizes and a variable that was not explicitly included in the proposed expression. We show that the velocity and density profiles at the outlet are self-similar and scale with the outlet size with the same functionalities as in the case of 1-mm particles. Nevertheless, some discrepancies are evidenced in the values of the fitting parameters. In particular, we observe that larger particles lead to higher velocities and lower packing fractions at the orifice. Intriguingly, both magnitudes seem to compensate giving rise to very similar flow rates. In order to shed light on the origin of this behavior we have computed fields of a solid fraction, velocity, and a kinetic-stress like variable in the region above the orifice. PMID- 28618487 TI - Measuring geometric frustration in twisted inextensible filament bundles. AB - We investigate with experiments and mapping the structure of a hexagonally ordered filament bundle that is held near its ends and progressively twisted around its central axis. The filaments are free to slide relative to each other and are further held under tension-free boundary conditions. Measuring the bundle packing with micro x-ray imaging, we find that the filaments develop the helical rotation Omega imposed at the boundaries. We then show that the observed structure is consistent with a mapping of the filament positions to disks packed on a dual non-Euclidean surface with a Gaussian curvature which increases with twist. We further demonstrate that the mean interfilament distance is minimal on the surface, which can be approximated by a hemisphere with an effective curvature K_{eff}=3Omega^{2}. Examining the packing on the dual surface, we analyze the geometric frustration of packing in twisted bundles and find the core to remain relatively hexagonally ordered with interfilament strains growing from the bundle center, driving the formation of defects at the exterior of highly twisted bundles. PMID- 28618488 TI - Torque and buckling in stretched intertwined double-helix DNAs. AB - We present a statistical-mechanical model for the behavior of intertwined DNAs, with a focus on their torque and extension as a function of their catenation (linking) number and applied force, as studied in magnetic tweezers experiments. Our model produces results in good agreement with available experimental data and predicts a catenation-dependent effective twist modulus distinct from what is observed for twisted individual double-helix DNAs. We find that buckling occurs near the point where experiments have observed a kink in the extension versus linking number, and that the subsequent "supercoiled braid" state corresponds to a proliferation of multiple small plectoneme structures. We predict a discontinuity in extension at the buckling transition corresponding to nucleation of the first plectoneme domain. We also find that buckling occurs for lower linking number at lower salt; the opposite trend is observed for supercoiled single DNAs. PMID- 28618489 TI - Extortion provides alternative routes to the evolution of cooperation in structured populations. AB - In this paper, we study the evolution of cooperation in structured populations (individuals are located on either a regular lattice or a scale-free network) in the context of repeated games by involving three types of strategies, namely, unconditional cooperation, unconditional defection, and extortion. The strategy updating of the players is ruled by the replicator-like dynamics. We find that extortion strategies can act as catalysts to promote the emergence of cooperation in structured populations via different mechanisms. Specifically, on regular lattice, extortioners behave as both a shield, which can enwrap cooperators inside and keep them away from defectors, and a spear, which can defeat those surrounding defectors with the help of the neighboring cooperators. Particularly, the enhancement of cooperation displays a resonance-like behavior, suggesting the existence of optimal extortion strength mostly favoring the evolution of cooperation, which is in good agreement with the predictions from the generalized mean-field approximation theory. On scale-free network, the hubs, who are likely occupied by extortioners or defectors at the very beginning, are then prone to be conquered by cooperators on small-degree nodes as time elapses, thus establishing a bottom-up mechanism for the emergence and maintenance of cooperation. PMID- 28618490 TI - Multiple random walks on complex networks: A harmonic law predicts search time. AB - We investigate multiple random walks traversing independently and concurrently on complex networks and introduce the concept of mean first parallel passage time (MFPPT) to quantify their search efficiency. The mean first parallel passage time represents the expected time required to find a given target by one or some of the multiple walkers. We develop a general theory that allows us to calculate the MFPPT analytically. Interestingly, we find that the global MFPPT follows a harmonic law with respect to the global mean first passage times of the associated walkers. Remarkably, when the properties of multiple walkers are identical, the global MFPPT decays in a power law manner with an exponent of unity, irrespective of network structure. These findings are confirmed by numerical and theoretical results on various synthetic and real networks. The harmonic law reveals a universal principle governing multiple random walks on networks that uncovers the contribution and role of the combined walkers in a target search. Our paradigm is also applicable to a broad range of random search processes. PMID- 28618491 TI - Minimum spanning tree filtering of correlations for varying time scales and size of fluctuations. AB - Based on a recently proposed q-dependent detrended cross-correlation coefficient, rho_{q} [J. Kwapien, P. Oswiecimka, and S. Drozdz, Phys. Rev. E 92, 052815 (2015)PLEEE81539-375510.1103/PhysRevE.92.052815], we generalize the concept of the minimum spanning tree (MST) by introducing a family of q-dependent minimum spanning trees (qMSTs) that are selective to cross-correlations between different fluctuation amplitudes and different time scales of multivariate data. They inherit this ability directly from the coefficients rho_{q}, which are processed here to construct a distance matrix being the input to the MST-constructing Kruskal's algorithm. The conventional MST with detrending corresponds in this context to q=2. In order to illustrate their performance, we apply the qMSTs to sample empirical data from the American stock market and discuss the results. We show that the qMST graphs can complement rho_{q} in disentangling "hidden" correlations that cannot be observed in the MST graphs based on rho_{DCCA}, and therefore, they can be useful in many areas where the multivariate cross correlations are of interest. As an example, we apply this method to empirical data from the stock market and show that by constructing the qMSTs for a spectrum of q values we obtain more information about the correlation structure of the data than by using q=2 only. More specifically, we show that two sets of signals that differ from each other statistically can give comparable trees for q=2, while only by using the trees for q?2 do we become able to distinguish between these sets. We also show that a family of qMSTs for a range of q expresses the diversity of correlations in a manner resembling the multifractal analysis, where one computes a spectrum of the generalized fractal dimensions, the generalized Hurst exponents, or the multifractal singularity spectra: the more diverse the correlations are, the more variable the tree topology is for different q's. As regards the correlation structure of the stock market, our analysis exhibits that the stocks belonging to the same or similar industrial sectors are correlated via the fluctuations of moderate amplitudes, while the largest fluctuations often happen to synchronize in those stocks that do not necessarily belong to the same industry. PMID- 28618492 TI - Spontaneous exchange of leader-laggard relationship in mutually coupled synchronized semiconductor lasers. AB - We investigate the instantaneous behavior of synchronized temporal wave forms in two mutually coupled semiconductor lasers numerically and experimentally. The temporal wave forms of two lasers are synchronized with a propagation delay time, with one laser oscillating in advance of the other, known as the leader-laggard relationship. The leader-laggard relationship can be determined by measuring the cross-correlation between the two temporal wave forms with the propagation delay time. The leader can be identified when the optical carrier frequency of the leader laser is higher than that of the other laser. However, spontaneous exchange between the leader and laggard lasers can be observed in low-frequency fluctuations by short-term cross-correlation measurements, even for a fixed initial optical frequency detuning. The spontaneous exchange of the leader laggard relationship originates from alternation of partial optical frequency locking between the two lasers. This observation is analyzed using a phase space trajectory on steady-state solutions for mutually coupled lasers with optical frequency detuning. PMID- 28618493 TI - Simple wealth distribution model causing inequality-induced crisis without external shocks. AB - We address the issue of the dynamics of wealth accumulation and economic crisis triggered by extreme inequality, attempting to stick to most possibly intrinsic assumptions. Our general framework is that of pure or modified multiplicative processes, basically geometric Brownian motions. In contrast with the usual approach of injecting into such stochastic agent models either specific, idiosyncratic internal nonlinear interaction patterns or macroscopic disruptive features, we propose a dynamic inequality model where the attainment of a sizable fraction of the total wealth by very few agents induces a crisis regime with strong intermittency, the explicit coupling between the richest and the rest being a mere normalization mechanism, hence with minimal extrinsic assumptions. The model thus harnesses the recognized lack of ergodicity of geometric Brownian motions. It also provides a statistical intuition to the consequences of Thomas Piketty's recent "r>g" (return rate > growth rate) paradigmatic analysis of very long-term wealth trends. We suggest that the "water-divide" of wealth flow may define effective classes, making an objective entry point to calibrate the model. Consistently, we check that a tax mechanism associated to a few percent relative bias on elementary daily transactions is able to slow or stop the build-up of large wealth. When extreme fluctuations are tamed down to a stationary regime with sizable but steadier inequalities, it should still offer opportunities to study the dynamics of crisis and the inner effective classes induced through external or internal factors. PMID- 28618494 TI - Radiation dynamics of a cavitation bubble in a liquid-filled cavity surrounded by an elastic solid. AB - A specific cavitation phenomenon occurs inside the stems of trees. The internal pressure in tree conduits can drop down to significant negative values, which causes the nucleation of bubbles. The bubbles exhibit high-frequency oscillations just after their nucleation. In the present study, this phenomenon is modeled by taking into account acoustic waves produced by bubble oscillations. A dispersion equation is derived, which is then used to calculate the resonance frequency and the attenuation coefficient of the bubble oscillations. Radiation damping is found to be predominant in comparison with viscous damping, except for very small bubbles. A typical number of oscillation cycles before the complete damping of the oscillation is found to be of the order of 10, as observed for cavitation bubbles in biomimetic synthetic trees. PMID- 28618495 TI - Robustness of synthetic oscillators in growing and dividing cells. AB - Synthetic biology sets out to implement new functions in cells, and to develop a deeper understanding of biological design principles. Elowitz and Leibler [Nature (London) 403, 335 (2000)NATUAS0028-083610.1038/35002125] showed that by rational design of the reaction network, and using existing biological components, they could create a network that exhibits periodic gene expression, dubbed the repressilator. More recently, Stricker et al. [Nature (London) 456, 516 (2008)NATUAS0028-083610.1038/nature07389] presented another synthetic oscillator, called the dual-feedback oscillator, which is more stable. Detailed studies have been carried out to determine how the stability of these oscillators is affected by the intrinsic noise of the interactions between the components and the stochastic expression of their genes. However, as all biological oscillators reside in growing and dividing cells, an important question is how these oscillators are perturbed by the cell cycle. In previous work we showed that the periodic doubling of the gene copy numbers due to DNA replication can couple not only natural, circadian oscillators to the cell cycle [Paijmans et al., Proc. Natl. Acad. Sci. (USA) 113, 4063 (2016)PNASA60027-842410.1073/pnas.1507291113], but also these synthetic oscillators. Here we expand this study. We find that the strength of the locking between oscillators depends not only on the positions of the genes on the chromosome, but also on the noise in the timing of gene replication: noise tends to weaken the coupling. Yet, even in the limit of high levels of noise in the replication times of the genes, both synthetic oscillators show clear signatures of locking to the cell cycle. This work enhances our understanding of the design of robust biological oscillators inside growing and diving cells. PMID- 28618496 TI - Plasma high-order-harmonic generation from ultraintense laser pulses. AB - Plasma high-order-harmonic generation from an extremely intense short-pulse laser is explored by including the effects of ion motion, electron-ion collisions, and radiation reaction force in the plasma dynamics. The laser radiation pressure induces plasma ion motion through the hole-boring effect, resulting in frequency shifting and widening of the harmonic spectra. The classical radiation reaction force slightly mitigates the frequency broadening caused by the ion motion. Based on the results and physical considerations, parameter maps highlighting the optimum regions for generating a single intense attosecond pulse and coherent XUV radiation are presented. PMID- 28618497 TI - Synchronization of fluctuating delay-coupled chaotic networks. AB - We study the synchronization of chaotic units connected through time-delayed fluctuating interactions. Focusing on small-world networks of Bernoulli and Logistic units with a fixed chiral backbone, we compare the synchronization properties of static and fluctuating networks in the regime of large delays. We find that random network switching may enhance the stability of synchronized states. Synchronization appears to be maximally stable when fluctuations are much faster than the time-delay, whereas it disappears for very slow fluctuations. For fluctuation time scales of the order of the time-delay, we report a resynchronizing effect in finite-size networks. Moreover, we observe characteristic oscillations in all regimes, with a periodicity related to the time-delay, as the system approaches or drifts away from the synchronized state. PMID- 28618498 TI - Magnetohydrodynamics of laser-produced high-energy-density plasma in a strong external magnetic field. AB - Recent progress in the generation in the laboratory of a strong (>100-T) magnetic field enables us to investigate experimentally unexplored magnetohydrodynamics phenomena of a high-energy-density plasma, which an external magnetic field of 200-300 T notably affects due to anisotropic thermal conduction, even when the magnetic field pressure is much lower than the plasma pressure. The external magnetic field reduces electron thermal conduction across the external magnetic field lines because the Larmor radius of the thermal electrons in the external magnetic field is much shorter than the mean free path of the thermal electrons. The velocity of a thin polystyrene foil driven by intense laser beams in the strong external magnetic field is faster than that in the absence of the external magnetic field. Growth of sinusoidal corrugation imposed initially on the laser driven polystyrene surface is enhanced by the external magnetic field because the plasma pressure distribution becomes nonuniform due to the external magnetic field structure modulated by the perturbed plasma flow ablated from the corrugated surface. PMID- 28618499 TI - Social contagions on time-varying community networks. AB - Time-varying community structures exist widely in real-world networks. However, previous studies on the dynamics of spreading seldom took this characteristic into account, especially those on social contagions. To study the effects of time varying community structures on social contagions, we propose a non-Markovian social contagion model on time-varying community networks based on the activity driven network model. A mean-field theory is developed to analyze the proposed model. Through theoretical analyses and numerical simulations, two hierarchical features of the behavior adoption processes are found. That is, when community strength is relatively large, the behavior can easily spread in one of the communities, while in the other community the spreading only occurs at higher behavioral information transmission rates. Meanwhile, in spatial-temporal evolution processes, hierarchical orders are observed for the behavior adoption. Moreover, under different information transmission rates, three distinctive patterns are demonstrated in the change of the whole network's final adoption proportion along with the growing community strength. Within a suitable range of transmission rate, an optimal community strength can be found that can maximize the final adoption proportion. Finally, compared with the average activity potential, the promoting or inhibiting of social contagions is much more influenced by the number of edges generated by active nodes. PMID- 28618500 TI - Recovery of mechanical pressure in a gas of underdamped active dumbbells with Brownian noise. AB - In contrast with a gas at thermodynamic equilibrium, the mean force exerted on a wall by a gas of active particles usually depends on the confining potential, thereby preventing a proper definition of mechanical pressure. In this paper, we investigate numerically the properties of a gas of underdamped self-propelled dumbbells subject to Brownian noise of increasing intensity, in order to understand how the notion of pressure is recovered as noise progressively masks the effects of self-propulsion and the system approaches thermodynamic equilibrium. The simulations performed for a mobile asymmetric wall separating two chambers containing an equal number of active dumbbells highlight some subtle and unexpected properties of the system. First, Brownian noise of moderate intensity is sufficient to let mean forces equilibrate for small values of the damping coefficient, while much stronger noise is required for larger values of the damping coefficient. Moreover, the displacement of the mean position of the wall upon increase of the intensity of the noise is not necessarily monotonous and may instead display changes of direction. Both facts actually reflect the existence of several mechanisms leading to the rupture of force balance, which tend to displace the mean position of the wall towards different directions and display different robustness against an increase of the intensity of Brownian noise. This work therefore provides a clear illustration of the fact that driving an autonomous system towards (or away from) thermodynamic equilibrium may not be a straightforward process, but may instead proceed through the variations of the relative weights of several conflicting mechanisms. PMID- 28618501 TI - Asymptotic prime partitions of integers. AB - In this paper, we discuss P(n), the number of ways a given integer n may be written as a sum of primes. In particular, an asymptotic form P_{as}(n) valid for n->infinity is obtained analytically using standard techniques of quantum statistical mechanics. First, the bosonic partition function of primes, or the generating function of unrestricted prime partitions in number theory, is constructed. Next, the density of states is obtained using the saddle-point method for Laplace inversion of the partition function in the limit of large n. This gives directly the asymptotic number of prime partitions P_{as}(n). The leading term in the asymptotic expression grows exponentially as sqrt[n/ln(n)] and agrees with previous estimates. We calculate the next-to-leading-order term in the exponent, proportional to ln[ln(n)]/ln(n), and we show that an earlier result in the literature for its coefficient is incorrect. Furthermore, we also calculate the next higher-order correction, proportional to 1/ln(n) and given in Eq. (43), which so far has not been available in the literature. Finally, we compare our analytical results with the exact numerical values of P(n) up to n~8*10^{6}. For the highest values, the remaining error between the exact P(n) and our P_{as}(n) is only about half of that obtained with the leading-order approximation. But we also show that, unlike for other types of partitions, the asymptotic limit for the prime partitions is still quite far from being reached even for n~10^{7}. PMID- 28618502 TI - Kinetic percolation. AB - We demonstrate that kinetic aggregation forms superaggregates that have structures identical to static percolation aggregates, and these superaggregates appear as a separate phase in the size distribution. Diffusion limited cluster cluster aggregation (DLCA) simulations were performed to yield fractal aggregates with a fractal dimension of 1.8 and superaggregates with a fractal dimension of D=2.5 composed of these DLCA supermonomers. When properly normalized to account for the DLCA fractal nature of their supermonomers, these superaggregates have the exact same monomer packing fraction, scaling law prefactor, and scaling law exponent (the fractal dimension) as percolation aggregates; these are necessary and sufficient conditions for same structure. The size distribution remains monomodal until these superaggregates form to alter the distribution. Thus the static percolation and the kinetic descriptions of gelation are now unified. PMID- 28618503 TI - Anomalous diffusion on a fractal mesh. AB - We present exact analytical results for properties of anomalous diffusion on a fractal mesh. The fractal mesh structure is a direct product of two fractal sets, one belonging to a main branch of backbones, the other to the side branches of fingers. Both fractal sets are constructed on the entire (infinite) y and x axes. We suggest a special algorithm in order to construct such sets out of standard Cantor sets embedded in the unit interval. The transport properties of the fractal mesh are studied, in particular, subdiffusion along the backbones is obtained with the dispersion relation ?t^{beta}, where the transport exponent beta<1 is determined by the fractal dimensions of both backbone and fingers. Superdiffusion with beta>1 has been observed as well when the environment is controlled by means of a memory kernel. PMID- 28618504 TI - Wave propagation reversal for wavy vortices in wide-gap counter-rotating cylindrical Couette flow. AB - We present a numerical study of wavy supercritical cylindrical Couette flow between counter-rotating cylinders in which the wavy pattern propagates either prograde with the inner cylinder or retrograde opposite the rotation of the inner cylinder. The wave propagation reversals from prograde to retrograde and vice versa occur at distinct values of the inner cylinder Reynolds number when the associated frequency of the wavy instability vanishes. The reversal occurs for both twofold and threefold symmetric wavy vortices. Moreover, the wave propagation reversal only occurs for sufficiently strong counter-rotation. The flow pattern reversal appears to be intrinsic in the system as either periodic boundary conditions or fixed end wall boundary conditions for different system sizes always result in the wave propagation reversal. We present a detailed bifurcation sequence and parameter space diagram with respect to retrograde behavior of wavy flows. The retrograde propagation of the instability occurs when the inner Reynolds number is about two times the outer Reynolds number. The mechanism for the retrograde propagation is associated with the inviscidly unstable region near the inner cylinder and the direction of the global average azimuthal velocity. Flow dynamics, spatio-temporal behavior, global mean angular velocity, and torque of the flow with the wavy pattern are explored. PMID- 28618505 TI - Forces and torques on rigid inclusions in an elastic environment: Resulting matrix-mediated interactions, displacements, and rotations. AB - Embedding rigid inclusions into elastic matrix materials is a procedure of high practical relevance, for instance, for the fabrication of elastic composite materials. We theoretically analyze the following situation. Rigid spherical inclusions are enclosed by a homogeneous elastic medium under stick boundary conditions. Forces and torques are directly imposed from outside onto the inclusions or are externally induced between them. The inclusions respond to these forces and torques by translations and rotations against the surrounding elastic matrix. This leads to elastic matrix deformations, and in turn results in mutual long-ranged matrix-mediated interactions between the inclusions. Adapting a well-known approach from low-Reynolds-number hydrodynamics, we explicitly calculate the displacements and rotations of the inclusions from the externally imposed or induced forces and torques. Analytical expressions are presented as a function of the inclusion configuration in terms of displaceability and rotateability matrices. The role of the elastic environment is implicitly included in these relations. That is, the resulting expressions allow a calculation of the induced displacements and rotations directly from the inclusion configuration, without having to explicitly determine the deformations of the elastic environment. In contrast to the hydrodynamic case, compressibility of the surrounding medium is readily taken into account. We present the complete derivation based on the underlying equations of linear elasticity theory. In the future, the method will, for example, be helpful to characterize the behavior of externally tunable elastic composite materials, to accelerate numerical approaches, as well as to improve the quantitative interpretation of microrheological results. PMID- 28618506 TI - Phase diagram and aggregation dynamics of a monolayer of paramagnetic colloids. AB - We have developed a tunable colloidal system and a corresponding theoretical model for studying the phase behavior of particles assembling under the influence of long-range magnetic interactions. A monolayer of paramagnetic particles is subjected to a spatially uniform magnetic field with a static perpendicular component and a rapidly rotating in-plane component. The sign and strength of the interactions vary with the tilt angle theta of the rotating magnetic field. For a purely in-plane field, theta=90^{?}, interactions are attractive and the experimental results agree well with both equilibrium and out-of-equilibrium predictions based on a two-body interaction model. For tilt angles 50^{?}?theta?55^{?}, the two-body interaction gives a short-range attractive and long-range repulsive interaction, which predicts the formation of equilibrium microphases. In experiments, however, a different type of assembly is observed. Inclusion of three-body (and higher-order) terms in the model does not resolve the discrepancy. We further characterize the anomalous regime by measuring the time-dependent cluster size distribution. PMID- 28618507 TI - Contractile actuation and dynamical gel assembly of paramagnetic filaments in fast precessing fields. AB - Flexible superparamagnetic filaments are studied under the influence of fast precessing magnetic fields using simulations and a continuum approximation analysis. We find that individual filaments can be made to exert controllable tensile forces along the precession axis. These forces are exploited for microscopic actuation. In bulk, the filaments can be rapidly assembled into different configurations whose material properties depend on the field parameters. The precession frequency affects filament aggregation and conformation by changing the net torques on the filament ends. Using a time dependent precession angle allows considerable freedom in choosing properties for filament aggregates. As an example, we design a field that twists chains together to dynamically assemble a self-healing gel. PMID- 28618508 TI - Similarity law for Widom lines and coexistence lines. AB - The coexistence line of a fluid separates liquid and gaseous states at subcritical pressures, ending at the critical point. Only recently, it became clear that the supercritical state space can likewise be divided into regions with liquidlike and gaslike properties, separated by an extension to the coexistence line. This crossover line is commonly referred to as the Widom line, and is characterized by large changes in density or enthalpy, manifesting as maxima in the thermodynamic response functions. Thus, a reliable representation of the coexistence line and the Widom line is important for sub- and supercritical applications that depend on an accurate prediction of fluid properties. While it is known for subcritical pressures that nondimensionalization with the respective species critical pressures p_{cr} and temperatures T_{cr} only collapses coexistence line data for simple fluids, this approach is used for Widom lines of all fluids. However, we show here that the Widom line does not adhere to the corresponding states principle, but instead to the extended corresponding states principle. We resolve this problem in two steps. First, we propose a Widom line functional based on the Clapeyron equation and derive an analytical, species specific expression for the only parameter from the Soave-Redlich-Kwong equation of state. This parameter is a function of the acentric factor omega and compares well with experimental data. Second, we introduce the scaled reduced pressure p_{r}^{*} to replace the previously used reduced pressure p_{r}=p/p_{cr}. We show that p_{r}^{*} is a function of the acentric factor only and can thus be readily determined from fluid property tables. It collapses both subcritical coexistence line and supercritical Widom line data over a wide range of species with acentric factors ranging from -0.38 (helium) to 0.34 (water), including alkanes up to n-hexane. By using p_{r}^{*}, the extended corresponding states principle can be applied within corresponding states principle formalism. Furthermore, p_{r}^{*} provides a theoretical foundation to compare Widom lines of different fluids. PMID- 28618509 TI - Spreading law on a completely wettable spherical substrate: The energy balance approach. AB - The spreading of a cap-shaped spherical droplet on a completely wettable spherical substrate is studied. The nonequilibrium thermodynamic formulation is used to derive the thermodynamic driving force of spreading including the line tension effect. Then the energy balance approach is adopted to derive the evolution equation of the spreading droplet. The time evolution of the contact angle theta of a droplet obeys a power law theta~t^{-alpha} with the exponent alpha, which is different from that derived from Tanner's law on a flat substrate. Furthermore, the line tension must be positive to promote complete wetting on a spherical substrate, while it must be negative on a flat substrate. PMID- 28618510 TI - Lateral diffusion induced by active proteins in a biomembrane. AB - We discuss the hydrodynamic collective effects due to active protein molecules that are immersed in lipid bilayer membranes and modeled as stochastic force dipoles. We specifically take into account the presence of the bulk solvent that surrounds the two-dimensional fluid membrane. Two membrane geometries are considered: the free membrane case and the confined membrane case. Using the generalized membrane mobility tensors, we estimate the active diffusion coefficient and the drift velocity as a function of the size of a diffusing object. The hydrodynamic screening lengths distinguish the two asymptotic regimes of these quantities. Furthermore, the competition between the thermal and nonthermal contributions in the total diffusion coefficient is characterized by two length scales corresponding to the two membrane geometries. These characteristic lengths describe the crossover between different asymptotic behaviors when they are larger than the hydrodynamic screening lengths. PMID- 28618511 TI - Evaluating the morphological completeness of a training image. AB - Understanding the three-dimensional (3D) stochastic structure of a porous medium is helpful for studying its physical properties. A 3D stochastic structure can be reconstructed from a two-dimensional (2D) training image (TI) using mathematical modeling. In order to predict what specific morphology belonging to a TI can be reconstructed at the 3D orthogonal slices by the method of 3D reconstruction, this paper begins by introducing the concept of orthogonal chords. After analyzing the relationship among TI morphology, orthogonal chords, and the 3D morphology of orthogonal slices, a theory for evaluating the morphological completeness of a TI is proposed for the cases of three orthogonal slices and of two orthogonal slices. The proposed theory is evaluated using four TIs of porous media that represent typical but distinct morphological types. The significance of this theoretical evaluation lies in two aspects: It allows special morphologies, for which the attributes of a TI can be reconstructed at a special orthogonal slice of a 3D structure, to be located and quantified, and it can guide the selection of an appropriate reconstruction method for a special TI. PMID- 28618512 TI - Cavity master equation for the continuous time dynamics of discrete-spin models. AB - We present an alternate method to close the master equation representing the continuous time dynamics of interacting Ising spins. The method makes use of the theory of random point processes to derive a master equation for local conditional probabilities. We analytically test our solution studying two known cases, the dynamics of the mean-field ferromagnet and the dynamics of the one dimensional Ising system. We present numerical results comparing our predictions with Monte Carlo simulations in three different models on random graphs with finite connectivity: the Ising ferromagnet, the random field Ising model, and the Viana-Bray spin-glass model. PMID- 28618513 TI - Recurrence measure of conditional dependence and applications. AB - Identifying causal relations from observational data sets has posed great challenges in data-driven causality inference studies. One of the successful approaches to detect direct coupling in the information theory framework is transfer entropy. However, the core of entropy-based tools lies on the probability estimation of the underlying variables. Here we propose a data-driven approach for causality inference that incorporates recurrence plot features into the framework of information theory. We define it as the recurrence measure of conditional dependence (RMCD), and we present some applications. The RMCD quantifies the causal dependence between two processes based on joint recurrence patterns between the past of the possible driver and present of the potentially driven, excepting the contribution of the contemporaneous past of the driven variable. Finally, it can unveil the time scale of the influence of the sea surface temperature of the Pacific Ocean on the precipitation in the Amazonia during recent major droughts. PMID- 28618514 TI - Dynamics of a bistable Miura-origami structure. AB - Origami-inspired structures and materials have shown extraordinary properties and performances originating from the intricate geometries of folding. However, current state of the art studies have mostly focused on static and quasistatic characteristics. This research performs a comprehensive experimental and analytical study on the dynamics of origami folding through investigating a stacked Miura-Ori (SMO) structure with intrinsic bistability. We fabricate and experimentally investigated a bistable SMO prototype with rigid facets and flexible crease lines. Under harmonic base excitation, the SMO exhibits both intrawell and interwell oscillations. Spectrum analyses reveal that the dominant nonlinearities of SMO are quadratic and cubic, which generate rich dynamics including subharmonic and chaotic oscillations. The identified nonlinearities indicate that a third-order polynomial can be employed to approximate the measured force-displacement relationship. Such an approximation is validated via numerical study by qualitatively reproducing the phenomena observed in the experiments. The dynamic characteristics of the bistable SMO resemble those of a Helmholtz-Duffing oscillator (HDO); this suggests the possibility of applying the established tools and insights of HDO to predict origami dynamics. We also show that the bistability of SMO can be programmed within a large design space via tailoring the crease stiffness and initial stress-free configurations. The results of this research offer a wealth of fundamental insights into the dynamics of origami folding, and provide a solid foundation for developing foldable and deployable structures and materials with embedded dynamic functionalities. PMID- 28618515 TI - Numerical simulations of vesicle and bubble dynamics in two-dimensional four-roll mill flows. AB - We use a computational technique based on the immersed boundary method to construct a four-roll mill device with which we can generate a broad spectrum of flow types from an extensional flow to a rotational one. We put a vesicle or a bubble in the constructed four-roll mill device to investigate their interaction with the surrounding fluid. The vesicle dynamics are determined by its bending rigidity, inextensibility, and hydrodynamical force, whereas the bubble dynamics is governed by the surface tension and the hydrodynamic interaction. Depending on the type of the flow, these suspended objects go through either a tank-treading motion or a tumbling motion. We validate our numerical method by a convergence study and discuss the transition between tank-treading and tumbling motions for the vesicles and bubbles. PMID- 28618516 TI - Viral self-assembly pathway and mechanical stress relaxation. AB - The final shape of a virus is dictated by the self-assembly pathway of its constituents. Using standard thin-shell elasticity, we highlight the prominent role of the viral shell's spontaneous curvature in determining the assembly pathway. In particular, we demonstrate that the mechanical stress inherent to the growth of a curved surface can be relaxed in two different ways in the early steps of assembly, depending on the value of the spontaneous curvature of the surface. This important result explains why most viral shells have either a compact shape with icosahedral symmetry or an elongated shape lacking this symmetry. PMID- 28618517 TI - Microscopic derivation of the hydrodynamics of active-Brownian-particle suspensions. AB - We derive the hydrodynamic equations of motion for a fluid of active particles described by underdamped Langevin equations that reduce to the active-Brownian particle model, in the overdamped limit. The contraction into the hydrodynamic description is performed by locally averaging the particle dynamics with the nonequilibrium many-particle probability density, whose formal expression is found in the physically relevant limit of high friction through a multiple-time scale analysis. This approach permits us to identify the conditions under which self-propulsion can be subsumed into the fluid stress tensor and thus to define systematically and unambiguously the local pressure of the active fluid. PMID- 28618518 TI - Random walks on activity-driven networks with attractiveness. AB - Virtually all real-world networks are dynamical entities. In social networks, the propensity of nodes to engage in social interactions (activity) and their chances to be selected by active nodes (attractiveness) are heterogeneously distributed. Here, we present a time-varying network model where each node and the dynamical formation of ties are characterized by these two features. We study how these properties affect random-walk processes unfolding on the network when the time scales describing the process and the network evolution are comparable. We derive analytical solutions for the stationary state and the mean first-passage time of the process, and we study cases informed by empirical observations of social networks. Our work shows that previously disregarded properties of real social systems, such as heterogeneous distributions of activity and attractiveness as well as the correlations between them, substantially affect the dynamical process unfolding on the network. PMID- 28618519 TI - Limiting the stroke of a Schmitt trigger with multiplicative noise. AB - We have devised an experiment whereby a bistable system is confined away from its deterministic attractors by means of multiplicative noise. Together with previous numerical results, our experimental results validate the hypothesis that the higher the slope of the noise's multiplicative factor, the more it shifts the stationary states. PMID- 28618520 TI - Torque-coupled thermodynamic model for F_{o}F_{1}-ATPase. AB - F_{o}F_{1}-ATPase is a motor protein complex that utilizes transmembrane ion flow to drive the synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate (Pi). While many theoretical models have been proposed to account for its rotary activity, most of them focus on the F_{o} or F_{1} portions separately rather than the complex as a whole. Here, we propose a simple but new torque-coupled thermodynamic model of F_{o}F_{1}-ATPase. Solving this model at steady state, we find that the monotonic variation of each portion's efficiency becomes much more robust over a wide range of parameters when the F_{o} and F_{1} portions are coupled together, as compared to cases when they are considered separately. Furthermore, the coupled model predicts the dependence of each portion's kinetic behavior on the parameters of the other. Specifically, the power and efficiency of the F_{1} portion are quite sensitive to the proton gradient across the membrane, while those of the F_{o} portion as well as the related Michaelis constants for proton concentrations respond insensitively to concentration changes in the reactants of ATP synthesis. The physiological proton gradient across the membrane in the F_{o} portion is also shown to be optimal for the Michaelis constants of ADP and phosphate in the F_{1} portion during ATP synthesis. Together, our coupled model is able to predict key dynamic and thermodynamic features of the F_{o}F_{1}-ATPase in vivo semiquantitatively, and suggests that such coupling approach could be further applied to other biophysical systems. PMID- 28618521 TI - Local time of Levy random walks: A path integral approach. AB - The local time of a stochastic process quantifies the amount of time that sample trajectories x(tau) spend in the vicinity of an arbitrary point x. For a generic Hamiltonian, we employ the phase-space path-integral representation of random walk transition probabilities in order to quantify the properties of the local time. For time-independent systems, the resolvent of the Hamiltonian operator proves to be a central tool for this purpose. In particular, we focus on the local times of Levy random walks (Levy flights), which correspond to fractional diffusion equations. PMID- 28618522 TI - Role of length polydispersity in the phase behavior of freely rotating hard rectangle fluids. AB - We use the density-functional formalism, in particular the scaled-particle theory, applied to a length-polydisperse hard-rectangle fluid to study its phase behavior as a function of the mean particle aspect ratio kappa_{0} and polydispersity Delta_{0}. The numerical solutions of the coexistence equations are calculated by transforming the original problem with infinite degrees of freedoms to a finite set of equations for the amplitudes of the Fourier expansion of the moments of the density profiles. We divide the study into two parts. The first one is devoted to the calculation of the phase diagrams in the packing fraction eta_{0}-kappa_{0} plane for a fixed Delta_{0} and selecting parent distribution functions with exponential (the Schulz distribution) or Gaussian decays. In the second part we study the phase behavior in the eta_{0}-Delta_{0} plane for fixed kappa_{0} while Delta_{0} is changed. We characterize in detail the orientational ordering of particles and the fractionation of different species between the coexisting phases. Also we study the character (second vs first order) of the isotropic-nematic phase transition as a function of polydispersity. We particularly focus on the stability of the tetratic phase as a function of kappa_{0} and Delta_{0}. The isotropic-nematic transition becomes strongly of first order when polydispersity is increased: The coexistence gap widens and the location of the tricritical point moves to higher values of kappa_{0} while the tetratic phase is slightly destabilized with respect to the nematic one. The results obtained here can be tested in experiments on shaken monolayers of granular rods. PMID- 28618523 TI - Compressive elasticity of polydisperse biopolymer gels. AB - We theoretically predict the nonlinear elastic responses of polydisperse biopolymer gels to uniaxial compression. We analyze the competition between compressive stiffening due to polymer densification by out-going solvent flow and compressive softening due to continuous polymer buckling. We point out that the polydispersity in polymer lengths can result in an intrinsic, equilibrium mode of nonaffine compression: nonuniform strain but with uniform force distribution, which is found to be more energetically preferable than affine deformation. In this case, the gel softens significantly after the onset of polymer buckling at small compression, but as compression increases, densification-induced stiffening becomes important and a modulus plateau should be observed for a large range of strain. We also relate our results to recent compression experiments on collagen gels and fibrin gels. PMID- 28618524 TI - Experimental velocity study of non-Boussinesq Rayleigh-Benard convection. AB - The effects of strongly varying fluid properties, beyond the validity range of the so-called Boussinesq approximation, were experimentally studied in Rayleigh Benard (RB) convection. Two experiments were conducted in the same cubical RB convection cell at similar Rayleigh and Prandtl numbers. In one experiment water was used as working fluid and the imposed temperature difference between the top and bottom plates of the cell was such to ensure non-Boussinesq conditions. In the other experiment, taken as a reference for Boussinesq conditions, methanol was used as working fluid, allowing a smaller temperature difference between the plates. In both experiments the instantaneous and time-averaged flow fields were determined experimentally in a vertical cross section of the cell by using particle image velocimetry. Results show a non-Boussinesq effect that manifests itself as an increase of the time-averaged horizontal velocity component close to the bottom wall of the cell and as a global top-bottom asymmetry of the velocity field. This is an experimental study of the whole velocity field of RB convection at non-Boussinesq conditions. PMID- 28618525 TI - Influence of liquid crystalline phases on the tunability of a random laser. AB - In this paper, we report the temperature behavior of an optimized disordered photonic system-based liquid crystal by means of heat capacity and refractive index measurements. The scattering system is formed by a porous borosilicate glass random matrix (about 60%) infiltrated with a smectogenic liquid crystal (about 16%) and a small amount of laser dye (0.1%). The rest of the scattering system is about 24% air, giving rise to a high refractive index contrast scattering system. Such a system has the functionality to change the refractive index contrast with temperature due to the liquid crystal temperature behavior. The system, optically pumped by the second harmonic of a Q-switched Nd:YAG pulsed laser working at 532 nm, exhibits random laser action, the threshold of which depends upon the liquid crystalline mesophase. Temperatures of existence of the smectic-B phase correspond to the most optimized random laser. In such a mesophase, the transport mean free path has been determined as about 16 MUm in a coherent backscattering experiment. PMID- 28618526 TI - Comparative study of the anchoring strength of reactive mesogens and industrial polyimides used for the alignment of liquid crystals. AB - We measured the Rapini-Papoular polar anchoring strength coefficient W for 4^{'} pentyl-4-cyanobiphenyl (5CB) on alignment layers formed by the reactive mesogen photopolymers RM 257, RM 82, and RM 84 [4,4^{'}-bis(acryloyl)biphenyl] (by Merck). These materials are commonly used for the photostabilization of the liquid crystal (LC) director in the bulk as well as at the surface of the LC layer via the formation of a loose polymer network that captures the director orientation. We developed a method of fabrication of alignment layers from these polymers, and estimated W from the measurements of the optical retardation as a function of applied voltage in uniformly aligned cells. We found that RM 257 yielded W of about 6*10^{-4}J/m^{2}, whereas RM 82 and RM 84 provided anchoring strengths of about 2*10^{-4} and 4*10^{-4}J/m^{2}, respectively. Subsequent heating of the sample either destroyed the alignment layer, or substantially decreased W to about 1*10^{-4}J/m^{2}, which was comparable to the anchoring strength of weakly rubbed commercial polyimides. PMID- 28618527 TI - Implementation of dual time-stepping strategy of the gas-kinetic scheme for unsteady flow simulations. AB - In our study, the dual time-stepping strategy of the gas-kinetic scheme is constructed and used for the simulation of unsteady flows. In comparison to the previous implicit gas-kinetic scheme, both the inviscid and viscous flux Jacobian are considered in our work, and the linear system of the pseudo-steady-state is solved by applying generalized minimal residual algorithm. The accuracy is validated by several numerical cases, the incompressible flow around blunt bodies (stationary circular cylinder and square cylinder), and the transonic buffet on the NACA0012 airfoil under hybrid mesh. The numerical cases also demonstrate that the present method is applicable to approach the fluid flows from laminar to turbulent and from incompressible to compressible. Finally, the case of acoustic pressure pulse is carried out to evaluate the effects of enlarged time step, and the side effect of enlarged time step is explained. Compared with the explicit gas-kinetic scheme, the proposed scheme can greatly accelerate the computation and reduce the computational costs for unsteady flow simulations. PMID- 28618528 TI - Dynamics of spiral waves rotating around an obstacle and the existence of a minimal obstacle. AB - Pinning of vortices by obstacles plays an important role in various systems. In the heart, anatomical reentry is created when a vortex, also known as the spiral wave, is pinned to an anatomical obstacle, leading to a class of physiologically very important arrhythmias. Previous analyses of its dynamics and instability provide fine estimates in some special circumstances, such as large obstacles or weak excitabilities. Here, to expand theoretical analyses to all circumstances, we propose a general theory whose results quantitatively agree with direct numerical simulations. In particular, when obstacles are small and pinned spiral waves are destabilized, an accurate explanation of the instability in two dimensional media is provided by the usage of a mapping rule and dimension reduction. The implications of our results are to better understand the mechanism of arrhythmia and thus improve its early prevention. PMID- 28618529 TI - Completeness of inertial modes of an incompressible inviscid fluid in a corotating ellipsoid. AB - Inertial modes are the eigenmodes of contained rotating fluids restored by the Coriolis force. When the fluid is incompressible, inviscid, and contained in a rigid container, these modes satisfy Poincare's equation that has the peculiarity of being hyperbolic with boundary conditions. Inertial modes are, therefore, solutions of an ill-posed boundary-value problem. In this paper, we investigate the mathematical side of this problem. We first show that the Poincare problem can be formulated in the Hilbert space of square-integrable functions, with no hypothesis on the continuity or the differentiability of velocity fields. We observe that with this formulation, the Poincare operator is bounded and self adjoint, and as such, its spectrum is the union of the point spectrum (the set of eigenvalues) and the continuous spectrum only. When the fluid volume is an ellipsoid, we show that the inertial modes form a complete base of polynomial velocity fields for the square-integrable velocity fields defined over the ellipsoid and meeting the boundary conditions. If the ellipsoid is axisymmetric, then the base can be identified with the set of Poincare modes, first obtained by Bryan [Philos. Trans. R. Soc. London 180, 187 (1889)PTRMAD1364 503X10.1098/rsta.1889.0006], and completed with the geostrophic modes. PMID- 28618530 TI - Time-dependent breakdown of fiber networks: Uncertainty of lifetime. AB - Materials often fail when subjected to stresses over a prolonged period. The time to failure, also called the lifetime, is known to exhibit large variability of many materials, particularly brittle and quasibrittle materials. For example, a coefficient of variation reaches 100% or even more. Its distribution shape is highly skewed toward zero lifetime, implying a large number of premature failures. This behavior contrasts with that of normal strength, which shows a variation of only 4%-10% and a nearly bell-shaped distribution. The fundamental cause of this large and unique variability of lifetime is not well understood because of the complex interplay between stochastic processes taking place on the molecular level and the hierarchical and disordered structure of the material. We have constructed fiber network models, both regular and random, as a paradigm for general material structures. With such networks, we have performed Monte Carlo simulations of creep failure to establish explicit relationships among fiber characteristics, network structures, system size, and lifetime distribution. We found that fiber characteristics have large, sometimes dominating, influences on the lifetime variability of a network. Among the factors investigated, geometrical disorders of the network were found to be essential to explain the large variability and highly skewed shape of the lifetime distribution. With increasing network size, the distribution asymptotically approaches a double exponential form. The implication of this result is that, so-called "infant mortality," which is often predicted by the Weibull approximation of the lifetime distribution, may not exist for a large system. PMID- 28618531 TI - Noise focusing in neuronal tissues: Symmetry breaking and localization in excitable networks with quenched disorder. AB - We introduce a coarse-grained stochastic model for the spontaneous activity of neuronal cultures to explain the phenomenon of noise focusing, which entails localization of the noise activity in excitable networks with metric correlations. The system is modeled as a continuum excitable medium with a state dependent spatial coupling that accounts for the dynamics of synaptic connections. The most salient feature is the emergence at the mesoscale of a vector field V(r), which acts as an advective carrier of the noise. This entails an explicit symmetry breaking of isotropy and homogeneity that stems from the amplification of the quenched fluctuations of the network by the activity avalanches, concomitant with the excitable dynamics. We discuss the microscopic interpretation of V(r) and propose an explicit construction of it. The coarse grained model shows excellent agreement with simulations at the network level. The generic nature of the observed phenomena is discussed. PMID- 28618532 TI - Reducing microwave absorption with fast frequency modulation. AB - We study the response of a two-level quantum system to a chirp signal, using both numerical and analytical methods. The numerical method is based on numerical solutions of the Schrodinger solution of the two-level system, while the analytical method is based on an approximate solution of the same equations. We find that when two-level systems are perturbed by a chirp signal, the peak population of the initially unpopulated state exhibits a high sensitivity to frequency modulation rate. We also find that the aforementioned sensitivity depends on the strength of the forcing, and weaker forcings result in a higher sensitivity, where the frequency modulation rate required to produce the same reduction in peak population would be lower. We discuss potential applications of this result in the field of microwave power transmission, as it shows applying fast frequency modulation to transmitted microwaves used for power transmission could decrease unintended absorption of microwaves by organic tissue. PMID- 28618533 TI - Dynamics of interacting electrons under effect of a Morse potential. AB - We consider interacting electrons moving in a nonlinear Morse lattice. We set the initial conditions as follows: electrons were initially localized at the center of the chain and a solitonic deformation was produced by an impulse excitation on the center of the chain. By solving quantum and classical equations for this system numerically, we found that a fraction of electronic wave function was trapped by the solitonic excitation, and trapping specificities depend on the degree of interaction among electrons. Also, there is evidence that the effective electron velocity depends on Coulomb interaction and electron-phonon coupling in a nontrivial way. This association is explained in detail along this work. In addition, we briefly discuss the dependence of our results with the type of initial condition we choose for the electrons and lattice. PMID- 28618534 TI - Simultaneous influence of helicity and compressibility on anomalous scaling of the magnetic field in the Kazantsev-Kraichnan model. AB - Using the field theoretic renormalization group technique and the operator product expansion, the systematic investigation of the influence of the spatial parity violation on the anomalous scaling behavior of correlation functions of the weak passive magnetic field in the framework of the compressible Kazantsev Kraichnan model with the presence of a large-scale anisotropy is performed up to the second order of the perturbation theory (two-loop approximation). The renormalization group analysis of the model is done and the two-loop explicit expressions for the anomalous and critical dimensions of the leading composite operators are found as functions of the helicity and compressibility parameters and their anisotropic hierarchies are discussed. It is shown that for arbitrary values of the helicity parameter and for physically acceptable (small enough) values of the compressibility parameter, the main role is played by the composite operators near the isotropic shell in accordance with the Kolmogorov's local isotropy restoration hypothesis. The anomalous dimensions of the relevant composite operators are then compared with the anomalous dimensions of the corresponding leading composite operators in the Kraichnan model of passively advected scalar field. The significant difference between these two sets of anomalous dimensions is discussed. The two-loop inertial-range scaling exponents of the single-time two-point correlation functions of the magnetic field are found and their dependence on the helicity and compressibility parameters is studied in detail. It is shown that while the presence of the helicity leads to more pronounced anomalous scaling for correlation functions of arbitrary order, the compressibility, in general, makes the anomalous scaling more pronounced in comparison to the incompressible case only for low-order correlation functions. The persistence of the anisotropy deep inside the inertial interval is investigated using the appropriate odd ratios of the correlation functions. It is shown that, in general, the persistence of the anisotropy is much more pronounced in the helical systems, while in the compressible turbulent environments this is true only for low-order odd ratios of the correlation functions. PMID- 28618535 TI - Work distributions for random sudden quantum quenches. AB - The statistics of work performed on a system by a sudden random quench is investigated. Considering systems with finite dimensional Hilbert spaces we model a sudden random quench by randomly choosing elements from a Gaussian unitary ensemble (GUE) consisting of Hermitian matrices with identically, Gaussian distributed matrix elements. A probability density function (pdf) of work in terms of initial and final energy distributions is derived and evaluated for a two-level system. Explicit results are obtained for quenches with a sharply given initial Hamiltonian, while the work pdfs for quenches between Hamiltonians from two independent GUEs can only be determined in explicit form in the limits of zero and infinite temperature. The same work distribution as for a sudden random quench is obtained for an adiabatic, i.e., infinitely slow, protocol connecting the same initial and final Hamiltonians. PMID- 28618536 TI - Driven Brownian particle as a paradigm for a nonequilibrium heat bath: Effective temperature and cyclic work extraction. AB - We apply the concept of a frequency-dependent effective temperature based on the fluctuation-dissipation ratio to a driven Brownian particle in a nonequilibrium steady state. Using this system as a thermostat for a weakly coupled harmonic oscillator, the oscillator thermalizes according to a canonical distribution at the respective effective temperature across the entire frequency spectrum. By turning the oscillator from a passive thermometer into a heat engine, we realize the cyclic extraction of work from a single thermal reservoir, which is feasible only due to its nonequilibrium nature. PMID- 28618537 TI - Heat fluctuations of Brownian oscillators in nonstationary processes: Fluctuation theorem and condensation transition. AB - We study analytically the probability distribution of the heat released by an ensemble of harmonic oscillators to the thermal bath, in the nonequilibrium relaxation process following a temperature quench. We focus on the asymmetry properties of the heat distribution in the nonstationary dynamics, in order to study the forms taken by the fluctuation theorem as the number of degrees of freedom is varied. After analyzing in great detail the cases of one and two oscillators, we consider the limit of a large number of oscillators, where the behavior of fluctuations is enriched by a condensation transition with a nontrivial phase diagram, characterized by reentrant behavior. Numerical simulations confirm our analytical findings. We also discuss and highlight how concepts borrowed from the study of fluctuations in equilibrium under symmetry breaking conditions [Gaspard, J. Stat. Mech. (2012) P0802110.1088/1742 5468/2012/08/P08021] turn out to be quite useful in understanding the deviations from the standard fluctuation theorem. PMID- 28618538 TI - Study of dynamic heterogeneity of an active particle system. AB - We have studied spatial and temporal dynamic heterogeneity (DH) in a system of hard-sphere particles, subjected to active forces with constant amplitude and random direction determined by rotational diffusion with correlation time tau. We have used a variety of observables to characterize the DH behavior, including the deviation from standard Stokes-Einstein (SE) relation, a non-Gaussian parameter alpha_{2}(Deltat) for the distribution of particle displacement within a certain time interval Deltat, a four-point susceptibility chi_{4}(Deltat,DeltaL) for the correlation in dynamics between any two points in space separated by distance DeltaL within some time window Deltat, and a vector spatial-temporal correlation function S_{vec}(R,Deltat) for vector displacements within time interval Deltat of particle pairs originally separated by R. By mapping the particle motion into a continuous-time random walk with constant jump length, we can obtain the average waiting time ?D_{s}^{-1} and persistence time ?eta, with D_{s} the self-diffusion coefficient and eta the shear viscosity, such that the observable lambda=/?D_{s}eta can be calculated as a function of the control parameter tau to show how it deviates from its SE value lambda_{0}. Interestingly, we find lambda/lambda_{0} shows a nonmonotonic behavior for large volume fraction phi_{a}, wherein lambda/lambda_{0} undergoes a minimum at a certain intermediate value of tau, indicating that both small and large particle activity may lead to strong DH. Such a reentrance phenomenon is further demonstrated in terms of the non-Gaussian parameters alpha_{2}, four-point susceptibility chi_{4}, and vector spatiotemporal correlation functions S_{vec}, respectively. Detail analysis shows that it is the competition between the dual roles of particle activity, namely, activity-induced higher effective temperature and activity-induced clustering, that leads to such nontrivial nonmonotonic behaviors. In addition, we find that DH may also show a maximum level at an intermediate value of phi_{a} if tau is large enough, implying that a more crowded system may be less heterogeneous than a less crowded one for a system with high particle activity. PMID- 28618539 TI - Highly efficient optical director reorientation of liquid-crystalline polymer induced by dye additives. AB - Light-induced director orientation of polymeric liquid-crystalline systems was investigated. The materials under study were composed of a nematic liquid crystalline polymer (NLCP) and a small amount (0.05-0.5 wt.%) of conformationally active (azobenzene) or stable (anthraquinone) dye impurity. Light action on the homogeneously aligned polymer films above glass transition temperature leads to the director reorientation and, consequently, to a change in the extraordinary refractive index. The effect is associated with the dye molecule excitation and related change of intermolecular forces. In the case of NLCP with conformationally active dye dopant, an extremely high orientational optical response was detected (nonlinear coefficient is n_{2}~0.1cm^{2}/W). In contrast, the efficiency of orientational light action on NLCP with conformationally stable dye dopant is of the same order of magnitude as that of dye-doped low-molar-mass liquid crystals. At the normal light incidence on the NLCP doped with azo-dye, the threshold director orientation is observed which is similar to the Freedericksz transition under the action of magnetic and electric fields. The obtained high-orientational optical response of NLCP caused by azo-dye dopant in combination with the possibility of the recording of deformed structure in the glassy state, typical for polymer compounds, reveals new opportunities in photonics applications. PMID- 28618540 TI - Six-vertex model and Schramm-Loewner evolution. AB - Square ice is a statistical mechanics model for two-dimensional ice, widely believed to have a conformally invariant scaling limit. We associate a Peano (space-filling) curve to a square ice configuration, and more generally to a so called six-vertex model configuration, and argue that its scaling limit is a space-filling version of the random fractal curve SLE_{kappa}, Schramm-Loewner evolution with parameter kappa, where 40 limit. PMID- 28618547 TI - Optimal cost for strengthening or destroying a given network. AB - Strengthening or destroying a network is a very important issue in designing resilient networks or in planning attacks against networks, including planning strategies to immunize a network against diseases, viruses, etc. Here we develop a method for strengthening or destroying a random network with a minimum cost. We assume a correlation between the cost required to strengthen or destroy a node and the degree of the node. Accordingly, we define a cost function c(k), which is the cost of strengthening or destroying a node with degree k. Using the degrees k in a network and the cost function c(k), we develop a method for defining a list of priorities of degrees and for choosing the right group of degrees to be strengthened or destroyed that minimizes the total price of strengthening or destroying the entire network. We find that the list of priorities of degrees is universal and independent of the network's degree distribution, for all kinds of random networks. The list of priorities is the same for both strengthening a network and for destroying a network with minimum cost. However, in spite of this similarity, there is a difference between their p_{c}, the critical fraction of nodes that has to be functional to guarantee the existence of a giant component in the network. PMID- 28618548 TI - Probability of noise- and rate-induced tipping. AB - We propose an approximation for the probability of tipping when the speed of parameter change and additive white noise interact to cause tipping. Our approximation is valid for small to moderate drift speeds and helps to estimate the probability of false positives and false negatives in early-warning indicators in the case of rate- and noise-induced tipping. We illustrate our approximation on a prototypical model for rate-induced tipping with additive noise using Monte Carlo simulations. The formula can be extended to close encounters of rate-induced tipping and is otherwise applicable to other forms of tipping. We also provide an asymptotic formula for the critical ramp speed of the parameter in the absence of noise for a general class of systems undergoing rate induced tipping. PMID- 28618549 TI - Breakdown of the Stokes-Einstein relation in pure Lennard-Jones fluids: From gas to liquid via supercritical states. AB - We have examined the conditions under which the breakdown of the Stokes-Einstein (SE) relation occurs in pure Lennard-Jones (LJ) fluids over a wide range of temperatures and packing fractions beyond the critical point. To this end, the temperature and packing-fraction dependence of the self-diffusion coefficient, D, and the shear viscosity, eta_{sv}, were evaluated for Xe using molecular dynamics calculations with the Green-Kubo formula. The results showed good agreement with the experimental values. The breakdown was determined in light of the SE equation which we have recently derived for pure LJ liquids: Deta_{sv}=(k_{B}T/2pi)(N/V)^{1/3}, where k_{B} is the Boltzmann constant, T is the temperature, and N is the particle number included in the system volume V. We have found that the breakdown occurs in the lower range of the packing fraction, eta<0.2, and derived the SE relation in its broken form as Deta_{sv}=0.007(1 eta)^{-5}eta^{-4/3}(k_{B}T/epsilon)^{n}k_{B}T(N/V)^{1/3}, where n increases from 0 up to 1 with the decreasing eta. The equation clearly shows that the breakdown mainly occurs because the packing-fraction dependence does not cancel out between D and eta_{sv} in this region, which is attributed to the gaseous behavior in the packing-fraction dependence of the shear viscosity under a constant number density. In addition, the gaseous behavior in the temperature dependence of the shear viscosity also partially causes the breakdown. PMID- 28618550 TI - General expression for the component size distribution in infinite configuration networks. AB - In the infinite configuration network the links between nodes are assigned randomly with the only restriction that the degree distribution has to match a predefined function. This work presents a simple equation that gives for an arbitrary degree distribution the corresponding size distribution of connected components. This equation is suitable for fast and stable numerical computations up to the machine precision. The analytical analysis reveals that the asymptote of the component size distribution is completely defined by only a few parameters of the degree distribution: the first three moments, scale, and exponent (if applicable). When the degree distribution features a heavy tail, multiple asymptotic modes are observed in the component size distribution that, in turn, may or may not feature a heavy tail. PMID- 28618551 TI - Measuring effective temperatures in a generalized Gibbs ensemble. AB - The local physical properties of an isolated quantum statistical system in the stationary state reached long after a quench are generically described by the Gibbs ensemble, which involves only its Hamiltonian and the temperature as a parameter. If the system is instead integrable, additional quantities conserved by the dynamics intervene in the description of the stationary state. The resulting generalized Gibbs ensemble involves a number of temperature-like parameters, the determination of which is practically difficult. Here we argue that in a number of simple models these parameters can be effectively determined by using fluctuation-dissipation relationships between response and correlation functions of natural observables, quantities which are accessible in experiments. PMID- 28618552 TI - Plateau-Rayleigh instability in solids is a simple phase separation. AB - A long elastic cylinder, with radius a and shear-modulus MU, becomes unstable given sufficient surface tension gamma. We show this instability can be simply understood by considering the energy, E(lambda), of such a cylinder subject to a homogenous longitudinal stretch lambda. Although E(lambda) has a unique minimum, if surface tension is sufficient [Gamma=gamma/(aMU)>sqrt[32]] it loses convexity in a finite region. We use a Maxwell construction to show that, if stretched into this region, the cylinder will phase-separate into two segments with different stretches lambda_{1} and lambda_{2}. Our model thus explains why the instability has infinite wavelength and allows us to calculate the instability's subcritical hysteresis loop (as a function of imposed stretch), showing that instability proceeds with constant amplitude and at constant (positive) tension as the cylinder is stretched between lambda_{1} and lambda_{2}. We use full nonlinear finite-element calculations to verify these predictions and to characterize the interface between the two phases. Near Gamma=sqrt[32] the length of such an interface diverges, introducing a new length scale and allowing us to construct a one-dimensional effective theory. This treatment yields an analytic expression for the interface itself, revealing that its characteristic length grows as l_{wall}~a/sqrt[Gamma-sqrt[32]]. PMID- 28618553 TI - Mechanism of unconfined dust explosions: Turbulent clustering and radiation induced ignition. AB - It is known that unconfined dust explosions typically start off with a relatively weak primary flame followed by a severe secondary explosion. We show that clustering of dust particles in a temperature stratified turbulent flow ahead of the primary flame may give rise to a significant increase in the radiation penetration length. These particle clusters, even far ahead of the flame, are sufficiently exposed and heated by the radiation from the flame to become ignition kernels capable to ignite a large volume of fuel-air mixtures. This efficiently increases the total flame surface area and the effective combustion speed, defined as the rate of reactant consumption of a given volume. We show that this mechanism explains the high rate of combustion and overpressures required to account for the observed level of damage in unconfined dust explosions, e.g., at the 2005 Buncefield vapor-cloud explosion. The effect of the strong increase of radiation transparency due to turbulent clustering of particles goes beyond the state of the art of the application to dust explosions and has many implications in atmospheric physics and astrophysics. PMID- 28618554 TI - Memory-induced diffusive-superdiffusive transition: Ensemble and time-averaged observables. AB - The ensemble properties and time-averaged observables of a memory-induced diffusive-superdiffusive transition are studied. The model consists in a random walker whose transitions in a given direction depend on a weighted linear combination of the number of both right and left previous transitions. The diffusion process is nonstationary, and its probability develops the phenomenon of aging. Depending on the characteristic memory parameters, the ensemble behavior may be normal, superdiffusive, or ballistic. In contrast, the time averaged mean squared displacement is equal to that of a normal undriven random walk, which renders the process nonergodic. In addition, and similarly to Levy walks [Godec and Metzler, Phys. Rev. Lett. 110, 020603 (2013)PRLTAO0031 900710.1103/PhysRevLett.110.020603], for trajectories of finite duration the time averaged displacement apparently become random with properties that depend on the measurement time and also on the memory properties. These features are related to the nonstationary power-law decay of the transition probabilities to their stationary values. Time-averaged response to a bias is also calculated. In contrast with Levy walks [Froemberg and Barkai, Phys. Rev. E 87, 030104(R) (2013)PLEEE81539-375510.1103/PhysRevE.87.030104], the response always vanishes asymptotically. PMID- 28618555 TI - Viscosity of a classical gas: The rare-collision versus the frequent-collision regime. AB - The shear viscosity eta for a dilute classical gas of hard-sphere particles is calculated by solving the Boltzmann kinetic equation in terms of the weakly absorbed plane waves. For the rare-collision regime, the viscosity eta as a function of the equilibrium gas parameters-temperature T, particle number density n, particle mass m, and hard-core particle diameter d-is quite different from that of the frequent-collision regime, e.g., from the well-known result of Chapman and Enskog. An important property of the rare-collision regime is the dependence of eta on the external ("nonequilibrium") parameter omega, frequency of the sound plane wave, that is absent in the frequent-collision regime at leading order of the corresponding perturbation expansion. A transition from the frequent to the rare-collision regime takes place when the dimensionless parameter nd^{2}(T/m)^{1/2}omega^{-1} goes to zero. The scaled absorption coefficient for sound waves calculated in the rare and frequent-collision regimes is found to be in qualitative agreement with the experimental data. PMID- 28618556 TI - Strain tensor selection and the elastic theory of incompatible thin sheets. AB - The existing theory of incompatible elastic sheets uses the deviation of the surface metric from a reference metric to define the strain tensor [Efrati et al., J. Mech. Phys. Solids 57, 762 (2009)JMPSA80022 509610.1016/j.jmps.2008.12.004]. For a class of simple axisymmetric problems we examine an alternative formulation, defining the strain based on deviations of distances (rather than distances squared) from their rest values. While the two formulations converge in the limit of small slopes and in the limit of an incompressible sheet, for other cases they are found not to be equivalent. The alternative formulation offers several features which are absent in the existing theory. (a) In the case of planar deformations of flat incompatible sheets, it yields linear, exactly solvable, equations of equilibrium. (b) When reduced to uniaxial (one-dimensional) deformations, it coincides with the theory of extensible elastica; in particular, for a uniaxially bent sheet it yields an unstrained cylindrical configuration. (c) It gives a simple criterion determining whether an isometric immersion of an incompatible sheet is at mechanical equilibrium with respect to normal forces. For a reference metric of constant positive Gaussian curvature, a spherical cap is found to satisfy this criterion except in an arbitrarily narrow boundary layer. PMID- 28618557 TI - Scale-free networks emerging from multifractal time series. AB - Methods connecting dynamical systems and graph theory have attracted increasing interest in the past few years, with applications ranging from a detailed comparison of different kinds of dynamics to the characterization of empirical data. Here we investigate the effects of the (multi)fractal properties of a signal, common in time series arising from chaotic dynamics or strange attractors, on the topology of a suitably projected network. Relying on the box counting formalism, we map boxes into the nodes of a network and establish analytic expressions connecting the natural measure of a box with its degree in the graph representation. We single out the conditions yielding to the emergence of a scale-free topology and validate our findings with extensive numerical simulations. We finally present a numerical analysis on the properties of weighted and directed network projections. PMID- 28618558 TI - Measurement of the shell decompression in direct-drive inertial-confinement fusion implosions. AB - A series of direct-drive implosions performed on OMEGA were used to isolate the effect of an adiabat on the in-flight shell thickness. The maximum in-flight shell thickness was measured to decrease from 75+/-2 to 60+/-2MUm when the adiabat of the shell was reduced from 6 to 4.5, but when decreasing the adiabat further (1.8), the shell thickness increased to 75+/-2MUm due to the growth of the Rayleigh-Taylor instability. Hydrodynamic simulations suggest that a laser imprint is the dominant seed for these nonuniformities. PMID- 28618559 TI - Universal spatiotemporal scaling of distortions in a drifting lattice. AB - We study the dynamical response to small distortions of a lattice about its uniform state, drifting through a dissipative medium due to an external force, and show, analytically and numerically, that the fluctuations, both transverse and longitudinal to the direction of the drift, exhibit spatiotemporal scaling belonging to the Kardar-Parisi-Zhang universality class. Further, we predict that a colloidal crystal drifting in a constant electric field is linearly stable against distortions and the distortions propagate as underdamped waves. PMID- 28618560 TI - Topology-dependent rationality and quantal response equilibria in structured populations. AB - Given that the assumption of perfect rationality is rarely met in the real world, we explore a graded notion of rationality in socioecological systems of networked actors. We parametrize an actors' rationality via their place in a social network and quantify system rationality via the average Jensen-Shannon divergence between the games Nash and logit quantal response equilibria. Previous work has argued that scale-free topologies maximize a system's overall rationality in this setup. Here we show that while, for certain games, it is true that increasing degree heterogeneity of complex networks enhances rationality, rationality-optimal configurations are not scale-free. For the Prisoner's Dilemma and Stag Hunt games, we provide analytic arguments complemented by numerical optimization experiments to demonstrate that core-periphery networks composed of a few dominant hub nodes surrounded by a periphery of very low degree nodes give strikingly smaller overall deviations from rationality than scale-free networks. Similarly, for the Battle of the Sexes and the Matching Pennies games, we find that the optimal network structure is also a core-periphery graph but with a smaller difference in the average degrees of the core and the periphery. These results provide insight on the interplay between the topological structure of socioecological systems and their collective cognitive behavior, with potential applications to understanding wealth inequality and the structural features of the network of global corporate control. PMID- 28618561 TI - Capturing Brownian dynamics with an on-lattice model of hard-sphere diffusion. AB - Conventional master equation approaches approximate the diffusion of molecules in continuum space by the process of particles hopping on a spatial lattice. The hopping probability from one voxel (spatial lattice point) to its neighbor is usually considered to be constant throughout space. Such an assumption is only consistent with pointlike molecules and thus neglects volume-exclusion effects due to finite particle size. A few studies have attempted to introduce volume exclusion effects by choosing the hopping probability from one voxel to a neighboring one to be a linear function of the number density. Here, we formulate an alternative master equation in which the hopping probability is equal to the fraction of available space in the neighboring voxel as estimated using scaled particle theory. This leads to the hopping probability being a nonlinear function of the number density. A mean-field approximation (mfa) leads to a partial differential equation of the advection-diffusion type. We show that the time evolution of the particle number density sampled using the stochastic simulation algorithm associated with the new master equation and the number density obtained by numerical integration of the mfa are in good agreement with each other. They are also distinctly different than the time evolution predicted by the conventional master equation and those with hopping probabilities which are linear functions of the number density. The results from the new lattice description are also shown to be in very good agreement with the lattice-free method of Brownian dynamics, even for highly crowded scenarios. PMID- 28618562 TI - Evolution of moments and correlations in nonrenewal escape-time processes. AB - The theoretical description of nonrenewal stochastic systems is a challenge. Analytical results are often not available or can be obtained only under strong conditions, limiting their applicability. Also, numerical results have mostly been obtained by ad hoc Monte Carlo simulations, which are usually computationally expensive when a high degree of accuracy is needed. To gain quantitative insight into these systems under general conditions, we here introduce a numerical iterated first-passage time approach based on solving the time-dependent Fokker-Planck equation (FPE) to describe the statistics of nonrenewal stochastic systems. We illustrate the approach using spike-triggered neuronal adaptation in the leaky and perfect integrate-and-fire model, respectively. The transition to stationarity of first-passage time moments and their sequential correlations occur on a nontrivial time scale that depends on all system parameters. Surprisingly this is so for both single exponential and scale-free power-law adaptation. The method works beyond the small noise and time scale separation approximations. It shows excellent agreement with direct Monte Carlo simulations, which allow for the computation of transient and stationary distributions. We compare different methods to compute the evolution of the moments and serial correlation coefficients (SCCs) and discuss the challenge of reliably computing the SCCs, which we find to be very sensitive to numerical inaccuracies for both the leaky and perfect integrate-and-fire models. In conclusion, our methods provide a general picture of nonrenewal dynamics in a wide range of stochastic systems exhibiting short- and long-range correlations. PMID- 28618563 TI - Nonmonotonic dynamic correlations in quasi-two-dimensional confined glass-forming liquids. AB - It has been broadly accepted that the behavior of glass-forming liquids, where their relaxation dynamics exhibit a pronounced slowdown as they are cooled toward the glass transition temperature, is caused by the increase in one or more correlation lengths. However, the role of length scales in the dynamics of glass forming liquids is not clearly established, and past simulation work that suggests a surprising nonmonotonic temperature evolution of spatial dynamical correlations near the mode-coupling crossover temperature has been both questioned and supported by subsequent work. Here, using molecular dynamics simulation, we also show a striking maximum in the dynamic length scale xi_{c}^{dyn} at a given temperature, but the temperature of this maximum is found to shift as the size of the confined system increases. Furthermore, we find that such a maximum disappears for all geometry sizes considered when a rough wall is replaced with a smooth, hard wall, suggesting that the nature of the nonmonotonic temperature dependence of xi_{c}^{dyn} does not reflect an intrinsic property of bulk liquids, but originates from wall effects. Our results provide new insights into the dynamics of glass-forming liquids, particularly for quasi-two dimensional systems. PMID- 28618564 TI - Bounds of memory strength for power-law series. AB - Many time series produced by complex systems are empirically found to follow power-law distributions with different exponents alpha. By permuting the independently drawn samples from a power-law distribution, we present nontrivial bounds on the memory strength (first-order autocorrelation) as a function of alpha, which are markedly different from the ordinary +/-1 bounds for Gaussian or uniform distributions. When 13, the upper bound remains +1 while the lower bound descends below 0. Theoretical bounds agree well with numerical simulations. Based on the posts on Twitter, ratings of MovieLens, calling records of the mobile operator Orange, and the browsing behavior of Taobao, we find that empirical power-law-distributed data produced by human activities obey such constraints. The present findings explain some observed constraints in bursty time series and scale-free networks and challenge the validity of measures such as autocorrelation and assortativity coefficient in heterogeneous systems. PMID- 28618565 TI - Freak oscillation in a dusty plasma. AB - The freak oscillation in one-dimensional dusty plasma is studied numerically by particle-in-cell method. Using a perturbation method, the basic set of fluid equations is reduced to a nonlinear Schrodinger equation (NLSE). The rational solution of the NLSE is presented, which is proposed as an effective tool for studying the rogue waves in dusty plasma. Additionally, the application scope of the analytical solution of the rogue wave described by the NLSE is given. PMID- 28618566 TI - Towards a unified lattice kinetic scheme for relativistic hydrodynamics. AB - We present a systematic derivation of relativistic lattice kinetic equations for finite-mass particles, reaching close to the zero-mass ultrarelativistic regime treated in the previous literature. Starting from an expansion of the Maxwell Juttner distribution on orthogonal polynomials, we perform a Gauss-type quadrature procedure and discretize the relativistic Boltzmann equation on space filling Cartesian lattices. The model is validated through numerical comparison with standard tests and solvers in relativistic fluid dynamics such as Boltzmann approach multiparton scattering and previous relativistic lattice Boltzmann models. This work provides a significant step towards the formulation of a unified relativistic lattice kinetic scheme, covering both massive and near massless particles regimes. PMID- 28618567 TI - Optimizing diffusion in multiplexes by maximizing layer dissimilarity. AB - Diffusion in a multiplex depends on the specific link distribution between the nodes in each layer, but also on the set of the intralayer and interlayer diffusion coefficients. In this work we investigate, in a quantitative way, the efficiency of multiplex diffusion as a function of the topological similarity among multiplex layers. This similarity is measured by the distance between layers, taken among the pairs of layers. Results are presented for a simple two layer multiplex, where one of the layers is held fixed, while the other one can be rewired in a controlled way in order to increase or decrease the interlayer distance. The results indicate that, for fixed values of all intra- and interlayer diffusion coefficients, a large interlayer distance generally enhances the global multiplex diffusion, providing a topological mechanism to control the global diffusive process. For some sets of networks, we develop an algorithm to identify the most sensitive nodes in the rewirable layer, so that changes in a small set of connections produce a drastic enhancement of the global diffusion of the whole multiplex system. PMID- 28618568 TI - Finite-size corrections in the random assignment problem. AB - We analytically derive, in the context of the replica formalism, the first finite size corrections to the average optimal cost in the random assignment problem for a quite generic distribution law for the costs. We show that, when moving from a power-law distribution to a Gamma distribution, the leading correction changes both in sign and in its scaling properties. We also examine the behavior of the corrections when approaching a delta-function distribution. By using a numerical solution of the saddle-point equations, we provide predictions that are confirmed by numerical simulations. PMID- 28618569 TI - Chaos in the band structure of a soft Sinai lattice. AB - We study the effect of broken spatial and dynamical symmetries on the band structure of two lattices with unit cells that are soft versions of the classic Sinai billiard. We find significant signatures of chaos in the band structure of these lattices, in energy regimes where the underlying classical unit cell undergoes a transition to chaos. Broken dynamical symmetries and the presence of chaos can diminish the feasibility of changing and controlling band structure in a wide variety of two-dimensional lattice-based devices, including two dimensional solids, optical lattices, and photonic crystals. PMID- 28618570 TI - Thermal Rayleigh-Marangoni convection in a three-layer liquid-metal-battery model. AB - The combined effects of buoyancy-driven Rayleigh-Benard convection (RC) and surface tension-driven Marangoni convection (MC) are studied in a triple-layer configuration which serves as a simplified model for a liquid metal battery (LMB). The three-layer model consists of a liquid metal alloy cathode, a molten salt separation layer, and a liquid metal anode at the top. Convection is triggered by the temperature gradient between the hot electrolyte and the colder electrodes, which is a consequence of the release of resistive heat during operation. We present a linear stability analysis of the state of pure thermal conduction in combination with three-dimensional direct numerical simulations of the nonlinear turbulent evolution on the basis of a pseudospectral method. Five different modes of convection are identified in the configuration, which are partly coupled to each other: RC in the upper electrode, RC with internal heating in the molten salt layer, and MC at both interfaces between molten salt and electrode as well as anticonvection in the middle layer and lower electrode. The linear stability analysis confirms that the additional Marangoni effect in the present setup increases the growth rates of the linearly unstable modes, i.e., Marangoni and Rayleigh-Benard instability act together in the molten salt layer. The critical Grashof and Marangoni numbers decrease with increasing middle layer thickness. The calculated thresholds for the onset of convection are found for realistic current densities of laboratory-sized LMBs. The global turbulent heat transfer follows scaling predictions for internally heated RC. The global turbulent momentum transfer is comparable with turbulent convection in the classical Rayleigh-Benard case. In summary, our studies show that incorporating Marangoni effects generates smaller flow structures, alters the velocity magnitudes, and enhances the turbulent heat transfer across the triple-layer configuration. PMID- 28618571 TI - Evidence for equivalence of diffusion processes of passive scalar and magnetic fields in anisotropic Navier-Stokes turbulence. AB - The influence of the uniaxial small-scale anisotropy on the kinematic magnetohydrodynamic turbulence is investigated by using the field theoretic renormalization group technique in the one-loop approximation of a perturbation theory. The infrared stable fixed point of the renormalization group equations, which drives the scaling properties of the model in the inertial range, is investigated as the function of the anisotropy parameters and it is shown that, at least at the one-loop level of approximation, the diffusion processes of the weak passive magnetic field in the anisotropically driven kinematic magnetohydrodynamic turbulence are completely equivalent to the corresponding diffusion processes of passively advected scalar fields in the anisotropic Navier Stokes turbulent environments. PMID- 28618572 TI - Functional window of the avian compass. AB - The functional window is an experimentally observed property of the avian compass that refers to its selectivity around the geomagnetic-field strength. We show that the simple radical-pair model, using biologically feasible hyperfine parameters, can qualitatively explain the salient features of the avian compass as observed in behavioral experiments: its functional window, as well as disruption of the compass action by radio-frequency fields of specific frequencies. Further, we show that adjustment of the hyperfine parameters can tune the functional window, suggesting a possible mechanism for its observed adaptation to field variation. While these lend support to the radical-pair model, we find that in its simplest form-or even with minor augmentations-it cannot quantitatively explain the observed width of the functional window. This suggests deeper generalization of the model, possibly in terms of more nuclei or more subtle environmental interaction than has been considered hitherto. Finally, we examine a possible biological purpose for the functional window; even assuming evolutionary benefit from radical-pair magnetoreception, it seems likely that the functional window could be just a corollary thereof, imparting no additional advantage. PMID- 28618573 TI - beta-Cyclodextrin polymer binding to DNA: Modulating the physicochemical parameters. AB - Cyclodextrins and cyclodextrins-modified molecules have interesting and appealing properties due to their capacity to host components that are normally insoluble or poorly soluble in water. In this work, we investigate the interaction of a beta-cyclodextrin polymer (poly-beta-CD) with lambda-DNA. The polymers are obtained by the reaction of beta-CD with epichlorohydrin in alkaline conditions. We have used optical tweezers to characterize the changes of the mechanical properties of DNA molecules by increasing the concentration of poly-beta-CD in the sample. The physical chemistry of the interaction is then deduced from these measurements by using a recently developed quenched-disorder statistical model. It is shown that the contour length of the DNA does not change in the whole range of poly-beta-CD concentration (<300MUM). On the other hand, significant alterations were observed in the persistence length that identifies two binding modes corresponding to the clustering of ~2.6 and ~14 polymer molecules along the DNA double helix, depending on the polymer concentration. Comparing these results with the ones obtained for monomeric beta-CD, it was observed that the concentration of CD that alters the DNA persistence length is considerably smaller when in the polymeric form. Also, the binding constant of the polymer-DNA interaction is three orders of magnitude higher than the one found for native (monomeric) beta-CD. These results show that the polymerization of the beta-CD strongly increases its binding affinity to the DNA molecule. This property can be wisely used to modulate the binding of cyclodextrins to the DNA double helix. PMID- 28618574 TI - Contact angles of a drop pinned on an incline. AB - For a drop on an incline with small tilt angle alpha, when the contact line is a circle of radius r, we derive the relation mgsinalpha=gammarpi/2(costheta^{min} costheta^{max}) at first order in alpha, where theta^{min} and theta^{max} are the contact angles at the back and at the front, m is the mass of the drop and gamma the surface tension of the liquid. We revisit in this way the Furmidge model for a large range of contact angles. We also derive the same relation at first order in the Bond number B=rhogR^{2}/gamma, where R is the radius of the spherical cap at zero gravity. The drop profile is computed exactly in the same approximation. Results are compared with surface evolver simulations, showing a surprisingly large range of contact angles for applicability of first-order approximations. PMID- 28618575 TI - Hydrodynamics of viscous inhalant flows. AB - Inhalant flows draw fluid into an orifice from a reservoir and are ubiquitous in engineering and biology. Surprisingly, there is a lack of quantitative information on viscous inhalant flows. We consider here laminar flows (Reynolds number Re<=100) developing after impulsive inhalation begins. We implement finite element simulations of flows with varying Re and extraction height h (orifice height above a bottom bed). Numerical results are experimentally validated using particle image velocimetry measurements in a physical model for a representative flow case in the middle of the Re-h parameter space. We use two metrics to characterize the flow in space and time: regions of influence (ROIs), which describe the spatial extent of the flow field, and inhalation volumes, which describe the initial distribution of inhaled fluid. The transient response for all Re features an inviscid sinklike component at early times followed by a viscous diffusive component. At lower Re, diffusion entrains an increasing volume of fluid over time, enlarging the ROI indefinitely. In some geometries, these flows spatially bifurcate, with some fluid being inhaled through the orifice and some bypassing into recirculation. At higher Re, inward advection dominates outward viscous diffusion and the flow remains trapped in a sinklike state. Both ROIs and inhalation volumes are strongly dependent on Re and extraction height, suggesting that organisms or engineers could tune these parameters to achieve specific inhalation criteria. PMID- 28618576 TI - Diffusion of chiral molecules and propagation of structural chirality in anisotropic liquids. AB - Diffusion in nature is usually considered as a smooth redistribution process. However, it appears that the diffusion of chiral molecules and the propagation of chirality may proceed in quite different ways. Indeed, in the present work, unexpected quantization of the spatial concentration of chiral molecules is discovered in self-aligned molecular liquids. It is shown that the interpenetration of two liquids is forming discrete diffusion barrier walls resulting in steplike concentration distribution of chiral molecules in space. The concentration gradient is at least an order of magnitude stronger from both sides of the barrier wall compared to the gradient between those walls. It is also shown that this microscopic diffusion process may be controlled by macroscopic boundary conditions imposed on the host molecular system. Both of those phenomena are related to the collective long-range orientational "elastic" interactions of molecules of the host. The observed phenomena may radically change our understanding of diffusion of chiral molecules, among others, in biological tissue, which contains many examples of self-aligned molecular liquids. This, in turn, has the potential to revolutionize drug design and delivery techniques. PMID- 28618577 TI - Double diffusivity model under stochastic forcing. AB - The "double diffusivity" model was proposed in the late 1970s, and reworked in the early 1980s, as a continuum counterpart to existing discrete models of diffusion corresponding to high diffusivity paths, such as grain boundaries and dislocation lines. It was later rejuvenated in the 1990s to interpret experimental results on diffusion in polycrystalline and nanocrystalline specimens where grain boundaries and triple grain boundary junctions act as high diffusivity paths. Technically, the model pans out as a system of coupled Fick type diffusion equations to represent "regular" and "high" diffusivity paths with "source terms" accounting for the mass exchange between the two paths. The model remit was extended by analogy to describe flow in porous media with double porosity, as well as to model heat conduction in media with two nonequilibrium local temperature baths, e.g., ion and electron baths. Uncoupling of the two partial differential equations leads to a higher-ordered diffusion equation, solutions of which could be obtained in terms of classical diffusion equation solutions. Similar equations could also be derived within an "internal length" gradient (ILG) mechanics formulation applied to diffusion problems, i.e., by introducing nonlocal effects, together with inertia and viscosity, in a mechanics based formulation of diffusion theory. While being remarkably successful in studies related to various aspects of transport in inhomogeneous media with deterministic microstructures and nanostructures, its implications in the presence of stochasticity have not yet been considered. This issue becomes particularly important in the case of diffusion in nanopolycrystals whose deterministic ILG-based theoretical calculations predict a relaxation time that is only about one-tenth of the actual experimentally verified time scale. This article provides the "missing link" in this estimation by adding a vital element in the ILG structure, that of stochasticity, that takes into account all boundary layer fluctuations. Our stochastic-ILG diffusion calculation confirms rapprochement between theory and experiment, thereby benchmarking a new generation of gradient-based continuum models that conform closer to real-life fluctuating environments. PMID- 28618578 TI - Nearly maximally predictive features and their dimensions. AB - Scientific explanation often requires inferring maximally predictive features from a given data set. Unfortunately, the collection of minimal maximally predictive features for most stochastic processes is uncountably infinite. In such cases, one compromises and instead seeks nearly maximally predictive features. Here, we derive upper bounds on the rates at which the number and the coding cost of nearly maximally predictive features scale with desired predictive power. The rates are determined by the fractal dimensions of a process' mixed state distribution. These results, in turn, show how widely used finite-order Markov models can fail as predictors and that mixed-state predictive features can offer a substantial improvement. PMID- 28618579 TI - Charge and spin current statistics of the open Hubbard model with weak coupling to the environment. AB - Based on generalization and extension of our previous work [Phys. Rev. Lett. 112, 067201 (2014)PRLTAO0031-900710.1103/PhysRevLett.112.067201] to multiple independent Markovian baths we will compute the charge and spin current statistics of the open Hubbard model with weak system-bath coupling up to next-to leading order in the coupling parameter. Only the next-to-leading and higher orders depend on the Hubbard interaction parameter. The physical results are related to those for the XXZ model in the analogous setup implying a certain universality, which potentially holds in this class of nonequilibrium models. PMID- 28618580 TI - Entropy of international trades. AB - The organization of international trades is highly complex under the collective efforts towards economic profits of participating countries given inhomogeneous resources for production. Considering the trade flux as the probability of exporting a product from a country to another, we evaluate the entropy of the world trades in the period 1950-2000. The trade entropy has increased with time, and we show that it is mainly due to the extension of trade partnership. For a given number of trade partners, the mean trade entropy is about 60% of the maximum possible entropy, independent of time, which can be regarded as a characteristic of the trade fluxes' heterogeneity and is shown to be derived from the scaling and functional behaviors of the universal trade-flux distribution. The correlation and time evolution of the individual countries' gross-domestic products and the number of trade partners show that most countries achieved their economic growth partly by extending their trade relationship. PMID- 28618581 TI - Symplectic and antiplectic waves in an array of beating cilia attached to a closed body. AB - By taking into account the hydrodynamic interactions in a one dimensional array of model cilia attached to a no-slip cylinderical surface, we investigate their synchronized motion. We show how the emergence of metachronal waves depends on the initial state of the system and investigate the conditions under which the formation of symplectic and antiplectic waves are possible. PMID- 28618582 TI - Interacting opinion and disease dynamics in multiplex networks: Discontinuous phase transition and nonmonotonic consensus times. AB - Opinion formation and disease spreading are among the most studied dynamical processes on complex networks. In real societies, it is expected that these two processes depend on and affect each other. However, little is known about the effects of opinion dynamics over disease dynamics and vice versa, since most studies treat them separately. In this work we study the dynamics of the voter model for opinion formation intertwined with that of the contact process for disease spreading, in a population of agents that interact via two types of connections, social and contact. These two interacting dynamics take place on two layers of networks, coupled through a fraction q of links present in both networks. The probability that an agent updates its state depends on both the opinion and disease states of the interacting partner. We find that the opinion dynamics has striking consequences on the statistical properties of disease spreading. The most important is that the smooth (continuous) transition from a healthy to an endemic phase observed in the contact process, as the infection probability increases beyond a threshold, becomes abrupt (discontinuous) in the two-layer system. Therefore, disregarding the effects of social dynamics on epidemics propagation may lead to a misestimation of the real magnitude of the spreading. Also, an endemic-healthy discontinuous transition is found when the coupling q overcomes a threshold value. Furthermore, we show that the disease dynamics delays the opinion consensus, leading to a consensus time that varies nonmonotonically with q in a large range of the model's parameters. A mean-field approach reveals that the coupled dynamics of opinions and disease can be approximately described by the dynamics of the voter model decoupled from that of the contact process, with effective probabilities of opinion and disease transmission. PMID- 28618583 TI - Phase transitions at high energy vindicate negative microcanonical temperature. AB - The notion of negative absolute temperature emerges naturally from Boltzmann's definition of "surface" microcanonical entropy in isolated systems with a bounded energy density. Recently, the well-posedness of such construct has been challenged, on account that only the Gibbs "volume" entropy-and the strictly positive temperature thereof-would give rise to a consistent thermodynamics. Here we present analytical and numerical evidence that Boltzmann microcanonical entropy provides a consistent thermometry for both signs of the temperature. In particular, we show that Boltzmann (negative) temperature allows the description of phase transitions occurring at high energy densities, at variance with Gibbs temperature. Our results apply to nonlinear lattice models standardly employed to describe the propagation of light in arrays of coupled wave guides and the dynamics of ultracold gases trapped in optical lattices. Optically induced photonic lattices, characterized by saturable nonlinearity, are particularly appealing because they offer the possibility of observing states and phase transitions at both signs of the temperature. PMID- 28618584 TI - Model of the best-of-N nest-site selection process in honeybees. AB - The ability of a honeybee swarm to select the best nest site plays a fundamental role in determining the future colony's fitness. To date, the nest-site selection process has mostly been modeled and theoretically analyzed for the case of binary decisions. However, when the number of alternative nests is larger than two, the decision-process dynamics qualitatively change. In this work, we extend previous analyses of a value-sensitive decision-making mechanism to a decision process among N nests. First, we present the decision-making dynamics in the symmetric case of N equal-quality nests. Then, we generalize our findings to a best-of-N decision scenario with one superior nest and N-1 inferior nests, previously studied empirically in bees and ants. Whereas previous binary models highlighted the crucial role of inhibitory stop-signaling, the key parameter in our new analysis is the relative time invested by swarm members in individual discovery and in signaling behaviors. Our new analysis reveals conflicting pressures on this ratio in symmetric and best-of-N decisions, which could be solved through a time-dependent signaling strategy. Additionally, our analysis suggests how ecological factors determining the density of suitable nest sites may have led to selective pressures for an optimal stable signaling ratio. PMID- 28618585 TI - Uniform description of polymer ejection dynamics from capsid with and without hydrodynamics. AB - We use stochastic rotation dynamics (SRD) to examine the dynamics of the ejection of an initially strongly confined flexible polymer from a spherical capsid with and without hydrodynamics. The results obtained using stochastic rotation dynamics (SRD) are compared to similar Langevin simulations. Inclusion of hydrodynamic modes speeds up the ejection but also allows the part of the polymer outside the capsid to expand closer to equilibrium. This shows as higher values of radius of gyration when hydrodynamics are enabled. By examining the waiting times of individual polymer beads, we find that the waiting time t_{w} grows with the number of ejected monomers s as a sum of two exponents. When ~63% of the polymer has ejected, the ejection enters the regime of slower dynamics. The functional form of t_{w} versus s is universal for all ejection processes starting from the same initial monomer densities. Inclusion of hydrodynamics only reduces its magnitude. Consequently, we define a universal scaling function h such that the cumulative waiting time t=N_{0}h(s/N_{0}) for large N_{0}. Our unprecedentedly precise measurements of force indicate that this form for t_{w}(s) originates from the corresponding force toward the pore decreasing superexponentially at the end of the ejection. Our measured t_{w}(s) explains the apparent superlinear scaling of the ejection time with the polymer length for short polymers. However, for asymptotically long polymers, t_{w}(s) predicts linear scaling. PMID- 28618586 TI - Pattern of a confined chemical garden controlled by injection speed. AB - Pattern of confined chemical garden was controlled by the speed of injected fluid, and their mechanism is discussed. A confined chemical garden system was constructed where an aqueous solution of cobalt chloride was injected into a cell filled with sodium silicate solution. The reaction of these two solutions resulted in the formation of precipitation. The viscosities of the prepared aqueous solutions were set to be similar in order to rule out the possibility of Saffman-Taylor instability. The injection front showed three distinctive patterns: algaes, shells, and filaments, which were dependent on injection speed. The injection pressure and the spatio-temporal pattern of the injected fluid were measured, and a significant increase in the injection pressure was observed when the filament pattern appeared, which indicated the existence of thin lubrication layer between the precipitation and the substrate. The filament pattern was further analyzed quantitatively, and the number of active filaments was determined to be proportional to the injection speed. A mathematical model was constructed that considered both the viscous effect from the thin lubrication layer and the Laplace pressure. This model successfully reproduced the characteristic filament dynamics. PMID- 28618587 TI - General scaling relations for locomotion in granular media. AB - Inspired by dynamic similarity in fluid systems, we have derived a general dimensionless form for locomotion in granular materials, which is validated in experiments and discrete element method (DEM) simulations. The form instructs how to scale size, mass, and driving parameters in order to relate dynamic behaviors of different locomotors in the same granular media. The scaling can be derived by assuming intrusion forces arise from resistive force theory or equivalently by assuming the granular material behaves as a continuum obeying a frictional yield criterion. The scalings are experimentally confirmed using pairs of wheels of various shapes and sizes under many driving conditions in a common sand bed. We discuss why the two models provide such a robust set of scaling laws even though they neglect a number of the complexities of granular rheology. Motivated by potential extraplanetary applications, the dimensionless form also implies a way to predict wheel performance in one ambient gravity based on tests in a different ambient gravity. We confirm this using DEM simulations, which show that scaling relations are satisfied over an array of driving modes even when gravity differs between scaled tests. PMID- 28618588 TI - Multiscale model for pedestrian and infection dynamics during air travel. AB - In this paper we develop a multiscale model combining social-force-based pedestrian movement with a population level stochastic infection transmission dynamics framework. The model is then applied to study the infection transmission within airplanes and the transmission of the Ebola virus through casual contacts. Drastic limitations on air-travel during epidemics, such as during the 2014 Ebola outbreak in West Africa, carry considerable economic and human costs. We use the computational model to evaluate the effects of passenger movement within airplanes and air-travel policies on the geospatial spread of infectious diseases. We find that boarding policy by an airline is more critical for infection propagation compared to deplaning policy. Enplaning in two sections resulted in fewer infections than the currently followed strategy with multiple zones. In addition, we found that small commercial airplanes are better than larger ones at reducing the number of new infections in a flight. Aggregated results indicate that passenger movement strategies and airplane size predicted through these network models can have significant impact on an event like the 2014 Ebola epidemic. The methodology developed here is generic and can be readily modified to incorporate the impact from the outbreak of other directly transmitted infectious diseases. PMID- 28618589 TI - Emergence of chaos in starlike networks of dissipative nonlinear oscillators by localized parametric excitations. AB - We study the effectiveness of locally controlling the impulse transmitted by parametric periodic excitations at inducing and suppressing chaos in starlike networks of driven damped pendula, leading to asynchronous chaotic states and equilibria, respectively. We found that the inducing (suppressor) effect of increasing (decreasing) the impulse transmitted by the parametric excitations acting on particular nodes depends strongly on their number and degree of connectivity as well as the coupling strength. Additionally, we provide a theoretical analysis explaining the basic physical mechanisms of the emergence and suppression of chaos as well as the main features of the chaos-control scenario. Our findings constitute proof of the impulse-induced control of chaos in a simple model of complex networks, thus opening the way to its application to real-world networks. PMID- 28618590 TI - Multidimensional Chebyshev interpolation for warm and hot dense matter. AB - We propose a scheme based on a multidimensional Chebyshev interpolation to approximate smooth functions that depend on more than one variable. The present method generalizes the one dimensional Chebyshev approximation. The multidimensional approach can be used for generating databases like equation of state in the warm and hot dense matter. It is well suited to the present advance of massively parallel supercomputers. PMID- 28618591 TI - Origin of the inverse energy cascade in two-dimensional quantum turbulence. AB - We establish a statistical relationship between the inverse energy cascade and the spatial correlations of clustered vortices in two-dimensional quantum turbulence. The Kolmogorov spectrum k^{-5/3} on inertial scales r corresponds to a pair correlation function between the vortices with different signs that decays as a power law with the pair distance given as r^{-4/3}. To test these scaling relations, we propose a forced and dissipative point vortex model that captures the turbulent dynamics of quantized vortices by the emergent clustering of same sign vortices. The inverse energy cascade developing in a statistically neutral system originates from this vortex clustering that evolves with time. PMID- 28618592 TI - Condensation of Lee-Yang zeros in scalar field theory. AB - We show that, at the critical temperature, there is a class of Lee-Yang zeros of the partition function in a general scalar field theory, which location scales with the size of the system with a characteristic exponent expressed in terms of the isothermal critical exponent delta. In the thermodynamic limit the zeros belonging to this class condense to the critical point zeta=1 on the real axis in the complex fugacity plane while the complementary set of zeros (with Rezeta<1) covers the unit circle. Although the aforementioned class degenerates to a single point for an infinite system, when the size is finite it contributes significantly to the partition function and reflects the self-similar structure (fractal geometry, scaling laws) of the critical system. This property opens up the perspective to formulate finite-size scaling theory in effective QCD, near the chiral critical point, in terms of the location of Lee-Yang zeros. PMID- 28618593 TI - Wetting and dewetting processes in the axial retraction of liquid filaments. AB - We study the hydrodynamic mechanisms involved in the motion of the contact line formed at the end region of a liquid filament laying on a planar and horizontal substrate. Since the flow develops under partially wetting conditions, the tip of the filament recedes and forms a bulged region (head) that subsequently develops a neck region behind it. Later the neck breaks up leading to a separated drop, while the rest of the filament restarts the sequence. One main feature of this flow is that the whole dynamics and final drop shapes are strongly influenced by the hysteresis of the contact angle typical in most of the liquid-substrate systems. The time evolution till breakup is studied experimentally and pictured in terms of a hybrid wettability theory which involves the Cox-Voinov hydrodynamic approach combined with the molecular kinetic theory developed by Blake. The parameters of this theory are determined for our liquid-substrate system (silicone oil-coated glass). The experimental results of the retracting filament are described in terms of a simple heuristic model and compared with numerical simulations of the full Navier-Stokes equations. This study is of special interest in the context of pulsed laser-induced dewetting. PMID- 28618594 TI - Alliance formation with exclusion in the spatial public goods game. AB - Detecting defection and alarming partners about the possible danger could be essential to avoid being exploited. This act, however, may require a huge individual effort from those who take this job, hence such a strategy seems to be unfavorable. But structured populations can provide an opportunity where a largely unselfish excluder strategy can form an effective alliance with other cooperative strategies, hence they can sweep out defection. Interestingly, this alliance is functioning even at the extremely high cost of exclusion where the sole application of an exclusion strategy would be harmful otherwise. These results may explain why the emergence of extreme selfless behavior is not necessarily against individual selection but could be the result of an evolutionary process. PMID- 28618595 TI - Anticipated synchronization in neuronal circuits unveiled by a phase-response curve analysis. AB - Anticipated synchronization (AS) is a counterintuitive behavior that has been observed in several systems. When AS occurs in a sender-receiver configuration, the latter can predict the future dynamics of the former for certain parameter values. In particular, in neuroscience AS was proposed to explain the apparent discrepancy between information flow and time lag in the cortical activity recorded in monkeys. Despite its success, a clear understanding of the mechanisms yielding AS in neuronal circuits is still missing. Here we use the well-known phase-response-curve (PRC) approach to study the prototypical sender-receiver interneuron neuronal motif. Our aim is to better understand how the transitions between delayed to anticipated synchronization and anticipated synchronization to phase-drift regimes occur. We construct a map based on the PRC method to predict the phase-locking regimes and their stability. We find that a PRC function of two variables, accounting simultaneously for the inputs from sender and interneuron into the receiver, is essential to reproduce the numerical results obtained using a Hodgkin-Huxley model for the neurons. On the contrary, the typical approximation that considers a sum of two independent single-variable PRCs fails for intermediate to high values of the inhibitory coupling strength of the interneuron. In particular, it loses the delayed-synchronization to anticipated synchronization transition. PMID- 28618596 TI - Language competition in a population of migrating agents. AB - Influencing various aspects of human activity, migration is associated also with language formation. To examine the mutual interaction of these processes, we study a Naming Game with migrating agents. The dynamics of the model leads to formation of low-mobility clusters, which turns out to break the symmetry of the model: although the Naming Game remains symmetric, low-mobility languages are favored. High-mobility languages are gradually eliminated from the system, and the dynamics of language formation considerably slows down. Our model is too simple to explain in detail language competition of migrating human communities, but it certainly shows that languages of settlers are favored over nomadic ones. PMID- 28618597 TI - Role of the displacement current on Warburg-type behavior. AB - We investigate the role of the displacement current in the analysis of the electric response of an electrolytic cell to an external stimulus. We show that several models proposed to interpret the spectra deduced by means of the impedance spectroscopy technique are questionable. In particular, we demonstrate that even in the frequency range below the Debye frequency the role of the displacement current is fundamental, and its omission leads to incorrect results for the impedance of the cell. In our analysis, the boundary conditions on the bulk current density are of Nernstian and of Ohmic type. The analysis is limited to a fully dissociated electrolyte, and for only one type of mobile ions, as discussed in several papers devoted to the subject. Particular attention is given to the spatial dependence of the current density. We show that Warburg-like behavior is never predicted in the framework of the Poisson-Nernst-Planck model, if the electric impedance of the cell is correctly evaluated. From this conclusion, valid for media with only one type of mobile ions, it follows that if Warburg-like behavior is experimentally observed the theoretical interpretation is still an open problem, and its origin is probably related to the boundary conditions. PMID- 28618598 TI - Designing nucleosomal force sensors. AB - About three quarters of our DNA is wrapped into nucleosomes: DNA spools with a protein core. It is well known that the affinity of a given DNA stretch to be incorporated into a nucleosome depends on the geometry and elasticity of the basepair sequence involved, causing the positioning of nucleosomes. Here we show that DNA elasticity can have a much deeper effect on nucleosomes than just their positioning: it affects their "identities". Employing a recently developed computational algorithm, the mutation Monte Carlo method, we design nucleosomes with surprising physical characteristics. Unlike any other nucleosomes studied so far, these nucleosomes are short-lived when put under mechanical tension whereas other physical properties are largely unaffected. This suggests that the nucleosome, the most abundant DNA-protein complex in our cells, might more properly be considered a class of complexes with a wide array of physical properties, and raises the possibility that evolution has shaped various nucleosome species according to their genomic context. PMID- 28618599 TI - Grain coarsening in two-dimensional phase-field models with an orientation field. AB - In the literature, contradictory results have been published regarding the form of the limiting (long-time) grain size distribution (LGSD) that characterizes the late stage grain coarsening in two-dimensional and quasi-two-dimensional polycrystalline systems. While experiments and the phase-field crystal (PFC) model (a simple dynamical density functional theory) indicate a log-normal distribution, other works including theoretical studies based on conventional phase-field simulations that rely on coarse grained fields, like the multi-phase field (MPF) and orientation field (OF) models, yield significantly different distributions. In a recent work, we have shown that the coarse grained phase field models (whether MPF or OF) yield very similar limiting size distributions that seem to differ from the theoretical predictions. Herein, we revisit this problem, and demonstrate in the case of OF models [R. Kobayashi, J. A. Warren, and W. C. Carter, Physica D 140, 141 (2000)PDNPDT0167-278910.1016/S0167 2789(00)00023-3; H. Henry, J. Mellenthin, and M. Plapp, Phys. Rev. B 86, 054117 (2012)PRBMDO1098-012110.1103/PhysRevB.86.054117] that an insufficient resolution of the small angle grain boundaries leads to a log-normal distribution close to those seen in the experiments and the molecular scale PFC simulations. Our paper indicates, furthermore, that the LGSD is critically sensitive to the details of the evaluation process, and raises the possibility that the differences among the LGSD results from different sources may originate from differences in the detection of small angle grain boundaries. PMID- 28618600 TI - Relation between the porosity and tortuosity of a membrane formed by disconnected irregular pores and the spatial diffusion coefficient of the Fick-Jacobs model. AB - In this work, we provide a theoretical relationship between the spatial-dependent diffusion coefficient derived in the Fick-Jacobs (FJ) approximation and the macroscopic diffusion coefficient of a membrane that depends on the porosity, tortuosity, and the constriction factors. Based on simple mass conservation arguments under equilibrium as well as in nonequilibrium conditions, we generalize previous expressions for the effective diffusion coefficient of an irregular pore, originally obtained by Festa and d'Agliano for horizontal and periodic pores, and then extended by Bradley for tortuous periodic pores, to the case of pores with arbitrary geometry. Through a formal definition of the constrictivity factor in terms of the geometry of the pore, our results provide very clear physical interpretation of experimental measurements since they link the local properties of the flow with macroscopic quantities of experimental relevance in the design and optimization of porous materials. The macroscopic diffusion coefficient as well as the spatiotemporal evolution of the concentration profiles inside a pore have been recently measured by using pulse field gradient NMR techniques. The advantage of using the FJ approach is that the spatiotemporal concentration profile inside a pore of irregular geometry is directly related to the pore's shape and, therefore, that the macroscopic diffusion coefficient can be obtained by comparing the spatiotemporal concentration profiles from such experiments with those of the theoretical model. Hence, the present study is relevant for the understanding of the transport properties of porous materials where the shape and arrangement of pores can be controlled at will. PMID- 28618601 TI - Dual time scales in simulated annealing of a two-dimensional Ising spin glass. AB - We apply a generalized Kibble-Zurek out-of-equilibrium scaling ansatz to simulated annealing when approaching the spin-glass transition at temperature T=0 of the two-dimensional Ising model with random J=+/-1 couplings. Analyzing the spin-glass order parameter and the excess energy as functions of the system size and the annealing velocity in Monte Carlo simulations with Metropolis dynamics, we find scaling where the energy relaxes slower than the spin-glass order parameter, i.e., there are two different dynamic exponents. The values of the exponents relating the relaxation time scales to the system length, tau~L^{z}, are z=8.28+/-0.03 for the relaxation of the order parameter and z=10.31+/-0.04 for the energy relaxation. We argue that the behavior with dual time scales arises as a consequence of the entropy-driven ordering mechanism within droplet theory. We point out that the dynamic exponents found here for T->0 simulated annealing are different from the temperature-dependent equilibrium dynamic exponent z_{eq}(T), for which previous studies have found a divergent behavior: z_{eq}(T->0)->infinity. Thus, our study shows that, within Metropolis dynamics, it is easier to relax the system to one of its degenerate ground states than to migrate at low temperatures between regions of the configuration space surrounding different ground states. In a more general context of optimization, our study provides an example of robust dense-region solutions for which the excess energy (the conventional cost function) may not be the best measure of success. PMID- 28618602 TI - Finite-thickness effects on the Rayleigh-Taylor instability in accelerated elastic solids. AB - A physical model has been developed for the linear Rayleigh-Taylor instability of a finite-thickness elastic slab laying on top of a semi-infinite ideal fluid. The model includes the nonideal effects of elasticity as boundary conditions at the top and bottom interfaces of the slab and also takes into account the finite transit time of the elastic waves across the slab thickness. For Atwood number A_{T}=1, the asymptotic growth rate is found to be in excellent agreement with the exact solution [Plohr and Sharp, Z. Angew. Math. Mech. 49, 786 (1998)10.1007/s000330050121], and a physical explanation is given for the reduction of the stabilizing effectiveness of the elasticity for the thinner slabs. The feedthrough factor is also calculated. PMID- 28618603 TI - Analytical solution of the steady membrane voltage fluctuation caused by a single ion channel. AB - An analytical steady-state solution of the stochastic model describing the integrated dynamics of the membrane voltage and the gating of a single channel is presented. The voltage density function experiences bifurcation in the parameter space, and the threshold is determined by the comparison between the rates of the voltage evolution and that of the channel gating. It is singular at the reversal potential if the voltage evolves faster than the channel gating. As an application, the entropy production rate associated with the gating currents is calculated; its variation tendency in parameter space is consistent to that of the number of transitions counted from the sample paths. The analysis in this paper identifies the values of parameters that justify the formation of the voltage pulse and the efficient energy cost, which is associated with the singularity of the voltage density functions. PMID- 28618604 TI - Taylor cone and electrospraying at a free surface of superfluid helium charged from below. AB - Electrically charged metallic micro- and nanoparticles are trapped under a free surface of superfluid He in a vertical static electric field. We observe a static deformation of the charged liquid surface in the form of a Taylor cone and the emission of a charged liquid helium jet (electrospray). Our numeric calculations reproduce the static shape of the cone. PMID- 28618605 TI - Measurements of ionization states in warm dense aluminum with betatron radiation. AB - Time-resolved measurements of the ionization states of warm dense aluminum via K shell absorption spectroscopy are demonstrated using betatron radiation generated from laser wakefield acceleration as a probe. The warm dense aluminum is generated by irradiating a free-standing nanofoil with a femtosecond optical laser pulse and was heated to an electron temperature of ~20-25 eV at a close-to solid mass density. Absorption dips in the transmitted x-ray spectrum due to the Al^{4+} and Al^{5+} ions are clearly seen during the experiments. The measured absorption spectra are compared to simulations with various ionization potential depression models, including the commonly used Stewart-Pyatt model and an alternative modified Ecker-Kroll model. The observed absorption spectra are in approximate agreement with these models, though indicating a slightly higher state of ionization and closer agreement for simulations with the modified Ecker Kroll model. PMID- 28618606 TI - Instabilities in bilayer complex plasmas: Wake-induced mode coupling. AB - Stability principles for bilayer complex plasmas are studied. To mimic bilayer crystals and identify the main melting mechanism of such structures, a simple binary-chain model is employed. This approach provides adequate representation of the collective effects and accurate description of the interaction nonreciprocity, associated with the wake-mediated interparticle forces. It is shown that the wake-induced coupling of the wave modes sustained in different crystalline layers can trigger the dynamical instability. Furthermore, the mode coupling is demonstrated to be a universal instability mechanism, operating also in bilayer fluids. General stability criteria for the crystalline and fluid bilayers are derived. PMID- 28618607 TI - Fully kinetic simulation study of ion-acoustic solitons in the presence of trapped electrons. AB - The nonlinear fluid theory developed by Schamel suggests a modified KdV equation to describe the temporal evolution of ion acoustic (IA) solitons in the presence of trapped electrons. The validity of this theory is studied here by verifying solitons' main characteristic, i.e., stability against successive mutual collisions. We have employed a kinetic model as a more comprehensive theory than the fluid one, and utilized a fully kinetic simulation approach (both ions and electrons are treated based on the Vlasov equation). In the simulation approach, these solitons are excited self-consistently by employing the nonlinear process of IA solitons formation from an initial density perturbation (IDP). The effect of the size of IDPs on the chain formation is proved by the simulation code as a benchmark test. It is shown that the IA solitons, in the presence of trapped electrons, can retain their features (both in spatial and velocity direction) after successive mutual collisions. The collisions here include encounters of IA solitons with the same trapping parameter, while differing in size. Kinetic simulation results reveal a complicated behavior during a collision between IA solitons in contrast to the fluid theory predictions and simulations. In the range of parameters considered here, two oppositely propagating solitons rotate around their collective center in the phase space during a collision, independent of their trapping parameters. Furthermore, they exchange some portions of their trapped populations. PMID- 28618608 TI - Hydrodynamic theory of freezing: Nucleation and polycrystalline growth. AB - Structural aspects of crystal nucleation in undercooled liquids are explored using a nonlinear hydrodynamic theory of crystallization proposed recently [G. I. Toth et al., J. Phys.: Condens. Matter 26, 055001 (2014)JCOMEL0953 898410.1088/0953-8984/26/5/055001], which is based on combining fluctuating hydrodynamics with the phase-field crystal theory. We show that in this hydrodynamic approach not only homogeneous and heterogeneous nucleation processes are accessible, but also growth front nucleation, which leads to the formation of new (differently oriented) grains at the solid-liquid front in highly undercooled systems. Formation of dislocations at the solid-liquid interface and interference of density waves ahead of the crystallization front are responsible for the appearance of the new orientations at the growth front that lead to spherulite like nanostructures. PMID- 28618609 TI - Splitting in the pinning-depinning transition of fronts in long-delayed bistable systems. AB - We investigate the formation of localized domains through front pinning in a periodically forced, bistable semiconductor laser with long-delayed optoelectronic feedback. At difference with 1D spatially extended systems, the transition from the pinning to the propagation regime occurs via two separated bifurcations, each corresponding to the unpinning of one of the fronts surrounding the localized domain. The bifurcation splitting is systematically explored, unveiling the crucial role played by the forcing frequency. The experimental results are reproduced and interpreted by means of a prototypical model of our system. PMID- 28618610 TI - Estimating higher-order structure functions from geophysical turbulence time series: Confronting the curse of the limited sample size. AB - Utilizing synthetically generated random variates and laboratory measurements, we document the inherent limitations of the conventional structure function approach in limited sample size settings. We demonstrate that an alternative approach, based on the principle of maximum likelihood, can provide nearly unbiased structure function estimates with far less uncertainty under such unfavorable conditions. The superiority of this approach over the conventional approach does not diminish even in the case of strongly correlated samples. Two entirely different types of probability distributions, which have been reported in the turbulence literature, are found to be compatible with the proposed approach. PMID- 28618611 TI - Large-scale structure of randomly jammed spheres. AB - We numerically analyze the density field of three-dimensional randomly jammed packings of monodisperse soft frictionless spherical particles, paying special attention to fluctuations occurring at large length scales. We study in detail the two-point static structure factor at low wave vectors in Fourier space. We also analyze the nature of the density field in real space by studying the large distance behavior of the two-point pair correlation function, of density fluctuations in subsystems of increasing sizes, and of the direct correlation function. We show that such real space analysis can be greatly improved by introducing a coarse-grained density field to disentangle genuine large-scale correlations from purely local effects. Our results confirm that both Fourier and real space signatures of vanishing density fluctuations at large scale are absent, indicating that randomly jammed packings are not hyperuniform. In addition, we establish that the pair correlation function displays a surprisingly complex structure at large distances, which is however not compatible with the long-range negative correlation of hyperuniform systems but fully compatible with an analytic form for the structure factor. This implies that the direct correlation function is short ranged, as we also demonstrate directly. Our results reveal that density fluctuations in jammed packings do not follow the behavior expected for random hyperuniform materials, but display instead a more complex behavior. PMID- 28618612 TI - Simon's fundamental rich-get-richer model entails a dominant first-mover advantage. AB - Herbert Simon's classic rich-get-richer model is one of the simplest empirically supported mechanisms capable of generating heavy-tail size distributions for complex systems. Simon argued analytically that a population of flavored elements growing by either adding a novel element or randomly replicating an existing one would afford a distribution of group sizes with a power-law tail. Here, we show that, in fact, Simon's model does not produce a simple power-law size distribution as the initial element has a dominant first-mover advantage, and will be overrepresented by a factor proportional to the inverse of the innovation probability. The first group's size discrepancy cannot be explained away as a transient of the model, and may therefore be many orders of magnitude greater than expected. We demonstrate how Simon's analysis was correct but incomplete, and expand our alternate analysis to quantify the variability of long term rankings for all groups. We find that the expected time for a first replication is infinite, and show how an incipient group must break the mechanism to improve their odds of success. We present an example of citation counts for a specific field that demonstrates a first-mover advantage consistent with our revised view of the rich-get-richer mechanism. Our findings call for a reexamination of preceding work invoking Simon's model and provide an expanded understanding going forward. PMID- 28618613 TI - Describing magnetorheology under a colloidal glass approach. AB - The equilibrium structure and dynamics of magnetorheological (MR) fluids are studied in this work by simulations, where particles are modeled as dipoles with a quasihard spherical core. Upon increasing the interaction strength, controlled experimentally by the magnetic field, elongated clusters grow and, for intense fields, thick columns form, aligned with the field. The dynamics of the system is monitored by the mean-squared displacement and density correlation functions, which show an increasing slowing down with the attraction strength. The correlation function shows a two-step decay, with a separation between microscopic and long time dynamics, a typical hallmark of undercooled fluids. We have therefore analyzed the dynamics of this MR fluid using the typical concepts for undercooled fluids. Thus, the second decay of the density correlation function is fitted with a stretched exponential, and the wave-vector dependence of the fitting parameters studied. Both the amplitude and the time scale oscillate in phase with the structure factor. Our results support the idea that the magnetorheological effect is in fact the manifestation of a colloidal system approaching an attractive glass transition (or gel transition). PMID- 28618614 TI - Temperature distribution and heat radiation of patterned surfaces at short wavelengths. AB - We analyze the equilibrium spatial distribution of surface temperatures of patterned surfaces. The surface is exposed to a constant external heat flux and has a fixed internal temperature that is coupled to the outside heat fluxes by finite heat conductivity across the surface. It is assumed that the temperatures are sufficiently high so that the thermal wavelength (a few microns at room temperature) is short compared to all geometric length scales of the surface patterns. Hence the radiosity method can be employed. A recursive multiple scattering method is developed that enables rapid convergence to equilibrium temperatures. While the temperature distributions show distinct dependence on the detailed surface shapes (cuboids and cylinder are studied), we demonstrate robust universal relations between the mean and the standard deviation of the temperature distributions and quantities that characterize overall geometric features of the surface shape. PMID- 28618615 TI - Electrostatic Debye layer formed at a plasma-liquid interface. AB - We construct an analytic model for the electrostatic Debye layer formed at a plasma-liquid interface by combining the Gouy-Chapman theory for the liquid with a simple parabolic band model for the plasma sheath. The model predicts a nonlinear scaling between the plasma current density and the solution ionic strength, and we confirmed this behavior with measurements using a liquid-anode plasma. Plots of the measured current density as a function of ionic strength collapse the data and curve fits yield a plasma electron density of ~10^{19}m^{ 3} and an electric field of ~10^{4}V/m on the liquid side of the interface. Because our theory is based firmly on fundamental physics, we believe it can be widely applied to many emerging technologies involving the interaction of low temperature, nonequilibrium plasma with aqueous media, including plasma medicine and various plasma chemical synthesis techniques. PMID- 28618616 TI - Solvent-dependent critical properties of polymer adsorption. AB - Advanced chain-growth computer simulation methodologies have been employed for a systematic statistical analysis of the critical behavior of a polymer adsorbing at a substrate. We use finite-size scaling techniques to investigate the solvent quality dependence of critical exponents, critical temperature, and the structure of the phase diagram. Our study covers all solvent effects from the limit of super-self-avoiding walks, characterized by effective monomer-monomer repulsion, to poor solvent conditions that enable the formation of compact polymer structures. The results significantly benefit from taking into account corrections to scaling. PMID- 28618617 TI - Extended lattice Boltzmann scheme for droplet combustion. AB - The available lattice Boltzmann (LB) models for combustion or phase change are focused on either single-phase flow combustion or two-phase flow with evaporation assuming a constant density for both liquid and gas phases. To pave the way towards simulation of spray combustion, we propose a two-phase LB method for modeling combustion of liquid fuel droplets. We develop an LB scheme to model phase change and combustion by taking into account the density variation in the gas phase and accounting for the chemical reaction based on the Cahn-Hilliard free-energy approach. Evaporation of liquid fuel is modeled by adding a source term, which is due to the divergence of the velocity field being nontrivial, in the continuity equation. The low-Mach-number approximation in the governing Navier-Stokes and energy equations is used to incorporate source terms due to heat release from chemical reactions, density variation, and nonluminous radiative heat loss. Additionally, the conservation equation for chemical species is formulated by including a source term due to chemical reaction. To validate the model, we consider the combustion of n-heptane and n-butanol droplets in stagnant air using overall single-step reactions. The diameter history and flame standoff ratio obtained from the proposed LB method are found to be in good agreement with available numerical and experimental data. The present LB scheme is believed to be a promising approach for modeling spray combustion. PMID- 28618618 TI - Critical behavior of the two-dimensional Ising model with a slit. AB - The two-dimensional Ising model with a slit is studied. The slit free energy is defined, in which the bulk term, edge terms, and corner terms other than that of the slit are canceled. The bond propagation algorithm is used to calculate the free energy, internal energy, and heat capacity numerically. At the critical point, the slit free energy has a logarithmic correction L^{-1}lnL, in addition to the correction lnL, where L is the typical length of the system. The fitted coefficients of these terms agree with the conformal field theory very well. The integral constant and extrapolation length, which are pending in the conformal field theory, are obtained. In the slit internal energy, the leading term is proportional to L. There is a correction term, ln^{2}L, that has a geometry independent coefficient, the exact value of which is conjectured to be sqrt[2]/(2pi^{2}). The leading term in the slit heat capacity is proportional to L^{2}. There is also a ln^{2}L term; however, its coefficient depends on the geometry. In the infinitely long strip limit, its exact value is conjectured to be 5/pi^{2}. Near the critical point, for different size lattices, the rescaled slit free energies, internal energies, and heat capacities collapse onto the corresponding universal curves. According to the scaling and conformal field theory, the leading term of the slit free energy should be -c/8ln|t| for L|t|?1 and |t|?1, where t is the reduced temperature. The amplitude c/8 is universal, and c is the central charge. Our results validate these predictions qualitatively. For L|t|?1 and |t|?1, the slit internal energy and heat capacity scale as t^{-1} and t^{-2}, respectively. PMID- 28618619 TI - Coarse graining atomistic simulations of plastically deforming amorphous solids. AB - The primary mode of failure in disordered solids results from the formation and persistence of highly localized regions of large plastic strains known as shear bands. Continuum-level field theories capable of predicting this mechanical response rely upon an accurate representation of the initial and evolving states of the amorphous structure. We perform molecular dynamics simulations of a metallic glass and propose a methodology for coarse graining discrete, atomistic quantities, such as the potential energies of the elemental constituents. A strain criterion is established and used to distinguish the coarse-grained degrees-of-freedom inside the emerging shear band from those of the surrounding material. A signal-to-noise ratio provides a means of evaluating the strength of the signal of the shear band as a function of the coarse graining. Finally, we investigate the effect of different coarse graining length scales by comparing a two-dimensional, numerical implementation of the effective-temperature description in the shear transformation zone (STZ) theory with direct molecular dynamics simulations. These comparisons indicate the coarse graining length scale has a lower bound, above which there is a high level of agreement between the atomistics and the STZ theory, and below which the concept of effective temperature breaks down. PMID- 28618620 TI - Levy flights versus Levy walks in bounded domains. AB - Levy flights and Levy walks serve as two paradigms of random walks resembling common features but also bearing fundamental differences. One of the main dissimilarities is the discontinuity versus continuity of their trajectories and infinite versus finite propagation velocity. As a consequence, a well-developed theory of Levy flights is associated with their pathological physical properties, which in turn are resolved by the concept of Levy walks. Here, we explore Levy flight and Levy walk models on bounded domains, examining their differences and analogies. We investigate analytically and numerically whether and under which conditions both approaches yield similar results in terms of selected statistical observables characterizing the motion: the survival probability, mean first passage time, and stationary probability density functions. It is demonstrated that the similarity of the models is affected by the type of boundary conditions and the value of the stability index defining the asymptotics of the jump length distribution. PMID- 28618621 TI - Tracer diffusion in active suspensions. AB - We study the diffusion of a Brownian probe particle of size R in a dilute dispersion of active Brownian particles of size a, characteristic swim speed U_{0}, reorientation time tau_{R}, and mechanical energy k_{s}T_{s}=zeta_{a}U_{0}^{2}tau_{R}/6, where zeta_{a} is the Stokes drag coefficient of a swimmer. The probe has a thermal diffusivity D_{P}=k_{B}T/zeta_{P}, where k_{B}T is the thermal energy of the solvent and zeta_{P} is the Stokes drag coefficient for the probe. When the swimmers are inactive, collisions between the probe and the swimmers sterically hinder the probe's diffusive motion. In competition with this steric hindrance is an enhancement driven by the activity of the swimmers. The strength of swimming relative to thermal diffusion is set by Pe_{s}=U_{0}a/D_{P}. The active contribution to the diffusivity scales as Pe_{s}^{2} for weak swimming and Pe_{s} for strong swimming, but the transition between these two regimes is nonmonotonic. When fluctuations in the probe motion decay on the time scale tau_{R}, the active diffusivity scales as k_{s}T_{s}/zeta_{P}: the probe moves as if it were immersed in a solvent with energy k_{s}T_{s} rather than k_{B}T. PMID- 28618622 TI - Production of high-angular-momentum electron beams in laser-plasma interactions. AB - It was shown that in the interactions of ultra-intense circularly polarized laser pulse with the near-critical plasmas, the angular momentum can be transferred efficiently from the laser beam to electrons through the resonance acceleration process. The transferred angular momentum increases almost linearly with the acceleration time t_{a} when the electrons are resonantly accelerated by the laser field. In addition, it is shown analytically that the averaged angular momentum of electrons is proportional to the laser amplitude a_{L}, and the total angular momentum of the accelerated electron beam is proportional to the square of the laser amplitude a_{L}^{2} for a fixed parameter of n_{e}/n_{c}a_{L}. These results are verified by three-dimensional particle-in-cell simulations. This regime provides an efficient and compact alternative for the production of high angular momentum electron beams, which may have many potential applications in condensed-matter spectroscopy, new electron microscopes, and bright x-ray vortex generation. PMID- 28618623 TI - Macroscopically constrained Wang-Landau method for systems with multiple order parameters and its application to drawing complex phase diagrams. AB - A generalized approach to Wang-Landau simulations, macroscopically constrained Wang-Landau, is proposed to simulate the density of states of a system with multiple macroscopic order parameters. The method breaks a multidimensional random-walk process in phase space into many separate, one-dimensional random walk processes in well-defined subspaces. Each of these random walks is constrained to a different set of values of the macroscopic order parameters. When the multivariable density of states is obtained for one set of values of fieldlike model parameters, the density of states for any other values of these parameters can be obtained by a simple transformation of the total system energy. All thermodynamic quantities of the system can then be rapidly calculated at any point in the phase diagram. We demonstrate how to use the multivariable density of states to draw the phase diagram, as well as order-parameter probability distributions at specific phase points, for a model spin-crossover material: an antiferromagnetic Ising model with ferromagnetic long-range interactions. The fieldlike parameters in this model are an effective magnetic field and the strength of the long-range interaction. PMID- 28618624 TI - Delayed bet-hedging resilience strategies under environmental fluctuations. AB - Many biological populations, such as bacterial colonies, have developed through evolution a protection mechanism, called bet hedging, to increase their probability of survival under stressful environmental fluctuation. In this context, the concept of preadaptation refers to a common type of bet-hedging protection strategy in which a relatively small number of individuals in a population stochastically switch their phenotypes to a dormant metabolic state in which they increase their probability of survival against potential environmental shocks. Hence, if an environmental shock took place at some point in time, preadapted organisms would be better adapted to survive and proliferate once the shock is over. In many biological populations, the mechanisms of preadaptation and proliferation present delays whose influence in the fitness of the population are not well understood. In this paper, we propose a rigorous mathematical framework to analyze the role of delays in both preadaptation and proliferation mechanisms in the survival of biological populations, with an emphasis on bacterial colonies. Our theoretical framework allows us to analytically quantify the average growth rate of a bet-hedging bacterial colony with stochastically delayed reactions with arbitrary precision. We verify the accuracy of the proposed method by numerical simulations and conclude that the growth rate of a bet-hedging population shows a nontrivial dependency on their preadaptation and proliferation delays. Contrary to the current belief, our results show that faster reactions do not, in general, increase the overall fitness of a biological population. PMID- 28618625 TI - Hierarchical structure in sharply divided phase space for the piecewise linear map. AB - We have studied a two-dimensional piecewise linear map to examine how the hierarchical structure of stable regions affects the slow dynamics in Hamiltonian systems. In the phase space there are infinitely many stable regions, each of which is polygonal-shaped, and the rest is occupied by chaotic orbits. By using symbolic representation of stable regions, a procedure to compute the edges of the polygons is presented. The stable regions are hierarchically distributed in phase space and the edges of the stable regions show the marginal instability. The cumulative distribution of the recurrence time obeys a power law as ~t^{-2}, the same as the one for the system with phase space, which is composed of a single stable region and chaotic components. By studying the symbol sequence of recurrence trajectories, we show that the hierarchical structure of stable regions has no significant effect on the power-law exponent and that only the marginal instability on the boundary of stable regions is responsible for determining the exponent. We also discuss the relevance of the hierarchical structure to those in more generic chaotic systems. PMID- 28618626 TI - Stochastic lattice model of synaptic membrane protein domains. AB - Neurotransmitter receptor molecules, concentrated in synaptic membrane domains along with scaffolds and other kinds of proteins, are crucial for signal transmission across chemical synapses. In common with other membrane protein domains, synaptic domains are characterized by low protein copy numbers and protein crowding, with rapid stochastic turnover of individual molecules. We study here in detail a stochastic lattice model of the receptor-scaffold reaction diffusion dynamics at synaptic domains that was found previously to capture, at the mean-field level, the self-assembly, stability, and characteristic size of synaptic domains observed in experiments. We show that our stochastic lattice model yields quantitative agreement with mean-field models of nonlinear diffusion in crowded membranes. Through a combination of analytic and numerical solutions of the master equation governing the reaction dynamics at synaptic domains, together with kinetic Monte Carlo simulations, we find substantial discrepancies between mean-field and stochastic models for the reaction dynamics at synaptic domains. Based on the reaction and diffusion properties of synaptic receptors and scaffolds suggested by previous experiments and mean-field calculations, we show that the stochastic reaction-diffusion dynamics of synaptic receptors and scaffolds provide a simple physical mechanism for collective fluctuations in synaptic domains, the molecular turnover observed at synaptic domains, key features of the observed single-molecule trajectories, and spatial heterogeneity in the effective rates at which receptors and scaffolds are recycled at the cell membrane. Our work sheds light on the physical mechanisms and principles linking the collective properties of membrane protein domains to the stochastic dynamics that rule their molecular components. PMID- 28618628 TI - Two-dimensional implosion simulations with a kinetic particle code. AB - We perform two-dimensional implosion simulations using a Monte Carlo kinetic particle code. The application of a kinetic transport code is motivated, in part, by the occurrence of nonequilibrium effects in inertial confinement fusion capsule implosions, which cannot be fully captured by hydrodynamic simulations. Kinetic methods, on the other hand, are able to describe both continuum and rarefied flows. We perform simple two-dimensional disk implosion simulations using one-particle species and compare the results to simulations with the hydrodynamics code rage. The impact of the particle mean free path on the implosion is also explored. In a second study, we focus on the formation of fluid instabilities from induced perturbations. We find good agreement with hydrodynamic studies regarding the location of the shock and the implosion dynamics. Differences are found in the evolution of fluid instabilities, originating from the higher resolution of rage and statistical noise in the kinetic studies. PMID- 28618627 TI - Experimental comparison of forces resisting viral DNA packaging and driving DNA ejection. AB - We compare forces resisting DNA packaging and forces driving DNA ejection in bacteriophage phi29 with theoretical predictions. Ejection of DNA from prohead motor complexes is triggered by heating complexes after in vitro packaging and force is inferred from the suppression of ejection by applied osmotic pressure. Ejection force from 0% to 80% filling is found to be in quantitative agreement with predictions of a continuum mechanics model that assumes a repulsive DNA-DNA interaction potential based on DNA condensation studies and predicts an inverse spool conformation. Force resisting DNA packaging from ~80% to 100% filling inferred from optical tweezers studies is also consistent with the predictions of this model. The striking agreement with these two different measurements suggests that the overall energetics of DNA packaging is well described by the model. However, since electron microscopy studies of phi29 do not reveal a spool conformation, our findings suggest that the spool model overestimates the role of bending rigidity and underestimates the role of intrastrand repulsion. Below ~80% filling the inferred forces resisting packaging are unexpectedly lower than the inferred ejection forces, suggesting that in this filling range the forces are less accurately determined or strongly temperature dependent. PMID- 28618629 TI - Global stability and H theorem in lattice models with nonconservative interactions. AB - In kinetic theory, a system is usually described by its one-particle distribution function f(r,v,t), such that f(r,v,t)drdv is the fraction of particles with positions and velocities in the intervals (r,r+dr) and (v,v+dv), respectively. Therein, global stability and the possible existence of an associated Lyapunov function or H theorem are open problems when nonconservative interactions are present, as in granular fluids. Here, we address this issue in the framework of a lattice model for granularlike velocity fields. For a quite general driving mechanism, including both boundary and bulk driving, we show that the steady state reached by the system in the long-time limit is globally stable. This is done by proving analytically that a certain H functional is nonincreasing in the long-time limit. Moreover, for a quite general energy injection mechanism, we are able to demonstrate that the proposed H functional is nonincreasing for all times. Also, we put forward a proof that clearly illustrates why the "classical" Boltzmann functional H_{B}[f]=?drdvf(r,v,t)lnf(r,v,t) is inadequate for systems with nonconservative interactions. This is done not only for the simplified kinetic description that holds in the lattice models analyzed here but also for a general kinetic equation, like Boltzmann's or Enskog's. PMID- 28618630 TI - Pattern formation in a reaction-diffusion system of Fitzhugh-Nagumo type before the onset of subcritical Turing bifurcation. AB - We investigate numerically the behavior of a two-component reaction-diffusion system of Fitzhugh-Nagumo type before the onset of subcritical Turing bifurcation in response to local rigid perturbation. In a large region of parameters, the initial perturbation evolves into a localized structure. In a part of that region, closer to the bifurcation line, this structure turns out to be unstable and covers all the available space over the course of time in a process of self completion. Depending on the parameter values in two-dimensional (2D) space, this process happens either through generation and evolution of new peaks on oscillatory tails of the initial pattern, or through the elongation, deformation, and rupture of initial structure, leading to space-filling nonbranching snakelike patterns. Transient regimes are also possible. Comparison of these results with 1D simulations shows that the prebifurcation region of parameters where the self completion process is observed is much larger in the 2D case. PMID- 28618631 TI - Two coupled, driven Ising spin systems working as an engine. AB - Miniaturized heat engines constitute a fascinating field of current research. Many theoretical and experimental studies are being conducted that involve colloidal particles in harmonic traps as well as bacterial baths acting like thermal baths. These systems are micron-sized and are subjected to large thermal fluctuations. Hence, for these systems average thermodynamic quantities, such as work done, heat exchanged, and efficiency, lose meaning unless otherwise supported by their full probability distributions. Earlier studies on microengines are concerned with applying Carnot or Stirling engine protocols to miniaturized systems, where system undergoes typical two isothermal and two adiabatic changes. Unlike these models we study a prototype system of two classical Ising spins driven by time-dependent, phase-different, external magnetic fields. These spins are simultaneously in contact with two heat reservoirs at different temperatures for the full duration of the driving protocol. Performance of the model as an engine or a refrigerator depends only on a single parameter, namely the phase between two external drivings. We study this system in terms of fluctuations in efficiency and coefficient of performance (COP). We find full distributions of these quantities numerically and study the tails of these distributions. We also study reliability of the engine. We find the fluctuations dominate mean values of efficiency and COP, and their probability distributions are broad with power law tails. PMID- 28618632 TI - Relaxation of twist helicity in the cascade process of linked quantum vortices. AB - By numerically solving the three-dimensional Gross-Pitaevskii equation we analyze the cascade process associated with the evolution and decay of a pair of linked vortex rings. The system decays through a series of reconnections to produce finally three unlinked, unfolded, almost planar vortex loops. Total helicity, initially zero, remains unchanged throughout the process. The gradual transfer from writhe (due to initial linking) to twist helicity, followed by a continuous relaxation of twist across scales during the evolution is shown to be a generic mechanism that consistently takes place on each individual component. PMID- 28618633 TI - Numerical study of the F model with domain-wall boundaries. AB - We perform a numerical study of the F model with domain-wall boundary conditions. Various exact results are known for this particular case of the six-vertex model, including closed expressions for the partition function for any system size as well as its asymptotics and leading finite-size corrections. To complement this picture we use a full lattice multicluster algorithm to study equilibrium properties of this model for systems of moderate size, up to L=512. We compare the energy to its exactly known large-L asymptotics. We investigate the model's infinite-order phase transition by means of finite-size scaling for an observable derived from the staggered polarization in order to test the method put forward in our recent joint work with Duine and Barkema. In addition we analyze local properties of the model. Our data are perfectly consistent with analytical expressions for the arctic curves. We investigate the structure inside the temperate region of the lattice, confirming the oscillations in vertex densities that were first observed by Syljuasen and Zvonarev and recently studied by Lyberg et al. We point out "(anti)ferroelectric" oscillations close to the corresponding frozen regions as well as "higher-order" oscillations forming an intricate pattern with saddle-point-like features. PMID- 28618634 TI - Zero-temperature coarsening in the Ising model with asymmetric second-neighbor interactions in two dimensions. AB - We consider the zero-temperature coarsening in the Ising model in two dimensions where the spins interact within the Moore neighborhood. The Hamiltonian is given by H=-?_{}S_{i}S_{j}-kappa?_{}S_{i}S_{j^{'}}, where the two terms are for the first neighbors and second neighbors, respectively, and kappa>=0. The freezing phenomenon, already noted in two dimensions for kappa=0, is seen to be present for any kappa. However, the frozen states show more complicated structure as kappa is increased; e.g., local antiferromagnetic motifs can exist for kappa>2. Finite-sized systems also show the existence of an isoenergetic active phase for kappa>2, which vanishes in the thermodynamic limit. The persistence probability shows universal behavior for kappa>0; however, it is clearly different from the kappa=0 results when a nonhomogeneous initial condition is considered. Exit probability shows universal behavior for all kappa>=0. The results are compared with other models in two dimensions having interactions beyond the first neighbor. PMID- 28618635 TI - Enhanced drainage and thinning of liquid films between bubbles and solids that support surface waves. AB - We study the thinning and drainage of the intermediate liquid film between a bubble and a solid surface at close proximity in the presence of a surface acoustic wave (SAW) in the solid. Specifically, we employ the diffraction of light to observe a long air bubble confined in a solid rectangular channel filled with silicone oil. This setup, constituting a two-dimensional physical model of thin film drainage, allows us to analyze the influence of a SAW on the rate of thinning of the micron-thick liquid film separating the bubble and the solid substrate. The viscous penetration of the SAW into the liquid imposes a convective drift of mass, redistributing the fluid in the film against capillary resistance and producing a net drift of liquid out of the film. The rate of drainage of liquid from the film increases by one to several orders of magnitude in comparison to the rate of drainage due to the Laplace pressure of the bubble alone. The experimental findings agree well with a newly developed theory describing the SAW-enhanced drainage as a competition between the capillary flow and SAW-induced streaming. PMID- 28618636 TI - Entropy of diluted antiferromagnetic Ising models on frustrated lattices using the Wang-Landau method. AB - We use a Monte Carlo simulation to study the diluted antiferromagnetic Ising model on frustrated lattices including the pyrochlore lattice to show the dilution effects. Using the Wang-Landau algorithm, which directly calculates the energy density of states, we accurately calculate the entropy of the system. We discuss the nonmonotonic dilution concentration dependence of residual entropy for the antiferromagnetic Ising model on the pyrochlore lattice, and compare it to the generalized Pauling approximation proposed by Ke et al. [Phys. Rev. Lett. 99, 137203 (2007)PRLTAO0031-900710.1103/PhysRevLett.99.137203]. We also investigate other frustrated systems, the antiferromagnetic Ising model on the triangular lattice and the kagome lattice, demonstrating the difference in the dilution effects between the system on the pyrochlore lattice and that on other frustrated lattices. PMID- 28618638 TI - Localized dark solitons and vortices in defocusing media with spatially inhomogeneous nonlinearity. AB - Recent studies have demonstrated that defocusing cubic nonlinearity with local strength growing from the center to the periphery faster than r^{D}, in space of dimension D with radial coordinate r, supports a vast variety of robust bright solitons. In the framework of the same model, but with a weaker spatial-growth rate ~r^{alpha} with alpha<=D, we test here the possibility to create stable localized continuous waves (LCWs) in one-dimensional (1D) and 2D geometries, localized dark solitons (LDSs) in one dimension, and localized dark vortices (LDVs) in two dimensions, which are all realized as loosely confined states with a divergent norm. Asymptotic tails of the solutions, which determine the divergence of the norm, are constructed in a universal analytical form by means of the Thomas-Fermi approximation (TFA). Global approximations for the LCWs, LDSs, and LDVs are constructed on the basis of interpolations between analytical approximations available far from (TFA) and close to the center. In particular, the interpolations for the 1D LDS, as well as for the 2D LDVs, are based on a deformed-tanh expression, which is suggested by the usual 1D dark-soliton solution. The analytical interpolations produce very accurate results, in comparison with numerical findings, for the 1D and 2D LCWs, 1D LDSs, and 2D LDVs with vorticity S=1. In addition to the 1D fundamental LDSs with the single notch and 2D vortices with S=1, higher-order LDSs with multiple notches are found too, as well as double LDVs, with S=2. Stability regions for the modes under consideration are identified by means of systematic simulations, the LCWs being completely stable in one and two dimensions, as they are ground states in the corresponding settings. Basic evolution scenarios are identified for those vortices that are unstable. The settings considered in this work may be implemented in nonlinear optics and in Bose-Einstein condensates. PMID- 28618639 TI - Nonscaling displacement distributions as may be seen in fluorescence correlation spectroscopy. AB - A continuous time random walk (CTRW) model with waiting times following the Levy stable distribution with exponential cutoff in equilibrium is a simple theoretical model giving rise to normal, yet non-Gaussian, diffusion. The distribution of the particles' displacements is explicitly time dependent and does not scale. Since fluorescent correlation spectroscopy (FCS) is often used to investigate diffusion processes, we discuss the influence of this lack of scaling on the possible outcome of the FCS measurements and calculate the FCS autocorrelation curves for such equilibrated CTRWs. The results show that although the deviations from Gaussian behavior may be detected when analyzing the short- and long-time asymptotic behavior of the corresponding curves, their bodies are still perfectly fitted by the fit forms used for normal diffusion. The diffusion coefficients obtained from the fits may however differ considerably from the true tracer diffusion coefficients as describing the time dependence of the mean squared displacement. PMID- 28618637 TI - Actin growth profile in clathrin-mediated endocytosis. AB - Clathrin-mediated endocytosis in yeast is driven by a protein patch containing close to 100 different types of proteins. Among the proteins are 5000-10000 copies of polymerized actin, and successful endocytosis requires growth of the actin network. Since it is not known exactly how actin network growth drives endocytosis, we calculate the spatial distribution of actin growth required to generate the force that drives the process. First, we establish the force distribution that must be supplied by actin growth, by combining membrane-bending profiles obtained via electron microscopy with established theories of membrane mechanics. Next, we determine the profile of actin growth, using a continuum mechanics approach and an iterative procedure starting with an actin growth profile obtained from a linear analysis. The profile has fairly constant growth outside a central hole of radius 45-50 nm, but very little growth in this hole. This growth profile can reproduce the required forces if the actin shear modulus exceeds 80 kPa, and the growing filaments can exert very large polymerization forces. The growth profile prediction could be tested via electron-microscopy or super-resolution experiments in which the turgor pressure is suddenly turned off. PMID- 28618640 TI - Epidemic extinction paths in complex networks. AB - We study the extinction of long-lived epidemics on finite complex networks induced by intrinsic noise. Applying analytical techniques to the stochastic susceptible-infected-susceptible model, we predict the distribution of large fluctuations, the most probable or optimal path through a network that leads to a disease-free state from an endemic state, and the average extinction time in general configurations. Our predictions agree with Monte Carlo simulations on several networks, including synthetic weighted and degree-distributed networks with degree correlations, and an empirical high school contact network. In addition, our approach quantifies characteristic scaling patterns for the optimal path and distribution of large fluctuations, both near and away from the epidemic threshold, in networks with heterogeneous eigenvector centrality and degree distributions. PMID- 28618641 TI - Kinetic simulations of ladder climbing by electron plasma waves. AB - The energy of plasma waves can be moved up and down the spectrum using chirped modulations of plasma parameters, which can be driven by external fields. Depending on whether the wave spectrum is discrete (bounded plasma) or continuous (boundless plasma), this phenomenon is called ladder climbing (LC) or autoresonant acceleration of plasmons. It was first proposed by Barth et al. [Phys. Rev. Lett. 115, 075001 (2015)PRLTAO0031 900710.1103/PhysRevLett.115.075001] based on a linear fluid model. In this paper, LC of electron plasma waves is investigated using fully nonlinear Vlasov-Poisson simulations of collisionless bounded plasma. It is shown that, in agreement with the basic theory, plasmons survive substantial transformations of the spectrum and are destroyed only when their wave numbers become large enough to trigger Landau damping. Since nonlinear effects decrease the damping rate, LC is even more efficient when practiced on structures like quasiperiodic Bernstein-Greene Kruskal (BGK) waves rather than on Langmuir waves per se. PMID- 28618642 TI - Effect of antifreeze protein on heterogeneous ice nucleation based on a two dimensional random-field Ising model. AB - Antifreeze proteins (AFPs) are the key biomolecules that protect many species from suffering the extreme conditions. Their unique properties of antifreezing provide the potential of a wide range of applications. Inspired by the present experimental approaches of creating an antifreeze surface by coating AFPs, here we present a two-dimensional random-field lattice Ising model to study the effect of AFPs on heterogeneous ice nucleation. The model shows that both the size and the free-energy effect of individual AFPs and their surface coverage dominate the antifreeze capacity of an AFP-coated surface. The simulation results are consistent with the recent experiments qualitatively, revealing the origin of the surprisingly low antifreeze capacity of an AFP-coated surface when the coverage is not particularly high as shown in experiment. These results will hopefully deepen our understanding of the antifreeze effects and thus be potentially useful for designing novel antifreeze coating materials based on biomolecules. PMID- 28618643 TI - Statistical characterization of microstructure of packings of polydisperse hard cubes. AB - Polydisperse packings of cubic particles arise in several important problems. Examples include zeolite microcubes that represent catalytic materials, fluidization of such microcubes in catalytic reactors, fabrication of new classes of porous materials with precise control of their morphology, and several others. We present the results of detailed and extensive simulation and microstructural characterization of packings of nonoverlapping polydisperse cubic particles. The packings are generated via a modified random sequential-addition algorithm. Two probability density functions (PDFs) for the particle-size distribution, the Schulz and log-normal PDFs, are used. The packings are analyzed, and their random close-packing density is computed as a function of the parameters of the two PDFs. The maximum packing fraction for the highest degree of polydispersivity is estimated to be about 0.81, much higher than 0.57 for the monodisperse packings. In addition, a variety of microstructural descriptors have been calculated and analyzed. In particular, we show that (i) an approximate analytical expression for the structure factor of Percus-Yevick fluids of polydisperse hard spheres with the Schulz PDF also predicts all the qualitative features of the structure factor of the packings that we study; (ii) as the packings become more polydisperse, their behavior resembles increasingly that of an ideal system "ideal gas"-with little or no correlations; and (iii) the mean survival time and mean relaxation time of a diffusing species in the packings increase with increasing degrees of polydispersivity. PMID- 28618644 TI - Intrinsic flow structure and multifractality in two-dimensional bacterial turbulence. AB - The active interaction between the bacteria and fluid generates turbulent structures even at zero Reynolds number. The velocity of such a flow obtained experimentally has been quantitatively investigated based on streamline segment analysis. There is a clear transition at about 16 times the organism body length separating two different scale regimes, which may be attributed to the different influence of the viscous effect. Surprisingly the scaling extracted from the streamline segment indicates the existence of scale similarity even at the zero Reynolds number limit. Moreover, the multifractal feature can be quantitatively described via a lognormal formula with the Hurst number H=0.76 and the intermittency parameter MU=0.20, which is coincidentally in agreement with the three-dimensional hydrodynamic turbulence result. The direction of cascade is measured via the filter-space technique. An inverse energy cascade is confirmed. For the enstrophy, a forward cascade is observed when r/R<=3, and an inverse one is observed when r/R>3, where r and R are the separation distance and the bacteria body size, respectively. Additionally, the lognormal statistics is verified for the coarse-grained energy dissipation and enstrophy, which supports the lognormal formula to fit the measured scaling exponent. PMID- 28618645 TI - Localization in random bipartite graphs: Numerical and empirical study. AB - We investigate adjacency matrices of bipartite graphs with a power-law degree distribution. Motivation for this study is twofold: first, vibrational states in granular matter and jammed sphere packings; second, graphs encoding social interaction, especially electronic commerce. We establish the position of the mobility edge and show that it strongly depends on the power in the degree distribution and on the ratio of the sizes of the two parts of the bipartite graph. At the jamming threshold, where the two parts have the same size, localization vanishes. We found that the multifractal spectrum is nontrivial in the delocalized phase, but still near the mobility edge. We also study an empirical bipartite graph, namely, the Amazon reviewer-item network. We found that in this specific graph the mobility edge disappears, and we draw a conclusion from this fact regarding earlier empirical studies of the Amazon network. PMID- 28618646 TI - Hydrodynamic mobility of a solid particle near a spherical elastic membrane. II. Asymmetric motion. AB - In this paper, we derive analytical expressions for the leading-order hydrodynamic mobility of a small solid particle undergoing motion tangential to a nearby large spherical capsule whose membrane possesses resistance toward shearing and bending. Together with the results obtained in the first part [Daddi Moussa-Ider and Gekle, Phys. Rev. E 95, 013108 (2017)2470 004510.1103/PhysRevE.95.013108], where the axisymmetric motion perpendicular to the capsule membrane is considered, the solution of the general mobility problem is thus determined. We find that shearing resistance induces a low-frequency peak in the particle self-mobility, resulting from the membrane normal displacement in the same way, although less pronounced, to what has been observed for the axisymmetric motion. In the zero-frequency limit, the self-mobility correction near a hard sphere is recovered only if the membrane has a nonvanishing resistance toward shearing. We further compute the in-plane mean-square displacement of a nearby diffusing particle, finding that the membrane induces a long-lasting subdiffusive regime. Considering capsule motion, we find that the correction to the pair-mobility function is solely determined by membrane shearing properties. Our analytical calculations are compared and validated with fully resolved boundary integral simulations where a very good agreement is obtained. PMID- 28618647 TI - Shear banding, discontinuous shear thickening, and rheological phase transitions in athermally sheared frictionless disks. AB - We report on numerical simulations of simple models of athermal, bidisperse, soft core, massive disks in two dimensions, as a function of packing fraction phi, inelasticity of collisions as measured by a parameter Q, and applied uniform shear strain rate gamma[over ]. Our particles have contact interactions consisting of normally directed elastic repulsion and viscous dissipation, as well as tangentially directed viscous dissipation, but no interparticle Coulombic friction. Mapping the phase diagram in the (phi,Q) plane for small gamma[over ], we find a sharp first-order rheological phase transition from a region with Bagnoldian rheology to a region with Newtonian rheology, and show that the system is always Newtonian at jamming. We consider the rotational motion of particles and demonstrate the crucial importance that the coupling between rotational and translational degrees of freedom has on the phase structure at small Q (strongly inelastic collisions). At small Q, we show that, upon increasing gamma[over ], the sharp Bagnoldian-to-Newtonian transition becomes a coexistence region of finite width in the (phi,gamma[over ]) plane, with coexisting Bagnoldian and Newtonian shear bands. Crossing this coexistence region by increasing gamma[over ] at fixed phi, we find that discontinuous shear thickening can result if gamma[over ] is varied too rapidly for the system to relax to the shear-banded steady state corresponding to the instantaneous value of gamma[over ]. PMID- 28618648 TI - Affine and topogical structural entropies in granular statistical mechanics: Explicit calculations and equation of state. AB - We identify two orthogonal sources of structural entropy in rattler-free granular systems: affine, involving structural changes that only deform the contact network, and topological, corresponding to different topologies of the contact network. We show that a recently developed connectivity-based granular statistical mechanics separates the two naturally by identifying the structural degrees of freedom with spanning trees on the graph of the contact network. We extend the connectivity-based formalism to include constraints on, and correlations between, degrees of freedom as interactions between branches of the spanning tree. We then use the statistical mechanics formalism to calculate the partition function generally and the different entropies in the high-angoricity limit. We also calculate the degeneracy of the affine entropy and a number of expectation values. From the latter, we derive an equipartition principle and an equation of state relating the macroscopic volume and boundary stress to the analog of the temperature, the contactivity. PMID- 28618649 TI - Cafestol, a diterpene molecule found in coffee, induces leukemia cell death. AB - To evaluate the antitumor properties of Cafestol four leukemia cell lines were used (NB4, K562, HL60 and KG1). Cafestol exhibited the highest cytotoxicity against HL60 and KG1 cells, as evidenced by the accumulation of cells in the sub G1 fraction, mitochondrial membrane potential reduction, accumulation of cleaved caspase-3 and phosphatidylserine externalization. An increase in CD11b and CD15 differentiation markers with attenuated ROS generation was also observed in Cafestol-treated HL60 cells. These results were similar to those obtained following exposure of the same cell line to cytarabine (Ara-C), an antileukemic drug. Cafestol and Ara-C reduced the clonogenic potential of HL60 cells by 100%, but Cafestol spared murine colony forming unit- granulocyte/macrophage (CFU-GM), which retained their clonogenicity. The co-treatment of Cafestol and Ara-C reduced HL60 cell viability compared with both drugs administered alone. In conclusion, despite the distinct molecular mechanisms involved in the activity of Cafestol and Ara-C, a similar cytotoxicity towards leukemia cells was observed, which suggests a need for prophylactic-therapeutic pre-clinical studies regarding the anticancer properties of Cafestol. PMID- 28618650 TI - Anti-amnesic effects of Ganoderma species: A possible cholinergic and antioxidant mechanism. AB - Mushrooms are valued for their nutritional as well as medicinal properties. Ganoderma species are used traditionally to treat neurological disorders but scientific evidence for this is insufficient. The present study was designed to systematically evaluate the anti-amnesic effect of selected Ganoderma species i.e. G. mediosinense and G. ramosissimum. Extracts of selected mushroom species were evaluated for their antioxidant activity and acetylcholinesterase (AChE) inhibition using in-vitro assays (DPPH and Ellman tests respectively). The anti amnesic potential of the most active extract (i.e. 70% methanol extract of G. mediosinense) was confirmed using mouse model of scopolamine-induced amnesia. Mice were treated with bioactive extract and donepezil once orally before the induction of amnesia. Cognitive functions were evaluated using passive shock avoidance (PSA) and novel object recognition (NOR) tests. The effect on brain AChE activity, brain oxidative stress (TBARS level) and neuronal damage (H & E staining) were also assessed. In-vitro results showed strong antioxidant and AChE inhibitory activities by G. mediosinense extract (GME). Therefore, it was selected for in-vivo studies. GME pre-treatment (800mg/kg, p.o.) reversed the effect of scopolamine in mice, evident by significant decrease (p <0.05) in the transfer latency time and increase in object recognition index in PSA and NOR, respectively. GME significantly reduced the brain AChE activity and oxidative stress. Histopathological examination of brain tissues showed decrease in vacuolated cytoplasm and increase in pyramidal cells in brain hippocampal and cortical regions. GME exerts anti-amnesic effect through AChE inhibition and antioxidant mechanisms. PMID- 28618651 TI - Modulatory effects of Caralluma fimbriata extract against high-fat diet induced abnormalities in carbohydrate metabolism in Wistar rats. AB - The present study was aimed to evaluate the modulatory effects of hydroalcoholic extract of Caralluma fimbriata (CFE) by assaying the activities of key enzymes of carbohydrate metabolism and changes in glycogen content (liver and muscle) in high-fat (HF) diet-induced diabetic rats. In vitro glucose uptake studies were carried out in both psoas muscle and adipose tissue. The inhibitory effect of the extract on alpha-amylase was determined in in vitro studies. Male Wistar rats of body weight around 180g were divided into five groups (n=8), two of these groups were fed with standard pellet diet and the other three groups were fed with HF- (60%) diet. CFE (200mg/kg body weight/day) was administered through oral route to each group of standard pellet diet rats and HF-fed rats and Metformin (Met) (20mg/kg body weight/day) was administered through oral route to HFD+Met group for 90 days. At the end of the experimental period, biochemical parameters related to glycogen content in liver and muscle, and intestinal disaccharidases like maltase, sucrase and lactase were assayed. Alterations in the activities of enzymes of glucose metabolism (hexokinase, phosphorfructoki nase, pyruvate kinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and glucose-6 phosphate dehydrogenase), intestinal disaccharidases and glycogen content as observed in the high fat diet-fed rats were prevented with CFE/Met administration. From this study, we observed that CFE/Met could significantly restore the levels of glycogen in liver and muscle and key enzymes of carbohydrate metabolism to near normal in groups-HFD+CFE and HFD+Met. The skeletal muscle of HF-diet fed rats showed degenerative changes of muscle myofibers with fat deposition. These changes were attenuated in the HFD group treated with CFE/Met and retained their normal structure appearance. It can be concluded from these results that CFE might be of value in reducing the alterations related to carbohydrate metabolism under high calorie diet consumption. PMID- 28618653 TI - Myosin regulatory light chain phosphorylation is associated with leiomyosarcoma development. AB - Leiomyosarcoma is a rare malignant smooth muscle tumor which can be very unpredictable. Myosin II is involved in many functions, including cell contraction, migration, and adhesion. The phosphorylation of myosin regulatory light chain (MLC) by myosin light chain kinase (MLCK) determines the activity of Myosin II. However, it is still unclear whether MLC phosphorylation is involved in cell proliferation in leiomyosarcoma. In this study, we aimed to explore the role of MLCK-dependent MLC phosphorylation in leiomyosarcoma development. We found that the expression of MLCK, phosphorylated MLC, and Ki67 in leiomyosarcoma was significantly higher than in leiomyoma and adjacent normal smooth muscle cells. MLCK expression was significantly correlated with phosphorylated MLC level. Kaplan-Meier survival analysis revealed that patients with high expression of MLCK or phosphorylated MLC had shorter overall survival times compared with the patients with low expression of MLCK or phosphorylated MLC. In vitro studies revealed a causative link between MLC phosphorylation and cellular proliferation as expression of phosphomimetic MLC (T19D, S20D) increased cellular proliferation as assessed by Ki67 staining. In contrast, MLCK specific inhibitor reduced cellular proliferation. We concluded that MLCK, phosphorylated MLC and Ki67 were overexpressed in leiomyosarcoma. MLCK dependent MLC phosphorylation might be responsible for the high proliferative state in leiomyosarcoma. MLCK and phosphorylated MLC are potential prognostic indicators of leiomyosarcoma. PMID- 28618652 TI - Cross-talk of MicroRNA and hydrogen sulfide: A novel therapeutic approach for bone diseases. AB - Bone homeostasis requires a balance between the bone formation of osteoblasts and bone resorption of osteoclasts to maintain ideal bone mass and bone quality. An imbalance in bone remodeling processes results in bone metabolic disorders such as osteoporosis. Hydrogen sulfide (H2S), a gasotransmitter, has attracted the focus of many researchers due to its multiple physiological functions. It has been implicated in anti-inflammatory, vasodilatory, angiogenic, cytoprotective, anti-oxidative and anti-apoptotic mechanisms. H2S has also been shown to exert osteoprotective activity through its anti-inflammatory and anti-oxidative effects. However, the underlying molecular mechanisms by which H2S mitigates bone diseases are not completely understood. Experimental evidence suggests that H2S may regulate signaling pathways by directly influencing a gene in the cascade or interacting with some other gasotransmitter (carbon monoxide or nitric oxide) or both. MicroRNAs (miRNAs) are short non-coding RNAs which regulate gene expression by targeting, binding and suppressing mRNAs; thus controlling cell fate. Certainly, bone remodeling is also regulated by miRNAs expression and has been reported in many studies. MicroRNAs also regulate H2S biosynthesis. The inter regulation of microRNAs and H2S opens a new possibility for exploring the H2S microRNA crosstalk in bone diseases. However, the relationship between miRNAs, bone development, and H2S is still not well explained. This review focuses on miRNAs and their roles in regulating bone remodeling and possible mechanisms behind H2S mediated bone loss inhibition, H2S-miRNAs crosstalk in relation to the pathophysiology of bone remodeling, and future perspectives for miRNA-H2S as a therapeutic agent for bone diseases. PMID- 28618654 TI - Comparison of honey and dextrose solution on post-operative peritoneal adhesion in rat model. AB - BACKGROUND: Peritoneal adhesion between abdominal organs is a complication of surgery. It causes major complications like pain, bowel obstruction, infertility and increases risk of death. Honey is known to have anti-inflammatory and antioxidant properties potentially relevant for adhesive protection. METHODS: Thirty rats were divided into five groups: negative control without any surgical procedure (normal group), control group treated with normal saline, experimental group I treated with 1ml of 10% honey, experimental group II treated with honey at half concentration of group I (honey0.5), and positive control group receiving 1ml of dextrose 5%. Inflammatory, growth and angiogenesis factors (TNF-alpha, Il 6, IL-1beta, TGF-beta1 and VEGF) of the adhesion tissue were assessed using ELISA. Antioxidant factors (NO, GSH and MDA) were also assessed using biochemical procedures. RESULTS: The difference between peritoneal adhesion scores, TNF alpha, IL-1beta, IL-6, TGF-beta1, VEGF, NO, GSH and MDA value of all groups was strongly significant (p<0.001). We showed that honey can decrease peritoneal adhesion (p<0.001), TNF-alpha (p<0.001), IL-1beta (p<0.001), IL-6 (p<0.001), TGF beta1 (p<0.001), VEGF (p<0.001), NO (p<0.001), MDA (p<0.001) and increase GSH (p<0.001) compared with control group. Honey 0.5 also significantly decreased peritoneal adhesion (p<0.001), TNF-alpha (p<0.001), IL-1beta (p<0.01), IL-6 (p<0.001), VEGF (p<0.001), NO (p<0.001), MDA (p<0.01) and increase GSH (p<0.001) compared with control group. CONCLUSIONS: We find that honey can decrease inflammatory, growth and angiogenesis factors which can advance peritoneal adhesion and increase antioxidant factors. Honey could serve as a protective agent for peritoneal adhesion. PMID- 28618655 TI - Eugenia uniflora fruit (red type) standardized extract: a potential pharmacological tool to diet-induced metabolic syndrome damage management. AB - The aim of this study was to investigate the effect of Eugenia uniflora fruit (red type) extract on metabolic status, as well as on neurochemical and behavioral parameters in an animal model of metabolic syndrome induced by a highly palatable diet (HPD). Rats were treated for 150days and divided into 4 experimental groups: standard chow (SC) and water orally, SC and E. uniflora extract (200mg/kg daily, p.o), HPD and water orally, HPD and extract. Our data showed that HPD caused glucose intolerance, increased visceral fat, weight gain, as well as serum glucose, triacylglycerol, total cholesterol and LDL cholesterol; however, E. uniflora prevented these alterations. The extract decreased lipid peroxidation and prevented the reduction of superoxide dismutase and catalase activities in the prefrontal cortex, hippocampus and striatum of animals submitted to HPD. We observed a HPD-induced reduction of thiol content in these cerebral structures. The extract prevented increased acetylcholinesterase activity in the prefrontal cortex caused by HPD and the increase in immobility time observed in the forced swim test. Regarding chemical composition, LC/MS analysis showed the presence of nine anthocyanins as the major compounds. In conclusion, E. uniflora extract showed benefits against metabolic alterations caused by HPD, as well as exhibited antioxidant and antidepressant-like effects. PMID- 28618656 TI - Role of growth factor receptor-bound 2 in CCl4-induced hepatic fibrosis. AB - BACKGROUND: Growth Factor Receptor-bound 2 (GRB2) plays a crucial role in regulation of cellular function including proliferation and differentiation, and we previously identified GRB2 as promoting HSCs (HSCs) proliferation. However, the underlying mechanisms that are involving in the regulation of GRB2 in hepatic fibrogenesis remain unknown. METHODS: In the present study, we tested the function of GRB2 in hepatic fibrosis. Hepatic fibrosis was induced by subcutaneous CCl4 administration at a dose of 3mL/kg in rats. The rat HSC cell line HSC-T6 were cultured for proliferation investigation by CCK-8 and BrdU incorporation method. The levels of GRB2, HMGB1, PI3K/AKT, COL1A1 and alpha-SMA were analyzed by western blot or real-time PCR. RESULTS: showed that the expression of GRB2 and HMGB1 was obviously increased in liver tissues of hepatic fibrosis rats accompanied by up-regulation of COL1A1 and alpha-SMA. In cultured HSCs, application of exogenous HMGB1 induced cell proliferation and cell proliferation rate concomitantly with up-regulation of GRB2 expression and PI3K/AKT phosphorylation. The effects of HMGB1-induced proliferation of HSCs and up-regulation of COL1A1 and alpha-SMA were abolished by GRB2 siRNA. HMGB1-induced proliferation of HSCs and up-regulation of COL1A1 and alpha-SMA was reversed in the presence of LY294002, an inhibitor of PI3K inhibitor. CONCLUSIONS: These findings suggest that GRB2 plays an important role in CCl4-induced hepatic fibrosis by regulating HSCs' function, and up-regulation of GRB2 induced by HMGB1 is mediated via the PI3K/AKT pathway. PMID- 28618657 TI - Antidepressive effects of ginsenoside Rg1 via regulation of HPA and HPG axis. AB - BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is a well established pathological feature of major depression, accompanied by the persistent increase of glucocorticoid level and the dysfunction of hypothalamic pituitary-gonadal (HPG) axis. Ginsenoside Rg1 (Rg1) is one of the most active ingredients of Panax ginseng, which has various biological activity. OBJECTIVE: This study aimed to investigate the antidepressive effects of Rg1 and elucidate its impact on neuroendocrine system. METHODS: The antidepressive effects of Rg1 were first analysed in mice, and was further identified in the chronic unpredictable-mild-stress (CUMS) model and the gonadectomized (GDX) model. The effects of Rg1 on depression-like behaviour were analysed by the forced swimming test (FST), tail suspension test (TST), sucrose preference test, and measurement of pentobarbital-induced sleep. The serum corticosterone and testosterone levels were detected by ELISA. The protein levels of glucocorticoid receptor (GR) and androgen receptor (AR) were analysed by western blot and immunohistochemistry analysis. RESULTS: Rg1 significantly decreased the immobility time of mice in FST and TST. Furthermore, Rg1 alleviated anhedonia and hopelessness, decreased serum corticosterone level, and increased serum testosterone level, and the GR protein level in the PFC and hippocampus of the CUMS-treated rats. Moreover, Rg1 improved sleep disruption, down-regulated the serum corticosterone level, and increased AR protein level in the PFC of the GDX-treated mice. CONCLUSION: Together, these studies suggest that Rg1 displayed antidepressant activity through the modulation of the HPA and the HPG axis. These findings provide new mechanism involved in the antidepressive effects of Rg1 and propose theoretical clues for clinical therapies. PMID- 28618658 TI - The impact of multiple stressors on the biomarkers response in gills and liver of freshwater breams during different seasons. AB - Biomarkers attract increasing attention in environmental studies, as a tool for detection of exposure and effects of pollution, from both natural and anthropogenic sources. This study aims to assess the impact of multiple stressors during distinctive seasons, covering also extreme hydrological events (extensive flooding in the mid May 2014), on different levels of biological organization in the liver and gills of three closely related freshwater breams. Our previous study on DNA damage in blood cells of these specimens showed increased DNA damage in June 2014, one month after the flooding event. As a continuation of that research, the present study was conducted. As a biomarker of exposure DNA damage was measured by applying the alkaline comet assay, while histopathological alterations were monitored as a biomarker of effect. Additionally, concentrations of metals and metalloids in gills, liver and muscle were assessed. Sampling of fish tissues was performed in 2014, during winter (January and February), spring (March and early June) and summer (late June, July and August). Significant seasonal difference in DNA damage was observed for both tissues. During spring and summer the level of DNA damage in gills was significantly higher when compared to the liver. Histopathological analyses showed higher frequency of alterations in gills during spring, and in liver during summer, but without a significant seasonal difference. Gills had the highest concentration of metals and metalloids during the spring and summer, and liver during winter. Muscle was the least affected tissue during all three seasons. This study highlighted the importance of the multiple biomarker approach and the use of different fish tissues in assessment of surface water pollution. PMID- 28618659 TI - Projected impact of climate change and chemical emissions on the water quality of the European rivers Rhine and Meuse: A drinking water perspective. AB - Low river discharges of the rivers Rhine and Meuse are expected to occur more often and more prolonged in a changing climate. During these dry periods the dilution of point sources such as sewage effluents is reduced leading to a decline in chemical water quality. This study projects chemical water quality of the rivers Rhine and Meuse in the year 2050, based on projections of chemical emissions and two climate scenarios: moderate and fast climate change. It focuses on specific compounds known to be relevant to drinking water production, i.e. four pharmaceuticals, a herbicide and its metabolite and an artificial sweetener. Hydrological variability, climate change, and increased emission show a significant influence on the water quality in the Rhine and Meuse. The combined effect of changing future emissions of these compounds and reduced dilution due to climate change has leaded to increasing (peak) concentrations in the river water by a factor of two to four. Current water treatment efficiencies in the Netherlands are not sufficient to reduce these projected concentrations in drinking water produced from surface water below precautionary water target values. If future emissions are not sufficiently reduced or treatment efficiencies are not improved, these compounds will increasingly be found in drinking water, albeit at levels which pose no threat to human health. PMID- 28618660 TI - Relative roles of spatial processes, natural factors and anthropogenic stressors in structuring a lake macroinvertebrate metacommunity. AB - Studies of aquatic metacommunities have so far been focused almost entirely on relatively isolated systems, such as a set of streams, lakes or ponds. Here, we aimed to quantify the relative importance of spatial processes, natural factors and anthropogenic stressors in structuring of a macroinvertebrate metacommunity within a large, highly-connected shallow lake system. The roles of different drivers were evaluated for the entire metacommunity, 10 trait-based deconstructed metacommunities and four common species by incorporating extensive sampling and a large number of abiotic explanatory variables. Contrary to our expectations, we found that variation in community structure among sites was mostly correlated to spatial and wind-wave variables rather than anthropogenic disturbance factors even though the lake presented strong environmental gradients associated with long-term human pressures. In addition, the relative importance of the three groups of drivers varied slightly among the deconstructed trait matrices (i.e. based on dispersal ability, feeding mode and degree of occurrence). Importantly, the distributions of the most common species showed significant and strong spatial autocorrelation, indicating the prominent role of high dispersal rate for their distributions. These findings suggest that the influences of high dispersal rates and natural disturbance may even override the roles of anthropogenic stressors in metacommunity organization in highly-connected aquatic systems. Hence, we strongly encourage that spatial processes and natural drivers are taken into account in the development of bioassessment approaches in highly-connected aquatic systems. PMID- 28618661 TI - Probabilistic quantitative microbial risk assessment model of norovirus from wastewater irrigated vegetables in Ghana using genome copies and fecal indicator ratio conversion for estimating exposure dose. AB - The need to replace the commonly applied fecal indicator conversions ratio (an assumption of 1:10-5 virus to fecal indicator organism) in Quantitative Microbial Risk Assessment (QMRA) with models based on quantitative data on the virus of interest has gained prominence due to the different physical and environmental factors that might influence the reliability of using indicator organisms in microbial risk assessment. The challenges facing analytical studies on virus enumeration (genome copies or particles) have contributed to the already existing lack of data in QMRA modelling. This study attempts to fit a QMRA model to genome copies of norovirus data. The model estimates the risk of norovirus infection from the intake of vegetables irrigated with wastewater from different sources. The results were compared to the results of a corresponding model using the fecal indicator conversion ratio to estimate the norovirus count. In all scenarios of using different water sources, the application of the fecal indicator conversion ratio underestimated the norovirus disease burden, measured by the Disability Adjusted Life Years (DALYs), when compared to results using the genome copies norovirus data. In some cases the difference was >2 orders of magnitude. All scenarios using genome copies met the 10-4 DALY per person per year for consumption of vegetables irrigated with wastewater, although these results are considered to be highly conservative risk estimates. The fecal indicator conversion ratio model of stream-water and drain-water sources of wastewater achieved the 10-6 DALY per person per year threshold, which tends to indicate an underestimation of health risk when compared to using genome copies for estimating the dose. PMID- 28618662 TI - A one-year, on-line, multi-site observational study on water-soluble inorganic ions in PM2.5 over the Pearl River Delta region, China. AB - As the significant components of PM2.5, almost all of previous studies on water soluble inorganic ions (WSIIs) have been limited by the use of single sampling station, short sampling times or low temporal resolution. This paper focuses on analysing one-year (2012) observations of WSIIs at a regional central (RCEN) site, a coastal urban (CURB) site and a coastal rural (CRUR) site in the Pearl River Delta region. On average, secondary inorganic aerosols (SIA) were the most abundant component and accounted for over 80% of the total WSIIs. The ratio among sulfate, nitrate and ammonium mass concentrations was close to 2:1:1 (5:2:1) at the RCEN and CURB sites (CRUR site). Most components (except Na+) showed higher concentrations in the dry season. The diurnal variations of different ions showed obvious differences, which were partially controlled by photochemical reactions and diffusion conditions in the boundary layer. Ionic formation patterns were different among the three sites. Secondary inorganic pollution was much more serious in the northwestern PRD, and it had a significant effect on pollution in the coastal areas. High SO42- concentrations at the CRUR site may be associated with local emissions, such as dimethysulfide (DMS). Long-range transport along the southeastern coastline also played an important role in SO42- pollution over the PRD region. Sea salt aerosols were an important source in coastal regions; they contributed large amounts of Cl-, Na+, Mg2+ at the CRUR site and large amounts of Na+, Mg2+ at the CURB site. The case studies found that sea salt aerosols concentrations increased obviously during the heavy precipitation period of typhoon. The presence of warm-wet air masses before continuous moist weather (CMW) was favourable for the formation of SIA. On the other hand, during CMW periods, SIA concentrations decreased rapidly. PMID- 28618663 TI - Chemical characteristics and source apportionment of PM2.5 in Lanzhou, China. AB - Daily PM2.5 samples were collected during winter 2012 and summer 2013 at an urban site in Lanzhou and were analyzed for chemical compounds including water soluble inorganic ions (WSIN), trace elements, water soluble organic carbon (WSOC), carbonaceous species (OC/EC), polycyclic aromatic hydrocarbons (PAHs), and humic like substances (HULIS). The seasonal-average reconstructed PM2.5 mass was 120.5MUgm-3 in winter and 34.1MUgm-3 in summer. The top three groups of species in PM2.5 were OC (35.4+/-13.9MUgm-3), WSIN (34.89+/-14.21MUgm-3), and EC (13.80+/ 5.41MUgm-3) in winter and WSIN (11.25+/-3.25MUgm-3), OC (9.74+/-3.30MUgm-3), and EC (4.44+/-2.00MUgm-3) in summer. EC exceeded SO42- on most of the days. Several anthropogenic produced primary pollutants such as PAHs, Cl-, Pb, Cd and OCpri were 4-22 times higher in winter than summer. Carcinogenic substances such as Arsenic, BaP, Pb, and Cd in PM2.5 exceeded the WHO guideline limits by 274%, 153%, 23% and 7%, respectively. Positive Matric Factorization analysis identified seven source factors including steel industry, secondary aerosols, coal combustion, power plants, vehicle emissions, crustal dust, and smelting industry, which contributed 7.1%, 33.0%, 28.7%, 3.12%, 8.8%, 13.3%, and 6.0%, respectively, to PM2.5 in winter, and 6.7%, 14.8%, 3.1%, 3.4%, 25.2%, 11.6% and 35.2% in summer. Smelting industry and steel industry were identified for the first time as sources of PM2.5 in this city, and power plant was distinguished from industrial boiler and residential coal burning. PMID- 28618664 TI - An epidemiological approach to characterise the human exposure pathways in a contaminated estuarine environment. AB - This study's aim was to develop and implement an integrative epidemiologic cross sectional study that allows identifying and characterising exposure pathways of populations living and working on the shores of a contaminated estuarine environment. Population residing in Carrasqueira, located on the Sado estuary with known contaminated areas was compared to another population on a noncontaminated estuary (Vila Nova de Mil Fontes - VNMF), considered a nonexposed population. Simple random samples of individuals were selected in each study population from the National Health Service Lists: 140 individuals were selected in Carrasqueira and 219 in VNMF. Participation rates were higher in the exposed group (62.5%, n=102 in Carrasqueira and 48.3%, n=100 individuals in VNMF). The same structured questionnaire was used in both populations, including questions on occupational activities, leisure activities, consumption of food (including fish and mollusks from the estuary) and use of water for human intake and agriculture. Results showed that a significantly higher proportion of Carrasqueira participants reported doing tasks in their job that promote direct (48.8% vs 1.2% in VNMF, p-value<0.001) or indirect (30% vs 11.9% in VNMF, p value=0.004) contact with water from the estuary. Regarding seafood consumption, the exposed population of Carrasqueira had a higher frequency of consumption of cuttlefish (23.5% vs 9% in VNMF, p-value=0.007), sole (22.5% vs 4% in VNMF, p value<0.001) and clams (18.6% vs 5.0 in VNMF, p-value=0.004). The comparative study design, with exposed and nonexposed populations living on the shores of two different estuaries allowed us to confirm the hypothesis of a higher risk of contamination from the contaminated estuarine environment. The study design and the selection of both populations were adequate for this type of epidemiologic study of potential routes of human contamination in a mixture of contaminated estuarine environment and can be used in other estuarine areas with similar environmental risk. PMID- 28618665 TI - Metal accumulation in soils derived from volcano-sedimentary rocks, Rio Itapicuru Greenstone Belt, northeastern Brazil. AB - Many countries and some Brazilian regions have defined the guideline values for metals in soils. However, the local geological features may be so heterogeneous that global or even regional guideline values cannot be applied. The Greenstone Belts are worldwide geological formations of vast extension, containing mineralization of various metals (e.g., Au, Cr, Ni, and Ag). Natural concentrations of soils must be known to correctly assess the impact of mining. We studied the soils of the Rio Itapicuru Greenstone Belt (RIGB), of Paleoproterozoic age, sampling at 24 sites (0-0.20m) in the areas not or minimally human impacted, equally distributed in the three units of the RIGB: Volcanic Mafic Unit (VMU), Volcanic Felsic Unit (VFU), and Volcano-clastic Sedimentary Unit (SU). The natural pseudo-total concentrations of Cr, Ni, Cu, Zn, Pb, Fe, and Mn were obtained by acid digestion (EPA3050b) both in the soil and the particle-size fractions (sand and clay+silt). The concentrations of metals in RIGB soils, especially Cr and Ni, are generally higher than those reported for other regions of Brazil or other countries. Even the sedimentary soils have relatively high metal values, naturally contaminated by the VMU of the RIGB; a potential impact on Mesozoic and Cenozoic sedimentary rocks located near the study region is highly expected. Metals are concentrated (80%) in the fine particle-size fraction, implying an easy availability through surface transport (wind and runoff). We introduced a new index, called the Fe-independent accumulation factor - AF-Fe, which reveals that 90-98% of the dynamics of the trace metals is associated with the iron geochemical cycle. We primarily conclude that determining the guideline values for different soil classes in variable geological/geochemical environment and under semiarid climate is meaningless: the concentration of metals in soils is clearly more related to the source material than to the pedogenesis processes. PMID- 28618666 TI - The toxicity of oil sands process-affected water (OSPW): A critical review. AB - Large volumes of oil sands process-affected water (OSPW) are produced by the surface-mining oil sands industry in Alberta. Both laboratory and field studies have demonstrated that the exposure to OSPW leads to many physiological changes in a variety of organisms. Adverse effects include compromised immunological function, developmental delays, impaired reproduction, disrupted endocrine system, and higher prevalence of tissue-specific pathological manifestations. The composition of OSPW varies with several factors such as ore sources, mining process, and tailings management practices. Differences in water characteristics have confounded interpretation or comparison of OSPW toxicity across studies. Research on individual fractions extracted from OSPW has helped identify some target pollutants. Naphthenic acids (NAs) are considered as the major toxic components in OSPW, exhibiting toxic effects through multiple modes of action including narcosis and endocrine disruption. Other pollutants, like polycyclic aromatic hydrocarbons (PAHs), metals, and ions may also contribute to the overall OSPW toxicity. Studies have been conducted on OSPW as a whole complex effluent mixture, with consideration of the presence of unidentified components, and the interactions (potential synergistic or antagonistic reactions) among chemicals. This review summarizes the toxicological data derived from in vitro and in vivo exposure studies using different OSPW types, and different taxa of organisms. In general, toxicity of OSPW was found to be dependent on the OSPW type and concentration, duration of exposures (acute versus sub chronic), and organism studied. PMID- 28618668 TI - Re: Diagnostic Accuracy of Multi-Parametric MRI and TRUS Biopsy in Prostate Cancer (PROMIS): A Paired Validating Confirmatory Study. PMID- 28618667 TI - Re: Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. PMID- 28618669 TI - Re: Rb1 and Trp53 Cooperate to Suppress Prostate Cancer Lineage Plasticity, Metastasis, and Antiandrogen Resistance. PMID- 28618670 TI - Re: Low CD38 Identifies Progenitor-Like Inflammation-Associated Luminal Cells that Can Initiate Human Prostate Cancer and Predict Poor Outcome. PMID- 28618671 TI - Re: Targeted Molecular-Genetic Imaging and Ligand-Directed Therapy in Aggressive Variant Prostate Cancer. PMID- 28618672 TI - Re: Vasectomy and Prostate Cancer Incidence and Mortality in a Large US Cohort. PMID- 28618673 TI - Re: Increase in Prostate Cancer Distant Metastases at Diagnosis in the United States. PMID- 28618674 TI - Re: Identifying Drivers of Episode Cost Variation with Radical Prostatectomy. PMID- 28618675 TI - Re: Interim 18F-Fluorodeoxyglucose Positron Emission Tomography for Early Metabolic Assessment of Response to Cisplatin, Etoposide, and Bleomycin Chemotherapy for Metastatic Seminoma: Clinical Value and Future Directions. PMID- 28618676 TI - Re: The Effect of Sevoflurane versus Desflurane on Postoperative Catheter-Related Bladder Discomfort in Patients Undergoing Transurethral Excision of a Bladder Tumour: A Randomized Controlled Trial. PMID- 28618677 TI - Re: Thiazide Treatment in Primary Hyperparathyroidism-A New Indication for an Old Medication? PMID- 28618678 TI - Re: Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients. PMID- 28618679 TI - Re: Outcomes of Percutaneous Nephrolithotomy in Spinal Cord Injury Patients as Compared to a Matched Cohort. PMID- 28618680 TI - Re: Perirenal Hematoma after Ureteroscopy: A Systematic Review. PMID- 28618681 TI - Re: Defining the Rate of Negative Ureteroscopy in the General Population Treated for Upper Tract Urinary Stone Disease. PMID- 28618682 TI - Re: Outcomes of Pyeloplasty in Very Poorly Functioning Kidneys: Examining the Myths. PMID- 28618683 TI - Re: Short- and Long-Term Complications and Outcomes of Radiation and Surgically Induced Rectourethral Fistula Repair with Buccal Mucosa Graft and Muscle Interposition Flap. PMID- 28618685 TI - Re: Suspected Penile Fracture after Xiaflex Injection and Use of a VED. PMID- 28618684 TI - Re: The Impact of Diabetes Mellitus and Obesity on Artificial Urinary Sphincter Outcomes in Men. PMID- 28618686 TI - Re: Comprehensive Geriatric Assessment is a Useful Predictive Tool for Postoperative Delirium after Gastrointestinal Surgery in Old-Old Adults. PMID- 28618687 TI - Re: Cognitive Reserve and Postoperative Delirium in Older Adults. PMID- 28618688 TI - Re: Association of Pre-Operative Medication Use with Post-Operative Delirium in Surgical Oncology Patients Receiving Comprehensive Geriatric Assessment. PMID- 28618689 TI - Re: Standardized Pelvic Floor Exercises Improve Stress Urinary Incontinence in Women with Intrinsic Sphincter Deficiency. PMID- 28618690 TI - Re: Summary of European Association of Urology (EAU) Guidelines on Neuro-Urology. PMID- 28618691 TI - Re: More than 15 Years of Experience with Intradetrusor OnabotulinumtoxinA Injections for Treating Refractory Neurogenic Detrusor Overactivity: Lessons to be Learned. PMID- 28618692 TI - Re: Different Number of Intravesical OnabotulinumtoxinA Injections for Patients with Refractory Detrusor Overactivity do Not Affect Treatment Outcome: A Prospective Randomized Comparative Study. PMID- 28618693 TI - Re: Comparison of Flowrates and Voided Volumes during Non-Instrumented Uroflowmetry and Pressure-Flow Studies in Women with Stress Incontinence. PMID- 28618694 TI - Re: Change in Urinary Storage Symptoms following Treatment for Female Stress Urinary Incontinence. PMID- 28618695 TI - Re: Anticholinergic Medication Use and Falls in Postmenopausal Women: Findings from the Women's Health Initiative Cohort Study. PMID- 28618696 TI - Re: Effect of Potentially Inappropriate Use of Antimuscarinic Medications on Healthcare Use and Cost in Individuals with Overactive Bladder. PMID- 28618697 TI - Re: Urinary Incontinence and Social Function in Older Australian Women. PMID- 28618698 TI - Re: Greenlight High-Performance System (HPS) 120-W Laser Vaporization versus Transurethral Resection of the Prostate for the Treatment of Benign Prostatic Hyperplasia: A Meta-Analysis of the Published Results of Randomized Controlled Trials. PMID- 28618699 TI - Re: Do Baseline Estrogen and Testosterone Affect Lower Urinary Tract Symptoms (LUTS) Prior to or after Pharmacologic Treatment with Tadalafil? PMID- 28618700 TI - Re: Meta-Analysis of Metabolic Syndrome and Benign Prostatic Hyperplasia in Chinese Patients. PMID- 28618701 TI - Re: The Undescended Testicles of West Virginia: A Single Center Experience. PMID- 28618702 TI - Re: The Anatomic Findings during Operative Exploration for Non-Palpable Testes: A Prospective Evaluation. PMID- 28618703 TI - Re: Barriers to Use of Semen Analysis in the Adolescent with a Varicocele: Survey of Patient, Parental, and Practitioner Attitudes. PMID- 28618704 TI - Re: Vitamin B12 Deficiency in Patients after Enterocystoplasty. PMID- 28618705 TI - Re: Should we Question Early Feminizing Genitoplasty for Patients with Congenital Adrenal Hyperplasia and XX Karyotype? PMID- 28618706 TI - Re: Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations. PMID- 28618707 TI - Re: Cryoablation versus Partial Nephrectomy for Clinical T1b Renal Tumors: A Matched Group Comparative Analysis. PMID- 28618708 TI - Re: Impact of Anticoagulant and Antiplatelet Drugs on Perioperative Outcomes of Robotic-Assisted Partial Nephrectomy. PMID- 28618709 TI - Re: Visual Assessment of the Intensity and Pattern of T1 Hyperintensity on MRI to Differentiate Hemorrhagic Renal Cysts from Renal Cell Carcinoma. PMID- 28618710 TI - Re: Sustained-Release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study. PMID- 28618711 TI - Re: EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-Specific and Overall Survival in Non-Muscle-Invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guerin. PMID- 28618712 TI - Re: Phase II Drug-Metabolizing Polymorphisms and Smoking Predict Recurrence of Non-Muscle-Invasive Bladder Cancer: A Gene-Smoking Interaction. PMID- 28618713 TI - Re: SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor. PMID- 28618714 TI - Lsp family proteins regulate antibiotic biosynthesis in Lysobacter enzymogenes OH11. AB - Ax21 family proteins have been shown to play regulatory roles in plant- and animal-pathogenic species in the bacterial family Xanthomonadaceae, but the protein have not been investigated previously in the non-pathogenic members of this bacterial family. Lysobacter enzymogenes, is a non-pathogenic species known for its capacity as a biocontrol agent of plant pathogens. It is also noted for the production of antimicrobial secondary metabolites, heat stable antifungal factor (HSAF) and WAP-8294A2, that have potential for agricultural and pharmaceutical applications. The species also displays type IV pili-dependent twitching motility and the production of multiple extracellular lytic enzymes as additional biocontrol-related traits. Here, we show that L. enzymogenes strain OH11 possesses three genes widely separated in the OH11 genome that code for unique Ax21-like proteins (Lsp). By comparing the wildtype OH11 with mutant strains having a single lsp gene or a combination of lsp genes deleted, we found that each Lsp protein individually is involved in positive regulation of HSAF and WAP-8294A2 biosynthesis, but the proteins collectively do not exert additive effects in this regulation. None of the Lsp proteins were found to influence twitching motility or the production of three extracellular lytic enzymes. This study is the first to provide evidence linking Ax21-family proteins to antibiotic biosynthesis and, hence, adds new insights into the diversity of regulatory functions of Ax21 family proteins in bacteria. PMID- 28618715 TI - Retention Model of TaO/HfO x and TaO/AlO x RRAM with Self-Rectifying Switch Characteristics. AB - A retention behavior model for self-rectifying TaO/HfO x - and TaO/AlO x -based resistive random-access memory (RRAM) is proposed. Trapping-type RRAM can have a high resistance state (HRS) and a low resistance state (LRS); the degradation in a LRS is usually more severe than that in a HRS, because the LRS during the SET process is limited by the internal resistor layer. However, if TaO/AlO x elements are stacked in layers, the LRS retention can be improved. The LRS retention time estimated by extrapolation method is more than 5 years at room temperature. Both TaO/HfO x - and TaO/AlO x -based RRAM structures have the same capping layer of TaO, and the activation energy levels of both types of structures are 0.38 eV. Moreover, the additional AlO x switching layer of a TaO/AlO x structure creates a higher O diffusion barrier that can substantially enhance retention, and the TaO/AlO x structure also shows a quite stable LRS under biased conditions. PMID- 28618716 TI - RF Electromagnetic Field Treatment of Tetragonal Kesterite CZTSSe Light Absorbers. AB - In this work, we propose a method to improve electro-optical and structural parameters of light-absorbing kesterite materials. It relies on the application of weak power hydrogen plasma discharges using electromagnetic field of radio frequency range, which improves homogeneity of the samples. The method allows to reduce strain of light absorbers and is suitable for designing solar cells based on multilayered thin film structures. Structural characteristics of tetragonal kesterite Cu2ZnSn(S, Se)4 structures and their optical properties were studied by Raman, infrared, and reflectance spectroscopies. They revealed a reduction of the sample reflectivity after RF treatment and a modification of the energy band structure. PMID- 28618717 TI - The Electrical Properties of Hybrid Composites Based on Multiwall Carbon Nanotubes with Graphite Nanoplatelets. AB - In the present work, we have investigated the concentration dependences of electrical conductivity of monopolymer composites with graphite nanoplatelets or multiwall carbon nanotubes and hybrid composites with both multiwall carbon nanotubes and graphite nanoplatelets. The latter filler was added to given systems in content of 0.24 vol%. The content of multiwall carbon nanotubes is varied from 0.03 to 4 vol%. Before incorporation into the epoxy resin, the graphite nanoplatelets were subjected to ultraviolet ozone treatment for 20 min. It was found that the addition of nanocarbon to the low-viscosity suspension (polymer, acetone, hardener) results in formation of two percolation transitions. The percolation transition of the composites based on carbon nanotubes is the lowest (0.13 vol%).It was determined that the combination of two electroconductive fillers in the low-viscosity polymer results in a synergistic effect above the percolation threshold, which is revealed in increase of the conductivity up to 20 times. The calculation of the number of conductive chains in the composite and contact electric resistance in the framework of the model of effective electrical resistivity allowed us to explain the nature of synergistic effect. Reduction of the electric contact resistance in hybrid composites may be related to a thinner polymer layer between the filler particles and the growing number of the particles which take part in the electroconductive circuit. PMID- 28618718 TI - Modulation of Electronic and Optical Anisotropy Properties of ML-GaS by Vertical Electric Field. AB - We investigate the electric-field-dependent optical properties and electronic behaviors of GaS monolayer by using the first-principles calculations. A reversal of the dipole transition from E//c to E?c anisotropy is found with a critical external electric field of about 5 V/nm. Decomposed projected band contributions exhibit asymmetric electronic structures in GaS interlayers under the external electric field, which explains the evolution of the absorption preference. Spatial distribution of the partial charge and charge density difference reveal that the strikingly reversed optical anisotropy in GaS ML is closely linked to the additional crystal field originated from the external electric field. These results pave the way for experimental research and provide a new perspective for the application of the monolayer GaS-based two-dimensional electronic and optoelectronic devices. PMID- 28618719 TI - A Short Progress Report on High-Efficiency Perovskite Solar Cells. AB - Faced with the increasingly serious energy and environmental crisis in the world nowadays, the development of renewable energy has attracted increasingly more attention of all countries. Solar energy as an abundant and cheap energy is one of the most promising renewable energy sources. While high-performance solar cells have been well developed in the last couple of decades, the high module cost largely hinders wide deployment of photovoltaic devices. In the last 10 years, this urgent demand for cost-effective solar cells greatly facilitates the research of solar cells. This paper reviews the recent development of cost effective and high-efficient solar cell technologies. This report paper covers low-cost and high-efficiency perovskite solar cells. The development and the state-of-the-art results of perovskite solar cell technologies are also introduced. PMID- 28618720 TI - Structure and Electronic Properties of Transition Metal Doped Kaolinite Nanoclay. AB - In this work, a series of transition metal (Cr, Mn, Fe, and Co) doped kaolinite nanoclays were investigated by density functional theory (DFT) calculations. The influence of metal doping on geometric structure and electronic structure of kaolinite was analyzed. The ferromagnetic (FM), antiferromagnetic (AFM), and nonmagnetic (NM) states of transition metal (TM) doped kaolinite structures were studied. The crystal volume, lattice parameters, bond length, charge, and spin were calculated by dispersion-corrected density functional theory (DFT-D2). The results indicated that Cr3+ and Fe3+ dopants showed more stable under AFM state, while Mn3+ preferred both AFM and FM states, and Co3+ dopant preferred NM state. Also, the transition metal doping could induce lattice volume expansion and some dopant states in the band gap. PMID- 28618721 TI - The relationship between sleep quality and depressive symptoms in adolescents. AB - BACKGROUND/AIM: While poor sleep quality and sleep problems are signs of depression in adolescents, depressive symptoms among this age group further deteriorate sleep quality. The aim of this study was to explore the relationship between sleep quality and depressive symptoms in adolescents of 14 to 20 years of age. MATERIALS AND METHODS: This study was conducted with a descriptive and cross sectional research design. The sample group consisted of 313 adolescents in Istanbul, Turkey. The data were collected using a questionnaire form, the Beck Depression Inventory (BDI), and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The mean BDI score of the adolescents was 12.99 +/- 8.94 (range: 0-53) and 4.8% had severe depressive symptoms. The global PSQI score of the adolescents was 4.69 +/- 2.87 (range: 0-16) and 63.6% had good sleep quality, whereas the remaining 36.4% had poor sleep quality. There was a moderate positive correlation between BDI and PSQI scores. The factors affecting the quality of sleep of adolescents were mild and moderate-severe depressive symptom level, smoking, and the presence of sleep problems in a family member. CONCLUSION: This study shows a relationship between sleep quality and depressive symptom levels of adolescents. The findings of the current research will contribute to the development of school wellbeing programs that will be prepared with the aim of improving sleep quality and reducing depressive symptoms. PMID- 28618722 TI - Antioxidants status in type 2 diabetic patients in Morocco. AB - BACKGROUND/AIM: Type 2 diabetes is a heterogeneous and multifactorial metabolic disorder with some relationship to oxidative stress (OS). Since no studies were conducted in the Moroccan population, this clinical investigation aimed at evaluating the antioxidants status in Moroccan patients with type 2 diabetes. MATERIALS AND METHODS: Blood samples of 60 type 2 diabetic patients and 40 healthy controls subjects were analyzed for determination of glycemia, hemoglobin, CRP, glycated hemoglobin, lipid parameters, malondialdehyde (MDA), vitamins E and C, copper (Cu), zinc (Zn), and selenium (Se). RESULTS: CRP and triglycerides were higher in the diabetic group while high-density lipoprotein levels were significantly lower compared to the control group. Plasma MDA, Cu concentrations, and Cu/Zn ratio were found to be higher in diabetic patients compared to healthy subjects, while vitamin E, Zn, and Se concentrations were lower compared to the control group. No significant difference was found in vitamin C levels between the two groups. Plasma HbA1c was positively correlated to MDA levels. CONCLUSION: This study shows that antioxidant status is impaired in diabetics compared to healthy controls. PMID- 28618723 TI - Evaluation of quality of life and cost-effectiveness of definitive surgery and the levonorgestrel intrauterine system as treatment options for heavy menstrual bleeding. AB - BACKGROUND/AIM: This study aimed to compare the levonorgestrel intrauterine system (LNG-IUS) with abdominal hysterectomy (TAH) and total laparoscopic hysterectomy (TLH) as first-line treatments for heavy menstrual bleeding (HMB). MATERIALS AND METHODS: Ninety-eight patients aged 20-55 years who complained of regular heavy menstrual bleeding were enrolled in the study. The TAH group included 29 patients, the LNG-IUS group included 34, and the TLH group included 35. These groups were compared in terms of quality of life and the cost effectiveness of the selected methods. Quality of life was assessed using the 36 Item Short Form (SF-36), and cost-effectiveness was assessed according to the current cost of each approach. RESULTS: The quality of life parameters, with the exception of mental health, improved significantly in the LNG-IUS, TAH, and TLH groups. The mean costs of the LNG-IUS, TAH, and TLH procedures were $99.15 +/- 4.90, $538.82 +/- 193.00 and $1617.05 +/- 258.44, respectively (P < 0.05). Overall, LNG-IUS was the most cost-effective treatment option. CONCLUSION: The outcome measures of the SF-36 revealed that after 6 months, these treatments were equal in terms of quality of life, except for mental health. LNG-IUS was the most cost-effective approach. PMID- 28618724 TI - Vitamin E as a novel therapy in the treatment of acute aluminum phosphide poisoning. AB - BACKGROUND/AIM: Aluminum phosphide (AlP) is commonly used as a fumigant in developing countries. Induction of oxidative stress is one of the most important mechanisms of its toxicity. In this regard, and considering that there is no specific antidote for its treatment, the aim of this study was to evaluate the effect of vitamin E in the treatment of acute AlP poisoning. MATERIALS AND METHODS: This was a clinical trial on acute AlP poisoned patients. All patients received supportive treatment. In addition, the treatment group received vitamin E (400 mg/BD/IM). Level of malondialdehyde (MDA) and total antioxidant capacity of plasma were measured. RESULTS: There was no significant difference between the treatment and control groups with regard to demographic, clinical, or paraclinical data or Simplified Acute Physiology Score II (SAPSII) on admission. Systolic blood pressure significantly increased during the first 24 h in the treatment group (P < 0.05). The plasma MDA level significantly decreased in the treatment group (P < 0.05). Vitamin E administration decreased the necessity (30% vs. 62%, P < 0.05) and duration of intubation and mechanical ventilation (P < 0.05). It significantly reduced the mortality rate in the treatment group compared to the control group (15% vs. 50%, respectively, P < 0.05). CONCLUSION: Vitamin E along with supportive treatment could have a therapeutic effect in acute AlP poisoning. PMID- 28618725 TI - Performing ICSI with commercial microinjection pipettes enhanced pregnancy rates. AB - BACKGROUND/AIM: Many technical factors can affect intracytoplasmic sperm injection (ICSI) outcomes. The role of the injection micropipette could be of vital importance in ICSI programs. The main goal was to compare ICSI pregnancy outcomes between commercial and home-made injection micropipettes in a large population with male factor infertility. MATERIALS AND METHODS: Five-hundred and eleven ICSI cycles with severe male factor were included in this retrospective study. ICSI cycles were divided into two groups: A (home-made micropipettes, n = 267) and B (commercial micropipettes, n = 244). Rates of fertilization, embryo formation, and chemical and clinical pregnancies were compared between the groups. The independent samples t-test, chi-square test, and Fisher's exact test were used, whenever appropriate, for statistical analysis. RESULTS: A total of 3621 MII oocytes were retrieved, of which 2003 were fertilized. The rate of normal fertilization was significantly higher in group A (57.9%) compared to group B (52.5%). However, the rate of embryo formation showed an increase in group B compared to group A (90.4% and 85.9%, respectively, P = 0.002). In addition, the clinical pregnancy outcomes improved in group B. CONCLUSION: Our findings indicate that clinical pregnancy improves when commercial injection micropipettes are used in ICSI programs. PMID- 28618726 TI - The evaluation of cervical spinal angle in patients with acute and chronic neck pain. AB - BACKGROUND/AIM: Clinicians associate the changes in cervical lordosis with neck pain, but there is no clear consensus on this. We aimed to investigate the relationships of cervical angles, neck pain, disability, and the psychological status of the patients with acute and chronic neck pain. MATERIALS AND METHODS: A total of 110 patients with neck pain were included in this study. Demographic and clinical characteristics of the patients were recorded. The lordosis angle was determined by the posterior tangent method. A visual analog scale (VAS), the Neck Disability Index (NDI), and the Hospital Anxiety and Depression (HAD) scale were administered to all patients. RESULTS: The mean cervical lordosis angle was 23.10 +/- 8.07 degrees. A statistically negative correlation was detected between cervical angle and duration of disease (P < 0.05). The cervical angle of the acute neck pain group was higher than that of the chronic pain group (P < 0.05). There was no difference between the acute and chronic neck pain groups with respect to VAS, NDI, and HAD scores (P > 0.05). CONCLUSION: We found that the cervical angle was significantly lower in chronic neck pain patients when compared to acute patients, and patients with higher pain scores had more severe disability and that disability increased with the duration of disease. PMID- 28618727 TI - Analysis of epidemiology and risk factors for mortality in ventilator-associated pneumonia attacks in intensive care unit patients. AB - BACKGROUND/AIM: The aim of this study was to investigate the epidemiologic characteristics, the causative microorganisms and their antimicrobial susceptibility patterns, and the prognostic risk factors for mortality in critically ill patients with ventilator-associated pneumonia (VAP). MATERIALS AND METHODS: In this retrospective observational study, all the critically ill patients with VAP hospitalized in a medical/surgical intensive care unit (ICU) between January 2010 and June 2015 were evaluated. Patients' demographic features and microbiological data were reviewed. RESULTS: A total of 417 patients were clinically diagnosed with VAP; 51.1% of them were male and the average age was found as 69.9 +/- 15.9 years. VAP was detected at approximately 25.0 +/- 18.0 days of ICU stay and 17.9 +/- 12.6 days after intubation. Acinetobacter baumannii (69.5%) was isolated as the most frequent VAP agent, and the most effective antibiotic was colistin. The crude mortality rate was detected as 39.8% among the patients. The presence of dyspnea at admission, coronary heart disease as a comorbidity, unconsciousness at admission, steroid usage, and prolonged hospital stay were observed as independent risk factors in multivariate analysis (P < 0.01). CONCLUSION: According to the etiological microorganisms and antimicrobial susceptibility patterns, colistin was found to be the most reliable antibiotic for empirical antimicrobial therapy. PMID- 28618728 TI - Epidemiology of under-five mortality in Istanbul: changes from 1988 to 2011. AB - BACKGROUND/AIM: Understanding the causes of under-five deaths is key to realizing sustainable developmental goals. The aim of this descriptive study was to investigate the causes of under-five mortality in Istanbul during 2011 and compare the findings to those of 1988 and 2000. MATERIALS AND METHODS: All burial records of Istanbul were evaluated, and cemetery records of 1494 children, who died at under five years of age and were buried in Istanbul Metropolitan Municipality Cemeteries between 1 January and 31 December 2011, were analyzed. Several sociodemographic characteristics and causes of death were compared with the results of studies carried out in 1988 and 2000 in Istanbul with similar methods. RESULTS: Under-five mortality rate was lower in 2011 than in 1988 and 2000. Of all deaths, 58.8% had occurred in the neonatal period and most were in the first day of life, similarly to those of 1988 and 2000. The proportion of deaths in the age group of 1-4 years was found to be increasing. Prematurity and perinatal causes remained the main cause of death under five years of age in Istanbul during the 23-year period. Unknown causes, due to misclassification, were still seen in a relatively high proportion. CONCLUSION: Under-five mortality rate and death due to infectious diseases decreased in Istanbul from 1988 to 2011. Our findings showed a need for more emphasis on perinatal events and better evaluation of causes of death in clinical practice. PMID- 28618729 TI - Risk factors associated with poor outcome in diabetic foot ulcer patients. AB - BACKGROUND/AIM: Diabetic foot ulcers and related complications are a major cause of morbidity and hospital admissions. Our aim was to evaluate the risk factors associated with poor outcome in diabetic foot ulcers. MATERIALS AND METHODS: A prospective study was conducted on patients with diabetic foot ulceration attending the Madinah Teaching Hospital from June 2014 to December 2015. Potential risk factors and laboratory test results at presentation were recorded and their association with outcome (healing vs. amputation) was analyzed using IBM SPSS Statistics for Windows, Version 22.0. RESULTS: In total, 112 patients were studied during our study period. The majority of the patients were male (60.7%) and aged 50 years and older (62.5%). Regarding the outcome, 68% healed completely, 27.7% underwent amputation, and 4.5% died during this period. Patient age of 50 and older, long duration of diabetes (>10 years), rural origin, and heel ulcers were significantly associated with poor outcome (P < 0.05). CONCLUSION: Patients with diabetes should have a detailed annual foot examination; those having risk factors for poor outcome require more frequent foot care, patient education, and early referral to tertiary care centers. PMID- 28618730 TI - Possible triggering factors and comorbidities in newly diagnosed autoimmune bullous diseases. AB - BACKGROUND/AIM: The distribution and the demographic, etiological, and clinical features of autoimmune bullous diseases (ABDs) vary according to geographic regions of the world. The limited number of reported studies in Turkey are mostly retrospective and generally include only pemphigus. The aim of our study was to evaluate the demographic data, clinical features, associated triggering factors, and comorbidities in patients newly diagnosed with ABDs. MATERIALS AND METHODS: In this descriptive and prospective study, the demographic data, inhabited regions, smoking and drinking habits, presence of comorbidities, and specific and general potential triggering factors of ABDs considered by the patients were examined. Furthermore, the distribution of lesions and autoimmune bullous skin disorder intensity scores were recorded. RESULTS: Of the total 59 ABD patients, 26 (44.1%) were diagnosed with pemphigus, 25 (42.4%) were diagnosed with pemphigoid, and 8 (13.5%) were diagnosed with dermatitis herpetiformis. Although there were some differences between the subgroups of ABDs, the onset of the disease was associated with a triggering factor (stress, foods, physical trauma, chemical agents, ultraviolet rays, medications, infections, malignancies, and pregnancy, in a decreasing frequency) in 96.6% of the patients. Autoimmune diseases, neuropsychiatric disorders, diabetes mellitus, and hypertension were found to be statistically significantly higher in the pemphigoid group compared to the pemphigus and dermatitis herpetiformis groups. CONCLUSION: Evaluation of triggering factors and comorbidities before starting treatment may assist in controlling the disease more swiftly and reducing the side effects of treatment in the management of ABDs. However, to evaluate the frequency and significance of our findings in order to determine whether they are statistically significant or not, we suggest a multicenter prospective clinical trial, which would include control groups and a higher number of patients for each of the disease groups and clinical subtypes. PMID- 28618731 TI - Impact of adjuvant treatment on oncologic outcomes in patients with stage I leiomyosarcoma of the uterus. AB - BACKGROUND/AIM: This study aimed to evaluate the role of adjuvant therapy for stage I uterine leiomyosarcoma (LMS). MATERIALS AND METHODS: Clinicopathological data of cases of stage I uterine LMS from 1998 to 2015 were retrieved from the computerized database of Hacettepe University Hospital. The Kaplan-Meier method was used to estimate survival and progression-free survival, and survival differences were analyzed by log-rank test. Cox regression analysis was performed to account for the potential influence of confounding factors. RESULTS: We evaluated the outcomes of 35 patients with histologically proven stage I LMS. The median age at diagnosis was 50 years. All patients underwent surgical treatment and 20 patients (57.1%) received adjuvant therapy. Twelve of these patients (34.3%) received adjuvant chemotherapy, 3 (8.6%) received adjuvant pelvic irradiation, and 5 (14.2%) received adjuvant chemotherapy with pelvic irradiation. The median follow-up duration was 34 months (range: 3-231 months). Twenty-three (65.7%) patients had a recurrence during follow-up. Adjuvant therapy did not significantly improve median progression-free survival or median overall survival. Cox regression analysis did not demonstrate any significant impact of the factors studied, including age, menopausal status, tumor size, mitotic count, staging surgery, or adjuvant therapy. CONCLUSION: Adjuvant therapy for surgically treated stage I uterine LMS did not improve oncologic outcomes. PMID- 28618732 TI - Prevalence and risk factors for vitamin D deficiency in patients with widespread musculoskeletal pain. AB - BACKGROUND/AIM: The aim of this study was to examine the prevalence of 25 hydroxyvitamin D (25(OH) vitamin D) deficiency in patients complaining of widespread musculoskeletal pain. MATERIALS AND METHODS: In this cross-sectional study, 14,925 patients (13,589 females and 1336 males; mean age: 47.0 years, range: 20-99 years) were included. Serum 25(OH) vitamin D was measured by ELISA. The patients were classified into two groups: 1) patients with vitamin D deficiency (<20 ng/mL) and 2) patients without vitamin D deficiency (>20 ng/mL). RESULTS: The prevalence of vitamin D deficiency was 73.9%. A multivariate logistic regression model showed that low 25(OH) vitamin D level was associated with sex, age, and month in which 25(OH) hypovitaminosis was determined. The risk of a low 25(OH) vitamin D was level was 1.74 times higher in female patients than in males. The risk of low 25(OH) vitamin D level was highest in March during the year. CONCLUSION: Our results indicate that vitamin D deficiency should be considered in patients with widespread musculoskeletal pain and some precautions, such as sunbathing during summer, should be recommended for patients with a risk of vitamin D deficiency. PMID- 28618733 TI - Pain, depression levels, fatigue, sleep quality, and quality of life in elderly patients with rheumatoid arthritis. AB - BACKGROUND/AIM: The aim of this study was to evaluate and determine the relationships (if any) among pain, depression levels, fatigue, sleep quality, and quality of life in patients with rheumatoid arthritis (RA) aged 65 years and over, and to compare the results with those of RA patients under 65 years of age. MATERIALS AND METHODS: The study included 52 patients with RA aged 65 years and over (Group 1) and 84 patients with RA under 65 years of age (Group 2). Pain, depression levels, fatigue, sleep quality, quality of life, and disease activity of all of the participants were evaluated using a visual analog scale (VAS), the Beck Depression Inventory (BDI), the Checklist Individual Strength (CIS), the Pittsburgh Sleep Quality Index (PSQI), the Short Form-36 (SF-36), and the Disease Activity Score-28, respectively. RESULTS: When the two groups were compared, higher scores for the VAS, BDI, total CIS, and PSQI were found in Group 1 compared to Group 2 (P = 0.003, P = 0.003, P = 0.007, and P = 0.001, respectively). The SF-36 subscales of the physical component summary and mental component summary were not statistically significantly different between the two groups (P > 0.05). CONCLUSION: This study evaluated the situation in elderly patients with RA and showed that pain, depression level, fatigue, and sleep quality worsen with age. PMID- 28618734 TI - A comparison of usage of the laryngeal mask UniqueTM in denticulate and edentulate geriatric patients. AB - BACKGROUND/AIM: Mask ventilation in geriatric and edentulous patients can be ineffective or even impossible because of the shape inside the patients' cheeks. For patients for whom a mask cannot be used for long, the use of a laryngeal mask can ease the administration of anesthesia. The aim of this study was to compare the use of the laryngeal mask UniqueTM in denticulate and edentulate patients aged over 65 years. MATERIALS AND METHODS: This prospective study included patients according to the American Society of Anesthesiologists I-III classification, aged 65 years or more. The patients were divided into two groups: a dentulous group (n = 33) and an edentulous group (n = 33). The success of the first attempt of insertion, ease of insertion, time taken to insert, and oropharyngeal leak pressure were measured. After insertion of the laryngeal mask UniqueTM, a researcher who was unaware of whether the patients had teeth or not conducted an oropharyngeal leak test. RESULTS: The success rate of inserting the laryngeal mask UniqueTM on the first attempt was higher in the dentulous group than in the edentulous group. Ease of insertion, time taken to insert, oropharyngeal leak pressure, and laryngopharyngeal morbidity were similar for each group. CONCLUSION: In this study, successful insertion of the laryngeal mask UniqueTM was higher in dentulous than in edentulous patients. We conclude that this effect could have important implications for anesthesiologists managing edentulous geriatric patients with supraglottic airway devices. PMID- 28618735 TI - Three-layer primary closure of the bipedicled TRAM flap donor site for unilateralbreast reconstruction: a 15-year experience with 124 consecutive patients. AB - BACKGROUND/AIM: The pedicled transverse rectus abdominis myocutaneous (TRAM) flap remains widely used as a breast reconstruction technique. The bipedicled TRAM flap is not as preferable as it was formerly, mainly because of its donor site complications. However, in a number of situations, a bipedicled TRAM flap may be the only alternative. Therefore, a three-layer primary closure technique used with bipedicled TRAM flap breast reconstructions that can avoid donor site complications without using a mesh is presented. MATERIALS AND METHODS: A retrospective study was performed that included patients who underwent bipedicled TRAM flap breast reconstruction with the three-layer primary closure technique. Between 2000 and 2015, 124 breast reconstruction patients were reviewed for donor site morbidity. RESULTS: During the 15-year study period, 106 patients had conventional bipedicled TRAM flaps and 18 had bipedicled TRAM flaps with a surgical delay procedure. For all groups, none of the patients developed abdominal wall hernia, but three patients had bulging. Partial flap loss was the most common flap complication, present in 6 flaps (4.8%). CONCLUSION: The suturing technique studied provided abdominal wall closure without the use of a mesh even when utilizing a bilateral pedicle with very low complication rates. PMID- 28618736 TI - Frequency of human parvovirus 4 (PARV4) viremia among HBV-infected patients and healthy donors in Shiraz, Iran. AB - BACKGROUND/AIM: PARV4, a small DNA virus belonging to the family Parvoviridae, was first isolated in an HBV injecting drug user. Several studies have investigated PARV4 co-infection with HBV and HCV and its effect on the progression of liver disease. The aim of this study was to determine the frequency of PARV4 among HBV-infected patients and healthy individuals. MATERIALS AND METHODS: A group of 90 HBV patients and a group of 90 healthy subjects were included in this study. Samples were selected after screening tests such as HBsAg ELISA, anti-HCV ELISA, and anti-HIV ELISA. Nested-PCRs were conducted to detect the PARV4 genome. Positive samples were then subjected to DNA sequencing. RESULTS: PARV4 DNA was detected in 4.4% of HBV patients in comparison with 1.1% of healthy individuals (P-value: 0.36). DNA sequencing results revealed that PARV4 in all five positive samples was genotype I.Conclusions: Although this pilot study showed no significant difference between the frequency of PARV4 among HBV patients and healthy donors, further studies with a larger sample size are suggested to determine the association of PARV4 with HBV co-infection and the impact of this virus on the progression of liver disease in patients with hepatitis B. PMID- 28618737 TI - Effects of Artcure Diffusional Patch application on pain and functional status in lumbar disc herniation patients: a prospective randomized controlled study. AB - BACKGROUND/AIM: The aim of this study was to assess the efficacy of the Artcure Diffusional Patch, which contains a mixture of 6 herbal oils (oleum thymi, oleum limonis, oleum nigra, oleum rosmarini, oleum chamomilla, oleum lauriexpressum) and has a hypoosmolar lipid structure, in the conservative treatment of lumbar disc herniation patients and to show the advantages and/or possibility of using this as an alternative method to surgery. MATERIALS AND METHODS: Of the 120 patients enrolled, 79 clinically diagnosed patients were included in the study. Clinical evaluations were performed on patients who had findings of protrusion or extrusion in their magnetic resonance results. The treatment group was treated with the Artcure Diffusional Patch while the control group received a placebo transdermal diffusional patch. The functional state of patients was measured using the Oswestry Disability Index and pain intensity was measured with a visual analog scale as primary outcomes. Secondary outcomes of the study were Lasegue's sign, the femoral stretching test, and paravertebral muscle spasm. RESULTS: The treatment group showed a dramatic recovery in the first month following the application in regards to Oswestry Disability Index scores and visual analog scale values. The patients treated with the Artcure Diffusional Patch showed a statistically significant difference in recovery as compared to the control group. CONCLUSION: These findings suggest that the Artcure Diffusional Patch may be an alternative for the conservative treatment of lumbar disc herniation with radiculopathy. PMID- 28618738 TI - Groin and thigh reconstructions with pedicled rectus abdominis myocutaneous flaps. AB - BACKGROUND/AIM: Resection of tumors from the groin and thigh regions with safe margins often results in significant soft tissue defects, which preclude primary closure. This study presents a series of rectus abdominis myocutaneous flaps for irradiated thigh and groin wounds with the purpose of evaluating the efficacy and outcomes of these flaps in this population. MATERIALS AND METHODS: From 2008 to 2015, all patients who underwent resection of thigh or groin region tumors and reconstruction with an inferiorly based rectus abdominis myocutaneous flap were retrospectively identified. Medical records of the patients were reviewed. RESULTS: A total of 27 patients, aged 20-67 years, were operated on for defects in the groin and upper thigh region. Nine patients underwent immediate reconstruction. The remaining 18 patients underwent late reconstruction. There was neither total flap loss nor partial flap loss. We chose to utilize 15 ipsilateral and 12 contralateral pedicles. The mean length of stay in hospital was 13.7 days. CONCLUSION: A rectus abdominis myocutaneous flap can be successfully used in patients with groin and upper thigh defects due to its predictable and robust vascular supply, bulky muscle content, wide arc of rotation, and large skin island. PMID- 28618739 TI - An investigation of sagittal thoracic spinal curvature and mobility in subjects with and without chronic neck pain: cut-off points and pain relationship. AB - BACKGROUND/AIM: Thoracic spine insufficiency is a subject of interest in neck problems. The aim was to investigate thoracic spinal curvature and mobility in subjects with and without chronic neck pain (CNP), cut-off points, and the relationship with pain. MATERIALS AND METHODS: Fifty-six patients with CNP (CNP group) and 53 healthy volunteers (control group) were included. Neck pain intensity of the patients was assessed by visual analogue scale and sagittal thoracic curvature and mobility of all participants were assessed by Spinal Mouse (Idiag, Fehraltorf, Switzerland). RESULTS: Thoracic curvature was higher (P < 0.001) and mobility lower in the CNP group in comparison to the control group (P = 0.013). There was a positive correlation between pain intensity and thoracic curvature (r = 0.391, P < 0.001), while there was a negative correlation between pain intensity and thoracic mobility (r = -0.260, P = 0.006). For detecting neck pain, it was observed that the cut-off points for thoracic curvature and mobility were 45.5 degrees and 30.0 degrees , respectively. CONCLUSION: An increase in thoracic curvature of more than 45 degrees and a decrease in mobility more than 30 degrees may be critical for CNP patients. PMID- 28618740 TI - Screening of immunocompromised patients at risk of strongyloidiasis in western Turkey using ELISA and real-time PCR. AB - BACKGROUND/AIM: Strongyloides stercoralis causes life-threatening hyperinfection or disseminated strongyloidiasis in immunocompromised patients such as HIV positive, organ transplantation, and cancer patients. This study investigated the presence of strongyloidiasis in immunocompromised patients for the first time in Turkey. MATERIALS AND METHODS: Serum and stool samples were collected from 108 patients (25.9% of them were chronic renal failure and 74.1% were renal transplantation patients) who were admitted to Ege University Medical School in Izmir, located in western Turkey. Serum samples were analyzed by ELISA (DRG, Germany) and the presence of 18S rRNA gene of S. stercoralis was detected in stool samples by real-time PCR. RESULTS: The analysis of serum samples showed that only one patient was anti-S. stercoralis IgG antibody and real-time PCR positive (0.92%). The patient was treated twice with albendazole (400 mg/day for 3 days) at 2-week intervals. Follow up real-time PCR was negative and the patient became seronegative 6 months after the initial diagnosis. CONCLUSION: This screening showed that the prevalence of strongyloidiasis in this small group of patients who were at risk of strongyloidiasis was 0.92%. Overall, the results showed that more systematic studies are required in Turkey to show the prevalence of strongyloidiasis. PMID- 28618741 TI - Routine assessment of occupational exposure and its relation to semen quality in infertile men: a cross-sectional study. AB - BACKGROUND/AIM: Concerns about the detrimental effects of occupational and environmental exposure on male reproductive function have been raised by reports of declining sperm quality over the last decades. The aim of this study was to investigate the association between altered semen parameters and exposure to occupational risk factors as assessed by questionnaire. MATERIALS AND METHODS: We conducted a cross-sectional questionnaire-based study among a population of 2122 men who underwent andrological investigation for couple infertility. All participants were interviewed and their semen samples were analyzed. Information about medical history and occupational exposure was used to classify participants into exposed and unexposed groups. RESULTS: Exposure to pesticides was associated with a significantly higher risk of asthenozoospermia (adjusted odds ratio [OR] = 1.6; 95% CI, 1.0-2.4) and necrozoospermia (OR = 2.6; 95% CI, 1.4-4.7). Exposure to cement was found to be correlated with a higher risk of oligozoospermia (OR = 1.1; 95% CI, 0.9-1.4). There was no association between semen impairment and exposure to solvents, excess heat, or mechanical vibrations. CONCLUSION: We found an association between self-reported occupational exposure and altered semen parameters. These results support the usefulness of questionnaires for routine assessment and management of occupational exposures in infertile men. PMID- 28618742 TI - The Turkish version of the Physical Activity Scale for the Elderly (PASE): its cultural adaptation, validation, and reliability. AB - BACKGROUND/AIM: This study aimed to describe the cultural adaptation of the Turkish Physical Activity Scale for the Elderly (PASE) and to examine the reliability and validity of the scale in older Turkish adults. MATERIALS AND METHODS: Eighty elderly people were recruited for the study. The assessments included the PASE, the International Physical Activity Questionnaire (IPAQ), the Short Physical Performance Battery and Short Form-36 Quality of Life Questionnaire (SF-36), and the Mini Mental State Test. Outcome measures were conducted twice within a week (test-retest) for reliability. RESULTS: Cronbach's alpha coefficient was 0.714 for the initial evaluation. The intraclass correlation coefficient for the test-retest reliability was 0.995 with a 95% confidence interval of 0.993-0.997. A high level of positive correlation (0.742, P < 0.001) was found between the total score of PASE and the total scores of IPAQ. There were strong positive correlations between the PASE and the total score of SPPB (0.622, P < 0.001), while an average level of positive correlation with SF-36 was found (0.432, P < 0.001). CONCLUSION: The results of the study suggest that the Turkish version of the PASE has powerful measurement qualities, which makes it a reliable and valid scale for the fields of research and practice. PMID- 28618743 TI - Social support and quality of life in a group of cancer patients (Ankara, Turkey). AB - BACKGROUND/AIM: Cancer has become an important public health challenge all around the world. Though the demographic and clinical features of cancer patients are well documented in Turkey, the establishment of social support networks has been somewhat neglected. The aim of the study was to assess cancer patients' perceived social support and quality of life characteristics. MATERIALS AND METHODS: The Multidimensional Perceived Social Support Scale, European Organization of Research and Treatment of Cancer Quality of Life Questionnaire, and Turkish version of the EUROHIS measurements were obtained from the study group. Associations between the scores and sociodemographic variables of the patients were evaluated. Determination of the best predictors that affect social support perception scores was performed by multiple linear regression analysis. RESULTS: A total of 364 patients (217 females, 147 males) were analyzed. Regarding the mean scores of perceived social support, statistically significant differences were found between education, perceived economic status, and ECOG groups (P < 0.001). CONCLUSION: The best predictors that have an effect on perceived social support need to be studied in depth with further research. PMID- 28618744 TI - Comparative analysis of selected cagPAI genes and different vacA genotypes in Iranian and Turkish H. pylori-positive patients suffering from gastric adenocarcinoma and active chronic gastritis. AB - BACKGROUND/AIM: Helicobacter pylori is a pathogen that colonizes a majority of the world's population. Genetic diversity within the virulence genes of bacteria such as cagPAI and vacA may have a modified effect on the pathogenic potential of the bacteria. This study aimed to investigate which genes can be suggested as potentially related virulence factors for H. pylori-associated active chronic gastritis and stomach adenocarcinoma in the northwest of Iran and south of Turkey. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded stomach biopsy tissue samples were obtained from Iranian and Turkish patients from selected geographical regions. The prevalence of selected cagPAI genes and vacA genotypes were studied in H. pylori-positive samples by using polymerase chain reaction and specific primers. RESULTS: Out of 320 patients, H. pylori was detected in 28.43% of patients. We found that the vacAs1, vacAm2, and cagA genes with mean prevalences of 82.41%, 71.42%, and 69.23%, respectively, were dominant in Iranian and Turkish patients. CONCLUSION: In the south of Turkey and northwest of Iran the studied genes were homogeneous and there were no significant differences in bacterial genetics. The results of this study indicate that cagA and vacAs1 are dominant genes in people with gastric disorders in our selected geographical regions. PMID- 28618745 TI - Effects of a closed system suction connector on airway resistance in ventilated neonates. AB - BACKGROUND/AIM: Increased airway resistance reduces the effectiveness of ventilation treatment. Endotracheal tubes (ETTs) and connectors contribute to resistance. However, the effect of a closed system suction (CSS) connector is not well known. We compared the in vivo resistance occurring with a CSS connector with that of the standard connector. MATERIALS AND METHODS: This prospective study was conducted at Gazi University Hospital's neonatal intensive care unit. Intubated neonates were studied for two cycles; each cycle contained two periods of ETT + connector pairs (15 min/period) as follows: cycle 1 [A: long ETT + standard connector; B: long ETT + CSS connector] and cycle 2 [C: shortened ETT + standard connector; D: shortened ETT + CSS connector]. Resistance of 40 breaths/period was averaged for each case, and the means were analyzed by Wilcoxon test for pairwise comparisons between standard and CSS connectors. As each case provided two cycle data, 16 cycle data were compared. RESULTS: The CSS connector increased resistance by 13.8% (range: 3.0%-22.1%) compared to the standard connector; P < 0.001. The resistance increase was similar between long [17.3% (range: 3.0%-17.7%)] and shortened ETTs [15.3% (range: 5.0%-29.6%)]; P = 0.834. CONCLUSION: CSS connectors were found to increase airway resistance in ventilated neonates. The contribution of CSS should be considered during ventilation, particularly in the presence of difficulty in providing sufficient tidal volume. PMID- 28618746 TI - Male infertility is significantly associated with multiple deletions in an 8.7-kb segment of sperm mtDNA in Pakistan. AB - BACKGROUND/AIM: This study aimed to find a link between sperm mitochondrial DNA mutations and male infertility in Pakistan. MATERIALS AND METHODS: DNA from semen samples was extracted and amplified by PCR using 7.8-kb deletion-specific primers. The PCR products were separated on agarose gel, visualized under UV illumination, and then photographed. The results were genotyped and the data were analyzed using SPSS. RESULTS: Deletion analysis of the 8.7-kb fragment by long PCR revealed multiple deletions. The frequency of deletion was much higher in infertile groups as compared to the control group. Further, on comparison between different subtypes of infertile groups, the deletions were highest in the oligoasthenoteratozoospermia (OAT) group. The statistical analysis of case and control groups showed a significant association of the 8.7-kb deletion with human male infertile groups (P = 0.031), and particularly a very significant association with the OAT subgroup (P = 0.019). CONCLUSION: A significant association has been found between human male infertility and mtDNA deletions in an 8.7-kb segment of sperm mtDNA in a Pakistani population. PMID- 28618747 TI - First trimester ultrasonographic parameters in prediction of the course and outcome of monochorionic twin pregnancies. AB - BACKGROUND/AIM: The aim of the study was to evaluate the association and the potential predictive value of first trimester ultrasonographic parameters on the course and outcome of monochorionic diamniotic twin pregnancies. MATERIALS AND METHODS: A prospective cohort study was undertaken of 39 healthy women with consecutive monochorionic diamniotic twin pregnancies. During first-trimester screening, crown-rump length (CRL) and nuchal translucency (NT) were measured. The intertwin discordance in CRL and NT was determined. As pregnancy outcomes we assessed twins' live-born rates, Apgar scores, birth weight, pregnancy complications, and gestational week of delivery. RESULTS: None of the assessed pregnancy outcomes significantly correlated with standard CRL discordance >=10%. The newly established cut-off was 3.75 mm for CRL and 1.3 mm for NT. Monochorionic diamniotic twins were delivered in a later gestational week and had better chance of survival if CRL intertwin difference was <3.75 mm. Apgar scores significantly negatively correlated only with NT of corresponding twins. When intertwin NT difference was >=1.3 mm, twins had lower birth weight and pregnancy complications were more frequent. Regression models show that intertwin CRL difference <3.75 mm is a significant predictor of live-born monochorionic diamniotic twins. CONCLUSION: CRL and NT in monochorionic diamniotic twin pregnancies could indicate pregnancy complications and outcomes. PMID- 28618748 TI - Evaluation of polyneuropathy and associated risk factors in children with type 1 diabetes mellitus. AB - BACKGROUND/AIM: Diabetes mellitus (DM) is one of the most common metabolic diseases seen in the world today. Diabetic neuropathy (DN) is a chronic complication of the disease that is rarely reported in children, since it has a relatively longer latency period. Our main objective in this study is to determine the incidence rate of DN in pediatric DM patients and assess the risk factors associated with DN. MATERIALS AND METHODS: Data from 111 patients from January 2011 to May 2014 were reviewed in a retrospective manner. Nerve conduction studies were performed as the gold standard in diagnosis. RESULTS: The incidence rate of symptomatic DN was 13.5% according to our study results. The EMG-diagnosed DN incidence rate was calculated as 22.5%. Following linear regression analysis, positive correlation was found between diabetes duration, diabetic ketoacidosis, and DN presence. CONCLUSION: Our study results demonstrate the fact that poor metabolic control, especially during early stages of the disease, is a major risk factor for neuropathy development. Planning prospective studies with long-term evaluations on nerve conduction in children with DM will be beneficial for this subject. PMID- 28618749 TI - Serum ischemic modified albumin (IMA) concentration and IMA/albumin ratio in patients with hepatitis B-related chronic liver diseases. AB - BACKGROUND/AIM: Albumin is the most important protein synthesized by the liver. Posttranscriptional changes occur in the molecular structure of albumin due to various factors and isoforms arise. Ischemic modified albumin (IMA) is one such isoform. This study was conducted to evaluate serum IMA concentrations in patients with hepatitis B virus (HBV)-related chronic liver diseases. MATERIALS AND METHODS: This study included 74 treatment-naive chronic hepatitis B patients, 25 patients with HBV-related cirrhosis, and 49 healthy controls. Serum IMA concentration was measured spectrophotometrically using the albumin cobalt binding test. RESULTS: The mean IMA concentrations in the chronic hepatitis B group and healthy controls were 0.33 +/- 0.11 ABSU and 0.27 +/- 0.70 ABSU, respectively, and the difference was statistically significant (P < 0.001). Mean IMA/albumin ratios (IMAR) in the chronic hepatitis B and control groups were 0.08 +/- 0.04 and 0.06 +/- 0.17, respectively, and the difference was also statistically significant (P < 0.001). Higher serum IMA concentrations and IMAR were detected in patients with advanced fibrosis. CONCLUSION: Serum IMA concentration and IMAR are increased in patients with HBV-related chronic liver diseases and IMA and IMAR are associated with the degree of liver fibrosis. IMA and IMAR may have potential use as noninvasive markers of fibrosis in chronic hepatitis B patients. PMID- 28618750 TI - Morphometric study of the true S1 and S2 of the normal and dysmorphic sacralized sacra. AB - BACKGROUND/AIM: This study aimed to generate data for the S1 and S2 alar pedicle and body and the alar orientations for both dysmorphic and normal sacra. MATERIALS AND METHODS: The study comprised two groups: Group N consisted of 53 normal sacra and Group D included 10 dysmorphic sacra. Various features such as alar pedicle circumference; anterior, middle, and posterior axis of the sacral ala; sacral body height and width; and sagittal thickness were measured. RESULTS: In group N, the median anterior axis of the alae was observed to be 30 degrees on the right and 25 degrees on the left, the median midline axis was found to be 20 degrees on the right and 15 degrees on the left, and the median posterior alar axis was -15 degrees on the right and -20 degrees on the left. The true S1 and S2 alar pedicle circumferences were observed to be significantly smaller in group D, which demonstrated a shorter S1 alar pedicle mean circumference, significantly narrower S1 body mean width, and considerably tapered sagittal thickness. CONCLUSION: Our analysis indicated that dysmorphic sacra have a lower sagittal thickness and width of bodies and smaller alar pedicles, which explains the difficulties in their percutaneous fixation. PMID- 28618751 TI - Frequency and molecular characterization of human norovirus in Erzurum, Turkey. AB - BACKGROUND/AIM: There are limited studies on genotyping and phylogenetic analysis of norovirus in Turkey, and this has not previously been studied in the Eastern Anatolia region. The aim of the present study was to determine the norovirus profile in this region with genotyping and phylogenetic analysis. MATERIALS AND METHODS: Included in the study were stool samples obtained from 427 people from different age groups in Eastern Anatolia. The nucleic acid samples isolated by the automatic system and nucleic acid sequence reactions and phylogenetic analyses were performed on RNA samples. RESULTS: The presence of norovirus was detected in 86 (20.1%) of the 427 stool samples by RT-PCR analysis. Twenty-six samples selected randomly from norovirus-RNA positive samples were subjected to the sequence reaction. In 24 of the 26 samples, genogroup GII was determined, as well as one each from GI and GIV in sequence reactions. Four different genotypes were detected in genogroup GII, which were determined to be the dominant types. These were GII.1, GII.4, GII.16, and GII.21. The GI.6 and GIV.1 genotypes were determined in genogroups GI and GIV, respectively. CONCLUSION: The high frequency and genetic diversity of these infections are risk factors for disease and so vaccine studies should be undertaken in consideration of this situation. PMID- 28618752 TI - A comparison of culture and PCR methods for identifying Propionibacterium acnes in lesions isolated from patients with acne. AB - BACKGROUND/AIM: One of the factors that affect the occurrence of acne is the presence of Propionibacterium acnes. The present study was conducted to compare the culture and polymerase chain reaction (PCR) methods for identifying P. acnes in lesions isolated from patients with acne. MATERIALS AND METHODS: To examine the presence of P. acnes, 70 samples of acne lesions were collected. Microbial culture and the PCR molecular technique were used to identify P. acnes. RESULTS: Of the total of 70 samples, 14 cases (20%) were identified as P. acnes positive using microbial culture and 58 cases (82.85%) using PCR. The results obtained showed the lack of a relationship between the frequency of P. acnes and factors such as sex, family history of acne, and history of treatment with either of the techniques examined (i.e. the microbial culture and PCR). In contrast, a significant relationship was observed between the frequency of P. acnes and age with the culture method. CONCLUSION: Given the limitations in the identification of P. acnes using microbial culture, PCR is proposed as a better method with a higher efficiency. PMID- 28618753 TI - Development of a new real-time PCR screening kit for HbS and common beta thalassemia mutations observed in Turkey. AB - BACKGROUND/AIM: IVSI-110 (G>A), IVSI-6 (T>C), IVSII-1 (G>A), IVSII-745 (C>G), IVSI-1 (G>A), and HbS are mutations covering 76% of all the beta-globin mutations in the Turkish population. In this study, our aim is to develop a reliable, fast, real-time kit for these mutations using the TaqMan probe method. MATERIALS AND METHODS: This study included 100 individuals with beta-thalassemia or sickle cell anemia who had unknown mutations, and 21 controls with known mutations. RESULTS: We designed a kit containing the IVSI-110 (G>A), IVSI-6 (T>C), IVSII-1 (G>A), IVSII-745 (C>G), IVSI-1 (G>A), and HbS mutations by using the real-time PCR method. One hundred patients were studied with our developed TaqMan real-time PCR kit. Of these patients, 73 (73%) were identified with the beta gene mutation. Among those 73 patients, 16 were homozygous, 54 were heterozygous, and 3 were compound heterozygous. CONCLUSION: This reliable kit provided rapid diagnosis including 76% of the beta-thalassemia mutations in Turkey. PMID- 28618754 TI - Evaluation and comparison of radiologic-pathologic findings in invasive cribriform carcinoma of the breast. AB - BACKGROUND/AIM: This study aimed to report invasive cribriform carcinoma (ICC) with radiological and histopathologic correlations. MATERIALS AND METHODS: Seventy patients with ICC were classified into two groups; pure ICC patients and patients with >50% cribriform carcinoma component were included in group 1, while patients with <50% cribriform carcinoma component were included in group 2. All patients were reviewed according to American College of Radiology (ACR) breast imaging reporting and data system (BI-RADS) lexicon of mammography (MG), ultrasonography (US), and magnetic resonance imaging (MRI). One-way analysis of variance tests and t-tests were used for analysis. P < 0.05 was accepted as statistically significant. RESULTS: Eighteen patients were in group 1 and 52 were in group 2. All patients had MG and US, while 24 patients needed MRI. According to MG ACR BI-RADS lexicon evaluation, irregular shape, spiculated margin and indistinct margin, and high density were statistically significantly higher in group 2 than the other group (respectively P = 0.001, P = 0.001, and P= 0.04). Equal density was statistically significantly higher in group 1 than the other group (P = 0.008). According to US ACR BI-RADS lexicon evaluation, irregular shape, spiculated margins, angular margins, microlobulated margins, and nonparallel orientation were more common US findings in group 2 than the other group (respectively P = 0.001, P = 0.001, P = 0.003, P = 0.04, and P = 0.04). The rate of parallel orientation was higher in group 1 than the other group (P = 0.02). CONCLUSION: Few cases showed benign characteristics and most ICCs appear with typical features of malignancy. Radiologic features of ICC could be better understood and would be helpful for radiologists in diagnosing this rare type of malignancy. PMID- 28618755 TI - Isolation rates and antibiotic susceptibilities of different Enterobacteriaceae species as urinary tract infection agents in Turkey: a systematic review. AB - BACKGROUND/AIM: In Turkey, few systematic reviews have analyzed the results of studies on the isolation rates of urinary tract infection agents and their antibiotic susceptibilities. This review was done to fill this gap and enable the correct application of guideline-based medical therapy by determining the isolation rates and antibiotic susceptibilities of different Enterobacteriaceae species in Turkey. MATERIALS AND METHODS: Relevant studies found from various databases with the help of previously specified search strategies were examined and eliminated according to eligibility criteria. The remaining 22 studies were included in this systematic review. RESULTS: Escherichia coli was the most frequently isolated species among all agents in both in- and outpatient settings. Only the antibiotic susceptibility data of E. coli could be analyzed because among the 22 studies only E. coli had adequate antibiotic susceptibility data to be analyzed. The calculated resistance rates of the most frequently preferred antibiotics (trimethoprim/sulfamethoxazole, ciprofloxacin, and ceftriaxone) were 46%, 32%, and 19% for outpatients and 54%, 48%, and 28% for inpatients, respectively. CONCLUSION: The resistance profiles of commonly used antimicrobial agents are much higher than the thresholds set by international guidelines. Hence, treatment algorithms for urinary tract infections should be designed according to Turkey's antimicrobial resistance patterns. PMID- 28618756 TI - Rational design of rabies vaccine formulation for enhanced stability. AB - BACKGROUND/AIM: Vaccines are often lyophilized in order to retain their stability and efficacy for a longer period of time. However, the same lyophilization process may also cause a major degradation of the vaccine, especially during early phases of manufacturing, leading to a loss of potency of the product. Many viral diseases, such as rabies, are acute and fatal unless the vaccine is administered prior to exposure or the onset of symptoms in the case of postexposure treatment. MATERIALS AND METHODS: We investigated the effect of lyophilization on the stability of the virus structure during rabies vaccine manufacturing using dynamic light scattering and transmission electron microscopy. RESULTS: Our results indicate that some viruses lose their stability and efficacy in the course of lyophilization if the pH of the cell culture medium is controlled by solvated CO2 because the structure of the rabies virus is very sensitive to the solution pH: the virus either aggregates or its shape is deformed at low solution pH, whereas at high pH empty capsid shells are formed. CONCLUSION: Based on our findings, we developed a new formulation for the rabies vaccine that is stable in different buffers owing to the prevention of pH upshift upon lyophilization. PMID- 28618757 TI - The effect of acetylsalicylic acid on vasopressin, serum insulin levels, insulin resistance, and biochemical parameters in rats induced with experimental diabetes type 2. AB - BACKGROUND/AIM: Acetylsalicylic acid (ASA) treatment in diabetic patients is very important owing to the increasing hyperactivity of thrombocytes and atherosclerosis. In several investigations, it was reported that diabetes caused increased coronary artery disease, cerebrovascular disease, and death. In this study, we aimed to investigate the effect of ASA on osmoregulation, glycemic control, and some biochemical parameters in rats induced with experimental diabetes type 2. MATERIALS AND METHODS: Twenty-four rats were randomly divided in four groups: control (I), ASA control (II), diabetic (III), and ASA diabetic (IV). Diabetes was induced by streptozotocin treatment (30 mg/kg, twice, intraperitoneal injection) in obese rats. ASA (150 mg/kg body weight, orally) was administered for 5 weeks in the ASA control and ASA diabetic groups. Serum electrolytes, creatinine, albumin, and total protein levels were analyzed with an autoanalyzer. Arginine vasopressin (AVP) and insulin were analyzed by ELISA techniques. RESULTS: At the end of the study ASA treatments had decreased the fasting blood glucose levels but had interestingly increased the serum AVP levels in diabetics rats. CONCLUSION: AVP levels were increased 2-fold by ASA treatment in diabetic rats. For the first time in this study, the hypoglycemic effect of ASA was attributed to an increase in blood volume by AVP levels. This explanation may be a new approach to the literature on this topic. PMID- 28618758 TI - Investigation of the behavioral and neurochemical effects of monosodium glutamate on neonatal rats. AB - BACKGROUND/AIM: The objective of this study was to investigate and analyze the behavioral and neurochemical effects of monosodium glutamate (MSG) injections at various and subsequent dosages on male Wistar rats during the neonatal period. MATERIALS AND METHODS: In order to determine the behavioral and neurochemical effects of MSG, the experiment was implemented on neonatal male Wistar rats and the test was repeated for various MSG dosages. After completing the experiment, additionally, levels of dopamine, GABA, catecholamine (dopamine, noradrenaline, and adrenaline) and glutamate in the brain cells of the decapitated rats were also measured using the ELISA method. RESULTS: Considering the results of the behavioral test, when we compared the test values of the control group with the values of the MSG-injected groups we noted that there were significant differences in the statistical figures obtained. Additionally, we found that the statistical figures of some neurochemical parameters were also significantly different when we compared the values of the MSG group with the control values. CONCLUSION: MSG injection has a clear effect on the neurochemical parameters, learning memory, and locomotor activities of rats. PMID- 28618759 TI - The effect of trimetazidine on renal oxidative stress in partial and complete ureteral obstructions in a rat model. AB - BACKGROUND/AIM: Renal oxidative stress occurs in ureteral obstructions. The purpose of this study was to investigate the effect of the antioxidant and antiischemic agent trimetazidine (TMZ) on oxidative stress following ureteral obstruction. MATERIALS AND METHODS: Ten groups were established. Sham groups were checked as controls after 1 and 3 weeks. The other 8 groups had partial or complete ureteral obstruction while receiving or not receiving trimetazidine (TMZ) at 5 mg/kg daily and were evaluated after either 1 week or 3 weeks. Creatinine and cystatin C measurements were performed in the serum. Malondialdehyde, myeloperoxidase, catalase, and glutathione peroxidase activity were measured in renal tissue and serum. RESULTS: In the 1-week groups, tissue malondialdehyde, serum myeloperoxidase, and glutathione peroxidase activity increased significantly with obstruction and TMZ use compared to the control group (P < 0.005). In the 3-week TMZ group, cystatin C, tissue malondialdehyde, serum and tissue myeloperoxidase, and tissue glutathione peroxidase differed significantly (P < 0.05). There was no significant difference in all parameters after 3 weeks of partial obstruction (P > 0.05), with only serum malondialdehyde being significantly elevated (P < 0.05). CONCLUSION: TMZ did not exhibit a renal oxidative stress-lowering effect in obstruction. It causes mild impairment of renal functions in obstruction. Patients using TMZ must be closely monitored in terms of kidney function in the event of any ureteral obstruction. PMID- 28618760 TI - Changes in the serum, liver, and renal cortical lipids and electrolytes in rabbits with cisplatin-induced nephrotoxicity. AB - BACKGROUND/AIM: Cisplatin is an anticancer drug that can induce nephrotoxicity. Its toxicity is associated with dyslipidemia and disturbed electrolyte balance. In the present study we investigated the changes in serum lipid profile and electrolyte levels and their contents in kidney and liver tissues of rabbits treated with cisplatin. MATERIALS AND METHODS: Twenty-eight adult male New Zealand White rabbits were used in the experiment. Animals of groups C, P1, and P2 were injected with saline, cisplatin (4.0 mg/kg bw), and cisplatin (6.5 mg/kg bw), respectively, and killed 3 days after the injections. Animals of group R were given cisplatin (6.5 mg/kg bw) and killed after 7 days. All animals were killed after an overnight fast. RESULTS: The P2 animals showed reductions in their body weights, significant (P < 0.001) increases in serum creatinine and urea levels, and significant (P < 0.001) drops in cortical alkaline phosphatase activity and necrotic kidney histology. The treatments had no effect on liver function. Moreover, the P2 animals showed increased serum cholesterol, TAG, and elevated LDL-cholesterol, with significant accumulations of the kidney cholesterol and TAG, but no change in serum phospholipid and depleted hepatic cholesterol. Moreover, the P2 animals had depressed serum levels of potassium, calcium, and magnesium, and reduced renal cortical calcium and magnesium contents and depressed liver calcium but not magnesium. However, the P1 animals had no significant alterations in their lipid or electrolyte levels. Most of the perturbed parameters returned to normal levels in the recovery group. CONCLUSION: Cisplatin nephrotoxicity in rabbits is accompanied by reductions in body weight, secondary dyslipidemia, and reduced serum potassium, calcium, and magnesium with depleted renal cortical magnesium and calcium and accumulated cortical lipids. PMID- 28618761 TI - The effects of iloprost and alprostadil on ischemia-reperfusion injury in preventing inflammation, tissue degeneration, and apoptosis in rat skeletal muscle. AB - BACKGROUND/AIM: The protective effects of prostaglandin (PG) analogs on ischemia reperfusion (I/R) have been well documented; however, comparative studies are lacking. The aim of the present study was to determine whether iloprost or alprostadil is more effective in preventing muscle I/R injury. MATERIALS AND METHODS: Thirty-two rats were divided into four groups (n = 8): sham, control, IL (I/R + iloprost), and AL (I/R + alprostadil). I/R was induced by a tourniquet in the hindlimb for 3 h/3 h. The IL and AL groups received iloprost (0.5 ng kg-1 min 1) and alprostadil (0.05 ug kg-1 min-1) during reperfusion, respectively. After 6 h, blood and muscles were collected for analyses. RESULTS: Serum TNF-alpha and IL 1beta levels were decreased in the IL and AL groups compared with the control group (P < 0.05), whereas IL-6 levels did not change significantly. Tissue malondialdehyde levels were significantly lower in the IL and AL groups (P < 0.05). Tissue catalase levels showed no difference. The histological damage scores and apoptosis scores were both significantly decreased in the IL and AL groups compared with the control group (P< 0.05). CONCLUSION: The present study indicated that iloprost and alprostadil attenuated I/R injury in skeletal muscle. However, no comparable difference was evident regarding the efficacies of either PG analog. PMID- 28618762 TI - Antiinflammatory and antioxidant effects of gemcitabine in collagen-induced arthritis model. AB - BACKGROUND/AIM: Gemcitabine (GEM) has antiproliferative effects on lymphocytes, which are potent pathogenic actors of rheumatoid arthritis (RA). The aim of the study was to investigate the therapeutic potential of GEM on collagen-induced arthritis (CIA). MATERIALS AND METHODS: Arthritis was induced by the intradermal injection of chicken type II collagen with incomplete Freund's adjuvant into albino Wistar rats. Doses of 5 and 20 mg/kg GEM were administered twice a week after the 14th day, which marked the onset the arthritis. Serum IL-17, TNF-alpha, malondialdehyde, catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx) levels and tissue heme oxygenase-1 (HO-1) and nuclear factor erythroid 2 related factor 2 (Nrf2) levels were analyzed. RESULTS: Histopathologically prevalent inflammation and cartilage/bone destruction were observed in the arthritis group. Moreover, in the arthritis group serum IL-17, TNF-alpha, and malondialdehyde levels were significantly increased while catalase, SOD, GPx, HO 1, and Nrf2 levels were significantly decreased. However, in the GEM-treated groups, decreased TNF-alpha, IL-17, and malondialdehyde levels; increased SOD, catalase, GPx, Nrf2, and HO-1 levels; and ameliorated perisynovial inflammation and cartilage/bone destruction were observed. CONCLUSION: GEM suppresses cytokine levels and enhances antioxidant activity. It also prevents cartilage/bone destruction in the CIA model. GEM may be a viable candidate for research into the treatment of RA. PMID- 28618763 TI - Comparison of endothelin and nitric oxide synthase blockers on hemorheological parameters in endotoxemic rats. AB - BACKGROUND/AIM: Septic shock is an important health problem that vastly alters cardiovascular and hemodynamic status. Increased production of nitric oxide (NO) and endothelin is a counterpart of this endotoxemic state. This study was conducted to test the hypothesis that nonselective NO synthesis blocker (L-NAME), inducible NO synthesis blocker (L-canavanine), or endothelin receptor antagonist (bosentan) will reverse the effects of sepsis on hemorheological parameters. MATERIALS AND METHODS: Forty-eight male Sprague-Dawley rats were used in 8 groups: saline (control), endotoxin, bosentan, L-NAME, L-canavanine, endotoxin + bosentan, endotoxin + L-NAME, and endotoxin + L-canavanine. Blood was withdrawn at the 4th hour of endotoxemic state. Erythrocyte deformability and erythrocyte aggregation were determined by laser-assisted optical rotational cell analyzer at 37 degrees C. Plasma viscosity (mPa.s) was measured by a cone-plate viscometer with 0.5 mL of plasma. RESULTS: Endotoxin administration significantly increased aggregation half-time and lowered erythrocyte aggregation amplitude and aggregation index compared to the control, indicating a slower and weaker aggregation pattern. L-NAME and L-canavanine alleviated the effects of endotoxin on erythrocyte aggregation without altering the values in the control animals. However, bosentan did not perform such a restoration. CONCLUSION: This finding suggests that these restoration effects of the blockers occur via their modulation of nitric oxide synthesis rather than through the endothelin pathway. PMID- 28618764 TI - What is the rectal colonization rate of carbapenem-resistant Enterobacteriaceae (CRE)-infected patients? What is the decolonization rate of CRE-colonized patients in the hospital? PMID- 28618765 TI - The influence of intraabdominal pressure on the mortality rate of patients with acute pancreatitis. AB - BACKGROUND/AIM: Intraabdominal hypertension (IAH) is a common clinical finding in patients with acute pancreatitis and is associated with poor prognosis. This study aimed to determine the impact of intraabdominal pressure (IAP) on the mortality rate in patients with acute pancreatitis in an intensive care unit. MATERIALS AND METHODS: A total of 50 patients with acute pancreatitis were included in this prospective cohort study. Based on the obtained values of IAP, the patients were divided into two groups: those with normal IAP (n = 14) and increased IAP (n = 36). Mean values of IAP were compared with examined variables. RESULTS: The mortality rate of the study group was 40%. Comparing the IAP and treatment outcomes, it was proved that there were statistically highly significant differences (P = 0.012). Increasing the value of IAP increased the mortality rate. Deceased patients in the IAH group had greater statistical significance of APACHE II score (P = 0.016), abdominal perfusion pressure (P = 0.048), lactate (P = 0.049), hematocrit (P = 0.039), Ranson's criteria on admission (P = 0.017), Ranson's criteria after 48 h (P = 0.010), Sequential Organ Failure Assessment score (P = 0.014), and body mass index (P = 0.012) compared to the surviving patients. CONCLUSION: IAP has an impact on the increase of mortality rates in patients with acute pancreatitis. PMID- 28618766 TI - Relationship between blood glucose levels and cardiovascular risk in the Spanish Mediterranean population. AB - BACKGROUND/AIM: Diabetes is associated with an increased prevalence of cardiovascular disease. Impaired fasting glucose (IFG) is an intermediate clinical situation between normal glucose levels and type 2 diabetes. The aim of this study is to determine how fasting glucose concentrations affect different cardiovascular risk scales. MATERIALS AND METHODS: A descriptive study was conducted with 59,041 Mediterranean Spanish workers. IFG was determined using the American Diabetes Association (ADA) and the World Health Organization (WHO) criteria. Different indicators of cardiovascular risk were analyzed: body mass index, waist circumference, waist-to-height ratio, blood pressure, lipid parameters, atherogenic indices, metabolic syndrome, and various scales of cardiovascular risk such as REGICOR, DORICA, SCORE, Heart Age, and Vascular Age. RESULTS: All cardiovascular scales showed statistically significant differences between the IFG group and the normal glucose group. In all cases, values were worse in the IFG group; furthermore, men exhibited more unfavorable levels of cardiovascular risk factors than women. Higher odds ratio values were present in employees with metabolic syndrome according to ATP III criteria (9.42, 95% CI: 8.56-10.37 using WHO criteria and 9.25, 95% CI: 8.67-9.87 using ADA criteria).Conclusions: IFG increases cardiovascular risk whether using classical scales (REGICOR, SCORE, and metabolic syndrome) or other less studied scales (atherogenic indices, Heart Age, and Vascular Age). PMID- 28618767 TI - Skin findings in autoimmune and nonautoimmune thyroid disease with respect to thyroid functional status and healthy controls. AB - BACKGROUND/AIM: Thyroid disorders are associated with a wide variety of skin disorders that respond to treatment of hormone imbalance in most cases and thus are of vital importance to dermatologists. This study aimed to evaluate skin findings associated with autoimmune and nonautoimmune thyroid disease with respect to thyroid functional status and healthy controls. MATERIALS AND METHODS: A total of 300 consecutive patients with either autoimmune (n = 173) or nonautoimmune (n = 127) thyroid disease and 100 healthy control subjects were included in this cross-sectional study. Data on patient demographics, thyroid function tests, and skin findings were recorded for patient and control groups. RESULTS: Compared to control subjects, patients had higher proportions in populations with alopecia (P < 0.001), nail thinning (P = 0.02), brittle nails (P = 0.001), pruritus (P < 0.001), diffuse hyperhidrosis (P = 0.01), flushing (P = 0.001), and xerosis (P < 0.001). Onycholysis (P = 0.02), yellow skin (P = 0.04), periorbital edema (P = 0.03), psoriasis (P = 0.001), and palmoplantar hyperkeratosis (P = 0.007) were significantly more common in patients with autoimmune than nonautoimmune thyroid disease. A significantly higher percentage of patients with autoimmune rather than nonautoimmune thyroid disease had overall skin findings (P = 0.03) among the hyperthyroid patients.Conclusions: Our findings indicate that the presence of skin findings in a majority of thyroid patients significantly differs for certain cutaneous manifestations with respect to controls, autoimmune etiology, and thyroid functional status. PMID- 28618768 TI - Psychosocial functioning in pediatric patients with pectus excavatum and pectus carinatum. AB - BACKGROUND/AIM: Pectus excavatum and pectus carinatum are the most commonly seen anterior chest wall deformities. Recent studies reveal that minimal invasive repair of pectus deformities improves the quality of life. Our aim is to assess the psychosocial functioning and sociodemographic characteristics of pediatric patients with pectus deformities and evaluate the differences between patients operated on with minimal invasive repair techniques and nonoperated patients. MATERIALS AND METHODS: Thirty-two patients with pectus deformities who were operated on 6 months or more before and 31 nonoperated patients participated in the study. The Children's Depression Inventory, Piers-Harris Children's Self Concept Scale, Capa Social Phobia Scale for Children and Adolescents, Strengths and Difficulties Questionnaire - Self-Report Version (SDQ-SR), and State-Trait Anxiety Inventory for Children - Trait Version were completed by the patients. The SDQ-Parent Report Version (SDQ-PR) was completed by their parents. RESULTS: There were no statistically significant differences between operated and nonoperated patient groups in terms of total scores on the psychiatric rating scales. Prosocial behavior subscale scores in SDQ-SR (P = 0.013) and SDQ-PR (P = 0.019) were lower in the operated group. CONCLUSION: Prosocial behavior levels were lower in the operated group. Further exploration of the psychosocial profile of pediatric patients with pectus deformities would better elucidate their needs in the course of their socioemotional development. PMID- 28618769 TI - Association study of CTLA-4 +49A/G gene polymorphism with recurrent pregnancy loss in the Iranian Azeri Turkish ethnic group. AB - BACKGROUND/AIM: Recurrent pregnancy loss (RPL) is defined as two or more pregnancy losses. T-regulatory cells play an important role in the feto-maternal interface. Cytotoxic-T-lymphocyte antigen-4 (CTLA-4) is a molecule that downregulates the activation and proliferation of T cells. The objective of the current study was to investigate the possible association of CTLA-4+49A/G gene polymorphism with RPL among patients from the Iranian Azeri Turkish ethnic group. MATERIALS AND METHODS: The study group/patients consisted of 101 women with the experience of two or more pregnancy losses and the control group consisted of 101 women with at least two live births, without any previous history of pregnancy loss and autoimmune diseases from the same ethnic group. The CTLA-4+49A/G was detected by polymerase chain reaction-restriction fragment length polymorphisms assay. RESULTS: The distribution of CTLA-4+49A/G genotype was AA, 38.61%; AG, 51.48%; GG, 9.9% in patients and AA, 37.62%; AG, 47.52%; GG,14.85% in controls (P value: 0.2). Furthermore, no association in G-allele was observed in the patient and control groups (P-value: 0.5). CONCLUSION: The results of the present study suggest that CTLA-4 does not have any association with RPL in the Iranian Azeri Turkish ethnic group. PMID- 28618770 TI - Clinical significance of renal cortical thickness in patients with chronic kidney disease. AB - PURPOSE: The aim of this study was to evaluate the correlations between laboratory findings and ultrasonographic measurements of renal length and cortical thickness in patients receiving follow-up for chronic kidney disease (CKD). METHODS: A total of 41 CKD patients (18 males and 23 females; mean age, 65.2 years; range, 42 to 85 years) with a low glomerular filtration rate who did not require renal replacement therapy were included in this prospective study. Patients were followed up with laboratory assays at bimonthly intervals and with ultrasonography performed twice a year. Renal cortical thickness, renal length, and estimated glomerular filtration rate (eGFR) values were compared using the paired-samples t test. Additionally, Pearson correlation analysis was conducted between renal length and cortical thickness measurements and eGFR values to assess kidney function. RESULTS: At the beginning of the study and after 24 months, mean eGFR values of the 41 patients were 35.92 mL/min and 28.38 mL/min, respectively. The mean renal length was 91.29 mm at the beginning of the study and 90.24 mm at the end of the study. The mean cortical thickness was 5.76+/-2.05 mm at the beginning of the study and 5.28+/-1.99 mm at the end of the study. A statistically significant positive association was found between eGFR and mean renal length (r=0.66, P<0.01) and between eGFR and mean cortical thickness (r=0.85, P<0.01), with the latter being more prominent. CONCLUSION: Our study suggests that ultrasonographic cortical thickness measurements may be an important imaging technique in the follow-up care of patients with CKD. PMID- 28618771 TI - Logistic LASSO regression for the diagnosis of breast cancer using clinical demographic data and the BI-RADS lexicon for ultrasonography. AB - PURPOSE: The aim of this study was to compare the performance of image analysis for predicting breast cancer using two distinct regression models and to evaluate the usefulness of incorporating clinical and demographic data (CDD) into the image analysis in order to improve the diagnosis of breast cancer. METHODS: This study included 139 solid masses from 139 patients who underwent a ultrasonography guided core biopsy and had available CDD between June 2009 and April 2010. Three breast radiologists retrospectively reviewed 139 breast masses and described each lesion using the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We applied and compared two regression methods-stepwise logistic (SL) regression and logistic least absolute shrinkage and selection operator (LASSO) regression-in which the BI-RADS descriptors and CDD were used as covariates. We investigated the performances of these regression methods and the agreement of radiologists in terms of test misclassification error and the area under the curve (AUC) of the tests. RESULTS: Logistic LASSO regression was superior (P<0.05) to SL regression, regardless of whether CDD was included in the covariates, in terms of test misclassification errors (0.234 vs. 0.253, without CDD; 0.196 vs. 0.258, with CDD) and AUC (0.785 vs. 0.759, without CDD; 0.873 vs. 0.735, with CDD). However, it was inferior (P<0.05) to the agreement of three radiologists in terms of test misclassification errors (0.234 vs. 0.168, without CDD; 0.196 vs. 0.088, with CDD) and the AUC without CDD (0.785 vs. 0.844, P<0.001), but was comparable to the AUC with CDD (0.873 vs. 0.880, P=0.141). CONCLUSION: Logistic LASSO regression based on BI-RADS descriptors and CDD showed better performance than SL in predicting the presence of breast cancer. The use of CDD as a supplement to the BI-RADS descriptors significantly improved the prediction of breast cancer using logistic LASSO regression. PMID- 28618773 TI - Painful nodule on umbilicus: Sister Mary Joseph nodule as an unusual but important manifestation of widespread gallbladder cancer. PMID- 28618772 TI - Efficacy and safety of pitavastatins in patients with acute myocardial infarction: Livalo in Acute Myocardial Infarction Study (LAMIS) II. AB - BACKGROUND/AIMS: We evaluated the efficacy and safety and influence on glucose tolerance by different doses of pitavastatins in acute myocardial infarction (AMI) patients. METHODS: Consecutive 1,101 AMI patients who were enrolled in Livalo in Acute Myocardial Infarction Study (LAMIS)-II were randomly assigned to receive either 2 mg of pitavastatin or 4 mg of pitavastatin orally per day. Primary efficacy endpoint was composite of cardiac death, nonfatal myocardial infarction, target-lesion revascularization, and hospitalization for unstable angina, heart failure or arrhythmic events at 12-month. RESULTS: There was no significant difference in primary efficacy endpoint between 2 mg and 4 mg groups (9.07% vs. 9.13%, p = 0.976). The degree of the reduction of low density lipoprotein cholesterol (LDL-C) was significantly greater in 4 mg group compared to 2 mg group from baseline to follow-up (-42.05 +/- 32.73 mg/dL vs. -34.23 +/- 31.66 mg/dL, p = 0.002). Fasting plasma glucose level was reduced significantly in both groups (-20.16 +/- 54.49 mg/dL in 4 mg group and -24.45 +/- 63.88 mg/dL in 2 mg group, p < 0.001 and p < 0.001, respectively) and there was no significant change of glycated hemoglobin in two groups from baseline to follow up (-0.13% +/- 1.21% in 4 mg group and -0.04% +/- 1.10% in 2 mg group, p = 0.256 and p = 0.671, respectively). CONCLUSIONS: Although LDL-C was reduced more significantly by using 4 mg of pitavastatin compared to 2 mg of pitavastatin, the event rate was comparable without adverse effects on glucose tolerance in both groups in AMI patients who were enrolled in LAMIS-II. PMID- 28618774 TI - Low-Dose Radiation Therapy for Primary Conjunctival Marginal Zone B-Cell Lymphoma. AB - PURPOSE: The purpose of this study was to evaluate the clinical features and the long-term outcomes of primary conjunctival marginal zone B-cell lymphoma (MZBCL) patients who were treated with radiation therapy (RT). MATERIALS AND METHODS: Retrospective data of 79 patients with 121 primary conjunctival MZBCL lesions were collected from January 1, 2001 till June 30, 2014. All lesions were treated by local RT (26 Gy) with patient-specific customized lens-shielding device. RESULTS: The current Korean patients' cohort showed younger median age at diagnosis (38 years), great female preponderance (78.5%) and more frequent bilateral involvement (53.2%) than the previous studies. Following 26 Gy's RT, excellent clinical outcomes were achieved: 5-year rates of overall survival, local relapse-free survival, and contralateral relapse-free survival were 100%, 98.1%, and 91.5%, respectively. Two patients (2.5%) developed local relapse and five (6.3%) developed relapse at initially uninvolved contralateral conjunctiva with median interval of 52.9 months, and late adverse events of grade 2 and 3 occurred in seven (8.8%) and two (2.5%) patients, respectively. CONCLUSION: 26 Gy's RT was highly effective and safe, with the use of lens-shielding device, in treating patients with primary conjunctival MZBCL. PMID- 28618775 TI - Thermal Decomposition of 2,3,3,3- and trans-1,3,3,3-Tetrafluoropropenes. AB - The thermal decomposition reactions of 2,3,3,3- and trans-1,3,3,3 tetrafluoropropenes (TFPs) have been studied both experimentally and computationally to elucidate their kinetics and mechanism. The experiments were performed by observing the temporal profiles of HF produced in the decomposition of the tetrafluoropropenes behind shock waves at temperatures of 1540-1952 K (for 2,3,3,3-TFP) or 1525-1823 K (for trans-1,3,3,3-TFP) and pressure of 100-200 kPa in Ar bath. The reaction pathways responsible for the profiles were explored based on quantum chemical calculations. The decomposition of 2,3,3,3-TFP was predicted to proceed predominantly via direct 1,2-HF elimination to yield CHCCF3, while trans-1,3,3,3-TFP was found to decompose to HF and a variety of isomeric C3HF3 products including CHCCF3, CF2CCHF, CCHCF3, and CF2CHCF. The C3HF3 isomers can subsequently decompose to either CF2 + CHCF or CF2CC + HF products. Multichannel RRKM/master equation calculations were performed for the identified decomposition channels. The observed formation rates and apparent yields of HF are shown to be consistent with the computational predictions. PMID- 28618776 TI - Salicylideneanilines-Based Covalent Organic Frameworks as Chemoselective Molecular Sieves. AB - Porous materials such as covalent organic frameworks (COFs) are good candidates for molecular sieves due to the chemical diversity of their building blocks, which allows fine-tuning of their chemical and physical properties by design. Tailored synthesis of inherently functional building blocks can generate framework materials with chemoresponsivity, leading to controllable functionalities such as switchable sorption and separation. Herein, we demonstrate a chemoselective, salicylideneanilines-based COF (SA-COF), which undergoes solvent-triggered tautomeric switching. This is unique compared to solid-state salicylideneanilines' counterpart, which typically requires high energy input such as photo or thermal activation to trigger the enol-keto tautomerisim and cis-trans isomerization. Accompanying the tautomerization, the ionic properties of the COF can be tuned reversibly, thus forming the basis of size-exclusion, selective ionic binding or chemoseparation in SA-COF demonstrated in this work. PMID- 28618777 TI - Rare Earth pcu Metal-Organic Framework Platform Based on RE4(MU3-OH)4(COO)62+ Clusters: Rational Design, Directed Synthesis, and Deliberate Tuning of Excitation Wavelengths. AB - The Td point group symmetry of rare earth (RE3+) metal clusters RE4(MU3 OH)4(COO)62+ makes them attractive building blocks for creating metal-organic frameworks (MOFs) with controllable topologies. Herein, we describe the design and synthesis of a series of isoreticular MOFs featuring pcu topology [MOF 1114(RE) and MOF-1115(RE)] with variable rare earth metal ions (RE3+ = Y3+, Sm3+, Eu3+, Gd3+, Tb3+, Dy3+, Ho3+, Er3+, Tm3+, Yb3+) and linear amino-functionalized dicarboxylate linkers of different lengths. In total, we report 22 MOFs that vary in both composition and structure yet share the same RE4(MU3-OH)4 cluster motif. We demonstrate that these pcu MOFs are cationic and that anion exchange can be used to affect the MOF properties. We also investigate the luminescence properties of a representative member of this MOF series [MOF-1114(Yb)] that exhibits near-infrared emission. We show that the excitation energy for Yb3+ sensitization can be carefully adjusted to lower energy via covalent postsynthetic modification at the amino group sites within the MOF. PMID- 28618778 TI - Tunable Large Pore Mesoporous Carbons for the Enhanced Adsorption of Humic Acid. AB - Tunable large pore soft templated mesoporous carbons (SMC) were obtained via the organic self-assembly of resorcinol/formaldehyde with the triblock copolymer F127 and by investigating the effect of carbon precursor to surfactant (p/s) ratio and carbonization temperature on the material characteristics. The p/s ratio and carbonization temperature were varied respectively from 0.83 to 0.25 and from 400 to 1200 degrees C. The resulting SMCs had various average pore sizes, tunable from 7 up to 50 nm. At lower p/s ratios, the pore size increased, pore size distributions broadened, and pore volumes increased. An increase of hydrophobicity was observed at elevated carbonization temperatures. A 2D hexagonal ordered SMC with a narrow pore size distribution was obtained at a ratio of 0.83. Lower ratios (0.5 and 0.25) transformed into disordered porous carbons containing micropores, mesopores, and even macropores. The SMCs were tested for adsorption of a large organic molecule, humic acid (HA), from water. The material characteristics that significantly affected HA adsorption capacity were pore size and mass % (wt %) carbon. The novel SMCs showed an unprecedented high adsorption of HA in the entire molecular weight distribution range. SMCs with large mesopores resulted in higher maximum adsorption capacities and improved HA adsorption kinetics compared to activated carbon. PMID- 28618779 TI - Photofragmentation of Tetranitromethane: Spin-Unrestricted Time-Dependent Excited State Molecular Dynamics. AB - In this study, the photofragmentation dynamics of tetranitromethane (TNM) is explored by a spin-unrestricted time-dependent excited-state molecular dynamics (u-TDESMD) algorithm based on Rabi oscillations and principles similar to trajectory surface hopping, with a midintensity field approximation. The leading order process is represented by the molecule undergoing cyclic excitations and de excitations. During excitation cycles, the nuclear kinetic energy is accumulated to overcome the dissociation barriers in the reactant and a sequence of intermediates. The dissociation pathway includes the ejection of NO2 groups followed by the formation of NO and CO. The simulated mass spectra at the ab initio level, based on the bond length in possible fragments, are extracted from simulation trajectories. The recently developed methodology has the potential to model and monitor photoreactions with open-shell intermediates and radicals. PMID- 28618780 TI - Amorphous Metal Polysulfides: Electrode Materials with Unique Insertion/Extraction Reactions. AB - A unique charge/discharge mechanism of amorphous TiS4 is reported. Amorphous transition metal polysulfide electrodes exhibit anomalous charge/discharge performance and should have a unique charge/discharge mechanism: neither the typical intercalation/deintercalation mechanism nor the conversion-type one, but a mixture of the two. Analyzing the mechanism of such electrodes has been a challenge because fewer tools are available to examine the "amorphous" structure. It is revealed that the electrode undergoes two distinct structural changes: (i) the deformation and formation of S-S disulfide bonds and (ii) changes in the coordination number of titanium. These structural changes proceed continuously and concertedly for Li insertion/extraction. The results of this study provide a novel and unique model of amorphous electrode materials with significantly larger capacities. PMID- 28618781 TI - Cavity-Type DNA Origami-Based Plasmonic Nanostructures for Raman Enhancement. AB - DNA origami has been established as addressable templates for site-specific anchoring of gold nanoparticles (AuNPs). Given that AuNPs are assembled by charged DNA oligonucleotides, it is important to reduce the charge repulsion between AuNPs-DNA and the template to realize high yields. Herein, we developed a cavity-type DNA origami as templates to organize 30 nm AuNPs, which formed dimer and tetramer plasmonic nanostructures. Transmission electron microscopy images showed that high yields of dimer and tetramer plasmonic nanostructures were obtained by using the cavity-type DNA origami as the template. More importantly, we observed significant Raman signal enhancement from molecules covalently attached to the plasmonic nanostructures, which provides a new way to high sensitivity Raman sensing. PMID- 28618782 TI - Ab Initio Nonadiabatic Dynamics with Coupled Trajectories: A Rigorous Approach to Quantum (De)Coherence. AB - We report the first nonadiabatic molecular dynamics study based on the exact factorization of the electron-nuclear wave function. Our approach (a coupled trajectory mixed quantum-classical, CT-MQC, scheme) is based on the quantum classical limit derived from systematic and controlled approximations to the full quantum-mechanical problem formulated in the exact-factorization framework. Its strength is the ability to correctly capture quantum (de)coherence effects in a trajectory-based approach to excited-state dynamics. We show this by benchmarking CT-MQC dynamics against a revised version of the popular fewest-switches surface hopping scheme that is able to fix its well-documented overcoherence issue. The CT-MQC approach is successfully applied to investigation of the photochemistry (ring-opening) of oxirane in the gas phase, analyzing in detail the role of decoherence. This work represents a significant step forward in the establishment of the exact factorization as a powerful tool to study excited-state dynamics, not only for interpretation purposes but mainly for nonadiabatic ab initio molecular dynamics simulations. PMID- 28618783 TI - Pulsed Light-Emitting Diodes for a Higher Phytochemical Level in Microgreens. AB - A novel research of pulsed light-emitting diode (LED) lighting versus continuous lighting was conducted by analyzing phytochemical levels in microgreens. Red pak choi (Brassica rapa var. chinensis), mustard (Brassica juncea L.), and tatsoi (Brassica rapa var. rosularis) were grown indoors under HPS lamps supplemented with monochromatic (455, 470, 505, 590, and 627 nm) LEDs [total photosynthetic photon flux density (PPFD) of 200 +/- 10 MUmol m-2 s-1, for 16 h day-1]. For pulsed light treatments, the frequencies at 2, 32, 256, and 1024 Hz with a duty cycle of 50% monochromatic LEDs were applied. The results were compared to those under the continuous light (0 Hz) condition in terms of total phenolic content, anthocyanins, and antiradical activity (DPPH). The summarized data suggested that pulsed light affected accumulation of secondary metabolites both positive and negative in microgreens. The significant differences in the response of phytochemicals between pulsed light at several frequencies and continuous light were determined. The most positive effects of 2, 256, and 1024 Hz for total phenolic compounds in mustard under all wavelength LEDs were achieved. The LED frequencies at 2 and 32 Hz were the most suitable for accumulation of anthocyanins in red pak choi and tatsoi. The highest antiradical activity under the treatments of 32, 256, and 1024 Hz in mustard and under the 2 Hz frequency in red pak choi and tatsoi was determined. PMID- 28618784 TI - Gold-Catalyzed Oxidation Terminal Alkyne: An Approach to Synthesize Substituted Dihydronaphthalen-2(1H)-ones and Phenanthrenols. AB - A facile gold-catalyzed oxidation terminal alkynes to synthesize substituted dihydronaphthalen-2(1H)-ones 3 and phenanthrenols 5 was realized. Various useful structures and drug precursors were generated in up to 99% yield under mild condition and low catalyst loading. PMID- 28618790 TI - Estimation of surface impedance at oblique incidence based on sparse array processing. AB - A method is proposed to estimate the surface impedance of a large absorptive panel from free-field measurements with a spherical microphone array. The method relies on the reconstruction of the pressure and the particle velocity on the studied surface using an equivalent source method based on spherical array measurements. The sound field measured by the array is mainly composed of an incident and a reflected wave, so it can be represented as a spatially sparse problem. This makes it possible to use compressive sensing in order to enhance the resolution and the quality of the estimation. The results indicate an accurate reconstruction for angles of incidence between 0 degrees and 60 degrees , and between approximately 200 and 4000 Hz. Additionally, experimental challenges are discussed, such as the sample's finiteness at low frequencies and the estimation of the background noise. PMID- 28618791 TI - Broadband classification and statistics of echoes from aggregations of fish measured by long-range, mid-frequency sonar. AB - For horizontal-looking sonar systems operating at mid-frequencies (1-10 kHz), scattering by fish with resonant gas-filled swimbladders can dominate seafloor and surface reverberation at long-ranges (i.e., distances much greater than the water depth). This source of scattering, which can be difficult to distinguish from other sources of scattering in the water column or at the boundaries, can add spatio-temporal variability to an already complex acoustic record. Sparsely distributed, spatially compact fish aggregations were measured in the Gulf of Maine using a long-range broadband sonar with continuous spectral coverage from 1.5 to 5 kHz. Observed echoes, that are at least 15 decibels above background levels in the horizontal-looking sonar data, are classified spectrally by the resonance features as due to swimbladder-bearing fish. Contemporaneous multi frequency echosounder measurements (18, 38, and 120 kHz) and net samples are used in conjunction with physics-based acoustic models to validate this approach. Furthermore, the fish aggregations are statistically characterized in the long range data by highly non-Rayleigh distributions of the echo magnitudes. These distributions are accurately predicted by a computationally efficient, physics based model. The model accounts for beam-pattern and waveguide effects as well as the scattering response of aggregations of fish. PMID- 28618792 TI - Effect of evaporation and condensation on a thermoacoustic engine: A Lagrangian simulation approach. AB - Acoustic oscillations of a fluid (a mixture of gas and vapor) parcel in a wet stack of a thermoacoustic engine are numerically simulated with a Lagrangian approach taking into account Rott equations and the effect of non-equilibrium evaporation and condensation of water vapor at the stack surface. In a traveling wave engine, the volume oscillation amplitude of a fluid parcel always increases by evaporation and condensation. As a result, pV work done by a fluid parcel is enhanced, which means enhancement of acoustic energy in a thermoacoustic engine. On the other hand, in a standing-wave engine, the volume oscillation amplitude sometimes decreases by evaporation and condensation, and pV work is suppressed. Presence of a tiny traveling-wave component, however, results in the enhancement of pV work by evaporation and condensation. PMID- 28618793 TI - Finite Element and Boundary Methods in Structural Acoustics and Vibration. PMID- 28618795 TI - Sound Propagation Through the Stochastic Ocean. PMID- 28618794 TI - Sound trapping and dredging barriers. AB - When sound barriers are installed on both sides of a noise source, degradation in performance is observed. Barriers having negative-phase-gradient surfaces successfully eliminate this drawback by trapping sound energy in between the barriers. In contrast, barriers can also be designed to "dredge" the energy flux out. An extended model considering higher-order diffractions, which resulted from the interplay of the induced surface wave and barrier surface periodicity, is presented. It is found that the sound dredging barriers provide a remarkable enhancement over the trapping ones, and hence have the potential to be widely used in noise control engineering. PMID- 28618796 TI - Low frequency acoustic properties of Posidonia oceanica seagrass leaf blades. AB - The acoustics of seagrass meadows impacts naval and oceanographic sonar applications. To study this environment, a one-dimensional resonator was used to assess the low-frequency (1-5 kHz) acoustic response of the leaf blades of the Mediterranean seagrass Posidonia oceanica in water. Three separate collections of plants from Crete, Greece, and Sicily, Italy were investigated. A high consistency in effective sound speed was observed within each collection while a strong variability was observed between different collections. Average size, mass, and epiphytic coverage within each collection were quantified, and discoloration and stiffness are discussed qualitatively with respect to the observed acoustic variability. PMID- 28618797 TI - The dynamic excitation of a granular chain: Contact mechanics finite element analysis and experimental validation. AB - There is currently interest in transmitting acoustic signals along granular chains to produce waveforms of relevance to biomedical ultrasound applications. The study of such a transduction mechanism is greatly aided by the use of validated theoretical models. In view of this, a finite element analysis is presented in this paper. The dynamics of a granular chain of six, 1 mm diameter chrome steel spherical beads, was excited at one end using a sinusoidal displacement signal at 73 kHz, and terminated by a rigid support. Output from this model was compared with the solution provided by the equivalent discrete dynamics model, and good agreement obtained. An experimental configuration involving the same chain, but terminated by an annular support made of a liquid photopolymer resin was also simulated and the velocity of the last sphere obtained through simulation was compared with laser vibrometer measurement, with good agreement. This model was then extended whereby the granular chain was coupled to an acoustic medium with the properties of water, via a thin vitreous carbon cylinder. Finite element predictions of the acoustic pressure indicate that, for a 73 kHz excitation frequency, harmonic rich acoustic pulses with harmonic content close to 1 MHz are predicted. PMID- 28618798 TI - No correlation between headphone frequency response and retail price. AB - This study quantifies variability of measured headphone response patterns and aims to uncover any correlations between headphone type, retail price, and frequency response. For this purpose, the mean, variance, and covariance of the frequency magnitude responses were analyzed and correlated with headphone type and retail value. The results indicate that neither the measured response nor an attempt to objectively quantify perceived quality is related to price. On average, in-ear headphones have a slightly higher measured bass response than circumaural and supra-aural headphones. Furthermore, in-ear and circumaural headphones have a slightly lower deviation from an assumed target curve than supra-ear models. Ninety percent of the variance across all headphone measurements can be described by a set of six basis functions. The first basis function is similar to published target responses, while the second basis function represents a spectral tilt. PMID- 28618799 TI - Biosonar signal propagation in the harbor porpoise's (Phocoena phocoena) head: The role of various structures in the formation of the vertical beam. AB - Harbor porpoises (Phocoena phocoena) use narrow band echolocation signals for detecting and locating prey and for spatial orientation. In this study, acoustic impedance values of tissues in the porpoise's head were calculated from computer tomography (CT) scan and the corresponding Hounsfield Units. A two-dimensional finite element model of the acoustic impedance was constructed based on CT scan data to simulate the acoustic propagation through the animal's head. The far field transmission beam pattern in the vertical plane and the waveforms of the receiving points around the forehead were compared with prior measurement results, the simulation results were qualitatively consistent with the measurement results. The role of the main structures in the head such as the air sacs, melon and skull in the acoustic propagation was investigated. The results showed that air sacs and skull are the major components to form the vertical beam. Additionally, both beam patterns and sound pressure of the sound waves through four positions deep inside the melon were demonstrated to show the role of the melon in the biosonar sound propagation processes in the vertical plane. PMID- 28618800 TI - Effects of tempo, swing density, and listener's drumming experience, on swing detection thresholds for drum rhythms. AB - Swing, a popular technique in music performance, has been said to enhance the "groove" of the rhythm. Swing works by delaying the onsets of even-numbered subdivisions of each beat (e.g., 16th-note swing delays the onsets of the second and fourth 16th-note subdivisions of each quarter-note beat). The "swing magnitude" (loosely speaking, the amount of delay) is often quite small. And there has been little investigation, using musical stimuli, into what swing magnitudes listeners can detect. To that end, this study presented continually looped electronic drum rhythms, with 16th-note swing in the hi-hat on every other bar, to drummers and non-drummers. Swing magnitude was adjusted using a staircase procedure, to determine the magnitude where the difference between swinging and not-swinging bars was just-noticeable. Different tempi (60 to 140 quarter-notes per minute) and swing densities (how often notes occurred at even-numbered subdivisions) were used. Results showed that all subjects could detect smaller swing magnitudes when swing density was higher, thus confirming a previous speculation that the perceptual salience of swing increases with swing density. The just-noticeable magnitudes of swing for drummers differed from those of non drummers, in terms of both overall magnitude and sensitivity to tempo, thus prompting questions for further exploration. PMID- 28618801 TI - Relative contributions of formants to the intelligibility of sine-wave sentences in Mandarin Chinese. AB - Early sine-wave speech (SWS) studies showed that the first three formants contain sufficient intelligibility information. The present work assessed the relative perceptual contributions of the first three formants. Mandarin sentences were edited to generate two SWS conditions: removal of one of the first three formant trajectories, and preservation of only one formant trajectory. In addition, SWS synthesis was implemented in the absence of sine-wave amplitude modulation. The results consistently showed that the trajectory of the second formant contributed the most to intelligibility, and the effect of amplitude modulation was smaller than that of the formant number. PMID- 28618802 TI - Non-negative intensity for coupled fluid-structure interaction problems using the fast multipole method. AB - The non-negative intensity (NNI) method is applied to large-scale coupled fluid structure interaction (FSI) problems using the fast multipole boundary element method (FMBEM). The NNI provides a field on the radiating structure surface that consists of positive-only contributions to the radiated sound power, thus avoiding the near-field cancellation effects that otherwise occur with the sound intensity field. Thus far the NNI has been implemented with the boundary element method (BEM) for relatively small problem sizes to allow for the full BEM coefficient and inverse matrices to be explicitly constructed and stored. In this work, the FMBEM is adapted to the NNI by calculating the eigenvalue solution of the symmetric acoustic impedance matrix using the FMBEM via a two-stage solution method. The FMBEM implementation of the NNI is demonstrated for a large-scale model of a submerged cylindrical shell. The coupled FSI problem is first solved using a finite element-FMBEM model and the resulting surface fields are then used in the FMBEM calculation of the NNI. An equivalent reactive NNI field representing the evanescent near-field radiation is demonstrated and the effect of the chosen number eigenvectors on the NNI field is investigated. PMID- 28618803 TI - Effects of linear and nonlinear speech rate changes on speech intelligibility in stationary and fluctuating maskers. AB - Algorithmic modifications to the durational structure of speech designed to avoid intervals of intense masking lead to increases in intelligibility, but the basis for such gains is not clear. The current study addressed the possibility that the reduced information load produced by speech rate slowing might explain some or all of the benefits of durational modifications. The study also investigated the influence of masker stationarity on the effectiveness of durational changes. Listeners identified keywords in sentences that had undergone linear and nonlinear speech rate changes resulting in overall temporal lengthening in the presence of stationary and fluctuating maskers. Relative to unmodified speech, a slower speech rate produced no intelligibility gains for the stationary masker, suggesting that a reduction in information rate does not underlie intelligibility benefits of durationally modified speech. However, both linear and nonlinear modifications led to substantial intelligibility increases in fluctuating noise. One possibility is that overall increases in speech duration provide no new phonetic information in stationary masking conditions, but that temporal fluctuations in the background increase the likelihood of glimpsing additional salient speech cues. Alternatively, listeners may have benefitted from an increase in the difference in speech rates between the target and background. PMID- 28618804 TI - An optical flow-based state-space model of the vocal folds. AB - High-speed movies of the vocal fold vibration are valuable data to reveal vocal fold features for voice pathology diagnosis. This work presents a suitable Bayesian model and a purely theoretical discussion for further development of a framework for continuum biomechanical features estimation. A linear and Gaussian nonstationary state-space model is proposed and thoroughly discussed. The evolution model is based on a self-sustained three-dimensional finite element model of the vocal folds, and the observation model involves a dense optical flow algorithm. The results show that the method is able to capture different deformation patterns between the computed optical flow and the finite element deformation, controlled by the choice of the model tissue parameters. PMID- 28618805 TI - Explosion yield estimation from pressure wave template matching. AB - A method for estimating the yield of explosions from shock-wave and acoustic-wave measurements is presented. The method exploits full waveforms by comparing pressure measurements against an empirical stack of prior observations using scaling laws. The approach can be applied to measurements across a wide-range of source-to-receiver distances. The method is applied to data from two explosion experiments in different regions, leading to mean relative errors in yield estimates of 0.13 using prior data from the same region, and 0.2 when applied to a new region. PMID- 28618806 TI - Testing two crackle criteria using modified jet noise waveforms. AB - The jet sound quality "crackle" has historically been studied and quantified using the statistics of the pressure waveform. Some investigators have suggested crackle, and its associated shock content, may be better quantified using the statistics of the time derivative of the waveform. Modified waveforms are used to evaluate crackle prediction criteria based on the skewness of each variable. The resultant waveforms are provided as direct evidence that the pressure distribution does not directly predict or quantify a crackling sound quality while the statistics of the derivative appear to do so. PMID- 28618808 TI - Semi-analytical modeling of ground/plate interaction for general elastic boundary conditions. AB - This letter introduces ground/plate interaction using the concept of ground cross modal impedance in the case of general elastic boundary conditions. Navier equations are generally used to account for ground vibration with two propagating waves, the dilatational wave and the shear wave. The plate equation of motion follows the Kirchhoff-Love hypothesis, where shear and rotational inertia are neglected in the plate thickness. The general elastic boundary conditions are expressed analytically through a two-dimensional Fourier series in the plate displacement solution. This study shows that the plate general boundary conditions have a small influence on the plate velocity. However, two categories of boundary conditions could be implemented, especially at low frequency. PMID- 28618807 TI - The effect of presentation level and stimulation rate on speech perception and modulation detection for cochlear implant users. AB - In order to improve speech understanding for cochlear implant users, it is important to maximize the transmission of temporal information. The combined effects of stimulation rate and presentation level on temporal information transfer and speech understanding remain unclear. The present study systematically varied presentation level (60, 50, and 40 dBA) and stimulation rate [500 and 2400 pulses per second per electrode (pps)] in order to observe how the effect of rate on speech understanding changes for different presentation levels. Speech recognition in quiet and noise, and acoustic amplitude modulation detection thresholds (AMDTs) were measured with acoustic stimuli presented to speech processors via direct audio input (DAI). With the 500 pps processor, results showed significantly better performance for consonant-vowel nucleus consonant words in quiet, and a reduced effect of noise on sentence recognition. However, no rate or level effect was found for AMDTs, perhaps partly because of amplitude compression in the sound processor. AMDTs were found to be strongly correlated with the effect of noise on sentence perception at low levels. These results indicate that AMDTs, at least when measured with the CP910 Freedom speech processor via DAI, explain between-subject variance of speech understanding, but do not explain within-subject variance for different rates and levels. PMID- 28618810 TI - Enhancement effects of clear speech and word-initial position in Korean glides. AB - The current study investigated the enhancement effect in Korean speakers' clear speech and word-initial position, using acoustic analyses of the Korean glides /w/ and /j/. The results showed that the transitions of glides /w/ and /j/ at onset were enhanced in clear speech with an expanded vowel space. An expanded vowel space was also observed in the word-initial position, but the expansion was not statistically significant. However, the significant interaction between speaking style and word position revealed that the articulatory and global modifications in clear speech were noticeably greater at onset in the word-medial compared to the word-initial position. Also, the mid-front vowel /e/ shifted downward and leftward in clear speech, indicating that mid-front vowels are fronted and lowered in clear speech. As a language-specific issue, no phonetic evidence was found supporting the existence of two Korean glides, /wepsilon/ and /we/, even in clear speech and word-initial position, indicating a diachronic sound merger of these two glides. In addition, the glide /je/ after a consonant was neutralized into /e/ in casual speech. These findings suggest a relationship between speaking style effects, word position effects, and changing phonetic targets due to diachronic sound change. PMID- 28618809 TI - Binaural sensitivity in children who use bilateral cochlear implants. AB - Children who are deaf and receive bilateral cochlear implants (BiCIs) perform better on spatial hearing tasks using bilateral rather than unilateral inputs; however, they underperform relative to normal-hearing (NH) peers. This gap in performance is multi-factorial, including the inability of speech processors to reliably deliver binaural cues. Although much is known regarding binaural sensitivity of adults with BiCIs, less is known about how the development of binaural sensitivity in children with BiCIs compared to NH children. Sixteen children (ages 9-17 years) were tested using synchronized research processors. Interaural time differences and interaural level differences (ITDs and ILDs, respectively) were presented to pairs of pitch-matched electrodes. Stimuli were 300-ms, 100-pulses-per-second, constant-amplitude pulse trains. In the first and second experiments, discrimination of interaural cues (either ITDs or ILDs) was measured using a two-interval left/right task. In the third experiment, subjects reported the perceived intracranial position of ITDs and ILDs in a lateralization task. All children demonstrated sensitivity to ILDs, possibly due to monaural level cues. Children who were born deaf had weak or absent sensitivity to ITDs; in contrast, ITD sensitivity was noted in children with previous exposure to acoustic hearing. Therefore, factors such as auditory deprivation, in particular, lack of early exposure to consistent timing differences between the ears, may delay the maturation of binaural circuits and cause insensitivity to binaural differences. PMID- 28618811 TI - Vocal repertoire of long-finned pilot whales (Globicephala melas) in northern Norway. AB - The knowledge of the vocal repertoire of pilot whales is very limited. In this paper, the vocal repertoire of long-finned pilot whales recorded during different encounters in the Vestfjord in northern Norway between November 2006 and August 2010 are described. Sounds were analysed using two different methods: (1) an observer-based audio-visual inspection of FFT-derived spectrograms, with which, besides a general variety of clicks, buzzes, nonharmonic sounds, and whistles, 129 different distinct call types and 25 subtypes were distinguished. These call types included pulsed calls and discrete structured whistles varying from simple to highly complex structures composed of several segments and elements. In addition, ultrasonic whistles previously not described for pilot whales were found. In addition to the diversity of single calls, call sequences consisting of repetitions and combinations of specific call types were recorded and (2) a parametric approach that permitted the confirmation of the high variability in pilot whale call structures was developed. It is concluded that the pilot whale vocal repertoire is among the most complex for the mammalian species and the high structural variability, along with call repetitions and combinations, require a closer investigation to judge their importance for vocal communication. PMID- 28618812 TI - Auditory feature representation using convolutional restricted Boltzmann machine and Teager energy operator for speech recognition. AB - In this letter, authors propose an auditory feature representation technique with the filterbank learned using an annealing dropout convolutional restricted Boltzmann machine (ConvRBM) and noise-robust energy estimation using the Teager energy operator (TEO). TEO is applied on each subband of ConvRBM filterbank and pooled later to get the short-term spectral features. Experiments on AURORA 4 database show that the proposed features perform better than the Mel filterbank features. The relative improvement of 2.59%-11.63% and 1.26%-6.87% in word error rate is achieved using the time delay neural network and the bidirectional long short-term memory models, respectively. PMID- 28618813 TI - Ultrasonic attenuation of polycrystalline materials with a distribution of grain sizes. AB - Elastic wave scattering at grain boundaries in polycrystalline media can be quantified to determine microstructural properties. The amplitude drop observed for coherent wave propagation (attenuation) as well as diffuse-field scattering events have been extensively studied. In all cases, the scattering shows a clear dependence on grain size, grain shape, and microstructural texture. Models used to quantify scattering experiments are often developed assuming dependence on a single spatial length scale, usually, mean grain diameter. However, several microscopy studies suggest that most metals have a log normal distribution of grain sizes. In this study, grain size distribution is discussed within the context of previous attenuation models valid for arbitrary crystallite symmetries. Results are presented for titanium using a range of distribution means and widths assuming equiaxed grains and no preferred crystallographic orientation. The longitudinal and shear attenuations are shown to vary with respect to the frequency dependence for varying distribution widths even when the volumetric mean grain size is held constant. Furthermore, the results suggest that grain size estimates based on attenuation can have large errors if the distribution is neglected. This work is anticipated to play an important role in microstructural characterization research associated with ultrasonic scattering. PMID- 28618814 TI - Three-dimensional-printed membrane-type acoustic metamaterial for low frequency sound attenuation. AB - Membrane-type acoustic metamaterials have received much attention for low frequency sound manipulation, especially in the form of decorated membrane resonators. In this paper, such resonators are obtained using fused deposition modeling. Beyond the practical aspects provided by this manufacturing method, the low density of the flexible filament used increases their effectiveness. Indeed, the mass usually added to the membrane center can easily be divided into several disjoint elements. Using rotary inertia of the added structures, new peaks of efficiency in both absorption and normal transmission loss appear when compared to usual decorated membrane resonators. PMID- 28618815 TI - Convolutional neural network-based automatic classification of midsagittal tongue gestural targets using B-mode ultrasound images. AB - Tongue gestural target classification is of great interest to researchers in the speech production field. Recently, deep convolutional neural networks (CNN) have shown superiority to standard feature extraction techniques in a variety of domains. In this letter, both CNN-based speaker-dependent and speaker-independent tongue gestural target classification experiments are conducted to classify tongue gestures during natural speech production. The CNN-based method achieves state-of-the-art performance, even though no pre-training of the CNN (with the exception of a data augmentation preprocessing) was carried out. PMID- 28618816 TI - Test of single degree of freedom acoustic treatment impedance models for multimodal acoustic propagation in duct with flow. AB - Passive acoustic treatments, also called liners, are the main solution to noise problems. The Single Degree Of Freedom (SDOF) acoustic treatment, composed of a thin material (perforated plate) affixed to air cavities with a rigid bottom, constitutes a solution. Predicting sound level reduction by an SDOF treatment requires reliable acoustic impedance models. An experimental/numerical method has been developed for a duct with an acoustic treatment to test acoustic impedance models of SDOF treatment with a multimodal propagation in the presence of a mean flow. This method is based on the comparison of experimental results from an aeroacoustic bench composed of a circular duct with a treated area, and numerical results from an FEM-PML axisymmetric model based on Galbrun's equation. The numerical results are confronted with experimental results to test impedance models up to M0=+/-0.25. PMID- 28618818 TI - Passive bottom reflection-loss estimation using ship noise and a vertical line array. AB - An existing technique for passive bottom-loss estimation from natural marine surface noise (generated by waves and wind) is adapted to use noise generated by ships. The original approach-based on beamforming of the noise field recorded by a vertical line array of hydrophones-is retained; however, additional processing is needed in order for the field generated by a passing ship to show features that are similar to those of the natural surface-noise field. A necessary requisite is that the ship position, relative to the array, varies over as wide a range of steering angles as possible, ideally passing directly over the array to ensure coverage of the steepest angles. The methodology is illustrated through simulation and applied to data from a field experiment conducted offshore of San Diego, CA in 2009. PMID- 28618817 TI - An algorithm to increase intelligibility for hearing-impaired listeners in the presence of a competing talker. AB - Individuals with hearing impairment have particular difficulty perceptually segregating concurrent voices and understanding a talker in the presence of a competing voice. In contrast, individuals with normal hearing perform this task quite well. This listening situation represents a very different problem for both the human and machine listener, when compared to perceiving speech in other types of background noise. A machine learning algorithm is introduced here to address this listening situation. A deep neural network was trained to estimate the ideal ratio mask for a male target talker in the presence of a female competing talker. The monaural algorithm was found to produce sentence-intelligibility increases for hearing-impaired (HI) and normal-hearing (NH) listeners at various signal-to noise ratios (SNRs). This benefit was largest for the HI listeners and averaged 59%-points at the least-favorable SNR, with a maximum of 87%-points. The mean intelligibility achieved by the HI listeners using the algorithm was equivalent to that of young NH listeners without processing, under conditions of identical interference. Possible reasons for the limited ability of HI listeners to perceptually segregate concurrent voices are reviewed as are possible implementation considerations for algorithms like the current one. PMID- 28618819 TI - Evaluation of uncertainty for regularized deconvolution: A case study in hydrophone measurements. AB - An estimation of the measurand in dynamic metrology usually requires a deconvolution based on a dynamic calibration of the measuring system. Since deconvolution is, mathematically speaking, an ill-posed inverse problem, some kind of regularization is required to render the problem stable and obtain usable results. Many approaches to regularized deconvolution exist in the literature, but the corresponding evaluation of measurement uncertainties is, in general, an unsolved issue. In particular, the uncertainty contribution of the regularization itself is a topic of great importance, because it has a significant impact on the estimation result. Here, a versatile approach is proposed to express prior knowledge about the measurand based on a flexible, low-dimensional modeling of an upper bound on the magnitude spectrum of the measurand. This upper bound allows the derivation of an uncertainty associated with the regularization method in line with the guidelines in metrology. As a case study for the proposed method, hydrophone measurements in medical ultrasound with an acoustic working frequency of up to 7.5 MHz are considered, but the approach is applicable for all kinds of estimation methods in dynamic metrology, where regularization is required and which can be expressed as a multiplication in the frequency domain. PMID- 28618820 TI - Onset of barotrauma injuries related to number of pile driving strike exposures in hybrid striped bass. AB - Previous studies exploring injury response to pile driving in fishes presented exposure paradigms (>900 strikes) that emulated circumstances where fish would not leave an area being ensonified. Those studies did not, however, address the question of how many strikes are needed before injuries appear. Thus, the number of strikes paired with a constant single strike sound exposure level (SELss) that can cause injuries is not yet clear. In order to examine this question, hybrid striped bass (white bass Morone chrysops * striped bass Morone saxatilis) were exposed to 8-384 strikes in three different SELss treatments that generated different cumulative sound exposure level values. The treatment with the highest SELss values caused swim bladder injuries in fish exposed to as few as eight pile strikes. These results have important implications for pile driving operations where SELss values meet or exceed the exposure levels used in this study. PMID- 28618821 TI - Low-intensity ultrasound activates vestibular otolith organs through acoustic radiation force. AB - The present study examined the efficacy of 5 MHz low-intensity focused ultrasound (LiFU) as a stimulus to remotely activate inner ear vestibular otolith organs. The otolith organs are the primary sensory apparati responsible for detecting orientation of the head relative to gravity and linear acceleration in three dimensional space. These organs also respond to loud sounds and vibration of the temporal bone. The oyster toadfish, Opsanus tau, was used to facilitate unobstructed acoustic access to the otolith organs in vivo. Single-unit responses to amplitude-modulated LiFU were recorded in afferent neurons identified as innervating the utricle or the saccule. Neural responses were equivalent to direct mechanical stimulation, and arose from the nonlinear acoustic radiation force acting on the otolithic mass. The magnitude of the acoustic radiation force acting on the otolith was measured ex vivo. Results demonstrate that LiFU stimuli can be tuned to mimic directional forces occurring naturally during physiological movements of the head, loud air conducted sound, or bone conducted vibration. PMID- 28618822 TI - Precision and bias in estimating detection distances for beaked whale echolocation clicks using a two-element vertical hydrophone array. AB - Detection distances are critical for cetacean density and abundance estimation using distance sampling methods. Data from a drifting buoy system consisting of an autonomous recorder and a two-element vertical hydrophone array at ~100-m depth are used to evaluate three methods for estimating the horizontal distance (range) to beaked whales making echolocation clicks. The precision in estimating time-differences-of-arrival (TDOA) for direct- and surface-reflected-path clicks is estimated empirically using repeated measures over short time periods. A Teager-Kaiser energy detector is used to improve estimates of TDOA for surface reflected signals. Simulations show that array tilt in the direction of the source cannot be reliably estimated given this array geometry and these measurements of TDOA error, which means that range cannot be reliably estimated. If array tilt can be reduced to less than 0.5 degrees , range can be reliably estimated up to ~3000 m. If array depth is increased to 200 m and array tilt is less than 1 degrees , range can be reliably estimated up to ~5000 m. Prior information on the depth of vocalizing beaked whales and estimates of declination angle can be used to precisely estimate range, but different analytical methods are required to avoid bias and to treat distributions of depth probabilistically. PMID- 28618823 TI - Effects of rhythm and phrase-final lengthening on word-spotting in Korean. AB - A word-spotting experiment was conducted to investigate whether rhythmic consistency and phrase-final lengthening facilitate performance in Korean. Listeners had to spot disyllabic and trisyllabic words in nonsense strings organized in phrases with either the same or variable syllable count; phrase final lengthening was absent, or occurring either in all phrases or only in the phrase immediately preceding the target. The results show that, for disyllabic targets, inconsistent syllable count and lengthening before the target led to fewer errors. For trisyllabic targets, accuracy was at ceiling, but final lengthening in all phrases reduced reaction times. The results imply that both rhythmic consistency (i.e., regular syllable count) and phrase-final lengthening play a role in word-spotting and, by extension, in speech processing in Korean, as in other languages. However, the results also reflect the language specific role of prosodic cues. First, the cues here were used primarily with disyllabic targets, which were cognitively more demanding to process partly due to their high phonological neighborhood density. Second, the facilitating effect of rhythmic consistency was weak, possibly because strict consistency is not present in spoken Korean. Overall, rhythmic consistency facilitated spotting when targets mapped onto phrases, confirming the importance of phrasal organization in Korean speech processing. PMID- 28618824 TI - Space-frequency coded orthogonal signal-division multiplexing over underwater acoustic channels. AB - Orthogonal signal-division multiplexing (OSDM) is a newly emerged modulation scheme which provides a generalized framework unifying conventional orthogonal frequency-division multiplexing (OFDM) and single-carrier frequency domain equalization. In this letter, a space-frequency block coding (SFBC) scheme based on OSDM is proposed for time-varying underwater acoustic channels. The receiver processing includes Doppler compensation, channel estimation, space-frequency decoding, and equalization. Simulation and experimental results demonstrate its superiority over the existing SFBC-OFDM counterpart. PMID- 28618825 TI - Spectral equalization in binaural signals represented by order-truncated spherical harmonics. AB - The synthesis of binaural signals from spherical microphone array recordings has been recently proposed. The limited spatial resolution of the reproduced signal due to order-limited reproduction has been previously investigated perceptually, showing spatial perception ramifications, such as poor source localization and limited externalization. Furthermore, this spatial order limitation also has a detrimental effect on the frequency content of the signal and its perceived timbre, due to the rapid roll-off at high frequencies. In this paper, the underlying causes of this spectral roll-off are described mathematically and investigated numerically. A digital filter that equalizes the frequency spectrum of a low spatial order signal is introduced and evaluated. A comprehensive listening test was conducted to study the influence of the filter on the perception of the reproduced sound. Results indicate that the suggested filter is beneficial for restoring the timbral composition of order-truncated binaural signals, while conserving, and even improving, some spatial properties of the signal. PMID- 28618826 TI - A Marchenko equation for acoustic inverse source problems. AB - From acoustics to medical imaging and seismology, one strives to make inferences about the structure of complex media from acoustic wave observations. This study proposes a solution that is derived from the multidimensional Marchenko equation, to learn about the acoustic source distribution inside a volume, given a set of observations outside the volume. Traditionally, this problem has been solved by backpropagation of the recorded signals. However, to achieve accurate results through backpropagation, a detailed model of the medium should be known and observations should be collected along a boundary that completely encloses the volume of excitation. In practice, these requirements are often not fulfilled and artifacts can emerge, especially in the presence of strong contrasts in the medium. On the contrary, the proposed methodology can be applied with a single observation boundary only, without the need of a detailed model. In order to achieve this, additional multi-offset ultrasound reflection data must be acquired at the observation boundary. The methodology is illustrated with one-dimensional synthetics of a photoacoustic imaging experiment. A distribution of simultaneously acting sources is recovered in the presence of sharp density perturbations both below and above the embedded sources, which result in significant scattering that complicates the use of conventional methods. PMID- 28618828 TI - Pavement type and wear condition classification from tire cavity acoustic measurements with artificial neural networks. AB - Tire road noise is the major contributor to traffic noise, which leads to general annoyance, speech interference, and sleep disturbances. Standardized methods to measure tire road noise are expensive, sophisticated to use, and they cannot be applied comprehensively. This paper presents a method to automatically classify different types of pavement and the wear condition to identify noisy road surfaces. The methods are based on spectra of time series data of the tire cavity sound, acquired under normal vehicle operation. The classifier, an artificial neural network, correctly predicts three pavement types, whereas there are few bidirectional mis-classifications for two pavements, which have similar physical characteristics. The performance measures of the classifier to predict a new or worn out condition are over 94.6%. One could create a digital map with the output of the presented method. On the basis of these digital maps, road segments with a strong impact on tire road noise could be automatically identified. Furthermore, the method can estimate the road macro-texture, which has an impact on the tire road friction especially on wet conditions. Overall, this digital map would have a great benefit for civil engineering departments, road infrastructure operators, and for advanced driver assistance systems. PMID- 28618829 TI - Detection of an undersea acoustic communications network by an energy detector. AB - A theory is presented for the upper bound on the mean time tau to the detection of an undersea acoustic communications network by an energy detector whose initial position and heading are uniformly distributed random variables. The network is an infinite square grid of omnidirectional transmit-receive nodes on a flat bottom. Each node transmits to one nearest neighbor at a bit-rate R equal to Shannon's capacity, maximizing tau. The network sets a signaling bandwidth W and node-spacing D. The detector sets a false-alarm rate, integration time, height above the bottom, and speed. For W = 5 kHz and D = 1 km, tau is computed as a function of R in 200 -m water with propagation varying from spherical to cylindrical spreading, volume absorption of 2 dB per km (corresponding approximately to 15 kHz), and illustrative values for other parameters. PMID- 28618830 TI - Acoustic levitation of an object larger than the acoustic wavelength. AB - Levitation and manipulation of objects by sound waves have a wide range of applications in chemistry, biology, material sciences, and engineering. However, the current acoustic levitation techniques are mainly restricted to particles that are much smaller than the acoustic wavelength. In this work, it is shown that acoustic standing waves can be employed to stably levitate an object much larger than the acoustic wavelength in air. The levitation of a large slightly curved object weighting 2.3 g is demonstrated by using a device formed by two 25 kHz ultrasonic Langevin transducers connected to an aluminum plate. The sound wave emitted by the device provides a vertical acoustic radiation force to counteract gravity and a lateral restoring force that ensure horizontal stability to the levitated object. In order to understand the levitation stability, a numerical model based on the finite element method is used to determine the acoustic radiation force that acts on the object. PMID- 28618831 TI - Effect of inhomogeneous temperature fields on acoustic streaming structures in resonators. AB - Acoustic streaming in 2D rectangular resonant channels filled with a fluid with a spatial temperature distribution is studied within this work. An inertial force is assumed for driving the acoustic field; the temperature inhomogeneity is introduced by resonator walls with prescribed temperature distribution. The method of successive approximations is employed to derive linear equations for calculation of primary acoustic and time-averaged secondary fields including the streaming velocity. The model equations have a standard form which allows their numerical integration using a universal solver; in this case, COMSOL Multiphysics was employed. The numerical results show that fluid temperature variations in the direction perpendicular to the resonator axis influence strongly the streaming field if the ratio of the channel width and the viscous boundary layer thickness is big enough; the streaming in the Rayleigh vortices can be supported as well as opposed, which can ultimately lead to the appearance of additional vortices. PMID- 28618832 TI - Broadband focusing of underwater sound using a transparent pentamode lens. AB - An inhomogeneous acoustic metamaterial lens based on spatial variation of refractive index for broadband focusing of underwater sound is reported. The index gradient follows a modified hyperbolic secant profile designed to reduce aberration and suppress side lobes. The gradient index (GRIN) lens is comprised of transversely isotropic hexagonal microstructures with tunable quasi-static bulk modulus and mass density. In addition, the unit cells are impedance-matched to water and have in-plane shear modulus negligible compared to the effective bulk modulus. The flat GRIN lens is fabricated by cutting hexagonal centimeter scale hollow microstructures in aluminum plates, which are then stacked and sealed from the exterior water. Broadband focusing effects are observed within the homogenization regime of the lattice in both finite element simulations and underwater measurements (20-40 kHz). This design approach has potential applications in medical ultrasound imaging and underwater acoustic communications. PMID- 28618833 TI - Formulae for predicting non-acoustical parameters of deformed fibrous porous materials. AB - Formulae to predict non-acoustical parameters (i.e., flow resistivity, tortuosity, and viscous and thermal characteristic lengths) of deformed fibrous porous materials are proposed provided that the original values of these parameters are known in advance. These formulae are developed using numerical fluid analyses. The flow resistivity was calculated by using the finite element method for a two-dimensional incompressible viscous fluid approximated by Oseen flow. The tortuosity and characteristic lengths were calculated by using the complex variable boundary element method for a two-dimensional potential flow. These calculations showed that the flow resistivity was inversely proportional to the porosity multiplied by the three-halves power of the compression ratio, that the tortuosity can be represented by a linear expression of the porosity, and that both characteristic lengths changed in the same manner with respect to the porosity. These tendencies agreed well with measurements of real glass wools of various bulk densities. The proposed prediction formulae for the parameters were then derived from the tendencies obtained from the numerical analyses. The predicted parameter values were compared with the calculated parameters and good agreement was obtained, confirming the validity of the proposed formulae. PMID- 28618835 TI - Effect of Psychosocial Factors on Eating Behaviors and BMI Among African American Women. AB - Psychosocial stress and negative emotions have been associated with the consumption of highly palatable foods and excess weight. Few studies have examined these variable relationships among young African American women. The purpose of this cross-sectional study was to examine the relationship of perceived stress, depressive symptoms, eating behaviors, and body mass index (BMI) among 191 African American women who were 18 to 40 years old. Multivariate analysis indicated that depressive symptoms had a greater impact on highly palatable eating behaviors compared with perceived stress. This study extends understanding of depressive symptoms on eating behaviors among young African American women. PMID- 28618834 TI - Psychophysical and modeling approaches towards determining the cochlear phase response based on interaural time differences. AB - The cochlear phase response is often estimated by measuring masking of a tonal target by harmonic complexes with various phase curvatures. Maskers yielding most modulated internal envelope representations after passing the cochlear filter are thought to produce minimum masking, with fast-acting cochlear compression as the main contributor to that effect. Thus, in hearing-impaired (HI) listeners, reduced cochlear compression hampers estimation of the phase response using the masking method. This study proposes an alternative approach, based on the effect of the envelope modulation strength on the sensitivity to interaural time differences (ITDs). To evaluate the general approach, ITD thresholds were measured in seven normal-hearing listeners using 300-ms Schroeder-phase harmonic complexes with nine different phase curvatures. ITD thresholds tended to be lowest for phase curvatures roughly similar to those previously shown to produce minimum masking. However, an unexpected ITD threshold peak was consistently observed for a particular negative phase curvature. An auditory-nerve based ITD model predicted the general pattern of ITD thresholds except for the threshold peak, as well as published envelope ITD data. Model predictions simulating outer hair cell loss support the feasibility of the ITD-based approach to estimate the phase response in HI listeners. PMID- 28618836 TI - Comparing EEG Nonlinearity in Deficit and Nondeficit Schizophrenia Patients: Preliminary Data. AB - Electroencephalogram (EEG) contains valuable information obtained noninvasively that can be used for assessment of brain's processing capacity of patients with psychiatric disorders. The purpose of the present work was to evaluate possible differences in EEG complexity between deficit (DS) and nondeficit (NDS) subtypes of schizophrenia as a reflection of the cognitive processing capacities in these groups. A particular nonlinear metric known as Lempel-Ziv complexity (LZC) was used as a computational tool in order to determine the randomness in EEG alpha band time series from 3 groups (deficit schizophrenia [n = 9], nondeficit schizophrenia [n = 10], and healthy controls [n = 10]) according to time series randomness. There was a significant difference in frontal EEG complexity between the DS and NDS subgroups ( p = .013), with DS group showing less complexity. A significant positive correlation was found between LZC values and Positive and Negative Syndrome Scale (PANSS) general psychopathology scores (ie, larger frontal EEG complexity correlated with more severe psychopathology), explained partially by the emotional component subscore of the PANSS. These findings suggest that cognitive processing occurring in the frontal networks in DS is less complex compared to NDS patients as reflected by EEG complexity measures. The data also suggest that there may be a relationship between the degree of emotionality and the complexity of the frontal EEG signal. PMID- 28618837 TI - Fish and Meat Are Often Withheld From the Diets of Infants 6 to 12 Months in Fish Farming Households in Rural Bangladesh. AB - BACKGROUND: Fish is a widely available animal-source food in Bangladesh and a rich source of nutrients, yet little is known about practices related to incorporating fish into the diets of infants and young children. OBJECTIVE: Use dietary diversity data to explore consumption patterns of fish and high-quality food items within the household and examine factors associated with delayed introduction of fish to infants and young children. METHODS: Cross-sectional survey of 496 households with children <36 months participating in the Aquaculture for Income and Nutrition project in Bangladesh. Data collected included household characteristics, women's dietary diversity score, and minimum dietary diversity score along with data on Infant and Young Child Feeding practices. RESULTS: Most children (63.4%) met the threshold for minimum dietary diversity. Despite having received extensive nutrition education related to including fish in complementary foods, only half of the caretakers introduced fish at 6 months and the mean age of introduction of small fish was 8.7 months. Meat and fish were not common in infant diets but increased with child age. Concerns about bones were a major barrier to incorporating fish into infant diets. CONCLUSION: Given its nutrient profile and widespread availability in certain contexts, fish could be an underutilized opportunity to improve nutrition and health outcomes of infants and young children. Further research, including utilizing food processing technologies, is needed to develop appropriate responses to overcome these barriers. PMID- 28618838 TI - Regression tree analysis of ecological momentary assessment data. AB - An increasingly popular form of data collection in health psychology research is Ecological Momentary Assessment (EMA); that is, using diaries or smartphones to collect intensive longitudinal data. This method is increasingly applied to the study of relationships between state-based aspects of individuals' functioning and health outcomes (e.g., binge eating, alcohol use). Analysis of such data is challenging and regression tree modelling (RTM) may be a useful alternative to multilevel modelling for investigating the association between a set of explanatory variables and a continuous outcome. Furthermore, RTM outputs 'decision trees' that could be used by health practitioners to guide assessment and tailor intervention. In contrast to regression, RTM is able to easily accommodate many complex, higher-order interactions between predictor variables (without the need to create explicit interaction terms). These benefits make the technique useful for those interested in monitoring and intervening upon health and psychological outcomes (e.g., mood, eating behaviour, risky alcohol use, and treatment adherence). Using real data, this paper demonstrates both the benefits and limitations of RTM and how to extend these models to accommodate analysis of nested data; that is, data that arise from EMA where repeated observations are nested within individuals. PMID- 28618840 TI - Cardiac surgery in solid organ transplant recipients: a clinical challenge. AB - INTRODUCTION: Due to continuous improvement of transplant medicine, the number of solid organ transplant recipients in need of cardiac surgery is constantly growing. The objective of this work was to compare different reports on outcomes in patients with previous solid organ transplant after cardiac surgery. Areas covered: Published studies containing data about solid organ transplant recipients: renal, hepatic, pancreas or combined were identified through med-line research. Reported outcomes were categorized according to short- and long term follow up and the presence or absence of a match-group. All data reported was analyzed in a retrospective manner. Throughout the studies, authors have reported acceptable short term mortality and morbidity for solid organ transplant recipients, which however was increased when compared to matched population. Expert commentary: This review summarizes chief findings concerning cardiac surgery in recipients of solid organ transplantations, as reported in current literature, with the aim of highlighting clinical aspects, which play a potential role in the short and long term-outcome of these patients. PMID- 28618841 TI - Assessment of solid microneedle rollers to enhance transmembrane delivery of doxycycline and inhibition of MMP activity. AB - Many chronic wounds exhibit high matrix metalloproteinase (MMP) activity that impedes the normal wound healing process. Intradermal delivery (IDD) of sub antimicrobial concentrations of doxycycline, as an MMP inhibitor, could target early stages of chronic wound development and inhibit further wound progression. To deliver doxycycline intradermally, the skin barrier must be disrupted. Microneedle rollers offer a minimally invasive technique to penetrate the skin by creating multiple microchannels that act as temporary conduits for drugs to diffuse through. In this study, an innovative and facile approach for delivery of doxycycline across Strat-MTM membrane was investigated using microneedle rollers. The quantity and rate of doxycycline diffusing through the micropores directly correlated with increasing microneedle lengths (250, 500 and 750 MUm). Treatment of Strat-MTM with microneedle rollers resulted in a reduction in fibroblast mediated collagen gel contraction and MMP activity compared with untreated Strat MTM. Our results show that treatment of an epidermal mimetic with microneedle rollers provides sufficient permeabilization for doxycycline diffusion and inhibition of MMP activity. We conclude that microneedle rollers are a promising, clinically ready tool suitable for delivery of doxycycline intradermally to treat chronic wounds. PMID- 28618839 TI - Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology. AB - Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. Many stimuli increase sphingosine kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P specific G protein-coupled receptors (S1PR1-5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, and liver fibrosis. Here, we review recent research on the importance of sphingosine kinases, S1P, and S1PRs in liver pathobiology, with a focus on exciting insights for new therapeutic modalities that target S1P signaling axes for a variety of liver diseases. PMID- 28618842 TI - ALSUntangled 40: Ayahuasca. PMID- 28618843 TI - Risk of cardiac death among cancer survivors in the United States: a SEER database analysis. AB - BACKGROUND: Population-based data on the risk of cardiac death among cancer survivors are needed. This scenario was evaluated in cancer survivors (>5 years) registered within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: The SEER database was queried using SEER*Stat to determine the frequency of cardiac death compared to other causes of death; and to determine heart disease-specific and cancer-specific survival rates in survivors of each of the 10 most common cancers in men and women in the SEER database. RESULTS: For cancer specific survival rate, the highest rates were related to thyroid cancer survivors; while the lowest rates were related to lung cancer survivors. For heart disease-specific survival rate, the highest rates were related to thyroid cancer survivors; while the lowest rates were related to both lung cancer survivors and urinary bladder cancer survivors. The following factors were associated with a higher likelihood of cardiac death: male gender, old age at diagnosis, black race and local treatment with radiotherapy rather than surgery (P < 0.0001 for all parameters). CONCLUSION: Among cancer survivors (>5 years), cardiac death is a significant cause of death and there is a wide variability among different cancers in the relative importance of cardiac death vs. cancer related death. PMID- 28618844 TI - Endovascular treatment of malignant superior vena cava syndrome secondary to lung cancer. AB - OBJECTIVES: Superior Vena Cava obstruction results in severe oedema of the upper thorax. Endovascular treatment allows a rapid restoration of the blood flow with a rapid resolution of symptoms. We retrospectively report a single institution's experience in stent placement for malignant Superior Vena Cava Syndrome (SVCS) caused by lung cancer. METHODS: Thirty-three consecutive patients (23 men, 10 women; median age, 57.6 years; range 34-71 years) who underwent endovascular SVCS palliative treatment were enrolled between August 2002 and June 2015. All patients presented SVCS secondary to lung cancer. Signs and symptoms of SVCS were scored. RESULTS: All procedures were successfully completed (100% technical success rate). Twenty-eight patients showed a progressive clinical improvement after endovascular treatment of SVCS (84.8% clinical success rate) within 48 hours, there were five clinical failures which improved progressively with posterior radiotherapy. During follow-up, three patients (9%) suffered intra or post-procedural complications (1 cardiac arrhythmia, 2 stent thrombosis). CONCLUSIONS: Stent placement in malignant SVCS seems to be an effective and rapid treatment for the relief of symptoms and quality of life improvement with a relatively low complications rate with a rapid resolution of symptoms. Therefore, it should be seriously considered as the first option in the SVC obstruction treatment. PMID- 28618845 TI - Evaluation of cognitive and social functioning in patients requiring long-term inpatient psychiatric care using the International Classification of Functioning, Disability, and Health: a large-scale, multi-institutional observational study. AB - PURPOSE: We comprehensively evaluated cognitive and social functioning in patients requiring long-term inpatient psychiatric care using the International Classification of Functioning, Disability, and Health. METHOD: We surveyed 1967 patients receiving long-term inpatient psychiatric care. Patients were further categorized into an old long-stay group (n = 892, >5 years in hospitals) and a new long-stay group (n = 1075, 1-5 years in hospitals). We obtained responses for all the International Classification of Functioning, Disability, and Health items in domain b (Body Functions) and domain d (Activities and Participation). We estimated weighted means for each item using the propensity score to adjust for confounding factors. RESULTS: Responses were received from 307 hospitals (response rate of hospitals: 25.5%). Cognitive and social functioning in the old long-stay group was more severely impaired than in the new long-stay group. No statistically significant differences were observed regarding the International Classification of Functioning, Disability, and Health items associated with basic activities of daily living between the two groups. CONCLUSION: Combined therapy consisting of cognitive remediation and rehabilitation on social functioning for this patient population should be started from the early stage of hospitalization. Non-restrictive, independent environments may also be optimal for this patient population. Implications for rehabilitation Rehabilitation of cognitive and social functioning for patients requiring long-term inpatient psychiatric care should be started in the early stages of hospitalization. In psychiatric fields, the International Classification of Functioning, Disability, and Health checklist could facilitate individualized rehabilitation planning by allowing healthcare professionals to visually assess the comprehensive functioning of each patient using graphics such as radar charts. PMID- 28618846 TI - Comparison of Direct Iliofemoral Stenting Following AngioJet Rheolytic Thrombectomy vs Staged Stenting After AngioJet Rheolytic Thrombectomy Plus Catheter-Directed Thrombolysis in Patients With Acute Deep Vein Thrombosis. AB - PURPOSE: To compare the treatment outcomes in patients with acute proximal deep vein thrombosis (DVT) and iliofemoral stenosis who underwent either direct stenting after AngioJet rheolytic thrombectomy or staged stenting after AngioJet thrombectomy plus catheter-directed thrombolysis with urokinase. METHODS: From June 2014 to February 2016, 91 DVT patients underwent 2 treatments for duplex verified iliofemoral stenosis: direct stenting (n = 46; mean age 54.8 years; 32 men) or staged stenting (n = 45; mean age 56.5 years; 27 men). The degree of patency after thrombectomy or thrombolysis was evaluated using the Venous Registry Index (VRI), while the risk of postthrombotic syndrome (PTS) was evaluated according to the Villalta scale. Patients were followed with periodic duplex ultrasound scans up to 1 year. RESULTS: The technical success rates were 100% in both groups; there was no 30-day mortality. Immediate (24-hour) clinical improvement was achieved in 42 (91%) of 46 direct group patients vs 33 (73%) of 45 staged group patients (p<0.001). A significant reduction (p<0.001) in the length of hospital stay was noted in the direct group (4.59+/-0.91) compared with that in the staged group (5.8+/-1.6). The stents used in the direct group were longer but with similar diameter compared with the staged group. The thrombolysis rates were 81.50%+/-5.76% in the direct group and 85.67%+/-3.84% in the staged group (p<0.001). The VRIs declined (improved) significantly in both groups (11.68+/-1.92 to 3.21+/-1.44 in the direct group and 12.17+/-2.29 to 2.36+/-1.19 in the staged group, both p<0.001). The Villalta scores were significantly better in the staged group (p<0.001). Recurrent DVT occurred in 2 patients in the direct group. The primary patency rates at 1 year were 93.5% in the direct group and 97.8% in the staged group (p=0.323). CONCLUSION: Both direct and staged stenting are effective treatment modalities for patients with acute proximal DVT. Compared with staged stenting, direct stenting provides similar treatment success and a significant reduction in the length of hospital stay; however, it has lower thrombolysis efficacy, and the risk of PTS at 1 year is greater with direct stenting. PMID- 28618847 TI - A Fatal Aortic Arch Rupture Due to Descending Necrotizing Mediastinitis in a 24 year-old Woman. AB - Descending necrotizing mediastinitis (DNM) is a life-threatening disease which often develops from a purulent infection of the oral cavity and is associated with high rates of mortality. Here we report the case of a young patient who died from an aortic arch rupture in context of DNM developed from an odontogenic infection caused by Prevotella buccae. Based on the current knowledge on this very rare vascular complication, we discuss factors that may have contributed to this fatal issue and future issues to optimize care provided to patients. PMID- 28618848 TI - The stroke caregiving trajectory in relation to caregiver depressive symptoms, burden, and intervention outcomes. AB - BACKGROUND: Caregiver depression and burden have a detrimental effect on stroke survivors' rehabilitation and are contributors to stroke survivors' hospital readmission and institutionalization. The stroke caregiving trajectory is unique compared to other illnesses, and the effect of length of caregiving on stroke caregiver outcomes is poorly understood. Interventions can improve caregiver outcomes, but the optimal timing of these interventions is unclear. OBJECTIVES: We sought to determine the relationship between: (1) length of caregiving and stroke caregiver depressive symptoms and burden, and (2) length of caregiving and amount of change in depressive symptoms and burden following the Resources and Education for Stroke Caregivers' Understanding and Empowerment (RESCUE) intervention - an online and telephone problem-solving, education, and support intervention. METHODS: We analyzed retrospective data collected from 72 stroke caregivers who participated in the RESCUE intervention. Outcomes were caregiver depressive symptoms and burden. Data were analyzed using mixed-effects regression analysis. RESULTS: Baseline depressive symptoms and burden were both negatively related to length of caregiving (p < 0.05). We found significant improvement in caregiver depressive symptoms and burden following an intervention. The interaction between changes in outcomes and length of caregiving was not significant for either depressive symptoms (p = 0.26) or burden (p = 0.10). CONCLUSIONS: This study contributes to the understanding of the relationship between length of caregiving and depression, burden, and intervention outcomes. Clinicians should recognize that the stroke caregiving trajectory can be nonlinear. Routine and repeated clinical assessment of caregiver well-being is needed, along with implementation of interventions when necessary, regardless of how much time has passed since the stroke. PMID- 28618849 TI - Mycotoxins, trace elements, and phthalates in marketed rice of different origin and exposure assessment. AB - The aim of this study was to determine levels of 11 mycotoxins, 10 trace elements, and 6 phthalates in rice samples from Serbian and Chinese market. Mycotoxins were not detected in any of the analysed rice samples. Results revealed similar median levels for following elements: Mn, 17.5 and 15.7 mg kg-1; Fe, 2.47 and 2.12 mg kg-1; Cu, 1.95 and 1.59 mg kg-1 in marketed samples from Serbia and China, respectively. Median concentration of Ni in Serbian marketed samples was 1.9 times higher than in Chinese ones. The median levels (ug kg-1) of phthalates ranged from 1.2 (benzylbutyl phthalate [BBP]) - 566 (di(2-ethyl-hexyl) phthalate [DEHP]) and 1.7 (BBP) - 348 (DEHP) in Serbian and Chinese marketed samples, respectively. The results were used to assess daily exposure of Serbian and Chinese adult consumers. The calculated target hazard quotients indicated that the potential risk attributable to the analysed contaminants in rice samples should not be of concern neither for the Serbian nor the Chinese consumers. PMID- 28618850 TI - Polycyclic aromatic hydrocarbons in Cambodian smoked fish. AB - More than 85% of the population in Cambodia is strongly dependent on agriculture, of which freshwater aquaculture is one of the most important sources of food production. The smoked fish represents an important source of nutrients for Cambodian population; however, it can also lead to excessive intake of polycyclic aromatic hydrocarbons (PAHs). A field survey was conducted among selected smoked fish producers near to Tonle Sap river in Kampong Chhnang province, Cambodia. The study revealed that maximal limits for benzo[a]pyrene and the sum of four PAHs given by EC 1881/2006 were exceeded 2-50 times. Such burden can lead to increased risk of development of carcinogenic diseases. PMID- 28618851 TI - Crush Deformation of a Balloon-Expandable Stent Implanted in an Infrainguinal Bypass Graft. AB - A 59-year-old man with critical claudication underwent left femoro-anterior bypass grafting, which was uneventful. The graft was tunneled medially across the knee, then anterior to the tibia. His symptoms recurred 1 year later and he was found to have critical stenosis of the vein graft just proximal to the anterior tibial arterial anastomosis. This was treated with scaffolded balloon angioplasty and implantation of a coronary, zotarolimus-eluting balloon-expandable stent, which was also uneventful. However, his claudication again recurred 1 year later. Diagnostic angiography revealed crush, deformation and restenosis of the balloon expandable stent requiring surgical revision of the bypass graft. PMID- 28618852 TI - Low Vitamin D is Associated With Infections and Proinflammatory Cytokines During Pregnancy. AB - Vitamin D is known to regulate innate and adaptive immune processes at the cellular level, but the role of vitamin D status on associated inflammatory processes across pregnancy is unclear. Our primary objective was to evaluate the relationships between serum biomarkers of inflammation (interleukin [IL]-6, IL 10, tumor necrosis factor [TNF]-alpha), acute-phase proteins (C-reactive protein and hepcidin) and vitamin D status, 25-hydroxyvitamin D (25(OH)D) and 1,25 dihydroxyvitamin D (1,25(OH)2D), measured across pregnancy and in the neonate at birth. A second objective was to identify associations between vitamin D status and clinically diagnosed infections. In this study, 158 racially and ethnically diverse pregnant adolescents were recruited from the Rochester Adolescent Maternity Program (RAMP) in Rochester, NY. Serum 1,25(OH)2D was significantly lower in adolescents and neonates with IL-6 concentrations above the 75th percentile at delivery ( P = .04) and at birth ( P = .004), respectively. After adjusting for other potential covariates of inflammation, maternal serum 1,25(OH)2D was significantly positively associated with TNF-alpha during pregnancy ( P = .02), but at delivery 1,25(OH)2D and TNF-alpha were inversely associated with one another ( P = .02). Teens with 25(OH)D concentrations <30 ng/mL were more likely to test positive for candida ( P = .002) and bacterial vaginosis ( P = .02) during pregnancy. African Americans exhibited significantly lower TNF-alpha concentrations at both mid-gestation ( P = .009) and delivery ( P = .001) compared to the Caucasian adolescents. These results suggest that lower maternal vitamin D status may increase risk of infection across gestation. PMID- 28618853 TI - Editor's presentation. PMID- 28618854 TI - Verification of organ doses calculated by a dose monitoring software tool based on Monte Carlo Simulation in thoracic CT protocols. AB - Background The importance of monitoring of the radiation dose received by the human body during computed tomography (CT) examinations is not negligible. Several dose-monitoring software tools emerged in order to monitor and control dose distribution during CT examinations. Some software tools incorporate Monte Carlo Simulation (MCS) and allow calculation of effective dose and organ dose apart from standard dose descriptors. Purpose To verify the results of a dose monitoring software tool based on MCS in assessment of effective and organ doses in thoracic CT protocols. Material and Methods Phantom measurements were performed with thermoluminescent dosimeters (TLD LiF:Mg,Ti) using two different thoracic CT protocols of the clinical routine: (I) standard CT thorax (CTT); and (II) CTT with high-pitch mode, P = 3.2. Radiation doses estimated with MCS and measured with TLDs were compared. Results Inter-modality comparison showed an excellent correlation between MCS-simulated and TLD-measured doses ((I) after localizer correction r = 0.81; (II) r = 0.87). The following effective and organ doses were determined: (I) (a) effective dose = MCS 1.2 mSv, TLD 1.3 mSv; (b) thyroid gland = MCS 2.8 mGy, TLD 2.5 mGy; (c) thymus = MCS 3.1 mGy, TLD 2.5 mGy; (d) bone marrow = MCS 0.8 mGy, TLD 0.9 mGy; (e) breast = MCS 2.5 mGy, TLD 2.2 mGy; (f) lung = MCS 2.8 mGy, TLD 2.7 mGy; (II) (a) effective dose = MCS 0.6 mSv, TLD 0.7 mSv; (b) thyroid gland = MCS 1.4 mGy, TLD 1.8 mGy; (c) thymus = MCS 1.4 mGy, TLD 1.8 mGy; (d) bone marrow = MCS 0.4 mGy, TLD 0.5 mGy; (e) breast = MCS 1.1 mGy, TLD 1.1 mGy; (f) lung = MCS 1.2 mGy, TLD 1.3 mGy. Conclusion Overall, in thoracic CT protocols, organ doses simulated by the dose-monitoring software tool were coherent to those measured by TLDs. Despite some challenges, the dose monitoring software was capable of an accurate dose calculation. PMID- 28618855 TI - Stability of and Factors Related to Medical Student Specialty Choice of Psychiatry. AB - OBJECTIVE: Targeted efforts are needed to increase the number of medical students choosing psychiatry, but little is known about when students decide on their specialty or what factors influence their choice. The authors examined the timing and stability of student career choice of psychiatry compared with other specialties and determined what pre- and intra-medical school factors were associated with choosing a career in psychiatry. METHOD: Using survey data from students who graduated from U.S. allopathic medical schools in 2013 and 2014 (N=29,713), the authors computed rates of psychiatry specialty choice at the beginning and end of medical school and assessed the stability of that choice. A multivariate-adjusted logistic regression and recursive partitioning were used to determine the association of 29 factors with psychiatry specialty choice. RESULTS: Choice of psychiatry increased from 1.6% at the start of medical school to 4.1% at graduation. The stability of psychiatry specialty choice from matriculation to graduation, at just over 50%, was greater than for any other specialty. However, almost 80% of future psychiatrists did not indicate an inclination toward the specialty at matriculation. A rating of "excellent" for the psychiatry clerkship (odds ratio=2.66), a major in psychology in college (odds ratio=2.58), and valuing work-life balance (odds ratio=2.25) were the factors most strongly associated with psychiatry career choice. CONCLUSIONS: Students who enter medical school planning to become psychiatrists are likely to do so, but the vast majority of students who choose psychiatry do so during medical school. Increasing the percentage of medical students with undergraduate psychology majors and providing an exemplary psychiatry clerkship are modifiable factors that may increase the rate of psychiatry specialty choice. PMID- 28618858 TI - Equivalence of Laptop and Tablet Administrations of the Minnesota Multiphasic Personality Inventory-2 Restructured Form. AB - The present study investigated the comparability of laptop computer- and tablet based administration modes for the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF). Employing a counterbalanced within-subjects design, the MMPI-2-RF was administered via both modes to a sample of college undergraduates ( N = 133). Administration modes were compared in terms of mean scale scores, internal consistency, test-retest consistency, external validity, and administration time. Mean scores were generally similar, and scores produced via both methods appeared approximately equal in terms of internal consistency and test-retest consistency. Scores from the two modalities also evidenced highly similar patterns of associations with external criteria. Notably, tablet administration of the MMPI-2-RF was substantially longer than laptop administration in the present study (mean difference 7.2 minutes, Cohen's d = .95). Overall, results suggest that varying administration mode between laptop and tablet has a negligible influence on MMPI-2-RF scores, providing evidence that these modes of administration can be considered psychometrically equivalent. PMID- 28618857 TI - State-Independent and Dependent Neural Responses to Psychosocial Stress in Current and Remitted Depression. AB - OBJECTIVE: Stress is a strong risk factor for major depressive disorder, while sensitization to stress in remitted individuals plays a key role in depression recurrence. The present study explored the state-independent (trait) and dependent (state) neural responses to psychosocial stress in major depressive disorder. METHOD: Thirty-six patients with medication-naive first-episode current depression, 33 patients with remitted depression, and 36 demographically matched healthy control participants were administered the Montreal Imaging Stress Task during functional MRI. One-way analyses of variance were used to assess differences in stress responses in the three groups. RESULTS: Both currently depressed and remitted patients exhibited higher stress levels and cortisol responses than control subjects. Compared with control subjects, both depressed and remitted patients exhibited reduced activation in the ventromedial prefrontal cortex and increased activation in the precuneus. The stress-induced ventromedial prefrontal cortex activation changes negatively correlated with cortisol increases in all three groups. Additional increased activations were found in the dorsolateral prefrontal cortex and bilateral striatum in remitted patients compared with control subjects, and activation in these regions correlated inversely with depressive symptoms in the remitted group. CONCLUSIONS: These findings provide novel evidence regarding the trait and state markers of depression on neural responses to psychosocial stress. Regional activation changes in the ventromedial prefrontal cortex and precuneus may reflect the trait markers of depression. Hyperactivation in the dorsolateral prefrontal cortex and striatum may represent a state-dependent compensatory mechanism during depression remission. PMID- 28618856 TI - Psychosocial Stress and Brain Function in Adolescent Psychopathology. AB - OBJECTIVE: The authors sought to explore how conduct, hyperactivity/inattention, and emotional symptoms are associated with neural reactivity to social-emotional stimuli, and the extent to which psychosocial stress modulates these relationships. METHOD: Participants were community adolescents recruited as part of the European IMAGEN study. Bilateral amygdala regions of interest were used to assess the relationship between the three symptom domains and functional MRI neural reactivity during passive viewing of dynamic angry and neutral facial expressions. Exploratory functional connectivity and whole brain multiple regression approaches were used to analyze how the symptoms and psychosocial stress relate to other brain regions. RESULTS: In response to the social emotional stimuli, adolescents with high levels of conduct or hyperactivity/inattention symptoms who had also experienced a greater number of stressful life events showed hyperactivity of the amygdala and several regions across the brain. This effect was not observed with emotional symptoms. A cluster in the midcingulate was found to be common to both conduct problems and hyperactivity symptoms. Exploratory functional connectivity analyses suggested that amygdala-precuneus connectivity is associated with hyperactivity/inattention symptoms. CONCLUSIONS: The results link hyperactive amygdala responses and regions critical for top-down emotional processing with high levels of psychosocial stress in individuals with greater conduct and hyperactivity/inattention symptoms. This work highlights the importance of studying how psychosocial stress affects functional brain responses to social emotional stimuli, particularly in adolescents with externalizing symptoms. PMID- 28618859 TI - Sitagliptin Attenuates Endothelial Dysfunction of Zucker Diabetic Fatty Rats: Implication of the Antiperoxynitrite and Autophagy. AB - Although the contributions of sitagliptin to endothelial function in diabetes mellitus were previously reported, the potential mechanisms still remain undefined. Our research was intended to explore the underlying mechanisms of protective effects of sitagliptin treatment on endothelial dysfunction in Zucker diabetic fatty (ZDF) rats. Male lean nondiabetic Zucker rats were used as control and male obese ZDF rats were randomly divided into ZDF and ZDF + sitagliptin groups. The significant decrease in endothelium-dependent relaxation induced by acetylcholine was observed in mesenteric arteries and thoracic aorta rings of ZDF rats. The administration of sitagliptin restored the vascular function effectively. The morphology study showed severe endothelial injuries in thoracic aortas of ZDF rats, and sitagliptin treatment attenuated these changes. The increased malondialdehyde levels and decreased superoxide dismutase activities in serum of ZDF rats were reversed by sitagliptin treatment. Sitagliptin also increased the expression of endothelial nitric oxide synthase and microtubule associated protein 1 light chain 3 (LC3) and decreased the expression of inducible nitric oxide synthase, 3-nitrotyrosine, and p62 in ZDF rats. After giving Fe (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride porphyrin pentachloride (FeTMPyP, a peroxynitrite [ONOO-] scavenger) or sitagliptin to high glucose (30 mmol/L, 48 hours) cultured human umbilical vein endothelial cells (HUVECs), the increased levels of Beclin-1 and lysosome-associated membrane protein type 2 were detected. Both FeTMPyP and sitagliptin also significantly increased the number of mRFP-GFP-LC3 dots per cell, suggesting that autophagic flux was increased in HUVECs. Our study indicated that sitagliptin treatment can improve the endothelium-dependent relaxation and attenuate the endothelial impairment of ZDF rats. The protective effects of sitagliptin are possibly related to antiperoxynitrite and promoting autophagy. PMID- 28618860 TI - The effects of the Lactobacillus casei strain on obesity in children: a pilot study. AB - There are few data regarding the role of probiotics as a dietary intervention in the management of obesity in children. An open prospective examination was conducted to clarify the effects of Lactobacillus casei strain Shirota (LcS) containing beverages in obese children. We compared the intestinal microbiota and organic acid levels between 12 obese (average age, 10.8 years; body mass index (BMI) Z score, 2.7+/-1.7) and 22 control children(average age, 8.5 years; BMI Z score, 0.1+/-0.7), and pre- and post-intervention in the obese children. The obese group underwent diet and exercise therapy for 6 months and then were given an LcS beverage daily for another 6 months and the body weight and serological markers were monitored. Significant reductions in the faecal concentrations of Bifidobacterium (obese group, 7.9+/-1.5 vs non-obese group, 9.8+/-0.5 Log10cells/g; P<0.01) along with a significant decline in the Bacteroides fragilis group, Atopobium cluster and Lactobacillus gasseri subgroup, and acetic acid (obese group, 45.1+/-16.9 vs non-obese group, 57.9+/-17.6 MUmol/g; P<0.05) were observed in the obese group at baseline. A significant decline in body weight (-2.9+/-4.6%; P<0.05) and an elevation in the high density lipoprotein cholesterol level (+11.1+/-17.6%; P<0.05) were observed 6 months after ingestion of the LcS beverage compared to baseline. Furthermore, a significant increase in the faecal concentration of Bifidobacterium (7.0+/-1.2 before ingestion vs 9.1+/ 1.2 Log10cells/g after ingestion; P<0.01) and an apparent increase in the acetic acid concentration (7.0+/-1.2 before ingestion vs 9.1+/-1.2 Log10cells/g after ingestion; P<0.01) were observed 6 months after ingestion. LcS contributed to weight loss while also improving the lipid metabolism in obese children via a significant increase in the faecal Bifidobacterium numbers and the acetic acid concentration. PMID- 28618861 TI - Potentially probiotic Lactobacillus strains with anti-proliferative activity induce cytokine/chemokine production and neutrophil recruitment in mice. AB - Lactobacillus pentosus B281 and Lactobacillus plantarum B282 are two Lactobacillus strains previously isolated from fermented table olives. Both strains were found to possess probiotic properties and displayed desirable technological characteristics for application as starters in novel functional food production. In the present study the anti-proliferative and immunostimulatory activities of the two strains were investigated. Firstly, we demonstrated that live L. pentosus B281 and L. plantarum B282 significantly inhibited the growth of human colon cancer cells (Caco-2) in a time- and dose dependent manner. By employing the air pouch system in mice, we showed that administration of both strains led to a rapid and statistically significant infiltration of leukocytes in the air pouch exudates. The phenotypical characterisation of the recruited immune cells was performed by flow cytometry analysis. We demonstrated that the majority of the infiltrated leukocytes were neutrophils. Finally by using the Mouse Cytokine Array Panel A Detection Antibody cocktail, we showed that both strains induced the expression of granulocyte colony stimulating factor, interleukin (IL)-1alpha, IL-1beta, IL-6, chemokine (C X-C motif) ligand (CXCL)-1, chemokine (C-C motif) ligand (CCL)-3, CCL-4, and CXCL 2 and diminished the expression levels of soluble intercellular adhesion molecule, macrophage colony-stimulating factor and metallopeptidase inhibitor 1. Our results showed that both strains display anti-proliferative and immunostimulatory properties equal or even better in some cases than those of established and commonly used probiotic strains. These findings further support the probiotic character of the two strains. PMID- 28618862 TI - Probiotic guidelines and physician practice: a cross-sectional survey and overview of the literature. AB - Probiotic use by patients and physicians has dramatically increased over the last decade, although definitive evidence is often lacking for their use. We examined probiotic-prescribing practices among health care providers (HCP) at a tertiary medical centre and compared these practices to clinical guidelines. HCP at the Stanford Medical Center received a survey on probiotic prescribing practices including choice of probiotic and primary indications. A broad overview of the literature was performed. Among 2,331 HCP surveyed, 632 responded. Of the 582 of these who routinely prescribed medications, 61% had recommended probiotic foods or supplements to their patients. Women and gastroenterologists were more likely to prescribe probiotics (odds ratio (OR): 1.5, 95% confidence interval (CI): 1.0 2.1; OR: 3.9, 95% CI: 1.5-10.1, respectively). Among probiotic prescribers, 50% prescribed inconsistently or upon patient request, and 40% left probiotic choice to the patient. Common indications for probiotics, particularly Lactobacillus GG, were prevention and treatment of antibiotic-associated diarrhoea (79 and 66%, respectively). Probiotics were often prescribed for 'general bowel health' or at patient request (27 and 39% of responders, respectively). Most respondents (63%) thought an electronic medical record (EMR) pop-up would change probiotic prescribing patterns. However, a review of published guidelines and large trials found inconsistencies in probiotic indications, dosages and strain selection. Probiotic prescribing is common but lacks consistency, with choice of probiotic frequently left to the patient, even for indications with some strain-specific evidence. Implementation of EMR pop-ups/pocket guides may increase consistency in probiotic prescribing, although the lack of clear and consistent guidelines must first be addressed with large, well-designed clinical trials. PMID- 28618863 TI - Interaction of vaginal Lactobacillus strains with HeLa cells plasma membrane. AB - Vaginal lactobacilli offer protection against recurrent urinary and vaginal infections. The precise mechanisms underlying the interaction between lactobacilli and the host epithelium remain poorly understood at the molecular level. Deciphering such events can provide valuable information on the mode of action of commensal and probiotic bacteria in the vaginal environment. We investigated the effects exerted by five Lactobacillus strains of vaginal origin (Lactobacillus crispatus BC1 and BC2, Lactobacillus gasseri BC9 and BC11 and Lactobacillus vaginalis BC15) on the physical properties of the plasma membrane in a cervical cell line (HeLa). The interaction of the vaginal lactobacilli with the cervical cells determined two kinds of effects on plasma membrane: (1) modification of the membrane polar lipid organisation and the physical properties (L. crispatus BC1 and L. gasseri BC9); (2) modification of alpha5beta1 integrin organisation (L. crispatus BC2, L. gasseri BC11 and L. vaginalis BC15). These two mechanisms can be at the basis of the protective role of lactobacilli against Candida albicans adhesion. Upon stimulation with all Lactobacillus strains, we observed a reduction of the basal oxidative stress in HeLa cells that could be related to modifications in physical properties and organisation of the plasma membrane. These results confirm the strictly strain-specific peculiarities of Lactobacillus and deepen the understanding of the mechanisms underlying the health-promoting role of this genus within the vaginal ecosystem. PMID- 28618864 TI - Gut microbiota composition strongly correlates to peripheral insulin sensitivity in obese men but not in women. AB - Gut microbiota composition may play an important role in the development of obesity-related comorbidities. However, only few studies have investigated gender differences in microbiota composition and gender-specific associations between microbiota or microbial products and insulin sensitivity. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), substrate oxidation (indirect calorimetry), systemic inflammatory markers and microbiota composition (PCR) were determined in male (n=15) and female (n=14) overweight and obese subjects. Bacteroidetes/Firmicutes ratio was higher in men than in women (P=0.001). Bacteroidetes/Firmicutes-ratio was inversely related to peripheral insulin sensitivity only in men (men: P=0.003, women: P=0.882). This association between Bacteroidetes/Firmicutes-ratio and peripheral insulin sensitivity did not change after adjustment for dietary fibre and saturated fat intake, body composition, fat oxidation and markers of inflammation. Bacteroidetes/Firmicutes-ratio was not associated with hepatic insulin sensitivity. Men and women differ in microbiota composition and its impact on insulin sensitivity, implying that women might be less sensitive to gut microbiota-induced metabolic aberrations than men. This trial was registered at clinicaltrials.gov as NCT02381145. PMID- 28618865 TI - Streptococcus thermophilus NCIMB 41856 ameliorates signs of colitis in an animal model of inflammatory bowel disease. AB - Treatment of inflammatory bowel disease (IBD) is mainly based on suppression of symptoms, often with numerous side effects. Trials of probiotics in IBD have frequently produced disappointing results. The majority of probiotics are unusual, since they do not require iron for growth, unlike many bacteria resident in the intestine. The IBD intestine is iron-rich due to bleeding and use of oral iron supplements; conventional probiotics would be rapidly outcompeted. We have evaluated an iron-responsive Streptococcus thermophilus strain for its potential to reduce signs of colitis. Efficacy of S. thermophilus was evaluated in the dextran sodium sulphate mouse model of colitis. Treated animals were given 1*108 cfu S. thermophilus per day and clinical observations were taken daily. At termination, gross and histopathological signs of disease, cellular infiltration, location of bacteria, and cytokine expression in the intestine were determined. S. thermophilus delayed onset of colitis and reduced clinical signs of disease, including bodyweight loss and gastrointestinal bleeding. It reduced bacterial translocation into the colonic tissue. Increased numbers of CD8+ intraepithelial lymphocytes were seen in control animals treated with S. thermophilus. S. thermophilus had no effect on gross pathology, histopathology or cytokine production in either colitic or control animals. We propose that S. thermophilus promotes maintenance of mucosal barrier function which reduces bacterial translocation, thereby reducing immune stimulation and associated inflammation. This allows mucosal healing, reducing gastrointestinal bleeding and weight loss. This could be studied as a locally-acting adjunct or alternative to current IBD treatments. PMID- 28618866 TI - Characterization of Articular Cartilage Recovery and Its Correlation with Optical Response in the Near-Infrared Spectral Range. AB - OBJECTIVES: In this study, we examine the capacity of a new parameter, based on the recovery response of articular cartilage, to distinguish between healthy and damaged tissues. We also investigate whether or not this new parameter correlates with the near-infrared (NIR) optical response of articular cartilage. DESIGN: Normal and artificially degenerated (proteoglycan-depleted) bovine cartilage samples were nondestructively probed using NIR spectroscopy. Subsequently they were subjected to a load and unloading protocol, and the recovery response was logged during unloading. The recovery parameter, elastic rebound ( ER), is based on the strain energy released as the samples underwent instantaneous elastic recovery. RESULTS: Our results reveal positive relationship between the rebound parameter and cartilage proteoglycan content (normal samples: 2.20 +/- 0.10 N mm; proteoglycan-depleted samples: 0.50 +/- 0.04 N mm for 1 hour of enzymatic treatment and 0.13 +/- 0.02 N mm for 4 hours of enzymatic treatment). In addition, multivariate analysis using partial least squares regression was employed to investigate the relationship between ER and NIR spectral data. The results reveal significantly high correlation ( R2cal = 98.35% and R2val = 79.87%; P < 0.0001), with relatively low error (14%), between the recovery and optical response of cartilage in the combined NIR regions 5,450 to 6,100 cm-1 and 7,500 to 12,500 cm-1. CONCLUSION: We conclude that ER can indicate the mechanical condition and state of health of articular cartilage. The correlation of ER with cartilage optical response in the NIR range could facilitate real-time evaluation of the tissue's integrity during arthroscopic surgery and could also provide an important tool for cartilage assessment in tissue engineering and regeneration research. PMID- 28618867 TI - Human Articular Chondrocytes Induce Interleukin-2 Nonresponsiveness to Allogeneic Lymphocytes. AB - Introduction We previously showed that articular chondrocytes (ACs) have immune privilege and immunomodulatory functions like those of mesenchymal stem cells. To elucidate these mechanisms, we focused on interleukin-2 (IL-2), which plays critical roles in lymphocyte mitogenic activity. The purpose of this study was to explore whether ACs affect the role of IL-2 underlying immunomodulatory functions. Material and Methods Irradiated human ACs from osteoarthritis donors were used. Third-party ACs were added to the mixed lymphocyte reaction (MLR) with or without recombinant human IL-2 (rhIL-2), and the levels of IL-2 and the soluble form of the IL-2 receptor alpha (sIL-2Ralpha) protein in supernatant were measured by enzyme-linked immunosorbent assay. Recombinant human IL-2 (rhIL-2) was also added to the MLR. To detect the expression of IL-2 receptor alpha (CD25) on lymphocytes in the MLR, flow cytometric analysis was performed. Last, ACs and allogeneic activated CD4+ T cell were co-cultured, and the expression of CD25 on activated T cells was examined by flow cytometry. Results Third-party ACs significantly inhibited the MLR and reduced the level of sIL-2Ralpha in a dose dependent manner, but did not affect the concentration of IL-2. Exogenous rhIL-2 accelerated MLR but did not rescue the inhibitory effect of ACs. ACs inhibited the expression of CD25 on activated CD4+ T cells. Discussion Our results showed that third-party ACs inhibited the proliferation of allogeneic activated lymphocytes, thereby inhibiting production sIL-2Ralpha, although ACs did not affect IL-2 secretion from lymphocytes. Also, ACs inhibited CD25 expression on activated CD4+ T cells. Thus, ACs inhibited the immune response of allogeneic lymphocytes by inducing IL-2 nonresponsiveness. PMID- 28618868 TI - Appropriate Use Criteria for Hyaluronic Acid in the Treatment of Knee Osteoarthritis in the United States. AB - OBJECTIVE: A workgroup of clinical experts has developed an Appropriate Use Criteria (AUC) for the use of hyaluronic acid (HA) in the treatment of osteoarthritis (OA) of the knee. The increasingly broad and varied use of HA injections, lack of published clinical guidance, and limited coverage for their use has created the imperative to establish appropriateness criteria. METHODS: The experts of this workgroup represent rheumatology, orthopedic surgery, physiatry, sports medicine, and nursing clinicians with substantive knowledge of intra-articular HA therapy. This workgroup utilized the results of a systematic review of evidence, expert clinical opinion, and current evidence-based clinical practice guidelines to develop appropriateness criteria for the use of intra articular HA for knee OA in 17 real-world clinical scenarios. RESULTS: The workgroup scored the appropriateness of treatment of each patient scenario using a 9-point scale to designate a treatment as appropriate (7-9), uncertain (4-6), or inappropriate (1-3). Six scenarios were scored as appropriate, 10 scenarios were scored as uncertain, and 1 scenario was scored as inappropriate. CONCLUSION: This article can assist clinicians in shared decision-making by providing best practices in considering HA injections for knee OA treatment. Moreover, this AUC article can aid payers and policy makers in determining reimbursement and preauthorization policies and more appropriately managing health care resources. It is clear that further research is still necessary-particularly in patient populations differentiated by OA severity-that may benefit the greatest from the use of HA injections for the treatment of knee OA. PMID- 28618869 TI - Review of Soluble Biomarkers of Osteoarthritis: Lessons From Animal Models. AB - Objective Osteoarthritis (OA) is one of the leading causes of disability within the adult population. Currently, its diagnosis is mainly based on clinical examination and standard radiography. To date, there is no way to detect the disease at a molecular level, before the appearance of structural changes and symptoms. So an attractive alternative for monitoring OA is the measurement of biochemical markers in blood, urine, or synovial fluid, which could reflect metabolic changes in joint tissue and therefore disease onset and progression. Animal models are relevant to investigate the early stage of OA and metabolic changes occurring in joint tissues. The goal of this narrative review is to summarize the scientific data available in the literature on soluble biomarkers in animal models of OA. Design A literature search was conducted using the PubMed/Medline and Scopus databases between February 1995 and December 2015. All original articles, systematic and narrative reviews published in French or in English were considered. Results We summarized the data of 69 studies and proposed a classification scheme for OA biomarkers in animal studies, largely inspired by the BIPEDS classification. Conclusions Studies about biomarkers and animal models indicate that some markers could be valuable to monitor OA progression and assess therapeutic response in some animal models. PMID- 28618870 TI - Molecular Validation of Chondrogenic Differentiation and Hypoxia Responsiveness of Platelet-Lysate Expanded Adipose Tissue-Derived Human Mesenchymal Stromal Cells. AB - OBJECTIVE: To determine the optimal environmental conditions for chondrogenic differentiation of human adipose tissue-derived mesenchymal stromal/stem cells (AMSCs). In this investigation we specifically investigate the role of oxygen tension and 3-dimensional (3D) culture systems. DESIGN: Both AMSCs and primary human chondrocytes were cultured for 21 days in chondrogenic media under normoxic (21% oxygen) or hypoxic (2% oxygen) conditions using 2 distinct 3D culture methods (high-density pellets and poly-epsilon-caprolactone [PCL] scaffolds). Histologic analysis of chondro-pellets and the expression of chondrocyte-related genes as measured by reverse transcriptase quantitative polymerase chain reaction were used to evaluate the efficiency of differentiation. RESULTS: AMSCs are capable of expressing established cartilage markers including COL2A1, ACAN, and DCN when grown in chondrogenic differentiation media as determined by gene expression and histologic analysis of cartilage markers. Expression of several cartilage-related genes was enhanced by low oxygen tension, including ACAN and HAPLN1. The pellet culture environment also promoted the expression of hypoxia inducible cartilage markers compared with cells grown on 3D scaffolds. CONCLUSIONS: Cell type-specific effects of low oxygen and 3D environments indicate that mesenchymal cell fate and differentiation potential is remarkably sensitive to oxygen. Genetic programming of AMSCs to a chondrocytic phenotype is effective under hypoxic conditions as evidenced by increased expression of cartilage-related biomarkers and biosynthesis of a glycosaminoglycan-positive matrix. Lower local oxygen levels within cartilage pellets may be a significant driver of chondrogenic differentiation. PMID- 28618871 TI - Five-Year Follow-up of Knee Joint Distraction: Clinical Benefit and Cartilaginous Tissue Repair in an Open Uncontrolled Prospective Study. AB - Objective In end-stage knee osteoarthritis, total knee arthroplasty (TKA) may finally become inevitable. At a relatively young age, this comes with the risk of future revision surgery. Therefore, in these cases, joint preserving surgery such as knee joint distraction (KJD) is preferred. Here we present 5-year follow-up data of KJD. Design Patients ( n = 20; age <60 years) with conservative therapy resistant tibiofemoral osteoarthritis considered for TKA were treated. Clinical evaluation was performed by questionnaires. Change in cartilage thickness was quantified on radiographs and magnetic resonance images (MRI). The 5-year changes after KJD were evaluated and compared with the natural progression of osteoarthritis using Osteoarthritis Initiative data. Results Five-years posttreatment, patients still reported clinical improvement from baseline: DeltaWOMAC (Western Ontario and McMaster Universities Arthritis Index) +21.1 points (95% CI +8.9 to +33.3; P = 0.002), DeltaVAS (visual analogue scale score) pain -27.6 mm (95%CI -13.3 to -42.0; P < 0.001), and minimum radiographic joint space width (JSW) of the most affected compartment (MAC) remained increased as well: Delta +0.43 mm (95% CI +0.02 to +0.84; P = 0.040). Improvement of mean JSW (x-ray) and mean cartilage thickness (MRI) of the MAC, were not statistically different from baseline anymore (Delta +0.26 mm; P = 0.370, and Delta +0.23 mm; P = 0.177). Multivariable linear regression analysis indicated that KJD treatment was associated with significantly less progression in mean and min JSW (x-ray) and mean cartilage thickness (MRI) compared with natural progression (all Ps <0.001). Conclusions KJD treatment results in prolonged clinical benefit, potentially explained by an initial boost of cartilaginous tissue repair that provides a long-term tissue structure benefit as compared to natural progression. Level of evidence, II. PMID- 28618872 TI - Outcomes of Patellofemoral Osteochondral Lesions Treated With Structural Grafts in Patients Older Than 40 Years. AB - Background Chondral lesions in the patellofemoral compartment represent a difficult entity to treat among active patients, with no clear consensus on the optimal treatment strategy. The purpose of this study was to review the functional outcomes of patients >40 years old with primary patellofemoral osteochondral lesions who underwent a cartilage restoration procedure with a structural graft. Methods Following institutional review board approval, 35 patients >40 years treated for patellofemoral chondral or osteochondral injuries were retrospectively identified. Seventeen (47%) had prior surgery (mean 1.4 procedures, range 1-4). Average follow-up was 3.6 +/- 1.6 years. Average patient age was 51.5 years (range 40-72 years); 54% were male. Twenty-six (74%) had isolated trochlear lesions, 7 had isolated patellar lesions (20%), while 2 (6%) had bipolar lesions. Twenty patients (57%) were treated with synthetic biphasic scaffold plugs (SS), 9 (26%) with fresh osteochondral allograft (OCA) and 6 (17%) with osteochondral autograft transfer (OAT). Outcomes were measured with validated measures: Activity of Daily Living Score (ADL), International Knee Documentation Committee (IKDC) Subjective Evaluation form, and Marx Activity Scale (MAS). Results The average lesion size for the entire cohort was 3.1 +/- 1.7 cm2. Average defect size was 2.6 +/- 1.7 cm2 for the SS group, 4.3+/-1.5 cm2 for the OCA group, and 2.9 +/- 0.8 cm2 for the OAT group ( P > 0.051). Outcome scores for the entire population demonstrated significant improvement in ADL ( P = 0.002) and IKDC scores ( P = 0.004) between baseline and final follow-up, while MAS scores were maintained ( P = 0.51). Conclusion Structural grafts are a viable treatment option for symptomatic focal osteochondral lesions of the patellofemoral joint in patients 40 years and older, with anticipated improvements in pain and function and maintenance of preoperative activity levels. PMID- 28618873 TI - Magnetic Resonance Imaging Score and Classification System (AMADEUS) for Assessment of Preoperative Cartilage Defect Severity. AB - Objective To design a simple magnetic resonance (MR)-based assessment system for quantification of osteochondral defect severity prior to cartilage repair surgery at the knee. Design The new scoring tool was supposed to include 3 different parameters: (1) cartilage defect size, (2) depth/morphology of the cartilage defect, and (3) subchondral bone quality, resulting in a specific 3-digit code. A clearly defined numeric score was developed, resulting in a final score of 0 to 100. Defect severity grades I through IV were defined. For intra- and interobserver agreement, defects were assessed by 2 independent readers on preoperative knee MR images of n = 44 subjects who subsequently received cartilage repair surgery. For statistical analyses, mean values +/- standard deviation (SD), interclass correlation coefficients (ICC), and linear weighted kappa values were calculated. Results The mean total Area Measurement And DEpth & Underlying Structures (AMADEUS) score was 48 +/- 24, (range, 0-85). The mean defect size was 2.8 +/- 2.6 cm2. There were 36 of 44 full-thickness defects. The subchondral bone showed defects in 21 of 44 cases. Kappa values for intraobserver reliability ranged between 0.82 and 0.94. Kappa values for interobserver reliability ranged between 0.38 and 0.85. Kappa values for AMADEUS grade were 0.75 and 0.67 for intra- and interobserver agreement, respectively. ICC scores for the AMADEUS total score were 0.97 and 0.96 for intra- and interobserver agreement, respectively. Conclusions The AMADEUS score and classification system allows reliable severity encoding, scoring and grading of osteochondral defects on knee MR images, which is easily clinically applicable in daily practice. PMID- 28618874 TI - Von Willebrand Factor: Multimeric Structure and Functional Activity in Patients With Atrial Fibrillation With and Without Oral Anticoagulation. AB - von Willebrand factor (vWF) is a multimeric glycoprotein present in blood plasma. It is synthesized in megakaryocytes and endothelial cells, secreted into circulation in the form of high-molecular-weight multimers (HMWMs), and cleaved into shorter, less active multimers by ADAMTS13. It is essential for platelet adhesion and aggregation. Previous studies have investigated the relationship between vWF levels and thromboembolic events with little regard to vWF multimeric structure. Patients with atrial fibrillation (AF) exhibit higher plasma vWF and lower ADAMTS13 levels. One hundred seven patients with AF, 51 anticoagulated and 56 nonanticoagulated, were eligible for the study. Plasma samples were analyzed for vWF antigen, vWF activity, and ADAMTS13; vWF multimers were analyzed by Western blot in 1% to 1.3% sodium dodecyl sulfate agarose gel electrophoresis. Patients with AF without oral anticoagulation (OAC) had significantly higher vWF plasma levels (154.00 [75-201] UI/dL) and vWF activity (60.00% [20%-210%]) compared to patients with OAC (133.50 [90-192] UI/dL, P = <.001; 50.00% [20% 160%], P = .02). Both were specially decreased in patients treated with acenocumarin. Patients without OAC also showed lower ADAMTS13 levels and presence of vWF HMWMs. Patients with AF show higher plasma levels and vWF activity. Moreover, treatment with traditional OAC (acenocumarin) significantly reduced vWF levels. Patients without OAC might have an increased risk of thrombotic events showing lower ADAMTS13 and higher vWF levels. Patients with stroke had higher plasma levels, vWF activity, and HMWMs. Our study suggests that increased vWF levels and presence of HMWMs could be related to cerebrovascular disease and may represent useful biomarkers for stroke in AF. PMID- 28618876 TI - Niosomes for oral delivery of nateglinide: in situ-in vivo correlation. AB - Niosomes have been claimed to enhance intestinal absorption and to widen the absorption window of acidic drugs. This was reported after monitoring the intestinal absorption in situ. Accordingly, the aim of this work was to investigate the effect of niosomal encapsulation on intestinal absorption and oral bioavailability of nateglinide. This was conducted with the goal of correlation between in situ intestinal absorption and in vivo availability. The drug was encapsulated into proniosomes. The niosomes resulting after hydration of proniosomes were characterized with respect to vesicle size and drug entrapment efficiency. The in situ rabbit intestinal absorption of nateglinide was monitored from its aqueous solution and niosomes. Streptozotocin was used to induce diabetes in albino rats which were then used to assess the hypoglycemic effect of nateglinide after oral administration of aqueous dispersion and niosomal systems. The prepared vesicles were in the nanoscale with the recorded size being 283 nm. The entrapment efficiency depended on the pH of the formulation. The in situ intestinal absorption reflected non-significant alteration in the membrane transport parameters of the drug after niosomal encapsulation compared with the free drug solution. In contrast, niosomes showed significant improvement in the rate and extent of the hypoglycemic effect compared with the unprocessed drug. This discrepancy can be attributed to different transport pathway for the drug after niosomal inclusion with the vesicles undergoing translymphatic transport which can minimize presystemic metabolism. However, this requires confirmatory investigations. In conclusion niosomes can enhance oral bioavailability of nateglinide with the absorption being through nontraditional pathway. PMID- 28618875 TI - Implementation of guideline-based therapy for chronic obstructive pulmonary disease: Differences between men and women veterans. AB - Chronic obstructive pulmonary disease (COPD) is common among both men and women, and guidelines recommend the same therapy for both sexes. While previous studies have identified gender differences in other chronic disease management, few studies have examined how implementation of COPD guidelines differs between men and women. We performed a cross-sectional study of veterans admitted to Veterans Affairs (VA) hospitals for COPD during October 1, 2008, to September 30, 2011. We collected information on baseline COPD medications during the 6 months prior to hospitalization and categorized therapies as "appropriate" or "inappropriate" based on current guidelines. We used multivariable logistic regression to examine the differences in COPD medications between men and women, after controlling for baseline patient characteristics. We also examined the differences in hospital outcomes, including length of stay and hospital readmission. We identified 33,558 veterans, including 1149 women and 32,409 men who were admitted to 130 VA hospitals. Women were significantly less likely to have received inhaler therapies prior to admission, with lower rates of short-acting beta agonists, short-acting muscarinic antagonists, long-acting beta agonists, and long-acting muscarinic antagonists compared to men. Women also received fewer appropriate inhaler combinations (odds ratio [OR] = 0.83, 95% confidence interval [CI] 0.74 0.93) and more inappropriate combinations (OR = 1.33, 95% CI 1.17-1.51). Women and men were prescribed similar rates of inhaled steroid and oral steroids. Hospital outcomes were also similar between the two groups. These findings highlight a potential gender disparity in appropriate outpatient COPD therapy. Improving the quality of care for patients with COPD should include equitable implementation of guideline-based COPD management. PMID- 28618877 TI - Effect of natural polymers on the survival of Lactobacillus casei encapsulated in alginate microspheres. AB - Linseed and okra mucilages, the fungal exopolysaccharide botryosphaeran, and commercial fructo-oligosaccharides (FOS) were used to microencapsulate Lactobacillus casei LC-01 and L. casei BGP 93 in sodium alginate microspheres by the extrusion technique in calcium chloride. The addition of carbohydrate biopolymers from linseed, okra and the fungal exocellular (1 -> 3)(1 -> 6)-beta-D glucan, named botryosphaeran provided higher encapsulation efficiency (EE) (>93% and >86%) for L. casei LC 01 and L. casei BGP 93, respectively. The use of linseed, okra and botryosphaeran improved the stability of probiotics encapsulated in the microspheres during the storage period over 15 d at 5 degrees C when compared to microspheres formulated with sodium alginate alone as the main encapsulating agent (p <= 0.05). In in vitro gastrointestinal simulation tests, the use of FOS combined with linseed mucilage was shown to be more effective in protecting L. casei cells LC-01 and L. casei BGP 93. PMID- 28618878 TI - Rachael Crabb, Sonya Reeder & Diana Calvin, Listening In: Building Faith and Friendship Thorough Conversations That Matter Crabb Rachael , Reeder Sonya & Calvin Diana , Listening In: Building Faith and Friendship Thorough Conversations That Matter , Intervarsity Press: Downers Grove, IL, 2015. PMID- 28618879 TI - Contemplative Listening: A Rhetorical-Critical Approach To Facilitate Internal Dialog. AB - This article presents a discussion technique that is tailored to clients needing to reorient their convictions following a critical life event. The technique has three distinctive characteristics. The client's statements are not classified into categories from conventional layer models that are designed to track the themes or content of talk. Instead, we adopt a rhetorical approach because of the fundamental metaphysical nature of conviction that this article assumes. The primary focus is on how clients talk about themselves and their convictions. This focus allows the professional to support clients in their personal work. The technique is a tool that professionals can use during the discussion to monitor whether they themselves are in fact doing what they promised the client they would do. Finally, the technique is a third way, alongside a kerygmatic and therapeutic approach, in which chaplains can conduct discussions. The terminology it employs can be used as a common language for much of the work carried out by chaplains from different philosophical backgrounds. PMID- 28618880 TI - Contemplative Listening in Moral Issues: Moral Counseling Redefined in Principles and Method. AB - We present a listening grid for moral counseling, in which we pay particular attention, alongside the what, to how clients talk about themselves: as if they were spectators; aware what this talking does to them; how they perceive what is good from the past; and what they will strive for in the future. By this moral talk, clients discover a picture of the conviction that will enable them to make a decision. PMID- 28618882 TI - Superman Goes to the Emergency Room. PMID- 28618883 TI - The Freedom of the Octogenarian to Find Grace and Humor in the Lasting Personal Strength Gained Through CAPPE* Education. PMID- 28618884 TI - Art, Objects, and Beautiful Stories: A "New" Approach to Spiritual Care. AB - The use of story, and the use of art or various arts-based techniques have become popular in a number of helping professions, including spiritual care. There remains a gap in the literature, however, in which an approach comprised of both story and art or objects is explored. This paper addresses this gap by discussing the experience, theory, benefits, and technique of combining story and art or object-based techniques for the provision of spiritual care. PMID- 28618885 TI - An Exploration of Current Approaches to and Facilities for Spiritual Care Provision in the Republic of Ireland. AB - This study aimed to explore current approaches to and facilities for spiritual care provision in the Republic of Ireland. The findings identify that providing spiritual care to patients is a key component of hospital policy. Spiritual support is identified as the responsibility of the whole healthcare team with specific responsibility being attributed to the healthcare chaplain. Most sites provided a sacred space or quiet place for clients, visitors and staff to contemplate. PMID- 28618886 TI - Emotional Sequelae of Elective Abortion: The Role of Guilt and Shame. AB - Although estimates vary, many women experience long-term emotional, spiritual, psychological and interpersonal difficulties following abortion, including complicated grief, depression, post-traumatic stress disorder (PTSD) and relationship disturbances. Developmental, drive, object-relations and narcissism models for perinatal loss also illuminate the dynamics of post-abortion syndromes. Guilt and shame play important roles in generating and concealing post abortion sequelae. Pastoral care and healthcare providers can increase their awareness of post-abortion sequelae and provide effective care for women experiencing these syndromes. PMID- 28618887 TI - Scene from a Lapel Cross: Bad Day. PMID- 28618888 TI - Moonlight. PMID- 28618889 TI - Fake Awareness. PMID- 28618890 TI - The Journal of Pastoral Care & Counseling Quiz June 2017: (Continuing Education Quiz). PMID- 28618891 TI - Musculoskeletal manifestations as determinants of quality of life impairment in patients with systemic lupus erythematosus. AB - Objective The objective of this study was to identify determinants of health related quality of life (HRQoL) impairment in patients with systemic lupus erythematosus (SLE). Methods Overall, 101 SLE patients were recruited; 37 healthy subjects and 35 rheumatoid arthritis (RA) patients served as controls. HRQoL was evaluated using three patient reported outcomes (PROs): the Short Form-36 version 2 (SF-36v2) health survey, the fatigue scale version 4 (FACITv4) and the Heath Assessment Questionnaire (HAQ). A large set of demographic and clinical variables, including SLE arthritis subtypes, was evaluated searching for factors independently associated with worse QoL. Multivariate models were applied to identify factors independently associated with outcomes. Bonferroni's corrected p values < 0.05 were considered significant. Results SLE patients showed worse results than healthy controls ( p < 0.01) in all SF-36v2 domains and, with reference to the mental QoL, also than RA patients ( p < 0.01). Jaccoud's deformities, active arthritis, and fibromyalgia were the only factors independently associated with worse results in both physical and mental components summary of the SF-36v2 ( p < 0.01) and FACITv4 fatigue scale ( p < 0.01). Fragility fractures, deformities, and active arthritis negatively affected disability perception measured by the HAQ ( p < 0.01). No statistically significant differences in perceived HRQoL were highlighted between patients with deforming and erosive arthritis. However, they had significantly worse results than patients with non-deforming non-erosive arthritis across all investigated PROs ( p < 0.01). Conclusion In order to limit musculoskeletal manifestations as a source of impaired QoL in SLE patients, therapeutic strategies targeted to successfully manage active arthritis and fibromyalgia and to prevent deforming damage are needed. PMID- 28618892 TI - Cutaneous lupus erythematosus and the risk of deep venous thrombosis and pulmonary embolism: A Danish nationwide cohort study. AB - Background Venous thromboembolism (VTE) is a major public health concern. Lupus erythematosus (LE) is a chronic autoimmune disease ranging from localized cutaneous disease (CLE) to systemic involvement (SLE). Patients with SLE have an increased risk of venous thromboembolism (VTE), but little is known about the CLE related risk of VTE. Methods To evaluate the risk of VTE in patients with SLE and CLE as compared to the general population, a retrospective cohort study was conducted. Incidence rates and hazard ratios (HRs) with 95% confidence intervals (CIs) from multivariable Cox regression models were used to evaluate and compare the risk of VTE. Registries of hospitalizations, outpatient visits, and prescription drug use were studied to determine the risk of VTE in patients with CLE and SLE and the general population between 1997 and 2011. Results A total of 3234 patients with CLE and 3627 patients with SLE were identified and compared to 5,590,070 individuals in the reference population. The incidence rates per 1000 year of VTE were higher in patients with LE, i.e. 1.20, 3.06, and 5.24 for the reference population, CLE, and SLE, respectively. In adjusted models, both CLE (HR 1.39; 95% CI 1.10-1.78) and SLE (HR 3.32; 95% CI 2.73-4.03) were associated with a statistically significant increased risk of VTE, compared to the reference population. Conclusion In this nationwide study, both CLE and SLE were significant risk factors for VTE. The results add to our understanding of comorbidities in patients with LE, and call for further studies and increased awareness of thromboembolic complications in patients with CLE. PMID- 28618893 TI - Corrigendum to "The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort". PMID- 28618894 TI - Pneumonic tularaemia: experience of 58 cases from 2000 to 2012 in Northern Finland. AB - BACKGROUND: Pneumonic tularaemia is less common clinical form of tularaemia compared with the ulceroglandular form, with only a limited number of case reports and case series in Europe. In Finland, Northern Ostrobothnia is an endemic area of tularaemia with occasional seasonal outbreaks. METHODS: In our study, a consecutive series of 58 pneumonic tularaemia cases diagnosed and treated in Oulu University Hospital in 2000-2012 were retrospectively analysed in terms of epidemiology, clinical course, and prognosis. RESULTS: The incidence of pneumonic tularaemia showed peaks in cycles of a few years and most cases were diagnosed in late summer or early autumn. Respiratory symptoms were absent in 47% of patients, and 7% had normal chest X-ray. The chest computed tomography (CT) was performed in 81% of patients, demonstrating variable findings associated with pneumonic tularaemia. Bronchoscopy was performed for 22 (38%) patients and four (18%) of these also proceeded into mediastinoscopy. Moreover, thoracoscopy was performed for one (2%) patient. Two (3%) patients were treated shortly in the intensive care unit (ICU) during their stay in hospital. No mortality was observed. CONCLUSIONS: Most cases of pneumonic tularaemia are diagnosed during the seasonal outbreaks. The lack of specific symptoms often complicates the diagnosis and leads to unnecessarily invasive examinations. PMID- 28618895 TI - Silver nanoparticles inhaled during pregnancy reach and affect the placenta and the foetus. AB - Recently, interest for the potential impact of consumer-relevant engineered nanoparticles on pregnancy has dramatically increased. This study investigates whether inhaled silver nanoparticles (AgNPs) reach and cross mouse placental barrier and induce adverse effects. Apart from their relevance for the growing use in consumer products and biomedical applications, AgNPs are selected since they can be unequivocally identified in tissues. Pregnant mouse females are exposed during the first 15 days of gestation by nose-only inhalation to a freshly produced aerosol of 18-20 nm AgNPs for either 1 or 4 h, at a particle number concentration of 3.80 * 107 part./cm-3 and at a mass concentration of 640 MUg/m3. AgNPs are identified and quantitated in maternal tissues, placentas and foetuses by transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy and single-particle inductively coupled plasma mass spectrometry. Inhalation of AgNPs results in increased number of resorbed foetuses associated with reduced oestrogen plasma levels, in the 4 h/day exposed mothers. Increased expression of pregnancy-relevant inflammatory cytokines is also detected in the placentas of both groups. These results prove that NPs are able to reach and cross the mouse placenta and suggest that precaution should be taken with respect to acute exposure to nanoparticles during pregnancy. PMID- 28618896 TI - Managing risk during care transitions when approaching end of life: A qualitative study of patients' and health care professionals' decision making. AB - BACKGROUND: Increasing importance is being placed on the coordination of services at the end of life. AIM: To describe decision-making processes that influence transitions in care when approaching the end of life. DESIGN: Qualitative study using field observations and longitudinal semi-structured interviews. SETTING/PARTICIPANTS: Field observations were undertaken in three sites: a residential care home, a medical assessment unit and a general medical unit in New Zealand. The Supportive and Palliative Care Indicators Tool was used to identify participants with advanced and progressive illness. Patients and family members were interviewed on recruitment and 3-4 months later. Four weeks of fieldwork were conducted in each site. A total of 40 interviews were conducted: 29 initial interviews and 11 follow-up interviews. Thematic analysis was undertaken. FINDINGS: Managing risk was an important factor that influenced transitions in care. Patients and health care staff held different perspectives on how such risks were managed. At home, patients tolerated increasing risk and used specific support measures to manage often escalating health and social problems. In contrast, decisions about discharge in hospital were driven by hospital staff who were risk-adverse. Availability of community and carer services supported risk management while a perceived need for early discharge decision making in hospital and making 'safe' discharge options informed hospital discharge decisions. CONCLUSION: While managing risk is an important factor during care transitions, patients should be able to make choices on how to live with risk at the end of life. This requires reconsideration of transitional care and current discharge planning processes at the end of life. PMID- 28618897 TI - Shared decision making about palliative chemotherapy: A qualitative observation of talk about patients' preferences. AB - BACKGROUND: Particularly at the end of life, treatment decisions should be shared and incorporate patients' preferences. This study examines elaboration and preference construction. AIM: To examine the values, appraisals and preferences that patients express, as well as the oncologists' communicative behaviour that facilitates these expressions in consultations on palliative chemotherapy. DESIGN: Verbatim transcripts of audio-recorded consultations ( n = 60) were analysed in MAXqda10 software. Two independent coders identified and categorised patients' preference-related utterances and oncologists' utterances, preceding and following such expressions. SETTING/PARTICIPANTS: Cancer patients ( n = 41) with a median life expectancy <1 year and oncologists ( n = 13) meeting with them in either initial or evaluative follow-up consultations. RESULTS: Most frequent were patients' expressions of treatment preferences (65% of consultations), often the simple wish to have treatment. Expressions of underlying values (48%) and appraisals of treatment aspects (50%) were less common. Most preference-related utterances concerned single statements (59%); in 51% of the consultations, true dialogue was observed. Preference-related utterances were least common in follow up consultations concerning stable disease or response. Preference-related fragments were patient-initiated (42%), oncologist-facilitated (28%) or oncologist-invited (30%). Oncologist responses likely to trigger more preference related talk were showing empathy, checking and probe questioning. Likely to reduce space were providing information, personally agreeing and neutral responses. CONCLUSION: Elaboration and joint preference construction is not standard practice in consultations on palliative chemotherapy. Oncologists may benefit from realising this and training skills that support this key step of shared decision making. Also, repeated shared decision making throughout the course of palliative chemotherapy should be stimulated. PMID- 28618898 TI - A metasynthesis study of family caregivers' transition experiences caring for community-dwelling persons with advanced cancer at the end of life. AB - BACKGROUND: Family caregivers (broadly defined as family and friends) experience multiple concurrent transitions when caring for a person with advanced cancer. AIMS: To (a) explore the transition experience of family caregivers caring for persons with advanced cancer living in the community, (b) describe potential triggers for transitions, (c) identify what influences this experience, and (d) develop a conceptual framework of their transition experience. DESIGN: Sandelowski and Barroso's methodology for synthesizing qualitative research included (a) a comprehensive search of empirical literature, (b) quality appraisal of qualitative studies, (c) classification of studies, and (d) synthesis of the findings. DATA SOURCES: Literature was sourced from six electronic data bases. Inclusion criteria were as follows: (a) published qualitative studies (and mixed-method designs) of the caregiving experience of family caregivers of community-living persons with advanced cancer at the end of life, (b) participants (caregivers and care recipients) of 18 years of age and above, (c) studies published in English in any country, and (d) studies published between 2004 and 2014. RESULTS: A total of 72 studies were included in the metasynthesis. Family caregivers experience a "life transition" whereby their lives are permanently altered. The participants described the process of redefining normal which consisted of coming to terms with their situation and connecting with others. Outcomes of these processes were as follows: (a) maintaining a sense of personhood, (b) reframing hope, (c) maintaining self efficacy, (d) finding meaning, and (e) preparing for the death of their care recipient. CONCLUSION: The findings provide a framework to guide the development of supportive programs and future research. PMID- 28618899 TI - Development of a caregiver-reported measure to support systematic assessment of people with dementia in long-term care: The Integrated Palliative care Outcome Scale for Dementia. AB - BACKGROUND: Symptom burden is common for long-term care residents with dementia which if untreated compromises quality of life. Measurement tools can support assessment of symptoms and problems but are not widely used in long-term care settings. We developed the Integrated Palliative care Outcome Scale for Dementia derived from the Palliative care Outcome Scale, Palliative care Outcome Scale Symptom and Integrated Palliative care Outcome Scale. AIM: To examine the content validity, acceptability and comprehension of Integrated Palliative care Outcome Scale for Dementia for routine use in long-term care settings for people with dementia and to refine Integrated Palliative care Outcome Scale for Dementia. DESIGN: A multi-method qualitative study consisting of focus groups, semi structured interviews and cognitive interviews. SETTING/PARTICIPANTS: Three residential long-term care settings in London, UK. Focus group and semi structured interview participants included caregiver staff, family, general practitioners and district nurses. Caregiver staff were sampled purposively for cognitive interviews. RESULTS: A total of 26 respondents participated in the focus groups ( n = 21) or semi-structured interviews ( n = 5) and 10 caregiver staff completed cognitive interviews. Additional symptoms and problems included agitation, wandering, sleep problems, communication problems and diarrhoea. Refinements or lay terms were required to improve comprehension and consistency of item response for nausea, drowsiness, delusions/hallucinations, agitation, loss of interest, communication problems and interaction. A video presentation was required to support comprehension of instructions and assessment of verbally compromised residents. CONCLUSION: Integrated Palliative care Outcome Scale for Dementia is a comprehensive and acceptable caregiver-reported measure to detect symptoms and problems in dementia. It is suitable for caregiver staff without professional training as it has been refined and tailored to maximise caregiver expertise, ready for further psychometric testing. PMID- 28618900 TI - Shared decision-making in palliative care: Research priorities to align care with patients' values. PMID- 28618901 TI - Health inequalities in secondary prevention. AB - Health inequalities are differences in health status or the distribution of health determinants between distinct populations or groups. These have important impacts on the accessibility and effectiveness of cardiovascular disease preventive measures. This article discusses the most relevant issues on this topic. PMID- 28618902 TI - Secondary prevention: Where we are. AB - The Sixth Joint Task Force of the European Society of Cardiology (ESC) and Other Societies on Cardiovascular Disease Prevention in Clinical Practice Guidelines have been published in 2016: greater emphasis has been placed on a population based approach, on disease-specific interventions and on female-specific conditions, younger individuals and ethnic minorities. The ESC guidelines underscore that a lifetime approach to cardiovascular risk is important as both risk and prevention are dynamic and continuous. The guidelines can assist healthcare professionals, patients, and are valuable for the healthcare system but implementation of secondary cardiovascular disease prevention is far from optimal. Although there is no single way to ensure the use of guidelines in practice, multifaceted interventions based on known barriers are most appropriate. Essential components for implementation are: (a) taking action; (b) strengthening capacity; (c) evaluating impact; (d) advancing policy; and (e) engaging in regional and global partnerships. The strategy depends on a balanced investment in all available intervention approaches, from policy and environmental changes designed to prevent risk factors to assurance of quality care for individuals with cardiovascular disease. Our greatest challenges represent our greatest opportunities. PMID- 28618903 TI - Planning secondary prevention: Room for improvement. AB - The prognosis of patients after acute coronary syndromes is still suboptimal, mainly due to the risk of recurrent adverse coronary events, which is greatest during the first year, but persists over one's lifetime. Meaningful progress in preventing cardiovascular events has been achieved. However, there remains much room for improvement by embracing innovative therapies and investing in multidisciplinary approaches. Pharmacological interventions focused on optimising antithrombotic and lipid-lowering therapies are both pillars of secondary prevention that have seen recent ground-breaking advances. Moreover, new approaches in diabetic patients with cardiovascular disease and new targets for anti-inflammatory treatment may significantly improve prevention strategies in the future. However, pharmacological treatments are expensive and can have significant side effects. Developing better tools in order to identify high-risk patients and promote more personalised strategies for each patient should be an absolute priority. Furthermore, adherence to medication is still low and represents a real challenge; several strategies to improve low adherence to treatment are currently under discussion. Non-pharmacological interventions are also essential. Improving communication with patients and advanced surveillance for those secondary risk factors that may negatively impact prognosis are crucial. Encouraging multidisciplinary teams that work effectively to optimise all aspects of secondary prevention, including a cardiac rehabilitation programme, is the optimal approach. Current secondary prevention strategies and suggestions for areas of improvement are discussed in this manuscript. However, the question remains: will research in secondary prevention continue to focus on stronger and more expensive drugs, or is it time for us to embrace a more patient centred clinical and research model? PMID- 28618904 TI - Antiplatelet and antithrombotic treatment for secondary prevention in ischaemic heart disease. AB - Platelets play a key role in the pathogenesis of acute coronary syndromes and this is why antiplatelet drugs are essential, both in the acute phase and in the long-term follow-up in preventing recurrent myocardial infarction, stroke and cardiovascular death. Aspirin is the most used agent and still remains the first choice drug for lifelong administration in secondary prevention after myocardial infarction. Dual antiplatelet therapy, targeting more than one pathway of platelet activation, has significantly improved the outcome of patients with acute coronary syndromes despite an increased risk of bleeding complications. The aim of this article is to provide an overview of the evidence from randomized clinical trials with a focus on the best association between aspirin and a P2Y12 inhibitor such as clopidogrel, prasugrel or ticagrelor, on the selection of the appropriate agent based on the revascularization strategy and on the optimal duration of such an intensive treatment. We will also provide the latest evidence regarding new antithrombotic agents, such as vorapaxar or low dose rivaroxaban, that could be associated with dual antiplatelet therapy in high risk patients with the aim of further reducing the rate of major ischaemic complications. Finally we will address the issue of patients presenting with atrial fibrillation and a concomitant acute coronary syndrome who frequently need a percutaneous coronary intervention, with a specific focus on the combination therapy of antiplatelet and anticoagulant agents and on the current recommendations of the guidelines. PMID- 28618905 TI - Effective low-density lipoprotein-lowering therapy: Implementation in clinical practice. AB - Although age-adjusted mortality of coronary heart disease has been successfully reduced over recent years, coronary heart disease still represents a leading cause of death and morbidity, in particular in patients at very high cardiovascular risk. Dyslipidaemia plays a major and causal role in the development and clinical progression of coronary heart disease. At present, low density lipoprotein cholesterol represents the primary target of lipid-directed therapies for the prevention of cardiovascular disease and events. The new European guidelines recommend intensive statin therapy and the possible addition of ezetimibe to reduce low-density lipoprotein cholesterol to a goal of less than 1.8 mmol/L (<70 mg/dL) or by at least 50% if the baseline low-density lipoprotein cholesterol is between 1.8 and 3.5 mmol/L (70-135 mg/dL) in patients at very high cardiovascular risk. Also, the new European guidelines now mention the potential use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors in very high-risk patients with persistently high levels of low-density lipoprotein cholesterol despite maximally tolerated statin treatment in combination with ezetimibe or in patients with statin intolerance. A recent European consensus document discusses the practical clinical use of PCSK9 inhibitors and provides more detailed recommendations. However, despite the overwhelming scientific evidence of the beneficial effects of lipid-lowering therapies, a large proportion of patients at very high cardiovascular risk are not treated according to the current European guideline recommendations. Reinforcing lipid-lowering therapies provides an excellent chance effectively to reduce morbidity and mortality from coronary heart disease. PMID- 28618906 TI - Quality assurance and the need to evaluate interventions and audit programme outcomes. AB - Evidence-based clinical guidelines provide standards for the provision of healthcare. However, these guidelines have been poorly implemented in daily practice. Clinical audit is a quality improvement tool to promote quality of care in daily practice and to improve outcomes through the systematic review of care delivery and implementation of changes. A major priority in the management of subjects with cardiovascular disease (CVD) management is secondary prevention by controlling cardiovascular risk factors and providing appropriate medical treatment. Clinical audits can be applied to monitor modifiable risk factors and evaluate quality improvements of CVD management in daily practice. Existing clinical audits have provided an overview of the burden of risk factors in subjects with CVD and reflect real-world risk factor recording and management. However, consistent and representative data from clinic audits are still insufficient to fully monitor quality improvement of CVD management. Data are lacking in particular from low- and middle-income countries, limiting the evaluation of CVD management quality by clinical audit projects in many settings. To support the development of clinical standards, monitor daily practice performance, and improve quality of care in CVD management at national and international levels, more widespread clinical audits are warranted. PMID- 28618907 TI - Lifestyle modification in secondary prevention. AB - A healthy lifestyle is the cornerstone of prevention. Its promotion is a major task for all healthcare providers with the collaboration of the family and caregivers. It includes intervention in personal behaviour and risk factors (such as lack of physical activity, use of tobacco, unhealthy food habits and overweight), and all interventions aimed at changing lifestyle should be lifelong. PMID- 28618908 TI - Psychosocial perspectives in cardiovascular disease. AB - Adaptation to living with cardiovascular disease may differ from patient to patient and is influenced not only by disease severity and limitations incurred by the disease but also by socioeconomic factors (e.g. health literacy), the patients' psychological make-up and susceptibility to distress. Co-morbid depression and/or anxiety is prevalent in 20% of patients with cardiovascular disease, which may be either transient or chronic. Distress, such as depression, reduces adherence, serves as a barrier to behaviour change and the adoption of a healthy lifestyle, and increases the risk that patients drop out of cardiac rehabilitation, impacting on patients' quality of life, risk of hospitalisation and mortality. Hence it is paramount to identify this subset of high-risk patients in clinical practice. This review provides a general overview of the prevalence of selected psychosocial risk factors, their impact on patient reported and clinical outcomes, and biological and behavioural mechanisms that may explain the association between psychosocial factors and health outcomes. The review also provides recommendations on which self-report screening measures to use to identify patients at high risk due to their psychosocial profile, and the effectiveness of available trials that target these risk factors. Despite challenges and barriers associated with screening of patients combined with appropriate treatment, it is paramount that we treat not only the heart but also the mind in order to improve the quality of care and patient and clinical outcomes. PMID- 28618909 TI - Improving adherence to medication for secondary cardiovascular disease prevention. AB - Survivors of myocardial infarction are at risk of recurrent events and have an annual death rate of 5%. Advances in treatment and, in particular, the interventional management of myocardial infarction have seen important mortality gains over recent decades, yet cardiovascular diseases remain the biggest killer in many European countries. Change in lifestyle and adherence to medication to prevent further events are key to the recurrence of future events following myocardial infarction, but adherence to medication for the secondary prevention of cardiovascular disease is a profound problem. This article outlines a growing evidence base about the complex nature of adherence as a psychological phenomenon that is influenced by the nature of the event itself, illness perception and factors related to medication beliefs that cannot be addressed simply through a combination of educational approaches. A whole-systems approach is advocated, starting with the education of health professionals to understand the psychology of adherence, and to react comfortably to patients decisions about medication, with a pivotal role for follow-up in secondary care and cardiac rehabilitation. PMID- 28618910 TI - Diabetes: Prevalence, prognosis and management of a potent cardiovascular risk factor. AB - This review highlights the increased risk of cardiovascular disease and the dismal prognosis after acute coronary events when diabetes is present. Although there have been improvements in this area, diabetes still confers an increased risk. In order to achieve successful outcomes in individuals with diabetes, extensive treatment of risk factors and the use of all available evidence-based therapies are needed. In this context, glucose-lowering therapies and antithrombotic and revascularisation strategies are detailed in this review. Emerging data indicate that novel glucose-lowering drugs may impact cardiovascular outcome with mechanisms that are beyond glucose control. In addition, this review addresses hidden diabetes and impaired glucose tolerance in patients with acute and stable coronary artery disease and how they influence future cardiovascular risk. PMID- 28618911 TI - Secondary prevention of cardiovascular disease: Unmet medical need, implementation and innovation. PMID- 28618912 TI - Hypertension: Overly important but under-controlled. AB - Hypertension is the leading cause of cardiovascular disease and death. Despite increased knowledge of its importance in cardiovascular disease, the worldwide prevalence is still increasing and there is considerable scope for improvement of awareness, treatment and control. In this review, five major issues in hypertension management in secondary prevention of cardiovascular disease will be outlined. The first two issues will address hypertension diagnosis: out-of-office blood pressure measurements and the detection of secondary hypertension. The last three issues will address hypertension treatment: lifestyle modification, medication adherence and blood pressure targets. For each of the five issues, we will outline existing knowledge, gaps in existing knowledge, barriers preventing full implementation of guideline recommendations, and possible solutions to improve management of the current disquieting situation. PMID- 28618913 TI - A multidisciplinary approach to prevention. AB - Cardiovascular disease accounts for 17,500 deaths globally, representing nearly half of all non-communicable disease deaths. The World Health Organization has set nine lifestyle, risk factor and medicines targets to achieve by 2025 with the aim of reducing premature mortality from non-communicable diseases by 25%. In order to succeed in this, we need to equip our global health professional workforce with the skills to support patients and their families with making lifestyle changes and being in concordance with cardioprotective medication regimes at every opportunity. Success depends on collegiate working through effective interdisciplinary team-based care characterised by shared goals, clear roles, mutual trust, effective communication and measurable processes and outcomes, with the patient and family at the centre of care. Nurses are the largest sector of the health professional workforce and their role in prevention should be optimised. Nurse coordinated care is proven to be effective, especially where they work in an interdisciplinary way with other health professionals such as doctors, pharmacists and psychologists, who provide equally important expertise for supporting holistic care. Successful care models are those that comprehensively target all adverse lifestyles and risk factors that are responsible for the development of cardiovascular disease. These characteristics should be reflected in the standards and core components of prevention and rehabilitation programmes. PMID- 28618914 TI - Role of the polypill for secondary prevention in ischaemic heart disease. AB - In 2011, for the first time in the history of humankind, non-communicable diseases became the leading cause of death worldwide. This change in trend is obviously multifactorial and very complex, as it is the paradoxical result of social, economic and health system growth worldwide. Vaccination and infectious diseases control, changing dietary habits worldwide, sedentary behaviour, globalisation, industrialisation (resulting in a shift from manual to sedentary labour), tobacco and sugary beverage surges in low- and middle-income countries and rapid urbanisation have all played a role in this epidemic transition. At the same time, the increase in cardiovascular risk factors, together with a decline in mortality in high-income countries in the past two decades, has led to a significant upsurge in the prevalence of secondary prevention of ischaemic heart disease. With this, the effect that non-adherence to cardioprotective drugs is having has become progressively clear, both in terms of clinical outcomes and as a driver of increased healthcare expenditure. The cardiovascular polypill, which was originally proposed as a strategy to improve accessibility to cardioprotective drugs worldwide, has proven to be a mainstay therapeutic approach for improving medication adherence in cardiovascular disease. In the current paper, we aim to review the need for a polypill strategy in the present scenario of cardiovascular disease, the available data that support such a strategy and the various clinical trials that are in progress that will help further shape future indications for the cardiovascular polypill. PMID- 28618915 TI - Coronary artery disease: Risk stratification and patient selection for more aggressive secondary prevention. AB - In patients with stable coronary artery disease, clinical outcomes are predominantly characterized by the consequences of atherosclerosis on the myocardium, but also by complications of atherosclerosis, notably recurrent acute coronary syndrome or stroke. Secondary prevention therapy is therefore key in this patient population. Intensification of secondary prevention therapy is possible, at the price of a therapeutic risk or a high cost, therefore justifying careful selection of patients with a high residual risk and low therapeutic risk. Two lines of therapy can be intensified, independently of each other, namely anti thrombotics and lipid-lowering agents. Intensification of anti-thrombotic therapy is efficacious in terms of ischaemic events and cardiovascular mortality, but incurs an excess haemorrhagic risk. Patients aged over 65 years of age and those with a history of intra-cranial haemorrhage are not eligible for intensification of anti-thrombotic therapy. Conversely, patients with prior or recurrent myocardial infarction may benefit from this strategy, especially if they are current smokers or have diabetes mellitus. Intensification of lipid-lowering therapy can be achieved through an association of high-intensity statins with ezetimibe or PCSK9 inhibitors. This strategy engenders little risk, but the cost of PCSK9 inhibition is high, and should be considered based on the level of low density lipoprotein cholesterol achieved with statin treatment at the maximal tolerated dose. In addition to this patient selection based on low-density lipoprotein cholesterol levels, the presence of diabetes or documented progression of atherosclerosis should be considered. PMID- 28618916 TI - Who needs secondary prevention? AB - Secondary prevention for ischaemic heart disease can be defined as a comprehensive set of measures, aiming to reduce the recurrence of cardiovascular disease and to improve long-term prognosis. Despite its proven efficacy, uptake and adherence rates remain poor. This paper summarises the available European recommendations for secondary prevention in varying ischaemic heart disease populations, including those patients with specific co-morbidities. The scientific evidence supporting these recommendations is provided. The article relates to the European Association of Preventive Cardiology, the Acute Cardiovascular Care Association and the Council on Cardiovascular Nursing and Allied Professions Secondary Prevention After Acute Myocardial Infarction framework in that it clarifies accurately who needs secondary prevention. PMID- 28618917 TI - Reduced cardiovascular activation following chronic stress in caregivers of people with anorexia nervosa. AB - Caring for offspring diagnosed with eating disorders (EDs) puts caregivers under high levels of chronic stress, which have negative consequences for their health. Unfortunately, caregivers have received little attention from mental health professionals. Chronic stress experienced by informal caregivers has been associated with the alteration of body homeostasis, and therefore, the functioning of various physiological systems. This could be the basis of health problems in informal caregivers of people with EDs. The main objective of this study was to analyze physiological response, in terms of heart rate (HR) and heart rate variability (HRV), to an acute laboratory stressor in a sample of informal caregivers of individuals with anorexia nervosa (n = 24) compared to a sample of noncaregivers (n = 26). In addition, the relationship between depressive mood and the aforementioned cardiovascular response parameters was analyzed in the group of caregivers. Caregivers had higher high-frequency (HF) power HRV, and lower HR, low-frequency (LF) power HRV and LF/HF ratio values than noncaregivers, which suggests lower cardiovascular reactivity to the acute stressor than noncaregivers. Moreover, a blunted HR response to stress was associated with high depressive mood scores in caregivers. Hence, it seems that the worse the mood the lower the cardiovascular reactivity to stressful events in this population. Developing and implementing psychotherapeutic interventions focused on stress management would help caregivers to reduce their stress levels and cope more effectively with stressors. PMID- 28618918 TI - Does Guiding Toward Task-Relevant Information Help Improve Graph Processing and Graph Comprehension of Individuals with Low or High Numeracy? An Eye-Tracker Experiment. AB - BACKGROUND: Individuals with low numeracy have difficulties with understanding complex graphs. Combining the information-processing approach to numeracy with graph comprehension and information-reduction theories, we examined whether high numerates' better comprehension might be explained by their closer attention to task-relevant graphical elements, from which they would expect numerical information to understand the graph. Furthermore, we investigated whether participants could be trained in improving their attention to task-relevant information and graph comprehension. DESIGN: In an eye-tracker experiment ( N = 110) involving a sample from the general population, we presented participants with 2 hypothetical scenarios (stomach cancer, leukemia) showing survival curves for 2 treatments. In the training condition, participants received written instructions on how to read the graph. In the control condition, participants received another text. We tracked participants' eye movements while they answered 9 knowledge questions. The sum constituted graph comprehension. We analyzed visual attention to task-relevant graphical elements by using relative fixation durations and relative fixation counts. RESULTS: The mediation analysis revealed a significant ( P < 0.05) indirect effect of numeracy on graph comprehension through visual attention to task-relevant information, which did not differ between the 2 conditions. Training had a significant main effect on visual attention ( P < 0.05) but not on graph comprehension ( P < 0.07). CONCLUSIONS: Individuals with high numeracy have better graph comprehension due to their greater attention to task-relevant graphical elements than individuals with low numeracy. With appropriate instructions, both groups can be trained to improve their graph-processing efficiency. Future research should examine (e.g., motivational) mediators between visual attention and graph comprehension to develop appropriate instructions that also result in higher graph comprehension. PMID- 28618919 TI - Discontinuation of Vasopressin Before Norepinephrine in the Recovery Phase of Septic Shock. AB - BACKGROUND: Guidance for the discontinuation of vasopressors in the recovery phase of septic shock is limited. Norepinephrine is more easily titrated; however, septic shock is a vasopressin deficient state, which exogenous vasopressin endeavors to resolve. Discontinuation of vasopressin before norepinephrine may result in clinically significant hypotension. METHODS: This retrospective, cohort study compared discontinuation of norepinephrine and vasopressin in medically, critically ill patients in the recovery phase of septic shock from May 2014 to June 2016. Difference in clinically significant hypotension after norepinephrine or vasopressin discontinuation was evaluated with chi2 test. Linear regression was performed, examining the effect of agent discontinuation on clinically significant hypotension. Baseline variables were examined for a bivariate relationship with clinically significant hypotension; those with P < .2 were included in the model. RESULTS: Vasopressin was discontinued first or last in 62 and 92 patients, respectively. Sequential Organ Failure Assessment scores at 72 hours (7.9 vs 7.6, P = .679) were similar. In unadjusted analysis, when vasopressin was discontinued first, more clinically significant hypotension developed (10.9% vs 67.8%, P < .001). There was no difference in intensive care unit (174 vs 216 hours, P = .178) or hospital duration (470 vs 473 hours, P = .977). In adjusted analyses, discontinuing vasopressin first was associated with increased clinically significant hypotension (odds ratio [OR]: 13.837, 95% confidence interval [CI]: 3.403-56.250, P < .001) but not in-hospital (OR: 0.659, 95% CI: 0.204-2.137, P = .488) or 28 day mortality (OR: 0.215, 95% CI: 0.037-1.246, P = .086). CONCLUSION: Adult patients receiving norepinephrine and vasopressin in the resolving phase of septic shock may be less likely to develop clinically significant hypotension if vasopressin is the final vasopressor discontinued. PMID- 28618920 TI - Castor oil for induction of labour: a retrospective study. AB - PURPOSE: The aim of this study is to investigate the safety and efficacy of castor oil to induce labour. MATERIALS AND METHODS: A retrospective observational case control study was conducted over five years. Castor oil was proposed to women referred to the Birth Centre (Castor Oil group (COG)). They were compared to women who chose to be followed by the traditional doctor-led unit (control group (CG)). Castor oil was administered in a 60 ml single dose in 200 ml of warm water. Inclusion criteria were gestational age between 40 and 41 weeks plus premature rupture of membranes between 12 and 18 hours or amniotic fluid index <=4 or Bishop Score of <=4 or absence of spontaneous labour over 41 + 4 weeks. RESULTS: Pharmacological induction of labour was required for 18 women in the COG (45%) and 36 in the CG (90%) (p < .001). The mode of delivery differed significantly between groups: women assuming castor oil showed a higher incidence of vaginal delivery, whereas the incidence of caesarean section was lower in the COG, but no statistical significance was reached. CONCLUSIONS: The use of castor oil is related to a higher probability of labour initiation within 24 hours. Castor oil can be considered a safe non-pharmacological method for labour induction. PMID- 28618921 TI - Surgical evacuation of acute subdural hematoma in octogenarians: a ten-year experience from a single trauma center. AB - BACKGROUND: Elderly patients presenting with an acute subdural hematoma (aSDH) have historically had unfavorable outcomes. METHODS: We retrospectively reviewed patient records from 2005 through 2015 that were >=80 years of age and underwent surgical evacuation of aSDH. RESULTS: Thirty-four patients met inclusion criteria, with a mean age of 84 years (range 80-91). Glascow Outcome Scale (GOS) of 4-5 was deemed a good outcome and a GOS 1-3 was deemed to be a poor outcome. Six patients had good outcome at last follow up and 27 patients had poor outcome. Patients with a higher presenting Glascow Coma Scale (GCS) trended towards better outcome [(good: mean 13.1, median 14.5, IQR 12.5-15) vs. (poor: mean 9.6, median 10, IQR 6-14) p = 0.06]. Patients with a higher in-hospital post-operative GCS score had significantly better overall outcome than patients who left the hospital with a lower GCS score [(good: mean 14.5, median 14.5, IQR 14-15) vs. (poor: mean 8.4, median 9, IQR 4-11) p = 0.001]. Patients with a good outcome had a median aSDH thickness of 17mm (IQR 12.75-19.75) while patients with a poor outcome had a median thickness of 20mm (IQR 16-24.5); p = 0.17. In addition, patients with a good outcome had a median midline shift of 10mm (IQR 6-12.5), while patients with a poor outcome had a median midline shift of 14mm (IQR 10 20); p = 0.07. CONCLUSIONS: The prognosis for elderly patients with large aSDH remains poor, but a subset of patients can benefit from surgical intervention. PMID- 28618922 TI - High expression of C-X-C chemokine receptor 4 and Notch1 is predictive of lymphovascular invasion and poor prognosis in lung adenocarcinoma. AB - C-X-C chemokine receptor 4 and Notch1 have been shown to play oncogenic role individually. This study aimed to determine the combinatorial role of C-X-C chemokine receptor 4 and Notch1 in lung adenocarcinoma. Expression of C-X-C chemokine receptor 4 and Notch1 was detected in resected tumor samples from 185 patients with lung adenocarcinoma at stage I-IIIa by immunohistochemistry. Correlations of their immunoscores with clinicopathological characteristics and disease-specific survival were retrospectively investigated. A three-dimensional capillary-like sprouting model was established to assess the effects of C-X-C chemokine receptor 4 and Notch1 on angiogenesis in vitro. The results revealed that expression of C-X-C chemokine receptor 4 and Notch1 was elevated in lung adenocarcinoma tissues. The high co-expression of C-X-C chemokine receptor 4 and Notch1 was significantly correlated with tumor size, tumor status, nodal status, tumor stage, and lymphovascular invasion, as well as decreased disease-specific survival. Multivariate analysis showed that lymphovascular invasion (hazard ratio: 0.205, 95% confidence interval: 0.086-0.491, p < 0.0001) and co-expression of C-X-C chemokine receptor 4 and Notch1 (hazard ratio: 0.293, 95% confidence interval: 0.168-0.510, p < 0.0001) were independent indicators of poor prognosis in lung adenocarcinoma. Furthermore, Notch1 enhanced the effects of C-X-C chemokine receptor 4 to promote angiogenesis by regulating Flt1 and Flt4 in vitro. In conclusion, co-expression of C-X-C chemokine receptor 4 and Notch1 is associated with tumor progression and lymphovascular invasion and is an independent indicator of poor survival in lung adenocarcinoma. In lung adenocarcinoma patients with high C-X-C chemokine receptor 4 and Notch1 expression, simultaneous inhibition of both factors might be an effective treatment strategy. PMID- 28618923 TI - Serum autoantibodies against a panel of 15 tumor-associated antigens in the detection of ovarian cancer. AB - In this study, enzyme-linked immunosorbent assay has been used to examine the frequencies of serum autoantibodies against two candidate tumor-associated antigens intensively selected from the Human Protein Atlas database, in combination with 13 tumor-associated antigens available from our lab in sera from 44 OC patients and 50 normal healthy controls. Conventional evaluation (mean + 3SD as the cutoff value to determine a positive reactivity), receiver operating characteristic curve analyses, and classification tree analysis were further used to evaluate the diagnostic performance of autoantibodies against these tumor associated antigens (anti-tumor-associated antigens) in ovarian cancer. For single anti-tumor-associated antigen, when the cutoff values were set as mean + 3SD of normal healthy controls, NPM1, MDM2, PLAT, p53, and c-Myc could achieve sensitivity higher than 20% at 98% specificity. Combinational utilization of autoantibodies against MDM2, PLAT, NPM1, 14-3-3 Zeta, p53, and RalA achieved the optimal diagnostic performance with 72.7% sensitivity at 96% specificity. Receiver operating characteristic curve analysis showed that the area under the receiver operating characteristic curves of autoantibodies against c-Myc, NPM1, MDM2, p16, p53, and 14-3-3 Zeta were greater than 0.80. This indicated that these tumor-associated antigens held high potential to serve as diagnostic biomarkers in ovarian cancer detection. Decision tree analysis indicated that anti-c-Myc held high potential in the detection of ovarian cancer. Further studies are warranted to validate the diagnostic performance of these anti-tumor-associated antigens with high area under the receiver operating characteristic curve, including autoantibodies against c-Myc, MDM2, PLAT, NPM1, 14-3-3 Zeta, p53, and RalA. PMID- 28618924 TI - Expression and clinical significance of placenta-specific 1 in pancreatic ductal adenocarcinoma. AB - The limited efficacy of conventional therapies for pancreatic ductal adenocarcinoma has led to the growing interest for identifying potential antigenic targets for immunotherapy. Placenta-specific 1 (PLAC1) is a new member of cancer-testis antigens with restricted expression in normal tissues. Ectopic activation of PLAC1 has been found in different types of cancers, but its role in pancreatic ductal adenocarcinoma remains unknown. This study evaluated the protein expression of PLAC1 and its clinical significance in pancreatic ductal adenocarcinoma. We examined PLAC1 expression in 93 pancreatic ductal adenocarcinoma samples by immunohistochemistry. The expression of PLAC1 was detected in 41 (44.1%) patients. Among patients' clinicopathological characteristics, PLAC1 expression was only significantly correlated with tumor differentiation (p = 0.028). Univariate analysis revealed that PLAC1 expression (p = 0.016) and tumor differentiation (p = 0.003) were significantly correlated with poor survival in the whole cohort. Subgroup analysis showed that PLAC1 expression was an independent prognostic biomarker in the perineural invasion positive subgroup (p < 0.05). This study demonstrated that the protein expression of PLAC1 was significantly associated with decreased overall survival in patients with pancreatic ductal adenocarcinoma, indicating that it was a valuable prognostic marker for pancreatic ductal adenocarcinoma and might be a potential target for immunotherapy. PMID- 28618925 TI - DJ-1 is a reliable serum biomarker for discriminating high-risk endometrial cancer. AB - New reliable approaches to stratify patients with endometrial cancer into risk categories are highly needed. We have recently demonstrated that DJ-1 is overexpressed in endometrial cancer, showing significantly higher levels both in serum and tissue of patients with high-risk endometrial cancer compared with low risk endometrial cancer. In this experimental study, we further extended our observation, evaluating the role of DJ-1 as an accurate serum biomarker for high risk endometrial cancer. A total of 101 endometrial cancer patients and 44 healthy subjects were prospectively recruited. DJ-1 serum levels were evaluated comparing cases and controls and, among endometrial cancer patients, between high and low-risk patients. The results demonstrate that DJ-1 levels are significantly higher in cases versus controls and in high- versus low-risk patients. The receiver operating characteristic curve analysis shows that DJ-1 has a very good diagnostic accuracy in discriminating endometrial cancer patients versus controls and an excellent accuracy in distinguishing, among endometrial cancer patients, low- from high-risk cases. DJ-1 sensitivity and specificity are the highest when high- and low-risk patients are compared, reaching the value of 95% and 99%, respectively. Moreover, DJ-1 serum levels seem to be correlated with worsening of the endometrial cancer grade and histotype, making it a reliable tool in the preoperative decision-making process. PMID- 28618926 TI - Diagnostic relevance of a novel multiplex immunoassay panel in breast cancer. AB - Multiple factors contribute to the development and progression of breast cancer. Markers of tumor growth and invasion, cell death, immune activation, and angiogenesis can be assessed in parallel by a novel multiplex immunoassay panel. The diagnostic performance of a multiplex cancer biomarker magnetic bead panel comprising 24 tumor associated parameters was evaluated in sera of 154 women including 77 patients with breast cancer, 10 with precancerous lesions, 31 with benign breast diseases, and 36 healthy controls. Marker levels were log transformed for variance stabilization. Significance testing was done using t test or Wilcoxon rank-sum test with correction of p values for multiple testing. Furthermore, receiver operating characteristic analyses were performed. Serum levels of several biomarkers were significantly (p <= 0.001) higher in cancer patients than in healthy controls, particularly alpha-fetoprotein, cancer antigen 15-3, cancer antigen 19-9, migration inhibitory factor, carcinoembryonic antigen, cancer antigen 125, hepatocyte growth factor, soluble Fas, tumor necrosis factor alpha, stem cell factor, and osteopontin. As most markers were also elevated in benign breast diseases, only cancer antigen 15-3 showed significant differences to cancer patients (p <= 0.001). The resulting areas under the curve in receiver operating characteristic curves for discrimination between benign and malignant breast diseases achieved 0.71 with a sensitivity of 33.8% at 95% specificity. Multiplexing enables parallel analysis of different biomarker classes for cancer detection. Established cancer antigen 15-3 proved to be most relevant for differential diagnosis. PMID- 28618927 TI - Long non-coding RNA MSTO2P promotes the proliferation and colony formation in gastric cancer by indirectly regulating miR-335 expression. AB - Long non-coding RNAs are emerging as new players in gene regulation, but whether long non-coding RNAs influence the expression of microRNA is unclear. The expression levels of misato family member 2, pseudogene were significantly associated with lymphatic metastasis and distal metastasis in 80 paired gastric cancer tissues using real-time quantitative reverse transcription polymerase chain reaction experiments. The effects of long non-coding RNA misato family member 2, pseudogene were assessed by overexpressing or downexpressing long non coding RNA misato family member 2, pseudogene in gastric cancer cells. Long non coding RNA misato family member 2, pseudogene promoted gastric cancer cell growth, colony formation, migration, and invasion in gastric cancer cells. Long non-coding RNA misato family member 2, pseudogene influenced biologic functions in gastric cancer cells via indirectly regulating the activation of miR-335. Our results reveal long non-coding RNA misato family member 2, pseudogene as an oncogenic long non-coding RNA that promotes cell growth and invasion. Therefore, long non-coding RNAs might function as key regulatory hubs in gastric cancer progression. PMID- 28618928 TI - Overexpression of TRIM44 is related to invasive potential and malignant outcomes in esophageal squamous cell carcinoma. AB - Recent studies have shown that some members of the tripartite motif-containing protein family function as important regulators for carcinogenesis. In this study, we investigated whether tripartite motif-containing protein 44 acts as a cancer-promoting gene through its overexpression in esophageal squamous cell carcinoma. We analyzed esophageal squamous cell carcinoma cell lines to evaluate malignant potential and also analyzed 68 primary tumors to evaluate clinical relevance of tripartite motif-containing protein 44 protein in esophageal squamous cell carcinoma patients. Expression of the tripartite motif-containing protein 44 protein was detected in esophageal squamous cell carcinoma cell lines (8/14 cell lines; 57%) and primary tumor samples of esophageal squamous cell carcinoma (39/68 cases; 57%). Knockdown of tripartite motif-containing protein 44 expression in esophageal squamous cell carcinoma cells using several specific small interfering RNAs inhibited cell migration and invasion, but not cell proliferation. Immunohistochemical analysis demonstrated that the overexpression of the tripartite motif-containing protein 44 protein in the tumor infiltrated region was associated with the status of lymph node metastasis ( p = 0.049), and the overall survival rates were significantly worse among patients with tripartite motif-containing protein 44-overexpressing tumors than those with non expressing tumors ( p = 0.029). Moreover, multivariate Cox regression model identified that overexpression of the tripartite motif-containing protein 44 protein was an independent worse prognostic factor (hazard ratio = 2.815; p = 0.041), as well as lymphatic invasion (hazard ratio = 2.735; p = 0.037). These results suggest that tripartite motif-containing protein 44 protein could play a crucial role in tumor invasion through its overexpression and highlight its usefulness as a predictor and potential therapeutic target in esophageal squamous cell carcinoma. PMID- 28618929 TI - Anti-tumorigenic effects of a novel digitoxin derivative on both estrogen receptor-positive and triple-negative breast cancer cells. AB - While there are targeted treatments for triple positive breast cancers, lack of specific biomarkers for triple-negative breast cancers (TNBC) has hindered the development of therapies for this subset of cancers. In this study, we evaluated the anticancer properties of cardiac glycoside Digitoxin (Dtx) and its synthetic analog MonoD on breast cancer cell lines MCF-7 (estrogen receptor-positive breast cancer) and MDA-MB-468 (triple-negative breast cancer). Both cardiac glycosides, at concentrations within the therapeutic range, increased the fraction of cells in the G0/G1 phase of the cell cycle, decreased viability, and inhibited the migration of MCF-7 and MDA-MB-468 cells. Both cardiac glycosides increased production of superoxide and induced apoptosis in both cell types. Reduced protein levels of nuclear factor kappa B and IkappaB kinase-beta were found in cardiac glycoside-treated cells, indicating that the cellular effects of these compounds are mediated via nuclear factor kappa B pathway. This study demonstrates the cytotoxic potential of digitoxin, and more importantly its synthetic analog MonoD, in the treatment of triple-positive breast cancer and more importantly the aggressive triple-negative breast cancer. Collectively, this study provides a basis for the reevaluation of cardiac glycosides in the treatment of breast cancer and more importantly reveals their potential in the treatment of triple-negative breast cancers. PMID- 28618930 TI - Gallic acid against hepatocellular carcinoma: An integrated scheme of the potential mechanisms of action from in vivo study. AB - The global burden of hepatocellular carcinoma is increasing; actually, it is estimated as 750,000 new cases annually. This study was initiated to emphasize the possibility that gallic acid could alleviate hepatocarcinogenesis in vivo. In this study, 40 rats were enrolled and distributed as follows; group 1 was set as negative control, while all of groups 2, 3, and 4 were orally received N nitrosodiethylamine for hepatocellular carcinoma induction. Group 2 was left untreated, whereas groups 3 and 4 were orally treated with gallic acid and doxorubicin, respectively. The current data indicated that gallic acid administration in hepatocellular carcinoma bearing rats yielded significant decline in serum levels of alpha-fetoprotein, glypican-3, and signal transducer and activator of transcription 3 along with significant enhancement in serum suppressors of cytokine signaling 3 level. Also, gallic acid-treated group displayed significant downregulation in the gene expression levels of hepatic gamma glutamyl transferase and heat shock protein gp96. Intriguingly, treatment with gallic acid remarkably ameliorated the destabilization of liver tissue architecture caused by N-nitrosodiethylamine intoxication as evidenced by histopathological investigation. In conclusion, this study demonstrates that the hepatocarcinogenic effect of N-nitrosodiethylamine can be abrogated by gallic acid supplementation owing to its affinity to regulate signal transducer and activator of transcription 3 signaling pathway through its outstanding bioactivities including antioxidant, anti-inflammatory, apoptotic, and antitumor effects. PMID- 28618931 TI - Detection of FAM172A expressed in circulating tumor cells is a feasible method to predict high-risk subgroups of colorectal cancer. AB - Previous studies used to enumerate circulating tumor cells to predict prognosis and therapeutic effect of colorectal cancer. However, increasing studies have shown that only circulating tumor cells enumeration was not enough to reflect the heterogeneous condition of tumor. In this study, we classified different metastatic-potential circulating tumor cells from colorectal cancer patients and measured FAM172A expression in circulating tumor cells to improve accuracy of clinical diagnosis and treatment of colorectal cancer. Blood samples were collected from 45 primary colorectal cancer patients. Circulating tumor cells were enriched by blood filtration using isolation by size of epithelial tumor cells, and in situ hybridization with RNA method was used to identify and discriminate subgroups of circulating tumor cells. Afterwards, FAM172A expression in individual circulating tumor cells was measured. Three circulating tumor cell subgroups (epithelial/biophenotypic/mesenchymal circulating tumor cells) were identified using epithelial-mesenchymal transition markers. In our research, mesenchymal circulating tumor cells significantly increased along with tumor progression, development of distant metastasis, and vascular invasion. Furthermore, FAM172A expression rate in mesenchymal circulating tumor cells was significantly higher than that in epithelial circulating tumor cells, which suggested that FAM172A may correlate with malignant degree of tumor. This hypothesis was further verified by FAM172A expression in mesenchymal circulating tumor cells, which was strictly related to tumor aggressiveness factors. Mesenchymal circulating tumor cells and FAM172A detection may predict highrisk stage II colorectal cancer. Our research proved that circulating tumor cells were feasible surrogate samples to detect gene expression and could serve as a predictive biomarker for tumor evaluation. PMID- 28618932 TI - Intimate cross-talk between cancer cells and the tumor microenvironment of B-cell lymphomas: The key role of exosomes. AB - B-cell lymphomas are composed of tumor cells and the tumor microenvironment, which is conventionally thought to be composed of a mixture of stromal cells, blood vessels, immune cells, and non-cell components, such as extracellular matrix, cytokines, and chemokines. Exosomes, small endocytically derived vesicles that have been proved to be present in a variety of tumor niches and involved in mediating cell signaling networks, are increasingly regarded as important components of tumor microenvironment. In this review, we first focus on the biogenesis, biodistribution, transportation, and other general characteristics of exosomes and then highlight the vital roles of exosomes in lymphomagenesis and disease progression, particularly from the perspective of immune dysfunction, virus infection, and therapeutic resistance mechanisms. PMID- 28618933 TI - High expression of long non-coding RNA ZEB1-AS1 promotes colorectal cancer cell proliferation partially by suppressing p15 expression. AB - This study aims to investigate the function of long non-coding RNA ZEB1-AS1, reveal its molecular mechanism in colorectal cancer cell growth, and evaluate its clinical significance in colorectal cancer patients. ZEB1-AS1 has reported in the development of several cancers, but the biological role of it in colorectal cancer has not been discussed. In this report, ZEB1-AS1 expression level was measured with quantitative real-time polymerase chain reaction in 63 pairs of colorectal cancer tissues and paired adjacent non-tumor colorectal tissues. The relationship between ZEB1-AS1 expression and overall survival was analyzed by virtue of Kaplan-Meier analysis. Subsequently, small interfering RNA or lentivirus vector-mediated lncRNA ZEB1-AS1 was transfected into colorectal cancer cell lines. Cell viability and apoptosis were examined. Later, nude mouse transplantation experiment was conducted to evaluate the effect of ZEB1-AS1 on colorectal cancer development in vivo. It turns out that ZEB1-AS1 is upregulated in colorectal cancer tissues and its expression is significantly associated with overall survival rate and recurrence-free survival. Upregulation of ZEB1-AS1 colorectal cancer promotes cell proliferation and inhibits cell apoptosis. In addition, cell cycle inhibitory protein p15 participates in the oncogenic function of ZEB1-AS1. Collectively, ZEB1-AS1 has asignificant effect on colorectal cancer pathological process and serves as a valuable prognostic biomarker for colorectal cancer. PMID- 28618934 TI - Identification of curcumin-inhibited extracellular matrix receptors in non-small cell lung cancer A549 cells by RNA sequencing. AB - Curcumin is a potent anti-cancer drug in several types of human cancers. Despite of several preclinical and clinical studies of curcumin, the precise mechanism of curcumin in cancer prevention has remained unclear. In our study, we for the first time investigated whole transcriptome alteration in A549 non-small cell lung cancer (NSCLC) cell lines after treatment with curcumin using RNA sequencing. We found that lots of genes and signaling pathways were significantly altered after curcumin treatment in A549 cells. With bioinformatics approaches (gene ontology, Kyoto Encyclopedia of Genes and Genomes, and STRING), we found that those curcumin altered genes were not only the genes that induce cell death but also those extracellular matrix receptors and mitogen-activated protein kinase signaling pathway genes which regulate cell migration and proliferation. Among those significantly altered genes, eight genes ( COL1A1, COL4A1, COL5A1, LAMA5, ITGA3, ITGA2B, DDIT3, and DUSP1) were further examined by quantitative reverse transcription polymerase chain reaction and western blot analysis in four non-small cell lung cancer cell lines. Both in cell lines and in mouse model, the extracellular matrix receptors including the integrin ( ITGA3 and ITGA2B), collagen ( COL5A1), and laminin ( LAMA5) were significantly inhibited by curcumin at messenger RNA and protein levels. Functional studies confirmed that curcumin not only induced A549 cell death but also repressed cell proliferation and migration by regulating extracellular matrix receptors. Collectively, our study suggests that curcumin may be used as a promising drug candidate for intervening lung cancer in future studies. PMID- 28618935 TI - Heterogeneous DNA methylation status in same-cell subpopulations of ovarian cancer tissues. AB - This study aims to explore the heterogeneous DNA methylation differences between individual single ovarian cancer cells isolated from the same formalin-fixed and paraffin-embedded human ovarian cancer tissue. Single cells were isolated by laser microdissection. Whole genome amplification and polymerase chain reaction purification were performed on the converted genomic DNA. Target primers designed for checking DNA methylation were used in polymerase chain reaction reactions to amplify special fragments. Sequencing was performed to analyze the heterogeneous DNA methylation statuses of different single ovarian cancer cells. Three of nine single human ovarian cancer cells showed positive bands (33.3%) on separating gel. The methylated and unmethylated CpGs were shown at the same loci in different single cells. We show heterogeneous DNA methylation statuses in same cell subpopulations. PMID- 28618936 TI - Detection and a possible link between parvovirus B19 and thyroid cancer. AB - Human parvovirus B19 (B19) is a small, non-enveloped virus and belongs to Parvoviridae family. B19 persists in many tissues such as thyroid tissue and even thyroid cancer. The main aim of this study was to determine the presence of B19, its association with increased inflammation in thyroid tissue, and thus its possible role in thyroid cancer progression. Studies have shown that virus replication in non-permissive tissue leads to overexpression of non-structural protein and results in upregulation of proinflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha. A total of 36 paraffin-embedded thyroid specimens and serum were collected from patients and 12 samples were used as control. Various methods were employed, including polymerase chain reaction, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay. The results have shown the presence of B19 DNA in 31 of 36 samples (86.11%). Almost in all samples, the levels of non-structural protein 1, nuclear factor kappa B, tumor necrosis factor alpha, and interleukin 6 were simultaneously high. The presence of parvovirus B19 has a significant positive correlation with nuclear factor kappa B, tumor necrosis factor alpha, and interleukin 6 levels. This study suggests that B19 infection may play an important role in tumorigenesis and thyroid cancer development via the inflammatory mechanisms. PMID- 28618937 TI - 37LRP induces invasion in hypoxic lung adenocarcinoma cancer cells A549 through the JNK/ERK/c-Jun signaling cascade. AB - We previously reported that 37-kDa laminin receptor precursor involved in metastasis of lung adenocarcinoma cancer cells. In this study, we further revealed that hypoxia induced 37-kDa laminin receptor precursor expression and activation of extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase in lung adenocarcinoma cancer cells. In addition, we further demonstrated that the c-Jun N-terminal kinase inhibitor SP600125 and extracellular signal-regulated protein kinase inhibitor U0126 blocked the c-Jun activity and abolished hypoxia-induced 37-kDa laminin receptor precursor expression and promoter activity in a concentration-dependent manner. However, the p38 mitogen-activated protein kinase inhibitor did not affect 37-kDa laminin receptor precursor expression and c-Jun activity in response to hypoxia. Furthermore, downregulated c-Jun expression by short interfering RNA could also inhibit hypoxia-induced 37-kDa laminin receptor precursor expression and transcriptional activity. The inhibition of 37-kDa laminin receptor precursor expression by SP600125 and U0126 could be rescued by c Jun overexpression. Studies using luciferase promoter constructs revealed a significant increase in the activity of promoter binding in the cells exposed to hypoxia, which was lost in the cells with mutation of the activator protein 1 binding site. Electrophoresis mobility shift assay and chromatin immunoprecipitation demonstrated a functional activator protein 1 binding site within 37-kDa laminin receptor precursor gene regulatory sequence located at -271 relative to the transcriptional initiation point. Hypoxia-induced invasion of A549 cells was inhibited by the pharmacologic inhibitors of c-Jun N-terminal kinase (SP600125) and extracellular signal-regulated protein kinase (U0126) as well as 37-kDa laminin receptor precursor-specific siRNA or antibody. Our results suggest that hypoxia-elicited c-Jun/activator protein 1 regulates 37-kDa laminin receptor precursor expression, which modulates migration and invasion of lung adenocarcinoma cells. PMID- 28618938 TI - Laboratory validation of formal concept analysis of the methylation status of microarray-detected genes in primary breast cancer. AB - Breast cancer is the leading cause of cancer-related mortality. DNA methylations play important roles in cancer development and progression. Formal concept analysis was previously utilized for data mining hypermethylated and hypomethylated genes in breast cancer molecular subtypes in illumina methylation based microarray database, to laboratory validate their outputs; HS3ST2 (heparan sulfate d-glucosaminyl 3-O-sulfonyl transferase-2) and MUC1 (mucin-1) were retrieved. Both play important roles in progression and invasion of breast cancer. The methylation status of both genes was laboratory validated using methylation-based polymerase chain reaction in breast cancer subtypes luminal A (early stages) and luminal B (late stages) in comparison with benign conditions and normal breast to conclude their roles in tumor invasion and to validate the newly developed algorithm (formal concept analysis). Significant cancer-specific hypermethylation of HS3ST2 was detected in luminal B (chi square = 30.6, p = 0.000), while significant cancer-specific hypomethylation of MUC1 was detected in luminal B (chi square = 30.5, p = 0.001) breast cancer. The median levels of the percentage of methylated allele of both genes were significantly discriminative between luminal A and luminal B subtypes and benign and healthy control groups. Detection of MUC1 and HS3ST2 promoter methylation status appears to be useful molecular markers for assessing the progressive state of the disease and could be helpful in discriminating breast cancer molecular subtypes. These results validate the methylation-based microarray analysis, thus trust their output in the future. PMID- 28618939 TI - Rapamycin enhances the anti-angiogenesis and anti-proliferation ability of YM155 in oral squamous cell carcinoma. AB - YM155, a small molecule inhibitor of survivin, has been studied in many tumors. It has been shown that YM155 inhibited oral squamous cell carcinoma through promoting apoptosis and autophagy and inhibiting proliferation. It was found that YM155 also inhibited the oral squamous cell carcinoma-mediated angiogenesis through the inactivation of the mammalian target of rapamycin pathway. Rapamycin, a mammalian target of rapamycin inhibitor, played an important role in the proliferation and angiogenesis of oral squamous cell carcinoma cell lines. In our study, cell proliferation assay, transwell assay, tube formation assay, and western blot assay were used to investigate the synergistic effect of rapamycin on YM155 in oral squamous cell carcinoma. Either in vitro or in vivo, rapamycin and YM155 exerted a synergistic effect on the inhibition of survivin and vascular endothelial growth factor through mammalian target of rapamycin pathway. Overall, our results revealed that low-dose rapamycin strongly promoted the sensitivity of oral squamous cell carcinoma cell lines to YM155. PMID- 28618940 TI - Association of Wnt1-inducible signaling pathway protein-1 with the proliferation, migration and invasion in gastric cancer cells. AB - Wnt1-inducible signaling pathway protein-1 is a cysteine-rich protein that belongs to the CCN family, which has been implicated in mediating the occurrence and progression through distinct molecular mechanisms in several tumor types. However, the association of Wnt1-inducible signaling pathway protein-1 with gastric cancer and the related molecular mechanisms remain to be elucidated. Therefore, this study aimed to clarify the biological role of Wnt1-inducible signaling pathway protein-1 in the proliferation, migration, and invasion in gastric cancer cells and further investigated the associated molecular mechanism on these biological functions. We first detected the expression level of Wnt1 inducible signaling pathway protein-1 in gastric cancer, and the reverse transcription polymerase chain reaction have shown that Wnt1-inducible signaling pathway protein-1 expression levels were upregulated in gastric cancer tissues. The expression of Wnt1-inducible signaling pathway protein-1 in gastric cancer cell lines was also detected by quantitative real-time polymerase chain reaction and Western blotting. Furthermore, two gastric cancer cell lines with high expression of Wnt1-inducible signaling pathway protein-1 were selected to explore the biological function of Wnt1-inducible signaling pathway protein-1 in gastric cancer. Function assays indicated that knockdown of Wnt1-inducible signaling pathway protein-1 suppressed cell proliferation, migration, and invasion in BGC 823 and AGS gastric cancer cells. Further investigation of mechanisms suggested that cyclinD1 was identified as one of Wnt1-inducible signaling pathway protein-1 related genes to accelerate proliferation in gastric cancer cells. In addition, one pathway of Wnt1-inducible signaling pathway protein-1 induced migration and invasion was mainly through the enhancement of epithelial-to-mesenchymal transition progression. Taken together, our findings presented the first evidence that Wnt1-inducible signaling pathway protein-1 was upregulated in gastric cancer and acted as an oncogene by promoting proliferation, migration, and invasion in gastric cancer cells. PMID- 28618941 TI - Molecular interplay of pro-inflammatory transcription factors and non-coding RNAs in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma is the sixth most common cancer in the developing world. The aggressive nature of esophageal squamous cell carcinoma, its tendency for relapse, and the poor survival prospects of patients diagnosed at advanced stages, represent a pressing need for the development of new therapies for this disease. Chronic inflammation is known to have a causal link to cancer pre-disposition. Nuclear factor kappa B and signal transducer and activator of transcription 3 are transcription factors which regulate immunity and inflammation and are emerging as key regulators of tumor initiation, progression, and metastasis. Although these pro-inflammatory factors in esophageal squamous cell carcinoma have been well-characterized with reference to protein-coding targets, their functional interactions with non-coding RNAs have only recently been gaining attention. Non-coding RNAs, especially microRNAs and long non-coding RNAs demonstrate potential as biomarkers and alternative therapeutic targets. In this review, we summarize the recent literature and concepts on non-coding RNAs that are regulated by/regulate nuclear factor kappa B and signal transducer and activator of transcription 3 in esophageal cancer progression. We also discuss how these recent discoveries can pave way for future therapeutic options to treat esophageal squamous cell carcinoma. PMID- 28618942 TI - Prognostic role of fibroblast growth factor receptor 2 in human solid tumors: A systematic review and meta-analysis. AB - In the past decades, the oncogenic role of fibroblast growth factor receptor 2 has been demonstrated in a number of cancer types. However, studies have reported contradictory findings concerning the correlation between fibroblast growth factor receptor 2 expression and prognosis in solid tumors. To address this discrepancy, we performed a meta-analysis with 18 published studies (2975 patients) retrieved from PubMed, EMBASE, and Web of science. Data were extracted and computed into odds ratios. The results showed that fibroblast growth factor receptor 2 overexpression was significantly associated with decreased 3-year overall survival (odds ratio = 1.93, 95% confidence interval: 1.30-2.85, p = 0.001) and 5-year overall survival (odds ratio = 1.62, 95% confidence interval: 1.07-2.44, p = 0.02) in patients with solid tumors. Subgroup analysis revealed that high fibroblast growth factor receptor 2 expression was also associated with poor prognosis of gastric cancer, hepatocellular carcinoma, and esophageal cancer, but not correlated with pancreatic cancer. In conclusion, fibroblast growth factor receptor 2 overexpression is correlated with decreased survival in most solid tumors, suggesting that the expression status of fibroblast growth factor receptor 2 is a valuable prognostic biomarker and a novel therapeutic target in human solid tumors. PMID- 28618944 TI - Demethoxycurcumin in combination with ultraviolet radiation B induces apoptosis through the mitochondrial pathway and caspase activation in A431 and HaCaT cells. AB - Photodynamic therapy is widely used in the clinical treatment of tumors, especially skin cancers. It has been reported that the photosensitizer curcumin, in combination with ultraviolet radiation B, induces HaCaT cell apoptosis, and this effect may be due to the activation of caspase pathways. In this study, we examined the photodynamic effects of demethoxycurcumin, a more stable analogue of curcumin, to determine whether it could induce apoptosis in skin cancer cells. We investigated the effects of a combination of ultraviolet radiation B and demethoxycurcumin on apoptotic cell death in A431 and HaCaT cells and determined the molecular mechanism of action. Our results showed increased apoptosis with a combination of ultraviolet radiation B with demethoxycurcumin, as compared to ultraviolet radiation B or demethoxycurcumin alone. The combination of ultraviolet radiation B irradiation with demethoxycurcumin synergistically induced apoptotic cell death in A431 and HaCaT cells through activation of p53 and caspase pathways, as well as through upregulation of Bax and p-p65 expression and downregulation of Bcl-2, Mcl-1, and nuclear factor-kappaB expression. In addition, we found that reactive oxygen species significantly increased with treatment, and mitochondrial membrane potential depolarization was remarkably enhanced. In conclusion, our data indicate that demethoxycurcumin may be a promising photosensitizer for use in photodynamic therapy to induce apoptosis in skin cancer cells. PMID- 28618943 TI - Long non-coding RNA DANCR, a prognostic indicator, promotes cell growth and tumorigenicity in gastric cancer. AB - Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and proliferation of gastric cancer represents the major reason for its poor prognosis. Recent evidence indicates that long non-coding RNAs play crucial roles in development and progression of gastric cancer. Long non-coding RNA differentiation antagonizing non-protein coding RNA is upregulated in hepatic cell carcinoma, but the role of lncRNA differentiation antagonizing non-protein coding RNA in gastric cancer has not been explored. In this article, we found that differentiation antagonizing non-protein coding RNA is also upregulated in gastric cancer. Experiments revealed that silencing differentiation antagonizing non-protein coding RNA significantly inhibited gastric cancer cell proliferation in vitro and in vivo. Overexpression of differentiation antagonizing non-protein coding RNA notably increases gastric cancer cell proliferation. From RNA-seq and gene ontology annotations, we found that differentiation antagonizing non-protein coding RNA influences the gene expression programs in cell metabolic and cycle process. Taken together, our findings suggest that the long non-coding RNA differentiation antagonizing non-protein coding RNA promotes the proliferation of gastric cancer and is a potential prognostic biomarker and therapeutic target in gastric cancer. PMID- 28618945 TI - The expression profiling of serum miR-92a, miR-375, and miR-760 in colorectal cancer: An Egyptian study. AB - Dysregulation in microRNA expression is a common feature in colorectal cancer. Due to the inconsistent results regarding serum miR-92a expression pattern and the insufficient studies on serum miR-375 and miR-760, we aimed in this study to investigate their expression profile and diagnostic and prognostic power in Egyptian colorectal cancer patients. The expression profile of miR-92a, miR-375, and miR-760 was determined in the sera of 64 colorectal cancer patients using quantitative real-time reverse transcription polymerase chain reaction in comparison to 27 healthy control subjects. The expression fold change of the studied microRNAs was correlated with patients' clinicopathological features. Receiver operating characteristic curve analysis was done to determine the role of these microRNAs in colorectal cancer diagnosis and follow-up according to the yielded area under the curve. The expression pattern of miR-92a was significantly upregulated (3.38 +/- 2.52, p < 0.0001), while both of miR-375 and 760 were significantly downregulated (-1.250 +/- 1.80, p< 0.0001; -1.710 +/- 1.88, p < 0.0001, respectively) in colorectal cancer than the control. MiR-92a was positively correlated ( r = 0.671, p = 0.0001), while miR-375 and miR-760 were inversely correlated ( r = -0.414, p = 0.001; r = -0.644, p = 0.0001) with advanced colorectal cancer stages. Receiver operating characteristic curve analysis disclosed the highest diagnostic potential for miR-760 to discriminate colorectal cancer patients and early-stage colorectal cancer from the control (area under the curve = 0.922 and 0.875, respectively), while the highest prognostic potential for discrimination between colorectal cancer stages was for miR-92a. In conclusion, serum level of miR-92a, miR-375, and miR-760 may serve as biomarkers of colorectal cancer in Egyptian patients with high diagnostic power for miR-760 and high prognostic power for miR-92a. PMID- 28618946 TI - A comparative proteomic analysis of bile for biomarkers of cholangiocarcinoma. AB - Cholangiocarcinoma is a primary malignant tumor of the bile duct epithelium. Cholangiocarcinoma is usually detected at an advanced stage when successful treatment is no longer possible. As the tumor originates from the bile duct epithelium, bile is an ideal source of tumor biomarkers for cholangiocarcinoma. In this study, we used a quantitative proteomics approach to identify potential tumor-associated proteins in the bile fluid of six cholangiocarcinoma patients. Three different gross-appearance tumor types were used in the analysis: mass forming type ( n = 2), periductal infiltrating type ( n = 2), and intraductal growth type ( n = 2). Two bile samples from non-cancerous patients were used as controls. Isobaric labeling, coupled with Tandem mass spectrometry, was used to quantify protein levels in the bile of cholangiocarcinoma and control patients. In all, 63 proteins were significantly increased in cholangiocarcinoma bile compared to normal bile. Alpha-1-antitrypsin was one of the overexpressed proteins that increased in cholangiocarcinoma bile samples. Immunohistochemical analysis revealed that alpha-1-antitrypsin was detected in 177 (50%) of 354 cholangiocarcinoma tissues from our Tissue Bank. Immunoblotting of 54 cholangiocarcinoma bile samples showed that alpha-1-antitrypsin was positive in 38 (70%) samples. Fecal enzyme-linked immunosorbent assay showed that alpha-1 antitrypsin level was able to distinguish cholangiocarcinoma patients from normal individuals. In conclusion, alpha-1-antitrypsin is a potential marker for early diagnosis of cholangiocarcinoma. PMID- 28618947 TI - Treatment outcome comparisons between exons 19 and 21 EGFR mutations for non small-cell lung cancer patients with malignant pleural effusion after first-line and second-line tyrosine kinase inhibitors. AB - Recent studies demonstrated a significantly increased frequency of epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC) patients with malignant pleural effusions (MPEs). The purpose of this study is to investigate the effect of first-line and second-line EGFR-tyrosine kinase inhibitors (TKIs) in the treatment of NSCLC with MPEs harboring exon 19 deletion and L858R mutation. From 2010 to 2015, 203 NSCLC patients with MPEs harboring EGFR mutation treated with EGFR-TKIs were reviewed. The efficacy were evaluated with Pearson chi-square or Fisher's exact tests, Log-rank test and Cox proportional hazards model. The objective response rate (ORR) and disease control rate (DCR) for patients treated with first-line and second-line EGFR-TKIs were 21.9%, 91.4% and 14.7%, 85.3%, respectively. The overall median PFS and OS of enrolled NSCLC patients with MPE were 9.3 months (95% CI, 8.4-10.2 months), 20.9 months (95% CI, 18.9-22.9 months) after first-line TKIs, and 7.6 months (95% CI, 6.6-8.6 months), 15.3 months (95% CI, 13.6-15.9 months) after second-line TKIs. The exon 19 deletion arm had a longer median PFS (9.4 vs 7.1 months, p=0.003) and OS (16.8 vs 13.8 months, p=0.003) compared with the L858R mutation arm after second-line TKIs. In a conclusion, EGFR genotype was an independent predictor of PFS and OS. No significant side effects differences between the two mutation groups was observed for first or second-line EGFR-TKIs. This study demonstrated that EGFR mutations are significant predictors for advanced NSCLC patients with MPE receiving second-line EGFR-TKIs treatment. PMID- 28618948 TI - Tissue-specific significance of BAP1 gene mutation in prognostic prediction and molecular taxonomy among different types of cancer. AB - BAP1 is an emerging tumor suppressor whose inactivating mutations have been found to play critical roles in tumor development. This study was conducted to elucidate the potential value of BAP1 mutation in guiding prognostic prediction and clinical stratification. We conducted a comprehensive analysis of relevant studies from multiple databases, to determine the impact of BAP1 mutation on the overall survival and disease-free survival of patients in various cancers. A total of 2457 patients from 21 studies were included in the final analysis. Although the pooled results demonstrated that BAP1 mutation was a negative indicator of overall survival (hazard ratio = 1.73; 95% confidence interval = 1.23-2.42) and disease-free survival (hazard ratio = 2.25; 95% confidence interval = 1.47-3.45), this prognostic value was only applicable to uveal melanoma and clear cell renal cell carcinoma, but not to malignant pleural mesothelioma or cholangiocarcinoma. Consistently, BAP1 mutation was correlated with critical clinicopathological features only in uveal melanoma and clear cell renal cell carcinoma. In uveal melanoma, BAP1 mutation and SF3B1/EIF1AX mutations were negatively correlated, and BAP1-mutant tumors indicated significant worse prognosis than SF3B1/EIF1AX-mutant tumors ( p = 0.028). While in clear cell renal cell carcinoma, BAP1 mutation was mutually exclusive with PBRM1 mutations, and BAP1-mutant clear cell renal cell carcinomas also showed significantly worse prognosis than PBRM1-mutant clear cell renal cell carcinomas ( p = 0.001). Our study revealed a unique tissue-specific significance of BAP1 mutation in prognostic prediction among different types of cancer. Clinically, combining detection of BAP1 mutation and other driver mutations may further allow for a more precise molecular taxonomy to stratify patients into distinct subgroups in uveal melanoma and clear cell renal cell carcinoma. PMID- 28618949 TI - IQ-domain GTPase-activating protein 1 promotes the malignant phenotype of invasive ductal breast carcinoma via canonical Wnt pathway. AB - IQ-domain GTPase-activating protein 1 is a scaffolding protein with multidomain which plays a role in modulating dishevelled (Dvl) nuclear translocation in canonical Wnt pathway. However, the biological function and mechanism of IQ domain GTPase-activating protein 1 in invasive ductal carcinoma (IDC) remain unknown. In this study, we found that IQ-domain GTPase-activating protein 1 expression was elevated in invasive ductal carcinoma, which was positively correlated with tumor grade, lymphatic metastasis, and poor prognosis. Coexpression of IQ-domain GTPase-activating protein 1 and Dvl in the nucleus and cytoplasm of invasive ductal carcinoma was significantly correlated but not in the membrane. Postoperative survival in the patients with their coexpression in the nucleus and cytoplasm was obviously lower than that without coexpression. The positive expression rates of c-myc and cyclin D1 were significantly higher in the patients with nuclear coexpression of Dvl and IQ-domain GTPase-activating protein 1 than that with cytoplasmic coexpression, correlating with poor prognosis. IQ domain GTPase-activating protein 1 significantly enhanced cell proliferation and invasion in invasive ductal carcinoma cell lines by interacting with Dvl in cytoplasm to promote Dvl nuclear translocation so as to upregulate the expression of c-myc and cyclin D1. Collectively, our data suggest that IQ-domain GTPase activating protein 1 may promote the malignant phenotype of invasive ductal carcinoma via canonical Wnt signaling, and it could be used as a potential prognostic biomarker for breast cancer patients. PMID- 28618950 TI - MiR-1-3p inhibits the proliferation and invasion of bladder cancer cells by suppressing CCL2 expression. AB - We attempted to analyze the effects of miR-1-3p and CCL2 on the proliferation, migration, and invasion of bladder cancer cells. A total of 18 pairs of bladder cancer tissues with corresponding adjacent tissues and the 6 cases of normal tissues were collected. The expressions of miR-1-3p and CCL2 in the cancer tissues were evaluated using quantitative real-time polymerase chain reaction and western blot. The relationship between miR-1-3p and CCL2 was assessed using luciferase reporter assay. The UM-UC-3 bladder cancer cells were transfected with CCL2 small interfering RNA and miR-1-3p mimics. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, colony formation assay, wound healing assay, Transwell assay, and the flow cytometry test were used to detect the proliferation, migration, invasion, and apoptosis of bladder cancer cells. Bladder cancer tissues had lower levels of miR-1-3p but higher levels of CCL2 than normal tissues ( p < 0.05). The transfection of miR-1-3p mimics and CCL2 small interfering RNA remarkably suppressed cell proliferation and invasion and promoted apoptosis of cells ( p < 0.05). Results of the luciferase reporter gene assay demonstrated that miR-1-3p targeted CCL2. MiR-1-3p suppresses the proliferation and invasion of urinary bladder cancer cells by targeting CCL2. PMID- 28618951 TI - Biological evaluation of octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives as potent anticancer agents. AB - In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways. PMID- 28618952 TI - MicroRNA-105 inhibits human glioma cell malignancy by directly targeting SUZ12. AB - Glioma accounts for the majority of primary malignant brain tumors in adults and is highly aggressive. Although various therapeutic approaches have been applied, outcomes of glioma treatment remain poor. MicroRNAs are a class of small noncoding RNAs that function as regulators of gene expression. Accumulating evidence shows that microRNAs are associated with tumorigenesis and tumor progression. In this study, we found that miR-105 is significantly downregulated in glioma tissues and glioma cell lines. We identified suppressor of Zeste 12 homolog as a novel direct target of miR-105 and showed that suppressor of Zeste 12 homolog protein levels were inversely correlated with the levels of miR-105 expression in clinical specimens. Overexpression of miR-105 inhibited cell proliferation, tumorigenesis, migration, invasion, and drug sensitivity, whereas overexpression of suppressor of Zeste 12 homolog antagonized the tumor suppressive functions of miR-105. Taken together, our results indicate that miR 105 plays a significant role in tumor behavior and malignant progression, which may provide a novel therapeutic strategy for the treatment of glioma and other cancers. PMID- 28618953 TI - Overexpression of microRNA-194 suppresses the epithelial-mesenchymal transition in targeting stem cell transcription factor Sox3 in endometrial carcinoma stem cells. AB - The epithelial-mesenchymal transition is the key process driving cancer metastasis. MicroRNA-194 inhibits epithelial-mesenchymal transition in several cancers and its downregulation indicates a poor prognosis in human endometrial carcinoma. Self-renewal factor Sox3 induces epithelial-mesenchymal transition at gastrulation and is also involved epithelial-mesenchymal transition in several cancers. We intended to determine the roles of Sox3 in inducing epithelial mesenchymal transition in endometrial cancer stem cells and the possible role of microRNA-194 in controlling Sox3 expression. Firstly, we found that Sox3 and microRNA-194 expressions were associated with the status of endometrial cancer stem cells in a panel of endometrial carcinoma tissue, the CD133+ cell was higher in tumorsphere than in differentiated cells, and overexpression of microRNA-194 would decrease CD133+ cell expression. Silencing of Sox3 in endometrial cancer stem cell upregulated the epithelial marker E-cadherin, downregulated the mesenchymal marker vimentin, and significantly reduced cell invasion in vitro; overexpression of Sox3 reversed these phenotypes. Furthermore, we discovered that the expression of Sox3 was suppressed by microRNA-194 through direct binding to the Sox3 3'-untranslated region. Ectopic expression of microRNA-194 in endometrial cancer stem cells induced a mesenchymal-epithelial transition by restoring E-cadherin expression, decreasing vimentin expression, and inhibiting cell invasion in vitro. Moreover, overexpression of microRNA-194 inhibited endometrial cancer stem cell invasion or metastasis in vivo by injection of adenovirus microRNA-194. These findings demonstrate the novel mechanism by which Sox3 contributes to endometrial cancer stem cell invasion and suggest that repression of Sox3 by microRNA-194 may have therapeutic potential to suppress endometrial carcinoma metastasis. The cancer stem cell marker, CD133, might be the surface marker of endometrial cancer stem cell. PMID- 28618954 TI - Prognostic value of pretreatment inflammatory biomarkers in advanced lung adenocarcinoma patients receiving first-line pemetrexed/platinum doublet. AB - Inflammation is a new hallmark feature of cancer initiation and progression. We aimed to investigate the association between inflammatory response biomarkers and progression-free survival and overall survival in advanced lung adenocarcinoma patients treated with first-line pemetrexed and platinum doublet chemotherapy. Patients hospitalized between April 2012 and March 2015 were enrolled and eliminated according to the inclusion and exclusion criteria. The pretreatment neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, derived neutrophil to-lymphocyte ratio, and platelet-to-lymphocyte ratio were calculated. Besides the well-established clinical prognostic factors, the prognostic values of the four markers were evaluated by the Kaplan-Meier method and Cox's proportional hazards regression model. A total of 78 patients were enrolled in this study. Elevated neutrophil-to-lymphocyte ratio and derived neutrophil-to-lymphocyte ratio were correlated with poor treatment response ( p = 0.014, 0.012, respectively). A high pretreatment neutrophil-to-lymphocyte ratio, derived neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio, as well as low lymphocyte-to-monocyte ratio, were associated with worse progression-free survival and overall survival. Multivariate analysis revealed that high neutrophil-to-lymphocyte ratio (hazard ratio = 2.056; 95% confidence interval, 1.281-3.299; p = 0.003) and >=3 metastasis organs (hazard ratio = 1.989; 95% confidence interval, 1.069-3.702; p = 0.030) were independent prognostic factors for progression-free survival. Meanwhile, high neutrophil-to-lymphocyte ratio (hazard ratio = 5.540; 95% confidence interval, 2.974-10.321; p < 0.001) and habitual smoking (hazard ratio = 2.806; 95% confidence interval, 1.509-5.221; p = 0.001) were independent prognostic factors for overall survival. In conclusion, Pretreatment neutrophil-to-lymphocyte ratio was an independent prognostic factor for advanced lung adenocarcinoma patients treated with first-line pemetrexed/platinum doublet chemotherapy. Elevated pretreatment derived neutrophil-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio might be potential biomarkers for poorer responses to chemotherapy. To verify these findings, larger well-designed prospective studies are needed. PMID- 28618955 TI - Oridonin synergizes with Nutlin-3 in osteosarcoma cells by modulating the levels of multiple Bcl-2 family proteins. AB - The small-molecule inhibitors of p53-murine double minute 2 interaction, such as Nutlin-3, are effective against cancers bearing wild-type p53. However, murine double minute 2 inhibitors often are unable to completely eliminate solid tumor cells. To address this issue, we investigated the anticancer effects of Nutlin-3 in combination with Oridonin in osteosarcoma cells. We found that Oridonin at sub toxic concentrations synergistically enhanced Nutlin-3-mediated cell viability inhibition in wild-type p53 U2OS and SJSA-1, but not in p53-mutant MNNG/HOS and in null-p53 Saos-2 osteosarcoma cell lines. Importantly, in the presence of Oridonin, Nutlin-3 could completely abolish cell viability in the wild-type p53 osteosarcoma cell lines. Western blotting analysis showed that Oridonin treatment rapidly and distinctly increased the levels of all three forms of Bim and also markedly reduced the levels of Bcl-2 and Bcl-xl in osteosarcoma cells. Western blotting analysis further showed that Oridonin considerably enhanced Nutlin-3 triggered activation of caspases-9 and -3 and poly(ADP-ribose) polymerase cleavage. Flow cytometry assay showed that Oridonin significantly enhanced Nutlin 3-mediated apoptosis in wild-type p53 osteosarcoma cells. Overall, our results suggest that the combined treatment of Nutlin-3 plus Oridonin may offer a novel therapeutic strategy for osteosarcoma. PMID- 28618956 TI - Acid-sensing ion channels contribute to the effect of extracellular acidosis on proliferation and migration of A549 cells. AB - Acid-sensing ion channels, a proton-gated cation channel, can be activated by low extracellular pH and involved in pathogenesis of some tumors such as glioma and breast cancer. However, the role of acid-sensing ion channels in the growth of lung cancer cell is unclear. In this study, we investigated the expression of acid-sensing ion channels in human lung cancer cell line A549 and their possible role in proliferation and migration of A549 cells. The results show that acid sensing ion channel 1, acid-sensing ion channel 2, and acid-sensing ion channel 3 are expressed in A549 cells at the messenger RNA and protein levels, and acid sensing ion channel-like currents were elicited by extracellular acid stimuli. Moreover, we found that acidic extracellular medium or overexpressing acid sensing ion channel 1a promotes proliferation and migration of A549 cells. In addition psalmotoxin 1, a specific acid-sensing ion channel 1a inhibitor, or acid sensing ion channel 1a knockdown can abolish the effect of acid stimuli on A549 cells. In addition, acid-sensing ion channels mediate increase of [Ca2+]i induced by low extracellular pH in A549 cells. All these results indicate that acid sensing ion channel-calcium signal mediate lung cancer cell proliferation and migration induced by extracellular acidosis, and acid-sensing ion channels may serve as a prognostic marker and a therapeutic target for lung cancer. PMID- 28618957 TI - Addition of peritonectomy to gastrectomy can predict good prognosis of gastric adenocarcinoma patients with intraoperatively proven single P1/P2 carcinomatosis. AB - This study was to evaluate the prognosis of peritonectomy following gastrectomy for gastric adenocarcinoma patients with intraoperatively proven single P1/P2 carcinomatosis and to define the best therapeutic strategy of the patient cohort. The patients with intraoperatively proven single P1/P2 carcinomatosis from a prospectively maintained database were divided into resection group and non resection group based on complete gross resection of peritoneal carcinomatosis. From 2005 to 2012, there were 103 patients in the resection group and 122 patients in the non-resection group. There was no difference in morbidity and mortality between groups. The patients did not have improved median survival in P1 carcinomatosis compared to P2 carcinomatosis (15.53 vs 14.80 months, p = 0.450). The median survival was significantly improved in the resection group compared to the patients in the non-resection group (21.07 vs 13.37 months, p < 0.001). The patients undergoing complete gross peritonectomy plus postoperative chemotherapy had a significantly longer median survival than patients who had complete gross peritonectomy alone, patients receiving postoperative chemotherapy alone, and patients receiving neither peritonectomy nor postoperative chemotherapy (27.33 vs 12.00 vs 16.00 vs 10.33 months, p < 0.001). In the multivariate analysis, poor performance status ( p = 0.036), absence of complete gross peritonectomy ( p < 0.001), and lack of postoperative chemotherapy ( p < 0.001) were identified as independently associated with poor survival. The data indicate complete gross peritonectomy following gastrectomy confers a survival benefit to gastric cancer patients with intraoperatively proven single P1/P2 carcinomatosis. In addition, postoperative chemotherapy improves survival regardless of resection of peritoneal carcinomatosis and should be recommended. PMID- 28618958 TI - Current and future biomarkers for pancreatic adenocarcinoma. AB - Although pancreatic cancer is only the twelfth most common type of cancer in the world, it features a very unfavorable prognosis. The mortality rate almost equals the incidence rate, corroborating the very poor prognosis of pancreatic cancer. The 5-year survival rate for all stages of pancreatic ductal adenocarcinoma is only 7%. Surgical resection represents the only potentially curative treatment option for pancreatic ductal adenocarcinoma patients but is often not feasible due to the advanced stage of the disease upon diagnosis. For advanced disease, palliative chemotherapy is the treatment of choice although the regimens available to date are untargeted and have extensive side-effect profiles, making them unsuitable for patients with a low performance status. For this reason, early detection of pancreatic cancer is essential in order to provide patients with an optimal therapeutic approach. Up to the present day, carbohydrate antigen 19-9 is the only diagnostic marker approved by the U.S. Food and Drug Administration but its diagnostic potential is limited due to its restricted sensitivity and specificity, supporting the urgent need for novel biomarkers. In addition, prognostic and treatment-predictive biomarkers might provide essential information regarding personalized treatment decisions for individual patients. In this article, we aim to review current and future diagnostic, prognostic, and treatment-predictive biomarkers for pancreatic cancer. PMID- 28618959 TI - Achaete-scute complex homologue-1 promotes development of laryngocarcinoma via facilitating the epithelial-mesenchymal transformation. AB - Laryngeal cancer is one of the most common fatal cancers among head and neck carcinomas, whose mechanism, however, remains unclear. The proneural basic-helix loop-helix protein achaete-scute complex homologue-1, a member of the basic helix loop-helix family, plays a very important role in many cancers. This study aims to explore the clinical value and mechanism of achaete-scute complex homologue-1 in laryngeal cancer. Methods including Cell Counting Kit-8, flow cytometry, Transwell invasion assays, and scratch assay were adopted to further explore the bio-function of achaete-scute complex homologue-1, whose expression was examined in fresh and paraffin chip of laryngeal carcinoma tissues by means of western blot and immunohistochemistry, after the interference of achaete-scute complex homologue-1; achaete-scute complex homologue-1, an overexpression in laryngeal carcinoma whose carcinogenicity potential was confirmed via western blot, was correlative with T classification (p = 0.002), histological differentiation (p = 0.000), lymph node metastasis (p = 0.000), and poor survival (p = 0.000). Multivariate analysis shows that achaete-scute complex homologue-1 overexpression is an independent prognostic factor unfavorable to laryngeal carcinoma patients (p = 0.000). Moreover, knocking down achaete-scute complex homologue-1 expression could significantly suppress the proliferation, migration, and invasion of laryngeal carcinoma cell in vitro and disorder epithelial-mesenchymal transformation-associated protein expression. Achaete-scute complex homologue-1 plays an important role in the genesis and progression of laryngeal carcinoma and may act as a potential biomarker for therapeutic target and prognostic prediction. PMID- 28618960 TI - Role of patient-, tumor- and systemic inflammatory response-related factors in predicting survival of patients with node-negative gastric cancer. AB - It is currently unclear as to which patients with node-negative gastric cancer can benefit from adjuvant chemotherapy. This study aimed to develop a prognostic model based on patient-, tumor-, and host-related factors to stratify high-risk patients eligible for adjuvant therapy. Correlations of clinicopathological and hematological features with overall survival were analyzed using a Cox model. A score to identify risk classes was derived from hazard ratios in multivariate analysis. In all, 436 patients with node-negative gastric cancer (stage pT1 4aN0M0) were analyzed in this study. Multivariate analysis showed that age, depth of invasion, and neutrophil-lymphocyte ratio were independent prognostic indicators of overall survival, and a prognostic model was developed using these significant factors. Patients were stratified into three risk groups with significant differences in the 3-year survival rates (98.5%, 91.6%, and 70.7%, respectively; p < 0.001) according to their scores. The prognostic model improved the predictive accuracy of postoperative 3-year survival rate by 7% when compared with the pathological T stage. A model based on age, depth of invasion, and neutrophil-lymphocyte ratio is more effective than traditional staging systems in predicting the prognosis of node-negative gastric cancer. High-risk patients could be considered for adjuvant therapy. PMID- 28618961 TI - MicroRNA-208b inhibits human osteosarcoma progression by targeting ROR2. AB - MicroRNAs are widely involved in cancer progression by inhibiting the expression levels of oncogenes or tumor suppressor genes, and dysregulation of microRNAs may contribute to tumorigenesis. Here, we found that overexpressed miR-208b can reduce the proliferation of human osteosarcoma cell lines U-2OS and Saos-2 by arresting cell cycle progression. The in vivo xenograft tumors induced by Saos-2 cells overexpressing miR-208b had smaller size and grew more slowly than those induced by the control cells. The mobility of U-2OS or Saos-2 cells was also downregulated by miR-208b. MiR-208b targeted a site in the 3' untranslated region of receptor tyrosine kinase-like orphan receptor 2. Inhibition of receptor tyrosine kinase-like orphan receptor 2 suppresses osteosarcoma metastasis in vitro. Recovering the expression levels of receptor tyrosine kinase-like orphan receptor 2 in miR-208b-overexpressed U-2OS or Saos-2 cells attenuated the inhibitory effects of miR-208b. In addition, the expression levels of miR-208b are significantly reduced in human osteosarcoma tissue samples compared to normal tissue samples, and miR-208b levels correlated inversely with receptor tyrosine kinase-like orphan receptor 2 levels. On these bases, we identified that miR-208b targets receptor tyrosine kinase-like orphan receptor 2 gene by which miR-208b can regulate the development of osteosarcoma. PMID- 28618962 TI - Amelioration of Dalton's lymphoma-induced angiogenesis by melatonin. AB - For tumor to grow beyond 1-2 mm3 size, tumor recruits new blood vessels referred as angiogenesis; therefore, targeting angiogenesis can be a promising strategy to suppress cancer progression. In this study, in order to develop a good angiogenesis model, we investigated effect of Dalton's lymphoma on angiogenesis and further monitored the role of melatonin on regulation of angiogenesis. To evaluate angiogenesis, endothelial cells were isolated from main thoracic aorta and cultured in vitro in the presence or absence of Dalton's lymphoma supplemented with or without melatonin to monitor their role on its proliferation and migration, a hallmark of angiogenesis. Chick chorioallantoic membrane as well as mice mesentery which allows in vivo studies of tumor angiogenesis and testing of anti-angiogenic molecules was used to validate the in vitro analysis. To further extend our understanding about the regulation of the angiogenesis, we evaluated expression of tissue inhibitor of metalloproteinases 3, vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor in Dalton's lymphoma cells and mesentery by semiquantitative and quantitative reverse transcription polymerase chain reaction analysis. Dalton's lymphoma ascites induced significant increase in endothelial cell proliferation, migration, and sprouting of the tertiary branching in chorioallantoic membrane and mesentery of Dalton's lymphoma-bearing mice, whereas melatonin treatment led to their inhibition in a dose-dependent manner. Semiquantitative and quantitative reverse transcription polymerase chain reaction analysis of melatonin-treated Dalton's lymphoma cells and mesentery tissue clearly demonstrated restoration of angiogenesis-related genes tissue inhibitor of metalloproteinases 3 and reduction of vascular endothelial growth factor, vascular endothelial growth factor receptor, and fibroblast growth factor messenger RNA expression. Taken together, our results strongly demonstrate that Dalton's lymphoma provides pro-angiogenic environment leading to significant increase in angiogenesis, and further melatonin treatment reduced the Dalton's lymphoma ascites-induced angiogenesis implying that Dalton's lymphoma can serve as a very good model to study angiogenesis as well as for screening of drugs that can target angiogenesis. PMID- 28618964 TI - Role of antibodies to human papillomavirus 16 in prostate cancer: A seroscreening by peptide microarray. AB - Evidence is accumulating in estimating the potential role of human papillomavirus infection in prostate carcinogenesis. However, the results remain inconclusive. We measured the serostatus of antibodies to one of the high-risk human papillomaviruses, human papillomavirus 16, with a newly developed peptide microarray. Serum samples were collected from 75 untreated prostate cancer patients, along with 80 control subjects. We identified 12 peptides with significant differences in prostate cancer samples from all 241 peptides derived from human papillomavirus 16. Our results showed human papillomavirus 16 infection in 64.0% of prostate cancer serum samples, which is significantly different compared with the controls ( p < 0.01) because only 17.5% of the control serum was considered seropositive. The area under the receiver operator characteristic curve was 0.793 (95% confidence interval 0.721-0.864), indicating that the new microarray technique may have diagnostic value. The results showed an association between serological evidence for human papillomavirus 16 infection and risk of prostate cancer. The different serostatus of antibodies in the two subgroups indicated that human papillomavirus 16 infection might occur and play a potential role of progression in a minority of prostate cancer. PMID- 28618963 TI - Noxin promotes proliferation of breast cancer cells via P38-ATF2 signaling pathway. AB - Noxin (also called chromosome 11 open reading frame 82 or DNA damage-induced apoptosis suppressor) is associated with anti-apoptosis and cell proliferation in response to stress signals. However, to our knowledge, the role of Noxin in regulating cell proliferation is still controversial and there are no reports of the function and clinicopathological association in breast cancer. In this study, immunohistochemistry results showed that Noxin expression was significantly correlated with advanced tumor-node-metastasis stage ( p = 0.027), positive regional lymph node metastasis ( p = 0.002), and poor overall survival ( p = 0.002). Proliferation assay results showed that Noxin obviously promoted the ability of proliferation of normal breast cells. Subsequent western blot results revealed that Cyclin D1 and Cyclin E1 were upregulated by overexpressing Noxin, whereas Cyclin D1 and Cyclin E1 were downregulated after depleting Noxin. The levels of phosphorylated P38 and activating transcription factor 2 were obviously increased after overexpressing Noxin, and their expression was downregulated accordingly by transfecting Noxin-small interfering RNA. Moreover, P38 inhibitor counteracted the elevating expression of phosphorylated activating transcription factor 2, Cyclin D1, and Cyclin E1 induced by Noxin overexpression and thereby reversed the effect of Noxin overexpression on facilitating cell growth. Taken together, our studies indicated that Noxin was overexpressed in breast cancer and its positive expression was significantly correlated with advance tumor-node metastasis stage, positive lymph node metastasis, and poor prognosis. Noxin facilitated the expression of Cyclin D1 and Cyclin E1 through activating P38 activating transcription factor 2 signaling pathway, thus enhanced cell growth of breast cancer. PMID- 28618965 TI - Time-dependent effects of prognostic biomarkers of systemic inflammation in patients with metastatic renal cell carcinoma. AB - The goal of this study was to examine time-dependent effects of prognostic biomarkers of systemic inflammation in patients with metastatic renal cell carcinoma. Retrospective chart reviews were conducted at the Winship Cancer Institute of Emory University and the Atlanta Veterans Administration Medical Center with authorization from the Emory University Institutional Review Board and the Veterans Administration Research and Development Committee. Inclusion criteria included age ?18 years, treatment with targeted therapy for clear cell or non-clear cell metastatic renal cell carcinoma and concomitant assessment of C reactive protein and albumin levels on ?3 occasions that were ?10 days apart. Discovery, expansion, and external validation cohorts were identified. Established prognostic variables were evaluated by univariate and multivariate analyses. Intensity of systemic inflammation was assessed at all time points with C-reactive protein and albumin as prognostic covariates for overall survival in an extended Cox regression model. Intensity of systemic inflammation was assessed on 3186 occasions in 181 patients. Risk status changed in 131 patients (72%). The hazard ratio for overall survival was 21.41 (95% confidence interval = 8.26 55.50) with a type 3 p value of <0.001 for the reference cohort and 9.68 (2.07 45.31) with a type-3 p value of 0.006 for the external validation cohort when time points associated with severe systemic inflammation were compared to all other time points. The bias-corrected c-statistic was 0.839 (0.773-0.905) and 0.818 (0.691-0.946), respectively. Terminal disease progression with severe systemic inflammation was detected in 87% of the 90 patients who died. In conclusion, time-dependent effects are a prominent feature of intensity of systemic inflammation, a powerful prognostic biomarker for metastatic renal cell carcinoma. PMID- 28618966 TI - 68Ga/177Lu-labeled DOTA-TATE shows similar imaging and biodistribution in neuroendocrine tumor model. AB - Somatostatin receptors are overexpressed in neuroendocrine tumors, whose endogenous ligands are somatostatin. DOTA-TATE is an analogue of somatostatin, which shows high binding affinity to somatostatin receptors. We aim to evaluate the 68Ga/177Lu-labeling DOTA-TATE kit in neuroendocrine tumor model for molecular imaging and to try human-positron emission tomography/computed tomography imaging of 68Ga-DOTA-TATE in neuroendocrine tumor patients. DOTA-TATE kits were formulated and radiolabeled with 68Ga/177Lu for 68Ga/177Lu-DOTA-TATE (M-DOTA TATE). In vitro and in vivo stability of 177Lu-DOTA-TATE were performed. Nude mice bearing human tumors were injected with 68Ga-DOTA-TATE or 177Lu-DOTA-TATE for micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging separately, and clinical positron emission tomography/computed tomography images of 68Ga-DOTA-TATE were obtained at 1 h post intravenous injection from patients with neuroendocrine tumors. Micro-positron emission tomography and micro-single-photon emission computed tomography/computed tomography imaging of 68Ga-DOTA-TATE and 177Lu-DOTA-TATE both showed clear tumor uptake which could be blocked by excess DOTA-TATE. In addition, 68Ga-DOTA-TATE positron emission tomography/computed tomography imaging in neuroendocrine tumor patients could show primary and metastatic lesions. 68Ga-DOTA-TATE and 177Lu-DOTA TATE could accumulate in tumors in animal models, paving the way for better clinical peptide receptor radionuclide therapy for neuroendocrine tumor patients in Asian population. PMID- 28618967 TI - Association of lysosomal protein transmembrane 4 beta gene polymorphism with pancreatic carcinoma susceptibility in the Chinese population. AB - Pancreatic carcinoma is an aggressive malignancy with particularly low 5-year survival rate. In order to improve the dismal survival rate, identification of new potential susceptibility risk factors for the prevention and early detection of pancreatic carcinoma is of utmost importance. Lysosomal protein transmembrane 4 beta has two alleles designated as LAPTM4B*1 and LAPTM4B*2. The aim of this study was to investigate the association between lysosomal protein transmembrane 4 beta gene polymorphism and the risk of pancreatic carcinoma in China. A population-based case-control analysis was performed in 233 patients with pancreatic carcinoma and 842 control subjects. The genotypes of lysosomal protein transmembrane 4 beta were determined by utilizing polymerase chain reaction based on specific primers. The chi2 test was used to analyze the differences of categorical variables and Hardy-Weinberg equilibrium. Odds ratio and 95% confidence intervals were computed using an unconditional logistic regression model. A significant difference in the frequency of LAPTM4B*2 was observed between the patients and the controls (33.05% vs 27.55%, p = 0.03). LAPTM4B*2 had a 1.33-fold (95% confidence interval: 1.04-1.71) higher risk for developing pancreatic carcinoma when compared with LAPTM4B*1 carriers. We found that the frequency of LAPTM4B*1/2 + *2/2 in pancreatic carcinoma group was higher than that in the control group (57.94% vs 48.34%, p = 0.01). However, no significant association was observed between lysosomal protein transmembrane 4 beta genotypes and gender, age, family history of cancer, smoking/alcohol status, histopathological differentiation, lymph node metastasis, clinical stage, or serum cancer antigen 19-9 level. These findings indicate that the LAPTM4B*2 allele is associated with the high risk of pancreatic carcinoma and carrying LAPTM4B*2 may be a susceptible factor to Chinese pancreatic carcinoma patients. PMID- 28618968 TI - miR-221 and miR-222 synergistically regulate hepatocyte growth factor activator inhibitor type 1 to promote cell proliferation and migration in gastric cancer. AB - Gastric cancer is a common malignancy with limited treatment options and poor prognosis. Introduction of novel pathways of gastric cancer will provide candidates for target therapy. Hepatocyte growth factor activator inhibitor type 1 is an integral-membrane proteinase inhibitor. Hepatocyte growth factor activator inhibitor type 1 abnormality is found in various cancers and correlates with tumor progression and metastasis. However, the mechanisms underlying the dysregulation of hepatocyte growth factor activator inhibitor type 1 expression in gastric cancer remain unclear. Although microRNAs have been reported to be involved in the development of cancer, the roles of miR-221 and miR-222 in gastric cancer have not been reported yet. In this study, we showed that hepatocyte growth factor activator inhibitor type 1 protein was downregulated, while miR-221 and miR-222 were significantly increased in gastric cancer tissues. Bioinformatic predictions and luciferase assay verified that the 3'-untranslated region of the HAI-1 gene is a direct target site for miR-221 and miR-222. Overexpression of miR-221 and miR-222 in MGC-803 cells leads to the inhibition of hepatocyte growth factor activator inhibitor type 1 protein expression, thus promoting cell proliferation and migration; whereas knockdown of miR-221 and miR 222 showed opposite effects. Moreover, we found that the expression level of hepatocyte growth factor activator protein was increased when hepatocyte growth factor activator inhibitor type 1 was knocked down in MGC-803 cells. Thus, gastric cancer is probably an autocrine tumor, and the antitumor mechanism of hepatocyte growth factor activator inhibitor type 1 in vitro might be mediated by regulating the expression of hepatocyte growth factor activator protein. Therefore, our data illustrated a novel pathway comprising miR-221and miR-222 and hepatocyte growth factor activator inhibitor type 1 in gastric cancer, which is a potential target for future clinical use. PMID- 28618970 TI - Letter regarding Zhao et al. entitled " DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia". AB - Zhao et al. investigated the association between germline genetic polymorphisms in DPYD, the gene encoding dihydropyrimidine dehydrogenase, and (1) the risk of developing pediatric acute lymphoblastic leukemia and (2) outcome of acute lymphoblastic leukemia following the treatment with 5-fluorouracil plus oxaliplatin (FOLFOX). The authors found that the common DPYD variant c.85T>C (rs1801265, DPYD*9A) was significantly associated with (1) risk of developing pediatric acute lymphoblastic leukemia, (2) complete response rate, (3) event free survival, and (4) treatment-related toxicity. The authors conclude that patients carrying the c.85T>C C allele have an increased risk of developing acute lymphoblastic leukemia and have inferior outcome, and that DPYD c.85T>C can be used as a guide for individualized treatment and the decision to utilize 5 fluorouracil in acute lymphoblastic leukemia patients. In our view, the published article gives rise to multiple critical issues regarding the study's rationale and the methodology used, which strongly question the validity of the authors' conclusions. PMID- 28618969 TI - Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer. AB - Pancreatic cancer is one of the most aggressive and difficult to treat cancers. Experimental and clinical evidence suggests that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapy. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy mediated apoptosis both in vitro and in vivo; however, the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum stress could lead to autophagy and inhibit tumor progression. In this study, we demonstrated that penfluridol induced endoplasmic reticulum stress in BxPC-3, AsPC-1, and Panc-1 pancreatic cancer cell lines as indicated by upregulation of endoplasmic reticulum stress markers such as binding protein (BIP), C/EBP homologous protein (CHOP) and inositol requiring 1alpha (IRE1alpha) after treatment with penfluridol in a concentration-dependent manner. Inhibiting endoplasmic reticulum stress by pretreatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOP small interfering RNA, blocked penfluridol-induced autophagy. These results clearly indicate that penfluridol-induced endoplasmic reticulum stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP, and IRE1alpha expression in the tumor lysates from penfluridol-treated mice as compared to tumors from control mice. Altogether, our study establishes that penfluridol-induced endoplasmic reticulum stress leads to autophagy resulting in reduced pancreatic tumor growth. Our study opens a new therapeutic target for advanced chemotherapies against pancreatic cancer. PMID- 28618971 TI - Inversin correlates with the malignant phenotype of non-small cell lung cancer and promotes the invasiveness of lung cancer cells. AB - Inversin, encoded by NPHP2, is one of the 10 NPHP proteins known to be involved in nephronophthisis (an autosomal recessive cystic kidney). Although the previous reports showed that inversin played an important role in embryonic development and renal diseases, its function in cancer was not revealed clearly so far. As measured by immunohistochemical staining, inversin was highly expressed in the cytoplasm of lung cancer samples (63.4%, 161/254) compared with adjacent normal lung tissues (22.0%, 11/50, p < 0.01). Moreover, its expression was positively correlated with differentiation ( p = 0.014), tumor node metastasis staging ( p = 0.007), and lymph node metastasis ( p = 0.020). The overall survival of non-small cell lung cancer patients with inversin positive expression (45.41 +/- 1.800 months) was significantly reduced compared with those with inversin negative expression (51.046 +/- 2.238 months, p = 0.042). Consistently, we found that the invasion capacity of A549 cells transfected with inversin was significantly stronger than that of control cells ( p < 0.05), while inversin siRNA-treatment significantly reduced cell invasion in H1299 cells ( p < 0.05). Additionally, we demonstrated that inversin could upregulate the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Collectively, these results indicated that inversin might promote the tumorigenicity of lung cancer cells and serve as a novel therapeutic target of non-small cell lung cancer. PMID- 28618972 TI - Techniques and modifications for TMJ arthrocentesis: A literature review. AB - OBJECTIVES: To discuss advantages and disadvantages of TMJ arthrocentesis techniques, identifying modifications as reported in the literature. METHODS: A PubMed web-based search was carried out, using the terms TMJ and arthrocentesis, to determine the scope of coverage in well-documented articles in English. RESULTS: Among 237 articles, 12 distinct techniques were described for TMJ arthrocentesis in 12 articles. Among 12 techniques, 5 were classified as double puncture arthrocentesis (DPA) and 7 as single puncture arthrocentesis (SPA). In total, 17 well documented articles about SPA were found in literature. DISCUSSION: Arthrocentesis of the temporomandibular joint (TMJ) was first described in 1991. To make the traditional procedure even less invasive, many arthrocentesis methods have been described. However, in 2015, TMJ arthrocentesis techniques were divided into two groups to limit the complexities surrounding the concepts related to TMJ arthrocentesis techniques. PMID- 28618973 TI - From clinical uncertainties to precision medicine: the emerging role of the gut barrier and microbiome in small bowel functional diseases. AB - INTRODUCTION: Over the last decade, remarkable progress has been made in the understanding of disease pathophysiology. Many new theories expound on the importance of emerging factors such as microbiome influences, genomics/omics, stem cells, innate intestinal immunity or mucosal barrier complexities. This has introduced a further dimension of uncertainty into clinical decision-making, but equally, may shed some light on less well-understood and difficult to manage conditions. Areas covered: Comprehensive review of the literature on gut barrier and microbiome relevant to small bowel pathology. A PubMed/Medline search from 1990 to April 2017 was undertaken and papers from this range were included. Expert commentary: The scenario of clinical uncertainty is well-illustrated by functional gastrointestinal disorders (FGIDs). The movement towards achieving a better understanding of FGIDs is expressed in the Rome IV guidelines. Novel diagnostic and therapeutic protocols focused on the GB and SB microbiome can facilitate diagnosis, management and improve our understanding of the underlying pathological mechanisms in FGIDs. PMID- 28618974 TI - Cystic dilation of a ventriculus terminalis. Case report and review of the literature. AB - The ventriculus terminalis (VT) is a small ependyma-lined cavity within the conus medullaris that is in direct continuity with the central canal of the spinal cord. Cystic dilatation of the ventriculus terminalis on its own is an extremely rare pathological event in adults whose pathogenesis is uncertain. VT has been described in children as a normal developmental phenomenon. These lesions are often diagnosed incidentally during imaging and are in most cases asymptomatic, especially in children. Symptomatic dilatation of VT in adults is a rare condition with 61cases being reported to date. Symptomatic dilatation of VT in children has not been reported till now. We present a 5 year-old-boy with a sphincteric and walking disorder. The patient was assessed by clinical, electrophysiological and urodynamic investigations as well as magnetic resonance imaging (MRI) of the lumbar-sacral segment with and without gadolinium enhancement. Lumbar-sacral MRI demonstrated the presence of a cystic lesion containing cerebrospinal fluid (CSF), which did not enhance after gadolinium, compatible with the diagnosis of the ventriculus terminalis dilation.The patient underwent laminectomy and the cyst wall was fenestrated with a midline myelotomy. In 6-month of follow-up, urinary problems and gait disturbance improved. PMID- 28618975 TI - A Black Cohosh Extract Causes Hematologic and Biochemical Changes Consistent with a Functional Cobalamin Deficiency in Female B6C3F1/N Mice. AB - Black cohosh rhizome, available as a dietary supplement, is most commonly marketed as a remedy for dysmenorrhea and menopausal symptoms. A previous subchronic toxicity study of black cohosh dried ethanolic extract (BCE) in female mice revealed a dose-dependent ineffective erythropoiesis with a macrocytosis consistent with the condition known as megaloblastic anemia. The purpose of this study was to investigate potential mechanisms by which BCE induces these particular hematological changes. B6C3F1/N female mice (32/group) were exposed by gavage to vehicle or 1,000 mg/kg BCE for 92 days. Blood samples were analyzed for hematology, renal and hepatic clinical chemistry, serum folate and cobalamin, red blood cell (RBC) folate, and plasma homocysteine and methylmalonic acid (MMA). Folate levels were measured in liver and kidney. Hematological changes included decreased RBC count; increased mean corpuscular volume; and decreased reticulocyte, white blood cell, neutrophil, and lymphocyte counts. Blood smear evaluation revealed increased Howell-Jolly bodies and occasional basophilic stippling in treated animals. Plasma homocysteine and MMA concentrations were increased in treated animals. Under the conditions of our study, BCE administration caused hematological and clinical chemistry changes consistent with a functional cobalamin, and possibly folate, deficiency. Further studies are needed to elucidate the mechanism by which BCE causes increases in homocysteine and MMA. PMID- 28618976 TI - Bromelain-decorated hybrid nanoparticles based on lactobionic acid-conjugated chitosan for in vitro anti-tumor study. AB - In this work, lactobionic acid-modified chitosan (CLA) was chosen as an initial material to prepare tumor-targeted nanoparticles (CLA NPs). To improve the nanoparticles' tumor penetration ability, bromelain was then decorated on the surface of CLA NPs to give CLAB NPs. The micromorphology of CLA and CLAB NPs was observed by transmission electron microscopy and scanning electron microscopy. The stability of CLA and CLAB NPs was then investigated at different pH values (4.0-9.0) and physiological environment by dynamic light scattering. Doxorubicin as a model drug was successfully encapsulated into these two nanoparticles and drug release profiles were also investigated at pH 5.5, 6.5 and 7.4, respectively. Cellular uptake and MTT results against HepG2 and SH-SY5Y cells demonstrated that the LA-conjugated tumor-targeting NPs can be efficiently internalized into hepatoma carcinoma cells, leading to higher cytotoxicity than free doxorubicin. CLAB NPs show considerable cell cytotoxicity and are expected to improve the penetration ability and therapeutic effect in the subsequent in vivo studies. PMID- 28618977 TI - Sacrificial template method for the synthesis of three-dimensional nanofibrous 58S bioglass scaffold and its in vitro bioactivity and cell responses. AB - Three-dimensional nanofibrous scaffolds that morphologically mimic natural extracellular matrices hold great promises in tissue engineering and regenerative medicine due to their increased cell attachment and differentiation compared with block structure. In this work, for the first time, three-dimensional porous nanofibrous 58S bioglass scaffolds have been fabricated using a sacrificial template method. During the process, a natural three-dimensional nanofibrous bacterial cellulose was used as the sacrificial template on which precursor 58S glass was deposited via a sol-gel route. SEM and TEM results verify that the as prepared 58S scaffolds can inherit the three-dimensional nanofibrous feature of bacterial cellulose. Pore structure characterizations by nitrogen adsorption desorption and mercury intrusion porosimetry demonstrate that the 58S scaffolds are highly porous with a porosity of 75.1% and contain both mesopores (39.4 nm) and macropores (60 um) as well as large BET surface area (127.4 m2 g-1). In vitro cell studies suggest that the 58S scaffold is bioactive and biocompatible with primary mouse osteoblast cells, suggesting that the nanofibrous structure of 58S is able to provide an appropriate environment for cellular functioning. These results strongly suggest that the three-dimensional nanofibrous 58S scaffold has great potential for application in bone tissue engineering and regenerative medicine. PMID- 28618978 TI - Properties of poly(lactic acid)/hydroxyapatite composite through the use of epoxy functional compatibilizers for biomedical application. AB - A composite of 70/30 poly(lactic acid)/hydroxyapatite was systematically prepared using various amounts of glycidyl methacrylate as reactive compatibilizer or Joncryl ADR(r)-4368 containing nine glycidyl methacrylate functions as a chain extension/branching agent to improve the mechanical and biological properties for suitable usage as internal bone fixation devices. The effect of glycidyl methacrylate/Joncryl on mechanical properties of poly(lactic acid)/hydroxyapatite was investigated through flexural strength. Cell proliferation and differentiation of osteoblast-like MC3T3-E1 cells cultured on the composite samples were determined by Alamar Blue assay and alkaline phosphatase expression, respectively. Result shows that flexural strength tends to decrease, as glycidyl methacrylate content increases except for 1 wt.% glycidyl methacrylate. With an addition of dicumyl peroxide, the flexural strength shows an improvement than that of without dicumyl peroxide probably due to the chemical bonding of the hydroxyapatite and poly(lactic acid) as revealed by FTIR and NMR, whereas the composite with 5 wt.% Joncryl shows the best result, as the flexural strength increases getting close to pure poly(lactic acid). The significant morphology change could be seen in composite with Joncryl where the uniform agglomeration of hydroxyapatite particles oriented in poly(lactic acid) matrix. Addition of the epoxy functional compatibilizers at suitable percentages could also have benefits to cellular attachment, proliferation, differentiation and mineralization. So that, this poly(lactic acid)/hydroxyapatite composite could be a promising material to be used as internal bone fixation devices such as screws, pins and plates. PMID- 28618979 TI - Complications and post-operative sequelae of temporomandibular joint arthrocentesis. AB - OBJECTIVE: To evaluate intraoperative complications and postsurgical sequelae associated with arthrocentesis of the TMJ, including injection of Sodium Hyaluronate. METHODS: This retrospective study evaluated 433 arthrocentesis procedures performed in 315 patients between January 2009 and August 2016. The authors reviewed the complications identified during the procedure and the follow up period. RESULTS: Temporary swelling of the periarticular tissues (95.1%) or the external auditory canal (23.5%), ipsilateral temporary open bite (68.8%), frontalis and orbicularis oculis paresis (65.1%), preauricular hematoma (0.4%), and a case of vertigo (0.2%) were the complications detected. CONCLUSIONS: TMJ arthrocentesis remains a procedure with a minimum number of important complications. If present, complications are generally temporary, caused by the anesthetic effect or by the soft tissue edema created by the fluid extravasation created by the irrigation procedure, and can be managed on an outpatient basis. PMID- 28618980 TI - Evaluating the care cascade after antiretroviral therapy initiation in Latin America. AB - Accelerating antiretroviral therapy (ART) administration, improving retention, and achieving viral suppression in low- and middle-income countries must be prioritized. We evaluated trends and disparities in these milestones in a large Latin American cohort. Adults starting ART (ARTstart) from 2003 to 2014 at Caribbean, Central, and South America network for HIV epidemiology sites were assessed for care cascade outcomes: CD4 cell count >200 cells/mm3 at ARTstart; retention (>=1 visit at one year after ARTstart); viral suppression (>=1 HIV-1 RNA <200 copies/ml at one year after ARTstart). Modified Poisson regression provided adjusted prevalence ratios by age, gender, and HIV transmission risk, accounting for site and year of ARTstart. Proportions achieving ARTstart and suppression improved over time (p < 0.05). Older age was associated with better retention and viral suppression, but not ARTstart at CD4 cell count >200 cells/mm3. Females and men who have sex with men (MSM) were more likely to have CD4 cell count >200 cells/mm3 at ARTstart. Injection drug users (IDUs) were less likely to be retained while MSM were more likely to achieve viral suppression (all p < 0.05). Despite improvements in these outcomes over the course of a decade in this cohort, significant disparities existed, disadvantaging younger patients, men, and IDUs. These gaps indicate continued progress in providing early diagnosis and ARTstart remain critical. PMID- 28618981 TI - Perceived effectiveness of antiretroviral therapy, self-rated health and treatment adherence among HIV-positive people who inject drugs in Estonia. AB - The HIV epidemic in Estonia affects the population of people who inject drugs (PWID) the most, but factors associated with adherence to antiretroviral therapy (ART) among PWID have not been thoroughly examined in Estonia, with particularly limited data regarding beliefs and attitudes of PWID. The objective of this study was to explore the association between ART adherence and individual beliefs, perceived effectiveness of ART, and self-rated health in particular, in this specific population. The study used baseline survey data from a longitudinal intervention study of HIV prevention among PWID in Estonia, in which 107 HIV infected participants reported current use of ART. Current adherence was measured through the use of a visual analog scale. Approximately half (49%) of the participants reported optimal (>=95%) adherence. The vast majority (81%) believed in the effectiveness of ART. Less than a quarter of the participants (22%) rated their health as good or very good, and a half (52%) reported average health. Individual beliefs and self-reported health were not associated with ART adherence in both bivariate and multivariable analyses. Participants with problem drinking reported significant suboptimal adherence to ART (adjusted odds ratio [AOR] 0.42, 95% CI 0.19-0.97). Daily injection drug use was also associated with suboptimal adherence (AOR 0.34, 95% CI 0.13-0.91). Problem drinking has not been commonly reported as a factor of suboptimal ART adherence among PWID; further research would be useful to identify the pathways that might be involved. PMID- 28618983 TI - Regulatory T Cells Show Dynamic Behavior During Late Pregnancy, Delivery, and the Postpartum Period. AB - Regulatory T cells (Tregs) are critical immunomodulators during early pregnancy by preventing maternal T-cell activation against fetal cells. However, how populations of maternal Tregs vary during and after pregnancy in humans is still unclear. Therefore, we investigated Treg subsets in the peripheral blood of pregnant women from late pregnancy through the postpartum period. To accomplish this, the following circulating Treg subsets were analyzed in 43 healthy pregnant women and 35 nonpregnant women by flow cytometry during the third trimester, on the day of delivery, and postpartum: CD4DimCD25Hi, CD4+CD25HiFoxp3+, and CD4+CD25HiCD127-/dim. Additionally, the expression levels of the transcription factor Foxp3 in CD4DimCD25Hi Treg were analyzed. We have found that CD4DimCD25Hi Treg subset significantly decreased in the pregnant women on the day of delivery relative to the third trimester ( P < .05), and that all Treg subsets significantly increased postpartum compared to the third trimester and the day of delivery ( P < .05). Moreover, the Foxp3 expression ratios within the CD4DimCD25Hi Treg subset decreased during pregnancy and until delivery compared to those measured in the nonpregnant women and significantly increased postpartum compared to the third trimester and the day of delivery ( P < .05). Thus, despite their established role in offering immunoprotection to the fetus in early pregnancy, the number of circulating Tregs also varies from late pregnancy to the postpartum period. Our results offer an explanation for the possible effects of pregnancy on the clinical outcomes of some autoimmune diseases during the postpartum period. PMID- 28618984 TI - Glycemic Variability and Insulin Needs in Patients with Type 1 Diabetes Mellitus Supplemented with Vitamin D: A Pilot Study Using Continuous Glucose Monitoring System. AB - BACKGROUND: Recent studies suggest that glycemic variability could influence the risk of complications in Type 1 Diabetes Mellitus (T1DM). There are no data about the action of Vitamin D (VD) on glycemic variability. Our pilot study aims to evaluate glycemic variability and insulin needs in patients with T1DM supplemented with VD. METHODS: 22 Patients received doses of 4000 and 10000 IU/day of cholecalciferol for 12 weeks, according to the patient's baseline VD levels and underwent continuous glucose monitoring system. RESULTS: Correlations were found between percentage variation (Delta) of glycemia standard deviation (DeltaSDG), calculated using continuous glucose monitoring, with Delta of basal (r = 0.6; p <0.01) and total insulin dose (r = 0.6; p <0.01). Correlations between VD status after supplementation and Delta of prandial (r = 0.5; p <0.05) and total insulin dose (r = 0.4; p <0.05) were found, suggesting that the dose of insulin needed by patients is lower when VD status is better. We divided patients in two subgroups: SDG improved (subgroup 1; N = 12 (55%)) and SDG worsened (subgroup 2; N = 10 (45%)). Group 1, compared to subgroup 2, required a lower insulin dose (Deltabasal insulin dose = -8.0 vs. 6.3%; p <0.05) and had a lower frequency of hypoglycemia (27% vs. 64%, hypoglycemias/days evaluated; p <0.01). CONCLUSION: Our study suggests a relation between VD supplementation, improved glycemic variability, lower insulin needs and lower frequency of hypoglycemia in patients with T1DM. PMID- 28618985 TI - Dendrimers: General Aspects, Applications and Structural Exploitations as Prodrug/Drug-delivery Vehicles in Current Medicine. AB - Dendrimers are hyper branched macro molecules with well-defined structure and high degree of functionality on the surface. The dendrimer architecture allows control over properties such as shape, size, density, polarity, reactivity, solubility etc. These special features can be exploited to design molecules having desired properties used for biomedical applications. Recent advancements in correlation between structure and biodegradability and in vivo performance are opening up new avenues for these molecules; particularly, in biological applications like drug delivery. The unique structure of dendrimers provides enough attachment sites for drugs. Further, it is possible to tune the molecules in such a way so that the drug molecules are encapsulated outside the target area and are released only in the local environment of targets. This review presents some general aspects of dendrimers and how their properties are exploited for drug delivery applications. PMID- 28618986 TI - Inflammatory and Oxidative Stress Markers as Indicator of Atherogenesis in Rats: Antioxidants as Preventive Pharmacological Methods. AB - OBJECTIVE: The oxidative process in atherogenesis generated by proinflammatory induction and response to antioxidants vitamins in an experimental model were analyzed. METHODS: Male rats were used: (A)Control, (B)Control+vitamin E plus C, (C)Hyperfibrinogenemia and (D)Hyperfibrinogenemia+vitamins E plus C. Hyperfibrinogenemia induced by daily injection of adrenaline (0.1mg/day/rat) for 120 days. TREATMENT: 3.42 mg/kg of vitamin E plus 2.14 mg/kg of vitamin C, fifteen days after induction. Vascular histology analyzed by optical microscopy. Fibrinogen, nitrites and superoxide dismutase analyzed by spectrophotometry. STATISTICS: MANOVA, Hotelling test for post testing, significance level p<0.05. RESULTS: (C) group showed higher fibrinogen than (A) and (B)(p<0.001). Compared to (C) group, (D) showed a decrease of fibrinogen (p<0.001). A marked increase in nitrites was found in (C) versus (A), (B) and (D) groups (p<0.001). Superoxide dismutase activity increased in (C) group compared to groups (A) and (B) (p<0.001). In the group (D) an increase of the activity of this enzyme was observed in comparison to groups (C)(p<0.001), (A) and (B) (p<0.0001 in both). The (C) group shown endothelial denudation, thickening of the vascular intima and extracellular matrix enlargement with foam cells(p<0.001). CONCLUSION: These results strongly suggest that vitamins E plus C produce regression of inflammatory and oxidative stress processes in this experimental model. PMID- 28618987 TI - Synthesis of New Thiazolyl Coupled Pyrazoles Bearing 2,4-Thiazolidinedionyl Pharmacophore and Their Anti-Inflammatory and Antibacterial Evaluation. AB - BACKGROUND: 2, 4-Thiazolidinedione (TZD), pyrazole and thiazole heterocyclic rings exhibit a wide range of pharmacological activities. Medicinal chemists use these heterocyclic moieties as scaffolds in drug designing and discovery. The existing medicaments, celecoxib and meloxicam, used for treating inflammation and pain are having, pyrazole and thiazole, respectively as key scaffolds. Pyrazoles coupled with 2, 4-thiazolidinediones may display enhanced anti-inflammatory activity. With this hope the bench work was carried out. METHODS: Heterocyclic aldehydes, 3-(4-methyl-2-substituted thiazol-5-yl)-1-phenyl-1Hpyrazole- 4- carbaldehydes (4a-b) have been allowed to undergo Knoevenagel condensation with N substituted 2,4-thiazolidinediones (5a-e) in PEG-400 in the presence of L-proline at 110 degrees C and obtained the condensed products (6a-j). COX-2 evaluation of the titled product has been carried out using in vitro COX-2 ELISA Kit. Antibacterial activity of these compounds (6a-j) has also been determined. RESULTS: On the basis of 1H NMR, 13C NMR and Mass spectral data of the condensed products the structures have been assigned to (Z)-5-((3-(4-methyl-2-substituted thiazol-5-yl)-1- phenyl-1H-pyrazol-4-yl)methylene) 3-substituted thiazolidine-2,4 diones (6a-j). Among the evaluated compounds (6a-j), 6f, 6g, 6h, 6i and 6j have shown notable COX-2 inhibitory activity. CONCLUSION: Compounds, 6a, 6b, 6c, 6d, 6e and 6f have inhibited the growth of the Bacillus cereus NCIM 2106, Bacillus subtilis NCIM 2063, Pseudomonas aeruginosa NCIM 2074, Salmonella typhimurium NCIM 2501 and Staphylococcus aureus NCIM 2079. However, compound 6f has emerged as a suitable candidate with dual properties i.e. COX-2 inhibitory and antibacterial in the present study. PMID- 28618988 TI - Synthesis, Docking and Anti-Inflammatory Activity of Triazole Amine Derivatives as Potential Phosphodiesterase-4 Inhibitors. AB - BACKGROUND: Phosphodiesterase 4 (PDE4), is one of the members of PDE superfamily which catalyzes the hydrolysis of cyclic adenosine monophosphate to adenosine monophosphate in pro-inflammatory and immunomodulatory cells, leading to increased inflammatory processes. PDE4 has been reported as an attractive therapeutic target involved in various inflammatory disorders. OBJECTIVE: The present work was designed to synthesize and evaluate the anti-inflammatory activity of some new triazole amine derivatives as potential PDE4 inhibitors. METHOD: The present work involved the synthesis of a series of newer substituted triazole amine derivatives followed by characterization using FTIR and 1H-NMR spectroscopy and their in silico evaluation by docking studies to determine the binding interactions for the best fit conformations in the binding site of PDE4 protein. Based on the results of the in silico studies, the selected compounds were tested for the anti-inflammatory activity using carrageenan-induced paw oedema method. RESULTS: The yields of synthesized compounds were moderate and amongst the synthesized molecules, compound 5 demonstrated high anti-inflammatory activity. The results of experimental studies were found to be in concordance with that of the in silico docking results. Most of the synthesized molecules were also found to possess drug like properties as contrived by Lipinski's rule of five. CONCLUSION: These newly synthesized molecules could act as the starting hits for the design of effective, potent and selective PDE4 inhibitors for the promising treatment of inflammatory disorders. PMID- 28618989 TI - Anti-Inflammatory Activity of Novel 12-N-methylcytisine Derivatives. AB - BACKGROUND AND OBJECTIVES: Neurodegenerative diseases and inflammation are always linked to each other; therefore the elaboration of new chemical compounds, which interact with pharmacological targets involved into these two processes, can become one of ways of correction of these types of human CNS pathology. In the field of this problem the anti-inflammatory activity of ten 3-amino derivatives of quinolizidine alkaloid (.)-cytisine (the data about nootropic activity of these compounds are outlined by us previously) was studied by using in vivo, in vitro and in silico approaches. METHODS: The anti-inflammatory activity of novel compounds was investigated on carrageenan- induced model of inflammation in Rat paw following an established protocol. COX-1 (ovin) and COX-2 (human recombinant) inhibition activities of tested compounds assessed using a COX Fluorescent Inhibitor Screening Assay Kit. And as part of an in silico screening the leading compounds were docked into the tyrosine sites of COX-1/COX-2 enzymes (PDB code: 1DIY and 1CVU). RESULTS: It was established that ability of 3-(2 hydroxyphenyl)amino, 3-(4-hydroxyphenyl) amino and 3-(3-phenylprop-2-en-1 yl)amino derivatives of 12-N-metylcytisine to inhibit the carrageenan-induced paw oedema in rats is comparable with reference drug diclofenac. The results of in vitro COX-1/COX-2 inhibition assay showed no significant activity of tested compounds, except compounds with 2-hydroxyphenyl, 3-phenylprop-2-en-1-yl, furyl and thiophenyl fragments which slightly reduce the activity of COX-2. CONCLUSION: The tendency to occurrence of anti-inflammatory properties of synthesized derivatives of quinolizidine alkaloid (-)-cytisine can be explained on the basis of molecular docking results, which assume the possibility of interaction of more potent compounds with key amino acids of COX-1/COX-2 active sites. PMID- 28618990 TI - Biological Roles of the Eclectic Chromogranin-A-derived Peptide Catestatin. AB - BACKGROUND: Research on Chromogranin A (CGA) and its derived fragments convincingly demonstrated the multifunctional activity of the 21 amino acid peptide named Catestatin (CST: human CGA352-372, bovine CGA344-364, rat CGA367 387). This review aims to provide a synopsis of the current information concerning the biological role of CST in health and disease. METHODS: Structured search of bibliographic databases for peer-reviewed research literature. RESULTS: CST is mainly known as an inhibitor of the nicotinic-dependent Catecholamine (CA) release, and an anti-hypertensive peptide, but its role includes a modulation of antioxidant and immune defense, epidermal function, and adipose tissue homeostasis. CST influences the cardiocirculatory system acting both indirectly, via the autonomic nervous system, and directly by influencing the basal cardiac function, and the stretch-dependent myocardial performance. It also counteracts the effects of adrenergic stimulation on the heart and protects the myocardium from ischemia/reperfusion (I/R) injury, acting in pre- and postconditioning protection. CONCLUSIONS: The knowledge on CST is constantly expanding, thanks to a growing number of human studies that document its involvement in physiological modulation and in many severe diseases, also revealing its applicative potential as a clinical biomarker. PMID- 28618991 TI - Effects of Polyphenolic Derivatives on Heme Oxygenase-System in Metabolic Dysfunctions. AB - BACKGROUND: The aim of this review is to summarize the effects of various naturally occurring polyphenols in the management of metabolic dysfunctions. This cluster of metabolic abnormalities comprises insulin resistance, increased levels of free fatty acids, hypercholesterolemia, obesity, hyperglycemia and hypertension, diabetes mellitus (DM) type 1 (T1DM) and type 2 (T2DM) along with DM-induced complications. Most of them are included in the well-known metabolic syndrome (MS). These metabolic dysfunctions in turn are tightly associated to a high risk of development of cardiovascular diseases. Although molecular mechanisms underlying the onset of metabolic dysfunctions and related complications are not yet clear, it is widely recognized that they are associated to oxidative stress and chronic low-grade of inflammatory levels. METHODS: We undertook a structured search of bibliographic references through the use of SciFinder. The database was provided by a division of ACS (American Chemical Society) and guarantees access to the world's most extensive and authoritative source of references. The search was performed using "heme oxygenase-1" as research topic and a subsequent refinement was done by using inclusion/exclusion criteria. The quality of retrieved papers was evaluated on the basis of standard tools. RESULTS: From a careful review of the selected literature, of interest, the use of natural antioxidant polyphenols seems to be the ideal pharmacological treatment since they are endowed with strong antioxidant and anti-inflammatory properties. In particular, some polyphenols such as curcumin, quercetin, genistein, and caffeic acid phenethyl ester are able to potently activate nuclear factor erythroid 2-related factor 2 (Nrf2) and related downstream expression of enzymes such as heme oxygenase-1 (HO-1). Indeed, an overexpression of HO-1 has been demonstrated to play a beneficial role in metabolic diseases. CONCLUSION: The following review is intended to stimulate interest in the role of natural occurring HO-1 inducers in metabolic dysfunction, focusing on the clinical potential of HO-1 activity to restore the balance between pro-oxidant and anti oxidants systems. PMID- 28618992 TI - Modulating mitophagy in mitochondrial disease. AB - Mitochondrial diseases may result from mutations in the maternally-inherited mitochondrial DNA (mtDNA) or from mutations in nuclear genes encoding mitochondrial proteins. Their bi-genomic nature makes mitochondrial diseases a very heterogeneous group of disorders that can present at any age and can affect any type of tissue. The autophagic-lysosomal degradation pathway plays an important role in clearing dysfunctional and redundant mitochondria through a specific quality control mechanism termed mitophagy. Mitochondria could be targeted for autophagic degradation for a variety of reasons including basal turnover for recycling, starvation induced degradation, and degradation due to damage. While the core autophagic machinery is highly conserved and common to most pathways, the signaling pathways leading to the selective degradation of damaged mitochondria are still not completely understood. Type 1 mitophagy due to nutrient starvation is dependent on PI3K (phosphoinositide 3-kinase) for autophagosome formation but independent of mitophagy proteins, PINK1 (PTEN induced putative kinase 1) and Parkin. Whereas type 2 mitophagy that occurs due to damage is dependent on PINK1 and Parkin but does not require PI3K. Autophagy and mitophagy play an important role in human disease and hence could serve as therapeutic targets for the treatment of mitochondrial as well as neurodegenerative disorders. Therefore, we reviewed drugs that are known modulators of autophagy (AICAR and metformin) and may effect this by activating the AMP-activated protein kinase signaling pathways. Furthermore, we reviewed data available on supplements, such as Coenzyme Q and the quinone idebenone, that we assert rescue increased mitophagy in mitochondrial disease by benefiting mitochondrial function. PMID- 28618993 TI - New Perspectives on Biomedical Applications of Iron Oxide Nanoparticles. AB - Iron oxide nanomaterials are considered promising tools for improved therapeutic efficacy and diagnostic applications in biomedicine. Accordingly, engineered iron oxide nanomaterials are increasingly proposed in biomedicine, and the interdisciplinary researches involving physics, chemistry, biology (nanotechnology) and medicine have led to exciting developments in the last decades. The progresses of the development of magnetic nanoparticles with tailored physico-chemical and surface properties produced a variety of clinically relevant applications, spanning from magnetic resonance imaging (MRI), drug delivery, magnetic hyperthermia, to in vitro diagnostics. Notwithstanding the wellknown conventional synthetic procedures and their wide use, along with recent advances in the synthetic methods open the door to new generations of naked iron oxide nanoparticles possessing peculiar surface chemistries, suitable for other competitive biomedical applications. New abilities to rationally manipulate iron oxides and their physical, chemical, and biological properties, allow the emersion of additional possibilities for designing novel nanomaterials for theranostic applications. PMID- 28618994 TI - Role of Anti-PCSK9 Antibodies in the Treatment of Patients with Statin Intolerance. AB - Statin intolerance is usually defined as the inability of a patient to tolerate statintreatment due to muscle-related complaints. While randomised trials show that these complaints occure with similar frequency in patients receiving placebo, namely in up to ~5% of the subjects, and data from registries as well as clinical experience indicate a much higher frequency of up to ~30%. The lack of standard definition or of a diagnostic marker of statin intolerance confounds the problem. The diagnosis remains subjective based on the symptoms the patient reports. Therefore, a large number of patients who need a statin are not receiving it, or receiving only very-low and/or intermittent doses unable to achieve a robust decrease in low-density lipoprotein cholesterol (LDL-C), leaving patients at high or very high risk for cardiovascular events requiring an alternative form of lipid-lowering therapy. Until recently, the only available alternatives were niacin, ezetimibe, bile-acid sequestrants and fibrates that decrease LDL-C concentrations by up to 15-20%. Recently the fully human monoclonal antibodies against proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab (Praluent(r)) and evolocumab (Repatha(r)), which have been shown to decrease LDL-C by up to 70% have been approved in Europe for use in patients with primary hypercholesterolemia not at LDL-C target while on maximally tolerated lipid-lowering therapy and specifically for patients with statin intolerance and in the USA for patients with atherosclerotic cardiovascular disease or familial hypercholesterolemia requiring additional LDL-C lowering. Ongoing large clinical trials with cardiovascular endpoints will provide a definitive answer for the role of anti-PCSK9 antibodies in clinical practice. PMID- 28618995 TI - The Complexity of Omega-3 Fatty Acid Modulation of Signaling Pathways Related to Pancreatic Cancer. AB - Cancer is a major public health problem worldwide and is the second leading cause of death in the United States. Although cancer death rate has dropped by 23% since 1991, there are certain types of cancer for which death rates are still increasing, such as pancreatic cancer. There is an urgent need to find new therapies that could help improve this dreadful outcome. In this regard, the role of nutrition in health and disease has attracted much attention. Several dietary components are involved in metabolic, physiologic and cell signaling affecting tumor growth and progression. Although lipids, and more specifically polyunsaturated fatty acids, have been traditionally studied due to their health effects in cardiovascular disease, it is now clear that they can impact an extensive array of cellular processes that influence a wide range of diseases such as type II diabetes, inflammatory disorders and cancer. These biological activities may be grouped as regulation of: (1) membrane structure and function, (2) intracellular signaling pathways, (3) transcription factor activity, (4) gene expression, and (5) production of bioactive lipid mediators. The aim of this review is to assimilate the current state of knowledge about these potential mechanism(s) of action and signaling pathways modulated by polyunsaturated fatty acids in pancreatic cancer. PMID- 28618996 TI - The Influence of Obese Insulin-Resistance on the Outcome of the Ischemia/Reperfusion Insult to the Heart. AB - BACKGROUND: Obese insulin-resistance is one of the most important risk factor for cardiovascular diseases including ischemic heart disease (IHD). Growing evidences suggest that the susceptibility to myocardial ischemia-reperfusion (I/R) injury is increased in an obese insulin-resistance condition. Based on the currently available evidence from human and animal studies, this review mainly focuses on the influence of obese insulinresistance on the outcome of the I/R insult to the heart. Moreover, we have discussed whether improving insulin sensitivity by pharmacological interventions could ameliorate reperfusion induced myocardial injury. METHODS: The electronic database Pubmed was used as the source of selected peerreviewed research articles published in English. Both pre-clinical studies and clinical trials were obtained using obesity, insulin resistance, ischemia-reperfusion injury and myocardial infarction as keywords. RESULTS: Twenty-seven pre-clinical studies were obtained using obesity, insulin resistance, and cardiac ischemia-reperfusion injury as keywords, and five clinical trials were obtained using obesity, insulin resistance, and myocardial infarction as keywords. The underlying mechanisms responsible for the exacerbation of I/R injury in obese insulinresistance were the main subject of our review. CONCLUSION: The findings of this review suggest that the susceptibility to I/R injury is increased in an obese insulin-resistance condition. However, the underlying mechanisms responsible for the exacerbation of I/R injury in obese insulin-resistance have not been fully elucidated, but increased basal oxidative stress, the impairment of anti-oxidant capacities, insulin signaling and pro-survival signaling and increased inflammation, likely play an important role. PMID- 28618997 TI - VDAC1 as a Player in Mitochondria-Mediated Apoptosis and Target for Modulating Apoptosis. AB - BACKGROUND: The voltage-dependent anion channel 1 (VDAC1), an outer mitochondria membrane protein, functions as a mitochondrial governor, controlling transport of metabolites in and out of the mitochondria and energy production, while also coordinating glycolysis and oxidative phosphorylation. VDAC1 plays a key role in mitochondria-mediated apoptosis by functioning in the release of apoptotic proteins located in the inter-membranal space and due to its association with pro and anti-apoptotic proteins. Thus, VDAC1 is considered as a promising target for controlling apoptosis. METHODS: We reviewed published data presenting accumulated evidence suggesting that VDAC1 oligomerization represents an important step in the intrinsic mitochondria-mediated apoptosis pathway. RESULTS: The published data support the proposal that VDAC1 oligomerization leads to the formation of a large pore that allows the release of pro-apoptotic proteins to the cytosol, thereby, activation of apoptosis. Evidence for the relationship between VDAC1 expression levels and induction of apoptosis are presented. This includes the finding that almost all apoptosis stimuli induce VDAC1 over-expression shifting VDAC1 from a monomeric to an oligomeric assembly, corresponding to the Cyto c release channel. Compounds or conditions inducing VDAC1 over-expression, VDAC1 oligomerization and apoptosis are presented. Likewise, VDAC1-interacting molecules, that inhibit both VDAC1 oligomerization and apoptosis are also presented. CONCLUSION: This review highlights the findings about VDAC1 oligomerization as a potential target for controlling apoptosis, specifically using drugs to induce apoptotic cell death in cancer and inhibit apoptosis in neurodegenerative diseases, as well as possible VDAC1-based therapeutic applications. PMID- 28618998 TI - The role of mitochondrial dysfunction in the progression of Alzheimer's disease. AB - The current molecular understanding of Alzheimer's disease (AD) has still not resulted in successful interventions. Mitochondrial dysfunction of the AD brain is currently emerging as a hallmark of this disease. One mitochondrial function often affected in AD is oxidative phosphorylation responsible for ATP production, but also for production of reactive oxygen species (ROS) and for the de novo synthesis of pyrimidines. This paper reviews the role of mitochondrial produced ROS and pyrimidines in the aetiology of AD and their proposed role in oxidative degeneration of macromolecules, synthesis of essential phospholipids and maintenance of mitochondrial viability in the AD brain. PMID- 28618999 TI - Biomarkers for Diagnosing and Staging of Fabry Disease. AB - BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of alpha -galactosidase A which leads to progressive intracellular accumulation of globotriaosylceramide in tissues and organs including heart, kidney, vascular endothelium, the nervous system, the eyes and the skin. Cardiac involvement is common, leads to fatal complications and is mainly responsible for reduced life expectancy in Fabry disease. The exact staging of disease progression and timely initiation of treatment is essential in Fabry disease. Therefore, it is essential to use the possibilities of specific biomarkers for early detection of organ involvement or early diagnosis. METHODS: By the use of Pubmed all relevant papers for biomarkers in Fabry disease were screened. The quality of retrieved papers was appraised using standard tools. Finally, 70 peer reviewed paper were included. RESULTS: In the past biomarkers for Fabry disease biomarkers did not have clinical relevance. Nowadays, a lot of research is focusing on identification of new biomarkers and their clinical relevance. Only two biomarkers reached clinical applicability. Lyso-GB3 for identification of atypical FD variants and hsTNT for identification of cardiac involvement, which should indicate further diagnostics. Treatment response to ERT can be monitored by lyso-GB3 but data for long-time outcome are missing. A lot of GB3-related analogs are identified in urine and plasma, some of which might play an important role for managing Fabry disease in future. CONCLUSION: In conclusion, we suggest to measure lyso-GB3 and hsTNT at least once a year. The routine measurement of these two biomarkers will help now for the staging of every individual patient and in addition, will help for a better general understanding of Fabry disease. PMID- 28619000 TI - Astrocytes Pathology in ALS: A Potential Therapeutic Target? AB - The mechanisms underlying neurodegeneration in amyotrophic lateral sclerosis (ALS) are multifactorial and include genetic and environmental factors. Nowadays, it is well accepted that neuronal loss is driven by non-cell autonomous toxicity. Non-neuronal cells, such as astrocytes, have been described to significantly contribute to motoneuron cell death and disease progression in cell culture experiments and animal models of ALS. Astrocytes are essential for neuronal survival and function by regulating neurotransmitter and ion homeostasis, immune response, blood flow and glucose uptake, antioxidant defence and growth factor release. Based on their significant functions in "housekeeping" the central nervous system (CNS), they are no longer thought to be passive bystanders but rather contributors to ALS pathogenesis. Findings from animal models have broadened our knowledge about different pathomechanisms in ALS, but therapeutic approaches to impede disease progression failed. So far, there is no cure for ALS and effective medication to slow down disease progression is limited. Targeting only a single aspect of this multifactorial disease may exhibit therapeutic limitations. Hence, novel cellular targets must be defined and new pharmaceutical strategies, such as combinatorial drug therapies are urgently needed. The present review discusses the physiological role of astrocytes and current hypotheses of astrocyte pathology in ALS. Furthermore, recent investigation of potential drug candidates in astrocyte cell culture systems and animal models, as well as data obtained from clinical trials, will be addressed. The central role of astrocytes in ALS pathogenesis makes them a promising target for pharmaceutical interventions. PMID- 28619001 TI - Icariin Attenuates Interleukin-1beta-Induced Inflammatory Response in Human Nucleus Pulposus Cells. AB - BACKGROUND: Low back pain is a common problem, mainly caused by intervertebral disc degeneration (IDD). An important pathophysiological characteristic of IDD is the loss of homeostatic balance of the extracellular matrix metabolism. Interleukin-1beta (IL-1beta) is one of the inflammatory mediators stimulating the degradation of extracellular matrix in the nucleus pulposus (NP) and contributing to IDD pathogenesis. Icariin, which is isolated from Epimedium brevicornum, acts as an anti-inflammatory drug. OBJECTIVE: This study aimed to explore the pharmacological effects of icariin in IDD by simulating NP inflammation in vitro. METHOD: Human NP cells were isolated and cultured in vitro. NP cells were pretreated with icariin (0.1, 1 and 10 uM) and stimulated by IL-1beta (10 ng/ml). The concentration of Prostaglandin E2 was determined by enzymelinked immunosorbent assay. Nitric oxide was determined by Griess reagent assay. The expression of cyclooxygenase- 2 (COX-2), inducible nitric oxide synthase (iNOS), degrading enzymes, collagen II, aggrecan, mitogenactivated protein kinase (MAPK), and nuclear factor-kappa B (NF-kappaB)-related signaling molecules was assessed via western blotting. RESULTS: IL-1beta induced pronounced expression of COX-2 and iNOS, and stimulated production of prostaglandin E2 and nitric oxide. Icariin exhibited significant anti-inflammatory effect, inhibiting IL-1beta-induced production of degrading enzymes, as well as extracellular matrix reduction. Finally, icariin suppressed IL-1beta-induced activation of MAPK- and NF-kappaB related signaling pathways. CONCLUSION: The present findings suggest that icariin may have a protective effect on NP cells. The antiinflammatory effect may contribute to the therapeutic action of icariin in IDD. PMID- 28619002 TI - Targeting Astrocytes for Treatment in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting upper and lower motoneurons. The two types, sporadic and familial differ in the aetiopathogenesis but have a similar neuropathology characterized by oxidative stress, excitotoxicity and inflammation. The disease is also characterized by a non-cell autonomous mechanism with astrocytes playing a central role by affecting synaptic glutamate, the blood-brain barrier, and metabolic and trophic support. Two types of therapeutic approaches focusing on astrocytes are presented: a) emerging molecular targets (potassium inward rectifier channels and aquaporins at the astrocyte endfeet, and IP3 receptor signaling pathway), and b) cell therapy with stem cell - generated and transplanted astrocytes. PMID- 28619003 TI - Hydroxyapatite as a Nanomaterial for Advanced Tissue Engineering and Drug Therapy. AB - Hydroxyapatite (HAp) is a complicated ceramic material that varies between the way it appears in biological systems and how it is synthesized as various calcium phosphates. HAp varies in chemical composition of substituting atoms, crystallinity, grain size and electrical polarization. HAp can form solid to macro-, micro- and nanoporous structures. Also, particulate HAp can have highly porous structure. HAp can be used as coatings for metal implants in thicknesses from hundreds of microns down to hundreds of nanometers. Cotton wool-like HAp fibers can be electrospun compounded with polymers (or without) for tissue engineering (TE) scaffolds. This review describes the features of HAp that may be utilized further in developing novel applications. As a nanomaterial HAp has been applied for drug delivery. The adsorption of proteins and other compounds can be adjusted by modifying HAp composition, electrical polarization and wettability. Of special interest are the bisphosphonates that bind to HAp and thereby can be used to treat bone loss and also couple other drugs to the mineral. A new area for HAp constructs may appear in treating metallosis. HAp coating may function as a scavenger for the ions release from metal implants and thereby inhibit the adverse effects of the ion burden for the body. So far HAp is considered as safe biomaterial but nano HAp may insidiously possess adverse effects especially when ingested by cells and eliciting excess intracellular calcium. Thereby critical approach also for HAp biomaterials is of utmost importance. PMID- 28619004 TI - Albumin Nanocarriers, gamma- Irradiated Crosslinked, Combined with Therapeutic Drugs for Cancer Therapy>. AB - Albumin polymeric Nanoparticles (NPs) have opened a great expectancy as for controlled drug delivery due to their therapeutic potency. Concomitantly biodegradable NPs technologies with target linked structures to pave the way of personalised medicine are becoming increasingly important in sight of a therapeutically effective research technology. This is particularly attractive for nanoparticle-based cancer delivery systems, based on the known limitations and efforts to overcome. This new group of gamma irradiated-NPs inherited both the protein delivery properties and robustness of polymer forming structures, and gamma irradiation techniques that leave clean, innocuous and biodegradable NPs. These protein NPs made of serum albumin are referred to SA NPs that possesses several characteristics making them especially attractive to be considered as a drug delivery system. This review focused on methodologies actually being used in the synthesis and characterisation of albumin NPs and different author's opinions on strategic ways to treat cancerous cell-lines with NPs. Utterly, challenges being overthrown by researchers are brought up to anneal an effective, all in one targeted albumin NPs to passed through in vitro and preclinical trials. PMID- 28619005 TI - Effects of immunonutrition on biomarkers in traumatic brain injury patients in Malaysia: a prospective randomized controlled trial. AB - BACKGROUND: Head injury is one of the top three diagnosis leading to intensive care unit (ICU) admission in Malaysia. There has been growing interest in using immunonutrition as a mode of modulating the inflammatory response to injury or infection with the aim of improving clinical outcome. The aim of the present study was to evaluate the effect of an immunonutrition on biomarkers (IL-6, glutathione, CRP, total protein and albumin) in traumatic brain injury patients. METHODS: Thirty six patients with head injury admitted to neurosurgical ICU in University Malaya Medical Centre were recruited for this study, over a 6-month period from July 2014 to January 2015. Patients were randomized to receive either an immunonutrition (Group A) or a standard (Group B) enteral feed. Levels of biomarkers were measured at day 1, 5 and 7 of enteral feeding. RESULTS: Patients in Group A showed significant reduction of IL-6 at day 5 (p < 0.001) with concurrent rise in glutathione levels (p = 0.049). Patients in Group A also demonstrated a significant increase of total protein level at the end of the study (day 7). CONCLUSION: These findings indicate the potential of immunonutrition reducing cytokines and increasing antioxidant indices in patients with TBI. However, further studies incorporating patient outcomes are needed to determine its overall clinical benefits. TRIAL REGISTRATION: National Medical Research Register (NMRR) ID: 14-1430-23,171. ClinicalTrials.gov identifier: NCT03166449 . PMID- 28619006 TI - Tag SNP selection for prediction of tick resistance in Brazilian Braford and Hereford cattle breeds using Bayesian methods. AB - BACKGROUND: Cattle resistance to ticks is known to be under genetic control with a complex biological mechanism within and among breeds. Our aim was to identify genomic segments and tag single nucleotide polymorphisms (SNPs) associated with tick-resistance in Hereford and Braford cattle. The predictive performance of a very low-density tag SNP panel was estimated and compared with results obtained with a 50 K SNP dataset. RESULTS: BayesB (pi = 0.99) was initially applied in a genome-wide association study (GWAS) for this complex trait by using deregressed estimated breeding values for tick counts and 41,045 SNP genotypes from 3455 animals raised in southern Brazil. To estimate the combined effect of a genomic region that is potentially associated with quantitative trait loci (QTL), 2519 non-overlapping 1-Mb windows that varied in SNP number were defined, with the top 48 windows including 914 SNPs and explaining more than 20% of the estimated genetic variance for tick resistance. Subsequently, the most informative SNPs were selected based on Bayesian parameters (model frequency and t-like statistics), linkage disequilibrium and minor allele frequency to propose a very low-density 58-SNP panel. Some of these tag SNPs mapped close to or within genes and pseudogenes that are functionally related to tick resistance. Prediction ability of this SNP panel was investigated by cross-validation using K-means and random clustering and a BayesA model to predict direct genomic values. Accuracies from these cross-validations were 0.27 +/- 0.09 and 0.30 +/- 0.09 for the K-means and random clustering groups, respectively, compared to respective values of 0.37 +/- 0.08 and 0.43 +/- 0.08 when using all 41,045 SNPs and BayesB with pi = 0.99, or of 0.28 +/- 0.07 and 0.40 +/- 0.08 with pi = 0.999. CONCLUSIONS: Bayesian GWAS model parameters can be used to select tag SNPs for a very low-density panel, which will include SNPs that are potentially linked to functional genes. It can be useful for cost-effective genomic selection tools, when one or a few key complex traits are of interest. PMID- 28619007 TI - Whole genome sequencing analyses of Listeria monocytogenes that persisted in a milkshake machine for a year and caused illnesses in Washington State. AB - BACKGROUND: In 2015, in addition to a United States multistate outbreak linked to contaminated ice cream, another outbreak linked to ice cream was reported in the Pacific Northwest of the United States. It was a hospital-acquired outbreak linked to milkshakes, made from contaminated ice cream mixes and milkshake maker, served to patients. Here we performed multiple analyses on isolates associated with this outbreak: pulsed-field gel electrophoresis (PFGE), whole genome single nucleotide polymorphism (SNP) analysis, species-specific core genome multilocus sequence typing (cgMLST), lineage-specific cgMLST and whole genome-specific MLST (wgsMLST)/outbreak-specific cgMLST. We also analyzed the prophages and virulence genes. RESULTS: The outbreak isolates belonged to sequence type 1038, clonal complex 101, genetic lineage II. There were no pre-mature stop codons in inlA. Isolates contained Listeria Pathogenicity Island 1 and multiple internalins. PFGE and multiple whole genome sequencing (WGS) analyses all clustered together food, environmental and clinical isolates when compared to outgroup from the same clonal complex, which supported the finding that L. monocytogenes likely persisted in the soft serve ice cream/milkshake maker from November 2014 to November 2015 and caused 3 illnesses, and that the outbreak strain was transmitted between two ice cream production facilities. The whole genome SNP analysis, one of the two species-specific cgMLST, the lineage II-specific cgMLST and the wgsMLST/outbreak-specific cgMLST showed that L. monocytogenes cells persistent in the milkshake maker for a year formed a unique clade inside the outbreak cluster. This clustering was consistent with the cleaning practice after the outbreak was initially recognized in late 2014 and early 2015. Putative prophages were conserved among prophage-containing isolates. The loss of a putative prophage in two isolates resulted in the loss of the AscI restriction site in the prophage, which contributed to their AscI-PFGE banding pattern differences from other isolates. CONCLUSIONS: The high resolution of WGS analyses allowed the differentiation of epidemiologically unrelated isolates, as well as the elucidation of the microevolution and persistence of isolates within the scope of one outbreak. We applied a wgsMLST scheme which is essentially the outbreak-specific cgMLST. This scheme can be combined with lineage-specific cgMLST and species-specific cgMLST to maximize the resolution of WGS. PMID- 28619008 TI - Trends in mortality rates by subtypes of heart disease in Mississippi, 1980-2013. AB - BACKGROUND: Heart disease (HD) is the leading cause of death among Mississippians. However, trends in mortality rates for HD subtypes in Mississippi have not been adequately described. This study examined trends in mortality rates for HD subtypes among adults in Mississippi from 1980 through 2013. METHODS: We used Mississippi Vital Statistics data to calculate age-specific mortality rates for HD subtypes for Mississippians age 35 and older. Cases were identified via underlying cause of death codes from the International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10). We used Joinpoint software to calculate the average annual percent change (AAPC) in mortality rates for HD subtypes by race, sex, and age group. RESULTS: Overall, the age-adjusted coronary heart disease (CHD) mortality rate among Mississippi adults decreased by 62.7% between 1980 and 2013, with an AAPC of -3.0% (95% CI -3.7 to -2.3), while the age-adjusted heart failure mortality rate increased by 66.7%, with an AAPC of 1.4% (95% CI 0.5 to 2.3). Trends varied across HD subtypes: Annual rates of hypertensive HD mortality increased significantly for men, for individuals age 35 to 54, and for individuals age 75 and older. CHD mortality experienced a significant annual decrease among all race, sex, and age subgroups, while heart failure increased significantly among women, whites, and individuals age 75 and older. CONCLUSIONS: From 1980 to 2013, CHD mortality decreased significantly while heart failure mortality increased significantly among adult Mississippians. However, HD subtype trends differed by race, sex, and age group. PMID- 28619009 TI - Measuring influenza laboratory capacity: use of a tool to measure improvements. AB - BACKGROUND: To collect information, identify training needs, and assist with influenza capacity building voluntary laboratory capacity assessments were conducted using a standardized tool in CDC cooperative agreement countries. To understand the usefulness of comparing results from repeat assessments and to determine if targeted training supported improvements, this paper details comparison of assessment results of conducting 17 repeat laboratory assessments between 2009 and 2013. METHODS: Laboratory assessments were conducted by SMEs in 17 laboratories (16 countries). We reviewed the quantitative assessment results of the laboratories that conducted both an initial and follow up assessment between 2009 to 2013 using repeated measures of Anova, (Mixed procedure of SAS (9.3)). Additionally, we compared the overall summary scores and the assessor recommendations from the two assessments. RESULTS: We were able to document a statistically significant improvement between the first and second assessments both on an aggregate as well as individual indicator score. Within the international capacity tool three of the eight categories recorded statistically significant improvement (equipment, management, and QA/QC), while the other tool categories (molecular, NIC, specimen, safety and virology) showed improvement in scores although not statistically significant. CONCLUSIONS: We found that using a standardized tool and quantitative framework is useful for documenting capacity and performance improvement in identified areas over time. The use of the tool and standard reports with assessor recommendations assisted laboratories with establishing, maintaining, and improving influenza laboratory practices. On-going assessments and the consistent application of the analytic framework over time will continue to aid in building a measurement knowledge base for laboratory capacity. PMID- 28619010 TI - Did online publishers "get it right"? Using a naturalistic search strategy to review cognitive health promotion content on internet webpages. AB - BACKGROUND: One of the most common uses of the Internet is to search for health related information. Although scientific evidence pertaining to cognitive health promotion has expanded rapidly in recent years, it is unclear how much of this information has been made available to Internet users. Thus, the purpose of our study was to assess the reliability and quality of information about cognitive health promotion encountered by typical Internet users. METHODS: To generate a list of relevant search terms employed by Internet users, we entered seed search terms in Google Trends and recorded any terms consistently used in the prior 2 years. To further approximate the behaviour of typical Internet users, we entered each term in Google and sampled the first two relevant results. This search, completed in October 2014, resulted in a sample of 86 webpages, 48 of which had content related to cognitive health promotion. An interdisciplinary team rated the information reliability and quality of these webpages using a standardized measure. RESULTS: We found that information reliability and quality were moderate, on average. Just one retrieved page mentioned best practice, national recommendations, or consensus guidelines by name. Commercial content (i.e., product promotion, advertising content, or non-commercial) was associated with differences in reliability and quality, with product promoter webpages having the lowest mean reliability and quality ratings. CONCLUSIONS: As efforts to communicate the association between lifestyle and cognitive health continue to expand, we offer these results as a baseline assessment of the reliability and quality of cognitive health promotion on the Internet. PMID- 28619011 TI - To be active through indoor-climbing: an exploratory feasibility study in a group of children with cerebral palsy and typically developing children. AB - BACKGROUND: Cerebral Palsy (CP) is the most common cause of motor disabilities in children and young adults and it is also often associated with cognitive and physiological challenges. Climbing requires a multifaceted repertoire of movements, participants at all levels of expertise may be challenged functionally and cognitively, making climbing of great potential interest in (re)habilitation settings. However, until now only few research projects have investigated the feasibility of climbing as a potential activity for heightening physical activity in children with CP and the possible beneficial effects of climbing activities in populations with functional and/or cognitive challenges. The aim of this study was therefore to test the feasibility of an intensive 3 weeks indoor-climbing training program in children with CP and typically developing (TD) peers. In addition we evaluated possible functional and cognitive benefits of 3 weeks of intensive climbing training in 11 children with cerebral palsy (CP) aged 11-13 years and six of their TD peers. METHOD: The study was designed as a feasibility and interventional study. We evaluated the amount of time spent being physically active during the 9 indoor-climbing training sessions, and climbing abilities were measured. The participants were tested in a series of physiological, psychological and cognitive tests: two times prior to and one time following the training in order to explore possible effects of the intervention. RESULTS: The children accomplished the training goal of a total of nine sessions within the 3 week training period. The time of physical activity during a 2:30 h climbing session, was comparably high in the group of children with CP and the TD children. The children with CP were physically active on average for almost 16 h in total during the 3 weeks. Both groups of participants improved their climbing abilities, the children with CP managed to climb a larger proportion of the tested climbing route at the end of training and the TD group climbed faster. For the children with CP this was accompanied by significant improvements in the Sit to-stand test (p < 0.01), increased rate of force development in the least affected hand during an explosive pinch test and increased muscular-muscular coherence during a pinch precision test (p < 0.05). We found no improvements in maximal hand or finger strength and no changes in cognitive abilities or psychological well-being in any of the groups. CONCLUSIONS: These findings show that it is possible to use climbing as means to make children with CP physically active. The improved motor abilities obtained through the training is likely reflected by increased synchronization between cortex and muscles, which results in a more efficient motor unit recruitment that may be transferred to daily functional abilities. TRIAL REGISTRATION: ISRCTN18006574; day of registration: 09/05/2017; the trial is registered retrospectively. PMID- 28619012 TI - Genetic analysis of varicella-zoster virus in the aqueous humor in uveitis with severe hyphema. AB - BACKGROUND: Genetic variations have been identified in the genome of varicella zoster virus (VZV) strains using vesicle fluid, varicella scabs and throat swab samples. We report a rare case of VZV-associated uveitis with severe hyphema, which was immediately diagnosed by polymerase chain reaction (PCR) using the aqueous humor, in which we were able to analyze the VZV genotype for the first time. CASE PRESENTATION: A 16-year-old Japanese boy was referred to our hospital with a 20-day history of unilateral anterior uveitis and 11-day history of hyphema. At presentation, details of the iris, the iridocorneal angle, and the fundus were not visible due to the severe hyphema. Serum anti-VZV IgG and anti VZV IgM were elevated, and 1.61 * 109 copies/mL of VZV-DNA were detected by real time PCR using the aqueous humor. As there were no eruptions on his face or body, we diagnosed zoster sine herpete and started intravenous administration of prednisolone and acyclovir. The hyphema completely disappeared 2 weeks after presentation, while sectorial iris atrophy and mild periphlebitis of the fundus became gradually apparent. Anterior inflammation and periphlebitis gradually improved and VZV-DNA in the aqueous humor was reduced to 1.02 * 106 copies/mL at 4 weeks after presentation. Examination by slit lamp microscope revealed no inflammation after 5 months, and VZV-DNA could no longer be detected in the aqueous humor. Serum anti-VZV IgG and anti-VZV IgM also showed a gradual decrease along with improvement in ocular inflammation. The genetic analysis of multiple open reading frames and the R5 variable repeat region in the VZV genes, using DNA extracted from the aqueous humor at presentation, showed that the isolate was a wild-type clade 2 VZV strain (prevalent in Japan and surrounding countries) with R5A allele and one SNP unique to clade 1 (both are major types in Europe and North America). CONCLUSIONS: VZV-associated uveitis may develop hyphema that obscures ocular inflammation, thus PCR analysis using the aqueous humor is the key investigation necessary for the diagnosis. The measurement of VZV-DNA copies by real-time PCR would be useful for evaluation of therapeutic effects. We could amplify and analyze VZV genotype using the aqueous humor including a very large number of VZV-DNA copies (1.61 * 109 copies/mL). PMID- 28619013 TI - MLST genotypes of Campylobacter jejuni isolated from broiler products, dairy cattle and human campylobacteriosis cases in Lithuania. AB - BACKGROUND: Campylobacter (C.) jejuni is the leading cause of human campylobacteriosis worldwide. We performed a molecular epidemiological study to investigate the genetic relationship among C. jejuni strains isolated from human diarrhoeal patients, broiler products and dairy cattle in Lithuania. METHODS: The C. jejuni isolates from human clinical cases, dairy cattle and broiler products were genotyped using multilocus sequence typing (MLST). Allele numbers for each housekeeping gene, sequence type (ST), and clonal complex (CC) were assigned by submitting the DNA sequences to the C. jejuni MLST database ( http://pubmlst.org/campylobacter ). Based on the obtained sequence data of the housekeeping genes a phylogenetic analysis of the strains was performed and a minimum spanning tree (MST) was calculated. RESULTS: Among the 262 C. jejuni strains (consisting of 43 strains isolated from dairy cattle, 102 strains isolated from broiler products and 117 clinical human C. jejuni strains), 82 different MLST sequence types and 22 clonal complexes were identified. Clonal complexes CC21 and CC353 predominated among the C. jejuni strains. On ST-level, five sequence types (ST-5, ST-21, ST-50, ST-464 and ST-6410) were dominating and these five STs accounted for 35.9% (n = 94) of our isolates. In addition, 51 (19.5%) C. jejuni strains representing 27 (32.9%) STs were reported for the first time in the PubMLST database ( http://pubmlst.org/campylobacter ). The highest Czekanowski index or proportional similarity index (PSI) was calculated for C. jejuni strains isolated from human campylobacteriosis cases and broiler products (PSI = 0.32) suggesting a strong link between broiler strains and human cases. The PSI of dairy cattle and human samples was lower (PSI = 0.11), suggesting a weaker link between bovine strains and human cases. The calculated Simpson's index of all C. jejuni isolates showed a high genetic diversity (D = 0.96). CONCLUSION: Our results suggest that broiler products are the most important source of human campylobacteriosis in Lithuania. The study provides information on MLST type distribution and genetic relatedness of C. jejuni strains from humans, broiler products and dairy cattle in Lithuania for the first time, enabling a better understanding of the transmission pathways of C. jejuni in this country. PMID- 28619014 TI - Prognostic impact of blood and urinary angiogenic factor levels at diagnosis and during treatment in patients with osteosarcoma: a prospective study. AB - BACKGROUND: Angiogenesis is essential for the progression and metastatic spread of solid tumours. Expression of vascular endothelial growth factor (VEGF) has been linked to poor survival among osteosarcoma patients but the clinical relevance of monitoring blood and urine angiogenic factors is uncertain. The aim of this study was to determine the prognostic significance of blood VEGF and blood and urinary basic fibroblast growth factor (bFGF) levels in osteosarcoma patients, both at diagnosis and during treatment. METHODS: Patients with localised or metastatic osteosarcoma enrolled in OS2005 and OS2006 studies between 2005 and 2011 were prospectively included in this study. VEGF and bFGF levels in serum and plasma and bFGF levels in urine were measured by ELISA at diagnosis, before surgery, and at the end of treatment. Endpoints considered for the prognostic analysis were histological response, progression-free and overall survival. Kruskal-Wallis tests were used to compare the distribution of baseline biomarker values across the different subgroups, and paired sample Wilcoxon rank tests were used to analyze changes over time. Association between biomarker levels and outcomes were assessed in multivariable models (logistic regression for histologic response, and Cox models for survival). RESULTS: Samples were available at diagnosis for 269 patients (54% males; age <= 18 years: 73%; localised disease in 68%, doubtful lung lesions in 17%, and metastases in 15%). High serum VEGF and bFGF levels were observed in respectively 61% and 51% of patients. Serum and plasma VEGF values were not strongly correlated with one another (r = 0.53). High serum and plasma VEGF levels were significantly more frequent in patients with large tumours (>=10 cm; p = 0.003 and p = 0.02, respectively). VEGF levels fell significantly during pre-operative chemotherapy (p < 0.0001). No significant correlation was found between this variation and either the histological response, progression-free survival or overall survival (p = 0.26, p = 0.67, and p = 0.87, respectively). No significant association was found between blood or urinary bFGF levels and clinical characteristics, histological response, or survival. CONCLUSIONS: Levels of VEGF and bFGF angiogenic factors are high in most osteosarcoma patients, but have no significant impact on response to chemotherapy or outcome in this large prospective series. OS 2006 TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT00470223; date of registration: May 3th 2007. PMID- 28619015 TI - Nontuberculosis mycobacterial infections at a specialized tuberculosis treatment centre in the Republic of Korea. AB - BACKGROUND: The incidence of nontuberculous mycobacteria (NTM) infections is increasing worldwide, however formal evaluations of the epidemiology of NTM infections are limited. Understanding the trends and true prevalence of NTM is a major priority for optimizing infection control programmes and resources. The purpose of this study was to investigate the epidemiology, clinical manifestations, and radiologic findings in NTM-infected patients at specialized Tuberculosis (Tb) treatment centre in South Korea, which is endemic to Tb, and find solutions to control NTM infections. METHODS: A retrospective descriptive study was conducted among patients who were diagnosed with NTM from November 2011 to January 2016 at Seoul Metropolitan Government Seobuk hospital, Korea, using medical records and chest radiography results. Prevalence of NTM using national health insurance data was compared to the prevalence and incidence of Tb using National statistics data. RESULTS: The age- and sex- adjusted prevalence of NTM infection per 100,000 population increased between 2009 (9.4) and 2016 (36.1). However, the prevalence and incidence of Tb per 100,000 population decreased from 106.5 to 74.4, and 81.2 to 61.8, respectively. In total, 64 patients (37 [57.8%] men) were enrolled in the study. Among 33 (51.6%) patients with slowly growing nontuberculous mycobacteria (SGM) infection, 29 were detected with Mycobacterium avium complex (n = 13, M. avium; n = 16, M. intracellulare), and 4 with M. kansasii. Among 31 (48.4%) patients with rapidly growing nontuberculous mycobacteria (RGM) infection, 27 and 4 patients were detected with M. abscessus complex and M. fortuitum complex, respectively. RGM patients were more likely to have current Tb (P = 0.041), cough (P < 0.05), and sputum (P < 0.01) than SGM patients in the univariate analysis, but not in the multivariate analysis. CONCLUSION: Given the increasing prevalence of NTM infections, precise epidemiological and surveillance data should be obtained by reporting NTM infections to public health authorities. Introducing nucleic acid amplification tests to differentiate between Tb and NTM in smear-positive specimens should be considered. PMID- 28619016 TI - Clinical application of a novel endoscopic mask: a randomized controlled, multi center trial in patients undergoing awake fiberoptic bronchoscopic intubation. AB - BACKGROUND: Awake fiberoptic bronchoscopic tracheal intubation is usually regarded as an effective method in the management of predicted difficult airway. Hypoxia during awake nasal fiberoptic bronchoscopic intubation leads to discontinuation of the procedure, prolonged manipulation time and increased risk of severe complications. The main aim of the study was to test whether the novel endoscopic mask is helpful for hypoxia during the intubation. METHODS: This was a randomized, controlled, multi-center study. 55 patients were recruited, but one patient was lost to follow-up. Finally, 54 patients (19 man and 35 women) were analyzed. After entering the operating room, nasal catheter oxygen-providing was given in the control group, and the treatment group received endoscopic mask oxygen-providing, with a flow rate of 3 L/min, lasting into the end of the intubation. Primary outcomes included mean arterial pressure, heart rate, minimum pulse oxygen saturation and incidence of pulse oxygen saturation <= 90%. Secondary outcomes included number of intubation attempts and time to intubation. All outcomes were finally measured. RESULTS: Minimum pulse oxygen saturation during awake nasal fiberoptic bronchoscopic tracheal intubation was significantly higher in the endoscopic mask intubation group (91.7% +/- 4.7%) than that the nasal catheter intubation group (87.6% +/- 8.2%, P = 0.031. Furthermore, the incidence of pulse oxygen saturation <= 90% was significantly lower in the endoscopic mask intubation group (20.0%, 5/25) than that in the nasal catheter intubation group (51.7%, 15/29, P = 0.037). But mean arterial pressure of during intubation was significantly higher in the endoscopic mask group (100.0 +/- 13.3 vs 90.3 +/- 21.8, P = 0.049). In addition, there were no differences in the number of intubation attempts (P = 0.45) or time to intubation between the two groups (P = 0.38). CONCLUSIONS: The endoscopic mask was safely used in awake fiberoptic bronchoscopic tracheal intubation, with advantages of stable blood pressure and potential prevention of desaturation. Beginners for the intubation procedure and patients at high risk of hypoxia could benefit from the use of the endoscopic mask. TRIAL REGISTRATION: Trial registration: www.chictr.org.cn . Registration No.: ChiCTR-TRC-13004086. Date of Registration: 8th, Sep, 2013. PMID- 28619018 TI - Efficient soluble expression of disulfide bonded proteins in the cytoplasm of Escherichia coli in fed-batch fermentations on chemically defined minimal media. AB - BACKGROUND: The production of recombinant proteins containing disulfide bonds in Escherichia coli is challenging. In most cases the protein of interest needs to be either targeted to the oxidizing periplasm or expressed in the cytoplasm in the form of inclusion bodies, then solubilized and re-folded in vitro. Both of these approaches have limitations. Previously we showed that soluble expression of disulfide bonded proteins in the cytoplasm of E. coli is possible at shake flask scale with a system, known as CyDisCo, which is based on co-expression of a protein of interest along with a sulfhydryl oxidase and a disulfide bond isomerase. With CyDisCo it is possible to produce disulfide bonded proteins in the presence of intact reducing pathways in the cytoplasm. RESULTS: Here we scaled up production of four disulfide bonded proteins to stirred tank bioreactors and achieved high cell densities and protein yields in glucose fed batch fermentations, using an E. coli strain (BW25113) with the cytoplasmic reducing pathways intact. Even without process optimization production of purified human single chain IgA1 antibody fragment reached 139 mg/L and hen avidin 71 mg/L, while purified yields of human growth hormone 1 and interleukin 6 were around 1 g/L. Preliminary results show that human growth hormone 1 was also efficiently produced in fermentations of W3110 strain and when glucose was replaced with glycerol as the carbon source. CONCLUSIONS: Our results show for the first time that efficient production of high yields of soluble disulfide bonded proteins in the cytoplasm of E. coli with the reducing pathways intact is feasible to scale-up to bioreactor cultivations on chemically defined minimal media. PMID- 28619017 TI - Borderline personality disorder and childhood trauma: exploring the affected biological systems and mechanisms. AB - BACKGROUND: According to several studies, the onset of the Borderline Personality Disorder (BPD) depends on the combination between genetic and environmental factors (GxE), in particular between biological vulnerabilities and the exposure to traumatic experiences during childhood. We have searched for studies reporting possible alterations in several biological processes and brain morphological features in relation to childhood trauma experiences and to BPD. We have also looked for epigenetic mechanisms as they could be mediators of the effects of childhood trauma in BPD vulnerability. DISCUSSION: We prove the role of alterations in Hypothalamic-Pituitary-Adrenal (HPA) axis, in neurotrasmission, in the endogenous opioid system and in neuroplasticity in the childhood trauma associated vulnerability to develop BPD; we also confirm the presence of morphological changes in several BPD brain areas and in particular in those involved in stress response. Not so many studies are available on epigenetic changes in BPD patients, although these mechanisms are widely investigated in relation to stress-related disorders. A better comprehension of the biological and epigenetic mechanisms, affected by childhood trauma and altered in BPD patients, could allow to identify "at high risk" subjects and to prevent or minimize the development of the disease later in life. PMID- 28619019 TI - Life after prostate cancer treatment: a mixed methods study of the experiences of men with sexual dysfunction and their partners. AB - BACKGROUND: Prostate cancer is the most common non-skin cancer in men and sexual dysfunction is the most frequently reported long-term side effect of prostate cancer surgery or radiation. The aim of this study was to examine the experiences of men with sexual dysfunction and their partners following prostate cancer treatment. METHODS: Men with sexual dysfunction from either surgical removal or radiation therapy 1-5 years after treatment were interviewed, as well as their partners. A mixed method design was used to determine the lived experience of men with sexual dysfunction. Open-ended questions guided the interviews. RESULTS: Twenty seven men completed the study with a mean age of 61 years (SD = 8.0; range = 44-77 years). Nine partners also participated. The majority of men (92.6%) had surgery. The average time from treatment to the interview was 23.5 months (SD = 11.7). Themes were frustration with sexual dysfunction, importance of support and understanding from others, depression and anxiety related to sexual dysfunction, importance of intimacy with partner, factors that impact treatment satisfaction, and education and comprehensive information about sex. CONCLUSIONS: Prostate cancer survivors and partners need accurate information about sexual side effects before during and after treatment. Men and partners required individualized help and guidance to manage sexual dysfunction. Support and understanding from partners, family, and others was also identified as an important aspect of healing and adjustment after prostate cancer treatment. Prostate cancer education/support groups played a key role in helping men and partners gain advocacy, education, and support. Psychological problems such as depression and anxiety need to be identified and addressed in men after prostate cancer treatment. Men and partners need assistance in understanding and navigating their way through intimacy to move forward with connectedness in their relationship. Satisfaction with treatment and with providers is dependent on patient education and understanding of all aspects of prostate cancer treatment including sexual side effects and incontinence. PMID- 28619020 TI - Medical students can teach communication skills - a mixed methods study of cross year peer tutoring. AB - BACKGROUND: Cross-year peer tutoring (CYPT) of medical students is recognized as an effective learning tool. The aim of this study is to investigate the non inferiority of the objective outcome of medical interview training with CYPT compared with the results of faculty-led training (FLT), and to explore qualitatively the educational benefits of CYPT. METHODS: We conducted a convergent mixed methods study including a randomized controlled non-inferiority trial and two focus groups. For the CYPT group, teaching was led by six student tutors from year 5. In the FLT group, students were taught by six physicians. Focus groups for student learners (four tutees) and student teachers (six tutors) were conducted following the training session. RESULTS: One hundred sixteen students agreed to participate. The OSCE scores of the CYPT group and FLT group were 91.4 and 91.2, respectively. The difference in the mean score was 0.2 with a 95% CI of -1.8 to 2.2 within the predetermined non-inferiority margin of 3.0. By analyzing the focus groups, we extracted 13 subordinate concepts and formed three categories including 'Benefits of CYPT', 'Reflections of tutees and tutors' and 'Comparison with faculty', which affected the interactions among tutees, tutors, and faculty. CONCLUSIONS: CYPT is effective for teaching communication skills to medical students and for enhancing reflective learning among both tutors and tutees. PMID- 28619021 TI - Treatment of thoracolumbar burst fractures by short-segment pedicle screw fixation using a combination of two additional pedicle screws and vertebroplasty at the level of the fracture: a finite element analysis. AB - BACKGROUND: Traditional one-above and one-below four-screw posterior short segment instrumentation is used for unstable thoracolumbar burst fractures. However, this method has a high rate of implant failure and early loss of reduction. The purpose of this study was to use finite element (FE) analysis to determine the effect of treating thoracolumbar burst fractures by short-segment pedicle screw fixation using a combination of two additional pedicle screws and vertebroplasty at the level of the fracture. METHODS: An intact T11-L1 spine FE model was created from the computed tomography images of a male subject. Four fixation models with posterior fusion devices (pedicle screws, rods, cross-link) were established to simulate an unstable thoracolumbar fracture with different fusion surgeries: short-segment fixation with: 1) a link (S-L); 2) intermediate bilateral screws (S-I); 3) a link and calcium sulfate cement (S-L-C); 4) intermediate bilateral screws and calcium sulfate cement (S-I-C). Different loading conditions (flexion, extension, lateral bending, and axial rotation) were applied on the models and analyzed with a FE package. The range of motion (ROM), and the maximum value and distribution of the implant stress, and the stress in the facet joint, were compared between the intact and fixation models. RESULTS: The ROM in flexion, extension, axial rotation, and lateral bending was the smallest in the S-I-C model, followed by the S-I, S-L-C, and S-L models. Maximum von Mises stress values were larger under lateral bending and axial rotation loadings than under flexion and extension loading. High stress was concentrated at the crosslink and rod junctions. Maximal von Mises stress on the superior vertebral body for all loading conditions was larger than that on the inferior vertebral body. The maximal von Mises stress of the pedicle screws during all states of motion were 265.3 MPa in S-L fixation, 192.9 MPa in S-I fixation, 258.4 MPa in S-L-C fixation, and 162.3 MPa in S-I-C fixation. CONCLUSIONS: Short segment fixation with two intermediate pedicle screws together with calcium sulfate cement at the fractured vertebrae may provide a stiffer construct and less von Mises stress of the pedicle screws and rods as compared to other types of short-segment fixation. PMID- 28619022 TI - Effect of low-magnitude different-frequency whole-body vibration on subchondral trabecular bone microarchitecture, cartilage degradation, bone/cartilage turnover, and joint pain in rabbits with knee osteoarthritis. AB - BACKGROUD: Whole-body vibration(WBV) has been suggested for the prevention of subchondral bone loss of knee osteoarthritis (OA) . This study examined the effects of different frequency of whole-body vibration on subchondral trabecular bone microarchitecture, cartilage degradation and metabolism of the tibia and femoral condyle bone, and joint pain in an anterior cruciate ligament transection (ACLT)-induced knee osteoarthritisrabbit model. METHOD: Ninety adult rabbits were divided into six groups: all groups received unilateral ACLT; Group 1, ACLT only; Group 2, 5 Hz WBV; Group 3, 10 Hz WBV; Group 4, 20 Hz WBV; Group 5, 30 Hz WBV; and Group 6, 40 Hz WBV. Pain was tested via weight-bearing asymmetry. Subchondral trabecular bone microarchitecture was examined using in vivo micro-computed tomography. Knee joint cartilage was evaluated by gross morphology, histology, and ECM gene expression level (aggrecan and type II collagen [CTX-II]). Serum bone-specific alkaline phosphatase, N-mid OC, cartilage oligometric protein, CPII, type I collagen, PIIANP, G1/G2 aggrecan levels, and urinary CTX-II were analyzed. RESULTS: After 8 weeks of low-magnitude WBV, the lower frequency (10 Hz and 20 Hz) WBV treatment decreased joint pain and cartilage resorption, accelerated cartilage formation, delayed cartilage degradation especially at the 20 Hz regimen. However, the higher frequencies (30 Hz and 40 Hz) had worse effects, with worse limb function and cartilage volume as well as higher histological scores and cartilage resorption. In contrast, both prevented loss of trabeculae and increased bone turnover. No significant change was observed in the 5 Hz WBV group. CONCLUSION: Our data demonstrate that the lower frequencies (10 Hz and 20 Hz) of low-magnitude WBV increased bone turnover, delayed cartilage degeneration, and caused a significant functional change of the OA-affected limb in ACLT-induced OA rabbit model but did not reverse OA progression after 8 weeks of treatment. PMID- 28619023 TI - Potential for adaptation to climate change: family-level variation in fitness related traits and their responses to heat waves in a snail population. AB - BACKGROUND: On-going global climate change poses a serious threat for natural populations unless they are able to evolutionarily adapt to changing environmental conditions (e.g. increasing average temperatures, occurrence of extreme weather events). A prerequisite for evolutionary change is within population heritable genetic variation in traits subject to selection. In relation to climate change, mainly phenological traits as well as heat and desiccation resistance have been examined for such variation. Therefore, it is important to investigate adaptive potential under climate change conditions across a broader range of traits. This is especially true for life-history traits and defences against natural enemies (e.g. parasites) since they influence organisms' fitness both directly and through species interactions. We examined the adaptive potential of fitness-related traits and their responses to heat waves in a population of a freshwater snail, Lymnaea stagnalis. We estimated family-level variation and covariation in life history (size, reproduction) and constitutive immune defence traits [haemocyte concentration, phenoloxidase (PO) like activity, antibacterial activity of haemolymph] in snails experimentally exposed to typical (15 degrees C) and heat wave (25 degrees C) temperatures. We also assessed variation in the reaction norms of these traits between the treatments. RESULTS: We found that at the heat wave temperature, snails were larger and reproduced more, while their immune defence was reduced. Snails showed high family-level variation in all examined traits within both temperature treatments. The only negative genetic correlation (between reproduction and antibacterial activity) appeared at the high temperature. However, we found no family-level variation in the responses of most examined traits to the experimental heat wave (i.e. largely parallel reaction norms between the treatments). Only the reduction of PO-like activity when exposed to the high temperature showed family-level variation, suggesting that the cost of heat waves may be lower for some families and could evolve under selection. CONCLUSION: Our results suggest that there is genetic potential for adaptation within both thermal environments and that trait evolution may not be strongly affected by trade-offs between them. However, rare differences in thermal reaction norms across families indicate limited evolutionary potential in the responses of snails to changing temperatures during extreme weather events. PMID- 28619024 TI - Communication with young people in paediatric and adult endocrine consultations: an intervention development and feasibility study. AB - BACKGROUND: Communication is complex in endocrine care, particularly during transition from paediatric to adult services. The aims of this study were to examine the feasibility of interventions to support young people to interact with clinicians. METHODS: Development and evaluation of a complex intervention in 2 phases: Pre-intervention observational study; Intervention feasibility study. Purposive sample of recordings of 62 consultations with 58 young people aged 11 25 years with long-term endocrine conditions in two paediatric and two adult endocrine clinics. Proportion of time talked during consultations, number and direction of questions asked; Paediatric Consultation Assessment Tool (PCAT); OPTION shared decision making tool; Medical Information Satisfaction Scale (MISS- 21). Young people were invited to use one or more of: a prompt sheet to help them influence consultation agendas and raise questions; a summary sheet to record key information; and the www.explain.me.uk website. RESULTS: Nearly two thirds of young people (63%) chose to use at least one communication intervention. Higher ratings for two PCAT items (95% CI 0.0 to 1.1 and 0.1 to 1.7) suggest interventions can support consultation skills. A higher proportion of accompanying persons (83%) than young people (64%) directed questions to clinicians. The proportion of young people asking questions was higher (84%) in the intervention phase than in the observation phase (71%). CONCLUSIONS: Interventions were acceptable and feasible. The Intervention phase was associated with YP asking more questions, which implies that the availability of interventions could promote interactivity. PMID- 28619026 TI - Elevated serum fibroblast growth factor 23 levels as an indicator of lower extremity atherosclerotic disease in Chinese patients with type 2 diabetes mellitus. AB - BACKGROUND: Recently, basic and clinical studies have provided evidence supporting the relationship between circulating levels of fibroblast growth factor (FGF) 23 and the development of atherosclerosis. Given that diabetes is an established risk factor for lower extremity atherosclerotic disease (LEAD), the goal of the present study was to explore the relationship between serum FGF23 levels and LEAD, as well as the related factors, in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 401 hospitalized T2DM patients (201 subjects with LEAD and 200 subjects without LEAD) were enrolled in this study. Serum FGF23 levels were determined by a sandwich enzyme-linked immunosorbent assay. Femoral intima-media thickness (F-IMT) and lower limb atherosclerotic plaque were assessed through color Doppler ultrasound. RESULTS: The median (interquartile range) serum FGF23 levels in the entire study population was 42.08 (35.59-49.17) pg/mL. Subjects with LEAD had significantly higher serum FGF23 levels compared with those without LEAD (44.00 [37.54-51.30] pg/mL versus 40.42 [32.61-48.23] pg/mL, P < 0.001). Logistic regression showed that serum FGF23 levels were independently and positively correlated with the presence of LEAD (odds ratio 1.039, 95% confidence interval 1.012-1.067, P = 0.004). In addition, multiple liner regression analysis revealed that serum FGF23 levels were positively associated with F-IMT (standardized beta = 0.175, P < 0.001). Furthermore, this relationship remained significant after additional adjustment for gender and factors potentially affecting serum FGF23 levels (serum calcium, serum phosphorus, and glomerular filtration rate), respectively (both P < 0.01). CONCLUSIONS: In Chinese patients with T2DM, serum FGF23 levels were independently and positively correlated with the presence of LEAD. PMID- 28619027 TI - : health is my capital: a qualitative study of access to healthcare by Chinese migrants in Singapore. AB - BACKGROUND: Since the 1970s, Singapore has turned into one of the major receiving countries of foreign workers in Southeast Asia. Over the years, challenges surrounding access to healthcare by Chinese migrant workers have surfaced globally. This study aims to explore the experiences of Chinese migrants accessing primary and secondary/tertiary healthcare in Singapore, and the opportunities for overcoming these barriers. METHODS: We conducted 25 in-depth interviews of 20 Chinese migrants and five staff from HealthServe, a non governmental organization serving Chinese migrants in Singapore from October 2015 to January 2016. Interviews were transcribed and analysed inductively adopting thematic analysis. RESULTS: Chinese migrants in Singapore who were interviewed are mainly middle-aged breadwinners with multiple dependents. Their concept of health is encapsulated in a Chinese proverb "", meaning "health is my capital". Health is defined by them as a personal asset, needed to provide for their families. From their health-seeking behaviors, six pathways were identified, highlighting different routes chosen and resulting outcomes depending on whether their illness was perceived as major or minor, and if they sought help from the private or public sector private or public sector. Key barriers were identified relating to vulnerabilities during the migration process, during their illness, when consulting with healthcare providers, and during repatriation. A transactional doctor-patient culture in China contrasts with the trust migrants place in Singaporean's public health system, perceived as equitable and personable. However, challenges remain for injured migrants who sought help from the private sector and those with chronic diseases. CONCLUSIONS: Policy recommendations to increase patient autonomy enabling choice of healthcare provider and provide for non-work related illnesses are suggested. Partnerships between migrant advocacy organizations and various stakeholders such as hospitals, government agencies and employers can be strengthened. PMID- 28619025 TI - Evaluating the effectiveness of a healthy lifestyle clinician in addressing the chronic disease risk behaviours of community mental health clients: study protocol for a randomised controlled trial. AB - BACKGROUND: People with a mental illness experience a greater morbidity and mortality from chronic diseases relative to the general population. A higher prevalence of modifiable health risk behaviours such as smoking, poor nutrition, physical inactivity and harmful alcohol consumption contribute substantially to this disparity. Despite clinical practice guidelines recommending that mental health services routinely provide care to address these risk behaviours, the provision of such care is consistently reported to be low internationally and in Australia. This protocol describes a randomised controlled trial that aims to assess the effectiveness of allocating a clinician within a community mental health service to the specific role of providing assessment, advice and referral for clients' chronic disease risk behaviours. METHODS/DESIGN: Approximately 540 clients of one community mental health service will be randomised to receive either usual care for chronic disease risks provided in routine consultations or usual care plus an additional face-to-face consultation and follow-up telephone call with a 'healthy lifestyle clinician'. The clinician will assess clients' chronic disease risk behaviours, provide advice to change behaviours, and refer at-risk clients to free telephone coaching services (New South Wales (NSW) Quitline and NSW Get Healthy Information and Coaching Service) for specialist behaviour change care. The primary outcomes, regarding referral to and client uptake of the telephone services, will be obtained from the respective services. Telephone interviews of clients at baseline and at 1 and 6 months post baseline follow-ups will assess secondary outcomes: receipt of any assessment, advice and referral from the mental health service; satisfaction with the receipt of such care; satisfaction with the receipt of any care provided by the telephone services; interest and confidence in and perceived importance of changing risk behaviours; and risk behaviour status. DISCUSSION: This study will add to the limited literature regarding effective strategies to address chronic disease prevention among the higher risk population of community mental health clients. The results will inform the development of future policies and service delivery initiatives to address the high prevalence of chronic disease risk behaviours among people with a mental illness. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12616001519448 . Registered on 3 November 2016. PMID- 28619029 TI - Rapid deterioration of Mooren's ulcers after conjunctival flap: a review of 2 cases. AB - BACKGROUND: Conjunctival flaps are a widely used treatment for numerous corneal ulcers that are caused by microorganismal infections. However, whether it can be performed on immune-mediated corneal ulcers is controversial. CASE PRESENTATION: We present two cases of Mooren's ulcer that were treated using conjunctival flap in an attempt to prevent further corneal perforation at their local hospital. A rapid acceleration in ulcer progression was observed after a conjunctival flap was applied. Ultimately, the two patients underwent corneal transplantation, which required the postoperative use of topical immunosuppressants and resulted in a final cure. In the current report, we also discussed this incorrect surgical choice via a review of conventional interventions that are used to treat Mooren's ulcer. CONCLUSIONS: These two cases demonstrate that keratoplasty combined with topical immunosuppressants is effective in treating Mooren's ulcer. Application of conjunctival flaps or autografting could promote progression of ulceration in Mooren's ulcers. PMID- 28619028 TI - In vitro downregulated hypoxia transcriptome is associated with poor prognosis in breast cancer. AB - BACKGROUND: Hypoxia is a characteristic of breast tumours indicating poor prognosis. Based on the assumption that those genes which are up-regulated under hypoxia in cell-lines are expected to be predictors of poor prognosis in clinical data, many signatures of poor prognosis were identified. However, it was observed that cell line data do not always concur with clinical data, and therefore conclusions from cell line analysis should be considered with caution. As many transcriptomic cell-line datasets from hypoxia related contexts are available, integrative approaches which investigate these datasets collectively, while not ignoring clinical data, are required. RESULTS: We analyse sixteen heterogeneous breast cancer cell-line transcriptomic datasets in hypoxia-related conditions collectively by employing the unique capabilities of the method, UNCLES, which integrates clustering results from multiple datasets and can address questions that cannot be answered by existing methods. This has been demonstrated by comparison with the state-of-the-art iCluster method. From this collection of genome-wide datasets include 15,588 genes, UNCLES identified a relatively high number of genes (>1000 overall) which are consistently co-regulated over all of the datasets, and some of which are still poorly understood and represent new potential HIF targets, such as RSBN1 and KIAA0195. Two main, anti-correlated, clusters were identified; the first is enriched with MYC targets participating in growth and proliferation, while the other is enriched with HIF targets directly participating in the hypoxia response. Surprisingly, in six clinical datasets, some sub-clusters of growth genes are found consistently positively correlated with hypoxia response genes, unlike the observation in cell lines. Moreover, the ability to predict bad prognosis by a combined signature of one sub-cluster of growth genes and one sub-cluster of hypoxia-induced genes appears to be comparable and perhaps greater than that of known hypoxia signatures. CONCLUSIONS: We present a clustering approach suitable to integrate data from diverse experimental set-ups. Its application to breast cancer cell line datasets reveals new hypoxia-regulated signatures of genes which behave differently when in vitro (cell-line) data is compared with in vivo (clinical) data, and are of a prognostic value comparable or exceeding the state-of-the-art hypoxia signatures. PMID- 28619030 TI - Integrative analysis of DNA methylation, mRNAs, and small RNAs during maize embryo dedifferentiation. AB - BACKGROUND: Maize (Zea mays) is an important model crop for transgenic studies. However, genetic transformation of maize requires embryonic calli derived from immature embryo, and the impact of utilizing tissue culture methods on the maize epigenome is poorly understood. Here, we generated whole-genome MeDIP-seq data examining DNA methylation in dedifferentiated and normal immature maize embryos. RESULTS: We observed that most of the dedifferentiated embryos exhibited a methylation increase compared to normal embryos. Increased methylation at promoters was associated with down-regulated protein-coding gene expression; however, the correlation was not strong. Analysis of the callus and immature embryos indicated that the methylation increase was induced during induction of embryonic callus, suggesting phenotypic consequences may be caused by perturbations in genomic DNA methylation levels. The correlation between the 21 24nt small RNAs and DNA methylation regions were investigated but only a statistically significant correlation for 24nt small RNAs was observed. CONCLUSIONS: These data extend the significance of epigenetic changes during maize embryo callus formation, and the methylation changes might explain some of the observed embryonic callus variation in callus formation. PMID- 28619031 TI - Healthy people and healthy profits? Elaborating a conceptual framework for governing the commercial determinants of non-communicable diseases and identifying options for reducing risk exposure. AB - BACKGROUND: Non-communicable diseases (NCDs) represent a significant threat to human health and well-being, and carry significant implications for economic development and health care and other costs for governments and business, families and individuals. Risks for many of the major NCDs are associated with the production, marketing and consumption of commercially produced food and drink, particularly those containing sugar, salt and transfats (in ultra processed products), alcohol and tobacco. The problems inherent in primary prevention of NCDs have received relatively little attention from international organizations, national governments and civil society, especially when compared to the attention paid to secondary and tertiary prevention regimes (i.e. those focused on provision of medical treatment and long-term clinical management). This may in part reflect that until recently the NCDs have not been deemed a priority on the overall global health agenda. Low political priority may also be due in part to the complexity inherent in implementing feasible and acceptable interventions, such as increased taxation or regulation of access, particularly given the need to coordinate action beyond the health sector. More fundamentally, governing determinants of risk frequently brings public health into conflict with the interests of profit-driven food, beverage, alcohol and tobacco industries. MATERIALS: We use a conceptual framework to review three models of governance of NCD risk: self-regulation by industry; hybrid models of public-private engagement; and public sector regulation. We analyse the challenges inherent in each model, and review what is known (or not) about their impact on NCD outcomes. CONCLUSION: While piecemeal efforts have been established, we argue that mechanisms to control the commercial determinants of NCDs are inadequate and efforts at remedial action too limited. Our paper sets out an agenda to strengthen each of the three governance models. We identify reforms that will be needed to the global health architecture to govern NCD risks, including to strengthen its ability to consolidate the collective power of diverse stakeholders, its authority to develop and enforce clear measures to address risks, as well as establish monitoring and rights-based accountability systems across all actors to drive measurable, equitable and sustainable progress in reducing the global burden of NCDs. PMID- 28619033 TI - Social representations of malaria in the Guna indigenous population of Comarca Guna de Madungandi, Panama. AB - BACKGROUND: The purpose of the study was to recognize the social representation of the Guna indigenous population by identifying cultural elements related to malaria, in order to create an intercultural approach to any health intervention to control and prevent the disease. METHODS: This qualitative study has an anthropological focus that used participant observation, informal conversations, focus groups, interviews, in-depth interviews with key actors. Analyses included review, classification and categorization of interviews. RESULTS: Malaria within the Guna culture is in harmony with several cultural factors, such as magic, religion, beliefs, myths, and nature. The health system must include these factors in its intercultural approach to ensure the sustainability of anti malarial intervention measures. Until this is not properly addressed, the Guna population of Madungandi will remain a permanent source of risk for malaria transmission in this region and for the rest of the country. CONCLUSION: The findings of this study contribute new variables that can facilitate an intercultural approach to improve the perception of malaria in the indigenous population of Comarca Guna de Madungandi, Panama. PMID- 28619032 TI - The role of intracellular trafficking of CdSe/ZnS QDs on their consequent toxicity profile. AB - BACKGROUND: Nanoparticle interactions with cellular membranes and the kinetics of their transport and localization are important determinants of their functionality and their biological consequences. Understanding these phenomena is fundamental for the translation of such NPs from in vitro to in vivo systems for bioimaging and medical applications. Two CdSe/ZnS quantum dots (QD) with differing surface functionality (NH2 or COOH moieties) were used here for investigating the intracellular uptake and transport kinetics of these QDs. RESULTS: In water, the COOH- and NH2-QDs were negatively and positively charged, respectively, while in serum-containing medium the NH2-QDs were agglomerated, whereas the COOH-QDs remained dispersed. Though intracellular levels of NH2- and COOH-QDs were very similar after 24 h exposure, COOH-QDs appeared to be continuously internalised and transported by endosomes and lysosomes, while NH2 QDs mainly remained in the lysosomes. The results of (intra)cellular QD trafficking were correlated to their toxicity profiles investigating levels of reactive oxygen species (ROS), mitochondrial ROS, autophagy, changes to cellular morphology and alterations in genes involved in cellular stress, toxicity and cytoskeletal integrity. The continuous flux of COOH-QDs perhaps explains their higher toxicity compared to the NH2-QDs, mainly resulting in mitochondrial ROS and cytoskeletal remodelling which are phenomena that occur early during cellular exposure. CONCLUSIONS: Together, these data reveal that although cellular QD levels were similar after 24 h, differences in the nature and extent of their cellular trafficking resulted in differences in consequent gene alterations and toxicological effects. PMID- 28619034 TI - Evaluation of two intervention models on contraceptive attitudes and behaviors among nulliparous women in Shanghai, China: a clustered randomized controlled trial. AB - BACKGROUND: With increasing acceptance of premarital sex among young Chinese women, the rates of unintended pregnancies and induced abortions are becoming alarmingly high, suggesting the needs of educating women with adequate contraceptive knowledge and providing them with accessible contraceptive services. Previous studies have shown that knowledge and attitudes towards contraception could be modified through intervention strategies. This study aimed to evaluate the effects of two community intervention models on modifying contraceptive attitudes and behaviors among nulliparous women. METHODS: In this clustered randomized controlled trial, nulliparous women aged 18-40 years from 18 communities were enrolled and randomized to either the traditional community intervention model (TC model) or the more comprehensive new community-based intervention model (NC model) with a ratio of 1:2. Contraceptive attitudes and behaviors were assessed before and after the interventions. RESULTS: A total of 901 nulliparous women were followed. The most common contraceptive method in both groups was condom (approximately 80%) before or after interventions. The rates of using effective contraceptive methods were very low (<5%) even after the intervention. Comparing the NC with TC group, the adjusted ORs and 95% CIs regarding natural family planning, emergency contraceptive usage and short-acting OCPs were1.53 (95% CI: 1.11-2.13), 2.87 (95% CI: 2.05-4.02), and 2.71 (95% CI: 1.65-4.47), respectively; while the ORs and 95%CIs of gynecological examination and contraceptive use were 2.31 (95% CI: 1.63-3.27) and 2.89 (95% CI: 1.98-4.23), respectively. No statistical significant difference was found for the use of effective contraceptive methods at post-intervention among the two models. CONCLUSIONS: High proportions of nulliparous women held negative attitudes and behaviors towards effective contraceptive methods. The NC model, integrating existing health resources, had more positive influence than the TC model on the favorable contraceptive attitudes and behaviors towards the use of any contraceptive methods, but had limited impact on the use of effective contraceptive methods. Our study suggested the feasibility of applying the NC model in Shanghai. Interventions on contraceptive attitudes and behaviors should base on the existing health service system, synthesize resources and selectively apply to populations with distinct characteristics. PMID- 28619035 TI - An evolutionary optimization of a rhodopsin-based phototrophic metabolism in Escherichia coli. AB - BACKGROUND: The expression of the Gloeobacter rhodopsin (GR) in a chemotrophic Escherichia coli enables the light-driven phototrophic energy generation. Adaptive laboratory evolution has been used for acquiring desired phenotype of microbial cells and for the elucidation of basic mechanism of molecular evolution. To develop an optimized strain for the artificially acquired phototrophic metabolism, an ancestral E. coli expressing GR was adaptively evolved in a chemostat reactor with constant illumination and limited glucose conditions. This study was emphasized at an unexpected genomic mutation contributed to the improvement of microbial performance. RESULTS: During the chemostat culture, increase of cell size was observed, which were distinguished from that of the typical rod-shaped ancestral cells. A descendant ET5 strain was randomly isolated from the chemostat culture at 88-days. The phototrophic growth and the light-induced proton pumping of the ET5 strain were twofold and eightfold greater, respectively, than those of the ancestral E. coli strain. Single point mutation of C1082A at dgcQ gene (encoding diguanylate cyclase, also known as the yedQ gene) in the chromosome of ET5 strain was identified from whole genome sequencing analysis. An ancestral E. coli complemented with the same dgcQ mutation from the ET5 was repeated the subsequently enhancements of light-driven phototrophic growth and proton pumping. Intracellular c-di-GMP, the product of the diguanylate cyclase (dgcQ), of the descendant ET5 strain was suddenly increased while that of the ancestral strain was negligible. CONCLUSIONS: Newly acquired phototrophic metabolism of E. coli was further improved via adaptive laboratory evolution by the rise of a point mutation on a transmembrane cell signaling protein followed by increase of signal molecule that eventually led an increase proton pumping and phototrophic growth. PMID- 28619036 TI - Monocyte differentiation and macrophage priming are regulated differentially by pentraxins and their ligands. AB - BACKGROUND: Circulating bone marrow-derived monocytes can leave the blood, enter a tissue, and differentiate into M1 inflammatory, M2a remodeling/fibrotic, or M2c/Mreg resolving/immune-regulatory macrophages. Macrophages can also convert from one of the above types to another. Pentraxins are secreted proteins that bind to, and promote efficient clearance of, microbial pathogens and cellular debris during infection, inflammation, and tissue damage. The pentraxins C reactive protein (CRP), serum amyloid P (SAP), and pentraxin-3 (PTX3) can also bind a variety of endogenous ligands. As monocytes and macrophages are exposed to differing concentrations of pentraxins and their ligands during infection, inflammation, and tissue damage, we assessed what effect pentraxins and their ligands have on these cells. RESULTS: We found that many polarization markers do not discriminate between the effects of pentraxins and their ligands on macrophages. However, pentraxins, their ligands, and cytokines differentially regulate the expression of the hemoglobin-haptoglobin complex receptor CD163, the sialic acid-binding lectin CD169, and the macrophage mannose receptor CD206. CRP, a pentraxin generally thought of as being pro-inflammatory, increases the extracellular accumulation of the anti-inflammatory cytokine IL-10, and this effect is attenuated by GM-CSF, mannose-binding lectin, and factor H. CONCLUSIONS: These results suggest that the presence of pentraxins and their ligands regulate macrophage differentiation in the blood and tissues, and that CRP may be a potent inducer of the anti-inflammatory cytokine IL-10. PMID- 28619037 TI - IFN-lambda1 with Th17 axis cytokines and IFN-alpha define different subsets in systemic lupus erythematosus (SLE). AB - BACKGROUND: Interferon (IFN)-alpha is thought to have a pivotal role in systemic lupus erythematosus (SLE), and type III IFNs (IFN-lambda) were recently also associated with SLE. In this study, we measured levels of IFN-alpha, IFN-lambda1, and related cytokines, such as IL-17A, IL-23, and interferon-gamma-induced protein 10 (IP-10), in a Karolinska University Hospital cohort of patients with SLE and control subjects. The objective of the study was to investigate if cytokine measurements could identify different subsets of patients with active SLE and higher disease damage. METHODS: We included 261 patients with SLE and 261 population control subjects. All participants underwent a standardized clinical examination. Medical files were reviewed. Patients with SLE were assessed for current organ manifestations, disease activity, and damage. Routine blood parameters, complement levels, and serology were analyzed at the time of inclusion. Levels of IFN-lambda1, IFN-alpha, IL-17A, IL-23, and IP-10 were measured by enzyme-linked immunosorbent assay. RESULTS: IFN-lambda1 and IFN-alpha were detected in 29% and 44% of patients, respectively, but their levels did not correlate. High serum levels of IFN-lambda1 were positively associated with antinucleosome antibodies and lymphopenia but negatively with musculoskeletal damage. Positive correlations between levels of IFN-lambda1, IL-17A, and IL-23 were observed. Patients with high levels of these three cytokines had more disease damage, especially renal impairment. High levels of IFN-alpha were associated with mucocutaneous disease; leukopenia; and low complement, Ro/SSA, and La/SSB. Vascular events and antiphospholipid antibodies were uncommon. We identified two subgroups with high disease activity: one with double-high IFN lambda1 and IFN-alpha and another with IP-10high. The former had more neuropsychiatric manifestations, and the latter had more arthritis. Increased levels of both types I and III IFNs were found in a proportion of population control subjects. Therefore, high IFN levels do not seem to be SLE-specific biomarkers. CONCLUSIONS: Measurements of circulating IFN-lambda1 and IFN-alpha define subsets of patients with SLE with different characteristics. Levels of IFN lambda1 correlate with T-helper type 17 cytokines and identify a subgroup with more damage. High disease activity is associated with either simultaneous upregulation of IFN-lambda1 and IFN-alpha or independently with IP-10. Our findings could be of major importance when tailoring therapy for patients with SLE with agents targeting IFN pathways. PMID- 28619038 TI - The experiences of women with maternal near miss and their perception of quality of care in Kelantan, Malaysia: a qualitative study. AB - BACKGROUND: Maternal mortality has been the main way of ascertaining the outcome of maternal and obstetric care. However, maternal morbidities occur more frequently than maternal deaths; therefore, maternal near miss was suggested as a more useful indicator for the evaluation and improvement of maternal health services. Our study aimed to explore the experiences of women with maternal near miss and their perception of the quality of care in Kelantan, Malaysia. METHODS: A qualitative phenomenological approach with in-depth interview method was conducted in two tertiary hospitals in Kelantan, Malaysia. All women admitted to labour room, obstetrics and gynaecology wards and intensive care units in 2014 were screened for the presence of any vital organ dysfunction or failure based on the World Health Organization criteria for maternal near miss. Pregnancy irrespective of the gestational age was included. Women younger than 18 years old, with psychiatric disorder and beyond 42 days of childbirth were excluded. RESULTS: Thirty women who had experienced maternal near miss events were included in the analysis. All were Malays between the ages of 22 and 45. Almost all women (93.3%) had secondary and tertiary education and 63.3% were employed. The women's perceptions of the quality of their care were influenced by the competency and promptness in the provision of care, interpersonal communication, information sharing and the quality of physical resources. The predisposition to seek healthcare was influenced by costs, self-attitude and beliefs. CONCLUSIONS: Self appraisal of maternal near miss, their perception of the quality of care, their predisposition to seek healthcare and the social support received were the four major themes that emerged from the experiences and perceptions of women with maternal near miss. The women with maternal near miss viewed their experiences as frightening and that they experienced other negative emotions and a sense of imminent death. The factors influencing women's perceptions of quality of care should be of concern to those seeking to improve services at healthcare facilities. The addition of a maternal near miss case review programme, allows for understanding on the factors related to providing care or to the predisposition to seek care; if addressed, may improve future healthcare and patient outcomes. PMID- 28619039 TI - Food insecurity and food consumption by season in households with children in an Arctic city: a cross-sectional study. AB - BACKGROUND: High rates of food insecurity are documented among Inuit households in Canada; however, data on food insecurity prevalence and seasonality for Inuit households with children are lacking, especially in city centres. This project: (1) compared food consumption patterns for households with and without children, (2) compared the prevalence of food insecurity for households with and without children, (3) compared food consumption patterns and food insecurity prevalence between seasons, and (4) identified factors associated with food insecurity in households with children in Iqaluit, Nunavut, Canada. METHODS: Randomly selected households were surveyed in Iqaluit in September 2012 and May 2013. Household food security status was determined using an adapted United States Department of Agriculture Household Food Security Survey Module. Univariable logistic regressions were used to examine unconditional associations between food security status and demographics, socioeconomics, frequency of food consumption, and method of food preparation in households with children by season. RESULTS: Households with children (n = 431) and without children (n = 468) participated in the survey. Food insecurity was identified in 32.9% (95% CI: 28.5-37.4%) of households with children; this was significantly higher than in households without children (23.2%, 95% CI: 19.4-27.1%). The prevalence of household food insecurity did not significantly differ by season. Demographic and socioeconomic characteristics of the person responsible for food preparation, including low formal education attainment (ORSept = 4.3, 95% CI: 2.3-8.0; ORMay = 3.2, 95% CI: 1.8-5.8), unemployment (ORSept = 1.1, 95% CI: 1.1-1.3; ORMay = 1.3, 95% CI: 1.1 1.5), and Inuit identity (ORSept = 8.9, 95% CI: 3.4-23.5; ORMay = 21.8, 95% CI: 6.6-72.4), were associated with increased odds of food insecurity in households with children. Fruit and vegetable consumption (ORSept = 0.4, 95% CI: 0.2-0.8; ORMay = 0.5, 95% CI: 0.2-0.9), as well as eating cooked (ORSept = 0.5, 95% CI: 0.3-1.0; ORMay = 0.5, 95% CI: 0.3-0.9) and raw (ORSept = 1.7, 95% CI: 0.9-3.0; ORMay = 1.8, 95% CI: 1.0-3.1) fish were associated with decreased odds of food insecurity among households with children, while eating frozen meat and/or fish (ORSept = 2.6, 95% CI: 1.4-5.0; ORMay = 2.0, 95% CI: 1.1-3.7) was associated with increased odds of food insecurity. CONCLUSIONS: Food insecurity is high among households with children in Iqaluit. Despite the partial subsistence livelihoods of many Inuit in the city, we found no seasonal differences in food security and food consumption for households with children. Interventions aiming to decrease food insecurity in these households should consider food consumption habits, and the reported demographic and socioeconomic determinants of food insecurity. PMID- 28619040 TI - Helicobacter suis induces changes in gastric inflammation and acid secretion markers in pigs of different ages. AB - Gastric mRNA expression of markers for acid secretion and inflammation and presence of gastric ulceration was studied in naturally Helicobacter suis infected and non-infected 2-3 months old, 6-8 months old and adult pigs. In H. suis-infected 2-3 months old pigs, IL-8 and IL-1beta transcript levels were upregulated in the pyloric gland zone, indicating an innate immune response. A similar response was demonstrated in the fundic gland zone of adult pigs, potentially due to a shift of H. suis colonization from the pyloric to the fundic gland zone. A Treg response in combination with decreased expressions of IL-8, IL 17A and IFN-gamma was indicated to be present in the H. suis-infected 6-8 months old pigs, which may have contributed to persistence of H. suis. In H. suis infected adult pigs, a Treg response accompanied by a Th17 response was indicated, which may have played a role in the decreased number of H. suis bacteria in the stomach of this age group. The decreased G-cell mass and upregulated expression of somatostatin indicated decreased acid secretion in H. suis-infected 6-8 months old pigs. In H. suis-infected adult pigs, upregulation of most markers for gastric acid secretion and increased G-cell mass was detected. Presence of severe hyperkeratosis and erosions in the non-glandular part of the stomach were mainly seen in the H. suis-positive groups. These results show that H. suis infection affects the expression of markers for acid secretion and inflammation and indicate that these effects differ depending on the infection phase. PMID- 28619041 TI - Assessment of short and long-term outcomes of diabetes patient education using the health education impact questionnaire (HeiQ). AB - BACKGROUND: Type 2 diabetes is a progressive chronic illness that will affect more than 500 million people worldwide by 2030. It is a significant cause of morbidity and mortality. Finding the right care management for diabetes patients is necessary to effectively address the growing population of affected individuals and escalating costs. Patient education is one option for improving patient self-management. However, there are large discrepancies in the outcomes of such programs and long-term data are lacking. We assessed the short and long term outcomes of diabetes patient education using the health education impact questionnaire (HeiQ). METHODS: We conducted a observational cohort study of 83 type 2 diabetes patients participating in patient education programs in Denmark. The seven-scale HeiQ was completed by telephone interview at baseline and 2 weeks (76 participants, 93%) and 12 months (66, 80%) after the patient education ended. Changes over time were assessed using mean values and standard deviation at each time point and Cohen effect sizes. RESULTS: Patients reported improvements 2 weeks after the program ended in 4 of 7 constructs: skills and technique acquisition (ES = 0.59), self-monitoring and insight (ES = 0.52), constructive attitudes and approaches (ES = 0.43) and social integration and support (ES = 0.27). After 12 months, patients reported improvements in 3 of 7 constructs: skills and technique acquisition (ES = 0.66), constructive attitudes and approaches (ES = 0.43), and emotional wellbeing (ES = 0.44). Skills and technique showed the largest short- and long-term effect size. No significant changes were found in health-related activity or positive and active engagement in life over time. CONCLUSION: After 12 months, diabetes patients who participated in patient education demonstrated increased self-management skills, improved acceptance of their chronic illness and decreased negative emotional response to their disease. Applying HeiQ as an outcome measure yielded new knowledge as to what patients with diabetes can obtain by participating in a patient education. PMID- 28619042 TI - Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors. AB - BACKGROUND: A high rate of glycolysis leading to elevated lactate content has been linked to poor clinical outcomes in patients with head and neck and cervical cancer treated with radiotherapy. Although the biological explanation for this relationship between lactate and treatment response remains unclear, there is a continued interest in evaluating strategies of targeting metabolism to enhance the effectiveness of radiotherapy. The goal of this study was to investigate the effect of metabolic-targeting through HIF-1alpha inhibition and the associated changes in glycolysis, oxygen consumption and response on the efficacy of high dose single-fraction radiotherapy (HD-SFRT). METHODS: HIF-1alpha wild-type and HIF-1alpha knockdown FaDu and ME180 xenograft tumors were grown in the hind leg of mice that were placed in an environmental chamber and exposed to different oxygen conditions (air-breathing and hypoxia). Ex vivo bioluminescence microscopy was used to measure lactate and ATP levels and the hypoxic fraction was measured using EF5 immunohistochemical staining. The oxygen consumption rate (OCR) in each cell line in response to in vitro hypoxia was measured using an extracellular flux analyzer. Tumor growth delay in vivo was measured following HD-SFRT irradiation of 20 Gy. RESULTS: Targeting HIF-1alpha reduced lactate content, and increased both oxygen consumption and hypoxic fraction in these tumors after exposure to short-term continuous hypoxia. Tumors with intact HIF-1alpha subjected to HD-SFRT immediately following hypoxia exposure were less responsive to treatment than tumors without functional HIF-1alpha, and tumors irradiated under air breathing conditions regardless of HIF-1alpha status. CONCLUSIONS: Blocking the HIF1 response during transient hypoxic stress increased hypoxia, reduced lactate levels and enhanced response to HD-SFRT. This strategy of combining hypofractionated radiotherapy with metabolic reprogramming to inhibit anaerobic metabolism may increase the efficacy of HD-SFRT through increased oxygen consumption and complementary killing of radiosensitive and hypoxic, radioresistant cells. PMID- 28619043 TI - Effect of transcutaneous electrical stimulation treatment on lower urinary tract symptoms after class III radical hysterectomy in cervical cancer patients: study protocol for a multicentre, randomized controlled trial. AB - BACKGROUND: Class III radical hysterectomy (RH III)_plus pelvic lymphadenectomy is the standard surgery for early stage cervical cancer (CC) patients, the 5 year survival rate is about 90%, but pelvic floor disorders especially bladder dysfunction are common due to damaged vessels and nerve fibers following surgery. Transcutaneous electrical stimulation (TENS) treatment has been used to treat bladder disorders for many years, but its effect on cervical cancer patients, the best treatment time point and stimulated protocol, had never been assessed. The aim of this study is to investigate the efficacy of TENS treatment on lower urinary tract symptoms (LUTS) after RH III in CC patients. METHODS/DESIGN: The study will be conducted as a clinical, multicentre, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 208 participants (at 1:1 ratio, 104 subjects in each group). At 5-7 days after RH III, patients are screened according to operative and pathological findings. Enrolled participants are randomised into an intervention group (TENS plus conventional clinical care) or control group (conventional clinical care), with stratification by menopausal status (menopause vs. non-menopause) and surgical modality (laparoscopic RH or abdominal RH). Participants in both groups will be followed up at 14 days, 21 days, 28 days, 3 months, 6 months, 12 months, 18 months and 24 months after surgery. The primary endpoint is improvement rate of urination function which is defined as recovery (residual urine <=50 ml) or improvement (residual urine 50-100 ml). Secondary endpoints include urodynamic parameter, urinary incontinence, anorectal function, pelvic function, quality of life (QOL), disease-free survival and adverse events. Primary endpoint analyses will be carried out by Cochran-Mantel-Haenszel tests taking into center effect. DISCUSSION: To our knowledge this is the first trial to investigate the effect of TENS treatment on bladder function recovery after RH III among CC patients. This study will provide new information on TENS efficacy for bladder function recovery. Once confirmed, it may help to provide a new, non-invisive treatment for those postoperative CC patients with poor pelvic function, which would help improve their quality of life. TRIAL REGISTRATION: The study is registered to Clinical Trials.gov ( NCT02492542 ) on June 25, 2015. PMID- 28619044 TI - Differing specificities and isotypes of anti-citrullinated peptide/protein antibodies in palindromic rheumatism and rheumatoid arthritis. AB - BACKGROUND: To analyze differences in the recognition of anti-citrullinated peptide/protein antibody (ACPA) citrullinated epitopes and isotypes in patients with palindromic rheumatism (PR) and rheumatoid arthritis (RA). METHODS: ACPA fine specificities (citrullinated peptides of enolase, fibrin, and vimentin) and isotypes (IgG, IgM, and IgA) were analyzed in 54 patients with longstanding PR and 54 patients with established RA. RESULTS: CCP2 tested positive in 66.7% of patients with PR and RA. The ACPA distribution of fine specificities and isotypes differed between PR and RA patients. PR patients had a lower frequency of fine ACPA specificities than RA patients, which was significant in the case of a peptide derived from vimentin (PR 24.1% vs. 59.3% RA; p < 0.001). The mean number of ACPA specificities was lower in PR than in RA patients, and only 25.9% of PR patients recognized >=2 additional specificities compared with 46.3% of RA patients. Significantly less isotype usage, especially IgA, was observed in PR patients. CONCLUSION: The ACPA immune response differed in patients with PR and RA, with fewer fine specificities and isotype usage in patients with PR. Some patients with PR may have impaired maturation of the B-cell response against citrullinated peptides with no progression to RA. PMID- 28619045 TI - Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO. AB - BACKGROUND: Long-term survival of lung transplantation is hindered by the development of obliterative bronchiolitis (OB). Adipose-derived stem cells (ASCs) were documented to have more potent immunosuppressive ability than mesenchymal stem cells (MSCs) from bone marrow and placenta. The goal of our study is to evaluate the effect of repeated administration of ASCs on OB and the involvement of indoleamine 2,3-dioxygenase (IDO) mediating the protective effect of ASCs in a heterotopic tracheal transplantation (HTT) model. METHODS: For studies in vitro, ASCs were treated with interferon-gamma (IFN-gamma). For in vivo study, tracheas from BALB/c or C57BL/6 donors were transplanted into C57BL/6 recipients to create a HTT model. On days 0, 1, 3, 5, 8, 12, 15, 20 and 25 post-transplant, the allogeneic recipient mice were administered intravenously with phosphate buffered saline, 1 * 106 human ASCs, or 1 * 106 human ASCs plus 1-methyltryptophan (1-MT), an IDO inhibitor. On days 3, 7, 14 and 28, serum, trachea and spleen samples were harvested for analysis. RESULTS: ASCs homed to heterotopic tracheal grafts after infusion. Multiple doses of ASCs significantly increased tracheal IDO levels in allografts. There were significant increases in graft and serum IFN-gamma levels in allografts compared with isografts. IFN-gamma elevated IDO expression and activity in ASCs in vitro. ASCs alleviated OB in allografts as evidenced by reduced epithelial loss, epithelial apoptosis, and intraluminal obstruction. The effects of ASCs on OB were blocked by 1-MT. 1-MT also blocked the alterations in pro and anti-inflammatory cytokines as well as CD3+ T cell infiltration induced by ASCs. ASCs induced not only splenic levels of CD4+CD25+Foxp3+ regulatory T cells (Treg) but also IL-10 and TGF-beta-producing Treg. Furthermore, IDO inhibition abolished the changes of splenic Treg induced by ASCs. In addition, Treg reduction by cyclophosphamide treatment did not alter the effects of ASCs on tracheal IDO expression in allografts confirming Treg induction is downstream of IDO. CONCLUSIONS: Repeated doses of ASCs are capable of ameliorating OB. ASCs act at least in part via elevating IDO expression. ASCs promote the generation of Treg and suppress T cell infiltration via an IDO-dependent mechanism. PMID- 28619046 TI - Identification of a novel CTCF mutation responsible for syndromic intellectual disability - a case report. AB - BACKGROUND: Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor. CASE PRESENTATION: This study presents, clinically and molecularly, an Emirati patient with de novo frameshift mutation in CTCF. This novel mutation was uncovered using whole exome sequencing and was confirmed by Sanger sequencing in the trio. In silico analysis, using SIFT Indel, indicates that this frameshift; p.Lys206Profs*13 is functionally damaging with the likely involvement of nonsense-mediated mRNA decay. CONCLUSIONS: Upon comparing the clinical picture of the herewith-reported individual with previously reported cases of MRD21, there seems to be many common symptoms, and few new ones that were not observed before. This helps to further define this rare condition and its molecular underpinnings. PMID- 28619047 TI - Environmental isolation explains Iberian genetic diversity in the highly homozygous model grass Brachypodium distachyon. AB - BACKGROUND: Brachypodium distachyon (Poaceae), an annual Mediterranean Aluminum (Al)-sensitive grass, is currently being used as a model species to provide new information on cereals and biofuel crops. The plant has a short life cycle and one of the smallest genomes in the grasses being well suited to experimental manipulation. Its genome has been fully sequenced and several genomic resources are being developed to elucidate key traits and gene functions. A reliable germplasm collection that reflects the natural diversity of this species is therefore needed for all these genomic resources. However, despite being a model plant, we still know very little about its genetic diversity. As a first step to overcome this gap, we used nuclear Simple Sequence Repeats (nSSR) to study the patterns of genetic diversity and population structure of B. distachyon in 14 populations sampled across the Iberian Peninsula (Spain), one of its best known areas. RESULTS: We found very low levels of genetic diversity, allelic number and heterozygosity in B. distachyon, congruent with a highly selfing system. Our results indicate the existence of at least three genetic clusters providing additional evidence for the existence of a significant genetic structure in the Iberian Peninsula and supporting this geographical area as an important genetic reservoir. Several hotspots of genetic diversity were detected and populations growing on basic soils were significantly more diverse than those growing in acidic soils. A partial Mantel test confirmed a statistically significant Isolation-By-Distance (IBD) among all studied populations, as well as a statistically significant Isolation-By-Environment (IBE) revealing the presence of environmental-driven isolation as one explanation for the genetic patterns found in the Iberian Peninsula. CONCLUSIONS: The finding of higher genetic diversity in eastern Iberian populations occurring in basic soils suggests that these populations can be better adapted than those occurring in western areas of the Iberian Peninsula where the soils are more acidic and accumulate toxic Al ions. This suggests that the western Iberian acidic soils might prevent the establishment of Al-sensitive B. distachyon populations, potentially causing the existence of more genetically depauperated individuals. PMID- 28619048 TI - Hematochezia caused by eosinophilic proctocolitis in a newborn before oral feeding: a case report. AB - BACKGROUND: Hematochezia is a frequent symptom in early infancy. However, it occurs very rarely within the immediate neonatal period, and its occurrence before any oral intake is particularly rare. Because of the "congenital" presentation of hematochezia in our patient, we initially considered our case to be a non-classical, potentially severe type of food protein-induced allergic proctocolitis. This diagnosis needs to be confirmed by an abnormal oral challenge test once the hematochezia has disappeared. If such a challenge cannot demonstrate an allergic origin, then the etiology of the hematochezia could be a neonatal transient eosinophilic colitis. Only two similar cases have been described so far. CASE PRESENTATION: We report the case of a black baby boy of African origin born at 36 weeks 5 days of gestational age who presented with massive hematochezia immediately after birth. A rectosigmoidoscopy revealed a severe inflammation associated with diffuse eosinophilic infiltration on biopsy. His clinical outcome was favorable after introduction of an amino acid formula diet. We initially considered our case to be a non-classical, potentially severe type of food protein-induced allergic proctocolitis but reintroduction of standard formula milk at the age of 3 months was successful. So, our patient is the first newborn in Europe who fits the diagnosis of "neonatal transient eosinophilic colitis." CONCLUSIONS: We discuss the possible etiology of "congenital" eosinophilic inflammation of the distal colon and conclude that hematochezia in well-looking neonates, in the absence of negative challenge tests later on, is more likely to be a neonatal transient eosinophilic colitis than an allergic proctocolitis. This new entity could be more frequent than previously thought, changing our medical care strategies for this kind of neonatal symptom. PMID- 28619049 TI - Non-inferiority versus superiority drug claims: the (not so) subtle distinction. AB - BACKGROUND: Current regulatory guidance and practice of non-inferiority trials are asymmetric in favor of the test treatment (Test) over the reference treatment (Control). These trials are designed to compare the relative efficacy of Test to Control by reference to a clinically important margin, M. MAIN TEXT: Non inferiority trials allow for the conclusion of: (a) non-inferiority of Test to Control if Test is slightly worse than Control but by no more than M; and (b) superiority if Test is slightly better than Control even if it is by less than M. From Control's perspective, (b) should lead to a conclusion of non-inferiority of Control to Test. The logical interpretation ought to be that, while Test is statistically better, it is not clinically superior to Control (since Control should be able to claim non-inferiority to Test). This article makes a distinction between statistical and clinical significance, providing for symmetry in the interpretation of results. Statistical superiority and clinical superiority are achieved, respectively, when the null and the non-inferiority margins are exceeded. We discuss a similar modification to placebo-controlled trials. CONCLUSION: Rules for interpretation should not favor one treatment over another. Claims of statistical or clinical superiority should depend on whether or not the null margin or the clinically relevant margin is exceeded. PMID- 28619050 TI - A standardized crisis management model for self-harming and suicidal individuals with three or more diagnostic criteria of borderline personality disorder: The Brief Admission Skane randomized controlled trial protocol (BASRCT). AB - BACKGROUND: Brief Admission is a crisis and risk management strategy in which self-harming and suicidal individuals with three or more diagnostic criteria of borderline personality disorder self-admit to hospital at times of increasing risk when other efforts to stay safe are failing. Standardized in the current randomized controlled trial, the intensity of Brief Admission Skane is implemented in durations of three days, with a maximum frequency of three times a month. Brief Admission is integrated into existing treatment plans in advance of crises to prevent reliance on general psychiatric admissions for risk management, as these may be lengthy, unstructured, and of uncertain therapeutic value. METHODS/DESIGN: The overall objective of the Brief Admission Skane randomized controlled trial is to determine if Brief Admission can replace general psychiatric admission for self-harming and suicidal individuals with complex mental illness at times of escalating risk. Other objectives of the study are to evaluate whether Brief Admission increases daily functioning and enhances coping, reduces psychiatric symptoms including frequency and severity of self-harm and suicidal behaviours. A final objective is to determine if Brief Admission is an effective crisis management model for this population. Participants are randomized at an individual level to either Brief Admission Skane plus Treatment as Usual or Treatment As Usual. Based on a priori power analyses, N = 124 participants will be recruited to the study. Data collection is in progress, and will continue until June 2018. All participant data are single-blinded and will be handled with intention-to-treat analysis. DISCUSSION: Based on the combined clinical experience of our international research group, the Brief Admission Skane randomized controlled trial upon which the current protocol is based represents the first initiative to standardize, implement and evaluate Brief Admission amongst self-harming and suicidal individuals, including those with borderline traits. Objectively measuring protocol fidelity and developing English language Brief Admission study protocols and training materials are implementation and dissemination targets developed in order to facilitate adherent international export of Brief Admission Skane. TRIAL REGISTRATION: NCT02985047 . Registered November 25, 2016. Retrospectively registered. PMID- 28619051 TI - Spatial patterns of childhood diarrhea in Ethiopia: data from Ethiopian demographic and health surveys (2000, 2005, and 2011). AB - BACKGROUND: Childhood diarrhea is a major public health problem, especially in developing countries, including Ethiopia. Exploring the spatial pattern of childhood diarrhea is important to monitor and design effective intervention programs. Therefore, this study aimed to explore the spatial patterns of childhood diarrhea in Ethiopia over the past one decade. METHODS: A total of 29,358 under-five children were retrieved from three consecutive Ethiopian demographic and health surveys (2000, 2005, and 2011) and included into the study. Spatial cluster and autocorrelation analysis was done to explore the patterns of childhood diarrhea. RESULTS: Childhood diarrhea clustered spatially at a national level in all survey periods (Moran's I: 0.3830-1.3296, p < 0.05). Significant spatial clusters were found in different survey periods across the regions. The most likely spatial clusters were found in Southern Nations Nationalities and people, West Oromia, Gambella, Benshangul-Gumuz, and Somali regions. Childhood diarrhea also clustered at the border areas of Southern Nations Nationalities and People and Tigray, Central Somali and Western Oromia, Gambella and Amhara (West Gojam, Awi, Oromia, and Wag Himra) regions. In 2000, the most likely clusters were found in Southern Nations Nationalities and People, West Oromia, and Gambella regions (LLR = 55.37, p < 0.001); in 2005, at Southern Nations Nationalities and People (LLR: 45.69, p < 0.001); and in 2011, at Gambella, West Southern Nations Nationalities and People and Oromia, and Benshangul-Gumuz regions (LLR: 51.09, p < 0.001). CONCLUSION: In this study, childhood diarrhea remains public health problem and had a spatial variation across the regions. Identifying the risk areas would help in designing effective interventions to reduce childhood diarrhea in these areas. PMID- 28619053 TI - Who needs registered reports? AB - Registered Reports, an article format initiated to help promote transparency and reproducibility in the preclinical and social sciences, are spreading into the biological literature. The format is now offered by BMC Biology, in a spirit of experiment. PMID- 28619052 TI - Heterologous expression of an alpha-amylase inhibitor from common bean (Phaseolus vulgaris) in Kluyveromyces lactis and Saccharomyces cerevisiae. AB - BACKGROUND: Phaseolamin or alpha-amylase inhibitor 1 (alphaAI) is a glycoprotein from common beans (Phaseolus vulgaris L.) that inhibits some insect and mammalian alpha-amylases. Several clinical studies support the beneficial use of bean alphaAI for control of diabetes and obesity. Commercial extracts of P. vulgaris are available but their efficacy is still under question, mainly because some of these extracts contain antinutritional impurities naturally present in bean seeds and also exhibit a lower specific activity alphaAI. The production of recombinant alphaAI allows to overcome these disadvantages and provides a platform for the large-scale production of pure and functional alphaAI protein for biotechnological and pharmaceutical applications. RESULTS: A synthetic gene encoding alphaAI from the common bean (Phaseolus vulgaris cv. Pinto) was codon optimised for expression in yeasts (alphaAI-OPT) and cloned into the protein expression vectors pKLAC2 and pYES2. The yeasts Kluyveromyces lactis GG799 (and protease deficient derivatives such as YCT390) and Saccharomyces cerevisiae YPH499 were transformed with the optimised genes and transformants were screened for expression by antibody dot blot. Recombinant colonies of K. lactis YCT390 that expressed and secreted functional alphaAI into the culture supernatants were selected for further analyses. Recombinant alphaAI from K. lactis YCT390 was purified using anion-exchange and affinity resins leading to the recovery of a functional inhibitor. The identity of the purified alphaAI was confirmed by mass spectrometry. Recombinant clones of S. cerevisiae YPH499 expressed functional alphaAI intracellularly, but did not secrete the protein. CONCLUSIONS: This is the first report describing the heterologous expression of the alpha-amylase inhibitor 1 (alphaAI) from P. vulgaris in yeasts. We demonstrated that recombinant strains of K. lactis and S. cerevisiae expressed and processed the alphaAI precursor into mature and active protein and also showed that K. lactis secretes functional alphaAI. PMID- 28619054 TI - HGPEC: a Cytoscape app for prediction of novel disease-gene and disease-disease associations and evidence collection based on a random walk on heterogeneous network. AB - BACKGROUND: Finding gene-disease and disease-disease associations play important roles in the biomedical area and many prioritization methods have been proposed for this goal. Among them, approaches based on a heterogeneous network of genes and diseases are considered state-of-the-art ones, which achieve high prediction performance and can be used for diseases with/without known molecular basis. RESULTS: Here, we developed a Cytoscape app, namely HGPEC, based on a random walk with restart algorithm on a heterogeneous network of genes and diseases. This app can prioritize candidate genes and diseases by employing a heterogeneous network consisting of a network of genes/proteins and a phenotypic disease similarity network. Based on the rankings, novel disease-gene and disease-disease associations can be identified. These associations can be supported with network- and rank-based visualization as well as evidences and annotations from biomedical data. A case study on prediction of novel breast cancer-associated genes and diseases shows the abilities of HGPEC. In addition, we showed prominence in the performance of HGPEC compared to other tools for prioritization of candidate disease genes. CONCLUSIONS: Taken together, our app is expected to effectively predict novel disease-gene and disease-disease associations and support network- and rank-based visualization as well as biomedical evidences for such the associations. PMID- 28619055 TI - Molecular typing of Leptospira interrogans serovar Hardjo isolates from leptospirosis outbreaks in Brazilian livestock. AB - BACKGROUND: Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira spp. This zoonotic disease is distributed globally and affects domestic animals, including cattle. Leptospira interrogans serogroup Sejroe serovar Hardjo and Leptospira borgpetersenii serogroup Sejroe serovar Hardjo remain important species associated with this reproductive disease in livestock production. Previous studies on Brazilian livestock have reported that L. interrogans serovar Hardjo is the most prevalent leptospiral agent in this country and is related to clinical signs of leptospirosis, which lead to economic losses in production. Here, we described the isolation of three clinical strains (Norma, Lagoa and Bolivia) obtained from leptospirosis outbreaks that occurred in Minas Gerais state in 1994 and 2008. RESULTS: Serological and molecular typing using housekeeping (secY and 16SrRNA) and rfb locus (ORF22 and ORF36) genes were applied for the identification and comparative analysis of Leptospira spp. Our results identified the three isolates as L. interrogans serogroup Sejroe serovar Hardjo and confirmed the occurrence of this bacterial strain in Brazilian livestock. Genetic analysis using ORF22 and ORF36 grouped the Leptospira into serogroup Sejroe and subtype Hardjoprajitno. Genetic approaches were also applied to compare distinct serovars of L. interrogans strains by verifying the copy numbers of the IS1500 and IS1533 insertion sequences (ISs). The IS1500 copy number varied among the analyzed L. interrogans strains. CONCLUSION: This study provides evidence that L. interrogans serogroup Sejroe serovar Hardjo subtype Hardjoprajitno causes bovine leptospirosis in Brazilian production. The molecular results suggested that rfb locus (ORF22 and ORF36) could improve epidemiological studies by allowing the identification of Leptospira spp. at the serogroup level. Additionally, the IS1500 and IS1533 IS copy number analysis suggested distinct genomic features among closely related leptospiral strains. PMID- 28619056 TI - Ophthalmic artery occlusion following neuro-embolization of the external carotid artery, a case report. AB - BACKGROUND: Embozene(r) is a new neuroembolizing microsphere used to reduce intraoperative bleeding for head and neck tumours. We report a case of iatrogenic ophthalmic artery occlusion after Embozene(r) embolization of the external carotid artery (ECA). CASE PRESENTATION: A 22-year-old African gentleman presented with left nasal obstruction and epistaxis for 2 years and was diagnosed with nasopharyngeal carcinoma. He subsequently underwent embolization of the maxillary branch of the left ECA using Embozene(r) Microspheres - 250 MUm in size before endoscopic tumour excision to reduce intra-operative bleeding. He complained of sudden painless profound visual loss in the left eye (LE) two hours after embolization. Visual acuity in LE was no light perception. Fundus examination showed pale retina with no cherry red spot. Arterial narrowing and segmentation were seen in all quadrants. A diagnosis of left ophthalmic artery occlusion was made. Despite immediate management including ocular massage and lowering of intraocular pressure, the visual loss remained. Retrospective review of digital subtraction angiogram showed an anastomosis between the left ophthalmic artery and anterior deep temporal artery as a potential route for microspheres migration. CONCLUSION: Pre-operative angio-architecture understanding and diligent selection of embolic material are helpful in preventing this adverse event. The use of newer agents for embolotherapy may cause migration of embolic material from the external to the internal carotid system leading to ophthalmic artery occlusion and blindness. PMID- 28619057 TI - Polysaccharide compositions of collenchyma cell walls from celery (Apium graveolens L.) petioles. AB - BACKGROUND: Collenchyma serves as a mechanical support tissue for many herbaceous plants. Previous work based on solid-state NMR and immunomicroscopy suggested collenchyma cell walls (CWs) may have similar polysaccharide compositions to those commonly found in eudicotyledon parenchyma walls, but no detailed chemical analysis was available. In this study, compositions and structures of cell wall polysaccharides of peripheral collenchyma from celery petioles were investigated. RESULTS: This is the first detailed investigation of the cell wall composition of collenchyma from any plant. Celery petioles were found to elongate throughout their length during early growth, but as they matured elongation was increasingly confined to the upper region, until elongation ceased. Mature, fully elongated, petioles were divided into three equal segments, upper, middle and lower, and peripheral collenchyma strands isolated from each. Cell walls (CWs) were prepared from the strands, which also yielded a HEPES buffer soluble fraction. The CWs were sequentially extracted with CDTA, Na2CO3, 1 M KOH and 4 M KOH. Monosaccharide compositions of the CWs showed that pectin was the most abundant polysaccharide [with homogalacturonan (HG) more abundant than rhamnogalacturonan I (RG-I) and rhamnogalacturonan II (RG-II)], followed by cellulose, and other polysaccharides, mainly xyloglucans, with smaller amounts of heteroxylans and heteromannans. CWs from different segments had similar compositions, but those from the upper segments had slightly more pectin than those from the lower two segments. Further, the pectin in the CWs of the upper segment had a higher degree of methyl esterification than the other segments. In addition to the anticipated water-soluble pectins, the HEPES-soluble fractions surprisingly contained large amounts of heteroxylans. The CDTA and Na2CO3 fractions were rich in HG and RG-I, the 1 M KOH fraction had abundant heteroxylans, the 4 M KOH fraction was rich in xyloglucan and heteromannans, and cellulose was predominant in the final residue. The structures of the xyloglucans, heteroxylans and heteromannans were deduced from the linkage analysis and were similar to those present in most eudicotyledon parenchyma CWs. Cross polarization with magic angle spinning (CP/MAS) NMR spectroscopy showed no apparent difference in the rigid and semi-rigid polysaccharides in the CWs of the three segments. Single-pulse excitation with magic-angle spinning (SPE/MAS) NMR spectroscopy, which detects highly mobile polysaccharides, showed the presence of arabinan, the detailed structure of which varied among the cell walls from the three segments. CONCLUSIONS: Celery collenchyma CWs have similar polysaccharide compositions to most eudicotyledon parenchyma CWs. However, celery collenchyma CWs have much higher XG content than celery parenchyma CWs. The degree of methyl esterification of pectin and the structures of the arabinan side chains of RG-I show some variation in the collenchyma CWs from the different segments. Unexpectedly, the HEPES-soluble fraction contained a large amount of heteroxylans. PMID- 28619059 TI - Critical shoulder angle combined with age predict five shoulder pathologies: a retrospective analysis of 1000 cases. AB - BACKGROUND: Acromial morphology has previously been defined as a risk factor for some shoulder pathologies. Yet, study results are inconclusive and not all major shoulder diseases have been sufficiently investigated. Thus, the aim of the present study was to analyze predictive value of three radiological parameters including the critical shoulder angle, acromion index, and lateral acromion angle in relationship to symptomatic patients with either cuff tear arthropathy, glenohumeral osteoarthritis, rotator cuff tear, impingement, and tendinitis calcarea. METHODS: A total of 1000 patients' standardized true-anteroposterior radiographs were retrospectively assessed. Receiver-operating curve analyses and multinomial logistic regression were used to examine the association between shoulder pathologies and acromion morphology. The prediction model was derived from a development cohort and applied to a validation cohort. Prediction model's performance was statistically evaluated. RESULTS: The majority of radiological measurements were significantly different between shoulder pathologies, but the critical shoulder angle was an overall better parameter to predict and distinguish between the different pathologies than the acromion index or lateral acromion angle. Typical critical shoulder angle-age patterns for the different shoulder pathologies could be detected. Patients diagnosed with rotator cuff tears had the highest, whereas patients with osteoarthritis had the lowest critical shoulder angle. The youngest patients were in the tendinitis calcarea and the oldest in the cuff tear arthropathy group. CONCLUSIONS: The present study showed that critical shoulder angle and age, two easily assessable variables, adequately predict different shoulder pathologies in patients with shoulder complaints. PMID- 28619058 TI - The regulatory role of DPP4 in atherosclerotic disease. AB - The increasing prevalence of atherosclerosis has become a worldwide health concern. Although significant progress has been made in the understanding of atherosclerosis pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. There has been increasing clinical and pre-clinical evidence showing DPP4 incretin axis is involved in cardiovascular disease. Although the cardiovascular outcome of DPP4 inhibition or incretin analogues has been or being evaluated by several large scale clinical trials, the exact role of DPP4 in atherosclerotic diseases is not completely understood. In the current review, we will summarize the recent advances in direct and indirect regulatory role of DPP4 in atherosclerosis. PMID- 28619060 TI - Incidence, disease onset and short-term outcome in urea cycle disorders -cross border surveillance in Germany, Austria and Switzerland. AB - BACKGROUND: Urea cycle disorders (UCDs) are a group of rare inherited metabolic disorders. Affected individuals often present with hyperammonemic encephalopathy (HE) and have an increased risk of severe neurologic disease and early death. The study aims to provide epidemiologic data and to describe the disease manifestation and short-term outcome. METHOD: Cross-border surveillance of newly diagnosed patients with UCDs - below 16 years of age - was performed from July 2012 to June 2015 in Germany and Austria and from January 2012 to December 2015 in Switzerland. Inquiries were sent monthly to all Pediatric Departments in Germany and Switzerland, and quarterly to the Austrian Metabolic Group. In addition, data were collected via a second source (metabolic laboratories) in all three countries. RESULTS: Between July 2012 and June 2015, fifty patients (Germany: 39, Austria: 7, Switzerland: 4) with newly diagnosed UCDs were reported and later confirmed resulting in an estimated cumulative incidence of 1 in 51,946 live births. At diagnosis, thirty-nine patients were symptomatic and 11 asymptomatic [10 identified by newborn screening (NBS), 1 by high-risk-family screening (HRF)]. The majority of symptomatic patients (30 of 39 patients) developed HE with (n = 25) or without coma (n = 5), 28 of them with neonatal onset. Despite emergency treatment 15 of 30 patients with HE already died during the newborn period. Noteworthy, 10 of 11 patients diagnosed by NBS or HRF remained asymptomatic. Comparison with the European registry and network for intoxication type metabolic diseases (E-IMD) demonstrated that cross-national surveillance identified a higher number of clinically severe UCD patients characterized by earlier onset of symptoms, higher peak ammonium concentrations in plasma and higher mortality. CONCLUSION: Cross-border surveillance is a powerful tool to identify patients with UCDs demonstrating that (1) the cumulative incidence of UCDs is lower than originally suggested, (2) the mortality rate is still high in patients with neonatal onset of symptoms, and (3) onset type and peak plasma ammonium concentration predict mortality. PMID- 28619061 TI - Rituximab versus cyclophosphamide for the treatment of connective tissue disease associated interstitial lung disease (RECITAL): study protocol for a randomised controlled trial. AB - BACKGROUND: Interstitial lung disease (ILD) frequently complicates systemic autoimmune disorders resulting in considerable morbidity and mortality. The connective tissue diseases (CTDs) most frequently resulting in ILD include: systemic sclerosis, idiopathic inflammatory myositis (including dermatomyositis, polymyositis and anti-synthetase syndrome) and mixed connective tissue disease. Despite the development, over the last two decades, of a range of biological therapies which have resulted in significant improvements in the treatment of the systemic manifestations of CTD, the management of CTD-associated ILD has changed little. At present there are no approved therapies for CTD-ILD. Following trials in scleroderma-ILD, cyclophosphamide is the accepted standard of care for individuals with severe or progressive CTD-related ILD. Observational studies have suggested that the anti-CD20 monoclonal antibody, rituximab, is an effective rescue therapy in the treatment of refractory CTD-ILD. However, before now, there have been no randomised controlled trials assessing the efficacy of rituximab in this treatment population. METHODS/DESIGN: RECITAL is a UK, multicentre, prospective, randomised, double-blind, double-dummy, controlled trial funded by the Efficacy and Mechanism Evaluation Programme of the Medical Research Council and National Institute for Health Research. The trial will compare rituximab 1 g given intravenously, twice at an interval of 2 weeks, with intravenously administered cyclophosphamide given monthly at a dose of 600 mg/m2 body surface area in individuals with ILD due to systemic sclerosis, idiopathic inflammatory myositis (including anti-synthetase syndrome) or mixed connective tissue disease. A total of 116 individuals will be randomised 1:1 to each of the two treatment arms, with stratification based on underlying CTD, and will be followed for a total of 48 weeks from first dose. The primary endpoint for the study will be change in forced vital capacity (FVC) at 24 weeks. Key secondary endpoints include: safety, change in FVC at 48 weeks as well as survival, change in oxygen requirements, total 48-week corticosteroid exposure and utilisation of health care resources. DISCUSSION: This is the first randomised control trial to study the efficacy of rituximab as first-line treatment in CTD-associated ILD. The results generated should provide important information on the treatment of a life threatening complication affecting a rare group of CTDs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01862926. Registered on 22 May 2013. PMID- 28619062 TI - Platinum-containing compound platinum pyrithione suppresses ovarian tumor proliferation through proteasome inhibition. AB - BACKGROUND: Ovarian carcinoma is one of the most aggressive gynecological malignant neoplasms and makes up 25-30% of all cancer cases of the female genital tract. Currently, resistance to traditional chemotherapy is a great challenge for patients with Epithelial ovarian cancer (EOC). Therefore, identifying novel agents for EOC treatment is essential and urgent. METHOD: MTS assay was used to analyze the cell viability and proliferation of cancer cells. Flow cytometry was employed to analyze cell cycle distribution and cell apoptosis. Protein signaling pathways were detected by western blot and immunohistochemical staining. Nude mouse experiment was performed to test the in vivo effect of platinum pyrithione (PtPT). RESULTS: PtPT is a chemically well-characterized synthetic complex of platinum that potently inhibits proteasome-associated deubiquitinases USP14 and UCHL5 activity and shows selective cytotoxicity to multiple cancer cells without damaging DNA. We found that PtPT significantly accumulated ubquitinated-proteins and suppressed the proliferation of multiple EOC cells. Additionally, PtPT induced G2 phase arrest and apoptosis in both A2780 and SKOV3 cells. More importantly, animal experiments showed that PtPT dramatically suppressed the growth of EOC xenografts without obvious side effects. CONCLUSION: These results suggest that through proteasome inhibition, PtPT significantly suppressed the proliferation of EOC in vitro and in vivo and could be developed as a novel agent for EOC treatment in the future. PMID- 28619063 TI - More preoperative flexibility implies adequate neural pliability for curve correction without prophylactic untethering in scoliosis patients with asymptomatic tethered spinal cord, a retrospective study. AB - BACKGROUND: Tethered spinal cord is frequently associated with scoliosis. It is still controversial whether a prophylactic untethering is necessary before correction procedure in scoliosis patients with tethered spinal cord. In this study we determined the clinical outcome of a one-stage posterior scoliosis correction without a prophylactic untethering for treating scoliosis with an asymptomatic tethered spinal cord. METHODS: Seventeen (5 males and 12 females) scoliosis patients with tethered spinal cords were retrospectively reviewed. All patients underwent a one-stage posterior scoliosis correction without preventive untethering. Parameters of radiograph were used to assess correction result. The Scoliosis Research Society (SRS)-22 questionnaire was analyzed pre- and post operatively to evaluate the clinical outcomes. The modified Japanese Orthopaedic Association (mJOA) score was used to assess the pre- and post-operative spinal cord function. RESULTS: The post-operative coronal Cobb angle was significantly decreased compared with preoperative. (23.8 +/- 6.4 degrees vs. 58.4 +/- 12.6 degrees , P < 0.01). The coronal Cobb angle was 22.4 +/- 6.8 degrees at the final follow-up evaluation. The apical vertebral translation (AVT) was also decreased significantly. (27.5 mm vs. 60.9 mm, P < 0.01). The SRS-22 total score was improved at the 1-year follow-up evaluation compared with the pre-operative SRS-22 total score (87 +/- 4 vs. 70 +/- 5, p < 0.05). The functional activities, pain, self-image, mental health, and surgery satisfactory scores at the final follow-up evaluation were all improved compared with the corresponding pre operative scores, especially the self-image and mental health scores (p < 0.05). The spinal cord function was stable and there was no new neurological symptoms after scoliosis correction. No difference existed between the pre- and post operative total mJOA score (26 +/- 2 vs. 27 +/- 2, p = 0.39), which including subjective symptom (p = 0.07), clinical symptom (p = 0.33), daily activities (p = 0.44) and bladder function (p = 0.67). CONCLUSION: One-stage posterior scoliosis correction is a safe and effective surgical procedure for scoliosis patients combined with asymptomatic tethered spinal cord who have adequate spinal cord function reserve. PMID- 28619064 TI - Protective effect of rutin supplementation against cisplatin-induced Nephrotoxicity in rats. AB - BACKGROUND: Cisplatin (CP) is commonly used in the treatment of different types of cancer but nephrotoxicity has been a major limiting factor. Therefore, the present study aimed to study the possible protective effect of rutin against nephrotoxicity induced by cisplatin in rats. METHODS: Forty male Wistar albino rats were randomly divided into 4 groups. Rats of group 1 control group intraperitoneal (i.p.) received 2.5 ml/kg, group 2 CP group received single dose 5 mg/kg cisplatin i.p. group 3 rutin group orally received 30 mg/kg rutin group 4 (CP plus rutin) received CP and rutin as in group 2 and 3. Kidneys were harvested for histopathology and for the study the gene expression of c-Jun N-terminal kinases (JNK), Mitogen-activated protein kinase 4 (MKK4), MKK7, P38 mitogen activated protein kinases (P38), tumor necrosis factors alpha (TNF-alpha), TNF Receptor-Associated Factor 2 (TRAF2), and interleukin-1 alpha (IL-1-alpha). RESULTS: The cisplatin single dose administration to rats induced nephrotoxicity associated with a significant increase in blood urea nitrogen (BUN) and serum creatinine and significantly increase Malondialdehyde (MDA) in kidney tissues by 230 +/- 5.5 nmol/g compared to control group. The animal treated with cisplatin showed a significant increase in the expression levels of the IL-1alpha (260%), TRFA2 (491%), P38 (410%), MKK4 (263%), MKK7 (412%), JNK (680%) and TNF-alpha (300%) genes compared to control group. Additionally, histopathological examination showed that cisplatin-induced interstitial congestion, focal mononuclear cell inflammatory, cell infiltrate, acute tubular injury with reactive atypia and apoptotic cells. Rutin administration attenuated cisplatin induced alteration in gene expression and structural and functional changes in the kidney. Additionally, histopathological examination of kidney tissues confirmed gene expression data. CONCLUSION: The present study suggested that the anti-oxidant and anti-inflammatory effect of rutin may prevent CP-induced nephrotoxicity via decreasing the oxidative stress, inhibiting the interconnected ROS/JNK/TNF/P38 MAPK signaling pathways, and repairing the histopathological changes against cisplatin administration. PMID- 28619065 TI - Open issues in Mucopolysaccharidosis type I-Hurler. AB - Mucopolysaccharidosis I-Hurler (MPS I-H) is the most severe form of a metabolic genetic disease caused by mutations of IDUA gene encoding the lysosomal alpha-L iduronidase enzyme. MPS I-H is a rare, life-threatening disease, evolving in multisystem morbidity including progressive neurological disease, upper airway obstruction, skeletal deformity and cardiomyopathy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the gold standard for the treatment of MPS I-H in patients diagnosed and treated before 2-2.5 years of age, having a high rate of success. Beyond the child's age, other factors influence the probability of treatment success, including the selection of patients, of graft source and the donor type employed. Enzyme replacement therapy (ERT) with human recombinant laronidase has also been demonstrated to be effective in ameliorating the clinical conditions of pre-transplant MPS I-H patients and in improving HSCT outcome, by peri-transplant co-administration. Nevertheless the long-term clinical outcome even after successful HSCT varies considerably, with a persisting residual disease burden. Other strategies must then be considered to improve the outcome of these patients: one is to pursue early pre-symptomatic diagnosis through newborn screening and another one is the identification of novel treatments. In this perspective, even though newborn screening can be envisaged as a future attractive perspective, presently the best path to be pursued embraces an improved awareness of signs and symptoms of the disorder by primary care providers and pediatricians, in order for the patients' timely referral to a qualified reference center. Furthermore, sensitive new biochemical markers must be identified to better define the clinical severity of the disease at birth, to support clinical judgement during the follow-up and to compare the effects of the different therapies. A prolonged neuropsychological follow-up of post-transplant cognitive development of children and residual disease burden is needed. In this perspective, the reference center must guarantee a multidisciplinary follow-up with an expert team. Diagnostic and interventional protocols of reference centers should be standardized whenever possible to allow comparison of clinical data and evaluation of results. This review will focus on all these critical issues related to the management of MPS I-H. PMID- 28619066 TI - Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression. AB - BACKGROUND: The influence of lung fibroblasts on lung cancer progression is not fully understood. METHODS: Lung fibroblasts (HFL1, MRC5, and IMR90 cells) and non small cell lung cancer (NSCLC)-derived cell lines (A549, EBC1, and HI1017) were cultured under serum-free conditions, and the resulting culture media were designated "cell-conditioned media". Cell survival (viability) was assessed by WST-1 assay. Concentrations of hepatocyte growth factor (HGF) were measured by ELISA. The BALB/c-nu mouse strain was used for the xenograft model. RESULTS: Lung fibroblast-conditioned media enhanced the survival of the three NSCLC cell lines tested. HGF was produced to a greater extent by lung fibroblasts than NSCLC cells. Exogenous HGF enhanced the survival of NSCLC cells. Either an anti-HGF neutralizing antibody or the Met inhibitor PHA-665752 inhibited the fibroblast conditioned media-enhanced survival of NSCLC cells. The co-inoculation of mice with NSCLC cells and fibroblasts enhanced tumorigenicity and tumor progression in a mouse xenograft model. PHA-665752 significantly inhibited tumor progression that occurred after the co-inoculation of NSCLC cells and fibroblasts. In addition, HGF production by fibroblasts was stimulated by NSCLC cells. CONCLUSIONS: The current study provides evidence for an interaction between fibroblasts and NSCLC cells via the HGF/Met signaling pathway, which affects NSCLC cell survival and tumor progression. These findings may contribute to the development of anti-cancer-associated fibroblast therapeutic strategies. TRIAL REGISTRATION: No trial registration is required because this study is not a clinical trial. This study does not include any participants or patients. PMID- 28619067 TI - Design and initial implementation of the WHO FP umbrella project- to strengthen contraceptive services in the sub Saharan Africa. AB - BACKGROUND: Strengthening contraceptive services in sub Saharan Africa is critical to achieve the FP 2020 goal of enabling 120 million more women and girls to access and use contraceptives by 2020 and the Sustainable Development Goals (SDG) targets of universal access to sexual and reproductive health (SRH) services including family planning by 2030. METHOD: The World Health Organization (WHO) and partners have designed a multifaceted project to strengthen health systems to reduce the unmet need of contraceptive and family planning services in sub Saharan Africa. The plan leverages global, regional and national partnerships to facilitate and increase the use of evidence based WHO guidelines with a specific focus on postpartum family planning. The four key approaches undertaken are i) making WHO Guidelines adaptable & appropriate for country use ii) building capacity of WHO regional/country staff iii) providing technical support to countries and iv) strengthening partnerships for introduction and implementation of WHO guidelines. This paper describes the project design and elaborates the multifaceted approaches required in initial implementation to strengthen contraceptive services. CONCLUSION: The initial results from this project reflect that simultaneous application these approaches may strengthen contraceptive services in Sub Saharan Africa and ensure sustainability of the efforts. The lessons learned may be used to scale up and expand services in other countries. PMID- 28619068 TI - Late-onset jaw and teeth pain mimicking trigeminal neuralgia associated with chronic vagal nerve stimulation: case series and review of the literature. AB - BACKGROUND: Vagal nerve stimulation (VNS) for refractory epilepsy is well established. Trigeminal neuralgia itself is a common disease in adults, and thus, late-onset pain in the trigeminal region under VNS, which is extremely rare, may not be recognized as caused by VNS. CASE PRESENTATION: Two patients with drug resistant symptomatic epilepsy treated with chronic VNS experienced stimulation related pain in the lower and upper jaw and teeth on the side of stimulation. No evidence of local spread of the stimulation current was present. The pain started with a delay of years after device implantation and weeks after the last increase in the pacing parameters. At the time of onset, the pain was not recognized as VNS-related, leading to extensive examinations. The trigeminal neuralgia-like pain resolved after adjustment of the stimulation current intensity. In one of the patients, the pain disappeared within one to two days following every epileptic seizure. To our knowledge, this is the first case report of late-onset trigeminal pain under VNS revealing a direct link between epileptogenic and pain processes. CONCLUSION: A painless interval between the last change of the pacing parameters and trigeminal pain can lead to the erroneous interpretation that this is a typical trigeminal neuralgia. The lack of its recognition as a side effect of VNS can lead to unnecessary examinations and delayed adjustment of stimulation parameters. In patients with signs of late-onset trigeminal pain under VNS with normal electrode impedance and no evidence of local current spread, the replacement of the VNS lead does not seem to be beneficial. A review of the literature on VNS side effects including pain and device malfunctions was undertaken. PMID- 28619069 TI - Social determinants of depression and suicidal behaviour in the Caribbean: a systematic review. AB - BACKGROUND: Depressive disorder is the largest contributor to years lived with disability in the Caribbean, adding 948 per 100,000 in 2013. Depression is also a major risk factor for suicidal behaviour. Social inequalities influence the occurrence of depression, yet little is known about the social inequalities of this condition in the Caribbean. In support of the 2011 Rio Political Declaration on addressing health inequities, this article presents a systematic review of the role of social determinants on depression and its suicidal behaviours in the Caribbean. METHODS: Eight databases were searched for observational studies reporting associations between social determinants and depression frequency, severity, or outcomes. Based on the PROGRESS-plus checklist, we considered 9 social determinant groups (of 15 endpoints) for 6 depression endpoints, totalling 90 possible ways ('relationship groups') to explore the role of social determinants on depression. Studies with >=50 participants conducted in Caribbean territories between 2004 and 2014 were eligible. The review was conducted according to STROBE and PRISMA guidelines. Results were planned as a narrative synthesis, with meta-analysis if possible. RESULTS: From 3951 citations, 55 articles from 45 studies were included. Most were classified as serious risk of bias. Fifty-seven relationship groups were reported by the 55 included articles, leaving 33 relationship groups (37%) without an evidence base. Most associations were reported for gender, age, residence, marital status, and education. Depression, its severity, and its outcomes were more common among females (except suicide which was more common among males), early and middle adolescents (among youth), and those with lower levels of education. Marriage emerged as both a risk and protective factor for depression score and prevalence, while several inequality relationships in Haiti were in contrast to typical trends. CONCLUSION: The risk of bias and few numbers of studies within relationship groups restricted the synthesis of Caribbean evidence on social inequalities of depression. Along with more research focusing on regional social inequalities, attempts at standardizing reporting guidelines for observational studies of inequality and studies examining depression is necessitated. This review offers as a benchmark to prioritize future research into the social determinants of depression frequency and outcomes in the Caribbean. PMID- 28619070 TI - Genome and Transcriptome sequence of Finger millet (Eleusine coracana (L.) Gaertn.) provides insights into drought tolerance and nutraceutical properties. AB - BACKGROUND: Finger millet (Eleusine coracana (L.) Gaertn.) is an important staple food crop widely grown in Africa and South Asia. Among the millets, finger millet has high amount of calcium, methionine, tryptophan, fiber, and sulphur containing amino acids. In addition, it has C4 photosynthetic carbon assimilation mechanism, which helps to utilize water and nitrogen efficiently under hot and arid conditions without severely affecting yield. Therefore, development and utilization of genomic resources for genetic improvement of this crop is immensely useful. RESULTS: Experimental results from whole genome sequencing and assembling process of ML-365 finger millet cultivar yielded 1196 Mb covering approximately 82% of total estimated genome size. Genome analysis showed the presence of 85,243 genes and one half of the genome is repetitive in nature. The finger millet genome was found to have higher colinearity with foxtail millet and rice as compared to other Poaceae species. Mining of simple sequence repeats (SSRs) yielded abundance of SSRs within the finger millet genome. Functional annotation and mining of transcription factors revealed finger millet genome harbors large number of drought tolerance related genes. Transcriptome analysis of low moisture stress and non-stress samples revealed the identification of several drought-induced candidate genes, which could be used in drought tolerance breeding. CONCLUSIONS: This genome sequencing effort will strengthen plant breeders for allele discovery, genetic mapping, and identification of candidate genes for agronomically important traits. Availability of genomic resources of finger millet will enhance the novel breeding possibilities to address potential challenges of finger millet improvement. PMID- 28619071 TI - New adenovirus-based vaccine vectors targeting Pfs25 elicit antibodies that inhibit Plasmodium falciparum transmission. AB - BACKGROUND: An effective malaria transmission-blocking vaccine (TBV) would be a major advance in the current efforts to eliminate and, ultimately, eradicate malaria. Antibodies against Plasmodium falciparum surface protein, Pfs25, are known to block parasite development in the mosquito vector. However, in initial clinical trials the limited immunogenicity of recombinant Pfs25 protein-in adjuvant vaccines has been a challenge. METHODS: Novel human adenovirus type 5 (Ad5) vectors were used in heterologous prime boost vaccination strategies to augment the immune response against Pfs25. Specifically, an Ad5 vector that directs expression of full-length, membrane-bound Pfs25 was used as a priming immunization followed by a boost with Ad5 viral particles displaying only the Pfs25 epitope targeted by transmission-blocking antibodies 4B7 and 1D2 (Pfs25 aa 122-134) in hypervariable region 5 of the hexon capsid protein. RESULTS: This heterologous prime-boost vaccine strategy induced antibodies that significantly inhibit P. falciparum transmission to mosquitoes in a standard membrane-feeding assay. Further, immunized mice generated a robust anti-Pfs25 antibody response characterized by higher titer, higher relative avidity and a broader IgG subclass profile than observed with a homologous prime-boost with recombinant Pfs25/alum. CONCLUSION: The data suggest that focusing the immune response against defined epitopes displayed on the viral capsid is an effective strategy for transmission blocking vaccine development. PMID- 28619072 TI - The Arabidopsis SWI/SNF protein BAF60 mediates seedling growth control by modulating DNA accessibility. AB - BACKGROUND: Plant adaptive responses to changing environments involve complex molecular interplays between intrinsic and external signals. Whilst much is known on the signaling components mediating diurnal, light, and temperature controls on plant development, their influence on chromatin-based transcriptional controls remains poorly explored. RESULTS: In this study we show that a SWI/SNF chromatin remodeler subunit, BAF60, represses seedling growth by modulating DNA accessibility of hypocotyl cell size regulatory genes. BAF60 binds nucleosome free regions of multiple G box-containing genes, opposing in cis the promoting effect of the photomorphogenic and thermomorphogenic regulator Phytochrome Interacting Factor 4 (PIF4) on hypocotyl elongation. Furthermore, BAF60 expression level is regulated in response to light and daily rhythms. CONCLUSIONS: These results unveil a short path between a chromatin remodeler and a signaling component to fine-tune plant morphogenesis in response to environmental conditions. PMID- 28619074 TI - Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy: studies in rodents and nonhuman primates. AB - Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (alpha-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of alpha syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing alpha-syn in oligodendroglia using a novel oligotrophic adeno associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with >95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90-94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the alpha-syn transgene. Histological analysis 3-months after injection demonstrated widespread alpha-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 alpha-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-alpha-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-alpha-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA. PMID- 28619073 TI - Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. METHODS: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. RESULTS: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. CONCLUSIONS: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE. PMID- 28619075 TI - Anti-inflammatory effect of Chang-An-Shuan on TNBS-induced experimental colitis in rats. AB - BACKGROUND: Inflammatory bowel disease (IBD), denominated by Crohn's disease and ulcerative colitis, is often associated with abdominal pain, diarrhea and bloody stool. The standard protocols for treating colitis conditions are not satisfactory; thus, complementary and alternative medicines have been increasingly accepted by IBD sufferers worldwide. In this study, we aimed to elucidate the anti-inflammatory effect of Chang-An-Shuan (CAS), a 6-herb Chinese medicinal formula, on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats and the underlying mechanisms. METHODS: Sprague-Dawley rats were administered with rectal gavage of 2.5% TNBS in 50% ethanol for the induction of experimental colitis which is considered as a model for Crohn's disease. Upon the TNBS induction, rats were given CAS at 0.5 g/kg/day or 5 g/kg/day for 10 days. The application of salicylazosulfapyridine (0.5 g/kg/day) was served as a positive reference drug for the colitis condition. The efficacy and mechanistic action of CAS were evaluated by means of histopathological and biochemical approaches such as histological staining, real-time polymerase chain reaction, Western blotting analysis and enzyme-linked immunosorbent assay. RESULTS: Oral administration of CAS at 5 g/kg/day, but not 0.5 g/kg/day, significantly ameliorated the severity of TNBS-induced colitis as evidenced by the reduced loss of body weight, alleviated diarrhea and decreased bloody stool. While lowering the disease activity index, the administration of CAS lessened mucosal lesions thus mucosal integrity of the colitis rats was notably improved. Further, the CAS treatment also significantly suppressed the mRNA and protein levels of pro inflammatory cytokines, namely interleukin-1beta and tumor necrosis factor-alpha while enhancing the level of anti-inflammatory cytokine IL-10 in the TNBS-treated rats. Importantly, the ameliorative effect of CAS was related to an inhibition of the nuclear factor-kappaB (NF-kappaB) signaling pathway by downregulating the expression levels of NF-kappaBp-65, p-38 and p-AKT. CONCLUSIONS: We suggest that CAS is a potential alternative remedial approach for treating IBD conditions, and the anti-inflammatory effect of CAS is associated with the down-regulation of the NF-kappaB signaling pathway and the balanced production of pro- and anti inflammatory cytokines. PMID- 28619076 TI - Effectiveness and equity of the Tanzania National Voucher Scheme for mosquito nets over 10 years of implementation. AB - BACKGROUND: The Tanzania National Voucher Scheme (TNVS) was a public private partnership managed by the Ministry of Health that provided pregnant women and infants with highly subsidized (long-lasting) insecticide-treated nets between 2004 and 2014. It was implemented in the context of the National Insecticide Treated Nets (NATNETS) Programme and was the main keep up strategy for vulnerable populations. CASE DESCRIPTION: The programme design was adjusted considerably over time to incorporate new evidence, shifting public health policies, and changing donor priorities. Three TNVS models can be distinguished: (1) the fixed discount; (2) the fixed top-up; (3) the hybrid voucher model. The changes improved equity and effectiveness, but also had a profound effect on how the programme was managed and implemented. RESULTS: The TNVS reached the majority of beneficiaries with vouchers, and significantly increased household ownership and use of LLINs. While two mass distribution campaigns implemented between 2009 and 2011 achieved universal coverage and equity, the TNVS ensured continuous protection of the vulnerable populations before, during and after the campaigns. The TNVS stimulated and maintained a large national retail network which managed the LLIN supply chain. DISCUSSION AND LESSONS LEARNED: The effectiveness of the TNVS was a function of several interdependent factors, including the supply chain of vouchers through the public health system; the supply chain of nets in the commercial sector; the demand for nets from voucher recipients; management and risk mitigation measures; and the influence of global and donor objectives. CONCLUSION: The TNVS was a highly innovative and globally influential programme, which stimulated the thinking around effectively and equitably distributing ITNs, and contributed directly to the evolution of global policy. It was a fundamental component of the NATNETS programme which protected a malaria-vulnerable population for over a decade. PMID- 28619077 TI - What is the impact of local control in Ewing sarcoma: analysis of the first Brazilian collaborative study group - EWING1. AB - BACKGROUND: Relapse in localized Ewing sarcoma patients has been a matter of concern regarding poor prognosis. Therefore, we investigated the impact of local control modality (surgery, surgery plus radiotherapy, and radiotherapy) on clinical outcomes such as survival and recurrence in patients with non-metastatic Ewing sarcoma treated on the first Brazilian Collaborative Group Trial of the Ewing Family of Tumors (EWING1). METHODS: Seventy-three patients with localized Ewing sarcoma of bone aged < 30 years were included. The treating physicians defined the modality of local control based on the recommendations of the coordinating center and the patient and tumor characteristics. Possible associations of local control modality with local failure (LF), disease-free survival (DFS), event-free survival (EFS), overall survival (OS), and clinical characteristics were analyzed. RESULTS: Mean patient age was 12.8 years (range, 2 to 25 years) and median follow-up time was 4.5 years (range, 2.3 to 6.7 years). Forty-seven patients underwent surgery, 13 received radiotherapy, and 13 received both. The 5-year EFS, OS, and DFS for all patients was 62.1%, 63.3%, and 73.1%, respectively. The 5-year cumulative incidence (CI) of LF was 7.6% for surgery, 11.1% for radiotherapy, and 0% for postoperative radiotherapy (PORT) (p = 0.61). The 5-year EFS was 71.7% for surgery, 30.8% for radiotherapy, and 64.1% for PORT (p = 0.009). CONCLUSIONS: There was a significant effect of local control modality on EFS and OS in the study. Surgery and PORT modalities yielded very close results. The group treated with radiotherapy alone had considerably worse outcomes. This may be confounded by greater risk factors in these patients. There was no significant effect of local control modality on the CI of LF and DFS. PMID- 28619078 TI - Psychological interventions for the treatment of depression, anxiety, alcohol misuse or anger in armed forces veterans and their families: systematic review and meta-analysis protocol. AB - BACKGROUND: Evidence highlights a high prevalence of common mental health disorders in armed forces veterans and their families, with depression, anxiety, alcohol misuse and anger being more common than PTSD. This paper presents a protocol for a systematic review and meta-analysis to identify existing randomised controlled trial (RCT) research testing the effectiveness of psychological interventions for these difficulties in armed forces veterans and their family members. METHODS: Electronic databases (CENTRAL, PsycInfo, MEDLINE, CINAHL, The Cochrane Register of Clinical Trials, EMBASE and ASSIA) will be searched to identify suitable studies for inclusion in the review supplemented by forward and backward reference checking, grey literature searches and contact with subject authors. Research including armed forces veterans and their family members will be included in the review with research including serving personnel or individuals under the age of 18 being excluded. Few RCTs examining the treatment of depression, anxiety, alcohol misuse or anger exist in armed forces veterans to date. The primary outcome will be symptomatic change following intervention for these difficulties. The secondary outcomes will include methodological aspects of interest such as discharge type and recruitment setting if data permits. In the event that the number of studies identified is too low to undertake a meta-analysis, a narrative review will be conducted. Quality assessment will be undertaken using the Cochrane Collaboration Tool and Cochran's Q statistic calculated to test for heterogeneity as suggested by the Cochrane handbook. DISCUSSION: The review will examine the findings of existing intervention research for depression, anxiety, alcohol misuse or anger in armed forces veterans and their families, along with any effect sizes that may exist. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016036676. PMID- 28619080 TI - The management of a cystic hepatic lesion ruptured in the bile ducts: a case report. AB - BACKGROUND: Hepatic cystadenoma is a rare benign cystic tumor; it tends to recur after incomplete surgical resection and has malignant potential. We report the case of a patient with a ruptured biliary cystadenoma in the common bile duct that caused diagnostic and therapeutic problems. CASE PRESENTATION: A 34-year-old North African woman, admitted for angiocholitis, was operated 2 months before for a hepatic cystic lesion taken for a hydatid cyst compressing her common bile duct. The clinical and the complementary examinations converged toward recurrence of the hydatid cyst for which a surgical resection was decided. Intraoperative findings as well as the histological study of the "membranes" extracted from her common bile duct indicated a hepatic cystadenoma. CONCLUSIONS: The rarity of hepatic cystadenoma and the non-specificity of clinical and imaging signs make diagnosis of hepatic cystadenoma difficult, especially when it is complicated by rupture in the bile ducts; this contributes to a delay in diagnosis and an inadequate therapeutic approach. PMID- 28619079 TI - Association between high-density lipoprotein-cholesterol and hypertension in relation to circulating CD34-positive cell levels. AB - BACKGROUND: Although high-density lipoprotein-cholesterol (HDL) level is inversely correlated with cardiovascular events, HDL is also reported to be positively associated with hypertension, which is a known endothelial impairment factor. Since HDL mediates important protective actions on the vascular endothelium by increasing the number of circulating endothelial progenitor cells (CD34-positive cells), the level of circulating CD34-positive cells should influence the association between HDL and hypertension. METHODS: To investigate the association between HDL and hypertension in relation to the level of circulating CD34-positive cells, we conducted a cross-sectional study of 477 elderly men aged 60-69 years who participated in general health checkup. RESULTS: HDL was found to be significantly positively associated with hypertension in subjects with a high level of circulating CD34-positive cells, while no significant association was observed for subjects with low circulating CD34 positive cells. Known cardiovascular risk factors adjusted odds (ORs) and 95% confidence intervals (CIs) of hypertension for increments of one standard deviation (SD) in HDL (13.8 mg/dL) were 1.44 (1.06, 1.96) for subjects with a high level of circulating CD34-positive cells and 0.87 (0.63, 1.19) for subjects with low circulating CD34-positive cells. We also revealed a significant association between HDL level and CD34-positive cell level on hypertension, with fully adjusted p values for the effect of this interaction on hypertension at 0.022. CONCLUSIONS: Independent of known cardiovascular risk factors, HDL was found to be positively associated with hypertension in subjects with a high level of circulating CD34-positive cells but not for subjects with low circulating CD34 positive cells. PMID- 28619081 TI - Burnout among workers in emergency Departments in Palestinian hospitals: prevalence and associated factors. AB - BACKGROUND: Working in Emergency Departments (EDs) entails high work pressure and stress due to witnessing human suffering and the unpredictable nature of the work. This environment puts personnel at risk of burnout. This analysis aims to assess burnout levels and associated risk factors among health workers in EDs in Palestinian hospitals. Also, it examines the association between burnout and workplace violence, as well as with job turnover. METHODS: Cross-sectional design utilising a self-administered questionnaire was used to collect data from all workers at 14 EDs; 8 from the West Bank and 6 from the Gaza Strip. Burnout was measured using Maslach Burnout Inventory-Human Services Survey. RESULTS: A total of 444 workers (response rate 74.5%) participated: 161(36.3%) nurses, 142(32.0%) physicians and 141(31.7%) administrative personnel. Results showed high levels of burnout among EDs workers; 64.0% suffered from high emotional exhaustion, 38.1% from high depersonalization and 34.6% from low personal accomplishment. In addition, high levels of emotional exhaustion (72.3%) was significantly prevalent among physicians compared to nurses (69.8%) and administrative workers (51.4%) (p < 0.05). In comparison, high levels of depersonalization was significantly prevalent among nurses (48.8%) compared to physicians (32.1%) and administrative workers (31.9%) (p < 0.05). However, there were no significant differences in the levels of personal accomplishment burnout among the three groups (p > 0.05). Moreover, high degree of burnout was more prevalent among EDs workers in the West Bank than among those working in the Gaza Strip (OR 2.02, 95% CI = 1.11-3.69, p = 0.019), and higher among younger workers (aged <=30 years old) than their older counterparts (OR 2.4, 95% CI = 1.302-4.458, p = 0.005). Exposure to physical violence was significantly associated with having a high degree of burnout (OR 2.017 95% CI = 1.121-3.631, p = 0.019), but no association was observed with regards to exposure to verbal violence (p > 0.05). Finally, burnout was significantly associated with workers' intention to leave work at EDs (p < 0.05). CONCLUSIONS: Burnout is considerably prevalent among EDs' workers, especially nurses and physicians. Burnout is positively associated with job turnover intention and also with exposure to workplace violence. Therefore, there is a need for prevention and management strategies to address occupational burnout and reduce negative consequences on workers, patients and organisations. PMID- 28619082 TI - Assessing changes in knowledge, attitude and practices on dengue diagnosis and management among primary care physicians after the largest dengue epidemic in Singapore. AB - BACKGROUND: Dengue results in high morbidity and mortality globally. The knowledge, attitude and practices (KAP) of dengue management, including diagnosis, among primary care physicians (PCPs) are important to reduce dengue transmission and burden. However, there is a lack of understanding on the impact of dengue epidemic on dengue management. Hence, the aim of this study is to examine the changes in KAP on dengue management among PCPs before and after the largest dengue epidemic in 2013 in Singapore. METHODS: Surveys were mailed to 2000 and 1514 PCPs registered under the Singapore Medical Council in March of year 2011 and 2014, respectively. Survey data were then collected between April and June of that year. Chi-square or Fisher's exact test was used for comparing categorical variables. A multivariate logistic regression model was implemented to determine independent factors for frequent use of dengue diagnostic tests (DDTs). All tests were conducted at 5% level of significance. Adjusted odds ratio and corresponding 95% confidence intervals were reported, where applicable. Qualitative data were descriptively coded for themes and analysis. RESULTS: Among PCPs surveyed in 2011 and 2014, 89.9% and 86% had good knowledge on dengue management respectively. The usage of DDTs had increased significantly in 2014 (N = 164;56%) as compared to 2011 (N = 107;29.5%) in both private and public clinics (p < 0.001). Dengue Duo point-of-care test (POCT) kits was independently associated with frequent use of DDTs (adjusted odds ratio = 2.15; 95% confidence interval = 1.25-3.69). There was a significant reduction in referral of dengue patients to hospital (31.4% in 2011; 13.3% in 2014; p < 0.001), and a significant increase in frequency of clinic follow-ups (18.4% in 2011; 28.5% in 2014; p = 0.003). One key theme highlighted was that dengue management can be improved with availability of POCT kit, better awareness of the disease and any revised clinical guidelines. CONCLUSION: The knowledge on dengue management remained high, while the attitude and practices, particularly on the usage of DDTs improved significantly after a large epidemic. Furthermore, PCPs had more confident in managing dengue patients in primary care settings and in educating patients on the importance of vector control and dengue warning signs to reduce dengue transmission and burden. PMID- 28619083 TI - On marker-based parentage verification via non-linear optimization. AB - BACKGROUND: Parentage verification by molecular markers is mainly based on short tandem repeat markers. Single nucleotide polymorphisms (SNPs) as bi-allelic markers have become the markers of choice for genotyping projects. Thus, the subsequent step is to use SNP genotypes for parentage verification as well. Recent developments of algorithms such as evaluating opposing homozygous SNP genotypes have drawbacks, for example the inability of rejecting all animals of a sample of potential parents. This paper describes an algorithm for parentage verification by constrained regression which overcomes the latter limitation and proves to be very fast and accurate even when the number of SNPs is as low as 50. The algorithm was tested on a sample of 14,816 animals with 50, 100 and 500 SNP genotypes randomly selected from 40k genotypes. The samples of putative parents of these animals contained either five random animals, or four random animals and the true sire. Parentage assignment was performed by ranking of regression coefficients, or by setting a minimum threshold for regression coefficients. The assignment quality was evaluated by the power of assignment (P[Formula: see text]) and the power of exclusion (P[Formula: see text]). RESULTS: If the sample of putative parents contained the true sire and parentage was assigned by coefficient ranking, P[Formula: see text] and P[Formula: see text] were both higher than 0.99 for the 500 and 100 SNP genotypes, and higher than 0.98 for the 50 SNP genotypes. When parentage was assigned by a coefficient threshold, P[Formula: see text] was higher than 0.99 regardless of the number of SNPs, but P[Formula: see text] decreased from 0.99 (500 SNPs) to 0.97 (100 SNPs) and 0.92 (50 SNPs). If the sample of putative parents did not contain the true sire and parentage was rejected using a coefficient threshold, the algorithm achieved a P[Formula: see text] of 1 (500 SNPs), 0.99 (100 SNPs) and 0.97 (50 SNPs). CONCLUSION: The algorithm described here is easy to implement, fast and accurate, and is able to assign parentage using genomic marker data with a size as low as 50 SNPs. PMID- 28619084 TI - Unusual clinical outcome of primary Hyperoxaluria type 1 in Tunisian patients carrying 33_34InsC mutation. AB - BACKGROUND: Primary hyperoxaluria type 1 (PH1), is a rare and heterogeneous disease and one of major causes of renal insufficiency in Tunisia, caused by mutations in the AGXT gene. 33-34InsC mutation, was mainly described in children with a severe clinical feature leading to early death, but it was uncommonly reported in adult patients. METHODS: Common mutations in AGXT were tested using PCR/RFLP technique in 111 patients (68 adult, 43 children) with suspected PH1. RESULTS: We described 16 cases (eight adult and eight children) with a 33-34InsC mutation with a median age of 24 years [6 months - 73 years]. All children were in end stage renal disease (ESRD) at the median age of 3 years due to lithiasis and/or nephrocalcinosis. Unfortunately, 75% of them died with a median age of 2.5 years. For the majority of adults only spontaneous elimination of urolithiasis were noted, 37.5% preserved until now a normal renal function and 62.5% of them reached ESRD at the median age of 55.8 +/- 12.31 years old. CONCLUSION: In this study 33-34InsC mutation gives a controversial clinical effect in children and adults. The implication of other genetic and/or environmental factors can play a crucial role in determining the ultimate phenotype. PMID- 28619085 TI - Validity of a family-centered approach for assessing infants' social-emotional wellbeing and their developmental context: a prospective cohort study. AB - BACKGROUND: Family-centered care seems promising in preventive pediatrics, but evidence is lacking as to whether this type of care is also valid as a means to identify risks to infants' social-emotional development. We aimed to examine the validity of such a family-centered approach. METHODS: We conducted a prospective cohort study. During routine well-child visits (2-15 months), Preventive Child Healthcare (PCH) professionals used a family-centered approach, assessing domains as parents' competence, role of the partner, social support, barriers within the care-giving context, and child's wellbeing for 2976 children as protective, indistinct or a risk. If, based on the overall assessment (the families were labeled as "cases", N = 87), an intervention was considered necessary, parents filled in validated questionnaires covering the aforementioned domains. These questionnaires served as gold standards. For each case, two controls, matched by child-age and gender, also filled in questionnaires (N = 172). We compared PCH professionals' assessments with the parent-reported gold standards. Moreover, we evaluated which domain mostly contributed to the overall assessment. RESULTS: Spearman's rank correlation coefficients between PCH professionals' assessments and gold standards were overall reasonable (Spearman's rho 0.17-0.39) except for the domain barriers within the care-giving context. Scores on gold standards were significantly higher when PCH assessments were rated as "at risk" (overall and per domain).We found reasonable to excellent agreement regarding the absence of risk factors (negative agreement rate: 0.40-0.98), but lower agreement regarding the presence of risk factors (positive agreement rate: 0.00-0.67). An "at risk" assessment for the domain Barriers or life events within the care-giving context contributed most to being overall at risk, i.e. a case, odds ratio 100.1, 95% confidence interval: 22.6 - infinity. CONCLUSION: Findings partially support the convergent validity of a family-centered approach in well-child care to assess infants' social-emotional wellbeing and their developmental context. Agreement was reasonable to excellent regarding protective factors, but lower regarding risk factors. TRIAL REGISTRATION: Netherlands Trialregister, NTR2681. Date of registration: 05-01-2011, URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2681 . PMID- 28619086 TI - Patterns of venous thromboembolism risk in patients with localized colorectal cancer undergoing adjuvant chemotherapy or active surveillance: an observational cohort study. AB - BACKGROUND: Venous thromoboembolism (VTE) is a frequent and burdensome complication of metastatic colorectal cancer (CRC). However, the epidemiology of VTE in patients with localized CRC after surgery in curative intent is incompletely understood. In this single-center observational cohort study, we investigate patterns of VTE risk in localized CRC, and define its relationship with baseline risk factors, adjuvant chemotherapy and CRC recurrence. METHODS: Five-hundred-sixteen patients with stage II/III CRC were included retrospectively at the time of surgery, and followed until the occurrence of VTE, CRC recurrence, or death (median age = 65.1 years, stage II and III: n = 151 (29.5%), n = 361 (70.5%); adjCTX: n = 339 (65.7%)). RESULTS: During a median follow-up of 2.7 years, 15 VTEs (2.7%) and 116 recurrences (22.5%) occurred, and 46 patients (8.9%) died. Six-month, 1-year, and 5-year VTE risks were 1.6%, 2.0% and 3.2%, respectively. In competing risk time-to-VTE regression, adjCTX was not associated with an increased risk of VTE (Subdistribution hazard ratio = 0.98, 95% CI:0.33 2.88, p = 0.97). The occurrence of disease recurrence strongly increased the risk of VTE (Multi-state model: Transition hazard ratio (THR) = 13.03, 95% CI:4.39 38.74, p < 0.0001)). Conversely, the onset of VTE did not predict for recurrence (THR = 1.95, 95% CI: 0.62-6.16, p = 0.25). CONCLUSION: VTE risk is very low in localized CRC and does not appear to be increased by adjuvant chemotherapy. Thus, primary thromboprophylaxis is unlikely to result in clinical benefit in this population. The strongest determinant of VTE risk appears to be disease recurrence. PMID- 28619087 TI - Longitudinal estimation of intramuscular Tibialis Anterior coherence during subacute spinal cord injury: relationship with neurophysiological, functional and clinical outcome measures. AB - BACKGROUND: Estimation of surface intramuscular coherence has been used to indirectly assess pyramidal tract activity following spinal cord injury (SCI), especially within the 15-30 Hz bandwidth. However, change in higher frequency (>40 Hz) muscle coherence during SCI has not been characterised. Thus, the objective of this study was to identify change of high and low frequency intramuscular Tibialis Anterior (TA) coherence during incomplete subacute SCI. METHODS: Fifteen healthy subjects and 22 subjects with motor incomplete SCI (American Spinal Injury Association Impairment Scale, AIS, C or D grade) were recruited and tested during 4 sessions performed at 2-week intervals up to 8 months after SCI. Intramuscular TA coherence estimation was calculated within the 10-60 Hz bandwidth during controlled maximal isometric and isokinetic foot dorsiflexion. Maximal voluntary dorsiflexion torque, gait function measured with the WISCI II scale, and TA motor evoked potentials (MEP) were recorded. RESULTS: During subacute SCI, significant improvement in total lower limb manual muscle score, TA muscle strength and gait function were observed. No change in TA MEP amplitude was identified. Significant increase in TA coherence was detected in the 40-60 Hz, but not the 15-30 Hz bandwidth. The spasticity syndrome was associated with lower 15-30 Hz TA coherence during maximal isometric dorsiflexion and higher 10-60 Hz coherence during fast isokinetic movement (p < 0.05). CONCLUSIONS: Longitudinal estimation of neurophysiological and clinical measures during subacute SCI suggest that estimation of TA muscle coherence during controlled movement provides indirect information regarding adaptive and maladaptive motor control mechanisms during neurorehabilitation. PMID- 28619088 TI - Chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells. AB - BACKGROUND: The peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu. We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: PB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy. Receptors for osteoclastogenic factors (CD115 and receptor activator of nuclear factor-kappaB [RANK]) and selected chemokines (CC chemokine receptor 1 [CCR1], CCR2, CCR4, CXC chemokine receptor 3 [CXCR3], CXCR4) were determined in an OCP-rich subpopulation (CD3-CD19-CD56-CD11b+CD14+) by flow cytometry. In parallel, levels of CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), CXCL10, and CXCL12 were measured using cytometric bead array or enzyme-linked immunosorbent assay. Sorted OCPs were stimulated in culture by macrophage colony stimulating factor and receptor activator of nuclear factor-kappaB ligand, and they were differentiated into mature osteoclasts that resorb bone. Selected chemokines (CCL2, CCL5, CXCL10, and CXCL12) were tested for their osteoclastogenic and chemotactic effects on circulatory OCPs in vitro. RESULTS: The OCP population was moderately enlarged among PB cells in RA and correlated with levels of tumor necrosis factor-alpha (TNF-alpha), rheumatoid factor, CCL2, and CCL5. Compared with PB, the RANK+ subpopulation was expanded in SF and correlated with the number of tender joints. Patients with PsA could be distinguished by increased RANK expression rather than total OCP population. OCPs from patients with arthritis had higher expression of CCR1, CCR2, CCR4, CXCR3, and CXCR4. In parallel, patients with RA had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, with significant elevation in SF vs PB for CXCL10. The subset expressing CXCR4 positively correlated with TNF-alpha, bone resorption marker, and rheumatoid factor, and it was reduced in patients treated with disease-modifying antirheumatic drugs. The CCR4+ subset showed a significant negative trend during anti-TNF treatment. CCL2, CCL5, and CXCL10 had similar osteoclastogenic effects, with CCL5 showing the greatest chemotactic action on OCPs. CONCLUSIONS: In our study, we identified distinct effects of selected chemokines on stimulation of OCP mobilization, tissue homing, and maturation. Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA. PMID- 28619089 TI - Light manipulation of mosquito behaviour: acute and sustained photic suppression of biting activity in the Anopheles gambiae malaria mosquito. AB - BACKGROUND: Host-seeking behaviours in anopheline mosquitoes are time-of-day specific, with a greater propensity for nocturnal biting. We investigated how a short exposure to light presented during the night or late day can inhibit biting activity and modulate flight activity behaviour. RESULTS: Anopheles gambiae (s.s.), maintained on a 12:12 LD cycle, were exposed transiently to white light for 10-min at the onset of night and the proportion taking a blood meal in a human biting assay was recorded every 2 h over an 8-h duration. The pulse significantly reduced biting propensity in mosquitoes 2 h following administration, in some trials for 4 h, and with no differences detected after 6 h. Conversely, biting levels were significantly elevated when mosquitoes were exposed to a dark treatment during the late day, suggesting that light suppresses biting behaviour even during the late daytime. These data reveal a potent effect of a discrete light pulse on biting behaviour that is both immediate and sustained. We expanded this approach to develop a method to reduce biting propensity throughout the night by exposing mosquitoes to a series of 6- or 10 min pulses presented every 2 h. We reveal both an immediate suppressive effect of light during the exposure period and 2 h after the pulse. This response was found to be effective during most times of the night: however, differential responses that were time-of-day specific suggest an underlying circadian property of the mosquito physiology that results in an altered treatment efficacy. Finally, we examined the immediate and sustained effects of light on mosquito flight activity behaviour following exposure to a 30-min pulse, and observed activity suppression during early night, and elevated activity during the late night. CONCLUSIONS: As mosquitoes and malaria parasites are becoming increasingly resistant to insecticide and drug treatment respectively, there is a necessity for the development of innovative control strategies beyond insecticide-treated nets (ITNs) and residual spraying. These data reveal the potent inhibitory effects of light exposure and the utility of multiple photic pulses presented at intervals during the night/late daytime, may prove to be an effective tool that complements established control methods. PMID- 28619090 TI - Truffle renaissance in Poland - history, present and prospects. AB - The use of truffles in Poland has a long tradition, yet due to some historical aspects, this knowledge was lost. Currently, truffles and truffle orchards are again receiving attention, and thanks to, e.g., historical data, they have solid foundations to be established. Publications relating to truffles between 1661 and 2017 were searched for in international and national databases, such as the database of PhD theses, Google Scholar, and catalogues of the National Library of Poland, the Jagiellonian Digital Library, the University Library of J. Giedroyc in Bialystok and the Lower Silesian Digital Library (DBC). A very meticulous survey of the literature on truffles showed that truffles have been known since at least 1661. In the 18th century, the fungi were considered a non-timber forest product. It is interesting to mention the impact of Polish Count Michal Jan Borch in understanding the nature of truffles. The whitish truffle (Tuber borchii) is named after him. The greatest number of publications regarding truffles can be observed at the first half of the 19th and 20th centuries. The fungi were present not only in cookbooks but also in scientific literature, and aspects of their ecology and medicinal use are considered. The "dark ages" for truffles, mainly for social reasons, occurred after the Second World War. In tough times, when Poland was under Soviet communist control (1945-1989), truffles as a luxurious product have been completely forgotten. However, at the end of the 20th century, truffles started receiving attention in Polish society. Yet, the real awakening began in the first decade of the twenty-first century when the first truffle orchards were established. One of them has already produced the first fruit bodies of summer truffle (Tuber aestivum). Truffles have been present in Polish culture for centuries. Their renaissance indicates the need for fostering sustainable agroforestry-centred initiatives aimed at helping truffle growers in growing the precious fungi and thus meeting market demands. PMID- 28619091 TI - The usefulness of flexible cystoscopy for preventing double-J stent malposition after laparoscopic ureterolithotomy. AB - BACKGROUND: The aim of this study was to evaluate the role of flexible cystoscopy in preventing malpositioning of the ureteral stent after laparoscopic ureterolithotomy in male patients. METHODS: From April 2009 to June 2015, 97 male patients with stones >1.8 cm in the upper ureter underwent intracorporeal double J stenting of the ureter after laparoscopic ureterolithotomy performed by four different surgeons. In the last 50 patients who underwent laparoscopic ureterolithotomy flexible cystoscopy was performed through the urethral route to confirm the position of the double-J stent, while in the first 47 correct positioning of the stent was confirmed through postoperative KUB. The demographic data and perioperative outcomes were reviewed retrospectively. Penalized logistic regression analysis was used to evaluate the effects of flexible cystoscopy. RESULTS: Upward malpositioning of the ureteral stent was found in 9 of the 47 (19.1%) patients who underwent surgery without flexible cystoscopy. Among the 50 most recent patients who underwent surgery with flexible cystoscopy through the urethral route, upward malpositioning was observed in 10 (20%) patients. The factors preventing upward malpositioning of the double-J catheter in multivariate analysis were surgeon (p = 0.039) and use of flexible cystoscopy (p = 0.008). CONCLUSION: Flexible cystoscopy is a simple, safe, quick, and effective method to identify and correct malpositioning of double-J stents, especially in male patients. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov Registry on May 11, 2017 (retrospective registration) with a trial registration number of NCT03150446 . PMID- 28619092 TI - Prevalence and patterns of use of mantra, mindfulness and spiritual meditation among adults in the United States. AB - BACKGROUND: Despite a growing body of scientific literature exploring the nature of meditation there is limited information on the characteristics of individuals who use it. This is particularly true of comparative studies examining prevalence and predictors of use of various forms of meditation. METHODS: A secondary analysis was conducted using data from the 2012 National Health Interview Survey (n = 34,525). Three popular forms of meditation were compared-mantra, mindfulness, and spiritual-to determine lifetime and 12-month use related to key sociodemographic, health behavior, health status, and healthcare access variables. RESULTS: The 12-month prevalence for meditation practice was 3.1% for spiritual meditation, 1.9% for mindfulness meditation, and 1.6% for mantra meditation. This represents approximately 7.0, 4.3, and 3.6 million adults respectively. A comparison across the three meditation practices found many similarities in user characteristics, suggesting interest in meditation may be more related to the type of person meditating than to the type of practice selected. Across meditation styles use was more prevalent among respondents who were female, non-Hispanic White, college educated, physically active; who used other complementary health practices; and who reported depression. Higher utilization of conventional healthcare services was one of the strongest predictors of use of all three styles. In addition to similarities, important distinctions were observed. For example, spiritual meditation practice was more prevalent among former drinkers. This may reflect use of spiritual meditation practices in support of alcohol treatment and sobriety. Reasons for use of meditation were examined using the sample of respondents who practiced mindfulness meditation. Wellness and prevention (74%) was a more common reason than use to treat a specific health condition (30%). Common reasons for use included stress management (92%) and emotional well-being (91%), and to support other health behaviors. Meditation was viewed positively because it was self-care oriented (81%) and focused on the whole person (79%). CONCLUSION: Meditation appears to provide an accessible, self-care resource that has potential value for mental health, behavioral self-regulation, and integrative medical care. Considering consumer preference for distinct types of meditation practices, understanding the underlying mechanisms, benefits, and applications of practice variations is important. PMID- 28619093 TI - Serial immunomonitoring of cancer patients receiving combined antagonistic anti CD40 and chemotherapy reveals consistent and cyclical modulation of T cell and dendritic cell parameters. AB - BACKGROUND: CD40 signalling can synergise with chemotherapy in preclinical cancer models, and early clinical studies are promising. We set out to define the immunological changes associated with this therapeutic combination to identify biomarkers for a response to the therapy. Here, we present serial immunomonitoring examining dendritic cell and T cell subpopulations over sequential courses of chemoimmunotherapy. METHODS: Fifteen patients with mesothelioma received up to six 21-day cycles of pemetrexed plus cisplatin chemotherapy and anti-CD40 (CP-870,893). Peripheral blood was collected weekly, and analysed by flow cytometry. Longitudinal immunophenotyping data was analysed by linear mixed modelling, allowing for variation between patients. Exploratory analyses testing for any correlation between overall survival and immunophenotyping data were undertaken up to the third cycle of treatment. RESULTS: Large statistically significant cyclical variations in the proportions of BDCA-1+, BDCA-2+ and BDCA-3+ dendritic cells were observed, although all subsets returned to baseline levels after each cycle and no significant changes were observed between start and end of treatment. Expression levels of CD40 and HLA-DR on dendritic cells were also cyclically modulated, again without significant change between start and end of treatment. CD8 and CD4 T cell populations, along with regulatory T cells, effector T cells, and markers of proliferation and activation, showed similar patterns of statistically significant cyclical modulation in response to therapy without changes between start and end of treatment. Exploratory analysis of endpoints revealed that patients with a higher than average proportion of BDCA-2+ dendritic cells (p = 0.010) or a higher than average proportion of activated (ICOS+) CD8 T cells (0.022) in pretreatment blood samples had better overall survival. A higher than average proportion of BDCA-3+ dendritic cells was associated with poorer overall survival at both the second (p = 0.008) and third (p = 0.014) dose of anti-CD40. CONCLUSIONS: Substantial cyclical variations in DC and T cell populations during sequential cycles of chemoimmunotherapy highlight the critical importance of timing of immunological biomarker assessments in interpretation of results and the value of linear mixed modelling in interpretation of longitudinal change over a full treatment course. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry number ACTRN12609000294257 (18th May 2009). PMID- 28619094 TI - Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses. AB - BACKGROUND: Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). METHODS: Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. RESULTS: Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. CONCLUSIONS: This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis associated cancer. PMID- 28619095 TI - Integrated pharmacokinetic-Pharmacodynamic (PK/PD) model to evaluate the in vivo antimicrobial activity of Marbofloxacin against Pasteurella multocida in piglets. AB - BACKGROUND: Marbofloxacin is a veterinary fluoroquinolone with high activity against Pasteurella multocida. We evaluated it's in vivo activity against P. multocida based on in vivo time-kill data in swine using a tissue-cage model. A series of dosages ranging from 0.15 to 2.5 mg/kg were administered intramuscularly after challenge with P. multocida type B, serotype 2. RESULTS: The ratio of the 24 h area under the concentration-time curve divided by the minimum inhibitory concentration (AUC24TCF/MIC) was the best PK/PD index correlated with the in vivo antibacterial effectiveness of marbofloxacin (R2 = 0.9279). The AUC24TCF/MIC necessary to achieve a 1-log10 CFU/ml reduction and a 3 log10 CFU/ml (90% of the maximum response) reduction as calculated by an inhibitory sigmoid Emax model were 13.48 h and 57.70 h, respectively. CONCLUSIONS: Marbofloxacin is adequate for the treatment of swine infected with P. multocida. The tissue-cage model played a significant role in achieving these PK/PD results. PMID- 28619096 TI - Presenilins regulate synaptic plasticity and mitochondrial calcium homeostasis in the hippocampal mossy fiber pathway. AB - BACKGROUND: Presenilins play a major role in the pathogenesis of Alzheimer's disease, in which the hippocampus is particularly vulnerable. Previous studies of Presenilin function in the synapse, however, focused exclusively on the hippocampal Schaffer collateral (SC) pathway. Whether Presenilins play similar or distinct roles in other hippocampal synapses is unknown. METHODS: To investigate the role of Presenilins at mossy fiber (MF) synapses we performed field and whole cell electrophysiological recordings and Ca2+ imaging using acute hippocampal slices of postnatal forebrain-restricted Presenilin conditional double knockout (PS cDKO) and control mice at 2 months of age. We also performed quantitative electron microscopy (EM) analysis to determine whether mitochondrial content is affected at presynaptic MF boutons of PS cDKO mice. We further conducted behavioral analysis to assess spatial learning and memory of PS cDKO and control mice at 2 months in the Morris water maze. RESULTS: We found that long-term potentiation and short-term plasticity, such as paired-pulse and frequency facilitation, are impaired at MF synapses of PS cDKO mice. Moreover, post-tetanic potentiation (PTP), another form of short-term plasticity, is also impaired at MF synapses of PS cDKO mice. Furthermore, blockade of mitochondrial Ca2+ efflux mimics and occludes the PTP deficits at MF synapses of PS cDKO mice, suggesting that mitochondrial Ca2+ homeostasis is impaired in the absence of PS. Quantitative EM analysis showed normal number and area of mitochondria at presynaptic MF boutons of PS cDKO mice, indicating unchanged mitochondrial content. Ca2+ imaging of dentate gyrus granule neurons further revealed that cytosolic Ca2+ increases induced by tetanic stimulation are reduced in PS cDKO granule neurons in acute hippocampal slices, and that inhibition of mitochondrial Ca2+ release during high frequency stimulation mimics and occludes the Ca2+ defects observed in PS cDKO neurons. Consistent with synaptic plasticity impairment observed at MF and SC synapses in acute PS cDKO hippocampal slices, PS cDKO mice exhibit profound spatial learning and memory deficits in the Morris water maze. CONCLUSIONS: Our findings demonstrate the importance of PS in the regulation of synaptic plasticity and mitochondrial Ca2+ homeostasis in the hippocampal MF pathway. PMID- 28619097 TI - Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. AB - Adipose/fat tissue provides an abundant source of stromal vascular fraction (SVF) cells for immediate administration and can also give rise to a substantial number of cultured, multipotent adipose-derived stromal cells (ADSCs). Recently, both SVF and ADSCs have gained wide-ranging translational significance in regenerative medicine. Initially used for cosmetic breast enhancement, this mode of treatment has found use in many diseases involving immune disorders, tissue degeneration, and ischaemic conditions. In this review, we try to address several important aspects of this field, outlining the biology, technology, translation, and challenges related to SVF- and ADSC-based therapies. Starting from the basics of SVF and ADSC isolation, we touch upon recently developed technologies, addressing elements of novel methods and devices under development for point-of-care isolation of SVF. Characterisation of SVF cells and ADSCs is also an evolving area and we look into unusual expression of CD34 antigen as an interesting marker for such purposes. Based on reports involving different cells of the SVF, we draw a potential mode of action, focussing on angiogenesis since it involves multiple cells, unlike immunomodulation which is governed predominantly by ADSCs. We have looked into the latest research, experimental therapies, and clinical trials which are utilising SVF/ADSCs in conditions such as multiple sclerosis, Crohn's disease, peripheral neuropathy, osteoarthritis, diabetic foot ulcer, and so forth. However, problems have arisen with regards to the lack of proper regulatory guidelines for such therapies and, since the introduction of US Food and Drug Administration draft guidelines and the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act, the debate became more public with regards to safe and efficacious use of these cells. PMID- 28619098 TI - Interventions to prevent hemodynamic instability during renal replacement therapy for acute kidney injury: a systematic review protocol. AB - BACKGROUND: Hemodynamic instability during renal replacement therapy (HIRRT) in the form of intradialytic hypotension (IDH) is a frequent complication of hemodialysis in end-stage kidney disease (ESKD), and most studies have focused on this chronic population. However, HIRRT is also an important concern for critically ill ICU patients with acute kidney injury (AKI), complicating an estimated 30% of dialysis treatments in this population. HIRRT can exacerbate organ hypoperfusion in the setting of critical illness and may negatively impact renal recovery in the AKI population. This is a protocol for a systematic review to synthesize the evidence surrounding dialysis-related interventions used to minimize HIRRT in critically ill patients with RRT-requiring AKI. This protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) database. METHODS/DESIGN: We will search MEDLINE, EMBASE, and CENTRAL databases in collaboration with a health information specialist using a comprehensive search strategy. We will also supplement our search with a scan of the "gray literature" to identify relevant ongoing trials or conference abstracts. Observational studies and clinical trials will be included in our analysis. Our outcomes will include the incidence of HIRRT, dialysis-related complications, in-hospital mortality, and renal recovery. Prior to our search, we performed an initial search of these databases and PROSPERO, which yielded no prior or ongoing systematic reviews on this topic. Two reviewers will independently screen the list of identified abstracts using pre-defined inclusion and exclusion criteria. Two reviewers will then independently extract data from selected studies and undertake an assessment of their quality using validated tools. DISCUSSION: HIRRT is a common complication of renal replacement therapy not only in ESKD but also in the critically ill AKI population. It can result in early discontinuation of dialysis, further organ injury from hypoperfusion, and possibly negatively impact renal recovery. This systematic review will synthesize the existing evidence on the interventions employed to predict or prevent episodes HIRRT in critically ill patients with RRT-requiring AKI. This systematic review will allow for an understanding the current evidence for interventions to limit HIRRT in AKI and, in doing so, may also highlight areas in need of further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037754. PMID- 28619100 TI - Cyclophilin B facilitates the replication of Orf virus. AB - BACKGROUND: Viruses interact with host cellular factors to construct a more favourable environment for their efficient replication. Expression of cyclophilin B (CypB), a cellular peptidyl-prolyl cis-trans isomerase (PPIase), was found to be significantly up-regulated. Recently, a number of studies have shown that CypB is important in the replication of several viruses, including Japanese encephalitis virus (JEV), hepatitis C virus (HCV) and human papillomavirus type 16 (HPV 16). However, the function of cellular CypB in ORFV replication has not yet been explored. METHODS: Suppression subtractive hybridization (SSH) technique was applied to identify genes differentially expressed in the ORFV-infected MDBK cells at an early phase of infection. Cellular CypB was confirmed to be significantly up-regulated by quantitative reverse transcription-PCR (qRT-PCR) analysis and Western blotting. The role of CypB in ORFV infection was further determined using Cyclosporin A (CsA) and RNA interference (RNAi). Effect of CypB gene silencing on ORFV replication by 50% tissue culture infectious dose (TCID50) assay and qRT-PCR detection. RESULTS: In the present study, CypB was found to be significantly up-regulated in the ORFV-infected MDBK cells at an early phase of infection. Cyclosporin A (CsA) exhibited suppressive effects on ORFV replication through the inhibition of CypB. Silencing of CypB gene inhibited the replication of ORFV in MDBK cells. In conclusion, these data suggest that CypB is critical for the efficient replication of the ORFV genome. CONCLUSIONS: Cellular CypB was confirmed to be significantly up-regulated in the ORFV-infected MDBK cells at an early phase of infection, which could effectively facilitate the replication of ORFV. PMID- 28619099 TI - Differentiated demographic histories and local adaptations between Sherpas and Tibetans. AB - BACKGROUND: The genetic relationships reported by recent studies between Sherpas and Tibetans are controversial. To gain insights into the population history and the genetic basis of high-altitude adaptation of the two groups, we analyzed genome-wide data in 111 Sherpas (Tibet and Nepal) and 177 Tibetans (Tibet and Qinghai), together with available data from present-day human populations. RESULTS: Sherpas and Tibetans show considerable genetic differences and can be distinguished as two distinct groups, even though the divergence between them (~3200-11,300 years ago) is much later than that between Han Chinese and either of the two groups (~6200-16,000 years ago). Sub-population structures exist in both Sherpas and Tibetans, corresponding to geographical or linguistic groups. Differentiation of genetic variants between Sherpas and Tibetans associated with adaptation to either high-altitude or ultraviolet radiation were identified and validated by genotyping additional Sherpa and Tibetan samples. CONCLUSIONS: Our analyses indicate that both Sherpas and Tibetans are admixed populations, but the findings do not support the previous hypothesis that Tibetans derive their ancestry from Sherpas and Han Chinese. Compared to Tibetans, Sherpas show higher levels of South Asian ancestry, while Tibetans show higher levels of East Asian and Central Asian/Siberian ancestry. We propose a new model to elucidate the differentiated demographic histories and local adaptations of Sherpas and Tibetans. PMID- 28619101 TI - In vitro production of bovine embryos derived from individual donors in the Corral(r) dish. AB - BACKGROUND: Since the identity of the embryo is of outmost importance during commercial in vitro embryo production, bovine oocytes and embryos have to be cultured strictly per donor. Due to the rather low yield of oocytes collected after ovum pick-up (OPU) per individual cow, oocyte maturation and embryo culture take place in small groups, which is often associated with inferior embryo development. The objective of this study was to improve embryonic development in small donor groups by using the Corral(r) dish. This commercial dish is designed for human embryo production. It contains two central wells that are divided into quadrants by a semi-permeable wall. In human embryo culture, one embryo is placed per quadrant, allowing individual follow-up while embryos are exposed to a common medium. In our study, small groups of oocytes and subsequently embryos of different bovine donors were placed in the Corral(r) dish, each donor group in a separate quadrant. RESULTS: In two experiments, the Corral(r) dish was evaluated during in vitro maturation (IVM) and/or in vitro culture (IVC) by grouping oocytes and embryos of individual bovine donors per quadrant. At day 7, a significantly higher blastocyst rate was noted in the Corral(r) dish used during IVM and IVC than when only used during IVM (12.9% +/- 2.10 versus 22.8% +/- 2.67) (P < 0.05). However, no significant differences in blastocyst yield were observed anymore between treatment groups at day 8 post insemination. CONCLUSIONS: In the present study, the Corral(r) dish was used for in vitro embryo production (IVP) in cattle; allowing to allocate oocytes and/or embryos per donor. As fresh embryo transfers on day 7 have higher pregnancy outcomes, the Corral(r) dish offers an added value for commercial OPU/IVP, since a higher blastocyst development at day 7 is obtained when the Corral(r) dish is used during IVM and IVC. PMID- 28619102 TI - Dl-3-n-butylphthalide protects the heart against ischemic injury and H9c2 cardiomyoblasts against oxidative stress: involvement of mitochondrial function and biogenesis. AB - BACKGROUND: Myocardial infarction (MI) is an acute and fatal condition that threatens human health. Dl-3-n-butylphthalide (NBP) has been used for the treatment of acute ischemic stroke. Mitochondria may play a protective role in MI injury. However, there are few reports on the cardioprotective effect of NBP or the potential mitochondrial mechanism for the NBP-induced protection against cardiac ischemia injury. We investigated the therapeutic effects of NBP in an in vivo MI model and an in vitro oxidative stress model, as well as the potential mitochondrial mechanism. METHODS: This study comprised two different experiments. The aim of experiment 1 was to determine the protective effects of NBP on MI and the underlying mechanisms in vivo. In part 1, myocardial infarct size was measured by staining with 2,3,5-triphenyltetrazoliumchloride (TTC). Myocardial enzymes and mitochondrial enzymes were assayed. The aim of experiment 2 was to investigate the role of NBP in H2O2-induced myocardial ischemic injury in H9c2 cells and to determine the potential mechanism. In part 2, H9c2 cell viability was evaluated. ROS levels, mitochondrial morphology, and mitochondrial membrane potential of H9c2 cells were measured. ATP levels were evaluated using an assay kit; mitochondrial DNA (mtDNA), the expressions of NRF-1 and TFAM, and mitochondrial biogenesis factors were determined. RESULTS: NBP treatment significantly reduced the infarct ratio, as observed by TTC staining, decreased serum myocardial enzymes in MI, and restored heart mitochondrial enzymes (isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), and a-ketoglutarate dehydrogenase (a-KGDH) activities after MI. Moreover, in in vitro studies, NBP significantly increased the viability of H9c2 cells in a dose-dependent manner, reduced cell apoptosis, protected mitochondrial functions, elevated the cellular ATP levels, and promoted H2O2 induced mitochondrial biogenesis in H9c2 cardiomyoblasts. CONCLUSION: Collectively, the results from both the in vivo and in vitro experiments suggested that NBP exerted a cardioprotective effect on cardiac ischemic injury via the regulation of mitochondrial function and biogenesis. PMID- 28619103 TI - Effects of muscle dysmorphia, social comparisons and body schema priming on desire for social interaction: an experimental approach. AB - BACKGROUND: Muscle dysmorphia (MD) is a relatively young diagnosis referring to the desire for a high degree in lean muscle mass, while simultaneously believing that one is insufficiently muscular, mostly found in men. It goes along with a risk for social withdrawal to maintain rigid exercise and dietary regimen. The aim of the current study was thus, to explore differences in men with and without a risk for muscle dysmorphia regarding their desire for social interaction. Furthermore, we investigated potential effects of individual social comparison tendencies (the tendency to compare oneself with persons who are perceived to be superior or inferior to oneself on a certain dimension) and of one's own body schema on the desire for social interaction. METHODS: One hundred physically active, college aged Austrian men were recruited via social media and flyers at fitness centers and the sports department of the University of Vienna. Participants were randomly assigned to a priming condition evoking their own body schema or a control condition and had to state their desire for social interaction with male or female stimulus persons of high or average attractiveness. We conducted a 2 (group of participant; men with vs. without a risk for MD) * 2 (priming condition; priming vs. non-priming) * 2 (attractiveness of stimulus person; highly attractive vs. less attractive) experimental design with different social comparison tendencies as covariates. RESULTS: Men with a risk for muscle dysmorphia showed lesser desire for social interaction than men without this risk, which can be seen as a risk factor for psychopathological outcomes. Generally, men with and without a risk for muscle dysmorphia did not differ with regard to their preferences for attractive stimulus persons as subjects for social interaction. We confirmed the notion that a tendency for downward social comparisons goes along with a diminished desire for social interaction. CONCLUSIONS: This study showed that men with a risk for muscle dysmorphia appeared to be at higher risk for social withdrawal and that this is associated with social comparison tendencies. Future investigations on clinical populations are needed, for this population is highly prone to social isolation and negative outcomes related to it. PMID- 28619104 TI - Individualized dual antiplatelet therapy based on platelet function testing in patients undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials. AB - BACKGROUND: High on-treatment platelet reactivity (HPR) represents a strong risk factor for thrombotic events after PCI. We aim to evaluate the efficacy and safety of individualizing intensified dual antiplatelet therapy (DAPT) in PCI treated patients with HPR based on platelet function testing (PFT). METHODS: Electronic databases were searched for randomized control trials that reported the clinical outcomes of using an intensified antiplatelet protocol with P2Y12 receptor inhibitor comparing with standard maintenance dose of clopidogrel on the basis of platelet function testing. Clinical endpoints were assessed. RESULTS: From 2005 to 2016, thirteen clinical studies comprising 7290 patients were included for analysis. Compared with standard antiplatelet therapy with clopidogrel, the intensified protocol based on platelet function testing was associated with a significant reduction in major adverse cardiovascular events (RR:0.55, 95% CI: 0.36-0.84, p = 0.005), cardiovascular death (RR:0.60, 95% CI: 0.38-0.96, p = 0.03), stent thrombosis (RR:0.58, 95% CI: 0.36-0.93, p = 0.02) and target vessel revascularization (RR:0.33, 95% CI: 0.14-0.76, p = 0.009). No significant difference was found in the rate of bleeding events between intensified and standard protocol. CONCLUSIONS: Compared with standard clopidogrel therapy, individualized intensified antiplatelet therapy on the basis of platelet reactivity testing reduces the incidence of cardiovascular events in patient undergoing PCI, without increasing the risk of bleeding. PMID- 28619105 TI - Patterns of antimicrobial resistance in intensive care unit patients: a study in Vietnam. AB - BACKGROUND: Antimicrobial resistance has emerged as a major concern in developing countries. The present study sought to define the pattern of antimicrobial resistance in ICU patients with ventilator-associated pneumonia. METHODS: Between November 2014 and September 2015, we enrolled 220 patients (average age ~ 71 yr) who were admitted to ICU in a major tertiary hospital in Ho Chi Minh City, Vietnam. Data concerning demographic characteristics and clinical history were collected from each patient. The Bauer-Kirby disk diffusion method was used to detect the antimicrobial susceptibility. RESULTS: Antimicrobial resistance was commonly found in ceftriaxone (88%), ceftazidime (80%), ciprofloxacin (77%), cefepime (75%), levofloxacin (72%). Overall, the rate of antimicrobial resistance to any drug was 93% (n = 153/164), with the majority (87%) being resistant to at least 2 drugs. The three commonly isolated microorganisms were Acinetobacter (n = 75), Klebsiella (n = 39), and Pseudomonas aeruginosa (n = 29). Acinetobacter baumannii were virtually resistant to ceftazidime, ceftriaxone, piperacilin, imipenem, meropenem, ertapenem, ciprofloxacin and levofloxacin. High rates (>70%) of ceftriaxone and ceftazidime-resistant Klebsiella were also observed. CONCLUSION: These data indicated that critically ill patients on ventilator in Vietnam were at disturbingly high risk of antimicrobial resistance. The data also imply that these Acinetobacter, Klebsiella, and Pseudomonas aeruginosa and multidrug resistance pose serious therapeutic problems in ICU patients. A concerted and systematic effort is required to rapidly identify high risk patients and to reduce the burden of antimicrobial resistance in developing countries. PMID- 28619106 TI - Bone mesenchymal stem cells ameliorate ischemia/reperfusion-induced damage in renal epithelial cells via microRNA-223. AB - BACKGROUND: Recent studies have indicated that microRNA-223 (miR-223) plays a role in the tissue-protective effect of mesenchymal stem cells (MSCs). NLR family pyrin domain containing 3 (NLRP3) was reported to affect a renal ischemia/reperfusion (I/R) injury by exerting a direct effect on the renal tubular epithelium. Therefore, we investigated how miR-223 and NLRP3 might function in kidneys exposed to conditions of ischemia and subsequent reperfusion. METHODS: Hypoxia/reoxygenation (H/R) murine renal tubular epithelial cells (RTECs) were cocultured with either MSCs or hypoxia-pretreated MSCs (htMSCs), after which the RTECs were examined for their viability and evidence of apoptosis. Next, miR-223 expression in the MSCs was downregulated to verify that MSCs protected RTECs via the transport of miR-223. Kidney I/R KM/NIH mouse models were created and used for in vivo studies. RESULTS: The results showed that coculture with MSCs significantly increased the viability of RTECs and decreased their rates of apoptosis. The levels of hepatocyte growth factor (HGF), insulin like growth factor-1 (IGF-1), transforming growth factor beta (TGF-beta), and vascular endothelial growth factor (VEGF) in samples of coculture supernatants were higher than those in samples of non-coculture supernatants. A bioinformatics analysis revealed a targeting relationship between miR-223 and NLRP3. A dual luciferase assay showed that miR-223 inhibited NLRP3 expression. The htMSCs displayed a protective function associated with an upregulation of miR-223 as induced by Notch1 and the downregulation of NLRP3. Conversely, inhibition of miR 223 impeded the protective effect of MSCs. In the I/R mouse models, injection of either MSCs or htMSCs ameliorated the damage to kidney tissue, while suppression of miR-223 expression in MSCs reduced their protective effect on mouse kidneys. CONCLUSIONS: Our results demonstrate that miR-223 and NLRP3 play important roles in the treatment of renal tissue injuries with transplanted MSCs. PMID- 28619107 TI - Risk factors of suicide attempt among people with suicidal ideation in South Korea: a cross-sectional study. AB - BACKGROUND: Suicide is a serious public health concern worldwide, and the fourth leading cause of death in Korea. Few studies have focused on risk factors for suicide attempt among people with suicidal ideation. The aim of the present study was to investigate the risk factors and develop prediction models for suicide attempt among people with suicidal ideation in the Korean population. METHOD: This study included 1567 men and 3726 women aged 20 years and older who had suicidal ideation from the Korea National Health and Nutrition Examination Survey from 2007 to 2012. Among them, 106 men and 188 women attempted suicide. Multivariate logistic regression analysis with backward stepwise elimination was performed to find risk factors for suicide attempt. Sub-group analysis, dividing participants into under 50 and at least 50 years old was also performed. RESULTS: Among people with suicidal ideation, age, education, cancer, and depressive disorder were selected as risk factors for suicide attempt in men. Age, education, national basic livelihood security, daily activity limitation, depressive disorder, stress, smoking, and regular exercise were selected in women. Area under curves of our prediction models in men and women were 0.728 and 0.716, respectively. CONCLUSIONS: It is important to pay attention to populations with suicidal ideation and the risk factors mentioned above. Prediction models using the determined risk factors could be useful to detect high-risk groups early for suicide attempt among people with suicidal ideation. It is necessary to develop specific action plans for these high-risk groups to prevent suicide. PMID- 28619108 TI - Scavenging on a pulsed resource: quality matters for corvids but density for mammals. AB - BACKGROUND: Human food subsidies can provide predictable food sources in large quantities for wildlife species worldwide. In the boreal forest of Fennoscandia, gut piles from moose (Alces alces) harvest provide a potentially important food source for a range of opportunistically scavenging predators. Increased populations of predators can negatively affect threatened or important game species. As a response to this, restrictions on field dressing of moose are under consideration in parts of Norway. However, there is a lack of research to how this resource is utilized. In this study, we used camera-trap data from 50 gut piles during 1043 monitoring days. We estimated depletion of gut piles separately for parts with high and low energy content, and used these results to scale up gut pile density in the study area. We identified scavenger species and analyzed the influences of gut pile quality and density on scavenging behavior of mammals and corvids (family Corvidae). RESULTS: Main scavengers were corvids and red fox (Vulpes vulpes). Parts with high energy content were rapidly consumed, mainly by corvids that were present at all gut piles shortly after the remains were left at the kill site. Corvid presence declined with days since harvest, reflecting reduction in gut pile quality over time independent of gut pile density. Mammals arrived 7-8 days later at the gut piles than corvids, and their presence depended only on gut pile density with a peak at intermediate densities. The decline at high gut pile densities suggest a saturation effect, which could explain accumulation of gut pile parts with low energy content. CONCLUSIONS: This study shows that remains from moose harvest can potentially be an important food resource for scavengers, as it was utilized to a high degree by many species. This study gives novel insight into how energy content and density of resources affect scavenging patterns among functional groups of scavengers. PMID- 28619109 TI - Type II CRISPR/Cas9 approach in the oncological therapy. AB - CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a prokaryotic adaptable immune mechanism used by many bacteria and archaea to protect themselves from foreign nucleic acids. This complex system can recognize and cut non-self DNA in order to provide the prokaryotic organisms a strong defense against foreign viral or plasmid attacks and make the cell immune from further assaults. Today, it has been adapted to be used in vitro and in vivo in eukaryotic cells to perform a complete and highly selective gene knockout or a specific gene editing. The ease of use and the low cost are only two features that have made it very popular among the scientific community and the possibility to be used as a clinical treatment in several genetic derived pathologies has rapidly spread its fame worldwide. However, CRISPR is still not fully understood and many efforts need to be done in order to make it a real power tool for the human clinical treatment especially for oncological patients. Indeed, since cancer originates from non-lethal genetic disorders, CRISPR discovery fuels the hope to strike tumors on their roots. More than 4000 papers regarding CRISPR were published in the last ten years and only few of them take in count the possible applications in oncology. The purpose of this review is to clarify many problematics on the CRISPR usage and highlight its potential in oncological therapy. PMID- 28619110 TI - Effect of aspartic acid and glutamate on metabolism and acid stress resistance of Acetobacter pasteurianus. AB - BACKGROUND: Acetic acid bacteria (AAB) are widely applied in food, bioengineering and medicine fields. However, the acid stress at low pH conditions limits acetic acid fermentation efficiency and high concentration of vinegar production with AAB. Therefore, how to enhance resistance ability of the AAB remains as the major challenge. Amino acids play an important role in cell growth and cell survival under severe environment. However, until now the effects of amino acids on acetic fermentation and acid stress resistance of AAB have not been fully studied. RESULTS: In the present work the effects of amino acids on metabolism and acid stress resistance of Acetobacter pasteurianus were investigated. Cell growth, culturable cell counts, acetic acid production, acetic acid production rate and specific production rate of acetic acid of A. pasteurianus revealed an increase of 1.04, 5.43, 1.45, 3.30 and 0.79-folds by adding aspartic acid (Asp), and cell growth, culturable cell counts, acetic acid production and acetic acid production rate revealed an increase of 0.51, 0.72, 0.60 and 0.94-folds by adding glutamate (Glu), respectively. For a fully understanding of the biological mechanism, proteomic technology was carried out. The results showed that the strengthening mechanism mainly came from the following four aspects: (1) Enhancing the generation of pentose phosphates and NADPH for the synthesis of nucleic acid, fatty acids and glutathione (GSH) throughout pentose phosphate pathway. And GSH could protect bacteria from low pH, halide, oxidative stress and osmotic stress by maintaining the viability of cells through intracellular redox equilibrium; (2) Reinforcing deamination of amino acids to increase intracellular ammonia concentration to maintain stability of intracellular pH; (3) Enhancing nucleic acid synthesis and reparation of impaired DNA caused by acid stress damage; (4) Promoting unsaturated fatty acids synthesis and lipid transport, which resulted in the improvement of cytomembrane fluidity, stability and integrity. CONCLUSIONS: The present work is the study to show the effectiveness of Asp and Glu on metabolism and acid stress resistance of A. pasteurianus as well as their working mechanism. The research results will be helpful for development of nutrient salts, the optimization and regulation of high concentration of cider vinegar production process. PMID- 28619111 TI - Two-minute disconnection technique with a double-lumen tube to speed the collapse of the non-ventilated lung for one-lung ventilation in thoracoscopic surgery. AB - BACKGROUND: Thoracic surgery requires the effective collapse of the non ventilated lung. In the majority of cases, we accomplished, accelerated lung collapse using a double-lumen tube (DLT). We hypothesized that using the two minute disconnection technique with a DLT would improve lung collapse during subsequent one-lung ventilation. METHODS: Fifty patients undergoing thoracoscopic surgery with physical classification I or II according to the American Society of Anesthesiologists were randomly divided into two groups for respiratory management of one-lung ventilation (OLV). In group N, OLV was initiated after the DLT was disconnected for 2 min; the initiation time began when the surgeon made the skin incision. In group C, OLV was initiated when the surgeon commenced the skin incision and scored the quality of lung collapse (using a four-point ordinal scale). The surgeon's satisfaction or comfort with the surgical conditions was assessed using a visual analogue scale. rSO2 level, mean arterial pressure, pulse oxygen saturation, arterial blood gas analysis, intraoperative hypoxaemia, intraoperative use of CPAP during OLV, and awakening time were determined in patients at the following time points: while inhaling air (T0), after anaesthesia induction andinhaling 100% oxygen in the supine position under double lung ventilation for five mins (T1), at two mins after skin incision (T2), at ten mins after skin incision (T3), and after the lung recruitment manoeuvres and inhaling 50% oxygen for five mins (T4). RESULTS: The two-minute disconnection technique was associated with a significantly shorter time to total lung collapse compared to that of the conventional OLV ventilation method (15 mins vs 22 mins, respectively; P < 0.001), and the overall surgeon's satisfaction was higher (9 vs 7, respectively; P < 0.001). At T2, the PaCO2, left rSO2 and right rSO2 were higher in group N than in group C. There were no statistically significant differences between the incidence of intraoperative hypoxaemia and intraoperative use of CPAP during OLV (10% vs 5%, respectively; P = 1.000), duration of awakening (18 mins vs 19 mins, respectively; P = 0.616). CONCLUSIONS: A two minute disconnection technique using a double-lumen tube was used to speed the collapse of the non-ventilated lung during one-lung ventilation for thoracoscopic surgery. The surgeon was satisfied with the surgical conditions. TRIAL REGISTRATION: Chinese Clinical Trial Registry number, ChiCTR-IPR-17010352 . Registered on Jan, 7, 2017. PMID- 28619112 TI - Docosahexaenoic acid regulates vascular endothelial cell function and prevents cardiovascular disease. AB - Docosahexaenoic acid (DHA) is present in high concentrations in salmon, herring, and trout. Epidemiologic studies have shown that high dietary consumption of these and other oily fish is associated with reduced rates of myocardial infarction, atherosclerosis, and other ischemic pathologies. Atherosclerosis is induced by inflammation and can lead to acute cardiovascular events and extensive plaque. DHA inhibits the development of inflammation in endothelial cells, alters the function and regulation of vascular biomarkers, and reduces cardiovascular risk. It also affects vascular relaxation and constriction by controlling nitric oxide and endothelin 1 production in endothelial cells. DHA also contributes to the prevention of arteriosclerosis by regulating the expression of oxidized low density lipoprotein receptor 1, plasminogen activator inhibitor 1, thromboxane A2 receptor, and adhesion molecules such as vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and intercellular adhesion molecule 1 in endothelial cells. Recent research showed that DHA reduces the increase in adhesion factor expression induced by lipopolysaccharide by suppressing toll-like receptor 4. A new mechanism of action of DHA has been described that is mediated through endothelial free fatty acid receptor 4, associated with heme oxygenase 1 induction by Nrf2. However, the efficacy and mechanisms of action of DHA in cardiovascular disease prevention are not yet completely understood. The aim of this paper was to review the effects of DHA on vascular endothelial cells and recent findings on their potential for the prevention of circulatory diseases. PMID- 28619113 TI - Mechanisms underlying extensive Ser129-phosphorylation in alpha-synuclein aggregates. AB - Parkinson's disease (PD) is characterized neuropathologically by intracellular aggregates of fibrillar alpha-synuclein, termed Lewy bodies (LBs). Approximately 90% of alpha-synuclein deposited as LBs is phosphorylated at Ser129 in brains with PD. In contrast, only 4% of total alpha-synuclein is phosphorylated at Ser129 in brains with normal individuals. It is unclear why extensive phosphorylation occurs in the pathological process of PD. To address this issue, we investigated a mechanism and role of Ser129-phosphorylation in regulating accumulation of alpha-synuclein. In CHO cells, the levels of Ser129 phosphorylated soluble alpha-synuclein were maintained constantly to those of total alpha-synuclein in intracellular and extracellular spaces. In SH-SY5Y cells and rat primary cortical neurons, mitochondrial impairment by rotenone or MPP+ enhanced Ser129-phosphorylation through increased influx of extracellular Ca2+. This elevation was suppressively controlled by targeting Ser129-phosphorylated alpha-synuclein to the proteasome pathway. Rotenone-induced insoluble alpha synuclein was also targeted by Ser129-phosphoryation to the proteasome pathway. Experiments with epoxomicin and chloroquine showed that proteasomal targeting of insoluble Ser129-phosphorylated alpha-synuclein was enhanced under lysosome inhibition and it reduced accumulation of insoluble total alpha-synuclein. However, in a rat AAV-mediated alpha-synuclein overexpression model, there was no difference in the number of total alpha-synuclein aggregates between A53T mutant and A53T plus S129A double mutant alpha-synuclein, although Ser129-phosphorylated alpha-synuclein-positive aggregates were increased in rats expressing A53T alpha synuclein. These findings suggest that Ser129-phosphorylation occurs against stress conditions, which increases influx of extracellular Ca2+, and it prevents accumulation of insoluble alpha-synuclein by evoking proteasomal clearance complementary to lysosomal one. However, Ser129-phosphorylation may provide an ineffective signal for degradation-resistant aggregates, causing extensive phosphorylation in aggregates. PMID- 28619115 TI - Effectiveness of a physical activity program on cardiovascular disease risk in adult primary health-care users: the "Pas-a-Pas" community intervention trial. AB - BACKGROUND: Physical activity is a major, modifiable, risk factor for cardiovascular disease (CVD) that contributes to the prevention and management of CVD. The aim of this study was to assess the short- and medium-term effectiveness of 9 months of a supervised physical activity program, including sociocultural activities, on CVD risk in adults. METHODS: Multicentered, randomized, controlled community intervention involving 364 patients in four primary care centers. The participants were randomly assigned to a Control Group (CG = 104) or Intervention Group (IG = 260); mean age 65.19 years; 76.8% women. The intervention consisted of 120 min/week walking (396 METs/min/week) and sociocultural gathering once a month. Clinical history, physical activity, dietary intake, CVD risk factors (smoking, systolic and diastolic blood pressure, weight, waist circumference, BMI, total cholesterol, LDL- and HDL-cholesterol, triglycerides, glycosylated hemoglobin and glucose) and global CVD risk were assessed at baseline and at the end of the intervention and multivariate models were applied to the data. Incidence of adverse cardiovascular events and continued adherence to the physical activity were assessed 2 years after intervention. RESULTS: At the end of the intervention period, in the IG relative to the CG group, there was a significant increase in physical activity (774.81 METs/min/week), a significant change during the intervention period in systolic blood pressure (-6.63 mmHg), total cholesterol (-10.12 mg/dL) and LDL-cholesterol (-9.05 mg/dL) even after adjustment for potential confounders. At 2 years after the intervention, in the IG, compared with the CG, tthe incidence of adverse cardiovascular events was significantly lower (2.5% vs. 10.5%) and the adherence to regular physical activity was higher (72.8% vs 27.2%) in IG compared to CG. CONCLUSIONS: This community-based physical activity program improved cardiovascular health in the short- as well as medium-term, and promoted regular physical activity in the medium-term in older Spanish adults. TRIALS REGISTRATION: Clinicaltrials.gov ID NCT02767739 . Trial registered on May 5th, 2016. Retrospectively registered. PMID- 28619114 TI - Reducing the rate and duration of Re-ADMISsions among patients with unipolar disorder and bipolar disorder using smartphone-based monitoring and treatment - the RADMIS trials: study protocol for two randomized controlled trials. AB - BACKGROUND: Unipolar and bipolar disorder combined account for nearly half of all morbidity and mortality due to mental and substance use disorders, and burden society with the highest health care costs of all psychiatric and neurological disorders. Among these, costs due to psychiatric hospitalization are a major burden. Smartphones comprise an innovative and unique platform for the monitoring and treatment of depression and mania. No prior trial has investigated whether the use of a smartphone-based system can prevent re-admission among patients discharged from hospital. The present RADMIS trials aim to investigate whether using a smartphone-based monitoring and treatment system, including an integrated clinical feedback loop, reduces the rate and duration of re-admissions more than standard treatment in unipolar disorder and bipolar disorder. METHODS: The RADMIS trials use a randomized controlled, single-blind, parallel-group design. Patients with unipolar disorder and patients with bipolar disorder are invited to participate in each trial when discharged from psychiatric hospitals in The Capital Region of Denmark following an affective episode and randomized to either (1) a smartphone-based monitoring system including (a) an integrated feedback loop between patients and clinicians and (b) context-aware cognitive behavioral therapy (CBT) modules (intervention group) or (2) standard treatment (control group) for a 6-month trial period. The trial started in May 2017. The outcomes are (1) number and duration of re-admissions (primary), (2) severity of depressive and manic (only for patients with bipolar disorder) symptoms; psychosocial functioning; number of affective episodes (secondary), and (3) perceived stress, quality of life, self-rated depressive symptoms, self-rated manic symptoms (only for patients with bipolar disorder), recovery, empowerment, adherence to medication, wellbeing, ruminations, worrying, and satisfaction (tertiary). A total of 400 patients (200 patients with unipolar disorder and 200 patients with bipolar disorder) will be included in the RADMIS trials. DISCUSSION: If the smartphone-based monitoring system proves effective in reducing the rate and duration of re-admissions, there will be basis for using a system of this kind in the treatment of unipolar and bipolar disorder in general and on a larger scale. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03033420 . Registered 13 January 2017. Ethical approval has been obtained. PMID- 28619116 TI - Feasibility of a physical activity intervention during and shortly after chemotherapy for testicular cancer. AB - BACKGROUND: Given the risk of developing acute and long-term adverse effects in patients receiving cisplatin-based chemotherapy for testicular cancer (TC), risk reducing interventions, such as physical activity (PA), may be relevant. Limited knowledge is available on the challenges met when conducting PA intervention trials in patients with TC during and shortly after chemotherapy. The aims of the present feasibility study are therefore to determine patient recruitment, compliance and adherence to a PA intervention. RESULTS: Patients with metastatic TC referred to cisplatin-based chemotherapy were eligible. They followed an individual low-threshold PA intervention, including counseling from a personal coach during and 3 months after chemotherapy. Outcomes were recruitment rate, compliance rate and adherence to the intervention including preferences for type of PA and barriers for PA. During 8 months 12 of 18 eligible patients were invited, all consented, but three dropped out. Walking and low intensity activities were preferred and nausea and feeling unwell were the most often reported barriers towards PA. DISCUSSION: In order to achieve adequate recruitment, compliance and complete data in future PA intervention trials, close cooperation with treating physicians, individual PA plans and availability of personalized coaching are required. Trial registration NCT01749774, November 2012, ClinicalTrials.gov. PMID- 28619117 TI - The elevation of plasma concentrations of apoB-48-containing lipoproteins in familial hypercholesterolemia is independent of PCSK9 levels. AB - BACKGROUND: Previous studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B-48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized. The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH). METHODS: A total of 118 HeFH, 6 HoFH, and 117 controls were included in the study. Plasma PCSK9 and apoB-48 concentrations were measured in the fasting state. RESULTS: Plasma PCSK9 and apoB-48 levels were higher in FH subjects compared with controls (PCSK9: HoFH: 642.6 +/- 246.9 vs. HeFH: 324.9 +/- 119.8 vs. CONTROLS: 194.5 +/- 65.9 ng/mL, P < 0.0001; apoB-48: HoFH: 14.71 +/- 4.36 vs. HeFH: 6.55 +/- 4.24 vs. CONTROLS: 3.03 +/- 2.07 MUg/mL; P < 0.0001). There were no correlations between apoB-48 and PCSK9 plasma levels in both controls (rho = 0.06, P = 0.5) and HeFH subjects (rho = 0.07, P = 0.4). Multiple linear regression analysis showed that the FH status was the only independent factor associated with apoB-48 levels, contributing to 28.7% of the variance (P < 0.0001). CONCLUSIONS: These data indicate that the elevation in plasma apoB-48 levels associated with FH is independent of PCSK9 levels. TRIAL REGISTRATION: NCT02225340 . PMID- 28619119 TI - Transmission of a novel sonotubometry acoustic click stimulus in healthy and patulous eustachian tube subjects: a retrospective case -control study. AB - BACKGROUND: Eustachian tube (ET) dysfunction can be very difficult to diagnose accurately. Our aim is to determine whether a newly developed sonotubometric test using clicks can reliably detect ET opening during swallowing in normal ET subjects, and patulous ET (PET) in subjects with ET dysfunction. METHODS: Sixteen subjects (19 normal ET ears and 6 PET ears) were individually placed in a sound isolated audiometry booth and subjected to a 1000Hz click train stimulus, played through the nose. PET subjects were identified through the ET clinic at our institution, while healthy subjects were recruited. Transmission through the ET was recorded by a microphone in the ear ipsilateral to the presenting nostril, during no swallow and swallow states, and this was used to compute a power ratio (power in the frequency range of interest to the whole frequency range). The power transmission ratio both before and after the swallow was averaged, and represented the baseline (BaseR). The power transmission ratio during swallow represented the peak (PeakR). The same process was repeated in the absence of a stimulus to account for swallowing noise. Wilcoxon rank rum tests were performed to determine statistical significance. RESULTS: It was found that for healthy ET patients, the median difference between the PeakR and BaseR was 0.51 (p = 0.004). For the PET patients in this study, the median difference between the PeakR and the BaseR was 3.30 (p = 0.041). Comparing the baseline between groups revealed that PET patients had a median BaseR 1.05 higher than healthy ET patients. PET patients had a median PeakR of 3.84 higher than healthy ET patients. Both were deemed to be statistically significant (p = 0.003, p = 0.003 respectively). A significant difference was found between median PeakR for the stimulus and no stimulus condition for the healthy ET group (0.59, p < 0.001) and for the PET group (4.39, p = 0.031), indicating that it was unlikely that swallowing noise caused false positive results. CONCLUSION: The results of this study suggest that a novel click stimulus is capable of detecting ET opening during swallowing in healthy patients as well as highlighting PET in diseased subjects. PMID- 28619118 TI - Serum levels of leptin and high molecular weight adiponectin are inversely associated with radiographic spinal progression in patients with ankylosing spondylitis: results from the ENRADAS trial. AB - BACKGROUND: Previous research indicates a role of adipokines in inflammation and osteogenesis. Hence adipokines might also have a pathophysiological role in inflammation and new bone formation in patients with ankylosing spondylitis (AS). The aim of this study was to investigate the role of adipokine serum levels as predictors of radiographic spinal progression in patients with AS. METHODS: A total of 120 patients with definite AS who completed a 2-year follow up in the ENRADAS trial were included in the current study. Radiographic spinal progression was defined as: (1) worsening of the modified Stoke Ankylosing Spondylitis spine (mSASSS) score by >=2 points and/or (2) new syndesmophyte formation or progression of existing syndesmophytes after 2 years. Serum levels of adipokines (adiponectin (APN) and its high molecular weight form (HMW-APN), chemerin, leptin, lipocalin-2, omentin, resistin, visfatin) were measured using enzyme linked immunosorbent assays. RESULTS: There was a significant association between radiographic spinal progression and both leptin and HMW-APN. Baseline serum levels of both adipokines were lower in patients who showed radiographic spinal progression after 2 years. This association was especially evident in men; they had generally lower leptin and HMW-APN serum levels as compared to women. The inverse association between adipokines and radiographic spinal progression was confirmed in the logistic regression analysis: the odds ratios (OR) for the outcome "no mSASSS progression >=2 points" were 1.16 (95% CI 1.03 to 1.29) and 1.17 (95% CI 0.99 to 1.38), for leptin and HMW-APN, respectively; for "no syndesmophyte formation/progression" the respective OR were 1.29 (95% CI 1.11 to 1.50) and 1.18 (95% CI 0.98 to 1.42), adjusted for the presence of syndesmophytes at baseline, C-reactive protein at baseline, sex, body mass index (BMI), non steroidal anti-inflammatory drugs intake score over 2 years, and smoking status at baseline. CONCLUSION: Serum leptin and HMW-APN predict protection from spinal radiographic progression in patients with AS. Women generally have higher leptin and HMW-APN serum levels that might explain why they have less structural damage in the spine as compared to male patients with AS. TRIAL REGISTRATION: EudraCT: 2007-007637-39. ClinicalTrials.gov, NCT00715091 . Registered on 14 July 2008. PMID- 28619121 TI - Exploring patients' treatment journeys following randomisation in mental health trials to improve future trial conduct: a synthesis of multiple qualitative data sets. AB - BACKGROUND: The way in which pragmatic trials are designed suggests that there are differences between the experiences of participants randomised to usual care and intervention arms. These potential differences relate not only to which treatment participants receive but also how they access and engage with their allocated treatment. Such differences could affect trial results. The aim of this study was to assess whether such differences exist and, if they do, to consider their implications for the design of future trials. METHODS: Interview transcripts were sampled from data sets gathered during three qualitative studies, all of which had been nested within large, primary care depression trials. Each study had explored trial participants' views and experiences of treatments received following randomisation. Transcripts from 37 participants were purposefully sampled, 20 of which were from interviews held with individuals allocated to receive usual GP care. Data were analysed thematically. RESULTS: There was evidence of differences between trial arms across all three data sets. Intervention participants were willing and able to engage with the treatment to which they had been allocated. Randomisation had led to them embarking upon a clear treatment pathway and receiving care in a context where they felt comfortable discussing their mental health and had sufficient time to do so. Intervention participants also had continuity with and confidence in the practitioners they saw. A few usual-care participants talked about having continuity with and confidence in their GPs. However, most of the usual-care participants reported a reluctance to consult GPs about mental health, difficulties in securing treatment appointments, and little or no changes in care following randomisation. Additionally, most reported a lack of continuity of care and a lack confidence in the treatment available to them. CONCLUSIONS: There are important differences between usual-care and intervention arms that go beyond treatment received, and they relate to how participants experience accessing and engaging with their allocated care. As these differences could affect trial results, researchers may want to measure or reduce them in order to fully appreciate or control for the range of factors that might affect treatment outcomes. PMID- 28619122 TI - Long-term results of percutaneous balloon valvuloplasty in neonatal critical pulmonary valve stenosis: a 20-year, single-centre experience. AB - : Introduction Percutaneous balloon valvuloplasty is the primary treatment for critical pulmonary valve stenosis in neonates. Thus far, a few studies have reported long-term results of this technique in neonatal critical pulmonary valve stenosis. METHODS: We carried out a retrospective study of all consecutive newborns with critical pulmonary valve stenosis subjected to percutaneous balloon valvuloplasty at a single centre, between 1994 and 2014, to assess its immediate and long-term safety and efficacy. RESULTS: A total of 24 neonates presented with critical pulmonary valve stenosis. The mean diameter of the pulmonary annulus was 7 mm (+/-1.19); 33.3% had a dysplastic pulmonary valve, and 92% were started on prostaglandin E1 treatment. Percutaneous balloon valvuloplasty was performed at a mean age of 4.0+/-4.3 days using, on average, a balloon-to-pulmonary annulus ratio of 1.18 mm (with a range from 0.9 to 1.43). Immediate success was achieved in 22/24 patients (92%) with a reduction in the pulmonary transvalvular peak gradient (p<0.05) and in the right ventricle/systemic pressure ratio (p<0.05). There was one death (4%) 6 days after the procedure, and 29.2% of them had transient rhythm complications. For a mean follow-up time of 8.4 years, the re intervention rate was 42.9%. In total, 14 re-interventions were performed in nine neonates, including surgery in six. Freedom from re-intervention was 50% at 8 years and 43% at 10 and 15 years. CONCLUSION: This series, to the best of our knowledge, has had the longest follow-up of neonates with critical pulmonary valve stenosis. Percutaneous balloon valvuloplasty is a safe and effective treatment, and in our study 75% of the patients were exclusively treated using this technique. PMID- 28619120 TI - G6PD deficiency alleles in a malaria-endemic region in the Western Brazilian Amazon. AB - BACKGROUND: Plasmodium vivax parasites are the predominant cause of malaria infections in the Brazilian Amazon. Infected individuals are treated with primaquine, which can induce haemolytic anaemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals and may lead to severe and fatal complications. This X-linked disorder is distributed globally and is caused by allelic variants with a geographical distribution that closely reflects populations exposed historically to endemic malaria. In Brazil, few studies have reported the frequency of G6PD deficiency (G6PDd) present in malaria-endemic areas. This is particularly important, as G6PDd screening is not currently performed before primaquine treatment. The aim of this study was to determine the prevalence of G6PDd in the region of Alto do Jurua, in the Western Brazilian Amazon, an area characterized by a high prevalence of P. vivax infection. METHODS: Five-hundred and sixteen male volunteers were screened for G6PDd using the fluorescence spot test (Beutler test) and CareStartTM G6PD Biosensor system. Demographic and clinical-epidemiological data were acquired through an individual interview. To assess the genetic basis of G6PDd, 24 SNPs were genotyped using the Kompetitive Allele Specific PCR assay. RESULTS: Twenty-three (4.5%) individuals were G6PDd. No association was found between G6PDd and the number of malaria cases. An increased risk of reported haemolysis symptoms and blood transfusions was evident among the G6PDd individuals. Twenty-two individuals had the G6PDd A( ) variant and one the G6PD A(+) variant. The Mediterranean variant was not present. Apart from one polymorphism, almost all SNPs were monomorphic or with low frequencies (0-0.04%). No differences were detected among ethnic groups. CONCLUSIONS: The data indicates that ~1/23 males from the Alto do Jurua could be G6PD deficient and at risk of haemolytic anaemia if treated with primaquine. G6PD A(-) is the most frequent deficiency allele in this population. These results concur with reported G6PDd in other regions in Brazil. Routine G6PDd screening to personalize primaquine administration should be considered, particularly as complete treatment of patients with vivax malaria using chloroquine and primaquine, is crucial for malaria elimination. PMID- 28619123 TI - CHD and respiratory syncytial virus: global expert exchange recommendations. AB - BACKGROUND: Palivizumab is the standard immunoprophylaxis against serious disease due to respiratory syncytial virus infection. Current evidence-based prophylaxis guidelines may not address certain children with CHD within specific high-risk groups or clinical/management settings. METHODS: An international steering committee of clinicians with expertise in paediatric heart disease identified key questions concerning palivizumab administration; in collaboration with an additional international expert faculty, evidence-based recommendations were formulated using a quasi-Delphi consensus methodology. RESULTS: Palivizumab prophylaxis was recommended for children with the following conditions: <2 years with unoperated haemodynamically significant CHD, who are cyanotic, who have pulmonary hypertension, or symptomatic airway abnormalities; <1 year with cardiomyopathies requiring treatment; in the 1st year of life with surgically operated CHD with haemodynamically significant residual problems or aged 1-2 years up to 6 months postoperatively; and on heart transplant waiting lists or in their 1st year after heart transplant. Unanimous consensus was not reached for use of immunoprophylaxis in children with asymptomatic CHD and other co-morbid factors such as arrhythmias, Down syndrome, or immunodeficiency, or during a nosocomial outbreak. Challenges to effective immunoprophylaxis included the following: multidisciplinary variations in identifying candidates with CHD and prophylaxis compliance; limited awareness of severe disease risks/burden; and limited knowledge of respiratory syncytial virus seasonal patterns in subtropical/tropical regions. CONCLUSION: Evidence-based immunoprophylaxis recommendations were formulated for subgroups of children with CHD, but more data are needed to guide use in tropical/subtropical countries and in children with certain co-morbidities. PMID- 28619124 TI - Multiplex tests to identify gastrointestinal bacteria, viruses and parasites in people with suspected infectious gastroenteritis: a systematic review and economic analysis. AB - BACKGROUND: Gastroenteritis is a common, transient disorder usually caused by infection and characterised by the acute onset of diarrhoea. Multiplex gastrointestinal pathogen panel (GPP) tests simultaneously identify common bacterial, viral and parasitic pathogens using molecular testing. By providing test results more rapidly than conventional testing methods, GPP tests might positively influence the treatment and management of patients presenting in hospital or in the community. OBJECTIVE: To systematically review the evidence for GPP tests [xTAG(r) (Luminex, Toronto, ON, Canada), FilmArray (BioFire Diagnostics, Salt Lake City, UT, USA) and Faecal Pathogens B (AusDiagnostics, Beaconsfield, NSW, Australia)] and to develop a de novo economic model to compare the cost-effectiveness of GPP tests with conventional testing in England and Wales. DATA SOURCES: Multiple electronic databases including MEDLINE, EMBASE, Web of Science and the Cochrane Database were searched from inception to January 2016 (with supplementary searches of other online resources). REVIEW METHODS: Eligible studies included patients with acute diarrhoea; comparing GPP tests with standard microbiology techniques; and patient, management, test accuracy or cost effectiveness outcomes. Quality assessment of eligible studies used tailored Quality Assessment of Diagnostic Accuracy Studies-2, Consolidated Health Economic Evaluation Reporting Standards and Philips checklists. The meta-analysis included positive and negative agreement estimated for each pathogen. A de novo decision tree model compared patients managed with GPP testing or comparable coverage with patients managed using conventional tests, within the Public Health England pathway. Economic models included hospital and community management of patients with suspected gastroenteritis. The model estimated costs (in 2014/15 prices) and quality-adjusted life-year losses from a NHS and Personal Social Services perspective. RESULTS: Twenty-three studies informed the review of clinical evidence (17 xTAG, four FilmArray, two xTAG and FilmArray, 0 Faecal Pathogens B). No study provided an adequate reference standard with which to compare the test accuracy of GPP with conventional tests. A meta-analysis (of 10 studies) found considerable heterogeneity; however, GPP testing produces a greater number of pathogen-positive findings than conventional testing. It is unclear whether or not these additional 'positives' are clinically important. The review identified no robust evidence to inform consequent clinical management of patients. There is considerable uncertainty about the cost-effectiveness of GPP panels used to test for suspected infectious gastroenteritis in hospital and community settings. Uncertainties in the model include length of stay, assumptions about false positive findings and the costs of tests. Although there is potential for cost effectiveness in both settings, key modelling assumptions need to be verified and model findings remain tentative. LIMITATIONS: No test-treat trials were retrieved. The economic model reflects one pattern of care, which will vary across the NHS. CONCLUSIONS: The systematic review and cost-effectiveness model identify uncertainties about the adoption of GPP tests within the NHS. GPP testing will generally correctly identify pathogens identified by conventional testing; however, these tests also generate considerable additional positive results of uncertain clinical importance. FUTURE WORK: An independent reference standard may not exist to evaluate alternative approaches to testing. A test treat trial might ascertain whether or not additional GPP 'positives' are clinically important or result in overdiagnoses, whether or not earlier diagnosis leads to earlier discharge in patients and what the health consequences of earlier intervention are. Future work might also consider the public health impact of different testing treatments, as test results form the basis for public health surveillance. STUDY REGISTRATION: This study is registered as PROSPERO CRD2016033320. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28619125 TI - Uptake, prevalence and predictors of first-time use for the 75+ Health Assessment Scheme. AB - In 1999, the Australian Federal Government introduced Medicare items for Health Assessments for people aged 75 years and older (75+ health assessments). This research examined uptake of these assessments and identified predictors of use by women from the Australian Longitudinal Study on Women's Health (ALSWH). Assessments were identified for each year from 1999 to 2013 using linked Medicare data. Time to first assessment was examined, as well as social and health factors associated with having an assessment. From 1999 to 2013, 61.8% of women had at least one assessment. Almost one-third had an assessment within 2 years of their introduction, 25% of women died before having an assessment and 13% survived but did not have an assessment. Factors associated with assessment included being widowed, private health insurance, marital status, education, having arthritis and urinary incontinence, and less difficulty managing on income. Many women never received an assessment, and many only received one. Promotion of the 75+ health assessments is necessary among older women to increase uptake. PMID- 28619126 TI - Health and wellbeing outcomes of programs for Indigenous Australians that include strategies to enable the expression of cultural identities: a systematic review. AB - Indigenous people have long maintained that strong cultural identities are critical to health and wellbeing. The purpose of this systematic review is to examine whether interventions that entail strategies to enable expression of cultural identities for Australian Indigenous peoples are associated with measurable improvements in health and wellbeing. Peer-reviewed articles that reported quantitatively expressed health and wellbeing outcomes involving Indigenous Australian participants only were included. The cultural intervention component was defined and assessed by Indigenous researchers on the team. A narrative analysis was conducted. The protocol was registered on PROSPERO (CRD42015027387). Thirteen articles describing eleven studies were identified, including one randomised control trial (RCT), one cluster RCT and two studies with non-randomised controls. Other studies reported on case series or cross sectional studies. All except two studies described multiple intervention strategies. Eight studies showed significant improvement in at least one psychosocial, behavioural or clinical measure, with two showing a positive direction of effect and one showing no improvement. Publication bias may discourage researchers to report negative findings of these interventions. Although studies vary in quality, this review provides evidence that interventions that include opportunities for expression of cultural identities can have beneficial effects for Australian Indigenous peoples. PMID- 28619127 TI - Bone mineral disturbances in patients with chronic kidney disease stage 5 not yet on dialysis. AB - AIMS: This retrospective study evaluates the success of a treatment strategy for secondary hyperparathyroidism in our cohort of patients with chronic kidney disease stage 5 who were not yet on dialysis. MATERIALS AND METHODS: 81 predialysis patients from the outpatient clinic of the Department of Nephrology, University Medical Center Ljubljana were reviewed. We focused on serum markers for bone mineral metabolism including intact parathyroid hormone (PTH), phosphate, corrected calcium, and the usage of phosphate-binding agents and vitamin D analogs. Results of intact PTH and phosphorus and calcium concentrations were related to treatment options for secondary hyperparathyroidism. RESULTS: The average intact PTH concentration was 198.8 +/- 162.5 ng/L, serum phosphate was 1.52 +/- 0.35 mmol/L, and corrected calcium was 2.23 +/- 0.2 mmol/L. Phosphate-binding agents were prescribed in 62% patients, 44% of these patients were on calcium-containing phosphate binders. Active vitamin D or synthetic vitamin D analogs were given to 65% of patients, and 48% of all received a combination of active vitamin D derivate and inactive vitamin D supplementation. Serum intact PTH was between 150 and 300 ng/L in 30%, under 150 ng/L in 46%, and over 300 ng/L in 24% of patients, respectively. CONCLUSIONS: Our data show that 76% of our patients with CKD stage 5 not yet on dialysis achieved adequate control of secondary hyperparathyroidism. Marked reduction of intact PTH levels in a significant proportion of our patients prompt us to assess the administration of excessive amounts of calcium and/or vitamin D supplements to prevent over-suppression of PTH, which can induce adynamic bone disease.?. PMID- 28619128 TI - Bioimpedance-based rather than weight-based ultrafiltration prescription for children on maintenance hemodialysis?. AB - The determination of dry weight (DW) in young children on hemodialysis (HD) remains challenging. Bioimpedance analysis (BIA) is a potentially helpful means of estimating the need for ultrafiltration and monitoring body fluids in patients on renal replacement therapy, but its role has not yet been clearly defined. The aim of this paper is to share our experience of prescribing ultrafiltration on the basis of BIA parameters alone. The body weight (BW), resistance (Rx), and reactance (Xc) of a 3-year-old girl on chronic HD were recorded pre- and post-HD over a period of 16 months. The BIA parameter that best correlated with actual ultrafiltration (the difference between pre- and post-HD BW) was identified, and the equivalence between actual ultrafiltration and changes in Xc was derived to obtain the following equation: 1 ohm of Xc = 27.4 g of ultrafiltration. Finally, during 21 consecutive HD sessions, ultrafiltration was exclusively prescribed on the basis of the derived equation (BIA-based prescription) after having defined a target post-HD Xc of 45 ohm. The BIA-based prescription period was compared with 21 consecutive HD sessions in which ultrafiltration was prescribed using the conventional approach based on BW (BW-based prescription). Comparison of BIA based and BW-based ultrafiltration prescription showed significantly fewer HD sessions complicated by hypotension (19 vs. 50%) or by the need for reinfusion (5 vs. 50%), and a better overall quality of HD sessions (86 vs. 37%). No difference in blood pressure was observed, and no acute fluid overload event was detected in either period. BIA-based ultrafiltration seems to be safe, feasible, and effective. The described approach can be particularly useful in the case of patients with problems in setting or maintaining the correct DW.?. PMID- 28619129 TI - Randomized, two-way crossover bioequivalence study of levamlodipine besylate tablets in healthy Chinese subjects?. AB - OBJECTIVE: The present bioequivalence study was designed to compare the newly developed levamlodipine besylate 2.5-mg tablet (test) with that of its 2.5-mg marketed counterpart (reference) in healthy Chinese adult male volunteers. METHODS: A single-dose, randomized, open-label, two-period, and two-treatment self-crossover study was conducted in healthy Chinese volunteers after informed consent was obtained. In each part of the study, the subjects were randomly assigned to receive the test or reference product (5 mg levamlodipine) in a 1 : 1 ratio, and then received the alternative product, following a 14-day washout period. Plasma levamlodipine concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters (noncompartmental model) were assessed with WinNonlin software. Analysis of variance (ANOVA) and FDA (USA) bioequivalence statistical criterion of 90% CI for 80 - 125% range (set at p <= 0.05) of geometric means ratios of test : reference product for Cmax, AUC0-t, and AUC0-infinity were determined. Tolerability was assessed during the entire study period. RESULTS: ANOVA indicated that the period, sequence, and formulation had no significant effect on the PK parameters (p >= 0.05), although there was a statistically significant difference between formulations in AUC0-t (p <= 0.05). The test formulation was bioequivalent to the marketed formulation as the 90% CI for the ratio of geometric means of Cmax (84.52 - 103.00%), AUC0 t (87.49 - 98.23%), and AUC0-infinity (84.30 - 103.25%) were within equivalence limits (80 - 125%) under fasting condition. No serious adverse events were found among the subjects. CONCLUSION: This study confirmed that test and reference levamlodipine besylate tablets were bioequivalent under fasting condition.?. PMID- 28619130 TI - Occurrence of Mycoplasma hyorhinis infections in fattening pigs and association with clinical signs and pathological lesions of Enzootic Pneumonia. AB - Respiratory disorders in fattening pigs are of major concern worldwide. Particularly Enzootic Pneumonia remains a problem for the pig industry. This chronic respiratory disease is primarily caused by Mycoplasma hyopneumoniae (M. hyopneumoniae). However, more recently it was hypothesised that M. hyorhinis can also cause similar lung lesions. To investigate the relevance of M. hyorhinis as a cause of pneumonia in fattening pigs 10 farms in Switzerland (considered free of Enzootic Pneumonia) and 20 farms in Germany (regarded as endemic for Enzootic Pneumonia) with a history of chronic and/or recurrent respiratory diseases were included in the study. During a one-time farm visit the coughing index was determined in the batch of oldest fattening pigs in each farm before submission to slaughter. In total, 1375 lungs from these pigs were collected at the abattoir and individually scored for lesions. Furthermore, 600 lungs with, if present, indicative lesions for Enzootic Pneumonia (purple to grey areas of tissue consolidation in the cranio-ventral lung lobes) were tested for mycoplasma species by culture and by real-time PCR for the presence of M. hyorhinis and M. hyopneumoniae. In total, 15.7% of the selected lungs were tested positive for M. hyorhinis by real-time PCR. The prevalence of M. hyorhinis was 10% in Switzerland and 18.5% in Germany and differed significantly between these two countries (p=0.007). M. hyorhinis was detected significantly more often in pneumonic lungs (p=0.004) but no significant association was found between M. hyorhinis and the coughing index or the M. hyopneumoniae status of the pig. M. hyopneumoniae was detected in 0% and 78.5% of the selected lungs in Switzerland and Germany, respectively. We found no evidence that M. hyorhinis alone can lead to similar lung lesions as seen by an infection with M. hyopneumoniae in fattening pigs. In addition, a simultaneous infection with both M. hyorhinis and M. hyopneumoniae did not aggravate the observed lung lesions. Moreover, the presence of M. hyorhinis showed no clinical effect in terms of coughing at least at the end of the fattening phase. However, different levels of virulence of M. hyorhinis isolates as well as interactions with viral pathogens like porcine reproductive and respiratory syndrome virus (PRRSV) or porcine circovirus type 2 (PCV2) were reported in the literature and need to be further investigated. PMID- 28619131 TI - Comparison of sample types and diagnostic methods for in vivo detection of Mycoplasma hyopneumoniae during early stages of infection. AB - Detection of Mycoplasma hyopneumoniae in live pigs during the early stages of infection is critical for timely implementation of control measures, but is technically challenging. This study compared the sensitivity of various sample types and diagnostic methods for detection of M. hyopneumoniae during the first 28days after experimental exposure. Twenty-one 8-week old pigs were intra tracheally inoculated on day 0 with M. hyopneumoniae strain 232. Two age matched pigs were mock inoculated and maintained as negative controls. On post inoculation days 0, 2, 5, 9, 14, 21 and 28, nasal swabs, laryngeal swabs, tracheobronchial lavage fluid, and blood samples were obtained from each pig and oral fluid samples were obtained from each room in which pigs were housed. Serum samples were assayed by ELISA for IgM and IgG M. hyopneumoniae antibodies and C reactive protein. All other samples were tested for M. hyopneumoniae DNA by species-specific real-time PCR. Serum antibodies (IgG) to M. hyopneumoniae were detected in challenge-inoculated pigs on days 21 and 28. M. hyopneumoniae DNA was detected in samples from experimentally inoculated pigs beginning at 5days post inoculation. Laryngeal swabs at all samplings beginning on day 5 showed the highest sensitivity for M. hyopneumoniae DNA Detection, while oral fluids showed the lowest sensitivity. Although laryngeal swabs are not considered the typical M. hyopneumoniae diagnostic sample, under the conditions of this study laryngeal swabs tested by PCR proved to be a practical and reliable diagnostic sample for M. hyopneumoniae detection in vivo during early-stage infection. PMID- 28619132 TI - Co-infection of H9N2 subtype avian influenza virus and infectious bronchitis virus decreases SP-A expression level in chickens. AB - Chicken surfactant protein A (cSP-A) is a collectin believed to play an important role in antiviral immunity. However, cSP-A expression in the respiratory tract of chickens after viral co-infection remains unclear. The aim of this study was the detection and characterization of cSP-A in co-infected chickens. For this purpose, four-week-old specific pathogen-free (SPF) chickens were divided into five groups and inoculated intranasally with H9N2 subtype avian influenza virus (AIV), infectious bronchitis virus (IBV), or Newcastle disease virus (NDV). Chickens were sacrificed at three days post inoculation, and the lung, trachea, and air sac samples were taken to determine histological changes and expression levels of cSP-A mRNA and cSP-A protein. The cSP-A mRNA and its protein were detected separately using real-time quantitative reverse transcriptional polymerase chain reaction (qRT-PCR), a sandwich enzyme-linked immunosorbent assay (S-ELISA), and an immunohistochemistry assay (IHC). In comparison, for the PBS group as the negative group and the NDV-infected group as the positive group, the histological changes showed that the lesions of the AIV+ IBV co-infected group were more serious compared to the AIV-infected group and the IBV-infected group. Consequently, the expression level of cSP-A in the AIV+IBV co-infected group significantly decreased when compared to the AIV-infected group and the IBV infected group by qRT-PCR, ELISA, and IHC analysis. The mechanism of the downregulation of SP-A expression level will be addressed in future. PMID- 28619133 TI - Equine herpesvirus type 1 induces both neurological and respiratory disease in Syrian hamsters. AB - The equine herpesvirus type 1 (EHV-1) is an important cause of myeloencephalopathy and respiratory disease in horses. Animal models for EHV-1 infection have been specially developed using mice and Syrian hamsters (Mesocricetus auratus). However, few studies have attempted to evaluate the pathogenesis of EHV-1 infection in the central nervous system (CNS) and respiratory system of hamsters. Therefore, the aim of this study was to evaluate the pathogenesis of four Brazilian EHV-1 strains within the CNS and lungs of Syrian hamsters. Hamsters intranasally infected with A4/72, A9/92, A3/97, and Iso/72 EHV-1 strains developed severe neurological and respiratory signs and died during acute EHV-1 infection within 3 to 5days post-inoculation. However, neurological signs were more severe in A4/72 and A9/92-infected hamsters, whereas respiratory signs were more prominent in A3/97 and Iso/72-infected hamsters. In the latter, lesions in the CNS were predominantly inflammatory, whereas in A4/72 and A9/92-infected hamsters, neuronal and liquefactive necrosis were the predominant lesions. EHV-1 infected hamsters also developed an interstitial pneumonia with infiltration of alveolar septa by macrophages, neutrophils, and lymphocytes, with the exception of A9/92-infected hamsters, which developed severe hemorrhages within the airways. EHV-1 antigens were detected along with CNS and pulmonary lesions. EHV-1 was also recovered from CNS of all infected hamsters, whereas the virus was recovered from the lungs of A4/72, A9/92, and Iso/72-infected hamsters. Brazilian EHV-1 strains caused both severe CNS and respiratory disease in hamsters, thus making this species an interesting model for EHV-1 infection in the CNS and respiratory system. PMID- 28619134 TI - Genetic, antigenic, and pathogenic characteristics of avian infectious bronchitis viruses genotypically related to 793/B in China. AB - In this study, 20 infectious bronchitis virus (IBV) strains, which were genotypically related to 793/B, as assessed by an S1 gene comparison and a complete genomic sequence analysis, were isolated and identified from 2009 to 2014 in China. Phylogenetic analysis, network tree, similarity plot analysis, Recombination Detection Program 4(RDP4) and sequence comparison revealed that 12 of the 20 isolates were likely the reisolated vaccine virus. One isolate, ck/CH/LSD/110857, was shown to have originated from recombination events between H120- and 4/91-like vaccine strains that did not result in changes of antigenicity and pathogenicity. The remaining seven IBV isolates were shown to have originated from recombination events between a 4/91-like vaccine strain and a GX-LY9-like virus, which were responsible for the emergence of a novel serotype. A vaccination-challenge test found that vaccination with the 4/91 vaccine strain did not provide protection against challenge with the recombinant viruses. In addition, the results showed that the recombination events between the vaccine and field strains resulted in altered genetics, serotype, antigenicity, and pathogenicity compared with those of their deduced parental viruses. The results are important not only because this virus is of economic importance to poultry industry, but also because it is important for elucidating the origin and evolution of other coronaviruses. PMID- 28619135 TI - In vitro adherence and invasion of primary chicken oviduct epithelial cells by Gallibacterium anatis. AB - Gallibacterium anatis (G. anatis) has been suggested to have a causal role in salpingitis and peritonitis in egg-laying chickens, leading to decreased egg production and increased mortality worldwide. Adherence and invasion of epithelial cells are thought to play a role in the pathogenesis of G. anatis infection. The purpose of this article was to study adherence and invasion of G. anatis using two G. anatis strains of different virulence (Yu-PDS-RZ-1-SLG strain, highly virulent and F149T strain, non-virulent) via infection of the primary chicken oviduct epithelial cells (PCOECs).The results showed that Yu-PDS RZ-1 -SLG strain was able to attach to PCOECs at higher levels than that of F149T strain, but no invasion was observed with either strain. However, cell debris and cell apoptosis were observed after being exposed to G. anatis Yu-PDS-RZ-1-SLG for 90min, whereas G. anatis F149T did not cause cell damage, and adherence was prevented by trypsin treatment of bacterial cells. Cytokines were detected by ELISA after infection, and the results showed that the expression of IL-6, TNF alpha, and IFN-gamma levels was higher in virulent strain infection than that of the avirulent group. Results also indicated that the highly virulent strain G. anatis displayed an increased level of adherence. Changes in cytokine profiles in this study suggested that the production of cytokines might influence the microenvironment of oviduct and promote adherence, serving as a possible mechanism inducing cell damage. PMID- 28619136 TI - Coimmunization with recombinant epitope-expressing baculovirus enhances protective effects of inactivated H5N1 vaccine against heterologous virus. AB - H5N1, a highly pathogenic avian influenza virus (HPAIV), poses a significant threat to poultry and human health. However, currently available inactivated influenza vaccines are less efficacious against viruses that display antigenic drift. In this study, we constructed a recombinant baculovirus (BV-HMNN) expressing four conserved antigen epitopes: H5N1 hemagglutinin stem area amino acids 76-130 (HA2 76-130); three tandem repeats from the ectodomain of the conserved influenza matrix protein M2 (3M2e); nucleoprotein amino acids 55-69 (NP55-69); and nucleoprotein amino acids 380-393 (NP380-393). We evaluated the immunogenicity and protective efficacy of coimmunization with an inactivated avian influenza virus vaccine (Re6) and the recombinant baculovirus (BV-HMNN) against heterologous viral infection in specific-pathogen-free chickens. The chickens immunized with both vaccines (Re6+BV-HMNN) achieved complete protection, was significantly greater than that of chickens vaccinated with Re6 alone. BV HMNN-supplemented vaccination also reduced viral shedding more effectively than nonsupplemented vaccination. We conclude that coimmunization with both vaccines was superior to immunization with the inactivated vaccine alone in inducing cross protection against heterologous H5N1 virus. PMID- 28619137 TI - Determinants of virulence and of resistance to ceftiofur, gentamicin, and spectinomycin in clinical Escherichia coli from broiler chickens in Quebec, Canada. AB - Antimicrobials are frequently used for the prevention of avian colibacillosis, with gentamicin used for this purpose in Quebec until 2003. Ceftiofur was also used similarly, but voluntarily withdrawn in 2005 due to increasing resistance. Spectinomycin-lincomycin was employed as a replacement, but ceftiofur use was partially reinstated in 2007 until its definitive ban by the poultry industry in 2014. Gentamicin resistance frequency increased during the past decade in clinical Escherichia coli isolates from broiler chickens in Quebec, despite this antimicrobial no longer being used. Since this increase coincided with the use of spectinomycin-lincomycin, co-selection of gentamicin resistance through spectinomycin was suspected. Therefore, relationships between spectinomycin, gentamicin, and ceftiofur resistance determinants were investigated here. The distribution of 13 avian pathogenic E. coli virulence-associated genes and their association with spectinomycin resistance were also assessed. A sample of 586 E. coli isolates from chickens with colibacillosis in Quebec between 2009 and 2013 was used. The major genes identified for resistance to ceftiofur, gentamicin, and spectinomycin were blaCMY, aac(3)-VI, and aadA, respectively. The aadA and aac(3) VI genes were strongly associated and shown to be located on a modified class 1 integron. The aadA and blaCMY genes were negatively associated, but when present together, were generally located on the same plasmids. No statistical positive association was observed between aadA and virulence genes, and virulence genes were only rarely detected on plasmids encoding spectinomycin resistance. Thus, the use of spectinomycin-lincomycin may likely select for gentamicin but not ceftiofur resistance, nor for any of the virulence-associated genes investigated. PMID- 28619138 TI - Newcastle disease virus-like particles induce DC maturation through TLR4/NF kappaB pathway and facilitate DC migration by CCR7-CCL19/CCL21 axis. AB - Newcastle disease virus-like particles (NDV VLPs) are a potential candidate vaccine, as shown by eliciting specific immune response against NDV in mice and chickens. Activation of dendritic cells (DCs) is critical to initiate immune response. However, the mechanism of how NDV VLPs induce DC maturation and migration remains elusive. In this study, we found that NDV VLPs are efficient in DC activation by up-regulating surface MHC II and costimulatory molecules, and proinflammatory cytokines through the TLR4/NF-kappaB pathway. Furthermore, NDV VLPs elevated CCR7 expression on DCs, resulting in DC migration towards CCL19/CCL21 both in vitro and ex vivo. As a consequence of DC maturation and migration, CD4+ T cells were also activated in vivo, demonstrating increased intracellular IFN-gamma and IL-4 levels. Together, these results present new insights for NDV VLPs induced DC maturation and migration, providing a better understanding of VLP-triggered innate immune responses. PMID- 28619139 TI - Analysis of antigenicity and pathogenicity reveals major differences among QX like infectious bronchitis viruses and other serotypes. AB - Avian coronavirus infectious bronchitis virus (IBV) causes considerable damage to the poultry industry worldwide and the proportion of QX-like genotype isolates have increased over time. Here, to better understand the antigenicity and pathogenicity of this genotype, we conducted sequence analyses, cross neutralization tests, and also examined the pathogenicity of two strains, SD and SZ. Sequence analyses revealed that SD and SZ isolates belong to the QX-like IBV genotype and share high homology in their full-length genomes. Cross neutralization tests showed high cross neutralization between SD and SZ, but distant relationships with other representative strains of the classical IBV serotypes. Virus infection experiments showed that SD caused high mortality with strong respiratory and renal pathogenicity in chickens, whereas SZ caused milder lesions by comparison. This study highlights the big discrepancy in antigenicity that exists between QX-like strains and other serotypes. Collectively, these findings provide important information about the epidemiology and pathogenicity of IBV, which may benefit the control of IB in the poultry industry. PMID- 28619140 TI - Decreased egg production in laying hens associated with infection with genotype 3 avian hepatitis E virus strain from China. AB - To determine the relationship between decreased egg production and avian HEV infection, thirty healthy 23-week-old Hy-Line Variety Brown layer hens were randomly divided into 3 groups with 10 hens per group. Next, a genotype 3 avian HEV strain from China was used to inoculate laying hens via oronasal or intravenous routes using a 50% chicken infectious dose of 500. All hens were necropsied at 14 weeks postinoculation (wpi). Fecal virus shedding, viremia, seroconversion, serum alanine aminotransferase (ALT) increases and liver lesions showed that after intravenous (i.v.) and oronasal inoculation, the laying hens were successfully infected. Compared with the uninoculated group, the i.v. and oronasally inoculated groups exhibited egg production decreases at 1wpi and 2wpi, reaching peak production at 3wpi and 8wpi, respectively. In both groups, decreased production was evident for 12 weeks and overall decreases ranged from 10% to 30%. In addition, in the 7 field layer farms exhibiting decreased egg production, vaccination regimens had been completed against Newcastle disease, infectious bronchitis, avian influenza H9N2 and H5N1 and egg drop syndrome virus. However, circulating avian HEV was confirmed on these farms using tests to detect avian HEV IgG antibodies and RNA. Therefore, the experimental and field data indicate that avian HEV infection acting alone could account for observed decreases in egg production in laying hens. PMID- 28619141 TI - A cross-sectional study of oral antibacterial treatment patterns in relation to specific diarrhoeal pathogens in weaner pigs. AB - According to international guidelines, the use of antibacterials should be evidence based and prudent. This register-based, cross-sectional study investigates the potential effect of laboratory findings on the patterns of antibacterial oral (batch) medication of weaner pigs, and the level of compliance with national guidelines for antibacterial use. The study population includes 1,736 weaner herds (~65% of all Danish weaner pigs) that were subject to laboratory analysis from the National Veterinary Institute on Brachyspira pilosicoli, Lawsonia intracellularis, and E.coli (F4 and F18) in 2014. Antibacterial prescription data were obtained from the national database, VetStat. These showed that antibacterial prescriptions for use in weaner pigs was 8.6% lower in spring 2015 compared to spring 2014. The antibacterial use per pig tended (p=0.08) to decrease more in herds with negative laboratory results compared to herds with a moderate or massive occurrence of either of the pathogens. Irrespective of the laboratory findings on diarrhoeal pathogens, tetracyclines were the most frequently used antibacterials by a substantial margin, both 3 months prior to and 2-5 months after laboratory analysis. According to the national guidelines, tetracyclines are the second or third choice antibacterial for treatment of diarrhoeal pathogens, due to resistance and co-resistance patterns. Compliance with the guidelines increased in 14% of the herds, mostly following identification of B. pilosicoli within the herd. Between 10% and 20% of the herds did not use batch treatment, despite the presence of moderate-massive amounts of the pathogens. PMID- 28619142 TI - Drivers of Bartonella infection in micromammals and their fleas in a Mediterranean peri-urban area. AB - People living at the human/wildlife interface are at risk of becoming infected with Bartonella for which micromammals act as reservoir. We aimed to determine the factors related to the prevalence of Bartonella and its haplotype diversity in micromammals and in their fleas in a Mediterranean peri-urban environment. We analyzed 511 micromammals, chiefly 407 wood mice (Apodemus sylvaticus), captured into Barcelona metropolitan area (Spain) in spring and autumn from 2011 to 2013 in two natural and two adjacent residential areas, their fleas (grouped in 218 monospecific pools) and 29 fetuses from six Bartonella-positive female wood mice. Amplification of a fragment of ITS was carried out by real time PCR. Prevalence was 49% (57% in the dominant species, the wood mouse), and 12 haplotypes were detected. In general, prevalence was higher in those hosts more heavily infested by fleas, coincident with higher rates of capture, in autumn than in spring, and in adults than in juveniles. Prevalence did not differ between natural and residential areas except for one prevalent haplotype, which was more frequent in natural areas. Prevalence in flea pools (58%) was only explained by Bartonella occurrence in the pool host. In 56.4% of the flea pools with identified Bartonella haplotypes, we found the same haplotype in the host and in its flea pool. Prevalence in wood mouse fetuses was 69%, with at least one infected fetus in all litters, and two litters with all the fetuses infected. indicating that vertical transmission might be important in Bartonella epidemiology in the wood mouse. There is a hazard of Bartonella infection for people living in residential areas and those visiting peri-urban natural areas in Barcelona. PMID- 28619143 TI - A bacterial ghost improves the immunological efficacy of a Newcastle disease virus inactivated vaccine. AB - Newcastle disease (ND) is one of the most common contagious viral infectious diseases of poultry. Vaccination is an effective way to protect chickens from Newcastle disease virus (NDV), and large efforts have been made to acquire not only new vaccines but also new adjuvants to improve the efficiency of existing inactivated vaccines. Here, we observed the adjuvanticity of the bacterial ghost (BG) on the effectiveness of inactivated NDV vaccine in a chicken model. We found that BG, as an adjuvant with inactivated NDV vaccine, substantially strengthened the ND-specific antibody response and protection against lethal challenge in a chicken model, reduced viral shedding, strengthened the time duration of antibody titers, produced an available immunization effect with a low dose of vaccine, and improved serum IL-2 and IFN-gamma concentrations. Our results demonstrate that BG significantly improved the immunogenicity of an inactivated NDV vaccine and is a new immune adjuvant candidate. PMID- 28619144 TI - Recombinant human adenovirus-5 expressing capsid proteins of Indian vaccine strains of foot-and-mouth disease virus elicits effective antibody response in cattle. AB - Recombinant adenovirus-5 vectored foot-and-mouth disease constructs (Ad5- FMD) were made for three Indian vaccine virus serotypes O, A and Asia 1. Constructs co expressing foot-and- mouth disease virus (FMDV) capsid and viral 3C protease sequences, were evaluated for their ability to induce a neutralizing antibody response in indigenous cattle (Bos indicus). Purified Ad5-FMD viruses were inoculated in cattle as monovalent (5*109 pfu/animal) or trivalent (5*109 pfu/animal per serotype) vaccines. Animals vaccinated with monovalent Ad5-FMD vaccines were boosted 63days later with the same dose. After primary immunization, virus neutralization tests (VNT) showed seroconversion in 83, 67 and 33% of animals vaccinated with Ad5-FMD O, A and Asia 1, respectively. Booster immunization elicited seroconversion in all of the animals (100%) in the monovalent groups. When used in a trivalent form, the Ad5-FMD vaccine induced neutralizing antibodies in only 33, 50 and 16% of animals against serotypes O, A and Asia 1, respectively on primo-vaccination, and titers were significantly lower than when the same vectors were used in monovalent form. Neutralizing antibody titers differed by serotype for both Ad5-FMD monovalent and trivalent vaccines, with Asia 1 serotype inducing the lowest titers. Antibody response to Ad5 vector in immunized cattle was also assessed by VNT. It appeared that the vector immunity did not impact the recall responses to expressed FMDV antigens on booster immunization. In summary, the study suggested that the recombinant Ad5 FMD vaccine has a potential use in monovalent form, while its application in multivalent form is not currently encouraging. PMID- 28619145 TI - Thymol kills bacteria, reduces biofilm formation, and protects mice against a fatal infection of Actinobacillus pleuropneumoniae strain L20. AB - Actinobacillus pleuropneumoniae is the causative agent of the highly contagious and deadly respiratory infection porcine pleuropneumonia, resulting in serious losses to the pig industry worldwide. Alternative to antibiotics are urgently needed due to the serious increase in antimicrobial resistance. Thymol is a monoterpene phenol and efficiently kills a variety of bacteria. This study found that thymol has strong bactericidal effects on the A. pleuropneumoniae 5b serotype strain, an epidemic strain in China. Sterilization occurred rapidly, and the minimum inhibitory concentration (MIC) is 31.25MUg/mL; the A. pleuropneumoniae density was reduced 1000 times within 10min following treatment with 1 MIC. Transmission electron microscopy (TEM) analysis revealed that thymol could rapidly disrupt the cell walls and cell membranes of A. pleuropneumoniae, causing leakage of cell contents and cell death. In addition, treatment with thymol at 0.5 MIC significantly reduced the biofilm formation of A. pleuropneumoniae. Quantitative RT-PCR results indicated that thymol treatment significantly increased the expression of the virulence genes purC, tbpB1 and clpP and down-regulated ApxI, ApxII and Apa1 expression in A. pleuropneumoniae. Therapeutic analysis of a murine model showed that thymol (20mg/kg) protected mice from a lethal dose of A. pleuropneumoniae, attenuated lung pathological lesions. This study is the first to report the use of thymol to treat A. pleuropneumoniae infection, establishing a foundation for the development of new antimicrobials. PMID- 28619146 TI - Dynamics of CMY-2 producing E. coli in a broiler parent flock. AB - Extended-spectrum beta-lactamase and plasmid mediated AmpC beta-lactamase (ESBL/pAmpC) producing bacteria are resistant to Extended Spectrum Cephalosporins (ESC), and are present in all levels of the broiler production chain. We determined the prevalence, concentration, and persistence of ESBL/pAmpC Escherichia coli in a broiler parent flock during the rearing and laying period. One-day old chickens were housed in four separate pens. Until week 33 no antibiotics or coccidiostatics were used. During rearing 57 chickens in each pen (n=228), and in the laying period two groups of 33 chickens were individually sampled (n=66). Environmental samples were taken from week 16 onwards. ESBL/pAmpC E. coli presence was determined by selective culturing. In the samples of week 16 19 the concentration of ESBL/pAmpC-E. coli was determined. All ESC-resistant isolates found were positive for pAmpC gene blaCMY-2 located on IncA/C plasmids, in several E. coli MLST types. CMY-2-E. coli prevalence decreased from 91% (95%CI 86-94%) at day 7 (week 1) to 0% (95%CI 0-5%) in week 21. However, CMY-2-E. coli remained present in the environmental samples during the whole study. CMY-2-E. coli concentration varied between detection limit (<10^3) and 2.10^4 cfu/g faeces. The sharp reduction of CMY-2-E. coli in this broiler parent flock in absence of antibiotics suggests a selective disadvantage of blaCMY-2 on IncA/C plasmids on animal level. The underlying mechanism should be studied further as this may provide new insights on how to reduce ESBL/pAmpC prevalence and transmission in the broiler production chain. PMID- 28619147 TI - Detection of Mycoplasma hyopneumoniae in naturally infected gilts over time. AB - Mycoplasma hyopneumoniae causes a chronic respiratory infection in pigs and its transmission occurs mainly by direct contact and by vertical transmission (sow-to piglet). The objective of this study was to assess the detection dynamics and persistence of M. hyopneumoniae natural infection in replacement gilts. Forty four twenty-day-old gilts were selected from a M. hyopneumoniae positive farm and followed up to one day prior to their first weaning. Laryngeal swabs were collected every 30days, starting at day 20, for M. hyopneumoniae detection by real-time PCR, resulting in 12 samplings. Piglets born to selected females were sampled via laryngeal swabs one day prior to weaning to evaluate sow-to-piglet transmission. The M. hyopneumoniae prevalence was estimated at each one of the 12 samplings in gilts and a multiple comparison test and Bonferroni correction were performed. Bacterial detection in gilts started at 110days of age (doa) and a significant increase (p<0.05) occurred at 140 doa. The M. hyopneumoniae prevalence remained above 20% from 140 to 230 doa, decreasing thereafter. However, it did not reach 0% at any sampling after 110 doa. In this study, M. hyopneumoniae was not detected in piglets sampled prior to weaning. The M. hyopneumoniae detection pattern showed that in natural infections, gilts were positive for M. hyopneumoniae for one to three months, but occasionally long-term detection may occur. Moreover, the lack of M. hyopneumoniae detection throughout the study in 18.2% of gilts indicated the existence of negative subpopulations in positive herds. PMID- 28619148 TI - Antigenic diversity of Brazilian isolates of HoBi-like pestiviruses. AB - Hobi-like viruses comprise an unclassified group of bovine pestiviruses related to bovine viral diarrhea virus 1 (BVDV-1) and 2 (BVDV-2). These viruses were originally identified in fetal bovine serum from Brazilian origin and, subsequently, isolated from diseased animals in several countries. Herein we performed an antigenic characterization of eight Brazilian HoBi-like viruses isolated from persistently infected (PI) animals and from gastroenteric disease (2007-2015). Phylogenetic analysis based on the 5' unstranslated region (UTR) clustered these viruses with other HoBi-like viruses from European and Asiatic origin. Monoclonal antibody (MAb) binding indicated variability in the Hobi-like virus glycoprotein E2 and significant differences from the homologous BVDV-1 and BVDV-2 glycoprotein. Analysis of antigenic relatedness based on virus neutralizing titers using virus-specific antisera revealed that HoBi-like viruses are antigenically very different from BVDV-1 and, to a lesser extent, from BVDV 2. Cross-neutralizing assays between pairs of HoBi-like viruses and their respective antisera indicated the existence of antigenic variability among these viruses, even for viruses isolated from the same herd in different occasions. Moreover, the identification of a HoBi-like isolate with low antigenic similarity with the other isolates indicates the potential existence of antigenic subgroups among HoBi-like virus isolates. Finally, sera of lambs immunized with commercial BVDV vaccines showed low or undetectable neutralizing activity against HoBi-like isolates. These results indicate significant antigenic differences between BVDV genotypes and Brazilian HoBi-like viruses and the existence of antigenic variability within this atypical group of pestiviruses. These findings extend the knowledge about the antigenic diversity of HoBi-like viruses and reinforce the need for their inclusion in current BVDV vaccines. PMID- 28619149 TI - Abortion and mortality in farm mink (Neovison vison) associated with feed-born Clostridium limosum. AB - Disease in mink clinically characterized by abortion and increased mortality among pregnant female mink on 28 Danish farms was observed during April and May 2015. Most of these farms suffered extensive disease problems, including a significant increase in the number of mated females without litters. Pathological, microbiological and molecular biological methods were applied to investigate the cause of disease. Necropsies of animals found dead revealed fragile and partially dissolved (liquefying) uterine tissue, with the presence of Gram positive rod-shaped bacteria. These slow growing bacteria were isolated by anaerobic culturing and identified as Clostridium limosum by both MALDI-TOF mass spectrometry analysis and 16S rRNA gene sequencing. All the performed tests for relevant differential diagnoses were negative. Foodborne disease was indicated because all the affected farms were served by the same feed factory. A specific PCR-based analysis was developed for positive identification of C. limosum and used to screen archived feed samples from the implicated feed factory. Both C. limosum 16S rRNA genes and C. limosum collagenase genes were identified in both mixed feed and more specifically in raw chicken carcass used as one of the components in the mixed feed, which was therefore identified as the most likely source of contamination. Based on the results of this investigation it is concluded that C. limosum can be associated with abortion and increased mortality in pregnant mink females and it is consequently recommended that raw materials contaminated with C. limosum should be avoided in mink feed, in particular during the whelping season. PMID- 28619150 TI - Alpha/beta interferon receptor deficiency in mice significantly enhances susceptibility of the animals to pseudorabies virus infection. AB - Pseudorabies virus, one of the neurotropic viruses, can infect numerous mammals. In particular, pseudorabies virus infection of swine occurs worldwide, and is a major threat to swine industry. However, the mechanism underlying the interaction between pseudorabies virus and host innate immune system is not fully understood. Here, we investigated the involvement of interferon alpha/beta (IFN-alpha/beta) receptor (IFNAR) in the pathogenesis of pseudorabies virus in a mouse model. The results showed that IFNAR-deficient (IFNAR-/-) mice were highly susceptible to the virus infection, as evidenced by markedly reduced survival rate of infected animals and increased viral replication. The expression of IFN-alpha/beta and relevant interferon-stimulated genes in IFNAR-/- mice was significantly lower than that in wild-type (WT) littermates after the viral infection. Moreover, in response to the virus challenge, IFNAR-/- mice displayed elevated levels of inflammatory cytokines including interleukin 6 (IL-6) and IL-1beta, and IFNAR-/- cells showed increased phosphorylation of STAT3. Collectively, these data reveal that the IFNAR-/- mice are more sensitive to pseudorabies virus infection than WT animals, and excessive IL-6/STAT3 response in IFNAR-/- mice may contribute to the pathogenesis. Our findings suggest that type I IFNs/IFNAR-dependent homeostatic control of the innate immunity is required for host defense against pseudorabies virus infection. PMID- 28619151 TI - Effects of vitamin D and its metabolites on cell viability and Staphylococcus aureus invasion into bovine mammary epithelial cells. AB - Vitamin D has been found have various biological effects that may be potent in preventing bovine mastitis. Two forms of vitamin D, vitamin D2 (D2) and vitamin D3 (D3), can be hydroxylated to functional metabolites in cattle. The objectives of the present study were to investigate the potential of vitamin D compounds for controlling bovine mastitis using in vitro cell models, and to compare the differences between D2 and D3 compounds. Results showed that D2 compounds have comparable effects to their D3 analogues on inhibiting MAC-T cell viability in vitro. S. aureus growth was inhibited by high concentrations of D2, D3, 25(OH)D2 and 25(OH)D3. 25(OH)D2 and 25(OH)D3 induced CYP24A1 expression but reduced VDR mRNA expression, whereas the expression of CYP27B1, occludin, and E-cadherin did not change. Additionally, the induction of CYP24A1 expression by 25(OH)D3 was higher than that of 25(OH)D2, which may contribute to their differences in inhibiting cell viability. S. aureus invaded into MAC-T cells and universally inhibited gene expressions. Pre-treat MAC-T cells with 25(OH)D2 reduced S. aureus adhesion while pre-treatment with 25(OH)D3 inhibited S. aureus invasion, but neither of the compounds attenuated the S. aureus-induced gene expression reduction. In conclusion, the present study shows that D2 compounds have comparable effects on inhibiting cell viability and S. aureus invasion to their D3 analogues in vitro, suggesting that D2 and its metabolites have potential in controlling bovine mastitis. PMID- 28619152 TI - The newly emerging duck-origin goose parvovirus in China exhibits a wide range of pathogenicity to main domesticated waterfowl. AB - Short beak and dwarfism syndrome virus (SBDSV) is a newly emerging distinct duck origin goose parvovirus that belongs to the genus Dependovirus. Our previous studies have found that SBDSV was highly pathogenic to Cherry Valley ducklings and mule ducklings. However, little is known about its pathogenicity to other waterfowls. In the present study, the pathogenicity of SBDSV was evaluated in domesticated waterfowl including Muscovy ducklings, Sheldrake ducklings and domestic goslings. All experimentally infected birds exhibited remarkable growth retardation, anorexia and diarrhea similar to naturally infected birds. Interestingly, atrophic beaks and protruded tongues were not observed in all infection groups. At necropsies, no diagnostic pathological lesions were observed. Viral antigens existed in most organ tissues such as heart, liver, spleen, kidney, pancreas and intestine. All ducks in Muscovy duckling and Sheldrake duckling infected groups and 70% goslings in infected groups were seropositive for goose parvovirus (GPV) antibodies at 21dpi with the average titers as 28.4, 26.9, 24.0, respectively. Muscovy ducklings were more prominent in viral load and weight loss with a higher GPV antibodies titer than Sheldrake ducklings and goslings. Taken together, SBDSV exhibits a wide range of pathogenicity to main domesticated waterfowl with variable symptoms and cause considerable economic losses in China. PMID- 28619153 TI - Identification of candidate protein markers of Bovine Parainfluenza Virus Type 3 infection using an in vitro model. AB - Bovine Parainfluenza Virus Type 3 (BPI3V) infections are often asymptomatic, causing respiratory tissue damage and immunosuppression, predisposing animals to severe bacterial pneumonia, the leading cause of Bovine Respiratory Disease (BRD) mortality. As with many pathogens, routine BPI3V serology does not indicate the presence of damaged respiratory tissue or active infection. In vitro proteomic marker screening using disease relevant cell models could help identify markers of infection and tissue damage that are also detectable during in vivo infections. This study utilised a proteomic approach to investigate in vitro cellular responses during BPI3V infection to enhance the current understanding of intracellular host-virus interactions and identify putative markers of in vivo infection. Through 2D gel electrophoresis proteomic analysis, BPI3V Phosphoprotein P and host T-complex Protein 1 subunit theta were found to be accumulated at the latter stages of infection within bovine fibroblasts. These proteins were subsequently detected using targeted multiple reaction monitoring (MRM) mass spectrometry in the plasma of animals challenged with BPI3V, with differential protein level profiles observed dependant on animal vaccination status. Potential mechanisms by which BPI3V overcomes host cellular immune response mechanisms allowing for replication and production of viral proteins were also revealed. Assessment of circulating protein marker levels identified through an in vitro approach as described may enable more effective diagnosis of active viral infection and diseased or damaged respiratory tissue in animals and allow for more effective utilisation of preventative therapeutic interventions prior to bacterial disease onset and significantly aid the management and control of BRD. PMID- 28619154 TI - An unusual culprit: Klebsiella pneumoniae causing septicaemia outbreaks in neonatal pigs? AB - This study investigated the cause of recent outbreaks of septicaemia in neonatal pigs in Australia (Victoria and Queensland). Septicaemia in neonatal pigs is commonly caused by enterotoxigenic E. coli, extraintestinal pathogenic E. coli and beta-haemolytic streptococci. Infrequent causes of septicaemia are Actinobacillus suis and Citrobacter freundii. Therefore, it was quite unexpected when Klebsiella pneumoniae was isolated in predominant growth from multiple organs of pigs dying of septicaemia from six days of age. Two cases in Victoria were associated with multilocus sequence type 25 (ST25), whereas the cases on a single farm in Queensland were associated with two different sequence types (ST278 and ST1978). Similar outbreaks of septicaemia have also occurred in England, but all were associated with K. pneumoniae ST25. The K. pneumoniae sequence types did not cluster phylogenetically into groups of isolates from the same geographical location or into groups which caused either septicaemia or pneumonia. Antibiotic resistance also varied between isolates and showed neomycin resistance in Queensland. These results suggest that several sequence types of K. pneumoniae are involved in causing outbreaks of septicaemia in neonatal pigs, in addition to its previously recognised role in pneumonia and mastitis. PMID- 28619155 TI - Black-pigmented anaerobic bacteria associated with ovine periodontitis. AB - Periodontitis is a polymicrobial infectious disease that causes occlusion change, tooth loss, difficulty in rumination, and premature culling of animals. This study aimed to detect species of the genera Porphyromonas and Prevotella present in the periodontal pocket of sheep with lesions deeper than 5mm (n=14) and in the gingival sulcus of animals considered periodontally healthy (n=20). The presence of microorganisms was evaluated by polymerase chain reaction (PCR) using specific primers for Porphyromonas asaccharolytica, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas gulae, Prevotella buccae, Prevotella intermedia, Prevotella loescheii, Prevotella melaninogenica, Prevotella nigrescens, Prevotella oralis, and Prevotella tannerae. Prevalence and risk analysis were performed using Student's t-test and Spearman's correlation. Among the Prevotella and Porphyromonas species detected in the periodontal lesions of sheep, P. melaninogenica (85.7%), P. buccae (64.3%), P. gingivalis (50%), and P. endodontalis (50%) were most prevalent. P. gingivalis (15%) and P. oralis (10%) prevailed in the gingival sulcus. P. gulae and P. tannerae were not detected in the 34 samples studied. Data evaluation by t-test verified that occurrence of P. asaccharolytica, P. endodontalis, P. gingivalis, P. buccae, P. intermedia, P. melalinogenica, and P. nigrescens correlated with sheep periodontitis. The findings of this study will be an important contribution to research on pathogenesis of sheep periodontitis and development of its control measures. PMID- 28619156 TI - Preserved immunogenicity of an inactivated vaccine based on foot-and-mouth disease virus particles with improved stability. AB - Foot-and-mouth disease virus (FMDV) is the etiological agent of a highly contagious disease that affects important livestock species. Vaccines based on inactivated FMDV virions provide a useful tool for the control of this pathogen. However, long term storage at 4 degrees C (the temperature for vaccine storage) or ruptures of the cold chain, provoke the dissociation of virions, reducing the immunogenicity of the vaccine. An FMDV mutant carrying amino acid replacements VP1 N17D and VP2 H145Y isolated previously rendered virions with increased resistance to dissociation at 4 degrees C. We have evaluated the immunogenicity in swine (a natural FMDV host) of a chemically inactivated vaccine based on this mutant. The presence of these amino acid substitutions did not compromise the immunological potential, including its ability to elicit neutralizing antibodies. These results support the feasibility of this kind of mutants with increased capsid stability as suitable viruses for producing improved FMDV vaccines. PMID- 28619157 TI - Occurrence of a lethal ranavirus in hybrid mandarin (Siniperca scherzeri*Siniperca chuatsi) in Guangdong, South China. AB - A novel ranavirus with features similar to largemouth bass virus (LMBV) was isolated and then characterized from a natural mass mortality of adult hybrid mandarin (Siniperca scherzeri*Siniperca chuatsi). The isolated LMBV-like iridovirus was designated as mandarin ranavirus (MRV)-GD1301. The results of artificial infection showed that MRV-GD1301 was highly virulent to hybrid mandarin juveniles, and 100% mortality was observed within 5days after infection via intraperitoneal injection. Moribund fishes typically have abnormally swollen abdomens with extremely severe ascites and exhibit exophthalmia. The characteristic clinical signs have been rarely recorded in other LMBV-associated fish diseases and other viral diseases in mandarin aquaculture. In contrast to the high lethality in hybrid mandarin, MRV-GD1301 showed avirulence to koi Cyprinus carpio, a susceptible fish species to LMBV-like koi ranavirus (KIRV) found recently in India. Our findings suggest that MRV is an emerging causative agent of mass mortality in mandarin species. PMID- 28619158 TI - Low genetic diversity of bovine Mycobacterium avium subspecies paratuberculosis isolates detected by MIRU-VNTR genotyping. AB - Mycobacterial interspersed repetitive unit and variable number tandem repeat (MIRU-VNTR) has been developed as a simple, rapid and cost efficient molecular typing method to differentiate Mycobacterium avium subspecies paratuberculosis (MAP) isolates. The aim of this study was to determine the genomic diversity of MAP across the Republic of Ireland by utilising the MIRU-VNTR typing method on a large collection of MAP isolates. A total of 114 MAP isolates originated from 53 herds across 19 counties in the Republic of Ireland were genotyped based on eight established MIRU-VNTR loci. Four INMV groups were observed during this study. INMV 1 was found in 67 MAP isolates (58.8%) and INMV 2 was observed in 45 isolates (39.4%). INMV 3 and INMV 116 recorded only one isolate each (0.9%). The unique INMV 116 group has never been reported among herds thus far and the molecular pattern of the MAP isolate classified in INMV 116 showed a difference at the MIRU-VNTR X3 locus compared to the other three INMV groups observed. INMV 1, INMV 2 and INMV 3 are observed frequently in Europe and comprised 99.1% of the total MAP isolates characterised in this study, indicating that MAP exhibited low level of genetic diversity across the Republic of Ireland using the MIRU-VNTR method. By the implementation of SNP analysis or MLSSR as an additional typing method, MAP genetic diversity would increase. INMV 3 is unique to Ireland and whereas INMV 116 has never been previously reported among herds by MIRU-VNTR typing. PMID- 28619159 TI - Original Mycobacterial Sin, a consequence of highly homologous antigens? AB - The role of antigens shared between Mycobacteria in in-vivo cross-reactive immune responses in host animals, have been reported to be responsible for reduced BCG vaccination efficacy as well reduced specificity of routine immunological diagnostic tests. This presents with significant disease control challenges in humans and animals. The present review highlights the results of previous studies on the effect of pre-sensitization to environmental mycobacteria on either pathogenic mycobacteria and/or M. bovis BCG, in experimental animals. It also takes an in-depth view into assessing the genetic similarities and relationships between atypical mycobacteria and Mycobacterium tuberculosis complex (MTBC) and how they might explain the immunological imprint of environmental mycobacteria in directing the hosts' immune response upon subsequent exposure to other classes of mycobacteria. The outcome of this review suggests that genetic closeness between particular atypical mycobacteria and MTBC usually indicate a higher level of homology for certain shared protective antigens. This ultimately results in a higher level of cross reactive immune responses as compared with other atypical mycobacteria that are further away genetically. This would explain the different effects of environmental mycobacteria on MTBC that have been reported in the different studies. In other words the direction of the host immune system in response to exposure to MTBC would depend on the type of environmental mycobacteria that was encountered in the initial exposure. We also explain these mycobacterial interactions in the context of the phenomenon of "Original Mycobacterial Sin". The effects of these inevitable mycobacterial interactions on field diagnosis and control by vaccination and how to circumvent them are discussed. PMID- 28619160 TI - Protein misfolding cyclic amplification corroborates the absence of PrPSc accumulation in placenta from foetuses with the ARR/ARQ genotype in natural scrapie. AB - Ovine scrapie is a worldwide spread prion disease that is transmitted horizontally under field conditions. Placenta from scrapie-infected ewes is an important source of infection, since this tissue can accumulate high amounts of PrPSc depending on the foetal genotype. Therefore, placentas carrying susceptible foetuses can accumulate PrPSc but there is not PrPSc accumulation in presence of foetuses with at least one ARR haplotype. In scrapie eradication programs, ARR/ARR males are used for breeding to increase the resistant progeny and reduce the horizontal transmission of the disease through the placenta. The development of highly sensitive techniques, that allow the detection of minimal amounts of PrPSc, has caused many secretions/excretions and tissues that had previously been deemed negative to be relabeled as positive for PrPSc. This has raised concerns about the possible presence of minimal amounts of PrPSc in placentas from ARR foetuses that conventional techniques had indicated were negative. In the present study we examined 30 placentas from a total of 23 gestations; 15 gestations resulted from naturally ARQ/ARQ scrapie-infected ewes mated with ARR/ARR rams. The absence of PrPSc in placentas carrying the foetal ARR haplotype (n=19) was determined by IDEXX HerdChek scrapie/BSE Antigen EIA Test, Prionics(r)-Check WESTERN and corroborated by the highly sensitive Protein Misfolding Cyclic Amplification technique (PMCA). By immunohistochemistry, several unspecific stainings that might mislead a diagnosis were observed. The results of the present study support that using ARR/ARR males in scrapie eradication programs efficiently decreases the spreading of the agent in the environment via shed placentas. PMID- 28619161 TI - Antimicrobials used for surgical prophylaxis by companion animal veterinarians in Australia. AB - Antimicrobials are widely used in veterinary practices, but there has been no investigation into the classes of antimicrobials used or the appropriateness of their use in surgical prophylaxis. Antimicrobial usage guidelines were published by the Australian Infectious Disease Advisory Panel (AIDAP) in 2013, but there has been no investigation of compliance with them. This study aimed to investigate antimicrobial use for surgical prophylaxis in companion animal practice and assess compliance with AIDAP guidelines for selected conditions by conducting a cross-sectional study of antimicrobial usage patterns of Australian veterinarians using an online questionnaire. Information solicited included: details of the respondent, the frequency with which antimicrobials were used for specific surgical conditions (including dose and duration) and practice antimicrobial use policies and sources of information about antimicrobial drugs and their uses. A total of 886 members of the Australian veterinary profession completed the survey. Few (22%) reported that their practice that had an antimicrobial use policy. Generally, the choice of antimicrobial drug was appropriate for the given surgical conditions. There was poor compliance with AIDAP guidelines for non-use of antimicrobials for routine neutering. Veterinarians caring solely for companion animals had higher odds of optimal compliance with guidelines than veterinarians in mixed species practices (OR 1.4, 95%CI 1.1-1.9). Recent graduates (>2011) had lower odds of compliance than older graduates (OR 0.8, 95%CI 0.6-0.9). The findings suggest that antimicrobial use guidelines need to be expanded and promoted to improve the responsible use of antimicrobials in small animal practice in Australia. PMID- 28619162 TI - Impact of treatments for recycled broiler litter on the viability and infectivity of microorganisms. AB - The microbiological risk of recycled litter depends on the efficacy of the management system applied to inactivate residual microorganisms and preserve the health of the successive broiler flock. This study aimed to assess the viability and infectivity of the Newcastle Disease Virus (NDV), Infectious Bursal Disease Virus (IBDV) and Salmonella Heidelberg in recycled litter exposed to different treatments. The litter was contaminated with microorganisms and submitted to the treatments (T): T1: shallow fermentation; T2: quicklime (calcium oxide); T3: shallow fermentation followed by addition of quicklime; T4: no treatment. Sentinel chicks housed on the treated litter showed that T1 and T3 inactivated residual IBDV. Analysis of the litter subjected to T1 also showed reduced levels of total enterobacteria. T2 was not able to reduce the microorganisms assessed and its association with T1 (T3) failed to enhance the effect of the treatment. NDV did not survive in the broiler litter, regardless of the treatment applied, and it was also not detected in the sentinel chicks. S. Heidelberg remained viable in the litter submitted to all studied treatments, being isolated from the sentinel chicks of all the experimental groups. The antimicrobial activity of T1 and T3 was associated to higher ammonia contents in the broiler litter. The results indicate that the shallow fermentation treatment is efficient for controlling residual IBDV and total enterobacteria in the recycled litter. PMID- 28619163 TI - Frequent occurrence of nonprimate hepacivirus infections in Thoroughbred breeding horses - A cross-sectional study for the occurrence of infections and potential risk factors. AB - Recently, several new hepaciviruses have been identified of which the nonprimate hepacivirus (NPHV) - the closest relative to hepatitis C virus (HCV) discovered to date - is highly prevalent in horses. However, potential risk factors for the transmission of NPHV among horses remain still unknown. Therefore, the objective of this study was to investigate the occurrence of NPHV infections in Thoroughbreds in northern and western Germany and to identify potential risk factors associated with NPHV infections. Using a cross-sectional study design, a total of 733 serum samples from Thoroughbred broodmares and stallions from northern and western Germany were analyzed for the presence of anti-NPHV nonstructural protein 3 (NS3) antibodies and NPHV RNA using the luciferase immunoprecipitation system (LIPS) and a quantitative real-time PCR, respectively. Information regarding signalment, stud farm, breeding history and international transportation history of each horse were collected and evaluated. A frequent occurrence of NPHV was found in the study population with 453 seropositive horses (61.8%) and 134 horses (18.3%) carrying NPHV RNA. Furthermore, statistical analysis revealed that the probability of being infected decreased for horses with a transportation history with increasing age by 20% each year. For horses that stayed in Germany no association between age and infection could be observed. In conclusion, the high occurrence of NPHV infections in breeding Thoroughbreds suggests circulating NPHV infections, endemic herds or persistent shedding in these animals and revealed the association of age and international transportation as risk factor for NPHV infections. PMID- 28619164 TI - Impact of environmental bacterial communities on fish health in marine recirculating aquaculture systems. AB - Marine cultured fish diseases caused by bacteria in recirculating aquaculture systems (RASs) greatly threaten fish aquaculture. To date, the dynamics of bacterial populations in RAS and their impacts to fish health remain largely unknown. In the present study, the bacterial communities in the water from two different marine RASs were analyzed using pyrosequencing technique. Fish disease syndromes and mortality had been reported from one RAS (RAS-d) while the fish in the other RAS remained healthy (RAS-h). The diversity of bacteria in each RAS and the abundance of each bacterium were identified based on sequencing the V4 hypervariable region of the 16S rRNA gene. A total number of 107,476 effective sequences were obtained from the pyrosequencing results. 640 and 844 operational taxonomic units (OTUs) were identified in RAS-d and RAS-h, respectively. In order level, tags annotation showed that Vibrionales and Flavobacteriales were the predominant strains in RAS-d with a relative abundance 50.5% and 36.5%, respectively. In contrast, the bacterial community in RAS-h contained 35.8% Vibrionales, 17.3% Alteromonadales, 10.7% Rhodobacterales, 7.43% Kordiimonadales, and 6.26% Oceanospirillales. In addition, the Vibrionaceae in the RAS-d represented 6.98% of the population which was significantly higher than that in RAS-h (0.40%). More potential pathogenic bacteria in fish, such as Vibrio harveyi, Vibrio rotiferianus were also found in the bacterial population in RAS d. The results also showed that the bacteria community in RAS-h was more diverse and balanced than in RAS-d. These findings of this study suggested a potential correlation between fish diseases and environmental bacterial populations. PMID- 28619165 TI - The use of animals as a surveillance tool for monitoring environmental health hazards, human health hazards and bioterrorism. AB - This review discusses the utilization of wild or domestic animals as surveillance tools for monitoring naturally occurring environmental and human health hazards. Besides providing early warning to natural hazards, animals can also provide early warning to societal hazards like bioterrorism. Animals are ideal surveillance tools to humans because they share the same environment as humans and spend more time outdoors than humans, increasing their exposure risk. Furthermore, the biologically compressed lifespans of some animals may allow them to develop clinical signs more rapidly after exposure to specific pathogens. Animals are an excellent channel for monitoring novel and known pathogens with outbreak potential given that more than 60 % of emerging infectious diseases in humans originate as zoonoses. This review attempts to highlight animal illnesses, deaths, biomarkers or sentinel events, to remind human and veterinary public health programs that animal health can be used to discover, monitor or predict environmental health hazards, human health hazards, or bioterrorism. Lastly, we hope that this review will encourage the implementation of animals as a surveillance tool by clinicians, veterinarians, ecosystem health professionals, researchers and governments. PMID- 28619166 TI - Surveillance of antimicrobial resistance among Escherichia coli from chicken and swine, China, 2008-2015. AB - The objective of this study was to investigate the antimicrobial resistance trend in Escherichia coli from food animals in China. During 2008-2015, a total of 15,130 E. coli were isolated from chicken and swine from seven provinces. The susceptibilities of these isolates to nine classes of antimicrobial agents were determined using broth microdilution susceptibility method. The findings of this study include: (1) multi-drug resistance was highly prevalent in E. coli; (2) these E. coli isolates showed high resistant rate (>80%) to several old drugs, including ampicillin, tetracycline and sulfisoxazole; (3) increasing resistance to colistin, florfenicol and ceftiofur was observed; (4) the E. coli isolates from different provinces had different resistance patterns. All these data highlight the rising problem of antimicrobial resistance. It is urgent to improve the management of animal production and enhance the proper use of antimicrobials in China as well as the other countries. PMID- 28619167 TI - Effect of vaccination against pneumonia on the survival of bighorn sheep (Ovis canadensis) commingled with carrier animals. AB - Leukotoxin producing (lkt+) members of Pasteurellaceae, particularly Mannheimia haemolytica and Bibersteinia trehalosi are important pathogens of pneumonia in bighorn sheep (BHS; Ovis canadensis), causing fatal disease. Predisposing or concurrent infection with Mycoplasma ovipneumoniae enhances the severity of the disease, resulting in increased morbidity and mortality. Several studies have investigated the effectiveness of vaccines against lkt+ members of Pasteurellaceae in preventing fatal pneumonia in BHS. In all of these studies, however, vaccinated animals were challenged experimentally, by direct inoculation of the pathogens, rather than by natural challenge. Moreover, none has investigated the efficacy of the vaccines under conditions of concurrent infection with M. ovipneumoniae. We immunized three bighorn rams and one pregnant ewe with an experimental multivalent vaccine along with a commercial vaccine. The immunized animals were then commingled with two bighorn ewes known to be carriers of lkt+ members of Pasteurellaceae, to simulate natural infection or disease transmission. All vaccinated animals remained healthy. We then inoculated the two carrier ewes with nasal washings from domestic sheep containing M. ovipneumoniae. Within a week, all animals developed mild to moderate signs of pneumonia. While the rams died within two-three months post-inoculation (p.i.), the vaccinated ewe and her lamb died five and eight months p.i., respectively. Taken together, these results suggest that vaccination of BHS against lkt+ members of Pasteurellaceae alone can protect them from natural challenge by these pathogens. However, it may not be adequate to protect them against pneumonia compounded by concurrent infection with M. ovipneumoniae. PMID- 28619168 TI - Comparison of Asian porcine high fever disease isolates of porcine reproductive and respiratory syndrome virus to United States isolates for their ability to cause disease and secondary bacterial infection in swine. AB - Epidemiologic data from Asian outbreaks of highly-pathogenic (HP) porcine reproductive and respiratory syndrome virus (PRRSV) suggest that disease severity was associated with both the virulence of the PRRSV isolates and secondary bacterial infections. Previous reports have indicated that U.S. isolates of PRRSV predispose to secondary bacterial infections as well, but the severity of disease that occurred in Asia in pigs infected with these HP-PRRSV strains has not been reported in the U.S. The objectives of this research were to compare the pathogenesis of Asian and U.S. PRRSV isolates with regard to their ability to cause disease and predispose to secondary bacterial infections in swine. To address these objectives groups of pigs were infected with 1 of 2 Asian HP-PRRSV strains (rJXwn06 or rSRV07) or 1 of 2 U.S. PRRSV strains (SDSU73 or VR-2332) alone or in combination with Streptococcus suis, Haemophilus parasuis, and Actinobacillus suis. Pigs infected with rJXwn06 exhibited the most severe clinical disease while the pigs infected with rSRV07 and SDSU73 exhibited moderate clinical disease, and pigs infected with VR-2332 exhibited minimal clinical signs. The frequency of secondary bacterial pneumonia was associated with the clinical severity induced by the PRRSV strains evaluated. The levels of proinflammatory cytokines in the serum were often lower for pigs coinfected with virus and bacteria compared to pigs infected with PRRSV alone indicating an alteration in the immune response in coinfected pigs. Combined our results demonstrate that severity of disease appears to be dependent on virulence of the PRRSV strain, and development of secondary bacterial infection. PMID- 28619169 TI - Inter-laboratory validation of foot-and-mouth disease diagnostic capability in Germany. AB - Germany has been free from foot-and-mouth disease virus (FMDV) without vaccination since 1992, but diagnostic capability at regional laboratories is maintained for FMDV exclusion in suspect cases and as surge capacity for outbreak preparedness. A proficiency test was initiated in 2015 to evaluate the diagnostic performance of 20 regional veterinary laboratories. A panel of two identical samples of FMDV genome for real-time reverse transcription polymerase chain reaction (RT-PCR), four lyophilized bovine sera for antibody detection and eight samples of inactivated vaccine antigen for analysis with a lateral-flow device (LFD) were tested with the systems routinely used at the participating institutions. With only one exception, all laboratories reliably detected viral RNA with two real-time RT-PCR assays down to a dilution of 10(-4) of the original material. The LFD pen-side test was evaluated at 8 of 20 laboratories, and FMDV antigen was detected by all participants down to a dilution of 1:81. Serological diagnosis was also very consistent at most participating institutions. Very few false-negative results were returned for the diluted positive sera, and testing of a large cohort of negative samples demonstrated a high specificity of over 99% for the two commercial ELISA kits used (PrioCHECK(r) FMDV NS and ID Screen(r) FMD NSP). In conclusion, the proficiency test demonstrated the reliable and robust FMDV diagnostic capability of the German regional veterinary diagnostic laboratories. Furthermore, the suitability of the commercially available ELISA systems for the detection of FMDV-specific antibodies was confirmed. Proficiency tests are an important quality assurance measure for transboundary diseases like FMDV where diagnostic capacity in free countries has to be available at the highest possible standard. PMID- 28619170 TI - Seroprevalence for norovirus genogroup II, IV and VI in dogs. AB - Molecular and serological data suggest that noroviruses (NoVs) might be transmitted between humans and domestic carnivores. In this study we screened an age-stratified collection of canine sera (n=516) by using an ELISA assay based on virus-like particles (VLPs) of human NoVs GII.4 and GIV.1 and carnivore NoVs GIV.2 and GVI.2. Antibodies against GII.4 and GIV.1 human NoVs and GIV.2 and GVI.2 NoVs from carnivores were identified in dog sera (13.0%, 67/516) suggesting their exposure to homologous and heterologous NoVs. Analysis of the trends of age class prevalence showed a gradual increase in the positive rate from 9.0% and 7.0%, in young dogs <1year of age to 15.0% in dogs older than 12 years, for GII.4 and GVI.2 NoVs, respectively. A significant difference in the IgG distribution by age classes was observed for GIV.1 NoVs, with the highest rate of antibodies (7.0%) in the age group <1year and the lowest (1.0%) in the age-classes 7-9 (P=0.049). High correlation between the reactivity to GII.4 and GVI.2 NoVs was observed, likely due to conserved epitopes in the capsid structure. PMID- 28619171 TI - Proteomic and bioinformatic analyses of putative Mannheimia haemolytica secretome by liquid chromatography and tandem mass spectrometry. AB - Mannheimia haemolytica is a major bacterial contributor to bovine respiratory disease complex that costs the livestock industry a billion dollars a year in USA. Commercial vaccines are only partially efficacious under field conditions. Earlier studies found that outer membrane protein preparations and culture supernatants can induce immune responses that enhance resistance to challenge by M. haemolytica strains. The objective of this study was to characterize secretome of two M. haemolytica stains grown under two different media. Bacteria-free concentrated supernatants from M. haemolytica culture was subjected to LC-MS/MS. The secretome of M. haemolytica from both strains yielded 923 proteins. Using bioinformatic tools, 283 were identified as secreted proteins. Further breakdown of 283 proteins showed that 114 (40.2%), 184 (65.0%), 138(48.7%), 151 (53.3%) and 172 (60.7%) were characterized as secreted proteins by SignalP 4.1, SecretomeP 2.0, LipoP, Phobius, and PRED-TAT, respectively. A total of 95 (33.56%) proteins were characterized as being secreted via non-classical pathway as opposed to the majority that were secreted in signal peptide dependent pathway. The demonstrated proteins include all previously immunologically characterized M. haemolytica proteins. The potential of using secretome analysis in the design and development of a multivalent vaccine is discussed. PMID- 28619172 TI - Genetic analysis of Salmonella enterica serovar Gallinarum biovar Pullorum based on characterization and evolution of CRISPR sequence. AB - Salmonella enterica serovar Gallinarum biovar Pullorum (S. Pullorum) is the cause of pullorum disease, characterized by white diarrhea, which leads to high mortality in poultry. In this study, we aimed to assess the genetic diversity of 655 S. Pullorum strains from 1962 to 2015 in China, Europe, and South America. A sequence typing scheme based on clustered regularly interspaced short palindromic repeats (CRISPR) was used to reveal the genetic relationships among these strains in this study. Overall, a total of 20 Pullorum sequence types (PSTs) of CRISPR were identified in the 655 isolates with PST7 (74%, 486/655) and PST3 (13%, 86/655) to be the most two frequent PSTs belonging to two different lineages, which confirmed the genetic conservation of S. Pullorum strains isolated from six provinces and two direct-controlled municipalities (Beijing and Shanghai) in China. However, the identification of seven new PSTs distributed in strains isolated since 2001 implied that genetic variation continues to develop in S. Pullorum. Interestingly, the whole-genome single-nucleotide polymorphism typing (WGST) of 96 strains out of the 655 isolates divided them into four lineages based on SNP analysis of core genomic sequence and exhibit good correspondence with the CRISPR subtyping method. Notably, 22 out of 26 isolates from Europe and South America were distributed in five distinctive PSTs (with no Chinese strains). Additionally, CRISPR data of spacers and their arrangement exhibit subtle but distinct specificity between different strains, and the dynamic adaptive nature of CRISPR loci provides critical insights into the evolution of S. Pullorum as the bacteria are influenced by their environment. PMID- 28619173 TI - Vaccine immune pressure influences viral population complexity of avian influenza virus during infection. AB - Vaccines are useful tools to control influenza A virus infection in poultry, but they need to be periodically reformulated to guarantee appropriate protection from infection and to limit viral replication and circulation, which could favour the emergence of new variants. In this study, a deep sequencing approach was used to characterize and follow the evolution of the hemagglutinin of the H5N1 highly pathogenic avian influenza viral population in infected animals vaccinated with two vaccines conferring different protection levels. Results from this preliminary investigation suggested that the evolution of the viral population, as well as the abundance and heterogeneity of minority variants could be influenced by the immune pressure conferred by vaccination. PMID- 28619174 TI - Experimental infection with highly pathogenic H5N8 avian influenza viruses in the Mandarin duck (Aix galericulata) and domestic pigeon (Columba livia domestica). AB - Wild birds play a major role in the evolution, maintenance, and dissemination of highly pathogenic avian influenza viruses (HPAIV). Sub-clinical infection with HPAI in resident wild birds could be a source of dissemination of HPAIV and continuous outbreaks. In this study, the pathogenicity and infectivity of two strains of H5N8 clade 2.3.4.4 virus were evaluated in the Mandarin duck (Aix galericulata) and domestic pigeon (Columba livia domestica). None of the birds experimentally infected with H5N8 viruses showed clinical signs or mortality. The H5N8 viruses efficiently replicated in the virus-inoculated Mandarin ducks and transmitted to co-housed Mandarin ducks. Although relatively high levels of viral shedding were noted in pigeons, viral shedding was not detected in some of the pigeons and the shedding period was relatively short. Furthermore, the infection was not transmitted to co-housed pigeons. Immunohistochemical examination revealed the presence of HPAIV in multiple organs of the infected birds. Histopathological evaluation showed the presence of inflammatory responses primarily in HPAIV-positive organs. Our results indicate that Mandarin ducks and pigeons can be infected with H5N8 HPAIV without exhibiting clinical signs; thus, they may be potential healthy reservoirs of the H5N8 HPAIV. PMID- 28619175 TI - Sodium oxybate treatment in narcolepsy and its effect on muscle tone. AB - AIMS: To estimate the effect of the compound sodium oxybate (SO) on chin muscle tone in sleep, a re-analysis of the results of the international multicenter study SXB-15 was performed, applying a validated semi-automatic analysis of muscle tone. This analysis distinguishes short (<0.5 s) and long (>0.5 s) muscle activity indices per hour (SMI, LMI) in 116 patients with narcolepsy-cataplexy. While stable stimulant medication was permitted, tricyclics and SSRIs were withdrawn. Polysomnographies were performed at baseline (V5), four weeks after titration of SO to 4.5 g, 6 g, or 9 g or placebo (V6) and after another four weeks on stable SO dose (V7). RESULTS: SMI and LMI decreased significantly during light sleep. LMI remained stable in all SO groups during slow wave sleep (SWS), but decreased significantly during REM sleep. SMI decreased non-significantly, but consistently during SWS and REM in the 9 g group only. A subgroup analysis of patients who stayed on stimulants showed that they had higher SMIs and LMIs in all groups. Patients who had been treated with anticataplectic medication prior to study inclusion had lower LMIs in the 9 g group during REM sleep in all visits. CONCLUSION: SO has a differential effect on muscle tone that is dose and sleep stage dependent. Low dosages increase short muscle activity, possibly enabling the occurrence of parasomnias. High doses are especially efficacious in REM sleep, suggesting that SO could be used to treat REM sleep behavior disorder. Comedication with stimulants and prior medication with anticataplectic medication exerts an influence on muscle tone. PMID- 28619176 TI - Evaluation of the effect of JZP-110 in patients with narcolepsy assessed using the Maintenance of Wakefulness Test censored to 20 minutes. AB - OBJECTIVE: To evaluate the effects of JZP-110 on the Maintenance of Wakefulness Test (MWT) with data censored to include only the first 20 min of a 40-min MWT. METHODS: In a 4-week, placebo-controlled crossover design (Study 201; N = 33) and a 12-week parallel-group design (Study 202; N = 93), JZP-110 was evaluated in narcolepsy patients using changes from baseline in the 40-min MWT as the primary endpoint. Effect sizes based on the change from baseline in mean MWT sleep latency were calculated using 20-min censored MWT data and compared to 40-min MWT data. RESULTS: In Study 201, mean (standard deviation) changes in MWT sleep latency were 12.7 (10.6) min with JZP-110 versus 0.9 (6.0) min with placebo (P = 0.0002) for 40-min data, and 8.9 (6.3) versus 0.4 (4.6) min for 20-min censored data (P < 0.0001). In Study 202, mean changes in MWT sleep latency were 12.8 (10.3) min with JZP-110 versus 2.1 (7.9) min with placebo (P < 0.0001) for 40-min data, and 8.9 (5.5) versus 1.1 (5.6) min for 20-min censored data (P < 0.0001). In Studies 201 and 202, respectively, Cohen's d effect sizes were large and numerically greater for 20-min censored data (1.54 and 1.41) versus 40-min data (1.37 and 1.17). CONCLUSIONS: In patients with narcolepsy, JZP-110 significantly improved the ability to stay awake compared with placebo, with large effect sizes using both the 40-min and 20-min censored MWT data. PMID- 28619177 TI - Women with symptoms of sleep-disordered breathing are less likely to be diagnosed and treated for sleep apnea than men. AB - BACKGROUND: Women are often underrepresented at sleep clinics evaluating sleep disordered breathing (SDB). The aim of the present study was to analyze gender differences in sleep apnea diagnosis and treatment in men and women with similar symptoms of SDB. METHODS: Respiratory Health in Northern Europe (RHINE) provided information about snoring, excessive daytime sleepiness (EDS), BMI and somatic diseases at baseline (1999-2001) and follow-up (2010-2012) from 4962 men and 5892 women. At follow-up participants were asked whether they had a diagnosis of and/or treatment for sleep apnea. RESULTS: Among those with symptoms of SDB (snoring and EDS), more men than women had been given the diagnosis of sleep apnea (25% vs. 14%, p < 0.001), any treatment (17% vs. 11%, p = 0.05) and CPAP (6% vs. 3%, p = 0.04) at follow-up. Predictors of receiving treatment were age, BMI, SDB symptoms at baseline and weight gain, while female gender was related to a lower probability of receiving treatment (adj. OR 0.3, 95% CI 0.3-0.5). In both genders, the symptoms of SDB increased the risk of developing hypertension (adj OR, 95% CI: 1.5, 1.2-1.8) and diabetes (1.5, 1.05-2.3), independent of age, BMI, smoking and weight gain. CONCLUSIONS: Snoring females with daytime sleepiness may be under-diagnosed and under-treated for sleep apnea compared with males, despite running a similar risk of developing hypertension and diabetes. PMID- 28619179 TI - Agreement between sleep diary and actigraphy in a highly educated Brazilian population. AB - OBJECTIVE: This study evaluated the agreement between a sleep diary and actigraphy on the assessment of sleep parameters among school teachers from Brazil. METHODS: A total of 163 teachers (66.3% women; aged 45 +/- 9 years) filled out a sleep diary and wore a wrist actigraph device for seven consecutive days. Data were collected from August 2014 to March 2015 in Londrina, a large city in southern Brazil. Intraclass correlation coefficients (ICC) and Pearson correlation coefficients (r) were used to compare self-reported and actigraphic data. RESULTS: Self-reported total sleep time (TST), sleep onset latency (SOL), and sleep efficiency were higher than measured by actigraphy (mean difference: 22.6 +/- 46.9 min, 2.6 +/- 13.3 min, and 7.3+/- 5.7%, respectively). Subjective total time in bed (TIB) and wake-up time were lower than measured by actigraphy (mean difference: -10.7 +/- 37.6 and -19.7 +/- 29.6, respectively). Moderate or good agreement and correlation were found between the sleep diary and the actigraphic data for TST (ICC = 0.70; r = 0.60), TIB (ICC = 0.83; r = 0.73), bedtime (ICC = 0.95; r = 0.91), sleep start time (ICC = 0.94; r = 0.88), and wake up time (ICC = 0.87; r = 0.78). However, SOL (ICC = 0.49; r = 0.38) and sleep efficiency (ICC = 0.16; r = 0.22) showed only fair or poor agreement and correlation. CONCLUSION: In this highly educated population, the sleep diary and the actigraphy showed moderate or good agreement to assess several sleep parameters. However, these methods seemed to measure different dimensions of sleep regarding sleep onset latency and efficiency. These findings moderately varied according to the individual's subjective sleep quality. PMID- 28619178 TI - Changes in subcortical shape and cognitive function in patients with chronic insomnia. AB - OBJECTIVE: The aim of this study was to examine morphological changes in subcortical structures via surface-based analysis and to correlate local shape changes with cognitive function. METHODS: We analyzed subcortical brain morphology and compared the shape changes with clinical and neuropsychological features in patients with chronic insomnia. RESULTS: Hippocampal atrophy was associated with higher Pittsburgh Sleep Quality Index scores (r = -0.4, p = 0.0408) and higher arousal indices (r = -0.4, p = 0.0332). Local volume loss of the putamen was associated with higher arousal indices (r = -0.5, p = 0.0416). Atrophic change of subcortical structures including the hippocampus, amygdala, basal ganglia, and thalamus, correlated negatively with verbal fluency, frontal function, verbal memory, and visual memory, respectively, in these patients (|r| >= 0.3, p < 0.05). CONCLUSIONS: This study shows that sleep quality and fragmentation are closely related to atrophic changes in hippocampus and putamen. In addition, atrophic changes in global subcortical structures are associated with impaired cognitive function in patients with chronic insomnia. PMID- 28619180 TI - Are the Insomnia Severity Index and Pittsburgh Sleep Quality Index valid outcome measures for Cognitive Behavioral Therapy for Insomnia? Inquiry from the perspective of response shifts and longitudinal measurement invariance in their Chinese versions. AB - OBJECTIVE: The purpose of this study was to examine whether the Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) are valid outcome measures for Cognitive Behavioral Therapy for Insomnia (CBT-I). Specifically, we tested whether the factorial parameters of the ISI and the PSQI could remain invariant against CBT-I, which is a prerequisite to using their change scores as an unbiased measure of the treatment outcome of CBT-I. METHODS: A clinical data set including scores on the Chinese versions of the ISI and the PSQI obtained from 114 insomnia patients prior to and after a 6-week CBT-I program in Taiwan was analyzed. A series of measurement invariance (MI) tests were conducted to compare the factorial parameters of the ISI and the PSQI before and after the CBT-I treatment program. RESULTS: Most factorial parameters of the ISI remained invariant after CBT-I. However, the factorial model of the PSQI changed after CBT I treatment. An extra loading with three residual correlations was added into the factorial model after treatment. CONCLUSIONS: The partial strong invariance of the ISI supports that it is a valid outcome measure for CBT-I. In contrast, various changes in the factor model of the PSQI indicate that it may not be an appropriate outcome measure for CBT-I. Some possible causes for the changes of the constructs of the PSQI following CBT-I are discussed. PMID- 28619181 TI - Multifactorial sleep disturbance in Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder, ranking only behind Alzheimer's disease and affecting 2% of the population over the age of 65. Pathophysiologically, PD is characterized by selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and striatal dopamine depletion. Patients may also exhibit mild-to-severe degeneration of other central and peripheral nervous tissues. The most dramatic symptoms of the disease are profound dopamine-responsive motor disturbances, including bradykinesia, akinesia, rigidity, resting tremor, and postural instability. PD patients commonly present with debilitating non-motor symptoms, including cognitive impairment, autonomic nervous system dysfunction, and sleep disturbance. Of these, sleep disturbance is the most consistently reported, and likely represents a disorder integrative of PD-related motor impairment, autonomic nervous system dysfunction, iatrogenic insult, and central neurodegeneration. The pathophysiology of PD may also indirectly disrupt sleep by increasing susceptibility to sleep disorders, including sleep disordered breathing, periodic limb movements, and REM behavior disorder. In this review, we will discuss these systems representing a multifactorial etiology in PD sleep disturbance. PMID- 28619182 TI - Evolution of circadian rhythms: from bacteria to human. AB - The human body persists in its rhythm as per its initial time zone, and transition always occur according to solar movements around the earth over 24 h. While traveling across different latitudes and longitudes, at the pace exceeding the earth's movement, the changes in the external cues exceed the level of toleration of the body's biological clock. This poses an alteration in our physiological activities of sleep-wake pattern, mental alertness, organ movement, and eating habits, causing them to temporarily lose the track of time. This is further re-synchronized with the physiological cues of the destination over time. The mechanism of resetting of the clocks with varying time zones and cues occur in organisms from bacteria to humans. It is the result of the evolution of different pathways and molecular mechanisms over the time. There has been evolution of numerous comprehensive mechanisms using various research tools to get a deeper insight into the rapid turnover of molecular mechanisms in various species. This review reports insights into the evolution of the circadian mechanism and its evolutionary shift which is vital and plays a major role in assisting different organisms to adapt in different zones and controls their internal biological clocks with changing external cues. PMID- 28619183 TI - Association between sleep duration and menstrual cycle irregularity in Korean female adolescents. AB - OBJECTIVE: The association between sleep and the menstrual cycle in the adolescent population has been scarcely studied. This study aimed to investigate the association between sleep duration and menstrual cycle irregularity among female adolescents using nationwide representative data from the South Korean population. METHODS: This population-based, cross-sectional study used the data collected from Korea National Health and Nutrition Examination Survey 2010-2012, and the data from 801 female adolescents were analyzed. Hierarchical multivariable logistic regression analysis was performed to assess the risk of menstrual cycle irregularity in relation to sleep duration. RESULTS: Subjects with menstrual cycle irregularity accounted for 15% (N = 120). The mean sleep duration in subjects with menstrual cycle irregularity was significantly shorter than that in those without (p = 0.003). Menstrual cycle irregularity prevalence tended to decrease as sleep duration increased (p for trend = 0.004), which was significantly different based on sleep duration and presence of depressive mood (p = 0.011). Sleep duration <=5 h per day was significantly associated with increased risk of menstrual cycle irregularity compared with that in the subjects whose sleep duration is >=8 h per day even after adjusting for confounding variables. The odds ratios of menstrual cycle irregularity tended to increase for shorter sleep duration in all adjusted models. CONCLUSION: This study found a significant inverse association between sleep duration and menstrual cycle irregularity among Korean female adolescents. Increasing sleep duration is required to improve the reproductive health of female adolescents. PMID- 28619184 TI - Sleep quality subtypes predict health-related quality of life in children. AB - OBJECTIVE: This paper aimed to investigate whether distinct sleep quality subtypes predicted health-related quality of life in a nonclinical sample of children. METHODS: This paper utilized data from two waves of the Longitudinal Study of Australian Children, a cohort study that follows a representative population of children in Australia. This paper examined data from Waves 4 and 5 of the LSAC (covering the period 2010-2012) and included 3974 children aged 10-11 years at Wave 4 (51.4% male). Multiple dimensions of sleep quality were assessed using a combination of child- and parent-reported measures. Health-related quality of life (HRQOL) was assessed through the Pediatric Quality of Life Inventory. RESULTS: Latent class analysis indicated six distinct sleep quality classes in children, namely good sleep, moderate sleep quality, mild sleep disturbances, short sleep, long sleep, and disordered sleep. In general, the disordered sleep and minor sleep disturbance classes had poorer HRQOL, which worsened over time. The long sleep and moderate sleep quality classes also showed some decreases in HRQOL over time. CONCLUSIONS: This study demonstrates that there are distinct sleep quality subtypes in children that could have implications for HRQOL. These findings may inform future strategies to promote improved sleep and HRQOL in children. PMID- 28619185 TI - High prevalence of restless legs syndrome/Willis Ekbom Disease (RLS/WED) among people living at high altitude in the Indian Himalaya. AB - BACKGROUND: At high altitude, prevalence of restless legs syndrome has been found to be greater than expected in small population-based studies, which did not use validated tools for identification of RLS. However, it is not known as to whether this increased prevalence is associated with altitude or increased risk factors for RLS in these populations or errors in identification of RLS. METHOD: This population based, door-to-door study was conducted at low altitude (400 m above sea level) and high altitudes (1900-2000 m and 3200 m above sea level) using random stratified sampling in Himalayan and sub-Himalayan region of India. Subjects between 18 and 84 years were screened for restless-legs-syndrome using the validated Cambridge-Hopkins RLS diagnostic questionnaire. Medical comorbidities were ascertained from their medical records. Their anthropometric measurements were obtained and wake resting oxygen saturation was monitored using finger pulse-oximeter. Physical activity during leisure time was evaluated by using the Goldin leisure time exercise questionnaire. RESULTS: A total of 1689 subjects were included. Average age of the included subjects was 35.2 years; 55.2% were women. RLS was identified in 9.4% subjects with higher prevalence among women (13.6% women vs. 4.1% men; P < 0.001). RLS was significantly more prevalent at higher altitudes (12.2% at 1900-2000 m and 11.8% at 3200 m) compared to low altitude (2.5% at 400 m). The low altitude prevalence matched that reported in prior studies of RLS in India. Subjects with medical disorders sometimes related to RLS (eg, peripheral neuropathy, COPD, varicose veins and anemia) also had higher prevalence of RLS. Binary logistic regression controlling for female gender, number of pregnancies, peripheral neuropathy, varicose veins, anemia showed that high altitude independently significantly increased the likelihood of RLS (OR: 5.4, 95% CI: 2.8, 10.4). CONCLUSION: RLS is about five times more prevalent at high than low altitudes even when controlling for effects of other medical conditions associated with increased risk of RLS. PMID- 28619186 TI - Ankle-brachial index and peripheral artery disease are not related to restless legs syndrome. AB - OBJECTIVE: Our aim was to investigate the relationship between impaired peripheral arterial circulation as measured by ankle-brachial index (ABI) and restless legs syndrome (RLS) in the general population. METHODS: Data are derived from three independent, German population-based, prospective studies: the control sample of BiDirect (N = 966), the second follow-up of SHIP (N = 2333), and a subsample of SHIP-Trend (N = 1269). RLS was assessed with questions based on the RLS minimal criteria. ABI was measured with an automated method in BiDirect and with Doppler ultrasound in both SHIP studies. An ABI score below 0.9 was indicative of peripheral arterial disease (PAD). Co-morbidities, medications and behavioural factors were self-reported. Additional measurements included body mass index and haemoglobin from blood serum. For BiDirect, a follow-up with identical methodology was performed after a median of 2.5 years. RESULTS: In cross-sectional analyses, decreased ABI was not significantly associated with RLS as outcome in multivariable logistic regression models adjusted for several potential confounders (BiDirect: odds ratio (OR) = 1.07 for a -0.1 change in ABI, 95% confidence interval (CI): 0.81-1.42, p = 0.62; SHIP-2: OR = 0.99, CI: 0.85 1.16, p = 0.94; SHIP-Trend: OR = 0.99, CI: 0.87-1.13, p = 0.88). Similar non significant results were achieved using PAD (instead of ABI) as an independent variable. In BiDirect, baseline ABI was not a significant predictor of incident RLS in longitudinal analysis (OR = 0.77, CI: 0.53-1.12, p = 0.17). CONCLUSION: Results from three independent studies suggest that reduced ABI is not a risk factor for RLS in the general population. PMID- 28619187 TI - Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice. AB - BACKGROUND: Sodium oxybate is licensed in Europe for the treatment of narcolepsy with cataplexy in adults. The aim of this study was to assess the efficacy and safety of sodium oxybate in clinical practice in patients with narcolepsy and cataplexy refractory to other treatments. MATERIALS AND METHODS: This was a retrospective single centre study including patients with severe narcolepsy with cataplexy refractory to other treatments, who were initiated on sodium oxybate between 2009 and 2015. Patients were allowed to be on other stimulants or/and anti-cataplectic agents. Epworth sleepiness scale (ESS) and weekly cataplexy events were recorded. Side effects (SEs) were recorded at every follow-up visit. RESULTS: 90 patients were prescribed sodium oxybate, with a total of 3116 patient months of drug exposure. ESS and weekly cataplexy events were significantly reduced by sodium oxybate for all patients (DeltaESS = 4.3 +/- 4.4 and Deltacataplexy = 21.8 +/- 18.5 events/week; p < 0.0001, respectively). The required maintenance dose could not be predicted based upon gender, body mass index, or clinical factors. 60% of patients were able to reduce or come off other medications. Half of the patients experienced at least one SE, and 26.6% had to stop treatment due to limiting SEs. Nausea, mood swings and enuresis were the most commonly reported SEs. SEs that led to drug discontinuation, particularly psychosis, were associated with increasing age and were observed early after the initiation of the drug. CONCLUSIONS: Sodium oxybate provides a good clinical efficacy and acceptable safety profile in routine clinical practice for the treatment of patients suffering from narcolepsy with cataplexy. A quarter of patients experience SEs requiring withdrawal of the drug with older patients being more vulnerable to the more serious SEs. PMID- 28619188 TI - How to Use Beta-Blockers in Heart Failure With Reduced Ejection Fraction and Atrial Fibrillation. PMID- 28619190 TI - Preventing Myocardial Infarction in Patients With Atrial Fibrillation: Another Piece of the Puzzle. PMID- 28619189 TI - Antithrombotic Therapy and First Myocardial Infarction in Patients With Atrial Fibrillation. AB - BACKGROUND: Patients with atrial fibrillation (AF) have increased risk of thromboembolic events such as stroke and myocardial infarction (MI). Although it has been established that the efficacy of anticoagulation is superior to that of antiplatelet agents for stroke prophylaxis in AF, the optimal antithrombotic treatment remains uncertain for primary protection against MI. OBJECTIVES: The authors investigated the incidence of first-time MI in patients with AF according to antithrombotic treatment and estimated the risk of stroke and bleeding. METHODS: Subjects with first-time AF diagnosed from 1997 to 2012 without history of coronary artery disease were identified using Danish nationwide administrative registries. Subjects were divided into time varying exposure groups according to antithrombotic treatment. The relative risks of outcomes were estimated by Poisson regression models. RESULTS: A total of 71,959 patients (median 75 years of age; females: 47%). At baseline, 37,539 patients (52%) were treated with vitamin K antagonist (VKA) monotherapy, 25,458 (35%) with acetylsalicylic acid (ASA) monotherapy and 8,962 (13%) with dual-therapy (VKA + ASA). The incidence of MI was 3% (n = 2,275). Relative to the VKA-treated group, the associated risk of MI was significantly higher for ASA (incidence rate ratio [IRR]: 1.54; 95% confidence interval [CI]: 1.40 to 1.68) and dual-therapy (IRR: 1.22; 95% CI: 1.06 to 1.40). The bleeding risk was significantly higher for dual-therapy (IRR: 1.93; 95% CI: 1.81 to 2.07). The risk of stroke relative to that of VKA therapy was significantly higher for both ASA (IRR: 2.00; 95% CI: 1.88 to 2.12) and dual therapy (IRR: 1.30; 95% CI: 1.18 to 1.43). CONCLUSIONS: VKA monotherapy in patients with AF was associated with a lower risk of first-time MI and stroke than ASA monotherapy. Combination of ASA and VKA therapy was not associated with a lower risk of MI but was associated with increased bleeding risk. PMID- 28619192 TI - PCI Volume Benchmarks: Still Adequate for Quality Assessment in 2017? PMID- 28619191 TI - Outcomes of PCI in Relation to Procedural Characteristics and Operator Volumes in the United States. AB - BACKGROUND: Professional guidelines have reduced the recommended minimum number to an average of 50 percutaneous coronary intervention (PCI) procedures performed annually by each operator. Operator volume patterns and associated outcomes since this change are unknown. OBJECTIVES: The authors describe herein PCI operator procedure volumes; characteristics of low-, intermediate-, and high-volume operators; and the relationship between operator volume and clinical outcomes in a large, contemporary, nationwide sample. METHODS: Using data from the National Cardiovascular Data Registry collected between July 1, 2009, and March 31, 2015, we examined operator annual PCI volume. We divided operators into low- (<50 PCIs per year), intermediate- (50 to 100 PCIs per year), and high- (>100 PCIs per year) volume groups, and determined the adjusted association between annual PCI volume and in-hospital outcomes, including mortality. RESULTS: The median annual number of procedures performed per operator was 59; 44% of operators performed <50 PCI procedures per year. Low-volume operators more frequently performed emergency and primary PCI procedures and practiced at hospitals with lower annual PCI volumes. Unadjusted in-hospital mortality was 1.86% for low-volume operators, 1.73% for intermediate-volume operators, and 1.48% for high-volume operators. The adjusted risk of in-hospital mortality was higher for PCI procedures performed by low- and intermediate-volume operators compared with those performed by high volume operators (adjusted odds ratio: 1.16 for low versus high; adjusted odds ratio: 1.05 for intermediate vs. high volume) as was the risk for new dialysis post PCI. No volume relationship was observed for post-PCI bleeding. CONCLUSIONS: Many PCI operators in the United States are performing fewer than the recommended number of PCI procedures annually. Although absolute risk differences are small and may be partially explained by unmeasured differences in case mix between operators, there remains an inverse relationship between PCI operator volume and in-hospital mortality that persisted in risk-adjusted analyses. PMID- 28619193 TI - Protein-Losing Enteropathy in Patients With Congenital Heart Disease. AB - BACKGROUND: Protein-losing enteropathy (PLE), characterized by loss of proteins in the intestine, is a devastating complication in patients with congenital heart disease. The cause of PLE is unknown, but lymphatic involvement has been suspected. OBJECTIVES: The authors evaluated the use of lymphangiographic imaging and liver lymphatic embolization as a treatment for PLE. METHODS: This was a single-center, retrospective review of imaging and interventions used in 8 consecutive patients with liver lymphatic embolization and congenital heart disease with elevated central venous pressure complicated by PLE. RESULTS: Liver lymphangiography was performed in 8 patients (5 males, 3 females; median age, 21 years), 7 of whom demonstrated leakage of liver lymph into the duodenum through abnormal hepatoduodenal lymphatic communications. This was confirmed by duodenoscopy with simultaneous injection of isosulfan blue dye into the liver lymphatics in 6 of 7 patients. Liver lymphatic embolization with ethiodized oil in 2 patients resulted in a temporary increase in albumin blood level and symptom improvement in 1 patient, but was complicated by duodenal bleeding in both patients. Of the remaining 6 patients, liver lymphatic embolization with n-butyl cyanoacrylate glue resulted in sustained improvement of the serum albumin level and symptoms in 3 patients, temporary improvement in 2 patients, and no change in 1 patient with median follow-up of 135 days (range, 84 to 1,005 days). CONCLUSIONS: The authors demonstrated liver lymph leakage as a cause of PLE in patients with congenital heart disease and elevated central venous pressure. Lymphatic embolization led to improved albumin levels and relief of symptoms. Further experience with the technique is needed to determine long-term outcome of this procedure. PMID- 28619194 TI - Once More Unto the Breach: A New Treatment Paradigm for Protein-Losing Enteropathy. PMID- 28619196 TI - Genetics and Valve Calcification. PMID- 28619197 TI - Traditional Chinese Medicine for Cardiovascular Disease: Evidence and Potential Mechanisms. AB - Traditional Chinese medicine (TCM) has more than 2,000 years of history and has gained widespread clinical applications. However, the explicit role of TCM in preventing and treating cardiovascular disease remains unclear due to a lack of sound scientific evidence. Currently available randomized controlled trials on TCM are flawed, with small sample sizes and diverse outcomes, making it difficult to draw definite conclusions about the actual benefits and harms of TCM. Here, we systematically assessed the efficacy and safety of TCM for cardiovascular disease, as well as the pharmacological effects of active TCM ingredients on the cardiovascular system and potential mechanisms. Results indicate that TCM might be used as a complementary and alternative approach to the primary and secondary prevention of cardiovascular disease. However, further rigorously designed randomized controlled trials are warranted to assess the effect of TCM on long term hard endpoints in patients with cardiovascular disease. PMID- 28619195 TI - Association of Triglyceride-Related Genetic Variants With Mitral Annular Calcification. AB - BACKGROUND: Mitral annular calcium (MAC), commonly identified by cardiac imaging, is associated with cardiovascular events and predisposes to the development of clinically important mitral valve regurgitation and mitral valve stenosis. However, its biological determinants remain largely unknown. OBJECTIVES: The authors sought to evaluate whether a genetic predisposition to elevations in plasma lipids is associated with the presence of MAC. METHODS: The authors used 3 separate Mendelian randomization techniques to evaluate the associations of lipid genetic risk scores (GRS) with MAC in 3 large patient cohorts: the Framingham Health Study, MESA (Multiethnic European Study of Atherosclerosis), and the AGE RS (Age, Gene/Environment Susceptibility-Reykjavik Study). The authors provided cross-ethnicity replication in the MESA Hispanic-American participants. RESULTS: MAC was present in 1,149 participants (20.4%). In pooled analyses across all 3 cohorts, a triglyceride GRS was significantly associated with the presence of MAC (odds ratio [OR] per triglyceride GRS unit: 1.73; 95% confidence interval [CI]: 1.24 to 2.41; p = 0.0013). Neither low- nor high-density lipoprotein cholesterol GRS was significantly associated with MAC. Results were consistent in cross ethnicity analyses among the MESA Hispanic-Americans cohort (OR per triglyceride GRS unit: 2.04; 95% CI: 1.03 to 4.03; p = 0.04). In joint meta-analysis across all included cohorts, the triglyceride GRS was associated with MAC (OR per triglyceride GRS unit: 1.79; 95% CI: 1.32 to 2.41; p = 0.0001). The results were robust to several sensitivity analyses that limit both known and unknown forms of genetic pleiotropy. CONCLUSIONS: Genetic predisposition to elevated triglyceride levels was associated with the presence of MAC, a risk factor for clinically significant mitral valve disease, suggesting a causal association. Whether reducing triglyceride levels can lower the incidence of clinically significant mitral valve disease requires further study. PMID- 28619199 TI - Changing Demographics: A New Approach to Global Health Care Due to the Aging Population. PMID- 28619198 TI - Cardiovascular Disease in Incarcerated Populations. AB - Currently, 2.2 million individuals are incarcerated, and more than 11 million have been released from U.S. correctional facilities. Individuals with a history of incarceration are more likely to be of racial and ethnic minority populations, poor, and have higher rates of cardiovascular risk factors, especially smoking and hypertension. Cardiovascular disease is a leading cause of death among incarcerated individuals, and those recently released have a higher risk of being hospitalized and dying of cardiovascular disease compared with the general population, even after accounting for differences in racial identity and socioeconomic status. In this review, the authors: 1) present information on the cardiovascular health of justice-involved populations, and unique prevention and care conditions in correctional facilities; 2) identify knowledge gaps; and 3) propose promising areas for research to improve the cardiovascular health of this population. An Executive Summary of a National Heart, Lung, and Blood Institute workshop on this topic is available. PMID- 28619200 TI - Patient Outcomes With STEMI Caused by Aneurysmal Coronary Artery Disease and Treated With Primary PCI. PMID- 28619201 TI - Lafora Disease Is an Inherited Metabolic Cardiomyopathy. PMID- 28619202 TI - Directly Observed Therapy: A Possible Tool to Tackle Medication Nonadherence in the CVD Epidemic. PMID- 28619203 TI - Reply: Directly Observed Therapy: A Possible Tool to Tackle Medication Nonadherence in the CVD Epidemic. PMID- 28619204 TI - RAS Fingerprint. PMID- 28619205 TI - Reply: RAS Fingerprint. PMID- 28619206 TI - Editorial Overview. PMID- 28619207 TI - Trends in dental caries in children and adolescents according to poverty status in the United States from 1999 through 2004 and from 2011 through 2014. AB - BACKGROUND: Except for a small increase in caries prevalence in young children from 1999 through 2004, the prevalence of pediatric caries in the United States has remained consistent for the past 3 decades. METHODS: The authors used data from the National Health and Nutrition Examination Survey (NHANES) (from 1999 through 2004 and from 2011 through 2014) to ascertain changes in caries prevalence in youth aged 2 to 19 years. The authors evaluated changes in the prevalence of caries experience, untreated caries, and severe caries (3 or more teeth with untreated caries) in the primary, mixed, and permanent dentition according to poverty status. RESULTS: Untreated dental caries in the primary dentition decreased (24% versus 14%) for children aged 2 to 8 years regardless of poverty status from the period from 1999 through 2004 to the period from 2011 through 2014. Severe caries in primary teeth decreased between the period from 1999 through 2004 and the period from 2011 through 2014 for 2- to 8-year-olds (10% versus 6%). Among preschool-aged children in families with low incomes, caries experience decreased from nearly 42% to 35%, and untreated caries decreased from 31% to 18%. Furthermore, there were significant reductions in the number of carious dental surfaces and significant increases in the number of restored dental surfaces. Overall, there was little change in the prevalence of caries in older children and adolescents. CONCLUSIONS: The prevalence of caries in primary teeth in preschool-aged children has improved in the previous decade in the United States; however, the prevalence of having no caries experience in permanent teeth in children and adolescents remains unchanged. PRACTICAL IMPLICATIONS: Although the oral health status of young children has improved in the previous decade, few changes have occurred for many older children and adolescents. PMID- 28619208 TI - Inconclusive evidence on using antibiotic prophylaxis before dental procedures to prevent infective endocarditis. PMID- 28619209 TI - Gravitating towards universal health coverage in the new WHO era. PMID- 28619210 TI - Uncovering difference: a glimpse at patients with heart failure in low-income and middle-income countries. PMID- 28619211 TI - Making sense of consensus: comparative modelling of malaria interventions. PMID- 28619212 TI - Treatment of preschool children for schistosomiasis. PMID- 28619213 TI - Positive steps with negative studies in the WASH sector. PMID- 28619214 TI - Reframing non-communicable diseases as socially transmitted conditions. PMID- 28619215 TI - New INDEPTH strategy for the SDGs using robust population data. PMID- 28619216 TI - Counting disability: emerging consensus on the Washington Group questionnaire. PMID- 28619217 TI - Preventing deaths from pesticide self-poisoning-learning from Sri Lanka's success. PMID- 28619218 TI - Renaming non-communicable diseases. PMID- 28619219 TI - Renaming non-communicable diseases. PMID- 28619220 TI - Renaming non-communicable diseases. PMID- 28619221 TI - Renaming non-communicable diseases. PMID- 28619222 TI - The predicament of patients with suspected Ebola. PMID- 28619223 TI - The predicament of patients with suspected Ebola. PMID- 28619224 TI - The predicament of patients with suspected Ebola. PMID- 28619226 TI - Correction to Lancet Glob Health 2017; 5: e537-44. PMID- 28619225 TI - The predicament of patients with suspected Ebola - Authors' reply. PMID- 28619227 TI - Efficacy and safety of praziquantel in preschool-aged and school-aged children infected with Schistosoma mansoni: a randomised controlled, parallel-group, dose ranging, phase 2 trial. AB - BACKGROUND: Praziquantel has been the drug of choice for schistosomiasis control for more than 40 years, yet surprisingly, the optimal dose for children younger than 4 years is not known. We aimed to assess the efficacy and safety of escalating praziquantel dosages in preschool-aged children (PSAC). METHODS: We did a randomised controlled, parallel-group, single-blind, dose-ranging, phase 2 trial in PSAC (2-5 years) and school-aged children (SAC; aged 6-15 years) as a comparator group in southern Cote d'Ivoire. Children were randomly assigned (1:1:1:1) to 20 mg/kg, 40 mg/kg, or 60 mg/kg praziquantel or placebo. Participants, investigators, and laboratory technicians were masked to group assignment, while the investigator providing treatment was aware of the treatment group. The primary objective was to estimate the nature of the dose-response relation in terms of cure rate using the Kato Katz technique. Dose-response curves were estimated using Emax models. Available case analysis was done including all participants with primary endpoint data. This trial is registered with International Standard Randomised Controlled Trial, number ISRCTN15280205. FINDINGS: Between Nov 11, 2014, and Feb 18, 2015, 660 PSAC and 225 SAC were assessed for eligibility; of whom 161 (24%) PSAC and 180 (80%) SAC had a detectable Schistosoma mansoni infection. 161 PSAC were randomly allocated of whom 154 received treatment: 42 were assigned to 20 mg/kg praziquantel, of whom 40 received treatment; 38 were assigned to 40 mg/kg praziquantel, of whom 38 received treatment; 41 were assigned to 60 mg/kg praziquantel, of whom 39 received treatment; and 40 were assigned to placebo, of whom 37 received placebo. 180 SAC were randomly allocated of whom 177 received treatment: 49 were assigned to 20 mg/kg praziquantel, of whom 47 received treatment; 46 were assigned to 40 mg/kg praziquantel, of whom 46 received treatment; 42 were assigned to 60 mg/kg praziquantel, of whom 42 received treatment; and 43 were assigned to placebo, of whom 43 received treatment. Follow-up (available-case) data were available for 143 PSAC and 174 SAC. In PSAC, the 20 mg/kg dose resulted in cure in 23 children (62%; 95% CI 44.8-77.5), 40 mg/kg in 26 children (72%; 54.8-85.8), 60 mg/kg in 25 children (71%; 53.7-85.4), and placebo in 13 children (37%; 21.5-55.1). In SAC, the 20 mg/kg dose resulted in cure in 14 children (30%; 95% CI 17.7-45.8), 40 mg/kg in 31 children (69%; 53.4-81.8), 60 mg/kg in 34 children (83%; 67.9-92.8), and placebo in five children (12%; 4.0-25.6). For both age groups, the number of adverse events was similar among the three praziquantel treatment groups, with fewer adverse events observed in the placebo groups. The most common adverse events in PSAC were diarrhoea (11 [9%] of 124) and stomach ache (ten [8%]) and in SAC were diarrhoea (50 [28%] of 177), stomach ache (66 [37%]), and vomiting (26 [15%]) 3 h post treatment. No serious adverse events were reported. INTERPRETATION: Praziquantel shows a flat dose-response and overall lower efficacy in PSAC compared with in SAC. In the absence of treatment alternatives, a single dose of praziquantel of 40 mg/kg, recommended by the WHO for S mansoni infections in SAC can be endorsed for PSAC in preventive chemotherapy programmes. FUNDING: European Research Council. PMID- 28619228 TI - Effect of community health clubs on child diarrhoea in western Rwanda: cluster randomised controlled trial. AB - BACKGROUND: Community health clubs are multi-session village-level gatherings led by trained facilitators and designed to promote healthy behaviours mainly related to water, sanitation, and hygiene. They have been implemented in several African and Asian countries but have never been evaluated rigorously. We aimed to evaluate the effect of two versions of the community health club model on child health and nutrition outcomes. METHODS: We did a cluster-randomised trial in Rusizi district, western Rwanda. We defined villages as clusters. We assessed villages for eligibility then randomly selected 150 for the study using a simple random sampling routine in Stata. We stratified villages by wealth index and by the proportion of children younger than 2 years with caregiver-reported diarrhoea within the past 7 days. We randomly allocated these villages to three study groups: no intervention (control; n=50), eight community health club sessions (Lite intervention; n=50), or 20 community health club sessions (Classic intervention; n=50). Households in these villages were enrolled in 2013 for a baseline survey, then re-enrolled in 2015 for an endline survey. The primary outcome was caregiver-reported diarrhoea within the previous 7 days in children younger than 5 years. Analysis was by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT01836731. FINDINGS: At the baseline survey undertaken between May, 2013, and August, 2013, 8734 households with children younger than 5 years of age were enrolled. At the endline survey undertaken between Sept 21, 2015, and Dec 22, 2015, 7934 (91%) of the households were re-enrolled. Among children younger than 5 years, the prevalence of caregiver-reported diarrhoea in the previous 7 days was 514 (14%) of 3616 assigned the control, 453 (14%) of 3196 allocated the Lite intervention (prevalence ratio compared with control 0.97, 95% CI 0.81-1.16; p=0.74), and 495 (14%) of 3464 assigned the Classic intervention (prevalence ratio compared with control 0.99, 0.85-1.15; p=0.87). INTERPRETATION: Community health clubs, in this setting in western Rwanda, had no effect on caregiver-reported diarrhoea among children younger than 5 years. Our results question the value of implementing this intervention at scale for the aim of achieving health gains. FUNDING: Bill & Melinda Gates Foundation. PMID- 28619230 TI - Innovative financing instruments for global health 2002-15: a systematic analysis. AB - Development assistance for health (DAH), the value of which peaked in 2013 and fell in 2015, is unlikely to rise substantially in the near future, increasing reliance on domestic and innovative financing sources to sustain health programmes in low-income and middle-income countries. We examined innovative financing instruments (IFIs)-financing schemes that generate and mobilise funds to estimate the quantum of financing mobilised from 2002 to 2015. We identified ten IFIs, which mobilised US$8.9 billion (2.3% of overall DAH) in 2002-15. The funds generated by IFIs were channelled mostly through GAVI and the Global Fund, and used for programmes for new and underused vaccines, HIV/AIDS, malaria, tuberculosis, and maternal and child health. Vaccination programmes received the largest amount of funding ($2.6 billion), followed by HIV/AIDS ($1080.7 million) and malaria ($1028.9 million), with no discernible funding targeted to non communicable diseases. PMID- 28619229 TI - Cost-effectiveness of Xpert MTB/RIF for tuberculosis diagnosis in South Africa: a real-world cost analysis and economic evaluation. AB - BACKGROUND: In 2010 a new diagnostic test for tuberculosis, Xpert MTB/RIF, received a conditional programmatic recommendation from WHO. Several model-based economic evaluations predicted that Xpert would be cost-effective across sub Saharan Africa. We investigated the cost-effectiveness of Xpert in the real world during national roll-out in South Africa. METHODS: For this real-world cost analysis and economic evaluation, we applied extensive primary cost and patient event data from the XTEND study, a pragmatic trial examining Xpert introduction for people investigated for tuberculosis in 40 primary health facilities (20 clusters) in South Africa enrolled between June 8, and Nov 16, 2012, to estimate the costs and cost per disability-adjusted life-year averted of introducing Xpert as the initial diagnostic test for tuberculosis, compared with sputum smear microscopy (the standard of care). FINDINGS: The mean total cost per study participant for tuberculosis investigation and treatment was US$312.58 (95% CI 252.46-372.70) in the Xpert group and $298.58 (246.35-350.82) in the microscopy group. The mean health service (provider) cost per study participant was $168.79 (149.16-188.42) for the Xpert group and $160.46 (143.24-177.68) for the microscopy group of the study. Considering uncertainty in both cost and effect using a wide range of willingness to pay thresholds, we found less than 3% probability that Xpert introduction improved the cost-effectiveness of tuberculosis diagnostics. INTERPRETATION: After analysing extensive primary data collection during roll-out, we found that Xpert introduction in South Africa was cost-neutral, but found no evidence that Xpert improved the cost-effectiveness of tuberculosis diagnosis. Our study highlights the importance of considering implementation constraints, when predicting and evaluating the cost-effectiveness of new tuberculosis diagnostics in South Africa. FUNDING: Bill & Melinda Gates Foundation. PMID- 28619231 TI - Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death. AB - The folding of secretory proteins is a well-understood mechanism, based on decades of research on endoplasmic reticulum (ER) chaperones. These chaperones interact with newly imported polypeptides close to the ER translocon. Classic examples for these proteins include the immunoglobulin binding protein (BiP/GRP78), and the lectins calnexin and calreticulin. Although not considered chaperones per se, the ER oxidoreductases of the protein disulfide isomerase (PDI) family complete the folding job by catalyzing the formation of disulfide bonds through cysteine oxidation. Research from the past decade has demonstrated that ER chaperones are multifunctional proteins. The regulation of ER mitochondria Ca2+ crosstalk is one of their additional functions, as shown for calnexin, BiP/GRP78 or the oxidoreductases Ero1alpha and TMX1. This function depends on interactions of this group of proteins with the ER Ca2+ handling machinery. This novel function makes perfect sense for two reasons: i. It allows ER chaperones to control mitochondrial apoptosis instantly without a lengthy bypass involving the upregulation of pro-apoptotic transcription factors via the unfolded protein response (UPR); and ii. It allows the ER protein folding machinery to fine-tune ATP import via controlling the speed of mitochondrial oxidative phosphorylation. Therefore, the role of ER chaperones in regulating ER mitochondria Ca2+ flux identifies the progression of secretory protein folding as a central regulator of cell survival and death, at least in cell types that secrete large amount of proteins. In other cell types, ER protein folding might serve as a sentinel mechanism that monitors cellular well-being to control cell metabolism and apoptosis. The selenoprotein SEPN1 is a classic example for such a role. Through the control of ER-mitochondria Ca2+-flux, ER chaperones and folding assistants guide cellular apoptosis and mitochondrial metabolism. PMID- 28619232 TI - Corrigendum to "Microbial pesticide removal in rapid sand filters for drinking water treatment - Potential and kinetics" [Water Res. 48 (2014) 71-81]. PMID- 28619233 TI - Do we have distinct systems for immediate and delayed actions? A selective review on the role of visual memory in action. AB - The perception-action model with its assumptions of distinct visual pathways for perception and visuomotor control has been highly influential but also contentious. The controversy largely focused on the evidence from studies on perceptual illusions and this scientific field has been reviewed quite a few times in recent years. In contrast another aspect of the model, namely the role of visual memory in action control, received comparatively little attention. With respect to visual memory the perception-action model proposes that only the perceptual or ventral stream can maintain a sustained representation of the visual world while the visuomotor system or dorsal stream has to rely on currently available visual information. Consequently, visual information from the dorsal system cannot guide actions that are based on memorized visual information. We call this feature of the perception-action model: the dorsal amnesia hypothesis. There are at least two reasons for why this hypothesis is of special relevance. Firstly, it provides a particularly clear criterion to distinguish between functions of the ventral and dorsal stream. Secondly, this hypothesis led to some unexpected discoveries which provided particularly compelling evidence in favour of the model. In this review, we will revisit all relevant empirical areas, ranging from physiological examinations and neuropsychological studies to behavioural experiments in neurologically intact participants. Based on this review, we conclude that the dorsal amnesia hypothesis is in our view no longer tenable. PMID- 28619234 TI - What is the heterogeneity in the impact seen with pneumococcal conjugate vaccines telling us? AB - Pneumococcal conjugate vaccines have proven highly effective in decreasing invasive disease and pneumonia in young children. However, there is considerable geographic variability in the impact of these vaccines on other disease endpoints and in other age groups. Investigation of the possible causes of this variability would greatly improve our understanding of pneumococcal pathophysiology and stimulate the effort to design more broadly effective vaccines. PMID- 28619235 TI - Morphological and pharmacological determinants of peri-procedural myocardial infarction following elective stent implantation: Optical coherence tomography sub-analysis of the PRASFIT-Elective study. AB - BACKGROUND: Previous studies have suggested that peri-procedural myocardial infarction (PMI) following percutaneous coronary intervention (PCI) is associated with adverse short- and long-term outcomes, and several morphological predictors of PMI have been studied. However, the determinants of PMI under novel anti platelet therapy are not fully elucidated. METHODS AND RESULTS: PRASFIT-Elective is a multicenter, parallel-group study of PCI patients in non-acute settings receiving either prasugrel or clopidogrel in addition to aspirin. Among 742 study patients, 94 (116 lesions) underwent optical coherence tomography (OCT) to evaluate the area of intra-stent tissue (IST, which comprises tissue protrusion and thrombus) after stenting in addition to standard parameters. We investigated the relationship between the peak creatine kinase (CK)-MB fraction levels after PCI and post-stent OCT findings, as well as on-treatment platelet reactivity determined by the P2Y12 reaction units (PRU) at PCI, in a post hoc manner. The multivariate linear analysis revealed that a larger total IST area (standardized coefficient: 0.370, p<0.001) and smaller minimal stent diameter (standardized coefficient: -0.242, p<0.014), but not the PRU value (p=0.988), were independently associated with CK-MB leakage. The IST area after stenting was mainly determined by the target lesion lipid index (averaged lipid arc*lipid length) (r=0.583, p<0.001). CONCLUSION: Following elective PCI, a large IST area originating from a lipid-rich plaque and a smaller minimal stent diameter were associated with PMI. PMID- 28619236 TI - The effect of isolated soy protein adjunctive with flaxseed oil on markers of inflammation, oxidative stress, acute phase proteins, and wound healing of burn patients; a randomized clinical trial. AB - INTRODUCTION: The objective was to determine the effect of isolated soy protein (ISP) and flaxseed oil (FO) on inflammatory and oxidative stress indices, acute phase proteins, and wound healing of burn patients. METHODS: One hundred eighty eight patients were assessed for eligibility in this randomized controlled trial. Of these, seventy-three eligible patients (total burn surface area 20-50%) were randomly assigned to 3 isocaloric groups, labeled as control (wheat flour+corn oil (CO)), ISP+FO, and ISP+CO, to receive these nutrients for 3 weeks. We used intention to treat analysis to overcome bias. Because of the large perturbation in water compartments, patients received nutrients from 4th to 25th day of admission. Serum high sensitivity C-reactive protein (hs-CRP), malondialdehyde (MDA), superoxide dismutase (SOD), ferritin, albumin, and transferrin were measured. The wound area was evaluated by stereological test. RESULTS: During the 3-week intervention, hs-CRP (-19.4+/-5.6, -11.7+/-4.7MUg/ml) and ferritin ( 83.8+/-20.5, -80.1+/-19.6ng/ml) levels changes significantly reduced compared to the control group (P<0.05). MDA level (-0.05+/-0.21MUmol/l) significantly decreased in group A (P<0/05) but was not significant in groups B and control (P>0.05). Albumin level (0.59+/-0.14, 0.30+/-0.12g/dl) significantly increased in group A compared to the control group (P<0.05), but no significant relationship was found between other groups (P>0.05). Transferrin level (4.9+/-3.6, 2.9+/ 5.1g/dl) significantly increased in ISP groups compared to the control (P<0.05). SOD improved in all groups with no significant difference between them (P>0.05). The stereology examination showed significant improvement in wound healing in the ISP groups on days 22 and 25 compared to the control group. CONCLUSION: Nutritional supplements with ISP may attenuate post-burn oxidative stress and inflammation, leading to improved wound healing in burn patients. Flaxseed oil may not exert a beneficial effect over the ISP. PMID- 28619237 TI - Influence of recycling programmes on waste separation behaviour. AB - To achieve high rates of waste reuse and recycling, waste separation in households is essential. This study aimed to reveal how recycling programmes in Sweden and Bulgaria influenced inhabitants' participation in separation of household waste. The waste separation behaviour of 111 university students from Kalmar, Sweden and 112 students from Plovdiv, Bulgaria was studied using the Theory of Planned Behaviour framework. The results showed that a lack of proper conditions for waste separation can prevent individuals from participating in this process, regardless of their positive attitudes. When respondents were satisfied with the local conditions for waste separation their behaviour instead depended on their personal attitudes towards waste separation and recycling. PMID- 28619238 TI - Mesenchymal stem cell in venous leg ulcer: An intoxicating therapy. AB - Venous leg ulcers (VLU) are a prevalent and reoccurring type of complicated wound, turning as a considerable public healthcare issue, with critical social and economic concern. There are both medical and surgical therapies to treat venous leg ulcers; however, a cure does not yet exist. Mesenchymal stem cells (MSC) are capable and proved of accelerating wound healing in vivo and their study with human chronic wounds is currently awaited. MSCs are a promising source of adult progenitor cells for cellular therapy and have been demonstrated to differentiate into various mesenchymal cell lineages. They have a crucial and integral role in native wound healing by regulating immune response and inflammation. Improved understanding of the cellular and molecular mechanisms at work in delayed wound healing compels to the development of cellular therapy in VLU. This review focuses on the current treatment option of VLU and further emphasizing the role of MSCs in accelerating the healing process. With further understanding of the mechanism of action of these cells in wound improvement and, the involvement of cytokines can also be revealed that could be used for the therapeutic purpose for VLU healing. Clinical uses of MSCs have been started already, and induced MSCs are surely a promising tool or compelling therapy for VLU. PMID- 28619239 TI - Antimicrobial susceptibility of Haemophilus influenzae strains isolated from the urethra of men with acute urethritis and/or epididymitis. AB - We determined minimum inhibitory concentrations (MICs) of 41 antimicrobial agents for 73 clinical strains of Haemophilus influenzae isolated from the urethra of men with acute urethritis and/or epididymitis and examined the strains for the production of beta-lactamase. We also compared their antimicrobial susceptibilities with those of H. influenzae strains from respiratory tract or otorhinolaryngological infections that were reported in Japan. The proportion of beta-lactamase-nonproducing ampicillin-resistant strains from acute urethritis and/or epididymitis appeared to be lower, but that of beta-lactamase-producing ampicillin-resistant strains appeared to be higher, compared with those from respiratory tract or otorhinolaryngological infections. However, their antimicrobial susceptibilities to a variety of other antimicrobial agents would be similar to those from respiratory tract or otorhinolaryngological infections. Almost all of the strains of H. influenzae from acute urethritis and/or epididymitis were susceptible to the agents, including ceftriaxone, quinolones, macrolides, and tetracyclines, commonly prescribed for treatment of acute urethritis based on the MIC breakpoints recommended by the Clinical and Laboratory Standards Institute. Ceftriaxone and quinolones could be effective on H. influenzae-induced urethritis. However, azithromycin treatment failures were reported in acute urethritis caused by H. influenzae strains considered susceptible to azithromycin. Further studies will be needed to determine MIC breakpoints of antimicrobial agents, which are recommended for treatment of urogenital infections, for H. influenzae strains causing these infections. Nevertheless, this study provides useful data regarding antimicrobial susceptibilities of H. influenzae strains isolated from the urogenital tract, which have rarely been studied. PMID- 28619241 TI - Increased subclinical atherosclerosis burden in familial hypercholesterolemia phenotype: What do genetic defects tell us and what are the clinical implications? PMID- 28619240 TI - What is Language and How Could it Have Evolved? PMID- 28619242 TI - Insurance coverage and diabetes quality indicators among patients with diabetes in the US general population. AB - This study explores associations between health insurance and diabetes quality indicators. Data were obtained from 8305 patients with diabetes who reported no insurance, Medicaid or private insurance in the 2013 BRFSS in 26 states in the US. Six diabetes quality indicators were assessed: HgbA1c testing, foot exam, eye exam, influenza immunization, pneumococcal immunization and diabetes education. Logistic regression was performed comparing quality indicators by insurance group adjusting for covariates. Subjects with private insurance or Medicaid were more likely than the uninsured to have HgbA1c testing (OR=2.60, 95%CI: 2.02-3.35; OR=2.04, 95%CI: 1.55-2.69, respectively), a foot exam (OR=1.72, 95%CI: 1.32-2.25; OR=1.64, 95%CI: 1.23-2.18, respectively) and an eye exam (OR=2.01, 95%CI: 1.56 2.58; OR=2.50, 95%CI: 1.91-3.27, respectively). Those with private insurance were more likely than the uninsured to have influenza immunization (OR=1.75, 95%CI: 1.37-2.25) and diabetes education (OR=1.36, 95%CI: 1.06-1.74). Uninsured persons with diabetes are less likely to receive standard diabetes services compared to the insured, but most quality indicators were similar in publicly and privately insured groups. PMID- 28619243 TI - Unfolding the genetic pathways of dyslexia in Asian population: A review. AB - Dyslexia also known as specific reading disorder is a complex heritable disorder with unexpected difficulty in learning to read and spell despite adequate intelligence, education, environment, and normal senses. Over past decades, researchers have attempted to characterize dyslexia neurobiological and genetic levels and unfold its pathophysiology. The genetic research on dyslexia has received attention in Asia from the last decade. Though limited by different constraints the studies from Asia have been able to gather significant evidence in this field. We present a review of studies of genetics in Asian population and suggest future directions. PMID- 28619244 TI - Impact of avascular areas, as measured by contrast-enhanced harmonic EUS, on the accuracy of FNA for pancreatic adenocarcinoma. AB - BACKGROUND AND AIMS: EUS-guided FNA (EUS-FNA) is used for the diagnosis of pancreatic adenocarcinoma, but sometimes the method results in a false negative. Occasionally, an avascular area may be observed within the pancreatic adenocarcinoma tumor during contrast-enhanced harmonic EUS (CH-EUS). The aim of this study was to evaluate whether the diagnostic sensitivity of EUS-FNA for pancreatic adenocarcinoma was affected by the presence of avascularity on CH-EUS. METHODS: Two hundred ninety-two patients with pancreatic adenocarcinoma who presented at Kindai University Hospital for EUS-FNA and CH-EUS between June 2009 and August 2013 were retrospectively evaluated. This was a single-center retrospective analysis of prospectively collected data held in a registry. The overall sensitivity of EUS-FNA for the diagnosis of pancreatic adenocarcinoma was calculated. The sensitivities of cytology, histology, and the combination of cytology and histology were also evaluated. These variables were individually evaluated according to the presence or absence of an avascular area on CH-EUS to assess whether the diagnostic sensitivity of EUS-FNA for pancreatic adenocarcinoma was related to the presence of an avascular area within the tumors. RESULTS: The overall sensitivity of EUS-FNA was 90.8% (265/292). The sensitivities of EUS-FNA for lesions with and without an avascular area were 72.9% (35/48) and 94.3% (230/244), respectively, with the difference being statistically significant (P < .001). CONCLUSIONS: EUS-FNA has lower sensitivity for pancreatic adenocarcinoma with avascular areas on CH-EUS. PMID- 28619245 TI - Risk of metachronous neoplasia on surveillance colonoscopy in young patients with colorectal neoplasia. AB - BACKGROUND AND AIMS: Few prior reports exist that address the appropriate colonoscopy surveillance interval for individuals <50 years old. We compared the risk of metachronous neoplasia between younger (20-49 years) and older (50-54 years) cohorts. METHODS: This multicenter retrospective cohort study compared the incidence of metachronous neoplasia in younger and older cohorts according to baseline risk stratification. Subjects were eligible if they underwent their first colonoscopy between June 2006 and May 2010 and had at least 1 or more surveillance colonoscopy up to June 2015. RESULTS: Among a total of 10,477 subjects who underwent baseline colonoscopy, 9722 were eligible after excluding 755 subjects. Of those 9722 subjects, 43% underwent surveillance colonoscopy. In the baseline high-risk adenoma group (n = 840), the 3-year risk of metachronous advanced neoplasia was 10.7% in the younger patients on screening colonoscopy and 8.9% in the older patients (P > .1). In the baseline low-risk adenoma group (n = 1869), the 5-year risk of metachronous advanced neoplasia was 4.9% in the younger patients on screening colonoscopy and 5.1% in the older patients (P > .1). Similarly, in the baseline no neoplasia group (n = 7013), the 5-year risk of metachronous advanced neoplasia was 4.1% in the younger patients on screening colonoscopy and 5.6% in the older patients (P > .1). CONCLUSIONS: Considering the similar risk of metachronous advanced neoplasia in younger and older individuals, we suggest a 3-year surveillance interval for high-risk adenoma and a 5-year surveillance interval for low-risk adenoma in young individuals without a strong family history. PMID- 28619246 TI - Using the Ornstein-Uhlenbeck process to model the evolution of interacting populations. AB - The Ornstein-Uhlenbeck (OU) process plays a major role in the analysis of the evolution of phenotypic traits along phylogenies. The standard OU process includes random perturbations and stabilizing selection and assumes that species evolve independently. However, evolving species may interact through various ecological process and also exchange genes especially in plants. This is particularly true if we want to study phenotypic evolution among diverging populations within species. In this work we present a straightforward statistical approach with analytical solutions that allows for the inclusion of adaptation and migration in a common phylogenetic framework, which can also be useful for studying local adaptation among populations within the same species. We furthermore present a detailed simulation study that clearly indicates the adverse effects of ignoring migration. Similarity between species due to migration could be misinterpreted as very strong convergent evolution without proper correction for these additional dependencies. Finally, we show that our model can be interpreted in terms of ecological interactions between species, providing a general framework for the evolution of traits between "interacting" species or populations. PMID- 28619247 TI - Childhood maltreatment severity is associated with elevated C-reactive protein and body mass index in adults with schizophrenia and bipolar diagnoses. AB - BACKGROUND: Several studies have described an association between childhood maltreatment and inflammatory markers in the psychotic disorders (schizophrenia [SZ] and bipolar disorder [BD]). Previous studies have been relatively small (<50 participants), and the severity of abuse and the putative influence of body mass index (BMI) have not been properly investigated. METHODS: The combined effects of childhood abuse severity and clinical diagnosis on inflammatory markers were investigated in a large sample (n=483) of patients with a disorder on the psychosis spectrum and in healthy controls (HCs). Plasma levels of inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], soluble tumor necrosis factor receptor type 1 [TNFR-R1], glycoprotein 130 [gp130]) were analyzed, and BMI and data on childhood trauma events, on the basis of the Childhood Trauma Questionnaire (CTQ), were obtained from all participants. RESULTS: Patients had increased levels of hs-CRP (P<0.001, Cohens d=0.4), lower levels of gp130 (P<0.001, Cohens d=0.5), higher BMI (P<0.001, Cohens d=0.5) and reported more childhood maltreatment experiences (P<0.001, Cohens d=1.2) than the HC group. The severity of childhood abuse (up to three types of abuse: sexual abuse, physical abuse, and emotional abuse) was associated with elevated BMI (f=8.46, P<0.001, Cohen's d=0.5) and hs-CRP (f=5.47, P=0.001, Cohen's d=0.3). Combined effects of patient status and severity of childhood abuse were found for elevated hs-CRP (f=4.76, P<0.001, Cohen's d=0.4). Differences among the groups disappeared when BMI was added to the model. DISCUSSION: Trauma-altered immune activation via elevated hs-CRP in patients with SZ and BD may be mediated by higher BMI; however, the direction of this association needs further clarification. PMID- 28619248 TI - The effectiveness of behavioural and cognitive behavioural therapies for insomnia on depressive and fatigue symptoms: A systematic review and network meta analysis. AB - This review aimed to assess the impact of behavioural therapy for insomnia administered alone (BT-I) or in combination with cognitive techniques (cognitive behavioural therapy for insomnia, CBT-I) on depressive and fatigue symptoms using network meta-analysis. PubMed, Scopus and Web of Science were searched from 1986 to May 2015. Studies were included if they incorporated sleep restriction, a core technique of BT-I treatment, and an adult insomnia sample, a control group and a standardised measure of depressive and/or fatigue symptoms. Face-to-face, group, self-help and internet therapies were all considered. Forty-seven studies were included in the meta-analysis. Eleven classes of treatment or control conditions were identified in the network. Cohen's d at 95% confidence interval (CI) was calculated to assess the effect sizes of each treatment class as compared with placebo. Results showed significant effects for individual face-to-face CBT-I on depressive (d = 0.34, 95% CI: 0.06-0.63) but not on fatigue symptoms, with high heterogeneity between studies. The source of heterogeneity was not identified even after including sex, age, comorbidity and risk of bias in sensitivity analyses. Findings highlight the need to reduce variability between study methodologies and suggest potential effects of individual face-to-face CBT-I on daytime symptoms. PMID- 28619249 TI - Metabolism of sex steroids is influenced by acquired adiposity-A study of young adult male monozygotic twin pairs. AB - Obesity and ageing are associated with lower serum testosterone levels in men. How fat distribution or adipose tissue metabolism, independent of genetic factors and age, are related to sex steroid metabolism is less clear. We studied the associations between adiposity and serum sex hormone concentrations, and mRNA expression of genes regulating sex hormone metabolism in adipose tissue in young adult male monozygotic (MZ) twin pairs. The subjects [n=18 pairs; mean age, 32 years; individual body mass indexes (BMIs) 22-36kg/m2] included 9 male MZ twin pairs discordant for BMI [intra-pair difference (Delta) in BMI >=3kg/m2]. Sex steroid concentrations were determined by liquid chromatography-tandem mass spectrometry, body composition by dual-energy X-ray absorptiometry and magnetic resonance imaging, and mRNA expressions from subcutaneous adipose tissue by Affymetrix. In BMI-discordant pairs (mean DeltaBMI=5.9kg/m2), serum dihydrotestosterone (DHT) was lower [mean 1.9 (SD 0.7) vs. 2.4 (1.0) nmol/l, P=0.040] and mRNA expressions of DHT-inactivating AKR1C2 (P=0.021) and cortisol producing HSD11B1 (P=0.008) higher in the heavier compared to the leaner co twins. Serum free 17beta-estradiol (E2) was higher [2.3 (0.5) vs. 1.9 (0.5) pmol/l, P=0.028], and in all twin pairs, serum E2 and estrone concentrations were higher in the heavier than in the leaner co-twins [107 (28) vs. 90 (22) pmol/l, P=0.006; and 123 (43) vs. 105 (27) pmol/l, P=0.025]. Within all twin pairs, i.e. independent of genetic effects and age, 1) the amount of subcutaneous fat inversely correlated with serum total and free testosterone, DHT, and sex hormone binding globulin (SHBG) concentrations (P<0.01 for all), 2) intra-abdominal fat with total testosterone and SHBG (P<0.05), and 3) liver fat with SHBG (P=0.006). Also, 4) general and intra-abdominal adiposity correlated positively with mRNA expressions of AKR1C2, HSD11B1, and aromatase in adipose tissue (P<0.05). In conclusion, acquired adiposity was associated with decreased serum DHT and increased estrogen concentrations, independent of genetic factors and age. The reduction of DHT could be linked to its increased degradation (by AKR1C2 and HSD11B1) and increased estrogen levels to increased adiposity-related expression of aromatase in adipose tissue. PMID- 28619250 TI - Biotypes: Promise and Pitfalls. PMID- 28619251 TI - Increases of Calbindin-Containing Chandelier Cartridges in Schizophrenia: Fact or Artifact? PMID- 28619252 TI - ZNF804A: Insights From the First Genome-wide Significant Schizophrenia Gene. PMID- 28619253 TI - The N-Methyl-D-Aspartate Receptor: Memory, Madness, and More. PMID- 28619254 TI - 22q11.2 Deletion Syndrome: Characterization of Psychosis Spectrum and Future Directions. PMID- 28619255 TI - Infant nutrition and maternal obesity influence the risk of non-alcoholic fatty liver disease in adolescents. AB - BACKGROUND & AIMS: The pathway to non-alcoholic fatty liver disease (NAFLD) in adolescents may have its origins in adiposity gains, nutrition and sedentary lifestyle established during childhood. There is inadequate knowledge regarding the associations between infant nutrition and subsequent NAFLD. We examined the association of maternal factors and infant nutrition, with the subsequent diagnosis of NAFLD in adolescents. METHODS: Adolescents aged 17years in the Western Australian Pregnancy (Raine) Cohort study had fatty liver assessment using liver ultrasound. Prospectively recorded data on maternal pregnancy and infant feeding were examined against a NAFLD outcome during late adolescence. RESULTS: NAFLD was diagnosed in 15.2% of the 1,170 adolescents examined. Ninety four percent had been breastfed as infants. The duration of breastfeeding before starting supplementary milk was ?4months in 54.4% and ?6months in 40.6%. Breastfeeding without supplementary milk ?6months (adjusted odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.43-0.94, p=0.02), maternal pre-pregnancy obesity (adjusted OR: 2.29; 95% CI: 1.21-4.32, p=0.01) and adolescent obesity (adjusted OR: 9.08; 95% CI: 6.26-13.17, p<0.001) were associated with NAFLD independent of a Western dietary pattern at 17years of age. Adolescents with NAFLD who had been breastfed for ?6months had a less adverse metabolic profile compared with adolescents breastfed for <6months. Supplementary milk intake starting before 6months was associated with a higher prevalence and ultrasound severity of NAFLD compared with intake starting after 6months (17.7% vs. 11.2%, p=0.003 and 7.8% vs. 3.4%, p=0.005 respectively). CONCLUSION: Though NAFLD is generally mediated through adiposity gains, breastfeeding for at least 6months, avoidance of early supplementary formula milk feeding, and normal maternal pre pregnancy BMI may reduce the odds of a NAFLD diagnosis during adolescence. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a common liver disorder in which there is too much fat in the liver of people who do not consume excessive amounts of alcohol. In this large study, we found that infants who consumed breast milk for less than 6months before starting infant formula milk, infants who were obese as teenagers or had mothers who were obese at the start of pregnancy, were much more likely to have NAFLD at 17years of age. Based on our findings we consider that reducing the risk of NAFLD in teenagers needs to start before birth, by encouraging normal body mass index before pregnancy, as well as breastfeeding without infant formula milk consumption for the first 6months of life. PMID- 28619256 TI - Pre-natal and post-natal environment monitoring to prevent non-alcoholic fatty liver disease development. PMID- 28619257 TI - WITHDRAWN: The Role of capsule endoscopy and device assisted enteroscopy for small bowel lesions in hereditary hemorrhagic telangiectasia. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28619258 TI - Rho kinase-dependent desensitization of GPR39; a unique mechanism of GPCR downregulation. AB - GPR39, a G-protein-coupled receptor activated by zinc, reportedly activates multiple intracellular signaling pathways via Gs, Gq, G12/13, and beta-arrestin, but little is known about downregulation of the receptor upon its activation. To our knowledge, this is the first report on the mechanism of feedback regulation of GPR39 function determined in GPR39-expressing HEK293 cells (HEK293-GPR39) as a model cell system. In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activated cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and beta-arrestin recruitment. GPR39-C3 induced dose- and time-dependent loss of response in cAMP production by second challenge of the compound. This functional desensitization was blocked by the Rho kinase (ROCK) inhibitor, Y 27632, but not by Gq or Gs-pathway inhibitors or inhibition of beta-arrestin recruitment. In the receptor localization assay, GPR39-C3 induced internalization of GFP-tagged GPR39. This internalization was also inhibited by Y-27632, which suggested that ROCK activation is critical for internalization and desensitization of GPR39. A novel biased GPR39 positive allosteric modulator, 5 [2-[(2,4-dichlorophenyl)methoxy]phenyl]-2,2-dimethyl-1,3,5,6 tetrahydrobenzo[a]phenanthridin-4-one (GSB-118), which activated cAMP responses and beta-arrestin recruitment but showed no effect on SRF-RE-dependent transcription, did not induce desensitization. These results revealed a unique mechanism of desensitization of GPR39. PMID- 28619259 TI - Astroglial versus Neuronal D-Serine: Fact Checking. PMID- 28619260 TI - Neural correlates of decision making on whole body yaw rotation: An fNIRS study. AB - Prominent accounts of decision making state that decisions are made on the basis of an accumulation of sensory evidence, orchestrated by networks of prefrontal and parietal neural populations. Here we assess whether these findings generalize to decisions on self-motion. Participants were presented with whole body yaw rotations of different durations in a 2-Interval-Forced-Choice paradigm, and tasked to discriminate motions on the basis of their amplitude. The cortical hemodynamic response was recorded using functional near-infrared spectroscopy (fNIRS) while participants were performing the task. The imaging data was used to predict the specific response on individual experimental trials, and to predict whether the comparison stimulus would be judged larger than the reference. Classifier performance on the former variable was negligible. However, considerable performance was achieved for the latter variable, specifically using parietal imaging data. The findings provide support for the notion that activity in the parietal cortex reflects modality independent decision variables that represent the strength of the neural evidence in favor of a decision. The results are encouraging for the use of fNIRS as a method to perform neuroimaging in moving individuals. PMID- 28619261 TI - Sequestosome 1 (SQSTM1/p62) maintains protein folding capacity under endoplasmic reticulum stress in mouse hypothalamic organotypic culture. AB - Sequestosome 1 (SQSTM1) also known as ubiquitin-binding protein p62 (p62) is a cargo protein involved in the degradation of misfolded proteins via selective autophagy. Disruption of autophagy and resulting accumulation of misfolded proteins in the endoplasmic reticulum (ER) leads to ER stress. ER stress is implicated in several neurodegenerative diseases and obesity. As knockout of p62 (p62KO) reportedly induces obesity in mice, we examined how p62 contributes to ER stress and the ensuing unfolded protein response (UPR) in hypothalamus using mouse organotypic cultures in the present study. Cultures from p62KO mice showed significantly reduced formation of LC3-GFP puncta, an index of autophagosome formation, in response to the chemical ER stressor thapsigargin compared to wild type (WT) cultures. Hypothalamic cultures from p62KO mice exhibited higher basal expression of the UPR/ER stress markers CHOP mRNA and ATF4 mRNA than WT cultures. Thapsigargin enhanced CHOP, ATF4, and BiP mRNA as well as p-eIF2alpha protein expression in both WT and p62KO cultures, but all peak values were greater in p62KO cultures. A proteasome inhibitor increased p62 expression in WT cultures and upregulated the UPR/ER stress markers CHOP mRNA and ATF4 mRNA in both genotypes, but to a greater extent in p62KO cultures. Therefore, p62 deficiency disturbed autophagosome formation and enhanced both basal and chemically induced ER stress, suggesting that p62 serves to prevent ER stress in mouse hypothalamus by maintaining protein folding capacity. PMID- 28619262 TI - The Parkland grading scale for cholecystitis. AB - BACKGROUND: Gallbladders (GBs) with severe inflammation have longer operative times and an increased risk for complications. We propose a grading system using intraoperative images to better stratify GB inflammation. METHODS: After reviewing the intraoperative images of GBs obtained during several hundred laparoscopic cholecystectomies, we developed a five-tiered grading system based on anatomy and inflammatory changes. Fifty intraoperative photographs were taken prior to dissection and then distributed to 11 surgeons who rated each GB's severity per the grading system. The two-way random effects Intraclass Correlation Coefficient (ICC) was used to assess the reliability among the raters. RESULTS: The ICC among the raters of GB severity was 0.804 (95% CI: 0.733 to 0.867; p = 0.0001). Nineteen GB images had greater than 82% agreement and 16 were clustered around GBs with severe inflammation (grades 3-5). CONCLUSION: This study proposes a simple, reliable grading system that characterizes GB complexity based on inflammation and anatomy. PMID- 28619263 TI - Cancer care in the developed world: A comparison of surgical oncology training programs. PMID- 28619264 TI - Institutional variants for lymph node counts after pancreatic resections. AB - BACKGROUND: Lymph node (LN) counts from pancreatectomy are postulated as quality metric for surgical therapy of pancreatic malignancy. METHODS: Prospectively collected data from a single surgeon's pancreatectomy experience were analyzed for predictors of LN counts. RESULTS: Of 315 consecutive patients (54% female, median age: 65, range 18-88), 239 had a proven cancer diagnosis (76%). Operations included pancreatoduodenectomy (69%), distal pancreatectomy (26%), total pancreatectomy (1%) and others (4%). Patients were treated in 4 different tertiary cancer center settings (Institution A: 11%; B: 46%; C: 27%; D: 16%) with consistent regional dissection standards. Mean total LN counts differed between institutions for malignancies (A: 18, B: 13, C: 26, D: 26, p < 0.0001) and benign diseases (p = 0.003). At least 15 LNs were reported in 63% of cancer patients (institution range: 34-92%, p < 0.0001). CONCLUSIONS: Pathologic processing should be standardized if LN numbers are to be adopted as quality metric for pancreatic cancer resections. PMID- 28619265 TI - Comparison of surgical incision complete closure versus leaving skin open in wound class IV in emergent colon surgery. AB - INTRODUCTION: Our aim was to compare the effect of techniques of wound closure in the emergent colon surgery with wound class IV. METHODS: Using 2014 the colectomy targeted ACS-NSQIP dataset; we identified patients undergoing emergent colectomy with wound class IV. Comparison of surgical incision complete closure versus leaving the skin open and multivariate logistic regression analyses was performed. RESULTS: Of 1792 patients undergoing emergent colectomy with wound class IV, the complete closure cohort had 1376 patients and the incision skin open cohort had 416 patients. The incidence of deep SSI was 2.3% in the complete closure cohort vs. 1.2% in the incision skin open, p = 0.15, and intra-abdominal abscess rate was 11.8% in the complete closure cohort vs. 12.3% in the incision skin open, p = 0.78. The dehiscence rate, readmission rate, and reoperation rates were not statistically significant between two cohorts. A multivariate model for dehiscence did not yield significant association between the complete closure cohort and incision skin open cohort. CONCLUSIONS: Surgical incision complete wound closure in the emergent colon surgery with wound class III/IV is safe and effective. PMID- 28619266 TI - Patterns of use and factors associated with early discontinuation of opioids following major trauma. AB - BACKGROUND: Inappropriate use of prescription opioids is a growing public-health issue. We sought to estimate the proportion of traumatic injury patients using legal prescription opioids up to 1-year after hospitalization. METHODS: We used 2006-2014 claims data from TRICARE insurance to identify adults hospitalized secondary to trauma between 2007 and 2013. Prescription opioid use was evaluated for one-year post-discharge. Risk-adjusted Cox Proportional-hazards models were used to evaluate predictors of opioid discontinuation. RESULTS: Only 1% of patients sustained legal prescription opioid use at 1-year following trauma. Lower socioeconomic status (HR 0.92, 95% CI 0.87-0.98) and higher injury severity (HR 0.88, 95% CI 0.84-0.91) were associated with sustained use. Younger patients (HR 1.12, 95% CI 1.04-1.21) and Black patients (HR 1.09, 95% CI 1.04-1.15) were found to have a higher likelihood of opioid discontinuation. CONCLUSIONS: In this population, adult patients who sustained trauma were not at high risk of sustained legal prescription opioid use. PMID- 28619267 TI - Multiple paternity in the cultured yellow pond turtles (Mauremys mutica). AB - As a result of hunting and habitat loss, wild populations of the yellow pond turtle, Mauremys mutica, are decreasing. The International Union for Conservation of Nature considers M. mutica to be an endangered species. All studied freshwater turtles have polyandrous mating with multiple paternity. To survey the mating strategies of M. mutica, 1year's genetic data of parents and all offspring in an artificially captive population were analyzed. Two groups of multiplex PCR containing 16 microsatellite loci were used to analyze the paternity of 302 hatchlings from 132 parents and from 159 clutches. The genetic data indicated that multiple paternity is rare in M. mutica, occurring in only seven of 138 clutches. Although the frequency of multiple paternity was only 5.07%, results of the present research indicate that M. mutica has a polyandrous mating system. In the breeding season, the successive clutches of 34 females each had the same paternity as the previous clutches. It was observed that four males (f85, f58, f87, and f76) had more than 20 offspring each, totaling 99 and representing 32.78% of all offspring. This finding implies that paternity is competitive in this artificially captive population and might bias the genetic diversity of the offspring. PMID- 28619268 TI - RETRACTED: Ankle-hindfoot after calcaneal fractures: A biomechanical study. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor-in-Chief.The decision to retract this article is based on the fact that it contains much of the same information that the authors stated in the following report, which was published in another journal: Xu C, Liu H, Li M, Wang C, Li K. A Three-Dimensional Finite Element Analysis of Displaced Intra-Articular Calcaneal Fractures. J Foot Ankle Surg. 2017 Mar-Apr; 56(2): 319 326. https://doi.org/10.1053/j.jfas.2016.09.018. PMID: 28231965.A review of the timeline of events related to our publication indicated that the manuscript was originally submitted and accepted for publication shortly after the other report was published in Journal of Foot and Ankle Surgery.The authors were aware that the two reports contained much of the same (in large part, identical) information, and that the two manuscripts were under consideration by two different journals, despite indication from the corresponding authors to each journal that the work that each journal was considering was original.Because of this breach of scientific publication ethics, specifically self-plagiarism, this report (PMID: 28619268) has been retracted from Orthopaedics & Traumatology: Surgery & Research / Orthop Traumatol Surg Res. PMID- 28619269 TI - Comparing effects of cervical anterior approach and laminoplasty in surgical management of cervical ossification of posterior longitudinal ligament by a prospective nonrandomized controlled study. AB - INTRODUCTION: The laminoplasty has been the most widely used surgical method for OPLL. In recent years, increasing attention has been drawn to the anterior operative approaches for surgical treatment of cervical OPLL. However, which method is the optimum selection for therapy of cervical OPLL is still obscure. Therefore, we performed this prospective nonrandomized clinical study in patients with multilevel cervical myelopathy due to OPLL and compare the therapeutic efficiency of laminoplasty and anterior approach (cervical discectomy and/or cervical corpectomy) in the management of multilevel cervical OPLL. HYPOTHESIS: There is no difference in clinical effects between anterior cervical spine surgery and laminoplasty in the treatment of multilevel cervical OPLL. MATERIAL AND METHODS: A total of 150 consecutive patients with multilevels of cervical OPLL underwent anterior approaches (ACDF, ACCF and HDF) from July 2010 to June 2014, which were enrolled in this study. During the same period, one hundred and two patients receiving the laminoplasty were enrolled in the study. The clinical effects, alignment and range of motion (ROM) of cervical spine in patients of the anterior group and posterior group were assessed, respectively. The effects of high signals in T2 weighed MRI scans and percentage of spinal canal stenosis in these patients were also evaluated. Finally, postoperative complications regarding each group were analyzed. RESULTS: Although significant differences in types of OPLL and preoperative sagittal alignment of cervical spine occurred in the two groups (P<0.05), clinical effects of the two groups were similar (P>0.05). The cervical curvature in laminoplasty group showed significant decrease at final follow-up (P<0.05). For ROM of cervical spine, no significant alteration was observed in both groups. The high T2 weighed signals and rate of spinal canal stenosis can influence clinical effects of both anterior group and laminoplasty group. In addition, significantly higher complication rate was observed in laminoplasty group compared with anterior group (P<0.05). DISCUSSION: Both anterior and laminoplasty approaches can be considered effective and safe procedures in the treatment of the multilevel OPLL. However, the anterior approach with relatively lower incidence of postoperative complications is a better choice for cases with poor cervical curvature and serious spinal canal stenosis. TYPE OF STUDY AND LEVEL OF PROOF: Level 3 nonrandomized, controlled clinical trials. PMID- 28619270 TI - What is symptom meaning? A framework analysis of communication in palliative care consultations. AB - OBJECTIVE: There is a limited understanding of symptom meaning and its significance to clinical practice within symptom experience literature. This study aims to qualitatively explore the ways in which symptom meanings are discussed by patients and responded to by palliative care physicians during consultations. METHODS: Framework analysis was conducted with 40 palliative care consultation transcripts. RESULTS: 55% of consultations discussed symptom meaning. Six themes regarding patients' symptom meanings emerged while four themes conveyed physicians' responses to these utterances. Key symptom meanings included symptoms representing diminished function and uncertainty about symptom cause or future. Physicians usually gave scientific medical responses concerning symptom cause and treatment, versus reassurance or empathy. CONCLUSION: This study has provided greater insight into the different symptom meanings that exist for palliative care patients. Physicians' responses highlight their reliance on medical information when patients are distressed. Future studies should explore the impact of different responses on patient outcomes, and health practitioners' views about optimal responses. PRACTICE IMPLICATIONS: Physicians could explore symptom meanings with their patients, looking out for those identified here. Apart from information-giving and treatment, active listening to these concerns as they present in consultations may help improve the therapeutic relationship and better guide optimal care. PMID- 28619271 TI - The impact of motivational interviewing on adherence and symptom severity in adolescents and young adults with chronic illness: A systematic review. AB - OBJECTIVE: Given the negative consequences associated with non-adherence in adolescents and young adults (AYAs) with chronic illness, it is important to identify interventions to address this issue. Therefore, this review's primary objective is to evaluate the impact of motivational interviewing (MI) on adherence and symptom level/severity in AYAs with chronic illness using a modified Cochrane method. METHOD: Four databases (e.g., CINAHL, Medline, PsychINFO, and International Pharmaceutical Abstracts) were systematically reviewed. 121 articles were identified in the initial search. Article eligibility was assessed on two tiers using the inclusion criteria. RESULTS: Twelve articles were retained for data extraction. Diabetes, asthma, and HIV were the most common chronic illness populations examined in the study. Eleven of the twelve articles provided support for either improved adherence, symptom reduction, or a combination of both after participants received MI. Quality of life was also enhanced in three studies. CONCLUSION: Because adherence and symptom levels were positively impacted, it appears that MI may be a promising intervention for AYAs with chronic illness in addressing non-adherence and potentially improving quality of life. PRACTICE IMPLICATIONS: Healthcare providers should consider implementing MI in their practice to establish rapport and potentially improve long-term health outcomes for AYAs with chronic illness. PMID- 28619272 TI - Patient participation during oncological encounters: Barriers and need for supportive interventions experienced by elderly cancer patients. AB - OBJECTIVE: To enhance patient participation during (oncological) encounters, this study aims to gain insight into communication barriers and supportive interventions experienced by elderly patients with cancer. METHOD: A mixed method design, including both quantitative (secondary survey data analysis) and qualitative (interviews) methods Survey data were used to identify communication barriers and need for supportive interventions of elderly cancer patients, compared to younger patients. Next, interviews provided in-depth insight into elderly patients' experiences and underlying mechanisms. RESULTS: A majority of the 70 participating elderly cancer patients (53%) felt confident in communicating and participating during medical encounters. However, 47% of patients experienced barriers to effectively communicate with their healthcare provider and felt the need for supportive interventions. The 14 interviewed patients mentioned barriers and facilitators related to attributes of themselves (e.g. feeling sick, self-efficacy), the provider (e.g. taking patient seriously) and the healthcare system (e.g. time constraints). CONCLUSIONS: Although many elderly cancer patients feel confident, offering support to patients who feel less confident in communicating with their provider is recommended. PRACTICE IMPLICATIONS: The outcomes of this study can be used as a first step for developing interventions for elderly cancer patients to overcome communication barriers, and help providers to facilitate this process. PMID- 28619273 TI - The many "Disguises" of patient-centered communication: Problems of conceptualization and measurement. AB - OBJECTIVE: To critically examine different approaches to the measurement of patient-centered communication. METHODS: Provides a critique of 7 different measures of patient-centered communication with respect to differences in their assumptions about what constitutes patient-centeredness and in their approaches to measurement. RESULTS: The measures differed significantly with regard to whether the measure captured behavior (what the interactants did) or judgment (how well the behavior was performed), focused on the individual clinician or on the interaction as a whole, and on who makes the assessment (participant or observer). A multidimensional framework for developing patient-centered communication measures is presented that encompasses the patient's perspective and participation, the biopsychosocial context of the patient's health, the clinician-patient relationship, quality of information-exchange, shared understanding, and shared, evidence-based decision-making. CONCLUSIONS: The state of measurement of the patient-centered communication construct lacks coherence, in part because current measures were developed either void of a conceptual framework or from very different theoretical perspectives. PRACTICE IMPLICATIONS: Assessment of patients' experiences with quality of communication in medical encounters should drill down into specific domains of patient-centeredness. PMID- 28619274 TI - The importance of acknowledgement of emotions in routine patient psychological assessment: The example of the dental setting. AB - OBJECTIVE: To investigate, by means of a conceptual model, the effect of dental staff engaging with their patients who share their level of dental anxiety in a short screening questionnaire. METHODS: Three consecutive studies based in the UK primary dental care services were conducted. Each study adopted a randomised group design to focus on the possible influence on patient state anxiety of the dentist becoming aware of their patients' dental anxiety from the self-reports of the Modified Dental Anxiety Scale (MDAS). RESULTS: A consistent finding in the first two studies was that the presentation of MDAS score sheet to the dentist was effective in reducing patient state anxiety when leaving the surgery. The third study provided supportive evidence that a more permanent anxiolytic effect of the presentation of the MDAS to the dentist was associated with the dentist responding openly to their patient about the fears expressed. CONCLUSION: The active engagement of dental staff in the formal presentation of dental anxiety screening confers a reliable benefit to dentally anxious patients. CLINICAL IMPLICATIONS: Anxiety assessments in clinical service may give patients significant relief when staff acknowledge and engage patients when presented with their self-reported ratings. PMID- 28619275 TI - Differentiation Affects the Release of Exosomes from Colon Cancer Cells and Their Ability to Modulate the Behavior of Recipient Cells. AB - Exosomes are involved in intercellular communication. We previously reported that sodium butyrate-induced differentiation of HT29 colon cancer cells is associated with a reduced CD133 expression. Herein, we analyzed the role of exosomes in the differentiation of HT29 cells. Exosomes were prepared using ultracentrifugation. Gene expression levels were evaluated by real-time PCR. The cell proliferation rate was assessed by MTT assay and with the electric cell-substrate impedance sensing system, whereas cell motility was assessed using the scratch test and confocal microscopy. Sodium butyrate-induced differentiation of HT29 and Caco-2 cells increased the levels of released exosomes and their expression of CD133. Cell differentiation and the decrease of cellular CD133 expression levels were prevented by blocking multivesicular body maturation. Exosomes released by HT29 differentiating cells carried increased levels of miRNAs, induced an increased proliferation and motility of both colon cancer cells and normal fibroblasts, increased the colony-forming efficiency of cancer cells, and reduced the sodium butyrate-induced differentiation of HT29 cells. Such effects were associated with an increased phosphorylation level of both Src and extracellular signal regulated kinase proteins and with an increased expression of epithelial-to-mesenchymal transition-related genes. Release of exosomes is affected by differentiation of colon cancer cells; exosomes might be used by differentiating cells to get rid of components that are no longer necessary but might continue to exert their effects on recipient cells. PMID- 28619276 TI - Arginine vasopressin relates with spatial learning and memory in a mouse model of spinocerebellar ataxia type 3. AB - Spinocerebellar ataxia is an inherited neurodegenerative disorder that the most prevalent type is type 3 (SCA3). Arginine vasopressin (AVP) is released within the lateral septum for controlling the learning and memory. This communication studied the effect of AVP on the spatial learning and memory of SCA3 mice. The spatial learning and memory were analyzed by Morris water maze test (MWM), and AVP concentration was measured by radioimmunoassay. The results showed that (Alves et al., 2010) the swimming velocity, distance traveled and latency to the platform of MWM in SCA3 mice were reduced slower than those in WT mice over 4 training days (p<0.05, 0.01 or 0.001); (Antunes and Zimmerman, 1978) SCA3 mice showed a lower performance of spatial learning and memory of MWM during the fifth day (test day) compared to WT mice; (Bao et al., 2014) SCA3 mice had a decrease of AVP concentration in cerebral cortex (6.3+/-0.6pg/mg vs. 11.4+/-1.0pg/mg, p<0.01), hypothalamus (6.1+/-1.3ng/mg vs. 10.3+/-2.1ng/mg, p<0.05), hippocampus (3.2+/-0.5pg/mg vs. 5.2+/-1.0pg/mg, p<0.01) and cerebellum (4.7+/-0.9pg/mg vs. 8.3+/-1.1pg/mg, p<0.01), not in spinal cord, pituitary and serum; and (Barberies and Tribollet, 1996) intraventricular AVP could significantly quicken swimming velocity, cut down distance traveled and reduce latency to the platform of MWM in a dose-dependent manner, but intraventricular AVP receptor antagonist weakened the spatial learning and memory of MWM in SCA3 mice during the fifth day. The data suggested that AVP in the brain, not spinal cord and peripheral system of SCA3 mice related with the change of the spatial learning and memory of MWM. PMID- 28619277 TI - Non-invasive Estimation of Temperature during Physiotherapeutic Ultrasound Application Using the Average Gray-Level Content of B-Mode Images: A Metrological Approach. AB - Healing therapies that make use of ultrasound are based on raising the temperature in biological tissue. However, it is not possible to heal impaired tissue by applying a high dose of ultrasound. The temperature of the tissue is ultimately the physical quantity that has to be assessed to minimize the risk of undesired injury. Invasive temperature measurement techniques are easy to use, despite the fact that they are detrimental to human well being. Another approach to assessing a rise in tissue temperature is to derive the material's general response to temperature variations from ultrasonic parameters. In this article, a method for evaluating temperature variations is described. The method is based on the analytical study of an ultrasonic image, in which gray-level variations are correlated to the temperature variations in a tissue-mimicking material. The physical assumption is that temperature variations induce wave propagation changes modifying the backscattered ultrasound signal, which are expressed in the ultrasonographic images. For a temperature variation of about 15 degrees C, the expanded uncertainty for a coverage probability of 0.95 was found to be 2.5 degrees C in the heating regime and 1.9 degrees C in the cooling regime. It is possible to use the model proposed in this article in a straightforward manner to monitor temperature variation during a physiotherapeutic ultrasound application, provided the tissue-mimicking material approach is transferred to actual biological tissue. The novelty of such approach resides in the metrology-based investigation outlined here, as well as in its ease of reproducibility. PMID- 28619278 TI - Poor Apgar score and high mortality in puppies born by caesarean section from bitches anaesthetized with a propofol constant rate infusion. PMID- 28619279 TI - Intra-abdominal pressure and intra-abdominal hypertension in critically ill obstetric patients: a prospective cohort study. AB - BACKGROUND: Critically ill obstetric patients may have risk factors for intra abdominal hypertension. This study evaluated the intra-abdominal pressure and its effect on organ function and the epidemiology of intra-abdominal hypertension. METHODS: Obstetric patients admitted to an Intensive Care Unit, with an anticipated stay greater than 24hours, were included. Intra-abdominal pressure was measured daily via a Foley catheter, based on intravesical pressure. RESULTS: One-hundred-and-one patients were enrolled. The intra-abdominal pressure was 5 7mmHg in 34%; 7-12mmHg in 60%; and >=12mmHg (intra-abdominal hypertension) in 6%. All six patients with intra-abdominal hypertension were pregnant at the time of admission. The intra-abdominal pressure in four patients normalized to <12mmHg following delivery, but in the remaining two it persisted >=12mmHg and both these patients died. Correlation between intra-abdominal pressure and organ dysfunction was weak (r=0.211). Statistical comparison between patients with and without intra-abdominal hypertension for risk factors, daily intra-abdominal pressures, and Sequential Organ Failure Assessment score could not be done due to the disproportionately small number of patients with intra-abdominal hypertension as opposed to those without (6 versus 95). Intra-abdominal pressure did not significantly differ between survivors and non-survivors (8.5+/-1.1 vs 7.9+/ 1.7mmHg, P=0.079). CONCLUSIONS: The incidence of intra-abdominal hypertension in critically ill obstetric patients was lower than previously defined for mixed Intensive Care Unit populations, with an association with the pregnant state. Normalization of intra-abdominal pressure after delivery was associated with better survival. There was no correlation between intra-abdominal pressure and organ function or mortality. PMID- 28619280 TI - It All Depends on Who Does What: A Survey of Patient and Family Member Comfort With Surgical Trainees Operating. AB - OBJECTIVE: To measure patient and family member comfort with surgical trainees of varying levels performing different portions of surgery. DESIGN, SETTING, AND PARTICIPANTS: An electronic survey dividing surgery into 6 steps (prepping and positioning, initial incision, deep dissection, critical portions, deep suturing, and closing incision), differentiating surgical trainees by 4 levels of experience (medical student, intern, resident, and fellow), and specifying whether or not an attending surgeon is in the operating room (OR) was given to 200 patients and family members in the surgical waiting area of a single academic medical center. Responses were on a 7-point Likert scale from "Not Comfortable at All" to "Completely Comfortable". RESULTS: Patient and family member comfort significantly increased as trainee experience increased. It reached a nadir for all trainees performing "critical portions" of surgery. However, their average response was "Comfortable" for residents and fellows performing any surgical step when the attending surgeon is present in the OR. The percentage of "Comfortable" responses was significantly lower for all trainee levels performing any surgical step when the attending surgeon is absent from the OR. CONCLUSIONS: Patient and family member comfort with surgical trainees operating varies based on the trainee's level of experience, the step the trainee performs, and whether or not the attending surgeon is present in the OR. Patients and family members are on average "Comfortable" with surgical residents and fellows performing any surgical step when the attending surgeon is present. PMID- 28619281 TI - Metabolism of KO143, an ABCG2 inhibitor. AB - The ATP-binding cassette sub-family G member 2 (ABCG2) plays an important role in modulating drug disposition and endobiotic homeostasis. KO143 is a potent and relatively selective ABCG2 inhibitor. We found that the metabolic stability of KO143 was very poor in human liver microsomes (HLM). Our further studies illustrated that the tert-butyl ester group in KO143 can be rapidly hydrolyzed and removed by carboxylesterase 1. This metabolic pathway was confirmed as a major pathway of KO143 metabolism in both HLM and mice. K1 is an analog of KO143 without the ester group. We found that the metabolic stability of K1 was significantly improved in HLM when compared to KO143. These data suggest that the ester group in KO143 is the major cause of the poor metabolic stability of KO143. The data from this study can be used to guide the development of KO143 analogs with better metabolic properties. PMID- 28619282 TI - The first CUB-domain containing serine protease from Chlamys farreri which might be involved in larval development and immune response. AB - Serine proteases (SPs) are one of the most well understood enzyme families, which play an important role in regulating many physiological events. In the present study, one CUB-domain containing serine protease was identified from Chlamys farreri (designated as CfCUBSP). The full-length cDNA of CfCUBSP was of 3181 bp with an open reading frame of 2688 bp encoding a polypeptide of 896 amino acids. CfCUBSP shared closer phylogenetic relationship with those multi-domain SPs which consisted of one SP domain, and different numbers of CUB domain and LDLa domain than other SPs. The mRNA transcripts of CfCUBSP were detected in all developmental stages with the highest expression level in fertilized eggs and the lowest in trochophore larvae. In adult scallop, the CfCUBSP mRNA could be detected in all examined tissues with the highest level in hepatopancreas, and CfCUBSP protein was dominantly located in the gills, hepatopancreas, gonad and kidney. The mRNA expression of CfCUBSP in hemocytes was significantly up regulated after the stimulation of lipopolysaccharide (LPS), peptidoglycan (PGN) and beta-glucan (GLU) (P < 0.05). All the results collectively indicated that CfCUBSP was a primitive member of the invertebrate SPs which might be involved in larval development and immune response against Gram-negative (G-) and Gram positive (G+) bacteria and fungus in scallop. PMID- 28619283 TI - Preparation and in vitro assessment of wet-spun gemcitabine-loaded polymeric fibers: Towards localized drug delivery for the treatment of pancreatic cancer. AB - BACKGROUND/OBJECTIVES: There has been minimal improvement in the prognosis of pancreatic cancer cases in the past 3 decades highlighting the crucial need for more effective therapeutic approaches. A drug delivery system capable of locally delivering high concentrations of chemotherapeutics directly at the site of the tumor is clearly required. The aim of this study was to fabricate and characterize the biophysical properties of gemcitabine-eluting wet-spun polymeric fibers for localized drug delivery applications. METHODS/RESULTS: Fibers spun from alginate or chitosan solutions with or without the anticancer drug gemcitabine had a uniform surface area, were internally homogeneous and ranged from 50-120 MUm in diameter. Drug encapsulation ranged from 13-52%, depending on the type and concentration of polymer used. Gemcitabine displayed first-order release kinetics where 64-82% of the loaded drug was rapidly released within the first 10 h followed by a sustained release over the next 134 h. A time dependent inhibition of ex vivo tumor spheroid growth and cell viability was observed after incubation with gemcitabine-loaded fibers but not control fibers. CONCLUSION: With further development these studies could lead to the manufacture of a safe and effective delivery system designed to combat non-resectable pancreatic cancer for which currently there is minimal chance of cure. PMID- 28619284 TI - Assessment of disease aggression in cystic pancreatic neuroendocrine tumors: A CT and pathology correlation study. AB - BACKGROUND/OBJECTIVES: There are inconsistencies in the literature regarding the clinical significance of cystic components in pancreatic neuroendocrine tumors (NET). This may be related to differences in the identification of cystic NET through imaging and/or pathology. Tumors may also be microscopically or macroscopically cystic. Our primary objective is to determine radiology-pathology correlation for the identification of cystic components. Our secondary objective is to determine if cystic components are associated with indices of tumor aggression. METHODS: 60 tumors with correlative surgical pathology were assessed retrospectively for cystic components on CT and pathology. Tumor was categorized as solid or cystic on CT and pathology. If cystic on pathology, cystic components were categorized as macroscopic or microscopic. Cystic components were estimated as <50% and >=50% tumor volume. WHO/Hochwald grade and presence of metastases were used to stratify disease aggression. Associations were tested with Chi square/Fisher's exact test and differences were tested with t-test/Wilcoxon rank sums test. RESULTS: There is moderate agreement between CT and histology for presence of cystic components. Discrepancies were mostly attributable to the presence of microscopic cystic components in tumors appearing solid on CT. There was no difference in size between cystic and solid tumors on CT or pathology. No association between CT-determined cystic components and tumor grade was found. Tumors with cystic components (cystic by CT, and macroscopically cystic by pathology) demonstrated less association with metastases than solid tumors. CONCLUSIONS: Cystic components, comprising >=50% of the tumor by CT and observed macroscopically on pathology, are associated with less aggressive disease. PMID- 28619285 TI - 5-Fluorouracil biomarkers in pancreatic neuroendocrine tumours. PMID- 28619286 TI - Neuroprotective potential of Aloe arborescens against copper induced neurobehavioral features of Parkinson's disease in rat. AB - Copper (Cu) is an important trace element for the organism survival, which ensures the normal functioning of different biosystems. However, excessive levels of this heavy metal are responsible for profound physiological alterations including the central nervous system. Numerous findings sustain the involvement of heavy metals, as an environmental risk factor such as copper (Cu), in the neuropathology of Parkinson's disease (PD) which is a chronic neurodegenerative disorder that principally affects the motor system. The classic and evident symptoms of PD namely rigidity, tardiness of movement, and difficulty with walking, result from progressive dopaminergic neurons death within substantia nigra. Whereas, few pharmacological trials have shown a beneficial role against Cu neurotoxicity, Aloe arborescens is one of the powerful medicinal plants with an array of therapeutic effects. Thus, we aimed through the present study, to evaluate the impact of acute Cu intoxication (10MUg/g B.W. i.p) for 3days on the dopaminergic system and locomotor performance, together with the possible restorative effect of oral administration of aqueous extract of Aloe arborescens gel (AEAAG) (200mg/kg B.W.). By means of immunohistochemistry, we noted, in the Cu intoxicated rats, a significant loss of TH (tyrosine hydroxylase) expression within substantia nigra compacta (SNc), ventral tegmental area (VTA) and the subsequent striatal outputs, those alterations were correlated to behavioral abnormalities such as a severe drop of locomotor performance. While AEAAG administration to Cu intoxicated rats showed a noticeable beneficial effect; this potential was featured by a complete recovery of the TH expression and locomotor behavior deficiencies in the intoxicated rats. The present investigation have brought, on the one hand, an experimental evidence of an altered dopaminergic innervations following Cu intoxication and on the other hand, a new pharmacological property of Aloe arborescens that may be used as a neuroprotective plant for neurodegenerative disorders, such as PD, touching the dopaminergic system trigged by heavy metals. PMID- 28619287 TI - The impact of black seed oil on tramadol-induced hepatotoxicity: Immunohistochemical and ultrastructural study. AB - : The natural herb, black seed (Nigella Sativa; NS) is one of the most important elements of folk medicine. The aim was to evaluate the impact of Nigella Sativa Oil (NSO) on the changes induced by tramadol in rat liver. Twenty four albino rats were used. CONTROL GROUP: given intraperitoneal and oral saline for 30days. TR-group: given intraperitoneal tramadol (20, 40, 80mg/kg/day) in the first, middle and last 10days of the experiment, respectively. TR+NS group: administered intraperitoneal tramadol in similar doses to TR-group plus oral NSO (4ml/kg/day) for 30days. Immunohistochemical, electron microscopic, biochemical and statistical studies were performed. TR-group displayed disarranged hepatic architecture, hepatic congestion, hemorrhage and necrosis. Apoptotic hepatocytes, mononuclear cellular infiltration and a significant increase in the number of anti-CD68 positive cells were observed. Ultrastructurally, hepatocytes showed shrunken nuclei, swollen mitochondria, many lysosomes and autophagic vacuoles. Activated Ito and Von Kupffer cells were also demonstrated. Elevated serum levels of AST, ALT, ALP and bilirubin were noticed. NSO administration resulted in preservation of hepatic histoarchitecture and ultrastructure and significant reductions in the number of anti-CD68 positive cells and serum levels of liver seromarkers. In conclusion, NSO administration could mitigate the alterations induced by tramadol in rat liver. PMID- 28619288 TI - Effects of exogenous leptin on seasonal reproductive responses to interacting environmental cues in female Siberian hamsters. AB - Animals living in temperate climates respond to environmental cues that signal current and future resource availability to ensure that energy resources are available to support reproduction. Siberian hamsters (Phodopus sungorus) undergo robust gonadal regression in short, winter-like photoperiods as well as in response to mild food restriction in intermediate photoperiods. The goal of the present study was to investigate whether leptin is a relevant metabolic signal in regulating gonadal regression in response to diminishing food availability. Adult female hamsters housed in short-day (winter-like) or intermediate (fall-like) photoperiods received either ad libitum access to food or mild food restriction (90% of ad libitum intake) and were treated with either leptin or a vehicle for five weeks in order to determine the ability of leptin to inhibit gonadal regression. At the end of five weeks, vehicle-treated hamsters showed physiological signs associated with ongoing gonadal regression, such as decreases in body mass and food intake, cessation of estrous cycling, and small decreases in reproductive tissue mass. Leptin did not modify changes in body mass, food intake, hormone concentration, or tissue mass, but showed a tendency to support estrous cycling, particularly in response to food restriction in the intermediate photoperiod treatment. Overall, leptin appears to play a minor role in coordinating reproductive responses to multiple environmental cues, at least in the early stages of gonadal regression. PMID- 28619289 TI - Validation of a method for "dose of the day" calculation in head-neck tomotherapy by using planning ct-to-MVCT deformable image registration. AB - PURPOSE: The aim of this study was to test the feasibility and dosimetric accuracy of a method that employs planning CT-to-MVCT deformable image registration (DIR) for calculation of the daily dose for head and neck (HN) patients treated with Helical Tomotherapy (HT). METHODS: For each patient, the planning kVCT (CTplan) was deformably registered to the MVCT acquired at the 15th therapy session (MV15) with a B-Spline Free Form algorithm using Mattes mutual information (open-source software 3D Slicer), resulting in a deformed CT (CTdef). On the same day as MVCT15, a kVCT was acquired with the patient in the same treatment position (CT15). The original HT plans were recalculated both on CTdef and CT15, and the corresponding dose distributions were compared; local dose differences <2% of the prescribed dose (DD2%) and 2D/3D gamma-index values (2% 2mm) were assessed respectively with Mapcheck SNC Patient software (Sun Nuclear) and with 3D-Slicer. RESULTS: On average, 87.9%+/-1.2% of voxels were found for DD2% (on average 27 slices available for each patient) and 94.6%+/-0.8% of points passed the 2D gamma analysis test while the 3D gamma test was satisfied in 94.8%+/-0.8% of body's voxels. CONCLUSIONS: This study represents the first demonstration of the dosimetric accuracy of kVCT-to-MVCT DIR for dose of the day computations. The suggested method is sufficiently fast and reliable to be used for daily delivered dose evaluations in clinical strategies for adaptive Tomotherapy of HN cancer. PMID- 28619290 TI - Sparing dysphagia/aspiration related structures using novel hybrid volumetric modulated arc therapy. AB - PURPOSE: Studies using split field IMRT to spare dysphagia/aspiration related structures (DARS) have raised concern regarding dose uncertainty at matchline. This study explores the utility of hybrid VMAT in sparing the DARS and assesses matchline dose uncertainty in postoperative oral cavity cancer patients and compares it with VMAT. METHODS & MATERIALS: Ten postoperative oral cavity cancer patients were planned with h-VMAT and VMAT using the same planning CT dataset. PTV and DARS were contoured using standard delineation guidelines. In h-VMAT 80% of the neck dose was planned using AP/PA technique and then VMAT optimization was done for the total PTV by keeping the corresponding AP/PA plan as the base dose. Planning goal for PTV was V95%>=95% and for DARS, adequate sparing. Plans and dose volume histograms were analyzed using dosimetric indices. Absolute point and portal dose measurements were done for h-VMAT plans to verify dose at the matchline. RESULTS: Coverage in both the techniques was comparable. Significant differences were observed in mean doses to DARS (Larynx: 24.36+/-2.51 versus 16.88+/-2.41Gy; p<0.0006, Pharyngeal constrictors: 25.16+/-2.41 versus 21.2+/ 2.1Gy; p<0.005, Esophageal inlet: 18.71+/-2 versus 12.06+/-0.79Gy; p<0.0002) favoring h-VMAT. Total MU in both the techniques was comparable. Average percentage variations in point dose measurements in h-VMAT done at +3.5 and -3.5 positions were (1.47+/-1.48 and 2.28+/-1.35%) respectively. Average gamma agreement for portal dose measured was 97.07%. CONCLUSION: h-VMAT achieves better sparing of DARS with no matchline dose uncertainty. Since these patients have swallowing dysfunction post-operatively, attempts should be made to spare these critical structures as much as possible. PMID- 28619291 TI - Body mass modulates huddling dynamics and body temperature profiles in rabbit pups. AB - Altricial mammals typically lack the physiological capacity to thermoregulate independently during the early postnatal period, and in litter-bearing species the young benefit strongly from huddling together with their litter siblings. Such litter huddles are highly dynamic systems, often characterized by competition for energetically favorable, central positions. In the present study, carried out in domestic rabbits Oryctolagus cuniculus, we asked whether individual differences in body mass affect changes in body temperature during changes in the position within the huddle. We predicted that pups with relatively lower body mass should be more affected by such changes arising from huddle dynamics in comparison to heavier ones. Changes in pups' maximum body surface temperature (determined by infrared thermography) were significantly affected by changes in the number of their neighbors in the litter huddle, and indeed these temperature changes largely depended on the pups' body mass relative to their litter siblings. Lighter pups showed significant increases in their maximum body surface temperature when their number of huddling partners increased by one or two siblings whereas pups with intermediate or heavier body mass did not show such significant increases in maximum body temperature when experiencing such changes. A similar pattern was found with respect to average body surface temperature. This strong link between changes in the number of huddling partners and body surface temperature in lighter pups might, on the one hand, arise from a higher vulnerability of such pups due to their less favorable body surface area to-volume ratio. On the other hand, as lighter pups generally had fewer neighbors than heavier ones and thus typically a comparatively smaller body surface in contact with siblings, they potentially had more to gain from increasing their number of neighbors. The present findings might help to understand how individual differences in body mass within a litter lead to the emergence of individual differences in sibling interactions during early postnatal life in different species of altricial and litter-bearing mammals. PMID- 28619292 TI - Psychophysiological response in parachute jumps, the effect of experience and type of jump. AB - We aimed to analyse the effect of experience and type of parachute jump on the psychophysiological responses of jumpers. We analysed blood oxygen saturation, heart rate, blood glucose, lactate and creatinkinase, leg strength, isometric hand strength, cortical arousal, specific fine motor skills, self-confidence and cognition, and somatic and state anxiety, before and after four different parachute jumps: a sport parachute jump, a manual tactical parachute jump, tandem pilots, and tandem passengers. Independently of the parachute jump, the psychophysiological responses of experienced paratroopers were not affected by the jumps, except for an increase in anaerobic metabolism. Novice parachute jumpers presented a higher psychophysiological stress response than the experienced jumpers, together with a large anticipatory anxiety response before the jump; however, this decreased after the jump, although the high physiological activation was maintained. This information could be used by civil and military paratroopers' instructors to improve their training programmes. PMID- 28619293 TI - Efficacy and safety of traditional Chinese medicine on thromboembolic events in patients with atrial fibrillation: A systematic review and meta-analysis. AB - OBJECTIVES: Traditional Chinese medicine (TCM) in combination with Western medicine (WM) has been widely used worldwide. This systematic review aimed to evaluate the efficacy and safety of TCM in prevention of thromboembolic events in patients with atrial fibrillation (AF). METHODS: Potential studies were searched through the Cochrane Library, PubMed, EMBASE, CBM, VIP, CNKI, and Wanfang databases up to February 2016. Randomized controlled trials (RCTs) investigating the thromboembolic events and/or safety outcome of TCM in patients with AF were included. RESULTS: A total of 905 AF patients from 9 RCTs were identified. Meta analysis showed that TCM in combination with warfarin was better than warfarin alone for preventing total thromboembolic events with a 68% reduction of risk (risk ratio [RR] 0.32; 95% confidence interval [CI] 0.13-0.78) without increasing the risk of total bleeding (RR 0.71; 95% CI 0.29-1.72). Compared with warfarin, TCM therapy was associated with lower risk of total bleeding (RR 0.13; 95% CI 0.04-0.47), but increased the risk of total thromboembolic events (RR 1.84; 95% CI 1.03-3.27). CONCLUSIONS: This meta-analysis suggests that TCM combined with warfarin is superior to warfarin alone for the prevention of total thromboembolic events in patients with AF, with equal risk of bleeding as warfarin alone. PMID- 28619294 TI - Impact of mulberry leaf extract on type 2 diabetes (Mul-DM): A randomized, placebo-controlled pilot study. AB - AIMS: Mulberry leaves have been used anecdotally in Asia to treat many disease states, including glucose abnormalities. Animal and human studies illustrate potential benefit of mulberry leaf extract (MLE) in type 2 diabetes mellitus (DM2). The purpose of this study is to evaluate the glycemic and safety effects of MLE in patients with DM2. MATERIALS & METHODS: This randomized, double-blind, placebo-controlled pilot study evaluated MLE (1000mg standardized) versus matching placebo given three times daily with meals. Patients (n=24) were included if they had DM2 on single or combination oral therapy with a stable hemoglobin A1C (A1C). A 2-week placebo run-in (baseline) was followed by initiation of randomized medication for 3 months. Primary endpoints were change in A1C and self-monitoring blood glucoses (SMBG). Safety was also evaluated. RESULTS: Of 24 patients enrolled, 17 patients completed the study. Post-prandial SMBG was significantly decreased at 3 months in the MLE group versus baseline (16.1%; p<0.05). This improvement in post-prandial SMBG persisted when compared to placebo (18.2%; p<0.05). A1C decreased from 7.30% at baseline to 6.94% in the MLE group but did not reach statistical significance (p=0.079). There was no difference in A1C between MLE and placebo. A significant 15% increase occurred in serum creatinine when the MLE group was compared to baseline or placebo (p<0.05 for both). There was no significant effect on weight, fasting SMBG, blood pressure, hypoglycemia, or other safety evaluation markers. CONCLUSIONS: These results suggest that mulberry leaf extract may be a useful complementary mealtime glucose option for patients with DM2. ClinicalTrials.gov Identifier NCT00795704. PMID- 28619295 TI - Effects of massage therapy on anxiety, depression, hyperventilation and quality of life in HIV infected patients: A randomized controlled trial. AB - INTRODUCTION: HIV infection is often preceded or accompanied by psychiatric comorbidities. These disorders improve with complementary therapies. The aim of this study was to measure the effect of massage therapy on anxiety, depression, hyperventilation and quality of life in HIV infected patients. METHOD: Adult HIV infected patients were randomized (n=29) in massage therapy group (one hour a week during four weeks) and control group. Anxiety and depression (HADS-A and HADS-D), hyperventilation (Nijmegen questionnaire) and quality of life (WHOQOL HIV) were evaluated at inclusion and after 4 weeks. RESULTS: At inclusion, 51% and 17% of the patients had a positive HADS-A and HADS-D score respectively. Two facets from WHOQOL-HIV ("Home environment" and "Death and dying" (p=0.04)) were different between groups. After the four week massage therapy, a significant improvement was observed only for Nijmegen questionnaire (p=0.01) and HADS-A (p=0.04) contrarily to WHOQOL-HIV and HADS-D. Domains of the WHOQOL-HIV did not improve following the massage therapy. Only "Pain and discomfort" facet improved after massage therapy (p=0.04). CONCLUSION: This study highlights the positive impact of a four week massage therapy on anxiety and hyperventilation in HIV infected patients. However, neither benefit of this program was observed on depression and quality of life. PMID- 28619296 TI - Understanding North American yoga therapists' attitudes, skills and use of evidence-based practice: A cross-national survey. AB - INTRODUCTION: Little is known about the adoption of evidence-based practice (EBP) by yoga therapists (YTs). OBJECTIVE: To determine the attitudes, skills, training, use, barriers and facilitators to the use of EBP amongst North American YTs DESIGN: Cross-sectional, descriptive survey METHODS: Self-identified YTs practicing in North America were invited to participate in an online survey. YT attitudes, skills, training, utilisation, barriers to use, and facilitators of EBP use were measured using the 84-item Evidence-Based practice Attitude and utilization SurvEy (EBASE). RESULTS: 367 members responded (~20% of eligible participants). Attitudes towards EBP were generally positive with 88% agreeing that professional literature and research findings were useful for the practice of yoga therapy. Most (80%) were interested in improving their skills and the majority agreed that EBP improves the quality of care (68%), assists in making decisions (74%) and takes into account the YTs clinical experience when making clinical decisions (59%). Moderate to moderately-high levels of perceived skill in EBP were reported mostly utilizing online search engines (51%). Lack of clinical evidence was the only notable barrier to uptake reported by YTs (48%). Facilitators to EBP included access to online EBP education materials (70.6%), ability to download full-text journal articles and access to free online databases in the workplace (67.3%). CONCLUSION: North American YTs report positive attitudes, moderate to moderately-high levels of perceived skill and moderate uptake of EBP. This aligns them with other complementary and integrative health practitioners. Initiatives to support the adoption of EBP are proposed as a means of improving best practice in yoga therapy. PMID- 28619297 TI - Corrigendum to "Using a questionnaire among patient, resident doctor and senior supervisor: Are their answers the same?" [Complement. Ther. Med. 22 (April (2)) (2014) 296-303]. PMID- 28619298 TI - Alternative medicine, worker health, and absenteeism in the United States. AB - : Health related absenteeism costs an estimated $153 billion annually in the United States (Witters and Agrawal, 2011).1 Chronic conditions (major contributors to absenteeism) are often successfully managed by Complementary and Alternative Medicine (CAM). As CAM becomes an increasingly visible component of healthcare, firms may wish to consider whether CAM therapies can help reduce illness-related absenteeism. This paper aims to extend the literature on healthcare utilization and absenteeism by exploring whether CAM treatment is associated with fewer workdays missed due to illness. METHODS: Using the 2007 National Health Interview Survey (NHIS) and propensity score matching (PSM), this study estimates the relationship between visits to CAM practitioners, health, and illness-related absenteeism. RESULTS: In a sample of 8820 workers, the average annual number of workdays lost due to illness is 3.69. Visiting an acupuncturist correlates with lower absenteeism among men (1.182 fewer workdays missed, p<0.05), whereas visiting a naturopathic doctor correlates with 2.359 and 2.521 fewer workdays missed for women and men, respectively (both p<0.001). Active mind body practices, massage, chiropractic and acupuncture treatments are all significantly associated with improved health. CONCLUSIONS: Estimates suggest that some CAM modalities correlate with lower absenteeism, and many correlate with improved health. Two limitations of this study are worth noting. First, a small proportion of the sample uses CAM, limiting the generalizability of results. Second, if health conscious individuals are more likely to use CAM, then health attitudes may be contributing to lower absenteeism among the treated. Further research is needed to identify a causal relationship between CAM treatment, health, and absenteeism. PMID- 28619299 TI - Comparative cost analysis of inpatient integrative medicine-Results of a pilot study. AB - BACKGROUND: Costs of integrative treatment alone and in comparison with other treatment approaches have scarcely been reported in the past. This study presents results of a comparative cost analysis of an inpatient integrative medicine treatment costs. METHODS: Data from 2006 for inpatients referred to a Department of Integrative Medicine in Germany were used. Case-related treatment costs were calculated, and transformed into Casemix-Indices and revenues per DRG. Costs were compared between departments at the same hospital and between different hospitals using univariate statistics and Chi-Square tests. RESULTS: In total 1253 inpatients (81.4% female, 61.1+/-14.4years) were included in the current analysis. Most patients were treated for diseases of the musculoskeletal system (57.2%), followed by diseases of the digestive system (11.4%), and diseases of the nervous system (10.4%). The department received an additional payment for most of the patients (88.0%), which led to an effective appreciation of 10.8% per case compared to the standardized Casemix-Index. In-house comparisons with other departments found the department in close vicinity to the departments of Internal medicine with regards to CMI and mean revenue, however the Patient Clinical Complexity Level was significantly lower in the Integrative medicine department. The interhospital comparison revealed comparable Casemix-Index and DRG-revenue, however the additional payment increased the mean revenue significantly. CONCLUSION: Modern integrative in-patient treatment is mostly cost-equivalent to conventional treatment. Cost effectiveness studies should be considered to further investigate the potential of integrative in patient treatment. PMID- 28619300 TI - Clinical effect of traditional Chinese spinal orthopedic manipulation in treatment of Functional Abdominal Pain Syndrome. AB - OBJECTIVE: To evaluate the clinical effect of Traditional Chinese Spinal Orthopedic Manipulation (TCSOM) in treating Functional Abdominal Pain Syndrome (FAPS) in comparison with Pinaverium Bromide (Dicetel, PBD), and to assess a possible cause for FAPS. METHODS: 60 cases of FAPS patients were randomly assigned to the TCSOM group and PBD group according to the random number table method. The TCSOM group was treated with thumb pressing manipulation, every other day in the first week, and once every three days in the second week, for 5 times treatments. Patients in the PBD group were instructed to take 50mg 3 times a day, consistently for 2 weeks. The symptoms of pre-treatment and post-treatment were assessed on a visual analog scale (VAS) pain score. A symptom improvement rating (SIR) was implemented in order to evaluate the effects of the treatments, and to statistically compare the two groups. RESULTS: The symptoms of 21 patients of the TCSOM group were resolved soon after the first spinal manipulation treatment and 4 cases were significantly improved. The VAS pain scores in the TCSOM group were significantly lower than those in the PBD group after 2 weeks treatment. According to the SIR based on VAS, the TCSOM research group included 20 cases with excellent results, 8 cases with good, and 2 cases with poor. There were no side effects in the TCSOM group after treatment. Based on VAS, the PBD research group reported 6 cases with excellent results, 8 cases with good and 16 cases with poor. All cases were statistically analyzed, revealing a significant difference (P<0.001) between the two groups. CONCLUSION: TCSOM group performed much better than PBD group for relief of the symptoms of FAPS. Thumb pressing manipulation on the thoracic and/or lumbar region can correct the displacement of inter-vertebral discs and/or vertebra, resolving the stimuli caused by pressure exerting on the nerves and vessels around the spine. TREATMENT: with thumb pressing manipulation on the Back-Shu acupoints, the Jiaji (EX-B2) and the governor vessel acupoint had a very good clinical effect for abdominal pain indicating that it is an effective treatment for FAPS. PMID- 28619302 TI - Chinese herbal medicine for treating menopausal symptoms in London women: developing a good practice protocol via the factor analysis of prescribing patterns in a clinical study. AB - The objective of the study described in this paper was to define Chinese medicine formula patterns for the treatment of menopausal women in London. These formula patterns are intended to inform the development of best practice guidelines for a future pragmatic randomised controlled trial, with the ultimate goal of evaluating the possibility of integrating Chinese medicine treatment strategies for menopausal symptoms into the UK National Health Service. Data from a clinical study that had demonstrated the effectiveness and safety of Chinese medicine in treating 117 perimenopausal women at the Westminster University Polyclinic in London were analysed for symptom occurrence and herb use. The frequency of occurrence of different presenting symptoms and the frequency of use of individual herbs is described, the patterns of combined herb use were analysed by means of factor analysis, and the correlations between these patterns and the presenting symptoms were analysed using the chi square test. Treating the emergent use patterns as Chinese herbal medicine formulas, five distinctive formula patterns emerged in the course of this study. While there is some overlap between these formulas and their associated symptom patterns and those described in Chinese medicine textbooks and guidelines, some formula patterns appear to be unique to London women. This indicates that best practice guidelines for the Chinese medicine treatment of menopausal symptoms, which have been shown to vary cross-culturally, need to be derived from local clinical practice. PMID- 28619301 TI - The effects of Gua sha on symptoms and inflammatory biomarkers associated with chronic low back pain: A randomized active-controlled crossover pilot study in elderly. AB - OBJECTIVE: To address the challenges for trialing with elderly and the lacking of valid sham/placebo control, a randomized crossover pilot study is designed and its feasibility on elderly subjects is evaluated. DESIGN: A pilot randomized crossover study was conducted with hydrocollator-based hot pack therapy as active control. Pain intensity, physical disability, depression, general health status, and salivary biomarkers were assessed as outcome measures. RESULTS: Despite there was no significant difference observed between any outcome measures attained by the two interventions, several important differences were noted during the one week follow-up period. The magnitudes of pain reduction (21-25% versus 16-18%) and disability improvement (45-52% versus 39-42%) were greater in the Gua sha treated group than the hot pack group. Both treatments were shown to improve flexion, extension and bending movements of the lower back, whereas areas of improvement varied between the two interventions. Decreasing trends were observed in both tumor necrosis factor-alpha (TNF-alpha) and heme-oxygenase-1 (HO-1) levels following Gua sha. However, rebounds of the biomarkers were observed one week following hot pack. Furthermore, in response to Gua sha, the decrease of TNF alpha was strongly correlated with the improvement of physical disability, whereas the physical disability was correlated with the VAS pain intensity. CONCLUSION: It demonstrated a feasible clinical trial protocol for evaluating the effectiveness of Gua sha and other therapeutic modalities. Gua sha may exhibit a more long-lasting anti-inflammatory effect relative to hot pack for pain relief and improved mobility in elderly patients with chronic low back pain. PMID- 28619303 TI - Effect of light pressure stroking massage with sesame (Sesamum indicum L.) oil on alleviating acute traumatic limbs pain: A triple-blind controlled trial in emergency department. AB - OBJECTIVES: Due to adverse effects of common medications used for traumatic pain management, it is crucial to use complementary methods to alleviate this pain. Present study aimed to assess the effect of light pressure stroking massage with topical sesame oil on pain severity of patients with limbs trauma. METHODS: This triple-blinded randomized trial was conducted on 40 patients with upper or lower extremities trauma in emergency department of Busheher Amir Al-Momenian Hospital, Busheher, Iran, in 2015-2016. Patients received a 5min massage with either liquid paraffin (placebo) or sesame oil on trauma site twice a day for 9days duration. Pain severity was assessed by visual analogue scale in first day (baseline), 3th, 6th and 9th days of intervention in the both groups. RESULTS: Mean changes of pain severity between two groups was significant in the 6th (-0.20+/-1.36; P=0.036) and 9th (-0.36+/-1.12; P<0.001) days of intervention. Regarding to intake of diclofenac, no significant difference was seen between sesame oil and placebo groups during 9days of intervention (575.23+/-3.11 and 625.13+/-4.23 respectively, P=0.601). There were no adverse effects during the study in the both groups. CONCLUSION: Massage with topical sesame oil was associated with significant reduction in pain severity of patients with limbs trauma. Therefore, it is suggested to use this oil on complementary medicine for pain relief due to low cost, easy usage and lack of adverse effects. PMID- 28619304 TI - The prevalence rate of deviations in body constitutions and related factors in follow-up stage breast cancer patients-A nationwide study. AB - OBJECTIVES: The aim of this study was to apply a rigorous traditional Chinese medicine (TCM) body constitution questionnaire (BCQ) to survey the prevalence rate of deviations in body constitution and to explore the health-related lifestyle behavior factors of deviations in body constitution. DESIGN: A cross sectional study was administered through postal mail. Subjects were recruited from a national organization for breast cancer patients (Taiwan Breast Cancer Alliance). SETTING/MAIN OUTCOME MEASURES: Data were obtained from 311 breast cancer patients by questionnaires including a demographic record sheet, lifestyle behavior scales and the BCQ (Yang-Xu, Yin-Xu, and Stasis). Differences concerning the presence of body constitutions were analyzed by Chi-square tests and analyses of variance, and potential predictive factors were analyzed using multivariate logistic regression. RESULTS: In total, 55.3% of the subjects had a Yang-Xu constitution, 61.0% had a Yin-Xu constitution, and 47.6% had a Stasis constitution. A total of 42.8% of the patients displayed a combination of the three types of body constitutions. Feeling stressed, physical exercise, and favoring fried food were predictors of the combined Yang-Xu, Yin-Xu and Stasis constitutions (p<0.05). Staying up late was significantly associated with Yin-Xu (p=0.017), and favoring salty food was significantly associated with Stasis (p=0.019). CONCLUSIONS: A high prevalence of deviations in body constitutions was observed in the follow-up stage of breast cancer patients. Increasing the adherence to healthy lifestyle behaviors might strengthen and balance body constitution, which could improve supportive care in breast cancer survivors. PMID- 28619305 TI - Effects of music listening on anxiety and physiological responses in patients undergoing awake craniotomy. AB - OBJECTIVE: The purpose of this study was to explore the effects of music listening on the level of anxiety and physiological responses for awake craniotomy. METHODS: An experimental design with randomization was applied in this study. Participants in experimental group (19 patients) selected and listened music at their preferences in the waiting room and throughout the entire surgical procedure in addition to usual care while control group (19 patients) only gave usual care. State-Trait Anxiety Inventory (STAI), heartbeat, breathing, and blood pressure were collected for analysis. RESULTS: The results of this study showed that after music listening, there was significant decrease in the level of anxiety (p<.001). The findings also showed that the music intervention significantly reduced heartbeat rate 84.5 (p<.004), systolic pressure 42 (p<.001), and diastolic pressure 38 (p<.001) over time. We concluded that music listening is associated with a decreased level of anxiety and distress after awake craniotomy patients. CONCLUSION: The results of this study can provide perioperative nursing care in providing music listening when patients were in the waiting room and during surgery to reduce the anxiety so as to reach the goal of human care and improve perioperative nursing care. PMID- 28619306 TI - Management of viral oral ulcers in children using Chinese herbal medicine: A report of two cases. AB - OBJECTIVE: Viral oral ulcers are common presentations in pediatric clinics. Although self-limiting, painful ulcerative lesions and inflamed mucosa can decrease oral intake and lead to dehydration. Despite the widespread use of Chinese herbal medicine (CHM) for pediatric upper respiratory disease in Taiwan, there is little evidence for its effectiveness as an antipyretic or in aiding ulcer healing for children with viral oral ulcers. We report two cases of children who presented with viral oral ulcers to illustrate the potential efficacy of CHM treatment in recovery from herpangina (HA) and herpetic gingivostomatitis (HGS). CLINICAL FEATURES AND OUTCOME: A 10-year-old girl with HA presented with an acute febrile illness associated with small vesicular or ulcerative lesions on the posterior oropharyngeal structures. The family refused western medicine due to a prior anaphylactic skin rash when she had taken sulfa drugs. The other patient was a 4-year-old boy with complaints of painful ulcers and hemorrhagic crusts on the lips. He was diagnosed with HGS and had received ibuprofen and supportive treatments such as hydration and local anesthesia spray for days, characterized by fever, anorexia, and nausea to no effect. Because the patients were suffering from the damp-heat syndrome according to Traditional Chinese Medicine (TCM) differentiation, both were treated using the same herbal formulas powder prescription, named Liang Ge San (LGS) and Gan Lu Xiao Du Dan (GLXDD). After several days of CHM treatment, the oral ulcers were in regression. Follow-up of the frontal view in both patients showed satisfactory disappearance of the sick furred tongue. CONCLUSIONS: The results of these case reports show that the early prescription of CHM is an effective modality of alternative treatment for viral oral ulcers. To our knowledge, this is the first report of CHM treatment hastening the recovery from febrile disease with viral oral ulcers in Taiwan. Future experimental studies to determine the definitive mechanism and clinical trials are warranted. PMID- 28619307 TI - Pilot randomized controlled trial of a mindfulness-based group intervention in adolescent girls at risk for type 2 diabetes with depressive symptoms. AB - OBJECTIVE: (1) Evaluate feasibility and acceptability of a mindfulness-based group in adolescent girls at-risk for type 2 diabetes (T2D) with depressive symptoms, and (2) compare efficacy of a mindfulness-based versus cognitive behavioral group for decreasing depressive symptoms and improving insulin resistance. DESIGN AND SETTING: Parallel-group, randomized controlled pilot trial conducted at a university. PARTICIPANTS: Thirty-three girls 12-17y with overweight/obesity, family history of diabetes, and elevated depressive symptoms were randomized to a six-week mindfulness-based (n=17) or cognitive-behavioral program (n=16). INTERVENTIONS: Both interventions included six, one-hour weekly group sessions. The mindfulness-based program included guided mindfulness awareness practices. The cognitive-behavioral program involved cognitive restructuring and behavioral activation. MAIN OUTCOME MEASURES: Adolescents were evaluated at baseline, post-intervention, and six-months. Feasibility/acceptability were measured by attendance and program ratings. Depressive symptoms were assessed by validated survey. Insulin resistance was determined from fasting insulin and glucose, and dual energy x-ray absorptiometry was used to assess body composition. RESULTS: Most adolescents attended >=80% sessions (mindfulness: 92% versus cognitive-behavioral: 87%, p=1.00). Acceptability ratings were strong. At post-treatment and six-months, adolescents in the mindfulness condition had greater decreases in depressive symptoms than adolescents in the cognitive-behavioral condition (ps<.05). Compared to the cognitive-behavioral condition, adolescents in the mindfulness-based intervention also had greater decreases in insulin resistance and fasting insulin at post treatment, adjusting for fat mass and other covariates (ps<.05). CONCLUSIONS: A mindfulness-based intervention shows feasibility and acceptability in girls at risk for T2D with depressive symptoms. Compared to a cognitive-behavioral program, after the intervention, adolescents who received mindfulness showed greater reductions in depressive symptoms and better insulin resistance. ClinicalTrials.gov identifier: NCT02218138 clinicaltrials.gov. PMID- 28619308 TI - What the public think about hypnosis and hypnotherapy: A narrative review of literature covering opinions and attitudes of the general public 1996-2016. AB - OBJECTIVES: To describe the public's understanding of hypnosis and openness to hypnotherapy. METHODS: A comprehensive search of English language peer reviewed journal articles from 1st January 1996-11th March 2016 was performed over 9 databases (Medline, PubMed, PsycARTICLES, CINAHL, Embase (excerpta medica), PsychInfo, Cochrane, Science citation index-expanded, Conference citation index) and a title-only search of Google scholar. 39 keyword combinations were employed: hypnosis, hypnotherapy, hypnotic, perception, beliefs, knowledge, view, opinion and understanding, in singular and plural where appropriate. A search of the bibliographies of eligible articles was undertaken. Inclusion criteria - Articles containing original data regarding the general public's attitudes towards hypnotherapy or hypnosis. Exclusion criteria - Non-therapy hypnosis (forensic, entertainment) materials and those concerned with groups likely to possess prior or professional knowledge of hypnosis, (hypnotists, clinicians and psychologists). Analysis was conducted in line with the questions. RESULTS: 31 articles were identified, covering diverse populations. Most people believe that: hypnosis is an altered state which requires collaboration to enter; once hypnotized perception changes; hypnotherapy is beneficial for psychological issues and is supportive of medical interventions; hypnosis can also enhance abilities especially memory. People are open to hypnotherapy subject to validation from the psychological or medical establishment. Similarity of opinion is more apparent than difference. CONCLUSION: Most people are positive towards hypnotherapy, and would consider its use under the right circumstances. PMID- 28619309 TI - Scalp acupuncture attenuates neurological deficits in a rat model of hemorrhagic stroke. AB - BACKGROUND: Hemorrhagic stroke accounts for approximately 15% of all stroke cases, and is associated with high morbidity and mortality. Limited human studies suggested that scalp acupuncture could facilitate functional recovery after cerebral hemorrhage. In the current study, we used an animal model of cerebral hemorrhage to examine the potential effects of scalp acupuncture. METHODS: Adult male Sprague-Dawley rats received autologous blood (50MUL) into the right caudate nucleus on the right side under pentobarbital anesthesia, and then received scalp acupuncture (DU20 through GB7 on the lesion side) or sham acupuncture (1cm to the right side of the acupoints) (n=10 per group). A group of rats receiving autologous blood into the caudate nucleus but no other intervention, as well as a group of rats receiving anesthesia but no blood injection to the brain (n=10 per group) were included as additional controls. Composite neuroscore, corner turn test, forelimb placing test, wire hang task and beam walking were used to evaluate the behavior of rats. Hematoxylin and Eosin (HE) staining was used to observe the histopathological changes. Western blot was used to detect the content of tumor necrosis factor alpha (TNF-alpha) and nuclear factor-KappaB (NFkappaB) protein expression. RESULTS: Scalp acupuncture attenuated neurological deficits (p<0.01 or <0.05 vs. sham acupuncture using a variety of behavioral tests) at 1-7days after the treatment. The brain content of TNF-alpha and NFkappaB was decreased (p<0.01 for both). CONCLUSIONS: Scalp acupuncture could improve neurological deficits in a rat model of hemorrhagic stroke. PMID- 28619310 TI - Dance for Parkinson's-The effects on whole body co-ordination during turning around. AB - OBJECTIVE: To investigate the effects of ballroom and Latin American dancing classes on turning in people with Parkinson's. DESIGN: This study employed a randomised, controlled, experimental design. SETTING: Dance classes were performed in a community dance centre in Southern England and all assessments took place a gait laboratory. PARTICIPANTS: Twenty-seven people with mild moderate Parkinson's participated. INTERVENTION: Participants were randomly allocated to receive either 20, 1-h dancing classes over 10 weeks (n=15), or a 'usual care' control group (n=12). MAIN OUTCOME MEASURE: Twelve, 180 degrees on the-spot turns to the predicted/un-predicted and preferred/un-preferred direction were analysed for each participant, using 3-dimensional motion analysis before and after the intervention period, alongside clinical measures. RESULTS: Movement of the head, pelvis, and feet during turning in people with Parkinson's are affected by dancing with tighter coupling of body segments. Significant 4-way interactions between the groups, over time and turn style, with longer latency of the head (p=0.008) and greater rotation in the pelvis (p=0.036), alongside a trend of slower movement of the first (p=0.063) and second (p=0.081) foot in controls were shown, with minimal change in dancers. All interactions were affected by the type of turn. No significant differences were found in the centre of mass displacement, turn time or clinical measures. CONCLUSION: Those who danced were better able to coordinate their axial and perpendicular segments and surprisingly became more 'en bloc' in their turning behaviour, suggesting this may be a beneficial adaptation, rather than a maladaptive result of Parkinson's, as previously suggested. PMID- 28619311 TI - Treating individuals with amputations in therapeutic massage and bodywork practice: A qualitative study. AB - INTRODUCTION: Best practices for massage therapy and bodywork (TMB) treatment of individuals with amputations are not well established. Although anecdotal observations are available, they have limited applicability for informing effective massage therapy and bodywork approaches for individuals with amputations. This study is part of a multifaceted research program seeking to establish a foundation for education and investigation of TMB for amputation related conditions/symptomology. The purpose of this study was to understand how TMB practitioners approach and treat individuals with amputations and their perceptions of outcomes. The TMB practitioner perspective is important in informing the development of a TMB practice framework for people with amputation. METHODS: The methodology of this study was informed by the phenomenological approach to qualitative inquiry. Semi-structured telephone interviews were conducted between June and September 2015, recorded and transcribed. Analysis consisted of descriptive coding and themes emerged through an iterative process. Codes and themes were discussed and verified with the research team. Participants were invited to review developed themes to indicate the extent to which results accurately encompassed their experiences as TMB practitioners. RESULTS: Twenty five community practicing, professional TMB practitioners from 16 states consented to participate and all completed one interview. Analysis identified four themes which indicated TMB practitioners: value touch and consider it a core aspect of treatment for individuals with amputations; operate under a core belief that individuals with amputations greatly benefit from TMB; and consider relief that stems from TMB to be multidimensional, including physical, mental, and emotional aspects; and, certain components of treatment approach are unique to amputation clients. CONCLUSIONS: Findings support that individuals with amputation benefit from TMB, at least from the perspective of TMB practitioners. Findings of this exploratory research identify important questions regarding approaches to treatment and potential TMB effectiveness hypotheses for amputation populations. Next steps will consider TMB approach and effects from the perspective of those with amputation(s). PMID- 28619312 TI - Pay dirt! human health depends on soil health. PMID- 28619313 TI - Reply: CHA2DS2-VASc score in the prediction of ischemic bowel disease among patients with atrial fibrillation: Insights from a nationwide cohort. PMID- 28619314 TI - Does PEDF improve atherosclerotic plaque stability by inhibiting VSMCs' apoptosis? PMID- 28619315 TI - Response to letter "Does PEDF improve atherosclerotic plaque stability by inhibiting VSMCs apoptosis". PMID- 28619316 TI - Cancer and takotsubo cardiomyopathy: More questions than answers. PMID- 28619317 TI - Reply to "Cancer and Takotsubo Cardiomyopathy: More questions than answers". PMID- 28619318 TI - The frontier of the comprehensive information of the coronary plaque together with functional assessment is at the gates. PMID- 28619319 TI - In reply to "The hard task of the anatomic characterization in improving the prognostic stratification of CAD". PMID- 28619320 TI - The hard task of the anatomic characterization in improving the prognostic stratification of CAD. PMID- 28619321 TI - Insight of forced diuresis with matched controlled hydration strategy to prevent contrast-induced acute kidney injury in patients undergoing cardiovascular intervention. PMID- 28619322 TI - Author's reply to: Insight of forced diuresis with matched controlled hydration strategy to prevent contrast-induced acute kidney injury in patients undergoing cardiovascular intervention. PMID- 28619323 TI - Assessment of isolated systolic hypertension with lower diastolic and the risk of cardiovascular disease in older adults. PMID- 28619324 TI - Treatment of systolic hypertension and low diastolic blood pressure in older adults: How low is too low?! PMID- 28619325 TI - Comment on "Aldosterone pathway blockade to prevent atrial fibrillation: A systematic review and meta-analysis" by Neefs et al. PMID- 28619326 TI - Response to "comment on "aldosterone pathway blockade to prevent atrial fibrillation: A systematic review and meta-analysis" by Neefs et al." PMID- 28619327 TI - A new technique to deal with challenging transseptal puncture. PMID- 28619328 TI - Reply to the letter to editor: "A new technique to deal with challenging transseptal puncture". PMID- 28619329 TI - Palmitoylethanolamide (PEA): A promising biomarker for coronary dysfunction in MOB individuals. PMID- 28619330 TI - The need of identifying circulating biomarkers of coronary dysfunction. PMID- 28619331 TI - Copeptin and its clinical implications in the setting of vasovagal syncope. PMID- 28619332 TI - Response to the letter to editor: Copeptin and its clinical implications in the setting of vasovagal syncope. PMID- 28619333 TI - Reply to "Physically triggered takotsubo cardiomyopathy has a worse prognosis: Potential roles of systemic inflammation and coronary slow flow phenomenon". PMID- 28619334 TI - Physically triggered takotsubo cardiomyopathy has a worse prognosis: Potential roles of systemic inflammation and coronary slow flow phenomenon. PMID- 28619335 TI - Impact of stress on Takotsubo syndrome. PMID- 28619336 TI - Assessment of current use of guideline-based medical therapy in elderly patients with heart failure. PMID- 28619337 TI - Prognostic value of left atrial size and function in adults with tetralogy of Fallot. PMID- 28619338 TI - Reply: Letter to the editor: Prognostic value of left atrial size and function in adults with tetralogy of Fallot. PMID- 28619339 TI - Kounis syndrome: A review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome: Mastocytosis and post-mortem diagnosis. PMID- 28619340 TI - In reply: Kounis syndrome: A review article on epidemiology, diagnostic findings, management and complications of allergic acute coronary syndrome: Mastocytosis and post-mortem diagnosis. PMID- 28619341 TI - Paclitaxel eluting balloon and sirolimus eluting balloon, many weapons against a common enemy: The in-stent restenosis. PMID- 28619342 TI - On parsimony and tautology in the study of acute coronary syndrome. PMID- 28619343 TI - Exhaustion is associated with poor recovery of physical performance independently of depression in ACS patients In reply to Bianchi, Schonfeld, & Laurent. PMID- 28619344 TI - Abdominal aortic aneurysm size and mortality. PMID- 28619345 TI - Dissecting the diagnosis of biventricular myocarditis. PMID- 28619346 TI - Differentiation of Takotsubo syndrome from infarct-like myocarditis. PMID- 28619347 TI - Activating transcription factor 3 in cardiac remodeling: Angel or demon? PMID- 28619348 TI - Activating Transcription 3's role in cardiac remodeling. PMID- 28619349 TI - Is flat QRS complex in lead aVL the characteristic of ventricular arrhythmias originating from the junction of the right ventricular outflow tract and tricuspid annulus? PMID- 28619350 TI - Norton score is designed for pressure ulcer risk, not for prognosis of acute myocardial infarction. PMID- 28619351 TI - Treatment for in-stent restenosis using drug-eluting balloon: Importance of procedural optimization rather than device itself. PMID- 28619352 TI - Comparison of outcomes after treatment of in-stent restenosis using newer generation drug-eluting stents versus first generation drug-eluting balloon. A balanced comparison? PMID- 28619353 TI - Comments on cardiovascular mortality - Comparing risk factor associations within couples and in the total population - The HUNT study. PMID- 28619354 TI - Reply to Letter to the editor "Comments on cardiovascular mortality - Comparing risk factor associations within couples and in the total population - The HUNT Study". PMID- 28619355 TI - Comments on CHA2DS2-VASc score in the prediction of ischemic bowel disease among patients with atrial fibrillation. PMID- 28619356 TI - Operative and 1-Year Outcomes of the Custom-Made Fenestrated Anaconda Aortic Stent Graft-A UK Multicenter Study. AB - BACKGROUND: Early and 1-year outcomes are presented for fenestrated endovascular aneurysm repair (FEVAR) of complex aortic aneurysmal disease with the custom-made Anaconda fenestrated stent graft in 101 patients. METHODS: Retrospective site reported data from the first 101 elective cases (2010-2014) from 4 UK centers were studied to evaluate patient demographics, aneurysm morphology, clinical success, and 1-year outcomes in patients undergoing fenestrated aneurysm repair with the custom-made Anaconda device. RESULTS: 101 fenestrated grafts (median age 76, 85% male) were implanted with a total of 255 fenestrations (196 renal arteries, 48 superior mesenteric artery, and 11 celiac arteries) with 3% mortality, 98.4% target vessel patency (TVP) at 30 day follow-up. Although 15 type I or III endoleaks were demonstrated at completion angiography, all 10 type Ia endoleaks resolved spontaneously. Survival by Kaplan-Meier analysis was 97% and 91% at 1 month and 1 year, respectively; with 75.8% showing reduction in abdominal aortic aneurysm diameter and only 1 patient with sac expansion. Freedom from loss of TVP was 97.6%. CONCLUSIONS: Custom-made fenestrated Anaconda devices demonstrate low procedural mortality and a high rate of technical and clinical success at 30 days and 1 year. PMID- 28619357 TI - A case of cystic type intraductal papillary neoplasm of the bile duct diagnosed by SpyGlass DS, a novel peroral cholangioscopy. PMID- 28619358 TI - Integrating a facial scan, virtual smile design, and 3D virtual patient for treatment with CAD-CAM ceramic veneers: A clinical report. AB - This clinical report describes a digital workflow using the virtual smile design approach augmented with a static 3-dimensional (3D) virtual patient with photorealistic appearance to restore maxillary central incisors by using computer aided design and computer-aided manufacturing (CAD-CAM) monolithic lithium disilicate ceramic veneers. PMID- 28619360 TI - Further delineation of COG8-CDG: A case with novel compound heterozygous mutations diagnosed by targeted exome sequencing. AB - Congenital disorders of glycosylation (CDG) are a rapidly expanding group of inherited metabolic disorders with highly variable clinical presentations caused by deficient glycosylation of proteins and/or lipids. CDG-IIh is a very rare subgroup of CDG caused by mutations in the conserved oligomeric Golgi (COG) complex gene, COG8, and so far, only two cases have been reported in the medical literature. Here, we describe an 8-year-old Korean boy with psychomotor retardation, hypotonia, failure to thrive, elevated serum liver enzymes, microcephaly, and talipes equinovarus. A liver biopsy of the patient showed only interface hepatitis with mild lobular activity, and brain magnetic resonance imaging revealed cerebellar atrophy. Compared with the previous two reported cases, our patient showed relatively mild psychomotor retardation without a seizure history. The transferrin isoelectric focusing profiles in the patient showed a CDG type II pattern with increased disialo- and trisialo-transferrin. Targeted exome sequencing was performed to screen all CDG type II-related genes, and two novel frameshift mutations were found: c.171dupG (p.Leu58Alafs*29) and c.1656dupC (p.Ala553Argfs*15) in COG8. The parents were heterozygous carriers of each variant. CDG should be included in the initial differential diagnosis for children with a suspected unknown syndrome or unclassified inherited metabolic disorder or children with diverse clinical presentations, such as psychomotor retardation, hypotonia, skeletal deformity, microcephaly, cerebellar atrophy, and unexplained transient elevated liver enzyme. PMID- 28619359 TI - Postpartum estrogen withdrawal impairs GABAergic inhibition and LTD induction in basolateral amygdala complex via down-regulation of GPR30. AB - Postpartum estrogen (E2) withdrawal is known to be a particularly vulnerable time for depressive symptoms. In this study, ovariectomized (OVX) mice were treated with co-administration of estradiol benzoate and progesterone (E2/P4) followed by administration of E2 alone (E2) and a subsequent E2 withdrawal (EW) to mimic the hormonal changes during pregnancy and postpartum. The objective of this study was to investigate the influence of E2 withdrawal after hormone-simulated pregnancy on synaptic function and plasticity in basolateral amygdala complex (BLA). In comparison to control mice, EW mice spent less time in the central portion of open-field test and open arms of elevated plus-maze. Excitatory postsynaptic potentials (EPSPs) slopes at external capsule BLA synapse were reduced in E2/P4 mice, recovered in E2-mice, and increased in EW-mice. EW-mice showed a significant increase in duration of EPSPs and paired-pulse inhibition (PPI) with multi-spike responses of EPSPs and impairment of long-term depression (LTD) induction, which were corrected by GABAAR agonist muscimol. Levels of estrogen receptor (ER) GPR30, ERalpha and ERbeta expression in BLA of EW-mice were lower than those in control mice. The bath-application of GPR30 agonist G-1 in BLA of EW-mice recovered the GABAAR-mediated inhibition and LTD indication, but ERbeta agonist DPN or ERalpha agonist PPT could not. A single BLA-injection of G-1 rather than DPN or PPT in EW-mice could partially relieve the anxiety-like behaviors. The results indicate that postpartum E2 withdrawal causes dysfunction of GABAAR-mediated inhibition in the BLA through reducing GPR30 expression, which impairs LTD induction and causes anxiety-like behaviors. PMID- 28619361 TI - alpha-lipoic acid ameliorates n-3 highly-unsaturated fatty acids induced lipid peroxidation via regulating antioxidant defenses in grass carp (Ctenopharyngodon idellus). AB - This study evaluated the protective effect of alpha-lipoic acid (LA) on n-3 highly unsaturated fatty acids (HUFAs)-induced lipid peroxidation in grass carp. The result indicated that diets with n-3 HUFAs increased the production of malondialdehyde (MDA) (P < 0.05), thereby inducing lipid peroxidation in liver and muscle of grass carp. Meanwhile, compared with control group, the hepatosomatic index (HSI) and kidney index (KI) of grass carp were markedly increased in n-3 HUFAs-only group. However, diets with LA remarkably inhibited the n-3 HUFAs-induced increase of HSI, KI, and MDA level in serum, liver and muscle (P < 0.05). Interestingly, LA also significantly elevated the ratio of total n-3 HUFAs in fatty acid composition of muscle and liver (P < 0.05). Furthermore, LA significantly promoted the activity of antioxidant enzymes in serum, muscle and liver of grass carp (P < 0.05), including superoxide dismutase (SOD), catalase (CAT), and glutathione s-transferase (GST). The further results showed that LA significantly elevated mRNA expression of antioxidant enzymes with promoting the mRNA expression of NF-E2-related nuclear factor 2 (Nrf2) and decreasing Kelch-like-ECH-associated protein 1 (Keap1) mRNA level. From the above, these results suggested that LA could attenuate n-3 HUFAs-induced lipid peroxidation, remit the toxicity of the lipid peroxidant, and protect n-3 HUFAs against lipid peroxidation to promote its deposition in fish, likely strengthening the activity of antioxidant enzymes through regulating mRNA expressions of antioxidant enzyme genes via mediating Nrf2-Keap1 signaling pathways. PMID- 28619362 TI - Peroxiredoxin 1 from cuttlefish (Sepiella maindroni): Molecular characterization of development and its immune response against Vibrio alginolyticus. AB - The aim of this work was constructive to understand the function of peroxiredoxin (PRDX) family member Peroxiredoxin 1 in Sepiella maindroni (SmPrx1) through molecular mechanisms of reproduction, embryonic development and immune responses to Vibrio alginolyticus. The full-length cDNA of SmPrx1 was of 1062 bp, contains a 5' untranslated region (UTR) of 79bp, a 3' UTR of 359 bp, an open reading frame of 624 bp encoding 207 amino acids. The conserved peroxidase catalytic center "FYPLDFTFVCPTEI" and "GEVCPA" were observed in the sequence of SmPrx1; this indicated that it was a member of 2-Cys Prx. Quantitative real-time (qRT)-PCR assays revealed that SmPrx1 was ubiquitously expressed in all examined tissues, muscle, ink sac, liver, ovary, testis, intestine, gill and totally blood cells, and showed high levels in testis. SmPrx1 mRNA was ubiquitously detected in all tested tissues, and the expression was comparatively high in testis, hemocyte, liver and ovary. Moreover, the SmPrx1 gene transcript was detected at all five stages of embryonic development phases that were respectively the zygote stage, the pre-embryonic stage, the organogenesis stage, the morphological integrity stage, the pre-hatching stage. The general tendency of expression was gradually increased and rapidly decreased. High expressed in progenitive tissues and embryonic development exhibit the proliferation-associated protein characterization like in mammal. The expression levels of SmPrx1 in liver and hemocytes grew swiftly and quickly reached peak value after Vibrio alginolyticus challenge. As hours passed by, the expression level began to reduce and resumed to normal levels after 48 h. The antioxidant activity and peroxidase activity of SmPrx1 were 6.17 U/mg. The results showed that the recombined protein of SmPrx1 had antioxidant activity and was the importance part of the antioxidant system in Sepiella maindroni. This study provides useful information to help further understand the functional mechanism of Prx 1 in marine cephalopod immunity. PMID- 28619363 TI - Acute hypoxic stress: Effect on blood parameters, antioxidant enzymes, and expression of HIF-1alpha and GLUT-1 genes in largemouth bass (Micropterus salmoides). AB - Dissolved oxygen (DO) plays a crucial role in survival, growth, and normal physiological functions of aquatic organisms. Nevertheless, the mechanisms involved in hypoxic stress and adaptation have not been fully elucidated in Largemouth bass (Micropterus salmoides). To reveal the effect of acute hypoxia on Largemouth bass, we simulated acute hypoxia (DO: 1.2 +/- 0.2 mg/L) in the laboratory and analyzed physiological parameters (RBCs, Hb, SOD, CAT, NA+/K+ ATPase, GPx, and MDA) and gene expression (HIF-1alpha and GLUT-1) in Largemouth bass exposed to various durations of acute hypoxia (0, 1, 2, 4, 8, 12, and 24 h). Our results indicated that acute hypoxic exposure significantly increased RBCs but decreased Hb. In addition, antioxidant enzyme activity was enhanced significantly in the liver and muscles at the initial stage of acute hypoxic exposure, but decreased significantly in gills during the entire process of hypoxic exposure. Furthermore, the expression levels of HIF-1alpha and GLUT-1 mRNA were significantly up-regulated in Largemouth bass under acute hypoxic exposure. In conclusion, our study provides a valuable basis for further elucidation of hypoxic adaptation and facilitates husbandry for an economically valuable species. PMID- 28619364 TI - Outcome of arterial ischemic stroke in children with heart disease. AB - : Arterial ischemic strokes (AIS) are rare in childhood. Congenital and acquired heart diseases are one of the most important risk factors of AIS in children. OBJECTIVE: Study the outcome of children with heart disease that have suffered AIS and the factors that influence on prognosis. PATIENTS AND METHODS: We evaluated all children with heart disease who had suffered AIS between 2000 and 2014 in our hospital. RESULTS: Seventy-four children with heart disease suffered an arterial ischemic stroke. 20% of them died and 10% had new AIS during the study period. Fifty-two patients were evaluated an average of six years after AIS. According to the Paediatric Stroke Outcome Scale (PSOM), most of the patients had some degree of impairment, mainly in sensorimotor and in cognitive behavioural areas. The modified Rankin scale (mRS) showed an unfavourable outcome in 70% of patients (including patients that have died). Upper limb was more functionally impaired than lower limb. Strokes in neonatal period and early life were associated with poor prognosis. Size of stroke, cortical and subcortical involvement and basal ganglia stroke were associated with an unfavourable outcome. Fever in the acute phase and hemiparesis at presentation were also poor prognostic factors. Epilepsy at time of evaluation was also associated with unfavourable outcome. On the other hand, a normal electroencephalogram was associated with favourable outcome. CONCLUSIONS: AIS in children with heart disease had an unfavourable outcome, with impairment in different areas. Epilepsy happened in one third of the patients. PMID- 28619365 TI - Aucklandia lappa DC. extract enhances gefitinib efficacy in gefitinib-resistance secondary epidermal growth factor receptor mutations. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aucklandia lappa DC. is a widely used medicinal plant in China, India and Pakistan for a long time. Previously, a number of different pharmacological experiments in vitro and in vivo have convincingly demonstrated the abilities of it to exhibit anticancer activities. Reynoutria japonica Houtt. has also been widely used as traditional Chinese medicinal plant. Previous studies have demonstrated that it is bioactive to exhibit anticancer activities. AIM OF THE STUDY: This study aims to investigate whether the extracts of Aucklandia lappa DC. and Reynoutria japonica Houtt. are capable of treating drug-resistant non-small cell lung cancer (NSCLC), providing support for novel usage beyond traditional uses. MATERIALS AND METHODS: Extracts combined with gefitinib have been tested taking the vulval development of transgenic C. elegans (jgIs25) as an effective and simple in vivo model system, evaluating their efficacy against acquired NSCLC. Synchronous larval 1 (L1) larvae were treated with extracts plus gefitinib and cultured to obtain mainly L4 larvae. The multivulva (Muv) phenotype was recorded at the adult stage. RESULTS: Our data showed that Aucklandia lappa DC. extract could significantly enhance the efficacy of gefitinib, suppressing the Muv phenotype of jgIs25. Meanwhile, it could also down-regulate the mRNA and protein expression of EGFR in jgIs25. Collectively, our results verified that the capability of Aucklandia lappa DC. to inhibit Muv phenotype may be based on the EGFR signaling pathway inhibition. CONCLUSION: We demonstrated that the co-administration of Aucklandia lappa DC. with gefitinib may provide an effective strategy for the therapy of EGFR inhibitor resistant NSCLCs. PMID- 28619366 TI - BPI-3016, a novel long-acting hGLP-1 analogue for the treatment of Type 2 diabetes mellitus. AB - Glucagon-like peptide-1 (GLP-1) analogues have been commonly used as add-on medications for patients with Type 2 diabetes mellitus (T2DM). Currently, the development of long-acting GLP-1 analogues which allow the freedom and flexibility of once-weekly injections while maintaining their potency for a relatively long period has become the mainstream. Here, we successfully developed a long-acting human GLP-1(7-37) analogue (BPI-3016) with significantly extended half-life and increased resistance to dipeptidyl peptidase IV (DPP-IV) cleavage by structural modifications of human GLP-1. In vitro activity of BPI-3016 including GLP-1 receptor affinity and stimulation of cyclic adenosine monophosphate (cAMP) production was measured. In vivo activity of BPI-3016 such as its effects on glycemic control, beta-cell mass and body weight was evaluated in ob/ob mice, db/db mice, and spontaneous diabetic cynomolgus monkeys. The results indicated that BPI-3016 preserved receptor affinity to GLP receptors, and was capable of stimulating cAMP production. In in vivo pharmacokinetic study, the half-life of BPI-3016 was more than 95h after single dosing in diabetic cynomolgus monkeys. Also, BPI-3016 reduced fasting and post-prandial plasma glucose levels for up to a week after a single dose; It reduced body mass index (BMI), body fat, improved glucose tolerance and showed insulinotropic effects after once-weekly injection for 7 weeks. In conclusion, BPI-3016 retains the effects of GLP-1 with significantly prolonged half-life, making it a promising therapy for type 2 diabetes with once-weekly treatment in the clinic. PMID- 28619368 TI - Preliminary evidence for associations between molecular markers and quantitative traits in a set of bread wheat (Triticum aestivum L.) cultivars and breeding lines. AB - The identification of polymorphic markers associated with various quantitative traits allows us to test their performance for the exploitation of the extensive quantitative variation maintained in gene banks. In the current study, a set of 97 wheat germplasm accessions including 48 cultivars and 49 breeding lines were evaluated for 18 agronomic traits. The accessions were also genotyped with 23 ISSR, nine IRAP and 20 REMAP markers, generating a total of 658 clear and scorable bands, 86% of which were polymorphic. Both neighbor-joining dendrogram and Bayesian analysis of clustering of individuals revealed that the accessions could be divided into four genetically distinct groups, indicating the presence of a population structure in current wheat germplasm. Associations between molecular markers and 18 agronomic traits were analyzed using the mixed linear model (MLM) approach. A total of 94 loci were found to be significantly associated with agronomic traits (P<=0.01). The highest number of bands significantly associated with the 18 traits varied from 11 for number of spikelets spike-1 (NSS) to two for grain yield in row (GRY). Loci ISSR16-9 and REMAP13-10 were associated with three different traits. The results of the current study provide useful information about the performance of retrotransposon based and ISSR molecular markers that could be helpful in selecting potentially elite gene bank samples for wheat-breeding programs. PMID- 28619369 TI - Mechanisms of atherosclerosis and cardiovascular disease in antiphospholipid syndrome and systemic lupus erythematosus. New therapeutic approaches. AB - Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are 2 highly related autoimmune-rheumatic diseases associated with an increased risk of developing cardiovascular (CV) diseases. Despite the great progresses made in understanding the pathological mechanisms leading to CV diseases in those pathologies, there is still the unmet need to improve long term prognosis. CV diseases in SLE and APS is thought to happen as the result of a complex interaction between traditional CV risk factors, immune deregulation and disease activity, including the synergic effect of cytokines, chemokines, adipokines, proteases, autoantibodies, adhesion receptors, oxidative stress and a plethora of intracellular signalling molecules. Genomic and epigenomic analyses have further allowed the identification of specific signatures explaining the proathero thrombotic profiles of APS and SLE patients. This review examines the complex role of these heterogeneous factors, and analyses new therapeutic approaches under study to reduce the CV risk in these autoimmune disorders. PMID- 28619370 TI - Sleep Duration and Impaired Glycemic Control. PMID- 28619371 TI - The Reply. PMID- 28619367 TI - The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. AB - The renin-angiotensin system (RAS) is undisputedly one of the most prominent endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) vasoactive systems in the physiological regulation of neural, cardiovascular, blood pressure, and kidney function. The importance of the RAS in the development and pathogenesis of cardiovascular, hypertensive and kidney diseases has now been firmly established in clinical trials and practice using renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, type 1 (AT1) angiotensin II (ANG II) receptor blockers (ARBs), or aldosterone receptor antagonists as major therapeutic drugs. The major mechanisms of actions for these RAS inhibitors or receptor blockers are mediated primarily by blocking the detrimental effects of the classic angiotensinogen/renin/ACE/ANG II/AT1/aldosterone axis. However, the RAS has expanded from this classic axis to include several other complex biochemical and physiological axes, which are derived from the metabolism of this classic axis. Currently, at least five axes of the RAS have been described, with each having its key substrate, enzyme, effector peptide, receptor, and/or downstream signaling pathways. These include the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor, the ANG II/APA/ANG III/AT2/NO/cGMP, the ANG I/ANG II/ACE2/ANG (1-7)/Mas receptor, the prorenin/renin/prorenin receptor (PRR or Atp6ap2)/MAP kinases ERK1/2/V-ATPase, and the ANG III/APN/ANG IV/IRAP/AT4 receptor axes. Since the roles and therapeutic implications of the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor axis have been extensively reviewed, this article will focus primarily on reviewing the roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases. PMID- 28619372 TI - The Reply. PMID- 28619373 TI - Blood Pressure Goals in Functionally Limited Elderly Patients. PMID- 28619374 TI - The Reply. PMID- 28619375 TI - A Child With Progressive Leg Weakness. PMID- 28619376 TI - Early Imaging and Adverse Neurodevelopmental Outcome in Asphyxiated Newborns Treated With Hypothermia. AB - BACKGROUND: Brain injury can be identified as early as day two of life in asphyxiated newborns treated with hypothermia, when using diffusion magnetic resonance imaging (MRI). However, it remains unclear whether these diffusion changes can predict future neurodevelopment. This study aimed to determine whether abnormal early diffusion changes in newborns treated with hypothermia are associated with adverse neurodevelopmental outcome at age two years. METHODS: Asphyxiated newborns treated with hypothermia were enrolled prospectively. They underwent magnetic resonance imaging (MRI) at specific time points over the first month of life, including diffusion-weighted imaging and diffusion-tensor imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured in different regions of interest. Adverse neurodevelopmental outcome was defined as cerebral palsy, global developmental delay, and/or seizure disorder around age two years. ADC and FA values were compared between the newborns developing or not developing adverse outcome. RESULTS: Twenty-nine asphyxiated newborns treated with hypothermia were included. Among the newborns developing adverse outcome, ADC values were significantly decreased on days two to three of life and increased around day ten of life in the thalamus, posterior limb of the internal capsule, and the lentiform nucleus. FA values decreased in the same regions around day 30 of life. These newborns also had increased ADC around day ten of life and around day 30 of life, and decreased FA around day 30 of life in the anterior and posterior white matter. CONCLUSIONS: Diffusion changes that were evident as early as day two of life, when the asphyxiated newborns were still treated with hypothermia, were associated with later abnormal neurodevelopmental outcome. PMID- 28619378 TI - Improving Efficiency in the Cardiac Catheterization Laboratory. PMID- 28619377 TI - Cumulative Incidence of Seizures and Epilepsy in Ten-Year-Old Children Born Before 28 Weeks' Gestation. AB - OBJECTIVE: We evaluated the incidence of seizures and epilepsy in the first decade of life among children born extremely premature (less than 28 weeks' gestation). METHOD: In a prospective, multicenter, observational study, 889 of 966 eligible children born in 2002 to 2004 were evaluated at two and ten years for neurological morbidity. Complementing questionnaire data to determine a history of seizures, all caregivers were interviewed retrospectively for postneonatal seizures using a validated seizure screen followed by a structured clinical interview by a pediatric epileptologist. A second pediatric epileptologist established an independent diagnosis based on recorded responses of the interview. A third epileptologist determined the final diagnosis when evaluators disagreed (3%). Life table survival methods were used to estimate seizure incidence through ten years. RESULTS: By age ten years, 12.2% (95% confidence interval: 9.8, 14.5) of children had experienced one or more seizures, 7.6% (95% confidence interval: 5.7, 9.5) had epilepsy, 3.2% had seizure with fever, and 1.3% had a single, unprovoked seizure. The seizure incidence increased with decreasing gestational age. In more than 75% of children with seizures, onset was after one year of age. Seizure incidence was comparable in both sexes. Two-thirds of those with epilepsy had other neurological disorders. One third of children with epilepsy were not recorded on the medical history questionnaire. SIGNIFICANCE: The incidence of epilepsy through age ten years among children born extremely premature is approximately 7- to 14-fold higher than the 0.5% to 1% lifetime incidence reported in the general pediatric population. Seizures in this population are under-recognized, and possibly underdiagnosed, by parents and providers. PMID- 28619379 TI - Visualization of the Ankle Lateral Collateral Ligament Complex. PMID- 28619380 TI - Early Intra-articular Corticosteroid Injection Improves Pain and Function in Adhesive Capsulitis of the Shoulder: 1-Year Retrospective Longitudinal Study. AB - BACKGROUND: Intra-articular corticosteroid injection is a commonly used therapy for adhesive capsulitis, but not enough studies exist on the optimal timing of the injection. OBJECTIVE: To determine whether intra-articular corticosteroid injection has better outcomes in patients with earlier stage than later stage of adhesive capsulitis. STUDY DESIGN: Retrospective longitudinal study SETTING: University-affiliated tertiary care hospital. PARTICIPANTS: Primary adhesive capsulitis patients (n=339) who were unresponsive to at least 1 month of conservative treatment and who had ultrasound-guided corticosteroid injection. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASUREMENTS: Visual analogue scale, Shoulder Pain and Disability Index, and passive range of motion (flexion, abduction, external rotation, and internal rotation and extension) were evaluated at pretreatment, month 1 and 12 after the first injection. RESULTS: The result of the multiple regressions, which considered the main and the interaction effect of confounding variables, showed that the differences of all outcomes in both short term effect at month 1 and long-term effect at month 12 are greater when the duration of pain prior to injection is shorter. Among the confounders, the injection number in the difference of internal rotation and extension between month 0 and 12 (IRE Delta(0-12)) was statistically significant. IRE Delta(0-12) was also greater when the pain duration was shorter, though the decrease in IRE Delta(0-12) differed depending on the number of injections. CONCLUSIONS: Early injection improves outcomes of adhesive capsulitis at both short- and long-term follow-ups. If pain persists despite non-invasive and conservative treatments, early injection may be considered to shorten its natural history. LEVEL OF EVIDENCE: III. PMID- 28619381 TI - Recent experimental advances for understanding bubble-particle attachment in flotation. AB - Bubble-particle interaction is of great theoretical and practical importance in flotation. Significant progress has been achieved over the past years and the process of bubble-particle collision is reasonably well understood. This, however, is not the case for bubble-particle attachment leading to three-phase contact line formation due to the difficulty in both theoretical analysis and experimental verification. For attachment, surface forces play a major role. They control the thinning and rupture of the liquid film between the bubble and the particle. The coupling between force, bubble deformation and film drainage is critical to understand the underlying mechanism responsible for bubble-particle attachment. In this review we first discuss the advances in macroscopic experimental methods for characterizing bubble-particle attachment such as induction timer and high speed visualization. Then we focus on advances in measuring the force and drainage of thin liquid films between an air bubble and a solid surface at a nanometer scale. Advances, limits, challenges, and future research opportunities are discussed. By combining atomic force microscopy and reflection interference contrast microscopy, the force, bubble deformation, and liquid film drainage can be measured simultaneously. The simultaneous measurement of the interaction force and the spatiotemporal evolution of the confined liquid film hold great promise to shed new light on flotation. PMID- 28619382 TI - Does early motion lead to a higher failure rate or better outcomes after arthroscopic rotator cuff repair? A systematic review of overlapping meta analyses. AB - BACKGROUND: The aims of the study were as follows: to perform a systematic review of meta-analyses comparing "early motion" and "delayed motion" after arthroscopic rotator cuff repair; to provide a framework to analyze the best available evidence to develop recommendations; and to identify gaps where suggestions could be made for future investigations. METHODS: Literature searches were performed to identify meta-analyses examining arthroscopic rotator cuff repair with early motion vs. delayed-motion rehabilitation protocols. Clinical data were extracted, and meta-analysis quality was assessed using the Quality of Reporting of Meta analyses and Oxman-Guyatt scales. RESULTS: Nine meta-analyses met inclusion criteria. No clear superiority was noted in clinical outcome scores for early motion or delayed-motion rehabilitation. Results of tendon healing were found to be either no different or in favor of delayed motion, but no differences were noted in rotator cuff tear recurrence rates postoperatively. The majority of meta analyses found significantly better range of motion with early motion up to a year postoperatively for forward elevation and up to 6 months for external rotation, but significant differences were not reported for functional improvements and strength at 12 months postoperatively. Subgroup analyses suggested that larger preoperative tear sizes have significantly greater retear rates with early-motion rehabilitation. CONCLUSIONS: The current highest level of evidence suggests that early-motion rehabilitation after rotator cuff repair results in superior postoperative range of motion up to 1 year. Whereas early motion and delayed motion after cuff repair may lead to comparable functional outcomes and retear rates, concern exists that early motion may result in greater retear rates, particularly with larger tear sizes. PMID- 28619383 TI - Cardiac rehabilitation and readmissions after heart transplantation. AB - BACKGROUND: Exercise-based cardiac rehabilitation (CR) is under-utilized. CR is indicated after heart transplantation, but there are no data regarding CR participation in transplant recipients. We characterized current CR utilization among heart transplant recipients in the United States and the association of CR with 1-year readmissions using the 2013-2014 Medicare files. METHODS: The study population included Medicare beneficiaries enrolled due to disability (patients on the transplant list are eligible for disability benefits under Medicare regulations) or age >=65 years. We identified heart transplant patients by diagnosis codes and cumulative CR sessions occurring within 1 year after the transplant hospitalization. RESULTS: There were 2,531 heart transplant patients in the USA in 2013, of whom 595 (24%) received Medicare coverage and were included in the study. CR utilization was low, with 326 patients (55%) participating in CR programs. The Midwest had the highest proportion of transplant recipients initiating CR (68%, p = 0.001). Patients initiating CR attended a mean of 26.7 (standard deviation 13.3) sessions, less than the generally prescribed program of 36 sessions. Transplant recipients age 35 to 49 years were less likely to initiate CR (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.23 to 0.66, p < 0.001) and attended 8.2 fewer sessions (95% CI 3.5 to 12.9, p < 0.001) than patients age >=65 years. CR participation was associated with a 29% lower 1-year readmission risk (95% CI 13% to 42%, p = 0.001). CONCLUSIONS: Only half of cardiac transplant recipients participate in CR, and those who do have a lower 1-year readmission risk. These data invite further study on barriers to CR in this population. PMID- 28619384 TI - Risk stratification to determine the impact of induction therapy on survival, rejection and adverse events after pediatric heart transplant: A multi institutional study. AB - BACKGROUND: Induction therapy is increasingly being used in pediatric heart transplantation. General versus risk-adapted use remains controversial. We aimed to determine the impact of induction therapy on outcomes after stratifying patients by diagnosis and risk. METHODS: The Pediatric Heart Transplant Study (PHTS) database was used to identify patients (age <=18 years) who underwent transplantation between January 1, 2001 and December 31, 2014. Patients were excluded if they survived <48 hours or received multiple induction agents. Patients were stratified using a multivariable model to predict 1-year mortality. Patients within the top 25% risk of predicted mortality were defined as high risk (HR) and the bottom 75% as low risk (LR). RESULTS: Of the 2,860 patients studied, 1,370 received anti-lymphocyte antibody (ALA), 707 received an interleukin-2 receptor antagonist (IL-2RA) and 783 received no induction (NI) therapy. Overall, patients with NI had lower survival (p < 0.01); however, multivariable analysis did not demonstrate an association with graft loss. Freedom from rejection was greater among LR congenital heart disease (CHD) and all cardiomyopathy (CMP) patients who received induction therapy (p < 0.01, for both), as confirmed in a multivariable analysis for CMP patients. Frequency of graft vasculopathy was higher in LR CMP patients who received NI. Freedom from infection was lower with IL-2RA in the LR groups. CONCLUSIONS: Pediatric heart transplant survival has improved in the recent era, in concert with increased use of induction therapy. Although induction therapy is associated with decreased rejection, it was not found to directly influence survival on multivariable analysis. Lower risk patients may benefit the most from induction therapy, particularly IL-2RA, which may be correlated with decreased infection and rejection in this cohort. PMID- 28619385 TI - Rectum and bladder spacing in cervical cancer brachytherapy using a novel injectable hydrogel compound. AB - PURPOSE: The aim of this study was to evaluate injection of a novel hydrogel (TraceIT; Augmenix, Waltham, MA) between the cervix, rectum, and bladder in female cadavers compared with, and in addition to, the current standard of gauze packing, for organ-at-risk sparing in cervical cancer brachytherapy planning. METHODS AND MATERIALS: This brachytherapy cadaver study used T2-weighted MRI and CT imaging to compare three scenarios: (1) gauze packing alone, (2) hydrogel injection placed in the cervical fornices and rectovaginal septum, and (3) gauze packing in conjunction with hydrogel injection. Hydrogel distribution was evaluated. Doses to 2 cm3 volumes (D2cc) for the rectum, bladder, and sigmoid were collected. Statistical significance (p < 0.05) was evaluated using a two tailed paired t test. RESULTS: Hydrogel was successfully injected to space the bladder and rectum from the cervix in all five cadavers. The spacer was easily identifiable on both CT and MRI. The use of hydrogel in addition to packing resulted in a 22% decrease in rectum D2cc dose (p = 0.02), a 10% decrease in bladder D2cc (p = 0.27), and no change in sigmoid D2cc dose. No difference was observed between hydrogel only vs. gauze packing only. CONCLUSIONS: Our results revealed a significant clinically meaningful decrease in rectal D2cc associated with the use of hydrogel in addition to gauze packing-TraceIT hydrogel holds promise as a spacer in cervical cancer therapy. PMID- 28619386 TI - A novel 17beta-hydroxysteroid dehydrogenase in Rhodococcus sp. P14 for transforming 17beta-estradiol to estrone. AB - 17beta-hydroxysteroid dehydrogenases (17beta-HSD) are a group of oxidoreductase enzymes that exhibit high specificity for 17C reduction/oxidation. However, the mechanism of 17beta-HSD in oxidizing steroid hormone 17beta-estradiol to estrone in bacterium is still unclear. In this work, a functional bacterium Rhodococcus sp. P14 was identified having rapid ability to oxidize estradiol into estrone in mineral salt medium (MSM) within 6 h. The functional genes encoding NADH dependent oxidoreductase were successfully detected with the help of bioinformatics, and it was identified that it contained two consensus regions affiliated to the short-chain dehydrogenase/reductase (SDR) superfamily. Expression of 17beta-HSD could be induced by estradiol in strain P14. The 17beta HSD gene from Rhodococcus sp. P14 was expressed in Escherichia coli strain BL21. Furthermore, recombinant 17beta-HSD-expressing BL21 cells showed a high transformation rate, they are capable of transforming estradiol to estrone up to 94%. The purified His-17beta-HSD protein also exhibited high catalyzing efficiency. In conclusion, this study provides the first evidence that a novel 17beta-HSD in Rhodococcus sp. P14 can catalyze the oxidation of estradiol. PMID- 28619388 TI - Metabolomics highlights pharmacological bioactivity and biochemical mechanism of traditional Chinese medicine. AB - Traditional Chinese medicine (TCM) has attracted increasing interest throughout the world because of its potential complementary therapy and an abundant source for new drug discovery. TCM possesses the significant bioactivity of the use of multi-component drugs and can act multiple targets by multiple components. Metabolomics is a holistic investigation of numerous metabolite responses of complex biology systems to pathological stimuli and drug treatments based on the global metabolic profiles in complex biological matrixes. It provides variation of systematic metabolic networks for characterizing pathological states in animal models and clinical studies. In agreement with the holistic thinking of TCM, metabolomics has shown potential in bioactivity evaluation and action mechanism of TCM as well as pharmaceutical research and development. Recently, different metabolomic technologies have been applied to the modernization of TCM and treatments of different diseases such as cardiovascular disease, kidney disease, liver disease and metabolic disease. Based on the reported literature, this paper introduced the application of metabolomics in efficacy evaluation of TCM and its biochemical action mechanism. PMID- 28619387 TI - Evaluation of ameliorative ability of Silibinin against zidovudine and isoniazid induced hepatotoxicity and hyperlipidaemia in rats: Role of Silibinin in Phase I and II drug metabolism. AB - HIV/AIDS patients have suppressed immune system, making them vulnerable to many opportunistic infections including tuberculosis (TB). The patients who are co infected with TB undergo combined regimens with anti-retroviral drugs such as zidovudine (AZT) and anti-tubercular drug such as isoniazid (INH) for therapy leading to hepatotoxicty. Silibinin (SBN), extracted from Silybum marianum commonly called as "Milk thistle" is used against several drugs-induced hepatotoxicity. The present study evaluates the ameliorative effect of SBN against AZT alone, INH alone, and INH + AZT-induced toxic insults to liver of rats. Wistar albino rats (n = 6/groups) were given INH and AZT (25 and 50 mg mg/kg b.w.) respectively either alone or in combination for a sub-chronic period of 45 days orally. Another group of rats received SBN (100 mg/kg b.w.) along with INH and AZT. The group that received propylene glycol served as control. AZT alone, INH alone and INH + AZT treatments showed parenchymal cell injury and cholestasis by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin and protein. The presence of hyperlipidaemia was observed by analyzing lipid profiles in serum/liver/adipose tissue, gene expression (RT-PCR) of Phase-I and II metabolizing enzymes and western blot. Transmission electron microscopy study also revealed large vacuoles with membraneous debri, pleomorphic mitochondria, disruption of endoplasmic reticulum, presence of lipid droplets, breakage in cellular and nuclear membrane. SBN simultaneous treatment showed ameliorative effect against INH + AZT-induced hepatotoxicity and hyperlipidemia in rats. PMID- 28619389 TI - The promising effect of linagliptin and/or indole-3-carbinol on experimentally induced polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) is one of the most common medical conditions that lead to female infertility worldwide. The aim of this study was to assess the effect of linagliptin and/or indole-3-carbinol (I3C) on PCOS in female rats. Fifty female Wistar rats were randomly allocated into five equal groups: Control group; Letrozole-induced PCOS group; Letrozole + Linagliptin group; Letrozole + I3C group and Letrozole + Linagliptin + I3C group. Body weight, body mass index, Lee index and ovarian indices were determined. Plasma levels of luteinizing hormone (LH), free testosterone, estradiol, progesterone, prolactin, fasting blood glucose (FBG) and fasting plasma insulin were measured. Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated. Tissue antioxidant status, transforming growth factor beta 1 (TGF-beta1), tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10) and Nrf2/HO-1 content were assessed. Histopathological and immunohistochemical examination of the ovaries were done. Linagliptin and/or I3C induced significant decrease in tissue TGF-beta1, TNF alpha, IL-10, plasma free testosterone, luteinizing hormone, progesterone, estradiol, FBG and insulin levels associated with significant improvement of insulin resistance whereas tissue Nrf2/HO-1 content and antioxidant enzymes were significantly increased compared to PCOS group. In addition, final body weight, final body mass and Lee indices were significantly decreased compared to PCOS group. Also, there was significant improvement of the ovarian morphology compared to PCOS group. This improvement was significant with linagliptin/I3C combination compared to the use of each of these drugs alone. In conclusion, linagliptin/I3C combination might represent a beneficial therapeutic modality for amelioration of PCOS. PMID- 28619390 TI - The Effect of Massage on Acute Postoperative Pain in Critically and Acutely Ill Adults Post-thoracic Surgery: Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - Critical care practice guidelines identify a lack of clear evidence on the effectiveness of massage for pain control. To assess the effect of massage on acute pain in critically and acutely ill adults post-thoracic surgery. Medline, Embase, CINAHL, PsychInfo, Web of Science, Scopus and Cochrane Library databases were searched. Eligible studies were randomized controlled trials (RCTs) evaluating the effect of massage compared to attention control/sham massage or standard care alone on acute pain intensity post-thoracic surgery. Twelve RCTs were included. Of these, nine evaluated massage in addition to standard analgesia, including 2 that compared massage to attention control/sham massage in the intensive care unit (ICU), 6 that compared massage to standard analgesia alone early post-ICU discharge, and 1 that compared massage to both attention control and standard care in the ICU. Patients receiving massage with analgesia reported less pain (0-10 scale) compared to attention control/sham massage (3 RCTs; N = 462; mean difference -0.80, 95% confidence interval [CI] -1.25 to 0.35; p < 0.001; I2 = 13%) and standard care (7 RCTs; N = 1087; mean difference 0.85, 95% CI -1.28 to -0.42; p < 0.001; I2 = 70%). Massage, in addition to pharmacological analgesia, reduces acute post-cardiac surgery pain intensity. PMID- 28619391 TI - Pharmacists' attitudes regarding provision of sexual and reproductive health services. AB - OBJECTIVES: The primary objective was to assess attitudes from Ohio pharmacists about contraceptive authority. Secondary objectives included determining pharmacists' perceptions of benefits, barriers, and preparedness for offering such services and examining attitudes about and experiences with other reproductive health topics to inform future research. METHODS: An anonymous 26 question Institutional Review Board-approved electronic survey was developed and distributed via Qualtrics to a random sample of 500 licensed pharmacists in Ohio. Two months were allotted for survey completion. A link to free Accreditation Council for Pharmacy Education-approved continuing pharmacy education (CPE) through Ohio Northern University was offered as an incentive for completing the survey. RESULTS: One hundred thirty-eight pharmacists completed the survey (62% female). Fifty-eight percent worked in community pharmacy and 34% in health system pharmacy. The majority indicated that oral and transdermal contraceptive methods should be pharmacist-initiated (57% and 54%, respectively) through a collaborative practice agreement or statewide protocol. More pharmacists supported provision of hormonal contraception through a collaborative practice agreement rather than a statewide protocol. Increased access to care and convenience for patients were identified most frequently as potential benefits. Time constraints, concerns of increased liability, and other barriers for initiating such services were identified by pharmacists. Pharmacists most frequently listed clinical guidelines, CPE, and patient education materials as tools needed to successfully initiate contraceptive therapy regimens. Pharmacists responding to the survey were also proponents of increasing involvement in other aspects of sexual and reproductive health, such as expedited partner therapy (64%) and human papilloma virus vaccination (67%). Respondents indicated a potential lack of experience or training in topics such as expedited partner therapy and intimate partner violence. CONCLUSION: Pharmacists surveyed showed interest in providing sexual and reproductive health services, including pharmacist-provided prescription contraceptive products and preventive health services. Further studies are needed to evaluate pharmacists' roles in other sexual and reproductive health services. PMID- 28619392 TI - Platelet satellitism in autoimmune hemolytic anemia. AB - Platelet satellitism is a rare phenomenon observed in blood smears obtained from blood anticoagulated with EDTA with an estimated frequency at 0.008%. It is characterized by platelet rosetting around neutrophils and in rare cases around other blood cells, which may causes pseudothrombocytopenia. Our case involves a 26-year-old female patient with autoimmune hemolytic anemia (AIHA). Blood smear with EDTA as an anticoagulant had platelet satellitism whereas the phenomenon was not observed in tubes with different anticoagulants (citrate, heparin) and capillary blood. This phenomenon was still observed four weeks after the patient's discharge. Furthermore, we discuss the possible pathophysiological mechanisms of platelet satellitism proposed in the literature. To our knowledge, this is the first case of platelet satellitism reported in AIHA. PMID- 28619393 TI - Advanced oxidation protein products and their relationship with cardiovascular risk factors in young apparently healthy people. AB - INTRODUCTION: Advanced oxidation protein products (AOPPs) are used as a marker to estimate oxidative stress in plasma proteins. Oxidative stress is considered a factor of cardiovascular risk (CVRF) related to increased blood pressure, and dyslipidaemia. The aim of this study was to evaluate the association between plasma AOPPs and CVRF in apparently healthy young adults. METHODS: A prospective cross-sectional study was conducted on 120 students of the Faculty of Chemical Pharmacobiology of the UMSNH. Body mass index (BMI) and blood pressure were determined. A blood specimen was also collected to quantify AOPPs, glucose, total cholesterol, lipoproteins (high, low, and very low density), and triglycerides. RESULTS: Differences were observed in the groups with and without CVRF, with significant differences in BMI, waist, body fat (P<.05), and lipid profile (P<.0001). AOPPs were higher in the group of young people with three and four CVRF (F: 4.651; P=.002). A negatively correlation was found between AOPPs and LDL cholesterol (r=-0.364; P=.0001). CONCLUSIONS: It was observed that AOPPs concentrations are increased as CVRF increase in young adults. Thus, this could be considered an important risk factor, because their deposition in the atherosclerotic plaque favours the atherogenic process, and thus the development of cardiovascular disease. Quantification of AOPPs contributes to the indirect determination of oxidative status in the body. The study of metabolic and oxidative state of apparently healthy young adults is important in the prevention of cardiovascular disease in later life. More longitudinal studies are required to study its evolution. PMID- 28619394 TI - Understanding real-world adherence in the directly acting antiviral era: A prospective evaluation of adherence among people with a history of drug use at a community-based program in Toronto, Canada. AB - BACKGROUND: Direct acting antiviral (DAA) treatments for Hepatitis C (HCV) are now widely available with sustained virologic response (SVR) rates of >90%. A major predictor of response to DAAs is adherence, yet few real-world studies evaluating adherence among marginalized people who use drugs and/or alcohol exist. This study evaluates patterns and factors associated with non-adherence among marginalized people with a history of drug use who were receiving care through a primary care, community-based HCV treatment program where opiate substitution is not offered on-site. METHODS: Prospective evaluation of chronic HCV patients initiating DAA treatment. Self-report medication adherence questionnaires were completed weekly. Pre/post treatment questionnaires examined socio-demographics, program engagement and substance use. Missing adherence data was counted as a missed dose. RESULTS: Of the 74 participants, who initiated treatment, 76% were male, the average age was 54 years, 69% reported income from disability benefits, 30% did not have stable housing and only 24% received opiate substitution therapy. Substance use was common in the month prior to treatment initiation with, 11% reported injection drug use, 30% reported non-injection drug use and 18% moderate to heavy alcohol use. The majority (85%) were treatment naive, with 76% receiving sofosbuvir/ledipasvir (8-24 weeks) and 22% Sofosbuvir/Ribarvin (12-24 weeks). The intention to treat proportion with SVR12 was 87% (60/69). In a modified ITT analysis (excluding those with undetectable RNA at end of treatment), 91% (60/66) achieved SVR12. Overall, 89% of treatment weeks had no missed doses. 41% of participants had at least one missed dose. In multivariate analysis the only factor independently associated with weeks with missed doses was moderate to heavy alcohol use (p=0.05). CONCLUSION: This study demonstrates that strong adherence and SVR with DAAs is achievable, with appropriate supports, even in the context of substance use, and complex health/social issues. PMID- 28619395 TI - The new front in the war on doping: Amateur athletes. AB - The war on drugs is usually associated with criminal policies aimed at stemming consumption of drugs such as heroin, cocaine, and cannabis, less so with enhancement drugs like those used in sport. As drug use in sport, or doping, has become more visibly widespread, policies aimed at combating the issue have become more restrictive, intrusive, and harsh. In this article we draw new comparisons between the wider war on drugs and recent developments in sports anti-doping. We identify a growing trend towards criminalisation of traffickers and users, and associate that with another growing trend: the testing of amateur athletes. This article reviews the current anti-doping system, including the recent amateur policies, then considers of the results of one such program in amateur cycling. We then shift to consider the possible implications for amateurs of criminal doping laws and the recent debates about allowing medical exemptions for therapeutic use of banned substances. We show that drug use in sport can be understood as a new front in the war on drugs, with some extreme measures and many negative unintended consequences. To remedy this, we argue that amateur athletes require a separate anti-doping policy focused on minimising harms of use. PMID- 28619396 TI - Robot-assisted Laparoscopic Implantation of Brachytherapy Catheters in Bladder Cancer. AB - BACKGROUND: Robot-assisted laparoscopic (RAL) implantation of brachytherapy catheters (BTCs) can be a minimally invasive alternative to open retropubic implantation. Descriptions of the surgical technique and outcomes are sparse. OBJECTIVE: To describe our technique and perioperative outcomes for RAL BTC implantation in urothelial carcinoma (UC) and urachal carcinoma (UraC). DESIGN, SETTING AND PARTICIPANTS: Between June 2011 and May 2016, 26 patients with cN0M0 solitary T1G3 or T2G1-3 UC of <=5cm or cN0M0 UraC were scheduled for external beam radiotherapy (20*2Gy), RAL BTC implantation, and pulsed-dose (29*1.04Gy) or high-dose rate brachytherapy (10*2.50Gy). Median follow-up was 12 mo (interquartile range 4-20). SURGICAL PROCEDURE: RAL BTC implantation with or without pelvic lymph node dissection and/or partial cystectomy. MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative data, complications, disease-free-survival (DFS), local recurrence-free survival (LRFS), and cystectomy-free survival (CFS) were evaluated as well as the feasibility of the technique. RESULTS AND LIMITATIONS: BTC implantation was successful in 92% of the patients. Median hospitalisation was 5 d (interquartile range 4-7) and blood loss <50ml in all cases. DFS was 74% at 1 yr and 63% at 2 yr. LRFS was 80% at 1 and 2 yr, and CFS was 87% at 1 and 2 yr. Early (<=30 d) high-grade complications (Clavien-Dindo >=3) occurred in 8% of the patients. The study is limited by the small sample size and short follow-up time. CONCLUSIONS: RAL BTC implantation is technically feasible and could serve as safe, minimally invasive alternative to open surgery in selected patients. The results of this study should be confirmed in larger studies. PATIENT SUMMARY: Brachytherapy catheter (BTC) implantation is traditionally carried out via open retropubic surgery. We describe robot-assisted laparoscopic BTC implantation as a minimally invasive alternative. Perioperative outcomes are described and confirm the safety and feasibility of this procedure. PMID- 28619397 TI - Development of Environmental Health Indicators for the Child Population: Report on a Brazilian Experience. AB - BACKGROUND: This report presents the Brazilian experience on the elaboration of a matrix of children's environmental health indicators to the Brazilian Health Surveillance System. This experience was part of a project with the financial support of the Ministry of Health of Brazil to develop appropriate indicators for identification, measuring, and monitoring of the environmental risk factors to the children's health. METHODS: The methodology adopted for the development of the matrix of indicators of children's environmental health to Brazil comprised 3 steps. In the first step, the main causes of morbidity and mortality in the Brazilian population, aged 0-14 years, were identified, according to the data available from the Ministry of Health. The second step consisted of the identification of the Brazilian public-access information systems, with available official data regarding environmental, health, and socioeconomic conditions. In the third step, a preliminary matrix was elaborated. Correlation analyses were done to determine the indicators that would constitute the final matrix. FINDINGS: The selected indicators allowed the identification and surveillance of cancer, injuries, adverse birth outcomes, diarrheic and respiratory diseases, associated with environmental risk factors, in the Brazilian child population. The existing Brazilian official information systems provided data with the necessary quality for the construction of children's environmental health indicators. Nevertheless, some official systems on health information presented limitations related to the data availability over the course of time and timeliness of data capture. Concerning the environmental information, the major limitation was accessibility. CONCLUSIONS: A matrix of indicators of children's environmental health to Brazil can come to contribute to the implementation of a surveillance system of children's exposure to environmental contaminants in Brazil. PMID- 28619398 TI - Global Burden of Disease of Mercury Used in Artisanal Small-Scale Gold Mining. AB - BACKGROUND: Artisanal small-scale gold mining (ASGM) is the world's largest anthropogenic source of mercury emission. Gold miners are highly exposed to metallic mercury and suffer occupational mercury intoxication. The global disease burden as a result of this exposure is largely unknown because the informal character of ASGM restricts the availability of reliable data. OBJECTIVE: To estimate the prevalence of occupational mercury intoxication and the disability adjusted life years (DALYs) attributable to chronic metallic mercury vapor intoxication (CMMVI) among ASGM gold miners globally and in selected countries. METHODS: Estimates of the number of artisanal small-scale gold (ASG) miners were extracted from reviews supplemented by a literature search. Prevalence of moderate CMMVI among miners was determined by compiling a dataset of available studies that assessed frequency of intoxication in gold miners using a standardized diagnostic tool and biomonitoring data on mercury in urine. Severe cases of CMMVI were not included because it was assumed that these persons can no longer be employed as miners. Cases in workers' families and communities were not considered. Years lived with disability as a result of CMMVI among ASG miners were quantified by multiplying the number of prevalent cases of CMMVI by the appropriate disability weight. No deaths are expected to result from CMMVI and therefore years of life lost were not calculated. Disease burden was calculated by multiplying the prevalence rate with the number of miners for each country and the disability weight. Sensitivity analyses were performed using different assumptions on the number of miners and the intoxication prevalence rate. FINDINGS: Globally, 14-19 million workers are employed as ASG miners. Based on human biomonitoring data, between 25% and 33% of these miners-3.3-6.5 million miners globally-suffer from moderate CMMVI. The resulting global burden of disease is estimated to range from 1.22 (uncertainty interval [UI] 0.87-1.61) to 2.39 (UI 1.69-3.14) million DALYs. CONCLUSIONS: This study presents the first global and country-based estimates of disease burden caused by mercury intoxication in ASGM. Data availability and quality limit the results, and the total disease burden is likely undercounted. Despite these limitations, the data clearly indicate that mercury intoxication in ASG miners is a major, largely neglected global health problem. PMID- 28619400 TI - A Standard of Care. PMID- 28619399 TI - Rural-Urban Differences in Trends in the Wealth Index in Kenya: 1993-2009. AB - BACKGROUND: The aim of this study was to construct a wealth index that could be compared over time in order to understand the trends in wealth in Kenya and determine predictors of change in wealth index. METHODS: Data were from the Demographic and Health Survey program collected in Kenya between 1993 and 2009. Variable categories were collapsed to match and factor analysis was performed on the 4-year pooled data to generate a harmonized wealth index. Possible predictors of wealth were selected from household variables available for all 4 years. Household sampling weights and stratification by rural/urban was used. RESULTS: Overall, wealth increased in Kenya between 1993 and 2008; however, when stratified, no significant increase existed in urban areas and a significant increase was identified in rural areas specifically between 2003 and 2008. The strongest predictor was education, with more than a standard deviation difference for secondary or higher levels of education over those with no education. The association of gender of the head of household and whether the head of household had a partner differed between rural and urban areas, with household heads who were women and those who had a partner having more wealth in urban areas but less wealth in rural areas. CONCLUSION: Wealth in Kenya increased over time, specifically in rural regions. Differences were identified in predictors of wealth by urban/rural residence, educational level, and gender of the head of household and should be taken into account when planning interventions to target those in disproportionately low wealth brackets. PMID- 28619401 TI - Assessment of Surgical and Trauma Capacity in Potosi, Bolivia. AB - BACKGROUND: Scaling up surgical and trauma care in low- and middle-income countries could prevent nearly 2 million annual deaths. Various survey instruments exist to measure surgical and trauma capacity, including Personnel, Infrastructure, Procedures, Equipment, and Supplies (PIPES) and International Assessment of Capacity for Trauma (INTACT). OBJECTIVE: We sought to evaluate surgical and trauma capacity in the Bolivian department of Potosi using a combined PIPES and INTACT tool, with additional questions to further inform intervention targets. METHODS: In June and July 2014 a combined PIPES and INTACT survey was administered to 20 government facilities in Potosi with a minimum of 1 operating room: 2 third-level, 10 second-level, and 8 first-level facilities. A surgeon, head physician, director, or obstetrician-gynecologist completed the survey. Additional personnel responded to 4 short-answer questions. Survey items were divided into subsections, and PIPES and INTACT indices calculated. Medians were compared via Wilcoxon rank sum and Kruskal-Wallis tests. FINDINGS: Six of 20 facilities were located in the capital city and designated urban. Urban establishments had higher median PIPES (8.5 vs 6.7, P = .11) and INTACT (8.5 vs 6.9, P = .16) indices compared with rural. More than half of surgeons and anesthesiologists worked in urban hospitals. Urban facilities had higher median infrastructure and procedure scores compared with rural. Fifty-three individuals completed short-answer questions. Training was most desired in laparoscopic surgery and trauma management; less than half of establishments reported staff with trauma training. CONCLUSIONS: Surgical and trauma capacity in Potosi was most limited in personnel, infrastructure, and procedures at rural facilities, with greater personnel deficiencies than previously reported. Interventions should focus on increasing the number of surgical and anesthesia personnel in rural areas, with a particular focus on the reported desire for trauma management training. Results have been made available to key stakeholders in Potosi to inform targeted quality improvement interventions. PMID- 28619402 TI - Global Health Values of a Multidirectional Near Peer Training Program in Surgery, Pathology, Anatomy, Research Methodology, and Medical Education for Haitian, Rwandan, and Canadian Medical Students. AB - BACKGROUND: As health care delivery increasingly requires providers to cross international borders, medical students at McGill University, Canada, developed a multidirectional exchange program with Haiti and Rwanda. The program integrates surgery, pathology, anatomy, research methodology, and medical education. OBJECTIVE: The aim of the present study was to explore the global health value of this international training program to improve medical education within the environment of developing countries, such as Haiti and Rwanda, while improving sociocultural learning of Canadian students. METHODS: Students from the University of Kigali, Rwanda and Universite Quisqueya, Haiti, participated in a 3 week program at McGill University. The students spanned from the first to sixth year of their respective medical training. The program consisted of anatomy dissections, surgical simulations, clinical pathology shadowing, and interactive sessions in research methodology and medical education. To evaluate the program, a survey was administered to students using a mixed methodology approach. FINDINGS: Common benefits pointed out by the participants included personal and professional growth. The exchange improved career development, sense of responsibility toward one's own community, teaching skills, and sociocultural awareness. The participants all agreed that the anatomy dissections improved their knowledge of anatomy and would make them more comfortable teaching the material when the returned to their university. The clinical simulation activities and shadowing experiences allowed them to integrate the different disciplines. However, the students all felt the research component had too little time devoted to it and that the knowledge presented was beyond their educational level. CONCLUSION: The development of an integrated international program in surgery, pathology, anatomy, research methodology, and medical education provided medical students with an opportunity to learn about differences in health care and medical education between the 3 countries. This exchange demonstrated that a crosscultural near-peer teaching environment can be an effective and sustainable method of medical student-centered development in global health. PMID- 28619403 TI - Practice, Knowledge, and Barriers for Screening of Hepatocellular Carcinoma Among High-Risk Chinese Patients. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is among the leading causes of cancer deaths in China. Considering its poor prognosis when diagnosed late, Chinese guidelines recommend biannual screening for HCC with abdominal ultrasound and serum alpha-fetoprotein (AFP) test for high-risk populations. OBJECTIVES: To investigate the practice, knowledge, and self-perceived barriers for HCC screening among high-risk hospital patients in China. METHODS: An interview-based questionnaire was conducted among Chinese patients with chronic hepatitis B and/or chronic hepatitis C infection from outpatient clinics at 2 tertiary medical institutions in Shanghai and Wuhan, China. FINDINGS: Among 352 participating patients, 50.0% had routine screening, 23.3% had irregular screening, and 26.7% had incomplete or no screening. Significant determinants for screening included higher level of education, underlying liver cirrhosis, a family history of HCC, and better knowledge concerning viral hepatitis, HCC, and HCC screening guidelines. Moreover, factors associated with better knowledge were younger age, female gender, urban residency, education level of college or above, annual household income of greater than 150,000 RMB, and longer duration of hepatitis infection. The 3 most common barriers reported for not receiving screening were not aware that screening for HCC exists (41.5%), no symptoms or discomfort (38.3%), and lack of recommendation from physicians (31.9%). CONLUSIONS: Health care professionals and community leaders should actively inform patients regarding the benefits of HCC screening through design of educational programs. Such interventions are expected to increase knowledge about HCC and HCC screening, as well as improve screening adherence and earlier diagnosis. PMID- 28619404 TI - Prevalence of Pediatric Asthma Risk in Santo Domingo, Dominican Republic. AB - BACKGROUND: Early detection and treatment of pediatric asthma could reduce morbidity and lessen burden on society. Currently there is no known research on the prevalence of pediatric asthma in the Dominican Republic (DR) and no known asthma risk assessment tool for one-time encounters in a fast-paced clinic. OBJECTIVES: To pilot a streamlined version of previously validated screening tools to estimate the prevalence of pediatric asthma risk in Santo Domingo Norte, DR. METHODS: A combined asthma questionnaire and clinical assessment tool was developed and administered to patients aged 2-12 years. FINDINGS: We found that 25.7% of the 74 study participants were categorized as probable asthma, 21.6% were at high risk for asthma, 14.9% elevated risk, and 37.8% not at risk. CONCLUSION: If the prevalence of 25.7% is representative of the DR as a whole, the DR would have one of the highest national rates in Latin America. The study assessment tool was convenient to use, but tool validation is needed. PMID- 28619405 TI - Treating Childhood Malnutrition in Rural Haiti: Program Outcomes and Obstacles. AB - BACKGROUND: Haiti has the worst malnutrition rate in the Western hemisphere. In October 2010, a cholera epidemic erupted and spread rapidly throughout the country, straining Haiti's already fragile health infrastructure across all levels of care. This study reviews data from an outpatient therapeutic feeding program (OTP) for acute childhood malnutrition at a clinic in rural Haiti with a focus on the effect of the 2010 cholera epidemic on program operations. METHODS: A retrospective chart review was conducted for the complete set of patients who were enrolled in the OTP from its inception in March 2009 through January 2014. FINDINGS: A total of 187 charts were retrieved representing 176 unique patients, of whom 5 were currently enrolled in care. At admission, 96 (51.3%) met criteria for severe acute malnutrition, 88 (47.1%) met criteria for moderate acute malnutrition, and 3 (1.6%) did not meet criteria for acute malnutrition. Of the 182 completed charts, 119 (65.4%) reached their target weight (>=-1 weight-for height z-score) by discharge (ie, were "cured"), 43 (23.6%) defaulted, 11 (6.0%) were discharged prematurely, 8 (4.4%) died, and 1 (0.5%) was hospitalized. A total of 11 patients (6.3%) who were initially admitted relapsed after discharge and were later readmitted. Data from 170 complete records (93.4%) were included in a multivariate logistic regression. Severe (vs moderate) acute malnutrition was negatively associated with likelihood of being cured when controlling for other patient- and care-related factors (OR = 0.261, P = .002). Average cholera burden was negatively correlated with likelihood of OTP treatment cure when controlling for patient- and care-related variables (OR = 0.859, P = .002) but was insignificant when controlling for year. CONCLUSIONS: Results from the study have been used to inform a restructuring of the clinic's acute malnutrition program toward a more community-centered model of management, the context and implications of which are discussed in relation to the existing literature. PMID- 28619407 TI - Should They Also Have Babies? Community Attitudes Toward Sexual and Reproductive Rights of People Living With HIV/AIDS in Nigeria. AB - BACKGROUND: People living with HIV have the right to healthy, satisfying sex lives and to appropriate services to ensure their sexual and reproductive health, including having healthy children. The reproductive rights of people living with HIV/AIDS are, however, often met with skepticism and discrimination, despite recent advances in HIV treatment. OBJECTIVE: To assess the attitudes of community members in Kano, Nigeria, toward the right of persons living with HIV/AIDS to have healthy sexual relationships and bear children. METHODS: A cross-section of 399 adults was interviewed using pretested structured questionnaires. Logistic regression analysis was used to obtain adjusted estimates for predictors of agreement with the rights of persons with HIV/AIDS to bear children. FINDINGS: A substantial proportion of respondents (28.6%) strongly agreed and agreed (10.5%) that persons with HIV/AIDS should not be allowed to marry. More than a fifth of the respondents disagreed (16.0%) and strongly disagreed (8.0%) with the rights of HIV-infected persons to bear children. Agreement with the statement "HIV infected persons should have biological children" was independently associated with higher educational status (adjusted odds ratio: 2.26, 95% confidence interval: 1.82-6.73) and awareness of prevention of mother-to-child HIV transmission effectiveness (adjusted odds ratio: 2.53, 95% confidence interval: 1.92-5.37). Of those who agreed that HIV-infected persons should have children (n = 253), 17.8% and 26.1% strongly agreed and agreed, respectively, that persons living with HIV/AIDS should be restricted to having fewer children. Further, 11.5% and 4.8% of respondents disagreed and strongly disagreed, respectively, that infertile HIV-infected couples should receive fertility treatment. CONCLUSIONS: People living with HIV/AIDS face discriminatory attitudes to their reproductive rights in northern Nigeria. There is a need for effective, culturally appropriate information, education, and communication approaches to improving community perceptions of sexual and reproductive rights of people living with HIV/AIDS. PMID- 28619406 TI - Physical Activity, Sleep, and BMI Percentile in Rural and Urban Ugandan Youth. AB - BACKGROUND: Uganda is experiencing a dual burden of over- and undernutrition, with overweight prevalence increasing while underweight remains common. Potential weight-related factors, particularly physical activity, sleep, and rural/urban status, are not currently well understood or commonly assessed in Ugandan youth. OBJECTIVE: The purpose of this study was to pilot test a survey measuring weight related factors in rural and urban Ugandan schoolchildren. METHODS: A cross sectional survey measured sociodemographics, physical activity, sleep patterns, and dietary factors in 148 rural and urban schoolchildren aged 11-16 in central Uganda. Height and weight were objectively measured. Rural and urban youth were compared on these factors using chi2 and t tests. Regression was used to identify correlates of higher body mass index (BMI) percentile in the full sample and nonstunted youth. FINDINGS: Youth were on average 12.1 +/- 1.1 years old; underweight (10%) was more common than overweight (1.4%). Self-reported sleep duration and subjective sleep quality did not differ by rural/urban residence. Rural children overall had higher BMI percentile and marginally higher stunting prevalence. In adjusted analyses in both the full and nonstunted samples, higher BMI percentile was related to living in a rural area, higher frequency of physical activity, and higher subjective sleep quality; it was negatively related to being active on weekends. In the full sample, higher BMI percentile was also related to female gender, whereas in nonstunted youth, higher BMI was related to age. BMI percentile was unrelated to sedentary time, performance of active chores and sports, and dietary factors. CONCLUSIONS: This study is one of the first to pilot test a survey assessing weight-related factors, particularly physical activity and sleep, in Ugandan schoolchildren. BMI percentile was related to several sociodemographic, sleep, and physical activity factors among primarily normal-weight school children in Uganda, providing a basis for understanding weight status in the context of the nutrition transition. PMID- 28619408 TI - Children Crossing Streets: The Cognitive Task of Pedestrians Across Nations. AB - BACKGROUND: About 100,000 children die worldwide in pedestrian crashes, more than 90% of whom live in low- and middle-income countries (LMICs). However, most existing research on children's ability to cross the street is conducted in high income countries (HICs). OBJECTIVE: The present study discusses 4 ways pedestrian behavior in LMICs differs from that in HICs, influencing both children's ability to cross streets safely and adult efforts to train children in pedestrian safety. FINDINGS: First, in many LMICs one cannot simply wait for a traffic gap that is large enough to permit crossing at a typical walking pace. Instead, pedestrians must enter traffic gaps they deem large enough to permit the oncoming driver to stop, slow, or swerve around them. Second, decisions in LMICs must be made very quickly to maximize safety. In many cases, pedestrians must anticipate how oncoming drivers will behave as a crossing is initiated. Third, multilane LMIC crossings sometimes involve separated decisions to cross each lane and then evaluate safety in the middle of the roadway rather than making a single decision to cross the entire span within a safe traffic gap. Last, children's short stature may substantially influence behavior in LMIC settings. When gaps are small and open spaces limited, the ability to see over oncoming vehicles and perceive them approaching, including how spread they are and at what speeds they are traveling, offers a distinct advantage to the taller pedestrian CONCLUSIONS: Taken together, it is concluded that safe child pedestrian engagement in LMICs is more complex, and may require more developed cognitive skill, than safe child pedestrian engagement in HICs. PMID- 28619409 TI - Student Reflection Papers on a Global Clinical Experience: A Qualitative Study. AB - BACKGROUND: Many of the 70,000 graduating US medical students [per year] have reported participating in a global health activity at some stage of medical school. This case study design provided a method for understanding the student's experience that included student's learning about culture, health disparities, exposure and reaction to a range of diseases actually encountered. The broad diversity of themes among students indicated that the GCE provided a flexible, personalized experience. We need to understand the student's experience in order to help design appropriate curricular experiences [and valid student assessment]. OBJECTIVE: Our research aim was to analyze medical student reflection papers to understand how they viewed their Global Clinical Experience (GCE). METHODS: A qualitative case study design was used to analyze student reflection papers. All 28 students who participated in a GCE from 2008-2010 and in 2014-2015 and submitted a reflection paper on completion of the GCE were eligible to participate in the study. One student did not submit a reflection paper and was not included in the study. FINDINGS: All 27 papers were coded by paragraph for reflection and for themes. System of Care/Range of Care was mentioned most often, Aids to Adjustment Process was mentioned least. The theme, "Diseases," referred to any mention of a disease in the reflection papers, and 44 diseases were mentioned in the papers. The analysis for depth of reflection yielded the following data: Observation, 81/248 paragraphs; Observation and Interpretation, 130/248 paragraphs; and Observation, Interpretation, and Suggestions for change, 36/248 paragraphs; 9 reflection papers contained 27 separate accounts of a transformational experience. CONCLUSIONS: This study provided a method for understanding the student's experience that included student's learning about culture, health disparities, and exposure and reaction to a range of diseases actually encountered. The broad diversity of themes among students indicated that the GCE provided a flexible, personalized experience. How we might design a curriculum to facilitate transformational learning experiences needs further research. PMID- 28619410 TI - An International Collaboration for the Training of Medical Chief Residents in Rwanda. AB - BACKGROUND: The year-long position of chief medical resident is a time-honored tradition in the United States that serves to provide the trainee with an opportunity to gain further skills as a clinician, leader, teacher, liaison, and administrator. However, in most training programs in the developing world, this role does not exist. OBJECTIVES: We sought to develop a collaborative program to train the first medical chief residents for the University of Rwanda and to assess the impact of the new chief residency on residency training, using questionnaires and qualitative interviews with Rwandan faculty, chief residents, and residents. METHODS: The educational context and the process leading up to the appointment of Rwandan chief residents, including selection, job description, and necessary training (in the United States and Rwanda), are described. One year after implementation, we used a parallel, mixed methods approach to evaluate the new chief medical resident program through resident surveys as well as semistructured interviews with key informants, including site chief residents, chief residents, and faculty. We also observed chief residents and site chief residents at work and convened focus groups with postgraduate residents to yield additional qualitative information. RESULTS: Rwandan faculty and residents generally felt that the new position had improved the educational and administrative structure of the teaching program while providing a training ground for future academicians. CONCLUSIONS: A collaborative training program between developing and developed world academic institutions provides an efficient model for the development of a new chief residency program in the developing world. PMID- 28619411 TI - Where We Fall Down: Tensions in Teaching Social Medicine and Global Health. AB - BACKGROUND: As global health interest has risen, so too has the relevance of education on the social determinants of health and health equity. Social medicine offers a particularly salient framework for educating on the social determinants of health, health disparities, and health equity. SocMed and EqualHealth, 2 unique but related organizations, offer annual global health courses in Uganda, Haiti, and the United States, which train students to understand and respond to the social determinants of health through praxis, self-reflection and self awareness, and building collaborative partnerships across difference. OBJECTIVES: The aim of this paper is to describe an innovative pedagogical approach to teaching social medicine and global health. We draw on the notion of praxis, which illuminates the value of iterative reflection and action, to critically examine our points of weakness as educators in order to derive lessons with broad applicability for those engaged in global health work. METHODS: The data for this paper were collected through an autoethnography of teaching 10 global health social medicine courses in Uganda and Haiti since 2010. It draws on revealing descriptions from participant observation, student feedback collected in anonymous course evaluations, and ongoing relationships with alumni. FINDINGS: Critical analysis reveals 3 significant and complicated tensions raised by our courses. The first point of weakness pertains to issues of course ownership by North American outsiders. The second tension emerges from explicit acknowledgment of social and economic inequities among our students and faculty. Finally, there are ongoing challenges of sustaining positive momentum toward social change after transformative course experiences. CONCLUSIONS: Although successful in generating transformative learning experiences, these courses expose significant fracture points worth interrogating as educators, activists, and global health practitioners. Ultimately, we have identified a need for building equitable partnerships and intentional community, embracing discomfort, and moving beyond reflection to praxis in global health education. PMID- 28619412 TI - Ethical Considerations When Sending Medical Trainees Abroad for Global Health Experiences. PMID- 28619413 TI - Visiting Trainees in Global Settings: Host and Partner Perspectives on Desirable Competencies. AB - BACKGROUND: Current competencies in global health education largely reflect perspectives from high-income countries (HICs). Consequently, there has been underrepresentation of the voices and perspectives of partners in low- and middle income countries (LMICs) who supervise and mentor trainees engaged in short-term experiences in global health (STEGH). OBJECTIVE: The objective of this study was to better understand the competencies and learning objectives that are considered a priority from the perspective of partners in LMICs. METHODS: A review of current interprofessional global health competencies was performed to design a web-based survey instrument in English and Spanish. Survey data were collected from a global convenience sample. Data underwent descriptive statistical analysis and logistic regression. FINDINGS: The survey was completed by 170 individuals; 132 in English and 38 in Spanish. More than 85% of respondents rated cultural awareness and respectful conduct while on a STEGH as important. None of the respondents said trainees arrive as independent practitioners to fill health care gaps. Of 109 respondents, 65 (60%) reported that trainees gaining fluency in the local language was not important. CONCLUSIONS: This study found different levels of agreement between partners across economic regions of the world when compared with existing global health competencies. By gaining insight into host partners' perceptions of desired competencies, global health education programs in LMICs can be more collaboratively and ethically designed to meet the priorities, needs, and expectations of those stakeholders. This study begins to shift the paradigm of global health education program design by encouraging North-South/East-West shared agenda setting, mutual respect, empowerment, and true collaboration. PMID- 28619414 TI - Health Information Needs and Reliability of Sources Among Nondegree Health Sciences Students: A Prerequisite for Designing eHealth Literacy. AB - BACKGROUND: Understanding health information needs and health-seeking behavior is a prerequisite for developing an electronic health information literacy (EHIL) or eHealth literacy program for nondegree health sciences students. At present, interest in researching health information needs and reliable sources paradigms has gained momentum in many countries. However, most studies focus on health professionals and students in higher education institutions. OBJECTIVE: The present study was aimed at providing new insight and filling the existing gap by examining health information needs and reliability of sources among nondegree health sciences students in Tanzania. METHOD: A cross-sectional study was conducted in 15 conveniently selected health training institutions, where 403 health sciences students were participated. Thirty health sciences students were both purposely and conveniently chosen from each health-training institution. The selected students were pursuing nursing and midwifery, clinical medicine, dentistry, environmental health sciences, pharmacy, and medical laboratory sciences courses. Involved students were either in their first year, second year, or third year of study. RESULTS: Health sciences students' health information needs focus on their educational requirements, clinical practice, and personal information. They use print, human, and electronic health information. They lack eHealth research skills in navigating health information resources and have insufficient facilities for accessing eHealth information, a lack of specialists in health information, high costs for subscription electronic information, and unawareness of the availability of free Internet and other online health-related databases. CONCLUSION: This study found that nondegree health sciences students have limited skills in EHIL. Thus, designing and incorporating EHIL skills programs into the curriculum of nondegree health sciences students is vital. EHIL is a requirement common to all health settings, learning environments, and levels of study. Our future intention is to design EHIL to support nondegree health sciences students to retrieve and use available health information resources on the Internet. PMID- 28619415 TI - International Travelers' Sociodemographic, Health, and Travel Characteristics: An Italian Study. AB - BACKGROUND: Approximately the 8% of travelers requires medical care, with the diagnosis of a vaccine-preventable disease. The aim of our study was to analyze the socio-demographic, health and travel characteristics of the Italian international travelers. METHODS: We conducted a cross sectional study from January 2015 to June 2016, at the Travel Medicine Clinic of Siena, asking the doctor to interview patients who attended the Clinic, recording socio-demographic and travel information, malaria prophylaxis, vaccinations. The data were organized in a database and processed by software Stata(r). RESULTS: We collected 419 questionnaires. Patients chose 71 countries for their travels; the favorite destinations were: India (6.31%), Thailand (6.31%), and Brazil (5.10%). The mean length of stay was 36.17 days. Italians, students, and freelancers tended to stay abroad for a longer time (mean: 36.4 days, 59.87 days and 64.16 days respectively). 33.17% of our sample used drugs for malaria chemoprophylaxis: 71.9% of them used Atovaquone/Proguanil (Malarone(r)), 26.6% used Mefloquine (Lariam(r)), 1.5% other drugs. The vaccinations that travelers mostly got in our study were to prevent hepatitis A (n = 264), the typhoid fever (n = 187), the Tetanus + Diphtheria + Pertussis (n = 165), the Yellow fever (n = 118) and the cholera (n = 78). Twenty-eight (6.68%) refused some recommended vaccinations. The vaccines mostly refused were for Typhoid fever (n = 20), hepatitis a (n = 9), and cholera (n = 9). CONCLUSION: Our results demonstrated that Italian international travelers are at-risk because of their poor vaccinations adherence. This implies that pre-travel counseling is fundamental to increase the knowledge of the risks and the compliance of future travelers. PMID- 28619416 TI - Mass Gatherings and Public Health: Case Studies from the Hajj to Mecca. AB - BACKGROUND: Many new and challenging risks can be introduced during mass gatherings. The Hajj, as one of the largest mass gatherings, provides an excellent annual opportunity to reflect on the public health risk posed by international and multicultural crowds and the value of mitigation strategies. OBJECTIVES: To identify the gap between preparation and training taken before being exposed to the mass gathering and postexposure experiences, and the breach between the expectations and reality of the holy place. METHODS: This was a qualitative study with in-depth interviews using semistructured questionnaires among Hajjis from 4 different countries (Bangladesh, Pakistan, Myanmar, and New Zealand). Purposive sampling was done. The present study was also supported by literature review. FINDINGS: Findings pointed to weaknesses in implementation and enforcement of law, for both the custodian country and countries of origin of Hajjis. Disparities among developed and developing countries were also noticeable. CONCLUSIONS: From a global health and human security perspective, strengthening of core capacities in managing mass gatherings as well as researching risks posed by such gatherings are paramount to safeguard the public's health. Attention of health professionals worldwide and adoption of strategic planning at custodian country and sending countries are obligatory. PMID- 28619417 TI - Point-of-Care Testing for Anemia, Diabetes, and Hypertension: A Pharmacy-Based Model in Lima, Peru. AB - BACKGROUND: Prevention and control of chronic diseases is a high priority for many low- and middle-income countries. This study evaluated the feasibility and acceptability of training pharmacy workers to provide point-of-care testing for 3 chronic diseases-hypertension, diabetes, and anemia-to improve disease detection and awareness through private pharmacies. METHODS: We developed a multiphase training curriculum for pharmacists and pharmacy technicians to build capacity for identification of risk factors, patient education, point-of-care testing, and referral for abnormal results. We conducted a pre-post evaluation with participants and evaluated results using Student t test for proportions. We conducted point-of-care testing with pharmacy clients and evaluated acceptability by patient characteristics (age, gender, and type of patient) using multiple logistic regression. RESULTS: In total, 72 pharmacy workers (66%) completed the full training curriculum. Pretest scores indicated that pharmacists had more knowledge and skills in chronic disease risk factors, patient education, and testing than pharmacy technicians. All participants improved their knowledge and skills after the training, and post-test scores indicated that pharmacy technicians achieved the same level of competency as pharmacists (P < .01). Additionally, 698 clients received at least 1 test during the study; 53% completed the acceptability survey. Nearly 100% thought the pharmacy could provide faster results, faster and better attention, and better access to basic screening for hypertension, diabetes, and anemia than a traditional health center. Fast service was very important: 41% ranked faster results and 30% ranked faster attention as the most important factor for receiving diagnostic testing in the pharmacy. DISCUSSION: We found that it is both feasible for pharmacies and acceptable to clients to train pharmacy workers to provide point-of-care testing for anemia, diabetes, and hypertension. This innovative approach holds potential to increase early detection of risk factors and bolster disease prevention and management efforts in Peru and other low- and middle-income settings. PMID- 28619418 TI - Corrigendum to "There's No App for That: Assessing the Impact of mHealth on the Supervision, Motivation, Engagement, and Satisfaction of Community Health Workers in Sierra Leone" [Annals of Global Health 82 (2016) 936-949]. PMID- 28619419 TI - Usefulness of scintigraphy with labelled leucocytes and SPECT/CT in vascular graft infection. AB - Vascular graft infections are a rare complication in this type of procedure. However, when they do occur, they usually have high morbidity, and even a high mortality. Proper identification and location is crucial for the appropriate and early management, whether medical or surgical, thus knowledge of the right tools is paramount. Nuclear medicine studies play an important role in this regard, either by using labelled white blood cells scintigraphy or 18F-FDG. The choice, among other factors, will depend on the experience with both techniques by the different groups, their knowledge of them, as well as their availability. Two cases are presented in which 99mTc-HMPAO-white blood cells SPECT/CT scintigraphy was very useful in the diagnosis and location of the suspected infectious compromise, which led to the subsequent appropriate and guided management. Both cases were confirmed clinically and microbiologically. PMID- 28619420 TI - Study of factors that influence the outcome of 131I treatment in hyperthyroidism secondary to nodular goitre. AB - OBJECTIVE: To assess the outcome after 131I treatment in patients with multinodular (MNG) and nodular toxic goitre (NTG) according to the administered dose and other factors related to the patient, pathology, or previous treatments. MATERIAL AND METHODS: A retrospective study was conducted on 108 patients (67 MNG and 41 NTG) treated in our department, with a follow-up period of at least 2 years. Development of hypothyroidism and treatment failure were evaluated along with their relationship with the administered dose and other factors such as age, sex, grade of hyperthyroidism, type of goitre, presence of autoimmunity, or previous antithyroid medication. RESULTS: More than one-third (36.9%) of MNG patients, and even higher proportion of NTG patients (51.2%) developed non transient hypothyroidism, particularly in those receiving 740MBq (66.7%). No relationship was found with any other variable. The development of early hypothyroidism (before one year) was also not related to any variable. Treatment failure was not related to the dose, but in MNG there was a relationship with male gender, presence of autoimmunity, or previous antithyroid drugs use. CONCLUSIONS: The high rate of hypothyroidism obtained with high doses of 131I in hyperthyroidism secondary to nodular goitre treatment suggests that lower doses might be sufficient to control the disease without an increase in treatment failures. Only patients with positive autoimmunity, in previous anti-thyroid medication, and perhaps male gender in MNG might be given higher doses, as the failure rate increases, but further studies are required. PMID- 28619421 TI - The protective role of maternal posttraumatic growth and cognitive trauma processing among Palestinian mothers and infants. AB - War survivors use multiple cognitive and emotional processes to protect their mental health from the negative impacts of trauma. Because mothers and infants may be especially vulnerable to trauma in conditions of war, it is urgent to determine which cognitive and emotional processes are effective for preventing negative trauma impacts." This study examined whether mothers' high posttraumatic growth (PTG) and positive posttraumatic cognitions (PTC) protected (a) their own mental health and (b) their infants' stress regulation and sensorimotor and language development from the effects of war trauma. The participants were 511 Palestinian mothers and their infants living in the Gaza strip. The mothers were interviewed in their second trimester of pregnancy (T1) as well as when the infant was four months (T2) and twelve months (T3). Mothers reported posttraumatic growth (PTG; Tedeschi & Calhoun, 1996) at T1 and posttraumatic cognitions (PTCI; Foa et al., 1999) at T2. They also reported their exposure to traumatic war events both at T1 and T3 and described their mental health conditions (e.g., PTSD and/or depressive and dissociation symptoms) at T3. The Infant Behaviour Questionnaire (IBQ) was used to measure infants' stress regulation at T2 and sensorimotor and language development at T3. The results, based on regression analyses with interaction terms between trauma and PTG, showed that high levels of traumatic war events were not associated with high levels of PTSD, depressive, or dissociation symptoms among mothers showing high levels of PTG. This suggests that PTG may protect maternal mental health from the effects of trauma. In turn, positive maternal PTCs appeared to protect the infants' stress regulation from the effects of war trauma. The study concludes by discussing ways to develop and implement preventive interventions for mother infant dyads in war conditions. PMID- 28619422 TI - Joint engagement in infants and its relationship to their visual impairment measurements. AB - Coordination of attention between a social partner and an external focus of shared interest, called joint engagement, is associated with positive developmental outcomes such as better language, socio-emotional, and theory of mind skills in sighted infants. Current measures of joint engagement rely on an infant's visual behaviors, making it difficult to study joint engagement in infants with low or no vision. In a naturalistic observational study, 20 infants with various levels of visual impairments - mean ages: 1.08 years (N=9) and 1.62 years (N=18), were videotaped during 30-min free play sessions with their caregivers. Seven infants were tested at both ages. Videos were coded to determine the percentage of time the dyads participated in joint engagement. Results showed that all visually impaired infants participated in joint engagement, with a significant increase between earlier and later ages. Infants' visual impairment levels were described in terms of visual acuity and contrast sensitivity as measured using both visual evoked potential and preferential looking techniques. Of the visual measurements, infants' reduction in contrast sensitivity measured with preferential looking, alone, predicted the infants' percentage of time in joint engagement across ages. Contrary to prior research that exclusively focused on visual acuity, this finding supports the need to include contrast sensitivity measurements in studies with visually impaired infants. PMID- 28619423 TI - Acute respiratory distress syndrome following alemtuzumab therapy for relapsing multiple sclerosis. AB - We present the case of a 54 year old woman with known relapsing-remitting multiple sclerosis who presented with acute respiratory deterioration five weeks after a first course of alemtuzumab. Imaging showed bilateral ground glass changes and extensive investigations confirmed chest infection with dual pathogens - Pneumocystis jirovecii and Cytomegalovirus. She responded to standard anti-PJP and CMV therapy and was discharged on oral prophylaxis. Opportunistic infections in the weeks immediately following alemtuzumab therapy remain an uncommon complication but one that requires clinical vigilance, careful monitoring and appropriate prophylactic therapy. PMID- 28619424 TI - Cerebrospinal fluid and serum levels of interleukin-8 in patients with multiple sclerosis and its correlation with Q-albumin. AB - INTRODUCTION: Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS). Autoimmune inflammation is common in the early stages of MS and is followed by neurodegenerative processes. The result of these changes is axon and myelin breakdown. The paraclinical examination methods are an important part of the diagnostic process. Magnetic resonance imaging of the brain and the cervical spinal cord and an examination of cerebrospinal fluid (CSF) are common paraclinical examinations. An increasing number of studies deal with CSF and serum levels of biomarkers and their role in MS. We hypothesized that the level of interleukin-8 (IL-8) could be different in MS patients than in controls. These differences may be related to damage of the blood-brain barrier (BBB). BBB damage is quantified by the quotient of albumin (Q-alb). METHODS: CSF and serum levels of IL-8 were assessed in 102 patients with newly diagnosed MS meeting McDonald's revised diagnostic criteria and in 102 subjects as a control group. We then correlated these results with Q-alb. RESULTS: Levels of IL-8 in CSF were significantly higher in MS patients than in controls (Mann-Whitney U test, p<0.0001). Serum levels of IL-8 were significantly lower in MS patients than in controls (Mann-Whitney U test, p=0.018). Spearman's correlation analysis proved a significant correlation between levels of IL-8 and Q-alb. CONCLUSION: As the etiology of MS is only partially known, research dealing with biomarkers in MS should continue. Better knowledge of etiology can provide a new perspective, especially for treatment. PMID- 28619425 TI - Using endogenous saccades to characterize fatigue in multiple sclerosis. AB - PURPOSE: Multiple Sclerosis (MS) is likely to cause dysfunction of neural circuits between brain regions increasing brain working load or a subjective overestimation of such working load leading to fatigue symptoms. The aim of this study was to investigate if saccades can reveal the effect of fatigue in patients with MS. METHODS: Patients diagnosed with MS (EDSS<=3) and age matched controls were recruited. Eye movements were monitored using an infrared eyetracker. Each participant performed 40 trials in an endogenous generated saccade paradigm (valid and invalid trials). The fatigue severity scale (FSS) was used to assess the severity of fatigue. FSS scores were used to define two subgroups, the MS fatigue group (score above normal range) and the MS non-fatigue. Differences between groups were tested using linear mixed models. RESULTS: Thirty-one MS patients and equal number of controls participated in this study. FSS scores were above the normal range in 11 patients. Differences in saccade latency were found according to group (p<0.001) and trial validity (p=0.023). Differences were 16.9ms, between MS fatigue and MS non-fatigue, 15.5ms between MS fatigue and control. The mean difference between valid and invalid trials was 7.5ms. Differences in saccade peak velocity were found according to group (p<0.001), the difference between MS fatigue and control was 22.3 degrees /s and between MS fatigue and non-fatigue was 12.3 degrees /s. Group was a statistically significant predictor for amplitude (p<0.001). FSS scores were correlated with peak velocity (p=0.028) and amplitude (p=0.019). CONCLUSION: Consistent with the initial hypothesis, our study revealed altered saccade latency, peak velocity and amplitude in patients with fatigue symptoms. Eye movement testing can complement the standard inventories when investigating fatigue because they do not share similar limitations. Our findings contribute to the understanding of functional changes induced by MS and might be useful for clinical trials and treatment decisions. PMID- 28619426 TI - Hospitalization is associated with subsequent disability in multiple sclerosis. AB - BACKGROUND: Although an increasing amount of research has evaluated interactions between MS and comorbid chronic disease, few data exist regarding the interactions between MS and acute illness. As compared to age and sex-matched persons without MS, persons with MS experience higher rates of hospitalization and critical illness, and higher mortality rates and health care utilization following critical illness. We aimed to determine whether acute illness requiring hospitalization is associated with progression of multiple sclerosis (MS). METHODS: We conducted this population-based, retrospective cohort study by linking data from the regional MS Clinic in Calgary, Canada with the Canadian Discharge Abstract Database to identify non-obstetric hospitalizations. We included individuals with a confirmed diagnosis of MS, at least one recorded Expanded Disability Status Scale (EDSS) measurement, and known age of symptom onset of age 10 years or older. Using data from 2009 to 2014, we used generalized linear models with generalized estimating equations to establish the association within individuals between hospitalization and the time course of MS-related disability (as measured by the EDSS), adjusting for sex, age, disease course at onset, and use of disease-modifying therapies. RESULTS: We included 2104 individuals with MS in the analysis, who had a median of 4 EDSS measurements each. Of these 491 (23.3%) had at least one hospitalization. Most subjects were female, with a relapsing disease course at onset, and a mean (SD) age at symptom onset of 33.0 (10.0) years. The underlying rate of disability progression averaged 0.9 EDSS points per decade. Following hospitalization, there was a step increase in EDSS, averaging 0.23 points, equivalent to 2.5 years of time-related disease progression. Hospitalization did not alter the subsequent temporal rate of disability progression. The findings did not differ in those hospitalized for MS versus other reasons. CONCLUSIONS: Acute illness requiring hospitalization is associated with a worsening of MS-related disability. PMID- 28619427 TI - Soluble CD40 ligand derived from serum is not correlated with early MS. AB - BACKGROUND: Soluble CD40 ligand (sCD154) is a proinflammatory and prothrombotic ligand belonging to the tumor necrosis factor family. It has been shown by a variety of studies that sCD154 is elevated in the serum of patients afflicted with system autoimmune diseases. The aim of our study was to address whether sCD154 is increased in disease affected by Multiple Sclerosis (MS). METHODS: Twenty MS patients who have been newly diagnosed as clinically definite multiple sclerosis (CDMS) along with twenty age and sex matched healthy individuals were recruited for this study. Serum cCD154 was measured by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: The results showed no statistically meaningful difference between newly diagnosed MS patients (3.07ng/ul+/-0.66) and control group (2.95ng/ul+/-0.79; p=0.62) CONCLUSION: Regarding our study, it seems that soluble CD40 ligand derived from serum is not correlated with early stage of MS disease. PMID- 28619428 TI - Neuromyelitis optica presenting with horner syndrome: A case report and review of literature. AB - Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system that predominantly affects the spinal cord and optic nerves. We describe a 19 years old woman with left Horner syndrome (HS), who was diagnosed as NMO with characteristic longitudinally extensive myelitis and positive serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Our report describes one of the very rare ocular motor symptoms in NMO patients. PMID- 28619429 TI - Vitamin D and multiple sclerosis: An update. AB - The most recent findings linking exposure to sun and vitamin D insufficiency to multiple sclerosis (MS) are reviewed. Due to insufficient sunshine and changing lifestyles, hypovitaminosis D is widespread in temperate countries. Numerous epidemiological studies have strongly suggested that sunshine and vitamin D insufficiency contributes to MS risk in these countries. Moreover, several large genetic studies in MS patients have recently stated unequivocally that diverse abnormalities involving vitamin D metabolism are related to the risk of the disease. The important implications of such results are discussed here. Then, the interactions of hypovitaminosis D with the other genetic and environmental protective and risk factors, such as the allele HLA DRB1*1501, Epstein-Barr virus infection, obesity, smoking and sexual hormones, are summarized. Vitamin D insufficiency and sufficiency could be a risk and a protective factor, respectively, among many other factors possibly continuously modulating the global MS risk from the mother's pregnancy to the triggering of MS in adulthood. However, many interactions between these different factors occur more particularly between conception and the end of adolescence, which corresponds to the period of maturation of the immune system and thymus and may be related to the dysimmune nature of the disease. The main mechanisms of action of vitamin D in MS appear to be immunomodulatory, involving the various categories of T and B lymphocytes in the general immune system, but neuroprotector and neurotrophic mechanisms could also be exerted at the central nervous system level. Furthermore, several controlled immunological studies performed in MS patients have recently confirmed that vitamin D supplementation has multiple beneficial immunomodulatory effects. However, there is still an enduring absence of major conclusive randomized clinical trials testing vitamin D supplementation in MS patients because of the quasi-insurmountable practical difficulties that exist nowadays in conducting and completing over several years such studies involving the use of a vitamin. Nevertheless, it should be noted that similar robust statistical models used in five different association studies have already predicted a favorable vitamin D effect reducing relapses by 50-70%. If there is now little doubt that vitamin D exerts a beneficial action on the inflammatory component of MS, the results are as yet much less clear for the progressive degenerative component. Lastly, until more information becomes available, vitamin D supplementation of MS patients, using a moderate physiological dose essentially correcting their vitamin insufficiency, is recommended. PMID- 28619430 TI - Effect of fingolimod (FTY720) on choroidal thickness in patients with multiple sclerosis. AB - OBJECTIVE: Using spectral domain optical coherence tomography (SD-OCT), to compare the choroidal thickness in a healthy population (group 1), with newly diagnosed multiple sclerosis (MS) patients (group 2), with MS patients who underwent beta-interferon monotherapy (group 3) and MS patients who underwent fingolimod therapy for 1 year (group 4) METHODS: Twenty-five control subjects (25 eyes), 24 newly diagnosed (24 eyes) MS patients, 22 MS patients who underwent fingolimod monotherapy for 1 year (22 eyes), and 24 MS patients who underwent beta-interferon monotherapy for 1 year (24 eyes) were included in this study. The control group consisted of age- and gender-matched healthy individuals. The choroidal thickness measurements were performed using a high-speed and high resolution SD-OCT device. The choroidal thickness measurements were compared using a One Way Anova and Post-Hoc Tukey test. RESULTS: Ninety-five eyes of 95 participants were included in this study. The mean age of the control group was 27.83+/-4.60, and it was 26.83+/-6.79, 27.87+/-6. 46 and 27.58+/-6.65 in the newly diagnosed MS group, fingolimod group and beta-interferon group, respectively. In fingolimod group N-1000, N-1500 and T-1500 was significantly lower than control group. (p=0.026, p=0.06 p=0.13) CONCLUSION: Choroidal thickness values at N-1000, N-1500 and T-1500 levels in fingolimod group were found lower than in control but higher than in newly diagnosed MS group. This result can be explained with the therapeutic effect of the fingolimod on MS. PMID- 28619431 TI - Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis. AB - BACKGROUND: Multiple sclerosis (MS) is often considered to be a CD4, T cell mediated disease. This is largely based on the capacity of CD4 T cells to induce relapsing experimental autoimmune encephalomyelitis (EAE) in rodents. However, CD4-depletion using a monoclonal antibody was considered unsuccessful and relapsing MS responds well to B cell depletion via CD20 B cell depleting antibodies. The influence of CD20 B cell depletion in relapsing EAE was assessed. METHODS: Relapsing EAE was induced in Biozzi ABH mice. These were treated with CD20-specific (18B12) antibody and the influence on CD45RA-B220 B cell depletion and clinical course was analysed. RESULTS: Relapsing EAE in Biozzi ABH failed to respond to the marked B cell depletion induced with a CD20-specific antibody. In contrast to CD20 and CD8-specific antibodies, CD4 T cell depletion inhibited EAE. CONCLUSION: Spinal cord antigen-induced disease in ABH mice is CD4 T cell dependent. The lack of influence of CD20 B cell depletion in relapsing EAE, coupled with the relatively marginal and inconsistent results obtained in other mouse studies, suggests that rodents may have limited value in understanding the mechanism occurring following CD20 B cell depletion in humans. PMID- 28619432 TI - Computerized posturography is more sensitive than clinical Romberg Test in detecting postural control impairment in minimally impaired Multiple Sclerosis patients. AB - Balance impairment, frequent in Multiple Sclerosis patients (MS), is difficult to detect promptly with routine clinical examination. Computerized platforms can measure subtle deficit but, given the complexity of postural system, multiple tests should be adopted. To evaluate whether platform was more sensitive than Romberg Test (RT) in detecting balance abnormalities, we 1) chose a battery of posturographic tests, 2) collected normative data from 58 healthy subjects 3) applied the tests to Clinically Isolated Syndrome (n=42) and minimally impaired MS (n=76). Subjects underwent 3 trials of quiet standing with eyes open and closed (modified Clinical Test of Sensory Interaction on Balance, mCTSIB) and 4 trials of voluntary anterior and lateral maximal leaning on right and left sides (Limits of Stability, LOS), giving 10 postural indexes. For every subject, the best trials were selected for subsequent analysis. Normative values were established in a range from 1st to 99th percentile, defining balance impairment by the presence of at least 2 indexes out of range. Even adopting the above mentioned strict definition of balance impairment, the forceplate resulted more sensitive than RT, detecting abnormalities in 25% of patients, while RT was abnormal in 7% only. In RT-negative patients with 1-year follow-up (n =67) the detection of a single abnormal index was able to predict a subsequent onset of symptomatic balance impairment. The proposed procedure is quick, easy to perform and can improve the assessment of the clinical course of MS, from a pre-clinical stage up to medium degree of disability. PMID- 28619433 TI - Infectious mononucleosis and multiple sclerosis - Updated review on associated risk. AB - BACKGROUND: There has been substantial evidence accumulating on the role of infectious mononucleosis (IM) and the subsequent risk of obtaining Multiple Sclerosis (MS). Up to date studies not previously explored were reviewed by the author to further clarify the association. METHODS: Medline and Web of Science were searched with no time constraints for articles exploring an association between Multiple Sclerosis and Infectious Mononucleosis. 24 articles were found, totalling 1063 cases and 13,227 cohort/controls. RESULTS: 23/24 (96%) articles reported a significant association of Infectious Mononucleosis on the risk of subsequent multiple sclerosis. DISCUSSION: Overall, new literature on IM and risk of MS categorically supports the association. Future work should focus on other risk factors such as age and gender on IM and subsequent risk of MS. PMID- 28619434 TI - Terminalia chebula attenuates quinolinate-induced oxidative PC12 and OLN-93 cell death. AB - BACKGROUND: Quinolinic acid (QA) is a product of tryptophan degradation and its pathologic accumulation has been found to induce neuroinflammatory and demyelinating diseases such as multiple sclerosis via excessive free radicals generation. Recent studies showed that Terminalia chebula has several pharmacological effects such as antioxidant, anti-inflammatory and neuroprotective properties. The aim of this study was evaluation of the protective effect of T. chebula alcoholic extract (TCAE) on oxidative PC12 and OLN-93 cells death induced by QA. METHODS: The cells were pretreated with TCAE (6.25-50MUg/mL) for 2h and then subjected to QA (8mM) for 24h. Cell viability and the parameters of redox status including the levels of intracellular reactive oxygen species (ROS), lipid peroxidation and oxidative DNA damage were measured using 2-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT), 2,7 dicholorofluorecin diacetate (DCF-DA), thiobarbituric acid and comet assays, respectively. RESULTS: Based on Folin-Ciocalteu method, the total phenolic compounds in TCAE were estimated about 1.18%. TCAE at concentration ranges of 6.25-50MUg/mL had no toxic effect on cell viability (p>0.05). Treatment with TCAE significantly increased cell viability following QA insult at concentrations above 25MUg/mL (p<0.01). Cytoprotective potential of TCAE also ameliorated ROS accumulation, lipid peroxidation and DNA damage induced by QA. CONCLUSION: These data suggest that TCAE exhibits neuroprotection and oligoprotection potential by means of alleviating oxidative stress parameters. PMID- 28619435 TI - Video head impulse test can detect brainstem dysfunction in multiple sclerosis. AB - BACKGROUND: The aim of this study was to investigate the potential role of video head impulse test (vHIT) in the detection of brainstem lesions in patients with multiple sclerosis (MS). METHODS: Sixty-eight participants were enrolled and divided into two groups: 39 healthy subjects (HC) (78 ears, 20 females, mean age 25,3+/-6,3) and 29 MS patients (58 ears, 14 females, mean age 33,7+/-7,7). Both groups underwent vHIT, and in MS group MRI was analyzed for the presence of brainstem lesions. vHIT pathology was defined as presence of overt saccades (<200ms) or lateral gain lower than 0.8 for lateral canal, and presence of overt saccades (<200ms) or posterior/anterior slope lower than 0.7. RESULTS: In HC, decreased gain on horizontal canals was found in 8 out of 78 ears (11%), while 16 out of 58 ears (38%) had pathological results in the MS group. Mean gain of the lateral canals (60ms) was significantly reduced in MS group compared to HC (0.874+/-0143 vs. 0.954+/-0,170, p=0.004, respectively). Compared to HC overt saccades <200ms in the lateral canals (p=0.018) and in the posterior canals (p=0.011), overt saccades >200ms in lateral (p<0.001), anterior (p=0.019) and posterior canals (p=0.009), and covert saccades in the anterior (p=0.042) and posterior canals (p=0.046) were more frequent in the MS group. There was statistically significant association between the presence of BS MR lesions and bilateral pathology on vHIT for lateral semicircular canal (chi(1)=3.982, p=0.046). CONCLUSION: These results indicate that vHIT can detect brainstem dysfunction in patients with MS. PMID- 28619436 TI - Tumefactive demyelinating lesions: A comprehensive review. AB - Tumefactive multiple sclerosis or tumefactive demyelinating lesion (TDL) is one of the rare variants of multiple sclerosis (MS) posing a diagnostic challenge and a therapeutic enigma since it is difficult to distinguish from a true central nervous system (CNS) neoplasm or other CNS lesions on magnetic resonance imaging (MRI). The prevalence of TDL is estimated to be 1-3/1000 cases of MS with an annual incidence of 0.3/100,000. This could be an underestimate due to unavailability of a global MS registry and under-reporting of this condition. TDL may occur at any age with the ages between the 20s and 30s being more frequently affected. The pathogenesis of TDL remains unknown, but some speculations have been made. These include the autoimmune theory based on the close relationship between TDLs and MS, Fingolimod use, Fingolimod cessation, and Natalizumab use. The clinical presentation of patients with TDL is variable and atypical for demyelinating disease due to the differences in size and location of the lesion. In this article, we aim to explore TDL comprehensively and provide an evidence based approach for diagnosis and treatment. This will result in recommendations that may improve the diagnostic accuracy and treatment outcomes. Detailed history, physical examination, and several MRI imaging can spare patients the need for a brain biopsy. Treatment of acute lesions includes corticosteroids and plasma exchange therapy. When a diagnosis of relapsing-remitting MS is fulfilled, conventional first line MS disease modifying therapy should be used. Available recently published data suggests that Fingolimod should not be used in TDL patients, mainly due to the possibility of more than just a chance association between TDLs and initiation of Fingolimod. The use of several new MS disease modifying therapy for the management of TDL remains to be studied. Further well conducted research including multi-center trials is needed to explain several ambiguous aspects related to the etiology and management of TDL. PMID- 28619437 TI - Fatigue evaluation in fingolimod treated patients: An observational study. AB - BACKGROUND: Fatigue is one of the most disabling symptoms in Multiple Sclerosis (MS) patients and is associated with a low quality of life. Fingolimod (Fg), a sphingosine 1-phosphate receptor modulator, is the first oral MS disease modifying treatment. Little is known about its effect on fatigue. To assess the impact of Fg on fatigue within the first 6 months of treatment in MS patients, we conducted a prospective, open label study, in real life setting. METHODS: Change of Modified Fatigue Impact Scale (MFIS) between Fg treatment start and at 6 months was used as a first outcome. Secondary outcomes were changes of MFIS subscales, Fatigue severity scale (FSS) and Visual Analogic Scale of Fatigue (VAS F) scores, RESULTS: 54 completed the study at M6. No significant change was noted in global MFIS (and neither in sub analysis of MFIS), FSS or VAS-F at M6. Patients with high level of fatigue (MFIS or >=38) had a higher EDSS score than patients with lower level of fatigue (MFIS <38), (mean 3.3, [SD 1.6] versus 1.6 [SD1.1], p=0.0002) but showed no significant difference in MFIS evolution at M6. There was no significant statistical difference in fatigue parameters evolution at M6 within patients Nz+ or Nz-. CONCLUSION: There is no significant impact of Fg on fatigue after 6 months of treatment. PMID- 28619438 TI - Editors' welcome. PMID- 28619439 TI - Origin, prevalence and response to therapy of hepatitis C virus genotype 2k/1b chimeras. AB - BACKGROUND & AIMS: Little is known about the epidemiology and frequency of recombinant HCV genotype 2/1 strains, which may represent a challenge for direct antiviral therapy (DAA). This study aims to identify the epidemiology and phylogeny of HCV genotype 2/1 strains and encourages genotype screening, to select the DAA-regimen that achieves the optimal sustained virologic response. METHODS: Consecutive samples from HCV genotype 2 infected patients, according to commercial genotyping, from Germany, Italy and Israel were re-genotyped by Sanger based sequencing. Virologic, epidemiological, and phylogenetic analyses including other published chimeras were performed. RESULTS: Sequence analysis of 442 supposed HCV genotype 2 isolates revealed 61 (genotype 2k/1b (n=59), 2a/1b (n=1) or 2b/1a (n=1)) chimeras. No chimeras were observed in Italy, but the frequency was 14% and 25% in Germany and Israel. Treatment of viral chimera with sofosbuvir/ribavirin led to virologic relapse in 25/27 patients (93%). Nearly all patients treated with genotype 1-based DAA-regimens initially (n=8/9), or after relapse (n=13/13), achieved a sustained virologic response. Most patients with 2k/1b chimeras (88%) were originally from eight different areas of the former Soviet Union. All known 2k/1b chimeras harbour the same recombination breakpoint and build one phylogenetic cluster, while all other chimeras have different phylogenies. CONCLUSIONS: The HCV genotype 2k/1b variant derives from one single recombination event most likely in the former Soviet Union, while other chimeras are unique and develop independently. A relatively high frequency has been observed along the migration flows, in Germany and Israel. In countries with little migration from the former Soviet Union the prevalence of 2k/1b chimeras is expected to be low. Treatment with sofosbuvir plus ribavirin is insufficient, but genotype 1-based regimens seem to be effective. Lay summary: The frequency of recombinant HCV is higher than expected. A novel recombinant variant (HCV genotype 2a/1b) was identified. Screening for recombinant viruses would contribute to increased response rates to direct antiviral therapy. PMID- 28619440 TI - Breaking Bad News: A Survey of Radiology Residents' Experiences Communicating Results to Patients. AB - PURPOSE: The practice of radiology often includes routine communication of diagnostic test results directly to patients in breast imaging and interventional radiology. There is increasing interest in expanding direct communication throughout radiology. Though these conversations can substantially affect patient well-being, there is limited evidence indicating that radiology residents are specifically taught methods to effectively convey imaging results to patients. Our purpose is to evaluate resident experience communicating imaging results to patients. MATERIALS AND METHODS: An IRB-approved study with a total of 11 pilot tested questions was used. Surveyed programs included radiology residents (PGY2 PGY5) at 2 urban residency programs. Online surveys were administered using SurveyMonkey and e-mailed to residents at both programs (starting November 20, 2015, completed March 31, 2016). Demographics were obtained with survey proportions compared using logistic regression (P < 0.05, statistically significant). RESULTS: A total of 73 residents responded (93.6% response rate) with similar response rates at each institution (P = 0.689). Most were male (71.2%) with 17.8% planning to go into breast imaging (21.9%, interventional radiology (IR)). Furthermore, 83.6% described no training in communicating radiology results to patients; 91.8% of residents communicated results with patients (87.7% diagnostic imaging tests and 57.5% biopsies). Residents most commonly communicated results in person (75.3%) followed by phone (64.4%), and 79.4% agreed or strongly agreed that additional training relaying results would be helpful. CONCLUSIONS: A large majority of radiology residents have communicated test results to patients, yet few have received training in how to communicate these results. A large majority of residents expressed interest in obtaining additional communication training. Additional research is required to determine ideal methods to educate residents on communicating test results. PMID- 28619441 TI - Radiologic Guide to Surgical Treatment of Kienbock's Disease. AB - Kienbock's disease, or avascular necrosis of the lunate, is a progressive disease ultimately resulting in end-stage arthrosis of the wrist. Various surgical treatments are available for different Lichtman stages of disease. We review the surgical options and indications, expected radiologic post-operative appearance, as well as detail potential surgical complications, as they relate to Kienbock's disease. PMID- 28619442 TI - Quantification of bleeding during dental extraction in patients on dual antiplatelet therapy. AB - In spite of the possibility of triggering thromboembolic events, many professionals indicate the suspension of antiplatelet agents before dental surgical procedures. The aim of this study was to perform a quantitative assessment of intraoperative bleeding in patients on dual antiplatelet therapy. A case-control study was conducted in patients on dual antiplatelet therapy (APT group) and in patients who did not use these medications (control group). The following examinations were requested: complete blood cell count, blood coagulation tests, and platelet aggregation. The quantity of bleeding was measured intraoperatively by collection of aspirated blood. The mean volume of blood lost during the surgical procedure was 6.10ml in the control group and 16.07ml in the APT group (P=0.002). The mean volume of blood lost per minute was 0.60ml/min in the control group and 1ml/min in the APT group (P=0.001), with local haemostatic methods being sufficient to control the bleeding. There was no postoperative bleeding complication in any case. Patients on dual antiplatelet therapy presented a larger volume of bleeding, but this could be controlled by means of local haemostatic measures. Therefore, there is no need to stop either of the two dual antiplatelet therapy medications before dental extractions. PMID- 28619443 TI - CT-guided hook-wire localisation prior to video-assisted thoracoscopic surgery of pulmonary lesions. AB - AIM: To assess the feasibility, safety, and efficacy of computed tomography (CT) guided pulmonary nodule localisation using a hooked guide wire before video assisted thoracoscopic surgery (VATS). MATERIALS AND METHODS: The study included 79 patients with a history of malignancies outside the lung associated with pulmonary nodules. Mean lesion size was 0.7 cm (range 0.5-1.8 cm) and the mean lesion distance to the pleural surface was 1.5 cm (range 0.2-5 cm). All lesions (n=82) were marked with a 22-G hook wire. The technique was designed to insert the tip of the hook wire within or maximally 1 cm from the edge of the lesion. The Mann-Whitney U-test was used for univariate analyses and Fisher's exact test for categorical values. RESULTS: The hooked guide wire was positioned successfully in all 82 pulmonary nodules within mean time of 9 minutes (8-20 minutes, SD: 2.5 minutes). The procedure time was inversely proportional to the size of the lesion (Spearman correlation factor 0.7). Minimal pneumothoraces were observed in five patients (7.6%). Pneumothorax was not correlated to the histopathology of the pulmonary nodules (p>0.09). Focal perilesional pulmonary haemorrhage developed in four patients (5%). Both haemorrhage and pneumothorax were significantly correlated to lesions <10 mm (p=0.02 and 0.01 respectively). The volume of resected lung tissue was significantly correlated to lesions of increased distance from the pleural surface >=2.5 cm in comparison to lesions of <2.5 cm from the pleural surface. CONCLUSION: CT-guided pulmonary nodule localisation prior to VATS could enable safe, accurate surgical guidance for the localisation of small pulmonary nodules. PMID- 28619444 TI - Single-step production of the simvastatin precursor monacolin J by engineering of an industrial strain of Aspergillus terreus. AB - Monacolin J is a key precursor for the synthesis of simvastatin (Zocor), an important drug for treating hypercholesterolemia. Industrially, monacolin J is manufactured through alkaline hydrolysis of lovastatin, a fungal polyketide produced by Aspergillus terreus. Multistep chemical processes for the conversion of lovastatin to simvastatin are laborious, cost expensive and environmentally unfriendly. A biocatalysis process for monacolin J conversion to simvastatin has been developed. However, direct bioproduction of monacolin J has not yet been achieved. Here, we identified a lovastatin hydrolase from Penicillium chrysogenum, which displays a 232-fold higher catalytic efficiency for the in vitro hydrolysis of lovastatin compared to a previously patented hydrolase, but no activity for simvastatin. Furthermore, we showed that an industrial A. terreus strain heterologously expressing this lovastatin hydrolase can produce monacolin J through single-step fermentation with high efficiency, approximately 95% of the biosynthesized lovastatin was hydrolyzed to monacolin J. Our results demonstrate a simple and green technical route for the production of monacolin J, which makes complete bioproduction of the cholesterol-lowering drug simvastatin feasible and promising. PMID- 28619445 TI - Effects of kallidinogenase on retinal edema and size of non-perfused areas in mice with retinal vein occlusion. AB - Kallidinogenase has been used to treat retinal vein occlusion (RVO) in patients, although there are no evidences on the effects of kallidinogenase on the retinal edema and the non-perfused areas in eyes with a RVO. We have established a murine RVO model with retinal edema and non-perfused areas. The purpose of this study was to evaluate the effects of kallidinogenase on the retinal edema and size of the non-perfused areas in the mouse RVO model. We evaluated the thickness of the retinal layers and size of the non-perfused areas, and the blood flow by laser speckle flowgraphy in RVO model. The effects of an intravenous injection of kallidinogenase on the retinal edema and size of the non-perfused areas were determined. In addition, the expressions of phosphorylated protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) were measured by Western blotting. Our results showed that kallidinogenase reduced the degree of retinal edema and size of the non-perfused areas by an increase in the blood flow in RVO model. Kallidinogenase also increased the levels of phosphorylated Akt and eNOS. These findings indicate that kallidinogenase acted through Akt/eNOS-dependent phosphorylation. Thus, kallidinogenase should be considered as a possible therapeutic agent for RVO patients. PMID- 28619446 TI - Design, synthesis, and evaluation of DNA topoisomerase II-targeted nucleosides. AB - We developed novel nucleoside-based topoisomerase II selective inhibitors and showed that small structural units, such as catechols, are essential for DNA topoisomerase II inhibitory activity. Moreover, nucleoside analogues containing TBS and 1,3-dithian moieties had potent and selective DNA topoisomerase II inhibitory activities. In further experiments, compound 25b having a beta configuration of the thymine moiety showed relatively strong growth inhibitory activity against cancer cell lines, and was more potent against all cancer cell lines than compound 26b, which carries a thymine moiety in the alpha configuration. PMID- 28619447 TI - Similar movements are associated with drastically different muscle contraction velocities. AB - We investigated how kinematic redundancy interacts with the neurophysiological control mechanisms required for smooth and accurate, rapid limb movements. Biomechanically speaking, tendon excursions are over-determined because the rotation of few joints determines the lengths and velocities of many muscles. But how different are the muscle velocity profiles induced by various, equally valid hand trajectories? We used an 18-muscle sagittal-plane arm model to calculate 100,000 feasible shoulder, elbow, and wrist joint rotations that produced valid basketball free throws with different hand trajectories, but identical initial and final hand positions and velocities. We found large differences in the eccentric and concentric muscle velocity profiles across many trajectories; even among similar trajectories. These differences have important consequences to their neural control because each trajectory will require unique, time-sensitive reflex modulation strategies. As Sherrington mentioned a century ago, failure to appropriately silence the stretch reflex of any one eccentrically contracting muscle will disrupt movement. Thus, trajectories that produce faster or more variable eccentric contractions will require more precise timing of reflex modulation across motoneuron pools; resulting in higher sensitivity to time delays, muscle mechanics, excitation/contraction dynamics, noise, errors and perturbations. By combining fundamental concepts of biomechanics and neuroscience, we propose that kinematic and muscle redundancy are, in fact, severely limited by the need to regulate reflex mechanisms in a task-specific and time-critical way. This in turn has important consequences to the learning and execution of accurate, smooth and repeatable movements-and to the rehabilitation of everyday limb movements in developmental and neurological conditions, and stroke. PMID- 28619448 TI - The future of pharmaceutical quality and the path to get there. AB - While six sigma quality has long been achieved in other industries, it is rarely seen in the pharmaceutical sector. However, consumers and patients deserve six sigma quality pharmaceuticals with minimal risks of shortages or recalls. We propose that the future of pharmaceutical quality is six sigma, meaning that no more than 3.4 defects occur per million opportunities. We discuss the path to get there, including economic drivers, performance-based regulation, Quality by Design, advanced manufacturing technologies, and continuous improvement and operational excellence. This article outlines an ambitious goal and is intended to be thought-provoking in spite of the challenging path to get there. This goal is envisioned because it is in the best interest of patients and consumers and is realizable with continued advances and investments in science and technology. The fundamental destination of pharmaceutical quality has been long envisioned: a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight. PMID- 28619449 TI - Development of semisolid self-microemulsifying drug delivery systems (SMEDDSs) filled in hard capsules for oral delivery of aciclovir. AB - The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six self-dispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50 degrees C and physically stable and compatible with HPMC capsules for 3 months storage at 25 degrees C and 4 degrees C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200mg, may control partitioning of the solubilized drug from in situ formed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug. PMID- 28619450 TI - Tocosome: Novel drug delivery system containing phospholipids and tocopheryl phosphates. AB - The potential of two derivatives of vitamin E, i.e. alpha-tocopheryl phosphate (TP) and di-alpha-tocopheryl phosphate (T2P), for the protection and delivery of therapeutics is being investigated in our laboratory and some promising results have been obtained so far. Novel nanocarrier systems containing TP, T2P and different lipids/phospholipids (phosphatidylcholine, stearyl amine, Phospholipon 90H, Phospholipon 100H) with and without cholesterol were prepared using Mozafari method. The preparation method did not require utilization of potentially toxic solvents, detergents or employment of harsh treatments such as sonication or high shear force homogenization. Tocosomes, containing 5-fluorouracil (as a model drug), were shown to possess narrow size distribution, acceptable encapsulation efficiency and long-term stability (more than two years). PMID- 28619451 TI - Ribbon thickness influences fine generation during dry granulation. AB - Uncontrolled fine generation during the milling process is a challenge for dry granulation by roller compaction. Here, we report the observation that ribbon thickness can significantly influence percentage of fines. Thus, among other parameters, ribbon thickness needs to be controlled for the development of a robust roller compaction process and ensure successful scale up. PMID- 28619452 TI - The role of lecithin degradation on the pH dependent stability of halofantrine encapsulated fat nano-emulsions. AB - We report on the successful incorporation of the antimalarial drug, halofantrine, into laboratory based soybean oil emulsions which were designed to mimic the commercially available parenteral fat emulsion, Intralipid(r). A high pH (minimum of pH 9, preferable pH of 11) was required for the drug laden emulsion to remain stable on storage and also to resist breaking under various stresses. Ageing of lecithin samples on storage was noted to result in degradation and a decrease in pH. We argue that this is the main reason for a similar decrease in pH for lecithin based emulsions and subsequent instability in drug laden emulsions. As expected, incorporation of the drug (halofantrine) resulted in lower stability. The (intensity weighted) particle size increased from 281nm for the drug free emulsion to 550nm following a loading of 1gL-1 of halofantrine, indicative of a lowering in stability and this was reflected in a shorter shelf life. Interestingly, incorporation of even higher concentrations of drug then resulted in better stability albeit never as stable as the drug free emulsion. We also report on unusual and complex surface tension behaviour for fresh lecithin where multiple critical concentration points were observed. PMID- 28619453 TI - Poly(ethylene oxide)/hydroxypropyl-beta-cyclodextrin films for oromucosal delivery of hydrophilic drugs. AB - In this study, we highlight the potential of the mucoadhesive film made from a poly(ethylene oxide)/hydroxypropyl-beta-cyclodextrin (PEO/CD) mixture in the oromucosal delivery of hydrophilic drugs, with a specific focus on dexamethasone phosphate disodium salt (Dexa). CD formed a complex with Dexa in solution and did not interact with mucin as highlighted from the spectrophotometric and spectrofluorimetric analysis. Similarly, CD and PEO did not affect mucin conformation, suggesting no direct interaction between the unstirred water layer and film components. Remarkably, PEO/CD/Dexa films dissolved more slowly than those made of PEO alone also in phosphate-buffered saline (PBS) pH 6.8 and gave a time-control on Dexa delivered dose. These combined effects resulted in a higher amount of Dexa accumulated in the mucosa, which can be highly beneficial in case of local diseases. Furthermore, Dexa amount able to diffuse through porcine buccal mucosa was lower when film contained CD, highlighting how CD can act as a modulator of drug transport also in the case of water-soluble drugs. In summary, our results demonstrate the versatility of PEO/CD films in mucosal delivery of hydrophilic corticosteroids paving the way to a novel approach in the treatment of mouth diseases. PMID- 28619454 TI - Carvacrol/clay hybrids loaded into in situ gelling films. AB - The aim of the present work was the development of polymer films loaded with a carvacrol (CVR)/clay hybrid (HYBD) for the delivery of CRV in infected skin ulcer treatment. Different clays were considered: montmorrilonite, halloysite and palygorskite (PHC). CRV incorporation in PHC reduced its volatility. HYBD showed 20% w/w CRV loading capacity and was able to preserve CRV antioxidant properties. HYBD was characterized by improved antimicrobial properties against S. aureus and E. coli and cytocompatibility towards human fibroblasts with respect to pure CRV. Films were prepared by casting an aqueous dispersion containing poly(vinylalcohol) (PVA), poly(vinylpyrrolidone) (PVP), chitosan glutamate (CS), sericin and HYBD. Optimization of film composition was supported by a Design of Experiments (DoE) approach. In a screening phase, a full factorial design (FFD) was used and the following factors were investigated at two levels: PVA (12 14%w/w), PVP (2-4%w/w) and CS (0.134-0.5%w/w) concentrations. For the optimization phase, FFD was expanded to a "central composite design". The response variables considered were: elongation, tensile strength and buffer absorption of films, durability of the gels formed after film hydration. Upon hydration, the optimized film formed a viscoelastic gel able to protect the lesion area and to modulate CRV release. PMID- 28619455 TI - In vitro release profiles of PLGA core-shell composite particles loaded with theophylline and budesonide. AB - We investigated the effects of drug loading location, matrix material and shell thickness on the in vitro release of combinational drugs from core-shell PLGA (i.e., poly(lactic-co-glycolic acid)) particles. Budesonide and Theophylline were selected as highly hydrophobic and hydrophilic model drugs, respectively. The dual-capillary electrospray (ES) technique, operated at the cone-jet mode, was used to produce samples of drug-loaded core-shell composite particles with selected overall sizes, polymer materials, and shell thicknesses. Theophylline and Budesonide were loaded at different locations in a PLGA composite particle. This study illustrated how the aforementioned factors affect the release rates of Budesonide and Theophylline loaded in core-shell PLGA composites. We further identified that core-shell composite particles with both model drugs loaded in the core and with matrix PLGA polymers of low molecular weights and low LA/GA ratios are the best formulation for the sustained release of highly hydrophilic and hydrophobic active pharmaceutical ingredients from PLGA composite particles. The formulation strategy obtained in this study can be in principle generalized for biopharmaceutical applications in fixed-dose combination therapy. PMID- 28619456 TI - How does secondary processing affect the physicochemical properties of inhalable salbutamol sulphate particles? A temporal investigation. AB - As pulmonary drug delivery is extended from low doses to high doses, physicochemical characteristics of the active pharmaceutical ingredient gain importance in the development of dry powder inhalers. Therefore, the present work aims to understand the impact of distinct engineering techniques on the process induced physicochemical characteristics of salbutamol sulphate particles over time. The particle engineering techniques chosen were jet-milling and spray drying, two well used processes in the production of predominately crystalline and amorphous inhalable particles, respectively. Fourier transform infrared spectroscopy, modulated differential scanning calorimetry, particle size distribution and tensiometry experiments were used to characterise the engineered powders immediately, 7, 14 and 21 days after production. The rugged spherical amorphous particles (3.75+/-0.08MUm) obtained via spray-drying showed that they were capable of forming strong agglomerates (5.01+/-0.22MUm) through "amorphous bridging". On the other hand, jet-milling produced smaller (2.06+/-0.08MUm), crystalline, irregular shaped particles with a very large surface area (11.04+/ 0.10m2/g) that, over time, formed looser particle aggregates of decreasing size (3.76+/-0.10MUm). Temporal evolution of the properties of spray-dried and jet milled particles showed a notable influence on the efficiency of blending with a model carrier at 0, 7 and 21 days (e.g. relative standard deviation of drug content of 11.3, 7.0 and 21.6%, respectively). PMID- 28619457 TI - In vitro studies of phospholipid-modified PAMAM-siMDR1 complexes for the reversal of multidrug resistance in human breast cancer cells. AB - The application of RNAi therapeutics is promising in combating several major human diseases including malignant tumors. However, this approach is limited due to its delivery barriers. In this study, we designed a new carrier system loaded with a functional siRNA targeting MDR1 gene to reverse multi-drug resistance (MDR) in human breast cancer MCF-7/ADR cells. Phospholipid-modified PAMAM-siMDR1 complexes were designed on the external decoration of polyamidoamine (PAMAM) with phospholipid (PL) and the electrostatical interaction between PAMAM and siMDR1 to form hybrid nanocomplexes (PL-dendriplexes). Compared with siMDR1 and dendriplexes (PAMAM-siMDR1), this delivery system represented higher gene silencing efficiency, enhanced cellular uptake of siMDR1, decreased p-gp expression, raised cellular accumulation of doxorubicin (DOX) and inhibited the tumor cell migration. Moreover, the siMDR1 loaded PL-dendriplexes worked synergistically with paclitaxel (PTX) for treating MDR, leading to increased cell apoptosis and cell phase regulation. Overall, this study shows that the PL dendriplexes hold great promise in reversing the drug-resistance in MCF-7/ADR cells. PMID- 28619458 TI - Development and validation of an HPLC-fluorescence method for the quantification of IR780-oleyl dye in lipid nanoparticles. AB - A reversed-phase (RP) high-performance liquid chromatography (HPLC) method for the content determination of IR780-oleyl (IRO) dye in lipid nanoparticles was developed and validated. Chromatographic separation was performed on a RP C18 column with a gradient program of water and acetonitrile both with 0.1% (v/v) TFA, at a flow rate of 1.0mL/min and a total run of 21min. IRO dye detection was made by fluorescence at emission wavelength of 773nm (excitation wavelength: 744nm). According to ICH guidelines, the developed method was shown to be specific, linear in the range 3-8MUg/mL (R2=0.9998), precise at the intra-day and inter-day levels as reflected by the coefficient of variation (CV<=1.98%) at three different concentrations (4, 6 and 8 MUg/mL) and accurate, with recovery rates between 98.2-101.6% and 99.2-100.5%. The detection and quantitation limits were 0.41 and 1.24MUg/mL, respectively. Stability studies of sample processing showed that IRO dye was stable after 24h in the autosampler or after three freeze/thaw cycles. Combined with fluorescence measurements, the developed method was successfully applied to optimize the loading capacity of IRO dye in the core of lipid nanoparticles. PMID- 28619459 TI - Reflections on experiential learning in evaluation capacity building with a community organization, Dancing With Parkinson's. AB - This paper discusses what was learned about evaluation capacity building with community organizations who deliver services to individuals with neurological disorders. Evaluation specialists engaged by the Ontario Brain Institute Evaluation Support Program were paired with community organizations, such as Dancing With Parkinson's. Some of the learning included: relationship building is key for this model of capacity building; community organizations often have had negative experiences with evaluation and the idea that evaluations can be friendly tools in implementing meaningful programs is one key mechanism by which such an initiative can work; community organizations often need evaluation most to be able to demonstrate their value; a strength of this initiative was that the focus was not just on creating products but mostly on developing a learning process in which capacities would remain; evaluation tools and skills that organizations found useful were developing a theory of change and the concept of heterogeneous mechanisms (informed by a realist evaluation lens). PMID- 28619460 TI - Critical appraisal leaves our upper limb therapy intervention trial misrepresented. PMID- 28619461 TI - Predictability of BRCA1/2 mutation status in patients with ovarian cancer: How to select women for genetic testing in middle-income countries. AB - OBJECTIVES: To evaluate the accuracy of algorithms for predicting BRCA1/2 germ line mutation carrier probability, and to identify factors that could improve their performance among Brazilian women with ovarian cancer (OC). STUDY DESIGN: In this cross-sectional study, we enrolled patients (unselected for family history of cancer) undergoing treatment or follow-up for OC in a single centre in Brazil. Clinical and demographic data, including family history of cancer, were obtained. Blood samples were collected for genetic testing. MAIN OUTCOME MEASURES: The entire coding sequence of BRCA1 and BRCA2 was evaluated for mutations. Mutation carrier probability was calculated using BOADICEA, BRCAPRO, Myriad and the Manchester score. Sensitivity, specificity, positive and negative predictive values, and area under the receiver operating characteristic curves (AUC) were calculated for each algorithm. Logistic regression was used to detect additional factors associated with BRCA1/2 status, and these were added to the algorithms before recalculating the AUCs. RESULTS: BRCA1/2 mutations were identified in 19 of the 100 included patients. BOADICEA outperformed other algorithms (sensitivity, 73.7%; specificity, 87.7%; AUC, 0.87, with a threshold of a 10% risk of mutation). Later menarche was associated with the presence of a BRCA1/2 mutation. Although adding age at menarche resulted in a larger AUC for all models, this increase was significant only for the Myriad algorithm. CONCLUSION: A BOADICEA risk evaluation of 10% or more most accurately predicted BRCA1/2 status, and the inclusion of age at menarche tended to improve the performance of all algorithms. Using these tools could reduce the number of tests, but at the expense of missing a significant proportion of mutation carriers. PMID- 28619462 TI - Perceptions of an educational programme for registered nurses who work at non major trauma services in Victoria, Australia: The Nursing Emergency eXternal Trauma Programme. AB - BACKGROUND: Emergency nurses working in non-Major Trauma Service (non-MTS) facilities face the challenge of providing immediate care to seriously injured patients, despite infrequent presentations at their workplace. A one-day education programme endorsed by the Australian College of Nursing was developed to provide contemporary trauma education for nurses. The aim of this study was to report participants' perceptions of their experience of this programme. METHODS: Peer reviewed lesson plans were developed to guide educational activities. Of 32 participants, 24 consented to and completed pre and post-programme surveys. Thematic analysis and descriptive statistics were used to report study findings. RESULTS: Most participants were nurses with greater than two years' experience in Emergency Nursing (92%). Trauma patient transfers each year from a non-MTS to a Major Trauma Service occurred infrequently; eight nurses (33.3%) reported greater than10 trauma transfers per year. Participant expectations of the programme included personal growth, knowledge acquisition, increased confidence and a focus on technical skills. Participants reported the day to be worthwhile and valuable; improved confidence, increased knowledge, and the opportunity to discuss current evidence based practice were highly regarded. Recommendations for future programmes included extending to two days and include burns and more complex pathophysiology. CONCLUSIONS: With centralisation of trauma care to major trauma services, frequent and continuing education of nurses is essential. Nurses from non-Major Trauma Service facilities in Victoria found this programme worthwhile as they gained knowledge and skills and increased confidence to care for trauma patients. PMID- 28619463 TI - In this Issue June 2017. PMID- 28619464 TI - The ageing society and emergency hospital admissions. AB - There is strong policy interest, in England as elsewhere, in slowing the growth in emergency hospital admissions, which for older people increased by 3.3% annually between 2001/2 and 2012/3. Resource constrains have increased the importance of understanding rising emergency admissions, which in policy discourse is often explained by population aging. This study examines how far the rise in emergency admissions of people over 65 was due to population ageing, how far to the changing likelihood of entering hospital at each age, and how far to other factors which might be more amenable to policy measures. It shows that: admission rates rose with age from age 40 upward but each successive birth cohort experienced lower emergency admission rates after standardising for age and other effects. This downward cohort effect largely offset the consequences of an older and larger population aged over 65. Other factors which could explain increasing admissions, such as new technologies or rising expectations, appear more important than the changing size and age structure of the population as drivers of rising emergency admissions in old age. These findings suggest that stemming the rate of increase in emergency admissions of older people may be feasible, if challenging, despite population ageing. PMID- 28619465 TI - A systematic review of soft-to-hard tissue ratios in orthognathic surgery. Part IV: 3D analysis - Is there evidence? AB - OBJECTIVE: The objective of this study was to determine the soft-to-hard tissue ratio using 3D analysis in different types of orthognathic surgery. MATERIAL AND METHODS: A systematic search for relevant studies published in different languages through December 2016 was performed in the Medline, Embase, Lilacs, Scopus, and Science Direct databases. Additional studies were identified by reference analysis. The methodological quality of the included studies was evaluated using the method proposed by the Effective Public Health Practice Project. The level of evidence was assessed using the Level of Evidence (LOE) scale from the Oxford Center for Evidence-Based Medicine. RESULTS: A total of 11 articles with 461 patients were included in the review, comprising 5 retrospective study and 6 prospective studies. The latter included 5 studies that performed anatomical area analyses of postoperative soft tissue results in the context of software-based planned surgeries without regard to hard tissues and 6 articles that presented analyses related to soft tissue in the preoperative and postoperative stage with certain points to be considered in hard tissues. The analysis of bias in the articles revealed a weak methodology in all included studies, which made it impossible to perform any type of comparison. CONCLUSION: Bias governs many of the published studies related to 3D analysis. There are no data that can be applied to determine the soft-to-hard tissue ratio using 3D analysis in orthognathic surgery. PMID- 28619466 TI - Drosophila mitotypes determine developmental time in a diet and temperature dependent manner. AB - It is well known that specific mitochondrial (mt) DNA mutations can reduce organismal fitness and influence mitochondrial-nuclear interactions. However, determining specific mtDNA mutations that are beneficial has been elusive. In this study, we vary the diet and environmental temperature to study larval development time of two Drosophila melanogaster mitotypes (Alstonville and Dahomey), in two nuclear genetic backgrounds, and investigate developmental differences through weight, feeding rate, and movement. To manipulate the diet, we utilize the nutritional geometric framework to manipulate isocaloric diets of differing macronutrient ratios (1:2 and 1:16 protein: carbohydrate (P:C) ratios) and raise flies at three temperatures (19 degrees C, 23 degrees C and 27 degrees C). Larvae with Dahomey mtDNA develop more slowly than Alstonville when fed the 1:2 P:C diet at all temperatures and developed more quickly when fed the 1:16 P:C diet at 23 degrees C and 27 degrees C. We determined that Dahomey larvae eat more, move less, and weigh more than Alstonville larvae when raised on the 1:16 P:C diet and that these physiological responses are modified by temperature. We suggest that 1 (or more) of 4 mtDNA changes is likely responsible for the observed effects and posit the mtDNA changes moderate a physiological trade-off between consumption and foraging. PMID- 28619467 TI - [Synthesis and binding affinity to human steroid hormone receptors of 3-phenoxy-4 hydroxycoumarins and 3-phenoxy-4-phenylcoumarins]. AB - The synthesis and the study of the binding affinity to human receptors of glucocorticoids, mineralcorticoids, androgens, estrogens and progesterone of 3 phenoxy-4-hydroxycoumarins and 3-phenoxy-4-phenylcoumarins were performed. It shows the absence of any binding affinity of all these derivatives to glucocorticoid and mineralcorticoid receptors and a non-selective binding affinity to androgen, oestrogen and progesterone receptors with 3-phenoxy-4 phenyl-coumarins. PMID- 28619468 TI - Preface for the HIV issue. PMID- 28619469 TI - A pattern-based approach to reactive lymphadenopathies. AB - A crucial task in histopathological examination of enlarged lymph nodes is to discriminate malignant form benign processes. The central importance of this issue is reflected by the fact that benign lymphadenopathies mistaken for lymphomas belong to the most commonly misdiagnosed cancers. In addition, recognition of distinct histopathological patterns of reactive lymph node changes narrow down the potential number of causative agents, especially of those that can be specifically identified by means of often very resource-consuming ancillary techniques; thus, the more precise the differential diagnosis established upon histopathological examination is, the more targetable and efficient the application of these techniques will be. This review provides a synopsis on a histopathological pattern-based approach towards reactive lymphadenopathies. PMID- 28619470 TI - Whole-body hyperthermia and a subthreshold dose of citalopram act synergistically to induce antidepressant-like behavioral responses in adolescent rats. AB - BACKGROUND: Open and randomized, double blind, placebo-controlled clinical trials have demonstrated clinical efficacy of infrared whole-body hyperthermia in treatment of major depressive disorder (MDD). Demonstration of antidepressant like behavioral effects of whole-body hyperthermia in preclinical rodent models would provide further support for the clinical use of infrared whole-body hyperthermia for the treatment of MDD, and would provide additional opportunities to explore underlying mechanisms. METHODS: Adolescent male Wistar rats were habituated daily for 7days to an incubator (23 degrees C, 15min), then exposed, 24h later, to an 85-min period of whole-body hyperthermia (37 degrees C) or control conditions (23 degrees C), with or without pretreatment with a subthreshold dose of the selective serotonin reuptake inhibitor, citalopram (5mg/kg, s.c., 23h, 5h, and 1h before behavioral testing in a 5-min forced swim test). Rectal temperature was monitored daily and immediately before and after the forced swim test to determine the relationship between body temperature and antidepressant-like behavioral responses. RESULTS: Whole-body hyperthermia and citalopram independently increased body temperature and acted synergistically to induce antidepressant-like behavioral responses, as measured by increased swimming and decreased immobility in the absence of any effect on climbing behaviors in the forced swim test, consistent with a serotonergic mechanism of action. CONCLUSIONS: Preclinical data support use of infrared whole-body hyperthermia in the treatment of MDD. PMID- 28619471 TI - Oral haloperidol or olanzapine intake produces distinct and region-specific increase in cannabinoid receptor levels that is prevented by high fat diet. AB - Clinical studies show higher levels of cannabinoid CB1 receptors (CB1R) in the brain of schizophrenic patients while preclinical studies report a significant functional interaction between dopamine D2 receptors and CB1Rs as well as an upregulation of CB1Rs after antipsychotic treatment. These findings prompted us to study the effects of chronic oral intake of a first and a second generation antipsychotic, haloperidol and olanzapine, on the levels and distribution of CB1Rs in the rat brain. Rats consumed either regular chow or high-fat food and drank water, haloperidol drinking solution (1.5mg/kg), or olanzapine drinking solution (10mg/kg) for four weeks. Motor and cognitive functions were tested at the end of treatment week 3 and upon drug discontinuation. Two days after drug discontinuation, rats were euthanized and brains were processed for in vitro receptor autoradiography. In chow-fed animals, haloperidol and olanzapine increased CB1R levels in the basal ganglia and the hippocampus, in a similar, but not identical pattern. In addition, olanzapine had unique effects in CB1R upregulation in higher order cognitive areas, in the secondary somatosensory cortex, in the visual and auditory cortices and the geniculate nuclei, as well as in the hypothalamus. High fat food consumption prevented antipsychotic-induced increase in CB1R levels in all regions examined, with one exception, the globus pallidus, in which they were higher in haloperidol-treated rats. The results point towards the hypothesis that increased CB1R levels could be a confounding effect of antipsychotic medication in schizophrenia that is circumveneted by high fat feeding. PMID- 28619472 TI - Gasdermins: Effectors of Pyroptosis. AB - Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family. PMID- 28619473 TI - Cocaine adulteration. AB - Cocaine is a naturally occurring and illicitly used psychostimulant drug. Cocaine acts at monoaminergic neurotransmitter transporters to block uptake of the monoamines, dopamine, serotonin and norepinephrine. The resulting increase of monoamines in the extracellular space underlies the positively reinforcing effects that cocaine users seek. In turn, this increase in monoamines underlies the development of addiction, and can also result in a number of severe side effects. Currently, cocaine is one of the most common illicit drugs available on the European market. However, cocaine is increasingly sold in impure forms. This trend is driven by cocaine dealers seeking to increase their profit margin by mixing ("cutting") cocaine with numerous other compounds ("adulterants"). Importantly, these undeclared compounds put cocaine consumers at risk, because consumers are not aware of the additional potential threats to their health. This review describes adulterants that have been identified in cocaine sold on the street market. Their typical pharmacological profile and possible reasons why these compounds can be used as cutting agents will be discussed. Since a subset of these adulterants has been found to exert effects similar to cocaine itself, we will discuss levamisole, the most frequently used cocaine cutting agent today, and its metabolite aminorex. PMID- 28619474 TI - High metabolic versatility of different toxigenic and non-toxigenic Clostridioides difficile isolates. AB - Clostridioides difficile (formerly Clostridium difficile) is a major nosocomial pathogen with an increasing number of community-acquired infections causing symptoms from mild diarrhea to life-threatening colitis. The pathogenicity of C. difficile is considered to be mainly associated with the production of genome encoded toxins A and B. In addition, some strains also encode and express the binary toxin CDT. However; a large number of non-toxigenic C. difficile strains have been isolated from the human gut and the environment. In this study, we characterized the growth behavior, motility and fermentation product formation of 17 different C. difficile isolates comprising five different major genomic clades and five different toxin inventories in relation to the C. difficile model strains 630Deltaerm and R20291. Within 33 determined fermentation products, we identified two yet undescribed products (5-methylhexanoate and 4-(methylthio) butanoate) of C. difficile. Our data revealed major differences in the fermentation products obtained after growth in a medium containing casamino acids and glucose as carbon and energy source. While the metabolism of branched chain amino acids remained comparable in all isolates, the aromatic amino acid uptake and metabolism and the central carbon metabolism-associated fermentation pathways varied strongly between the isolates. The patterns obtained followed neither the classification of the clades nor the ribotyping patterns nor the toxin distribution. As the toxin formation is strongly connected to the metabolism, our data allow an improved differentiation of C. difficile strains. The observed metabolic flexibility provides the optimal basis for the adaption in the course of infection and to changing conditions in different environments including the human gut. PMID- 28619475 TI - Post-partum depression-a glimpse of light in the darkness? PMID- 28619476 TI - Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. AB - BACKGROUND: Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of gamma-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. METHODS: For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (<=6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score >=26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. FINDINGS: This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21.0 points (SE 2.9) in the brexanolone group compared with 8.8 points (SE 2.8) in the placebo group (difference -12.2, 95% CI 20.77 to -3.67; p=0.0075; effect size 1.2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). INTERPRETATION: In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. FUNDING: Sage Therapeutics, Inc. PMID- 28619477 TI - A novel body frame based approach to aerospacecraft attitude tracking. AB - In the common practice of designing an attitude tracker for an aerospacecraft, one transforms the Newton-Euler rotation equations to obtain the dynamic equations of some chosen inertial frame based attitude metrics, such as Euler angles and unit quaternions. A Lyapunov approach is then used to design a controller which ensures asymptotic convergence of the attitude to the desired orientation. Although this design methodology is pretty standard, it usually involves singularity-prone coordinate transformations which complicates the analysis process and controller design. A new, singularity free error feedback method is proposed in the paper to provide simple and intuitive stability analysis and controller synthesis. This new body frame based method utilizes the concept of Euleraxis and angles to generate the smallest error angles from a body frame perspective, without coordinate transformations. Global tracking convergence is illustrated with the use of a feedback linearizing PD tracker, a sliding mode controller, and a model reference adaptive controller. Experimental results are also obtained on a quadrotor platform with unknown system parameters and disturbances, using a boundary layer approximated sliding mode controller, a PIDD controller, and a unit sliding mode controller. Significant tracking quality is attained. PMID- 28619478 TI - Constrained tracking control for nonlinear systems. AB - This paper proposes a tracking control strategy for nonlinear systems without needing a prior knowledge of the reference trajectory. The proposed method consists of a set of local controllers with appropriate overlaps in their stability regions and an on-line switching strategy which implements these controllers and uses some augmented intermediate controllers to ensure steering the system states to the desired set points without needing to redesign the controller for each value of set point changes. The proposed approach provides smooth transient responses despite switching among the local controllers. It should be mentioned that the stability regions of the proposed controllers could be estimated off-line for a range of set-point changes. The efficiencies of the proposed algorithm are illustrated via two example simulations. PMID- 28619479 TI - A demonstration of analytical similarity comparing a proposed biosimilar pegfilgrastim and reference pegfilgrastim. AB - BACKGROUND: Recombinant human granulocyte-colony stimulating factor (G-CSF, filgrastim) is used primarily to reduce incidence and duration of severe neutropenia and its associated complications in cancer patients that have received a chemotherapy regimen. The pegylated form of filgrastim, "pegfilgrastim", is a long-acting form that requires only a once-per-cycle administration for the management of chemotherapy-induced neutropenia. Apobiologix, a division of ApoPharma USA, Inc., and Intas Pharmaceuticals Limited have co-developed a proposed pegfilgrastim biosimilar to US-licensed pegfilgrastim. METHODS: The analytical similarity of Apobiologix pegfilgrastim and US-licensed pegfilgrastim with respect to their physicochemical profile was established using a wide range of rigorous orthogonal analytical techniques. Biological function was compared using receptor binding analyses, in vitro proliferation assays, and in vivo hematopoietic progenitor mobilization. RESULTS: Apobiologix pegfilgrastim and the US-licensed pegfilgrastim reference product were found to be highly similar analytically with respect to molecular mass, primary, secondary and tertiary protein structures, purity, charge, and hydrophobicity. No differences in receptor binding affinity were observed, and all samples demonstrated similar in vitro and in vivo bioactivity. CONCLUSION: These studies provide robust evidence supporting the structural and functional similarity between Apobiologix pegfilgrastim and the US-licensed reference pegfilgrastim, and hence their biosimilarity. PMID- 28619480 TI - Online resources for malaria in travellers. PMID- 28619481 TI - Computational Psychosomatics and Computational Psychiatry: Toward a Joint Framework for Differential Diagnosis. AB - This article outlines how a core concept from theories of homeostasis and cybernetics, the inference-control loop, may be used to guide differential diagnosis in computational psychiatry and computational psychosomatics. In particular, we discuss 1) how conceptualizing perception and action as inference control loops yields a joint computational perspective on brain-world and brain body interactions and 2) how the concrete formulation of this loop as a hierarchical Bayesian model points to key computational quantities that inform a taxonomy of potential disease mechanisms. We consider the utility of this perspective for differential diagnosis in concrete clinical applications. PMID- 28619482 TI - Correction of sunken upper eyelid with orbital fat transposition flap and dermofat graft. AB - BACKGROUND: Sunken upper eyelid is a commonly found deformity among Asians, mostly due to the aging process and excessive orbital fat removal during oriental blepharoplasty procedures. This deformity is frequently accompanied by multiple, poorly defined upper eyelid folds and blepharoptosis. To date, autologous fat graft has been the treatment of choice for this group of patients. However, accurate placement of the graft in the orbital fat is quite challenging, and it can result in contour irregularities when injected into the preseptal plane. METHODS: From 2008 to 2013, 60 patients with sunken upper eyelids were treated with either an orbital fat transposition flap or a dermofat graft according to the severity of the deformity. Mild sunken upper eyelids were corrected during upper blepharoplasty by exposing the central orbital fat sac and transposing it in a flap-like manner. In more severe cases, a dermofat graft harvested from the intergluteal crease was used. RESULTS: Postoperative complications included difficulty in eye opening because of the weight of the dermofat graft and swelling of the periorbit, which gradually resolved with time. Mild bruising, tenderness, asymmetry, and blepharoptosis were also noted, but no additional treatments were necessary. During the 13-month follow-up period, two patients from the orbital fat transposition flap group and one patient from the dermofat graft group underwent revision surgeries. CONCLUSIONS: Anatomy of the orbit, prior surgical history, and sunkenness of the upper eyelid were all considered during preoperative planning. Either an orbital fat transposition flap or a dermofat graft was applied, according to the severity of the deformity, with successful results. Particularly in mild cases of sunken upper eyelid deformity, an orbital fat transposition flap is an easy and effective method that requires no additional procedures. PMID- 28619483 TI - Characterizing infections in prosthetic breast reconstruction: A validity assessment of national health databases. AB - INTRODUCTION: Current guidelines in the United States require reporting only the 30-day postoperative outcomes to standardized databases, including the National Surgical Quality Improvement Program (NSQIP). Thus, many breast implant-related complications go unreported in standard databases. We sought to characterize late periprosthetic infections following implant-based breast reconstruction. METHODS: We conducted a retrospective analysis of all women who underwent expander/implant reconstruction from 2005 to 2014 at two institutions. All periprosthetic infections were identified and divided into early and late cohorts (<=30 days or >30 days). Infection was defined as any episode where antibiotics were initiated or a prosthetic device was explanted because of clinical evidence of the infection. RESULTS: In the 1820 patients (2980 breasts) identified, 421 periprosthetic infections occurred (14%). Of these, 173 (41%) were early and 248 (59%) were late (mean time to infection = 66.4 +/- 101.9 days). Patients with late infections were more likely to be current smokers or have diabetes than patients with early infections (p < 0.034 for both). Infections caused by gram negative bacteria and antimicrobial-resistant strains of Staphylococcus were more common in the early infection group (p < 0.001 for both). Implant loss due to infection was more common in the late infection group (p = 0.037). DISCUSSION: Late periprosthetic infections following implant-based breast reconstruction are underestimated in national outcome databases and have unique risk factors and microbiology compared to early infections. A system-level change in reevaluating and redefining a timeline for tracking and treating implant infections is necessary, given the substantial morbidity associated with, and frequency of, late periprosthetic infections. PMID- 28619484 TI - The new opt-out Dutch National Breast Implant Registry - Lessons learnt from the road to implementation. AB - An estimated 1-3% of all women in the Netherlands carry breast implants. Since the introduction five decades ago, problems with a variety of breast implants have emerged with direct consequences for the patients' health. Plastic surgeons worldwide reacted through campaigning for auditing on long-term implant quality, surgeon performance, and institutional outcomes in implant registries. Especially, the PIP implant scandal of 2010 demonstrated the paucity of epidemiological data and uncovered a weakness in our ability to even 'track and trace' patients. In addition, a recent report of the Dutch Institute of National Health showed a lack of compliance of 100% of breast implant producers to CE requirements. These arguments stress the need for an independent implant registry. Insufficient capture rates or dependence from the implant producers made the variety of national and international patient registries unreliable. The Dutch Breast Implant Registry (DBIR) is unique because it is an opt-out registry without the need for informed consent and thus a high capture rate. Furthermore, an estimated 95% of breast implants are implanted by board-certified plastic surgeons. Funding was received from a non-governmental organisation to increase the quality of health care in the Netherlands, and maintenance is gathered by 25 euros per implant inserted. This article describes the way the Dutch have set up their system, with special attention to the well-known hurdles of starting a patient registry. Examples include: funding, medical ethical issues, opt out system, benchmarking, quality assurance as well as governance and collaboration. The Dutch consider their experience and data shareware for others to be used globally to the benefit of patient safety and quality improvement. PMID- 28619485 TI - Reliability and validity of Mamma Balance(r): Novel software to assess the symmetry of the nipple-areola-complex position. PMID- 28619486 TI - Extended depth of focus contact lenses vs. two commercial multifocals: Part 2. Visual performance after 1 week of lens wear. AB - PURPOSE: To compare the visual performance of prototype contact lenses designed via deliberate manipulation of higher-order spherical aberrations to extend-depth of-focus with two commercial multifocals, after 1 week of lens wear. METHODS: In a prospective, participant-masked, cross-over, randomized, 1-week dispensing clinical-trial, 43 presbyopes [age: 42-63 years] each wore AIROPTIX Aqua multifocal (AOMF), ACUVUE OASYS for presbyopia (AOP) and extended-depth-of-focus prototypes (EDOF) appropriate to their add requirements. Measurements comprised high-contrast-visual-acuity (HCVA) at 6m, 70cm, 50cm and 40cm; low-contrast visual-acuity (LCVA) and contrast-sensitivity (CS) at 6m and stereopsis at 40cm. A self-administered questionnaire on a numeric-rating-scale (1-10) assessed subjective visual performance comprising clarity-of-vision and lack-of-ghosting at various distances during day/night-viewing conditions and overall-vision satisfaction. RESULTS: EDOF was significantly better than AOMF and AOP for HCVA averaged across distances (p<=0.038); significantly worse than AOMF for LCVA (p=0.021) and significantly worse than AOMF for CS in medium and high add-groups (p=0.006). None of these differences were clinically significant (<=2 letters). EDOF was significantly better than AOMF and AOP for mean stereoacuity (36 and 13 seconds-of-arc, respectively: p<=0.05). For clarity-of-vision, EDOF was significantly better than AOP at all distances and AOMF at intermediate and near (p<=0.028). For lack-of-ghosting averaged across distances, EDOF was significantly better than AOP (p<0.001) but not AOMF (p=0.186). EDOF was significantly better than AOMF and AOP for overall-vision-satisfaction (p<=0.024). CONCLUSIONS: EDOF provides better intermediate and near vision performance than either AOMF or AOP with no difference for distance vision after 1 week of lens wear. PMID- 28619487 TI - Viscerocutaneous Loxoscelism. PMID- 28619488 TI - Financial risk protection from social health insurance. AB - This paper estimates the impact of social health insurance on financial risk by utilizing data from a natural experiment created by the phased roll-out of a social health insurance program for the poor in India. We estimate the distributional impact of insurance on of out-of-pocket costs and incorporate these results with a stylized expected utility model to compute associated welfare effects. We adjust the standard model, accounting for conditions of developing countries by incorporating consumption floors, informal borrowing, and asset selling which allow us to separate the value of financial risk reduction from consumption smoothing and asset protection. Results show that insurance reduces out-of-pocket costs, particularly in higher quantiles of the distribution. We find reductions in the frequency and amount of money borrowed for health reasons. Finally, we find that the value of financial risk reduction outweighs total per household costs of the insurance program by two to five times. PMID- 28619489 TI - Predictors of Outcomes in Fourth Ventricular Epidermoid Cysts: A Case Report and a Review of Literature. AB - OBJECTIVE: To present an illustrative case of fourth ventricular epidermoid cyst and review the literature to identify predictors of surgical outcomes. METHODS: A case of fourth ventricular epidermoid cyst is presented and a systematic review of 5 popular databases was performed by independent authors. Stepwise logistic regression was performed to identify clinical predictors of outcomes. RESULTS: A 21-year-old woman presented with 3 months of headaches and visual obscurations and was diagnosed with a multilobulated mass in the fourth ventricle. The patient underwent suboccipital craniotomy. Complete removal of the mass was achieved and the final diagnosis was consistent with an epidermoid cyst. The systematic review identified 23 studies that reported 37 patients. Mean age was 42.8 years. Mean length of time between symptom onset and diagnosis was 4.43 years. Age (P = 0.049) and duration of symptoms (P < 0.001) were significantly different between patients who experienced symptom improvement and those who did not. Duration of symptom onset to diagnosis was a significant predictor of poor outcomes (odds ratio, 1.19, 95% confidence interval, 1.003-4.785). CONCLUSIONS: Our review found that in patients with fourth ventricular epidermoid cysts, unfavorable outcomes were predicted by older age and by longer intervals from symptom onset to diagnosis. Clinicians should maintain a high index of suspicion for fourth ventricular epidermoid cysts in patients presenting with cerebellar signs and visual disturbances. PMID- 28619490 TI - Use of Simple Neck Extension to Improve Guiding Catheter Accessibility in Tortuous Cervical Internal Carotid Artery for Endovascular Embolization of Intracranial Aneurysm: A Technical Note. AB - BACKGROUND: In endovascular embolization of intracranial aneurysms, a tortuous cervical internal carotid artery can limit guiding catheter access to a sufficiently high position. Although intermediate distal access catheters can go beyond the tortuous segment of internal carotid arteries, they may increase the risk of procedure-related complications, require significantly complex technical procedures, and limit the use of adjunctive techniques. Using simple neck extension alone, we successfully improved guiding catheter access in 2 patients. METHODS: Through a provocative test, we confirmed suitability of manual neck extension in 2 patients with severe posterior curvature of a tortuous internal carotid artery. Intraoperatively, we manually extended the neck and stretched the curvatures. We guided a 6F guiding catheter superiorly and performed coil embolization with an occlusion balloon catheter in 1 case and with the balloon assisted neck remodeling technique in 1 case. RESULTS: Coil embolization was completed without any adverse events in both cases. CONCLUSIONS: The simple neck extension technique successfully improved accessibility of the guiding catheter. As the need for safe and highly skilled intervention increases, our technique may be useful because it can reduce procedure-related complications and allow balloon assisted techniques. PMID- 28619491 TI - The Accuracy of Multimodality Intraoperative Neuromonitoring to Predict Postoperative Neurologic Deficits Following Cervical Laminoplasty. AB - BACKGROUND: Intraoperative neuromonitoring (IONM) has been reported to be sensitive and specific in the detection of neurologic injury during spinal surgery. The purpose of this study was to clarify the incidence of C5 palsy using multimodality IONM and to compare the accuracy of multimodality IONM to predict postoperative C5 palsy with isolated transcranial motor evoked potentials (MEPs). METHODS: We retrospectively reviewed 135 consecutive patients at a single institution with cervical spondylotic myelopathy who underwent open door laminoplasty using MEPs combined with somatosensory evoked potentials and free running electromyography. RESULTS: Multimodality IONM was obtained in 131 cases. Ossification of the posterior longitudinal ligament was present in 19 patients (14.1%). Postoperative C5 palsy occurred in 3 patients (2.2%). Significant MEP alerts occurred in 12 patients. Significant somatosensory evoked potential change was not observed. To predict acute-onset C5 palsy, MEP alerts in the deltoid or biceps had 100% sensitivity and 98.4% specificity. Transient or persistent MEP alerts in the deltoid or biceps had same positive predictive value with sensitivity of 50.0% and specificity 99.2%. CONCLUSIONS: Incidence of any neurologic deficit, including C5 palsy, during laminoplasty while using multimodality IONM was relatively low. MEP alerts in the deltoids or biceps had 100% sensitivity and 98.4% specificity for predicting a postoperative deficit. Somatosensory evoked potentials did not appear to be helpful in predicting postoperative deficits. PMID- 28619492 TI - Case of Familial Moyamoya Disease Presenting 10 Years After Initial Negative Magnetic Resonance Screening in Childhood. AB - BACKGROUND: Both genetic and environmental factors are considered to contribute to the onset of moyamoya disease, but the exact mechanism has not yet been clarified. Furthermore, the typical time course of progression to vessel occlusion has not been established, even in the genetically high-risk population. CASE DESCRIPTION: We present the case of a 21-year-old female with familial history of moyamoya disease. She underwent screening for moyamoya disease 10 years prior, but no abnormalities in magnetic resonance imaging or magnetic resonance angiography were found. She presented to our hospital for transient numbness of the left upper and lower extremities and dysarthria at the age of 21. She was diagnosed with moyamoya disease and underwent bilateral encephaloduroarteriosynangiosis. Gene analysis on the point mutation of RNF213, p.R4810K, was conducted for this patient, her younger sister with moyamoya disease, and their nonsymptomatic parents. A rare variant (p.R4810K) was positive in these sisters and their mother. CONCLUSION: We show a case of familial moyamoya disease diagnosed 10 years after the magnetic resonance imaging screening in childhood. We must carefully consider when, how, and for whom screening for moyamoya disease should be performed, taking into account familial history of the disease. PMID- 28619493 TI - Dynamic Four-Dimensional Computed Tomography Angiography for Neurovascular Pathologies. AB - BACKGROUND: This article illustrates, summarizes, and reviews the multifaceted application of four-dimensional (4D) computed tomography angiography (CTA) in the characterization and diagnosis of various cerebrovascular and tumor-associated vascular pathologies through the presentation of clinical cases, including acute and chronic stroke, arteriovenous malformations, aneurysm, moyamoya disease, and hypervascularity associated with a tumor and its relationship to preoperative embolization. The technical nuances and limitations of the 4D-CTA technique are also discussed. CASE DESCRIPTION: We present 6 cases that best elucidate the application and technical nuances of 4D-CTA and its advantages over traditional digital subtraction angiography. Along with discussion of the utility of 4D-CTA, we also examine the limitations of this technique. CONCLUSIONS: Intracranial vascular lesions can be detected with 4D-CTA and clinically evaluated using information related to vascular flow dynamics. The use of 4D-CTA provides data related to ongoing vascular changes as well as accurate spatial delineation of cerebrovascular pathologies. Overall, 4D-CTA is increasing its role in neuroimaging by providing superior information regarding structural three dimensional imaging quality and real-time flow. PMID- 28619494 TI - Role of Hemodynamic Forces in Unruptured Intracranial Aneurysms: An Overview of a Complex Scenario. AB - BACKGROUND: An understanding of the natural history of unruptured intracranial aneurysms (IAs) has always played a critical role in presurgical or endovascular planning, to avoid possibly fatal events. Size, shape, morphology, and location are known risk factors for rupture of an aneurysm, but morphologic parameters alone may not be sufficient to perform proper rupture risk stratification. METHODS: We performed a systematic PubMed search and focused on hemodynamics forces that may influence aneurysmal initiation, growth, and rupture. RESULTS: We included 223 studies describing several hemodynamic parameters related to aneurysm natural history. In these studies, different modalities of aneurysm model creation have been used to evaluate flow and to comprehensively analyze the evolution of IAs. Controversy exists about the correlation between these parameters and initiation, growth, rupture risk, or stabilization of the aneurysmal sac. Recent findings have also shown the importance of flow patterns in this process and the relationship between unruptured IA geometry and hemodynamic parameters. CONCLUSIONS: The role of hemodynamic forces in evaluation of the natural history of unruptured IAs presents is inherently complex and is still not completely understood. In this complex scenario, although several attempts have been described in the literature, a proper risk rupture stratification and treatment strategy selection based on hemodynamic forces has not yet been created. Further efforts should be made to accomplish this important goal. PMID- 28619495 TI - Results of Atypical Hemifacial Spasm with Microvascular Decompression: 14 Case Reports and Literature Review. AB - BACKGROUND: Few studies have examined atypical hemifacial spasm (AHFS), and the mechanism of AHFS remains unclear. In this study, we examined the etiology, prognosis, and treatment of AHFS. METHODS: We retrospectively analyzed the clinical data for 14 consecutive patients that underwent microvascular decompression (MVD) for AHFS between January 2014 and December 2015. Clinical features, outcomes, and complications were evaluated. RESULTS: The incidence of AHFS is 1.52%. There were no significant differences in sex, age, side and duration between the typical hemifacial spasm and AHFS. During the follow-up period, the effective rate of MVD for patients with AHFS was 92.3%. Three patients developed delayed facial nerve palsy postoperatively, 1 patient experienced occipital sensory disturbance, and 1 patient suffered hearing loss. CONCLUSIONS: Most of the cases of AHFS studied here were caused by neurovascular conflict in zone IV of the facial nerve distal to the root entry zone. MVD surgery is the first choice treatment for AHFS. PMID- 28619496 TI - Injury to the Lumbar Plexus and its Branches After Lateral Fusion Procedures: A Cadaver Study. AB - INTRODUCTION: Neurologic deficits from lumbar plexus nerve injuries commonly occur in patients undergoing lateral approaches. However, it is not yet clear what types of injury occur, where anatomically they are located, or what mechanism causes them. We aimed to study 1) the topographic anatomy of lumbar plexus nerves and their injuries in human cadavers after lateral transpsoas approaches to the lumbar spine, 2) the structural morphology of those injuries, and 3) the topographic anatomy of the lumbar plexus throughout the mediolateral approach corridor. METHODS: Fifteen adult fresh frozen cadaveric torsos (26 sides) underwent lateral approaches (L1-L5) by experienced lateral spine surgeons. The cadavers were subsequently opened and the entire plexus dissected and examined for nerve injuries. The topographic anatomy of the lumbar plexus and its branches, their injuries, and the morphology of these injuries were documented. RESULTS: Fifteen injuries were found with complete or partial nerve transections (Sunderland IV and V). Injuries were found throughout the mediolateral approach corridor. At L1/2, the iliohypogastric, ilioinguinal, and subcostal nerves were injured within the psoas major muscle, the retroperitoneal space, or the outer abdominal muscles and subcutaneous tissues. Genitofemoral nerve injuries were found in the retroperitoneal space. Nerve root injuries occurred within the retroperitoneal space and psoas muscle. Femoral nerve injuries were found only within the psoas major muscle. No obturator nerve injuries occurred. CONCLUSIONS: Lateral approaches can lead to structural nerve damage. Knowledge of the complex plexus anatomy, specifically its mediolateral course, is critical to avoid approach-related injuries. PMID- 28619497 TI - Long-Term Functional Outcome of Symptomatic Unruptured Intracranial Aneurysms in an Interdisciplinary Treatment Concept. AB - OBJECTIVE: In symptomatic unruptured intracranial aneurysms (UIAs), data on long term functional outcome are sparse in the literature, even in the light of modern interdisciplinary treatment decisions. We therefore analyzed our in-house database for prognostic factors and long-term outcome of neurologic symptoms after microsurgical/endovascular treatment. METHODS: Patients treated between 2000 and 2016 after interdisciplinary vascular board decision were included. UIAs were categorized as symptomatic in cases of cranial nerve or brainstem compression. Symptoms were categorized as mild/severe. Long-term development of symptoms after treatment was assessed in a standardized and independent fashion. RESULTS: Of 98 symptomatic UIAs (microsurgery/endovascular 43/55), 84 patients presented with cranial nerve (NII-VI) compression and 14 patients with brainstem compression symptoms. Permanent morbidity occurred in 9% of patients. Of 119 symptoms (mild/severe 71/48), 60.4% recovered (full/partial 22%/39%) and 29% stabilized by the time of last follow-up; median follow-up was 19.5 months. Symptom recovery was higher in the long-term compared with that at discharge (P = 0.002). Optic nerve compression symptoms were less likely to improve compared with abducens nerve palsies and brainstem compression. Prognostic factors for recovery were duration and severity of symptoms, treatment modality (microsurgery) and absence of ischemia in the multivariate analysis. CONCLUSIONS: This recent study presents for the first time a detailed analysis of relevant prognostic factors for long-term recovery of cranial nerve/brainstem compression symptoms in an interdisciplinary treatment concept, which was excellent in most patients, with lowest recovery rates in optic nerve compression. Symptom recovery was remarkably higher in the long-term compared with recovery at discharge. PMID- 28619498 TI - Microsurgical Treatment of Colloid Cysts of the Third Ventricle. AB - BACKGROUND: This study analyzes the results of surgical treatment in 377 patients with colloid cysts (CCs) of the third ventricle who were treated at the Burdenko Neurosurgery Institute from 1981 to 2015. Operations were performed by a single surgeon (the first author of the article). METHODS: The transcallosal approach was used to remove CCs in 97% of cases. Total cyst removal was performed in 96% of cases (in 4% of cases, a small cyst capsule fragment was left on the veins and fornix); in 3 cases, the cyst recurred, which required its repeated removal. RESULTS: Hydrocephalus symptoms regressed in 98% of patients. The most frequent complications in the early postoperative period were memory impairments of varying severity, with a tendency to regress by the time of discharge. Two patients had an intraventricular hematoma, which required operative exploration in 1 patient. There were 4 cases of meningitis (including 1 shunt-associated meningitis) and 5 cases of transient pyramidal insufficiency. CONCLUSIONS: We made a preliminary assessment of the reasonability of the infratentorial supracerebellar approach for removal of CCs in 10 cases. PMID- 28619499 TI - Results of Early High-Flow Bypass and Trapping for Ruptured Blood Blister-Like Aneurysms of the Internal Carotid Artery. AB - OBJECTIVE: The aim of this study is to clarify the efficacy and safety of early surgery using trapping of the affected internal carotid artery (ICA) and high flow bypass between the second portion of the middle cerebral artery and cervical external carotid artery with radial artery graft for ruptured blood blister-like aneurysms (BBAs) arising from the anterior wall of the ICA. METHODS: Medical charts of 16 consecutive patients (7 men and 9 women; mean, 59 years) with subarachnoid hemorrhage (World Federation of Neurosurgical Societies grade I, n = 2; grade II, n = 5; grade III, n = 2; grade IV, n = 4; grade V, n = 3) caused by ruptured BBA surgically treated between July 2010 and October 2015 were retrospectively reviewed. Eleven patients underwent acute surgery within 24 hours after the onset, whereas surgery was performed between 3 and 17 days after the onset because of referral delay or associated vasospasm in 5 patients. All patients underwent the same surgical procedure. RESULTS: Elimination of the BBA and patency of the bypass were achieved in all patients. Postoperatively, 2 patients showed small infarction in the Heubner artery area, and 2 others suffered symptomatic vasospasm, but no patient suffered infarction in the posterior communicating/anterior choroidal artery territories. Identically, no patient showed ischemic optic neuropathy. At the last follow-up (mean, 36 months), favorable clinical outcome (good recovery or mild disability in Glasgow Outcome Scale) was achieved in 14 (88%) of the patients without rebleeding or refilling of the aneurysms. CONCLUSIONS: Early surgical repair of BBAs by trapping of the affected ICA with high-flow bypass is safe and effective treatment with satisfactory midterm outcome. PMID- 28619500 TI - Was Cavum Septum Pellucidum the Cause of Intractable Seizure in a 17-Year-Old Boy with Wilson Disease? AB - BACKGROUND: Cavum septum pellucidum (CSP), which is often found incidentally in a few populations, occasionally becomes symptomatic if enlarged significantly. Wilson disease (WD) is an uncommon autosomal recessive inborn defect in copper metabolism characterized by abnormal accumulation of copper in various tissues, particularly in the liver and the brain. Seizure disorder, although rare both in CSP and WD, may happen in a few patients with either of the conditions. CASE DESCRIPTION: We report a case of 17-year-old boy, a patient with known WD, who developed intractable seizure for a year, which was not controlled with a large amount of antiepileptics. Magnetic resonance imaging showed enlargement of his preexisting CSP, which was small and asymptomatic at the time of diagnosis of WD. His WD was in a state of remission when he developed the seizure disorder. On endoscopic cyst fenestration, he was relieved of the seizure. CONCLUSIONS: Symptomatic CSP is a rare disorder, but the coexistence of WD is even rarer. Endoscopic cyst fenestration is a novel procedure that can be successful in properly selected cases. To the best of our knowledge, CSP associated with WD has not been reported in any English literature. We present this case for its rarity along with a relevant literature review. PMID- 28619501 TI - Irreversible Total Loss of Brain Function and Organ Donation in Patients with Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening disease with an often fatal clinical course leading to irreversible loss of brain function (ILBF) (i.e., brain death). The purpose of this study was to assess the prevalence and characteristics of patients with aSAH who became organ donors after diagnosis of ILBF. METHODS: Anonymized clinical data sets of 395 patients treated for aSAH at a university medical center from January 2011 to December 2016 were retrospectively analyzed. Prevalence of consent for organ donation and clinical characteristics, including parameters for diagnosis of irreversible loss of brain function, were assessed. RESULTS: After initial admission to the intensive care unit, 18.0% of patients (n = 71) died (Glasgow Outcome Scale score 1). Intracerebral hemorrhage occurred in 42.3% of patients who died, aneurysmal rebleeding occurred in 19.7%, and intraventricular hemorrhage occurred in 87.3%. In 50.7% of patients who died (n = 36), ILBF was diagnosed, and 32.4% (n = 23) of these patients became organ donors. In 55.6%, additional diagnostic electroencephalography was performed. Male patients significantly more often became organ donors than female patients (P = 0.008). ILBF with subsequent organ donation was predominantly seen in patients <60 years old. A total 85 of organs were explanted for donation, including 42 kidneys, 21 livers, 3 pancreas, 11 hearts and 8 lungs. CONCLUSIONS: ILBF in the setting of fatal aSAH is a prevalent diagnosis with complex demands for neurointensive care physicians. We demonstrated the clinical characteristics and epidemiologic factors of patients with aSAH converting to organ donors. PMID- 28619502 TI - "Outside Support": Curious Case of Duplicated Posterior Elements. PMID- 28619503 TI - Clinical Pharmacokinetics of Levornidazole in Elderly Subjects and Dosing Regimen Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis. AB - PURPOSE: Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. METHODS: Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years). The PK profiles of levornidazole and its metabolites in elderly subjects were evaluated and compared with those in the young group. WinNonlin software was used for simulating the PK profile of levornidazole in the elderly population following the dosing regimens of 500 mg BID and 750 mg once daily for 7 days. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment of both dosing regimens against Bacteroides spp. RESULTS: The Cmax, AUC0-24, and AUC0-infinity values of levornidazole in the elderly group were 11.98 MUg/mL, 131.36 MUg.h/mL, and 173.61 MUg.h/mL, respectively. The t1/2, CLt, and mean residence time from time 0 to infinity were 12.21 hours, 2.91 L/h, and 16.46 hours. The metabolic ratios of metabolites (M) 1, 2, 4, and 6 were <3.0%, and that of M16 was 17.70%. The urinary excretion values of levornidazole, M1, M2, M4, M6, and M16 over 96 hours were 10.21%, 0.92%, ~0%, 2.69%, 0.54%, and 41.98%. The PK properties of levornidazole and the urinary excretion of all metabolites were not statistically different between the 2 groups. The cumulative fraction of response was >90% against B fragilis and other Bacteroides spp, and the probability of target attainment was >90% when the minimum inhibitory concentration was <=1 MUg/mL, in both groups. IMPLICATIONS: No dosing regimen adjustment is suggested when levornidazole is used in elderly patients with normal hepatic functioning and mild renal dysfunction. The findings from the PK/PD analysis imply that both regimens may achieve satisfactory clinical and microbiological efficacy against anaerobic infections in elderly patients. Chinese Clinical Trial Registry (http://www.chictr.org.cn) identifier: ChiCTR-OPC-16007938. PMID- 28619504 TI - Kolaviron shows anti-proliferative effect and down regulation of vascular endothelial growth factor-C and toll like receptor-2 in Wuchereria bancrofti infected blood lymphocytes. AB - The anti-proliferative effect and down regulation of vascular endothelial growth factor C and toll like receptor-2 by kolaviron on Wuchereria bancrofti infected peripheral blood lymphocytes were investigated. Blood were collected from consenting volunteers in Talata Mafara, Nigeria, between the hours of 10pm to 12am, and microscopically identified for microfilariae. W. bancrofti positive samples were cultured for 72h treated with Doxycycline (2MUg/ml) and kolaviron (5MUg/ml) in vitro. Mitotic index, expression of vascular endothelial growth factor-C (VEGF-c), toll like receptor-2 (TLR-2) were determined using standard procedures. Mitotic index was significantly (P<0.05) reduced in the kolaviron treated group compared to negative control. Kolaviron also significantly (P<0.05) down regulated the expression of VEGF-c and TLR-2 when compared with the untreated group. In both cases, the effects of kolaviron was not significantly different (P<0.05) to that of doxycycline. Furthermore, strong positive correlations between mitotic index, VEGF-c and TLR-2 expressions were observed. The study suggests that kolaviron rich portion of Garcinia kola exhibited anti proliferative effect and down regulation of VEGF-c and TLR-2 in W. bancrofti infected blood. Thus, the results from this study might have unravelled the potency of kolaviron in the management of complications associated with lymphatic filariasis. PMID- 28619505 TI - Application of CRISPR-Cas9 in eye disease. AB - The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease (Cas)9 is an effective instrument for revising the genome with great accuracy. This system has been widely employed to generate mutants in genomes from plants to human cells. Rapid improvements in Cas9 specificity in eukaryotic cells have opened great potential for the use of this technology as a therapeutic. Herein, we summarize the recent advancements of CRISPR-Cas9 use in research on human cells and animal models, and outline a basic and clinical pipeline for CRISPR-Cas9-based treatments of genetic eye diseases. PMID- 28619506 TI - Near infra-red light attenuates corneal endothelial cell dysfunction in situ and in vitro. AB - In the present study mechanical damage to the corneal endothelium was induced by elevation of intraocular pressure (IOP, 140 mmHg, 60 min) to one eye of rats, delivered either in complete darkness or in the presence of red light (16.5 W/m2, 3000 lx, 625-635 nm). IOP raised in the dark revealed the endothelium to be damaged as staining for the gap junction protein ZO-1 was irregular in appearance with some cells displaced in position or lost to leave gaps or holes. This damage was clearly attenuated when red light was focused through the pupil during the insult of raised IOP. Moreover, staining of endothelium with JC-1 dye showed mitochondria to be activated by both elevated IOP and red light but the activation of mitochondria persisted longer for red light. We interpret this finding to suggest that raised IOP causes apoptosis of endothelial cells and that their mitochondria are activated in the initial stages of the process. In contrast, red light activates mitochondria to induce a protective mechanism to counteract the negative influence of raised IOP on endothelial cells. Evidence is provided to support this notion by the finding that red light stimulates mitochondrial cytochrome oxidase IV (COX IV). Moreover, mitochondria in corneal endothelial cell cultures are activated by red light, revealed by staining with JC-1, that results in an increased rate of proliferation and are also able to counteract toxic insults (sodium azide or cobalt chloride) to the cultures. The present studies therefore show that a non-toxic level of red light attenuates damage to the corneal endothelium both in situ and in vitro through action on COX IV located in mitochondria that results in an enhancement of a cell's survival mechanisms. The study provides proof of principle for the non-invasive use of red light therapy to attenuate any dysfunctions associated with the corneal endothelium and so preserve maximum visual acuity. PMID- 28619507 TI - Sensitivity of mitochondrial DNA depleted rho0 cells to H2O2 depends on the plasma membrane status. AB - To clarify the relationship between mitochondrial DNA (mtDNA)-depleted rho0 cells and the cellular sensitivity to hydrogen peroxide (H2O2), we established HeLa and SAS rho0 cell lines and investigated their survival rate in H2O2, radical scavenging enzymes, plasma membrane potential status, and chronological change in intracellular H2O2 amount under the existence of extracellular hydrogen peroxide compared with the parental cells. The results revealed that rho0 cells had higher sensitivity to H2O2 than their parental cells, even though the catalase activity of rho0 cells was up-regulated, and the membrane potential of the rho0 cells was lower than their parental cells. Furthermore, the internal H2O2 amount significantly increased only in rho0 cells after 50 MUM H2O2 treatment for 1 h. These results suggest that plasma membrane status of rho0 cells may cause degradation, and the change could lead to enhanced membrane permeability to H2O2. As a consequence, rho0 cells have a higher H2O2 sensitivity than the parental cells. PMID- 28619508 TI - MiR-129-5p inhibits non-small cell lung cancer cell stemness and chemoresistance through targeting DLK1. AB - Non-small cell lung cancer (NSCLC) stemness and chemoresistance represent significant barriers to successful treatment. Downregulation of microRNA 129 (miR 129) has been implicated in a variety of cancers, and miR-129-5p has recently been shown to reduce lung cancer proliferation and metastasis. In this study, we used NSCLC cell lines A549 and H460 to investigate the effects of miR-129-5p on NSCLC stemness and chemoresistance. CD133 + stem cells in both lines showed reduced miR-129-5p expression, and introducing miR-129-5p into these cells reduced stem cell markers and self-renewal ability, as measured by qRT-PCR, western blot, MTT assays, and sphere formation assays. MTT, colony formation, and DAPI staining assays further revealed that miR-129-5p inhibits NSCLC chemoresistance when the cells are treated with varying doses of CDDP. The target prediction algorithm TargetScan allowed us to identify notch signaling receptor delta-like 1 homolog (DLK1) as a potential target for miR-129-5p in its inhibition of NSCLC stemness and chemoresistance. Indeed, our DLK1 luciferase reporter plasmid demonstrated that miR-129-5p reduces DLK1 expression. Furthermore, DLK1 overexpression partially rescued inhibition of NSCLC stemness and chemoresistance caused by miR-129-5p. Overall, these results demonstrate that miR-129-5p inhibits NSCLC stemness and chemoresistance through direct targeting of DLK1. They suggest that miR-129-5p and DLK1 can play a role in an effective treatment strategy for NSCLC. PMID- 28619509 TI - miR-141-3p inhibits fibroblast proliferation and migration by targeting GAB1 in keloids. AB - Keloids are benign dermal fibroproliferative tumors that develop as a result of several dysregulated processes. Emerging evidence has revealed that miRNAs contribute to keloid formation. However, the molecular mechanisms of keloid pathogenesis remain unclear. In our study, we found that miR-141-3p in keloid tissues and keloid fibroblasts was significantly decreased compared with the levels in normal tissues and normal skin fibroblasts, respectively. miR-141-3p overexpression resulted in significantly decreased proliferation and migration and the promotion of apoptosis in keloid fibroblasts, whereas miR-141-3p knockdown in keloid fibroblasts yielded the opposite results. Growth factor receptor binding 2-associated binding protein 1 (GAB1) was identified and confirmed as a direct target of miR-141-3p. The expression of GAB1 was up regulated in keloid tissues, and the restoration of GAB1 partially reversed the inhibitory effects of miR-141-3p on the proliferation and migration of keloid fibroblasts. All data suggested that miR-141-3p decreased the proliferation and migration of keloid fibroblasts by repressing GAB1 expression, providing a useful target for keloid management. PMID- 28619510 TI - Crystal structure of BrlR with c-di-GMP. AB - The transcriptional regulator BrlR is a member of the MerR family of multidrug transport activators in Pseudomonas aeruginosa. Recent study indicates that BrlR is a novel 3',5'-cyclic diguanylic acid (c-di-GMP) receptor and can be activated by c-di-GMP. To gain insight into BrlR function, we determined the structure of BrlR with c-di-GMP complex structure to 2.5 A. The structure and size exclusion chromatography (SEC) data revealed BrlR forms a tetramer and each BrlR protomer consists of three parts, DNA-binding domain, a coiled-coil region and GyrI-like domain. There are two different c-di-GMP binding sites located mainly at the DNA binding domain of each BrlR protomer and do not overlap with the GyrI-like domain. The drug-binding pocket in GyrI-like domain is much conserved indicating it can also bind flat-shaped molecules like other multidrug resistance (MDR) proteins. PMID- 28619511 TI - AQP5 promotes hepatocellular carcinoma metastasis via NF-kappaB-regulated epithelial-mesenchymal transition. AB - Aquaporin 5 (AQP5), a transmembrane protein, is known for its involvement in the progress of many diseases such as chronic kidney disease and systemic disease. Recently, AQP5 has been reported to play an important role in cancer progression. However, little is known about its precise functions in hepatocellular carcinoma (HCC). This study aimed to investigate the specific role of AQP5 in HCC. The results showed that AQP5 was highly expressed in HCC cell lines and its down regulation inhibited HCC cell invasion and tumor metastasis in vitro and in vivo. In addition, down-regulation of AQP5 suppressed the epithelial-mesenchymal transition (EMT) process in HCC cells by modulating EMT-related molecules such as E-cadherin, alpha-catenin, N-cadherin and Vimentin. Further studies on corresponding mechanisms indicated that AQP5 down-regulation inhibited HCC metastasis and EMT partly via inactivation of the NF-kappaB signaling pathway. Taken together, these findings suggest that AQP5 may be a potential therapeutic target for HCC. PMID- 28619512 TI - PART-1 functions as a competitive endogenous RNA for promoting tumor progression by sponging miR-143 in colorectal cancer. AB - LncRNAs were altered in several cancers and played a crucial role in various biological activities and progressions of different diseases, including proliferation, chemical resistance, and metastasis. In the present study, we revealed that prostrate androgen-regulated transcript-1 (PART-1) was highly expressed in colorectal cancer cells and tissues, and knockdown of PART-1 suppressed cell proliferation and metastasis, both in vitro and in vivo. In addition, PART-1 functioned as a ceRNA of DNMT3A, by sponging miR-143. Finally,PART-1 induced tumor progression by regulating DNMT3A. PMID- 28619513 TI - Myricetin ameliorates scopolamine-induced memory impairment in mice via inhibiting acetylcholinesterase and down-regulating brain iron. AB - The aim of our study was to investigate to investigate the effect of myricetin on Alzheimer's disease (AD) and its underlying mechanisms. In our study, Myricetin effectively attenuated Fe2+-induced cell death in SH-SY5Y cells in vitro. In a mouse model of AD, myricetin treatment significantly reversed scopolamine-induced cognitive deficits deriving from a novel action of inhibiting acetylcholinesterase (AChE) and down-regulating brain iron. Furthermore, Myricetin treatment reduced oxidative damage and increased antioxidant enzymes activity in mice. Interestingly, the effect of myricetin was largely abolished by high iron diet. Therefore we suggested that treatment with myricetin attenuated cognitive deficits in mice via inhibiting AChE and brain iron regulation. In addition, myricetin reduce iron contents may via inhibiting transferrin receptor 1 (TrR1) expression. In conclusion, accumulated data demonstrates that myricetin is a potential multifunctional drug for AD. PMID- 28619514 TI - The frequency of Th17 cells in the small intestine exhibits a day-night variation dependent on circadian clock activity. AB - Interleukin-17-producing CD4+ T helper (Th17) cells are a key immune lineage that protects against bacterial and fungal infections at mucosal surfaces. At steady state, Th17 cells are abundant in the small intestinal mucosa of mice. There are several mechanisms for regulating the population of Th17 cells in the small intestine, reflecting the importance of maintaining their numbers in the correct balance. Here we demonstrate the existence of a time-of-day-dependent variation in the frequency of Th17 cells in the lamina propria of the small intestine in wild-type mice, which was not observed in mice with a loss-of-function mutation of the core circadian gene Clock or in mice housed under aberrant light/dark conditions. Consistent with this, expression of CCL20, a chemokine that regulates homeostatic trafficking of Th17 cells to the small intestine, exhibited circadian rhythms in the small intestine of wild-type, but not Clock-mutated, mice. In support of these observations, the magnitude of ovalbumin (OVA)-specific antibody and T-cell responses in mice sensitized with OVA plus cholera toxin, a mucosal Th17 cell-dependent adjuvant, was correlated with daily variations in the proportion of Th17 cells in the small intestine. These results suggest that the proportion of Th17 cells in the small intestine exhibits a day-night variation in association with CCL20 expression, which depends on circadian clock activity. The findings provide novel insight into the regulation of the Th17 cell population in the small intestine at steady state, which may have translational potential for mucosal vaccination strategies. PMID- 28619515 TI - Dynamic accommodation without feedback does not respond to isolated blur cues. AB - The aim of this study was to determine whether dynamic accommodation responds to isolated blur cues without feedback, and without changes in the distance of the object. Nine healthy subjects aged 21-40years were recruited. Four different aberration patterns were used as stimuli to induce blur with (1) the eye's natural, uncorrected, optical aberrations, (2) all aberrations corrected, (3) spherical aberration only, or (4) astigmatism only. The stimulus was a video animation based on computer-generated images of a monochromatic Maltese cross. Each individual video was generated for each subject off-line, after measuring individual aberrations at different accommodation levels. The video simulated sinusoidal changes in defocus at 0.2Hz. Dynamic images were observed through a 0.8mm pinhole placed at a plane conjugated with the eye's pupil, thus effectively removing potential feedback stemming from accommodation changes. Accommodation responses were measured with a Hartmann-Shack aberrometer for the four different aberration patterns. The results showed that seven out of nine subjects did not respond to any stimuli, whereas the response of the other two subjects was erratic and they seemed to be searching rather than following the stimulus. A significant reduction in average accommodative gain (from 0.52 to 0.11) was obtained when the dioptric demand cue was removed. No statistically significant differences were found among the experimental conditions used. We conclude that aberration related blur does not drive the accommodation response in the absence of feedback from accommodation. PMID- 28619517 TI - Acute sialadenitis as adverse reaction to iodinated contrast. AB - Swelling of the salivary glands after administration of iodinated contrast is a very rare adverse reaction. Its etiology is not clear and although it has a benign course associated complications have been reported. We report two cases of acute bilateral sialadenitis after intravenous iodinated contrast in 60 and 63 year-old men who underwent a computed tomography scan in the previous days. PMID- 28619518 TI - In vitro cytotoxic potential of friedelin in human MCF-7 breast cancer cell: Regulate early expression of Cdkn2a and pRb1, neutralize mdm2-p53 amalgamation and functional stabilization of p53. AB - We aimed to explore the cytotoxic and apoptotic effect of friedelin on breast cancer MCF-7 cells. Cytotoxic effect of friedelin on MCF-7 cells was analyzed using MTT, cell and nuclear morphology. The apoptosis mechanism of friedelin on MCF-7 cells was analyzed using real-time PCR. Friedelin potentially inhibit 78% of MCF-7 cell's growth, the IC50 value was 1.8MUM in 24h and 1.2MUM in 48h. Friedelin increased ROS significantly and DNA damage was confirmed by tunel assay. We found characteristically 52% apoptotic cells and 6% necrotic cells in PI, AO/ErBr staining after 48h treatment with 1.2MUM of friedelin. Apoptosis was confirmed by significantly (p<=0.001) increased tumor suppressor gene Cdkn1a, pRb2, p53, Nrf2, caspase-3 and decreased Bcl-2, mdm2 & PCNA expression after 48h. In conclusion, friedelin effectively inhibit breast cancer MCF-7 cell growth, it was associated with early expression of Cdkn1a, pRb2 and activation of p53 and caspases. PMID- 28619519 TI - A Diagnostic Challenge: Focal Fatty Liver or Metastasis? PMID- 28619516 TI - The inner blood-retinal barrier: Cellular basis and development. AB - The blood-retinal barrier (BRB) regulates transport across retinal capillaries maintaining proper neural homeostasis and protecting the neural tissue from potential blood borne toxicity. Loss of the BRB contributes to the pathophysiology of a number of blinding retinal diseases including diabetic retinopathy. In this review, we address the basis of the BRB, including the molecular mechanisms that regulate flux across the retinal vascular bed. The routes of transcellular and paracellular flux are described as well as alterations in these pathways in response to permeabilizing agents in diabetes. Finally, we provide information on exciting new studies that help to elucidate the process of BRB development or barriergenesis and how understanding this process may lead to new opportunities for barrier restoration in diabetic retinopathy. PMID- 28619520 TI - Cardiac Complications, Earlier Treatment, and Initial Disease Severity in Kawasaki Disease. AB - OBJECTIVES: To assess if observed higher observed risks of cardiac complications for patients with Kawasaki disease (KD) treated earlier may reflect bias due to confounding from initial disease severity, as opposed to any negative effect of earlier treatment. STUDY DESIGN: We used data from Japanese nationwide KD surveys from 1997 to 2004. Receipt of additional intravenous immunoglobulin (IVIG) (data available all years) or any additional treatment (available for 2003-2004) were assessed as proxies for initial disease severity. We determined associations between earlier or later IVIG treatment (defined as receipt of IVIG on days 1-4 vs days 5-10 of illness) and cardiac complications by stratifying by receipt of additional treatment or by using logistic modeling to control for the effect of receiving additional treatment. RESULTS: A total of 48 310 patients with KD were included in the analysis. In unadjusted analysis, earlier IVIG treatment was associated with a higher risk for 4 categories of cardiac complications, including all major cardiac complications (risk ratio, 1.10; 95% CI, 1.06-1.15). Stratifying by receipt of additional treatment removed this association, and earlier IVIG treatment became protective against all major cardiac complications when controlling for any additional treatment in logistic regressions (OR, 0.90; 95% CI, 0.80-1.00). CONCLUSIONS: Observed higher risks of cardiac complications among patients with KD receiving IVIG treatment on days 1-4 of the illness are most likely due to underlying higher initial disease severity, and patients with KD should continue to be treated with IVIG as early as possible. PMID- 28619521 TI - Overview of long non-coding RNA and mRNA expression in response to methamphetamine treatment in vitro. AB - Long non-coding RNAs (lncRNAs) display multiple functions including regulation of neuronal injury. However, their impact in methamphetamine (METH)-induced neurotoxicity has rarely been reported. Here, using microarray analysis, we investigated the expression profiling of lncRNAs and mRNAs in primary cultured prefrontal cortical neurons after METH treatment. We observed a difference in lncRNA and mRNA expression between the experimental and sham control groups. Using bioinformatics, we analyzed the highest enriched gene ontology (GO) terms of biological process, cellular component, and molecular function, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and pathway network analysis. Furthermore, an lncRNA-mRNA co-expression sub-network for aberrantly expressed terms revealed possible interactions of lncRNA NR_110713 and NR_027943 with their related genes. Afterwards, three lncRNAs (NR_110713, NR_027943, GAS5) and two mRNAs (Ddit3, Casp12) were targeted to validate the microarray data by qRT-PCR. This presented an overview of lncRNA and mRNA expression profiling and indicated that lncRNA might participate in METH-induced neuronal apoptosis by regulating the coding genes of neurons. PMID- 28619522 TI - Integrated analysis of paraquat-induced microRNAs-mRNAs changes in human neural progenitor cells. AB - Paraquat (PQ), one of the most widely used fast-acting and non-selective herbicides in the world is believed to act as a neurotoxicant, which increases the risk of developing Parkinson's disease (PD) by selectively impairing dopaminergic neurons. However, the mechanism of PQ on neural progenitor cells remains unclear. As regulator of mRNA expression, miRNA play a crucial role in neurotoxicity. Based on our previous study, we chose 10MUM PQ, which induced ROS production and inhibited proliferation but not reduced the cell viability. In this study, we present an integrative analysis of PQ-induced whole transcriptome changes and its regulatory miRNA networks in human neural progenitor cells (hNPCs). Integrated analysis of PQ-induced miRNA-mRNA alteration reveals differential expression of 3972 mRNAs and 52 miRNAs. Based on the GO analysis and pathway analysis of the intersection genes, we found 48 significantly altered GO terms and 22 significant pathways, among which, Wnt signaling being the top ranked pathway. We verified that the expression of 9 miRNAs and 11 mRNAs related to the Wnt signaling pathway were altered in a dose-dependent manner by qPCR. These results indicate that PQ changes mRNAs and miRNAs expression in hNPCs, leading to the alteration of several neurodevelopment related key biological processes and crucial pathways, especially Wnt signaling pathway. Moreover, it suggests that PQ could downregulate Wnt signaling pathway via miRNA to induce developmental neurotoxicity. PMID- 28619523 TI - Affective associations with negativity: Why popular peers attract youths' visual attention. AB - Visual attention to high-status peers is well documented, but whether this attentional bias is due to high-status individuals' leadership and prosocial characteristics or due to their more agonistic behaviors has yet to be examined. To identify the affective associations that may underlie visual attention for high-status versus low-status peers, 122 early adolescents (67 girls; Mage=11.0years, SD=0.7) completed a primed attention paradigm. Visual attention was measured using eye tracking as participants looked simultaneously at photographs of two classmates: one nominated by peers as popular and one nominated by peers as unpopular. Prior to each trial, the early adolescents were presented with a positive prime, the word "nice"; a negative prime, the word "stupid"; or no prime. Primary analyses focused on first-gaze preference and total gaze time The results showed a stronger first gaze preference for popular peers than for unpopular peers in the no-prime and negative prime trials than in the positive prime trials. The visual preference for a popular peer, thus, was attenuated by the positive prime. These findings are consistent with the notion that youths may visually attend to high-status peers due to their association with more negative characteristics and the threat they may pose to youths' own social standing and ability to gain interpersonal resources. PMID- 28619524 TI - Molecular determinants of radiosensitivity in normal and tumor tissue: A bioinformatic approach. AB - Although radiation therapy is a treatment of choice for cancer, a high percentage of patients develop adverse effects in normal tissue following radiotherapy, mainly, due to genetic factors. Notably, although it is established that a lower dose of ionizing radiation can minimize the tumor cell population in radiosensitive cancer patients, the sensitivity of tumor cells to radiation has not gained enough attention. In this mini-review, the molecular pathways/mechanisms and the related molecules involved in clinically relevant radiotoxicity, as well as normal and tumor cell radiosensitivity, were investigated for various types of cancers employing bioinformatics approaches. A total of 255 genes/gene products were retrieved and investigated in this study, which are implicated in pathways related mainly to DNA damage repair, oxidative stress, apoptosis and fibrosis. Furthermore, a novel molecular gene signature of normal tissue radiotoxicity was identified. The findings of our study could be utilized by healthcare professionals in personalized clinical decision-making, in order to efficiently sensitize tumor cells to radiation and yet minimize adverse effects in the adjacent normal tissues as well as to improve the quality of life in cancer patients undergoing radiotherapy. PMID- 28619525 TI - Murine and human pancreatic tumor exosome recovery in mouse serum: Diagnostic and prognostic potential and target cell delivery. AB - Exosomes (Exo), powerful intercellular communicators, are recovered in all body fluids, suggesting suitability for diagnosis and prognosis. Easy in vitro manipulation recommends Exo as drug vehicles. Aiming to consolidate diagnostic and therapeutic potential of Exo, we evaluated recovery and fate of tumor (TEX) and exogenous Exo in syngeneic and xenogeneic mice bearing a murine or a human pancreatic adenocarcinoma. A significant increase in serum (S)-TEX was observed 2 weeks after tumor cell application. Instead, S-TEX declined within 3-6 days after tumor excision. Intravenously injected dye-labeled TEX were rapidly cleared from the serum. Partly being degraded in the liver, the majority is taken-up by PBL, liver, bone marrow and lung cells. In the tumor-bearing host TEX persisted longer becoming enriched in tumor cells and metastatic organs. Accordingly, an antibody blockade of a TEX marker hampered disseminated tumor cell settlement in selected organs. In brief, a tumor marker panel appears suited for S-TEX recovery. In murine models, S-TEX are qualified for therapy control and follow-up studies. Despite rapid clearance from the serum, Exo uptake by host cells is most promising for tailored Exo as drug transporter. PMID- 28619526 TI - Auto-induction of Pichia pastoris AOX1 promoter for membrane protein expression. AB - Pichia pastoris is a highly successful recombinant protein expression system due to its ability to quickly generate large quantities of recombinant proteins in simple media. P. pastoris has been used to successfully generate milligram quantities of many important human membrane proteins, including G-protein coupled receptors, ion channels, and transporters, which are becoming increasingly important therapeutic targets. Despite these successes, protein expression in P. pastoris is still cumbersome due to a need to change growth media from glycerol media to methanol induction media, which minimizes inhibition of the AOX1 promoter by residual glycerol. Taking advantage of this behavior of the AOX1 promoter, we developed Buffered extra-YNB Glycerol Methanol (BYGM) auto-induction media (100 mM potassium phosphate pH 6.0, 2.68% w/v YNB, 0.4% v/v glycerol, 0.5% v/v methanol, and 8 * 10-5% w/v biotin) which not only simplified the protein expression process, but also optimized protein expression levels in P. pastoris. We successfully used this auto-induction method to overexpress the target in both MutS and Mut+ strains. Moreover, we show that this method can facilitate screening high-expressing clones, as well as enable parallel protein production in P. pastoris. PMID- 28619527 TI - Expression of full-length HER2 protein in Sf9 insect cells and its presentation on the surface of budded virus-like particles. AB - Biomarkers of cancer are often glycosylated membrane receptor proteins present on the cellular surface. In order to develop new antibodies for cancer diagnostics or treatment, it is a main pre-requisite that these target proteins are available in a native conformation. However, membrane receptor proteins are notoriously difficult to produce due to their hydrophobic nature and complex architecture. Here, we used the baculovirus-insect cell expression system to produce budded virus-like particles (VLPs) as the scaffold for the presentation of complex membrane proteins. Since the human epidermal growth factor receptor 2 (HER2) is known to be overexpressed in a number of cancers it was chosen as model for a tumor antigen. VLPs displaying full-length HER2 on the surface were produced in Spodoptera frugiperda 9 (Sf9) insect cells and purified by sucrose gradient ultracentrifugation. The number of secreted particles was quantified by nanoparticle tracking analysis. To confirm the presence of HER2 protein on the surface, VLPs were labeled with gold-conjugated antibodies and analyzed by transmission electron microscopy. Functionality of displayed HER2 was investigated by ELISA and a newly established biolayer interferometry based technique. Detection was accomplished using the specific monoclonal antibody Herceptin and filamentous phages displaying a single-chain variable fragment of an anti-HER2 antibody. Significant stronger binding of Herceptin and anti-HER2 phages to HER2-displaying VLPs as compared to control VLPs was demonstrated. Thus, we suggest that Sf9 insect cells are highly feasible for the fast and easy production of various budded VLPs that serve as a platform for full-length membrane receptor presentation. PMID- 28619528 TI - Ineffective cough and mechanical mucociliary clearance techniques. AB - Cough is a fundamental defense mechanism for keeping the airway free of foreign elements. Life-threatening situations may arise when cough proves ineffective as a result of muscle weakness or altered mucociliary function. When a patient is unable to cough effectively, techniques are required to either reinforce or replace cough capacity. The use of mechanical systems that facilitate or substitute cough function is increasingly common in Intensive Care Units, where it is relatively frequent to find situations of ineffective cough due to different clinical causes. This review examines the current clinical practice recommendations referred to the indication and use of mechanical cough assist and intrapulmonary percussive ventilation systems. PMID- 28619530 TI - Neural networks underlying language and social cognition during self-other processing in Autism spectrum disorders. AB - The social communication impairments defining autism spectrum disorders (ASD) may be built upon core deficits in perspective-taking, language processing, and self other representation. Self-referential processing entails the ability to incorporate self-awareness, self-judgment, and self-memory in information processing. Very few studies have examined the neural bases of integrating self other representation and semantic processing in individuals with ASD. The main objective of this functional MRI study is to examine the role of language and social brain networks in self-other processing in young adults with ASD. Nineteen high-functioning male adults with ASD and 19 age-sex-and-IQ-matched typically developing (TD) control participants made "yes" or "no" judgments of whether an adjective, presented visually, described them (self) or their favorite teacher (other). Both ASD and TD participants showed significantly increased activity in the medial prefrontal cortex (MPFC) during self and other processing relative to letter search. Analyses of group differences revealed significantly reduced activity in left inferior frontal gyrus (LIFG), and left inferior parietal lobule (LIPL) in ASD participants, relative to TD controls. ASD participants also showed significantly weaker functional connectivity of the anterior cingulate cortex (ACC) with several brain areas while processing self-related words. The LIFG and IPL are important regions functionally at the intersection of language and social roles; reduced recruitment of these regions in ASD participants may suggest poor level of semantic and social processing. In addition, poor connectivity of the ACC may suggest the difficulty in meeting the linguistic and social demands of this task in ASD. Overall, this study provides new evidence of the altered recruitment of the neural networks underlying language and social cognition in ASD. PMID- 28619529 TI - On the partnership between neural representations of object categories and visual features in the ventral visual pathway. AB - A dominant view in the cognitive neuroscience of object vision is that regions of the ventral visual pathway exhibit some degree of category selectivity. However, recent findings obtained with multivariate pattern analyses (MVPA) suggest that apparent category selectivity in these regions is dependent on more basic visual features of stimuli. In which case a rethinking of the function and organization of the ventral pathway may be in order. We suggest that addressing this issue of functional specificity requires clear coding hypotheses, about object category and visual features, which make contrasting predictions about neuroimaging results in ventral pathway regions. One way to differentiate between categorical and featural coding hypotheses is to test for residual categorical effects: effects of category selectivity that cannot be accounted for by visual features of stimuli. A strong method for testing these effects, we argue, is to make object category and target visual features orthogonal in stimulus design. Recent studies that adopt this approach support a feature-based categorical coding hypothesis according to which regions of the ventral stream do indeed code for object category, but in a format at least partially based on the visual features of stimuli. PMID- 28619531 TI - [Find your way in the jungle of mAbs]. AB - The rapidly increasing number of approved monoclonal antibodies (mAbs) and the huge number of mAbs in clinical development are a matter of concern for who wants to easily identify targets, indications, mechanisms of action and possible adverse effects. The current nomenclature being of limited interest, simple rationales will be presented for helping practitioners in rapidly classify mAbs depending on their structure-pharmacology relationship and in evaluating their potential effects, particularly in transfusion medicine. PMID- 28619533 TI - [Dyslipidemia management in patients with high cardiovascular risk in Spain. ALMA study]. AB - OBJECTIVE: To assess the attitude of primary care (PCPs) and specialized care (SCPs) physicians towards the general set of patients with dyslipidemia, particularly those with cardiovascular risk factors. DESIGN: Observational, descriptive, multi-center study based on a survey. LOCATION: Different healthcare regions in Spain. PARTICIPANTS: 1,402 PCPs, and 596 SCPs. MAIN MEASUREMENTS: Physician's profile, routine practices in the management of patients with dyslipidemia. RESULTS: 84.3% took the global cardiovascular risk into account when prescribing the treatment. Target LDL-C concentration in patients without cardiovascular risk factors was <130mg/dL and <160mg/dL for 51.9% and 29.0% of physicians, respectively. In smokers and patients with hypertension or diabetes, the LDL target was <100mg/dL for 49-55% of physicians, whereas in patients with cardiovascular complication, ischemic cardiopathy or stroke, target LDL-C was <70mg/dL in 71-88% of them. First-line treatment for patients without cardiovascular risk factors was atorvastatin (66%), whereas in patients with diabetes, kidney disease or metabolic syndrome, most physicians (80-89%) used pitavastatin. SCPs showed a greater trend than PCPs to establish a LDL-C target of <70mg/dL in patients with previous stroke (77.5% vs 66.8%) or coronary disease (92.1% vs 80.6%) (P<.0001), as well as to prescribe a combined treatment in patients not achieving the target LDL-C concentrations (58.1% vs 50.2%, P=.0013). CONCLUSIONS: Although CVR assessment is generally accepted, there is broad disagreement in defining the objectives of LDL-C. Most often than PCPs, the SCPs consider more ambitious targets for LDL-C and the association of lipid-lowering drugs. PMID- 28619532 TI - Major Physical Health Conditions and Risk of Suicide. AB - INTRODUCTION: Most individuals make healthcare visits before suicide, but many do not have a diagnosed mental health condition. This study seeks to investigate suicide risk among patients with a range of physical health conditions in a U.S. general population sample and whether risk persists after adjustment for mental health and substance use diagnoses. METHODS: This study included 2,674 individuals who died by suicide between 2000 and 2013 along with 267,400 controls matched on year and location in a case-control study conducted in 2016 across eight Mental Health Research Network healthcare systems. A total of 19 physical health conditions were identified using diagnostic codes within the healthcare systems' Virtual Data Warehouse, including electronic health record and insurance claims data, during the year before index date. RESULTS: Seventeen physical health conditions were associated with increased suicide risk after adjustment for age and sex (p<0.001); nine associations persisted after additional adjustment for mental health and substance use diagnoses. Three conditions had a more than twofold increased suicide risk: traumatic brain injury (AOR=8.80, p<0.001); sleep disorders; and HIV/AIDS. Multimorbidity was present in 38% of cases versus 15.5% of controls, and represented nearly a twofold increased risk for suicide. CONCLUSIONS: Although several individual conditions, for example, traumatic brain injury, were associated with high risk of suicide, nearly all physical health conditions increased suicide risk, even after adjustment for potential confounders. In addition, having multiple physical health conditions increased suicide risk substantially. These data support suicide prevention based on the overall burden of physical health. PMID- 28619534 TI - Cryptochrome photoreceptors in green algae: Unexpected versatility of mechanisms and functions. AB - Green algae have a highly complex and diverse set of cryptochrome photoreceptor candidates including members of the following subfamilies: plant, plant-like, animal-like, DASH and cryptochrome photolyase family 1 (CPF1). While some green algae encode most or all of them, others lack certain members. Here we present an overview about functional analyses of so far investigated cryptochrome photoreceptors from the green algae Chlamydomonas reinhardtii (plant and animal like cryptochromes) and Ostreococcus tauri (CPF1) with regard to their biological significance and spectroscopic properties. Cryptochromes of both algae have been demonstrated recently to be involved to various extents in circadian clock regulation and in Chlamydomonas additionally in life cycle control. Moreover, CPF1 even performs light-driven DNA repair. The plant cryptochrome and CPF1 are UVA/blue light receptors, whereas the animal-like cryptochrome responds to almost the whole visible spectrum including red light. Accordingly, plant cryptochrome, animal-like cryptochrome and CPF1 differ fundamentally in their structural response to light as revealed by their visible and infrared spectroscopic signatures, and in the role of the flavin neutral radical acting as dark form or signaling state. PMID- 28619535 TI - Evolution and regulation of Bigelowiella natans light-harvesting antenna system. AB - Bigelowiella natans is a mixotrophic flagellate and member of the chlorarachniophytes (Rhizaria), whose plastid is derived from a green algal endosymbiont. With the completion of the B. natans nuclear genome we are able to begin the analysis of the structure, function and evolution of the photosynthetic apparatus. B. natans has undergone substantial changes in photosystem structure during the evolution of the plastid from a green alga. While Photosystem II (PSII) composition is well conserved, Photosystem I (PSI) composition has undergone a dramatic reduction in accessory protein subunits. Coinciding with these changes, there was a loss of green algal LHCI orthologs while the PSII-like antenna system has the expected green algal-like proteins (encoded by genes Lhcbm1-8, Lhcb4). There are also a collection of LHCX-like proteins, which are commonly associated with stramenopiles and other eukaryotes with red-algal derived plastids, along with two other unique classes of LHCs- LHCY and LHCZ- whose function remains cryptic. To understand the regulation of the LHC gene family as an initial probe of function, we conducted an RNA-seq experiment under a short-term, high-light (HL) and low-light stress. The most abundant LHCII transcript (Lhcbm6) plus two other LHCBM types (Lhcbm1, 2) were down regulated under HL and up-regulated following a shift to very-low light (VL), as is common in antenna specializing in light harvesting. Many of the other LHCII and LHCY genes had a small, but significant increase in HL and most were only moderately affected under VL. The LHCX and LHCZ genes, however, had a strong up-regulation under HL-stress and most declined under VL, suggesting that they primarily have a role in photoprotection. This contrasts to the LHCY family that is only moderately responsive to light and a much higher basal level of expression, despite being within the LHCSR/LHCX clade. The expression of LHCX/Z proteins under HL-stress may be related to the induction of long-term, non-photochemical quenching mechanisms. PMID- 28619536 TI - Discovery of the selective sphingomyelin synthase 2 inhibitors with the novel structure of oxazolopyridine. AB - Sphingomyelin synthase (SMS) is a key enzyme in sphingomyelin biosynthetic pathway, whose activity is highly related to the atherosclerosis progression. SMS2 could serve as a promising therapeutic target for atherosclerosis. Based on the structure of lead compound D2, a series of oxazolopyridine derivatives were designed, synthesized, and their inhibitory activities against purified SMS1 and SMS2 enzymes were evaluated respectively. The representative molecules QY4 and QY16 possess micromolar inhibitory activities against SMS2 and excellent isoform preferences over SMS1, qualified to be selected as potential molecules in further discovery of specific SMS2 inhibitors. PMID- 28619537 TI - Synthesis and biological evaluation of caffeic acid derivatives as potent inhibitors of alpha-MSH-stimulated melanogenesis. AB - We have disclosed our effort to develop caffeic acid derivatives as potent and non-toxic inhibitors of alpha-MSH-stimulated melanogenesis to treat pigmentation disorders and skin medication including a cosmetic skin-whitening agent. The SAR studies revealed that cyclohexyl ester and secondary amide derivatives of caffeic acid showed significant inhibitory activities. PMID- 28619538 TI - Synthesis and biological evaluation of 2-(3,4-dimethoxyphenyl)-6-(2 [18F]fluoroethoxy)benzothiazole ([18F]FEDBT) for PET imaging of breast cancer. AB - Given the ever-present demand for improved PET radiotracer in oncology imaging, we have synthesized 2-(3,4-dimethoxyphenyl)-6-(2-[18F]fluoroethoxy)benzothiazole ([18F]FEDBT), a fluorine-18-containing fluoroethylated benzothiazole to explore its utility as a PET imaging tracer. [18F]FEDBT was prepared via kryptofix mediated nucleophilic substitution of the tosyl group precursor. Fractionated ethanol-based solid-phase (SPE cartridge-based) purification afforded [18F]FEDBT in 60% radiochemical yield (EOB), with radiochemical purity in excess of 98% and the specific activity was 35GBq/MUmol. The radiotracer displayed clearly higher cellular uptake ratio in various breast cancer cell lines MCF7, MDA-MB-468 and MDA-MB-231. However, both biodistribution and microPET studies have showed an higher abdominal accumulation of [18F]FEDMBT and the tumor/muscle ratio of 1.8 was observed in the MDA-MB-231 xenograft tumors mice model. Further the lipophilic improvement is needed for the reducement of hepatobilliary accumulation and to promote the tumor uptake for PET imaging of breast cancer. PMID- 28619539 TI - Systemic Immunological changes in patients with distinct clinical outcomes during Mycobacterium tuberculosis infection. AB - BACKGROUND: The lung lesions in an individual infected with tuberculosis (TB) are surprisingly variable and independent of each other. However, there is no circulating biomarker yet able to segregate patients according to the extent of lung lesions. MATERIALS AND METHODS: In this study, the phenotypic and functional profile of leukocytes of patients with active pulmonary tuberculosis (TB) and controls (CO) were fully scrutinized by immunophenotyping assays and in vitro short-term whole blood culture. The TB group was subdivided according to the extent of lung lesions as unilateral (UNI) and bilateral (BI). RESULTS: The results show that TB group display an altered leukocyte profile in the peripheral blood with significant lower counts of NK-cells, CD3+CD56+CD16+/- NKT-cells, CD4+T-cells, CD19+B-cells when compared to CO. Increased CD4+T-cells and CD8+T cell activation was observed by the upregulation of activation markers (HLA-DR) as well as of chemokine receptors (CCR2, CCR3, and CXCR4). In addition, TB group presented a significant decrease proportion of CD14LowCD16+ monocytes despite the increase in HLA-DR expression. Regarding the severity of the disease, in the BI group a reduction in frequency of CD19+CD5+ B-cells and expression of HLA-DR in CD14LowCD16+ monocytes was observed. Furthermore, the extent of lung lesions influences the production of molecules as observed by significantly larger production of IL-4 by neutrophils, total T-cells, CD4+T-cells, CD8+T-cells and CD19+B-cells in UNI as compared to BI. By contrast, in BI group the frequency of high producers of both IL-17+CD4+T-cells and IL-17+CD8+T-cells were significantly increased than UNI, suggesting the deleterious role of these subsets during active pulmonary Mtb infection. CONCLUSION: The immunophenotypic characterization of unilateral and bilateral active TB performed in the present study indicates that the extent of lung lesion could be associated with a fine-tuning between immunological responses during untreated Mtb infection. PMID- 28619540 TI - Video-Assisted Thoracic Surgery Thymectomy Versus Sternotomy Thymectomy in Patients With Thymoma. AB - BACKGROUND: This study was designed to evaluate the feasibility of video-assisted thoracoscopic surgery (VATS) and to compare the oncologic outcomes of VATS with those of sternotomy in patients with thymoma. METHODS: The clinical outcomes of 2,835 patients with thymic epithelial tumors treated between 1991 and 2010 in 32 Japanese institutions were collected retrospectively. The study compared postoperative complications, positive surgical margins, location of recurrence, and survival in 140 of 142 VATS-treated patients (VATS group) matched with 140 of 1,294 sternotomy-treated patients (ST group) by using propensity scores. RESULTS: Postoperative complications were observed in 8 patients in the VATS group. The morbidity rate in the VATS group was not different from that of the ST group (p = 0.25). Positive surgical margins were noted in 4 patients (3 in the VATS group; 1 in the ST group). There was no statistically significant difference in the recurrence rate between groups (median follow-up period: 3.7 years in the VATS group; 5.2 years in the ST group). In total the most frequent site of recurrence was pleural dissemination. In the VATS group, the 5-year recurrence-free survival rate was 93.8%, and the 5-year overall survival rate was 97.9%. There was no difference in the recurrence-free survival and overall survival rates between the VATS group and the ST group (p = 0.91 and p = 0.74, respectively). CONCLUSIONS: VATS thymectomy was feasible and comparable to sternotomy for the treatment of patients with thymoma with regard to morbidity, incomplete resection rate, and prognosis. However, additional follow-up is required to evaluate long-term outcomes. PMID- 28619542 TI - Development of a Multidisciplinary Program to Expedite Care of Esophageal Emergencies. AB - BACKGROUND: Level 1 programs have improved outcomes by expediting the multidisciplinary care of critically ill patients. We established a novel level 1 program for the management of esophageal emergencies. METHODS: After institutional review board approval, we performed a retrospective analysis of patients referred to our level 1 esophageal emergency program from April 2013 through November 2015. A historical comparison group of patients treated for the same diagnosis in the previous 2 years was used. RESULTS: Eighty patients were referred and transported an average distance of 56 miles (range, 1-163 miles). Median time from referral to arrival was 2.4 hours (range, 0.4-12.9 hours). Referrals included 6 (7%) patients with esophageal obstruction and 71 (89%) patients with suspected esophageal perforation. Of the patients with suspected esophageal perforation, causes included iatrogenic (n = 26), Boerhaave's syndrome (n = 32), and other (n = 13). Forty-six percent (n = 33) of patients were referred because of pneumomediastinum, but perforation could not be subsequently demonstrated. Initial management of patients with documented esophageal perforation included operative treatment (n = 25), endoscopic intervention (n = 8), and supportive care (n = 5). Retrospective analysis demonstrated a statistically significant difference in mean Pittsburgh severity index score (PSS) between esophageal perforation treatment groups (p < 0.01). In patients with confirmed perforations, there were 3 (8%) mortalities within 30 days. More patients in the esophageal level 1 program were transferred to our institution in less than 24 hours after diagnosis than in the historical comparison group (p < 0.01). CONCLUSIONS: Development of an esophageal emergency referral program has facilitated multidisciplinary care at a high-volume institution, and early outcomes appear favorable. PMID- 28619541 TI - Can Renal Resistive Index Predict Acute Kidney Injury After Acute Type A Aortic Dissection Repair? AB - BACKGROUND: This study sought to determine whether assessment of the renal resistive index (RRI) can predict the short-term reversibility of acute kidney injury (AKI) after repair of acute type A aortic dissection (TAAD). METHODS: This prospective study included 62 patients undergoing repair of acute TAAD. Doppler based RRIs were obtained preoperatively, immediately after the surgical procedure, and 6, 24, and 48 hours postoperatively. The occurrence of AKI was evaluated daily according to Acute Kidney Injury Network criteria. Persistent AKI was defined as AKI lasting longer than 3 days. The association between the maximum RRI level at different time points and persistent AKI was analyzed by the receiver-operating characteristic curve. RESULTS: Of the 62 patients, 22 (35.5%) had no AKI, 21 (33.9%) had transient AKI, and 19 (30.6%) had persistent AKI. The maximum RRI was 0.67 +/- 0.03 (0.62 to 0.71), 0.71 +/- 0.05 (0.59 to 0.79), and 0.78 +/- 0.05 (0.70 to 0.92) in the no AKI, transient AKI, and persistent AKI groups, respectively. The maximum level of RRI was significantly correlated with that of SCr during the first 48 hours postoperatively (rho = 0.606; p < 0.001). RRI could predict persistent AKI with an area under the receiver-operating characteristic curve of 0.918 (95% confidence interval, 0.850 to 0.986; p < 0.001). A postoperative RRI of 0.725 or higher was a marker for early detection of persistent AKI with high sensitivity and specificity (94.7% and 72.1%, respectively). CONCLUSIONS: An elevated maximum RRI may be a predictor of persistent AKI after repair of acute TAAD. This is helpful for management decision making and improving the prognosis of patients with AKI. PMID- 28619543 TI - Circumferential Three-Dimensional-Printed Tracheal Grafts: Research Model Feasibility and Early Results. AB - BACKGROUND: Methods for tracheal graft research have presented persistent challenges to investigators, and three-dimensional (3D)-printed biosynthetic grafts offer one potential development platform. We aimed to develop an efficient research platform for customizable circumferential 3D-printed tracheal grafts and evaluate feasibility and early structural integrity with a large-animal model. METHODS: Virtual 3D models of porcine subject tracheas were generated using preoperative computed tomography scans. Two designs were used to test graft customizability and the limits of the construction process. Designs I and II used 270-degree and 360-degree external polycaprolactone scaffolds, respectively, both encompassing a circumferential extracellular matrix collagen layer. The polycaprolactone scaffolds were made in a fused-deposition modeling 3D printer and customized to the recipient's anatomy. Design I was implanted in 3 pigs and design II in 2 pigs, replacing 4-ring tracheal segments. Data collected included details of graft construction, clinical outcomes, bronchoscopy, and gross and histologic examination. RESULTS: The 3D-printed biosynthetic grafts were produced with high fidelity to the native organ. The fabrication process took 36 hours. Grafts were implanted without immediate complication. Bronchoscopy immediately postoperatively and at 1 week demonstrated patent grafts and appropriate healing. All animals lived beyond a predetermined 1-week survival period. Bronchoscopy at 2 weeks showed significant paraanastomotic granulation tissue, which, along with partial paraanastomotic epithelialization, was confirmed on pathology. Overall survival was 17 to 34 days. CONCLUSIONS: We propose a rapid, reproducible, resource efficient method to develop various anatomically precise grafts. Further graft refinement and strategies for granulation tissue management are needed to improve outcomes. PMID- 28619544 TI - Changes in Tracheostomy- and Intubation-Related Tracheal Stenosis: Implications for Surgery. AB - BACKGROUND: This study sought to identify the changing characteristic patterns and locations of stenosis after tracheostomy or intubation and to assess the risk factors associated with perioperative complication and restenosis after primary resection and reconstruction. METHODS: A retrospective review was performed (January /2012 to March 2015) on patients treated at the University of Arizona Medical Center (Tucson, Arizona) who had symptomatic tracheal stenosis secondary to prolonged intubation or tracheostomy. Data on demographics, surgical approach, and outcome were obtained. Analysis was performed using the chi2 test, Kaplan Meier estimate of survival, Cox proportional hazards survival analysis, and univariate and multivariate logistic regression. RESULTS: Forty-eight patients were referred for surgical resection, and 36 patients underwent primary resection and reconstruction; 72% of patients had previous endobronchial treatments for stenosis. Fourteen patients had postintubation tracheal stenosis, and 22 had tracheostomy-related stenosis (16 percutaneous, 6 open tracheostomy). Among all patients, 52.8% had stenosis proximal to or involving the cricoid; 72.7% of patients with tracheostomy-related stenosis had stenosis at or proximal to the cricoid, whereas only 21.4% of the patients with intubation-related stenosis had a similar location. Nineteen patients underwent laryngotracheal resection, and 17 patients had tracheal resection. The mean length of resection was 3.6 cm. A body mass index greater than 35 was associated with increased perioperative complications (p = 0.012). In multivariate analysis, patients younger than 30 years of age at operation had an increased relative risk of recurrence. CONCLUSIONS: Recent advances in percutaneous tracheostomy have increased the numbers of patients presenting with proximal tracheal stenosis, thus necessitating more complex subglottic resection and reconstruction. The anastomotic and overall complication rate remains low despite these more complex operations. PMID- 28619546 TI - Screening in Developmental Dysplasia of the Hip (DDH). AB - : Screening for Developmental Dysplasia of the Hip (DDH) is a controversial subject. Screening may be by universal neonatal clinical examination (Ortolani or Barlow manoeuvres) with the addition of sonographic imaging of the hip (selective 'at risk' hips or universal screening in the neonate). In the UK, the NIPE guidelines recommend universal neonatal clinical assessment of the hip joints, a General Practitioner 6-8 week clinical 'hip check' and assessment clinically with sonographic imaging at 4-6 weeks for certain 'at risk' hips for pathological DDH. The effectiveness and difficulties arising from the UK current screening policy (clinical and sonographic) are highlighted. The purpose of the review was to assess the risk factors and efficacy of diagnostic methods in DDH, based on longitudinal cohort studies of 10 years or more. CONCLUSION: Hip screening in DDH does not meet most of the World Health Organisation's criteria for an effective screening programme and should only be considered as surveillance due to its low sensitivity and positive predictive value (PPV). There is a significant risk of over diagnosis and over treatment. There is no International consensus on screening in DDH. Pathological DDH is mainly a female condition and 'at risk'/General Practitioner screening identifies few pathological cases in male subjects. The General Practitioner 6-8 week 'hip check' has a very low PPV for pathological DDH and is of doubtful value in screening and diagnosis. Unilateral limitation of hip abduction is a time dependent and useful clinical sign in the diagnosis of pathological DDH. The majority of the previously considered 'at risk' factors are not true risk factors with little or no association with pathological DDH. PMID- 28619545 TI - Blast-related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release. AB - Mild traumatic brain injury (mTBI) caused by exposure to high explosives has been called the "signature injury" of the wars in Iraq and Afghanistan. There is a wide array of chronic neurological and behavioral symptoms associated with blast induced mTBI. However, the underlying mechanisms are not well understood. Here we used a battlefield-relevant mouse model of blast-induced mTBI and in vivo fast scan cyclic voltammetry (FSCV) to investigate whether the mesolimbic dopamine system contributes to the mechanisms underlying blast-induced behavioral dysfunction. In mice, blast exposure increased novelty seeking, a behavior closely associated with disinhibition and risk for subsequent maladaptive behaviors. In keeping with this, we found that veterans with blast-related mTBI reported greater disinhibition and risk taking on the Frontal Systems Behavior Scale (FrSBe). In addition, in mice we report that blast exposure causes potentiation of evoked phasic dopamine release in the nucleus accumbens. Taken together these findings suggest that blast-induced changes in the dopaminergic system may mediate aspects of the complex array of behavioral dysfunctions reported in blast-exposed veterans. PMID- 28619547 TI - A systematic review of the management and outcome of ERCP related duodenal perforations using a standardized classification system. AB - INTRODUCTION: The incidence of duodenal perforation after ERCP ranges from 0.09% to 1.67% and mortality up to 8%. METHODS: This systematic review was registered in Prospective Register of Systematic Reviews, PROSPERO. Stapfer classification of ERCP-related duodenal perforations was used. RESULTS: The systematic search yielded 259 articles. Most frequent post-ERCP perforation was Stapfer type II (58.4%), type I second most frequent perforation (17.8%) followed by Stapfer type III in 13.2% and type IV in 10.6%. Rate of NOM was lowest in Stapfer type I perforations (13%), moderate in type III lesions (58.1%) and high in other types of perforations (84.2% in type II and 84.6% in IV). In patients underwent early surgical treatment (<24 h from ERCP) the most frequent operation was simple duodenal suture with or without omentopexy (93.7%). In patients undergoing late surgical treatment (>24 h from ERCP) interventions performed were more complex. In type I lesions post-operative mortality rate was higher in patients underwent late operation (>24 h). In type I lesions, failure of NOM occurred in 42.8% of patients. In type II failure of NOM occurred in 28.9% of patients and in type III there was failure of NOM in only 11.1%, none in type IV. Postoperative mortality after NOM failure was 75% in type I, 22.5% in type II and none died after surgical treatment for failure of NOM in type III perforations. CONCLUSIONS: This systematic review showed that in patients with Stapfer type I lesions, early surgical treatment gives better results, however the opposite seems true in Stapfer III and IV lesions. PMID- 28619549 TI - Fetal exposure to lead during pregnancy and the risk of preterm and early-term deliveries. AB - Studies have reported the association between lead exposure during pregnancy and preterm birth. However, findings are still inconsistent. This prospective birth cohort study evaluated the risks of preterm and early-term births and its association with prenatal lead exposure in Hubei, China. A total of 7299 pregnant women were selected from the Healthy Baby Cohort. Maternal urinary lead levels were measured by the Inductively Coupled Plasma Mass Spectrometry. The associations between tertiles of urinary lead levels and the risks of preterm and early-term deliveries were assessed using multiple logistic regression models. The geometric mean of creatinine-adjusted urinary lead concentrations among all participating mothers, preterm birth, and early-term birth were 3.19, 3.68, and 3.17MUg/g creatinine, respectively. A significant increase in the risk of preterm births was associated with the highest urinary lead tertile after adjusting for confounders with odds ratio (OR) of 1.96. The association was more pronounced among 25-36 years old mothers with OR of 2.03. Though significant p trends were observed between lead exposure (medium and high tertiles) and the risk of early term births, their ORs were not significant. Our findings indicate that the risk of preterm birth might increase with higher fetal lead exposure, particularly among women between the age of 25 and 36 years. PMID- 28619550 TI - New discoveries in the pathogenesis and classification of vitiligo. AB - Vitiligo is a common autoimmune disease that progressively destroys melanocytes in the skin, resulting in the appearance of patchy depigmentation. This disfiguring condition frequently affects the face and other visible areas of the body, which can be psychologically devastating. The onset of vitiligo often occurs in younger individuals and progresses for life, resulting in a heavy burden of disease and decreased quality of life. Presentation patterns of vitiligo vary, and recognition of these patterns provides both diagnostic and prognostic clues. Recent insights into disease pathogenesis offer a better understanding of the natural history of the disease, its associations, and potential for future treatments. The first article in this continuing medical education series outlines typical and atypical presentations of vitiligo, how they reflect disease activity, prognosis, and response to treatment. Finally, we discuss disease associations, risk factors, and our current understanding of disease pathogenesis. PMID- 28619548 TI - Review: Emerging concepts in the pathogenesis of tendinopathy. AB - Tendinopathy is a common clinical problem and has a significant disease burden attached, not only in terms of health care costs, but also for patients directly in terms of time off work and impact upon quality of life. Controversy surrounds the pathogenesis of tendinopathy, however the recent systematic analysis of the evidence has demonstrated that many of the claims of an absence of inflammation in tendinopathy were more based around belief than robust scientific data. This review is a summary of the emerging research in this topical area, with a particular focus on the role of neuronal regulation and inflammation in tendinopathy. PMID- 28619551 TI - Evidence-based recommendations for the management of acne fulminans and its variants. AB - BACKGROUND: Acne fulminans (AF) is a severe variant of inflammatory acne. It typically manifests as an explosive worsening and ulceration of skin lesions, and can be associated with systemic symptoms. However, there is a paucity of evidence based information and no clear guidelines concerning the classification and treatment of AF. OBJECTIVE: To better define the spectrum of AF and its variants, devise optimal therapeutic approaches, and identify areas of future research. METHODS: A panel of physicians with expertise in severe acne vulgaris was convened after a comprehensive literature review of severe acne variants. Priority topics were reviewed and presented by each panelist at a 5-hour conference. Following review of the audiotape and scribed notes from the conference, surveys were utilized to address points of controversy and to clarify consensus recommendations. RESULTS: Appropriate clinical case presentations and consensus survey questions were utilized to create final recommendations based on both the literature and the expert consensus. LIMITATIONS: Limited evidenced based data and prospective studies in the literature concerning the treatment of AF is available. CONCLUSION: These guidelines better characterize AF and provide health care practitioners approaches to the classification, treatment, and prevention of AF and its variants. PMID- 28619552 TI - Surgical outcomes of patients on isotretinoin in the perioperative period: A single-center, retrospective analysis. PMID- 28619553 TI - Methotrexate treatment in patients with a history of cutaneous melanoma and the risk of a consecutive primary melanoma: A national retrospective registry-based cohort study. PMID- 28619554 TI - A prospective evaluation of the candle wax sign: A visual clue to diagnose aggressive basal cell carcinoma. PMID- 28619555 TI - Optimal time to provide skin cancer and photoprotection education to pediatric solid organ transplant recipients. PMID- 28619556 TI - Topical Janus kinase inhibitors for the treatment of pediatric alopecia areata. PMID- 28619557 TI - Current and emerging treatments for vitiligo. AB - Clinicians should be aware that vitiligo is not merely a cosmetic disease and that there are safe and effective treatments available for vitiligo. It is important to recognize common and uncommon presentations and those with active disease, as well as their implications for clinical management; these were discussed in the first article in this continuing medical education series. Existing treatments include topical and systemic immunosuppressants, phototherapy, and surgical techniques, which together may serve to halt disease progression, stabilize depigmented lesions, and encourage repigmentation. We discuss how to optimize the currently available treatments and highlight emerging treatments that may improve treatment efficacy in the future. PMID- 28619558 TI - Systematic review and quality analysis of studies on the efficacy of topical diphenylcyclopropenone treatment for alopecia areata. PMID- 28619559 TI - Unusual patterns of presentation of frontal fibrosing alopecia: A clinical and trichoscopic analysis of 98 patients. PMID- 28619560 TI - Rotterdam criteria-based diagnostic subtype is not a strong predictor of cutaneous phenotype in patients with polycystic ovary syndrome: A cross-sectional study. PMID- 28619561 TI - Risk of Alzheimer's disease is not increased among patients with hidradenitis suppurativa: A retrospective population-based cohort analysis. PMID- 28619562 TI - Apremilast treatment of atopic dermatitis and other chronic eczematous dermatoses. PMID- 28619563 TI - Ethnicity affects the presenting severity of psoriasis. PMID- 28619564 TI - Clinical registries: Should physicians accept payments for enrolling patients? PMID- 28619565 TI - Commentary: Clinical registries: The good, the bad, and the ugly. PMID- 28619566 TI - Comorbidities in patients with psoriasis: The role of the dermatologist. PMID- 28619567 TI - Beyond JAAD July 2017: Articles of interest to dermatologists from the nondermatologic literature. PMID- 28619569 TI - Imprinting lesion size and surgical margins to facilitate patient education. PMID- 28619570 TI - Removal of large epidermoid cysts by use of a minimal-incision technique. PMID- 28619571 TI - Temporary application of transparent adhesive film dressing for the prevention of splash-back during local anesthetic administration in dermatologic surgery. PMID- 28619572 TI - Inaccuracies in SEER registry data on melanoma thickness. PMID- 28619573 TI - Reply to: "Inaccuracies in SEER registry data on melanoma thickness". PMID- 28619575 TI - Reduction of early nodules after injection of hyaluronic acid filler. PMID- 28619576 TI - Preapplication of white petroleum jelly to adjacent skin to prevent aluminum chloride-induced irritant dermatitis. PMID- 28619577 TI - Ingenol mebutate for the management of genital warts in sensitive anatomic locations. PMID- 28619578 TI - Analysis of Pressure Distribution During Direct Microlaryngoscopy. AB - OBJECTIVE: This study aimed to investigate the pressure distribution during direct microlaryngoscopy and its relation with the positioning of the patient. STUDY DESIGN: This is a prospective study in cadavers. MATERIALS AND METHODS: The pressure distribution during direct microlaryngoscopy was investigated in five adult fresh cadavers by using matrix-based piezoresistive thin-film sensors. The pressure among three head and neck positions (extension-extension, neutral, and flexion-extension) was studied. RESULTS: The real-time pressure and its distribution were recorded as 3-D contours. The map commonly showed two peak pressure points, with one focused on the middle of the laryngoscope (peak pressure 1) and the other one focused on the distal part of the laryngoscope (peak pressure 2). The mean average pressure in this study was 38 +/- 13 kPa, and the flexion-extension position had the lowest average pressure and peak pressure. However, the average pressure and peak pressure 1 showed no significant difference among the three positions (P > 0.05); peak pressure 2 in the flexion extension position was significantly lower than that in the extension-extension position (P = 0.024) and the neutral position (P = 0.020). CONCLUSIONS: The results of this study indicate that the flexion-extension position induced lower pressure exerted on the laryngoscope and is an optimal position for direct microlaryngoscopy. Hyoid bone may play an important role in the pressure exerted. PMID- 28619580 TI - Corrigendum to "MKP-1 negatively regulates LPS-mediated IL-1beta production through p38 activation and HIF-1alpha expression". (Cell Signal. 34 (1-10) (2017) Epub 2017 Feb 24). PMID- 28619579 TI - Recording sympathetic nerve activity from the skin. AB - Sympathetic tone is important in cardiac arrhythmogenesis; however, methods to estimate sympathetic tone are either invasive or require proper sinus node function that may be abnormal in disease states. Because of the direct and extensive connections among various nerve structures, it is possible for the sympathetic nerves in the various structures to activate simultaneously. Therefore, we hypothesized that nerve activity can be recorded from the skin and it can be used to estimate the cardiac sympathetic tone. Preclinical studies in canines demonstrated that nerve activity is detectable using conventional ECG electrodes and can be used to estimate cardiac sympathetic tone. Subsequent clinical studies further supported this concept. In addition to studying the autonomic mechanisms of cardiac arrhythmia, these new methods may have broad application in studying both cardiac and non-cardiac diseases. PMID- 28619581 TI - [Cardiovascular risk of smoking by gender]. AB - In France, the increase in the prevalence of women's smoking has been major over the past 30 years. The consequences are a significant increase and an unusual precocity of all the women's cardiovascular (CV) pathologies (myocardial infarction, stroke and aortic pathologies). Associated factors (combined oral contraception, unequal distribution of other CV risk factors by sex) increase the CV impact of women's smoking. For the same tobacco use, women have a 25% higher risk of coronary heart disease than men. The risk awareness is lower in women than in men and medical management insufficient. For women, medications are more often needed to quit smoking. The medical management of women's smoking is a major public health priority. PMID- 28619582 TI - [Why I am an intern in occupational medicine and why I am delighted!] PMID- 28619583 TI - Trans-oesophageal echocardiography for acute systemic embolism: Check the heart don't forget the aorta. PMID- 28619584 TI - Application of C8 liquid chromatography-tandem mass spectrometry for the analysis of enniatins and bassianolides. AB - Several moderately pathogenic Fusarium species produce enniatins, a family of cyclohexadepsipeptides with insecticidal and phytotoxic activities. A semi targeted LC-MS/MS approach utilizing reversed-phase C8 UHPLC column chromatography that combines both product ion and neutral loss filtering was developed to detect enniatins and structurally-related compounds in a sample. Using this methodology, resolution of all major enniatins was achieved with a 6 min LC run. From extracts of F. avenaceum, F. acuminatum and F. subglutinans, 23 enniatins and 16 previously unreported bassianolide-like cyclooctadepsipeptides were detected. Enniatins B, B1, A1 and A were the most frequently detected enniatins from silage and inoculated maize. The newly discovered bassianolide compounds were also detected, in lesser amounts on inoculated maize and in naturally contaminated silage. PMID- 28619586 TI - Determination of acidity constants and prediction of electrophoretic separation of amyloid beta peptides. AB - In this paper we describe a strategy to estimate by CE the acidity constants (pKa) of complex polyprotic peptides from their building peptide fragments. CE has been used for the determination of the pKas of five short polyprotic peptides that cover all the sequence of amyloid beta (Abeta) peptides 1-40 and 1-42 (Abeta fragments 1-15, 10-20, 20-29, 25-35 and 33-42). First, the electrophoretic mobility (me) was measured as a function of pH of the background electrolyte (BGE) in the pH range 2-12 (bare fused silica capillary, I=25mM and T=25 degrees C). Second, the mes were fitted to equations modelling the ionisable behaviour of the different fragments as a function of pH to determine their pKas. The accuracy of the pKas was demonstrated predicting the electrophoretic behaviour of the studied fragments using the classical semiempirical relationships between me and peptide charge-to-mass ratio (me vs. q/Mr1/2, classical polymer model, q=charge and Mr=relative molecular mass). Separation selectivity in a mixture of the fragments as a function of pH was evaluated, taking into account the influence of the electroosmotic flow (EOF) at each pH value, and a method for the simple and rapid simulation of the electropherograms at the optimum separation pH was described. Finally, the pKas of the fragments were used to estimate the pKas of the Abeta peptides 1-40 and 1-42 (tC and D 3.1, E 4.6 and Y 10.8 for acidic amino acids and tN-D 8.6, H 6.0, K 10.6 and R 12.5 for basic amino acids), which were used to predict their behaviour and simulate their electropherograms with excellent results. However, as expected due to the very small differences on q/Mr1/2 values, separation resolution of their mixtures was poor over the whole pH range. The use of poly(vinyl alcohol) (PVA) coated capillaries allowed reducing the EOF and a slight improvement of resolution. PMID- 28619585 TI - Sensitivity enhancement by chromatographic peak concentration with ultra-high performance liquid chromatography-nuclear magnetic resonance spectroscopy for minor impurity analysis. AB - High performance liquid chromatography can be coupled with nuclear magnetic resonance (NMR) spectroscopy to give a powerful analytical method known as liquid chromatography-nuclear magnetic resonance (LC-NMR) spectroscopy, which can be used to determine the chemical structures of the components of complex mixtures. However, intrinsic limitations in the sensitivity of NMR spectroscopy have restricted the scope of this procedure, and resolving these limitations remains a critical problem for analysis. In this study, we coupled ultra-high performance liquid chromatography (UHPLC) with NMR to give a simple and versatile analytical method with higher sensitivity than conventional LC-NMR. UHPLC separation enabled the concentration of individual peaks to give a volume similar to that of the NMR flow cell, thereby maximizing the sensitivity to the theoretical upper limit. The UHPLC concentration of compound peaks present at typical impurity levels (5.0 13.1 nmol) in a mixture led to at most three-fold increase in the signal-to-noise ratio compared with LC-NMR. Furthermore, we demonstrated the use of UHPLC-NMR for obtaining structural information of a minor impurity in a reaction mixture in actual laboratory-scale development of a synthetic process. Using UHPLC-NMR, the experimental run times for chromatography and NMR were greatly reduced compared with LC-NMR. UHPLC-NMR successfully overcomes the difficulties associated with analyses of minor components in a complex mixture by LC-NMR, which are problematic even when an ultra-high field magnet and cryogenic probe are used. PMID- 28619587 TI - Chemicalome and metabolome profiling of polymethoxylated flavonoids in Citri Reticulatae Pericarpium based on an integrated strategy combining background subtraction and modified mass defect filter in a Microsoft Excel Platform. AB - Detection of metabolites in complex biological matrixes is a great challenge because of the background noise and endogenous components. Herein, we proposed an integrated strategy that combined background subtraction program and modified mass defect filter (MMDF) data mining in a Microsoft Excel platform for chemicalome and metabolome profiling of the polymethoxylated flavonoids (PMFs) in Citri Reticulatae Pericarpium (CRP). The exogenously-sourced ions were firstly filtered out by the developed Visual Basic for Applications (VBA) program incorporated in the Microsoft Office. The novel MMDF strategy was proposed for detecting both target and untarget constituents and metabolites based on narrow, well-defined mass defect ranges. The approach was validated to be powerful, and potentially useful for the metabolite identification of both single compound and homologous compound mixture. We successfully identified 30 and 31 metabolites from rat biosamples after oral administration of nobiletin and tangeretin, respectively. A total of 56 PMFs compounds were chemically characterized and 125 metabolites were captured. This work demonstrated the feasibility of the integrated approach for reliable characterization of the constituents and metabolites in herbal medicines. PMID- 28619588 TI - A system map for the ionic liquid stationary phase 1,12 di(tripropylphosphonium)dodecane bis(trifluoromethylsulfonyl)imide trifluoromethanesulfonate for gas chromatography. AB - The solvation parameter model is used to prepare a system map for the retention of volatile organic compounds on the ionic liquid stationary phase 1,12 di(tripropylphosphonium)dodecane bis(trifluoromethylsulfonyl)imide trifluoromethanesulfonate (SLB-IL61) over the temperature range 80-260 degrees C. Retention is governed by dispersion, dipole-type and hydrogen-bonding interactions each with its own temperature dependence. The exchange of a bis(trifluoromethylsulfonyl)imide anion in SLB-IL60 for a trifluromethanesulfonate anion (SLB-IL61) results in a change in selectivity indicated by an increase in the hydrogen-bond basicity and a decrease in hydrogen bond acidity of the stationary phase without change in either the cohesion or dipolarity/polarizability of the stationary phases. At high temperatures there are small differences in electron lone pair interactions but these are relatively unimportant in terms of selectivity differences. Since the disclosed chemical structures for SLB-IL60 and SLB-IL61 does not contain obvious hydrogen-bond acid functional groups the modest hydrogen-bond acidity of these stationary phases was unexpected but does not appear to be obviously connected to adsorption sites at the column wall. The polarity number is shown to be a poor indicator of column retention properties for SLB-IL61. Principal component analysis with the system constants as variables indicates that the retention properties of SLB-IL61 are not duplicated by any of the common poly(siloxane) and poly(ethylene glycol) stationary phase chemistries in current use for column preparation. The SLB-IL61 column is closest in separation properties to poly(cyanopropylphenyldimethylsiloxane) and poly(cyanopropylmethyldimethysiloxane) stationary phases with a high percentage of cyanopropyl-containing monomer but the two stationary phase types are not selectivity equivalent. PMID- 28619589 TI - Isolation of sutherlandins A, B, C and D from Sutherlandia frutescens (L.) R. Br. by counter-current chromatography using spiral tubing support rotors. AB - Spiral countercurrent-chromatography has great potential for improving the capacity and efficiency of purification of secondary metabolites, and here we describe applications useful for the isolation of flavonoids from the widely used South African medicinal plant, Sutherlandia frutescens (L.) R. Br. In the spiral tubing support rotor, STS-4 for high-speed counter-current chromatography, several polar butanol aqueous solvent systems were selected using a logK plot, and the novel flavonol glycosides (sutherlandins A-D) were well separated by the optimized solvent system (ethyl acetate:n-butanol:acetic acid:water; 5:1:0.3:6 by vol.). The yield of purified flavonoids from 0.9g extract varied from 8.6mg to 54mg of the sutherlandins for a total of 85.3mg. The same extract was fractionated in the new STS-12 rotor of the same outside dimensions but with more radial channels forming 12 loops of the tubing instead of 4. The rotor holds more layers and increased length of tubing. From 0.9g extract the STS-12 rotor yielded more recovery of 110.4mg total with amounts varying from 11.2mg to 64mg of the sutherlandins and apparent increased separation efficiency as noted by less volume of each fraction peak. Thus from 1-g amounts of extract, good recovery of the flavonoids was achieved in the butanol aqueous solvent system. PMID- 28619590 TI - Prototyping of thermoplastic microfluidic chips and their application in high performance liquid chromatography separations of small molecules. AB - The present paper discusses practical aspects of prototyping of microfluidic chips using cyclic olefin copolymer as substrate and the application in high performance liquid chromatography. The developed chips feature a 60mm long straight separation channel with circular cross section (500MUm i.d.) that was created using a micromilling robot. To irreversibly seal the top and bottom chip substrates, a solvent-vapor-assisted bonding approach was optimized, allowing to approximate the ideal circular channel geometry. Four different approaches to establish the micro-to-macro interface were pursued. The average burst pressure of the microfluidic chips in combination with an encasing holder was established at 38MPa and the maximum burst pressure was 47MPa, which is believed to be the highest ever report for these polymer-based microfluidic chips. Porous polymer monolithic frits were synthesized in-situ via UV-initiated polymerization and their locations were spatially controlled by the application of a photomask. Next, high-pressure slurry packing was performed to introduce 3MUm silica reversed-phase particles as the stationary phase in the separation channel. Finally, the application of the chip technology is demonstrated for the separation of alkyl phenones in gradient mode yielding baseline peak widths of 6s by applying a steep gradient of 1.8min at a flow rate of 10MUL/min. PMID- 28619591 TI - Doxycycline as a new chiral selector in capillary electrophoresis. AB - Doxycycline (DOX) is one of the tetracycline class of antibiotics and has not been examined for its enantioseparation abilities previously. The purpose of the present work was to evaluate DOX as a chiral selector (CS) using capillary electrophoresis (CE) in nonaqueous mode. Systematic experiments were performed to investigate the effects of concentration of CS, compositions of organic solvents and background electrolytes, applied voltage on chiral separation of a set of acidic chiral compounds. Excellent resolutions of enantiomers of acidic chiral compounds were attained in a background electrolytes composed of 50:50 acetonitrile/methanol+214mM acetic acid+ 63mM triethylamine and 38mM DOX. The results show that DOX is a viable chiral selector in CE for the enantioseparation of the type of chiral compounds investigated. PMID- 28619592 TI - Hyphenation of ultra high performance supercritical fluid chromatography with atmospheric pressure chemical ionisation high resolution mass spectrometry: Part 1. Study of the coupling parameters for the analysis of natural non-polar compounds. AB - An analytical method based on Ultra-High-Performance Supercritical Fluid Chromatography (UHPSFC) coupled with Atmospheric Pressure Chemical Ionization - High-resolution mass spectrometry (APCI-Q-TOF-HRMS) was developed for compounds screening from oily samples. The hyphenation was made using a commercial UHPLC device coupled to a CO2 pump in order to perform the chromatographic analysis. An adaptation of the injection system for compressible fluids was accomplished for this coupling: this modification of the injection sequence was achieved to prevent unusual variations of the injected volume related to the use of a compressible fluid. UHPSFC-HRMS hyphenation was optimized to enhance the response of the varied compounds from a seed extract (anthraquinones, free fatty acids, diacylglycerols, hydroxylated triacylglycerols and triacylglycerols). No split was used prior to the APCI ionization source, allowing introducing all the compounds in the spectrometer, ensuring a better sensitivity for minor compounds. The effects of a mechanical make-up (T-piece) added before this ionization source was discussed in terms of standard deviation of response, response intensity and fragmentation percentage. The location of the T-piece with regards to the backpressure regulator (BPR), the flow rate and the nature of the make-up solvent were studied. Results show that the effects of the studied parameters depend on the nature of the compounds, whereas the make-up addition favours the robustness of the mass response (quantitative aspect). PMID- 28619593 TI - On the halt of spontaneous capillary flows in diverging open channels. AB - Due to their compactness and independence of exterior energy sources, capillary microsystems are increasingly used in many different scientific domains, from biotechnology to medicine and biology, chemistry, energy and space. Obtaining a capillary flow depends on channel geometry and contact angle. A general condition for the establishment of a spontaneous capillary flow in a uniform cross section channel has already been derived from Gibbs free energy. In this work, we consider spontaneous capillary flows (SCF) in diverging open rectangular channels and suspended channels, and we show that they do not flow indefinitely but stop at some location in the channel. In the case of linearly diverging open channels, we derive the expression that determines the location where the flow stops. The theoretical approach is verified by using the Surface Evolver numerical program and is checked by experiments. The approach is extended to sudden enlargements, and it is shown that the enlargements can act as stop and trigger valves. PMID- 28619594 TI - Characterisation of medical microfluidic systems regarding fast changing flow rates using optical front tracking methods. AB - The presented optical flow metering methods are appropriate to characterise the dynamic properties of microfluidic systems. The dynamic behaviour of clinical or medical devices, micro pumps and flow sensors based on thermal methods were investigated. The Camera-System covers a flow range from 50nl/min to 500ul/min. The uncertainty is less than 4%, sample rates up to 5kS/s. The Displacement Sensor-System covers a flow range between 100ul/min and 50ml/min. The uncertainty is less than 3% at sample rates up to 49kS/s. It was shown that measuring pulsating flow rates with thermal flow sensors is possible, but the signal is low pass filtered. The low pass behaviour is determined by the thermal properties, thermal resistance and heat capacity, of the flow channel. But the mean flow rate was always measured properly. The fluidic properties of two different types of micro pumps were examined and characterised exemplary. PMID- 28619595 TI - Eutrophication affects the resistance of fucoids to an introduced alga spread. AB - This study investigates whether eutrophication can affect the capacity of the canopy alga Cystoseira brachycarpa to impede or limit the spread of the introduced species Caulerpa cylindracea. By means of a manipulative field study (16 months long), the effects of nutrient enrichment and C. cylindracea removal were tested on the canopy-alga and the associated macroalgal community. Results highlighted deep changes through time due to nutrient enrichment, as C. brachycarpa decreased and Halopteris scoparia increased in cover. Furthermore, C. brachycarpa was also affected by the presence of the introduced species Caulerpa cylindracea which, in turn, was found significantly advantaged by nutrient enrichment. Overall, our findings suggest that eutrophication can drive the substitution of Cystoseira with H. scoparia, leading to the shift from canopy to opportunistic species, which are unable to avoid the spread of C. cylindracea. PMID- 28619596 TI - Selective p300 inhibitor C646 inhibited HPV E6-E7 genes, altered glucose metabolism and induced apoptosis in cervical cancer cells. AB - High risk HPV infection is a causative factor of cervical cancer. The constitutive expression of HPV E6-E7 genes is important for the maintenance of cancer phenotypes. The cellular transcription co-activator p300 plays a crucial role in the regulation of HPV genes thus it was targeted for the inhibition of HPV-associated cervical cancer. In the present study, HPV positive cervical cells were treated with C646, a selective inhibitor of p300, to investigate its influence on HPV E6-E7 expression and cancer cell growth. Results of RT-qPCR, Western-blot and promoter activity assays showed that C646 inhibited the transcription of HPV E6-E7, which was accompanied with the accumulation of p53 protein. Meanwhile, cell proliferation was suppressed, glucose metabolism was disrupted and apoptosis was induced via the intrinsic pathway. Generally, the anti-cervical cancer potential of C646 was demonstrated and a novel mechanism was proposed in this study. PMID- 28619597 TI - The Andalusian Bipolar Family (ABiF) Study: Protocol and sample description. AB - INTRODUCTION: Here, we present the first description of the Andalusian Bipolar Family (ABiF) Study. This longitudinal investigation of families from Andalusia, Spain commenced in 1997 with the aim of elucidating the molecular genetic causes of bipolar affective disorder. The cohort has since contributed to a number of key genetic findings, as reported in international journals. However, insight into the genetic underpinnings of the disorder in these families remains limited. METHOD: In the initial 1997-2003 study phase, 100 multiplex bipolar disorder and other mood disorder families were recruited. The ongoing second phase of the project commenced in 2013, and involves follow-up of a subgroup of the originally recruited families. The aim of the follow-up investigation is to generate: i) longitudinal clinical data; ii) results from detailed neuropsychological assessments; and iii) a more extensive collection of biomaterials for future molecular biological studies. RESULTS: The ABiF Study will thus generate a valuable resource for future investigations into the aetiology of bipolar affective disorder; in particular the causes of high disease loading within multiply affected families. DISCUSSION: We discuss the value of this approach in terms of new technologies for the identification of high-penetrance genetic factors. These new technologies include exome and whole genome sequencing, and the use of induced pluripotent stem cells or model organisms to determine functional consequences. PMID- 28619598 TI - Incremental prognostic value of a complex left ventricular remodeling classification in asymptomatic for heart failure hypertensive patients. AB - We evaluated the prognostic impact of a complex remodeling classification (CRC) in asymptomatic patients with arterial hypertension (AH). We retrospectively included 749 hypertensive patients (female 325, 43.4% age 62 +/- 11.3 years) in Stages A and B of heart failure. CRC was evaluated including indexed left ventricular mass, end-diastolic volume, and relative wall thickness. After 45 month follow-up, we considered a composite endpoint: total mortality, myocardial infarction, myocardial revascularization, cerebrovascular events, and acute pulmonary edema. Blood pressure was controlled in 265 patients (35.4%), 317 (42.3%) were in Grade 1 of AH, 123 (16.4%) in Grade 2, and 44 (5.9%) in Grade 3. Considering CRC, 292 patients (38%) presented normal/physiological hypertrophy, 102 (13.6%) concentric remodeling, 29 (3.9%) eccentric remodeling, 157 (21%) concentric hypertrophy, 11 (1.5%) mixed hypertrophy, 52 (6.9%) dilated hypertrophy, and 36 (4.8%) eccentric hypertrophy. We observed a total of 73 events (9.7%). Kaplan-Meier method demonstrated a significant different survival in CRC-derived classes (P < .001). Cox regression demonstrated CRC as independent predictor (P = .01), after adjusting for age, gender, diabetes mellitus, grade of hypertension, antihypertensive therapy, stable ischemic heart disease, obesity, systolic and diastolic dysfunction, and classic remodeling classification. In asymptomatic patients with AH, CRC is an independent predictor of poor outcome. PMID- 28619599 TI - Impact of sulfuric and nitric acids on carbonate dissolution, and the associated deficit of CO2 uptake in the upper-middle reaches of the Wujiang River, China. AB - Carbonate weathering and the CO2 consumption in karstic area are extensive affected by anthropogenic activities, especially sulfuric and nitric acids usage in the upper-middle reaches of Wujiang River, China. The carbonic acid would be substituted by protons from sulfuric and nitric acids which can be reduce CO2 absorption. Therefore, The goal of this study was to highlight the impacts of sulfuric and nitric acids on carbonate dissolution and the associated deficit of CO2 uptaking during carbonate weathering. The hydrochemistries and carbon isotopic signatures of dissolved inorganic carbon from groundwater were measured during the rainy season (July; 41 samples) and post-rainy season (October; 26 samples). Our results show that Ca2+ and Mg2+ were the dominant cations (55.87 98.52%), and HCO3- was the dominant anion (63.63-92.87%). The combined concentrations of Ca2+ and Mg2+ commonly exceeded the equivalent concentration of HCO3-, with calculated [Ca2++Mg2+]/[HCO3-] equivalent ratios of 1.09-2.12. The mean measured groundwater delta13CDIC value (-11.380/00) was higher than that expected for carbonate dissolution mediated solely by carbonic acid (-11.50/00), and the strong positive correlation of these values with [SO42-+NO3-]/HCO3- showed that additional SO42- and NO3- were required to compensate for this cation excess. Nitric and sulfuric acids are, therefore, suggested to have acted as the additional proton-promoted weathering agents of carbonate in the region, alongside carbonic acid. The mean contribution of atmospheric/pedospheric CO2 to the total aquatic HCO3- decreased by 15.67% (rainy season) and 14.17% (post-rainy season) due to the contributions made by these acids. The annual mean deficit of soil CO2 uptake by carbonate weathering across the study area was 14.92%, which suggests that previous workers may have overestimated the absorption of CO2 by carbonate weathering in other karstic areas worldwide. PMID- 28619600 TI - Corrigendum to "Assessment of immunotoxicity of dibutyl phthalate using live zebrafish" [Fish & Shellfish Immunology (Fish & Shellfish Immunol.) 45 (2) (2015) 286-292]. PMID- 28619601 TI - LDL cholesterol was more strongly associated with percent body fat than body mass index and waist circumference in a health screening population. AB - AIMS: To compare correlations between changes in cardiovascular risk factors and those in obesity indices and to compare associations with incident hyper-LDL cholesterolemia among obesity indices. METHODS: Correlation coefficients were calculated between 7-year changes in cardiovascular risk factors and those in body mass index (BMI), waist circumference (WC) and percent body fat (PBF) in 634 men and 396 women who used no antihypertensive, antidiabetic or antihyperlipidemic drugs. Odds ratios of incident hyper-LDL cholesterolemia after 7 years were calculated for BMI, WC and PBF in 738 men and 388 women. RESULTS: There were no significant differences in the correlations with 7-year changes in cardiovascular risk factors between 7-year changes in BMI and WC. The correlation with 7-year change in LDL cholesterol was stronger for that in PBF than that in BMI or WC (p=0.021 or 0.089, respectively in men and 0.022 or 0.020, respectively in women). The correlations with 7-year changes in log triglycerides, HDL cholesterol and log high-sensitivity CRP were stronger for those in BMI and WC than that in PBF in men. Incident hyper-LDL cholesterolemia after 7 years was significantly associated with PBF, but not BMI or WC, in men after adjusted for age and other covariates. However, the association was not significant after further adjusted for LDL cholesterol. CONCLUSIONS: The correlation with 7-year change in LDL cholesterol was stronger for that in PBF than that in BMI or WC. Incident hyper-LDL cholesterolemia was significantly associated with PBF, but not with BMI or WC, in men. PMID- 28619602 TI - Optimized method for isolation of immature intracytoplasmic retroviral particles from mammalian cells. AB - To biochemically and structurally characterize viral intracytoplasmic particles (ICAPs), a sample of high purity and homogeneity is usually required. Production of ICAPs in the system closely related to their natural host cells is crucial for the analysis of host-cell binding proteins involved in ICAPs assembly, transport and budding. However, this approach is often hampered by problems with low yield of the ICAPs due to either low expression or fast release from the host cell. Another obstacle may be a low stability or fragility of the intracellular particles. The published methods for ICAPs isolation often involved several time consuming centrifugation steps yielding damaged particles. Other papers describe the ICAPs production in non-natural host cells. Here, we optimized the method for purification of unstable Mason-Pfizer monkey virus (M-PMV) ICAPs from non-human primate derived cells, commonly used to study MPMV replication i.e. African green monkey kidney fibroblast cell line (COS-1). Our simple and rapid procedure involved separation of the intracytoplasmic particles from the cell debris and organelles by differential, low-speed centrifugation, their purification using sucrose velocity gradient and final concentrating by low-speed centrifugation. Importantly, the method was established for unstable and fragile M-PMV intracytoplasmic particles. Therefore, it may be suitable for isolation of ICAPs of other viruses. PMID- 28619603 TI - Water-Soluble Combretastatin A4 Phosphate Orally Delivered via Composite Nanoparticles With Improved Inhibition Effect Toward S180 Tumors. AB - Combretastatin A4 phosphate (CA4P) is a novel vascular disrupting agent for cancer therapy. However, frequent dosing and negative patient compliance have been encountered over CA4P by injection administration due to its quite short term action and acute side effects. Therefore, it is significant to develop an oral formulation of CA4P. We established a novel method to prepare CA4P-loaded nanoparticles (CA4P-NPs) for oral administration by combining methoxy poly(ethylene glycol)-b-polylactide (PELA) and poly(d,l-lactic-co-glycolic acid) (PLGA) polymers. Transport study in vitro was evaluated on Madin-Darby canine kidney cell models, and antitumor effect evaluation in vivo was performed on S180 subcutaneous xenotransplanted tumor models in mice. The highest entrapment efficiency of CA4P-NPs was achieved when the weight ratio of PELA to PLGA was optimized to 1:1. The apparent permeability coefficient of CA4P-NPs was found to be 2.08-fold higher than that of free CA4P in transport study. CA4P-NPs reached an absolute bioavailability of 77.6% with the tumor inhibition ratio of 41.2% that was significantly superior to free CA4P. These results suggest a promising application of this composite nanoparticle for the oral delivery of water-soluble drugs. PMID- 28619604 TI - Clinical Implementation of Pharmacogenomics for Personalized Precision Medicine: Barriers and Solutions. AB - Clinical implementation of pharmacogenomics (PGx) leads to personalized medicine, which improves the efficacy, safety, and cost-effectiveness of treatments. Although PGx-based research has been conducted for more than a decade, several barriers have slowed down its widespread implementation in clinical practice. Globally, there is an imbalance in programs and solutions required to empower the clinical implementation of PGx between countries. Therefore, we aimed to review these issues comprehensively, determine the major barriers, and find the best solutions. Through an extensive review of ongoing clinical implementation programs, scientific, educational, ethical, legal, and social issues, information technology, and reimbursement were identified as the key barriers. The pace of global implementation of genomic medicine coincided with the resource limitations of each country. The key solutions identified for the earlier mentioned barriers are as follows: building of secure and suitable information technology infrastructure with integrated clinical decision support systems along with increasing PGx evidence, more regulations, reimbursement strategies for stakeholder's acceptance, incorporation of PGx education in all institutions and clinics, and PGx promotion to all health care professionals and patients. In conclusion, this review will be helpful for the better understanding of common barriers and solutions pertaining to the clinical application of PGx. PMID- 28619605 TI - The prognostic value of proton magnetic resonance spectroscopy in term newborns treated with therapeutic hypothermia following asphyxia. AB - OBJECTIVE: The purpose of this study was to correlate brain metabolism assessed shortly after therapeutic hyperthermia by 1H magnetic resonance spectroscopy (MRS), with neurodevelopmental outcome. METHODS: At the age of 6.0+/-1.8days, brain metabolites of 35 term asphyxiated newborns, treated with therapeutic hypothermia, were quantified by multivoxel proton MRS of a volume cranial to the corpus callosum, containing both gray and white matter. At the age of 30months the Bayley Scale of Infant Development-III was performed. RESULTS: Infants that died had lower gray matter NAA levels than infants that survived (P=0.005). In surviving infants (28 of 35) there was a trend of negative correlation between gray matter choline levels and gross motor outcome (r=-0.45). In the white matter, choline correlated negatively with fine motor skills (r=-0.40), and creatine positively with gross motor skills (r=0.58, P=0.02). There was no relationship between lactate levels and outcome. CONCLUSION: MRS of asphyxiated neonates treated by therapeutic hypothermia can serve as predictor of outcome. Unlike previously reported associations in untreated asphyxiates, lactate levels had no relationship with outcome, which indicates that one of the working mechanisms of therapeutic hypothermia is reduction of the metabolic rate. PMID- 28619607 TI - Revisiting syntactic development in deaf and hearing children from a dependency approach: Comment on "Dependency distance: a new perspective on syntactic patterns in natural languages" by Haitao Liu et al. PMID- 28619606 TI - Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and represents the second most frequently cancer and third most common cause of death from cancer worldwide. At advanced stage, HCC is a highly aggressive tumor with a poor prognosis and with very limited response to common therapies. Therefore, there is still the need for new effective and well-tolerated therapeutic strategies. Molecular-targeted therapies hold promise for HCC treatment. One promising molecular target is the multifunctional serine/threonine kinase glycogen synthase kinase 3 (GSK-3). The roles of GSK-3beta in HCC remain controversial, several studies suggested a possible role of GSK-3beta as a tumor suppressor gene in HCC, whereas, other studies indicate that GSK-3beta is a potential therapeutic target for this neoplasia. In this review, we will focus on the different roles that GSK-3 plays in HCC and its interaction with signaling pathways implicated in the pathogenesis of HCC, such as Insulin-like Growth Factor (IGF), Notch, Wnt/beta-catenin, Hedgehog (HH), and TGF-beta pathways. In addition, the pivotal roles of GSK3 in epithelial-mesenchymal transition (EMT), invasion and metastasis will be also discussed. PMID- 28619608 TI - Real-world Direct Health Care Costs for Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab-containing Regimens in First-line or First line Through Second-line Therapy. AB - BACKGROUND: The present study examined real-world direct health care costs for metastatic colorectal cancer (mCRC) patients initiating first-line (1L) bevacizumab (BEV)- or cetuximab (CET)-containing regimen in 1L or 1L-through second-line (1L-2L) therapy. PATIENTS AND METHODS: Using a large US insurance claims database, patients with mCRC initiating 1L BEV- or 1L CET-containing regimen from January 1, 2008 to September 30, 2014 were identified. The per patient per-month (PPPM) all-cause health care costs (2014 US dollars) were measured during 1L therapy and, for patients continuing to a 2L biologic containing regimen, 1L-2L therapy. Multivariable regression analyses were used to compare PPPM total health care costs between patients initiating a 1L BEV- versus 1L CET-containing regimen. RESULTS: A total of 6095 patients initiating a 1L BEV- and 453 initiating a 1L CET-containing regimen were evaluated for 1L costs; 2218 patients initiating a 1L BEV- and 134 initiating a 1L CET-containing regimen were evaluated for 1L-2L costs. In 1L therapy, 1L CET had adjusted PPPM costs that were $3135 (95% confidence interval [CI], $1174-$5040; P < .001) greater on average than 1L BEV. In 1L-2L therapy, 1L BEV-2L CET had adjusted PPPM costs that were $1402 (95% CI, $1365-$1442; P = .010) greater than those for 1L BEV-2L BEV, and 1L CET-2L BEV had adjusted PPPM costs that were $4279 (95% CI, $4167-$4400; P = .001) greater on average than those for 1L BEV-2L BEV. The adjusted PPPM cost differences for 1L BEV-2L other biologic or 1L CET-2L other biologic agent were numerically greater but statistically insignificant. CONCLUSION: PPPM total health care costs for 1L and 2L therapy tended to be greater for patients treated with 1L CET-containing regimens than for 1L BEV-containing regimens. Also, continuing treatment with BEV-containing regimens 1L-2L was less costly than switching between BEV and CET. The cost differences between BEV and CET hold important implications for treatment decisions of mCRC patients in real-world clinical practice. PMID- 28619609 TI - Recommendations to prevent shoulder and elbow injuries due to over training in elementary school baseball players. PMID- 28619610 TI - Forecasting gastrointestinal precipitation and oral pharmacokinetics of dantrolene in dogs using an in vitro precipitation testing coupled with in silico modeling and simulation. AB - The aim of the current research was to determine the precipitation kinetics of dantrolene sodium using canine biorelevant in vitro testing and to model the precipitation kinetics by appropriately coupling the data with an in silico tool adapted for dogs. The precipitation profiles of dantrolene sodium solutions were obtained with the in vitro paddle apparatus at a revolution rate of 50rpm. The in silico prediction tool was designed using STELLA software and the predicted plasma concentration profiles of dantrolene using the in vitro precipitation data were compared with the observed in vivo pharmacokinetics in beagle dogs. The plasma profiles of dantrolene, which served as a model weakly acidic drug which precipitates in the upper gastrointestinal tract, was successfully predicted using the in vitro precipitation testing coupled with the in silico modeling and simulation approach. The approach was subsequently used to forecast the effect of pharmaceutical excipients (HPMC/PG) on the ability of the drug to supersaturate in the gut and the resulting pharmacokinetics. The agreement of the simulated pharmacokinetics with the observed values confirms the ability of canine biorelevant media to predict oral performance of enhanced dosage forms in dogs. PMID- 28619611 TI - An insight into selection specificity of quinolone resistance determinants within Enterobacteriaceae family. AB - OBJECTIVES: Quinolone antimicrobials are frequently misused due to self medication and suboptimal dose administration, leading to the development of resistance as well as treatment failure. The present study aimed to characterise plasmid-mediated quinolone resistance (PMQR) determinants and their genetic selection in the presence of quinolone stress within members of the Enterobacteriaceae. METHODS: A total of 209 non-duplicate Enterobacteriaceae isolates were collected from hospital and community health centres over the period July 2013-June 2014. Molecular characterisation of phenotypically screened quinolone-resistant isolates was done by multiplex PCR. Plasmids bearing the qnr and aac(6')-Ib-cr genes were transformed into Escherichia coli DH5alpha and were selected on Muller-Hinton agar plates containing 0.25MUg/mL and 0.5MUg/mL ciprofloxacin, norfloxacin, ofloxacin, levofloxacin and moxifloxacin. Conjugation experiments were performed to determine whether the aac(6')-Ib-cr- and qnr carrying plasmids were self-transferable. RESULTS: The transformation assay revealed that transformants carrying qnrA could be selected in media containing norfloxacin, ciprofloxacin and levofloxacin, whereas qnrB and aac(6')-Ib-cr were selected on media containing norfloxacin and ciprofloxacin. Transformed qnrD could be selected in media containing norfloxacin and ofloxacin, and qnrS was selected only in the presence of levofloxacin. CONCLUSIONS: The presence of qnr genes has been associated with an increase in quinolone minimum inhibitory concentrations (MICs) and therefore leads to treatment failure when quinolones are used as selective therapeutic drugs. Since PMQR determinants have a high prevalence, effective measures should be taken and surveillance should be performed in order to avoid treatment failures using this group of antimicrobials. PMID- 28619612 TI - Improving the acetylcholinesterase inhibitory effect of Illigera henryi by solid state fermentation with Clonostachys rogersoniana. AB - Illigera henryi, an endemic traditional Chinese medicine, contains abundant aporphine alkaloids that possess various bioactivities. In the present study, tubers of I. henryi were fermented by several fungi, and the acetylcholinesterase (AChE) inhibitory activities of non-fermented and fermented I. henryi were measured. The results showed that the fermentation of I. henryi with Clonostachys rogersoniana 828H2 is effective for improving the AChE inhibitory activity. A key biotransformation was found during the C. rogersoniana fermentation for clarifying the improvement of the AChE inhibitory activity of I. henryi: (S) actinodaphnine (1) was converted to a new 4-hydroxyaporphine alkaloid (4R,6aS)-4 hydroxyactinodaphnine (2) that possessed a stronger AChE inhibitory activity, with an IC50 value of 17.66+/-0.06 MUM. This paper is the first to report that the pure strain fermentation processing of I. henryi and indicated C. rogersoniana fermentation might be a potential processing method for I. henryi. PMID- 28619613 TI - Does supplemental photodynamic therapy optimize the disinfection of bacteria and endotoxins in one-visit and two-visit root canal therapy? A randomized clinical trial. AB - AIM: To evaluate the effectiveness of supplemental photodynamic therapy (PDT) in optimizing the removal of bacteria and endotoxins from primarily infected root canals after one-visit and two-visit treatments. METHODOLOGY: Twenty-four primarily infected root canals with apical periodontitis were selected and randomly divided into one-visit (n=12) and two-visit treatment groups (n=12). Chemo-mechanical preparation (CMP) was performed by using the single-file reciprocating technique+2.5% NaOCL and a final rinse with 17% EDTA. The photosensitizer agent (methylene blue 0.1mg/mL) was applied to root canals for 60s before application of laser with a potency of 60mW and energy density of 129J/cm2 for 120s after CMP in the one-visit treatment and after 14-day inter appointment medication with Ca(OH)2+Saline solution (SSL) in the two-visit treatment. Samples were collected before and after root canal procedures. Endotoxins were quantified by chromogenic limulus amebocyte lysate assay. Culture techniques were used to determine bacterial colony-forming unit counts. RESULTS: Bacteria and endotoxins were detected in 100% of the initial samples, with median values of 1.97*105 CFU/mL and 24.983EU/mL, respectively. The CMP using single file reciprocating technique was effective in the reduction of bacteria and endotoxins (All, p<0.05). The supplemental PDT was effective in reducing bacterial load in the one-visit (p<0.05) but not in the two-visit treatment after use of Ca(OH)2 medication for 14days (p>0.05). In the two-visit group, after 14days of inter-appointment medication with Ca(OH)2, a significant reduction in the median levels of endotoxins was found in comparison to CMP alone (from 1.041 to 0.094EU/mL) (p<0.05). Despite the type of treatment, the supplemental PDT was not effective against endotoxins (p>0.05). CONCLUSIONS: The photodynamic therapy optimized the disinfection of bacteria from root canals in one-visit but not for two visit treatment modality with the accomplishment of calcium hydroxide medication. Despite the type of treatment, the supplemental PDT was not effective against endotoxins. PMID- 28619614 TI - Rapid ex vivo examination of Mohs specimens using optical coherence tomography. AB - BACKGROUND: Mohs micrographic surgery (MMS) is an effective treatment for certain non-melanoma skin cancers. Optical coherence tomography (OCT) is a biomedical imaging modality that permits high-resolution imaging of the epidermis and dermis with the potential to detect both healthy tissue and tumour. OCT may also provide a means of detecting and differentiating between the various histological subtypes of basal cell carcinomas (BCC) in vivo. OBJECTIVE: The aim of this prospective ex vivo study was to evaluate the efficacy of OCT in recognising healthy and pathological margins of excised BCC lesions and detecting different BCC subtypes. METHODS: Seventy-three subjects with biopsy-proven BCCs on the facial region undergoing MMS were recruited. Narrow clinically healthy margins of the skin surrounding the tumour were included in the excisional biopsy. Biopsies were scanned with the OCT instrument immediately ex vivo and processed to obtain horizontal Mohs frozen sections and compared with their corresponding OCT images. RESULTS: Histopathological analysis of 280 margins showed 232 tumour free margins and 48 tumour-involved margins. OCT showed very good sensitivity (81.2%) and specificity (94.3%) in detecting healthy from tumour-involved margins. OCT accuracy was 93.4%, and the intra- and inter-observer reliability was substantial (Kappa value ranged between 0.63-0.76). CONCLUSION: This study shows the accuracy of ex vivo OCT in identifying the margin status of BCCs of the head and neck region. Moreover, this modality has demonstrated good capability in distinguishing different BCC subtypes and the potential for in vivo in situ diagnostics. PMID- 28619615 TI - Evaluation of antimicrobial activity of association of chlorhexidine to photosensitizer used in photodynamic therapy in root canals infected by Enterococcus faecalis. AB - INTRODUCTION: The aim of the present study was to evaluate, in vitro, the influence of the addition of chlorhexidine to photosensitiser in the antimicrobial activity of photodynamic therapy in root canals infected by Enterococcus faecalis. METHODS: The root canals of 50 single-rooted human extracted teeth were enlarged up to a file F3 of Pro-Taper system, autoclaved, inoculated with Enterococcus faecalis and incubated for 14days. The samples were divided into five groups (n=10) according to the protocol of decontamination: G1 (control group) - no procedure was performed; G2-photosensitiser (0.01% methylene blue); G3-2% chlorhexidine gel; G4-photodynamic therapy; and G5-photodynamic therapy with photosensitiser modified by chlorhexidine. Microbiological test (CFU counting) was performed to evaluate the effectiveness of proposed treatments. Data were subjected to one-way ANOVA followed by post-hoc Tukey test (alpha=0.05). RESULTS: Group 3 (CHX) showed the lowest mean contamination (2.03 log10 CFU/mL), being statistically different from all other all groups (p<0.05). There was no statistically significant difference between groups 4 (PDT) and 5 (PDT+CHX) (p<0.05), being more effectives against E. faecalis when compared to groups 1 (NT) and 2 (MB), and less effective when compared to group 2 (CHX). CONCLUSIONS: The addition of chlorhexidine to photosensitiser did not result in a better decontamination potential of photodynamic therapy alone over root canals infected by E. faecalis. PMID- 28619616 TI - Activity-independent screening of secreted proteins using split GFP. AB - The large-scale industrial production of proteins requires efficient secretion, as provided, for instance, by the Sec system of Gram-positive bacteria. Protein engineering approaches to optimize secretion often involve the screening of large libraries, e.g. comprising a target protein fused to many different signal peptides. Respective high-throughput screening methods are usually based on photometric or fluorimetric assays enabling fast and simple determination of enzymatic activities. Here, we report on an alternative method for quantification of secreted proteins based on the split GFP assay. We analyzed the secretion by Bacillus subtilis of a homologous lipase and a heterologous cutinase by determination of GFP fluorescence and enzyme activity assays. Furthermore, we identified from a signal peptide library a variant of the biotechnologically relevant B. subtilis protein swollenin EXLX1 with up to 5-fold increased secretion. Our results demonstrate that the split GFP assay can be used to monitor secretion of enzymatic and non-enzymatic proteins in B. subtilis in a high-throughput manner. PMID- 28619617 TI - Maximising the data potential in COPD research. PMID- 28619618 TI - NMR in drug design. AB - The use of NMR as a tool to determine 3 dimensional protein solution structures, once a darling of the pharmaceutical industry, has largely given way to study of the interaction of prospective drugs with macromolecular targets. Many of these approaches involve ligand-centered studies, which have the advantage of speed and efficiency, but there are also many approaches that take directly from our learnings in macromolecular NMR and provide greater structural detail yet are still optimized for rapid turn-around of information. In the evolution of NMR in the pharmaceutical industry, the unique strengths of NMR to provide dynamic and atomic level information continue to be exploited to discover and design new drugs. Numerous methods have been developed over the past two decades that fall into the categories of fragment-based pre-lead discovery, ligand binding studies and qualitative structural screening. PMID- 28619619 TI - Flavin-catalyzed redox tailoring reactions in natural product biosynthesis. AB - Natural products are distinct and often highly complex organic molecules that constitute not only an important drug source, but have also pushed the field of organic chemistry by providing intricate targets for total synthesis. How the astonishing structural diversity of natural products is enzymatically generated in biosynthetic pathways remains a challenging research area, which requires detailed and sophisticated approaches to elucidate the underlying catalytic mechanisms. Commonly, the diversification of precursor molecules into distinct natural products relies on the action of pathway-specific tailoring enzymes that catalyze, e.g., acylations, glycosylations, or redox reactions. This review highlights a selection of tailoring enzymes that employ riboflavin (vitamin B2) derived cofactors (FAD and FMN) to facilitate unusual redox catalysis and steer the formation of complex natural product pharmacophores. Remarkably, several such recently reported flavin-dependent tailoring enzymes expand the classical paradigms of flavin biochemistry leading, e.g., to the discovery of the flavin-N5 oxide - a novel flavin redox state and oxygenating species. PMID- 28619620 TI - Development of a solid dosage platform for the oral delivery of bilayer vesicles. AB - Within this work, we develop vesicles incorporating sub-unit antigens as solid dosage forms suitable for the oral delivery of vaccines. Using a combination of trehalose, dextran and mannitol, freeze-dried oral disintegrating tablets were formed which upon rehydration release bilayer vesicles incorporating antigen. Initial studies focused on the optimisation of the freeze-dry cycle and subsequently excipient content was optimised by testing tablet hardness, disintegration time and moisture content. The use of 10% mannitol and 10% dextran produced durable tablets which offered strong resistance to mechanical damage yet appropriate disintegration times and dispersed to release niosomes-entrapping antigen. From these studies, we have formulated a bilayer vesicle vaccine delivery system as rapid disintegrating tablets and capsules. PMID- 28619622 TI - The spectraplakins of Caenorhabditis elegans: Cytoskeletal crosslinkers and beyond. AB - Spectraplakins are evolutionary conserved cytolinkers with characteristics of both the spectrin and the plakin family proteins. Caenorhabditis elegans possesses two categories of spectraplakin isoforms encoded by a single locus termed vab-10. Here we summarize the structure, homology, expression and functions of these spectraplakin family proteins in the nematode. We particularly focus on the diverse roles of VAB-10 isoforms in a number of organs and tissue types, as well as the similarities and distinctions of the underlying mechanisms. We also discuss the functional partners of VAB-10 in different contexts, plus the involvement of VAB-10 isoforms in physiological processes beyond cytoskeletal integration. We emphasize the importance of spectraplakin-related studies using Caenorhabditis elegans as the model, and their contributions to our understanding of spectraplakins across species. PMID- 28619623 TI - Intracellular trafficking of particles inside endosomal vesicles is regulated by particle size. AB - Little comparative information is available on the detailed intracellular dynamics (diffusion, active movement, and distribution mechanisms) of nanoparticles (<=100nm) and sub-micron particles (>100nm). Here, we quantitatively examined the intracellular movements of different-sized particles and of the endosomal vesicles containing those particles. We showed that silica nanoparticles of various sizes (30 to 100nm) had greater motility than sub-micron particles in A549 cells. Although particles of different sizes localized in the early endosomes, late endosomes, and lysosomes in different proportions, their motilities did not vary, regardless of the vesicles in which they were localized. However, surprisingly, endosomal vesicles containing silica nanoparticles moved faster than those containing sub-micron particles. These results suggest that nanoparticles included within endosomal vesicles do not suppress the motility of the vesicles, whereas sub-micron particles perturb endosomal vesicle transport. Our data support a new hypothesis that differences in particle size influence membrane trafficking of endosomal vesicles. PMID- 28619624 TI - Fetal stem cell and gene therapy. AB - Advances in our understanding of stem cells, gene editing, prenatal imaging and fetal interventions have opened up new opportunities for the treatment of congenital diseases either through in-utero stem cell transplantation or in-utero gene therapy. Improvements in ultrasound-guided access to the fetal vasculature have also enhanced the safety and efficacy of cell delivery. The fetal environment offers accessible stem cell niches, localized cell populations with large proliferative potential, and an immune system that is able to acquire donor specific tolerance. In-utero therapy seeks to take advantage of these factors and has the potential to cure diseases prior to the onset of symptoms, a strategy that offers substantial social and economic benefits. In this article, we examine previous studies in animal models as well as clinical attempts at in-utero therapy. We also discuss the barriers to successful in-utero therapy and future strategies for overcoming these obstacles. PMID- 28619621 TI - Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study. AB - BACKGROUND: Epithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM. METHODS: Immunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression free survival (PFS). RESULTS: Inter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1-5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS. CONCLUSION: E1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM. PMID- 28619625 TI - HMGB1, an innate alarmin, plays a critical role in chronic inflammation of adipose tissue in obesity. AB - Obesity has emerged as an imminent global public health concern over the past several decades. It has now become evident that obesity is characterized by the persistent and low-grade inflammation in the adipose tissue, and serves as an independent risk factor for many metabolic disorders such as diabetes and cardiovascular disease. Particularly, adipocytes originated from obese mice and humans likely predominate necrosis upon stressful insults, leading to passive release of cellular contents including the high mobility group box 1 (HMGB1) into the extracellular milieu. Extracellular HMGB1 acts as an innate alarmin to stimulate the activation of resident immune cells in the adipose tissue. Upon activation, those resident immune cells actively secrete additional HMGB1, which in turn activates/recruits additional immune cells, and induces adipocyte death. This review summarizes those novel discoveries in terms of HMGB1 in the initiation and maintenance of chronic inflammatory state in adipose tissue in obesity, and discusses its potential application in clinical settings. PMID- 28619626 TI - Assessment of heavy metal and petroleum hydrocarbon contamination in the Sultanate of Oman with emphasis on harbours, marinas, terminals and ports. AB - The assessment here includes data on levels of contaminants (petroleum hydrocarbons and heavy metals) in sediments and biomonitor organisms, including the eulittoral rock oyster Saccostrea cucullata and subtidal biomonitors, the barnacle Balanus trigonus and the antipatharian coral Antipathes sp., at harbours, marinas, terminals and large ports along the coastline of Oman. TBT levels in harbour and port sediments up to a maximum of 100ppb TBT dry weight are highlighted. Oysters contained concentrations up to 367ppm mg TPH/kg dry weight. The maximum levels of Cd, Cu, Pb and Zn were found in the subtidal sediments and barnacles at the oil tanker loading Single Buoy Mooring stations in Mina Al Fahal. In general, the levels of most of the contaminants analysed are at low to moderate concentrations compared to those in highly contaminated sites such as shipyards and dry docks, but continued monitoring is recommended especially during any dredging campaigns. PMID- 28619627 TI - Composition, spatial distribution and sources of macro-marine litter on the Gulf of Alicante seafloor (Spanish Mediterranean). AB - The composition, spatial distribution and source of marine litter in the Spanish Southeast Mediterranean were assessed. The data proceed from a marine litter retention programme implemented by commercial trawlers and were analysed by GIS. By weight, 75.9% was plastic, metal and glass. Glass and plastics were mainly found close to the coast. A high concentration of metal was observed in some isolated zones of both open and coastal waters. Fishing activity was the source of 29.16% of the macro-marine litter, almost 68.1% of the plastics, and 25.1% of the metal. The source of the other 60.84% could not be directly identified, revealing the high degree of uncertainty regarding its specific origin. Indirectly however, a qualitative analysis of marine traffic shows that the likely sources were merchant ships mainly in open waters and recreational and fishing vessels in coastal waters. PMID- 28619628 TI - Environmental background values of trace elements in sediments from the Jiaozhou Bay catchment, Qingdao, China. AB - Selected trace elements (As, Cr, Zn, Cu, Cd, Co, Pb and Ni) in 76 surface sediment samples collected from the rivers and the intertidal zone of Jiaozhou Bay (JZB) were evaluated to assess their environmental background values in the JZB catchment. Overall, the sediment quality in the area meets the China Marine Sediment Quality criteria. The background values (ranges) of the elements As, Cr, Zn, Cu, Cd, Co, Pb and Ni were, respectively, 8.28 (4.10-12.46), 67.96 (38.40 97.52), 56.80 (16.42-196.51), 19.13 (5.71-64.06), 0.10 (0.02-0.42), 6.51 (2.08 20.40), 17.97 (12.26-55.84) and 20.69 (10.43-30.95)mg/kg. The background values of most of the trace elements were lower than those in Chinese soil, the upper continental crust, global shales and global preindustrial sediments. The results may assist in defining future coastal and river management measures specifically targeted at monitoring trace element contamination in the JZB catchment. PMID- 28619629 TI - Scales and drivers of seasonal pCO2 dynamics and net ecosystem exchange along the coastal waters of southeastern Arabian Sea. AB - The impact of seasonal coastal upwelling on the dynamics of dissolved inorganic carbon (DIC) and sea-air fluxes of CO2 along the coastal waters of Kochi was investigated during 2015, as a part of Ecosystem Modelling Project. The surface water pCO2 varied from 396 to 630MUatm during the study period. Significant inter seasonal variations were found in the distribution of physico-chemical variables and surface pCO2. An increase of 102.1MUatm of pCO2 was noticed over a two-decade period with a rate of 5.3MUatmy-1. There was an agreement between the fluxes of CO2 and net ecosystem production (NEP) with respect to the trophic status while NEP was higher than CO2 fluxes by a factor of 3.9. The annual net ecosystem exchange (NEE) was estimated to be 15.02mmolCm-2d-1 indicating that the coastal waters of Kochi are highly heterotrophic in nature. PMID- 28619630 TI - Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment. AB - INTRODUCTION: The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. MATERIALS AND METHODS: In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. RESULTS: HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. CONCLUSION: HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation. PMID- 28619631 TI - Histopathologic analysis of tumor bed and peritumoral pseudocapsule after in vitro tumor enucleation on radical nephrectomy specimen for clinical T1b renal cell carcinoma. AB - PURPOSE: This study was designed to assess the feasibility and histopathologic safety of tumor enucleation for renal cell carcinoma, through histopathologic analysis of the tumor bed and peritumoral pseudocapsule (PC) after in vitro tumor enucleation. MATERIALS AND METHODS: We studied 176 radical nephrectomy specimens for clinical T1b renal cell carcinoma in our institution, from January 2013 February 2016. Immediately after the kidney was excised, the tumor of radical specimen was enucleated in vitro. The tumor bed parenchyma of 15mm beyond the PC was examined to investigate the possible presence of tumor invasion or satellite lesions. The PC invasion was also evaluated. RESULTS: The average tumor size was 5.7+/-0.7cm. The histopathologic evaluation revealed that 68.2% of tumors were clear cell renal cell carcinoma (RCC). The pathological staging showed that 92.6% of tumors were pT1b, 2.8% were pT2, and 4.5% were pT3a. For clinical T1b RCC, tumor infiltration on tumor bed was detected in 6 cases (3.4%), and satellite lesion was detected in 3 (1.7%). In the group of grade 1 to 2, 4 (2.3%) were found with residual tumor, and 5 (2.8%) in the group of grade 3 to 4 (P = 0.133). Papillary RCC had the highest rate of residual tumors (8.8%). A statistically significant association of peritumoral PC invasion with tumor size and pathologic grade was observed. Median follow-up was 23 months (range: 6-43) with a recurrence rate of 6.3% (11 of 176) and a cancer-specific mortality rate of 2.8% (5 of 176). CONCLUSIONS: For clinical T1b renal cell carcinoma, the risks of tumor infiltration or satellite lesions on enucleation tumor bed or both are relatively low. Peritumoral PC invasion is associated with tumor size and pathologic stage. Tumor enucleation is a histopathologically safe technique for patients undergoing partial nephrectomy. PMID- 28619632 TI - Enhancing prostate cancer survivorship care through self-management. AB - The lack of clear roles for prostate cancer survivorship care providers places prostate cancer survivors at significant risk of inappropriate use of services delivered piecemeal by different providers, persistent bothersome symptoms, and silent suffering. Optimizing quality of care for prostate cancer survivors hinges on decreasing fragmentation of care, and providing quality symptom management. This is achieved through comprehensive, appropriate medical, surgical, pharmacological and psychosocial care, coupled with self-management, as highlighted in several recent resources addressing long-term and late effects of treatment. Although further study is warranted, prostate cancer survivors engaging in self-management may reduce the negative impact of prostate cancer in their lives through better quality of care (better symptom management and efficient use of services) and quality of life. PMID- 28619633 TI - Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular targeted therapy. AB - OBJECTIVES: The effect of response to first-line tyrosine kinase inhibitor (TKI) therapy on second-line survival in patients with metastatic renal cell carcinoma who receive second-line molecular-targeted therapy (mTT) after first-line failure remains unclear. MATERIALS AND METHODS: Sixty patients who developed disease progression after first-line TKI, without prior cytokine therapy, were enrolled. According to the median first-line time to progression (1L-TTP), patients were divided into 2 groups (i.e., short vs. long). Second-line progression-free survival (2L-PFS) and second-line overall survival (2L-OS) were defined as the time from second-line mTT initiation. Survival was calculated with the Kaplan Meier method and compared using the log-rank test between patients with short and long 1L-PFS. Predictors for survivals were identified using Cox proportional hazards regression models. RESULTS: The median 1L-TTP was 8.84 months. Thirty patients (50.0%) with short 1L-TTP (<8.84mo) had significantly shorter 2L-PFS and 2L-OS compared to patients with long 1L-TTP (2L-PFS: 4.96 vs. 10.2mo, P = 0.0002; 2L-OS: 9.6 vs. 28.0mo, P = 0.0036). Multivariable analyses for 2L-PFS and 2L-OS showed that 1L-TTP was an independent predictor both as a categorical classification (cutoff: 8.84mo) and as a continuous variable (both P<0.05). The median follow-up duration was 13.1 months (interquartile range: 6.56-24.7). CONCLUSIONS: Patients who achieve a long-term response after first-line TKI therapy could have a favorable prognosis with second-line mTT. PMID- 28619634 TI - Enhancement of Siglec-8 expression predicts adverse prognosis in patients with clear cell renal cell carcinoma. AB - PURPOSE: Sialic acid-binding immunoglobulin-like lectins (siglecs) family has important functions in tumor progression. The purpose of our study is to figure out the correlation between the expression level of Siglec-8 and prognosis of patients with clear cell renal cell carcinoma (ccRCC), and then to predict the overall survival (OS) via a novel nomogram. MATERIALS AND METHODS: A group of patients (n = 267) histologically diagnosed with ccRCC from Zhongshan Hospital were included into our study. Immunohistochemistry of Siglec-8 was performed in the tissue microarray, and the staining intensity was divided into high/low according to the median value of the H-score grading. Survival analyses including Kaplan-Meier analyses and Cox regression analyses were performed to evaluate the association between Siglec-8 expression and the survival of patients in different risk groups. Stage, size, grade, and necrosis score and University of California Los Angeles Integrated Staging System score were used in the risk stratification. A nomogram incorporating Siglec-8 and several other clinical parameters was plotted for predicting the 5-year and 8-year OS. RESULTS: Siglec-8 was observed dominantly on the membrane of tumor cells. The enhanced expression level of Siglec-8 had significant correlation with adverse overall and disease-free survival of patients (P<0.0001 and P = 0.0186, respectively). The association was more significant in patients with lower risk. Cox regression analyses defined Siglec-8 as an independent prognostic factor of OS (P<0.001 for univariate analysis, P = 0.003 for multivariate analysis). The new nomogram integrating Siglec-8 with several traditional prognostic factors proved to be more accurate than conventional prognostic system using tumor node metastasis stage only (Harrell c-index: 0.801, 95% CI: 0.755-0.847 vs. 0.717, 95% CI: 0.662-0.772). CONCLUSION: Our study has found that the elevated expression level of Siglec-8 was correlated with poor prognosis of patients with ccRCC. Siglec-8, incorporation with other clinical parameters, could perform better in prediction of patients' OS. PMID- 28619635 TI - Production and characterization of polyhydroxyalkanoic acid from Bacillus thuringiensis using different carbon substrates. AB - Polyhydroxyalkanoic acids (PHA) are biodegradable microbially synthesised polymers which can act as alternatives to conventional petrochemical based plastics. Bacterial isolates from soil and sewage samples were screened for the ability to accumulate PHA using Sudan Black B dye, and growth conditions of the best PHA accumulating bacterium was optimized. The PHA produced was characterized by FTIR spectroscopy. Eight PHA-producing bacteria were isolated and isolate SBC4 which had the highest percentage accumulation of 30% was genotypically identified as Bacillus thuringiensis and selected for further studies. Glucose and ammonium sulfate supplementation afforded the optimum cultural conditions for cell growth and PHA accumulation yielding 0.33g/l and 0.40g/l respectively. B. thuringiensis SBC4 utilized corn bran, corn cob and wheat bran for PHA production, with corn cob yielding the highest PHA content of 21.05%. The optimum pH, temperature and incubation time for PHA productions were 7.0, 37 degrees C and 48h. The use of all the optimum conditions in a newly modified medium increased the PHA content, with an overall increase in PHA accumulation from 30% to 44.96% equivalent to an increase of 50% in PHA yield. The presence of major peaks such as CO stretching, CH vibrations, COC stretching confirmed PHA production. PMID- 28619636 TI - Isolation and characterization of a non-specific lipid transfer protein from Chelidonium majus L. latex. AB - Plant non-specific lipid transfer proteins (nsLTPs) are small basic proteins, which mostly play a role in intracellular lipid transport and antimicrobial defense. Recently it was shown using shotgun proteomic approach that the whole plant extract of Chelidonium majus L. (Papaveraceae) contains relatively abundant nsLTPs. Therefore the aim of the work was to isolate and characterize nsLTP from C. majus latex. Results obtained using PCR approach with degenerate primers showed the presence of nsLTP protein in C. majus root latex, named CmLTP 9.5. The protein consists of 93 aa with a molecular weight of 9.5kDa (NCBI GenBank accession no. ALT21495, coded by KP733898). The mature form of CmLTP 9.5 has a molecular weight of 7.147kDa and contains typical eight strictly conserved cysteine residues. A 3D model of CmLTP 9.5 displays a hydrophobic cavity. The isolated protein fraction tested using diffusion method and critical dilution assay showed strong antibacterial activity towards Gram-negative Campylobacter jejuni as well as Gram-positive Listeria greyi and Clostridium perfringens. Further studies using protein expression system are required to fully understand CmLTP 9.5 mode of action. PMID- 28619637 TI - Preparation and characterization of silk sericin/PVA blend film with silver nanoparticles for potential antimicrobial application. AB - Sericin has great potentials in biomedical applications for its good reactive activity, biocompatibility and biodegradability. However, the undesirable mechanical performance limits its application. Here, we developed a green, facile and economic approach to prepare sericin/polyvinyl alcohol (PVA) blend film. Further, silver nanoparticles (AgNPs) were synthesized in situ on the surface of sericin/PVA film via UV-assisted green synthesis method. Mechanical performance, swelling, mass losing and water retention tests showed the blend film had good mechanical performance, hygroscopicity, water retention capacity and low mass losing ratio. Scanning electron microscopy, fourier transfer infrared spectroscopy, X-ray diffractometry diffraction and X-ray photoelectron spectroscopy indicated the blending of PVA and sericin promoted the formation of hydrogen bond network between sericin and PVA, thus enhanced the mechanical performance and the stability of sericin, as well as the hygroscopicity and water retention capacity. UV irradiation and AgNPs modification did not affect the inner crystalline structure of sericin/PVA blend film. The inhibition zone and bacteria growth curve assay suggested AgNPs-sericin/PVA film had good antibacterial activities against E. coli and S. aureus. This novel AgNPs sericin/PVA film shows great potentials in biomedical materials such as wound dressing and skin tissue engineering. PMID- 28619638 TI - Development and characterization of cuttlefish (Sepia officinalis) skin gelatin protein isolate blend films. AB - In the present study, cuttlefish skin gelatin (CSG) and protein isolate (CSPI) blend films were prepared and their physicochemical and antioxidant properties were characterized. CSG (4%, w/v) was blended with CSPI (3%, w/v) at different ratios and 15% of glycerol (w/w, plasticizer/polymer dry matter). Results showed that increasing of CSPI content induced lower lightness but higher redness, yellowness and color difference values compared to CSG film. In addition, CSPI film had the lowest tensile strength (TS) and elongation at break (EAB) values. The FTIR spectra of blend films showed a shift in the position of peaks related to the amide-I group, suggesting that they were involved in the interaction between the biopolymers. The structural properties evaluated by DSC showed a total miscibility between both polymers. This result was also confirmed by the SEM study, revealing a compact and homogenous structure in the blend films. Moreover, the water contact angle decreased in blend films, especially for those having higher proportion of CSPI. The antioxidant activity of films was markedly favored by the CSPI incorporation. Therefore, CSPI addition into gelatin matrix allowed to improve the blend films properties, mainly governed by the CSG/CSPI ratio. PMID- 28619639 TI - Chitosan doped with nanoparticles of copper, nickel and cobalt. AB - Metal colloids in 2 propanol using nanoparticles (NPs) of copper, nickel and cobalt were prepared by Chemical Liquid Deposition (CLD) method. The resulting colloidal dispersions were characterized by Transmission Electron Microscopy (TEM). The colloids were supported in chitosan. Then, microbiological assays were performed using E. coli and S. aureus in order to determine the bactericide/bacteriostatic activity of nanoparticles (NPs) trapped or chelated with chitosan. Finally, the toxicity of the metal colloids Cu, Ni and Co was tested. Bio-assays were conducted in three different animal species. First of all on earth warms (Eisenia foetida) to evaluate the toxicity and the biocompatibility of chitosan in lactic acid (1% and 0.5%). Secondly bio-assay done in fishes (rainbow trout), the liver toxicity of NPs in vivo was evaluated. Finally, a bio-assay was conducted in Sprange-Dawley rats of 100g weight, which were injected intraperitoneally with different solutions of chitosan metal colloids. Then, the minimum and maximum concentration were determined for copper, nickel and cobalt. The purpose of the use of chitosan was acting as a carrier for some magnetic NPs, which toxicity would allow to obtain new polymeric materials with potential applications as magnet future drugs carrier. PMID- 28619640 TI - Potential of amino-riched nano-structured MnFe2O4@cellulose for biosorption of toxic Cr (VI): Modeling, kinetic, equilibrium and comparing studies. AB - In this work, amine riched MnFe2O4-cellulose was employed to remove toxic Cr (VI). To find out the optimum conditions R (3.3.1) software was used. The results of Cr (VI) adsorption onto three-step adsorbents were compared by interpreting kinetic and isotherm studies. The kinetic studies reveal that the adsorption of Cr (VI) onto cellulose and magnetic cellulose (MC) followed pseudo-first order model whereas the adsorption of Cr (VI) onto amine modified cellulose (AFMC) followed pseudo-second order kinetic model. From the obtained intraparticle diffusion model results it is evident that the adsorption is an external surface process. The adsorption isotherm parameters for Cr (VI) adsorption onto MC and AFMC showed that the correlation coefficient (R2: 0.96, 0.88) of Freundlich isotherm is more than that of Langmuir isotherm (R2: 0.50, 0.76); hence, it is suggested that the adsorption of Cr (VI) onto these sorbents occurs in multilayer possessing heterogeneous sorption sites whereas the adsorption onto cellulose followed Langmuir model. The maximum adsorption capacities of cellulose, MC and AFMC under optimum conditions were found to be 25, 125 and 250mg/g, respectively; thus, it is confirmed that adsorption efficiency has been improved after modification steps. PMID- 28619641 TI - Optimal conditions for producing bactericidal sodium hyaluronate-TiO2 bionanocomposite and its characterization. AB - In this research, the creation of optimum conditions for the formation of sodium hyaluronate-TiO2 bionanocomposite and its antibacterial effect on gram positive and gram negative bacteria was evaluated. The Fourier transform infrared spectroscopy spectra, scanning electron microscopy images and energy dispersive X ray spectroscopy pattern confirmed the formation of the bionanocomposite. Thermogravimetric analysis and differential thermal analysis indicated that the thermal stability rate had significantly improved with formation of the bionanocomposite. Nine experiments were designed based on the Taguchi method by applying different proportions of sodium hyaluronate biopolymer and TiO2 nanoparticles at different stirring times. Bionanocomposite produced under conditions of experiment 5 (TiO2 4mg/ml, sodium hyaluronate 1mg/ml and stirring time of 90min) and experiment 9 (TiO2 8mg/ml, sodium hyaluronate 2mg/ml and stirring time of 60min) completely prevented the growth of Staphylococcus aureus and Escherichia coli. It can be concluded that sodium hyaluronate-TiO2 bionanocomposite can be used as an effective antimicrobial compound in food, pharmaceutical, medical and environmental sectors. PMID- 28619642 TI - Polysaccharides and their depolymerized fragments from Costaria costata: Molecular weight and sulfation-dependent anticoagulant and FGF/FGFR signal activating activities. AB - Crude polysaccharides from Costaria costata were extracted by hot water and further fractionated by anion exchange chromatography into three polysaccharide fractions. Three low molecular weight fragments were then prepared by degradation of the polysaccharides with hydrogen peroxide and ascorbic acid. The structural features of the polysaccharides and their low molecular weight fragments were elucidated for the first time based on the HGPC, FT-IR, NMR, MS, monosaccharide composition, and other chemical analyses. Their anticoagulant and FGF-1, -2, -7, 8, -9, -10/FGFR1c signaling activation activities in BaF3 cells were also examined. Our studies showed that the polysaccharides were sulfated at different positions of galactose and fucose residues. The APTT-, PT- and TT-based anticoagulant assay results indicated that a high molecular weight and a higher degree of sulfation were essential for their anticoagulant activities. In contrast, not only the polysaccharides but also the depolymerized fragments showed significant FGF/FGFR signal activating activities in a FGF-, molecular weight-, and sulfation-dependent manner. The results presented in current study demonstrated the potential use of the polysaccharides and their fragments as anticoagulants and FGF signal regulators. PMID- 28619643 TI - Superior transfection efficiency of phagocytic astrocytes by large chitosan/DNA nanoparticles. AB - PURPOSE: Mechanism study of why astrocytes isolated from experimental autoimmune encephalomyelitis (EAE)-induced B6 mice or after being exposed to inflammatory factors had the highest transfection efficiency to larger-sized, but not compacted, pspCS/pDNA particles. METHODS: Phosphorylatable short peptide conjugated chitosan (pspCS) was compounded with plasmid DNA (pDNA) at different N:P ratios to form pspCS/pDNA particles of different size and zeta potentials. These pspCS/pDNA particles were used for the transfection of astrocytes isolated from either EAE induced or healthy B6 mice. Transfection efficiency and cell permeability of the particles were determined by the internalization of radio [H3]-labeled plasmid and the expression of a luciferase reporter gene respectively. Phagocytosis of EAE-astrocytes was determined by the internalization of FITC labeled dextran beads. By comparing the transfection efficiency of differently-sized pspCS/pDNA particles to normal and phagocytic astrocytes, with or without cytochalasin D, a phagocytosis inhibitor, in the presence, the contribution of phagocytosis to cell permeability and transfection efficiency was evaluated. RESULTS: In vivo EAE-induction or in vitro inflammatory factors treatment transferred normal astrocytes to be phagocytic astrocytes which underwent phagocytosis, had the highest cell permeability and transfection efficiency to larger-sized pspCS/pDNA particles formed at lower N:P ratios. When phagocytosis was inhibited by cytochalasin D, both cell permeability and transfection efficiency of phagocytic astrocytes to larger were significantly decreased. Thereafter, particle size, not zeta potential, was verified as the key factor for determining whether the particles could be phagocytosed. In addition phagocytosis was successfully induced in ARPE-19 cells as well, which also improved the transfection efficiency of larger pspCS/pDNA particles. CONCLUSION: A generally accepted concept is that the internalization of cationic polymer/pDNA particles, chitosan-DNA complex for instance, is mainly through the procedure of endocytosis of the transfected cells. More compacted particles with higher zeta potential were used to be considered had higher cell permeability and transfection efficiency. However, here we reported that phagocytosis is another important procedure for determining internalization and transfection efficiency of cationic polymer/pDNA nanoparticles, especially for advanced transfection efficiency of large pspCS/pDNA particles. Thus, for gene delivery applications, the environmental condition of the target cells should be seriously considered for selecting an appropriate gene transfer strategies. PMID- 28619644 TI - Management and outcomes of symptomatic abdominal aortic aneurysms during the past 20 years. AB - OBJECTIVE: We compared the management of patients with symptomatic, unruptured abdominal aortic aneurysms (AAAs) treated at a tertiary care center between two decades. This 20-year period encapsulated a shift in surgical approach to aortic aneurysms from primarily open to primarily endovascular, and we sought to determine the effect of this shift in the evaluation, treatment, and clinical outcomes of patients with symptomatic AAA. METHODS: We reviewed 1429 consecutive patients with unruptured AAAs treated at a tertiary care hospital by six staff surgeons between 1995 and 2004 (era 1) and between 2005 and 2014 (era 2). Of those patients, 160 (11%) were symptomatic from their aneurysm and were included in our study. Patient demographics, operative approach, and outcomes were analyzed and compared for each period. RESULTS: Era 1 included 75 patients (71% men; average age, 73.1 +/- 10.0 years) treated for symptomatic AAA (91.9% infrarenal, 4.0% juxtarenal, and 4.0% pararenal); of these, 68% were treated with open repair and 32.0% were treated with an endovascular repair. Perioperative mortality during this period was 5.3% (7.8% for the open cohort and 0% for the endovascular cohort). Era 2 included 85 patients (72.9% men; average age 72.0 +/- 9.5 years) treated for symptomatic AAA (90.1% infrarenal, 7.5% juxtarenal, and 2.4% pararenal); of these, 29% were treated open and 71% underwent endovascular repair. Perioperative mortality was 5.9% (8.0% for the open cohort and 5.0% for the endovascular cohort). Era 2 had a significantly higher rate of endovascular repair compared with era 1 (71% vs 32%; P < .0001) and a trend toward decreased long-term mortality. The length of stay for era 2 was significantly reduced compared with era 1 (4 days vs 6 days; P = .005). CONCLUSIONS: To our knowledge, this is the largest single-institution cohort of symptomatic AAAs, which comprise 10% to 11% of overall aneurysms. As expected, we found a significant shift over time in the approach to these patients from a primarily open to a primarily endovascular technique. The modern era was also associated with decreased lengths of stay and fewer gastrointestinal and wound complications but no significant differences in overall perioperative mortality. PMID- 28619645 TI - Introduction of arteriovenous grafts with graft insertion anastomosis for hemodialysis access. AB - OBJECTIVE: An arteriovenous bridging graft is a viable option for patients with compromised arteries or veins because of advanced age or diabetes. Arteriovenous graft with graft insertion anastomosis (AVGI) is the novel technique for graft vein anastomosis where the prosthesis is inserted into the vein, and the anastomosis is performed on the surface of the prosthesis. This study assessed the short-term and long-term results of AVGI to clarify the efficacy of this technique. METHODS: Between 2010 and 2015, AVGI was performed in graft-vein anastomosis of prosthetic forearm loop access. Characteristics and level of complications were assessed. To evaluate the long-term results, functional graft patency and frequency of percutaneous transluminal angioplasty were examined. RESULTS: The study comprised 58 patients. There were no deaths related to the surgery. The time of hemostasis after AVGI was recorded at 0 seconds because no bleeding from the suture holes was seen. At 1, 2, and 3 years, primary patency were 45.1% +/- 7.5%, 23.1% +/- 7.5%, and 23.1% +/- 7.5%, respectively, and assisted primary patency rates were 59.4% +/- 7.2%, 50.8% +/- 7.6%, and 50.8% +/- 7.6%, respectively. Secondary patency rates at 4 and 5 years were 100% +/- 0% and 94.1% +/- 5.7%, respectively. The frequency of percutaneous balloon angioplasty to maintain the patency was 1.61 +/- 0.53 times per year. Graft infection occurred in four patients (6.9%). CONCLUSIONS: AVGI is an advantageous technique for graft vein anastomosis in an arteriovenous bridging graft in both the short term and long-term. PMID- 28619646 TI - Time-dependent effects of HJP272, an endothelin receptor antagonist, in bleomycin induced pulmonary fibrosis. AB - Using a lipopolysaccharide (LPS) model of acute lung injury, we have previously shown that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a "gatekeeper" for the influx of inflammatory cells into the lung. To further investigate the potential of ET-1 to limit the progression of lung injury, hamsters were treated with an endothelin receptor antagonist (ERA), HJP272, either 1 h prior to intratracheal instillation of bleomycin (BLM) or 24 h afterwards. Lung injury and repair were examined by measuring the following parameters: 1) histopathological changes; 2) neutrophil content in bronchoalveolar lavage fluid (BALF); 3) lung collagen content; 4) tumor necrosis factor receptor 1 (TNFR1) expression by BALF macrophages; 5) BALF levels of: a) transforming growth factor beta-1 (TGF-beta1), b) stromal cell-derived factor 1 (commonly referred to as CXCL12), and c) platelet-derived growth factor BB (PDGF BB); 6) alveolar septal cell apoptosis (as measured by the TUNEL assay). For each of these parameters, animals pretreated with HJP272 showed significant reductions compared to those receiving BLM alone. In contrast, post-treatment with HJP272 was either ineffective or produced only marginally significant changes. The efficacy of a single pretreatment with HJP272 prior to induction of lung injury suggests that subsequent features of the disease are determined at a very early stage. This may explain why ERAs are not an effective treatment for human pulmonary fibrosis. Nevertheless, our findings suggest that they may be useful as prophylactic agents when given in combination with drugs that have fibrogenic potential. PMID- 28619648 TI - Biophysical characterization of nanostructured TiO2 as a good substrate for hBM MSC adhesion, growth and differentiation. AB - Mesenchymal stem cells from human bone marrow (hBM-MSC) are widely utilized for clinical applications involving bone healing. In this context, their use has been often optimized in association to variously designed titanium substrates, being this material of great use in orthopaedic implants. According to recent findings, the ability of hBM-MSC to differentiate towards a specific lineage is not only driven by biochemical signals, but physical stimuli, such as rigidity or roughness of the substrate, can also support a commitment towards osteogenic differentiation. Moreover, the presence of features with defined dimensional scales, in particular nanometer-size, also proved to elicit specific biological effects. Here we evaluated the effectiveness of a nano-patterned titanium surface in sustaining hBM-MSC adhesion, growth and differentiation by means of a panel of biophysical tools: morphometry, electrophysiology, intracellular calcium measurements and immunocytochemistry. The results substantiate the idea that this micro-textured titanium dioxide is a good surface for growth and differentiation of hBM-MSC and it exhibits a stimulating action mainly in the initial period of differentiation. Moreover, the basal concentration of free cytosolic Calcium [Ca2+]i is confirmed to be a good hallmark of the hBM-MSC maturation stage. The study could provide relevant hints to help improving the biocompatibility and osteointegration potential of clinical titanium implants. PMID- 28619647 TI - Using CRISPR-Cas9 to Generate Gene-Corrected Autologous iPSCs for the Treatment of Inherited Retinal Degeneration. AB - Patient-derived induced pluripotent stem cells (iPSCs) hold great promise for autologous cell replacement. However, for many inherited diseases, treatment will likely require genetic repair pre-transplantation. Genome editing technologies are useful for this application. The purpose of this study was to develop CRISPR Cas9-mediated genome editing strategies to target and correct the three most common types of disease-causing variants in patient-derived iPSCs: (1) exonic, (2) deep intronic, and (3) dominant gain of function. We developed a homology directed repair strategy targeting a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) and demonstrated restoration of the retinal transcript and protein in patient cells. We generated a CRISPR-Cas9-mediated non homologous end joining (NHEJ) approach to excise a major contributor to Leber congenital amaurosis, the IVS26 cryptic-splice mutation in CEP290, and demonstrated correction of the transcript and protein in patient iPSCs. Lastly, we designed allele-specific CRISPR guides that selectively target the mutant Pro23His rhodopsin (RHO) allele, which, following delivery to both patient iPSCs in vitro and pig retina in vivo, created a frameshift and premature stop that would prevent transcription of the disease-causing variant. The strategies developed in this study will prove useful for correcting a wide range of genetic variants in genes that cause inherited retinal degeneration. PMID- 28619650 TI - Advancing pharmacy practice through implementation science. PMID- 28619649 TI - The School Inner-City Asthma Intervention Study: Design, rationale, methods, and lessons learned. AB - Asthma is the most common chronic disease of childhood in the United States, causes significant morbidity, particularly in the inner-city, and accounts for billions of dollars in health care utilization. Home environments are established sources of exposure that exacerbate symptoms and home-based interventions are effective. However, elementary school children spend 7 to 12h a day in school, primarily in one classroom. From the observational School Inner-City Asthma Study we learned that student classroom-specific exposures are associated with worsening asthma symptoms and decline in lung function. We now embark on a randomized, blinded, sham-controlled school environmental intervention trial, built on our extensively established school/community partnerships, to determine the efficacy of a school-based intervention to improve asthma control. This factorial school/classroom based environmental intervention will plan to enroll 300 students with asthma from multiple classrooms in 40 northeastern inner-city elementary schools. Schools will be randomized to receive either integrated pest management versus control and classrooms within these schools to receive either air purifiers or sham control. The primary outcome is asthma symptoms during the school year. This study is an unprecedented opportunity to test whether a community of children can benefit from school or classroom environmental interventions. If effective, this will have great impact as an efficient, cost effective intervention for inner city children with asthma and may have broad public policy implications. PMID- 28619651 TI - Structure and electrochemistry of proteins harboring iron-sulfur clusters of different nuclearities. Part I. [4Fe-4S]+[2Fe-2S] iron-sulfur proteins. AB - In a recent series of review papers we have updated structure/electrochemistry of metalloproteins harboring single types of iron-sulfur clusters, namely {Fe(Cys)4}, {[Fe2S2](Cys)4}, {[Fe2S2](Cys)3(X)} (X=Asp, Arg, His), {[Fe2S2](Cys)2(His)2}, {[Fe3S4](Cys)3}, {[Fe4S4](Cys)4} and {[Fe4S4](SgammaCys)3(nonthiolate ligand)} cores, and their synthetic analogs. We now face with iron-sulfur proteins harboring iron-sulfur centres of different nuclearities. In this picture we start with proteins containing [4Fe-4S]+[2Fe-2S] clusters. PMID- 28619653 TI - On optimal spatial filtering for the detection of phase coupling in multivariate neural recordings. AB - INTRODUCTION: Neuronal oscillations synchronize processing in the brain over large spatiotemporal scales and thereby facilitate integration of individual functional modules. Up to now, the relation between the phases of neuronal oscillations and behavior or perception has mainly been analyzed in sensor space of multivariate EEG/MEG recordings. However, sensor-space analysis distorts the topographies of the underlying neuronal sources and suffers from low signal-to noise ratio. Instead, we propose an optimized source reconstruction approach (Phase Coupling Optimization, PCO). METHODS: PCO maximizes the 'mean vector length', calculated from the phases of recovered neuronal sources and a target variable of interest (e.g., experimental performance). As pre-processing, the signal-to-noise ratio in the search-space is maximized by spatio-spectral decomposition. PCO was benchmarked against several competing algorithms and sensor-space analysis using realistic forward model simulations. As a practical example, thirteen 96-channel EEG measurements during a simple reaction time task were analyzed. After time-frequency decomposition, PCO was applied to the EEG to examine the relation between the phases of pre-stimulus EEG activity and reaction times. RESULTS: In simulations, PCO outperformed other spatial optimization approaches and sensor-space analysis. Scalp topographies of the underlying source patterns and the relation between the phases of the source activity and the target variable could be reconstructed accurately even for very low SNRs (-10dB). In a simple reaction time experiment, the phases of pre-stimulus delta waves (<0.1Hz) with widely distributed fronto-parietal source topographies were found predictive of the reaction times. DISCUSSION AND CONCLUSIONS: From multivariate recordings, PCO can reconstruct neuronal sources that are phase-coupled to a target variable using a data-driven optimization approach. Its superiority has been shown in simulations and in the analysis of a simple reaction time experiment. From this data, we hypothesize that the phase entrainment of slow delta waves (<1Hz) facilitates sensorimotor integration in the brain and that this mechanism underlies the faster processing of anticipated stimuli. We further propose that the examined slow delta waves, observed to be phase-coupled to reaction times, correspond to the compound potentials typically observed in paradigms of stimulus anticipation and motor preparation. PMID- 28619652 TI - Frontal temporal and parietal systems synchronize within and across brains during live eye-to-eye contact. AB - Human eye-to-eye contact is a primary source of social cues and communication. In spite of the biological significance of this interpersonal interaction, the underlying neural processes are not well-understood. This knowledge gap, in part, reflects limitations of conventional neuroimaging methods, including solitary confinement in the bore of a scanner and minimal tolerance of head movement that constrain investigations of natural, two-person interactions. However, these limitations are substantially resolved by recent technical developments in functional near-infrared spectroscopy (fNIRS), a non-invasive spectral absorbance technique that detects changes in blood oxygen levels in the brain by using surface-mounted optical sensors. Functional NIRS is tolerant of limited head motion and enables simultaneous acquisitions of neural signals from two interacting partners in natural conditions. We employ fNIRS to advance a data driven theoretical framework for two-person neuroscience motivated by the Interactive Brain Hypothesis which proposes that interpersonal interaction between individuals evokes neural mechanisms not engaged during solo, non interactive, behaviors. Within this context, two specific hypotheses related to eye-to-eye contact, functional specificity and functional synchrony, were tested. The functional specificity hypothesis proposes that eye-to-eye contact engages specialized, within-brain, neural systems; and the functional synchrony hypothesis proposes that eye-to-eye contact engages specialized, across-brain, neural processors that are synchronized between dyads. Signals acquired during eye-to-eye contact between partners (interactive condition) were compared to signals acquired during mutual gaze at the eyes of a picture-face (non interactive condition). In accordance with the specificity hypothesis, responses during eye-to-eye contact were greater than eye-to-picture gaze for a left frontal cluster that included pars opercularis (associated with canonical language production functions known as Broca's region), pre- and supplementary motor cortices (associated with articulatory systems), as well as the subcentral area. This frontal cluster was also functionally connected to a cluster located in the left superior temporal gyrus (associated with canonical language receptive functions known as Wernicke's region), primary somatosensory cortex, and the subcentral area. In accordance with the functional synchrony hypothesis, cross brain coherence during eye-to-eye contact relative to eye-to-picture gaze increased for signals originating within left superior temporal, middle temporal, and supramarginal gyri as well as the pre- and supplementary motor cortices of both interacting brains. These synchronous cross-brain regions are also associated with known language functions, and were partner-specific (i.e., disappeared with randomly assigned partners). Together, both within and across brain neural correlates of eye-to-eye contact included components of previously established productive and receptive language systems. These findings reveal a left frontal, temporal, and parietal long-range network that mediates neural responses during eye-to-eye contact between dyads, and advance insight into elemental mechanisms of social and interpersonal interactions. PMID- 28619654 TI - Representational precision in visual cortex reveals outcome encoding and reward modulation during action preparation. AB - According to ideomotor theory, goal-directed action involves the active perceptual anticipation of actions and their associated effects. We used multivariate analysis of fMRI data to test if preparation of an action promotes precision in the perceptual representation of the action. In addition, we tested how reward magnitude modulates this effect. Finally, we examined how expectation and uncertainty impact neural precision in the motor cortex. In line with our predictions, preparation of a hand or face action increased the precision of neural activation patterns in the extrastriate body area (EBA) and fusiform face area (FFA), respectively. The size of this effect of anticipation predicted individuals' efficiency at performing the prepared action. In addition, increasing reward magnitude increased the precision of perceptual representations in both EBA and FFA although this effect was limited to the group of participants that learned to associate face actions with high reward. Surprisingly, examination of representations in the hand motor cortex and face motor cortex yielded effects in the opposite direction. Our findings demonstrate that the precision of representations in visual and motor areas provides an important neural signature of the sensorimotor representations involved in goal-directed action. PMID- 28619655 TI - Comparison of the spatial resolution of source imaging techniques in high-density EEG and MEG. AB - BACKGROUND: The present study aims at evaluating and comparing electrical and magnetic distributed source imaging methods applied to high-density Electroencephalography (hdEEG) and Magnetoencephalography (MEG) data. We used resolution matrices to characterize spatial resolution properties of Minimum Norm Estimate (MNE), dynamic Statistical Parametric Mapping (dSPM), standardized Low Resolution Electromagnetic Tomography (sLORETA) and coherent Maximum Entropy on the Mean (cMEM, an entropy-based technique). The resolution matrix provides information of the Point Spread Functions (PSF) and of the Crosstalk functions (CT), this latter being also called source leakage, as it reflects the influence of a source on its neighbors. METHODS: The spatial resolution of the inverse operators was first evaluated theoretically and then with real data acquired using electrical median nerve stimulation on five healthy participants. We evaluated the Dipole Localization Error (DLE) and the Spatial Dispersion (SD) of each PSF and CT map. RESULTS: cMEM showed the smallest spatial spread (SD) for both PSF and CT maps, whereas localization errors (DLE) were similar for all methods. Whereas cMEM SD values were lower in MEG compared to hdEEG, the other methods slightly favored hdEEG over MEG. In real data, cMEM provided similar localization error and significantly less spatial spread than other methods for both MEG and hdEEG. Whereas both MEG and hdEEG provided very accurate localizations, all the source imaging methods actually performed better in MEG compared to hdEEG according to all evaluation metrics, probably due to the higher signal-to-noise ratio of the data in MEG. CONCLUSION: Our overall results show that all investigated methods provide similar localization errors, suggesting very accurate localization for both MEG and hdEEG when similar number of sensors are considered for both modalities. Intrinsic properties of source imaging methods as well as their behavior for well-controlled tasks, suggest an overall better performance of cMEM in regards to spatial resolution and spatial leakage for both hdEEG and MEG. This indicates that cMEM would be a good candidate for studying source localization of focal and extended generators as well as functional connectivity studies. PMID- 28619656 TI - The large-scale functional connectivity correlates of consciousness and arousal during the healthy and pathological human sleep cycle. AB - Advances in neuroimaging have greatly improved our understanding of human sleep from a systems neuroscience perspective. However, cognition and awareness are reduced during sleep, hindering the applicability of standard task-based paradigms. Methods recently developed to study spontaneous brain activity fluctuations have proven useful to overcome this limitation. In this review, we focus on the concept of functional connectivity (FC, i.e. statistical covariance between brain activity signals) and its application to functional magnetic resonance imaging (fMRI) data acquired during sleep. We discuss how FC analyses of endogenous brain activity during sleep have contributed towards revealing the large-scale neural networks associated with arousal and conscious awareness. We argue that the neuroimaging of deep sleep can be used to evaluate the predictions of theories of consciousness; at the same time, we highlight some apparent limitations of deep sleep as an experimental model of unconsciousness. In resting state fMRI experiments, the onset of sleep can be regarded as the object of interest but also as an undesirable confound. We discuss a series of articles contributing towards the disambiguation of wakefulness from sleep on the basis of fMRI-derived dynamic FC, and then outline a plan for the development of more general and data-driven sleep classifiers. To complement our review of studies investigating the brain systems of arousal and consciousness during healthy sleep, we then turn to pathological and abnormal sleep patterns. We review the current literature on sleep deprivation studies and sleep disorders, adopting the critical stance that lack of independent vigilance monitoring during fMRI experiments is liable for false positives related to atypical sleep propensity in clinical and sleep-deprived populations. Finally, we discuss multimodal neuroimaging as a promising future direction to achieve a better understanding of the large-scale FC of the brain during sleep and its relationship to mechanisms at the cellular level. PMID- 28619657 TI - Low-frequency oscillations employ a general coding of the spatio-temporal similarity of dynamic faces. AB - Brain networks use neural oscillations as information transfer mechanisms. Although the face perception network in occipitotemporal cortex is well-studied, contributions of oscillations to face representation remain an open question. We tested for links between oscillatory responses that encode facial dimensions and the theoretical proposal that faces are encoded in similarity-based "face spaces". We quantified similarity-based encoding of dynamic faces in magnetoencephalographic sensor-level oscillatory power for identity, expression, physical and perceptual similarity of facial form and motion. Our data show that evoked responses manifest physical and perceptual form similarity that distinguishes facial identities. Low-frequency induced oscillations (< 20Hz) manifested more general similarity structure, which was not limited to identity, and spanned physical and perceived form and motion. A supplementary fMRI constrained source reconstruction implicated fusiform gyrus and V5 in this similarity-based representation. These findings introduce a potential link between "face space" encoding and oscillatory network communication, which generates new hypotheses about the potential oscillation-mediated mechanisms that might encode facial dimensions. PMID- 28619658 TI - Tender swelling of the posterior mandible. PMID- 28619659 TI - Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes. AB - BACKGROUND: Sodium glucose co-transporter 2 inhibitors may reduce cardiovascular and heart failure risk in patients with type 2 diabetes mellitus (T2DM). OBJECTIVES: The goal of this study was to examine the effects of canagliflozin on cardiovascular biomarkers in older patients with T2DM. METHODS: In 666 T2DM patients randomized to receive canagliflozin 100 or 300 mg or placebo, the study assessed the median percent change in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), soluble (s)ST2, and galectin-3 from baseline to 26, 52, and 104 weeks. RESULTS: Both serum NT-proBNP and serum hsTnI levels increased in placebo recipients, but they remained largely unchanged in those randomized to canagliflozin. Hodges-Lehmann estimates of the difference in median percent change between pooled canagliflozin and placebo were -15.0%, -16.1%, and -26.8% for NT-proBNP, and -8.3%, -11.9%, and -10.0% for hsTnI at weeks 26, 52, and 104, respectively (all p < 0.05). Serum sST2 was unchanged with canagliflozin and placebo over 104 weeks. Serum galectin-3 modestly increased from baseline with canagliflozin versus placebo, with significant differences observed at 26 and 52 weeks but not at 104 weeks. These results remained unchanged when only patients with complete samples were assessed. CONCLUSIONS: Compared with placebo, treatment with canagliflozin delayed the rise in serum NT-proBNP and hsTnI for over 2 years in older T2DM patients. These cardiac biomarker data provide support for the beneficial cardiovascular effect of sodium glucose co-transporter 2 inhibitors in T2DM. (A Safety and Efficacy Study of Canagliflozin in Older Patients [55 to 80 Years of Age] With Type 2 Diabetes Mellitus; NCT01106651). PMID- 28619660 TI - Corrigendum to "Fluorescence evaluations for porphyrin formation during topical PDT using ALA and methyl-ALA mixtures in pig skin models" [Photodiagn. Photodyn. Ther. 15 (2016) 236-244]. PMID- 28619661 TI - Corrigendum to "The optimization of fluorescence imaging of brain tumor tissue differentiated from brain edema-in vivo kinetic study of 5-aminolevulinic acid and talaporfin sodium" [Photodiagn. Photodyn. Ther. 6 (2009), 19-27]. PMID- 28619662 TI - Rapid detection of Salmonella with Recombinase Aided Amplification. AB - Rapid Salmonella detection using Recombinase Aided Amplification was established. The reaction completes in 20 min at 39 degrees C and can be performed with a portable device. Once further improved, this method should be a great choice for monitoring contamination, such as foodborne Salmonella or for similar purposes. PMID- 28619664 TI - Nailfold capillaroscopic changes in patients with idiopathic pulmonary arterial hypertension and systemic sclerosis-related pulmonary arterial hypertension. AB - : Pulmonary arterial hypertension (PAH) represents one of the main clinical expressions of the vascular changes in systemic sclerosis (SSc). Lung microvascular changes can play a role in the pathogenesis of idiopathic PAH (IPAH) also. The aim of this study is to investigate the presence of capillaroscopic abnormalities in patients with IPAH and to evaluate the differences in capillary nailfold changes between patients with IPAH and patients with SSc with and without PAH. METHODS: 39 SSc patients (19 with PAH - SSc-PAH and 20 without - SSc-noPAH), 21 subjects with IPAH and 20 healthy subjects were recruited. PAH was diagnosed by right heart catheterization. Nailfold videocapillaroscopy was performed (NVC) in all recruited subjects; capillary quantitative parameters (loops length and width, capillary density, neoangiogenesis) were evaluated and a semiquantitative scoring was used (normal, minor or major abnormalities for healthy controls and IPAH subjects and specific patterns - early, active and late - for SSc subjects) to define microvascular alterations. RESULTS: The presence of capillaroscopic abnormalities was detected in 38,1% subjects with IPAH; particularly, compared to healthy controls, capillary density was significantly lower (7,5+/-1,65loops/mm vs 9+/-1,37loops/mm p<0,05) and mean capillary width was significantly higher (21+/-13MUm vs 17+/ 3MUm p<0,05). A more severe NVC pattern (active/late) was described. SSc-PAH patients compared to SSc-noPAH patients (73,2% vs 50% respectively, p<0,05), with a significantly lower capillary density (5,64+/-1,9loops/mm vs 6,5+/-1,3loops/mm p<0,05) and a significantly higher capillary width (55+/-7MUm vs 35+/-8MUm - p<0,05) and mean number of neoangiogenesis (N/mm) (1+/-0,33 vs 0,2+/-0,22 respectively p<0,05). CONCLUSIONS: These data, beyond to confirm the role of microvascular damage in SSc-related PAH, support the hypothesis of systemic microvascular involvement in IPAH also, which can be detected by NVC, although further studies are needed to establish whether the changes in the systemic microcirculation are causal or consequential to PAH. PMID- 28619663 TI - Captive wild birds as reservoirs of enteropathogenic E. coli (EPEC) and Shiga toxin producing E. coli (STEC). AB - Psittacine birds have been identified as reservoirs of diarrheagenic Escherichia coli, a subset of pathogens associated with mortality of children in tropical countries. The role of other orders of birds as source of infection is unclear. The aim of this study was to perform the molecular diagnosis of infection with diarrheagenic E. coli in 10 different orders of captive wild birds in the state of Sao Paulo, Brazil. Fecal samples were analyzed from 516 birds belonging to 10 orders: Accipitriformes, Anseriformes, Columbiformes, Falconiformes, Galliformes, Passeriformes, Pelecaniformes, Piciformes, Psittaciformes and Strigiformes. After isolation, 401 E. coli strains were subjected to multiplex PCR system with amplification of genes eae and bfp (EPEC), stx1 and stx2 for STEC. The results of these tests revealed 23/401 (5.74%) positive strains for eae gene, 16/401 positive strains for the bfp gene (3.99%) and 3/401 positive for stx2 gene (0.75%) distributed among the orders of Psittaciformes, Strigiformes and Columbiformes. None of strains were positive for stx1 gene. These data reveal the infection by STEC, typical and atypical EPEC in captive birds. The frequency of these pathotypes is low and restricted to few orders, but the data suggest the potential public health risk that these birds represent as reservoirs of diarrheagenic E. coli. PMID- 28619665 TI - Computer modelling of electro-osmotically augmented three-layered microvascular peristaltic blood flow. AB - A theoretical study is presented here for the electro-osmosis modulated peristaltic three-layered capillary flow of viscous fluids with different viscosities in the layers. The layers considered here are the core layer, the intermediate layer and the peripheral layer. The analysis has been carried out under a number of physical restrictions viz. Debye-Huckel linearization (i.e. wall zeta potential <=25mV) is assumed sufficiently small, thin electric double layer limit (i.e. the peripheral layer is much thicker than the electric double layer thickness), low Reynolds number and large wavelength approximations. A non dimensional analysis is used to linearize the boundary value problem. Fluid-fluid interfaces, peristaltic pumping characteristics, and trapping phenomenon are simulated. Present study also evaluates the responses of interface, pressure rise, time-averaged volume flow rate, maximum pressure rise, and the influence of Helmholtz-Smoluchowski velocity on the mechanical efficiency (with two different cases of the viscosity of fluids between the intermediate and the peripheral layer). Trapping phenomenon along with bolus dynamics evolution with thin EDL effects are analyzed. The findings of this study may ultimately be useful to control the microvascular flow during the fractionation of blood into plasma (in the peripheral layer), buffy coat (intermediate layer) and erythrocytes (core layer). This work may also contributes in electrophoresis, hematology, electrohydrodynamic therapy and, design and development of biomimetic electro osmotic pumps. PMID- 28619666 TI - Treatment of rectal cancer in the East and West: Should it be different? PMID- 28619667 TI - Taking the Good with the Bad: Survival and Late Toxicity among Young Hematopoietic Cell Transplantation Survivors. PMID- 28619668 TI - US Registered Dietitian Nutritionists' Knowledge and Attitudes of Intuitive Eating and Use of Various Weight Management Practices. AB - BACKGROUND: Researchers have been advocating for a new weight-inclusive paradigm that focuses on health rather than weight. One important component of this model is intuitive eating. Although registered dietitian nutritionists (RDNs) are the nation's food and nutrition experts, RDNs' knowledge of and attitudes toward intuitive eating and use of traditional or restrictive strategies are unknown. OBJECTIVE: The purpose of this study was to characterize RDNs' knowledge of and attitudes toward an intuitive eating lifestyle and describe use of traditional weight management and nonrestrictive lifestyle practices with clients. DESIGN: This was a cross-sectional study. PARTICIPANTS: A validated survey was distributed using online survey software to 88,834 RDNs. RESULTS: There were 18,622 respondents who completed the survey (25%). The majority of RDNs were knowledgeable about intuitive eating, answering 71% of items correctly. The majority of RDNs had a positive view on each attitude item. RDNs who work in weight management reported using nonrestrictive/intuitive eating practices more than traditional/restrictive practices. RDNs who were women (P<0.001), had advanced education (P<0.001), worked in a private practice setting (P<0.001), completed at least one certificate of training in weight management (P<0.001), had more experience in weight management counseling (P<0.001), and had greater intuitive eating knowledge (P<0.001) were more likely to report greater use of nonrestrictive/intuitive eating practices. CONCLUSIONS: This study provides evidence that RDNs are using an intuitive eating approach more often than traditional weight management practices. PMID- 28619669 TI - Sex pheromone in the moth Heliothis virescens is produced as a mixture of two pools: de novo and via precursor storage in glycerolipids. AB - Most species of moths use a female-produced volatile sex pheromone, typically produced via de novo fatty acid synthesis in a specialized gland, for communication among mates. While de novo biosynthesis of pheromone (DNP) is rapid, suggesting transient precursor acids, substantial amounts of pheromone precursor (and other) acids are stored, predominantly in triacylglycerols in the pheromone gland. Whether these stored acids are converted to pheromone later or not has been the subject of some debate. Using a tracer/tracee approach, in which we fed female Heliothis virescens U-13C-glucose, we were able to distinguish two pools of pheromone, in which precursors were temporally separated (after and before feeding on labeled glucose): DNP synthesized from a mixed tracer/tracee acetyl CoA pool after feeding, and pheromone made from precursor acids primarily synthesized before feeding, which we call recycled precursor fat pheromone (RPP). DNP titer varied from high (during scotophase) to low (photophase) and with presence/absence of pheromone biosynthesis activating neuropeptide (PBAN), in accord with native pheromone titer previously observed. By contrast, RPP was constant throughout the photoperiod and did not change with PBAN presence/absence. The amount of RPP (6.3-10.3 ng/female) was typically much lower than that of DNP, especially during the scotophase (peak DNP, 105 ng/female). We propose an integral role for stored fats in pheromone biosynthesis, in which they are hydrolyzed and re-esterified throughout the photoperiod, with a small proportion of liberated precursor acyl CoAs being converted to pheromone. During the sexually active period, release of PBAN results in increased flux of glucose (from trehalose) and hydrolyzed acids entering the mitochondria, producing acetyl CoA precursor for de novo fat and pheromone biosynthesis. PMID- 28619670 TI - Hyponatraemia diagnosis and treatment clinical practice guidelines. AB - Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the management of hyponatremia patients remains problematic. The prevalence of hyponatremia in a wide variety of conditions and the fact that hyponatremia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and specialty-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed clinical practice guidelines on the diagnostic approach and treatment of hyponatremia as a joint venture of 3societies representing specialists with a natural interest in hyponatremia. In addition to a rigorous approach to the methodology and evaluation of the evidence, the document focuses on patient positive outcomes and on providing a useful tool for clinicians involved in everyday practice. In this article, we present an abridged version of the recommendations and suggestions for the diagnosis and treatment of hyponatremia extracted from the full guide. PMID- 28619671 TI - Combination of five diagnostic tests to estimate the prevalence of hookworm infection among school-aged children from a rural area of colombia. AB - BACKGROUND: Public health programs for the control of soil-transmitted helminthiases require valid diagnostic tests for surveillance and parasitic control evaluation. However, there is currently no agreement about what test should be used as a gold standard for the diagnosis of hookworm infection. Still, in presence of concurrent data for multiple tests it is possible to use statistical models to estimate measures of test performance and prevalence. The aim of this study was to estimate the diagnostic accuracy of five parallel tests (direct microscopic examination, Kato-Katz, Harada-Mori, modified Ritchie-Frick, and culture in agar plate) to detect hookworm infections in a sample of school aged children from a rural area in Colombia. METHODS AND RESULTS: We used both, a frequentist approach, and Bayesian latent class models to estimate the sensitivity and specificity of five tests for hookworm detection, and to estimate the prevalence of hookworm infection in absence of a Gold Standard. The Kato-Katz and agar plate methods had an overall agreement of 95% and kappa coefficient of 0.76. Different models estimated a sensitivity between 76% and 92% for the agar plate technique, and 52% to 87% for the Kato-Katz technique. The other tests had lower sensitivity. All tests had specificity between 95% and 98%. The prevalence estimated by the Kato-Katz and Agar plate methods for different subpopulations varied between 10% and 14%, and was consistent with the prevalence estimated from the combination of all tests. The Harada-Mori, Ritchie-Frick and direct examination techniques resulted in lower and disparate prevalence estimates. Bayesian approaches assuming imperfect specificity resulted in lower prevalence estimates than the frequentist approach. PMID- 28619672 TI - Point of care diagnosis of multiple schistosome parasites: Species-specific DNA detection in urine by loop-mediated isothermal amplification (LAMP). AB - Schistosomes are easily transmitted and high chance of repeat infection, so if control strategies based on targeted mass drug administration (MDA) are to succeed it is essential to have a test that is sensitive, accurate and simple to use. It is known and regularly demonstrated that praziquantel does not always eliminate an infection so in spite of the successes of control programs a residual of the reservoir survives to re-infect snails. The issue of diagnostic sensitivity becomes more critical in the assessment of program effectiveness. While serology, such as antigen capture tests might improve sensitivity, it has been shown that the presence of species-specific DNA fragments will indicate, most effectively, the presence of active parasites. Polymerase chain reaction (PCR) can amplify and detect DNA from urine residue captured on Whatman No. 3 filter paper that is dried after filtration. Previously we have detected S. mansoni and S. haematobium parasite-specific small repeat DNA fragment from filtered urine on filter paper by PCR. In the current study, we assessed the efficacy of detection of 86 urine samples for either or both schistosome parasites by PCR and loop-mediated isothermal amplification (LAMP) that were collected from a low to moderate transmission area in Ghana. Two different DNA extraction methods, standard extraction kit and field usable LAMP-PURE kit were also evaluated by PCR and LAMP amplification. With S. haematobium LAMP amplification for both extractions showed similar sensitivity and specificity when compared with PCR amplification (100%) verified by gel electrophoresis. For S. mansoni sensitivity was highest for LAMP amplification (100%) for standard extraction than PCR and LAMP with LAMP-PURE (99% and 94%). The LAMP-PURE extraction produced false negatives, which require further investigation for this field usable extraction kit. Overall high positive and negative predictive values (90% - 100%) for both species demonstrated a highly robust approach. The LAMP approach is close to point of care use and equally sensitive and specific to detection of species-specific DNA by PCR. LAMP can be an effective means to detect low intensity infection due to its simplicity and minimal DNA extraction requirement. This will enhance the effectiveness of surveillance and MDA control programs of schistosomiasis. PMID- 28619673 TI - Molecular characterization of Blastocystis from pigs in Shaanxi province of China. AB - Blastocystis is an enteric eukaryote of mystery for its ubiquitous presence in animals and humans worldwide and a broad diversity genetically. The animals have been suggested to be an important reservoir to transmit Blastocystis to humans because of high colonization frequency and the presence of zoonotic subtypes. In the present study, the prevalence and subtypes of Blastocystis in pigs in Shaanxi province of China were determined using the molecular technique based on the small subunit rRNA (SSU rRNA) gene fragment. Of 560 pig faecal samples collected from different geographical origins, 419 (74.8%) were positive for Blastocystis colonization. The prevalence was significant affected by the age and the geographical origin. Four subtypes, including three zoonotic (ST1, ST3 and ST5) and one animal specific (ST10) subtypes, were identified. To our knowledge, this study provides the first run-through information for colonization of Blastocystis in pigs in China. PMID- 28619674 TI - Frontal cranioplasty in fronto-metaphyseal dysplasia. AB - INTRODUCTION: Fronto-metaphyseal dysplasia (FMD), also called Gorlin-Cohen syndrome, is a rare syndrome initially described in 1969 by Gorlin and Cohen. Patients present skeletal dysplasia, craniofacial malformations and digit abnormalities. Craniofacial phenotype of FMD is characterized by supraorbital hyperostosis, hypertelorism, down-slanting palpebral fissures, broad nasal bridge and micrognathia. Here, we report the first adult case of craniofacial reconstruction with frontal cranioplasty in a patient with FMD. OBSERVATION: A 21 year-old male patient presented with aesthetic requests related to his facial abnormalities. The patient underwent a fronto-orbital cranioplasty using a coronal approach. Orbital, frontal and nasal hyperostoses were contoured in order to obtain a symmetric result. The patient had no postoperative complication. Aesthetic results were satisfactory and stable after 6 months of follow-up. DISCUSSION: The density and the quality of craniofacial bones were normal and this may account for the stability of cranioplasty results over time. Because bone was normal, cranioplasty is safety and stable in FMD. PMID- 28619675 TI - A pilot exploration of the effect of designated Function Focused Care on mobility, functional dependence and falls frequency in Dutch nursing home residents. AB - In recent years, there has been a gradual change in nursing home care from care providers doing as many things as possible for residents to a philosophy where patients are encouraged to become more involved in their care and activities of daily living. Function Focused Care (FFC) is a methodology to stimulate the involvement of residents on a daily basis that has shown to be safe and effective in improving ADL-functioning. We implemented FFC in four nursing homes with 53 residents. This first pilot project in Dutch nursing homes has replicated the finding that FFC inspires functional independence, but also revealed a reduction in the number of falls among fallers. PMID- 28619676 TI - Peroxynitrite-modified histone as a pathophysiological biomarker in autoimmune diseases. AB - Under physiological conditions, reactive nitrogen and oxygen species are produced continuously. However, excess of these radicals may damage biomolecules like lipids, proteins and nucleic acids. These reactive species have been implicated in many disease conditions including acute/chronic inflammation, rheumatoid arthritis (RA), neurodegenerative diseases and systemic lupus erythematosus (SLE). Peroxynitrite, an oxidant and nitrating molecule, formed in in vivo, when nitric oxide reacts with superoxide radical. The abnormal levels of nitrotyrosine detected in tissues affected by autoimmune diseases have been attributed to peroxynitrite-mediated enhanced nitration of tyrosine residues in proteins. The chromosomal histone proteins are conserved and weak immunogens. However, they exhibit strong immunogenicity after nitration. Rabbits challenged with peroxynitrite-modified histone induce high titre antibodies, indicating that peroxynitrite modification generated immunogenic epitopes. The preferential binding of peroxynitrite-modified histones by autoantibodies derived from SLE and RA sera shows oxidatively and nitrated modified histones involve in the initiation and progression of autoimmune diseases. This review article presents the literature review of the physicochemical and immunological studies on histone proteins modified with peroxynitrite with an objective of the possible role of oxidatively nitrated histones in the initiation/progression of autoimmune inflammatory diseases. PMID- 28619677 TI - i-motif structures in long cytosine-rich sequences found upstream of the promoter region of the SMARCA4 gene. AB - Cytosine-rich oligonucleotides are capable of forming complex structures known as i-motif with increasingly studied biological properties. The study of sequences prone to form i-motifs located near the promoter region of genes may be difficult because these sequences not only contain repeats of cytosine tracts of disparate length but also these may be separated by loops of varied nature and length. In this work, the formation of intramolecular i-motif structures by a long sequence located upstream of the promoter region of the SMARCA4 gene has been demonstrated. Nuclear Magnetic Resonance, Circular Dichroism, Gel Electrophoresis, Size-Exclusion Chromatography, and multivariate analysis have been used. Not only the wild sequence (5'-TC3T2GCTATC3TGTC2TGC2TCGC3T2G2TCATGA2C4 3') has been studied but also several other truncated and mutated sequences. Despite the apparent complex sequence, the results showed that the wild sequence may form a relatively stable and homogeneous unimolecular i-motif structure, both in terms of pH or temperature. The model ligand TMPyP4 destabilizes the structure, whereas the presence of 20% (w/v) PEG200 stabilized it slightly. This finding opens the door to the study of the interaction of these kind of i-motif structures with stabilizing ligands or proteins. PMID- 28619678 TI - APRIL:TACI axis is dispensable for the immune response to rabies vaccination. AB - There is significant need to develop a single-dose rabies vaccine to replace the current multi-dose rabies vaccine regimen and eliminate the requirement for rabies immune globulin in post-exposure settings. To accomplish this goal, rabies virus (RABV)-based vaccines must rapidly activate B cells to secrete antibodies which neutralize pathogenic RABV before it enters the CNS. Increased understanding of how B cells effectively respond to RABV-based vaccines may improve efforts to simplify post-exposure prophylaxis (PEP) regimens. Several studies have successfully employed the TNF family cytokine a proliferation inducing ligand (APRIL) as a vaccine adjuvant. APRIL binds to the receptors TACI and B cell maturation antigen (BCMA)-expressed by B cells in various stages of maturation-with high affinity. We discovered that RABV-infected primary murine B cells upregulate APRIL ex vivo. Cytokines present at the time of antigen exposure affect the outcome of vaccination by influencing T and B cell activation and GC formation. Therefore, we hypothesized that the presence of APRIL at the time of RABV-based vaccine antigen exposure would support the generation of protective antibodies against RABV glycoprotein (G). In an effort to improve the response to RABV vaccination, we constructed and characterized a live recombinant RABV-based vaccine vector which expresses murine APRIL (rRABV-APRIL). Immunogenicity testing in mice demonstrated that expressing APRIL from the RABV genome does not impact the primary antibody response against RABV G compared to RABV alone. In order to evaluate the necessity of APRIL for the response to rabies vaccination, we compared the responses of APRIL-deficient and wild-type mice to immunization with rRABV. APRIL deficiency does not affect the primary antibody response to vaccination. Furthermore, APRIL expression by the vaccine did not improve the generation of long-lived antibody-secreting plasma cells (PCs) as serum antibody levels were equivalent in response to rRABV-APRIL and the vector eight weeks after immunization. Moreover, APRIL is dispensable for the long-lived antibody secreting PC response to rRABV vaccination as anti-RABV G IgG levels were similar in APRIL-deficient and wild-type mice six months after vaccination. Mice lacking the APRIL receptor TACI demonstrated primary anti-RABV G antibody responses similar to wild-type mice following immunization with the vaccine vector indicating that this response is independent of TACI-mediated signals. Collectively, our findings demonstrate that APRIL and associated TACI signaling is dispensable for the immune response to RABV-based vaccination. PMID- 28619679 TI - Antiviral activity of [1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones against chikungunya virus targeting the viral capping nsP1. AB - Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted to humans by Aedes mosquitoes. Since 2005, CHIKV has been spreading worldwide resulting in epidemics in Africa, the Indian Ocean islands, Asia and more recently in the Americas. CHIKV is thus considered as a global health concern. There is no specific vaccine or drug available for the treatment of this incapacitating viral infection. We previously identified 3-aryl-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H) ones as selective inhibitors of CHIKV replication and proposed the viral capping enzyme nsP1 as a target. This work describes the synthesis of novel series of related compounds carrying at the aryl moiety a methylketone and related oximes combined with an ethyl or an ethyl-mimic at 5-position of the triazolopyrimidinone. These compounds have shown antiviral activity against different CHIKV isolates in the very low MUM range based on both virus yield reduction and virus-induced cell-killing inhibition assays. Moreover, these antivirals inhibit the in vitro guanylylation of alphavirus nsP1, as determined by Western blot using an anti-cap antibody. Thus, the data obtained seem to indicate that the anti-CHIKV activity might be related to the inhibition of this crucial step in the viral RNA capping machinery. PMID- 28619680 TI - Quality of life and functional capacity of patients with adhesive capsulitis: identifying risk factors associated to better outcomes after treatment with nerve blocking. AB - INTRODUCTION: The objectives of this study were to assess the quality of life and functional capacity of adhesive capsulitis patients at the beginning and end of procedure and to identify risk factors associated to better outcomes after treatment with nerve blocking. METHODS: A prospective cohort study was performed. Inclusion criteria were clinical signs of adhesive capsulitis and disease changes on shoulder imaging exams. The short form of World Health Organization Quality of life and Disabilities of the Arm, Shoulder and Hand questionnaires were administered at the beginning and end of treatment. A score of 55 points or more on the Constant index was used for discontinuation of treatment. We used the Wilcoxon test for paired samples. Multiple regression analysis of Poisson was carried out using exposure variables with p<0.20 in the univariate analysis and the satisfactory quality of life and better functional capability as outcomes. The significance level was 5%. RESULTS: 43 patients were evaluated. For the comparison between medians values at the beginning and end of treatment (physical domain: 46.43-67.86; psychologic domain: 66.67-79.17; social domain: 66.67-75; environment domain: 62.5-68.75; DASH: 64.16-38.33), p was <0.05. Aging (physical/psychologic/DASH), higher educational level (physical/environment/DASH), less severity (only physical) and fewer nerve blocking (only psychologic) were these independent risk factors. CONCLUSIONS: Quality of life and functional capacity of the patients improve at the end of procedure. Older patients and higher education levels are the risk factors most associated to satisfactory quality of life and better functional capacity after treatment with nerve blocking. PMID- 28619681 TI - Gastric carcinoma after sleeve gastrectomy for obesity. AB - Obesity is associated with an increased risk of cancer development in the upper gastrointestinal tract. We present the case of a female patient with gastric carcinoma after sleeve gastrectomy. Before bariatric surgery, one rationale for performing routine endoscopy is to detect clinically relevant conditions with the potential to change the surgical procedure. After bariatric surgery in symptomatic patients and in patients with unspecific symptoms, early upper endoscopy should be performed to detect potential carcinomas of the upper gastrointestinal tract. PMID- 28619682 TI - Air quality and acute deaths in California, 2000-2012. AB - Many studies have shown an association between air quality and acute deaths, and such associations are widely interpreted as causal. Several factors call causation and even association into question, for example multiple testing and multiple modeling, publication bias and confirmation bias. Many published studies are difficult or impossible to reproduce because of lack of access to confidential data sources. Here we make publically available a dataset containing daily air quality levels, PM2.5 and ozone, daily temperature levels, minimum and maximum and daily maximum relative humidity levels for the eight most populous California air basins, thirteen years, >2M deaths, over 37,000 exposure days. The data are analyzed using standard time series analysis, and a sensitivity analysis is computed varying model parameters, locations and years. Our analysis finds little evidence for association between air quality and acute deaths. These results are consistent with those for the widely cited NMMAPS dataset when the latter are restricted to California. The daily death variability was mostly explained by time of year or weather variables; Neither PM2.5 nor ozone added appreciably to the prediction of daily deaths. These results call into question the widespread belief that association between air quality and acute deaths is causal/near-universal. PMID- 28619683 TI - Functional assessment and quality of life in patients following replantation of the distal half of the forearm (except fingers): A review of 11 cases. AB - The aims of this study were to evaluate the function and quality of life in patients who have undergone replantation of the hand or forearm. We carried out a retrospective single-center study of cases performed between 1977 and 2015. Our hospital's database was searched for patients who underwent replantation of the distal half of the forearm and hand (except the fingers). The evaluation included sensitivity, joint mobility, strength and quality of life. Conventional functional scores were used. Seventeen replantation cases were identified. Four patients were lost to follow-up. Of the 13 available patients, two suffered a replantation failure. Ultimately 11 patients were included in the study. Three patients were evaluated based on their medical records and eight were reviewed in person. The mean patient age was 31+/-11.8 years. The sensory evaluation resulted in five patients being classified as S1 and one as S3+. The mean Kapandji score was 4.3+/-2.3 [0-6]. The mean grip strength was 39.4+/-20% [0-80], and the pinch strength was 36.2+/-16% [0-60] compared to the healthy contralateral side. The mean DASH was 36.2+/-30.4 [4.5-79.5]. According to Chen's classification, two patients were at stage IV. For 50% of patients, the overall quality of life was at least equivalent to that of the general population. Replantation of the distal half of the forearm and hand should be attempted whenever possible. Although replantation causes some disability, good quality of life seems to be maintained. PMID- 28619684 TI - Is Usutu virus ready for prime time? AB - Although considered a neglected tropical disease, the mosquito-borne Usutu virus has demonstrated signs of emergence from Africa to Europe. While human cases are infrequent, the potential for neuroinvasive infection, even in immunocompetent individuals, suggests a need for increased research into virus biology and pathogenesis, as well as rapid measures for diagnosis and environmental surveillance. PMID- 28619685 TI - Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer. AB - This review examines the general cellular and molecular underpinnings of human papillomavirus (HPV)-related carcinogenesis in the context of head and neck squamous cell carcinoma (HNSCC) and focuses on HPV-positive oropharyngeal squamous cell carcinoma in areas for which specific data is available. It covers the major pathways dysregulated in HPV-positive HNSCC and the genome-wide changes associated with this disease. PMID- 28619686 TI - Low-dose BMP-2 is sufficient to enhance the bone formation induced by an injectable, PLGA fiber-reinforced, brushite-forming cement in a sheep defect model of lumbar osteopenia. AB - BACKGROUND CONTEXT: Bioresorbable calcium phosphate cement (CPC) may be suitable for vertebroplasty/kyphoplasty of osteoporotic vertebral fractures. However, additional targeted delivery of osteoinductive bone morphogenetic proteins (BMPs) in the CPC may be required to counteract the augmented local bone catabolism and support complete bone regeneration. PURPOSE: This study aimed at testing an injectable, poly (l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite forming cement (CPC) containing low-dose bone morphogenetic protein BMP-2 in a sheep lumbar osteopenia model. STUDY DESIGN/ SETTING: This is a prospective experimental animal study. METHODS: Bone defects (diameter 5 mm) were generated in aged, osteopenic female sheep and filled with fiber-reinforced CPC alone (L4; CPC+fibers) or with CPC containing different dosages of BMP-2 (L5; CPC+fibers+BMP 2; 1, 5, 100, and 500 ug BMP-2; n=5 or 6 each). The results were compared with those of untouched controls (L1). Three and 9 months after the operation, structural and functional effects of the CPC (+/-BMP-2) were analyzed ex vivo by measuring (1) bone mineral density (BMD); (2) bone structure, that is, bone volume/total volume (assessed by micro-computed tomography [micro-CT] and histomorphometry), trabecular thickness, and trabecular number; (3) bone formation, that is, osteoid volume/bone volume, osteoid surface/bone surface, osteoid thickness, mineralizing surface/bone surface, mineral apposition rate, and bone formation rate/bone surface; (4) bone resorption, that is, eroded surface/bone surface; and (5) compressive strength. RESULTS: Compared with untouched controls (L1), CPC+fibers (L4) and/or CPC+fibers+BMP-2 (L5) significantly improved all parameters of bone formation, bone resorption, and bone structure. These effects were observed at 3 and 9 months, but were less pronounced for some parameters at 9 months. Compared with CPC without BMP-2, additional significant effects of BMP-2 were demonstrated for bone structure (bone volume/total volume, trabecular thickness, trabecular number) and formation (osteoid surface/bone surface and mineralizing surface/bone surface), as well as for the compressive strength. The BMP-2 effects on bone formation at 3 and 9 months were dose-dependent, with 5-100 ug as the optimal dosage. CONCLUSIONS: BMP 2 significantly enhanced the bone formation induced by a PLGA fiber-reinforced CPC in sheep lumbar osteopenia. A single local dose as low as <=100 ug BMP-2 was sufficient to augment middle to long-term bone formation. The novel CPC+BMP-2 may thus represent an alternative to the bioinert, supraphysiologically stiff polymethylmethacrylate cement presently used to treat osteoporotic vertebral fractures by vertebroplasty/kyphoplasty. PMID- 28619687 TI - Use of the Central Sensitization Inventory (CSI) as a treatment outcome measure for patients with chronic spinal pain disorder in a functional restoration program. AB - BACKGROUND CONTEXT: The Central Sensitization Inventory (CSI) is a valid and reliable patient-reported instrument designed to identify patients whose presenting symptoms may be related to central sensitization (CS). Part A of the CSI measures a full array of 25 somatic and emotional symptoms associated with CS, and Part B asks if patients have previously been diagnosed with one or more specific central sensitivity syndromes (CSSs) and related disorders. The CSI has previously been validated in a group of patients with chronic pain who were screened by a trained psychiatrist for specific CSS diagnoses. It is currently unknown if the CSI can be a useful treatment-outcome assessment tool for patients with chronic spinal pain disorder (CSPD) who are not screened for comorbid CSSs. It is known, however, that previous studies have identified CS-related symptoms, and comorbid CSSs, in subsets of patients with CSPDs. Studies have also shown that CS-related symptoms can be influenced by cognitive and psychosocial factors, including abuse history in both childhood and adulthood, sleep disturbance, catastrophic and fear-avoidant cognitions, and symptoms of depression and anxiety. PURPOSE: This study aimed to evaluate CSI scores, and their associations with other clinically relevant psychosocial variables, in a cohort of patients with CSPD who entered and completed a functional restoration program. STUDY DESIGN/SETTING: A retrospective study of prospectively collected data from a cohort study of patients with CSPD, who completed the CSI at admission to, and discharge from, an interdisciplinary function restoration program (FRP) was carried out. PATIENT SAMPLE: A cohort of 763 patients with CSPD comprised the study sample. OUTCOME MEASURES: Clinical interviews evaluated mood disorders and abuse history. A series of self-reported measures evaluated comorbid psychosocial symptoms, including pain intensity, pain-related anxiety, depressive symptoms, somatization symptoms, perceived disability, and sleep disturbance, at FRP admission and discharge. METHODS: Patients were grouped into five severity level groups, from mild to extreme, based on total CSI scores, at FRP admission, and then again at discharge. The FRP included a quantitatively directed and medically supervised exercise process, as well as a multimodal psychosocial disability management component. RESULTS: The CSI severity groups were strongly associated with Major Depressive Disorder and previous abuse history (p<.01), which are known risk factors for CS-related symptoms and diagnoses. The CSI scores were also strongly associated with patient-reported CSS diagnoses on CSI Part B. The percentage of patients who reported a comorbid CSS diagnosis increased in each higher CSI-severity group, from 11% in the Subclinical group, to 56% in the Extreme group. The CSI severity groups were significantly related to other CS related patient-reported symptoms, including pain intensity, pain-related anxiety, depressive symptoms, somatization symptoms, perceived disability, and sleep disturbance (p's<.001). The CSI scores, along with all other psychosocial measures, decreased at treatment discharge. CONCLUSIONS: In the present study, admission CSI scores were highly associated with previous CSS diagnoses, CS related symptoms, and clinically relevant patient-reported psychosocial variables. All psychosocial variables, as well as scores on the CSI, were significantly improved at FRP discharge. The CSI may have important clinical utility, as a screener and as a treatment outcome measure, for patients with CSPD participating in an interdisciplinary FRP. PMID- 28619688 TI - Single-port laparoscopy in gynecologic oncology: seven years of experience at a single institution. AB - BACKGROUND: Single-port laparoscopy has gained popularity within minimally invasive gynecologic surgery for its feasibility, cosmetic outcomes, and safety. However, within gynecologic oncology, there are limited data regarding short-term adverse outcomes and long-term hernia risk in patients undergoing single-port laparoscopic surgery. OBJECTIVE: The objective of the study was to describe short term outcomes and hernia rates in patients after single-port laparoscopy in a gynecologic oncology practice. STUDY DESIGN: A retrospective, single-institution study was performed for patients who underwent single-port laparoscopy from 2009 to 2015. A univariate analysis was performed with chi2 tests and Student t tests; Kaplan-Meier and Cox proportional hazards determined time to hernia development. RESULTS: A total of 898 patients underwent 908 surgeries with a median follow-up of 37.2 months. The mean age and body mass index were 55.7 years and 29.6 kg/m2, respectively. The majority were white (87.9%) and American Society of Anesthesiologists class II/III (95.5%). The majority of patients underwent surgery for adnexal masses (36.9%) and endometrial hyperplasia/cancer (37.3%). Most women underwent hysterectomy (62.7%) and removal of 1 or both fallopian tubes and/or ovaries (86%). Rate of adverse outcomes within 30 days, including reoperation (0.1%), intraoperative injury (1.4%), intensive care unit admission (0.4%), venous thromboembolism (0.3%), and blood transfusion, were low (0.8%). The rate of urinary tract infection was 2.8%; higher body mass index (P = .02), longer operative time (P = .02), smoking (P = .01), hysterectomy (P = .01), and cystoscopy (P = .02) increased the risk. The rate of incisional cellulitis was 3.5%. Increased estimated blood loss (P = .03) and endometrial cancer (P = .02) were independent predictors of incisional cellulitis. The rate for surgical readmissions was 3.4%; higher estimated blood loss (P = .03), longer operative time (P = .02), chemotherapy alone (P = .03), and combined chemotherapy and radiation (P < .05) increased risk. The rate of incisional hernia rate was 5.5% (n = 50) with a mean occurrence at 570.2 +/- 553.3 days. Higher American Society of Anesthesiologists class (P = .04), diabetes (P < .001), hypertension (P = .043), increasing age (P = .017; hazard ratio [HR], 1.03), and body mass index (P < .001; HR, 1.08) were independent predictors for incisional hernia development. Previous abdominal surgeries (P = .24) and hand assist (P = .64) were not associated with increased risk for incisional hernia. Patients with American Society of Anesthesiologists class III/IV had a 3 year hernia rate of 12.8% (HR, 1.81). Patients with diabetes mellitus had a 3 year hernia rate of 23.0% (HR, 3.60). CONCLUSION: In this large cohort of patients undergoing single-port laparoscopy, the incidence of short-term adverse outcomes is low. While the rate of incisional hernia was 5.5%, incidence reached 23.0% at 3 years in high-risk groups. Previous studies with short follow-up duration may underestimate the risk of hernia, especially in patients with significant comorbidities. PMID- 28619689 TI - Risks and benefits of opportunistic salpingectomy during vaginal hysterectomy: a decision analysis. AB - BACKGROUND: Fallopian tubes are commonly removed during laparoscopic and open hysterectomy to prevent ovarian and tubal cancer but are not routinely removed during vaginal hysterectomy because of perceptions of increased morbidity, difficulty, or inadequate surgical training. OBJECTIVE: We sought to quantify complications and costs associated with a strategy of planned salpingectomy during vaginal hysterectomy. STUDY DESIGN: We created a decision analysis model using TreeAgePro. Effectiveness outcomes included ovarian cancer incidence and mortality as well as major surgical complications. Modeled complications included transfusion, conversion to laparotomy or laparoscopy, abscess/hematoma requiring intervention, ileus, readmission, and reoperation within 30 days. We also modeled subsequent benign adnexal surgery beyond the postoperative window. Those whose procedures were converted from a vaginal route were assumed to undergo bilateral salpingectomy, regardless of treatment group, following American College of Obstetricians and Gynecologists guidelines. Costs were gathered from published literature and Medicare reimbursement data, with internal cost data from 892 hysterectomies at a single institution used to estimate costs when necessary. Complication rates were determined from published literature and from 13,397 vaginal hysterectomies recorded in the National Surgical Quality Improvement Program database from 2008 through 2013. RESULTS: Switching from a policy of vaginal hysterectomy alone to a policy of routine planned salpingectomy prevents a diagnosis of ovarian cancer in 1 of every 225 women having surgery and prevents death from ovarian cancer in 1 of every 450 women having surgery. Overall, salpingectomy was a less expensive strategy than not performing salpingectomy ($7350.62 vs $8113.45). Sensitivity analysis demonstrated the driving force behind increased costs was the increased risk of subsequent benign adnexal surgery among women retaining their tubes. Planned opportunistic salpingectomy had more major complications than hysterectomy alone (7.95% vs 7.68%). Major complications included transfusion, conversion to laparotomy or laparoscopy, abscess/hematoma requiring intervention, ileus, readmission, and reoperation within 30 days. Therefore, routine salpingectomy results in 0.61 additional complications per case of cancer prevented and 1.21 additional complications per death prevented. A surgeon therefore must withstand an additional ~3 complications to prevent 5 cancer diagnoses and ~6 additional complications to prevent 5 cancer deaths. CONCLUSION: Salpingectomy should routinely be performed with vaginal hysterectomy because it was the dominant and therefore cost effective strategy. Complications are minimally increased, but the trade-off with cancer prevention is highly favorable. PMID- 28619692 TI - A randomized trial of motivational interviewing and facilitated contraceptive access to prevent rapid repeat pregnancy among adolescent mothers. AB - BACKGROUND: Most interventions designed to reduce teen pregnancy rates have not focused on pregnant and/or parenting adolescents. Therefore, a large randomized controlled trial was conducted regarding a motivational interviewing program entitled Teen Options to Prevent Pregnancy in a low-income sample of adolescent mothers. This program recommended monthly sessions between a participant and a registered nurse over 18 months. This program also featured facilitated birth control access through transportation assistance and a part-time contraceptive clinic. OBJECTIVE: The impact of this program on rapid repeat pregnancies at 18 months after enrollment was evaluated. STUDY DESIGN: Five hundred ninety-eight adolescent females were enrolled from 7 obstetrics-gynecology clinics and 5 postpartum units of a large hospital system in a Midwestern city. Each participant was enrolled at least 28 weeks pregnant or less than 9 weeks postpartum. Each participant was randomized to either the Teen Options to Prevent Pregnancy intervention or a usual-care control condition. Intervention participants averaged 4.5 hours of assistance. Participants were contacted by blinded research staff at 6 and 18 months to complete self-report surveys. Differences in outcomes between the intervention and control groups were assessed using ordinary least-squares regression. RESULTS: There was an 18.1% absolute reduction in self-reported repeat pregnancy in the intervention group relative to the control group (20.5% vs 38.6%%; P < .001). There was a 13.7% absolute increase in self-reported long-acting reversible contraception use in the intervention group relative to the control group (40.2% vs 26.5%, P = .002). There was no evidence of harmful effects of the intervention on sexual risk behaviors, such as having sexual intercourse without a condom or greater number of partners. CONCLUSION: The Teen Options to Prevent Pregnancy program represents one of the few evidence-based interventions to reduce rapid repeat teen pregnancy. This relatively brief intervention may be a viable alternative to more time-intensive programs that adolescent mothers may be unable or unwilling to receive. PMID- 28619691 TI - A mouse model of antepartum stillbirth. AB - BACKGROUND: Many stillbirths of normally formed fetuses in the third trimester could be prevented via delivery if reliable means to anticipate this outcome existed. However, because the etiology of these stillbirths is often unexplained and although the underlying mechanism is presumed to be hypoxia from placental insufficiency, the placentas often appear normal on histopathological examination. Gestational age is a risk factor for antepartum stillbirth, with a rapid rise in stillbirth rates after 40 weeks' gestation. We speculate that a common mechanism may explain antepartum stillbirth in both the late-term and postterm periods. Mice also show increasing rates of stillbirth when pregnancy is artificially prolonged. The model therefore affords an opportunity to characterize events that precede stillbirth. OBJECTIVE: The objective of the study was to prolong gestation in mice and monitor fetal and placental growth and cardiovascular changes. STUDY DESIGN: From embryonic day 15.5 to embryonic day 18.5, pregnant CD-1 mice received daily progesterone injections to prolong pregnancy by an additional 24 hour period (to embryonic day 19.5). To characterize fetal and placental development, experimental assays were performed throughout late gestation (embryonic day 15.5 to embryonic day 19.5), including postnatal day 1 pups as controls. In addition to collecting fetal and placental weights, we monitored fetal blood flow using Doppler ultrasound and examined the fetoplacental arterial vascular geometry using microcomputed tomography. Evidence of hypoxic organ injury in the fetus was assessed using magnetic resonance imaging and pimonidazole immunohistochemistry. RESULTS: At embryonic day 19.5, mean fetal weights were reduced by 14% compared with control postnatal day 1 pups. Ultrasound biomicroscopy showed that fetal heart rate and umbilical artery flow continued to increase at embryonic day 19.5. Despite this, the embryonic day 19.5 fetuses had significant pimonidazole staining in both brain and liver tissue, indicating fetal hypoxia. Placental weights at embryonic day 19.5 were 21% lower than at term (embryonic day 18.5). Microcomputed tomography showed no change in quantitative morphology of the fetoplacental arterial vasculature between embryonic day 18.5 and embryonic day 19.5. CONCLUSION: Prolongation of pregnancy renders the murine fetus vulnerable to significant growth restriction and hypoxia because of differential loss of placental mass rather than any compromise in fetoplacental blood flow. Our data are consistent with a hypoxic mechanism of antepartum fetal death in human term and postterm pregnancy and validates the inability of umbilical artery Doppler to safely monitor such fetuses. New tests of placental function are needed to identify the late-term fetus at risk of hypoxia to intervene by delivery to avoid antepartum stillbirth. PMID- 28619693 TI - Oral astringent stimuli alter the enamel pellicle's ultrastructure as revealed by electron microscopy. AB - OBJECTIVES: This electron microscopic study aimed at investigating effects of oral astringent stimuli on the enamel pellicle's morphology. METHODS: Pellicles were formed in situ within 30min on bovine enamel slabs, fixed to individuals' upper jaw splints. The pellicle-coated specimens were immersed in vitro in seven diverse astringent solutions and subsequently analyzed by scanning electron microscopy (SEM), energy dispersive X-ray (EDX) spectroscopy, as well as transmission electron microscopy (TEM). Four biocompatible astringents, namely the polyphenol epigallocatechin gallate, the metal salt iron(III) sulfate, the basic protein lysozyme, and the aminopolysaccharide chitosan, were additionally applied in situ. After rinsing the oral cavity with these compounds, the pellicle's ultrastructure was imaged by SEM and TEM, respectively. Untreated pellicle samples served as controls. RESULTS: Exposure to polyphenols and lysozyme induced particularly thicker and electron-denser pellicles in comparison to the control pellicle with similar characteristics in vitro and in situ. In contrast, acidic chitosan and metal salt solutions, respectively, revealed minor pellicle alterations. The incorporation of Fe and Al into the pellicles treated with the corresponding inorganic salts was verified by EDX analysis. CONCLUSIONS: Astringent-induced pellicle modifications were for the first time visualized by TEM. The ultrastructural alterations of the dental pellicle may partly explain the tooth-roughening effect caused by oral astringent stimuli. CLINICAL SIGNIFICANCE: Astringents might modify the pellicle's protective properties against dental erosion, attrition, as well as bacterial adhesion, and by this means may influence tooth health. The findings may thus be particularly relevant for preventive dentistry. PMID- 28619694 TI - Reply to alternative effects of transportation time in out-of-hospital cardiac arrests. PMID- 28619695 TI - A prolonged PR interval, an unfavorable shareholder of the profits of cardiac resynchronization therapy? PMID- 28619690 TI - Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. AB - Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic agent, its role as a therapeutic agent is expanding to include treatment of prediabetes mellitus, gestational diabetes mellitus, and polycystic ovarian disease; more recently, experimental studies and observations in randomized clinical trials suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes mellitus and reviews the results of metaanalyses of metformin in gestational diabetes mellitus as well as the treatment of obese, non-diabetic, pregnant women to prevent macrosomia. We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for gestational-age infants (the primary endpoint) but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the improvement of endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by rapamycin, a mechanistic target. Metformin has a molecular weight of 129 Daltons and therefore readily crosses the placenta. There is considerable evidence to suggest that this agent is safe during pregnancy. New literature on the role of metformin as a chemotherapeutic adjuvant in the prevention of cancer and in prolonging life and protecting against aging is reviewed briefly. Herein, we discuss the mechanisms of action and potential benefits of metformin. PMID- 28619696 TI - Postoperative Pain Management in Spanish Hospitals: A Cohort Study Using the PAIN OUT Registry. AB - : Pain after surgery remains a problem worldwide, although there are no published data on postoperative outcomes in Spain. We evaluated 2,922 patients on the first day after surgery in 13 tertiary care Spanish hospitals, using the PAIN-OUT questionnaire. The aims were to: assess postoperative outcomes and anesthetic/analgesic management in Orthopedics (ORT) and General Surgery (GEN) patients; explore the influence of the analgesic therapy on outcomes and opioid requirements; evaluate and compare outcomes and analgesic management according to surgical procedure. Mean worst pain and percentage of patients in severe pain were 5.6 (on a numeric rating scale of 0-10) and 39.4%, respectively, slightly lower than those reported in Western countries (range, 5.0-8.4 and 33-55%). Patients' pain assessment (83.1%) and information were high (63.3%), but participation in decision-making (4.8) was lower than in the United States (7.0) and Europe (Germany, France, Norway, and Denmark; mean, 5.9). Patients after orthopedic surgery had the worst outcomes. General anesthesia was more frequent in GEN patients, whereas regional (central and peripheral) was more frequent in ORT surgery patients. Mean opioid consumption (20.2 mg per patient per 24 hours, oral morphine equivalents), was lower than reported and decreased >50% after regional analgesia. Intravenous morphine patient-controlled analgesia was seldom used (6.2%). Acute opioid treatments were associated with worsened outcomes whereas multimodal analgesia (mainly antipyretic analgesics-nonsteroidal anti inflammatory drugs-opioids) were associated with improved results. Epidurals in abdominal surgery (16.7%) were also associated with better outcomes. Presurgical chronic pain (>7) and/or chronic opioid consumption, were associated with worsened pain outcomes; the latter with a 50% increase in postoperative opioid requirements. Tibia/fibula and foot surgeries (ORT), and gastric, small intestine, and anterior abdominal wall procedures (GEN) were the most painful. Rigorous control of chronic pain before surgery, and combining opioids with adjuvants and other analgesics perioperatively, might improve postoperative outcomes. PERSPECTIVE: We analyzed postoperative outcomes and analgesic management in patients from tertiary care Spanish hospitals. The study serves as a point of comparison with other Western countries and shows that pain intensity outcomes and opioid consumption were slightly better in the Spanish population. Chronic pain before surgery (numeric rating scale score >7) and/or chronic opioid consumption, were associated with worsened pain outcomes, suggesting that rigorous control of chronic pain before surgery, and combining opioids with adjuvants and other analgesics perioperatively, might improve outcomes. Patients' pain participation in decision-making was inadequate and should be improved in Spanish hospitals. PMID- 28619697 TI - Depression and Pain in Asian and White Americans With Knee Osteoarthritis. AB - : Few studies have examined the underlying psychosocial mechanisms of pain in Asian Americans. Using the biopsychosocial model, we sought to determine whether variations in depression contribute to racial group differences in symptomatic knee osteoarthritis pain between Asian Americans and non-Hispanic white Americans. The sample consisted of 100 participants, including 50 Asian Americans (28 Korean Americans, 9 Chinese Americans, 7 Japanese Americans, 5 Filipino Americans, and 1 Indian American) and 50 age- and sex-matched non-Hispanic white Americans with symptomatic knee osteoarthritis pain. The Centers for Epidemiologic Studies Depression Scale was used to assess symptoms of depression, and the Western Ontario and McMaster Universities Osteoarthritis Index and the Graded Chronic Pain Scale were used to measure clinical pain. In addition, quantitative sensory testing was used to measure experimental sensitivity to heat and mechanically-induced pain. The results indicated that higher levels of depression in Asian Americans may contribute to greater clinical pain and experimental pain sensitivity. These findings add to the growing literature regarding ethnic and racial differences in pain and its associated psychological conditions, and additional research is warranted to strengthen these findings. PERSPECTIVE: This article shows the contribution of depression to clinical pain and experimental pain sensitivity in Asian Americans with knee osteoarthritis. Our results suggest that Asian Americans have higher levels of depressive symptoms and that depression plays a relevant role in greater clinical pain and experimental pain sensitivity in Asian Americans. PMID- 28619698 TI - Neuropathic Pain in Low Back-Related Leg Pain Patients: What Is the Evidence of Prevalence, Characteristics, and Prognosis in Primary Care? A Systematic Review of the Literature. AB - : This systematic review synthesizes literature describing prevalence, characteristics, and prognosis of low back-related leg pain (LBLP) patients with neuropathic pain in primary care and/or similar settings. Inclusion and exclusion criteria were developed and used by independent reviewers to screen citations for eligibility. The initial search yielded 24,948 citations; after screening 12 studies were included. Neuropathic pain was identified using case ascertainment tools (n = 5), clinical history with examination (n = 4), and using LBLP samples assumed neuropathic (n = 3). Neuropathic pain prevalence varied from 19% to 80%. There was consistent evidence for higher back-related disability (n = 3), poorer health-related quality of life (n = 2), and some evidence for more severe depression (n = 2), anxiety (n = 3), and pain intensity (n = 4) in patients with neuropathic pain. Results were less consistent when cases were identified through clinical history with examination than those identified using case ascertainment tools. Prognosis (n = 1) of LBLP patients with neuropathic pain was worse compared with those without, in all outcomes (leg pain intensity, leg and back related disability, self-reported general health) except back pain intensity. No studies described prognostic factors. This systematic review highlights the evidence gap in neuropathic pain in LBLP in primary care, especially with respect to prognosis. PERSPECTIVE: Patients with LBLP may have neuropathic pain. This systematic review emphasizes the paucity of evidence describing the characteristics and prognosis of neuropathic pain in this patient population. Future research investigating prognosis of these patients with neuropathic pain is likely to contribute to better understanding and management. PMID- 28619699 TI - The Relationship Between Blood Pressure and Sleep Duration in Turkish Children: A Cross-Sectional Study. AB - OBJECTIVE: As in adults, hypertension is also an important risk factor for cardiovascular disease in children. We aimed to evaluate the effect of sleep duration on blood pressure in normal weight Turkish children aged between 11-17 years. METHODS: This cross-sectional study was conducted in the primary and secondary schools of the two central and ten outlying districts of Kayseri, Turkey. Subjects were 2860 children and adolescents (1385 boys, 1475 girls). Systolic and diastolic blood pressures were measured according to the recommendations of the Fourth Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. Sleep duration was classified as follows: <=8 hours, 8.1-8.9 hours, 9.0-9.9 hours or >=10 hours. RESULTS: For short sleeper boys and girls (participants with a sleep duration <=8 h) the prevalence of prehypertension and hypertension was 35.0% and 30.8%, respectively. In univariate binary logistic regression analyses (age-adjusted), each unit increment in sleep duration (hours) in boys and girls, decreased the prehypertension and hypertension risk by 0.89 [odds ratio (OR)] [confidance interval (CI); 0.82-0.98] and 0.88 (OR) (CI; 0.81 0.97), respectively (p<0.05). In multiple binary logistic regression analyses [age- and body mass index (BMI)-adjusted] the location of the school and sleep duration categories were shown to be the most important factors for prehypertension and hypertension in both genders, while household income was the most important factor, only in boys. CONCLUSIONS: A sleep duration <=8 h is an independent risk factor for prehypertension and hypertension in Turkish children aged 11-17 years. PMID- 28619700 TI - Integrated Detection and Prediction of Influenza Activity for Real-Time Surveillance: Algorithm Design. AB - BACKGROUND: Influenza is a viral respiratory disease capable of causing epidemics that represent a threat to communities worldwide. The rapidly growing availability of electronic "big data" from diagnostic and prediagnostic sources in health care and public health settings permits advance of a new generation of methods for local detection and prediction of winter influenza seasons and influenza pandemics. OBJECTIVE: The aim of this study was to present a method for integrated detection and prediction of influenza virus activity in local settings using electronically available surveillance data and to evaluate its performance by retrospective application on authentic data from a Swedish county. METHODS: An integrated detection and prediction method was formally defined based on a design rationale for influenza detection and prediction methods adapted for local surveillance. The novel method was retrospectively applied on data from the winter influenza season 2008-09 in a Swedish county (population 445,000). Outcome data represented individuals who met a clinical case definition for influenza (based on International Classification of Diseases version 10 [ICD-10] codes) from an electronic health data repository. Information from calls to a telenursing service in the county was used as syndromic data source. RESULTS: The novel integrated detection and prediction method is based on nonmechanistic statistical models and is designed for integration in local health information systems. The method is divided into separate modules for detection and prediction of local influenza virus activity. The function of the detection module is to alert for an upcoming period of increased load of influenza cases on local health care (using influenza-diagnosis data), whereas the function of the prediction module is to predict the timing of the activity peak (using syndromic data) and its intensity (using influenza-diagnosis data). For detection modeling, exponential regression was used based on the assumption that the beginning of a winter influenza season has an exponential growth of infected individuals. For prediction modeling, linear regression was applied on 7-day periods at the time in order to find the peak timing, whereas a derivate of a normal distribution density function was used to find the peak intensity. We found that the integrated detection and prediction method detected the 2008-09 winter influenza season on its starting day (optimal timeliness 0 days), whereas the predicted peak was estimated to occur 7 days ahead of the factual peak and the predicted peak intensity was estimated to be 26% lower than the factual intensity (6.3 compared with 8.5 influenza-diagnosis cases/100,000). CONCLUSIONS: Our detection and prediction method is one of the first integrated methods specifically designed for local application on influenza data electronically available for surveillance. The performance of the method in a retrospective study indicates that further prospective evaluations of the methods are justified. PMID- 28619701 TI - Effectiveness of a Web-Based Intervention in Reducing Depression and Sickness Absence: Randomized Controlled Trial. AB - BACKGROUND: Depression is highly prevalent in the working population and is associated with significant loss of workdays; however, access to evidence-based treatment is limited. OBJECTIVE: This study evaluated the effectiveness of a Web based intervention in reducing mild to moderate depression and sickness absence. METHODS: In an open-label randomized controlled trial, participants were recruited from a large-scale statutory health insurance and were assigned to two groups. The intervention group had access to a 12 week Web-based program consisting of structured interactive sessions and therapist support upon request. The wait-list control group had access to unguided Web-based psycho-education. Depressive symptoms were self-assessed at baseline, post-treatment, and follow-up (12 weeks after treatment) using the Patient Health Questionnaire (PHQ-9) and Beck Depression Inventory (BDI-II) as primary outcome measures. Data on sickness absence was retrieved from health insurance records. Intention-to-treat (ITT) analysis and per-protocol (PP) analysis were performed. RESULTS: Of the 180 participants who were randomized, 88 completed the post-assessment (retention rate: 48.8%, 88/180). ITT analysis showed a significant between-group difference in depressive symptoms during post-treatment in favor of the intervention group, corresponding to a moderate effect size (PHQ-9: d=0.55, 95% CI 0.25-0.85, P<.001, and BDI-II: d=0.41, CI 0.11-0.70, P=.004). PP analysis partially supported this result, but showed a non-significant effect on one primary outcome (PHQ-9: d=0.61, 95% CI 0.15-1.07, P=.04, and BDI-II: d=0.25 95% CI -0.18 to 0.65, P=.37). Analysis of clinical significance using reliable change index revealed that significantly more participants who used the Web-based intervention (63%, 63/100) responded to the treatment versus the control group (33%, 27/80; P<.001). The number needed to treat (NNT) was 4.08. Within both groups, there was a reduction in work absence frequency (IG: -67.23%, P<.001, CG: -82.61%, P<.001), but no statistical difference in sickness absence between groups was found (P=.07). CONCLUSIONS: The Web-based intervention was effective in reducing depressive symptoms among adults with sickness absence. As this trial achieved a lower power than calculated, its results should be replicated in a larger sample. Further validation of health insurance records as an outcome measure for eHealth trials is needed. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 02446836; http://www.isrctn.com/ISRCTN02446836 (Archived by WebCite at http://www.webcitation.org/6jx4SObnw). PMID- 28619702 TI - Computerized Childbirth Monitoring Tools for Health Care Providers Managing Labor: A Scoping Review. AB - BACKGROUND: Proper monitoring of labor and childbirth prevents many pregnancy related complications. However, monitoring is still poor in many places partly due to the usability concerns of support tools such as the partograph. In 2011, the World Health Organization (WHO) called for the development and evaluation of context-adaptable electronic health solutions to health challenges. Computerized tools have penetrated many areas of health care, but their influence in supporting health staff with childbirth seems limited. OBJECTIVE: The objective of this scoping review was to determine the scope and trends of research on computerized labor monitoring tools that could be used by health care providers in childbirth management. METHODS: We used key terms to search the Web for eligible peer-reviewed and gray literature. Eligibility criteria were a computerized labor monitoring tool for maternity service providers and dated 2006 to mid-2016. Retrieved papers were screened to eliminate ineligible papers, and consensus was reached on the papers included in the final analysis. RESULTS: We started with about 380,000 papers, of which 14 papers qualified for the final analysis. Most tools were at the design and implementation stages of development. Three papers addressed post-implementation evaluations of two tools. No documentation on clinical outcome studies was retrieved. The parameters targeted with the tools varied, but they included fetal heart (10 of 11 tools), labor progress (8 of 11), and maternal status (7 of 11). Most tools were designed for use in personal computers in low-resource settings and could be customized for different user needs. CONCLUSIONS: Research on computerized labor monitoring tools is inadequate. Compared with other labor parameters, there was preponderance to fetal heart monitoring and hardly any summative evaluation of the available tools. More research, including clinical outcomes evaluation of computerized childbirth monitoring tools, is needed. PMID- 28619703 TI - Identifying Nonclinical Factors Associated With 30-Day Readmission in Patients with Cardiovascular Disease: Protocol for an Observational Study. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of hospitalization in older adults and high readmission rates have attracted considerable attention as actionable targets to promote efficiency in care and to reduce costs. Despite a plethora of research over the past decade, current strategies to predict readmissions have been largely ineffective and efforts to identify novel clinical predictors have been largely unsuccessful. OBJECTIVE: The objective of this study is to examine a wide array of socioeconomic, psychosocial, behavioral, and clinical factors to predict risks of 30-day hospital readmission in cardiovascular patients. METHODS: The study includes patients (aged 18 years and older) admitted for the treatment of cardiovascular-related illnesses at the Duke Heart Center, which is among the nation's largest and top-ranked cardiovascular care hospitals. The study uses a novel standardized survey to ascertain data on a comprehensive array of patient characteristics that will be linked to their electronic medical records. A series of univariate and multivariate models will be used to estimate the associations between the patient-level factors and 30-day readmissions. The performance of the risk models will be examined based on 2 components of accuracy-model calibration and discrimination-to determine how closely the predicted outcome agrees with the observed (actual) outcome and how well the model distinguishes patients who were readmitted and those who were not. The purpose of this paper is to present the protocol for the implementation of this study. RESULTS: The study was launched in February 2014 and is actively recruiting patients from the Heart Center. Approximately 550 patients have been enrolled to date and the study is expected to continue recruitment until February 2018. Preliminary results show that participants in the study were aged 63.6 years on average (SD 14.0), predominately male (61.2%), and primarily non Hispanic white (64.6%) or non-Hispanic black (31.7%). The demographic characteristics of study participants were not significantly different from all patients admitted to the Heart Center during this period with an average age of 65.0 years (SD 15.3) and predominately male (58.6%), non-Hispanic white (62.9%) or non-Hispanic black (31.8%) The integration of the interview data with clinical data from the patient electronic medical records is currently underway. The study has received funding and ethical approval. CONCLUSIONS: Many US hospitals continue to struggle with high readmission rates in patients with cardiovascular disease. The primary objective of this study is to collect and integrate a comprehensive array of patient attributes to develop a powerful yet parsimonious model to stratify risks of rehospitalization in cardiovascular patients. The results of this research also have the potential to identify actionable targets for tailored interventions to improve patient outcomes. PMID- 28619704 TI - Applying STOPP Guidelines in Primary Care Through Electronic Medical Record Decision Support: Randomized Control Trial Highlighting the Importance of Data Quality. AB - BACKGROUND: Potentially Inappropriate Prescriptions (PIPs) are a common cause of morbidity, particularly in the elderly. OBJECTIVE: We sought to understand how the Screening Tool of Older People's Prescriptions (STOPP) prescribing criteria, implemented in a routinely used primary care Electronic Medical Record (EMR), could impact PIP rates in community (non-academic) primary care practices. METHODS: We conducted a mixed-method, pragmatic, cluster, randomized control trial in research naive primary care practices. Phase 1: In the randomized controlled trial, 40 fully automated STOPP rules were implemented as EMR alerts during a 16-week intervention period. The control group did not receive the 40 STOPP rules (but received other alerts). Participants were recruited through the OSCAR EMR user group mailing list and in person at user group meetings. Results were assessed by querying EMR data PIPs. EMR data quality probes were included. Phase 2: physicians were invited to participate in 1-hour semi-structured interviews to discuss the results. RESULTS: In the EMR, 40 STOPP rules were successfully implemented. Phase 1: A total of 28 physicians from 8 practices were recruited (16 in intervention and 12 in control groups). The calculated PIP rate was 2.6% (138/5308) (control) and 4.11% (768/18,668) (intervention) at baseline. No change in PIPs was observed through the intervention (P=.80). Data quality probes generally showed low use of problem list and medication list. Phase 2: A total of 5 physicians participated. All the participants felt that they were aware of the alerts but commented on workflow and presentation challenges. CONCLUSIONS: The calculated PIP rate was markedly less than the expected rate found in literature (2.6% and 4.0% vs 20% in literature). Data quality probes highlighted issues related to completeness of data in areas of the EMR used for PIP reporting and by the decision support such as problem and medication lists. Users also highlighted areas for better integration of STOPP guidelines with prescribing workflows. Many of the STOPP criteria can be implemented in EMRs using simple logic. However, data quality in EMRs continues to be a challenge and was a limiting step in the effectiveness of the decision support in this study. This is important as decision makers continue to fund implementation and adoption of EMRs with the expectation of the use of advanced tools (such as decision support) without ongoing review of data quality and improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT02130895; https://clinicaltrials.gov/ct2/show/NCT02130895 (Archived by WebCite at http://www.webcitation.org/6qyFigSYT). PMID- 28619707 TI - Purpura in a 5 year old girl. PMID- 28619708 TI - ARHGAP18 Downregulation by miR-200b Suppresses Metastasis of Triple-Negative Breast Cancer by Enhancing Activation of RhoA. AB - Rho GTPases activated in cancer cells drive proliferation, migration, and metastasis. Thus, RhoGAP proteins, which negatively regulate Rho GTPases, are generally thought to function as tumor suppressors. Here this expectation was challenged by characterization of ARHGAP18, a RhoGAP family member that is selectively overexpressed in highly migratory triple-negative breast cancer (TNBC) cells. In human breast tumors, higher ARHGAP18 levels associated with worse overall survival, recurrence-free survival, and metastasis-free survival. In TNBC cells, ARHGAP18 deletion increased RhoA activation but reduced growth, migration, and metastatic capacity. Mechanistic investigations revealed that ARHGAP18 levels were controlled by miR-200b, the enforced expression of which was sufficient to activate RhoA, enhanced formation of focal adhesions and actin stress fibers, and reduced migration and metastasis. Enforced elevation of ARHGAP18 where miR-200b was stably expressed reduced RhoA activity but increased cell migration. Pharmacologic inhibition of the Rho effector kinase ROCK blocked RhoA signaling and reversed the inhibitory effect of miR-200b on cell migration. Finally, ARHGAP18 overexpression or ROCK inhibition was sufficient to overcome metastatic blockade by miR-200b. Taken together, these results define opposing roles for oncogenic ARHGAP18 and tumor suppressive miR-200b in determining TNBC cell migration and metastatic prowess. Cancer Res; 77(15); 4051-64. (c)2017 AACR. PMID- 28619710 TI - Heme-oxygenase-1 Production by Intestinal CX3CR1+ Macrophages Helps to Resolve Inflammation and Prevents Carcinogenesis. AB - CX3CR1+ macrophages in the intestinal lamina propria contribute to gut homeostasis through the immunomodulatory interleukin IL10, but there is little knowledge on how these cells or the CX3CR1 receptor may affect colorectal carcinogenesis. In this study, we show that CX3CR1-deficient mice fail to resolve gut inflammation despite high production of IL10 and have increased colitis and adenomatous polyps in chemical and genetic models of colon carcinogenesis. Mechanistically, CX3CL1-mediated engagement of the CX3CR1 receptor induced upregulation of heme-oxygenase-1 (HMOX-1), an antioxidant and anti-inflammatory enzyme. CX3CR1-deficient mice exhibited significantly lower expression of HMOX-1 in their adenomatous colon tissues. Combining LPS and CX3CL1 displayed a strong synergistic effect in vitro, but HMOX-1 levels were significantly lower in KO macrophages. Cohousing of wild-type and CX3CR1-/- mice during the AOM/DSS treatment attenuated disease severity in CX3CR1-/- mice, indicating the importance of the microbiome, but did not fully reinstate HMOX-1 levels and did not abolish polyp formation. In contrast, pharmacologic induction of HMOX-1 in vivo by cobalt protoporphyrin-IX treatment eradicated intestinal inflammation and fully protected KO mice from carcinogenesis. Taken together, our results establish an essential role for the receptor CX3CR1 in gut macrophages in resolving inflammation in the intestine, where it helps protects against colitis associated cancer by regulating HMOX-1 expression. Cancer Res; 77(16); 4472-85. (c)2017 AACR. PMID- 28619709 TI - Loss of FAM46C Promotes Cell Survival in Myeloma. AB - FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous FAM46C enhanced multiple myeloma cell growth, decreased Ig light chain and HSPA5/BIP expression, activated ERK and antiapoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in FAM46C-depleted cells were enriched for signaling pathways regulating estrogen, glucocorticoid, B-cell receptor signaling, and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival and identify FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis. Cancer Res; 77(16); 4317 27. (c)2017 AACR. PMID- 28619711 TI - IGFBP7 Deletion Promotes Hepatocellular Carcinoma. AB - Activation of IGF signaling is a major oncogenic event in diverse cancers, including hepatocellular carcinoma (HCC). In this setting, the insulin-like growth factor binding protein IGFBP7 inhibits IGF signaling by binding the IGF1 receptor (IGF1R), functioning as a candidate tumor suppressor. IGFBP7 abrogates tumors by inhibiting angiogenesis and inducing cancer-specific senescence and apoptosis. Here, we report that Igfbp7-deficient mice exhibit constitutively active IGF signaling, presenting with proinflammatory and immunosuppressive microenvironments and spontaneous liver and lung tumors occurring with increased incidence in carcinogen-treated subjects. Igfbp7 deletion increased proliferation and decreased senescence of hepatocytes and mouse embryonic fibroblasts, effects that were blocked by treatment with IGF1 receptor inhibitor. Significant inhibition of genes regulating immune surveillance was observed in Igfbp7-/- murine livers, which was associated with a marked inhibition in antigen cross presentation by Igfbp7-/- dendritic cells. Conversely, IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice. Depletion of CD4+ or CD8+ T lymphocytes abolished this growth inhibition, identifying it as an immune-mediated response. Our findings define an immune component of the pleiotropic mechanisms through which IGFBP7 suppresses HCC. Furthermore, they offer a genetically based preclinical proof of concept for IGFBP7 as a therapeutic target for immune management of HCC. Cancer Res; 77(15); 4014-25. (c)2017 AACR. PMID- 28619712 TI - Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. AB - Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve-airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ~3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation. We found that allergen exposure in neonatal mice, but not in adult mice, elevated the level and activity of cholinergic nerves (termed neuroplasticity). We demonstrated that cholinergic neuroplasticity is necessary for the induction of persistent AHR after neonatal exposure during rescue assays in mice deficient in neuroplasticity. In addition, early intervention with cholinergic receptor muscarinic (ChRM)-3 blocker reversed the progression of AHR in the neonatal exposure model, whereas beta2-adrenoceptor agonists had no such effect. Together, our findings demonstrate a functional relationship between cholinergic neuroplasticity and ASM contractile phenotypes that operates uniquely in early life to induce persistent AHR after allergen exposure. Targeting ChRM3 may have disease-modifying benefits in childhood asthma.-Patel, K. R., Bai, Y., Trieu, K. G., Barrios, J., Ai, X. Targeting acetylcholine receptor M3 prevents the progression of airway hyperreactivity in a mouse model of childhood asthma. PMID- 28619715 TI - Liquefied gas electrolytes for electrochemical energy storage devices. AB - Electrochemical capacitors and lithium-ion batteries have seen little change in their electrolyte chemistry since their commercialization, which has limited improvements in device performance. Combining superior physical and chemical properties and a high dielectric-fluidity factor, the use of electrolytes based on solvent systems that exclusively use components that are typically gaseous under standard conditions show a wide potential window of stability and excellent performance over an extended temperature range. Electrochemical capacitors using difluoromethane show outstanding performance from -78 degrees to +65 degrees C, with an increased operation voltage. The use of fluoromethane shows a high coulombic efficiency of ~97% for cycling lithium metal anodes, together with good cyclability of a 4-volt lithium cobalt oxide cathode and operation as low as -60 degrees C, with excellent capacity retention. PMID- 28619713 TI - Molecular model of fission yeast centrosome assembly determined by superresolution imaging. AB - Microtubule-organizing centers (MTOCs), known as centrosomes in animals and spindle pole bodies (SPBs) in fungi, are important for the faithful distribution of chromosomes between daughter cells during mitosis as well as for other cellular functions. The cytoplasmic duplication cycle and regulation of the Schizosaccharomyces pombe SPB is analogous to centrosomes, making it an ideal model to study MTOC assembly. Here, we use superresolution structured illumination microscopy with single-particle averaging to localize 14 S. pombe SPB components and regulators, determining both the relationship of proteins to each other within the SPB and how each protein is assembled into a new structure during SPB duplication. These data enabled us to build the first comprehensive molecular model of the S. pombe SPB, resulting in structural and functional insights not ascertained through investigations of individual subunits, including functional similarities between Ppc89 and the budding yeast SPB scaffold Spc42, distribution of Sad1 to a ring-like structure and multiple modes of Mto1 recruitment. PMID- 28619714 TI - The G protein-coupled receptor GPR31 promotes membrane association of KRAS. AB - The product of the KRAS oncogene, KRAS4B, promotes tumor growth when associated with the plasma membrane (PM). PM association is mediated, in part, by farnesylation of KRAS4B, but trafficking of nascent KRAS4B to the PM is incompletely understood. We performed a genome-wide screen to identify genes required for KRAS4B membrane association and identified a G protein-coupled receptor, GPR31. GPR31 associated with KRAS4B on cellular membranes in a farnesylation-dependent fashion, and retention of GPR31 on the endoplasmic reticulum inhibited delivery of KRAS4B to the PM. Silencing of GPR31 expression partially mislocalized KRAS4B, slowed the growth of KRAS-dependent tumor cells, and blocked KRAS-stimulated macropinocytosis. Our data suggest that GPR31 acts as a secretory pathway chaperone for KRAS4B. PMID- 28619717 TI - Photoinduced decarboxylative borylation of carboxylic acids. AB - The conversion of widely available carboxylic acids into versatile boronic esters would be highly enabling for synthesis. We found that this transformation can be effected by illuminating the N-hydroxyphthalimide ester derivative of the carboxylic acid under visible light at room temperature in the presence of the diboron reagent bis(catecholato)diboron. A simple workup allows isolation of the pinacol boronic ester. Experimental evidence suggests that boryl radical intermediates are involved in the process. The methodology is illustrated by the transformation of primary, secondary, and tertiary alkyl carboxylic acids as well as a diverse range of natural-product carboxylic acids, thereby demonstrating its broad utility and functional group tolerance. PMID- 28619716 TI - Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. AB - Hsp100 polypeptide translocases are conserved members of the AAA+ family (adenosine triphosphatases associated with diverse cellular activities) that maintain proteostasis by unfolding aberrant and toxic proteins for refolding or proteolytic degradation. The Hsp104 disaggregase from Saccharomyces cerevisiae solubilizes stress-induced amorphous aggregates and amyloids. The structural basis for substrate recognition and translocation is unknown. Using a model substrate (casein), we report cryo-electron microscopy structures at near-atomic resolution of Hsp104 in different translocation states. Substrate interactions are mediated by conserved, pore-loop tyrosines that contact an 80-angstrom-long unfolded polypeptide along the axial channel. Two protomers undergo a ratchet like conformational change that advances pore loop-substrate interactions by two amino acids. These changes are coupled to activation of specific nucleotide hydrolysis sites and, when transmitted around the hexamer, reveal a processive rotary translocation mechanism and substrate-responsive flexibility during Hsp104 catalyzed disaggregation. PMID- 28619719 TI - Hypothalamic regulation of regionally distinct adult neural stem cells and neurogenesis. AB - Neural stem cells (NSCs) in specialized niches in the adult mammalian brain generate neurons throughout life. NSCs in the adult mouse ventricular subventricular zone (V-SVZ) exhibit a regional identity and, depending on their location, generate distinct olfactory bulb interneuron subtypes. Here, we show that the hypothalamus, a brain area regulating physiological states, provides long-range regionalized input to the V-SVZ niche and can regulate specific NSC subpopulations. Hypothalamic proopiomelanocortin neurons selectively innervate the anterior ventral V-SVZ and promote the proliferation of Nkx2.1+ NSCs and the generation of deep granule neurons. Accordingly, hunger and satiety regulate adult neurogenesis by modulating the activity of this hypothalamic-V-SVZ connection. Our findings reveal that neural circuitry, via mosaic innervation of the V-SVZ, can recruit distinct NSC pools, allowing on-demand neurogenesis in response to physiology and environmental signals. PMID- 28619720 TI - Bullying in NHS must be "called out," says head of NHS Improvement. PMID- 28619718 TI - Click chemistry enables preclinical evaluation of targeted epigenetic therapies. AB - The success of new therapies hinges on our ability to understand their molecular and cellular mechanisms of action. We modified BET bromodomain inhibitors, an epigenetic-based therapy, to create functionally conserved compounds that are amenable to click chemistry and can be used as molecular probes in vitro and in vivo. We used click proteomics and click sequencing to explore the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors. In our studies of mouse models of acute leukemia, we used high-resolution microscopy and flow cytometry to highlight the heterogeneity of drug activity within tumor cells located in different tissue compartments. We also demonstrate the differential distribution and effects of BET inhibitors in normal and malignant cells in vivo. This study provides a potential framework for the preclinical assessment of a wide range of drugs. PMID- 28619721 TI - Hagfish slime exudate stabilization and its effect on slime formation and functionality. AB - Hagfish produce vast amounts of slime when under attack. The slime is the most dilute hydrogel known to date, and is a highly interesting material for biomaterial research. It forms from a glandular secrete, called exudate, which deploys upon contact with seawater. To study slime formation ex vivo and to characterize its material properties, stabilization of the sensitive slime exudate is crucial. In this study, we compared the two main stabilization methods, dispersion in high osmolarity citrate/PIPES (CP) buffer and immersion in oil, and tested the influence of time, temperature and pH on the stability of the exudate and functionality of the slime. Using water retention measurements to assess slime functionality, we found that CP buffer and oil preserved the exudate within the first 5 hours without loss of functionality. For longer storage times, slime functionality decreased for both stabilization methods, for which the breakdown mechanisms differed. Stabilization in oil likely favored temperature sensitive osmotic-driven swelling and rupture of the mucin vesicles, causing the exudate to gel and clump. Extended storage in CP buffer resulted in an inhibited unraveling of skeins. We suggest that a water soluble protein glue, which mediates skein unraveling in functional skeins, denatures and gradually becomes insoluble during storage in CP buffer. The breakdown was accentuated when the pH of the CP buffer was raised from pH 6.7 to pH 8.5, probably caused by increased denaturation of the protein glue or by inferior vesicle stabilization. However, when fresh exudate was mixed into seawater or phosphate buffer at pH 6-9, slime functionality was not affected, showing pH insensitivity of the slime formation around a neutral pH. These insights on hagfish exudate stabilization mechanisms will support hagfish slime research at a fundamental level, and contribute to resolve the complex mechanisms of skein unraveling and slime formation. PMID- 28619723 TI - Government must lift pay cap to keep staff, says NHS Confederation. PMID- 28619722 TI - Corticosteroid Therapy During Acute Bronchiolitis in Patients Who Later Develop Asthma. AB - BACKGROUND AND OBJECTIVE: Meta-analyses show that corticosteroids are not effective in patients with bronchiolitis. However, risk factors for asthma such as eczema or familial atopy prompt some practitioners to prescribe corticosteroids for bronchiolitis. We assessed if corticosteroid prescription is associated with shorter hospitalization for bronchiolitis among patients who later develop asthma. METHODS: The Pediatric Health Information System database was interrogated for patients with bronchiolitis aged <2 years hospitalized between 2006 and 2015. Only patients who also later had a hospitalization for asthma and prescription of inhaled corticosteroids were included. For the initial bronchiolitis admission, use of mechanical ventilation defined "severe illness," and ICU admission without mechanical ventilation defined "moderate illness"; all other patients were deemed to have "mild illness." Variables associated (P < .10) with length of stay (LOS) in bivariate analysis were included in linear regression analysis. RESULTS: During the bronchiolitis admission of 2479 children who were later hospitalized for asthma, corticosteroid prescription (n = 857) was associated with longer LOS in bivariate analysis (3 [2-4] vs 2 [2-4] days; P < .01) but not the multivariate model (P = .18) that included age, sex, comorbid conditions, bacterial pneumonia, and illness severity. Corticosteroid prescription was associated with shorter LOS among previously healthy children with moderate illness (4 [2-6] vs 5 [3-7] days; P = .02) but not those with mild or severe illness. CONCLUSIONS: Corticosteroids were not associated with improved outcome in patients with bronchiolitis who were later hospitalized with asthma. Moderately ill patients with no comorbidities may warrant further study. PMID- 28619724 TI - Impact of Relative Conditional Survival Estimates on Patient Prognosis After Percutaneous Coronary Intervention. AB - BACKGROUND: Some aspects of prognosis are not reflected by cumulative survival estimates. These aspects include information on the time already survived by the patient and the patient's survival compared with the general population. Conditional survival (ie, conditional on having survived a certain period of time already) and relative conditional survival (ie, compared with the general population) do incorporate these aspects. We investigated these measures of prognosis in patients undergoing percutaneous coronary intervention. METHODS AND RESULTS: We studied 17 903 consecutive patients undergoing percutaneous coronary intervention between 2000 and 2014. Cumulative survival was estimated for patients with ST-segment-elevation myocardial infarction (n=5996, 853 deaths), non-ST-segment-elevation myocardial infarction (n=5371, 901 deaths), and stable angina pectoris (n=6536, 965 deaths) in 4 age categories. One-year conditional and relative conditional survival up to 10 years post-percutaneous coronary intervention was calculated. The results demonstrated that 1-year cumulative survival for patients with ST-segment-elevation myocardial infarction aged >=76 years was 83%. One-year conditional survival, conditional on surviving the first month, was 92% in this group, and relative conditional survival (relative to the general population) was 99%. In younger age categories and in patients with non ST-segment-elevation myocardial infarction and stable angina pectoris , similar patterns were found albeit less pronounced. Five-year relative conditional rendered similar results. CONCLUSIONS: Relative conditional survival provides a comprehensive picture of patient prognosis, particularly for older patients with ST-segment-elevation myocardial infarction. Although, as expected, their cumulative survival is low, once they survive the first month after percutaneous coronary intervention, their prognosis is comparable to that of the general population. Therefore, relative conditional survival estimates provide an important, meaningful addition when discussing prognosis with patients. PMID- 28619725 TI - Referral to Cardiac Rehabilitation After Percutaneous Coronary Intervention, Coronary Artery Bypass Surgery, and Valve Surgery: Data From the Clinical Outcomes Assessment Program. AB - BACKGROUND: Despite guideline recommendations that patients undergoing percutaneous coronary intervention (PCI), coronary artery bypass surgery, or valve surgery be referred to cardiac rehabilitation, cardiac rehabilitation is underused. The objective of this study was to examine hospital-level variation in cardiac rehabilitation referral after PCI, coronary artery bypass surgery, and valve surgery. METHODS AND RESULTS: We analyzed data from the Clinical Outcomes Assessment Program, a registry of all nonfederal hospitals performing PCI and cardiac surgery in Washington State. We included eligible PCI, coronary artery bypass surgery, and valve surgery patients from 2010 to 2015. We analyzed PCI and cardiac surgery separately by performing multivariable hierarchical logistic regression for the outcome of cardiac rehabilitation referral at discharge, clustered by hospital. Patient-level covariates included age, sex, race/ethnicity, comorbidities, and procedure indication/status. Cardiac rehabilitation referral was reported in 48% (34 047/71 556) of PCI patients and 91% (21 831/23 972) of cardiac surgery patients. The hospital performing the procedure was a stronger predictor of referral than any individual patient characteristic for PCI (hospital referral range 3%-97%; median odds ratio, 5.94; 95% confidence interval, 4.10-9.49) and cardiac surgery (range 54%-100%; median odds ratio, 7.09; 95% confidence interval, 3.79-17.80). Hospitals having an outpatient cardiac rehabilitation program explained only 10% of PCI variation and 0% of cardiac surgery variation. CONCLUSIONS: Cardiac rehabilitation referral at discharge was less prevalent after PCI than cardiac surgery. The strongest predictor of cardiac rehabilitation referral was the hospital performing the procedure. Efforts to improve cardiac rehabilitation referral should focus on increasing referral after PCI, especially in low referral hospitals. PMID- 28619726 TI - Putting Prognosis Into Perspective. PMID- 28619727 TI - RNA-seq implicates deregulation of the immune system in the pathogenesis of diverticulitis. AB - Individuals with diverticula or outpouchings of the colonic mucosa and submucosa through the colonic wall have diverticulosis, which is usually asymptomatic. In 10-25% of individuals, the diverticula become inflamed, resulting in diverticulitis. Very little is known about the pathophysiology or gene regulatory pathways involved in the development of diverticulitis. To identify these pathways, we deep sequenced RNAs isolated from full-thickness sections of sigmoid colon from diverticulitis patients and control individuals. Specifically for diverticulitis cases, we analyzed tissue adjacent to areas affected by chronic disease. Since the tissue was collected during elective sigmoid resection, the disease was in a quiescent state. A comparison of differentially expressed genes found that gene ontology (GO) pathways associated with the immune response were upregulated in diverticulitis patients compared with nondiverticulosis controls. Next, weighted gene coexpression network analysis was performed to identify the interaction among coexpressed genes. This analysis revealed RASAL3, SASH3, PTPRC, and INPP5D as hub genes within the brown module eigengene, which highly correlated (r = 0.67, P = 0.0004) with diverticulitis. Additionally, we identified elevated expression of downstream interacting genes. In summary, transcripts associated with the immune response were upregulated in adjacent tissue from the sigmoid colons of chronic, recurrent diverticulitis patients. Further elucidating the genetic or epigenetic mechanisms associated with these alterations can help identify those at risk for chronic disease and may assist in clinical decision management.NEW & NOTEWORTHY By using an unbiased approach to analyze transcripts expressed in unaffected colonic tissues adjacent to those affected by chronic diverticulitis, our study implicates that a defect in the immune response may be involved in the development of the disease. This finding expands on the current data that suggest the pathophysiology of diverticulitis is mediated by dietary, age, and obesity-related factors. Further characterizing the immunologic differences in diverticulitis may better inform clinical decision making. PMID- 28619728 TI - Activated Notch signaling cascade is correlated with stem cell differentiation toward absorptive progenitors after massive small bowel resection in a rat. AB - Notch signaling is thought to act to drive cell versification in the lining of the small intestine. The purpose of the present study was to evaluate the role of the Notch signaling pathway in stem cell differentiation in the late stages of intestinal adaptation after massive small bowel resection in a rat. Male Sprague Dawley rats were randomly assigned to one of two experimental groups of eight rats each: Sham rats underwent bowel transection and reanastomosis, while SBS rats underwent 75% small bowel resection. Rats were euthanized on day 14 Illumina's Digital Gene Expression (DGE) analysis was used to determine Notch signaling gene expression profiling. Notch-related gene and protein expression was determined using real-time PCR, Western blot analysis, and immunohistochemistry. From seven investigated Notch-related (by DGE analysis) genes, six genes were upregulated in SBS vs. control animals with a relative change in gene expression level of 20% or more. A significant upregulation of Notch signaling-related genes in resected animals was accompanied by a significant increase in Notch-1 protein levels (Western blot analysis) and a significant increase in the number of Notch1 and Hes1 (target gene)-positive cells (immunohistochemistry) compared with sham animals. Evaluation of cell differentiation has shown a strong increase in total number of absorptive cells (unchanged secretory cells) compared with control rats. In conclusion, 2 wk after bowel resection in rats, stimulated Notch signaling directs the crypt cell population toward absorptive progenitors.NEW & NOTEWORTHY This study provides novel insight into the mechanisms of cell proliferation following massive small bowel resection. We show that 2 wk after bowel resection in rats, enhanced stem cell activity was associated with stimulated Notch signaling pathway. We demonstrate that activated Notch signaling cascade directs the crypt cell population toward absorptive progenitors. PMID- 28619729 TI - Characterization and mechanisms of the supragastric belch in the cat. AB - A response in which a belch occurs without gastric involvement, i.e., the supragastric belch (SGB), has been characterized in humans. The aims of this study were to determine whether animals have an SGB and, if so, to determine its mechanisms. Studies were conducted in decerebrate cats (n = 30) with electromyographic electrodes on hyoid, pharyngeal, esophageal, and diaphragm muscles. The effects of distending different regions of the esophagus in different manners using a balloon were quantified to determine the most appropriate stimulus for activating the cat SGB. The effects of esophageal perfusion of lidocaine (n = 3), vagus nerve transection (n = 3), or esophageal acidification (n = 5) on activation of the SGB were determined. Rapid large distensions of the thoracic esophagus best activated responses similar to the human SGB, i.e., rapid inhalation followed by a belch. The rapid inhalation was associated with activation of hiatal fibers and the belch with activation of dome fibers of the diaphragm. The rapid inhalation response was independent of the belch response. Lidocaine perfusion of the esophagus blocked the belch response without blocking the rapid inhalation, HCl perfusion sensitized the esophagus to activation of both the rapid inhalation and the belch response, and vagotomy blocked both responses. We conclude that the cat has an SGB that is composed of two independent reflex responses, i.e., rapid inhalation and belch, that are mediated by the vagus nerves and tension/mucosal receptors of the esophagus and sensitized by esophageal acid exposure. We hypothesize that the SGB is a learned voluntarily activated reflex response.NEW & NOTEWORTHY Rapid strong distension of the thoracic esophagus activates rapid inhalation followed by a belch, which is the sequence of responses that compose the human supragastric belch (SGB). The rapid inhalation and belch phases of the cat SGB are activated by hiatal and dome fibers of the diaphragm, respectively, and are mediated by the vagus nerves and tension/mucosal receptors of the esophagus and sensitized by esophageal acid exposure. There are many similarities between the cat and human SGB. PMID- 28619730 TI - Consumption of a High-Iron Diet Disrupts Homeostatic Regulation of Intestinal Copper Absorption in Adolescent Mice. AB - High-iron feeding of rodents has been commonly used to model human iron-overload disorders. We recently noted that high-iron consumption impaired growth and caused severe systemic copper deficiency in growing rats, but the mechanism by which this occurred could not be determined due to technical limitations. In the current investigation, we thus utilized mice; first to determine if the same phenomenon occurred in another mammalian species, and secondly since we could assess in vivo copper absorption in mice. We hypothesized that excessive dietary iron impaired intestinal copper absorption. Weanling, male mice were thus fed AIN 93G-based diets containing high (HFe) (~8800 ppm) or adequate (AdFe) (~80 ppm) iron in combination with low (~0.9 ppm), adequate (~9 ppm) or high (~180 ppm) copper for several weeks. Iron and copper homeostasis was subsequently assessed. Mice consuming the HFe diets grew slower, were anemic, and had lower hepatic copper levels and serum ceruloplasmin activity. These physiologic perturbations were all prevented by higher dietary copper, demonstrating that copper depletion was the underlying cause. Furthermore, homeostatic regulation of copper absorption was noted in the mice consuming the AdFe diets, with absorption increasing as dietary copper decreased. HFe-fed mice did not have impaired copper absorption (disproving our hypothesis), but homeostatic control of absorption was disrupted. There were also noted perturbations in the tissue distribution of copper in the HFe-fed mice, suggesting that altered storage and thus bioavailability contributed to the noted copper deficiency. Dietary iron loading thus antagonizes copper homeostasis leading to pathological symptoms of severe copper depletion. PMID- 28619731 TI - USP25 regulates Wnt signaling by controlling the stability of tankyrases. AB - Aberrant activation of the Wnt signaling pathway plays an important role in human cancer development. Wnt signaling is negatively regulated by Axin, a scaffolding protein that controls a rate-limiting step in the destruction of beta-catenin, the central activator of the Wnt pathway. In Wnt-stimulated cells, Axin is rapidly modified by tankyrase-mediated poly(ADP-ribosyl)ation, which promotes the proteolysis of Axin and consequent stabilization of beta-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling. Here, we identify ubiquitin-specific protease 25 (USP25) as a positive regulator of Wnt/beta-catenin signaling. We found that USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization. We demonstrated that USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling. We further characterized the interaction between TNKS1 and USP25 by X ray crystal structure determination. Our results provide important new insights into the molecular mechanism that regulates the turnover of tankyrases and the possibility of targeting the stability of tankyrases by antagonizing their interaction with USP25 to modulate the Wnt/beta-catenin pathway. PMID- 28619732 TI - Genital herpes. PMID- 28619733 TI - Reply: Repeatability of Quantitative Whole-Body 18F-FDG PET/CT Uptake Measures in Patients with Non-Small Cell Lung Cancer: Dynamic Versus Test-Retest Design. PMID- 28619734 TI - 68Ga-PSMA-11 PET/CT in Newly Diagnosed Carcinoma of the Prostate: Correlation of Intraprostatic PSMA Uptake with Several Clinical Parameters. AB - 68Ga-prostate-specific membrane antigen (PSMA) PET/CT is a promising diagnostic tool for patients with prostate cancer. Our study evaluates SUVs in benign prostate tissue and malignant, intraprostatic tumor lesions and correlates results with several clinical parameters. Methods: One hundred four men with newly diagnosed prostate carcinoma and no previous therapy were included in this study. SUVmax was measured and correlated with biopsy findings and MRI. Afterward, data were compared with current prostate-specific antigen (PSA) values, Gleason score (GS), and d'Amico risk classification. Results: In this investigation a mean SUVmax of 1.88 +/- 0.44 in healthy prostate tissue compared with 10.77 +/- 8.45 in malignant prostate lesions (P < 0.001) was observed. Patients with higher PSA, higher GS, and higher d'Amico risk score had statistically significant higher PSMA uptake on PET/CT (P < 0.001 each). Conclusion: PSMA PET/CT is well suited for detecting the intraprostatic malignant lesion in patients with newly diagnosed prostate cancer. Our findings indicate a significant correlation of PSMA uptake with PSA, GS, and risk classification according to the d'Amico scale. PMID- 28619735 TI - The Evolving Role of Succinate in Tumor Metabolism: An 18F-FDG-Based Study. AB - In recent years, inherited and acquired mutations in the tricarboxylic acid (TCA) cycle enzymes have been reported in diverse cancers. Pheochromocytomas and paragangliomas often exhibit dysregulation of glucose metabolism, which is also driven by mutations in genes encoding the TCA cycle enzymes or by activation of hypoxia signaling. Pheochromocytomas and paragangliomas associated with succinate dehydrogenase (SDH) deficiency are characterized by high 18F-FDG avidity. This association is currently only partially explained. Therefore, we hypothesized that accumulation of succinate due to the TCA cycle defect could be the major connecting hub between SDH-mutated tumors and the 18F-FDG uptake profile. Methods: To test whether succinate modifies the 18F-FDG metabolic profile of tumors, we performed in vitro and in vivo (small-animal PET/CT imaging and autoradiography) experiments in the presence of succinate, fumarate, and phosphate-buffered saline (PBS) in different cell models. As a control, we also evaluated the impact of succinate on 18F-fluorocholine uptake and retention. Glucose transporter 1 (GLUT1) immunohistochemistry was performed to assess whether 18F-FDG uptake correlates with GLUT1 staining. Results: Intratumoral injection of succinate significantly increased 18F-FDG uptake at 24 h on small animal PET/CT imaging and autoradiography. No effect of succinate was observed on cancer cells in vitro, but interestingly, we found that succinate caused increased 18F-FDG uptake by human umbilical vein endothelial cells in a concentration-dependent manner. No significant effect was observed after intratumoral injection of fumarate or PBS. Succinate, fumarate, and PBS have no effect on cell viability, regardless of cell lineage. Intramuscular injection of succinate also significantly increases 18F-FDG uptake by muscle when compared with either PBS or fumarate, highlighting the effect of succinate on connective tissues. No difference was observed between PBS and succinate on 18F fluorocholine uptake in the tumor and muscle and on hind limb blood flow. GLUT1 expression quantification did not significantly differ between the study groups. Conclusion: The present study shows that succinate stimulates 18F-FDG uptake by endothelial cells, a finding that partially explains the 18F-FDG metabotype observed in tumors with SDH deficiency. Although this study is an 18F-FDG-based approach, it provides an impetus to better characterize the determinants of 18F FDG uptake in various tumors and their surrounding microenvironment, with a special emphasis on the role of tumor-specific oncometabolites. PMID- 28619736 TI - Effects of Hypercapnia on Myocardial Blood Flow in Healthy Human Subjects. AB - Elevation of the end-tidal partial pressure of CO2 (PETco2) increases cerebral and myocardial blood flow (MBF), suggesting that it may be a suitable alternative to pharmacologic stress or exercise for myocardial perfusion imaging. The purpose of this study was to document the pharmacodynamics of CO2 for MBF using prospective end-tidal targeting to precisely control arterial Pco2 and PET to measure the outcome variable, MBF. Methods: Ten healthy men underwent serial 82Rb PET/CT imaging. Imaging was performed at rest and during 6-min hypercapnic plateaus (baseline; PETco2 at 50, 55, and 60 mm Hg; repeat of PETco2 at 60 mm Hg; and repeat of baseline). MBF was measured using 82Rb injected 3 min after the beginning of hypercapnia and a 1-tissue-compartment model with flow-dependent extraction correction. Results were compared with those obtained during an adenosine stress test (140 MUg/kg/min). Results: Baseline PETco2 was 38.9 +/- 0.8 (mean +/- SD) mm Hg (range, 35-43 mm Hg). All PETco2 targets were sustained, with SDs of less than 1.5 mm Hg. Heart rate, systolic blood pressure, rate * pressure product, and respiratory frequency increased with progressive hypercapnia. MBF increased significantly at each level of hypercapnia to 1.92-fold over baseline (0.86 +/- 0.24 vs. 0.45 +/- 0.08 mL/min/g; P = 0.002) at a PETco2 of 60 mm Hg. MBF after the administration of adenosine was significantly greater than that with the maximal hypercapnic stimulus (2.00 vs. 0.86 mL/min/g; P < 0.0001). Conclusion: To our knowledge, this study is the first to assess the response of MBF to different levels of hypercapnia in healthy humans with PET. MBF increased with increasing levels of hypercapnia; MBF at a PETco2 of 60 mm Hg was double that at baseline. PMID- 28619737 TI - Acute massive gastric dilatation causing ischaemic necrosis and perforation of the stomach. AB - Acute massive gastric dilatation (AMGD) is a rare distinctive condition but associates with high morbidity and mortality. Though usually seen in patients with eating disorders, many aetiologies of AMGD have been described. The distension has been reported to cause gastric necrosis with or without perforation, usually within 1-2 days of an inciting event of AMGD.We report the case of a 58-year-old male who presented with gastric perforation associated with AMGD 11 days after surgical relief of a proximal small bowel obstruction. The AMGD arose from a closed loop obstruction between a tumour at the gastro oesophageal junction and a small bowel obstruction as a result of volvulus around a jejunal feeding tube.To our knowledge, this is the first case of a closed loop obstruction of this aetiology reported in the literature, and the presentation of this patient's AMGD was notable for the delayed onset of gastric necrosis. The patient underwent an exploratory laparotomy and a partial gastrectomy to excise a portion of his perforated stomach. Surgeons should be aware of the possibility of delayed ischaemic gastric perforation in cases of AMGD. PMID- 28619738 TI - Fingolimod-associated macular oedema. PMID- 28619739 TI - Renal cell carcinoma with isolated breast metastasis. AB - Renal cell carcinoma (RCC) is a highly prevalent disease worldwide with many cases being metastasised to various organs during the time of initial presentation. Metastatic RCC to the breast is a rare entity and can mimic primary breast carcinoma. In this article, we present a 63-year-old Caucasian woman presented with a breast mass that was detected by screening mammography and found to have a biopsy proven grade-II clear RCC in the breast tissue. Despite the high incidence and prevalence of primary breast cancer, metastasis from extramammary should be suspected in patients with a prior history of other cancers. In this brief literature review, we also highlight the survival benefit from surgery and close follow-up in selected group of patients with metastatic, metachronous and solitary RCC. PMID- 28619740 TI - Gamma-delta T-cell lymphoma of skin, eye and brain presenting with visual loss. AB - A young man presented with rapid, predominantly right-sided visual loss with a background of multifocal skin lesions. Visual acuity was right hand movements, left 6/5 Snellen, deteriorating to 6/38. He showed panuveitis with bilateral multifocal retinal infiltrates and retinal vasculitis. Multifocal brain lesions were identified. Biopsy of both skin and vitreous showed atypical lymphocytes, and immunohistochemistry confirmed T-cell lymphoma of gamma-delta subtype. Management with the CODOX-M/IVAC polychemotherapy regimen achieved rapid response including resolution of intraocular changes and substantial improvement of visual acuity to right 6/7.5, left 6/6. However, he relapsed before planned stem cell transplantation. Salvage with the gemcitabine/dexamethasone/cisplatin regimen, although temporarily effective, was followed by further relapse including widespread brain involvement, and he succumbed 10 months after presentation. PMID- 28619741 TI - Saddle-nose and bilateral cauliflower ear deformities with pyoderma gangrenosum like ulcers, cavitary pulmonary lesions, digital gangrene and pulselessness in a young female. AB - We report a young female who presented with saddle-nose and bilateral cauliflower ear deformities along with pyoderma gangrenosum-like ulcers, digital gangrene and pulselessness. Subsequently, she was found to have bilateral conductive hearing loss, a corneal opacity, mild aortic regurgitation and radiological evidence of cavitary changes in lungs and aortoarteritis. Our patient had a constellation of symptoms which posed a diagnostic challenge. Finally, a diagnosis of relapsing polychondritis with several unusual features was made. Overlap with Takayasu's arteritis and granulomatosis with polyangitis, which has been reported rarely in the literature, cannot be excluded. PMID- 28619742 TI - Postgastric bypass hypoglycaemia in a patient with end-stage renal disease: a diagnostic and management pitfall. AB - Roux-en-Y gastric bypass (RYGB) surgery is currently one of the most popular procedures to aid weight loss. Hypoglycaemia associated with gastric bypass surgery is an underdiagnosed but life-threatening potential consequence of the surgical procedure. We present a case of a 44-year-old woman with end-stage renal disease presenting with refractory hypoglycaemia after 10 years of RYGB. Extensive history and work-up excluded medications, renal disease, insulinoma and dumping syndrome as the cause of hypoglycaemia. Dietary modifications or pharmacological trial of drugs did not ameliorate her symptoms with progressive worsening of hypoglycaemia leading to continuous dextrose infusion. Distal pancreatectomy was performed with subsequent resolution of hypoglycaemia. Surgical pathology results showed diffuse hyperplastic islet cells, confirming the diagnosis of postgastric bypass hypoglycaemia. PMID- 28619745 TI - Many parts make a whole: Calcium transients sum for slow waves. AB - New JGP study shows how calcium events drive long intestinal slow wave plateaus. PMID- 28619746 TI - Informal regionalization of pediatric fracture care in the Greater Toronto Area: a retrospective cross-sectional study. AB - BACKGROUND: Operative management of pediatric fractures is an expected competency in the specialty of Orthopedic Surgery. However, specialized pediatric centres may be providing care for increasing numbers of patients with fractures previously treated at community hospitals. The primary objective of this study was to examine trends in presentation of children with fractures to a specialized pediatric centre. METHODS: We performed a detailed chart review to examine trends in presentation of children aged 14 years or less with supracondylar humerus or femur fractures to a specialized pediatric centre (Hospital for Sick Children, Toronto) from anywhere in the Greater Toronto Area between Apr. 1, 2008, and Mar. 31, 2015. Consecutive patients admitted to hospital and requiring operative intervention for a supracondylar humerus or femur fracture were considered. We calculated changes in operation incidence rates per year using multivariable negative binomial regression models. RESULTS: A total of 945 children with supracondylar humerus fractures and 421 with femur fractures underwent operative intervention during the study period. The baseline characteristics of the 2 groups were similar irrespective of which year fixation occurred. The annual incidence rate of supracondylar humerus fractures increased from 108 to 169 (56.5%) over the study period, at an adjusted rate of 7.5% per year (adjusted incidence rate ratio [IRR] 1.075, 95% confidence interval [CI] 1.072-1.079, p < 0.001). The annual incidence rate of femur fractures increased from 49 to 69 (40.8%), at an adjusted rate of 5.3% per year (adjusted IRR 1.053, 95% CI 1.044 1.062, p < 0.001). Significant increases were observed independent of fracture classification, stabilization method, whether patients were transferred from an outside hospital or presented directly, patient geographic location or the season in which the fracture occurred. INTERPRETATION: Adjusted annual incidence rates of supracondylar humerus and femur fractures increased significantly over the study period. Further work is needed to assess the clinical impact of informal regionalization of care and to determine whether the phenomenon occurs in other specialties. PMID- 28619747 TI - Successful immune checkpoint blockade in a patient with advanced stage microsatellite-unstable biliary tract cancer. AB - Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and reactivate antitumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/programmed death receptor ligand (PD-L1) pathway have shown clinical efficacy. The effects were particularly pronounced in tumors with DNA mismatch repair (MMR) deficiency and a high mutational load, which typically occur in the colon and endometrium. Here, we report on a 24-yr-old woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and durable response to the immune checkpoint inhibitor pembrolizumab, although treatment was initiated at an advanced stage of disease. The patient's tumor displayed DNA MMR deficiency and microsatellite instability (MSI) but lacked other features commonly discussed as predictors of response toward checkpoint blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells. Notably, high levels of HLA class I and II antigen expression were detected in the tumor, suggesting a potential causal relation between functionality of the tumor's antigen presentation machinery and the success of immune checkpoint blockade. We suggest determining MSI status in combination with HLA class I and II antigen expression in tumors potentially eligible for immune checkpoint blockade even in the absence of conventional markers predictive for anti-PD-1/PD L1 therapy and in entities not commonly linked to the MSI phenotype. Further studies are required to determine the value of these markers for predicting the success of immune checkpoint blockade. PMID- 28619748 TI - Pore Polarity and Charge Determine Differential Block of Kir1.1 and Kir7.1 Potassium Channels by Small-Molecule Inhibitor VU590. AB - VU590 was the first publicly disclosed, submicromolar-affinity (IC50 = 0.2 MUM), small-molecule inhibitor of the inward rectifier potassium (Kir) channel and diuretic target, Kir1.1. VU590 also inhibits Kir7.1 (IC50 ~ 8 MUM), and has been used to reveal new roles for Kir7.1 in regulation of myometrial contractility and melanocortin signaling. Here, we employed molecular modeling, mutagenesis, and patch clamp electrophysiology to elucidate the molecular mechanisms underlying VU590 inhibition of Kir1.1 and Kir7.1. Block of both channels is voltage- and K+ dependent, suggesting the VU590 binding site is located within the pore. Mutagenesis analysis in Kir1.1 revealed that asparagine 171 (N171) is the only pore-lining residue required for high-affinity block, and that substituting negatively charged residues (N171D, N171E) at this position dramatically weakens block. In contrast, substituting a negatively charged residue at the equivalent position in Kir7.1 enhances block by VU590, suggesting the VU590 binding mode is different. Interestingly, mutations of threonine 153 (T153) in Kir7.1 that reduce constrained polarity at this site (T153C, T153V, T153S) make wild-type and binding-site mutants (E149Q, A150S) more sensitive to block by VU590. The Kir7.1 T153C mutation enhances block by the structurally unrelated inhibitor VU714 but not by a higher-affinity analog ML418, suggesting that the polar side chain of T153 creates a barrier to low-affinity ligands that interact with E149 and A150. Reverse mutations in Kir1.1 suggest that this mechanism is conserved in other Kir channels. This study reveals a previously unappreciated role of membrane pore polarity in determination of Kir channel inhibitor pharmacology. PMID- 28619749 TI - Chaand Nagpaul: a calm and persuasive negotiator. PMID- 28619750 TI - Trusts boost ratings by engaging staff and including clinicians in management. PMID- 28619751 TI - Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation. AB - Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. (c)2017 AACR. PMID- 28619752 TI - The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy. AB - Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. (c)2017 AACR. PMID- 28619754 TI - Antitumor Effect of the Atypical Retinoid ST1926 in Acute Myeloid Leukemia and Nanoparticle Formulation Prolongs Lifespan and Reduces Tumor Burden of Xenograft Mice. AB - Acute myeloid leukemia (AML) is one of the most frequent types of blood malignancies. It is a complex disorder of undifferentiated hematopoietic progenitor cells. The majority of patients generally respond to intensive therapy. Nevertheless, relapse is the major cause of death in AML, warranting the need for novel treatment strategies. Retinoids have demonstrated potent differentiation and growth regulatory effects in normal, transformed, and hematopoietic progenitor cells. All-trans retinoic acid (ATRA) is the paradigm of treatment in acute promyelocytic leukemia, an AML subtype. The majority of AML subtypes are, however, resistant to ATRA. Multiple synthetic retinoids such as ST1926 recently emerged as potent anticancer agents to overcome such resistance. Despite its lack of toxicity, ST1926 clinical development was restricted due to its limited bioavailability and rapid excretion. Here, we investigate the preclinical efficacy of ST1926 and polymer-stabilized ST1926 nanoparticles (ST1926-NP) in AML models. We show that sub-MUmol/L concentrations of ST1926 potently and selectively inhibited the growth of ATRA-resistant AML cell lines and primary blasts. ST1926 induced-growth arrest was due to early DNA damage and massive apoptosis in AML cells. To enhance the drug's bioavailability, ST1926-NP were developed using Flash NanoPrecipitation, and displayed comparable anti growth activities to the naked drug in AML cells. In a murine AML xenograft model, ST1926 and ST1926-NP significantly prolonged survival and reduced tumor burden. Strikingly, in vivo ST1926-NP antitumor effects were achieved at four fold lower concentrations than the naked drug. These results highlight the promising use of ST1926 in AML therapy and encourage its further development. Mol Cancer Ther; 16(10); 2047-57. (c)2017 AACR. PMID- 28619753 TI - Inhibition of Hsp90 Suppresses PI3K/AKT/mTOR Signaling and Has Antitumor Activity in Burkitt Lymphoma. AB - Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779-90. (c)2017 AACR. PMID- 28619755 TI - Epidermal Growth Factor Receptor (EGFR)-targeted Photoimmunotherapy (PIT) for the Treatment of EGFR-expressing Bladder Cancer. AB - The use of light as a means of therapy for bladder cancer has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT), which targets EGFR-expressing bladder cancer. Anti-EGFR antibody panitumumab was labeled with the photoabsorber (PA), IRDye 700Dx (IR700), to create a panitumumab-IR700 antibody-PA conjugate that is activated by near-infrared radiation (NIR). Bladder cancer tissue microarray (TMA) and bladder cancer cell lines were analyzed for expression of EGFR. Mechanism of PIT-induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive oxygen species. Finally, the in vivo effect was studied in xenografts. EGFR staining of TMAs showed that while most bladder cancers have expression of EGFR to a varying degree, squamous cell carcinomas (SCC) have the highest expression of EGFR. Panitumumab-IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Panitumumab alone, panitumumab-IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species contributed toward cell death. NIR-PIT with panitumumab-IR700 reduced growth compared with only panitumumab-IR700-treated UMUC-5 xenograft tumors. PIT is a new targeted treatment for bladder cancer. Panitumumab-IR700-induced PIT selectively kills EGFR-expressing bladder cancer cells in vitro and in vivo and therefore warrants further therapeutic studies in orthotopic xenografts of bladder cancer and ultimately in patients. Mol Cancer Ther; 16(10); 2201-14. (c)2017 AACR. PMID- 28619756 TI - Alpha Particle Enhanced Blood Brain/Tumor Barrier Permeabilization in Glioblastomas Using Integrin Alpha-v Beta-3-Targeted Liposomes. AB - Glioblastoma (GBM) is the most common primary malignant astrocytoma characterized by extensive invasion, angiogenesis, hypoxia, and micrometastasis. Despite the relatively leaky nature of GBM blood vessels, effective delivery of antitumor therapeutics has been a major challenge due to the complications caused by the blood-brain barrier (BBB) and the highly torturous nature of newly formed tumor vasculature (blood tumor barrier-BTB). External beam radiotherapy was previously shown to be an effective means of permeabilizing central nervous system (CNS) barriers. By using targeted short-ranged radionuclides, we show for the first time that our targeted actinium-225-labeled alphavbeta3-specific liposomes (225Ac IA-TLs) caused catastrophic double stranded DNA breaks and significantly enhanced the permeability of BBB and BTB in mice bearing orthotopic GBMs. Histologic studies revealed characteristic alpha-particle induced double strand breaks within tumors but was not significantly present in normal brain regions away from the tumor where BBB permeability was observed. These findings indicate that the enhanced vascular permeability in these distal regions did not result from direct alpha-particle-induced DNA damage. On the basis of these results, in addition to their direct antitumor effects, 225Ac-IA-TLs can potentially be used to enhance the permeability of BBB and BTB for effective delivery of systemically administered antitumor therapeutics. Mol Cancer Ther; 16(10); 2191-200. (c)2017 AACR. PMID- 28619757 TI - CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest. AB - Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5 cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow. Here we describe the development of a synergistic combination treatment strategy that may be applicable in both soft tissue sarcomas as well as sarcomas of bone that takes advantage of targeting the cell cycle. We show that Rb-positive cell lines treated with the CDK4/6 inhibitor palbociclib reversibly arrest in the G1 phase of the cell cycle, and upon drug removal cells progress through the cell cycle as expected within 6-24 hours. Using a long-term high-throughput assay that allows us to examine drugs in different sequences or concurrently, we found that palbociclib-induced cell-cycle arrest poises Rb-positive sarcoma cells (SK-LMS1 and HT-1080) to be more sensitive to agents that work preferentially in S-G2 phase such as doxorubicin and Wee1 kinase inhibitors (AZD1775). The synergy between palbociclib and AZD1775 was also validated in vivo using SK-LMS1 xenografts as well as Rb-positive patient-derived xenografts (PDX) developed from leiomyosarcoma patients. This work provides the necessary preclinical data in support of a clinical trial utilizing this treatment strategy. Mol Cancer Ther; 16(9); 1751-64. (c)2017 AACR. PMID- 28619758 TI - Cotargeting of MEK and PDGFR/STAT3 Pathways to Treat Pancreatic Ductal Adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human diseases and remains largely refractory to available drug treatments. Insufficient targeting of the known oncogenic drivers and activation of compensatory feedback loops and inability to prevent metastatic spread contribute to poor prognosis for this disease. The KRAS-driven MEK pathway is mutationally activated in most pancreatic cancers and is an important target for therapeutics. Using a two dimensional monolayer culture system as well as three-dimensional spheroid culture system, we conducted a screen of a large panel of anticancer agents and found that MAP2K (MEK) inhibitors were most effective in targeting PDAC spheroids in comparison with monolayer cultures. Combination treatment with an MEK inhibitor and the multikinase inhibitor ponatinib was effective in targeting pancreatic cancer cells both in monolayer and spheroids by effectively blocking signaling via the PDGFRalpha and MEK kinases, while also preventing the activation of STAT3- and S6-mediated compensatory feedback loops in cancer cells. Furthermore, using xenograft models, we demonstrate that cotreatment with a MEK inhibitor and ponatinib causes significant tumor regression. PDAC patient samples also provided evidence of increased STAT3 activation in PDAC tumors and MAPK1 (ERK) activation in liver metastases, implicating STAT3 and ERK as key drivers in primary tumors and metastases, respectively. These results reveal a combination drug treatment strategy that may be effective in pancreatic cancer. Mol Cancer Ther; 16(9); 1729-38. (c)2017 AACR. PMID- 28619759 TI - Modeling Therapy Resistance in BRCA1/2-Mutant Cancers. AB - Although PARP inhibitors target BRCA1- or BRCA2-mutant tumor cells, drug resistance is a problem. PARP inhibitor resistance is sometimes associated with the presence of secondary or "revertant" mutations in BRCA1 or BRCA2 Whether secondary mutant tumor cells are selected for in a Darwinian fashion by treatment is unclear. Furthermore, how PARP inhibitor resistance might be therapeutically targeted is also poorly understood. Using CRISPR mutagenesis, we generated isogenic tumor cell models with secondary BRCA1 or BRCA2 mutations. Using these in heterogeneous in vitro culture or in vivo xenograft experiments in which the clonal composition of tumor cell populations in response to therapy was monitored, we established that PARP inhibitor or platinum salt exposure selects for secondary mutant clones in a Darwinian fashion, with the periodicity of PARP inhibitor administration and the pretreatment frequency of secondary mutant tumor cells influencing the eventual clonal composition of the tumor cell population. In xenograft studies, the presence of secondary mutant cells in tumors impaired the therapeutic effect of a clinical PARP inhibitor. However, we found that both PARP inhibitor-sensitive and PARP inhibitor-resistant BRCA2 mutant tumor cells were sensitive to AZD-1775, a WEE1 kinase inhibitor. In mice carrying heterogeneous tumors, AZD-1775 delivered a greater therapeutic benefit than olaparib treatment. This suggests that despite the restoration of some BRCA1 or BRCA2 gene function in "revertant" tumor cells, vulnerabilities still exist that could be therapeutically exploited. Mol Cancer Ther; 16(9); 2022-34. (c)2017 AACR. PMID- 28619761 TI - Exhaled breath condensate biomarkers for the early diagnosis of lung cancer using proteomics. AB - We explored whether the proteomic analysis of exhaled breath condensate (EBC) may provide biomarkers for noninvasive screening for the early detection of lung cancer (LC). EBC was collected from 192 individuals [49 control (C), 49 risk factor-smoking (S), 46 chronic obstructive pulmonary disease (COPD) and 48 LC]. With the use of liquid chromatography and tandem mass spectrometry, 348 different proteins with a different pattern among the four groups were identified in EBC samples. Significantly more proteins were identified in the EBC from LC compared with other groups (C: 12.4 +/- 1.3; S: 15.3 +/- 1; COPD: 14 +/- 1.6; LC: 24.2 +/- 3.6; P = 0.0001). Furthermore, the average number of proteins identified per sample was significantly higher in LC patients, and receiver operating characteristic curve (ROC) analysis showed an area under the curve of 0.8, indicating diagnostic value. Proteins frequently detected in EBC, such as dermcidin and hornerin, along with others much less frequently detected, such as hemoglobin and histones, were identified. Cytokeratins (KRTs) were the most abundant proteins in EBC samples, and levels of KRT6A, KRT6B, and KRT6C isoforms were significantly higher in samples from LC patients (P = 0.0031, 0.0011, and 0.0009, respectively). Moreover, the amount of most KRTs in EBC samples from LC patients showed a significant positive correlation with tumor size. Finally, we used a random forest algorithm to generate a robust model using EBC protein data for the diagnosis of patients with LC where the area under the ROC curve obtained indicated a good classification (82%). Thus this study demonstrates that the proteomic analysis of EBC samples is an appropriated approach to develop biomarkers for the diagnosis of lung cancer. PMID- 28619760 TI - FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors. AB - Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well-understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive colorectal cancer cells lack degradation of Mcl-1, a prosurvival Bcl-2 family protein. Hsp90 inhibition promotes GSK3beta dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be overcame by Mcl-1 selective small-molecule inhibitors. Collectively, our findings demonstrate a key role of GSK3beta/FBW7-dependent Mcl-1 degradation in killing of colorectal cancer cells by Hsp90 inhibitors and suggest FBW7 mutational status as a biomarker for Hsp90-targeted therapy. Mol Cancer Ther; 16(9); 1979-88. (c)2017 AACR. PMID- 28619762 TI - Impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation. AB - CD4+ T-cell differentiation plays an important role in allergic airway diseases. Tumor necrosis factor receptor 2 (TNFR2) has been shown to regulate CD4+ T lymphocyte differentiation, but its role in allergic airway inflammation is not clear. Here, we investigated the role of TNFR2 in allergic airway inflammation. The mouse model was generated by immunization with ovalbumin and intranasal administration of TNFR2 antibody. Airway inflammation and CD4+ T-cell differentiation were measured in vivo and in vitro. Inhibited TNFR2 signaling aggravated airway inflammation and increased the expression of inflammatory cytokines (IL-4, IL-5, IL-17, and TNF-alpha) in serum and bronchoalveolar lavage fluid. Impaired TNFR2 signaling promoted Th2 and Th17 polarization but inhibited Th1 and CD4+CD25+ T-cell differentiation in vivo. Furthermore, TNFR2 signaling inhibition promoted Th2 and Th17 polarization in vitro, which may occur through the activation of TNF receptor-associated factor 2 and NF-kappaB signaling. Therefore, our findings indicate that impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation. PMID- 28619763 TI - Stress at work. PMID- 28619764 TI - Medicoeconomic analysis of lobectomy using thoracoscopy versus thoracotomy for lung cancer: a study protocol for a multicentre randomised controlled trial (Lungsco01). AB - INTRODUCTION: In the last decade, video-assisted thoracoscopic surgery (VATS) lobectomy for non-small cell lung cancer (NSCLC) has had a major effect on thoracic surgery. Retrospective series have reported benefits of VATS when compared with open thoracotomy in terms of postoperative pain, postoperative complications and length of hospital stay. However, no large randomised control trial has been conducted to assess the reality of the potential benefits of VATS lobectomy or its medicoeconomic impact. METHODS AND ANALYSIS: The French National Institute of Health funded Lungsco01 to determine whether VATS for lobectomy is superior to open thoracotomy for the treatment of NSCLC in terms of economic cost to society. This trial will also include an analysis of postoperative outcomes, the length of hospital stay, the quality of life, long-term survival and locoregional recurrence. The study design is a two-arm parallel randomised controlled trial comparing VATS lobectomy with lobectomy using thoracotomy for the treatment of NSCLC. Patients will be eligible if they have proven or suspected lung cancer which could be treated by lobectomy. Patients will be randomised via an independent service. All patients will be monitored according to standard thoracic surgical practices. All patients will be evaluated at day 1, day 30, month 3, month 6, month 12 and then every year for 2 years thereafter. The recruitment target is 600 patients. ETHICS AND DISSEMINATION: The protocol has been approved by the French National Research Ethics Committee (CPP Est I: 09/06/2015) and the French Medicines Agency (09/06/2015). Results will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02502318. PMID- 28619765 TI - Early termination of cardiovascular trials as a consequence of poor accrual: analysis of ClinicalTrials.gov 2006-2015. AB - OBJECTIVES: To present a snapshot of experimental cardiovascular research with a focus on geographical and temporal patterns of early termination due to poor accrual. SETTING: The Aggregate Analysis of ClinicalTrials.gov (AACT) database, reflecting ClinicalTrials.gov as of 27 March 2016. DESIGN: The AACT database was searched for all cardiovascular clinical trials that started from January 2006 up to December 2015. RESULTS: Thirteen thousand and seven hundred twenty-nine cardiovascular trials were identified. Of these, 8900 (65%) were classified as closed studies. Globally, 11% of closed trials were terminated. This proportion varied from 9.6% to 14% for trials recruiting from Europe and Americas, respectively, with a slightly decreasing trend (p=0.02) over the study period. The most common reason for trials failing to complete was poor accrual (41%). Intercontinental trials exhibited lower figures of poor accrual as the reason for their early stopping, as compared with trials recruiting in a single continent (28% vs 44%, p=0.002). CONCLUSIONS: Poor accrual significantly challenges the successful completion of cardiovascular clinical trials. Findings are suggestive of a positive effect of globalisation of cardiovascular clinical research on the achievement of enrolment goals within a reasonable time frame. PMID- 28619766 TI - Diagnostic performance of an automatic blood pressure measurement device, Microlife WatchBP Home A, for atrial fibrillation screening in a real-world primary care setting. AB - OBJECTIVE: To evaluate the diagnostic performance of a UK National Institute for Health and Care Excellence-recommended automatic oscillometric blood pressure (BP) measurement device incorporated with an atrial fibrillation (AF) detection algorithm (Microlife WatchBP Home A) for real-world AF screening in a primary healthcare setting. SETTING: Primary healthcare setting in Hong Kong. INTERVENTIONS: This was a prospective AF screening study carried out between 1 September 2014 and 14 January 2015. The Microlife device was evaluated for AF detection and compared with a reference standard of lead-I ECG. PRIMARY OUTCOME MEASURES: Diagnostic performance of Microlife for AF detection. RESULTS: 5969 patients (mean age: 67.2+/-11.0 years; 53.9% female) were recruited. The mean CHA2DS2-VASc ( C : congestive heart failure [1 point]; H : hypertension [1 point]; A2 : age 65-74 years [1 point] and age >=75 years [2 points]; D : diabetes mellitus [1 point]; S : prior stroke or transient ischemic attack [2 points]; VA : vascular disease [1 point]; and Sc : sex category [female] [1 point])score was 2.8+/-1.3. AF was diagnosed in 72 patients (1.21%) and confirmed by a 12-lead ECG. The Microlife device correctly identified AF in 58 patients and produced 79 false-positives. The corresponding sensitivity and specificity for AF detection were 80.6% (95% CI 69.5 to 88.9) and 98.7% (95% CI 98.3 to 98.9), respectively. Among patients with a false-positive by the Microlife device, 30.4% had sinus rhythm, 35.4% had sinus arrhythmia and 29.1% exhibited premature atrial complexes. With the low prevalence of AF in this population, the positive and negative predictive values of Microlife device for AF detection were 42.4% (95% CI 34.0 to 51.2) and 99.8% (95% CI 99.6 to 99.9), respectively. The overall diagnostic performance of Microlife device to detect AF as determined by area under the curves was 0.90 (95% CI 0.89 to 0.90). CONCLUSIONS: In the primary care setting, Microlife WatchBP Home was an effective means to screen for AF, with a reasonable sensitivity of 80.6% and a high negative predictive value of 99.8%, in addition to its routine function of BP measurement. In a younger patient population aged <65 years with a lower prevalence of AF, Microlife WatchBP Home A demonstrated a similar diagnostic accuracy. PMID- 28619767 TI - Association of hypercapnia on admission with increased length of hospital stay and severity in patients admitted with community-acquired pneumonia: a prospective observational study from Pakistan. AB - OBJECTIVE: To determine whether the presence of hypercapnia on admission in adult patients admitted to a university-based hospital in Karachi, Pakistan with community-acquired pneumonia (CAP) correlates with an increased length of hospital stay and severity compared with no hypercapnia on admission. STUDY DESIGN: A prospective observational study. SETTINGS: Tertiary care hospital in Karachi, Pakistan. METHODS: Patients who met the inclusion criteria were enrolled in the study. The severity of pneumonia was assessed by CURB-65 and PSI scores. An arterial blood gas analysis was obtained within 24 hours of admission. Based on arterial PaCO2 levels, patients were divided into three groups: hypocapnic (PaCO2 <35 mm Hg), hypercapnic (PaCO2 >45 mm Hg) and normocapnic (PaCO2 <35-45 mm Hg). OUTCOMES: The primary outcome was the association of hypercapnia on admission with mean length of hospital stay. Secondary outcomes were the need for mechanical ventilation, ICU admission and in-hospital mortality. RESULTS: A total of 295 patients of mean age 60.20+/-17.0 years (157 (53.22%) men) were enrolled over a 1-year period. Hypocapnia was found in 181 (61.35%) and hypercapnia in 57 (19.32%) patients. Hypercapnic patients had a longer hospital stay (mean 9.27+/ 7.57 days), increased requirement for non-invasive mechanical ventilation (NIMV) on admission (n=45 (78.94%)) and longer mean time to clinical stability (4.39+/ 2.0 days) compared with the other groups. Overall mortality was 41 (13.89%), but there was no statistically significant difference in mortality (p=0.35) and ICU admission (p=0.37) between the three groups. On multivariable analysis, increased length of hospital stay was associated with NIMV use, ICU admission, hypercapnia and normocapnia. CONCLUSION: Hypercapnia on admission is associated with severity of CAP, longer time to clinical stability, increased length of hospital stay and need for NIMV. It should be considered as an important criterion to label the severity of the illness and also a determinant of patients who will require a higher level of hospital care. However, further validation is required. PMID- 28619768 TI - Liquorice-induced hypokalaemia in patients treated with Yokukansan preparations: identification of the risk factors in a retrospective cohort study. AB - OBJECTIVE: To evaluate serum potassium levels and rates of hypokalaemia in patients treated with liquorice-containing Japanese traditional Kampo-medicines Yokukansan (YK) and Yokukansan-ka-chinpihange (YKCH). DESIGN: Retrospective cohort study. SETTING: Patients receiving YK preparations for dementia and other psychiatric disorders in the University of Tsukuba Hospital in Japan. PARTICIPANTS: 389 patients (male/female: 174/215, 68.6+/-16.1 years) were treated with YK preparations for 231 days (range 6-2788 days). Patients whose potassium levels were <3.6 mEq/L before administration of YK preparations, and drug non compliant patients, were excluded. MAIN OUTCOME MEASURE: The occurrence rate of hypokalaemia and assessment of the risk factors for YK preparation-induced hypokalaemia. RESULTS: Of the 389 patients treated with YK preparations, 94 (24.2%) developed hypokalaemia (potassium levels <3.6 mEq/L) 34 days (range 1 1600 days) after administration of the preparations. 36 (38.3%) patients had co administration with lower potassium-inducing drugs (LPIDs; diuretics, glucocorticoids, mineralocorticoids and glycyrrhizin), which was more frequent in the patients without hypokalaemia (17.3%) (p<0.05). A Cox proportional hazard model identified four risk factors for hypokalaemia: YK administration (not YKCH) (HR 3.093, 95% CI 1.408 to 6.798), co-administration of LPIDs (HR 2.743, 95% CI 1.754 to 4.289), hypoalbuminaemia at baseline (HR 2.145, 95% 1.360 to 3.384), and full dosage administration (7.5 g/day) (HR 1.600, 95% CI 1.005 to 2.549). CONCLUSIONS: Serum potassium monitoring should be done at least monthly in patients with the following risk factors: LPID co-administration, YK administration, hypoalbuminaemia, and full dosage administration. PMID- 28619769 TI - Detection of peripheral and central sensitisation at acupoints in patients with unilateral shoulder pain in Beijing: a cross-sectional matched case-control study. AB - OBJECTIVE: To investigate the pattern of experimental pain responses at acupoints in patients with unilateral shoulder pain. DESIGN: A cross-sectional matched study. SETTING: Acupuncture and Moxibustion Department, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University. PARTICIPANTS: Volunteer samples of 60 participants (30 patients with unilateral shoulder pain, 30 healthy controls). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Pressure pain thresholds (PPTs) were measured at four acupoints-namely, Tianzong (SI 11), Jianliao (SJ 14), Jianyu (LI 15) and Jianzhen (SI 9), on the painful/non-painful side in patients with unilateral shoulder pain or healthy controls, respectively. The correlations between the Peripheral Sensitisation Index (PSI) and Central Sensitisation Index (CSI) were compared. RESULTS: Analysis showed significantly lower PPT values at acupoints on the painful side compared with the non-painful side in patients with shoulder pain (p<0.025). Meanwhile, PPTs on the non-painful side of these patients were lower than those on the ipsilateral side of healthy controls (p<0.025). No significant differences in PPT values were found between the non-acupoint of the painful/non-painful side in patients with shoulder pain and the ipsilateral side of healthy controls (p>0.05). Additionally, it was observed that the pressure pain assessment acupoints have a strong association with PSI and CSI; three acupoints, in particular, SJ 14, LI 15 and SI 9, showed a correlation with PSI and CSI. CONCLUSION: The results suggest the presence of peripheral and central sensitisation at acupoints in participants with unilateral shoulder pain. There exists an obvious relationship among the three acupoints SJ 14, LI 15 and SI 9, which are usually chosen to treat shoulder pain. The results provide evidence for the selection of acupoints to treat shoulder pain by acupuncture. PMID- 28619770 TI - Return to work of cancer patients after a multidisciplinary intervention including occupational counselling and physical exercise in cancer patients: a prospective study in the Netherlands. AB - OBJECTIVES: To support return to work (RTW) among cancer patients, a multidisciplinary rehabilitation programme was developed which combined occupational counselling with a supervised physical exercise programme during chemotherapy. The aim was to investigate RTW rates of cancer patients and to evaluate changes in work-related quality of life and physical outcomes. DESIGN: Longitudinal prospective intervention study using a one-group design. SETTING: Two hospitals in the Netherlands. PARTICIPANTS: Of the eligible patients, 56% participated; 93 patients with a primary diagnosis of cancer receiving chemotherapy and on sick leave were included. Patients completed questionnaires on RTW, the importance of work, work ability (WAI), RTW self-efficacy, fatigue (MFI), and quality of life (EORTC QLQ C-30) at baseline and 6, 12 and 18 months follow-up. Before and after the exercise programme 1-repetition maximum (1RM) muscle strength and cardiorespiratory fitness (VO2 peak) were assessed. RESULTS: Six months after the start of a multidisciplinary rehabilitation programme that combined occupational counselling with a supervised physical exercise programme, 59% of the cancer patients returned to work, 86% at 12 months and 83% at 18 months. In addition, significant improvements (p<0.05) in the importance of work, work ability, RTW self-efficacy, and quality of life were observed, whereas fatigue levels were significantly reduced. After completing the exercise programme, 1RM muscle strength was significantly increased but there was no improvement in VO2 peak level. CONCLUSIONS: RTW rates of cancer patients were high after completion of the multidisciplinary rehabilitation programme. A multidisciplinary rehabilitation programme which combines occupational counselling with a supervised physical exercise programme is likely to result in RTW, reduced fatigue and increased importance of work, work ability, and quality of life. PMID- 28619771 TI - Revealed versus concealed criteria for placental insufficiency in an unselected obstetric population in late pregnancy (RATIO37): randomised controlled trial study protocol. AB - INTRODUCTION: Fetal growth restriction (FGR) affects 5%-10% of all pregnancies, contributing to 30%-50% of stillbirths. Unfortunately, growth restriction often is not detected antenatally. The last weeks of pregnancy are critical for preventing stillbirth among babies with FGR because there is a pronounced increase in stillbirths among growth-restricted fetuses after 37 weeks of pregnancy. Here we present a protocol (V.1, 23 May 2016) for the RATIO37 trial, which evaluates an integrated strategy for accurately selecting at-risk fetuses for delivery at term. The protocol is based on the combination of fetal biometry and cerebroplacental ratio (CPR). The primary objective is to reduce stillbirth rates. The secondary aims are to detect low birth weights and adverse perinatal outcomes. METHODS AND ANALYSIS: The study is designed as multicentre (Spain, Chile, Mexico,Czech Republic and Israel), open-label, randomised trial with parallel groups. Singleton pregnancies will be invited to participate after routine second-trimester ultrasound scan (19+0-22+6 weeks of gestation), and participants will be randomly allocated to receive revealed or concealed CPR evaluation. Then, a routine ultrasound and Doppler scan will be performed at 36+0 37+6 weeks. Sociodemographic and clinical data will be collected at enrolment. Ultrasound and Doppler variables will be recorded at 36+0-37+6 weeks of pregnancy. Perinatal outcomes will be recorded after delivery. Univariate (with estimated effect size and its 95% CI) and multivariate (mixed-effects logistic regression) comparisons between groups will be performed. ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 23May 2016. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT02907242; pre-results. PMID- 28619772 TI - Cost-effectiveness of HPV-based cervical cancer screening in the public health system in Nicaragua. AB - OBJECTIVES: To evaluate the cost-effectiveness of human papillomavirus (HPV) DNA testing (versus Papanicolaou (Pap)-based screening) for cervical cancer screening in Nicaragua. DESIGN: A previously developed Monte Carlo simulation model of the natural history of HPV infection and cervical cancer was calibrated to epidemiological data from Nicaragua. Cost data inputs were derived using a micro costing approach in Carazo, Chontales and Chinandega departments; test performance data were from a demonstration project in Masaya department. SETTING: Nicaragua's public health sector facilities. PARTICIPANTS: Women aged 30-59 years. INTERVENTIONS: Screening strategies included (1) Pap testing every 3 years, with referral to colposcopy for women with an atypical squamous cells of undetermined significance or worse result ('Pap'); (2) HPV testing every 5 years, with referral to cryotherapy for HPV-positive eligible women (HPV cryotherapy or 'HPV-Cryo'); (3) HPV testing every 5 years, with referral to triage with visual inspection with acetic acid (VIA) for HPV-positive women ('HPV-VIA'); and (4) HPV testing every 5 years, with referral to Pap testing for HPV-positive women ('HPV Pap'). OUTCOME MEASURES: Reduction in lifetime risk of cancer and incremental cost-effectiveness ratios (ICER; 2015 US$ per year of life saved (YLS)). RESULTS: HPV-based screening strategies were more effective than Pap testing. HPV-Cryo was the least costly and most effective strategy, reducing lifetime cancer risk by 29.5% and outperforming HPV-VIA, HPV-Pap and Pap only, which reduced cancer risk by 19.4%, 12.2% and 10.8%, respectively. With an ICER of US$320/YLS, HPV-Cryo every 5 years would be very cost-effective using a threshold based on Nicaragua's per capita gross domestic product of US$2090. Findings were robust across sensitivity analyses on test performance, coverage, compliance and cost parameters. CONCLUSIONS: HPV testing is very cost-effective compared with Pap testing in Nicaragua, due to higher test sensitivity and the relatively lower number of visits required. Increasing compliance with recommended follow-up will further improve the health benefits and value for public health dollars. PMID- 28619773 TI - Herbal medicine (Hyeolbuchukeo-tang or Xuefu Zhuyu decoction) for treating primary dysmenorrhoea: protocol for a systematic review of randomised controlled trials. AB - INTRODUCTION: Primary dysmenorrhoea is menstrual pain without pelvic pathology and is the most common gynaecological condition in women. Xuefu Zhuyudecoction (XZD) or Hyeolbuchukeo-tang, a traditional herbal formula, has been used as a treatment for primary dysmenorrhoea. The purpose of this study is to assess the current published evidence regarding XZD as treatment for primary dysmenorrhoea. MATERIALS AND METHODS: The following databases will be searched from their inception until April 2017: MEDLINE (via PubMed), Allied and Complementary Medicine Database (AMED), EMBASE, The Cochrane Library, six Korean medical databases (Korean Studies Information Service System, DBPia, Oriental Medicine Advanced Searching Integrated System, Research Information Service System, Korea Med and the Korean Traditional Knowledge Portal), three Chinese medical databases (China National Knowledge Infrastructure (CNKI), Wan Fang Database and Chinese Scientific Journals Database (VIP)) and one Japanese medical database (CiNii). Randomised clinical trials (RCTs) that will be included in this systematic review comprise those that used XZD or modified XZD. The control groups in the RCTs include no treatment, placebo, conventional medication or other treatments. Trials testing XZD as an adjunct to other treatments and studies where the control group received the same treatment as the intervention group will be also included. Data extraction and risk of bias assessments will be performed by two independent reviewers. The risk of bias will be assessed with the Cochrane risk of bias tool. All statistical analyses will be conducted using Review Manager software (RevMan V.5.3.0). ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print. The review will benefit patients and practitioners in the fields of traditional and conventional medicine. PROSPERO REGISTRATION NUMBER: CRD42016050447. PMID- 28619774 TI - Protocol for a multicentre, multistage, prospective study in China using system based approaches for consistent improvement in surgical safety. AB - INTRODUCTION: Surgical safety has emerged as a crucial global health issue in the past two decades. Although several safety-enhancing tools are available, the pace of large-scale improvement remains slow, especially in developing countries such as China. The present project (Modern Surgery and Anesthesia Safety Management System Construction and Promotion) aims to develop and validate system-based integrated approaches for reducing perioperative deaths and complications using a multicentre, multistage design. METHODS AND ANALYSIS: The project involves collection of clinical and outcome information for 1 20 000 surgical inpatients at four regionally representative academic/teaching general hospitals in China during three sequential stages: preparation and development, effectiveness validation and improvement of implementation for promotion. These big data will provide the evidence base for the formulation, validation and improvement processes of a system-based stratified safety intervention package covering the entire surgical pathway. Attention will be directed to managing inherent patient risks and regulating medical safety behaviour. Information technology will facilitate data collection and intervention implementation, provide supervision mechanisms and guarantee transfer of key patient safety messages between departments and personnel. Changes in rates of deaths, surgical complications during hospitalisation, length of stay, system adoption and implementation rates will be analysed to evaluate effectiveness and efficiency. ETHICS AND DISSEMINATION: This study was approved by the institutional review boards of Peking Union Medical College Hospital, First Hospital of China Medical University, Qinghai Provincial People's Hospital, Xiangya Hospital Central South University and the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. Study findings will be disseminated via peer-reviewed journals, conference presentations and patent papers. PMID- 28619775 TI - Retrospective cohort study of all deaths among infants born between 22 and 27 completed weeks of gestation in Switzerland over a 3-year period. AB - OBJECTIVES: The aim of this research is to assess causes and circumstances of deaths in extremely low gestational age neonates (ELGANs) born in Switzerland over a 3-year period. DESIGN: Population-based, retrospective cohort study. SETTING: All nine level III perinatal centres (neonatal intensive care units (NICUs) and affiliated obstetrical services) in Switzerland. PATIENTS: ELGANs with a gestational age (GA) <28 weeks who died between 1 July 2012 and 30 June 2015. RESULTS: A total of 594 deaths were recorded with 280 (47%) stillbirths and 314 (53%) deaths after live birth. Of the latter, 185 (59%) occurred in the delivery room and 129 (41%) following admission to an NICU. Most liveborn infants dying in the delivery room had a GA <=24 weeks and died following primary non intervention. In contrast, NICU deaths occurred following unrestricted life support regardless of GA. End-of-life decision-making and redirection of care were based on medical futility and anticipated poor quality of life in 69% and 28% of patients, respectively. Most infants were extubated before death (87%). CONCLUSIONS: In Switzerland, most deaths among infants born at less than 24 weeks of gestation occurred in the delivery room. In contrast, most deaths of ELGANs with a GA >=24 weeks were observed following unrestricted provisional intensive care, end-of-life decision-making and redirection of care in the NICU regardless of the degree of immaturity. PMID- 28619776 TI - A cross-sectional study of the prevalence, awareness, treatment and control of hypertension in Shenzhen, China. AB - OBJECTIVES: An understanding of the awareness, treatment and control of hypertension is helpful to guide decision-making regarding interventions to reduce the risk for diseases with hypertension as a key risk factor. This study aimed to estimate the prevalence, awareness, treatment, and control of hypertension in Shenzhen, China. METHODS: A cross-sectional study was conducted. We employed multistage cluster random sampling methods to select participants. A survey involving face-to-face interviews was conducted to collect the data. A total of 1676 participants finished the survey and formed the final analysis. RESULTS: We found that the prevalence of hypertension was 17.6%. The rates of hypertension awareness, treatment and control were 48.8%, 51.4% and 43.2% respectively. Only 6.8% hypertensives were found to be managed by community health centres. Compared with the female participants, the males were found to have higher rates of prevalence (19.7% vs 15.7%; OR 1.47, 95% CI 1.10 to 1.97) and awareness (42.9% vs 38.1%; OR 2.35, 95% CI 1.28 to 4.33), but lower rates of medication treatments (20.5% vs 30.2%; OR 0.83, 95% CI 0.05 to 0.92) and control (12.8% vs 23.0%; OR 0.45, 95% CI 0.21 to 0.96). Migrants were more likely to be aware of hypertension (32.5% vs 44.3%; OR 0.57, 95% CI 0.30 to 0.90), reduce their salt intake (8.8% vs 18.1%; OR 0.40, 95% CI 0.15 to 0.94), and undertake regular monitoring of hypertension (1.3% vs 11.0%; OR 0.14, 95% CI 0.02 to 0.92) when compared with the locals. CONCLUSIONS: Our study finds that hypertension is an important public health burden in Shenzhen. It implies that strategies need to be developed to improve effective primary care management of hypertension. It also suggests a need to develop gender and household register tailored strategies for the prevention, detection, treatment and control of hypertension. PMID- 28619778 TI - In patients with severe uncontrolled asthma, does knowledge of adherence and inhaler technique using electronic monitoring improve clinical decision making? A protocol for a randomised controlled trial. AB - INTRODUCTION: Many patients with asthma remain poorly controlled despite the use of inhaled corticosteroids and long-acting beta agonists. Poor control may arise from inadequate adherence, incorrect inhaler technique or because the condition is refractory. Without having an objective assessment of adherence, clinicians may inadvertently add extra medication instead of addressing adherence. This study aims to assess if incorporating objectively recorded adherence from the Inhaler Compliance Assessment (INCA) device and lung function into clinical decision making provides more cost-effective prescribing and improves outcomes. METHODS AND ANALYSIS: This prospective, randomised, multicentre study will compare the impact of using information on adherence to influence asthma treatment. Patients with severe uncontrolled asthma will be included. Data on adherence, inhaler technique and electronically recorded peak expiratory flow rate will be used to promote adherence and guide a clinical decision protocol to guide management in the active group. The control group will receive standard inhaler and adherence education. Medications will be adjusted using a protocol based on Global Initiativefor Asthma (GINA) recommendations. The primary outcome is the between-group difference in the proportion of patients who have refractory disease and are prescribed appropriate medications at the end of 32 weeks. A co primary outcome is the difference between groups in the rate of adherence to salmeterol/fluticasone inhaler over the last 12 weeks. Secondary outcomes include changes in symptoms, lung function, type-2 cytokine biomarkers and clinical outcomes between both groups. Cost-effectiveness and cost-utility analyses of the INCA device intervention will be performed. The economic impact of a national implementation of the INCA-SUN programme will be evaluated. ETHICS AND DISSEMINATION: The results of the study will be published as a manuscript in peer reviewed journals. The study has been approved by the ethics committees in the five participating hospitals. TRIAL REGISTRATION: NCT02307669; Pre-results. PMID- 28619777 TI - Peripherally InSerted CEntral catheter dressing and securement in patients with cancer: the PISCES trial. Protocol for a 2x2 factorial, superiority randomised controlled trial. AB - INTRODUCTION: Around 30% of peripherally inserted central catheters (PICCs) fail from vascular, infectious or mechanical complications. Patients with cancer are at highest risk, and this increases morbidity, mortality and costs. Effective PICC dressing and securement may prevent PICC failure; however, no large randomised controlled trial (RCT) has compared alternative approaches. We designed this RCT to assess the clinical and cost-effectiveness of dressing and securements to prevent PICC failure. METHODS AND ANALYSIS: Pragmatic, multicentre, 2*2 factorial, superiority RCT of (1) dressings (chlorhexidine gluconate disc (CHG) vs no disc) and (2) securements (integrated securement dressing (ISD) vs securement device (SED)). A qualitative evaluation using a knowledge translation framework is included. Recruitment of 1240 patients will occur over 3 years with allocation concealment until randomisation by a centralised service. For the dressing hypothesis, we hypothesise CHG discs will reduce catheter-associated bloodstream infection (CABSI) compared with no CHG disc. For the securement hypothesis, we hypothesise that ISD will reduce composite PICC failure (infection (CABSI/local infection), occlusion, dislodgement or thrombosis), compared with SED. SECONDARY OUTCOMES: types of PICC failure; safety; costs; dressing/securement failure; dwell time; microbial colonisation; reversible PICC complications and consumer acceptability. Relative incidence rates of CABSI and PICC failure/100 devices and/1000 PICC days (with 95% CIs) will summarise treatment impact. Kaplan-Meier survival curves (and log rank Mantel-Haenszel test) will compare outcomes over time. Secondary end points will be compared between groups using parametric/non-parametric techniques; p values <0.05 will be considered to be statistically significant. ETHICS AND DISSEMINATION: Ethical approval from Queensland Health (HREC/15/QRCH/241) and Griffith University (Ref. No. 2016/063). Results will be published. TRIAL REGISTRATION: Trial registration number is: ACTRN12616000315415. PMID- 28619780 TI - Qualitative analysis of 6961 free-text comments from the first National Cancer Patient Experience Survey in Scotland. AB - OBJECTIVES: To analyse free-text responses from the first Scottish Cancer Patient Experience Survey (SCPES) to understand patients' experiences of care, identify valued aspects and areas for improvement. DESIGN: Inductive thematic analysis of seven free-text comment boxes covering all stages of the cancer experience, from a national cohort survey. SETTING AND PARTICIPANTS: Adult cancer patients diagnosed across all Health Boards in Scotland between July 2013 and March 2014, and who had an inpatient stay or hospital visit between January and September 2014. 2663 respondents (of n=4835 survey respondents) provided 6961 free-text comments. MAIN OUTCOME MEASURES: Positive and negative themes of patients' experiences. Differences in the proportion of positive to negative comments by demographics. METHODS: Data were analysed as follows: (1) comments were initially categorised at a high level (eg, positive, negative, miscellaneous, etc); (2) inductive codes were derived and applied to all relevant comments; (3) codes sharing similar meaning were amalgamated into subthemes, and code frequencies were measured; (4) subthemes were mapped into overarching themes; (5) difference in the proportion of positive to negative comments by demographics were analysed using chi2 tests. RESULTS: Participants made more positive than negative comments (1:0.78). Analysis highlighted the importance to patients of Feeling that Individual Needs Are Met and Feeling Confident Within the System. Comments also provided insight into how Processes and Structures within the system of care can negatively impact on patients' experience. Particular issues were identified with care experiences in the lead-up to diagnosis. CONCLUSIONS: This analysis provides a detailed understanding of patients' cancer care experiences, therefore indicating what aspects matter in those experiences. Although the majority of comments were positive, there were a significant number of negative comments, especially about the lead-up to diagnosis. Comments suggest patients would value greater integration of care from services involved in their treatment for cancer. PMID- 28619779 TI - Multiple health behaviour change interventions for primary prevention of cardiovascular disease in primary care: systematic review and meta-analysis. AB - BACKGROUND: It is uncertain whether multiple health behaviour change (MHBC) interventions are effective for the primary prevention of cardiovascular disease (CVD) in primary care. A systematic review and a meta-analysis were performed to evaluate the effectiveness of MHBC interventions on CVD risk and CVD risk factors; the study also evaluated associations of theoretical frameworks and intervention components with intervention effectiveness. METHODS: The search included randomised controlled trials of MHBC interventions aimed at reducing CVD risk in primary prevention population up to 2017. Theoretical frameworks and intervention components were evaluated using standardised methods. Meta-analysis with stratification and meta-regression were used to evaluate intervention effects. RESULTS: We identified 31 trials (36 484 participants) with a minimum duration of 12 months follow-up. Pooled net change in systolic blood pressure (16 trials) was -1.86 (95% CI -3.17 to -0.55; p=0.01) mm Hg; diastolic blood pressure (15 trials), -1.53 (-2.43 to -0.62; p=0.001) mm Hg; body mass index (14 trials), 0.13 (-0.26 to -0.01; p=0.04) kg/m2; serum total cholesterol (14 trials), -0.13 ( 0.19 to -0.07; p<0.001) mmol/L. There was no significant association between interventions with a reported theoretical basis and improved intervention outcomes. No association was observed between intervention intensity (number of sessions and intervention duration) and intervention outcomes. There was significant heterogeneity for some risk factor analyses, leading to uncertain validity of some pooled net changes. CONCLUSIONS: MHBC interventions delivered to CVD-free participants in primary care did not appear to have quantitatively important effects on CVD risk factors. Better reporting of interventions' rationale, content and delivery is essential to understanding their effectiveness. PMID- 28619781 TI - Perception of different formats of front-of-pack nutrition labels according to sociodemographic, lifestyle and dietary factors in a French population: cross sectional study among the NutriNet-Sante cohort participants. AB - OBJECTIVE: Four formats for a front-of-pack (FOP) nutrition label are currently considered in France: the Nutriscore (or 5-Colour Nutrition Label, developed by a public research team), the SENS (supported by retailers), Multiple Traffic Lights (MTL, currently used in UK) and a modified version of the Reference Intakes (mRIs, supported by industry). Our objective was to investigate the perception of these FOP labels, according to sociodemographic, lifestyle and dietary factors. DESIGN: Cross-sectional study. SETTING: Web-based French cohort. MAIN OUTCOME MEASURE: FOP labels perception. PARTICIPANTS: Participants in the NutriNet-Sante cohort received a specific questionnaire on the perceptions of the four label formats identified. Sociodemographic, lifestyle and dietary data (three 24-hours dietary records) were collected through self-administered questionnaires. Mutually exclusive clusters of FOP labels perception were identified through a multiple correspondence analysis followed by a hierarchical clustering procedure. Sociodemographic, lifestyle and dietary factors associated with the clusters were explored using multivariable multinomial logistic regression. All analyses were weighted according to 2009 French census data. RESULTS: Among the 21,702 participants in the study, the Nutriscore received the most important number of favourable responses on positive perception dimensions by participants, followed by MTL and SENS. The five identified clusters were characterised by marked preferences for Nutriscore (cluster 1, 43.2% of participants, crude n=9,399), MTL (cluster 2, 27.3%, crude n=6,163), SENS (cluster 3, 17.05%, crude n=3,546), mRIs (cluster 4, 7.31%, crude n=1,632) and none of the presented formats (cluster 5, 5.10%, crude n=965). The cluster 1 (Nutriscore) was associated with lower adherence to nutritional recommendations, while cluster 2 (MTL) was associated with younger age and higher level of education. CONCLUSION: The Nutriscore appears to have a wide reach in the population and to appeal to subjects with lower adherence to nutritional recommendations. PMID- 28619782 TI - What stage are low-income and middle-income countries (LMICs) at with patient safety curriculum implementation and what are the barriers to implementation? A two-stage cross-sectional study. AB - OBJECTIVES: The improvement of safety in healthcare worldwide depends in part on the knowledge, skills and attitudes of staff providing care. Greater patient safety content in health professional education and training programmes has been advocated internationally. While WHO Patient Safety Curriculum Guides (for Medical Schools and Multi-Professional Curricula) have been widely disseminated in low-income and middle-income countries (LMICs) over the last several years, little is known about patient safety curriculum implementation beyond high-income countries. The present study examines patient safety curriculum implementation in LMICs. METHODS: Two cross-sectional surveys were carried out. First, 88 technical officers in Ministries of Health and WHO country offices were surveyed to identify the pattern of patient safety curricula at country level. A second survey followed that gathered information from 71 people in a position to provide institution-level perspectives on patient safety curriculum implementation. RESULTS: The majority, 69% (30/44), of the countries were either considering whether to implement a patient safety curriculum or actively planning, rather than actually implementing, or embedding one. Most organisations recognised the need for patient safety education and training and felt a safety curriculum was compatible with the values of their organisation; however, important faculty level barriers to patient safety curriculum implementation were identified. Key structural markers, such as dedicated financial resources and relevant assessment tools to evaluate trainees' patient safety knowledge and skills, were in place in fewer than half of organisations studied. CONCLUSIONS: Greater attention to patient safety curriculum implementation is needed. The barriers to patient safety curriculum implementation we identified in LMICs are not unique to these regions. We propose a framework to act as a global standard for patient safety curriculum implementation. Educating leaders through the system in order to embed patient safety culture in education and clinical settings is a critical first step. PMID- 28619783 TI - Community gardening, community farming and other local community-based gardening interventions to prevent overweight and obesity in high-income and middle-income countries: protocol for a systematic review. AB - INTRODUCTION: The worldwide prevalence of overweight/obesity has continued to rise over the last decades. To reverse this trend, public health authorities are exploring cost-effective interventions, especially in high-income and middle income countries. Community gardening offers a unique opportunity for individuals to enhance physical activity levels and improve their diet. However, synthesised evidence on the short-term or long-term effectiveness and on the costs of community gardening interventions to prevent overweight/obesity remains limited. Therefore, this review will investigate: (1) the effectiveness of voluntary participation in community gardening compared with no or a control intervention on overweight/obesity and associated health outcomes, (2) effects on different subgroups of populations and (3) the costs of community gardening interventions. METHODS AND ANALYSIS: We will conduct a systematic review, limited to evaluations of community gardening interventions with controlled quantitative and interrupted time series designs. To identify relevant articles, we will systematically search 12 academic and 5 grey literature databases, as well as 2 trial registers and 6 websites. Articles will then be assessed for eligibility based on a predefined set of criteria. At least two independent reviewers will assess each article for relevance, before evaluating the methodological quality and potential bias of the studies. Data relevant to the objectives of this review will be extracted and cross-validated. Any disagreements will be mediated by a third reviewer. If feasible, meta-analyses of primary outcomes (overweight/obesity, physical activity, food intake, energy intake) will be conducted. We will use the Grading of Recommendations Assessment, Development and Evaluation method to assess the overall quality of evidence. ETHICS AND DISSEMINATION: For this review, no ethical approval is required as we will only extract and analyse secondary data. We aim to submit the final review manuscript to an open access journal for publication and disseminate results via conferences and social media. TRIAL REGISTRATION NUMBER: International Prospective Register of Systematic Reviews (PROSPERO)(CRD42017043696). PMID- 28619785 TI - Correction: Comparison of acupuncture pretreatment followed by letrozole versus letrozole alone on live birth in anovulatory infertile women with polycystic ovary syndrome: a study protocol for a randomised controlled trial. PMID- 28619786 TI - Correction. PMID- 28619784 TI - Relationships between socioeconomic position and objectively measured sedentary behaviour in older adults in three prospective cohorts. AB - OBJECTIVES: To investigate whether sedentary behaviour in older adults is associated with a systematic and comprehensive range of socioeconomic position (SEP) measures across the life course. SEP measures included prospective measures of social class, income, educational qualifications and parental social class and contemporaneous measures of area deprivation. SETTING: Glasgow and the surrounding (West of Scotland) combined with Edinburgh and the surrounding area (the Lothians). PARTICIPANTS: Community-dwelling adults aged around 79, 83, and 64 years from, respectively, the Lothian Birth Cohort 1936 (LBC1936) (n=271) and the 1930s (n=119) and 1950s (n=310) cohorts of the West of Scotland Twenty-07 study. PRIMARY OUTCOME MEASURE: Sedentary behaviour was measured objectively using an activPAL activity monitor worn continuously for 7 days and used to calculate percentage of waking time spent sedentary. RESULTS: Among retired participants, for most cohort and SEP combinations, greater social disadvantage was associated with increased sedentary time. For example, in the Twenty-07 1930s cohort, those most deprived on the Carstairs measure spent 6.5% (95% CI 0.3 to 12.7) more of their waking time sedentary than the least deprived. However, for employed people, the relationship between SEP and sedentary behaviour was much weaker. For example, in terms of social class differences, among the retired, the most disadvantaged spent 5.7% more waking time sedentary (95% CI 2.6% to 87%), whereas among the employed, there was effectively no difference (-0.5%; 95% CI 9.0 to 8.0). CONCLUSIONS: Diverse SEP measures were associated with increased sedentary behaviour among retired people. There was little evidence for a relationship between SEP measures and sedentary behaviour among employed older adults. Prior to retirement, the constraints of the workplace may be masking effects that are only apparent at weekends. PMID- 28619787 TI - Draft Genome Sequences of Four Pseudomonas aeruginosa Isolates Obtained from Patients with Chronic Obstructive Pulmonary Disease. AB - Patients suffering chronic obstructive pulmonary disease are frequently infected by Pseudomonas aeruginosa Nevertheless, the number of sequenced isolates causing this type of infection is low. Here, we present the draft genomes of four P. aeruginosa isolates obtained from patients presenting chronic obstructive pulmonary disease. PMID- 28619788 TI - Complete Genome Sequence of Edwardsiella ictaluri Isolate RUSVM-1 Recovered from Nile Tilapia (Oreochromis niloticus) in the Western Hemisphere. AB - Edwardsiella ictaluri is a Gram-negative bacillus that has recently been implicated in disease outbreaks in tilapia and zebrafish. We report here the complete and annotated genome sequence of an isolate from a Nile tilapia (Oreochromis niloticus), which contains a chromosome of 3,630,639 bp and two plasmids. PMID- 28619789 TI - First Complete Squash leaf curl China virus Genomic Segment DNA-A Sequence from East Timor. AB - We present here the first complete Squash leaf curl China virus (SLCCV) genomic segment DNA-A sequence from East Timor. It was isolated from a pumpkin plant. When compared with 15 complete SLCCV DNA-A genome sequences from other world regions, it most resembled the Malaysian isolate MC1 sequence. PMID- 28619790 TI - Complete Genome Sequence of Acinetobacter calcoaceticus CA16, a Bacterium Capable of Degrading Diesel and Lignin. AB - We report here the complete assembled genome sequence of Acinetobacter calcoaceticus CA16, which is capable of utilizing diesel and lignin as a sole carbon source. CA16 contains a 4,110,074-bp chromosome and a 5,920-bp plasmid. The assembled sequences will help elucidate potential metabolic pathways and mechanisms responsible for CA16's hydrocarbon degradation ability. PMID- 28619791 TI - Draft Genome Sequence of Aeromonas hydrophila Strain BSK-10 (Serotype O97), Isolated from Carassius carassius with Motile Aeromonad Septicemia in China. AB - We report here a draft genome sequence of Aeromonas hydrophila strain BSK-10, belonging to serotype O97, isolated from crucian carp (Carassius carassius) with motile aeromonad septicemia in Zhejiang, China. The assembly resulted in 34 scaffolds totaling approximately 4.97 Mb, with an average G+C content of 60.97% and 4,594 predicted coding genes. PMID- 28619792 TI - Whole-Genome Sequence of Bacillus stratosphericus Strain 5Co, Isolated from Lichen Usnea florida in Central Florida, United States, with High Tolerance to Salt and Heavy Metal. AB - Bacillus stratosphericus strain 5Co was isolated from lichen Usnea florida in central Florida, United States. Here, we report a draft genome sequence of this strain, which consists of 159 contigs spanning 3,628,496 bp, with a G+C content of 41.3% and comprises 3,729 predicted coding sequences. PMID- 28619793 TI - Draft Genome Sequence of Methylocapsa palsarum NE2T, an Obligate Methanotroph from Subarctic Soil. AB - Methylocapsa palsarum NE2T is an aerobic, mildly acidophilic, obligate methanotroph. Similar to other Methylocapsa species, it possesses only a particulate methane monooxygenase and is capable of atmospheric nitrogen fixation. The genome sequence of this typical inhabitant of subarctic wetlands and soils also contains genes indicative of aerobic anoxygenic photosynthesis. PMID- 28619794 TI - Complete Genome Sequence of Biocontroller Bacillus velezensis Strain JTYP2, Isolated from Leaves of Echeveria laui. AB - Bacillus velezensis JTYP2 was isolated from the leaves of Echeveria laui in Qingzhou, China, and may control some of the fungal pathogens of the plant. Here, we present the complete genome sequence of B. velezensis JTYP2. Several gene clusters related to its biosynthesis of antimicrobial compounds were predicted. PMID- 28619795 TI - Genome Sequence of Leuconostoc citreum DmW_111, Isolated from Wild Drosophila. AB - Isolates of the lactic acid bacterium Leuconostoc citreum are a major part of fermentation processes, especially in Korean kimchi. Here, we present the genome of L. citreum DmW_111, isolated from wild Drosophila melanogaster; analysis of this genome will expand the diversity of genome sequences for non-Lactobacillus spp. isolated from D. melanogaster. PMID- 28619796 TI - Draft Genome Sequence of Campylobacter jejuni CAM970 and C. coli CAM962, Associated with a Large Outbreak of Foodborne Illness in Fukuoka, Japan, in 2016. AB - Here, we report the draft genome sequences of Campylobacter jejuni CAM970 and C. coli CAM962, which were associated with a large outbreak of foodborne illness originating from undercooked chicken sushi in Fukuoka, Japan, in May 2016. Their genome sizes were 1,690,901 and 1,704,736 bp, with 22 and 23 rRNAs, 9 and 9 tRNAs, and 411* and 419* coverage for C. jejuni CAM970 and C. coli CAM962, respectively. PMID- 28619797 TI - Complete Genome Sequence of a Mycobacterium tuberculosis Strain Belonging to the East African-Indian Family in the Indo-Oceanic Lineage, Isolated in Hanoi, Vietnam. AB - The East African-Indian (EAI) family of Mycobacterium tuberculosis is an endemic group mainly observed in Southeast Asia. Here, we report the complete genome sequence of an M. tuberculosis strain isolated as a member of the EAI family in Hanoi, Vietnam, a country with a high incidence of tuberculosis. PMID- 28619798 TI - Metagenomes of Soil Samples from an Established Perennial Cropping System of Asparagus Treated with Biostimulants in Southern France. AB - We report here the metagenomes of soil samples from a perennial cropping system of asparagus that was treated with two biostimulants. Two treatments were compared to an untreated control. Control soil samples were taken at the beginning and at end of the experiment. PMID- 28619799 TI - Genome Sequence of Weissella cibaria DmW_103, Isolated from Wild Drosophila. AB - Lactic acid bacteria are commonly associated with Drosophila spp. Here, we report on the isolation of a strain of Weissella cibaria and the sequencing, assembly, and annotation of its genome. A total of 35 contigs were generated, with 2,349 coding sequences found. PMID- 28619800 TI - Complete Genome Sequences of the p1 Gene Type 2b and 2c Strains Mycoplasma pneumoniae KCH-402 and KCH-405. AB - Here, we present the complete genome sequences of Mycoplasma pneumoniae KCH-402 and KCH-405, which are p1 gene type 2b and 2c strains, respectively. These strains harbor variations in the orf6 gene, which encodes the cytadherence related proteins P40 and P90. PMID- 28619801 TI - Draft Genome Sequence of Sphingomonas sp. Strain Sph1(2015), Isolated from a Fouled Membrane Filter Used To Produce Drinking Water. AB - We report here the high-quality draft genome sequence of Sphingomonas sp. strain Sph1(2015), isolated from a fouled reverse osmosis membrane used for the production of high-quality drinking water. The draft sequence provides insights into the modus operandi of this strain to form biofilms on membrane surfaces. This knowledge offers tools to develop novel antifouling strategies. PMID- 28619802 TI - Draft Genome Sequences of Extended-Spectrum-Beta-Lactamase-Producing Morganella morganii Strains AA1 and AV1, Isolated from a Freshwater Lake and Eicchorniacrassipes Roots. AB - Two strains of Morganella morganii, AA1 and AV1, were isolated from freshwater and Eicchornia crassipes roots, respectively. Here, we report their draft genome sequences, which are ~3.6 Mb and have 51% G+C content. The predicted coding sequences (3,259 for strain AA1 and 3,345 for strain AV1) encode beta-lactamases, transpeptidases, and penicillin-binding proteins. PMID- 28619803 TI - Complete Genome Sequence of the Photoautotrophic and Bacteriochlorophyll e Synthesizing Green Sulfur Bacterium Chlorobaculum limnaeum DSM 1677T. AB - Chlorobaculum limnaeum DSM 1677T is a mesophilic, brown-colored, chlorophototrophic green sulfur bacterium that produces bacteriochlorophyll e and the carotenoid isorenieratene as major pigments. This bacterium serves as a model organism in molecular research on photosynthesis, sulfur metabolism, and bacteriochlorophyll biosynthesis. We report here the complete genome sequence. PMID- 28619804 TI - Permanent Draft Genome Sequence for Frankia sp. Strain Cc1.17, a Nitrogen-Fixing Actinobacterium Isolated from Root Nodules of Colletia cruciata. AB - Frankia sp. strain Cc1.17 is a member of the Frankia lineage 3, the organisms of which are able to reinfect plants of the Eleagnaceae, Rhamnaceae, and Myricaceae families and the genera Gynmnostoma and Alnus Here, we report the 8.4-Mbp draft genome sequence, with a G+C content of 72.14% and 6,721 candidate protein-coding genes. PMID- 28619805 TI - Complete Genome Sequences of Two Human Oral Microbiome Commensals, Streptococcus salivarius ATCC 25975 and S. salivarius ATCC 27945. AB - Streptococcus salivarius strains are significant contributors to the human oral microbiome. Some possess unique fimbriae that give them the ability to coaggregate and colonize particular oral structures. We present here the complete genomes of Streptococcus salivarius Lancefield K-/K+ strains ATCC 25975 and ATCC 27945, which can and cannot, respectively, produce fimbriae. PMID- 28619806 TI - Draft Genome Sequence of Geobacter pelophilus Strain Dfr2, a Ferric Iron-Reducing Bacterium. AB - Here, we report a draft genome sequence of Geobacter pelophilus strain Dfr2, a ferric iron-reducing bacterium. This genome information will further our understanding of the mechanisms underlying electron transfer from microorganisms to ferric iron oxides. PMID- 28619807 TI - Genome Sequence of Prosthecochloris sp. Strain HL-130-GSB from the Phylum Chlorobi. AB - The genome of the green sulfur bacterium Prosthecochloris sp. strain HL-130-GSB, isolated from a cyanobacterial mat obtained from Hot Lake, a saline meromictic lake in Washington, USA, comprises 2,437,774 bp in a single contig. The genome is predicted to encode 2,565 proteins and contain 47 tRNA genes and 2 rRNA operons. PMID- 28619808 TI - First Insights into the Genome Sequence of Clostridium oryzae DSM 28571, Isolated from the Soil of a Japanese Rice Field. AB - Clostridium oryzae was originally isolated from the soil of a Japanese rice field. C. oryzae represents a novel species within the genus Clostridium and is associated with anaerobic rice straw degradation. Here, we present the draft genome sequence of C. oryzae DSM 28571 (5.076 Mbp), containing 4,590 predicted protein-coding genes. PMID- 28619809 TI - Draft Genome Sequence of Pseudoruegeria sp. SK021, a Representative of the Marine Roseobacter Group, Isolated from North Sea Sediment. AB - Pseudoruegeria sp. SK021 is a member of the Roseobacter group, isolated under aerobic conditions from North Sea sediment. The draft genome comprises 3.95 Mb and contains 3,747 protein-coding sequences. Although the strain is nonmotile under laboratory conditions, the entire set of genes for the formation of a flagellar apparatus was found. PMID- 28619810 TI - Complete Genome Sequence of the Campylobacter cuniculorum Type Strain LMG 24588. AB - Campylobacter cuniculorum is a thermotolerant species isolated from farmed rabbits (Oryctolagus cuniculus). Although C. cuniculorum is highly prevalent in rabbits farmed for human consumption, the pathogenicity of this organism in humans is still unknown. This study describes the whole-genome sequence of the C. cuniculorum type strain LMG 24588 (=CCUG 56289T). PMID- 28619811 TI - Full-Genome Sequence of Listeria monocytogenes Strain H34, Isolated from a Newborn with Sepsis in Uruguay. AB - The foodborne pathogen Listeria monocytogenes causes severe disease mainly in the vulnerable populations of the young, old, pregnant, and immunocompromised. Here, we present the genome sequence of L. monocytogenes H34, a serotype 1/2b, lineage I, sequence type 489 (ST489) strain, isolated from a neonatal sepsis case in Uruguay. PMID- 28619812 TI - Draft Genome Sequences of Six Enterococcus faecalis Strains Isolated from Malaysian Clinical and Environmental Origins. AB - Enterococcus faecalis is known to cause a variety of nosocomial infections, including urinary tract infections. Antibiotic resistance and virulence properties in this species are of public concern. The draft genome sequences of six E. faecalis strains isolated from clinical and environmental sources in Malaysia are presented here. PMID- 28619813 TI - Complete Genome Sequences of the Endophytic Streptomyces sp. Strains LUP30 and LUP47B, Isolated from Lucerne Plants. AB - The complete genome sequences of two endophytic Streptomyces sp. strains, LUP30 and LUP47B, were analyzed. These strains were isolated from surface-sterilized roots of lucerne plants from South Australia and were found to promote the growth of the rhizobial partner in vitro and significantly increased nodulation and nitrogen fixation in lucerne plants. PMID- 28619814 TI - Genome Sequence of the Saprophytic Ascomycete Epicoccumnigrum Strain ICMP 19927, Isolated from New Zealand. AB - Epicoccum nigrum is a common mitosporic fungus of the Didymellaceae (Ascomycota) family known for the production of numerous secondary metabolites. Here, we present the 34.7-Mbp draft genome sequence of strain ICMP 19927 assembled from a range of short-insert and long-insert Illumina libraries. PMID- 28619815 TI - Complete Genome Sequence of a Legionella longbeachae Serogroup 1 Strain Isolated from a Patient with Legionnaires' Disease. AB - Legionella longbeachae serogroup 1, predominantly found in soil and composted plant material, causes the majority of cases of Legionnaires' disease (LD) in New Zealand. Here, we report the complete genome sequence of an L. longbeachae serogroup 1 (sg1) isolate derived from a patient hospitalized with LD in Christchurch, New Zealand. PMID- 28619816 TI - Correction for Vazquez-Hernandez et al., "Draft Genome Sequence of Streptomyces scabrisporus NF3, an Endophyte Isolated from Amphipterygium adstringens". PMID- 28619817 TI - Synergism between canoe and scribble mutations causes tumor-like overgrowth via Ras activation in neural stem cells and epithelia. AB - Over the past decade an intriguing connection between asymmetric cell division, stem cells and tumorigenesis has emerged. Neuroblasts, which are the neural stem cells of the Drosophila central nervous system, divide asymmetrically and constitute an excellent paradigm for investigating this connection further. Here we show that the simultaneous loss of the asymmetric cell division regulators Canoe (afadin in mammals) and Scribble in neuroblast clones leads to tumor-like overgrowth through both a severe disruption of the asymmetric cell division process and canoe loss-mediated Ras-PI3K-Akt activation. Moreover, canoe loss also interacts synergistically with scribble loss to promote overgrowth in epithelial tissues, here just by activating the Ras-Raf-MAPK pathway. discs large 1 and lethal (2) giant larvae, which are functionally related to scribble, contribute to repress the Ras-MAPK signaling cascade in epithelia. Hence, our work uncovers novel cooperative interactions between all these well-conserved tumor suppressors that ensure tight regulation of the Ras signaling pathway. PMID- 28619818 TI - Antagonistic regulation of the second mitotic wave by Eyes absent-Sine oculis and Combgap coordinates proliferation and specification in the Drosophila retina. AB - The transition from proliferation to specification is fundamental to the development of appropriately patterned tissues. In the developing Drosophila eye, Eyes absent (Eya) and Sine oculis (So) orchestrate the progression of progenitor cells from asynchronous cell division to G1 arrest and neuronal specification at the morphogenetic furrow. Here, we uncover a novel role for Eya and So in promoting cell cycle exit in the second mitotic wave (SMW), a synchronized, terminal cell division that occurs several hours after passage of the furrow. We show that Combgap (Cg), a zinc-finger transcription factor, antagonizes Eya-So function in the SMW. Based on the ability of Cg to attenuate Eya-So transcriptional output in vivo and in cultured cells and on meta analysis of their chromatin occupancy profiles, we speculate that Cg limits Eya-So activation of select target genes posterior to the furrow to ensure properly timed mitotic exit. Our work supports a model in which context-specific modulation of transcriptional activity enables Eya and So to promote both entry into and exit from the cell cycle in a distinct spatiotemporal sequence. PMID- 28619819 TI - Yorkie and Hedgehog independently restrict BMP production in escort cells to permit germline differentiation in the Drosophila ovary. AB - Multiple signaling pathways guide the behavior and differentiation of both germline stem cells (GSCs) and somatic follicle stem cells (FSCs) in the Drosophila germarium, necessitating careful control of signal generation, range and responses. Signal integration involves escort cells (ECs), which promote differentiation of the GSC derivatives they envelop, provide niche signals for FSCs and derive directly from FSCs in adults. Hedgehog (Hh) signaling induces the Hippo pathway effector Yorkie (Yki) to promote proliferation and maintenance of FSCs, but Hh also signals to ECs, which are quiescent. Here, we show that in ECs both Hh and Yki limit production of BMP ligands to allow germline differentiation. Loss of Yki produced a more severe germarial phenotype than loss of Hh signaling and principally induced a different BMP ligand. Moreover, Yki activity reporters and epistasis tests showed that Yki does not mediate the key actions of Hh signaling in ECs. Thus, both the coupling and output of the Hh and Yki signaling pathways differ between FSCs and ECs despite their proximity and the fact that FSCs give rise directly to ECs. PMID- 28619820 TI - SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development. AB - Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SoxF binding sites established a clear requirement for members of this group of transcription factors (SOX7, SOX17 and SOX18) to drive the activity of these enhancers in vivo Endogenous deletion of the notch1b enhancer led to a significant loss of arterial connections to the dorsal aorta in Notch pathway deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for NOTCH1 and notch1b enhancer activity and for correct endogenous transcription of these genes. These findings position SoxF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates. PMID- 28619821 TI - Convergence of signaling pathways underlying habenular formation and axonal outgrowth in zebrafish. AB - The habenular nuclei are a conserved integrating center in the vertebrate epithalamus, where they modulate diverse behaviors. Despite their importance, our understanding of habenular development is incomplete. Time-lapse imaging and fate mapping demonstrate that the dorsal habenulae (dHb) of zebrafish are derived from dbx1b-expressing (dbx1b+ ) progenitors, which transition into cxcr4b-expressing neuronal precursors. The precursors give rise to differentiated neurons, the axons of which innervate the midbrain interpeduncular nucleus (IPN). Formation of the dbx1b+ progenitor population relies on the activity of the Shh, Wnt and Fgf signaling pathways. Wnt and Fgf function additively to generate dHb progenitors. Surprisingly, Wnt signaling also negatively regulates fgf8a, confining expression to a discrete dorsal diencephalic domain. Moreover, the Wnt and Fgf pathways have opposing roles in transcriptional regulation of components of the Cxcr4-chemokine signaling pathway. The chemokine pathway, in turn, directs the posterior outgrowth of dHb efferents toward the IPN and, when disrupted, results in ectopic, anteriorly directed axonal projections. The results define a signaling network underlying the generation of dHb neurons and connectivity with their midbrain target. PMID- 28619822 TI - COP9 signalosome subunits protect Capicua from MAPK-dependent and -independent mechanisms of degradation. AB - The COP9 signalosome removes Nedd8 modifications from the Cullin subunits of ubiquitin ligase complexes, reducing their activity. Here, we show that mutations in the Drosophila COP9 signalosome subunit 1b (CSN1b) gene increase the activity of ubiquitin ligases that contain Cullin 1. Analysis of CSN1b mutant phenotypes revealed a requirement for the COP9 signalosome to prevent ectopic expression of Epidermal growth factor receptor (EGFR) target genes. It does so by protecting Capicua, a transcriptional repressor of EGFR target genes, from EGFR pathway dependent ubiquitylation by a Cullin 1/SKP1-related A/Archipelago E3 ligase and subsequent proteasomal degradation. The CSN1b subunit also maintains basal Capicua levels by protecting it from a separate mechanism of degradation that is independent of EGFR signaling. As a suppressor of tumor growth and metastasis, Capicua may be an important target of the COP9 signalosome in cancer. PMID- 28619824 TI - Setd1b, encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program. AB - Germ cell development involves major reprogramming of the epigenome to prime the zygote for totipotency. Histone 3 lysine 4 (H3K4) methylations are universal epigenetic marks mediated in mammals by six H3K4 methyltransferases related to fly Trithorax, including two yeast Set1 orthologs: Setd1a and Setd1b. Whereas Setd1a plays no role in oogenesis, we report that Setd1b deficiency causes female sterility in mice. Oocyte-specific Gdf9-iCre conditional knockout (Setd1bGdf9 cKO) ovaries develop through all stages; however, follicular loss accumulated with age and unfertilized metaphase II (MII) oocytes exhibited irregularities of the zona pellucida and meiotic spindle. Most Setd1bGdf9 cKO zygotes remained in the pronuclear stage and displayed polyspermy in the perivitelline space. Expression profiling of Setd1bGdf9 cKO MII oocytes revealed (1) that Setd1b promotes the expression of the major oocyte transcription factors including Obox1, 2, 5, 7, Meis2 and Sall4; and (2) twice as many mRNAs were upregulated than downregulated, suggesting that Setd1b also promotes the expression of negative regulators of oocyte development with multiple Zfp-KRAB factors implicated. Together, these findings indicate that Setd1b serves as maternal effect gene through regulation of the oocyte gene expression program. PMID- 28619825 TI - SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation. AB - Sperm differentiation requires specific protein transport for correct sperm tail formation and head shaping. A transient microtubular structure, the manchette, appears around the differentiating spermatid head and serves as a platform for protein transport to the growing tail. Sperm flagellar 2 (SPEF2) is known to be essential for sperm tail development. In this study we investigated the function of SPEF2 during spermatogenesis using a male germ cell-specific Spef2 knockout mouse model. In addition to defects in sperm tail development, we observed a duplication of the basal body and failure in manchette migration resulting in an abnormal head shape. We identified cytoplasmic dynein 1 and GOLGA3 as novel interaction partners for SPEF2. SPEF2 and dynein 1 colocalize in the manchette and the inhibition of dynein 1 disrupts the localization of SPEF2 to the manchette. Furthermore, the transport of a known SPEF2-binding protein, IFT20, from the Golgi complex to the manchette was delayed in the absence of SPEF2. These data indicate a possible novel role of SPEF2 as a linker protein for dynein 1-mediated cargo transport along microtubules. PMID- 28619823 TI - Sin3a regulates epithelial progenitor cell fate during lung development. AB - Mechanisms that regulate tissue-specific progenitors for maintenance and differentiation during development are poorly understood. Here, we demonstrate that the co-repressor protein Sin3a is crucial for lung endoderm development. Loss of Sin3a in mouse early foregut endoderm led to a specific and profound defect in lung development with lung buds failing to undergo branching morphogenesis and progressive atrophy of the proximal lung endoderm with complete epithelial loss at later stages of development. Consequently, neonatal pups died at birth due to respiratory insufficiency. Further analysis revealed that loss of Sin3a resulted in embryonic lung epithelial progenitor cells adopting a senescence-like state with permanent cell cycle arrest in G1 phase. This was mediated at least partially through upregulation of the cell cycle inhibitors Cdkn1a and Cdkn2c. At the same time, loss of endodermal Sin3a also disrupted cell differentiation of the mesoderm, suggesting aberrant epithelial-mesenchymal signaling. Together, these findings reveal that Sin3a is an essential regulator for early lung endoderm specification and differentiation. PMID- 28619826 TI - A toolkit for GFP-mediated tissue-specific protein degradation in C. elegans. AB - Proteins that are essential for embryo production, cell division and early embryonic events are frequently reused later in embryogenesis, during organismal development or in the adult. Examining protein function across these different biological contexts requires tissue-specific perturbation. Here, we describe a method that uses expression of a fusion between a GFP-targeting nanobody and a SOCS-box containing ubiquitin ligase adaptor to target GFP-tagged proteins for degradation. When combined with endogenous locus GFP tagging by CRISPR-Cas9 or with rescue of a null mutant with a GFP fusion, this approach enables routine and efficient tissue-specific protein ablation. We show that this approach works in multiple tissues - the epidermis, intestine, body wall muscle, ciliated sensory neurons and touch receptor neurons - where it recapitulates expected loss-of function mutant phenotypes. The transgene toolkit and the strain set described here will complement existing approaches to enable routine analysis of the tissue specific roles of C. elegans proteins. PMID- 28619828 TI - The Association of Telomere Length in Peripheral Blood Cells with Cancer Risk: A Systematic Review and Meta-analysis of Prospective Studies. AB - The association between telomere length (TL) in peripheral blood cells and cancer risk remains inconclusive. We carried out a meta-analysis on prospective studies. The study-specific RR estimates were first transformed to a common comparable scale and then were pooled by a random-effects model. The dataset was composed of 13,894 cases and 71,672 controls from 28 studies in 25 articles. In the comparison of the longest versus shortest third of TL, we observed a marginally positive association between longer TL and higher risk of total cancers [OR = 1.086; 95% confidence interval (CI), 0.952-1.238]. Subgroup analyses showed that the association was stronger in lung cancer (n = 3; OR = 1.690; 95% CI, 1.253 2.280), in men (n = 6; OR = 1.302; 95% CI, 1.120-1.514) and in studies with more precise methods for DNA extraction (phenol-chloroform, salting-out or magnetic bead, n = 6, OR = 1.618; 95% CI, 1.320-1.985) and TL measurement (multiplex Q PCR, n = 8; OR = 1.439; 95% CI, 1.118-1.852). Our meta-analysis suggested longer TL in peripheral blood cells is a likely risk factor for lung cancer or cancers in men. Accurate DNA extraction and TL measurement methods make it more liable to find significant associations between TL and cancer risk and thus should be taken into consideration in future epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 26(9); 1381-90. (c)2017 AACR. PMID- 28619827 TI - Architectural protein Pita cooperates with dCTCF in organization of functional boundaries in Bithorax complex. AB - Boundaries in the Bithorax complex (BX-C) of Drosophila delimit autonomous regulatory domains that drive parasegment-specific expression of homeotic genes. BX-C boundaries have two crucial functions: they must block crosstalk between adjacent regulatory domains and at the same time facilitate boundary bypass. The C2H2 zinc-finger protein Pita binds to several BX-C boundaries, including Fab-7 and Mcp To study Pita functions, we have used a boundary replacement strategy by substituting modified DNAs for the Fab-7 boundary, which is located between the iab-6 and iab-7 regulatory domains. Multimerized Pita sites block iab-6<->iab-7 crosstalk but fail to support iab-6 regulation of Abd-B (bypass). In the case of Fab-7, we used a novel sensitized background to show that the two Pita-binding sites contribute to its boundary function. Although Mcp is from BX-C, it does not function appropriately when substituted for Fab-7: it blocks crosstalk but does not support bypass. Mutation of the Mcp Pita site disrupts blocking activity and also eliminates dCTCF binding. In contrast, mutation of the Mcp dCTCF site does not affect Pita binding, and this mutant boundary retains partial function. PMID- 28619829 TI - Germline Genetic Variants and Lung Cancer Survival in African Americans. AB - Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases.Methods: Incident non-small cell lung cancer cases (N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies (N = 316 and 298) were used for replication.Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54-0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71-0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33 0.66).Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene-environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival.Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288-95. (c)2017 AACR. PMID- 28619831 TI - Stool DNA Test of Methylated Syndecan-2 for the Early Detection of Colorectal Neoplasia. AB - Background: Although the incidence of colorectal cancer is steadily increasing, screening for colorectal cancer with conventional approaches is not routinely performed in China. Noninvasive screening methods are attractive options to resolve this issue. Syndecan-2 (SDC2) is frequently methylated in colorectal cancer. However, the value of a stool test of methylated SDC2 for the detection of colorectal cancer is unknown.Methods: Methylation status of SDC2 was tested in cell lines and 398 colorectal tissue samples and further evaluated with 497 stool samples, including 196 from colorectal cancer patients, 122 from adenoma patients, and 179 from normal individuals, using real-time methylation-specific PCR. The impacts of one quantitative partial stool sampling device and 17 potentially interfering substances on the performance of fecal methylated SDC2 were also analyzed. SDC2 expression was also measured.Results:SDC2 methylation level was higher in 96.8% (120/124) of colorectal cancer tissues compared with paired adjacent normal epithelia. Stool test of methylated SDC2 detected 81.1% (159/196) of colorectal cancer and 58.2% (71/122) of adenomas at a specificity of 93.3% (167/179). No significant difference was found between partial and whole stool collection on colorectal cancer detection (P > 0.05, R2 = 0.80). Among 17 interfering substances, only berberine at high concentrations inhibited fecal detection of methylated SDC2SDC2 was overexpressed in colorectal cancer tissues compared with normal epithelia.Conclusions: Fecal methylated SDC2 is a valuable biomarker for the noninvasive detection of colorectal neoplasms.Impact: Stool DNA test of methylated SDC2 would serve as an alternative method for screening colorectal neoplasms. Cancer Epidemiol Biomarkers Prev; 26(9); 1411-9. (c)2017 AACR. PMID- 28619830 TI - Differential and Joint Effects of Metformin and Statins on Overall Survival of Elderly Patients with Pancreatic Adenocarcinoma: A Large Population-Based Study. AB - Background: Published evidence indicates that individual use of metformin and statin is associated with reduced cancer mortality. However, their differential and joint effects on pancreatic cancer survival are inconclusive.Methods: We identified a large population-based cohort of 12,572 patients ages 65 years or older with primary pancreatic ductal adenocarcinoma (PDAC) diagnosed between 2008 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. Cox proportional hazards models with time-varying covariates adjusted for propensity scores were used to assess the association while controlling for potential confounders.Results: Of 12,572 PDAC patients, 950 (7.56%) had used metformin alone, 4,506 (35.84%) had used statin alone, and 2,445 (19.45%) were dual users. Statin use was significantly associated with improved overall survival [HR, 0.94; 95% confidence interval (CI), 0.90-0.98], and survival was more pronounced in postdiagnosis statin users (HR, 0.69; 95% CI, 0.56-0.86). Metformin use was not significantly associated with overall survival (HR, 1.01; 95% CI, 0.94-1.09). No beneficial effect was observed for dual users (HR, 1.00; 95% CI, 0.95-1.05).Conclusions: Our findings suggest potential benefits of statins on improving survival among elderly PDAC patients; further prospective studies are warranted to corroborate the putative benefit of statin therapy in pancreatic cancer.Impact: Although more studies are needed to confirm our findings, our data add to the body of evidence on potential anticancer effects of statins. Cancer Epidemiol Biomarkers Prev; 26(8); 1225-32. (c)2017 AACR. PMID- 28619833 TI - CT Angiography ASPECTS Predicts Outcome Much Better Than Noncontrast CT in Patients with Stroke Treated Endovascularly. AB - BACKGROUND AND PURPOSE: Noncontrast CT ASPECTS has been investigated as a predictor of outcome in patients with acute ischemic stroke. Our purpose was to investigate whether CTA source images are a better predictor of clinical and radiologic outcomes than NCCT ASPECTS in candidates for endovascular stroke therapy. MATERIALS AND METHODS: CT scans of patients (n = 124) were independently evaluated by 2 readers for baseline NCCT and CTA source image ASPECTS and for follow-up ASPECTS. An mRS of <=2 at 3 months was considered a favorable outcome. Receiver operating characteristic curve analysis was used to assess the ability of NCCT and CTA source image ASPECTS to identify patients with favorable outcomes. A stepwise multiple regression analysis was performed to find independent predictors of outcome. RESULTS: Baseline CTA source image ASPECTS correlated better than NCCT ASPECTS with follow-up ASPECTS (r = 0.76 versus r = 0.51; P for comparison of the 2 coefficients < .001). Receiver operating characteristic curve analysis showed that baseline CTA source image ASPECTS compared with NCCT ASPECTS can better identify patients with favorable outcome (CTA source image area under the curve = 0.83; 95% CI, 0.76-0.91; NCCT area under the curve = 0.67; 95% CI, 0.58-0.77; P < .001). Finally, the stepwise regression analysis showed that lower age, good recanalization, lower time to recanalization, and good baseline CTA source image ASPECTS, not NCCT ASPECTS, were independent predictors of favorable outcome. CONCLUSIONS: CTA source image ASPECTS predicts outcome better than NCCT ASPECTS; this finding suggests CTA rather than NCCT as a main step in the decision-making process for patients with acute ischemic stroke. PMID- 28619832 TI - Excess Mortality among HIV-Infected Individuals with Cancer in the United States. AB - Background: Human immunodefieciency virus (HIV)-infected persons are living longer in the era of effective HIV treatment, resulting in an increasing cancer burden in this population. The combined effects of HIV and cancer on mortality are incompletely understood.Methods: We examined whether individuals with both HIV and cancer have excess mortality using data from the HIV/AIDS Cancer Match Study and the National Center for Health Statistics (1996-2010). We compared age, sex, and race-stratified mortality between people with and without HIV or one of the following cancers: lung, breast, prostate, colorectum, anus, Hodgkin lymphoma, or non-Hodgkin lymphoma. We utilized additive Poisson regression models that included terms for HIV, cancer, and an interaction for their combined effect on mortality. We report the number of excess deaths per 1,000 person-years for models with a significant interaction (P < 0.05).Results: For all cancers examined except prostate cancer, at least one demographic subgroup of HIV infected cancer patients experienced significant excess mortality. Excess mortality was most pronounced at younger ages (30-49 years), with large excesses for males with lung cancer (white race: 573 per 1,000 person-years; non-white: 503) and non-Hodgkin lymphoma (white: 236; non-white: 261), and for females with Hodgkin lymphoma (white: 216; non-white: 136) and breast cancer (non-white: 107).Conclusions: In the era of effective HIV treatment, overall mortality in patients with both HIV and cancer was significantly higher than expected on the basis of mortality rates for each disease separately.Impact: These results suggest that HIV may contribute to cancer progression and highlight the importance of improved cancer prevention and care for the U.S. HIV population. Cancer Epidemiol Biomarkers Prev; 26(7); 1027-33. (c)2017 AACR. PMID- 28619835 TI - Regarding "What Is the Ideal Core Number for Ultrasonography-Guided Thyroid Biopsy of Cytologically Inconclusive Nodules?" PMID- 28619834 TI - Temporal and Spatial Variances in Arterial Spin-Labeling Are Inversely Related to Large-Artery Blood Velocity. AB - BACKGROUND AND PURPOSE: The relationship between extracranial large-artery characteristics and arterial spin-labeling MR imaging may influence the quality of arterial spin-labeling-CBF images for older adults with and without vascular pathology. We hypothesized that extracranial arterial blood velocity can explain between-person differences in arterial spin-labeling data systematically across clinical populations. MATERIALS AND METHODS: We performed consecutive pseudocontinuous arterial spin-labeling and phase-contrast MR imaging on 82 individuals (20-88 years of age, 50% women), including healthy young adults, healthy older adults, and older adults with cerebral small vessel disease or chronic stroke infarcts. We examined associations between extracranial phase contrast hemodynamics and intracranial arterial spin-labeling characteristics, which were defined by labeling efficiency, temporal signal-to-noise ratio, and spatial coefficient of variation. RESULTS: Large-artery blood velocity was inversely associated with labeling efficiency (P = .007), temporal SNR (P < .001), and spatial coefficient of variation (P = .05) of arterial spin-labeling, after accounting for age, sex, and group. Correction for labeling efficiency on an individual basis led to additional group differences in GM-CBF compared to correction using a constant labeling efficiency. CONCLUSIONS: Between-subject arterial spin-labeling variance was partially explained by extracranial velocity but not cross-sectional area. Choosing arterial spin-labeling timing parameters with on-line knowledge of blood velocity may improve CBF quantification. PMID- 28619836 TI - Risk Factor Analysis of Recanalization Timing in Coiled Aneurysms: Early versus Late Recanalization. AB - BACKGROUND AND PURPOSE: Long-term documentation of anatomic and angiographic characteristics pertaining to the timing of recanalization in coiled aneurysms has been insufficient. Our intent was to analyze and compare early and late-phase recanalization after coiling, identifying respective risk factors. MATERIALS AND METHODS: A total of 870 coiled saccular aneurysms were monitored for extended periods (mean, 30.8 +/- 8.3 months). Medical records and radiologic data were also reviewed, stratifying patients as either early (n = 128) or late (n = 52) recanalization or as complete occlusion (n = 690). Early recanalization was equated with confirmed recanalization within 6 months after the procedure, whereas late recanalization was defined as verifiable recanalization after imaging confirmation of complete occlusion at 6 months. A multinomial regression model served to assess potential risk factors, the reference point being early recanalization. RESULTS: Posterior circulation (P = .009), subarachnoid hemorrhage at presentation (P = .011), second attempt for recanalized aneurysm (P < .001), and aneurysm size >7 mm (P < .001) emerged as variables significantly linked with early recanalization (versus complete occlusion). Late (versus early) recanalization corresponded with aneurysms <=7 mm (P = .013), and in a separate subanalysis of lesions <=7 mm, aneurysms 4-7 mm showed a significant predilection for late recanalization (P = .008). However, the propensity for complete occlusion in smaller lesions (<=7 mm) increased as the size diminished. CONCLUSIONS: Although long-term complete occlusion after coiling was more likely in aneurysms <=7 mm, such lesions were more prone to late (versus early) recanalization, particularly those of 4-7 mm in size. Long-term follow-up imaging is thus appropriate in aneurysms >4 mm to detect late recanalization of those formerly demonstrating complete occlusion. PMID- 28619837 TI - Differentiation between Treatment-Induced Necrosis and Recurrent Tumors in Patients with Metastatic Brain Tumors: Comparison among 11C-Methionine-PET, FDG PET, MR Permeability Imaging, and MRI-ADC-Preliminary Results. AB - BACKGROUND AND PURPOSE: In patients with metastatic brain tumors after gamma knife radiosurgery, the superiority of PET using 11C-methionine for differentiating radiation necrosis and recurrent tumors has been accepted. To evaluate the feasibility of MR permeability imaging, it was compared with PET using 11C-methionine, FDG-PET, and DWI for differentiating radiation necrosis from recurrent tumors. MATERIALS AND METHODS: The study analyzed 18 lesions from 15 patients with metastatic brain tumors who underwent gamma knife radiosurgery. Ten lesions were identified as recurrent tumors by an operation. In MR permeability imaging, the transfer constant between intra- and extravascular extracellular spaces (/minute), extravascular extracellular space, the transfer constant from the extravascular extracellular space to plasma (/minute), the initial area under the signal intensity-time curve, contrast-enhancement ratio, bolus arrival time (seconds), maximum slope of increase (millimole/second), and fractional plasma volume were calculated. ADC was also acquired. On both PET using 11C-methionine and FDG-PET, the ratio of the maximum standard uptake value of the lesion divided by the maximum standard uptake value of the symmetric site in the contralateral cerebral hemisphere was measured (11C-methionine ratio and FDG ratio, respectively). The receiver operating characteristic curve was used for analysis. RESULTS: The area under the receiver operating characteristic curve for differentiating radiation necrosis from recurrent tumors was the best for the 11C-methionine ratio (0.90) followed by the contrast-enhancement ratio (0.81), maximum slope of increase (millimole/second) (0.80), the initial area under the signal intensity-time curve (0.78), fractional plasma volume (0.76), bolus arrival time (seconds) (0.76), the transfer constant between intra- and extravascular extracellular spaces (/minute) (0.74), extravascular extracellular space (0.68), minimum ADC (0.60), the transfer constant from the extravascular extracellular space to plasma (/minute) (0.55), and the FDG-ratio (0.53). A significant difference in the 11C-methionine ratio (P < .01), contrast enhancement ratio (P < .01), maximum slope of increase (millimole/second) (P < .05), and the initial area under the signal intensity-time curve (P < .05) was evident between radiation necrosis and recurrent tumor. CONCLUSIONS: The present study suggests that PET using 11C-methionine may be superior to MR permeability imaging, ADC, and FDG-PET for differentiating radiation necrosis from recurrent tumors after gamma knife radiosurgery for metastatic brain tumors. PMID- 28619838 TI - State of Practice: Endovascular Treatment of Acute Aneurysmal SAH in Germany. AB - BACKGROUND AND PURPOSE: Acute aneurysmal SAH is a severe disease that requires prompt treatment. Endovascular coiling and neurosurgical clipping are established treatment options. Our intention was to determine the state of current practice in acute aneurysmal SAH treatment in Germany, with emphasis on logistic and temporal aspects. MATERIALS AND METHODS: We interviewed 74 German university and nonuniversity hospitals with an anonymous questionnaire comprising 15 questions concerning the practice of treatment and diagnostics of acute aneurysmal SAH at their respective institutions. The response rate was 74% among all institutions (55/74); among university hospitals, 77%; and among nonuniversity hospitals, 72%. RESULTS: The majority of all aneurysms were treated endovascularly (66% of acute aneurysmal SAH, 66% of unruptured aneurysms). Treatment on weekends was provided by 100% of endovascular and 96% of neurosurgical facilities. Average patients with acute aneurysmal SAH were not treated during the night (98%). Seventy percent of endovascular and 78% of neurosurgical treatments were not started later than 8:00 pm. Fifty-three percent of hospitals would not start a same-day diagnostic angiography in acute aneurysmal SAH if treatment was scheduled for the following day. Eighty-two percent of all centers performed DSA after clipping to evaluate the treatment results. CONCLUSIONS: Our survey gives a detailed summary of the current practice of endovascular treatment and related topics in acute aneurysmal SAH in Germany and also reveals considerable changes in practice in comparison with older data. PMID- 28619839 TI - Transcranial Duplex Sonography Predicts Outcome following an Intracerebral Hemorrhage. AB - BACKGROUND AND PURPOSE: Several radiologic features such as hematoma volume are related to poor outcome following an intracerebral hemorrhage and can be measured with transcranial duplex sonography. We sought to determine the prognostic value of transcranial duplex sonography in patients with intracerebral hemorrhage. MATERIALS AND METHODS: We conducted a prospective study of patients diagnosed with spontaneous intracerebral hemorrhage. Transcranial duplex sonography examinations were performed within 2 hours of baseline CT, and we recorded the following variables: hematoma volume, midline shift, third ventricle and lateral ventricle diameters, and the pulsatility index in both MCAs. We correlated these data with the CT scans and assessed the prognostic value of the transcranial duplex sonography measurements. We assessed early neurologic deterioration during hospitalization and mortality at 1-month follow-up. RESULTS: We included 35 patients with a mean age of 72.2 +/- 12.8 years. Median baseline hematoma volume was 9.85 mL (interquartile range, 2.74-68.29 mL). We found good agreement and excellent correlation between transcranial duplex sonography and CT when measuring hematoma volume (r = 0.791; P < .001) and midline shift (r = 0.827; P < .001). The logistic regression analysis with transcranial duplex sonography measurements showed that hematoma volume was an independent predictor of early neurologic deterioration (OR, 1.078; 95% CI, 1.023-1.135) and mortality (OR, 1.089; 95% CI, 1.020-1.160). A second regression analysis with CT variables also demonstrated that hematoma volume was associated with early neurologic deterioration and mortality. When we compared the rating operation curves of both models, their predictive power was similar. CONCLUSIONS: Transcranial duplex sonography showed an excellent correlation with CT in assessing hematoma volume and midline shift in patients with intracerebral hemorrhage. Hematoma volume measured with transcranial duplex sonography was an independent predictor of poor outcome. PMID- 28619840 TI - Does 3T Fetal MRI Improve Image Resolution of Normal Brain Structures between 20 and 24 Weeks' Gestational Age? AB - BACKGROUND AND PURPOSE: Stronger magnetic fields have the potential to improve fetal image resolution. Our objective was to detect whether there was better anatomic resolution of brain structures in fetuses imaged with a 3T magnet compared with a 1.5T magnet. MATERIALS AND METHODS: Multiple cerebral and facial anatomic structures were retrospectively assessed in 28 fetal MR imaging scans with normal findings (12 at 3T and 16 at 1.5T) with a 0-3 grading score. Fetuses were assessed during the second trimesters (gestational age, 20-24 weeks). The association between the quality ratings and magnetic field strengths (1.5T versus 3T) was evaluated by a linear mixed-effects model. A quantitative assessment of the signal intensity was also performed in the different layers of the developing brain. Comparative log-ratios were calculated across the different layers of the fetal brain. RESULTS: There was a statistically significant interaction between location and magnetic field strength (P < .001). The cerebral structures of the cerebellum, pons, venous system, semicircular canal, and cochlea showed statistically significant higher values on the 3T magnet. Similarly, statistical significance was also obtained on the quantitative assessment of the multilayer appearance of the brain; the 3T magnet had a median factor of 8.38 higher than the 1.5T magnet (95% CI, 4.73-14.82). Other anatomic structures assessed in the supratentorial compartment of the brain showed higher values on the 3T magnet with no statistical significance. CONCLUSIONS: Both magnets depict cerebral and facial normal anatomic structures; however, our data indicates better anatomic detail on the 3T than on the 1.5T magnet. PMID- 28619841 TI - The Concept of "Number Needed to Image". PMID- 28619842 TI - Cumulative Dose of Macrocyclic Gadolinium-Based Contrast Agent Improves Detection of Enhancing Lesions in Patients with Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Gadolinium-enhanced MR imaging is currently the reference standard for detecting active inflammatory lesions in patients with multiple sclerosis. The sensitivity of MR imaging for this purpose may vary according to the physicochemical characteristics of the contrast agent used and the acquisition strategy. The purpose of this study was to compare detection of gadolinium-enhancing lesions or active disease following a single or cumulative dose of a macrocyclic gadolinium-based contrast agent with different image acquisition delays in patients with clinically isolated syndrome or relapsing multiple sclerosis. MATERIALS AND METHODS: All patients received a first dose (0.1 mmol/kg) of gadobutrol and, 20 minutes later, a second dose (0.1 mmol/kg), with a cumulative dose of 0.2 mmol/kg. Two contrast-enhanced T1-weighted sequences were performed at 5 and 15 minutes after the first contrast administration, and 2 additional T1-weighted sequences at 5 and 15 minutes after the second contrast administration with a 3T magnet. RESULTS: One hundred fifteen patients were considered evaluable. A significantly larger number of lesions were detected in scans obtained at 5 and 15 minutes after the second contrast injection compared with scans obtained at 5 and 15 minutes after the first injection (P < .001). The number of patients with active lesions on MR imaging was significantly higher after the second dose administration (52.0%, first dose versus 59.2%, second dose; P < .001). CONCLUSIONS: Cumulative dosing of a macrocyclic gadolinium-based contrast agent increases detection of enhancing lesions and patients with active lesions. These data could be considered in the design of MR imaging protocols aimed at detecting active multiple sclerosis lesions. PMID- 28619843 TI - Stefania Jablonska. PMID- 28619844 TI - People in US are less concerned about health inequality than those in other countries. PMID- 28619846 TI - Acute lymphoblastic leukemia cells create a leukemic niche without affecting the CXCR4/CXCL12 axis. PMID- 28619845 TI - The prohibitin-binding compound fluorizoline induces apoptosis in chronic lymphocytic leukemia cells through the upregulation of NOXA and synergizes with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax. AB - Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In the study herein, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespective of patients' clinical or genetic features, whereas normal T lymphocytes were less sensitive. Fluorizoline increased the protein levels of the pro-apoptotic B-cell lymphoma 2 family member NOXA in chronic lymphocytic leukemia cells. Furthermore, fluorizoline synergized with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax to induce apoptosis. These results suggest that targeting prohibitins could be a new therapeutic strategy for chronic lymphocytic leukemia. PMID- 28619847 TI - Targeted activation of the SHP-1/PP2A signaling axis elicits apoptosis of chronic lymphocytic leukemia cells. AB - Lyn, a member of the Src family of kinases, is a key factor in the dysregulation of survival and apoptotic pathways of malignant B cells in chronic lymphocytic leukemia. One of the effects of Lyn's action is spatial and functional segregation of the tyrosine phosphatase SHP-1 into two pools, one beneath the plasma membrane in an active state promoting pro-survival signals, the other in the cytosol in an inhibited conformation and unable to counter the elevated level of cytosolic tyrosine phosphorylation. We herein show that SHP-1 activity can be elicited directly by nintedanib, an agent also known as a triple angiokinase inhibitor, circumventing the phospho-S591-dependent inhibition of the phosphatase, leading to the dephosphorylation of pro-apoptotic players such as procaspase-8 and serine/threonine phosphatase 2A, eventually triggering apoptosis. Furthermore, the activation of PP2A by using MP07-66, a novel FTY720 analog, stimulated SHP-1 activity via dephosphorylation of phospho-S591, which unveiled the existence of a positive feedback signaling loop involving the two phosphatases. In addition to providing further insights into the molecular basis of this disease, our findings indicate that the PP2A/SHP-1 axis may emerge as an attractive, novel target for the development of alternative strategies in the treatment of chronic lymphocytic leukemia. PMID- 28619848 TI - Red blood cell Gardos channel (KCNN4): the essential determinant of erythrocyte dehydration in hereditary xerocytosis. PMID- 28619851 TI - Culture, Bias, and Understanding: We Can Do Better. PMID- 28619852 TI - Right to Counsel in Juvenile Court 50 Years After In re Gault. PMID- 28619849 TI - The house fly Y Chromosome is young and minimally differentiated from its ancient X Chromosome partner. AB - Canonical ancient sex chromosome pairs consist of a gene rich X (or Z) Chromosome and a male-limited (or female-limited) Y (or W) Chromosome that is gene poor. In contrast to highly differentiated sex chromosomes, nascent sex chromosome pairs are homomorphic or very similar in sequence content. Nascent sex chromosomes can arise if an existing sex chromosome fuses to an autosome or an autosome acquires a new sex-determining locus/allele. Sex chromosomes often differ between closely related species and can even be polymorphic within species, suggesting that nascent sex chromosomes arise frequently over the course of evolution. Previously documented sex chromosome transitions involve changes to both members of the sex chromosome pair (X and Y, or Z and W). The house fly has sex chromosomes that resemble the ancestral fly karyotype that originated ~100 million yr ago; therefore, the house fly is expected to have X and Y Chromosomes with different gene content. We tested this hypothesis using whole-genome sequencing and transcriptomic data, and we discovered little evidence for genetic differentiation between the X and Y in house fly. We propose that the house fly has retained the ancient X Chromosome, but the ancestral Y was replaced by an X Chromosome carrying a new male determining gene. Our proposed hypothesis provides a mechanism for how one member of a sex chromosome pair can experience evolutionary turnover while the other member remains unaffected. PMID- 28619853 TI - The Relevance of Stress and Trauma to Forensic Psychiatry. PMID- 28619854 TI - Dissociation: Defining the Concept in Criminal Forensic Psychiatry. AB - Claims of amnesia and dissociative experiences in association with a violent crime are not uncommon. Research has shown that dissociation is a risk factor for violence and is seen most often in crimes of extreme violence. The subject matter is most relevant to forensic psychiatry. Peritraumatic dissociation for instance, with or without a history of dissociative disorder, is quite frequently reported by offenders presenting for a forensic psychiatric examination. Dissociation or dissociative amnesia for serious offenses can have legal repercussions stemming from their relevance to the legal constructs of fitness to stand trial, criminal responsibility, and diminished capacity. The complexity in forensic psychiatric assessments often lies in the difficulty of connecting clinical symptomatology reported by violent offenders to a specific condition included in the Diagnostic and Statistical Manual of Mental Disorders (DSM). This article provides a review of diagnostic considerations with regard to dissociation across the DSM nomenclature, with a focus on the main clinical constructs related to dissociation. Forensic implications are discussed, along with some guides for the forensic evaluator of offenders presenting with dissociation. PMID- 28619855 TI - Pediatric PTSD: Clinical, Forensic, and Diagnostic Understanding. AB - Exposure to trauma is a common event in the lives of children and adolescents living in the United States. Although a minority of youth develop full posttraumatic stress disorder (PTSD) after a traumatic event, those who do tend to have an extended course of symptoms in multiple functional domains and higher rates of psychiatric comorbidities. Pediatric PTSD can play an important role in legal settings, and requires that an expert witness be well versed in advances in clinical and conceptual models of this diagnosis and familiar with current research devoted to the posttraumatic response in youth. This review is designed to be a resource for the forensic evaluator and outlines the current understanding of epidemiological and clinical features of pediatric PTSD, as well as the neurobiological, dimensional, and developmental conceptual models that describe it. PMID- 28619856 TI - Childhood Trauma, PTSD, and the Cautious Forensic Expert. AB - For centuries, medicine and psychiatry mirrored society's equivocations regarding childhood trauma. Those conflicts have mostly resolved, with widespread agreement that children are commonly exposed to traumatic events that may lead to PTSD and other mental conditions. The psychiatric and legal arguments should no longer be about the reality of childhood trauma in general; instead, experts should focus on the methodology of translating a particular child's narrative truth of maltreatment into a historical account, so that the expert can be qualified to offer criminal or civil court testimony after examining the child. In this commentary, we explore the daunting forensic challenges of eliciting admissible evidence to confirm or dispute the allegations and of offering scientifically credible opinions about whether any present and future harm related to the trauma and PTSD was directly caused by the incident. PMID- 28619857 TI - Pediatric PTSD in the DSM-5 and the Forensic Interview of Traumatized Youth. AB - Since the Third Edition, the Diagnostic and Statistical Manual of Mental Disorders (DSM) has increasingly incorporated developmentally informed criteria for posttraumatic stress disorder (PTSD) because of recognition that children and adolescents can manifest PTSD differently from adults. The most recent edition, DSM-5, among other changes, has introduced a developmental subtype for children six years of age or younger. As pediatric PTSD features very prominently in both civil and criminal proceedings, it is vital that the expert witness be familiar with the updated criteria and know how to interview traumatized youth appropriately in the forensic setting. In this review, we discuss the importance of the evolution of PTSD from past DSM editions to the current one, and the implications of using the new diagnostic criteria and current conceptual models in the forensic evaluation of pediatric PTSD. PMID- 28619858 TI - PTSD, Acute Stress, Performance and Decision-Making in Emergency Service Workers. AB - Despite research identifying high levels of stress and traumatic stress symptoms among those in the emergency services, the impact of these symptoms on performance and hence public safety remains uncertain. This review paper discusses a program of research that has examined the effects of prior critical incident exposure, acute stress, and current post-traumatic symptoms on the performance and decision-making during an acutely stressful event among police officers, police communicators, paramedics and child protection workers. Four studies, using simulation methods involving video simulators, human-patient simulators, and/or standardized patients, examined the performance of emergency workers in typical workplace situations related to their individual profession. Results varied according to level of acuity of stress and the nature of performance and decision-making. There was no evidence that PTSD had a direct impact on global performance on tasks for which emergency responders are highly trained. However, PTSD was associated with assessment of risk in situations that required professional judgement. Further, individuals experiencing PTSD symptoms reported higher levels of acute stress when faced with high acuity situations. Acute stress in these studies was associated with performance deficits on complex cognitive tasks, verbal memory impairment and heightened assessment of risk. PMID- 28619859 TI - Criminal Charges for Child Harm from Substance Use in Pregnancy. AB - Despite the opposition of medical and public health professionals, several state legislatures are considering laws that permit child abuse charges for substance use during pregnancy. We reviewed legal decisions regarding women charged with a crime against a fetus or child as a result of substance use during pregnancy. We identified 24 judicial opinions published between 1977 and 2015 in cases involving 29 women prosecuted in 19 states. Charges included child endangerment, child abuse, drug delivery, attempted aggravated child abuse, chemical endangerment of a child, child neglect, child mistreatment, homicide, manslaughter, and reckless injury to a child. The substances related to the charges included cocaine, heroin, methamphetamine, marijuana, and prescription pills. Proceedings resulted in dismissal of the charges or convictions overturned for 86.2 percent of the women. In all of the cases, the judicial decision depended on the disposition of the question of whether, for the purpose of adjudicating the criminal charges, a fetus is a child. The balance in the courts in favor of treating substance use during pregnancy as a medical problem depends on the definition of a child for the purposes of criminal statutes. Professional advocacy may best be directed at state legislatures. PMID- 28619860 TI - Motherhood and Apple Pie: A UK Perspective on Mothers Who Misuse Drugs. AB - In this commentary, I explore two questions raised by Angelotta and Appelbaum's study. First, I offer an English legal perspective on the protection of children from their mothers, looking at both civil (family) and criminal law. Second, I discuss the idealization of motherhood that is implied by the prosecution of pregnant women; the denigration of those who fail this ideal; and the way that idealization and denigration contribute to injustice for women. I conclude by offering comments on the implications for those assessing women accused of harming their unborn child. PMID- 28619861 TI - Geriatrics and the Legal System. AB - Correctional systems, already struggling to meet the basic and functional requirements of older prisoners, will be further challenged by the increasing medical and psychiatric needs of this population. Mental health and general medical care for older adults requires specific on-site or consultation expertise in geriatric medicine and psychiatry, as well as potential changes in infrastructure, both of which may be prohibitively expensive. However, compassionate and effective treatment of older prisoners requires that prison and legal systems facilitate this expert care. To address this situation, strategic revisions of the criminal justice system are needed to alleviate prison overcrowding and consequent inadequate medical care for inmates, especially the elder ones. The unique, age-related demands of this older population predict an increased need for forensic psychiatrists with a thorough knowledge and expertise in geriatrics, as more forensic psychiatric evaluations will be needed before trial in both civil and criminal cases, during incarceration, and at the time of parole. In this article, we review the current state of elder inmates in correctional institutions and advocate for increased geriatric training for forensic psychiatrists in anticipation of this growing need. PMID- 28619862 TI - The Elephant in the Courtroom. PMID- 28619863 TI - Military Trauma's Unusual Appearance. PMID- 28619864 TI - Introduction to the Special Section on the Goldwater Rule. PMID- 28619865 TI - Reflections on the Goldwater Rule. AB - The APA's Goldwater Rule, precluding psychiatrists from rendering opinions to the media about public figures whom they have not examined, has often engendered controversy. Here, I consider the justifications for the rule, how well they stand up to criticism, and the extent, if any, to which modifications might be called for. Although embarrassment to the profession is often cited as the basis for the Rule, it reflects more substantive concerns, including the risk of harm to living persons and discouraging persons in need of treatment from seeking psychiatric attention. The most potent criticisms of the Rule are that it discourages public education about mental illness and its effects and precludes legitimate scholarly endeavors by psychiatrists studying foreign leaders, historical figures, and others. However, there are many ways of providing education about mental illness without violating the Rule, and read properly, it should not prevent legitimate historical investigation, though some clarification of the Rule on this point might be helpful. Even psychiatrists who seek to aid policymakers in dealing with international or domestic threats should not find that the Rule interferes with their efforts. On balance, the Goldwater Rule continues to be an important underpinning of ethical behavior by psychiatrists. PMID- 28619866 TI - Interpreting the Goldwater Rule. AB - Section 7.3 of the Principles of Medical Ethics With Annotations Especially Applicable to Psychiatry (the so-called Goldwater Rule) provides guidance on the ethics of making psychiatric comments about public figures who have not been interviewed and have not given consent. I argue that the wording of Section 7.3 is ambiguous, and I document disagreement over the scope of the rule and consider the implications of this disagreement. If one reads Section 7.3 narrowly, as banning media comments without interview and consent, but allowing such comments in institutional settings, then the general principle articulated in the text and often repeated in the media begins to appear insubstantial. If one reads Section 7.3 broadly, then the work of psychiatrists in the courts, in government agencies such as the Central Intelligence Agency, in insurance companies, and in the academy becomes ethically problematic. I trace the American Psychiatric Association's own interpretation of Section 7.3 and conclude that the APA has advocated a narrow reading. I assert the need for an integrated theory of psychiatric ethics for settings where interview and consent are absent. Such a theory, articulating why comments in institutional settings are ethical, but comments to media are not, may reduce public confusion and provide a basis for revising Section 7.3. PMID- 28619867 TI - Journalism Ethics and the Goldwater Rule in a "Post-Truth" Media World. AB - This article strongly supports the Goldwater Rule, a position arrived at through an exploration of journalism ethics and practice norms for reporting on public figures, and justified by three claims. First, there is a seldom-acknowledged contradiction in ethics when it comes to journalistic reporting on public figures, one that is increasingly difficult to navigate in the current media climate. Second, the goal of informing and educating the public through offering a professional opinion about the mental health of public figures is often misaligned with the realities of journalistic storytelling. Third, there are ways to inform and educate the public about mental health and public figures that do not violate the Goldwater Rule. PMID- 28619868 TI - A Resident Perspective on the Goldwater Rule. AB - Section 7.3 of the Principles of Medical Ethics with Annotations Especially Applicable to Psychiatry, more commonly known as the Goldwater rule, admonishes psychiatrists to avoid offering professional opinions about public figures in the absence of an in-person evaluation. To our knowledge, no peer-reviewed articles have been published considering resident perspectives on the Goldwater rule. Furthermore, we have found little published guidance that deals specifically with teaching the Goldwater rule in a general residency curriculum. We propose that residency programs should incorporate a brief (one hour) but thoughtful discussion of the Goldwater rule into their general curriculum. We recommend that such a didactic hour should introduce arguments for and against the rule in its present form. Covered topics could include whether there should be exceptions to the rule, whether the rule is defensible on ethical grounds, and what contexts exist in which psychiatric opinions can be rendered without personal examination. We hope to make the case that a more nuanced exploration of the Goldwater rule could help open a door to discussions that would foster the growth of a mature professional identity. PMID- 28619869 TI - Exploring a Defense of Extreme Emotional Disturbance. PMID- 28619870 TI - Duty to Warn for Federal Parole Officers. PMID- 28619871 TI - Miranda Warnings in Noncustodial Interrogation of Juveniles and Voluntariness of Statements Made at the Request of Interested Adults. PMID- 28619872 TI - Disability Claims Under ERISA. PMID- 28619873 TI - Psychiatric Record Discoverable as Brady Material. PMID- 28619874 TI - Necessary Services Must Be Proven Futile Before Parental Rights Termination. PMID- 28619875 TI - Involuntary Administration of Medication in Mental Health Facilities. PMID- 28619876 TI - Eligibility for Special Education Services Under the Individuals with Disabilities Education Act. PMID- 28619877 TI - Government Management of Accompanied Minors Held in the Custody of Immigration Authorities. PMID- 28619878 TI - Clarification to Prison Litigation Reform Act "Three Strikes" Rule. PMID- 28619882 TI - Doctor convicted of manslaughter is suspended from register for a year. PMID- 28619884 TI - Effect of an obesogenic diet on circadian activity and serum hormones in old monkeys. AB - Like women, old female rhesus macaques undergo menopause and show many of the same age-associated changes, including perturbed activity/rest cycles and altered circulating levels of many hormones. Previous studies showed that administration of an estrogen agonist increased activity in female monkeys, that hormone therapy (HT) increased activity in postmenopausal women and that obesity decreased activity in women. The present study sought to determine if postmenopausal activity and circulating hormone levels also respond to HT when monkeys are fed a high-fat, high-sugar Western style diet (WSD). Old female rhesus macaques were ovo-hysterectomized (OvH) to induce surgical menopause and fed a WSD for 2 years. Half of the animals received estradiol-17beta (E), beginning immediately after OvH, while the other half received placebo. Animals in both groups showed an increase in body weight and a decrease in overall activity levels. These changes were associated with a rise in both daytime and nocturnal serum leptin concentrations, but there was no change in serum concentrations of either cortisol or dehydroepiandrosterone sulfate (DHEAS). These data suggest that 2 years of HT has little or no effect on locomotor activity or circadian hormone patterns in menopausal macaques fed an obesogenic diet. PMID- 28619883 TI - Spatiotemporal Monitoring of Pseudomonas syringae Effectors via Type III Secretion Using Split Fluorescent Protein Fragments. AB - Pathogenic gram-negative bacteria cause serious diseases in animals and plants. These bacterial pathogens use the type III secretion system (T3SS) to deliver effector proteins into host cells; these effectors then localize to different subcellular compartments to attenuate immune responses by altering biological processes of the host cells. The fluorescent protein (FP)-based approach to monitor effectors secreted from bacteria into the host cells is not possible because the folded FP prevents effector delivery through the T3SS Therefore, we optimized an improved variant of self-assembling split super-folder green fluorescent protein (sfGFPOPT) system to investigate the spatiotemporal dynamics of effectors delivered through bacterial T3SS into plant cells. In this system, effectors are fused to 11th beta-strand of super-folder GFP (sfGFP11), and when delivered into plant cells expressing sfGFP1-10 beta-strand (sfGFP1-10OPT), the two proteins reconstitute GFP fluorescence. We generated a number of Arabidopsis thaliana transgenic lines expressing sfGFP1-10OPT targeted to various subcellular compartments to facilitate localization of sfGFP11-tagged effectors delivered from bacteria. We demonstrate the efficacy of this system using Pseudomonas syringae effectors AvrB and AvrRps4 in Nicotiana benthamiana and transgenic Arabidopsis plants. The versatile split sfGFPOPT system described here will facilitate a better understanding of bacterial invasion strategies used to evade plant immune responses. PMID- 28619885 TI - Maximizing the right stuff: The trade-off between membrane permeability and selectivity. AB - Increasing demands for energy-efficient separations in applications ranging from water purification to petroleum refining, chemicals production, and carbon capture have stimulated a vigorous search for novel, high-performance separation membranes. Synthetic membranes suffer a ubiquitous, pernicious trade-off: highly permeable membranes lack selectivity and vice versa. However, materials with both high permeability and high selectivity are beginning to emerge. For example, design features from biological membranes have been applied to break the permeability-selectivity trade-off. We review the basis for the permeability selectivity trade-off, state-of-the-art approaches to membrane materials design to overcome the trade-off, and factors other than permeability and selectivity that govern membrane performance and, in turn, influence membrane design. PMID- 28619886 TI - Tubular clathrin/AP-2 lattices pinch collagen fibers to support 3D cell migration. AB - Migrating cells often use focal adhesions in order to move. Focal adhesions are less prominent in cells migrating in three-dimensional (3D) as compared with 2D environments. We looked for alternative adhesion structures supporting cell migration. We analyzed the dynamics of clathrin-coated pits in cells migrating in a 3D environment of collagen fibers. Both topological cues and local engagement of integrins triggered the accumulation of clathrin-coated structures on fibers. Clathrin/adaptor protein 2 (AP-2) lattices pinched collagen fibers by adopting a tube-like morphology and regulated adhesion to fibers in an endocytosis independent manner. During migration, tubular clathrin/AP-2 lattices stabilized cellular protrusions by providing anchoring points to collagen fibers. Thus, tubular clathrin/AP-2 lattices promote cell adhesion that, in coordination with focal adhesions, supports cell migration in 3D. PMID- 28619887 TI - Comment on "Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing". AB - Chen et al (Reports, 28 October 2016, p. 468) proposed that an interaction between Xist RNA and Lamin B receptor (LBR) is necessary and sufficient for Xist spreading during X-chromosome inactivation. We reanalyzed their data and found that reported genotypes of mutants are not supported by the sequencing data. These inconsistencies preclude assessment of the role of LBR in Xist spreading. PMID- 28619889 TI - News at a glance. PMID- 28619888 TI - Response to Comment on "Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing". AB - Wang et al question whether Lamin B receptor is required for Xist-mediated silencing because they claim that our cells contain an inversion rather than a deletion. We present evidence that these cells contain a proper deletion and that the confusion is caused by DNA probes used in the experiment. Accordingly, the points raised have no effect on the conclusions in our paper. PMID- 28619890 TI - Designers squabble over giant Chinese scope. PMID- 28619891 TI - NIH abandons grant cap, offers new help to younger scientists. PMID- 28619892 TI - Mini-livers reveal fine details of organ development. PMID- 28619894 TI - In a major shift, cancer drugs go 'tissue-agnostic'. PMID- 28619893 TI - Spooky action achieved at record distance. PMID- 28619895 TI - Supply of promising T cell therapy is strained. PMID- 28619896 TI - Chimps in waiting. PMID- 28619897 TI - A composite window into human history. PMID- 28619898 TI - Growing anisotropic crystals at the nanoscale. PMID- 28619899 TI - Glycophorin alleles link to malaria protection. PMID- 28619900 TI - Deciphering microglial diversity in Alzheimer's disease. PMID- 28619901 TI - Scaling pain threshold with microRNAs. PMID- 28619902 TI - Tracking the dynamics of electron expulsion. PMID- 28619903 TI - Linking job loss, inequality, mental health, and education. PMID- 28619904 TI - There's more to a meal. PMID- 28619905 TI - Unlikely allies. PMID- 28619906 TI - Invest in insects. PMID- 28619907 TI - Chile unprepared for Ph.D. influx. PMID- 28619908 TI - NIH's ineffective funding policies. PMID- 28619910 TI - Go with the flow in drug manufacturing. PMID- 28619909 TI - Food for fungi. PMID- 28619911 TI - Bigger and badder. PMID- 28619912 TI - Saving earthquakes for the wet season. PMID- 28619913 TI - Space calling Earth, on the quantum line. PMID- 28619914 TI - Early life stress in depression susceptibility. PMID- 28619915 TI - Preparing for the feast during the fast. PMID- 28619916 TI - Engaging local stakeholders. PMID- 28619917 TI - A site-specific switch for cancer cells. PMID- 28619918 TI - Filtering through to what's important. PMID- 28619919 TI - Silently taking up the slack. PMID- 28619920 TI - Pathogens select for genomic variants. PMID- 28619921 TI - Helping a cell to migrate in 3D space. PMID- 28619922 TI - Two different combs from a single source. PMID- 28619923 TI - Quick eruption after a long bake. PMID- 28619924 TI - A detailed look at an electron's exit. PMID- 28619925 TI - The vegetation-climate loop. PMID- 28619927 TI - Joined-up research brings rewards. PMID- 28619926 TI - MicroRNAs in functional and dysfunctional pain. PMID- 28619928 TI - An antisensible approach to target KRAS. PMID- 28619929 TI - Selecting against cis conformers. PMID- 28619930 TI - Finding foreshocks in the damage zone. PMID- 28619931 TI - Immune control of hair growth. PMID- 28619932 TI - Thinking about what others believe is hard work. PMID- 28619933 TI - TET function in development. PMID- 28619934 TI - I know what you know. PMID- 28619935 TI - Revealing the hidden movers. PMID- 28619936 TI - Bipolar light-emitting junctions. PMID- 28619937 TI - Satellite-based entanglement distribution over 1200 kilometers. AB - Long-distance entanglement distribution is essential for both foundational tests of quantum physics and scalable quantum networks. Owing to channel loss, however, the previously achieved distance was limited to ~100 kilometers. Here we demonstrate satellite-based distribution of entangled photon pairs to two locations separated by 1203 kilometers on Earth, through two satellite-to-ground downlinks with a summed length varying from 1600 to 2400 kilometers. We observed a survival of two-photon entanglement and a violation of Bell inequality by 2.37 +/- 0.09 under strict Einstein locality conditions. The obtained effective link efficiency is orders of magnitude higher than that of the direct bidirectional transmission of the two photons through telecommunication fibers. PMID- 28619939 TI - Coherent imaging of an attosecond electron wave packet. AB - Electrons detached from atoms or molecules by photoionization carry information about the quantum state from which they originate, as well as the continuum states into which they are released. Generally, the photoelectron momentum distribution is composed of a coherent sum of angular momentum components, each with an amplitude and phase. Here we show, by using photoionization of neon, that a train of attosecond pulses synchronized with an infrared laser field can be used to disentangle these angular momentum components. Two-color, two-photon ionization via a Stark-shifted intermediate state creates an almost pure f-wave with a magnetic quantum number of zero. Interference of the f-wave with a spherically symmetric s-wave provides a holographic reference that enables phase resolved imaging of the f-wave. PMID- 28619938 TI - Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous flow CGMP conditions. AB - Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound. PMID- 28619940 TI - Rapid cooling and cold storage in a silicic magma reservoir recorded in individual crystals. AB - Silicic volcanic eruptions pose considerable hazards, yet the processes leading to these eruptions remain poorly known. A missing link is knowledge of the thermal history of magma feeding such eruptions, which largely controls crystallinity and therefore eruptability. We have determined the thermal history of individual zircon crystals from an eruption of the Taupo Volcanic Zone, New Zealand. Results show that although zircons resided in the magmatic system for 103 to 105 years, they experienced temperatures >650 degrees to 750 degrees C for only years to centuries. This implies near-solidus long-term crystal storage, punctuated by rapid heating and cooling. Reconciling these data with existing models of magma storage requires considering multiple small intrusions and multiple spatial scales, and our approach can help to quantify heat input to and output from magma reservoirs. PMID- 28619941 TI - Recurring and triggered slow-slip events near the trench at the Nankai Trough subduction megathrust. AB - The discovery of slow earthquakes has revolutionized the field of earthquake seismology. Defining the locations of these events and the conditions that favor their occurrence provides important insights into the slip behavior of tectonic faults. We report on a family of recurring slow-slip events (SSEs) on the plate interface immediately seaward of repeated historical moment magnitude (Mw) 8 earthquake rupture areas offshore of Japan. The SSEs continue for days to several weeks, include both spontaneous and triggered slip, recur every 8 to 15 months, and are accompanied by swarms of low-frequency tremors. We can explain the SSEs with 1 to 4 centimeters of slip along the megathrust, centered 25 to 35 kilometers (km) from the trench (4 to 10 km depth). The SSEs accommodate 30 to 55% of the plate motion, indicating frequent release of accumulated strain near the trench. PMID- 28619942 TI - Seasonal water storage, stress modulation, and California seismicity. AB - Establishing what controls the timing of earthquakes is fundamental to understanding the nature of the earthquake cycle and critical to determining time dependent earthquake hazard. Seasonal loading provides a natural laboratory to explore the crustal response to a quantifiable transient force. In California, water storage deforms the crust as snow and water accumulates during the wet winter months. We used 9 years of global positioning system (GPS) vertical deformation time series to constrain models of monthly hydrospheric loading and the resulting stress changes on fault planes of small earthquakes. The seasonal loading analysis reveals earthquakes occurring more frequently during stress conditions that favor earthquake rupture. We infer that California seismicity rates are modestly modulated by natural hydrological loading cycles. PMID- 28619943 TI - Increase in predator-prey size ratios throughout the Phanerozoic history of marine ecosystems. AB - The escalation hypothesis posits that predation by increasingly powerful and metabolically active carnivores has been a major driver of metazoan evolution. We test a key tenet of this hypothesis by analyzing predatory drill holes in fossil marine shells, which provide a ~500-million-year record of individual predator prey interactions. We show that drill-hole size is a robust predictor of body size among modern drilling predators and that drill-hole size (and thus inferred predator size and power) rose substantially from the Ordovician to the Quaternary period, whereas the size of drilled prey remained stable. Together, these trends indicate a directional increase in predator-prey size ratios. We hypothesize that increasing predator-prey size ratios reflect increases in prey abundance, prey nutrient content, and predation among predators. PMID- 28619944 TI - Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. AB - Early life stress increases risk for depression. Here we establish a "two-hit" stress model in mice wherein stress at a specific postnatal period increases susceptibility to adult social defeat stress and causes long-lasting transcriptional alterations that prime the ventral tegmental area (VTA)-a brain reward region-to be in a depression-like state. We identify a role for the developmental transcription factor orthodenticle homeobox 2 (Otx2) as an upstream mediator of these enduring effects. Transient juvenile-but not adult-knockdown of Otx2 in VTA mimics early life stress by increasing stress susceptibility, whereas its overexpression reverses the effects of early life stress. This work establishes a mechanism by which early life stress encodes lifelong susceptibility to stress via long-lasting transcriptional programming in VTA mediated by Otx2. PMID- 28619946 TI - Controlling guest conformation for efficient purification of butadiene. AB - Conventional adsorbents preferentially adsorb the small, high-polarity, and unsaturated 1,3-butadiene molecule over the other C4 hydrocarbons from which it must be separated. We show from single-crystal x-ray diffraction and computational simulation that a hydrophilic metal-organic framework, [Zn2(btm)2], where H2btm is bis(5-methyl-1H-1,2,4-triazol-3-yl)methane, has quasi-discrete pores that can induce conformational changes in the flexible guest molecules, weakening 1,3-butadiene adsorption through a large bending energy penalty. In a breakthrough operation at ambient temperature and pressure, this guest conformation-controlling adsorbent eluted 1,3-butadiene first, then butane, butene, and isobutene. Thus, 1,3-butadiene can be efficiently purified (>=99.5%) while avoiding high-temperature conditions that can lead to its undesirable polymerization. PMID- 28619947 TI - Drawing connections. PMID- 28619945 TI - Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. AB - The mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosome by Rag guanosine triphosphatases (GTPases) and regulates anabolic pathways in response to nutrients. We found that MiT/TFE transcription factors master regulators of lysosomal and melanosomal biogenesis and autophagy-control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD. In mice, this mechanism mediated adaptation to food availability after starvation and physical exercise and played an important role in cancer growth. Up-regulation of MiT/TFE genes in cells and tissues from patients and murine models of renal cell carcinoma, pancreatic ductal adenocarcinoma, and melanoma triggered RagD-mediated mTORC1 induction, resulting in cell hyperproliferation and cancer growth. Thus, this transcriptional regulatory mechanism enables cellular adaptation to nutrient availability and supports the energy-demanding metabolism of cancer cells. PMID- 28619948 TI - Administration of immunobiotic Lactobacillus plantarum delays but does not prevent lethal pneumovirus infection in Rag1-/- mice. AB - Administration of immunobiotic Lactobacillus plantarum (Lp) directly to the respiratory mucosa promotes cross-protection against lethal pneumovirus infection via B-cell-independent mechanisms. In this study, we examined Lp-mediated cross protection in Rag1-/- mice which cannot clear virus from lung tissue. Although Lp was initially protective, Rag1-/- mice ultimately succumbed to a delayed lethal outcome associated with local production of the proinflammatory cytokines CCL1, 2, and -7, granulocyte recruitment, and ongoing virus replication. By contrast, CD8null mice, which are fully capable of clearing virus, are protected by Lp with no delayed lethal outcome, granulocyte recruitment to the airways, or induction of CCL7. Repeated administration of Lp to virus-infected Rag1-/- mice had no impact on delayed mortality. Moreover, administration of Lp to the respiratory mucosa resulted in no induction of IFN-alpha or -beta in Rag1-/- or wild-type mice, and IFN-abR gene deletion had no impact on Lp-mediated protection. Overall, our findings indicate that although Lp administered to the respiratory tract has substantial impact on lethal virus-induced inflammation in situ, endogenous virus clearance mechanisms are needed to promote sustained protection. Our results suggest that a larger understanding of the mechanisms and mediators that limit acute virus-induced inflammation may yield new and useful therapeutic modalities. PMID- 28619949 TI - Expansion and activation of granulocytic, myeloid-derived suppressor cells in childhood precursor B cell acute lymphoblastic leukemia. AB - Precursor B cell acute lymphoblastic leukemia (B-ALL) is a B cell-derived, malignant disorder with the highest incidence among children. In addition to the genetic abnormality, a dysregulated immune system also has an important role in the pathogenesis of B-ALL. Myeloid-derived suppressor cells (MDSCs) represent one of the key drivers in immune tolerance against tumor cells, including various solid tumors and hematologic malignancies. The role of MDSCs in B-ALL remains poorly understood. Here, we showed that the granulocytic (G)-MDSC population was significantly elevated in both the peripheral blood and BM of patients with B ALL, when compared with age-matched healthy controls. G-MDSCs levels correlated positively with clinical therapeutic responses and B-ALL disease prognostic markers, including minimal residual disease, and the frequencies of CD20+ and blast cells. The immunosuppressive function of B-ALL-derived G-MDSCs was mediated through the production of reactive oxygen species and required direct cell-cell contact, with the potential participation of STAT3 signaling. Overall, the results of our study support accumulation and activation of G-MDSCs as a novel mechanism of immune evasion of tumor cells in patients with B-ALL and may be a new therapeutic target. PMID- 28619950 TI - How neutrophils resist shear stress at blood vessel walls: molecular mechanisms, subcellular structures, and cell-cell interactions. AB - Neutrophils are the first cells arriving at sites of tissue injury or infection to combat invading pathogens. Successful neutrophil recruitment to sites of inflammation highly depends on specific molecular mechanisms, fine-tuning the received information into signaling pathways and converting them into well described recruitment steps. This review highlights the impact of vascular flow conditions on neutrophil recruitment and the multitude of mechanisms developed to enable this sophisticated process under wall shear stress conditions. The recruitment process underlies a complex interplay between adhesion and signaling molecules, as well as chemokines, in which neutrophils developed specific mechanisms to travel to sites of lesion in low and high shear stress conditions. Rolling, as the first step in the recruitment process, highly depends on endothelial selectins and their ligands on neutrophils, inducting of intracellular signaling and subsequently activating beta2 integrins, enabling adhesion and postadhesion events. In addition, subcellular structures, such as microvilli, tethers, and slings allow the cell to arrest, even under high wall shear stress. Thereby, microvilli that are pulled out from the cell body form tethers that develop into slings upon their detachment from the substrate. In addition to the above-described primary capture, secondary capture of neutrophils via neutrophil-neutrophil or neutrophil-platelet interaction promotes the process of neutrophil recruitment to sites of lesion. Thus, precise mechanisms based on a complex molecular interplay, subcellular structures, and cell-cell interactions turn the delicate process of neutrophil trafficking during flow into a robust response allowing effective neutrophil accumulation at sites of injury. PMID- 28619953 TI - Solar ultraviolet B exposure and global variation in tuberculosis incidence: an ecological analysis. AB - Epidemiological evidence supports vitamin D deficiency as a risk factor for tuberculosis. Differences in solar ultraviolet B (UV-B) exposure, the major source of vitamin D, might therefore partially explain global variation in tuberculosis incidence.In a global country-based ecological study, we explored the correlation between vitamin D-proxies, such as solar UV-B exposure, and other relevant variables with tuberculosis incidence, averaged over the period 2004 2013.Across 154 countries, annual solar UV-B exposure was associated with tuberculosis incidence. Tuberculosis incidence in countries in the highest quartile of UV-B exposure was 78% (95% CI 57-88%, p<0.001) lower than that in countries in the lowest quartile, taking into account other vitamin D-proxies and covariates. Of the explained global variation in tuberculosis incidence, 6.3% could be attributed to variations in annual UV-B exposure. Exposure to UV-B had a similar, but weaker association with tuberculosis notification rates in the multilevel analysis with sub-national level data for large countries (highest versus lowest quartile 29% lower incidence; p=0.057).The potential preventive applications of vitamin D supplementation in high-risk groups for tuberculosis merits further investigation. PMID- 28619952 TI - Cardiometabolic correlates of sleep disordered breathing in Andean highlanders. AB - Associations between sleep disordered breathing (SDB) and cardiometabolic outcomes have not been examined in highlanders.We performed nocturnal polygraphy in Peruvian highlanders (3825 m). Multivariable linear regression models examined associations between SDB metrics and haemoglobin, glucose tolerance (haemoglobin A1c (HbA1c)), fasting glucose, homeostatic model-based assessments of insulin resistance and beta-cell function (HOMA-IR and HOMA-beta, respectively), blood pressure, and lipids, while adjusting for age, sex, body mass index (BMI) and wake oxygenation.Participants (n=187; 91 men) were (median (interquartile range)) 52 (45-62) years old, and had a BMI of 27.0 (24.3-29.5) kg.m-2 and 87% (85-88%) oxyhaemoglobin (arterial oxygen) saturation during wakefulness. In fully adjusted models, worsening nocturnal hypoxaemia was associated with haemoglobin elevations in men (p=0.03), independent of wake oxygenation and apnoea-hypopnoea index (AHI), whereas worsening wake oxygenation was associated with haemoglobin elevations in older women (p=0.02). In contrast, AHI was independently associated with HbA1c elevations (p<0.05). In single-variable models, nocturnal hypoxaemia was associated with higher HbA1c, HOMA-IR and HOMA-beta (p<0.001, p=0.02 and p=0.04, respectively), whereas AHI was associated with HOMA-IR, systolic blood pressure and triglyceride elevations (p=0.02, p=0.01 and p<0.01, respectively). These associations were not significant in fully adjusted models.In highlanders, nocturnal hypoxaemia and sleep apnoea were associated with distinct cardiometabolic outcomes, conferring differential risk for excessive erythrocytosis and glucose intolerance, respectively. PMID- 28619954 TI - A novel immune biomarker IFI27 discriminates between influenza and bacteria in patients with suspected respiratory infection. AB - Host response biomarkers can accurately distinguish between influenza and bacterial infection. However, published biomarkers require the measurement of many genes, thereby making it difficult to implement them in clinical practice. This study aims to identify a single-gene biomarker with a high diagnostic accuracy equivalent to multi-gene biomarkers.In this study, we combined an integrated genomic analysis of 1071 individuals with in vitro experiments using well-established infection models.We identified a single-gene biomarker, IFI27, which had a high prediction accuracy (91%) equivalent to that obtained by multi gene biomarkers. In vitro studies showed that IFI27 was upregulated by TLR7 in plasmacytoid dendritic cells, antigen-presenting cells that responded to influenza virus rather than bacteria. In vivo studies confirmed that IFI27 was expressed in influenza patients but not in bacterial infection, as demonstrated in multiple patient cohorts (n=521). In a large prospective study (n=439) of patients presented with undifferentiated respiratory illness (aetiologies included viral, bacterial and non-infectious conditions), IFI27 displayed 88% diagnostic accuracy (AUC) and 90% specificity in discriminating between influenza and bacterial infections.IFI27 represents a significant step forward in overcoming a translational barrier in applying genomic assay in clinical setting; its implementation may improve the diagnosis and management of respiratory infection. PMID- 28619955 TI - Pulmonary artery to aorta ratio and risk of all-cause mortality in the general population: the Rotterdam Study. AB - A pulmonary artery to aorta ratio (PA:A) >1 is a proxy of pulmonary hypertension. It is not known whether this measure carries prognostic information in the general population and in individuals with chronic obstructive pulmonary disease (COPD).Between 2003 and 2006, 2197 participants from the population-based Rotterdam Study (mean+/-sd age 69.7+/-6.7 years; 51.3% female), underwent cardiac computed tomography (CT) scanning with PA:A quantification, defined as the ratio between the diameters of the pulmonary artery and the aorta. COPD was diagnosed based on spirometry or clinical presentation and obstructive lung function measured by a treating physician. Cox regression was used to investigate the risk of mortality.We observed no association between 1-sd increase of PA:A and mortality in the general population. Larger PA:A was associated with an increased risk of mortality in individuals with COPD, particularly in moderate-to-severe COPD (hazard ratio 1.36, 95% CI 1.03-1.79). We demonstrated that the risk of mortality in COPD was driven by severe COPD, and that this risk increased with decreasing diffusing capacity.Larger PA:A is not associated with mortality in an older general population, but is an independent determinant of mortality in moderate-to-severe COPD. Measuring PA:A in CT scans obtained for other indications may yield important prognostic information in individuals with COPD. PMID- 28619956 TI - A longitudinal modelling study estimates acute symptoms of community acquired pneumonia recover to baseline by 10 days. AB - Our aims were to address three fundamental questions relating to the symptoms of community-acquired pneumonia (CAP): Do patients completely recover from pneumonia symptoms? How long does this recovery take? Which factors influence symptomatic recovery?We prospectively recruited patients at two hospitals in Liverpool, UK, into a longitudinal, observational cohort study and modelled symptom recovery from CAP. We excluded patients with cancer, immunosuppression or advanced dementia, and those who were intubated or palliated from admission. We derived a statistical model to describe symptom patterns.We recruited 169 (52% male) adults. Multivariable analysis demonstrated that the time taken to recover to baseline was determined by the initial severity of symptoms. Severity of symptoms was associated with comorbidity and was inversely related to age. The pattern of symptom recovery was exponential and most patients' symptoms returned to baseline by 10 days.These results will inform the advice given to patients regarding the resolution of their symptoms. The recovery model described here will facilitate the use of symptom recovery as an outcome measure in future clinical trials. PMID- 28619957 TI - Chronic pulmonary aspergillosis complicating sarcoidosis. AB - Chronic pulmonary aspergillosis (CPA) complicating sarcoidosis (SA) is associated with high mortality, and there is a lack of clarity regarding the relative contributions of SA or CPA.This was a retrospective single-centre study on CPA SA.In total, 65 patients (44 men), aged 41.4+/-13.5 and 48.3+/-11.9 years at the time of SA and CPA diagnoses, respectively, were included between 1980 and 2015. Of these, 64 had fibrocystic SA, most often advanced, with composite physiological index (CPI) >40 (65% of patients) and pulmonary hypertension (PH) (31%), and 41 patients (63%) were treated for SA (corticosteroids or immunosuppressive drugs). Chronic cavitary pulmonary aspergillosis (CCPA) was the most frequent CPA pattern. Regarding treatment, 55 patients required long-term antifungals, 14 interventional radiology, 11 resection surgery and two transplantation. Nearly half of the patients (27; 41.5%) died (mean age 55.8 years); 73% of the patients achieved 5-year survival and 61% 10-year survival. Death most often resulted from advanced SA and rarely from haemoptysis. CPI, fibrosis extent and PH predicted survival. Comparison with paired healthy controls without CPA did not show any difference in survival, but a higher percentage of patients had high-risk mould exposure.CPA occurs in advanced pulmonary SA. CPA-SA is associated with high mortality due to the underlying advanced SA rather than to the CPA. CPI, fibrosis extent and PH best predict outcome. PMID- 28619958 TI - Monocytes inhibit NK activity via TGF-beta in patients with obstructive sleep apnoea. AB - Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.Quantitative reverse transcriptase PCR, flow cytometry and in vitro assays were used to analyse the phenotype and immune response activity in 92 patients with OSA (60 recently diagnosed untreated patients and 32 patients after 6 months of treatment with continuous positive airway pressure (CPAP)) and 29 healthy volunteers (HV).We determined that monocytes in patients with OSA exhibit an immunosuppressive phenotype, including surface expression of glycoprotein-A repetitions predominant protein (GARP) and transforming growth factor-beta (TGF beta), in contrast to those from the HV and CPAP groups. High levels of TGF-beta were detected in OSA sera. TGF-beta release by GARP+ monocytes impaired NK cytotoxicity and maturation. This altered phenotype correlated with the hypoxic severity clinical score (CT90). Reoxygenation eventually restored the altered phenotypes and cytotoxicity.This study demonstrates that GARP+ monocytes from untreated patients with OSA have an NK-suppressing role through their release of TGF-beta. Our findings show that monocyte plasticity immunomodulates NK activity in this pathology, suggesting a potential role in cancer incidence. PMID- 28619959 TI - Defining asthma and assessing asthma outcomes using electronic health record data: a systematic scoping review. AB - There is currently no consensus on approaches to defining asthma or assessing asthma outcomes using electronic health record-derived data. We explored these approaches in the recent literature and examined the clarity of reporting.We systematically searched for asthma-related articles published between January 1, 2014 and December 31, 2015, extracted the algorithms used to identify asthma patients and assess severity, control and exacerbations, and examined how the validity of these outcomes was justified.From 113 eligible articles, we found significant heterogeneity in the algorithms used to define asthma (n=66 different algorithms), severity (n=18), control (n=9) and exacerbations (n=24). For the majority of algorithms (n=106), validity was not justified. In the remaining cases, approaches ranged from using algorithms validated in the same databases to using nonvalidated algorithms that were based on clinical judgement or clinical guidelines. The implementation of these algorithms was suboptimally described overall.Although electronic health record-derived data are now widely used to study asthma, the approaches being used are significantly varied and are often underdescribed, rendering it difficult to assess the validity of studies and compare their findings. Given the substantial growth in this body of literature, it is crucial that scientific consensus is reached on the underlying definitions and algorithms. PMID- 28619960 TI - Airway inflammation and inhaled corticosteroids in COPD. PMID- 28619961 TI - Recovery from community acquired pneumonia: the view from the top of the iceberg. PMID- 28619962 TI - Sarcoidosis and aspergillosis: a tough combination. PMID- 28619963 TI - In Rotterdam, size really does matter: implications of pulmonary artery enlargement on mortality. PMID- 28619964 TI - Airway inflammation in COPD after long-term withdrawal of inhaled corticosteroids. PMID- 28619965 TI - Host transcriptomics for diagnosis of infectious diseases: one step closer to clinical application. PMID- 28619966 TI - The Art of Breathing: Kiai. PMID- 28619967 TI - A Four-Factor Immunoscore System That Predicts Clinical Outcome for Stage II/III Gastric Cancer. AB - The American Joint Committee on Cancer (AJCC) staging system is insufficiently prognostic for operable gastric cancer patients; therefore, complementary factors are under intense investigation. Although the focus is on immune markers, the prognostic impact of a single immune factor is minimal, due to complex antitumor immune responses. A more comprehensive evaluation may engender more accurate predictions. We analyzed immune factors by immunohistochemical staining in two independent cohorts. The association with patients' survival was analyzed by the Kaplan-Meier method. Our immunoscore system was constructed using Cox proportional hazard analysis. PD-L1+ immune cells (IC), PD-L1+ tumor cells (TC), PD-1hi, and CD8More were found among 33.33%, 31.37%, 33.33%, and 49%, respectively, of patients from the discovery cohort, and 41.74%, 17.4%, 38.26%, and 30.43% from the validation cohort. PD-L1+ ICs and PD-1hi ICs correlated with poorer overall survival (OS), but PD-L1+ TCs correlated with better OS and clinical outcomes and infiltration of more CD8+ T cells. These four factors were independently prognostic after tumor/lymph nodes/metastasis (TNM) stage adjustment. An immunoscore system based on hazard ratios of the four factors further separated gastric cancer patients with similar TNM staging into low-, medium-, or high-risk groups, with significantly different survival. Our prognostic model yielded an area under the receiver operating characteristic curve (AUC) of 0.856 for prediction of mortality at 5 years, superior to that of TNM staging (AUC of 0.676). Thus, this more comprehensive immunoscore system can provide more accurate prognoses and is an essential complement to the AJCC staging system for operable gastric cancer patients. Cancer Immunol Res; 5(7); 524-34. (c)2017 AACR. PMID- 28619969 TI - Tension enterothorax and hepatothorax due to a diaphragmatic hernia: successful emergency repair of a life-threatening condition. AB - A 70-year-old female patient presented with acute severe respiratory distress at a district general hospital. Medical history included type 2 diabetes, recurrent pulmonary embolisms and pre-existing diaphragmatic hernia containing part of the liver. Despite initial treatment with steroid inhalers, her clinical picture rapidly deteriorated requiring emergency intubation and positive pressure ventilation. Imaging investigations revealed tension enterothorax and hepatothorax with tracheal deviation. The patient was transferred and underwent an emergency laparotomy at the Regional Oesophagogastric Unit. A large diaphragmatic hernia (central tendon defect) which contained the duodenum, porta hepatis, right lobe of liver, gallbladder and right colon was reduced and successfully repaired. Her postoperative course was uneventful with no signs of recurrence at 2 months follow-up.This case describes an extremely rare and life threatening condition of tension enterothorax and hepatothorax, which should be considered in the differential diagnosis of acute respiratory distress with tracheal deviation. PMID- 28619968 TI - Breast Cancer Neoantigens Can Induce CD8+ T-Cell Responses and Antitumor Immunity. AB - Next-generation sequencing technologies have provided insights into the biology and mutational landscape of cancer. Here, we evaluate the relevance of cancer neoantigens in human breast cancers. Using patient-derived xenografts from three patients with advanced breast cancer (xenografts were designated as WHIM30, WHIM35, and WHIM37), we sequenced exomes of tumor and patient-matched normal cells. We identified 2,091 (WHIM30), 354 (WHIM35), and 235 (WHIM37) nonsynonymous somatic mutations. A computational analysis identified and prioritized HLA class I-restricted candidate neoantigens expressed in the dominant tumor clone. Each candidate neoantigen was evaluated using peptide-binding assays, T-cell cultures that measure the ability of CD8+ T cells to recognize candidate neoantigens, and preclinical models in which we measured antitumor immunity. Our results demonstrate that breast cancer neoantigens can be recognized by the immune system, and that human CD8+ T cells enriched for prioritized breast cancer neoantigens were able to protect mice from tumor challenge with autologous patient-derived xenografts. We conclude that next-generation sequencing and epitope-prediction strategies can identify and prioritize candidate neoantigens for immune targeting in breast cancer. Cancer Immunol Res; 5(7); 516-23. (c)2017 AACR. PMID- 28619970 TI - Large bladder calculus masking a stone in single-system ureterocele. AB - Ureterocele in an elderly is a rare entity. The presence of stone within ureterocele along with a large bladder calculus is an even rarer presentation. This phenomenon has not been reported so far to the best of our knowledge. We present an unusual case of a large bladder calculus with a concomitant stone in the associated ureterocele. The diagnosis was missed in the first instance due to the masking effect by the larger bladder calculus. Herein, we discuss this case and its management. PMID- 28619971 TI - McSwain type V appendix intussusception. PMID- 28619972 TI - Staged curative treatment of a complex direct carotid-cavernous fistula with a large arterial defect and an 'oversized' internal carotid artery. AB - This is a case of a high-flow, post-traumatic direct carotid-cavernous fistula with a widened arterial defect and a large-diameter internal carotid artery (ICA). The unique aspect of this case is the oversized ICA, >8mm in diameter, which is both a pathological and a therapeutic challenge, given the lack of available neuroendovascular devices for full vessel reconstruction. We present a planned two-stage embolisation paradigm for definitive treatment. Transarterial coil embolisation is performed as the first stage to disconnect the fistula and normalise flow in the ICA. A 3-month recovery period is then allowed for reduction in carotid diameter. Repair of the large vessel defect and pseudoaneurysm is performed as a second stage in a delayed fashion with a flow diverting device. Follow-up angiography at 6 months demonstrates obliteration of the fistula and curative ICA reconstruction to a diameter <5mm. PMID- 28619973 TI - Marjolin's squamous cell carcinoma of the hallux following recurrent ingrown toenail infections. AB - Marjolin's squamous cell carcinoma (SCC) affecting the toe is rare. Due to resemblance with benign conditions it can often result in misdiagnosis. We report a case of Marjolin's SCC affecting the proximal hallux in a patient with recurrent ingrown toenail infections. A 58-year-old woman with a background of wedge resections for ingrown toenail and distal phalanx amputation for osteomyelitis presented with pain and hyperkeratotic raised ulcer around the proximal phalanx. MRI scan revealed soft tissue mass infiltrating the proximal phalanx with biopsies confirming a SCC. The patient underwent first ray amputation and made a good clinical recovery and remains disease free. Due to clinical similarities with benign conditions, awareness of Marjolin's SCC as a potential diagnosis when treating patients with recurrent ingrown toenail is imperative. We recommend patients with recurrent ingrown toenail or ulceration with a background of chronic infection have biopsies performed to exclude potential malignancy. PMID- 28619974 TI - Twenty-nine-month follow-up of a paediatric zirconia dental crown. AB - The aim of this paper is to present the long-term follow-up of one paediatric zirconia crown on a deciduous molar. Preformed crowns are part of the armamentarium in paediatric dentistry. In recent years, aesthetic alternatives to preformed metal crowns have been developed, first preveneered crowns and then zirconia crowns. This paper describes the restoration of a primary molar with a zirconia crown (EZ-Pedo, Loomis, California, USA) in an 8-year-old boy. In this clinical case, the protocol for the implementation and maintenance of zirconia crowns is detailed. The patient was followed up for 29 months until the natural exfoliation of his primary molar. The adaptation of the zirconia crown, the gingival health and the wear on the opposing tooth were considered. In this case, the paediatric zirconia crown allowed sustainable functional restoration while restoring a natural appearance of the tooth. PMID- 28619975 TI - Antibiotic-associated haemorrhagic colitis: not always Clostridium difficile. AB - Antibiotic-associated colitis is a gastrointestinal complication of antibiotic use commonly seen in hospitalised patients, with Clostridium difficile (C. difficile) colitis being the most common type. We present a case of haemorrhagic colitis secondary to Klebsiella oxytoca following self-initiated amoxicillin clavulanic acid use. An 85-year-old woman presented to the emergency department with abdominal pain and mucobloody diarrhoea. History was notable for an ongoing 5-day course of amoxicillin-clavulanic acid use. The CT scan of her abdomen revealed extensive diffuse thickening of the ascending and transverse colon. Stool culture grew K. oxytoca, an established cause of haemorrhagic colitis. She declined colonoscopy but recovered with withdrawal of all antibiotics and conservative treatment. We should be vigilant to haemorrhagic colitis following antibiotic use which is not always C. difficile related. PMID- 28619976 TI - Vesical dermoid: a rare bladder tumour. AB - Dermoid cysts are benign developmental lesions consisting of tissues of more than one germ cell lineage origin. The urinary bladder is a very rare location of dermoid cysts. We report a case of an 18-year-old woman who presented with suprapubic pain, dysuria and turbid urine. Blood and serum chemistry was normal. Contrast-enhanced CT revealed a heterogeneously enhancing mass of 2.5*2 cm within the urinary bladder infiltrating fundus of urinary bladder with extraluminal extension. At cystoscopy, an irregular mass arising from the dome of the urinary bladder with a covering of hair and whitish scales was seen. The patient was managed by transperitoneal laparoscopic partial cystectomy with left oophorectomy. Histology revealed dermoid cyst arising from the urinary bladder and simple serous cyst in the ovary. Postoperative course was uneventful. PMID- 28619977 TI - Infectious crystalline keratopathy after Descemeta?TMs stripping endothelial keratoplasty. AB - A 68-year-old woman presented with infectious crystalline keratopathy 4 months after she underwent a combined phacoemulsification and Descemet's stripping endothelial keratoplasty for Fuch's endothelial dystrophy in her left eye. After 5 months of topical moxifloxacin 1%, the infiltrate responded well but had not completely resolved, with the resulting endothelial failure requiring a penetrating keratoplasty 9 months after the initial operation. Microbiology identified Enterococcus faecalis with the histopathology demonstrating bacterial colonies within the graft interface. Postoperatively she developed endophthalmitis, needing vitrectomy and intravitreal antibiotics. The infection settled with no recurrence, with topical and oral antibiotics continued for 2 months. A sutured toric piggyback intraocular lens was performed 18 months postvitrectomy for graft astigmatism, achieving a best-corrected vision of 6/15.Infectious crystalline keratopathy can occur following Descemet's stripping endothelial keratoplasty, requiring long-term topical therapy and potentially leading to graft failure with the necessity for further keratoplasty. PMID- 28619978 TI - Rheumatoid arthritis causing diffuse alveolar haemorrhage: a novel therapeutic approach. AB - Pulmonary vascular involvement due to rheumatoid arthritis, presenting as diffuse alveolar haemorrhage (DAH), is a rare phenomenon, especially if there are no signs of systemic vasculitides. Furthermore, how to proceed with the management of these patients is challenging, as in the case of our patient, who had recurrent DAH. We present a case of a patient with known rheumatoid arthritis who had recurrence of DAH that spanned over several years, often presenting with life threatening respiratory failure. While her DAH presentation improved with high dose glucocorticoids, to resolve her recurrence, we opted to initiate treatment with rituximab, with a short course of azathioprine. After the second round of rituximab, the patient continues to do well without any further DAH-related complications. We also summarise prior cases of such patients to highlight variable treatment options. PMID- 28619979 TI - Modeling Cancer Mutations in 3-D. AB - Researchers from the Wellcome Trust Sanger Institute have launched COSMIC-3D, a tool that allows scientists to explore how cancer mutations affect the structure and function of more than 8,000 human proteins. They hope COSMIC-3D, which is freely available on the web, will facilitate the design of new cancer drugs. PMID- 28619980 TI - Pan-Cancer Analysis Pinpoints Targets in PI3K Pathway. AB - A new study of all 32 cancer types in The Cancer Genome Atlas identifies genomic alterations that increase the activity of the PI3K/AKT/mTOR pathway. The study, which combines mutation data with measures of protein levels and phosphorylation status, suggests that mutations in IDH1, VHL, and STK11 promote activation of the pathway and may point to new drug targets. PMID- 28619983 TI - Failure to replicate thrombomodulin genetic variant predictors of venous thromboembolism in African Americans. PMID- 28619981 TI - Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. AB - Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll like receptors with NF-kappaB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110alpha/p110delta or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018-29. (c)2017 AACR.See related commentary by Lakshmanan and Byrd, p. 940This article is highlighted in the In This Issue feature, p. 920. PMID- 28619982 TI - JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell induced protection of AML. AB - The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be a result of the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the effect of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions. In the stroma-based conditions, the AML patient cells exhibited significantly reduced sensitivity to 12% of the tested compounds, including topoisomerase II, B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2), and many tyrosine kinase inhibitors (TKIs). The loss of TKI sensitivity was most pronounced in patient samples harboring FLT3 or PDGFRB alterations. In contrast, the stroma-derived conditions enhanced sensitivity to Janus kinase (JAK) inhibitors. Increased cell viability and resistance to specific drug classes in the BM stroma-derived conditions was a result of activation of alternative signaling pathways mediated by factors secreted by BM stromal cells and involved a switch from BCL2 to BCLXL-dependent cell survival. Moreover, the JAK1/2 inhibitor ruxolitinib restored sensitivity to the BCL2 inhibitor venetoclax in AML patient cells ex vivo in different model systems and in vivo in an AML xenograft mouse model. These findings highlight the potential of JAK inhibitors to counteract stroma-induced resistance to BCL2 inhibitors in AML. PMID- 28619984 TI - Mitochondrial Integrity and Function in the Progression of Early Pressure Overload-Induced Left Ventricular Remodeling. AB - BACKGROUND: Following pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload-induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction. METHODS AND RESULTS: Sprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post-ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium-calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p-phospholamban, S16, increased sodium-calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl-2). CONCLUSIONS: After pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction. PMID- 28619985 TI - Long-Term Improvements After Multimodal Rehabilitation in Late Phase After Stroke: A Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Treatments that improve function in late phase after stroke are urgently needed. We assessed whether multimodal interventions based on rhythm-and-music therapy or horse-riding therapy could lead to increased perceived recovery and functional improvement in a mixed population of individuals in late phase after stroke. METHODS: Participants were assigned to rhythm-and-music therapy, horse-riding therapy, or control using concealed randomization, stratified with respect to sex and stroke laterality. Therapy was given twice a week for 12 weeks. The primary outcome was change in participants' perception of stroke recovery as assessed by the Stroke Impact Scale with an intention-to-treat analysis. Secondary objective outcome measures were changes in balance, gait, grip strength, and cognition. Blinded assessments were performed at baseline, postintervention, and at 3- and 6-month follow-up. RESULTS: One hundred twenty-three participants were assigned to rhythm-and-music therapy (n=41), horse-riding therapy (n=41), or control (n=41). Post-intervention, the perception of stroke recovery (mean change from baseline on a scale ranging from 1 to 100) was higher among rhythm-and-music therapy (5.2 [95% confidence interval, 0.79-9.61]) and horse-riding therapy participants (9.8 [95% confidence interval, 6.00-13.66]), compared with controls (-0.5 [-3.20 to 2.28]); P=0.001 (1 way ANOVA). The improvements were sustained in both intervention groups 6 months later, and corresponding gains were observed for the secondary outcomes. CONCLUSIONS: Multimodal interventions can improve long-term perception of recovery, as well as balance, gait, grip strength, and working memory in a mixed population of individuals in late phase after stroke. CLINICAL TRIAL REGISTRATION: URL: http//www.ClinicalTrials.gov. Unique identifier: NCT01372059. PMID- 28619986 TI - Contribution of Established Stroke Risk Factors to the Burden of Stroke in Young Adults. AB - BACKGROUND AND PURPOSE: As stroke in young adults is assumed to have different etiologies and risk factors than in older populations, the aim of this study was to examine the contribution of established potentially modifiable cardiovascular risk factors to the burden of stroke in young adults. METHODS: A German nationwide case-control study based on patients enrolled in the SIFAP1 study (Stroke In Young Fabry Patients) 2007 to 2010 and controls from the population based GEDA study (German Health Update) 2009 to 2010 was performed. Cases were 2125 consecutive patients aged 18 to 55 years with acute first-ever stroke from 26 clinical stroke centers; controls (age- and sex-matched, n=8500, without previous stroke) were from a nationwide community sample. Adjusted population attributable risks of 8 risk factors (hypertension, hyperlipidemia, diabetes mellitus, coronary heart disease, smoking, heavy episodic alcohol consumption, low physical activity, and obesity) and their combinations for all stroke, ischemic stroke, and primary intracerebral hemorrhage were calculated. RESULTS: Low physical activity and hypertension were the most important risk factors, accounting for 59.7% (95% confidence interval, 56.3-63.2) and 27.1% (95% confidence interval, 23.6-30.6) of all strokes, respectively. All 8 risk factors combined explained 78.9% (95% confidence interval, 76.3-81.4) of all strokes. Population-attributable risks of all risk factors were similar for all ischemic stroke subtypes. Population-attributable risks of most risk factors were higher in older age groups and in men. CONCLUSIONS: Modifiable risk factors previously established in older populations also account for a large part of stroke in younger adults, with 4 risk factors explaining almost 80% of stroke risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583. PMID- 28619987 TI - Letter by Iguchi and Nango Regarding Article, "Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis". PMID- 28619988 TI - Another Enchantment From ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study): Are Savings and Safety More Salutary Than Efficacy? PMID- 28619990 TI - Response by Lee et al to Letter Regarding Article, "Pioglitazone for Secondary Stroke Prevention: A Systematic Review and Meta-Analysis". PMID- 28619989 TI - Low- Versus Standard-Dose Alteplase in Patients on Prior Antiplatelet Therapy: The ENCHANTED Trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study). AB - BACKGROUND AND PURPOSE: Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2-6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. RESULTS: There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81 1.26; P=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75-1.20; P=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87-1.21; P=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00-3.30; P=0.051) according to the safe implementation of thrombolysis in stroke monitoring study definition. Although not significant (P-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2-6; OR, 0.84; 95% CI, 0.62-1.12 versus OR, 1.16; 95% CI, 0.99-1.36). CONCLUSIONS: Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616. PMID- 28619991 TI - Evidence that differentiation-inducing factor-1 controls chemotaxis and cell differentiation, at least in part, via mitochondria in D. discoideum. AB - Differentiation-inducing factor-1 [1-(3,5-dichloro-2,6-dihydroxy-4 methoxyphenyl)hexan-1-one (DIF-1)] is an important regulator of cell differentiation and chemotaxis in the development of the cellular slime mold Dictyostelium discoideum However, the entire signaling pathways downstream of DIF 1 remain to be elucidated. To characterize DIF-1 and its potential receptor(s), we synthesized two fluorescent derivatives of DIF-1, boron-dipyrromethene (BODIPY)-conjugated DIF-1 (DIF-1-BODIPY) and nitrobenzoxadiazole (NBD)-conjugated DIF-1 (DIF-1-NBD), and investigated their biological activities and cellular localization. DIF-1-BODIPY (5 uM) and DIF-1 (2 nM) induced stalk cell differentiation in the DIF-deficient strain HM44 in the presence of cyclic adenosine monosphosphate (cAMP), whereas DIF-1-NBD (5 uM) hardly induced stalk cell differentiation under the same conditions. Microscopic analyses revealed that the biologically active derivative, DIF-1-BODIPY, was incorporated by stalk cells at late stages of differentiation and was localized to mitochondria. The mitochondrial uncouplers carbonyl cyanide m-chlorophenylhydrazone (CCCP), at 25 50 nM, and dinitrophenol (DNP), at 2.5-5 uM, induced partial stalk cell differentiation in HM44 in the presence of cAMP. DIF-1-BODIPY (1-2 uM) and DIF-1 (10 nM), as well as CCCP and DNP, suppressed chemotaxis in the wild-type strain Ax2 in shallow cAMP gradients. These results suggest that DIF-1-BODIPY and DIF-1 induce stalk cell differentiation and modulate chemotaxis, at least in part, by disturbing mitochondrial activity. PMID- 28619993 TI - Low extracellular potassium prolongs repolarization and evokes early afterdepolarization in human induced pluripotent stem cell-derived cardiomyocytes. AB - Long QT syndrome (LQTS) is characterized by a prolonged QT-interval on electrocardiogram and by increased risk of sudden death. One of the most common and potentially life-threatening electrolyte disturbances is hypokalemia, characterized by low concentrations of K+ Using a multielectrode array platform and current clamp technique, we investigated the effect of low extracellular K+ concentration ([K+]Ex) on the electrophysiological properties of hiPSC-derived cardiomyocytes (CMs) generated from a healthy control subject (WT) and from two symptomatic patients with type 1 of LQTS carrying G589D (LQT1A) or IVS7-2A>G mutation (LQT1B) in KCNQ1 The baseline prolongations of field potential durations (FPDs) and action potential durations (APDs) were longer in LQT1-CMs than in WT CMs. Exposure to low [K+]Ex prolonged FPDs and APDs in a concentration-dependent fashion. LQT1-CMs were found to be more sensitive to low [K+]Ex compared to WT CMs. At baseline, LQT1A-CMs had more prolonged APDs than LQT1B-CMs, but low [K+]Ex caused more pronounced APD prolongation in LQT1B-CMs. Early afterdepolarizations in the action potentials were observed in a subset of LQT1A CMs with further prolonged baseline APDs and triangular phase 2 profiles. This work demonstrates that the hiPSC-derived CMs are sensitive to low [K+]Ex and provide a platform to study acquired LQTS. PMID- 28619992 TI - Patterning and gastrulation defects caused by the tw18 lethal are due to loss of Ppp2r1a. AB - The mouse t haplotype, a variant 20 cM genomic region on Chromosome 17, harbors 16 embryonic control genes identified by recessive lethal mutations isolated from wild mouse populations. Due to technical constraints so far only one of these, the tw5 lethal, has been cloned and molecularly characterized. Here we report the molecular isolation of the tw18 lethal. Embryos carrying the tw18 lethal die from major gastrulation defects commencing with primitive streak formation at E6.5. We have used transcriptome and marker gene analyses to describe the molecular etiology of the tw18 phenotype. We show that both WNT and Nodal signal transduction are impaired in the mutant epiblast, causing embryonic patterning defects and failure of primitive streak and mesoderm formation. By using a candidate gene approach, gene knockout by homologous recombination and genetic rescue, we have identified the gene causing the tw18 phenotype as Ppp2r1a, encoding the PP2A scaffolding subunit PR65alpha. Our work highlights the importance of phosphatase 2A in embryonic patterning, primitive streak formation, gastrulation, and mesoderm formation downstream of WNT and Nodal signaling. PMID- 28619994 TI - Simultaneous stimulation of glycolysis and gluconeogenesis by feeding in the anterior intestine of the omnivorous GIFT tilapia, Oreochromis niloticus. AB - The present study was performed to investigate the roles of anterior intestine in the postprandial glucose homeostasis of the omnivorous Genetically Improved Farmed Tilapia (GIFT). Sub-adult fish (about 173 g) were sampled at 0, 1, 3, 8 and 24 h post feeding (HPF) after 36 h of food deprivation, and the time course of changes in intestinal glucose transport, glycolysis, glycogenesis and gluconeogenesis at the transcription and enzyme activity level, as well as plasma glucose contents, were analyzed. Compared with 0 HPF (fasting for 36 h), the mRNA levels of both ATP-dependent sodium/glucose cotransporter 1 and facilitated glucose transporter 2 increased during 1-3 HPF, decreased at 8 HPF and then leveled off. These results indicated that intestinal uptake of glucose and its transport across the intestine to blood mainly occurred during 1-3 HPF, which subsequently resulted in the increase of plasma glucose level at the same time. Intestinal glycolysis was stimulated during 1-3 HPF, while glucose storage as glycogen was induced during 3-8 HPF. Unexpectedly, intestinal gluconeogenesis (IGNG) was also strongly induced during 1-3 HPF at the state of nutrient assimilation. The mRNA abundance and enzyme activities of glutamic-pyruvic and glutamic-oxaloacetic transaminases increased during 1-3 HPF, suggesting that the precursors of IGNG might originate from some amino acids. Taken together, it was concluded that the anterior intestine played an important role in the regulation of postprandial glucose homeostasis in omnivorous tilapia, as it represented significant glycolytic potential and glucose storage. It was interesting that postprandial IGNG was stimulated by feeding temporarily, and its biological significance remains to be elucidated in fish. PMID- 28619995 TI - Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-beta in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. AB - OBJECTIVE: We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly. APPROACH AND RESULTS: Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-beta1 (TGFbeta1). Thus, we considered whether BMPs like TGFbeta1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFbeta1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFbeta1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFbeta1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFbeta1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFbeta1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension. CONCLUSIONS: Disrupting BMPR2 impairs TGFbeta1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH. PMID- 28619999 TI - PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. AB - Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated.Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab.Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012-<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2-positive than PD-L2-negative patients.Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients. Clin Cancer Res; 23(12); 3158-67. (c)2017 AACR. PMID- 28619996 TI - Farnesoid X Receptor and Liver X Receptor Ligands Initiate Formation of Coated Platelets. AB - OBJECTIVES: The liver X receptors (LXRs) and farnesoid X receptor (FXR) have been identified in human platelets. Ligands of these receptors have been shown to have nongenomic inhibitory effects on platelet activation by platelet agonists. This, however, seems contradictory with the platelet hyper-reactivity that is associated with several pathological conditions that are associated with increased circulating levels of molecules that are LXR and FXR ligands, such as hyperlipidemia, type 2 diabetes mellitus, and obesity. APPROACH AND RESULTS: We, therefore, investigated whether ligands for the LXR and FXR receptors were capable of priming platelets to the activated state without stimulation by platelet agonists. Treatment of platelets with ligands for LXR and FXR converted platelets to the procoagulant state, with increases in phosphatidylserine exposure, platelet swelling, reduced membrane integrity, depolarization of the mitochondrial membrane, and microparticle release observed. Additionally, platelets also displayed features associated with coated platelets such as P selectin exposure, fibrinogen binding, fibrin generation that is supported by increased serine protease activity, and inhibition of integrin alphaIIbbeta3. LXR and FXR ligand-induced formation of coated platelets was found to be dependent on both reactive oxygen species and intracellular calcium mobilization, and for FXR ligands, this process was found to be dependent on cyclophilin D. CONCLUSIONS: We conclude that treatment with LXR and FXR ligands initiates coated platelet formation, which is thought to support coagulation but results in desensitization to platelet stimuli through inhibition of alphaIIbbeta3 consistent with their ability to inhibit platelet function and stable thrombus formation in vivo. PMID- 28620000 TI - Inhibitor of Pancreatic Cancer by RHIL1RA-Letter. PMID- 28619997 TI - Cardiotonic Steroids Stimulate Macrophage Inflammatory Responses Through a Pathway Involving CD36, TLR4, and Na/K-ATPase. AB - OBJECTIVE: Circulating levels of cardiotonic steroids (CTS) are elevated in various chronic inflammatory conditions, but the role of CTS in inflammation remains largely unknown. We have previously shown that the CTS ouabain stimulates proinflammatory responses in murine macrophages. In this study, we aim to explore the mechanism how CTS induce proinflammatory responses in primary murine and human macrophages. APPROACH AND RESULTS: Using both murine peritoneal macrophages and human monocyte-derived macrophages, we demonstrated that ouabain activated NF kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells), leading to proinflammatory cytokine (eg, MCP-1 [monocyte chemotactic protein 1], TNF alpha [tumor necrosis factor-alpha], IL-1beta [interleukin-1beta], and IL-6) production. By applying siRNA techniques and murine peritoneal macrophages isolated from genetically modified mice, we showed that macrophages partially deficient in Na/K-ATPase, the receptor for CTS, or fully deficient in the scavenger receptor CD36 or TLR4 (Toll-like receptor) were resistant to ouabain induced NF-kappaB activation, suggesting an indispensable role of these 3 receptors in this pathway. Mechanistically, this effect of ouabain was independent of the ion transport function of the Na/K-ATPase. Instead, ouabain stimulated a signaling complex, including Na/K-ATPase, CD36, and TLR4. Subsequently, TLR4 recruited MyD88 adaptor protein for NF-kappaB activation. Furthermore, intraperitoneal injection of ouabain into mice specifically recruited Ly6C+CCR2+ monocyte subtypes to the peritoneal cavities, indicating that the CTS ouabain triggers inflammation in vivo. CONCLUSIONS: CTS activate NF kappaB leading to proinflammatory cytokine production in primary macrophages through a signaling complex, including CD36, TLR4, and Na/K-ATPase. These findings warrant further studies on endogenous CTS in chronic inflammatory diseases, such as atherosclerosis. PMID- 28620001 TI - Inhibition of Pancreatic Cancer by RhIL1RA-Response. PMID- 28620002 TI - Correction: Frequent Overexpression of HMGA2 in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with let-7a3/let-7b miRNA. PMID- 28620003 TI - Correction: Indole-3-Carbinol Synergizes with and Restores Fludarabine Sensitivity in Chronic Lymphocytic Leukemia Cells Irrespective of p53 Activity and Treatment Resistances. PMID- 28620004 TI - Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1. AB - Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46-e53. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28620005 TI - Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders. AB - The neurofibromatoses consist of at least three autosomal-dominant inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. For over 80 years, these conditions were inextricably tied together under generalized neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis. The last 26 years have seen a great improvement in understanding of the clinical and molecular features of these conditions as well as insights into management. Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multitumor disease course. Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central nervous system (CNS) tumors necessitating MRI surveillance to optimize management. At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic. Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of tumor involvement. The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition. Clin Cancer Res; 23(12); e54-e61. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28620006 TI - Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. AB - Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU)SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive "rhabdoid" term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations. Clin Cancer Res; 23(12); e62-e67. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28620007 TI - Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. AB - Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors. Clin Cancer Res; 23(12); e68-e75. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28620008 TI - PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood. AB - PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76-e82. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28620010 TI - An unusual pelvis radiograph. PMID- 28620009 TI - Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk. AB - In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83-e90. (c)2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series. PMID- 28620011 TI - Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Delta/- mice. AB - DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model (Ercc1Delta/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1Delta/ mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Delta/- DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Delta/- mice. Ercc1Delta/- mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective. PMID- 28620012 TI - Metabolic disturbances of non-alcoholic fatty liver resemble the alterations typical for type 2 diabetes. AB - Non-alcoholic fatty liver (NAFL) is an independent risk factor for the development of type 2 diabetes (T2DM). We examined metabolic perturbations in patients with NAFL, patients with T2DM, and control (CON) subjects with normal intrahepatic lipid (IHL) content.A two-step (10 mU/m2 /min; 40 mU/m2/min) hyperinsulinemic-euglycemic clamp was performed in 11 NAFL, 13 T2DM, and 11 CON subjects, all matched for BMI, and aerobic fitness. IHL content was measured using proton magnetic resonance spectroscopy. Because of high IHL content variability in T2DM patients, this group was separated into a high IHL content group (IHL >= 5.0%, T2DM+NAFL) and a normal IHL content group (IHL < 5.0%, T2DM non-NAFL) for further analysis.IHL content was increased in NAFL and T2DM+NAFL subjects (P<0.050 versus CON and T2DM-non-NAFL subjects). Adipose tissue insulin sensitivity index (Adipo-IRi) was higher in NAFL (P<0.050 versus CON and T2DM-non NAFL subjects) and in T2DM+NAFL subjects (P=0.055 versus CON subjects, P<0.050 versus T2DM-non-NAFL subjects). Suppression of plasma-free fatty acids (P=0.046) was lower in NAFL compared with CON subjects, with intermediate values for T2DM non-NAFL, and T2DM+NAFL subjects. Suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disposal (DeltaRd) was comparable between NAFL, T2DM-non-NAFL, and T2DM+NAFL subjects (all P>0.05), and was lower in comparison with CON subjects (all P<0.01). Metabolic flexibility was lower in T2DM-non-NAFL subjects (P=0.047) and NAFL subjects (P=0.059) compared with CON subjects. Adipo-IRi (r=0.652, P<0.001), hepatic insulin resistance index (HIRi) (r=0.576, P=0.001), and DeltaRd (r=-0.653, P<0.001) correlated with IHL content.Individuals with NAFL suffer from metabolic perturbations to a similar degree as T2DM patients. NAFL is an important feature leading to severe insulin resistance and should be viewed as a serious health threat for the development of T2DM. ClinicalTrials.gov: NCT01317576. PMID- 28620013 TI - The evolution of vertical climbing in primates: evidence from reaction forces. AB - Vertical climbing is an essential behavior for arboreal animals, yet limb mechanics during climbing are poorly understood and rarely compared with those observed during horizontal walking. Primates commonly engage in both arboreal walking and vertical climbing, and this makes them an ideal taxa in which to compare these locomotor forms. Additionally, primates exhibit unusual limb mechanics compared with most other quadrupeds, with weight distribution biased towards the hindlimbs, a pattern that is argued to have evolved in response to the challenges of arboreal walking. Here we test an alternative hypothesis that functional differentiation between the limbs evolved initially as a response to climbing. Eight primate species were recorded locomoting on instrumented vertical and horizontal simulated arboreal runways. Forces along the axis of, and normal to, the support were recorded. During walking, all primates displayed forelimbs that were net braking, and hindlimbs that were net propulsive. In contrast, both limbs served a propulsive role during climbing. In all species, except the lorisids, the hindlimbs produced greater propulsive forces than the forelimbs during climbing. During climbing, the hindlimbs tends to support compressive loads, while the forelimb forces tend to be primarily tensile. This functional disparity appears to be body-size dependent. The tensile loading of the forelimbs versus the compressive loading of the hindlimbs observed during climbing may have important evolutionary implications for primates, and it may be the case that hindlimb-biased weight support exhibited during quadrupedal walking in primates may be derived from their basal condition of climbing thin branches. PMID- 28620014 TI - The tendinopathic Achilles tendon does not remain iso-volumetric upon repeated loading: insights from 3D ultrasound. AB - Mid-portion Achilles tendinopathy (MAT) alters the normal three-dimensional (3D) morphology of the Achilles tendon (AT) at rest and under a single tensile load. However, how MAT changes the 3D morphology of the AT during repeated loading remains unclear. This study compared the AT longitudinal, transverse and volume strains during repeated loading of the tendinopathic AT with those of the contralateral tendon in people with unilateral MAT. Ten adults with unilateral MAT performed 10 successive 25 s submaximal (50%) voluntary isometric plantarflexion contractions with both legs. Freehand 3D ultrasound scans were recorded and used to measure whole AT, free AT and proximal AT longitudinal strains and free AT cross-sectional area (CSA) and volume strains. The free AT experienced higher longitudinal and CSA strain and reached steady state following a greater number of contractions (five contractions) in the tendinopathic AT compared with the contralateral tendon (three contractions). Further, free tendon CSA and volume strain were greater in the tendinopathic AT than in the contralateral tendon from the first contraction, whereas free AT longitudinal strain was not greater than that of the contralateral tendon until the fourth contraction. Volume loss from the tendon core therefore preceded the greater longitudinal strain in the tendinopathic AT. Overall, these findings suggest that the tendinopathic free AT experiences an exaggerated longitudinal and transverse strain response under repeated loading that is underpinned by an altered interaction between solid and fluid tendon matrix components. These alterations are indicative of accentuated poroelasticity and an altered local stress-strain environment within the tendinopathic free tendon matrix, which could affect tendon remodelling via mechanobiological pathways. PMID- 28620016 TI - Correction for Doller et al., "Tandem Phosphorylation of Serines 221 and 318 by Protein Kinase Cdelta Coordinates mRNA Binding and Nucleocytoplasmic Shuttling of HuR". PMID- 28620015 TI - Genetic editing of the androgen receptor contributes to impaired male courtship behavior in zebrafish. AB - Elucidating the genes that contribute to behavioral variation has become an important endeavor in behavioral studies. While advances in genomics have narrowed down the list of candidate genes, functional validation of them has lagged behind, partly because of challenges associated with rapid gene manipulations. Consequently, few studies have demonstrated causal genetic changes linked to behaviors. The 'gene editing revolution' has offered unprecedented opportunities to investigate candidate genes responsible for critical behaviors. Here, we edited the androgen receptor gene (AR), which is associated with male reproductive behavior in zebrafish, using TAL effector nucleases (TALENs), and tested whether modifications at the AR impacted courtship during mating trials. We reveal that males lacking AR courted females significantly less, showing reduced levels of stereotypic behaviors. Consistent with previous studies, disrupting androgen mechanisms can lead to behavioral changes with potential fitness consequences. Our study highlights the possibility of genetically altering a reproductive behavior, further solidifying the link between genotype and behavior. PMID- 28620017 TI - Correction for Guo et al., "Poly(A) Signals Located near the 5' End of Genes Are Silenced by a General Mechanism That Prevents Premature 3'-End Processing". PMID- 28620018 TI - Correction for Papa and Germain, "SirT3 Regulates a Novel Arm of the Mitochondrial Unfolded Protein Response". PMID- 28620019 TI - Correction for Carmon et al., "LGR5 Interacts and Cointernalizes with Wnt Receptors To Modulate Wnt/beta-Catenin Signaling". PMID- 28620020 TI - Correction for Panasenko and Collart, "Not4 E3 Ligase Contributes to Proteasome Assembly and Functional Integrity in Part through Ecm29". PMID- 28620021 TI - Correction for Wolff et al., "Cell-Type-Dependent Regulation of mTORC1 by REDD1 and the Tumor Suppressors TSC1/TSC2 and LKB1 in Response to Hypoxia". PMID- 28620023 TI - Synthetic biology engineering of biofilms as nanomaterials factories. AB - Bottom-up fabrication of nanoscale materials has been a significant focus in materials science for expanding our technological frontiers. This assembly concept, however, is old news to biology - all living organisms fabricate themselves using bottom-up principles through a vast self-organizing system of incredibly complex biomolecules, a marvelous dynamic that we are still attempting to unravel. Can we use what we have gleaned from biology thus far to illuminate alternative strategies for designer nanomaterial manufacturing? In the present review article, new synthetic biology efforts toward using bacterial biofilms as platforms for the synthesis and secretion of programmable nanomaterials are described. Particular focus is given to self-assembling functional amyloids found in bacterial biofilms as re-engineerable modular nanomolecular components. Potential applications and existing challenges for this technology are also explored. This novel approach for repurposing biofilm systems will enable future technologies for using engineered living systems to grow artificial nanomaterials. PMID- 28620024 TI - Signalling assemblies: the odds of symmetry. AB - The assembly of proteins into complexes is fundamental to nearly all biological signalling processes. Symmetry is a dominant feature of the structures of experimentally determined protein complexes, observed in the vast majority of homomers and many heteromers. However, some asymmetric structures exist, and asymmetry also often forms transiently, intractable to traditional structure determination methods. Here, we explore the role of protein complex symmetry and asymmetry in cellular signalling, focusing on receptors, transcription factors and transmembrane channels, among other signalling assemblies. We highlight a recurrent tendency for asymmetry to be crucial for signalling function, often being associated with activated states. We conclude with a discussion of how consideration of protein complex symmetry and asymmetry has significant potential implications and applications for pharmacology and human disease. PMID- 28620025 TI - Growing functions of the ESCRT machinery in cell biology and viral replication. AB - The vast expansion in recent years of the cellular processes promoted by the endosomal sorting complex required for transport (ESCRT) machinery has reinforced its identity as a modular system that uses multiple adaptors to recruit the core membrane remodelling activity at different intracellular sites and facilitate membrane scission. Functional connections to processes such as the aurora B dependent abscission checkpoint also highlight the importance of the spatiotemporal regulation of the ESCRT machinery. Here, we summarise the role of ESCRTs in viral budding, and what we have learned about the ESCRT pathway from studying this process. These advances are discussed in the context of areas of cell biology that have been transformed by research in the ESCRT field, including cytokinetic abscission, nuclear envelope resealing and plasma membrane repair. PMID- 28620026 TI - Learning to read and write in evolution: from static pseudoenzymes and pseudosignalers to dynamic gear shifters. AB - We present a systems biology view on pseudoenzymes that acknowledges that genes are not selfish: the genome is. With network function as the selectable unit, there has been an evolutionary bonus for recombination of functions of and within proteins. Many proteins house a functionality by which they 'read' the cell's state, and one by which they 'write' and thereby change that state. Should the writer domain lose its cognate function, a 'pseudoenzyme' or 'pseudosignaler' arises. GlnK involved in Escherichia coli ammonia assimilation may well be a pseudosignaler, associating 'reading' the nitrogen state of the cell to 'writing' the ammonium uptake activity. We identify functional pseudosignalers in the cyclin-dependent kinase complexes regulating cell-cycle progression. For the mitogen-activated protein kinase pathway, we illustrate how a 'dead' pseudosignaler could produce potentially selectable functionalities. Four billion years ago, bioenergetics may have shuffled 'electron-writers', producing various networks that all served the same function of anaerobic ATP synthesis and carbon assimilation from hydrogen and carbon dioxide, but at different ATP/acetate ratios. This would have enabled organisms to deal with variable challenges of energy need and substrate supply. The same principle might enable 'gear-shifting' in real time, by dynamically generating different pseudo-redox enzymes, reshuffling their coenzymes, and rerouting network fluxes. Non-stationary pH gradients in thermal vents together with similar such shuffling mechanisms may have produced a first selectable proton-motivated pyrophosphate synthase and subsequent ATP synthase. A combination of functionalities into enzymes, signalers, and the pseudo-versions thereof may offer fitness in terms of plasticity, both in real time and in evolution. PMID- 28620027 TI - Metal coordination in kinases and pseudokinases. AB - Protein phosphorylation, mediated by protein kinases, is a key event in the regulation of eukaryotic signal transduction. The majority of eukaryotic protein kinases perform phosphoryl transfer, assisted by two divalent metal ions. About 10% of all human protein kinases are, however, thought to be catalytically inactive. These kinases lack conserved residues of the kinase core and are classified as pseudokinases. Yet, it has been demonstrated that pseudokinases are critically involved in biological functions. Here, we show how pseudokinases have developed strategies by modifying amino acid residues in order to achieve stable, active-like conformations. This includes binding of the co-substrate ATP in a two metal-, one metal- or even no metal-binding mode. Examples of the respective pseudokinases are provided on a structural basis and compared with a canonical protein kinase, Protein Kinase A. Moreover, the functional roles of both independent metal-binding sites, Me1 and Me2, are discussed. Lack of phosphotransferase activity does not implicate a loss of function and can easily point to alternative roles of pseudokinases, i.e. acting as switches or scaffolds, and having evolved as components crucial for cellular cross-talk and signaling. Interestingly, pseudokinases are present in all kingdoms of life and their specific roles remain enigmatic. More studies are needed to unravel the crucial functions of those interesting proteins. PMID- 28620028 TI - The secret life of kinases: insights into non-catalytic signalling functions from pseudokinases. AB - Over the past decade, our understanding of the mechanisms by which pseudokinases, which comprise ~10% of the human and mouse kinomes, mediate signal transduction has advanced rapidly with increasing structural, biochemical, cellular and genetic studies. Pseudokinases are the catalytically defective counterparts of conventional, active protein kinases and have been attributed functions as protein interaction domains acting variously as allosteric modulators of conventional protein kinases and other enzymes, as regulators of protein trafficking or localisation, as hubs to nucleate assembly of signalling complexes, and as transmembrane effectors of such functions. Here, by categorising mammalian pseudokinases based on their known functions, we illustrate the mechanistic diversity among these proteins, which can be viewed as a window into understanding the non-catalytic functions that can be exerted by conventional protein kinases. PMID- 28620029 TI - How RNA acts as a nuclease: some mechanistic comparisons in the nucleolytic ribozymes. AB - Recent structural and mechanistic studies have shed considerable light on the catalytic mechanisms of nucleolytic ribozymes. The discovery of several new ribozymes in this class has now allowed comparisons to be made, and the beginnings of mechanistic groupings to emerge. PMID- 28620031 TI - TSPAN7, effector of actin nucleation required for dendritic cell-mediated transfer of HIV-1 to T cells. AB - Dendritic cells (DCs) have essential roles in early detection of pathogens and activation of both innate and adaptive immune responses. Whereas human DCs are resistant to productive HIV-1 replication, they have a unique ability to take up virus and transmit it efficiently to T lymphocytes. By doing that, HIV-1 may evade, at least in part, the first line of defense of the immune system, exploiting DCs instead to facilitate rapid infection of a large pool of immune cells. While performing an shRNA screen in human primary monocyte-derived DCs, to gain insights into this cell biological process, we discovered the role played by tetraspanin-7 (TSPAN7). This member of the tetraspanin family appears to be a positive regulator of actin nucleation and stabilization, through the ARP2/3 complex. By doing so, TSPAN7 limits HIV-1 endocytosis and maintains viral particles on actin-rich dendrites for an efficient transfer toward T lymphocytes. While studying the function of TSPAN7 in the control of actin nucleation, we also discovered the existence in DCs of two opposing forces at the plasma membrane: actin nucleation, a protrusive force which seems to counterbalance actomyosin contraction. PMID- 28620030 TI - Functions of protein phosphatase-6 in NF-kappaB signaling and in lymphocytes. AB - Protein phosphatase-6 (PP6) is a member of the PPP family of Ser/Thr phosphatases involved in intracellular signaling. PP6 is conserved among all eukaryotes, and genetics in model organisms indicates it has non-redundant functions relative to other PPP phosphatases. PP6 functions in association with conserved SAPS subunits and, in vertebrate species, forms heterotrimers with Ankrd subunits. Multiple studies have demonstrated how PP6 exerts negative control at different steps of nuclear factor kappaB signaling. Expression of PP6 catalytic subunit and the PPP6R1 subunit is especially high in hematopoietic cells and lymphoid tissues. Recent efforts at conditionally knocking out genes for PP6c or PP6R1 (SAPS1) have revealed distinctive effects on development of and signaling in lymphocytes. PMID- 28620032 TI - A moving target: structure and disorder in pursuit of Myc inhibitors. AB - The Myc proteins comprise a family of ubiquitous regulators of gene expression implicated in over half of all human cancers. They interact with a large number of other proteins, such as transcription factors, chromatin-modifying enzymes and kinases. Remarkably, few of these interactions have been characterized structurally. This is at least in part due to the intrinsically disordered nature of Myc proteins, which adopt a defined conformation only in the presence of binding partners. Owing to this behaviour, crystallographic studies on Myc proteins have been limited to short fragments in complex with other proteins. Most recently, we determined the crystal structure of Aurora-A kinase domain bound to a 28-amino acid fragment of the N-Myc transactivation domain. The structure reveals an alpha-helical segment within N-Myc capped by two tryptophan residues that recognize the surface of Aurora-A. The kinase domain acts as a molecular scaffold, independently of its catalytic activity, upon which this region of N-Myc becomes ordered. The binding site for N-Myc on Aurora-A is disrupted by certain ATP-competitive inhibitors, such as MLN8237 (alisertib) and CD532, and explains how these kinase inhibitors are able to disrupt the protein protein interaction to affect Myc destabilization. Structural studies on this and other Myc complexes will lead to the design of protein-protein interaction inhibitors as chemical tools to dissect the complex pathways of Myc regulation and function, which may be developed into Myc inhibitors for the treatment of cancer. PMID- 28620034 TI - Structural insights into the alternative oxidases: are all oxidases made equal? AB - The alternative oxidases (AOXs) are ubiquinol-oxidoreductases that are members of the diiron carboxylate superfamily. They are not only ubiquitously distributed within the plant kingdom but also found in increasing numbers within the fungal, protist, animal and prokaryotic kingdoms. Although functions of AOXs are highly diverse in general, they tend to play key roles in thermogenesis, stress tolerance (through the management of radical oxygen species) and the maintenance of mitochondrial and cellular energy homeostasis. The best structurally characterised AOX is from Trypanosoma brucei In this review, we compare the structure of AOXs, created using homology modelling, from many important species in an attempt to explain differences in activity and sensitivity to AOX inhibitors. We discuss the implications of these findings not only for future structure-based drug design but also for the design of novel AOXs for gene therapy. PMID- 28620035 TI - Molecular interactions shaping the tetraspanin web. AB - To facilitate the myriad of different (signaling) processes that take place at the plasma membrane, cells depend on a high degree of membrane protein organization. Important mediators of this organization are tetraspanin proteins. Tetraspanins interact laterally among themselves and with partner proteins to control the spatial organization of membrane proteins in large networks called the tetraspanin web. The molecular interactions underlying the formation of the tetraspanin web were hitherto mainly described based on their resistance to different detergents, a classification which does not necessarily correlate with functionality in the living cell. To look at these interactions from a more physiological point of view, this review discusses tetraspanin interactions based on their function in the tetraspanin web: (1) intramolecular interactions supporting tetraspanin structure, (2) tetraspanin-tetraspanin interactions supporting web formation, (3) tetraspanin-partner interactions adding functional partners to the web and (4) cytosolic tetraspanin interactions regulating intracellular signaling. The recent publication of the first full-length tetraspanin crystal structure sheds new light on both the intra- and intermolecular tetraspanin interactions that shape the tetraspanin web. Furthermore, recent molecular dynamic modeling studies indicate that the binding strength between tetraspanins and between tetraspanins and their partners is the complex sum of both promiscuous and specific interactions. A deeper insight into this complex mixture of interactions is essential to our fundamental understanding of the tetraspanin web and its dynamics which constitute a basic building block of the cell surface. PMID- 28620033 TI - Scissor sisters: regulation of ADAM10 by the TspanC8 tetraspanins. AB - A disintegrin and metalloprotease 10 (ADAM10) is a ubiquitously expressed transmembrane protein which is essential for embryonic development through activation of Notch proteins. ADAM10 regulates over 40 other transmembrane proteins and acts as a 'molecular scissor' by removing their extracellular regions. ADAM10 is also a receptor for alpha-toxin, a major virulence factor of Staphylococcus aureus Owing to the importance of its substrates, ADAM10 is a potential therapeutic target for cancer, neurodegenerative diseases such as Alzheimer's and prion diseases, bacterial infection and inflammatory diseases such as heart attack, stroke and asthma. However, targetting ADAM10 is likely to result in toxic side effects. The tetraspanins are a superfamily of 33 four transmembrane proteins in mammals which interact with and regulate specific partner proteins within membrane nanodomains. Tetraspanins appear to have a cone shaped structure with a cholesterol-binding cavity, which may enable tetraspanins to undergo cholesterol-regulated conformational change. An emerging paradigm for tetraspanin function is the regulation of ADAM10 by the TspanC8 subgroup of tetraspanins, namely Tspan5, 10, 14, 15, 17 and 33. This review will describe how TspanC8s are required for ADAM10 trafficking from the endoplasmic reticulum and its enzymatic maturation. Moreover, different TspanC8s localise ADAM10 to different subcellular localisations and may cause ADAM10 to adopt distinct conformations and cleavage of distinct substrates. We propose that ADAM10 should now be regarded as six different scissor proteins depending on the interacting TspanC8. Therapeutic targetting of specific TspanC8/ADAM10 complexes could allow ADAM10 targetting in a cell type- or substrate-specific manner, to treat certain diseases while minimising toxicity. PMID- 28620036 TI - Substrate selectivity in the zDHHC family of S-acyltransferases. AB - S-acylation is a reversible lipid modification occurring on cysteine residues mediated by a family of membrane-bound 'zDHHC' enzymes. S-acylation predominantly results in anchoring of soluble proteins to membrane compartments or in the trafficking of membrane proteins to different compartments. Recent work has shown that although S-acylation of some proteins may involve very weak interactions with zDHHC enzymes, a pool of zDHHC enzymes exhibit strong and specific interactions with substrates, thereby recruiting them for S-acylation. For example, the ankyrin-repeat domains of zDHHC17 and zDHHC13 interact specifically with unstructured consensus sequences present in some proteins, thus contributing to substrate specificity of these enzymes. In addition to this new information on zDHHC enzyme protein substrate specificity, recent work has also identified marked differences in selectivity of zDHHC enzymes for acyl-CoA substrates and has started to unravel the underlying molecular basis for this lipid selectivity. This review will focus on the protein and acyl-CoA selectivity of zDHHC enzymes. PMID- 28620037 TI - The more the merrier: high-throughput single-molecule techniques. AB - The single-molecule approach seeks to understand molecular mechanisms by observing biomolecular processes at the level of individual molecules. These methods have led to a developing understanding that for many processes, a diversity of behaviours will be observed, representing a multitude of pathways. This realisation necessitates that an adequate number of observations are recorded to fully characterise this diversity. The requirement for large numbers of observations to adequately sample distributions, subpopulations, and rare events presents a significant challenge for single-molecule techniques, which by their nature do not typically provide very high throughput. This review will discuss many developing techniques which address this issue by combining nanolithographic approaches, such as zero-mode waveguides and DNA curtains, with single-molecule fluorescence microscopy, and by drastically increasing throughput of force-based approaches such as magnetic tweezers and laminar-flow techniques. These methods not only allow the collection of large volumes of single-molecule data in single experiments, but have also made improvements to ease-of-use, accessibility, and automation of data analysis. PMID- 28620038 TI - APPL1 is a multifunctional endosomal signaling adaptor protein. AB - Endosomal adaptor proteins are important regulators of signaling pathways underlying many biological processes. These adaptors can integrate signals from multiple pathways via localization to specific endosomal compartments, as well as through multiple protein-protein interactions. One such adaptor protein that has been implicated in regulating signaling pathways is the adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (APPL1). APPL1 localizes to a subset of Rab5 positive endosomes through its Bin-Amphiphysin-Rvs and PH domains, and it coordinates signaling pathways through its interaction with many signaling receptors and proteins through its PTB domain. This review discusses our current understanding of the role of APPL1 in signaling and trafficking, as well as highlights recent work into the function of APPL1 in cell migration and adhesion. PMID- 28620039 TI - CSBB: synthetic biology research at Newcastle University. AB - The Centre for Synthetic Biology and the Bioeconomy (CSBB) brings together a far reaching multidisciplinary community across all Newcastle University's faculties Medical Sciences, Science, Agriculture and Engineering, and Humanities, Arts and Social Sciences. The CSBB focuses on many different areas of Synthetic Biology, including bioprocessing, computational design and in vivo computation, as well as improving understanding of basic molecular machinery. Such breadth is supported by major national and international research funding, a range of industrial partners in the North East of England and beyond, as well as a large number of doctoral and post-doctoral researchers. The CSBB trains the next generation of scientists through a 1-year MSc in Synthetic Biology. PMID- 28620040 TI - Cell-free synthetic biology for in vitro prototype engineering. AB - Cell-free transcription-translation is an expanding field in synthetic biology as a rapid prototyping platform for blueprinting the design of synthetic biological devices. Exemplar efforts include translation of prototype designs into medical test kits for on-site identification of viruses (Zika and Ebola), while gene circuit cascades can be tested, debugged and re-designed within rapid turnover times. Coupled with mathematical modelling, this discipline lends itself towards the precision engineering of new synthetic life. The next stages of cell-free look set to unlock new microbial hosts that remain slow to engineer and unsuited to rapid iterative design cycles. It is hoped that the development of such systems will provide new tools to aid the transition from cell-free prototype designs to functioning synthetic genetic circuits and engineered natural product pathways in living cells. PMID- 28620041 TI - A standard-enabled workflow for synthetic biology. AB - A synthetic biology workflow is composed of data repositories that provide information about genetic parts, sequence-level design tools to compose these parts into circuits, visualization tools to depict these designs, genetic design tools to select parts to create systems, and modeling and simulation tools to evaluate alternative design choices. Data standards enable the ready exchange of information within such a workflow, allowing repositories and tools to be connected from a diversity of sources. The present paper describes one such workflow that utilizes, among others, the Synthetic Biology Open Language (SBOL) to describe genetic designs, the Systems Biology Markup Language to model these designs, and SBOL Visual to visualize these designs. We describe how a standard enabled workflow can be used to produce types of design information, including multiple repositories and software tools exchanging information using a variety of data standards. Recently, the ACS Synthetic Biology journal has recommended the use of SBOL in their publications. PMID- 28620042 TI - Long noncoding RNAs: lincs between human health and disease. AB - Long noncoding RNAs (lncRNAs) represent one of the largest classes of transcripts and are highly diverse in terms of characteristics and functions. Advances in high-throughput sequencing platforms have enabled the rapid discovery and identification of lncRNAs as key regulatory molecules involved in various cellular processes and their dysregulation in various human diseases. Here, we summarize the current knowledge of the functions and underlying mechanisms of lncRNA activity with a particular focus on cancer biology. We also discuss the potential of lncRNAs as diagnostic and therapeutic targets for clinical applications. PMID- 28620043 TI - Mitochondrial cytochrome c oxidase: catalysis, coupling and controversies. AB - Mitochondrial cytochrome c oxidase is a member of a diverse superfamily of haem copper oxidases. Its mechanism of oxygen reduction is reviewed in terms of the cycle of catalytic intermediates and their likely chemical structures. This reaction cycle is coupled to the translocation of protons across the inner mitochondrial membrane in which it is located. The likely mechanism by which this occurs, derived in significant part from studies of bacterial homologues, is presented. These mechanisms of catalysis and coupling, together with current alternative proposals of underlying mechanisms, are critically reviewed. PMID- 28620044 TI - Let there be light: how to use photoswitchable cross-linker to reprogram proteins. AB - Azobenzene is a photo-isomerizing molecule whose end-to-end distance changes upon external illumination. When combined with site-specific reactive groups, it can be used as molecular tweezers to remote-control the structure and function of protein targets. The present study gives a brief overview over the rational design strategies that use an azobenzene-based photoswitchable cross-linker to engineer ON/OFF switches into functional proteins or to reprogram proteins for novel functions. The re-engineered proteins may be used as remote controls for cellular pathways, as light-gated drug delivery platforms or as light-powered machinery of synthetic cells and micro-scaled factories. PMID- 28620045 TI - Fundamental principles of vascular network topology. AB - The vascular system is arguably the most important biological system in many organisms. Although the general principles of its architecture are simple, the growth of blood vessels occurs under extreme physical conditions. Optimization is an important aspect of the development of computational models of the vascular branching structures. This review surveys the approaches used to optimize the topology and estimate different geometrical parameters of the vascular system. The review is focused on optimizations using complex cost functions based on the minimum total energy principle and the relationship between the laws of growth and precise vascular network topology. Experimental studies of vascular networks in different species are also discussed. PMID- 28620046 TI - Role of ESCRT component HD-PTP/PTPN23 in cancer. AB - Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the Endosomal Sorting Complexes Required for Transport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the bona fide role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/PTPN23 was recently identified as a novel haplo insufficient tumour suppressor in vitro and in vivo, in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/PTPN23 in tumorigenesis. PMID- 28620047 TI - Squamous cell carcinoma-related oncogene (SCCRO) neddylates Cul3 protein to selectively promote midbody localization and activity of Cul3KLHL21 protein complex during abscission. AB - Squamous cell carcinoma-related oncogene (SCCRO)/DCUN1D1, a component of the neddylation E3 complex, regulates the activity of the cullin-RING-ligase type of ubiquitination E3s by promoting neddylation of cullin family members. Studies have shown that SCCRO regulates proliferation in vitro and in vivo Here we show that inactivation of SCCRO results in prolonged mitotic time because of delayed and/or failed abscission. The effects of SCCRO on abscission involve its role in neddylation and localization of Cul3 to the midbody. The Cul3 adaptor KLHL21 mediates the effects of SCCRO on abscission, as it fails to localize to the midbody in SCCRO-deficient cells during abscission, and its inactivation resulted in phenotypic changes identical to SCCRO inactivation. Ubiquitination-promoted turnover of Aurora B at the midbody was deficient in SCCRO- and KLHL21-deficient cells, suggesting that it is the target of Cul3KLHL21 at the midbody. Correction of abscission delays in SCCRO-deficient cells with addition of an Aurora B inhibitor at the midbody stage suggests that Aurora B is the target of SCCRO promoted Cul3KLHL21 activity. The activity of other Cul3-anchored complexes, including Cul3KLHL9/KLHL13, was intact in SCCRO-deficient cells, suggesting that SCCRO selectively, rather than collectively, neddylates cullins in vivo Combined, these findings support a model in which the SCCRO, substrate, and substrate adaptors cooperatively provide tight control of neddylation and cullin-RING ligase activity in vivo. PMID- 28620048 TI - Chaperone-client interactions: Non-specificity engenders multifunctionality. AB - Here, we provide an overview of the different mechanisms whereby three different chaperones, Spy, Hsp70, and Hsp60, interact with folding proteins, and we discuss how these chaperones may guide the folding process. Available evidence suggests that even a single chaperone can use many mechanisms to aid in protein folding, most likely due to the need for most chaperones to bind clients promiscuously. Chaperone mechanism may be better understood by always considering it in the context of the client's folding pathway and biological function. PMID- 28620049 TI - The X-linked deubiquitinase USP9X is an integral component of centrosome. AB - The X-linked deubiquitinase USP9X has been implicated in multiple pathological disorders including malignancies and X-linked intellectual disability. However, its biological function and substrate repertoire remain to be investigated. In this study, we utilized the tandem mass tag labeling assay to identify USP9X regulated proteins and revealed that the expression of multiple genes is altered in USP9X-deficient cells. Interestingly, we showed that USP9X promotes stabilization of centrosome proteins PCM1 and CEP55 through its catalytic activity. Remarkably, we demonstrated that USP9X is physically associated and spatially co-localized with PCM1 and CEP55 in the centrosome, and we revealed that either PCM1 or CEP55 loss resulted in impairment of USP9X centrosome localization. Moreover, we showed that USP9X is required for centrosome duplication, and this effect is dependent on its catalytic activity and its N terminal module, which is responsible for physical association of USP9X with PCM1 and CEP55. Collectively, our experiments identified USP9X as an integral component of the centrosome where it functions to stabilize PCM1 and CEP55 and promote centrosome biogenesis. PMID- 28620051 TI - The role of the Met20 loop in the hydride transfer in Escherichia coli dihydrofolate reductase. AB - A key question concerning the catalytic cycle of Escherichia coli dihydrofolate reductase (ecDHFR) is whether the Met20 loop is dynamically coupled to the chemical step during catalysis. A more basic, yet unanswered question is whether the Met20 loop adopts a closed conformation during the chemical hydride transfer step. To examine the most likely conformation of the Met20 loop during the chemical step, we studied the hydride transfer in wild type (WT) ecDHFR using hybrid quantum mechanics-molecular mechanics free energy simulations with the Met20 loop in a closed and disordered conformation. Additionally, we investigated three mutant forms (I14X; X = Val, Ala, Gly) of the enzyme that have increased active site flexibility and donor-acceptor distance dynamics in closed and disordered Met20 loop states. We found that the conformation of the Met20 loop has a dramatic effect on the ordering of active site hydration, although the Met20 loop conformation only has a moderate effect on the hydride transfer rate and donor-acceptor distance dynamics. Finally, we evaluated the pKa of the substrate N5 position in closed and disordered Met20 loop states and found a strong correlation between N5 basicity and the conformation of the Met20 loop. PMID- 28620050 TI - Engineering the fragment crystallizable (Fc) region of human IgG1 multimers and monomers to fine-tune interactions with sialic acid-dependent receptors. AB - Multimeric fragment crystallizable (Fc) regions and Fc-fusion proteins are actively being explored as biomimetic replacements for IVIG therapy, which is deployed to manage many diseases and conditions but is expensive and not always efficient. The Fc region of human IgG1 (IgG1-Fc) can be engineered into multimeric structures (hexa-Fcs) that bind their cognate receptors with high avidity. The critical influence of the unique N-linked glycan attached at Asn-297 on the structure and function of IgG1-Fc is well documented; however, whether the N-linked glycan has a similarly critical role in multimeric, avidly binding Fcs, is unknown. Hexa-Fc contains two N-linked sites at Asn-77 (equivalent to Asn-297 in the Fc of IgG1) and Asn-236 (equivalent to Asn-563 in the tail piece of IgM). We report here that glycosylation at Asn-297 is critical for interactions with Fc receptors and complement and that glycosylation at Asn-563 is essential for controlling multimerization. We also found that introduction of an additional fully occupied N-linked glycosylation site at the N terminus at position 1 (equivalent to Asp-221 in the Fc of IgG1) dramatically enhances overall sialic acid content of the Fc multimers. Furthermore, replacement of Cys-575 in the IgM tail piece of multimers resulted in monomers with enhanced sialic acid content and differential receptor-binding profiles. Thus insertion of additional N-linked glycans into either the hinge or tail piece of monomers or multimers leads to molecules with enhanced sialylation that may be suitable for managing inflammation or blocking pathogen invasion. PMID- 28620053 TI - Exercise training improves cardiac autonomic control, cardiac function, and arrhythmogenesis in rats with preserved-ejection fraction heart failure. AB - Chronic heart failure is characterized by autonomic imbalance, cardiac dysfunction, and arrhythmogenesis. It has been shown that exercise training (ExT) improves central nervous system oxidative stress, autonomic control, and cardiac function in heart failure with reduced ejection fraction; however, to date no comprehensive studies have addressed the effects of ExT, if any, on oxidative stress in brain stem cardiovascular areas, cardiac autonomic balance, arrhythmogenesis, and cardiac function in heart failure with preserved ejection fraction (HFpEF). We hypothesize that ExT reduces brain stem oxidative stress, improves cardiac autonomic control and cardiac function, and reduces arrhythmogenesis in HFpEF rats. Rats underwent sham treatment or volume overload to induce HFpEF. ExT (60 min/day, 25 m/min, 10% inclination) was performed for 6 wk starting at the second week after HFpEF induction. Rats were randomly allocated into Sham+sedentary (Sed) (n = 8), Sham+ExT (n = 6), HFpEF+Sed (n = 8), and HFpEF+ExT (n = 8) groups. Compared with the HFpEF+Sed condition, HFpEF+ExT rats displayed reduced NAD(P)H oxidase activity and oxidative stress in the rostral ventrolateral medulla (RVLM), improved cardiac autonomic balance, and reduced arrhythmogenesis. Furthermore, a threefold improvement in cardiac function was observed in HFpEF+ExT rats. These novel findings suggest that moderate-intensity ExT is an effective means to attenuate the progression of HFpEF through improvement in RVLM redox state, cardiac autonomic control, and cardiac function.NEW & NOTEWORTHY In the present study, we found that exercise reduced oxidative stress in key brain stem areas related to autonomic control, improved sympathovagal control of the heart, reduced cardiac arrhythmias, and delayed deterioration of cardiac function in rats with heart failure with preserved ejection fraction (HFpEF). Our results provide strong evidence for the therapeutic efficacy of exercise training in HFpEF. PMID- 28620052 TI - The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis. AB - The Mycobacterium tuberculosis rv2466c gene encodes an oxidoreductase enzyme annotated as DsbA. It has a CPWC active-site motif embedded within its thioredoxin fold domain and mediates the activation of the prodrug TP053, a thienopyrimidine derivative that kills both replicating and nonreplicating bacilli. However, its mode of action and actual enzymatic function in M. tuberculosis have remained enigmatic. In this study, we report that Rv2466c is essential for bacterial survival under H2O2 stress. Further, we discovered that Rv2466c lacks oxidase activity; rather, it receives electrons through the mycothiol/mycothione reductase/NADPH pathway to activate TP053, preferentially via a dithiol-disulfide mechanism. We also found that Rv2466c uses a monothiol disulfide exchange mechanism to reduce S-mycothiolated mixed disulfides and intramolecular disulfides. Genetic, phylogenetic, bioinformatics, structural, and biochemical analyses revealed that Rv2466c is a novel mycothiol-dependent reductase, which represents a mycoredoxin cluster of enzymes within the DsbA family different from the glutaredoxin cluster to which mycoredoxin-1 (Mrx1 or Rv3198A) belongs. To validate this DsbA-mycoredoxin cluster, we also characterized a homologous enzyme of Corynebacterium glutamicum (NCgl2339) and observed that it demycothiolates and reduces a mycothiol arsenate adduct with kinetic properties different from those of Mrx1. In conclusion, our work has uncovered a DsbA-like mycoredoxin that promotes mycobacterial resistance to oxidative stress and reacts with free mycothiol and mycothiolated targets. The characterization of the DsbA-like mycoredoxin cluster reported here now paves the way for correctly classifying similar enzymes from other organisms. PMID- 28620054 TI - An assessment of the autonomic nervous system in the electrohypersensitive population: a heart rate variability and skin conductance study. AB - The aim of the study was twofold: first, to compare the activity of the autonomic nervous system (ANS) between the population self-declared as electrohypersensitive (EHS) and their matched control individuals without intended exposure to electromagnetic fields (EMF). The second objective was to determine whether acute exposure to different radiofrequency signals modifies ANS activity in EHS. For that purpose, two different experiments were undertaken, in which ANS activity was assessed through heart rate variability (HRV) and skin conductance (SC). In the first experiment, a comparison between the EHS group (n = 30) and the control group (n = 25) showed that the EHS has an increased number of responses to auditory stimuli as measured by skin conductance activity, and that none of the short-term heart rate variability parameters differ between the two matched study groups. The second experiment, performed in a shielded chamber, involved 10 EHS from the first experiment. The volunteers participated in two different sessions (sham and exposure). The participants were consecutively exposed to four EMF signals (GSM 900, GSM 1800, DECT, and Wi-Fi) at environmental level (1 V/m). The experiment was double blinded and counterbalanced. The HRV variables studied did not differ between the two sessions. Concerning electrodermal activity, the data issued from skin conductance and tonic activity did not differ between the sessions, but showed a time variability. In conclusion, the HRV and SC profiles did not significantly differ between the EHS and control populations under no exposure. Exposure did not have an effect on the ANS parameters we have explored.NEW & NOTEWORTHY This study provided analysis on the skin conductance parameters using a newly developed method (peak/min, extraction of skin conductance responses) that had not been performed previously. Additionally, the skin conductance signal was decomposed, considering tonic and phasic activities to be a distinct compound. Moreover, this is the first time a study has been designed into two steps to understand whether the autonomic nervous system is disturbed in the EHS population. PMID- 28620055 TI - The effects of RSR13 on microvascular Po2 kinetics and muscle contractile performance in the rat arterial ligation model of peripheral arterial disease. AB - Exercise intolerance and claudication are symptomatic of peripheral arterial disease. There is a close relationship between muscle O2 delivery, microvascular oxygen partial pressure (PmvO2), and contractile performance. We therefore hypothesized that a reduction of hemoglobin-oxygen affinity via RSR13 would maintain a higher PmvO2 and enhance blood-muscle O2 transport and contractile function. In male Wistar rats (12 wk of age), we created hindlimb ischemia via right-side iliac artery ligation (AL). The contralateral (left) muscle served as control (CONT). Seven days after AL, phosphorescence-quenching techniques were used to measure PmvO2 at rest and during contractions (electrical stimulation; 1 Hz, 300 s) in tibialis anterior muscle (TA) under saline (n = 10) or RSR13 (n = 10) conditions. RSR13 at rest increased TA PmvO2 in CONT (13.9 +/- 1.6 to 19.3 +/ 1.9 Torr, P < 0.05) and AL (9.0 +/- 0.5 to 9.9 +/- 0.7 Torr, P < 0.05). Furthermore, RSR13 extended maintenance of the initial TA force (i.e., improved contractile performance) such that force was not decreased significantly until contraction 240 vs. 150 in CONT and 80 vs. 20 in AL. This improved muscle endurance with RSR13 was accompanied by a greater DeltaPmvO2 (PmvO2 decrease from baseline) (CONT, 7.4 +/- 1.0 to 11.2 +/- 1.3; AL, 6.9 +/- 0.5 to 8.6 +/- 0.6 Torr, both P < 0.05). Whereas RSR13 did not alter the kinetics profile of PmvO2 (i.e., mean response time) substantially during contractions, muscle force was elevated, and the ratio of muscle force to PmvO2 increased. In conclusion, reduction of hemoglobin-oxygen affinity via RSR13 in AL increased PmvO2 and improved muscle contractile performance most likely via enhanced blood-muscle O2 diffusion.NEW & NOTEWORTHY This is the first investigation to examine the effect of RSR13 (erythrocyte allosteric effector) on skeletal muscle microvascular oxygen partial pressure kinetics and contractile function using an arterial ligation model of peripheral arterial disease in experimental animals. The present results provide strong support for the concept that reducing hemoglobin O2 affinity via RSR13 improved tibialis anterior muscle contractile performance most likely via enhanced blood-muscle O2 diffusion. PMID- 28620057 TI - Applied physiology: Research that makes a difference. PMID- 28620056 TI - Postnatal airway growth in cystic fibrosis piglets. AB - Mutations in the gene encoding the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) anion channel cause CF. The leading cause of death in the CF population is lung disease. Increasing evidence suggests that in utero airway development is CFTR-dependent and that developmental abnormalities may contribute to CF lung disease. However, relatively little is known about postnatal CF airway growth, largely because such studies are limited in humans. Therefore, we examined airway growth and lung volume in a porcine model of CF. We hypothesized that CF pigs would have abnormal postnatal airway growth. To test this hypothesis, we performed CT-based airway and lung volume measurements in 3-wk-old non-CF and CF pigs. We found that 3-wk-old CF pigs had tracheas of reduced caliber and irregular shape. Their bronchial lumens were reduced in size proximally but not distally, were irregularly shaped, and had reduced distensibility. Our data suggest that lack of CFTR results in aberrant postnatal airway growth and development, which could contribute to CF lung disease pathogenesis.NEW & NOTEWORTHY This CT scan-based study of airway morphometry in the cystic fibrosis (CF) postnatal period is unique, as analogous studies in humans are greatly limited for ethical and technical reasons. Findings such as reduced airway lumen area and irregular caliber suggest that airway growth and development are CF transmembrane conductance regulator-dependent and that airway growth defects may contribute to CF lung disease pathogenesis. PMID- 28620058 TI - Intermittent hypercapnic hypoxia during sleep does not induce ventilatory long term facilitation in healthy males. AB - Intermittent hypoxia-induced ventilatory neuroplasticity is likely important in obstructive sleep apnea pathophysiology. Although concomitant CO2 levels and arousal state critically influence neuroplastic effects of intermittent hypoxia, no studies have investigated intermittent hypercapnic hypoxia effects during sleep in humans. Thus the purpose of this study was to investigate if intermittent hypercapnic hypoxia during sleep induces neuroplasticity (ventilatory long-term facilitation and increased chemoreflex responsiveness) in humans. Twelve healthy males were exposed to intermittent hypercapnic hypoxia (24 * 30 s episodes of 3% CO2 and 3.0 +/- 0.2% O2) and intermittent medical air during sleep after 2 wk washout period in a randomized crossover study design. Minute ventilation, end-tidal CO2, O2 saturation, breath timing, upper airway resistance, and genioglossal and diaphragm electromyograms were examined during 10 min of stable stage 2 sleep preceding gas exposure, during gas and intervening room air periods, and throughout 1 h of room air recovery. There were no significant differences between conditions across time to indicate long-term facilitation of ventilation, genioglossal or diaphragm electromyogram activity, and no change in ventilatory response from the first to last gas exposure to suggest any change in chemoreflex responsiveness. These findings contrast with previous intermittent hypoxia studies without intermittent hypercapnia and suggest that the more relevant gas disturbance stimulus of concomitant intermittent hypercapnia frequently occurring in sleep apnea influences acute neuroplastic effects of intermittent hypoxia. These findings highlight the need for further studies of intermittent hypercapnic hypoxia during sleep to clarify the role of ventilatory neuroplasticity in the pathophysiology of sleep apnea.NEW & NOTEWORTHY Both arousal state and concomitant CO2 levels are known modulators of the effects of intermittent hypoxia on ventilatory neuroplasticity. This is the first study to investigate the effects of combined intermittent hypercapnic hypoxia during sleep in humans. The lack of neuroplastic effects suggests a need for further studies more closely replicating obstructive sleep apnea to determine the pathophysiological relevance of intermittent hypoxia-induced ventilatory neuroplasticity. PMID- 28620059 TI - Anakinra in a Cohort of Children with Chronic Nonbacterial Osteomyelitis. AB - OBJECTIVE: To report efficacy and safety in patients with chronic nonbacterial osteomyelitis (CNO) unresponsive to nonsteroidal antiinflammatory drugs (NSAID) and bisphosphonates and/or glucocorticoids treated with anakinra. METHODS: Nine patients (6 females) with refractory CNO were treated with anakinra for at least 6 months. We recorded, at baseline and after 6 months of treatment, clinical and laboratory features, and number and distribution of bone lesions detected by 99mTc-MDP bone scintigraphy. Disease activity was evaluated using a physician's global assessment (PGA). RESULTS: At baseline, 9/9 patients had mild to severe PGA. After 6 months of treatment, in 5 patients the PGA score was graded from none to minimal. At baseline, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated in 8 out of 9 patients. After 6 months, 5/9 patients had normalized CRP and ESR and in all except 1, CRP and ESR decreased. Before starting anakinra, a total of 77 bone lesions were detected by bone scintigraphy. After 6 months of treatment of the 77 lesions, 42 had resolved and 35 were stable. In 7/9 patients, 20 new lesions appeared during treatment; 2 of these 7 patients were symptomatic. At the last followup visit (median 1.7 yrs, range 0.8 2.8), 6/9 patients maintained a PGA graded as none to minimal. CONCLUSION: Anakinra is a possible therapeutic alternative in patients with refractory CNO. The practical significance of clinically silent bone lesions detected by bone scintigraphy remains to be established. PMID- 28620060 TI - Hospitalizations in Patients with Systemic Lupus Erythematosus in an Academic Health Science Center. AB - OBJECTIVE: Hospitalization occurs in about 10% of patients with systemic lupus erythematosus (SLE) each year and accounts for most of the direct cost of SLE patient care. We aimed to determine the frequency of admissions of patients with SLE and describe their causes and outcomes. METHODS: We identified all hospitalizations at University Health Network in the periods 2011-2012 and 2013 2015 with an International Classification of Diseases, 10th ed. code of M32 (SLE). A retrospective chart review of these patients categorized them based on SLE care provider and cause of admission. Frequency of emergency room visits and duration of hospitalization were ascertained. Poisson and linear regressions were performed to determine factors associated with frequency and duration of hospitalizations. RESULTS: There were 247 unique patients with SLE who were hospitalized a total of 491 times: 87.4% were women, average age of 43.9 +/- 17.9 years, and disease duration 13.7 +/- 12.3 years. Incidental causes were most common (35.6%); 21.4% and 22.4% of admissions were because of active SLE and infection, respectively. The patients with SLE averaged 1.6 hospitalizations lasting 8.5 days. Thirteen percent of hospitalizations resulted in intensive care unit admission, and 2.8% of hospitalizations resulted in death. Patient employment was associated with fewer hospitalizations during 2011-2015. Antimalarial use was associated with fewer hospitalizations as well as shorter length of stay during 2011-2012. The presence of damage correlated with increased hospitalizations. Higher educational level and antimalarial use correlated with shorter length of stay. CONCLUSION: Patients with SLE are frequently hospitalized, often because of active SLE or infection, and re-hospitalized within a short period of time. PMID- 28620061 TI - Whole-body Magnetic Resonance Imaging in Inflammatory Arthritis: Systematic Literature Review and First Steps Toward Standardization and an OMERACT Scoring System. AB - OBJECTIVE: Whole-body magnetic resonance imaging (WB-MRI) is a relatively new technique that can enable assessment of the overall inflammatory status of people with arthritis, but standards for image acquisition, definitions of key pathologies, and a quantification system are required. Our aim was to perform a systematic literature review (SLR) and to develop consensus definitions of key pathologies, anatomical locations for assessment, a set of MRI sequences and imaging planes for the different body regions, and a preliminary scoring system for WB-MRI in inflammatory arthritis. METHODS: An SLR was initially performed, searching for WB-MRI studies in arthritis, osteoarthritis, spondyloarthritis, or enthesitis. These results were presented to a meeting of the MRI in Arthritis Working Group together with an MR image review. Following this, preliminary standards for WB-MRI in inflammatory arthritides were developed with further iteration at the Working Group meetings at the Outcome Measures in Rheumatology (OMERACT) 2016. RESULTS: The SLR identified 10 relevant original articles (7 cross-sectional and 3 longitudinal, mostly focusing on synovitis and/or enthesitis in spondyloarthritis, 4 with reproducibility data). The Working Group decided on inflammation in peripheral joints and entheses as primary focus areas, and then developed consensus MRI definitions for these pathologies, selected anatomical locations for assessment, agreed on a core set of MRI sequences and imaging planes for the different regions, and proposed a preliminary scoring system. It was decided to test and further develop the system by iterative multireader exercises. CONCLUSION: These first steps in developing an OMERACT WB MRI scoring system for use in inflammatory arthritides offer a framework for further testing and refinement. PMID- 28620062 TI - Urine Biomarkers to Predict Response to Lupus Nephritis Therapy in Children and Young Adults. AB - OBJECTIVE: To delineate urine biomarkers that forecast response to therapy of lupus nephritis (LN). METHODS: Starting from the time of kidney biopsy, patients with childhood-onset systemic lupus erythematosus who were diagnosed with LN were studied serially. Levels of 15 biomarkers were measured in random spot urine samples, including adiponectin, alpha-1-acid glycoprotein (AGP), ceruloplasmin, hemopexin, hepcidin, kidney injury molecule 1, monocyte chemotactic protein-1, lipocalin-like prostaglandin D synthase (LPGDS), transforming growth factor-beta (TGF-beta), transferrin, and vitamin D binding protein (VDBP). RESULTS: Among 87 patients (mean age 15.6 yrs) with LN, there were 37 treatment responders and 50 nonresponders based on the American College of Rheumatology criteria. At the time of kidney biopsy, levels of TGF-beta (p < 0.0001) and ceruloplasmin (p = 0.006) were significantly lower among responders than nonresponders; less pronounced differences were present for AGP, hepcidin, LPGDS, transferrin, and VDBP (all p < 0.05). By Month 3, responders experienced marked decreases of adiponectin, AGP, transferrin, and VDBP (all p < 0.01) and mean levels of these biomarkers were all outstanding (area under the receiver-operating characteristic curve >= 0.9) for discriminating responders from nonresponders. Patient demographics and extrarenal disease did not influence differences in biomarker levels between response groups. CONCLUSION: Low urine levels of TGF-beta and ceruloplasmin at baseline and marked reduction of AGP, LPGDS, transferrin, or VDBP and combinations of other select biomarkers by Month 3 are outstanding predictors for achieving remission of LN. If confirmed, these results can be used to help personalize LN therapy. PMID- 28620063 TI - Clinical and Patient-reported Outcomes in Patients with Psoriatic Arthritis (PsA) by Body Surface Area Affected by Psoriasis: Results from the Corrona PsA/Spondyloarthritis Registry. AB - OBJECTIVE: Psoriatic arthritis (PsA) is commonly comorbid with psoriasis; the extent of skin lesions is a major contributor to psoriatic disease severity/burden. We evaluated whether extent of skin involvement with psoriasis [body surface area (BSA) > 3% vs <= 3%] affects overall clinical and patient reported outcomes (PRO) in patients with PsA. METHODS: Using the Corrona PsA/Spondyloarthritis Registry, patient characteristics, disease activity, and PRO at registry enrollment were assessed for patients with PsA aged >= 18 years with BSA > 3% versus <= 3%. Regression models were used to evaluate associations of BSA level with outcome [modified minimal disease activity (MDA), Health Assessment Questionnaire (HAQ) score, patient-reported pain and fatigue, and the Work Productivity and Activity Impairment questionnaire score]. Adjustments were made for age, sex, race, body mass index, disease duration, and history of biologics, disease-modifying antirheumatic drug, and prednisone use. RESULTS: This analysis included 1240 patients with PsA with known BSA level (n = 451, BSA > 3%; n = 789, BSA <= 3%). After adjusting for potential confounding variables, patients with BSA > 3% versus <= 3% had greater patient-reported pain and fatigue and higher HAQ scores (p = 2.33 * 10-8, p = 0.002, and p = 1.21 * 10-7, respectively), were 1.7* more likely not to be in modified MDA (95% CI 1.21-2.41, p = 0.002), and were 2.1* more likely to have overall work impairment (1.37-3.21, p = 0.0001). CONCLUSION: These Corrona Registry data show that substantial skin involvement (BSA > 3%) is associated with greater PsA disease burden, underscoring the importance of assessing and effectively managing psoriasis in patients with PsA because this may be a contributing factor in PsA severity. PMID- 28620064 TI - Sleep Disturbance in Psoriatic Disease: Prevalence and Associated Factors. AB - OBJECTIVE: We aimed to determine the prevalence and quality of sleep in patients with psoriatic arthritis (PsA) and those with psoriasis without PsA (PsC) followed in the same center, to identify factors associated with sleep disturbance, and to compare findings to those of healthy controls (HC). METHODS: The study included 113 PsA [ClASsification for Psoriatic ARthritis (CASPAR) criteria] and 62 PsC (PsA excluded by a rheumatologist) patients and 52 HC. Clinical variables were collected using a standard protocol. The sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). Other patient reported outcomes collected included the Health Assessment Questionnaire (HAQ), Dermatology Life Quality Index, EQ-5D, Medical Outcomes Study Short Form-36 survey, patient's global assessment, and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) scale. Statistical analyses included descriptive statistics, Wilcoxon rank-sum test, and linear regression. RESULTS: The prevalence of poor sleep quality was 84%, 69%, and 50% in PsA, PsC, and HC, respectively. Total PSQI score was higher in both patients with PsA and patients with PsC compared with HC (p < 0.01) and higher in patients with PsA compared to patients with PsC (p < 0.0001). EQ-5D anxiety component, EQ-5D final, and FACIT fatigue were independently associated with worse PSQI in patients with PsC and those with PsA (p < 0.05). Actively inflamed (tender or swollen) joints are independently associated with worse PSQI in patients with PsA (p < 0.01). CONCLUSION: Patients with psoriatic disease have poor sleep quality. Poor sleep is associated with fatigue, anxiety, and lower EQ-5D. In patients with PsA, poor sleep is associated with active joint inflammation. PMID- 28620065 TI - Critical Outcomes in Longitudinal Observational Studies and Registries in Patients with Rheumatoid Arthritis: An OMERACT Special Interest Group Report. AB - OBJECTIVE: Outcomes important to patients are those that are relevant to their well-being, including quality of life, morbid endpoints, and death. These outcomes often occur over the longterm and can be identified in prospective longitudinal observational studies (PLOS). There are no standards for which outcome domains should be considered. Our overarching goal is to identify critical longterm outcome domains for patients with rheumatic diseases, and to develop a conceptual framework to measure and classify them within the scope of OMERACT Filter 2.0. METHODS: The steps of this initiative primarily concern rheumatoid arthritis (RA) and include (1) performing a systematic review of RA patient registries and cohorts to identify previously collected and reported outcome domains and measurement instruments; (2) developing a conceptual framework and taxonomy for identification and classification of outcome domains; (3) conducting focus groups to identify domains considered critical by patients with RA; and (4) surveying patients, providers, and researchers to identify critical outcomes that can be evaluated through the OMERACT filter. RESULTS: In our initial evaluation of databases and registries across countries, we found both commonalities and differences, with no clear standardization. At the initial group meeting, participants agreed that additional work is needed to identify which critical outcomes should be collected in PLOS, and suggested several: death, independence, and participation, among others. An operational strategy for the next 2 years was proposed. CONCLUSION: Participants endorsed the need for an initiative to identify and evaluate critical outcome domains and measurement instruments for data collection in PLOS. PMID- 28620067 TI - Allele-Specific Silencing of Mutant mRNA Rescues Ultrastructural and Arrhythmic Phenotype in Mice Carriers of the R4496C Mutation in the Ryanodine Receptor Gene (RYR2). AB - RATIONALE: Mutations in the cardiac Ryanodine Receptor gene (RYR2) cause dominant catecholaminergic polymorphic ventricular tachycardia (CPVT), a leading cause of sudden death in apparently healthy individuals exposed to emotions or physical exercise. OBJECTIVE: We investigated the efficacy of allele-specific silencing by RNA interference to prevent CPVT phenotypic manifestations in our dominant CPVT mice model carriers of the heterozygous mutation R4496C in RYR2. METHODS AND RESULTS: We developed an in vitro mRNA and protein-based assays to screen multiple siRNAs for their ability to selectively silence mutant RYR2-R4496C mRNA over the corresponding wild-type allele. For the most performant of these siRNAs (siRYR2-U10), we evaluated the efficacy of an adeno-associated serotype 9 viral vector (AAV9) expressing miRYR2-U10 in correcting RyR2 (Ryanodine Receptor type 2 protein) function after in vivo delivery by intraperitoneal injection in neonatal and adult RyR2R4496C/+ (mice heterozygous for the R4496C mutation in the RyR2) heterozygous CPVT mice. Transcriptional analysis showed that after treatment with miRYR2-U10, the ratio between wild-type and mutant RYR2 mRNA was doubled (from 1:1 to 2:1) confirming the ability of miRYR2-U10 to selectively inhibit RYR2 R4496C mRNA, whereas protein quantification showed that total RyR2 was reduced by 15% in the heart of treated mice. Furthermore, AAV9-miRYR2-U10 effectively (1) reduced isoproterenol-induced delayed afterdepolarizations and triggered activity in infected cells, (2) reduced adrenergically mediated ventricular tachycardia in treated mice, (3) reverted ultrastructural abnormalities of junctional sarcoplasmic reticulum and transverse tubules, and (4) attenuated mitochondrial abnormalities. CONCLUSIONS: The study demonstrates that allele-specific silencing with miRYR2-U10 prevents life-threatening arrhythmias in CPVT mice, suggesting that the reduction of mutant RyR2 may be a novel therapeutic approach for CPVT. PMID- 28620066 TI - Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing. AB - RATIONALE: Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as a critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and the mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing, remain unresolved. OBJECTIVES: To investigate the role of the pulmonary-specific isoform 2 of subunit 4 of the mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary oxygen sensing and signaling. METHODS AND RESULTS: Isolated ventilated and perfused lungs from Cox4i2-/- mice lacked acute HPV. In parallel, pulmonary arterial smooth muscle cells (PASMCs) from Cox4i2-/- mice showed no hypoxia-induced increase of intracellular calcium. Hypoxia-induced superoxide release which was detected by electron spin resonance spectroscopy in wild-type PASMCs was absent in Cox4i2-/- PASMCs and was dependent on cysteine residues of Cox4i2. HPV could be inhibited by mitochondrial superoxide inhibitors proving the functional relevance of superoxide release for HPV. Mitochondrial hyperpolarization, which can promote mitochondrial superoxide release, was detected during acute hypoxia in wild-type but not Cox4i2-/- PASMCs. Downstream signaling determined by patch-clamp measurements showed decreased hypoxia-induced cellular membrane depolarization in Cox4i2-/- PASMCs compared with wild-type PASMCs, which could be normalized by the application of hydrogen peroxide. In contrast, chronic hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling were not or only slightly affected by Cox4i2 deficiency, respectively. CONCLUSIONS: Cox4i2 is essential for acute but not chronic pulmonary oxygen sensing by triggering mitochondrial hyperpolarization and release of mitochondrial superoxide which, after conversion to hydrogen peroxide, contributes to cellular membrane depolarization and HPV. These findings provide a new model for oxygen-sensing processes in the lung and possibly also in other organs. PMID- 28620068 TI - X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis. AB - RATIONALE: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear. OBJECTIVE: To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells. METHODS AND RESULTS: We combined a model of specific antibody deficiency, B cell-specific CD79a-Cre x XBP1 (X-box binding protein-1) floxed mice (XBP1-conditional knockout), with antibody-mediated depletion of CD4+ T cells. Ldlr knockout mice transplanted with XBP1-conditional knockout (or wild-type control littermate) bone marrow were fed western diet for 8 weeks with or without anti-CD4 depletion. All groups had similar levels of serum cholesterol. In Ldlr/XBP1-conditional knockout mice, serum levels of IgG, IgE, and IgM were significantly attenuated, and local antibody deposition in atherosclerotic plaque was absent. Antibody deficiency significantly accelerated atherosclerosis at both the aortic root and aortic arch. T cell and monocyte responses were not modulated, but necrotic core size was greater, even when adjusting for plaque size, and collagen deposition significantly lower. Anti-CD4 depletion in Ldlr/wild-type mice led to a decrease of serum IgG1 and IgG2c but not IgG3, as well as decreased IgM, associated with increased atherosclerosis and necrotic cores, and a decrease in plaque collagen. The combination of antibody deficiency and anti-CD4 depletion has no additive effects on aortic root atherosclerosis. CONCLUSIONS: The endogenous T cell dependent humoral response can be protective. This has important implications for novel vaccine strategies for atherosclerosis and in understanding the impacts of immunotherapies used in patients at high risk for cardiovascular disease. PMID- 28620069 TI - Prediction of Adulthood Obesity Using Genetic and Childhood Clinical Risk Factors in the Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the genetic risk factors in predicting adulthood obesity using machine learning methods. METHODS AND RESULTS: A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3-18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve [AUC=0.787 versus AUC=0.744, P<0.0001) and validation data (AUC=0.769 versus AUC=0.747, P=0.026). WGRS97 improved the accuracy in training (AUC=0.782 versus AUC=0.744, P<0.0001) but not in validation data (AUC=0.749 versus AUC=0.747, P=0.785). Higher WGRS19 associated with higher body mass index at 9 years and WGRS97 at 6 years. Replication in BHS confirmed our findings that WGRS19 and WGRS97 are associated with body mass index. CONCLUSIONS: WGRS19 improves prediction of adulthood obesity. Predictive accuracy is highest among young children (3-6 years), whereas among older children (9-18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity. PMID- 28620070 TI - Prediction of Adult Dyslipidemia Using Genetic and Childhood Clinical Risk Factors: The Cardiovascular Risk in Young Finns Study. AB - BACKGROUND: Dyslipidemia is a major modifiable risk factor for cardiovascular disease. We examined whether the addition of novel single-nucleotide polymorphisms for blood lipid levels enhances the prediction of adult dyslipidemia in comparison to childhood lipid measures. METHODS AND RESULTS: Two thousand four hundred and twenty-two participants of the Cardiovascular Risk in Young Finns Study who had participated in 2 surveys held during childhood (in 1980 when aged 3-18 years and in 1986) and at least once in a follow-up study in adulthood (2001, 2007, and 2011) were included. We examined whether inclusion of a lipid-specific weighted genetic risk score based on 58 single-nucleotide polymorphisms for low-density lipoprotein cholesterol, 71 single-nucleotide polymorphisms for high-density lipoprotein cholesterol, and 40 single-nucleotide polymorphisms for triglycerides improved the prediction of adult dyslipidemia compared with clinical childhood risk factors. Adjusting for age, sex, body mass index, physical activity, and smoking in childhood, childhood lipid levels, and weighted genetic risk scores were associated with an increased risk of adult dyslipidemia for all lipids. Risk assessment based on 2 childhood lipid measures and the lipid-specific weighted genetic risk scores improved the accuracy of predicting adult dyslipidemia compared with the approach using only childhood lipid measures for low-density lipoprotein cholesterol (area under the receiver operating characteristic curve 0.806 versus 0.811; P=0.01) and triglycerides (area under the receiver-operating characteristic curve 0.740 versus area under the receiver-operating characteristic curve 0.758; P<0.01). The overall net reclassification improvement and integrated discrimination improvement were significant for all outcomes. CONCLUSIONS: The inclusion of weighted genetic risk scores to lipid-screening programs in childhood could modestly improve the identification of those at highest risk of dyslipidemia in adulthood. PMID- 28620071 TI - Multiancestry Study of Gene-Lifestyle Interactions for Cardiovascular Traits in 610 475 Individuals From 124 Cohorts: Design and Rationale. AB - BACKGROUND: Several consortia have pursued genome-wide association studies for identifying novel genetic loci for blood pressure, lipids, hypertension, etc. They demonstrated the power of collaborative research through meta-analysis of study-specific results. METHODS AND RESULTS: The Gene-Lifestyle Interactions Working Group was formed to facilitate the first large, concerted, multiancestry study to systematically evaluate gene-lifestyle interactions. In stage 1, genome wide interaction analysis is performed in 53 cohorts with a total of 149 684 individuals from multiple ancestries. In stage 2 involving an additional 71 cohorts with 460 791 individuals from multiple ancestries, focused analysis is performed for a subset of the most promising variants from stage 1. In all, the study involves up to 610 475 individuals. Current focus is on cardiovascular traits including blood pressure and lipids, and lifestyle factors including smoking, alcohol, education (as a surrogate for socioeconomic status), physical activity, psychosocial variables, and sleep. The total sample sizes vary among projects because of missing data. Large-scale gene-lifestyle or more generally gene-environment interaction (G*E) meta-analysis studies can be cumbersome and challenging. This article describes the design and some of the approaches pursued in the interaction projects. CONCLUSIONS: The Gene-Lifestyle Interactions Working Group provides an excellent framework for understanding the lifestyle context of genetic effects and to identify novel trait loci through analysis of interactions. An important and novel feature of our study is that the gene lifestyle interaction (G*E) results may improve our knowledge about the underlying mechanisms for novel and already known trait loci. PMID- 28620072 TI - Genes, Environment, and the Heart: Putting the Pieces Together. PMID- 28620073 TI - Translating Polygenic Analysis for Prevention: From Who to How. PMID- 28620074 TI - Regulatory BC1 RNA in cognitive control. AB - Dendritic regulatory BC1 RNA is a non-protein-coding (npc) RNA that operates in the translational control of gene expression. The absence of BC1 RNA in BC1 knockout (KO) animals causes translational dysregulation that entails neuronal phenotypic alterations including prolonged epileptiform discharges, audiogenic seizure activity in vivo, and excessive cortical oscillations in the gamma frequency band. Here we asked whether BC1 RNA control is also required for higher brain functions such as learning, memory, or cognition. To address this question, we used odor/object attentional set shifting tasks in which prefrontal cortical performance was assessed in a series of discrimination and conflict learning sessions. Results obtained in these behavioral trials indicate that BC1 KO animals were significantly impaired in their cognitive flexibility. When faced with conflicting information sources, BC1 KO animals committed regressive errors as they were compromised in their ability to disengage from recently acquired memories even though recall of such memories was in conflict with new situational context. The observed cognitive deficits are reminiscent of those previously described in subtypes of human autism spectrum disorders. PMID- 28620075 TI - Experience-dependent epigenomic reorganization in the hippocampus. AB - Using a hippocampus-dependent contextual threat learning and memory task, we report widespread, coordinated DNA methylation changes in CA1 hippocampus of Sprague-Dawley rats specific to threat learning at genes involved in synaptic transmission. Experience-dependent alternations in gene expression and DNA methylation were observed as early as 1 h following memory acquisition and became more pronounced after 24 h. Gene ontology analysis revealed significant enrichment of functional categories related to synaptic transmission in genes that were hypomethylated at 24 h following threat learning. Integration of these data sets with previously characterized epigenetic and transcriptional changes in brain disease states suggested significant overlap between genes regulated by memory formation and genes altered in memory-related neurological and neuropsychiatric diseases. These findings provide a comprehensive resource to aid in the identification of memory-relevant therapeutic targets. Our results shed new light on the gene expression and DNA methylation changes involved in memory formation, confirming that these processes are dynamic and experience-dependent. Finally, this work provides a roadmap for future studies to identify linkage of memory-associated genes to altered disease states. PMID- 28620076 TI - Superior long-term synaptic memory induced by combining dual pharmacological activation of PKA and ERK with an enhanced training protocol. AB - Developing treatment strategies to enhance memory is an important goal of neuroscience research. Activation of multiple biochemical signaling cascades, such as the protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) pathways, is necessary to induce long-term synaptic facilitation (LTF), a correlate of long-term memory (LTM). Previously, a computational model was developed which correctly predicted a novel enhanced training protocol that augmented LTF by searching for the protocol with maximal overlap of PKA and ERK activation. The present study focused on pharmacological approaches to enhance LTF. Combining an ERK activator, NSC, and a PKA activator, rolipram, enhanced LTF to a greater extent than did either drug alone. An even greater increase in LTF occurred when rolipram and NSC were combined with the Enhanced protocol. These results indicate superior memory can be achieved by enhanced protocols that take advantage of the structure and dynamics of the biochemical cascades underlying memory formation, used in conjunction with combinatorial pharmacology. PMID- 28620077 TI - The influence of recollection and familiarity in the formation and updating of associative representations. AB - Prior representations affect future learning. Little is known, however, about the effects of recollective or familiarity-based representations on such learning. We investigate the ability to reuse or reassociate elements from recollection- and familiarity-based associations to form new associations. Past neuropsychological research suggests that hippocampal, and presumably recollective, representations are more flexible than extra-hippocampal, presumably familiarity-based, representations. We therefore hypothesize that the elements of recollective associations, as opposed to familiarity-based representations, may be more easily manipulated and decoupled from each other, and facilitate the formation of new associations. To investigate this hypothesis we used the AB/AC learning paradigm. Across two recall studies we observed an advantage in learning AC word pairs if AB word pairs were initially recollected. Furthermore, AB word pairs were more likely to intrude during a final AC test if those AB word pairs were initially familiarity-based. A third experiment using a recognition version of the AB/AC paradigm ruled out the possibility that our findings were due to memory strength. Our results support the idea that elements in recollective associative traces may be more discretely coded, leading to their flexible use, whereas elements in familiarity-based associative traces are less flexible. PMID- 28620078 TI - Role of the anterior cingulate cortex in the retrieval of novel object recognition memory after a long delay. AB - Previous in vivo electrophysiological studies suggest that the anterior cingulate cortex (ACgx) is an important substrate of novel object recognition (NOR) memory. However, intervention studies are needed to confirm this conclusion and permanent lesion studies cannot distinguish effects on encoding and retrieval. The interval between encoding and retrieval tests may also be a critical determinant of the role of the ACgx. The current series of experiments used micro-infusion of the GABAA receptor agonist, muscimol, into ACgx to reversibly inactivate the area and distinguish its role in encoding and retrieval. ACgx infusions of muscimol, before encoding did not alter NOR assessed after a delay of 20 min or 24 h. However, when infused into the ACgx before retrieval muscimol impaired NOR assessed after a delay of 24 h, but not after a 20-min retention test. Together these findings suggest that the ACgx plays a time-dependent role in the retrieval, but not the encoding, of NOR memory, neuronal activation being required for the retrieval of remote (24 h old), but not recent (20 min old) visual memory. PMID- 28620079 TI - Starvation promotes odor/feeding-time associations in flies. AB - Starvation causes a motivational state that facilitates diverse behaviors such as feeding, walking, and search. Starved Drosophila can form odor/feeding-time associations but the role of starvation in encoding of "time" is poorly understood. Here we show that the extent of starvation is correlated with the fly's ability to establish odor/feeding-time memories. Prolonged starvation promotes odor/feeding-time associations after just a single cycle of reciprocal training. We also show that starvation is required for acquisition but is dispensable for retrieval of odor/feeding-time memory. Finally, even with extended starvation, a functional circadian oscillator is indispensable for establishing odor/feeding-time memories. PMID- 28620080 TI - The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated Polycystin Channel Complex. AB - Autosomal dominant polycystic kidney disease (ADPKD) is caused by inactivating mutations in PKD1 (85%) or PKD2 (15%). The ADPKD proteins encoded by these genes, polycystin-1 (PC1) and polycystin-2 (PC2), form a plasma membrane receptor-ion channel complex. However, the mechanisms controlling the subcellular localization of PC1 and PC2 are poorly understood. Here, we investigated the involvement of the retromer complex, an ancient protein module initially discovered in yeast that regulates the retrieval, sorting, and retrograde transport of membrane receptors. Using yeast two-hybrid, biochemical, and cellular assays, we determined that PC2 binds two isoforms of the retromer-associated protein sorting nexin 3 (SNX3), including a novel isoform that binds PC2 in a direct manner. Knockdown of SNX3 or the core retromer protein VPS35 increased the surface expression of endogenous PC1 and PC2 in vitro and in vivo and increased Wnt activated PC2-dependent whole-cell currents. These findings indicate that an SNX3 retromer complex regulates the surface expression and function of PC1 and PC2. Molecular targeting of proteins involved in the endosomal sorting of PC1 and PC2 could lead to new therapeutic approaches in ADPKD. PMID- 28620082 TI - Turning the Tide: Improving Fluid Management in Dialysis through Technology. PMID- 28620083 TI - Interpreting iron studies. PMID- 28620084 TI - Multidimensional Genetic Analysis of Repeated Seizures in the Hybrid Mouse Diversity Panel Reveals a Novel Epileptogenesis Susceptibility Locus. AB - Epilepsy has many causes and comorbidities affecting as many as 4% of people in their lifetime. Both idiopathic and symptomatic epilepsies are highly heritable, but genetic factors are difficult to characterize among humans due to complex disease etiologies. Rodent genetic studies have been critical to the discovery of seizure susceptibility loci, including Kcnj10 mutations identified in both mouse and human cohorts. However, genetic analyses of epilepsy phenotypes in mice to date have been carried out as acute studies in seizure-naive animals or in Mendelian models of epilepsy, while humans with epilepsy have a history of recurrent seizures that also modify brain physiology. We have applied a repeated seizure model to a genetic reference population, following seizure susceptibility over a 36-d period. Initial differences in generalized seizure threshold among the Hybrid Mouse Diversity Panel (HMDP) were associated with a well-characterized seizure susceptibility locus found in mice: Seizure susceptibility 1 Remarkably, Szs1 influence diminished as subsequent induced seizures had diminishing latencies in certain HMDP strains. Administration of eight seizures, followed by an incubation period and an induced retest seizure, revealed novel associations within the calmodulin-binding transcription activator 1, Camta1 Using systems genetics, we have identified four candidate genes that are differentially expressed between seizure-sensitive and -resistant strains close to our novel Epileptogenesis susceptibility factor 1 (Esf1) locus that may act individually or as a coordinated response to the neuronal stress of seizures. PMID- 28620085 TI - A SINE Insertion in ATP1B2 in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2). AB - Spongy degeneration with cerebellar ataxia (SDCA) is a genetically heterogeneous neurodegenerative disorder with autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. Using a combined linkage and homozygosity mapping approach we identified an ~10.6 Mb critical interval on chromosome 5 in a Malinois family with four puppies affected by cerebellar dysfunction. Visual inspection of the 10.6 Mb interval in whole-genome sequencing data from one affected puppy revealed a 227 bp SINE insertion into the ATP1B2 gene encoding the beta2 subunit of the Na+/K+-ATPase holoenzyme (ATP1B2:c.130_131insLT796559.1:g.50_276). The SINE insertion caused aberrant RNA splicing. Immunohistochemistry suggested a reduction of ATP1B2 protein expression in the central nervous system of affected puppies. Atp1b2 knockout mice had previously been reported to show clinical and neurohistopathological findings similar to the affected Malinois puppies. Therefore, we consider ATP1B2:c.130_131ins227 the most likely candidate causative variant for a second subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia subtype 2 (SDCA2). Our study further elucidates the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population in Malinois and the other varieties of the Belgian Shepherd breed. ATP1B2 thus represents another candidate gene for human inherited cerebellar ataxias, and SDCA2-affected Malinois puppies may serve as a naturally occurring animal model for this disorder. PMID- 28620081 TI - Re-Examining Neutrophil Participation in GN. AB - Significant advances in understanding the pathogenesis of GN have occurred in recent decades. Among those advances is the finding that both innate and adaptive immune cells contribute to the development of GN. Neutrophils were recognized as key contributors in early animal models of GN, at a time when the prevailing view considered neutrophils to function as nonspecific effector cells that die quickly after performing antimicrobial functions. However, advances over the past two decades have shown that neutrophil functions are more complex and sophisticated. Specifically, research has revealed that neutrophil survival is regulated by the inflammatory milieu and that neutrophils demonstrate plasticity, mediate microbial killing through previously unrecognized mechanisms, demonstrate transcriptional activity leading to the release of cytokines and chemokines, interact with and regulate cells of the innate and adaptive immune systems, and contribute to the resolution of inflammation. Therefore, neutrophil participation in glomerular diseases deserves re-evaluation. In this review, we describe advances in understanding classic neutrophil functions, review the expanded roles of neutrophils in innate and adaptive immune responses, and summarize current knowledge of neutrophil contributions to GN. PMID- 28620087 TI - Daily Activity of the Housefly, Musca domestica, Is Influenced by Temperature Independent of 3' UTR period Gene Splicing. AB - Circadian clocks orchestrate daily activity patterns and free running periods of locomotor activity under constant conditions. While the first often depends on temperature, the latter is temperature-compensated over a physiologically relevant range. Here, we explored the locomotor activity of the temperate housefly Musca domestica Under low temperatures, activity was centered round a major and broad afternoon peak, while high temperatures resulted in activity throughout the photophase with a mild midday depression, which was especially pronounced in males exposed to long photoperiods. While period (per) mRNA peaked earlier under low temperatures, no temperature-dependent splicing of the last per 3' end intron was identified. The expression of timeless, vrille, and Par domain protein 1 was also influenced by temperature, each in a different manner. Our data indicated that comparable behavioral trends in daily activity distribution have evolved in Drosophila melanogaster and M. domestica, yet the behaviors of these two species are orchestrated by different molecular mechanisms. PMID- 28620086 TI - A Genetic Screen Reveals an Unexpected Role for Yorkie Signaling in JAK/STAT Dependent Hematopoietic Malignancies in Drosophila melanogaster. AB - A gain-of-function mutation in the tyrosine kinase JAK2 (JAK2V617F ) causes human myeloproliferative neoplasms (MPNs). These patients present with high numbers of myeloid lineage cells and have numerous complications. Since current MPN therapies are not curative, there is a need to find new regulators and targets of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling that may represent additional clinical interventions . Drosophila melanogaster offers a low complexity model to study MPNs as JAK/STAT signaling is simplified with only one JAK [Hopscotch (Hop)] and one STAT (Stat92E). hopTumorous-lethal(Tum-l) is a gain-of-function mutation that causes dramatic expansion of myeloid cells, which then form lethal melanotic tumors. Through an F1 deficiency (Df) screen, we identified 11 suppressors and 35 enhancers of melanotic tumors in hopTum-l animals. Dfs that uncover the Hippo (Hpo) pathway genes expanded (ex) and warts (wts) strongly enhanced the hopTum-l tumor burden, as did mutations in ex, wts, and other Hpo pathway genes. Target genes of the Hpo pathway effector Yorkie (Yki) were significantly upregulated in hopTum-l blood cells, indicating that Yki signaling was increased. Ectopic hematopoietic activation of Yki in otherwise wild-type animals increased hemocyte proliferation but did not induce melanotic tumors. However, hematopoietic depletion of Yki significantly reduced the hopTum-l tumor burden, demonstrating that Yki is required for melanotic tumors in this background. These results support a model in which elevated Yki signaling increases the number of hemocytes, which become melanotic tumors as a result of elevated JAK/STAT signaling. PMID- 28620088 TI - The R148.3 Gene Modulates Caenorhabditis elegans Lifespan and Fat Metabolism. AB - Despite many advances, the molecular links between energy metabolism and longevity are not well understood. Here, we have used the nematode model Caenorhabditis elegans to study the role of the yet-uncharacterized gene R148.3 in fat accumulation and lifespan. In wild-type worms, a R148.3p::GFP reporter showed enhanced expression throughout life in the pharynx, in neurons, and in muscles. Functionally, a protein fusing a predicted 22 amino acid N-terminal signal sequence (SS) of R148.3 to mCherry displayed robust accumulation in coelomyocytes, indicating that R148.3 is a secreted protein. Systematic depletion of R148.3 by RNA interference (RNAi) at L1 but not at young-adult stage enhanced triglyceride accumulation, which was associated with increased food uptake and lower expression of genes involved in lipid oxidation. However, RNAi of R148.3 at both L1 and young-adult stages robustly diminished mean and maximal lifespan of wild-type worms, and also abolished the long-lived phenotypes of eat-2 and daf 2/InsR mutants. Based on these data, we propose that R148.3 is an SS that modulates fat mass and longevity in an independent manner. PMID- 28620091 TI - Correction: TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors. PMID- 28620092 TI - The Evolution of Clinical Trials in Oncology: Defining Who Benefits from New Drugs Using Innovative Study Designs. PMID- 28620089 TI - Development and validation of risk prediction equations to estimate survival in patients with colorectal cancer: cohort study. AB - Objective To develop and externally validate risk prediction equations to estimate absolute and conditional survival in patients with colorectal cancer. Design Cohort study.Setting General practices in England providing data for the QResearch database linked to the national cancer registry.Participants 44 145 patients aged 15-99 with colorectal cancer from 947 practices to derive the equations. The equations were validated in 15 214 patients with colorectal cancer from 305 different QResearch practices and 437 821 patients with colorectal cancer from the national cancer registry.Main outcome measures The primary outcome was all cause mortality and secondary outcome was colorectal cancer mortality.Methods Cause specific hazards models were used to predict risks of colorectal cancer mortality and other cause mortality accounting for competing risks, and these risk estimates were combined to obtain risks of all cause mortality. Separate equations were derived for men and women. Several variables were tested: age, ethnicity, deprivation score, cancer stage, cancer grade, surgery, chemotherapy, radiotherapy, smoking status, alcohol consumption, body mass index, family history of bowel cancer, anaemia, liver function test result, comorbidities, use of statins, use of aspirin, clinical values for anaemia, and platelet count. Measures of calibration and discrimination were determined in both validation cohorts at 1, 5, and 10 years.Results The final models included the following variables in men and women: age, deprivation score, cancer stage, cancer grade, smoking status, colorectal surgery, chemotherapy, family history of bowel cancer, raised platelet count, abnormal liver function, cardiovascular disease, diabetes, chronic renal disease, chronic obstructive pulmonary disease, prescribed aspirin at diagnosis, and prescribed statins at diagnosis. Improved survival in women was associated with younger age, earlier stage of cancer, well or moderately differentiated cancer grade, colorectal cancer surgery (adjusted hazard ratio 0.50), family history of bowel cancer (0.62), and prescriptions for statins (0.77) and aspirin (0.83) at diagnosis, with comparable results for men. The risk equations were well calibrated, with predicted risks closely matching observed risks. Discrimination was good in men and women in both validation cohorts. For example, the five year survival equations on the QResearch validation cohort explained 45.3% of the variation in time to colorectal cancer death for women, the D statistic was 1.86, and Harrell's C statistic was 0.80 (both measures of discrimination, indicating that the scores are able to distinguish between people with different levels of risk). The corresponding results for all cause mortality were 42.6%, 1.77, and 0.79.Conclusions Risk prediction equations were developed and validated to estimate overall and conditional survival of patients with colorectal cancer accounting for an individual's clinical and demographic characteristics. These equations can provide more individualised accurate information for patients with colorectal cancer to inform decision making and follow-up. PMID- 28620093 TI - Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C Peptide. AB - OBJECTIVE: Many patients with long-standing type 1 diabetes have remaining functional beta-cells. This study investigated immunological differences between patients with or without measurable remaining endogenous insulin production after >=10 years duration of disease. RESEARCH DESIGN AND METHODS: Patients (n = 113; >=18 years of age) with type 1 diabetes and with disease duration of >=10 years were recruited at Uppsala University Hospital. Residual beta-cell function was determined with an ultrasensitive C-peptide ELISA. Circulating cytokines, including interleukin-35 (IL-35), were determined in plasma. Additional blood samples were collected from 14 of the identified C-peptide-positive patients and 12 of the C-peptide-negative patients, as well as from 15 healthy control subjects, and were used for immediate investigation of peripheral blood mononuclear cells. RESULTS: The blood concentration of the cytokine IL-35 was markedly lower in C-peptide-negative patients, and this was associated with a simultaneous decrease in the proportion of IL-35+ regulatory T cells (Tregs), IL 35+ regulatory B cells, and IL-35-producing CD8+Foxp3+ cells. IL-35 has previously been shown to maintain the phenotype of Tregs, block the differentiation of T-helper 17 cells, and thereby dampen immune assaults to beta cells. We found that the proportions of IL-17a+ cells among the Tregs, CD4+ T cells, and CD8+ T cells were lower in the C-peptide-positive patients. CONCLUSIONS: Patients with remaining endogenous beta-cell function after >10 years duration of type 1 diabetes differ immunologically from other patients with long-standing type 1 diabetes. In particular, they have a much higher IL-35 production. PMID- 28620095 TI - Responses to Cytokines and Interferons that Depend upon JAKs and STATs. AB - Many cytokines and all interferons activate members of a small family of kinases (the Janus kinases [JAKs]) and a slightly larger family of transcription factors (the signal transducers and activators of transcription [STATs]), which are essential components of pathways that induce the expression of specific sets of genes in susceptible cells. JAK-STAT pathways are required for many innate and acquired immune responses, and the activities of these pathways must be finely regulated to avoid major immune dysfunctions. Regulation is achieved through mechanisms that include the activation or induction of potent negative regulatory proteins, posttranslational modification of the STATs, and other modulatory effects that are cell-type specific. Mutations of JAKs and STATs can result in gains or losses of function and can predispose affected individuals to autoimmune disease, susceptibility to a variety of infections, or cancer. Here we review recent developments in the biochemistry, genetics, and biology of JAKs and STATs. PMID- 28620094 TI - An Interrupted Time Series Analysis to Determine the Effect of an Electronic Health Record-Based Intervention on Appropriate Screening for Type 2 Diabetes in Urban Primary Care Clinics in New York City. AB - OBJECTIVE: To determine the impact of a health system-wide primary care diabetes management system, which included targeted guidelines for type 2 diabetes (T2DM) and prediabetes (dysglycemia) screening, on detection of previously undiagnosed dysglycemia cases. RESEARCH DESIGN AND METHODS: Intervention included electronic health record (EHR)-based decision support and standardized providers and staff training for using the American Diabetes Association guidelines for dysglycemia screening. Using EHR data, we identified 40,456 adults without T2DM or recent screening with a face-to-face visit (March 2011-December 2013) in five urban clinics. Interrupted time series analyses examined the impact of the intervention on trends in three outcomes: 1) monthly proportion of eligible patients receiving dysglycemia testing, 2) two negative comparison conditions (dysglycemia testing among ineligible patients and cholesterol screening), and 3) yield of undiagnosed dysglycemia among those tested. RESULTS: Baseline monthly proportion of eligible patients receiving testing was 7.4-10.4%. After the intervention, screening doubled (mean increase + 11.0% [95% CI 9.0, 13.0], proportion range 18.6-25.3%). The proportion of ineligible patients tested also increased (+5.0% [95% CI 3.0, 8.0]) with no concurrent change in cholesterol testing (+0% [95% CI -0.02, 0.05]). About 59% of test results in eligible patients showed dysglycemia both before and after the intervention. CONCLUSIONS: Implementation of a policy for systematic dysglycemia screening including formal training and EHR templates in urban academic primary care clinics resulted in a doubling of appropriate testing and the number of patients who could be targeted for treatment to prevent or delay T2DM. PMID- 28620096 TI - Interleukin-6 Family Cytokines. AB - The interleukin (IL)-6 family cytokines is a group of cytokines consisting of IL 6, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine (CLC), and IL-27. They are grouped into one family because the receptor complex of each cytokine contains two (IL-6 and IL-11) or one molecule (all others cytokines) of the signaling receptor subunit gp130. IL-6 family cytokines have overlapping but also distinct biologic activities and are involved among others in the regulation of the hepatic acute phase reaction, in B-cell stimulation, in the regulation of the balance between regulatory and effector T cells, in metabolic regulation, and in many neural functions. Blockade of IL-6 family cytokines has been shown to be beneficial in autoimmune diseases, but bacterial infections and metabolic side effects have been observed. Recent advances in cytokine blockade might help to minimize such side effects during therapeutic blockade. PMID- 28620098 TI - Cytokine Signaling in the Development and Homeostasis of Regulatory T cells. AB - Cytokine signaling is indispensable for regulatory T-cell (Treg) development in the thymus, and also influences the homeostasis, phenotypic diversity, and function of Tregs in the periphery. Because Tregs are required for establishment and maintenance of immunological self-tolerance, investigating the role of cytokines in Treg biology carries therapeutic potential in the context of autoimmune disease. This review discusses the potent and diverse influences of interleukin (IL)-2 signaling on the Treg compartment, an area of knowledge that has led to the use of low-dose IL-2 as a therapy to reregulate autoaggressive immune responses. Evidence suggesting Treg-specific impacts of the cytokines transforming growth factor beta (TGF-beta), IL-7, thymic stromal lymphopoietin (TSLP), IL-15, and IL-33 is also presented. Finally, we consider the technical challenges and knowledge limitations that must be overcome to bring other cytokine-based, Treg-targeted therapies into clinical use. PMID- 28620099 TI - Correction: RAG1/2 induces genomic insertions by mobilizing DNA into RAG1/2 independent breaks. PMID- 28620100 TI - Restoring leukemia cell function from the inside out. PMID- 28620097 TI - Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications. AB - The cytokines of the interleukin 17 (IL-17) family play a central role in the control of infections, especially extracellular fungi. Conversely, if unrestrained, these inflammatory cytokines contribute to the pathology of numerous autoimmune and chronic inflammatory conditions. Recent advances have led to the approval of IL-17A-blocking biologics for the treatment of moderate to severe plaque psoriasis, but much remains to be understood about the biological functions, regulation, and signaling pathways downstream of these factors. In this review, we outline the current knowledge of signal transduction and known physiological activities of IL-17 family cytokines. We will highlight in particular the current understanding of these cytokines in the context of skin manifestations of disease. PMID- 28620101 TI - Barcodes show family trees in ALL. PMID- 28620102 TI - Novel oncogenic noncoding mutations in T-ALL. PMID- 28620103 TI - Pre-PMF emerging as important subgroup of MPN. PMID- 28620104 TI - From tumor suppressor to thrombus resolver. PMID- 28620105 TI - Erdheim-Chester disease presenting as bradycardia in an elderly man. PMID- 28620106 TI - Coarse basophilic stippling in lead poisoning. PMID- 28620107 TI - Cicalese MP, Ferrua F, Castagnaro L, et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016;128(1):45-54. PMID- 28620108 TI - Marini O, Costa S, Bevilacqua D, et al. Mature CD10+ and immature CD10- neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood. 2017;129(10):1343-1356. PMID- 28620109 TI - Prefibrotic/early vs overt PMF. PMID- 28620110 TI - Predicting survival in patients with colorectal cancer. PMID- 28620111 TI - Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association. AB - Cardiovascular disease (CVD) is the leading global cause of death, accounting for 17.3 million deaths per year. Preventive treatment that reduces CVD by even a small percentage can substantially reduce, nationally and globally, the number of people who develop CVD and the costs of caring for them. This American Heart Association presidential advisory on dietary fats and CVD reviews and discusses the scientific evidence, including the most recent studies, on the effects of dietary saturated fat intake and its replacement by other types of fats and carbohydrates on CVD. In summary, randomized controlled trials that lowered intake of dietary saturated fat and replaced it with polyunsaturated vegetable oil reduced CVD by ~30%, similar to the reduction achieved by statin treatment. Prospective observational studies in many populations showed that lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD and of other major causes of death and all-cause mortality. In contrast, replacement of saturated fat with mostly refined carbohydrates and sugars is not associated with lower rates of CVD and did not reduce CVD in clinical trials. Replacement of saturated with unsaturated fats lowers low-density lipoprotein cholesterol, a cause of atherosclerosis, linking biological evidence with incidence of CVD in populations and in clinical trials. Taking into consideration the totality of the scientific evidence, satisfying rigorous criteria for causality, we conclude strongly that lowering intake of saturated fat and replacing it with unsaturated fats, especially polyunsaturated fats, will lower the incidence of CVD. This recommended shift from saturated to unsaturated fats should occur simultaneously in an overall healthful dietary pattern such as DASH (Dietary Approaches to Stop Hypertension) or the Mediterranean diet as emphasized by the 2013 American Heart Association/American College of Cardiology lifestyle guidelines and the 2015 to 2020 Dietary Guidelines for Americans. PMID- 28620112 TI - Midwifery and women's health. AB - EBN Perspectives bring together key issues from the commentaries in one of our nursing topic themes. PMID- 28620118 TI - Role of p38-MAPK pathway in the effects of high-magnitude compression on nucleus pulposus cell senescence in a disc perfusion culture. AB - Nucleus pulposus (NP) cell senescence is a typical pathological feature within the degenerative intervertebral disc. As a potential inducing and aggregating factor of disc degeneration, mechanical overloading affects disc biology in multiple ways. The present study was to investigate the NP cell senescence associated phenotype under intermittent high compression in an ex vivo disc bioreactor culture, and the role of the p38-MAPK pathway in this regulatory process. Porcine discs were cultured in culture chambers of a self-developed mechanically active bioreactor and subjected to different magnitudes of dynamic compression (low-magnitude and high-magnitude: 0.1 and 1.3 MPa at a frequency of 1.0 Hz for 2 h per day respectively) for 7 days. Non-compressed discs were used as controls. The inhibitor SB203580 was used to study the role of the p38-MAPK pathway in this process. Results showed that intermittent high-magnitude compression clearly induced senescence-associated changes in NP cells, such as increasing beta-galactosidase-positive NP cells, decreasing PCNA-positive NP cells, promoting the formation of senescence-associated heterochromatic foci (SAHF), up-regulating the expression of senescence markers (p16 and p53), and attenuating matrix production. However, inhibition of the p38-MAPK pathway partly attenuated the effects of intermittent high-magnitude (1.3 MPa) compression on those described NP cell senescence-associated parameters. In conclusion, intermittent high-magnitude compression can induce NP cell senescence-associated changes in an ex vivo disc bioreactor culture, and the p38-MAPK pathway is involved in this process. PMID- 28620119 TI - Tripartite motif containing 25 promotes proliferation and invasion of colorectal cancer cells through TGF-beta signaling. AB - Tripartite motif containing 25 (TRIM25) is a member of TRIM proteins and functions as an E3 (ubiquitin ligase). It has been found to act as an oncogene in gastric cancer cells and is abnormally expressed in cancers in female reproductive system. Here, we investigated the function of TRIM25 in colorectal cancer. TRIM25 was found to be significantly up-regulated in colorectal cancer tissues and cancer cell lines through real-time PCR assay. Colorectal cancer cells (CRCs) overexpressing TRIM25 exhibited a two-fold higher proliferation and migration rate compared with their parental lines in vitro Moreover, TRIM25 also promoted tumor progression in vivo Further study indicated that TRIM25 worked through positively regulating transforming growth factor beta (TGF-beta) signaling pathway to regulate the proliferation and invasion of CRCs. In summary, our results indicate that TRIM25 also acts as an oncogene in colorectal cancer and it functions through TGF-beta signaling pathway. Thus, TRIM25 represents potential targets for the treatment of colorectal cancer. PMID- 28620121 TI - Social norms: More details, please. PMID- 28620120 TI - Ethyl Vanillin Activates TRPA1. AB - The nonselective cation channel transient receptor potential ankryn subtype family 1 (TRPA1) is expressed in neurons of dorsal root ganglia and trigeminal ganglia and also in vagal afferent neurons that innervate the lungs and gastrointestinal tract. Many TRPA1 agonists are reactive electrophilic compounds that form covalent adducts with TRPA1. Allyl isothiocyanate (AITC), the common agonist used to identify TRPA1, contains an electrophilic group that covalently binds with cysteine residues of TRPA1 and confers a structural change on the channel. There is scientific motivation to identify additional compounds that can activate TRPA1 with different mechanisms of channel gating. We provide evidence that ethyl vanillin (EVA) is a TRPA1 agonist. Using fluorescent calcium imaging and whole-cell patch-clamp electrophysiology on dissociated rat vagal afferent neurons and TRPA1-transfected COS-7 cells, we discovered that EVA activates cells also activated by AITC. Both agonists display similar current profiles and conductances. Pretreatment with A967079, a selective TRPA1 antagonist, blocks the EVA response as well as the AITC response. Furthermore, EVA does not activate vagal afferent neurons from TRPA1 knockout mice, showing selectivity for TRPA1 in this tissue. Interestingly, EVA appears to be pharmacologically different from AITC as a TRPA1 agonist. When AITC is applied before EVA, the EVA response is occluded. However, they both require intracellular oxidation to activate TRPA1. These findings suggest that EVA activates TRPA1 but via a distinct mechanism that may provide greater ease for study in native systems compared with AITC and may shed light on differential modes of TRPA1 gating by ligand types. PMID- 28620122 TI - NHS cyberattack may prove to be a valuable wake up call. PMID- 28620123 TI - Correction: Work injuries among migrant workers in Denmark. PMID- 28620124 TI - A High-Throughput, Field-Based Phenotyping Technology for Tall Biomass Crops. AB - Recent advances in omics technologies have not been accompanied by equally efficient, cost-effective, and accurate phenotyping methods required to dissect the genetic architecture of complex traits. Even though high-throughput phenotyping platforms have been developed for controlled environments, field based aerial and ground technologies have only been designed and deployed for short-stature crops. Therefore, we developed and tested Phenobot 1.0, an auto steered and self-propelled field-based high-throughput phenotyping platform for tall dense canopy crops, such as sorghum (Sorghum bicolor). Phenobot 1.0 was equipped with laterally positioned and vertically stacked stereo RGB cameras. Images collected from 307 diverse sorghum lines were reconstructed in 3D for feature extraction. User interfaces were developed, and multiple algorithms were evaluated for their accuracy in estimating plant height and stem diameter. Tested feature extraction methods included the following: (1) User-interactive Individual Plant Height Extraction (UsIn-PHe) based on dense stereo three dimensional reconstruction; (2) Automatic Hedge-based Plant Height Extraction (Auto-PHe) based on dense stereo 3D reconstruction; (3) User-interactive Dense Stereo Matching Stem Diameter Extraction; and (4) User-interactive Image Patch Stereo Matching Stem Diameter Extraction (IPaS-Di). Comparative genome-wide association analysis and ground-truth validation demonstrated that both UsIn-PHe and Auto-PHe were accurate methods to estimate plant height, while Auto-PHe had the additional advantage of being a completely automated process. For stem diameter, IPaS-Di generated the most accurate estimates of this biomass-related architectural trait. In summary, our technology was proven robust to obtain ground-based high-throughput plant architecture parameters of sorghum, a tall and densely planted crop species. PMID- 28620137 TI - Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. AB - Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has diarrhea and fatigue as dose-limiting toxicities. In preclinical models, palbociclib has been extensively studied and induces cell cycle inhibition in an RB-dependent manner. Thus far, abemaciclib has been less extensively evaluated. We found that abemaciclib cell cycle inhibitory activity is RB-dependent at clinically achievable concentrations. Abemaciclib elicited potent suppression of RB/E2F regulated genes associated with prognosis in ER-positive breast cancer. However, unlike palbociclib, at 250nM-1 uM doses abemaciclib induced cell death in RB-deficient cell lines. This response was associated with a rapidly-induced multi-vacuolar phenotype indicative of lysosomal membrane permeabilization that could be ameliorated with chloroquine. This event was not a reflection of inhibition of other CDK family members, but could be recapitulated with CBX4945 that inhibits casein and DYRK/HIPK kinases. To determine if these "off-target" features of abemaciclib were observed in vivo, mice harboring matched RB-positive and negative xenografts were treated with palbociclib and abemaciclib. In vivo, all of the apparent activity of abemaciclib was RB-dependent and strongly elicited suppression of cell cycle regulatory genes in a fashion markedly similar to palbociclib. Using gene expression data from cell lines and tumors treated with abemaciclib and palbociclib a composite signature of response to CDK4/6 inhibition was developed that included many genes that are individually required for tumor cell proliferation or viability. These data indicate that while abemaciclib and palbociclib can exert distinct biological and molecular effects, there are common gene expression features that could be broadly utilized in measuring the response to CDK4/6 inhibition. PMID- 28620138 TI - New perspectives for colorectal cancer. PMID- 28620148 TI - CFC1 is a cancer stemness-regulating factor in neuroblastoma. AB - BACKGROUND: Despite the use of aggressive therapy, survival rates among high-risk neuroblastoma (NB) patients remain poor. Cancer stem cells (CSCs) are considered to be critically involved in the recurrence and metastasis of NB and are isolated as NB spheres. METHODS: The gene expression profiling of adherent (control) and sphere-forming primary NB cells was conducted using a gene expression microarray. CFC1, which functions in the development of embryos and decides the left-right axis, was strongly expressed in sphere-forming cells only and was related to the unfavorable prognosis of NB patients. The knockdown and overexpression of CFC1 were performed using a lentiviral system in NB cell lines. Sphere formation, cell proliferation, colony formation in soft agar, and xenograft tumor formation were analyzed. RESULTS: The overexpression of CFC1 increased sphere formation, cell growth, and colony formation. These phenotypes, particularly sphere formation, and xenograft tumor formation were significantly suppressed by the knockdown of CFC1. CFC1 inhibited Activin A-induced NB cell differentiation and Smad2 phosphorylation in NB cell lines, indicating its involvement in tumorigenesis related to EGF-CFC co-receptor family molecule pathways. Collectively, these results indicate that CFC1 is a candidate molecule for the development of CSC targeted therapy for NB. PMID- 28620149 TI - Adult neurogenesis in intellectual disabilities. PMID- 28620146 TI - Mitochondrial ASncmtRNA-1 and ASncmtRNA-2 as potent targets to inhibit tumor growth and metastasis in the RenCa murine renal adenocarcinoma model. AB - Knockdown of antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptosis in several human and mouse tumor cell lines, but not normal cells, suggesting this approach for a selective therapy against different types of cancer. Here we show that in vitro knockdown of murine ASncmtRNAs induces apoptotic death of mouse renal adenocarcinoma RenCa cells, but not normal murine kidney epithelial cells. In a syngeneic subcutaneous RenCa model, treatment delayed and even reversed tumor growth. Since the subcutaneous model does not reflect the natural microenviroment of renal cancer, we used an orthotopic model of RenCa cells inoculated under the renal capsule. These studies showed inhibition of tumor growth and metastasis. Direct metastasis assessment by tail vein injection of RenCa cells also showed a drastic reduction in lung metastatic nodules. In vivo treatment reduces survivin, N-cadherin and P-cadherin levels, providing a molecular basis for metastasis inhibition. In consequence, the treatment significantly enhanced mouse survival in these models. Our results suggest that the ASncmtRNAs could be potent and selective targets for therapy against human renal cell carcinoma. PMID- 28620150 TI - Mutational cascades in cancer. PMID- 28620151 TI - Reproductive innovation and the recognition of a new genus within the Polystomatidae (Monogenea) infecting chelonian vertebrates. AB - Polystomatid monogeneans have a wide diversity of life cycles correlated with the varied ecology and behaviour of their aquatic vertebrate hosts. Typically, transmission involves a swimming infective larva but most hosts are amphibious and invasion is interrupted when hosts leave water. A key life cycle adaptation involves a uterus that, in the most specialised cases, may contain several hundred fully-developed larvae prepared for instant host-to-host transmission. By contrast, one subfamily of the Polystomatidae - the Polystomoidinae, specific to chelonians (freshwater turtles) - has a simplified reproductive system without a uterus. Recently, Polystomoides nelsoni Du Preez et Van Rooyen, 2015 has been described with a uterus containing multiple eggs. The present study explores the exceptional interest of this parasite - for the functional biology of egg production, for the evolution of a reproductive system unique amongst ca 60 species in the subfamily, and for systematic relationships. A new genus is proposed, Uteropolystomoides gen. n., separate from the four currently-recognised genera Polystomoides Ward, 1917, Uropolystomoides Tinsley et Tinsley, 2016, Neopolystoma Price, 1939 and Polystomoidella Price, 1939 which lack a uterus. In addition, U. nelsoni (Du Preez et Van Rooyen, 2015) comb. n. has a suite of distinctive copulatory stuctures: a massive genital bulb with an exceptionally large number of very long genital spines and hyper-development of the vaginal openings. These characters set U. nelsoni apart from all other polystomoidines worldwide except Polystomoides multifalx Stunkard, 1924 and P. stunkardi Harwood, 1931. Missing data for these latter species preclude definitive assessment of inter-relationships but the distinguishing characters of U. nelsoni, especially the unique occurrence of the uterus, suggest a novel evolutionary pathway isolated from other lineages of polystomatids infecting chelonians. PMID- 28620152 TI - Cryptosporidium meleagridis and C. baileyi (Apicomplexa) in domestic and wild birds in Algeria. AB - A total of 345 faecal samples were collected from domestic, captive and wild birds in rural areas, urban areas and a Zoo in Algeria. Samples were screened for the presence of parasites belonging to the genus Cryptosporidium Tyzzer, 1910 by microscopy and PCR analysis of the small-subunit rRNA (SSU), actin and 60-kDa glycoprotein (gp60) genes. Cryptosporidium spp. were detected in 31 samples. Sequence analysis of SSU and actin genes revealed the presence of C. baileyi Current, Upton et Haynes, 1986 in domestic chicken broilers (n = 12), captive ostriches (n = 4) and a wild mallard (n = 1), and C. meleagridis Slavin, 1955 in a graylag goose (n = 1), chickens (n = 11) and turkeys (n = 2). Twenty-three chicken and two turkey broilers from five farms were positive for cryptosporidia, with an overall prevalence of 2% and 6%, respectively. Both C. meleagridis and C. baileyi were detected in farmed chicken broilers, with a prevalence ranging from 9% to 69%. Farmed turkeys broilers were positive only for C. meleagridis, with a 13% prevalence at the animal level. Subtyping of C. meleagridis isolates at the gp60 locus showed the presence of subtype IIIgA22G3R1 in graylag goose and chicken broilers and IIIgA23G2R1 in chicken and turkey broilers. Infection with cryptosporidia was not associated with any clinical diseases. The results of the present study, which provides the first data on the prevalence of Cryptosporidium spp. in wild birds in Africa, demonstrate the presence of human pathogenic C. meleagridis in both domestic and wild birds in Algeria. PMID- 28620153 TI - Premature Labor and Neonatal Septicemia Caused by Capnocytophaga Ochracea. AB - BACKGROUND Capnocytophaga ochracea is a gram-negative anaerobic organism commonly found in human oral flora. It is characteristically sensitive to beta-lactams and resistant to aminoglycosides. CASE REPORT A 23-year-old woman presented with lower abdominal pain and was admitted for premature labor at 24-weeks of gestation. At presentation, the cervix was closed and the membrane was intact; however, contractions continued, the membrane subsequently ruptured before receiving any steroids or magnesium, and the mother gave birth to a 540-gram female baby. At birth, Apgar scores were 1 at 5 minutes, 1 at 10 minutes, and 2 at 15 minutes. On the fifth day of life, the blood culture grew Capnocytophaga species. Consequently, Cefotaxime was started and ampicillin continued for a total of 14 days; however, on the 6th day, the head ultrasound showed grade 4 intraventricular hemorrhage and a Do Not Resuscitate (DNR) order was placed in the chart. The patient's health continued to deteriorate, having multiple episodes of bradycardia and desaturation until cardiac arrest on the 17th day. CONCLUSIONS Capnocytophaga ochracea was isolated from the blood culture of a preterm neonate. It was thought to be the cause of the premature labor and subsequent neonatal septicemia. This case report suggests that the prevalence of Capnocytophaga infections is most likely underestimated and that additional premature labors and abortions could have been caused by Capnocytophaga infections that were never detected. Hence, more studies are needed to investigate the route of transmission. PMID- 28620154 TI - Influence of Donor Lung Surfactant-A and -B Protein Expression on the Development of Primary Graft Dysfunction After Lung Transplantation: A Pilot Study. AB - BACKGROUND Primary graft dysfunction (PGD) is responsible of high early mortality in lung transplanted patients. We measured the rate of surfactant proteins in the organ donor, and we observed the occurrence of lung PGD in the recipient. The co relation between these two parameters was evaluated. MATERIAL AND METHODS In this pilot study, we prospectively collected blood samples and lung biopsies in thirteen donors at the time of recovery of organs before preservation. Gene expression of SP-A, SP-B, SP-D, and CC16 was evaluated by real-time quantitative PCR. Surfactant proteins plasma levels were evaluated by ELISA. Post-transplant assessments included hemodynamic, arterial blood gas measurements, and radiographic evaluation to determine PGD and lung biopsies. RESULTS Nine of the thirteen recipients (69%) developed lung infiltrates and four (31%) developed PGD at either stages 2 or 3. SP-A and SP-B expressions were dramatically reduced in lung allografts of these patients, while lung expression of SP-D and CC16 remained unchanged. Plasma levels of SP-A, SP-B, SP-D, and CC16 did not differ. CONCLUSIONS Primary graft dysfunction may be initiated in the donor. Lung allografts with low lung SP-A and SP-B gene expression prior to implantation are associated with increased incidence of lung infiltrates after transplantation. PMID- 28620155 TI - SHP-2 Activating Mutation Promotes Malignant Biological Behaviors of Glioma Cells. AB - BACKGROUND This study investigated the mechanism underlying the activating mutation of SHP-2 in promoting malignant biological behaviors of glioma cells. MATERIAL AND METHODS The SHP-2 empty plasmid pcDNA3.1 and SHP-2 activating mutation plasmid pcDNA3.1 SHP-2 D61G mutant eukaryotic expression vectors were designed; stable SHP-2-expressing cells transfected with pcDNA3.1 SHP-2 D61G mutant were set as the mutation group; cells transfected with pcDNA3.1 were set as the empty vector group; and cells without transfection were set as the control group. The cell reproductive capacity in each group was measured by MTT method. The invasion ability of cells in vitro was detected by Transwell chamber assay, the cell apoptosis in each group was detected by Annexin-V/PE dual-staining method, and the clone formation ability of cells in vitro was detected by Tablet clone-forming assay. The activation of ERK1/2, ARK, and p38MAPK signal pathways in each group was determined by Western blot. RESULTS After transfection, the expression of SHP-2 protein in the mutant group was significantly higher than that in the control group and empty vector group. The proliferation ability of transfected cells, the apoptosis rate, the invasion ability, and the expression levels of phosphorylated ERK1/2, AKT, and p38 in the mutation group was significantly higher than in the empty vector group and the control group (P<0.05). Moreover, the cell clone formation ability of the mutation group was obviously enhanced (P<0.05). CONCLUSIONS The activating mutation of SHP-2 can lead to malignant changes in biological behaviors of glioma cells, and the specific mechanism may be related to the activation of ERK1/2, AKT, and p38 signal pathway. SHP-2 protein may become a new target for anti-malignant transformation of glioma. PMID- 28620156 TI - The effect of Lasik surgery on myopic anisometropes' sensory eye dominance. AB - Lasik is a common surgery for treating anisometropia. In this study, we asked a specific question: what's the effect of Lasik surgery on anisometropes' sensory eye dominance ? Fifteen myopic anisometropes (mean age: 23 +/- 6.9 years old; 6 females) participated in our experiment. We quantitatively measured participants' sensory eye dominance before and after the Lasik surgery using a binocular phase combination paradigm. We found no significant change of sensory eye dominance within 16 weeks (measured between 8 to 96 days, for one or two repetitions) after the surgery (t(14) = -1.44, p = 0.17). A further following on eight patients showed that patients' two eyes were much more balanced at 16 weeks or more (measured one or two times between 112 to 408 days) after the surgery (t(7) = 3.79, p = 0.007). Our results suggest that the benefit of Lasik surgery on anisometropes' sensory eye dominance is not immediate, a long-term 'adaptation' period (16 weeks or more) is necessary to enable the surgery to be truly effective. PMID- 28620157 TI - A novel cell membrane affinity sample pretreatment technique for recognition and preconcentration of active components from traditional Chinese medicine. AB - We describe a novel biomembrane affinity sample pretreatment technique to quickly screen and preconcentrate active components from traditional Chinese medicine (TCM), which adopts cell membrane coated silica particles (CMCSPs) as affinity ligands which benefit the biomembrane's ability to maximize simulation of drug receptor interactions in vivo. In this study, the prepared CMCSPs formed by irreversible adsorption of fibroblast growth factor receptor 4 (FGFR4) cell membrane on the surface of silica were characterized using different spectroscopic and imaging instruments. Drug binding experiments showed the excellent adsorption rate and adsorption capacity of FGFR4/CMCSPs compared with non-coated silica particles. The FGFR4/CMCSPs were used as solid-phase extraction sorbents to pretreat the TCM Aconitum szechenyianum Gay. The resultant FGFR4/CMCSPs exhibited good performance. In addition, high selectivity and recognition ability of the FGFR4/CMCSPs were determined by selectivity experiments. Four alkaloid were screened and identified, one of these alkaloid, napellonine, showed favorable anti-tumor activity in preliminary pharmacological verification trials including cell proliferation and molecular docking assays. The proposed cell membrane affinity sample pretreatment method is a reliable, effective and time-saving method for fast screening and enriching active compounds and can be extended to pretreat other TCMs as leading compounds resources. PMID- 28620158 TI - Clinical Features and Sleep Analysis of Chinese Patients with Fatal Familial Insomnia. AB - This study aimed to examine clinical features, sleep, abnormal sleep-wake transition and non-sleep disturbances as well as lab tests in Chinese fatal familial insomnia (FFI) subjects. Patients with confirmed clinical and laboratory diagnosis of FFI have been retrospectively reviewed. The clinical features and the results of the complementary tests, including polysomnography (PSG), brain imaging and genetic analysis, were used. Two male and three female patients were recruited in this study. Three of the five patients had more comprehensive family medical records. The most typical clinical manifestations in all 5 patients were sleep disturbances, including insomnia, laryngeal stridor, sleep breath disturbance, and sleep-related involuntary movements. PSG of all these five cases showed reduction in total sleep time, sleep fragmentation, abnormal short non rapid eye movement - rapid eye movement (REM) cycling, REM sleep reduction or loss, and REM sleep instruction in wakefulness. Patient 2's emission tomography scan demonstrated a reduction in glucose uptake in the left thalamus and bilateral inferior parietal lobe. In summary, Chinese FFI patients are typically characterized by organic sleep related symptoms, rapidly progressive dementia and sympathetic symptoms. We propose that structural damages in the thalamus and cortex are mostly responsible for clinical manifestations of FFI. PMID- 28620159 TI - Main and epistatic loci studies in soybean for Sclerotinia sclerotiorum resistance reveal multiple modes of resistance in multi-environments. AB - Genome-wide association (GWAS) and epistatic (GWES) studies along with expression studies in soybean [Glycine max (L.) Merr.] were leveraged to dissect the genetics of Sclerotinia stem rot (SSR) [caused by Sclerotinia sclerotiorum (Lib.) de Bary], a significant fungal disease causing yield and quality losses. A large association panel of 466 diverse plant introduction accessions were phenotyped in multiple field and controlled environments to: (1) discover sources of resistance, (2) identify SNPs associated with resistance, and (3) determine putative candidate genes to elucidate the mode of resistance. We report 58 significant main effect loci and 24 significant epistatic interactions associated with SSR resistance, with candidate genes involved in a wide range of processes including cell wall structure, hormone signaling, and sugar allocation related to plant immunity, revealing the complex nature of SSR resistance. Putative candidate genes [for example, PHYTOALEXIN DEFFICIENT 4 (PAD4), ETHYLENE INSENSITIVE 3-LIKE 1 (EIL3), and ETHYLENE RESPONSE FACTOR 1 (ERF1)] clustered into salicylic acid (SA), jasmonic acid (JA), and ethylene (ET) pathways suggest the involvement of a complex hormonal network typically activated by both necrotrophic (ET/JA) and biotrophic (SA) pathogens supporting that S. sclerotiorum is a hemibiotrophic plant pathogen. PMID- 28620160 TI - Small-diameter hybrid vascular grafts composed of polycaprolactone and polydioxanone fibers. AB - Electrospun polycaprolactone (PCL) vascular grafts showed good mechanical properties and patency. However, the slow degradation of PCL limited vascular regeneration in the graft. Polydioxanone (PDS) is a biodegradable polymer with high mechanical strength and moderate degradation rate in vivo. In this study, a small-diameter hybrid vascular graft was prepared by co-electrospinning PCL and PDS fibers. The incorporation of PDS improves mechanical properties, hydrophilicity of the hybrid grafts compared to PCL grafts. The in vitro/vivo degradation assay showed that PDS fibers completely degraded within 12 weeks, which resulted in the increased pore size of PCL/PDS grafts. The healing characteristics of the hybrid grafts were evaluated by implantation in rat abdominal aorta replacement model for 1 and 3 months. Color Doppler ultrasound demonstrated PCL/PDS grafts had good patency, and did not show aneurysmal dilatation. Immunofluorescence staining showed the coverage of endothelial cells (ECs) was significantly enhanced in PCL/PDS grafts due to the improved surface hydrophilicity. The degradation of PDS fibers provided extra space, which facilitated vascular smooth muscle regeneration within PCL/PDS grafts. These results suggest that the hybrid PCL/PDS graft may be a promising candidate for the small-diameter vascular grafts. PMID- 28620161 TI - Different signaling patterns contribute to loss of keratinocyte cohesion dependent on autoantibody profile in pemphigus. AB - Pemphigus is an autoimmune blistering skin disease caused primarily by autoantibodies against desmoglein (Dsg)1 and 3. Here, we characterized the mechanisms engaged by pemphigus IgG from patients with different clinical phenotypes and autoantibody profiles. All pemphigus vulgaris (PV) and pemphigus foliaceus (PF) IgG and AK23, a monoclonal mouse antibody against Dsg3, caused loss of cell cohesion, cytokeratin retraction and p38MAPK activation. Strong alterations in Dsg3 distribution were caused by mucosal (aDsg3 antibodies), mucocutaneous (aDsg1 + aDsg3) as well as atypical (aDsg3) PV-IgG. All PV-IgG fractions and AK23 compromised Dsg3 but not Dsg1 binding and enhanced Src activity. In contrast, rapid Ca2+ influx and Erk activation were induced by mucocutaneous PV-IgG and pemphigus foliaceus (PF) IgG (aDsg1) whereas cAMP was increased by mucosal and mucocutaneous PV-IgG only. Selective inhibition of p38MAPK, Src or PKC blocked loss of keratinocyte cohesion in response to all autoantibody fractions whereas Erk inhibition was protective against mucocutaneous PV-IgG and PF-IgG only. These results demonstrate that signaling patterns parallel the clinical phenotype as some mechanisms involved in loss of cell cohesion are caused by antibodies targeting Dsg3 whereas others correlate with autoantibodies against Dsg1. The concept of key desmosome regulators may explain observations from several experimental models of pemphigus. PMID- 28620162 TI - Characterization of an iron oxide nanoparticle labelling and MRI-based protocol for inducing human mesenchymal stem cells into neural-like cells. AB - The aim of the current study was to develop an iron oxide nanoparticle (ION) labelling and magnetic resonance imaging (MRI)-based protocol to allow visualization of the differentiation process of mesenchymal stem cells (MSCs) into neural-like cells (NCs) in vitro. Ferucarbotran, a clinically available ION, which can be visualized under MRI, is used for tracking cells implanted in vivo. The NCs were verified morphologically and histologically by light microscopy, and their functions were verified by measuring their action potentials. Conformational conversion of axon-like structures was observed under light microscopy. These NCs exhibited frequent, active action potentials compared with cells that did not undergo neural differentiation. The labelling of ION had no influence on the morphological and functional differentiation capacity of the MSCs. We conclude that the MSCs that were differentiated into NCs exhibited in vitro activity potential firing and may be used to replace damaged neurons. PMID- 28620163 TI - Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study. AB - Introduction of new myeloma therapies offers new options for patients refractory to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). In this multicenter study, patients with relapsed multiple myeloma, who have received at least three prior lines of therapy, are refractory to both an IMiD (lenalidomide or pomalidomide) and a PI (bortezomib or carfilzomib), and have been exposed to an alkylating agent were identified. The time patients met the above criteria was defined as time zero (T0). Five hundred and forty-three patients diagnosed between 2006 and 2014 were enrolled in this study. Median age at T0 was 62 years (range 31-87); 61% were males. The median duration between diagnosis and T0 was 3.1 years. The median number of lines of therapy before T0 was 4 (range 3-13). The median overall survival (OS) from T0 for the entire cohort was 13 (95% confidence interval (CI) 11, 15) months. At least one regimen recorded after T0 in 462 (85%) patients, with a median (95% CI) progression-free survival and OS from T0 of 5 (4, 6), and 15.2 (13, 17) months, respectively. The study provides the expected outcome of relapsed multiple myeloma that is refractory to a PI and an IMiD, a benchmark for comparison of new therapies being evaluated. PMID- 28620164 TI - Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging. AB - As concerns increase about adenovirus type 5 (Ad5) being a safe gene transfer vector, it is important to evaluate its distribution, residence time, and possible toxicity in immunodeficient populations. To characterize the potential risk associated with different Ad5 vector delivery modes, we used immunocompetent and immunodeficient Rag2 -/- animals to establish mouse and rat models that could be monitored with bioluminescent imaging following intramuscular or intravascular infection with an engineered replication-incompetent Ad5 virus carrying the firefly luciferase gene (Ad5-Fluc). The Ad5 vector was less well-tolerated by Rag2 -/- animals than by wildtype ones, with delayed residence time, wider virus dissemination, less weight gain, and relatively severe pathological changes. In intravascularly Ad5-Fluc-infected Rag2 -/- mice, systemic virus dissemination extended from the abdomen to the limbs and head on day 9 post-infection. Additionally, significant increases in plasma TNF-alpha and IFN-gamma, which may be important factors in the heightened immunopathology in the liver and brain, were detected in the Rag2 -/- mice 30 days after intravascular delivery. The Ad5 vector was better tolerated after intramuscular delivery than after intravascular delivery. Ad5-Fluc/Rag2 -/- mice and rats can be used as reliable models of an immunodeficient population in which to evaluate the safety of Ad5-vectored vaccines or gene therapy products. PMID- 28620165 TI - Applying modern psychometric techniques to melodic discrimination testing: Item response theory, computerised adaptive testing, and automatic item generation. AB - Modern psychometric theory provides many useful tools for ability testing, such as item response theory, computerised adaptive testing, and automatic item generation. However, these techniques have yet to be integrated into mainstream psychological practice. This is unfortunate, because modern psychometric techniques can bring many benefits, including sophisticated reliability measures, improved construct validity, avoidance of exposure effects, and improved efficiency. In the present research we therefore use these techniques to develop a new test of a well-studied psychological capacity: melodic discrimination, the ability to detect differences between melodies. We calibrate and validate this test in a series of studies. Studies 1 and 2 respectively calibrate and validate an initial test version, while Studies 3 and 4 calibrate and validate an updated test version incorporating additional easy items. The results support the new test's viability, with evidence for strong reliability and construct validity. We discuss how these modern psychometric techniques may also be profitably applied to other areas of music psychology and psychological science in general. PMID- 28620166 TI - Ab initio molecular dynamics simulation of low energy radiation responses of alpha-Al2O3. AB - In this study, an ab initio molecular dynamics method is employed to investigate the response behavior of alpha-Al2O3 to low energy irradiation. Different from the previous experiments, our calculations reveal that the displacements of oxygen dominate under electron irradiation and the created defects are mainly oxygen vacancy and interstitial. The experimental observation of the absorption peaks appearing at 203, 233 and 256 nm for alpha-Al2O3 under electron irradiations should be contributed by the oxygen defects and these defects will reduce the transmittance of alpha-Al2O3, which agrees well with the very recent experiment. This study demonstrates the necessity to reinvestigate the threshold displacement energies of alpha-Al2O3, and to introduce recombination center for oxygen defects to improve its optical properties and performance under radiation environment. PMID- 28620167 TI - High-throughput rapid-prototyping of low-cost paper-based microfluidics. AB - Paper-based micro analytical devices offer significant advantages compared to the conventional microfluidic chips including cost-effectiveness, ease of fabrication, and ease of use while preserving critical features including strong capillary action and biological compatibility. In this work, we demonstrate an inexpensive, rapid method for high-throughput fabrication of paper-based microfluidics by patterning hydrophobic barriers using a desktop pen plotter integrated with a custom-made, low-cost paper feeder. We tested various types of commercial permanent markers and compared their water-resistant capabilities for creating hydrophobic barriers. Additionally, we studied the performance of markers with different types of paper, plotting speeds, and pattern dimensions. To verify the effectiveness of the presented fabrication method, colorimetric analysis was performed on the results of a glucose assay. PMID- 28620169 TI - Structural insight for the recognition of G-quadruplex structure at human c-myc promoter sequence by flavonoid Quercetin. AB - Small molecule ligands that could stabilize G-quadruplex structure formed at the promoter region of human c-myc oncogene will regulate its expression in cancer cells. Flavonoids, a group of naturally available small molecule, have been known for their various promising effects on human health. In present study, we have performed detailed biophysical studies for the interaction of human c-myc G quadruplex DNA with nine representative flavonoids: Luteolin, Quercetin, Rutin, Genistein, Kaempferol, Puerarin, Hesperidin, Myricetin and Daidzein. We found by using fluorescence titration that Quercetin interacts with c-myc G-quadruplex DNA sequence Pu24T with highest affinity. This interaction was further explored by using NMR spectroscopy and we have derived the first solution structure for the complex formed between Quercetin and biologically significant c-myc promoter DNA sequence forming G-quadruplex structure. In present solution structure, Quercetin stacks at 5' and 3' G-tetrads of Pu24T G-quadruplex structure and stabilize it via pi-pi stacking interactions. Furthermore, in vitro studies on HeLa cells suggested that Quercetin induces apoptosis-mediated cell death and down-regulated c-myc gene expression. This study emphasizes the potential of flavonoids as a promising candidate for targeting c-myc promoter region and thus, could act as a potential anti-cancer agent. PMID- 28620168 TI - Dynamics of maternally transferred trace elements in oyster larvae and latent growth effects. AB - Understanding the maternal transfer of contaminants and their potential effects has great implications for a valid ecological assessment of environmental pollution. However, relevant studies on marine bivalves are very limited. Here, we examined the maternal transfer of trace metals in populations of oyster Crassostrea hongkongensis with contrasting metal exposure histories. Elevated accumulation of trace metals was observed in eggs and larvae from contaminated sites, suggesting maternal transfer of multi-metals in natural oyster populations. The dynamics of maternally transferred metals was for the first time documented in this study. We demonstrated that excessively transferred metals in contaminated larvae were rapidly eliminated during the early developmental stage, and the efflux rate of metals in larvae was greatly dependent on environmental contamination level. These results provided the first field evidence of modified metal biokinetics in offsprings due to exposure history of adults in marine bivalves. Moreover, egg production was negatively correlated with the contamination level of metals in eggs. There was a further lagged growth in the contaminated larvae, indicating the potential adverse and latent effects of maternally transferred metals on the viability of oyster offspring. Our findings highlighted the importance of transgenerational studies on long-term metal exposure in marine bivalves. PMID- 28620170 TI - Validation of optimal reference genes for quantitative real time PCR in muscle and adipose tissue for obesity and diabetes research. AB - The global incidence of obesity has led to an increasing need for understanding the molecular mechanisms that drive this epidemic and its comorbidities. Quantitative real-time RT-PCR (RT-qPCR) is the most reliable and widely used method for gene expression analysis. The selection of suitable reference genes (RGs) is critical for obtaining accurate gene expression information. The current study aimed to identify optimal RGs to perform quantitative transcriptomic analysis based on RT-qPCR for obesity and diabetes research, employing in vitro and mouse models, and human tissue samples. Using the ReFinder program we evaluated the stability of a total of 15 RGs. The impact of choosing the most suitable RGs versus less suitable RGs on RT-qPCR results was assessed. Optimal RGs differed between tissue and cell type, species, and experimental conditions. By employing different sets of RGs to normalize the mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha), we show that sub-optimal RGs can markedly alter the PGC1alpha gene expression profile. Our study demonstrates the importance of validating RGs prior to normalizing transcriptional expression levels of target genes and identifies optimal RG pairs for reliable RT-qPCR normalization in cells and in human and murine muscle and adipose tissue for obesity/diabetes research. PMID- 28620172 TI - Endocrinology: Reducing fat and building bone. PMID- 28620171 TI - Mechanical stability of talin rod controls cell migration and substrate sensing. AB - Cells adhere to the surrounding tissue and probe its mechanical properties by forming cell-matrix adhesions. Talin is a critical adhesion protein and participates in the transmission of mechanical signals between extracellular matrix and cell cytoskeleton. Force induced unfolding of talin rod subdomains has been proposed to act as a cellular mechanosensor, but so far evidence linking their mechanical stability and cellular response has been lacking. Here, by utilizing computationally designed mutations, we demonstrate that stepwise destabilization of the talin rod R3 subdomain decreases cellular traction force generation, which affects talin and vinculin dynamics in cell-matrix adhesions and results in the formation of talin-rich but unstable adhesions. We observed a connection between talin stability and the rate of cell migration and also found that talin destabilization affects the usage of different integrin subtypes and sensing of extracellular matrix proteins. Experiments with truncated forms of talin confirm the mechanosensory role of the talin R3 subdomain and exclude the possibility that the observed effects are caused by the release of talin head-rod autoinhibition. In conclusion, this study provides evidence into how the controlled talin rod domain unfolding acts as a key regulator of adhesion structure and function and consequently controls central cellular processes such as cell migration and substrate sensing. PMID- 28620175 TI - Ageing: Old bone removal. PMID- 28620177 TI - Market watch: Upcoming market catalysts in Q3 2017. PMID- 28620178 TI - Collision-induced activation: Towards industrially scalable approach to graphite nanoplatelets functionalization for superior polymer nanocomposites. AB - Scale-up manufacturing of engineered graphene-like nanomaterials to deliver the industry needs for development of high-performance polymer nanocomposites still remains a challenge. Herein, we introduce a quick and cost-effective approach to scalable production of functionalized graphite nanoplatelets using "kitchen blender" approach and Diels-Alder chemistry. We have shown that, in a solvent free process and through a cycloaddition mechanism, maleic anhydride can be grafted onto the edge-localized electron rich active sites of graphite nanoplatelets (GNP) resulting from high collision force, called "graphite collision-induced activation". The mechanical impact was modelled by applying the point charge method using density functional theory (DFT). The functionalization of GNP with maleic anhydride (m-GNP) was characterized using various spectroscopy techniques. In the next step, we used a recyclable process to convert m-GNP to the highly-reactive GNP (f-GNP) which exhibits a strong affinity towards the epoxy polymer matrix. It was found that at a low content of f-GNP e.g., 0.5 wt%, significant enhancements of ~54% and ~65% in tensile and flexural strengths of epoxy nanocomposite can be achieved, respectively. It is believed that this new protocol for functionalization of graphene nanomaterials will pave the way for relatively simple industrial scale fabrication of high performance graphene based nanocomposites. PMID- 28620179 TI - Ferroelectric-assisted gold nanoparticles array for centimeter-scale highly reproducible SERS substrates. AB - Assemble metal nanoparticles into various ordered structures with scale up to centimeter area is required to meet diverse needs of lab-on-a-chips and analytic components. Here, we present the uniform and high-yield fabrication of centimeter scale gold nanoparticles (AuNPs) array for SERS substrates. Ferroelectric assisted assembly of AuNPs line array is successfully fabricated by using a periodically poled LiNbO3 (PPLN) single crystal as a template. SNOM-Raman shows that the uniform assembly of AuNPs exhibits a high density of "hot spots" arising from strong electromagnetic (EM) field coupling induced by adjacent AuNPs. Quantitative analysis based on SERS detection describes an excellent reproducibility with an intensity variation less than 7% at 1649 cm-1 of Rhodamine 6G. SERS spectra combined with 3D-FDTD modelling indicate that the EM enhancement occurs at all three excitation wavelength of 515, 561 and 633 nm and the 561-nm-laser displays the strongest Raman enhancement with an enhancement factor in an order of 109. The corresponding experimental and theoretical results present a new strategy to fabricate large-area, highly reproducible and sensitive SERS substrates for practical applications. PMID- 28620180 TI - A functional SUMO-motif in the active site of PIM1 promotes its degradation via RNF4, and stimulates protein kinase activity. AB - The PIM1 serine/threonine protein kinase mediates growth factor and survival signalling, and cooperates potently with c-MYC during tumorigenesis. PIM1 is overexpressed in many human cancers and is a promising target for drug development. PIM1 levels are regulated mainly through cytokine-induced transcription and protein degradation, but mechanisms regulating its activity and levels remain largely unexplored. Here, we show that PIM1 is modified in vitro and in cultured cells by the Small ubiquitin-like modifier (SUMO) on two independent sites: K169, within a consensus SUMOylation motif (IK169DE171) in the active site of PIM1, and also at a second promiscuous site. Alanine substitution of E171 (within the consensus motif) abolished SUMOylation, significantly increased the half-life of PIM1, and markedly reduced its ubiquitylation. Mechanistically, SUMOylation promoted ubiquitin-mediated degradation of PIM1 via recruitment of the SUMO-targeted ubiquitin ligase, RNF4. Additionally, SUMOylated PIM1 showed enhanced protein kinase activity in vitro. Interestingly, the E171A mutant was active in vitro but displayed altered substrate specificity in cultured cells, consistent with the idea that SUMOylation may govern PIM1 substrate specificity under certain contexts. Taken together, these data demonstrate that the protein kinase activity and levels of PIM1 can be regulated by a covalent post-translational modification. PMID- 28620181 TI - Hair bundles of cochlear outer hair cells are shaped to minimize their fluid dynamic resistance. AB - The mammalian sense of hearing relies on two types of sensory cells: inner hair cells transmit the auditory stimulus to the brain, while outer hair cells mechanically modulate the stimulus through active feedback. Stimulation of a hair cell is mediated by displacements of its mechanosensitive hair bundle which protrudes from the apical surface of the cell into a narrow fluid-filled space between reticular lamina and tectorial membrane. While hair bundles of inner hair cells are of linear shape, those of outer hair cells exhibit a distinctive V shape. The biophysical rationale behind this morphology, however, remains unknown. Here we use analytical and computational methods to study the fluid flow across rows of differently shaped hair bundles. We find that rows of V-shaped hair bundles have a considerably reduced resistance to crossflow, and that the biologically observed shapes of hair bundles of outer hair cells are near-optimal in this regard. This observation accords with the function of outer hair cells and lends support to the recent hypothesis that inner hair cells are stimulated by a net flow, in addition to the well-established shear flow that arises from shearing between the reticular lamina and the tectorial membrane. PMID- 28620182 TI - Residential radon exposure and brain cancer: an ecological study in a radon prone area (Galicia, Spain). AB - We aimed to know if radon concentration is associated with municipal mortality due to brain cancer in Galicia, Spain. We designed an ecological study taking as study unit Galician municipalities. To be included, municipalities had to have at least three radon measurements. We correlated radon concentrations with municipal mortality due to these malignant tumors during the period 1999-2008. We calculated the relative risk of dying of brain cancers for each municipality and correlated this value with municipal radon concentration using Spearman's Rho. 251 municipalities were included, with close to 3,500 radon measurements and an average of 14 radon measurements at each municipality. We observed a significant correlation between residential radon with brain cancer mortality for males and females and the intensity of the correlation was higher for females. These results were reinforced when the analysis was restricted to municipalities with more than 5 radon measurements: Spearman's Rho 0.286 (p-value < 0.001) and Spearman's Rho 0.509 (p-value < 0.001) for males and females, respectively. These results suggest an association between residential radon and brain cancer mortality. More research using more robust epidemiological designs is needed to confirm these findings. PMID- 28620183 TI - De novo assembly and annotation of the Zhe-Maidong (Ophiopogon japonicus (L.f.) Ker-Gawl) transcriptome in different growth stages. AB - Zhe-Maidong (Ophiopogon japonicus (L.f.) Ker-Gawl) is a traditional medicinal herb in the family Liliaceae that has significant pharmacological effects on immunity and cardiovascular disease. In this study, three different growth stages of Zhe-Maidong were investigated using RNA-seq, and a total of 16.4 Gb of raw data was obtained. After filtering and assembling, 96,738 unigenes with an average length of 605.3 bp were ultimately generated. A total of 77,300 unigenes were annotated using information from five databases, including the NT, NR, SwissProt, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases. Additionally, the mechanisms of flavonoid, saponin and polysaccharide biosynthesis and of accumulation at different stages of tuber development were also characterized. From the first to third years, the contents of flavonoids, saponins and polysaccharides all increased, whereas the expression levels of related genes decreased in the flavonoid and saponin pathways and first increased and then decreased in the polysaccharide pathway. The results of this study provide the most comprehensive expressed sequence resource for Zhe-Maidong and will expand the available O. japonicus gene library and facilitate further genome wide research and analyses of this species. PMID- 28620184 TI - Transcriptomic Analysis of the Regulation of Lipid Fraction Migration and Fatty Acid Biosynthesis in Schizochytrium sp. AB - Schizochytrium sp. is the main source of docosahexaenoic acid-rich oil, which is widely used in food additive and pharmaceutical industry. In this study, using RNA-seq, comparative transcriptomic analyses were performed at four stages of DHA fermentation by Schizochytrium sp to get potential genes related to cell transition from cell growth to lipid accumulation and then to lipid turnover. 1406, 385, 1384 differently expressed genes were identified by comparisons in pairs of S2 vs S1, S3 vs S2 and S4 vs S3. Functional analysis revealed that binding and single-organism process might be involve in the cell transition from cell growth to lipid accumulation while oxidation-reduction process played an important role in the transition from lipid accumulation to lipid turnover. pfaC in the PKS pathway showed higher sensitivity to the environmental change, which might be the key regulator for enhancing PUFA biosynthesis in the future. Some other genes in signal transduction and cell transport were revealed to be related to lipid turnover, which would enrich the current knowledge regarding lipid metabolism and help to enhance the DHA production and enrich different lipid fractions by Schizochytrium in the future. PMID- 28620185 TI - c-Abl regulates gastrointestinal muscularis propria homeostasis via ERKs. AB - The gastrointestinal tract is responsible for food digestion and absorption. The muscularis propria propels the foodstuff through the GI tract and defects in intestine motility may cause obstruction disorders. Our present genetic studies identified non-receptor tyrosine kinase c-Abl as an important regulator of the muscularis propria homeostasis and a risk factor for rectal prolapse. Mouse deficient for c-Abl showed defects in the muscularis propria of gastrointestinal tract and older c-Abl -/- mice developed megaesophagus and rectal prolapse. Inhibition of c-Abl with imatinib mesylate, an anti-CML drug, or ablation of c Abl using Prx1-Cre, which marks smooth muscle cells, recapitulated most of the muscularis propria phenotypes. The pathogenesis of rectal prolapse was attributable to overproliferation of smooth muscle cells, which was caused by enhanced ERK1/2 activation. Administration of ERK inhibitor U0126 impeded the development of rectal prolapse in c-Abl deficient mice. These results reveal a role for c-Abl-regulated smooth muscle proliferation in the pathogenesis of rectal prolapse, and imply that long-term use of imatinib mesylate may cause gastrointestinal problems in patients while ERK inhibitor may be effective in treating rectal prolapse. PMID- 28620186 TI - Phenotypic, genotypic and antigenic characterization of emerging avian reoviruses isolated from clinical cases of arthritis in broilers in Saskatchewan, Canada. AB - In recent years, emerging strains of pathogenic arthrogenic avian reovirus (ARV) have become a challenge to the chicken industry across USA and Canada causing significant economic impact. In this study, we characterized emerging variant ARV strains and examined their genetic and antigenic relationship with reference strains. We isolated 37 emerging variant ARV strains from tendons of broiler chickens with clinical cases of arthritis/tenosynovitis at commercial farms in Saskatchewan, Canada. Viral characterization using immunocytochemistry, gold immunolabeling and electron microscopy revealed distinct features characteristic of ARV. Polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) analyses of the viral Sigma C gene revealed genetic heterogeneity between the field isolates. On phylogenetic analyses, the Sigma C amino acid sequences of the isolates were clustered into four distinct genotypic groups. These ARV field strains were genetically diverse and quite distant from the vaccine and vaccine related field strains. Antibodies produced against a commercial Reo 2177 (r) vaccine did not neutralize these variants. Moreover, structure based analysis of the Sigma C protein revealed significant antigenic variability between the cluster groups and the vaccine strains. To the best of our knowledge, this is the first report on the genetic, phenotypic and antigenic characterization of emerging ARVs in Canada. PMID- 28620187 TI - Discovery and identification of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol 3-yl) phenyl) phosphorothioate (XP-1408) as a novel mode of action of organophosphorus insecticides. AB - Organophosphorus (OP) insecticides play an important role in pest control. Many OP insecticides have been removed from the market because of their high toxicity to humans. We designed and synthesized a new OP insecticide with the goal of providing a low cost, and less toxic insecticide. The mode of action of O, O diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP 1408) was studied in Drosophila melanogaster. Bioassays showed that XP-1408 at a concentration of 50 mg/L delayed larval development. Molecular docking into Drosophila acetylcholinesterase (AChE) and voltage-gated sodium channels suggested that XP-1408 fitted into their active sites and could be inhibitory. Whole-cell patch clamp recordings indicated that XP-1408 exhibited synergistic effects involving the inhibition of cholinergic synaptic transmission and blockage of voltage-gated potassium (Kv) channels and sodium (Nav) channels. In conclusion, the multiple actions of XP-1408 rendered it as a lead compound for formulating OP insecticides with a novel mode of action. PMID- 28620189 TI - Switching and extension of transmission response, based on bending metamaterials. AB - The electromagnetically-induced transparency (EIT)-like effects in planar and non planar metamaterials (MMs) were investigated for microwave (GHz) frequencies. The specific MMs used in this study consisted of a cut-wire resonator and a ring resonator, where were placed on the top and the bottom layers, respectively. A transmission window was produced, due to the interference between bright- and bright-mode coupling. Using the numerical and the experimental results, we demonstrate that the bending of MM leads to enhanced transmission and bandwidth, as well as an additional EIT-like peak. This provides an effective way of realizing the tunable devices, including the switching sensors. PMID- 28620188 TI - Ecological diversity and co-occurrence patterns of bacterial community through soil profile in response to long-term switchgrass cultivation. AB - Switchgrass (Panicum virgatum L.) is a cellulosic biofuel feedstock and their effects on bacterial communities in deep soils remain poorly understood. To reveal the responses of bacterial communities to long-term switchgrass cultivation through the soil profile, we examined the shift of soil microbial communities with depth profiles of 0-60 cm in five-year switchgrass cultivation and fallow plots. The Illumina sequencing of the 16S rRNA gene showed that switchgrass cultivation significantly increased microbial OTU richness, rather than microbial Shannon diversity; however, there was no significant difference in the structure of microbial communities between switchgrass cultivation and fallow soils. Both switchgrass cultivation and fallow soils exhibited significant negative vertical spatial decay of microbial similarity, indicating that more vertical depth distant soils had more dissimilar communities. Specifically, switchgrass cultivation soils showed more beta-diversity variations across soil depth profile. Through network analysis, more connections and closer relationships of microbial taxa were observed in soils under switchgrass cultivation, suggesting that microbial co-occurrence patterns were substantially influenced by switchgrass cultivation. Overall, our study suggested that five year switchgrass cultivation could generated more beta-diversity variations across soil depth and more complex inter-relationships of microbial taxa, although did not significantly shape the structure of soil microbial community. PMID- 28620190 TI - Formation of Biphasic Hydroxylapatite-Beta Magnesium Tricalcium Phosphate in Heat Treated Salmonid Vertebrae. AB - Ichthyoarchaeological evidence is uncommon at ancient hunter-gatherer sites from various regions and timeframes. This research contributes to the development of microarchaeological techniques useful for identifying fishing economies in situations where classifiable bones are unavailable. Specifically, traces of heat altered bone mineral in domestic hearths are expected to provide markers for discarded fish remains. We used a series of laboratory incineration experiments to characterize the mineralogy of burned salmonid vertebrae. Fourier transform infrared spectroscopy and x-ray diffraction distinguished the formation of beta magnesium tricalcium phosphate (betaMgTCP) at temperatures as low as 600 degrees C. Bones from a sample of game mammals and birds did not form this phase at temperatures below 1,000 degrees C. We propose that this neoformed mineral can serve as a proxy for hunter-gatherer salmonid fishing when typical ichthyoarchaeological evidence is absent. Using Fourier transform infrared spectroscopy, it will be possible to rapidly and inexpensively determine the presence of betaMgTCP in fragmentary burned bone remains associated with combustion features. The occurrence of betaMgTCP in archaeological hearth features will offer a new means of further evaluating the temporal, geographic, and cultural scope of salmonid harvesting. We also acknowledge the value of biphasic hydroxylapatite-betaMgTCP recovered from Atlantic salmon vertebrae as a bioceramic. PMID- 28620191 TI - Density-wave fronts on the brink of wet granular condensation. AB - Density-wave fronts in a vibrofluidized wet granular layer undergoing a gas liquid-like transition are investigated experimentally. The threshold of the instability is governed by the amplitude of the vertical vibrations. Fronts, which are curved into a spiral shape, propagate coherently along the circular rim of the container with leading edges. They are stable beyond a critical distance from the container center. Based on an analysis of the emerging time and length scales, we propose a model for the pattern formation by considering the competition between the time scale for the condensation of wet granular particles from a gas-like state and that of the energy injection resisting this process. PMID- 28620192 TI - Luminescent turn-on detection of Hg(II) via the quenching of an iridium(III) complex by Hg(II)-mediated silver nanoparticles. AB - A novel luminescent turn-on detection method for Hg(II) was developed. The method was based on the silver nanoparticle (AgNP)-mediated quenching of Ir(III) complex 1. The addition of Hg(II) ions causes the luminescence of complex 1 to be recovered due to the oxidation of AgNPs by Hg(II) ions to form Ag(I) and Ag/Hg amalgam. The luminescence intensity of 1 increased in accord with an increased Hg(II) concentration ranging from 0 nM to 180 nM, with the detection limit of 5 nM. This approach offers an innovative method for the quantification of Hg(II). PMID- 28620194 TI - Prognostic value of olfactory nerve damage measured with thallium-based olfactory imaging in patients with idiopathic olfactory dysfunction. AB - Idiopathic olfactory disorder is resistant to treatment, and the recovery time is long. This study investigated the prognostic value of the migration of nasally administered thallium-201 to the olfactory bulb (thallium migration to the OB), a measure of olfactory nerve damage, in patients with idiopathic olfactory disorders. Twenty-four patients with idiopathic olfactory disorders were enrolled in the study (7 women and 17 men; aged 23-73 years). We retrospectively analyzed potential prognostic markers in subjects who underwent thallium-based olfactory imaging with the nasal administration of thallium-201 before conventional treatment with the Japanese herbal medicine tokishakuyakusan and compared those data with the prognosis. Log-rank tests were performed to assess the relationship between thallium migration to the OB (<4.6% [low] vs. >=4.6% [high]; data dichotomized at the optimal cutoff value) and the duration until recovery of the odor recognition threshold determined by a standard olfactory function test (T&T olfactometry) after the treatment. Upon statistical analysis, we found that high thallium migration to the OB was significantly correlated with better prognosis in patients. Our results suggest that patients with intact olfactory nerve fibers could be selected using thallium-based imaging for the long-term follow-up of olfactory dysfunction. PMID- 28620193 TI - MicroRNA-29a Counteracts Synovitis in Knee Osteoarthritis Pathogenesis by Targeting VEGF. AB - Synovitis contributes to the development of osteoarthritis (OA) of the knee. MicroRNAs regulate joint microenvironment homeostasis and deterioration. This study was undertaken to characterize the actions of microRNA-29a (miR-29a) to synovial remodeling in OA joints. Synovial specimens isolated from patients with end-stage OA knees showed abundant fibrotic matrix and vessel histopathology concomitant with weak miR-29a expression. In vitro, miR-29a knockdown caused synovial fibroblasts to exhibit high expressions of collagen III, TGF-beta1, MMP9, MMP13, and ADAMTS5, whereas miR-29a overexpression diminished these joint deleterious factors. In collagenase-mediated OA pathogenesis, miR-29a overexpressing transgenic mice showed minor responses to hyperplasia, macrophage infiltration, fibrosis, hyperangiogenesis, and VEGF expression in synovial lesions. These effects mitigated articular cartilage loss and gait aberrance of injured joints. Intra-articular administration of miR-29a precursor lessened the collagenase aggravation of excessive synovial remodeling reactions and thereby sustained joint tissue integrity. miR-29a lowered VEGF production and angiogenic activities in synovial fibroblasts through targeting the 3'-UTR of VEGF. Taken together, miR-29a deficiency exacerbated synovitis pathogenesis in the end-stage OA knees. miR-29a signaling fends off excessive synovial angiogenesis and fibrosis, which delays joint destruction. This study sheds new light on the protective effects against synovial deterioration and the therapeutic advantage of miR-29a in OA knees. PMID- 28620195 TI - Attenuation of cGVHD by C5a/C5aR blockade is associated with increased frequency of Treg. AB - C5aR signaling plays an important role in the regulation of T cell activation and alloimmune responses in chronic graft-versus-host disease (cGVHD). However, direct evidence of this modulation and the efficacy of C5aR blockade in the treatment of cGVHD have not been demonstrated. We observed higher expression of C5aR on both monocytes and T cells of patients with cGVHD compared with healthy controls and non-GVHD patients after allogeneic hematopoietic stem cell transplantation. Our data also demonstrated a significant negative correlation between C5aR expression and regulatory T cells (Treg) frequency in cGVHD patients, indicating a potential role of C5aR in the generation and regulation of Treg. In addition, an in vitro experiment revealed C5aR deficiency promoted the development of Treg whereas C5a activation abolished the differentiation of Treg. Importantly, we found C5aR blockade by PMX53 attenuated the pathology of cGVHD and improved the survival of cGVHD mice. PMX53 had a direct regulatory effect on Treg commitment and increased TGF-beta1 expression. Thus, C5aR signaling may induce and intensify cGVHD by down-regulating Treg induction. The modulation of C5aR activation by PMX53 may provide a potential therapy for cGVHD. PMID- 28620196 TI - Integration of DNA methylation and gene transcription across nineteen cell types reveals cell type-specific and genomic region-dependent regulatory patterns. AB - Despite numerous studies done on understanding the role of DNA methylation, limited work has focused on systems integration of cell type-specific interplay between DNA methylation and gene transcription. Through a genome-wide analysis of DNA methylation across 19 cell types with T-47D as reference, we identified 106,252 cell type-specific differentially-methylated CpGs categorized into 7,537 differentially (46.6% hyper- and 53.4% hypo-) methylated regions. We found 44% promoter regions and 75% CpG islands were T-47D cell type-specific methylated. Pyrosequencing experiments validated the cell type-specific methylation across three benchmark cell lines. Interestingly, these DMRs overlapped with 1,145 known tumor suppressor genes. We then developed a Bayesian Gaussian Regression model to measure the relationship among DNA methylation, genomic segment distribution, differential gene expression and tumor suppressor gene status. The model uncovered that 3'UTR methylation has much less impact on transcriptional activity than other regions. Integration of DNA methylation and 82 transcription factor binding information across the 19 cell types suggested diverse interplay patterns between the two regulators. Our integrative analysis reveals cell type-specific and genomic region-dependent regulatory patterns and provides a perspective for integrating hundreds of various omics-seq data together. PMID- 28620197 TI - Interleukin-28B dampens airway inflammation through up-regulation of natural killer cell-derived IFN-gamma. AB - Interleukin-28A (IL-28A) modulates CD11c+ dendritic cell (DC) function and promotes type 1T helper (Th1) differentiation, thus suppressing allergic airway diseases. However, the function of the IL-28A isoform IL-28B in these diseases remains largely unknown. In this study, we revealed a novel role of IL-28B in inducing type 1 immunity and protecting against ovalbumin (OVA)-induced allergic asthma in mice. IL-28B overexpression in wild-type mice promoted natural killer (NK) cell polarization in the lung, leading to the increased number of interferon (IFN)-gamma-producing NK1 cells as well as Th1 differentiation. Importantly, IL 28B overexpression had no protective effect on OVA-induced asthma in IFN-gamma knockout (IFN-gamma-/-) mice. These results demonstrate that IL-28B ameliorates experimental allergic asthma via enhancing NK cell polarization, which might be useful for prevention and treatment of allergic asthma. PMID- 28620198 TI - Hydrogen gas protects IP3Rs by reducing disulfide bridges in human keratinocytes under oxidative stress. AB - Based on the oxidative stress theory, aging derives from the accumulation of oxidized proteins induced by reactive oxygen species (ROS) in the cytoplasm. Hydrogen peroxide (H2O2) elicits ROS that induces skin aging through oxidation of proteins, forming disulfide bridges with cysteine or methionine sulfhydryl groups. Decreased Ca2+ signaling is observed in aged cells, probably secondary to the formation of disulfide bonds among Ca2+ signaling-related proteins. Skin aging processes are modeled by treating keratinocytes with H2O2. In the present study, H2O2 dose-dependently impaired the adenosine triphosphate (ATP)-induced Ca2+ response, which was partially protected via co-treatment with beta mercaptoethanol, resulting in reduced disulfide bond formation in inositol 1, 4, 5-trisphosphate receptors (IP3Rs). Molecular hydrogen (H2) was found to be more effectively protected H2O2-induced IP3R1 dysfunction by reducing disulfide bonds, rather than quenching ROS. In conclusion, skin aging processes may involve ROS induced protein dysfunction due to disulfide bond formation, and H2 can protect oxidation of this process. PMID- 28620199 TI - Predicting the outcomes of organic reactions via machine learning: are current descriptors sufficient? AB - As machine learning/artificial intelligence algorithms are defeating chess masters and, most recently, GO champions, there is interest - and hope - that they will prove equally useful in assisting chemists in predicting outcomes of organic reactions. This paper demonstrates, however, that the applicability of machine learning to the problems of chemical reactivity over diverse types of chemistries remains limited - in particular, with the currently available chemical descriptors, fundamental mathematical theorems impose upper bounds on the accuracy with which raction yields and times can be predicted. Improving the performance of machine-learning methods calls for the development of fundamentally new chemical descriptors. PMID- 28620200 TI - Urinary metabolomics reveals the therapeutic effect of HuangQi Injections in cisplatin-induced nephrotoxic rats. AB - The side effects of cisplatin (CDDP), notably nephrotoxicity, greatly limited its use in clinical chemotherapy. HuangQi Injections (HI), a commonly used preparation of the well-known Chinese herbal medicine Astragali radix, appeared to be promising treatment for nephrotoxicity without compromising the anti-tumor activity of CDDP. In this study, the urinary metabolomics approach using liquid chromatography time of flight mass spectrometry (LC-TOF/MS) was developed to assess the toxicity-attenuation effects and corresponding mechanisms of HI on CDDP-exposed rats. As a result, successive administration of HI significantly recovered the decline of body weight and downregulated the abnormal increase of serum creatinine and urea. HI partly restored the CDDP-induced alteration of metabolic profiling back into normal condition. Totally 43 toxicity-attenuation potential biomarkers were screened and tentatively identified, which were involved in important metabolic pathways such as amino acid metabolism, TCA cycle, fatty acid metabolism, vitamin B6 metabolism and purine metabolism. The results clearly revealed that HI could alleviate CDDP-induced nephrotoxicity and improve the disturbed metabolic balance induced by repeated CDDP exposure. The present study provided reliable evidence for the protective effect of HI on CDDP induced toxicity with the multi-target pharmacological characteristics. PMID- 28620201 TI - Interactions between the developmental and adult social environments mediate group dynamics and offspring traits in Drosophila melanogaster. AB - Developmental conditions can strongly influence adult phenotypes and social interactions, which in turn affect key evolutionary processes such as sexual selection and sexual conflict. While the implications of social interactions in phenotypically mixed populations at the individual level are increasingly well known, how these effects influence the fate of groups remains poorly understood, which limits our understanding of the broader ecological implications. To address this problem we manipulated adult phenotypes and social composition in Drosophila melanogaster - by experimentally manipulating the larval density of the group members - and measured a range of group-level outcomes across the lifespan of groups. Adult groups composed of exclusively low larval-density individuals showed high courtship levels, and low early reproductive rates, group growth rates, offspring mass and offspring eclosion success, relative to high larval density or mixed larval-density groups. Furthermore, high larval-density groups had lower survival. Offspring mass increased with time, but at a reduced rate in groups when male group members (but not females) were from a mixture of larval densities; peak reproductive rates were also earlier in these groups. Our results suggest that that variation in developmental conditions experienced by adult group members can modify the reproductive output of groups. PMID- 28620203 TI - Prehistoric cooking versus accurate palaeotemperature records in shell midden constituents. AB - The reconstruction of pre-depositional cooking treatments used by prehistoric coastal populations for processing aquatic faunal resources is often difficult in archaeological shell midden assemblages. Besides limiting our knowledge of various social, cultural, economic and technological aspects of shell midden formation, unknown pre-depositional cooking techniques can also introduce large errors in palaeoclimate reconstructions as they can considerably alter the geochemical proxy signatures in calcareous skeletal structures such as bivalve shells or fish otoliths. Based on experimental and archaeological data, we show that carbonate clumped-isotope thermometry can be used to detect and reconstruct prehistoric processing methods in skeletal aragonite from archaeological shell midden assemblages. Given the temperature-dependent re-equilibration of clumped isotopes in aragonitic carbonates, this allows specific processing, cooking or trash dispersal strategies such as boiling, roasting, or burning to be differentiated. Besides permitting the detailed reconstruction of cultural or technological aspects of shell midden formation, this also allows erroneous palaeoclimate reconstructions to be avoided as all aragonitic shells subjected to pre-historic cooking methods show a clear alteration of their initial oxygen isotopic composition. PMID- 28620202 TI - Nanotopological plate stimulates osteogenic differentiation through TAZ activation. AB - The topographical environment, which mimics the stem cell niche, provides mechanical cues to regulate the differentiation of mesenchymal stem cells (MSC). Diverse topographical variations have been engineered to investigate cellular responses; however, the types of mechanical parameters that affect cells, and their underlying mechanisms remain largely unknown. In this study, we screened nanotopological pillars with size gradient to activate transcriptional coactivator with PDZ binding motif (TAZ), which stimulates osteogenesis of MSC. We observed that a nanotopological plate, 70 nm in diameter, significantly induces osteogenic differentiation with the activation of TAZ. TAZ activation via the nanotopological plate was mediated by actin polymerization and Rho signaling, as evidenced by the cytosolic localization of TAZ under F-actin or Rho kinase inhibitor. The FAK and MAPK pathways also play a role in TAZ activation by the nanotopological plate because the inhibitor of ERK and JNK blocked nanopattern plate induced osteogenic differentiation. Taken together, these results indicate that nanotopology regulates cell differentiation through TAZ activation. PMID- 28620204 TI - Neo-actinomycins A and B, natural actinomycins bearing the 5H-oxazolo[4,5 b]phenoxazine chromophore, from the marine-derived Streptomyces sp. IMB094. AB - Neo-actinomycins A and B (1 and 2), two new natural actinomycins featuring an unprecedented tetracyclic 5H-oxazolo[4,5-b]phenoxazine chromophore, were isolated from the marine-derived actinomycete Streptomyces sp. IMB094. Their structures were elucidated by spectroscopic analyses. The presence of this ring system was proposed to originate from a condensation between actinomycin D (3) with alpha ketoglutarate and pyruvate, respectively. Compound 1 showed potent cytotoxic activities against human cancer HCT116 and A549 cell lines in the nanomolar range (IC50: 38.7 and 65.8 nM, respectively) and moderate antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococci (VRE) strains. PMID- 28620205 TI - An anti vimentin antibody promotes tube formation. AB - In recent years, there has been an increasing appreciation of the importance of secreted and extracellular proteins that traditionally have been considered as intracellular components. Vimentin is a highly abundant intermediate filament protein, and its intracellular functions have been investigated in a large number of studies. Recently, however, vimentin has been shown to take part in significant processes outside the cell. Our understanding of the functions of extracellular vimentin is, however, limited. In this study we demonstrate that a vimentin specific antibody, obtained by phage antibody technology, promotes tube formation of endothelial cells in a 2D matrigel assay. By binding vimentin, the antibody increases the tube formation by 21% after 5 hours of incubation. Addition of the antibody directly to cultured endothelial cells does not influence endothelial cell migration or proliferation. The enhanced tube formation can be seen for up to 10 hours where after the effect decreases. It is shown that the antibody-binding site is located on the coil 2 domain of vimentin. To our knowledge this is the first study that demonstrates an enhanced tube formation by binding vimentin in a 2D matrigel assay under normoxic conditions. PMID- 28620206 TI - Analysis of Muller glia specific genes and their histone modification using Hes1 promoter driven EGFP expressing mouse. AB - Retinal neurons and Muller glia are generated from a common population of multipotent retinal progenitor cells. We purposed to identify Muller glia specific molecular signatures during retinal development. Using transgenic mice carrying the Hes1 promoter (pHes1) followed by EGFP, we purified EGFP-positive Muller glia and other EGFP-negative retinal cells from developing retinas and subjected them to RNA sequencing analysis. Gene expression pattern of EGFP positive cell was similar to genes expressed in retinal progenitors, and they were downregulated in other cell lineages. Then, we examined the modification profiles of H3K27me3 and H3K4me3 by referring to chromatin immunoprecipitation sequencing data of rods and other cells. Clustering of the H3K4me3 and H3K27me3 values followed by ontology analysis revealed a high incidence of transcription factors including Hes1 in clusters with high H3K27me3 levels. Hes1 expression level decreased dramatically, and the H3K27me3 level at the Hes1-locus was upregulated strongly during retinal development. Furthermore, the Hes1 expression level was upregulated in an Ezh2-knockout retina. These results suggest that downregulation of Muller glia-related genes in other lineage rather than upregulation of them in Muller glia contributed Muller-specific molecular features, and a role for modified H3K27me3 in suppressing Muller glia-related genes in other retinal cell lineages to avoid unfavorable expression. PMID- 28620207 TI - Dengue virus activates cGAS through the release of mitochondrial DNA. AB - Cyclic GMP-AMP synthetase (cGAS) is a DNA-specific cytosolic sensor, which detects and initiates host defense responses against microbial DNA. It is thus curious that a recent study identified cGAS as playing important roles in inhibiting positive-sense single-stranded RNA (+ssRNA) viral infection, especially since RNA is not known to activate cGAS. Using a dengue virus serotype 2 (DENV-2) vaccine strain (PDK53), we show that infection creates an endogenous source of cytosolic DNA in infected cells through the release of mitochondrial DNA (mtDNA) to drive the production of cGAMP by cGAS. Innate immune responses triggered by cGAMP contribute to limiting the spread of DENV to adjacent uninfected cells through contact dependent gap junctions. Our result thus supports the notion that RNA virus indirectly activates a DNA-specific innate immune signaling pathway and highlights the breadth of the cGAS-induced antiviral response. PMID- 28620208 TI - Bacterial Diversity of Intestinal Microbiota in Patients with Substance Use Disorders Revealed by 16S rRNA Gene Deep Sequencing. AB - Substance abuse and addiction are worldwide concerns. In China, populated with over 1.3 billion people, emerging studies show a steady increase in substance abuse and substance-related problems. Some of the major challenges include a lack of an effective evaluation platform to determine the health status of substance addicted subjects. It is known that the intestinal microbiota is associated to the occurrence and development of human diseases. However, the changes of bacterial diversity of intestinal microbiota in substance-addicted subjects have not been clearly characterized. Herein, we examined the composition and diversity of intestinal microbiota in 45 patients with substance use disorders (SUDs) and in 48 healthy controls (HCs). The results show that the observed species diversity index and the abundance of Thauera, Paracoccus, and Prevotella are significantly higher in SUDs compared to HCs. The functional diversity of the putative metagenomes analysis reveals that pathways including translation, DNA replication and repair, and cell growth and death are over-represented while cellular processes and signaling, and metabolism are under-represented in SUDs. Overall, the analyses show that there seem to be changes in the microbiota that are associated with substance use across an array of SUDs, providing fundamental knowledge for future research in substance-addiction assessment tests. PMID- 28620209 TI - Using variable importance measures to identify a small set of SNPs to predict heading date in perennial ryegrass. AB - Prior knowledge on heading date enables the selection of parents of synthetic cultivars that are well matched with respect to time of heading, which is essential to ensure plants put together will cross pollinate. Heading date of individual plants can be determined via direct phenotyping, which has a time and labour cost. It can also be inferred from family means, although the spread in days to heading within families demands roguing in first generation synthetics. Another option is to predict heading date from molecular markers. In this study we used a large training population consisting of individual plants to develop equations to predict heading date from marker genotypes. Using permutation-based variable selection measures we reduced the marker set from 217,563 to 50 without impacting the predictive ability. Opportunities exist to develop a cheap assay to sequence a small number of regions in linkage disequilibrium with heading date QTL in thousands of samples. Simultaneous use of these markers in non-linkage based marker-assisted selection approaches, such as paternity testing, should enhance the utility of such an approach. PMID- 28620211 TI - Multimode quantum states with single photons carrying orbital angular momentum. AB - We propose and experimentally demonstrate a scheme for generating multimode quantum states with single photons carrying orbital angular momentum (OAM). Various quantum states have been realized by superposing multiple OAM modes of single photons in two possible paths. These quantum states exhibit NOON-like "super-resolving" interference behavior for the multiple OAM modes of single photons. Compared with the NOON states using many photons, these states are not only easily prepared, but also robust to photon losses. They may find potential applications in quantum optical communication and recognizing defects or objects. The method to identify a particular kind of defect has been demonstrated both theoretically and experimentally. PMID- 28620210 TI - A bacterial acetyltransferase triggers immunity in Arabidopsis thaliana independent of hypersensitive response. AB - Type-III secreted effectors (T3Es) play critical roles during bacterial pathogenesis in plants. Plant recognition of certain T3Es can trigger defence, often accompanied by macroscopic cell death, termed the hypersensitive response (HR). Economically important species of kiwifruit are susceptible to Pseudomonas syringae pv. actinidiae (Psa), the causal agent of kiwifruit bacterial canker. Although Psa is non-pathogenic in Arabidopsis thaliana, we observed that a T3E, HopZ5 that is unique to a global outbreak clade of Psa, triggers HR and defence in Arabidopsis accession Ct-1. Ws-2 and Col-0 accessions are unable to produce an HR in response to Pseudomonas-delivered HopZ5. While Ws-2 is susceptible to virulent bacterial strain Pseudomonas syringae pv. tomato DC3000 carrying HopZ5, Col-0 is resistant despite the lack of an HR. We show that HopZ5, like other members of the YopJ superfamily of acetyltransferases that it belongs to, autoacetylates lysine residues. Through comparisons to other family members, we identified an acetyltransferase catalytic activity and demonstrate its requirement for triggering defence in Arabidopsis and Nicotiana species. Collectively, data herein indicate that HopZ5 is a plasma membrane-localized acetyltransferase with autoacetylation activity required for avirulence. PMID- 28620212 TI - Shaping electromagnetic waves using software-automatically-designed metasurfaces. AB - We present a fully digital procedure of designing reflective coding metasurfaces to shape reflected electromagnetic waves. The design procedure is completely automatic, controlled by a personal computer. In details, the macro coding units of metasurface are automatically divided into several types (e.g. two types for 1 bit coding, four types for 2-bit coding, etc.), and each type of the macro coding units is formed by discretely random arrangement of micro coding units. By combining an optimization algorithm and commercial electromagnetic software, the digital patterns of the macro coding units are optimized to possess constant phase difference for the reflected waves. The apertures of the designed reflective metasurfaces are formed by arranging the macro coding units with certain coding sequence. To experimentally verify the performance, a coding metasurface is fabricated by automatically designing two digital 1-bit unit cells, which are arranged in array to constitute a periodic coding metasurface to generate the required four-beam radiations with specific directions. Two complicated functional metasurfaces with circularly- and elliptically-shaped radiation beams are realized by automatically designing 4-bit macro coding units, showing excellent performance of the automatic designs by software. The proposed method provides a smart tool to realize various functional devices and systems automatically. PMID- 28620213 TI - Design for Fe-high Mn alloy with an improved combination of strength and ductility. AB - Recently, Fe-Mn twinning-induced plasticity steels with an austenite phase have been the course of great interest due to their excellent combination of tensile strength and ductility, which carbon steels have never been able to attain. Nevertheless, twinning-induced plasticity steels also exhibit a trade-off between strength and ductility, a longstanding dilemma for physical metallurgists, when fabricated based on the two alloy design parameters of stacking fault energy and grain size. Therefore, we investigated the tensile properties of three Fe-Mn austenitic steels with similar stacking fault energy and grain size, but different carbon concentrations. Surprisingly, when carbon concentration increased, both strength and ductility significantly improved. This indicates that the addition of carbon resulted in a proportionality between strength and ductility, instead of a trade-off between those characteristics. This new design parameter, C concentration, should be considered as a design parameter to endow Fe-Mn twinning-induced plasticity steel with a better combination of strength and ductility. PMID- 28620214 TI - Phylogenomic Insight into Salinispora (Bacteria, Actinobacteria) Species Designations. AB - Bacteria represent the most genetically diverse kingdom of life. While great progress has been made in describing this diversity, it remains difficult to identify the phylogenetic and ecological characteristics that delineate groups of bacteria that possess species-like properties. One major challenge associated with species delineations is that not all shared genes have the same evolutionary history, and thus the choice of loci can have a major impact on phylogenetic reconstruction. Sequencing the genomes of large numbers of closely related strains provides new opportunities to distinguish ancestral from acquired alleles and assess the effects of recombination on phylogenetic inference. Here we analyzed the genomes of 119 strains of the marine actinomycete genus Salinispora, which is currently comprised of three named species that share 99% 16S rRNA gene sequence identity. While 63% of the core genome showed evidence of recombination, this had no effect on species-level phylogenomic resolution. Recombination did however blur intra-species relationships and biogeographic resolution. The genome wide average nucleotide identity provided a new perspective on Salinispora diversity, revealing as many as seven new species. Patterns of orthologous group distributions reveal a genetic basis to delineation the candidate taxa and insight into the levels of genetic cohesion associated with bacterial species. PMID- 28620215 TI - Theta band transcranial alternating current stimulations modulates network behavior of dorsal anterior cingulate cortex. AB - Dorsal anterior cingulate cortex (dACC) is an important region in the processing of both cognition and affect. Recently, transcranial brain stimulation has been used to modulate cortical activity, but it is unclear whether this stimulation has a specific effect on dACC. Based on EEG evidence that frontal midline theta activity is generated in dACC, we hypothesized that transcranial alternating current stimulation (tACS) with theta band frequency would modulate neural networks including dACC. In this study, we examined the effects of theta band tACS on functional networks and emotional state. Graph theory analysis for resting-state functional MRI data revealed that theta band tACS decreased functional integration and hub capacity in dACC, and the attenuation of dACC network function was associated with emotional state change. Overall, these results demonstrate that theta band stimulation can modulate dACC. PMID- 28620216 TI - Chinese Milk Vetch Improves Plant Growth, Development and 15N Recovery in the Rice-Based Rotation System of South China. AB - Chinese milk vetch (CMV) is vital for agriculture and environment in China. A pot experiment combined with 15N labeling (including three treatments: control, no fertilizer N and CMV; 15N-labeled urea alone, 15NU; substituting partial 15NU with CMV, 15NU-M) was conducted to evaluate the impact of CMV on plant growth, development and 15NU recovery in rice-based rotation system. The 15NU-M mitigated oxidative damage by increasing antioxidant enzymes activities and chlorophyll content while decreased malondialdehyde content in rice root and shoot, increased the biomass, total N and 15N uptake of plant shoots by 8%, 12% and 39% respectively, thus inducing a noticeable increase of annual 15N recovery by 77% versus 15NU alone. Remarkable increases in soil NH4+ and populations of bacteria, actinomycetes and azotobacter were obtained in legume-rice rotation system while an adverse result was observed in soil NO3- content versus fallow-rice. CMV as green manure significantly increased the fungal population which was decreased with cultivating CMV as cover crop. Therefore, including legume cover crop in rice-based rotation system improves plant growth and development, annual N conservation and recovery probably by altering soil nitrogen forms plus ameliorating soil microbial communities and antioxidant system which alleviates oxidative damages in plants. PMID- 28620217 TI - Secretory laccase 1 in Bemisia tabaci MED is involved in whitefly-plant interaction. AB - The whitefly Bemisia tabaci is a phloem-feeding pest that lives predominantly on herbaceous species and causes serious damage to hosts. Whitefly saliva is thought to contain proteins that modulate plant defences and facilitate feeding. A predicted secreted protein, laccase 1 (LAC1), was found in the salivary gland transcriptome of B. tabaci and might be existed in the watery saliva of B. tabaci. As LAC1 has a potential role in detoxification of secondary plant compounds in insects, we speculated that it may participate in the insect's response to plant defences. Here, we cloned the complete cDNA of LAC1 and found that (1) LAC1 was highly expressed in the salivary gland (SG) and midgut; (2) LAC1 transcript level in head (containing SG) was 2.1 times higher in plant-fed than in diet-fed whiteflies and 1.6 times higher in the head and 23.8 times higher in the midgut of whiteflies that fed on jasmonic acid (JA)-sprayed plants than on control plants; and (3) silencing LAC1 decreased the survival rate of plant-fed whiteflies but had a marginal effect on whiteflies raised on an artificial diet. These results indicate that LAC1 enables whiteflies to overcome the chemical defences of host plants and might act as an effector in saliva. PMID- 28620218 TI - Bioinspired nanocoatings for biofouling prevention by photocatalytic redox reactions. AB - Aquaculture is a billion dollar industry and biofouling of aquaculture installations has heavy economic penalties. The natural antifouling (AF) defence mechanism of some seaweed that inhibits biofouling by production of reactive oxygen species (ROS) inspired us to mimic this process by fabricating ZnO photocatalytic nanocoating. AF activity of fishing nets modified with ZnO nanocoating was compared with uncoated nets (control) and nets painted with copper-based AF paint. One month experiment in tropical waters showed that nanocoatings reduce abundances of microfouling organisms by 3-fold compared to the control and had higher antifouling performance over AF paint. Metagenomic analysis of prokaryotic and eukaryotic fouling organisms using next generation sequencing platform proved that nanocoatings compared to AF paint were not selectively enriching communities with the resistant and pathogenic species. The proposed bio-inspired nanocoating is an important contribution towards environmentally friendly AF technologies for aquaculture. PMID- 28620219 TI - Molecular dynamics exploration of poration and leaking caused by Kalata B1 in HIV infected cell membrane compared to host and HIV membranes. AB - The membrane disruption activities of kalata B1 (kB1) were investigated using molecular dynamics simulations with membrane models. The models were constructed to mimic the lipid microdomain formation in membranes of HIV particle, HIV infected cell, and host cell. The differences in the lipid ratios of these membranes caused the formation of liquid ordered (lo) domains of different sizes, which affected the binding and activity of kB1. Stronger kB1 disruptive activity was observed for the membrane with small sized lo domain. Our results show that kB1 causes membrane leaking without bilayer penetration. The membrane poration mechanism involved in the disorganization of the lo domain and in cholesterol inter-leaflet translocation is described. This study enhances our understanding of the membrane activity of kB1, which may be useful for designing novel and potentially therapeutic peptides based on the kB1 framework. PMID- 28620220 TI - Coupling killing to neutralization: combined therapy with ceftriaxone/Pep19-2.5 counteracts sepsis in rabbits. AB - Sepsis, which is induced by severe bacterial infections, is a major cause of death worldwide, and therapies combating the disease are urgently needed. Because many drugs have failed in clinical trials despite their efficacy in mouse models, the development of reliable animal models of sepsis is in great demand. Several studies have suggested that rabbits reflect sepsis-related symptoms more accurately than mice. In this study, we evaluated a rabbit model of acute sepsis caused by the intravenous inoculation of Salmonella enterica. The model reproduces numerous symptoms characteristic of human sepsis including hyperlactatemia, hyperglycemia, leukopenia, hypothermia and the hyperproduction of several pro-inflammatory cytokines. Hence, it was chosen to investigate the proposed ability of Pep19-2.5-an anti-endotoxic peptide with high affinity to lipopolysaccharide and lipoprotein-to attenuate sepsis-associated pathologies in combination with an antibiotic (ceftriaxone). We demonstrate that a combination of Pep19-2.5 and ceftriaxone administered intravenously to the rabbits (1) kills bacteria and eliminates bacteremia 30 min post challenge; (2) inhibits Toll-like receptor 4 agonists in serum 90 min post challenge; (3) reduces serum levels of pro-inflammatory cytokines (interleukin-6 and tumor necrosis factor alpha); and (4) reverts to hypothermia and gives rise to temperature values indistinguishable from basal levels 330 min post challenge. The two components of the combination displayed synergism in some of these activities, and Pep19-2.5 notably counteracted the endotoxin-inducing potential of ceftriaxone. Thus, the combination therapy of Pep19-2.5 and ceftriaxone holds promise as a candidate for human sepsis therapy. PMID- 28620221 TI - Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. AB - The administration of mesenchymal stem cells (MSCs) as a therapy for liver disease holds great promise. MSCs can differentiate into hepatocytes, reduce liver inflammation, promote hepatic regeneration and secrete protective cytokines. However, the risks of iatrogenic tumor formation, cellular rejection and infusional toxicity in MSC transplantation remain unresolved. Accumulating evidence now suggests that a novel cell-free therapy, MSC-secreted exosomes, might constitute a compelling alternative because of their advantages over the corresponding MSCs. They are smaller and less complex than their parent cells and, thus, easier to produce and store, they are devoid of viable cells, and they present no risk of tumor formation. Moreover, they are less immunogenic than their parent cells because of their lower content in membrane-bound proteins. This paper reviews the biogenesis of MSC exosomes and their physiological functions, and highlights the specific biochemical potential of MSC-derived exosomes in restoring tissue homeostasis. In addition, we summarize the recent advances in the role of exosomes in MSC therapy for various liver diseases, including liver fibrosis, acute liver injury and hepatocellular carcinoma. This paper also discusses the potential challenges and strategies in the use of exosome-based therapies for liver disease in the future. PMID- 28620222 TI - Nitric oxide mediated transcriptional modulation enhances plant adaptive responses to arsenic stress. AB - Arsenic (As) contamination in rice leads to yield decline and causes carcinogenic risk to human health. Although the role of nitric oxide (NO) in reducing As toxicity is known, NO-mediated genetic modulation in the plant during arsenic toxicity has not yet been established. We analyzed the key components of NO metabolism and the correlations between NO interaction and arsenic stress using rice as a relevant model plant. Illumina sequencing was used to investigate the NO-mediated genome-wide temporal transcriptomic modulation in rice root upon AsIII exposure during 12 days (d) of the growth period. Sodium nitroprusside (SNP) was used as NO donor. SNP supplementation resulted in marked decrease in ROS, cell death and As accumulation during AsIII stress. NO was found to modulate metal transporters particularly NIP, NRAMP, ABC and iron transporters, stress related genes such as CytP450, GSTs, GRXs, TFs, amino acid, hormone(s), signaling and secondary metabolism genes involved in As detoxification. We detected NO mediated change in jasmonic acid (JA) content during AsIII stress. The study infers that NO reduces AsIII toxicity through modulating regulatory networks involved in As detoxification and JA biosynthesis. PMID- 28620224 TI - Comparing the plant diversity between artificial forest and nature growth forest in a giant panda habitat. AB - Artificial restoration is an important way to restore forests, but little is known about its effect on the habitat restoration of the giant panda. In the present study, we investigated the characteristics of artificial forest in the Wanglang Nature Reserve to determine whether through succession it has formed a suitable habitat for the giant panda. We compared artificial forest characteristics with those of natural habitat used by the giant panda. We found that the dominant tree species in artificial forest differed from those in the natural habitat. The artificial forest had lower plant species richness and diversity in the tree and shrub layers than did the latter, and its community structure was characterized by smaller tree and bamboo sizes, and fewer and lower bamboo clumps, but more trees and larger shrub sizes. The typical community collocation of artificial forest was a "Picea asperata + no-bamboo" model, which differs starkly from the giant panda's natural habitat. After several years of restoration, the artificial forest has failed to become a suitable habitat for the giant panda. Therefore, a simple way of planting individual trees cannot restore giant panda habitat; instead, habitat restoration should be based on the habitat requirements of the giant panda. PMID- 28620223 TI - A Facile Green Synthetic Route for the Preparation of Highly Active gamma-Al2O3 from Aluminum Foil Waste. AB - A novel green preparation route to prepare nano-mesoporous gamma-Al2O3 from AlCl3.6H2O derived from aluminum foil waste and designated as ACFL550 is demonstrated, which showed higher surface area, larger pore volume, stronger acidity and higher surface area compared to gamma-Al2O3 that is produced from the commercial AlCl3 precursor, AC550. The produced crystalline AlCl3.6H2O and Al(NO3)3.9H2O in the first stage of the preparation method were characterized by single-crystal XRD, giving two crystal structures, a trigonal (R-3c) and monoclinic (P21/c) structure, respectively. EDX analysis showed that ACFL550 had half the chlorine content (Cl%) relative to AC550, which makes ACFL550 a promising catalyst in acid-catalysed reactions. Pure and modified ACFL550 and AC550 were applied in acid-catalysed reactions, the dehydration of methanol to dimethyl ether and the total methane oxidation reactions, respectively. It was found that ACFL550 showed higher catalytic activity than AC550. This work opens doors for the preparation of highly active and well-structured nano-mesoporous alumina catalysts/supports from aluminum foil waste and demonstrates its application in acid-catalysed reactions. PMID- 28620225 TI - Significance of Natural Scene Statistics in Understanding the Anisotropies of Perceptual Filling-in at the Blind Spot. AB - Psychophysical experiments reveal our horizontal preference in perceptual filling in at the blind spot. On the other hand, tolerance in filling-in exhibit vertical preference. What causes this anisotropy in our perception? Building upon the general notion that the functional properties of the early visual system are shaped by the innate specification as well as the statistics of the environment, we reasoned that the anisotropy in filling-in could be understood in terms of anisotropy in orientation distribution inherent in natural scene statistics. We examined this proposition by investigating filling-in of bar stimuli in a Hierarchical Predictive Coding model network. The model network, trained with natural images, exhibited anisotropic filling-in performance at the blind spot, which is similar to the findings of psychophysical experiments. We suggest that the over-representation of horizontal contours in the natural scene contributes to the observed horizontal superiority in filling-in and the broader distribution of vertical contours contributes to the observed vertical superiority of tolerance in filling-in. These results indicate that natural scene statistics plays a significant role in determining the filling-in performance at the blind spot and shaping the associated anisotropies. PMID- 28620226 TI - Anger provocation in violent offenders leads to emotion dysregulation. AB - Anger and anger regulation problems that result in aggressive behaviour pose a serious problem for society. In this study we investigated differences in brain responses during anger provocation or anger engagement, as well as anger regulation or distraction from anger, and compared 16 male violent offenders to 18 non-offender controls. During an fMRI adapted provocation and regulation task participants were presented with angry, happy and neutral scenarios. Prior research on violent offenders indicates that a combination of increased limbic activity (involved in emotion), along with decreased prefrontal activity (involved in emotion regulation), is associated with reactive aggression. We found increased ventrolateral prefrontal activity during anger engagement in violent offenders, while decreased dorsolateral and ventrolateral prefrontal activity was found during anger distraction. This activity pattern was specific for anger. We found no exclusive pattern for happiness. In violent offenders, this suggests an increased need to regulate specifically during anger engagement and regulation difficulties when explicitly instructed to distract. The constant effort required for violent offenders to regulate anger might exhaust the necessary cognitive resources, resulting in a risk for self-control failure. Consequently, continuous provocation might ultimately contribute to reactive aggression. PMID- 28620228 TI - A Sensory Material Approach for Reducing Variability in Additively Manufactured Metal Parts. AB - Despite the recent growth in interest for metal additive manufacturing (AM) in the biomedical and aerospace industries, variability in the performance, composition, and microstructure of AM parts remains a major impediment to its widespread adoption. The underlying physical mechanisms, which cause variability, as well as the scale and nature of variability are not well understood, and current methods are ineffective at capturing these details. Here, a Nickel Titanium alloy is used as a sensory material in order to quantitatively, and rather rapidly, observe compositional and/or microstructural variability in selective laser melting manufactured parts; thereby providing a means to evaluate the role of process parameters on the variability. We perform detailed microstructural investigations using transmission electron microscopy at various locations to reveal the origins of microstructural variability in this sensory material. This approach helped reveal how reducing the distance between adjacent laser scans below a critical value greatly reduces both the in-sample and sample to-sample variability. Microstructural investigations revealed that when the laser scan distance is wide, there is an inhomogeneity in subgrain size, precipitate distribution, and dislocation density in the microstructure, responsible for the observed variability. These results provide an important first step towards understanding the nature of variability in additively manufactured parts. PMID- 28620227 TI - Gene-physical activity interactions in lower extremity performance: inflammatory genes CRP, TNF-alpha, and LTA in community-dwelling elders. AB - We assessed gene-gene and gene-physical activity interactions of polymorphisms in C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and lymphotoxin alpha (LTA) genes on lower extremity performance in community dwelling elders in Taiwan. Five SNPs (rs1205, rs1130864, rs1800947, rs2794520, and rs3093059) of CRP gene, three SNPs (rs909253, rs1041981, and rs2239704) of LTA gene, and three SNPs (rs3093662, rs1800629, and rs1799964) of TNF-alpha gene of 472 unrelated elders were genotyped. Lower extremity performance included timed up-and-go test (TUG), walking speed, weight-adjusted leg press (waLP), and timed chair stand (TCS). We detected significant interactions between physical activity with CRP rs2794520, rs1205, and rs3093059; LTA rs909253 and rs1041981; and TNF-alpha rs1799964 for TCS in women after covariate adjustment (all P < 0.05). In men, significant interactions between physical activity with CRP rs2794520, rs1205, and rs3093059; and LTA rs909253 and rs1041981 for TUG; with CRP rs2794520, rs1205, rs1130864, and rs3093059; and LTA rs909253 and rs1041981 for walking speed; and with TNF-alpha rs3093662 for waLP after covariate adjustment (all P < 0.05). These variants also significantly interacted with physical activity on TCS in women and on walking speed in men. These results show inflammatory genes are involved in lower extremity performance, likely via gene physical activity interactions. PMID- 28620229 TI - Novel bioactive glass based injectable bone cement with improved osteoinductivity and its in vivo evaluation. AB - Recently, more and more attention has been paid to the development of a new generation of injectable bone cements that are bioactive, biodegradable and are able to have appropriate mechanical properties for treatment of vertebral compression fractures (VCFs). In this study, a novel PSC/CS composite cement with high content of PSC (a phytic acid-derived bioactive glass) was prepared and evaluated in both vitro and vivo. The PSC/CS cement showed excellent injectability, good resistance to disintegration, radiopacity and suitable mechanical properties. The in vitro test showed that the cement was bioactive, biocompatible and could maintain its shape sustainably, which made it possible to provide a long-term mechanical support for bone regeneration. Radiography, microcomputed tomography and histology of critical sized rabbit femoral condyle defects implanted with the cements proved the resorption and osteoinductivity of the cement. Compared with the PMMA and CSPC, there were more osteocyte and trabeculae at the Bone-Cement interface in the group PSC/CS cement. The volume of the residual bone cement suggested that PSC/CS had certain ability of degradation and the resorption rate was much lower than that of the CSPC cement. Together, the results indicated that the cement was a promising bone cement to treat the VCFs. PMID- 28620230 TI - Measurement of the magnetic moment of single Magnetospirillum gryphiswaldense cells by magnetic tweezers. AB - Magnetospirillum gryphiswaldense is a helix-shaped magnetotactic bacterium that synthesizes iron-oxide nanocrystals, which allow navigation along the geomagnetic field. The bacterium has already been thoroughly investigated at the molecular and cellular levels. However, the fundamental physical property enabling it to perform magnetotaxis, its magnetic moment, remains to be elucidated at the single cell level. We present a method based on magnetic tweezers; in combination with Stokesian dynamics and Boundary Integral Method calculations, this method allows the simultaneous measurement of the magnetic moments of multiple single bacteria. The method is demonstrated by quantifying the distribution of the individual magnetic moments of several hundred cells of M. gryphiswaldense. In contrast to other techniques for measuring the average magnetic moment of bacterial populations, our method accounts for the size and the helical shape of each individual cell. In addition, we determined the distribution of the saturation magnetic moments of the bacteria from electron microscopy data. Our results are in agreement with the known relative magnetization behavior of the bacteria. Our method can be combined with single cell imaging techniques and thus can address novel questions about the functions of components of the molecular magnetosome biosynthesis machinery and their correlation with the resulting magnetic moment. PMID- 28620231 TI - Facile preparation of water-soluble hyperbranched polyamine functionalized multiwalled carbon nanotubes for high-efficiency organic dye removal from aqueous solution. AB - Water-soluble hyperbranched polyamine functionalized multiwalled carbon nanotubes nanocomposite (WHPA-OMCNT) was successfully prepared and applied to water remediation in this paper. WHPA-OMCNT was characterized by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), zeta potential, scanning electron microscopy (SEM) and transmission electron microscope (TEM) analyses. WHPA-OMCNT exhibited excellent adsorption performance for removal of organic dyes e.g., methylene blue (MB), malachite green (MG) and methyl violet (MV). The equilibrium adsorption capacity was 800.0 mg g-1 for MB, 840.3 mg g-1 for MG and 970.9 mg g-1 for MV under the optimal conditions. The pseudo-second order equation and the Langmuir model exhibited good correlation with the adsorption kinetic and isotherm data for all three pollutants, respectively. The thermodynamic results (DeltaG < 0, DeltaH < 0, DeltaS < 0) implied that the adsorption process of MB, MG and MV was feasible, exothermic and spontaneous in nature. A possible adsorption mechanism has been proposed, where H-bonding, electrostatic attraction and pi-pi stacking interactions dominated the adsorption of the organic dyes. In addition, the excellent reproducibility endowed WHPA OMCNT with the potential for application in water treatment. PMID- 28620232 TI - Real-time monitoring of laser powder bed fusion process using high-speed X-ray imaging and diffraction. AB - We employ the high-speed synchrotron hard X-ray imaging and diffraction techniques to monitor the laser powder bed fusion (LPBF) process of Ti-6Al-4V in situ and in real time. We demonstrate that many scientifically and technologically significant phenomena in LPBF, including melt pool dynamics, powder ejection, rapid solidification, and phase transformation, can be probed with unprecedented spatial and temporal resolutions. In particular, the keyhole pore formation is experimentally revealed with high spatial and temporal resolutions. The solidification rate is quantitatively measured, and the slowly decrease in solidification rate during the relatively steady state could be a manifestation of the recalescence phenomenon. The high-speed diffraction enables a reasonable estimation of the cooling rate and phase transformation rate, and the diffusionless transformation from beta to alpha ' phase is evident. The data present here will facilitate the understanding of dynamics and kinetics in metal LPBF process, and the experiment platform established will undoubtedly become a new paradigm for future research and development of metal additive manufacturing. PMID- 28620233 TI - Dating early animal evolution using phylogenomic data. AB - Information about the geological timeframe during which animals radiated into their major subclades is crucial to understanding early animal ecology and evolution. Unfortunately, the pre-Cambrian fossil record is sparse and its interpretation controversial. Relaxed molecular-clock methods provide an alternative means of estimating the timing of cladogenesis deep in the metazoan tree of life. So far, thorough molecular clock studies focusing specifically on Metazoa as a whole have been based on relatively small datasets or incomplete representation of the main non-bilaterian lineages (such as sponges and ctenophores), which are fundamental for understanding early metazoan evolution. Here, we use a previously published phylogenomic dataset that includes a fair sampling of all relevant groups to estimate the timing of early animal evolution with Bayesian relaxed-clock methods. According to our results, all non-bilaterian phyla, as well as total-group Bilateria, evolved in an ancient radiation during a geologically relatively short time span, before the onset of long-term global glaciations ("Snowball Earth"; ~720-635 Ma). Importantly, this result appears robust to alterations of a number of important analytical variables, such as models of among-lineage rate variation and sets of fossil calibrations used. PMID- 28620234 TI - EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion. AB - Enhancer of zeste homolog 2 (EZH2) is often increased in malignant tumors and is involved in metastasis. EZH2 silences gene expression by tri-methylating the lysine 27 residue of histone H3 (H3K27me3). However, the mechanism underlying EZH2 promotion of ovarian cancer metastasis remains elusive. Here, we showed that EZH2 is up-regulated in ovarian cancer and is associated with tumor metastasis and poor survival by mRNA sequencing and microarray results from databases. Tissue microarray and immunohistochemistry results revealed that EZH2 was negatively correlated with the expression of tissue inhibitor of metalloproteinases 2 (TIMP2). EZH2 overexpression inhibited TIMP2 expression and promoted proteolytic activities of matrix metalloproteinases 2 and 9 and vice versa. EZH2 promoted ovarian cancer invasion and migration, which could be largely reversed by TIMP2 down-regulation in vitro and in vivo. Both H3K27me3 inhibition and demethylation could reduce methylation of the TIMP2 promoter and finally reactivate TIMP2 transcription. The presence of EZH2 and H3K27me3 at the TIMP2 promoter was confirmed by chromatin immunoprecipitation. H3K27me3 and DNA methyltransferases at the promoter were significantly increased by EZH2 overexpression. These results suggest that EZH2 inhibits TIMP2 expression via H3K27me3 and DNA methylation, which relieve the repression of MMP and facilitate ovarian cancer invasion and migration. PMID- 28620236 TI - Quadratic Characteristics of Environment Induced Voltage Shot Noise in Josephson Junctions. AB - We investigate theoretically and experimentally the environment-induced voltage shot noise in current biased Josephson junctions induced by phase particle tunneling. Quantum mechanical treatment based on the Caldeira-Leggett model with tight-binding formulation in local Wannier bases gives a clear picture of the voltage shot noise. A universal form of the zero-frequency noise spectrum is obtained, which exhibits a quadratic dependence on the mean voltage in small bias region. The quadratic dependence is verified experimentally on junctions covering a wide range of parameters, and is found also in junction arrays of various array sizes. PMID- 28620235 TI - A non-ionotropic activity of NMDA receptors contributes to glycine-induced neuroprotection in cerebral ischemia-reperfusion injury. AB - NMDA receptor (NMDAR) is known for its ionotropic function. But recent evidence suggests that NMDAR also has a non-ionotropic property. To determine the role of non-ionotropic activity of NMDARs in clinical relevant conditions, we tested the effect of glycine, a co-agonist of NMDARs, in rat middle cerebral artery occlusion (MCAO), an animal model of cerebral ischemia-reperfusion injury after the animals were injected with the NMDAR channel blocker MK-801 and the glycine receptor antagonist strychnine. We show that glycine reduces the infarct volume in the brain of ischemic stroke animals pre-injected with MK-801 and strychnine. The effect of glycine is sensitive to the antagonist of glycine-GluN1 binding site and blocked by Akt inhibition. In the neurobehavioral tests, glycine improves the functional recovery of stroke animals pre-injected with MK-801 and strychnine. This study suggests that glycine-induced neuroprotection is mediated in part by the non-ionotropic activity of NMDARs via Akt activation in cerebral ischemia-reperfusion injury. PMID- 28620237 TI - LEA29Y expression in transgenic neonatal porcine islet-like cluster promotes long lasting xenograft survival in humanized mice without immunosuppressive therapy. AB - Genetically engineered pigs are a promising source for islet cell transplantation in type 1 diabetes, but the strong human anti-pig immune response prevents its successful clinical application. Here we studied the efficacy of neonatal porcine islet-like cell clusters (NPICCs) overexpressing LEA29Y, a high-affinity variant of the T cell co-stimulation inhibitor CTLA-4Ig, to engraft and restore normoglycemia after transplantation into streptozotocin-diabetic NOD-SCID IL2rgamma-/- (NSG) mice stably reconstituted with a human immune system. Transplantation of INSLEA29Y expressing NPICCs resulted in development of normal glucose tolerance (70.4%) and long-term maintenance of normoglycemia without administration of immunosuppressive drugs. All animals transplanted with wild type NPICCs remained diabetic. Immunohistological examinations revealed a strong peri- and intragraft infiltration of wild-type NPICCs with human CD45+ immune cells consisting of predominantly CD4+ and CD8+ lymphocytes and some CD68+ macrophages and FoxP3+ regulatory T cells. Significantly less infiltrating lymphocytes and only few macrophages were observed in animals transplanted with INSLEA29Y transgenic NPICCs. This is the first study providing evidence that beta cell-specific LEA29Y expression is effective for NPICC engraftment in the presence of a humanized immune system and it has a long-lasting protective effect on inhibition of human anti-pig xenoimmunity. Our findings may have important implications for the development of a low-toxic protocol for porcine islet transplantation in patients with type 1 diabetes. PMID- 28620238 TI - A data driven approach to understanding the organization of high-level visual cortex. AB - The neural representation in scene-selective regions of human visual cortex, such as the PPA, has been linked to the semantic and categorical properties of the images. However, the extent to which patterns of neural response in these regions reflect more fundamental organizing principles is not yet clear. Existing studies generally employ stimulus conditions chosen by the experimenter, potentially obscuring the contribution of more basic stimulus dimensions. To address this issue, we used a data-driven approach to describe a large database of scenes (>100,000 images) in terms of their visual properties (orientation, spatial frequency, spatial location). K-means clustering was then used to select images from distinct regions of this feature space. Images in each cluster did not correspond to typical scene categories. Nevertheless, they elicited distinct patterns of neural response in the PPA. Moreover, the similarity of the neural response to different clusters in the PPA could be predicted by the similarity in their image properties. Interestingly, the neural response in the PPA was also predicted by perceptual responses to the scenes, but not by their semantic properties. These findings provide an image-based explanation for the emergence of higher-level representations in scene-selective regions of the human brain. PMID- 28620239 TI - Shared and Specific Intrinsic Functional Connectivity Patterns in Unmedicated Bipolar Disorder and Major Depressive Disorder. AB - Identifying brain differences and similarities between bipolar disorder (BD) and major depressive disorder (MDD) is necessary for increasing our understanding of the pathophysiology and for developing more effective treatments. However, the features of whole-brain intrinsic functional connectivity underlying BD and MDD have not been directly compared. We collected resting-state fMRI data from 48 BD patients, 48 MDD patients, and 51 healthy subjects. We constructed voxel-wise whole-brain functional networks and computed regional functional connectivity strength (FCS) using graph-theory and further divided the regional FCS into long range FCS (lFCS) and short-range FCS (sFCS). Relative to the controls, both the BD and MDD patients showed decreased sFCS in the bilateral precuneus. In addition, the BD patients showed increased and the MDD patients showed decreased lFCS and sFCS in the bilateral cerebellum. The BD patients also showed increased lFCS in the right middle temporal gyrus and increased sFCS in the bilateral thalamus compared to either the MDD patients or the controls. These findings suggest that BD and MDD may have some shared as well as a greater number of specific impairments in their functional connectivity patterns, providing new evidence for the pathophysiology of BD and MDD at the large-scale whole brain connectivity level. PMID- 28620240 TI - miR-200c-driven Mesenchymal-To-Epithelial Transition is a Therapeutic Target in Uterine Carcinosarcomas. AB - Uterine carcinosarcomas (UCSs) are highly aggressive malignancies associated with poor prognoses and limited treatment options. These tumors are hypothesized to develop from the endometrial adenocarcinoma (EAC) through epithelial-mesenchymal transition (EMT). We test this long-standing hypothesis by depleting miR-200, a family of microRNAs critical for EMT, in EAC cell lines. Our data suggest that UCSs do not develop from EACs via EMT. Clinically more relevant, we show that miR 200 expression in UCS cells induces a robust mesenchymal-epithelial transition (MET). Using in vitro and murine xenograft models, we demonstrate decreased growth and aggressiveness of miR-200-overexpressing UCS cell lines. Whole transcriptome analysis confirmed changes consistent with an MET and also revealed changes in angiogenic genes expression. Finally, by treatment of UCS-xenografted mice with miR-200c incorporated in DOPC nanoliposomes, we demonstrate anti-tumor activities. These findings suggest that ectopic miR-200 expression using advanced microRNA therapeutics may be a potential treatment approach for patients with UCS. PMID- 28620241 TI - TGF-beta/atRA-induced Tregs express a selected set of microRNAs involved in the repression of transcripts related to Th17 differentiation. AB - Regulatory T cells (Tregs) are essential regulators of immune tolerance. atRA and TGF-beta can inhibit the polarization of naive T cells into inflammatory Th17 cells, favoring the generation of stable iTregs, however the regulatory mechanisms involved are not fully understood. In this context, the roles of individual microRNAs in Tregs are largely unexplored. Naive T cells were immunomagnetically isolated from umbilical cord blood and activated with anti human CD2/CD3/CD28 beads in the presence of IL-2 alone (CD4Med) or with the addition of TGF-beta and atRA (CD4TGF/atRA). As compared to CD4Med, the CD4TGF/atRA condition allowed the generation of highly suppressive CD4+CD25hiCD127-FOXP3hi iTregs. Microarray profiling allowed the identification of a set of microRNAs that are exclusively expressed upon TGF-beta/atRA treatment and that are predicted to target a set of transcripts concordantly downregulated. This set of predicted targets were enriched for central components of IL 6/JAK/STAT and AKT-mTOR signaling, whose inhibition is known to play important roles in the generation and function of regulatory lymphocytes. Finally, we show that mimics of exclusively expressed miRs (namely miR-1299 and miR-30a-5p) can reduce the levels of its target transcripts, IL6R and IL6ST (GP130), and increase the percentage of FoxP3+ cells among CD4+CD25+/hi cells. PMID- 28620242 TI - Salivary testosterone measurement in women with and without polycystic ovary syndrome. AB - Clinical and/or biochemical hyperandrogenism is one of the diagnostic criteria for PCOS. An evaluation of the role of salivary testosterone (salT) and androstenedione (salA) for the diagnosis of PCOS was undertaken in a cross sectional study involving 65 women without PCOS and 110 women with PCOS fulfilling all 3 diagnostic Rotterdam criteria. Serum and salivary androgen measurements were determined by LC-MS/MS. salT and salA were significantly elevated in PCOS compared to controls (P < 001). No androgen marker was more predictive than another using ROC curves, but multiple logistic regression suggested salT was more predictive than free androgen index (FAI) (p < 0.01). The combination of salT or FAI identified 100% of PCOS women. PCOS women with both biochemical and clinical hyperandrogenism as opposed to clinical hyperandrogenism alone showed a metabolic phenotype (p < 0.05) and insulin resistance (p < 0.001). PCOS patients with an isolated elevated FAI showed increased insulin resistance compared to those with an isolated salT (P < 0.05). salT appeared to be at least as predictive as FAI for the diagnosis of the classical PCOS phenotype, and the combination of salT or FAI identified 100% of PCOS patients. This suggests that salT measurement by LC-MS/MS holds the promise of complementing existing laboratory tests as a means of assessing hyperandrogenemia. PMID- 28620243 TI - Targeting glioma stem cells in vivo by a G-quadruplex-stabilizing synthetic macrocyclic hexaoxazole. AB - G-quadruplex (G4) is a higher-order nucleic acid structure that is formed by guanine-rich sequences. G4 stabilization by small-molecule compounds called G4 ligands often causes cytotoxicity, although the potential medicinal impact of this effect has not been fully established. Here we demonstrate that a synthetic G4 ligand, Y2H2-6M(4)-oxazole telomestatin derivative (6OTD), limits the growth of intractable glioblastoma (grade IV glioma) and glioma stem cells (GSCs). Experiments involving a human cancer cell line panel and mouse xenografts revealed that 6OTD exhibits antitumor activity against glioblastoma. 6OTD inhibited the growth of GSCs more potently than it did the growth of differentiated non-stem glioma cells (NSGCs). 6OTD caused DNA damage, G1 cell cycle arrest, and apoptosis in GSCs but not in NSGCs. These DNA damage foci tended to colocalize with telomeres, which contain repetitive G4-forming sequences. Compared with temozolomide, a clinical DNA-alkylating agent against glioma, 6OTD required lower concentrations to exert anti-cancer effects and preferentially affected GSCs and telomeres. 6OTD suppressed the intracranial growth of GSC-derived tumors in a mouse xenograft model. These observations indicate that 6OTD targets GSCs through G4 stabilization and promotion of DNA damage responses. Therefore, G4s are promising therapeutic targets for glioblastoma. PMID- 28620244 TI - Specific ablation of mouse Fam20C in cells expressing type I collagen leads to skeletal defects and hypophosphatemia. AB - FAM20C mutations in humans cause Raine syndrome and our previous studies showed that global inactivation of mouse Fam20C led to bone and dental defects. By crossbreeding 2.3 kb Col 1a1-Cre mice with Fam20C flox/flox mice, we created 2.3 kb Col 1a1-Cre;Fam20C foxl/flox (cKO) mice, in which Fam20C was inactivated in cells expressing Type I collagen. This study showed that the long bones of cKO mice were shorter and had a lower level of mineralization compared to the normal mice. The collagen fibrils in Fam20C-deficient bone were disorganized and thicker while the growth plate cartilage in cKO mice was disorganized and wider compared to the normal mice. The Fam20C-deficient bone had a lower level of dentin matrix protein 1, and higher levels of osteopontin and bone sialoprotein than the normal. The blood of cKO mice had an elevated level of fibroblast growth factor 23 and reduced level of phosphorus. These findings indicate that inactivation of Fam20C in cells expressing type I collagen led to skeletal defects and hypophosphatemia. The altered levels of dentin matrix protein 1 and osteopontin in Fam20C-deficient bone may be significant contributors to the mineralized tissue defects in human patients and animals suffering from the functional loss of FAM20C. PMID- 28620245 TI - Catching up? The educational mobility of migrants' and natives' children in Europe. AB - Migrants into European countries are often less educated than European natives. We analyse whether migrants' children are more or less likely than natives' children to achieve upward educational mobility across generations, and study differences in the factors, which contribute to differences in mobility for the two groups. We find that migrants' descendants are more often upwardly mobile (and less often downwardly mobile) than their native peers in the majority of countries studied, and show that the main factor contributing to these patterns is the education level of parents. Although a lower parental education means that their children are less likely to access the same amount of human, social and financial capital as children of more highly educated parents, migrants' descendants over the last two generations were able to make significant progress in reducing education gaps with natives. PMID- 28620246 TI - "I'll Be There for You": Teen Parents' Coparenting Relationships. AB - Marriage promotion policy agendas have focused research attention on coparenting relationships, but little is known about coparenting among teen parents. Qualitative interviews with 76 teen mothers and fathers, supplemented with site observations at a school and clinic, investigated coparenting relationships and those relationships' embeddedness in extended families and social institutions. We identified prevalent coparenting trajectories and analyzed individual-, interaction-, and institutional-level influences on coparenting. Coparenting trajectories diverged depending on whether the couple stayed together and assumed traditionally gendered parenting roles. Participants perceived that coparenting relationships strongly shaped their current and future socioeconomic, emotional, and practical circumstances and their success at "being there" for their child. Extended families, institutions, and social programs often pushed teen parents apart, although many participants felt they needed a functional relationship with the other parent. Coparenting relationships, considered jointly with extended families and social institutions, are fundamental for understanding teen parenthood and shaping effective social policies. PMID- 28620247 TI - 3D-3D Registration of partial capitate bones using spin-images. AB - It is often necessary to register partial objects in medical imaging. Due to limited FOV, the entirety of an object cannot always be imaged. This study presents a novel application of an existing registration algorithm to this problem. The spin-image algorithm [1] creates pose-invariant representations of global shape with respect to individual mesh vertices. These 'spin-images,' are then compared for two different poses of the same object to establish correspondences and subsequently determine relative orientation of the poses. In this study, the spin-image algorithm is applied to 4DCT-derived capitate bone surfaces to assess the relative accuracy of registration with various amounts of geometry excluded. The limited longitudinal coverage under the 4DCT technique (38.4mm, [2]), results in partial views of the capitate when imaging wrist motions. This study assesses the ability of the spin-image algorithm to register partial bone surfaces by artificially restricting the capitate geometry available for registration. Under IRB approval, standard static CT and 4DCT scans were obtained on a patient. The capitate was segmented from the static CT and one phase of 4DCT in which the whole bone was available. Spin-image registration was performed between the static and 4DCT. Distal portions of the 4DCT capitate (10 70%) were then removed and registration was repeated. Registration accuracy was evaluated by angular errors and the percentage of sub-resolution fitting. It was determined that 60% of the distal capitate could be omitted without appreciable effect on registration accuracy using the spin-image algorithm (angular error < 1.5 degree, sub-resolution fitting > 98.4%). PMID- 28620248 TI - Relative gene expression of fatty acid synthesis genes at 60 days postpartum in bovine mammary epithelial cells of Surti and Jafarabadi buffaloes. AB - AIM: Aim of the study was to study the relative gene expression of genes associated with fatty acid synthesis at 60 days postpartum (pp) in bovine mammary epithelial cells (MECs) of Surti and Jafarabadi buffaloes. MATERIALS AND METHODS: A total of 10 healthy Surti and Jafarabadi buffaloes of each breed were selected at random from Livestock Research Station, Navsari and Cattle Breeding Farm, Junagadh, Gujarat, respectively, for this study. Milk sample was collected from each selected buffalo at day 60 pp from these two breeds to study relative gene expression of major milk fat genes using non-invasive approach of obtaining primary bovine MECs (pBMEC) from milk samples. RESULTS: In this study overall, the relative expression of the six major milk lipogenic genes butyrophilin subfamily 1 member A1 (BTN1A1), stearoyl-CoA desaturase (SCD), lipoprotein lipase (LPL), glycerol-3-phosphate acyltransferase mitochondrial (GPAM), acetyl-coenzyme A carboxylase alpha (ACACA), and lipin (LPIN) did not show changes in expression patterns at 60th day of lactation in both Surti and Jafarabadi buffaloes. CONCLUSION: The pBMEC can be successfully recovered from 1500 ml of milk of Surti and Jafarabadi buffaloes using antibody-mediated magnetic bead separation and can be further used for recovering RNA for down step quantification of major milk lipogenic gene expression. The relative expression of the six major milk lipogenic genes BTN1A1, SCD, LPL, GPAM, ACACA, and LPIN did not show changes in expression patterns in both Surti and Jafarabadi buffaloes, suggesting expression levels of lipogenic genes are maintained almost uniform till peak lactation without any significant difference. PMID- 28620249 TI - Comparison of Surti goat milk with cow and buffalo milk for physicochemical characteristics, selected processing-related parameters and activity of selected enzymes. AB - AIM: The study was undertaken to find out the physicochemical characteristics, selected processing-related parameters and activity of selected enzymes in Surti goat milk. MATERIALS AND METHODS: Milk samples from Surti goats and buffalo milk samples were collected during the period from July 2013 to January 2014 at Reproductive Biology Research Unit, Anand Agricultural University (AAU), Anand. Milk samples from Kankrej cows were collected from Livestock Research Station, AAU, Anand. Samples were analyzed for physicochemical characteristics such as acidity, viscosity, surface tension, specific gravity, refractive index, freezing point, and electrical conductivity. Samples were also analyzed for selected processing-related parameters such as heat coagulation time (HCT), rennet coagulation time (RCT), rate of acid production by starter culture, alcohol stability, and activity of selected enzymes such as alkaline phosphatase activity, catalase activity, proteolytic activity, and lipase activity. RESULTS: Goat milk had the highest acidity, viscosity and surface tension, followed by cow milk and buffalo milk. However, the differences in acidity, specific gravity, surface tension, refractive index, electrical conductivity, HCT and lipase activity of three types of milk studied, viz., goat, cow, and buffalo milk were found statistically non-significant (p<0.05). The buffalo milk had the highest specific gravity, followed by those found in cow and goat milk. The viscosity, freezing point and RCT of goat milk was significantly lower (p>0.05) than that of the buffalo milk. However, the difference in viscosity, freezing point and RCT of goat milk and that of the cow milk was statistically non-significant. The cow milk had the highest refractive index, followed by goat and buffalo milk. The cow milk had the highest proteolytic activity and heat coagulation time (HCT), followed by those found in buffalo and goat milk. The goat milk had the lowest freezing point, lipase activity, and RCT, followed by those found in cow and buffalo milk. The goat milk had the highest electrical conductivity, followed by those found in buffalo and cow milk. The collected goat, cow and buffalo milk samples showed negative stability at 68% (v/v) alcohol concentration. Goat milk showed positive alcohol test at 75% (v/v) alcohol concentration. Acidity was found to increase proportionally with time. After 14 h, it was found that goat milk became thicker, but the curd had a very low consistency. Cow milk had the highest alkaline phosphatase activity and catalase activity followed by those found in goat milk and lowest alkaline phosphatase activity and catalase activity was found in buffalo milk. The alkaline phosphatase activity and proteolytic activity of goat milk was significantly lower (p>0.05) than that of the cow milk. However, the difference in alkaline phosphatase activity and proteolytic activity of goat milk and that of the buffalo milk was statistically non-significant. Alkaline phosphatase activity of buffalo milk was significantly lower (p>0.05) than that of the alkaline phosphatase activity in cow milk. CONCLUSION: It can be concluded from the study that the goat milk has highest acidity, viscosity, electrical conductivity, and surface tension compared to that of cow and buffalo milk. The goat milk has lowest specific gravity, freezing point, proteolytic activity, lipase activity, RCT and HCT compared to cow and buffalo milk. Goat milk had highest refractive index compared to buffalo milk, whereas lowest refractive index compared to cow milk. Goat milk showed positive alcohol test at 75% (v/v) alcohol concentration. The curd formed from goat milk after 14 h was having very weak consistency. The goat milk has higher alkaline phosphatase activity, catalase activity compared to buffalo milk while it has lower alkaline phosphatase activity, catalase activity compared to cow milk. PMID- 28620250 TI - Influence of clinical mastitis and its treatment outcome on reproductive performance in crossbred cows: A retrospective study. AB - AIM: Evaluation of the effect of clinical mastitis (CM) and its treatment outcome on the reproductive performance in crossbred cows retrospectively. MATERIALS AND METHODS: Datasets of 835 lactating cows affected with CM during a period of 12 years (2001-2012) were considered for this study. Mastitis treatment related data and reproductive parameters such as days to first detected heat (DTFDH), days to first insemination (DTFI), days open (DO), and number of services per conception (SC) were collected from mastitis treatment and artificial insemination registers, respectively. Data were analyzed by ANOVA using SPSS 20 software. The means were compared with the Duncan's multiple comparison post-hoc test. RESULTS: CM affected cows had significantly (p<0.05) higher DTFDH, DTFI, DO and SC compared to clinically healthy cows. Cows diagnosed with a single episode of CM had significantly (p<0.05) delayed DTFDH while, DO and SC were significantly higher (p<0.05) in cows diagnosed by multiple episodes of CM. SC was significantly (p<0.05) higher in cows diagnosed with both relapse and recurrence. Severe CM affected cows had significantly (p<0.05) altered reproductive parameters. The reproductive parameters were altered to high extent when CM occurred during the breeding period. CONCLUSION: CM-affected cows had higher DTFDH, DTFI, DO and SC compared to clinically healthy cows. The negative effects of CM on reproduction parameters were higher when CM occurred during the breeding period. PMID- 28620251 TI - Physiological alteration, quality of anesthesia and economy of isoflurane in domestic chickens (Gallus domesticus). AB - AIM: Aim of the study was to evaluate the effect of isoflurane anesthesia on physiological parameters, assessment of anesthetic qualities, and economy of use of isoflurane in domestic chickens (Gallus domesticus). MATERIALS AND METHODS: In this study, 18 apparently healthy adult domestic chickens were selected randomly and divided into three groups. The birds were anesthetized by masked induction with isoflurane at a dose rate of 3.5%, 4%, and 5% and were maintained with 1.5%, 2%, and 2.5% isoflurane with oxygen by endotracheal intubation in Groups I, II, and III, respectively. Physiological parameters, viz., cloacal temperature, heart rate, and respiration rate were recorded at 0, 5, 10, 20, 30, 40, 50, and 60 min. The quality of anesthesia was assessed on the basis of induction time, induction behavior, quality of sedation, production of analgesia, degree of muscle relaxation, palpebral reflex, recovery time, and recovery behavior. The economy of anesthesia was calculated in terms of quantity of isoflurane utilized during 60 min of study. Statistical analysis was performed by analysis of variance, Duncan's multiple range tests. RESULTS: There was significant decrease (p<0.01) in physiological parameters such as in cloacal temperature, heart rate and respiration rate in the birds of all the groups from 0 to 60 min. The induction time was 5.83+/-0.33, 2.37+/-0.18, and 0.87+/-0.15 min, respectively, in Groups I, II, and III. Induction behavior was smooth in Group III, whereas mildly stormy in Group II and I. Quality of sedation was excellent in Group III, better in Group II as compared to Group I. Analgesia was moderate in Group III whereas poor in Group II and I. Degree of muscle relaxation was excellent in Group III, whereas good in Group I and II. Palpebral reflexes were absent in all the groups. Recovery time was 15.33+/-0.84, 18.83+/-0.94, and 26.50+/-0.85 in Groups I, II, and III respectively. Recovery behavior was smooth in birds of all the groups. The cost of the anesthesia was 158.22+/-1.04, 194.27+/-0.66, and 236.84+/-0.60 Indian National Rupee in Groups I, II, and III, respectively. Quantity of anesthesia utilized in each group was 7.62+/-0.05, 9.35+/-0.03, and 11.41+/-0.03 ml in Groups I, II, and III, respectively. CONCLUSION: The use of isoflurane at different concentration produces different level of physiological changes, quality of anesthesia and economy without causing any deleterious effect on the birds. The physiological parameters observed in this study can serve as reference values for the wild and endangered birds. PMID- 28620253 TI - Dactylogyrus barnae sp. n. (Platyhelminthes: Monogenoidea) infecting gills of Barilius barna Hamilton, 1822 (Pisces: Cyprinidae) from a global biodiversity hotspot - Arunachal Pradesh (India). AB - AIM: This study was a part of an ongoing parasitological survey to investigate the health status of hill stream fish in river systems of Arunachal Pradesh - A global biodiversity hotspot. MATERIALS AND METHODS: During the 2013/2015, 18 live specimens of Barilius barna (Cyprinidae) were captured from the local rivers of Arunachal Pradesh and examined for parasitic monogenoids. These fish, with their flatworms, were immediately fixed in hot (60 degrees C) 4% formalin for later examination. Identification and morphometric description used in this study followed Gussev (1976). Type specimens were deposited in the British Natural History Museum, UK. RESULTS: Dactylogyrus barnae sp. n. is described and illustrated from specimens of B. barna (Hamilton, 1822) from Arunachal Pradesh, India. The new species is characterized by a combination of the following characters: Copulatory tube coiled in 11/2 counterclockwise rings, vagina consisting of a vaginal tube and vaginal pore, a complex sclerotized plate of unknown function in between male copulatory organ and vagina, and an anteromedial knob-like process on the dorsal bar. CONCLUSION: D. barnae sp. n. is the fourth species of Dactylogyrus described from the Northeast India and brings the total number of species of Dactylogyrus in Indian waters to 56. B. barna represents a new host record for Dactylogyrus spp., and possibly the first report for any parasite. PMID- 28620252 TI - An immunological approach of sperm sexing and different methods for identification of X- and Y-chromosome bearing sperm. AB - Separation of X- and Y-chromosome bearing sperm has been practiced for selection of desired sex of offspring to increase the profit in livestock industries. At present, fluorescence-activated cell sorter is the only successful method for separation of X- and Y-chromosome bearing sperm. This technology is based on the differences in DNA content between these two types of sperm and has been commercialized for bovine sperm. However, this technology still has problems in terms of high economic cost, sperm damage, and lower pregnancy rates compared to unsorted semen. Therefore, an inexpensive, convenient, and non-invasive approach for sperm sexing would be of benefit to agricultural sector. Within this perspective, immunological sperm sexing method is one of the attractive choices to separate X- and Y-chromosome bearing sperm. This article reviews the current knowledge about immunological approaches, viz., H-Y antigen, sex-specific antigens, and differentially expressed proteins for sperm sexing. Moreover, this review also highlighted the different methods for identification of X- and Y sperm. PMID- 28620254 TI - Isolation, morphological identification and in vitro antibacterial activity of endophytic bacteria isolated from Azadirachta indica (neem) leaves. AB - AIM: The objective of this study was to isolate endophytic bacteria from Azadirachta indica (neem) leaves, their identification and investigate their antibacterial activity against three Gram-positive bacteria, Staphylococcus aureus, Streptococcus pyogenes and Bacillus cereus and Gram-negative bacteria Escherichia coli, Salmonella Typhimurium and Klebsiella pneumoniae. MATERIALS AND METHODS: Fresh leaves of A. indica (neem) was procured from the Department of Botany, JNKVV, Jabalpur. Five samples were taken, and each sample was divided into five subsamples and separated for further isolation of endophytic bacteria. For sterilization leaves were treated with double distilled water, 0.1% sodium hypochlorite, 0.01% bavistin, 0.05% and 70% ethanol. Sterilized leaves of the plants were embedded in Kings B (KB) petri plates and incubated at 37 degrees C for 24 h. Characterization of the bacteria was done according to its morphology and by Gram-staining. After that, a single colony was transferred into brain heart infusion (BHI) broth and incubated at 37 degrees C for 24 h. The antibacterial effect was studied by the disk diffusion method with known antibiotic ciprofloxacin (Ci) as standard. RESULTS: A total of 25 bacterial isolates from A. indica (neem) were obtained and identified morphologically. Most of the samples on KB media depicted irregular shape, flat elevation, undulated, rough, opaque, and white in color. Most of the samples on blood agar showed irregular, raise elevation, undulated, smooth, opaque and all the isolates were nonhemolytic and nonchromogenic. The growth of endophytic bacteria in BHI broth were all isolates showed turbidity. The microscopic examination revealed that maximum isolates were Gram-positive and rod shaped. Good antibacterial activity was observed against S. aureus, Streptococcus pyogenes, E. coli, Salmonella Typhimurium, and K. pneumoniae. CONCLUSIONS: Endophytic bacteria are present in leaves of A. indica (neem) and it possesses antibacterial activity against few Gram-positive and Gram-negative bacteria. PMID- 28620255 TI - Detection of emerging antibiotic resistance in bacteria isolated from subclinical mastitis in cattle in West Bengal. AB - AIM: The aim of this work was to detect antibiotic resistance in Gram-negative bacteria isolated from subclinical mastitis in cattle in West Bengal. MATERIALS AND METHODS: The milk samples were collected from the cattle suffering with subclinical mastitis in West Bengal. The milk samples were inoculated into the nutrient broth and incubated at 37 degrees C. On the next day, the growth was transferred into nutrient agar and MacConkey agar. All the pure cultures obtained from nutrient agar slant were subjected to Gram-staining and standard biochemical tests. All the bacterial isolates were tested in vitro for their sensitivity to different antibiotics commonly used in veterinary practices. All Gram-negative isolates including positive control were subjected to polymerase chain reaction (PCR) for detection of blaCTX-M, blaTEM, blaSHV, blaVIM, tetA, tetB, tetC, and tetM genes considered for extended-spectrum beta-lactamase (ESBL), metallo-beta lactamase, and tetracycline resistance. RESULTS: In total, 50 Gram-negative organisms (Escherichia coli, Proteus, Pseudomonas, Klebsiella, and Enterobacter) were isolated from milk samples of subclinical mastitis infected cattle. Among these Gram-negative isolates, 48% (24/50) were found either ESBL producing or tetracycline resistant. Out of total 50 Gram-negative isolates, blaCTX-M was detected in 18 (36%) isolates, and 6 (12%) harbored blaTEM genes in PCR. None of the isolates carried blaSHV genes. Further, in this study, 5 (10%) isolates harbored tet(A) gene, and 8 (16%) isolates carried tet(B) gene. No tet(C) gene was detected from the isolates. CONCLUSION: This study showed emerging trend of antibiotic-resistant Gram-negative bacteria associated with subclinical mastitis in cattle in West Bengal, India. PMID- 28620256 TI - Effects of season and artificial photoperiod on semen and seminal plasma characteristics in bucks of two goat breeds maintained in a semen collection center. AB - AIM: This study quantified the effects of season and photoperiodic treatment on semen and seminal plasma (SP) characteristics in 12 bucks of two Spanish goat breeds (Murciano-Granadina, and Payoya) for the past 1 year. MATERIALS AND METHODS: A total of 6 bucks (three of each breed) were exposed to the natural day length and the other six males (three of each breed) were exposed to alternating conditions of 2 months of long days (16 h light) and 2 months of short days (8 h light). Weekly concentrations of glutamic oxaloacetic transaminase/aspartate aminotransferase (GOT/AST), lactate dehydrogenase (LDH), potassium, testosterone, and protein in SP were measured. Reaction time and scrotal circumference were recorded, and plasma testosterone concentrations were measured before semen collection. RESULTS: Sperm volume, LDH, and potassium concentration in SP, and reaction time did not differ significantly between breeds, seasons, and photoperiodic treatment. Sperm concentrations were higher (p<0.001) in spring and summer than they were in autumn and winter. Mean percentage of positive hypo osmotic swelling test sperm was the highest in summer and under the artificial photoperiod (p<0.01). GOT/AST concentrations differed (p<0.01) between breeds and seasons. Breed, season, and photoperiod had significant (p<0.001) effects on protein and testosterone levels in SP. Plasma testosterone concentrations were highest in summer (p<0.001), and differed significantly (p<0.01) between breeds. Scrotal perimeter differed significantly (p<0.001) between breeds and photoperiod. CONCLUSION: Recognition of those seasonal and breed-specific differences in the performance of bucks should help to improve the management of individual semen samples for use in artificial insemination programs. PMID- 28620257 TI - Comparison of milk production and milk composition for an exotic and a local synthetic rabbit lines. AB - AIM: Basic objective of this research was to compare two rabbit lines: V-line (exotic line), Alexandria (local synthetic line) for yield and composition of milk product and their effect on productive performance of rabbits. MATERIALS AND METHODS: The experiment was conducted on 80 does and their kits. Milk yield (MY) of each doe and milk composition (MC) were recorded at 3rd week of lactation. RESULTS: The results of MY showed insignificant difference between V-line and Alexandria line. While the results of MC indicated significant differences in milk protein and fat between the two lines. The protein electrophoresis was used for assaying variation in milk proteins between the two lines. The banding protein patterns showed seven protein bands for Alexandria line and six bands for V line. The results demonstrated one specific protein marker at 48 KDa (kappa casein) in Alexandria doe's milk. Moreover, the results of individual body weight at weaning age indicated that Alexandria rabbits had significantly higher body weight compared with V-line rabbits (845.33 g, 664.05 g, respectively). Alexandria line had significantly lower mortality rate compared with V-line (1.5%, 2.7%, respectively). CONCLUSION: The differences which obtained in Alexandria line milk may play an important role in the productive performance of rabbits. PMID- 28620258 TI - Development of indirect enzyme-linked immunosorbent assay for diagnosis of canine leptospirosis. AB - AIM: This study was taken up to develop an indirect enzyme-linked immunosorbent assay (i-ELISA) for screening antibodies against Leptospira spp. in canines. MATERIALS AND METHODS: An i-ELISA was developed using outer membrane protein extracted from Leptospira interrogans serovar canicola used for coating the well with concentration of 0.5 ug/ul. A total of 250 serum samples from clinically affected and apparently healthy dogs were collected along with relevant epidemiological data at Teaching Veterinary Clinical Complex, Veterinary College and Research Institute, Namakkal, and subjected to i-ELISA. RESULTS: Out of 250 sera samples, 140 (56.00%) were found to be positive by i-ELISA. All the sera samples were subjected to microagglutination test (MAT) with panel of 12 different serovars. A total of 71 (28.40%) sera samples were positivity to MAT excluding the sera samples positive to L. interrogans serovars canicola and icterohaemorrhagiae in vaccinated dogs. Sensitivity and specificity of i-ELISA were higher in compared with MAT was 91.54% and 58.10%, respectively. CONCLUSION: An indirect ELISA developed for the detection of canine antileptospiral antibodies proved to be highly sensitive, rapid and easy to perform and overcome the drawbacks of MAT. PMID- 28620259 TI - Standardization of dot-enzyme-linked immmunosorbent assay for the diagnosis of bovine visceral schistosomiasis. AB - AIM: Bovine visceral schistosomiasis has been reported as an important disease entity as it affects animal health, productivity, causes economic losses due to liver condemnation, and produces a high morbidity. This study was conducted to standardize an easy, reliable dot-enzyme-linked immmunosorbent assay (ELISA) for the diagnosis of visceral schistosomiasis caused by Schistosoma spindale and to know the prevalence rate in and around Hyderabad. MATERIALS AND METHODS: A dot ELISA was standardized in the laboratory using whole worm antigen (WWA) and excretory-secretory antigen (ESA) of S. spindale. The standardized test was used for the diagnosis of bovine visceral schistosomiasis at field level. The sensitivity and specificity of the test was compared with counter current immunoelectrophoresis. In total, 288 sera (125 cattle and 163 buffalo) were screened by dot-ELISA. RESULTS: The dot-ELISA detected 32.63% of infection (94/288) using WWA and 40.62% of infection (117/288) using ESA. In cattle, the prevalence rate was 32.80% (41/125) using WWA and 40.80% (51/125) of infection. Similarly, in buffaloes, the prevalence rate was 32.51% (53/163) using WWA and 40.49% (66/163) of infection using ESA. The overall sensitivity of dot-ELISA was 76.74% and 80.48% with WWA and ESA, respectively, and specificity was 73.3% and 78.57% in WWA and ESA, respectively. CONCLUSION: As ante-mortem diagnosis of visceral schistosomiasis is difficult in subclinical conditions, dot-ELISA can be used as a reliable immunodiagnostic test for diagnosis at field level. PMID- 28620260 TI - The positive expression of genotype VII Newcastle disease virus (Malaysian isolate) in Japanese quails (Coturnix coturnix japonica). AB - AIM: Genotype VII Newcastle disease virus (NDV) is the most predominant NDV strains that circulating in Malaysia; thus, this study was aimed to determine the susceptibility of Japanese quails toward genotype VII NDV. Clinical signs, gross pathological lesions of organs, positive detection of virus in organs and cloacal swabs, as well as the expression of the antibody titer, were used as parameters to assess the susceptibility of Japanese quails following infection of genotype VII NDV. MATERIALS AND METHODS: About 20 quails were divided into three groups (n=8 for Groups A and B; n=4 for the control group). The quails in the Groups A and B were infected via intraocular route with 0.03 ml of 103.5 ELD50 and 107.0 ELD50 of NDV strain IBS 002, respectively, while the control group received 1* phosphate-buffered saline. Cloacal swabs and necropsy were taken on day 7 post infection for all quails were subjected to one-step reverse transcription real time quantitative polymerase chain reaction (RT-qPCR) for detection of virus and examination for gross pathological lesion, respectively. Blood serums of infected quails were taken on day 10, 14, and 21 post-day infections and were subjected for hemagglutination inhibition (HI) assay. RESULTS: Depression and ruffled feathers, trachea rales, leg paralysis, and torticollis were shown in some of the quails in both infected groups. Based on statistical analysis, there was no significant difference (p>0.05) in clinical signs between the infected groups. The results for RT-qPCR were found to be negative for all groups, and no gross pathological lesions of organs observed for quails in both infected groups. Trachea, proventriculus, and cecal tonsil were taken for the detection of NDV by RT-qPCR, and some of the organ samples showed positive detection of virus in both infected groups. HI assay showed an increase in mean titers of antibody across time and between infected groups. CONCLUSION: In summary, Japanese quails are susceptible to genotype VII NDV based on parameters assessed. PMID- 28620261 TI - Single-nucleotide polymorphism-based genetic diversity analysis of the Kilakarsal and Vembur sheep breeds. AB - AIM: The present study was thus undertaken to analyze the genetic diversity of Kilakarsal and Vembur sheep breeds using single-nucleotide polymorphism (SNP) markers within Toll-like receptor (TLR) 3, 5, 6, 9, and 10 genes. MATERIALS AND METHODS: Competitive allele-specific polymerase chain reaction (PCR)-based end point genotyping was performed using real-time PCR to type the SNPs. Allele discrimination module implemented in real-time PCR was utilized to call the genotypes based on fluorescence intensity recorded for each of the two alleles. Basic diversity indices, namely, gene frequencies, observed heterozygosity, expected heterozygosity, and inbreeding coefficient (FIS), and testing for Hardy Weinberg equilibrium (HWE) were estimated using package for elementary analysis of SNP data software program. RESULTS: Of the 25 SNPs, 22 were found to be polymorphic, whereas two SNPs, namely, TLR3_1081_AC and TLR9_2036_CT, were monomorphic in both Kilakarsal and Vembur sheep populations. The SNP TLR10_1180_AG was monomorphic in Kilakarsal but polymorphic in Vembur sheep. The observed heterozygosities were estimated as 0.289 and 0.309 in Kilakarsal and Vembur sheep, respectively, whereas the expected heterozygosity values were 0.305 and 0.309 in the two breeds, respectively. The overall mean FIS was 0.107 ranging from -0.005 to 0.241 in Kilakarsal sheep and -0.047 ranging from -0.005 to 0.255 in Vembur sheep. In Kilakarsal sheep, the test for HWE revealed TLR9_1308_GC SNP locus with significant deviation (p<0.05) due to heterozygosity deficit. In Vembur sheep, TLR10_82_CT and TLR10_292_CG loci showed significant deviation (p<0.05) due to heterozygosity excess. Other SNP loci did not deviate from HWE (p>0.05) revealing that the population was in HWE proportions. CONCLUSIONS: The SNP markers within five TLR genes (TLR3, TLR5, TLR6, TLR9, and TLR10) utilized for genotyping in this study were highly polymorphic in Kilakarsal and Vembur breeds of sheep. This study on the genetic diversity analysis of the Kilakarsal and Vembur sheep breeds revealed considerable genetic variation within the breeds and it can be utilized to improve desirable traits. PMID- 28620262 TI - Prevalence of multiple drug resistant Streptococcus suis in and around Guwahati, India. AB - AIM: This study was conducted to determine the prevalence and antimicrobial susceptibility of Streptococcus suis and their resistance patterns isolated from both clinically healthy carriers and diseased pigs in and around Guwahati, Assam, India. MATERIALS AND METHODS: A total of 497 samples were collected during October, 2012, to April, 2014, from clinically healthy (n=67) and diseased (n=230) pigs of varying age and either sex maintained under organized and unorganized farming systems. Samples were processed for isolation and identification of S. suis by biochemical characterization and polymerase chain reaction targeting the housekeeping gene glutamate dehydrogenase. In vitro antimicrobial susceptibility of the recovered isolates against nine antibiotic groups comprising 17 antimicrobial agents was studied by standard method. RESULTS: Of the 497 samples examined, 7 (1.41%) isolates were confirmed to be S. suis of which 5 (1.87%) and 2 (0.87%) were derived from clinically healthy and diseased pigs, respectively. All the isolates were susceptible to gentamicin, amikacin, and erythromycin (100%) followed by the penicillin group and enrofloxacin (85.71%), ceftriaxone, doxycycline HCL, ofloxacin and chloramphenicol (71.43%), to kanamycin, clindamycin and co-trimoxazole (42.85%). The isolates showed least susceptibility to cefalexin, tetracycline and streptomycin (28.57%). All the five S. suis isolates from clinically healthy pigs were susceptible to penicillin G, amoxyclav, doxycycline HCl, gentamicin, amikacin and erythromycin, 80.00% isolates susceptible to ampicillin, enrofloxacin and ofloxacin, 60.00% to ceftriaxone, kanamycin and chloramphenicol, 40% to cefalexin, tetracycline, clindamycin and co-trimoxazole, respectively. Only 20.00% isolates were susceptible to streptomycin. Both the isolates recovered from diseased pigs were susceptible to ampicillin, ceftriaxone, gentamicin, amikacin, enrofloxacin, erythromycin, and clindamycin. On the other hand, both the isolates were resistant to cefalexin, tetracycline, doxycycline HCL, and kanamycin. Altogether five different resistance patterns (multi-drug resistance) were observed. Of the seven S. suis isolates, two isolates were susceptible to all the 17 antimicrobial agents, one isolate was resistant to four antimicrobial agents, two isolates to seven agents, one isolate to nine agents, and one isolate exhibited resistance to 14 antimicrobial agents. CONCLUSION: This study was conducted to determine the prevalence of S. suis in clinically healthy and diseased pigs and their antimicrobial susceptibility patterns. All the isolates were susceptible to gentamicin, amikacin and erythromycin, and most of them were resistant to cefalexin, tetracycline and streptomycin. Five different patterns of antimicrobial resistance (multi-drug resistance) were observed. PMID- 28620263 TI - Immunopathological response of leukocytes against microfilariae and adult worms in white rats infected with Setaria cervi. AB - AIM: Aim of this study was to see the immunopathological changes against the microfilariae (Mf) and adult worms of a bovine filarid, Setaria cervi in the tissues of vital organs of experimentally infected white rats. The effect of diethylcarbamazine (DEC) was also observed on the Mf, as leukocytes especially lymphocytes produce immunoglobulins which opsonize and increase the efficacy of DEC against circulating Mf. Effect of this drug was also assessed on liver enzymes in the microfilaremic rats. MATERIALS AND METHODS: Microfilaremia was established by implanting adult worms intraperitoneally and by the infusion of Mf recovered from the uterus of gravid female worms. DEC was administered orally for six consecutive days in the rats having patent infection. Differential leukocyte count was recorded every 3rd day, and liver enzymes were estimated every 10th day in both treated and untreated rats. Pathological changes were observed in HE stained sections of vital organs where Mf or adult worms were trapped. RESULTS: Destruction and reduction in microfilarial density were noticed in microfilaremic rats treated with DEC. Trapped Mf and embedded worms revealed heavy cellular infiltrations by defensive cells which surrounded and attached with the body surface of the Mf as well as adult worms for their destruction and piece meal clearance. Immune-mediated pathology was observed in the tissue sections of lungs, spleen, and liver. Liver enzymes were elevated during the period of higher parasitemia. CONCLUSIONS: There was a moderate level of immunopathology against the Mf and adult worms by the leukocytes in experimentally infected microfilaremic rats. Mf were in the process of degeneration where they got trapped. Moderate increase in liver enzyme was noticed which was slightly more in untreated group. Although a fraction of Mf gets killed in the peritoneum, majority of them successfully enter the systemic circulation and survive for about 54 days, which is sufficient enough for conducting immunological and chemotherapeutic studies. PMID- 28620264 TI - Silencing of AQP3 induces apoptosis of gastric cancer cells via downregulation of glycerol intake and downstream inhibition of lipogenesis and autophagy. AB - Gastric cancer (GC) has a poor prognosis and is a leading cause of cancer-related death. Optimal therapeutic targets have not been identified. AQP3 is capable of transporting glycerol across the cytomembrane. Previous studies have shown that AQP3 is involved in proliferation, invasion and migration by regulating glycerol and lipid metabolism in diverse cancer cell types. However, the potential roles of glycerol and lipid metabolism in AQP3-related cell apoptosis in GC remain unclear. In this study, we observed that AQP3 expression was upregulated in tumor tissues, and positively correlated with tumor size, lymph node metastasis and glycerol concentration in human GC samples. Silencing of AQP3 resulted in decreased glycerol intake and impaired lipid synthesis, which contributed to increased cell apoptosis. Furthermore, inhibition of autophagy induced by AQP3 knockdown promoted cell apoptosis. Administration of either glycerol or rapamycin restored cell viability, and overexpression of AQP3 increased cell viability by upregulating cellular glycerol metabolism and autophagy. Our study demonstrates that the increase in cell apoptosis of AQP3-deficient GC cells is a consequence of reduced glycerol uptake and lipogenesis and is associated with autophagy inhibition induced by AQP3 deficiency. PMID- 28620265 TI - Panel of seven long noncoding RNA as a candidate prognostic biomarker for ovarian cancer. AB - Ovarian cancer is one of the most common and lethal gynecological malignancies. The diagnosis of ovarian cancer is often at an advanced stage. Accumulated evidence suggests that long noncoding RNAs (lncRNAs) play important roles during ovarian tumorigenesis. In this study, using the lncRNA-mining approach, we analyzed lncRNA expression profiles of 493 ovarian cancer patients from Gene Expression Omnibus datasets, and identified a signature group of seven lncRNAs (BC037530, AK021924, AK094536, AK094536, BC062365, BC004123 and BC007937) associated with patient survival in the training dataset GSE9891. We also formulated a risk score model to divide patients into low-risk and high-risk groups based on the expression of these seven lncRNAs. We further validated the predictive power of our risk score model in two other datasets, GSE26193 and GSE63885. Our analysis showed that the seven-lncRNA signature can serve as an independent predictor apart from Federation of Gynecology and Obstetrics (FIGO) stage and patient age. Further investigation revealed the seven-lncRNA signature correlated with few critical signaling pathways involved in cancer. Combined, all these findings strongly support that the seven-lncRNA signature can serve as a strong prognosis biomarker. PMID- 28620266 TI - Mechanistic Evaluation of the Impact of Smoking and Chronic Obstructive Pulmonary Disease on the Nasal Epithelium. AB - Chronic obstructive pulmonary disease (COPD) is one of the major causes of chronic morbidity and mortality worldwide. The development of markers of COPD onset is hampered by the lack of accessibility to the primary target tissue, and there is a need to consider other sample sources as surrogates for biomarker research. Airborne toxicants pass through the nasal epithelium before reaching the lower airways, and the similarity with bronchial histology makes it an attractive surrogate for lower airways. In this work, we describe the transcriptomics findings from the nasal epithelia of subjects enrolled in a clinical study focusing on the identification of COPD biomarkers. Transcriptomic data were analyzed using the biological network approach that enabled us to pinpoint the biological processes affected in the upper respiratory tract in response to smoking and mild-to-moderate COPD. Our results indicated that nasal and lower airway immune responses were considerably different in COPD subjects and caution should be exercised when using upper airway samples as a surrogate for the lower airway. Nevertheless, the network approach described here could present a sensitive means of identifying smokers at risk of developing COPD. PMID- 28620269 TI - Cold Steel, Weak Flesh: Mechanism, Masculinity and the Anxieties of Late Victorian Empire. AB - This article considers the reception and representation of advanced military technology in late nineteenth- and early twentieth-century Britain. It argues that technologies such as the breech-loading rifle and the machine gun existed in an ambiguous relationship with contemporary ideas about martial masculinities and in many cases served to fuel anxieties about the physical prowess of the British soldier. In turn, these anxieties encouraged a preoccupation in both military and popular domains with that most visceral of weapons, the bayonet, an obsession which was to have profound consequences for British military thinking at the dawn of the First World War. PMID- 28620267 TI - Differences in Multidisciplinary and Interdisciplinary Treatment Programs for Fibromyalgia: A Mapping Review. AB - Fibromyalgia is a multifaceted chronic pain syndrome and the integration of different health disciplines is strongly recommended for its care. The interventions based on this principle are very heterogeneous and the difference across their structures has not been extensively studied, leading to incorrect conclusions when their outcomes are pooled. The objective of this mapping review was to summarize the characteristics of these programs, with particular focus on the integration of their components. We performed a search of the literature about treatments for fibromyalgia involving multiple disciplines on PubMed and Scopus. Starting from 560 articles, we included 22 noncontrolled studies, 10 controlled studies, and 17 RCTs evaluating the effects of 38 multidisciplinary or interdisciplinary interventions. The average quality of the studies was low. Their outcomes were usually pain intensity, quality of life, and psychological variables. We created a map of the programs based on the degree of integration of the included disciplines, which ranged from a juxtaposition of few components to a complex harmonization of different perspectives obtained through teamwork strategies. The rehabilitation programs were then thoroughly described with regard to the duration, setting, therapeutic components, and professionals included. The implications for future quantitative reviews are discussed. PMID- 28620270 TI - Flucytosine and Amphotericin B Coadministration Induces Dose-Related Renal Injury. AB - Invasive fungal infections remain an important clinical problem, and despite recent approaches, they bring high morbidity and mortality. Combination therapies are the most effective; however, adverse effects need to be considered. In this study, we aimed to evaluate the nephrotoxicity induced by combined therapy of flucytosine (FL) and amphotericin B (AMF) at 3 different doses administered to mice for 14 days: 300 MUg/kg AMF+50 mg/kg FL; 600 MUg/kg AMF+100 mg/kg FL; 900 MUg/kg AMF+150 mg/kg FL. Antifungal coadministration triggered nuclear translocation of NF-kappaB and upregulated nuclear factor kappa-light-chain enhancer of activated B cells subunit p65 (NF-kappaB p65) messenger RNA mRNA level in dose-dependent manner. The immunopositivity of tumor necrosis factor alpha and interleukin-6 (IL-6), together with IL-6 gene expression, increased both in tubular and glomerular cells. Amphotericin B-flucytosine cotreatment increased significantly the number of terminal deoxy-nucleotidyl transferase (TdT)-mediated dUTP nick end-labeling positive nuclei. Apoptotic cells in renal tubuli were confirmed by electron microscopy. Histopathological analysis revealed collagen accumulation at the glomerular level. Collagen was also evidenced in the glomeruli at the dose of 900 MUg/kg AMF+150mg/kg FL by Masson-Goldner trichrome staining and electron microscopy. Moreover, antifungal cotherapy induced upregulation of transforming growth factor beta 1 (TGF-beta1) gene expression in a dose-dependent manner. Inflammation and epithelial tubular apoptosis are associated with TGF-beta1 activation and initiation of the early stage of glomerular fibrosis at higher doses, leading to tubule-interstitial fibrosis. PMID- 28620268 TI - Towards the genetic control of invasive species. AB - Invasive species remain one of the greatest threats to global biodiversity. Their control would be enhanced through the development of more effective and sustainable pest management strategies. Recently, a novel form of genetic pest management (GPM) has been developed in which the mating behaviour of insect pests is exploited to introduce genetically engineered DNA sequences into wild conspecific populations. These 'transgenes' work in one or more ways to reduce the damage caused by a particular pest, for example reducing its density, or its ability to vector disease. Although currently being developed for use against economically important insect pests, these technologies would be highly appropriate for application against invasive species that threaten biodiversity. Importantly, these technologies have begun to advance in scope beyond insects to vertebrates, which include some of the world's worst invasives. Here we review the current state of this rapidly progressing field and, using an established set of eradication criteria, discuss the characteristics which make GPM technologies suitable for application against invasive pests. PMID- 28620271 TI - Glutamine Ameliorates Mucosal Damage Caused by Immune Responses to Duck Plague Virus. AB - The immune-releasing effects of L-glutamine (Gln) supplementation in duck plague virus (DPV)-infected ducklings were evaluated in 120 seven-day-old ducklings that were divided into 8 groups. The ducklings in control and DPV, 0.5Gln and DPV + 0.5Gln, 1.0Gln and DPV + 1.0Gln, and 2.0Gln and DPV + 2.0Gln received 0, 0.5, 1.0, and 2.0 g of Gln/kg feed/d by gastric perfusion, respectively. Then, the ducklings in control to 2.0Gln were injected with 0.2 mL of phosphate-buffered saline, while those in DPV to DPV + 2.0Gln were injected with DPV at 0.2 mL of 2000 TCID50 (50% tissue culture infection dose) 30 minutes after gavage with Gln, sampled at 12 hours and days 1, 2, 4, and 6. Glutamine supplementation under physiological conditions enhanced immune function and toll-like receptor 4 (TLR4) expressions in a dose-dependent manner. An increase in Gln supplementation under DPV-infected conditions enhanced growth performance, decreased immunoglobulin (Ig) release in plasma and secretory IgA in the duodenum, ameliorated plasma cytokine levels, and suppressed overexpressions of the TLR4 pathway in the duodenum. The positive effects of Gln on the humoral immunity- and intestinal inflammation-related damage should be considered a mechanism by which immunonutrition can assist in the recovery from DPV infection. PMID- 28620272 TI - Short-term effects of a brief intervention to reduce alcohol use and sexual risk among homeless young adults: Results from a randomized controlled trial. AB - BACKGROUND: Homeless young adults are more likely than their never-homeless counterparts to abuse alcohol and engage in risky sexual behaviors, yet no interventions to simultaneously reduce both these behaviors among this vulnerable population have been systematically designed and evaluated. We therefore developed a brief intervention (BI) to reduce both alcohol use and sexual risk behaviors among homeless young adults. The results of a randomized trial testing the BI against an education comparison (EC) are presented. METHOD: Young adults (N=61; age 17-22 years) from an urban, Northeastern crisis shelter were randomly assigned to either the 2-session, individual-level BI or a time-matched, 2 session, individual-level EC. Generalized linear mixed models for repeated measures determined effects of treatment condition on outcomes. RESULTS: The BI significantly increased participant readiness to change alcohol use. However, it did not significantly decrease primary alcohol or HIV sexual risk outcomes, independently or relative to EC (all ps>.05). Participants in the EC reduced times engaged in unprotected sex between baseline and post-intervention to a significantly greater extent (p<.01) than those in the BI condition. Participants in both conditions reported satisfaction with respective interventions. CONCLUSIONS: Findings suggest that the BI was acceptable and successful in getting participants to consider changing their drinking. However, lack of change in alcohol and sexual behavior outcomes indicates the need for further research to determine how to translate readiness to change into actual behavioral change among homeless young adults. PMID- 28620273 TI - State-Dependent Decoding Algorithms Improve the Performance of a Bidirectional BMI in Anesthetized Rats. AB - Brain-machine interfaces (BMIs) promise to improve the quality of life of patients suffering from sensory and motor disabilities by creating a direct communication channel between the brain and the external world. Yet, their performance is currently limited by the relatively small amount of information that can be decoded from neural activity recorded form the brain. We have recently proposed that such decoding performance may be improved when using state dependent decoding algorithms that predict and discount the large component of the trial-to-trial variability of neural activity which is due to the dependence of neural responses on the network's current internal state. Here we tested this idea by using a bidirectional BMI to investigate the gain in performance arising from using a state-dependent decoding algorithm. This BMI, implemented in anesthetized rats, controlled the movement of a dynamical system using neural activity decoded from motor cortex and fed back to the brain the dynamical system's position by electrically microstimulating somatosensory cortex. We found that using state-dependent algorithms that tracked the dynamics of ongoing activity led to an increase in the amount of information extracted form neural activity by 22%, with a consequently increase in all of the indices measuring the BMI's performance in controlling the dynamical system. This suggests that state dependent decoding algorithms may be used to enhance BMIs at moderate computational cost. PMID- 28620274 TI - Influence of Estrogen Modulation on Glia Activation in a Murine Model of Parkinson's Disease. AB - Epidemiological data suggest a sexual dimorphism in Parkinson disease (PD), with women showing lower risk of developing PD. Vulnerability of the nigrostriatal pathway may be influenced by exposure to estrogenic stimulation throughout fertile life. To further address this issue, we analyzed the progression of nigrostriatal damage, microglia and astrocyte activation and microglia polarization triggered by intrastriatal injection of dopaminergic neurotoxin 6 hydroxydopamine (6-OHDA) in male, female and ovariectomized (OVX) mice, as well as in OVX mice supplemented with 17betaestradiol (OVX+E). Animals were sacrificed at different time points following 6-OHDA injection and brain sections containing striatum and substantia nigra pars compacta (SNc) underwent immunohistochemistry for tyrosine hydroxylase (TH) (dopaminergic marker), immunofluorescence for IBA1 and GFAP (markers of microglia and astrocyte activation, respectively) and triple immunoflorescent to identify polarization of microglia toward the cytotoxic M1 (DAPI/IBA1/TNFalpha) or cytoprotective M2 (DAPI/IBA1/CD206) phenotype. SNc damage induced by 6-OHDA was significantly higher in OVX mice, as compared to all other experimental groups, at 7 and 14 days after surgery. Astrocyte activation was higher in OVX mice with respect the other experimental groups, at all time points. Microglial activation in the SNc was detected at earlier time points in male, female and OVX+E, while in OVX mice was detected at all time-points. Microglia polarization toward the M2, but not the M1, phenotype was detected in female and OVX+E mice, while the M1 phenotype was observed only in male and OVX mice. Our results support the protective effects of estrogens against nigrostriatal degeneration, suggesting that such effects may be mediated by an interaction with microglia, which tend to polarize preferentially toward an M2, cytoprotective phenotype in the presence of intense estrogenic stimulation. PMID- 28620275 TI - Genome-Wide Target Analyses of Otx2 Homeoprotein in Postnatal Cortex. AB - Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin-positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondrial function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as KV3.1 had juvenile cortex specific binding sites, suggesting that Otx2 is involved in regulating fast spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 (Oxr1), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2-deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease. PMID- 28620276 TI - An Analysis of a Novel, Short-Term Therapeutic Psychoeducational Program for Children and Adolescents with Chronic Neurological Illness and Their Parents; Feasibility and Efficacy. AB - The purpose of this intervention was to develop a therapeutic psycho-educational program that improves quality of life in children and adolescents who are experiencing chronic neurological illness, including epilepsy, and their parents, and to analyze the intervention's feasibility and efficacy and participants' satisfaction. Participants were eight children (n = 8) and adolescents and their parents; participating children were experiencing chronic neurological illness with psychological comorbidity; children with intellectual impairment were excluded (IQ < 80). The program was carried out weekly for four sessions. In each of the 4 weeks, children's session content addressed self, emotion, coping skills, and finishing up, respectively; and parents' session content targeted family dynamic and emotional intervention, coping skills, childcare and education, and finishing up, respectively. Clinical psychologists administered psychological assessments (viz., Child Behavior Checklist, Pediatric Quality of Life Inventory, Parenting Stress Index, Beck Depression Inventory, Children's Depression Inventory, and Revised Children's Manifest Anxiety Scale) at pre- and post-intervention, and administered satisfaction surveys following the intervention. Participants' opinions about the program's necessity, contents, and process, and participants' overall program satisfaction were analyzed. Parents and children reported high levels of satisfaction with the program. Externalizing behavioral problems, anxiety/depression, and emotional functioning from quality of life showed improvement after the intervention. Although not statistically significant, total child stress trended downward from pre- to post-intervention. A four-session structured therapeutic psycho-educational program for children and adolescents with chronic neurological illness and their parents was successfully implemented, showing good compliance and high satisfaction and efficacy. PMID- 28620277 TI - Accumulating Evidence for Axonal Translation in Neuronal Homeostasis. AB - The specialized structure of the neuron requires that homeostasis is sustained over the meter or more that may separate a cell body from its axonal terminus. Given this impressive distance and an axonal volume that is many times that of the cell body, how is such a compartment grown during development, re-grown after injury, and maintained throughout adulthood? While early answers to these questions focused on the local environment or the cell soma as supplying the needs of the axon, it is now well-established that the axon has some unique needs that can only be met from within. Decades of research have revealed local translation as an indispensable mechanism of axonal homeostasis during development and regeneration in both invertebrates and vertebrates. In contrast, the extent to which the adult, mammalian axonal proteome is maintained through local translation remains unclear and controversial. This mini-review aims to highlight important experiments that have helped to shape the field of axonal translation, to discuss conceptual arguments and recent evidence that supports local translation as important to the maintenance of adult axons, and to suggest experimental approaches that have the potential to further illuminate the role of axonal translation in neuronal homeostasis. PMID- 28620278 TI - Revealing the Dysfunction of Schematic Facial-Expression Processing in Schizophrenia: A Comparative Study of Different References. AB - The use of event-related potential (ERP) recording technology during perceptual and cognitive processing has been studied in order to develop objective diagnostic indexes for people with neuropsychiatric disorders. For example, patients with schizophrenia exhibit consistent abnormalities in face-evoked early components of ERPs and mismatch negativities (MMNs). In most studies, the choice of reference has been the average reference (AVE), but whether this is the most suitable choice is still unknown. The aim of this study was to systematically compare the AVE and reference electrode standardization technique (REST) methods for assessing expressional face-evoked early visual ERPs and visual MMNs (vMMNs) in patients with schizophrenia and healthy controls. The results showed that both the AVE and REST methods could: (1) obtain primary visual-evoked ERPs in the two groups, (2) reveal the neutral and emotional expression discrimination deficit of the P1 component in the patients, which was normal in the healthy controls, (3) reflect reductions of happy vMMNs in the patients compared to the healthy controls, and (4) show right-dominant sad vMMNs only in the patients. On the other hand, compared to the energy distributions of the AVE-obtained potentials, those of REST-obtained early visual ERPs and vMMNs were more concentrated around the temporo-occipital areas. Furthermore, only the REST-obtained vMMNs revealed a significant difference between happy and sad mismatch stimuli in patients with schizophrenia. These results demonstrate that REST technology might provide new insights into neurophysiological factors associated with neuropsychiatric disorders. PMID- 28620279 TI - Interleukin-6 Deficiency Attenuates Retinal Ganglion Cell Axonopathy and Glaucoma Related Vision Loss. AB - The pleotropic cytokine interleukin-6 (IL-6) is implicated in retinal ganglion cell (RGC) survival and degeneration, including that associated with glaucoma. IL 6 protects RGCs from pressure-induced apoptosis in vitro. However, it is unknown how IL-6 impacts glaucomatous degeneration in vivo. To study how IL-6 influences glaucomatous RGC axonopathy, accompanying glial reactivity, and resultant deficits in visual function, we performed neural tracing, histological, and neurobehavioral assessments in wildtype (B6;129SF2/J; WT) and IL-6 knock-out mice (B6;129S2-IL6tm1kopf/J; IL-6-/-) after 8 weeks of unilateral or bilateral microbead-induced glaucoma (microbead occlusion model). IOP increased by 20% following microbead injection in both genotypes (p < 0.05). However, deficits in wound healing at the site of corneal injection were noted. In WT mice, elevated IOP produced degenerating axon profiles and decreased axon density in the optic nerve by 15% (p < 0.01). In IL-6-/- mice, axon density in the optic nerve did not differ between microbead- and saline-injected mice (p > 0.05) and degenerating axon profiles were minimal. Preservation of RGC axons was reflected in visual function, where visual acuity decreased significantly in a time-dependent manner with microbead-induced IOP elevation in WT (p < 0.001), but not IL-6-/- mice (p > 0.05). Despite this preservation of RGC axons and visual acuity, both microbead injected WT and IL-6-/- mice exhibited a 50% decrease in anterograde CTB transport to the superior colliculus, as compared to saline-injected controls (p < 0.01). Assessment of glial reactivity revealed no genotype- or IOP-dependent changes in retinal astrocytes. IOP elevation decreased microglia density and percent retinal area covered in WT mice (p < 0.05), while IL-6-/- mice exhibited only a decrease in density (p < 0.05). Together, our findings indicate that two defining features of RGC axonopathy-axon transport deficits and structural degeneration of axons-likely occur via independent mechanisms. Our data suggest that IL-6 is part of a mechanism that specifically leads to structural degeneration of axons. Furthermore, its absence is sufficient to prevent both structural degeneration of the optic nerve and vision loss. Overall, our work supports the proposition that functional deficits in axon transport represent a therapeutic window for RGC axonopathy and identify IL-6 signaling as a strong target for such a therapeutic. PMID- 28620281 TI - Inhibition of the Mitochondrial Glutamate Carrier SLC25A22 in Astrocytes Leads to Intracellular Glutamate Accumulation. AB - The solute carrier family 25 (SLC25) drives the import of a large diversity of metabolites into mitochondria, a key cellular structure involved in many metabolic functions. Mutations of the mitochondrial glutamate carrier SLC25A22 (also named GC1) have been identified in early epileptic encephalopathy (EEE) and migrating partial seizures in infancy (MPSI) but the pathophysiological mechanism of GC1 deficiency is still unknown, hampered by the absence of an in vivo model. This carrier is mainly expressed in astrocytes and is the principal gate for glutamate entry into mitochondria. A sufficient supply of energy is essential for the proper function of the brain and mitochondria have a pivotal role in maintaining energy homeostasis. In this work, we wanted to study the consequences of GC1 absence in an in vitro model in order to understand if glutamate catabolism and/or mitochondrial function could be affected. First, short hairpin RNA (shRNA) designed to specifically silence GC1 were validated in rat C6 glioma cells. Silencing GC1 in C6 resulted in a reduction of the GC1 mRNA combined with a decrease of the mitochondrial glutamate carrier activity. Then, primary astrocyte cultures were prepared and transfected with shRNA-GC1 or mismatch-RNA (mmRNA) constructs using the Neon(r) Transfection System in order to target a high number of primary astrocytes, more than 64%. Silencing GC1 in primary astrocytes resulted in a reduced nicotinamide adenine dinucleotide (Phosphate) (NAD(P)H) formation upon glutamate stimulation. We also observed that the mitochondrial respiratory chain (MRC) was functional after glucose stimulation but not activated by glutamate, resulting in a lower level of cellular adenosine triphosphate (ATP) in silenced astrocytes compared to control cells. Moreover, GC1 inactivation resulted in an intracellular glutamate accumulation. Our results show that mitochondrial glutamate transport via GC1 is important in sustaining glutamate homeostasis in astrocytes. Main Points: The mitochondrial respiratory chain is functional in absence of GC1Lack of glutamate oxidation results in a lower global ATP levelLack of mitochondrial glutamate transport results in intracellular glutamate accumulation. PMID- 28620282 TI - A Reward-Based Behavioral Platform to Measure Neural Activity during Head-Fixed Behavior. AB - Understanding the neural computations that contribute to behavior requires recording from neurons while an animal is behaving. This is not an easy task as most subcellular recording techniques require absolute head stability. The Go/No Go sensory task is a powerful decision-driven task that enables an animal to report a binary decision during head-fixation. Here we discuss how to set up an Ardunio and Python based platform system to control a Go/No-Go sensory behavior paradigm. Using an Arduino micro-controller and Python-based custom written program, a reward can be delivered to the animal depending on the decision reported. We discuss the various components required to build the behavioral apparatus that can control and report such a sensory stimulus paradigm. This system enables the end user to control the behavioral testing in real-time and therefore it provides a strong custom-made platform for probing the neural basis of behavior. PMID- 28620280 TI - Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy. AB - Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle leading to cell death and tumor degradation-and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches. PMID- 28620283 TI - Octopus Cells in the Posteroventral Cochlear Nucleus Provide the Main Excitatory Input to the Superior Paraolivary Nucleus. AB - Auditory streaming enables perception and interpretation of complex acoustic environments that contain competing sound sources. At early stages of central processing, sounds are segregated into separate streams representing attributes that later merge into acoustic objects. Streaming of temporal cues is critical for perceiving vocal communication, such as human speech, but our understanding of circuits that underlie this process is lacking, particularly at subcortical levels. The superior paraolivary nucleus (SPON), a prominent group of inhibitory neurons in the mammalian brainstem, has been implicated in processing temporal information needed for the segmentation of ongoing complex sounds into discrete events. The SPON requires temporally precise and robust excitatory input(s) to convey information about the steep rise in sound amplitude that marks the onset of voiced sound elements. Unfortunately, the sources of excitation to the SPON and the impact of these inputs on the behavior of SPON neurons have yet to be resolved. Using anatomical tract tracing and immunohistochemistry, we identified octopus cells in the contralateral cochlear nucleus (CN) as the primary source of excitatory input to the SPON. Cluster analysis of miniature excitatory events also indicated that the majority of SPON neurons receive one type of excitatory input. Precise octopus cell-driven onset spiking coupled with transient offset spiking make SPON responses well-suited to signal transitions in sound energy contained in vocalizations. Targets of octopus cell projections, including the SPON, are strongly implicated in the processing of temporal sound features, which suggests a common pathway that conveys information critical for perception of complex natural sounds. PMID- 28620285 TI - The Evidence for Altered BDNF Expression in the Brain of Rats Reared or Housed in Social Isolation: A Systematic Review. AB - There is evidence that development and maintenance of neural connections are disrupted in major mental disorders, which indicates that neurotrophic factors could play a critical role in their pathogenesis. Stress is a well-established risk factor for psychopathology and recent research suggests that disrupted signaling via brain-derived neurotrophic factor (BDNF) may be involved in mediating the negative effects of stress on the brain. Social isolation of rats elicits chronic stress and is widely used as an animal model of mental disorders such as schizophrenia and depression. We carried out a systematic search of published studies to review current evidence for an altered expression of BDNF in the brain of rats reared or housed in social isolation. Across all age groups (post-weaning, adolescent, adult), majority of the identified studies (16/21) reported a decreased expression of BDNF in the hippocampus. There are far less published data on BDNF expression in other brain regions. Data are also scarce to assess the behavioral changes as a function of BDNF expression, but the downregulation of BDNF seems to be associated with increased anxiety-like symptoms. The reviewed data generally support the putative involvement of BDNF in the pathogenesis of stress-related mental illness. However, the mechanisms linking chronic social isolation, BDNF expression and the elicited behavioral alterations are currently unknown. PMID- 28620286 TI - Audience Effects in Territorial Defense of Male Cichlid Fish Are Associated with Differential Patterns of Activation of the Brain Social Decision-Making Network. AB - Animals communicate by exchanging signals frequently in the proximity of other conspecifics that may detect and intercept signals not directed to them. There is evidence that the presence of these bystanders modulates the signaling behavior of interacting individuals, a phenomenon that has been named audience effect. Research on the audience effect has predominantly focused on its function rather than on its proximate mechanisms. Here, we have investigated the physiological and neuromolecular correlates of the audience effect in a cichlid fish (Mozambique tilapia, Oreochromis mossambicus). A male was exposed to a territorial intrusion in the presence or absence of a female audience. Results showed that the presence of the female audience increased territorial defense, but elicited a lower androgen and cortisol response to the territorial intrusion. Furthermore, analysis of the expression of immediate early genes, used as markers of neuronal activity, in brain areas belonging to the social decision-making network (SDMN) revealed different patterns of network activity and connectivity across the different social contexts (i.e., audience * intrusion). Overall, these results suggest that socially driven plasticity in the expression of territorial behavior is accommodated in the central nervous system by rapid changes in functional connectivity between nodes of relevant networks (SDMN) rather than by localized changes of activity in specific brain nuclei. PMID- 28620284 TI - Electrophysiological Measurements of Peripheral Vestibular Function-A Review of Electrovestibulography. AB - Electrocochleography (EcochG), incorporating the Cochlear Microphonic (CM), the Summating Potential (SP), and the cochlear Compound Action Potential (CAP), has been used to study cochlear function in humans and experimental animals since the 1930s, providing a simple objective tool to assess both hair cell (HC) and nerve sensitivity. The vestibular equivalent of ECochG, termed here Electrovestibulography (EVestG), incorporates responses of the vestibular HCs and nerve. Few research groups have utilized EVestG to study vestibular function. Arguably, this is because stimulating the cochlea in isolation with sound is a trivial matter, whereas stimulating the vestibular system in isolation requires significantly more technical effort. That is, the vestibular system is sensitive to both high-level sound and bone-conducted vibrations, but so is the cochlea, and gross electrical responses of the inner ear to such stimuli can be difficult to interpret. Fortunately, several simple techniques can be employed to isolate vestibular electrical responses. Here, we review the literature underpinning gross vestibular nerve and HC responses, and we discuss the nomenclature used in this field. We also discuss techniques for recording EVestG in experimental animals and humans and highlight how EVestG is furthering our understanding of the vestibular system. PMID- 28620287 TI - Changes of EEG Spectra and Functional Connectivity during an Object-Location Memory Task in Alzheimer's Disease. AB - Object-location memory is particularly fragile and specifically impaired in Alzheimer's disease (AD) patients. Electroencephalogram (EEG) was utilized to objectively measure memory impairment for memory formation correlates of EEG oscillatory activities. We aimed to construct an object-location memory paradigm and explore EEG signs of it. Two groups of 20 probable mild AD patients and 19 healthy older adults were included in a cross-sectional analysis. All subjects took an object-location memory task. EEG recordings performed during object location memory tasks were compared between the two groups in the two EEG parameters (spectral parameters and phase synchronization). The memory performance of AD patients was worse than that of healthy elderly adults The power of object-location memory of the AD group was significantly higher than the NC group (healthy elderly adults) in the alpha band in the encoding session, and alpha and theta bands in the retrieval session. The channels-pairs the phase lag index value of object-location memory in the AD group was clearly higher than the NC group in the delta, theta, and alpha bands in encoding sessions and delta and theta bands in retrieval sessions. The results provide support for the hypothesis that the AD patients may use compensation mechanisms to remember the items and episode. PMID- 28620288 TI - Age-Related Changes in Resting-State EEG Activity in Attention Deficit/Hyperactivity Disorder: A Cross-Sectional Study. AB - Numerous studies indicate that attention deficit/hyperactivity disorder (ADHD) is related to some developmental trends, as its symptoms change widely over time. Nevertheless, the etiology of this phenomenon remains ambiguous. There is a disagreement whether ADHD is related to deviations in brain development or to a delay in brain maturation. The model of deviated brain development suggests that the ADHD brain matures in a fundamentally different way, and does not reach normal maturity at any developmental stage. On the contrary, the delayed brain maturation model assumes that the ADHD brain indeed matures in a different, delayed way in comparison to healthy age-matched controls, yet eventually reaches proper maturation. We investigated age-related changes in resting-state EEG activity to find evidence to support one of the alternative models. A total of 141 children and teenagers participated in the study; 67 diagnosed with ADHD and 74 healthy controls. The absolute power of delta, theta, alpha, and beta frequency bands was analyzed. We observed a significant developmental pattern of decreasing absolute EEG power in both groups. Nonetheless, ADHD was characterized by consistently lower absolute EGG power, mostly in the theta frequency band, in comparison to healthy controls. Our results are in line with the deviant brain maturation theory of ADHD, as the observed effects of age-related changes in EEG power are parallel but different in the two groups. PMID- 28620289 TI - Dazzled by the Mystery of Mentalism: The Cognitive Neuroscience of Mental Athletes. PMID- 28620290 TI - How Stable Are Human Aesthetic Preferences Across the Lifespan? AB - How stable are human aesthetic preferences, and how does stability change over the lifespan? Here we investigate the stability of aesthetic taste in a cross sectional study. We employed a simple rank-order preference task using paintings and photographs of faces and landscapes. In each of the four stimulus classes, we find that aesthetic stability generally follows an inverted U-shaped function, with the greatest degree of stability appearing in early to middle adulthood. We propose that one possible interpretation of this result is that it indicates a role for cognitive control (i.e., the ability to adapt cognition to current situations) in the construction of aesthetic taste, since cognitive control performance follows a generally similar trajectory across the lifespan. However, human aesthetic stability is on the whole rather low: even the most stable age groups show ranking changes of at least 1 rank per item over a 2-week span. We discuss possible implications for these findings in terms of existing theories of visual aesthetics and in terms of methodological considerations, though we acknowledge that other interpretations of our results are possible. PMID- 28620291 TI - Network-Wide Adaptive Burst Detection Depicts Neuronal Activity with Improved Accuracy. AB - Neuronal networks are often characterized by their spiking and bursting statistics. Previously, we introduced an adaptive burst analysis method which enhances the analysis power for neuronal networks with highly varying firing dynamics. The adaptation is based on single channels analyzing each element of a network separately. Such kind of analysis was adequate for the assessment of local behavior, where the analysis focuses on the neuronal activity in the vicinity of a single electrode. However, the assessment of the whole network may be hampered, if parts of the network are analyzed using different rules. Here, we test how using multiple channels and measurement time points affect adaptive burst detection. The main emphasis is, if network-wide adaptive burst detection can provide new insights into the assessment of network activity. Therefore, we propose a modification to the previously introduced inter-spike interval (ISI) histogram based cumulative moving average (CMA) algorithm to analyze multiple spike trains simultaneously. The network size can be freely defined, e.g., to include all the electrodes in a microelectrode array (MEA) recording. Additionally, the method can be applied on a series of measurements on the same network to pool the data for statistical analysis. Firstly, we apply both the original CMA-algorithm and our proposed network-wide CMA-algorithm on artificial spike trains to investigate how the modification changes the burst detection. Thereafter, we use the algorithms on MEA data of spontaneously active chemically manipulated in vitro rat cortical networks. Moreover, we compare the synchrony of the detected bursts introducing a new burst synchrony measure. Finally, we demonstrate how the bursting statistics can be used to classify networks by applying k-means clustering to the bursting statistics. The results show that the proposed network wide adaptive burst detection provides a method to unify the burst definition in the whole network and thus improves the assessment and classification of the neuronal activity, e.g., the effects of different pharmaceuticals. The results indicate that the novel method is adaptive enough to be usable on networks with different dynamics, and it is especially feasible when comparing the behavior of differently spiking networks, for example in developing networks. PMID- 28620293 TI - A Manual Segmentation Tool for Three-Dimensional Neuron Datasets. AB - To date, automated or semi-automated software and algorithms for segmentation of neurons from three-dimensional imaging datasets have had limited success. The gold standard for neural segmentation is considered to be the manual isolation performed by an expert. To facilitate the manual isolation of complex objects from image stacks, such as neurons in their native arrangement within the brain, a new Manual Segmentation Tool (ManSegTool) has been developed. ManSegTool allows user to load an image stack, scroll down the images and to manually draw the structures of interest stack-by-stack. Users can eliminate unwanted regions or split structures (i.e., branches from different neurons that are too close each other, but, to the experienced eye, clearly belong to a unique cell), to view the object in 3D and save the results obtained. The tool can be used for testing the performance of a single-neuron segmentation algorithm or to extract complex objects, where the available automated methods still fail. Here we describe the software's main features and then show an example of how ManSegTool can be used to segment neuron images acquired using a confocal microscope. In particular, expert neuroscientists were asked to segment different neurons from which morphometric variables were subsequently extracted as a benchmark for precision. In addition, a literature-defined index for evaluating the goodness of segmentation was used as a benchmark for accuracy. Neocortical layer axons from a DIADEM challenge dataset were also segmented with ManSegTool and compared with the manual "gold-standard" generated for the competition. PMID- 28620292 TI - Dynamic Responses in Brain Networks to Social Feedback: A Dual EEG Acquisition Study in Adolescent Couples. AB - Adolescence is a sensitive period for the development of romantic relationships. During this period the maturation of frontolimbic networks is particularly important for the capacity to regulate emotional experiences. In previous research, both functional magnetic resonance imaging (fMRI) and dense array electroencephalography (dEEG) measures have suggested that responses in limbic regions are enhanced in adolescents experiencing social rejection. In the present research, we examined social acceptance and rejection from romantic partners as they engaged in a Chatroom Interact Task. Dual 128-channel dEEG systems were used to record neural responses to acceptance and rejection from both adolescent romantic partners and unfamiliar peers (N = 75). We employed a two-step temporal principal component analysis (PCA) and spatial independent component analysis (ICA) approach to statistically identify the neural components related to social feedback. Results revealed that the early (288 ms) discrimination between acceptance and rejection reflected by the P3a component was significant for the romantic partner but not the unfamiliar peer. In contrast, the later (364 ms) P3b component discriminated between acceptance and rejection for both partners and peers. The two-step approach (PCA then ICA) was better able than either PCA or ICA alone in separating these components of the brain's electrical activity that reflected both temporal and spatial phases of the brain's processing of social feedback. PMID- 28620294 TI - Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner. AB - Microglia are the resident immune cells of the brain, important for normal neural development in addition to host defense in response to inflammatory stimuli. Air pollution is one of the most pervasive and harmful environmental toxicants in the modern world, and several large scale epidemiological studies have recently linked prenatal air pollution exposure with an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Diesel exhaust particles (DEP) are a primary toxic component of air pollution, and markedly activate microglia in vitro and in vivo in adult rodents. We have demonstrated that prenatal exposure to DEP in mice, i.e., to the pregnant dams throughout gestation, results in a persistent vulnerability to behavioral deficits in adult offspring, especially in males, which is intriguing given the greater incidence of ASD in males to females (~4:1). Moreover, there is a striking upregulation of toll-like receptor (TLR) 4 gene expression within the brains of the same mice, and this expression is primarily in microglia. Here we explored the impact of gestational exposure to DEP or vehicle on microglial morphology in the developing brains of male and female mice. DEP exposure increased inflammatory cytokine protein and altered the morphology of microglia, consistent with activation or a delay in maturation, only within the embryonic brains of male mice; and these effects were dependent on TLR4. DEP exposure also increased cortical volume at embryonic day (E)18, which switched to decreased volume by post-natal day (P)30 in males, suggesting an impact on the developing neural stem cell niche. Consistent with this hypothesis, we found increased microglial-neuronal interactions in male offspring that received DEP compared to all other groups. Taken together, these data suggest a mechanism by which prenatal exposure to environmental toxins may affect microglial development and long-term function, and thereby contribute to the risk of neurodevelopmental disorders. PMID- 28620295 TI - Slow and Fast Neocortical Oscillations in the Senescence-Accelerated Mouse Model SAMP8. AB - The senescence-accelerated mouse prone 8 (SAMP8) model is characterized by accelerated, progressive cognitive decline as well as Alzheimer's disease (AD) like neurodegenerative changes, and resembles the etiology of multicausal, sporadic late-onset/age-related AD in humans. Our aim was to find whether these AD-like pathological features, together with the cognitive deficits present in the SAMP8 strain, are accompanied by disturbances in cortical network activity with respect to control mice (SAM resistance 1, SAMR1) and, if so, how the alterations in cortical activity progress with age. For this purpose, we characterized the extracellular spontaneous oscillatory activity in different regions of the cerebral cortex of SAMP8 and SAMR1 mice under ketamine anesthesia at 5 and 7 months of age. Under these conditions, slow oscillations and fast rhythms generated in the cortical network were recorded and different parameters of these oscillations were quantified and compared between SAMP8 and their control, SAMR1 mice. The average frequency of slow oscillations in SAMP8 mice was decreased with respect to the control mice at both studied ages. An elongation of the silent periods or Down states was behind the decreased slow oscillatory frequency while the duration of active or Up states remained stable. SAMP8 mice also presented increased cycle variability and reduced high frequency components during Down states. During Up states, the power peak in the gamma range was displaced towards lower frequencies in all the cortical areas of SAMP8 with respect to control mice suggesting that the spectral profile of SAMP8 animals is shifted towards lower frequencies. This shift is reminiscent to one of the principal hallmarks of electroencephalography (EEG) abnormalities in patients with Alzheimer's disease, and adds evidence in support of the suitability of the SAMP8 mouse as a model of this disease. Although some of the differences between SAMP8 and control mice were emphasized with age, the evolution of the studied parameters as SAMR1 mice got older indicates that the SAMR1 phenotype tends to converge with that of SAMP8 animals. To our knowledge, this is the first systematic characterization of the cortical slow and fast rhythms in the SAMP8 strain and it provides useful insights about the cellular and synaptic mechanisms underlying the reported alterations. PMID- 28620296 TI - Testosterone Propionate Exacerbates the Deficits of Nigrostriatal Dopaminergic System and Downregulates Nrf2 Expression in Reserpine-Treated Aged Male Rats. AB - There is a controversy over the effects of testosterone supplements on dopaminergic function. Both neuroprotective and toxic effects of testosterone supplements are reported. The status of oxidative stress seems to explain the neuroprotective or toxic properties of testosterone. To determine the efficacy of testosterone supplements in different status of oxidative stress, the present studies analyzed the dopamine (DA)-related behaviors and neurochemical indices, as well as markers of nigrostriatal dopaminergic (NSDA) system in reserpine treated aged male rats followed by testosterone propionate (TP) supplements. The status of oxidative stress of experimental animals was evaluated by analyzing oxidative stress parameters and nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway in substantia nigra (SN). Consistent with our previous studies, TP supplements to 21-month old aged male rats had the beneficial effects on NSDA system and DA-related behaviors and enhanced the antioxidative capabilities in SN. However, the beneficial effects of TP supplements on NSDA system and DA-related behaviors in aged male rats were reversed by reserpine pretreatment to them. Reserpine treatment induced the severe oxidative stress and reduced the expressions of Nrf2, heme oxygenase-1 (HO 1) and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the SN of aged male rats. The TP supplements to reserpine-pretreated aged male rats exacerbated the defects in NSDA system and DA-related behaviors, aggravated oxidative damages and downregulated the expression of Nrf2, HO-1 and NQO1 in the SN. These results suggested that the efficacy of TP supplements on impaired NSDA system was related to the status of oxidative stress in experimental rats. PMID- 28620297 TI - Racial Differences in Insular Connectivity and Thickness and Related Cognitive Impairment in Hypertension. AB - Hypertensive African-Americans have a greater risk of cognitive impairment than hypertensive Caucasian-Americans. The neural basis of this increased risk is yet unknown. Neuroimaging investigations suggest that the normal neural activity comprises complex interactions between brain networks. Recent studies consistently demonstrate that the insula, part of the salience network, provides modulation effects (information flow) over the default-mode and central-executive networks in cognitively normal subjects, and argue that the modulation effect is declined in cognitive impairment. The purpose of this study is to examine the information flow at the nodes of three networks using resting state functional magnetic resonance imaging (MRI) data in cognitively impaired hypertensive individuals with the African-Americans and the Caucasian-Americans races, and to compare the thickness of impaired node between two racial groups. Granger causality methodology was used to calculate information flow between networks using resting state functional MRI data, and FreeSurfer was used to measure cortical thickness from T1-weighted structural images. We found that negative information flow of the insula in both African-Americans and Caucasian-Americans, which was in contrast with previously reported positive information flow in this region of normal individuals. Also, significantly greater negative information flow in insula was found in African-Americans than Caucasian-Americans (Wilcoxon rank sum; Z = 2.06; p < 0.05). Significantly, lower insula thickness was found in African-Americans compared with Caucasian-Americans (median = 2.797 mm vs. 2.897 mm) (Wilcoxon rank sum; Z = 2.09; p < 0.05). Finally, the insula thickness correlated with the global cognitive testing measured by Montreal cognitive assessment (Spearman's correlation; r = 0.30; p < 0.05). These findings suggest that the insula is a potential biomarker for the racial disparity in cognitive impairment of hypertensive individuals. PMID- 28620298 TI - Anti-tumor Activity of Toll-Like Receptor 7 Agonists. AB - Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc. PMID- 28620299 TI - The Alkamide trans-Pellitorine Targets PPARgamma via TRPV1 and TRPA1 to Reduce Lipid Accumulation in Developing 3T3-L1 Adipocytes. AB - Adipose tissue is an important endocrine organ in the human body. However, pathological overgrowth is associated with chronic illness. Regulation of adipogenesis and maturation of adipocytes via bioactive compounds in our daily diet has been in focus of research in the past years and showed promising results for agonists of the ion channels transient receptor potential channel (TRP) V1 and A1. Here, we investigated the anti-adipogenic potential and underlying mechanisms of the alkamide trans-pellitorine present in Piper nigrum via TRPV1 and TRPA1 in 3T3-L1 cells. trans-pellitorine was found to suppress mean lipid accumulation, when applied during differentiation and maturation, but also during maturation phase solely of 3T3-L1 cells in a concentration range between 1 nM and 1 MUM by up to 8.84 +/- 4.97 or 7.49 +/- 5.08%, respectively. Blockage of TRPV1 using the specific inhibitor trans-tert-butyl-cyclohexanol demonstrated that the anti-adipogenic activity of trans-pellitorine depends on TRPV1. In addition, blockage of the TRPA1 channel using the antagonist AP-18 showed a TRPA1-dependent signaling in the early to intermediate stages of adipogenesis. On a mechanistic level, treatment with trans-pellitorine during adipogenesis led to reduced PPARgamma expression on gene and protein level via activation of TRPV1 and TRPA1, and increased expression of the microRNA mmu-let-7b, which has been associated with reduced PPARgamma levels. In addition, cells treated with trans-pellitorine showed decreased expression of the gene encoding for fatty acid synthase, increased expression of microRNA-103 and a decreased short-term fatty acid uptake on the functional level. In summary, these data point to an involvement of the TRPV1 and TRPA1 cation channels in the anti-adipogenic activity of trans pellitorine via microRNA-let7b and PPARgamma. Since trans-pellitorine does not directly activate TRPV1 or TRPA1, an indirect modulation of the channel activity is assumed and warrants further investigation. PMID- 28620301 TI - Chemopreventive Activity of Honokiol against 7, 12 - Dimethylbenz[a]anthracene Induced Mammary Cancer in Female Sprague Dawley Rats. AB - Breast cancer is a predominant cause of death in women across the globe. Chemoprevention by using natural, dietary or synthetic products has been appearing to be a fascinating approach to combat the growing burden of breast cancer. In the current study, we intended to explore the mechanisms of chemopreventive action of honokiol against 7, 12 - dimethylbenz[a]anthracene (DMBA)-induced mammary cancer in female Sprague Dawlely (SD) rats. We induced mammary cancer in SD rats by administering single dose of DMBA (80 mg/kg) through intra gastric route. Chemopreventive effects of honokiol (80 mg/kg, i.p.) were confirmed from its ameliorating effect on the DMBA-induced anomalies such as liver marker enzymes, Phases I and II metabolizing enzymes and oxidative stress markers. Further, honokiol reversed the DMBA-induced abnormalities in inflammatory cytokines levels and serum tumor markers. Additionally, histopathological examination of mammary tissue and protein expression analysis of NF-kappaB revealed that honokiol is effective against DMBA-induced mammary cancer. In summary, the results of our study support the chemopreventive feature of honokiol in mammary cancer. PMID- 28620302 TI - Adoption of Biosimilar Infliximab for Rheumatoid Arthritis, Ankylosing Spondylitis, and Inflammatory Bowel Diseases in the EU5: A Budget Impact Analysis Using a Delphi Panel. AB - Introduction: Introducing biosimilar infliximab for the treatment in rheumatology (rheumatoid arthritis and ankylosing spondylitis) and inflammatory bowel disease (Crohn's disease and ulcerative colitis) may reduce treatment costs associated with biologics. This study aimed to investigate the budget impact of adopting biosimilar infliximab in five European countries, considering that the budget impact includes the adoption of biosimilar infliximab and the availability of biologic alternatives such as vedolizumab, biosimilar etanercept, biosimilar rituximab, and other relevant factors. Methods: An existing budget impact model was adapted to forecast the budget impact in the UK, Germany, France, Spain, and Italy. Epidemiological parameters were derived from published literature reviewed in July 2015. Current market shares of biologics were derived from Therapy Watch (2012/2013 data). Respondents in a Delphi panel, conducted in 2015 and consisting of several leading rheumatologists and gastroenterologists from different nationalities, were asked to forecast uptake of biosimilar infliximab and estimate the proportion of patients eligible for a particular type of biological treatment, including biosimilar infliximab. Scenario analyses assessed the influence of various factors, including price reductions, on the budget. Results: Uptake of biosimilar infliximab was particularly expected for naive patients; switching patients that already received other biologics was not expected much. Market shares after 5 years of biosimilar infliximab were ~2% in rheumatology in all five countries and in gastroenterology ranged from 4% in France to over 30% in Italy. Except for France, budgets were expected to decrease for rheumatologic diseases. For gastroenterology, budgets were expected to decrease in Spain and Italy. Budgets were expected to increase substantially in the UK and Germany, due to the introduction of vedolizumab in the studied period. In France, budget was expected to slightly increase for ankylosing spondylitis, Crohn's Disease, and ulcerative collitis. Savings in budget were expected in all countries, for all diseases, when larger price discounts on biosimilar infliximab were used. Discussion and Conclusion: This study has shown that only when price reductions are large enough (i.e., 50% or more), physicians indicated that they will prescribe biosimilars. Policy makers should ensure substantial price reductions and stimulate physicians to use biosimilar products, to obtain savings in healthcare budgets. PMID- 28620303 TI - Effect of Genetic Variability in the CYP4F2, CYP4F11, and CYP4F12 Genes on Liver mRNA Levels and Warfarin Response. AB - Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. CYP4F2 is part of the CYP4F gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the CYP4F gene cluster on expression of the individual CYP4F genes and warfarin response. mRNA levels of the CYP4F gene cluster were quantified in human liver samples (n = 149) obtained from a well-characterized liver bank and fine mapping of the CYP4F gene cluster encompassing CYP4F2, CYP4F11, and CYP4F12 was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients (n = 711) was also analyzed for genetic variations across the CYP4F gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between CYP4F genes were explored in silico using publicly available data repositories. We found that SNPs in CYP4F2, CYP4F11, and CYP4F12 were associated with mRNA expression in the CYP4F gene cluster. In particular, CYP4F2 rs2108622 was associated with increased CYP4F2 expression while CYP4F11 rs1060467 was associated with decreased CYP4F2 expression. Interestingly, these CYP4F2 and CYP4F11 SNPs showed similar effects with warfarin stable dose where CYP4F11 rs1060467 was associated with a reduction in daily warfarin dose requirement (~1 mg/day, Pc = 0.017), an effect opposite to that previously reported with CYP4F2 (rs2108622). However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI), gender, baseline clotting factor II level, CYP2C9*2 rs1799853, CYP2C9*3 rs1057910, and VKORC1 rs9923231 improved warfarin dose variability only by 0.5 0.7% with an improvement in dose prediction accuracy of ~1-2%. Although there is complex regulation across the CYP4F gene cluster, the opposing effects between the two SNPs in the CYP4F gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant. PMID- 28620300 TI - Novel Anti-fibrotic Therapies. AB - Fibrosis is a major player in cardiovascular disease, both as a contributor to the development of disease, as well as a post-injury response that drives progression. Despite the identification of many mechanisms responsible for cardiovascular fibrosis, to date no treatments have emerged that have effectively reduced the excess deposition of extracellular matrix associated with fibrotic conditions. Novel treatments have recently been identified that hold promise as potential therapeutic agents for cardiovascular diseases associated with fibrosis, as well as other fibrotic conditions. The purpose of this review is to provide an overview of emerging antifibrotic agents that have shown encouraging results in preclinical or early clinical studies, but have not yet been approved for use in human disease. One of these agents is bone morphogenetic protein-7 (BMP7), which has beneficial effects in multiple models of fibrotic disease. Another approach discussed involves altering the levels of micro-RNA (miR) species, including miR-29 and miR-101, which regulate the expression of fibrosis related gene targets. Further, the antifibrotic potential of agonists of the peroxisome proliferator-activated receptors will be discussed. Finally, evidence will be reviewed in support of the polypeptide hormone relaxin. Relaxin is long known for its extracellular remodeling properties in pregnancy, and is rapidly emerging as an effective antifibrotic agent in a number of organ systems. Moreover, relaxin has potent vascular and renal effects that make it a particularly attractive approach for the treatment of cardiovascular diseases. In each case, the mechanism of action and the applicability to various fibrotic diseases will be discussed. PMID- 28620304 TI - Pu-erh Tea Extract Ameliorates Ovariectomy-Induced Osteoporosis in Rats and Suppresses Osteoclastogenesis In Vitro. AB - Background and Objective: Tea drinking is associated with positive effects on bone health and may protect against osteoporosis, especially in elderly women. Pu erh tea has many beneficial effects on human health; however, whether Pu-erh tea has anti-osteoporotic potential remains unclear. Thus, we investigated the effects of Pu-erh tea extract (PTE) on ovariectomy-induced osteoporosis in rats and on osteoclastogenesis in vitro. Methods: Female Wistar rats were divided into six groups: the sham, model, and Xian-Ling-Gu-Bao capsule (XLGB) groups, and the low-, medium-, and high-dose PTE groups. Ovariectomized (OVX) rats were used as an animal model of osteoporosis. The animals were intragastrically administered distilled water, XLGB, or different concentrations of PTE for 13 weeks. Body weight, blood biochemical indicators, relative organ coefficients, femoral bone mineral density (BMD), bone biomechanical properties, and bone microarchitecture were examined and analyzed. Additionally, the in vitro effects of PTE on osteoclastic activities were investigated using the RAW 264.7 cell line as an osteoclast differentiation model. The effects of PTE on osteoclast differentiation and the expression of osteoclast-specific genes and proteins were determined. Results: PTE reduced OVX-induced body weight gain after 6 weeks of treatment, and the high-dose exerted a significant effect. High-dose PTE significantly ameliorated OVX-induced estradiol (E2) deficiency. PTE treatment maintained calcium and phosphorus homeostasis and improved other blood biochemical parameters to various degrees. In addition, PTE treatment improved organ coefficients of the femur, uterus, and vagina and improved femoral BMD and bone biomechanical properties. PTE treatment strikingly ameliorated bone microarchitecture. Moreover, in the in vitro studies, osteoclast differentiation using the differentiation cell model was significantly inhibited by PTE without cytotoxic effects. Additionally, PTE efficaciously suppressed the expression of key osteoclast-specific genes and proteins. Conclusion: PTE can ameliorate ovariectomy-induced osteoporosis in rats and suppress osteoclastogenesis in vitro. PMID- 28620305 TI - Comparative Effects of Chloride Channel Inhibitors on LRRC8/VRAC-Mediated Chloride Conductance. AB - Chloride channels play an essential role in a variety of physiological functions and in human diseases. Historically, the field of chloride channels has long been neglected owing to the lack of powerful selective pharmacological agents that are needed to overcome the technical challenge of characterizing the molecular identities of these channels. Recently, members of the LRRC8 family have been shown to be essential for generating the volume-regulated anion channel (VRAC) current, a chloride conductance that governs the regulatory volume decrease (RVD) process. The inhibitory effects of six commonly used chloride channel inhibitors on VRAC/LRRC8-mediated chloride transport were tested in wild-type HEK-293 cells expressing LRRC8 proteins and devoid of other types of chloride channels (CFTR and ANO1/2). We explored the effectiveness of the inhibitors using the patch clamp whole-cell approach and fluorescence-based quantification of cellular volume changes during hypotonic challenge. Both DCPIB and NFA inhibited VRAC current in a whole-cell configuration, with IC50 values of 5 +/- 1 MUM and 55 +/- 2 MUM, respectively. Surprisingly, GlyH-101 and PPQ-102, two CFTR inhibitors, also inhibited VRAC conductance at concentrations in the range of their current use, with IC50 values of 10 +/- 1 MUM and 20 +/- 1 MUM, respectively. T16Ainh A01, a so-called specific inhibitor of calcium-activated Cl- conductance, blocked the chloride current triggered by hypo-osmotic challenge, with an IC50 of 6 +/- 1 MUM. Moreover, RVD following hypotonic challenge was dramatically reduced by these inhibitors. CFTRinh-172 was the only inhibitor that had almost no effect on VRAC/LRRC8-mediated chloride conductance. All inhibitors tested except CFTRinh 172 inhibited VRAC/LRRC8-mediated chloride conductance and cellular volume changes during hypotonic challenge. These results shed light on the apparent lack of chloride channel inhibitors specificity and raise the question of how these inhibitors actually block chloride conductances. PMID- 28620306 TI - Characterization of Antileishmanial Compounds from Lawsonia inermis L. Leaves Using Semi-High Resolution Antileishmanial Profiling Combined with HPLC-HRMS-SPE NMR. AB - This work describes an analytical platform based on semi-high-resolution antileishmanial profiling combined with hyphenation of high-performance liquid chromatography - high-resolution mass spectrometry - solid-phase extraction - nuclear magnetic resonance spectroscopy, i.e., semiHR-antileishmanial assay/HPLC HRMS-SPE-NMR. The platform enables fast pinpointing of HPLC peaks representing Leishmania tropica inhibitors in complex matrices, with subsequent structural identification of targeted inhibitors. Active analytes were cumulatively trapped on SPE cartridges and the structures elucidated by analysis of NMR spectra obtained in the HPLC-HRMS-SPE-NMR mode. This led to the identification of six known compounds 2,4,6-trihydroxyacetophenone-2-O-beta-D-glucopyranoside (1), lalioside (2), luteolin-4'-O-beta-D-glucopyranoside (3), apigenin-4'-O-beta-D glucopyranoside (4), luteolin (5), and apigenin (6). IC50 of the active compounds were determined with luteolin being the most potent inhibitor with an IC50 value of 4.15 MUg/ml. The platform proved to be an efficient method for the identification of L. tropica inhibitors. PMID- 28620307 TI - Peri- and Postoperative Treatment with the Interleukin-1 Receptor Antagonist Anakinra Is Safe in Patients Undergoing Renal Transplantation: Case Series and Review of the Literature. AB - In patients undergoing solid organ transplantation, the presence of an interleukin-1 (IL-1) driven disease may require the addition of IL-1 inhibiting drugs to the standard immunosuppressive regimen to protect against inflammation and negative graft outcome. Three patients undergoing renal transplantation were treated perioperatively with the interleukin-1 receptor antagonist anakinra. Kidney function increased rapidly in all three and the only complications seen were minor infections. In vitro studies report associations between serum and urinary levels of IL-1beta and IL-1 receptor antagonist and negative graft outcome, and studies in animals and two small human trials illustrate a possible protective effect of anti-IL-1 therapy after solid organ transplantation. Peri- and postoperative use of anakinra is safe and effective in patients undergoing renal transplantation. PMID- 28620308 TI - The Effect of Interdialytic Combined Resistance and Aerobic Exercise Training on Health Related Outcomes in Chronic Hemodialysis Patients: The Tunisian Randomized Controlled Study. AB - Background: Tunisia has the highest prevalence of hemodialysis patients compared to the other countries in North Africa. Dialysis centers rarely offer an exercise program to prevent physiological and psychological dialysis therapy-related alterations in chronic hemodialysis patients. Aim: To examine the effect of combined endurance-resistance training program on physiological and psychological outcomes in patients undergoing hemodialysis. Methods: We designed a single blinded, randomized, controlled study for a period of 4 months. Patients were randomized to intervention group or control group. Intervention group patients received 4 training sessions per week, held on non-hemodialysis days for a period of 4 months, whereas control group patients continued their regular lifestyle practice without direct intervention from the personnel of this investigation. Patients were evaluated at baseline (initial assessment) and after the four-month study period (final assessment) by the same investigator blinded to treatment group assignment using physical, physiological, and psychological measurements. Results: Compared with control group, intervention group showed significant improvement in physical performance during the sit-to-stand-to-sit tests (STS-10: -16.2%, ES = -1.65; STS-60: +23.43%, ES = 1.18), handgrip force task (+23.54%, ES = 1.16), timed up and go test (-13.86%, ES = -1.13), and 6-min walk test (+15.94%, ES = 2.09). Likewise, mini nutritional assessment long form scores after intervention period were significantly higher in the intervention group compared to the control group (ES = 1.43). Physical and mental component scores of SF-36 questionnaire increased significantly in the intervention group (ES = 1.10 and ES = 2.06, respectively), whereas hospital anxiety and depression scale scores decreased significantly (ES = -1.65 and ES = -2.72, respectively). Regarding biological parameters, intervention group displayed improvement in systolic and diastolic blood pressures (ES = -2.77 and ES = -0.87, respectively), HDL-cholesterol, LDL-cholesterol, and triglycerides systematic levels (ES = 1.15, ES = -0.98, and ES = -1.01, respectively); however no significant effect of intervention period was observed on C-reactive protein, hemoglobin, albumin, and total cholesterol levels (P > 0.05). Conclusion: The current study showed that combined endurance-resistance training program had a beneficial effect on physical capacity and quality of life in chronic hemodialysis patients. PMID- 28620309 TI - Inhibition of the TRPM2 and TRPV1 Channels through Hypericum perforatum in Sciatic Nerve Injury-induced Rats Demonstrates their Key Role in Apoptosis and Mitochondrial Oxidative Stress of Sciatic Nerve and Dorsal Root Ganglion. AB - Sciatic nerve injury (SNI) results in neuropathic pain, which is characterized by the excessive Ca2+ entry, reactive oxygen species (ROS) and apoptosis processes although involvement of antioxidant Hypericum perforatum (HP) through TRPM2 and TRPV1 activation has not been clarified on the processes in SNI-induced rat, yet. We investigated the protective property of HP on the processes in the sciatic nerve and dorsal root ganglion neuron (DRGN) of SNI-induced rats. The rats were divided into five groups as control, sham, sham+HP, SNI, and SNI+HP. The HP groups received 30 mg/kg HP for 4 weeks after SNI induction. TRPM2 and TRPV1 channels were activated in the neurons by ADP-ribose or cumene peroxide and capsaicin, respectively. The SNI-induced TRPM2 and TRPV1 currents and intracellular free Ca2+ and ROS concentrations were reduced by HP, N-(p amylcinnamoyl) anthranilic acid (ACA), and capsazepine (CapZ). SNI-induced increase in apoptosis and mitochondrial depolarization in sciatic nerve and DRGN of SNI group were decreased by HP, ACA, and CapZ treatments. PARP-1, caspase 3 and 9 expressions in the sciatic nerve, DRGN, skin, and musculus piriformis of SNI group were also attenuated by HP treatment. In conclusion, increase of mitochondrial ROS, apoptosis, and Ca2+ entry through inhibition of TRPM2 and TRPV1 in the sciatic nerve and DRGN neurons were decreased by HP treatment. The results may be relevant to the etiology and treatment of SNI by HP. PMID- 28620310 TI - Abdominal Binding Improves Neuromuscular Efficiency of the Human Diaphragm during Exercise. AB - We tested the hypothesis that elastic binding of the abdomen (AB) would enhance neuromuscular efficiency of the human diaphragm during exercise. Twelve healthy non-obese men aged 24.8 +/- 1.7 years (mean +/- SE) completed a symptom-limited constant-load cycle endurance exercise test at 85% of their peak incremental power output with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements under two randomly assigned conditions: unbound control (CTRL) and AB sufficient to increase end-expiratory gastric pressure (Pga,ee) by 5-8 cmH2O at rest. By design, AB increased Pga,ee by 6.6 +/- 0.6 cmH2O at rest. Compared to CTRL, AB significantly increased the transdiaphragmatic pressure swing-to-EMGdi ratio by 85-95% during exercise, reflecting enhanced neuromuscular efficiency of the diaphragm. By contrast, AB had no effect on spirometric parameters at rest, exercise endurance time or an effect on cardiac, metabolic, ventilatory, breathing pattern, dynamic operating lung volume, and perceptual responses during exercise. In conclusion, AB was associated with isolated and acute improvements in neuromuscular efficiency of the diaphragm during exercise in healthy men. The implications of our results are that AB may be an effective means of enhancing neuromuscular efficiency of the diaphragm in clinical populations with diaphragmatic weakness/dysfunction. PMID- 28620311 TI - Physiological Adaptations to Hypoxic vs. Normoxic Training during Intermittent Living High. AB - In the setting of "living high," it is unclear whether high-intensity interval training (HIIT) should be performed "low" or "high" to stimulate muscular and performance adaptations. Therefore, 10 physically active males participated in a 5-week "live high-train low or high" program (TR), whilst eight subjects were not engaged in any altitude or training intervention (CON). Five days per week (~15.5 h per day), TR was exposed to normobaric hypoxia simulating progressively increasing altitude of ~2,000-3,250 m. Three times per week, TR performed HIIT, administered as unilateral knee-extension training, with one leg in normobaric hypoxia (~4,300 m; TRHYP) and with the other leg in normoxia (TRNOR). "Living high" elicited a consistent elevation in serum erythropoietin concentrations which adequately predicted the increase in hemoglobin mass (r = 0.78, P < 0.05; TR: +2.6%, P < 0.05; CON: -0.7%, P > 0.05). Muscle oxygenation during training was lower in TRHYP vs. TRNOR (P < 0.05). Muscle homogenate buffering capacity and pH-regulating protein abundance were similar between pretest and posttest. Oscillations in muscle blood volume during repeated sprints, as estimated by oscillations in NIRS-derived tHb, increased from pretest to posttest in TRHYP (~80%, P < 0.01) but not in TRNOR (~50%, P = 0.08). Muscle capillarity (~15%) as well as repeated-sprint ability (~8%) and 3-min maximal performance (~10-15%) increased similarly in both legs (P < 0.05). Maximal isometric strength increased in TRHYP (~8%, P < 0.05) but not in TRNOR (~4%, P > 0.05). In conclusion, muscular and performance adaptations were largely similar following normoxic vs. hypoxic HIIT. However, hypoxic HIIT stimulated adaptations in isometric strength and muscle perfusion during intermittent sprinting. PMID- 28620313 TI - Digestive Physiology of Octopus maya and O. mimus: Temporality of Digestion and Assimilation Processes. AB - Digestive physiology is one of the bottlenecks of octopus aquaculture. Although, there are successful experimentally formulated feeds, knowledge of the digestive physiology of cephalopods is fragmented, and focused mainly on Octopus vulgaris. Considering that the digestive physiology could vary in tropical and sub-tropical species through temperature modulations of the digestive dynamics and nutritional requirements of different organisms, the present review was focused on the digestive physiology timing of Octopus maya and Octopus mimus, two promising aquaculture species living in tropical (22-30 degrees C) and sub-tropical (15-24 degrees C) ecosystems, respectively. We provide a detailed description of how soluble and complex nutrients are digested, absorbed, and assimilated in these species, describing the digestive process and providing insight into how the environment can modulate the digestion and final use of nutrients for these and presumably other octopus species. To date, research on these octopus species has demonstrated that soluble protein and other nutrients flow through the digestive tract to the digestive gland in a similar manner in both species. However, differences in the use of nutrients were noted: in O. mimus, lipids were mobilized faster than protein, while in O. maya, the inverse process was observed, suggesting that lipid mobilization in species that live in relatively colder environments occurs differently to those in tropical ecosystems. Those differences are related to the particular adaptations of animals to their habitat, and indicate that this knowledge is important when formulating feed for octopus species. PMID- 28620315 TI - You Are What You Eat: A Genomic Analysis of the Gut Microbiome of Captive and Wild Octopus vulgaris Paralarvae and Their Zooplankton Prey. AB - The common octopus (Octopus vulgaris) is an attractive species for aquaculture, however, several challenges inhibit sustainable commercial production. Little is known about the early paralarval stages in the wild, including diet and intestinal microbiota, which likely play a significant role in development and vitality of this important life stage. High throughput sequencing was used to characterize the gastrointestinal microbiome of wild O. vulgaris paralarvae collected from two different upwelling regions off the coast of North West Spain (n = 41) and Morocco (n = 35). These were compared to that of paralarvae reared with Artemia for up to 25 days in captivity (n = 29). In addition, the gastrointestinal microbiome of zooplankton prey (crabs, copepod and krill) was also analyzed to determine if the microbial communities present in wild paralarvae are derived from their diet. Paralarvae reared in captivity with Artemia showed a depletion of bacterial diversity, particularly after day 5, when almost half the bacterial species present on day 0 were lost and two bacterial families (Mycoplasmataceae and Vibrionaceae) dominated the microbial community. In contrast, bacterial diversity increased in wild paralarvae as they developed in the oceanic realm of both upwelling systems, likely due to the exposure of new bacterial communities via ingestion of a wide diversity of prey. Remarkably, the bacterial diversity of recently hatched paralarvae in captivity was similar to that of wild paralarvae and zooplankton, thus suggesting a marked effect of the diet in both the microbial community species diversity and evenness. This study provides a comprehensive overview of the bacterial communities inhabiting the gastrointestinal tract of O. vulgaris paralarvae, and reveals new research lines to challenge the current bottlenecks preventing sustainable octopus aquaculture. PMID- 28620312 TI - Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma. AB - Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1) and monocarboxylate lactate transporter 1 (MCT-1). Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH). Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid) cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated. PMID- 28620314 TI - Orexin System: The Key for a Healthy Life. AB - The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides synthesized by a cluster of neurons in the lateral hypothalamus and perifornical area. Orexin neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire CNS. Orexin neurons are "multi-tasking" neurons regulating a set of vital body functions, including sleep/wake states, feeding behavior, energy homeostasis, reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic system may underlie different pathological conditions. A selective loss orexin neurons was found in narcolepsia, supporting the crucial role of orexins in maintaining wakefulness. In animal models, orexin deficiency lead to obesity even if the consume of calories is lower than wildtype counterpart. Reduced physical activity appears the main cause of weight gain in these models resulting in energy imbalance. Orexin signaling promotes obesity resistance via enhanced spontaneous physical activity and energy expenditure regulation and the deficiency/dysfunction in orexins system lead to obesity in animal models despite of lower calories intake than wildtype associated with reduced physical activity. Interestingly, orexinergic neurons show connections to regions involved in cognition and mood regulation, including hippocampus. Orexins enhance hippocampal neurogenesis and improve spatial learning and memory abilities, and mood. Conversely, orexin deficiency results in learning and memory deficits, and depression. PMID- 28620316 TI - Incidence and Antimicrobial Sensitivity Profiles of Normal Conjunctiva Bacterial Flora in the Central Area of China: A Hospital-Based Study. AB - Objective: To study the distribution and patterns of resistance to antimicrobial agents of normal conjunctival bacteria. Materials and Methods: Conjunctival specimens were collected from 8,224 patients and then cultured, which underwent antimicrobial susceptibility test following standard methods. Patients with infectious symptoms such as erythema or oedema and those using systemic or topical antibiotics within 1 month were excluded. Results: In this study, the incidence of isolated bacteria was 24.2%. The middle aged group of 41-65 years presented the lowest rate of bacterial isolation which was 19.4%, while the highest isolation rate (83.1%) was found in patients in the age range of 0-6 years. In every age group, the incidence of bacterial isolation in men was higher than that in women. The top 3 most commonly isolated micro-organisms were Staphylococcus epidermidis (39.7%), Streptococcus pneumoniae (4.5%), and Staphylococcus aureus (2.7%), of which about 83.1% S. aureus were isolated in the group of 0-6 years. We found that coagulase-negative Staphylococcus (CONS) were more resistant to penicillin, macrolides, clindamycin and sulfonamides with the rate ranging from 57.9 to 90.8%, which were highly susceptible to vancomycin, linezolid, rifampin, tetracyclines, and aminoglycosides. Contrasting to CONS, the general resistance rate of S. aureus was significantly lower. Additionally, Streptococcus was susceptible well to the majority of antimicrobial agents, while highly resistant to macrolides and tetracyclines with the rate >80%. Conclusions: In conclusion, our study revealed the incidence and antimicrobial sensitivity profiles of normal conjunctiva bacterial flora in the central area of China, which could be useful in the prevention of ocular infections. Importantly, our data could be used to guide the selection of appropriate prophylactic agents. PMID- 28620317 TI - Comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells. AB - Background : Hypoxia inducible factor 1 alpha (HIF1A) is a master regulator of acute hypoxia; however, with chronic hypoxia, HIF1A levels return to the normoxic levels. Importantly, the genes that are involved in the cell survival and viability under chronic hypoxia are not known. Therefore, we tested the hypothesis that chronic hypoxia leads to the upregulation of a core group of genes with associated changes in the promoter DNA methylation that mediates the cell survival under hypoxia. Results : We examined the effect of chronic hypoxia (3 days; 0.5% oxygen) on human brain micro endothelial cells (HBMEC) viability and apoptosis. Hypoxia caused a significant reduction in cell viability and an increase in apoptosis. Next, we examined chronic hypoxia associated changes in transcriptome and genome-wide promoter methylation. The data obtained was compared with 16 other microarray studies on chronic hypoxia. Nine genes were altered in response to chronic hypoxia in all 17 studies. Interestingly, HIF1A was not altered with chronic hypoxia in any of the studies. Furthermore, we compared our data to three other studies that identified HIF-responsive genes by various approaches. Only two genes were found to be HIF dependent. We silenced each of these 9 genes using CRISPR/Cas9 system. Downregulation of EGLN3 significantly increased the cell death under chronic hypoxia, whereas downregulation of ERO1L, ENO2, adrenomedullin, and spag4 reduced the cell death under hypoxia. Conclusions : We provide a core group of genes that regulates cellular acclimatization under chronic hypoxic stress, and most of them are HIF independent. PMID- 28620318 TI - Extraction Protocols for Individual Zebrafish's Ventricle Myosin and Skeletal Muscle Actin for In vitro Motility Assays. AB - The in vitro motility assay (IVMA) is a technique that enables the measurement of the interaction between actin and myosin providing a relatively simple model to understand the mechanical muscle function. For actin-myosin IVMA, myosin is immobilized in a measurement chamber, where it converts chemical energy provided by ATP hydrolysis into mechanical energy. The result is the movement of fluorescently labeled actin filaments that can be recorded microscopically and analyzed quantitatively. Resulting sliding speeds and patterns help to characterize the underlying actin-myosin interaction that can be affected by different factors such as mutations or active compounds. Additionally, modulatory actions of the regulatory proteins tropomyosin and troponin in the presence of calcium on actin-myosin interaction can be studied with the IVMA. Zebrafish is considered a suitable model organism for cardiovascular and skeletal muscle research. In this context, straightforward protocols for the isolation and use of zebrafish muscle proteins in the IVMA would provide a useful tool in molecular studies. Currently, there are no protocols available for the mentioned purpose. Therefore, we developed fast and easy protocols for characterization of zebrafish proteins in the IVMA. Our protocols enable the interested researcher to (i) isolate actin from zebrafish skeletal muscle and (ii) extract functionally intact myosin from cardiac and skeletal muscle of individual adult zebrafish. Zebrafish tail muscle actin is isolated after acetone powder preparation, polymerized, and labeled with Rhodamine-Phalloidin. Myosin from ventricles of adult zebrafish is extracted directly into IVMA flow-cells. The same extraction protocol is applicable for comparably small tissue pieces as from zebrafish tail, mouse and frog muscle. After addition of the fluorescently labeled F-actin from zebrafish or other origin-and ATP, sliding movement can be visualized using a fluorescence microscope and an intensified CCD camera. Taken together, we introduce a method for functional analysis in zebrafish cardiac and skeletal muscle research to study mutations at the molecular level of thick or thin filament proteins. Additionally, preliminary data indicate the usefulness of the presented method to perform the IVMA with myosin extracted from muscles of other animal models. PMID- 28620319 TI - Vascular Endothelial Growth Factor-B Induces a Distinct Electrophysiological Phenotype in Mouse Heart. AB - Vascular endothelial growth factor B (VEGF-B) is a potent mediator of vascular, metabolic, growth, and stress responses in the heart, but the effects on cardiac muscle and cardiomyocyte function are not known. The purpose of this study was to assess the effects of VEGF-B on the energy metabolism, contractile, and electrophysiological properties of mouse cardiac muscle and cardiac muscle cells. In vivo and ex vivo analysis of cardiac-specific VEGF-B TG mice indicated that the contractile function of the TG hearts was normal. Neither the oxidative metabolism of isolated TG cardiomyocytes nor their energy substrate preference showed any difference to WT cardiomyocytes. Similarly, myocyte Ca2+ signaling showed only minor changes compared to WT myocytes. However, VEGF-B overexpression induced a distinct electrophysiological phenotype characterized by ECG changes such as an increase in QRSp time and decreases in S and R amplitudes. At the level of isolated TG cardiomyocytes, these changes were accompanied with decreased action potential upstroke velocity and increased duration (APD60-70). These changes were partly caused by downregulation of sodium current (INa) due to reduced expression of Nav1.5. Furthermore, TG myocytes had alterations in voltage gated K+ currents, namely decreased density of transient outward current (Ito) and total K+ current (Ipeak). At the level of transcription, these were accompanied by downregulation of Kv channel-interacting protein 2 (Kcnip2), a known modulatory subunit for Kv4.2/3 channel. Cardiac VEGF-B overexpression induces a distinct electrophysiological phenotype including remodeling of cardiomyocyte ion currents, which in turn induce changes in action potential waveform and ECG. PMID- 28620320 TI - Abnormal Haemodynamic Flow Patterns in Bicuspid Pulmonary Valve Disease. AB - Abnormal flow patterns in the aortas of those with bicuspid aortic valves (BAVs) are increasingly recognized as important in the pathogenesis of aortic dilatation but pulmonary flow patterns in bicuspid pulmonary valves have not been studied. Bicuspid pulmonary valve disease is rare and a small numbers of case reports describe concomitant pulmonary artery dilation similar to the dilation of the ascending aorta, which is often seen in BAVs disease. We examined three cases of bicuspid pulmonary valve disease, 10 healthy volunteers and 10 patients with BAV disease but a tricuspid pulmonary valve. All participants underwent anatomical and functional imaging of the pulmonary valve, pulmonary artery, and right ventricle as well as advanced time-resolved 3-dimensional cardiac magnetic resonance imaging (4D flow) to assess the flow pattern in the pulmonary artery. All patients with a bicuspid pulmonary valve had pulmonary artery dilation and showed distinct helical flow abnormalities with increased rotational flow and increased flow displacement compared to a mild left-handed flow pattern in the healthy volunteers. Additionally, there was marked asymmetry seen in the systolic wall shear stress (WSS) pattern, with the highest values in the anterior wall of the pulmonary artery. In comparison, patients with a BAV but a tricuspid pulmonary valve had normal flow patterns in the pulmonary artery. These haemodynamic findings are similar to recent studies in bicuspid aortic disease, and suggest the importance of flow patterns in the pathophysiology of vessel dilation in both aortic and pulmonary bicuspid valve disease. PMID- 28620321 TI - Treating Posttraumatic Stress Disorder in Female Victims of Trafficking Using Narrative Exposure Therapy: A Retrospective Audit. AB - BACKGROUND: Human trafficking is a form of modern slavery that involves the forced movement of people internally within countries, or externally across borders. Victims who are trafficked for sexual exploitation are subject to repeated, multiple trauma, and high rates of mental health problems including posttraumatic stress disorder (PTSD) have been found. Narrative exposure therapy (NET) is an evidence-based treatment for PTSD. METHODS: In this retrospective audit, we record the results of NET to treat 10 women who had been trafficked for sexual exploitation who were diagnosed with PTSD. RESULTS: All 10 women completed the therapy and experienced a reduction in PTSD severity scores at posttreatment, with improvements that were maintained or further improved at 3-month follow-up. General distress was also significantly reduced following treatment. CONCLUSION: Although limited by sample size and retrospective design, this audit demonstrates that NET is a feasible treatment for PTSD in this population and warrants further evaluation in a randomized controlled trial. Further adjunctive interventions may also be necessary to treat the additional psychological problems experienced by this population. PMID- 28620322 TI - The Relationship of Complex Post-traumatic Stress Disorder and Post-traumatic Stress Disorder in a Culturally Distinct, Conflict-Affected Population: A Study among West Papuan Refugees Displaced to Papua New Guinea. AB - BACKGROUND: Controversy continues about the validity of the construct of complex post-traumatic stress disorder (C-PTSD). In particular, questions remain whether C-PTSD can be differentiated from post-traumatic stress disorder (PTSD) and, secondarily, other common mental disorders. The examination of these issues needs to be expanded to populations of diverse cultural backgrounds exposed to prolonged persecution. We undertake such an inquiry among a community sample of West Papuan refugees exposed to extensive persecution and trauma. METHODS: We interviewed over 300 West Papuan refugees using the Refugee-Mental Health Assessment Package to record symptoms of PTSD, C-PTSD, major depressive disorder (MDD), and complex grief (CG). We used first- and second-order confirmatory factor analysis (CFA) to test aspects of the convergent and discriminant validity of C-PTSD. RESULTS: The CFA analysis supported both a one-factor and two-factor model of PTSD and C-PTSD. Nested model comparison tests provide support for the parsimonious one-factor model solution. A second-order CFA model of PTSD and C PTSD produced a poor fit. The modified three-factor multi-disorder solution combining a traumatic stress (TS) factor (amalgamating PTSD and C-PTSD), MDD, and CG yielded a good fit only after removing three CG domains (estrangement, yearning, and behavioral change), a model that produced large standardized residuals (>0.20). CONCLUSION: The most parsimonious model yielded a single TS factor combining symptom domains of C-PTSD and PTSD in this culturally distinct community exposed to extensive persecution and conflict-related trauma. There may be grounds for expanding the scope of psychological treatments for refugees to encompass this wider TS response. Our findings are consistent with theoretical frameworks focusing on the wider TS reaction of refugees exposed to human rights related traumas of mass conflict, persecution, and displacement. PMID- 28620323 TI - Integrated Trauma-Focused Cognitive-Behavioural Therapy for Post-traumatic Stress and Psychotic Symptoms: A Case-Series Study Using Imaginal Reprocessing Strategies. AB - Despite high rates of trauma in individuals with psychotic symptoms, post traumatic stress symptoms are frequently overlooked in clinical practice. There is also reluctance to treat post-traumatic symptoms in case the therapeutic procedure of reprocessing the trauma exacerbates psychotic symptoms. Recent evidence demonstrates that it is safe to use reprocessing strategies in this population. However, most published studies have been based on treating post traumatic symptoms in isolation from psychotic symptoms. The aims of the current case series were to assess the acceptability, feasibility, and preliminary effectiveness of integrating cognitive-behavioural approaches for post-traumatic stress and psychotic symptoms into a single protocol. Nine participants reporting distressing psychotic and post-traumatic symptoms were recruited from a specialist psychological therapies service for psychosis. Clients were assessed at five time points (baseline, pre, mid, end of therapy, and at 6+ months of follow-up) by an independent assessor on measures of current symptoms of psychosis, post-traumatic stress, emotional problems, and well-being. Therapy was formulation based and individualised, depending on presenting symptoms and trauma type. It consisted of five broad, flexible phases, and included imaginal reprocessing strategies (reliving and/or rescripting). The intervention was well received, with positive post-therapy feedback and satisfaction ratings. Unusually for this population, no-one dropped out of therapy. Post therapy, all but one (88% of participants) achieved a reliable improvement compared to pre-therapy on at least one outcome measure: post-traumatic symptoms (63%), voices (25%), delusions (50%), depression (50%), anxiety (36%), and well-being (40%). Follow-up assessments were completed by 78% (n = 7) of whom 86% (n = 6) maintained at least one reliable improvement. Rates of improvements following therapy (average of 44% across measures post therapy; 32% at follow-up) were over twice those found during the waiting list period (19%). No participant indicated a reliable worsening of any symptoms during or after therapy. The study shows that an integrative therapy incorporating reprocessing strategies was an acceptable and feasible intervention for this small sample, with promising effectiveness. A randomised controlled trial is warranted to test the efficacy of the intervention for this population. PMID- 28620324 TI - Description of Various Factors Contributing to Traffic Accidents in Youth and Measures Proposed to Alleviate Recurrence. AB - Traffic accidents are the leading cause of hospitalization in adolescence, with the 18-24-year-old age group accounting for 23% of deaths by traffic accidents. Recurrence rate is also high. One in four teenagers will have a relapse within the year following the first accident. Cognitive impairments known in adolescence could cause risky behaviors, defined as repetitive engagement in dangerous situations such as road accidents. Two categories of factors seem to be associated with traffic accidents: (1) factors specific to the traffic environment and (2) "human" factors, which seem to be the most influential. Moreover, the establishment of a stronger relation to high speed driving increases traffic accident risks and can also be intensified by sensation seeking. Other factors such as substance use (alcohol, drugs, and "binge drinking") are also identified as risk factors. Furthermore, cell phone use while driving and attention deficit disorder with or without hyperactivity also seem to be important risk factors for car accidents. The family environment strongly influences a young person's driving behavior. Some interventional driving strategies and preventive measures have reduced the risk of traffic accidents among young people, such as the graduated driver licensing program and advertising campaigns. So far, few therapeutic approaches have been implemented. Reason why, we decided to set up an innovative strategy consisting of a therapeutic postaccident group intervention, entitled the ECARR2 protocol, to prevent recurrence among adolescents and young adults identified at risk, taking into account the multiple risk factors. PMID- 28620325 TI - Reduced Consolidation, Reinstatement, and Renewal of Conditioned Fear Memory by Repetitive Treatment of Radix Polygalae in Mice. AB - The therapeutic goal for the treatment of posttraumatic stress disorder (PTSD) is to promote extinction and to prevent the relapse of fearful memories. Research has identified pharmacological treatments that may regulate the formation and extinction of fear memories, but not many reagents that block the relapse of extinguished fear are known. Radix Polygalae (RP) is an Asian herb used for sedation, and its ingredients have anxiolytic and antidepressant properties. As various neurological effects have been identified, we tested whether RP affects the relapse of fear. Freezing in response to a conditioned context and cues was used to measure the effects of RP in mice. In cohort 1 (n = 30), consolidation, extinction, and reinstatement were tested during the course of 18 days of treatment. In cohort 2 (n = 30), consolidation, extinction, and renewal were tested during 10 days of treatment. The consolidation, extinction, reinstatement, and possibly the renewal of context-induced freezing were inhibited due to the administration of RP in animal subjects. However, the effects of RP on the freezing responses of subjects elicited by conditioned auditory cues were less obvious. Because it effectively suppresses the consolidation of fear memories, RP may be used for primary and secondary prevention of symptoms in PTSD patients. Additionally, because it effectively suppresses the reinstatement and renewal of fear memories, RP may be applied for the prevention of fear relapse in PTSD patients who have undergone exposure therapy. PMID- 28620326 TI - Thought Control Ability Is Different from Rumination in Explaining the Association between Neuroticism and Depression: A Three-Study Replication. AB - Neuroticism is the most common vulnerability factor of depression. However, the mechanism underlying this vulnerability is still unclear. Previous studies suggested that rumination intensifies the negative effect of neuroticism on depression. However, whether cognitive control could explain the association between neuroticism and depression remains unclear to date. Therefore, this study evaluated the indirect effects of rumination and thought control on the relationship between neuroticism and depression. Seven self-report measures were employed among healthy and main depression disorder (MDD) participants. Three studies were used to examine the hypotheses. Results of the three studies showed significant correlations among neuroticism, rumination, thought control, and depression. Rumination mediated the link between neuroticism and depression among healthy young adults, and this finding replicated previous studies. This study provided new evidence that thought control mediates the association between neuroticism and depression in both healthy and MDD populations. In conclusion, rumination increases neuroticism risk for depression, but high-level thought control decreases the effect of neuroticism on depression. This study may serve as a reference to develop effective and focused interventions for MDD patients. PMID- 28620327 TI - Scale of Death Anxiety (SDA): Development and Validation. AB - This study developed and validated a new measure to assess the death anxiety (i.e., Scale of Death Anxiety, SDA) on an individual's somatic, cognitive, emotional, and behavioral reactions from a symptomatic perspective in Chinese youth samples. Following a systematic process, a four-factor structure of the SDA was identified through principle components analysis and confirmatory factor analysis that revealed four aspects of death anxiety: Dysphoria, Death Intrusion, Fear of Death, and Avoidance of Death. The results of this study indicate that the SDA has a clear factor structure and good psychometric properties. The SDA supports death anxiety as a multidimensional construct, and the foundational role of fear of death in the generation of death anxiety. This scale is valuable and beneficial to research on death anxiety. This study makes a significant contribution to the literature because the SDA is the first assessment of death anxiety to include the constructs of dysphoria and somatic symptoms. And the potential clinical practice of the SDA was discussed. PMID- 28620328 TI - Motivation Counts: Autonomous But Not Obligated Sharing Promotes Happiness in Preschoolers. AB - Research has demonstrated that prosocial sharing is emotionally rewarding, which leads to further prosocial actions; such a positive feedback loop suggests a proximal mechanism of human's tendency to act prosocially. However, it leaves open a question as to how the emotional benefits from sharing develop in young children and whether sharing under pressure promotes happiness as well. The current study directly compared 3- and 5-year-old Chinese children's happiness when sharing was autonomous (the recipient did not contribute to getting the reward) with when sharing was obligated (the recipient and the actor jointly earned the reward). We found that children shared more items overall when sharing was obligated than autonomous, demonstrating their conformity to social norms of merit-based sharing. In children who eventually shared with others, 5-year-olds gave out more stickers in the obligated sharing condition than in the autonomous sharing condition, but 3-year-olds shared the same amount between the conditions, suggesting that 5-year-olds adhered to the merit-based sharing norm more strictly than 3-year-olds. Moreover, in the autonomous sharing condition, children displayed greater happiness when they shared with the recipient than when they kept stickers for themselves, suggesting that costly prosocial giving benefited children with positive mood; however, children did not gain happiness when they shared with the recipient in the obligated sharing condition. These findings demonstrate that children's affective benefits depend on the motivation underlying their prosocial behavior, and further imply that normative force and emotional gains may independently drive preschoolers' prosocial behaviors. PMID- 28620329 TI - Job Satisfaction, Retirement Attitude and Intended Retirement Age: A Conditional Process Analysis across Workers' Level of Household Income. AB - In the contemporary workplace, insight into retirement behaviors is of crucial importance. Previous empirical evidence has found mixed results regarding the relationship between work attitudes, such as job satisfaction, and retirement behaviors, suggesting that further scholarly examination incorporating moderating and mediating variables into retirement models is needed. Drawing on comparative models of attitude to retirement, we hypothesized a direct relationship between job satisfaction and intended retirement age for workers with a high household income and an indirect relationship between job satisfaction and intended retirement age, via retirement attitude, for workers with a low or mean household income. We collected data from a sample of 590 United Kingdom workers aged 50+. Using conditional process analysis, we found that the underlying mechanisms in our research model differ according to socio-economic status. We found no direct effect between job satisfaction and intended retirement age. However, an indirect effect was observed between job satisfaction and intended retirement age, via retirement attitude, for both low- and mean-household income individuals. Specifically, the relationship between job satisfaction and retirement attitude differed according to socio-economic group: for high-household income older workers, there was no relationship between job satisfaction and retirement attitude. However, for low- and mean-household income older workers, we observed a negative relationship between job satisfaction and retirement attitude. Otherwise stated, increases in job satisfaction for mean and low household income workers are likely to make the prospect of retirement less attractive. Therefore, we argue that utmost care must be taken around the conditions under which lower income employees will continue their work when getting older in order to protect their sustainable employability. PMID- 28620330 TI - Can I Work with and Help Others in This Field? How Communal Goals Influence Interest and Participation in STEM Fields. AB - Although science, technology, engineering, and mathematics (STEM) disciplines as a whole have made advances in gender parity and greater inclusion for women, these increases have been smaller or nonexistent in computing and engineering compared to other fields. In this focused review, we discuss how stereotypic perceptions of computing and engineering influence who enters, stays, and excels in these fields. We focus on communal goal incongruity-the idea that some STEM disciplines like engineering and computing are perceived as less aligned with people's communal goals of collaboration and helping others. In Part 1, we review the empirical literature that demonstrates how perceptions that these disciplines are incongruent with communal goals can especially deter women and girls, who highly endorse communal goals. In Part 2, we extend this perspective by reviewing accumulating evidence that perceived communal goal incongruity can deter any individual who values communal goals. Communal opportunities within computing and engineering have the potential to benefit first generation college students, underrepresented minority students, and communally-oriented men (as well as communally-oriented women). We describe the implications of this body of literature: describing how opting out of STEM in order to pursue fields perceived to encourage the pursuit of communal goals leave the stereotypic (mis)perceptions of computing and engineering unchanged and exacerbate female underrepresentation. In Part 3, we close with recommendations for how communal opportunities in computing and engineering can be highlighted to increase interest and motivation. By better integrating and publically acknowledging communal opportunities, the stereotypic perceptions of these fields could gradually change, making computing and engineering more inclusive and welcoming to all. PMID- 28620331 TI - ViDa1: The Development and Validation of a New Questionnaire for Measuring Health Related Quality of Life in Patients with Type 1 Diabetes. AB - This study describes the development of a new questionnaire to measure health related quality of life (HRQoL) in patients with type 1 diabetes (the ViDa1 questionnaire) and provides information on its psychometric properties. For its development, open interviews with patients took place and topics relevant to patients' HRQoL were identified and items were generated. Qualitative analysis of items, expert review, and refinement of the questionnaire followed. A pilot study (N = 150) was conducted to explore the underlying structure of the 40-item ViDa1 questionnaire. A Principal Component Analysis (PCA) was performed and six of the items that did not load on any of the factors were eliminated. The results supported a four-dimensional structure for ViDa1, the dimensions being Interference of diabetes in everyday life, Self-care, Well-being, and Worry about the disease. Subsequently, the PCA was repeated in a larger sample (N = 578) with the reduced 34-item version of the questionnaire, and a Confirmatory Factor Analysis (CFA) was performed (N = 428). Overall fit indices obtained presented adequate values which supported the four-factor model initially proposed [([Formula: see text] 2601.93) (p < 0.001); Root Mean Square Error of Approximation = 0.060 (CI = 0.056 -0.064)]. As regards reliability, the four dimensions of the ViDa1 demonstrated good internal consistency, with Cronbach's alphas ranging between 0.71 and 0.86. Evidence of convergent-discriminant validity in the form of high correlations with another specific HRQoL questionnaire for diabetes and low correlations with other constructs such as self-efficacy, anxiety, and depression were presented. The ViDa1 also discriminated between different aspects of clinical interest such as type of insulin treatment, presence of chronic complications, and glycemic control, temporal stability, and sensitivity to change after an intervention. In conclusion, the ViDa1 questionnaire presents adequate psychometric properties and may represent a good alternative for the evaluation of HRQoL in type 1 diabetes. PMID- 28620332 TI - Combinations of Personal Responsibility: Differences on Pre-service and Practicing Teachers' Efficacy, Engagement, Classroom Goal Structures and Wellbeing. AB - Pre-service and practicing teachers feel responsible for a range of educational activities. Four domains of personal responsibility emerging in the literature are: student achievement, student motivation, relationships with students, and responsibility for ones own teaching. To date, most research has used variable centered approaches to examining responsibilities even though the domains appear related. In two separate samples we used cluster analysis to explore how pre service (n = 130) and practicing (n = 105) teachers combined personal responsibilities and their impact on three professional cognitions and their wellbeing. Both groups had low and high responsibility clusters but the third cluster differed: Pre-service teachers combined responsibilities for relationships and their own teaching in a cluster we refer to as teacher-based responsibility; whereas, practicing teachers combined achievement and motivation in a cluster we refer to as student-outcome focused responsibility. These combinations affected outcomes for pre-service but not practicing teachers. Pre service teachers in the low responsibility cluster reported less engagement, less mastery approaches to instruction, and more performance goal structures than the other two clusters. PMID- 28620333 TI - The Role of Perceived In-group Moral Superiority in Reparative Intentions and Approach Motivation. AB - Three studies examined how members of a national group react to in-group wrongdoings. We expected that perceived in-group moral superiority would lead to unwillingness to repair the aggression. We also expected that internal-focused emotions such as group-based guilt and group-based shame would predict specific, misdeed-related reparative intentions but not general approach motivation toward the victim groups. In Study 1, facing the in-group's recent aggression, participants who believed that the Hungarians have been more moral throughout their history than members of other nations, used more exonerating cognitions, experienced less in-group critical emotions and showed less willingness to provide reparations for the members of the victim group. Study 2 and Study 3 confirmed most findings of Study 1. Perceived in-group moral superiority directly or indirectly reduced willingness to provide either general or specific reparations, while internally focused in-group critical emotions predicted specific misdeed-related reparative intentions but not general approach motivation. The role of emotional attachment to the in-group is considered. PMID- 28620334 TI - Longitudinal Relationship between Self-efficacy and Posttraumatic Stress Symptoms 8 Years after a Violent Assault: An Autoregressive Cross-Lagged Model. AB - Self-efficacy is assumed to promote posttraumatic adaption, and several cross sectional studies support this notion. However, there is a lack of prospective longitudinal studies to further illuminate the temporal relationship between self efficacy and posttraumatic stress symptoms. Thus, an important unresolved research question is whether posttraumatic stress disorder (PTSD) symptoms affect the level of self-efficacy or vice versa or whether they mutually influence each other. The present prospective longitudinal study investigated the reciprocal relationship between general self-efficacy (GSE) and posttraumatic stress symptoms in 143 physical assault victims. We used an autoregressive cross-lagged model across four assessment waves: within 4 months after the assault (T1) and then 3 months (T2), 12 months (T3) and 8 years (T4) after the first assessment. Stress symptoms at T1 and T2 predicted subsequent self-efficacy, while self efficacy at T1 and T2 was not related to subsequent stress symptoms. These relationships were reversed after T3; higher levels of self-efficacy at T3 predicted lower levels of posttraumatic stress symptoms at T4, while posttraumatic tress symptoms at T3 did not predict self-efficacy at T4. In conclusion, posttraumatic stress symptoms may have a deteriorating effect on self efficacy in the early phase after physical assault, whereas self-efficacy may promote recovery from posttraumatic stress symptoms over the long term. PMID- 28620335 TI - A Different Way to Stay in Touch with 'Urban Nature': The Perceived Restorative Qualities of Botanical Gardens. AB - Botanical gardens represent interesting arenas for research in environmental psychology and environment-behavior relations. They can be considered a very particular type of restorative environment and also have a relevant social function for the promotion of a more sustainable lifestyle in current societies. In this paper, we present a study assessing the relationship between the perceived restorativeness, the psychological and physical benefits experienced, and the subjective well-being reported by visitors of botanical gardens in four different cities in Italy (N = 127). As expected, a bootstrapping mediation model supported the idea that perceived restorativeness of botanical gardens significantly predicts visitors' subjective well-being, both directly and indirectly through perceived physical and psychological benefits of the visit. A moderation model also revealed that the relationship between restorativeness and well-being varies across respondents with different socio-demographic characteristics, being stronger for singles as compared to couples with and without children, respectively. The theoretical and practical implications of these findings are discussed. PMID- 28620336 TI - How to Trick Your Opponent: A Review Article on Deceptive Actions in Interactive Sports. AB - Performing deceptive actions is a wide-spread phenomenon in sports and it is of considerable practical relevance to know whether or not a fake or a disguised action decreases the opponents' performance. Therefore, research on deceptive actions for various sport disciplines (e.g., cricket, rugby, martial arts, soccer, and basketball) has been conducted. This research is scattered, both across time and scientific disciplines. Here, we aim to systematically review the empirical work on deceptive actions in interactive sports and want to give an overview about several issues investigated in the last decades. Three main topics of the detected literature were discussed here: (1) the role of expertise for the recognition of deceptive actions, (2) the cognitive mechanisms underlying the processing of deceptive actions, and (3) the pros and cons of in situ research designs. None of these themes seems to be settled and therefore, they should be considered in future research agendas. PMID- 28620337 TI - The Acute Effects of Exercise Intensity on Inhibitory Cognitive Control in Adolescents. AB - Adolescence is an important stage for brain maturation. There are many studies of exercise-cognition relations, but there is still a lack of knowledge about the impact of combining different intensities of exercise on adolescents' cognitive responses. The main objective of this study was to analyze the effect of three physical education sessions (based on Zumba dance) of different intensities (no exercise, predominantly light intensity, and predominantly vigorous intensity) on the inhibition response (measured with the Stroop test) in adolescents. Forty four adolescent students (age 16.39 +/- 0.68) completed a Stroop test before and after the three different physical education sessions. The results show than the predominantly vigorous session represented the strongest stimulus to increase cognitive inhibitory control. This means that the cognitive effect of exercise can be conditioned by exercise intensity and implies the need to control exercise intensity in physical educational programs for adolescents. PMID- 28620338 TI - Worry and Metacognitions as Predictors of Anxiety Symptoms: A Prospective Study. AB - Both worry and metacognitive beliefs have been found to be related to the development of anxiety, but metacognitive theory (Wells and Matthews, 1994; Wells, 2009) suggest that metacognitive beliefs may play a more prominent role. The aim of the present prospective study was to examine whether worry, metacognitive beliefs or the interaction between worry and metacognitive beliefs, were the best predictor of anxiety over time, utilizing a longitudinal, prospective study design. An undergraduate student sample (N = 190) was assessed on measures of worry (PSWQ), metacognitive beliefs (MCQ-30) and anxiety (BAI) at three points in time over a 7-month period. A mixed-model analysis revealed that both worry and metacognitive beliefs predicted development of anxiety, independently of each other, with no indication of an interaction-effect (PSWQ * MCQ-30). Further, analyses of the MCQ-30 subscales indicated that negative metacognitive beliefs may be particularly important in the development of anxiety. While gender was correlated with worry, gender predicted anxiety beyond the effect of worry. Taken together, the results imply that both worry and metacognitive beliefs play a prominent role for the development of anxiety. PMID- 28620340 TI - A New Questionnaire for Estimating the Severity of Visual Height Intolerance and Acrophobia by a Metric Interval Scale. AB - AIMS: To construct and validate a short scale for the assessment of the severity of visual height intolerance (vHI) and acrophobia. METHODS: The questionnaire was developed from two earlier representative epidemiological studies (n = 5,529). Items were applied in a telephone survey of a representative population-based sample. RESULTS: A total of 1,960 persons were included. The life-time prevalence of vHI was 32.7% (f: 36.1%; m: 28.4%); 12% of these persons fulfilled the psychiatric criteria of acrophobia. Rasch analysis of 11 items on severity, symptoms, and triggers resulted in an 8-item scale with good fit to the model. The score differentiated well between persons with and without acrophobia. The distribution of the scores on the metric scale of the questionnaires of those individuals with acrophobia is separate and distinct from that of susceptibles without acrophobia, although there is some overlap. CONCLUSION: Our proposed short questionnaire (vHISS, see Table 1 and Supplementary Material) allows a continuous quantification of the severity of vHI within a metric interval scale from 0 to 13. The diagnosis of acrophobia can be established by including two additional questions. PMID- 28620339 TI - The Stress Acceleration Hypothesis of Nightmares. AB - Adverse childhood experiences can deleteriously affect future physical and mental health, increasing risk for many illnesses, including psychiatric problems, sleep disorders, and, according to the present hypothesis, idiopathic nightmares. Much like post-traumatic nightmares, which are triggered by trauma and lead to recurrent emotional dreaming about the trauma, idiopathic nightmares are hypothesized to originate in early adverse experiences that lead in later life to the expression of early memories and emotions in dream content. Accordingly, the objectives of this paper are to (1) review existing literature on sleep, dreaming and nightmares in relation to early adverse experiences, drawing upon both empirical studies of dreaming and nightmares and books and chapters by recognized nightmare experts and (2) propose a new approach to explaining nightmares that is based upon the Stress Acceleration Hypothesis of mental illness. The latter stipulates that susceptibility to mental illness is increased by adversity occurring during a developmentally sensitive window for emotional maturation-the infantile amnesia period-that ends around age 31/2. Early adversity accelerates the neural and behavioral maturation of emotional systems governing the expression, learning, and extinction of fear memories and may afford short-term adaptive value. But it also engenders long-term dysfunctional consequences including an increased risk for nightmares. Two mechanisms are proposed: (1) disruption of infantile amnesia allows normally forgotten early childhood memories to influence later emotions, cognitions and behavior, including the common expression of threats in nightmares; (2) alterations of normal emotion regulation processes of both waking and sleep lead to increased fear sensitivity and less effective fear extinction. These changes influence an affect network previously hypothesized to regulate fear extinction during REM sleep, disruption of which leads to nightmares. This network consists of a fear circuit that includes amygdala, hippocampus, and medial prefrontal cortex and whose substantial overlap with the stress acceleration findings allows the latter to be incorporated into a wider, more developmentally coherent framework. PMID- 28620342 TI - Challenges for Service Robots-Requirements of Elderly Adults with Cognitive Impairments. AB - OBJECTIVE: We focused on identifying the requirements and needs of people suffering from Alzheimer disease and early dementia stages with relation to robotic assistants. METHODS: Based on focus groups performed in two centers (Poland and Spain), we created surveys for medical staff, patients, and caregivers, including: functional requirements; human-robot interaction, the design of the robotic assistant and user acceptance aspects. Using Likert scale and analysis made on the basis of the frequency of survey responses, we identified users' needs as high, medium, and low priority. RESULTS: We gathered 264 completed surveys (100 from medical staff, 81 from caregivers, and 83 from potential users). Most of the respondents, almost at the same level in each of the three groups, accept robotic assistants and their support in everyday life. High level priority functional requirements were related to reacting in emergency situations (calling for help, detecting/removing obstacles) and to reminding about medication intake, about boiling water, turning off the gas and lights (almost 60% of answers). With reference to human-robot interaction, high priority was given to voice operated system and the capability of robotic assistants to reply to simple questions. CONCLUSION: Our results help in achieving better understanding of the needs of patients with cognitive impairments during home tasks in everyday life. This way of conducting the research, with considerations for the interests of three stakeholder groups in two autonomic centers with proven experience regarding the needs of our patient groups, highlights the importance of obtained results. PMID- 28620343 TI - International Differences in Multiple Sclerosis Health Outcomes and Associated Factors in a Cross-sectional Survey. AB - Multiple sclerosis (MS) is a major cause of disability and poor quality of life (QOL). Previous studies have shown differences in MS health outcomes between countries. This study aimed to examine the associations between international regions and health outcomes in people with MS. Self-reported data were taken from the Health Outcomes and Lifestyle In a Sample of people with Multiple Sclerosis online survey collected in 2012. The 2,401 participants from 37 countries were categorized into three regions: Australasia, Europe, and North America. Differences were observed between regions in disability, physical and mental health QOL, fatigue, and depression, but most of these disappeared after adjusting for sociodemographic, disease, and lifestyle factors in multivariable regression models. However, adjusted odds for disability were higher in Europe [odds ratio (OR): 2.17, 95% confidence interval (CI): 1.28 to 3.67] and North America (OR: 1.79, 95% CI: 1.28 to 2.51) compared to Australasia. There may be other unmeasured factors that vary between regions, including differences in access and quality of healthcare services, determining disability in MS. When assessing differences in MS health outcomes, lifestyle factors and medication use should be taken into consideration. PMID- 28620344 TI - The Role of Osteopontin and Its Gene on Glucocorticoid Response in Myasthenia Gravis. AB - Biomarkers that assess treatment response for patients with the autoimmune disorder, myasthenia gravis (MG), have not been evaluated to a significant extent. We hypothesized the pro-inflammatory cytokine, osteopontin (OPN), may be associated with variability of response to glucocorticoids (GCs) in patients with MG. A cohort of 250 MG patients treated with standardized protocol of GCs was recruited, and plasma OPN and polymorphisms of its gene, secreted phosphoprotein 1 (SPP1), were evaluated. Mean OPN levels were higher in patients compared to healthy controls. Carriers of rs11728697*T allele (allele definition: one of two or more alternative forms of a gene) were more frequent in the poorly GC responsive group compared to the GC responsive group indicating an association of rs11728697*T allele with GC non-responsiveness. One risk haplotype (AGTACT) was identified associated with GC non-responsiveness compared with GC responsive MG group. Genetic variations of SPP1 were found associated with the response to GC among MG patients. PMID- 28620345 TI - Memory for Spatial Locations in a Patient with Near Space Neglect and Optic Ataxia: Involvement of the Occipitotemporal Stream. AB - Previous studies suggested that the occipitoparietal stream orients attention toward the near/lower space and is involved in immediate reaching, whereas the occipitotemporal stream orients attention toward the far/upper space and is involved in delayed reaching. In the present study, we investigated the role of the occipitotemporal stream in attention orienting and delayed reaching in a patient (GP) with bilateral damage to the occipitoparietal areas and optic ataxia. GP and healthy controls took part in three experiments. In the experiment 1, the participants bisected lines oriented along radial, vertical, and horizontal axes. GP bisected radial lines farther, and vertical lines more above, than the controls, consistent with an attentional bias toward the far/upper space and near/lower space neglect. The experiment 2 consisted of two tasks: (1) an immediate reaching task, in which GP reached target locations under visual control and (2) a delayed visual reaching task, in which GP and controls were asked to reach remembered target locations visually presented. We measured constant and variable distance and direction errors. In immediate reaching task, GP accurately reached target locations. In delayed reaching task, GP overshot remembered target locations, whereas the controls undershot them. Furthermore, variable errors were greater in GP than in the controls. In the experiment 3, GP and controls performed a delayed proprioceptive reaching task. Constant reaching errors did not differ between GP and the controls. However, variable direction errors were greater in GP than in the controls. We suggest that the occipitoparietal damage, and the relatively intact occipitotemporal region, produced in GP an attentional orienting bias toward the far/upper space (experiment 1). In turns, the attentional bias selectively shifted toward the far space remembered visual (experiment 2), but not proprioceptive (experiment 3), target locations. As a whole, these findings further support the hypothesis of an involvement of the occipitotemporal stream in delayed reaching. Furthermore, the observation that in both delayed reaching tasks the variable errors were greater in GP than in the controls suggested that in optic ataxia is present not only a visuo- but also a proprioceptivo-motor integration deficit. PMID- 28620341 TI - The Intersection between Ocular and Manual Motor Control: Eye-Hand Coordination in Acquired Brain Injury. AB - Acute and chronic disease processes that lead to cerebral injury can often be clinically challenging diagnostically, prognostically, and therapeutically. Neurodegenerative processes are one such elusive diagnostic group, given their often diffuse and indolent nature, creating difficulties in pinpointing specific structural abnormalities that relate to functional limitations. A number of studies in recent years have focused on eye-hand coordination (EHC) in the setting of acquired brain injury (ABI), highlighting the important set of interconnected functions of the eye and hand and their relevance in neurological conditions. These experiments, which have concentrated on focal lesion-based models, have significantly improved our understanding of neurophysiology and underscored the sensitivity of biomarkers in acute and chronic neurological disease processes, especially when such biomarkers are combined synergistically. To better understand EHC and its connection with ABI, there is a need to clarify its definition and to delineate its neuroanatomical and computational underpinnings. Successful EHC relies on the complex feedback- and prediction mediated relationship between the visual, ocular motor, and manual motor systems and takes advantage of finely orchestrated synergies between these systems in both the spatial and temporal domains. Interactions of this type are representative of functional sensorimotor control, and their disruption constitutes one of the most frequent deficits secondary to brain injury. The present review describes the visually mediated planning and control of eye movements, hand movements, and their coordination, with a particular focus on deficits that occur following neurovascular, neurotraumatic, and neurodegenerative conditions. Following this review, we also discuss potential future research directions, highlighting objective EHC as a sensitive biomarker complement within acute and chronic neurological disease processes. PMID- 28620346 TI - Primary Progressive Multiple Sclerosis: Putting Together the Puzzle. AB - The focus of multiple sclerosis research has recently turned to the relatively rare and clearly more challenging condition of primary progressive multiple sclerosis (PPMS). Many risk factors such as genetic susceptibility, age, and Epstein-Barr virus (EBV) infection may interdepend on various levels, causing a complex pathophysiological cascade. Variable pathological mechanisms drive disease progression, including inflammation-associated axonal loss, continuous activation of central nervous system resident cells, such as astrocytes and microglia as well as mitochondrial dysfunction and iron accumulation. Histological studies revealed diffuse infiltration of the gray and white matter as well as of the meninges with inflammatory cells such as B-, T-, natural killer, and plasma cells. While numerous anti-inflammatory agents effective in relapsing remitting multiple sclerosis basically failed in treatment of PPMS, the B-cell-depleting monoclonal antibody ocrelizumab recently broke the dogma that PPMS cannot be treated by an anti-inflammatory approach by demonstrating efficacy in a phase 3 PPMS trial. Other treatments aiming at enhancing remyelination (MD1003) as well as EBV-directed treatment strategies may be promising agents on the horizon. In this article, we aim to summarize new advances in the understanding of risk factors, pathophysiology, and treatment of PPMS. Moreover, we introduce a novel concept to understand the nature of the disease and possible treatment strategies in the near future. PMID- 28620348 TI - The Utility of FDG-PET/CT in Clinically Suspected Paraneoplastic Neurological Syndrome: A Literature Review and Retrospective Case Series. AB - Paraneoplastic neurological syndrome (PNS) describes a spectrum of rare, heterogeneous neurological conditions associated with an underlying malignancy. Diagnosis of PNS is inherently difficult, with frequent misdiagnosis and delay. The literature suggests an underlying immune-mediated pathophysiology, and patients are usually tested for the presence of onconeural antibodies. With direct tumor therapy being the most effective method of stabilizing patients, there is a strong emphasis on detecting underlying tumors. The sensitivity of conventional CT imaging is often inadequate in such patients. While FDG-PET imaging has already been shown to be effective at detecting these tumors, FDG PET/CT, combining both structural and functional imaging in a single study, is a more recent technique. To study the utility of FDG-PET/CT, we conducted a systematic literature review and a retrospective study. We identified 41 patients who underwent imaging for clinically suspected PNS at the regional PET-CT and neurosciences center based at the Royal Preston Hospital between 2007 and 2014 and compared the results to conventional investigations. Five patients had FDG PET/CT tracer avidity suspicious of malignant disease, and four of these were subsequently diagnosed with cancer. Sensitivity and specificity were calculated to be 100 and 97.3%, respectively, with positive predictive value 80% and negative predictive value 100%. This compares to a sensitivity and specificity of 50 and 100%, respectively, for CT and 50 and 89%, respectively, for onconeural antibodies. These findings are in line with previous studies and support the diagnostic accuracy of FDG-PET/CT for the detection of underlying malignancy. PMID- 28620347 TI - Neural Consequences of Chronic Short Sleep: Reversible or Lasting? AB - Approximately one-third of adolescents and adults in developed countries regularly experience insufficient sleep across the school and/or work week interspersed with weekend catch up sleep. This common practice of weekend recovery sleep reduces subjective sleepiness, yet recent studies demonstrate that one weekend of recovery sleep may not be sufficient in all persons to fully reverse all neurobehavioral impairments observed with chronic sleep loss, particularly vigilance. Moreover, recent studies in animal models demonstrate persistent injury to and loss of specific neuron types in response to chronic short sleep (CSS) with lasting effects on sleep/wake patterns. Here, we provide a comprehensive review of the effects of chronic sleep disruption on neurobehavioral performance and injury to neurons, astrocytes, microglia, and oligodendrocytes and discuss what is known and what is not yet established for reversibility of neural injury. Recent neurobehavioral findings in humans are integrated with animal model research examining long-term consequences of sleep loss on neurobehavioral performance, brain development, neurogenesis, neurodegeneration, and connectivity. While it is now clear that recovery of vigilance following short sleep requires longer than one weekend, less is known of the impact of CSS on cognitive function, mood, and brain health long term. From work performed in animal models, CSS in the young adult and short-term sleep loss in critical developmental windows can have lasting detrimental effects on neurobehavioral performance. PMID- 28620349 TI - Localization of Deep Brain Stimulation Contacts Using Corticospinal/Corticobulbar Tracts Stimulation. AB - BACKGROUND: Successful deep brain stimulation (DBS) in Parkinson's disease (PD) requires optimal electrode placement. One technique of intraoperative electrode testing is determination of stimulation thresholds inducing corticospinal/corticobulbar tracts (CSBT) motor contractions. OBJECTIVE: This study aims to analyze correlations between DBS electrode distance to CSBT and contraction thresholds, with either visual or electromyography (EMG) detection, to establish an intraoperative tool devoted to ensure safe distance of the electrode to the CSBT. METHODS: Twelve PD patients with subthalamic nucleus DBS participated. Thresholds of muscular contractions were assessed clinically and with EMG, for three different sets of stimulation parameters, all monopolar: 130 Hz high-frequency stimulation (HFS); 2 Hz low-frequency stimulation with either 60 or 210 us (LFS-60, LFS-210). The anatomical distance of electrode contacts to CSBT was measured from fused CT-MRI. RESULTS: The best linear correlation was found for thresholds of visually detected contractions with HFS (r2 = 0.63, p < 0.0001) when estimated stimulation currents rather than voltages were used. This correlation was found in agreement with an accepted model of electrical spatial extent of activation (r2 = 0.50). When using LFS, the correlation found remained lower than for HFS but increased when EMG was used. Indeed, the detection of contraction thresholds with EMG versus visual inspection did allow more frequent detection of face contractions, contributing to improve that correlation. CONCLUSION: The correlation between electrode distance to the CSBT and contraction thresholds was found better when estimated with currents rather than voltage, eliminating the variance due to electrode impedance. Using LFS did not improve the precision of that evaluation, but EMG did. This technique provides a prediction band to ensure minimum distance of the electrode contacts to the CSBT, integrating the variance that can be encountered between prediction of models and practice. PMID- 28620351 TI - Determining Causation from Observational Studies: A Challenge for Modern Neuroepidemiology. PMID- 28620352 TI - Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + Luteinizing Hormone, Human Menopausal Gonadotropin or FSH + Human Chorionic Gonadotropin on Assisted Reproductive Technology Outcomes in the "Personalized" Medicine Era: A Meta analysis. AB - SETTING: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG) act on the same receptor, activating different signal transduction pathways. The role of LH or hCG addition to follicle-stimulating hormone (FSH) as well as menopausal gonadotropins (human menopausal gonadotropin; hMG) in controlled ovarian stimulation (COS) is debated. OBJECTIVE: To compare FSH + LH, or FSH + hCG or hMG vs. FSH alone on COS outcomes. DESIGN: A meta-analysis according to PRISMA statement and Cochrane Collaboration was performed, including prospective, controlled clinical trials published until July 2016, enrolling women treated with FSH alone or combined with other gonadotropins. Trials enrolling women with polycystic ovarian syndrome were excluded (PROSPERO registration no. CRD42016048404). RESULTS: Considering 70 studies, the administration of FSH alone resulted in higher number of oocytes retrieved than FSH + LH or hMG. The MII oocytes number did not change when FSH alone was compared to FSH + LH, FSH + hCG, or hMG. Embryo number and implantation rate were higher when hMG was used instead of FSH alone. Pregnancy rate was significantly higher in FSH + LH-treated group vs. others. Only 12 studies reported live birth rate, not providing protocol dependent differences. Patients' stratification by GnRH agonist/antagonist identified patient subgroups benefiting from specific drug combinations. CONCLUSION: In COS, FSH alone results in higher oocyte number. HMG improves the collection of mature oocytes, embryos, and increases implantation rate. On the other hand, LH addition leads to higher pregnancy rate. This study supports the concept of a different clinical action of gonadotropins in COS, reflecting previous in vitro data. PMID- 28620350 TI - Considerations for Experimental Animal Models of Concussion, Traumatic Brain Injury, and Chronic Traumatic Encephalopathy-These Matters Matter. AB - Animal models of concussion, traumatic brain injury (TBI), and chronic traumatic encephalopathy (CTE) are widely available and routinely deployed in laboratories around the world. Effective animal modeling requires careful consideration of four basic principles. First, animal model use must be guided by clarity of definitions regarding the human disease or condition being modeled. Concussion, TBI, and CTE represent distinct clinical entities that require clear differentiation: concussion is a neurological syndrome, TBI is a neurological event, and CTE is a neurological disease. While these conditions are all associated with head injury, the pathophysiology, clinical course, and medical management of each are distinct. Investigators who use animal models of these conditions must take into account these clinical distinctions to avoid misinterpretation of results and category mistakes. Second, model selection must be grounded by clarity of purpose with respect to experimental questions and frame of reference of the investigation. Distinguishing injury context ("inputs") from injury consequences ("outputs") may be helpful during animal model selection, experimental design and execution, and interpretation of results. Vigilance is required to rout out, or rigorously control for, model artifacts with potential to interfere with primary endpoints. The widespread use of anesthetics in many animal models illustrates the many ways that model artifacts can confound preclinical results. Third, concordance between key features of the animal model and the human disease or condition being modeled is required to confirm model biofidelity. Fourth, experimental results observed in animals must be confirmed in human subjects for model validation. Adherence to these principles serves as a bulwark against flawed interpretation of results, study replication failure, and confusion in the field. Implementing these principles will advance basic science discovery and accelerate clinical translation to benefit people affected by concussion, TBI, and CTE. PMID- 28620353 TI - The Distribution of Stroma and Antral Follicles Differs between Insulin Resistance and Hyperandrogenism-Related Polycystic Ovarian Syndrome. AB - INTRODUCTION: Although insulin resistance plays an important pathogenetic role in polycystic ovary syndrome (PCOS), no correlation between ultrasound PCOS pattern and insulin resistance has yet been reported. The aim of this retrospective observational study was to assess whether the ovarian ultrasonographic parameter differed between PCOS women with insulin resistance and those with a hyperandrogenic profile. MATERIALS AND METHODS: Women who fulfilled the Rotterdam criteria for PCOS were retrospectively studied. Anthropometric, biochemical, and clinical data were recorded. Women were divided into two groups based on specific transvaginal ultrasound parameters: subjects with more than half of the follicles measuring between 5 and 9 mm in diameter, an ultrasonographic determined stroma/total area (S/A) > 0.34 and a "necklace" sign of antral follicles (Group A); and subjects with more than half of the antral follicles measuring between 2 and 4 mm in diameter, an S/A <= 0.34; no "necklace" sign but ubiquitously distributed follicles determined by ultrasound (Group B). The association between these ultrasound patterns and the presence of insulin resistance was also evaluated. RESULTS: Seventy-eight patients were enrolled: 33 with ultrasound sound pattern A and 45 with pattern B. The latter pattern had a sensitivity of 88% and a specificity of 78% in predicting PCOS women with insulin resistance. There were no differences in age, Ferriman-Gallwey score, and serum gonadotropin or androgen levels between the two groups. Body mass index, the waist-to-hip ratio, and homeostasis model assessment were significantly higher in group B than in group A (p < 0.05). Conversely, sex hormone binding globulin levels and ovarian volume were significantly higher in group A (p < 0.05). Insulin resistance was more frequent in group B than in group A (36/41, 87.8% versus 7/32, 21.8%; p < 0.05). CONCLUSION: These results suggest that insulin resistance could be associated with a specific ultrasound pattern in PCOS patients. PMID- 28620354 TI - Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut-From Gut to Brain? AB - 3-Monoiodothyronamine (T1AM), first isolated from rat brain, is reported to be an endogenous, rapidly acting metabolite of thyroxine. One of its numerous effects is the induction of a "torpor-like" state in experimental animals. A critical analysis of T1AM, to serve as an endogenous cryogen, is given. The proposed biosynthetic pathway for formation of T1AM, which includes deiodinases and ornithine decarboxylase in the upper intestinum, is an unusual one. To reach the brain via systemic circulation, enterohepatic recycling and passage through the liver may occur. The possible role of gut microbiota is discussed. T1AM concentrations in human serum, measured by a specific monoclonal assay are up to three orders of magnitude higher compared to values obtained by MS/MS technology. The difference is explained by the presence of a high-affinity binder for T1AM (Apolipoprotein B-100) in serum, which permits the immunoassay to measure the total concentration of the analyte but limits MS/MS technology to detect only the unbound (free) analyte, a view, which is contested here. PMID- 28620356 TI - Quantifying Biochemical Alterations in Brown and Subcutaneous White Adipose Tissues of Mice Using Fourier Transform Infrared Widefield Imaging. AB - Stimulating increased thermogenic activity in adipose tissue is an important biological target for obesity treatment, and label-free imaging techniques with the potential to quantify stimulation-associated biochemical changes to the adipose tissue are highly sought after. In this study, we used spatially resolved Fourier transform infrared (FTIR) imaging to quantify biochemical changes caused by cold exposure in the brown and subcutaneous white adipose tissues (BAT and s WAT) of 6 week-old C57BL6 mice exposed to 30 degrees C (N = 5), 24 degrees C (N = 5), and 10 degrees C (N = 5) conditions for 10 days. Fat exposed to colder temperatures demonstrated greater thermogenic activity as indicated by increased messenger RNA expression levels of a panel of thermogenic marker genes including uncoupling protein 1 (UCP-1) and Dio2. Protein to lipid ratio, calculated from the ratio of the integrated area from 1,600 to 1,700 cm-1 (amide I) to the integrated area from 2,830 to 2,980 cm-1 (saturated lipids), was elevated in 10 degrees C BAT and s-WAT compared to 24 degrees C (p = 0.004 and p < 0.0001) and 30 degrees C (p = 0.0033 and p < 0.0001). Greater protein to lipid ratio was associated with greater UCP-1 expression level in the BAT (p = 0.021) and s-WAT (p = 0.032) and greater Dio2 expression in s-WAT (p = 0.033). The degree of unsaturation, calculated from the ratio of the integrated area from 2,992 to 3,020 cm-1 (unsaturated lipids) to the integrated area from 2,830 to 2,980 cm-1 (saturated lipids), showed stepwise decreases going from colder-exposed to warmer exposed BAT. Complementary 1H NMR measurements confirmed the findings from this ratio in BAT. Principal component analysis applied to FTIR spectra revealed pronounced differences in overall spectral characteristics between 30, 24, and 10 degrees C BAT and s-WAT. Spatially resolved FTIR imaging is a promising technique to quantify cold-induced biochemical changes in BAT and s-WAT in a label-free manner. PMID- 28620355 TI - Role of the Vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders. AB - Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. In animal models, experimental data demonstrate that intracerebroventricular injection of apelin into lactating rats inhibits the phasic electrical activity of arginine vasopressin (AVP) neurons, reduces plasma AVP levels, and increases aqueous diuresis. In the kidney, apelin increases diuresis by increasing the renal microcirculation and by counteracting the antidiuretic effect of AVP at the tubular level. Moreover, after water deprivation or salt loading, in humans and in rodents, AVP and apelin are conversely regulated to facilitate systemic AVP release and to avoid additional water loss from the kidney. Furthermore, apelin and vasopressin secretion are significantly altered in various water metabolism disorders including hyponatremia and polyuria-polydipsia syndrome. Since the in vivo half life of apelin is in the minute range, metabolically stable apelin analogs were developed. The efficacy of these lead compounds for decreasing AVP release and increasing both renal blood flow and diuresis, make them promising candidates for the treatment of water retention and/or hyponatremic disorders. PMID- 28620357 TI - The Effectiveness of Nitrate-Mediated Control of the Oil Field Sulfur Cycle Depends on the Toluene Content of the Oil. AB - The injection of nitrate is one of the most commonly used technologies to impact the sulfur cycle in subsurface oil fields. Nitrate injection enhances the activity of nitrate-reducing bacteria, which produce nitrite inhibiting sulfate reducing bacteria (SRB). Subsequent reduction of nitrate to di-nitrogen (N2) alleviates the inhibition of SRB by nitrite. It has been shown for the Medicine Hat Glauconitic C (MHGC) field, that alkylbenzenes especially toluene are important electron donors for the reduction of nitrate to nitrite and N2. However, the rate and extent of reduction of nitrate to nitrite and of nitrite to nitrogen have not been studied for multiple oil fields. Samples of light oil (PNG, CPM, and Tundra), light/heavy oil (Gryphon and Obigbo), and of heavy oil (MHGC) were collected from locations around the world. The maximum concentration of nitrate in the aqueous phase, which could be reduced in microcosms inoculated with MHGC produced water, increased with the toluene concentration in the oil phase. PNG, Gryphon, CPM, Obigbo, MHGC, and Tundra oils had 77, 17, 5.9, 4.0, 2.6, and 0.8 mM toluene, respectively. In incubations with 49 ml of aqueous phase and 1 ml of oil these were able to reduce 22.2, 12.3, 7.9, 4.6, 4.0, and 1.4 mM of nitrate, respectively. Nitrate reduced increased to 35 +/- 4 mM upon amendment of all these oils with 570 mM toluene prior to incubation. Souring control by nitrate injection requires that the nitrate is directed toward oxidation of sulfide, not toluene. Hence, the success of nitrate injections will be inversely proportional to the toluene content of the oil. Oil composition is therefore an important determinant of the success of nitrate injection to control souring in a particular field. PMID- 28620358 TI - The Transcriptional Regulators of the CRP Family Regulate Different Essential Bacterial Functions and Can Be Inherited Vertically and Horizontally. AB - One of the best-studied transcriptional regulatory proteins in bacteria is the Escherichia coli catabolite repressor protein (CRP) that when complexed with 3' 5'-cyclic AMP (cAMP) changes its conformation and interacts with specific DNA sequences. CRP DNA-binding can result in positive or negative regulation of gene expression depending on the position of its interaction with respect to RNA polymerase binding site. The aim of this work is to review the biological role and phylogenetic relations that some members of the CRP family of transcriptional regulators (also known as cAMP receptor protein family) have in different bacterial species. This work is not intended to give an exhaustive revision of bacterial CRP-orthologs, but to provide examples of the role that these proteins play in the expression of genes that are fundamental for the life style of some bacterial species. We highlight the conservation of their structural characteristics and of their binding to conserved-DNA sequences, in contrast to their very diverse repertoire of gene activation. CRP activates a wide variety of fundamental genes for the biological characteristic of each bacterial species, which in several instances form part of their core-genome (defined as the gene sequences present in all members of a bacterial species). We present evidence that support the fact that some of the transcriptional regulators that belong to the CRP family in different bacterial species, and some of the genes that are regulated by them, can be inherited by horizontal gene transfer. These data are discussed in the framework of bacterial evolution models. PMID- 28620359 TI - Genome-Wide Search for Genes Required for Bifidobacterial Growth under Iron Limitation. AB - Bacteria evolved over millennia in the presence of the vital micronutrient iron. Iron is involved in numerous processes within the cell and is essential for nearly all living organisms. The importance of iron to the survival of bacteria is obvious from the large variety of mechanisms by which iron may be acquired from the environment. Random mutagenesis and global gene expression profiling led to the identification of a number of genes, which are essential for Bifidobacterium breve UCC2003 survival under iron-restrictive conditions. These genes encode, among others, Fe-S cluster-associated proteins, a possible ferric iron reductase, a number of cell wall-associated proteins, and various DNA replication and repair proteins. In addition, our study identified several presumed iron uptake systems which were shown to be essential for B. breve UCC2003 growth under conditions of either ferric and/or ferrous iron chelation. Of these, two gene clusters encoding putative iron-uptake systems, bfeUO and sifABCDE, were further characterised, indicating that sifABCDE is involved in ferrous iron transport, while the bfeUO-encoded transport system imports both ferrous and ferric iron. Transcription studies showed that bfeUO and sifABCDE constitute two separate transcriptional units that are induced upon dipyridyl mediated iron limitation. In the anaerobic gastrointestinal environment ferrous iron is presumed to be of most relevance, though a mutation in the sifABCDE cluster does not affect B. breve UCC2003's ability to colonise the gut of a murine model. PMID- 28620360 TI - CytR Homolog of Pectobacterium carotovorum subsp. carotovorum Controls Air-Liquid Biofilm Formation by Regulating Multiple Genes Involved in Cellulose Production, c-di-GMP Signaling, Motility, and Type III Secretion System in Response to Nutritional and Environmental Signals. AB - Pectobacterium carotovorum subsp. carotovorum [Pcc (formerly Erwinia carotovora subsp. carotovora)] PC1 causes soft-rot disease in a wide variety of plant species by secreting multiple pathogenicity-related traits. In this study, regulatory mechanism of air-liquid (AL) biofilm formation was studied using a cytR homolog gene deletion mutant (DeltacytR) of Pcc PC1. Compared to the wild type (Pcc PC1), the DeltacytR mutant produced fragile and significantly (P < 0.001) lower amounts of AL biofilm on salt-optimized broth plus 2% glycerol (SOBG), yeast peptone dextrose adenine, and also on King's B at 27 degrees C after 72 h incubation in static condition. The wild type also produced significantly higher quantities of AL biofilm on SOBGMg- (magnesium deprived) containing Cupper (Cu2+), Zinc (Zn2+), Manganese (Mn2+), Magnesium (Mg2+), and Calcium (Ca2+) compared to the DeltacytR mutant. Moreover, the wild type was produced higher amounts of biofilms compared to the mutant while responding to pH and osmotic stresses. The DeltafliC (encoding flagellin), flhD::Tn5 (encoding a master regulator) and DeltamotA (a membrane protein essential for flagellar rotation) mutants produced a lighter and more fragile AL biofilm on SOBG compared to their wild counterpart. All these mutants resulted in having weak bonds with the cellulose specific dye (Calcofluor) producing lower quantities of cellulose compared to the wild type. Gene expression analysis using mRNA collected from the AL biofilms showed that DeltacytR mutant significantly (P < 0.001) reduced the expressions of multiple genes responsible for cellulose production (bcsA, bcsE, and adrA), motility (flhD, fliA, fliC, and motA) and type III secretion system (hrpX, hrpL, hrpA, and hrpN) compared to the wild type. The CytR homolog was therefore, argued to be able to regulate the AL biofilm formation by controlling cellulose production, motility and T3SS in Pcc PC1. In addition, all the mutants exhibited poorer attachment to radish sprouts and AL biofilm cells of the wild type was resistant than stationary-phase and planktonic cells to acidity and oxidative stress compared to the same cells of the DeltacytR mutant. The results of this study therefore suggest that CytR homolog is a major determinant of Pcc PC1's virulence, attachment and its survival mechanism. PMID- 28620361 TI - Genome Sequencing of Ralstonia solanacearum CQPS-1, a Phylotype I Strain Collected from a Highland Area with Continuous Cropping of Tobacco. AB - Ralstonia solanacearum, an agent of bacterial wilt, is a highly variable species with a broad host range and wide geographic distribution. As a species complex, it has extensive genetic diversity and its living environment is polymorphic like the lowland and the highland area, so more genomes are needed for studying population evolution and environment adaptation. In this paper, we reported the genome sequencing of R. solanacearum strain CQPS-1 isolated from wilted tobacco in Pengshui, Chongqing, China, a highland area with severely acidified soil and continuous cropping of tobacco more than 20 years. The comparative genomic analysis among different R. solanacearum strains was also performed. The completed genome size of CQPS-1 was 5.89 Mb and contained the chromosome (3.83 Mb) and the megaplasmid (2.06 Mb). A total of 5229 coding sequences were predicted (the chromosome and megaplasmid encoded 3573 and 1656 genes, respectively). A comparative analysis with eight strains from four phylotypes showed that there was some variation among the species, e.g., a large set of specific genes in CQPS-1. Type III secretion system gene cluster (hrp gene cluster) was conserved in CQPS-1 compared with the reference strain GMI1000. In addition, most genes coding core type III effectors were also conserved with GMI1000, but significant gene variation was found in the gene ripAA: the identity compared with strain GMI1000 was 75% and the hrpII box promoter in the upstream had significantly mutated. This study provided a potential resource for further understanding of the relationship between variation of pathogenicity factors and adaptation to the host environment. PMID- 28620362 TI - Commentary: Communication between Viruses Guides Lysis-Lysogeny Decisions. PMID- 28620363 TI - Proteomic Analysis of Trichinella spiralis Adult Worm Excretory-Secretory Proteins Recognized by Sera of Patients with Early Trichinellosis. AB - The most commonly used serodiagnostic antigens for trichinellosis are the excretory-secretory (ES) antigens from T. spiralis muscle larvae (ML), but the specific antibodies against the ML ES antigens are usually negative during early stage of Trichinella infection. The recent studies demonstrated that T. spiralis adult worm (AW) antigens were recognized by mouse or swine infection sera on Western blot as early as 7-15 days post-infection (dpi), the AW antigens might contain the early diagnostic markers for trichinellosis. The purpose of this study was to screen early diagnostic antigens in T. spiralis AW ES proteins recognized by sera of early patients with trichinellosis. T. spiralis AW were collected at 72 h post-infection (hpi), and their ES antigens were analyzed by SDS-PAGE and Western blot. Our results showed that 5 protein bands (55, 48-50, 45, 44, and 36 kDa) were recognized by sera of early patients with trichinellosis collected at 19 dpi, and were subjected to shotgun LC-MS/MS and bioinformatics analyses. A total of 185 proteins were identified from T. spiralis protein database, of which 116 (67.2%) proteins had molecular weights of 30~60 kDa, and 125 (67.6%) proteins with pI 4-7. Bioinformatic analyses showed that the identified proteins have a wide diversity of biological functions (binding of nucleotides, proteins, ions, carbohydrates, and lipids; hydrolase, transferase, and oxidoreductase, etc.). Several enzymes (e.g., adult-specific DNase II, serine protease and serine protease inhibitor) could be the invasion-related proteins and early diagnostic markers for trichinellosis. Moreover, recombinant T. spiralis serine protease (rTsSP-ZH68) was expressed in E. coli and its antigenicity was analyzed by Western blot with the early infection sera. The rTsSP-ZH68 was recognized by sera of infected mice at 8-10 dpi and sera of early patients with trichinellosis at 19 dpi. T. spiralis AW proteins identified in this study, especially serine protease, are the promising early diagnostic antigens and vaccine candidates for trichinellosis. PMID- 28620364 TI - A Multiplex RT-PCR Assay for S. aureus, L. monocytogenes, and Salmonella spp. Detection in Raw Milk with Pre-enrichment. AB - This study firstly developed a multiplex real-time PCR (RT-PCR) technique combined with a pre-enrichment step to simultaneously detect Staphylococcus aureus (S. aureus), Listeria monocytogenes (L. monocytogenes) and Salmonella spp. in raw milk and the dairy farm environment (feces, soil, feed, water) in one reaction. Brain heart infusion (BHI) broth was selected for the enrichment step to increase the density of the target bacteria by using an incubation of 4 h before multiplex RT-PCR. The results showed that the detection limit of the multiplex real-time assay was approximately 102 CFU/mL for pure cultures and artificially contaminated milk without enrichment, while 12, 14, and 10 CFU/25 mL, respectively, for S. aureus, L. monocytogenes, and Salmonella spp. after pre enrichment. The newly developed multiplex RT-PCR assay was applied to 46 dairy farm environmental samples and raw milk samples covering a wide variety of sample types. The results demonstrated that the multiplex RT-PCR assay coupled with the BHI enrichment broth was suitable for the simultaneous screening of S. aureus, L. monocytogenes, and Salmonella spp. in the pasture environment and in raw milk. The multiplex RT-PCR assay clearly and successfully shortened the total detection time and reduced labor compared to conventional culture-based methods for testing natural samples. PMID- 28620365 TI - Metabolic Value Chemoattractants Are Preferentially Recognized at Broad Ligand Range Chemoreceptor of Pseudomonas putida KT2440. AB - Bacteria have evolved a wide range of chemoreceptors with different ligand specificities. Typically, chemoreceptors bind ligands with elevated specificity and ligands serve as growth substrates. However, there is a chemoreceptor family that has a broad ligand specificity including many compounds that are not of metabolic value. To advance the understanding of this family, we have used the PcaY_PP (PP2643) chemoreceptor of Pseudomonas putida KT2440 as a model. Using Isothermal Titration Calorimetry we showed here that the recombinant ligand binding domain (LBD) of PcaY_PP recognizes 17 different C6-ring containing carboxylic acids with KD values between 3.7 and 138 MUM and chemoeffector affinity correlated with the magnitude of the chemotactic response. Mutation of the pcaY_PP gene abolished chemotaxis to these compounds; phenotype that was restored following gene complementation. Growth experiments using PcaY_PP ligands as sole C-sources revealed functional relationships between their metabolic potential and affinity for the chemoreceptor. Thus, only 7 PcaY_PP ligands supported growth and their KD values correlated with the length of the bacterial lag phase. Furthermore, PcaY_PP ligands that did not support growth had significantly higher KD values than those that did. The receptor has thus binds preferentially compounds that serve as C-sources and amongst them those that rapidly promote growth. Tightest binding compounds were quinate, shikimate, 3 dehydroshikimate and protocatechuate, which are at the interception of the biosynthetic shikimate and catabolic quinate pathways. Analytical ultracentrifugation studies showed that ligand free PcaY_PP-LBD is present in a monomer-dimer equilibrium (KD = 57.5 MUM). Ligand binding caused a complete shift to the dimeric state, which appears to be a general feature of four-helix bundle LBDs. This study indicates that the metabolic potential of compounds is an important parameter in the molecular recognition by broad ligand range chemoreceptors. PMID- 28620366 TI - Vibrio vulnificus: An Environmental and Clinical Burden. AB - Vibrio vulnificus is a Gram negative, rod shaped bacterium that belongs to the family Vibrionaceae. It is a deadly, opportunistic human pathogen which is responsible for the majority of seafood-associated deaths worldwide. V. vulnificus infection can be fatal as it may cause severe wound infections potentially requiring amputation or lead to sepsis in susceptible individuals. Treatment is increasingly challenging as V. vulnificus has begun to develop resistance against certain antibiotics due to their indiscriminate use. This article aims to provide insight into the antibiotic resistance of V. vulnificus in different parts of the world as well as an overall review of its clinical manifestations, treatment, and prevention. Understanding the organism's antibiotic resistance profile is vital in order to select appropriate treatment and initiate appropriate prevention measures to treat and control V. vulnificus infections, which should eventually help lower the mortality rate associated with this pathogen worldwide. PMID- 28620367 TI - Mycobacterial F420H2-Dependent Reductases Promiscuously Reduce Diverse Compounds through a Common Mechanism. AB - An unusual aspect of actinobacterial metabolism is the use of the redox cofactor F420. Studies have shown that actinobacterial F420H2-dependent reductases promiscuously hydrogenate diverse organic compounds in biodegradative and biosynthetic processes. These enzymes therefore represent promising candidates for next-generation industrial biocatalysts. In this work, we undertook the first broad survey of these enzymes as potential industrial biocatalysts by exploring the extent, as well as mechanistic and structural bases, of their substrate promiscuity. We expressed and purified 11 enzymes from seven subgroups of the flavin/deazaflavin oxidoreductase (FDOR) superfamily (A1, A2, A3, B1, B2, B3, B4) from the model soil actinobacterium Mycobacterium smegmatis. These enzymes reduced compounds from six chemical classes, including fundamental monocycles such as a cyclohexenone, a dihydropyran, and pyrones, as well as more complex quinone, coumarin, and arylmethane compounds. Substrate range and reduction rates varied between the enzymes, with the A1, A3, and B1 groups exhibiting greatest promiscuity. Molecular docking studies suggested that structurally diverse compounds are accommodated in the large substrate-binding pocket of the most promiscuous FDOR through hydrophobic interactions with conserved aromatic residues and the isoalloxazine headgroup of F420H2. Liquid chromatography-mass spectrometry (LC/MS) and gas chromatography-mass spectrometry (GC/MS) analysis of derivatized reaction products showed reduction occurred through a common mechanism involving hydride transfer from F420H- to the electron-deficient alkene groups of substrates. Reduction occurs when the hydride donor (C5 of F420H-) is proximal to the acceptor (electrophilic alkene of the substrate). These findings suggest that engineered actinobacterial F420H2-dependent reductases are promising novel biocatalysts for the facile transformation of a wide range of alpha,beta unsaturated compounds. PMID- 28620368 TI - An aroD Ochre Mutation Results in a Staphylococcus aureus Small Colony Variant That Can Undergo Phenotypic Switching via Two Alternative Mechanisms. AB - Staphylococcus aureus can undergo phenotypic switching between a normal colony phenotype (NCP) and a small colony variant (SCV). The SCV phenotype confers increased antibiotic resistance and the capacity to persist within human tissues and cells, and because these cells can revert back to the NCP they cause chronic and/or recurrent infections that are very difficult to treat. A complete picture of the genetic events that can lead to phenotypic switching in S. aureus is currently lacking. We describe the selection of an SCV with a previously unreported genetic alteration leading to an ochre mutation of aroD. In addition to the known mechanisms of phenotypic switching between the SCV and the NCP we describe a previously unreported mechanism involving tRNA ochre suppressors arising. The ochre suppressor strains had wild-type growth rates and restored antibiotic sensitivity, similar to the wild-type strain. However, whilst they had increased virulence compared to the SCV parent strain, their virulence was not restored to that of the NCP parental strain. These findings establish that phenotypic switching between the NCP and SCV states can give rise to strains with different pathogenic potential. PMID- 28620369 TI - Characterization of Bile Salt Hydrolase from Lactobacillus gasseri FR4 and Demonstration of Its Substrate Specificity and Inhibitory Mechanism Using Molecular Docking Analysis. AB - Probiotic bacteria are beneficial to the health of poultry animals, thus are used as alternative candidates for antibiotics used as growth promoters (AGPs). However, they also reduce the body weight gain due to innate bile salt hydrolase (BSH) activity. Hence, the addition of a suitable BSH inhibitor along with the probiotic feed can decrease the BSH activity. In this study, a BSH gene (981 bp) encoding 326-amino acids was identified from the genome of Lactobacillus gasseri FR4 (LgBSH). The LgBSH-encoding gene was cloned and purified using an Escherichia coli BL21 (DE3) expression system, and its molecular weight (37 kDa) was confirmed by SDS-PAGE and a Western blot analysis. LgBSH exhibited greater hydrolysis toward glyco-conjugated bile salts compared to tauro-conjugated bile salts. LgBSH displayed optimal activity at 52 degrees C at a pH of 5.5, and activity was further increased by several reducing agents (DTT), surfactants (Triton X-100 and Tween 80), and organic solvents (isopropanol, butanol, and acetone). Riboflavin and penicillin V, respectively, inhibited LgBSH activity by 98.31 and 97.84%. A homology model of LgBSH was predicted using EfBSH (4WL3) as a template. Molecular docking analysis revealed that the glycocholic acid had lowest binding energy of -8.46 kcal/mol; on the other hand, inhibitors, i.e., riboflavin and penicillin V, had relatively higher binding energies of -6.25 and 7.38 kcal/mol, respectively. Our results suggest that L. gasseri FR4 along with riboflavin might be a potential alternative to AGPs for poultry animals. PMID- 28620370 TI - Environmental T4-Family Bacteriophages Evolve to Escape Abortive Infection via Multiple Routes in a Bacterial Host Employing "Altruistic Suicide" through Type III Toxin-Antitoxin Systems. AB - Abortive infection is an anti-phage mechanism employed by a bacterium to initiate its own death upon phage infection. This reduces, or eliminates, production of viral progeny and protects clonal siblings in the bacterial population by an act akin to an "altruistic suicide." Abortive infection can be mediated by a Type III toxin-antitoxin system called ToxINPa consisting of an endoribonuclease toxin and RNA antitoxin. ToxINPa is a heterohexameric quaternary complex in which pseudoknotted RNA inhibits the toxicity of the toxin until infection by certain phages causes destabilization of ToxINPa, leading to bacteriostasis and, eventually, lethality. However, it is still unknown why only certain phages are able to activate ToxINPa. To try to address this issue we first introduced ToxINPa into the Gram-negative enterobacterium, Serratia sp. ATCC 39006 (S 39006) and then isolated new environmental S 39006 phages that were scored for activation of ToxINPa and abortive infection capacity. We isolated three T4-like phages from a sewage treatment outflow point into the River Cam, each phage being isolated at least a year apart. These phages were susceptible to ToxINPa-mediated abortive infection but produced spontaneous "escape" mutants that were insensitive to ToxINPa. Analysis of these resistant mutants revealed three different routes of escaping ToxINPa, namely by mutating asiA (the product of which is a phage transcriptional co-activator); by mutating a conserved, yet functionally unknown, orf84; or by deleting a 6.5-10 kb region of the phage genome. Analysis of these evolved escape mutants may help uncover the nature of the corresponding phage product(s) involved in activation of ToxINPa. PMID- 28620371 TI - Variation in Soil Microbial Community Structure Associated with Different Legume Species Is Greater than that Associated with Different Grass Species. AB - Plants are the essential factors shaping soil microbial community (SMC) structure. When most studies focus on the difference in the SMC structure associated different plant species, the variation in the SMC structure associated with phylogenetically close species is less investigated. Legume (Fabaceae) and grass (Poaceae) are functionally important plant groups; however, their influences on the SMC structure are seldom compared, and the variation in the SMC structure among legume or grass species is largely unknown. In this study, we grew three legume species vs. three grass species in mesocosms, and monitored the soil chemical property, quantified the abundance of bacteria and fungi. The SMC structure was also characterized using PCR-DGGE and Miseq sequencing. Results showed that legume and grass differentially affected soil pH, dissolved organic C, total N content, and available P content, and that legume enriched fungi more greatly than grass. Both DGGE profiling and Miseq-sequencing indicated that the bacterial diversity associated with legume was higher than that associated with grass. When legume increased the abundance of Verrucomicrobia, grass decreased it, and furthermore, linear discriminant analysis identified some group-specific microbial taxa as potential biomarkers of legume or grass. These data suggest that legume and grass differentially select for the SMC. More importantly, clustering analysis based on both DGGE profiling and Miseq-sequencing demonstrated that the variation in the SMC structure associated with three legume species was greater than that associated with three grass species. PMID- 28620372 TI - Deep Sequencing in Infectious Diseases: Immune and Pathogen Repertoires for the Improvement of Patient Outcomes. AB - The inaugural workshop "Deep Sequencing in Infectious Diseases: Immune and Pathogen Repertoires for the Improvement of Patient Outcomes" was held in Singapore on 13-14 October 2016. The aim of the workshop was to discuss the latest trends in using high-throughput sequencing, bioinformatics, and allied technologies to analyze immune and pathogen repertoires and their interplay within the host, bringing together key international players in the field and Singapore-based researchers and clinician-scientists. The focus was in particular on the application of these technologies for the improvement of patient diagnosis, prognosis and treatment, and for other broad public health outcomes. The presentations by scientists and clinicians showed the potential of deep sequencing technology to capture the coevolution of adaptive immunity and pathogens. For clinical applications, some key challenges remain, such as the long turnaround time and relatively high cost of deep sequencing for pathogen identification and characterization and the lack of international standardization in immune repertoire analysis. PMID- 28620374 TI - Canine Macrophage DH82 Cell Line As a Model to Study Susceptibility to Trypanosoma cruzi Infection. AB - Trypanosoma cruzi is an obligatory intracellular protozoan parasite, and it is the etiological agent of Chagas' disease that is endemic in the Americas. In addition to humans, a wide spectrum of mammals can be infected by T. cruzi, including dogs. Dogs develop acute and chronic disease, similar to human infection. T. cruzi can infect almost all cell types and after cell invasion, the metacyclics trypomastigotes localize in the cytoplasm, where they transform into amastigotes, the replicative form of T. cruzi in mammals. After amastigote multiplication and differentiation, parasites lyse host cells and spread through the body by blood circulation. In this work, we evaluated the in vitro ability of T. cruzi to infect a canine macrophage cell line DH82 compared with RAW264.7, a murine tissue culture macrophage. Our results have shown that the T. cruzi is able to infect, replicate and differentiate in DH82 cell line. We observed that following treatment with LPS and IFN-gamma DH82 cells were more resistant to infection and that resistance was not related reactive oxygen species production in our system. In this study, we also found that DH82 cells became more susceptible to T. cruzi infection when cocultured with apoptotic cells. The analysis of cytokine production has showed elevated levels of the TGF-beta, IL 10, and TNF-alpha produced by T. cruzi-infected canine macrophages. Additionally, we demonstrated a reduced expression of the MHC class II and CD80 by infected DH82 cell line. PMID- 28620375 TI - Comparative Gene Expression Analysis of Lymphocytes Treated with Exosomes Derived from Ovarian Cancer and Ovarian Cysts. AB - Cancer cells employ many strategies to evade immune defense and to facilitate tumor growth and angiogenesis. As a novel mode of intercellular communication, cancer-derived exosomes contribute to the recruitment and mediation of lymphocytes within the tumor environment. However, the mechanisms and key molecules mediating the effect of exosomes on lymphocytes are unclear. We treated healthy peripheral blood lymphocytes with exosomes from ovarian cancer and ovarian cysts and screened for differentially expressed genes using the RT2 Profiler Cancer Inflammation and Immunity Crosstalk PCR Array. A total of 26 upregulated genes (mainly pro-inflammatory genes and immunostimulatory and immunosuppressive factor) and two downregulated genes (antigen presentation HLA A/B) were identified. Western blotting using lymphocytes from malignant ascites and peritoneal washings of benign ovarian cysts suggested that the interferon and NF-kappaB signaling pathway were involved in the immune regulation of malignant exosomes. Out of 28 differentially expressed genes detected using the array, 11 were validated by real-time PCR using lymphocytes within ovarian cancer (n = 27) and ovarian cyst (n = 9) environments. In conclusion, our findings indicate that malignant cells secrete exosomes in the tumor microenvironment to recruit lymphocytes in order to suppress antitumor immunity (IL10, Foxp3, and HLA-A/B) and enhance tumor invasion, angiogenesis, and dissemination of proinflammatory cytokines (such as IL6 and VEGFA) via the interferon and NF-kappaB signaling pathways. These results clarify lymphocyte-cancer cell cross talk via exosomes and may facilitate the development of effective immunotherapeutic strategies for ovarian cancer. PMID- 28620376 TI - The N-Glycosylation of Mouse Immunoglobulin G (IgG)-Fragment Crystallizable Differs Between IgG Subclasses and Strains. AB - N-linked glycosylation of the fragment crystallizable (Fc)-region of immunoglobulin G (IgG) is known to have a large influence on the activity of the antibody, an effect reported to be IgG subclass specific. This situation applies both to humans and mice. The mouse is often used as experimental animal model to study the effects of Fc-glycosylation on IgG effector functions, and results are not uncommonly translated back to the human situation. However, while human IgG Fc-glycosylation has been extensively characterized in both health and disease, this is not the case for mice. To characterize the glycosylation profile of murine IgG-Fc and in addition evaluate the systematic glycosylation differences between mouse strains, sexes, and IgG subclasses, we used nanoliquid chromatography mass spectrometry (nanoLC-MS(/MS)) to look at the subclass specific IgG Fc-glycopeptides of male and female mice from the strains BALB/c, C57BL/6, CD-1, and Swiss Webster. The structural analysis revealed the presence of predominantly fucosylated, diantennary glycans, with varying amounts of galactosylation and alpha2,6-sialylation. In addition, we report glycosylation features not previously reported in an Fc-specific way on murine IgG, including monoantennary, hybrid, and high mannose structures, as well as diantennary structures without a core fucose, with a bisecting N-acetylglucosamine, or with alpha1,3-galactosylation. Pronounced differences were detected between strains and the IgG subclasses within each strain. Especially the large spread in galactosylation and sialylation levels found between both strains and subclasses may vastly influence IgG effector functions. Mouse strain-based and subclass specific glycosylation differences should be taken into account when designing and interpreting immunological and glycobiological mouse studies involving IgG effector functions. PMID- 28620377 TI - Anti-Double-Stranded DNA IgG Participates in Renal Fibrosis through Suppressing the Suppressor of Cytokine Signaling 1 Signals. AB - Suppressor of cytokine signaling 1 (SOCS1) participates in renal fibrosis by downregulating Janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1)-mediated cytokine signaling. Recently, it was found that anti-double-stranded DNA (dsDNA) IgG induces the synthesis of profibrotic cytokines by renal cells. To explore the potential effect of anti-dsDNA IgG on SOCS1-mediated renal fibrosis, kidney tissues were collected from patients with lupus nephritis (LN) as well as MRL/lpr lupus-prone mice. The SOCS1 expression was evaluated in tissue samples. In addition, SCID mice were injected with anti dsDNA IgG, followed by evaluation of SOCS1 levels. Renal resident cells were cultured in vitro, receiving the stimulation of anti-dsDNA IgG and then the measurement of SOCS1, JAK2, STAT1alpha, and profibrotic cytokines. Moreover, the binding of anti-dsDNA IgG to SOCS1 kinase inhibitory region (KIR) peptide was analyzed by surface plasmon resonance. We found that SOCS1 expression was inhibited, but JAK2/STAT1 activation was prominent in the kidney tissues of patients with LN, MRL/lpr mice, or anti-dsDNA IgG-injected SCID mice. The cultured renal cells also showed SOCS1 downregulation, JAK2/STAT1 activation, and profibrotic cytokine promotion upon anti-dsDNA IgG stimulation. Surprisingly, anti-dsDNA IgG showed high affinity to KIR peptide and competed with JAK2 loop for KIR. Additionally, a DNA-mimicking peptide (ALW) blocked the binding of anti dsDNA IgG to KIR, and even partially abrogated the activation of JAK2/STAT1alpha signals and the expression of profibrotic cytokines in SCID mice. In conclusion, anti-dsDNA IgG downregulates SOCS1 expression, activates JAK2/STAT1 signals, and contributes to renal fibrosis; its peptide blockade may restore the SOCS1 inhibitory effect on the production of profibrotic cytokine, and finally ameliorate renal fibrosis in LN. PMID- 28620378 TI - Nature and Consequences of Biological Reductionism for the Immunological Study of Infectious Diseases. AB - Evolution has conserved "economic" systems that perform many functions, faster or better, with less. For example, three to five leukocyte types protect from thousands of pathogens. To achieve so much with so little, biological systems combine their limited elements, creating complex structures. Yet, the prevalent research paradigm is reductionist. Focusing on infectious diseases, reductionist and non-reductionist views are here described. The literature indicates that reductionism is associated with information loss and errors, while non reductionist operations can extract more information from the same data. When designed to capture one-to-many/many-to-one interactions-including the use of arrows that connect pairs of consecutive observations-non-reductionist (spatial temporal) constructs eliminate data variability from all dimensions, except along one line, while arrows describe the directionality of temporal changes that occur along the line. To validate the patterns detected by non-reductionist operations, reductionist procedures are needed. Integrated (non-reductionist and reductionist) methods can (i) distinguish data subsets that differ immunologically and statistically; (ii) differentiate false-negative from positive errors; (iii) discriminate disease stages; (iv) capture in vivo, multilevel interactions that consider the patient, the microbe, and antibiotic mediated responses; and (v) assess dynamics. Integrated methods provide repeatable and biologically interpretable information. PMID- 28620373 TI - Mechanisms of Autoantibody-Induced Pathology. AB - Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein. PMID- 28620380 TI - Human Immunodeficiency Virus Playing Hide-and-Seek: Understanding the TFH Cell Reservoir and Proposing Strategies to Overcome the Follicle Sanctuary. AB - Human immunodeficiency virus (HIV) infects millions of people worldwide, and new cases continue to emerge. Once infected, the virus cannot be cleared by the immune system and causes acquired immunodeficiency syndrome. Combination antiretroviral therapeutic regimen effectively suppresses viral replication and halts disease progression. The treatment, however, does not eliminate the virus infected cells, and interruption of treatment inevitably leads to viral rebound. The rebound virus originates from a group of virus-infected cells referred to as the cellular reservoir of HIV. Identifying and eliminating the HIV reservoir will prevent viral rebound and cure HIV infection. In this review, we focus on a recently discovered HIV reservoir in a subset of CD4+ T cells called the follicular helper T (TFH) cells. We describe the potential mechanisms for the emergence of reservoir in TFH cells, and the strategies to target and eliminate this viral reservoir. PMID- 28620379 TI - Neuroimmune Interactions in Schizophrenia: Focus on Vagus Nerve Stimulation and Activation of the Alpha-7 Nicotinic Acetylcholine Receptor. AB - Schizophrenia is one of the most debilitating mental disorders and is aggravated by the lack of efficacious treatment. Although its etiology is unclear, epidemiological studies indicate that infection and inflammation during development induces behavioral, morphological, neurochemical, and cognitive impairments, increasing the risk of developing schizophrenia. The inflammatory hypothesis of schizophrenia is also supported by clinical studies demonstrating systemic inflammation and microglia activation in schizophrenic patients. Although elucidating the mechanism that induces this inflammatory profile remains a challenge, mounting evidence suggests that neuroimmune interactions may provide therapeutic advantages to control inflammation and hence schizophrenia. Recent studies have indicated that vagus nerve stimulation controls both peripheral and central inflammation via alpha-7 nicotinic acetylcholine receptor (alpha7nAChR). Other findings have indicated that vagal stimulation and alpha7nAChR-agonists can provide therapeutic advantages for neuropsychiatric disorders, such as depression and epilepsy. This review analyzes the latest results regarding: (I) the immune to-brain pathogenesis of schizophrenia; (II) the regulation of inflammation by the autonomic nervous system in psychiatric disorders; and (III) the role of the vagus nerve and alpha7nAChR in schizophrenia. PMID- 28620381 TI - FXYD5 Is an Essential Mediator of the Inflammatory Response during Lung Injury. AB - The alveolar epithelium secretes cytokines and chemokines that recruit immune cells to the lungs, which is essential for fighting infections but in excess can promote lung injury. Overexpression of FXYD5, a tissue-specific regulator of the Na,K-ATPase, in mice, impairs the alveolo-epithelial barrier, and FXYD5 overexpression in renal cells increases C-C chemokine ligand-2 (CCL2) secretion in response to lipopolysaccharide (LPS). The aim of this study was to determine whether FXYD5 contributes to the lung inflammation and injury. Exposure of alveolar epithelial cells (AEC) to LPS increased FXYD5 levels at the plasma membrane, and FXYD5 silencing prevented both the activation of NF-kappaB and the secretion of cytokines in response to LPS. Intratracheal instillation of LPS into mice increased FXYD5 levels in the lung. FXYD5 overexpression increased the recruitment of interstitial macrophages and classical monocytes to the lung in response to LPS. FXYD5 silencing decreased CCL2 levels, number of cells, and protein concentration in bronchoalveolar lavage fluid (BALF) after LPS treatment, indicating that FXYD5 is required for the NF-kappaB-stimulated epithelial production of CCL2, the influx of immune cells, and the increase in alveolo epithelial permeability in response to LPS. Silencing of FXYD5 also prevented the activation of NF-kappaB and cytokine secretion in response to interferon alpha and TNF-alpha, suggesting that pro-inflammatory effects of FXYD5 are not limited to the LPS-induced pathway. Furthermore, in the absence of other stimuli, FXYD5 overexpression in AEC activated NF-kappaB and increased cytokine production, while FXYD5 overexpression in mice increased cytokine levels in BALF, indicating that FXYD5 is sufficient to induce the NF-kappaB-stimulated cytokine secretion by the alveolar epithelium. The FXYD5 overexpression also increased cell counts in BALF, which was prevented by silencing the CCL2 receptor (CCR2), or by treating mice with a CCR2-blocking antibody, confirming that FXYD5-induced CCL2 production leads to the recruitment of monocytes to the lung. Taken together, the data demonstrate that FXYD5 is a key contributor to inflammatory lung injury. PMID- 28620382 TI - Phase II Study of Adjuvant Immunotherapy with the CSF-470 Vaccine Plus Bacillus Calmette-Guerin Plus Recombinant Human Granulocyte Macrophage-Colony Stimulating Factor vs Medium-Dose Interferon Alpha 2B in Stages IIB, IIC, and III Cutaneous Melanoma Patients: A Single Institution, Randomized Study. AB - The irradiated, allogeneic, cellular CSF-470 vaccine plus Bacillus Calmette Guerin (BCG) and recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) is being tested against medium-dose IFN-alpha2b in stages IIB III cutaneous melanoma (CM) patients (pts) after surgery in an open, randomized, Phase II/III study. We present the results of the Phase II part of the ongoing CASVAC-0401 study (ClinicalTrials.gov: NCT01729663). Thirty-one pts were randomized to the CSF-470 vaccine (n = 20) or to the IFN-alpha2b arm (n = 11). During the 2-year treatment, immunized pts should receive 13 vaccinations. On day 1 of each visit, 1.6 * 107 irradiated CSF-470 cells plus 106 colony-forming units BCG plus 100 ug rhGM-CSF were administered intradermally, followed on days 2-4 by 100 ug rhGM-CSF. IFN-alpha2b pts should receive 10 million units (MU)/day/5 days a week for 4 weeks; then 5 MU thrice weekly for 23 months. Toxicity and quality of life (QOL) were evaluated at each visit. With a mean and a maximum follow-up of 39.4 and 83 months, respectively, a significant benefit in the distant metastasis-free survival (DMFS) for CSF-470 was observed (p = 0.022). Immune monitoring showed an increase in antitumoral cellular and humoral response in vaccinated pts. CSF-470 was well tolerated; 20/20 pts presented grades 1-2 dermic reactions at the vaccination site; 3/20 pts presented grade 3 allergic reactions. Other adverse events (AEs) were grade 1. Pts in the IFN-alpha2b arm presented grades 2-3 hematological (7/11), hepatic (2/11), and cardiac (1/11) toxicity; AEs in 9/11 pts forced treatment interruptions. QOL was significantly superior in the vaccine arm (p < 0.0001). Our results suggest that CSF-470 vaccine plus BCG plus GM-CSF can significantly prolong, with lower toxicity, the DMFS of high-risk CM pts with respect to medium-dose IFN-alpha2b. The continuation of a Phase III part of the CASVAC-0401 study is encouraged. PMID- 28620383 TI - Ly6Chi Monocytes and Their Macrophage Descendants Regulate Neutrophil Function and Clearance in Acetaminophen-Induced Liver Injury. AB - Monocyte-derived macrophages (MoMF) play a pivotal role in the resolution of acetaminophen-induced liver injury (AILI). Timely termination of neutrophil activity and their clearance are essential for liver regeneration following injury. Here, we show that infiltrating Ly6Chi monocytes, their macrophage descendants, and neutrophils spatially and temporally overlap in the centrilobular necrotic areas during the necroinflammatory and resolution phases of AILI. At the necroinflammatory phase, inducible ablation of circulating Ly6Chi monocytes resulted in reduced numbers and fractions of reactive oxygen species (ROS)-producing neutrophils. In alignment with this, neutrophils sorted from monocyte-deficient livers exhibited reduced expression of NADPH oxidase 2. Moreover, human CD14+ monocytes stimulated with lipopolysaccharide or hepatocyte apoptotic bodies directly induced ROS production by cocultured neutrophils. RNA seq-based transcriptome profiling of neutrophils from Ly6Chi monocyte-deficient versus normal livers revealed 449 genes that were differentially expressed with at least twofold change (p <= 0.05). In the absence of Ly6Chi monocytes, neutrophils displayed gene expression alterations associated with decreased innate immune activity and increased cell survival. At the early resolution phase, Ly6Chi monocytes differentiated into ephemeral Ly6Clo MoMF and their absence resulted in significant accumulation of late apoptotic neutrophils. Further gene expression analysis revealed the induced expression of a specific repertoire of bridging molecules and receptors involved with apoptotic cell clearance during the transition from Ly6Chi monocytes to MoMF. Collectively, our findings establish a phase-dependent task division between liver-infiltrating Ly6Chi monocytes and their MoMF descendants with the former regulating innate immune functions and cell survival of neutrophils and the later neutrophil clearance. PMID- 28620384 TI - Measuring Leukocyte Adhesion to (Primary) Endothelial Cells after Photon and Charged Particle Exposure with a Dedicated Laminar Flow Chamber. AB - The vascular endothelium interacts with all types of blood cells and is a key modulator of local and systemic inflammatory processes, for example, in the adhesion of blood leukocytes to endothelial cells (EC) and the following extravasation into the injured tissue. The endothelium is constantly exposed to mechanical forces caused by blood flow, and the resulting shear stress is essential for the maintenance of endothelial function. Changes in local hemodynamics are sensed by EC, leading to acute or persistent changes. Therefore, in vitro assessment of EC functionality should include shear stress as an essential parameter. Parallel-plate flow chambers with adjustable shear stress can be used to study EC properties. However, commercially available systems are not suitable for radiation experiments, especially with charged particles, which are increasingly used in radiotherapy of tumors. Therefore, research on charged particle-induced vascular side effects is needed. In addition, alpha-particle emitters (e.g., radon) are used to treat inflammatory diseases at low doses. In the present study, we established a flow chamber system, applicable for the investigation of radiation induced changes in the adhesion of lymphocytes to EC as readout for the onset of an inflammatory reaction or the modification of a pre existing inflammatory state. In this system, primary human EC are cultured under physiological laminar shear stress, subjected to a proinflammatory treatment and/or irradiation with X-rays or charged particles, followed by a coincubation with primary human lymphocytes (peripheral blood lymphocytes (PBL)). Analysis is performed by semiautomated quantification of fluorescent staining in microscopic pictures. First results obtained after irradiation with X-rays or helium ions indicate decreased adhesion of PBL to EC under laminar conditions for both radiation qualities, whereas adhesion of PBL under static conditions is not clearly affected by irradiation. Under static conditions, no radiation-induced changes in surface expression of adhesion molecules and activation of nuclear factor kappa B (NF-kappaB) signaling were observed after single cell-based high throughput analysis. In subsequent studies, these investigations will be extended to laminar conditions. PMID- 28620385 TI - The Antibody-Secreting Cell Response to Infection: Kinetics and Clinical Applications. AB - Despite the availability of advances in molecular diagnostic testing for infectious disease, there is still a need for tools that advance clinical care and public health. Current methods focus on pathogen detection with unprecedented precision, but often lack specificity. In contrast, the host immune response is highly specific for the infecting pathogen. Serological studies are rarely helpful in clinical settings, as they require acute and convalescent antibody testing. However, the B cell response is much more rapid and short-lived, making it an optimal target for determining disease aetiology in patients with infections. The performance of tests that aim to detect circulating antigen specific antibody-secreting cells (ASCs) has previously been unclear. Test performance is reliant on detecting the presence of ASCs in the peripheral blood. As such, the kinetics of the ASC response to infection, the antigen specificity of the ASC response, and the methods of ASC detection are all critical. In this review, we summarize previous studies that have used techniques to enumerate ASCs during infection. We describe the emergence, peak, and waning of these cells in peripheral blood during infection with a number of bacterial and viral pathogens, as well as malaria infection. We find that the timing of antigen-specific ASC appearance and disappearance is highly conserved across pathogens, with a peak response between day 7 and day 8 of illness and largely absent following day 14 since onset of symptoms. Data show a sensitivity of ~90% and specificity >80% for pathogen detection using ASC-based methods. Overall, the summarised work indicates that ASC-based methods may be very sensitive and highly specific for determining the etiology of infection and have some advantages over current methods. Important areas of research remain, including more accurate definition of the timing of the ASC response to infection, the biological mechanisms underlying variability in its magnitude and the evolution and the B cell receptor in response to immune challenge. Nonetheless, there is potential of the ASC response to infection to be exploited as the basis for novel diagnostic tests to inform clinical care and public health priorities. PMID- 28620387 TI - Notch Regulates Macrophage-Mediated Inflammation in Diabetic Wound Healing. AB - Macrophages are essential immune cells necessary for regulated inflammation during wound healing. Recent studies have identified that Notch plays a role in macrophage-mediated inflammation. Thus, we investigated the role of Notch signaling on wound macrophage phenotype and function during normal and diabetic wound healing. We found that Notch receptor and ligand expression are dynamic in wound macrophages during normal healing. Mice with a myeloid-specific Notch signaling defect (DNMAMLfloxedLyz2Cre+ ) demonstrated delayed early healing (days 1-3) and wound macrophages had decreased inflammatory gene expression. In our physiologic murine model of type 2 diabetes (T2D), Notch receptor expression was significantly increased in wound macrophages on day 6, following the initial inflammatory phase of wound healing, corresponding to increased inflammatory cytokine expression. This increase in Notch1 and Notch2 was also observed in human monocytes from patients with T2D. Further, in prediabetic mice with a genetic Notch signaling defect (DNMAMLfloxedLyz2Cre+ on a high-fat diet), improved wound healing was seen at late time points (days 6-7). These findings suggest that Notch is critical for the early inflammatory phase of wound healing and directs production of macrophage-dependent inflammatory mediators. These results identify that canonical Notch signaling is important in directing macrophage function in wound repair and define a translational target for the treatment of non-healing diabetic wounds. PMID- 28620386 TI - The Rise of Allogeneic Natural Killer Cells As a Platform for Cancer Immunotherapy: Recent Innovations and Future Developments. AB - Natural killer (NK) cells are critical immune effector cells in the fight against cancer. As NK cells in cancer patients are highly dysfunctional and reduced in number, adoptive transfer of large numbers of cytolytic NK cells and their potential to induce relevant antitumor responses are widely explored in cancer immunotherapy. Early studies from autologous NK cells have failed to demonstrate significant clinical benefit. In this review, the clinical benefits of adoptively transferred allogeneic NK cells in a transplant and non-transplant setting are compared and discussed in the context of relevant NK cell platforms that are being developed and optimized by various biotech industries with a special focus on augmenting NK cell functions. PMID- 28620388 TI - Trichinella spiralis Calreticulin Binds Human Complement C1q As an Immune Evasion Strategy. AB - As a multicellular parasitic nematode, Trichinella spiralis regulates host immune responses by producing a variety of immunomodulatory molecules to escape from host immune attack, but the mechanisms underlying the immune evasion are not well understood. Here, we identified that T. spiralis calreticulin (Ts-CRT), a Ca2+ binding protein, facilitated T. spiralis immune evasion by interacting with the first component of human classical complement pathway, C1q. In the present study, Ts-CRT was found to be expressed on the surface of different developmental stages of T. spiralis as well as in the secreted products of adult and muscle larval worms. Functional analysis identified that Ts-CRT was able to bind to human C1q, resulting in the inhibition of C1q-initiated complement classical activation pathway reflected by reduced C4/C3 generation and C1q-dependent lysis of antibody sensitized sheep erythrocytes. Moreover, recombinant Ts-CRT (rTs-CRT) binding to C1q suppressed C1q-induced THP-1-derived macrophages chemotaxis and reduced monocyte-macrophages release of reactive oxygen intermediates (ROIs). Blocking Ts CRT on the surface of newborn larvae (NBL) of T. spiralis with anti-Ts-CRT antibody increased the C1q-mediated adherence of monocyte-macrophages to larvae and impaired larval infectivity. All of these results suggest that T. spiralis expressed Ts-CRT plays crucial roles in T. spiralis immune evasion and survival in host mostly by directly binding to host complement C1q, which not only reduces C1q-mediated activation of classical complement pathway but also inhibits the C1q induced non-complement activation of macrophages. PMID- 28620389 TI - 2-Deoxy-d-Glucose Treatment Decreases Anti-inflammatory M2 Macrophage Polarization in Mice with Tumor and Allergic Airway Inflammation. AB - As important effector cells in inflammation, macrophages can be functionally polarized into either inflammatory M1 or alternatively activated anti inflammatory M2 phenotype depending on surroundings. The key roles of glycolysis in M1 macrophage polarization have been well defined. However, the relationship between glycolysis and M2 polarized macrophages is still poorly understood. Here, we report that 2-deoxy-d-glucose (2-DG), an inhibitor of the glycolytic pathway, markedly inhibited the expressions of Arg, Ym-1, Fizz1, and CD206 molecules, the hall-markers for M2 macrophages, during macrophages were stimulated with interleukin 4. The impacted M2 macrophage polarization by 2-DG is not due to cell death but caused by the impaired cellular glycolysis. Molecular mechanism studies indicate that the effect of 2-DG on M2 polarized macrophages relies on AMPK-Hif 1alpha-dependent pathways. Importantly, 2-DG treatment significantly decreases anti-inflammatory M2 macrophage polarization and prevents disease progression in a series of mouse models with chitin administration, tumor, and allergic airway inflammation. Thus, the identification of the master role of glycolysis in M2 macrophage polarization offers potential molecular targets for M2 macrophages mediated diseases. 2-DG therapy may have beneficial effects in patients with tumors or allergic airway inflammation by its negative regulation on M2 macrophage polarization. PMID- 28620390 TI - Belatacept Does Not Inhibit Follicular T Cell-Dependent B-Cell Differentiation in Kidney Transplantation. AB - Humoral alloreactivity has been recognized as a common cause of kidney transplant dysfunction. B-cell activation, differentiation, and antibody production are dependent on IL-21+CXCR5+follicular T-helper (Tfh) cells. Here, we studied whether belatacept, an inhibitor of the costimulatory CD28-CD80/86-pathway, interrupts the crosstalk between Tfh- and B-cells more efficiently than the calcineurin inhibitor tacrolimus. The suppressive effects of belatacept and tacrolimus on donor antigen-driven Tfh-B-cell interaction were functionally studied in peripheral blood mononuclear cells from 40 kidney transplant patients randomized to a belatacept- or tacrolimus-based immunosuppressive regimen. No significant differences in uncultured cells or donor antigen-stimulated cells were found between belatacept- and tacrolimus-treated patients in the CXCR5+Tfh cell generation and activation (upregulation of PD-1). Belatacept and tacrolimus in vitro minimally inhibited Tfh-cell generation (by ~6-7%) and partially prevented Tfh-cell activation (by ~30-50%). The proportion of IL-21+-activated Tfh-cells was partially decreased by in vitro addition of belatacept or tacrolimus (by ~60%). Baseline expressions and proportions of activated CD86+ B cells, plasmablasts, and transitional B-cells after donor antigen stimulation did not differ between belatacept- and tacrolimus-treated patients. Donor antigen driven CD86 upregulation on memory B-cells was not fully prevented by adding belatacept in vitro (~35%), even in supratherapeutic doses. In contrast to tacrolimus, belatacept failed to inhibit donor antigen-driven plasmablast formation (~50% inhibition vs. no inhibition, respectively, p < 0.0001). In summary, donor antigen-driven Tfh-B-cell crosstalk is similar in cells obtained from belatacept- and tacrolimus-treated patients. Belatacept is, however, less potent in vitro than tacrolimus in inhibiting Tfh-cell-dependent plasmablast formation. PMID- 28620391 TI - Toll-like Receptor-Dependent Negative Effects of Opioids: A Battle between Analgesia and Hyperalgesia. AB - Our understanding of the pathophysiology of the pathological pain and the pharmacology of analgesic treatments has progressed tremendously over the past two decades. Among the well-documented pro-algesic factors, glia and other toll like receptors (TLRs)-expressing cells in the neuroimmune interface have been recognized for their role in the development of neuropathic pain and for compromising the analgesic effects of opioids. Here, we comprehensively review the molecular mechanisms of pain initiation and progression, the role of TLRs in these processes, and the molecular mechanisms of morphine and morphine-3 glucuronide in TLR-dependent central immune signaling. The data reviewed here suggest that, while targeting glia to treat neuropathic pain, both analgesic and analgesia-opposing effects of opioids must be considered by acknowledging their role in TLR-mediated signaling. PMID- 28620392 TI - Interleukin-25 Produced by Synoviocytes Has Anti-inflammatory Effects by Acting As a Receptor Antagonist for Interleukin-17A Function. AB - The production and function of cytokines are highly regulated. One mechanism is the balance between pro- and anti-inflammatory cytokines. As interleukin (IL)-17A and IL-25 share the IL-17RA receptor chain, we hypothesize that IL-25 acts as an IL-17A receptor antagonist and limits its pro-inflammatory effects. The production and expression kinetics of IL-25 and its receptor chains IL-17RA and RB were analyzed in rheumatoid synoviocytes alone or in coculture with peripheral blood mononuclear cells (PBMCs). The effects of autocrine or exogenous IL-25 on synoviocytes were investigated in the presence or not of an anti-IL-25 antibody. To study the regulatory effects of IL-25, synoviocytes and/or PBMCs were exposed to IL-25 before being treated with IL-17A and tumor necrosis factor alpha (TNF alpha) alone or combined. IL-25, IL-6, and bioactive IL-17A were quantified in rheumatoid arthritis (RA) patient plasma. Synoviocytes expressed and secreted IL 25, and expressed the two chains of its receptor IL-17RA and IL-17RB. IL-17RB expression was increased by TNF-alpha. IL-25 production occurred at a delayed time point (5 days) after stimulation with IL-17A and TNF-alpha. Synoviocytes pretreated with IL-25 were less responsive to IL-17A and TNF-alpha. PBMCs exposed to IL-25 showed a decreased production of pro-inflammatory mediators, including IL-17A with a 57% decrease; p = 0.002. IL-25 levels were elevated in the plasma of RA patients compared to healthy subjects (p = 0.03). However, these levels are not high enough to inhibit the function of circulating IL-17A. In conclusion, it was shown for the first time that synoviocytes produce IL-25, specifically at late time points and that IL-25 acts as a regulator of IL-17A-driven inflammation, as indicated by in vitro results and in vivo, in a long-term RA patient follow-up. These results may be important when considering IL-17A inhibition. PMID- 28620393 TI - TWEAK/Fn14 Activation Participates in Ro52-Mediated Photosensitization in Cutaneous Lupus Erythematosus. AB - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) binds to its sole receptor fibroblast growth factor-inducible 14 (Fn14), participating in various inflammatory responses. Recently, TWEAK/Fn14 activation was found prominent in the lesions of cutaneous lupus erythematosus (CLE). This study was designed to further reveal the potential role of this pathway in Ro52-mediated photosensitization. TWEAK, Fn14, and Ro52 were determined in the skin lesions of patients with CLE. Murine keratinocytes received ultraviolet B (UVB) irradiation or plus TWEAK stimulation and underwent detection for Ro52 and proinflammatory cytokines. The chemotaxis of J774.2 macrophages was evaluated on TWEAK stimulation of cocultured keratinocytes. We found that TWEAK, Fn14, and downstream cytokines were highly expressed in CLE lesions that overexpressed Ro52. Moreover, TWEAK enhanced the UVB-induced Ro52 upregulation in murine keratinocytes. Meanwhile, TWEAK stimulation of keratinocytes favored the migration of macrophages through promoting the production of chemokine C-C motif ligands 17 and 22. Furthermore, Fn14 siRNA transfection or nuclear factor-kappa B (NF-kappaB) inhibitor abrogated the TWEAK enhancement of Ro52 expression in keratinocytes. Similarly, TNF receptor associated factor 2 (TRAF2) siRNA reduced the protein level of Ro52 in these cells upon TWEAK stimulation. Interestingly, UVB irradiation increased the expression of TNF receptor type 1 (TNFR1) but not affecting TNFR2 expression in keratinocytes. In conclusion, the TWEAK/Fn14 signaling participates in Ro52-mediated photosensitization and involves the activation of NF-kappaB pathway as well as the function of the TRAF2/TNFR partners. PMID- 28620394 TI - Vitamin D Counteracts Mycobacterium tuberculosis-Induced Cathelicidin Downregulation in Dendritic Cells and Allows Th1 Differentiation and IFNgamma Secretion. AB - Tuberculosis (TB) presents a serious health problem with approximately one-third of the world's population infected with Mycobacterium tuberculosis in a latent state. Experience from the pre-antibiotic era and more recent clinical studies have established a beneficial role of sunlight and vitamin D in patients with TB. At the same time, experimental data have shown that Th1 cells through production of IFNgamma are crucial for cathelicidin release by macrophages, bacterial killing, and containment of M. tuberculosis in granulomas. Paradoxically, vitamin D has repeatedly been ascribed an immune-suppressive function inhibiting Th1 differentiation and production of IFNgamma in T cells. The aim of this study was to investigate this apparent paradox. We studied naive human CD4+ T cells activated either with CD3 and CD28 antibodies or with allogeneic dendritic cells (DC) stimulated with heat-killed M. tuberculosis (HKMT) or purified toll-like receptor (TLR) ligands. We show that vitamin D does not block differentiation of human CD4+ T cells to Th1 cells and that interleukin (IL)-12 partially counteracts vitamin D-mediated inhibition of IFNgamma production promoting production of equal amounts of IFNgamma in Th1 cells in the presence of vitamin D as in T cells activated in the absence of vitamin D and IL-12. Furthermore, we show that HKMT and TLR2 ligands strongly downregulate cathelicidin expression in DC and that vitamin D counteracts this by upregulating cathelicidin expression. In conclusion, we demonstrate that vitamin D counteracts M. tuberculosis-induced cathelicidin downregulation and allows Th1 differentiation and IFNgamma secretion. PMID- 28620395 TI - Genome-Wide Identification of Glyoxalase Genes in Medicago truncatula and Their Expression Profiling in Response to Various Developmental and Environmental Stimuli. AB - Glyoxalase is an evolutionary highly conserved pathway present in all organisms. Conventional glyoxalase pathway has two enzymes, glyoxalase I (GLYI) and glyoxalase II (GLYII) that act sequentially to detoxify a highly cytotoxic compound methylglyoxal (MG) to D-lactate with the help of reduced glutathione. Recently, proteins with DJ-1/PfpI domain have been reported to perform the same conversion in a single step without the help of any cofactor and thus termed as "unique glyoxalase III" enzyme. Genome-wide analysis of glyoxalase genes have been previously conducted in Arabidopsis, rice and Soybean plants, but no such study was performed for one of the agricultural important model legume species, Medicago truncatula. A comprehensive genome-wide analysis of Medicago identified a total of putative 29 GLYI, 14 GLYII genes, and 5 glyoxalase III (DJ-1) genes. All these identified genes and their corresponding proteins were analyzed in detail including their chromosomal distribution, gene duplication, phylogenetic relationship, and the presence of conserved domain(s). Expression of all these genes was analyzed in different tissues as well as under two devastating abiotic stresses- salinity and drought using publicly available transcript data. This study revealed that MtGLYI-4, MtGLYII-6, and MtDJ-1A are the constitutive members with a high level of expression at all 17 analyzed tissues; while MtGLYI-1, MtGLYI-11, MtGLYI-5, MtGLYI-7, and MtGLYII-13 showed tissue-specific expression. Moreover, most of the genes displayed similar pattern of expression in response to both salinity and drought stress, irrespective of stress duration and tissue type. MtGLYI-8, MtGLYI-11, MtGLYI-6, MtGLYI-16, MtGLYI-21, and MtGLYII-9 showed up-regulation, while MtGLYI-17 and MtGLYI-7/9 showed down-regulation in response to both stresses. Interestingly, MtGLYI-14/15 showed completely opposite pattern of expression in these two stresses. This study provides an initial basis about the physiological significance of glyoxalase genes in plant development and stress response of Medicago that could be explored further. PMID- 28620396 TI - Identification of a Potential ISR Determinant from Pseudomonas aeruginosa PM12 against Fusarium Wilt in Tomato. AB - Biocontrol of plant diseases through induction of systemic resistance is an environmental friendly substitute to chemicals in crop protection measures. Different biotic and abiotic elicitors can trigger the plant for induced resistance. Present study was designed to explore the potential of Pseudomonas aeruginosa PM12 in inducing systemic resistance in tomato against Fusarium wilt. Initially the bioactive compound, responsible for ISR, was separated and identified from extracellular filtrate of P. aeruginosa PM12. After that purification and characterization of the bacterial crude extracts was carried out through a series of organic solvents. The fractions exhibiting ISR activity were further divided into sub-fractions through column chromatography. Sub fraction showing maximum ISR activity was subjected to Gas chromatography/mass spectrometry for the identification of compounds. Analytical result showed three compounds in the ISR active sub-fraction viz: 3-hydroxy-5-methoxy benzene methanol (HMB), eugenol and tyrosine. Subsequent bioassays proved that HMB is the potential ISR determinant that significantly ameliorated Fusarium wilt of tomato when applied as soil drench method at the rate of 10 mM. In the next step of this study, GC-MS analysis was performed to detect changes induced in primary and secondary metabolites of tomato plants by the ISR determinant. Plants were treated with HMB and Fusarium oxysporum in different combinations showing intensive re- modulations in defense related pathways. This work concludes that HMB is the potential elicitor involved in dynamic reprogramming of plant pathways which functionally contributes in defense responses. Furthermore the use of biocontrol agents as natural enemies of soil borne pathogens besides enhancing production potential of crop can provide a complementary tactic for sustainable integrated pest management. PMID- 28620397 TI - Metabolome Dynamics of Smutted Sugarcane Reveals Mechanisms Involved in Disease Progression and Whip Emission. AB - Sugarcane smut disease, caused by the biotrophic fungus Sporisorium scitamineum, is characterized by the development of a whip-like structure from the plant meristem. The disease causes negative effects on sucrose accumulation, fiber content and juice quality. The aim of this study was to exam whether the transcriptomic changes already described during the infection of sugarcane by S. scitamineum result in changes at the metabolomic level. To address this question, an analysis was conducted during the initial stage of the interaction and through disease progression in a susceptible sugarcane genotype. GC-TOF-MS allowed the identification of 73 primary metabolites. A set of these compounds was quantitatively altered at each analyzed point as compared with healthy plants. The results revealed that energetic pathways and amino acid pools were affected throughout the interaction. Raffinose levels increased shortly after infection but decreased remarkably after whip emission. Changes related to cell wall biosynthesis were characteristic of disease progression and suggested a loosening of its structure to allow whip growth. Lignin biosynthesis related to whip formation may rely on Tyr metabolism through the overexpression of a bifunctional PTAL. The altered levels of Met residues along with overexpression of SAM synthetase and ACC synthase genes suggested a role for ethylene in whip emission. Moreover, unique secondary metabolites antifungal-related were identified using LC-ESI-MS approach, which may have potential biomarker applications. Lastly, a putative toxin was the most important fungal metabolite identified whose role during infection remains to be established. PMID- 28620398 TI - Genome-Wide Association Study of Grain Architecture in Wild Wheat Aegilops tauschii. AB - Aegilops tauschii, the D-genome progenitor of Triticum aestivum, encompasses huge diversity for various traits of potential economic importance such as yield, biotic and abiotic stress tolerance, quality and nutrition. In the present study, variation for grain size in Ae. tauschii germplasm was studied and its genetic basis dissected using genome-wide association study (GWAS). Grain length, width, and weight evaluated in 177 Ae. tauschii accessions over 3 years showed near normal distribution with 1.74-, 1.75-, and 2.82-fold variation, respectively. These lines were genetically characterized using genotyping-by-sequencing (GBS) protocol that produced 11,489 single nucleotide polymorphic (SNP) markers. Genetic diversity analysis revealed the presence of two distinct subgroups (designated as lineage 1 and 2) in Ae. tauschii. Based on GBS markers, the genetic similarity was calculated between the accessions and GWAS was conducted using 114 non-redundant accessions and 5,249 SNP markers. A total of 17 SNPs associated with grain size traits distributed over all the seven chromosomes were revealed with 6D, 5D, and 2D harboring most significant marker-trait associations. Some of the chromosomal regions such as 6D_66.4-71.1 cM, 1D_143.5 156.7 cM, and 2D_89.9-92.5 cM had associations with multiple traits. Candidate genes associated with cell division and differentiation were identified for some of the associated SNP markers. Further efforts to validate these loci will help to understand their role in determining grain size and allelic diversity in current germplasm and its effect on grain size upon transfer to bread wheat background. PMID- 28620399 TI - Timing Is Important: Unmanned Aircraft vs. Satellite Imagery in Plant Invasion Monitoring. AB - The rapid spread of invasive plants makes their management increasingly difficult. Remote sensing offers a means of fast and efficient monitoring, but still the optimal methodologies remain to be defined. The seasonal dynamics and spectral characteristics of the target invasive species are important factors, since, at certain time of the vegetation season (e.g., at flowering or senescing), plants are often more distinct (or more visible beneath the canopy). Our aim was to establish fast, repeatable and a cost-efficient, computer-assisted method applicable over larger areas, to reduce the costs of extensive field campaigns. To achieve this goal, we examined how the timing of monitoring affects the detection of noxious plant invaders in Central Europe, using two model herbaceous species with markedly different phenological, structural, and spectral characteristics. They are giant hogweed (Heracleum mantegazzianum), a species with very distinct flowering phase, and the less distinct knotweeds (Fallopia japonica, F. sachalinensis, and their hybrid F. * bohemica). The variety of data generated, such as imagery from purposely-designed, unmanned aircraft vehicle (UAV), and VHR satellite, and aerial color orthophotos enabled us to assess the effects of spectral, spatial, and temporal resolution (i.e., the target species' phenological state) for successful recognition. The demands for both spatial and spectral resolution depended largely on the target plant species. In the case that a species was sampled at the most distinct phenological phase, high accuracy was achieved even with lower spectral resolution of our low-cost UAV. This demonstrates that proper timing can to some extent compensate for the lower spectral resolution. The results of our study could serve as a basis for identifying priorities for management, targeted at localities with the greatest risk of invasive species' spread and, once eradicated, to monitor over time any return. The best mapping strategy should reflect morphological and structural features of the target plant and choose appropriate spatial, spectral, and temporal resolution. The UAV enables flexible data acquisition for required time periods at low cost and is, therefore, well-suited for targeted monitoring; while satellite imagery provides the best solution for larger areas. Nonetheless, users must be aware of their limits. PMID- 28620400 TI - Comparing Pixel and Object-Based Approaches to Map an Understorey Invasive Shrub in Tropical Mixed Forests. AB - The establishment of invasive alien species in varied habitats across the world is now recognized as a genuine threat to the preservation of biodiversity. Specifically, plant invasions in understory tropical forests are detrimental to the persistence of healthy ecosystems. Monitoring such invasions using Very High Resolution (VHR) satellite remote sensing has been shown to be valuable in designing management interventions for conservation of native habitats. Object based classification methods are very helpful in identifying invasive plants in various habitats, by their inherent nature of imitating the ability of the human brain in pattern recognition. However, these methods have not been tested adequately in dense tropical mixed forests where invasion occurs in the understorey. This study compares a pixel-based and object-based classification method for mapping the understorey invasive shrub Lantana camara (Lantana) in a tropical mixed forest habitat in the Western Ghats biodiversity hotspot in India. Overall, a hierarchical approach of mapping top canopy at first, and then further processing for the understorey shrub, using measures such as texture and vegetation indices proved effective in separating out Lantana from other cover types. In the first method, we implement a simple parametric supervised classification for mapping cover types, and then process within these types for Lantana delineation. In the second method, we use an object-based segmentation algorithm to map cover types, and then perform further processing for separating Lantana. The improved ability of the object-based approach to delineate structurally distinct objects with characteristic spectral and spatial characteristics of their own, as well as with reference to their surroundings, allows for much flexibility in identifying invasive understorey shrubs among the complex vegetation of the tropical forest than that provided by the parametric classifier. Conservation practices in tropical mixed forests can benefit greatly by adopting methods which use high resolution remotely sensed data and advanced techniques to monitor the patterns and effective functioning of native ecosystems by periodically mapping disturbances such as invasion. PMID- 28620401 TI - Transcriptome Profiling of Tomato Uncovers an Involvement of Cytochrome P450s and Peroxidases in Stigma Color Formation. AB - Stigma is a crucial structure of female reproductive organ in plants. Stigma color is usually regarded as an important trait in variety identification in some species, but the molecular mechanism of stigma color formation remains elusive. Here, we characterized a tomato mutant, yellow stigma (ys), that shows yellow rather than typical green color in the stigma. Analysis of pigment contents revealed that the level of flavonoid naringenin chalcone was increased in the ys stigma, possibly as a result of higher accumulation of p-coumaric acid, suggesting that naringenin chalcone might play a vital role in yellow color control in tomato stigma. To understand the genes and gene networks that regulate tomato stigma color, RNA-sequencing (RNA-Seq) analyses were performed to compare the transcriptomes of stigmas between ys mutant and wild-type (WT). We obtained 507 differentially expressed genes, in which, 84 and 423 genes were significantly up-regulated and down-regulated in the ys mutant, respectively. Two cytochrome P450 genes, SlC3H1 and SlC3H2 which encode p-coumarate 3-hydroxylases, and six peroxidase genes were identified to be dramatically inhibited in the yellow stigma. Further bioinformatic and biochemical analyses implied that the repression of the two SlC3Hs and six PODs may indirectly lead to higher naringenin chalcone level through inhibiting lignin biosynthesis, thereby contributing to yellow coloration in tomato stigma. Thus, our data suggest that two SlC3Hs and six PODs are involved in yellow stigma formation. This study provides valuable information for dissecting the molecular mechanism of stigma color control in tomato. Statement: This study reveals that two cytochrome P450s (SlC3H1 and SlC3H2) and six peroxidases potentially regulate the yellow stigma formation by indirectly enhancing biosynthesis of yellow-colored naringenin chalcone in the stigma of tomato. PMID- 28620402 TI - The xantha Marker Trait Is Associated with Altered Tetrapyrrole Biosynthesis and Deregulated Transcription of PhANGs in Rice. AB - The xantha marker trait, which is controlled by a down-regulating epi-mutation of OsGUN4, has been applied to the production of hybrid rice. However, the molecular basis for the ability of xantha mutants to attain high photosynthetic capacity even with decreased chlorophyll contents has not been characterized. In the present study, we observed that the total chlorophyll content of the xantha mutant was only 27.2% of that of the wild-type (WT) plants. However, the xantha mutant still accumulated 59.9% of the WT delta-aminolevulinic acid content, 72.8% of the WT Mg-protoporphyrin IX content, and 63.0% of the WT protochlorophyllide a content. Additionally, the protoporphyrin IX and heme contents in the mutant increased to 155.0 and 160.0%, respectively, of the WT levels. A search for homologs resulted in the identification of 124 rice genes involved in tetrapyrrole biosynthesis and photosynthesis. With the exception of OsGUN4, OsHO 1, and OsHO-2, the expression levels of the genes involved in tetrapyrrole biosynthesis were significantly higher in the xantha mutant than in the WT plants, as were all 72 photosynthesis-associated nuclear genes. In contrast, there were no differences between the xantha mutant and WT plants regarding the expression of all 22 photosynthesis-associated chloroplast genes. Furthermore, the abundance of 1O2 and the expression levels of 1O2-related genes were lower in the xantha mutant than in the WT plants, indicating 1O2-mediated retrograde signaling was repressed in the mutant plants. These results suggested that the abundance of protoporphyrin IX used for chlorophyll synthesis decreased in the mutant, which ultimately decreased the amount of chlorophyll in the xantha mutant. Additionally, the up-regulated expression of photosynthesis-associated nuclear genes enabled the mutant to attain a high photosynthetic capacity. Our findings confirm that OsGUN4 plays an important role in tetrapyrrole biosynthesis and photosynthesis in rice. GUN4, chlorophyll synthesis pathways, and photosynthetic activities are highly conserved in plants and hence, novel traits (e.g., xantha marker trait) may be generated in other cereal crops by modifying the GUN4 gene. PMID- 28620403 TI - Genetic Mechanisms of the Devious Intruder Candidatus Liberibacter in Citrus. PMID- 28620404 TI - Oral Administration of a Seed-based Bivalent Rotavirus Vaccine Containing VP6 and NSP4 Induces Specific Immune Responses in Mice. AB - Rotavirus is the leading cause of severe diarrheal disease among newborns. Plant based rotavirus vaccines have been developed in recent years and have been proven to be effective in animal models. In the present study, we report a bivalent vaccine candidate expressing rotavirus subunits VP6 and NSP4 fused with the adjuvant subunit B of E. coli heat-labile enterotoxin (LTB) in maize seeds. The RT-PCR and Western blot results showed that VP6 and LTB-NSP4 antigens were expressed and accumulated in maize seeds. The expression levels were as high as 0.35 and 0.20% of the total soluble protein for VP6 and LTB-NSP4, respectively. Oral administration of transgenic maize seeds successfully stimulated systemic and mucosal responses, with high titers of serum IgG and mucosal IgA antibodies, even after long-term storage. This study is the first to use maize seeds as efficient generators for the development of a bivalent vaccine against rotavirus. PMID- 28620405 TI - LeafletAnalyzer, an Automated Software for Quantifying, Comparing and Classifying Blade and Serration Features of Compound Leaves during Development, and among Induced Mutants and Natural Variants in the Legume Medicago truncatula. AB - Diverse leaf forms ranging from simple to compound leaves are found in plants. It is known that the final leaf size and shape vary greatly in response to developmental and environmental changes. However, changes in leaf size and shape have been quantitatively characterized only in a limited number of species. Here, we report development of LeafletAnalyzer, an automated image analysis and classification software to analyze and classify blade and serration characteristics of trifoliate leaves in Medicago truncatula. The software processes high quality leaf images in an automated or manual fashion to generate size and shape parameters for both blades and serrations. In addition, it generates spectral components for each leaflets using elliptic Fourier transformation. Reconstruction studies show that the spectral components can be reliably used to rebuild the original leaflet images, with low, and middle and high frequency spectral components corresponding to the outline and serration of leaflets, respectively. The software uses artificial neutral network or k-means classification method to classify leaflet groups that are developed either on successive nodes of stems within a genotype or among genotypes such as natural variants and developmental mutants. The automated feature of the software allows analysis of thousands of leaf samples within a short period of time, thus facilitating identification, comparison and classification of leaf groups based on leaflet size, shape and tooth features during leaf development, and among induced mutants and natural variants. PMID- 28620406 TI - Next-Generation Sequencing from Bulked-Segregant Analysis Accelerates the Simultaneous Identification of Two Qualitative Genes in Soybean. AB - Next-generation sequencing (NGS)-based bulked-segregant analysis (BSA) approaches have been proven successful for rapidly mapping genes in plant species. However, most such methods are based on mutants and usually only one gene controlling the mutant phenotype is identified. In this study, NGS-based BSA was employed to map simultaneously two qualitative genes controlling cotyledon color of seed in soybean. Yellow-cotyledon (YC) and green-cotyledon (GC) bulks from progenies of a biparental population (Zhonghuang 30 * Jiyu 102) were sequenced. The SNP-index of each SNP locus in YC and GC bulks was calculated and two genomic regions on chromosomes 1 and 11 harboring, respectively, loci qCC1 and qCC2 were identified by Delta(SNP-index) analysis. These two BSA-seq-derived loci were further validated with SSR markers and fine-mapped. qCC1 was mapped to a 30.7-kb region containing four annotated genes and qCC2 was mapped to a 67.7-kb region with nine genes. These two regions contained, respectively, genes D1 and D2, which had previously been identified by homology-based cloning as being associated with cotyledon color. Sequence analysis of the NGS data also identified a frameshift deletion in the coding region of D1. These results suggested that BSA-seq could accelerate the mapping of loci controlling qualitative traits, even if a trait is controlled by more than one locus. PMID- 28620407 TI - Antioxidant Responses Induced by UVB Radiation in Deschampsia antarctica Desv. AB - Deschampsia antarctica Desv. is one of two vascular plants that live in the Maritime Antarctic Territory and is exposed to high levels of ultraviolet-B (UVB) radiation. In this work, antioxidant physiology of D. antarctica was studied in response to UVB induced oxidative changes. Samples were collected from Antarctica and maintained in vitro culture during 2 years. Plants were sub-cultured in a hydroponic system and exposed to 21.4 kJ m-2 day-1, emulating summer Antarctic conditions. Results showed rapid and significant increases in reactive oxygen species (ROS) at 3 h, which rapidly decreased. No dramatic changes were observed in photosynthetic efficiency, chlorophyll content, and level of thiobarbituric acid reactive species (MDA). The enzymatic (superoxide dismutase, SOD and total peroxidases, POD) and non-enzymatic antioxidant activity (total phenolic) increased significantly in response to UVB treatment. These findings suggest that tolerance of D. antarctica to UVB radiation could be attributed to its ability to activate both enzymatic and non-enzymatic antioxidant systems. PMID- 28620408 TI - Quality Control of the Traditional Patent Medicine Yimu Wan Based on SMRT Sequencing and DNA Barcoding. AB - Substandard traditional patent medicines may lead to global safety-related issues. Protecting consumers from the health risks associated with the integrity and authenticity of herbal preparations is of great concern. Of particular concern is quality control for traditional patent medicines. Here, we establish an effective approach for verifying the biological composition of traditional patent medicines based on single-molecule real-time (SMRT) sequencing and DNA barcoding. Yimu Wan (YMW), a classical herbal prescription recorded in the Chinese Pharmacopoeia, was chosen to test the method. Two reference YMW samples were used to establish a standard method for analysis, which was then applied to three different batches of commercial YMW samples. A total of 3703 and 4810 circular-consensus sequencing (CCS) reads from two reference and three commercial YMW samples were mapped to the ITS2 and psbA-trnH regions, respectively. Moreover, comparison of intraspecific genetic distances based on SMRT sequencing data with reference data from Sanger sequencing revealed an ITS2 and psbA-trnH intergenic spacer that exhibited high intraspecific divergence, with the sites of variation showing significant differences within species. Using the CCS strategy for SMRT sequencing analysis was adequate to guarantee the accuracy of identification. This study demonstrates the application of SMRT sequencing to detect the biological ingredients of herbal preparations. SMRT sequencing provides an affordable way to monitor the legality and safety of traditional patent medicines. PMID- 28620409 TI - Real-Time Determination of Photosynthesis, Transpiration, Water-Use Efficiency and Gene Expression of Two Sorghum bicolor (Moench) Genotypes Subjected to Dry Down. AB - Plant growth and productivity are strongly affected by limited water availability in drought prone environments. The current climate change scenario, characterized by long periods without precipitations followed by short but intense rainfall, forces plants to implement different strategies to cope with drought stress. Understanding how plants use water during periods of limited water availability is of primary importance to identify and select the best adapted genotypes to a certain environment. Two sorghum genotypes IS22330 and IS20351, previously characterized as drought tolerant and drought sensitive genotypes, were subjected to progressive drought stress through a dry-down experiment. A whole-canopy multi chamber system was used to determine the in vivo water use efficiency (WUE). This system records whole-canopy net photosynthetic and transpiration rate of 12 chambers five times per hour allowing the calculation of whole-canopy instantaneous WUE daily trends. Daily net photosynthesis and transpiration rates were coupled with gene expression dynamics of five drought related genes. Under drought stress, the tolerant genotype increased expression level for all the genes analyzed, whilst the opposite trend was highlighted by the drought sensitive genotype. Correlation between gene expression dynamics and gas exchange measurements allowed to identify three genes as valuable candidate to assess drought tolerance in sorghum. PMID- 28620410 TI - Transcriptome Analysis of Differentially Expressed Genes Induced by Low and High Potassium Levels Provides Insight into Fruit Sugar Metabolism of Pear. AB - Potassium (K) deficiency is a common abiotic stress that can inhibit the growth of fruit and thus reduce crop yields. Little research has been conducted on pear transcriptional changes under low and high K conditions. Here, we performed an experiment with 7-year-old pot-grown "Huangguan" pear trees treated with low, Control or high K levels (0, 0.4, or 0.8 g.K2O/kg soil, respectively) during fruit enlargement and mature stages. We identified 36,444 transcripts from leaves and fruit using transcriptome sequencing technology. From 105 days after full blooming (DAB) to 129 DAB, the number of differentially expressed genes (DEGs) in leaves and fruit in response to low K increased, while in response to high K, the number of DEGs in leaves and fruit decreased. We selected 17 of these DEGs for qRT-PCR analysis to confirm the RNA sequencing results. Based on GO enrichment and KEGG pathway analysis, we found that low-K treatment significantly reduced K nutrient and carbohydrate metabolism of the leaves and fruit compared with the Control treatment. During the fruit development stages, AKT1 (gene39320) played an important role on K+ transport of the leaves and fruit response to K stress. At maturity, sucrose and acid metabolic pathways were inhibited by low K. The up regulation of the expression of three SDH and two S6PDH genes involved in sorbitol metabolism was induced by low K, promoting the fructose accumulation. Simultaneously, higher expression was found for genes encoding amylase under low K, promoting the decomposition of the starch and leading the glucose accumulation. High K could enhance leaf photosynthesis, and improve the distribution of the nutrient and carbohydrate from leaf to fruit. Sugar components of the leaves and fruit under low K were regulated by the expression of genes encoding 8 types of hormone signals and reactive oxygen species (ROS). Our data revealed the gene expression patterns of leaves and fruit in response to different K levels during the middle and late stages of fruit development as well as the molecular mechanism of improvement of fruit sugar levels by K and provided a scientific basis for improving fruit quality with supplemental K fertilizers. PMID- 28620411 TI - ViCAR: An Adaptive and Landmark-Free Registration of Time Lapse Image Data from Microfluidics Experiments. AB - In order to understand gene function in bacterial life cycles, time lapse bioimaging is applied in combination with different marker protocols in so called microfluidics chambers (i.e., a multi-well plate). In one experiment, a series of T images is recorded for one visual field, with a pixel resolution of 60 nm/px. Any (semi-)automatic analysis of the data is hampered by a strong image noise, low contrast and, last but not least, considerable irregular shifts during the acquisition. Image registration corrects such shifts enabling next steps of the analysis (e.g., feature extraction or tracking). Image alignment faces two obstacles in this microscopic context: (a) highly dynamic structural changes in the sample (i.e., colony growth) and (b) an individual data set-specific sample environment which makes the application of landmarks-based alignments almost impossible. We present a computational image registration solution, we refer to as ViCAR: (Vi)sual (C)ues based (A)daptive (R)egistration, for such microfluidics experiments, consisting of (1) the detection of particular polygons (outlined and segmented ones, referred to as visual cues), (2) the adaptive retrieval of three coordinates throughout different sets of frames, and finally (3) an image registration based on the relation of these points correcting both rotation and translation. We tested ViCAR with different data sets and have found that it provides an effective spatial alignment thereby paving the way to extract temporal features pertinent to each resulting bacterial colony. By using ViCAR, we achieved an image registration with 99.9% of image closeness, based on the average rmsd of 4.10-2 pixels, and superior results compared to a state of the art algorithm. PMID- 28620413 TI - The Effect of a Synthetic Heparan Sulfate on the Healing of Colonic Anastomoses. AB - BACKGROUND: The mimetic compound OTR4120 may replace endogenous-degraded heparan sulfates that normally maintain the bioactivity of growth factors that are important for tissue repair. Herein, we investigated the effect of OTR4120 on the healing of normal colonic anastomoses. METHODS: We evaluated the following two treatment groups of male Sprague Dawley rats (220-256 g): control-treated colonic anastomoses (n = 25) and OTR4120-treated colonic anastomoses (n = 25). We resected 10 mm of the left colon and then applied either saline alone (control) or OTR4120 (100 MUg/mL) in saline to the colonic ends before an end-to-end single layer anastomosis was constructed and again on the anastomosis before the abdomen and skin were closed. RESULTS: On postoperative day 3, the anastomotic breaking strengths were 1.47 +/- 0.32 N (mean +/- SD) in the control group and 1.52 +/- 0.27 N in the OTR4120-treated animals (P = 0.622). We also found that the hydroxyproline concentration (indicator of collagen) in the anastomotic wounds did not differ (P = 0.571) between the two groups. CONCLUSIONS: Our data demonstrate that a single local application of OTR4120 intraoperatively did not increase the biomechanical strength of colonic anastomoses at the critical postoperative day 3 when the anastomoses are the weakest. PMID- 28620412 TI - Single-Cell mRNA Sequencing in Cancer Research: Integrating the Genomic Fingerprint. AB - Critical cancer mutations are often regional and mosaic, confounding the efficacy of targeted therapeutics. Single cell mRNA sequencing (scRNA-seq) has enabled unprecedented studies of intra-tumor heterogeneity and its role in cancer progression, metastasis, and treatment resistance. When coupled with DNA sequencing, scRNA-seq allows one to infer the in vivo impact of genomic alterations on gene expression. This combination can be used to reliably distinguish neoplastic from non-neoplastic cells, to correlate paracrine signaling pathways between neoplastic cells and stroma, and to map expression signatures to inferred clones and phylogenies. Here we review recent advances in scRNA-seq, with a special focus on cancer. We discuss the challenges and prospects of combining scRNA-seq with DNA sequencing to assess intra-tumor heterogeneity. PMID- 28620414 TI - Immunological Aspects of Gastrointestinal Diseases. PMID- 28620415 TI - A Novel Surgical Technique for Fixation of Recurrent Acromioclavicular Dislocations: AC Dog Bone Technique in Combination with Autogenous Semitendinosus Tendon Graft. AB - Various surgical techniques have been described for the fixation of acromioclavicular (AC) dislocations. However, recurrent dislocation is one of the main complications associated with the majority of these techniques. We report a case of postoperative AC joint redislocation. In order to overcome recurrent dislocation after revision surgery, a reconstruction of the conoid and trapezoid ligament with the use of a free tendon graft in combination with a FiberTape was provided within a novel surgical technique. After 12 months, the patient was very satisfied with the functional outcome. The patient achieved excellent results in the Constant (98 points), SPADI (0 points), and QuickDASH score (0 points). The described technique results in an anatomic reconstruction of the AC joint. The nonrigid nature of the intervention seems to restore the normal arthrokinematics by reconstructing the coracoclavicular ligaments with an autograft which is then protected by the AC Dog Bone artificial ligaments during the healing period. The arthroscopic approach to the AC joint with minimal exposure reduces the risks and complications of the intervention. This is the first case in literature that utilizes the artificial dog bone ligament securing the autograft in an anatomic AC reconstruction. PMID- 28620416 TI - Antiphospholipid Syndrome: Multiple Manifestations in a Single Patient-A High Suspicion Is Still Needed. AB - Antiphospholipid Syndrome (APS) is an autoimmune disorder with clinical and laboratory features of vascular thrombosis, pregnancy loss, and persistent antiphospholipid antibodies (aPLs). The pathophysiology is thought to involve the activation of endothelial cells, monocytes, platelets, and complement by aPLs. Disease can range from asymptomatic to rapidly fatal catastrophic APS. We present a case of a 34-year-old male referred for pancytopenia and splenomegaly. On examination, he had decreased sensation and 4/5 power in the left upper extremity. A lacy, purplish rash was noted on the trunk and upper extremity. MRI of brain showed acute/subacute lacunar infarctions. Laboratory studies revealed an elevated lactate dehydrogenase level, bilirubin and ferritin, decreased haptoglobin, and positive Coombs test. Antinuclear antibody test was negative and antiphospholipid antibody panel revealed positivity for anti-cardiolipin IgG and IgM, antiphosphatidylserine IgG, and anti-beta2-glycoprotein IgG. The patient was diagnosed with primary APS. Pancytopenia is relatively rare in primary APS and is more often seen in secondary APS. Our patient demonstrated involvement of multiple organ systems as well as livedo reticularis and autoimmune-related findings such as Raynaud phenomenon and Coombs positive hemolytic anemia. We discuss the various clinical and laboratory findings in patients with APS that aid in diagnosis, as well as important management considerations. PMID- 28620417 TI - Molecular Targets and Associated Potential Pathways of Danlu Capsules in Hyperplasia of Mammary Glands Based on Systems Pharmacology. AB - Hyperplasia of mammary glands (HMG) is common in middle-aged women. Danlu capsules (DLCs) can effectively relieve pain and improve clinical symptoms and are safe for treating HMG. However, the active substances in DLCs and the molecular mechanisms of DLCs in HMG remain unclear. This study identified the bioactive compounds and delineated the molecular targets and potential pathways of DLCs by using a systems pharmacology approach. The candidate compounds were retrieved from the traditional Chinese medicine systems pharmacology (TCMSP) database and analysis platform. Each candidate's druggability was analyzed according to its oral bioavailability and drug-likeness indices. The candidate proteins and genes were extracted in the TCMSP and UniProt Knowledgebase, respectively. The potential pathways associated with the genes were identified by performing gene enrichment analysis with DAVID Bioinformatics Resources 6.7. A total of 603 compounds were obtained from DLCs, and 39 compounds and 66 targets associated with HMG were obtained. Gene enrichment analysis yielded 10 significant pathways with 34 targets. The integrated HMG pathway revealed that DLCs probably act in patients with HMG through multiple mechanisms of anti inflammation, analgesic effects, and hormonal regulation. This study provides novel insights into the mechanisms of DLCs in HMG, from the molecular level to the pathway level. PMID- 28620418 TI - The Changes in Rats with Sciatic Nerve Crush Injury Supplemented with Evening Primrose Oil: Behavioural, Morphologic, and Morphometric Analysis. AB - Nerve crush injuries are commonly used models for axonotmesis to examine peripheral nerve regeneration. As evening primrose oil (EPO) is rich in omega-6 essential fatty acid component and gamma-linolenic acid, studies have shown the potential role of EPO in myelination. Seventy-two healthy adult Sprague-Dawley rats were classified into three groups: normal group, control group, and experimental group. The result indicates that there was significant difference in toe-spreading reflex between the normal and the control groups (1.9 +/- 0.031, p < 0.05) and the normal and the EPO groups (0.4 +/- 0.031, p < 0.05) and significant difference between EPO and the control groups (1.5 +/- 0.031, p < 0.05). Regeneration of axons and myelin in nerve fibre in the EPO-treated group developed better and faster than in the control group. In the control group, the shape of the axon was irregular with a thinner myelin sheath. In the experimental group, the shape of the axons, the thickness of the myelin sheath, and the diameter of the axons were almost the same as in the normal group. In conclusion, EPO supplementation may be beneficial as a therapeutic option for disturbances of nerve interaction. PMID- 28620419 TI - Periplaneta americana Extracts Promote Skin Wound Healing via Nuclear Factor Kappa B Canonical Pathway and Extracellular Signal-Regulated Kinase Signaling. AB - Periplaneta americana extracts (PAEs) exhibit wound healing properties. However, the underlying molecular mechanisms are not well understood. Here, we treated human skin fibroblasts (HSF) with PAE and the proliferation was determined by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The wound healing and transwell migration assays were used to detect cell migration. Nuclear factor kappa B (NF-kappaB) and extracellular signal-regulated kinase (ERK) pathways were analyzed by Western blot (WB). Immunofluorescence staining was used to detect the key molecular localization in the cells. The results showed that PAE enhanced the proliferation and migration of HSF cells. The expression and activation of key proteins such as RelA and p-ERK were increased in NF-kappaB and ERK pathways followed by nuclear translocation. In vivo, both WB and immunohistochemical (IHC) staining showed that PAE enhanced p-IkappaBalpha and p-ERK activation and the nuclear translocation of RelA. Our study suggests that the protective function of PAE is mediated via enhanced NF-kappaB and ERK signaling. PMID- 28620420 TI - Pharmacokinetic Comparison of 20(R)- and 20(S)-Ginsenoside Rh1 and 20(R)- and 20(S)-Ginsenoside Rg3 in Rat Plasma following Oral Administration of Radix Ginseng Rubra and Sheng-Mai-San Extracts. AB - Ginsenosides Rh1 and Rg3, as the main bioactive components from Ginseng, are effective for prevention and treatment of cardiovascular diseases. Sheng-Mai-San (SMS), a classical complex prescription of traditional Chinese medicines, is composed of Radix Ginseng Rubra, Fructus Schisandrae, and Radix Ophiopogonis. In this research, a sensitive and specific liquid chromatography-mass spectrometric method was developed and validated for stereoselective determination and pharmacokinetic studies of 20(R)- and 20(S)-ginsenoside Rh1 and 20(R)- and 20(S) ginsenoside Rg3 epimers in rat plasma after oral administration of Radix Ginseng Rubra or SMS extracts. The main pharmacokinetic parameters including Tmax, Cmax, t1/2, and AUC were calculated by noncompartment model. Compared with Radix Ginseng Rubra, SMS could significantly increase the content of ginsenosides Rh1 and Rg3 in the decocting process. Ginsenosides Rh1 and Rg3 following SMS treatment displayed higher Cmax, AUC(0-t), and AUC(0-infinity) and longer t1/2 and tmax except for 20(R)-Rh1 in rat plasma. The results indicated SMS compound compatibility could influence the dissolution in vitro and the pharmacokinetic behaviors in vivo of ginsenosides Rh1 and Rg3, suggesting pharmacokinetic drug drug interactions between ginsenosides Rh1 and Rg3 and other ingredients from Fructus Schisandrae and Radix Ophiopogonis. This study would provide valuable information for drug development and clinical application of SMS. PMID- 28620421 TI - Is there role for vitamin D in the treatment of chronic pain? AB - Chronic pain is highly prevalent in the developed world, and levels of vitamin D are often lower among those with chronic pain conditions than those without. Supplementation of vitamin D has been investigated as a potential independent treatment for chronic pain. This paper presents an overview of the scientific evidence and provides recommendations for use of vitamin D in clinical practice with chronic pain patients. PMID- 28620422 TI - Special considerations for vitamin D in the south Asian population in the UK. AB - The human requirement for vitamin D is achieved primarily through the synthesis of this prehormone in the skin during exposure to ultraviolet B (UVB) radiation, with only a minor contribution from the diet, year round. Achieving optimal vitamin D status is therefore largely dependent upon adequate exposure of the skin to sunlight, however, the length of exposure required varies with latitude and season, and is also dependent upon skin pigmentation, with darker skin requiring greater exposure than fair skin due to the protective effects of melanin against UVB radiation. In northern European latitudes, where UVB radiation between the months of October and March is of insufficient intensity for the synthesis of vitamin D via this route, vitamin D deficiency is a public health concern, particularly for south Asian diaspora and other dark-skinned ethnic minority communities. The consequences of vitamin D deficiency include poor bone health, including rickets and osteomalacia. In addition, there is increasing awareness of an important role for vitamin D in the development and progression of chronic diseases, including type 2 diabetes, which is prevalent in south Asian populations. The aim of this review is to examine some of the most recent reports of vitamin D status in south Asian diaspora communities, and to explore its impact on bone health. In addition, we will examine the putative association between type 2 diabetes and vitamin D deficiency in south Asian populations and the current guidelines for treatment of vitamin D deficiency of south Asians in primary care settings. PMID- 28620425 TI - Breathe: biomedical engineering in respiratory disorders. AB - The June issue of Breathe looks at biomedical engineering in respiratory disorders http://ow.ly/rn7N30c2qvg. PMID- 28620426 TI - Re-certification of respiratory professionals: current practice and the future - educational forum report. AB - Re-certification of respiratory professionals: a report of an @ERStalk education forum held at #ERSLDN16 http://ow.ly/pUKY30bzcrK. PMID- 28620423 TI - Vitamin D in pregnancy: current perspectives and future directions. AB - As neonatal vitamin D status is determined by circulating maternal 25 hydroxyvitamin D [25(OH)D] concentrations, prevention of maternal vitamin D deficiency during pregnancy is essential for the avoidance of neonatal deficiency. However, a high prevalence of vitamin D deficiency has been extensively reported among gravidae and neonates from ethnic minorities and white populations resident at high latitude. Currently, regulatory authorities recommend vitamin D intakes for pregnant women that are similar to non-pregnant adults of the same age, at 10-15 ug/day (400-600 IU), to meet 25(OH)D thresholds of 25-50 nmol/liter. The lack of pregnancy-specific dietary recommendations is due to inadequate data indicating whether nutritional requirements for vitamin D during pregnancy differ from the non-pregnant state. In addition, there are few dose-response studies to determine the maternal 25(OH)D response to vitamin D intake throughout pregnancy at high latitude. These data are also required to determine vitamin D requirements during pregnancy for prevention of neonatal deficiency, an outcome which is likely to require a higher maternal 25(OH)D concentration than prevention of maternal deficiency only. With regard to the impact of vitamin D on perinatal health outcomes, which could guide pregnancy specific 25(OH)D thresholds, dietary intervention studies to date have been inconsistent and recent systematic reviews have highlighted issues of low quality and a high risk of bias as drawbacks in the trial evidence to date. Many observational studies have been hampered by a reliance on retrospective data, unclear reporting, suboptimal clinical phenotyping and incomplete subject characterization. Current investigations of vitamin D metabolism during pregnancy have potentially exciting implications for clinical research. This paper provides an update of current dietary recommendations for vitamin D in pregnant women and a synopsis of the evidence relating vitamin D status with maternal and infant health. PMID- 28620427 TI - ERS noninvasive ventilation course: basic concepts. AB - Faculty and delegates of the @ERStalk course on basic concepts in NIV describe their experiences http://ow.ly/zUPn30b7jLb. PMID- 28620429 TI - Novel approaches to ultrasonography of the lung and pleural space: where are we now? AB - : This review article is an update of what should be known for practicing basic lung ultrasound in the critically ill (LUCI) and is also of interest for less critical disciplines (e.g. pulmonology). It pinpoints on the necessity of a professional machine (not necessarily a sophisticated one) and probe. It lists the 10 main signs of LUCI and some of the main protocols made possible using LUCI: the BLUE protocol for a respiratory failure, the FALLS protocol for a circulatory failure, the SESAME protocol for a cardiac arrest and the investigation of a ventilated acute respiratory distress syndrome patient, etc. It shows how the field has been fully standardised to avoid confusion. KEY POINTS: A simple ultrasonography unit is fully adequate, with minimal filters, and provides a unique probe for integrating the lung into a holistic, whole-body approach to the critically ill.Interstitial syndrome is strictly defined. Its clinical relevance in the critically ill is standardised for defining haemodynamic pulmonary oedema, pneumonia and pulmonary embolism.Pneumothorax is strictly and sequentially defined by the A'-profile (at the anterior wall in a supine or semirecumbent patient, abolished lung siding plus the A-line sign) and then the lung point.The BLUE protocol integrates lung and venous ultrasound findings for expediting the diagnosis of acute respiratory failure, following pathophysiology, allowing prompt diagnosis of pneumonia, haemodynamic pulmonary oedema, exacerbated chronic obstructive pulmonary disease or asthma, pulmonary embolism or pneumothorax, even in clinically challenging presentations. EDUCATIONAL AIMS: To understand that the use of lung ultrasound, although long standardised, still needs educational efforts for its best use, a suitable machine, a suitable universal probe and an appropriate culture.To be able to use a terminology that has been fully standardised to avoid any confusion of useless wording.To understand the logic of the BLUE points, three points of interest enabling expedition of a lung ultrasound examination in acute respiratory failure.To be able to cite, in the correct hierarchy, the seven criteria of the B line, then those of interstitial syndrome.To understand the sequential thinking when making ultrasound diagnosis of pneumothorax.To be able to use the BLUE protocol for building profiles of pneumonia (or acute respiratory distress syndrome) and understand their limitations.To understand that lung ultrasound can be used for the direct analysis of an acute respiratory failure (the BLUE protocol), an acute circulatory failure (the FALLS protocol) and even a cardiac arrest (SESAME protocol), following a pathophysiological approach.To understand that the first sequential target in the SESAME protocol (search first for pneumothorax in cardiac arrest) can also be used in countless more quiet settings of countless disciplines, making lung ultrasound in the critically ill cost-, time- and radiation-saving.To be able to perform a BLUE protocol in challenging patients, understanding how the best lung ultrasound can be obtained from bariatric or agitated, dyspnoeic patients. PMID- 28620428 TI - Trends in mechanical ventilation: are we ventilating our patients in the best possible way? AB - : This review addresses how the combination of physiology, medicine and engineering principles contributed to the development and advancement of mechanical ventilation, emphasising the most urgent needs for improvement and the most promising directions of future development. Several aspects of mechanical ventilation are introduced, highlighting on one side the importance of interdisciplinary research for further development and, on the other, the importance of training physicians sufficiently on the technological aspects of modern devices to exploit properly the great complexity and potentials of this treatment. EDUCATIONAL AIMS: To learn how mechanical ventilation developed in recent decades and to provide a better understanding of the actual technology and practice.To learn how and why interdisciplinary research and competences are necessary for providing the best ventilation treatment to patients.To understand which are the most relevant technical limitations in modern mechanical ventilators that can affect their performance in delivery of the treatment.To better understand and classify ventilation modes.To learn the classification, benefits, drawbacks and future perspectives of automatic ventilation tailoring algorithms. PMID- 28620430 TI - Does sildenafil improve ventilatory function in asthmatic subjects? AB - Can sildenafil be used to treat asthma? http://ow.ly/13Y830bgExG. PMID- 28620431 TI - A 44-year-old, Caucasian, male nonsmoker with worsening difficulty in breathing and decreased exercise tolerance. AB - Can you diagnose this patient and identify the uncommon cause of his illness? http://ow.ly/t4nX30bzJFz. PMID- 28620432 TI - The curious incident of groaning in the night-time. AB - The first report of catathrenia in a child who has been symptomatic from birth http://ow.ly/XcY830bevOH. PMID- 28620433 TI - Opportunities for early career members. AB - Read about upcoming opportunities for @ERStalk Early Career Members http://ow.ly/QFyb30b7iKq. PMID- 28620434 TI - Top tips to deal with challenging situations: doctor-patient interactions. AB - When challenging situations arise in doctor-patient interactions, how can we best manage them? http://ow.ly/J1GI30bD5wp. PMID- 28620435 TI - To sleep, or not to sleep - that is the question, for polysomnography. AB - Have we reached the point where respiratory polygraphy can replace polysomnography in the assessment of OSAS? http://ow.ly/UxCU30bNopq. PMID- 28620436 TI - Hot topics from the Assemblies. AB - Pulmonary hypertension (PH) diagnostic criteria are currently defined as a mean pulmonary arterial pressure (mPAP) >=25 mmHg measured during a resting right heart catheterisation (RHC). However, the upper limit of normal for mPAP is believed to be around 20 mmHg. Patients with mPAP >20 mmHg but <25 mmHg are considered as having "borderline" PH. The clinical and prognostic relevance of this population is not completely understood. PMID- 28620437 TI - Radiology corner. PMID- 28620439 TI - Living well with COPD. AB - COPD is a group of conditions that includes chronic bronchitis and emphysema. PMID- 28620438 TI - Assembly 2: respiratory intensive care. AB - Meet @ERStalk Assembly 2: respiratory intensive care http://ow.ly/PnnB30b7nLU. PMID- 28620440 TI - Feeling cold and other underestimated symptoms in breast cancer: anecdotes or individual profiles for advanced patient stratification? AB - Breast cancer (BC) epidemic is recognised as being characteristic for the early twenty-first century. BC is a multifactorial disease, and a spectrum of modifiable (preventable) factors significantly increasing risks has been described. This article highlights a series of underestimated symptoms for consequent BC risk assessment and patient stratification. Phenomena of the deficient thermoregulation, altered sensitivity to different stimuli (pain, thirst, smell, light, stress provocation), dehydration, altered circadian and sleep patterns, tendency towards headache, migraine attacks and dizziness, as well as local and systemic hypoxic effects are discussed for BC patients providing functional links and proposing new approaches in the overall BC management. PMID- 28620442 TI - Efficacy of nanoceria for periodontal tissues alteration in glutamate-induced obese rats-multidisciplinary considerations for personalized dentistry and prevention. AB - BACKGROUND: Nowadays, we face the global epidemic of obesity, that is known to contribute to the development of many diseases, such as the oral cavity pathologies. Dental and oral pathologies are frequently caused by and overlapped with systemic multifactorial diseases such as obesity being its early indicators and risk factors. The aim was to study the influence of nanoceria on periodontal tissues alteration in glutamate (MSG)-induced obese rats. METHODS: We included 52 Wistar rats of both genders and divided into four groups: newborn rats in group 1 (control) received subcutaneously 8 MUl/g saline. Group 2 received 3 to 4 mg/g MSG subcutaneously on the second, fourth, sixth, eighth, and tenth day of life; group 3-intragastric administration of nanocrystalline cerium dioxide at a dose of 1 mg/kg volume of 2.9 ml/kg against the background of glutamate-induced obesity; the fourth group of animals was treated with a solution of sodium citrate intragastric volume of 2.9 ml/kg (solvent of nanocrystalline cerium). We determined the total proteolytic activity, the total antitrypsin activity, the content-free fucose and glycosaminoglycanes (GAG), content of TBA-active of products, the content of oxidation-modified proteins (OMB), and catalase activity in the homogenate of soft periodontal tissues of rats. RESULTS: Intragastric injection of nanoceria prevents activation of proteolytic processes, reducing the catabolism of glycoproteins and proteoglycans of periodontal tissue in MSG induced obese rats. Injection of nanoceria prevents activation of proteolytic processes, significantly decreases the total proteolytic activity, and inhibits the activation of free radical oxidation in periodontal tissues of rats compared with MSG-induced obesity model without corrections. Further, it significantly increases the total antitrypsin activity in periodontal tissues by 1.7 times, TBA reagents by 1.7 times, and content of OMB by 1.4 times compared with glutamate induced obese animals. CONCLUSIONS: MSG-induced obesity triggers periodontal tissue alterations in the rat model. Nanoceria contributes to the corrections of pathological changes in periodontal tissues in glutamate-induced obese rats via balancing protein-inhibitory capacity and reducing the depolymerization of fucosylated proteins and proteoglycans and antioxidative activity. PMID- 28620441 TI - Impaired wound healing: facts and hypotheses for multi-professional considerations in predictive, preventive and personalised medicine. AB - Whereas the physiologic wound healing (WH) successfully proceeds through the clearly defined sequence of the individual phases of wound healing, chronic non healing wounds/ulcers fail to complete the individual stages and the entire healing process. There are many risk factors both modifiable (such as stress, smoking, inappropriate alcohol consumption, malnutrition, obesity, diabetes, cardio-vascular disease, etc.) and non-modifiable (such as genetic diseases and ageing) strongly contributing to the impaired WH. Current statistics demonstrate that both categories are increasingly presented in the populations, which causes dramatic socio-economic burden to the healthcare sector and society at large. Consequently, innovative concepts by predictive, preventive and personalised medicine are crucial to be implemented in the area. Individual risk factors, causality, functional interrelationships, molecular signature, predictive diagnosis, and primary and secondary prevention are thoroughly analysed followed by the expert recommendations in this paper. PMID- 28620443 TI - Pattern recognition for predictive, preventive, and personalized medicine in cancer. AB - Predictive, preventive, and personalized medicine (PPPM) is the hot spot and future direction in the field of cancer. Cancer is a complex, whole-body disease that involved multi-factors, multi-processes, and multi-consequences. A series of molecular alterations at different levels of genes (genome), RNAs (transcriptome), proteins (proteome), peptides (peptidome), metabolites (metabolome), and imaging characteristics (radiome) that resulted from exogenous and endogenous carcinogens are involved in tumorigenesis and mutually associate and function in a network system, thus determines the difficulty in the use of a single molecule as biomarker for personalized prediction, prevention, diagnosis, and treatment for cancer. A key molecule-panel is necessary for accurate PPPM practice. Pattern recognition is an effective methodology to discover key molecule-panel for cancer. The modern omics, computation biology, and systems biology technologies lead to the possibility in recognizing really reliable molecular pattern for PPPM practice in cancer. The present article reviewed the pathophysiological basis, methodology, and perspective usages of pattern recognition for PPPM in cancer so that our previous opinion on multi-parameter strategies for PPPM in cancer is translated into real research and development of PPPM or precision medicine (PM) in cancer. PMID- 28620444 TI - Clinical utility of pretreatment prediction of chemoradiotherapy response in rectal cancer: a review. AB - Approximately 20% of all patients with locally advanced rectal cancer experience pathologically complete responses following neoadjuvant chemoradiotherapy (CRT) and standard surgery. The utility of radical surgery for patients exhibiting good CRT responses has been challenged. Organ-sparing strategies for selected patients exhibiting complete clinical responses include local excision or no immediate surgery. The subjects of this tailored management are patients whose presenting disease corresponds to current indications of neoadjuvant CRT, and their post-CRT tumor response is assessed by clinical and radiological examinations. However, a model predictive of the CRT response, applied before any treatment commenced, would be valuable to facilitate such a personalized approach. This would increase organ preservation, particularly in patients for whom upfront CRT is not generally prescribed. Molecular biomarkers hold the greatest promise for development of a pretreatment predictive model of CRT response. A combination of clinicopathological, radiological, and molecular markers will be necessary to render the model robust. Molecular research will also contribute to the development of drugs that can overcome the radioresistance of rectal tumors. Current treatments for rectal cancer are based on the expected prognosis given the presenting disease extent. In the future, treatment schemes may be modified by including the predicted CRT response evaluated at presentation. PMID- 28620446 TI - Canadian Urological Association: 72nd Annual Meeting - Toronto, ON - June 24-27, 2017. PMID- 28620445 TI - Unusual gastrointestinal and cutaneous toxicities by bleomycin, etoposide, and cisplatin: a case report with pharmacogenetic analysis to personalize treatment. AB - The standard treatment of testicular germ cell tumors is based on the combination of bleomycin, etoposide, and cisplatin (PEB). However, this treatment may be associated with severe adverse reactions, such as hematological and non hematological toxicities. Here, we report a case of a patient suffering from severe PEB-related toxicities, to whom pharmacogenetic analyses were performed, comprising a panel of genes involved in PEB metabolism. The analysis revealed the presence of a complex pattern of polymorphisms in GSTP1, UGT1A1 (TA)6/7, UGT1A7, and ABCB1. The present case shows that a pharmacogenetic approach can help in the management of adverse drug reactions in order to predict, prevent, and personalize treatments. PMID- 28620447 TI - Photoelectrochemistry by Design: Tailoring the Nanoscale Structure of Pt/NiO Composites Leads to Enhanced Photoelectrochemical Hydrogen Evolution Performance. AB - Photoelectrochemical hydrogen evolution is a promising avenue to store the energy of sunlight in the form of chemical bonds. The recent rapid development of new synthetic approaches enables the nanoscale engineering of semiconductor photoelectrodes, thus tailoring their physicochemical properties toward efficient H2 formation. In this work, we carried out the parallel optimization of the morphological features of the semiconductor light absorber (NiO) and the cocatalyst (Pt). While nanoporous NiO films were obtained by electrochemical anodization, the monodisperse Pt nanoparticles were synthesized using wet chemical methods. The Pt/NiO nanocomposites were characterized by XRD, XPS, SEM, ED, TEM, cyclic voltammetry, photovoltammetry, EIS, etc. The relative enhancement of the photocurrent was demonstrated as a function of the nanoparticle size and loading. For mass-specific surface activity the smallest nanoparticles (2.0 and 4.8 nm) showed the best performance. After deconvoluting the trivial geometrical effects (stemming from the variation of Pt particle size and thus the electroactive surface area), however, the intermediate particle sizes (4.8 and 7.2 nm) were found to be optimal. Under optimized conditions, a 20-fold increase in the photocurrent (and thus the H2 evolution rates) was observed for the nanostructured Pt/NiO composite, compared to the benchmark nanoparticulate NiO film. PMID- 28620448 TI - Influence of Film and Substrate Structure on Photoelectron Momentum Maps of Coronene Thin Films on Ag(111). AB - Angle-resolved ultraviolet photoelectron spectroscopy (ARUPS) was measured for one-monolayer coronene films deposited on Ag(111). The (kx ,ky )-dependent photoelectron momentum maps (PMMs), which were extracted from the ARUPS data by cuts at fixed binding energies, show finely structured patterns for the highest and the second-highest occupied molecular orbitals. While the substructure of the PMM main features is related to the 4 * 4 commensurate film structure, various features with three-fold symmetry imply an additional influence of the substrate. PMM simulations on the basis of both free-standing coronene assemblies and coronene monolayers on the Ag(111) substrate confirm a sizable molecule-molecule interaction because no substructure was observed for PMM simulations using free coronene molecules. PMID- 28620449 TI - Systematic Review and Meta-analysis of Prevalence of Coronary Artery Disease in Adult Patients with Cardiac Myxomas. AB - Background: Studies have reported varied prevalence estimates of coronary artery disease (CAD) in cardiac myxoma patients. We performed a systematic review and meta-analysis of observational studies to summarize the point prevalence of CAD in adults with cardiac myxomas. Methods and Results: Two independent investigators searched MEDLINE and LILACS databases using the terms " Myxoma", " Coronary Angiography" and " Coronary Disease" from inception through December 2014 for all relevant studies. We included 6 observational studies. Publication bias was evaluated through Egger's test and Trim and Fill method. A pooled estimate of CAD prevalence with corresponding 95% confidence interval (CI) was calculated based on a random-effects model. The pooled CAD prevalence in adult cardiac myxoma patients was 20.7% with low heterogeneity (I 2 = 14.86%). Conclusions: It is a matter of debate if preoperative coronary angiography must be done as a routine procedure. Although coronary disease and angiographically detectable neovascularity can alter surgical management, more studies are needed to evaluate this question. PMID- 28620451 TI - The refined biomimetic NeuroDigm GELTM Model of neuropathic pain in the mature rat. AB - Background: Many humans suffering with chronic pain have no clinical evidence of a lesion or disease. They are managed with a morass of drugs and invasive procedures. Opiates usually become less effective over time. In many, their persistent pain occurs after the healing of a soft tissue injury. Current animal models of neuropathic pain typically create direct neural damage with open surgeries using ligatures, neurectomies, chemicals or other forms of deliberate trauma. However, we have observed clinically that after an injury in humans, the naturally occurring process of tissue repair can cause chronic neural pain. Methods: We demonstrate how the refined biomimetic NeuroDigm GELTM Model, in the mature male rat, gradually induces neuropathic pain behavior with a nonsurgical percutaneous implant of tissue-derived hydrogel in the musculo-fascial tunnel of the distal tibial nerve. Morphine, Celecoxib, Gabapentin and Duloxetine were each screened in the model three times each over 5 months after pain behaviors developed. A pilot study followed in which recombinant human erythropoietin was applied to the GEL neural procedure site. Results: The GEL Model gradually developed neuropathic pain behavior lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses had profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months. Histology revealed a site of focal neural remodeling, with neural regeneration, as in human biopsies. Conclusion: The refined NeuroDigm GELTM Model induces localized neural remodeling resulting in robust neuropathic pain behavior. The analgesics responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin appears to heal the ectopic focal neural site, as demonstrated by the extinguishing of neuropathic pain behavior present for over 4 months. PMID- 28620450 TI - Predicting Outcomes of Hormone and Chemotherapy in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) Study by Biochemically-inspired Machine Learning. AB - Genomic aberrations and gene expression-defined subtypes in the large METABRIC patient cohort have been used to stratify and predict survival. The present study used normalized gene expression signatures of paclitaxel drug response to predict outcome for different survival times in METABRIC patients receiving hormone (HT) and, in some cases, chemotherapy (CT) agents. This machine learning method, which distinguishes sensitivity vs. resistance in breast cancer cell lines and validates predictions in patients, was also used to derive gene signatures of other HT (tamoxifen) and CT agents (methotrexate, epirubicin, doxorubicin, and 5 fluorouracil) used in METABRIC. Paclitaxel gene signatures exhibited the best performance, however the other agents also predicted survival with acceptable accuracies. A support vector machine (SVM) model of paclitaxel response containing the ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2, SLCO1B3, TUBB1, TUBB4A, TUBB4B genes was 78.6% accurate in 84 patients treated with both HT and CT (median survival >= 4.4 yr). Accuracy was lower (73.4%) in 304 untreated patients. The performance of other machine learning approaches were also evaluated at different survival thresholds. Minimum redundancy maximum relevance feature selection of a paclitaxel-based SVM classifier based on expression of ABCB11, ABCC1, BAD, BBC3 and BCL2L1 was 79% accurate in 53 CT patients. A random forest (RF) classifier produced a gene signature ( ABCB11, ABCC1, BAD, BCL2, CYP2C8, CYP3A4, MAP4, MAPT, NR1I2, TUBB1, GBP1, OPRK1) that predicted >3 year survival with 82.4% accuracy in 420 HT patients. A similar RF gene signature showed 79.6% accuracy in 504 patients treated with CT and/or HT. These results suggest that tumor gene expression signatures refined by machine learning techniques can be useful for predicting survival after drug therapies. PMID- 28620452 TI - Metabolic reprogramming during the Trypanosoma brucei life cycle. AB - Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism. PMID- 28620453 TI - Parallel pathways in the biosynthesis of aminoglycoside antibiotics. AB - Despite their inherent toxicity and the global spread of bacterial resistance, aminoglycosides (AGs), an old class of microbial drugs, remain a valuable component of the antibiotic arsenal. Recent studies have continued to reveal the fascinating biochemistry of AG biosynthesis and the rich potential in their pathway engineering. In particular, parallel pathways have been shown to be common and widespread in AG biosynthesis, highlighting nature's ingenuity in accessing diverse natural products from a limited set of genes. In this review, we discuss the parallel biosynthetic pathways of three representative AG antibiotics-kanamycin, gentamicin, and apramycin-as well as future directions towards the discovery and development of novel AGs. PMID- 28620454 TI - ELIXIR pilot action: Marine metagenomics - towards a domain specific set of sustainable services. AB - Metagenomics, the study of genetic material recovered directly from environmental samples, has the potential to provide insight into the structure and function of heterogeneous microbial communities. There has been an increased use of metagenomics to discover and understand the diverse biosynthetic capacities of marine microbes, thereby allowing them to be exploited for industrial, food, and health care products. This ELIXIR pilot action was motivated by the need to establish dedicated data resources and harmonized metagenomics pipelines for the marine domain, in order to enhance the exploration and exploitation of marine genetic resources. In this paper, we summarize some of the results from the ELIXIR pilot action "Marine metagenomics - towards user centric services". PMID- 28620455 TI - haploR: an R-package for querying web-based annotation tools. AB - There exists a set of web-based tools for integration and exploring information linked to annotated genetic variants. We developed haploR, an R-package for querying such web-based genome annotation tools (currently implementing on HaploReg and RegulomeDB) and gathering information in a format suitable for downstream bioinformatic analyses. This will facilitate post-genome wide association studies streamline analysis for rapid discovery and interpretation of genetic associations. PMID- 28620456 TI - Effects of physical activity on the link between PGC-1a and FNDC5 in muscle, circulating Iotarisin and UCP1 of white adipocytes in humans: A systematic review. AB - Background: Exercise may activate a brown adipose-like phenotype in white adipose tissue. The aim of this systematic review was to identify the effects of physical activity on the link between peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and fibronectin type III domain-containing protein 5 (FNDC5) in muscle, circulating Irisin and uncoupling protein one (UCP1) of white adipocytes in humans. Methods: Two databases (PubMed 1966 to 08/2016 and EMBASE 1974 to 08/2016) were searched using an appropriate algorithm. We included articles that examined physical activity and/or exercise in humans that met the following criteria: a) PGC-1a in conjunction with FNDC5 measurements, and b) FNDC5 and/or circulating Irisin and/or UCP1 levels in white adipocytes. Results: We included 51 studies (12 randomised controlled trials) with 2474 participants. Out of the 51 studies, 16 examined PGC-1a and FNDC5 in response to exercise, and only four found increases in both PGC-1a and FNDC5 mRNA and one showed increased FNDC5 mRNA. In total, 22 out of 45 studies that examined circulating Irisin in response to exercise showed increased concentrations when ELISA techniques were used; two studies also revealed increased Irisin levels measured via mass spectrometry. Three studies showed a positive association of circulating Irisin with physical activity levels. One study found no exercise effects on UCP1 mRNA in white adipocytes. Conclusions: The effects of physical activity on the link between PGC-1a, FNDC5 mRNA in muscle and UCP1 in white human adipocytes has attracted little scientific attention. Current methods for Irisin identification lack precision and, therefore, the existing evidence does not allow for conclusions to be made regarding Irisin responses to physical activity. We found a contrast between standardised review methods and accuracy of the measurements used. This should be considered in future systematic reviews. PMID- 28620457 TI - Early fruiting in Synsepalum dulcificum (Schumach. & Thonn.) Daniell juveniles induced by water and inorganic nutrient management. AB - Background. The miracle plant, Synsepalum dulcificum (Schumach. & Thonn.) Daniell is a native African orphan crop species that has recently received increased attention due to its promise as a sweetener and source of antioxidants in both the food and pharmaceutical industries. However, a major obstacle to the species' widespread utilization is its relatively slow growth rate and prolonged juvenile period. Method. In this study, we tested twelve treatments made up of various watering regimes and exogenous nutrient application (nitrogen, phosphorus and potassium, at varying dosages) on the relative survival, growth, and reproductive development of 15-months-old S. dulcificum juveniles. Results. While the plants survived under most tested growing conditions, nitrogen application at doses higher than 1.5 g [seedling] -1 was found to be highly detrimental, reducing survival to 0%. The treatment was found to affect all growth traits, and juveniles that received a combination of nitrogen, phosphorus, and potassium (each at a rate of 1.5 g [seedling] -1), in addition to daily watering, exhibited the most vegetative growth. The simple daily provision of adequate water was found to greatly accelerate the transition to reproductive maturity in the species (from >36 months to an average of 23 months), whereas nutrient application affected the length of the reproductive phase within a season, as well as the fruiting intensity. Conclusions. This study highlights the beneficial effect of water supply and fertilization on both vegetative and reproductive growth in S. dulcificum. Water supply appeared to be the most important factor unlocking flowering in the species, while the combination of nitrogen, phosphorus and potassium at the dose of 1.5 g (for all) consistently exhibited the highest performance for all growth and yield traits. These findings will help intensify S. dulcificum's breeding and horticultural development. PMID- 28620459 TI - On the origin of nonequivalent states: How we can talk about preprints. AB - Increasingly, preprints are at the center of conversations across the research ecosystem. But disagreements remain about the role they play. Do they "count" for research assessment? Is it ok to post preprints in more than one place? In this paper, we argue that these discussions often conflate two separate issues, the history of the manuscript and the status granted it by different communities. In this paper, we propose a new model that distinguishes the characteristics of the object, its "state", from the subjective "standing" granted to it by different communities. This provides a way to discuss the difference in practices between communities, which will deliver more productive conversations and facilitate negotiation, as well as sharpening our focus on the role of different stakeholders on how to collectively improve the process of scholarly communications not only for preprints, but other forms of scholarly contributions. PMID- 28620458 TI - Reproducibility2020: Progress and priorities. AB - The preclinical research process is a cycle of idea generation, experimentation, and reporting of results. The biomedical research community relies on the reproducibility of published discoveries to create new lines of research and to translate research findings into therapeutic applications. Since 2012, when scientists from Amgen reported that they were able to reproduce only 6 of 53 "landmark" preclinical studies, the biomedical research community began discussing the scale of the reproducibility problem and developing initiatives to address critical challenges. Global Biological Standards Institute (GBSI) released the "Case for Standards" in 2013, one of the first comprehensive reports to address the rising concern of irreproducible biomedical research. Further attention was drawn to issues that limit scientific self-correction, including reporting and publication bias, underpowered studies, lack of open access to methods and data, and lack of clearly defined standards and guidelines in areas such as reagent validation. To evaluate the progress made towards reproducibility since 2013, GBSI identified and examined initiatives designed to advance quality and reproducibility. Through this process, we identified key roles for funders, journals, researchers and other stakeholders and recommended actions for future progress. This paper describes our findings and conclusions. PMID- 28620460 TI - A putative antiviral role of plant cytidine deaminases. AB - BACKGROUND: A mechanism of innate antiviral immunity operating against viruses infecting mammalian cells has been described during the last decade. Host cytidine deaminases ( e.g., APOBEC3 proteins) edit viral genomes, giving rise to hypermutated nonfunctional viruses; consequently, viral fitness is reduced through lethal mutagenesis. By contrast, sub-lethal hypermutagenesis may contribute to virus evolvability by increasing population diversity. To prevent genome editing, some viruses have evolved proteins that mediate APOBEC3 degradation. The model plant Arabidopsis thaliana genome encodes nine cytidine deaminases ( AtCDAs), raising the question of whether deamination is an antiviral mechanism in plants as well. METHODS: Here we tested the effects of expression of AtCDAs on the pararetrovirus Cauliflower mosaic virus (CaMV). Two different experiments were carried out. First, we transiently overexpressed each one of the nine A. thalianaAtCDA genes in Nicotianabigelovii plants infected with CaMV, and characterized the resulting mutational spectra, comparing them with those generated under normal conditions. Secondly, we created A. thaliana transgenic plants expressing an artificial microRNA designed to knock-out the expression of up to six AtCDA genes. This and control plants were then infected with CaMV. Virus accumulation and mutational spectra where characterized in both types of plants. RESULTS: We have shown that the A. thalianaAtCDA1 gene product exerts a mutagenic activity, significantly increasing the number of G to A mutations in vivo, with a concomitant reduction in the amount of CaMV genomes accumulated. Furthermore, the magnitude of this mutagenic effect on CaMV accumulation is positively correlated with the level of AtCDA1 mRNA expression in the plant. CONCLUSIONS: Our results suggest that deamination of viral genomes may also work as an antiviral mechanism in plants. PMID- 28620461 TI - The "enemies within": regions of the genome that are inherently difficult to replicate. AB - An unusual feature of many eukaryotic genomes is the presence of regions that appear intrinsically difficult to copy during the process of DNA replication. Curiously, the location of these difficult-to-replicate regions is often conserved between species, implying a valuable role in some aspect of genome organization or maintenance. The most prominent class of these regions in mammalian cells is defined as chromosome fragile sites, which acquired their name because of a propensity to form visible gaps/breaks on otherwise-condensed chromosomes in mitosis. This fragility is particularly apparent following perturbation of DNA replication-a phenomenon often referred to as "replication stress". Here, we review recent data on the molecular basis for chromosome fragility and the role of fragile sites in the etiology of cancer. In particular, we highlight how studies on fragile sites have provided unexpected insights into how the DNA repair machinery assists in the completion of DNA replication. PMID- 28620462 TI - Immunoprofiling of human uterine mast cells identifies three phenotypes and expression of ERbeta and glucocorticoid receptor. AB - Background: Human mast cells (MCs) are long-lived tissue-resident immune cells characterised by granules containing the proteases chymase and/or tryptase. Their phenotype is modulated by their tissue microenvironment. The human uterus has an outer muscular layer (the myometrium) surrounding the endometrium, both of which play an important role in supporting a pregnancy. The endometrium is a sex steroid target tissue consisting of epithelial cells (luminal, glandular) surrounded by a multicellular stroma, with the latter containing an extensive vascular compartment as well as fluctuating populations of immune cells that play an important role in regulating tissue function. The role of MCs in the human uterus is poorly understood with little known about their regulation or the impact of steroids on their differentiation status. The current study had two aims: 1) To investigate the spatial and temporal location of uterine MCs and determine their phenotype; 2) To determine whether MCs express receptors for steroids implicated in uterine function, including oestrogen (ERalpha, ERbeta), progesterone (PR) and glucocorticoids (GR). Methods: Tissue samples from women (n=46) were used for RNA extraction or fixed for immunohistochemistry. Results: Messenger RNAs encoded by TPSAB1 (tryptase) and CMA1 (chymase) were detected in endometrial tissue homogenates. Immunohistochemistry revealed the relative abundance of tryptase MCs was myometrium>basal endometrium>functional endometrium. We show for the first time that uterine MCs are predominantly of the classical MC subtypes: (positive, +; negative, -) tryptase+/chymase- and tryptase+/chymase+, but a third subtype was also identified (tryptase-/chymase+). Tryptase+ MCs were of an ERbeta+/ERalpha-/PR-/GR+ phenotype mirroring other uterine immune cell populations, including natural killer cells. Conclusions: Endometrial tissue resident immune MCs have three protease-specific phenotypes. Expression of both ERbeta and GR in MCs mirrors that of other immune cells in the endometrium and suggests that MC function may be altered by the local steroid microenvironment. PMID- 28620463 TI - Recent advances in the management of Wilms' tumor. AB - The objective of this article is to present an overview of recent trends in the management of Wilms' tumor. With improved survival rates in the past few decades, critical long-term adverse therapy effects (such as renal insufficiency, secondary malignancies, and heart failure) and prevention measures (i.e. nephron sparing surgery and minimizing the use of radiotherapy) have gained worldwide attention. Specific disease biomarkers that could help stratify high-risk from low-risk patients, and therefore fine-tune management, are in great demand. Ultimately, we aim to enhance clinical outcomes and maintain or improve current survival rates while avoiding undesirable treatment side effects and minimizing the exposure and intensity of chemotherapy and radiotherapy. PMID- 28620464 TI - Recent insights on principles of synaptic protein degradation. AB - Maintaining synaptic integrity and function depends on the continuous removal and degradation of aged or damaged proteins. Synaptic protein degradation has received considerable attention in the context of synaptic plasticity and growing interest in relation to neurodegenerative and other disorders. Conversely, less attention has been given to constitutive, ongoing synaptic protein degradation and the roles canonical degradation pathways play in these processes. Here we briefly review recent progress on this topic and new experimental approaches which have expedited such progress and highlight several emerging principles. These include the realization that synaptic proteins typically have unusually long lifetimes, as might be expected from the remote locations of most synaptic sites; the possibility that degradation pathways can change with time from synthesis, cellular context, and physiological input; and that degradation pathways, other than ubiquitin-proteasomal-mediated degradation, might play key roles in constitutive protein degradation at synaptic sites. Finally, we point to the importance of careful experimental design and sufficiently sensitive techniques for studying synaptic protein degradation, which bring into account their slow turnover rates and complex life cycles. PMID- 28620465 TI - Nanoparticle-based drug delivery systems: What can they really do in vivo? AB - In the past few decades, there has been explosive growth in the construction of nanoparticle-based drug delivery systems (NDDSs), namely nanomedicines, owing to their unique properties compared with traditional drug formulations. However, because of a variety of challenges, few nanomedicines are on sale in the market or undergoing clinical trial at present. Thus, it is essential to look back and re-evaluate what these NDDSs can really do in vivo, why nanomedicines are regarded as potential candidates for next-generation drugs, and what the future of nanomedicine is. Here, we focus mainly on the properties of NDDSs that extend blood circulation, enhance penetration into deep tumor tissue, enable controllable release of the payload into the cytoplasm, and overcome multi-drug resistance. We further discuss how to promote the translation of nanomedicines into reality. This review may help to identify the functions of NDDSs that are really necessary before they are designed and to reduce the gap between basic research and clinical application. PMID- 28620466 TI - Harnessing the immune response to target tumors. AB - Development of "immune-based targeted therapy" in oncology has limited experience with signal pathway modulation. However, as we have become better versed in understanding immune function related to anticancer response, "hints" of specific targets associated with sensitivity and resistance have been identified with targeted immune therapy. This brief review summarizes the relationship of several targeted immune therapeutics and activity associated clinical responsiveness. PMID- 28620468 TI - Development of a food-based diet quality score for Japanese: associations of the score with nutrient intakes in young, middle-aged and older Japanese women. AB - Several previous studies have shown that a diet score based on the Japanese food guide Spinning Top (the original score) is associated with both favourable and unfavourable dietary intake patterns. We developed a food-based diet quality score (the modified score) and examined associations with nutrient intakes. Subjects were 3963 young (all aged 18 years), 3800 middle-aged (mean age 47.7 (sd 3.9) years) and 2211 older (mean age 74.4 (sd 5.2) years) Japanese women. Dietary intakes were assessed using comprehensive (for the young and middle-aged) and brief-type (for the older) diet history questionnaires. The original score was calculated based on intakes of grains, vegetables, fish/meat, milk, fruits, and snacks/alcoholic beverages. The modified score was similarly calculated, but included Na from seasonings and without applying the upper cut-off values for dietary components where increased consumption is advocated for Japanese women (grains, vegetables, fish/meat, milk, and fruits). The original score was positively associated with intakes of carbohydrate, dietary fibre, and all the vitamins and minerals examined including Na and inversely with intakes of fats and alcohol in young and middle-aged women. In older women, the original score was inversely associated with intakes of all nutrients except for carbohydrate and vitamin C. However, the modified score was associated positively with intakes of protein, carbohydrate, dietary fibre, K, Ca, Mg, Fe, vitamins A, C and E, and folate and inversely with intakes of fats, alcohol and Na in all generations. In conclusion, the modified diet score was positively associated with favourable nutrient intake patterns in Japanese women. PMID- 28620467 TI - Recent advances in understanding lung function development. AB - Recent years have witnessed critical contributions to our understanding of the determinants and long-term implications of lung function development. In this article, we review studies that have contributed to advances in understanding lung function development and its critical importance for lung health into adult life. In particular, we have focused on early life determinants that include genetic factors, perinatal events, environmental exposures, lifestyle, infancy lower respiratory tract infections, and persistent asthma phenotypes. Longitudinal studies have conclusively demonstrated that lung function deficits that are established by school age may track into adult life and increase the risk of adult lung obstructive diseases, such as chronic obstructive pulmonary disease. Furthermore, these contributions have provided initial evidence in support of a direct influence by early life events on an accelerated decline of lung function and an increased susceptibility to its environmental determinants well into adult life. As such, we argue that future health-care programs based on precision medicine approaches that integrate deep phenotyping with tailored medication and advice to patients should also foster optimal lung function growth to be fully effective. PMID- 28620469 TI - Infant formula containing galacto-and fructo-oligosaccharides and Bifidobacterium breve M-16V supports adequate growth and tolerance in healthy infants in a randomised, controlled, double-blind, prospective, multicentre study. AB - The objective of the present study was to evaluate the growth and tolerance in healthy, term infants consuming a synbiotic formula with daily weight gain as the primary outcome. In a randomised, controlled, double-blind, multicentre, intervention study infants were assigned to an extensively hydrolysed formula containing a specific combination of Bifidobacterium breve M-16V and a prebiotic mixture (short-chain galacto-oligosaccharides and long-chain fructo oligosaccharides in a 9:1 ratio; scGOS/lcFOS; synbiotic group), or the same formula without this synbiotic concept for 13 weeks (control group). Anthropometry, formula intake, tolerance, stool characteristics, blood parameters, faecal microbiota and metabolic faecal profile were assessed. Medically confirmed adverse events were recorded throughout the study. Equivalence in daily weight gain was demonstrated for the intention-to-treat (ITT) population (n 211). In the per-protocol (PP) population (n 102), the 90 % CI of the difference in daily weight gain slightly crossed the lower equivalence margin. During the intervention period, the mean weight-for-age and length-for age values were close to the median of the WHO growth standards in both groups, indicating adequate growth. The number of adverse events was not different between both groups. No relevant differences were observed in blood parameters indicative for liver and renal function. At 13 weeks, an increased percentage of faecal bifidobacteria (60 v. 48 %) and a reduced percentage of Clostridium lituseburense/C. histolyticum (0.2 v. 2.6 %) were observed in the synbiotic group (n 19) compared with the control group (n 27). In conclusion, this study demonstrates that an extensively hydrolysed formula with B. breve M-16V and the prebiotic mixture scGOS/lcFOS (9:1) supports an adequate infant growth. PMID- 28620470 TI - Bioavailability of n-3 fatty acids from n-3-enriched foods and fish oil with different oxidative quality in healthy human subjects: a randomised single-meal cross-over study. AB - Regular consumption of long-chain n-3 fatty acids (LC n-3 FA) reduces postprandial triacylglycerolaemia. Functional foods and supplements are alternative sources of LC n-3 FA; however, emulsification technologies, food matrices and altered lipid oxidation levels affect their bioavailability. Moreover, which functional foods are optimal LC n-3 FA carriers is unknown. The aim of the study was to determine the bioavailability of LC n-3 FA and the postprandial TAG response after the intake of oxidised or non-oxidised cod liver oil and after the intake of emulsified or non-emulsified LC n-3 FA using novel functional food items as LC n-3 FA carriers in a randomised cross-over acute study. A total of twenty-four healthy subjects completed the study in which subjects consumed one of four different test meals containing 1.5 g LC n-3 FA, or a control meal with no LC n-3 FA. Postprandial TAG-rich lipoproteins were isolated and their fatty acid composition was measured. The LC n-3 FA from emulsified foods were more rapidly incorporated into TAG-rich lipoproteins compared with non-emulsified foods. The incorporation of LC n-3 FA was similar for oils emulsified in yogurt or juice and was unaffected by the oxidative status of the oil. Postprandial TAG levels did not differ among the various test meals. In conclusion, emulsification increases the bioavailability of LC n-3 FA through a more rapid incorporation into TAG-rich lipoproteins, and juice and yogurt are equally suited as LC n-3 FA carriers. The acute intake of oxidised cod liver oil does not influence the incorporation of LC n-3 FA into TAG-rich lipoproteins. PMID- 28620471 TI - Effect of a plant sterol-enriched spread on biomarkers of endothelial dysfunction and low-grade inflammation in hypercholesterolaemic subjects. AB - Plant sterols (PS) lower LDL-cholesterol, an established risk factor for CHD. Endothelial dysfunction and low-grade inflammation are two important features in the development of atherosclerosis. Whether PS affect biomarkers of endothelial function and low-grade inflammation is not well studied. The aim of the present study was to investigate the effect of regular intake of PS on biomarkers of endothelial dysfunction and low-grade inflammation. In a double-blind, randomised, placebo-controlled, parallel-group study, which was primarily designed to investigate the effect of PS intake on vascular function (clinicaltrials.gov: NCT01803178), 240 hypercholesterolaemic but otherwise healthy men and women consumed a low-fat spread with added PS (3 g/d) or a placebo spread for 12 weeks. Endothelial dysfunction biomarkers (both vascular and intracellular adhesion molecules 1 and soluble endothelial-selectin) and low grade inflammation biomarkers (C-reactive protein, serum amyloid A, IL-6, IL-8, TNF-alpha and soluble intercellular adhesion molecule-1) were measured using a multi-array detection system based on electrochemiluminescence technology. Biomarkers were combined using z-scores. Differences in changes from baseline between the PS and the placebo groups were assessed. The intake of PS did not significantly change the individual biomarkers of endothelial dysfunction and low grade inflammation. The z-scores for endothelial dysfunction (-0.02; 95 % CI 0.15, 0.11) and low-grade inflammation (-0.04; 95 % CI -0.16, 0.07) were also not significantly changed after PS intake compared with placebo. In conclusion, biomarkers of endothelial dysfunction and low-grade inflammation were not affected by regular intake of 3 g/d PS for 12 weeks in hypercholesterolaemic men and women. PMID- 28620472 TI - A randomised, controlled, crossover study of the effect of diet on angiopoietin like protein 4 (ANGPTL4) through modification of the gut microbiome. AB - Angiopoietin-like protein 4 (ANGPTL4) is a lipoprotein lipase inhibitor that is involved in lipid metabolism and angiogenesis. Animal studies have suggested that the ANGPTL4 protein is modulated by the gut microbiota, possibly through increased concentrations of SCFA, such as C4, found in whole-fat milk or as a result of fermentation of inulin. This study investigated whether a standardised diet either high in fat content or supplemented with inulin powder would increase plasma ANGPTL4 in overweight men and whether this increase was mediated through a compositional change of the gut microbiota. The study had a crossover design with three arms, where participants were given a standardised isoenergetic diet supplemented with inulin powder, whole-fat milk or water (control). Plasma and urine samples were collected before and after each intervention period. Faecal samples and adipose tissue biopsies were collected after each intervention period. The study included twenty-one participants of whom eighteen completed the study. The dietary interventions did not change ANGPTL4 plasma concentration, nor was plasma ANGPTL4 associated with plasma lipids, TAG or NEFA concentration. The relative abundance of bifidobacteria following the inulin diet was higher, compared with the control diet. However, the changes in microbiota were not associated with plasma ANGPTL4 and the overall composition of the microbiota did not change between the dietary periods. Although weight was maintained throughout the dietary periods, weight was negatively associated with plasma ANGPTL4 concentration. In the adipose tissue, ANGPTL4 expression was correlated with leptin expression, but not with hypoxia-inducible factor 1alpha (HIF-1alpha) expression. PMID- 28620473 TI - Micronutrient deficiencies among children and women in Bangladesh: progress and challenges. AB - This paper provides a comprehensive review of the current situation regarding micronutrient deficiencies among children and women in Bangladesh. This review also discusses the successes and current challenges of existing intervention programmes. Data from nationally representative and selected small surveys since the 1980s that have reported on the status of at least one micronutrient in children and/or women have been examined. National policy documents/reports on existing interventions have been analysed. While the severity of various micronutrient deficiencies has declined since the 1980s, a significant proportion of preschool-age children remains with deficiencies in vitamin A (20.5 %), Zn (44.5 %) and vitamin D (39.6 %); about one-third of these children are anaemic, and 10.7 % of the children are Fe deficient. A high proportion of non-pregnant and non-lactating women is deficient in Zn (57 %) and I (42 %), while one-quarter of women live with anaemia and vitamin B12 and vitamin D (21 %) deficiencies. Nearly one-half of the pregnant and lactating women are anaemic. Suboptimal diets, poor hygiene, infection and infestation are identified as some of the key factors associated with high levels of deficiencies. Multiple approaches and interventions are being supported, and while some notable progress has been achieved, significant challenges continue, including those related to coverage, quality and compliance. It is concluded that although current intervention programmes have made some progress in controlling the severe deficiencies, micronutrient deficiencies in Bangladesh remain a considerable problem. More well integrated approaches for strengthening the existing intervention programmes are needed. In addition, new intervention strategies for alleviating and preventing specific micronutrient deficiencies are recommended. PMID- 28620475 TI - Plasma phylloquinone, menaquinone-4 and menaquinone-7 levels and coronary artery calcification. AB - Vitamin K is considered to be involved in the pathological mechanisms of coronary artery calcification (CAC). Correlation between CAC and plasma vitamin K levels was studied. A total of 103 patients, with at least one coronary risk factor, were studied. CAC was measured using 64-slice multislice computed tomography (MSCT) and divided into three groups: none (CAC score = 0; n 25), mild to moderate (0 < CAC score < 400; n 52) and severe (CAC score > 400; n 26). Phylloquinone (PK) and menaquinone (MK)-4 and MK-7 were measured by HPLC-tandem MS. Mean age of patients was 64 (sd 13) years, of which 57 % were male. Median CAC score was 57.2. Median levels of PK, MK-4 and MK-7 were 1.33, 0 and 6.99 ng/ml, showing that MK-7 was the dominant vitamin K in this population. MK-7 showed a significant inverse correlation with uncarboxylated osteocalcin (ucOC, P = 0.014), protein induced by vitamin K absence of antagonist-2 (PIVKA-2, P = 0.013), intact parathyroid hormone (P = 0.007) and bone-specific alkaline phosphatase (P = 0.018). CAC showed an inverse correlation with total circulating uncarboxylated matrix Gla protein (t-ucMGP, P = 0.018) and Hb (P = 0.05), and a positive correlation with age (P < 0.001), creatinine, collagen type 1 cross linked N-terminal telopeptide (NTX, P = 0.03), pulse wave velocity (P < 0.001) and osteoprotegerin (P < 0.001). However, CAC did not have a significant correlation with plasma levels of PK, MK-4 or MK-7. In conclusion, plasma MK-7, MK-4 or PK level did not show significant correlation with CAC despite the association between plasma vitamin K levels and vitamin K-dependent proteins such as ucOC or PIVKA-2. PMID- 28620474 TI - Flavonoids: an overview. AB - Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to isolation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction of flavonoids as potential drugs in preventing chronic diseases and future research directions. PMID- 28620476 TI - Vitamin D and inflammatory markers: cross-sectional analyses using data from the English Longitudinal Study of Ageing (ELSA). AB - Recent evidence suggests that low vitamin D concentrations are associated with increased levels of inflammatory markers. However, there are limited studies investigating associations between vitamin D levels and inflammatory markers in the general population and much of this evidence in older adults is inconclusive. Therefore, this study investigates the cross-sectional association of serum 25 hydroxyvitamin D (25(OH)D) levels with inflammatory markers in 5870 older English adults from wave 6 (2012-2013) of the English Longitudinal Study of Ageing (ELSA). ELSA is a large prospective observational study of community-dwelling people aged 50 years and over in England. Serum 25(OH)D levels, C-reactive protein (CRP) levels, plasma fibrinogen levels, white blood cell count (WBC), age, season of blood collection, waist circumference, total non-pension household wealth, measures of health and health behaviours that included depression, number of cardiovascular, non-cardiovascular conditions and difficulties in activities of daily living, smoking, and physical activity were measured. There was a significant negative association between low 25(OH)D levels (<=30 nmol/l) and CRP (OR 1.23, 95 % CI 1.00, 1.51) and WBC (OR 1.35, 95 % CI 1.13, 1.60) that remained after adjustment for a wide range of covariates of clinical significance. However, for fibrinogen, the association did not remain significant when waist circumference was entered in the final model. Our findings showed that 25(OH)D levels were associated with two out the three inflammatory markers investigated. The independent and inverse association between serum 25(OH)D levels and inflammation suggests a potential anti-inflammatory role for vitamin D in older English individuals from the general population. PMID- 28620477 TI - Micronutrient deficiencies in the elderly - could ready meals be part of the solution? AB - Micronutrient deficiencies contribute to many age-related disorders. One group at particular risk of micronutrient deficiencies is the elderly. Many elderly, such as the frail and those living in institutions, rely on ready meals of variable, often poor, nutritional quality for a significant part of their daily nutritional needs. New policies are needed to ensure that micronutrients (vitamins and minerals) and phytochemicals of known nutritional value are retained during the manufacture of ready meals. This together with increased awareness of the importance of micronutrients for health, and simple, clear labelling of the micronutrient content of ready meals would help in the choice of healthier products. Professionally prepared ready meals monitored by nutritionists and dietitians can help achieve these goals so that ready meals become part of the solution to poor nutrition in the elderly, rather than being viewed as part of the problem. PMID- 28620478 TI - A hot water extract of turmeric (Curcuma longa) suppresses acute ethanol-induced liver injury in mice by inhibiting hepatic oxidative stress and inflammatory cytokine production. AB - Turmeric (Curcuma longa) is a widely used spice that has various biological effects, and aqueous extracts of turmeric exhibit potent antioxidant activity and anti-inflammatory activity. Bisacurone, a component of turmeric extract, is known to have similar effects. Oxidative stress and inflammatory cytokines play an important role in ethanol-induced liver injury. This study was performed to evaluate the influence of a hot water extract of C. longa (WEC) or bisacurone on acute ethanol-induced liver injury. C57BL/6 mice were orally administered WEC (20 mg/kg body weight; BW) or bisacurone (60 ug/kg BW) at 30 min before a single dose of ethanol was given by oral administration (3.0 g/kg BW). Plasma levels of aspartate aminotransferase and alanine aminotransferase were markedly increased in ethanol-treated mice, while the increase of these enzymes was significantly suppressed by prior administration of WEC. The increase of alanine aminotransferase was also significantly suppressed by pretreatment with bisacurone. Compared with control mice, animals given WEC had higher hepatic tissue levels of superoxide dismutase and glutathione, as well as lower hepatic tissue levels of thiobarbituric acid-reactive substances, TNF-alpha protein and IL-6 mRNA. These results suggest that oral administration of WEC may have a protective effect against ethanol-induced liver injury by suppressing hepatic oxidation and inflammation, at least partly through the effects of bisacurone. PMID- 28620479 TI - Postprandial glycaemic response to berry nectars containing inverted sucrose. AB - Sucrose is commonly used for sweetening berry products. During processing and storage of berry products containing added sucrose, sucrose is inverted to glucose and fructose. We have previously shown that postprandial glycaemic response induced by intact sucrose is attenuated when sucrose is consumed with berries rich in polyphenols. It is not known how inversion of sucrose affects glycaemic response. We investigated postprandial glycaemic and insulinaemic responses to blackcurrant (Ribes nigrum) and lingonberry (Vaccinium vitis-idaea) nectars and a reference drink (water) sweetened with glucose and fructose, representing completely inverted sucrose. The nectars and reference drink (300 ml) contained 17.5 g glucose and 17.5 g fructose. Polyphenol composition of the nectars was analysed. A total of eighteen healthy volunteers participated in a randomised, controlled, cross-over study. Blood samples were collected at fasting and six times postprandially during 120 min. Inverted sucrose in the reference drink induced glycaemic and insulinaemic responses similar to those previously observed for intact sucrose. In comparison with the reference, the blackcurrant nectar attenuated the early glycaemic response and improved glycaemic profile, and the lingonberry nectar reduced the insulinaemic response. The responses induced by inverted sucrose in the berry nectars are similar to those previously observed for berry nectars containing intact sucrose, suggesting that inversion has no major impact on glycaemic response to sucrose-sweetened berry products. The attenuated glycaemic response after the blackcurrant nectar may be explained by inhibition of intestinal absorption of glucose by blackcurrant anthocyanins. PMID- 28620480 TI - Reduction of HbA1c levels by fucoxanthin-enriched akamoku oil possibly involves the thrifty allele of uncoupling protein 1 (UCP1): a randomised controlled trial in normal-weight and obese Japanese adults. AB - Lifestyle-related problems are becoming a major health threat in East Asian countries. Therefore, finding an efficacious nutraceutical for this population is important. One candidate is fucoxanthin (Fx), a carotenoid abundantly found in edible brown seaweed that has been associated with a number of valuable health promoting benefits. Unfortunately, clinical studies of Fx are limited. In the present study, we aimed to evaluate the effects of Fx on obesity-related parameters in Japanese subjects harbouring an SNP associated with lifestyle related problems. In all, sixty normal-weight and obese Japanese adults with BMI over 22 kg/m2 were single-blinded and randomly assigned to three Fx-dose cohorts and administered Fx-enriched akamoku oil containing Fx at 0, 1 or 2 mg/d for 8 weeks (n 20 per group). Parameters relating to obesity and serum Fx metabolites were measured before and after intervention, but no significant differences were observed between and within the groups. Despite no changes in visceral fat areas and resting energy expenditures after intervention, we observed a significant decline in HbA1c levels in the 2 mg/d Fx group compared with that in the 0 mg/d group (P < 0.05), which was correlated with an increase in serum fucoxanthinol (Fx metabolite) levels. In addition, HbA1c levels declined more significantly in subjects with G/G alleles of the uncoupling protein 1 (UCP1) gene than in those with the A/A and A/G alleles (P < 0.05). We conclude that although Fx supplementation does not affect visceral fat areas, it may reduce HbA1c levels in those harbouring the thrifty allele of UCP1-3826A/G. PMID- 28620481 TI - Tolerability and safety of the intake of bovine milk oligosaccharides extracted from cheese whey in healthy human adults. AB - Mechanistic research suggests a unique evolutionary relationship between complex milk oligosaccharides and cognate bifidobacteria enriched in breast-fed infants. Bovine milk oligosaccharides (BMO) were recently identified as structurally and functionally similar to human milk oligosaccharides. The present single-blind three-way crossover study is the first to determine the safety and tolerability of BMO consumption by healthy human participants (n 12) and its effects on faecal microbiota and microbial metabolism. Participants consumed each supplement (placebo-control; low- and high-BMO doses) for eleven consecutive days, followed by a 2-week washout period prior to initiating the next supplement arm. Low and high BMO doses were consumed as 25 and 35 % of each individual's daily fibre intake, respectively. Safety and tolerability were measured using standardised questionnaires on gut and stomach discomfort and stool consistency. Faecal extracts were profiled for bacterial populations by next-generation sequencing (NGS) and bifidobacteria presence was confirmed using quantitative PCR. Urine was analysed for changes in microbial metabolism using nuclear magnetic resonance spectroscopy (1H-NMR). Consumption of both the low and high BMO doses was well tolerated and did not change stool consistency from baseline. Multivariate analysis of the NGS results demonstrated no change in faecal microbiota phyla among the placebo-control and BMO supplement groups. In conclusion, BMO supplementation was well tolerated in healthy adults and has the potential to shift faecal microbiota toward beneficial strains as part of a synbiotic treatment with probiotic cultures that selectively metabolise oligosaccharides. PMID- 28620482 TI - Naturally occurring and added sugar in relation to macronutrient intake and food consumption: results from a population-based study in adults. AB - Associations between sugar intake and the remaining diet are poorly described in modern food environments. We aimed at exploring associations of high naturally occurring and added sugar intakes with sociodemographic characteristics, intake of macronutrients, fibre and selected food groups. Our data comprised 4842 Finnish adults aged 25-74 years, who participated in the population-based DIetary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) study. Diet was assessed by a validated 131-item FFQ. The food item disaggregation approach was used to estimate sucrose and fructose intakes from natural sources (naturally occurring sugar) and all other sources (added sugar). Sex-specific trends in macronutrient, fibre and food group intakes across sugar type quartiles were determined with general linear modelling adjusting for age, energy intake, leisure-time physical activity, smoking, education and BMI. Overall, results were similar across sexes. Young age was found to be a determinant of higher added sugar and lower naturally occurring sugar intakes (P < 0.0001). High added sugar intake was associated with low fibre intake (P < 0.0001) accompanied with lower fruit (P < 0.0001 women; P = 0.022 men) and vegetable consumption (P < 0.0001) and higher wheat consumption (P = 0.0003 women; P < 0.0001 men). Opposite results were found for naturally occurring sugar. Butter consumption increased by 28-32 % (P < 0.0001) when shifting from the lowest to the highest added sugar intake quartile, while a decrease of 26-38 % (P < 0.0001) was found for naturally occurring sugar. Therefore, the associations of sugar types with dietary carbohydrate and fat quality seem opposing. Proper adjustments with dietary variables are needed when studying independent relationships between sugar and health. PMID- 28620484 TI - The effect of changing the moisture levels of dry extruded and wet canned diets on physical activity in cats. AB - Obesity levels in cats are increasing and the main causative factor is higher energy intake v. energy expenditure over time. Therefore, altering energy expenditure by enhancing physical activity of the cat could be a strategy to reduce obesity. Hydrating commercial dry diets with water increased activity in cats; however, no study has compared this approach with feeding high-moisture canned diets. Eight healthy male neutered domestic shorthair cats were fed four different dietary treatments in a Latin square design. Treatments were a canned diet 'as is' (82 % moisture) and freeze-dried (4 %), a dry diet 'as is' (3 %) and with added water (70 %). Cat activity was measured continuously using Actical(r) accelerometers. Cats were group housed during the first 14 d of each period and then moved to individual cages for 7 d with faecal and urine production measured over the final 4 d. Intake was similar for each diet. The average activity over 24 h was not different between treatments (P > 0.05). However, the ratio between average activity during the day v. at night was higher when cats were fed the dry diet (P = 0.030). Total water intake and urine volume increased when the canned diet was fed (P < 0.001). The similarity in total activity of the cats on the treatments indicates that dietary moisture or diet type did not have a major effect on these cats. However, the stronger diurnal activity patterns observed in the cats when they were fed the dry diet are intriguing and require further study. PMID- 28620483 TI - Utilisation of supplemented l-carnitine for fuel efficiency, as an antioxidant, and for muscle recovery in Labrador retrievers. AB - The primary goal was to investigate the effects of l-carnitine on fuel efficiency, as an antioxidant, and for muscle recovery in Labrador retrievers. Dogs were split into two groups, with one group being supplemented with 250 mg/d of CarnikingTM l-carnitine powder. Two experiments (Expt 1 and Expt 2) were performed over a 2-year period which included running programmes, activity monitoring, body composition scans and evaluation of recovery using biomarkers. Each experiment differed slightly in dog number and design: fifty-six v. forty dogs; one endurance and two sprint runs per week v. two endurance runs; and differing blood collection time points. All dogs were fed a low-carnitine diet in which a fixed amount was offered based on maintaining the minimum starting weight. Results from Expt 1 found that the carnitine dogs produced approximately 4000 more activity points per km compared with the control group during sprint (P = 0.052) and endurance runs (P = 0.0001). Male carnitine dogs produced half the creatine phosphokinase (CPK) following exercise compared with male control dogs (P = 0.05). Carnitine dogs had lower myoglobin at 6.69 ng/ml following intensive exercise compared with controls at 24.02 ng/ml (P = 0.0295). Total antioxidant capacity (TAC) and thiobarbituric acid reactive substance (TBARS) results were not considered significant. In Expt 2, body composition scans indicated that the carnitine group gained more total tissue mass while controls lost tissue mass (P = 0.0006) and also gained lean mass while the control group lost lean mass (P < 0.0001). Carnitine dogs had lower CPK secretion at 23.06 v. control at 28.37 mU/ml 24 h after post-run (P = 0.003). Myoglobin levels were lower in carnitine v. control dogs both 1 h post-run (P = 0.0157; 23.83 v. 37.91 ng/ml) and 24 h post-run (P = 0.0189; 6.25 v.13.5 ng/ml). TAC indicated more antioxidant activity in carnitine dogs at 0.16 mm v. control at 0.13 mm (P = 0.0496). TBARS were also significantly lower in carnitine dogs both pre-run (P = 0.0013; 15.36 v. 23.42 um) and 1 h post-run (P = 0.056; 16.45 v. 20.65 um). Supplementing l-carnitine in the form of CarnikingTM had positive benefits in Labrador retrievers for activity intensity, body composition, muscle recovery and oxidative capacity. PMID- 28620485 TI - Variation in activity levels amongst dogs of different breeds: results of a large online survey of dog owners from the UK. AB - Regular physical activity is an important means of promoting health, both in people and their pets. Walking is the most common method used for dogs, but there is a lack of clarity on how much daily activity different breeds of dog require. Data from an online survey of UK dog owners were collected between June and August in 2014. The University of Liverpool Ethics Committee approved the project, and owners consented to data use. The initial dataset (17 028 dogs) was first cleaned to remove erroneous data, and then edited to remove mixed breed dogs, leaving a total of 12 314 dogs from known pedigree breeds. Other information collected included sex, age, neuter status, breed, and amount and frequency of exercise. Exercise frequency and duration were estimated across different breeds, and compared with Kennel Club recommendations, using chi2 tests and binary logistic regression. The online survey data indicated differences amongst breeds in the amount of walking reported (P < 0.001). Afghan hounds were the least exercised breed, whilst breeds reportedly exercised most included: English setter, foxhound, Irish setter and Old English sheepdog. Gundogs were most likely to be walked once per d or more (P < 0.001), whilst smaller dogs were more likely to meet their UK Kennel Club guidelines for dog walking (P < 0.001). The frequency of dog walking varies both within and amongst breeds, and many do not currently receive the recommended amount of exercise. This may constitute a canine welfare problem and also have an impact on the physical activity levels of their owners. PMID- 28620486 TI - Overweight dogs exercise less frequently and for shorter periods: results of a large online survey of dog owners from the UK. AB - Canine obesity is now the number one health concern in dogs worldwide. Regular physical activity can improve health, and owners are advised to exercise their dogs on a regular basis. However, limited information exists about associations between overweight status of dogs and walking activity. An online survey was conducted between June and August in 2014, coinciding with the broadcast of a national UK television programme, exploring dog behaviour. Information gathered included signalment, overweight status, and owner-reported information on duration and frequency of dog walking. The University of Liverpool Ethics Committee approved the project, and owners consented to data use. Simple and multiple logistic regression analyses were used to determine associations between overweight status and dog walking activity. Data were available from 11 154 adult dogs, and 1801 (16.1 %) of these were reported as overweight by their owners. Dogs reported to be overweight dogs were more likely to be neutered (P < 0.0001) and older (P < 0.0001). Various breeds were over-represented including beagle, Cavalier King Charles spaniel, golden retriever, Labrador retriever and pug (P < 0.0001 for all). Both frequency and duration of walking were negatively associated with overweight status (P < 0.0001 for both). On multiple regression analysis, duration and frequency were independently and negatively associated with the odds of being overweight, along with a range of other factors including age, neuter status and breed. This study has identified associations between overweight status and exercise. In the future, studies should determine the reason for this association, and whether changes in walking activity can influence weight status. PMID- 28620487 TI - Effect of enzyme supplements on macronutrient digestibility by healthy adult dogs. AB - Some enzyme supplement products claim benefits for healthy dogs to compensate for alleged suboptimal production of endogenous enzymes and the loss of enzymes in commercial pet foods secondary to processing. The objective of the current study was to determine macronutrient and energy digestibility by healthy adult dogs fed a commercial maintenance diet with or without supplementation with plant- and animal-origin enzyme products at the dosage recommended by their respective manufacturers. A group of fourteen healthy neutered adult Beagle dogs (average age 8 years) was divided into two equal groups and fed the basal diet alone and then with either the plant- or animal-origin enzyme supplement in three consecutive 10-d periods; the treatment groups received the opposite enzyme supplement in the third period. Digestibility in each period was performed by the total faecal collection method. Serum trypsin-like immunoreactivity (TLI) was measured at the end of each trial. Data were analysed by repeated measures and the alpha level of significance was set at 0.05. There were no differences in energy and nutrient digestibility between enzyme treatments. When comparing basal with enzyme supplementation, fat digestibility was higher for the basal diet compared with the animal-origin enzyme treatment, which could be a period effect and was not biologically significant (94.7 v. 93.5 %). Serum TLI was not affected by supplementation with either enzyme product. Exogenous enzyme supplementation did not significantly increase digestibility of a typical commercial dry diet in healthy adult dogs and routine use of such products is not recommended. PMID- 28620488 TI - Impact of faecal DM excretion on faecal calcium losses in dogs eating complete moist and dry pet foods - food digestibility is a major determinant of calcium requirements. AB - The recommendations for the Ca supply for maintenance of dogs have been reduced by about 75 % in the last decades. An important factor for Ca requirements is faecal Ca losses. In previous studies with experimental diets faecal Ca losses depended on Ca intake and on faecal DM excretion. A predictive equation for faecal Ca losses in mg/kg body weight (BW) developed in a fibre model is: faecal losses = -33.8 + (13.6 faecal DM excretion (g/kg BW)) + (0.78 Ca intake (mg/kg BW)). The present study aimed at testing this equation in pet food with material from trials carried out for other purposes. Digestion trials with twenty-five dry and fifteen moist foods (326 observations in total) were evaluated retrospectively. Faecal DM excretion and faecal Ca losses were significantly correlated (r2 0.86; P < 0.001). There was a highly significant correlation (r2 0.87; P < 0.001) between the experimentally determined faecal Ca excretion and the faecal Ca excretion predicted by the equation of Kienzle et al. The data from the previous fibre model study could be transferred to prepared moist and dry dog food. Faecal DM excretion has a considerable impact on faecal Ca losses in a practical feeding situation. In conclusion, Ca requirements for maintenance may vary with food DM intake and digestibility. PMID- 28620489 TI - Organizational knowledge and capabilities in healthcare: Deconstructing and integrating diverse perspectives. AB - Diverse concepts and bodies of work exist in the academic literature to guide research and practice on organizational knowledge and capabilities. However, these concepts have largely developed in parallel with minimal cross fertilization, particularly in the healthcare domain. This contributes to confusion regarding conceptual boundaries and relationships, and to a lack of application of potentially useful evidence. The aim of this article is to assess three concepts associated with organizational knowledge content-intellectual capital, organizational core competencies, and dynamic capabilities-and to propose an agenda for future research. We conducted a literature review to identify and synthesize papers that apply the concepts of intellectual capital, organizational core competencies, and dynamic capabilities in healthcare settings. We explore the meaning of these concepts, summarize and critique associated healthcare research, and propose a high-level framework for conceptualizing how the concepts are related to each other. To support application of the concepts in practice, we conducted a case study of a healthcare organization. Through document review and interviews with current and former leaders, we identify and describe the organization's intellectual capital, organizational core competencies, and dynamic capabilities. The review demonstrates that efforts to identify, understand, and improve organizational knowledge have been limited in health services research. In the literature on healthcare, we identified 38 papers on intellectual capital, 4 on core competencies, and 5 on dynamic capabilities. We link these disparate fields of inquiry by conceptualizing the three concepts as distinct, but overlapping concepts influenced by broader organizational learning and knowledge management processes. To aid healthcare researchers in studying and applying a knowledge based view of organizational performance, we propose an agenda for future research involving longitudinal comparative case studies. PMID- 28620490 TI - Ketogenic diet: Predictors of seizure control. AB - BACKGROUND: The ketogenic diet is an effective non-pharmacologic treatment for medically resistant epilepsy. The aim of this study was to identify any predictors that may influence the response of ketogenic diet. METHODS: A retrospective chart review for all patients with medically resistant epilepsy was performed at a tertiary care epilepsy center from 1996 to 2012. Patient- and diet related variables were evaluated with respect to seizure reduction at 1, 3, 6, 9 and 12-month intervals and divided into four possible outcome classes. RESULTS: Sixty-three patients met inclusion. Thirty-seven (59%) reported >50% seizure reduction at 3 months with 44% and 37% patients benefiting at 6-month and 12 month follow up, respectively. A trend toward significant seizure improvement was noted in 48% patients with seizure onset >1 year at 12-month (p = 0.09) interval and in 62% patients with >10 seizure/day at 6-month interval (p = 0.054). An ordinal logistic regression showed later age of seizure to have higher odds of favorable response at 1-month (p = 0.005) and 3-month (p = 0.013) follow up. Patients with non-fasting diet induction were more likely to have a favorable outcome at 6 months (p = 0.008) as do females (p = 0.037) and those treated with higher fat ratio diet (p = 0.034). CONCLUSION: Our study reports the effectiveness of ketogenic diet in children with medically resistant epilepsy. Later age of seizure onset, female gender, higher ketogenic diet ratio and non fasting induction were associated with better odds of improved seizure outcome. A larger cohort is required to confirm these findings. PMID- 28620491 TI - Pseudo-thrombotic thrombocytopenic purpura presenting as multi-organ dysfunction syndrome: A rare complication of pernicious anemia. AB - OBJECTIVE: We present a rare case of pernicious anemia presented as multi-organ dysfunction syndrome, later found to have pseudo-thrombotic thrombocytopenic purpura. METHODS: An 86-year-old female presented with respiratory distress, altered mental status, acute renal failure and was intubated in emergency room. She was found to have severe anemia, thrombocytopenia, high lactate, high lactate dehydrogenase and low haptoglobin. Peripheral smear revealed multilobulated neutrophils with schistocytes, poikilocytes and anisocytes. RESULTS: She was admitted to intensive care unit for altered mental status, multi-organ dysfunction syndrome with severe metabolic acidosis in setting of hemolysis. She was intubated and managed with intravenous antibiotics and blood transfusion. Patient improved significantly after blood transfusion. Lactic acid normalized, acute kidney injury resolved and mentation improved after transfusion. Laboratory investigation revealed low vitamin B12, high methylmalonic acid, high homocysteine, high lactate dehydrogenase, low haptoglobin, high anti-parietal antibody and high anti-intrinsic factor antibody. Patient was diagnosed with pernicious anemia and pseudo-thrombotic thrombocytopenic purpura with concomitant intramedullary hemolysis. Her hematological parameters and her clinical condition improved significantly after starting therapy with cyanocobalamin. CONCLUSION: Pernicious anemia is a chronic disease with subtle presentation but may present as life-threatening complications. Hemolysis and pseudo-thrombotic thrombocytopenic purpura may present as multi-organ dysfunction syndrome which has dramatic response to appropriate therapy. PMID- 28620492 TI - Tinnitus after administration of sublingual immunotherapy. AB - BACKGROUND/OBJECTIVES: Sublingual immunotherapy was first described in 1986. Since then, its use has been increased as an alternative to subcutaneously administered immunotherapy in the treatment of allergic rhinitis. The most common side effects are of oropharyngeal and gastrointestinal in nature, for example, itching, swelling, irritation, ulceration of the oropharynx and nausea, abdominal pain, diarrhoea, and vomiting. More severe side effects are dominated by systemic and respiratory tract manifestations. RESULTS: In this clinical case, the author reports a right-sided transient tinnitus lasting for 48 h after administration of sublingual immunotherapy for house dust mite in allergic rhinitis. CONCLUSIONS: This case provide important insights for clinical practice, as tinnitus has not been previously reported as a side effect of sublingual immunotherapy with house dust mite allergens. PMID- 28620493 TI - A bronchoscopic approach to benign subglottic stenosis. AB - OBJECTIVES: Subglottic stenosis is an abnormal narrowing of the tracheal lumen at the level of subglottis (the area in between the vocal cords and the cricoid cartilage). It can cause significant symptoms due to severe attenuation of airflow. We describe our experience in alleviating symptoms by addressing the stenosis using fibreoptic bronchoscopic methods. METHODS: We report all concurrent cases performed between September 2015 and July 2016. We use a combination of balloon dilation, electro-surgery knife to dilate and incise stenotic segments followed by steroid injection to modulate healing. RESULTS: We treated 10 patients in the study period, 8 of which were women. A total of 39 procedures were performed on these patients during this period. Gastro-esophageal reflux was the most common comorbidity associated with stenosis. The majority of the patients required more than 2 therapeutic procedures, but none required more than 4 procedures. There were no complications. CONCLUSION: Tracheal stenosis and in particular subglottic stenosis is a recurrent process and its management requires extensive collaboration amongst treating specialties. Our technique of steroid injection after dilation of the stenosis was effective in symptom control and decreased the number of repeat procedures. PMID- 28620494 TI - Endemic goitre and hypothyroidism in an adult female patient dependent on total parenteral nutrition. AB - : We present the case of a thirty-year-old female patient who was referred to the endocrinology team with an enlarging goitre and biochemical hypothyroidism. She had been dependent on total parenteral nutrition for the previous six years as a result of intestinal failure thought to be caused by possible underlying mitochondrial disease. The patient also suffers from a Desmin myopathy, and at present, the exact aetiology behind her intestinal failure is not certain. The goitre was smooth and had been enlarging slowly over the previous few months. Thyroid peroxidase antibodies were found to be within normal range. Further analysis of the case showed that twelve months earlier the patients total parenteral nutrition (TPN) feed had been altered as a result of manganese toxicity. The current feeding regimen did not contain a trace element additive which had previously supplied iodine supplementation. A little detective work established that iodine content to the TPN had been reduced, the trace element additive (Additrace) was recommenced providing 1 umol of iodine per day, equating to 130 ug of iodine. Following this change, thyroid-stimulating hormone levels returned to normal and the goitre quickly reduced in size. We present a rare case of endemic goitre and hypothyroidism in a patient receiving inadequate iodine supplementation through total parenteral nutrition. LEARNING POINTS: Endemic goitre and hypothyroidism secondary to iodine deficiency are rare in the developed world. However, the diagnosis should be considered in the setting of a diffuse goitre and negative thyroid antibodies.Although rare, endemic goitre should be considered in patients who present with hypothyroidism and who are dependent on total parenteral nutrition.Treatment with levothyroxine is not required in endemic goitre as thyroid function tests generally normalise with the addition of iodine to the diet/total parenteral nutrition regimen.Iodine supplementation at a level recommended by the European Society for Clinical Nutrition and Metabolism (ESPEN) was observed to quickly normalise this patient's thyroid function tests. PMID- 28620495 TI - Familial partial lipodystrophy and proteinuric renal disease due to a missense c.1045C > T LMNA mutation. AB - : Proteinuric renal disease is prevalent in congenital or acquired forms of generalized lipodystrophy. In contrast, an association between familial partial lipodystrophy (FPLD) and renal disease has been documented in very few cases. A 22-year-old female patient presented with impaired glucose tolerance, hyperinsulinemia, hirsutism and oligomenorrhea. On examination, there was partial loss of subcutaneous adipose tissue in the face, upper and lower limbs, bird-like facies with micrognathia and low set ears and mild acanthosis nigricans. Laboratory investigations revealed hyperandrogenism, hyperlipidemia, elevated serum creatine kinase and mild proteinuria. A clinical diagnosis of FPLD of the non-Dunnigan variety was made; genetic testing revealed a heterozygous c.1045C > T mutation in exon 6 of the LMNA gene, predicted to result in an abnormal LMNA protein (p.R349W). Electromyography and muscle biopsy were suggestive of non specific myopathy. Treatment with metformin and later with pioglitazone was initiated. Due to worsening proteinuria, a renal biopsy was performed; histological findings were consistent with mild focal glomerular mesangioproliferative changes, and the patient was started on angiotensin converting enzyme inhibitor therapy. This is the fourth report of FPLD associated with the c.1045C > T missense LMNA mutation and the second with co-existent proteinuric renal disease. Patients carrying this specific mutation may exhibit a phenotype that includes partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy. LEARNING POINTS: Lipodystrophy is a rare disorder characterized by the complete or partial loss of subcutaneous adipose tissue, insulin resistance, diabetes mellitus and hyperlipidemia.Proteinuric renal disease is a prevalent feature of generalized lipodystrophy but rare in familial partial lipodystrophy.Patients carrying the c.1045C > T missense LMNA mutation (p.R349W) may present with familial partial lipodystrophy, proteinuric nephropathy, cardiomyopathy and atypical myopathy. PMID- 28620496 TI - Growth hormone and insulin-like growth factor 1 affect the severity of Graves' disease. AB - : Graves' disease, the most common form of hyperthyroidism in iodine-replete countries, is associated with the presence of immunoglobulins G (IgGs) that are responsible for thyroid growth and hyperfunction. In this article, we report the unusual case of a patient with acromegaly and a severe form of Graves' disease. Here, we address the issue concerning the role of growth hormone (GH) and insulin like growth factor 1 (IGF1) in influencing thyroid function. Severity of Graves' disease is exacerbated by coexistent acromegaly and both activity indexes and symptoms and signs of Graves' disease improve after the surgical remission of acromegaly. We also discuss by which signaling pathways GH and IGF1 may play an integrating role in regulating the function of the immune system in Graves' disease and synergize the stimulatory activity of Graves' IgGs. LEARNING POINTS: Clinical observations have demonstrated an increased prevalence of euthyroid and hyperthyroid goiters in patients with acromegaly.The coexistence of acromegaly and Graves' disease is a very unusual event, the prevalence being <1%.Previous in vitro studies have showed that IGF1 synergizes the TSH-induced thyroid cell growth-activating pathways independent of TSH/cAMP/PKA cascade.We report the first case of a severe form of Graves' disease associated with acromegaly and show that surgical remission of acromegaly leads to a better control of symptoms of Graves' disease. PMID- 28620497 TI - Painful ovulation in a 46,XX SRY -ve adult male with SOX9 duplication. AB - : 46,XX disorders of sexual development (DSDs) occur rarely and result from disruptions of the genetic pathways underlying gonadal development and differentiation. We present a case of a young phenotypic male with 46,XX SRY negative ovotesticular DSD resulting from a duplication upstream of SOX9 presenting with a painful testicular mass resulting from ovulation into an ovotestis. We present a literature review of ovulation in phenotypic men and discuss the role of SRY and SOX9 in testicular development, including the role of SOX9 upstream enhancer region duplication in female-to-male sex reversal. LEARNING POINTS: In mammals, the early gonad is bipotent and can differentiate into either a testis or an ovary. SRY is the master switch in testis determination, responsible for differentiation of the bipotent gonad into testis.SRY activates SOX9 gene, SOX9 as a transcription factor is the second major gene involved in male sex determination. SOX9 drives the proliferation of Sertoli cells and activates AMH/MIS repressing the ovary. SOX9 is sufficient to induce testis formation and can substitute for SRY function.Assessing karyotype and then determination of the presence or absence of Mullerian structures are necessary serial investigations in any case of DSD, except for mixed gonadal dysgenesis identified by karyotype alone.Treatment is ideal in a multidisciplinary setting with considerations to genetic (implications to family and reproductive recurrence risk), psychological aspects (sensitive individualized counseling including patient gender identity and preference), endocrinological (hormone replacement), surgical (cosmetic, prophylactic gonadectomy) fertility preservation and reproductive opportunities and metabolic health (cardiovascular and bones). PMID- 28620498 TI - Diabetes insipidus and hypopituitarism in HIV: an unexpected cause. AB - : Central diabetes insipidus (DI) is a rare clinical entity characterized by low circulating levels of antidiuretic hormone (ADH) presenting with polyuria and volume depletion. Pituitary surgery is the most common cause of central DI in adults. Pituitary and hypothalamic disease, particularly invasive neoplasms, rarely cause DI, being idiopathic cases responsible for the majority of non surgical cases. HIV patients, especially those with poor virulogical control, are prone to the development of CNS neoplasms, particularly lymphomas. These neoplasms usually become manifest with mass effects and seizures. Central DI and hypopituitarism are uncommon initial manifestations of primary CNS lymphomas. The authors describe the case of 29-year-old female, HIV-positive patient whose CNS lymphoma presented with DI. LEARNING POINTS: Central diabetes insipidus has multiple causes and central nervous system lymphomas are not often considered in the differential diagnosis due to their low prevalence.Accurate biochemical diagnosis should always be followed by etiological investigation.The HIV population is at risk for many neoplasms, especially CNS lymphomas.New-onset polyuria in an HIV-positive patient in the absence of focal neurological signs should raise the suspicion for a central nervous system process of neoplastic nature.This clinical entity usually constitutes a therapeutical challenge, often requiring a multidisciplinary approach for optimal outcome. PMID- 28620499 TI - Intrauterine death following intraamniotic triiodothyronine and thyroxine therapy for fetal goitrous hypothyroidism associated with polyhydramnios and caused by a thyroglobulin mutation. AB - : In the absence of maternal thyroid disease or iodine deficiency, fetal goitre is rare and usually attributable to dyshormonogenesis, for which genetic ascertainment is not always undertaken in the UK. Mechanical complications include tracheal and oesophageal compression with resultant polyhydramnios, malpresentation at delivery and neonatal respiratory distress. We report an Indian kindred in which the proband (first-born son) had congenital hypothyroidism (CH) without obvious neonatal goitre. His mother's second pregnancy was complicated by fetal hypothyroid goitre and polyhydramnios, prompting amniotic fluid drainage and intraamniotic therapy (with liothyronine, T3 and levothyroxine, T4). Sadly, intrauterine death occurred at 31 weeks. Genetic studies in the proband demonstrated compound heterozygous novel (c.5178delT, p.A1727Hfs*26) and previously described (c.7123G > A, p.G2375R) thyroglobulin (TG) mutations which are the likely cause of fetal goitre in the deceased sibling. TG mutations rarely cause fetal goitre, and management remains controversial due to the potential complications of intrauterine therapy however an amelioration in goitre size may be achieved with intraamniotic T4, and intraamniotic T3/T4 combination has achieved a favourable outcome in one case. A conservative approach, with surveillance, elective delivery and commencement of levothyroxine neonatally may also be justified, although intubation may be required post delivery for respiratory obstruction. Our observations highlight the lethality which may be associated with fetal goitre. Additionally, although this complication may recur in successive pregnancies, our case highlights the possibility of discordance for fetal goitre in siblings harbouring the same dyshormonogenesis-associated genetic mutations. Genetic ascertainment may facilitate prenatal diagnosis and assist management in familial cases. LEARNING POINTS: CH due to biallelic, loss-of-function TG mutations is well-described and readily treatable in childhood however mechanical complications from associated fetal goitre may include polyhydramnios, neonatal respiratory compromise and neck hyperextension with dystocia complicating delivery.CH due to TG mutations may manifest with variable phenotypes, even within the same kindred.Treatment options for hypothyroid dyshormogenic fetal goitre in a euthyroid mother include intraamniotic thyroid hormone replacement in cases with polyhydramnios or significant tracheal obstruction. Alternatively, cases may be managed conservatively with radiological surveillance, elective delivery and neonatal levothyroxine treatment, although intubation and ventilation may be required to support neonatal respiratory compromise.Genetic ascertainment in such kindreds may enable prenatal diagnosis and anticipatory planning for antenatal management of further affected offspring. PMID- 28620500 TI - Lugol's solution-induced painless thyroiditis. AB - : Lugol's solution is usually employed for a limited period for thyroidectomy preparation in patients with Graves' disease and for the control of severe thyrotoxicosis and thyroid storm. We describe a rare case of Lugol's solution induced painless thyroiditis. In November 2014, a 59-year-old woman was prescribed Lugol's solution four drops per day for the alleviation of menopausal symptoms. She was referred to our clinic in June 2015 for fatigue, hair loss, and a 20-lb weight loss without thyroid pain or discomfort. Physical examination revealed a normal thyroid gland. On 7 May 2015, laboratory tests revealed a suppressed thyroid-stimulating hormone (TSH) 0.01 U/L with elevated free T4 3.31 ng/dL (42.54 pmol/L). Repeat testing on 25 May 2015 showed spontaneous normalization of the free thyroid hormone levels with persistently low TSH 0.10 U/L. Following these results, a family physician prescribed methimazole 10 mg PO TID and very soon after, the TSH concentration rose to >100 U/L along with subnormal free T4 and T3 levels. Methimazole was promptly discontinued, namely within 18 days of its initiation. Over the course of the next few months, the patient spontaneously achieved clinical and biochemical euthyroidism. To our knowledge, this is a unique case of painless thyroiditis induced by Lugol's solution, which has not been reported before. Lugol's solution is a short-term medication given for the preparation of thyroidectomy in patients with Graves' disease and for the control of severe thyrotoxicosis. Iodine excess can cause both hyperthyroidism and hypothyroidism. Rarely, Lugol's solution can cause acute painless thyroiditis. LEARNING POINTS: Lugol's solution is used for thyroidectomy preparation in patients with Graves' disease and for the control of severe thyrotoxicosis and thyroid storm.Iodine excess can cause both hypothyroidism and thyrotoxicosis. Thyroid glands with an underlying pathology are particularly susceptible to the adverse effect of iodine.The prolonged off-label use of Lugol's solution can be harmful. Rarely, Lugol's solution can cause acute painful thyroiditis. PMID- 28620501 TI - Efficacy of lenvatinib in a patient with anaplastic thyroid cancer. AB - : We experienced a case of an 82-year-old woman who presented to our hospital with a 1-month history of dysphagia and dyspnea. Cervical contrast-enhanced computed tomography revealed diffuse thyroid neoplasms causing significant tracheal stenosis with tumors, particularly of the superior mediastinum, which were associated with an embolism of the brachiocephalic vein and suspected invasion to the bilateral common carotid arteries. Anaplastic thyroid cancer (ATC) was diagnosed by fine-needle aspiration; thus, emergency tracheostomy and gastrostomy were performed. We made a definitive diagnosis of ATC (T4bN0M0 Stage IVB) and initiated continuous lenvatinib administration at 24 mg/day. Although several adverse events occurred, the tumor size reduced remarkably over a short period. However, the patient died from rupture of the common carotid artery 30 days after treatment initiation. Here, we report our experience with lenvatinib therapy for ATC and include a literature review. LEARNING POINTS: Lenvatinib is extremely effective for ATC.Lenvatinib has a much greater cytoreductive effect than traditional therapies, but it needs dose reduction or withdrawal because of treatment-related side effects.Lenvatinib may cause treatment-related carotid blowout syndrome, resulting in death for patients with invasion to the carotid artery. PMID- 28620502 TI - Balanitis xerotica obliterans: has its diagnostic accuracy improved with time? AB - OBJECTIVES: We observed whether general practitioners are referring more appropriately for balanitis xerotica obliterans in regards to circumcision, especially at a time of clinical concern, and whether their discriminative abilities were affected by age. We also aimed to explore if balanitis xerotica obliterans was over-diagnosed by surgeons potentially leading to unnecessary circumcisions of healthy foreskins. DESIGN: Cross-sectional descriptive study. SETTING: Leicester Royal Infirmary. PARTICIPANTS: All children less than 16 years of age were included and were subsequently split into two categories: those less than or equal to five years and those above five years. Circumcision was justified if surgeon found pathology under foreskin commissioning guidelines set by the Royal College of Surgeons of England. After clinical diagnosis of balanitis xerotica obliterans, the pathological database was searched for histological confirmation. MAIN OUTCOME MEASURES: Has diagnostic accuracy improved amongst general practitioners for balanitis xerotica obliterans and is there a high clinical to histological confirmation. RESULTS: Of the total patients, 14.5% were diagnosed clinically with balanitis xerotica obliterans. Only 66.7% of cases were histologically confirmed with chronic inflammation found in the rest; 5.5% of all boys referred had balanitis xerotica obliterans on histology; and 8.2% of children <5 had clinical balanitis xerotica obliterans with 1.7% confirmed histologically. This was in contrast with 18.1% and 9.2% found in the older cohort. CONCLUSION: There remains a high diagnostic inaccuracy amongst general practitioners when referring for balanitis xerotica obliterans. This is greatest in those under five years. Although balanitis xerotica obliterans was over-diagnosed, no healthy foreskin underwent unnecessary circumcision. PMID- 28620503 TI - General practice views of managing childhood obesity in primary care: a qualitative analysis. AB - OBJECTIVE: To explore general practice staff views of managing childhood obesity in primary care. DESIGN: A qualitative study to elicit the views of clinical and non-clinical general practice staff on managing childhood obesity. SETTING: Interviews were conducted at 30 general practices across England. These practices were interviewed as part of the Quality and Outcomes Framework Pilot Study. PARTICIPANTS: A total of 52 staff from 30 practices took part in a semi structured interview. MAIN OUTCOME MEASURES: Key themes were identified through thematic analysis of transcripts using an inductive approach. RESULTS: Three themes were identified: lack of contact with well children, sensitivity of the issue, and the potential impact of general practice. Identifying overweight children was challenging because well children rarely attended the practice. Interviewees felt ill equipped to solve the issue because they lacked influence over the environmental, economic and lifestyle factors underpinning obesity. They described little evidence to support general practice intervention and seemed unaware of other services. Raising the issue was described as sensitive. CONCLUSION: General practice staff were unconvinced that they could have a significant role in managing childhood obesity on a large scale. Participants believed schools have more contact with children and should coordinate the identification and management of overweight children. Future policy could recommend a minor role for general practice involving opportunistically identifying overweight children and signposting to obesity services. PMID- 28620504 TI - Atlantoaxial TB with paralysis: posterior-only cervical approach with good results. AB - Early posterior cervical approach is an effective strategy for patients with cervical tuberculosis in the appropriate circumstances. PMID- 28620505 TI - World medical schools: The sum also rises. AB - OBJECTIVE: There is a worldwide shortage of doctors, which is true in most countries and on most continents. To enumerate the number of medical schools in the world at two different times, showing the trends and relating this to population is a beginning. The number is actually going up and has done so for some time; this has increased the supply of physicians and broadened healthcare delivery. DESIGN: The number to count for geographic and regional information about the medical schools relates directly to the supply of doctors. Regions were chosen from WHO and Foundation for the Advancement of International Medical Education and Research data to illustrate geographic distributions, physicians per patient and kinetics. SETTING: The number of medical schools has consistently been rising around the world. However, world order is reverting to disorder, considering wars, disease and beleaguered stand-offs. PARTICIPANTS: None. MAIN OUTCOME MEASURES: Eight countries contain 40% of medical schools; however, several locations are rising faster than the rest. Some regions are stable, but sub-Saharan Africa, the Caribbean, South Asia and South America have increased the most in percentage recently, but not uniformly. RESULTS: Medical schools are related not only by geography, political boundaries and population but are concentrated in some regions. Graduate Medical Education positions appear to be short on a worldwide basis, as well as in some regions and countries. CONCLUSIONS: The number of medical schools is increasing worldwide and the identification of rapidly rising geographic areas is useful in exploring, planning and comparing regions. Controversy continues in a variety of locations, especially concerning Graduate Medical Education. In addition to funding, faculty candidates and accreditation, new schools are confronting a variety of choices in standards and quality, sizing and regional concerns. PMID- 28620506 TI - An unusual manifestation of diabetic ketoacidosis and acute colonic pseudo obstruction. AB - Patients presenting with diabetic ketoacidosis and acute colonic pseudo obstruction should undergo a focused evaluation to identify underlying precipitants. PMID- 28620507 TI - Laparoscopic uteroovarian ligament truncation and uterosacral oophoropexy for idiopathic recurrent ovarian torsion: case report and review of literature. AB - BACKGROUND: Unilateral recurrent ovarian torsion in adults is unusual following treatment of common underlying risk factors (e.g. benign cysts). Subtle anatomic etiologies, such as an elongated uteroovarian ligament and robust ovarian volume, are commonly underappreciated and may contribute to idiopathic recurrent unilateral torsion in adults. As seen in this case, combined surgical procedures may be required to prevent recurrence. CASE: 28 year old nulligravid woman with seven episodes of right ovarian torsion (without adnexal pathology)-six of those within 18 months-refractory to a series of previous surgical interventions. Laparoscopic uteroovarian ligament truncation with interval uterosacral ligament oophoropexy was employed. Ovarian torsion has not occurred in 45 months. CONCLUSION: Uteroovarian ligament truncation and uterosacral ligament oophoropexy is a feasible and effective combined surgical approach for the prevention of recurrent idiopathic ovarian torsion in adults without obvious risk factors. PMID- 28620508 TI - Pelvic pedicled omental flaps and autologous free omental grafts in a rabbit model. AB - BACKGROUND: There is a need to identify an inexpensive, effective method to prevent postoperative adhesion formation. The objective of this study was to create a novel model for studying omentum as a pelvic adhesion barrier. Randomized, prospective, controlled surgical intervention with serial follow-up in 16 female rabbits at a University-based Center for Comparative Medicine. Interventions included bilateral hysterotomy incision and repair. The left hysterotomy was randomized into coverage with an omental flap or graft; the right hysterotomy remained uncovered. Adhesions were scored via laparoscopy on postoperative days 2, 4, 8, and 12; postmortem evaluation and scoring took place on postoperative day 16. Statistical tests consisted of Kappa tests of agreement between adhesion scorers and Kruskal-Wallis nonparametric tests for the comparison of adhesion scores by intervention arm and by uterine horn. RESULTS: All omental flaps and grafts survived. The only significant difference in mean adhesion scores was seen in non-hysterotomy-associated adhesions, where grafts had a lower score than flaps (p = 0.03). CONCLUSIONS: Survival of all omental flaps and grafts demonstrates that this is a practical model for studying omentum as a pelvic adhesion barrier. Determining the efficacy of omentum as a pelvic adhesion barrier will require further investigation. PMID- 28620509 TI - Explaining fertility transition of a developing country: an analysis of quantum and tempo effect. AB - BACKGROUND: The Total Fertility Rate (TFR) is defined as the average number of births a woman would have if she were to live throughout the reproductive span and bear children at each age at the rates observed in a particular year or period. The current demographic explanation for decline in TFR is primarily attributed to an increase in postponement in pregnancy. Being cross-sectional, fertility measures can be confounded by changes in the timing of births across women's lifetimes (tempo) and by changes in the numbers of children that they have by the time they end their childbearing (quantum). After a sharp fall in the last two decades, TFR of Bangladesh is now 2.3; whereas the TFR was greater than 3 in the last decade. However, mean age at childbearing showed decreasing trend in the last decade. METHODS: This is a secondary analysis of data from the three consecutive Bangladesh Demographic Health Surveys; BDHS-2004, 2007 and 2011. The method of Bongaarts and Feeney has been applied to estimate the tempo of fertility. Life Table analyses were applied on birth intervals to explain the tempo effect. RESULTS: There was a sustained decline of the fertility quantum (the number of births per woman) as estimated by the conventional TFR; due to tempo effects during the last three BDHS surveys. Mean age at childbearing also showed decreasing trend in the last decade. CONCLUSIONS: The current study shows the presence of a significant tempo effect with variability of timing in having first or higher order births. If this trend continues, Bangladesh will be able to achieve below replacement level of fertility soon. PMID- 28620510 TI - Time to next pregnancy in spontaneous pregnancies versus treatment cycles in fertile patients with recurrent pregnancy loss. AB - BACKGROUND: The current standard of care for management of patients with recurrent pregnancy loss is expectant management. However, the emotional impact of pregnancy losses and the urgency to conceive often leads couples to consider a variety of fertility treatments. The objective of this study is to report the time to next pregnancy and subsequent live birth and miscarriage rates in fertile patients with recurrent pregnancy loss (RPL) who choose to attempt spontaneous conception compared to those that opt to pursue fertility treatment. METHODS: Retrospective cohort study of one hundred and fifty-eight fertile RPL patients treated at a university-based fertility center. Patients were followed for a minimum of 6 months. Patients were encouraged to attempt spontaneous conception, but allowed to initiate fertility treatments (ovarian stimulation, insemination, IVF or PGS) according to their preferences. Main outcome measures were time to next pregnancy and pregnancy outcome. RESULTS: For those patients who achieved a spontaneous conception, 88% conceived within 6 months, with a median time of 2 months and range of 1-10 months. Patients using IUI, IVF and PGS conceived in a median of 3, 4 and 5 months, respectively. The live birth rate and clinical miscarriage rate was not improved with any fertility treatment. CONCLUSIONS: In the fertile RPL patient population, there does not appear to be a benefit to proceeding directly with fertility treatment. Patients should be encouraged to attempt spontaneous conception for at least 6 months. PMID- 28620511 TI - Worldwide research productivity in emergency contraception: a bibliometric analysis. AB - BACKGROUND: The main goal of this study was to assess worldwide research activity in emergency contraception (EC) using bibliometric indicators. METHODS: Data in SciVerse Scopus were searched for documents pertaining to emergency contraception. Data obtained were then exported to Microsoft Excel and analyzed using Statistical Package for Social Sciences. RESULTS: A total of 2142 documents were published about EC worldwide. Documents were written in 27 different languages and were published from 78 countries. Publications in EC started on late 1960s. Total number of citations for published EC documents was 30154 while median citation per document was six. The h-index of the retrieved documents was 58. The leading country in EC research was United States of America with a total of 559 documents (26.10%). One hundred and ninety five (9.10%) documents were published in Contraception journal. The leading institution in EC research and publications was Princeton University (50; 2.33%) followed by University of California, San Francisco (34; 1.59%). CONCLUSIONS: The present data revealed that there is a worldwide increasing interest in EC research. Willingness of health policy makers to make EC accessible to the public will determine the future of EC research activity and future of EC as a contraceptive method. PMID- 28620512 TI - Hyperandrogenism in menopause: a case report and literature review. AB - Hyperandrogenism is an uncommon diagnosis in postmenopausal women. In this case, we report on a 69-year-old postmenopausal woman who presented with several months of worsening hirsutism of the face, neck, and chin, which was confirmed on examination. Laboratory testing revealed markedly elevated testosterone levels and typical post-menopausal gonadotropin levels. Transvaginal ultrasonography and pelvic and abdominal magnetic resonance imaging (MRI) failed to reveal an ovarian or adrenal abnormality. The patient was a poor surgical candidate and was counseled to start on gonadotropin releasing hormone (GnRH) agonist therapy. Administration of leuprolide resulted in a dramatic decline in testosterone levels. The patient reported significant "hot flashes", difficulty sleeping, anxiety, and depression secondary to treatment, and patient discontinued leuprolide therapy 3 months after initiation. To our knowledge, this is the first case that describes a woman being treated with a GnRH agonist for hyperandrogenism subsequently discontinuing GnRH agonist treatment due to significant side-effects. This case also highlights the difficulty of prescribing appropriate but off-label use of expensive medications not covered by insurance in a senior population of limited income. PMID- 28620513 TI - The CROWN Initiative: journal editors invite researchers to develop core outcomes in women's health. PMID- 28620514 TI - Hysterosalpingographic findings among Ghanaian women undergoing infertility work up: a study at the Korle-Bu Teaching Hospital. AB - BACKGROUND: Hysterosalpingography (HSG) is one of the commonly used radiological modalities for investigating infertility in women. In developing countries such as Ghana it remains the main tool for investigating some of the underlying causes of female infertility. The purpose of this study was to determine the predominance of various hysterosalpingographic results in patients that went through infertility work-up at the Korle-Bu Teaching Hospital between January 2011 and December, 2014. This is to help plan for preventive measures for the communities. RESULTS: This study collected retrospectively, 1140 consecutive radiologic reports from January 2011 to December, 2014 from the Department of Radiology, Korle-Bu Teaching Hospital. These reports were reviewed and diagnoses made were evaluated with Microsoft Excel. Secondary infertility was 52.4 % prevalent and primary infertility was 41 % prevalent. While 453 (39.7 %) patients presented with normal findings, 153 (13.4 %) had hydrosalpinx, 498 (43.6 %) had tubal blockage, and 290 (25.4 %) had fibroids. Also there were 10 (0.9 %) cases of patulous cervices, 8 (0.8 %) cases of uterine synechiae, 62 (5.4 %) of irregular uterine outline, 15 (1.3 %) of irregular cervical outline, 3 (0.3 %) of arcuate uteri, and 5 (0.4 %) cases of retroverted uteri. CONCLUSION: Tubal blockage which presented in 43.6 % of patients was the most common abnormal finding at HSG examinations carried out between January 2011 and December, 2014 at the KBTH. This was followed by fibroids with 25.4 % and hydrosalpinx with 13.4 %. Factors such as chronic pelvic inflammatory disease or pelvic infection following STIs, mismanaged pregnancies and septic abortions, may have accounted for this since the majority of the women presented with secondary infertility. PMID- 28620515 TI - Self-reported effects of infertility on marital relationships among fertility clients at a public health facility in Accra, Ghana. AB - BACKGROUND: There is little empirical literature on the effects of infertility on marital relationships in Ghana. This study sought to examine the effects of infertility on marital relationship among fertility clients at a Public Hospital in Accra, Ghana. RESULTS: The study revealed that infertility negatively affected the sexual life of participants as they generally reported that even though they still had regular sexual intercourse with their partners after realising they were infertile (61.6 %), sex was only for the purpose of reproduction and not for mutual sexual satisfaction (68.8 %). Sexual intercourse was reported to be unfulfilling as well as unenjoyable (64.3 %). The psychological well-being of participants (87.5 %) and stability within marital unions were also negatively affected by infertility, resulting in quarrels (72.3 %). CONCLUSIONS: Infertility has numerous negative implications for marital relationship. Thus, infertile persons should not be only physically examined and treated for infertility, but should also be given counselling to lessen the psychological trauma attached to infertility. PMID- 28620517 TI - Potential causes of subfertility in patients with intramural fibroids. AB - BACKGROUND: Intramural leiomyomas have been long debated as a potential cause of infertility and pregnancy loss. FINDINGS: Previous research has linked intramural fibroids to defective implantation, as well as to abnormal peristaltic events of the uterine smooth muscle. Previous reports describe the effects of intramural fibroids on normal human fertility and early pregnancy loss, specifically in regards to implantation failure. CONCLUSION: A thorough understanding of prior research may direct new research focus, leading to better understanding of leiomyoma-associated infertility. PMID- 28620516 TI - The impact of lifestyle modifications, diet, and vitamin supplementation on natural fertility. AB - BACKGROUND: Infertility is a relatively common condition. When patients are confronted with this diagnosis, there are medical, psychological, and financial sequelae. Patients often wonder if there is anything they can do to optimize their natural fertility or increase the effectiveness of infertility treatments. FINDINGS: If there is a clear impact on fertility, such as with smoking and alcohol, cessation should be advised. Similarly, weight loss should be recommended if the BMI is in the overweight and obese category, and weight gain should be recommended for an underweight BMI. The evidence surrounding other lifestyle modifications is less clear. There are conflicting data regarding an optimal fertility diet and consumption of vitamins and supplements. Antioxidants seem to improve semen parameters in men, but the effect on female fertility is less clear. If conflicting evidence exists, such as with caffeine consumption or exercise, moderation should be emphasized. Finally, the diagnosis of infertility and subsequent fertility treatments are stressful for both partners. The psychological aspects should not be ignored and methods such as yoga and cognitive behavioral therapy may be beneficial. CONCLUSION: Continued research will determine the optimal lifestyle modifications to achieve pregnancy. PMID- 28620518 TI - Fertility and pregnancy in rheumatoid arthritis and systemic lupus erythematosus. AB - BACKGROUND: Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are disorders that commonly impact reproductive aged women. FINDINGS: Both women with RA and SLE have smaller sized families than do controls. In the case of RA factors other than fertility contribute, while in women with SLE there may be diminished ovarian reserve due to cyclophosphamide therapy and advanced maternal age. RA pregnancies can be complicated by preterm birth and small-for-gestational aged infants. SLE pregnancies have higher rates of fetal loss, in particular in those patients with co-existing antiphospholipid syndrome. SLE pregnancies are also more likely to be complicated by pre-eclampsia and hypertension and to result in preterm birth and small-for-gestational aged infants. CONCLUSION: Appropriate fertility evaluation and careful pregnancy planning with coordinated obstetrical care help ensure better outcomes in these patient populations. PMID- 28620521 TI - The contribution of contraception, marriage and postpartum insusceptibility to fertility levels in Uganda: an application of the aggregate fertility model. AB - BACKGROUND: While recent studies have indicated that fertility has remained high in Uganda, no systematic attempt has been made to identify the factors responsible for this persistent trend and to quantify these factors. This paper uses the Uganda Demographic and Health Surveys (UDHS) of 2006 and 2011, to examine the contribution contraceptive use, marriage and postpartum infecundability on one hand and Total Fertility Rate (TFR) on the other. We constructed a database using the Woman's Questionnaire from the UDHS 2006 and 2011. We then apply Bongaarts aggregate fertility model procedures to derive estimates of total fertility rate for the different socioeconomic groups. RESULTS: The findings indicate that a woman's contraceptive behavior; marriage status and postpartum infecundability (also referred to as postpartum insusceptibility due to postpartum amenorrhea, which is intended to measure the effects on fertility breastfeeding), are important predictors of fertility outcomes. The results also show that higher education levels and urban residence are consistently associated with lower fertility rates and are positively associated with contraceptive use. Other key predictors of fertility include: wealth status, and region of residence. CONCLUSION: The country needs to scale-up target interventions that are aimed at uplifting the education status of women and improving their economic wellbeing, because such interventions have a positive impact on fertility reduction and on improving maternal and reproductive health outcomes. PMID- 28620523 TI - The level and patterns of fertility among women in Kersa Demographic Surveillance and Health Research Center (KDS-HRC) Field site, Kersa District, East Ethiopia. AB - BACKGROUND: Fertility is one of the three principal components of population dynamics. High fertility and rapid population growth exert negative influences on economic and social development. This study was aimed to estimate the level and trends of fertility among (15-49 years) old women in kersa demographic surveillance and health research center, kersa district Eastern Ethiopia. METHODS: The study was conducted at kersa demographic surveillance and health research center in kersa district, Eastern Ethiopia. The study utilized five years follow up data (2008-2012). All women (15 to 49 years old) who have been living at kersa demographic surveillance and health research center in kersa district from 2008 to 2012 were included in the analysis to estimate the level and pattern of fertility. Descriptive statistics was computed to determine level and pattern of fertility. RESULTS: Age specific fertility rate was highest in women of the age group 25-29 years old (233.2 per 1000 women in 2008; 205.8 per 1000 women in 2009; 279.0 per 1000 women in 2010; 186.6 per 1000 women in 2011 and 198.5 per 1000 women in 2012) in five consecutive years from 2008 to 2012. Total fertility rate didn't show any significant decline during the study period, i.e., 4.3, 4.5, 4.9, 3.5, 4.0 live births per woman throughout her reproductive period (15-49) years old in 2008, 2009, 2010, 2011 and 2012, respectively. On the other hand, general fertility rate declined from 110.3 births per 1000 women in 2008 to 95.9 per 1000 women in the reproductive age in 2012. CONCLUSION: The total fertility rate was found to be relatively high. Fertility rate is higher in rural residents and illiterate women than in urban residents and literate women. Strong information, education, communication and behavior change communication on family planning should be designed and implemented to prevent unwanted fertility. PMID- 28620520 TI - Incidence, diagnosis and management of tubal and nontubal ectopic pregnancies: a review. AB - BACKGROUND: Ectopic pregnancy is a potentially life-threatening condition occurring in 1-2 % of all pregnancies. The most common ectopic implantation site is the fallopian tube, though 10 % of ectopic pregnancies implant in the cervix, ovary, myometrium, interstitial portion of the fallopian tube, abdominal cavity or within a cesarean section scar. FINDINGS: Diagnosis involves a combination of clinical symptoms, serology, and ultrasound. Medical management is a safe and effective option in most clinically stable patients. Patients who have failed medical management, are ineligible, or present with ruptured ectopic pregnancy or heterotopic pregnancy are most often managed with excision by laparoscopy or, less commonly, laparotomy. Management of nontubal ectopic pregnancies may involve medical or surgical treatment, or a combination, as dictated by ectopic pregnancy location and the patient's clinical stability. Following tubal ectopic pregnancy, the rate of subsequent intrauterine pregnancy is high and independent of treatment modality. CONCLUSION: This review describes the incidence, risk factors, diagnosis, and management of tubal and non-tubal ectopic and heterotopic pregnancies, and reviews the existing data regarding recurrence and future fertility. PMID- 28620522 TI - Functional glycosylation in the human and mammalian uterus. AB - BACKGROUND: Glycosylation is the most common and structurally diverse of all the post-translational modifications of proteins. Lipids and extracellular matrices are also often glycosylated. The mammalian uterus is highly enriched in glycoconjugates that are associated with the apical surfaces of epithelial cells and the secretions released by both epithelial and stromal cells. These glycoconjugates interact primarily with sperm, the implanting embryo, the fetus, and any pathogen that happens to gain entry into the uterus. Secretions of the endometrial glands increase substantially during the luteal phase of the menstrual cycle. These secretions are highly enriched in glycoproteins and mucins that promote specific uterine functions. FINDINGS: Lectins and antibodies have been employed in the majority of the studies focused on uterine glycosylation have employed to define the expression of carbohydrate sequences. However, while these studies provide insight about potential glycosylation, precise information about glycan structure is lacking. Direct sequencing studies that employ biochemical or mass spectrometric methods are far more definitive, but have rarely been employed with uterine glycoproteins. Both lectin/antibody binding and direct carbohydrate sequencing studies that have been focused on the mammalian uterus are reviewed. The primary functional role of the eutherian uterus is to facilitate fertilization and nurture the developing embryo/fetus. Trophoblasts are the primary cells that mediate the binding of the embryo and placenta to the uterine lining. In mammals that utilize hemochorial placentation, they invade the decidua, the specialized endometrial lining that forms during pregnancy. Trophoblasts have also been analyzed for their lectin/antibody binding as a complement to the analysis of the uterine cells and tissues. They will also be reviewed here. CONCLUSIONS: The functional roles of the glycans linked to uterine and trophoblast glycoconjugates remain enigmatic. Another major question in the human is whether defects in placental or uterine glycosylation play a role in the development the Great Obstetrical Syndromes. More recent findings indicate that changes in glycosylation occur in trophoblasts obtained from patients that develop preeclampsia and preterm birth. The functional significance of these changes remain to be defined. Whether such shifts happen during the development of other types of obstetrical syndromes remains to be determined. PMID- 28620524 TI - Robotic single-site excision of ovarian endometrioma. AB - BACKGROUND: Conventional single-incision laparoscopic surgery has been successfully employed for treatment of ovarian endometriomas. However, this technique presents surgeons with formidable ergonomic challenges, that make its widespread adoption unlikely. Robotic assistance in single-incision laparoscopic surgery provides adequate instrument triangulation through a single fulcrum, while eliminating ergonomic challenges to the surgeon. The objective of this video is to describe a novel technique of laparoscopic excision and ablation of ovarian endometriomas with single-site robotic assistance. Footage from a single surgical case is shown in our video. The da Vinci Si surgical system with da Vinci Single-Site platform was utilized. A flexible CO2 laser fiber was employed as the main energy tool. To describe a technique of single-incision laparoscopic excision and ablation of endometriomas with robotic assistance. Footage from a single surgical case is shown in this video. The da Vinci Si surgical system with da Vinci Single-Site platform was utilized. A flexible CO2 laser fiber was employed as the main energy tool. RESULTS: Our technique achieved excellent surgical, clinical and cosmetic results, with complete excision and ablation of the endometriomas and no complications. The procedure was completed in day surgery setting. CONCLUSION: Our step-by-step video tutorial shows how the dedicated single incision laparoscopy technology for the da Vinci Si surgical system can be safely and effectively applied to the excision and ablation of ovarian endometriomas. PMID- 28620525 TI - Comparison of uterine and tubal pathology identified by transvaginal sonography, hysterosalpingography, and hysteroscopy in female patients with infertility. AB - BACKGROUND: The causes of female infertility are multifactorial and necessitate comprehensive evaluation including physical examination, hormonal testing, and imaging. Given the associated psychological and financial stress that imaging can cause, infertility patients benefit from a structured and streamlined evaluation. The goal of such a work up is to evaluate the uterus, endometrium, and fallopian tubes for anomalies or abnormalities potentially preventing normal conception. To date, the standard method for assessing these structures typically involves some combination of transvaginal sonography (TVS), hysterosalpingography (HSG), and hysteroscopy (HSC). The goal of this review is to compare the diagnostic accuracy of TVS, HSG, and HSC for diagnosing abnormalities in infertility patients to determine if all studies are necessary for pre-treatment evaluation. RESULTS: We identified infertility patients prior to initiation of assisted reproductive technology who had baseline TVS, HSG, and HSC within 180 days of each other. From medical record review, we compared frequencies of each finding between modalities. Of the 1274 patients who received a baseline TVS over 2 years, 327 had TVS and HSG within 180 days and 55 patients had TVS, HSG and HSC. Of the 327, TVS detected fibroids more often than HSG (74 vs. 5, p < .0001), and adenomyosis more often than HSG (7 vs. 2, p = .02). HSG detected tubal obstruction more often than TVS (56 vs. 8, p = .002). Four (1.2 %) patients had endometrial polyps on both HSG and TVS. In the 55 patients with HSG, TVS, and HSC, HSC identified endometrial polyps more often than TVS (10 vs. 1, p = .0001) and HSG (10 vs. 2, p = .0007). TVS detected more fibroids than HSC (17 vs. 5, p < .0001). Tubal obstruction was identified more often by HSG than HSC (19 vs. 5, p < .0001). CONCLUSIONS: TVS is superior for evaluation of myometrial pathology. HSG is superior for evaluation of tubal pathologies. Endometrial pathologies are best identified with HSC. PMID- 28620526 TI - Promoting the use of elective single embryo transfer in clinical practice. AB - BACKGROUND: The transfer of multiple embryos after in vitro fertilization (IVF) increases the risk of twins and higher-order births. Multiple births are associated with significant health risks and maternal and neonatal complications, as well as physical, emotional, and financial stresses that can strain families and increase the incidence of depression and anxiety disorders in parents. Elective single embryo transfer (eSET) is among the most effective methods to reduce the risk of multiple births with IVF. MAIN BODY: Current societal guidelines recommend eSET for patients <35 years of age with a good prognosis, yet even this approach is not widely applied. Many patients and clinicians have been reluctant to adopt eSET due to studies reporting higher live birth rates with the transfer of two or more embryos rather than eSET. Additional barriers to eSET include risk of treatment dropout after embryo transfer failure, patient preference for twins, a lack of knowledge about the risks and complications associated with multiple births, and the high costs of multiple IVF cycles. This review provides a comprehensive summary of strategies to increase the rate of eSET, including personalized counseling, access to educational information regarding the risks of multiple pregnancies and births, financial incentives, and tools to help predict the chances of IVF success. The use of comprehensive chromosomal screening to improve embryo selection has been shown to improve eSET outcomes and may increase acceptance of eSET. CONCLUSIONS: eSET is an effective method for reducing multiple pregnancies resulting from IVF. Although several factors may impede the adoption of eSET, there are a number of strategies and tools that may encourage the more widespread adoption of eSET in clinical practice. PMID- 28620527 TI - In-vitro fertilization and spontaneous pregnancies: matching outcomes in Douala, Cameroon. AB - BACKGROUND: Couples are considered infertile if they do not conceive over a 12 month period of unprotected intercourse. Studies have shown that female causes accounted for between 25 to 37 percent of infertility worldwide (with larger proportions in sub-Saharan Africa and Southeast Asia) and male causes accounted for between 8 to 22 percent. Both male and female causes accounted for between 21 to 38 percent. Although the majority of ART children are normal, there are concerns about the increased risk for adverse pregnancy outcomes. More than 30 % of ART pregnancies are twins or higher-order multiple gestations (triplets or greater) and more than one half of all ART neonates are the products of multifetal gestations, with an attendant increase in prematurity complications. The aim of this study was to evaiuate the outcome of pregnancies conceived by In vitro fertilisation compared to those conceived naturally in two hospitals in Douala, Cameroon. METHODS: This was a prospective study carried out from October 1, 2011 to September 30, 2012. Participants were recruited from two hospitals: the Douala General Hospital (DGH) and the Clinique de l' Aeroport (CDA), also in Douala. A total of 102 women were recruited for study: 51 who conceived by IVF (cases) and 51 who conceived naturally (controls). Of the 102 women, 52.9 % were between 31 - 39 years of age, while 21.6 % were above 40. RESULTS: Participants who conceived through IVF-ET were 4.1 times more likely to undergo cesarean delivery than those who conceived naturally [OR 4.10, 95 % CI 1.78-9.42]. Similarly, a higher percentage of patients in the IVF group than those in the control group have never given birth (33.3 % vs 2.0 %) (P < 0.0001). The percentage of multiple pregnancies was 7.5 times higher in the IVF group than in the control group (14.7 % vs.1.96 %) (P = 0.000). The leading indication for cesarean delivery was advanced maternal age (27.3 %) followed by IVF or precious pregnancy (18.2 %). CONCLUSIONS: Cesarean delivery was more frequent amongst the IVF group than in the control group. The leading indications for cesarean delivery were advanced maternal age and IVF or precious pregnancy. The long-term neonatal outcomes of IVF babies beyond 5-min Apgar scores should be studied in Cameroon and follow-up beyond 1 year encouraged. PMID- 28620528 TI - Efficiency of metaphase II oocytes following minimal/mild ovarian stimulation in vitro fertilization. AB - BACKGROUND: An inverse relationship between oocyte efficiency and ovarian response was reported in conventional IVF. The purpose of this study was to report metaphase II (MII) oocyte efficiency according to oocyte yield in minimal/mild stimulation IVF (mIVF) and to assess whether oocyte yield affects live birth rate (LBR). METHODS: Infertile women (n = 264) aged < 39 years old with normal ovarian reserve who had mIVF were recruited. All participants received the same protocol for ovarian stimulation. All the embryos were cultured to the blastocyst stage and vitrified using a freeze-all approach. This was followed by a single blastocyst transferred to each participant in subsequent cycles over a 6-month period. Ovarian response was categorized according to the number of MII oocyte yield (low: 1-2, intermediate: 3-6 and high >= 7 MII oocytes). MII oocyte utilization rate was calculated as the number of live births divided by the number of MII oocytes produced after only one oocyte retrieval and subsequent transfers of vitrified/warmed blastocysts. The main outcome measure was cumulative LBR over a 6-month period. RESULTS: Among all the participants, 1173 total retrieved oocytes (4.4 +/- 0.2 per patient) resulted in 1019 (3.9 +/- 0.2 per patient) total MII oocytes, a clinical pregnancy rate of 48.1 % and a LBR of 41.2 %. Oocyte utilization rate was inversely related to ovarian response where it was 30.3 % in the "low" vs. 9.3 % in the "intermediate" vs. 4.3 % in the "high" oocyte yield groups (p < 0.05). Implantation rate significantly dropped as the number of MII oocytes increased and was highest in the "low" oocyte yield group (p < 0.0001). Cumulative LBR was similar in "low," "intermediate," and "high" oocyte yield groups (p > 0.05). The number of MII oocytes had poor sensitivity and specificity for predicting a live birth. CONCLUSION: These data extend the hypothesis of oocyte efficiency reported in conventional IVF protocols to mIVF protocols. TRIAL REGISTRATION: Registration clinicaltrials.gov: NCT00799929. PMID- 28620529 TI - Transferring embryos with indeterminate PGD results: the ethical implications. AB - BACKGROUND: In vitro fertilization (IVF) and pre-implantation genetic diagnosis (PGD) are becoming increasingly common techniques to select embryos that are unaffected by a known genetic disorder. Though IVF-PGD has high success rates, 7.5 % of blastocysts have inconclusive results after testing. A recent case involving a known BRCA-1 carrier was brought before our Assisted Reproductive Technology Ethics Committee in order to gain a better appreciation for the ethical implications surrounding the transfer of embryos with indeterminate testing. THE CASE PRESENTATION: Thirty-nine year old G0 BRCA-1 carrier requiring IVF for male factor infertility. The couple elected for PGD to select against BRCA-1 gene carrier embryos. However, several embryos were returned with inconclusive results. The couple wished to proceed with the transfer of embryos with an unknown carrier status. The case was presented before our Assisted Reproductive Technology Ethics Committee. CONCLUSION: Many considerations were explored, including the physician's duty to protect patient autonomy, the physician's duty to act in the best interest of the future child, and the physician's duty towards society. Transferring both embryos with unknown carrier status and known-carrier status was debated. Ultimately, the transfer of inconclusive embryos was felt to be ethically permissible in most cases if patients had been adequately counseled. However, the re-biopsy of embryos with inconclusive testing results was encouraged. The transfer of known-carrier embryos was felt to be unethical for certain disease-states, depending on the severity of illness and timing of disease onset. We strongly encourage physicians to create an action plan in advance with their patients, prior to testing, in the event that embryos are returned with inconclusive PGD results. The committee's decision, though helpful in guiding practice, should not overshadow the individual physician-patient relationship, and the need for thorough counseling. PMID- 28620530 TI - Candidate gene analysis in a case of congenital absence of the endometrium. AB - BACKGROUND: Primary amenorrhea usually result from a genetic or anatomic abnormality. We present the first reported patient with the absence of endometrium and lumen in a small bicornuate uterus in a patient with primary amenorrhea. CASE PRESENTATION: A 41-year-old woman presented for evaluation of primary amenorrhea and infertility. She did develop normal secondary sexual characteristics but never had menses. Physical examination, hormone analyses, and karyotype analysis were normal. Transvaginal ultrasonography revealed a small uterus with absent endometrial stripe. Ovaries were normal in size. Pathology from hysterectomy for abnormal Pap smears revealed a hypoplastic bicornuate uterus with absence of lumen and absent endometrium. DNA analyses for mutations in the coding sequences of three members of HOXA gene family was performed, but no variants in the coding sequence of these genes were found. These findings support the hypothesis that mutations in the coding sequence of HOXA10, HOXA11, and HOXA13 are not responsible for congenital endometrial absence with bicornuate hypoplastic uterus. CONCLUSIONS: Congenital absence of the endometrium is an uncommon etiology for primary amenorrhea, and nonvisualization of the endometrial stripe on ultrasound imaging in association with primary amenorrhea should raise suspicion of this rare disorder in this case. PMID- 28620531 TI - Clinical vignettes and global health considerations of infertility care in under resourced patients. AB - The ability to receive standard of care for a diagnosis of infertility is a factor of one's financial state and educational level, which are often correlated. Providing infertility care in an under-resourced tertiary care environment provides challenges but also opportunities for unique successes in creating a family. Among the under-represented populations are recent immigrants and refugees. Challenges arise when the infertility treatment is futile or when the standard of care is inaccessible due to cost and scheduling. Unique accomplishments are noted when families are built and hope is restored for couples fleeing from genocide and war-inflicted countries. This article will highlight two clinical vignettes from the Division of Reproductive Endocrinology and Infertility clinic at Boston University School of Medicine/Boston Medical Center. Thereafter, the article will summarize the barriers to care in the United States among those with low socioeconomic status, with non-dominant racial status (non-Caucasian), and with refugee status. All identifiers have been removed and names altered in the patient vignettes. PMID- 28620533 TI - Satisfaction with in vitro fertilization treatment: patients' experiences and professionals' perceptions. AB - BACKGROUND: This paper investigates patients' satisfaction with various aspects of fertility care and seeks to determine to what extent fertility specialists are able to assess patient satisfaction. Patients' experiences with in-vitro fertilization (IVF) services and facilities have been compiled and examined in order to discover whether patients' satisfaction is correlated to psychological factors and demographic, socio-economic, and health characteristics, and whether patients' satisfaction has an influence on the willingness to pay (WTP) for IVF treatment. METHODS: The study was carried out on 204 patients and 19 fertility professionals from 8 public IVF units in Israel. RESULTS: The study found that, overall, infertile patients are satisfied with the care they received. Several demographic variables (age; education; income; number of fertility treatments) and psychological factors ('Pessimism' and 'Activeness'), were found to be significantly correlated with patient satisfaction with IVF. The results yielded a negative correlation between the WTP for IVF treatment and the satisfaction with access to care and physical conditions. CONCLUSIONS: Patient satisfaction is an important component in the evaluation of fertility treatments as well as other medical interventions. Insights into the quality of care as seen from the patients' perspective may help healthcare staff better meet patients' needs, wishes, and priorities. PMID- 28620534 TI - Selective use of percutaneous testis biopsy to optimize IVF-ICSI outcomes: a case series. AB - BACKGROUND: Sperm quality may degrade during transit through the male reproductive tract in some individuals. In this setting surgically retrieved testicular sperm may outperform ejaculated samples for use with in vitro fertilization (IVF) and intracytoplasmic sperm injection (IVF-ICSI). We sought to describe one center's experience with the use of fresh testicular sperm after prior failed IVF-ICSI with ejaculated samples. RESULTS: A retrospective review was conducted evaluating IVF-ICSI cycles performed at a tertiary IVF unit between 2009 and 2014. Couples who were managed with percutaneous testis biopsy to obtain sperm, despite availability of ejaculated sperm, were included. Four couples who underwent a total of 6 percutaneous testis biopsy/IVF-ICSI cycles were identified. Collectively, the couples had undergone 9 prior IVF-ICSI cycles using fresh ejaculated sperm without successful pregnancy. From the six cycles that used fresh testicular sperm four live births resulted (1 twin gestation, 3 singletons). Only 1 of the 4 couples remained childless. CONCLUSIONS: For patients who have had prior failed IVF-ICSI attempts, this small case series demonstrates a possible therapeutic benefit when freshly procured testicular sperm are used in lieu of ejaculated samples. PMID- 28620535 TI - Heavy menstrual bleeding and dysmenorrhea are improved by Magnetic Resonance Guided Focused Ultrasound Surgery (MRgFUS) of adenomyosis. AB - BACKGROUND: To assess reduction in heavy menstrual bleeding and dysmenorrhea following MRI guided Focused Ultrasound Surgery (MRgFUS) of focal and diffuse adenomyosis up to 12 months post-treatment a retrospective cohort study was done at a tertiary care academic medical center for obstetrics, gynecology and infertility. METHODS: MRgFUS for adenomyosis uterus was done for thirty-seven patients presenting with symptoms of heavy menstrual bleeding and dysmenorrhea with MRI-suspected adenomyosis. The main outcome measure, was reduction in heavy menstrual bleeding, dysmenorrhea and Symptom Severity Scoring (SSS) over a 3, 6 and 12 month period. Secondary outcome was evidence of fertility preservation post procedure. D'Agostino & Pearson omnibus normality test, one-way Ananova, Pearson's correlation coefficient analysis was performed on the data. Statistical significances, p-value and r-value were determined. RESULTS: Out of 37 patients who were treated by MRgFUS, 26 had sufficient follow-up to be included in the analysis. SSS calculated at 3, 6 and 12 months was significantly over the baseline. Both heavy menstrual bleeding and dysmenorrhea, which were assessed separately, were found to significantly improve over time with a positive correlation between the two. No other intervention was required. CONCLUSION: MRgFUS provides immediate and sustained relief for patients with focal and diffuse adenomyosis. PMID- 28620536 TI - Factors associated with uterine fibroid in Ghanaian women undergoing pelvic scans with suspected uterine fibroid. AB - BACKGROUND: Uterine fibroids are the most common benign tumours affecting premenopausal women and are often associated with considerable hospitalization and morbidity. Literature shows virtually no study concerning the quantification of the main factors associated with uterine fibroids in Ghanaian women. The purpose of this study was to assess the main factors associated with uterine fibroid among Ghanaian women presenting for ultrasound. METHOD: A prospective cross-sectional study design was employed in this study. A total of two hundred and forty-four (244) women were consecutively evaluated from November 2011 to February 2012 using a 2-5 MHz curvilinear probe of Philips HD3 ultrasound machines at three centres in Accra using a trans-abdominal pelvic approach. Data was analysed with (SPSS) version 20.0 for windows, 2010; Chicago. The Pearson's Chi-square test was used to determine associations between selected demographic and gynaecological characteristics and uterine fibroid appearance. All tests were two-tailed and p-value of less than 0.05 was interpreted as significant. RESULTS: The range, mean and standard deviation (SD) of the patients' age were 14-54 years, 31.89 years and +/- 7.92 respectively. Factors that associated significantly with uterine fibroid in Ghanaian women included obesity (X2 = 17.3, p-value = 0.001), participant's age range (X2 = 47.4, p-value = 0.001), parity (X2 = -10.169, p-value = 0.001), and age at last delivery (X2 = 34.579, p-value = 0.001). CONCLUSION: Uterine fibroid was mainly associated with women of older age group of the reproductive age than the younger age categories and also associated more with women with without children compared to those with more children. Moreover, it associated more with obese patients and patient with late age at last delivery. PMID- 28620537 TI - Fertility is below replacement in Harar Health and Demographic Surveillance System (Harar HDSS), Harar town, Eastern Ethiopia. AB - BACKGROUND: Population growth is determined by fertility, mortality and migration rates. Fertility is the prime determinant of population growth, which is highly associated with family planning, literacy, urbanization, and expansion of health system. In many part of Africa, its level is more than twice the replacement level. In Ethiopia, a significant decline in fertility mainly in the urban setting has been reported over the past decade, yet there is a paucity of information on the level of the decline. Therefore, this analysis aims to assess the level of fertility in Harar Health and Demographic Surveillance System (Harar HDSS) Eastern Ethiopia. METHODS: Harar HDSS is an urban HDSS located in the city of Harar, eastern Ethiopia. It was established in 2011. All the population under surveillance are followed regularly and updated every six month for any change in the population demographic characteristics. Data were collected on a face-to-face interview to record demographic and socio-economic characteristics. Data were entered into customized HRS-2 software used for capturing longitudinal data and exported to computational software for analysis. For this analysis fertility data of the year 2013 were used. Fertility levels were analyzed using descriptive statistics. RESULTS: The total population of Harar HDSS in 2013 was 30,055. Of these, 15,701 (52.2 %) were females and 14, 354 (47.8 %) were males. The crude birth rate and general fertility rate for the year 2013 were 20.3 and 64 births per 1000, respectively. In 2013, the Total Fertility Rate (TFR) was 1.9 births per women of reproductive age. The 25 to 29 age group has the highest age specific fertility rates (128.1 births per 1000 women), followed by the 20 to 24 year old women (89.3 births per 1000 women). CONCLUSION: Total fertility rate was relatively low. However, there were a significant number of births among adolescent women. Improving and sustaining access for reproductive health care for young women is highly recommended. PMID- 28620538 TI - Lifestyle and in vitro fertilization: what do patients believe? AB - BACKGROUND: Patients have many beliefs regarding lifestyle factors and IVF outcomes. METHODS: Observational study of 208 IVF patients at an academic infertility center. Main outcome measures were perceived influence of various lifestyle factors assessed by multivariable logistic regression and p-value tests for linear trend (Pt). RESULTS: A majority of participants believed that there were many women's lifestyle choices that were influential, compared to fewer male factors (cessation of tobacco (72 %), alcohol (69 %), caffeine (62 %), and use of vitamins (88 %)). Compared to participants with less education, participants with a higher education level were less likely to believe vitamins were helpful and some alcohol use was not harmful. As income decreased, participants were less likely to consider dietary factors contributory to IVF success, such as women (p trend, p = 0.02) and men (p-trend, p = 0.009) consuming a full-fat dairy diet. Participants' beliefs were most commonly influenced by physicians (84 %) and the internet (71 %). CONCLUSIONS: Patients believed many lifestyle factors are associated with IVF success. Understanding patients' assumptions regarding the effect of lifestyle factors on IVF success may better allow physicians to counsel patients about IVF outcomes. PMID- 28620539 TI - Successful pregnancy with donor eggs in-vitro fertilization after premature ovarian insufficiency in a tertiary hospital in a low-income setting: a case report. AB - BACKGROUND: Premature Ovarian Insufficiency (POI) is classically defined as 4-6 months of cessation of menses (amenorrhea) in women under 40, associated with menopausal level of serum gonadotropins FSH > 40 IU/L and hypo-estrogenism and is also referred to as hypergonadotropic hypogonadism. This disorder can manifest as primary amenorrhea without the onset of menses (menarche), or as secondary amenorrhea after menarche and pubertal development. The diagnosis of this condition in Cameroon is sometimes difficult because of the high cost of hormonal assays and the few laboratories offering these services. CASE PRESENTATION: The patient was a 38-year-old G2P0020, blood group O Rh positive, genotype AA and BMI 19 kg/m2 who came to our service because of secondary amenorrhea and infertility of 2 years' duration. She has a history of pulmonary tuberculosis that was treated in Cameroon. After laparoscopy and hormonal profile, the diagnosis of premature ovarian insufficiency was reached. The woman underwent a successful donor egg in-vitro fertilization cycle and delivered a female fetus. Two years later YE requested IVF with autologous eggs, which was not possible, and since then she has remained with one child. CONCLUSION: The diagnosis of premature ovarian insufficiency is difficult in Cameroon because of the high cost of laboratory investigations and difficult access to the tests. In-vitro fertilization with donor egg is a better treatment option. Unfortunately, it is not accessible to most Cameroonians because of lack of technical ability and the existence of cultural and financial barriers. PMID- 28620540 TI - A simple, less invasive stripper micropipetter-based technique for day 3 embryo biopsy. AB - BACKGROUND: Preimplantation genetic screening (PGS) is an important procedure for in vitro fertilization (IVF). A key step of PGS, blastomere removal, is abundant with many technical issues. The aim of this study was to compare a more simple procedure based on the Stipper Micropipetter, named S-biopsy, to the conventional aspiration method. METHODS: On Day 3, 368 high-quality embryos (>7 cells on Day3 with <10% fragmentation) were collected from 38 women. For each patient, their embryos were equally separated between the conventional method (n = 188) and S biopsy method (n = 180). The conventional method was performed using a standardized protocol. For the S-biopsy method, a laser was used to remove a significantly smaller portion of the zona pellucida. Afterwards, the complete embryo was aspirated with a Stripper Micropipetter, forcing the removal of the blastomere. Selected blastomeres went to PGS using CGH microarrays. Embryo integrity and blastocyst formation were assessed on Day 5. Differences between groups were assessed by either the Mann-Whitney test or Fisher Exact test. RESULTS: Both methods resulted in the removal of only one blastomere. The S biopsy and the conventional method did not differ in terms of affecting embryo integrity (95.0% vs. 95.7%) or blastocyst formation (72.7% vs. 70.7%). PGS analysis indicated that aneuploidy rate were similar between the two methods (63.1% vs. 65.2%). However, the time required to perform the S-biopsy method (179.2 +/- 17.5 s) was significantly shorter (5-fold) than the conventional method. CONCLUSION: The S-biopsy method is comparable to the conventional method that is used to remove a blastomere for PGS, but requires less time. Furthermore, due to the simplicity of the S-biopsy technique, this method is more ideal for IVF laboratories. PMID- 28620542 TI - Preconception consultations with Maternal Fetal Medicine for obese women: a retrospective chart review. AB - BACKGROUND: Obesity is associated with impaired fertility and pregnancy complications, and preconception weight loss may improve some of these outcomes. The purpose of this study was to evaluate the quality and effectiveness of Maternal Fetal Medicine (MFM) preconception consults for obese women. METHODS: We performed a retrospective chart review examining 162 consults at an academic medical center from 2008 to 2014. The main outcome measures included consultation content - e.g. discussion of obesity-related pregnancy complications, screening for comorbidities, and referrals for weight loss interventions - and weight loss. RESULTS: Screening for diabetes and hypertension occurred in 48% and 51% of consults, respectively. Discussion of obesity-related pregnancy complications was documented in 96% of consults. During follow-up (median 11 months), 27% of patients saw a nutritionist, 6% saw a provider for a medically supervised weight loss program, and 6% underwent bariatric surgery. The median weight change was a loss of 0.6% body weight. CONCLUSIONS: In this discovery cohort, a large proportion of MFM preconception consultations lacked appropriate screening for obesity-related comorbidities. While the vast majority of consultations included a discussion of potential pregnancy complications, relatively few patients achieved significant weight loss. More emphasis is needed on weight loss resources and delaying pregnancy to achieve weight loss goals. PMID- 28620543 TI - Tablet terminals: a useful tool to explain in vitro fertilization treatment. AB - BACKGROUND: Explanations that involve medical care treatment take time. This also applies to explanations of in vitro fertilization (IVF) in the field of infertility treatment. This is because the cause of infertility differs from couple to couple, and because the explanations must begin with the mechanism of pregnancy. Recently, explanations facilitated by tablet terminals have been used in the field of medicine. In the present study, the efficacy and problems of explanations facilitated by tablet terminals were evaluated and compared with the explanations of IVF facilitated by paper-based pamphlets. METHODS: A total of 249 couples were asked to read a paper-based pamphlet explaining IVF treatment, while 252 couples were asked to view an explanation on a tablet terminal. The patients then answered a seven-item questionnaire. The answers to the questionnaire were based on a three-point scale, and statistical analysis was performed with the Mann-Whitney U test. RESULTS: Patients responded that the explanation facilitated by the tablet terminal was significantly easier to understand for all seven questionnaire items (p <0.05). The answer 'I did not understand' was selected for the items related to 'The treatment fees' (4.8% of answers) and 'Things to take note of, such as consultation times' (6.7% of answers). CONCLUSION: While patients generally did not understand the mechanism of pregnancy, explanations of IVF treatment facilitated by a tablet terminal were found to be more effective than paper-based explanations, although there is room for improvement. PMID- 28620541 TI - Polycystic ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. The altered metabolic and hormonal environment among women with PCOS may increase their risk of some types of cancer. METHODS: We performed a comprehensive review of the literature using numerous search terms for all studies examining the associations between polycystic ovary syndrome and related characteristics and cancer published in English through October 2016. This review summarizes the epidemiological findings on the associations between PCOS and endometrial, ovarian, and breast cancers and discusses the methodological issues, complexities, and underlying mechanisms of these associations. RESULTS: We identified 11 individual studies and 3 meta-analyses on the associations between PCOS and endometrial cancer, 8 studies and 1 meta-analysis for ovarian cancer, and 10 studies and 1 meta-analysis for breast cancer. Multiple studies reported that women with PCOS were at a higher risk for endometrial cancer; however, many did not take into account body mass index (BMI), a strong and well-established risk factor for endometrial cancer. The association with ovarian cancer was less clear, but a potentially increased risk of the borderline serous subtype was reported by two studies. No consistent association between PCOS risk and breast cancer was observed. CONCLUSION: The associations between PCOS and endometrial, ovarian, and breast cancer are complex, with the need to consider many methodological issues in future analyses. Larger well-designed studies, or pooled analyses, may help clarify these complex associations. PMID- 28620544 TI - "I am anxious and desperate": psychological experiences of women with infertility in The Greater Accra Region, Ghana. AB - BACKGROUND: Research has shown that infertility affects millions of couples worldwide. Infertility is considered one of the most difficult life experiences and can result in psychological consequences for couples, especially for women. The purpose of this study was to explore the psychological experiences of women with infertility. METHODS: A qualitative exploratory descriptive approach was used to conduct in-depth interviews. The psychological component of the bio psychosocial model was used as a guiding framework to understand the experiences of women with infertility. Fourteen women were selected based on the purpose of the study and provided their informed consent, and were interviewed between November 2015 and January 2016. All the women were recruited from the Greater Accra Region of Ghana. Each interview lasted for 30 to 40 min. All interviews were audio taped, transcribed verbatim and analyzed using thematic content analysis. RESULTS: The findings from the study showed that women with fertility problems experienced many emotional difficulties such as loneliness, anxiety, depression, lack of concentration, worrying, and reduced sexual satisfaction. CONCLUSIONS: Women in this study encountered psychological challenges and experienced emotional distress. Such women would benefit from psychological support such as counseling to help alleviate their psychological problems. These findings have implications for the care of women with infertility in Ghana. PMID- 28620545 TI - Cardiovascular risk factors among women with self-reported infertility. AB - BACKGROUND: Amongst women with certain types of ovulatory disorder infertility, the studies are conflicting whether there is an increased risk of long-term cardiovascular disease risk. This paper evaluates the associations of several CVD risk factors among Framingham women with self-reported infertility. METHODS: Women who completed the Framingham Heart Study Third Generation and Omni Cohort 2 Exam 2 (2008-2011), and reported on past history of infertility and current cardiovascular disease status were included in this cross-sectional study. Directly measured CVD risk factors were: resting blood pressure, fasting lipid levels, fasting blood glucose, waist circumference, and body mass index (BMI). Multivariable models adjusted for age, smoking, physical activity, and cohort. Generalized estimating equations adjusted for family correlations. We performed sensitivity analyses to determine whether the association between infertility and CVD risk factors is modified by menopausal status and menstrual cycle length. RESULTS: Comparing women who self-reported infertility to those who did not, there was an average increase in BMI (beta = 1.03 kg/m2, 95% CI: 0.18, 1.89), waist circumference (beta = 3.08 in., 95% CI: 1.06, 5.09), triglycerides (beta = 4.47 mg/dl, 95% CI:-1.54, 10.49), and a decrease in HDL cholesterol (beta = -1.60 mg/dl, 95% CI: -3.76, 0.56). We estimated that infertile premenopausal women have an increased odds of obesity (BMI >= 30 kg/m2) (OR = 1.56, 95% CI: 1.11, 4.49) and diabetes (OR = 1.96, 95% CI: 0.86, 4.49). CONCLUSIONS: BMI and waist circumference were the most strongly correlated CVD risk factors amongst women reporting a history of infertility. PMID- 28620547 TI - JFMS Open Reports gains seal of approval from PubMed Central. PMID- 28620546 TI - Ovarian morphology is associated with insulin resistance in women with polycystic ovary syndrome: a cross sectional study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a very common disorder well known to be associated with insulin resistance and metabolic disease. Insulin resistance is likely involved in the promotion of the PCOS reproductive phenotype and may mediate some of the ovarian morphology seen in the disorder. The phenotype of each individual woman with PCOS can vary widely as can her metabolic risk. METHODS: This is a cross-sectional study of patients seen in a multidisciplinary PCOS clinic at the University of California at San Francisco between 2006 and 2014. All participants underwent systematic evaluation with anthropometric measurements, comprehensive skin exam, transvaginal ultrasound and laboratory studies at the time of their initial visit to the clinic. Serum samples were stored and androgen studies were carried out on all stored samples at the University of Virginia. Logistic regression was employed to evaluate the association between ovarian volume or follicle number and metabolic parameters (fasting insulin, HOMA-IR, fasting glucose, 2 h glucose, waist circumference) and hyperandrogenism (free testosterone, total testosterone, DHEAS, acanthosis nigricans), controlling for age. RESULTS: Three-hundred thirteen patients seen during the study period met Rotterdam criteria for PCOS and had sufficient measurements for inclusion in our analysis. The odds ratio of elevated HOMA-IR for patients with a maximum ovarian volume >10 cc was 1.9 compared to those with a maximum ovarian volume of <=10 cc (95% CI 1.0-3.4). The odds ratio of abnormal fasting insulin for patients with higher ovarian volume was 1.8 (95% CI 1.0-3.4) compared with those with lower ovarian volume. Follicle number was not significantly associated with any metabolic parameters. CONCLUSIONS: Increased ovarian volume is associated with markers of insulin resistance in PCOS. In concordance with prior studies, we did not find follicle number to be predictive of metabolic risk. Ovarian volume may serve as a useful tool to aid clinicians in their risk stratification and counseling of patients with PCOS. PMID- 28620548 TI - Small intestinal peripheral nerve sheath tumour in a cat. AB - CASE SUMMARY: A 5-year-old female spayed Chinchilla cat presented with a 4 week history of weight loss and inappetence. A thorough clinical investigation confirmed the presence of a distal jejunal mass. Histopathological and immunohistochemical analysis was consistent with a small intestinal peripheral nerve sheath tumour. RELEVANCE AND NOVEL INFORMATION: To the best of our knowledge, this is the first reported case of a small intestinal peripheral nerve sheath tumour in a cat. This case report demonstrates the use of immunohistochemistry in differentiating this entity from other mesenchymal neoplasms. The veterinary literature available in this field is very limited and this report adds a new differential diagnosis to feline patients presenting with an intestinal mass. PMID- 28620549 TI - Lamination of microfibrous PLGA fabric by electrospinning a layer of collagen hydroxyapatite composite nanofibers for bone tissue engineering. AB - BACKGROUND: To mimic the muscle inspired cells adhesion through proteins secretion, the lamination of collagen-hydroxyapatite nanorod (nHA) composite nanofibers has been carried out successfully on polydopamine (PDA)-coated microfibrous polylactide-co-glycolide (PLGA) fabrics. The lamination of collagen hydroxyapatite composite nanofibers on polydopamine-coated microfibrous PLGA fabrics was carried through electrospinning the solution of collagen containing L glutamic acid-grafted hydroxyapatite nanorods (nHA-GA) at a flow rate of 1.5 mL/h and an applied voltage of 15 kV. RESULTS: In comparison to pristine PLGA, dopamine-coated PLGA and collagen-hydroxyapatite composite nanofiber lamination has produced more wettable surfaces and surface wettability is found to higher with dopamine-coated PLGA fabrics then pristine PLGA. The SEM micrographs have clearly indicated that the lamination of polydopamine-coated PLGA fabric with collagen-hydroxyapatite composite nanofibers has shown increased adhesion of MC3T3E1 cells in comparison to pristine PLGA fabrics. CONCLUSION: The results of these studies have clearly demonstrated that collagen-nHA composites fibers may be used to create bioactive 3D scaffolds using PLGA as an architectural support agent. PMID- 28620550 TI - Generation of Recombinant Antibodies against the beta-(1,6)-Branched beta-(1,3)-D Glucan Schizophyllan from Immunized Mice via Phage Display. AB - beta-(1,6)-Branched beta-(1,3)-D-glucans like schizophyllan from the basidiomycete Schizophyllum commune excite various immunostimulatory effects and have been clinically tested as adjuvants. Some of the glucans are also applicable in food or petrol industry due to their viscosity and temperature stability in aqueous solution. Antibodies against these glucans could be used as tool for analysis of glucan preparations or for further research of its bioactivity. Therefore, an immune phage display library was constructed from mice immunized with schizophyllan. Three recombinant monoclonal antibodies were isolated from this library by affinity selection (panning) on schizophyllan. The half-maximal effective concentration (EC50) values for those antibodies varied between 16.4 ng mL-1 and 21.3 ng mL-1. The clones showed binding specificity not only for schizophyllan but also for other beta-(1,6)-branched beta-(1,3)-D-glucans of similar macromolecular structure. Denaturation of the secondary structure led to a reduced antibody binding, indicating an epitope requiring the correct conformation of the triple helical structure of the glucans. PMID- 28620551 TI - Mitochondrial Cardiomyopathy Presenting as Dilated Phase of Hypertrophic Cardiomyopathy Diagnosed with Histological and Genetic Analyses. AB - We report a case with 46-year-old man diagnosed with mitochondrial cardiomyopathy in the dilated phase of hypertrophic cardiomyopathy. Since cardiac magnetic resonance imaging, beta-methyl-p-123I-iodophenyl-pentadecanoic myocardial scintigraphy, and positron emission tomography/computed tomography revealed no remarkable findings, we performed electron microscopic examination, which aided in diagnosing mitochondrial cardiomyopathy. Muscle biopsy was also compatible with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and DNA analysis also concluded it. Since muscle biopsy is less invasive for patients compared to endomyocardial biopsy, cardiologists need to consider it. The diagnosis of mitochondrial cardiomyopathy is helpful because it is a genetic condition and also for consideration of device therapy, as well as management for acute crisis. PMID- 28620552 TI - Refractory Lactic Acidosis in Small Cell Carcinoma of the Lung. AB - BACKGROUND: Elevated lactate levels in critically ill patients are most often thought to be indicative of relative tissue hypoxia or type A lactic acidosis. Shock, severe anemia, and thromboembolic events can all cause elevated lactate due to tissue hypoperfusion, as well as the mitochondrial dysfunction thought to occur in sepsis and other critically ill states. Malignancy can also lead to elevation in lactate, a phenomenon described as type B lactic acidosis, which is much less commonly encountered in the critically ill. CASE PRESENTATION: We present the case of a 73-year-old Caucasian woman with type 2 diabetes and hypertension who presented with abdominal pain, nausea, vomiting, nonbloody diarrhea, and weight loss over five weeks and was found to have unexplained refractory lactic acidosis despite fluids and antibiotics. She was later diagnosed with small cell carcinoma of the lung. CONCLUSIONS: In this case report, we describe a critically ill patient whose elevated lactate was incorrectly attributed to her acute illness, when in truth it was an indicator of an underlying, as yet undiagnosed, malignancy. We believe this case is instructive to the critical care clinician as a reminder of the importance of considering malignancy on the differential diagnosis of a patient presenting with elevated lactate out of proportion to their critical illness. PMID- 28620553 TI - Unusual Case of Extraction of Maxillary Lateral Incisors and Mandibular Central Incisors. AB - INTRODUCTION: This article's purpose is to report a case where maxillary lateral incisors and mandibular central incisors are extracted and a canine substitution was performed as the best therapeutic option in order to obtain symmetry in a malocclusion with an upper lateral incisor with poor prognostic, solve moderate crowding, get enough space for the permanent dentition, and provide stability to the results. CASE REPORT: An 11-year-old boy with straight profile with acute-to normal nasolabial angle and protruded lips, mixed dentition, lower and upper severe crowding, and a bilateral molar angle Class I. The left maxillary lateral incisor failed endodontic treatment secondary to an intrusive traumatic lesion in the primary and permanent dentition. The treatment of choice was the extraction of both upper lateral incisors and both central lower incisors. The patient finished with molar and canine angle Class I and coincident midlines and was functionally stable; both lateral and protrusive jaw movements were effectively made by the first premolars and central incisors and canines without improper contacts of the rest of the teeth. Overbite of one-third and correct overjet were also achieved, and the esthetic outcome was satisfactory due to the composed material restorations of both the central and lateral incisors, as well as recontouring of the first maxillary premolars. PMID- 28620554 TI - Clinical Phenotype in a Toddler with a Novel Heterozygous Mutation of the Vitamin D Receptor. AB - We present the clinical phenotype of a toddler who presented with vitamin D resistant rickets, with one of the highest initial levels of alkaline phosphatase and parathyroid hormone (PTH) levels reported in the literature. The toddler had novel compound heterozygous mutations in the ligand-binding site of the vitamin D receptor and had an excellent response to calcitriol (1,25(OH)2D). PMID- 28620555 TI - A Discussion of High-Risk HPV in a 6-Year-Old Female Survivor of Child Sexual Abuse. AB - BACKGROUND: Human papilloma viruses (HPVs) cause a variety of clinical manifestations in children including skin warts, laryngeal papillomas, and condyloma acuminatum. Whereas the mode of transmission is well understood and management of HPV infection is clearly defined by guidelines in adults, less is known about the mode of transmission, natural history of disease, and appropriate management of high-risk anogenital HPV infections in children. CASE: The patient is a previously healthy 6-year-old female who presented with multiple vaginal lesions causing pain and discomfort and was diagnosed with HPV 18 positive CIN I. SUMMARY AND CONCLUSION: Children infected with high-risk HPV subtypes remain a vulnerable patient population, and there is minimal literature on the natural history of disease and effects of overtreatment. Based on a literature review, conservative management, HPV vaccination, and consideration of the cervical cancer screening guidelines for adolescent females are an appropriate treatment course until more studies are reported on cervical cancer screening in survivors of child sexual abuse. PMID- 28620556 TI - Tracheal Chondrosarcoma: Systematic Review of Tumor Characteristics, Diagnosis, and Treatment Outcomes with Case Report. AB - To our knowledge this is the first systematic review of tracheal chondrosarcoma treatment outcomes. Management insights are thoroughly discussed. Men constitute 93.8% of cases, and most of these occur in the distal trachea. The most common symptom, dyspnea, occurs in virtually all patients. Extratracheal extension had occurred in 78.6% of patients. Definitive treatment with tracheal resection showed no recurrences in 10 patients with mean follow-up of 3.1 years. Adjuvant radiotherapy may be utilized for improving local control when open complete resection cannot be performed, but only after endoscopic excision of gross tumor. PMID- 28620557 TI - Suprascapular Nerve Entrapment Caused by Protrusion of an Intraosseous Ganglion of the Glenoid into the Spinoglenoid Notch: A Rare Cause of Posterior Shoulder Pain. AB - We describe a case of suprascapular nerve entrapment caused by protrusion of an intraosseous ganglion of the glenoid into the spinoglenoid notch. A 47-year-old man with left shoulder pain developed an intraosseous cyst in the left glenoid, which came into contact with the suprascapular nerve. The area at which the patient experienced spontaneous shoulder pain was innervated by the suprascapular nerve, and 1% xylocaine injection into the spinoglenoid notch under ultrasonographic guidance relieved the pain. Therefore, we concluded that the protrusion of an intraosseous cyst of the glenoid into the spinoglenoid notch was a cause of the pain, and performed curettage. Consequently, the shoulder pain was resolved promptly without suprascapular nerve complications, and the cyst was histologically diagnosed as an intraosseous ganglion. This case demonstrated that the intraosseous ganglion of the glenoid was a benign lesion but could be a cause of suprascapular nerve entrapment syndrome. Curettage is a useful treatment option for a ganglion inside bone and very close to the suprascapular nerve. PMID- 28620558 TI - Primary Renal Carcinoid with Bilateral Multiple Clear Cell Papillary Renal Cell Carcinomas. AB - Clear cell papillary renal cell carcinoma (CCPRCC) is a newly recognized entity in the 2016 WHO classification and usually presents as a small, circumscribed, solitary mass of indolent nature. CCPRCCs could seldom occur in conjunction with other synchronous or metachronous kidney tumors and even less frequently as bilateral masses. To our knowledge, multiple bilateral CCPRCCs have never been described with the existence of a synchronous well-differentiated neuroendocrine tumor of the kidney and hence reported here as a unique case. This case report highlights the importance in considering this entity and its unusual presentation in the differential diagnosis as a possible mimicker of Von Hippel-Lindau syndrome. PMID- 28620559 TI - IVIG Associated Aseptic Meningitis in a Renal Transplant Patient. AB - The management of antibody-mediated rejection in renal transplant recipients involves plasmapheresis with IVIG. Aseptic meningitis is a rare adverse effect of IVIG therapy and is a diagnosis of exclusion. We report a case of a renal transplant patient who developed IVIG associated aseptic meningitis in the context of management of antibody-mediated rejection, four years after transplantation. PMID- 28620560 TI - Propionibacterium acnes Is an Unusual Cause of Acute Scrotal Abscess in a Preterm Infant. AB - Acute scrotal abscess is an extremely rare condition in neonates and may mimic testicular torsion. Most of these abscesses have reportedly been due to Staphylococcus and Salmonella spp. infections. We herein report a unilateral acute scrotal abscess in a preterm infant born at 26 weeks in whom Propionibacterium acnes was isolated from the collected scrotal fluid culture. To our knowledge, this is the first case report implicating P. acnes as a causative agent of neonatal scrotal abscess. Based on such findings, P. acnes infection should be considered in differential diagnosis of acute scrotal abscess in neonates, particularly in preterm infants. PMID- 28620561 TI - Patient-Specific QA of Spot-Scanning Proton Beams using Radiochromic Film. AB - Radiochromic film for spot-scanning QA provides high spatial resolution and efficiency gains from one-shot irradiation for multiple depths. However, calibration can be a tedious procedure which may limit widespread use. Moreover, since there may be an energy dependence, which manifests as a depth dependence, this may require additional measurements for each patient. We present a one-scan protocol to simplify the procedure. A calibration using an EBT3 film, exposed by a 6-level step-wedge plan on a Proteus(r)PLUS proton system (IBA, Belgium), was performed at depths of 18, 20, 24cm using Plastic Water(r) (CIRS, Norfolk, VA). The calibration doses ranged from 65-250 cGy(RBE) (relative biological effectiveness) for proton energies of 170-200 MeV. A clinical prostate+nodes plan was used for validation. The planar doses at selected depths were measured with EBT3 films and analyzed using One-scan protocol (one-scan digitization of QA film and at least one film exposed to a known dose). The gamma passing rates, dose difference maps, and profiles of 2D planar doses measured with EBT3 film and IBA MatriXX-PT, versus the RayStation TPS calculations were analyzed and compared. The EBT3 film measurement results matched well with the TPS calculation data with an average passing rate of ~95% for 2%/2mm and slightly lower passing rates were obtained from an ion chamber array detector. We were able to demonstrate that the use of a proton step-wedge provided clinically acceptable results and minimized variations between film-scanner orientation, inter-scan, and scanning conditions. Furthermore, for relative dosimetry (calibration is not done at the time of experiment) it could be derived from no more than two films exposed to known doses (one could be zero) for rescaling the master calibration curve at each depth. The sensitivity of the calibration to depth variations has been explored. One-scan protocol results appear to be comparable to that of the ion chamber array detector. The use of a proton step-wedge for calibration of EBT3 film potentially increases efficiency in patient-specific QA of proton beams. PMID- 28620562 TI - Delayed Chyle Leak Following Anterior Cervical Spinal Surgery: A Case Report and Management Algorithm. AB - Injury to the thoracic duct during anterior cervical spine surgery is a rare occurrence. A delayed chyle leak following an elective anterior cervical spinal surgery has not been reported in the literature. We present a report of a 59-year old female with multiple prior neck surgeries who underwent an anterior cervical corpectomy and fusion (ACCF). The patient developed a delayed thoracic duct injury on postoperative day (POD) one, as no injury was noted intraoperatively. She was managed with conservative care involving a low-fat diet along with octreotide which led to the resolution of her symptoms. We present this case report because of its unique presentation and to assist spine surgeons with initial management. Surgeons should have increased awareness when performing anterior cervical approaches to the lower cervical and upper thoracic levels from the left side. PMID- 28620563 TI - Pharmacological Threat to Lungs: A Case Series and Literature Review. AB - Drug-induced organ damage stands as a prevalent yet much-neglected issue globally. Keeping in view it's rising frequency, health care providers stand obliged to be well versed with the de-merits of the agents they prescribe. Drug therapies causing damage present with a non-specific clinical presentation, histological findings or radiology, which further elaborates on the necessity of a conscientious diagnosis. Pulmonary architecture ranging from the airways, lung parenchyma, mediastinum, pleura, pulmonary vasculature or the neuromuscular system, all can fall victim to the dreaded outcomes of this menace. In order to establish successful diagnosis, the definite temporal relation between initiation of drug therapy and the development of the respiratory symptoms needs to be drawn. The most common form of pharmacologically arising lung toxicity is drug induced pneumonitis or interstitial lung disease. Unfortunately, there is no adequate data available to review the extensiveness of this medication-associated risk in Pakistan which further highlights the necessity of carefully monitoring this overlooked yet assessable malady. Furthermore, identification and surveillance of this drug attributed peril shall help diminish burden on healthcare resources of the country. We present three recent cases of different types of drug-induced lung damage under treatment at our University Hospital. PMID- 28620564 TI - Moyamoya Syndrome in a Child with Neurofibromatosis Type 1: Magnetic Resonance Imaging as a Tool for Clinical Decision Making. AB - Moyamoya syndrome is a rare cerebrovasculopathy of unknown etiology which is associated with multiple risk factors. Moyamoya was first discovered in Japan and is reported to have an increased prevalence in the Japanese population. The term "Moyamoya" translates into "puff of smoke" and is named after the finding of the collateral cerebral vasculature that develops secondary to occlusion of an internal carotid artery at the entrance into the circle of Willis. This collateral vasculature characterizes the disease. Moyamoya should be included in the differential diagnosis in the pediatric population when a patient presents with stroke or stroke-like symptoms. Diagnosis can be made with catheter angiogram or magnetic resonance angiogram. Recent use of magnetic resonance perfusion imaging has been shown to be useful in clinical decision making while assessing the need for revascularization surgery. We present the case of a 15 year-old with comorbid psychiatric illness, neurofibromatosis type I with brainstem glioma, and Moyamoya syndrome. Considering our patient's complex medical history of psychiatric illness and previously diagnosed neurofibromatosis, magnetic resonance imaging (MRI) with magnetic resonance angiogram (MRA) and magnetic resonance perfusion proved instrumental in helping rule out the progression of arteriopathy as the cause of his worsening seizures and behavior. In our patient, it was determined that the relative perfusion for each hemisphere of the patient's brain quantitatively lacked significant differences and he was therefore not a candidate for surgical revascularization. These modalities proved instrumental in surgical decision-making and clinical management of the patient. PMID- 28620565 TI - Pattern and Predictors of Unmet Supportive Care Needs in Cancer Patients. AB - The incidence of cancers is increasing and this is associated with an increase in the burden of the disease. Patients with cancer have to deal with reduced physical functioning, emotional instability, difficulty in concentrating, and an overall diminished feeling of well-being. This creates deficits that have not been well catered for by traditional cancer care, leading to an overall dissatisfaction with care and a reduced quality of life. This review aims at assessing the pattern of unmet needs in cancer patients and to provide information as to the factors that influence the perception of unmet needs. Studies directly focused on unmet needs in cancer patients which were retrieved from Medical Literature Analysis and Retrieval System Online (MEDLINE), Public/Publisher Medline (PubMed), PsychINFO, Excerpta Medica database (EMBASE), and Google Scholar; from the earliest records till 2016. Unmet needs in cancer patients have been measured with a wide variety of tools, with the supportive care needs survey (SCNS) being the most commonly used as a result of its strong psychometric properties, ease of use, responsiveness, and its coverage of the major domains of unmet needs. The most common unmet needs were in the domains of health system and information, psychological, and physical and daily living. These needs are influenced by sociodemographic factors such as age, sex, marital status, income level; and clinical factors such as location of cancer, stage of disease, and tumor size. It is clear that cancer patients experience a wide range of unmet supportive needs, for which solutions need to be devised in order to improve the supportive care services for these patients and their overall quality of life. PMID- 28620566 TI - Leukemia Cutis Associated with Secondary Plasma Cell Leukemia. AB - Plasma cell leukemia is an uncommon, aggressive variant of leukemia that may occur de novo or in association with multiple myeloma. Leukemia cutis is the cutaneous manifestation of leukemia, and indicates an infiltration of the skin by malignant leukocytes or their precursors. Plasma cell leukemia cutis is a rare clinical presentation of leukemia. We present a man who developed plasma cell leukemia cutis in association with multiple myeloma. Cutaneous nodules developed on his arms and legs 50 days following an autologous stem cell transplant. Histopathologic examination showed CD138-positive nodular aggregates of atypical plasma cells with kappa light chain restriction, similar to the phenotype of his myeloma. In spite of systemic treatment of his underlying disease, he died 25 days after the presentation of leukemia cutis. Pub-Med was searched for the following terms: cutaneous plasmacytomas, leukemia cutis, plasma cell leukemia nodules, plasma cell leukemia cutis, and secondary cutaneous plasmacytoma. Papers were reviewed and appropriate references evaluated. Leukemia cutis in plasma cell leukemia patients is an infrequent occurrence. New skin lesions in patients with plasma cell leukemia should be biopsied for pathology and for tissue cultures to evaluate for cancer or infection, respectively. The diagnosis plasma cell leukemia cutis is associated with a very poor prognosis. PMID- 28620567 TI - A Retrospective Cohort Study to Assess Patient and Physician Reported Outcome Measures After Decompressive Hemicraniectomy for Malignant Middle Cerebral Artery Stroke. AB - INTRODUCTION: Decompressive hemicraniectomy for malignant middle cerebral artery (MCA) infarction is known to reduce mortality. However, there are on-going concerns in terms of the quality of life in survivors. We aimed to examine the correlation between patient and physician reported outcome measures in decompressive hemicraniectomy. PATIENTS AND METHODS: We analyzed outcomes in 21 patients who underwent decompressive hemicraniectomy for malignant MCA infarction between September 2003 and August 2013 within a regional health system. Patient and physician reported outcome measures were collected at follow-up. These were Stroke Impact Scale (SIS) Version 3, modified Rankin Scale (mRS), National Hospital Seizure Severity Scale, Headache Impact Test and Patient Health Questionnaire for depression. RESULTS: There was a good correlation between physician and patient reported outcome measures. The Spearman's rank correlation coefficient between mRS and structured SIS Version 3 was -0.887 (p < 0.001); with unstructured SIS results, the correlation coefficient was -0.663 (p = 0.001). There was no statistically significant correlation between life worth and modified Rankin Scale: r = -0.3383 (p = 0.087). DISCUSSION: Our findings of a statistically significant correlation between mRS and SIS have not previously been reported in patients with this condition. These findings provide further information to inform patient and next of kin discussions regarding outcomes from decompressive hemicraniectomy in malignant MCA infarction. PMID- 28620568 TI - Bilateral Myelomatous Pleural Effusion in a Patient with IgA Kappa Multiple Myeloma. AB - Multiple myelomas is a neoplastic plasma cell disorder that accounts for one percent of all cancers and 13% of hematologic malignancies. Although primarily known to be a bone marrow disorder, it can metastasize to extramedullary sites or it can present as a solitary extramedullary plasmacytoma. Primary pleural effusion from myeloma is rare, occurring in less than one percent of the patients. The following case report highlights a case of bilateral pleural effusion, directly attributable to multiple myeloma after other causes were ruled out. The diagnosis was made using cytology and immunohistochemical (IHC) staining of the pleural fluid. Myelomatous pleural effusion (MPE) is a poor prognostic feature heralding an aggressive underlying disease state, as represented in this case. PMID- 28620569 TI - The Optimal Pain Management Approach for a Laboring Patient: A Review of Current Literature. AB - There is a general agreement that a patient in labor should be given the option to have an epidural block for pain management. Despite this consensus, there are differences in practice patterns as to when to initiate an epidural and how to minimize its impact on the duration and outcome of a patient's labor. A review of the literature suggests epidural analgesia does prolong stages one and two of labor, but not significantly. Cesarean delivery rates are not affected by the early initiation of epidural analgesia. The use of various adjuvants such as opioids, clonidine, and neostigmine in conjunction with local anesthetics solution can significantly reduce the severity of motor blockade and the need for assisted vaginal delivery. PMID- 28620570 TI - Perforated Bladder as a Cause of Abdominal Ascites in a Patient Presenting with Acute Onset Abdominal Pain. AB - Bladder perforation, especially when atraumatic, is a rare cause of ascites and is often difficult to differentiate from other causes of abdominal pain and ascites in the acute setting. A 43-year-old Caucasian woman with a history of multiple sclerosis presented with acute abdominal pain. A computed tomography (CT) scan of her abdomen and pelvis without contrast revealed ascites, acute kidney injury (AKI) was noted on laboratory workup, and very little urine was drained by Foley catheter. Over the next several days, the patient's clinical condition deteriorated with no definitive diagnosis. A repeat CT of her abdomen and pelvis without contrast showed worsening ascites. She underwent paracentesis, which revealed a markedly elevated ascitic fluid creatinine consistent with bladder rupture. She then underwent an urgent cystogram to confirm the diagnosis, and the urologic consultant recommended conservative management with a Foley catheter to allow for bladder healing. Conservative treatment failed however, and she underwent a surgical repair with drain placement which was followed by an improvement in her clinical condition. This case illustrates a unique presentation of a young woman with multiple sclerosis whose bladder perforation presented as abdominal pain and ascites. The multidisciplinary approach required here highlights the difficulty in reaching this diagnosis which is often undermined in patients who lack a history of traumatic injury. Such delays led to a complicated hospital course for our patient. Maintaining a broad differential for abdominal pain and ascites is essential. PMID- 28620571 TI - Leptomeningeal Carcinomatosis in Recurrent Non-Small Cell Lung Cancer: A Case Report and Review of Current Treatment Modalities. AB - Leptomeningeal carcinomatosis (LC) is an uncommon sequelae of non-small cell lung cancer. The treatment modalities for LC have historically been limited with an overall poor prognosis. This case report outlines a 76-year-old female who presented with recurrence of non-small cell lung cancer as LC. LC is difficult to treat, and options include radiation, chemotherapy (systemic and intrathecal), as well as targeted therapies. This case outlines a unique approach and reviews the current literature on the effectiveness of these options in non-small cell lung cancer. PMID- 28620572 TI - Unexpected Seed Migration in Prostate Brachytherapy Implants Coincident with Change in Seed Stranding Product. AB - PURPOSE: This study was undertaken to determine if significant seed migration occurred when our institution changed seed products by comparing patterns of seed migration in implants containing different stranding material. METHODS AND MATERIALS: Day 0 and Day 30 CT scans were registered by the contoured prostate center of mass. An implant reconstruction program identified seeds on CT according to the pre-plan, enabling one-to-one correspondence between Day 0 and Day 30 seeds. Significant seed migration was defined by review of seeds that migrated > 2 cm outside the prostate or appearance in unexpected locations. Results: Twenty-five (149, 16.8%) new strands displayed movement > 2 cm between Day 0 and Day 30 compared with just 2/118 (1.7%) of the standard strands. Six out of 26 (23%) patients with new strands displayed significant migration compared with 2/13 (14%) of patients with standard strands. In the six patients with new strands and significant migration, a mean of four strands (17%, range: 2-8 per patient) migrated significantly with 65% due to whole strand migration, 25% due to strand breakage, and 10% strand clumping. In the control group, only two strands (2%) migrated significantly, both due to strand breakage. Despite the greater seed movement with the new strands, Day 0 and Day 30 dosimetry was acceptable. CONCLUSION: In this short report, we identified that a change to a new strand type was associated with unexpected significant seed movement compared to our typical strands. Since seed movement can arise from unexpected causes, it is important to maintain quality assurance practices when a change in technique or infrastructure is instituted. PMID- 28620573 TI - Clinical Characteristics and Outcomes of Patients with Ischemic and Non-Ischemic Complete Heart Block. AB - INTRODUCTION: Third degree or complete heart block (CHB) is a medical emergency and usually requires permanent pacemaker placement. CHB can be caused by cardiac ischemia or non-ischemic conditions such as infiltrative diseases or fibrosis. The purpose of this study is to identify the baseline clinical characteristics associated with ischemic versus non-ischemic causes of complete heart block and compare their outcomes. MATERIALS AND METHODS: An institutional review broad approval was granted by the Cleveland Clinic Health System. In our study, 216 patients with CHB presenting to Fairview Hospital between January 2014 and June 2016 were initially identified using the International Classification of Disease (ICD) codes at discharge. Only the patients with a new diagnosis of complete heart block (CHB) were included in the study (total N=62), which led to the exclusion of 154 patients. The patients were characterized into non-ischemic and ischemic groups based on cardiac marker elevation, electrocardiogram changes and/or cardiac catheterization findings. In all the patients, data including the following was collected: demographics such as age, gender, ethnicity and body mass index; pre-existing comorbidities such as hypertension, chronic kidney disease, diabetes mellitus, thyroid disease, previous coronary artery disease, history of cancer; use of nodal blocking agents, electrolyte abnormalities on admission, echocardiographic parameters such as ejection fraction (EF), right ventricular systolic pressure (RVSP), left ventricular end diastolic and systolic volumes (LVEDV and LVESV, respectively). The primary outcome was all-cause mortality and the secondary outcome was pacemaker placement. Categorical variables were analyzed using chi-square and continuous variables using ANOVA. RESULTS: Out of 62 patients (N=62), 48 had non-ischemic and 14 had ischemic CHB. The mean age was 67 years (95% CI, 60.55-74.73) in the ischemic group and 75 years (95% CI, 71.52-78.80) in the non-ischemic group, p=0.04. Patients with ischemic CHB had a lower mean EF of 49.6% (95% CI, 42.04%-57.23%) compared to 57.42% in non-ischemic CHB patients (95% CI, 53.97%-60.87%), p=0.05. History of coronary artery disease was present in 71.4% (10/14) patients with ischemic CHB compared to 37.5% (18/48) patients with non-ischemic CHB, p=0.02. There was no statistically significant difference between the two groups in terms of gender, diabetes, hypertension, thyroid dysfunction, chronic kidney disease, nodal blocking agents, electrolyte abnormalities or smoking status. For outcomes, 6/48 (12.5%) of patients with non-ischemic CHB had died compared to 3/14 (21.4%) ischemic CHB (p=0.327). Permanent pacemaker was implanted in 45/48 patients (93.75%) of the non-ischemic CHB compared to 6/14 (42.83%) in the ischemic group (p<0.001). CONCLUSIONS: Patients with ischemic CHB are younger, and they have a lower ejection fraction but they are less likely to get a pacemaker compared to non-ischemic CHB. Further studies with a bigger sample size are required to understand the long term mortality outcomes of patients with CHB. PMID- 28620574 TI - Complications of Advanced Kadish Stage Esthesioneuroblastoma: Single Institution Experience and Literature Review. AB - INTRODUCTION: In esthesioneuroblastoma, greater disease extent and Kadish staging correlate with greater recurrence, complications, and mortality. These advanced stage malignancies require extensive resections and aggressive adjuvant therapy. This increases the risk of complications such as cerebrospinal fluid leak, neurologic deficits, and osteomyelitis. We present our case series and then analyze the literature to ascertain whether advanced stage tumors corresponds to greater rates of complications. METHODS: A retrospective review of consecutive patients with histologically-proven esthesioneuroblastoma who were aggressively managed at our institution was performed. This was followed by an extensive literature search of published original data, in large series from 2006-2016, where both surgery and adjuvant therapy were used for the treatment of esthesioneuroblastoma. RESULTS : Single institution review revealed eight patients with esthesioneuroblastoma, half with advanced Kadish staging. All Kadish A patients ( Kadish A: confined to nasal cavity) underwent endoscopic approaches alone, while Kadish C patients (Kadish C: extends beyond nasal cavity and paranasal sinuses) and D patients (Kadish D: lymph node or distant metastases) underwent craniofacial approaches, while all patients received post operative adjuvant therapies. Complications such as cerebrospinal fluid (CSF) leak, seizures, meningitis, and abscess only occurred in high Kadish stage patients. Literature review demonstrated a higher proportion of advanced Kadish stage cases correlated with increasing rates of pneumocephalus, infection, and recurrence. A higher proportion of Kadish C and D tumors was inversely correlated with CSF leak rate and overall survival. DISCUSSION: Advanced stage tumors are often associated with a higher incidence of adverse events up to 33%, both due to disease burden and treatment effect. There is increasing use of endoscopy and neoadjuvant therapy, which have the potential to decrease complication rates. CONCLUSION : Advanced Kadish stage esthesioneuroblastoma necessitates meticulous surgical resection and aggressive adjuvant therapies, together, these increase the likelihood of adverse events, including CSF leak, neurologic deficits, and infections, and may represent the real morbidity cost of radically treating these tumors to achieve an improvement in overall survival. In selected patients, less invasive approaches or neo-adjuvant therapies can be used without compromising on a curative resection. PMID- 28620575 TI - Osteoporosis Management in Ankylosing Spondylitis. AB - Low bone mineral density (BMD) is increasingly recognized as a common comorbid condition in ankylosing spondylitis (AS). As low BMD increases fracture risk, it is important to identify and treat low BMD in patients with AS who have been shown to be at increased risk for fractures above the population normal. Since low BMD occurs early in disease, we screen during the first year of diagnosis with dual energy x-ray absorptiometry (DXA). If patients are found to have osteoporosis by T-score of less than -2.5 or if their Z-score on DXA is more than two standard deviations below the mean, we initiate therapy with bisphosphonates in males and in females who are not planning any future pregnancies. While reduction in fracture risk with bisphosphonate therapy has not been clearly defined in patients with AS, reduction in vertebral and hip fractures has been well established in primary osteoporosis and thus it is our first line treatment. If there are contraindications to the use of bisphosphonates in the treatment of low BMD, we will consider the use of denosumab. If the patient is not receiving a TNF-alpha inhibitor (TNFi) and has active disease, we also favor early initiation of TNFi due to their positive effects on BMD though the outcome on reduction in vertebral fractures remains unclear. We counsel all patients regarding the importance of adequate intake of vitamin D and calcium per the Institute of Medicine guidelines. All patients should be encouraged to participate in weight bearing activities with a focus on core strength and gait training. PMID- 28620576 TI - Polish Experience of Implementing Vision Zero. AB - PURPOSE OF REVIEW: The aim of this study is to present an outline and the principles of Poland's road safety strategic programming as it has developed over the last 25 years since the first Integrated Road Safety System with a strong focus on Sweden's "Vision Zero". RECENT FINDINGS: Countries that have successfully improved road safety have done so by following strategies centred around the idea that people are not infallible and will make mistakes. The human body can only take a limited amount of energy upon impact, so roads, vehicles and road safety programmes must be designed to address this. SUMMARY: The article gives a summary of Poland's experience of programming preventative measures that have "Vision Zero" as their basis. It evaluates the effectiveness of relevant programmes. PMID- 28620577 TI - Population structure of the soft tick Ornithodoros maritimus and its associated infectious agents within a colony of its seabird host Larus michahellis. AB - The epidemiology of vector-borne zoonoses depends on the movement of both hosts and vectors, which can differ greatly in intensity across spatial scales. Because of their life history traits and small size, vector dispersal may be frequent, but limited in distance. However, little information is available on vector movement patterns at local spatial scales, and particularly for ticks, transmitting the greatest diversity of recognized infectious agents. To test the degree to which ticks can disperse and disseminate pathogens at local scales, we investigated the temporal dynamics and population structure of the soft tick Ornithodoros maritimus within a colony of its seabird host, the Yellow-legged gull Larus michahellis. Ticks were repeatedly sampled at a series of nests during the host breeding season. In half of the nests, ticks were collected (removal sampling), in the other half, ticks were counted and returned to the nest. A subsample of ticks was screened for known bacteria, viruses and parasites using a high throughput real-time PCR system to examine their distribution within the colony. The results indicate a temporal dynamic in the presence of tick life stages over the season, with the simultaneous appearance of juvenile ticks and hatched chicks, but no among-nest spatial structure in tick abundance. Removal sampling significantly reduced tick numbers, but only from the fourth visit onward. Seven bacterial isolates, one parasite species and one viral isolate were detected but no spatial structure in their presence within the colony was found. These results suggest weak isolation among nests and that tick dispersal is likely frequent enough to quickly recolonize locally-emptied patches and disseminate pathogens across the colony. Vector-mediated movements at local scales may therefore play a key role in pathogen emergence and needs to be considered in conjunction with host movements for predicting pathogen circulation and for establishing effective control strategies. PMID- 28620579 TI - Delineation of the Prostate Bed: The "Invisible Target" Is Still an Issue? AB - For pathological high-risk prostate cancer, adjuvant irradiation has shown a survival benefit. Phase III studies have highlighted that half men would face biochemical relapse and would be candidate for radiotherapy at adjuvant or salvage times. Despite at least four published international contouring guidelines from different collaborative groups, discrepancies remain for volumes, delineation, and margins to be considered in order to optimize radiotherapy planning. This article from "Groupe d'Etude des Tumeurs UroGenitales (GETUG)" members will focus on controversies to help clinicians to create best volume delineation for adjuvant or salvage post prostatectomy radiotherapy. PMID- 28620578 TI - Surgical Management of Advanced and Metastatic Renal Cell Carcinoma: A Multidisciplinary Approach. AB - The past decade has seen a rapid proliferation in the number and types of systemic therapies available for renal cell carcinoma. However, surgery remains an integral component of the therapeutic armamentarium for advanced and metastatic kidney cancer. Cytoreductive surgery followed by adjuvant cytokine based immunotherapy (predominantly high-dose interleukin 2) has largely given way to systemic-targeted therapies. Metastasectomy also has a role in carefully selected patients. Additionally, neoadjuvant systemic therapy may increase the feasibility of resecting the primary tumor, which may be beneficial for patients with locally advanced or metastatic disease. Several prospective trials examining the role of adjuvant therapy are underway. Lastly, the first immune checkpoint inhibitor was approved for metastatic renal cell carcinoma (mRCC) in 2015, providing a new treatment mechanism and new opportunities for combining systemic therapy with surgery. This review discusses current and historical literature regarding the surgical management of patients with advanced and mRCC and explores approaches for optimizing patient selection. PMID- 28620580 TI - The Human NADPH Oxidase, Nox4, Regulates Cytoskeletal Organization in Two Cancer Cell Lines, HepG2 and SH-SY5Y. AB - NADPH oxidases of human cells are not only functional in defense against invading microorganisms and for oxidative reactions needed for specialized biosynthetic pathways but also during the past few years have been established as signaling modules. It has been shown that human Nox4 is expressed in most somatic cell types and produces hydrogen peroxide, which signals to remodel the actin cytoskeleton. This correlates well with the function of Yno1, the only NADPH oxidase of yeast cells. Using two established tumor cell lines, which are derived from hepatic and neuroblastoma tumors, respectively, we are showing here that in both tumor models Nox4 is expressed in the ER (like the yeast NADPH oxidase), where according to published literature, it produces hydrogen peroxide. Reducing this biochemical activity by downregulating Nox4 transcription leads to loss of F actin stress fibers. This phenotype is reversible by adding hydrogen peroxide to the cells. The effect of the Nox4 silencer RNA is specific for this gene as it does not influence the expression of Nox2. In the case of the SH-SY5Y neuronal cell line, Nox4 inhibition leads to loss of cell mobility as measured in scratch assays. We propose that inhibition of Nox4 (which is known to be strongly expressed in many tumors) could be studied as a new target for cancer treatment, in particular for inhibition of metastasis. PMID- 28620581 TI - Third-Generation Tyrosine Kinase Inhibitors Targeting Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer. AB - Sensitizing mutations in the epidermal growth factor receptor (EGFR) predict response to EGFR tyrosine kinase inhibitors (TKIs) and both first- and second generation TKIs are available as first-line treatment options in patients with advanced EGFR-mutant non-small cell lung cancer. Eventual resistance develops with multiple mechanisms identifiable both upon repeat biopsy and in plasma circulating tumor DNA. The T790M gatekeeper mutation is responsible for almost 60% of cases. A number of third-generation TKIs are in clinical development, and osimertinib has been approved by the US Food and Drug Administration for the treatment of patients with EGFR T790M mutant lung cancer after failure of initial EGFR kinase therapy. Resistance mechanisms are being identified to these novel agents, and the treatment landscape of EGFR-mutant lung cancer continues to evolve. The sequence of EGFR TKIs may change in the future and combination therapies targeting resistance appear highly promising. PMID- 28620582 TI - Physicochemical and Nutritional Requirements for Axenic Replication Suggest Physiological Basis for Coxiella burnetii Niche Restriction. AB - Bacterial obligate intracellular parasites are clinically significant animal and human pathogens. Central to the biology of these organisms is their level of adaptation to intracellular replication niches associated with physicochemical and nutritional constraints. While most bacterial pathogens can adapt to a wide range of environments, severe niche restriction-an inability to thrive in diverse environments-is a hallmark of bacterial obligate intracellular parasites. Herein the physicochemical and nutritional factors underlying the physiological basis for niche restriction in the zoonotic bacterial obligate intracellular parasite and Q fever agent Coxiella burnetii are characterized. Additionally, these factors are reviewed in the context of C. burnetii evolution and continued (patho) adaptation. C. burnetii replication was strictly dependent on a combination of moderately acidic pH, reduced oxygen tension, and presence of carbon dioxide. Of macronutrients, amino acids alone support replication under physicochemically favorable conditions. In addition to utilizing gluconeogenic substrates for replication, C. burnetii can also utilize glucose to generate biomass. A mutant with a disruption in the gene pckA, encoding phosphoenolpyruvate carboxykinase (PEPCK), the first committed step in gluconeogenesis, could be complemented chemically by the addition of glucose. Disruption of pckA resulted in a moderate glucose-dependent growth defect during infection of cultured host cells. Although, C. burnetii has the theoretical capacity to synthesize essential core metabolites via glycolysis and gluconeogenesis, amino acid auxotrophy essentially restricts C. burnetii replication to a niche providing ample access to amino acids. Overall, the described combination of physiochemical and nutritional growth requirements are strong indicators for why C. burnetii favors an acidified phagolysosome-derived vacuole in respiring tissue for replication. PMID- 28620584 TI - IFN-gamma, IL-2, IP-10, and MIG as Biomarkers of Exposure to Leishmania spp., and of Cure in Human Visceral Leishmaniasis. AB - New biomarkers are needed for monitoring the effectiveness of treatment for visceral leishmaniasis (VL). They might also improve the detection of the asymptomatic population in Leishmania-endemic areas. This paper examines the IL 2, IFN-gamma, IFN-gamma-induced protein 10 (IP-10), and monokine-induced-by-IFN gamma (MIG) levels in whole blood-stimulated in vitro with soluble Leishmania antigen (SLA)-taken from asymptomatic individuals and patients treated for VL living in a post-outbreak (Leishmania infantum) area in Spain, and in an endemic (Leishmania donovani) area of Bangladesh. IP-10 was found to be an accurate global marker of asymptomatic subjects with positive cellular/humoral tests, while MIG was found to be a better marker of contact with L. donovani than IL-2 but no for those with L. infantum. Determining IP-10, MIG, and IFN-gamma levels proved useful in monitoring the cellular immune response following treatment for active disease caused by L. infantum. PMID- 28620583 TI - Engineering of Genetically Arrested Parasites (GAPs) For a Precision Malaria Vaccine. AB - Continuous stage conversion and swift changes in the antigenic repertoire in response to acquired immunity are hallmarks of complex eukaryotic pathogens, including Plasmodium species, the causative agents of malaria. Efficient elimination of Plasmodium liver stages prior to blood infection is one of the most promising malaria vaccine strategies. Here, we describe different genetically arrested parasites (GAPs) that have been engineered in Plasmodium berghei, P. yoelii and P. falciparum and compare their vaccine potential. A better understanding of the immunological mechanisms of prime and boost by arrested sporozoites and experimental strategies to enhance vaccine efficacy by further engineering existing GAPs into a more immunogenic form hold promise for continuous improvements of GAP-based vaccines. A critical hurdle for vaccines that elicit long-lasting protection against malaria, such as GAPs, is safety and efficacy in vulnerable populations. Vaccine research should focus on solutions toward turning malaria into a vaccine-preventable disease, which would offer an exciting new path of malaria control. PMID- 28620585 TI - Identification of a Large Family of Slam-Dependent Surface Lipoproteins in Gram Negative Bacteria. AB - The surfaces of many Gram-negative bacteria are decorated with soluble proteins anchored to the outer membrane via an acylated N-terminus; these proteins are referred to as surface lipoproteins or SLPs. In Neisseria meningitidis, SLPs such as transferrin-binding protein B (TbpB) and factor-H binding protein (fHbp) are essential for host colonization and infection because of their essential roles in iron acquisition and immune evasion, respectively. Recently, we identified a family of outer membrane proteins called Slam (Surface lipoprotein assembly modulator) that are essential for surface display of neisserial SLPs. In the present study, we performed a bioinformatics analysis to identify 832 Slam related sequences in 638 Gram-negative bacterial species. The list included several known human pathogens, many of which were not previously reported to possess SLPs. Hypothesizing that genes encoding SLP substrates of Slams may be present in the same gene cluster as the Slam genes, we manually curated neighboring genes for 353 putative Slam homologs. From our analysis, we found that 185 (~52%) of the 353 putative Slam homologs are located adjacent to genes that encode a protein with an N-terminal lipobox motif. This list included genes encoding previously reported SLPs in Haemophilus influenzae and Moraxella catarrhalis, for which we were able to show that the neighboring Slams are necessary and sufficient to display these lipoproteins on the surface of Escherichia coli. To further verify the authenticity of the list of predicted SLPs, we tested the surface display of one such Slam-adjacent protein from Pasteurella multocida, a zoonotic pathogen. A robust Slam-dependent display of the P. multocida protein was observed in the E. coli translocation assay indicating that the protein is a Slam-dependent SLP. Based on multiple sequence alignments and domain annotations, we found that an eight-stranded beta-barrel domain is common to all the predicted Slam-dependent SLPs. These findings suggest that SLPs with a TbpB-like fold are found widely in Proteobacteria where they exist with their interaction partner Slam. In the future, SLPs found in pathogenic bacteria can be investigated for their role in virulence and may also serve as candidates for vaccine development. PMID- 28620586 TI - Tracking Proteins Secreted by Bacteria: What's in the Toolbox? AB - Bacteria have acquired multiple systems to expose proteins on their surface, release them in the extracellular environment or even inject them into a neighboring cell. Protein secretion has a high adaptive value and secreted proteins are implicated in many functions, which are often essential for bacterial fitness. Several secreted proteins or secretion machineries have been extensively studied as potential drug targets. It is therefore important to identify the secretion substrates, to understand how they are specifically recognized by the secretion machineries, and how transport through these machineries occurs. The purpose of this review is to provide an overview of the biochemical, genetic and imaging tools that have been developed to evaluate protein secretion in a qualitative or quantitative manner. After a brief overview of the different tools available, we will illustrate their advantages and limitations through a discussion of some of the current open questions related to protein secretion. We will start with the question of the identification of secreted proteins, which for many bacteria remains a critical initial step toward a better understanding of their interactions with the environment. We will then illustrate our toolbox by reporting how these tools have been applied to better understand how substrates are recognized by their cognate machinery, and how secretion proceeds. Finally, we will highlight recent approaches that aim at investigating secretion in real time, and in complex environments such as a tissue or an organism. PMID- 28620587 TI - A Dual Luciferase Reporter System for B. burgdorferi Measures Transcriptional Activity during Tick-Pathogen Interactions. AB - Knowledge of the transcriptional responses of vector-borne pathogens at the vector-pathogen interface is critical for understanding disease transmission. Borrelia (Borreliella) burgdorferi, the causative agent of Lyme disease in the United States, is transmitted by the bite of infected Ixodes sp. ticks. It is known that B. burgdorferi has altered patterns of gene expression during tick acquisition, persistence and transmission. Recently, we and others have discovered in vitro expression of RNAs found internal, overlapping, and antisense to annotated open reading frames in the B. burgdorferi genome. However, there is a lack of molecular genetic tools for B. burgdorferi for quantitative, strand specific, comparative analysis of these transcripts in distinct environments such as the arthropod vector. To address this need, we have developed a dual luciferase reporter system to quantify B. burgdorferi promoter activities in a strand-specific manner. We demonstrate that constitutive expression of a B. burgdorferi codon-optimized Renilla reniformis luciferase gene (rlucBb ) allows normalization of the activity of a promoter of interest when fused to the B. burgdorferi codon-optimized Photinus pyralis luciferase gene (flucBb) on the same plasmid. Using the well characterized, differentially regulated, promoters for flagellin (flaBp), outer surface protein A (ospAp) and outer surface protein C (ospCp), we document the efficacy of the dual luciferase system for quantitation of promoter activities during in vitro growth and in infected ticks. Cumulatively, the dual luciferase method outlined herein is the first dual reporter system for B. burgdorferi, providing a novel and highly versatile approach for strand-specific molecular genetic analyses. PMID- 28620588 TI - Immunogenicity and Protective Efficacy of a Fusion Protein Tuberculosis Vaccine Combining Five Esx Family Proteins. AB - One strategy to develop the next generation of tuberculosis vaccines is to construct subunit vaccines based on T cell antigens. In this study, we have evaluated the vaccine potential of a fusion protein combining EsxB, EsxD, EsxG, EsxU, and EsxM of Mycobacterium tuberculosis (M. tb). This recombinant protein, named BM, was expressed in and purified from Escherichia coli. Immunization of C57BL/6 mice with purified BM protein formulated in Freund's incomplete adjuvant induced the production of Th1 cytokines (IFN-gamma, TNF, and IL-2) and multifunctional CD4+ T cells. Vaccination of BALB/c mice with BM protein followed by intravenous challenge with Mycobacterium bovis BCG resulted in better levels of protection than the two leading antigens, Ag85A and PPE18. Taken together, these results indicate that BM is a protective antigen. Future studies to combine BM with other antigens and evaluate its effectiveness as a booster of BCG or as a therapeutic vaccine are warranted. PMID- 28620591 TI - The BrainHealthRegistry.org: Using the Internet for identification, assessment, screening, recruitment, and longitudinal monitoring of subjects for neuroscience and Alzheimer's disease studies. PMID- 28620590 TI - Functional Redundancy and Ecological Innovation Shape the Circulation of Tick Transmitted Pathogens. AB - Ticks are vectors of pathogens affecting human and animal health worldwide. Nevertheless, the ecological and evolutionary interactions between ticks, hosts, and pathogens are largely unknown. Here, we integrated a framework to evaluate the associations of the tick Ixodes ricinus with its hosts and environmental niches that impact pathogen circulation. The analysis of tick-hosts association suggested that mammals and lizards were the ancestral hosts of this tick species, and that a leap to Aves occurred around 120 M years ago. The signature of the environmental variables over the host's phylogeny revealed the existence of two clades of vertebrates diverging along a temperature and vegetation split. This is a robust proof that the tick probably experienced a colonization of new niches by adapting to a large set of new hosts, Aves. Interestingly, the colonization of Aves as hosts did not increase significantly the ecological niche of I. ricinus, but remarkably Aves are super-spreaders of pathogens. The disparate contribution of Aves to the tick-host-pathogen networks revealed that I. ricinus evolved to maximize habitat overlap with some hosts that are super-spreaders of pathogens. These results supported the hypothesis that large host networks are not a requirement of tick survival but pathogen circulation. The biological cost of tick adaptation to non-optimal environmental conditions might be balanced by molecular mechanisms triggered by the pathogens that we have only begun to understand. PMID- 28620589 TI - Transcriptomic Profiling of High-Density Giardia Foci Encysting in the Murine Proximal Intestine. AB - Giardia is a highly prevalent, understudied protistan parasite causing significant diarrheal disease worldwide. Its life cycle consists of two stages: infectious cysts ingested from contaminated food or water sources, and motile trophozoites that colonize and attach to the gut epithelium, later encysting to form new cysts that are excreted into the environment. Current understanding of parasite physiology in the host is largely inferred from transcriptomic studies using Giardia grown axenically or in co-culture with mammalian cell lines. The dearth of information about the diversity of host-parasite interactions occurring within distinct regions of the gastrointestinal tract has been exacerbated by a lack of methods to directly and non-invasively interrogate disease progression and parasite physiology in live animal hosts. By visualizing Giardia infections in the mouse gastrointestinal tract using bioluminescent imaging (BLI) of tagged parasites, we recently showed that parasites colonize the gut in high-density foci. Encystation is initiated in these foci throughout the entire course of infection, yet how the physiology of parasites within high-density foci in the host gut differs from that of cells in laboratory culture is unclear. Here we use BLI to precisely select parasite samples from high-density foci in the proximal intestine to interrogate in vivo Giardia gene expression in the host. Relative to axenic culture, we noted significantly higher expression (>10-fold) of oxidative stress, membrane transporter, and metabolic and structural genes associated with encystation in the high-density foci. These differences in gene expression within parasite foci in the host may reflect physiological changes associated with high density growth in localized regions of the gut. We also identified and verified six novel cyst-specific proteins, including new components of the cyst wall that were highly expressed in these foci. Our in vivo transcriptome data support an emerging view that parasites encyst early in localized regions in the gut, possibly as a consequence of nutrient limitation, and also impact local metabolism and physiology. PMID- 28620592 TI - The Role of Fibular Fixation in the Treatment of Combined Distal Tibia and Fibula Fracture: A Randomized, Control Trial. AB - BACKGROUND: This randomized, parallel-group, non-blinded study was designed to determine the role of fibular fixation in the treatment outcomes of combined distal tibia and fibula fractures. MATERIALS AND METHODS: Sixty patients with distal tibial and fibular fractures were randomly divided in two groups of case and controls. In the case group, fibula was fixed prior to the fixation of tibia. In the control group, tibia was fixed without fibular fixation. Primary outcomes were varus-valgus angulation, anterior-posterior angulation, union and side effects. Follow-up visit and radiographs were taken 2 and 4 weeks as well as 3, 6 and 9 months after surgery. RESULTS: During the follow-up, 11 out of 60 patients in case and control groups were excluded. We recruited 24 and 25 patients in the case and control group, respectively. Intramedullary nailing was used in 8 patients of case and 11 patients of control group. Plate and screw were used in 16 patients in the case and 14 patients in the control group. Varus/valgus and anterior-posterior angulation were not statistically significant between two groups (P >= 0.05). The frequency of tibial and fibula union after 1, 3, 6 and 9 months in case and controls groups were not statistically significant (P >= 0.05). The frequency of nonunion of tibia and fibula, infection and nerve injury in studied groups were not statistically significant (P >= 0.05). CONCLUSION: We did not observe any significant improvement using fibular fixation in the treatment outcomes of tibia distal fractures. PMID- 28620593 TI - Phenotypic and Molecular Identification of Nocardia in Brain Abscess. PMID- 28620594 TI - Hypokalemia at the Time of Admission to the Intensive Care Unit (ICU) Increases the Need for Mechanical Ventilation and Time of Ventilation in Critically Ill Trauma Patients. PMID- 28620595 TI - The Predicting Ability of Serum Phosphorus to Assess the Duration of Mechanical Ventilation in Critically Ill Patients. AB - BACKGROUND: No previous study exists to evaluate serum phosphorus (Ph) level as a predictor of the need to mechanical ventilation (MV). This study was designed to determine the predictive ability of admission serum Ph level on MV in patients admitted in Intensive Care Unit (ICU). MATERIALS AND METHODS: This prospective study was conducted on 100 patients (>16 years old), admitted to our ICU over 1 year. Patients were classified into two groups according to the days of the need to MV. Group A: Patients who required equal or <5 days MV, and Group B: Patients who required more than 5 days of MV. We measured total serum Ph concentrations at the times of ICU admission, connecting to the ventilator and weaning from the ventilator. RESULTS: There were significant differences between serum Ph concentration on admission to ICU (Group A: 3.39 +/- 0.39 mg/dl, Group B: 2.89 +/ 0.31 mg/dl, P < 0.001), at the time of connecting to ventilator (Group A: 2.49 +/- 0.38 mg/dl, Group B: 2.25 +/- 0.26 mg/dl, P = 0.004) and weaning from ventilator (Group A: 3.42 +/- 0.33 mg/dl, Group B: 2.98 +/- 0.34 mg/dl, P < 0.001) between two groups. Duration of ICU stay in Group A was 6.08 +/- 1.48 days and in Group B was 15.35 +/- 6.45, this difference was significant (P < 0.001). We found the best cut-off point of 3.07 for serum Ph concentration to predict the longer duration of MV. CONCLUSION: According to the results of our study, hypophosphatemia may increase the need to MV. Therefore, monitoring serum Ph level is a good prognostic factor to predict the need to ventilation. PMID- 28620596 TI - Optimal Length of Follow-up for the Detection of Unsuccessful Pediatric Pyeloplasty: A Single-Center Experience. AB - OBJECTIVES: To assess the optimal length of follow-up for patients undergoing both open and minimally invasive pyeloplasties to ensure prompt detection of a recurrent obstruction. There are no standard guidelines on ideal follow-up and imaging post-pediatric pyeloplasty currently. METHODS: A retrospective chart review identified 264 patients (<18 years old) who underwent pyeloplasty for ureteropelvic junction obstruction between April 2002 and December 2014. Ultrasound was obtained every 3-4 months for the first year following pyeloplasty and thereafter at discretion of treating physician. Patient characteristics including symptoms and imaging were reviewed. RESULTS: Of the 264 patients, 72% were male with mean age of 51 months and follow-up of 26.8 months. Approximately 73% followed up to 3 years. Fourteen patients (5.3%) had a recurrent obstruction. Among the failures, 85% were diagnosed and underwent successful redo pyeloplasty within 3 years. Six infants had a recurrence (43% of all unsuccessful surgeries) and were diagnosed within 3 years of the initial surgery. Patients undergoing a minimally invasive procedure were less likely to be followed for more than 3 years compared to an open procedure (p < 0.001). Patients with severe hydronephrosis preoperatively were followed longer (p = 0.031). Age at surgery and type of surgical approach (p < 0.01) were significant predictors of length of follow-up in a negative binomial regression. CONCLUSION: Based on the results, a minimum of 3 years of follow-up is necessary to detect the majority of recurrent obstructions. Those patients who have higher than average lengths of follow-up tend to be younger and/or underwent an open surgical approach. PMID- 28620598 TI - Editorial: Ventricular Mechanics in Congenital Heart Disease. PMID- 28620597 TI - Feeding Problems and Their Underlying Mechanisms in the Esophageal Atresia Tracheoesophageal Fistula Patient. AB - Feeding difficulties such as dysphagia, coughing, choking, or vomiting during meals, slow eating, oral aversion, food refusal, and stressful mealtimes are common in children with repaired esophageal atresia (EA) and the reasons for this are often multifactorial. The aim of this review is to describe the possible underlying mechanisms contributing to feeding difficulties in patients with EA and approaches to management. Underlying mechanisms for these feeding difficulties include esophageal dysphagia, oropharyngeal dysphagia and aspiration, and aversions related to prolonged gastrostomy tube feeding. The initial diagnostic evaluation for feeding difficulties in a patient with EA may involve an esophagram, videofluoroscopic imaging or fiberoptic endoscopic evaluation during swallowing, upper endoscopy with biopsies, pH-impedance testing, and/or esophageal motility studies. The main goal of management is to reduce the factors contributing to feeding difficulties and may include reducing esophageal stasis, maximizing reflux therapies, treating underlying lung disease, dilating strictures, and altering feeding methods, routes, or schedules. PMID- 28620599 TI - Dysmotility in Esophageal Atresia: Pathophysiology, Characterization, and Treatment. AB - Esophageal dysmotility is almost universal after esophageal atresia (EA) repair and is mainly related to the developmental anomaly of the esophagus. Esophageal dysmotility is involved in the pathophysiology of numerous symptoms and comorbidities associated with EA such as gastroesophageal reflux disease, aspiration and respiratory complications, and symptoms of dysphagia and feeding disorders. High-resolution esophageal manometry (HREM) has facilitated the characterization of the dysmotility, but there is an incomplete correlation between symptoms and manometrical patterns. Impedance coupled to HREM should help to predict the clinical outcome and therefore personalize patient management. Nowadays, the management of esophageal dysmotility in patients with EA is essentially based on treatment of associated inflammation related to peptic or eosinophilic esophagitis. PMID- 28620600 TI - Biosafety and Biosecurity in European Containment Level 3 Laboratories: Focus on French Recent Progress and Essential Requirements. AB - Even if European Union (EU) Member States are obliged to implement EU Directives 2000/54/EC on the protection of workers from risks related to exposure to biological agents at work, national biosafety regulations and practices varied from country to country. In fact, EU legislation on biological agents and genetically modified microorganisms is often not specific enough to ensure harmonization leading to difficulties in implementation for most laboratories. In the same way, biosecurity is a relatively new concept and a few EU Member States are known to have introduced national laboratory biosecurity legislation. In France, recent regulations have reinforced biosafety/biosecurity in containment level 3 (CL-3) laboratories but they concern a specific list of pathogens with no correlation in other European Members States. The objective of this review was to summarize European biosafety/biosecurity measures concerning CL-3 facilities focusing on French specificities. Essential requirements needed to preserve efficient biosafety measures when manipulating risk group 3 biological agents are highlighted. In addition, International, European and French standards related to containment laboratory planning, operation or biosafety equipment are described to clarify optimal biosafety and biosecurity requirements. PMID- 28620601 TI - The Deaths of 94 Mental Health-care Users in Gauteng, South Africa. PMID- 28620602 TI - Caprylate Salts Based on Amines as Volatile Corrosion Inhibitors for Metallic Zinc: Theoretical and Experimental Studies. AB - The interaction of volatile corrosion inhibitors (VCI), caprylate salt derivatives from amines, with zinc metallic surfaces is assessed by density functional theory (DFT) computer simulations, electrochemical impedance (EIS) measurements and humid chamber tests. The results obtained by the different methods were compared, and linear correlations were obtained between theoretical and experimental data. The correlations between experimental and theoretical results showed that the molecular size is the determining factor in the inhibition efficiency. The models used and experimental results indicated that dicyclohexylamine caprylate is the most efficient inhibitor. PMID- 28620604 TI - Medical Students' Knowledge of Fertility Awareness-Based Methods of Family Planning. AB - OBJECTIVE: Traditional medical school curricula have not addressed fertility awareness-based methods (FABMs) of family planning. The objective of this study was to assess (1) 3-year medical students' knowledge of FABMs of family planning, (2) their confidence in utilizing that knowledge in patient care, and (3) to implement focused education on FABMs to improve knowledge and confidence. METHODS: Third-year medical students at one institution in the United States were given a 10-question assessment at the beginning of their OB-GYN rotation. Two lectures about FABMs and their clinical applications were given during the rotation. Students were given the same questions at the end of the rotation. Each questionnaire consisted of eight questions to assess a student's knowledge of FABMs and two questions to assess the student's confidence in sharing and utilizing that information in a clinical setting. McNemar's test was used to analyze the data. RESULTS: Two hundred seventy-seven students completed a pretest questionnaire and 196 students completed the posttest questionnaire. Medical knowledge improved from an initial test score of 38.99% to final test score of 53.57% (p < 0.05). Confidence in sharing FABM information with patients (0 = very uncomfortable; 5 = very comfortable) improved from 1.51 to 3.00 (p < 0.05). Confidence in utilizing FABM to diagnose and treat gynecologic/reproductive problems (0 = not very confident and 5 = very confident) improved from 1.01 to 3.15 (p < 0.05). CONCLUSION: Medical schools may not include FABMs in OB-GYN curriculum; however, to patients, these methods remain a sought after and valid form of family planning. This study shows that brief, focused education can increase medical students' knowledge of and confidence with FABMs of family planning. PMID- 28620606 TI - Editorial: Hip Arthroscopy. PMID- 28620603 TI - Advances in the Knowledge about Kidney Decellularization and Repopulation. AB - End-stage renal disease (ESRD) is characterized by the progressive deterioration of renal function that may compromise different tissues and organs. The major treatment indicated for patients with ESRD is kidney transplantation. However, the shortage of available organs, as well as the high rate of organ rejection, supports the need for new therapies. Thus, the implementation of tissue bioengineering to organ regeneration has emerged as an alternative to traditional organ transplantation. Decellularization of organs with chemical, physical, and/or biological agents generates natural scaffolds, which can serve as basis for tissue reconstruction. The recellularization of these scaffolds with different cell sources, such as stem cells or adult differentiated cells, can provide an organ with functionality and no immune response after in vivo transplantation on the host. Several studies have focused on improving these techniques, but until now, there is no optimal decellularization method for the kidney available yet. Herein, an overview of the current literature for kidney decellularization and whole-organ recellularization is presented, addressing the pros and cons of the actual techniques already developed, the methods adopted to evaluate the efficacy of the procedures, and the challenges to be overcome in order to achieve an optimal protocol. PMID- 28620605 TI - Regulation of Eosinophil Recruitment and Activation by Galectins in Allergic Asthma. AB - Eosinophils are differentiated granulocytes that are recruited from the bone marrow to sites of inflammation via the vascular system. Allergic asthma is characterized by the presence of large numbers of eosinophils in the lungs and airways. Due to their capacity to rapidly release inflammatory mediators such as cytokines, chemokines, growth factors, and cytotoxic granule proteins upon stimulation, eosinophils play a critical role in pro-inflammatory processes in allergen-exposed lungs. Identifying key players and understanding the molecular mechanisms directing eosinophil trafficking and recruitment to inflamed airways is a key to developing therapeutic strategies to limit their influx. Recent studies have brought to light the important role of glycans and glycan binding proteins in regulating recruitment of eosinophils. In addition to the role of previously identified eosinophil- and endothelial-expressed adhesion molecules in mediating eosinophil trafficking and recruitment to the inflamed airways, studies have also indicated a role for galectins (galectin-3) in this process. Galectins are mammalian lectins expressed by various cell types including eosinophils. Intracellularly, they can regulate biological processes such as cell motility. Extracellularly, galectins interact with beta-galactosides in cell surface expressed glycans to regulate cellular responses like production of inflammatory mediators, cell adhesion, migration, and apoptosis. Eosinophils express galectins intracellularly or on the cell surface where they interact with cell surface glycoconjugate receptors. Depending on the type (galectin-1, -3, etc.) and location (extracellular or intracellular, endogenous or exogenously delivered), galectins differentially regulate eosinophil recruitment, activation, and apoptosis and thus exert a pro- or anti-inflammatory outcome. Here, we have reviewed information pertaining to galectins (galectin-1, -3 -9, and -10) that are expressed by eosinophils themselves and/or other cells that play a role in eosinophil recruitment and function in the context of allergic asthma and their potential use as disease biomarkers or therapeutic targets for immunomodulation. PMID- 28620608 TI - A Path to Implement Precision Child Health Cardiovascular Medicine. AB - Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine. PMID- 28620607 TI - Metabolic and Biochemical Stressors in Diabetic Cardiomyopathy. AB - Diabetic cardiomyopathy (DCM) or diabetes-induced cardiac dysfunction is a direct consequence of uncontrolled metabolic syndrome and is widespread in US population and worldwide. Despite of the heterogeneous and distinct features of DCM, the clinical relevance of DCM is now becoming established. DCM progresses to pathological cardiac remodeling with the higher risk of heart attack and subsequent heart failure in diabetic patients. In this review, we emphasize lipid substrate quality and the phenotypic, metabolic, and biochemical stressors of DCM in the rodent and human pathophysiology. We discuss lipoxygenase signaling in the inflammatory pathway with multiple contributing and confounding factors leading to DCM. Additionally, emerging biochemical pathways are emphasized to make progress toward therapeutic advancement to treat DCM. PMID- 28620609 TI - Antibiotic Resistances in Livestock: A Comparative Approach to Identify an Appropriate Regression Model for Count Data. AB - Antimicrobial resistance in livestock is a matter of general concern. To develop hygiene measures and methods for resistance prevention and control, epidemiological studies on a population level are needed to detect factors associated with antimicrobial resistance in livestock holdings. In general, regression models are used to describe these relationships between environmental factors and resistance outcome. Besides the study design, the correlation structures of the different outcomes of antibiotic resistance and structural zero measurements on the resistance outcome as well as on the exposure side are challenges for the epidemiological model building process. The use of appropriate regression models that acknowledge these complexities is essential to assure valid epidemiological interpretations. The aims of this paper are (i) to explain the model building process comparing several competing models for count data (negative binomial model, quasi-Poisson model, zero-inflated model, and hurdle model) and (ii) to compare these models using data from a cross-sectional study on antibiotic resistance in animal husbandry. These goals are essential to evaluate which model is most suitable to identify potential prevention measures. The dataset used as an example in our analyses was generated initially to study the prevalence and associated factors for the appearance of cefotaxime-resistant Escherichia coli in 48 German fattening pig farms. For each farm, the outcome was the count of samples with resistant bacteria. There was almost no overdispersion and only moderate evidence of excess zeros in the data. Our analyses show that it is essential to evaluate regression models in studies analyzing the relationship between environmental factors and antibiotic resistances in livestock. After model comparison based on evaluation of model predictions, Akaike information criterion, and Pearson residuals, here the hurdle model was judged to be the most appropriate model. PMID- 28620610 TI - Molecular Detection of Tick-Borne Pathogen Diversities in Ticks from Livestock and Reptiles along the Shores and Adjacent Islands of Lake Victoria and Lake Baringo, Kenya. AB - Although diverse tick-borne pathogens (TBPs) are endemic to East Africa, with recognized impact on human and livestock health, their diversity and specific interactions with tick and vertebrate host species remain poorly understood in the region. In particular, the role of reptiles in TBP epidemiology remains unknown, despite having been implicated with TBPs of livestock among exported tortoises and lizards. Understanding TBP ecologies, and the potential role of common reptiles, is critical for the development of targeted transmission control strategies for these neglected tropical disease agents. During the wet months (April-May; October-December) of 2012-2013, we surveyed TBP diversity among 4,126 ticks parasitizing livestock and reptiles at homesteads along the shores and islands of Lake Baringo and Lake Victoria in Kenya, regions endemic to diverse neglected tick-borne diseases. After morphological identification of 13 distinct Rhipicephalus, Amblyomma, and Hyalomma tick species, ticks were pooled (<=8 individuals) by species, host, sampling site, and collection date into 585 tick pools. By supplementing previously established molecular assays for TBP detection with high-resolution melting analysis of PCR products before sequencing, we identified high frequencies of potential disease agents of ehrlichiosis (12.48% Ehrlichia ruminantium, 9.06% Ehrlichia canis), anaplasmosis (6.32% Anaplasma ovis, 14.36% Anaplasma platys, and 3.08% Anaplasma bovis,), and rickettsiosis (6.15% Rickettsia africae, 2.22% Rickettsia aeschlimannii, 4.27% Rickettsia rhipicephali, and 4.95% Rickettsia spp.), as well as Paracoccus sp. and apicomplexan hemoparasites (0.51% Theileria sp., 2.56% Hepatozoon fitzsimonsi, and 1.37% Babesia caballi) among tick pools. Notably, we identified E. ruminantium in both Amblyomma and Rhipicephalus pools of ticks sampled from livestock in both study areas as well as in Amblyomma falsomarmoreum (66.7%) and Amblyomma nuttalli (100%) sampled from tortoises and Amblyomma sparsum (63.6%) sampled in both cattle and tortoises at Lake Baringo. Similarly, we identified E. canis in rhipicephaline ticks sampled from livestock and dogs in both regions and Amblyomma latum (75%) sampled from monitor lizards at Lake Victoria. These novel tick-host-pathogen interactions have implications on the risk of disease transmission to humans and domestic animals and highlight the complexity of TBP ecologies, which may include reptiles as reservoir species, in sub-Saharan Africa. PMID- 28620611 TI - Dogs with Acute Myeloid Leukemia Have Clonal Rearrangements in T and B Cell Receptors. AB - Clonality testing for rearrangements in the complementarity-determining region 3 of the immunoglobulin heavy chain of B lymphocytes (B cell receptor) and the T cell receptor of T lymphocytes helps distinguish between clonal and non-clonal expansions of lymphocytes. There are rare reports of clonally rearranged T and B cell receptors in dogs with acute myeloid leukemia (AML). Our objective was to determine the frequency of clonally rearranged T and B cell receptors in dogs with AML. Archived slides from historical cases of AML (from January 2010 to June 2013) and slides or liquid specimens [blood, bone marrow (BM), body cavity fluid, or tissue aspirates] from cases of AML diagnosed between June 2013 and February 2017 were used in the study. A diagnosis of AML was made on the basis of more than 20% immature neoplastic cells ("blasts") in blood, BM, or extramedullary tissues, displaying features of myeloid differentiation. Myeloid differentiation was based on a combination of morphologic criteria, positive flow cytometric labeling for surface antigens typical of myeloid origin (e.g., CD11b, CD11c, CD14 with a general lack of expression of T or B cell markers), or positive cytochemical staining reactions for myeloid-associated enzymes (e.g., alkaline phosphatase, chloroacetate esterase). There were 63 cases of AML diagnosed during this period; however, slides or liquid specimens with sufficient DNA for testing were only obtained from 25 dogs. Affected dogs represented various breeds and were a median of 8 years old, with more male (64%) than female (36%) dogs. Common clinical signs were peripheral or internal lymphadenopathy (10/25 dogs, 40%) and hepatomegaly or splenomegaly (10/25 dogs combined, 40%). Typical hematologic findings were bi- or pancytopenia (23/25 dogs, 92%), with circulating blasts (21/25, 84%). Solitary clonal (4 B cell, 6 T cell) and biclonal (6 B and T cell) rearrangements in B or T cell receptors were found in 16 dogs (64%). Our results indicate that dogs with AML can have a high frequency of clonally rearranged T or B cell receptors, including biclonality, and clonality testing should not be used as a tool to distinguish between acute leukemia of myeloid or lymphoid origin. PMID- 28620612 TI - Potential Role of Pet Cats As a Sentinel Species for Human Exposure to Flame Retardants. AB - Flame retardants are a wide group of chemicals used by the industry to avoid combustion of materials. These substances are commonly found in plastics, electronic equipment, fabrics, and in many other everyday articles. Subsequently, ubiquitous environmental contamination by these common chemical is frequently reported. In the present study, we have evaluated the level of exposure to polychlorinated biphenyls (PCBs), brominated diphenyl ethers (BDEs), and organophosphorous flame retardants (OPFRs) in pet cats through the analysis of their serum. We also analyzed the level exposure to such chemicals in a series of 20 cat owners, trying to disclose the role of pet cats as sentinel species of human exposure to FRs. Our results showed that PCBs, banned 40 years ago, showed the lowest levels of exposure, followed by BDEs-banned recently. Congeners PCB 138 and PCB-180 were detected in >=50% of the series, while BDE-47 was detected in near 90% of the pet cats. On the other hand, the highest levels were that of OPFRs, whose pattern of detection was similar to that observed in humans, thus suggesting a potential role of cats as a sentinel species for human exposure to these currently used FRs. Six out of 11 OPFRs determined [2-ethylhexyldiphenyl phosphate, tributylphosphate, triisobutylphosphate, triphenylphosphate, tris (2 chloroethyl) phosphate, and tris (2-chloroisopropyl) phosphate] were detected in 100% of the samples. It will be interesting to perform future studied aimed to elucidating the potential toxicological effects of these highly detected chemicals both, in cats and humans. PMID- 28620613 TI - Evidence of Divergent Amino Acid Usage in Comparative Analyses of R5- and X4 Associated HIV-1 Vpr Sequences. AB - Vpr is an HIV-1 accessory protein that plays numerous roles during viral replication, and some of which are cell type dependent. To test the hypothesis that HIV-1 tropism extends beyond the envelope into the vpr gene, studies were performed to identify the associations between coreceptor usage and Vpr variation in HIV-1-infected patients. Colinear HIV-1 Env-V3 and Vpr amino acid sequences were obtained from the LANL HIV-1 sequence database and from well-suppressed patients in the Drexel/Temple Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. Genotypic classification of Env-V3 sequences as X4 (CXCR4 utilizing) or R5 (CCR5-utilizing) was used to group colinear Vpr sequences. To reveal the sequences associated with a specific coreceptor usage genotype, Vpr amino acid sequences were assessed for amino acid diversity and Jensen-Shannon divergence between the two groups. Five amino acid alphabets were used to comprehensively examine the impact of amino acid substitutions involving side chains with similar physiochemical properties. Positions 36, 37, 41, 89, and 96 of Vpr were characterized by statistically significant divergence across multiple alphabets when X4 and R5 sequence groups were compared. In addition, consensus amino acid switches were found at positions 37 and 41 in comparisons of the R5 and X4 sequence populations. These results suggest an evolutionary link between Vpr and gp120 in HIV-1-infected patients. PMID- 28620614 TI - Postmenopausal Iron Overload Exacerbated Bone Loss by Promoting the Degradation of Type I Collagen. AB - 117 postmenopausal women were divided into Normal, Bone loss (BL), and Osteoporosis group. Compared with Normal group (120.96 +/- 43.18 MUg/L), the serum ferritin (Fer) in BL (223.37 +/- 130.27 MUg/L) and Osteoporosis group (307.50 +/- 161.48 MUg/L) was significantly increased (p < 0.05). Fer level was negatively correlated with BMD (p < 0.01). TRACP levels in Osteoporosis group (4.37 +/- 1.69 U/L) were significantly higher than Normal group (4.10 +/- 1.60 U/L, p < 0.05). ALP levels in Osteoporosis group (112.06 +/- 62.05 U/L) were significantly upregulated compared with Normal group (80.22 +/- 14.94 U/L, p < 0.05). beta-CTX and PINP were the degradation products of type I collagen. beta CTX levels in Osteoporosis group (667.90 +/- 316.55 ng/L) were significantly increased compared with Normal group (406.06 +/- 112.12 ng/L, p < 0.05). PINP levels in Osteoporosis group (78.03 +/- 37.31 MUg/L) were significantly higher than Normal group (37.60 +/- 13.17 MUg/L, p < 0.01). More importantly, there was a positive correlation between serum Fer and PINP (p < 0.01). Serum Fer showed a positive correlation of serum beta-CTX (p < 0.01). The overloaded iron improved the degradation of type I collagen. PMID- 28620615 TI - Component Release and Mechanical Properties of Endodontic Sealers following Incorporation of Antimicrobial Agents. AB - Root canal sealers with antimicrobial activity are highly beneficial; therefore, their antimicrobial properties could be improved by incorporation of antimicrobial agents. In the present study, the release of the quaternary ammonium compounds from endodontic sealers admixed with either benzalkonium chloride (BC) or cetylpyridinium chloride (CPC) at loadings of 2% wt was monitored. The effect of these additives on the compressive strengths and their release from the sealers was determined after 1 and 4 weeks. All of the materials studied were found to be capable of releasing antimicrobial additive in useful quantities. The release of CPC occurred to a statistically significant greater extent than BC for all materials. The addition of both BC and CPC generally decreased the compressive strength of all the endodontic sealers, with the exception of CPC in AH Plus, where the compressive strength was significantly increased. This suggests that, for these endodontic sealers, the antimicrobial additives alter the setting chemistry. AH Plus is an epoxy-based material cured with an amine, and in this case the increase in compressive strength with CPC is attributed to an enhanced cure reaction with this system. In all other cases, the additive inhibited the cure reaction to a greater or lesser extent. PMID- 28620617 TI - Application of Biotechnology for the Production of Biomass-Based Fuels. PMID- 28620616 TI - The Impact of Combining a Low-Tube Voltage Acquisition with Iterative Reconstruction on Total Iodine Dose in Coronary CT Angiography. AB - OBJECTIVES: To assess the impact of combining low-tube voltage acquisition with iterative reconstruction (IR) techniques on the iodine dose in coronary CTA. METHODS: Three minipigs underwent CCTA to compare a standard of care protocol with two alternative study protocols combining low-tube voltage and low iodine dose with IR. Image quality was evaluated objectively by the CT value, signal-to noise ratio (SNR), and contrast-to-noise ratio (CNR) in the main coronary arteries and aorta and subjectively by expert reading. Statistics were performed by Mann-Whitney U test and Chi-square analysis. RESULTS: Despite reduced iodine dose, both study protocols maintained CT values, SNR, and CNR compared to the standard of care protocol. Expert readings confirmed these findings; all scans were perceived to be of at least diagnostically acceptable quality on all evaluated parameters allowing image interpretation. No statistical differences were observed (all p values > 0.11), except for streak artifacts (p = 0.02) which were considered to be more severe, although acceptable, with the 80 kVp protocol. CONCLUSIONS: Reduced tube voltage in combination with IR allows a total iodine dose reduction between 37 and 50%, by using contrast media with low iodine concentrations of 200 and 160 mg I/mL, while maintaining image quality. PMID- 28620618 TI - Histopathological and Reproductive Evaluation in Male Rats Fed Jatropha curcas Seed Cake with or without Alkaline Hydrolysis and Subjected to Heat Treatment. AB - Jatropha curcas cake, a by-product of biodiesel production, is rich in protein and has potential to be used in livestock feed; however, the presence of antinutritional factors and phorbol esters limits its use. Thus, this study investigated toxicological and reproductive effects in male Wistar rats after subchronic exposure to J. curcas cake subjected to detoxification procedures. Rats were divided into seven groups (n = 10) and treated for 60 days. The control group received commercial feed, while experimental groups received a diet containing 5% J. curcas cake nonhydrolyzed or hydrolyzed with 5 M NaOH. The cakes were unwashed or washed with ethanol or water and were autoclaved at 121 degrees C for 30 minutes. Alkaline hydrolysis combined with ethanol washing decreased the phorbol ester concentration in the cake by 98%. Histopathological findings included diffuse degeneration of the liver and edema around the pulmonary vessels in the nonhydrolyzed groups. In addition, nontreated females mated with males of nonhydrolyzed unwashed group showed a decreased number of live fetuses and an increased placental weight. There were no signs of toxicity in rats given hydrolyzed cakes washed and unwashed, indicating that alkaline hydrolysis associated with heat treatment is an efficient method for detoxification of the J. curcas cake. PMID- 28620619 TI - Effects of (1E,4E)-2-Methyl-1,5-bis(4-nitrophenyl)penta-1,4-dien-3-one on Trypanosoma cruzi and Its Combinational Effect with Benznidazole, Ketoconazole, or Fluconazole. AB - This study reports the activity induced by (1E,4E)-2-methyl-1,5-bis(4 nitrophenyl)penta-1,4-dien-3-one (A3K2A3) against Trypanosoma cruzi. This compound showed trypanocidal activity against the multiplicative epimastigote and amastigote forms of this protozoan, with IC50 values of 1.99 +/- 0.17 and 1.20 +/ 0.16 MUM, respectively, and EC50 value of 15.57 +/- 0.34 MUM against trypomastigotes. The combination of A3K2A3 with benznidazole or ketoconazole demonstrated strong synergism, increasing effectiveness against trypomastigotes or epimastigotes of T. cruzi. In addition, the drug combination of A3K2A3 with benznidazole or ketoconazole on LLCMK2 cells demonstrated an antagonist effect, which resulted in greater protection of the cells from drug damage. The combination of the compound with fluconazole was not effective. Transmission and scanning electron micrographs showed changes on parasites, mainly in the cytoplasmatic membrane, nucleus, mitochondrion, and Golgi complex, and a large increase in the number of autophagosome-like structures and lipid-storage bodies, accompanied by volume reduction and rounding of the parasite. A3K2A3 might be a promising compound against T. cruzi. PMID- 28620620 TI - NGAL as an Early Predictive Marker of Diabetic Nephropathy in Children and Young Adults with Type 1 Diabetes Mellitus. AB - AIMS: Type 1 diabetes (T1D) is often associated with early microvascular complications. Previous studies demonstrated that increased systolic (SAP) and diastolic arterial blood pressures (DAP) are linked to microvascular morbidity in T1D. The aim of the study was to investigate the predictive role of neutrophil gelatinase-associated lipocalin (NGAL) in unravelling early cardio-renal dysfunction in T1D. METHODS: Two T1D patient groups participating in two-centre prospective cohorts were studied. Group A consisted of 57 participants aged 13.9 years (SD: 3.1) and group B consisted of 59 patients aged 28.0 years (SD: 4.4). Forty-nine healthy children [age: 10.5 years (SD: 6.6)] and 18 healthy adults [age 27.7 years (SD: 4.2)] served as controls. Serum concentrations of NGAL (ELISA) were determined, and SAP and DAP were examined (SAP and DAP also expressed as z-scores in the younger group). RESULTS: NGAL correlated positively with SAP in both patient groups (P = 0.020 and P = 0.031, resp.) and SAP z-score (P = 0.009) (group A) and negatively with eGFR in both groups (P < 0.001 and P < 0.001, resp.). CONCLUSIONS: NGAL may be proposed as a biomarker of early renal dysfunction even in nonalbuminuric T1D patients, since it was strongly associated with renal function decline and increasing systolic arterial pressure even at prehypertensive range in people with T1D, in a broad age range. PMID- 28620621 TI - Matrix-Assisted Autologous Chondrocyte Transplantation in the Knee: A Systematic Review of Mid- to Long-Term Clinical Outcomes. AB - BACKGROUND: Matrix-assisted autologous chondrocyte transplantation (MACT) is a surgical treatment option for articular cartilage lesions of the knee joint. PURPOSE: To investigate mid- to long-term clinical outcomes of MACT in the patellofemoral (PF) and tibiofemoral (TF) joints. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review was performed by searching PubMed, Embase, and the Cochrane Library to find studies evaluating minimum 5-year clinical outcomes of patients undergoing MACT in the knee joint. Search terms used were knee, matrix, and autologous chondrocyte. Patients were evaluated based on treatment failure rates, magnetic resonance imaging, and subjective outcome scores. Study methodology was assessed using the Modified Coleman Methodology Score (MCMS). RESULTS: Ten studies (two level 1, one level 2, one level 3, and six level 4 evidence) were identified that met inclusion and exclusion criteria, for a total of 442 TF patients and 136 PF patients. Treatment failure occurred in 9.7% of all patients, including 4.7% of PF patients and 12.4% of TF patients (P = .037). Weighted averages of subjective outcome scores, including Knee injury and Osteoarthritis Outcome Score, Short Form-36 Health Survey, and Tegner scores, improved from baseline to latest follow-up in both TF and PF patients. The mean MCMS was found to be 57.4, with a standard deviation of 18.5. CONCLUSION: Patients undergoing MACT in the knee show favorable mid- to long-term clinical outcomes. A significantly higher treatment failure rate was found in patients undergoing MACT in the TF joint compared with the PF joint. PMID- 28620622 TI - Intrahepatic Migration of Gastrostomy Tube after Inadvertent Transhepatic PEG Placement. PMID- 28620623 TI - Resolution of Diffuse Intrahepatic Biliary Strictures after Chemotherapy for Metastatic Ovarian Cancer. AB - Sclerosing cholangitis and cholestatic jaundice secondary to metastatic disease is a rare complication. We report a rare case of secondary sclerosing cholangitis (SSC) due to lymphatic spread from ovarian cancer with complete resolution after chemotherapy. The diagnosis of SSC from metastatic ovarian cancer was clinically challenging, as endoscopic retrograde cholangiopancreatography revealed irregular hepatic ducts consistent with sclerosing cholangitis, but it did not identify any malignant cells. The final diagnosis was made with liver biopsy revealing high grade metastatic Mullerian carcinoma. The patient responded well to chemotherapy and is in remission. A timely diagnosis is important and can lead to complete resolution of the disease. PMID- 28620624 TI - Early Gastric Cancer Associated with a Gastric Lipoma. PMID- 28620625 TI - Hematopoietic Aging Biomarkers in Peromyscus leucopus Mice. AB - We analyzed hematopoietic phenotypes in Peromyscus leucopus (PL) mice at young (2 9 months), middle (22-23 months) and old (33-46 months) ages aimed at characterizing age-associated changes in this unique rodent species. We found a significantly higher number of monocytes in old PL mice in peripheral blood, and higher proportions of CD44+ cells in blood, spleen and bone marrow in old PL mice than in middle and young counterparts. We conclude that elevated blood monocyte counts and up-regulated hematopoietic cell CD44 expression are two useful aging biomarkers for PL mice. PMID- 28620626 TI - Tobacco Smoke Constituents Trigger Cytoplasmic Calcium Release. AB - Cytosolic Ca2+ is a universal second messenger that is involved in many processes throughout the body, including the regulation of cell growth/cell division, apoptosis, and the secretion of both ions, and macromolecules. Tobacco smoke exerts multiple effects on airway epithelia and we have previously shown that Kentucky reference cigarette smoke exposure elevated the second messenger Ca2+, leading to dysfunctional ion secretion. In this study, we tested whether little cigar and commercial cigarette smoke exposure exerts similar effects on intracellular Ca2+ levels. Indeed, Swisher Sweets, Captain Black, and Cheyenne little cigars, as well as Camel, Marlboro, and Newport cigarettes, triggered a comparable increase in intracellular Ca2+ as seen with Kentucky reference cigarettes in human bronchial epithelia. We also found that Kentucky reference cigarette smoke exposure caused increases in Ca2+ in HEK293T cells and that similar increases in Ca2+ were seen with the tobacco smoke metabolites 1-NH2 naphthalene, formaldehyde, nicotine, and nicotine-derived nitrosamine ketone. Given the large number of physiological processes governed by changes in cytosolic Ca2+, our data suggest that Ca2+ signaling is a useful and reproducible assay that can be used to probe the propensity of tobacco products and their constituents to cause toxicity. PMID- 28620628 TI - Reduction of Sugar-Sweetened Beverage Consumption in Elementary School Students Using an Educational Curriculum of Beverage Sugar Content. AB - Introduction: Given the known association between sugar-sweetened beverage (SSB) intake and poorer health, we instituted an educational curriculum to reduce student consumption of SSBs. Methods: The program included third- to fifth-grade students. A simple demonstration using teaspoons of sugar or small candies showed students the quantity of added sugar in common beverages. This amount of sugar was compared to the daily limit recommended by the American Heart Association. Key principles were reinforced over a 4-month period. Anonymous beverage recall surveys were distributed to 213 students at baseline and 211 students 6 months after exposure to the curriculum. Primary endpoints included evaluation of SSB, real fruit juice (RFJ), diet soda, and water servings in the last 24 hours. Results: The proportion of children consuming 2 or more beverages daily decreased from 8.9% to 4.3% (P = .0546) for diet soda, from 70.0% to 58.3% (P = .0123) for SSB + RFJ, and from 60.1% to 47.4% (P = .0087) for SSB. At baseline, students reported an average consumption of 3.5 SSB, 4.5 SSB + RFJ, 0.4 diet soda, and 3.3 water servings per day. At 6 months after exposure, the average daily beverage consumption decreased to 2.7 servings per day for SSB (P = .014), 3.8 for SSB + RFJ (P = .039), and 0.2 for diet soda (P = .027). Water consumption increased from 3.3 to 3.6 servings per day (P = .075). Discussion: Our data suggest grade school students are receptive to information about the adverse effects of SSBs on health. Adding similar educational programs to elementary school curriculum may help reduce long-term SSB consumption. PMID- 28620627 TI - Perspectives on Living With Fibromyalgia. AB - Perceptions of people living with chronic illness change over time, contributing to health-related stress that necessitates coping skills. Paterson's shifting perspectives model provides an explanation of chronically ill people's variations in attention to their symptoms. In this qualitative study, 20 people with fibromyalgia living in a rural setting were interviewed in 2013 with the aim of gaining insight into their experiences and the meaning-making associated with their chronic condition. Analysis of the interview data categorized five recurrent, or common, themes: experiences of loss, feelings of fear and uncertainty, influence of stress, stigmatization of the disease, and coping through courage. Difficulties attendant to losses, distress, and stigma associated with this chronic condition led the participants to report poor health related quality of life. The study findings can be useful across clinical settings to nurses and other health care providers in understanding those diagnosed with fibromyalgia and their care needs. PMID- 28620629 TI - Pediatric Hypertension: Provider Perspectives. AB - Pediatric hypertension is a risk for adult cardiovascular disease, making early detection important. The prevalence of pediatric essential hypertension is rising due to the increased prevalence of obesity. Though guidelines for screening, diagnosis, evaluation, and management are available, there are barriers to accurate diagnosis of pediatric hypertension, including lack of knowledge and complexity of blood pressure standards. We aimed to gain insights into reasons for low rates of diagnosis and treatment from primary care providers. As part of a multisite randomized controlled trial, we interviewed 8 providers in a community health center network. We used a grounded theoretical approach to analyze transcripts. Providers reflected on numerous barriers to diagnosis, management, and follow-up; recommendations for educational content; and how community health center systems can be improved. Findings informed development of a multifaceted intervention. Despite lack of training on essential hypertension, providers were comfortable recommending lifestyle changes to promote healthier weight and reduced blood pressure. PMID- 28620630 TI - Etiology, Diagnosis and Management of Oromandibular Dystonia: an Update for Stomatologists. AB - Oromandibular dystonia (OMD) is a rare focal neurological disorder that affects mouth, face, and jaws. This comprehensive literature review aimed to summarize the current evidence for etiology, diagnosis, and management of OMD and assess the possibility of dental origin of the disease and dental treatment plans for these patients. Different online databases namely PubMed, Google scholar, and Scopus were searched. The keywords "oromandibular dystonia", "orofaciomandibular dystonia", "orofacial-buccal dystonia", "lingual dystonia", "jaw dystonia", "cranial dystonia", and "adult-onset facial dystonia" were searched in the title and abstract of publications from 1970 to 2016. The inclusion criterion was the dental etiology and/or dental treatment. Out of 1260 articles, only 37 articles met the inclusion criteria. OMD can be caused or exacerbated through different dental treatments within which anyone is likely to be involved due to various reasons. Some novel methods employed to relieve this syndrome have led to certain cure or improvement of symptoms in several cases. OMD patients may refer to dentists with involuntary jaw movements and intraoral presentations. Thus, the dentists should be aware of the symptoms and signs and refer the suspicious cases. Dentists should also be familiar with special considerations when managing OMD patients. PMID- 28620632 TI - Prevalence of Soft Tissue Calcifications in CBCT Images of Mandibular Region. AB - STATEMENT OF THE PROBLEM: Most of the soft tissue calcifications within the head and neck region might not be accompanied by clinical symptoms but may indicate some pathological conditions. PURPOSE: The aim of this research was to determine the prevalence of soft tissue calcifications in cone beam computed tomography (CBCT) images of mandibular region. MATERIALS AND METHOD: In this cross sectional study the CBCT images of 602 patients including 294 men and 308 women with mean age 41.38+/-15.18 years were evaluated regarding the presence, anatomical location; type (single or multiple) and size of soft tissue calcification in mandibular region. All CBCT images were acquired by NewTom VGi scanner. Odds ratio and chi-square tests were used for data analysis and p< 0.05 was considered to be statistically significant. RESULTS: 156 out of 602 patients had at least one soft tissue calcification in their mandibular region (25.9%. of studied population with mean age 51.7+/-18.03 years). Men showed significantly higher rate of soft tissue calcification than women (30.3% vs. 21.8%). Soft tissue calcification was predominantly seen at posterior region of the mandible (88%) and most of them were single (60.7%). The prevalence of soft tissue calcification increased with age. Most of the detected soft tissue calcifications were smaller than 3mm (90%). CONCLUSION: Soft tissue calcifications in mandibular area were a relatively common finding especially in posterior region and more likely to happen in men and in older age group. PMID- 28620631 TI - The Effect of Titanium Tetrafluoride and Sodium Hypochlorite on the Shear Bond Strength of Methacrylate and Silorane Based Composite Resins: an In-Vitro Study. AB - STATEMENT OF THE PROBLEM: The bond strength of composites with different adhesive systems with dentin is an important factor in long term durability of composite restorations. The effect of titanium tetrafluoride (TiF4) as anti caries agent and sodium hypochlorite (NaOCl) as disinfectant on the shear bond of nanofilled and silorane based composite resins have not been investigated in previous studies. PURPOSE: This study was conducted to determine bond strength between dentin and two composite systems, by means of shear bond test using TiF4 and NaOCl. MATERIALS AND METHOD: Middle dentin of 60 intact extracted maxillary premolar teeth were exposed by sectioning the crowns at a depth of 2mm from central groove and parallel to the occlusal surface. Standardized smear layer was created using a 600-grit silicon carbide paper and then samples were embedded in acrylic resin blocks. Then the samples were randomly divided into 6 ?groups summarized as Group I: Z350, Group II: Z350+ NaOCl, Group III: Z350+ TiF4, Group IV: P90, Group V: P90+ NaOCl, Group VI: P90+ TiF4 according to manufacturer's instruction. Then samples were subjected to shear bond strength (SBS) test using universal testing machine and data were analyzed using ANOVA and Tukey tests (p< 0.05). RESULTS: Application of 5% NaOCl caused a significant decrease in SBS of nanofilled composite resin (p= 0.004), and also silorane based composite resin (p= 0.006). Application of 4% TiF4 caused a significant increase in SBS of silorane based composite resin (p= 0.001). The effect of TiF4 on nanofilled composite was not statistically significant. CONCLUSION: Using TiF4 has a positive effect on increasing the shear bond while NaOCl has negative effect on bond strength. PMID- 28620633 TI - Efficacy of Human Umbilical Stem Cells Cultured on Polylactic/ Polyglycolic Acid Membrane in the Treatment of Multiple Gingival Recession Defects: a Randomized Controlled Clinical Study. AB - STATEMENT OF THE PROBLEM: Recently allogenic mesenchymal stem cells are proposed to have multipotential progenitor cell capabilities to differentiate into cementoblasts, osteoblasts, and periodontal ligament fibroblasts. PURPOSE: The aim of the present study was to compare the efficacy of human umbilical stem cells cultured on polylactic acid (PLA), polyglycolic acid (PGA) membrane with PLA/PGA membrane alone in the treatment of multiple gingival recession defects. MATERIALS AND METHOD: A total number of 14 cases of multiple gingival recession (Miller's Class I or II) located in the anterior region were randomly selected and divided into test (stem cells in combination with PLA/PGA membrane) and control group (PLA/PGA membrane alone). Clinical parameters including gingival recession, probing pocket depth, clinical attachment level, and width of keratinized gingiva were recorded at baseline, and at 6 months postoperative. RESULTS: At baseline, there was 2.28 mm and 2.14mm mean gingival recession at 16 sites and 14 sites in test and control groups respectively. At 6 months post surgery, test group showed 1.57 mm mean reduction of gingival recession indicating 66% root coverage, while the control group showed 1.24mm mean reduction of gingival recession indicating 57% root coverage. CONCLUSION: In the present study, the stem cell with PLA/PGA membrane showed significantly higher mean root coverage compared to only PLA/PGA membrane group. PMID- 28620634 TI - Dental Caries and Associated Factors in Children Aged 2-4 Years Old in Mbeya City, Tanzania. AB - STATEMENT OF THE PROBLEM: Dental caries in infants and young children is prevalent worldwide; its magnitude and associated factors vary between communities because of cultural and social economic differences. No such information was available for pre-school children in Mbeya city. PURPOSE: To determine dental caries status and associated factors in 2 to 4-year-old children in Mbeya city. MATERIALS AND METHOD: A cross sectional study was conducted among 525 children aged 2-4 years and their parents/caregivers. Caries was assessed using caries assessment spectrum and treatment index, oral hygiene by visual inspection for visible plaque on index teeth, and dietary and oral hygiene habits by a questionnaire. Kappa statistics was used to test reliability of study instruments, chi2-test and logistic regression was employed for studying associations. RESULTS: Caries free children for dmft1, dmft2 and dmft3 were 79.8%, 83.8% and 94.7% and caries experience was 0.49 (1.23), 0.4 (1.14) and 0.10 (0.53) respectively. Older age [(OR =2.722 (1.617-4.582) p=< 0.001)]; and frequent consumption of factory made sugary foods/snacks at age 1-2 years [(OR=3.061 (1.188-7.887) p=0.021] were associated with caries. Prolonged breastfeeding for more than 1 year and breastfeeding at night had no association with dental caries. CONCLUSION: The prevalence of dental caries was very low. Older age and frequent consumption of factory made sugary foods at age 1-2 years were associated with higher odds of developing dental caries. Prolonged breasfeeding and breastfeeding at night had no association with dental caries. Prevention of dental caries should be instituted as soon as primary teeth start erupting, especially through discouraging consumption of factory made sugary foods/snacks. PMID- 28620635 TI - Pioneering Strategies for Relieving Dental Anxiety in Hearing Impaired Children: a Randomized Controlled Clinical Study. AB - STATEMENT OF THE PROBLEM: Hearing impaired children have a problem in understanding and comprehending with dental treatments. Visual language is the sensible answer of how to improve communication with them. PURPOSE: To evaluate the applicability of dental sign language in Hearing impaired children in relieving anxiety during stressful dental treatment by improving their means of communication. MATERIALS AND METHOD: This randomized clinical trial was carried out in the Department of Pedodontics and Preventive Dentistry which included 40 Hearing Impaired children meeting inclusion criteria. The selected children were randomly divided into the study and control group comprising of 20 each. In the control group, initial oral examination and dental treatment (oral prophylaxis and class I restoration) were performed without the use of dental sign language. In the study group, the dental sign language specific to dental treatment was educated and during their subsequent visit to the dental clinic after dental sign language reinforcement, oral prophylaxis and class I restoration were done. Subjective and objective measurements of anxiety were recorded for both groups using facial image scale (FIS), pulse oximeter and electronic blood pressure apparatus to compare for correlation. The obtained data were subjected to statistical analysis using unpaired t-test. RESULTS: There was a statistically significant reduction in the anxiety levels (p< 0.05) in the study group compared to the control group. CONCLUSION: Dental sign language was effective in reducing the level of anxiety in children who are hard of hearing. Dental sign language was able to improve behavior positively during dental treatment and may also aid in developing a positive dental attitude among children who are hard of hearing. PMID- 28620636 TI - A Scanning Electron Microscopic Evaluation of the Effectiveness of Etidronic Acid, SmearClear and MTAD in Removing the Intracanal Smear Layer. AB - STATEMENT OF THE PROBLEM: Root canal therapy should not simply be the extirpation of the pulp and widening of the canal. But one should also focus on how to completely remove the loosely-attached smear layer because it has adverse effects on the final outcome of the treatment. PURPOSE: This study compared the efficacy of Etidronic acid, SmearClear and MTAD to remove the smear layer created during instrumentation in different regions of the root canal. MATERIALS AND METHOD: Fifty single-rooted mandibular premolars were decoronated from the cementoenamel junction and instrumented using the ProTaper universal rotary file system along with copious irrigation by 1.0% sodium hypochlorite and distilled water. On the basis of the type of chelating agent used for irrigation, samples (n=10) were then randomized into five groups as: Group I- 9% etidronic acid, Group II- 18% etidronic acid, Group III- SmearClear, Group IV- MTAD and Group V- normal saline. Subsequent to irrigation, all samples were rinsed, dried and sectioned longitudinally for evaluation of the smear layer removal under scanning electron microscope (2000X). Data were statistically analyzed by two-way analysis of variance and Tukey's post hoc test with statistical significance set at p< 0.5. RESULTS: The result showed that SmearClear was the most efficient in removing the smear layer. However, etidronic acid was found inferior than both SmearClear and MTAD. CONCLUSION: Chelators are essential for complete smear layer removal in association with organic solvent. PMID- 28620638 TI - Evaluation of the Color Stability of Methyl Methacrylate and Nylon Base Polymer. AB - STATEMENT OF THE PROBLEM: Evaluation of the color stability of materials used for the fabrication of the base of complete and partial removable dentures provides important information in relation to their clinical service. The color stability of nylon-based polymers as denture bases, compared to that of acrylic resins, has not been extensively evaluated since to date. PURPOSE: The aim of the present in vitro study was to evaluate the color stability of conventional polymethyl methacrylate and nylon-based polymer materials used for the fabrication of the base of complete and partial removable dentures. MATERIALS AND METHOD: Twenty samples were evaluated in the present in vitro study. One nylon-based polymer and one heat-cured acrylic resin were seleted for the purpose of the study. Ten disk samples, measuring 10 mm in diameter and 2 mm in thickness, were prepared from each material according to the manufacturers' instructions. The samples were evaluted with the CIELAB sysem using spectrophtometery at baseline and after irradiation with UV light for 100 and 200 hours and thermocycling. One-way ANOVA and post hoc paired t-test were used to compare the color stability of the two groups. Statistical significance was set at p< 0.05. RESULTS: After 100 hours of irradiation with UV light and thermocycling, color changes were tangible in both materials. After 200 hours of irradiation with UV light and thermocycling, both materials exhibited a decrease in glaze. In general, chromatic changes in the acrylic resin were more noticeable. CONCLUSION: Accelerated aging affected the color stability of the acrylic resin and nylon-based polymer, p< 0.05 for Deltaa200 and Deltab200 and DeltaL100; however, at the end of the study both materials exhibited clinically acceptable color stability (DeltaE<3.7). PMID- 28620637 TI - Evaluation of the Effects of Three Plant Species (Myrtus Communis L., Camellia Sinensis L., Zataria Multiflora Boiss.) on the Healing Process of Intraoral Ulcers in Rats. AB - STATEMENT OF THE PROBLEM: Use of traditional medicine to relieve human sufferings has a very long history. The effects of these plants in wound curing and subsequently making the best mucosa patch for treatment of oral ulcers is still under investigation. PURPOSE: The main goal of present research work is to assess the efficacy of Myrtus communis L., Camellia sinensis L. and Zataria multiflora Boiss. on oral ulcer recovery process in rats. MATERIALS AND METHOD: In this study, 60 healthy adult male rats in 5 groups were investigated. A wound with 2 mm diameter was punched into the hard palate of each rat. For topical application, a mucosa patch of materials or blank was packed into the wound. Histological samples were harvested on post injury days 2, 4, 6, and 8. RESULTS: This study showed that there were no significant differences between groups in the reduction of weight. Comparison of clinical wound size showed that group Myrtus communis L had the greatest reduction in wound size on days 4, 6 and 8, which was significantly different from the other groups. The highest thickness of epithelium was observed in groups Myrtus communis L and Camellia sinensis L on days 6 and 8. Group Myrtus communis L showed the highest values on days 6 and 8. This study showed a lower mononuclear cell counts in group Myrtus communis L on days 6 and 8 compared to other groups which was statistically significant. CONCLUSION: The results of the present study showed that Myrtus communis L. has significant effects on oral wound healing processes. These favorable results might introduce a new group of material or medicine derived from this plant. PMID- 28620639 TI - Prevalence of Human Papilloma Virus in Sinonasal Papilloma in Southern Iranian Population. AB - STATEMENT OF THE PROBLEM: Sinonasal papilloma (SNP) is a rare benign lesion characterized by high recurrence rate and malignant transformation. PURPOSE: This study aimed to investigate the prevalence of human papilloma virus (HPV) infection in these lesions in South of Iran. MATERIALS AND METHOD: In this cross sectional retrospective study, a total of 41 patients, 38 SNP and 3 SNP/Squamous cell carcinoma cases, from 2007 to 2014 were studied. Human papilloma virus (HPV) DNA detection was performed by nested PCR method and positive cases were analyzed for high risk HPV-16 and HPV-18. RESULTS: HPV was detected in 31.7%; HPV- 16 in 4.9% and HPV 18 was not detected at all. Dysplastic epithelium was detected in 53% that was not associated with HPV. Three cases were accompanied with malignant transformation that HPV genome was detected in only one case and none of them were positive for HPV16 /18 genomic DNA. CONCLUSION: Current research suggests that HPV may be involved in the development of SNP. But the high risk HPV is not important in malignant transformation. More studies are needed to elucidate the possible etiologic mechanism between HPV, inverted papilloma, and squamous cell carcinoma. PMID- 28620640 TI - Solitary Fibrous Tumor of Retromolar Pad; a Rare Challenging Case. AB - Solitary fibrous tumor has a wide spectrum of histopathologic features and many tumors show similar microscopic features. This similarity poses diagnostic challenges to the pathologists and immunohistochemical analysis is required in many cases. Moreover, it is a rare entity in orofacial region which consequently would make its diagnosis more challenging in oral cavity. The knowledge of various microscopic patterns of this tumor contributes to a proper diagnosis and prevents unnecessary treatment. This study reports a case of solitary fibrous tumor in the retromolar pad area and discusses its various histological features and differential diagnoses. PMID- 28620641 TI - A Rare Condition of Bimaxillary Primary Molar Taurodontism. AB - Taurodontism is a relatively rare variance with a very low incidence in primary dentition and only a few cases have been reported in the literature. It stands a challenge when these teeth require pulp therapy. This case report illustrates the oral rehabilitation of multiple primary molars with taurodontism involving both the maxillary and mandibular arches, which is a rare occurrence. PMID- 28620642 TI - Early Intervention With Live Donor Liver Transplantation Reduces Resource Utilization in NASH: The Toronto Experience. AB - BACKGROUND: In parallel with the obesity epidemic, liver transplantation for nonalcoholic steatohepatitis (NASH) is increasing dramatically in North America. Although survival outcomes are similar to other etiologies, liver transplantation in the NASH population has been associated with significantly increased resource utilization. We sought to compare outcomes between live donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) at a high volume North American transplant center, with a particular focus on resource utilization. METHODS: The study population consists of primary liver transplants performed for NASH at Toronto General Hospital from 2000 to 2014. Recipient characteristics, perioperative outcomes, graft and patient survivals, and resource utilization were compared for LDLT versus DDLT. RESULTS: A total of 176 patients were included in the study (48 LDLT vs 128 DDLT). LDLT recipients had a lower model for end-stage liver disease score and were less frequently hospitalized prior to transplant. Estimated blood loss and early markers of graft injury were lower for LDLT. LDLT recipients had a significantly shorter hospitalization (intensive care unit, postoperative, and total hospitalization). CONCLUSIONS: LDLT for NASH facilitates transplantation of patients at a less severe stage of disease, which appears to promote a faster postoperative recovery with less resource utilization. PMID- 28620643 TI - Activin Biology After Lung Transplantation. AB - BACKGROUND: Activins A and B, members of the TGF-beta superfamily, are produced as part of the physiological response to tissue damage and the resulting proinflammatory response. Given that lung allograft reperfusion results in an inflammatory response, it is likely that the activins and their binding protein follistatin will form part of the regulatory response. There is a need to document the response of these proteins to allograft reperfusion to determine if there is a role for the use of follistatin to control the biological actions of the activins because some of these are potentially damaging. METHODS: Serum from 48 consecutive patients undergoing lung transplantation (LTx) was collected at 2, 6, 12, and 26 weeks post-LTx. The serum levels of activin A and B and follistatin were measured by enzyme-linked immunosorbent assay and specific radioimmunoassays and compared with clinical events. RESULTS: Serum activin A and B levels were at the upper limit of the normal ranges at 2 weeks post-LTx decreasing thereafter to 12 weeks post-LTx (P < 0.05). In contrast, serum follistatin levels were unchanged between 2 and 12 weeks, with a late significant increase at 24 week post-LTx (P < 0.01). Patients with primary graft dysfunction had lower serum follistatin levels (7.7 vs 9.5 ng/mL; P = 0.04) and a higher activin A/follistatin ratio (13.1 vs 10.4; P = 0.02) at 2 weeks post-LTx. CONCLUSIONS: Activin and follistatin levels vary with time form LTX and reflect a proinflammatory environment. Future studies will elucidate associations with chronic lung allograft dysfunction and the therapeutic potential of exogenous follistatin administration. PMID- 28620644 TI - Topical Application of Mesenchymal Stromal Cells Ameliorated Liver Parenchyma Damage After Ischemia-Reperfusion Injury in an Animal Model. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is commonly encountered after liver surgery. This study evaluated the hepatoprotective effects of topically applied adipose-derived mesenchymal stromal cells (ADMSCs) on hepatic IRI in a rat model. METHODS: ADMSCs from transgenic green fluorescent protein Sprague-Dawley rats were topically applied to the liver surface of Sprague-Dawley rats after hepatic IRI and fixed in position by fibrin glue (group A, n = 24). An equivalent amount of ADMSCs were administered through the portal (group B, n = 24) or tail vein (group C, n = 24). In the control group (group D, n = 20), no treatment was given to the IRI liver. RESULTS: All the rats in group A and group D survived. Within 2 days after hepatic IRI, only 50% of rats survived in group B, and ADMSCs were detected in thromboemboli within large vessels. 62.5% of the rats died in group C because most of the ADMSCs were trapped in the lungs. ADMSCs migrated across the liver capsule and homed to the injured liver parenchyma 3 days after topical application in group A. The homed ADMSCs expressed hepatocyte nuclear factor 4alpha and hepatocyte nuclear factor-1. Compared with group D, the rate of hepatic regeneration in group A was enhanced with less inflammation, smaller necrotic areas, and improved liver function. Proinflammatory cytokines IL-6, IL 21, and CD70 were significantly downregulated in group A by 6.3-, 2.7-, and 12.7 fold, respectively (P < 0.05). The neurogenic locus NOTCH homolog protein pathway was activated in the topical ADMSCs. CONCLUSIONS: Topically applied adipose derived mesenchymal stromal cells demonstrated hepatoprotective effects on hepatic IRI in an animal model. PMID- 28620645 TI - Alloimmunity But Not Viral Immunity Promotes Allograft Loss in a Mouse Model of Polyomavirus-Associated Allograft Injury. AB - BACKGROUND: The interplay between viral infection and alloimmunity is known to influence the fate of transplanted organs. Clarifying how local virus-associated inflammation/injury and antiviral immunity can alter host alloimmune responses in transplantation remains a critical question. METHODS: We used a mouse model of polyomavirus (PyV) infection and kidney transplantation to investigate the roles of direct viral pathology, the antiviral immune response, and alloimmunity in the pathogenesis of PyV-associated allograft injury. We have previously shown that an effective primary T cell response is required in PyV-associated graft injury. RESULTS: Here we show that the transfer of primed antidonor, but not antiviral, T cells results in PyV-associated allograft injury. In further studies, we use a surrogate minor antigen model (ovalbumin) and show that only antidonor specific T cells and not antiviral specific T cells are sufficient to mediate injury. Lastly, we demonstrate that local but not systemic virus-mediated inflammation and injury within the graft itself are required. CONCLUSIONS: These data suggest that in this mouse model, the predominant mechanism of allograft injury in PyV associated injury is due to an augmented alloimmune T cell response driven by virus-induced inflammation/injury within the graft. These studies highlight the important interplay between viral infection and alloimmunity in a model system. PMID- 28620646 TI - Kidney Transplant Recipients' Perspectives on Cardiovascular Disease and Related Risk Factors After Transplantation: A Qualitative Study. AB - BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality among kidney transplant recipients (KTRs). These patients have a high prevalence of risk factors, such as hypertension, diabetes, and dyslipidemia. Despite regular medical care, few of them reach the recommended therapeutic targets. The objective of this study is to describe KTRs' perspectives on CVD and related risk factors, as well as their priorities for posttransplant care. METHODS: Twenty-six KTRs participated in a semistructured interview about their personal experience and offered their perspectives on CVD risk factors posttransplant. The interview was digitally recorded and the transcripts were analyzed using a thematic and content methodology. RESULTS: CVD and related risk factors appear to be underestimated and trivialized. Only 2 of 26 patients identified CVD prevention and treatment as a priority. The most important posttransplant priorities identified by patients were related to immunosuppressive drugs (13 of 26), posttransplant follow-up (10) and graft survival (9). However, 21 of 26 patients stated they wanted to be better informed about posttransplant CVD risk factors. CONCLUSIONS: CVD and related risk factors are not a priority for KTRs, and the importance of CVD is underestimated and trivialized. KTRs did recommend that tailored information be provided by various professionals and at several points in the transplantation process. This knowledge will help us develop a new approach to increase awareness of posttransplant CVD and related risk factors. PMID- 28620647 TI - The Effect and Safety of Prostaglandin Administration in Pediatric Liver Transplantation. AB - BACKGROUND: Prostaglandins are often administered after liver transplantation (LT) to diminish ischemia-reperfusion injury (IRI), to favor liver recovery and to prevent vascular thrombosis. Possible beneficial effects in adult liver recipients are controversial, but the single existing pediatric small case series shows no significant impact of prostaglandin administration after LT. The purpose of this study was to analyze the effect of the prostaglandin dinoprostone in pediatric liver recipients. METHODS: A retrospective analysis of 41 children (<16 years) who underwent LT between March 2008 and December 2013 was performed. Dinoprostone was administered at a rate from 0.1 to a maximum of 0.6 MUg/kg per hour immediately after LT and for a maximum of 5 days. Effect of dinoprostone on post-LT IRI and hepatic function up to 60 postoperative days and number of hypotensive episodes were analyzed. RESULTS: The median cumulative dose of dinoprostone was 28 MUg/kg (interquartile range, 23.2). Dinoprostone had no significant effect on post-LT liver function tests and factor V levels at any of the administered dosages. There was no significant association between the total quantity of vasopressor given and the number of hypotensive episodes observed in 8 patients. One patient showed a short-lasting hypotension, possibly related to the administration of dinoprostone. CONCLUSIONS: This study did not show, at any dosage between 0.1 and 0.6 MUg/kg per hour, any differences in beneficial or harmful effects of high- or low-dose dinoprostone administered immediately after pediatric LT on markers of IRI, hepatic function, or hypotension. PMID- 28620648 TI - Effect of Fc-gamma Receptor Polymorphism on Rituximab-Mediated B Cell Depletion in ABO-Incompatible Adult Living Donor Liver Transplantation. AB - BACKGROUND: The affinity of IgG Fc receptor (FcgammaR) for rituximab, an anti CD20 IgG1, differs based on single-nucleotide polymorphisms (SNPs) in FcgammaRs. This study aimed to explore the effect of such SNPs on clinical response to rituximab and outcomes in patients of ABO-incompatible (ABOi) living donor liver transplantation (LDLT). METHODS: SNPs of FCGR2A[131H/R] and FCGR3A[158F/V], alleles encoding FcgammaR, were identified in 20 patients desensitized with rituximab before ABOi LDLT. The effect of these SNPs on B cell elimination and outcomes was analyzed in the patients. RESULTS: The isoform encoded by FCGR2A[131H/H] had a higher affinity for IgG1, and accordingly, the effects of rituximab on B cells were more profound in individuals with FCGR2A[131H/H] than in individuals with FCGR2A[131H/R or R/R]. Specifically, the time to B-cell reappearance in the peripheral blood was significantly delayed, and total serum IgM levels were significantly lower early after LDLT in individuals with FCGR2A[131H/H], even though these SNPs did not significantly affect the reduction of antiblood group A/B antibodies. The incidence of blood stream infection was also significantly higher in individuals with FCGR2A[131H/H], and this SNP was associated with poor prognosis. Despite no significant effect of FCGR3A[158F/V] on survival after ABOi liver grafts, the incidence of infection was significantly higher in individuals with FCGR3A[158F/V or F/F] than in individuals with FCGR3A[158V/V]. CONCLUSIONS: Our findings indicate FCGR SNPs influence the effect of rituximab on B-cell depletion and are possibly predisposing factors for infectious complications after ABOi LDLT. This study will be a good foundation for further studies on larger cohorts. PMID- 28620649 TI - Hepatoblastoma: Transplant Versus Resection Experience in a Latin American Transplant Center. AB - BACKGROUND: Hepatoblastoma is the most common primary malignant liver tumor in children and is usually diagnosed during the first 3 years of life. Overall survival has increased 50% due to chemotherapeutic schemes, expertise surgery centers, and liver transplantation. METHODS: A retrospective collection of data was performed from pediatric patients with diagnosis of hepatoblastoma. Variables included demographic, diagnostic tools and histological classification; chemotherapy and surgical treatment; and outcomes and patient survival. The PRETEXT classification was applied, which included the risk evaluation, and according to the medical criterion in an individualized way, underwent resection or transplant. The morbidity of patients was evaluated by the Clavien-Dindo classification. Statistical analysis was performed according to the distribution of data and the survival analysis was carried out using the Kaplan-Meier method. RESULTS: The patients (n = 16) were divided in a resection group (n = 8) and a transplant group (n = 8). The median age at the time of diagnosis was 13.5 months. The motive for the initial consultation was the discovery of a mass; all patients had high levels of alpha-fetoprotein and an imaging study. Ten of 16 patients required chemotherapy before the surgical procedure. In the resection group, 5 of 8 patients were classified as Clavien I and 4 of 8 patients of the transplant group were classified as Clavien II. Patient survival at 30 months was 100% in the resection group and 65% in the liver transplantation group. CONCLUSIONS: To our knowledge, this is the first case report of pediatric patients with hepatoblastoma and liver resection or transplant in Colombia and Latin America. Our results are comparable with the series worldwide, showing that resection and transplant increase the survival of the pediatric patients with hepatoblastoma. It is important to advocate for an increase of reporting in the scientific literature in Latin America. PMID- 28620650 TI - Graft Function and Intermediate-Term Outcomes of Kidney Transplants Improved in the Last Decade: Analysis of the United States Kidney Transplant Database. AB - BACKGROUND: Previous analyses of the United States transplant database regarding long-term outcomes in kidney transplantation have shown minimal improvement in the rate of long-term graft loss. This study sought to analyze intermediate-term outcomes and graft function at 6 months in kidney transplantation in adult living and deceased donor recipients in the last decade. METHODS: Survival analysis was performed based on the year of transplant between 6 months and 3 years' posttransplant. The Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate (eGFR) was determined at 6 months. RESULTS: The unadjusted graft survival between 6 months and 3 years improved significantly in the latter half of the decade in both deceased and living donor kidney recipients. Cox analysis showed a 33% reduction in the rate of graft loss and that the improvement in graft survival was due to similar improvements in both death-censored graft and death with graft function survival. A 10% improvement in median eGFR occurred despite worsening donor demographics over time in both donor types. This improvement in eGFR and graft survival occurred in association with a consolidation of chronic discharge immunosuppression from a variety of combinations to over 85% of recipients receiving tacrolimus and mycophenolate derivative immunosuppression. CONCLUSIONS: In the latter half of last decade graft survival improved in adult kidney transplant recipients. The improvement in graft survival occurred in temporal association with an improvement in median eGFR at 6 months and consolidation of discharge immunosuppression in most patients to tacrolimus and mycophenolate derivatives. PMID- 28620651 TI - Role of an adenylyl cyclase isoform in ethanol's effect on cAMP regulated gene expression in NIH 3T3 cells. AB - Previous research has indicated that the cyclic AMP (cAMP) signal transduction system plays an important role in the predisposition to and development of ethanol abuse in humans. Our laboratory has demonstrated that ethanol is capable of enhancing adenylyl cyclase (AC) activity. This effect is AC isoform-specific; type 7 AC (AC7) is most enhanced by ethanol. Therefore, we hypothesized that the expression of a specific AC isoform will play a role on the effect of ethanol on cAMP regulated gene expression. We employed NIH 3T3 cells transfected with AC7 or AC3 as a model system. To evaluate ethanol's effects on cAMP regulated gene expression, a luciferase reporter gene driven by a cAMP inducing artificial promoter was utilized. Stimulation of AC activity leads to an increase in the reporter gene activity. This increase was enhanced in the presence of ethanol in cells expressing AC7, while cells expressing AC3 did not respond to ethanol. cAMP reporter gene expression was increased in the presence of 8-bromo-cAMP; this expression was not enhanced by ethanol. These observations are consistent with our hypothesis. The basal level of CREB phosphorylation was high and did not change by cAMP stimulation or in the presence of ethanol. However, there were significant changes in the TORC3 amount in nuclei depending on stimulation conditions. The results suggest that nuclear translocation of TORC3 plays a more important role than CREB phosphorylation in the observed changes in the cAMP driven reporter gene activity. PMID- 28620652 TI - Visual and Morphologic Outcomes in Eyes with Hard Exudate in the Comparison of Age-Related Macular Degeneration Treatments Trials. AB - PURPOSE: To compare baseline characteristics, visual acuity (VA) and morphological outcomes between eyes with baseline hard exudates (HE) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factors (anti-VEGF). DESIGN: Prospective cohort study within the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). PARTICIPANTS: Patients with NVAMD. METHODS: Readers evaluated baseline and follow-up morphology on digital color images, fluorescein angiography (FA), and optical coherence tomography (OCT) in eyes with NVAMD that were randomly assigned to treatment with either ranibizumab or bevacizumab. Ophthalmologists identified HE on color images in the study eye. MAIN OUTCOME MEASURES: VA; scar; geographic atrophy; retinal thickness, fluid; and number of anti-VEGF injections. RESULTS: HE was present in 128 of 1185 (11%) study eyes at baseline, 77% within 1 disc diameter of the foveal center. Patients with study eye HE were more likely female (81% vs 60%; p<0.001) and non-smokers (53% vs 42%; p=0.004). Both groups had similar proportions of hypercholesterolemia and hypertriglyceridemia. At baseline, eyes with HE had worse VA (mean 57 vs 61 letters; p=0.003), larger total lesion size (3.3 vs 2.4 DA; p <0.001), greater total foveal thickness (522um vs 452um; p<0.001), more retinal angiomatous proliferation (18% vs 10%; p=0.009) and sub-RPE fluid (65% vs 47%; p<0.001). At 1 year, VA was similar in both groups; more eyes with baseline HE had no fluid (45% vs 29%; p<0.001) and greater reduction in total foveal thickness (-266um vs -158u; p<0.001). VA at year 2 was similar but retinas of eyes with baseline HE were thinner (267um vs 299um; p=0.03) and fewer eyes had sub-retinal fluid (23% vs 36%; p=0.008). HE was present in 19% of eyes at 1 year and 5% of eyes at 2 years. LIPC promoter SNP rs10468017 was not associated with NVAMD HE. CONCLUSION: Eyes with HE have larger CNV lesions and more RAP. Their initially thicker retina rapidly becomes thinner on anti-VEGF treatment. HE is not significantly associated with hyperlipidemia. HE at baseline does not significantly influence VA, scar and GA outcomes in eyes with NVAMD treated with anti-VEGF. Few eyes have HE at year 2. PMID- 28620653 TI - Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells. AB - T follicular helper (Tfh) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTfh, have similarity to lymphoid Tfh, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTfh respond in an antigen-specific manner and whether they form long-lasting memory. Here, we identified a cTfh population that expressed multiple T cell activation markers and could be readily identified by coexpression of ICOS and CD38. This subset expressed more Bcl-6, c-Maf, and IL-21 than other blood CD4 subsets. Influenza vaccination induced a strong response in the ICOS+CD38+ cTfh at day 7, and this population included hemagglutinin-specific cells by tetramer staining and antigen-stimulated Activation Induced Marker (AIM) expression. Moreover, TCRB sequencing identified a clonal response in ICOS+CD38+ cTfh that correlated strongly with the increased circulating ICOS+CD38+ cTfh frequency and the circulating plasmablast response. In subjects who received successive annual vaccinations, a recurrent oligoclonal response was identified in the ICOS+CD38+ cTfh subset at 7 days after every vaccination. These oligoclonal responses in ICOS+CD38+ cTfh after vaccination persisted in the ICOS-CD38- cTfh repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more stable ICOS-CD38- cTfh subset. These data highlight the antigen-specificity, lineage relationships and memory properties of human cTfh responses to vaccination, providing new avenues for tracking and monitoring cTfh responses during infection and vaccination in humans. PMID- 28620655 TI - A Commentary on Attitudes Towards Deep Brain Stimulation for Addiction. AB - Deep brain stimulation (DBS) has proven to be an effective treatment for neurologic disorders such as Parkinson's disease, and is currently being investigated as a therapy for psychiatric diseases such as addiction, major depressive disorder, and obsessive compulsive disorder. In this commentary, we review and discuss the findings presented in the Letter to the Editor entitled "Attitudes towards treating addiction with deep brain stimulation," written by Ali et al1. The survey presented in this Letter reported general approval for examining the effects of DBS on addictive disorders in a clinical trial, but highlighted critical areas of concern including informed consent, patient autonomy, appropriate medical practice, passing of clinical trial milestones, and implications on law enforcement. PMID- 28620656 TI - Oxidative T Cell Modifications in Lupus and Sjogren's Syndrome. AB - OBJECTIVES: Lupus flares are triggered by environmental agents that cause oxidative stress, but the mechanisms involved are unclear. The flares are characterized by oxidative modifications of proteins by 4-hydroxynonenals, malondialdehydes, carbonyls and nitration. These modifications have been proposed to induce and perpetuate lupus flares by "altered self" mechanisms. An epigenetically altered CD4+CD28+ T cell subset, caused at least in part by nitration of T cell signaling molecules, is found in patients with active lupus, and nitrated T cells are sufficient to cause lupus-like autoimmunity in animal models. The relation of protein 4-hydroxynonenals, malondialdehydes, carbonyls and nitration to lupus flares though, is unknown. We tested if the size of the epigenetically altered subset is related to disease activity and one or more of these oxidative modifications in lupus patients. We also tested the relationship between subset size, disease activity and the same oxidative modifications in Sjogren's syndrome, another autoimmune disease also associated with oxidative stress and characterized by anti-nuclear antibodies and the presence of the subset. METHODS: Lupus flare severity was quantitated using the Systemic Lupus Erythematosus Disease Activity Index, and Sjogren's flare severity using the European Sjogren's Syndrome Disease Activity Index. Subset size was determined by flow cytometry. Protein modifications were determined by ELISA. RESULTS: Only protein nitration correlated with the size of the subset in lupus and Sjogren's syndrome. CONCLUSIONS: These results support a role for protein nitration in subset size and lupus flare severity. Protein nitration may also contribute to autoantibody formation in Sjogren's syndrome. PMID- 28620654 TI - Insights into the Brain: Neuroimaging of Brain Development and Maturation. AB - The study of how the human brain develops has always been a challenge and an interest to the scientific community. In recent years, new evidence has suggested that many neuropsychiatric disorders may originate from aberrations early in development. This discovery necessitates the application of methodologies that make possible the investigation of human brain development in vivo and across the lifespan. In this commentary, we present evidence that the advent of structural neuroimaging has specifically and significantly contributed critical information about the developmental trajectories of postnatal human brain development that would otherwise not have been possible. We believe that this is particularly relevant to present day research as it has become increasingly clear that growth trajectories within the brain might serve as an endophenotype for a number of factors, ranging from IQ to psychiatric illness. We highlight seminal early works that helped to jumpstart the field of developmental neuroimaging and which inspired incredible new advances in neuroimaging methodologies that are being developed and applied in the field today. PMID- 28620657 TI - Exfoliation of two-dimensional zeolites in liquid polybutadienes. AB - Layered zeolite precursors were successfully exfoliated by brief shearing or sonication with the assistance of commercially available telechelic liquid polybutadienes at room temperature. The exfoliated zeolite nanosheets can form a stable suspension in an organic solvent, providing exciting potential for the fabrication of zeolite membranes, composite materials and hierarchical zeolites. PMID- 28620658 TI - Band gap modulation of SrTiO3 upon CO2 adsorption. AB - Herein, CO2 chemisorption on SrTiO3(001) surfaces is studied using ab initio calculations to establish new chemical sensing mechanisms. It was found that CO2 adsorption opens the band gap of the material. However, the mechanisms are different: the CO2 adsorption on the TiO2-terminated surface neutralizes the surface states at the valence band (VB) maximum, whereas for the SrO-terminated surface it suppresses the conduction band (CB) minimum. For the TiO2-terminated surface, the effect is explained by the passivation of dangling bonds, whereas for the SrO-terminated surface, the suppression is caused by surface relaxation. Modulation of the VB states implies a more direct change in charge distribution, and thus, the induced change in the band gap is more prominent at the TiO2 termination. Further, it has been shown that both CO2 adsorption energy and surface band gap are strongly dependent on CO2 coverage, suggesting that the observed effect can be utilized in sensing applications for a wide range of CO2 concentrations. PMID- 28620659 TI - Regioselective addition of C(sp3)-H bonds of alkyl pyridines to olefins catalysed by cationic zirconium complexes. AB - In situ generated cationic zirconium complexes stabilized by amine-bridged bis(phenolato) ligands have been developed to catalyse C(sp3)-H addition of alkyl pyridines to olefins, which are the first examples of group 4 metal based catalysts in this transformation. Ligand-controlled regioselectivity was observed, which was verified by DFT study. PMID- 28620660 TI - Carpatizine, a novel bridged oxazine derivative generated by non-enzymatic reactions. AB - Carpatizine (1), a new bridged oxazine derivative, was isolated from a marine derived Streptomyces strain SNE-011. The structure was fully determined by spectroscopic analysis, ECD calculations and chemical methods. A plausible non enzymatic reaction mechanism from daryamide D leading to carpatizine was presented, which was confirmed by chemical transformation. PMID- 28620662 TI - Hexagonal boron nitride nanosheets as a multifunctional background-free matrix to detect small molecules and complicated samples by MALDI mass spectrometry. AB - Here we report the innovation of using hexagonal boron nitride (h-BN) nanosheets as the first background-free matrix among the full laser pulse energy range for the analysis and imaging of small molecule metabolites and as an adsorbent for the enrichment of samples. Due to its totally free background and high efficiency as an adsorbent and matrix, h-BN has promising prospects in metabolomics, MALDI imaging, and environmental analysis. PMID- 28620663 TI - Reductive dissolution of supergrowth carbon nanotubes for tougher nanocomposites by reactive coagulation spinning. AB - Long single-walled carbon nanotubes, with lengths >10 MUm, can be spontaneously dissolved by stirring in a sodium naphthalide N,N-dimethylacetamide solution, yielding solutions of individualised nanotubide ions at concentrations up to 0.74 mg mL-1. This process was directly compared to ultrasonication and found to be less damaging while maintaining greater intrinsic length, with increased individualisation, yield, and concentration. Nanotubide solutions were spun into fibres using a new reactive coagulation process, which covalently grafts a poly(vinyl chloride) matrix to the nanotubes directly at the point of fibre formation. The grafting process insulated the nanotubes electrically, significantly enhancing the dielectric constant to 340% of the bulk polymer. For comparison, samples were prepared using both Supergrowth nanotubes and conventional shorter commercial single-walled carbon nanotubes. The resulting nanocomposites showed similar, high loadings (ca. 20 wt%), but the fibres formed with Supergrowth nanotubes showed significantly greater failure strain (up to ~25%), and hence more than double the toughness (30.8 MJ m-3), compared to composites containing typical ~1 MUm SWCNTs. PMID- 28620661 TI - BRUTUS and its paralogs, BTS LIKE1 and BTS LIKE2, encode important negative regulators of the iron deficiency response in Arabidopsis thaliana. AB - Iron (Fe) is required for plant health, but it can also be toxic when present in excess. Therefore, Fe levels must be tightly controlled. The Arabidopsis thaliana E3 ligase BRUTUS (BTS) is involved in the negative regulation of the Fe deficiency response and we show here that the two A. thaliana BTS paralogs, BTS LIKE1 (BTSL1) and BTS LIKE2 (BTSL2) encode proteins that act redundantly as negative regulators of the Fe deficiency response. Loss of both of these E3 ligases enhances tolerance to Fe deficiency. We further generated a triple mutant with loss of both BTS paralogs and a partial loss of BTS expression that exhibits even greater tolerance to Fe-deficient conditions and increased Fe accumulation without any resulting Fe toxicity effects. Finally, we identified a mutant carrying a novel missense mutation of BTS that exhibits an Fe deficiency response in the root when grown under both Fe-deficient and Fe-sufficient conditions, leading to Fe toxicity when plants are grown under Fe-sufficient conditions. PMID- 28620664 TI - Development of an RNA aptamer that acquires binding capacity against HIV-1 Tat protein via G-quadruplex formation in response to potassium ions. AB - For the development of K+-responsive RNA aptamers, we proposed a new general strategy that makes use of a G-quadruplex formation in response to K+. This is the first report of developing an RNA aptamer that demonstrates ON/OFF switching of its target-binding activity by sensing the addition/removal of K+. PMID- 28620666 TI - Exfoliation of a two-dimensional cationic inorganic network as a new paradigm for high-capacity CrVI-anion capture. AB - We have discovered a rare example of a non-LDH cationic inorganic layered material [Cu4(OH)6][O3S(CH2)4SO3]. Its in situ exfoliation achieves record high adsorption capacities for chromate and dichromate. This phenomenon is ascribed to the combination of the strong host-anion electrostatic interactions and the high surface area of our cuprate material, which overcomes the memory effect problem of LDHs. Moreover, our material also selectively captures CrVI with a negligible decrease in capacity when non-toxic, monovalent anions are present. PMID- 28620667 TI - Amorphous-amorphous transition in a porous coordination polymer. AB - The amorphous state plays a key role in porous coordination polymer and metal organic framework phase transitions. We investigate a crystalline-to-amorphous-to amorphous-to-crystalline (CAAC) phase transition in a Zn based coordination polymer, by X-ray absorption fine structure (XAFS) and X-ray pair distribution function (PDF) analysis. We show that the system shows two distinct amorphous phases upon heating. The first involves a reversible transition to a desolvated form of the original network, followed by an irreversible transition to an intermediate phase which has elongated Zn-I bonds. PMID- 28620668 TI - Nanoscale spectroscopic and mechanical characterization of individual aerosol particles using peak force infrared microscopy. AB - Atmospheric aerosol particles of sizes less than 2.5 microns affect public health in cities. Understanding the fine structures of aerosol particles is important to decipher their source. Here, we use a novel spectroscopic and mechanical microscopy technique of 10 nm spatial resolution to reveal the nanoscale structures of individual aerosol particles. PMID- 28620665 TI - Influence of iron metabolism on manganese transport and toxicity. AB - Although manganese (Mn) is critical for the proper functioning of various metabolic enzymes and cofactors, excess Mn in the brain causes neurotoxicity. While the exact transport mechanism of Mn has not been fully understood, several importers and exporters for Mn have been identified over the past decade. In addition to Mn-specific transporters, it has been demonstrated that iron transporters can mediate Mn transport in the brain and peripheral tissues. However, while the expression of iron transporters is regulated by body iron stores, whether or not disorders of iron metabolism modify Mn homeostasis has not been systematically discussed. The present review will provide an update on the role of altered iron status in the transport and toxicity of Mn. PMID- 28620669 TI - Linear and orthogonal peptide templating of silicified protein fibres. AB - Biomineralisation is essential for biology. Specialist proteins use peptide motifs that catalyse mineral deposition into nano-to-microscale inorganic materials. Unlike in native proteins, the motifs incorporated into self-assembled fibres can persistently propagate on the microscopic scale enabling empirically defined silica nanostructures. Herein we show that the two main modes of motif templating - linear and orthogonal - in self-assembling, fibre-forming peptide sequences effectively silicify protein fibres. We show that the mere charge and morphology of protein fibres are not sufficient for silica deposition, but it is the synergy between fibrillogenesis and silica-specific motifs regularly spaced in fibres that ensures silica templating, regardless of the relative orientation of the motifs. PMID- 28620670 TI - Pesticide vapor sensing using an aptamer, nanopore, and agarose gel on a chip. AB - A pesticide vapor sensor was developed using an agarose gel-based chip containing a nanopore sensing system. Vaporized omethoate was detected by the absorption into the gel, the complex formation with a DNA aptamer, and its obstruction at the nanopore. This strategy is applicable to other vapors, expanding the versatility of nanopore sensors. PMID- 28620672 TI - Re: Tarazona et al. (2017): Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC. doi: 10.1007/s00204-017-1962-5. PMID- 28620671 TI - An oligodeoxynucleotide with AAAG repeats significantly attenuates burn-induced systemic inflammatory responses via inhibiting interferon regulatory factor 5 pathway. AB - Previously, we showed that an oligodeoxynucleotide with AAAG repeats (AAAG ODN) rescued mice from fatal acute lung injury (ALI) induced by influenza virus and inhibited production of tumor necrosis factor-alpha (TNF-alpha) in the injured lungs. However, the underlying mechanisms remain to be elucidated. Upon the bioinformatic analysis revealing that the AAAG ODN is consensus to interferon regulatory factor 5 (IRF5) binding site in the cis-regulatory elements of proinflammatory cytokines, we tried to explore whether the AAAG ODN could attenuate burn injury induced systemic inflammatory responses via inhibiting IRF5 pathway. Using the mouse model with sterile systemic inflammation induced by burn injury, we found that AAAG ODN prolonged the life span of the mice, decreased the expression of IRF5 at injured skin, reduced the production of TNF-alpha and IL-6 in blood and injured skin, and attenuated the ALI. Furthermore, AAAG ODN could bind IRF5 and inhibit the nuclear translocation of IRF5 in THP-1 cells. The data suggested that the AAAG ODN could act as a cytoplasmic decoy capable of interfering the function of IRF5, and be developed as a drug candidate for the treatment of inflammatory diseases. PMID- 28620673 TI - First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans. AB - Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular proteins to generate pyrrole-protein adducts, leading to hepatotoxicity. PA N-oxides coexist with their corresponding PAs in plants with varied quantities, sometimes even higher than that of PAs, but the toxicity of PA N-oxides remains unclear. The current study unequivocally identified PA N-oxides as the sole or predominant form of PAs in 18 Gynura segetum herbal samples ingested by patients with liver damage. For the first time, PA N-oxides were recorded to induce HSOS in human. PA N-oxide-induced hepatotoxicity was further confirmed on mice orally dosed of herbal extract containing 170 MUmol PA N-oxides/kg/day, with its hepatotoxicity similar to but potency much lower than the corresponding PAs. Furthermore, toxicokinetic study after a single oral dose of senecionine N-oxide (55 MUmol/kg) on rats revealed the toxic mechanism that PA N-oxides induced hepatotoxicity via their biotransformation to the corresponding PAs followed by the metabolic activation to form pyrrole-protein adducts. The remarkable differences in toxicokinetic profiles of PAs and PA N-oxides were found and attributed to their significantly different hepatotoxic potency. The findings of PA N-oxide-induced hepatotoxicity in humans and rodents suggested that the contents of both PAs and PA N-oxides present in herbs and foods should be regulated and controlled in use. PMID- 28620674 TI - Organ Dysfunction and Failure Following Brain Death Do Not Preclude Successful Donation. AB - BACKGROUND: Organ dysfunction is common after neurologic determination of death (NDD) but before organ collection. Reliable markers for graft success following transplant of these organs would be useful. We sought to determine the relationship between the donor after neurologic determination of death (DNDD) pathophysiology and successful organ donation. METHODS: Donor information was obtained through the local organ procurement organization. Donor demographics and clinical data points for cardiovascular, renal, respiratory, hepatic, hematological and neuroendocrine systems were reviewed 12 h before and 12 h after neurologic determination of death was declared. The worst values were utilized for analysis and generation of the organ-specific Sequential Organ Failure Assessment (SOFA) scores. SOFA scores were calculated and used to quantify the degree of organ dysfunction. The NDD non-donors for a specific organ were used as a comparison control group. The control group refers to DNDD patients whose specific organs were not transplanted. Lack of use was mostly due to discard by the transplant team as a result of unsuitability of the organ caused by deterioration or possible donor-specific pathology. RESULTS: One hundred and five organ donors were analyzed. Mean age was 35.0 (+/- 13.6), 78.1% male, median GCS 3, interquartile range (IQR) 3-4 and median injury severity score 32 (IQR 25-43). Of the successful donors, organ-specific severe dysfunction (SOFA 3 or 4) occurred in 96, 27.5 and 3.3% of cardiac, lung and liver donors, respectively. There was no significant difference between the levels of organ dysfunction in donors versus non-donors except lung donors, in which the median lowest partial pressure of arterial oxygen-to-fraction of inspired oxygen (P/F) ratio in the non donor was 194 (IQR 121.8-308.3) compared to the median lowest P/F ratio in the donor which was 287 (IQR 180-383.5), p = 0.02. In the recipients, graft failure 6 months after transplantation was reported in one kidney recipient (0.74%) (peak donor creatinine = 1 mg/dL) and in five pancreas recipients (11.4%). The median peak glucose of the pancreas donors in failed recipients was 178 mg/dL (IQR 157 213), whereas in the functioning recipients, the median glucose of their donors was not different (185 mg/dL, IQR 157-216), p = 0.394. CONCLUSION: Current measures of organ failure and dysfunction do not predict the success of organ donation. Successful donor management in the face of severe organ dysfunction and failure can result in lives saved. PMID- 28620675 TI - Sphincter-Preserving Surgery for Low Rectal Cancers: Incidence and Risk Factors for Permanent Stoma. AB - BACKGROUND: Advances in surgical techniques and paradigm changes in rectal cancer treatment have led to a drastic decline in the abdominoperineal resection rate, and sphincter-preserving operation is possible in distal rectal cancer. OBJECTIVE: The aim of this study is to evaluate the long-term incidence of permanent stoma after sphincter-preserving surgery for low rectal cancer and its corresponding risk factors. METHOD: From 2000 to 2014, patients who underwent sphincter-preserving low anterior resection for low rectal cancer (within 5 cm from the anal verge) were included. The occurrence of permanent stoma over time and its risk factors were investigated by using a Cox proportional hazards regression model. RESULTS: This study included 194 patients who underwent ultra low anterior resection for distal rectal cancer, and the median follow-up period was 77 months for the surviving patients. Forty-six (23.7%) patients required a permanent stoma eventfully. Anastomotic-related complications and disease progression were the main reasons for permanent stoma. Clinical anastomotic leakage (HR 5.72; 95% CI 2.31-14.12; p < 0.001) and neoadjuvant chemoradiation (HR 2.34; 95% CI 1.12-4.90; p = 0.024) were predictors for permanent primary stoma. Local recurrence (HR 16.09; 95% CI 5.88-44.03; p < 0.001) and T4 disease (HR 11.28; 95% CI 2.99-42.49; p < 0.001) were predictors for permanent secondary stoma. The 5- and 10-year cumulative incidence for permanent stoma was 24.1 and 28.0%, respectively. CONCLUSION: Advanced disease, prior chemoradiation, anastomotic leakage and local recurrence predispose patients to permanent stoma should be taken into consideration when contemplating sphincter-preserving surgery. PMID- 28620676 TI - Retrospective Study of the Correlation Between Pathological Tumor Size and Survival After Curative Resection of T3 Pancreatic Adenocarcinoma: Proposal for Reclassification of the Tumor Extending Beyond the Pancreas Based on Tumor Size. AB - BACKGROUND: Even though most patients who undergo resection of pancreatic adenocarcinoma have T3 disease with extra-pancreatic tumor extension, T3 disease is not currently classified by tumor size. The aim of this study was to modify the current TNM classification of pancreatic adenocarcinoma to reflect the influence of tumor size. METHODS: A total of 847 consecutive pancreatectomy patients were recruited from multiple centers. Optimum tumor size cutoff values were calculated by receiver operating characteristics analysis for tumors limited to the pancreas (T1/2) and for T3 tumors. In our modified TNM classification, stage II was divided into stages IIA (T3aN0M0), IIB (T3bN0M0), and IIC (T1 3bN1M0) using tumor size cutoff values. The usefulness of the new classification was compared with that of the current classification using Akaike's information criterion (AIC). RESULTS: The optimum tumor size cutoff value distinguishing T1 and T2 was 2 cm, while T3 was divided into T3a and T3b at a tumor size of 3 cm. The median survival time of the stages IIA, IIB, and IIC were 44.7, 27.6, and 20.3 months, respectively. There were significant differences of survival between stages IIA and IIB (P = 0.02) and between stages IIB and IIC (P = 0.03). The new classification showed better performance compared with the current classification based on the AIC value. CONCLUSIONS: This proposed new TNM classification reflects the influence of tumor size in patients with extra-pancreatic tumor extension (T3 disease), and the classification is useful for predicting mortality. PMID- 28620677 TI - Efficacy of peloid therapy in patients with chronic lateral epicondylitis: a randomized, controlled, single blind study. AB - The aim of this study was to assess the effect of peloid on pain, functionality, daily life activities, and quality of life of lateral epicondylitis (LE) patients. In this randomized, controlled, single-blind study, 75 patients who were diagnosed with chronic LE were enrolled to the study. Patients were randomized into two groups using the random number table. The patients in the first group (group 1) (n = 33), were given lateral epicondylitis band (LEB) (during the day for 6 weeks) + peloid therapy (five consecutive days a week for 2 weeks), and the second group (group 2) (n = 32), received LEB treatment alone. The patients were assessed by using Patient Rated Tennis Elbow Evaluation (PRTEE) and Nottingham Health Profile (NHP). The data were obtained before treatment (W0), immediately after treatment (W2), and 1 month after treatment (W6). In analysis of the collected data, the Wilcoxon signed rank test for intra-group comparisons and Mann-Whitney U test for comparisons between groups were used. Both in groups 1 and 2, there was a statistically significant improvement in all the evaluation parameters at W2 and W6 when compared to W0 (p < 0.05). In comparison of difference scores between groups, although there was no statistically significant difference between the two groups at W2 when compared to W0 (p > 0.05), a statistically significant difference was found in favor of group 1 for all the evaluation parameters at W6 (p < 0.05). Our results have shown that peloid treatment could be effective in providing improvement in pain relief, function, daily life activities, and quality of life in LE patients. PMID- 28620678 TI - Effect of lifestyle improvement program on the biomarkers of adiposity, inflammation and gut hormones in overweight/obese Asian Indians with prediabetes. AB - AIMS: While lifestyle modification is known to offer several metabolic benefits, there is paucity of comprehensive data on changes in biomarkers of adiposity, inflammation as well as gut hormones. We investigated these biomarkers in overweight/obese individuals with prediabetes randomized to either 4 months of a lifestyle improvement program or standard care and followed them up for a year. METHODS: Participants [standard care and intervention arm (n = 75 each)] were randomly selected from the Diabetes Community Lifestyle Improvement Program trial. Glycemic and lipid control and anthropometric measurements were assessed by standard protocols. Adipokines, inflammatory markers and gut hormones were measured using multiplex and standard ELISA kits. RESULTS: Along with modest benefits in primary outcomes (glycemic and lipid control and weight reduction), participants in the intervention group showed significant reductions (p < 0.001) in plasma levels of leptin (17.6%), TNF-alpha (35%), IL-6 (33.3%), MCP-1 (22.3%) and PYY (28.3%) and increased levels of adiponectin (33.1%) and ghrelin (23.6%) at the end of 4 months of lifestyle intervention. The changes were independent of weight and persisted even at 1 year of follow-up. In contrast, participants from the standard care arm did not show any statistically significant improvements on the above parameters. CONCLUSIONS: Participants who underwent an intensive lifestyle improvement program showed metabolic benefits as well as favorable beneficial changes in systemic levels of adipokines, cytokines and gut hormones, not only during the intervention period, but also during 12-month follow-up period. PMID- 28620679 TI - Are Poultry or Wild Birds the Main Reservoirs for Avian Influenza in Bangladesh? AB - Avian influenza viruses (AIV) are of great socioeconomic and health concern, notably in Southeast Asia where highly pathogenic strains, such as highly pathogenic avian influenza (HPAI) H5N1 and other H5 and H7 AIVs, continue to occur. Wild bird migrants are often implicated in the maintenance and spread of AIV. However, little systematic surveillance of wild birds has been conducted in Southeast Asia to evaluate whether the prevalence of AIV in wild birds is higher than in other parts of the world where HPAI outbreaks occur less frequently. Across Bangladesh, we randomly sampled a total of 3585 wild and domestic birds to assess the prevalence of AIV and antibodies against AIV and compared these with prevalence levels found in other endemic and non-endemic countries. Our study showed that both resident and migratory wild birds in Bangladesh do not have a particularly elevated AIV prevalence and AIV sero-prevalence compared to wild birds from regions in the world where H5N1 is not endemic and fewer AIV outbreaks in poultry occur. Like elsewhere, notably wild birds of the orders Anseriformes were identified as the main wild bird reservoir, although we found exceptionally high sero-prevalence in one representative of the order Passeriformes, the house crow (Corvus splendens), importantly living on offal from live bird markets. This finding, together with high sero- and viral prevalence levels of AIV in domestic birds, suggests that wild birds are not at the base of the perpetuation of AIV problems in the local poultry sector, but may easily become victim to AIV spill back from poultry into some species of wild birds, potentially assisting in further spread of the virus. PMID- 28620680 TI - Landscape, Climate and Hantavirus Cardiopulmonary Syndrome Outbreaks. AB - We performed a literature review in order to improve our understanding of how landscape and climate drivers affect HCPS outbreaks. Anthropogenic landscape changes such as forest loss, fragmentation and agricultural land uses are related with a boost in hantavirus reservoir species abundance and hantavirus prevalence in tropical areas, increasing HCPS risk. Additionally, higher precipitation, especially in arid regions, favors an increase in vegetational biomass, which augments the resources for reservoir rodents, also increasing HCPS risk. Although these relationships were observed, few studies described it so far, and the ones that did it are concentrated in few places. To guide future research on this issue, we build a conceptual model relating landscape and climate variables with HCPS outbreaks and identified research opportunities. We point out the need for studies addressing the effects of landscape configuration, temperature and the interaction between climate and landscape variables. Critical landscape thresholds are also highly relevant, once HCPS risk transmission can increase rapidly above a certain degree of landscape degradation. These studies could be relevant to implement preventive measures, creating landscapes that can mitigate disease spread risk. PMID- 28620682 TI - Infectious bursal disease: outbreak investigation, molecular characterization, and vaccine immunogenicity trial in Ethiopia. AB - The study was conducted with the objective of isolation and molecular characterization of infectious bursal disease virus (IBDV) circulating in Ethiopia and to assess the immunogenicity of different commercially available live attenuated IBD vaccines and finally to select the appropriate vaccine strain for the existing IBDV. Outbreak samples collected from different poultry farms with IBD infection between 2013 and 2015 were used for the virus isolation and molecular characterization. IBD vaccine immunogenicity test was conducted using four different commercially available live attenuated IBD vaccine strains: namely D78, B2K, LC75, and EXTREM. Day-old Bowman brown chickens purchased from commercial farm in Debre Zeit were used for the experiment. Serum samples were collected at days 14 and 21 and screened for the presence of maternal IBDv antibodies. The screening test result revealed that most of the chickens from vaccinated progeny were positive at the age of day 14 with mean antibody titer of .42, but declined at day 21 to 0.049 below cut-off point (S/P < 0.3). Chickens were divided into five different groups (four vaccinal and one control) and vaccinated at the age of day 21 and boosted after 14 days. Serum samples were collected and all of them were challenged at their 42 days of age with locally isolated very virulent infectious bursal disease virus (vvIBDV). From four of the vaccine strains used for immunogenicity study, the intermediate plus strains (LC75 and EXTREM) found to be superior and efficiently cross protect against the challenge with locally isolated vvIBDV. The development of clinical signs was studied and post-mortem examinations were conducted both on dead and sacrificed birds. From a total of 25 tissue samples processed for virus isolation on chicken fibroblast cell culture, 95% (18/20) of bursa and 80% (4/5) of the spleen samples showed visible cytopathic effect (CPE). The positive samples were tested by PCR and 19 of them had the expected band (643 bp). Further 11 representative samples were sequenced and confirmed that the circulating virus among poultry population in the country is vvIBDV. The study has recommended to produce vaccine using intermediate plus strains to prevent and control currently circulating vvIBDV. PMID- 28620681 TI - Cardiac T1 mapping in congenital heart disease: bolus vs. infusion protocols for measurements of myocardial extracellular volume fraction. AB - Myocardial extracellular volume fraction (ECV) reflecting diffuse myocardial fibrosis can be measured with T1 mapping cardiovascular magnetic resonance (CMR) before and after the application of a gadolinium-based extracellular contrast agent. The equilibrium between blood and myocardium contrast concentration required for ECV measurements can be obtained with a primed contrast infusion (equilibrium contrast-CMR). We hypothesized that equilibrium can also be achieved with a single contrast bolus to accurately measure diffuse myocardial fibrosis in patients with congenital heart disease (CHD). Healthy controls (n = 17; median age 24.0 years) and patients with CHD (n = 19; 25.0 years) were prospectively enrolled. Using modified Look-Locker inversion recovery T1 mapping before, 15 min after bolus injection, and during constant infusion of gadolinium-DOTA, T1 values were obtained for blood pool and myocardium of the left ventricle (LV), the interventricular septum (IVS), and the right ventricle (RV) in a single midventricular plane in short axis or in transverse orientation. ECV of LV, IVS and RV by bolus-only and bolus-infusion correlated significantly in CHD patients (r = 0.94, 0.95, and 0.74; p < 0.01, respectively) and healthy controls (r = 0.96, 0.89, and 0.64; p < 0.05, respectively). Bland-Altman plots revealed no significant bias between the techniques for any of the analyzed regions. ECV of LV and RV myocardium measured by bolus-only T1 mapping agrees well with bolus infusion measurements in patients with CHD. The use of a bolus-only approach facilitates the integration of ECV measurements into existing CMR imaging protocols, allowing for assessment of diffuse myocardial fibrosis in CHD in clinical routine. PMID- 28620683 TI - Modeling production functions and economic weights in intensive meat production of guinea pigs. AB - A profit function for a typical commercial farm of intensive guinea pig production was designed. The simulated farm contained 86 cages with a ratio of 7:1 females/males, with continuous mating. Kits were weaned at 15 days of age and slaughtered for meat production at 90 days of age. The absolute (EW) and relative economic weights of the main traits were calculated. The highest EW were kits produced per kindling (US$25), kits weaned per kindling (US$22), kits born alive per kindling (US$20), and the number of kindlings per female and year (US$12). Profit, returns, and costs per female and year were US$15, 68, and 53, respectively. Returns came from the production of young guinea pigs and discarded reproductive adults for meat production, 90 and 10% of the total returns. The highest costs were feeding and labor, 44 and 23% of the total cost. The EW and profit did not substantially change when simulating variations of +/-20% in the prices of kilograms of fattening feed and kilograms of live weight of guinea pig, showing their robustness to future variations in market prices or to variations in prices between countries. The results obtained highlight the importance of the feeding costs in the guinea pig meat production. PMID- 28620684 TI - Response to "Men and women show similar survival rates after breast cancer", Yin Pan, Ze-Zhou Song. PMID- 28620685 TI - The efficacy of a new high intensity focused ultrasound therapy for locally advanced pancreatic cancer. AB - PURPOSE: To compare the survival benefit and safety of the low power cumulative and traditional high intensity focused ultrasound (HIFU) for locally advanced pancreatic cancer. METHOD: We retrospectively analyzed 38 patients with locally advanced, inoperable, stage III pancreatic patients received HIFU treatment between January 2008 and April 2014 in the Department of Surgery, the Second Affiliated Hospital, Zhejiang University, School of Medicine. 11 of them received the low power cumulative HIFU treatment, while other 27 received the traditional HIFU treatment. The HIFU device used was the FEP-BY02 (Yuande Biomedical Engineering Co. Ltd, Beijing, China). Serum biochemistry and adverse events were assessed before and after treatment. All the patients were followed up until death. The survival rate and adverse events of two groups were compared. RESULTS: In 38 patients, the baseline characteristics including gender, age, Karnofsky performance status (KPS) score, tumor location of two groups were generally well balanced (P > 0.05). The median overall survival (OS) for low power cumulative HIFU group was 10.3 months (95% CI, 6.3-14.3 months), which is significantly longer than traditional HIFU group with 6.0 months (95% CI, 5.2-6.8 months) (P = 0.018). In low power cumulative HIFU group, the 6-month and 12-month survival rates were higher than traditional group, 100% v.s 44.4%, 11.1% v.s 36.4%, respectively. The adverse events in both groups include abdominal pain, fever, C reactive protein (CRP) elevated. The incidence was lower in low power cumulative HIFU group, however, without statistical significance. CONCLUSION: The low power cumulative HIFU treatment showed a statistical significance in survival benefit with better safety profile compared to the traditional HIFU treatment in patients with locally advanced pancreatic cancer. PMID- 28620686 TI - Evaluation and optimization of PCR primers for selective and quantitative detection of marine ANME subclusters involved in sulfate-dependent anaerobic methane oxidation. AB - Since the discovery that anaerobic methanotrophic archaea (ANME) are involved in the anaerobic oxidation of methane coupled to sulfate reduction in marine sediments, different primers and probes specifically targeting the 16S rRNA gene of these archaea have been developed. Microbial investigation of the different ANME subtypes (ANME-1; ANME-2a, b, and c; and ANME-3) was mainly done in sediments where specific subtypes of ANME were highly enriched and methanogenic cell numbers were low. In different sediments with higher archaeal diversity and abundance, it is important that primers and probes targeting different ANME subtypes are very specific and do not detect other ANME subtypes or methanogens that are also present. In this study, primers and probes that were regularly used in AOM studies were tested in silico on coverage and specificity. Most of the previously developed primers and probes were not specific for the ANME subtypes, thereby not reflecting the actual ANME population in complex samples. Selected primers that showed good coverage and high specificity for the subclades ANME-1, ANME-2a/b, and ANME-2c were thoroughly validated using quantitative polymerase chain reaction (qPCR). From these qPCR tests, only certain combinations seemed suitable for selective amplification. After optimization of these primer sets, we obtained valid primer combinations for the selective detection and quantification of ANME-1, ANME-2a/b, and ANME-2c in samples where different ANME subtypes and possibly methanogens could be present. As a result of this work, we propose a standard workflow to facilitate selection of suitable primers for qPCR experiments on novel environmental samples. PMID- 28620687 TI - Identification and characterization of a biosynthetic gene cluster for tryptophan dimers in deep sea-derived Streptomyces sp. SCSIO 03032. AB - Tryptophan dimers (TDs) are an important class of natural products with diverse bioactivities and share conserved biosynthetic pathways. We report the identification of a partial gene cluster (spm) responsible for the biosynthesis of a class of unusual TDs with non-planar skeletons including spiroindimicins (SPMs), indimicins (IDMs), and lynamicins (LNMs) from the deep-sea derived Streptomyces sp. SCSIO 03032. Bioinformatics analysis, targeted gene disruptions, and heterologous expression studies confirmed the involvement of the spm gene cluster in the biosynthesis of SPM/IDM/LNMs, and revealed the indispensable roles for the halogenase/reductase pair SpmHF, the amino acid oxidase SpmO, and the chromopyrrolic acid (CPA) synthase SpmD, as well as the positive regulator SpmR and the putative transporter SpmA. However, the spm gene cluster was unable to confer a heterologous host the ability to produce SPM/IDM/LNMs. In addition, the P450 enzyme SpmP and the monooxygenase SpmX2 were found to be non-relevant to the biosynthesis of SPM/IDM/LNMs. Sequence alignment and structure modeling suggested the lack of key conserved amino acid residues in the substrate-binding pocket of SpmP. Furthermore, feeding experiments in the non-producing DeltaspmO mutant revealed several biosynthetic precursors en route to SPMs, indicating that key enzymes responsible for the biosynthesis of SPMs should be encoded by genes outside of the identified spm gene cluster. Finally, the biosynthetic pathways of SPM/IDM/LNMs are proposed to lay a basis for further insights into their intriguing biosynthetic machinery. PMID- 28620688 TI - Controlling microbial PHB synthesis via CRISPRi. AB - Microbial polyhydroxyalkanoates (PHA) are a family of biopolyesters with properties similar to petroleum plastics such as polyethylene (PE) or polypropylene (PP). Polyhydroxybutyrate (PHB) is the most common PHA known so far. Clustered regularly interspaced short palindromic repeats interference (CRISPRi), a technology recently developed to control gene expression levels in eukaryotic and prokaryotic genomes, was employed to regulate PHB synthase activity influencing PHB synthesis. Recombinant Escherichia coli harboring an operon of three PHB synthesis genes phaCAB cloned from Ralstonia eutropha, was transformed with various single guided RNA (sgRNA with its guide sequence of 20 23 bases) able to bind to various locations of the PHB synthase PhaC, respectively. Depending on the binding location and the number of sgRNA on phaC, CRISPRi was able to control the phaC transcription and thus PhaC activity. It was found that PHB content, molecular weight, and polydispersity were approximately in direct and reverse proportion to the PhaC activity, respectively. The higher the PhaC activity, the more the intracellular PHB accumulation, yet the less the PHB molecular weights and the wider the polydispersity. This study allowed the PHB contents to be controlled in the ranges of 1.47-75.21% cell dry weights, molecular weights from 2 to 6 millions Dalton and polydispersity of 1.2 to 1.43 in 48 h shake flask studies. This result will be very important for future development of ultrahigh molecular weight PHA useful to meet high strength application requirements. PMID- 28620689 TI - Silencing of a second dimethylallyltryptophan synthase of Penicillium roqueforti reveals a novel clavine alkaloid gene cluster. AB - Penicillium roqueforti produces several prenylated indole alkaloids, including roquefortine C and clavine alkaloids. The first step in the biosynthesis of roquefortine C is the prenylation of tryptophan-derived dipeptides by a dimethylallyltryptophan synthase, specific for roquefortine biosynthesis (roquefortine prenyltransferase). A second dimethylallyltryptophan synthase, DmaW2, different from the roquefortine prenyltransferase, has been studied in this article. Silencing the gene encoding this second dimethylallyltryptophan synthase, dmaW2, proved that inactivation of this gene does not prevent the production of roquefortine C, but suppresses the formation of other indole alkaloids. Mass spectrometry studies have identified these compounds as isofumigaclavine A, the pathway final product and prenylated intermediates. The silencing does not affect the production of mycophenolic acid and andrastin A. A bioinformatic study of the genome of P. roqueforti revealed that DmaW2 (renamed IfgA) is a prenyltransferase involved in isofumigaclavine A biosynthesis encoded by a gene located in a six genes cluster (cluster A). A second three genes cluster (cluster B) encodes the so-called yellow enzyme and enzymes for the late steps for the conversion of festuclavine to isofumigaclavine A. The yellow enzyme contains a tyrosine-181 at its active center, as occurs in Neosartorya fumigata, but in contrast to the Clavicipitaceae fungi. A complete isofumigaclavines A and B biosynthetic pathway is proposed based on the finding of these studies on the biosynthesis of clavine alkaloids. PMID- 28620690 TI - Acquired Resistance to Erlotinib in EGFR Mutation-Positive Lung Adenocarcinoma among Hispanics (CLICaP). AB - BACKGROUND: Lung cancer harboring epidermal growth factor receptor (EGFR) mutations and treated with EGFR tyrosine kinase inhibitors (TKIs) all eventually develop acquired resistance to the treatment, with half of the patients developing EGFR T790M resistance mutations. OBJECTIVE: The purpose of this study was to assess histological and clinical characteristics and survival outcomes in Hispanic EGFR mutated lung cancer patients after disease progression. PATIENTS AND METHODS: EGFR mutation-positive lung cancer patients (n = 34) with acquired resistance to the EGFR-TKI erlotinib were identified from 2011 to 2015. Post progression tumor specimens were collected for molecular analysis. Post progression interventions, response to treatment, and survival were assessed and compared among all patients and those with and without T790M mutations. RESULTS: Mean age was 59.4 +/- 13.9 years, 65% were never-smokers, and 53% had a performance status 0-1. All patients received erlotinib as first-line treatment. Identified mutations included: 60% DelE19 (Del746-750) and 40% L858R. First-line erlotinib overall response rate (ORR) was 61.8% and progression free survival (PFS) was 16.8 months (95% CI: 13.7-19.9). Acquired resistance mutations identified were T790M mutation (47.1%); PI3K mutations (14.7%); EGFR amplification (14.7%); KRAS mutation (5.9%); MET amplification (8.8%); HER2 alterations (5.9%, deletions/insertions in e20); and SCLC transformation (2.9%). Of patients, 79.4% received treatment after progression. ORR for post-erlotinib treatment was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (95% CI: 2.2 36.6). Median overall survival (OS) from treatment initiation was 32.9 months (95% CI: 30.4-35.3), and only the use of post-progression therapy affected OS in a multivariate analysis (p = 0.05). CONCLUSIONS: Hispanic patients with acquired resistance to erlotinib continued to be sensitive to other treatments after progression. The proportion of T790M+ patients appears to be similar to that previously reported in Caucasians. PMID- 28620691 TI - Biomarkers for the Management of Castration-Resistant Prostate Cancer: We Are Not There Yet. AB - In recent years, there has been a marked increase in the number of approved therapies that increase survival of patients with castration-resistant prostate cancer. Current treatment guidelines provide therapeutic management recommendations, but these are primarily based on clinical factors such as performance status or site of metastasis (bone vs. visceral), and not on underlying molecular or cellular features of disease that may predict response. The ability to tailor treatment based on molecular or cellular features of disease could potentially reduce the occurrence of unnecessary side effects and ineffective treatments, and thereby reduce both direct and indirect medical costs. As such, it is important to identify and validate new prognostic and predictive molecular biomarkers that can be used to direct cancer treatment. This review will focus on existing and potential biomarkers in the context of castration-resistant prostate cancer management and discuss the need for continued discovery and validation of new biomarkers and biomarker panels for prostate cancer. PMID- 28620692 TI - The enteric nervous system is a potential autoimmune target in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socioeconomic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS degeneration was evident prior to the development of CNS lesions and the onset of neurological deficits in mice. The pathology was antibody mediated and caused a significant decrease in gastrointestinal motility, which was associated with ENS gliosis and neuronal loss. We identified autoantibodies against four potential target antigens derived from enteric glia and/or neurons by immunoprecipitation and mass spectrometry. Antibodies against three of the target antigens were also present in the plasma of MS patients as confirmed by ELISA. The analysis of human colon resectates provided evidence of gliosis and ENS degeneration in MS patients compared to non-MS controls. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and ENS pathology in MS, which might provide a paradigm shift in our current understanding of the immunopathogenesis of the disease with broad diagnostic and therapeutic implications. PMID- 28620693 TI - Comparative studies of reaction of cobalamin (II) and cobinamide (II) with sulfur dioxide. AB - The kinetics of reactions of cobalamin (II) and cobinamide (II) with sulfur dioxide was studied by UV-visible (UV-vis) spectroscopy. Reaction results in oxidation of Co(II) center and involves two aquated SO2 moieties. The final product is suggested to be complex Co(III)-S2O 4*- . The absence of corrin ring modifications during the reactions was proved. PMID- 28620694 TI - Results of day-case ureterorenoscopy (DC-URS) for stone disease: prospective outcomes over 4.5 years. AB - PURPOSE: To investigate the prospective outcomes of day-case ureterorenoscopy (DC URS) for stone disease. With the rising prevalence of stone disease in the face of finite resources, there is increasing pressure to undertake procedures as a day case avoiding in-patient stay. There are a limited number of studies reporting on the feasibility of ureteroscopy as a day-case procedure. This study aimed to investigate the prospective outcomes and predictors precluding to DC-URS for stone disease in patients treated in our university teaching hospital. MATERIALS AND METHODS: Between March 2012 and July 2016, consecutive cases of adult stone ureteroscopy performed or supervised by a single surgeon were recorded in a prospective database. Patients underwent pre-operative counselling in a specialist stone clinic and were admitted to a dedicated 'Surgical day unit' on the day of surgery. A standardised anaesthetic protocol was adhered to in all cases. Data on patient demographics, stone parameters, pre-operative assessment, operative details, length of stay, stone-free rate and complication rates were collected and analysed. RESULTS: A total of 544 consecutive adult ureteroscopy for stone disease were conducted over the study period with a day-case rate of 77.7%. Thirty-nine percent of failed day-case ureteroscopy were due to late completion of ureteroscopy and due to associated social circumstances of patients. The mean stone size, operating time duration and post-operative stent insertion rates for DC-URS patients were 14 mm, 46 min and 96.5%, respectively. Post-operatively, the mean stone-free rate (SFR), unplanned re-admissions and complications for DC-URS patients were 95, 4 and 4%, respectively. A higher failure of DC-URS was related to patient's age (p = 0.003), positive pre operative urine culture (p < 0.001), elevated pre-operative serum creatinine (p < 0.001) and higher mean operating time (p < 0.02). CONCLUSION: Based on our results, a day-case ureteroscopy rate of nearly 78% can be achieved. With its acceptable complication rate, and low re-admission rates, DC-URS is a safe and feasible option in a majority of patients with stone disease. PMID- 28620695 TI - Liposomes modified by mono- and bis-phthalocyanines: A comprehensive EPR study. AB - The impact of selected metallophthalocyanines, featuring diverse molecular structure, upon the fluidity of liposome membranes was studied using the spin label EPR technique. The "mono"-type MPc's (M = Zn, Sn; Pc = C32H16N8 is the phthalocyanine ligand) and sandwich LnPc2 complexes (Ln = Nd, Sm, Gd) were explored. Liposomes were obtained in a sonication process, from egg yolk lecithin (EYL) in water. TEMPO and 16-DOXYL spin labels were used to monitor the peripheral and central part of the lipid double layer, respectively, which allowed to localize the phthalocyanine additive within the bilayer, as well as to perform independent measurements of changes in fluidity upon addition thereof. All the complexes tested were found to increase the fluidity in the middle of the lipid bilayer. However, at the water-lipid interface the LnPc2 compounds showed a relative small effect upon the phospholipids' arrangement, whereas in the case of ZnPc and SnPc it was found much more pronounced. EPR results were supplemented by measurements of static electrical charge, the investigated phthalocyanines may potentially feed into the membrane thus affecting its stability. PMID- 28620696 TI - Tuning ubiquinone position in biomimetic monolayer membranes. AB - Artificial lipid bilayers have been extensively studied as models that mimic natural membranes (biomimetic membranes). Several attempts of biomimetic membranes inserting ubiquinone (UQ) have been performed to enlighten which the position of UQ in the lipid layer is, although obtaining contradictory results. In this work, pure components (DPPC and UQ) and DPPC:UQ mixtures have been studied using surface pressure-area isotherms and Langmuir-Blodgett (LB) films of the same compounds have been transferred onto solid substrates being topographically characterized on mica using atomic force microscopy and electrochemically on indium tin oxide slides. DPPC:UQ mixtures present less solid like physical state than pure DPPC indicating a higher-order degree for the latter. UQ influences considerably DPPC during the fluid state, but it is mainly expelled after the phase transition at [Formula: see text] 26 mN.m^-1 for the 5:1 ratio and at [Formula: see text] 21 mN.m^-1 for lower UQ content. The thermodynamic studies confirm the stability of the DPPC:UQ mixtures before that event, although presenting a non-ideal behaviour. The results indicate that UQ position can be tuned by means of the surface pressure applied to obtain LB films and the UQ initial content. The UQ positions in the biomimetic membrane are distinguished by their formal potential: UQ located in "diving" position with the UQ placed in the DPPC matrix in direct contact with the electrode surface ( 0.04+/-0.02 V), inserted between lipid chains without contact to the substrate ( 0.00+/-0.01 V) and parallel to the substrate, above the lipid chains ( 0.09+/ 0.02 V). PMID- 28620697 TI - Calreticulin localizes to plant intra/extracellular peripheries of highly specialized cells involved in pollen-pistil interactions. AB - Calcium (Ca2+) plays essential roles in generative reproduction of angiosperms, but the sites and mechanisms of Ca2+ storage and mobilization during pollen pistil interactions have not been fully defined. Both external and internal Ca2+ stores are likely important during male gametophyte communication with the sporophytic and gametophytic cells within the pistil. Given that calreticulin (CRT), a Ca2+-buffering protein, is able to bind Ca2+ reversibly, it can serve as a mobile store of easily releasable Ca2+ (so called an exchangeable Ca2+) in eukaryotic cells. CRT has typical endoplasmic reticulum (ER) targeting and retention signals and resides primarily in the ER. However, localization of this protein outside the ER has also been revealed in both animal and plant cells, including Golgi/dictyosomes, nucleus, plasma membrane/cell surface, plasmodesmata, and even extracellular matrix. These findings indicate that CRT may function in a variety of different cell compartments and specialized structures. We have recently shown that CRT is highly expressed and accumulated in the ER of plant cells involved in pollen-pistil interactions in Petunia, and we proposed an essential role for CRT in intracellular Ca2+ storage and mobilization during the key reproductive events. Here, we demonstrate that both CRT and exchangeable Ca2+ are localized in the intra/extracellular peripheries of highly specialized plant cells, such as the pistil transmitting tract cells, pollen tubes, nucellus cells surrounding the embryo sac, and synergids. Based on our present results, we propose that extracellularly located CRT is also involved in Ca2+ storage and mobilization during sexual reproduction of angiosperms. PMID- 28620698 TI - Potential disease biomarkers: dipeptidyl peptidase 4 and fibroblast activation protein. AB - The importance of the dipeptidyl peptidase 4 (DPP4) gene family in regulating critical biochemical pathways continues to emerge. The two most well-studied members of the family, DPP4 and fibroblast activation protein (FAP), have been investigated both as therapeutic targets for disease and as diagnostic biomarkers. The interest in DPP4 and FAP as potential disease biomarkers has been driven primarily by observations of altered expression profiles in inflammatory diseases and cancer. Furthermore, the stability and persistence of soluble DPP4 and FAP in the serum make them attractive candidate serology markers. This review summarises investigations into DPP4 and FAP as biomarkers of autoimmune disease, gut inflammation, psychosomatic disorders and malignancy and discusses their potential likelihood as clinically useful tools. PMID- 28620699 TI - Evolution of Chlamydomonas reinhardtii ferredoxins and their interactions with [FeFe]-hydrogenases. AB - Ferredoxins are soluble iron sulphur proteins which function as electron donors in a number of metabolic pathways in a broad range of organisms. In photosynthetic organisms, PETF, or ferredoxin 1 (FDX1), is the most studied ferredoxin due to its essential role in photosynthesis, where it transfers electrons from photosystem I to ferredoxin-NADP+ oxidoreductase. However, PETF can also transfer electrons to a large number of other proteins. One important PETF electron acceptor found in green microalgae is the biologically and biotechnologically important [FeFe]-hydrogenase HYDA, which catalyses the production of molecular hydrogen (H2) from protons and electrons. The interaction between PETF and HYDA is of considerable interest, as PETF is the primary electron donor to HYDA and electron supply is one of the main limiting factors for H2 production on a commercial scale. Although there is no three dimensional structure of the PETF-HYDA complex available, protein variants, nuclear magnetic resonance titration studies, molecular dynamics and modelling have provided considerable insight into the residues essential for forming and maintaining the interaction. In this review, we discuss the most recent findings with regard to ferredoxin-HYDA interactions and the evolution of the various Chlamydomonas reinhardtii ferredoxin isoforms. Finally, we provide an outlook on new PETF-based biotechnological approaches for improved H2 production efficiencies. PMID- 28620700 TI - Gender-varying associations between physical activity intensity and mental quality of life in older cancer survivors. AB - PURPOSE: Physical activity can enhance quality of life in cancer survivors, but this conclusion is based largely on research linking moderate-to-vigorous physical activity with quality of life. Light-intensity physical activity may be more feasible than more strenuous exercise for many older cancer survivors. This study reports a secondary analysis of baseline data from a lifestyle behavior intervention trial and examines the hypothesis that older cancer survivors who engage in more light-intensity physical activity, independent of moderate-to vigorous activity, will report better mental quality of life. METHODS: Older (>=65 years), overweight or obese breast, prostate, or colorectal cancer survivors (n = 641, 54% female) self-reported their physical activity and mental quality of life (i.e., mental health, emotional role functioning, vitality, and social role functioning from the Short-Form 36 Health Status Survey) as a part of the RENEW trial baseline assessment. Analysis of covariance was used to test hypotheses. RESULTS: For older women (but not men), light physical activity was positively associated with mental quality of life after adjusting for moderate-to vigorous physical activity. Light physical activity that involved social participation appeared to be responsible for this association. For older men (but not women), moderate-to-vigorous physical activity was positively associated with mental quality of life. CONCLUSIONS: Some activity appears to be better than none for important dimensions of mental quality of life. Experimental research is needed to test the hypothesis that older cancer survivors should strive to avoid inactivity regardless of whether they are able to engage in moderate-to-vigorous physical activity. PMID- 28620702 TI - Optic neuropathy due to nutritional deficiency in a male adolescent with Avoidant/Restrictive Food Intake Disorder: a case report. PMID- 28620701 TI - Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex. AB - Chronic cerebral hypoperfusion (CCH) evokes mild cognitive impairment (MCI) and contributes to the progression of vascular dementia and Alzheimer's disease (AD). How CCH induces these neurodegenerative processes that may spread along the synaptic network and whether they are detectable at the synaptic proteome level of the cerebral cortex remains to be established. In the present study, we report the synaptic protein changes in the cerebral cortex after stepwise bilateral common carotid artery occlusion (BCCAO) induced CCH in the rat. The occlusions were confirmed with magnetic resonance angiography 5 weeks after the surgery. Synaptosome fractions were prepared using sucrose gradient centrifugation from cerebral cortex dissected 7 weeks after the occlusion. The synaptic protein differences between the sham operated and CCH groups were analyzed with label free nanoUHPLC-MS/MS. We identified 46 proteins showing altered abundance due to CCH. In particular, synaptic protein and lipid metabolism, as well as GABA shunt related proteins showed increased while neurotransmission and synaptic assembly related proteins showed decreased protein level changes in CCH rats. Protein network analysis of CCH-induced protein alterations suggested the importance of increased synaptic apolipoprotein E (APOE) level as a consequence of CCH. Therefore, the change in APOE level was confirmed with Western blotting. The identified synaptic protein changes would precede the onset of dementia-like symptoms in the CCH model, suggesting their importance in the development of vascular dementia. PMID- 28620703 TI - Epidemiology and biology of physical activity and cancer recurrence. AB - Physical activity is emerging from epidemiologic research as a lifestyle factor that may improve survival from colorectal, breast, and prostate cancers. However, there is considerably less evidence relating physical activity to cancer recurrence and the biologic mechanisms underlying this association remain unclear. Cancer patients are surviving longer than ever before, and fear of cancer recurrence is an important concern. Herein, we provide an overview of the current epidemiologic evidence relating physical activity to cancer recurrence. We review the biologic mechanisms most commonly researched in the context of physical activity and cancer outcomes, and, using the example of colorectal cancer, we explore hypothesized mechanisms through which physical activity might intervene in the colorectal recurrence pathway. Our review highlights the importance of considering pre-diagnosis and post-diagnosis activity, as well as cancer stage and timing of recurrence, in epidemiologic studies. In addition, more epidemiologic research is needed with cancer recurrence as a consistently defined outcome studied separately from survival. Future mechanistic research using randomized controlled trials, specifically those demonstrating the exercise responsiveness of hypothesized mechanisms in early stages of carcinogenesis, are needed to inform recommendations about when to exercise and to anticipate additive or synergistic effects with other preventive behaviors or treatments. PMID- 28620704 TI - Ranibizumab versus dexamethasone implant for central retinal vein occlusion: the RANIDEX study. AB - PURPOSE: To compare intravitreal ranibizumab and dexamethasone implant in patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO). METHODS: Participants were 42 treatment naive patients with ME due to CRVO, who received either intravitreal 0.5 mg ranibizumab (n = 25) or intravitreal 0.7 mg dexamethasone implant (n = 17). The main outcomes included the mean change in best corrected visual acuity (BCVA) and central subfield thickness (CST) at month 12 compared to baseline in the two groups. RESULTS: At month 12, there was no statistically significant difference in BCVA and CST change between the two groups. However, there was recurrence in ME at month 5 in the dexamethasone group. CONCLUSIONS: Both ranibizumab and dexamethasone implant were found to be safe and effective at the 12-month follow-up in patients with ME secondary to CRVO. Since there was a recurrence in ME at month 5 in the dexamethasone group, we suggested that intravitreal injection of dexamethasone implant should be potentially administered sooner than 6 months. PMID- 28620705 TI - Topical bevacizumab treatment in aniridia. AB - PURPOSE: To report the results of long-term topical treatment with bevacizumab (Avastin) 5 mg/mL eyedrops in a case of aniridia-related neovacularization of the cornea. METHODS: Interventional case report. A female patient with aniridia had a decrease in the best corrected visual acuity from 0.32 to 0.02 in the OS over the course of 4 years, secondary to central corneal neovascularization and epithelial breakdown. Vision in the OD was 0.2. In 2008, at age 28, a shared decision was made to start off-label treatment with bevacizumab eyedrops 0.5% in both eyes. After 9 years, the visual acuity in the OD remained stable, with stability of the macropannus and maintenance of central corneal clarity. In the OS, the central corneal neovascularization regressed, the epithelium regained its clarity, and after cataract surgery visual acuity was regained to 0.32. RESULTS: After 9 years of treatment with topical bevacizumab, vision acuity is comparable to the situation of 12 years previously: Visual acuity remained stable in the ODS. CONCLUSION: In a young patient with progressive corneal neovascularization secondary to aniridia, stability of central corneal neovascularization was obtained and corneal clarity was preserved by adding a daily drop of bevacizumab 5 mg/mL. No adverse events occurred. Vessel growth was inhibited, and as such, the progression of the natural history of the patient's disease was halted. More clinical study with longer follow-up is needed to investigate the applicability of treatment with topical VEGF inhibitors in aniridia. PMID- 28620706 TI - Complete corneal ring (MyoRing) implantation versus MyoRing implantation combined with corneal collagen crosslinking for keratoconus: 3-year follow-up. AB - PURPOSE: To estimate the effectiveness of complete corneal ring (MyoRing) implantation compared with MyoRing implantation combined with corneal collagen crosslinking (CXL) for keratoconus treatment for 36 months follow-up. DESIGN: Retrospective cohort study. MATERIALS AND METHODS: MyoRing implantation was performed in a series of 78 patients (80 eyes) with keratoconus II-III Amsler classification, of these 39 eyes had MyoRing implantation combined with CXL. Implantation of a MyoRing in the corneal pocket was performed using a PocketMaker microkeratome and corneal intrastromal implantation system. During CXL, riboflavin solution 0.1% was injected into the corneal pocket through the incision tunnel and standard surface UVA irradiation (370 nm, 3 mW/cm2) was then applied from 5-cm distance for 30 min. RESULTS: Significant improvements in uncorrected distance visual acuity and corrected distance visual acuity were observed for both groups, which was relatively better 12 months after procedure in MyoRing alone group; however, in 36 months there was no difference between groups. Keratometry was reduced in both groups; after MyoRing implantation for 8.45 D and MyoRing + CXL for 9.43 D, the spherical equivalent decreased from 8.45 to 7.72 D and from 9.43 to 6.25 D, respectively. The cylinder decreased to 3.33 D with MyoRing alone and to 3.31 D with MyoRing + CXL. Corneal thickness remained nearly unchanged (from 433.69 +/- 38.76 to 434.21 +/- 34.98) in MyoRing group and decreased from baseline (from 426.93 +/- 46.58 to 401.24 +/- 39.12 um) in MyoRing + CXL group 36 months postoperatively, which corresponds with pachymetry reduction after conventional CXL. CONCLUSION: Both MyoRing implantation and MyoRing combined with CXL were effective for treating keratoconus. At 36 months, there were slightly better outcomes in MyoRing + CXL group; however, in MyoRing alone group visual and refractive outcomes were stable overtime. PMID- 28620707 TI - Treatment of patients with neurotrophic keratitis stages 2 and 3 with plasma rich in growth factors (PRGF-Endoret) eye-drops. AB - PURPOSE: To provide preliminary data about efficacy and safety of plasma rich in growth factors (PRGF) eye-drops in neurotrophic keratitis (NK) and to analyze the possible influence of certain variables on treatment outcomes. METHODS: This retrospective study included patients with stages 2-3 of NK treated with PRGF eye drops. Primary endpoint was the resolution time of corneal ulcer defect. Outcome measures including percentage of ulcer closure at 4 weeks, Ocular Surface Disease Index (OSDI), Best-Corrected Visual Acuity (BCVA) and Visual Analogue Scale (VAS) were also evaluated before and after treatment with PRGF. The influence of some patients' clinical variables on results was assessed. Safety assessment was also performed reporting all adverse events. RESULTS: Thirty-eight treated eyes in a total of thirty-one patients were evaluated, of which five cases had no prior response to autologous serum treatment. Most cases (97.4%) achieved the complete resolution of corneal defect/ulcer. Mean resolution time was 11.4 weeks (SD = 13.7). A statistical significant (p < 0.05) reduction in OSDI (60.9%), VAS frequency (59.9%), VAS severity (57.0%) and improvement in BCVA (52.8%) was observed. The results were stratified according to the pathology stage and to the identified potential effect modifiers variables. Only one adverse event was reported in one patient (2.6%). CONCLUSIONS: PRGF eye-drops could be a safe and effective therapeutic option for patients with stages 2-3 of NK, showing high rates of corneal defect/ulcer resolution in short times, either in reducing signs and symptoms of NK, and therefore preventing the progression of NK to greater ocular complications. PMID- 28620709 TI - Artificial hearts-recent progress: republication of the article published in the Japanese Journal of Artificial Organs. AB - This review was created based on a translation of the Japanese review written in the Japanese Journal of Artificial Organs in 2015 (Vol.44, No. 3, pp.130-135), with some modifications regarding several references published in 2015 or later. PMID- 28620708 TI - Validation of Fourier analysis of videokeratographic data. AB - PURPOSE: The aim was to assess the repeatability of Fourier transfom analysis of videokeratographic data using Pentacam in normal (CG), keratoconic (KC) and post CXL (CXL) corneas. METHODS: This was a prospective, clinic-based, observational study. One randomly selected eye from all study participants was included in the analysis: 62 normal eyes (CG group), 33 keratoconus eyes (KC group), while 34 eyes, which had already received CXL treatment, formed the CXL group. Fourier analysis of keratometric data were obtained using Pentacam, by two different operators within each of two sessions. Precision, repeatability and Intraclass Correlation Coefficient (ICC), were calculated for evaluating intrassesion and intersession repeatability for the following parameters: Spherical Component (SphRmin, SphEcc), Maximum Decentration (Max Dec), Regular Astigmatism, and Irregularitiy (Irr). Bland-Altman analysis was used for assessing interobserver repeatability. RESULTS: All parameters were presented to be repeatable, reliable and reproductible in all groups. Best intrasession and intersession repeatability and reliability were detected for parameters SphRmin, SphEcc and Max Dec parameters for both operators using ICC (intrasession: ICC > 98%, intersession: ICC > 94.7%) and within subject standard deviation. Best precision and lowest range of agreement was found for the SphRmin parameter (CG: 0.05, KC: 0.16, and CXL: 0.2) in all groups, while the lowest repeatability, reliability and reproducibility was detected for the Irr parameter. CONCLUSIONS: The Pentacam system provides accurate measurements of Fourier tranform keratometric data. A single Pentacam scan will be sufficient for most clinical applications. PMID- 28620710 TI - Investigation of some disinfection chemicals and water quality parameters in swimming pools in the city center and districts of Canakkale, Turkey. AB - In this study, the variations in concentrations of some disinfection chemicals such as cyanuric acid (CyA), free chlorine (FC), and residual chlorine (RC), which affect human health, were investigated in the water of swimming pools. In addition, quality parameters such as temperature, pH, and total alkalinity (TA) in 44 swimming pools located in the city center and districts of Canakkale, Turkey, were examined in the summer period. While FC and RC amounts were analyzed using tablet tests with N-N-diethyl phenylenediamine (DPD 1) and potassium iodine (DPD 3) using the colorimetric method in the comparator, TA and CyA levels were measured with a photometric method. Temperature and pH were measured using YSI 556 MPS. Levels of CyA, FC, RC, pH, temperature, and TA varied between 0.00 and 725.0 mg L-1 (108.0 +/- 111.4 mg L-1), 0.00 and 5.00 mg L-1 (1.60 +/- 0.962 mg L 1), 0 and 0.55 mg L-1 (0.087 +/- 0.059), 6.40 and 8.20 mg L-1 (7.30 +/- 0.038 mg L-1), 22.0 and 32.0 degrees C (27.6 +/- 1.45 degrees C), and 0.00 and 391.0 mg L-1 (129.3 +/- 89.0), respectively. The findings were compared to standard limit values of the Ministry of Health of the Turkish Republic and other countries. Not only maximum concentrations of CyA but also the average concentrations exceeded the standard limit values of different countries in July and August with high tourism activity in Turkey. Although there is no problem in view of average values of other quality parameters, there are some problems in view of the maximum values in pool waters compared to standard limit values. PMID- 28620712 TI - Challenges in the Provision of Sexual and Reproductive Health Care to Refugee and Migrant Women: A Q Methodological Study of Health Professional Perspectives. AB - This Q methodological study was conducted to examine the perspectives of health professionals in providing sexual and reproductive health (SRH) care to refugee and migrant women. Forty-seven health professionals rank-ordered 42 statements and commented on their rankings in subsequent open-ended questions. A bi-person factor analysis was performed and factors were extracted according to the centroid method with a varimax rotation. Seven factors each with a distinct and meaningful viewpoint were identified. These factors are: "Communication difficulties-hurdles to counselling", "Lack of access to culturally appropriate care", "Navigating SRH care", "Cultural constraints on effective communication", "Effects of the lack of cultural competency", "Impacts of low income and language barrier" and "SRH services are accessible, but not culturally relevant". A more culturally adaptive healthcare model that considers refugee and migrant women's linguistic, cultural and socio-economic backgrounds; and engages health professionals on an ongoing process of building cultural competency is central to improve SRH access to these women. PMID- 28620711 TI - Evaluating expected outcomes of acid remediation in an intensively mined Appalachian watershed. AB - Assessments of watershed-based restoration efforts are rare but are essential for the science of stream restoration to advance. We conducted a watershed scale assessment of Abram Creek before and after implementation of a watershed-based plan designed to maximize ecological recovery from acid mine drainage (AMD) impairment. We surveyed water chemistry, physical habitat, benthic macroinvertebrates, and fish community structure in three stream types: AMD impacted (14 streams), AMD-treated (13 streams), and unimpaired reference (4 streams). We used in-stream measurements to quantify ecological loss from AMD, the amount of ecological recovery expected through remediation, and the observed degree of post-treatment recovery. Sites impaired by AMD improved in water quality with AMD treatment. Dissolved metals and acidity declined significantly in treated streams, but sulfate and specific conductance did not. Likewise, sites impaired by AMD improved in bio-condition scores with AMD treatment. EPT genera increased significantly but were lower compared to unimpaired streams. We found fish at nine treated sites that had none before treatment. Community-level analyses indicated improved but altered assemblages with AMD treatment. Analysis of pre-treatment conditions indicated that only 30% of the historic fishery remained. Remediation was expected to recover 66% of the historic fishery value, and assessment of post-treatment conditions indicates that 52% of the historic fishery has been recovered after 3 years. Developing expected endpoints for restoration outcomes provides a tool to objectively evaluate successes and can guide adaptive management strategies. PMID- 28620713 TI - Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma. AB - Primary congenital glaucoma (PCG) is a severe autosomal recessive ocular disorder associated with considerable clinical and genetic heterogeneity. Recently, rare heterozygous alleles in the angiopoietin receptor-encoding gene TEK were implicated in PCG. We undertook this study to ascertain the second mutant allele in a large cohort (n = 337) of autosomal recessive PCG cases that carried heterozygous TEK mutations. Our investigations revealed 12 rare heterozygous missense mutations in TEK by targeted sequencing. Interestingly, four of these TEK mutations (p.E103D, p.I148T, p.Q214P, and p.G743A) co-occurred with three heterozygous mutations in another major PCG gene CYP1B1 (p.A115P, p.E229K, and p.R368H) in five families. The parents of these probands harbored either of the heterozygous TEK or CYP1B1 alleles and were asymptomatic, indicating a potential digenic mode of inheritance. Furthermore, we ascertained the interactions of TEK and CYP1B1 by co-transfection and pull-down assays in HEK293 cells. Ligand responsiveness of the wild-type and mutant TEK proteins was assessed in HUVECs using immunofluorescence analysis. We observed that recombinant TEK and CYP1B1 proteins interact with each other, while the disease-associated allelic combinations of TEK (p.E103D)::CYP1B1 (p.A115P), TEK (p.Q214P)::CYP1B1 (p.E229K), and TEK (p.I148T)::CYP1B1 (p.R368H) exhibit perturbed interaction. The mutations also diminished the ability of TEK to respond to ligand stimulation, indicating perturbed TEK signaling. Overall, our data suggest that interaction of TEK and CYP1B1 contributes to PCG pathogenesis and argue that TEK-CYP1B1 may perform overlapping as well as distinct functions in manifesting the disease etiology. PMID- 28620714 TI - The outcome of I-131 ablation therapy for intermediate and high-risk differentiated thyroid cancer using a strict definition of successful ablation. AB - PURPOSE: This article examines the outcome of radioactive iodine ablation therapy for thyroid cancer in high-risk patients and investigates background factors influencing ablation failure. MATERIALS AND METHODS: We included 91 patients in this retrospective analysis and evaluated the ablation success rate. Successful ablation was defined as the absence of visible iodine-131 (I-131) accumulation in the thyroid bed after whole-body scans and thyroglobulin levels <2 ng/ml in a TSH stimulated state after ablation. We extracted data on patients' age, sex, I-131 dose, pathology, resection stump findings, tumor T category and thyroglobulin levels, which could affect ablation outcome. RESULTS: Successful ablation was achieved in only 14 patients (15.4%). Pre-ablation serum thyroglobulin levels were significantly higher in the ablation failure group than in the success group (P < 0.001), while no significant differences were found for other factors between the groups. Furthermore, thyroglobulin levels >10 ng/ml were significantly related to ablation failure after multivariate analysis (odds ratio 27.2; 95% confidence interval 2.469-299.7; P = 0.007). CONCLUSION: The ablation success rate was very low because of high thyroglobulin levels, even with high dose I-131. High-risk patients, especially those with high thyroglobulin levels (>10 ng/ml), are unlikely to reach levels low enough to meet successful ablation criteria. PMID- 28620715 TI - Neurogenic orthostatic hypotension: the very basics. PMID- 28620716 TI - Factors affecting responsiveness to hepatitis B immunization in dialysis patients. AB - BACKGROUND: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are widespread health problems all over the world and have high morbidity and mortality. Hemodialysis patients are more frequently exposed to these viruses as they have poor immune system and frequently undergo parenteral interventions. The vaccination against HBV prevents infection and it has been recommended for the prevention of HBV infection in all susceptible dialysis patients. This study aimed to determine the seroprevalence of HBV and HCV infections and analyzed the factors affecting inadequate response to HBV vaccine in dialysis patients. METHODS: The data for 584 dialysis patients that were followed up at seven dialysis centers were analyzed. The patients received four doses of 40 MUg recombinant hepatitis B vaccine at 0, 1, 2, and 6 months and were tested for anti HBs titer after one month of completion of vaccination. If patients showed a titer of anti-HBs <10 IU/mL, an additional 40 MUg in four vaccine doses was administered immediately and they were retested for the anti-HBs following the same schedule. The patients were divided into two groups: responders and non responders. RESULTS: HBsAg and anti-HCV seroprevalence was 3.4% and 10.3%, respectively. After vaccination schedule, 264 (83.5%) patients had antibody response to HBV vaccine and 52 (16.5%) had no response. Hepatitis B vaccine unresponsiveness is more common in the patients with hepatitis C positivity (p = 0.011), BMI >30 (p = 0.019), over the age of 65 years (p = 0.009), and duration of dialysis treatment >5 years (p = 0.001). There was no statistically significant difference between gender, causes of renal disease, erythropoietin treatment, and the type of dialysis. CONCLUSION: Hepatitis C infection, obesity, being elderly, and having long hemodialysis period reduced the hepatitis B vaccination response in hemodialysis patients. PMID- 28620717 TI - Multiple variants in families with amyotrophic lateral sclerosis and frontotemporal dementia related to C9orf72 repeat expansion: further observations on their oligogenic nature. AB - The C9orf72 repeat expansion (RE) is one of the most frequent causative mutations of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, it is still unclear how the C9orf72 RE can lead to a heterogeneous phenotype. Several reports have shown the coexistence of mutations in multiple ALS/FTD causative genes in the same family, suggesting an oligogenic etiology for ALS and FTD. Our aim was to investigate this phenomenon in an Italian group of ALS/FTD pedigrees carrying the C9orf72 RE. We included 11 subjects from 11 pedigrees with ALS/FTD and the C9orf72 RE. Mutation screening of FUS, SOD1 and TARDBP genes was performed by direct sequencing. A dementia-specific custom designed targeted next-generation sequencing panel was used for screening dementia-associated genes mutations. We found genetic variants in additional ALS or dementia-related genes in four pedigrees, including the p.V47A variant in the TYROBP gene. As a group, double mutation carriers displayed a tendency toward a younger age at onset and a higher frequency of positive familiar history and of parkinsonism. Our observation supports the hypothesis that the co-presence of mutations in different genes may be relevant for the clinical expression of ALS/FTD and of their oligogenic nature. PMID- 28620718 TI - The phenotypic spectrum of ARHGEF9 includes intellectual disability, focal epilepsy and febrile seizures. AB - Mutations or structural genomic alterations of the X-chromosomal gene ARHGEF9 have been described in male and female patients with intellectual disability. Hyperekplexia and epilepsy were observed to a variable degree, but incompletely described. Here, we expand the phenotypic spectrum of ARHGEF9 by describing a large Ethiopian-Jewish family with epilepsy and intellectual disability. The four affected male siblings, their unaffected parents and two unaffected female siblings were recruited and phenotyped. Parametric linkage analysis was performed using SNP microarrays. Variants from exome sequencing in two affected individuals were confirmed by Sanger sequencing. All affected male siblings had febrile seizures from age 2-3 years and intellectual disability. Three developed afebrile seizures between age 7-17 years. Three showed focal seizure semiology. None had hyperekplexia. A novel ARHGEF9 variant (c.967G>A, p.G323R, NM_015185.2) was hemizygous in all affected male siblings and heterozygous in the mother. This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features. Our findings suggest that pathogenic variants in ARHGEF9 may be more common than previously assumed in patients with intellectual disability and mild epilepsy. PMID- 28620719 TI - Large coverage MR neurography in CIDP: diagnostic accuracy and electrophysiological correlation. AB - The objective of this study was to evaluate large coverage magnetic resonance neurography (MRN) in chronic inflammatory demyelinating polyneuropathy (CIDP). In this prospective study, 18 patients with CIDP and 18 healthy controls were examined by a standardized MRN protocol at 3 T. Lumbosacral plexus was imaged by a T2-weighted 3D sequence and peripheral nerves of the upper and lower extremity by axial T2-weighted turbo spin-echo sequences. Lesions were characterized by nerve cross-sectional area (CSA) and T2-weighted signal (nT2). Additionally, T2 relaxometry of the sciatic nerve was performed using a multi-spin-echo sequence. All patients received a complementary electrophysiological exam. Patients with CIDP exhibited increased nerve CSA and nT2 compared to controls (p < 0.05) in a proximally predominating pattern. Receiver operating characteristic analysis revealed the best diagnostic accuracy for CSA of the lumbosacral plexus (AUC = 0.88) and nT2 of the sciatic nerve (AUC = 0.88). CSA correlated with multiple electrophysiological parameters of demyelinating neuropathy (F wave latency, nerve conduction velocity) of sciatic and median nerve, while nT2 only correlated with F wave latency of sciatic and not median nerve. T2 relaxometry indicated that MR signal increase in CIDP was due to an increase in proton-spin-density (p < 0.05), and not due to the increase in T2 relaxation time. Both nT2 and CSA might aid in the diagnosis of CIDP, but CSA correlates more robustly with established electrophysiological parameters for CIDP. Since the best diagnostic accuracy was shown for proximal nerve locations, MRN may be a useful complementary tool in selected CIDP cases. PMID- 28620720 TI - Lower medulla hypoplasia in Friedreich ataxia: MR Imaging confirmation 140 years later. PMID- 28620721 TI - A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca2+ signal patterns. AB - We report three affected members, a mother and her two children, of a non consanguineous Irish family who presented with a suspected autosomal dominant spinocerebellar ataxia characterized by early motor delay, poor coordination, gait ataxia, and dysarthria. Whole exome sequencing identified a novel missense variant (c.106C>T; p.[Arg36Cys]) in the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor gene (ITPR1) as the cause of the disorder, resulting in a molecular diagnosis of spinocerebellar ataxia type 29. In the absence of grandparental DNA, microsatellite genotyping of healthy family members was used to confirm the de novo status of the ITPR1 variant in the affected mother, which supported pathogenicity. The Arg36Cys variant exhibited a significantly higher IP3-binding affinity than wild-type (WT) ITPR1 and drastically changed the property of the intracellular Ca2+ signal from a transient to a sigmoidal pattern, supporting a gain-of-function disease mechanism. To date, ITPR1 mutation has been associated with a loss-of-function effect, likely due to reduced Ca2+ release. This is the first gain-of-function mechanism to be associated with ITPR1 related SCA29, providing novel insights into how enhanced Ca2+ release can also contribute to the pathogenesis of this neurological disorder. PMID- 28620722 TI - Testing the Amotivational Syndrome: Marijuana Use Longitudinally Predicts Lower Self-Efficacy Even After Controlling for Demographics, Personality, and Alcohol and Cigarette Use. AB - The marijuana amotivational syndrome posits that cannabis use fosters apathy through the depletion of motivation-based constructs such as self-efficacy. The current study pursued a two-round design to rule out concomitant risk factors responsible for the connection from marijuana intake to lower general self efficacy. College students (N = 505) completed measures of marijuana use, demographics (age, gender, and race), personality (extraversion, agreeableness, conscientiousness, openness, and neuroticism), other substance use (alcohol and tobacco), and general self-efficacy (initiative, effort, and persistence) in two assessments separated by a month. Hierarchical regression models found that marijuana use forecasted lower initiative and persistence, even after statistically ruling out 13 pertinent baseline covariates including demographics, personality traits, alcohol use, tobacco use, and self-efficacy subscales. A cross-lagged panel model involving initiative, effort, persistence, alcohol use, cigarette use, and marijuana use sought to unravel the temporal precedence of processes. Results showed that only marijuana (but not alcohol or tobacco) intake significantly and longitudinally prompted lower initiative and persistence. Furthermore, in the same model, the opposite temporal direction of events from lower general self-efficacy subscales to marijuana use was untenable. Findings provide partial support for the marijuana amotivational syndrome, underscore marijuana as a risk factor for decreased general self-efficacy, and offer implications and insights for marijuana prevention and future research. PMID- 28620723 TI - Advances in EBI Development for Diverse Populations: Towards a Science of Intervention Adaptation. AB - This introduction examines major issues and challenges as presented in this special issue of Prevention Science, "Challenges to the Dissemination and Implementation of Evidence Based Prevention Interventions for Diverse Populations." We describe the Fidelity-Adaptation Dilemma that became the origin of dynamic tensions in prevention science. It generated controversies and debates and new perspectives on the dissemination and implementation of evidence-based interventions (EBIs) within diverse populations. The five articles in this special issue address many of these challenges. These dynamic tensions have culminated in a reframing of this dilemma that now argues that fidelity and adaptation are both equally important imperatives. These five articles also examine the abiding challenges of engagement and sustainability. Also, two commentaries from expert research investigators reflect on these five articles and their contributions to prevention science. The current introduction describes this "second generation" of EBIs as they may contribute towards a reduction of the health disparities and inequities that disproportionately affect sectors of the major ethnocultural populations in the USA. We also present a systems analysis of approaches and challenges in the dissemination and implementation of EBIs within the contemporary integrative care environment. Finally, we mention an initiative for, "building a science of intervention adaptation," that proposes systematic research and the creation of an archive of scientific data on the benefits and problems of intervention adaptation. Collectively, these new directions can integrate scientific rigor and sensitivity to cultural factors, for enhancing the effectiveness and reach of this second generation of evidence based interventions with diverse ethnocultural populations. PMID- 28620724 TI - European perspective: Comparing the AHA/ACC and ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. PMID- 28620725 TI - Understanding adaptations to patient-centered medical home activities: The PCMH adaptations model. AB - Primary care practices have increasingly adopted the patient-centered medical home (PCMH) model and often adapted quality improvement efforts to fit local context. This paper implemented a modified framework for understanding adaptations in the context of primary care PCMH transformation efforts. We combined an adaptations model by Stirman et al. that categorized adaptations to evidence-based interventions in research studies with dimensions from the RE-AIM framework, as well as items specific to PCMH. The resulting constructs were translated into a "plain English" adaptations interview. We conducted interviews with 27 practices and used resulting descriptive categories to inform exploratory analyses of the relationships between adaptation characteristics and improvement outcomes in PCMH domains of team-based care and data capacity. Practices most commonly focused on development and use of disease registries and enhancements to team-based care (not disease-specific outcomes). Adaptations were common, with practices most frequently making changes to format or personnel. Adaptations were most often intended to increase effectiveness and based on pragmatic considerations. Generally similar adaptation themes emerged across different content topics (registry and quality improvement team). Adaptations initiated or carried out by the entire team or made in early to middle stages of the project were most related to outcome measures of team-based care and data capacity. This paper extends adaptation models from specific interventions in research studies to PCMH quality improvement efforts. Despite limitations, the PCMH Adaptations Model provided a useful framework to understand adaptations in this context. PMID- 28620726 TI - Determination of the Cadmium, Chromium, Nickel, and Lead Ions Relays in Selected Polish Medicinal Plants and Their Infusion. AB - Concentration of Cd, Cr, Ni, and Pb were determined in peppermint leaves (Folium Menthae piperitae), chamomile blossom (Anthodium Chamomillae), and their infusions by atomic absorption spectrometry (AAS) after microwave digestion of plants samples. Peppermint and chamomile preparations by five different producers were purchased at various pharmacies in Poland. Infusions were made from herbs according to prescription for patients, provided by the producer of medicine on the package. Results show that in exam of medicinal plants the content of cadmium exceeds World Health Organization (WHO) standards. The highest level of extraction was observed for Ni (50-70% of the total content in herb), Cr (28 36%), Cd (14-16%), and the lowest for Pb (about 6%). The calculated daily intake all analyzed elements was very low. Phytotherapy with using of these herbs is safe for health of patient even in case of long time therapy. PMID- 28620727 TI - Investigation of Trace Element Content in the Seeds, Pulp, and Peel of Mashui Oranges Using Microwave Digestion and ICP-MS Analysis. AB - Fresh Mashui orange samples were pretreated with microwave digestion using an HNO3-H2O2 system. The levels of Mg, K, Ca, Fe, Mn, Cu, Zn, As, Cd, and Pb in the seeds, pulp, and peel were then determined using inductively coupled plasma mass spectrometry (ICP-MS) combined with collision cell technology (CCT) and kinetic energy discrimination (KED). The standard curve coefficient of determinations of the ten tested elements were between 0.9995 and 0.9999. The instrument detection limit was between 0.112 ng/L and 3.05 ng/mL. The method detection limit was between 0.0281 and 763 ng/g. The average recovery rate was between 85.0 and 117%. The current results showed that Mashui oranges are rich in three elements, namely Mg, K, and Ca. The concentrations of K and Ca were significantly higher than that of Mg in the peel. The content of K was the highest in the seeds. Fe, Mn, Cu, and Zn had the second highest concentrations, and Fe was the highest in the seeds, while Cu was the lowest in the peel. As, Cd, and Pb (hazardous elements) had the lowest concentrations of all the tested elements. PMID- 28620728 TI - Contents of Heavy Metals in Chinese Edible Herbs: Evidence from a Case Study of Epimedii Folium. AB - Toxic heavy metal contamination in Chinese edible herbs has raised a worldwide concern. In this study, heavy metals in Epimedii Folium, an edible medicinal plant in China, were quantitatively analyzed. Variations of heavy metals in different species, in various organs (i.e., leaves, stems, and roots), in wild growing and cultivated plants, and in 35 market samples of Epimedii Folium, were systematically investigated. In all of Epimedium samples, Hg (mercury) was not detectable (0.00 MUg/g). Four species, Epimedium pubescens, Epimedium sagittatum, Epimedium brevicornu, and Epimedium wushanense, were found to contain Cu (copper) and Pb (lead). And contents of Cu and Pb in E. brevicornu were significantly higher than those in other species (P < 0.01). In wild-growing and cultivated Epimedium plants, Cd (cadmium) and As (arsenic) were not detectable, and concentrations of Cu and Pb in wild-growing plants were significantly higher than those in cultivated plants (P < 0.01). Cd was not detectable in leaves, roots, and stems, while organ specificity was apparent in the distribution of Cu, As, and Pb. And the highest levels of Cu and Pb were observed in roots and leaves, respectively. In Chinese markets, several samples of Epimedii Folium contained excessive Cu, Cd, As, and Pb beyond the national permissible limits. In summary, there was a large variation of heavy metals among Epimedii Folium samples, and Cu and Pb were the most important heavy metals contaminating the edible medicinal plant. Application of Epimedii Folium to drug and food industries will need to focus more on toxic heavy metal contamination. PMID- 28620729 TI - Subchronic Arsenism Disorders mRNA Expression of Cytokines and Immunoglobulins in the Intestinal Tract of the Cock. AB - Provision of feed containing arsenic may cause intestinal flora imbalance and consequently, the dysfunction of immunological protection of the cock. To understand the intricate tuning of immune responses in the intestinal tract elicited by subchronic arsenism, a cock model (1-day-old Hy-line cocks) was established by subjecting cocks to different environmentally relevant concentrations of arsenic in the diet for 90 days. Intestinal cytokine and immunoglobulin (Ig) messenger RNA (mRNA) expression levels were determined using real-time PCR on days 30, 60, and 90. Results showed that, compared to those of the control groups, the mRNA levels of interleukin (IL)-1beta, IL-2, IL-4, and interferon (IFN)-gamma displayed increases on day 30 then decreases on days 60 and 90 dose-dependently in every tissue. Except for the decrease in the jejunum, the mRNA levels of IL-6 and IL-8 were increased in the duodenum, ileum, cecum, and rectum. However, the mRNA levels of IL-12beta decreased in every tissue and every time point compared to those of the control groups. In contrast, chicks showed considerably higher expression levels of IgA, IgM, and IgG after exposure to arsenic. These results demonstrated that immune strategies of cocks were disturbed when suffered from subchronic arsenism, at least on the intestinal level. PMID- 28620730 TI - Advances Towards Painless Vaccination and Newer Modes of Vaccine Delivery. AB - Vaccines have been successful in reducing the mortality and morbidity, but most of them are delivered by intramuscular or intravenous route. They are associated with pain to the baby and bring lot of anxiety for the parents. There has been a marked increase in the number of injections required in first two years of life for completing the vaccination schedule. Hence, there is a need to have a painless vaccine delivery system. Numerous new routes of vaccination like, oral, nasal and transdermal routes are being tried. Oral polio and intranasal influenza have already been a success. Other newer approaches like edible vaccines, nasal sprays, dry powder preparations, jet injectors, microneedles and nanopatches are promising in delivering painless vaccines. Many of them are under clinical trials. These vaccine delivery systems will not only be painless but also cost effective, safe and easy to administer in mass population. They may be devoid of the need of cold chain. Painless delivery system will ensure better compliance to vaccination schedule. PMID- 28620732 TI - Mucolipidosis Type IV Due to Novel MCOLN1 Mutation. PMID- 28620731 TI - Retinoblastoma. AB - Retinoblastoma represents 3% of all childhood cancers, and is the most common intraocular malignancy of childhood. It is fatal, if untreated. White eye reflex, also known as leukocoria, is the commonest sign, followed by strabismus. The pediatricians have a very important role to play in the diagnosis of this relatively rare, but easily detectable tumor. Early diagnosis yields better results. The management of retinoblastoma has gradually evolved over the past few decades, with an aim to not only preserve life and eye, but also optimize residual vision. The treatment of retinoblastoma is multimodal, with chemotherapy, focal treatment including trans-pupillary thermotherapy, cryotherapy and laser photocoagulation, radiation therapy and surgery, all playing a vital role. Intravenous chemotherapy has been the mainstay of treatment for the past two decades, and still continues to be the most extensively used eye saving modality of treatment. Periocular and intravitreal chemotherapy have specific indications in the management of retinoblastoma. Intra-arterial chemotherapy has emerged as a promising alternative for advanced and refractory retinoblastoma, both as a primary and secondary therapy. Recent advances in genetics of retinoblastoma have also helped in improving the overall clinical management of this malignancy. PMID- 28620733 TI - Management of Congenital Diaphragmatic Hernia in Newborn - Paradigm Shift and Ethical Issues. AB - Management of congenital diaphragmatic hernia (CDH) begins soon after it is detected, whether antenatally or postnatally. Assessment of the severity of the condition, associated congenital anomalies, maternal health and related issues, weight of the fetus/baby, mode of delivery, timing of delivery, immediate appropriate management of the baby with CDH at birth, appropriate utilization of available treatment modalities as well as infrastructure of the treating institute have an impact on the outcome of the neonate. Survival without significant long-term/permanent morbidity is considered as good outcome. With advances in antenatal diagnosis, several legal and ethical considerations have cropped up. While on one hand there are proponents of early antenatal diagnosis and medical termination of pregnancy (MTP), on the other hand there are several socio-cultural groups who look upon human life as precious and argue against MTP. There is an ongoing ethical battle between maternal vs. fetal rights; there is no way to put a lid on the controversy whether the mother be allowed to choose in favor of MTP after being aware of the anomalous fetus or, we must attempt to save every fetus irrespective of the antenatal diagnosis of life-threatening anomalies. Notwithstanding, appropriate assessment of the condition, thorough counseling and sound evidence-based decisions could avert ethical dilemma in most cases. This review article provides information about the various choices available in the diagnostic and treatment armamentarium, though it should be kept in mind that the entire spectrum of management strategies may not be universally available. PMID- 28620734 TI - Erratum to: A best practice position statement on pregnancy in chronic kidney disease: the Italian Study Group on Kidney and Pregnancy. PMID- 28620735 TI - Meningocele manque: a comprehensive review of this enigmatic finding in occult spinal dysraphism. AB - The term meningocele manque (MM) was coined in 1972 to describe a broad range of surgical findings characterized by intradural bands tethering neural structures to the dorsal dura. Over the following decades, reports continued to lump intradural tethering bands associated with a variety of comorbidities under the umbrella term MM. In more recent years, disorders previously called MM have been identified as embryologically distinct and were reclassified. While this sectioning continues, there remains a set of intradural tethering disorders for which no better term than MM exists. Herein, we comprehensively review the literature surrounding MM, including embryological disorders, clinical, radiographic, and surgical presentation, as well as alternative classification methods and MM treatment. PMID- 28620736 TI - Revisiting Prostate Cancer Screening Practices Among Vermont Primary Care Physicians. AB - The objective of this study was to assess the prostate cancer screening practices of Vermont primary care physicians and compare them with a prior study in 2001. An electronic survey was created and emailed to all currently practicing primary care physicians in Vermont. Data was stratified by practice length, practice location, university affiliation, and internal medicine versus family practice. Surveys were received from 123 (27.2%) primary care physicians. 27.7% of physicians in practice <10 years recommended prostate specific antigen (PSA) testing, compared with 55.9% of those practicing >=10 years (p = 0.006). Of those who modified their recommendations in the past 5 years, 96.1% reported that the United States Preventive Services Task Force (USPSTF) 2012 statement influenced them. Respondents who continued to use PSA testing were less likely to stop screening after age 80 compared with those surveyed in 2001 (51% in 2014 vs. 74% in 2001; p <0.001). Primary care physicians in practice for 10 or more years were more likely to recommend PSA-based screening than those in practice for less time. The USPSTF statement discouraging PSA-based screening for prostate cancer has had significant penetrance among Vermont primary care physicians. PMID- 28620737 TI - Analysis of BMAA enantiomers in cycads, cyanobacteria, and mammals: in vivo formation and toxicity of D-BMAA. AB - Chronic dietary exposure to the cyanobacterial toxin beta-N-methylamino-L-alanine (BMAA) triggers neuropathology in non-human primates, providing support for the theory that BMAA causes a fatal neurodegenerative illness among the indigenous Chamorro people of Guam. However, since there are two stereoisomers of BMAA, it is important to know if both can occur in nature, and if so, what role they might play in disease causation. As a first step, we analysed both BMAA enantiomers in cyanobacteria, cycads, and in mammals orally dosed with L-BMAA, to determine if enantiomeric changes could occur in vivo. BMAA in cyanobacteria and cycads was found only as the L-enantiomer. However, while the L-enantiomer in mammals was little changed after digestion, we detected a small pool of D-BMAA in the liver (12.5%) of mice and in the blood plasma of vervets (3.6%). Chiral analysis of cerebrospinal fluid of vervets and hindbrain of mice showed that the free BMAA in the central nervous system was the D-enantiomer. In vitro toxicity investigations with D-BMAA showed toxicity, mediated through AMPA rather than NMDA receptors. These findings raise important considerations concerning the neurotoxicity of BMAA and its relationship to neurodegenerative disease. PMID- 28620738 TI - Variation in sex pheromone emission does not reflect immunocompetence but affects attractiveness of male burying beetles-a combination of laboratory and field experiments. AB - Life history theory predicts a trade-off between male sexual trait expression and immunocompetence. Using burying beetles, Nicrophorus vespilloides, as a model, we investigated the relationship between male immune function, sex pheromone emission, and attractiveness under field conditions. In the first experiment, we tested whether there is a positive correlation between immune capacity, sex pheromone characteristics (quantity, relative composition, and time invested in pheromone emission), and male attractiveness. As a measurement of immune capacity, we used an individual's encapsulation ability against a novel antigen. In the second experiment, we specifically examined whether a trade-off between chemical trait expression and immune function existed. To this end, we challenged the immune system and measured the subsequent investment in sex pheromone emission and the attractiveness of the male under field conditions. We found that a male's immunocompetence was neither related to the emission of the male's sex pheromone nor to its attractiveness in the field. Furthermore, none of the immune challenge treatments affected the subsequent investment in pheromone emission or number of females attracted. However, we showed that the same males that emitted a high quantity of their sex pheromone in the laboratory were able to attract more females in the field. Our data suggest that the chemical signal is not a reliable predictor of a male's immunocompetence but rather is a general important fitness-related trait, with a higher emission of the sex pheromone measured in the laboratory directly affecting the attractiveness of a male under field conditions. PMID- 28620739 TI - Injuries of the spine and of the spinal cord in the Hippocratic Corpus of medicine. AB - The purpose of this review article is to summarize the views presented in the Hippocratic Corpus of Medicine regarding injuries of the spine, their effect on the spinal cord and the optimal treatment modulus. It is shown that the treatment dilemmas of ancient times in these injuries remain modern since Hippocrates suggested that conservative treatment and letting nature take its course is preferable over a devastating surgical treatment if the spinal cord structural integrity is not compromised. There is also a detailed account of the conservative treatment suggested in the Hippocratic Corpus concerning devices and method of closed spinal relocations. PMID- 28620740 TI - CORR Insights(r): Combined Administration of ASCs and BMP-12 Promotes an M2 Macrophage Phenotype and Enhances Tendon Healing. PMID- 28620741 TI - A potential new, stable state of the E-cadherin strand-swapped dimer in solution. AB - E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution. PMID- 28620742 TI - Multireflection propagation of conformational kinks in a two-component model of DNA as the transfer mode of the transcriptional replication fork. AB - The propagation, or movement, of a conformational kink along a linear structure can occur in capture, transfer, or multireflection modes. Here we use a model for two-component bistable polymer molecules with energetically non-equivalent stable states to model the propagation of the DNA transcription bubble via movement of a non-linear longitudinal stretching region along the DNA chain. We show that under certain conditions the longitudinal excitation can act as a reflector for a conformational kink and, furthermore, that conformational switching may propagate in a multireflection mode alongside conformational kink transition and conformational kink trapping. PMID- 28620743 TI - Understanding the interactions of human follicle stimulating hormone with single walled carbon nanotubes by molecular dynamics simulation and free energy analysis. AB - Interactions of carbon nanotubes (CNTs) and blood proteins are of interest for nanotoxicology and nanomedicine. It is believed that the interactions of blood proteins and glycoproteins with CNTs may have important biological effects. In spite of many experimental studies of single-walled carbon nanotubes (SWCNT) and glycoproteins with different methods, little is known about the atomistic details of their association process or of structural alterations occurring in adsorbed glycoproteins. In this study, we have applied molecular dynamics simulation to investigate the interaction of follicle stimulating hormone (hFSH) with SWCNT. The aim of this work is to investigate possible mechanisms of nanotoxicity at a molecular level. We present details of the molecular dynamics, structure, and free energy of binding of hFSH on the surface of SWCNT. We find that hFSH in aqueous solution strongly adsorbs onto SWCNT via their concave surface as evidenced by high binding free energies for residues in both protein subunits. It was found that hydrophobic, pi-cation, and pi-pi stacking interactions are the main driving forces for the adsorption of the protein at the nanotube surface. PMID- 28620744 TI - Introduction to the Special Issue: Myocardial Imaging in Heart Failure. PMID- 28620745 TI - Strain imaging using cardiac magnetic resonance. AB - The objective assessments of left ventricular (LV) and right ventricular (RV) ejection fractions (EFs) are the main important tasks of routine cardiovascular magnetic resonance (CMR). Over the years, CMR has emerged as the reference standard for the evaluation of biventricular morphology and function. However, changes in EF may occur in the late stages of the majority of cardiac diseases, and being a measure of global function, it has limited sensitivity for identifying regional myocardial impairment. On the other hand, current wall motion evaluation is done on a subjective basis and subjective, qualitative analysis has a substantial error rate. In an attempt to better quantify global and regional LV function; several techniques, to assess myocardial deformation, have been developed, over the past years. The aim of this review is to provide a comprehensive compendium of all the CMR techniques to assess myocardial deformation parameters as well as the application in different clinical scenarios. PMID- 28620746 TI - Uniparental disomy as an unexpected cause of Meckel-Gruber syndrome: report of a case. AB - BACKGROUND: Meckel-Gruber syndrome (MKS, OMIM #607361) is a rare pre- or perinatal lethal autosomal recessive ciliopathy caused by mutations in at least 12 known genes. It has a clinical and genetic overlap with other viable ciliopathies, especially Joubert syndrome and Joubert syndrome-related disorders. MKS is characterized by multicystic kidney dysplasia, central nervous system malformations (usually occipital encephalocele), ductal plate malformation of the liver, and postaxial polydactyly. CASE DIAGNOSIS: We identified a homozygous mutation in TMEM67 (MKS3) in a fetus affected by MKS; however, only the mother was a carrier of the respective mutation. Genotyping with polymorphic microsatellite markers and single nucleotide polymorphism (SNP) array revealed a maternal uniparental disomy (UPD) of the entire chromosome 8 (upd(8)mat), harboring TMEM67. CONCLUSIONS: This is the first reported case of UPD as a cause of MKS. The possible underlying mechanisms for uniparental disomy (UPD) are reviewed. Even if rare, awareness of UPD and comprehensive work-up in the case of unexpected homozygosity for a recessive mutation is essential for accurate genetic counseling and assessment of the risk of recurrence. PMID- 28620747 TI - Amniotic fluid cells: current progress and emerging challenges in renal regeneration. AB - Amniotic fluid (AF) contains a heterogeneous population of cells that have been identified to possess pluripotent and progenitor-like characteristics. These cells have been applied in various regenerative medicine applications ranging from in vitro cell differentiation to tissue engineering to cellular therapies for different organs including the heart, the liver, the lung, and the kidneys. In this review, we examine the different methodologies used for the derivation of amniotic fluid stem cells and renal progenitors, and their application in renal repair and regeneration. Moreover, we discuss the recent achievements and newly emerging challenges in our understanding of their biology, their immunoregulatory characteristics, and their paracrine-mediated therapeutic potential for the treatment of acute and chronic kidney diseases. PMID- 28620748 TI - Diversity of the Most Commonly Reported Facultative Symbionts in Two Closely Related Aphids with Different Host Ranges. AB - Richness and abundance of facultative symbionts vary strongly with aphid species and genotype, symbiont strain, host plant, biogeography, and a number of abiotic factors. Despite indications that aphids in the same ecological niche show similar levels of facultative symbiont richness, existing reports do not consider the potential role of host plants on aphid microbial community. Little is known about how oligophagy and polyphagy may be influenced by secondary symbiont distribution, mainly because studies on secondary symbiont diversity are biased towards polyphagous aphids from the Northern Hemisphere. Here, we demonstrate the richness and abundance of the most common aphid-associated facultative symbionts in two tropical aphid species, the oligophagous Aphis (Toxoptera) citricidus (Kirkaldy) (Hemiptera: Aphididae) and the polyphagous Aphis aurantii (Boyer de Fonscolombe) (Hemiptera: Aphididae). Aphis citricidus is restricted to Citrus sp. host plants and closely related genera, whereas A. aurantii successfully exploits a wide variety of host plants from different families. Both were collected in the same ecological niche and our data basically indicated the same richness of secondary symbionts, but the abundance at which secondary symbionts occurred was very distinct between the two species. Spiroplasma was the most abundant facultative symbiont associated with A. citricidus and A. aurantii in the ecological niche studied. Single and multiple secondary symbiont infections were observed, but diversity of multiple infections was particularly high in A. citricidus. We discuss our findings and suggest hypotheses to explain causes and consequences of the differences in secondary symbiont diversity observed between these two aphid species. PMID- 28620749 TI - Bundles Prevent Surgical Site Infections After Colorectal Surgery: Meta-analysis and Systematic Review. AB - INTRODUCTION: Colorectal surgeries (CRS) have one of the highest rates of surgical site infections (SSIs) with rates 15 to >30%. Prevention "bundles" or sets of evidence-based interventions are structured ways to improve patient outcomes. The aim sof this study is to evaluate CRS SSI prevention bundles, bundle components, and implementation and compliance strategies. METHODS: A meta analysis of studies with pre- and post-implementation data was conducted to assess the impact of bundles on SSI rates (superficial, deep, and organ/space). Subgroup analysis of bundle components identified optimal bundle designs. RESULTS: Thirty-five studies (51,413 patients) were identified and 23 (17,557 patients) were included in the meta-analysis. A SSI risk reduction of 40% (p < 0.001) was noted with 44% for superficial SSI (p < 0.001) and 34% for organ/space (p = 0.048). Bundles with sterile closure trays (58.6 vs 33.1%), MBP with oral antibiotics (55.4 vs 31.8%), and pre-closure glove changes (56.9 vs 28.5%) had significantly greater SSI risk reduction. CONCLUSION: Bundles can effectively reduce the risk of SSIs after CRS, by fostering a cohesive environment, standardization, and reduction in operative variance. If implemented successfully and complied with, bundles can become vital to improving patients' surgical quality of care. PMID- 28620750 TI - High-precision radiotherapy for meningiomas : Long-term results and patient reported outcome (PRO). AB - OBJECTIVE: To evaluate long-term outcome after high-precision radiotherapy (RT) of meningioma patients in terms of survival and side effects. METHODS: We analyzed 275 meningioma cases: 147 low-grade and 43 high-grade meningiomas (WHO II: n = 40, III: n = 3). In all, 85 patients had no pathologically confirmed histology but were determined as low-grade based on multimodal imaging. Surgery was performed in 183 cases. RT was delivered as either radiosurgery (RS, n = 16), fractionated stereotactic radiotherapy (FSRT, n = 241), or intensity-modulated radiation therapy (IMRT, n = 18). Of 218 patients contacted for patient-reported outcome (PRO), 207 responded (95%). RESULTS: Median follow-up was 7.2 years. For low-grade meningioma the survival rate (OS) was 97% at 3 years, 85% at 10 years, and 64% at 15 years, for atypical meningioma 91% at 3 years, 62% at 10 years, and 50% at 15 years. Local control rate (PFS) for low-grade meningioma was 91% at 3 years, 87% at 5 years, and 86% at 10 years, for atypical cases 67% at 3 years and 55% at 5 years. Of all, 3.0% of patients reported worsened or new symptoms grade >=3 during RT and the first 6 months thereafter; 17.5% reported a deterioration after more than 2 years. We found the prognostic factors tumor volume and age significantly influencing OS and PFS. CONCLUSION: Complemented by PRO, we found long-term low toxicity rates in addition to excellent local control. Thus, due to the beneficial risk-benefit profile of benign and high-risk meningiomas, RT should be performed as adjuvant treatment and should not be postponed until tumor progression. PMID- 28620751 TI - Impact of a rectal and bladder preparation protocol on prostate cancer outcome in patients treated with external beam radiotherapy. AB - PURPOSE AND OBJECTIVE: To test the hypothesis that a rectal and bladder preparation protocol is associated with an increase in prostate cancer specific survival (PCSS), clinical disease free survival (CDFS) and biochemical disease free survival (BDFS). PATIENTS AND METHODS: From 1999 to 2012, 1080 prostate cancer (PCa) patients were treated with three-dimensional conformal radiotherapy (3DCRT). Of these patients, 761 were treated with an empty rectum and comfortably full bladder (RBP) preparation protocol, while for 319 patients no rectal/bladder preparation (NRBP) protocol was adopted. RESULTS: Compared with NRBP patients, patients with RBP had significantly higher BDFS (64% vs 48% at 10 years, respectively), CDFS (81% vs 70.5% at 10 years, respectively) and PCSS (95% vs 88% at 10 years, respectively) (log-rank test p < 0.001). Multivariate analysis (MVA) indicated for all treated patients and intermediate high-risk patients that the Gleason score (GS) and the rectal and bladder preparation were the most important prognostic factors for PCSS, CDFS and BDFS. With regard to high- and very high risk patients, GS, RBP, prostate cancer staging and RT dose were predictors of PCSS, CDFS and BDFS in univariate analysis (UVA). CONCLUSION: We found strong evidence that rectal and bladder preparation significantly decreases biochemical and clinical failures and the probability of death from PCa in patients treated without daily image-guided prostate localization, presumably since patients with RBP are able to maintain a reproducibly empty rectum and comfortably full bladder across the whole treatment compared with NRPB patients. PMID- 28620752 TI - Fatty metaplasia quantification and impact on regional myocardial function as assessed by advanced cardiac MR imaging. AB - OBJECTIVE: This study aimed to investigate the advantages of recently developed cardiac imaging techniques of fat-water separation and feature tracking to characterize better individuals with chronic myocardial infarction (MI). MATERIALS AND METHODS: Twenty patients who had a previous MI underwent CMR imaging. The study protocol included routine cine and late gadolinium enhancement (LGE) technique. In addition, mDixon LGE imaging was performed in every patient. Left ventricular (LV) circumferential (EccLV) and radial (ErrLV) strain were calculated using dedicated software (CMR42, Circle, Calgary, Canada). The extent of global scar was measured in LGE and fat-water separated images to compare conventional and recent CMR imaging techniques. RESULTS: The infarct size derived from conventional LGE and fat-water separated images was similar. However, detection of lipomatous metaplasia was only possible with mDixon imaging. Subjects with fat deposition demonstrated a significantly smaller percentage of fibrosis than those without fat (10.68 +/- 5.07% vs. 13.83 +/- 6.30%; p = 0.005). There was no significant difference in EccLV or ErrLV between myocardial segments containing fibrosis only and fibrosis with fat. However, EccLV and ErrLV values were significantly higher in myocardial segments adjacent to fibrosis with fat deposition than in those adjacent to LGE only. CONCLUSIONS: Advanced CMR imaging ensures more detailed tissue characterization in patients with chronic MI without a relevant increase in imaging and post-processing time. Fatty metaplasia may influence regional myocardial deformation especially in the myocardial segments adjacent to scar tissue. A simplified and shortened myocardial viability CMR protocol might be useful to better characterize and stratify patients with chronic MI. PMID- 28620753 TI - Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center. AB - PURPOSE: Cyclosporine A (CyA), a potent immunosuppressive agent used in renal transplantation, has a narrow therapeutic window and a large variability in blood concentrations. This study aimed to develop a population pharmacokinetic (PPK) model of CyA in living-donor renal transplant patients at a single center and identify factors influencing CyA pharmacokinetics (PK). METHODS: A total of 660 points (preoperative) and 4785 points (postoperative) of blood concentration data from 98 patients who underwent renal transplantation were used. Pre- and postoperative CyA model structure and PPK parameters were separately estimated with a non-linear mixed-effect model, and subsequently, covariate analysis of postoperative data were comprehensively estimated, including preoperative PK parameters. RESULTS: A two-compartment model with first-order absorption and absorption lag time was selected in this study. Aspartate aminotransferase, body surface area (BSA), pretransplant area under the whole blood concentration-time curve/dose, and postoperative days were identified as the covariates on oral clearance. BSA was selected as a covariate of the distribution volume of the central compartment. In addition, diabetes mellitus was selected as a covariate of the first-order absorption rate. CONCLUSIONS: This PPK study used the largest number of blood concentration data among previous reports of living-donor renal transplant patients. Moreover, all patients received the same immunosuppressive regimen in a single center. Therefore, the validity of the selected covariates is reliable with high precision. The developed PPK model and selected covariates provide useful information about factors influencing CyA PK and greatly contributes to the identification of the most suitable dosing regimen for CyA. PMID- 28620754 TI - Variation in Pediatric Post-Ablation Care: A Survey of the Pediatric and Congenital Electrophysiology Society (PACES). AB - Although catheter ablation is a standard treatment for pediatric arrhythmias, there are no consensus guidelines for follow-up care. This study describes the variation in post-ablation practices identified through a survey of the pediatric and congenital electrophysiology society (PACES). Pediatric and congenital electrophysiology society members were invited to participate in an online survey of post-ablation practices in September 2014. Survey questions targeted routine post-ablation practices for three common arrhythmia substrates: atrioventricular nodal reentry tachycardia, concealed accessory pathways (AP), and manifest APs. Significant practice variation was defined as <90% concordance among respondents. There were 70 respondents from 67 centers, 29 (41%) in practice for <10 years. Uniform practices included aspirin after left side ablation by 65 (93%), immediate post-procedure ECG by 63 (90%), and performance of outpatient follow-up in 69 (99%) including ECG in 97-100% depending on substrate. The majority, 57 (81%), have standardized follow-up independent of substrate. Post-procedural observation is highly variable, with 25 (36%) discharging patients on the day of ablation, 22 (33%) observing patients in hospital overnight, and 21 (30%) basing hospitalization on pre-defined criteria. Immediate post-procedure echo is performed after all ablations in only 16 (23%). Discharge from outpatient care occurs at a median time of 12 months for each arrhythmia substrate. Common post ablation practices are evident among pediatric electrophysiologists. However, they report significant variation in post-procedure monitoring practices and testing. The rationale for these variances, and their impact on costs and outcomes, should be defined. PMID- 28620755 TI - Predictive Value of Mean Platelet Volume for Pulmonary Embolism Recurrence. AB - PURPOSE: Recurrence is a major clinical problem in patients with pulmonary embolism and can affect mortality. The decision to discontinue treatment is important for recurrence and is based on patients' clinical features as well as certain blood parameters. Our aim in this study was to evaluate whether mean platelet volume (MPV) and platelet distribution width (PDW) have utility as new predictive parameters for recurrence and mortality in pulmonary embolism. MATERIALS AND METHODS: A total of 440 patients with pulmonary embolism underwent computed tomography, Doppler ultrasonography, and echocardiography before and at the conclusion of treatment. Thrombocyte count, MPV, PDW, and D-dimer parameters were also evaluated at the same time points. RESULTS: MPV and PDW were significantly higher in deceased patients (8.8 +/- 1.2 fl and 17.4 +/- 0.8) compared to surviving patients (7.7 +/- 0.9 fl and 17 +/- 0.9) (p < 0.0001). Initial MPV and PDW were also significantly higher in patients with recurrence (8.4 +/- 0.7 vs 7.6 +/- 0.8 fl, p < 0.0001 and 17.3 +/- 0.8 vs 16.9 +/- 0.9, p = 0.002, respectively) than in patients without recurrence. At the end of treatment, MPV was still higher in patients with recurrence compared to patients without recurrence (8.7 +/- 0.5 and 7.5 +/- 0.7 fl, respectively, p < 0.0001). MPV values over 8.05 fl at the end of treatment predicted recurrence with 91% sensitivity and 77% specificity. CONCLUSION: MPV seems to be an indicator of recurrence in pulmonary embolism and may have utility in the prediction of recurrence. Elevated MPV can also be used to predict mortality in pulmonary embolism. PMID- 28620756 TI - Preliminary data on utility of subcutaneous unfractionated heparin in patients with deep cerebral venous thrombosis. AB - Subcutaneous unfractionated heparin (SCUFH) has been proved effective in puerperal cerebral venous thrombosis (CVT), but its efficacy in the more serious form of the disease such as deep CVT patients (DCVT) unreported. We describe the outcomes of 37 (isolated:combined: 11:26) patients of DCVT diagnosed by MRI, treated with SCUFH in a tertiary care stroke unit. It was a prospective observational cohort study using 5000 U of SCUFH every 6 hourly for 10 days with oral Acenocoumarol started on day 7, with monitoring. The outcome was assessed by modified Rankin scale (mRS), National Institute of Health Stroke Scale (NIHSS) and Barthel's activities of daily life (BADL) at 3 months. The mean age of the cohort was 27.9 +/- 9.7 years, females (n = 24) outnumbering the males (n = 13). Mean duration of symptoms being 10.2 +/- 15.9 days. MRI showed vein of Galen and straight sinus involvement in 36 (97.3%) patients, with sparing of the basal vein of Rosenthal in 28 (75%). Thalamus 27 (73%) basal ganglia 21 (56.7%) were commonly involved areas with hemorrhagic lesions in 18 (48.6%) patients. The median NIHSS score at presentation was 11 (1-21). Mean duration of SCUFH treatment was 9.3 +/- 1.3 days and the mean aPTT on day 7 was 49.3 +/- 9.8 s (control 32-39 s), mean PT INR on day 13 was 1.5 +/- 0.45. All the patients improved with no mortality in the study group. At 3 months, good functional outcome (mRS: 0-2) was observed in 94.6% (n = 35) of patients. Two patients had mRS-3. The median mRS (3{1-5} to 0{0-3}) and BADL (8{0-20} to 20{8-20}) improved at 3 months. Complications seen were thrombocytopenia-1, infection-6 and deep vein thrombosis of leg-4. Our preliminary data suggests that SCUFH is safe, effective treatment option in patients with DCVT in a stroke unit with minimal monitoring. PMID- 28620757 TI - A novel homozygous complex deletion in CFTR caused cystic fibrosis in a Chinese patient. AB - Cystic fibrosis (CF) is the most frequent lethal genetic disorder among Caucasians, but is considered to be a very rare disease in Chinese population. Here, we present an 11-year-old Chinese CF patient with disseminated bronchiectasis and salty sweat, for whom exon sequencing followed by multiplex ligation-dependent probe amplification analysis of the CFTR gene was applied for mutation screening. A homozygous deletion involving exon 20 of CFTR was observed in the patient's genome. Molecular characterization of the breakpoints indicated that both alleles of this locus had an identical novel complex rearrangement (c.3140-454_c.3367+249del931ins13, p.R1048_G1123del), leading to an in-frame removal of 76 amino acid residues in the second transmembrane domains of the CFTR protein. Although a same haplotype containing this complex rearrangement was observed on both of the maternal and paternal alleles, the parents denied any blood relationship as far as they know. Genome-wide homozygosity mapping was performed through SNP microarray and only a single homozygous interval of ~14.1 Mb at chromosome 7 containing the CFTR gene was observed, indicating the possible origin of the deletion from a common ancestor many generations ago. This study expands the mutation spectrum of CFTR in patients of Chinese origin and further emphasizes the necessity of MLPA analysis in mutation screening for CF patients. PMID- 28620759 TI - Participative Spatial Scenario Analysis for Alpine Ecosystems. AB - Land use and land cover patterns are shaped by the interplay of human and ecological processes. Thus, heterogeneous cultural landscapes have developed, delivering multiple ecosystem services. To guarantee human well-being, the development of land use types has to be evaluated. Scenario development and land use and land cover change models are well-known tools for assessing future landscape changes. However, as social and ecological systems are inextricably linked, land use-related management decisions are difficult to identify. The concept of social-ecological resilience can thereby provide a framework for understanding complex interlinkages on multiple scales and from different disciplines. In our study site (Stubai Valley, Tyrol/Austria), we applied a sequence of steps including the characterization of the social-ecological system and identification of key drivers that influence farmers' management decisions. We then developed three scenarios, i.e., "trend", "positive" and "negative" future development of farming conditions and assessed respective future land use changes. Results indicate that within the "trend" and "positive" scenarios pluri activity (various sources of income) prevents considerable changes in land use and land cover and promotes the resilience of farming systems. Contrarily, reductions in subsidies and changes in consumer behavior are the most important key drivers in the negative scenario and lead to distinct abandonment of grassland, predominantly in the sub-alpine zone of our study site. Our conceptual approach, i.e., the combination of social and ecological methods and the integration of local stakeholders' knowledge into spatial scenario analysis, resulted in highly detailed and spatially explicit results that can provide a basis for further community development recommendations. PMID- 28620758 TI - Transcriptome analysis of drought-responsive genes regulated by hydrogen sulfide in wheat (Triticum aestivum L.) leaves. AB - Drought is an environmental factor that deeply impacts wheat yield and quality. Hydrogen sulfide (H2S) is a known regulator of drought resistance in plants. To preliminarily elucidate the regulatory mechanisms of H2S on drought tolerance, the effects of H2S on drought-responsive genes were investigated by transcriptome analysis. As a result, a total of 7552 transcripts not only responded to drought stress but also exhibited differential expression relative to the polyethylene glycol (PEG) treatment (P) and the NaHS pretreatment with PEG treatment (SP). GO categories of 'transport' were especially enriched under the SP treatment and ion transport categories (especially 'iron ion transport') were more significantly enriched among up-regulated transcripts in SP versus P treatments (SP.vs.P). Indeed, a higher translocation of iron from root to shoot and iron availability in shoots was detected in SP compared to P. The KEGG pathway of 'ribosome biogenesis in eukaryotes', 'protein processing in endoplasmic reticulum', 'fatty acid degradation', and 'cyanoamino acid metabolism' was induced by H2S under drought stress. Further, H2S was involved in plant hormones signal transduction, and drought-induced transcription factors, protein kinases, and functional genes exhibited higher expression levels under SP relative to P. Additionally, several effectors or master regulatory genes of H2S were identified genome-wide. Summarily, these results showed that H2S alleviated drought damage probably related to transport systems, plant hormones signal transduction, protein processing pathway, fatty acids and amino acids metabolism, which provides a guide for future experimentation to analyze hydrogen sulfide-dependent drought tolerance mechanisms in wheat. PMID- 28620760 TI - Notch: an interactive player in neurogenesis and disease. AB - Notch signaling is evolutionarily conserved from Drosophila to human. It plays critical roles in neural stem cell maintenance and neurogenesis in the embryonic brain as well as in the adult brain. Notch functions greatly depend on careful regulation and cross-talk with other regulatory mechanisms. Deregulation of Notch signaling is involved in many neurodegenerative diseases and brain disorders. Here, we summarize the fundamental role of Notch in neuronal development and specification and discuss how epigenetic regulation and pathway cross-talk contribute to Notch function. In addition, we cover aberrant alterations of Notch signaling in the diseased brain. The aim of this review is to provide an insight into how Notch signaling works in different contexts to control neurogenesis and its potential effects in diagnoses and therapies of neurodegeneration, brain tumors and disorders. PMID- 28620761 TI - Medicinal Chemistry of sigma1 Receptor Ligands: Pharmacophore Models, Synthesis, Structure Affinity Relationships, and Pharmacological Applications. AB - In the first part of this chapter, we summarize the various pharmacophore models for sigma1 receptor ligands. Common to all of them is a basic amine flanked by two hydrophobic regions, representing the pharmacophoric elements. The development of computer-based models like the 3D homology model is described as well as the first crystal structure of the sigma1 receptor. The second part focuses on the synthesis and biological properties of different sigma1 receptor ligands, identified as 1-9. Monocyclic piperazines 1 and bicyclic piperazines 2 and 3 were developed as cytotoxic compounds, thus the IC50 values of cell growth and survival inhibition studies are given for all derivatives. The mechanism of cell survival inhibition, induction of time-dependent apoptosis, of compound ent 2a is discussed. Experimentally determined sigma1 affinity shows good correlation with the results from molecular dynamics simulations based on a 3D homology model. Spirocyclic compounds 4 and 5 represent well-established sigma1 receptor ligands. The homologous fluoroalkyl derivatives 4 have favorable pharmacological properties for use as fluorinated PET tracers. The (S)-configured fluoroethyl substituted compound (S)-4b is under investigation as PET tracer for imaging of sigma1 receptors in the brain of patients affected by major depression. 1,3 Dioxanes 6c and 6d display a very potent sigma1 antagonist profile and the racemic 1,3-dioxane 6c has high anti-allodynic activity at low doses. The arylpropenylamines 7 are very potent sigma1 receptor ligands with high sigma1/sigma2 selectivity. The top compound 7g acts as an agonist as defined by its ability to potentiate neurite outgrowth at low concentrations. Among the morpholinoethoxypyrazoles 8, 8c (known as S1RA) reveals the most promising pharmacokinetic and physicochemical properties. Due to its good safety profile, 8c is currently being investigated in a phase II clinical trial for the treatment of neuropathic pain. The most potent ligand 9e of 3,4-dihydro-2(1H)-quinolones 9 shows promising anti-nociceptive activity in the formalin test. PMID- 28620762 TI - Using Raman Spectroscopy in Studying the Effect of Propylene Glycol, Oleic Acid, and Their Combination on the Rat Skin. AB - The permeability enhancement effect of oleic acid (OA) and propylene glycol (PG) as well as their (1:1 v/v) combined mixture was studied using rat skin. The percutaneous drug administration is a challenge and an opportunity for drug delivery. To date, there is limited research that illustrates the mechanism of penetration enhancers and their combinations on the skin. This project aims to explore the skin diffusion and penetration enhancement of PG, OA, and a combination of PG-OA (1:1 v/v) on rat skin and to identify the potential synergistic effect of the two enhancers utilizing Raman spectroscopy. Dissected dorsal skin was treated with either PG or OA or their combination for predetermined time intervals after which the Raman spectra of the treated skin were collected with the enhancer. A spectrum of the wiped and the washed skin were also collected. The skin integrity was tested before and after exposure to PG. The skin histology proved that the skin integrity has been maintained during experiments and the results indicated that OA disrupted rat skin lipid as evident by changes in the lipid peak. The results also showed that PG and OA improved the diffusion of each other and created faster, yet reversible changes of the skin peaks. In conclusion, Raman spectroscopy is a potential tool for ex vivo skin diffusion studies. We also concluded that PG and OA have potential synergistic reversible effect on the skin. PMID- 28620763 TI - Anticancer Efficacy of Self-Nanoemulsifying Drug Delivery System of Sunitinib Malate. AB - Sunitinib malate (SM) is reported as a weakly soluble drug in water due to its poor dissolution rate and oral bioavailability. Hence, in the current study, various "self-nanoemulsifying drug delivery systems (SNEDDS)" of SM were prepared, characterized and evaluated for the enhancement of its in vitro dissolution rate and anticancer efficacy. On the basis of solubilization potential of SM in various excipients, "Lauroglycol-90 (oil), Triton-X100 (surfactant) and Transcutol-P (cosurfactant)" were selected for the preparation of SM SNEDDS. SM-loaded SNEDDS were developed by spontaneous emulsification method, characterized and evaluated for "thermodynamic stability, self nanoemulsification efficiency, droplet size, polydispersity index (PDI), zeta potential (ZP), surface morphology, refractive index (RI), the percent of transmittance (% T) and drug release profile." In vitro dissolution rate of SM was significantly enhanced from an optimized SNEDDS in comparison with SM suspension. The optimized SNEDDS of SM with droplet size of 42.3 nm, PDI value of 0.174, ZP value of -36.4 mV, RI value of 1.339, % T value of 97.3%, and drug release profile of 95.4% (after 24 h via dialysis membrane) was selected for in vitro anticancer efficacy in human colon cancer cells (HT-29) by MTT assay. MTT assay indicated significant anticancer efficacy of optimized SM SNEDDS against HT 29 cells in comparison with free SM. The results of this study showed the great potential of SNEDDS in the enhancement of in vitro dissolution rate and anticancer efficacy of poorly soluble drug such as SM. PMID- 28620764 TI - Health-related quality of life associated with bullying and aggression: a cross sectional study in English secondary schools. AB - BACKGROUND: Associations between adolescent health-related quality of life (HRQoL), bullying, and aggression are not well understood. We used baseline data from a large-cluster randomized school trial to study the relationship between HRQoL, bullying experience, and other demographic factors. METHODS: Cross sectional self-reported questionnaires collected pre-randomization from the on going INCLUSIVE trial. The questionnaires were completed in the classroom. The Gatehouse Bullying Scale measured bullying victimization and the Edinburgh Study of Youth Transitions and Crime school misbehavior subscale (ESYTC) measured aggressive behaviors. HRQoL was assessed using the Child Health Utility 9 Dimensions (CHU-9D) and general quality of life using the Pediatric Quality of Life Inventory (PedsQL). Participants were a cohort of year 7 students (age 11-12 years) from 40 state secondary schools in England. Descriptive statistics for the CHU-9D and PedsQL were calculated using standard methods with tests for differences in median scores by sex assessed using quantile regression. Correlation between HRQoL measures was conducted using Spearman's rank correlation coefficients. Predictors of HRQoL were identified using univariate and multiple regressions. RESULTS: A total of 6667 students filled out the questionnaire. The CHU-9D was correlated with the PedsQL (0.63, p < 0.001). The multivariable regression results suggest that if students were bullied frequently and upset it resulted in a decrement in CHU-9D scores of (-0.108) and fall in PedsQL score of (-16.2). The impact of the antisocial/aggressive behavior on the ESYTC scale resulted in a utility decrement of -0.004 and fall of -.5 on the PedsQL. CONCLUSIONS: Adolescents' involvement in bullying and aggression is a strong correlate of HRQoL. These data have important implications for the potential cost-effectiveness of reducing bullying and aggression in schools. PMID- 28620765 TI - Autonomy and performance in the public sector: the experience of English NHS hospitals. AB - Since 2004, English NHS hospitals have been given the opportunity to acquire a more autonomous status known as a Foundation Trust (FT), whereby regulations and restrictions over financial, management, and organizational matters were reduced in order to create incentives to deliver higher-quality services in the most efficient way. Using difference-in-difference models, we test whether achieving greater autonomy (FT status) improved hospital performance, as proxied by measures of financial management, quality of care, and staff satisfaction. Results provide little evidence that the FT policy per se has made any difference to the performance of hospitals in most of these domains. Our findings have implications for health policy and inform the trend towards granting greater autonomy to public-sector organizations. PMID- 28620766 TI - Phenotype Transformation of Aortic Valve Interstitial Cells Due to Applied Shear Stresses Within a Microfluidic Chip. AB - Despite valvular heart diseases constituting a significant medical problem, the acquisition of information describing their pathophysiology remains difficult. Due to valvular size, role and location within the body, there is a need for in vitro systems that can recapitulate disease onset and progression. This study combines the development of an in vitro model and its application in the mechanical stimulation of valvular cell transformation. Specifically, porcine aortic valvular interstitial cells (PAVIC) were cultured on polydimethylsiloxane microfluidic devices with or without exposure to shear stresses. Mechanobiological responses of valvular interstitial cells were evaluated at shear stresses ranging from 0 to 4.26 dyn/cm2. When flow rates were higher than 0.78 dyn/cm2, cells elongated and aligned with the flow direction. In addition, we found that shear stress enhanced the formation of focal adhesions and up regulated PAVIC transformation, assessed by increased expression of alpha-smooth muscle actin and transforming growth factor beta. This study reveals a link between the action of shear forces, cell phenotype transformation and focal adhesion formation. This constitutes the first step towards the development of co cultures (interstitial-endothelial cells) on organ-on-a-chip devices, which will enable studies of the signaling pathways regulating force-induced valvular degeneration in microtissues and potential discovery of valvular degeneration therapies. PMID- 28620767 TI - A Novel Method for Mouse Retinal Temperature Determination Based on ERG Photoresponses. AB - This study introduces a novel retinal temperature determination method based on the temperature dependent properties of photoresponses recorded by electroretinography (ERG). The kinetics and amplitudes of ERG photoresponses depend on retinal temperature. Additionally, raising retinal temperature increases the probability of long-wavelength photon absorption, which manifests as temperature dependence of photoreceptor sensitivity. In this study we extract a number of features that represent these properties from the a- and b-waves of mouse ex vivo ERG flash responses and construct three multivariable regression models between temperature and the selected features. The performance of these models was evaluated against a separate test dataset and for two of the models, an RMS temperature determination error of less than 0.50 degrees C could be reached. Our results demonstrate that the method can be successfully used for reliable retinal temperature determination ex vivo. The method, reflecting the temperature of distal retina, can be applied also in the estimation of retinal pigment epithelium temperature. PMID- 28620768 TI - Carbon Nanotube Reinforced Collagen/Hydroxyapatite Scaffolds Improve Bone Tissue Formation In Vitro and In Vivo. AB - Current bone regeneration strategies faced major challenges in fabricating the bionic scaffolds with nano-structure, constituents and mechanical features of native bone. In this study, we developed a new porous scaffold by adding the multi-walled carbon nanotube (MWCNT) into collagen (Col)/hydroxyapatite (HA) composites. Data showed that 0.5%CNT/Col/HA (0.5%CNT) group was approximately tenfolds stiffer than Col-HA, and it was superior in promoting bone marrow mesenchymal stem proliferation and spreading, mRNA and protein expressions of bone sialoprotein (BSP) and osteocalcin (OCN) than Col-HA group. Moreover, we utilized 0.5%CNT composite to repair the rat calvarial defects (8 mm diameter) in vivo, and observed the new bone formation by 3D reconstruction of micro CT, HE and Masson staining, and BSP, OCN by immunohistochemical analysis. Results showed that newly formed bone in 0.5%CNT group was significantly higher than that in Col HA group at 12 weeks. These findings highlighted a promising strategy in healing of large area bone defect with MWCNT added into the Col-HA scaffold as they possessed the combined effects of mechanical strength and osteogenicity. PMID- 28620770 TI - Access to information on home- and community-based services and functional status. AB - OBJECTIVES: To examine differences in access to home- and community-based service (HCBS) information among older adults of different functional status. METHODS: Cross-sectional survey of 5435 out of 11,000 randomly selected Swiss older community dwellers from the state of Vaud. Analyses stratified by functional status examined characteristics associated with limited access to HCBS information, based on self-reported knowledge on where to find information on 13 HCBS. RESULTS: Proportionally, more individuals did not know where to look for information in the functionally vulnerable group than in the robust and dependent ones for virtually each service. Among robust individuals, males and persons with low financial status had increased odds of limited access. Low financial status was also negatively associated with access to information among vulnerable people. Belonging to the youngest group increased the odds of limited access for dependent individuals. CONCLUSIONS: Efforts should be made to improve elders' access to HCBS information by developing specific strategies relevant to each functional status group. Further studies on access to HCBS information should be conducted using complex conceptual frameworks as it has been done for HCBS use. PMID- 28620771 TI - Oviposition Preference for Young Plants by the Large Cabbage Butterfly (Pieris brassicae ) Does not Strongly Correlate with Caterpillar Performance. AB - The effects of temporal variation in the quality of short-lived annual plants on oviposition preference and larval performance of insect herbivores has thus far received little attention. This study examines the effects of plant age on female oviposition preference and offspring performance in the large cabbage white butterfly Pieris brassicae. Adult female butterflies lay variable clusters of eggs on the underside of short-lived annual species in the family Brassicaceae, including the short-lived annuals Brassica nigra and Sinapis arvensis, which are important food plants for P. brassicae in The Netherlands. Here, we compared oviposition preference and larval performance of P. brassicae on three age classes (young, mature, and pre-senescing) of B. nigra and S. arvensis plants. Oviposition preference of P. brassicae declined with plant age in both plant species. Whereas larvae performed similarly on all three age classes in B. nigra, preference and performance were weakly correlated in S. arvensis. Analysis of primary (sugars and amino acids) and secondary (glucosinolates) chemistry in the plant shoots revealed that differences in their quality and quantity were more pronounced with respect to tissue type (leaves vs. flowers) than among different developmental stages of both plant species. Butterflies of P. brassicae may prefer younger and smaller plants for oviposition anticipating that future plant growth and size is optimally synchronized with the final larval instar, which contributes >80% of larval growth before pupation. PMID- 28620773 TI - Antioxidant uric acid in treated and untreated subjects with major depressive disorder: a meta-analysis and meta-regression. AB - Pathophysiological mechanisms of major depressive disorder (MDD) seem to be associated with oxidative stress pathways and altered purinergic metabolism. We conducted a systematic review and meta-analysis to estimate if subjects with MDD might have reduced levels of antioxidant uric acid, considering also potential influence of antidepressant treatment. We searched the main Electronic Databases, identifying 14 studies that met our inclusion criteria. Meta-analyses were carried out generating pooled Hedges' g and mean differences (MDs), using random effects models. Heterogeneity across studies and risk of publication bias were estimated using standard methods. Relevant sensitivity and meta-regression analyses were conducted. Subjects with MDD had levels of uric acid lower than healthy controls (Hedges' g = -0.30; p = 0.003). Overall between-study heterogeneity was high (I 2 = 76.3%). The effect was significant among studies including drug naive/free MDD individuals (Hedges' g = -0.55; p = 0.023), but not among those involving treated subjects (Hedges' g = -0.15; p = 0.062). Relevant quality- and heterogeneity-based sensitivity analyses, as well as meta regressions, confirmed these findings. In addition, uric acid levels significantly, though inconsistently (I 2 = 79.2%), increased after treatment (MD = +0.71 mg/dL; p < 0.001), regardless of follow-up duration (p = 0.518). Our meta analysis shows that subjects with MDD have lower levels of uric acid. Since antidepressant treatment seems to influence this association, our findings support the hypothesis that uric acid levels may represent a state marker of MDD. Nevertheless, the potential role of additional factors that might clarify the nature of this association deserves further research. PMID- 28620774 TI - "In My Culture, We Don't Know Anything About That": Sexual and Reproductive Health of Migrant and Refugee Women. AB - PURPOSE: Migrant and refugee women are at risk of negative sexual and reproductive health (SRH) outcomes due to low utilisation of SRH services. SRH is shaped by socio-cultural factors which can act as barriers to knowledge and influence access to healthcare. Research is needed to examine constructions and experiences of SRH in non-English-speaking migrant and refugee women, across a range of cultural groups. METHOD: This qualitative study examined the constructions and experiences of SRH among recent migrant and refugee women living in Sydney, Australia, and Vancouver, Canada. A total of 169 women from Afghanistan, Iraq, Somalia, South Sudan, Sudan, India, Sri Lanka and South America participated in the study, through 84 individual interviews, and 16 focus groups comprised of 85 participants. Thematic analysis was used to analyse the data. RESULTS: Three themes were identified: "women's assessments of inadequate knowledge of sexual and reproductive health and preventative screening practices", "barriers to sexual and reproductive health" and "negative sexual and reproductive health outcomes". Across all cultural groups, many women had inadequate knowledge of SRH, due to taboos associated with constructions and experiences of menstruation and sexuality. This has implications for migrant and refugee women's ability to access SRH education and information, including contraception, and sexual health screening, making them vulnerable to SRH difficulties, such as sexually transmissible infections and unplanned pregnancies. CONCLUSION: It is essential for researchers and health service providers to understand socio-cultural constraints which may impede SRH knowledge and behaviour of recent migrant and refugee women, in order to provide culturally safe SRH education and services that are accessible to all women at resettlement irrespective of ethnicity or migration category. PMID- 28620775 TI - Normalization as a Strategy for Maintaining Quality of Life While Coping with Infertility in a Pronatalist Culture. AB - PURPOSE: Infertility could be highly stressful, particularly in a pronatalist culture. We aimed to develop the concept and a measure of normalization (maintaining normal life routines and feeling "normal") as a strategy that could enable women with infertility maintain their quality of life (QoL) while coping with this condition. We tested its associations with women's well-being, distress and QoL in Israel, where being childless is socially unacceptable and highly stigmatized. METHODS: One-hundred and eighty Israeli women undergoing infertility treatment at a fertility community clinic filled in questionnaires assessing normalization-related coping strategies, QoL, and psychological adjustment (distress, wellbeing). Eight months later, 55 women conceived; 55 women who had not conceived completed a second questionnaire. RESULTS: At baseline, normalization was related to higher QoL and better adjustment. Structural equation modeling showed that QoL was impaired mainly among women who felt different than others, compared, and blamed themselves. Over time, normalization was overall unrelated to conception or to changes in adjustment yet was protective against decrease in well-being among women who already had a child. CONCLUSIONS: Infertility is highly stressful in a pronatalist culture like Israel. It requires treatment yet is not disabling. Patients who manage to maintain normal routines and not feel different than other people their age may experience better QoL and psychological adjustment. PMID- 28620776 TI - Quantity discrimination in angelfish (Pterophyllum scalare) is maintained after a 30-s retention interval in the large but not in the small number range. AB - The ability to discriminate between sets that differ in the number of elements can be useful in different contexts and may have survival and fitness consequences. As such, numerical/quantity discrimination has been demonstrated in a diversity of animal species. In the laboratory, this ability has been analyzed, for example, using binary choice tests. Furthermore, when the different number of items first presented to the subjects are subsequently obscured, i.e., are not visible at the moment of making a choice, the task requires memory for the size of the sets. In previous work, angelfish (Pterophyllum scalare) have been found to be able to discriminate shoals differing in the number of shoal members both in the small (less than 4) and the large (4 or more) number range, and they were able to perform well even when a short memory retention interval (2-15 s) was imposed. In the current study, we increased the retention interval to 30 s during which the shoals to choose between were obscured, and investigated whether angelfish could show preference for the larger shoal they saw before this interval. Subjects were faced with a discrimination between numerically small shoals (<=4 fish) and also between numerically large (>=4 fish) shoals of conspecifics. We found angelfish not to be able to remember the location of larger versus smaller shoals in the small number range, but to exhibit significant memory for the larger shoal in the large number range as long as the ratio between these shoals was at least 2:1. These results, together with prior findings, suggest the existence of two separate quantity estimation systems, the object file system for small number of items that does not work with the longer retention interval and the analogue magnitude system for larger number of items that does. PMID- 28620778 TI - Intracecal appendix: an extremely rare anatomical variation. A case report and review of literature. AB - Appendicitis is the most common surgical abdominal emergency in the developed world. Most of the surprises encountered during an appendectomy are usually due to the various positions of the appendix tip. Anatomical variations are an extremely rare phenomenon, with only a few case reports scattered among volumes of literature on the vermiform appendix. A new variation is described in which the appendix was intracecal and cause for surprise during surgery. A review of literature of rare anatomical variations of the appendix is also presented. PMID- 28620777 TI - Concentrations of lead and other elements in the liver of the white-tailed eagle (Haliaeetus albicilla), a European flagship species, wintering in Eastern Poland. AB - As a top predator, the white-tailed eagle (Haliaeetus albicilla) may serve as a good indicator species, providing information about the bioavailability of contaminants and their transfer within the food chain. In this study, we aimed to determine the common sources of origin of 17 metals and other elements in the liver of white-tailed eagles, and to compare the variations in their hepatic concentrations by age (adults vs immatures) and sex (males vs females) in groups of white-tailed eagles wintering in Eastern Poland. The element concentrations followed the pattern of S > K > Na > Fe > Mg > Ca > Zn > Cu > Mn > Se > Pb > Hg > Cd > Cr > Sr > V > Sc. We found significant age-related differences in the hepatic concentrations of some of the elements. Adults showed higher concentrations of Pb, Cd, Ca, Fe, and Zn and lower concentrations of Cu and Se than immatures. These differences may be explained by age-related differences in wintering strategy (adults are sedentary, and immatures are migratory) and hunting skills (adults are more successful when hunting for agile prey). Our study indicates that ingested Pb ammunition poses a serious threat to the health and lives of white-tailed eagles in Poland (32% of the studied individuals had acute lead poisoning). Our study also indicates a serious need for banning the use of lead hunting ammunition in the parts of Europe (including Poland) where it is still allowed. PMID- 28620779 TI - The cost of a patient activation intervention for achieving successful outcomes: results from the PAADRN randomized controlled trial. AB - : In a large, pragmatic clinical trial, we calculated the costs of achieving four successful patient-centered outcomes using a tailored patient activation DXA result letter accompanied by a bone health brochure. The cost to achieve one successful outcome (e.g., a 0.5 standard deviation improvement in care satisfaction) ranged from $127.41 to $222.75. INTRODUCTION: Pragmatic randomized controlled trials (RCTs) should focus on patient-centered outcomes and report the costs for achieving those outcomes. We calculated per person incremental intervention costs, the number-needed-to-treat (NNT), and incremental per patient costs (cost per NNT) for four patient-centered outcomes in a direct-to-patient bone healthcare intervention. METHODS: The Patient Activation after DXA Result Notification (PAADRN) pragmatic RCT enrolled 7749 patients presenting for DXA at three health centers between February 2012 and August 2014. Interviews occurred at baseline and 52 weeks post-DXA. Intervention subjects received an individually tailored DXA result letter accompanied by an educational bone health brochure 4 weeks post-DXA, while the usual care subjects did not. Outcomes focused on patients (a) correctly identifying their results, (b) contacting their providers, (c) discussing their results with their providers, and (d) satisfaction with their bone healthcare. NNTs were determined using intention-to-treat linear probability models, per person incremental intervention costs were calculated, and costs per NNT were computed. RESULTS: Mean age was 66.6 years old, 83.8% were women, and 75.3% were non-Hispanic whites. The incremental per patient cost (costs per NNT) to increase the ability of a patient to (a) correctly identify their DXA result was $171.07; (b) contact their provider about their DXA result was $222.75; (c) discuss their DXA result with their provider was $193.55; and (d) achieve a 0.5 SD improvement in satisfaction with their bone healthcare was $127.41. CONCLUSION: An individually tailored DXA result letter accompanied by an educational brochure can improve four patient-centered outcomes at a modest cost. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT01507662. PMID- 28620781 TI - Psychopathology and socioeconomic position: what can be done to break the vicious circle? PMID- 28620780 TI - A novel large fragment deletion in PLS3 causes rare X-linked early-onset osteoporosis and response to zoledronic acid. AB - : We identified a novel large fragment deletion from intron 9 to 3'UTR in PLS3 (E10-E16del) in one Chinese boy with X-linked early-onset osteoporosis and vertebral fractures, which expanded the pathogenic spectrum of X-linked early onset osteoporosis. Treatment with zoledronic acid was beneficial for increasing BMD and reshaping the vertebral bodies of this patient. INTRODUCTION: X-linked early-onset osteoporosis is a rare disease, which is characterized by low bone mineral density (BMD), vertebral compression fractures (VCFs), and/or long bone fractures. We aimed to detect the phenotype and the underlying pathogenic mutation of X-linked early-onset osteoporosis in a boy from a nonconsanguineous Chinese family. METHODS: We investigated the pathogenic mutation of the patient with X-linked early-onset osteoporosis by targeted next-generation sequencing and confirmed it by Sanger sequencing. We also observed the effects of zoledronic acid on fracture frequency and BMD of the patient. RESULTS: Low BMD and multiple VCFs were the main phenotypes of X-linked early-onset osteoporosis. We identified a total of 12,229 bp deletion in PLS3, involving intron 9 to the 3'UTR (E10-E16 del). This large fragment deletion might be mediated by Alu repeats and microhomology of 26 bp at each breakpoint junction. Zoledronic acid treatment could significantly increase the Z-score of BMD and reshape the compressed vertebral bodies. CONCLUSION: We identified a large fragment deletion mutation in PLS3 for the first time and elucidated the possible mechanism of the deletion, which led to X-linked early-onset osteoporosis and multiple vertebral fractures. Our findings would enrich the etiology spectrum of this rare disease. PMID- 28620782 TI - Role of key genetic mutations on increasing migration of brain cancer cells through confinement. AB - Uncontrolled invasive cancer cell migration is among the major challenges for the treatment and management of brain cancer. Although the genetic profiles of brain cancer cells have been well characterized, the relationship between the genetic mutations and the cells' mobility has not been clearly understood. In this study, using microfluidic devices that provide a wide range of physical confinements from 20 * 5 MUm2 to 3 * 5 MUm2 in cross sections, we studied the effect of physical confinement on the migratory capacity of cell lines with different types of mutations. Human glioblastoma and genetically modified mouse astrocytes were used. Human glioblastoma cells with EGFRvIII mutation were found to exhibit high degree of migratory capacity in narrow confinement. From mouse astrocytes, cells with triple mutations (p53-/- PTEN-/- BRAF) were found to exhibit the highest level of migratory capacity in narrow confinement compared to both double (p53-/- PTEN-/-) and single (p53-/-) mutant cells. Furthermore, when treating the triple mutant astrocytes with AZD-6244, an inhibitor of the RAF/MEK/ERK pathway, we found significant reduction in migration through the confined channels when compared to that of controls (83% decrease in 5 * 5 MUm2 and 86% in 3 * 5 MUm2 channels). Our data correlate genetic mutations from different cell lines to their motility in different degrees of confinement. Our results also suggest a potential therapeutic target such as BRAF oncogene for inhibition of brain cancer invasion. PMID- 28620783 TI - Advanced Neuroimaging of Cerebral Small Vessel Disease. AB - OPINION STATEMENT: Cerebral small vessel disease (SVD) is characterised by damage to deep grey and white matter structures of the brain and is responsible for a diverse range of clinical problems that include stroke and dementia. In this review, we describe advances in neuroimaging published since January 2015, mainly with magnetic resonance imaging (MRI), that, in general, are improving quantification, observation and investigation of SVD focussing on three areas: quantifying the total SVD burden, imaging brain microstructural integrity and imaging vascular malfunction. Methods to capture 'whole brain SVD burden' across the spectrum of SVD imaging changes will be useful for patient stratification in clinical trials, an approach that we are already testing. More sophisticated imaging measures of SVD microstructural damage are allowing the disease to be studied at earlier stages, will help identify specific factors that are important in development of overt SVD imaging features and in understanding why specific clinical consequences may occur. Imaging vascular function will help establish the precise blood vessel and blood flow alterations at early disease stages and, together with microstructural integrity measures, may provide important surrogate endpoints in clinical trials testing new interventions. Better knowledge of SVD pathophysiology will help identify new treatment targets, improve patient stratification and may in future increase efficiency of clinical trials through smaller sample sizes or shorter follow-up periods. However, most of these methods are not yet sufficiently mature to use with confidence in clinical trials, although rapid advances in the field suggest that reliable quantification of SVD lesion burden, tissue microstructural integrity and vascular dysfunction are imminent. PMID- 28620784 TI - Inhibitory Effect of Taurine on Biofilm Formation During Alkane Degradation in Acinetobacter oleivorans DR1. AB - Taurine, 2-aminoethanesulfonate, is known to function as an antioxidant or membrane stabilizer in eukaryotic cells, but its role in bacteria has been poorly characterized. Biofilm formation of Acinetobacter oleivorans DR1 was significantly reduced by taurine only during alkane degradation, suggesting that taurine affects alkane-induced cell surface. Structurally similar compounds harboring an amine group such as hypotaurine or ethylenediamine have a similar effect, which was not observed with sulfonate-containing chemicals such as ethanesulfonic acid, hexanesulfonic acid. Our biochemical assays and physiological tests demonstrate that taurine reduced cell surface hydrophobicity, which resulted in interruption of the interactions between cells and oily substrate surfaces, such that cells utilized alkanes less effectively. Interestingly, taurine-mediated reduction of quorum sensing (QS) signal production and QS-control sapA gene expression indicated that membrane permeability of quorum signals was also interfered by taurine. Composition and biomass of extracellular polymeric saccharides were changed in taurine-amended conditions. Taken together, our data provide evidence that amine-containing taurine can inhibit biofilm formation of DR1 cells during alkane degradation by (i) changing cell surface charge and (ii) reducing membrane hydrophobicity and QS sensing. PMID- 28620785 TI - Microbial Interspecies Interactions Affect Arsenic Fate in the Presence of MnII. AB - Biotransformation of arsenic (As) plays an important role in its environmental fate. However, the impact of direct microbial interspecies interactions on valence state and migration of As is rarely reported and cognized. Here, by co cultivating two aerobic AsV-reducing bacteria (Arthrobacter sp. QXT-31 and Sphingopyxis sp. QXT-31) in a culture medium containing initial AsV (10 MUM) and bivalent manganese (MnII, 175 MUM), we demonstrated how the interactions between strains affect valence state and partition of As. The results showed that both the strains first reduced AsV to AsIII via a detoxification mechanism during aerobic growth, with participation of AsV-reducing gene arsC; the expression of a MnII-oxidizing gene of Arthrobacter sp. QXT-31 was then triggered in the presence of Sphingopyxis sp. QXT-31, and emerging MnII-oxidizing activity oxidized 90% of MnII to Mn oxides; the formed Mn oxides oxidized AsIII to AsV and adsorbed AsV; MnII-oxidizing activity decreased significantly in the later stage, resulting to desorption of AsV from Mn oxides and subsequent bioreduction in aqueous phase. Considering the universality of the two bacterial genera and the interspecies interactions, our study hints at the pervasive impact of direct microbial interspecies interactions on the environmental fate of As in an aquatic ecosystem containing Mn. PMID- 28620786 TI - Langerhans and Merkel: a nervous epidermal dispute. PMID- 28620787 TI - Do position and size matter? An analysis of cage and placement variables for optimum lordosis in PLIF reconstruction. AB - PURPOSE: To examine monosegmental lordosis after posterior lumbar interbody fusion (PLIF) surgery and relate lordosis to cage size, shape, and placement. METHODS: Eighty-three consecutive patients underwent single-level PLIF with paired identical lordotic cages involving a wide decompression and bilateral facetectomies. Cage parameters relating to size (height, lordosis, and length) and placement (expressed as a ratio relative to the length of the inferior vertebral endplate) were recorded. Centre point ratio (CPR) was the distance to the centre of both cages and indicated mean position of both cages. Posterior gap ratio (PGR) was the distance to the most posterior cage and indicated position and cage length indirectly. Relationships between lordosis and cage parameters were explored. RESULTS: Mean lordosis increased by 5.98 degrees (SD 6.86 degrees ). The cages used varied in length from 20 to 27 mm, in lordosis from 10 degrees to 18 degrees , and in anterior cage height from 10 to 17 mm. The mean cage placement as determined by CPR was 0.54 and by PGR was 0.16. The significant correlations were: both CPR and PGR with lordosis gain at surgery (r = 0.597 and 0.537, respectively, p < 0.001 both), cage lordosis with the final lordosis (r = 0.234, p < 0.05), and anterior cage height was negatively correlated with a change in lordosis (r = -0.297, p < 0.01). CONCLUSION: Cage size, shape, and position, in addition to surgical technique, determine lordosis during PLIF surgery. Anterior placement with sufficient "clear space" behind the cages is recommended. In addition, cages should be of moderate height and length, so that they act as an effective pivot for lordosis. PMID- 28620788 TI - Comparison of intraoperative neurophysiologic monitoring outcomes between cervical and thoracic spine surgery. AB - PURPOSE: The objective is to compare the intraoperative monitoring (IOM) outcomes between degenerative cervical and thoracic spine decompression surgery. METHOD: A total of 97 patients with cervical compression myelopathy (CCM) and 75 patients with thoracic compression myelopathy (TCM) were prospectively collected between December 2012 and June 2015 in our spine center. Somatosensory-evoked potentials (SSEP) and motor-evoked potentials (MEP) were used for IOM. The postoperative neurologic status of each patient was assessed immediately after surgery. And the IOM and neurological outcomes were mainly analyzed in this study. RESULTS: Under the same alarm criteria, the IOM changes present significant difference between the cervical and thoracic surgery. During the patients with monitoring alerts, the MEPs usually manifest as sudden loss in TCM whereas the gradual loss in CCM. And there were three permanent neurologic injuries in the thoracic cases, but none in cervical cases. CONCLUSION: The IOM loss between CCM and TCM patients present obvious difference and the sudden MEPs loss associated with spinal decompression need to be taken seriously especially in TCM. PMID- 28620789 TI - Reply to the Letter to the Editor of C. Brembilla et al. concerning "Spinal metallosis: a systematic review" by Goldenberg Y, Tee JW, Salinas-La Rosa CM, Murphy M (Eur Spine J; 2016, 25:1467-1473). PMID- 28620790 TI - Female double incontinence: prevalence, incidence, and risk factors from the SABE (Health, Wellbeing and Aging) study. AB - INTRODUCTION AND HYPOTHESIS: Double Incontinence (DI) is incontinence of urine and stool and is an extreme manifestation of pelvic floor dysfunction. The objective of this study was to estimate the prevalence and incidence of DI and the risk factors in elderly women in Sao Paulo, Brazil. METHODS: This was a prospective study in women aged 65 years or older evaluated in 2006 and re evaluated in 2010. The sample was selected by two-phase stratified sampling with replacement and probability proportional to size. The likelihood ratio test was performed and Cox regression curves were generated to evaluate the equality of survival. Poisson's regression was used to evaluate risk factors. RESULTS: This is the first study on the incidence of DI in elderly women. A total of 864 elderly women were interviewed in 2006. The prevalence rate of DI was 4.9%. The incidence rate of DI in the period between 2006 and 2010 was 13.8/1,000 person years. Associated factors were the presence of chronic obstructive pulmonary disease, hypertension, difficulty with basic activities of daily living (BADL) and instrumental activities of daily living (IADL), polypharmacy and falls in the last year. Poisson's regression analysis showed that falls in the last year and difficulty with at least three IADL were risk factors for DI. CONCLUSIONS: The incidence of DI seems to be high in this population. Falls in the last year and difficulty with at least three IADL were identified as risk factors. Preventive measures must be implemented with public health policies to prevent increases in DI. PMID- 28620791 TI - A prospective, double-blind, randomized, two-period crossover, multicenter study to evaluate tolerability and patient preference between mirabegron and tolterodine in patients with overactive bladder (PREFER study). AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to assess the tolerability and treatment preference in patients with overactive bladder (OAB) treated with mirabegron or tolterodine. METHODS: This was a two-period, 8-week crossover, double-blind, phase IV study (PREFER; NCT02138747) in treatment-naive adults with OAB for 3 months or longer randomized to one of four treatment sequences in a 5:5:1:1 ratio (mirabegron/tolterodine, tolterodine/mirabegron, mirabegron/mirabegron, or tolterodine/tolterodine), separated by a washout period of 2 weeks. The primary endpoint was drug tolerability using the Medication Tolerability scale of the OAB Treatment Satisfaction (OAB-S) questionnaire at end of treatment (EoT). Period-by-treatment interactions were analyzed to determine any effect of drug order. Patient preference, change from baseline in OAB symptoms, and treatment-emergent adverse events (TEAEs) were assessed. RESULTS: A total of 358 randomized patients completed the OAB-S Medication Tolerability scale questionnaire at one or more visits after the baseline evaluation. The mean (95% CI) OAB-S Medication Tolerability scores were significantly higher (better tolerability) for mirabegron (86.29 [83.50, 89.08]) than for tolterodine (83.40 [80.59, 86.20]; p = 0.004). The period-by-treatment interaction was not significant (p = 0.955). Improvements in OAB-S Medication Tolerability scores at EoT were more evident in women, patients aged >=65 years, and in patients without baseline incontinence, and were greater with mirabegron than with tolterodine extended release. There were no significant differences in patient preference or improvements in OAB symptoms. Significant differences in favor of mirabegron were observed for anticholinergic TEAEs (20.4% vs. 27.4%; p = 0.042) and specifically for gastrointestinal disorders (14.7% vs. 22.5%; p = 0.015). CONCLUSIONS: Tolerability of mirabegron was significantly higher than that of tolterodine, and patient preference and improvements in OAB symptoms were comparable. Both treatments were well tolerated; however, anticholinergic side effects were higher with tolterodine. PMID- 28620792 TI - Evaluation of coital incontinence by electronic questionnaire: prevalence, associations and outcomes in women attending a urogynaecology clinic. AB - INTRODUCTION AND HYPOTHESIS: Coital incontinence is the involuntary leakage of urine during sexual intercourse and is divided into that occurring with penetration and that occurring with orgasm. Mechanisms of coital incontinence are poorly understood. The aim of this retrospective study was to measure the prevalence of coital incontinence and evaluate the association among various types of coital incontinence with stress urinary incontinence (SUI), overactive bladder (OAB) and impact on quality-of-life in women attending a urogynaecology clinic. METHODS: A total of 2,312 women completed the electronic Personal Assessment Questionnaire-Pelvic Floor (ePAQ-PF) in advance of their urogynaecology consultation. Logistic regression and Spearman's rank-order correlation evaluated associations between types of coital incontinence and OAB and SUI. The Mann-Whitney test evaluated the relationship between coital incontinence and self-reported quality of sex life and self-avoidance and partner avoidance of sex. Subgroup analysis analysed outcomes in 84 women with coital incontinence undergoing treatment with tension-free vaginal tape (TVT). RESULTS: Prevalence of coital incontinence in the cohort was 30%. Symptoms of OAB (p < 0.005) and SUI (p < 0.005) were significantly and independently associated with both types of coital incontinence (orgasm and penetration). In women with coital incontinence compared with those without, there was significant self-avoidance of sex (p < 0.0005), partner avoidance of sex (p < 0.0005) and impaired quality of sex life due to sexual problems (p < 0.005). The impact of this was significant in each group. Subgroup analysis of 84 women undergoing TVT showed significant improvement in all coital incontinence symptoms 3 months post-operatively. CONCLUSION: Using an electronic questionnaire before consultation has identified coital incontinence to be a prevalent symptom, having a significant impact on the patient's sex life. Coital incontinence at orgasm and penetration are both significantly associated with SUI and OAB. PMID- 28620793 TI - Response to comment on the IUGA/ICS joint report on the terminology for the conservative and nonpharmacological management of female pelvic floor dysfunction. PMID- 28620794 TI - Evidence to justify retention of transvaginal mesh: comparison between laparoscopic sacral colpopexy and transvaginal ElevateTM mesh. AB - INTRODUCTION AND HYPOTHESIS: To determine if laparoscopic sacral colpopexy (LSC) offers better apical support with a lower exposure rate than transvaginal mesh surgery with ElevateTM. METHODS: This was a retrospective cohort study comparing patients with apical prolapse (POP-Q point C >= -1) who underwent ElevateTM mesh repair (n = 146) with patients who underwent laparoscopic sacral colpopexy (n = 267). RESULTS: The sacral colpopexy group had a mean age of 59 years and a BMI of 25.7. Patients in the ElevateTM group were older, with a mean age of 63 and a BMI of 26.3. Most of the patients of both groups presented with pelvic organ prolapse stage III (LSC 73.8% and ElevateTM 87.0%) and their mean POP-Q point C were not significantly different (LSC 1.4 vs ElevateTM 1.2 cm). Operative time was longer in the LSC group (113 vs 91 min, p < 0.001), but estimated blood loss was lower (75 cm3 vs 137 cm3, p < 0.001). No difference in mesh exposure rate could be found between the two groups at one year (ElevateTM 0.7% vs LSC 2.6%, OR 0.26, 95% CI 0.03 to 2.10, p = 0.21). One-year objective cure rate, defined as no descent beyond the hymen, was 97.0% in the LSC group and 96.6% in the ElevateTM group (p = .81). The overall recurrence (objective, subjective recurrence or reoperation) was also not different between the groups (LSC 4.5% vs Elevate 4.8%, p = 0.89). CONCLUSION: Transvaginal ElevateTM mesh delivers comparable apical support with a low exposure rate similar to that of laparoscopic sacral colpopexy. PMID- 28620795 TI - Levator ani defects and the severity of symptoms in women with anterior compartment pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: The aims of this study were to evaluate the prevalence of levator ani muscle (LAM) avulsions in a selected cohort of patients with primary anterior compartment pelvic organ prolapse (POP) and to assess whether LAM avulsions, as an independent factor, affect the degree of POP symptoms and sexual dysfunction. Additionally, clinical and demographic variables of women with and those without avulsions were compared. METHODS: We carried out a cross-sectional analysis of a prospective cohort study including 197 women scheduled for anterior compartment POP surgery. LAM avulsions were diagnosed on transperineal 4D ultrasound. Preoperative symptom severity and sexual dysfunction were evaluated using validated questionnaires (Pelvic Floor Disability Index [PFDI-20] and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire Short Form 12 [PISQ-12]). Linear regression was performed with avulsion as the main independent variable against total PFDI-20 and domain scores, bulge symptoms, and PISQ-12 score. Clinical and demographic variables for women with and without avulsions were compared using independent samples t test, Mann Whitney U test or Chi-squared test. RESULTS: The prevalence of LAM avulsions was 50.3%. Avulsions were not associated with symptom severity or sexual dysfunction. "Chronic disease causing pain, fatigue or increased intra-abdominal pressure" was the only independent factor associated with all domains of the PFDI-20. Women with avulsions were younger at presentation, older at their first delivery, had lower BMI, and more often had a history of forceps delivery (p < 0.01). CONCLUSIONS: LAM avulsions were highly prevalent in this preoperative POP cohort. Avulsions were not associated with the severity of POP symptoms or sexual dysfunction. Women with avulsions seem to require fewer additional cofactors for developing POP. PMID- 28620796 TI - Antioxidant Capacity of Beetroot: Traditional vs Novel Approaches. AB - Red beetroot has been ranked among the 10 most potent antioxidant vegetables, although only extraction-based methods have been used to evaluate its total antioxidant capacity. Therefore, the present study aims at comparing the traditional extraction-based method with two more recent approaches (QUENCHER QUick, Easy, New, CHEap and Reproducible- and GAR -global antioxidant response method), in order to establish their suitability in the case of beetroot. Our results indicate that the total antioxidant capacity of beetroot would be underestimated when using extraction-based procedures, since both QUENCHER and GAR methods resulted in a higher total antioxidant capacity. The effect of a thermal treatment on the total antioxidant capacity of beetroot varies among the methods evaluated and our findings suggest different compounds responsible for the total antioxidant capacity detected in each pre-processing method. Remarkably, the present study demonstrates that the traditional extraction-based method seems useful to screen for (changes in) the "bioavailable" antioxidant potential of the root. PMID- 28620800 TI - Non-uniform sampling in biomolecular NMR. PMID- 28620798 TI - "Inflammatory skin march" in atopic dermatitis and psoriasis. AB - BACKGROUND: Comorbidities of cardiovascular diseases (CVDs), metabolic syndrome and autoimmune diseases with systemic inflammation are recent topics in medicine. Inflammatory skin diseases such as atopic dermatitis and psoriasis are an active source of diverse proinflammatory cytokines and chemokines, which are readily detectable in the circulation and are likely to be involved in developing comorbidities. EVIDENCE: Both atopic dermatitis and psoriasis are frequently comorbid with CVD, metabolic syndrome and autoimmune diseases, the consequence of which is called "inflammatory skin march", "psoriatic march" or "march of psoriasis". CONCLUSION: In this review, we summarize the epidemiological evidence and pathogenetic concepts regarding inflammatory skin march in atopic dermatitis and psoriasis. PMID- 28620799 TI - Changes of fatty infiltration according to the immediate postoperative time point in magnetic resonance imaging after arthroscopic rotator cuff repair. AB - PURPOSE: Fatty infiltration (FI) is known to be an irreversible change which continues degeneration after rotator cuff repair. Previous studies evaluated postoperative changes in FI using a preoperative baseline. This study aimed to investigate the changes in FI using an immediate postoperative baseline. We hypothesized that FI was progressed more when measured relative to an immediate postoperative baseline than to a preoperative baseline. METHODS: From 2008 to 2010, 77 patients who met the following criteria were included in this study: arthroscopic rotator cuff repair of a full-thickness rotator cuff tear and presence of preoperative (approximately 1 month before surgery), immediate postoperative (approximately 3 days after surgery), and 1-year postoperative (at least 9 months to 1 year after surgery) magnetic resonance imaging (MRI) undertaken. The exclusion criteria were: absence of any of the three MRIs, isolated subscapularis repair, and rotator cuff repair with margin convergence only. The MRIs were examined to assess the Goutallier grade of the rotator cuff muscles for the assessment of FI. Structural integrity was evaluated using the Sugaya classification. Measurements 1 year after surgery were compared with those at the preoperative and immediate postoperative time points according to the integrity. RESULTS: In the total and retear group, FI in the supraspinatus and infraspinatus 1 year after surgery did not change significantly relative to the preoperative baseline (all n.s.), but progressed compared to the immediate postoperative baseline (all p < 0.001). In the retear group, FI in the supraspinatus and infraspinatus reduced for seven and two of 20 patients, respectively, compared with the preoperative baseline; however, no patients showed a reduced FI compared with the immediate postoperative baseline. CONCLUSIONS: The results of the study showed that the changes in FI reduced, remained or progressed in accordance with the baseline and structural integrity. FI progressed when compared with the immediate postoperative baseline than with the preoperative baseline. The immediate postoperative time point would be considered as the baseline to monitor the true changes of FI after repair. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 28620802 TI - At-Risk Alcohol Use Among HIV-Positive Patients and the Completion of Patient Reported Outcomes. AB - Heavy drinking is prevalent among people living with HIV. Studies use tools like patient-reported outcomes (PROs) to quantify alcohol use in a detailed, timely manner. However, if alcohol misuse influences PRO completion, selection bias may result. Our study included 14,145 adult HIV patients (133,036 visits) from CNICS who were eligible to complete PROs at an HIV primary care visit. We compared PRO completion proportions between patients with and without a clinical diagnosis of at-risk alcohol use in the prior year. We accounted for confounding by baseline and visit-specific covariates. PROs were completed at 20.8% of assessed visits. The adjusted difference in PRO completion proportions was -3.2% (95% CI -5.6 to 0.8%). The small association between receipt of an at-risk alcohol use diagnosis and decreased PRO completion suggests there could be modest selection bias in studies using the PRO alcohol measure. PMID- 28620801 TI - FTY720 Attenuates Infection-Induced Enhancement of Abeta Accumulation in APP/PS1 Mice by Modulating Astrocytic Activation. AB - It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-beta (Abeta) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amyloid pathology and deterioration of cognitive function. These changes are against a backdrop of an age- and AD-related increase in susceptibility to infection. Here we set out to determine whether FTY720, a molecule that binds sphingosine-1-phosphate (S1P) receptors and with known immunosuppressant effects mediating its therapeutic action in multiple sclerosis (MS), might modulate the impact of infection in a mouse model of AD. Transgenic mice that overexpress amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice) and their littermates were/were not infected with Bordetella pertussis and were treated orally with FTY720 or vehicle beginning 3 days before infection. Infection increased astrocytic activation and enhanced blood brain barrier (BBB) permeability and these changes were attenuated in FTY720-treated B. pertussis-infected mice. Significantly, infection increased Abeta containing plaques and soluble Abeta and these infection-related changes were also attenuated in FTY720-treated B. pertussis-infected mice. The data suggest that this effect results from an FTY720-induced increase in Abeta phagocytosis by astrocytes. FTY720 did not impact on genotype-related changes in the absence of an infection indicating that its potential usefulness is restricted to reducing the impact of acute inflammatory stimuli in AD. PMID- 28620803 TI - Impact of Pharmacy Proximity and Delivery Services on HIV Viral Suppression Among Low Income Urban Patients. AB - Adherence to antiretrovirals is essential to achieve viral suppression in HIV patients. Unfortunately, numerous barriers to adherence and subsequent viral suppression still exist. This study examines the association between pharmacy location and viral suppression for low income HIV patients. We evaluated whether home delivery services or closer proximity to in-store pharmacies was associated with viral suppression. Patients utilizing delivery pharmacy had increased likelihood of sustained viral suppression compared to in-store pharmacy patients (aOR = 3.430). For patients traveling to pharmacies, there were no differences in proximity for suppressed and non-suppressed patients. Home delivery may aid adherence and improve viral suppression. PMID- 28620804 TI - Core elements of general supportive care for patients with sepsis and septic shock in resource-limited settings. PMID- 28620805 TI - Action effect features, but not anatomical features, determine the Backward Crosstalk Effect: evidence from crossed-hands experiments. AB - The Backward Crosstalk Effect (BCE) indicates that response features of Task 2 in a dual-task paradigm influence even Task 1 performance. However, it can be assumed that responses are represented with multiple features in the cognitive system. In this regard, Ideomotor Theory suggests action effects as one central response feature in human action control and an earlier study by Janczyk, Pfister, Hommel, and Kunde (Cognition 132: 30-43, 2014) already provided some evidence that action effects are a crucial determinant of the BCE. The present study aimed to further investigate which response features are critical for the BCE. Therefore, a crossed-hands manipulation was implemented in two experiments to examine whether the spatial position of the actual response and thus its associated action effects or the body-side of the effectors' anatomical connection determine the BCE. Analyses revealed that even when participants press a left response key with the right hand and vice versa, the usual BCE occurs. These results indicate that the BCE depends on spatial features of the action effects rather than on anatomical features and thus provide additional support for the assumption that action effects have an important influence on the BCE and on action control in general. PMID- 28620806 TI - Familial hypocalciuric hypercalcemia type 1 due to a novel homozygous mutation of the calcium-sensing receptor gene. PMID- 28620807 TI - Predictive factors of maternal hypothermia during Cesarean delivery: a prospective cohort study. AB - PURPOSE: Although perioperative hypothermia may increase maternal morbidity, active warming is infrequently performed to maintain normothermia during Cesarean delivery (CD). The aim of this prospective observational study was to determine the factors associated with maternal hypothermia in this setting. METHODS: Women scheduled for elective or emergency CD were consecutively included in this study from November 2014 to October 2015. Maternal temperature was measured using an infrared tympanic thermometer on the patient's arrival in the operating room, at skin incision, and at the end of skin suture. Maternal hypothermia was defined by tympanic temperature < 36 degrees C at the end of skin suture. Univariate analysis was performed, followed by multivariate logistic regression analysis, in order to determine the factors associated with maternal hypothermia at the end of the surgery. RESULTS: Three hundred fifty-nine women were included and analyzed during this study. The incidence of hypothermia was 23% (95% confidence interval, 18 to 27) among the total population included. According to multivariate analysis, obesity, oxytocin augmentation of labour, and use of active forced-air warming were associated with a decreased risk of maternal hypothermia, while maternal temperature < 37.1 degrees C on arrival in the operating room, maternal temperature < 36.6 degrees C at skin incision, and an infused volume of fluids > 650 mL were significantly associated with maternal hypothermia. Both goodness of fit and predictive value of multivariate analysis were high. CONCLUSION: Several predictive factors for maternal hypothermia during CD were identified. These factors should be taken into account to help prevent maternal hypothermia during CD. PMID- 28620808 TI - Expression of CD44 variant 6 and its prognostic value in benign and malignant endometrial tissue. AB - PURPOSE: CD44 expression in both the early and metastatic phases of many epithelial and non-epithelial cancers is strongly prognostic. The objective of the study is to evaluate whether there is any relationship between the expression of CDD44v6 and endometrial cancer (EC) staging and prognosis. METHODS: This retrospective study included 60 EC patients for whom surgical staging was performed between 2000 and 2006. Twenty-eight randomly selected patients with normal endometria served as the control group. We immunohistochemically evaluated membranous and cytoplasmic CD44v6 staining in tissue paraffin blocks. The results were graded as positive or negative. RESULTS: Membranous staining in both advanced and early stage EC patients was significantly higher than that in the control group (p = 0.002). The extent of either membranous or cytoplasmic staining in both advanced- and early stage patients did not differ significantly by age, tumor grade, stage, extent of myometrial invasion, lymph node involvement, cytology, adnexal involvement, or omental spreading. In advanced stage patients, neither papillary serous not clear cell cancers exhibited cytoplasmic staining. CONCLUSIONS: CD44v6 membranous staining can be useful for differentiating malignant from benign endometrial tissue. However, staining is not associated with EC staging or prognosis. PMID- 28620809 TI - Single gene reassortment of highly pathogenic avian influenza A H5N1 in the low pathogenic H9N2 backbone and its impact on pathogenicity and infectivity of novel reassortant viruses. AB - Avian influenza A H5N1 and H9N2 viruses have been extensively circulating in various avian species and frequently infect mammals, including humans. The synchronous circulation of both viruses in Egypt provides an opportunity for possible genetic assortment, posing a probable threat to global public health. To assess the potential risk of the IAV reassortants derived from co-circulation of these two AI subtypes, reverse genetics technology was used to generate a set of IAV reassortants carrying single genetic segments of clade 2.2.1.2 virus A/duck/Egypt/Q4596D/2012 (H5N1), a representative of the most prevalent H5N1 clade in Egypt, in the genetic backbone of A/chicken/Egypt/S4456B/2011 (H9N2), a representative of G1-like H9N2 lineage which is widely circulating in Egypt. Furthermore, the genetic compatibility, growth kinetics and virulence were evaluated in vitro in mammalian systems using the MDCK cell line and avian system using SPF embryonated chicken eggs. Pathogenicity and virus shedding were further tested using SPF chickens. Out of the eight desired H9-reassortants, we could rescue only 5 reassortant viruses, either due to difficulty in cloning (PB1 of H5N1 virus) or genetic incompatibility (NP-H5/H9 and NA-H5/H9). Results revealed higher replication rates for the H9N2 virus having the NS segment of H5N1 virus. The lowest survival rate in both SPF eggs and SPF chickens was associated with the H5N1 parent virus infection, followed by the HA-H5/H9 virus. Our findings also suggest that all other reassortant viruses were of lower pathogenicity than the wild type H5N1 virus. PMID- 28620810 TI - c-Jun integrates signals from both MEK/ERK and MKK/JNK pathways upon vaccinia virus infection. AB - Usurpation of the host's signalling pathways is a common strategy employed by viruses to promote their successful replication. Here we show that infection with the orthopoxvirus vaccinia virus (VACV) leads to sustained stimulation of c-Jun activity during the entire infective cycle. This stimulation is temporally regulated through MEK/ERK or MKK/JNK pathways, i.e. during the early/mid phase (1 to 6 hpi) and in the late phase (9 to 24 hpi) of the infective cycle, respectively. As a transcriptional regulator, upon infection with VACV, c-Jun is translocated from the cytoplasm to the nucleus, where it binds to the AP-1 DNA sequence found at the promoter region of its target genes. To investigate the role played by c-Jun during VACV replication cycle, we generated cell lines that stably express a c-Jun-dominant negative (DNc-Jun) mutation. Our data revealed that c-Jun is required during early infection to assist with viral DNA replication, as demonstrated by the decreased amount of viral DNA found in the DNc-Jun cells. We also demonstrated that c-Jun regulates the expression of the early growth response gene (egr-1), a gene previously shown to affect VACV replication mediated by MEK/ERK signalling. VACV-induced stimulation of the MKK/JNK/JUN pathway impacts viral dissemination, as we observed a significant reduction in both viral yield, during late stages of infection, and virus plaque size. Collectively, our data suggest that, by modulating the host's signalling pathways through a common target such as c-Jun, VACV temporally regulates its infective cycle in order to successfully replicate and subsequently spread. PMID- 28620811 TI - Serological, molecular and clinical correlates of dengue from a tertiary care centre in Chennai, India. AB - Dengue disease is caused by dengue viruses 1-4 and has been ranked by the World Health Organisation (WHO) as the fastest spreading vector-borne viral disease. Dengue is often underreported and misdiagnosed due to a wide spectrum of clinical manifestations. Diagnosis of dengue is based on clinical case definitions and laboratory methods. Newer case definitions of dengue have been formulated by clinical studies in order to improve case detection. Owing to its epidemic potential, mortality and morbidity, there is a need for a rapid and accurate diagnostic assay for dengue in order to help the clinician in the early detection of cases and to prevent disease progression. A duplex real time PCR targeting the 3'UTR region for rapid and simultaneous detection of all dengue viruses serotypes (1-4) was standardized based on published literature. About 150 patients with acute undifferentiated febrile illness classified based on the 2009 WHO dengue case definition were tested using the duplex real time dengue PCR. Sequencing based PCR was performed on selected PCR positive samples for partial nucleotide sequence of the CprM gene and a phylogenetic tree was constructed. Statistical analysis was done using the MedCalc software. Out of the 126 patients classified as dengue disease positive, according to the 2009 WHO dengue case definition, 54% had "probable dengue", 43% had "dengue with warning signs" and 3% had "severe dengue". The performance of the duplex real time PCR was assessed among the various clinical groups of dengue and it was found that in the "dengue with warning signs group" PCR had a positive predictive value of 85.29% (range - 68.94% to 95.05%) when compared with dengue NS1 ELISA. The average time for PCR positivity was found to be four days from the onset of illness. The cycling threshold values obtained from real time PCR were used as a semi quantitative measure of viremia. Accordingly, there was a relatively low CT value among the "warning signs dengue group" when compared to the "probable dengue group". The use of the duplex PCR is suggested in the early diagnosis of dengue, especially in the 'warning signs' group of patients as they showed a higher positivity rate. Also, the use of the resultant CT value as a semi-quantitative measure of viremia will assist the clinician in early diagnosis and prevention of disease development. PMID- 28620797 TI - Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. AB - There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia Pacific region, where HCC is one of the leading public health problems. Since the "Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines" meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia-Pacific region, which has a diversity of medical environments. PMID- 28620812 TI - Case study of first episode schizophrenia in pregnancy and postpartum. AB - Patients with first-episode psychosis of peripartum onset commonly prove to have a mood-disorder diathesis; however, a proportion of cases represent first-episode schizophrenia. We present such a case and discuss the clinical relevance of recognizing this small but important population of new mothers. These patients are at considerable risk of misdiagnosis, resulting in ineffective maintenance therapy, poorer recovery of function, and development of treatment resistance. Accurate diagnosis in the peripartum period will impact treatment decisions and long-term therapy. Clinicians need to be vigilant, especially during maintenance therapy, to identify these patients and ensure appropriate antipsychotic therapy is provided. PMID- 28620813 TI - An in-silico insight into the substrate binding characteristics of the active site of amorpha-4, 11-diene synthase, a key enzyme in artemisinin biosynthesis. AB - The enzyme amorphadiene synthase (ADS) conducts the first committed step in the biosynthetic conversion of the substrate farnesyl pyrophosphate (FPP) to artemisinin, which is a highly effective natural product against multidrug resistant strains of malaria. Due to the either low abundance or low turn-over rate of the enzyme, obtaining artemisinin from both natural and synthetic sources is costly and laborious. In this in silico study, we strived to elucidate the substrate binding site specificities of the ADS, with the rational that unraveling enzyme features paves the way for enzyme engineering to increase synthesis rate. A homology model of the ADS from Artemisia annua L. was constructed based on the available crystal structure of the 5-epiaristolochene synthase (TEAS) and further analyzed with molecular dynamic simulations to determine residues forming the substrate recognition pocket. We also investigated the structural aspects of Mg2+ binding. Results revealed DDYTD and NDLMT as metal binding motifs in the putative active site gorge, which is composed of the D and H helixes and one loop region (aa519-532). Moreover, several representative residues including Tyr519, Asp444, Trp271, Asn443, Thr399, Arg262, Val292, Gly400 and Leu405, determine the FPP binding mode and its fate in terms of stereochemistry as well as the enzyme fidelity for the specific end product. These findings lead to inferences concerning key components of the ADS catalytic cavity, and provide evidence for the spatial localization of the FPP and Mg2+. Such detailed understanding will probably help to design an improved enzyme. PMID- 28620814 TI - Oil palm fiber biodegradation: physico-chemical and structural relationships. AB - MAIN CONCLUSION: X-ray microtomography results revealed that delignification process damaged the oil palm fibers, which correlated well with reduction of lignin components and increase of the phenolic content. Biodegradation investigation of natural fibers normally focuses on physico-chemical analysis, with less emphasis on physical aspect like fiber structures affect from microbial activity. In this work, the performance of Pycnoporus sanguineus to delignify oil palm empty fruit bunch fibers through solid-state fermentation utilizing various ratio of POME sludge was reported. In addition to tensile testing, physico chemical and X-ray microtomography (u-CT) analyses on the oil palm fibers were conducted to determine the effectiveness of the degradation process. The best ratio of fiber to fungi (60:40) was chosen based on the highest lignin loss and total phenolic content values and further investigation was performed to obtain fermentation kinetics data of both laccase and manganese peroxidase. u-CT results revealed that delignification process damaged the pre-treated and untreated fibers structure, as evident from volume reduction after degradation process. This is correlated with reduction of lignin component and increase of the phenolic content, as well as lower stress-strain curves of the pre-treated fibers compared to the untreated ones (from tensile testing). It is suggested that P. sanguineus preferred to consume the outer layer of the fiber, before it penetrates through the cellular structure of the inner fiber. PMID- 28620815 TI - Radiation-related toxicities and outcomes in endometrial cancer: are obese women at a disadvantage? AB - OBJECTIVE: To assess the impact of body mass index (BMI) on radiotherapy toxicities in endometrial cancer patients. METHODS: This was a retrospective cohort study of women diagnosed with endometrial cancer between January 2006 and December 2014 at the Royal Cornwall Hospital Trust. Women who received radiotherapy as part of their treatment, including external beam radiotherapy (EBRT) and/or vaginal brachytherapy were included. Radiation-related toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) guidelines. Toxicity outcomes were compared across BMI groups-non-obese (BMI <30 kg/m2) and obese (BMI >=30 kg/m2)-according to radiotherapy treatment received (EBRT, brachytherapy or a combination). RESULTS: Of a total of 159 women who received radiotherapy, 110 were eligible for inclusion in the study. Sixty-three women had a BMI <30 kg/m2 and 47 women were obese. Obese women had poorer Eastern Cooperative Oncology Group performance status (P = 0.021) and more comorbidities (P < 0.001) compared to the non-obese group. Total (any) toxicity rates were 60.3, 72.7 and 52.0% for EBRT and brachytherapy (N = 63), single-mode EBRT (N = 22) and brachytherapy (N = 25), respectively. BMI was not associated with the incidence of acute and late radiation toxicities in the different radiotherapy groups, and there were no differences in individual complications between the BMI groups. CONCLUSION: When comparing obese to non-obese women, obesity does not negatively impact the incidence of radiation toxicities in endometrial cancer. However, toxicities remain an important challenge as they are common and negatively influence the quality of life (QoL) of survivors. Future studies need to further explore the role of BMI and possible interventions to improve toxicities and QoL. PMID- 28620816 TI - Bioaccessibility of As, Cu, Pb, and Zn in mine waste, urban soil, and road dust in the historical mining village of Kank, Czech Republic. AB - Historical mining activities in the village of Kank (in the northern part of the Kutna Hora ore district, Czech Republic) produced large amounts of mine wastes which contain significant amounts of metal(loid) contaminants such as As, Cu, Pb, and Zn. Given the proximity of residential communities to these mining residues, we investigated samples of mine waste (n = 5), urban soil (n = 6), and road dust (n = 5) with a special focus on the solid speciation of As, Cu, Pb, and Zn using a combination of methods (XRD, SEM/EDS, oxalate extractions), as well as on in vitro bioaccessibility in simulated gastric and lung fluids to assess the potential exposure risks for humans. Bulk chemical analyses indicated that As is the most important contaminant in the mine wastes (~1.15 wt%), urban soils (~2900 mg/kg) and road dusts (~440 mg/kg). Bioaccessible fractions of As were quite low (4-13%) in both the simulated gastric and lung fluids, while the bioaccessibility of metals ranged between <0.01% (Pb) and 68% (Zn). The bioaccessibilities of the metal(loid)s were dependent on the mineralogy and different adsorption properties of the metal(loid)s. Based on our results, a potential health risk, especially for children, was recognized from the ingestion of mine waste materials and highly contaminated urban soil. Based on the risk assessment, arsenic was found to be the element posing the greatest risk. PMID- 28620817 TI - Effect of biosolid hydrochar on toxicity to earthworms and brine shrimp. AB - The hydrothermal carbonization of sewage sludge has been studied as an alternative technique for the conversion of sewage sludge into value-added products, such as soil amendments. We tested the toxicity of biosolid hydrochar (Sewchar) to earthworms. Additionally, the toxicity of Sewchar process water filtrate with and without pH adjustment was assessed, using brine shrimps as a model organism. For a Sewchar application of 40 Mg ha-1, the earthworms significantly preferred the side of the vessel with the reference soil (control) over side of the vessel with the Sewchar treatments. There was no acute toxicity of Sewchar to earthworms within the studied concentration range (up to 80 Mg ha 1). Regarding the Sewchar process water filtrate, the median lethal concentration (LC50) to the shrimps was 8.1% for the treatments in which the pH was not adjusted and 54.8% for the treatments in which the pH was adjusted to 8.5. The lethality to the shrimps significantly increased as the amount of Sewchar process water filtrate increased. In the future, specific toxic substances in Sewchar and its process water filtrate, as well as their interactions with soil properties and their impacts on organisms, should be elucidated. Additionally, it should be identified whether the amount of the toxic compounds satisfies the corresponding legal requirements for the safe application of Sewchar and its process water filtrate. PMID- 28620818 TI - Effects of atorvastatin and simvastatin on oxidative stress in diet-induced hyperhomocysteinemia in Wistar albino rats: a comparative study. AB - Considering the well-known antioxidant properties of statins, it seems important to assess their impact on major markers of oxidative stress (superoxide anion radical, nitric oxide, and index of lipid peroxidation) to compare the antioxidative potentials of atorvastatin and simvastatin during the different degrees of hyperhomocysteinemia (HHcy) in rats. This study was conducted on adult male Wistar albino rats (n = 90; 4 weeks old; 100 +/- 15 g body mass) in which HHcy was achieved by dietary manipulation. For 4 weeks, the animals were fed with one of the following diets: standard rodent chow, diet enriched in methionine with no deficiency in B vitamins (folic acid, B6, and B12), or diet enriched in methionine and deficient in B vitamins (folic acid, B6, and B12). At the same time, animals were treated with atorvastatin at doses of 3 mg/kg/day i.p. or simvastatin at doses of 5 mg/kg/day i.p. Levels of superoxide anion radical and TBARS were significantly decreased by administration of simvastatin in normal and high-homocysteine (Hcy) groups (p < 0.05). At 4 weeks after feeding with purified diets, the concentrations of the GSH, CAT, and SOD antioxidants were significantly affected among all groups (p < 0.05). Our results indicated that statin therapy had variable effects on the redox status in hyperhomocysteinemic rats, and simvastatin demonstrated stronger antioxidant effects than did atorvastatin. PMID- 28620819 TI - Cellular growth and tube formation of HTR8/SVneo trophoblast: effects of exogenously added fatty acid-binding protein-4 and its inhibitor. AB - Adequate placental angiogenesis is critical for the establishment of the placental circulation and thus for normal feto-placental growth and development. Fatty acid-binding protein-4 (FABP4) plays a pro-angiogenic role in endothelial cells; however, very little information is available in placental first trimester trophoblast cells. Here we report that exogenously added FABP4 (exo-FABP4) stimulated tube formation (as a measure of in vitro angiogenesis) in HTR8/SVneo trophoblastic cells. HTR-8/SVneo cells were incubated in the presence of exogenously added FABP4 at different concentrations and time points. Cellular growth, proliferation, in vitro tube formation, expression of growth stimulatory , fatty acid transporters, and angiogenic genes were investigated. Internalization of exo-FABP4 was carried out using immunocytochemistry. Radioactive fatty acid uptake was determined in the presence and absence of FABP4 metabolic inhibitor. Exo-FABP4 (10-100 ng/ml) stimulated proliferation of HTR8/SVneo cells as compared to control. Exo-FABP4 dose dependently increased growth and viability of the cells to the similar extent as done by 50 uM of arachidonic acid. Exo-FABP4-induced tube formation and proliferation were significantly inhibited by FABP4 (BMS309403) inhibitor. Exo-FABP4 stimulated the expression of growth stimulatory genes such as tissue inhibitor of matrix metalloproteinases-1 (TIMP1), insulin-like growth factor 1 (IGF1), and also prokineticin 2 (PROK2), the pro-angiogenic mediators in these cells. In addition, expressions of genes associated with proliferation and differentiation such as sonic hedgehog (SHH) and WNT1 inducible signalling pathway protein 1 (WISP1) were significantly expressed when cells were exposed to exo-FABP4. Our findings reveal a pro-angiogenic role of FABP4 in first trimester placental trophoblast cells and its regulation may have impact in placental physiology. PMID- 28620820 TI - Cytoglobin inhibits migration through PI3K/AKT/mTOR pathway in fibroblast cells. AB - Cell proliferation and migration are crucial in many physiological processes including development, cancer, tissue repair, and wound healing. Cell migration is regulated by several signaling molecules. Identification of genes related to cell migration is required to understand molecular mechanism of non-healing chronic wounds which is a major concern in clinics. In the current study, the role of cytoglobin (CYGB) gene in fibroblast cell migration and proliferation was described. L929 mouse fibroblast cells were transduced with lentiviral particles for CYGB and GFP, and analyzed for cell proliferation and migration ability. Fibroblast cells overexpressing CYGB displayed decreased cell proliferation, colony formation capacity, and cell migration. Phosphorylation levels of mTOR and two downstream effectors S6 and 4E-BP1 which take part in PI3K/AKT/mTOR signaling declined in CYGB-overexpressing cells. Microarray analysis indicated that CYGB overexpression leads to downregulation of cell proliferation, migration, and tumor growth associated genes in L929 cell line. This study demonstrated the role of CYGB in fibroblast cell motility and proliferation. CYGB could be a promising candidate for further studies as a potential target for diseases related to cell migration such as cancer and chronic wound treatment. PMID- 28620821 TI - Administration of Exogenous Melatonin After the Onset of Systemic Inflammation Is Hardly Beneficial. AB - Melatonin improves survival and functional impairment including hemolysis, thrombocytopenia, and hypotension when administered in a prophylactic manner or early after initiation of sepsis or endotoxemia. In the present study, melatonin was given not before first symptoms of systemic inflammation became manifest. Lipopolysaccharide was infused at a rate of 0.5 mg/kg * h to induce systemic inflammation in male Wistar rats. Melatonin (single dose 3 mg/kg * 15 min) was intravenously administered 180 and 270 min after starting of the lipopolysaccharide infusion. Systemic and vital parameters (e.g., systemic blood pressure and breathing rate) as well as blood and plasma parameters (acid-base parameters; electrolytes; parameters of tissue injury such as glucose concentration, lactate concentration, hemolysis, and aminotransferase activities; parameters of thromboelastometry; and platelet count) were determined in regular intervals. Infusion of lipopolysaccharide led to characteristic symptoms of severe systemic inflammation including hypotension, metabolic acidosis and hypoglycemia, electrolyte and hemostatic disturbances, thrombocytopenia, and hemolysis. Melatonin neither decreased mortality nor reduced lipopolysaccharide dependent changes to vital, blood, and plasma parameters. Even though melatonin may have a beneficial effect in early stages of systemic inflammation, it can hardly be an option in therapy of manifest sepsis or endotoxemia in an intensive care unit. PMID- 28620822 TI - Digital imaging information technology for biospeckle activity assessment relative to bacteria and parasites. AB - This paper reports on the biospeckle processing of biological activity using a visualization scheme based upon the digital imaging information technology. Activity relative to bacterial growth in agar plates and to parasites affected by a drug is monitored via the speckle patterns generated by a coherent source incident on the microorganisms. We present experimental results to demonstrate the potential application of this methodology for following the activity in time. The digital imaging information technology is an alternative visualization enabling the study of speckle dynamics, which is correlated to the activity of bacteria and parasites. In this method, the changes in Red-Green-Blue (RGB) color component density are considered as markers of the growth of bacteria and parasites motility in presence of a drug. The RGB data was used to generate a two dimensional surface plot allowing an analysis of color distribution on the speckle images. The proposed visualization is compared to the outcomes of the generalized differences and the temporal difference. A quantification of the activity is performed using a parameterization of the temporal difference method. The adopted digital image processing technique has been found suitable to monitor motility and morphological changes in the bacterial population over time and to detect and distinguish a short term drug action on parasites. PMID- 28620823 TI - The VEGF-A inhibitor sFLT-1 improves renal function by reducing endothelial activation and inflammation in a mouse model of type 1 diabetes. AB - AIMS/HYPOTHESIS: Animal models of diabetic nephropathy show increased levels of glomerular vascular endothelial growth factor (VEGF)-A, and several studies have shown that inhibiting VEGF-A in animal models of diabetes can prevent albuminuria and glomerular hypertrophy. However, in those studies, treatment was initiated before the onset of kidney damage. Therefore, the aim of this study was to investigate whether transfecting mice with the VEGF-A inhibitor sFlt-1 (encoding soluble fms-related tyrosine kinase 1) can reverse pre-existing kidney damage in a mouse model of type 1 diabetes. In addition, we investigated whether transfection with sFlt-1 can reduce endothelial activation and inflammation in these mice. METHODS: Subgroups of untreated 8-week-old female C57BL/6J control (n = 5) and diabetic mice (n = 7) were euthanised 5 weeks after the start of the experiment in order to determine the degree of kidney damage prior to treatment with sFLT-1. Diabetes was induced with three i.p. injections of streptozotocin (75 mg/kg) administered at 2 day intervals. Diabetic nephropathy was then investigated in diabetic mice transfected with sFlt-1 (n = 6); non-diabetic, non transfected control mice (n = 5); non-diabetic control mice transfected with sFlt 1(n = 10); and non-transfected diabetic mice (n = 6). These mice were euthanised at the end of week 15. Transfection with sFlt-1 was performed in week 6. RESULTS: We found that transfection with sFlt-1 significantly reduced kidney damage by normalising albuminuria, glomerular hypertrophy and mesangial matrix content (i.e. glomerular collagen type IV protein levels) (p < 0.001). We also found that transfection with sFlt-1 reduced endothelial activation (p < 0.001), glomerular macrophage infiltration (p < 0.001) and glomerular TNF-alpha protein levels (p < 0.001). Finally, sFLT-1 decreased VEGF-A-induced endothelial activation in vitro (p < 0.001). CONCLUSIONS/INTERPRETATION: These results suggest that sFLT-1 might be beneficial in treating diabetic nephropathy by inhibiting VEGF-A, thereby reducing endothelial activation and glomerular inflammation, and ultimately reversing kidney damage. PMID- 28620824 TI - L-3-n-Butylphthalide Activates Akt/mTOR Signaling, Inhibits Neuronal Apoptosis and Autophagy and Improves Cognitive Impairment in Mice with Repeated Cerebral Ischemia-Reperfusion Injury. AB - L-3-n-Butylphthalide (L-NBP) exerts neuroprotective effects in animal models of cerebral ischemia, but its potential benefits in repeated cerebral ischemia reperfusion (RCIR) injury remain unknown. We investigated the effect of L-NBP on cognitive impairment induced by RCIR in mice. Male C57Bl/6 mice received sham surgery or bilateral common carotid artery occlusion (3 times, 20 min each) and were orally administered preoperative L-NBP (30 mg/kg/day, 7 days), postoperative L-NBP (30 or 60 mg/kg/day, 28 days) or postoperative vehicle (28 days). Learning and memory were assessed by the Morris water maze task and step-down passive avoidance test. Nissl staining was used to identify pathologic changes in the hippocampal CA1 region. The expressions of proteins associated with signaling, apoptosis and autophagy were assessed by quantitative PCR and western blot. RCIR induced deficits in learning and memory that were alleviated by preoperative or postoperative L-NBP administration. Pathologic lesions in the hippocampal CA1 region induced by RCIR were less severe in mice treated with L-NBP. Preoperative or postoperative L-NBP administration in mice receiving RCIR promoted hippocampal expression of phospho-Akt and phospho-mTOR (suggesting activation of Akt/mTOR signaling), increased the Bcl-2/Bax ratio (indicating suppression of apoptosis) and reduced the LC3-II/LC3-I ratio (implying inhibition of autophagy). Preoperative or postoperative L-NBP administration also depressed hippocampal levels of beclin-1 mRNA (indicating suppression of autophagy). These findings suggest that the effect of L-NBP to alleviate learning and memory deficits in mice following RCIR may involve activation of Akt/mTOR signaling and regulation of the expressions of proteins related to apoptosis and autophagy. PMID- 28620825 TI - Flow Cytometric Characterization of T Cell Subsets and Microglia After Repetitive Mild Traumatic Brain Injury in Rats. AB - Although, there is growing awareness in the progressive neurodegeneration of chronic traumatic encephalopathy, changes of immune reactions remain equivocal at best. Thus, in a clinically relevant rat repetitive mild traumatic brain injury (rmTBI) model, some immunologic cells (T cell subsets, microglia) in the injured brain and peripheral blood were analyzed by flow cytometry and immunofluorescence. In the injured brain, CD3+ T cells showed a bimodal increase during 42 days post-injury (dpi). CD3+CD4+ T cells firstly increased and then decreased, while CD3+CD8+ T cells had reversed tendency. CD86+/CD11b+ M1-like microglia increased at 42 dpi and CD206+/CD11b+ M2-like microglia peaked at 7 dpi. In addition, peripheral immune suppression was implicated in the chronic phase after rmTBI. Taken together, the study provided useful information on long term dynamic changes of some immune cells after rmTBI in rats. PMID- 28620827 TI - Asthma, Foot Drop, and Palpable Purpura in a Young Woman. PMID- 28620828 TI - Capsule Commentary on Timbie et al., Association Between Patient-Centered Medical Home Capabilities and Outcomes for Medicare Beneficiaries Seeking Care from Federally Qualified Health Centers. PMID- 28620826 TI - Individual Amino Acid Supplementation Can Improve Energy Metabolism and Decrease ROS Production in Neuronal Cells Overexpressing Alpha-Synuclein. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha synuclein accumulation and loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Increased levels of alpha-synuclein have been shown to result in loss of mitochondrial electron transport chain complex I activity leading to increased reactive oxygen species (ROS) production. WT alpha-synuclein was stably overexpressed in human BE(2)-M17 neuroblastoma cells resulting in increased levels of an alpha-synuclein multimer, but no increase in alpha synuclein monomer levels. Oxygen consumption was decreased by alpha-synuclein overexpression, but ATP levels did not decrease and ROS levels did not increase. Treatment with ferrous sulfate, a ROS generator, resulted in decreased oxygen consumption in both control and alpha-synuclein overexpressing cells. However, this treatment only decreased ATP levels and increased ROS production in the cells overexpressing alpha-synuclein. Similarly, paraquat, another ROS generator, decreased ATP levels in the alpha-synuclein overexpressing cells, but not in the control cells, further demonstrating how alpha-synuclein sensitized the cells to oxidative insult. Proteomic analysis yielded molecular insights into the cellular adaptations to alpha-synuclein overexpression, such as the increased abundance of many mitochondrial proteins. Many amino acids and citric acid cycle intermediates and their ester forms were individually supplemented to the cells with L-serine, L-proline, L-aspartate, or L-glutamine decreasing ROS production in oxidatively stressed alpha-synuclein overexpressing cells, while diethyl oxaloacetate or L valine supplementation increased ATP levels. These results suggest that dietary supplementation with individual metabolites could yield bioenergetic improvements in PD patients to delay loss of dopaminergic neurons. PMID- 28620829 TI - Appearance of cell-adhesion factor in osteoblast proliferation and differentiation of apatite coating titanium by blast coating method. AB - We have already reported that the apatite coating of titanium by the blast coating (BC) method could show a higher rate of bone contact from the early stages in vivo, when compared to the pure titanium (Ti) and the apatite coating of titanium by the flame spraying (FS) method. However, the detailed mechanism by which BC resulted in satisfactory bone contact is still unknown. In the present study, we investigated the importance of various factors including cell adhesion factor in osteoblast proliferation and differentiation that could affect the osteoconductivity of the BC disks. Cell proliferation assay revealed that Saos-2 could grow fastest on BC disks, and that a spectrophotometric method using a LabAssayTM ALP kit showed that ALP activity was increased in cells on BC disks compared to Ti disks and FS disks. In addition, higher expression of E-cadherin and Fibronectin was observed in cells on BC disks than Ti disks and FS disks by relative qPCR as well as Western blotting. These results suggested that the expression of cell-adhesion factors, proliferation and differentiation of osteoblast might be enhanced on BC disks, which might result higher osteoconductivity. PMID- 28620830 TI - Anatomy-driven multiple trajectory planning (ADMTP) of intracranial electrodes for epilepsy surgery. AB - PURPOSE: Epilepsy is potentially curable with resective surgery if the epileptogenic zone (EZ) can be identified. If non-invasive imaging is unable to elucidate the EZ, intracranial electrodes may be implanted to identify the EZ as well as map cortical function. In current clinical practice, each electrode trajectory is determined by time-consuming manual inspection of preoperative imaging to find a path that avoids blood vessels while traversing appropriate deep and superficial regions of interest (ROIs). We present anatomy-driven multiple trajectory planning (ADMTP) to find safe trajectories from a list of user-defined ROIs within minutes rather than the hours required for manual planning. METHODS: Electrode trajectories are automatically computed in three steps: (1) Target Point Selection to identify appropriate target points within each ROI; (2) Trajectory Risk Scoring to quantify the cumulative distance to critical structures (blood vessels) along each trajectory, defined as the skull entry point to target point. (3) Implantation Plan Computation: to determine a feasible combination of low-risk trajectories for all electrodes. RESULTS: ADMTP was evaluated on 20 patients (190 electrodes). ADMTP lowered the quantitative risk score in 83% of electrodes. Qualitative results show ADMTP found suitable trajectories for 70% of electrodes; a similar portion of manual trajectories were considered suitable. Trajectory suitability for ADMTP was 95% if traversing sulci was not included in the safety criteria. ADMTP is computationally efficient, computing between 7 and 12 trajectories in 54.5 (17.3-191.9) s. CONCLUSIONS: ADMTP efficiently compute safe and surgically feasible electrode trajectories. PMID- 28620831 TI - Cephalopod biology and care, a COST FA1301 (CephsInAction) training school: anaesthesia and scientific procedures. AB - Cephalopods are the sole invertebrates included in the list of regulated species following the Directive 2010/63/EU. According to the Directive, achieving competence through adequate training is a requisite for people having a role in the different functions (article 23) as such carrying out procedures on animals, designing procedures and projects, taking care of animals, killing animals. Cephalopod Biology and Care Training Program is specifically designed to comply with the requirements of the "working document on the development of a common education and training framework to fulfil the requirements under the Directive 2010/63/EU". The training event occurred at the ICM-CSIC in Barcelona (Spain) where people coming from Europe, America and Asia were instructed on how to cope with regulations for the use of cephalopod molluscs for scientific purposes. The training encompasses discussion on the guidelines for the use and care of animals and their welfare with particular reference to procedures that may be of interest for neuroscience. Intensive discussion has been carried out during the training sessions with focus on behavioural studies and paradigms, welfare assessment, levels of severity of scientific procedures, animal care, handling, transport, individual identification and marking, substance administration, anaesthesia, analgesia and humane killing. PMID- 28620833 TI - Assessment of serum uric acid as risk factor for tauopathies. AB - Low levels of serum uric acid (UA) are a risk factor for many neurodegenerative diseases but the role of UA in tauopathies has not been yet fully evaluated. In this study, we assessed the risk associated with serum UA levels in a large group of patients with tauopathies, either primary or secondary. The mean serum UA concentrations of 111 patients with tauopathies (TAU), including 41 with progressive supranuclear palsy (PSP), 45 with Alzheimer's disease (AD) and 25 with frontotemporal dementia (FTD) were compared to that of 130 controls (CTL). The association between serum UA and TAU condition, PSP, AD and FTD was calculated as odd ratio (OR) adjusted for age and gender. A cut-off value of serum UA was finally obtained to predict subjects at risk for TAU. The serum UA levels in TAU and PSP, AD and FTD subgroups were similar, and significantly lower than CTL. Linear regression revealed inverse relationships between UA and TAU (OR = 0.610), PSP (OR = 0.626), AD (OR = 0.685) and FTD (OR = 0.577). The cut-off value of 4.35 mg/dl (AUC = 0.655) discriminates TAU from CTL, although with poor specificity and sensitivity. Low concentrations of serum UA represent a common risk factor for different tauopathies (PSP, FTD and AD). These findings may represent a starting point for preventive strategies or novel therapeutic approaches in this group of severe neurodegenerative diseases. PMID- 28620832 TI - The (pro)renin receptor and its interaction partners. AB - The prorenin receptor was originally discovered as a receptor that binds renin and prorenin, thereby inducing pro-fibrotic intracellular signal cascades. These effects are partially mediated in vitro by angiotensin (ANG) and partially independent of ANG. Consequently, inhibitors of the interaction between the prorenin and the (pro)renin receptor (PRR) were designed hoping that they may prevent fibrotic tissue damage, for instance, in the kidney. However, this concept was challenged by the fact that overexpression of the PRR was not harmful at all, whereas depletion of the PRR was lethal or markedly detrimental. Furthermore, the high levels of prorenin needed to activate the PRR may not be reached in vivo. As it turned out, the PRR instead exhibited a variety of important functions that has nothing to do with the name given to the protein. Thus, the PRR was identified as an accessory subunit of vesicular (v)-ATPases, representing an essential chaperon for the assembly of v-ATPase subunits. In this respect, the gene encoding the PRR was also named ATP6AP2. Finally, the PRR is an essential component of the canonical and non-canonical PCP Wnt pathways. Thus, the PRR is essential for lysosomal functions, such as endocytosis, secretion, and autophagy as well as for cell division and differentiation, embryonic development, organogenesis, and stem cell biology. PMID- 28620834 TI - Dysregulation of striatal projection neurons in Parkinson's disease. AB - The loss of nigrostriatal dopamine (DA) is the primary cause of motor dysfunction in Parkinson's disease (PD), but the underlying striatal mechanisms remain unclear. In spite of abundant literature portraying structural, biochemical and plasticity changes of striatal projection neurons (SPNs), in the past there has been a data vacuum from the natural human disease and its close model in non human primates. Recently, single-cell recordings in advanced parkinsonian primates have generated new insights into the altered function of SPNs. Currently, there are also human data that provide direct evidence of profoundly dysregulated SPN activity in PD. Here, we review primate recordings that are impacting our understanding of the striatal dysfunction after DA loss, particularly through the analysis of physiologic correlates of parkinsonian motor behaviors. In contrast to recordings in rodents, data obtained in primates and patients demonstrate similar major abnormalities of the spontaneous SPN firing in the alert parkinsonian state. Furthermore, these studies also show altered SPN responses to DA replacement in the advanced parkinsonian state. Clearly, there is yet much to learn about the striatal discharges in PD, but studies using primate models are contributing unique information to advance our understanding of pathophysiologic mechanisms. PMID- 28620835 TI - Twenty years since the discovery of the parkin gene. AB - Nearly 20 years have passed since we identified the causative gene for a familial Parkinson's disease, parkin (now known as PARK2), in 1998. PARK2 is the most common gene responsible for young-onset Parkinson's disease. It codes for the protein Parkin RBR E3 ubiquitin-protein ligase (PARK2), which directly links to the ubiquitin-proteasome as a ubiquitin ligase. PARK2 is involved in mitophagy, which is a type of autophagy, in collaboration with PTEN-induced putative kinase 1 (PINK1). The PINK1 gene (previously known as PARK6) is also a causative gene for young-onset Parkinson's disease. Both gene products may be involved in regulating quality control within the mitochondria. The discovery of PARK2 as a cause of young-onset Parkinson's disease has had a major impact on other neurodegenerative diseases. The involvement of protein degradation systems has been implicated as a common mechanism for neurodegenerative diseases in which inclusion body formation is observed. The discovery of the involvement of PARK2 in Parkinson's disease focused attention on the involvement of protein degradation systems in neurodegenerative diseases. In this review, we focus on the history of the discovery of PARK2, the clinical phenotypes of patients with PARK2 mutations, and its functional roles. PMID- 28620837 TI - Retraction Note to: Nucleolin Promotes TGF-beta Signaling Initiation via TGF-beta Receptor I in Glioblastoma. PMID- 28620836 TI - SOX2 immunity and tissue resident memory in children and young adults with glioma. AB - Therapies targeting immune checkpoints are effective in tumors with a high mutation burden that express multiple neo-antigens. However, glial tumors including those seen in children carry fewer mutations and there is an unmet need to identify new antigenic targets of anti-tumor immunity. SOX2 is an embryonal stem cell antigen implicated in the biology of glioma initiating cells. Expression of SOX2 by pediatric glial tumors and the capacity of the immune system in these patients to recognize SOX2 has not been previously studied. We examined the expression of SOX2 on archived paraffin-embedded tissue from pediatric glial tumors. The presence of T-cell immunity to SOX2 was examined in both blood and tumor-infiltrating T-cells in children and young adults with glioma. The nature of tumor-infiltrating immune cells was analyzed with a 37 marker panel using single-cell mass cytometry. SOX2 is expressed by tumor cells but not surrounding normal tissue in pediatric gliomas of all grades. T-cells against this antigen can be detected in blood and tumor tissue in glioma patients. Glial tumors are enriched for CD8/CD4 T-cells with tissue resident memory (TRM; CD45RO+, CD69+, CCR7-) phenotype, which co-express multiple inhibitory checkpoints including PD-1, PD-L1 and TIGIT. Tumors also contain natural killer cells with reduced expression of lytic granzyme. Our data demonstrate immunogenicity of SOX2, which is specifically overexpressed on pediatric glial tumor cells. Harnessing tumor immunity in glioma will likely require the combined targeting of multiple inhibitory checkpoints. PMID- 28620839 TI - Probability density distribution of delta RR intervals: a novel method for the detection of atrial fibrillation. AB - Atrial fibrillation (AF) monitoring and diagnosis require automatic AF detection methods. In this paper, a novel image-based AF detection method was proposed. The map was constructed by plotting changes of RR intervals (?RR) into grid panes. First, the map was divided into grid panes with 20 ms fixed resolution in y-axes and 15-60 s step length in x-axes. Next, the blank pane ratio (BPR), the entropy and the probability density distribution were processed using linear support vector machine (LSVM) to classify AF and non-AF episodes. The performance was evaluated based on four public physiological databases. The Cohen's Kappa coefficients were 0.87, 0.91 and 0.64 at 50 s step length for the long-term AF database, the MIT-BIH AF database and the MIT-BIH arrhythmia database, respectively. Best results were achieved as follows: (1) an accuracy of 93.7%, a sensitivity of 95.1%, a specificity of 92.0% and a positive predictive value (PPV) of 93.5% were obtained for the long-term AF database at 60 s step length. (2) An accuracy of 95.9%, a sensitivity of 95.3%, a specificity of 96.3% and a PPV of 94.1% were obtained for the MIT-BIH AF database at 40 s step length. (3) An accuracy of 90.6%, a sensitivity of 94.5%, a specificity of 90.0% and a PPV of 55.0% were achieved for the MIT-BIH arrhythmia database at 60 s step length. (4) Both accuracy and specificity were 96.0% for the MIT-BIH normal sinus rhythm database at 40 s step length. In conclusion, the intuitive grid map of delta RR intervals offers a new approach to achieving comparable performance with previously published AF detection methods. PMID- 28620838 TI - Modelling FUS Mislocalisation in an In Vitro Model of Innervated Human Muscle. AB - Degeneration of distal axons and neuromuscular junctions is an early feature in the pathology of amyotrophic lateral sclerosis (ALS), which culminates in motor neuron loss due to axon retraction and muscle atrophy. The complex interactions in the pathogenesis of ALS between motor neurons, muscle cells and accompanying glia require an appropriate experimental model. Here, we have defined a co culture model based on human myotubes innervated by neurons from embryonic rat spinal cord explants to investigate the pathology and treatment of ALS. This model was first characterised for endogenous expression and distribution of ALS related proteins TDP-43 and FUS. Then, wild-type FUS and its mutants were introduced into these co-cultures to determine how FUS defects in nuclear transport modulate the pathological conditions. FUS-bearing plasmids were introduced by classical transfection and electroporation, as novel approaches to deliver plasmids into explants, and their cellular distributions were characterised. Endogenous nuclear expression of TDP-43 and FUS was observed in explants and myoblasts/myotubes. After transfection, wild-type FUS was expressed in nuclei of myoblasts, myotubes and explants, although with low transfection rates. Following successful electrotransfection into explants, the localisation of wild-type FUS was nuclear, and it was detected in neurons, astrocytes, Schwann cells and oligodendrocyte precursors, whereas the FUS?Y, FUSY526A and FUSY526E mutants were cytoplasmic, and the FUSY526F mutant was nuclear and cytoplasmic. This co-culture model is applicable to the study of neuronal and non-neuronal cell contributions to ALS and other neurodegenerative diseases, and it can be used to investigate drug targets amenable to intervention. PMID- 28620840 TI - Quality of life impairment in Behcet's disease and relationship with disease activity: a prospective study. AB - Our aim was to prospectively investigate the impact of Behcet's disease (BD), disease activity, and clinical and demographic characteristics on different aspects of quality of life (QoL) measured by the short-form (SF)-36 QoL scale. We administered the SF-36 to 37 consecutive BD patients in different moments of disease activity, and to 23 healthy controls (HC). The eight subcategories of the SF-36 underwent statistical analysis for identifying differences and correlations. Compared to HC, BD patients showed significantly lower mean scores in all SF-36 QoL subscales except mental health and role-emotional. Females showed a poorer QoL compared to males. Disease activity evaluated by the BD Current Activity Form inversely correlated with physical functioning (rho = 0.68, p < 0.0001), bodily pain (rho = -0.68, p < 0.0001), role-physical (rho = 0.64, p < 0.0001), vitality (rho = -0.64, p < 0.0001), general health (rho = 0.64, p < 0.0001), social functioning (rho = -0.50, p = 0.0002), mental health (rho = -0.48, p = 0.0004), and role-emotional (rho = -0.40, p = 0.003). Mucosal, central nervous system (CNS), musculoskeletal and ocular manifestations were the main factors that negatively affected QoL in BD. For ocular disease, physical functioning was significantly impaired in patients with panuveitis compared to other ocular manifestations (p = 0.0002). Best-corrected visual acuity was inversely correlated with social functioning (rho = -0.53, p < 0.0001), role physical (rho = -0.48, p < 0.0001), bodily pain (rho = -0.46, p = 0.02), and mental health (rho = -0.43, p < 0.0001). Patients with BD have a poorer QoL compared to HC, particularly for women, while the decline of QoL is closely related to the overall disease activity of BD. Single organ involvements may affect independently specific SF-36 subscales, especially mucosal, CNS, musculoskeletal, and ocular manifestations. PMID- 28620842 TI - Over-the-counter medications containing diphenhydramine and doxylamine used by older adults to improve sleep, a Letter. PMID- 28620841 TI - Device-Based Approaches for the Treatment of Arterial Hypertension. AB - Device-based antihypertensive treatments have primarily been developed and clinically tested for patients with hypertension refractory to pharmacological treatment. Most but not all device-based treatments target the sympathetic nervous system and provided important new insight in the mechanisms of human hypertension. This review provides an overview on the scientific rational and clinical data on recent device-based antihypertensive treatment approaches. Device-based treatments targeting the sympathetic nervous system include catheter based renal nerve ablation, electrical carotid sinus stimulation, modulation of baroreflex transduction through a dedicated carotid stent, carotid body denervation, and deep brain stimulation. Creation of a defined arteriovenous stent with a coupler device and removal of stimulatory antibodies against alpha adrenoreceptors have also been tested. The clinical evidence differs from therapy to therapy with the largest dataset for renal nerve ablation followed by electrical carotid sinus stimulation. Yet, none has been proven efficacious in sham-controlled clinical trials, and none has been shown to reduce cardiovascular morbidity or mortality. Before efficacy is proven, these treatments should not be part of routine medical care and only be applied in the setting of clinical studies. PMID- 28620843 TI - The coevolution of play and the cortico-cerebellar system in primates. AB - Primates are some of the most playful animals in the natural world, yet the reason for this remains unclear. One hypothesis posits that primates are so playful because playful activity functions to help develop the sophisticated cognitive and behavioural abilities that they are also renowned for. If this hypothesis were true, then play might be expected to have coevolved with the neural substrates underlying these abilities in primates. Here, we tested this prediction by conducting phylogenetic comparative analyses to determine whether play has coevolved with the cortico-cerebellar system, a neural system known to be involved in complex cognition and the production of complex behaviour. We used phylogenetic generalised least squares analyses to compare the relative volume of the largest constituent parts of the primate cortico-cerebellar system (prefrontal cortex, non-prefrontal heteromodal cortical association areas, and posterior cerebellar hemispheres) to the mean percentage of time budget spent in play by a sample of primate species. Using a second categorical data set on play, we also used phylogenetic analysis of covariance to test for significant differences in the volume of the components of the cortico-cerebellar system among primate species exhibiting one of three different levels of adult-adult social play. Our results suggest that, in general, a positive association exists between the amount of play exhibited and the relative size of the main components of the cortico-cerebellar system in our sample of primate species. Although the explanatory power of this study is limited by the correlational nature of its analyses and by the quantity and quality of the data currently available, this finding nevertheless lends support to the hypothesis that play functions to aid the development of cognitive and behavioural abilities in primates. PMID- 28620844 TI - Comparison of the characteristics of Mycobacterium tuberculosis isolates from sputum and lung lesions in chronic tuberculosis patients. AB - Mycobacterium tuberculosis (Mtb) in sputum originates from lung cavities in tuberculosis (TB) patients. But drug susceptibility testing (DST) of sputum Mtb can not be conducted the same as in the lung because mutagenesis of bacilli may be happening in the lung during treatment and result in the possibility of the presence of heterogeneous drug-resistant subpopulations in the different lung lesions. This could be one of the reasons for low cure rates for multi-drug resistant (MDR)-TB. We studied the resected lungs of nine surgery patients with chronic TB. The isolates isolated from the sputum and different lung lesions of each patient were tested for phenotypic DST and genotyped using restriction fragment length polymorphism (RFLP) typing method. Genetic analysis to resistance to first and second line drugs was also performed. Five of nine patients were MDR TB and three XDR-TB. DST results for ten anti-TB drugs were in accordance among different lung lesions in eight patients. However, only three of these eight patients showed the concordance of DST with sputum. Even though the isolates were heteroresistant, genotyping them by RFLP showed the clonal population in each individual patient. Six of eight followed-up patients achieved successful cure. In conclusion, the heteroresistance between sputum and lung lesions and a clonal population without mixed infection might provide useful information in establishing treatment regimen and surgery decision for MDR- and XDR-TB. PMID- 28620845 TI - Cross-resistance between voriconazole and fluconazole for non-albicans Candida infection: a case-case-control study. AB - Cross-resistance (CR) between voriconazole and fluconazole for non-albicans Candida (NAC) species is not uncommon, but little is known about the risk factors and clinical consequences associated with this resistance phenotype. A case-case control study was performed at a university-affiliated hospital in China between November 2012 and April 2016. The two case groups respectively comprised patients with a mono-resistance (MR) NAC infection (fluconazole or voriconazole resistance) and patients with a CR NAC infection (fluconazole and voriconazole resistance). Patients with a no-resistance (NR) NAC infection were included as the control group. Models were adjusted for demographic and clinical risk factors, and the risk of resistance associated with exposure to specific antibiotics or non-antibiotics were assessed. Of 259 episodes, 33 (12.7%) and 27 (10.4%) were identified as MR and CR NAC infections, respectively. The broad use of azoles was strongly associated with the emergence of MR and CR NAC infections (adjusted odds ratio [95% confidence interval] = 2.69 [1.10-6.58] and 2.53 [1.02 6.28], respectively). The time at risk (1.02 [1.00-1.03]) with 12 days as a breakpoint was also an independent risk factor for CR NAC infection. The number of species associated with a high minimum inhibitory concentration (>=128 MUg/mL) of fluconazole was higher for CR NAC infections than for MR NAC infections. Different resistance phenotypes (CR vs. MR vs. NR) were associated with all-cause mortality rates. These findings indicate a worrisome propensity of CR NAC infections and emphasize the need for strict antifungal stewardship. PMID- 28620846 TI - The Role of Mast Cells in Intracerebral Hemorrhage. AB - Mast cells are first responders to intracerebral hemorrhage. They release potent mediators that can disrupt the blood-brain barrier promoting injury, vasogenic edema formation, and hematoma exacerbation. Also, mast cells recruit other inflammatory cells that maintain and amplify brain damage. Given their early role in the cascade of events in intracerebral hemorrhage, mast cells may offer an alternative target for antichemotactic interventions. PMID- 28620847 TI - Faster, More Reproducible DESI-MS for Biological Tissue Imaging. AB - A new, more robust sprayer for desorption electrospray ionization (DESI) mass spectrometry imaging is presented. The main source of variability in DESI is thought to be the uncontrolled variability of various geometric parameters of the sprayer, primarily the position of the solvent capillary, or more specifically, its positioning within the gas capillary or nozzle. If the solvent capillary is off-center, the sprayer becomes asymmetrical, making the geometry difficult to control and compromising reproducibility. If the stiffness, tip quality, and positioning of the capillary are improved, sprayer reproducibility can be improved by an order of magnitude. The quality of the improved sprayer and its potential for high spatial resolution imaging are demonstrated on human colorectal tissue samples by acquisition of images at pixel sizes of 100, 50, and 20 MUm, which corresponds to a lateral resolution of 40-60 MUm, similar to the best values published in the literature. The high sensitivity of the sprayer also allows combination with a fast scanning quadrupole time-of-flight mass spectrometer. This provides up to 30 times faster DESI acquisition, reducing the overall acquisition time for a 10 mm * 10 mm rat brain sample to approximately 1 h. Although some spectral information is lost with increasing analysis speed, the resulting data can still be used to classify tissue types on the basis of a previously constructed model. This is particularly interesting for clinical applications, where fast, reliable diagnosis is required. Graphical Abstract ?. PMID- 28620848 TI - Cost Effectiveness of Pembrolizumab vs. Standard-of-Care Chemotherapy as First Line Treatment for Metastatic NSCLC that Expresses High Levels of PD-L1 in the United States. AB - OBJECTIVES: Our objectives were to evaluate the cost effectiveness of pembrolizumab compared with standard-of-care (SoC) platinum-based chemotherapy as first-line treatment in patients with metastatic non-small-cell lung cancer (NSCLC) that expresses high levels of programmed death ligand-1 (PD-L1) [tumour proportion score (TPS) >=50%], from a US third-party public healthcare payer perspective. METHODS: We conducted a partitioned-survival model with a cycle length of 1 week and a base-case time horizon of 20 years. Parametric models were fitted to Kaplan-Meier estimates of time on treatment, progression-free survival and overall survival from the KEYNOTE-024 randomized clinical trial (patients aged >=18 years with stage IV NSCLC, TPS >=50%, without epidermal growth factor receptor (EGFR)-activating mutations or anaplastic lymphoma kinase (ALK) translocations who received no prior systemic chemotherapy) and validated with long-term registry data. Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, year 2016 values) for drug acquisition/administration, adverse events and clinical management were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results. RESULTS: In the base-case scenario, pembrolizumab resulted in an expected gain of 1.31 life-years (LYs) and 1.05 QALYs and an incremental cost of $US102,439 compared with SoC. The incremental cost per QALY gain was $US97,621/QALY and the incremental cost per LY gain was $US78,344/LY. CONCLUSIONS: Pembrolizumab is projected to be a cost effective option compared with SoC platinum-based chemotherapy as first-line treatment in adults with metastatic NSCLC expressing high levels of PD-L1. PMID- 28620850 TI - The colloid hematite particle migration through the unsaturated porous bed at the presence of biosurfactants. AB - Colloidal particles have an ability to sorb heavy metals, metalloids, and organic compounds (e.g. biosurfactants) present in soil and groundwater. The pH and ionic strength changes may promote release of such particles causing potential contaminant transport. Therefore, it is very important to know how a colloid particle-mineral particle and colloid-mineral-biosurfactant system behaves in the natural environment. They can have negative impact on the environment and human health. This study highlighted the influence of biosurfactants produced by Pseudomonas aeruginosa on the transport of colloidal hematite (alpha-Fe2O3) through porous bed (materials collected from the Szklary and Zloty Stok solid waste heaps from Lower Silesia, Poland). Experiments were conducted using column set in two variants: colloid solution with porous bed and porous bed with adsorbed biosurfactants, in the ionic strengths of 5 * 10-4 and 5 * 10-3 M KCl. The zeta potential of mineral materials and colloidal hematite, before and after adsorption of biosurfactant, was determined. Obtained results showed that reduction in ionic strength facilitates colloidal hematite transport through the porous bed. The mobility of colloidal hematite was higher when the rhamnolipid adsorbed on the surface of mineral grain. PMID- 28620849 TI - Clinical Management of Dystonia in Childhood. AB - Dystonia is one of the most frequent movement disorders in childhood. It can impede normal motor development and cause significant motor disability. The diagnostic evaluation of childhood dystonia is challenging due to the phenotypic variability and heterogeneous etiologies. Evidence to guide the diagnostic evaluation and treatment is limited. Assessment is primarily directed by clinical history and distinctive examination findings. Neuroimaging is typically necessary to evaluate for acquired or complex inherited dystonias. A trial of levodopa can be both diagnostic and therapeutic in children with dopa-responsive dystonia. However, for the majority of children with early-onset dystonia, treatment is symptomatic with varying efficacy. There is a paucity of therapeutic trials for childhood dystonia and most treatment recommendations are consensus or expert opinion driven. This review summarizes the available evidence and guidelines on the diagnostic evaluation and pharmacological treatment of childhood-onset dystonia and provides practical frameworks to approach both issues based on best evidence. PMID- 28620851 TI - Changes of erythrocyte-metric parameters in Pelophylax ridibundus (Amphibia: Anura: Ranidae) inhabiting water bodies with different types of anthropogenic pollution in Southern Bulgaria. AB - The article presents the basic erythrocyte-metric parameters: cell length (EL) and width (EW), EL/EW, erythrocyte size (ES), nucleus length (NL) and width (NW), NL/NW, nucleus size (NS) and nucleocytoplasmic ratio (NS/ES) in the wild populations of marsh frogs Pelophylax ridibundus from five water bodies in Southern Bulgaria (two rivers and three reservoirs) with different degrees and types of anthropogenic pollution (less disrupted water basins, domestic sewage pollution and heavy metal pollution). The changes in erythrocyte-metric parameters depend on concentrations and types of toxicant and, to a lesser extent, on the type of water basin. We found that when P. ridibundus populations live in conditions of domestic sewage pollution, EL, EW and ES increase in comparison with the control samples, with regard to an elongated elliptical cell shape. Simultaneously, NL, NW and NS did not undergo any significant changes when compared with the control samples. The nuclei had elliptical shape. In the populations from the water basins with heavy metal pollution, EL, EW, ES, NL, NW and NS decreased. The cells and nuclei had a circular shape. NS/ES decreased when compared with the control sample, regardless of the type of toxicants. PMID- 28620852 TI - The generation of biogenic manganese oxides and its application in the removal of As(III) in groundwater. AB - The generation of biogenic manganese oxides (BMnOx) by Microbacterium sp. CSA40, and As(III) removal efficiency and mechanism by BMnOx were investigated in this study. The propagation and growth of Microbacterium sp. CSA40 was conducted in half-strength Luria Broth with 10 mg/L Mn(II), then high concentration of Microbacterium sp. CSA40 was added to PYG medium making its OD600 = 0.9 +/- 0.05 for BMnOx generation. The initial Mn(II) concentrations, excessively oligotrophic condition, and pH had great influence on generation of BMnOx by Microbacterium sp. CSA40. An appropriate Mn(II) concentration (50 mg/L) was obtained for generation of BMnOx, and higher or lower Mn(II) concentration would interfere Mn(II) oxidization performance. Mn(II) oxidation ability performed best in weak alkaline conditions and would be restricted in an excessively oligotrophic condition. As(III) oxidization and As(V) adsorption proceed simultaneously by BMnOx, what is more, more than 90% of total As was removed by 0.5 g/L BMnOx. During the application process, no Mn(II) was released in the solution, that is, BMnOx retained its ability for Mn(II) oxidization caused by activity of Microbacterium sp. CSA40. Therefore, BMnOx would be a pollution-free, cost effective, and high-efficiency material for As(III) treatment in groundwater. PMID- 28620853 TI - Effects of ozonation, powdered activated carbon adsorption, and coagulation on the removal of disinfection by-product precursors in reservoir water. AB - Effects of ozonation and powdered activated carbon on removal of dissolved organic matter (DOM) and disinfection by-product (DBP) in reservoir water were intensively investigated in this study. Both the formation of carbonaceous DBP (C DBP) and nitrogenous DBP (N-DBP) as well as their speciation were analyzed. Results exhibited that the addition of powdered activated carbon (PAC) greatly improved the removal of aromatic protein. Trihalomethanes (THMs) and haloacetonitriles (HANs) were the dominant species in C-DBP and N-DBP. The integrated coagulation and PAC processes could remove more than 70% of THMs and 93% of HANs precursors, while only 10.5 and 45% of capture were achieved by the single coagulation. The added ozone lowered the yields of HANs but synchronously increased the more toxic bromine-containing THMs from 78.5 to 128.1 MUg/L. Kinetics parameters for THM formation indicated that the precursor creating the THMs fast could be easily removed by both the coagulation and PAC adsorption. PMID- 28620854 TI - Renewable energy and greenhouse gas emissions from the waste sectors of European Union member states: a panel data analysis. AB - In the last two decades, there has been a rich debate about the environmental degradation that results from exposure to solid urban waste. Growing public concern with environmental issues has led to the implementation of various strategic plans for waste management in several developed countries, especially in the European Union. In this paper, the relationships were assessed between economic growth, renewable energy extraction and greenhouse gas (GHG) emissions in the waste sector. The Environmental Kuznets Curve hypothesis was analysed for the member states of the European Union, in the presence of electricity generation, landfill and GHG emissions for the period 1995 to 2012. The results revealed that there is no inverted-U-shaped relationship between income and GHG emissions in European Union countries. The renewable fuel extracted from waste contributes to a reduction in GHG, and although the electricity produced also increases emissions somewhat, they would be far greater if the waste-based generation of renewable energy did not take place. The waste sector needs to strengthen its political, economic, institutional and social communication instruments to meet its aims for mitigating the levels of pollutants generated by European economies. To achieve the objectives of the Horizon 2020 programme, currently in force in the countries of the European Union, it will be necessary to increase the share of renewable energy in the energy mix. PMID- 28620855 TI - Physicochemical characteristics, mutagenicity and genotoxicity of airborne particles under industrial and rural influences in Northern Lebanon. AB - In this work, the main objectives were to assess the mutagenic and genotoxic effects of fine particulate matter collected in an industrial influenced site in comparison with a non-industrial influenced one (rural site) and to relate the particulate matter (PM) composition to the observed genotoxic effects. At the industrial influenced site, higher concentrations of phosphates, trace metals, and polycyclic aromatic hydrocarbons (PAHs) in particles could be related to the contributions of quarries, fertilizer producer, cement plants, and tires burning. Gasoline and diesel combustion contributions were evidenced in particles collected at both sites. Particles collected under industrial influence showed a higher mutagenic potential on three tested strains of Salmonella typhimurium (TA98, YG1041, and TA102), and especially on the YG1041, compared to particles from the rural site. Furthermore, only particles collected in the vicinity of the industrial site showed a tendency to activate the SOS responses in Escherichia coli PQ37, which is indicative of DNA damage as a result of exposure of the bacteria cells to the action of mutagenic samples. The mutagenicity and genotoxicity of the industrial PM2.5-0.3 particulates may be attributed to its composition especially in organic compounds. This study showed that proximity of industries can affect local PM composition as well as PM genotoxic and mutagenic potential. PMID- 28620856 TI - Investigation on the effect of sintering temperature on kaolin hollow fibre membrane for dye filtration. AB - Despite its extraordinary price, ceramic membrane can still be able to surpass polymeric membrane in the applications that require high temperature and pressure conditions, as well as harsh chemical environment. In order to alleviate the high cost of ceramic material that still becomes one of the major factors that contributes to the high production cost of ceramic membrane, various attempts have been made to use low cost ceramic materials as alternatives to well-known expensive ceramic materials such as alumina, silica, and zirconia in the fabrication of ceramic membrane. Thus, local Malaysian kaolin has been chosen as the ceramic material in this study for the preparation of kaolin hollow fibre membrane since it is inexpensive and naturally abundant in Malaysia. Due to the fact that the sintering process plays a prominent role in obtaining the desired morphology, properties, and performances of prepared ceramic membrane, the aim of this work was to study the effect of different sintering temperatures applied (ranging from 1200 to 1500 degrees C) in the preparation of kaolin hollow fibre membrane via dry/wet phase inversion-based spinning technique and sintering process. The morphology and properties of membrane were then characterised by SEM, AFM, FTIR, XRD, and three-point bending test, while the performances of membrane were investigated by conducting water permeation and Reactive Black 5 (RB5) dye rejection tests. From the experimental results obtained, the sintering temperature of 1400 degrees C could be selected as the optimum sintering temperature in preparing the kaolin hollow fibre membrane with the dense sponge like structure of separation layer that resulted in the good mechanical strength of 70 MPa with the appreciable water permeation of 75 L/h m2 bar and RB5 rejection of 68%. PMID- 28620857 TI - Distribution of potentially toxic elements (PTEs) in tailings, soils, and plants around Gol-E-Gohar iron mine, a case study in Iran. AB - This study investigated the concentration of potentially toxic elements (PTEs) including Al, As, Cd, Co, Cr, Cu, Fe, Hg, Mn, Mo, Ni, Pb, Sb, V, and Zn in 102 soils (in the Near and Far areas of the mine), 7 tailings, and 60 plant samples (shoots and roots of Artemisia sieberi and Zygophylum species) collected at the Gol-E-Gohar iron ore mine in Iran. The elemental concentrations in tailings and soil samples (in Near and Far areas) varied between 7.4 and 35.8 mg kg-1 for As (with a mean of 25.39 mg kg-1 for tailings), 7.9 and 261.5 mg kg-1 (mean 189.83 mg kg-1 for tailings) for Co, 17.7 and 885.03 mg kg-1 (mean 472.77 mg kg-1 for tailings) for Cu, 12,500 and 400,000 mg kg-1 (mean 120,642.86 mg kg-1 for tailings) for Fe, and 28.1 and 278.1 mg kg-1 (mean 150.29 mg kg-1 for tailings) for Ni. A number of physicochemical parameters and pollution index for soils were determined around the mine. Sequential extractions of tailings and soil samples indicated that Fe, Cr, and Co were the least mobile and that Mn, Zn, Cu, and As were potentially available for plants uptake. Similar to soil, the concentration of Al, As, Co, Cr, Cu, Fe, Mn, Mo, Ni, and Zn in plant samples decreased with the distance from the mining/processing areas. Data on plants showed that metal concentrations in shoots usually exceeded those in roots and varied significantly between the two investigated species (Artemisia sieberi > Zygophylum). All the reported results suggest that the soil and plants near the iron ore mine are contaminated with PTEs and that they can be potentially dispersed in the environment via aerosol transport and deposition. PMID- 28620858 TI - Toxicity assessment of five emerging pollutants, alone and in binary or ternary mixtures, towards three aquatic organisms. AB - Despite a growing scientific attention on ecological impact of emerging pollutants (EPs) such as pharmaceuticals, personal care products, and pesticides, knowledge gaps remain regarding mixture toxicity and effects on aquatic organisms. Several EPs were screened in seawater (Normandy, France), and the ecotoxicity of five compounds, chosen on their occurrence in ecosystems and use worldwide, was assessed and were the biocides methylparaben (MP) and triclosan (TCS), a pesticide degradation product (AMPA), and the pharmaceuticals venlafaxine (VEN) and carbamazepine (CBZ). The acute or sub-chronic toxicity, alone or in binary/ternary mixtures of three of them (CBZ, AMPA, and MP), was assessed on one marine and two freshwater organisms: Crassostrea gigas, Pseudokirchneriella subcapitata, and Daphnia magna. TCS and AMPA were, respectively, the most (EC50 < 1 mg L-1) and the least (EC50 > 50 mg L-1) toxic chemicals for the four endpoints (algal growth inhibition, daphnia immobilization, oyster embryotoxicity, and metamorphosis). The anxiolytic VEN (EC50 < 1 mg L-1) was particularly toxic to oyster larvae showing sensitivity difference between freshwater and marine organisms. If all the mixtures appeared to be in the same range of toxicity, the joint-toxic effects mainly led to synergistic or antagonistic interactions compared to single-compound toxicity. The data also highlighted species-dependent differing models of toxicity and underscored the need for an awareness of cocktail effects for better ecological risk assessment. PMID- 28620859 TI - Perception and practices of tobacco smoking among medical students in the Nile Delta, Egypt. AB - This study was conducted to identify medical students' perception and practices towards tobacco smoking, as well as to identify factors affecting their adoption to smoking habit, among medical students in the Nile Delta. From December 2014 to February 2015, a questionnaire-based cross-sectional study was conducted at the four faculties of medicine in the Nile Delta. A total of 1715 students were targeted from the 2nd to 6th academic years to represent different levels of knowledge, awareness, and the influence of medical education on their attitude towards smoking. 5.6 and 1.2% of the students reported being smokers and ex smokers, respectively, with a higher prevalence among 6th-year students, 40% of them reported to be involved with substance abuse. In general, medical students had positive antismoking attitude. The prevalence of smoking among medicine students was not high. However, there is a need to address smoking cessation programs during their study. PMID- 28620861 TI - Testing a ratio of photosynthesis to O3 uptake as an index for assessing O3 induced foliar visible injury in poplar trees. AB - Visible foliar injury by ozone (ozone visible injury) is known as a biomarker to assess potential phytotoxicity of ozone. We investigated ozone visible injury in an ozone-sensitive poplar (Oxford clone) under a 2-year free-air controlled exposure (FACE) experiment and calculated three ozone indices (i.e., accumulative ozone exposure over 40 ppb during daylight hours (AOT40), phytotoxic ozone dose above a flux threshold of 0 nmol m-2 s-1 (POD0), and the cumulative value of the ratio of hourly ozone uptake to net photosynthesis (SigmaU/P n ) to assess the critical level (CL) at the time of the first symptom onset of ozone visible injury. We tested the hypothesis that ozone injury depends both on the amount of ozone entering a leaf and on the capacity for biochemical detoxification or repair with photosynthesis as a proxy. The CLs at the time of the first symptom onset of ozone visible injury were 19 ppm h for AOT40, 26 mmol m-2 for POD0, and 1.2 mol mol-1 for SigmaU/P n in Oxford clone at the ozone FACE experiment. Our findings were then verified by 4-year observation-based data in central Italy on Oxford clone and white poplar (Populus alba L.). These observation-based data indicated that we found ozone visible injury in Oxford clone even though AOT40 was relatively low (11.7 ppm h). On the other hand, when values of POD0 and SigmaU/P n exceeded over the CLs, the occurrence of initial symptoms in Oxford clone was shown. White poplar did not show ozone visible injury. SigmaU/P n of white poplar at the field sites reached ~1.0 mol mol-1 (less than the CL = 1.2 mol mol-1, which was obtained from O3 FACE) during May-September, although the values of POD0 were relatively high in white poplar (44-47 mmol m-2 during May September). The result implies that ozone injury may have occurred in poplars when stomatal ozone flux exceeded the critical range of tolerance due to the assimilate shortage for repair and defense against ozone stress. PMID- 28620862 TI - Palladium-catalyzed acid-free Fujiwara-Moritani alkenylation of 4 thiazolidinones. AB - Herein, we report a facile method for the alkenylation of a 4-thiazolidinone motif without using external acid and high-pressure gas, which are required in conventional Fujiwara-Moritani reactions. Mild reaction conditions, one-pot synthesis, and utilization of an oxidant made this process more feasible in comparison with previously reported methods. Functionalization of the slightly more acidic [Formula: see text] C-H bond with the less acidic [Formula: see text] C-H bond yielded the alkenylated motif. This pathway opens new possibilities for organic synthesis. PMID- 28620860 TI - Currently used organophosphate and brominated flame retardants in the environment of China and other developing countries (2000-2016). AB - This review summarizes the environmental occurrence of new brominated flame retardants (NBFRs) and organophosphate compounds (OPs) in the environment of developing countries since 2000. The ban on the production and use of commercial formulations of polybrominated diphenyl ethers (PBDEs) have paved the way for the high use of NBFRs and OPs in consumer products to fulfill the fire safety regulations. Recent studies have shown that the ever increasing production volumes and extensive use of these chemicals as additive FRs and plasticizers have resulted into their ubiquitous occurrence in all environmental compartments. Although presumed to be safe for use and the environment, recent studies on their occurrence and persistence in the environment have raised questions. Due to the lack of awareness, research interest, and availability of technical facilities, limited scientific data is available on the occurrence of these chemicals in developing countries. In this study, we collected reported data and provide an overview of environmental occurrence of NBFRs and OPs in abiotic and biotic matrices of different developing countries. Finally, research gaps were identified with recommendations for future research work and would be useful towards the environmental management of these toxic chemicals. PMID- 28620863 TI - Effect of ligamentum teres tear on the development of joint instability and articular cartilage damage: an in vivo rabbit study. AB - The contribution of the ligamentum teres to the stabilization of the hip joint and the clinical influence of a compromised ligamentum teres are not well known. This study aimed to investigate joint stability and cartilage damage in a rabbit model by surgically inducing a complete ligamentum teres tear. Twenty adult New Zealand rabbits were used in this study. Rabbits were divided into complete ligamentum teres tear with capsulotomy (n = 9, group I) and capsulotomy only (n = 10, group II) groups. Unilateral surgery was performed on the left hip. Joint instability was assessed by measuring the preoperative and postoperative acetabulofemoral (A-F) distances. Rabbits were euthanized to assess cartilage damage at 24 weeks postoperatively. The median postoperative A-F distance of the operated side in group I [0.68 cm (0.37-1.04 cm)] was larger than that in group II [0.50 cm (0.30-0.65 cm)] (p = 0.041). The median postoperative A-F distance was larger in the operated side [0.68 cm (0.37-1.04 cm)] compared to the nonoperated side [0.45 cm (0.30-0.75 cm)] in group I; it also was larger in the operated side [0.50 cm (0.30-0.65 cm)] compared to the nonoperated side [0.44 cm (0.32-0.67 cm)] in group II, but only group I showed a significant difference (p = 0.016 and 0.395, respectively). Articular cartilage damage was detected at the apex of the femoral head in two rabbits (22.2%) in group I only. Rabbits with a complete ligamentum teres tear showed significant instability at the hip joint and articular cartilage damage in our rabbit model, supporting the potential clinical importance of ligamentum teres as a hip joint stabilizer. PMID- 28620864 TI - Adipose tissue-derived stromal cells (ADSC) express oligodendrocyte and myelin markers, but they do not function as oligodendrocytes. AB - Mesenchymal cells cultured from the vasculo-stromal fraction of adipose tissue (ADSC) show adult stem cell characteristics and several groups have claimed generating neural cells from them. However, we have observed that many markers commonly used for the identification of neural cells are spontaneously expressed by ADSC in culture. In the present study, we have examined the expression of characteristic oligodendrocyte molecules in cultured ADSC, aiming to test if myelinating cells could be generated from accessible non-neural adult tissues. In basal growth conditions, rat ADSC spontaneously expressed CNPase, MBP, MOG, protein zero, GAP43, Sox10, and Olig2, as shown by immunocytrochemistry and western blot. A small population of cultured ADSC expressed membrane galactocerebroside (O1 antibody), but no cell stained with O4 antibody. RT-PCR analyses showed the expression of CNPase, MBP, DM20, and low levels of Olig2, Sox10, and Sox2 mRNA by rat ADSC. When rat ADSC were treated with combinations of factors commonly used in neural-inducing media (retinoic acid, dbcAMP, EGF, basic FGF, NT3, and/or PDGF), the number of O1-positive cells changed, but in no case, mRNA expression of Sox10 and Olig2 transcription factors approached CNS oligodendrocyte levels. In co-culture with rat dorsal root ganglion neurons, no sign of axonal myelination by rat ADSC was observed. These studies show that the expression of oligodendrocyte traits by cultured ADSC is not a proof of functional competence as oligodendroglia and suggest that in culture conditions, ADSC acquire intermediate, uncommitted phenotypes. PMID- 28620865 TI - Involvement of Atm and Trp53 in neural cell loss due to Terf2 inactivation during mouse brain development. AB - Maintenance of genomic integrity is one of the critical features for proper neurodevelopment and inhibition of neurological diseases. The signals from both ATM and ATR to TP53 are well-known mechanisms to remove neural cells with DNA damage during neurogenesis. Here we examined the involvement of Atm and Atr in genomic instability due to Terf2 inactivation during mouse brain development. Selective inactivation of Terf2 in neural progenitors induced apoptosis, resulting in a complete loss of the brain structure. This neural loss was rescued partially in both Atm and Trp53 deficiency, but not in an Atr-deficient background in the mouse. Atm inactivation resulted in incomplete brain structures, whereas p53 deficiency led to the formation of multinucleated giant neural cells and the disruption of the brain structure. These giant neural cells disappeared in Lig4 deficiency. These data demonstrate ATM and TP53 are important for the maintenance of telomere homeostasis and the surveillance of telomere dysfunction during neurogenesis. PMID- 28620866 TI - High levels of IGF-1 predict difficult intubation of patients with acromegaly. AB - PURPOSE: To investigate the characteristics of difficult intubation and identify novel efficient predictors in patients with acromegaly. METHODS: Patients with either untreated acromegaly or non-functional pituitary adenomas were enrolled. Patients with acromegaly underwent hormone assays, upper airway computed tomography and magnetic resonance imaging examinations and preoperative overnight polysomnography. The modified Mallampati classification, mouth opening, neck circumference, and neck extension were assessed, and the Cormack-Lehane grades and the time of tracheal intubation were recorded. RESULTS: Patients with acromegaly had a higher incidence of difficult intubation (62.5%). The time of tracheal intubation was prolonged, the neck circumference was enlarged, and the neck extension was confined. In patients with acromegaly and difficult intubation, the insulin-like growth factor 1 levels and apnea/hypoxia index were significantly higher compared to patients without difficult intubation (1115.40 +/- 253.73 vs. 791.67 +/- 206.62 ng/ml, P = 0.020; 22.17 +/- 23.25 vs. 2.47 +/- 2.84, P = 0.026, respectively). The bilateral regression analysis revealed that high levels of insulin-like growth factor 1 were an independent risk factor for developing difficult intubation (p = 0.042, Exp B = 1.006). The modified Mallampati classification was positively correlated with apnea/hypoxia index and could be calculated using the following logarithmic equation: MMC = 0.2982 * ln (AHI) + 2.1836. CONCLUSIONS: In patients with acromegaly, neck movement is confined, the time of tracheal intubation is prolonged, and the neck circumference is enlarged, and these patients suffer from an increased incidence of difficult intubation (62.5%) during anesthesia induction. The apnea/hypoxia index and insulin-like growth factor 1 levels are both increased in acromegalic patients with difficult intubation, and elevated insulin-like growth factor 1 levels are an independent risk factor of difficult intubation in acromegalic patients. PMID- 28620867 TI - Gut Microbiome and Bone: to Build, Destroy, or Both? AB - PURPOSE OF REVIEW: The gut microbiota can be considered a hidden organ that plays essential roles in host homeostasis. Exploration of the effects of microbiota on bone has just begun. Complimentary studies using germ-free mice, antibiotic, and probiotic treatments reveal a complicated relationship between microbiota and bone. Here, we review recent reports addressing the effect of gut microbiota on bone health, discuss potential reasons for discrepant findings, and explore potential mechanisms for these effects. RECENT FINDINGS: Manipulation of microbiota by colonization of germ-free mice, antibiotics, or probiotic supplementation significantly alters bone remodeling, bone development and growth, as well as bone mechanical strength. Different experimental models reveal context-dependent effects of gut microbiota on bone. By examining phenotypic effects, experimental context, and proposed mechanisms, revealed by recent reports, we hope to provide comprehensive and fresh insights into the many facets of microbiota and bone interactions. PMID- 28620869 TI - Right heart thrombus in transit: a series of two cases. AB - Right heart thrombus in transit is an increasingly recognized medical emergency with very high mortality rate. Echocardiography helps to establish the diagnosis and can differentiate between right heart thrombi that result from atrial fibrillation and those originating from deep venous thrombosis. We present two cases of right heart thrombus in transit diagnosed with echocardiography that were managed with different approaches. PMID- 28620868 TI - Osteoporosis in Children with Chronic Illnesses: Diagnosis, Monitoring, and Treatment. AB - PURPOSE OF REVIEW: Osteoporosis is an under-recognized complication of chronic illness in childhood. This review will summarize recent literature addressing the risk factors, evaluation, and treatment for early bone fragility. RECENT FINDINGS: Criteria for the diagnosis of pediatric osteoporosis include the presence of low trauma vertebral fractures alone or the combination of low bone mineral density and several long bone fractures. Monitoring for bone health may include screening for vertebral fractures that are common but often asymptomatic. Pharmacologic agents should be offered to those with fragility fractures especially when spontaneous recovery is unlikely. Controversies persist about the optimal bisphosphonate agent, dose, and duration. Newer osteoporosis drugs have not yet been adequately tested in pediatrics, though clinical trials are underway. The prevalence of osteoporosis is increased in children with chronic illness. To reduce the frequency of fragility fractures requires increased attention to risk factors, early intervention, and additional research to optimize therapy and potentially prevent their occurrence. PMID- 28620870 TI - Severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features are due to a homozygous QARS mutation. AB - Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92). Homozygosity mapping and whole exome sequencing revealed a homozygous missense (V476I) mutation in the QARS gene, located in the catalytic domain. The patient's fibroblasts demonstrated markedly reduced QARS amino acylation activity in vitro. Furthermore, the same homozygous mutation was found in an unrelated girl of Ashkenazi origin with the same phenotype. The clinical presentation of our patients differs from the original QARS-associated syndrome in the severe postnatal growth failure, absence of epilepsy, and minor MRI findings, thus further expanding the phenotypic spectrum of the glutaminyl-tRNA synthetase deficiency syndromes. PMID- 28620871 TI - Lipophilic Statins and the Risk of Intracranial Hemorrhage Following Ischemic Stroke: A Population-Based Study. AB - BACKGROUND: Statins are commonly prescribed for the secondary prevention of ischemic stroke, but there is conflicting evidence as to whether they increase the risk of intracranial hemorrhage. Lipophilic statins cross the blood-brain barrier more freely than hydrophilic statins and may therefore increase the risk of intracranial hemorrhage. OBJECTIVE: To determine whether, in older patients following ischemic stroke, receipt of lipophilic statins was associated with differences in the risk of intracranial hemorrhage. METHODS: We conducted a population-based nested case-control study linking multiple healthcare databases between 1 April, 2001 and 31 March, 2015 in Ontario, Canada. Cases were Ontarians aged 66 years or older receiving a statin within 100 days preceding the development of intracranial hemorrhage within 1 year following ischemic stroke. Each case was matched with up to four controls who experienced ischemic stroke not complicated by intracranial hemorrhage but who also received a statin. We classified statins as lipophilic (atorvastatin, simvastatin, lovastatin, fluvastatin, and cerivastatin) or hydrophilic (pravastatin and rosuvastatin) based on their octanol/water partition coefficients. We calculated the odds ratio for the association between intracranial hemorrhage and receipt of lipophilic statins, with hydrophilic statins as the reference group. RESULTS: We identified 2766 individuals who experienced intracranial hemorrhage during statin therapy after ischemic stroke and 11,060 matched controls. Relative to hydrophilic statins, lipophilic statins were not associated with an increased risk of intracranial hemorrhage (adjusted odds ratio 1.07; 95% confidence interval 0.97 1.19). CONCLUSION: Among patients treated with a statin following ischemic stroke, the risk of intracranial hemorrhage is not influenced by statin lipophilicity. PMID- 28620872 TI - Three New Pyridine Alkaloids from Vinca major Cultivated in Pakistan. AB - Three new pyridine type alkaloids, (-)-vinmajpyridines A-C (1-3), along with two known alkaloids, have been isolated from the aerial parts of Vinca major cultivated in Pakistan. Their structures have been elucidated by means of NMR and HRESIMS spectroscopic data. The new alkaloids were evaluated for their cytotoxicity against glioma initiating cell lines (GITC-3# and GITC-18#), glioblastoma cell lines (U-87MG and T98G), and lung cancer cell line A-549, but none of them was active at 20 MUg/mL concentration. PMID- 28620873 TI - Cytotoxic Acylphloroglucinol Derivatives from Callistemon salignus. AB - Callisalignenes G-I (1-3), three new meroterpenoids of beta-triketone and monoterpene, along with two known analogues (4 and 5), were isolated from Callistemon salignus. Their structures and absolute configurations were unambiguously established by a combination of NMR and MS analysis and electronic circular dichroism (ECD) evidence. Callisalignenes H (2) and I (3) have a rare sec-butyl moiety at C-7. Meroterpenoids 1-3 exhibited cytotoxicity against HCT116 cells with IC50 values of 8.51 +/- 1.8, 9.12 +/- 0.3, and 16.33 +/- 3.3 MUM, respectively. Cytotoxic Acylphloroglucinol Derivatives from Callistemon salignus. PMID- 28620874 TI - Moving from significance to real-world meaning: methods for interpreting change in clinical outcome assessment scores. AB - PURPOSE: Clinical outcome assessments (COAs) require evidence not only of reliability, validity, and ability to detect change, but also a definition of what constitutes a meaningful change on the instrument. The responder definition specifies the amount of change on the COA that may be interpreted as a treatment benefit and is critical for interpreting what constitutes a meaningful change on the COA scores. However, the literature that describes methods for developing and applying responder definitions can be difficult to navigate. Clear and concise guidelines regarding which methods to apply under what circumstances and how to interpret the results are lacking. This article provides a guide to the variety of available methods and issues that should be considered when establishing responder definitions for interpreting meaningful changes in COA scores. METHODS: An overview is provided for selecting anchors, developing study designs, planning psychometric analyses, using psychometric results to set responder thresholds, and applying responder thresholds in demonstrating treatment efficacy. RESULTS: There are a variety of anchor-based methods for consideration, but they all rely on a preference for strongly related and easily interpretable anchors. The benefits of applying multiple anchors and multiple analytic methods are discussed. The process of triangulation can synthesize results across multiple sources to gain confidence in a proposed responder definition. Though a link to meaningfulness from the patient's perspective is absent, distribution-based methods provide lower bound estimates of score precision and have a role in triangulation. Responder definitions are typically required within regulatory review, but their application may differ across clinical trial programs. CONCLUSIONS: By careful planning of anchor selection, study design, and psychometric methods, COA researchers can establish defensible responder thresholds that ultimately aid patients and clinicians in making informed treatment decisions. PMID- 28620875 TI - Predictors of health-related quality of life in maltreated children and adolescents. AB - PURPOSE: Research on the consequences of child maltreatment has primarily focused on behavior and mental health; the children's overall well-being has not received the same attention. A number of studies have investigated health-related quality of life (HRQoL) among victims of child maltreatment, but there is still a lack of knowledge about predictors of HRQoL in maltreated children and adolescents. This study seeks to bridge the gap by drawing data from the German multi-site study Child Abuse and Neglect Case-Management (CANMANAGE). METHODS: Parents or caregivers of 350 children and adolescents completed a proxy version of the Kidscreen-10-Index, a multidimensional instrument measuring child HRQoL. An additional 249 children age 8 years and older completed a self-report version. Multiple regression analyses were performed to identify potential predictors for both self- and proxy-rated HRQoL. RESULTS: Comparisons with the reference group revealed a significantly lower mean proxy-rated HRQoL, the self-rated HRQoL of the study sample was not significantly impaired. Predictors of impaired self reported HRQoL were older age, self-reported posttraumatic stress symptoms (PTSS), and self-reported emotional and behavioral symptoms. Predictors of impaired proxy-reported HRQoL again were older age, self-reported PTSS, and emotional and behavioral symptoms in the child/adolescent, as reported by the caregiver, as well as low socioeconomic status. Multivariate analysis explained 20% and 38% of the variability in self-reported and proxy-rated HRQoL, respectively. CONCLUSIONS: It is important to treat PTSS and emotional and behavioral symptoms in maltreated children, as these two phenomena are strong cross-sectional predictors of a child's HRQoL. Trauma-focused cognitive behavioral therapies are one possible option to address the needs of such children. PMID- 28620876 TI - English Orthographic Learning in Chinese-L1 Young EFL Beginners. AB - English orthographic learning, among Chinese-L1 children who were beginning to learn English as a foreign language, was documented when: (1) only visual memory was at their disposal, (2) visual memory and either some letter-sound knowledge or some semantic information was available, and (3) visual memory, some letter sound knowledge and some semantic information were all available. When only visual memory was available, orthographic learning (measured via an orthographic choice test) was meagre. Orthographic learning was significant when either semantic information or letter-sound knowledge supplemented visual memory, with letter-sound knowledge generating greater significance. Although the results suggest that letter-sound knowledge plays a more important role than semantic information, letter-sound knowledge alone does not suffice to achieve perfect orthographic learning, as orthographic learning was greatest when letter-sound knowledge and semantic information were both available. The present findings are congruent with a view that the orthography of a foreign language drives its orthographic learning more than L1 orthographic learning experience, thus extending Share's (Cognition 55:151-218, 1995) self-teaching hypothesis to include non-alphabetic L1 children's orthographic learning of an alphabetic foreign language. The little letter-sound knowledge development observed in the experiment-I control group indicates that very little letter-sound knowledge develops in the absence of dedicated letter-sound training. Given the important role of letter-sound knowledge in English orthographic learning, dedicated letter sound instruction is highly recommended. PMID- 28620878 TI - Incidental colorectal FDG uptake on PET/CT scan and lesions observed during subsequent colonoscopy: a systematic review. AB - BACKGROUND: Incidental colorectal fluorodeoxyglucose (FDG) uptake can be observed during a positron emission tomography/computed tomography (PET/CT) scan. For clinical and/or histological assessment of the cause, a colonoscopy is then performed. A systematic review was conducted to investigate the relationship between incidental colorectal FDG uptake and lesions observed during a subsequent colonoscopy. METHODS: A literature search was conducted using PubMed, Embase, and Web of Science with the keywords concerning PET/CT scan and colonoscopy. The studies were selected using inclusion criteria defined a priori and were described individually to examine the correlation between incidental colorectal FDG uptake and the lesions found at colonoscopy. RESULTS: Twenty-six of 1606 studies found were included. In total, 108,578 patients underwent an FDG-PET/CT scan as part of a diagnostic work-up or cancer staging. In total, 2546 incidental colorectal FDG uptakes were described in 2121 patients (mean age 62.7 years SD +/ 5.1), of which 2045 uptakes in 1635 patients were examined by colonoscopy, within a mean of 37 days (SD +/- 28). The colonoscopic lesions included neoplasms (n = 1097; 322 cancers), benign lesions (n = 273), and inflammatory lesions (n = 71). Colonoscopies were normal in 604 patients. In total, 82% of lesions were located in the same location as the FDG uptakes. The positive predictive value was 70% (95% CI [68-72]). CONCLUSIONS: Incidental colorectal FDG uptake, as evaluated by subsequent colonoscopy, often reveals neoplastic lesions. Predominantly, lesions were located at the same location as FDG uptake. Further investigation is warranted before recommending that incidental colorectal FDG uptake should always result in referral to diagnostic colonoscopy. PMID- 28620879 TI - Authors' reply to: Prophylactic mesh to prevent parastomal hernia: a meta analysis of randomized controlled studies (Tech Coloproctol (2017) 21:5-13). PMID- 28620877 TI - Pathogenesis and persistence of cryptoglandular anal fistula: a systematic review. AB - Anal fistulas continue to be a problem for patients and surgeons alike despite scientific advances. While patient and anatomical characteristics are important to surgeons who are evaluating patients with anal fistulas, their development and persistence likely involves a multifaceted interaction of histological, microbiological, and molecular factors. Histological studies have shown that anal fistulas are variably epithelialized and are surrounded by dense collagen tissue with pockets of inflammatory cells. Yet, it remains unknown if or how histological differences impact fistula healing. The presence of a perianal abscess that contains gut flora commonly leads to the development of anal fistula. This implies a microbiological component, but bacteria are infrequently found in chronic fistulas. Recent work has shown an increased expression of proinflammatory cytokines and epithelial to mesenchymal cell transition in both cryptoglandular and Crohn's perianal fistulas. This suggests that molecular mechanisms may also play a role in both fistula development and persistence. The aim of this study was to examine the histological, microbiological, molecular, and host factors that contribute to the development and persistence of anal fistulas. PMID- 28620880 TI - A preliminary study of the use of oral rehydration salts in decreasing ileostomy output. PMID- 28620881 TI - A Comparison of Methods for Calculating the Basic Reproductive Number for Periodic Epidemic Systems. AB - When using mathematics to study epidemics, oftentimes the goal is to determine when an infection can invade and persist within a population. The most common way to do so uses threshold quantities called reproductive numbers. An infection's basic reproductive number (BRN), typically denoted [Formula: see text], measures the infection's initial ability to reproduce in a naive population and is tied mathematically to the stability of the disease-free equilibrium. Next-generation methods have long been used to derive [Formula: see text] for autonomous continuous-time systems; however, many diseases exhibit seasonal behavior. Incorporating seasonality into models may improve accuracy in important ways, but the resulting non-autonomous systems are much more difficult to analyze. In the literature, two principal methods have been used to derive BRNs for periodic epidemic models. One, based on time-averages, is simple to apply but does not always describe the correct threshold behavior. The other, based on linear operator theory, is more general but also more complicated, and no detailed explanations of the necessary computations have yet been laid out. This paper reconciles the two methods by laying out an explicit procedure for the second and then identifying conditions (and some important classes of models) under which the two methods agree. This allows the use of the simpler method, which yields interpretable closed-form expressions, when appropriate, and illustrates in detail the simplest possible case where they disagree. Results show that seasonality alone cannot affect disease persistence, but must act in conjunction with non-hierarchical heterogeneity in the infected population, in order to do so. PMID- 28620882 TI - Intermediates and Generic Convergence to Equilibria. AB - Known graphical conditions for the generic and global convergence to equilibria of the dynamical system arising from a reaction network are shown to be invariant under the so-called successive removal of intermediates, a systematic procedure to simplify the network, making the graphical conditions considerably easier to check. PMID- 28620883 TI - Extended adjuvant endocrine therapy in early breast cancer: a meta-analysis of published randomized trials. AB - Adjuvant endocrine therapy for 5 years is the standard adjuvant treatment for estrogen receptor-positive breast cancer while the benefits of extended adjuvant endocrine therapy (EAET) beyond 5 years are still controversial. That controversy prompted this meta-analysis to compare 5 years of adjuvant endocrine therapy only versus EAET. Eligible 11 randomized, controlled trials comprising 29,000 women were included. EAET showed no advantage in overall survival (OS) from all causes mortality (odds ratio [OR] = 0.98 (95% confidence interval [CI], 0.87-1.09); P = 0.67). On the other hand, compared with standard therapy, the pooled effects showed that EAET was associated with improvement in breast cancer-specific survival (OR = 0.87; 95% CI 0.79-0.96; P = 0.004), disease-free survival (DFS) (OR = 0.87; 95% CI 0.75-0.99; P = 0.002), disease recurrence (OR = 0.76; 95% CI 0.64-0.90; P = 0.001), and contralateral breast recurrence (OR = 0.74; 95% CI 0.59-0.93; P = 0.008). Improvement in DFS or disease recurrence was not shown in studies that compared 5 years of tamoxifen versus tamoxifen beyond 5 years. Subgroup analysis showed that EAET conferred more benefit for patients with positive lymph nodes. Rates of positive lymph nodes, the study size, and the median duration of follow-up were identified as variables that explained most of the demonstrated data heterogeneity. EAET should be considered as a preferred strategy for high-risk hormone-positive early breast cancer patients with positive lymph nodes; however, the benefit on OS could not be demonstrated. PMID- 28620885 TI - Modulatory Effect of Aerobic Exercise Training on Doxorubicin-Induced Cardiotoxicity in Rats with Different Ages. AB - We tested the hypothesis that aerobic exercise training (AET) would modulate doxorubicin-induced cardiotoxicity in rats of various ages. Wistar male rats (n = 72) were assigned to three groups (young, adult, and elderly) with three subgroups for each age: doxorubicin (DG, n = 8), AET + doxorubicin (AETDG, n = 8), AET + Saline (AETSG, n = 8). Following the AET intervention, rats were anesthetized and killed to collect heart tissues in order to determine heat shock protein 70 (HSP70), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-10 (IL10), and c-reactive protein (CRP). Greater levels of SOD and lower levels of MDA were found in young as compared to elderly rats (P < 0.05). CRP was significantly lower in young as compared to adult and elderly rats, respectively (P < 0.05). IL10 also was significantly lower in young as compared to elderly rats (P < 0.05). Furthermore, lower HSP70 and SOD levels were found in DG as compared to AETDG and AETSG (P < 0.05). Conversely, MDA and CRP were significantly higher in DG as compared to other groups (P < 0.05). A significant higher IL10 was noted in DG as compared to AETDG (P < 0.05). Our findings suggest that AET prior to doxorubicin treatment could be useful in minimizing toxicity after chemotherapy with doxorubicin mainly up-regulating of antioxidant defense capacity, with greatest benefit in the young group. Future studies examining the exercise-induced changes and age-related differences following chemotherapy are necessary in human. PMID- 28620884 TI - Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone: CALGB 40502 (Alliance). AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and Smax drug effects were evaluated. The model was evaluated by comparing the predicted proportion of patients with CIPN (score >=8 or score >=12) to the observed proportion. An indirect response model with linear drug effect was able to describe the longitudinal CIPN data reasonably well. The proportion of patients that were falsely predicted to have CIPN or were falsely predicted not to have CIPN was 20% or less at any cycle. The model will be utilized to identify an early time point that can predict CIPN at later time points. This strategy will be utilized to inform dose adjustments to prospectively manage CIPN. Clinicaltrials.gov ID: NCT00785291. PMID- 28620886 TI - To Improve Translational Research in Subarachnoid Hemorrhage. PMID- 28620887 TI - Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds. AB - PURPOSE: To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds. METHODS: The IDR and apparent solubility (Sapp) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the MUDISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions. RESULTS: The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (MUg-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2-70.6 MUg/min/cm2 and the IDR/Sapp ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water soluble compounds. CONCLUSIONS: The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/Sapp is proposed as a measure of particle size sensitivity when significant solubilization may occur. PMID- 28620888 TI - Design of Isoniazid Smart Nanogel by Gamma Radiation-Induced Template Polymerization for Biomedical Application. AB - PURPOSE: Preparation of Isoniazid (INH) loaded nanogel particles using gamma radiation as safe, simple, cheap and reproducible technique for promoting mycobacterial killing in a lower-dose system aiming in developing of drug resistance. METHODS: Polymeric pH-sensitive nanogels were prepared by gamma radiation-induced polymerization of Acrylic acid (AAc) or Itaconic acid (IA), in aqueous solution of polyvinylpyrrolidone (PVP), as template polymer. The prepared nanogels were utilized for encapsulation of INH. 31X22 factorial design was employed for optimization and exploring the effect of radiation dose (X1) (30 50kGy), ratio of PVP: acid (X2) (50:50-30:70) and type of acid (X3) on the prepared nanogel characterization RESULTS: The optimized levels of X1, X2 and X3 were (50 KGy, 30:70 and Itaconic acid, respectively), with a desirability of 0.959. In-vitro INH release rate from the prepared nanogels decreased with increasing gamma radiation doses, with the predominance of the diffusion mechanism for drug release pattern. In addition, it was perceived that the minimum inhibitory concentration (MIC) of INH loaded PVP/PIA nanogels on Mycobacteria Tuberculosis was 8 folds lower than that of INH solution. CONCLUSION: The prospective of PVP-K90/PIA was recommended as a smart candidate for delivery of INH with promising achievements against tuberculosis than free drug. Graphical abstract Mechanism of formation and loading of Isoniazid PVP/PIA nanogel. PMID- 28620889 TI - Levels of MicroRNA Heterogeneity in Cancer Biology. AB - MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression, involved in the silencing of messenger RNA (mRNA) translation. The importance of miRNA signatures in disease screening, prognosis, and progression of different tumor types and subtypes is increasing. miRNA expression levels change depending on numerous factors. In this review, we are describing the circumstances under which miRNA levels can change, these are named 'levels' of heterogeneity of miRNAs. miRNAs can have oncogenic, tumor suppressive, or both roles depending on tumor type and target mRNA whose translation they silence. The expression levels of a single miRNA may vary across different cancer types and subtypes, indicating that a miRNA signature may be tissue specific. miRNA levels of expression also vary during disease formation and propagation, indicating the presence of a time profile for their expression. The complexity of the miRNA-mRNA interference network mirrors different genetic and epigenetic changes that influence miRNA and mRNA availability to each other, and hence, their binding ability. The potential role of miRNAs as biomarkers is two-fold; first, for monitoring of the phases of cancer pathogenesis, and second, to characterize the particular type/subtype of cancer. It is important that a particular miRNA should be characterized by examining as many types and subtypes of cancers as are available, as well as being extracted from different types of samples, in order to obtain a complete picture of its behavior and importance in the disease pathology. PMID- 28620890 TI - Identification and Characterization of a New BRCA2 Rearrangement in an Italian Family with Hereditary Breast and Ovarian Cancer Syndrome. AB - INTRODUCTION: Many studies document the involvement of BRCA1/2 gene rearrangements in genetic predisposition to breast and ovarian cancer. Large genomic rearrangements (LGRs) of BRCA1 account for 0-27% of all disease-causing mutations in various populations, while LGRs in BRCA2 are rarer. Here, we describe a novel BRCA2 LGR, involving the duplication of exons 4-26, in an Italian family with hereditary breast and ovarian cancer (HBOC) syndrome. OBJECTIVE: Our purpose was to provide an effective characterization of this variant using a combination of different methods able to establish the exact breakpoints of the duplication. METHODS: A multiplex amplicon quantification (MAQ) assay was used as the primary screening method in the detection of LGRs. Array comparative genomic hybridization (CGH), reverse transcriptase polymerase chain reaction (RT-PCR) and long-range PCR were used for the careful characterization of the rearrangement and breakpoint regions. The Repeat Masker program was employed to identify Alu sequences at breakpoint junctions. RESULTS: Array CGH and long-range PCR strategies revealed that the BRCA2 exons 4-26 duplication (g.12016_87170dup) involved exactly 75,154 bp nucleotides between intron 3 and intron 26 of the gene. Given that no Alu repeats were found at the junction sites, we support the hypothesis that the new duplication could be the result of a microhomology-mediated event (MH) involving very short homologous sequences at an upstream breakpoint. DISCUSSION: LGR investigation is mandatory in BRCA1/2 routine testing in order to provide a complete result for a targeted therapeutic decision. Nevertheless, the characterization and classification of novel BRCA1/2 variants represents a crucial step in the support of genetic counselling. Our results, including a comprehensive co-segregation analysis, indicate that the novel duplication identifed has a pathogenic role and would be considered a causing-disease variant in genetic and oncologic counselling. PMID- 28620891 TI - Population Pharmacokinetic Modeling of Olaratumab, an Anti-PDGFRalpha Human Monoclonal Antibody, in Patients with Advanced and/or Metastatic Cancer. AB - BACKGROUND AND OBJECTIVES: Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-alpha (PDGFRalpha). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population. METHODS: Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM(r). RESULTS: The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V 1), whereas tumor size significantly affected CL. A small subset of patients developed treatment emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy. CONCLUSION: The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents. PMID- 28620892 TI - A Prospective Study of the Concordance of DSM-IV and DSM-5 Diagnostic Criteria for Autism Spectrum Disorder. AB - The transition from DSM-IV to DSM-5 criteria for autism spectrum disorder (ASD) sparked considerable concern about the potential implications of these changes. This study was designed to address limitations of prior studies by prospectively examining the concordance of DSM-IV and final DSM-5 criteria on a consecutive sample of 439 children referred for autism diagnostic evaluations. Concordance and discordance were assessed using a consistent diagnostic battery. DSM-5 criteria demonstrated excellent overall specificity and good sensitivity relative to DSM-IV criteria. Sensitivity and specificity were strongest for children meeting DSM-IV criteria for autistic disorder, but poor for those meeting criteria for Asperger's disorder and pervasive developmental disorder. Higher IQ, older age, female sex, and less pronounced ASD symptoms were associated with greater discordance. PMID- 28620893 TI - Systemic antibiotics for preventing ventilator-associated pneumonia in comatose patients: a systematic review and meta-analysis. AB - BACKGROUND: Early-onset ventilator-associated pneumonia (EO-VAP) is the leading cause of morbidity and mortality in comatose patients. However, VAP prevention bundles focus mainly on late-onset VAP and may be less effective in preventing EO VAP in comatose patients. Systemic antibiotic administration at the time of intubation may have a role in preventing EO-VAP. Therefore, we evaluated the effectiveness of systemic antibiotic administration in VAP prevention in comatose patients through a systematic review and meta-analysis. METHODS: We searched for studies published through December 2015 that evaluated systemic antibiotic prophylaxis in comatose patients. Two authors independently selected and evaluated full-length reports of randomized clinical trials or prospective cohorts in patients aged >16 years that evaluated the impact of systemic antibiotics at the time of intubation on EO-VAP compared to placebo or no prophylaxis. The outcome variables were the incidence of EO-VAP, the duration of mechanical ventilation, ICU length of stay, and ICU mortality. RESULTS: We identified 10,988 citations, yielding 26 articles for further analysis; three studies with 267 patients were finally analyzed. Most patients (n = 135) were comatose due to head trauma. Systemic antibiotic administration was associated with decreased incidence of EO-VAP (RR 0.32; 95% CI 0.19-0.54) and shorter ICU LOS (standardized mean difference -0.32; 95% CI -0.56 to -0.08), but had no effect on mortality (RR 1.03; 95% CI 0.7-1.53) or duration of mechanical ventilation (standardized mean difference -0.16; 95% CI -0.41 to 0.08). CONCLUSIONS: Antibiotic prophylaxis in comatose patients reduced the incidence of EO-VAP and decreased the ICU stay slightly. Future trials are needed to confirm these results. PMID- 28620894 TI - Three-Trocar Sleeve Gastrectomy vs Standard Five-Trocar Technique: a Randomized Controlled Trial. AB - PURPOSE: Bariatric surgery is a treatment for morbid obesity. Different surgical procedures have been described in order to obtain excess weight loss (EWL), but currently laparoscopic sleeve gastrectomy is the most commonly performed procedure throughout the world. Reducing abdominal wall trauma and increasing the aesthetic result are important goals for all bariatric surgeons. We conducted a randomized, controlled trial in order to assess if the three-trocar sleeve gastrectomy can be safely carried out or should be abandoned. MATERIALS AND METHODS: From September 2016 to February 2017, 90 patients were enrolled in our trial. Each patients was evaluated by a multidisciplinary team before surgery. Two groups were created after application of the inclusion and exclusion criteria. The primary endpoint was to define the features of early post-operative complications of patients in group 1 (the three-trocar technique-the experimental group) compared to group 2 (five-trocar technique-the control group). The secondary endpoints were to evaluate any differences between the two groups concerning post-operative pain and patients' satisfaction with the aesthetic results. RESULTS: There was no difference between the two groups concerning age, sex distribution, weight, and BMI. The rate of co-morbidities was similar in both groups. Operative time was inferior in the control group, but patient satisfaction was better in the three-trocar sleeve gastrectomy group. CONCLUSIONS: The three-trocar sleeve gastrectomy can be safely carried out with a modest increase in operative time, without additional early surgical complications and with a greater patient aesthetic satisfaction. TRIAL REGISTRATION: researchregistry2386. PMID- 28620895 TI - The Standardized Postoperative Checklist for Bariatric Surgery; a Tool for Safe Early Discharge? AB - BACKGROUND: Morbidly obese patients are at higher risk of complications after surgery. In bariatric surgery, pre- and intra-operative checklists are commonly used to identify high-risk patients preoperatively, to decrease the number of postoperative complications. This pilot study evaluates the effect of a postoperative checklist in bariatric surgery, addressing regularly measured parameters, on the occurrence and early recognition of complications. METHODS: An in-house developed postoperative checklist was used on the first postoperative day after bariatric surgery and included information on nausea, pain, temperature, heart rate, and laboratory markers. Complications were scored using the Clavien-Dindo (CD) classification, and three groups were formed: no complications (CD0), minor complications (CD1 and 2), and major complications (>=CD3a). Differences between groups were analyzed using nonparametric tests. RESULTS: Six hundred ninety-four subjects were included (79.5% female, age 42.6 +/- 10.8 years, BMI 43.8 +/- 5.8 kg/m2). Twenty-nine subjects developed major complications within 30 days postoperatively. There were no significant differences in baseline characteristics between groups. Subjects with major complications were less willing to be discharged due to complaints, compared to subjects with no or minor complications (14.8 vs. 3.6 and 4.6%, respectively) and had a higher decrease of hemoglobin level (0.8 vs. 0.6 and 0.65 mmol/l, respectively). CONCLUSION: The patient's willingness for discharge, in combination with hemoglobin decrease, may be the best early predictors of major complications after bariatric surgery. This postoperative checklist may be an adequate instrument to identify patients who can be safely discharged home on the first postoperative day and thereby play a part in patient management after bariatric surgery. PMID- 28620896 TI - Video-assisted endocrine neck surgery: state of the art. AB - During the last two decades, several minimally invasive approaches for endocrine neck surgery have been developed. Minimally invasive video-assisted approaches (minimally invasive video-assisted parathyroidectomy and minimally invasive video assisted thyroidectomy) gained a quite large worldwide diffusion, maybe because these techniques combine the advantages related to the endoscopic magnification with those due to the close similarity with the conventional surgery that makes these surgical approaches reproducible and feasible in different surgical settings. Several comparative studies have demonstrated the advantages of minimally invasive video-assisted neck surgery in terms of reduced postoperative pain, better cosmetic result, and higher patients' satisfaction over the conventional endocrine neck surgery. An accurate patients' selection plays a key role to ensure the success of minimally invasive video-assisted approaches. To date, in selected cases and in experienced Center, minimally invasive video assisted endocrine neck surgery could be considered the standard treatment or at least a safe and effective surgical option. PMID- 28620898 TI - Managing Glioblastoma in the Elderly Patient: New Opportunities. AB - Managing elderly patients with glioblastoma presents a unique set of challenges, including a scarcity of available data, which limits evidence-based recommendations. Nearly half of patients with a new diagnosis of glioblastoma are over 65 years of age, a common cutoff point in the medical literature for identifying an elderly population. The current standard of care for glioblastoma patients younger than 70 years of age with satisfactory performance status is maximal safe resection, followed by radiation therapy of 60 Gy (delivered in 30 fractions over a 6-week period) with concurrent temozolomide chemotherapy, followed by adjuvant temozolomide. There is no consensus recommendation regarding the best available treatment for patients over age 70 with glioblastoma; however, multiple studies have shown molecular characterization of glioblastoma in this group-particularly MGMT promoter methylation status-to be valuable in treatment decision making. Results of the phase III CE6 study by the Canadian Cancer Trials Group challenge the existing treatment paradigms for glioblastoma in the elderly. This review discusses best practices for the treatment of glioblastoma in patients older than 65 years, and highlights management concerns in caring for this particular patient population. PMID- 28620899 TI - Heather Wakelee on the Role of Checkpoint Inhibitors in Advanced Lung Cancer. PMID- 28620897 TI - Enhanced recovery pathway in elderly patients undergoing colorectal surgery: is there an effect of increasing ages? Results from the perioperative Italian Society Registry. AB - Previous studies reported that enhanced recovery pathway (ERP) is safe in elderly who did not require a specifically tailored protocol. In previous studies, elderly have been considered as a homogeneous cohort and the cut-off value to identify them was different. The aim of the present study is to assess the compliance to ERP and its impact on postoperative outcome in three subgroups of elderly patients with increasing ages. Prospectively collected data entered in an electronic Italian registry specifically designed for ERP were reviewed. 315 elderly patients undergoing elective colorectal resection were divided into three groups. Group 1: 71-75 years (n = 105), Group 2: 76-80 years (n = 117), Group 3: over 80 years (n = 93). Primary endpoints of the study were adherence to ERP and time to readiness for discharge (TRD). Compliance to ERP was similar in the three groups. No difference among groups was found for mortality, overall morbidity, major complications, reoperation rate and readmission rate. Median TRD and length of hospital stay (LOS) were progressively longer with increasing age (p = 0.018 and p = 0.078, respectively). Increasing age did not impact on adherence to ERP and postoperative morbidity, but delayed both TRD and LOS. PMID- 28620900 TI - New Treatment Options and Management Considerations in Borderline Resectable Pancreatic Cancer. AB - In the United States, cancer of the pancreas accounts for nearly 40,000 deaths annually and is the fourth leading cause of cancer-related mortality. The vast majority of patients present with metastatic or unresectable disease. Only 20% of patients are candidates for surgery, and therefore curable. The 5-year survival rate for patients with pancreatic adenocarcinoma is only 6%, with surgical resection being essential for long-term survival. Recent research has identified a precise subset of patients with borderline resectable pancreatic cancer for whom resection yielding durable survival is possible. This population is being actively studied to identify optimal treatment strategies for long-term survival. In this article we will discuss the definitions of resectability, describe the current diagnostic tests for pancreatic cancer, and review strategies for maximizing treatment outcomes in patients with resectable pancreatic cancer. PMID- 28620901 TI - Point/Counterpoint: Primary Debulking Surgery vs Neoadjuvant Chemotherapy for Newly Diagnosed Advanced Ovarian Cancer. PMID- 28620903 TI - Emerging Categories of Disease in Advanced Prostate Cancer and Their Therapeutic Implications. AB - The treatment of advanced prostate cancer has changed significantly in the last decade, as a result of the introduction of multiple new systemic therapies that have had a positive impact on treatment outcomes. The increasing number of therapies, along with new insights into the biological underpinnings of prostate cancer, have led to a growing appreciation for the heterogeneity of the disease and an awareness of emerging subcategories that have direct therapeutic implications for the practicing clinician. In the metastatic hormone-naive setting, the extent of metastatic disease visible on scans can serve as a useful measure to guide treatment decisions; the addition of docetaxel chemotherapy to hormonal therapy has significant benefit in patients whose scans show more extensive disease. In the castration-resistant setting, abiraterone and enzalutamide have both had a transformative impact; however, the emergence of resistance to these therapies often heralds a more aggressive phenotype. Emerging clinically relevant subcategories include disease that demonstrates treatment emergent neuroendocrine differentiation, as well as tumors with somatic and/or germline alterations in the DNA repair pathway. Identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum based chemotherapy, poly (ADP-ribose) polymerase inhibitors, and likely further therapies as new therapeutic targets are identified in these groups. PMID- 28620904 TI - Nonpalpable Intratesticular Mass in a Young Man With a History of Contralateral Retractile Testis. PMID- 28620905 TI - Stereotactic Body Radiation Therapy as an Alternative to Surgery in Early-Stage Non-Small-Cell Lung Cancer. AB - Stereotactic body radiation therapy (SBRT) is a novel radiation technique that allows a high dose of radiation to be delivered to a tumor with relatively low dose to the surrounding normal tissue. SBRT has achieved extraordinary clinical success in patients with inoperable early-stage non-small-cell lung cancer (NSCLC). Local control of approximately 90% at 2 to 5 years has been demonstrated in multiple trials. In comparisons with surgical resection (in patients who are fit candidates for surgery), SBRT has provided similar local control, but was associated with worse survival, probably due to differences in the underlying patient populations. Three randomized trials of SBRT vs surgical resection closed due to poor accrual, but an analysis of patients treated in these trials suggested that SBRT might even be superior to surgery. New randomized trials are underway to further assess the question of whether SBRT can be the definitive treatment for early-stage NSCLC instead of surgery. PMID- 28620906 TI - Management of Primary Mediastinal B-Cell Lymphoma and Gray Zone Lymphoma. AB - Primary mediastinal B-cell lymphoma is a distinct clinicopathologic entity that has a predilection for young women. It is clinically and molecularly different from other subtypes of diffuse large B-cell lymphoma and has a unique paradigm of management. While the cure rate for patients with primary mediastinal B-cell lymphoma is high, approaches have historically included mediastinal radiation; in moving therapeutics forward, strategies that obviate the need for radiation while maintaining high cure rates are critical. Mediastinal gray zone lymphoma is a closely related disease that is exceedingly rare and more common in men. Over recent years, there has been much progress in elucidating the biology of these lymphomas, and this has paved the way for novel therapies that are currently under investigation in clinical trials. PMID- 28620907 TI - Stability of astaxanthin-loaded nanostructured lipid carriers in beverage systems. AB - BACKGROUND: Nanostructured lipid carriers (NLCs) offer many potential benefits for incorporating lipophilic molecules into clear to opaque food systems. This study examined the stability of astaxanthin-loaded NLCs (Ax-NLCs) in model (solutions with 0 or 12% sucrose; pH 3, 7), semi-actual (whey) and actual (non alcoholic beer) beverages during 30-60 days storage at 6 or 20 degrees C. RESULTS: Ax-NLCs (Z-average size: 94 nm), containing alpha-tocopherol and EDTA as antioxidants, were stabilised with Tween 80 and lecithin, and mixed with the aforementioned beverages at the volume ratio of 3:97. The presence of sucrose, improved the physical stability of Ax-NLCs in acidic model beverage. No astaxanthin loss and particle size growth were observed for Ax-NLCs-added whey. Carbonation and/or thermal pasteurisation of NLCs-added beer led to a major increase in its particles size and astaxanthin loss. Stability of Ax-NLCs in non pasteurised CO2 -free beer improved at low storage temperature. The organoleptic quality of NLCs-added beers was still acceptable. CONCLUSION: These results indicate that NLCs containing hydrophobic nutraceuticals have potential to be used for functional beverages/foods development. (c) 2017 Society of Chemical Industry. PMID- 28620908 TI - A Dirichlet process mixture model for clustering longitudinal gene expression data. AB - Subgroup identification (clustering) is an important problem in biomedical research. Gene expression profiles are commonly utilized to define subgroups. Longitudinal gene expression profiles might provide additional information on disease progression than what is captured by baseline profiles alone. Therefore, subgroup identification could be more accurate and effective with the aid of longitudinal gene expression data. However, existing statistical methods are unable to fully utilize these data for patient clustering. In this article, we introduce a novel clustering method in the Bayesian setting based on longitudinal gene expression profiles. This method, called BClustLonG, adopts a linear mixed effects framework to model the trajectory of genes over time, while clustering is jointly conducted based on the regression coefficients obtained from all genes. In order to account for the correlations among genes and alleviate the high dimensionality challenges, we adopt a factor analysis model for the regression coefficients. The Dirichlet process prior distribution is utilized for the means of the regression coefficients to induce clustering. Through extensive simulation studies, we show that BClustLonG has improved performance over other clustering methods. When applied to a dataset of severely injured (burn or trauma) patients, our model is able to identify interesting subgroups. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28620910 TI - Rational Engineering of a Dynamic, Entropy-Driven DNA Nanomachine for Intracellular MicroRNA Imaging. AB - We rationally engineered an elegant entropy-driven DNA nanomachine with three dimensional track and applied it for intracellular miRNAs imaging. The proposed nanomachine is activated by target miRNA binding to drive a walking leg tethered to gold nanoparticle with a high density of DNA substrates. The autonomous and progressive walk on the DNA track via the entropy-driven catalytic reaction of intramolecular toehold-mediated strand migration leads to continuous disassembly of DNA substrates, accompanied by the recovery of fluorescence signal due to the specific release of a dye-labeled substrate from DNA track. Our nanomachine outperforms the conventional intermolecular reaction-based gold nanoparticle design in the context of an improved sensitivity and kinetics, attributed to the enhanced local effective concentrations of working DNA components from the proximity-induced intramolecular reaction. Moreover, the nanomachine was applied for miRNA imaging inside living cells. PMID- 28620911 TI - Distortion of DNA Origami on Graphene Imaged with Advanced TEM Techniques. AB - While graphene may appear to be the ultimate support membrane for transmission electron microscopy (TEM) imaging of DNA nanostructures, very little is known if it poses an advantage over conventional carbon supports in terms of resolution and contrast. Microscopic investigations are carried out on DNA origami nanoplates that are supported onto freestanding graphene, using advanced TEM techniques, including a new dark-field technique that is recently developed in our lab. TEM images of stained and unstained DNA origami are presented with high contrast on both graphene and amorphous carbon membranes. On graphene, the images of the origami plates show severe unwanted distortions, where the rectangular shape of the nanoplates is significantly distorted. From a number of comparative control experiments, it is demonstrated that neither staining agents, nor screening ions, nor the level of electron-beam irradiation cause this distortion. Instead, it is suggested that origami nanoplates are distorted due to hydrophobic interaction of the DNA bases with graphene upon adsorption of the DNA origami nanoplates. PMID- 28620909 TI - Pregabalin and heart failure: A population-based study. AB - PURPOSE: The anticonvulsant pregabalin is increasingly prescribed for pain, seizures, and psychiatric disorders. Although evidence suggests pregabalin can cause edema and heart failure, its cardiac safety profile in clinical practice is unknown. We sought to examine the risk of heart failure among older patients receiving pregabalin compared to those receiving gabapentin. METHODS: We conducted a population-based cohort study of Ontarians aged 66 and older with a history of seizure who received pregabalin or gabapentin between April 2013 and March 2014. We used propensity scores to match patients commencing pregabalin to those commencing gabapentin. The primary outcome was an emergency department visit or hospitalization for heart failure within 90 days. RESULTS: We studied 9855 patients who initiated pregabalin and an equal number treated with gabapentin. In the primary analysis, we found no difference in the risk of heart failure with pregabalin compared to gabapentin (1.2% versus 1.3%, hazard ratio of 0.77; 95% CI 0.58-1.03). Secondary analyses stratified for baseline history of heart failure yielded similar findings. CONCLUSION: In a large cohort of older patients with a seizure disorder, pregabalin was not associated with an increased risk of heart failure relative to gabapentin. PMID- 28620912 TI - Oesophageal epidermal naevi as a feature of systematised epidermal naevus syndrome. AB - Systematised epidermal naevi are hamartomas developing from neural ectoderm that can be quite extensive, typically with involvement of the face, neck, scalp, arms, legs and trunk. Involvement of the gastrointestinal tract is rare. We report on a 38-year-old Caucasian woman with systematised epidermal naevus syndrome who presented with previously undescribed involvement of the oesophagus, as well as the right side of her scalp, forehead, cheeks, chin, oral mucosa, neck, arms and trunk. PMID- 28620913 TI - Efficacy of oral lipid-based formulations of apomorphine and its diester in a Parkinson's disease rat model. AB - OBJECTIVES: Apomorphine is used to symptomatically treat Parkinson's disease (PD). Oral delivery of apomorphine is generally limited by its short plasma half life and a hepatic first-pass metabolism. This study was aimed at evaluating the behavioural response of apomorphine and its prodrug administered in oral lipid based formulations. METHODS: The behavioural response of apomorphine and its prodrug administered in oral lipid-based formulations was evaluated using a 6 hydroxydopamine-lesioned rat model simulating PD symptomatology. Apomorphine or dipalmitoyl apomorphine (DPA) was incorporated into different lipid-based formulations and orally administered (0.24 mmol/kg) to the PD rat model. The rotations by the rats were counted. KEY FINDINGS: The duration of response lasted to about 2.5 h with oral apomorphine- and DPA-loaded o/w emulsion, while it was increased to 6 h when DPA was incorporated in self-emulsifying drug delivery systems compared to s.c. apomorphine (1 h). This suggests that the lipid-based formulations provide a sustained drug release allowing for a steady exposure to the brain. CONCLUSIONS: Oral lipid-based apomorphine delivery has a potential in achieving a steady response, though at a higher dose possibly eliminating the need for frequent s.c. apomorphine administration. PMID- 28620914 TI - Post-traumatic stress disorder and health-related quality of life in the siblings of the pediatric bone marrow transplantation survivors and post-traumatic stress disorder in their mothers. AB - Although BMT is lifesaving in many childhood diseases, it was found to be related to anxiety, depression, and PTSD in parents, and PTSD, anxiety and overall low self-esteem in siblings. Research on siblings' HRQoL is limited. The aim of this study was to investigate PTSD and HRQoL in siblings (donor and non-donor) of pediatric BMT survivors and PTSD in their mothers, compared to the healthy controls. Thirty-five siblings and their mothers and 35 healthy peers and their mothers were recruited as the study group and as the comparison group, respectively. In children, Child PTSD-Reaction Index for PTSD and PedsQL for HRQoL were used. PTSD Checklist-Civilian Version was used for PTSD in mothers. The study group, both children and mothers, obtained significantly higher PTSD rates than the control group. Children in the study group also reported significantly poorer HRQoL than the control group in all scales. As a novel finding, there was a significant negative correlation between siblings' and mothers' PTSD scores and siblings' PedsQL scores, indicating that PTSD symptoms in siblings and mothers significantly led to impairment in siblings' HRQoL or vice versa. Thus, the identification and treatment of siblings and mothers with PTSD seems imperative. PMID- 28620915 TI - Gas exchange recovery following natural drought is rapid unless limited by loss of leaf hydraulic conductance: evidence from an evergreen woodland. AB - Drought can cause major damage to plant communities, but species damage thresholds and postdrought recovery of forest productivity are not yet predictable. We used an El Nino drought event as a natural experiment to test whether postdrought recovery of gas exchange could be predicted by properties of the water transport system, or if metabolism, primarily high abscisic acid concentration, might delay recovery. We monitored detailed physiological responses, including shoot sapflow, leaf gas exchange, leaf water potential and foliar abscisic acid (ABA), during drought and through the subsequent rehydration period for a sample of eight canopy and understory species. Severe drought caused major declines in leaf water potential, elevated foliar ABA concentrations and reduced stomatal conductance and assimilation rates in our eight sample species. Leaf water potential surpassed levels associated with incipient loss of leaf hydraulic conductance in four species. Following heavy rainfall gas exchange in all species, except those trees predicted to have suffered hydraulic impairment, recovered to prestressed rates within 1 d. Recovery of plant gas exchange was rapid and could be predicted by the hydraulic safety margin, providing strong support for leaf vulnerability to water deficit as an index of damage under natural drought conditions. PMID- 28620916 TI - Ketamine does not enhance the quality of recovery following laparoscopic cholecystectomy: a randomized controlled trial. AB - BACKGROUND: Ketamine has been used as part of the multimodal analgesia technique in the acute perioperative period. The effect of perioperative intravenous small dose ketamine on the quality of recovery from the patient point-of-view has not been assessed. We hypothesized that low-dose ketamine would enhance recovery following laparoscopic cholecystectomy under total intravenous anesthesia. METHODS: One hundred thirty five patients undergoing laparoscopic cholecystectomy were enrolled in this randomized, double-blind placebo-controlled trial. Subjects were randomly assigned to one of three groups: saline, ketamine 0.2 mg/kg, or ketamine 0.4 mg/kg immediately following the induction of anesthesia and before skin incision. The primary endpoint was assessed using the Quality of Recovery Questionnaire (QoR-40), a 40-item quality of recovery scoring system. In addition, early clinical recovery variables, such as time to eye opening, occurrence of nausea and vomiting, pain score, analgesic use, and length of PACU stay were assessed. RESULTS: No differences were detected in the total or individual dimension scores of the QoR-40 questionnaire. The incidence of nausea, vomiting, and other complications did not differ among the three groups. CONCLUSIONS: Small doses of ketamine do not improve the quality of recovery after remifentanil-based anesthesia for laparoscopic cholecystectomy. PMID- 28620918 TI - Development of a H2 O2 -sensitive quantum dots-based fluorescent sandwich ELISA for sensitive detection of bovine beta-lactoglobulin by monoclonal antibody. AB - BACKGROUND: Bovine beta-lactoglobulin (BLG) is the major allergen in cows' milk, and the specific epitope plays a key role in food allergy. Developing a method specifically bind to the IgE epitope is necessary for testing BLG and its allergenic residues. RESULTS: The monoclonal antibody (1G9) specific to the IgE linear epitope for BLG was identified as high affinity and specificity. Based on 1G9, a sensitive fluorescent sandwich enzyme-linked immunosorbent assay (sELISA) was successfully developed using catalase-mediated fluorescence quenching of thiolated CdTe quantum dots in the presence of hydrogen peroxide as fluorescent signal output. The fluorescent sELISA showed high sensitivity and specificity, the limit of detection was 0.49 ng mL-1 , which was 16-fold lower than horseradish peroxidase (HRP)-based sELISA. The linear range for BLG detection were 125-4000 ng mL-1 (r = 0.9939) and 0.48-62.5 ng mL-1 (r = 0.9919). The recoveries and coefficients of variation were 94.25-109.83% and 4.38-20.29%, respectively. Allergenic residues were also detected in hydrolysed infant formulas. The results of fluorescent sELISA showed good performance as HRP-based sELISA and commercial sELISA kit. CONCLUSION: This proposed fluorescent sELISA could be employed to detect BLG and its allergenic residues in food with highly sensitivity, reliability, and recovery. (c) 2017 Society of Chemical Industry. PMID- 28620917 TI - 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. AB - OBJECTIVE: This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). METHODS: A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. RESULTS: The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. CONCLUSION: This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data. PMID- 28620919 TI - Meaningful use of computers has a potential therapeutic and preventative role in dementia care: A systematic review. AB - OBJECTIVE: Personal computers provide an increasingly accessible resource for leisure, social engagement and activities of daily living. This systematic review aimed to explore preventative or therapeutic benefits of such technology in people at risk of, or living with, dementia. METHODS: A systematic search of health databases combined key concepts of dementia and computer use. Inclusion criteria were applied, studies appraised for quality and results synthesised descriptively. RESULTS: Nine studies met inclusion criteria: Four population based studies and five small observational/intervention studies. Findings show an association between computer use in older age and decreased risk of dementia and provide preliminary evidence that computer-based activity interventions are feasible and enjoyable for people with dementia. CONCLUSION: Early findings are promising, but more rigorous studies are required to examine the nature of the relationship between computer use and dementia risk, and the potential of computer activities to improve outcomes for people experiencing cognitive decline. PMID- 28620921 TI - Consistency of total body surface area assessment in severe burns: Implications for practice. AB - BACKGROUND: Paediatric burn injury is common and often serious. Injuries occur across New South Wales (NSW), with specialised treatment provided in a centralised burns unit. Early management prior to transfer is essential but variation is seen. OBJECTIVES: To determine if differences exist between referring hospital estimates of the total body surface area (TBSA) of burns, and estimates for the same burns by the Burns Unit. To consider if differences in estimations influence initial and ongoing management, and decisions regarding transfer/retrieval. METHODS: A retrospective record review of all patients referred to NSW Newborn and Paediatric Emergency Transport Service (NETS) with burn injury between January 2009 and January 2011. Both NETS and NSW Burns Unit records were analysed. RESULTS: A total of 123 patients were referred to NETS with burn injury. Approximately half (55/123 = 45%) were referred with a TBSA >10% and transferred to the NSW Burns Unit, where just over half (33/55 = 60%) were assessed as >10%. This means 40% of cases received an initial overestimation of TBSA by referring hospitals. NETS medical teams transferred 34 patients to the Burns Unit, eight (24%) of which on retrospective review did not meet the NSW Burn Transfer Guidelines criteria for a medical team transfer. CONCLUSIONS: Our review demonstrated significant differences between the TBSA assessment of referring hospitals and the NSW Burns Unit. These inconsistencies may have resulted in children receiving treatment and transport not indicated based on accurate TBSA assessment. Potentially unnecessary transfers have implications for the displacement of children and families but also impact overall health costs and resource availability. PMID- 28620920 TI - Diet-induced early-stage atherosclerosis in baboons: Lipoproteins, atherogenesis, and arterial compliance. AB - BACKGROUND: The purpose of this study was to determine whether dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized non human primate model. METHODS: We fed 112 baboons a high-cholesterol, high-fat challenge diet for two years. We assayed circulating biomarkers of cardiovascular disease (CVD) risk, at 0, 7, and 104 weeks into the challenge; assessed arterial compliance noninvasively at 104 weeks; and measured atherosclerotic lesions in three major arteries at necropsy. RESULTS: We observed evidence of atherosclerosis in all but one baboon fed the two-year challenge diet. CVD risk biomarkers, the prevalence, size, and complexity of arterial lesions, plus consequent arterial stiffness, were increased in comparison with dietary control animals. CONCLUSIONS: Feeding baboons a high-cholesterol, high-fat diet for two years reliably induces atherosclerosis, with risk factor profiles, arterial lesions, and changes in vascular function also seen in humans. PMID- 28620922 TI - Supraspinal inhibitory effects of chimeric peptide MCRT on gastrointestinal motility in mice. AB - OBJECTIVES: Chimeric peptide MCRT, based on morphiceptin and PFRTic-NH2 , was a bifunctional ligand of MU- and delta-opioid receptors (MOR-DOR) and produced potent analgesia in tail-withdrawal test. The study focused on the supraspinal effects of morphiceptin, PFRTic-NH2 and MCRT on gastrointestinal motility. Moreover, opioid receptor antagonists, naloxone (non-selective), cyprodime (MOR selective) and naltrindole (DOR selective) were utilized to explore the mechanisms. METHODS: Intracerebroventricular administration was achieved via the implanted cannula. Gastric emptying and intestinal transit were measured to evaluate gastrointestinal motility. KEY FINDINGS: (1) At supraspinal level, morphiceptin, PFRTic-NH2 and MCRT significantly decreased gastric emptying and intestinal transit; (2) MCRT at 1 nmol/mouse, far higher than its analgesic dose (ED50 = 29.8 pmol/mouse), failed to regulate the gastrointestinal motility; (3) MCRT-induced gastrointestinal dysfunction could be completely blocked by naloxone and naltrindole, but not affected by cyprodime. CONCLUSIONS: (1) Morphiceptin and PFRTic-NH2 played important roles in the regulation of gastrointestinal motility; (2) MCRT possessed higher bioactivity of pain relief than gastrointestinal regulation, suggesting its promising analgesic property; (3) MCRT-induced motility disorders were sensitive to DOR but not to MOR blockade, indicating the pain-relieving specificity of speculated MOR subtype or splice variant or MOR-DOR heterodimer. PMID- 28620923 TI - Home phototherapy in vitiligo. AB - Vitiligo is a disorder characterized by the development of depigmented macules and patches. Narrowband ultraviolet B phototherapy is a standard of care treatment and is used both as monotherapy and in combination with other treatment modalities to induce repigmentation. Although phototherapy is safe and effective, its use is limited due to the significant time commitment required and associated costs. Home phototherapy is a safe and effective alternative to make phototherapy more accessible to patients. However, it is often underutilized due to lack of physician experience and comfort as well as misconceptions regarding its safety and efficacy. This article provides a brief overview of the use of phototherapy in vitiligo with a focus on home phototherapy in order to increase awareness and use of this treatment modality. PMID- 28620924 TI - Childhood preoperative anxiolysis: Is sedation and distraction better than either alone? A prospective randomized study. AB - BACKGROUND: Preoperative anxiety management receives special attention in pediatric anesthesia. Different pharmacological and nonpharmacological techniques can be employed. This study was designed to assess three different strategies for childhood preoperative anxiolysis: midazolam premedication, midazolam in combination with portable Digital Video-Disk player, or video distraction strategy alone. METHODS: In this prospective randomized study, children aged 2-12 years were assigned to one of the three study groups. The primary outcome was a change in preoperative children's anxiety, from baseline (before transfer to the preanesthetic holding area) to separation from parents, assessed by the Modified Yale Preoperative Anxiety Scale (mYPAS) and the Visual Analog Anxiety Scale (VAS Anxiety). Delirium emergence, postoperative pain, and parental satisfaction were also collected. RESULTS: One hundred and thirty-five patients were enrolled. The three preventive strategies allowed control of preoperative distress. Within the three study groups, no significant change was objectified in the anxiety level from baseline to separation from parents (mean change in mYPAS midazolam group: 2.4 95% CI [-1.7 to 6.3]; midazolam+Digital Video-Disk group: -1.0 95% CI [-5.9 to 3]; and Digital Video-Disk group: 1.4 95% CI [-4 to 6.7]). Comparison of change in preoperative children's anxiety between the groups did not show any difference. Emergence delirium, postoperative pain scores, and analgesic consumption were similar between the groups and parents' satisfaction was excellent. CONCLUSION: Both pharmacological premedication and video distraction are effective strategies for controlling preoperative childhood anxiety. The combination of midazolam and Digital Video-Disk player was not better than either alone. PMID- 28620925 TI - Validity of the National Center for Geriatrics and Gerontology-Functional Assessment Tool and Mini-Mental State Examination for detecting the incidence of dementia in older Japanese adults. AB - AIM: Numerous neuropsychological tests are implemented in the clinical setting. However, a readily available cognitive test is required to detect the risk of dementia in the community setting. METHODS: A total of 4151 persons aged >=65 years participated in the present prospective cohort study. We assessed cognitive performance using the Mini-Mental State Examination and the National Center for Geriatrics and Gerontology-Functional Assessment Tool. The National Center for Geriatrics and Gerontology-Functional Assessment Tool includes tests of story and word list memory, attention and executive function, processing speed, and visuospatial skill to screen for cognitive impairment. All measurements were transformed to Z-scores to compare among the cognitive tests. The incidence of dementia was determined using data collected by the Japanese Health Insurance System over 36 months. RESULTS: After an average of 43 months, 180 (4.3%) participants were diagnosed with dementia. Survival analyses showed that the probability of dementia was significantly associated with all cognitive tests, except for visuospatial skill. The processing speed test showed the highest hazard ratios for the incidence of dementia (Z-score: hazard ratio 0.61, 95% confidence interval 0.50-0.75, P < 0.01). In subgroup analysis, there were no significant relationships between cognitive tests and the incidence of dementia in participants without global cognitive impairment. CONCLUSIONS: We conclude that the National Center for Geriatrics and Gerontology-Functional Assessment Tool, as well as the Mini-Mental State Examination, play an important role in detecting the risk of dementia in the community setting. Further analysis is required to identify the risk of dementia in older people without global cognitive impairment. Geriatr Gerontol Int 2017; 17: 2383-2388. PMID- 28620926 TI - Human papillomavirus infection and lymphoma incidence using cervical conization as a surrogate marker: a Danish nationwide cohort study. AB - Persistent human papillomavirus (HPV) infection may promote carcinogenesis by hyperactivation of the immune system. We, therefore, explored the associations between HPV infection and risk of Hodgkin and non-Hodgkin lymphoma in a nationwide cohort study using conization as a surrogate marker. We identified all Danish women who underwent conization between 1978 and 2011. We computed standardized incidence ratios and 95% confidence intervals for Hodgkin and non Hodgkin lymphoma based on national cancer incidence rates. Among 87 435 women who underwent conization, we noted an increased incidence of Hodgkin (standardized incidence ratio 1.48, 95% confidence interval 1.05-2.02) but only a slight increase for non-Hodgkin lymphoma (standardized incidence ratio 1.10, 95% confidence interval 0.97-1.25). As measured by conization, HPV infection is associated with an increased risk of lymphoma. This association may be attributable to a chronic immune activation induced by persistent HPV infection and/or failure of the immune system both to clear HPV infection and to control lymphoma development. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28620927 TI - Bendamustine for relapsed blastic plasmacytoid dendritic cell leukaemia. AB - Optimal treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare entity of dismal prognosis previously described as CD4+/CD56+ hematodermic malignancies, is not defined. We report five cases of relapsed BPDCN treated with bendamustine hydrochloride, a well-tolerated bifunctional drug acting as an alkylating and antimetabolite agent. All patients were above the age of 50 years and in advanced disease (early first relapse in two, subsequent relapse in three; multi-organ involvement in four; previous intensive chemotherapy in five; and stem cell transplantation in four). Four patients were evaluable for response. Two failed therapy, one died from tumor lysis syndrome after rapid blast clearance from blood, and one reached and maintained complete remission for 7 months. Bendamustine should be further evaluated in BPDCN. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28620928 TI - The importance of the number of transplanted cells with dipeptidyl peptidase-4 expression on the haematopoietic recovery and lymphocyte reconstitution in patients with multiple myeloma after autologous haematopoietic stem-cell transplantation. AB - Autologous haematopoietic stem cell transplantation (AHSCT) remains recommended treatment in the first remission in multiple myeloma (MM). In earlier research it has been suggested that there is an influence of the expression of dipeptidyl peptidase-4 (CD26) on both the homing and lymphocyte reconstitution after AHSCT. The aim of the study is to investigate the influence of transplanted cells CD26+ on the haematopoietic recovery and lymphocyte reconstitution after AHSCT in MM. Forty eight patients with MM underwent AHSCT in our centre. Number of all CD26+ cells, CD26+ lymphocytes, CD26+ monocytes and CD26+ and CD34+ cells were measured in the harvested material. Number of lymphocyte's subpopulations (all lymphocytes CD3+, helpers, suppressors, natural killer (NK), cytotoxic NK and lymphocytes B) were measured in peripheral blood during regeneration after AHSCT. In both flow cytometry was used. On the basis of the analysis there was, as regards regeneration of haematopoietic cells after AHSCT, it was shown that a higher number of monocytes CD26+ improves the reconstitution of helper, suppressor and NK lymphocytes. A higher number of transplanted CD26+ lymphocytes accelerates the reconstitution of NK lymphocytes, whereas a higher number of all the cells CD26+ has a positive impact on the regeneration of cytotoxic NK lymphocytes. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28620929 TI - Cartilage canals in the distal intermediate ridge of the tibia of fetuses and foals are surrounded by different types of collagen. AB - Some epiphyseal growth cartilage canals are surrounded by a ring of hypereosinophilic matrix consisting of collagen type I. Absence of the collagen type I ring may predispose canal vessels to failure and osteochondrosis, which can lead to fragments in joints (osteochondrosis dissecans). It is not known whether the ring develops in response to programming or biomechanical force. The distribution that may reveal the function of the ring has only been described in the distal femur of a limited number of foals. It is also not known which cells are responsible for producing the collagen ring. The aims of the current study were to examine fetuses and foals to infer whether the ring forms in response to biomechanical force or programming, to describe distribution and to investigate which cell type produces the ring. The material consisted of 46 fetuses and foals from 293 days of gestation to 142 days old, of both sexes and different breeds, divided into three groups, designated the naive group up to and including the day of birth, the adapting group from 2 days up to and including 14 days old, and the loaded group from 15 days and older. The distal tibia was sawn into parasagittal slabs and the cranial half of the central slab from the intermediate ridge was examined by light microscopy and immunohistochemical staining for collagen type I. Presence, completeness and location of the collagen ring was compared, as was the quantity of perivascular mesenchymal cells. An eosinophilic ring present on HE-stained sections was seen in every single fetus and foal examined, which corresponded to collagen type I in immunostained sections. A higher proportion of cartilage canals were surrounded by an eosinophilic ring in the naive and adapting groups at 73 and 76%, respectively, compared with the loaded group at 51%. When considering only patent canals, the proportion of canals with an eosinophilic ring was higher in the adapting and loaded than the naive group of foals. The ring was present around 90 and 81% of patent canals in the deep and middle layers, respectively, compared with 58% in the superficial layer, and the ring was more often complete around deep compared with superficial canals. The ring was absent or partial around chondrifying canals. When an eosinophilic ring was present around patent canals, it was more common for the canal to contain one or more layers of perivascular mesenchymal cells rather than few to no layers. It was also more common for the collagen ring to be more complete around canals that contained many as opposed to few mesenchymal cells. In conclusion, the proportion of cartilage canals that had an eosinophilic ring was similar in all three groups of fetuses and foals, indicating that the presence of the collagen ring was mostly programmed, although some adaptation was evident. The ring was more often present around deep, compared with superficial canals, indicating a role in preparation for ossification. The collagen ring appeared to be produced by perivascular mesenchymal cells. PMID- 28620931 TI - Assault at the workplace in 147 patients resulting in cochleovestibular dysfunction. PMID- 28620930 TI - PRospective Imaging of CErvical cancer and neoadjuvant treatment (PRICE) study: role of ultrasound to predict partial response in locally advanced cervical cancer patients undergoing chemoradiation and radical surgery. AB - OBJECTIVE: Chemoradiation-based neoadjuvant treatment followed by radical surgery is an alternative therapeutic strategy for locally advanced cervical cancer (LACC), but ultrasound variables used to predict partial response to neoadjuvant treatment are not well defined. Our goal was to analyze prospectively the potential role of transvaginal ultrasound in early prediction of partial pathological response, assessed in terms of residual disease at histology, in a large, single-institution series of LACC patients triaged to neoadjuvant treatment followed by radical surgery. METHODS: Between October 2010 and June 2014, we screened 108 women with histologically documented LACC Stage IB2-IVA, of whom 88 were included in the final analysis. Tumor volume, three-dimensional (3D) power Doppler indices and contrast parameters were obtained before (baseline examination) and after 2 weeks of treatment. The pathological response was defined as complete (absence of any residual tumor after treatment) or partial (microscopic and/or macroscopic residual tumor at pathological examination). Complete-response and partial-response groups were compared and receiver operating characteristics (ROC) curves were generated for ultrasound variables that were statistically significant on univariate analysis to evaluate their diagnostic ability to predict partial pathological response. RESULTS: There was a complete pathological response to neoadjuvant therapy in 40 (45.5%) patients and a partial response in 48 (54.5%). At baseline examination, tumor volume did not differ between the two groups. However, after 2 weeks of neoadjuvant treatment, the tumor volume was significantly greater in patients with partial response than it was in those with complete response (P = 0.019). Among the 3D vascular indices, the vascularization index (VI) was significantly lower in the partial response compared with the complete-response group, both before and after 2 weeks of treatment (P = 0.037 and P = 0.024, respectively). At baseline examination in the contrast analysis, women with partial response had lower tumor peak enhancement (PE) as well as lower tumor wash-in rate (WiR) and longer tumor rise time (RT) compared with complete responders (P = 0.006, P = 0.003, P = 0.038, respectively). There was no difference in terms of contrast parameters after 2 weeks of treatment. ROC-curve analysis of baseline parameters showed that the best cut-offs for predicting partial pathological response were 41.5% for VI (sensitivity, 63.6%; specificity, 66.7%); 16123.5 auxiliary units for tumor PE (sensitivity, 47.9%; specificity, 84.2%); 7.8 s for tumor RT (sensitivity, 68.8%; specificity, 57.9%); and 4902 for tumor WiR (sensitivity, 77.1%; specificity, 60.5%). ROC curves of parameters after 2 weeks of treatment showed that the best cut-off for predicting partial pathological response was 18.1 cm3 for tumor volume (sensitivity, 70.8%; specificity 60.0%) and 39.5% for VI (sensitivity; 62.5%; specificity, 73.5%). CONCLUSIONS: Ultrasound and contrast parameters differ between LACC patients with complete response and those with partial response before and after 2 weeks of neoadjuvant treatment. However, neither ultrasound parameters before treatment nor those after 2 weeks of treatment had cut-off values with acceptable sensitivity and specificity for predicting partial pathological response to neoadjuvant therapy. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28620932 TI - Fiber type composition of the palmaris brevis muscle: implications for palmar function. AB - The palmaris brevis (PB) is a small muscle of variant morphology located on the ulnar aspect of the palm, superficial to the hypothenar eminence. Functionally, the PB has been proposed to protect the neurovasculature of the ulnar canal from compressive forces during repetitive or intermittent trauma associated with grasping. Although PB function has been inferred from cadaveric observations, it is unknown whether it has the contractile capacity and fatigue-resistance necessary to withstand these functional demands. Insight into the functional specialization of the PB can be provided through investigating the proportions of type I and type II muscle fibers by staining for myosin heavy chain (MHC) isoforms using immunohistochemical methods. Therefore, the purpose of this study was to quantify the proportion of type I and type II muscle fibers to provide insight into the role of the PB in palmar function based on its gross histological structure. Sixteen PB specimens were harvested from the hands (eight right, eight left) of eight formalin-embalmed cadavers (mean age: 75 +/- 14 years; three males, five females). PB muscle composition was determined by labeling serial cross-sections with MHC type I and type II monoclonal antibodies. The results indicate that the PB is primarily composed of type I muscle fibers (72.2 +/- 13.7%), with no significant differences between left and right hands. Given the predominance of type I muscle fibers, our findings indicate the PB may be fatigue-resistant and thus, capable of contracting for prolonged durations. This supports cadaveric observations indicating that the PB functions to protect the ulnar neurovasculature of the palm by providing a muscular barrier in addition to serving as a functional anchor to the hypothenar fat pad when objects are firmly compressed into the palm. PMID- 28620933 TI - Recollections of former editors of Clinical and Experimental Optometry. PMID- 28620934 TI - Fairness in cost-benefit analysis: A methodology for health technology assessment. AB - We evaluate the introduction of various forms of antihypertensive treatments in France with a distribution-sensitive cost-benefit analysis. Compared to traditional cost-benefit analysis, we implement distributional weighting based on equivalent incomes, a new concept of individual well-being that does respect individual preferences but is not subjectively welfarist. Individual preferences are estimated on the basis of a contingent valuation question, introduced into a representative survey of the French population. Compared to traditional cost effectiveness analysis in health technology assessment, we show that it is feasible to go beyond a narrow evaluation of health outcomes while still fully exploiting the sophistication of medical information. Sensitivity analysis illustrates the relevancy of this richer welfare framework, the importance of the distinction between an ex ante and an ex post approach, and the need to consider distributional effects in a broader institutional setting. PMID- 28620935 TI - Fast precision estimation in high-dimensional multivariate joint models. AB - A fast way is proposed based on the multiple outputation idea (Hoffman et al., ; Follmann et al., ) to calculate the precision of parameter estimates for high dimensional multivariate joint models using a pairwise approach (Fieuws and Verbeke, ; Fieuws et al., ). Simulation results as well as data analysis shows possibly more than 2500 times faster computations using the proposed method. In our real data illustration, the time gain is more than 330 times. PMID- 28620936 TI - Measuring pregnancy planning: A psychometric evaluation and comparison of two scales. AB - AIMS: To psychometrically test the London Measure of Unplanned Pregnancy and compare it with the Swedish Pregnancy Planning Scale. BACKGROUND: The incidence of unplanned pregnancies is an important indicator of reproductive health. The London Measure of Unplanned Pregnancy measures pregnancy planning by taking contraceptive use, timing, intention to become pregnant, desire for pregnancy, partner agreement, and pre-conceptual preparations into account. It has, however, previously not been psychometrically evaluated using confirmatory factor analysis. The Likert-scored single-item Swedish Pregnancy Planning Scale has been developed to measure the woman's own view of pregnancy planning level. DESIGN: Cross-sectional design. METHODS: In 2012-2013, 5493 pregnant women living in Sweden were invited to participate in the Swedish Pregnancy Planning study, of whom 3327 (61%) agreed to participate and answered a questionnaire. A test-retest pilot study was conducted in 2011-2012. Thirty-two participants responded to the questionnaire on two occasions 14 days apart. Data were analysed using confirmatory factor analysis, Cohen's weighted kappa and Spearman's correlation. RESULTS: All items of the London Measure of Unplanned Pregnancy contributed to measuring pregnancy planning, but four items had low item-reliability. The London Measure of Unplanned Pregnancy and Swedish Pregnancy Planning Scale corresponded reasonably well with each other and both showed good test-retest reliability. CONCLUSION: The London Measure of Unplanned Pregnancy may benefit from item reduction and its usefulness may be questioned. The Swedish Pregnancy Planning Scale is time-efficient and shows acceptable reliability and construct validity, which makes it more useful for measuring pregnancy planning. PMID- 28620937 TI - Testing for bioequivalence of highly variable drugs from TR-RT crossover designs with heterogeneous residual variances. AB - Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR-RTR-RRT and TRTR-RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR-RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR-RT designs. Under the assumption of zero subject-by-formulation interaction, this basic model is comparable to the FDA-recommended model for TRR-RTR-RRT and TRTR RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ-based testing procedure that evaluates HV drugs under practical TR-RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ-based procedure gives similar performance when the product's intersubject standard deviation is low (<=0.4) and is most useful when practical considerations restrict the crossover design to 2 periods. PMID- 28620938 TI - Anisotropic Metal Deposition on TiO2 Particles by Electric-Field-Induced Charge Separation. AB - Deposition of metals on TiO2 semiconductor particles (M-TiO2 ) results in hybrid Janus objects combining the properties of both materials. One of the techniques proposed to generate Janus particles is bipolar electrochemistry (BPE). The concept can be applied in a straightforward way for the site-selective modification of conducting particles, but is much less obvious to use for semiconductors. Herein we report the bulk synthesis of anisotropic M-TiO2 particles based on the synergy of BPE and photochemistry, allowing the intrinsic limitations, when they are used separately, to be overcome. When applying electric fields during irradiation, electrons and holes can be efficiently separated, thus breaking the symmetry of particles by modifying them selectively and in a wireless way on one side with either gold or platinum. Such hybrid materials are an important first step towards high-performance designer catalyst particles, for example for photosplitting of water. PMID- 28620939 TI - Engineering Novel Targeted Boron-10-Enriched Theranostic Nanomedicine to Combat against Murine Brain Tumors via MR Imaging-Guided Boron Neutron Capture Therapy. AB - Glioblastoma multiforme (GBM) is a very common type of "incurable" malignant brain tumor. Although many treatment options are currently available, most of them eventually fail due to its recurrence. Boron neutron capture therapy (BNCT) emerges as an alternative noninvasive therapeutic treatment modality. The major challenge in treating GBMs using BNCT is to achieve selective imaging, targeting, and sufficient accumulation of boron-containing drug at the tumor site so that effective destruction of tumor cells can be achieved without harming the normal brain cells. To tackle this challenge, this study demonstrates for the first time that an unprecedented 10 B-enriched (96% 10 B enrichment) boron nanoparticle nanomedicine (10 BSGRF NPs) surface-modified with a Fluorescein isothiocyanate (FITC)-labeled RGD-K peptide can pass through the brain blood barrier, selectively target at GBM brain tumor sites, and deliver high therapeutic dosage (50.5 ug 10 B g-1 cells) of boron atoms to tumor cells with a good tumor-to-blood boron ratio of 2.8. The 10 BSGRF NPs not only can enhance the contrast of magnetic resonance (MR) imaging to help diagnose the location/size/progress of brain tumor, but also effectively suppress murine brain tumors via MR imaging guided BNCT, prolonging the half-life of mice from 22 d (untreated group) to 39 d. PMID- 28620940 TI - Young children discover how to deceive in 10 days: a microgenetic study. AB - We investigated how the ability to deceive emerges in early childhood among a sample of young preschoolers (Mean age = 34.7 months). We did this via a 10 session microgenetic method that took place over a 10-day period. In each session, children played a zero-sum game against an adult to win treats. In the game, children hid the treats and had opportunities (10 trials) to win them by providing deceptive information about their whereabouts to the adult. Although children initially showed little or no ability to deceive, most spontaneously discovered deception and systematically used it to win the game by the tenth day. Both theory of mind and executive function skills were predictive of relatively faster patterns of discovery. These results are the first to provide evidence for the importance of cognitive skills and social experience in the discovery of deception over time in early childhood. PMID- 28620942 TI - A dose-escalation study of combretastatin A4-phosphate in healthy dogs. AB - Combretastatin A4-Phosphate (CA4P) is a vascular disrupting agent revealing promising results in cancer treatments for humans. The aim of this study was to investigate the safety and adverse events of CA4P in healthy dogs as a prerequisite to application of CA4P in dogs with cancer. Ten healthy dogs were included. The effects of escalating doses of CA4P on physical, haematological and biochemical parameters, systolic arterial blood pressure, electrocardiogram, echocardiographic variables and general wellbeing were characterised. Three different doses were tested: 50, 75 and 100 mg m-2 . At all 3 CA4P doses, nausea, abdominal discomfort as well as diarrhoea were observed for several hours following administration. Likewise, a low-grade neutropenia was observed in all dogs. Doses of 75 and 100 mg m-2 additionally induced vomiting and elevation of serum cardiac troponine I levels. At 100 mg m-2 , low-grade hypertension and high grade neurotoxicity were also observed. In healthy dogs, doses up to 75 mg m-2 seem to be well tolerated. The severity of the neurotoxicity observed at 100 mg m 2 , although transient, does not invite to use this dose in canine oncology patients. PMID- 28620941 TI - Endothelial mechanotransduction proteins and vascular function are altered by dietary sucrose supplementation in healthy young male subjects. AB - KEY POINTS: Mechanotransduction in endothelial cells is a central mechanism in the regulation of vascular tone and vascular remodelling Mechanotransduction and vascular function may be affected by high sugar levels in plasma because of a resulting increase in oxidative stress and increased levels of advanced glycation end-products (AGE). In healthy young subjects, 2 weeks of daily supplementation with 3 * 75 g of sucrose was found to reduce blood flow in response to passive lower leg movement and in response to 12 W of knee extensor exercise. This vascular impairment was paralleled by up-regulation of platelet endothelial cell adhesion molecule (PECAM)-1, endothelial nitric oxide synthase, NADPH oxidase and Rho family GTPase Rac1 protein expression, an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. There were no measurable changes in AGE levels. The findings of the present study demonstrate that daily high sucrose intake markedly affects mechanotransduction proteins and has a detrimental effect on vascular function. ABSTRACT: Endothelial mechanotransduction is important for vascular function but alterations and activation of vascular mechanosensory proteins have not been investigated in humans. In endothelial cell culture, simple sugars effectively impair mechanosensor proteins. To study mechanosensor- and vascular function in humans, 12 young healthy male subjects supplemented their diet with 3 * 75 g sucrose day-1 for 14 days in a randomized cross-over design. Before and after the intervention period, the hyperaemic response to passive lower leg movement and active knee extensor exercise was determined by ultrasound doppler. A muscle biopsy was obtained from the thigh muscle before and after acute passive leg movement to allow assessment of protein amounts and the phosphorylation status of mechanosensory proteins and NADPH oxidase. The sucrose intervention led to a reduced flow response to passive movement (by 17 +/- 2%) and to 12 W of active exercise (by 9 +/- 1%), indicating impaired vascular function. A reduced flow response to passive and active exercise was paralleled by a significant up-regulation of platelet endothelial cell adhesion molecule (PECAM-1), endothelial nitric oxide synthase, NADPH oxidase and the Rho family GTPase Rac1 protein expression in the muscle tissue, as well as an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. The phosphorylation status was not acutely altered with passive leg movement. These findings indicate that a regular intake of high levels of sucrose can impair vascular mechanotransduction and increase the oxidative stress potential, and suggest that dietary excessive sugar intake may contribute to the development of vascular disease. PMID- 28620943 TI - Drug repurposing for aging research using model organisms. AB - Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging. PMID- 28620944 TI - Independent housing and support for people with severe mental illness: systematic review. AB - OBJECTIVE: To systematically explore the outcomes of Independent Housing and Support (IHS) for people with severe mental disorders when compared to other residential settings. METHOD: Systematic review of Randomised and Non-Randomised Controlled Trials of publications that analyse the outcomes of living in independent settings versus institutionalised accommodation. Risk of bias assessment was adapted from the Cochrane Collaboration's ACROBAT-Tool. The analysis was conducted separately for publications with homeless and non-homeless people. RESULTS: Twenty-four publications from studies with homeless people and eight publications from studies with non-homeless people were included. Risk of bias was much lower in studies with the homeless. No RCT was found in the sample of publications with the non-homeless. Overall, results from Independent Housing and Support-settings are not inferior to results from institutionalised settings. CONCLUSION: The results indicate that Independent Housing and Support-settings provide at least similar outcomes than residential care. We propose that clients' preferences should determine the choice of housing setting. PMID- 28620945 TI - Measuring the statistical validity of summary meta-analysis and meta-regression results for use in clinical practice. AB - An important question for clinicians appraising a meta-analysis is: are the findings likely to be valid in their own practice-does the reported effect accurately represent the effect that would occur in their own clinical population? To this end we advance the concept of statistical validity-where the parameter being estimated equals the corresponding parameter for a new independent study. Using a simple ('leave-one-out') cross-validation technique, we demonstrate how we may test meta-analysis estimates for statistical validity using a new validation statistic, Vn, and derive its distribution. We compare this with the usual approach of investigating heterogeneity in meta-analyses and demonstrate the link between statistical validity and homogeneity. Using a simulation study, the properties of Vn and the Q statistic are compared for univariate random effects meta-analysis and a tailored meta-regression model, where information from the setting (included as model covariates) is used to calibrate the summary estimate to the setting of application. Their properties are found to be similar when there are 50 studies or more, but for fewer studies Vn has greater power but a higher type 1 error rate than Q. The power and type 1 error rate of Vn are also shown to depend on the within-study variance, between study variance, study sample size, and the number of studies in the meta analysis. Finally, we apply Vn to two published meta-analyses and conclude that it usefully augments standard methods when deciding upon the likely validity of summary meta-analysis estimates in clinical practice. (c) 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. PMID- 28620946 TI - Incidental detection of asymptomatic migration of Hem-o-lok clip into the bladder after laparoscopic radical prostatectomy. AB - Hem-o-lok clips have been widely used in laparoscopic or robot-assisted surgery. We report a case of an incidentally discovered Hem-o-lok migration into the bladder after laparoscopic radical prostatectomy. The patient was a 75-year-old man with localized prostate cancer who underwent laparoscopic radical prostatectomy in July 2009. At 3 postoperative years, follow-up ultrasonography revealed a small round mass in the bladder. No lower urinary tract symptoms were reported, and urinalysis results had never indicated hematuria or pyuria. Cystoscopy revealed a Hem-o-lok clip in the bladder, near the vesicourethral anastomotic site. We could not remove it with forceps in the outpatient clinic, so we performed the procedure again under general anesthesia and successfully removed the Hem-o-lok clip. To our knowledge, this is the first report of an asymptomatic Hem-o-lok migration into the bladder. PMID- 28620947 TI - Effect of applying cinnamaldehyde incorporated in wax on green mould decay in citrus fruits. AB - BACKGROUND: Green mould caused by Penicillium digitatum is the most damaging postharvest diseases of citrus fruit. Cinnamaldehyde (CA) is a food additive that has potential use in controlling postharvest disease of fruits and vegetables. In this study, the effectiveness of wax with CA (WCA) in controlling Ponkan (Citrus reticulata Blanco) green mould was investigated. RESULTS: The mycelial growth of P. digitatum was inhibited by CA in a dose-dependent manner. The minimum inhibitory concentration and minimum fungicidal concentration (MFC) were both 0.50 mL L-1 . In vivo tests demonstrated that WCA (1 * and 10 * MFC) applied to Ponkan fruits inoculated with P. digitatum could significantly decrease the incidence of green mould for up to 5 days. The WCA treatment increased the activities of catalase, superoxide dismutase, peroxidase, phenylalanine ammonia lyase, polyphenol oxidase, as well as the total phenols and flavonoids contents. Meanwhile, the treatment remarkably decreased the weight loss rate of fruits and maintained fruit quality. These results indicated that WCA treatment might induce defence responses against green mould in citrus fruit. CONCLUSION: Our findings suggest that WCA might be a promising approach in controlling green mould of citrus fruits. (c) 2017 Society of Chemical Industry. PMID- 28620949 TI - Nonintravenous rescue medications for pediatric status epilepticus: A cost effectiveness analysis. AB - OBJECTIVE: To quantify the cost-effectiveness of rescue medications for pediatric status epilepticus: rectal diazepam, nasal midazolam, buccal midazolam, intramuscular midazolam, and nasal lorazepam. METHODS: Decision analysis model populated with effectiveness data from the literature and cost data from publicly available market prices. The primary outcome was cost per seizure stopped ($/SS). One-way sensitivity analyses and second-order Monte Carlo simulations evaluated the robustness of the results across wide variations of the input parameters. RESULTS: The most cost-effective rescue medication was buccal midazolam (incremental cost-effectiveness ratio ([ICER]: $13.16/SS) followed by nasal midazolam (ICER: $38.19/SS). Nasal lorazepam (ICER: -$3.8/SS), intramuscular midazolam (ICER: -$64/SS), and rectal diazepam (ICER: -$2,246.21/SS) are never more cost-effective than the other options at any willingness to pay. One-way sensitivity analysis showed the following: (1) at its current effectiveness, rectal diazepam would become the most cost-effective option only if its cost was $6 or less, and (2) at its current cost, rectal diazepam would become the most cost-effective option only if effectiveness was higher than 0.89 (and only with very high willingness to pay of $2,859/SS to $31,447/SS). Second-order Monte Carlo simulations showed the following: (1) nasal midazolam and intramuscular midazolam were the more effective options; (2) the more cost-effective option was buccal midazolam for a willingness to pay from $14/SS to $41/SS and nasal midazolam for a willingness to pay above $41/SS; (3) cost-effectiveness overlapped for buccal midazolam, nasal lorazepam, intramuscular midazolam, and nasal midazolam; and (4) rectal diazepam was not cost-effective at any willingness to pay, and this conclusion remained extremely robust to wide variations of the input parameters. SIGNIFICANCE: For pediatric status epilepticus, buccal midazolam and nasal midazolam are the most cost-effective nonintravenous rescue medications in the United States. Rectal diazepam is not a cost-effective alternative, and this conclusion remains extremely robust to wide variations of the input parameters. PMID- 28620948 TI - 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. AB - OBJECTIVE: This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). METHODS: A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. RESULTS: The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. CONCLUSION: This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data. PMID- 28620950 TI - The risk typology of healthcare access and its association with unmet healthcare needs in Asian Americans. AB - Using data from the 2015 Asian American Quality of Life Survey (N = 2,609), latent profile analysis was conducted on general (health insurance, usual place for care and income) and immigrant-specific (nativity, length of stay in the U.S., English proficiency and acculturation) risk factors of healthcare access. Latent profile analysis identified a three-cluster model (low-risk, moderate-risk and high-risk groups). Compared with the low-risk group, the odds of having an unmet healthcare need was 1.52 times greater in the moderate-risk group and 2.24 times greater in the high-risk group. Challenging the myth of model minority, the present sample of Asian Americans demonstrates its vulnerability in access to healthcare. Findings also show the heterogeneity in healthcare access risk profiles. PMID- 28620952 TI - Operando 3D Visualization of Migration and Degradation of a Platinum Cathode Catalyst in a Polymer Electrolyte Fuel Cell. AB - The three-dimensional (3D) distribution and oxidation state of a Pt cathode catalyst in a practical membrane electrode assembly (MEA) were visualized in a practical polymer electrolyte fuel cell (PEFC) under fuel-cell operating conditions. Operando 3D computed-tomography imaging with X-ray absorption near edge structure (XANES) spectroscopy (CT-XANES) clearly revealed the heterogeneous migration and degradation of Pt cathode catalyst in an MEA during accelerated degradation test (ADT) of PEFC. The degradative Pt migration proceeded over the entire cathode catalyst layer and spread to MEA depth direction into the Nafion membrane. PMID- 28620951 TI - Persistent negative temperature response of mesophyll conductance in red raspberry (Rubus idaeus L.) leaves under both high and low vapour pressure deficits: a role for abscisic acid? AB - The temperature dependence of mesophyll conductance (gm ) was measured in well watered red raspberry (Rubus idaeus L.) plants acclimated to leaf-to-air vapour pressure deficit (VPDL) daytime differentials of contrasting amplitude, keeping a fixed diurnal leaf temperature (Tleaf ) rise from 20 to 35 degrees C. Contrary to the great majority of gm temperature responses published to date, we found a pronounced reduction of gm with increasing Tleaf irrespective of leaf chamber O2 level and diurnal VPDL regime. Leaf hydraulic conductance was greatly enhanced during the warmer afternoon periods under both low (0.75 to 1.5 kPa) and high (0.75 to 3.5 kPa) diurnal VPDL regimes, unlike stomatal conductance (gs ), which decreased in the afternoon. Consequently, the leaf water status remained largely isohydric throughout the day, and therefore cannot be evoked to explain the diurnal decrease of gm . However, the concerted diurnal reductions of gm and gs were well correlated with increases in leaf abscisic acid (ABA) content, thus suggesting that ABA can induce a significant depression of gm under favourable leaf water status. Our results challenge the view that the temperature dependence of gm can be explained solely from dynamic leaf anatomical adjustments and/or from the known thermodynamic properties of aqueous solutions and lipid membranes.. PMID- 28620953 TI - Molecular Characterisation of alpha- and beta-Thalassaemia among Indigenous Senoi Orang Asli Communities in Peninsular Malaysia. AB - Thalassaemia is a public health problem in Malaysia, with each ethnic group having their own common mutations. However, there is a lack on data on the prevalence and common mutations among the indigenous people. This cross-sectional study was performed to determine the common mutations of alpha- and beta thalassaemia among the subethnic groups of Senoi, the largest Orang Asli group in Peninsular Malaysia. Blood samples collected from six Senoi subethnic groups were analysed for full blood count and haemoglobin analysis (HbAn). Samples with abnormal findings were then screened for alpha- and beta-globin gene mutations. Out of the 752 samples collected, 255 showed abnormal HbAn results, and 122 cases showing abnormal red cell indices with normal HbAn findings were subjected to molecular screening. DNA analysis revealed a mixture of alpha- and beta-globin gene mutations with 25 concomitant cases. The types of gene abnormalities detected for alpha-thalassaemia were termination codon (T>C) Hb CS (alphaCS alpha), Cd59 (G>A) haemoglobin Adana (Hb Adana) (alphaCd59 alpha), initiation codon (ATG>A-G) (alphaIniCd alpha), two-gene deletion (-SEA ), and single-gene 3.7-kb deletion (-alpha3.7 ). For beta-thalassaemia, there were Cd26 (G>A) Hb E (betaE ), Cd19 (A>G) Haemoglobin Malay (Hb Malay) (betaCd19 ), and IVS 1-5 (G>C) (betaIVS 1-5 ). PMID- 28620954 TI - Propentofylline, phosphodiesterase and adenosine reuptake inhibitor modulates lymphocyte subsets and lymphocyte activity after in-vivo administration in non immunized and SRBC-immunized mice. AB - OBJECTIVES: The aim of the study was to investigate immunomodulatory effect of in vivo administered propentofylline on the subsets and activity of murine lymphocytes. METHODS: Propentofylline (3 mg/kg) was administered orally to 8-week old Balb/c mice, once or six times at 12-h intervals. The lymphocyte subsets, regulatory T cells, IL-5 and TNF levels were determined 12 h and 24 h after a single dose or after the sixth dose of the drug in non-immunized mice. Humoral immune response in sheep red blood cells (SRBC)-immunized mice was determined 4, 7 and 14 days after immunization. KEY FINDINGS: Propentofylline inhibited thymocyte maturation (increase in CD4- CD8- thymocyte subset and decrease in the percentage of CD4+ CD8+ thymocytes) and modulated the lymphocyte subsets in spleen and mesenteric lymph nodes. An increase in the absolute count and percentage of splenic regulatory T cells (CD4+ CD25+ Foxp3+ cells) was noticed 24 h after single administration of the drug. Propentofylline lowered serum level of IL-5 and did not affect TNF concentration. Only a weak inhibitory effect on anti SRBC humoral immune response was observed. CONCLUSIONS: Propentofylline administration induced inhibition of thymocyte maturation and an increase in Treg subset that might be beneficial for an inhibition of immune response. PMID- 28620955 TI - Editorial Comment from Dr Teishima and Dr Matsubara to Estimated glomerular filtration rate on postoperative day 1 is associated with renal functional outcome after percutaneous renal cryoablation for renal tumors. PMID- 28620956 TI - Functional characterization of two half-size ABC transporter genes in aluminium accumulating buckwheat. AB - Buckwheat (Fagopyrum esculentum Moench) is able to detoxify high aluminium (Al) internally by sequestering it to the vacuoles in the leaves; however, the molecular mechanisms underlying this sequestration are unknown. We performed proteomic analysis with the leaf tonoplast-rich fraction and identified two half size ABC transporters; FeASL1.1 and FeALS1.2. We investigated the gene expression patterns and subcellular localization. To demonstrate their physiological role, we expressed FeALS1.1 or FeALS1.2 in the Arabidopsis atals1 mutant under the control of AtALS1 promoter. FeALS1.1 expression was upregulated by Al in both the leaves and the roots, and its expression level in the roots was six times higher than its homologous gene (AtALS1) of Arabidopsis. FeALS1.2 expression, however, was not affected by Al but showed a 39 times higher expression level than AtALS1 in the leaves. When FeALS1.1 or FeALS1.2 was expressed in atals1, both of them recovered their Al tolerance through altering the subcellular localization of Al in root cells. Taken together, our results indicate that FeALS1.1 and FeALS1.2 are involved in the internal detoxification of Al in the roots and leaves, respectively, by sequestering Al into the vacuoles. Their high expression is probably required for high Al tolerance in buckwheat. PMID- 28620957 TI - Perceived social support and psychosocial adjustment in patients with coronary heart disease. AB - AIM: This study was performed to assess perceived social support and psychosocial adjustment in patients with coronary heart disease. METHODS: Participants were 250 patients referred to the cardiology outpatient clinic of a university hospital in Ankara, Turkey, between December 2013 and March 2014. Data were collected using a participant information form, the Multidimensional Scale of Perceived Social Support, and the Psychosocial Adjustment to Illness Scale-Self Report. Data were analysed using frequencies, percentages, mean scores, and Pearson's correlation coefficient. RESULTS: Patients' mean perceived social support scores were relatively low and patients' mean scores for psychosocial adjustment considered to be poor. Subgroups in the psychosocial adjustment and social support scales were significantly associated. CONCLUSION: This study's results indicate that patients' social support is linked to their psychosocial adjustment to coronary heart disease. As psychosocial adjustment is inhibited in patients who lack sufficient social support, sources of social support of patients should be identified and facilitated. PMID- 28620958 TI - A network meta-analysis of primary prophylaxis for invasive fungal infection in haematological patients. AB - WHAT IS KNOWN AND OBJECTIVE: Antifungal prophylaxis is an option to reduce the incidence of invasive fungal infection (IFI) in haematological patients. To date, no network meta-analysis (NMA) of high-quality evidence (double-blind randomized controlled trials) has been performed on this subject. This systematic review and NMA aimed to evaluate the safety and efficacy of different antifungal agents used for prophylaxis of IFI in patients with haematological disorders. METHODS: A systematic review was performed according to PRISMA and Cochrane recommendations. The search for articles was conducted on PubMed, Scopus and the Web of Science. We searched for double-blind randomized clinical trials comparing antifungal agents for IFI prophylaxis head-to-head vs placebo in patients with any blood cancer. Network meta-analyses were conducted using Addis version 1.16.6. Evaluation of the quality of included RCTs was also performed. RESULTS: Twenty five trials were included in the qualitative and quantitative analyses. Posaconazole stood out as the best IFI prophylaxis option and for avoiding IFI related mortality. For the incidence of candidiasis outcome, the azoles were superior to placebo. Voriconazole and posaconazole were, respectively, the first and second best options. For the incidence of aspergillosis outcome, the probability rank suggested that voriconazole followed by liposomal amphotericin B is, possibly, the best choice. The quality of studies was considered good, with a mean Jadad score of 4.0. WHAT IS NEW AND CONCLUSION: The results of our work support prophylaxis with antifungal agents as reducing the risk of IFI in haematological patients. Overall, the second-generation azoles were found to be the best option for preventing IFI in this population. PMID- 28620959 TI - Parental disease prevention health beliefs and triggers for keeping children home from childcare-a qualitative study in Sydney, Australia. AB - BACKGROUND: Infectious diseases cause considerable morbidity and mortality in children less than 5 years of age. Children attending childcare centres are at increased risk of contracting infections. It is of public health interest to understand what triggers and underpins parental decisions to send an unwell child to childcare, with the obvious attendant risks to other children and childcare staff as well as the affected child. This study aimed to examine parents' disease prevention health beliefs and practices with a particular focus on how these factors influence childcare attendance decisions. METHODS: Semistructured, in depth interviews were conducted between June 2009 and May 2011 with parents who had at least one child under 5 years of age enrolled in a childcare centre. Six centres in the metropolitan area of Sydney, Australia, were selected to include parents from a range of demographic and socio-economic backgrounds. RESULTS: Forty-two interviews were conducted, recorded, and transcribed. Themes emerging from the data included "vitamin dirt," contagion, and contagion prevention and control. These interacted with parents' decision-making about childcare attendance, and parents made choices in a complex context of obligations to their child, social contract obligations to others, peer expectations, and the need to work. Vaccination received only scant mention as a preventive health measure. Decision-making by parents concerning childcare attendance was made without reference to any external guidelines. CONCLUSIONS: This study provides insights into parental disease prevention beliefs, behaviours, and decision-making. It reveals a need for policies to support parents with unwell children. In addition, resources and educative efforts to raise awareness of vaccination as a preventive health measure, and awareness of infectious disease contagion more broadly, would assist in providing parents with a greater evidence base for making decisions about childcare attendance when their child is unwell. PMID- 28620960 TI - Prevalence of chronic obstructive pulmonary disease in independent community dwelling older adults: The Fujiwara-kyo study. AB - AIM: As the Japanese population ages, the number of older patients with chronic obstructive pulmonary disease (COPD) is expected to increase, but the prevalence of COPD in patients aged >=80 years remains unclear. The purpose of the present study was to determine the prevalence of COPD in independent community-dwelling older adults aged >=80 years. METHODS: We investigated the prevalence of COPD in 2862 independent community-dwelling older adults (1504 men, 1358 women, mean age 77.7 +/- 7.0 years) who underwent spirometry in the Fujiwara-kyo study, a study of successful aging in older adults. Those participants with airflow limitation (forced expiratory volume in 1 s/forced vital capacity <0.7) who indicated on a self-administered questionnaire that they had a history of smoking and did not have bronchial asthma were considered to have COPD. RESULTS: The prevalence of COPD was 16.9% among all participants and 37.4% among smokers. The prevalence among individuals aged >=80 years (19.7%) was significantly higher than that among those aged <80 years (16.0%; P < 0.05). When forced expiratory volume in 1 s/forced vital capacity lower limit of normal was used as the criterion for airflow limitation, the prevalence fell to 11.0%. Patients with mild-to-moderate airflow limitation (stage I/stage II) accounted for the great majority (91.2%) of COPD patients aged >=80 years. CONCLUSIONS: A high prevalence of mild-to-moderate COPD was observed even in the independent community-dwelling older adults aged >=80 years. However, the benefits of the spirometric screening and treatment for these patients needs to be determined. Geriatr Gerontol Int 2017; 17: 2421-2426. PMID- 28620961 TI - Normal ATXN2 alleles influences on the age at onset in spinocerebellar ataxia type 2. PMID- 28620962 TI - Isotretinoin and tattooing: a cautionary tale. PMID- 28620963 TI - Skeletal muscle characteristics and mitochondrial function in Huntington's disease patients. PMID- 28620964 TI - Does gene expression in laryngeal subsites differ between patients with laryngopharyngeal reflux and controls? AB - OBJECTIVE: To identify laryngeal mRNA gene changes in patients with laryngopharyngeal reflux (LPR). METHOD: Laryngeal biopsies from non-smoking LPR patients (n=10; Reflux Symptom Index (RSI) >12 and a Reflux Finding Score (RFS) >6) and controls (n=9; RSI <12 and RFS <6) were collected from four subsites (true vocal cord, false vocal cord, medial arytenoid and posterior commissure) of the larynx. qRT-PCR analyses were conducted on 20 reflux- and inflammation related genes, including interleukins 6 and 8, cytokeratins 8 and 14, mucin genes MUC1, MUC2, MUC3B, MUC4, MUC5B, MUC6 and MUC7 and carbonic anhydrase III. Statistical analysis (Mann-Whitney U test) compared gene expression levels between LPR and control groups at each subsite. RESULTS: Site-specific differences in squamous metaplasia and gene expression were noted in LPR patients, with the majority present in the medial arytenoid region. Significant.differences were noted in genes related to mucosal defence and inflammation, including CRNN, CD1d, TGFbeta-1, MUC2, MUC5B and CDH1. CONCLUSION: Whilst the posterior commissure is commonly identified as the area demonstrating the most significant macroscopic change in LPR, the histological changes and genes assessed here showed more pronounced LPR associated differences in the medial arytenoid. We identified differences in expression of mucin genes, cytokeratin-14 and molecular markers of inflammation. Whilst some of these changes may be metaplasia-related, further evaluation of the mRNA expression of these genes may provide a useful biomarker panel for diagnosis and therapeutic monitoring of LPR. PMID- 28620965 TI - Determination of retinal surface area. AB - Previous attempts at determining retinal surface area and surface area of the whole eye have been based upon mathematical calculations derived from retinal photographs, schematic eyes and retinal biopsies of donor eyes. 3-dimensional (3 D) ocular magnetic resonance imaging (MRI) allows a more direct measurement, it can be used to image the eye in vivo, and there is no risk of tissue shrinkage. The primary purpose of this study is to compare, using T2-weighted 3D MRI, retinal surface areas for superior-temporal (ST), inferior-temporal (IT), superior-nasal (SN) and inferior-nasal (IN) retinal quadrants. An ancillary aim is to examine whether inter-quadrant variations in area are concordant with reported inter-quadrant patterns of susceptibility to retinal breaks associated with posterior vitreous detachment (PVD). Seventy-three adult participants presenting without retinal pathology (mean age 26.25 +/- 6.06 years) were scanned using a Siemens 3-Tesla MRI scanner to provide T2-weighted MR images that demarcate fluid-filled internal structures for the whole eye and provide high contrast delineation of the vitreous-retina interface. Integrated MRI software generated total internal ocular surface area (TSA). The second nodal point was used to demarcate the origin of the peripheral retina in order to calculate total retinal surface area (RSA) and quadrant retinal surface areas (QRSA) for ST, IT, SN, and IN quadrants. Mean spherical error (MSE) was -2.50 +/- 4.03D and mean axial length (AL) 24.51 +/- 1.57 mm. Mean TSA and RSA for the RE were 2058 +/- 189 and 1363 +/- 160 mm2 , respectively. Repeated measures anova for QRSA data indicated a significant difference within-quadrants (P < 0.01) which, contrasted with ST (365 +/- 43 mm2 ), was significant for IT (340 +/- 40 mm2 P < 0.01), SN (337 +/- 40 mm2 P < 0.01) and IN (321 +/- 39 mm2 P < 0.01) quadrants. For all quadrants, QRSA was significantly correlated with AL (P < 0.01) and exhibited equivalent increases in retinal area/mm increase in AL. Although the differences between QRSAs are relatively small, there was evidence of concordance with reported inter-quadrant patterns of susceptibility to retinal breaks associated with PVD. The data allow AL to be converted to QRSAs, which will assist further work on inter-quadrant structural variation. PMID- 28620966 TI - The embodied nurse: Interdisciplinary knowledge exchange between compassionate nursing and recent developments in embodied leadership studies. AB - AIMS: To report a potential knowledge exchange between nursing studies and the results obtained from a study conducted into the attributes of embodied leadership. BACKGROUND: Leadership theories have been applied to evaluate, improve, and train nursing practitioners in several previous studies. However, leadership research has entered a new phase where the focus is to produce sustainable leaders through authenticity and compassion, the same two characteristics identified as being of most success in emergent nursing practice. There are few studies that have indicated a knowledge exchange between the latest developments in leadership studies and nursing. DESIGN: An exploratory and qualitative study. METHODS: Between February 2012 - July 2012, a focused sample of 14 medical care professionals was interviewed across a chain of hospitals. The aim was to evaluate embodied leadership characteristics and understand the factors that contribute to the manifestation of these characteristics. The transcribed interviews were analysed using thematic analysis. FINDINGS: Several factors that contribute to the characteristics of embodied leadership have been identified in the interviews and in subsequent literature searches on the characteristics and contributing factors found to be associated with nursing research. These could prompt a knowledge exchange. CONCLUSION: The results suggest common ground between nursing and contemporary leadership research in the exposition of behaviours; namely, being non-judgmental, listening actively, reflective practice and embracing uncertainty. Several implications can therefore be expected through the exchange of knowledge resulting from collaboration between researchers in the two disciplines. PMID- 28620968 TI - Clinical Practice Guidelines: Incorporating Input From a Patient Panel. AB - OBJECTIVE: To describe the integral role of a Patient Panel in the development of the 2017 American College of Rheumatology (ACR)/American Association of Hip and Knee Surgeons (AAHKS) clinical practice guideline. METHODS: We convened a Panel of 11 patients with rheumatoid arthritis and juvenile idiopathic arthritis, all of whom had undergone 1 or more arthroplasties, to review the evidence and provide guidance on recommendations for the 2017 ACR/AAHKS guideline to address the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. The guideline used the Grading of Recommendations Assessment, Development, and Evaluation methodology that acknowledges the critical role of patient values and preferences when the quality of the evidence base is low or when there are important trade-offs between benefits and harms. The Patient Panel considered the relative importance of complications including perioperative infection versus rheumatic disease flare and voted on the recommendations. Before the Voting Panel's own discussion of the recommendations, they reviewed a summary of the Patient Panel's discussion, including their perioperative experience, the relative importance they placed on infections versus flares in the perioperative period, and their votes on the recommendations. RESULTS: The Patient Panel placed higher importance on avoiding an infection than a disease flare despite the far greater frequency of flares than infections. The decisions of the Voting Panel were concordant with those of the Patient Panel. For the 7 recommendations that both Panels voted on, the Panels agreed on the direction as well as the strength of recommendation (which was conditional for all recommendations). CONCLUSION: The Voting Panel considered the importance that the patients placed on risk of infection. The Patient Panel's values informed the direction and strength of the recommendations in the final 2017 ACR/AAHKS guideline. PMID- 28620967 TI - Contribution of CARD9-mediated signalling to wound healing in skin. AB - The inflammatory response after skin injury involves the secretion of a variety of cytokines and growth factors that are necessary for tissue repair. Caspase recruitment domain-containing protein 9 (CARD9) is an essential signalling adaptor molecule for NF-kappaB activation upon triggering through C-type lectin receptors (CLRs), which are expressed in macrophages and dendritic cells. However, the role of CARD9 in inflammatory responses at the wound site has not been elucidated. In this study, we analysed the role of CARD9 in the healing process of skin wounds. Wounds were created on the backs of wild-type (WT) C57BL/6 mice and CARD9 gene-disrupted (knockout [KO]) mice. We analysed per cent wound closure, and the wound tissues were harvested for analysis of leucocyte accumulation and cytokine and chemokine expressions. CARD9KO mice exhibited significant attenuation of wound closure compared with WT mice on days 5, 7 and 10 postwounding, which was associated with decreased macrophage accumulation and reduced TNF-alpha, IL-1beta, CCL3 and CCL4 expressions. These results suggest that CARD9 may be involved in the wound-healing process through the regulation of macrophage-mediated inflammatory responses. PMID- 28620969 TI - Black and White Parents' Willingness to Seek Help for Children's Internalizing and Externalizing Symptoms. AB - OBJECTIVE: Understanding social and environmental factors that contribute to parental help-seeking intentions is an important step in addressing service underutilization for children in need of treatment. This study examined factors that contribute to parents' intentions to seek formal and informal help for child psychopathology (anxiety and attention-deficit/hyperactivity disorder [ADHD]). METHOD: A total of 251 parents (N = 128 mothers, N = 123 fathers; 49% Black, 51% White) read 3 vignettes describing children with anxiety, ADHD, and no diagnosis. Measures of problem recognition, perceived barriers, and formal (pediatricians, psychologists, teachers) and informal (religious leaders, family/friends, self help) help seeking were completed. Four separate hierarchical logistic regression models were used to examine parental help-seeking likelihood from formal and informal sources for internalizing and externalizing symptoms. Predictors were socioeconomic status, parent race, age, and sex, parent problem recognition (via study vignettes), and perceived barriers to mental health service utilization. RESULT: Mothers were more likely than fathers to seek help from pediatricians, psychologists, teachers, and religious leaders for child anxiety and pediatricians, religious leaders, and self-help resources for child ADHD. Black parents were more likely to seek help from religious leaders and White parents were more likely to use self-help resources. Problem recognition was associated with greater intentions to seek help from almost all formal and informal sources (except from friends/family). CONCLUSION: Understanding factors that contribute to parental help seeking for child psychopathology is critical for increasing service utilization and reducing the negative effects of mental health problems. This study highlights the importance of decreasing help-seeking barriers and increasing problem recognition to improve health equity. PMID- 28620970 TI - A Coating-Free Nonfouling Polymeric Elastomer. AB - Medical devices face nonspecific biofouling from proteins, cells, and microorganisms, which significantly contributes to complications and device failure. Imparting these devices with nonfouling capabilities remains a major challenge, particularly for those made from elastomeric polymers. Current strategies, including surface coating and copolymerization/physical blending, necessitate compromise among nonfouling properties, durability, and mechanical strength. Here, a new strategy is reported to achieve both high bulk mechanical strength and excellent surface nonfouling properties, which are typically contradictory, in one material. This is realized through a nonfouling polymeric elastomer based on zwitterionic polycarboxybetaine derivatives. By hiding both charged moieties of the zwitterionic compounds with hydrocarbon ester and tertiary amine groups, the bulk polymer itself is elastomeric and hydrophobic while its superhydrophilic surface properties are restored upon hydrolysis. This coating-free nonfouling elastomer is a highly promising biomaterial for biomedical and engineering applications. PMID- 28620971 TI - The adipokinetic hormone of the coleopteran suborder Adephaga: Structure, function, and comparison of distribution in other insects. AB - The aim of the current study is to identify the adipokinetic hormone(s) (AKHs) of a basal suborder of the species-rich Coleoptera, the Adephaga, and possibly learn more about the ancestral AKH of beetles. Moreover, we wanted to compare the ancestral AKH with AKHs of more advanced beetles, of which a number are pest insects. This would allow us to assess whether AKH mimetics would be suitable as insecticides, that is, be harmful to the pest species but not to the beneficial species. Nine species of the Adephaga were investigated and all synthesize only one octapeptide in the corpus cardiacum, as revealed by Edman degradation sequencing techniques or by mass spectrometry. The amino acid sequence pGlu-Leu Asn-Phe-Ser-Thr-Gly-Trp corresponds to Schgr-AKH-II that was first identified in the desert locust. It is assumed that Schgr-AKH-II-the peptide of a basal beetle clade-is the ancestral AKH for beetles. Some other beetle families, as well as some Hymenoptera (including honey bees) also contain this peptide, whereas most of the pest beetle species have different AKHs. This argues that those peptides and their receptors should be explored for developing mimetics with insecticidal properties. A scenario where Schgr-AKH-II (the only AKH of Adephaga) is used as basic molecular structure to derive almost all other known beetle AKHs via single step mutations is very likely, and supports the interpretation that Schgr-AKH-II is the ancestral AKH of Coleoptera. PMID- 28620972 TI - Structure-Property Relationships of Organic Electrolytes and Their Effects on Li/S Battery Performance. AB - Electrolytes, which are a key component in electrochemical devices, transport ions between the sulfur/carbon composite cathode and the lithium anode in lithium sulfur batteries (LSBs). The performance of a LSB mostly depends on the electrolyte due to the dissolution of polysulfides into the electrolyte, along with the formation of a solid-electrolyte interphase. The selection of the electrolyte and its functionality during charging and discharging is intricate and involves multiple reactions and processes. The selection of the proper electrolyte, including solvents and salts, for LSBs strongly depends on its physical and chemical properties, which is heavily controlled by its molecular structure. In this review, the fundamental properties of organic electrolytes for LSBs are presented, and an attempt is made to determine the relationship between the molecular structure and the properties of common organic electrolytes, along with their effects on the LSB performance. PMID- 28620973 TI - The effectiveness of strategies similar to the Magnet model to create positive work environments on nurse satisfaction. AB - AIM: The objective of this study was to identify the satisfaction levels of nurses with positive environment initiatives and positive management strategies. METHOD: In total, 235 and 259 nurses participated in the study before and after the application of the initiatives and strategies, respectively. Strategies adopted from the magnet model to create positive work environments and management styles were executed according to the forces of magnetism. Data related to satisfaction were collected twice, once before and once after the strategies to create positive working environments were implemented. RESULTS: The rates of working environment satisfaction in the nurses' department were 57.07% in 2011 and 69.01% in 2013. The rate of satisfaction with governance differed significantly between 2011 and 2013, especially in terms of the merit system, equity and equality, information flow between the administration and the employees, and the influence of the nursing managers on institutional decision making. CONCLUSION: This study showed that 24 months after the implementation of these strategies, nurse satisfaction with their work environment and management style increased significantly. PMID- 28620974 TI - Evaluation of the Nigerian Urban Reproductive Health Initiative (NURHI) Program. AB - Gaps remain in understanding whether family planning (FP) programs can change urban women's FP behaviors. Even less is known about what works among poor urban women. This article presents results of the impact evaluation of the Nigerian Urban Reproductive Health Initiative (NURHI). Findings are based on recently collected longitudinal data from women and facilities in six cities in Nigeria. Over the four-year follow-up period, there was an increase of about ten percentage points in modern method use. Impact evaluation analyses using fixed effects regression methods indicate that both demand- and supply-side program activities increased modern method use. Radio, television, community events, and living near program-enrolled health facilities all significantly increased modern method use or were related to a desire for no more children among all women and among poor women. Results are discussed with an eye toward the design and scale up of future family planning programs in urban Nigeria and elsewhere in sub Saharan Africa. PMID- 28620975 TI - Decision heuristic or preference? Attribute non-attendance in discrete choice problems. AB - This paper investigates if respondents' choice to not consider all characteristics of a multiattribute health service may represent preferences. Over the last decade, an increasing number of studies account for attribute non attendance (ANA) when using discrete choice experiments to elicit individuals' preferences. Most studies assume such behaviour is a heuristic and therefore uninformative. This assumption may result in misleading welfare estimates if ANA reflects preferences. This is the first paper to assess if ANA is a heuristic or genuine preference without relying on respondents' self-stated motivation and the first study to explore this question within a health context. Based on findings from cognitive psychology, we expect that familiar respondents are less likely to use a decision heuristic to simplify choices than unfamiliar respondents. We employ a latent class model of discrete choice experiment data concerned with National Health Service managers' preferences for support services that assist with performance concerns. We present quantitative and qualitative evidence that in our study ANA mostly represents preferences. We also show that wrong assumptions about ANA result in inadequate welfare measures that can result in suboptimal policy advice. Future research should proceed with caution when assuming that ANA is a heuristic. PMID- 28620977 TI - 2016 ASE undergraduate essay competition candidate information. AB - The aim of this review is to discuss the role of medicaments and materials used in teeth undergoing root canal treatment and how they affect the overall prognosis of root canal treated teeth. Irrigants, medicaments and materials play a vital role in RCT. They reduce the overall microbial load within the root canal system, help reduce inter-appointment pain, and induce apexification during RCT of permanent teeth with immature apices. In addition, they also help create a hermetic coronal and periradicular seal to entomb any residual microorganisms within the canals and prevent future ingress of contaminants into the root canal system and subsequent reinfection. Whilst the role of various materials in RCT has been thoroughly investigated, the available literature and longitudinal clinical studies evaluating the affect of such materials on the prognosis of RCT is scarce, and requires further investigation. PMID- 28620976 TI - Oral nutritional supplement use in relation to length of stay in heart failure patients at a regional medical center. AB - RATIONALE, AIMS, AND OBJECTIVES: Improving the nutritional status of hospitalized patients has been shown to reduce length of stay (LOS), hospital costs, readmission rates, complication rates, and mortality. Provision of nutrient-rich, liquid, oral nutrition supplements (ONS) is one approach to improve nutritional status. Little information is available on ONS use and LOS among heart failure patients. METHODS: This study used a retrospective design to examine whether routine ONS use was associated with hospital LOS among 570 heart failure inpatients (89 ONS = yes; 481 ONS = no) at a regional medical center, adjusting for significant personal, locational, and time variables using multiple logistic regression analysis. RESULTS: Oral nutrition supplement use was associated with high LOS in this sample (odds ratio = 2.43). High LOS was also associated with higher Charlson comorbidity index values, discharge destination, hospital room location, and dietitian consults. CONCLUSIONS: These results show that ONS orders alone are not adequate to reduce LOS among heart failure patients. Continued research is needed on ways to improve care to reduce LOS among hospitalized patients. PMID- 28620978 TI - Comparison of healthcare utilization and life-sustaining interventions between elderly patients with dementia and those with cancer near the end of life: A nationwide, population-based study in Taiwan. AB - AIM: Little is known about the pattern of healthcare services for end-of-life patients with dementia (PwD) in East Asia. We compared this pattern between PwD and cancer patients in their last year of life in Taiwan. METHODS: Taiwan's National Health Insurance Research Database was applied for this case-control analysis. The records of patients who had dementia and died between 2002 and 2011 were reviewed. The control group was decedents with cancer. The utilization of hospitalization, emergency department visits and life-sustaining interventions during the last year of life between the two groups were compared. RESULTS: Of the 2724 patients enrolled, 908 had dementia and 1816 had cancer. PwD were more likely to have a higher frequency of admission to hospital and intensive care unit, and longer stays compared with cancer patients. PwD had a higher risk of enteral tube insertion and feeding, endotracheal intubation and tracheostomy, mechanical ventilation, hemodialysis and cardiopulmonary resuscitation (OR 4.36, 95% CI 3.51-5.41), which was the highest among the selected procedures. CONCLUSIONS: PwD in their last year of life in Taiwan underwent aggressive interventions significantly more frequently than did their counterparts in Western countries. Providing comfort-centered care for better quality of life for end-of-life PwD is a priority of Taiwan's national health policy. Geriatr Gerontol Int 2017; 17: 2545-2551. PMID- 28620979 TI - An application of CIFAP for predicting the binding affinity of Chk1 inhibitors derived from 2-aminothiazole-4-carboxamide. AB - Investigation of protein-ligand interactions obtained from experiments has a crucial part in the design of newly discovered and effective drugs. Analyzing the data extracted from known interactions could help scientists to predict the binding affinities of promising ligands before conducting experiments. The objective of this study is to advance the CIFAP (compressed images for affinity prediction) method, which is relevant to a protein-ligand model, identifying 2D electrostatic potential images by separating the binding site of protein-ligand complexes and using the images for predicting the computational affinity information represented by pIC50 values. The CIFAP method has 2 phases, namely, data modeling and prediction. In data modeling phase, the separated 3D structure of the binding pocket with the ligand inside is fitted into an electrostatic potential grid box, which is then compressed through 3 orthogonal directions into three 2D images for each protein-ligand complex. Sequential floating forward selection technique is performed for acquiring prediction patterns from the images. In the prediction phase, support vector regression (SVR) and partial least squares regression are used for testing the quality of the CIFAP method for predicting the binding affinity of 45 CHK1 inhibitors derived from 2 aminothiazole-4-carboxamide. The results show that the CIFAP method using both support vector regression and partial least squares regression is very effective for predicting the binding affinities of CHK1-ligand complexes with low-error values and high correlation. As a future work, the results could be improved by working on the pose of the ligands inside the grid. PMID- 28620980 TI - Case of autoimmune autonomic ganglionopathy manifesting anhidrosis. AB - Autoimmune autonomic ganglionopathy (AAG), clinically characterized by gastrointestinal dysmotility, orthostatic hypotension and tonic pupils, is an idiopathic acquired disorder of the autonomic nervous system elicited by antibodies against ganglionic acetylcholine receptor (gAChR). We encountered a 60 year-old man who presented with severe anhidrosis, difficulty in thermoregulation, orthostatic hypotension, gastrointestinal dysmotility, tonic pupils and ptosis. Histologically, an anhidrotic skin sample was normal. Routine laboratory examinations of blood, urine and cerebrospinal fluid returned no abnormal findings. Serological examination revealed antibodies against alpha3 and beta4 subunits of gAChR. The diagnosis was AAG. As sudomotor dysfunction reflects ganglionic neuropathy in AAG, we concluded that his anhidrosis was attributable to AAG. Anhidrosis is an important clue for the diagnosis of AAG, a rare neurological disorder. PMID- 28620981 TI - Practical Alkoxythiocarbonyl Auxiliaries for Iridium(I)-Catalyzed C-H Alkylation of Azacycles. AB - The development of new and practical 3-pentoxythiocarbonyl auxiliaries for IrI catalyzed C-H alkylation of azacycles is described. This method allows for the alpha-C-H alkylation of a variety of substituted pyrrolidines, piperidines, and tetrahydroisoquinolines through alkylation with alkenes. While the practicality of these simple carbamate-type auxiliaries is underscored by the ease of installation and removal, the method's utility is demonstrated in its ability to functionalize biologically relevant l-proline and l-trans-hydroxyproline, delivering unique 2,5-dialkylated amino acid analogues that are not accessible by other C-H functionalization methods. PMID- 28620982 TI - Novice students navigating the clinical environment in an early medical clerkship. AB - CONTEXT: The black box that is student learning in clinical environments is an ongoing research project. Our previous research showed that despite the time that students are given to learn with, about and from patients, some lack confidence for those encounters and see few patients. The study reported here investigated individual and environmental factors affecting medical students' self-directed learning time in hospital. METHODS: We studied second year students in the four year postgraduate Melbourne Medical School programme as they undertook the first of their four 9-week hospital placements in medical wards. Each week approximately 10 hours of structured teaching is offered; the remaining time is spent in self-directed learning. Over six weeks, we observed 31 medical students and interviewed 17 of them. The interviews were subjected to content analysis procedures and the observation notes added contextual information to what was said in interviews. We considered the findings through the Experience-based Learning framework. RESULTS: We found four main themes in the data: finding and contacting patients challenges all students and overwhelms some; the educational design of the placement is a flawed navigational device providing inadequate clarity and security; the physical and social terrain of a large tertiary hospital is replete with obstacles making it easy for some students to stumble and retreat; finally, any positive connection with peers, staff and patients is empowering. CONCLUSIONS: This study throws light on to the uncertain path of the novice clinical learner illuminating both the intractable aspects of hospital environments and opportunities for pedagogical and affective supports that can compensate. The processes and conditions for self-directed learning time need attention in order to provide for a safe, efficient or successful clerkship experience for all students. Particular effort is needed to sensitively identify those individuals who struggle and suffer on the journey, and provide appropriate support. PMID- 28620983 TI - Effects of glycolic acid peeling on the cutaneous manifestation of generalized acanthosis nigricans caused by FGFR3 mutation: A report of one sporadic and two familial cases. PMID- 28620984 TI - Saliva testing for human papilloma virus in oropharyngeal squamous cell carcinoma: A diagnostic accuracy study. AB - BACKGROUND: New cases of oropharyngeal squamous cell carcinoma (OPSCC) are routinely tested for HPV. HPV in saliva can be detected with PCR, but its clinical applicability in the context of OPSCC remains unknown. METHODS: Forty six consecutive patients diagnosed with OPSCC had pre-treatment saliva specimens collected. PCR for HPV on saliva was compared to p16 IHC and HPV DNA in situ hybridisation (ISH) on surgical biopsies. RESULTS: The sensitivity and specificity of saliva testing when compared to the reference test of p16 IHC and HPV DNA ISH were 72.2% and 90%, and positive and negative predictive values were 96.3% and 47.4%. There were no adverse events. Time from last meal, smoking, alcohol drinking and physical exercise did not impact on results. CONCLUSIONS: Saliva testing is a promising test to detect HPV in patients with OPSCC. A positive result could avoid the need for surgical biopsies, thereby reducing costs, patient morbidity and expedite treatment. PMID- 28620985 TI - Development of a patient and institutional-based model for estimation of operative times for robot-assisted radical cystectomy: results from the International Robotic Cystectomy Consortium. AB - OBJECTIVES: To design a methodology to predict operative times for robot-assisted radical cystectomy (RARC) based on variation in institutional, patient, and disease characteristics to help in operating room scheduling and quality control. PATIENTS AND METHODS: The model included preoperative variables and therefore can be used for prediction of surgical times: institutional volume, age, gender, body mass index, American Society of Anesthesiologists score, history of prior surgery and radiation, clinical stage, neoadjuvant chemotherapy, type, technique of diversion, and the extent of lymph node dissection. A conditional inference tree method was used to fit a binary decision tree predicting operative time. Permutation tests were performed to determine the variables having the strongest association with surgical time. The data were split at the value of this variable resulting in the largest difference in means for the surgical time across the split. This process was repeated recursively on the resultant data sets until the permutation tests showed no significant association with operative time. RESULTS: In all, 2 134 procedures were included. The variable most strongly associated with surgical time was type of diversion, with ileal conduits being 70 min shorter (P < 0.001). Amongst patients who received neobladders, the type of lymph node dissection was also strongly associated with surgical time. Amongst ileal conduit patients, institutional surgeon volume (>66 RARCs) was important, with those with a higher volume being 55 min shorter (P < 0.001). The regression tree output was in the form of box plots that show the median and ranges of surgical times according to the patient, disease, and institutional characteristics. CONCLUSION: We developed a method to estimate operative times for RARC based on patient, disease, and institutional metrics that can help operating room scheduling for RARC. PMID- 28620986 TI - Conversion from wide to narrow QRS complex ventricular tachycardia: What is the mechanism? PMID- 28620987 TI - E3 M3+ (E=C-Pb, M=Li-Cs) Clusters: The Smallest Molecular Stars. AB - Extensive potential energy surface explorations of twenty-five clusters with the formula E3 M3+ (E=Group 14 element and M=Group 1 element) through density functional theory and high-level ab initio computations reveal that the lowest energy isomer for all these systems corresponds to a non-classical D3h star-like structure in the singlet state, where three M atoms interact electrostatically with the triangular E3 core, occupying three bridging positions around it. More than 18 200 calculations were done in the search for the minima structures, starting with a first phase at the PBE0/LANL2DZ level and ending with an analysis of the most representative clusters at the CCSD(T)/def2-TZVP//PBE0/def2-TZVP level. The title clusters represent the smallest molecular stars with three planar tetracoordinate E atoms (E=Group 14 element). All these E3 M3+ clusters behave like superalkali cations with small vertical electron affinities (smaller than Cs), large vertical electron detachment energies, and HOMO-LUMO energy gaps. Their energetics, bonding, and electron delocalization are discussed in detail. The high stability of these clusters is reflected from the large dissociation energy needed for different dissociation channels. The electron delocalization is confirmed by the presence of two delocalized pi electrons over the E3 core and strong diatropic responses. PMID- 28620988 TI - When do predatory mites (Phytoseiidae) attack? Understanding their diel and seasonal predation patterns. AB - Predatory mites of the Phytoseiidae family are considered one of the most important groups of natural enemies used in biological control. The behavioral patterns of arthropods can differ greatly daily and seasonally; however, there is a lack of literature related to Phytoseiidae diel and seasonal predation patterns. The predatory activity of three phytoseiid species (two Tetranychidae specialists, Phytoseiulus persimilis and Neoseiulus californicus, and one omnivore, Euseius stipulatus) that occur naturally in Spanish citrus orchards was observed under laboratory conditions in winter and summer. The temperature and photoperiod of the climatic chamber where the mites were reared did not change during the experiment. Our study demonstrates that phytoseiids can exhibit diel and seasonal predatory patterns when feeding on Tetranychus urticae (Acari: Tetranychidae). Neoseiulus californicus was revealed to be a nocturnal predator in summer but diurnal in winter. In contrast, P. persimilis activity was maximal during the daytime, and E. stipulatus showed no clear daily predation patterns. The predatory patterns described in this study should be taken into account when designing laboratory studies and also in field samplings, especially when applying molecular techniques to unveil trophic relationships. PMID- 28620989 TI - Recurrent angular cheilitis after secukinumab injections. PMID- 28620990 TI - Association Patterns of Endothelial Nitric Oxide Synthase Gene (NOS3) Variant Glu298Asp with Blood Pressure and Serum Lipid Levels in Subjects with Coronary Artery Disease from Pakistan. AB - Nitric oxide is an important antiatherosclerotic agent. The main determinant of nitric oxide levels is enzyme nitric oxide synthase encoded by the NOS3 gene, the common variants in this gene may be responsible for variations in plasma enzyme levels. The association of NOS3 variants with coronary artery disease (CAD) varies in different ethnicities. The current study aimed to determine the association of NOS3 Glu298Asp (rs1799983) with CAD and blood lipid levels in Pakistani subjects. Six hundred thirty-six samples (412 cases, 224 controls) were genotyped by TaqMan allelic discrimination assay and serum total cholesterol, and High Density Lipoprotein cholesterol (HDL-C)/Low Density Lipoprotein cholesterol (LDL-C) and triglycerides were measured. The genotype frequency was Glu/Glu = 64.6%, Glu/Asp = 30.1%, and Asp/Asp = 5.3% in cases, and Glu/Glu = 68.8%, Glu/Asp = 26.7%, and Asp/Asp = 4.5% in controls. The Asp298 (T) frequency was not significantly higher in cases than controls (20.4% vs 17.9%, P = 0.28) and risk allele was not associated with CAD (OR 1.15 (0.86-1.54), P = 0.33) and the tested lipid traits but had a strong association with blood pressure (for systolic and diastolic P = 1.9*10--56 and 4*10--40 , respectively). In conclusion, although Glu298Asp did not show association with CAD and lipid profile in the studied cohort, it may exert its effect through blood pressure; however, the mechanism of this effect needs to be explored in the future. PMID- 28620991 TI - Potential Positive Association between Cytochrome P450 1A1 Gene Polymorphisms and Recurrent Pregnancy Loss: a Meta-Analysis. AB - In order to discover the potential genetic risks associated with recurrent pregnancy loss (RPL), this meta-analysis was conducted to assess the association between CYP1A1 gene polymorphism and RPL. Studies were retrieved from the databases PubMed, Embase, HuGENet, and CNKI. Four models were then applied. Seven studies, including three datasets for the rs1048943 and five for the rs4646903 single-nucleotide polymorphism (SNP), were included in this analysis, involving 613 cases and 398 controls for the rs1048943; and 864 cases and 842 controls for the rs4646903 SNP. After comprehensive analysis, we found that rs4646903 was significantly associated with RPL [recessive (OR = 1.72, 95%CI: 1.13-2.61); codominant (CC vs TT; OR = 1.74, 95%CI: 1.12-2.71), (CC vs CT; OR = 1.67, 95%CI: 1.07-2.62) and allele analysis (OR = 1.27, 95%CI: 1.07-1.50)]. In the following subgroup analysis, a positive association was also discovered among people of Asian descent, especially South Asians. However, there was no obvious association between rs1048943 and RPL. In summary, our results suggest that CYP1A1 gene polymorphism (particularly for rs4646903) might be associated with RPL risk, especially among South Asians. Further studies are required to confirm this association. PMID- 28620992 TI - Detection of Imprinting Effects for Quantitative Traits on X Chromosome Using Nuclear Families with Multiple Daughters. AB - Genomic imprinting is an epigenetic phenomenon in which the expression of an allele copy depends on its parental origin. This mechanism has been found to play an important role in many complex diseases. Statistical tests for imprinting effects have been developed for more than 15 years, but they are only suitable for autosomes. It was not until recently that the parental-asymmetry test on the X chromosome (XPAT) was proposed to test for imprinting effects. However, this test can only be used for qualitative traits. Therefore, in this article, we propose a class of PAT-type tests to test for imprinting for quantitative traits on the X chromosome in the presence of association, namely, Q-XPAT(c), Q-1 XPAT(c) and Q-C-XPAT(c), where c is a constant. These methods can accommodate complete and incomplete nuclear families with an arbitrary number of daughters. Extensive simulation studies demonstrate that the proposed tests control the size well under the null hypothesis of no imprinting effects and are powerful under various family structures. Moreover, by setting the inbreeding coefficient in females to be nonzero and using the assortative mating pattern in simulations, the proposed tests are shown to be valid under Hardy-Weinberg disequilibrium. PMID- 28620993 TI - The Role of TLR4, TNF-alpha and IL-1beta in Type 2 Diabetes Mellitus Development within a North Indian Population. AB - This study investigated the role of IL-1beta-511 (rs16944), TLR4-896 (rs4986790) and TNF-alpha-308 (rs1800629) polymorphisms in type 2 diabetes mellitus (T2DM) among an endogamous Northern Indian population. Four hundred fourteen participants (204 T2DM patients and 210 nondiabetic controls) were genotyped for IL-1beta-511, TLR4-896 and TNF-alpha-308 loci. The C allele of IL-1beta-511 was shown to increase T2DM susceptibility by 75% (OR: 1.75 [CI 1.32-2.33]). Having two parents affected by T2DM increased susceptibility by 5.7 times (OR: 5.693 [CI 1.431-22.648]). In this study, we have demonstrated a conclusive association with IL-1beta-511 locus and IL-1beta-511-TLR4-896 diplotype (CC-AA) and T2DM, which warrants further comprehensive analyses in larger cohorts. PMID- 28620994 TI - Amphiphilic naproxen prodrugs: differential scanning calorimetry study on their interaction with phospholipid bilayers. AB - OBJECTIVES: Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers. METHODS: The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied. KEY FINDINGS: Naproxen conjugation to lipoamino acids improves its interaction with biomembrane models and affects the transfer from a lipophilic carrier to biomembrane model. LAA portion may localize between the phospholipid chains; the entity of the interaction depends not only on the presence of the spacer but also on the LAA chain length. CONCLUSIONS: Variation of LAA portion can modulate the naproxen prodrugs affinity towards the biological membrane as well as towards the lipophilic carrier. PMID- 28620995 TI - Effects of Tilianin on Proliferation, Migration and TGF-beta/Smad Signaling in Rat Vascular Smooth Muscle Cells Induced with Angiotensin II. AB - Flavonoid Tilianin was isolated from Dracocephalum moldavica, and its pharmacological mechanism on proliferation, migration and the TGF-beta/Smad signaling pathway in rat vascular smooth muscle cells (VSMCs) induced with Angiotensin II (Ang II) was systematically evaluated. Primary rat VSMCs were stimulated with Ang II to induce proliferation. The cells were then treated with Tilianin for 24 or 48 h. MTT assay and Transwell assays were used to evaluate the effects of Tilianin on proliferation and migration. The expression of intracellular proliferating cell nuclear antigen (PCNA), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured by immunohistochemistry as verification of effects on proliferation and migration. The expression of TGF-beta1, Smad2 and Smad3 mRNA was measured by qRT PCR, and the expression of TGF-beta1 and P-Smad2/3 protein was measured by Western blotting. The results show that Tilianin can inhibit proliferation and expression of intracellular PCNA in VSMCs induced with Ang II, in a dose dependent manner. Tilianin also mediates a dose-dependent inhibition of migration and the expression of intracellular ICAM-1, VCAM-1, MMP-2 and MMP-9. Furthermore, TGF-beta1, Smad2, Smad3, Smad2/3 and P-Smad2/3 in Ang II-induced VSMCs are suppressed by Tilianin. The inhibitory effects of Tilianin support its use in the suppression and treatment of atherosclerosis. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28620996 TI - Feasibility of Collecting Patient-Reported Outcomes for Inpatient Rehabilitation Quality Reporting. AB - OBJECTIVE: To evaluate rehabilitation inpatients' willingness and ability to complete patient-reported outcomes (PROs) and the burden of completion on patients and staff. DATA SOURCES/STUDY SETTING: Two inpatient rehabilitation facilities. STUDY DESIGN: Patients with neurological disorders were assigned randomly to receive a nominal monetary incentive during or 1 month after the stay. DATA COLLECTION: Patients responded using a tablet computer or paper. PRINCIPAL FINDINGS: Of the 1,055 admissions, 74 percent were eligible, and 51 percent of eligible patients completed the survey. Most answered without assistance. A majority completed the survey 1 month after discharge; incentive timing was unrelated to postdischarge completion. Half of the 285 follow-up respondents required at least two reminder calls. CONCLUSIONS: Collection of PROs from rehabilitation patients is feasible. Results inform policy makers regarding feasibility of PRO data in evaluating rehabilitation quality. PMID- 28620997 TI - Morphology and evolution of the oral shield in marsupial neonates including the newborn monito del monte (Dromiciops gliroides, Marsupialia Microbiotheria) pouch young. AB - Newborn marsupials can be arranged into three grades of developmental complexity based on their external form, as well as based on their organ systems and their cytology. The dasyurids are considered the least developed marsupials at birth, while didelphids and peramelids are intermediate, and macropods are the most developed. Currently there is still little information on caenolestid and microbiotherid development at birth. Developmental stages can be graded as G1, G2 and G3, with G1 being the least developed at birth, and G3 the most developed. Marsupials are also characterized by having an extremely developed craniofacial region at birth compared with placentals. However, the facial region is also observed to vary in development between different marsupial groups at birth. The oral shield is a morphological structure observed in the oral region of the head during late embryological development, which will diminish shortly after birth. Morphological variation of the oral shield is observed and can be arranged by developmental complexity from greatly developed, reduced to vestigial. In its most developed state, the lips are fused, forming together with the rhinarium, a flattened ring around the buccal opening. In this study, we examine the external oral shield morphology in different species of newborn marsupials (dasyurids, peramelids, macropods and didelphids), including the newborn monito del monte young (Dromiciops gliroides - the sole survivor of the order Microbiotheria). The adaptive value of the oral shield structure is reviewed, and we discuss if this structure may be influenced by developmental stage of newborn, pouch cover, species relatedness, or other reproductive features. We observe that the oral shield structure is present in most species of Marsupialia and appears to be exclusively present in this infraclass. It has never been described in Monotremata or Eutherians. It is present in unrelated taxa (e.g. didelphids, dasyurids and microbiotherids). We observe that a well-developed oral shield may be related to ultra altricial development at birth, large litter size (more than two), and is present in most species that lack a pouch in reproductive adult females or have a less prominent or less developed pouch with some exceptions. We try to explore the evolution of the oral shield structure using existing databases and our own observations to reconstruct likely ancestral character states that can then be used to estimate the evolutionary origin of this structure and if it was present in early mammals. We find that a simple to develop oral shield structure (type 2-3) may have been present in marsupial ancestors as well as in early therians, even though this structure is not present in the extant monotremes. This in turn may suggest that early marsupials may have had a very simple pouch or lacked a pouch as seen in some living marsupials, such as some dasyurids, didelphids and caenolestids. The study's results also suggest that different morphological stages of the oral shield and hindlimb development may be influenced by species size and reproductive strategy, and possibly by yet unknown species-specific adaptations. PMID- 28620998 TI - A survey of speech-language therapy provision for people with post-stroke dysarthria in the UK. AB - BACKGROUND: A large number of people who experience a stroke are affected by dysarthria. This may be in isolation or in association with aphasia and/or dysphagia. Despite evidence highlighting the psychological and social impact of having post-stroke dysarthria and a number of clinical guidelines that make recommendations for appropriate management, little is known currently about UK service delivery issues relating to speech and language therapy (SLT) assessment and treatment for this group. Such evidence is necessary in order to plan, develop and research services for people with post-stroke dysarthria. AIMS: To gain an overview of SLT practices in the management of people with dysarthria after stroke in the UK. METHODS & PROCEDURES: SLTs in the UK were asked to complete an online survey addressing referral patterns, caseload profiles, and their assessment and intervention methods for post-stroke dysarthria. In the absence of a national register of clinicians working with people with acquired dysarthria, a snowballing method was used to facilitate participant recruitment. Results were analysed using descriptive statistics. OUTCOMES & RESULTS: A total of 146 SLTs responded. The majority were employed by the National Health Service (NHS). Most patients were referred within 1 week post-stroke. Almost half the respondents did not regularly use formal assessments and the use of instrumentation was rare, including the use of video recording. The focus of therapy for mild, moderate and severe dysarthria did not differ significantly for clinicians. A little under half the respondents endorsed non-verbal oral exercises in rehabilitation. The survey demonstrated some appreciation of the centrality of regular intensive practice to effect change, but this was in a minority. CONCLUSIONS & IMPLICATIONS: Through this research it became clear that basic information regarding post-stroke dysarthria incidence, prevalence and core demographics is currently unavailable. More embedded NHS SLT reporting systems would make a significant contribution to this area. A more in-depth examination is required of the natural history of dysarthria over the months and years following stroke, of SLT practices in relation to post-stroke dysarthria, with investigations to understand more fully the choices SLTs make and how this relates to available evidence to support their clinical decision-making. PMID- 28621000 TI - How serious is bias in effect estimation in randomised trials with survival data given risk heterogeneity and informative censoring? AB - It is often assumed that randomisation will prevent bias in estimation of treatment effects from clinical trials, but this is not true of the semiparametric Proportional Hazards model for survival data when there is underlying risk heterogeneity. Here, a new formula is proposed for estimation of this bias, improving on a previous formula through ease of use and clarity regarding the role of the mid-study cumulative hazard rate, shown to be an important factor for the bias magnitude. Informative censoring (IC) is recognised as a source of bias. Here, work on selection effects among survivors due to risk heterogeneity is extended to include IC. A new formula shows that bias in causal effect estimation under IC has two sources: one consequent on heterogeneity and one from the additional impact of IC. The formula provides new insights not previously shown: there may less bias under IC than when there is no IC and even, in principle, zero bias. When tested against simulated data, the new formulae are shown to be very accurate for prediction of bias in Proportional Hazards and accelerated failure time analyses which ignore heterogeneity. These data are also used to investigate the performance of accelerated failure time models which explicitly model risk heterogeneity ('frailty models') and G estimation. These methods remove bias when there is simple censoring but not with informative censoring when they may lead to overestimation of treatment effects. The new formulae may be used to help researchers judge the possible extent of bias in past studies. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28620999 TI - Two Silene vulgaris copper transporters residing in different cellular compartments confer copper hypertolerance by distinct mechanisms when expressed in Arabidopsis thaliana. AB - Silene vulgaris is a metallophyte of calamine, cupriferous and serpentine soils all over Europe. Its metallicolous populations are hypertolerant to zinc (Zn), cadmium (Cd), copper (Cu) or nickel (Ni), compared with conspecific nonmetallicolous populations. These hypertolerances are metal-specific, but the underlying mechanisms are poorly understood. We investigated the role of HMA5 copper transporters in Cu-hypertolerance of a S. vulgaris copper mine population. Cu-hypertolerance in Silene is correlated and genetically linked with enhanced expression of two HMA5 paralogs, SvHMA5I and SvHMA5II, each of which increases Cu tolerance when expressed in Arabidopsis thaliana. Most Spermatophytes, except Brassicaceae, possess homologs of SvHMA5I and SvHMA5II, which originate from an ancient duplication predating the appearance of spermatophytes. SvHMA5II and the A. thaliana homolog AtHMA5 localize in the endoplasmic reticulum and upon Cu exposure move to the plasma membrane, from where they are internalized and degraded in the vacuole. This resembles trafficking of mammalian homologs and is apparently an extremely ancient mechanism. SvHMA5I, instead, neofunctionalized and always resides on the tonoplast, likely sequestering Cu in the vacuole. Adaption of Silene to a Cu-polluted soil is at least in part due to upregulation of two distinct HMA5 transporters, which contribute to Cu hypertolerance by distinct mechanisms. PMID- 28621001 TI - Early vocabulary development in children with bilateral cochlear implants. AB - BACKGROUND: Children with unilateral cochlear implants (CIs) may have delayed vocabulary development for an extended period after implantation. Bilateral cochlear implantation is reported to be associated with improved sound localization and enhanced speech perception in noise. This study proposed that bilateral implantation might also promote early vocabulary development. Knowledge regarding vocabulary growth and composition in children with bilateral CIs and factors associated with it may lead to improvements in the content of early speech and language intervention and family counselling. AIMS: To analyse the growth of early vocabulary and its composition during the first year after CI activation and to investigate factors associated with vocabulary growth. METHODS & PROCEDURES: The participants were 20 children with bilateral CIs (12 boys; eight girls; mean age at CI activation = 12.9 months). Vocabulary size was assessed with the Finnish version of the MacArthur Communicative Development Inventories (CDI) Infant Form and compared with normative data. Vocabulary composition was analysed in relation to vocabulary size. Growth curve modelling was implemented using a linear mixed model to analyse the effects of the following variables on early vocabulary growth: time, gender, maternal education, residual hearing with hearing aids, age at first hearing aid fitting and age at CI activation. OUTCOMES & RESULTS: Despite clear vocabulary growth over time, children with bilateral CIs lagged behind their age norms in receptive vocabulary during the first 12 months after CI activation. In expressive vocabulary, 35% of the children were able to catch up with their age norms, but 55% of the children lagged behind them. In receptive and expressive vocabularies of 1-20 words, analysis of different semantic categories indicated that social terms constituted the highest proportion. Nouns constituted the highest proportion in vocabularies of 101-400 words. The proportion of verbs remained below 20% and the proportion of function words and adjectives remained below 10% in the vocabularies of 1-400 words. There was a significant main effect of time, gender, maternal education and residual hearing with hearing aids before implantation on early receptive vocabulary growth. Time and residual hearing with hearing aids had a significant main effect also on expressive vocabulary growth. CONCLUSIONS & IMPLICATIONS: Vocabulary development of children with bilateral CIs may be delayed. Thus, early vocabulary development needs to be assessed carefully in order to provide children and families with timely and targeted early intervention for vocabulary acquisition. PMID- 28621002 TI - Real-world, single-centre experience of apremilast for the treatment of moderate to severe psoriasis. PMID- 28621004 TI - Epirubicin in the treatment of canine histiocytic sarcoma: sequential, alternating and rescue chemotherapy. AB - The aims of this study were to report treatment outcomes for dogs with histiocytic sarcoma (HS) treated with both lomustine and epirubicin, and to report response rates to epirubicin as a rescue therapy in dogs previously treated with lomustine. Medical records of dogs with a diagnosis of HS that were treated with both lomustine and epirubicin were retrospectively evaluated. Of 29 dogs receiving epirubicin alternating with, or subsequent to lomustine treatment, including in a rescue setting, response to epirubicin could be assessed in 20 with an overall response rate (ORR) of 29% and biological response rate (BRR) of 71%. Median time to progression (TTP) in 12 of these 20 dogs in which it was assessable was 69 days (range: 40-125 days). For dogs treated in the rescue setting epirubicin specific ORR was 19% and BRR 63%. Median TTP in the 9 of these 16 dogs in which it was assessable was 62 days (range: 40-125 days). Median survival time for all dogs treated with both epirubicin and lomustine was 185 days (range: 27-500 days). Some dogs with HS respond to epirubicin and dogs treated with combinations of epirubicin and lomustine have modestly improved survival times compared with single agent studies, and similar to dogs with HS treated with alternating lomustine and doxorubicin. Single agent epirubicin is also a valid short term rescue therapy for canine HS. PMID- 28621003 TI - Effect of periodontal therapy with systemic antimicrobials on parameters of metabolic syndrome: A randomized clinical trial. AB - AIM: To investigate the effect of basic periodontal therapy (BPT) with antimicrobials (AM) on the parameters of metabolic syndrome (MetS) (waist circumference, systolic/diastolic blood pressure [BP], HDL-cholesterol, triglycerides, glucose). METHODS: One hundred and ten periodontitis patients without known comorbidities and unaware of possible MetS were randomly assigned to BPT (n = 56) or BPT+AM (n = 54) and followed for 12 months post-therapy. Number of patients with undiagnosed MetS was also determined. RESULTS: In all patients, the periodontal condition improved; however, the BTP+AM group showed greater pocket depth reduction than the BPT group. Post-therapy, systolic BP (p < .05) and triglycerides (p < .05) reduced significantly during the follow-up period. No significant differences could be assessed between the BPT+AM and BPT group. Despite the absence of self-reported comorbidities, 27.2% (n = 30) periodontitis patients fulfilled the criteria of MetS at baseline. After therapy, this proportion changed to 14.5% at 3 months (p = .007), to 17.3% at 6 months (p = .017) and to 21.8% at 12-month follow-up (p = .383). CONCLUSION: Although a reduction in systolic BP and triglycerides and a temporarily improvement in the whole metabolic status were observed, the use of antimicrobials in conjunction with BTP does not yield any additional improvement in the parameters of MetS. PMID- 28621005 TI - Follow-up reply to Dr Paul Lawton's "A response to an expanded nationwide view of chronic kidney disease in Aboriginal Australians, Nephrology, 21 (2016), 916 922". PMID- 28621006 TI - Mesangial proliferative glomerulonephritis: A glomerular disease or a non specific morphological change? PMID- 28621007 TI - Effectiveness of a fixed combination formula of ombitasvir/paritaprevir/ritonavir for hepatitis C virus infection in patients on maintenance haemodialysis. AB - A fixed-dose formula that combines Ombitasvir (OBV), Paritaprevir (PTV) and Ritonavir (RTV) has been launched into the field of anti-HCV therapy in Japan for patients infected with HCV genotypes 1 and 2 in 2015. However, little is yet known as to the efficacy and safety of this novel therapy in patients on maintenance haemodialysis (HD). The present report describes a preliminary experience in 10 patients (five males and five females) who underwent maintenance HD. All of them had HCV genotype 1b, without having the resistance-associated variants at Y93 or L31 in the nonstructural proteins 5A (NS5A) region. After the treatment, eight patients successfully achieved virus eradication and sustained a virological response at 12 weeks (SVR12). In addition, mac-2 binding protein glycosylation isomer (M2BPGi), a biomarker for liver fibrosis, was reduced after the therapy. Two patients withdrew from the therapy due to the development of erythema multiforme and a strong drowsiness, respectively. These results suggest that triple therapy combining OBV, PTV and RTV is effective in achieving SVR12 in most of the HCV-infected patients on HD. In addition, this combination therapy contributed to retard the progression of liver fibrosis. However, we suggest that further trial will be required to establish its clinical efficacy and safety. PMID- 28621008 TI - Hypercalcaemia-induced acute kidney injury in an older patient with osteoporosis treated with alfacalcidol for denosumab-induced hypocalcaemia. PMID- 28621009 TI - Acute thyroiditis: An under-recognized complication of parathyroidectomy in end stage renal failure patients with secondary hyperparathyroidism. PMID- 28621011 TI - Yoga for the management of pain and sleep in rheumatoid arthritis: a pilot randomized controlled trial. AB - OBJECTIVE: The aim of the present study was to determine the feasibility of a relaxation-based yoga intervention for rheumatoid arthritis, designed and reported in accordance with Delphi recommendations for yoga interventions for musculoskeletal conditions. METHODS: Participants were recruited from a hospital database, and randomized to either eight weekly 75-min yoga classes or a usual care control. Feasibility was determined by recruitment rates, retention, protocol adherence, participant satisfaction and adverse events. Secondary physical and psychosocial outcomes were assessed using self-reported questionnaires at baseline (week 0), week 9 (primary time point) and week 12 (follow-up). RESULTS: Over a 3-month period, 26 participants with mild pain, mild to moderate functional disability and moderate disease activity were recruited into the study (25% recruitment rate). Retention rates were 100% for yoga participants and 92% for usual care participants at both weeks 9 and 12. Protocol adherence and participant satisfaction were high. Yoga participants attended a median of seven classes; additionally, seven of the yoga participants (54%) reported continuing yoga at home during the follow-up period. No serious adverse events were related to the study. Secondary outcomes showed no group effects of yoga compared with usual care. CONCLUSIONS: A relaxation-based yoga programme was found to be feasible and safe for participants with rheumatoid arthritis-related pain and functional disability. Adverse events were minor, and not unexpected from an intervention including physical components. This pilot provides a framework for larger intervention studies, and supports further exploration of yoga as a complex intervention to assist with the management of rheumatoid arthritis. PMID- 28621010 TI - Diversity of renal phenotypes in patients with WDR19 mutations: Two case reports. AB - WDR19 has been reported as a causative gene of nephronophthisis-related ciliopathies. Patients with WDR19 mutations can show various extrarenal manifestations such as skeletal disorders, Caroli disease, and retinal dystrophy, and typically display nephronophthisis as a renal phenotype. However, there is limited information on the renal phenotypes of patients with WDR19 mutations. We report two Japanese infants with Sensenbrenner syndrome caused by WDR19 mutations who demonstrated different features in renal ultrasound and histopathological results, despite several common extrarenal manifestations. Patient 1 had normal sized and hyperechogenic kidneys with several small cysts and histopathological findings compatible with infantile nephronophthisis. Renal ultrasound of Patient 2 showed enlarged kidneys with diffuse microcysts resembling those of autosomal recessive polycystic kidney disease. Her renal histopathology revealed dysplastic kidney with diffuse glomerular cysts. Genetic testing identified compound heterozygous mutations in WDR19 in both patients (Patient 1: c.953delA, c.3533G > A, Patient 2: c.2645 + 1G > T, c.3533G > A). Our patients suggest that WDR19 mutations can cause dysplastic kidney in addition to nephronophthisis pathologically. In addition, differences in pathology of the kidneys from WDR19 mutations may result in heterogeneous features in renal ultrasound findings. Renal phenotypes from WDR19 mutations may thus be more diverse than previously reported. Extrarenal manifestations and genetic testing can therefore help to diagnosis this disease more precisely. PMID- 28621012 TI - Supporting people with aphasia to 'settle into a new way to be': speech and language therapists' views on providing psychosocial support. AB - BACKGROUND: People with aphasia are at risk of becoming depressed and isolated. Online surveys have found that the majority of speech and language therapists (SLTs) lack confidence in addressing the psychological needs of people with aphasia. AIMS: To explore how SLTs conceptualize the scope of their role; barriers and facilitators to SLTs addressing psychosocial needs; and SLTs' experiences of specialist training and support, and working with mental health professionals (MHPs). METHODS & PROCEDURES: Focus groups were conducted in stroke healthcare settings. Purposive sampling was used when selecting sites so as to capture a range of experiences. Results were analysed using framework analysis. OUTCOMES & RESULTS: Twenty-three SLTs took part in six focus groups. Participants' psychosocial work included counselling-type interactions, psycho education, working with families, facilitating peer support and training other healthcare professionals. There was lack of consensus on the scope of the SLT role. Many expressed a sense of conflict, both perceiving it as valuable to spend time addressing psychological well-being, while simultaneously feeling uneasy if they deviated from 'direct SLT' work. Barriers to addressing psychosocial well being were: emotionally challenging nature of this work, particularly for those who felt unsupported; caseload and time pressures; attitudes of senior managers and commissioners; difficulties measuring and documenting more 'fluid' psychosocial work; and the complexity of the needs and backgrounds of some patients. Enabling factors were: specialist ongoing support; peer support from colleagues; experience; support of management; and personal belief. Specialist training was valued. It changed how participants viewed the therapist-client relationship (more client led); the assessment and goal-setting process; and gave them more confidence to acknowledge client emotions. However, many felt that there was a need for ongoing specialist advice, and to be able to see approaches modelled for this client group. In terms of MHPs, a subset of stroke-specialist clinical psychologists worked directly with people with marked aphasia and families, as well as supporting the multidisciplinary team to provide holistic care. However, a main theme was that participants perceived many MHPs did not consider people with aphasia as 'appropriate candidates' for psychological input. CONCLUSIONS & IMPLICATIONS: All participants cared about the emotional well-being of their clients; however, they identified a number of barriers to people with aphasia receiving appropriate psychological support. A cultural shift, whereby psychological care for people with aphasia is seen as valuable, feasible and necessary, delivered collaboratively by SLTs, MHPs and the wider team, may improve services. PMID- 28621013 TI - Daily Events for Clinical Couples: Examining Therapy Interventions, Positive Events, Arguments, and Exercise in the Beginning Stage of Therapy. AB - This study examined the daily association of several events within the beginning phase of couple therapy. Events examined were as follows: trying something from therapy, an argument, a positive event, and physical exercise. Participants were 33 couples in a treatment-as-usual setting who completed the Daily Diary of Events in Couple Therapy (DDECT). A dyadic multilevel model was used to explore the daily associations between predictor and outcome variables. Results showed when male partners tried something from therapy at rates greater than the average their female partners reported a more positive relationship while when female partners tried something from therapy at rates greater than the average it contributed to a more negative relationship. In addition, results showed that clients in couple therapy rarely try things from therapy on a daily basis. Finally, relative to other predictors trying something from therapy had a smaller, but significant relationship with outcomes. PMID- 28621014 TI - Cell-specific alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonism reveals new insights in the development of parkinson's disease. PMID- 28621015 TI - Perturbation-based balance training for falls reduction among older adults: Current evidence and implications for clinical practice. AB - Falls are a leading cause of injury, hospitalization and even death among older adults. Although various strength and balance exercise interventions have shown moderate reductions in falls incidence among healthy older adults, no significant falls incidence improvements have been consistently seen in frail older adults or in patient groups with an increased falls risk (e.g. people with Parkinson's disease and stroke). This might be due to a lack of task specificity of previous exercise interventions to the recovery actions required to prevent a fall. Perturbation-based balance training (PBT) is an emerging task-specific intervention that aims to improve reactive balance control after destabilizing perturbations in a safe and controlled environment. Although early studies were carried out predominantly in research laboratory settings, work in clinical settings with various patient groups has been proliferating. A systematic search of recent PBT studies showed a significant reduction of falls incidence among healthy older adults and certain patient groups (e.g. people with Parkinson's disease and stroke), with clinically relevant reductions in frail older adults. The most practical methods in clinical settings might be treadmill-based systems and therapist-applied perturbations, and PBT that incorporates multiple perturbation types and directions might be of most benefit. Although more controlled studies with long-term follow-up periods are required to better elucidate the effects of PBT on falls incidence, PBT appears to be a feasible and effective approach to falls reduction among older adults in clinical settings. Geriatr Gerontol Int 2017; 17: 2294-2303.. PMID- 28621016 TI - Acute effects of phenylbutyrate on glutamine, branched-chain amino acid and protein metabolism in skeletal muscles of rats. AB - Phenylbutyrate (PB) acts as chemical chaperone and histone deacetylase inhibitor, which is used to decrease ammonia in urea cycle disorders and has been investigated for use in the treatment of a number of lethal illnesses. We performed in vivo and in vitro experiments to examine the effects of PB on glutamine (GLN), branched-chain amino acid (BCAA; valine, leucine and isoleucine) and protein metabolism in rats. In the first study, animals were sacrificed one hour after three injections of PB (300mg/kg b.w.) or saline. In the second study, soleus (SOL, slow twitch) and extensor digitorum longus (EDL, fast twitch) muscles were incubated in a medium with or without PB (5 mM). L-[1-14 C] leucine was used to estimate protein synthesis and leucine oxidation, and 3 methylhistidine release was used to evaluate myofibrillar protein breakdown. PB treatment decreased GLN, BCAA and branched-chain keto acids (BCKAs) in blood plasma, decreased BCAA and increased GLN concentrations in muscles, and increased GLN synthetase activities in muscles. Addition of PB to incubation medium increased leucine oxidation (55% in EDL, 29% in SOL), decreased BCKA and increased GLN in medium of both muscles, increased GLN in muscles, decreased protein synthesis in SOL and increased proteolysis in EDL. It is concluded that PB decreases BCAA, BCKA and GLN in blood plasma, activates BCAA catabolism and GLN synthesis in muscle and exerts adverse effects on protein metabolism. The results indicate that BCAA and GLN supplementation is needed when PB is used therapeutically and that PB may be a useful prospective agent which could be effective in management of maple syrup urine disease. PMID- 28621017 TI - Overview of systematic reviews: Effective home support in dementia care, components and impacts-Stage 1, psychosocial interventions for dementia. AB - AIM: To synthesize evidence to identify the components of effective psychosocial interventions in dementia care to inform clinical practice, policy and research. BACKGROUND: With population ageing, dementia represents a significant care challenge with 60% of people with dementia living at home. DESIGN: Overview of systematic reviews with narrative summary. DATA SOURCES: Electronic searches of published systematic reviews in English using Cochrane Database of Systematic Reviews, DARE and EPPI-Centre, between September 2013 - April 2014. REVIEW METHODS: Systematic reviews were appraised against Cochrane Collaboration levels of effectiveness. Components of psychosocial interventions were identified with their theoretical rationale. Findings were explored with a Patient, Public and Carer Involvement group. RESULTS: Thirty-six systematic reviews were included. From interventions, 14 components were identified, nine for people with dementia and five for carers, mostly undertaken in nursing/care homes. For people with dementia, there was evidence of effectiveness for cognitive stimulation and cognitive training, but less evidence for sensory stimulation, reminiscence, staff education, behavioural therapy and ADL training. For carers, there was evidence of effectiveness for education and training, psychotherapy and counselling. CONCLUSION: There was a lack of definitive evidence of effectiveness for most psychosocial interventions. Further studies with stronger methodology or replication of existing studies would strengthen the evidence base. Few interventions were undertaken with people with dementia and their carers living at home. Further work will investigate the extent to which components identified here are present in models of home support for people with dementia and carers and their effectiveness. PMID- 28621018 TI - Sleep structure in blindness is influenced by circadian desynchrony. AB - We examined the structure, duration and quality of sleep, including non-rapid eye movement sleep and rapid eye movement sleep, in 11 blind individuals without conscious light perception and 11 age- and sex-matched sighted controls. Because blindness is associated with a greater incidence of free-running circadian rhythms, we controlled for circadian phase by a measure of melatonin onset timing. When circadian rhythm was entrained and melatonin onset occurred at normal times, sleep structure did not differ between blind and sighted individuals. On the other hand, an abnormal timing of the circadian phase, including delayed, shifted and unclassifiable melatonin onsets, led to larger rapid eye movement sleep latencies and increased wake times. No differences were observed for stages of non-rapid eye movement sleep, either between congenital and late blind and sighted individuals, or across the different circadian phases. Moreover, abnormal circadian phases were more common in the blind (n = 5) than the sighted (n = 2) sample. Our findings suggest that the sleep structure of blind individuals depends on entrainment of circadian phase, rather than on the absence of vision. PMID- 28621019 TI - One minute sit-to-stand test is an alternative to 6MWT to measure functional exercise performance in COPD patients. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is frequently associated with a reduced functional exercise performance. Even if this parameter is routinely evaluated using 6-minute walking test (6MWT), new field tests are regularly investigated as alternative tests. The aim of this study was to compare functional exercise performance evaluation by sit-to-stand test (STST) and 6MWT and to evaluate reliability and repeatability of the STST in COPD patients. METHOD: Forty-two COPD patients performed randomly two tests: 6MWT and STST. Each test was repeated two times. Distance (6MWD) and number of repetitions were measured. Cardiorespiratory parameters, dyspnea and lower limb fatigue (Borg) were recorded before and after the tests. RESULTS: Sit-to-stand repetitions (19 +/- 6) and 6MWD (441 +/- 104 m) were correlated (r = .716; P < .001). Good repeatability was found for STST and 6MWT. Good reliability was observed for STST (ICC = 0.902). Variations of heart rate and pulsed oxygen saturation were significantly different between these two tests (23% +/- 17% vs 13% +/- 11%; P = .022 and -7.6% +/- 4.6% vs -0.7% +/- 2.7%; P < .001 for 6MWT and STST, respectively). Variations of dyspnea and lower limb fatigue were similar between both tests (P = .827 and P = .467). CONCLUSION: The one minute sit-to-stand test is a valuable alternative to 6MWT to estimate functional exercise performance in COPD patients. The cardiorespiratory demand is different between both tests although the variation of dypsnea is similar. No learning effect was observed for STST. PMID- 28621020 TI - Conservation of alternative splicing in sodium channels reveals evolutionary focus on release from inactivation and structural insights into gating. AB - KEY POINTS: Sodium channels are critical for supporting fast action potentials in neurons; even mutations which cause small changes in sodium channel activity can have devastating consequences for the function of the nervous system. Alternative splicing also changes the activity of sodium channels, and while it is highly conserved, it is not known whether the functional role of this splicing is also conserved. Our data reveal that splicing has a highly conserved impact on the availability of sodium channels during trains of rapid stimulations, and suggest that in one mammalian channel, Nav1.1 encoded by SCN1A, the increased availability of one splice variant is detrimental. A model reproducing the effects of splicing on channel behaviour suggests that the voltage sensor in the first domain is a rate limiting step for release of the inactivation domain, and highlights the functional specialization of channel domains. ABSTRACT: Voltage gated sodium channels are critical for neuronal activity, and highly intolerant to variation. Even mutations that cause subtle changes in the activity these channels are sufficient to cause devastating inherited neurological diseases, such as epilepsy and pain. However, these channels do vary in healthy tissue. Alternative splicing modifies sodium channels, but the functional relevance and adaptive significance of this splicing remain poorly understood. Here we use a conserved alternate exon encoding part of the first domain of sodium channels to compare how splicing modifies different channels, and to ask whether the functional consequences of this splicing have been preserved in different genes. Although the splicing event is highly conserved, one splice variant has been selectively removed from Nav1.1 in multiple mammalian species, suggesting that the functional variation in Nav1.1 is less well tolerated. We show for three human channels (Nav1.1, Nav1.2 and Nav1.7) that splicing modifies the return from inactivated to deactivated states, and the differences between splice variants are occluded by antiepileptic drugs that bind to and stabilize inactivated states. A model based on structural data can replicate these changes, and indicates that splicing may exploit a distinct role of the first domain to change channel availability, and that the first domain of all three sodium channels plays a role in determining the rate at which the inactivation domain dissociates. Taken together, our data suggest that the stability of inactivated states is under tight evolutionary control, but that in Nav1.1 faster recovery from inactivation is associated with negative selection in mammals. PMID- 28621021 TI - Three-Dimensional Binder-Free Nanoarchitectures for Advanced Pseudocapacitors. AB - The ever-increasing energy demands for electrification of transportation and powering of portable electronics are driving the pursuit of energy-storage technologies beyond the current horizon. Pseudocapacitors have emerged as one of the favored contenders to fill in this technology gap, owing to their potential to deliver both high power and energy densities. The high specific capacitance of pseudocapacitive materials is rooted in the various available oxidation states for fast surface or near-surface redox charge transfer. However, the practical implementation of pseudocapacitors is plagued by the insulating nature of most pseudocapacitive materials. The wealth of the research dedicated to addressing these critical issues has grown exponentially in the past decade. Here, we briefly survey the current progress in the development of pseudocapacitive electrodes with a focus on the discussion of the recent most exciting advances in the design of three-dimensional binder-free nanoarchitectures, including porous metal/graphene-based electrodes, as well as metal-atom/ion-doping-enhanced systems, for advanced supercapacitors with comparable energy density to batteries, and high power density. PMID- 28621022 TI - Electrothermal Control of Graphene Plasmon-Phonon Polaritons. AB - Graphene plasmons are known to offer an unprecedented level of confinement and enhancement of electromagnetic field. They are hence amenable to interacting strongly with various other excitations (for example, phonons) in their surroundings and are an ideal platform to study the properties of hybrid optical modes. Conversely, the thermally induced motion of particles and quasiparticles can in turn interact with electronic degrees of freedom in graphene, including the collective plasmon modes via the Coulomb interaction, which opens up new pathways to manipulate and control the behavior of these modes. This study demonstrates tunable electrothermal control of coupling between graphene mid infrared (mid-IR) plasmons and IR active optical phonons in silicon nitride. This study utilizes graphene nanoribbons functioning as both localized plasmonic resonators and local Joule heaters upon application of an external bias. In the latter role, they achieve up to ~100 K of temperature variation within the device area. This study observes increased modal splitting of two plasmon-phonon polariton hybrid modes with temperature, which is a manifestation of increased plasmon-phonon coupling strength. Additionally, this study also reports on the existence of a thermally excited hybrid plasmon-phonon mode. This work can open the door for future optoelectronic devices such as electrically switchable graphene mid-infrared plasmon sources. PMID- 28621023 TI - Pediatric liver transplantation for fulminant hepatic failure secondary to intentional iron overdose. AB - Acute iron poisoning may lead to life-threatening hepatotoxicity. We present the cases of two pediatric patients with hepatotoxicity following intentional iron ingestion that progressed rapidly to fulminant hepatic failure despite treatment with deferoxamine. Liver transplantation was lifesaving in both patients. These cases emphasize the need for a high index of suspicion for iron ingestion, close monitoring for liver toxicity, and timely consideration for liver transplantation. PMID- 28621024 TI - The validity of nasal endoscopy in patients with chronic rhinosinusitis-An inter rater agreement study. AB - OBJECTIVES: Nasal endoscopy is a cornerstone in diagnosing sinonasal disease, but different raters might generate different results using the technique. Our study aims to evaluate the agreement between multiple raters to assess the validity of nasal endoscopy. DESIGN/PARTICIPANTS: Three independent and blinded raters evaluated 28 patients (56 nasal cavities) diagnosed with chronic rhinosinusitis according to the European Position Paper on Rhinosinusitis and Nasal Polyps. The ratings were compared using unweighted Fleiss' kappa coefficients (Kf ) for each objective parameter. SETTING: The department of Otorhinolaryngology, Odense University Hospital, Denmark. MAIN OUTCOME MEASURES: The ratings were quantified in a modified Lund-Kennedy endoscopy score and focused on the objective parameters specified in the diagnostic criteria: polyps, oedema and discharge. RESULTS: The raters agreed on the findings concerning polyps and discharge but not regarding oedema with the inter-rater agreement for the different parameters being: polyps Kf =.66 (SE .07, P<.001), oedema Kf =.05 (SE .07, P=.21), discharge Kf =.35 (SE .08, P<.001), oedema exclusively in middle meatus Kf =-.07 (SE .04, P=.8) and discharge exclusively in middle meatus Kf =.16 (SE .07, P=.01). CONCLUSION: Using nasal endoscopy, the evaluation of polyps by multiple raters showed sufficient reliability indicating an acceptable objective evaluation. The evaluation of discharge achieved a fair level of agreement while the assessment of oedema could not achieve a sufficient reliability questioning the inclusion of oedema in the criteria for diagnosing sinonasal disease. PMID- 28621025 TI - Dorsal Root Ganglion Stimulation as a Salvage Treatment for Complex Regional Pain Syndrome Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series. AB - OBJECTIVE: The efficacy of traditional spinal cord stimulation (t-SCS) tends to decay over time in patients with complex regional pain syndrome (CRPS). While it has been shown that dorsal root ganglion (DRG) stimulation is extremely effective in t-SCS-naive patients with CRPS, its efficacy in patients who had previously failed t-SCS is unknown. Given that DRG-SCS and t-SCS target different spinal pathways, a failure with t-SCS should not automatically preclude a patient from attempting DRG-SCS. MATERIALS AND METHODS: Two patients with lower extremity CRPS, previously implanted with t-SCS systems, experienced relapses in the pain despite exhaustive reprogramming. Both patients were offered DRG stimulation as a means to salvage treatment. RESULTS: Patient 1 reported 90% pain reduction with significant gait improvement during the DRG stimulation trial. The patient subsequently proceeded to implant and have the t-SCS implantable pulse generator explanted. Patient 2 was unable to undergo a trial with DRG-SCS because of health insurance constraints, so she elected to undergo a surgical revision of her existing system whereby a DRG-SCS system was added to the existing t-SCS to create a hybrid system with two implantable pulse generators. The patient reported an immediate improvement in pain because of the introduction of the DRG SCS. Additionally, she was instructed to document her pain scores with each system on individually, as well as with both on-her pain scores were at the lowest with the DRG-SCS on by itself. At eight-month follow-up, both patients reported sustained pain improvement and retained their functional gains. CONCLUSIONS: Our case series demonstrates that a failure of t-SCS is not necessarily a failure of neurostimulation as a whole. The efficacy of DRG-SCS is independent of prior t-SCS therapy outcomes in these two patients and a history of t-SCS failure serves no predictive value in these two patients for future DRG stimulation success. Therefore, DRG-SCS can be considered as a reasonable next step to salvage patients with CRPS who had failed other SCS treatments. PMID- 28621026 TI - Low-Density Open Cellular Sponges as Functional Materials. AB - Low-density macroporous sponges with densities less than 100 mg cm-3 are both a challenge and an opportunity for advanced chemistry and material science. The challenge lies in the precise preparation of the sponges with property combinations that lead to novel applications. Bottom-up and top-down chemical and engineering methods for the preparation of sponges are a major focus of this Review, with an emphasis on carbon and polymer materials. The light weight, sustainability, breathability, special wetting characteristics, large mass transfer, mechanical stability, and large pore volume are typical characteristics of sponges made of advanced materials and could lead to novel applications. Some selected sponge properties and potential applications are discussed. PMID- 28621028 TI - Climate change and temperature-linked hatchling mortality at a globally important sea turtle nesting site. AB - The study of temperature-dependent sex determination (TSD) in vertebrates has attracted major scientific interest. Recently, concerns for species with TSD in a warming world have increased because imbalanced sex ratios could potentially threaten population viability. In contrast, relatively little attention has been given to the direct effects of increased temperatures on successful embryonic development. Using 6603 days of sand temperature data recorded across 6 years at a globally important loggerhead sea turtle rookery-the Cape Verde Islands-we show the effects of warming incubation temperatures on the survival of hatchlings in nests. Incorporating published data (n = 110 data points for three species across 12 sites globally), we show the generality of relationships between hatchling mortality and incubation temperature and hence the broad applicability of our findings to sea turtles in general. We use a mechanistic approach supplemented by empirical data to consider the linked effects of warming temperatures on hatchling output and on sex ratios for these species that exhibit TSD. Our results show that higher temperatures increase the natural growth rate of the population as more females are produced. As a result, we project that numbers of nests at this globally important site will increase by approximately 30% by the year 2100. However, as incubation temperatures near lethal levels, the natural growth rate of the population decreases and the long-term survival of this turtle population is threatened. Our results highlight concerns for species with TSD in a warming world and underline the need for research to extend from a focus on temperature-dependent sex determination to a focus on temperature-linked hatchling mortalities. PMID- 28621027 TI - Aromatic amino acids and their relevance in the specificity of the PH domain. AB - Phosphoinositides are phosphatidylinositol derived, well known to be second messengers in various cell signaling pathways as well as in processes such as cell differentiation, cellular stress response, gene transcription, and chromatin remodeling. The pleckstrin homology domain of phospholipase C-delta 1 is responsible for recognizing and binding to PI(4,5)P2 and for this reason has been widely used to study this phosphoinositide as a biosensor when it is conjugated to a fluorescent tag. In this work, we modified the primary structure of pleckstrin homology domain by site-specific mutagenesis to change the specificity for phosphoinositides. We obtained 3 mutants: K30A, W36F, and W36Y with different specificity to phosphoinositides. Mutant domain K30A recognized PI(4,5)P2 , PI(3,4,5)P3 , phosphatidic acid (PA), and weakly PI(3,5)P2 . Mutant domain W36F recognized all the phosphoinositides studied and the PA. Finally, mutant domain W36Y seemed to interact with PA and all the other phosphoinositides studied, except PI(3)P. The changes in recognition argue against a simple charge and nonpolar region model for these interactions and more in favor of a specific docking region with a specific recognition site. We conducted in silico modeling that explains the mechanisms behind the observed changes and showed that aromatic amino acids appear to play more important role, than previously thought, in the specificity of phospholipids' binding domains. PMID- 28621029 TI - Urinary tract infection in patients with hip fracture: An underestimated event? AB - AIM: Urinary tract infections (UTI) represent a common perioperative complication among elderly patients with hip fracture. To determine the impact of UTI on the perioperative course of elderly patients with hip fractures, a prospective study was carried out. METHODS: A total of 402 surgically-treated geriatric hip fracture patients were consecutively enrolled at a level 1 trauma center. On admission, all patients received an indwelling urinary catheter. Clinically symptomatic patients were screened more closely for UTI. Patients diagnosed with UTI were compared with asymptomatic patients. Outcomes in both patient groups were measured using in-hospital mortality, overall length of hospital stay, wound infection, functional results and mobility at discharge. Multivariate regression analysis was carried out to control for influencing factors. RESULTS: A total of 97 patients (24%) sustained a UTI during in-hospital treatment. UTI were independently associated with inferior functional outcomes as assessed by the Barthel Index (beta = -0.091; P = 0.031), Timed Up and Go test (beta = 0.364; P = 0.001) and Tinetti test (beta = -0.169; P = 0.001) at discharge. Additionally, length of hospital stay was significantly longer for patients with a UTI diagnosis (beta = 0.123; P = 0.029) after controlling for all other variables. No differences were observed in the rate of wound infection (odds ratio 1.185; P = 0.898) or in-hospital mortality (P < 0.997). CONCLUSIONS: Patients with UTI seem to be at risk of inferior functional outcomes. In addition to an early detection of symptomatic UTI and a targeted antibiotic therapy, perioperative care should focus on preserving functional ability to protect these patients from further loss of independence and prolonged clinical courses. Geriatr Gerontol Int 2017; 17: 2369-2376. PMID- 28621030 TI - Plugging the patient evidence gap: what patients with swallowing disorders post stroke say about thickened liquids. AB - BACKGROUND: Oropharyngeal dysphagia post-stroke is well known, with its presence increasing the risk of poor outcomes in particular aspiration and aspiration pneumonia. Management to minimize the risk of aspiration and improve swallow safety post-stroke includes the treatment of thickened liquids (TL), an established bolus modification intervention. Despite widespread use, there is a lack of robust empirical evidence and minimal patient evidence as to the experience and acceptability of using thickeners by people who experience dysphagia after a stroke. AIMS: To explore people with swallowing disorders post stroke experiences of and acceptability regarding the bolus modification treatment of thickened liquids. METHODS & PROCEDURES: A qualitative, descriptive study exploring the experiences of individuals given TL after their stroke. A purposive sample of 14 adults was obtained with data collection and generation through the medium of individual semi-structured interviews. Inductive thematic analysis was used to analyse the data. OUTCOMES & RESULTS: Three overarching themes of 'uncertainty', 'an unpleasant experience' and 'a trade-off' were identified. These themes highlight that participants disliked TL and this dislike may have impacted clinically in terms of adherence, hydration and quality of life. Lack of sensory appeal was important in framing patient dislike. Participants' involvement in and understanding of reasons for prescription of TL was poor leading to uncertainty regarding the treatment. Notwithstanding, some participants felt it was necessary for their stroke recovery. CONCLUSIONS & IMPLICATIONS: TL can be considered a burdensome treatment from multiple perspectives including product palatability, treatment uncertainty and treatment adherence issues. Despite intensely disliking this treatment, some patients ultimately understand why the treatment is prescribed. Improvements in product palatability are required in order to improve adherence and patient quality of life. Consideration of other treatment options and newer products to manage aspiration post-stroke is also warranted. PMID- 28621031 TI - Article submission is the true obstacle of publishing. PMID- 28621032 TI - Applied genetic toxicology: From principles to practice. PMID- 28621033 TI - Dicephalic Parapagus Conjoined Twins in a Large Fruit-eating Bat, Genus Artibeus (Chiroptera, Phyllostomidae). AB - Conjoined twinning is an embryological anomaly rarely reported in wild mammals and with only two previous records in Chiroptera. Here, we report a case of dicephalic parapagus conjoined twins in the Neotropical phyllostomid genus Artibeus. These twins are males and present separated heads and necks, but a conjoined trunk with an expanded upper thoracic region. They developed two complete forelimbs and two complete hindlimbs, all laterally to the trunk. There is a volume in the upper midback and between the heads that resembles a third rudimentary medial forelimb, but X-ray images only suggest the presence of medial skeletal elements of the pectoral girdle (clavicle and scapulae) in this region. The X-ray images also show that vertebral columns run separated from head until the base of lumbar region, where they form a single structure. Using ultrasound images, we detected the presence of two similarly sized and apparently separated hearts. The accumulation of study cases like this will help in the understanding of patterns and process behind this phenomena, and collection material plays a key role in this context. PMID- 28621034 TI - Depletion of FoxP3+ Tregs improves control of larval Echinococcus multilocularis infection by promoting co-stimulation and Th1/17 immunity. AB - INTRODUCTION: The growth potential of the tumor-like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE) is directly linked to the nature/function of the periparasitic host immune-mediated processes. Previous studies had shown that regulatory T cells (Tregs) become gradually up-regulated in the course of both chronic human and murine AE. Thus we now tackled the role of FoxP3+ Tregs and FoxP3+ -Treg-regulated immune response in contributing to the control of this helminthic infection. METHODS: The infection outcome in E. multilocularis-infected DEREG mice was measured upon determining parasite load (wet weight of parasitic metacestode tissue). Flow cytometry and qRT-PCR were used to assess Treg, Th17-, Th1-, Th2-type immune responses and antigen presenting cell activation. RESULTS: We showed that E. multilocularis-infected DEREG-mice treated with DT (as compared to infected control DEREG-mice without DT application) exhibited a significantly lower parasite load, associated with a persisting capacity of co-stimulation, and an increased Th1/Th17-polarization. CONCLUSIONS: FoxP3+ Tregs appear as one of the key players in immune regulatory processes favoring (i) metacestode survival by inhibiting the maturation potential of co-stimulatory activity and (ii) T cell exhaustion (suppressing Th1/Th17-type immune responses). We showed as well that prospectively, targeting FoxP3+ Tregs could be an option to develop an immunotherapy against AE. PMID- 28621035 TI - Cyberchondria: Examining relations with problematic Internet use and metacognitive beliefs. AB - Cyberchondria refers to the repeated use of the Internet to search for health related information, which leads to negative consequences. This two-part study provides the first known examination of how cyberchondria relates to (a) problematic Internet use and (b) metacognitive beliefs. Participants were U.S. community adults who reported using the Internet to search for health-related information (Study 1: N = 337, Study 2: N = 260). In Study 1, cyberchondria shared a strong association with problematic Internet use, and that association was unaccounted for by age, gender, current reported medical status, negative affect, or health anxiety. In Study 2, cyberchondria was found to share moderate to strong associations with metacognitive beliefs. The association between cyberchondria and metacognitive beliefs about the uncontrollability of thoughts remained intact after accounting for the Study 1 covariates, as well as anxiety sensitivity and intolerance of uncertainty. Neither anxiety sensitivity nor intolerance of uncertainty shared unique associations with cyberchondria. These results provide a preliminary indication that a metacognitive conceptualization of problematic Internet use may be applicable to cyberchondria. PMID- 28621036 TI - Coupling of Magnetic and Elastic Domains in the Organic-Inorganic Layered Perovskite-Like (C6 H5 C2 H4 NH3 )2 FeII Cl4 Crystal. AB - Multiferroic materials coupling ferroelasticity and ferromagnetism show strong magnetoelastic effects as magnetization is induced by mechanical stress or alternately strain induced by applying a magnetic field. These effects were reported for inorganic multiferroics such as LaCox Sr1-x O3 . (C6 H5 C2 H4 NH3 )2 FeII Cl4 is the first example of an organic-inorganic perovskite to exhibit such effects below the canted antiferromagnetism at TC =98 K and ferroelasticity at TC =433 K. This is shown by switching the magnetic hysteresis on and off by uniaxial pressure through the strong coupling of the magnetic and elastic domains. The spin-canting direction was controlled by mechanical stress in the heating and cooling cycles. This unique observation gives additional impetus in the search for coupled hysteretic effect in organic-inorganic multiferroics. PMID- 28621037 TI - Gingival morphology-controlled design of the complete denture baseplate. AB - A removable complete denture is still the main selection for edentulous patients. Over the last 5 years, digital technologies for producing complete dentures have rapidly developed. Nevertheless, the design method for the baseplate has become the bottleneck of digital complete denture technology development. In this study, we report a novel method for the generation of esthetic gingiva and polished surfaces of complete dentures that are driven by the feature curve, which can be conveniently modified using the gingival shape factor. A solid modeling method based on Poisson surface reconstruction is used to generate a high-quality baseplate solid. This method can aid dentists to realize the rapid design process of personalized esthetic baseplate. Finally, the experimental results verify that the method of digital design for the baseplate proposed is efficient and accurate (standard deviation <0.01 mm). PMID- 28621038 TI - Aqueous vascular endothelial growth factor and aflibercept concentrations after bimonthly intravitreal injections of aflibercept for age-related macular degeneration. AB - IMPORTANCE: Clinical evidence supports the efficacy of bimonthly aflibercept injection for age-related macular degeneration. BACKGROUND: The study aimed to evaluate aqueous vascular endothelial growth factor and aflibercept concentrations and the efficacy of bimonthly aflibercept in patients with age related macular degeneration. DESIGN: This study is a prospective, interventional case series. PARTICIPANTS: Enrolled were 35 eyes with exudative age-related macular degeneration from 35 patients. METHODS: Patients received three bimonthly intravitreal aflibercept without loading doses. We collected the aqueous humor just before each injection, measured vascular endothelial growth factor and aflibercept concentrations by enzyme-linked immunosorbent assay and measured best corrected visual acuity and central retinal subfield thickness before and after the injections. MAIN OUTCOME MEASURES: Aqueous vascular endothelial growth factor and aflibercept concentrations were measured. RESULTS: The vascular endothelial growth factor concentration was 135.4 +/- 60.5 pg/mL (mean +/- standard deviation, range 60.6-323.4) at baseline and below the lowest detectable limit in all eyes at month 2 and in 32 eyes at month 4 (P < 0.001 [month 2] and P < 0.001 [month 4]). The mean aflibercept concentration was 20.3 ng/mL at month 2 and 28.0 ng/mL at month 4. The mean logarithm of the minimum angle of resolution visual acuity improved from 0.50 +/- 0.36 at baseline to 0.36 +/- 0.40 at month 6 (P < 0.001). The mean central retinal subfield thickness decreased from 353 +/- 100 MUm at baseline to 236 +/- 45 MUm at month 6 (P < 0.001). CONCLUSIONS AND RELEVANCE: Bimonthly aflibercept injections without loading doses may be considered a treatment option for age-related macular degeneration. PMID- 28621039 TI - wblA, a pleiotropic regulatory gene modulating morphogenesis and daptomycin production in Streptomyces roseosporus. AB - AIMS: The wblA gene, encoding a homologue of the WhiB family protein, was identified in the sequenced genome of daptomycin producer Streptomyces roseosporus. To explore the function of wblA, we construct wblA disruption strains, complemented strains and overexpression strains to test whether it can affect the production of secondary metabolites and morphogenesis. METHODS AND RESULTS: We constructed disruption strains by homologous recombination in S. roseosporus. The disruption mutant of wblA could block aerial mycelium sporulation and enhance the production of daptomycin by 51%. In contrast, overexpression of wblA resulted in significantly decreased the yield of daptomycin. In agreement with it, the transcription of key daptomycin regulatory genes atrA, dptR2 and dptR3 and structural gene dptE remarkably increased in the wblA disruption mutant. CONCLUSIONS: wblA plays a key role in control of daptomycin biosynthesis and is essential for sporulation. The disruption of wblA could accumulate the transcription level of some key genes involving in daptomycin biosynthesis. SIGNIFICANCE AND IMPACT OF THE STUDY: Daptomycin is an important antibiotic with potent activity against a variety of Gram-positive pathogens. This study demonstrates that valuable improvement in the yield of daptomycin can be achieved through modulating the expression of wblA transcription regulator. PMID- 28621040 TI - Bioactive Neolignans and Other Compounds from Magnolia grandiflora L.: Isolation and Antiplasmodial Activity. AB - Bioassay-guided fractionation of a methanol extract of Magnolia grandiflora against Plasmodium falciparum yielded two new (1 and 2) and six known (3 - 8) bioactive compounds. The structures of the new compounds were assigned by mass spectrometric and 1D- and 2D-NMR data. Known compounds were identified by comparison of 1 H-NMR and MS data with literature data. The two known neolignans 3 and 4 showed moderate antiplasmodial activity with the IC50 values of 2.8 +/- 0.1 and 3.4 +/- 0.1 MUm, respectively. Weak antiplasmodial activity was recorded for compounds 1, 2, 5, 6, 7, and 8, with the IC50 values of 38 +/- 2, 23 +/- 2, 16.5 +/- 0.2, 86 +/- 1, 44 +/- 4, and 114 +/- 9 MUm, respectively. PMID- 28621042 TI - Clinical evaluation of anomalous aortic origin of a coronary artery (AAOCA). AB - The clinical evaluation of patients with an anomalous aortic origin of a coronary artery (AAOCA), a congenital abnormality of the origin or course of a coronary artery that arises from the aorta, is challenging given its first presentation being sudden cardiac arrest in about half of the patients. Symptoms of chest pain, shortness of breath and syncope during exertion should be of concern in evaluating young athletes and nonathletes. The lack of abnormal signs on the physical exam and electrocardiogram further adds to the difficulty in establishing the diagnosis. Additional imaging with echocardiography, computed tomography angiography and/or cardiac magnetic resonance imaging (MRI) is often needed and establishes the diagnosis. High-risk lesions include origin of the coronary artery from the opposite sinus of Valsalva, intramural course and ostial abnormalities (stenosis, hypoplasia). Functional studies should be performed to assess myocardial perfusion at rest and during stress, such as nuclear imaging, stress echocardiography and stress cardiac MRI. PMID- 28621041 TI - Extraordinarily Stretchable All-Carbon Collaborative Nanoarchitectures for Epidermal Sensors. AB - Multifunctional microelectronic components featuring large stretchability, high sensitivity, high signal-to-noise ratio (SNR), and broad sensing range have attracted a huge surge of interest with the fast developing epidermal electronic systems. Here, the epidermal sensors based on all-carbon collaborative percolation network are demonstrated, which consist 3D graphene foam and carbon nanotubes (CNTs) obtained by two-step chemical vapor deposition processes. The nanoscaled CNT networks largely enhance the stretchability and SNR of the 3D microarchitectural graphene foams, endowing the strain sensor with a gauge factor as high as 35, a wide reliable sensing range up to 85%, and excellent cyclic stability (>5000 cycles). The flexible and reversible strain sensor can be easily mounted on human skin as a wearable electronic device for real-time and high accuracy detecting of electrophysiological stimuli and even for acoustic vibration recognition. The rationally designed all-carbon nanoarchitectures are scalable, low cost, and promising in practical applications requiring extraordinary stretchability and ultrahigh SNRs. PMID- 28621043 TI - Carbon Dioxide Electroreduction into Syngas Boosted by a Partially Delocalized Charge in Molybdenum Sulfide Selenide Alloy Monolayers. AB - Structural parameters of ternary transition-metal dichalcogenide (TMD) alloy usually obey Vegard law well, while interestingly it often exhibits boosted electrocatalytic performances relative to its two pristine binary TMDs. To unveil the underlying reasons, we propose an ideal model of ternary TMDs alloy monolayer. As a prototype, MoSeS alloy monolayers are successfully synthesized, in which X-ray absorption fine structure spectroscopy manifests their shortened Mo-S and lengthened Mo-Se bonds, helping to tailor the d-band electronic structure of Mo atoms. Density functional theory calculations illustrate an increased density of states near their conduction band edge, which ensures faster electron transfer confirmed by their lower work function and smaller charge transfer resistance. Energy calculations show the off-center charge around Mo atoms not only benefits for stabilizing COOH* intermediate confirmed by its most negative formation energy, but also facilitates the rate-limiting CO desorption step verified by CO temperature programmed desorption and electro-stripping tests. As a result, MoSeS alloy monolayers attain the highest 45.2 % Faradaic efficiency for CO production, much larger than that of MoS2 monolayers (16.6 %) and MoSe2 monolayers (30.5 %) at -1.15 V vs. RHE. This work discloses how the partially delocalized charge in ternary TMDs alloys accelerates electrocatalytic performances at atomic level, opening new horizons for manipulating CO2 electroreduction properties. PMID- 28621044 TI - Haemophilus influenzae vulvovaginitis associated with rhinitis caused by the same clone in a prepubertal girl. AB - Vulvovaginitis caused by upper respiratory flora is generally considered to be the most common gynecological problem in prepubertal girls. To date, however, no direct evidence has been obtained for the underlying mechanism of transmission. This report describes a case of non-capsulate Haemophilus influenzae vulvovaginitis in a 6-year-old girl with a history of foreign bodies (cotton wool) in her vagina. Moreover, this girl had recurrent rhinitis for approximately 3 years. On Pulsed Field Gel Electrophoresis (PFGE) analysis the H. influenzae strain isolated from vaginal secretions and the H. influenzae strain isolated from nasal secretions were derived from the same clone. The patient was successfully treated with appropriate antibiotics. The present case might provide the first direct evidence of the nose-hand-vagina method of transmission. PMID- 28621045 TI - Post-partum podocyturia following pre-eclamptic pregnancy. AB - AIM: Urine podocin mRNA expression and urine podocin : nephrin mRNA expression ratio (PNR) increase with increasing proteinuria during pregnancy complicated with pre-eclampsia (PE). This suggests that urine podocytes with reduced nephrin mRNA expression are abundant in pathological podocyturia. The aim of this study was therefore to determine post-partum changes in podocyturia and PNR in relation to proteinuria after pre-eclampsia (PE). METHODS: A total of 137 peripartum urine specimens, consisting of 72 and 65 from 24 and 30 women with PE and normotensive control pregnancies (NCP), respectively, were studied. Determination of urine protein and creatinine concentration and quantitative analysis of podocyte specific podocin and nephrin mRNA expression were carried out using reverse transcription-polymerase chain reaction in pelleted urine samples. Podocyturia was monitored via urine podocin mRNA expression. Podocyturia and proteinuria were normalized by urine creatinine concentration. RESULTS: Podocyturia and urine PNR decreased with decreasing proteinuria as well as with increasing time after delivery in the urine from PE women. In physiological proteinuria (i.e. protein : creatinine ratio [P/Cr] 0.005-0.1 mg/mg), however, both podocyturia and PNR were significantly greater in the urine from PE women compared with NPC women, although P/Cr was similar between the groups (median, 0.037 mg/mg for PE vs 0.029 mg/mg for NCP). CONCLUSIONS: Podocyturia decreases with decreasing proteinuria in PE women after childbirth. In PE women, however, pathological podocyturia consisting of podocytes with decreased nephrin mRNA expression persisted even after proteinuria decreased to a level similar to that in NCP women. PMID- 28621046 TI - Impact of borderline-subclinical hypothyroidism on subsequent pregnancy outcome in women with unexplained recurrent pregnancy loss. AB - AIM: Because subclinical hypothyroidism (thyroid-stimulating hormone [TSH] > 4.5 IU/mL) is associated with adverse pregnancy outcome, including early pregnancy loss, TSH is recommended to be titrated to <=2.5 mIU/L in levothyroxine-treated women before pregnancy. The purpose of this study was to determine whether borderline-subclinical hypothyroidism (borderline-SCH; 2.5 < TSH <= 4.5 IU/mL) affects the outcome of subsequent pregnancies in women with unexplained recurrent pregnancy loss (uRPL). METHODS: After workup for antinuclear antibody (ANA), anti phospholipid syndrome, thrombophilia, uterine abnormalities, hormone disorders, and/or chromosomal abnormalities, 317 women with a history of uRPL were enrolled. The women were classified into two groups: borderline-SCH, and euthyroidism (0.3 <= TSH <= 2.5 IU/mL). All women had normal serum free thyroxine (T4) and did not receive levothyroxine before or during the subsequent pregnancy. RESULTS: There were no significant differences in age, number of previous pregnancy losses, number of live births, or body mass index between the borderline-SCH (n = 56) and the euthyroid (n = 261) groups, but the rate of ANA positivity differed significantly (53.6% vs 33.7%, respectively; P = 0.005). The subsequent pregnancy rate did not differ between the two groups (55.4%, 31/56 vs 51.3%, 134/261, respectively). The pregnancy loss rate (<22 weeks of gestation) tended to be higher in the borderline-SCH than the euthyroid group (29.0%, 9/31 vs 17.9%, 24/134), although not significantly so (P = 0.16). CONCLUSIONS: Although some subset of uRPL is though to be due to as-yet-unidentified cause(s), borderline SCH is unlikely to be involved in uRPL. PMID- 28621047 TI - Clinical value of polymerase chain reaction in detecting group B streptococcus during labor. AB - AIM: To reduce the intrapartum use of antibiotics in women with prolonged rupture of the membranes (PROM) by restriction of antibiotics to women who are colonized with group B streptococci (GBS), as identified with the Cepheid Gene Xpert polymerase chain reaction (PCR) for detecting GBS. METHODS: We conducted a randomized controlled trial among full-term delivering women with PROM. Fifty four women were enrolled, based on a power calculation with a significance level of 5% and a power of 95%. Twenty-seven women received the standard treatment (rectovaginal swab [RVS] for bacterial culture and antibiotics). For another 27 women PCR was performed on the RVS and antibiotics were used only when the PCR was positive. The primary outcome was reduction in antibiotic use, defined as the percentage of women who received antibiotics during labor. RESULTS: 54 Women were enrolled in the study between 1 May and 18 November 2014. There were no significant differences in baseline characteristics. In total, 10 of the 54 women were GBS positive (18.5%). Of those 10 women, three were identified on bacterial culture and seven on PCR. In the bacterial culture group all the women received antibiotics. In the PCR group 10 women (37%) received antibiotics (P = 0.002). Two false-positive PCR tests were identified. There were no false-negative PCR tests. CONCLUSION: Real-time identification of GBS on PCR reduces the intrapartum use of antibiotics in women with PROM. PMID- 28621048 TI - Exploring the impact of endometriosis on partners. AB - AIM: This study aimed to determine how endometriosis affects the quality of life of partners of women who suffer from this disease and how it impacts their relationships, finances, mental states, and daily living. METHODS: This was a questionnaire-based cohort study that took place at a large tertiary hospital gynecology unit, which covered two sites. Fifty-one partners of women who had surgically diagnosed endometriosis agreed to participate in the study and returned completed surveys. RESULTS: Ninety-two percent (n = 46) of partners reported negative feelings about the diagnosis of endometriosis. Seventy percent (n = 35) reported that endometriosis affected their day-to-day life either moderately or severely. Over half (52%) also felt that their finances were affected. Only 34% (n = 17) of partners felt that health professionals had engaged them in decision-making processes and had been supportive of them. Eighty percent (n = 40) of partners reported that they had received no information about the impact of endometriosis on couples. Partners reported a significant affect on their sex life (74%) and their relationship as a whole (56%). Participants whose relationships had been affected by endometriosis had also more likely had their day-to-day life (P = 0.027), sex life (P = 0.001), and finances (P = 0.002) affected. CONCLUSION: Overall, our findings suggest that endometriosis can have a significant impact on partners with respect to day-to-day living, finances, sex lives, and relationships. Improvements can be made to engage partners in the treatment process, and to provide better education, support, and holistic management to women and families who suffer with endometriosis. PMID- 28621049 TI - Lower FOXO3 mRNA expression in granulosa cells is involved in unexplained infertility. AB - AIM: The aim of this study was to investigate whether FOXO1 and FOXO3 mRNA expression in granulosa cells is the cause of unexplained infertility. METHODS: Thirty-one patients aged <40 years (13 with unexplained infertility and 18 with male partner infertility as a control group) whose serum anti-Mullerian hormone level was >0.5 ng/MUL were enrolled in the study. All patients underwent oocyte retrieval under a short protocol from June 2012 to October 2013. Real-time PCR was carried out using mRNA extracted from granulosa cells retrieved from mature follicles. We compared FOXO1 and FOXO3 mRNA expression ratios in granulosa cells between the unexplained infertility group and the male infertility group. The relation between FOXO1 and FOXO3 mRNA expression ratios in granulosa cells and assisted reproduction technology clinical outcome was also examined. RESULTS: FOXO3 mRNA expression ratio was significantly lower in the unexplained infertility group than in the male infertility group. Moreover, FOXO3 mRNA expression ratio showed a positive correlation with both the number of retrieved oocytes and serum anti-Mullerian hormone level. A positive correlation was also identified between FOXO1 mRNA expression and total dose of hMG. As well, the number of retrieved oocytes in the unexplained infertility group was statistically lower than that in the male infertility group. CONCLUSION: A lower FOXO3 mRNA expression in granulosa cells leads to poor oocyte development in patients with unexplained infertility undergoing controlled ovarian stimulation for in vitro fertilization-embryo transfer. PMID- 28621050 TI - Maternal morbidity and associated factors at a tertiary care Centre in Karachi: A critical analysis. AB - AIM: The study was conducted to identify maternal morbidity and associated factors such intensive care unit admission and surgical intervention. METHODS: Pregnant and six-week post-partum women without any other comorbidy were recruited from January 2014 to December 2015 from the Department of Gynaecology and Obstetrics at Liaquat National Hospital, Karachi. A structurally designed questionnaire was used to record demographic data and factors related to the management and intervention of maternal conclusions. RESULTS: A total of 213 patients were included in the study, with an average age of 27.87 +/- 5.26 years, mean parity of 2.02 +/- 1.88 and mean gestational period of 32.48 +/- 7.93. The details of 186 neonatal cases were also recorded: 47 neonates were admitted to the intensive care unit, while 23 were kept on ventilation. The primary complication was post-partum hemorrhage. The most common intervention methods used was lower segment cesarean section. CONCLUSION: The concept of maternal morbidity is developing as a new indicator for the assessment of maternal healthcare services. Public health awareness programs should be conducted for health professionals to combat the high incidence of maternal morbidity. PMID- 28621051 TI - Plasma microRNA-16-5p, -17-5p and -20a-5p: Novel diagnostic biomarkers for gestational diabetes mellitus. AB - AIM: To explore whether plasma microRNA-16-5p, -17-5p and -20a-5p can be used as diagnostic biomarkers in gestational diabetes mellitus (GDM) and to investigate the relationship between those microRNAs and the risk factors of GDM (body mass index [BMI], insulin resistance [IR] and tumor necrosis factor-alpha (TNF alpha)). METHODS: A total of 85 pregnant women with GDM and 72 pregnant women without GDM were enrolled in this study. The plasma concentration of microRNAs (microRNA-16-5p, -17-5p, -19a-3p, -19b-3p, -20a-5p) was measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Spearman's correlation analysis was used to evaluate the correlation between those microRNAs and the risk factors of GDM, and receiver operating characteristic curve analysis was used to evaluate diagnostic sensitivity and specificity. RESULTS: Compared with non-GDM women, the relative and absolute expression of plasma microRNA-16-5p, -17-5p, -20a-5p from GDM women were significantly upregulated, when those women were diagnosed as GDM. During pregnancy, the expression of those microRNAs from GDM women also were significantly upregulated. The expression of those microRNAs was also positively correlated with IR, a risk factor of GDM. Plasma microRNA-16-5p, -17-5p, -20a-5p reflected an obvious separation between GDM women and non-GDM women, with areas under the curve of 0.92 (95%CI: 0.871-0.984), 0.88 (95%CI: 0.798-0.962), and 0.74 (95%CI: 0.618-0.870), respectively, cut-offs >2554, 1820, 3886 copies/MUL, respectively; sensitivity 41.6%, 21.4% and 17.8%, respectively; and specificity 95.8%, 95.4% and 95.4%, respectively. CONCLUSION: Plasma microRNA-16-5p, -17-5p and -20a-5p are potential diagnostic biomarkers in GDM. PMID- 28621052 TI - 10p15.3p13 duplication inherited from paternal balance translocation (46,XY,t(5;10)(q35.1;p13)) identified on non-invasive prenatal testing. AB - Balanced reciprocal translocations are relatively common human genetic abnormalities that involve the exchange of the terminal segments between different chromosomes and have an approximately 5-80% chance of generating an embryo with chromosomal abnormalities. Non-invasive prenatal testing (NIPT) has been increasingly used in clinical practice to detect fetal trisomies 21, 18 and 13 with a sensitivity and specificity of up to 99%. In this report, we describe a duplication on chromosome 10 and a deletion on chromosome 5 that were first detected on NIPT. Multiple follow-up invasive tests, such as prenatal BACs-on Beads (BoBs), GTG banding and single nucleotide polymorphism (SNP) array, confirmed the NIPT results. Furthermore, GTG banding identified a normal maternal karyotype and a paternal karyotype with a balanced translocation of 46, XY, t(5;10)(q35.1;p13), inherited by the child. Therefore, NIPT could be a new method for the prenatal diagnosis of fetal chromosomal abnormalities, which, in the present study, were confirmed on multiple clinical and molecular methods as being derived from paternal balanced chromosomal rearrangements. PMID- 28621053 TI - Factors affecting aging cognitive function among community-dwelling older adults. AB - AIM: The study purpose was to determine factors affecting aging cognitive function of 3,645 community-dwelling older adults in Korea. METHODS: The Hasegawa Dementia Scale assessed aging cognitive function, blood analyses and anthropometrics assessed cardio-metabolic risk factors, and the Geriatric Depression Scale Short Form Korean Version assessed depressive symptoms. RESULTS: Participants with poor aging cognitive function were more likely to be in the late age group (>=75 y) and currently smoking and have a medical history of stroke, high body mass index, and high level of depressive symptoms; they were also less likely to engage in regular meals and physical activities. CONCLUSION: Regular meals and physical activities may be primary factors for clinical assessment to identify older adults at risk for aging cognitive function. With aging, depressive symptoms and other unhealthy lifestyle behaviours should be managed to prevent cognitive function disorders. PMID- 28621054 TI - Delivery mode and breastfeeding outcomes among new mothers in Nicaragua. AB - Breastfeeding has been shown to benefit infants and mothers. Women who have caesarean deliveries (C-sections) are expected to be less likely to initiate and continue breastfeeding than those who have vaginal deliveries. Given the high rate of C-sections in Nicaragua, the importance of breastfeeding, and the centrality of culture in choices about breastfeeding, this study sought to examine if mode of delivery relates with breastfeeding initiation and exclusivity in Nicaragua. Two hundred fifty mothers were surveyed about birth experiences and breastfeeding behaviour in 3 public clinics in Leon, Nicaragua, between June and August 2015. Logistic regression analyses were performed to examine the association of mode of delivery with initiation of breastfeeding within 1 hr of birth (early initiation) and exclusive breastfeeding for 6 months post-partum. The rate of early initiation was 68.8% and that of exclusively breastfeeding for 6 months was 12.7%. Mode of delivery was not significantly associated with early initiation (p = .383) or exclusive breastfeeding (p = .518). Early initiation was negatively associated with prelacteal feeding, AOR = 0.30, 95% CI [0.16, 0.58]; p = .001. Mothers who had perceived their infants as large at birth were significantly less likely to exclusively breastfeed for 6 months, AOR (95%CI) = 0.25 (0.06-0.97); p = 0.046. Mode of delivery was not significantly associated with optimal breastfeeding initiation and exclusivity among mothers in Nicaragua. The 2 risk factors identified for delayed initiation of breastfeeding and lack of exclusive breastfeeding were prelacteal feeding and maternal perception of a large infant at birth, respectively. PMID- 28621055 TI - Impact of diagnostic ureteroscopy on intravesical recurrence in patients undergoing radical nephroureterectomy for upper tract urothelial cancer: a systematic review and meta-analysis. AB - Aim of this study was to analyse the association between the use of diagnostic ureteroscopy (URS) and the development of intravesical recurrence (IVR) in patients undergoing radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. A systematic review of the published data was performed up to December 2016, using multiple search engines to identify eligible studies. A formal meta-analysis was conducted of studies comparing patients who underwent URS before RNU with those who did not. Hazard ratios (HRs), with their 95% confidence intervals (CIs), from each study were used to calculate pooled HRs. Pooled estimates were calculated using a fixed-effects or random-effects model according to heterogeneity. Statistical analyses were performed using RevMan, version 5. Seven studies were included in the systematic review, but only six of these were deemed fully eligible for meta-analysis. Among the 2 382 patients included in the meta-analysis, 765 underwent diagnostic URS prior to RNU. All examined studies were retrospective, and the majority examined Asian populations. The IVR rate ranged from 39.2% to 60.7% and from 16.7% to 46% in patients with and without prior URS, respectively. In the pooled analysis, a statistically significant association was found between performance of URS prior to RNU and IVR (HR 1.56, 95% CI 1.33-1.88; P < 0.001). There was no heterogeneity in the observed outcomes, according to the I2 statistic of 2% (P = 0.40). Within the intrinsic limitations of this type of analysis, these findings suggest a significant association between the use of diagnostic URS and higher risk of developing IVR after RNU. Further research in this area should be encouraged to further investigate the possible causality behind this association and it potential clinical implications. PMID- 28621056 TI - Denervation effectively aggravates rat experimental periodontitis. AB - BACKGROUND: Nerve and its related factors in the occurrence and development of periodontitis are worthy of further study. Denervation research is a useful addition to nerve and innervation studies. The aim of this study is to establish a rat model of inferior alveolar nerve transection combined with ligature-induced periodontitis to elucidate the effects of denervation on ligature-induced rat periodontitis. MATERIAL AND METHODS: Sixty-four Wistar rats were distributed to the four groups randomly: ligation (L); denervation (D); ligation+denervation (LD); and normal (N) as control. A ligation-inducing rat experimental periodontitis model was established in the L and LD groups. Rats in the D and LD groups also underwent the transection of the right inferior alveolar nerve simultaneously. Four weeks after the operation, the mandibles were taken out for micro-computed tomography analysis. Osteoclast number was observed through TRAP staining. The gingival tissues around the first molars were homogenized and measured by enzyme-linked immunosorbent assay for interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha. Collagen fibers were observed using Picro Sirius Red staining. Nuclear factor (NF)-kappaB p65 and IkappaBalpha phosphorylation and osteoprotegerin (OPG)/receptor activator of NF-kappaB ligand (RANKL) ratio in the gingival tissues were detected by western blotting. RESULTS: Denervation strongly promoted ligature-induced alveolar bone loss in the LD group. The alveolar bone loss of the LD group was significantly increased compared with the L group. Furthermore, denervation aggravated trabecular bone breakdown in the bone specific parameters, including percentage bone area, trabecular thickness and bone mineral density. Increased TRAP-positive osteoclasts were detected in alveolar bone of the LD group. More serious collagen fiber destructions and increased expressions of IL-1beta and TNF-alpha were found in the LD group. NF-kappaB p65 and IkappaBalpha phosphorylation were also significantly upregulated in the LD group. OPG/RANKL ratio in the gingival extracts was markedly decreased in the LD group compared with the L group. Decreased OPG/RANKL ratio was observed in the D group, compared with the N group. CONCLUSION: Denervation effectively aggravates ligature-induced rat periodontitis by the NF-kappaB signaling pathway for excessive production of IL-1beta and TNF alpha and increased osteoclasts for decreased OPG/RANKL ratio. The rat model of inferior alveolar nerve transection that combined ligature-induced periodontitis provides an animal model to observe further the change of nerve-related factors in the occurrence and development of periodontitis, so as to select positive nerve-related factors to regulate inflammation and promote periodontal regeneration in the future. PMID- 28621057 TI - Prospective evaluation of toceranib phosphate in metastatic canine osteosarcoma. AB - Efficacious therapies for measurable metastatic canine osteosarcoma (OSA) are generally lacking. Preliminary retrospective studies suggested that approximately 50% of dogs with measurable metastatic OSA experienced clinical benefit (objective response or clinically meaningful disease stabilisation) following toceranib (TOC) treatment. The purpose of this clinical trial was to prospectively evaluate the clinical outcome following TOC treatment in dogs with measurable pulmonary metastatic OSA. A secondary goal was to identify potential biomarkers of clinical benefit by measuring changes in plasma vascular endothelial growth factor (VEGF) and circulating regulatory T-cell (Treg) percentage. Twenty-two dogs with pulmonary metastasis from appendicular OSA having undergone previous amputation were treated prospectively with TOC. Adverse events (AEs) were common but predominantly low grade. Nine patients were withdrawn from the study prior to the week 8 assessment of response either due to progressive disease (PD), decreased quality of life or owner perceived unacceptable AEs. Of the patients evaluable for disease progression at week 8 (or earlier), 3/17 (17.6 %) had stable disease with the remainder having PD. The median progression-free survival time for all patients was 57 days (range 7-176 days) with a median overall survival time of 89 days (range 7-574 days). Plasma VEGF concentrations were significantly elevated in patients after 4 weeks of TOC treatment, but no changes were observed in percentage of Treg in peripheral blood. Overall, the results of this clinical trial do not support the use of TOC as single agent therapy for canine metastatic OSA. PMID- 28621058 TI - Shift from protocol-based to personalized medicine in active surveillance: beginning of a new era. PMID- 28621059 TI - Biomarkers in chronic pelvic pain syndrome: did we find the Holy Grail? PMID- 28621060 TI - Prostate-specific membrane antigen radioguided surgery: a promising utility. PMID- 28621061 TI - Biomarkers for urological chronic pelvic pain: is there light at the end of the tunnel? PMID- 28621062 TI - Active surveillance in prostate cancer: new efforts, new voices, new hope. PMID- 28621063 TI - Pre-stenting and the risk of postoperative sepsis: a shorter dwell time is better. PMID- 28621064 TI - Sustainable Separations of C4 -Hydrocarbons by Using Microporous Materials. AB - Petrochemical refineries must separate hydrocarbon mixtures on a large scale for the production of fuels and chemicals. Typically, these hydrocarbons are separated by distillation, which is extremely energy intensive. This high energy cost can be mitigated by developing materials that can enable efficient adsorptive separation. In this critical review, the principles of adsorptive separation are outlined, and then the case for C4 separations by using zeolites and metal-organic frameworks (MOFs) is examined. By analyzing both experimental and theoretical studies, the challenges and opportunities in C4 separation are outlined, with a focus on the separation mechanisms and structure-selectivity correlations. Zeolites are commonly used as adsorbents and, in some cases, can separate C4 mixtures well. The pore sizes of eight-membered-ring zeolites, for example, are in the order of the kinetic diameters of C4 isomers. Although zeolites have the advantage of a rigid and highly stable structure, this is often difficult to functionalize. MOFs are attractive candidates for hydrocarbon separation because their pores can be tailored to optimize the adsorbate adsorbent interactions. MOF-5 and ZIF-7 show promising results in separating all C4 isomers, but breakthrough experiments under industrial conditions are needed to confirm these results. Moreover, the flexibility of the MOF structures could hamper their application under industrial conditions. Adsorptive separation is a promising viable alternative and it is likely to play an increasingly important role in tomorrow's refineries. PMID- 28621065 TI - Editorial: yoga for QoL in ulcerative colitis-any better than other supportive activities? Authors' reply. PMID- 28621066 TI - Editorial: which iron preparation for patients with IBD? PMID- 28621067 TI - Letter: the influence of direct acting agents for hepatitis C, on hepatitis B reactivation. PMID- 28621068 TI - Letter: HBV/HCV coinfection in the era of direct-acting antivirals. PMID- 28621069 TI - Editorial: lower gastrointestinal bleeding and low-dose aspirin-authors' reply. PMID- 28621070 TI - Editorial: food for thought-the low-FODMAP diet and IBS in perspective. PMID- 28621071 TI - Editorial: refractory GERD-good drug, wrong patients? Authors' reply. PMID- 28621072 TI - Letter: the efficacy of oltipraz in patients with non-alcoholic fatty liver disease has not been confirmed. PMID- 28621073 TI - Editorial: yoga for QoL in ulcerative colitis-any better than other supportive activities? PMID- 28621074 TI - Editorial: which iron preparation for patients with IBD? Authors' reply. PMID- 28621075 TI - Editorial: is ribavirin needed in the treatment of post-transplant hepatitis C recurrence? PMID- 28621076 TI - Editorial: lower gastrointestinal bleeding and low-dose aspirin. PMID- 28621077 TI - Editorial: does disease extension lead to disease progression in proctitis? PMID- 28621078 TI - Editorial: refractory GERD-good drug, wrong patients? PMID- 28621079 TI - Editorial: when to be suspicious of malignancy-associated pseudoachalasia. PMID- 28621080 TI - Letter: the efficacy of oltipraz in patients with non-alcoholic fatty liver disease has not been confirmed-authors' reply. PMID- 28621081 TI - Letter: anti-TNF dose de-escalation in Crohn's disease-a case-by-case decision. PMID- 28621082 TI - Editorial: tackling hepatorenal syndrome-terlipressin for all, or time for a stratified approach? PMID- 28621083 TI - Metacognition in speech and language therapy for children with social (pragmatic) communication disorders: implications for a theory of therapy. AB - BACKGROUND: Metacognition is a significant component of complex interventions for children who have developmental language disorders. Research into how metacognition operates in the content or process of developmental language therapy delivery is limited. Identification and description of proposed active therapy components, such as metacognition, may contribute to our understanding of how to deliver complex communication interventions in an optimal manner. AIMS: To analyse aspects of metacognition during therapy derived from a manualized speech and language intervention (the Social Communication Intervention Programme-SCIP) as delivered to children who have social (pragmatic) communication disorder (SPCD) and to examine the dynamic process of delivering therapy. METHODS & PROCEDURES: A purposive sample of eight filmed therapy sessions was selected from the video data corpus of intervention-arm participants within a randomized controlled trial. The child-therapist interactions during therapy sessions from five children (aged between 5;11 and 10;3) in the SCIP trial were transcribed. Filmed sessions represented a variety of communication profiles and SCIP therapy content. Starting from existing theory on metacognition, cycles of iterative analysis were performed using a mixed inductive-deductive qualitative analysis. A preliminary list of metacognitive content embedded in the intervention was developed into a metacognitive coding framework (MCF). A thematic analysis of the identified metacognitive content of the intervention was then carried out across the whole sample. OUTCOMES & RESULTS: Thematic analysis revealed the presence of metacognition in the content and delivery of SCIP intervention. Four main themes of metacognitive person, task and strategy knowledge, and monitoring/control were identified. Metacognition was a feature of how children's ability to monitor language, pragmatic and social interaction skills, in themselves and other people, was developed. Task design and delivery methods were found to play a particular role in adjusting the metacognitive content of the therapy activities. CONCLUSIONS & IMPLICATIONS: This study makes explicit the metacognitive content and delivery within a complex developmental communication intervention. Discussion of the findings about metacognitive content provides an explanation of how the skilled speech and language therapist manipulates task demands, person knowledge and therapy methods towards the therapy goal. Clinical applications of the metacognitive framework are discussed. We suggest that the process of making the tacit knowledge of the therapist explicit can contribute to the implementation of complex evidence-based interventions. PMID- 28621084 TI - Coregulation of the cyclic lipopeptides orfamide and sessilin in the biocontrol strain Pseudomonas sp. CMR12a. AB - Cyclic lipopeptides (CLPs) are synthesized by nonribosomal peptide synthetases (NRPS), which are often flanked by LuxR-type transcriptional regulators. Pseudomonas sp. CMR12a, an effective biocontrol strain, produces two different classes of CLPs namely sessilins and orfamides. The orfamide biosynthesis gene cluster is flanked up- and downstream by LuxR-type regulatory genes designated ofaR1 and ofaR2, respectively, whereas the sessilin biosynthesis gene cluster has one LuxR-type regulatory gene which is situated upstream of the cluster and is designated sesR. Our study investigated the role of these three regulators in the biosynthesis of orfamides and sessilins. Phylogenetic analyses positioned OfaR1 and OfaR2 with LuxR regulatory proteins of similar orfamide-producing Pseudomonas strains and the SesR with that of the tolaasin producer, Pseudomonas tolaasii. LC ESI-MS analyses revealed that sessilins and orfamides are coproduced and that production starts in the late exponential phase. However, sessilins are secreted earlier and in large amounts, while orfamides are predominantly retained in the cell. Deletion mutants in ofaR1 and ofaR2 lost the capacity to produce both orfamides and sessilins, whereas the sesR mutant showed no clear phenotype. Additionally, RT-PCR analysis showed that in the sessilin cluster, a mutation in either ofaR1 or ofaR2 led to weaker transcripts of the biosynthesis genes, sesABC, and putative transporter genes, macA1B1. In the orfamide cluster, mainly the biosynthesis genes ofaBC were affected, while the first biosynthesis gene ofaA and putative macA2B2 transport genes were still transcribed. A mutation in either ofaR1, ofaR2, or sesR genes did not abolish the transcription of any of the other two. PMID- 28621085 TI - Factors affecting survival in neonatal surgery unit in a tertiary care university hospital during 26 years. AB - This clinical study was designed to evaluate mortality rate and the factors that may affect survival in neonatal surgery unit. Randomly chosen 300 (beta: 0.20) patients among 1,439 patients treated in neonatal surgery unit during years 1983 to 2009, were evaluated retrospectively. The patients were separated into three groups according to date of treatment; Group A: 1983 - 1995, Group B: 1996 - 2005 and Group C: 2005 - 2009. M/F ratios did not differ between non-survived and survived patient populations. Mortality rates were 37%, 22% and 13% in Group A, B, and C respectively (p < 0.001). Parenteral nutrition, maternal age, time until admission and gestational age did not affect mortality rate, however median age of newborn was lower in non-survived cases (1 day vs. 3 days, p < 0.001). Associating abnormality, low birth weight ( < 1,500 g), associating sepsis, need of globulin and requirement of respiratory support were determinants of lower survival (p < 0.001). The mortality rate for patients that underwent thoracotomy (42%) and laparotomy (41%) were higher than patients that underwent other operations (8%) and observation (10%) (p < 0.001). Diaphragmatic hernia had higher mortality rates than the other pathologies (p < 0.001). Survival rate is increasing to date in newborn pediatric surgery unit; it is independent from parenteral nutrition, maternal age, time to admission and gestational age however it is affected adversely by the age of patient, associating abnormality, low birth weight, presence of sepsis and requirement of respiratory support. Increase in survival could be related to various additional factors such as development of delicate respiratory support machines, broad spectrum antibiotics, hospital infection control teams, central venous catheters, use of TPN by central route, volume adjustable infusion pumps, monitoring devices, neonatal surgical techniques, prenatal diagnosis of pediatric surgical conditions and developments of environmental control methods in neonatal surgical units. PMID- 28621086 TI - Asthma control test and pediatric asthma quality of life questionnaire association in children with poor asthma control. AB - The aim of this study was to evaluate the association between Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and Asthma Control Test (ACT) in patients with poor asthma control. Children between 7-17 years of age with diagnosis of persistent asthma who are not on daily inhaler corticosteroid therapy were involved. At enrollment, sociodemographic and asthmatic characteristics were investigated and pulmonary function test (PFT), ACT and PAQLQ were administered. Patients were reevaluated following six week regular inhaler therapy and ACT, PAQLQ and PFT were performed. Out of 77 patients, 35 (45%) were female. The mean age was 11.62 +/- 2.35 years. Following 6 weeks daily inhaler therapy, the scores of ACT, all the parameters of PAQLQ and all the parameters of PFT except FEV1/FVC were significantly increased (p < 0.05). There was a significant correlation between ACT and PAQLQ scores (r < 0.5, p=0.001). In conclusion, there is a correlation between ACT and PAQLQ. PMID- 28621087 TI - The efficacy and safety of naproxen in acute rheumatic fever: The comparative results of 11-year experience with acetylsalicylic acid and naproxen. AB - The objective was to compare the efficacy and safety of naproxen (NXN) to acetylsalicylic acid (ASA) in the treatment of acute rheumatic fever (ARF). The data of 338 children were retrospectively analyzed. The patients were grouped according to joint and valve involvement and also drug chosen [methyl prednisolone (mPSL), ASA or NXN]. The treatment results and adverse events in each group were compared. The mean age was 10.3 years and the median follow-up was 62 months. Median time for normalization of acute phase reactants was 1 week in patients given steroids and 2 weeks in patients given ASA or NXN. ASA was replaced with NXN in 18 patients (10.2%) due to hepatic toxicity. The rate of rebound, recurrence and the prevalence of rheumatic valve disease were not different in patients given NXN, ASA or mPSL. In conclusion, NXN is a safe and effective alternative to ASA in the treatment of ARF in children. PMID- 28621088 TI - Hepatitis A virus epidemiology in Turkey as universal childhood vaccination begins: seroprevalence and endemicity by region. AB - This paper presents the results of a comprehensive examination of current distribution of Hepatitis A virus (HAV) seroprevalence and endemicity in Turkey and the possible links between HAV endemicity and socioeconomic development. We performed a systematic search in online resources published between January 2000 and August 2015. The 22 provinces were able to be assigned a hepatitis A endemicity level based on this systematic review. The incidence rates for symptomatic hepatitis A infection are higher in the eastern part of Turkey than in the western and central region. These differences in socioeconomic indicators by region suggest the likelihood of lower seroprevalence rates in the western parts of the country and higher rates in the eastern region. Turkey's current policy of recommending hepatitis A immunization for all children without contraindications is an appropriate one and is likely to remain the best option for at least the next decade or two. PMID- 28621089 TI - A new emerging problem in pediatric emergency units: Synthetic cannabinoids. AB - Synthetic cannabinoids or synthetic marijuana derivatives known as "Bonzai" in Turkey are addictive substances that affect the brain and have serious side effects. In recent years, the use of these substances has also been increasing in our country as well as all over the world. These substances present with various names and brands, the most common names in Turkey are "Bonzai" and "Jamaika". In this study, we aimed to evaluate the demographic and clinical findings of these patients. We retrospectively evaluated patients admitted to our pediatric emergency department between March 2013 and March 2015 due to the complaints developing after the use of "Bonzai" in terms of age, gender, admission date, complaint, clinical findings, laboratory findings, consuming method of the substance, additional substance use, observation durations, hospitalization status and mortality rates. The most common complaint was faintness and drowsiness. Changes in the state of consciousness, tachycardia, hypertension were the most common clinical findings. Most common consuming method of the drug was in the form of smoking. The rate of "Bonzai" use among adolescents is increasing every day. Physicians in emergency departments should be educated on this issue and it must be kept in mind that most of the patients admitted are with complaints related to changes in the cognitive state (of consciousness) but they can also apply with complaints about all other systems. PMID- 28621090 TI - Cardiac nodal and cardiac autonomic functions in children with vasovagal syncope. AB - In the present study, cardiac nodal (sinoatrial node and atrioventricular node) and cardiac autonomic functions have been investigated in children with vasovagal syncope (VVS). Thus, the effect of existing autonomic status on the characteristics of cardiac conduction system has been demonstrated in children with VVS. The study included 51 pediatric patients (the mean age was 14.01+/-2.79 years, range 7 to 18 years; 30 females), who were evaluated for syncope using ECG, Holter monitoring, and echocardiography, all of which showed normal findings. All patients underwent head-up tilt testing (HUTT), and the parameters of heart rate variability (HRV) (SDNN, SDANN, SDANNi, rMSSD, pNN50, HF, LF, VLF) were evaluated with the analysis of 24-hour Holter testing. Corrected sinus node recovery time (CNRT) and Wenckebach point (WP) were measured in all patients using transesophageal atrial stimulation. The patients were divided into groups according to HUTT results and evaluated accordingly. Cardiac nodal functions were normal in all patients. HRV parameters (HF, rMSSD, pNN50) indicating parasympathetic effect were higher in patients with positive HUTT results. CNRT did not differ significantly between patients with positive HUTT results and patients with negative HUTT results. However, WP was found to be higher in patients with positive HUTT results. The studies evaluating the parameters of HRV has demonstrated increased parasympathetic tonus in children with VVS. Impairment in cardiac nodal functions may not be expected in children with VVS. However, these patients may exhibit prolonged WP due to increased autonomic tonus in favor of parasympathetic activity. PMID- 28621091 TI - Increased mean platelet volume in children with sepsis as a predictor of mortality. AB - Our aim is to investigate the correlation between the mean platelet volume (MPV) levels and platelet counts of the septic children with 28-day mortality risk. MPV at admission (MPV < sub > adm < /sub > ), MPV at 72 < sup > nd < /sup > hour (MPV < sub > 72h < /sub > ) and the difference between these two parameters (DeltaMPV < sub > 72h-adm < /sub > ) and platelet counts were recorded retrospectively. The control group consisted of 100 healthy children matched for age, gender, and ethnicity. One hundred eighty six children were enrolled into the study. The study group had significant higher MPV values than those of control group. There were 156 survivors and 32 nonsurvivors in study group with a mortality rate of 17%. Nonsurvivors had significantly higher MPV < sub > adm < /sub > (p: 0.001), MPV < sub > 72h < /sub > (p: 0.001), DeltaMPV < sub > 72h-adm < /sub > (p < 0.001) and lower platelet count (p: 0.002) than survivors. MPVadm (OR 2.39), MPV < sub > 72h < /sub > (OR 4.23), DeltaMPV < sub > 72h-adm < /sub > (OR 6.4), platelet count (OR 7.3), and need for mechanical ventilation support (OR 9.76) had significant effect on 28-day mortality risk at logistic regression analysis. At the receiver operating characteristic analysis (ROC) the cutoff values for MPV < sub > adm < /sub > , MPV < sub > 72h < /sub > , and DeltaMPV < sub > 72h-adm < /sub > were found to be 9 fL, 9.86 fL, and 0.79, respectively. Kaplan-Meier analysis and log-rank test proved that these cutoff values were significantly associated with the time of survival. Septic children who had high MPV levels at admission and whose MPV levels increased during follow up had higher risk of mortality. With the results of further researches targetting large groups of pediatric patients, MPV < sub > adm < /sub > , MPV < sub > 72h < /sub > , and DeltaMPV < sub > 72h-adm < /sub > values can be fast and reliable markers for early diagnosis of sepsis and mortality prediction. PMID- 28621092 TI - Comparison of risk scoring systems in congenital heart surgery. AB - Hacettepe University Faculty of Medicine Department of Cardiovascular Surgery; data of 413 patients under 18 years old who had congenital heart surgery were evaluated between 01.01.2011-30.10.2012 and risk scorings were made by "RACHS-1 (Risk Adjustment in Congenital Heart Surgery)", "Aristotle Basic Complexity Score (ABS)" and "Aristotle Comprehensive Complexity Score (ACS)" systems used in evaluation of the risk of mortality and morbidity in (ACS)" systems used in evaluation of the risk of mortality and morbidity in congenital heart surgery. Data obtained were compared by Mann-Whitney U test and how effective these systems were in evaluating mortality and morbidity and their superiorities over each other were examined. Following the research, it was observed that all three systems were effective in evaluating mortality and morbidity; the most successful of them in foreseeing the event was the ACS system, ACS system was followed by RACHS-1 system and ABS system was the most incapable of these in foreseeing the event. It was seen that in detecting time related mortality, rating of these tests changed, RACHS-1 system detected the time related mortality best. It was also seen that with RACHS-1 system, a previously evaluated concept, it was possible to determine morbidity. PMID- 28621093 TI - Waist to height ratio: a simple screening tool for nonalcoholic fatty liver disease in obese children. AB - Simple predictors are needed for the screening of nonalcoholic fatty liver disease (NAFLD) in obese children. We aimed to assess the role of anthropometric parameters in the prediction of NAFLD. Three hundred and thirty two obese children (152 male, 180 female) aged 4.6-17.0 years were included in this study. Weight, height, waist (WC), and hip circumference were measured. Body mass index (BMI), waist-hip-ratio (WHR), and waist-height-ratio (WHtR) were calculated. Obesity was defined as BMI for age and sex >= 95th percentile. NAFLD was diagnosed using ultrasonography (US). NAFLD was present in 60.8% of obese children. Fatty liver prevalence differed significantly by gender and puberty (55.0% of girls vs 67.7% of boys, and 28.7% in prepubertal vs 71.3% in pubertal children; p < 0.05). Significantly higher BMI, BMI standard deviation score (SDS), WC, and WHtR were found in obese children with NAFLD compared to obese children without NAFLD (p < 0.05). Only WHtR was found to be an independent predictor for NAFLD in a logistic regression analysis (p < 0.001, B:1.096, 95% CI 1.047-1.148). Fatty liver is common among obese children, particularly in obese boys. WHtR is a simple and easy index for predicting of NAFLD in obese children and can be used for mass screening in public health. PMID- 28621094 TI - Detection of gastroesophageal reflux in children with cerebral palsy using combined multichannel intraluminal impedance-ph procedure. AB - Gastroesophageal reflux (GER) is a very common condition in children with neurological impairment and this can influence nutritional and respiratory outcomes. The aim of this study was to investigate the presence of GER in children with cerebral palsy (CP) using multiple intraluminal impedance (MII)-pH monitoring. The use of combined MII-pH allows for the detection of both acid and non-acid reflux episodes. A total of 29 CP patients with symptoms suggesting GER, aged 2 to 10 years old, underwent 24-hour combined MII-pH monitoring. There were a total of 3899 reflux episodes, of which 29% were acid, 60% were weakly acid and 11% were alkaline. The number of non-acid reflux episodes was statistically significantly greater (p < 0.01). These findings confirm that GER disease is seen frequently in children with cerebral palsy and most of the reflux episodes are not acidic. Non-acid reflux can also influence the morbidity in patients with cerebral palsy. It can be concluded that 70% of the reflux episodes would not have been recognized by pH measurement alone. PMID- 28621095 TI - Primary intrarenal neuroblastoma in a 13-month-old girl presenting as a Wilms' tumor with pulmonary metastasis. AB - We report a 13-month-old girl with primary intrarenal neuroblastoma initially diagnosed as Wilms' tumor. Intrarenal neuroblastoma is exceedingly rare in pediatric age that may masquerade as Wilms' tumor clinically and radiographically and it is important to differentiate for management. PMID- 28621096 TI - Peutz-Jeghers syndrome: an unusual cause of recurrent intussusception in a 7-year old boy. AB - Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with mucocutaneous pigmentations. Main symptoms of PJS in childhood are abdominal pain, obstruction, intussusception, and bleeding from hamartomatous polyps. PJS carries a high risk of gastrointestinal cancer with advancing years. Although, intussusception has been reported as a well-known complication of PJS, recurrent intussusception as an alarming finding in a patient with normal gastrointestinal endoscopy is uncommon. A 7-year-old boy who had recurrent intussusception episodes and diagnosed with PJS histopathological confirmation after surgical excision of involved bowel segments is presented to discuss the clinical features and treatment options of recurrent intussusception as a presenting finding of PJS. PMID- 28621097 TI - Gonadoblastoma in a patient with 46, XY complete gonadal dysgenesis. AB - 46, XY complete gonadal dysgenesis (Swyer syndrome) is a rare cause of 46, XY sexual development disorder. The patient presented to our clinic with absence of breast development and lack of periods at the age of 17 years. Her history and familial history involved no relevant conditions. She had Tanner stage 1 thelarche, and Tanner stage 2 pubic hair development with no axillary hair development. External genital structure appearance was consistent with female phenotype and the patient had no palpable gonad. The patient diagnosed as 46, XY complete gonadal dysgenesis after evaluation of laboratory analyses, radiological methods and karyotype. The Sexual Orientation and Gender Identity Committee concluded that gonadectomy should be performed. Histopathologic analysis demonstrated gonadoblastoma. Gonad structures should be sought laparoscopically and once diagnosed, streak gonads should be removed prophylactically in patients with 46, XY complete gonadal dysgenesis. PMID- 28621098 TI - Seizures and diagnostic difficulties in hyperinsulinism-hyperammonemia syndrome. AB - Hyperinsulinism/hyperammonemia (HI/HA) syndrome is a rare disorder presented with recurrent hypoglycemia and elevated serum ammonia, which may lead to development delays, permanent neurologic damages, if it remains underdiagnosed. It is caused by activating mutations in the GLUD1 gene which encodes the intra-mitochondrial enzyme glutamate dehydrogenase (GDH). HI/HA syndrome is considered the second most common form of hyperinsulinism (HI), and usually associated with epileptic seizures, mental retardation and generalized dystonia. We reported a patient who was diagnosed as HI/HA with multiple episodes of seizures; and previously had been diagnosed and treated for epilepsy. She has heterozygous mutation in GLUD1 gene. Treatment with diazoxide enabled complete resolution of the seizures. One year later, when her brother was six months old, he was also diagnosed with HI/HA. Later, the same mutation of GLUD1 was detected in both her father and brother too. PMID- 28621099 TI - Coexistence of early onset sarcoidosis and partial interferon-gamma receptor 1 deficiency. AB - Pediatric sarcoidosis comprises a spectrum of childhood granulomatous inflammatory conditions. Pathological hallmark of the disease is granuloma formation that is seen in the affected tissues and almost any organ or system can be involved. There are two forms of pediatric sarcoidosis. One is seen in older children and the clinical picture is very similar to that of adult sarcoidosis and the other one is seen in early childhood. Sarcoidosis in early childhood can be divided as Blau syndrome (familial form) and early onset sarcoidosis (sporadic form). In both of the diseases there is a defect in the NOD2/CARD15 gene. The typical triad of early onset sarcoidosis is polyarthritis, dermatitis and uveitis. Interferon-gamma receptor 1 deficiency is caused by defects in the IFNgammaR1 gene and non-tuberculosis mycobacterial pathogens are the leading causes of infections that start in early childhood. Herein we report a patient who presented with the symptoms of early onset sarcoidosis and also had partial interferon-gamma receptor 1 deficiency that presented with BCG-osis. In addition to anti-mycobacterial treatment, methotrexate and prednisolone were used in therapy. PMID- 28621100 TI - Paracetamol infusion-related severe hypotension and cardiac arrest in a child. AB - Paracetamol (also known as Acetaminophen) is an antipyretic, non-opioid analgesic, and non-steroidal anti-inflammatory drug (NSAID), and is one of the most commonly used medications worldwide. In recent years, IV paracetamol has been frequently used in hospitalized patients to reduce fever and pain. Significant adverse reactions associated with intravenous paracetamol are extremely rare. Typically reported adverse events include hypotension, malaise, hypersensitivity reaction, liver enzyme elevation, and thrombocytopenia. We present herein a case of IV paracetamol infusion-related severe hypotension and cardiac arrest. PMID- 28621101 TI - Cerebrovascular complication of infective endocarditis complicated with abdominal trauma. AB - A 9-year-old boy presented to the emergency department with blunt abdominal trauma. Initial assessment was normal except for abdominal tenderness. On day 3, patient was transferred to the pediatric intensive care unit (PICU) for hemodynamic instability, and persistent fever despite antibiotic therapy. On PICU admission, his body temperature was 40 0C, heart rate was 160/min, respiratory rate was 36/min, blood pressure was 85/40 mmHg, and impaired consciousness was noticed. Complete blood count revealed hemoglobin of 11.5 g/dl, white blood cell count of 22,500/mm3 and platelet count of 145,000/mm3. Serum C-reactive protein and procalcitonin were 139 mg/dl and 8.80 ng/ml, respectively. Renal and liver function test results were normal. Cranial magnetic resonance imaging (MRI) was planned because of impaired consciousness and fever. On cranial MRI, multiple infarct areas were detected in both hemispheres and minimal hemorrhagic focus was found in the left temporal region. Because of the cranial MRI findings and fever echocardiographic examination was planned to exclude infective endocarditis. Transthoracic echocardiography successfully visualized mitral valve prolapse, 14x8 mm mobile vegetation on the atrial side of the posterior leaflet of the mitral valve, and severe mitral regurgitation. The left chambers were dilated. There was no evidence of a perivalvular abscess. On control transthoracic echocardiography, after 6 weeks of parenteral antibiotic treatment, there was no significant reduction of the visible vegetation therefore surgery was planned. Infective endocarditis should be considered in the differential diagnosis of fever of unknown origin. Especially during the early stage of disease, cranial MRI may be more useful to prevent fatal complications for patients with neurologic examination findings. PMID- 28621102 TI - Corynebacterium propinquum bronchopneumonia in a child with ataxia telangiectasia. AB - Nondiphtherial Corynebacterium species isolated from clinical specimens are usually considered as contaminants by many clinicians when reported by microbiologists. However, an increasing number of studies have confirmed the importance of Corynebacterium spp. in the etiology of a variety of infectious processes. In this report, we present a case of bronchopneumonia caused by Corynebacterium propinquum. The infection occurred in a seven-year-old child who had a history of immunosuppression due to ataxia telangiectasia. The purulent sputum of the patient yielded a large number of polymorphonuclear leucocytes with abundant gram-positive coryneform bacilli in gram staining and pure growth of coryneform bacteria in culture. Definitive identification as C. propinquum was made by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing. C. propinquum should be recognized as a potential pathogen and included in the etiologic diagnostic algorithm, particularly in patients with immunosuppressive conditions. PMID- 28621103 TI - Bone marrow aspiration complications: Iliopsoas abscess and sacroiliac osteomyelitis. AB - After bone marrow aspiration procedure; some complications like pain and bleeding at the puncture site may be expected but some serious complications like osteomyelitis and soft tissue infections may also rarely occur. In this case we present a boy with recurrent fever. During etiologic investigation, familial Mediterranean fever (FMF) gene M694V mutation was +/+. Patient was treated with oral colchicine however fever persisted. The patient was considered as colchicine resistant FMF and steroid treatment was planned. Bone marrow aspiration procedure was executed to rule out malignancy. Three months after bone marrow aspiration, he was readmitted with complaint of left pelvic pain, difficulty in walking without support and standing on his left foot. Radiological imaging demonstrated left iliopsoas abscess and left sacroiliac osteomyelitis. Patient was successfully treated with intravenous ampicillin-sulbactam and clindamycin treatment for 6 weeks. Then oral amoxicillin-clavulanic acid treatment was continued for 2 weeks. Patient was discharged without any surgical procedure. On 1-year follow-up he could walk without any support. PMID- 28621104 TI - Rosai-Dorfman disease of vertebra: Case report and literature review. AB - Rosai-Dorfman disease is a rare benign histiocytic disorder that arises predominantly in lymph nodes with fever and malaise, but can affect various organs, with or without lymphadenopathy. Solitary extranodal skeletal lesions are extremely rare. Herein, we describe a case of isolated disease of thoracic spine, with vertebral body fracture. A 14-year-old girl presented with cervical back pain for about one month as the only symptom. There was no lymphadenopathy. Results of laboratory tests were within reference ranges. The radiological examinations revealed collapse, osteolytic lesion and compressive fracture, which reduced vertical diameter of C4 vertebral body. The patient made a complete recovery after a limited C4 laminectomy, spondylodesis C3/C5 vertebra and biopsy of the lesion. Histologically, nonspecific cellular milieu and atypical histiocytic proliferation with emperipolesis, with CD68 and S100 positivity, confirmed a diagnosis of Rosai-Dorfman disease. Isolated extranodal skeletal Rosai-Dorfman disease should be considered among the differential diagnoses of similar changes, such as Langerhans cell histiocytosis, Erdheim-Cheister disease, eosinophilic granuloma, osteomyelitis, metastasis and lymphoma. PMID- 28621105 TI - Isolation, Purification, and Identification of Taxol and Related Taxanes from Taxol-Producing Fungus Aspergillus niger subsp. taxi. AB - The content of taxol in the bark of yews is very low, and this is not affordable from the environmental point of view. Thus, it is a necessity to look for alternative sources of taxol production to solve its supply. Currently, a large portion of the taxol in the market comes from chemical semi-synthesis, but the semi-synthetic precursors such as baccatin III and 10-deacetyl-baccatin III are extracted from needles and twigs of yew trees. Taxol-producing fungi as a renewable resource is a very promising way to increase the scale of taxol production. Our group has obtained a taxol-producing endophytic fungus, Aspergillus niger subsp. taxi HD86-9, to examine if A. niger can produce the taxanes. Six compounds from the fermentation broth of strain HD86-9 were isolated and identified by 1H NMR, 13C NMR, and ESI-MS. The results showed that the six compounds included four taxane diterpenoids (taxol, cephalomannine, baccatin III, and 10-deacetyl-baccatin III) and two non-taxane compounds (beta-sitosterol and flavonoid isovitexin). The study verified that the taxanes can be produced by the A. niger, which is very important to taxol production via chemical semi synthesis. Additionally, the finding is potentially very significant to solve the taxol semi-synthetic precursors extracted from needles and twigs of yew trees, and the precursor production can be easily increased through the culture condition optimization, genetic breeding, and metabolic engineering of the A. niger. PMID- 28621106 TI - A Rapid and Efficient Screening Method for Antibacterial Compound-Producing Bacteria. AB - Antibacterial compounds are widely used in the treatment of human and animal diseases. The overuse of antibiotics has led to a rapid rise in the prevalence of drug-resistant bacteria, making the development of new antibacterial compounds essential. This study focused on developing a fast and easy method for identifying marine bacteria that produce antibiotic compounds. Eight randomly selected marine target bacterial species (Agrococcus terreus, Bacillus algicola, Mesoflavibacter zeaxanthinifaciens, Pseudoalteromonas flavipulchra, P. peptidolytica, P. piscicida, P. rubra, and Zunongwangia atlantica) were tested for production of antibacterial compounds against four strains of test bacteria (B. cereus, B. subtilis, Halomonas smyrnensis, and Vibrio alginolyticus). Colony picking was used as the primary screening method. Clear zones were observed around colonies of P. flavipulchra, P. peptidolytica, P. piscicida, and P. rubra tested against B. cereus, B. subtilis, and H. smyrnensis. The efficiency of colony scraping and broth culture methods for antimicrobial compound extraction was also compared using a disk diffusion assay. P. peptidolytica, P. piscicida, and P. rubra showed antagonistic activity against H. smyrnensis, B. cereus, and B. subtilis, respectively, only in the colony scraping method. Our results show that colony picking and colony scraping are effective, quick, and easy methods of screening for antibacterial compound-producing bacteria. PMID- 28621107 TI - Bioconversion of Pinoresinol Diglucoside from Glucose Using Resting and Freeze Dried Phomopsis sp. XP-8 Cells. AB - Phomopsis sp. XP-8 (an endophytic fungus) was previously found to produce pinoresinol diglucoside (PDG), a major antihypertensive compound of Tu-Chung (the bark of Eucommia ulmoides Oliv.), which is widely used in Chinese traditional medicines. In the present study, two bioconversion systems were developed for the production of PDG in Tris-HCl buffer containing glucose and Phomopsis sp. XP-8 cells (both resting and freeze-dried). When other factors remained unchanged, the bioconversion time, glucose concentration, cell ages, cell dosage, pH, temperature, and stirring speed influenced PDG production in a similar and decreasing manner after an initial increase with increasing levels for each factor. Considering the simultaneous change of various factors, the optimal conditions for PDG production were established as 70 g/l cells (8-day-old), 14 g/l glucose, 28 degrees C, pH 7.5, and 180 rpm for systems employing resting cells, and 3.87 g/l cells, 14.67 g/l glucose, 28 degrees C, pH 7.5, and 180 rpm for systems employing freeze-dried cells. The systems employing freeze-dried cells showed lower peak PDG production (110.28 MUg/l), but at a much shorter time (12.65 h) compared with resting cells (23.62 mg/l, 91.5 h). The specific PDG production levels were 1.92 and 24 MUg per gram cells per gram glucose for freeze dried cells and resting cells, respectively. Both systems indicated a new and potentially efficient way to produce PDG independent of microbial cell growth. PMID- 28621109 TI - Comparative Genomic Analysis of Lactobacillus plantarum GB-LP1 Isolated from Traditional Korean Fermented Food. AB - As probiotics play an important role in maintaining a healthy gut flora environment through antitoxin activity and inhibition of pathogen colonization, they have been of interest to the medical research community for quite some time now. Probiotic bacteria such as Lactobacillus plantarum, which can be found in fermented food, are of particular interest given their easy accessibility. We performed whole-genome sequencing and genomic analysis on a GB-LP1 strain of L. plantarum isolated from Korean traditional fermented food; this strain is well known for its functions in immune response, suppression of pathogen growth, and antitoxin effects. The complete genome sequence of GB-LP1 is a single chromosome of 3,040,388 bp with 2,899 predicted open reading frames. Genomic analysis of GB LP1 revealed two CRISPR regions and genes showing accelerated evolution, which may have antibiotic and antitoxin functions. The aim of the present study was to predict strain specific-genomic characteristics and assess the potential of this new strain as lactic acid bacteria at the genomic level using in silico analysis. These results provide insight into the L. plantarum species as well as confirm the possibility of its utility as a candidate probiotic. PMID- 28621108 TI - Inhibitory Effects of Flavonoids from Spatholobus suberectus on Sortase A and Sortase A-Mediated Aggregation of Streptococcus mutans. AB - Seven flavonoids were isolated from Spatholobus suberectus via repetitive column chromatography and high-performance liquid chromatography. The chemical structures of these compounds were identified by spectroscopic analysis and comparison with values reported in the literature. Among the flavonoids tested, 7 hydroxy-6-methoxyflavanone (1) and formononetin (4) exhibited strong inhibitory activity against Streptococcus mutans SrtA, with IC50 values of 46.1 and 41.8 uM, respectively, but did not affect cell viability. The onset and magnitude of inhibition of saliva-induced aggregation in S. mutans treated with compounds 1 and 4 were comparable to the behavior of a srtA-deletion mutant without treatment. PMID- 28621110 TI - Characterization of Microbial Communities in Chinese Rice Wine Collected at Yichang City and Suzhou City in China. AB - Two typical microbial communities from Chinese rice wine fermentation collected in Yichang city and Suzhou city in China were investigated. Both communities could ferment glutinous rice to rice wine in 2 days. The sugar and ethanol contents were 198.67 and 14.47 mg/g, respectively, for rice wine from Yichang city, and 292.50 and 12.31 mg/g, respectively, for rice wine from Suzhou city. Acetic acid and lactic acid were the most abundant organic acids. Abundant fungi and bacteria were detected in both communities by high-throughput sequencing. Saccharomycopsis fibuligera and Rhizopus oryzae were the dominant fungi in rice wine from Suzhou city, compared with R. oryzae, Wickerhamomyces anomalus, Saccharomyces cerevisiae, Mucor indicus, and Rhizopus microsporus in rice wine from Yichang city. Bacterial diversity was greater than fungal diversity in both communities. Citrobacter was the most abundant genus. Furthermore, Exiguobacterium, Aeromonas, Acinetobacter, Pseudomonas, Enterobacter, Bacillus, and Lactococcus were highly abundant in both communities. PMID- 28621111 TI - Antiamoebic Activity of Petiveria alliacea Leaves and Their Main Component, Isoarborinol. AB - Petiveria alliacea L. (Phytolacaceae) is a medicinal plant with a broad range of traditional therapeutic properties, including the treatment of dysentery and intestinal infections caused by protozoan parasites. However, its effects against Entamoeba histolytica have not been reported yet. We investigated the antiamoebic activity present in the leaves of P. alliacea Antiamoebic activity was evaluated in methanolic and aqueous extracts, as well as in the hexanic, methanolic, and EtOAc fractions. The P. alliacea methanolic extract showed a better antiamoebic activity than the aqueous extract with an IC50 = 0.51 mg/ml. Likewise, the hexanic fraction was the most effective fraction, showing a dose-dependent activity against E. histolytica, with an IC50 = 0.68 mg/ml. Hexanic subfraction 12-19 showed the highest antiamoebic activity at 0.8 mg/ml, producing 74.3% growth inhibition without any toxicity in mammal cells. A major component in subfraction 12-19 was identified as isoarborinol, which produced 51.4% E. histolytica growth inhibition at 0.05 mg/ml without affecting mammal cells. The P. alliacea leaf extract has antiamoebic activity that can be attributed to a major metabolite known as isoarborinol. PMID- 28621112 TI - Increased Immunogenicity and Protective Efficacy of a P. aeruginosa Vaccine in Mice Using an Alum and De-O-Acylated Lipooligosaccharide Adjuvant System. AB - Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen that commonly causes fatal infections in cystic fibrosis and burn patients as well as in patients who are hospitalized or have impaired immune systems. P. aeruginosa infections are difficult to treat owing to the high resistance of the pathogen to conventional antibiotics. Despite several efforts, no effective prophylactic vaccines against P. aeruginosa are currently available. In this study, we investigated the activity of the CIA06 adjuvant system, which is composed of alum and de-O-acylated lipooligosaccharide, on a P. aeruginosa outer membrane protein (OMP) antigen vaccine in mice. The results indicated that CIA06 significantly increased the antigen-specific IgG titers and opsonophagocytic activity of immune sera against P. aeruginosa. In addition, the antibodies induced by the CIA06 adjuvanted vaccine exhibited higher cross-reactivity with heterologous P. aeruginosa strains. Finally, mice immunized with the CIA06-adjuvanted vaccine were effectively protected from lethal P. aeruginosa challenge. Based on these data, we suggest that the CIA06 adjuvant system might be used to promote the immunogenicity and protective efficacy of the P. aeruginosa OMP vaccine. PMID- 28621113 TI - Alteration of DNA Methylation in Gastric Cancer with Chemotherapy. AB - Epigenetic alterations such as DNA methylation, histone acetylation, and chromatin remodeling can control gene expression by regulating gene transcription. DNA methylation is one of the frequent epigenetic events that play important roles in cancer development. Cancer cells can gain significant resistance to anticancer drugs and escape programmed cell death through major epigenetic changes, including DNA methylation. To date, several research groups have identified instances of both (i) hypermethylation of tumor suppressor genes, and (ii) global hypomethylation of oncogenes. These changes in DNA methylation status could be used as biomarkers for the diagnosis and prognosis of cancer patients undergoing chemotherapies or other clinical therapies. Herein, we describe genes for which methylation is dependent upon anticancer drug resistance in patients with gastric cancer; we then suggest a significant epigenetic target to focus on for overcoming anticancer drug resistance. PMID- 28621114 TI - Investigating the potential for protective effect against non-melanoma skin cancer in cancer patients receiving oral niacin. PMID- 28621115 TI - Is there an association between neurofibromatosis type I and vitiligo? PMID- 28621116 TI - Tinea faciei incognito. PMID- 28621117 TI - Subungual squamous cell carcinoma: a common pitfall in clinical practice. PMID- 28621118 TI - Concurrent Sweet's Syndrome and erythema nodosum in a patient with bilio pancreatic diversion. PMID- 28621119 TI - Eruptive xanthomas and pancretitis: clinical, dermatoscopy, confocal and pathological correlation. PMID- 28621120 TI - Self-inflicted skin lesions and trichotillomania due to rolled hair. PMID- 28621121 TI - Pyoderma gangrenosum and burns: a special pathergy phenomenon. PMID- 28621122 TI - The intralesional interleukin-2 is an adequate palliative treatment in cutaneous metastases of melanoma. PMID- 28621123 TI - Focus on pemphigoid associated with malignancies. PMID- 28621124 TI - Duration of response in vitiligo lesions after narrowband UVB phototherapy combined with tacrolimus ointment. PMID- 28621125 TI - Superficial acral fibromyxoma with CD10 expression: an underrecognized feature. PMID- 28621126 TI - Identification of Organic Iodine Compounds and Their Transformation Products in Edible Iodized Salt Using Liquid Chromatography-High Resolution Mass Spectrometry. AB - The consumption of edible iodized salt is a key strategy to control and eliminate iodine deficiency disorders worldwide. We herein report the identification of the organic iodine compounds present in different edible iodized salt products using liquid chromatography combined with high resolution mass spectrometry. A total of 38 organic iodine compounds and their transformation products (TPs) were identified in seaweed iodine salt from China. Our experiments confirmed that the TPs were generated by the replacement of I atoms from organic iodine compounds with Cl atoms. Furthermore, the organic iodine compound contents in 4 seaweed iodine salt samples obtained from different manufacturers were measured, with significant differences in content being observed. We expect that the identification of organic iodine compounds in salt will be important for estimating the validity and safety of edible iodized salt products. PMID- 28621127 TI - Understanding the Charge Transfer at the Interface of Electron Donors and Acceptors: TTF-TCNQ as an Example. AB - Charge transfer between an electron donor and an electron acceptor is widely accepted as being independent of their relative configurations if the interaction between them is weak; however, the limit of this concept for an interacting system has not yet been well established. Our study of prototypical electron donor-acceptor molecules, tetrathiafulvalene-tetracyanoquinodimethane, using density functional theory based on an advanced functional, clearly demonstrates that for interacting molecules, their configurational arrangement is as important as their individual electronic properties in the asymptotic limit to determine the charge transfer direction. For the first time, we demonstrate that by changing their relative orientation, one can reverse the charge transfer direction of the pair, causing the molecules to exchange roles as donor and acceptor. Our theory has important implications for understanding the interfacial charge-transfer mechanism of hybrid systems and related phenomena. PMID- 28621128 TI - Nitrogen-Doped Graphene on Transition Metal Substrates as Efficient Bifunctional Catalysts for Oxygen Reduction and Oxygen Evolution Reactions. AB - Composites of transition metal and carbon-based materials are promising bifunctional catalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), and are widely used in rechargeable metal-air batteries. However, the mechanism of their enhanced bicatalytic activities remains elusive. Herein, we construct N-doped graphene supported by Co(111) and Fe(110) substrates as bifunctional catalysts for ORR and OER in alkaline media. First-principles calculations show that these heterostructures possess a large number of active sites for ORR and OER with overpotentials comparable to those of noble metal benchmark catalysts. The catalytic activity is modulated by the coupling strength between graphene and the metal substrates, as well as the charge distribution in the graphitic sheet, which is delicately mediated by N dopants. These theoretical results uncover the key parameters that govern the bicatalytic properties of hybrid materials and help prescribe the principles for designing multifunctional electrocatalysts of high performance. PMID- 28621129 TI - Multiscale Shear-Lag Analysis of Stiffness Enhancement in Polymer-Graphene Nanocomposites. AB - Graphene and other two-dimensional (2D) materials are of emerging interest as functional fillers in polymer-matrix composites. In this study, we present a multiscale atomistic-to-continuum approach for modeling interfacial stress transfer in graphene-high-density polyethylene (HDPE) nanocomposites. Via detailed characterization of atomic-level stress profiles in submicron graphene fillers, we develop a modified shear-lag model for short fillers. A key feature of our approach lies in the correct accounting of stress concentration at the ends of fillers that exhibits a power-law dependence on filler ("flaw") size, determined explicitly from atomistic simulations, without any ad hoc modeling assumptions. In addition to two parameters that quantify the end stress concentration, only one additional shear-lag parameter is required to quantify the atomic-level stress profiles in graphene fillers. This three-parameter model is found to be reliable for fillers with dimensions as small as ~10 nm. Our model predicts accurately the elastic response of aligned graphene-HDPE composites and provides appropriate upper bounds for the elastic moduli of nanocomposites with more realistic randomly distributed and oriented fillers. This study provides a systematic approach for developing hierarchical multiscale models of 2D material based nanocomposites and is of particular relevance for short fillers, which are, currently, typical of solution-processed 2D materials. PMID- 28621130 TI - Loading Cd0.5Zn0.5S Quantum Dots onto Onion-Like Carbon Nanoparticles to Boost Photocatalytic Hydrogen Generation. AB - Carbon dots (C dots, size < 10 nm) have been conventionally decorated onto semiconductor matrixes for photocatalytic H2 evolution, but the efficiency is largely limited by the low loading ratio of the C dots on the photocatalyst. Here, we propose an inverse structure of Cd0.5Zn0.5S quantum dots (QDs) loaded onto the onionlike carbon (OLC) matrix for noble metal-free photocatalytic H2 evolution. Cd0.5Zn0.5S QDs (6.9 nm) were uniformly distributed on an OLC (30 nm) matrix with both upconverted and downconverted photoluminescence property. Such an inverse structure allows the full optimization of the QD/OLC interfaces for effective energy transfer and charge separation, both of which contribute to efficient H2 generation. An optimized H2 generation rate of 2018 MUmol/h/g (under the irradiation of visible light) and 58.6 MUmol/h/g (under the irradiation of 550-900 nm light) was achieved in the Cd0.5Zn0.5S/OLC composite samples. The present work shows that using the OLC matrix in such a reverse construction is a promising strategy for noble metal-free solar hydrogen production. PMID- 28621132 TI - One-Pot Consecutive Sulfonamidation/ipso-Cyclization Strategy for the Construction of Azaspirocyclohexadienones. AB - Harnessing of Morita-Baylis-Hillman (MBH) carbonates of acetylenic aldehydes as handy synthons has allowed a facile synthesis of azaspirocyclohexadienones by sequential DABCO-promoted sulfonamidation/ICl-mediated ipso-iodocyclization reactions. A variety of MBH-carbonates having aryl or heteroaryl groups on the alkyne functionality fruitfully participated in the one-pot ipso-annulation reaction to provide the corresponding 3-iodo spirocyclohexadienones. The sulphonamide functionality was further utilized to construct the tricyclic fused sultam framework. PMID- 28621131 TI - NHC Ligands Tailored for Simultaneous Regio- and Enantiocontrol in Nickel Catalyzed Reductive Couplings. AB - An exceptionally hindered class of enantiopure NHC ligands has been developed. While racemic forms had previously been utilized, a scalable and practical route to the enantiopure form of this ligand class is described utilizing a Buchwald Hartwig N,N-diarylation in a highly sterically demanding environment. Using this newly accessible ligand class, nickel-catalyzed enantioselective reductive coupling reactions of aldehydes and alkynes have been developed. These studies illustrate that the newly available NHC ligands are well suited for simultaneous control of regio- and enantioselectivity, even in cases with internal alkynes possessing only very subtle steric differences between two aliphatic substituents. The steric demand of the new ligand class enables a complementary regiochemical outcome compared with previously described enantioselective processes. Using this method, a number of allylic alcohol derivatives were efficiently obtained with high regioselectivity (up to >95:5) and high enantioselectivity (up to 94% ee). The reaction conditions can also be extended to the reaction of aldehydes and allenes, providing silyl-protected allylic alcohol derivatives possessing a terminal methylene substituent. Computational studies have explained the origin of the exceptional steric demand of this ligand class, the basis for enantioselectivity, and the cooperative relationship of the aldehyde, alkyne, and ligand in influencing enantioselectivity. PMID- 28621133 TI - Development of a beta-C-H Bromination Approach toward the Synthesis of Jerantinine E. AB - The development of an asymmetric and highly convergent three-component synthesis of the functionalized ABC ring system of the Aspidosperma alkaloid jerantinine E is reported. The presented synthetic strategy relies on our recently developed method for the one-pot beta-C-H bromination of enones, which allows for rapid construction of the tricyclic tetrahydrocarbazolone core via a palladium catalyzed amination and oxidative indole formation. Moreover, a secondary amine building block that contains all carbon atoms of the D and E ring of the natural product could be installed in three additional steps. PMID- 28621134 TI - Surfactant- and Binder-Free Hierarchical Platinum Nanoarrays Directly Grown onto a Carbon Felt Electrode for Efficient Electrocatalysis. AB - The future of fuel cells that convert chemical energy to electricity relies mostly on the efficiency of oxygen reduction reaction (ORR) due to its sluggish kinetics. By effectively bypassing the use of organic surfactants, the postsynthesis steps for immobilization onto electrodes, catalytic ink preparation using binders, and the common problem of nanoparticles (NPs) detachment from the supports involved in traditional methodologies, we demonstrate a versatile electrodeposition method for growing anisotropic microstructures directly onto a three-dimensional (3D) carbon felt electrode, using platinum NPs as the elementary building blocks. The as-synthesized materials were extensively characterized by integrating methods of physical (thermogravimetric analysis, X ray diffraction, scanning electron microscopy, inductively coupled plasma, and X ray photoelectron spectroscopy) and electroanalytical (voltammetry, electrochemical impedance spectrometry) chemistry to examine the intricate relationship of material-to-performance and select the best-performing electrocatalyst to be applied in the model reaction of ORR for its practical integration into a microbial fuel cell (MFC). A tightly optimized procedure enables decorating an electrochemically activated carbon felt electrode by 40-60 nm ultrathin 3D-interconnected platinum nanoarrays leading to a hierarchical framework of ca. 500 nm. Half-cell reactions reveal that the highly rough metallic surface exhibits improved activity and stability toward ORR (Eonset ~ 1.1 V vs reversible hydrogen electrode, p(HO2-) < 0.1%) and the hydrogen evolution reaction (-10 mA cm-2 for only 75 mV overpotential). Owing to its unique features, the developed material showed distinguished performance as an air-breathing cathode in a garden compost MFC, exhibiting better current and faster power generation than those of its equivalent classical double chamber. The enhanced performance of the material obtained herein is explained by the absence of any organic surfactants on the surface of the nanoarrays, the good metal-support interaction, particular morphology of the nanoarrays, and the reduced aggregation/detachment of particles. It promises a radical improvement in current surface reactions and paves a new way toward electrodes with regulated surface roughness, allowing for their successful application in heterogeneous catalysis. PMID- 28621135 TI - (E)- and (Z)-Stereodefined Enol Sulfate Esters Derived from alpha-Aryl Aldehydes: Stereocomplementary Synthesis of Styryl Sulfate Natural Products. AB - A method for the stereoselective formation of enol sulfate esters from alpha-aryl aldehydes is described. This method involved the stereocontrolled enolization of a carbonyl group with DBU or t-BuOK followed by trapping with a reactive sulfuryl imidazolium salt, providing the corresponding styryl enol sulfate esters in good to excellent yields and stereoselectivities. This method was applied to the first total synthesis of the enol sulfate natural products in a stereocomplementary manner. PMID- 28621136 TI - Three-Dimensional Morphology Control Yielding Enhanced Hole Mobility in Air Processed Organic Photovoltaics: Demonstration with Grazing-Incidence Wide-Angle X-ray Scattering. AB - Polymer organic photovoltaic (OPV) device performance is defined by the three dimensional morphology of the phase-separated domains in the active layer. Here, we determine the evolution of morphology through different stages of tailored solvent vapor and thermal annealing techniques in air-processed poly(3 hexylthiophene-2,5-diyl)/phenyl-C61-butyric acid methyl ester-based OPV blends. A comparative evaluation of the effect of solvent type used for vapor annealing was performed using grazing-incidence wide-angle X-ray scattering, atomic force microscopy, and UV-vis spectroscopy to probe the active-layer morphology. A nonhalogenated orthogonal solvent was found to impart controlled morphological features within the exciton diffusion length scales, enhanced absorbance, greater crystallinity, increased paracrystalline disorder, and improved charge-carrier mobility. Low-boiling, fast-diffusing isopropanol allowed the greatest control over the nanoscale structure of the solvents evaluated and yielded a cocontinuous morphology with narrowed domains and enhanced paths for the charge carrier to reach the anode. PMID- 28621137 TI - Enantioselective Copper-Catalyzed Oxy-Alkynylation of Diazo Compounds. AB - Enantioselective catalytic methods allowing the addition of both a nucleophile and an electrophile onto diazo compounds give a fast access into important building blocks. Herein, we report the highly enantioselective oxyalkynylation of diazo compounds using ethynylbenziodoxol-(on)e reagents and a simple copper bisoxazoline catalyst. The obtained alpha-benzoyloxy propargylic esters are useful building blocks, which are difficult to synthesize in enantiopure form using other methods. The obtained products could be efficiently transformed into vicinal diols and alpha-hydroxy propargylic esters without loss in enantiopurity. PMID- 28621138 TI - Divergent Synthesis of Solanidine and 22-epi-Solanidine. AB - A divergent synthesis of solanidine and 22-epi-solanidine, two 25S natural steroidal alkaloids, from 25R-configured diosgenin acetate, is described. Initially, solanidine was synthesized through a series of transformations including a cascade ring-switching process of furostan-26-acid, an epimerization of C25 controlled by the conformation of six-membered lactone ring, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process. To address the epimerization issue during Schmidt reaction, an improved synthesis was developed, which also led to a synthesis of 22-epi-solanidine. In this synthesis, selective transformation of azido lactone to azido diol and amino diol was realized through a reduction relay tactic. The azido diol was transformed to solanidine via an intramolecular Schmidt reaction/N alkylation/reduction process and to 22-epi-solanidine via an intramolecular double N-alkylation process. PMID- 28621139 TI - Coupling Urinary Trihalomethanes and Metabolomic Profiles of Type II Diabetes: A Case-Control Study. AB - Abiding by the exposome paradigm, incorporation of external and internal exposure metrics using metabolomics tools is warranted to refine the etiology of type II diabetes (T2D). A small (n = 51) age- and sex-matched case-control study was conducted in Cyprus coupling urinary trihalomethanes (THMs) with T2D. The objectives were to (i) perform a comparative assessment of different deconvolution parameters in compound identification and (ii) evaluate the association between differentially expressed metabolites and either urinary THM or T2D status. Untargeted urinary metabolomics was performed with a GC-MS triple quadrupole mass spectrometry system. Results of three deconvolution searches each yielding >130 metabolites were used in subsequent analyses. The number of differentially expressed compounds by T2D status or the urinary THM levels (above or below median) differed among the three searches. The identity of these compounds was also confirmed using known standards (level 1 identification). In multivariate logistic regression, 3-aminoisobutyric acid was an important predictor of lower odds of T2D after adjusting for known risk factors. The widespread incorporation of metabolomics in population studies accounting for environmental exposures will eventually pave the way for the exposome characterization, also improving our understanding of the disease process. PMID- 28621140 TI - Long-Lived Photoinduced Polarons in Organohalide Perovskites. AB - The long diffusion length of charge carriers in the CH3NH3PbI3 perovskite is one of the most relevant properties for explaining the high photovoltaic efficiency of perovskite solar cells. As a possible mechanism for the large diffusion length of electrons and holes, several authors suggested a reduced coulomb attraction of the carriers due to the formation of polarons. Here we performed continuous wave far-infrared photoinduced absorption (PIA) experiments on CH3NH3PbI3; spectral changes are associated with local deformation of the lattice around the photogenerated long-lived charges, a typical signature of photoinduced polarons. Ab initio calculations show confinement of charge carriers at the interface between structural domains characterized by a different tilting of the PbI6 octahedra. The differential IR spectrum between unperturbed and perturbed simulated structures shows a close pattern to the experimental PIA. Positive and negative charges are confined in different varieties of the perovskites coherent with the low recombination and long diffusion length of photogenerated carriers. PMID- 28621142 TI - Androgen deprivation therapy and cardiovascular complications. AB - Cardiovascular complications associated with the use of antiandrogens have already been known for some time. Based on the results of the latest meta analyses and clinical studies published in the last few years, the attention of the scientific community is focused on the deleterious cardiovascular effects of gonadotropine-releasing hormon agonists in context of the androgen deprivating therapy. The cardiac toxicity is a problem especially in patients with preexisting cardiovascular comorbidities. Increased arterial wall thickening along with endothelial dysfunction has been observed in patients with descreased androgens levels in the peripheral blood. The treatment with gonadotropine releasing hormon agonists may disrupt the intracellular concentration of calcium ions and the contractile process and potentially result in pathological remodelling of heart. Here, we give several possible mechanisms of action of gonadotropine-releasing hormon agonists on the cardiovascular system that may be a potential explanation of the clinical observations (Ref. 44). PMID- 28621145 TI - Evaluating the Hierarchical Structure of ADHD Symptoms and Invariance Across Age and Gender. AB - The bifactor model of attention-deficit/hyperactivity disorder (ADHD) has been extensively explored, yet the tendency of the bifactor model to overfit data necessitates investigation of alternative, more parsimonious models, such as a modified bifactor structure. The present study used item response theory to compare unidimensional, correlated factors, bifactor, and modified bifactor models of ADHD symptoms in a clinical sample of youth ( N = 1,612) and examined differential item functioning (DIF) by age (<11 and >=11 years) and gender. Results suggested that two restricted bifactor models showed superior fit compared with alternative models, and support strong general and inattention dimensions, with unreliable hyperactivity and impulsivity dimensions. No DIF was found across gender or age. The present study confirms that the general dimension (i.e., inhibition) and one specific dimension (i.e., sustained attention) represent distinct variability in ADHD symptoms that may improve prediction of symptom persistence, treatment response, or functional outcomes. PMID- 28621146 TI - Dissociation of Executive and Attentional Elements of the Digit Span Task in a Population of Older Adults: A Latent Class Analysis. AB - The prevailing model for working memory proposes the existence of a "central executive" responsible for coordinating and prioritizing incoming information from sensory and association cortices. The Digit Span task is commonly used by clinicians to parse attentional and executive components of working memory; however, the interrelatedness of these constructs in the context of advanced age and neurodegenerative disease remains an area of active investigation. The current study details a procedure and rationale for the use of latent class analysis, a data-driven, person-centered method, in the investigation of older adults and dementia. Class analysis of digit span performance in older adults ( n = 874) drawn from a specialty clinic revealed four classes with distinct performance across task subcomponents. In three of the classes, attentional and executive elements demonstrated similar performance. The fourth class and implications of class structure are discussed in the context of aging. PMID- 28621147 TI - Confirmatory factor analysis of the revised version of the Thai multidimensional scale of perceived social support among the elderly with depression. AB - OBJECTIVE: Difficulties in modeling the Multidimensional Scale of Perceived Social Support (MSPSS) have occurred, and these were corrected in the revised version of the Thai MSPSS. However, the revised version has not been tested in elderly populations. The present study aimed at confirming the factor structure of the revised version of the MSPSS among the elderly with depressive disorders, in populations with or without depressive disorders. METHODS: Eight hundred and three elderly patients were recruited from four tertiary hospitals; 190 (23.7%) had depressive disorders. All completed the revised Thai MSPSS consisting of 12 items, using a 7-point Likert scale. Confirmatory factor analysis (CFA) of the MSPSS was conducted in both groups. RESULTS: The mean age was 69.24 years (SD 6.88), and 70% of the sample was female. There were no significant difference in demographic data between two groups. The revised version of the Thai MSPSS provided excellent internal consistency. The three-factor model was clearly superior to other alternative models in both depressed and non-depressed groups. CFA for the whole group revealed an acceptable model fit: chi2 = 147.44, df = 45, p < 0.001; Tucker-Lewis Index 0.975; Comparative Fit Index 0.982; Good Fit Index 0.966; and root-mean-square error of approximation 0.056. The fit statistics in the depressed group was better than in the non-depressed group across all models. CONCLUSIONS: Due to its robust factor structure, these data support the use of the revised MSPSS as a brief instrument for assessing perceived social support in the elderly with or without depressive disorders. PMID- 28621148 TI - Association between cognitive vulnerability to depression - dysfunctional attitudes and glycaemic control among in-patients with type 2 diabetes in a hospital in Beijing: a multivariate regression analysis. AB - This cross-sectional study aimed to investigate the relationship between glycosylated haemoglobin (HbA1c) and cognitive vulnerability to depression (dysfunctional attitudes) in patients with type 2 diabetes mellitus. A total of 245 valid records from June 2016 to December 2016 were collected from a hospital in Beijing. Participants were asked to complete four questionnaires (Dysfunctional Attitudes Scale, Automatic Thoughts Questionnaire, Zung Self rating Depression Scale, and World Health Organization Quality of Life Instrument Short Form) to assess mental health and quality of life. Multivariate regression analysis was conducted to determine the correlations between HbA1c, mental health, quality of life and other clinical variables. The results showed that dysfunctional attitudes were associated with HbA1c, with a standardized regression coefficient (beta) of .13 (p = .01), although 1 h C-peptide (beta = .75, p < .0001) was the most significant predictor of HbA1c in the regression model. The results indicated that dysfunctional attitudes, as a cognitive vulnerability to depression, were a relevant factor in HbA1c, although further studies are needed to establish the nature of the connection between dysfunctional attitudes and glycaemic control in diabetes patients. PMID- 28621150 TI - Caregiving Burden and Life Satisfaction Among Caregivers of Cancer Patients Admitted to the Emergency Department. AB - This descriptive and cross-sectional study aimed to determine caregiving burden and life satisfaction among caregivers of cancer patients admitted to the emergency department. The study included 272 caregivers. Data were collected using an information form, the Zarit Burden Interview (ZBI), and the Satisfaction With Life Scale (SWLS). Among the patients, 19.1% were diagnosed with lung cancer; 44.1% were in the fourth stage of their disease; and 52% had metastasis. The mean ZBI total score was 41.2 +/- 9.7, while the mean SWLS total score of caregivers was 17.6 +/- 4.0. It was concluded that the mean ZBI and SWLS scores of patients' caregivers were moderately and negatively correlated ( p < .001, r = -.485). There was a negative and significant relationship between caregiving burden and quality of life. PMID- 28621149 TI - Identification and evaluation of lncRNA and mRNA integrative modules in human peripheral blood mononuclear cells. AB - AIM: To identify sets of functionally related long noncoding RNAs (lncRNAs) and mRNAs and to evaluate the importance of lncRNAs in an lncRNA-mRNA network. METHODS: We carried out weighted gene co-expression network analysis and enrichment analyses to identify functional modules of co-expressed lncRNAs and mRNAs in human peripheral blood mononuclear cells of 43 females. RESULTS: We identified seven modules and found hub lncRNAs in each module. Four of the seven modules had significant gene ontology enrichments. Some of the hub lncRNAs (e.g., SSX8, UCA1, HOXA-AS2, STARD4-AS1 and PCBP1-AS1) have known functions related with diseases such as cancers. CONCLUSION: We identified seven biologically important lncRNA and mRNA integrative modules in females and showed that lncRNAs might play important roles in lncRNA-mRNA co-expression modules. PMID- 28621151 TI - Case report and literature review on contrast-induced encephalopathy. AB - Contrast-induced encephalopathy (CIE) is a rare neurological complication following the administration of injectable intravascular contrast media. Patients with CIE present a wide spectrum of symptoms such as headache, transient cortical blindness, seizure and focal neurological deficits. The diagnosis of CIE requires a high index of suspicion. Its early recognition is of paramount importance in instituting the appropriate supportive treatment in the form of intravenous fluids and also in avoiding unnecessary potentially harmful treatment such as intravenous thrombolysis for suspected ischemic stroke. Here, we report the case of a 62-year-old male patient with a typical presentation of CIE immediately following coronary angiography. We then continue to briefly review the relevant literature on CIE to date. PMID- 28621152 TI - Racial Disparities in Health Service Utilization Among Medicare Fee-for-Service Beneficiaries Adjusting for Multiple Chronic Conditions. AB - OBJECTIVE: To examine racial disparities in health services utilization in Hawaii among Medicare fee-for-service beneficiaries aged 65 years and above. METHOD: All cause utilization of inpatient, outpatient, emergency, home health agency, and skilled nursing facility admissions were investigated using 2012 Medicare data. For each type of service, multivariable logistic regression model was used to investigate racial disparities adjusting for sociodemographic factors and multiple chronic conditions. RESULTS: Of the 84,212 beneficiaries, 27.8% were White, 27.4% were Asian, 27.3% were Pacific Islanders; 70.3% had two or more chronic conditions and 10.5% had six or more. Compared with Whites, all racial groups experienced underutilization across all types of services. As the number of chronic conditions increased, the utilization of inpatient, home health care, and skilled nursing facility dramatically increased. DISCUSSION: Disparities persist among Asians and Pacific Islanders who encounter the problem of underutilization of various health services compared with Whites. PMID- 28621153 TI - Depression in primary Sjogren's syndrome: a systematic review and meta-analysis. AB - There is substantial uncertainty regarding the prevalence of depression in Primary Sjogren's syndrome (pSS). We conducted a systematic review aiming to evaluate the association of pSS with depression. PubMed, Web of Science, VIP, CNKI and Wanfang database were searched to find the published literatures (from these databases established to October 2016). Studies were screened according to inclusion and exclusion criteria and the qualities of included studies were evaluated. The data was analyzed using Revman5.2 software. A total of 12 studies including 1917 patients were eligible for inclusion in the systematic review and meta-analysis. In this meta-analysis, Severity of depression was assessed using psychometric measures, such as PHQ-9; HADS; CES-D; Zung depression scale and BDI. The result revealed that pSS was associated with an increased prevalence of depression (summary odds ratio (OR) = 5.36, 95% CI: 4.05-7.09, P < 0.01). The depression score in pSS patients (standardized mean difference (SMD) = 1.47, 95% CI: 0.81-2.12, P < 0.01) were higher than in the control group. Depression is highly prevalent in pSS than in healthy controls. Early recognition and appropriate intervention are therefore essential to reduce the negative impact of depression on the patient's quality of life and outcome of their disease. PMID- 28621154 TI - Sociodemographic Factors Associated With Changes in Successful Aging in Spain: A Follow-Up Study. AB - OBJECTIVE: Successful aging (SA) refers to maintaining well-being in old age. Several definitions or models of SA exist (biomedical, psychosocial, and mixed). We examined the longitudinal association between various SA models and sociodemographic factors, and analyzed the patterns of change within these models. METHOD: This was a nationally representative follow-up in Spain including 3,625 individuals aged >=50 years. Some 1,970 individuals were interviewed after 3 years. Linear regression models were used to analyze the survey data. RESULTS: Age, sex, and occupation predicted SA in the biomedical model, while marital status, educational level, and urbanicity predicted SA in the psychosocial model. The remaining models included different sets of these predictors as significant. In the psychosocial model, individuals tended to improve over time but this was not the case in the biomedical model. CONCLUSION: The biomedical and psychosocial components of SA need to be addressed specifically to achieve the best aging trajectories. PMID- 28621155 TI - The role of telemedicine in obstructive sleep apnea management. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is a common disease that leads in notorious symptoms and comorbidities. Although general measures are important, continuous positive airway pressure (CPAP) is the best treatment option. However, compliance can be suboptimal and telemedicine may play a role to improve it. Areas covered: Review authors searched EMBASE, PubMed and Cochrane data bases using the following keywords: continuous positive airway pressure, Obstructive sleep apnea, telemedicine, respiratory telemedicine, information and communication technology. Papers published between 2000 and 2016 in English language were considered. Expert commentary: To improve OSA management, there is a pressing need to develop new cost-effective strategies, particularly those related to OSA treatment, from measures such as lifestyle changes to CPAP use. Two broad strategies should be implemented: 1) adequate pre-, peri-, and post titration measures to ensure correct diagnosis, adequate training, and appropriate support during follow up; and 2) the use of technological advances including both the optimization of CPAP devices and the use of telemedicine, specially focused on the first days or weeks of treatment. Telemedicine can help with these processes, especially when it is personalized to the needs of each patient group. PMID- 28621156 TI - Pilot study: use of contrast-enhanced ultrasonography in feline renal transplant recipients. AB - Objectives The study aims were to evaluate the feasibility of contrast-enhanced ultrasonography in feline renal transplant recipients in the post-transplantation period and to report findings in a case with presumptive delayed allograft ischemia. Methods Cats were imaged postoperatively using contrast harmonic ultrasonography after a bolus injection of a microbubble contrast medium. Time/mean pixel intensity curves were generated for cortical and medullary regions of interest in the renal allograft in each cat. Arrival time, time to peak, wash-in slope, wash-out slope, mean transit time and renal blood flow were calculated for each area. Results Within the renal cortices of cats without ureteral obstruction 1 day post-transplantation, arrival time was 2.0-6.3 s, time to peak was 3.6-30.1 s, wash-in rate was 2.45-41.14 mean pixel intensity (MPI)/s, wash-out rate was -2.01 to -0.47 MPI/s and blood flow was 6.1-106.5 MPI/s. Ratio mean transit time was 0.29-1.29. Typical cortical and medullary perfusion patterns were observed in these cats. In one cat with delayed graft ischemia followed by presumptive acute transplant rejection, dynamic and heterogeneous cortical and medullary perfusion was demonstrated. Decreases in cortical blood flow were paralleled by elevated serum creatinine. Conclusions and relevance Contrast-enhanced ultrasonography can be used in feline renal transplant recipients and provides both qualitative and quantitative data regarding renal allograft perfusion. PMID- 28621157 TI - Predicting Individual Differences in Reading and Spelling Skill With Artificial Script-Based Letter-Speech Sound Training. AB - In this study, we examined the learning of letter-speech sound correspondences within an artificial script and performed an experimental analysis of letter speech sound learning among dyslexic and normal readers vis-a-vis phonological awareness, rapid automatized naming, reading, and spelling. Participants were provided with 20 min of training aimed at learning eight new basic letter-speech sound correspondences, followed by a short assessment of mastery of the correspondences and word-reading ability in this unfamiliar script. Our results demonstrated that brief training is moderately successful in differentiating dyslexic readers from normal readers in their ability to learn letter-speech sound correspondences. The normal readers outperformed the dyslexic readers for accuracy and speed on a letter-speech sound matching task, as well as on a word reading task containing familiar words written in the artificial orthography. Importantly, the new artificial script-related measures were related to phonological awareness and rapid automatized naming and made a unique contribution in predicting individual differences in reading and spelling ability. Our results are consistent with the view that a fundamental letter speech sound learning deficit is a key factor in dyslexia. PMID- 28621158 TI - Signaling pathway profiling using reverse-phase protein array and its clinical applications. AB - INTRODUCTION: Increased accessibility to next-generation sequencing within the last decade has led to a paradigm shift in cancer treatment from one-size-fits all medicine to precision medicine providing therapeutic strategies tailored to the requirements of individual patients. However, the effect of even the most successful agent yet tested is only transient, and durable efficacy has yet to be achieved. Genome- and transcriptome-based approaches cannot fully predict the diversity of protein expression patterns or post-translational modifications that directly contribute to cancer pathogenesis and physiology. This underscores the need for concordant proteomic analysis in the next stage of precision medicine. Areas covered: This review begins with an overview of the recent advances and trends in precision medicine that currently rely on genomics, and highlights the utility of antibody-based reverse-phase protein array (RPPA) technology as a proteomic tool in this context. Expert commentary: RPPA is well suited for pharmacodynamics analysis in view of its ability to precisely map signaling status using limited amounts of clinical samples. In addition, the cost effectiveness and rapid turn-around time of the RPPA platform offer a substantial advantage over existing molecular profiling technologies in clinical settings. PMID- 28621159 TI - Dual antiretroviral therapy for HIV infection. AB - INTRODUCTION: For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naive and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction maintenance. PMID- 28621161 TI - DNA methylation patterns in ulcerative colitis-associated cancer: a systematic review. AB - BACKGROUND: Evidence points to the role of DNA methylation in ulcerative colitis (UC)-associated cancer (UCC), the most serious complication of ulcerative colitis. A better understanding of the etiology of UCC may facilitate the development of new therapeutic targets and help to identify biomarkers of the disease risk. METHODS: A search was performed in three databases following PRISMA protocol. DNA methylation in UCC was compared with sporadic colorectal cancer (SCRC), and individual genes differently methylated in UCC identified. RESULTS: While there were some similarities in the methylation patterns of UCC compared with SCRC, generally lower levels of hypermethylation in promoter regions of individual genes was evident in UCC. Certain individual genes are, however, highly methylated in colitis-associated cancer: RUNX3, MINT1, MYOD and p16 exon1 and the promoter regions of EYA4 and ESR. CONCLUSION: Patterns of DNA methylation differ between UCC and SCRC. Seven genes appear to be promising putative biomarkers. PMID- 28621160 TI - Epigenome-wide association study of chronic obstructive pulmonary disease and lung function in Koreans. AB - AIM: To identify differentially methylated probes (DMPs) and regions (DMRs) in relation to chronic obstructive pulmonary disease (COPD) and lung function traits. METHODS: We performed an epigenome-wide association study of COPD and spirometric parameters, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC, in blood DNA using the Infinium HumanMethylation450 (n = 100, a Korean COPD cohort). RESULTS: We found one significant DMP (cg03559389, DIP2C) and 104 significant DMRs after multiple testing correction. Of these, 34 DMRs mapped to genes differential expressed with respect to the same trait. Five of the genes were associated with more than two traits: CTU2, USP36, ZNF516, KLK10 and CPT1B. CONCLUSION: We identified novel differential methylation loci related to COPD and lung function in blood DNA in Koreans and confirmed previous findings in non-Asians. Epigenetic modification could contribute to the etiology of these phenotypes. PMID- 28621162 TI - Single-centre experience of STENTYS Xposition S in treatment of left main stem lesions. AB - BACKGROUND: The second generation STENTYS Xposition S self-expanding stent with a novel balloon delivery system was launched in May 2015. The stents unique properties are well suited for the treatment of left main stem disease where large diameters, coverage of diameter differences and precise positioning are required. We report the first consecutive experience of using this device in the treatment of left main stem lesions. METHODS: 20 consecutive patients with a mean age of 73.9+/-10.1 years were treated over a period of 8 months at our institution and were assessed on the parameters of technical, angiographic and procedural success. RESULTS: Technical success was achieved in 95% of cases and angiographic success in 80% of cases. There was no incidence of geographical miss. Side branch access was straightforward, with no failure to recross stent struts, dilate or deploy a second stent if required. In this unselected clinical cohort, 2 critically ill patients with cardiogenic shock on presentation died despite successful revascularisation. There was no incidence of early stent related complications up to 30-day follow up. CONCLUSION: This first consecutive series of left main lesions treated with STENTYS Xposition S documents high acute technical and procedural success rates. PMID- 28621163 TI - Eribulin in advanced liposarcoma and leiomyosarcoma. AB - INTRODUCTION: The heterogeneity of soft tissue sarcomas (STS) presents a formidable management challenge. Consequently, one of the main research goals is to define specific tailored therapy for each histological subtype and to develop a more personalised approach to treatment. The standard first line chemotherapy for advanced STS is doxorubicin, with or without ifosfamide, however, a number of different drugs are emerging as active therapies beyond first-line. Areas covered: Eribulin has recently been approved for advanced liposarcoma, after an anthracycline-containing regimen, demonstrating an overall survival (OS) advantage in liposarcoma and leiomyosarcoma in a randomised Phase III clinical trial. In this manuscript, an overview of the efficacy and safety of eribulin in STS is presented, highlighting different clinical outcomes between histological subtypes and comparing data with other effective drugs used in the treatment of sarcomas. The potential mechanisms of action of eribulin are also described, including its activity as potent microtubule-destabilizing anticancer agent, which has other antitumor biological effects. Expert commentary: Eribulin is highly effective in some STS populations and also has an acceptable toxicity profile. Further studies are required to better understand the precise mechanism of action of this agent and potential role in combination schedules. PMID- 28621165 TI - Prolactin levels in risperidone treatment of first-episode schizophrenia. AB - OBJECTS: To evaluate the risperidone effect on prolactin (PRL) levels and to analyse the relation between PRL change and treatment response in first-episode schizophrenia patients. METHOD: Patients with a first-episode of schizophrenia who were consecutively admitted for hospitalisation participated in a longitudinal follow-up study that included clinical evaluation (PANSS) and PRL assessment. All patients were treated under open conditions with risperidone. RESULTS: Risperidone in an average dose lower than 4 mg significantly improved both positive and negative symptoms. Co-operating responders undergoing maintenance therapy showed a mild trend towards further long-term improvement. At the end of acute treatment the average elevation of PRL levels almost doubled the baseline value. There was a trend among responders to return to their initial values during long-term therapy. Three-quarters of the subjects had hyperprolactinaemia at the end of acute treatment (44 days), and after 1 year about one-quarter had hyperprolactinaemia. No significant correlation between PRL change and PANSS score change was found. CONCLUSION: There is a considerable variation of PRL elevation among subjects. In some patients the development of tolerance of the PRL-elevating effect was observed. Risperidone-induced changes of PRL levels may not be associated with treatment response. PMID- 28621164 TI - Effect of psoriasis activity and topical treatment on plasma epidermal growth factor (EGF) and its soluble receptor (sEGFR). AB - BACKGROUND: Pathogenesis of psoriasis involves epidermal growth factor (EGF) that participates in keratinocyte proliferation, angiogenesis and cell differentiation through binding to soluble epidermal growth factor receptor (sEGFR). It is synthesised by, among others, keratinocytes, especially within psoriatic skin. OBJECTIVE: To evaluate EGF and sEGFR plasma concentrations during topical psoriatic treatment. METHODS: Blood samples were collected from 51 patients with plaque psoriasis. EGF and sEGFR plasma concentrations were examined with immunoenzymatic method prior and 14 days after topical treatment. The outcomes were analyzed with respect to PASI. RESULTS: Mean EGF concentration was higher in the plasma of psoriatic patients compared to the control group (p = .401) while mean sEGFR concentration was over twofold lower compared to the control group (p < .001). After the therapy, an insignificant decrease in EGF plasma concentration (p = .835) and a significant increase in sEGFR concentration (p = .017) compared to initial values were observed. The coefficient of EGF/sEGFR concentration calculated for each individual had similar values before and after the treatment (p = .009), both of which were significantly higher compared to control group (respectively p < .001, p < .008). CONCLUSION: Epidermal growth factor and its soluble receptor may be a useful markers in monitoring clinical course of psoriasis and the effectiveness of therapy. PMID- 28621166 TI - L-Asparaginase for newly diagnosed extra-nodal NK/T-cell lymphoma: systematic review and meta-analysis. AB - OBJECTIVES: The aim of this review was to compare the efficacy of asparaginase (ASP)-containing vs ASP-absent regimens in the first-line treatment of ENKTL patients. METHODS: The PRISMA protocol was used to search PubMed and Embase for both controlled and uncontrolled studies of ASP or alternative chemotherapy (CT) for newly diagnosed ENKTL, published in English by March 2017. The regimens were compared to calculate relative risk (RR) with 95% confidence interval (CI) of the overall response rate (ORR), complete response (CR) or partial response (PR). RESULTS: Out of 38 studies included, eight were controlled trials, with the pooled RR of ORR in stage I-II 1.54 (95% CI 1.34-1.77); stage I-IV 1.34 (95% CI 1.09-1.64). In stage III-IV CT combined with radiotherapy (RT), RR of ORR was 2.30 (95% CI 1.66-3.18). ASP was also superior in achieving CR. When all single arms combined, RR of ORR after CT with ASP was 1.52 (95% CI 1.38-1.67) in stage I II (15 studies); 1.44 (95% CI 1.32-1.57) in all stages (29 studies); 1.31 (95% CI 1.24-1.38) and 1.66 (95% CI 1.18-2.34) in stages I-II and III-IV combined with RT, correspondingly. CONCLUSIONS: ASP-based CT significantly improved ORR and CR in patients with newly diagnosed both early-stage and advanced-stage ENKTL. PMID- 28621167 TI - Interview with Darrell Kotton. AB - Dr Kotton is the David Seldin Professor of Medicine and the founding Director of the Center for Regenerative Medicine of Boston University and Boston Medical Center. He conducts basic stem cell research as an NIH-funded Principle Investigator in the Kotton Laboratory (focused on stem cell biology and gene therapy related to lung injury and repair). In addition, he attends in the Medical Intensive Care Unit, the Pulmonary Consultation Service, the Alpha-1 Center and the Pulmonary Outpatient Clinic, all at Boston Medical Center. PMID- 28621169 TI - Reducing the risks for relapse of heart failure in a subsequent pregnancy after peripartum cardiomyopathy? PMID- 28621168 TI - Detection of Hb Rothschild HBB: c.[112T>A or 112T>C], Through High Index of Suspicion on Abnormal Pulse Oximetry. AB - We describe a case with a low oxygen affinity hemoglobin (Hb) variant who presented with cyanosis in the absence of cardiopulmonary disease. The patient, a 27-year-old pregnant female (P1G2), complained of a productive cough and bluish discoloration of the lips that started 3 days prior to seeking attention. She had no previous episodes and has generally been in good health. A positive family history of cyanosis was obtained in one sibling. Systematic examination, notably the cardiorespiratory system, revealed no abnormalities. The arterial Hb oxygen saturation (SpO2) on pulse oximetry was 81.0% and Hb separation studies revealed an Hb variant identified as Hb Rothschild [beta37(C3)Trp->Arg] (HBB: c.[112 T>A or 112 T>C]) by gene sequencing. The amino acid substitution (Trp->Arg) is an important contact point at the alpha1beta2 interface and favors a T-quaternary state of the Hb tetramer. This leads to a low oxygen affinity state, which results in premature release of oxygen and drop in oxygen saturation. In the absence of cardiopulmonary disease, a decreased oxygen saturation reading, with or without cyanosis, should arouse suspicion for a possible dysHb. PMID- 28621170 TI - Therapeutic efficacy of multipotent adult progenitor cells versus mesenchymal stem cells in experimental autoimmune encephalomyelitis. AB - AIM: In this study, we have evaluated the therapeutic efficacy of mouse multipotent adult progenitor cells (mMAPCs) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, and compared it with mouse mesenchymal stem cells (mMSCs). MATERIALS & METHODS: We administered PKH26-labeled mMAPC and mMSC into EAE mice and evaluated their therapeutic efficacy. RESULTS: The mMAPC-treated mice in comparison with the mMSC group exhibited a higher suppression of EAE (p < 0.05), and a higher fold expression of neuronal genes GAP43, NG2, PDGFR, Nestin, SMI 32, BDNF and NT 3 in spinal cord (p < 0.05), suggesting a better neuroprotective and regenerative potential of mMAPC than mMSC. CONCLUSION: MAPC may be a potential cell type, which is superior to mesenchymal stem cell for the treatment of EAE/multiple sclerosis. PMID- 28621171 TI - Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar. AB - AIM: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury. MATERIALS & METHODS: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing. RESULTS: hNPs and bNCSCs form similar gaps in the glial scar, but unlike hNPs, bNCSCs contribute Mts1/S100A4 (calcium-binding protein) expression to the scar and do not assist sensory axon regeneration. CONCLUSION: bNCSC transplants contribute nonpermissive Mts1/S100A4-expressing cells to the glial scar after dorsal root avulsion. PMID- 28621172 TI - Direct reprogramming into endothelial cells: a new source for vascular regeneration. PMID- 28621174 TI - Associations between family and clinician ratings of child mental health: A study of UK CAMHS assessments and outcomes. AB - BACKGROUND: The rated severity of child mental health problems depends on who is doing the rating, whether child, carer or clinician. It is important to know how these ratings relate to each other. AIMS: To investigate to what extent clinicians' views are associated with carers' and young people's views in routine care in the United Kingdom. METHOD: Ratings of clinician and parent/child viewpoints from a large Child and Adolescent Mental Health Services (CAMHS) sample ( ns 1773-47,299), as measured by the Children's Global Assessment Scale (CGAS) and Strengths and Difficulties Questionnaire (SDQ) respectively, were analysed. The parent SDQ added value score (AVS), which adjusts for regression to the mean and other non-treatment change, was also included in the analyses. RESULTS: Small-to-medium correlations were found between family and clinician ratings; however, ratings diverged for the lowest-function CGAS bands. Regression analyses showed that pro-social ratings from both child and parent contributed to clinician ratings. Knowing child-reported emotional problem severity made parent ratings of emotions irrelevant to clinician judgements. There was a positive association between SDQ AVS and CGAS; as hypothesised, CGAS showed more change than the SDQ AVS, suggesting that clinicians over-estimate change. CONCLUSION: This study shows the importance of multi-informant data gathering and the integration of multiple views by clinicians when monitoring outcomes. PMID- 28621173 TI - Evaluation and management approaches for scleroderma lung disease. AB - Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are leading causes of morbidity and mortality in systemic sclerosis (SSc). As symptoms are often under-reported in SSc, early screening of ILD and PAH is of paramount importance, and early treatment may be associated with better clinical outcomes. Serologies are particularly helpful in identifying patients at risk for pulmonary involvement. Pulmonary function testing, high-resolution computed tomography of the chest and echocardiography are important tools in the initial screening of these patients. Extensive research has also led to an improved understanding of the mediators involved in the pathogenesis of ILD and PAH. As a result, there have been significant advances in the development of novel targeted therapeutics and an increase in the number of early-phase clinical trials in SSc. PMID- 28621175 TI - In vivo investigation of tissue-engineered periosteum for the repair of allogeneic critical size bone defects in rabbits. AB - AIM: The aim of the study was to evaluate the efficacy of tissue-engineered periosteum (TEP) in repairing allogenic bone defects in the long term. MATERIALS & METHODS: TEP was biofabricated with osteoinduced rabbit bone marrow mesenchymal stem cells and porcine small intestinal submucosa (SIS). A total of 24 critical sized defects were created bilaterally in radii of 12 New Zealand White rabbits. TEP/SIS was implanted into the defect site. Bone defect repair was evaluated with radiographic and histological examination at 4, 8 and 12 weeks. RESULTS: Bone defects were structurally reconstructed in the TEP group with mature cortical bone and medullary canals, however this was not observed in the SIS group at 12 weeks. CONCLUSION: The TEP approach can effectively restore allogenic critical sized defects, and achieve maturity of long-bone structure in 12 weeks in rabbit models. PMID- 28621176 TI - Women's decision-making about self-protection during sexual activity in the deep south of the USA: a grounded theory study. AB - Many women continue to become infected with HIV, particularly in the Southeastern USA, despite widespread knowledge about methods to prevent its sexual transmission. This grounded theory investigation examined the decision-making process women use to guide their use or non-use of self-protective measures when engaging in sexual activity. Participants included women in the Mississippi cohort of the Women's Interagency HIV Study who were infected with or at high risk for HIV. Theoretical sampling was used to recruit a sample of 20 primarily African American women aged between 26 and 56 years, living in rural and urban areas. Data were analysed using constant comparative method to generate a theory of the process that guided women's self-protective decisions. Three key themes were identified: (1) sexual silence, an overall context of silence around sexuality in their communities and relationships; (2) the importance of relationships with male partners, including concepts of 'love and trust', 'filling the void' and 'don't rock the boat'; and (3) perceptions of risk, including 'it never crossed my mind', 'it couldn't happen to me' and 'assumptions about HIV'. These themes impacted on women's understandings of HIV-related risk, making it difficult to put self-protection above other interests and diminishing their motivation to protect themselves. PMID- 28621177 TI - Gender bias in reproductive behaviour in Georgia, Indonesia, and Vietnam: An application of the own-children method. AB - I present a method for estimating indicators of gender bias in reproductive behaviour, using microdata based on the own-children method. The method is first tested on a large sample from India with both birth history and household records. I then apply the method to Georgia, Indonesia, and Vietnam. My estimates demonstrate that the proportion of Georgian couples expressing a preference for sons in their fertility behaviour closely corresponds to the proportion resorting to sex selection at high parities. I show how individual Indonesian provinces provide examples of both son and daughter preference. The method also allows me to date the onset of sex imbalances at birth in Vietnam. The approach based on the own-children method therefore provides a unique tool for estimating the diversity and intensity of gender bias in reproductive behaviour. PMID- 28621178 TI - Interview with Bernard Siegel. AB - Bernard Siegel is the Founder and full-time Executive Director of the nonprofit Regenerative Medicine Foundation (FL, USA). He is the Founder and the Co-chair of the World Stem Cell Summit series of global conferences and Editor-in-Chief of the World Stem Cell Report. He received his undergraduate and law degrees from the University of Miami (BA, 1972; JD, 1975) and has been a member of the Florida Bar since 1975. As a recognized policy expert relating to stem cell research, regenerative medicine and cloning, Bernard works with the world's leading stem cell researchers and advocates. He is also a frequent panelist and keynote speaker on the subject of stem cells, public policy and the societal implications of longevity. PMID- 28621179 TI - An integrated experimental and economic evaluation of cell therapy affinity purification technologies. AB - AIM: To present an integrated techno-economic analysis assessing the feasibility of affinity purification technologies using the manufacture of induced pluripotent stem cell-derived progenitor photoreceptors for retinal dystrophies as a case study. MATERIALS & METHODS: Sort purity, progenitor yield and viable cell recovery were investigated for three cell sorting techniques: fluorescent activated cell sorting (FACS); magnetic-activated cell sorting (MACS); and a novel technology SpheriTech beads. Experimentally derived metrics were incorporated into an advanced bioprocess economics tool to determine cost of goods per dose for each technology. RESULTS & CONCLUSION: Technical and bioprocess benefits were noted with SpheriTech beads which, unlike FACS and MACS, require no cell labeling. This simplifies the bioprocess, reduces cell loss and leaves target cells label free. The economic tool predicted cost drivers and a critical dose (7 * 107 cells per dose) shifting the most cost-effective technology from FACS to MACS. Process optimization is required for SpheriTech to compete economically. PMID- 28621180 TI - Interview with Derek Connolly. AB - Dr Derek Connolly speaks to Adam Price-Evans, Commissioning Editor of Future Cardiology: Derek Leslie Connolly is a Consultant Interventional Cardiologist at Birmingham City Hospital (UK). He qualified from the University of Edinburgh (UK) summa cum laude in Pharmacology in 1985 and in Medicine in 1988 where he was the Brunton Medalist. As a Carnegie scholar at the University of California, San Diego (CA, USA) he saw the early promise of angioplasty and changed his career plan from cardiac surgery to coronary intervention. He then spent a decade training in Cardiology in Cambridge (UK) where he held a British Heart Foundation PhD Fellowship at the University of Cambridge. His main clinical and research interest is the detection and treatment of atherosclerosis. He was appointed to his current role in 2000 and has been integral to the early development of both primary angioplasty and cardiac CT programs. He was UK Chief Investigator for the FOURIER trial. PMID- 28621181 TI - [Advantages of transanal approach in low rectal cancer resections]. AB - Laparoscopic surgery is proven equal technique to open rectal surgery. Despite advantages, some problems in case of low rectal surgery are existing: visualization of the pelvis, securing safe distal resection margin, preparing single stapled rectal stump with safe conjunction to the colorectal anastomosis. Approximately 500 procedures have been performed worldwide until today by applying Transanal Total Mesorectal Excision (TaTME) technique, which evolved from a combination of laparoscopy and transanal approach. TaTME presents a solution to the low and mid-level rectal cases. The transanal path provides a better opportunity for preparing safe distal resection margin, an easier way for making a secure distal stump closure, and also offers perfect visualization even in the most difficult area, supporting the aim of nerve-sparing. We present a case, where we performed a synchronous laparoscopic and transanal TaTME resection of a down-sized low rectal tumor at 5 cm, after neoadjuvant radio-chemotherapy. To the best of our knowledge, this was the first case in Hungary, when TaTME was administered in a synchronous way. PMID- 28621182 TI - [Non-intubated, uniportal, video assisted thoracic surgery [VATS] lobectomy, as a new procedure in our department]. AB - AIM: Due to the emerging experience in VATS (video assisted thoracic surgery) lobectomies, in some centers the so called "non-intubated" VATS lobectomies (NITS - non-intubated thoracic surgery) gained increased authority, during which endotracheal intubation and muscle relaxation of the patient is not carried out, thus surgery is being performed with the patient breathing spontaneously. The recent study deals with our initial experience gained during uniportal NITS VATS lobectomies. PATIENTS AND METHOD: Between 24.01.2017 and 10.03.2017, 16 patients (female: 8; male: 8) with lung cancer underwent NITS VATS uniportal lobectomy. Mean age was 59.6 years (42-73 years). Mean FEV1 was 87.7% (62-109). Mean BMI was 27.1 (18.8-32.8). Prior to surgery, the patients received benzodiazepine premedication, local anesthetic (Lidocaine) for incision and Bupivacaine for intercostal and vagus nerve blockage. Besides routine monitoring Bispectoral Index (BIS) guided target-controlled infusion (TCI) Propofol sedation was carried out, with the help of laryngeal mask anesthesia. Skin and soft tissue incision was performed at the fifth intercostal space, in the axillary line. This single incision sight was the only one needed for the introduction of the camera, together with the instruments needed for dissection and resection of the lobe and placement of the chest tube. Complete atelectasis can develop. The following lobes were removed: 7 right upper lobes, 2 mid-lobes, 1 right lower lobe, 1 right lower lobe + right upper lobe wedge resection, 5 left lower lobes. After the resections, extended mediastinal sampling or block dissection was performed. RESULTS: There was no perioperative mortality. Conversion to endotracheal intubation was needed in non of the cases. Mean operative time was 96,5 minutes (80-120 min.), mean drainage periode was 2.9 days (2-8 days). Prolonged air leak was 1/16 (6.25%). Postoperative fever occurred in 1 patient and subcutaneous emphysema in 1 case, and 1 pneumonia. Because of a recurrent pneumothorax, a re drainage was necessary in 1 case. Pathology of the resected lobes were as follows: 1 endobronchial hamartochondroma causing complete atelectasis of the lobe, 1 chronic pneumonia, and 10 adenocarcinomas, 2 squamous cell carcinomas, 1 carcinosarcoma, and 1 typical carcinoid. Staging of the 14 malignant cases were as follows: 8 IA, 2 IB, 1 IIA, 2 IIB, and 1 IIIA. The average number of the removed mediastinal lymph nodes is 12 (7-20). CONCLUSION: Non-intubated (NITS) VATS lobectomy is considered a safe procedure, satisfying all aspects of oncological guidelines. The postoperative drainage period was shorter caused by the complete atelectasis during the surgery. PMID- 28621183 TI - [Colon reconstruction after the Hartmann procedure. Laparoscopy or laparotomy?] AB - The Hartmann procedure - primarily - was introduced for the treatment of cancerous diseases of sigmoid colon and rectum. In the last few years it was performed in cases with complicated inflammation of the left colon, colon cancers with bowel obstruction or perforation, or in the case of insufficiency of the anastomoses, or in urgent operations after traumatics bowel injuries, when making the anastomosis is at very high risk. Later on the restoration of the continuity of the GI tract can be done traditionally (by laparotomy) or laparoscopically. We present our experiences with the above technique, and also compare our results with traditional open surgeries in our patients. PMID- 28621184 TI - ? PMID- 28621185 TI - [Acute abdominal syndrome caused by benign ovarian tumors]. AB - The acute abdomen is a life threatening condition, its proper diagnosis and treatment is a great challenge until today in surgery. The authors aim to present the diagnostic difficulties in four cases of acute abdomen caused by large benign ovarian tumors. Vast majority of benign ovarian tumors are recognized accidentally through physical examination, X-ray and ultrasonography of the pelvis, abdominal operation is carried out for other reasons or investigations for acute abdominal pain. The case history, physical examination and radiological procedures do not always lead to the correct diagnosis. The authors diagnosed the disease through laparotomy, and an adequate operation was carried out subsequently. Following the operation, all four patients left the hospital in good condition. PMID- 28621186 TI - [1st National Congress of the Oncosurgery Section of the Hungarian Surgical Society, Szeged, March 23-25, 2017]. PMID- 28621187 TI - [Gastrointestinal lipomas - report of three cases and a short review of the literature]. AB - Lipoma in the alimentary tract is a rare entity, it can usually be found in the subcutaneous tissue. Generally, lipomas are asymptomatic. Gastrointestinal lipoma must be removed only in case of bleeding or obstruction. We report 3 successfully operated cases of gastrointestinal lipomas: one duodenal (a 4 cm in diameter lipoma was enucleated from the bulb), one in the small bowel (ileal lipoma causing intususception; due to the unusual masroscopical appearance, segmental resection was performed), and one in the large bowel (colonic lipoma located at 47 cm from the anus, causing intermittent obstruction was remowed by colotomy). PMID- 28621189 TI - ? PMID- 28621188 TI - [Investigation of laparoscopic bimanual technic education with laparoscopic training box]. AB - INTRODUCTION: In some surgical wards residents start to do laparoscopic operations using both hands, while in other places they only use their dominant hand, and only start to use both hands later. There are no data at the moment about which method is more effective. METHODS: We divided 20 students with no laparoscopic experience into 2 groups: one group practised one hand at a time (1K), the other group used both hands (2K) during the 5 days. On the last day both groups had to do every exercise with one hand and two hands as well, then they had to do 3 new exercises, which needed both hands. We measured the time taken, and gave points for the videos taken inside the training box based on OSATS. For statistical analysis we used t-tests, p < 0.05 being significant. RESULTS: On the first day, there was no significant difference between the 1K and 2K groups considering the time taken (518/500 s) and the OSATS points (87/84; 54/55 points). Both groups improved in the mean time and points (1K: 52%, 77% 2K: 50%, 70%) as well, but there was no significant difference between them. In the case of new exercises on the last day, there was no difference between mean time (1K: 425 s, 2K: 411 s) and points (53/59 and 56/52), but there was a significant difference considering the points given for bimanuality. CONCLUSION: Based on our study, we cannot exactly state that the bimanuality needed for expert laparoscopic surgery would be easier to learn with immediately practising with both hands. PMID- 28621190 TI - ["Watermelon stomach" can be the cause of severe gastrointestinal bleeding]. AB - Irregular vascular dilatation in the antrum or the cardia of the stomach can be the cause of severe gastrointestinal bleeding. The first term for it - in the beginning of the 50's of the previous century - was GAVE (Gastric Antral Vascular Ectasia) since at that time no similar phenomenon had been registered before. A quarter of a century later, after publishing a few cases, a witty internist described it as "watermelon stomach" because the macroscopic picture is similarly looking as the aforesaid fruit's appearing. This rare condition occured in one of our patient with many comorbid diseases. PMID- 28621191 TI - ? PMID- 28621193 TI - ? PMID- 28621192 TI - [Reconstruction of the inguinal ligament with fascia lata sling. First reported case in Hungary]. AB - INTRODUCTION: A technique of reconstructing the inguinal ligament using pedicled fascia lata flap is described. PRESENTATION OF CASE: A 66-year-old woman was referred with massive incarcerated left inguinal hernia, following acute surgery on a femoral vein leasion and numerous attempts at repair and subsequent recurrences. There was complete absence of the left inguinal ligament. The inguinal ligament was reconstructed using a strip of fascia lata, pedicled on the anterior superior iliac spine. This was transposed to cover the external iliac vessels, and sutured to the pubic tubercle. The musculoaponeurotic abdominal wall was reconstructed with 15*13 cm sheet of polypropylene mesh, placed preperitoneal and sutured to the remaining abdominal wall muscles and to the neo-Pouoart ligament. DISCUSSION: Complete destruction of the inguinal ligament is rare but can occur following multiple operative procedures or trauma. Published reports of inguinal ligament reconstruction have been performed using synthetic mesh. The use of autologous tissue should reduce the risk of erosion into the neurovascular bundle, seroma formation, and enhance integration into surrounding tissues. CONCLUSION: This new technique for autologous reconstruction of the inguinal ligament provides a safe alternative to the use of synthetic mesh in the operative armamentarium of plastic and general surgeons. This is the first reported case in Hungary. PMID- 28621195 TI - ? PMID- 28621194 TI - [Breast reconstruction surgery with endoscopic assisted latissimus dorsi muscle flap]. AB - The results obtaining with breast reconstruction surgery are not always satisfactory for the patients. Reconstruction with pure latissimus dorsi flap is useful option and due to endoscopic harvest large scar on the back can be avoided. The skin sparing mastectomy and even the sentinel lymph node biopsy or lymphadenectomy can be performed using a single incision in the axilla. Also the immediate reconstruction with endoscopically assisted harvest of the latissimus dorsi muscle flap in selective cases can be done using the same incision. The patient reported high satisfaction with the aesthetic and functional results due to preservation the breast shape and the absence of any scarring on the back. PMID- 28621196 TI - [Correction]. PMID- 28621197 TI - ? PMID- 28621198 TI - [News of the Society]. PMID- 28621199 TI - Sciatic nerve regeneration by transplantation of in vitro differentiated nucleus pulposus progenitor cells. AB - AIM: To assess the applicability of mouse intervertebral disc-derived nucleus pulposus (NP) progenitor cells as a cell source for sciatic nerve regeneration. MATERIALS & METHODS: P0-Cre/Floxed-EGFP-transgenic mouse-derived NP progenitor cells were differentiated to Schwann-like cells in conventional induction medium. Schwann-like cells were subsequently transplanted into a mouse model of sciatic nerve transection, and nerve regeneration assessed by immunohistochemistry, electron microscopy and functional walking track analysis and heat stimulus reflex. RESULTS & CONCLUSION: NP progenitor cells differentiated into Schwann like cells. Transplantation of these cells promoted myelinated axon formation, morphology restoration and nerve function improvement. NP progenitor cells have the capacity to differentiate into neuronal cells and are candidates for peripheral nerve regeneration therapy. PMID- 28621200 TI - Muscle-derived stem cells in peripheral nerve regeneration: reality or illusion? AB - Owing to the complicated and time-consuming regenerative process, the repair of injured peripheral nerves depends largely on ongoing stem-cell therapy. Decades ago, researchers successfully isolated and identified muscle-derived stem cells (MDSCs) and discovered their potential for multidifferentiation. MDSCs play an important role in trauma repair associated with neuromuscular and vascular injury by simultaneously promoting tissue regrowth via direct differentiation and systematic secretion under physiological conditions. However, the isolation, culture, induction and application of MDSCs require further methodological analysis before clinical application. In this review, we comprehensively discuss the challenges associated with neural regeneration and reviewed the progress of stem cell based regenerative medicine, in an effort to realize the potential of MDSCs in nerve regeneration. PMID- 28621201 TI - Effectiveness of antenatal care services in reducing neonatal mortality in Kenya: analysis of national survey data. AB - BACKGROUND: Although global neonatal mortality declined by about 40 percent from 1990 to 2013, it still accounted for about 2.6 million deaths globally and constituted 42 percent of global under-five deaths. Most of these deaths occur in developing countries. Antenatal care (ANC) is a globally recommended strategy used to prevent neonatal deaths. In Kenya, over 90 percent of pregnant women attend at least one ANC visit during pregnancy. However, Kenya is currently among the 10 countries that contribute the most neonatal deaths globally. OBJECTIVE: The aim of this study is to examine the effectiveness of ANC services in reducing neonatal mortality in Kenya. METHODS: We used binary logistic regression to analyse cross-sectional data from the 2014 Kenya Demographic and Health Survey to investigate the effectiveness of ANC services in reducing neonatal mortality in Kenya. We determined the population attributable neonatal mortality fraction for the lack of selected antenatal interventions. RESULTS: The highest odds of neonatal mortality were among neonates whose mothers did not attend any ANC visit (adjusted odds ratio [aOR] 4.0, 95% confidence interval [CI] 1.7-9.1) and whose mothers lacked skilled ANC attendance during pregnancy (aOR 3.0, 95% CI 1.4-6.1). Lack of tetanus injection relative to one tetanus injection was significantly associated with neonatal mortality (aOR 2.5, 95% CI 1.0-6.0). About 38 percent of all neonatal deaths in Kenya were attributable to lack of check-ups for pregnancy complications. CONCLUSIONS: Lack of check-ups for pregnancy complications, unskilled ANC provision and lack of tetanus injection were associated with neonatal mortality in Kenya. Integrating community ANC outreach programmes in the national policy strategy and training geared towards early detection of complications can have positive implications for neonatal survival. PMID- 28621202 TI - Is cognitive behavioural therapy effective in reducing suicidal ideation and behaviour when delivered face-to-face or via e-health? A systematic review and meta-analysis. AB - Cognitive Behavioural Therapy (CBT) is a widely used psychotherapeutic intervention for suicide prevention despite its efficacy for suicide prevention in adults remaining ambiguous. Reluctance or inability to access face-to-face help suggests that e-health delivery may be a valuable resource for suicidal people. The aim of this study was to systematically review and conduct meta analysis on research assessing the efficacy of CBT delivered via face-to-face and e-health for suicidal ideation and behaviour. A comprehensive literature search of MEDLINE, PsycINFO, Scopus, PubMed and The Cochrane Central Register of Controlled Trials was conducted. From 764 identified articles, 26 met the inclusion criteria for investigating CBT for suicidal ideation and behaviours in adult populations. Data were extracted on study characteristics and meta-analysis was performed where possible. There was a statistically significant, small to medium effect for face-to-face delivered CBT in reducing suicidal ideation and behaviour although there was significant heterogeneity between the included studies. CBT delivered via e-health was not found to be efficacious for reducing suicidal ideation and behaviour in adults though the number of studies reviewed was small. PMID- 28621203 TI - Soluble TNF inhibition leads to remyelination. PMID- 28621204 TI - A Pilot Study of Sleep, Work Practices, Visual Processing Speed, and 5-Year Motor Vehicle Crash Risk Among Truck Drivers. AB - The purpose of this pilot study was to explore the relationships between sleep, work practices, speed of processing, and 5-year motor vehicle crash risk among a group of older truck drivers. Anthropometric, demographic, and psychological data were recorded, along with health, sleep, and work histories from a sample of 23 truck drivers. Results from this pilot study suggest that physical fatigue may play a role in processing speed. Future studies should be designed with adequate power and include objective measures of sleep and repeated measures over time to determine 5-year MVC rates. Implications for occupational health nursing research, practice, and education are presented. PMID- 28621205 TI - Neurocognitive dysfunction in children with beta thalassemia major: psychometric, neurophysiologic and radiologic evaluation. AB - OBJECTIVE: To evaluate the impact of iron chelating drugs and serum ferritin on the neurocognitive functions of patients with beta thalassemia major (beta-TM), using psychometric, neurophysiologic and radiologic tests. METHODS: Eighty children with beta-TM were enrolled into the study and were compared to 40 healthy controls. All participants were evaluated by measuring serum ferritin, neurocognitive assessment by Benton Visual Retention Test, Wechsler Intelligence Scale for Children, Wisconsin Card Sort Test, P300 and magnetic resonance spectroscopy (MRS). RESULTS: WISC in our study showed that 40% of cases were borderline mental function as regards total IQ. Neurophysiologic tests were significantly impaired in patients compared to control group, with significant impairment in those receiving desferrioxamine (DFO). P300 amplitude was significantly lower in cases compared to controls (2.24 and 4.66 uv, respectively), recording the shortest amplitude in patients receiving DFO. Altered metabolic markers in the brain were detected by MRS in the form of reduced N-acetylaspartate to creatine ratio in 78.3% of our cases. There were significant correlations between psychometric tests and both neurophysiologic (P300) and radiologic (MRS) tests. CONCLUSION: beta-TM is associated with neurocognitive impairment that can be assessed by psychometric, neurophysiologic and radiologic tests. The role of hemosiderosis and iron chelation therapy on cognitive functioning still need more research. ABBREVIATIONS: beta-TM: beta thalassemia major; DFO: Dysferal; DFP: Deferiprone; DFX: Deferasirox; WISC: Wechsler Intelligence Scale for Children; VIQ: verbal IQ; PIQ: performance IQ; TIQ: total IQ; BVRT: Benton Visual Retention Test; WCST: Wisconsin Card Sort Test; MRS: Magnetic resonant spectroscopy; NAA/Cr ratio: N-acetylaspartate to creatine ratio. PMID- 28621206 TI - Baseline population health conditions ahead of a health system strengthening program in rural Madagascar. AB - BACKGROUND: A model health district was initiated through a program of health system strengthening (HSS) in Ifanadiana District of southeastern Madagascar in 2014. We report population health indicators prior to initiation of the program. METHODS: A representative household survey based on the Demographic Health Survey was conducted using a two-stage cluster sampling design in two strata - the initial program catchment area and the future catchment area. Chi-squared and t tests were used to compare data by stratum, using appropriate sampling weights. Madagascar data for comparison were taken from a 2013 national study. RESULTS: 1522 households were surveyed, representing 8310 individuals including 1635 women ages 15-49, 1685 men ages 15-59 and 1251 children under age 5. Maternal mortality rates in the district are 1044/100,000. 81% of women's last childbirth deliveries were in the home; only 20% of deliveries were attended by a doctor or nurse/midwife (not different by stratum). 9.3% of women had their first birth by age 15, and 29.5% by age 18. Under-5 mortality rate is high: 145/1000 live births vs. 62/1000 nationally. 34.6% of children received all recommended vaccines by age 12 months (compared to 51.5% in Madagascar overall). In the 2 weeks prior to interview, approximately 28% of children under age 5 had acute respiratory infections of whom 34.7% were taken for care, and 14% of children had diarrhea of whom 56.6% were taken for care. Under-5 mortality, illness, care-seeking and vaccination rates were not significantly different between strata. CONCLUSIONS: Indicators of population health and health care-seeking reveal low use of the formal health system, which could benefit from HSS. Data from this survey and from a longitudinal follow-up study will be used to target needed interventions, to assess change in the district and the impact of HSS on individual households and the population of the district. PMID- 28621207 TI - Glycosaminoglycan-based resorbable polymer composites in tissue refurbishment. AB - Regeneration of tissue structure with the aid of bioactive polymer matrices/composites and scaffolds for respective applications is one of the emerging areas of biomedical engineering. Recent advances in conjugated glycosaminoglycan (GAG) hybrids using natural and synthetic polymers have opened new avenues for producing a wide variety of resorbable polymer matrices. These hybrid scaffolds are low-immunogenic, highly biocompatible and biodegradable with incredible mechanical and tensile properties. GAG-based resorbable polymeric matrices are being exploited in migration of stem cells, cartilage and bone replacement/regeneration and production of scaffolds for various tissue engineering applications. In the current review, we will discuss the role of GAG based resorbable polymer matrices in the field of regenerative medicine. PMID- 28621208 TI - Stem cells in court: historical trends in US legal cases related to stem cells. AB - Using two legal research platforms, we identified 193 stem-cell-related legal cases that were decided in US courts. Classifying the cases by category, we examined historical trends in the types of legal cases related to stem cells. Major types of cases involved plaintiffs seeking to overturn denial of health insurance coverage decisions, disputes related to intellectual property, false advertising, breaches of contract, exposure to hazardous agents, regulatory decisions, stem cell procedures and professional standard of care, use of stems cells in research, and public funding of embryonic stem cell research. Analysis of court decisions provides insight into contemporary and historical legal issues related to stem cells and reveals the breadth of stem-cell-related cases now being decided by US courts. PMID- 28621209 TI - Habits and self-assessed quality of life, negative intrusive thoughts and depressed mood in patients with prostate cancer: a longitudinal study. AB - OBJECTIVE: The aim of this study was to evaluate the association of self-assessed preoperative physical activity, alcohol consumption and smoking with self assessed quality of life, negative intrusive thoughts and depressed mood after radical prostatectomy. MATERIALS AND METHODS: The Laparoscopic Prostatectomy Robot Open (LAPPRO) trial was a prospective, controlled, non-randomized longitudinal trial of patients (n = 4003) undergoing radical prostatectomy at 14 centers in Sweden. Validated patient questionnaires were collected at baseline, and 3, 12 and 24 months after surgery. RESULTS: Preoperative medium or high physical activity or low alcohol consumption or non-smoking was associated with a lower risk of depressed mood. High alcohol consumption was associated with increased risk of negative intrusive thoughts. Postoperatively, quality of life and negative intrusive thoughts improved gradually in all groups. Depressed mood appeared to be relatively unaffected. CONCLUSIONS: Evaluation of preoperative physical activity, tobacco and alcohol consumption habits can be used to identify patients with a depressed mood in need of psychological support before and immediately after surgery. Quality of life and intrusive thoughts improved postoperatively. PMID- 28621210 TI - Effects of Lucilia sericata on wound healing in streptozotocin-induced diabetic rats and analysis of its secretome at the proteome level. AB - The use of Lucilia sericata larvae on the healing of wounds in diabetics has been reported. However, the role of the excretion/secretion (ES) products of the larvae in treatment of diabetic wounds remains unknown. This study investigated whether application of the ES products of L. sericata on the wound surface could improve the impaired wound healing in streptozotocin-induced diabetic rats. Additional analysis was performed to understand proteome content of L. sericata secretome to understand ES contribution at the molecular level. For this purpose, full-thickness skin wounds were created on the backs of diabetic and control rats. A study was conducted to assess the levels of the ES-induced collagen I/III expression and to assay nuclear factor kappaB (NF-kappaB) (p65) activity in wound biopsies and ES-treated wounds of diabetic rat skin in comparison to the controls. The expression levels of collagen I/III and NF-kappaB (p65) activity were determined at days 3, 7, and 14 after wounding using immunohistological analyses and enzyme-linked immunosorbent assay technique. The results indicated that treatment with the ES extract increased collagen I expressions of the wound control and diabetic tissue. But the increase in collagen I expression in the controls was higher than the one in the diabetics. NF-kappaB (p65) activity was also increased in diabetic wounds compared to the controls, whereas it was decreased in third and seventh days upon ES treatment. The results indicated that ES products of L. sericata may enhance the process of wound healing by influencing phases such as inflammation, NF-kappaB (p65) activity, collagen synthesis, and wound contraction. These findings may provide new insights into understanding of therapeutic potential of ES in wound healing in diabetics. PMID- 28621211 TI - Copper doping enhanced the oxidative stress-mediated cytotoxicity of TiO2 nanoparticles in A549 cells. AB - Physicochemical properties of titanium dioxide nanoparticles (TiO2 NPs) can be tuned by doping with metals or nonmetals. Copper (Cu) doping improved the photocatalytic behavior of TiO2 NPs that can be applied in various fields such as environmental remediation and nanomedicine. However, interaction of Cu-doped TiO2 NPs with human cells is scarce. This study was designed to explore the role of Cu doping in cytotoxic response of TiO2 NPs in human lung epithelial (A549) cells. Characterization data demonstrated the presence of both TiO2 and Cu in Cu-doped TiO2 NPs with high-quality lattice fringes without any distortion. The size of Cu doped TiO2 NPs (24 nm) was lower than pure TiO2 NPs (30 nm). Biological results showed that both pure and Cu-doped TiO2 NPs induced cytotoxicity and oxidative stress in a dose-dependent manner. Low mitochondrial membrane potential and higher caspase-3 enzyme (apoptotic markers) activity were also observed in A549 cells exposed to pure and Cu-doped TiO2 NPs. We further observed that cytotoxicity caused by Cu-doped TiO2 NPs was higher than pure TiO2 NPs. Moreover, antioxidant N-acetyl cysteine effectively prevented the reactive oxygen species generation, glutathione depletion, and cell viability reduction caused by Cu doped TiO2 NPs. This is the first report showing that Cu-doped TiO2 NPs induced cytotoxicity and oxidative stress in A549 cells. This study warranted further research to explore the role of Cu doping in toxicity mechanisms of TiO2 NPs. PMID- 28621212 TI - Methamphetamine causes neurotoxicity by promoting polarization of macrophages and inflammatory response. AB - Macrophages, especially their activation state, are closely related to the progression of neurotoxicity. Classically activated macrophages (M1) are proinflammatory effectors, while alternatively activated macrophages (M2) exhibit anti-inflammatory properties. As a powerful addictive psychostimulant drug, coupled with its neurotoxicity, methamphetamine (Meth) abuse may lead to long lasting abnormalities in the neuronal system. The present study investigated the effect of Meth at subtoxic concentration on macrophage activation state and its underlying toxicity to neuronal cells. PC12 and Murine RAW264.7 cells were coincubated with Meth to test its toxicity. 3-(4,5-Dimethylthiazol)-2,5 diphenyltetrazolium-bromide, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blot assays were performed to evaluate the toxicity, cytokine secretion, gene, and protein expression. Results showed that cytotoxicity was enhanced on PC12 cells after coculturing with RAW264.7 stimulated with Meth. RAW264.7 macrophages tended to switch to the M1 phenotype, releasing more nitric oxide and proinflammatory cytokines, including tumor necrosis factor alpha (TNFalpha), interleukin (IL)-12, and IL-1beta, while decreasing the release of anti-inflammatory cytokine IL-10 after treatment with Meth. Meth upregulated the gene expression of IL-6, IL-1beta, and TNFalpha and downregulated the expression of Arg-1, IL-10, and KLF4. Meth could also upregulate the protein expression of IL-1beta and TNF alpha and downregulate the expression of Arg-1 and KLF4. However, the abovementioned effects induced by Meth were abolished by the addition of dopamine receptor D3 antagonist. In conclusion, our study demonstrated that Meth promoted macrophage polarization from M0 to M1 and enhanced inflammatory response, which provided the scientific rationale for the neurotoxicity caused by the chronic use of Meth. PMID- 28621217 TI - Occupational Therapists With Oncology Exposure: Perceived Needs on Adults and Older Adults With Cancer-Related Cognitive Impairments. AB - Cancer-related cognitive impairments (CRCI) can limit participation in meaningful activities before, during, and after cancer treatment. This study explored occupational therapists' perceived knowledge gaps and needs regarding CRCI in adults and older adults. An online survey was sent to a convenience sample of 60 practitioners at facilities throughout the continuum of care and 176 directors and faculty in accredited occupational therapy programs. Using a snowball sampling approach, recipients were asked to forward the survey to other occupational therapists. One hundred seven occupational therapists participated. The majority (92%) responded that it would be beneficial to attend a face-to-face continuing education program; preferences for the content and design of a continuing competency seminar are described. These findings support the development and delivery of continuing competence programs tailored toward occupational therapists' CRCI knowledge needs. PMID- 28621218 TI - Measuring Disability in Patients With Cervical Dystonia According to the International Classification of Functioning, Disability and Health. AB - Cervical Dystonia (CD) is a rare movement disorder characterized by an abnormal head position. This cross-sectional study describes the health status and severity of disability using an internationally agreed language by applying the International Classification of Functioning, Disability and Health (ICF). Two disease-specific rating scales were administered to 30 patients with CD. By linking the individual answers to the ICF model, the frequency and severity of reported impairments and restrictions were estimated using a count-based method. Results showed that patients most frequently reported impairments linked to "neuromusculoskeletal and movement-related functions" and "mental functions." Most restrictions in activities were related to "interpersonal interactions and relations," "major life areas," and "community, social, and civic life." One third of the reported impairments can be labeled as severe disability. The findings show that CD causes disability in multiple levels of a patients' functioning in life, well beyond the cervical area. PMID- 28621219 TI - Manualization of Occupational Therapy Using Ayres Sensory Integration(r) for Autism. AB - This article reports on the development of a Stage 3 manual (following pilot effectiveness study) for implementing occupational therapy using Ayres Sensory Integration(r) (OT/ASI) for children with autism spectrum disorders to enhance participation in daily occupations. Three stakeholder groups were surveyed to aid in translation of manual from research to practice (i.e., Stage 3 manual) and an expert consensus meeting was held to finalize recommendations. Data indicated that the manuals usability could be improved by including a section on frequently encountered problems and solutions, and by including video case examples. Also recommended were greater chapter uniformity, improved clarity of forms and charts, and inclusion of a glossary. Changes were made and subject to expert review and consensus using modified Delphi process. The Stage 3 manual has been rigorously vetted and is ready for practice and research replication. PMID- 28621220 TI - 2016-17 Pi Theta Epsilon Honor Society Inductees. PMID- 28621221 TI - Sexuality and Spinal Cord Injury: The Lived Experiences of Intimate Partners. AB - Although sexuality is an integral aspect of the human experience, individuals who sustain a spinal cord injury (SCI) often receive inadequate education to facilitate successful participation in sexual activities. Intimate partners are often not included in discussions related to sexuality during the rehabilitative process. The purpose of this study was to identify the lived experiences of intimate partners of individuals with SCI related to sexuality. Four intimate partners were selected to participate in semistructured interviews related to their lived experiences of sexuality. Participants identified aspects of SCI, extreme discomfort due to self-perceived sexual norms, and a lack of education as contributors to unsuccessful participation in sexual activity. Coupled sexual activity is a complex phenomenon which includes factors that influence both the injured individuals as well as their intimate partners. To provide effective interventions in addressing sexuality, practitioners should consider the entire issue, the couple. PMID- 28621222 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions, 1 January-28 February 2017. PMID- 28621223 TI - A generation at risk: a cross-sectional study on HIV/AIDS knowledge, exposure to mass media, and stigmatizing behaviors among young women aged 15-24 years in Ghana. AB - HIV/AIDS stigmatizing behaviors are a huge barrier to early detection and treatment of individuals with the AIDS virus. HIV/AIDS stigma and related consequences are debilitating, especially for vulnerable populations. This study sought to assess whether young women's HIV/AIDS knowledge levels and exposure to mass media (television and radio) have an influence on their stigmatizing behaviors and role as agents of stigma towards individuals living with HIV and AIDS. The data used for this study originated from the Ghana Multiple Indicator Cluster Survey 2011. Binary and multiple (stepwise) logistic regression analyses were used to examine the associations between HIV/AIDS knowledge, frequency of exposure to mass media, and HIV/AIDS stigmatizing behaviors among young women aged 15-24 years in Ghana. Of the 3573 young women, 80% of 15-19-year-olds and 76% of 20-24-year-olds had at least one stigmatizing behavior towards persons living with HIV/AIDS (PLHA). Young women with increased knowledge regarding HIV/AIDS and frequent exposure to mass media (television and radio) had lesser tendency to stigmatize or act as agents of stigma towards PLHA (proportion with at least one stigmatizing behavior per subgroup - HIV/AIDS knowledge: those with highest knowledge score 579 [70.1%], those with lowest knowledge score 28 [90.3%]; mass media: those with daily exposure 562 [73.4%], those not exposed at all 249 [89.2%]). There was a graded negative 'exposure-response' association between the ranked variables: HIV/AIDS knowledge, mass media, and HIV/AIDS stigmatizing behaviors. The significant inverse association between HIV/AIDS knowledge, frequency of exposure to mass media, and HIV/AIDS stigmatizing behaviors persisted even after adjusting for all other covariates in the multiple logistic regression models. It is extremely important to increase HIV/AIDS related knowledge and reduce stigma among young women in Ghana through targeted HIV/AIDS factual knowledge transfer. The use of mass media for communication of issues regarding HIV/AIDS, its mode of transmission, and associated stigma should be emphasized among women in Ghana. PMID- 28621224 TI - Hypermethylation of adjacent CpG sites is negatively correlated with the expression of lineage oncogene ASCL1 in pulmonary neuroendocrine tumors. AB - Achaete-scute homolog 1 is a lineage oncogene of high-grade pulmonary neuroendocrine tumors. Due to the relatively few studies investigating the epigenetic regulation of achaete-scute homolog 1 expression, we wanted to address whether DNA methylation of the achaete-scute homolog 1 CpG island is associated with clinicopathological features in pulmonary neuroendocrine tumors and to investigate its effect on the expression of this gene. Here, We performed multiplex immunohistochemistry (PerkinElmer, Waltham, MA, USA) to check for achaete-scute homolog 1 and Notch homolog 1 expression in 139 pulmonary neuroendocrine tumor samples. Quantitative measurements of achaete-scute homolog 1 CpG island methylation were conducted using the MassARRAY EpiTYPER (Sequenom, San Diego, CA, USA). The correlation between immunohistochemistry data, methylation data, and clinicopathological information was analyzed. Achaete-scute homolog 1 methylation levels were increased in pulmonary neuroendocrine tumors compared to those in normal controls (0.107 vs 0.061, p < 0.001), and among the achaete-scute homolog 1 CpG island, only CpG_6 and CpG_7.8 showed higher methylation levels in pulmonary neuroendocrine tumors (0.208 and 0.135, respectively) compared to those in normal lung tissues (0.072 and 0.087, respectively; p < 0.001). Moreover, the methylation level of CpG_6.7.8 was higher in patients with stage I pulmonary neuroendocrine tumors than in patients with stage II/III pulmonary neuroendocrine tumors (0.19 +/- 0.16 vs 0.14 +/- 0.07, p = 0.012). The hypermethylation of CpG_6.7.8 showed an inverse correlation with achaete-scute homolog 1 protein expression (r = -0.408, p = 0.007, Spearman test). Finally, we found that CpG_6.7.8 of the achaete-scute homolog 1 CpG island is frequently hypermethylated in early-stage pulmonary neuroendocrine tumors, and this aberrant hypermethylation is negatively correlated with achaete-scute homolog 1 expression in this tumor spectrum. PMID- 28621225 TI - Decreased expression of MGMT in correlation with aberrant DNA methylation in esophageal cancer patients from North India. AB - O-6-methylguanine-DNA methyltransferase, DNA repair gene, has been found to be involved with the pathogenesis of the esophageal cancer. DNA hypermethylation and other factors have been suggested to downregulate O-6-methylguanine-DNA methyltransferase. In this communication, the methylation status of O-6 methylguanine-DNA methyltransferase gene and the corresponding O-6-methylguanine DNA methyltransferase protein expression in esophageal cancer from North India has been studied. In all, 80 samples of tumor tissue along with adjacent normal tissue as controls were analyzed for messenger RNA level of O-6-methylguanine-DNA methyltransferase gene, protein expression, and subcellular localization. The messenger RNA expression was studied using real-time quantitative polymerase chain reaction, protein expression, and its subcellular localization by Western blotting and immunohistochemistry. DNA methylation was assessed through methylation-specific polymerase chain reaction. Clinicopathological parameters were recorded and correlated with the O-6-methylguanine-DNA methyltransferase expression. O-6-methylguanine-DNA methyltransferase messenger RNA expression was found to be downregulated in 65% cases (52/80). The expression of O-6 methylguanine-DNA methyltransferase at the protein level was also found to be absent in 65% (52/80) cases. In all, 52 cases had low or no expression of the protein, whereas out of those 28 remaining cases, 11.25% (09/80) cases had high O 6-methylguanine-DNA methyltransferase protein expression. The absence of O-6 methylguanine-DNA methyltransferase protein coincided with the methylated cases in 84% (38/45), whereas in 07 cases, out of the 45 methylated, O-6-methylguanine DNA methyltransferase protein was present. The aggressive esophageal cancer patients having methylated O-6-methylguanine-DNA methyltransferase had more than 50% cases with no/mild expression of the O-6-methylguanine-DNA methyltransferase protein ( p > 0.001). Loss of O-6-methylguanine-DNA methyltransferase protein was very frequent in the incidence of esophageal cancer from North Indian patients, and methylation of the promoter region of O-6-methylguanine-DNA methyltransferase was significantly associated in its downregulation. PMID- 28621226 TI - PTEN: A potential prognostic marker in virus-induced hepatocellular carcinoma. AB - PTEN is the second most frequently mutated tumor suppresser gene in cancers after p53. Genetic and epigenetic alterations in the PTEN gene and its regulatory regions have been reported in various studies. PTEN is a crucial downregulator of the pro-survival phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway and also suppresses insulin signaling. Failure to regulate these pathways leads to increase in cell proliferation and migration which in turn promotes tumorigenesis. PTEN underexpression is mediated by a variety of cytokines and stress kinases which seem to collectively induce the RAS/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. In the context of hepatocellular carcinoma, reduced expression of PTEN is seen in nearly half of the cases on average. In some cases, PTEN has been observed to be either mutated or methylated which can also lead to reduced expression or in some cases, complete loss of expression. On the cellular level, PTEN is also a target in the pathogenic pathway of hepatitis C virus core protein and hepatitis B virus X protein. These viruses appear to alter PTEN regulation and pro-apoptotic ability to enhance the process of tumor formation. In perspective of the crucial role PTEN plays in balancing proliferation and apoptosis, we propose PTEN as a valuable marker in the diagnosis, assessment of tumor grade, and disease stage in hepatocellular carcinoma patients. PMID- 28621227 TI - Expression of epithelial-mesenchymal transition driver brachyury and status of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in predicting treatment responses to neoadjuvant chemotherapy of breast cancer. AB - Brachyury has been characterized as a driver of epithelial-mesenchymal transition process which is regarded as an important mechanism of cancer cell invasion and metastatic progression. The status of tumor-infiltrating lymphocytes has been proposed to predict response to neoadjuvant chemotherapy in breast cancer. We investigated the clinical significance and value of tumor-infiltrating lymphocytes and brachyury as biomarkers to predict treatment responses to neoadjuvant chemotherapy in breast cancer. We also examined the correlation of the Neo-Bioscore with tumor-infiltrating lymphocytes and brachyury to indirectly predict long-term outcome. This retrospective study included a series of 44 consecutive patients treated between January 2011 and December 2015. All patient samples were obtained using core needle biopsy before neoadjuvant chemotherapy. The relationship of expression of Brachyury and tumor-infiltrating lymphocyte subsets (CD8+, forkhead box protein 3 tumor-infiltrating lymphocytes) with clinicopathological factors was assessed to identify its predictive role with respect to tumor response to neoadjuvant chemotherapy and the outcome. Of 44 patients, 6 showed no response, 31 had partial response, and 7 demonstrated pathological complete response. Forkhead box protein 3 was significantly higher in the response group than in the no response group (no response = 2.6, partial response = 7.0, complete response = 9.7, p = 0.020). Brachyury expression was inversely associated with response to neoadjuvant chemotherapy, but the difference was not statistically significant ( p = 0.62). We also observed a significant association between forkhead box protein 3 ( p = 0.001) and the Neo Bioscore, while only a marginal difference was observed with CD8+ expression ( p = 0.074). This study demonstrated that forkhead box protein 3 expression has value as the only independent marker that predicts a good response to neoadjuvant chemotherapy and that it is related with a good prognosis according to the Neo Bioscore. Brachyury was significantly associated with estrogen receptor positive and human epidermal growth factor receptor 2 negative status; further study would be needed to clarify how it affects treatment prognosis. PMID- 28621228 TI - Diagnostic performance of tumor markers AFP and PIVKA-II in Chinese hepatocellular carcinoma patients. AB - Alpha-fetoprotein is an effective biomarker as an aid in hepatocellular carcinoma detection in many countries. However, alpha-fetoprotein has its limitations, especially in early hepatocellular carcinoma diagnosis. Protein induced by vitamin K absence or antagonist-II is another biomarker that is used for hepatocellular carcinoma detection. The aim of this study is to compare the diagnostic performance of alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II alone and in combination to explore improving biomarker performance as an aid in early hepatocellular carcinoma detection. In this study a total of 582 serum samples including 132 hepatocellular carcinoma patients, 250 non-hepatocellular carcinoma patients, and 200 healthy volunteers were collected. Alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II levels were measured by both chemiluminescent enzyme immunoassay on LUMIPULSE platform and by chemiluminescent microparticle immunoassay on ARCHITECT platform. Receiver operation characteristic curve analyses were performed for each biomarker and in combination. The results showed that Alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II in combination have shown higher area under the curve compared to alpha-fetoprotein alone for diagnosis in whole patients (0.906 vs 0.870) in hepatocellular carcinoma early-stage patients (0.809 vs 0.77) and in hepatitis B virus-related hepatocellular carcinoma patients (0.851 vs 0.788) with ARCHITECT platform. Protein induced by vitamin K absence or antagonist-II showed higher area under the curve than alpha fetoprotein for diagnosis of hepatitis B virus-related hepatocellular carcinoma patients (0.901 vs 0.788).We conclude that Combining alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II may improve the diagnostic value for early detection of hepatocellular carcinoma. Protein induced by vitamin K absence or antagonist-II performs better than alpha-fetoprotein in diagnosis of hepatitis B virus-related hepatocellular carcinoma patients. PMID- 28621229 TI - The role of Nrf2-Keap1 axis in colorectal cancer, progression, and chemoresistance. AB - Colorectal cancer is the third common cancer after lung and genital cancers worldwide with more than 1.2 million new cases diagnosed annually. Although extensive progress has been made in the treatment of colorectal cancer, finding novel targets for early diagnosis and effective treatment of these patients is an urgent need. Nuclear factor-erythroid 2-kelch-like ECH-associated protein 1 signaling pathway plays a key role in protecting cells from the damage of intracellular oxidative stress and extracellular oxidizing agents. Nuclear factor erythroid 2 is a transcription factor that creates intracellular redox homeostasis via transcriptional activity and interaction with kelch-like ECH associated protein 1. Furthermore, it contributes to survival and chemoresistance of colorectal cancer cells which is mediated by overexpression of cytoprotective and multidrug resistance genes. In this review, the dual role of nuclear factor erythroid 2 signaling in induction of colorectal cancer cell survival and death as well as the possibility of targeting nuclear factor-erythroid 2-kelch-like ECH associated protein 1 axis as an advanced strategy in prevention and effective treatment of colorectal cancer patients have been discussed. PMID- 28621230 TI - LncRNA CRNDE triggers inflammation through the TLR3-NF-kappaB-Cytokine signaling pathway. AB - Colorectal neoplasia differentially expressed (CRNDE), an oncogene, is highly expressed in many tumor cells and affects cellular proliferation, migration, invasion, and apoptosis. Its function and mechanism of action is a research hotspot. In this study, microarray analysis was performed to discover the differentially expressed genes in CRNDE over-expression cells. RT2 Profiler PCR Array was used to study the expression of genes related to the toll-like receptor (TLR) pathway. We found that over-expression of CRNDE in astrocytes increased the expression of key factors in the toll-like receptor signaling pathway, especially toll-like receptor-3-mediated MyD88-independent pathway. Furthermore, it up regulated expression levels of downstream transcription factor such as nuclear factor kappa B and numerous cytokines. In contrast, CRNDE knockdown in glioma U87MG cell line showed an opposite trend in the expression of the above-mentioned genes. We speculated that CRNDE might trigger inflammation to regulate tumorigenesis and tumor development through the toll-like receptor pathway. PMID- 28621231 TI - DCAMKL1 is associated with the malignant status and poor outcome in bladder cancer. AB - DCAMKL1 (doublecortin and CaM kinase-like 1) has been found to be overexpressed and function as an oncogene in several types of cancer, but there are limited reports on the role of DCAMKL1 in bladder cancer. The messenger RNA and protein expression of DCAMKL1 in bladder cancer tissues and cell lines was measured by quantitative reverse transcription polymerase chain reaction, western blotting, or immunohistochemistry. The correlation between DCAMKL1 protein expression and clinicopathological characteristics was analyzed. Univariate and multivariate Cox regression models were adopted to evaluate prognostic significance of DCAMKL1 in bladder cancer patients. In our results, DCAMKL1 messenger RNA and protein were overexpressed in bladder cancer tissues compared with adjacent normal tissues. DCAMKL1 protein overexpression was positively associated with clinical stage, muscularis invasion, lymph node metastasis, and distant metastasis. The univariate and multivariate analyses suggested DCAMKL1 protein overexpression was an unfavorable prognostic factor in bladder cancer patients. In conclusion, DCAMKL1 is an independent poor prognostic factor for bladder cancer patients. PMID- 28621232 TI - Paving the path for invasion: The polyedric role of LASP1 in cancer. AB - Although usually referred to as a structural actin-binding protein, LIM and SH3 domain-containing protein may actually be dynamically involved in the control of a wide spectrum of cellular processes, by virtue of its interaction with several molecular partners. Alongside being ubiquitously expressed in physiological conditions, LIM and SH3 domain-containing protein is overexpressed in a growing number of human cancers, in which it may actively contribute to their aggressiveness by promoting cell proliferation and migration. In view of the recent findings, implicating the protein in cancer progression, we discuss here the most relevant discoveries highlighting the role of this versatile protein in various human tumors. The correlation between LIM and SH3 domain-containing protein expression levels in cancer and the poor outcome and metastatic behavior of tumors denotes the clinical significance of this protein and hints its potential value as a new cancer prognostic or even diagnostic biomarker. This may be decisive not only to optimize existing pharmacological regimes but also to delineate novel, more efficacious therapeutic and/or preventive approaches. PMID- 28621233 TI - Plasma fibrinogen level may be a possible marker for the clinical response and prognosis of patients with breast cancer receiving neoadjuvant chemotherapy. AB - Neoadjuvant chemotherapy has been established as standard treatments for advanced breast cancer among multidisciplinary therapies. A simple and instructive biomarker for the postoperative recurrence and metastasis is needed to evaluate the therapeutic effect. Plasma fibrinogen level has been shown to be associated with tumor progression and poor outcomes in breast cancer patients. This study aims to further evaluate the clinical and prognostic value of plasma fibrinogen level as a biomarker in breast cancer patients receiving neoadjuvant chemotherapy. In this study, data of 67 patients were retrospectively collected and analyzed to identify the relationship between the plasma fibrinogen level and the clinical progression and outcome of these patients. Patients with increased plasma fibrinogen level after neoadjuvant chemotherapy had significantly shorter disease-free survival and overall survival (p < 0.001 and p = 0.001, respectively). In a univariate survival analysis, molecular type (p = 0.0004/p = 0.005), clinical response (p = 0.008/p = 0.015), and changes in plasma fibrinogen level (p = 0.012/p = 0.007) were associated with disease-free survival and overall survival, and all of them, molecular type (p = 0.0003/p = 0.005), clinical response (p = 0.027/p = 0.021), and changes in plasma fibrinogen level (p = 0.035/p = 0.025), were associated with disease-free survival and overall survival in a multivariate survival analysis, respectively. The plasma fibrinogen level was found to be a possible biomarker for clinical response to chemotherapy and postoperative metastasis or death in advanced breast cancer patients who received neoadjuvant chemotherapy. PMID- 28621234 TI - Icarisid II inhibits the proliferation of human osteosarcoma cells by inducing apoptosis and cell cycle arrest. AB - Icarisid II, one of the main active components of Herba Epimedii extracts, shows potent antitumor activity in various cancer cell lines, including osteosarcoma cells. However, the anticancer mechanism of icarisid II against osteosarcoma U2OS needs further exploration. This study aims to investigate further antitumor effects of icarisid II on human osteosarcoma cells and elucidate the underlying mechanism. We cultivated human osteosarcoma USO2 cells in vitro using different concentrations of icarisid II (0-30 uM). Cell viability was detected at 24, 48, and 72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis. Cell cycle was tested by flow cytometry after treatment with icarisid II for 48 h. Annexin V-allophycocyanin and 7-aminoactinomycin D staining were conducted to detect cell apoptosis. Quantitative real-time polymerase chain reaction and Western blot assay were performed to measure the levels of genes and proteins related to cell cycle and apoptosis. Results showed that icarisid II significantly inhibited the proliferation and induced apoptosis of human osteosarcoma U2OS cells. The half maximal inhibitory concentration values were 14.44, 11.02, and 7.37 uM at 24, 48, and 72 h, respectively. Cell cycle was arrested in the G2/M phase in vitro. In addition, icarisid II upregulated the expression levels of P21 and CyclinB1 whereas downregulated the expression levels of CyclinD1, CDC2, and P-Cdc25C, which were related to cell cycle arrest in U2OS cells. The cell apoptotic rate increased in a dose-dependent manner after treatment with icarisid II for 48 h. Icarisid II induced apoptosis by upregulating Bax, downregulating Bcl-2, and activating apoptosis-related proteins, including cleaved caspase-3, caspase-7, caspase-9, and poly (ADP ribose) polymerase. These data indicate that icarisid II exhibits an antiproliferation effect on human osteosarcoma cells and induces apoptosis by activating the caspase family in a time- and dose-dependent manner in vitro. Therefore, icarisid II may be used as a candidate agent for the clinical treatment of osteosarcoma in the future. PMID- 28621235 TI - MMP-2 together with MMP-9 overexpression correlated with lymph node metastasis and poor prognosis in early gastric carcinoma. AB - The aim of this study was to correlate matrix metalloproteinase-2 and matrix metalloproteinase-9 expression with the clinicopathological features and outcome of patients with early gastric cancer and to clinically elucidate more information on the role of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein overexpression with regard to lymph node metastasis of early gastric cancer. The levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 protein expression were assessed by immunohistochemistry. An association was observed between matrix metalloproteinase-2, matrix metalloproteinase-9, and matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression and clinicopathological factors, such as ulceration and lymph node metastasis. Furthermore, matrix metalloproteinase-9 and matrix metalloproteinase 2/matrix metalloproteinase-9 overexpression both were strongly correlated with histological grade. In addition, matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression correlated with deep invasion. Multivariate Cox regression analysis revealed that matrix metalloproteinase-2 and matrix metalloproteinase-9 expression were both independent factors of overall survival in patients with early gastric cancer. In novelty, we found that matrix metalloproteinase-2/matrix metalloproteinase-9 overexpression was an independent indicator of lymph node metastasis in early gastric cancer which will be helpful in clinic to select the appropriate treatment of these patients. PMID- 28621236 TI - Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09 01) trial. AB - Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor-ligand inhibition should be investigated. PMID- 28621237 TI - Role of CXCR4 and SDF1 as prognostic factors for survival and the association with clinicopathology in colorectal cancer: A systematic meta-analysis. AB - C-X-C chemokine receptor type 4 and stromal cell-derived factor-1 were proven to play important roles in several types of cancer and in many biological processes connected with tumor growth, invasion, angiogenesis, and metastasis. However, the clinical significance of C-X-C chemokine receptor type 4 and stromal cell-derived factor-1 expression in colorectal cancer remains inaccurate. The purpose of this systematic meta-analysis is to investigate the role of C-X-C chemokine receptor type 4 and stromal cell-derived factor-1 as prognostic factors for survival and the association between C-X-C chemokine receptor type 4/ stromal cell-derived factor-1 and clinicopathology in colorectal cancer. Databases including PubMed, EMBASE, and Cochrane Library were searched for relevant literatures updated till January 2017. Review Manager 5.3 was used for data analysis. In our meta analysis, C-X-C chemokine receptor type 4 expression is related to tumor-node metastasis stage, tumor differentiation, liver metastasis, lymph node metastasis, distant metastasis, and diagnosis, and no correlation of C-X-C chemokine receptor type 4 expression with tumor size, gender, preoperative carcinoembryonic antigen, age, or vascular invasion has been observed. Stromal cell-derived factor-1 expression has no relationship with tumor-node-metastasis stage, lymph node metastasis, vascular invasion, age, gender, distant metastasis, or diagnosis. The expression of stromal cell-derived factor-1 has association with tumor differentiation. Moreover, the pooled hazard ratio for disease-free survival/overall survival showed that overexpression of C-X-C chemokine receptor type 4/stromal cell-derived factor-1 reduced disease-free survival/overall survival in colorectal cancer. Therefore, High expression of C-X-C chemokine receptor type 4/stromal cell-derived factor-1 which is essential in tumor progression can predict poor survival that may provide more advance prognostic clues to colorectal cancer patients. PMID- 28621238 TI - Long non-coding RNA CASC2 regulates cell biological behaviour through the MAPK signalling pathway in hepatocellular carcinoma. AB - Long non-coding RNAs have previously been demonstrated to play important roles in regulating human diseases, especially cancer. However, the biological functions and molecular mechanisms of long non-coding RNAs in hepatocellular carcinoma have not been extensively studied. The long non-coding RNA CASC2 (cancer susceptibility candidate 2) has been characterised as a tumour suppressor in endometrial cancer and gliomas. However, the role and function of CASC2 in hepatocellular carcinoma remain unknown. In this study, using quantitative real time polymerase chain reaction, we confirmed that CASC2 expression was downregulated in 50 hepatocellular carcinoma cases (62%) and in hepatocellular carcinoma cell lines compared with the paired adjacent tissues and normal liver cells. In vitro experiments further demonstrated that overexpressed CASC2 decreased hepatocellular carcinoma cell proliferation, migration and invasion as well as promoted apoptosis via inactivating the mitogen-activated protein kinase signalling pathway. Our findings demonstrate that CASC2 could be a useful tumour suppressor factor and a promising therapeutic target for hepatocellular carcinoma. PMID- 28621239 TI - A microRNA signature associated with pathological complete response to novel neoadjuvant therapy regimen in triple-negative breast cancer. AB - Neoadjuvant chemotherapy aims to improve the outcome of breast cancer patients, but only few would benefit from this treatment. Pathological complete response has been proposed as a surrogate marker for the prediction of long-term clinical benefits; however, 50%-85% patients have an unfavorable pathological complete response to chemotherapy. MicroRNAs are known biomarkers of breast cancer progression; nevertheless, their potential to identify patients with pathological complete response remains poorly understood. Here, we investigated whether a microRNA profile could be associated with pathological complete response in triple-negative breast cancer patients receiving 5-fluorouracil, adriamycin, cyclophosphamide-cisplatin/paclitaxel as a novel neoadjuvant chemotherapy. In the discovery cohort, the expression of 754 microRNAs was examined in tumors from 10 triple-negative breast cancer patients who achieved pathological complete response and 8 without pathological complete response using TaqMan Low-Density Arrays. Unsupervised hierarchical cluster analysis identified 11 microRNAs with significant differences between responder and no-responder patients (fold change >= 1.5; p < 0.05). The differential expression of miR-30a, miR-9-3p, miR-770, and miR-143-5p was validated in an independent group of 17 patients with or without pathological complete response. Moreover, Kaplan-Meier analysis showed that expression of these four microRNAs was associated with an increased disease-free survival. Gene ontology classification of predicted microRNA targets indicated that numerous genes are involved in pathways related to chemoresistance, such as vascular endothelial growth factor, focal adhesion kinase, WNT, ERbB, phosphoinositide 3-kinase, and AKT signaling. In summary, we identified a novel microRNA expression signature associated with pathological complete response in breast cancer. We propose that the four validated microRNAs could be used as molecular biomarkers of clinical response in triple-negative breast cancer patients with pathological complete response to neoadjuvant therapy. PMID- 28621240 TI - IL-36alpha suppresses proliferation of ovarian cancer cells. AB - Interleukin-36alpha (IL-36alpha), also formerly known as IL-1F6, is pertaining to IL-1 family members that has been shown to play an important pro-inflammatory role in chronic immune disorders. However, the role IL-36alpha in the setting of cancer remains unknown. Here, in our study, to investigate the clinical relevance of IL-36alpha in ovarian cancer, clinicopathological significance as well as expression level of IL-36alpha were analyzed in epithelial ovarian cancer clinical tissues and paired normal control. To explore the biological role of IL 36alpha in vitro in epithelial ovarian cancer cells, both overexpression and knockdown of IL-36alpha were performed. Based on the successful re-expression and silencing of IL-36alpha, proliferation, migration, and invasion were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, wound healing, and Transwell assays, respectively. To further confirm the effect over proliferation in vivo, nude mice xenografted with epithelial ovarian cancer cells whose endogenous IL-36alpha was stably upregulated or downregulated were employed. It was found that IL-36alpha was shown to be markedly downregulated in epithelial ovarian cancer tissues relative to paired normal control and that reduced IL-36alpha expression was significantly associated with poor overall prognosis. In addition, IL-36alpha was observed to be able to suppress the growth of epithelial ovarian cancer cells both in vivo and in vitro. Taken together, IL 36alpha was displayed to be able to suppress the growth of epithelial ovarian cancer cells in our setting, which is suggestive of its druggable potential in curing the epithelial ovarian cancer and that upregulation of IL-36alpha was found to be capable of inhibiting the growth of epithelial ovarian cancer cells. PMID- 28621241 TI - Hedgehog signaling pathway as a potential target in the treatment of advanced gastric cancer. AB - The sonic hedgehog signaling pathway is critical for cell proliferation, cell differentiation, and organ development during embryogenesis. Aberrant activation of the sonic hedgehog pathway has been associated with a variety of human cancers. Currently, there is no target molecular drug that clinically affects sonic hedgehog activation in patients with gastric cancer. In this review, we will focus on the current clinical treatment options for advanced gastric cancer and discuss the sonic hedgehog signaling pathway. We also review our understanding of the role of sonic hedgehog signaling in advanced gastric cancer progression. Finally, we will describe current known molecular pathways that crosstalk with the sonic hedgehog pathway in cancer stem cells. PMID- 28621242 TI - The gap between medical faculty's perceptions and use of e-learning resources. AB - BACKGROUND: e-Learning resources have become increasingly popular in medical education; however, there has been scant research on faculty perceptions and use of these resources. OBJECTIVE: To investigate medical faculty's use of e-learning resources and to draw on practical implications for fostering their use of such resources. DESIGN: Approximately 500 full-time faculty members in 35 medical schools across the nation in South Korea were invited to participate in a 30-item questionnaire on their perceptions and use of e-learning resources in medical education. The questionnaires were distributed in both online and paper formats. Descriptive analysis and reliability analysis were conducted of the data. RESULTS: Eighty faculty members from 28 medical schools returned the questionnaires. Twenty-two percent of respondents were female and 78% were male, and their rank, disciplines, and years of teaching experience all varied. Participants had positive perceptions of e-learning resources in terms of usefulness for student learning and usability; still, only 39% of them incorporated those resources in their teaching. The most frequently selected reasons for not using e-learning resources in their teaching were 'lack of resources relevant to my lectures,' 'lack of time to use them during lectures,' and 'was not aware of their availability.' CONCLUSIONS: Our study indicates a gap between medical faculty's positive perceptions of e-learning resources and their low use of such resources. Our findings highlight the needs for further study of individual and institutional barriers to faculty adoption of e-learning resources to bridge this gap. PMID- 28621243 TI - Retrospective evaluation of patients with organizing pneumonia: is cryptogenic organizing pneumonia different from secondary organizing pneumonia? AB - Introduction: Organizing pneumonia (OP) is an uncommon clinic opathological situation among lung diseases. If no underlying cause can be detected, it is named as cryptogenic OP (COP). In this study, the etiologic and clinical characteristics of patients diagnosed as OP in our hospital in the last ten years were evaluated retrospectively. It was also aimed to make a comparison between COP and secondary OP patients. Materials and Methods: One hundred sixty-five patients diagnosed as OP pathologically in the 10 year period from August 2003 to August 2013 were included into that study. Patients' data were evaluated retrospectively from the medical records. Result: One hundred sixty five patients pathologically diagnosed as OP were included. Diagnostic methods were trans thoracic fine-needle biopsy (TTFNB) in 89 (53.9%) patients, open lung biopsy (lobectomy, wedge resection, segmentectomy) in 52 (31.5%) patients and transbronchial biyopsy (TBB) in 24 (14.5%) patients. One hundred (60.6%) of the patients were defined as COP and 65 (39.4%) as secondary OP. Cough, fatigue and dyspnea were the most common symptoms on admission. We detected OP cases secondary to anthracosis and cyst hydatic besides other well known etiologies. In 61 patients, the main radiologic manifestation was multiple bilateral patchy consolidation typical for OP. In 76 patients focal lesions (solid mass, cavitating mass lesion) and in 6 patients infiltrative opacities were detected radiologically. Conclusions: There is no difference between properties of OP from clinical, laboratory and radiologic finding sin the criptogenic and seconder form of OP. Although it is not asserted, cyst hidatic and anthracosis could be kept in mind for the list of underlying ethiologies for secondary OP. PMID- 28621244 TI - [Evaluation of physians, patients, relatives and society of opinions on the told lung cancer diagnosis]. AB - Introduction: In our country, this is usually done by patient relatives. In this study, we aimed to investigate the thought of doctors who done the diagnosis, doctors who arrange the treatment, first degree relatives of patients with lung cancer, and population as a control. Materials and Methods: 310 subjects (100 doctors, 110 first degree realtives of patients, and 100 subjects as a control) were included to the study. The mean age was 39.77 +/- 11.44 years and there was 170 females. 46% of doctors were giving cancer treatment (chemotheraphy/radiotheraphy). Result: 84.5% of subjects were answered the question (Do you want to know the diagnosis of lung cancer if you are lung cancer?) as "yes" and the answers were not different between groups (p> 0.05). 72 of doctors were giving information about diagnosis of patients. This ratio was 89.1% in doctors who arrange lung cancer treatment whereas it was 57.4% in doctors who do not arrange cancer treatment. The percent age of learning of diagnosis of lung cancer throughout the time in doctors, population, and patient's relatives were 19%, 34%, and 59% respectively (p< 0.05). Information about quality of life was more important in relatives of patients (87%) than population (65%) and doctors (63%) (p< 0.05). Quality of life was more important for doctors who arrange lung cancer treatment (76.7)% than doctors who did not (48.8%) (p< 0.05). Patients who were more children wanted to stay with their family at end stage of disease (p< 0.05). Conclusions: According to this study we think that doctors should say the diagnosis of lung cancer in the form of they understand, inform the patients and relatives about treatment, and quality of life and this can increase patient trust to doctor and compliance of patients to the treatment. PMID- 28621245 TI - Evaluation of school teachers' sociodemographic characteristics and quality of life according to their cigarette smoking status: a cross-sectional study from the eastern Black Sea region of Turkey. AB - Introduction: Smoking related health disorders are particularly common after long term cigarette use and accordingly cumulative side effects of smoking usually do not appear in younger individuals. Therefore, for evaluating the contemporary effects of smoking in healthy individuals quality of life has become a fundamental criterion. In this study our aims are evaluating factors affecting school teachers' smoking status and comparing quality of life them according to their cigarette smoking status. Materials and Methods: This cross-sectional study, conducted between March 1 and June 30, 2015, included all government school teachers in Hopa. A sociodemographic data form and World Health Organisation Quality of Life-bref (WHOQL-bref) questionnaire were used. Statistical analysis was performed via SPSS 20. To evaluate the reliability of the WHOQOL-bref questionnaire, Cronbach's alpha co-efficiency was calculated for each domain separately. Result: Statistical analysis was performed on 327 participants' data. The mean age of the teachers was 34.2 +/- 8.73 and 50.2% of them were female. Most of the teachers were never smokers (67.8%) and current smokers' made up 20.1% of the population. Mean Fagerstrom score of current smokers was 4.1+/-1.96. Multinominal logistic regression analysis showed that there was a positive association between male gender and current smoking (OR= 2.25; 95% CI: 1.17-4.32; p< 0.05). Perception of quality of life and perception of health status scores were lower in the current smoker group as compared to never smokers (p< 0.05). However, other quality of life domains were not significantly different among smoking groups. Also, none of the quality of life domains differed significantly according to current smokers' nicotine dependence level. Conclusions: This study reflected a decrease in current smoking prevalence among school teachers compared to previous years. Also, the perception of quality of life and perception of health status scores were lower in the current smoker group as compared to never smokers. PMID- 28621246 TI - Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease. AB - Introduction: The prognostic significance of neutrophil-to-lymphocyte ratio (NLR), derived-neutrophil-to-lymphocyte ratio (d-NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have been shown in many diseases. To the best of our knowledge, there is no published report evaluation of those parameters in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The aims of this study are to evaluate the parameters in predicting in-hospital mortality in patients with AECOPD. Materials and Methods: This is a retrospective study in two referral hospitals in Tabriz and Urmia, Iran. NLRs, PLR, LMR, and d-NLR were calculated from the admission day complete blood count of patients with AECOPD. Comparison was made between patients who died in hospital and those discharged alive. Result: Of 315 patients, 70 (22.2%) died in the hospital and 245 (77.8%) were discharged alive. The mortality rate was higher in patients with NLR >= 4 than with NLR < 4 (24% vs. 9.5% p value < 0.001). Multivariate analysis revealed NLR (p= 0.001) were independently associated with in-hospital mortality. NLR had the highest odds ratio for death both in univariate (OR= 3.80) and multivariate (OR= 3.50) analyses. The area under the receiver-operating characteristic curve for NLR in predicting in hospital death was 0.72 (95% CI: 0.62-0.81; p< 0.001). PLR and LMR did not show significant relation to in-hospital death in AECOPD. Conclusions: This study shows for the first time that higher NLR is positively associated with in hospital mortality in AECOPD. PMID- 28621247 TI - [ARIA 2016 executive summary: integrated care pathways for predictive medicine across the life cycle]. AB - The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization (WHO) workshop in 1999. The initial goals were (i) to propose a new allergic rhinitis classification, (ii) to promote the concept of multi-morbidity in asthma and rhinitis and (iii) to develop guidelines with all stakeholders for global use in all countries and populations. ARIA- disseminated and implemented in over 70 countries globally- is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK (MACVIA (Contre les MAladies Chroniques pour un VIeillissement Actif)-ARIA Sentinel NetworK) uses mobile technology to develop care pathways in order to enable the management of rhinitis and asthma by a multi-disciplinary group or by patients themselves. An App (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease. PMID- 28621248 TI - [Imaging of pleural diseases: evaluation of imaging methods based on chest radiography]. AB - The most commonly employed radiologic method in diagnosis of pleural diseases is conventional chest radiograph. The commonest chest- X-Ray findings are the presence of pleural effusion and thickening. Small pleural effusions are not readily identified on posteroanterior chest radiograph. However, lateral decubitus chest radiograph and chest ultrasonography may show small pleural effusions. These are more efficient methods than posteroanterior chest radiograph in the erect position for demonstrating small amounts of free pleural effusions. Chest ultrasonograph may be able to help in distinguishing the pleural pathologies from parenchymal lesions. On chest radiograph pleural effusions or pleural thickening may obscure the visibility of the underlying disease or parenchymal abnormality. Thus, computed tomography (CT) may provide additional information of determining the extent and severity of pleural disease and may help to differentiate malign pleural lesions from the benign ones. Moreover, CT may provide the differentiation of parenchmal abnormalities from pleural pathologies. CT (coronal and sagittal reformatted images) that also show invasion of chest wall, mediastinum and diaphragm, as well as enlarged hilar or mediastinal lymph nodes. Standart non-invasive imaging techniques may be supplemented with magnetic resonans imaging (MRI). PMID- 28621249 TI - Tuberculosis masked by immunodeficiency: a review of two cases diagnosed with chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a genetically heterogeneous primary immunodeficiency that is characterized by recurrent and life-threatening infections resulting from defects in phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system and granuloma formation due to increased inflammatory response. The most commonly involved organs are the lungs, skin, lymph nodes, and liver due to infection. It may present with recurrent pneumonia, hilar lymphadenopathy, empyema, abscess, reticulonodular patterns, and granulomas due to lung involvement. In recent years, mycobacterial disease susceptibility has been reported in CGD cases. This article presents two male cases, one of whom is aged 18 months and the other is aged 5 years, who were diagnosed with CGD and tuberculosis during examination due to extended pneumonia. This report is presented because CGD should be considered not only in the presence of skin abscesses and Aspergillus infections, but also in the differential diagnosis for cases with BCG-itis and/or tuberculosis. It should be kept in mind that mycobacterial infections can occur during the course of the disease. PMID- 28621250 TI - Tuberculous bronchoesophageal fistula presenting as intractable cough. AB - Intractable cough is one of the debilitating conditions, which warrants immediate investigation to find out the underlying cause. There are numerous causes of intractable cough. We present one such young immunocompromised post renal transplant patient with pulmonary tuberculosis and severe uncontrolled cough due to bronchoesophageal fistula. Bronchoesophageal fistula representing abnormal communication between bronchus and esophagus is an uncommon condition. We emphasize the role of CT in such cases. PMID- 28621251 TI - Hemoptysis in a serum ANCA-positive elderly patient. PMID- 28621252 TI - Clinical course of community-acquired respiratory syncytial virus pneumonia in newborns hospitalized in neonatal intensive care unit. PMID- 28621253 TI - [Turkish translation and transcultural adaptation of Severe Respiratory Insufficiency (SRI) questionnaire]. PMID- 28621256 TI - Detection and Analysis of Microbes, Bioanalytes, and Micropollutants, Focusing on Food and Environmental Samples, Using Nanoparticle-Based Detection Systems, Microfluidic Analytical Devices, and Related Techniques. PMID- 28621259 TI - Clinical effectiveness and cost-effectiveness of a multifaceted podiatry intervention for falls prevention in older people: a multicentre cohort randomised controlled trial (the REducing Falls with ORthoses and a Multifaceted podiatry intervention trial). AB - BACKGROUND: Falls are a serious cause of morbidity and cost to individuals and society. Evidence suggests that foot problems and inappropriate footwear may increase the risk of falling. Podiatric interventions could help reduce falls; however, there is limited evidence regarding their clinical effectiveness and cost-effectiveness. OBJECTIVES: To determine the clinical effectiveness and cost effectiveness of a multifaceted podiatry intervention for preventing falls in community-dwelling older people at risk of falling, relative to usual care. DESIGN: A pragmatic, multicentred, cohort randomised controlled trial with an economic evaluation and qualitative study. SETTING: Nine NHS trusts in the UK and one site in Ireland. PARTICIPANTS: In total, 1010 participants aged >= 65 years were randomised (intervention, n = 493; usual care, n = 517) via a secure, remote service. Blinding was not possible. INTERVENTIONS: All participants received a falls prevention leaflet and routine care from their podiatrist and general practitioner. The intervention also consisted of footwear advice, footwear provision if required, foot orthoses and foot- and ankle-strengthening exercises. MAIN OUTCOME MEASURES: The primary outcome was the incidence rate of falls per participant in the 12 months following randomisation. The secondary outcomes included the proportion of fallers and multiple fallers, time to first fall, fear of falling, fracture rate, health-related quality of life (HRQoL) and cost effectiveness. RESULTS: The primary analysis consisted of 484 (98.2%) intervention and 507 (98.1%) usual-care participants. There was a non statistically significant reduction in the incidence rate of falls in the intervention group [adjusted incidence rate ratio 0.88, 95% confidence interval (CI) 0.73 to 1.05; p = 0.16]. The proportion of participants experiencing a fall was lower (50% vs. 55%, adjusted odds ratio 0.78, 95% CI 0.60 to 1.00; p = 0.05). No differences were observed in key secondary outcomes. No serious, unexpected and related adverse events were reported. The intervention costs L252.17 more per participant (95% CI -L69.48 to L589.38) than usual care, was marginally more beneficial in terms of HRQoL measured via the EuroQoL-5 Dimensions [mean quality adjusted life-year (QALY) difference 0.0129, 95% CI -0.0050 to 0.0314 QALYs] and had a 65% probability of being cost-effective at the National Institute for Health and Care Excellence threshold of L30,000 per QALY gained. The intervention was generally acceptable to podiatrists and trial participants. LIMITATIONS: Owing to the difficulty in calculating a sample size for a count outcome, the sample size was based on detecting a difference in the proportion of participants experiencing at least one fall, and not the primary outcome. We are therefore unable to confirm if the trial was sufficiently powered for the primary outcome. The findings are not generalisable to patients who are not receiving podiatry care. CONCLUSIONS: The intervention was safe and potentially effective. Although the primary outcome measure did not reach significance, a lower fall rate was observed in the intervention group. The reduction in the proportion of older adults who experienced a fall was of borderline statistical significance. The economic evaluation suggests that the intervention could be cost-effective. FUTURE WORK: Further research could examine whether or not the intervention could be delivered in group sessions, by physiotherapists, or in high-risk patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68240461. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 24. See the NIHR Journals Library website for further project information. PMID- 28621267 TI - Site-specific Oral Cancers are different Biological Entities. AB - One of the imperative features of the oral cavity is the presence of different areas, which are characterized by unique sets of tissue organization. These regions are divided into lining mucosa (buccal mucosa, labial mucosa, alveolar mucosa, mucosa lining the ventral surface of the tongue, floor of the mouth, and soft palate) and masticatory mucosa (hard palate, attached gingiva, and dorsal surface of the tongue).1. PMID- 28621268 TI - Assessment of Oral Hygiene Knowledge, Practices, and Concepts of Tobacco Usage among Engineering Students in Bhubaneswar, Odisha, India. AB - AIM: This study aimed to assess oral hygiene-related knowledge and practices among engineering students of Bhubaneswar city and also to evaluate the concepts about the side effects of tobacco usage among those students. MATERIALS AND METHODS: The study was conducted using a self-administered, close-ended questionnaire to assess the oral hygiene knowledge and practices and study the concepts on tobacco usage among 362 engineering students of Bhubaneswar city, Odisha, India. The obtained data were statistically analyzed using Statistical Package for the Social Sciences software version 20.0. RESULTS: This survey found that 26.51% of the students had never visited a dentist. Nearly 43.64% of the participants were cognizant of the fact that improper brushing is the reason of tooth decay. About 47% of the participants consumed alcohol and 32.6% had the habit of chewing tobacco, though 80% were aware that use of smokeless tobacco can impair oral health and cause cancer and use of alcohol has detrimental effect on oral health. CONCLUSION: Knowledge with respect to oral health among engineering students of Bhubaneswar city is adequate regarding using fluoridated toothpaste and flosses. However, an unhealthy snacking habit, overusage of toothbrushes, consumption of alcohol, and practicing tobacco habit show the lack of oral health knowledge in these students. CLINICAL SIGNIFICANCE: Our study provides an idea about the present scenario in terms of oral hygiene and tobacco usage in young individuals. This can form the basis for oral health education and tobacco cessation program. Moreover, as the habit of tobacco usage starts early during college life, adequate knowledge about its ill-effects would prevent deadly diseases, such as potentially malignant disorders and oral cancer. PMID- 28621269 TI - Tooth Wear Patterns among Khat and Shammah Users in Jazan City, Kingdom of Saudi Arabia: A Cross-sectional Survey. AB - AIM: The effect of Khat and Shammah habits, with the para-functional jaw activities that accompany them, on the structure and integrity of the natural dentition has not yet been investigated. The literature lacks studies that identify the patterns of tooth wear among Khat and Shammah users. Therefore, this study is the first attempt to address this concern in Jazan City population, Kingdom of Saudi Arabia. MATERIALS AND METHODS: A cross-sectional survey study was conducted among 300 recruits among dental clinics in Jazan City, Kingdom of Saudi Arabia from October 1, 2015, to April 30, 2016. Questionnaires were used for data collection on oral habits (Khat and Shammah use), age, gender, intake of acidic food or beverages, food habits (intake of fruits, grains, and vegetables), systemic diseases, oral hygiene habits (brushing frequency, technique, and type of toothbrush), parafunctional habits, stress, and acid reflux. Clinical examination was performed to assess the grade of tooth wear. Bivariate analysis was performed to determine the empirical relationship between the independent variables and outcomes. In addition, binary logistic regressions were used to measure the relationship between the independent variables and each of the dependent variables (presence of occlusal wear, tooth wear grade 0 through 4). RESULTS: Khat and Shammah use was statistically significantly associated with tooth wear (p < 0.05). A significant association of tooth wear was observed with age, gender, intake of acidic food and beverages, oral hygiene habits, and stress. CONCLUSION: Consumption of Khat and Shammah may be attributed as one of the major reasons associated with tooth wear among the Saudi population. CLINICAL SIGNIFICANCE: The habitual use of Khat and Shammah causes tooth wear of varying severity, which may negatively affect esthetics, phonetics, and function and necessitate a complex restorative treatment. PMID- 28621270 TI - Influence of Hand Instrumentation and Ultrasonic Scaling on the Microleakage of various Cervical Restorations: An in vitro Study. AB - INTRODUCTION: In cervical lesions, various restorative materials can be inserted, which can be affected by the application of periodontal scalers. This study evaluated and compared the marginal seal of class V glass ionomer, composite resin, and amalgam restorations after subjecting them to hand instrumentation and ultrasonic scaling. MATERIALS AND METHODS: In this experimental study, 30 sound human first premolars were selected. In each tooth, buccal and lingual cavities (4 mm mesiodistal width, 3 mm occlusogingival height, and 2 mm depth) were made. The teeth were randomly assigned to three groups of 10 teeth: (1) Glass ionomer group, (2) composite group, and (3) amalgam group. Teeth were subjected to thermocycling procedure for 1,000 cycles between 5 and 55 degrees C water baths and a 1-minute dwell time. Then, each group was randomly subdivided: (1) Margins of 30 restorations were exposed to hand instrumentation procedures by applying 10 working strokes, (2) margins of 30 restorations were exposed to a periodontal tip mounted on a piezoelectric ultrasonic handpiece working at 25 kHz for 10 seconds. The specimens were serially sectioned mesiodistally. Each section was examined under a stereomicroscope. The extent of microleakage was ranked using a 0 to 4 scale at both occlusal and cervical margins of the restorations. Data were analyzed initially using the Kruskal-Wallis test, followed by multiple comparisons using the Mann-Whitney and Wilcoxon test. RESULTS: The type of restorative material had a significant influence on dye penetration, whether in the enamel margin or in the dentinal margin (p < 0.001). The microleakage of glass ionomer group was the highest. No statistical differences were found in dye penetration between scaling groups (hand instrumentation and ultrasonic scaling) (p > 0.05). CONCLUSION: Type of restorative material had a significant influence on microleakage. No statistical differences were found in dye penetration between scaling groups. CLINICAL SIGNIFICANCE: The microleakage of glass ionomer restoration is greater than amalgam and composite restorations after subjecting them to hand instrumentation and ultrasonic scaling. PMID- 28621271 TI - Effect of Sandblasting Angle and Distance on Biaxial Flexural Strength of Zirconia-based Ceramics. AB - AIM: Surface treatment is necessarily required for bonding of zirconia to the veneering porcelain and luting cements. Sandblasting is the most common and probably the most efficient surface treatment method. Sandblasting roughens the surface and may affect the flexural strength of zirconia. Different sandblasting protocols may yield variable results. This study sought to assess the effect of sandblasting angle and distance on the biaxial flexural strength of zirconia based ceramics. MATERIALS AND METHODS: This in vitro experimental study was conducted on 50 zirconia discs measuring 1.2 +/- 0.2 mm in thickness and 15 +/- 0.2 mm in diameter, which were randomly divided into five groups (n = 10) of one control and four experimental groups subjected to sandblasting with 110 MUm aluminum oxide particles under 2 bar pressure for 10 seconds at 15 and 25 mm distances and 45 and 90 degrees angles (between the nozzle head and zirconia surface). Surface roughness was measured by a roughness tester and samples were subjected to thermocycling followed by biaxial flexural strength testing according to ISO6872. The data were analyzed using one-way analysis of variance (p < 0.05). RESULTS: No statistically significant difference was noted in the mean biaxial flexural strength of the five groups (p = 0.40). Different sandblasting protocols yielded significantly different surface roughness values (p < 0.001). The highest and the lowest mean surface roughness belonged to 15 mm/90 degrees (0.51 MUm) and control (0.001 MUm) groups respectively. CONCLUSION: Change in sandblasting angle and distance had no significant effect on the biaxial flexural strength of zirconia-based ceramic, but surface roughness was significantly different in the study groups. Clinical significances: Regardless of sandblasting angle, increasing distance to 25 mm significantly decreases surface roughness that may negatively affect zirconia bond strength. PMID- 28621272 TI - Radiopacity of Mineral Trioxide Aggregate with and without Inclusion of Silver Nanoparticles. AB - AIM: The aim of this study was to investigate the inclusion of silver nanoparticles (Ag NPs) in the mineral trioxide aggregate (MTA) composition to know which changes will result in the radiopacity of the material. MATERIALS AND METHODS: The experiment was performed according to the American National Standard Institute/American Dental Association specification no. 57/2000 and ISO 6876/2001. Five plates with five holes measuring 1 mm in depth and 5 mm in internal diameter were filled according to the different experimental groups as follows: white mineral trioxide aggregate (WMTA) + NP50 - W MTA with liquid Ag NP 50 ppm, WMTA + NP30 - W MTA with liquid Ag NP 30 ppm, WMTA + NP22 - W MTA with liquid Ag NP 22 ppm, WMTA + NPP - white MTA with liquid Ag NP and powder 1%, WMTA (control). After filling the plates, they were kept in an incubator at 37 degrees C in relative humidity for setting. Each sample was positioned along an aluminum step-wedge placed above the Opteo digital sensor system. The image was divided into four quadrants, and three readings were made for each quadrant to render the average of each quadrant. The resulting data were submitted to Kruskal-Wallis and Dunn's tests. RESULTS: The results showed statistically significant differences between WMTA + NP30, WMTA + NP22, and WMTA + NPP interactions compared with WMTA (control) (p < 0.05). The radiopacity was in descending order: WMTA + NPP, WMTA + NP22, WMTA + NP30, MTA + NP50, and WMTA. CONCLUSION: Silver NPs changed the radiopacity of WMTA, being more evident in WMTA + NP powder at 1% weight. CLINICAL SIGNIFICANCE: The low radiopacity of MTA makes it difficult for any radiographic observation. The Ag NPs appear as an alternative, being an excellent radiopacifier as they have excellent antimicrobial property and relatively low toxicity. PMID- 28621273 TI - Choice of Endodontic Fiber Posts and its Influence on Dental Malpractice: An in vitro Evaluation. AB - AIMS AND OBJECTIVES: The fiber post type used in restoring endodontically treated teeth may affect the dental expert decision in the case of dental malpractice. The aim of this study was to evaluate the low-cost commercial fiber post in comparison with a higher cost or well-known documented fiber post system. MATERIALS AND METHODS: A total of 20 premolars were selected for the study; following endodontic treatment, specimens were randomly divided into two groups of 10 specimens each according to the type of fiber post used: (1) Low-cost commercial fiber post (OYAPost, Taper Lucent, OYARICOM) and (2) higher cost well known fiber post (Rely X Fiber post, 3M ESPE). Both fiber posts were cemented using self-adhesive cement (Rely X Unicem). Samples were subjected to push-out bond strength and to failure analysis. One-way analysis of variance was used (p < 0.005). RESULTS: There was no significant difference between the bond strength of the two tested groups (p > 0.05), while statistically significant difference (p < 0.05) was noted between the different post space regions (cervical, middle, and apical). CONCLUSION: Based on the evidence from the study, it can be concluded that the type of fiber post should not affect the dental expert decision in the case of dental malpractice/lawsuit. CLINICAL SIGNIFICANCE: All types of low-cost fiber posts may behave similarly to other higher cost or well-documented fiber posts. PMID- 28621274 TI - Evaluation to prevent the Physical Changes in Colored Elastomeric Modules when exposed to various Dietary Media. AB - AIM AND OBJECTIVE: The aim of the study is to analyze and compare the variation of lumen size and thickness of the elastomeric colored modules when immersed in four selected dietary media. MATERIALS AND METHODS: Sample size of 40 modules on each color - such as red, blue, green, and black - was taken and immersed in four dietary media (artificial saliva, coke mixed with artificial saliva, turmeric mixed with artificial saliva, and coffee mixed with artificial saliva). Beakers containing different dietary media and color modules are kept in the incubator at 37 degrees C for 72 hours. After incubation period, all the segments of module strips removed from the dietary media were placed under the electric lamp and photographs were taken using Canon camera (SX400 IS). Photographs were transferred to GIMP software, and lumen size and thickness variation in the modules was measured. RESULTS: Statistical analysis were performed using analysis of variance and t-test in Statistical Package for the Social Sciences software. It showed significant difference in thickness of black module in all dietary media. Significant difference existed between all the lumen sizes of four color modules in four dietary media. CONCLUSION: This study was done to identify the material that has more changes in physical properties when exposed to various dietary media. CLINICAL SIGNIFICANCE: According to the results obtained, black color modules have increased in lumen size in all dietary media. In thickness, red color module showed less variation and black color module exhibited more variation. PMID- 28621275 TI - Measure and compare the Degree of Root Canal Transportation and Canal-centering ability of Twisted, ProTaper, and Conventional Stainless Steel K Files using Spiral Computed Tomography: An in vitro Study. AB - AIM: The aim of this study was to compare canal transportation and centering ability of Twisted files (TF) and ProTaper (PT) files with conventional stainless steel (SS) K files. MATERIALS AND METHODS: Thirty mandibular premolar teeth with root curvature of 25 to 35 degrees were selected. The samples were randomly divided into three groups of 10 each according to the type of files used for instrumentation. Group I was instrumented using TF, group II with PT files according to the manufacturer's recommendations, and group III with samples prepared with pre-curved SS K files using a step-back technique. After preparation, the samples were assessed using spiral computed tomography. Three sections were recorded at coronal, middle, and apical levels. Amount of transportation was assessed comparing with preinstrumentation images. Centering ability was calculated using Gambill's formula. The three groups were statistically compared using Student's t-test. RESULTS: Twisted files showed the least canal transportation and the best centering ability followed by PT file system. Stainless steel K files showed the highest transportation and least centering ability. CONCLUSION: Twisted files showed the least amount of transportation and better centering compared with the other file systems. CLINICAL SIGNIFICANCE: The study gives information of TF, a recently introduced rotary system (2008) with regard to its efficacy in preparing curved root canals. This study has shown that the centering ratio of rotary nickel titanium was better than that of SS files. PMID- 28621276 TI - Association of Palatal Rugae Pattern in Gender Identification: An Exploratory Study. AB - AIM: The present study's aim was to assess the pattern of palatine ridges/rugae to identify gender. MATERIALS AND METHODS: This study consists of a total of 50 participants (25 males and 25 females). Participants of the age range of 20 to 50 years were selected from the outpatient department. According to the shape and size of the patient's arches, maxillary impression trays were selected using alginate, and casts were poured subsequently. With the help of a sharp graphite pencil, the palatine ridges were delineated to make it prominent, and on either side of the midline, the number of rugae was counted and the length measured. Using these parameters, the pattern of rugae was determined. Data were analyzed using independent sample t-test. The level of significance was set at 5%. RESULTS: Males had more number of palatal rugae (mean 5.96 +/- 0.88) compared with females (5.24 +/- 0.77), and there was a statistically significant association between them. The mean length of palatal rugae was more in males (6.25 +/- 1.15 mm) than females (5.16 +/- 1.40 mm), and it was found to be a statistically significant association. The straight pattern was more common in both males and females (2.56 +/- 1.08, 2.32 +/- 0.85 respectively) than other patterns. CONCLUSION: This study concluded that straight rugae pattern has been found to be the most common pattern in both genders. However, the mean number of straight rugae pattern and length is slightly more in males than females. CLINICAL SIGNIFICANCE: The most challenging tasks in forensic medicine is human identification. Dental records, dactylogram, and comparing deoxyribonucleic acid are the widely used techniques in mass disasters, but these techniques have their own drawbacks and hence cannot be applied always. In such cases, less known techniques like rugoscopy will be helpful. PMID- 28621277 TI - Botulinum Toxin for the Treatment of Gummv Smile. AB - AIM: The aim was to evaluate the effect of botulinum toxin (Botox) injections as a conservative treatment for gummy smile. MATERIALS AND METHODS: An experimental in vivo study was conducted at a dermatology clinic in Riyadh in January 2016. The study included 23 female patients who ranged from 20 to 50 years and were treated with Botox injections due to excessive maxillary gingival display. The patients with short clinical crowns or long maxilla, those who were pregnant or breastfeeding, and patients with neuromuscular disorders were excluded. Patients received Botox type I, injected 3 mm lateral to the alar-fascial groove at the level of the nostril opening at the insertion of the levator labii superioris alaeque nasi muscle. Photos were taken of the patient's smile before and after the treatment and were then uploaded to the SketchUp program to calculate improvements in gingival display. The distance from the lower margin of the upper lip to the gingival margin was calculated pre- and posttreatment. The amount of improvement was calculated as (pre-Botox treatment - post-Botox treatment/pre Botox treatment * 100). The mean percentage of the total improvement was analyzed. RESULTS: A total of 23 female patients received treatment to improve their gummy smile. Improvement was clear 2 weeks after Botox injection. The mean percentage of improvement in the gingival display was 99.6%. CONCLUSION: Botox type I is an effective conservative technique to improve gummy smile caused by muscular hyperfunction. CLINICAL SIGNIFICANCE: Patients' retention highly indicated that they were satisfied with the provided treatment by Botox injections. Improving the quality of life with least painful experience and immediate results was the major advantage for Botox type I. PMID- 28621278 TI - Assessment of Root Resorption and Root Shape by Periapical and Panoramic Radiographs: A Comparative Study. AB - INTRODUCTION: One of the common findings encountered by the clinician at the end of orthodontic treatment is the apical root resorption. Root resorption occurs to various degrees. A severe form of root resorption is characterized by shortening of root for more than 4 mm or more than one-third of the total tooth length. A low incidence rate of resorption is observed based on radiographic findings for the diagnosis of root resorption, panoramic radiography, and periapical radiography. Hence, we evaluated the accuracy of panoramic radiographic films for assessing the root resorption in comparison with the periapical films. MATERIALS AND METHODS: This study included the assessment of all the cases in which pre- and post-treatment radiographs were available for analysis of the assessment of the amount of root resorption. Complete records of 80 patients were analyzed. Examination of a total of 900 teeth was done. Mean age of the patients in this study was 21 years ranging from 11 to 38 years. The majority of the patients in the present study were females. All the treatments were carried out by registered experienced orthodontists having minimum experience of more than 10 years. All the cases were divided into two study groups. Group I comprised panoramic radiographic findings, while group II consisted of periapical radiographic findings. For the measurement of crown portion, root portion, and the complete root length, magnification loops of over 100 powers with parallax correction with inbuilt grids were used. Assessment of the tooth length and the crown length was done by the same observers. All the results were analyzed by Statistical Package for the Social Sciences software version 6.0. RESULTS: Maximum amount of root resorption was observed in case of maxillary central incisors and canines among group I and II cases respectively. However, nonsignificant difference was obtained while comparing the mean root resorption in relation to maxillary incisors and canines among the two study groups. While comparing the overall value of root resorption among the two study groups, a significant difference was obtained. The maximum value of tooth length in both the groups was observed in cases of maxillary canines. Significant differences were observed while comparing the tooth length of various teeth among the two study groups. Among the deviated forms of root shape, dilacera-tion was the most common form of root shape detected in both the study groups. CONCLUSION: Periapical radiographs are more efficient in the assessment of the shape and resorption of the root. CLINICAL SIGNIFICANCE: Thorough evaluation of periapical radiographs is necessary for detection of even minute levels of root resorption. PMID- 28621279 TI - Comparative Evaluation of Stress developed on Rotary Retreatment Instruments during Retrieval of Gutta-percha. AB - AIM: The aim of the study is to compare the maximum stress distribution on the rotary retreatment instruments within the root canal at cervical, middle, and the apical one-third during retreatment of gutta-percha. MATERIALS AND METHODS: A human mandibular premolar was scanned, and three-dimensional geometry of the root was reconstructed using finite element analysis (FEA) software package (ANSYS). The basic model was kept unchanged; tooth models were created using the same dimensions and divided into two groups as follows: Group I: ProTaper Universal retreatment system and group II: Mtwo rotary retreatment system. The stress distribution on the surface and within the retreatment files was analyzed numerically in the FEA package (ANSYS). RESULTS: The FEA analysis revealed that the retreatment instruments received the greatest stress in the cervical third, followed by the apical third and the middle third. The stress generated on the ProTaper Universal retreatment system was less when compared with the Mtwo retreatment files. CONCLUSION: The study concludes that the retreatment instruments undergo higher stress in the cervical third region, and further in vivo and in vitro studies are necessary to evaluate the relationship between instrument designs, stress distribution, residual stresses after use, and the torsional fracture of the retreatment instrument. CLINICAL SIGNIFICANCE: The stress developed on the rotary retreatment instruments during retrieval of gutta percha makes the instrument to get separated. There is no instrument system, i.e., suitable for all clinical situations and it is important to understand how the structural characteristics could influence the magnitude of stresses on the instrument to prevent its fracture in use. PMID- 28621280 TI - Utility of Dermatoglyphic Pattern in Prediction of Caries in Children of Telangana Region, India. AB - INTRODUCTION: Dermatoglyphics is an extremely useful tool as a preliminary investigation method for diagnosing suspected genetic disorders. Caries being a multifactorial disease with the influence of genetic pattern, early identification of caries risk children with dermatoglyphics can help in using effective and efficient caries preventive measures. AIMS AND OBJECTIVES: The study was undertaken to record and know the frequency of occurrence of fingerprint patterns among children with caries and in children without caries. MATERIALS AND METHODS: A total of 400 schoolchildren in the age group of 5 to 12 years were selected from a private school, Warangal, Telangana, India. Of 400 schoolchildren, 200 children were with caries group and 200 children were in caries-free group. Children with dental caries in five or more teeth based on the decayed, missing, filled teeth index performed were considered as study group, and the control group was normal healthy children without any dental caries. The fingerprints of each child were recorded using stamp pad method, and type of dermatoglyphic pattern of each digit was recorded based on Cummins and Midlo method. Data obtained were put for statistical analysis; p < 0.001 was considered statistically significant. RESULTS: Although the frequency of whorl pattern was more prevalent in caries group, it was statistically significant on the left hand third digit of females and on the right hand third digit and the left hand fourth digit of males. Fingerprints of female caries-free group showed maximum of ulnar loop and males showed maximum of arches. There was a decrease in total ridge count in caries group, especially in males. CONCLUSION: Dermatoglyphics could be an appropriate method to explore the possibility of a noninvasive and an early predictor for dental caries. CLINICAL SIGNIFICANCE: Dermatoglyphics has a future role in identifying people with or at increased risk for dental caries so that risk reduction measures or earlier therapy may be instituted. PMID- 28621281 TI - Evaluation of Microleakage in Class V Restorations with Three different Adhesive Systems. AB - AIM: This study was conducted to evaluate the microleakage of class V cavities restored with composite resin and different adhesive systems. MATERIALS AND METHODS: In this experimental epidemiological investigation, a total of 75 freshly extracted human teeth were collected. The teeth were randomly divided into three groups (n = 25). Three different intermediate adhesive materials (Clearfil SE Bond, Single Bond, and Xeno III) were used for each group. RESULTS: On testing without the application of occlusal load, the maximum microleakage was seen for group III (Xeno III) followed by group I (Clearfil SE) and then group II (Single Bond). On application of occlusal load, the maximum micro-leakage was seen for group III (Xeno III) followed by group II (Single Bond) and then group I (Clearfil SE Bond). The data were analyzed statistically using Kruskal-Wallis and Mann-Whitney U test. CONCLUSION: Group III showed the maximum amount of micro leakage both with and without occlusal load. CLINICAL SIGNIFICANCE: All adhesives under investigation exhibited a certain amount of microleakage in enamel and dentin. PMID- 28621282 TI - Radiographic Screening of Patients in a Dental School using the Prosthodontic Diagnostic Index. AB - INTRODUCTION: Organization of the findings associated with various diagnostic aids plays a key role in formulating the treatment plan of the patients undergoing dental and medical treatment. Enhanced consistency in diagnosing and classifying prosthodontic patients is the basic purpose of various classification systems. Hence, we planned this study to classify partially edentulous patients and completely dentate patients at the undergraduate clinics using the prosthodontic diagnostic index (PDI). MATERIALS AND METHODS: This study included classification of 13,599 edentulous patients who attended the clinics of undergraduate students of all the levels. Screening of all the patients was done radiographically with a digital orthopantomograph (OPG), and the data were saved in the computer system. The intraoral periapical radiographs (IOPA) taken for all the affected areas were also saved in the system. Based on the OPG and IOPA, the patients were classified into various classes. All the data of the patients were recorded and analyzed. RESULTS: Total number of patients screened was 17,220, out of which 3,621 were under 18 years of age and were excluded from the study. Most of the patients belonged to the age group of 31 to 45 years: 5,360 (39.4%) patients (3,817 [43.0%] males and 1,543 [32.5%] females) were class I; 2,730 (20.0%) patients (1,729 [19.5%] males and 1,001 [21.1%] females) were class II; 4,576 (33.7%) patients (2,835 [32.0%] males and 1,741 [36.8%] females) were class III; and 933 (6.9%) patients (483 [5.5%] males and 450 [9.5%] females) were class IV. CONCLUSION: There is a need to introduce PDI as a screening tool during the initial examination of the patient and to achieve a proper distribution of the patients among various levels of students, interns, and postgraduates. CLINICAL SIGNIFICANCE: Introduction of PDI will improve the treatment planning and prognosis of edentulous patients. PMID- 28621283 TI - Assessment of Levels of Glycosylated Hemoglobin in Patients with Periodontal Pathologies: A Comparative Study. AB - INTRODUCTION: One of the potential sources for the occurrence of various systemic pathologies, such as cardiovascular diseases, cerebrovascular diseases, and respiratory diseases is periodontitis. Testing of glycosylated hemoglobin (HbA) is a highly standardized procedure and is becoming increasingly popular these days due to its cost-effectiveness and ease of use. Literature quotes numerous studies associating the peri-odontal diseases with various hemoglobin markers in diabetic and nondiabetic patients. Hence, we planned the present study to assess the levels of HbA in patients with periodontitis among nondiabetic patients. MATERIALS AND METHODS: For the present study, a total of 50 nondiabetic subjects who reported to the department with the chief complaint of periodontitis were included. Another set of 50 nondiabetic individuals were included in the present study of comparable age in whom no periodontitis was detected clinically. Clinical examination and radiographic evaluation was performed for the selection of the cases for the study group. The patients were sent to the laboratory after the clinical examination, for the testing of HbA. Testing of the hemoglobin A1c (HbA1c) levels of all the subjects and controls was performed and values were noted and evaluated. RESULTS: Nonsignificant results were obtained while comparing the mean HbA1c concentrations among the study group and the control group. Nonsignificant results were obtained while comparing the mean HbA1c levels among males and females. While comparing the mean HbA1c levels between the study group and the control group divided on the basis of body mass index, nonsignificant results were obtained. CONCLUSION: In nondiabetic subjects, no significant correlation could be observed between periodontitis and HbA1c levels. CLINICAL SIGNIFICANCE: The HbA1c cannot be used as a reliable maker for differentiation of patients with periodontal pathologies from patients free of periodontal pathologies. PMID- 28621284 TI - Comparison of Platform Switched and Sloping Shoulder Implants on Stress Reduction in various Bone Densities: Finite Element Analysis. AB - INTRODUCTION: Comparison of platform switched (PS), sloping shoulder, and regular implants on stress reduction in various bone densities with finite element analysis. MATERIALS AND METHODS: A total of 12 three-dimensional finite element models were built to analyze the stress distribution model. Nobel Biocare 4.3 * 8 mm regular platform replace select implant with matching diameter easy abutment, Nobel Biocare 4.3 * 8 mm replace select implant PS with 3.5 mm diameter easy abutment, Bicon 4 * 8 mm implant with 4 mm diameter sloping shoulder abutments were created virtually in compact bone density using software. The 130 N axial force and a 90 N oblique loading force were applied to the abutment to analyze the stress. RESULTS: Under horizontal and vertical loading, the sloping shoulder implant had lesser stresses in cancellous bone when compared with PS and regular implants. Sloping shoulder implant showed more stress distribution at implant abutment interface and at crestal area, whereas with regular implants, the stresses were distributed at cortical area. CONCLUSION: Sloping shoulder implant in subcrestal position is much favorable for bone growth, stress distribution, and preservation of remaining bone. CLINICAL SIGNIFICANCE: Use of sloping shoulder implant design distributes the stress apically and creates lesser stresses when compared with PS implants. PMID- 28621285 TI - Assessment of C-reactive Proteins, Cytokines, and Plasma Protein Levels in Hypertensive Patients with Apical Periodontitis. AB - INTRODUCTION: Chronic apical periodontitis (CAP) manifests mostly as periapical radiolucency. Various inflammatory mediators play a significant role in the pathogenesis of apical periodontitis. In acute inflammatory conditions, C reactive proteins (CRP) and fibrinogen show a rise in their concentrations. In chronic diseases with high inflammatory components, an increased prevalence of hypertension has been observed. Hence, we assessed the association of CAP and plasma levels of various inflammatory markers (CRP, interleukin 6 [IL-6], and fibrinogen) in severely hypertensive patients. MATERIALS AND METHODS: This study was conducted in the conservative wing of the institute and included assessment of 250 hypertensive patients with apical periodontitis. With the help of periapical radiographs and clinical examination, the assessment of following parameters was done: Amount of teeth present, visible plaque index, periodontal pocket probing depth, clinical attachment level, bleeding on probing, presence/absence of carious lesions, which included assessment of caries in crown portion, in the root portion, and residual tooth roots (RR), presence of CAP from each patient; 8 mm of venous blood was collected in the morning for the assessment of plasma levels of IL-6, CRP, and fibrinogen levels. Immediate collection and processing of the samples were done in the hospital laboratory. All the results were analyzed by Statistical Package for the Social Sciences software. RESULTS: Out of 250, 155 patients were females. Mean plasma levels of CRP observed in our study were 0.8 mg/dL. Mean plasma levels of IL-6 and fibrinogen were found to be 3.3 and 337.1 mg/dL respectively. A significant correlation was observed while comparing mean body mass index (BMI), RR, and CAP in hypertensive patients. While comparing the mean plasma IL-6 levels, mean BMI, and CAP in the patients, significant results were obtained. Significant correlation was observed while comparing the mean BMI and CAP in hypertensive patients. CONCLUSION: Systemic levels of CRP, IL-6, and fibrinogen levels are influenced by the presence of CAP in hypertensive patients. CLINICAL SIGNIFICANCE: In hypertensive patients, CAP alters the systemic levels of various inflammatory markers. PMID- 28621286 TI - Endodontic Management of Dilacerated Maxillary Central Incisor fused to a Supernumerary Tooth using Cone Beam Computed Tomography: An Unusual Clinical Presentation. AB - AIM: The purpose of this report is to present a case of endodontic management of a dilacerated maxillary central incisor fused to supernumerary tooth unusually appearing as a labial tubercle using cone beam computed tomography (CBCT) as a diagnostic aid. BACKGROUND: Anterior teeth are commonly encountered with aberrant anatomical variations in the crown, number of roots, and root canals. Fusion is an infrequent developmental abnormality in shape of the tooth caused by the union of two adjacent tooth germs. A complete knowledge of such complex anatomies is mandatory for a successful root canal treatment. It highlights the endodontic and restorative approach in the functional and esthetic rehabilitation of the involved tooth. CASE REPORT: Three-dimensional imaging using CBCT was used in this case to differentiate single labial canal and palatal C-shaped canal. The endodontic treatment was performed with the aid of dental operating microscope, and the root canals were obturated with a combination of single cone, carrier based, and cold flowable gutta-percha obturation system. The tooth remained asymptomatic without reinfection and symptoms of failure for 18 months. CONCLUSION: Cone beam computed tomography is indispensable in treatment planning for cases where the radiographs cannot reveal useful information regarding the root canal shape. Postobturation CBCT has helped in avoiding further retreatment of the tooth, which otherwise is a challenging task. CLINICAL SIGNIFICANCE: The use of sophisticated equipment, such as dental operating microscope and CBCT has helped in accurate diagnosis and treatment planning of fused central incisor respectively. PMID- 28621287 TI - Ibuprofen and Low-level Laser Therapy for Pain Control during Fixed Orthodontic Therapy: A Systematic Review of Randomized Controlled Trials and Meta-analysis. AB - INTRODUCTION: To systematically review high-quality randomized controlled trials (RCTs) and meta-analysis on the effectiveness of use of ibuprofen and low-level laser therapy (LLLT) for pain control during fixed orthodontic appliance therapy. MATERIALS AND METHODS: A web-based systematic search of PubMed and Medline database using relevant keywords was performed in August 2016 limited to the English language studies. Based on inclusion and exclusion criteria, RCTs utilizing blind approach were selected. The quality of studies was analyzed and only high-quality studies were included. Following data extraction, meta-analysis was performed by standardized mean difference Hedges' (adjusted) g with 95% confidence interval. RESULTS: A total number of six studies (four ibuprofen and two LLLT) comprising 315 patients were included. Heterogeneity among ibuprofen studies was small, while large heterogeneity was found among LLLT studies. The results showed that both ibuprofen and LLLT could reduce pain intensity during fixed orthodontic therapy and during 17 days follow-up period. However, this reduction was statistically significant only at 6 to 24 hours postoperatively for ibuprofen and 2 hours and 3 to 7 days for LLLT (p < 0.05). CONCLUSION: Considering the limitations of the current meta-analysis, ibuprofen could alleviate orthodontic archwire activation pain during the 1st day with relatively high level of evidence. Low-level laser therapy could reduce this pain in the long term with limited evidence. Further well-designed RCTs are required to provide more evidence. PMID- 28621288 TI - Photodvnamic Therapy in Endodontics. AB - : Commonly used irrigants do not always eradicate the entire microbial flora in infected root canals. Therefore, several other strategies, such as photodynamic therapy (PDT) have been developed. Photoactivated disinfection is based on the interaction of a photosensitive antibacterial agent and a light source. It uses a nontoxic dye named photosensitizer (PS) and low-intensity visible light. In oxygen presentation, these combine to produce some cytotoxic species. The PS molecules attach to bacteria membrane. Irradiation with a specific wavelength of the light may lead to the production of singlet oxygen, resulting in rupture of the microbial cell wall. There are several applications for PDT in dentistry. A successful periodontal treatment is based on elimination of bacteria from the infected area. Phenothiazinium PSs have been shown to be highly effective and safe for this purpose. However, scaling/root planing should be performed before the PDT. While performing the PDT, PS should be first injected in the periodontal pocket and allowed to pigment. Then, the special fiber should be inserted 1 mm short of the pocket base and lased. Photodynamic therapy has also been used to disinfect caries dentin before restoration, disinfecting oral tissues before or during surgical procedures, treating denture stomatitis, and treating oral candidiasis in immunocompromised patients. Photodynamic therapy can be used in combination with mechanical instrumentation and chemical antimicrobial agents, such as sodium hypochlo-rite, too. The purpose of this study was to review historical perspective, mechanism of action, and applications of PDT in dentistry and especially in endodontics was reviewed. Furthermore, the effects of PDT on dentin bonding and endo-toxin are discussed. CLINICAL SIGNIFICANCE: Photodynamic therapy has been advocated to increase the disinfection level of the root canal system. PMID- 28621289 TI - Nobody really knows how to perform endoscopic necrosectomy. PMID- 28621290 TI - Efficacy of laparoscopic ultrasonography in laparoscopic resection of insulinoma. AB - Insulinoma is the most common functioning islet cell tumor of the pancreas, with an annual incidence of 4 cases/1 million individuals. It is treated by surgical methods. Open surgery was once considered the standard approach for the treatment of insulinoma. However, the procedure is traumatic and requires a large incision, which does not satisfy the growing expectations of minimally invasive management of small-sized tumors. Insulinomas are usually benign solitary tumors and mostly occur sporadically, which makes them suitable candidates for laparoscopic management. The potential advantages of laparoscopic management of insulinoma over open surgery include shorter duration of hospitalization, quicker recovery, and better cosmetic effect. However, because of the small tumor size as well as the depth and uncertainty of the location of the tumor, laparoscopic localization of the lesion without tactile sensation is difficult. Laparoscopic ultrasonography can detect about 90% of insulinomas, and its sensitivity is comparable to that of manual palpation along with intraoperative ultrasonography during open surgery; thus, it ensures the feasibility of laparoscopic management of insulinoma and reinforces its advantage as a minimally invasive procedure. Laparoscopic ultrasonography is vital for the localization of insulinomas and characterization of the surrounding pancreatic structure and should, therefore, be considered an integral part of the laparoscopic management of insulinoma. PMID- 28621291 TI - Role of endoscopic ultrasound and endoscopic-ultrasound-guided fine-needle aspiration in endoscopic biopsy negative gastrointestinal lesions. AB - BACKGROUND AND OBJECTIVES: Many cases of gastrointestinal (GI) tumors as lymphoma, adenocarcinoma, and most of submucosal tumors (SMT) such as gastrointestinal stromal tumor (GIST) and leiomyoma are difficult to diagnose as they frequently yield negative endoscopic biopsies. We evaluated the accuracy of endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) in the diagnosis of endoscopic biopsy negative GI tumors. PATIENTS AND METHODS: One hundred and nine patients with biopsy negative GI tumors were included in this prospective study. EUS and EUS-FNA were performed to all patients with cytopathologic examination. RESULTS: There were 109 patients with endoscopic biopsy negative GI lesions, including 61 males (56%) and 48 females (44%), with the mean age of 54 years. Sixty-three cases (57.8%) were proved to have malignant lesions, among them there were 15 cases with high-risk GIST as proved by FNA and excision biopsy. Forty-six cases (42.2%) were proved to be benign; among them there were 21 cases presented with non-high-risk GIST. Endoscopic ultrasound had a sensitivity of 96.8%, specificity of 89.1%, positive predictive value (PPV) of 92.4%, negative predictive value (NPV) of 95.3%, and accuracy of 93.6%. EUS-FNA had a sensitivity of 87.3%, specificity of 100%, PPV of 100%, NPV of 85.2%, and accuracy of 92.7%. CONCLUSION: EUS with EUS-FNA is an accurate procedure in the diagnosis of GI tumors with negative endoscopic biopsies. PMID- 28621292 TI - Is endobronchial ultrasound-guided transbronchial needle aspiration an effective diagnostic procedure in restaging of non-small cell lung cancer patients? AB - BACKGROUND AND OBJECTIVES: Selecting the diagnostic procedure for mediastinal restaging after chemotherapy and/or radiotherapy in Stage IIIA-N2 non-small cell lung cancer (NSCLC) patients remains a problem. The aim of the study was to determine the efficacy of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the evaluation of mediastinal lymph nodes in the restaging of NSCLC patients. MATERIALS AND METHODS: The present multicentric study retrospectively analyzed the results of Stage IIIA-N2 NSCLC patients who had undergone EBUS for mediastinal restaging after preoperative chemotherapy or radiotherapy or both. RESULTS: In 44 patients with 73 N2 nodes, malignant cells were identified in EBUS-TBNA from 23 patients (57.5%) and 25 lymph nodes (34.2%). Twenty-one patients (42.5%) and 48 lymph nodes (65.8%) were negative for nodal metastasis. All of these patients with negative results subsequently underwent mediastinoscopy or surgery (n = 9 and n = 12, respectively). Metastasis was detected in 5 (23.8%) of 21 patients and 6 (12.5%) of 48 lymph nodes. The diagnostic sensitivity, specificity, positive predictive value, negative predicted value and accuracy of EBUS-TBNA based on number of patients were 82.1%, 100%, 100%, 76.2%, and 88.6%, respectively. CONCLUSIONS: EBUS-TBNA should be done before invasive procedures in restaging of the mediastinum in patients previously treated with neoadjuvant therapy because of high diagnostic accuracy rate. However, negative results should be confirmed with invasive procedures such as mediastinoscopy and thoracoscopy. PMID- 28621293 TI - Yield of endoscopic ultrasound-guided fine needle aspiration for subcentimetric lymph nodes: A comparison to larger nodes. AB - BACKGROUND AND OBJECTIVES: Subcentimetric (defined as <1 cm at short axis) lymph nodes are considered benign and there is limited literature on the results of fine needle aspiration (FNA) of these nodes. METHODS: Endoscopic ultrasound (EUS) guided FNA was done on 189 lymph nodes in 166 patients with pyrexia of unknown origin (n = 113) or malignancy (n = 53). Subcentimetric lymph nodes (Group A) were compared to nodes with short axis diameter >=1 cm (Group B). Data are shown as number, percentage, and median (25-75 interquartile range). RESULTS: There was no significant difference between Group A and Group B regarding site of lymph nodes (mediastinal in 73.6 and 72.5%, abdominal in 26.3 vs. 27.4%), number of slides (median 14 vs. 15), needle passes (median 2), and needle used (22 G needle in 85.5% vs. 69.9%). Group A had significantly lesser long axis diameter (1.5 [1.2-2] vs. 2.1 [1.6-2.9] cm) and short axis diameter (0.7 [0.6-0.8) vs. 1.4 [1.1 1.6] cm). A diagnosis (pathologic or reactive) could not be made in 2 (2.6%) and 11 (9.7%) lymph nodes in Group A and Group B, respectively (P = 0.078), due to inadequate material. Respective diagnoses in Group A and Group B were reactive lymphadenopathy (51.3% vs. 18.5%, P = 0.000), granulomatous lymphadenopathy (34.2% vs. 53%, P = 0.011), and malignancy (11.8% vs. 18.5%, P = 0.231). The lymph nodes with granulomatous and malignant change were significantly larger and had higher chances of having sharply demarcated borders as compared to reactive nodes. CONCLUSION: EUS-guided FNA of subcentimetric lymph nodes have comparable results to larger nodes. Almost half of the subcentimetric lymph nodes are pathologic. PMID- 28621294 TI - Endoscopic ultrasound with tissue sampling is accurate in the diagnosis and subclassification of gastrointestinal spindle cell neoplasms. AB - BACKGROUND AND OBJECTIVES: Mesenchymal (spindle cell) neoplasms (SCN) of the gastrointestinal (GI) tract are an important subtype of subepithelial lesions that need subclassification to assess their malignant potential. Reported success rates of accurate subclassification with endoscopic ultrasound (EUS)-guided biopsies are variable. Our goal was to analyze our experience using EUS-guided TruCut biopsy (EUS-TCB) in the majority of patients. METHODS: Retrospective analysis in patients who underwent EUS with biopsies for suspected SCN at our tertiary referral center between 2004 and 2013. RESULTS: A total of 146 patients with suspected SCN underwent EUS with tissue acquisition. Thirteen patients were excluded from analysis because tissue acquisition established a definite diagnosis other than SCN. In the remaining 133 patients, tissue acquisition was diagnostic of SCN in 118 (88.7%) and nondiagnostic in 15 (11.3%). Subclassification based on immunohistochemistry (IHC) was possible in 109 of the 133 cases (81.9%). The final diagnosis was GI stromal tumor in 64, leiomyoma in 39, and schwannoma in 6 cases. The percentage of patients who were subclassified by the various EUS-guided techniques together was 72.18%, and the percentage of patients who were subclassified specifically with EUS-TCB was 61.65%. Tissue specimens that enabled a specific diagnosis based on histological or cytological characteristics in conjunctions with IHC were obtained with EUS core biopsy in 83 (TCB in 82 and ProCore needle biopsy in 1), fine-needle aspiration in 13, mucosal resection in 10, and forceps biopsies (bite-on-bite) in 3 cases. CONCLUSION: EUS with endoscopic tissue acquisition is accurate in the diagnosis and subclassification of SCN. In experienced hands, the EUS-TruCut needle is a valuable tool with a high success rate for this indication. PMID- 28621295 TI - Efficacy and safety in case of technical success of endoscopic ultrasound-guided transhepatic antegrade biliary drainage: A report of a monocentric study. AB - BACKGROUND AND OBJECTIVES: Endoscopic ultrasound (EUS)-guided biliary drainage techniques are alternative procedures in cases of obstructive jaundice with altered anatomy or failed ERCP. Complications related to EUS-guided antegrade drainage (EUS-AD) are still present in up to 10% of cases, and combination of procedures is sometimes suggested to avoid adverse events. The purpose of our study is to evaluate the efficacy and safety of EUS-AD with transhepatic access in case of technical success. METHODS: We retrospectively reviewed patients who underwent EUS-AD in a single, tertiary care center. RESULTS: Twenty patients were included (mean age 68), malignant stenosis in 95%. The reasons for EUS-AD were failed ERCP in 13/20, duodenal stenosis in 4/20, and altered anatomy after surgery in 3/20. A cystostome 6 Fr was always used to create the hepaticogastric tract, without puncture site closure. Self-expandable metallic stent (SEMS) was transpapillary in 95%. Drainage was completed in intraoperative stage by a EUS hepaticogastrostomy (EUS-HGS) in 1/20 and by percutaneous drainage of the right liver (percutaneous transhepatic biliary drainage) in one out of 20. Overall clinical success was 17/20 (85%). One out of 20 presented a persistent obstructive cholangitis treated by another SEMS through ERCP. Two out of 20 patients died of infectious complications with incomplete drainage, in case of advanced neoplastic disease. One of these two patients was treated by EUS-AD and EUS-HGS at the same time. None of the 20 patients developed bilioma or bile leakage. CONCLUSION: EUS-AD by transhepatic way is clinically effective and safe. Closure of the gastric puncture site is not mandatory and complementary methods for biliary decompression should be combined in case of incomplete drainage and not to prevent potential adverse events. PMID- 28621296 TI - Accuracy of endoscopic ultrasound-fine needle aspiration of solid lesions over time: Experience from a new endoscopic ultrasound program at a Canadian community hospital. AB - BACKGROUND AND OBJECTIVES: A Canadian Community Hospital launched a new Endoscopic Ultrasound (EUS) Program in 2011. The aim of this study was to report the accuracy of EUS-fine needle aspiration (EUS-FNA) of solid lesions over time as it pertains to cytotechnologists' involvement and learning curves. METHODS: The electronic medical records of patients that had a EUS from July 2011 to January 2014 were retrospectively reviewed. Only solid lesions with FNA sampling were included in the study. The primary outcome assessed was the accuracy of specimen acquisition for pathological review. The secondary outcome was diagnostic accuracy. Cases were separated by chronological order into thirds for the assessment of learning curves. Cytotechnologists' involvement was correlated to determine its impact on accuracy. RESULTS: Two hundred and seventy-one EUS-FNA procedures were completed for solid lesions. Cytotechnologists' involvement resulted in a specimen acquisition accuracy of 82.6%, compared with 68.8% without a cytotechnologist (P = 0.009; 95% confidence interval [CI] 3.2%-25.0%). Diagnostic accuracy was 74.2% with a cytotechnologist while 62.4% without a cytotechnologist (P = 0.038; 95% CI 0.3%-23.7%). The specimen acquisition accuracy increased from 73.2% from the first third of cases to 92.3% for the last third with a cytotechnologist (P = 0.004; 95% CI 6%-33.0%). Without a cytotechnologist, the specimen accuracy was 67.6% for the first third while 57.7% for the last third of cases (P = 0.434; 95% CI - 33.9-14.4%). In the multivariable regression analysis, after adjusting for other predictors, a present cytotechnologist (P = 0.022) and lesion size 21 mm-30 mm (P = 0.039) and >30 mm (P = 0.001) were significantly associated with increased specimen acquisition accuracy. Only a present cytotechnologist (P = 0.046) was significantly associated with increased diagnostic accuracy. INTERPRETATION: Cytotechnologists' involvement significantly improved the accuracy of specimen acquisition. Although accuracy was impacted by a cytotechnologist learning curve, our results highlight the importance of a cytotechnologist being present for EUS FNA sampling of solid lesions. PMID- 28621297 TI - Endoscopic ultrasound with or without fine-needle aspiration has a meaningful impact on clinical care in the pediatric population. AB - BACKGROUND AND OBJECTIVES: The safety and utility of endoscopic ultrasound (EUS) for the evaluation and management of gastrointestinal (GI) tract disorders among adults has been established. The literature on safety and efficacy in a pediatric referral population (under 21 years of age) is limited. We hypothesized that EUS is safe and useful in the pediatric population. We reviewed the pediatric EUS experience at a single tertiary-care system. We describe the indications, findings, safety, technical success rate, and impact on clinical outcomes. PATIENTS AND METHODS: All patients 21 years of age or younger referred for EUS between 5, 2007 and 11, 2012 were identified from our electronic medical record databases. Retrospective chart review was then conducted to document demographics, procedure indications, procedure type (diagnostic or therapeutic), type of anesthesia used, EUS findings, and the clinical impact of EUS on the subsequent management of the patients. RESULTS: Seventy EUS procedures were attempted in 58 patients during the study. Of these, two EUS procedures were aborted due to inadequate moderate sedation and 68 were successfully completed. The median age at initial endoscopy was 18 years (range 6-21 years), 50% were male and 65% were Caucasian. Four patients underwent EUS-guided pseudocyst drainage. Among the remaining 54 patients, the indications for EUS were the evaluation of GI mucosal/submucosal lesions (n = 14), acute or recurrent pancreatitis (n = 10), localization of suspected insulinoma (n = 8), evaluation of pancreatic abnormalities seen on prior imaging (n = 6), surveillance of tumors or evaluation of luminal lesions in hereditary syndromes (n = 6), abdominal pain of suspected pancreatobiliary origin (n = 5), and other rare indications (n = 5). Fine-needle aspiration was performed in 13 (9 diagnostic, 4 therapeutic) and trans-gastric fine-needle contrast injection of the pancreatic duct was performed in one patient without any complications. Sedation (data available for 66 procedures) included general endotracheal anesthesia in 38 (57%), monitored anesthesia care (MAC) in 19 (29%), and moderate sedation in 9 (14%). There were 4 minor intra-procedural anesthesia-related complications (laryngospasm in 2 and hypoxemia from airway obstruction and secretions in 2) in MAC and general endotracheal anesthesia (GA) cases, and 1 postprocedural complication (fever after pseudocyst drainage). EUS can achieve the diagnostic or therapeutic goal and ruled out suspected pathology in 88% of cases precluding need for additional testing. CONCLUSIONS: (1) EUS in the pediatric population is technically successful and efficacious. (2) Therapeutic and diagnostic EUS impacted clinical care decisions. (3) There is a low risk of immediate significant complications. (4) The overall efficacy and safety support the performance of EUS in a pediatric population by experienced endoscopists. PMID- 28621298 TI - Is the StellaTM 5L system an effective cold sterilization technique for needle based confocal miniprobes? AB - BACKGROUND AND OBJECTIVE: Needle-based confocal laser endomicroscopy (nCLE) under endoscopic ultrasound guidance is a newly developed imaging technique for pancreatic lesions and lymph nodes, enabling a subcellular level of resolution. The confocal miniprobe is an invasive instrument designed to be reused up to 10 times. Therefore, a method that ensures the complete elimination of microbial contaminants on the device is necessary. We studied the bactericidal efficacy of the StellaTM system, which purports to achieve this objective. MATERIALS AND METHODS: The surfaces of three nCLE miniprobes were contaminated with suspensions of Bacillus atrophaeus (ATCC9372). One probe was randomly selected to count the bacterial load on the surface. The other two probes were manually cleaned and rinsed. One probe was randomly selected to count bacteria on the surface, and the other probe was sterilized using the StellaTM 5L endoscopic sterilization system before obtaining the bacterial count. The process was repeated for 20 cycles to evaluate the microbicidal efficacy of the StellaTM 5L endoscopic sterilization system. These miniprobes were immersed in the Stella Fuse disinfectant for 72 h. After the 72 h of immersion, the weight loss of probes was determined using a high precision electronic scale to examine corrosion following disinfection. The change in image quality was evaluated by an endoscopist. RESULTS: From an initial contamination level of 4.48 * 106 +/- 1.57 * 106 cfu/mL on the surface of the probes, the bacterial count was reduced to 4.25 * 102 +/- 1.95 * 102 cfu/mL after manual cleaning (including enzyme washing), and no microorganisms were recovered after 20 cycles with the StellaTM 5L system. The probe weights before and after 72 h of immersion were 45.769 (45.768-45.771) g and 45.762 (45.752-45.768) g, respectively. No change in image quality was observed. CONCLUSION: This study shows that the StellaTM 5L system is capable of the complete elimination of microorganism contamination in a short period and avoids the toxicity of typical disinfectants. It is a safe, cheap, and efficient sterilization approach that provides a new option for nCLE miniprobe sterilization. PMID- 28621299 TI - Conversion of transpapillary drainage to endoscopic ultrasound-guided hepaticogastrostomy and gallbladder drainage in a case of malignant biliary obstruction with recurrent cholangitis and cholecystitis (with videos). AB - Endoscopic ultrasound-guided biliary drainage (EUS-BD) has been increasingly reported as an alternative to percutaneous transhepatic biliary drainage in failed endoscopic retrograde cholangiopancreatography. Moreover, conversion to EUS-BD can be a good alternative when transpapillary biliary drainage is technically possible but complicated by cholangitis because EUS-BD enables one step internal drainage not traversing the tumor. Herein, we report a case of recurrent cholangitis due to hemobilia and cholecystitis due to tumor involvement to the cystic duct after transpapillary stent placement, which was successfully managed by conversion to EUS-BD and EUS-guided gallbladder drainage in one session. PMID- 28621300 TI - Endoscopic ultrasound of bile duct ascariasis (with video). PMID- 28621301 TI - Esophageal diagnosis of a malignant aspergilloma. PMID- 28621302 TI - Gastric bulging confirmed as a pancreatic solid pseudopapillary tumor by endoscopic ultrasound-guided fine needle aspiration. PMID- 28621303 TI - Endoscopic ultrasound-guided drainage of pancreatic pseudocyst after gastrogastric anastomosis in patient with Roux-en-Y gastric bypass: The dream becomes reality! PMID- 28621304 TI - Epigenetic and gene expression analysis of ankylosing spondylitis-associated loci implicate immune cells and the gut in the disease pathogenesis. AB - Ankylosing spondylitis (AS) is a common immune-mediated arthropathy primarily affecting the spine and pelvis. Most AS patients have subclinical intestinal inflammation, suggesting the gut microbiome and the immune response play a role in pathogenesis. Susceptibility to AS is primarily genetic, and at least 114 susceptibility variants have been identified to date. We applied bioinformatic methods utilizing epigenetic and gene and protein expression data to identify the cell types through which AS-associated variants operate. Variants were enriched in transcriptionally regulated regions in monocytes, CD4+ and CD8+ T cells, natural killer cells, regulatory T cells and B cells and mucosa from the small intestine, sigmoid colon and rectum. Weak signals were detected in bone cells, consistent with bone disease being a secondary manifestation. RNA sequencing of blood cells from AS patients and controls identified differentially expressed genes. Interrogation of expression databases showed that the upregulated genes were enriched in monocytes and downregulated genes were enriched in CD8+ T cells and natural killer cells. Gene Ontology term enrichment analysis identified microbes and the gut in the aetiology of AS. These findings identify the key immune cell types that drive the disease, and further highlight the involvement of the gut microbiome in the pathogenesis of AS. PMID- 28621305 TI - Structural insights into the function of ZRANB3 in replication stress response. AB - Strategies to resolve replication blocks are critical for the maintenance of genome stability. Among the factors implicated in the replication stress response is the ATP-dependent endonuclease ZRANB3. Here, we present the structure of the ZRANB3 HNH (His-Asn-His) endonuclease domain and provide a detailed analysis of its activity. We further define PCNA as a key regulator of ZRANB3 function, which recruits ZRANB3 to stalled replication forks and stimulates its endonuclease activity. Finally, we present the co-crystal structures of PCNA with two specific motifs in ZRANB3: the PIP box and the APIM motif. Our data provide important structural insights into the PCNA-APIM interaction, and reveal unexpected similarities between the PIP box and the APIM motif. We propose that PCNA and ATP dependency serve as a multi-layered regulatory mechanism that modulates ZRANB3 activity at replication forks. Importantly, our findings allow us to interpret the functional significance of cancer associated ZRANB3 mutations. PMID- 28621306 TI - Targeted two-photon chemical apoptotic ablation of defined cell types in vivo. AB - A major bottleneck limiting understanding of mechanisms and consequences of cell death in complex organisms is the inability to induce and visualize this process with spatial and temporal precision in living animals. Here we report a technique termed two-photon chemical apoptotic targeted ablation (2Phatal) that uses focal illumination with a femtosecond-pulsed laser to bleach a nucleic acid-binding dye causing dose-dependent apoptosis of individual cells without collateral damage. Using 2Phatal, we achieve precise ablation of distinct populations of neurons, glia and pericytes in the mouse brain and in zebrafish. When combined with organelle-targeted fluorescent proteins and biosensors, we uncover previously unrecognized cell-type differences in patterns of apoptosis and associated dynamics of ribosomal disassembly, calcium overload and mitochondrial fission. 2Phatal provides a powerful and rapidly adoptable platform to investigate in vivo functional consequences and neural plasticity following cell death as well as apoptosis, cell clearance and tissue remodelling in diverse organs and species. PMID- 28621307 TI - Bending strain engineering in quantum spin hall system for controlling spin currents. AB - Quantum spin Hall system can exhibit exotic spin transport phenomena, mediated by its topological edge states. Here the concept of bending strain engineering to tune the spin transport properties of a quantum spin Hall system is demonstrated. We show that bending strain can be used to control the spin orientation of counter-propagating edge states of a quantum spin system to generate a non-zero spin current. This physics mechanism can be applied to effectively tune the spin current and pure spin current decoupled from charge current in a quantum spin Hall system by control of its bending curvature. Furthermore, the curved quantum spin Hall system can be achieved by the concept of topological nanomechanical architecture in a controllable way, as demonstrated by the material example of Bi/Cl/Si(111) nanofilm. This concept of bending strain engineering of spins via topological nanomechanical architecture affords a promising route towards the realization of topological nano-mechanospintronics. PMID- 28621309 TI - Corrigendum: Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation. AB - This corrects the article DOI: 10.1038/ncomms15308. PMID- 28621308 TI - Inhalation toxicity of indoor air pollutants in Drosophila melanogaster using integrated transcriptomics and computational behavior analyses. AB - We conducted an inhalation toxicity test on the alternative animal model, Drosophila melanogaster, to investigate potential hazards of indoor air pollution. The inhalation toxicity of toluene and formaldehyde was investigated using comprehensive transcriptomics and computational behavior analyses. The ingenuity pathway analysis (IPA) based on microarray data suggests the involvement of pathways related to immune response, stress response, and metabolism in formaldehyde and toluene exposure based on hub molecules. We conducted a toxicity test using mutants of the representative genes in these pathways to explore the toxicological consequences of alterations of these pathways. Furthermore, extensive computational behavior analysis showed that exposure to either toluene or formaldehyde reduced most of the behavioral parameters of both wild-type and mutants. Interestingly, behavioral alteration caused by toluene or formaldehyde exposure was most severe in the p38b mutant, suggesting that the defects in the p38 pathway underlie behavioral alteration. Overall, the results indicate that exposure to toluene and formaldehyde via inhalation causes severe toxicity in Drosophila, by inducing significant alterations in gene expression and behavior, suggesting that Drosophila can be used as a potential alternative model in inhalation toxicity screening. PMID- 28621310 TI - Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system. AB - G-protein-coupled receptor (GPCR) expression is extensively studied in bulk cDNA, but heterogeneity and functional patterning of GPCR expression in individual vascular cells is poorly understood. Here, we perform a microfluidic-based single cell GPCR expression analysis in primary smooth muscle cells (SMC) and endothelial cells (EC). GPCR expression is highly heterogeneous in all cell types, which is confirmed in reporter mice, on the protein level and in human cells. Inflammatory activation in murine models of sepsis or atherosclerosis results in characteristic changes in the GPCR repertoire, and we identify functionally relevant subgroups of cells that are characterized by specific GPCR patterns. We further show that dedifferentiating SMC upregulate GPCRs such as Gpr39, Gprc5b, Gprc5c or Gpr124, and that selective targeting of Gprc5b modulates their differentiation state. Taken together, single-cell profiling identifies receptors expressed on pathologically relevant subpopulations and provides a basis for the development of new therapeutic strategies in vascular diseases. PMID- 28621311 TI - Dependence of the shape of graphene nanobubbles on trapped substance. AB - Van der Waals (vdW) interaction between two-dimensional crystals (2D) can trap substances in high pressurized (of order 1 GPa) on nanobubbles. Increasing the adhesion between the 2D crystals further enhances the pressure and can lead to a phase transition of the trapped material. We found that the shape of the nanobubble can depend critically on the properties of the trapped substance. In the absence of any residual strain in the top 2D crystal, flat nanobubbles can be formed by trapped long hydrocarbons (that is, hexadecane). For large nanobubbles with radius 130 nm, our atomic force microscopy measurements show nanobubbles filled with hydrocarbons (water) have a cylindrical symmetry (asymmetric) shape which is in good agreement with our molecular dynamics simulations. This study provides insights into the effects of the specific material and the vdW pressure on the microscopic details of graphene bubbles. PMID- 28621312 TI - Adaptive self-assembly and induced-fit transformations of anion-binding metal organic macrocycles. AB - Container-molecules are attractive to chemists due to their unique structural characteristics comparable to enzymes and receptors in nature. We report here a family of artificial self-assembled macrocyclic containers that feature induced fit transformations in response to different anionic guests. Five metal-organic macrocycles with empirical formula of MnL2n (M=Metal; L=Ligand; n=3, 4, 5, 6, 7) are selectively obtained starting from one simple benzimidazole-based ligand and square-planar palladium(II) ions, either by direct anion-adaptive self-assembly or induced-fit transformations. Hydrogen-bonding interactions between the inner surface of the macrocycles and the anionic guests dictate the shape and size of the product. A comprehensive induced-fit transformation map across all the MnL2n species is drawn, with a representative reconstitution process from Pd7L14 to Pd3L6 traced in detail, revealing a gradual ring-shrinking mechanism. We envisage that these macrocyclic molecules with adjustable well-defined hydrogen-bonding pockets will find wide applications in molecular sensing or catalysis. PMID- 28621314 TI - Directed self-assembly of liquid crystalline blue-phases into ideal single crystals. AB - Chiral nematic liquid crystals are known to form blue phases-liquid states of matter that exhibit ordered cubic arrangements of topological defects. Blue-phase specimens, however, are generally polycrystalline, consisting of randomly oriented domains that limit their performance in applications. A strategy that relies on nano-patterned substrates is presented here for preparation of stable, macroscopic single-crystal blue-phase materials. Different template designs are conceived to exert control over different planes of the blue-phase lattice orientation with respect to the underlying substrate. Experiments are then used to demonstrate that it is indeed possible to create stable single-crystal blue phase domains with the desired orientation over large regions. These results provide a potential avenue to fully exploit the electro-optical properties of blue phases, which have been hindered by the existence of grain boundaries. PMID- 28621313 TI - Lkb1 maintains Treg cell lineage identity. AB - Regulatory T (Treg) cells are a distinct T-cell lineage characterized by sustained Foxp3 expression and potent suppressor function, but the upstream dominant factors that preserve Treg lineage-specific features are mostly unknown. Here, we show that Lkb1 maintains Treg cell lineage identity by stabilizing Foxp3 expression and enforcing suppressor function. Upon T-cell receptor (TCR) stimulation Lkb1 protein expression is upregulated in Treg cells but not in conventional T cells. Mice with Treg cell-specific deletion of Lkb1 develop a fatal early-onset autoimmune disease, with no Foxp3 expression in most Treg cells. Lkb1 stabilizes Foxp3 expression by preventing STAT4-mediated methylation of the conserved noncoding sequence 2 (CNS2) in the Foxp3 locus. Independent of maintaining Foxp3 expression, Lkb1 programs the expression of a wide spectrum of immunosuppressive genes, through mechanisms involving the augmentation of TGF beta signalling. These findings identify a critical function of Lkb1 in maintaining Treg cell lineage identity. PMID- 28621315 TI - Research on miRNA-195 and target gene CDK6 in oral verrucous carcinoma. AB - Oral verrucous carcinoma (OVC) is a verrucous variant of oral cavity squamous carcinoma (OSCC). The expression of miRNA from OVC and OSCC including their matched normal oral mucosa tissues was profiled through the Affymetrix GeneChip miRNA Arrays. TargetScan and miRanda databases were used to predict the target gene of miRNA-195. The quantitative real-time PCR was applied to validate the expression of miRNA-195. The expression of CDK6 was investigated by the quantitative real-time PCR and immunohistochemistry. In this study, a total of 23 and 35 differentially expressed miRNAs were identified in OVC and OSCC, respectively. Moreover, 44 miRNAs were differentially expressed between OSCC and OVC. In addition, miRNA-195 was significantly decreased in both OVC and OSCC compared to normal oral mucosa. Target gene prediction demonstrated that CDK6 was a potential target gene of miRNA-195. In the quantitative real-time PCR, miR-195 was decreased in OVC and OSCC, which was consistent with the result of miRNA chip analysis. CDK6 was increased in OVC and OSCC, which was opposite to the expression of miRNA-195. In conclusion, miRNA-195 could be the potential diagnosis biomarker and therapy target of OVC. PMID- 28621316 TI - Combination of p53-DC vaccine and rAd-p53 gene therapy induced CTLs cytotoxic against p53-deleted human prostate cancer cells in vitro. AB - Recently, the US FDA approved sipuleucel-T, which is composed of autologous DCs stimulated with a recombinant fusion protein of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as the first immunotherapeutic agent for metastatic castration resistant prostate cancer (mCRPC). However, sipuleucel-T demonstrated only modest efficacy in mCPRC patients. Researchers are now investigating the potential of p53 protein as a tumor-associated antigen (TAA) loaded in DC-based cancer vaccine. Approximately half of all tumors overexpress p53, and up to 20% of prostate cancer cells overexpresses p53. In this study, we evaluated the feasibility of combining p53 DC vaccine and rAd-p53 gene therapy, using the p53-overexpressing and non expressing prostate cancer cells in vitro. We successfully generated the p53-DC vaccine by culturing autologous DCs infected with rAd-p53. This p53-DC vaccine can differentiate CTLs specifically cytotoxic to p53-overexpressing prostate cancer cells. In addition, rAd-p53 infection can induce overexpression of p53 and thus the cytotoxicity of CTLs differentiated by the p53-DC vaccine in p53 non expressing prostate cancer cells. These findings suggest that this combination therapy using p53-DC vaccine and rAd-p53 gene therapy together may represent a new paradigm for the treatment of mCRPC. PMID- 28621317 TI - p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status. AB - High-risk human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas have a more favorable prognosis than HPV-negative ones. p16 immunohistochemistry has been recommended as a prognostic test in clinical practice. Several p16 antibodies are available, and their performance has not been directly compared. We evaluated three commercially available p16 antibody clones (E6H4, JC8 and G175-405) utilizing 199 cases of oropharyngeal squamous cell carcinoma from a tissue microarray, read by three pathologists with three different cutoffs for positivity: any staining, >50% and >75%. Positive predictive values for high-risk HPV status by RNA in situ hybridization for the E6H4, JC8 and G175-405 clones were 98%, 100% and 99% at the 75% cutoff, but negative predictive values were much more variable at 86%, 69% and 56%, respectively. These improved using the 50% cutoff, becoming similar for all three antibodies. Intensity varied substantially, with 85% of E6H4, 72% of JC8 and 67% of G175-405 showing strong (3+) intensity. With Kaplan-Meier survival plots at the 75% cutoff, the E6H4 clone showed the largest differential in disease specific and overall survival between p16-positive and -negative results. Decreasing the cutoff to 50% increased correlation with HPV in situ hybridization and improved the survival differential for the JC8 and G175-405 clones without worsening of performance for the E6H4 clone. Interobserver agreement was also assessed by kappa scores and was highest for the E6H4 clone. Overall, these study results show modest but important performance differences between the three different p16 antibody clones, suggesting that the E6H4 clone performs best because of strongest staining intensity, greatest differential in outcomes between positive and negative results, lowest interobserver variability, and lowest background, nonspecific staining. The results also suggest that a 75% cutoff is very functional but that, in this patient population with high HPV incidence, 50% and any staining cutoffs may be more effective, particularly for the non-E6H4 clones. PMID- 28621318 TI - Natural killer-like signature observed post therapy in locally advanced rectal cancer is a determinant of pathological response and improved survival. AB - Around 12-15% of patients with locally advanced rectal cancer undergo a pathologically complete response (tumor regression grade 4) to long-course preoperative chemoradiotherapy; the remainder exhibit a spectrum of tumor regression (tumor regression grade 1-3). Understanding therapy-related transcriptional alterations may enable better prediction of response as measured by progression-free and overall survival, in addition to aiding the development of improved strategies based on the underlying biology of the disease. To this end, we performed high-throughput gene expression profiling in 40 pairs of formalin-fixed paraffin-embedded rectal cancer biopsies and matched resections following long-course preoperative chemoradiotherapy (discovery cohort). Differential gene expression analysis was performed contrasting tumor regression grades in resections. Enumeration of the tumor microenvironment cell population was undertaken using in silico analysis of the transcriptional data, and real time PCR validation of NCR1 undertaken. Immunohistochemistry and survival analysis was used to measure CD56+ cell populations in an independent cohort (n=150). Gene expression traits observed following long-course preoperative chemoradiotherapy in the discovery cohort suggested an increased abundance of natural killer cells in tumors that displayed a clinical response to CRT in a tumor regression grade-dependent manner. CD56+ natural killer-cell populations were measured by immunohistochemistry and found to be significantly higher in tumor regression grade 3 patients compared with tumor regression grade 1-2 in the validation cohort. Furthermore, it was observed that patients positive for CD56 cells after therapy had a better overall survival (HR=0.282, 95% CI=0.109-0.729, chi2=7.854, P=0.005). In conclusion, we have identified a novel post-therapeutic natural killer-like transcription signature in patients responding to long-course preoperative chemoradiotherapy. Furthermore, patients with a higher abundance of CD56-positive natural killer cells post long-course preoperative chemoradiotherapy had better overall survival. Therefore, harnessing a natural killer-like response after therapy may improve outcomes for locally advanced rectal cancer patients. Finally, we hypothesize that future assessment of this natural killer-like response in on-treatment biopsy material may inform clinical decision-making for treatment duration. PMID- 28621319 TI - FOXA2 is a sensitive and specific marker for small cell neuroendocrine carcinoma of the prostate. AB - The median survival of patients with small cell neuroendocrine carcinoma is significantly shorter than that of patients with classic acinar-type adenocarcinoma. Small cell neuroendocrine carcinoma is traditionally diagnosed based on histologic features because expression of current immunohistochemical markers is inconsistent. This is a challenging diagnosis even for expert pathologists and particularly so for pathologists who do not specialize in prostate cancer. New biomarkers to aid in the diagnosis of small cell neuroendocrine carcinoma are therefore urgently needed. We discovered that FOXA2, a pioneer transcription factor, is frequently and specifically expressed in small cell neuroendocrine carcinoma compared with prostate adenocarcinoma from published mRNA-sequencing data of a wide range of human prostate cancers. We verified the expression of FOXA2 in human prostate cancer cell lines and xenografts, patient biopsy specimens, tissue microarrays of prostate cancers with lymph node metastasis, primary small cell neuroendocrine carcinoma, and metastatic treatment-related small cell neuroendocrine carcinoma and cases from a rapid autopsy program. FOXA2 expression was present in NCI-H660 and PC3 neuroendocrine cell lines, but not in LNCAP and CWR22 adenocarcinoma cell lines. Of the human prostate cancer specimens, 20 of 235 specimens (8.5%) showed diagnostic histologic features of small cell neuroendocrine carcinoma as judged histologically. Fifteen of 20 small cell neuroendocrine carcinoma tissues (75%) showed strong expression of FOXA2 (staining intensity 2 or 3). FOXA2 expression was also detected in 9 of 215 prostate cancer tissues (4.2%) that were histologically defined as adenocarcinoma. Our findings demonstrate that FOXA2 is a sensitive and specific molecular marker that may be extremely valuable in the pathologic diagnosis of small cell neuroendocrine carcinoma. PMID- 28621320 TI - Genomic analysis of follicular dendritic cell sarcoma by molecular inversion probe array reveals tumor suppressor-driven biology. AB - Follicular dendritic cell sarcoma is a rare malignant neoplasm of dendritic cell origin that is currently poorly characterized by genetic studies. To investigate whether recurrent genomic alterations may underlie the biology of follicular dendritic cell sarcoma and to identify potential contributory regions and genes, molecular inversion probe array analysis was performed on 14 independent formalin fixed, paraffin-embedded samples. Abnormal genomic profiles were observed in 11 out of 14 (79%) cases. The majority showed extensive genomic complexity that was predominantly represented by hemizygous losses affecting multiple chromosomes. Alterations of chromosomal regions 1p (55%), 2p (55%), 3p (82%), 3q (45%), 6q (55%), 7q (73%), 8p (45%), 9p (64%), 11q (64%), 13q (91%), 14q (82%), 15q (64%), 17p (55%), 18q (64%), and 22q (55%) were recurrent across the 11 samples showing abnormal genomic profiles. Many recurrent genomic alterations in follicular dendritic cell sarcoma overlap deletions that are frequently observed across human cancers, suggesting selection, or an active role for these alterations in follicular dendritic cell sarcoma pathogenesis. In support of a tumor suppressor driven biology, homozygous deletions involving tumor suppressor genes CDKN2A, RB1, BIRC3, and CYLD were also observed. Neither recurrent gains nor amplifications were observed. This genomic characterization provides new information regarding follicular dendritic cell sarcoma biology that may improve understanding about the underlying pathophysiology, provide better prognostication, and identify potential therapeutic markers for this rare disease. PMID- 28621321 TI - BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. AB - Recognition of high-grade endometrial stromal sarcoma is important because of its aggressive clinical behavior. Morphologic features of YWHAE-NUTM2 high-grade endometrial stromal sarcoma may overlap with other uterine sarcoma types. BCOR immunoexpression was studied in these tumors and their morphologic mimics to assess its diagnostic utility. BCOR immunohistochemical staining was performed on archival tissue from 28 high-grade endometrial stromal sarcomas with classic morphology (20 YWHAE-NUTM2, 5 ZC3H7B-BCOR, 3 BCOR-ZC3H7B), 3 high-grade endometrial stromal sarcomas with unusual morphology and unknown gene rearrangement status, 66 low-grade endometrial stromal sarcomas, 21 endometrial stromal nodules, 38 uterine leiomyosarcomas, and 19 uterine leiomyomas. Intensity of nuclear staining and percentage of positive tumor cells were recorded. Strong diffuse nuclear BCOR staining (defined as >95% of tumor cells) was seen in the round cell component of all 20 (100%) classic YWHAE-NUTM2 high-grade endometrial stromal sarcomas and the 3 unusual high-grade endometrial stromal sarcomas which prompted FISH studies confirming YWHAE rearrangement in 2 tumors. Genomic PCR confirmed the presence of BCOR exon 16 internal tandem duplication in the third case. Diffuse BCOR staining was strong in three and weak in one BCOR-rearranged high-grade endometrial stromal sarcoma while absent in the remaining four BCOR rearranged tumors. BCOR staining was weakly positive in <5% of tumor cells in 4 of 66 (6%) low-grade endometrial stromal sarcomas and 1 of 18 (6%) endometrial stromal nodules and weakly to moderately positive in <5-40% of tumor cells in 6 of 31 (19%) leiomyosarcomas. No BCOR staining was seen in the remaining low-grade endometrial stromal sarcomas, endometrial stromal nodules, leiomyosarcomas, or any of the leiomyomas. BCOR immunohistochemical staining is a highly sensitive marker for YWHAE-NUTM2 high-grade endometrial stromal sarcoma with both classic and unusual morphology and identifies a subset of high-grade endometrial stromal sarcoma with BCOR alterations, including BCOR rearrangement and internal tandem duplication. PMID- 28621322 TI - Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer. AB - The presence of tumor-infiltrating lymphocytes (TIL), reflecting host immune activity, is frequently correlated with better clinical outcomes, particularly in HER2-positive and triple-negative breast cancer. Recent findings suggest that organization of immune infiltrates in tertiary lymphoid structures also has a beneficial effect on survival. This study investigated inter- and intra-observer variation in TIL assessment using conventional hematoxylin-eosin versus immunohistochemical staining to identify immune cells. Global, intratumoral, and stromal TIL, as well as tertiary lymphoid structures were scored independently by experienced pathologists on full-face tumor sections (n=124). The fidelity of scoring infiltrates in core biopsies compared to surgical specimens, and pathological assessment compared to quantitative digital analysis was also evaluated. The inter-observer concordance correlation coefficient was 0.80 for global, 0.72 for intratumoral, and 0.71 for stromal TIL, while the intra-observer concordance correlation coefficient was 0.90 for global, 0.77 for intratumoral, and 0.89 for stromal TIL using immunohistochemical stains. Correlations were lower with hematoxylin-eosin stains, particularly for intratumoral TIL, while global scores had the highest concordance correlation coefficients. Our study concluded that tertiary lymphoid structures are accurately and consistently scored using immunohistochemical but not hematoxylin-eosin stains. A strong association was observed between TIL in core biopsies and surgical samples (R2=0.74) but this did not extend to tertiary lymphoid structures (R2=0.26). TIL scored by pathologists and digital analysis were correlated but our analysis reveals a constant bias between these methods. These data challenge current criteria for TIL and tertiary lymphoid structure assessment in breast cancer and recommend that how pathologists evaluate immune infiltrates be reexamined for future studies. PMID- 28621323 TI - A robust methodology for the quantitative assessment of the rat jawbone microstructure. AB - Micro-computed tomography can be applied for the assessment of the micro architectural characteristics of the cortical and trabecular bones in either physiological or disease conditions. However, reports often lack a detailed description of the methodological steps used to analyse these images, such as the volumes of interest, the algorithms used for image filtration, the approach used for image segmentation, and the bone parameters quantified, thereby making it difficult to compare or reproduce the studies. This study addresses this critical need and aims to provide standardized assessment and consistent parameter reporting related to quantitative jawbone image analysis. Various regions of the rat jawbones were screened for their potential for standardized micro-computed tomography analysis. Furthermore, the volumes of interest that were anticipated to be most susceptible to bone structural changes in response to experimental interventions were defined. In the mandible, two volumes of interest were selected, namely, the condyle and the trabecular bone surrounding the three molars. In the maxilla, the maxillary tuberosity region and the inter-radicular septum of the second molar were considered as volumes of interest. The presented protocol provides a standardized and reproducible methodology for the analysis of relevant jawbone volumes of interest and is intended to ensure global, accurate, and consistent reporting of its morphometry. Furthermore, the proposed methodology has potential, as a variety of rodent animal models would benefit from its implementation. PMID- 28621324 TI - Marginal bone loss around non-submerged implants is associated with salivary microbiome during bone healing. AB - Marginal bone loss during bone healing exists around non-submerged dental implants. The aim of this study was to identify the relationship between different degrees of marginal bone loss during bone healing and the salivary microbiome. One hundred patients were recruited, and marginal bone loss around their implants was measured using cone beam computed tomography during a 3-month healing period. The patients were divided into three groups according to the severity of marginal bone loss. Saliva samples were collected from all subjected and were analysed using 16S MiSeq sequencing. Although the overall structure of the microbial community was not dramatically altered, the relative abundance of several taxonomic groups noticeably changed. The abundance of species in the phyla Spirochaeta and Synergistetes increased significantly as the bone loss became more severe. Species within the genus Treponema also exhibited increased abundance, whereas Veillonella, Haemophilus and Leptotrichia exhibited reduced abundances, in groups with more bone loss. Porphyromonasgingivalis, Treponemadenticola and Streptococcus intermedius were significantly more abundant in the moderate group and/or severe group. The severity of marginal bone loss around the non-submerged implant was associated with dissimilar taxonomic compositions. An increased severity of marginal bone loss was related to increased proportions of periodontal pathogenic species. These data suggest a potential role of microbes in the progression of marginal bone loss during bone healing. PMID- 28621325 TI - The oral commensal Streptococcus mitis activates the aryl hydrocarbon receptor in human oral epithelial cells. AB - Streptococcus mitis (S. mitis) is a pioneer commensal bacterial species colonizing many of the surfaces of the oral cavity in healthy individuals. Yet, not much information is available regarding its interaction with the host. We used examination of its transcriptional regulation in oral keratinocytes to elucidate some of its potential roles in the oral cavity. Transcription factor analysis of oral keratinocytes predicted S. mitis-mediated activation of aryl hydrocarbon receptor (AhR). Activation and functionality of AhR was confirmed through nuclear translocation determined by immunofluorescence microscopy and real-time polymerase chain reaction with reverse transcription analysis of CYP1A1, the hallmark gene for AhR activation. Addition of Streptococcus mutans or Streptococcus gordonii did not induce CYP1A1 transcription in the keratinocyte cultures. Introduction of an AhR-specific inhibitor revealed that S. mitis mediated transcription of CXCL2 and CXCL8 was regulated by AhR. Elevated levels of prostaglandin E2 (enzyme-linked immunosorbent assay) in supernatants from S. mitis-treated oral epithelial cells were also attenuated by inhibition of AhR activity. The observed AhR-regulated activities point to a contribution of S. mitis in the regulation of inflammatory responses and thereby to wound healing in the oral cavity. The concept that the oral commensal microbiota can induce AhR activation is important, also in view of the role that AhR has in modulation of T cell differentiation and as an anti-inflammatory factor in macrophages. PMID- 28621326 TI - Resin infiltration of deproteinised natural occlusal subsurface lesions improves initial quality of fissure sealing. AB - The aim of this ex vivo study was to evaluate the infiltration capability and rate of microleakage of a low-viscous resin infiltrant combined with a flowable composite resin (RI/CR) when used with deproteinised and etched occlusal subsurface lesions (International Caries Detection and Assessment System code 2). This combined treatment procedure was compared with the exclusive use of flowable composite resin (CR) for fissure sealing. Twenty premolars and 20 molars revealing non-cavitated occlusal carious lesions were randomly divided into two groups and were meticulously cleaned and deproteinised using NaOCl (2%). After etching with HCl (15%), 10 premolar and 10 molar lesions were infiltrated (Icon/DMG; rhodamine B isothiocyanate (RITC)-labelled) followed by fissure sealing (G-aenial Flo/GC; experimental group, RI/CR). In the control group (CR), the carious fissures were only sealed. Specimens were cut perpendicular to the occlusal surface and through the area of the highest demineralisation (DIAGNOdent pen, KaVo). Using confocal laser-scanning microscopy, the specimens were assessed with regard to the percentage of caries infiltration, marginal adaption and internal integrity. Within the CR group, the carious lesions were not infiltrated. Both premolar (57.9%+/-23.1%) and molar lesions (35.3%+/-22.1%) of the RI/CR group were uniformly infiltrated to a substantial extent, albeit with significant differences (P=0.034). Moreover, microleakage (n=1) and the occurrence of voids (n=2) were reduced in the RI/CR group compared with the CR group (5 and 17 specimens, respectively). The RI/CR approach increases the initial quality of fissure sealing and is recommended for the clinical control of occlusal caries. PMID- 28621327 TI - Dimeric structure of the uracil:proton symporter UraA provides mechanistic insights into the SLC4/23/26 transporters. AB - The Escherichia coli uracil:proton symporter UraA is a prototypical member of the nucleobase/ascorbate transporter (NAT) or nucleobase/cation symporter 2 (NCS2) family, which corresponds to the human solute carrier family SLC23. UraA consists of 14 transmembrane segments (TMs) that are organized into two distinct domains, the core domain and the gate domain, a structural fold that is also shared by the SLC4 and SLC26 transporters. Here we present the crystal structure of UraA bound to uracil in an occluded state at 2.5 A resolution. Structural comparison with the previously reported inward-open UraA reveals pronounced relative motions between the core domain and the gate domain as well as intra-domain rearrangement of the gate domain. The occluded UraA forms a dimer in the structure wherein the gate domains are sandwiched by two core domains. In vitro and in vivo biochemical characterizations show that UraA is at equilibrium between dimer and monomer in all tested detergent micelles, while dimer formation is necessary for the transport activity. Structural comparison between the dimeric UraA and the recently reported inward-facing dimeric UapA provides important insight into the transport mechanism of SLC23 transporters. PMID- 28621328 TI - Live cell screening platform identifies PPARdelta as a regulator of cardiomyocyte proliferation and cardiac repair. AB - Zebrafish can efficiently regenerate their heart through cardiomyocyte proliferation. In contrast, mammalian cardiomyocytes stop proliferating shortly after birth, limiting the regenerative capacity of the postnatal mammalian heart. Therefore, if the endogenous potential of postnatal cardiomyocyte proliferation could be enhanced, it could offer a promising future therapy for heart failure patients. Here, we set out to systematically identify small molecules triggering postnatal cardiomyocyte proliferation. By screening chemical compound libraries utilizing a Fucci-based system for assessing cell cycle stages, we identified carbacyclin as an inducer of postnatal cardiomyocyte proliferation. In vitro, carbacyclin induced proliferation of neonatal and adult mononuclear rat cardiomyocytes via a peroxisome proliferator-activated receptor delta (PPARdelta)/PDK1/p308Akt/GSK3beta/beta-catenin pathway. Inhibition of PPARdelta reduced cardiomyocyte proliferation during zebrafish heart regeneration. Notably, inducible cardiomyocyte-specific overexpression of constitutively active PPARdelta as well as treatment with PPARdelta agonist after myocardial infarction in mice induced cell cycle progression in cardiomyocytes, reduced scarring, and improved cardiac function. Collectively, we established a cardiomyocyte proliferation screening system and present a new drugable target with promise for the treatment of cardiac pathologies caused by cardiomyocyte loss. PMID- 28621330 TI - Erratum: SWIM: a computational tool to unveiling crucial nodes in complex biological networks. AB - This corrects the article DOI: 10.1038/srep44797. PMID- 28621329 TI - Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells. AB - Single-cell epigenome sequencing techniques have recently been developed. However, the combination of different layers of epigenome sequencing in an individual cell has not yet been achieved. Here, we developed a single-cell multi omics sequencing technology (single-cell COOL-seq) that can analyze the chromatin state/nucleosome positioning, DNA methylation, copy number variation and ploidy simultaneously from the same individual mammalian cell. We used this method to analyze the reprogramming of the chromatin state and DNA methylation in mouse preimplantation embryos. We found that within < 12 h of fertilization, each individual cell undergoes global genome demethylation together with the rapid and global reprogramming of both maternal and paternal genomes to a highly opened chromatin state. This was followed by decreased openness after the late zygote stage. Furthermore, from the late zygote to the 4-cell stage, the residual DNA methylation is preferentially preserved on intergenic regions of the paternal alleles and intragenic regions of maternal alleles in each individual blastomere. However, chromatin accessibility is similar between paternal and maternal alleles in each individual cell from the late zygote to the blastocyst stage. The binding motifs of several pluripotency regulators are enriched at distal nucleosome depleted regions from as early as the 2-cell stage. This indicates that the cis regulatory elements of such target genes have been primed to an open state from the 2-cell stage onward, long before pluripotency is eventually established in the ICM of the blastocyst. Genes may be classified into homogeneously open, homogeneously closed and divergent states based on the chromatin accessibility of their promoter regions among individual cells. This can be traced to step-wise transitions during preimplantation development. Our study offers the first single cell and parental allele-specific analysis of the genome-scale chromatin state and DNA methylation dynamics at single-base resolution in early mouse embryos and provides new insights into the heterogeneous yet highly ordered features of epigenomic reprogramming during this process. PMID- 28621331 TI - Corrigendum: Hepatic p63 regulates steatosis via IKKbeta/ER stress. AB - This corrects the article DOI: 10.1038/ncomms15111. PMID- 28621332 TI - Observing electron localization in a dissociating H2+ molecule in real time. AB - Dissociation of diatomic molecules with odd number of electrons always causes the unpaired electron to localize on one of the two resulting atomic fragments. In the simplest diatomic molecule H2+ dissociation yields a hydrogen atom and a proton with the sole electron ending up on one of the two nuclei. That is equivalent to breaking of a chemical bond-the most fundamental chemical process. Here we observe such electron localization in real time by performing a pump probe experiment. We demonstrate that in H2+ electron localization is complete in just 15 fs when the molecule's internuclear distance reaches 8 atomic units. The measurement is supported by a theoretical simulation based on numerical solution of the time-dependent Schrodinger equation. This observation advances our understanding of detailed dynamics of molecular dissociation. PMID- 28621333 TI - Francisella requires dynamic type VI secretion system and ClpB to deliver effectors for phagosomal escape. AB - Francisella tularensis is an intracellular pathogen that causes the fatal zoonotic disease tularaemia. Critical for its pathogenesis is the ability of the phagocytosed bacteria to escape into the cell cytosol. For this, the bacteria use a non-canonical type VI secretion system (T6SS) encoded on the Francisella pathogenicity island (FPI). Here we show that in F. novicida T6SS assembly initiates at the bacterial poles both in vitro and within infected macrophages. T6SS dynamics and function depends on the general purpose ClpB unfoldase, which specifically colocalizes with contracted sheaths and is required for their disassembly. T6SS assembly depends on iglF, iglG, iglI and iglJ, whereas pdpC, pdpD, pdpE and anmK are dispensable. Importantly, strains lacking pdpC and pdpD are unable to escape from phagosome, activate AIM2 inflammasome or cause disease in mice. This suggests that PdpC and PdpD are T6SS effectors involved in phagosome rupture. PMID- 28621335 TI - In the news: ECE2017 - highlights from the meeting. PMID- 28621334 TI - Telomere Length and Bipolar Disorder. AB - Variation in telomere length is heritable and is currently considered a promising biomarker of susceptibility for neuropsychiatric disorders, particularly because of its association with memory function and hippocampal morphology. Here, we investigate telomere length in connection to familial risk and disease expression in bipolar disorder (BD). We used quantitative PCRs and a telomere-sequence to single-copy-gene-sequence ratio method to determine telomere length in genomic DNA extracted from buccal smears from 63 patients with BD, 74 first-degree relatives (49 relatives had no lifetime psychopathology and 25 had a non-BD mood disorder), and 80 unrelated healthy individuals. Participants also underwent magnetic resonance imaging to determine hippocampal volumes and cognitive assessment to evaluate episodic memory using the verbal paired associates test. Telomere length was shorter in psychiatrically well relatives (p=0.007) compared with unrelated healthy participants. Telomere length was also shorter in relatives (regardless of psychiatric status; p<0.01) and patients with BD not on lithium (p=0.02) compared with lithium-treated patients with BD. In the entire sample, telomere length was positively associated with left and right hippocampal volume and with delayed recall. This study provides evidence that shortened telomere length is associated with familial risk for BD. Lithium may have neuroprotective properties that require further investigation using prospective designs. PMID- 28621336 TI - Obesity: Sweetener associated with increased adiposity in young adults. PMID- 28621337 TI - Diabetes: SGLT2 inhibitors and diabetic ketoacidosis - a growing concern. PMID- 28621338 TI - Adipose tissue: Crosstalk between adipocytes and neurons. PMID- 28621339 TI - Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. AB - Hepatic steatosis is an underlying feature of nonalcoholic fatty liver disease (NAFLD), which is the most common form of liver disease and is present in up to ~70% of individuals who are overweight. NAFLD is also associated with hypertriglyceridaemia and low levels of HDL, glucose intolerance, insulin resistance and type 2 diabetes mellitus. Hepatic steatosis is a strong predictor of the development of insulin resistance and often precedes the onset of other known mediators of insulin resistance. This sequence of events suggests that hepatic steatosis has a causal role in the development of insulin resistance in other tissues, such as skeletal muscle. Hepatokines are proteins that are secreted by hepatocytes, and many hepatokines have been linked to the induction of metabolic dysfunction, including fetuin A, fetuin B, retinol-binding protein 4 (RBP4) and selenoprotein P. In this Review, we describe the factors that influence the development of hepatic steatosis, provide evidence of strong links between hepatic steatosis and insulin resistance in non-hepatic tissues, and discuss recent advances in our understanding of how steatosis alters hepatokine secretion to influence metabolic phenotypes through inter-organ communication. PMID- 28621340 TI - Reproductive endocrinology: Elagolix in endometriosis. PMID- 28621341 TI - The gentle art of saying NO: how nitric oxide gets things done in the hypothalamus. AB - The chemical signalling molecule nitric oxide (NO), which freely diffuses through aqueous and lipid environments, subserves an array of functions in the mammalian central nervous system, such as the regulation of synaptic plasticity, blood flow and neurohormone secretion. In this Review, we consider the cellular and molecular mechanisms by which NO evokes short-term and long-term changes in neuronal activity. We also highlight recent studies showing that discrete populations of neurons that synthesize NO in the hypothalamus constitute integrative systems that support life by relaying metabolic and gonadal signals to the neuroendocrine brain, and thus gate the onset of puberty and adult fertility. The putative involvement and therapeutic potential of NO in the pathophysiology of brain diseases, for which hormonal imbalances during postnatal development could be risk factors, is also discussed. PMID- 28621342 TI - Prevalence of chronic kidney disease and association with cardiovascular risk factors among teachers in Cape Town, South Africa. AB - Background: There is a need to determine the feasibility of conducting studies of chronic diseases among large cohorts of African patients. One aim of the South African feasibility study was to determine the prevalence of chronic kidney disease (CKD) and its association with cardiovascular disease (CVD) risk factors among school teachers. Methods: In a cross-sectional survey of 489 teachers we captured data on demographics, CVD risk factors, anthropometry and blood pressure. Serum glucose, creatinine, cholesterol and urine protein/creatinine ratio was measured. Glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease study equations. Results: The mean (+/- standard deviation) age of the participants was 46.3 +/- 8.5 years, with 70.3% being female and 74.6% of mixed ethnicity. The crude prevalence of CKD using the CKD-EPI equation was 6.1% while the age-adjusted prevalence was 6.4% (95% confidence interval 3.2-9.7%). CKD was associated with the presence of diabetes and higher diastolic blood pressures. Conclusions: In our study population of relatively young, working individuals CKD was common, clinically silent and associated with cardiovascular risk factors. The long-term complications of CKD are serious and expensive to manage and this, therefore, constitutes an important public health problem for South Africa. PMID- 28621344 TI - Metal-organic frameworks meet metal nanoparticles: synergistic effect for enhanced catalysis. AB - Metal-organic frameworks (MOFs), established as a relatively new class of crystalline porous materials with high surface area, structural diversity, and tailorability, attract extensive interest and exhibit a variety of applications, especially in catalysis. Their permanent porosity enables their inherent superiority in confining guest species, particularly small metal nanoparticles (MNPs), for improved catalytic performance and/or the expansion of reaction scope. This is a rapidly developing interdisciplinary research field. In this review, we provide an overview of significant progress in the development of MNP/MOF composites, including various preparation strategies and characterization methods as well as catalytic applications. Special emphasis is placed on synergistic effects between the two components that result in an enhanced performance in heterogeneous catalysis. Finally, the prospects of MNP/MOF composites in catalysis and remaining issues in this field have been indicated. PMID- 28621343 TI - Current evidence on the discontinuation of eculizumab in patients with atypical haemolytic uraemic syndrome. AB - Background. Atypical haemolytic uraemic syndrome (aHUS) is a rare, life threatening disorder for which eculizumab is the only approved treatment. Life long treatment is indicated; however, eculizumab discontinuation has been reported. Methods. Unpublished authors' cases and published cases of eculizumab discontinuation are reviewed. We also report eculizumab discontinuation data from five clinical trials, plus long-term extensions and the global aHUS Registry. Results. Of six unpublished authors' cases, four patients had a subsequent thrombotic microangiopathy (TMA) manifestation within 12 months of discontinuation. Case reports of 52 patients discontinuing eculizumab were identified; 16 (31%) had a subsequent TMA manifestation. In eculizumab clinical trials, 61/130 patients discontinued treatment between 2008 and 2015. Median follow-up post-discontinuation was 24 weeks and during this time 12 patients experienced 15 severe TMA complications and 9 of the 12 patients restarted eculizumab. TMA complications occurred irrespective of identified genetic mutation, high risk polymorphism or auto-antibody. In the global aHUS Registry, 76/296 patients (26%) discontinued, 12 (16%) of whom restarted. Conclusions. The currently available evidence suggests TMA manifestations following discontinuation are unpredictable in both severity and timing. For evidence-based decision making, better risk stratification and valid monitoring strategies are required. Until these exist, the risk versus benefit of eculizumab discontinuation, either in specific clinical situations or at selected time points, should include consideration of the risk of further TMA manifestations. PMID- 28621347 TI - Nonlinear optical properties, upconversion and lasing in metal-organic frameworks. AB - The building block modular approach that lies behind coordination polymers (CPs) and metal-organic frameworks (MOFs) results not only in a plethora of materials that can be obtained but also in a vast array of material properties that could be aimed at. Optical properties appear to be particularly predetermined by the character of individual structural units and by the intricate interplay between them. Indeed, the "design principles" shaping the optical properties of these materials seem to be well explored for luminescence and second-harmonic generation (SHG) phenomena; these have been covered in numerous previous reviews. Herein, we shine light on CPs and MOFs as optical media for state-of-the-art photonic phenomena such as multi-photon absorption, triplet-triplet annihilation (TTA) and stimulated emission. In the first part of this review we focus on the nonlinear optical (NLO) properties of CPs and MOFs, with a closer look at the two photon absorption property. We discuss the scope of applicability of most commonly used measurement techniques (Z-scan and two-photon excited fluorescence (TPEF)) that can be applied for proper determination of the NLO properties of these materials; in particular, we suggest recommendations for their use, along with a discussion of the best reporting practices of NLO parameters. We also outline design principles, employing both intramolecular and intermolecular strategies, that are necessary for maximizing the NLO response. A review of recent literature on two-, three- and multi-photon absorption in CPs and MOFs is further supplemented with application-oriented processes such as two-photon 3D patterning and data storage. Additionally, we provide an overview of the latest achievements in the field of frequency doubling (SHG) and tripling (third harmonic generation, THG) in these materials. Apart from nonlinear processes, in the next sections we also target the photonic properties of MOFs that benefit from their porosity, and resulting from this their ability to serve as containers for optically-active molecules. Thus, we survey dye@MOF composites as novel media in which efficient upconversion via triplet energy migration (TEM) occurs as well as materials for stimulated emission and multi-photon pumped lasing. Prospects for producing lasing as an intrinsic property of MOFs has also been discussed. Overall, further development of the optical processes highlighted herein should allow for realization of various photonic, data storage, biomedical and optoelectronic applications. PMID- 28621350 TI - Photoinduced structural distortions and singlet-triplet intersystem crossing in Cu(i) MLCT excited states monitored by optically gated fluorescence spectroscopy. AB - Copper(i) phenanthroline complexes represent viable earth-abundant alternatives to the ubiquitous Ru(ii) tris-bipyridine photosensitizers owing to their similar metal-to-ligand charge transfer (MLCT) properties. A well-established complication of Cu(i) phenanthroline complexes is that they can undergo significant photo-induced structural rearrangements, leading to excited states that are highly susceptible to exciplex formation and short-lived. In this work, a comprehensive analysis of the photo-induced structural distortions and singlet triplet intersystem crossing dynamics of a series of four sterically encumbered Cu(i) phenanthroline chromophores has been conducted, namely, [Cu(dsbp)2]+ (dsbp = 2,9-di-sec-butyl-1,10-phenanthroline), [Cu(dsbtmp)2]+ (dsbtmp = 2,9-di-sec butyl-3,4,7,8-tetramethyl-1,10-phenanthroline), [Cu(dipp)2]+ (dipp = 2,9-di isopropyl-1,10-phenanthroline), and [Cu(diptmp)2]+ (diptmp = 2,9-di-isopropyl 3,4,7,8-tetramethyl-1,10-phenanthroline). Upconverted fluorescence decay kinetics were measured at wavelengths along the blue side of the photoluminescence spectrum. The experimental results displayed strong wavelength dependence of the singlet emission, with rapid sub-picosecond decay dominating at higher energies. At lower emission energies, increasing contribution of a longer decay component was revealed. This wavelength dependence is a signature of the excited state structural rearrangement of the phenanthroline ligands which concomitantly lower the excited state energy. The obtained time constants were in excellent agreement with those measured in the complementary ultrafast transient absorption experiments. The sub-picosecond component (prompt fluorescence) is associated with the photo-induced structural rearrangement that lowers the energy of the singlet excited state. The longer decay component represents the lifetime of the S1 excited state, and thus the time-scale of singlet-triplet intersystem crossing. Lastly, the observed dual emission was further characterized by constructing picosecond time-resolved emission spectra from the measured kinetic data. These qualitative luminescence spectra capture the resulting emission from both the S1 initial state and the S1 flattened state, providing further insight into the energy-lowering excited state distortion across the series. PMID- 28621351 TI - Ethylene tri-/tetramerization catalysts supported by diphosphinothiophene ligands. AB - Cr(iii) catalysts supported by a series of diphosphinothiophene ligands have been developed, all of which, upon activation with MMAO-3A, are active for ethylene tri-/tetramerization. The effect of ligand substitution on the catalytic performance has been examined. The Cr precatalyst supported by the diphosphinothiophene ligand containing one trimethylsilyl group at the C2 position achieved a high activity of up to 686 kg (g Cr h-1)-1 with a total selectivity of up to 69% toward 1-hexene (29.5%) and 1-octene (39.5%). Two representative Cr complexes bearing the diphosphinothiophene ligand were synthesized and structurally characterized by single-crystal X-ray diffraction. Comparison of the coordination structure data of the two Cr complexes with those of an analogous diphosphine Cr complex reveals a direct correlation between the bond length of two adjacent bridging carbon atoms and catalytic activity: a shorter bond length and hence smaller ligand bite angle lead to higher catalytic activity. These diphosphinothiophene ligands featuring a fine-tuned backbone provide a model for the precise understanding of the impact of ligand variations on the catalytic performance. PMID- 28621352 TI - Effects of oxygenation on the intercalation of 1,10-phenanthroline-5,6/4,7-dione between DNA base pairs: a computational study. AB - The effects of oxygen in positions 4,7 and 5,6 of phenanthroline when this ligand intercalates between guanine-cytosine and adenine-thymine DNA base pairs (GC/CG and AT/TA) have been studied at the M06-2X/6-31+G(d,p) level of calculation. We focused on the changes in the structure, stabilization and energy contributions in the analysis of the interaction. The obtained trends in stabilization are explained by a model including repulsive Pauli (DeltaEPauli) contributions, and attractive dispersion (DeltaEdisp), orbital (DeltaEorb) and electrostatic (DeltaEelstat) contributions to energy. When no solvation is considered, the intrinsic DeltaEelstat contribution results are crucial for the stabilization of the system. However, the inclusion of the solvation energy DeltaEsolv can reverse the final stability trend of the systems becoming, thus, the driving force of the process. Therefore, the solvent will have a relevant influence in the potential cytotoxicity of the intercalation drugs. PMID- 28621353 TI - Ternary gradient metal-organic frameworks. AB - Gradient MOFs contain directional gradients of either structure or functionality. We have successfully prepared two ternary gradient MOFs based on bMOF-100 analogues, namely bMOF-100/102/106 and bMOF-110/100/102, via cascade ligand exchange reactions. The cubic unit cell parameter discrepancy within an individual ternary gradient MOF crystal is as large as ~1 nm, demonstrating the impressive compatibility and flexibility of the component MOF materials. Because of the presence of a continuum of unit cells, the pore diameters within individual crystals also change in a gradient fashion from ~2.5 nm to ~3.0 nm for bMOF-100/102/106, and from ~2.2 nm to ~2.7 nm for bMOF-110/100/102, indicating significant porosity gradients. Like previously reported binary gradient MOFs, the composition of the ternary gradient MOFs can be easily controlled by adjusting the reaction conditions. Finally, X-ray diffraction and microspectrophotometry were used to analyse fractured gradient MOF crystals by comparing unit cell parameters and absorbance spectra at different locations, thus revealing the profile of heterogeneity (i.e. gradient distribution of properties) and further confirming the formation of ternary gradient MOFs. PMID- 28621354 TI - Density functional theory calculations for the band gap and formation energy of Pr4-xCaxSi12O3+xN18-x; a highly disordered compound with low symmetry and a large cell size. AB - A novel oxynitride compound, Pr4-xCaxSi12O3+xN18-x, synthesized using a solid state route has been characterized as a monoclinic structure in the C2 space group using Rietveld refinement on synchrotron powder X-ray diffraction data. The crystal structure of this compound was disordered due to the random distribution of Ca/Pr and N/O ions at various Wyckoff sites. A pragmatic approach for an ab initio calculation based on density function theory (DFT) for this disordered compound has been implemented to calculate an acceptable value of the band gap and formation energy. In general, for the DFT calculation of a disordered compound, a sufficiently large super cell and infinite variety of ensemble configurations is adopted to simulate the random distribution of ions; however, such an approach is time consuming and cost ineffective. Even a single unit cell model gave rise to 43 008 independent configurations as an input model for the DFT calculations. Since it was nearly impossible to calculate the formation energy and the band gap energy for all 43 008 configurations, an elitist non dominated sorting genetic algorithm (NSGA-II) was employed to find the plausible configurations. In the NSGA-II, all 43 008 configurations were mathematically treated as genomes and the calculated band gap and the formation energy as the objective (fitness) function. Generalized gradient approximation (GGA) was first employed in the preliminary screening using NSGA-II, and thereafter a hybrid functional calculation (HSE06) was executed only for the most plausible GGA relaxed configurations with lower formation and higher band gap energies. The final band gap energy (3.62 eV) obtained after averaging over the selected configurations, resembles closely the experimental band gap value (4.11 eV). PMID- 28621355 TI - Penta- and hexaorganostannate(iv) complexes based on O-heterocyclic ligands. AB - In the present study, the synthesis of homoleptic five- and six-coordinate heteroaryl tin(iv) compounds using two O-heterocyclic substituents, 2-furyl (2 fu) and 2-benzofuryl (2-fuBz) ligands is described. The compounds were obtained as their lithium salts [Li2(OEt2)2Sn(2-fu)6] (1), [Li(tmeda)2][Sn(2-fu)5] (tmeda = N,N,N',N'-tetramethylethylenediamine) (2) and [Li(thf)4][Sn(2-fuBz)5] (3), featuring both an intramolecular coordination of the counterions by the anionic hypercoordinate tin(iv) species found in 1 as well as solvent separated cation/anion pairs for compounds 2 and 3. In addition, the co-crystalline complex [K2(thf)6Sn(2-fuBz)6].[K2(thf)4Sn(2-fuBz)6] (4a.4b) was achieved. The characterization of all compounds by various spectroscopic methods and X-ray structural analysis complemented by density functional computations provided insights into the diversity of complex formation. PMID- 28621356 TI - Dye-sensitized lanthanide-doped upconversion nanoparticles. AB - Lanthanide-doped upconversion nanoparticles (UCNPs) are promising for applications as wide as biological imaging, multimodal imaging, photodynamic therapy, volumetric displays, and solar cells. Yet, the weak and narrow absorption of lanthanide ions poses a fundamental limit of UCNPs to withhold their brightness, creating a long-standing hurdle for the field. Dye-sensitized UCNPs are emerging to address this performance-limiting problem, yielding up to thousands-fold brighter luminescence than conventional UCNPs without dye sensitization. In their configuration, organic dyes with spectrally broad and intense absorption are anchored to the surface of UCNPs to harvest the excitation light energy, which is then transferred via Forster and/or Dexter mechanisms across the organic/inorganic interface to the lanthanides incorporated in UCNPs (with or devoid of a shell) to empower efficient upconversion. This tutorial review highlights recent progress in the development of dye sensitized UCNPs, with an emphasis on the theory of energy transfer, the geometric classification of the dye sensitized core and core/shell nanocrystals, and their emerging photonic and biophotonic applications. Opportunities and challenges offered by dye sensitized UCNPs are also discussed. PMID- 28621357 TI - Computational investigation of the human SOD1 mutant, Cys146Arg, that directs familial amyotrophic lateral sclerosis. AB - The genetic substitution mutation of Cys146Arg in the SOD1 protein is predominantly found in the Japanese population suffering from familial amyotrophic lateral sclerosis (FALS). A complete study of the biophysical aspects of this particular missense mutation through conformational analysis and producing free energy landscapes could provide an insight into the pathogenic mechanism of ALS disease. In this study, we utilized general molecular dynamics simulations along with computational predictions to assess the structural characterization of the protein as well as the conformational preferences of monomeric wild type and mutant SOD1. Our static analysis, accomplished through multiple programs, predicted the deleterious and destabilizing effect of mutant SOD1. Subsequently, comparative molecular dynamic studies performed on the wild type and mutant SOD1 indicated a loss in the protein conformational stability and flexibility. We observed the mutational consequences not only in local but also in long-range variations in the structural properties of the SOD1 protein. Long range intramolecular protein interactions decrease upon mutation, resulting in less compact structures in the mutant protein rather than in the wild type, suggesting that the mutant structures are less stable than the wild type SOD1. We also presented the free energy landscape to study the collective motion of protein conformations through principal component analysis for the wild type and mutant SOD1. Overall, the study assisted in revealing the cause of the structural destabilization and protein misfolding via structural characterization, secondary structure composition and free energy landscapes. Hence, the computational framework in our study provides a valuable direction for the search for the cure against fatal FALS. PMID- 28621358 TI - Photoswitchable and pH responsive organoplatinum(ii) complexes with azopyridine ligands. AB - Several platinum(ii) complexes with ligands containing azo groups have been prepared and structurally characterised, and their photoswitching between trans and cis azo group isomers has been studied. The azo groups in the cationic complexes [PtMe(bipy)(4-NC5H4-N[double bond, length as m-dash]N-4-C6H4X)][PF6], X = H, OH or NMe2, and in the dicationic complex [Pt(bipy)(4-H2NC6H4-N[double bond, length as m-dash]N-C6H5)2][OTf]2 undergo trans to cis photoswitching on irradiation at 365 nm. The complex [PtMe(bipy)(4-NC5H4-N[double bond, length as m dash]N-4-C6H4NMe)2][PF6] also exhibits a reversible halochromic effect on protonation to give the dicationic complex [PtMe(bipy)(4-NC5H4-NH[double bond, length as m-dash]N-4-C6H4NMe2]2+. The nature of the frontier orbitals in the platinum(ii) complexes depends on the charge on the complex and on the degree of metal-ligand pi-bonding. PMID- 28621359 TI - Low temperature synthesis study of metal-organic framework CPO-27: investigating metal, solvent and base effects down to -78 degrees C. AB - CPO-27-M (M = Co, Mg, Ni, Zn) metal-organic frameworks have been successfully synthesized at temperatures down to -78 degrees C in a range of solvent systems and their crystallinity and morphology analyzed by powder X-ray diffraction and scanning electron microscopy. CPO-27-Mg and -Zn could be synthesized at lower temperatures using MeOH-NaOH as the solvent with CPO-27-Zn showing the most crystalline material at -78 degrees C. CPO-27-Zn afforded the most crystalline samples of all studies in MeOH-TEA. However, in MeOH a non-porous monomeric [Zn(H2dhtp)(H2O)2] complex was formed when no base was present. In THF with base (NaOH, TEA) the reaction produced crystalline MOFs in a controlled and stable manner at low temperatures, whilst the reagents were insoluble in THF at low temperature when no base was present. SEM was used to analyze the morphologies of the products. PMID- 28621360 TI - An unprecedented antimonato-polyoxovanadate (SbPOV) based on both alpha [V14Sb8O42]4- and beta-[V14Sb8O42]4- isomers. AB - An unprecedented antimonato-polyoxovanadate (SbPOV) based on both alpha [V14Sb8O42]4- and beta-[V14Sb8O42]4- isomers has been hydrothermally synthesized. PMID- 28621361 TI - Single site silica supported tetramethyl niobium by the SOMC strategy: synthesis, characterization and structure-activity relationship in the ethylene oligomerization reaction. AB - A silica supported tetramethyl niobium complex [([triple bond, length as m dash]SiO)NbMe4] 2 has been isolated by the surface alkylation of [([triple bond, length as m-dash]SiO-)NbCl3Me] 1 with dimethyl zinc in pentane. 1 can be easily synthesized by grafting NbCl3Me2 onto the surface of partially dehydroxylated silica by the SOMC strategy. Precise structural analysis was carried out using FTIR, advanced solid state NMR, elemental analysis and mass balance techniques (gas quantification after treating 2 with degassed water). Complex 1 was found to be active in the ethylene oligomerization reaction, producing up to C30, whereas to our surprise complex 2 selectively dimerized ethylene into 1-butene in the absence of a co-catalyst at the same conversion level. PMID- 28621362 TI - Self-assembled mesoscopic surface domains of fluorocarbon-hydrocarbon diblocks can form at zero surface pressure: tilting of solid-like hydrocarbon moieties compensates for cross-section mismatch with fluorocarbon moieties. AB - At low molecular areas, fluorocarbon-hydrocarbon diblocks (CnF2n+1CmH2m+1, FnHm), when spread as Langmuir monolayers on water, form organized monodisperse circular self-assembled domains, one molecule high and tens of nanometers in diameter. Whether such domains form at high molecular areas (low surface pressures) could until now not be established. Furthermore, the common assumption was that the inner core hydrocarbon chains within these domains were in the liquid state in order to compensate for the difference in the cross-section area between the perfluoroalkyl (~30 A2) and alkyl (~20 A2) chains. Our IRRAS investigation of F8H16 now establishes (1) that these diblock surface domains do exist at the air/water interface at large molecular areas (zero surface pressure), (2) that they remain essentially unchanged throughout film compression, and (3) that the H16 moieties are actually stretched in an all-trans configuration and tilted by ~30 degrees with respect to the normal to the monolayer in order to satisfy the greater space requirement of the F8 moieties. Consequently, the core of the domains is in an ordered, crystalline-like state, and the domains can be visualized as solid particles at the air/water interface. PMID- 28621363 TI - CO2 reduction or HCO2- oxidation? Solvent-dependent thermochemistry of a nickel hydride complex. AB - The hydricity (DeltaGH-) of a newly synthesized nickel hydride was experimentally determined in acetonitrile (50.6 kcal mol-1), dimethyl sulfoxide (47.1 kcal mol 1), and water (22.8 kcal mol-1). The hydricity values indicate hydride transfer from [HNi(TMEPE)2][BF4] (TMEPE = 1,2-bis[di(methoxyethyl)phosphino]ethane) to CO2 is exergonic in water and endergonic in the organic solvents. PMID- 28621365 TI - Bio-inspired intelligent evaporation modulation in a thermo-sensitive nanogel colloid solution for self-thermoregulation. AB - Intelligent evaporation and temperature modulation plays an important role in self-regulation of living organisms and many industrial applications. Here we demonstrate that a poly(N-isopropylacrylamide) (PNIPAM) nanogel colloid solution can spontaneously and intelligently modulate its evaporation rate with temperature variation, which has a larger evaporation rate than distilled water at a temperature higher than its lower critical solution temperature (LCST) and a smaller evaporation rate at a temperature lower than its LCST. It performs just like human skin. Theoretical analysis based on the thermodynamic derivation reveals that the evaporation rate transition around the LCST may originate from the saturated vapor pressure transition caused by the status transformation of the PNIPAM additives. An intelligent thermoregulation system based on the PNIPAM colloid solution is also demonstrated, illustrating its potential for intelligent temperature control and acting as an artificial skin. PMID- 28621364 TI - Single-molecule probing of amyloid nano-ensembles using the polymer nanoarray approach. AB - Soluble amyloid-beta (Abeta) oligomers are the prime causative agents of cognitive deficits during early stages of Alzheimer's disease (AD). The transient nature of the oligomers makes them difficult to characterize by traditional techniques, suggesting that advanced approaches are necessary. Previously developed fluorescence-based tethered approach for probing intermolecular interactions (TAPIN) and AFM-based single-molecule force spectroscopy are capable of probing dimers of Abeta peptides. In this paper, a novel polymer nanoarray approach to probe trimers and tetramers formed by the Abeta(14-23) segment of Abeta protein at the single-molecule level is applied. By using this approach combined with TAPIN and AFM force spectroscopy, the impact of pH on the assembly of these oligomers was characterized. Experimental results reveal that pH affects the oligomer assembly process. At neutral pH, trimers and tetramers assemble into structures with a similar stability, while at acidic conditions (pH 3.7), the oligomers adopt a set of structures with different lifetimes and strengths. Models for the assembly of Abeta(14-23) trimers and tetramers based on the results obtained is proposed. PMID- 28621368 TI - Vaporization of protic ionic liquids derived from organic superbases and short carboxylic acids. AB - This work presents a comprehensive evaluation of the phase behaviour and cohesive enthalpy of protic ionic liquids (PILs) composed of 1,5-diazabicyclo[4.3.0]non-5 ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) organic superbases with short-chain length (acetic, propionic and butyric) carboxylic acids. Glass transition temperatures, Tg, and enthalpies of vaporization, DeltaHvap, were measured for six [BH][A] (1 : 1) PILs (B = DBN, DBU; A = MeCOO, EtCOO, nPrCOO), revealing more significant changes upon increasing the number of -CH2- groups in the base than in the acid. The magnitude of DeltaHvap evidences that liquid PILs have a high proportion of ions, although the results also indicate that in DBN PILs the concentration of neutral species is not negligible. In the gas phase, these PILs exist as a distribution of ion pairs and isolated neutral species, with speciation being dependent on the temperature and pressure conditions - at high temperatures and low pressures the separated neutral species dominate. The higher Tg and DeltaHvap of the DBU PILs are explained by the stronger basicity of DBU (as supported by NMR and computational calculations), which increases the extent of proton exchange and the ionic character of the corresponding PILs, resulting in stronger intermolecular interactions in condensed phases. PMID- 28621366 TI - Cation distribution: a key to ascertain the magnetic interactions in a cobalt substituted Mg-Mn nanoferrite matrix. AB - The effect of Co2+ substitution into nanocrystalline Mg-Mn ferrite synthesized by a solution combustion technique has been studied. The cation distribution has been inferred from X-ray diffraction, the magnetization technique, and Mossbauer spectroscopy. The X-ray analysis and cation distribution data have been used to investigate the detailed structural parameters such as hopping lengths, ionic radii of tetrahedral and octahedral sites, oxygen positional parameter, site bond as well as edge lengths, bond lengths, and bond angles. The variation in the theoretically predicted bond angles suggested the strengthening of the A-B super exchange interactions, and the same has been supported by M-H and M-T, as well as by Mossbauer studies. The ZFC-FC study revealed that anisotropy increases with the incorporation of cobalt ions. The values of magneton number, theoretical lattice parameter, and Curie temperature that have been calculated by using the cation distribution are found to match well with the experimentally obtained values. PMID- 28621369 TI - Transport of nanoparticles across pulmonary surfactant monolayer: a molecular dynamics study. AB - Pulmonary nanodrug delivery is an emerging concept, especially for targeted lung cancer therapy. Once inhaled, the nanoparticles (NPs) acting as drug carriers need to efficiently cross the pulmonary surfactant monolayer (PSM) of lung alveoli, which act as the first barrier for external particles entering the lung. Herein, by performing molecular dynamics simulations, we study how inhaled NPs interact with the PSM, particularly focusing on the transport of NPs with different properties across the PSM. While hydrophilic NPs translocate directly across the PSM, transport of hydrophobic NPs is achieved as the PSM wraps them. Intriguingly, when hydrophilic NPs are decorated with lipid molecules (LCNPs), they are wrapped by the PSM efficiently with mild PSM perturbation. Moreover, the structure formed is like a vesicle, which will likely fuse with cell membranes to accomplish the transport of hydrophilic NPs into secondary organs. This behavior makes the LCNP a prospective candidate for pulmonary nanodrug delivery. Herein, the effects of the physical properties of LCNPs on their transport are investigated. Increasing the LCNP size promotes its wrapping by reducing the PSM bending energy. The binding energy that drives transport can be strengthened by increasing the lipid coating density and the lipid tail length, both of which also reduce the risk of PSM rupture during transport. These results should help researchers understand how to better use surface decorations to achieve efficient pulmonary entry, which may provide useful guidance for the design of nano-based platforms for inhaled drug delivery. PMID- 28621370 TI - Ion dynamics in halogen-free phosphonium bis(salicylato)borate ionic liquid electrolytes for lithium-ion batteries. AB - This study was focused on the investigation of ion dynamics in halogen-free, hydrophobic, and hydrolytically stable phosphonium bis(salicylato)borate [P4,4,4,8][BScB] ionic liquid electrolytes for lithium-ion batteries. The structure and purity of the synthesized ionic liquid and lithium bis(salicylato)borate Li[BScB] salt were characterized using 1H, 13C, 31P, and 11B NMR spectroscopy. The Li[BScB] salt was mixed with an ionic liquid at the concentrations ranging from 2.5 mol% to 20 mol%. The physicochemical properties of the resulting electrolytes were characterized using thermal analysis (TGA and DSC), electrical impedance spectroscopy, and pulsed-field gradient (PFG) NMR and ATR-FTIR spectroscopy. The apparent transfer numbers of the individual ions were calculated from the diffusion coefficients of the cation and anion as determined via the PFG NMR spectroscopy. NMR and ATR-FTIR spectroscopic techniques revealed dynamic interactions between the lithium cation and bis(salicylato)borate anion in the electrolytes. The ion-ion interactions were found to increase with the increasing concentration of the Li[BScB] salt, which resulted in ionic clustering at the concentrations higher than 15 mol% of Li salt in the ionic liquid. PMID- 28621371 TI - Does Z' equal 1 or 2? Enhanced powder NMR crystallography verification of a disordered room temperature crystal structure of a p38 inhibitor for chronic obstructive pulmonary disease. AB - The crystal structure of the Form A polymorph of N-cyclopropyl-3-fluoro-4-methyl 5-[3-[[1-[2-[2-(methylamino)ethoxy]phenyl]cyclopropyl]amino]-2-oxo-pyrazin-1 yl]benzamide (i.e., AZD7624), determined using single-crystal X-ray diffraction (scXRD) at 100 K, contains two molecules in the asymmetric unit (Z' = 2) and has regions of local static disorder. This substance has been in phase IIa drug development trials for the treatment of chronic obstructive pulmonary disease, a disease which affects over 300 million people and contributes to nearly 3 million deaths annually. While attempting to verify the crystal structure using nuclear magnetic resonance crystallography (NMRX), we measured 13C solid-state NMR (SSNMR) spectra at 295 K that appeared consistent with Z' = 1 rather than Z' = 2. To understand this surprising observation, we used multinuclear SSNMR (1H, 13C, 15N), gauge-including projector augmented-wave density functional theory (GIPAW DFT) calculations, crystal structure prediction (CSP), and powder XRD (pXRD) to determine the room temperature crystal structure. Due to the large size of AZD7624 (ca. 500 amu, 54 distinct 13C environments for Z' = 2), static disorder at 100 K, and (as we show) dynamic disorder at ambient temperatures, NMR spectral assignment was a challenge. We introduce a method to enhance confidence in NMR assignments by comparing experimental 13C isotropic chemical shifts against site specific DFT-calculated shift distributions established using CSP-generated crystal structures. The assignment and room temperature NMRX structure determination process also included measurements of 13C shift tensors and the observation of residual dipolar coupling between 13C and 14N. CSP generated ca. 90 reasonable candidate structures (Z' = 1 and Z' = 2), which when coupled with GIPAW DFT results, room temperature pXRD, and the assigned SSNMR data, establish Z' = 2 at room temperature. We find that the polymorphic Form A of AZD7624 is maintained at room temperature, although dynamic disorder is present on the NMR timescale. Of the CSP-generated structures, 2 are found to be fully consistent with the SSNMR and pXRD data; within this pair, they are found to be structurally very similar (RMSD16 = 0.30 A). We establish that the CSP structure in best agreement with the NMR data possesses the highest degree of structural similarity with the scXRD-determined structure (RMSD16 = 0.17 A), and has the lowest DFT calculated energy amongst all CSP-generated structures with Z' = 2. PMID- 28621372 TI - Molecular dynamics simulation of the local concentration and structure in multicomponent aerosol nanoparticles under atmospheric conditions. AB - Molecular dynamics (MD) simulations were employed to investigate the local structure and local concentration in atmospheric nanoparticles consisting of an organic compound (cis-pinonic acid or n-C30H62), sulfate and ammonium ions, and water. Simulations in the isothermal-isobaric (NPT) statistical ensemble under atmospheric conditions with a prespecified number of molecules of the abovementioned compounds led to the formation of a nanoparticle. Calculations of the density profiles of all the chemical species in the nanoparticle, the corresponding radial pair distribution functions, and their mobility inside the nanoparticle revealed strong interactions developing between sulfate and ammonium ions. However, sulfate and ammonium ions prefer to populate the central part of the nanoparticle under the simulated conditions, whereas organic molecules like to reside at its outer surface. Sulfate and ammonium ions were practically immobile; in contrast, the organic molecules exhibited appreciable mobility at the outer surface of the nanoparticle. When the organic compound was a normal alkane (e.g. n-C30H62), a well-organized (crystalline-like) phase was rapidly formed at the free surface of the nanoparticle and remained separate from the rest of the species. PMID- 28621374 TI - Linker functionalisation triggers an alternative 3D-topology for Zn-isophthalate 4,4'-bipyridine frameworks. AB - A series of four Zn2+ metal-organic frameworks containing functionalised isophthalate linkers and 4,4'-bipyridine pillars have been prepared and characterised. Isophthalates which contain -OC3H2n+1 alkoxy side chains (with n = 1, 2 or 3) form frameworks with a 3D pillared-layer topology instead of the typical 2D layer topology of the renowned coordination polymers with an interdigitated structure (CIDs), which is found for shorter -OC2H5 side chains. The gas adsorption properties of the materials were analysed using N2, CO2 and O2 adsorption measurements at low temperatures. PMID- 28621375 TI - Roles of phenol groups and auxiliary ligand of copper(ii) complexes with tetradentate ligands in the aerobic oxidation of benzyl alcohol. AB - Herein, six copper(ii) complexes with multidentate ligands, [Cu(HL1)(OAc)(HOAc)] (1), [Cu(HL2)(OAc)] (2), [Cu(HL3)(OAc)] (3), [CuL4(OAc)] (4), [Cu(HL2)Cl] (5), and [Cu(HL3)Cl] (6) {H2L1 = [bis(3-tert-butyl-2-hydroxybenzyl)](2 pyridylmethyl)amine, H2L2 = [(3-tert-butyl-2-hydoxybenzyl)(3-trifluoromethyl-2 hydroxybenzyl) (2-pyridylmethyl)]amine, H2L3 = [bis(3-trifluoromethyl-2 hydroxybenzyl)] (2-pyridylmethyl)amine, and HL4 = [bis(2-pyridylmethyl)] (3-tert butyl-2-hydroxybenzyl)amine}, are reported. The complexes were characterized by UV-vis spectroscopy, high-resolution mass spectrometry, X-ray single-crystal diffraction analysis and electrochemistry. These copper(ii) complexes have been investigated as catalysts for the aerobic oxidation of benzyl alcohol to benzaldehyde mediated by TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxyl) radical in water at ambient temperature. Mechanistic investigations have revealed that the phenolate/phenol is involved in the intramolecular proton transfer with a bound substrate in catalysis. Hence, the presence of the trifluoromethyl group on the phenol ring significantly affects the catalysis process since the substituent affects the acidity of phenol, and subsequently, the intramolecular proton transfer from the bound substrate. During catalysis, the dissociation of the auxiliary ligand (Cl- or OAc-) occurred in the SN1 pathway, and it is necessary for the substrate to bind. To complete the catalytic cycle, the cleaved auxiliary ligand rebinds to the metal center to regenerate the catalyst. PMID- 28621376 TI - Current and future directions in electron transfer chemistry of graphene. AB - The participation of graphene in electron transfer chemistry, where an electron is transferred between graphene and other species, encompasses many important processes that have shown versatility and potential for use in important applications. Examples of these processes range from covalent functionalization of graphene to modify its properties and incorporate different functional groups, to electrochemical reactions and selective etching. In this paper, we review recent developments in these areas of the electron transfer chemistry of graphene. We address recent progress on controlling covalent functionalization through chemical and physical methods, and how carefully functionalized graphene can be incorporated into composite materials with enhanced properties. We review the selective etching of graphene to form edges and nanopores, which have unique chemical and physical properties. Nanoporous graphene is promising for new membrane and filtration applications. We also discuss the electrochemistry of graphene grown by chemical vapour deposition in two-dimensional and three dimensional geometries, which enables large surface areas and control over the distribution and concentration of edge and basal plane sites. We discuss the potential for each of these areas to have an impact in future applications such as filtration membranes, electronic devices, electrochemical electrodes, composite materials, and chemical sensors. PMID- 28621377 TI - Controlling the oxidation of bis-tridentate cobalt(ii) complexes having bis(2 pyridylalkyl)amines: ligand vs. metal oxidation. AB - Two bis-tridentate chelated cobalt(ii) complexes, which differ in the ligand structure by a methylene group, activate molecular oxygen (O2), and give different oxidation products. The O2 reaction of [CoII(pepma)2]2+ (1) with unsymmetrical 2-(2-pyridyl)-N-(2-pyridylmethyl)ethanamine (pepma) results in ligand oxidation, to the corresponding Co(ii) imine complex [CoII(pepmi)2]2+ (2). Contrastingly, the Co(ii) complex [CoII(bpma)2]2+ (3) of similar symmetrical bis(2-pyridylmethyl)amine (bpma), undergoes metal oxidation, yielding a cobalt(iii) complex, [CoIII(bpma)2]2+ (4). The reversibility of the amine to imine conversion and the stability of the Co(ii) imine complex (2) are investigated. Furthermore, the solution dynamics of Co(ii) complexes are highlighted with the help of paramagnetic 1H-NMR spectroscopy. PMID- 28621378 TI - The hypothiocyanite radical OSCN and its isomers. AB - A biologically relevant reactive sulfur species (RSS), the hypothiocyanite radical OSCN, is generated in the gas phase through flash vacuum pyrolysis (FVP) of trifluoromethyl sulfinyl cyanide CF3S(O)CN at ca. 1000 K. Upon UV light irradiation (365 nm), OSCN rearranges to novel isomers OSNC and SOCN, and further visible light irradiation (400 +/- 20 nm) leads to reverse isomerization. The identification of OSCN, OSNC, and SOCN in cryogenic matrices (Ar and N2, 2.8 K) with IR spectroscopy is supported by quantum chemical calculations up to the CCSD(T)-F12/VTZ-F12 level. The potential energy surface for the interconversion of OSCN isomers and their bonding properties are computationally explored by using the CCSD(T)-F12/VTZ-F12 and EDA-NOCV methods, respectively. PMID- 28621379 TI - Designing porous electronic thin-film devices: band offsets and heteroepitaxy. AB - Increasing numbers of electrically active porous framework materials are being reported, with conductivities that make them attractive for technological applications. As design strategies for efficient carrier transport emerge, the next challenge is to incorporate the materials into a functioning device. In thin film devices interface effects are of critical importance to overall function. In this article we present a method to identify compatible materials combinations to achieve mechanically robust, electronically optimal pairings. The computational screening is based on a two-step procedure: (i) matching of lattice constants to ensure interfaces with minimal epitaxial strain and therefore maximal mechanical and chemical stability; (ii) matching of absolute electron energies to construct energy-band-alignment diagrams, which can be used to screen for particular electronic applications. We apply the methodology to search for zeolitic imidazolate framework (ZIF) type materials that are compatible with native metal electrodes. The procedure allows us to predict simple routes for electrochemical deposition of ZIFs for application as conductive porous electrodes. PMID- 28621380 TI - Theoretical Investigation of Electrophilic Transannular Addition Reactions of Bromine to Face-to-Face (Juxtaposed) Double Bonds in Strained Polycyclic Hydrocarbons. AB - Transannular electrophilic addition reaction of halogens to face-to face(juxtaposed) double bonded strained alkenes were theoretically investigated. General rules that allow us to stipulate the factors that direct the main steps of the energy hypersurface of reactions as well as the products were established. Direction of the reaction flow is determined by direction of intramolecular skeletal isomerisation of cyclic-bridged halogenium cation and isomerisation takes place to create a more stable skeletal structure. Stability of resultant skeletal structure is determined by the number of sigma bonds between isolated double bonds of the alkene and bonding-type of double bonds (N- and U-type). When the number of sigma bonds between double bonds of the alkene is three (m = 3), the reaction takes place to predominantly give an N-type product, and when four (m = 4), N- and U-type products are formed. Structure and stability of cation intermediates (bridged, N- and U-type cations) of electrophilic addition reaction of homohipostrofen molecule, whose double bonds were linked by three sigma bonds, with bromine were investigated by DFT methods in detail. Also the addition reaction of endo,endo-tetracyclo[6.2.2.23,6.02,7]tetradeca-4,9-dien molecule, whose double bonds were linked by four sigma bonds, with bromine were investigated by quantum chemistry. PMID- 28621381 TI - The Methodology Applied in DPPH, ABTS and Folin-Ciocalteau Assays Has a Large Influence on the Determined Antioxidant Potential. AB - Antioxidant potential (AOP) is not only the property of the matrix analyzed but also depends greatly on the methodology used. The chromogenic radicals 2,2'-azino bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS*+), 2,2-diphenyl-1 picrylhydrazyl (DPPH*) and Folin-Ciocalteu (FC) assay were applied to estimate how the method and the composition of the assay solvent influence the AOP determined for coffee, tea, beer, apple juice and dietary supplements. Large differences between the AOP values depending on the reaction medium were observed, with the highest AOP determined mostly in the FC assay. In reactions with chromogenic radicals several fold higher values of AOP were obtained in buffer pH 7.4 than in water or methanol. The type of assay and solvent composition have similar influences on the reactivity of a particular antioxidant, either pure or as part of a complex matrix. The reaction kinetics of radicals with antioxidants in samples reveals that AOP depends strongly on incubation time, yet differently for each sample analyzed and the assay applied. PMID- 28621382 TI - Poly(N-methylpyrrole) Film on ZnNi Plated Carbon Steel Electrode. AB - In this study, zinc-nickel (ZnNi) particles were electrochemically deposited on carbon steel (CS) electrode applying constant current of 1 mA with chronopotentiometry technique. Poly(N-methylpyrrole) (PNMP) film on CS/ZnNi electrode was synthesized with cyclic voltammetry technique from 0.10 M N methylpyrrole containing 0.20 M sodium oxalate solution. The corrosion performances of coated and uncoated electrodes in 3.5% NaCl solution were evaluated with the help of AC impedance spectroscopy (EIS) and anodic polarisation curves. Scanning electron microscopy (SEM) and linear sweep voltammetry (LSV) were used to characterization of coatings. It was shown that the ZnNi particles exhibited important barrier effect on CS substrate. The highest 298350 ohm value of polarization resistance showed that PNMP film on the CS/ZnNi electrode exhibited an effective barrier property and electrocatalytic behaviour protection of substrate for longer exposure time. PMID- 28621383 TI - Peach and Cherry Agroindustrial Wastes: New and Economic Sources for the Production of Lignocellulolytic Enzymes. AB - Pleurotus eryngii was incubated on both peach and cherry agroindustrial wastes by solid state fermentation for 30 days without/with pretreatment conditions. The lignocellulosic substrates were pretreated with dilute acid and alkaline solutions, hot water before incubation. The maximum carboxymethyl cellulase and xylanase activities peaked on 3rd and 5th days under control conditions of both wastes, respectively. The highest laccase and manganese peroxidase activities reached to their maximum on 17th day as 2193.06 +/- 50.4 UL-1 and 732.73 +/- 19.8 UL-1, respectively. The highest aryl alcohol oxidase activity was obtained as 239.25 +/- 7.3 UL-1 in control condition of peach cultures. The used pretreatment methods had generally negative effects on lignocellulolytic enzyme production. The highest lignocellulolytic activities were detected using peach wastes. To results, these wastes could. PMID- 28621384 TI - Stability Indicating UHPLC-PDA Assay for Simultaneous Determination of Antazoline Hydrochloride and Naphazoline Hydrochloride in Ophthalmic Formulations. AB - In the present study, a newly developed method based on ultrahigh performance liquid chromatography (UHPLC) was optimized for the simultaneous determination of antazoline hydrochloride (ANZ) and naphazoline hydrochloride (NFZ) in ophthalmic formulations. Isocratic separation of ANZ and NFZ was performed at 40 degrees C with an ACE Excel 2 C18-PFP column (2 MUm, 2.1 * 100 mm) at a flow rate of 0.6 mL min-1 whereas the mobile phase consisted of acetonitrile/phosphate buffer (60:40, v/v, pH 3.0) containing 0.5% triethylamine. Both analytes were detected at a wavelength of 285 nm and the injection volume was 1.0 MUL. The overall run time per sample was 4.5 min with retention time of 0.92 and 1.86 min for NFZ and ANZ, respectively. The calibration curve was linear from 0.500-100 MUg mL-1 for ANZ and NFZ with a correlation coefficient >= 0.9981 while repeatability and reproducibility (expressed as relative standard deviation) were lower than 1.28 and 2.14%, respectively. In comparison with high-performance liquid chromatography (HPLC), the developed UHPLC method had remarkable advantages over HPLC as the run time was significantly reduced by 3.4-fold with a 5-fold decreased solvent consumption. Forced degradation studies indicated a complete separation of the analytes in the presence of their degradation products providing high degree of method specificity. The proposed UHPLC method was demonstrated to be simple and rapid for the determination of ANZ and NFZ in commercially available ophthalmic formulations providing recoveries between 99.6 and 100.4%. PMID- 28621385 TI - Electroanalytical Determination of Escitalopram Oxalate Using Nickel Nanoparticles Modified Carbon Paste Sensor. AB - A sensitive voltammetric method was described for the determination of escitalopram oxalate based on electrocatalytic oxidation at nickel nanoparticles modified chloranil carbon paste sensor in Britton-Robinson buffer (pH range from 2 to 10). The modified electrode was characterized by scanning electron microscopy, electrochemical impedance and cyclic voltammetry. The investigation of electrochemical behavior of escitalopram oxalate was performed using cyclic voltammetry and differential pulse voltammetry. The anodic peak current showed a linear range from 1.0 * 10-6 to 7.0 * 10-5 mol L-1. The detection limit is below 2.0 * 10-7 mol L-1. The proposed method is rapid, economical, simple, precise and sensitive voltammetric method for the determination of escitalopram oxalate in bulk, dosage form and urine. PMID- 28621386 TI - Functionalization of Graphene Oxide with 9-aminoanthracene for the Adsorptive Removal of Persistent Aromatic Pollutants from Aqueous Solution. AB - A novel modified graphene oxide nanocomposite was fabricated via a facial procedure, aiming to removal of the aromatic pollutants from aqueous solution. The graphene oxide (GO) was functionalized with 9-aminoanthracene and produced graphene oxide-9-aminoanthracene (GO-9-AA). FTIR, XRD, TGA, TEM and Raman spectroscopy techniques were used for characterization of the adsorbents. Adsorption of naphthalene (NAP), acenaphthylene (ACN), and phenanthrene (PHN) as a model of polycyclic aromatic hydrocarbons (PAHs) was investigated by GO-9-AA. The adsorbent showed excellent removal efficiency towards PAHs from aqueous solution. Equilibrium data of the adsorption process were successfully fitted with Freundlich model from single solute system, and the maximum adsorption capacities followed the order of NAP > ACN >PHN. The kinetic analysis revealed that the overall adsorption process was fast and successfully fitted with the pseudo-second-order kinetic model. The anthracene ring makes GO-9-AA pi-electron rich, thus facilitating pi-pi EDA interaction between NAP, ACN and PHN with GO-9 AA. PMID- 28621387 TI - Synthesis of MnO2 on Activated Carbon and its Potential Application in the Adsorption of As(V) and Pb(II) in Aqueous Solutions. AB - The conditions for the synthesis of a material with MnO2 (OMD) on activated carbon (AC) were studied. These conditions were: reaction time, temperature, stirring speed, concentrations of AC, H2SO4, and O3 in solution, and particle size. Agglomerates on AC were observed by means of scanning electron microscopy (SEM) and microanalysis by energy dispersive spectroscopy (EDS) and revealed the presence of OMD deposited on the surface. The activation energy and the factor of frequency for the reaction were determined as Ea = 1.2 kcal/mol and A = 2.2. The value of Ea indicates that the precipitation of OMD on the AC was controlled by mass transfer in aqueous solution and the order of reaction was zero. The adsorption capacities of AC were q = 14 mg Pb(II)/g AC and q = 9.1 mg As(V)/g AC. Whereas, for the OMD/AC obtained in the following conditions: [AC] 1 or 2 g/L, particle size of AC of +0.59 mm, [H2SO4] 1 or 2 mol/L, 25 degrees C, stirring speed 600 rpm, and [O3] 1.35 mol/L, the adsorption capacities were q = 90.5 mg Pb(II)/g OMD/AC and 25.4 mg As(V)/g OMD/AC. Therefore, the fixing of OMD on the surface of the AC greatly improved the removal of both Pb(II) and As(V) from aqueous solutions. PMID- 28621388 TI - First Direct Isolation of Stable alpha-Form Crystals of Mirabegron, a Selective beta3-Adrenoceptor Agonist. AB - An efficient and scalable method for the direct isolation of stable alpha-form crystals of Mirabegron (1) is developed. The developed method negates transformation of metastable beta-form crystals into alpha-form crystals thereby overcoming the limitations of reported methods and avoids additional processing steps during its manufacture. The developed method directly provides stable alpha form crystals of Mirabegron (1) with yield of around 84% and purity of >99.77% by HPLC in a single step. PMID- 28621389 TI - Adsorptive Removal of Malachite Green from Model Aqueous Solutions by Chemically Modified Waste Green Tea Biomass. AB - The adsorption of malachite green (MG) from aqueous solution by waste green tea (WGT) biomass was investigated. A series of experiments in batch conditions were conducted in order to assess the MG removal on WGT, following adsorbent quantity and temperature influences. Maximum removal efficiency for untreated WGT was 89% (4 g biomass, 100 mL solution of 94 mg/L, 316 K). It was found that the adsorption of MG increased by increasing temperature from 296 to 316 K. Thermodynamic parameters (DeltaH degrees , DeltaS degrees , DeltaG degrees ) were calculated, and indicated that dye adsorption onto the studied biomass was endothermic and non-spontaneous. Six chemical treatments were tested (four acidic - H3PO4, H2SO4, HCl, and tartaric acid, one oxidant - H2O2, and one basic - NaOH) in order to study the chemical groups responsible for MG adsorption onto WGT biomass. The alkali and acidic treatments led to an increase of adsorption efficiency up to 92% and 95% (H2SO4) respectively. The FTIR spectroscopy results emphasized the modifications of the biomass surface and how these are influencing the adsorption process. PMID- 28621390 TI - [Chemical Laboratory of Celje Queen (at 580th Anniversary of Bohemian coronation of Queen Barbara of Celje)]. AB - Barbara Celjska je bila gotovo najbogatejsa alkimistka vseh casov. Prispevek skusa pojasniti kaksni poskusi so potekali v njenem laboratoriju in nakazati, katere tehniske kemijske naprave je utegnila pri tem uporabljati. Ker je bila vecina leteh iz zlahka lomljivih snovi, bi bilo njihovo iskanje brskone brez haska, saj ni veliko upanja za njihovo ohranitev. Barbara of Cilli was certainly the richest female alchemist of all times. The article tries to explain what kind of experiments she carried out in her laboratory and indicate which technical chemical plant she likely has used. The major part of her expensive tools was made from easily breakable materials, therefore any contemporary pursuit to locate them will be probably in vain, because there is not much hope for their preservation. PMID- 28621391 TI - Trace Determination of Hg(II) in Human Saliva Using Disposable Electrochemically Pretreated Graphite Pencil Electrode Surfaces. AB - An electrochemically pretreated graphite pencil electrode (PGPE) was designed to assay trace levels of Hg(II) in human saliva. The GPE was pretreated in 0.1 mol/L nitric acid by cycling the potential between -1.6 and -0.6 V for 60 cycles at a scan rate of 50 mV/s. The effects of pretreatment conditions, including media constituents, pH, and various electrochemical techniques and parameters, were analyzed and optimum conditions determined. Square wave anodic stripping voltammetry (SWASV) was used for the determination of Hg(II). The calibration curve obtained under optimum conditions showed that the linear range of the PGPE was from 10.0 * 10-9 mol/L to 175.0 * 10-9 mol/L with a detection limit of 3.0 * 10-9 mol/L (S/N = 3). Relative to non-pretreated GPE surfaces, electrochemical pretreatment improved the electrochemical performance of GPE surfaces in detecting Hg(II). The present analytical method was used to measure Hg(II) released from dental amalgam in human saliva. PMID- 28621392 TI - A Natural Based Method for Hydrophobic Treatment of Natural Fiber Material. AB - A treatment for hydrophobic functionalization of natural fiber materials is developed. This hydrophobic treatment is based mainly on natural products. As hydrophobic component the natural Tung Oil is used, which is originally a compound used for wood conservation purposes. The application on textile is done in a padding process under presence of an oxidative agent. For the current investigations a fiber felt from linen was used. The hydrophobic effect is determined by the concentration of Tung Oil and the duration of a thermal drying process. The hydrophobic effect is investigated by capillary rise tests and contact angle measurements. Scanning electron microscopy SEM is used to investigate the surface topography of the fiber material and the deposited hydrophobic material. Altogether, an interesting and promising method for hydrophobisation of natural fibers is developed, which could especially be used as part of a production process of a fiber reinforced composite material, mainly based on natural products. PMID- 28621393 TI - Synthesis, Crystal Structures and Catalytic Oxidation of Manganese(III) Complexes Derived from Salen-Type Schiff Base N,N'-Bis(5-nitrosalicylidene)ethane-1,2 diamine. AB - Two mononuclear Schiff base manganese(III) complexes, [MnL(N3)(OH2)].CH3OH (1) and [MnL(NCS)(OH2)] . H2O (2), where L is the dianionic form of N,N'-bis(5 nitrosalicylidene)ethane-1,2-diamine, have been prepared and characterized by elemental analysis, IR and UV-Vis spectroscopy and single crystal X-ray diffraction. The Mn atom in each complex is in an octahedral coordination. Molecules of the complexes are linked through intermolecular hydrogen bonds. Catalytic properties for epoxidation of styrene by the complexes using PhIO and NaOCl as oxidant have been studied. PMID- 28621394 TI - Influence of Various Soluble Carbonates on the Hydration of Portland Cement studied by X-ray Diffraction. AB - The effect of limestone on the hydration of Portland cement has been studied by many researchers. However, a possible influence of adding more soluble carbonates was not explained. Therefore we executed a qualitative and quantitative research on the influence of slightly soluble (CaCO3, MgCO3, dolomite), medium soluble (Li2CO3) and highly soluble (K2CO3 and KHCO3) carbonates on the hydration. Blending of Portland cement with differently soluble carbonates was found to influence the hydrate assemblage of the hydrated cement. With the help of the Rietveld analysis, the study indicated that the amount of reacted carbonate in cement hydration at a 15% addition of slightly or medium soluble carbonates does not exceed 5% and is not affected by their solubility; at a 15% addition of the highly soluble carbonate K2CO3 the amount of reacted carbonate was around 6%. An increase in temperature (25 to 40 degrees C) gradually affects the rate of hydration and the quantity of stable phase assemblage. PMID- 28621395 TI - Anti-inflammatory and Anti-ulcer Activities of New Fused Thiazole Derivatives Derived from 2-(2-Oxo-2H-chromen-3-yl)thiazol-4(5H)-one. AB - The reaction of the 2-(4-oxo-4,5-dihydrothiazol-2-yl)acetonitrile (1) with salicylaldehyde (2) in 1,4-dioxane containing a catalytic amount of piperidine gave the coumarin derivative 3. The latter reacted with different reagents to give pyrano[4,5-b]thiazole, pyrido[4,5-b]thiazole and thieno[5,4-b]thiazole dereivatives. The anti-inflammatory and anti-ulcer activities of the newly synthesized products were evaluated and the results showed that compounds 7a, 8a, 10b, 13b, 15b, 18a, 19b, 19c, and 19d showed higher activity compared to the rest of the compounds. In addition to this, toxicity of such active compounds was studied against shrimp larvae where compounds 10b, 18a, 19c and 19d showed to be non-toxic against the tested organisms. PMID- 28621396 TI - Sodium Saccharin as an Effective Catalyst for Rapid One-pot Pseudo-five Component Synthesis of Dihydropyrano[2,3-g]chromenes under Microwave Irradiation. AB - One-pot microwave-assisted synthesis of dihydropyrano[2,3-g]chromenes catalyzed by sodium saccharin as an efficient, mild and green catalyst was studied. The method presented is a safe and eco-friendly approach for the multicomponent synthesis of dihydropyrano[2,3-g]chromene derivatives with many merits including short reaction times (in comparison with other reported results), high yields and easy work up. PMID- 28621397 TI - New Bioactive Heteroleptic Copper(II) Carboxylates: Structure, Enzymatic and DNA Binding Studies. AB - Two new binuclear O-bridged copper(II) carboxylates with chemical formulas [Cu2(3 ClC6H4CH2COO)4(phen)2] (1) and [Cu2(3-ClC6H4CH2COO)4(bipy)2] (2) where phen = 1,10-phenanthroline and bipy = 2,2'-bipyridine have been synthesized and characterized by FT-IR, UV-Visible spectroscopy, CHN analysis and single crystal XRD. The results revealed distorted square pyramidal geometry around each copper atom of 1 and 2. The DNA interaction studies showed strong binding with Kb = 5.07 * 103 and 4.62 * 103 M-1 for 1 and 2, respectively. Both complexes showed strong enzyme inhibition, i.e., 70% and 90% for alpha-glucosidase with IC50 = 34.6 and 30.1 MUM for 1 and 2, respectively, where acarbose was employed as control. However, both the complexes were found inactive against alpha-amylase. Using galantamine hydrobromide as control, 1 showed moderate inhibition activity (47%) with IC50 = 179.4 MUM for acetylcholine esterase whereas 2 showed strong inhibition activity (76%) with IC50 = 95.8 MUM for butyrylcholine esterase. The data reflects active anti-diabetic and anti-Alzheimer's nature of the synthesized complexes. PMID- 28621398 TI - AB Initio Prediction of Stable Confomeric Polymorphs of Benzocaine Molecule- a Local Anaesthatic Molecule. AB - An ab initio methodology to predict the crystal structures of thermodynamically stable polymorphs of benzocaine within the least energy region of energy landscape by analyzing the local minima from the initial gas phase optimization initiated through the flexible torsion using MP2/6-31G(d,p) method. The global search for the hypothetical dense packing for the structures within the energy penalty region of the local minima have revealed the possible stable conformers under a repulsion alone potential field. The generated hypothetical dense packings from the global search were selected for lattice minimization using the repulsion - dispersion potential field to authenticate the stability. The stability and the characteristics of the generated structures were analyzed from the comparative hydrogen bond analysis and second derivative properties with the known experimental polymorphs. The morphological studies of the global minima of benzocaine molecule from the valid lattice energy landscape was studied in detail to find the morphological important lattice. PMID- 28621399 TI - [MII(NCS)2(nia)2(OH2)2]: Preparation, Crystal Structure and Thermal Properties (MII = Mn, Fe; nia = nicotinamide). AB - Two novel isostructural coordination compounds of manganese(II) (1) and iron(II) (2) with common formulae [MII(NCS)2(nia)2(OH2)2] have been prepared from water solution of appropriate metal salt, nicotinamide and KSCN. Their crystal structures were determined by means of X-ray diffraction on single crystals. The mononuclear title compounds crystallize in a triclinic P-1 space group with six monodentate octahedrally arranged ligands around the metal centre. The coordination molecules are self-assembled with an extended network of hydrogen bonds into a three-dimensional structure. Additionally, 1 and 2 were characterized with infrared spectroscopy, magnetic measurements and thermal analysis. PMID- 28621400 TI - Study on the Equilibria of the Complex Formation of the Ion-pair of Germanium(IV) with 4-Nitrocatechol and 1,4-Diphenyl-3-(phenylamino)-1H-1,2,4-triazole. AB - The complex formation of the ion-pair formed between the anionic chelate of Ge(IV)-4-nitrocatechol (4-NC) and the cation of 1,4-diphenyl-3-(phenylamino)-1H 1,2,4-triazole (Nitron, Nt) in the liquid-liquid extraction system Ge(IV)-4-NC-Nt H2O-CHCl3 was studied by spectrophotometry. The optimum extraction spectrophotometric conditions for the complex formation were established. The validity of Beer's law was checked and some analytical characteristics of the system were calculated. The effect of co-existing ions and reagents on the process of complex formation was investigated. The association process in aqueous phase and the extraction equilibria were studied and quantitatively characterized. The following key constants of the processes were calculated: association constant, distribution constant, extraction constant and recovery factor. The molar ratio of the reagents was determined by independent methods. A reaction scheme and a general formula of the complex were suggested. PMID- 28621401 TI - Encapsulation of Sour Cherry Pomace Extract by Freeze Drying: Characterization and Storage Stability. AB - In this study sour cherry pomace was extracted with food-grade solvent (50% ethanol), concentrated and stabilized in whey and soy proteins by encapsulation. Soy proteins exhibited higher encapsulation efficiency (94.90%), but not significantly (p < 0.05), from whey (90.10%). Storage properties of whey (WP) and soy protein (SP) encapsulates in terms of total polyphenols, anthocyanins and antioxidant activity were tested for 6 weeks. At the end of storage period the retention of polyphenols in SP and WP was similar (67.33 and 69.30%, respectively), while the content of anthocyanins has increased in SP (for 47.97%) and decreased in WP (for 1.45%). The decrease in antioxidant activity in SP (12.22%) was lower than in WP (35.04%). Colour parameters of encapsulates have followed the similar trend as anthocyanin change during storage. The technique reported herewith can be used for obtaining quality encapsulates for their use as functional food additives, as a way of fruit waste valorization. PMID- 28621403 TI - Mixed Metal Oxides of the Type CoxZn1-xFe2O4 as Photocatalysts for Malachite Green Degradation Under UV Light Irradiation. AB - A combination of thermal and mechanical (high energy ball milling) treatment was applied in an attempt to obtain polycrystalline mixed metal binary and ternary oxides of the type CoxZn1-xFe2O4 (x = 0; 0.25; 0.5; 0.75; 1). The synthetic procedure used successfully produced single-phased, homogeneous ZnFe2O4, CoFe2O4, and Co0.75Zn0.25Fe2O4, as well as mixed oxides, whose composition depended both on the duration of the high energy ball milling and the ratio Zn(II)/Co(II). The formation of spinel-like structures was proved by XRD, Mossbauer spectroscopy and Raman spectroscopy. For the characterization of the samples low-temperature N2 adsorption, UV/Vis spectroscopy and transmission electron microscopy were applied. The energy band gap of the samples was calculated, suggesting they are promising photocatalysts. The decomposition of the Malachite Green in model water solutions under UV-light irradiation was successfully achieved in the presence of the samples as photocatalysts. The highest rate constant was obtained for the sample synthesized at longer milling time in combination with higher Zn(II)/Co(II) ratio. The photocatalytic activity of the ternary mixed oxides was compared with the pure hematite, alpha-Fe2O3, and the binary ZnFe2O4 and CoFe2O4 ferrites with spinel structure that were treated in the same way. A synergetic effect of alpha-Fe2O3 and the spinel-like structure on the photocatalytic properties of ternary mixed metal oxides was detected. PMID- 28621402 TI - Microwave-assisted Synthesis of Hybrid Heterocycles as Potential Anticancer Agents. AB - In a one pot procedure, a series of novel hybrid heterocycles 6a-g and 7a-g were prepared by condensation of (3aS,4S,6S,6aS)-6-((1-(4-chlorophenyl)-1H-1,2,3 triazol-4-yl)methoxy)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4 carbaldehyde 5 with mercapto acids and primary amines in the presence of ZnCl2 under both microwave irradiation and conventional heating conditions. Compound 5 was prepared from di-acetone D-mannose via a click reaction, primary acetonide deprotection and oxidative cleavage. Characterization of new compounds has been done by IR, NMR, MS and elemental analysis. Anticancer activity of the compounds has also been evaluated. PMID- 28621404 TI - Adsorption Kinetics of Malachite Green and Methylene Blue from Aqueous Solutions Using Surfactant-modified Organoclays. AB - The main objective of this research is to study the adsorption behaviour of malachite green and methylene blue dyes onto the surfactant modified natural clays. The results of SEM, XRD, IR, and thermal analysis confirms the intercalation of organic moiety in to the clay. The adsorption results show that pseudo-first order kinetics best fitted for both the dyes adsorbed on organo clay. The data also reveals that both dyes are in a good agreement with Langmuir isotherm in both types of modified clays. The value of separation factor, RL, from Langmuir equation and Freundlich constant, n, give an indication of favourable adsorption. The maximum adsorption capacity qm based on Langmuir model was found to be 294-303 mg/g at 25 degrees C, is in good agreement with the experimental values. PMID- 28621405 TI - Synthesis and Structural Characterization of a Double Helical Dinuclear Copper(II) Complex With Tetradentate Biacetyl Bis(benzoylhydrazone). AB - The reaction of tetradentate hydrazone ligand H2babh with Cu(CH3COO)2 in methanol solvent leads to the formation of the mono-nuclear complex [Cu(babh)]. However, on being dissolved in dichloromethane solvent and on addition of ethanol solvent, a dinuclear complex of [Cu2(MU1,3-babh)2(C2H5OH)2] is obtained. The X-ray crystallography indicates that the dinuclear helical complex formation is caused due to the unsymmetrical twisting of the H2babh ligand. One oxygen and two nitrogen atoms from the ligand and one oxygen atom from the other ligand coordinate to each copper(II) center. Both the copper(II) centers in a dinuclear unit are penta-coordinate with a slightly distorted square pyramidal geometry. The IR spectra of mono- and dinuclear copper(II) complexes have different bands. The absorption spectra of mono- and di-nuclear complexes are quite similar in methanol solvent. However, the electronic absorption spectra of the two complexes are basically different in the solid state. PMID- 28621406 TI - 2D Frameworks Self-assembled From a Hydrazone Ligand and Azide Salts: Synthesis, Structures, and Luminescent Property. AB - Three metal-organic coordination polymers [Cu(L)(N3)].(H2O)0.25n (1), [Zn(L)(N3)].(H2O)0.5n (2) and [Cd2(L)2(N3)2(H2O)]n (3) have been synthesized from hydrazone ligand N'-(1-(pyrazin-2-yl)ethylidene)isonicotinohydrazide (HL), NaN3 and corresponding metal nitrates. Complexes were characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction. All three complexes feature 2D coordination network in which L1- acts as NNON tetradentate ligand and azide acts as end-on bridging ligand. In complexes 1 and 2, only intra sheet hydrogen bonding interactions are found, while the hydrogen bonding interactions between water molecules and host framework result in 3D network for 3. In addition, complexes 2 and 3 exhibited intense fluorescent emissions in the solid state at room temperature. PMID- 28621407 TI - Determination of Microelements in Human Milk and Infant Formula Without Digestion by ICP-OES. AB - The concentrations of zinc (Zn), iron (Fe) and copper (Cu) in both human milk and infant formula were determined using a new sample preparation method, by inductively coupled plasma - optical emission spectometry (ICP-OES) and flame atomic absorption spectrometry (FAAS). Human milk samples were diluted in ultrapure water. The infant formula of powder samples (suitable for an infant 1-6 months of age) and standard reference material (SRM-1849) were analyzed in parallel. The results have shown that FAAS method was more sensitive for Fe determination in human milk while ICP-OES was more sensitive for both Zn and Cu detection. The limit of quantification for both Zn and Cu was 5 MUg L-1 and 10 MUg L-1 for Fe and the recovery for Zn, Fe and Cu was ranged from 90% to 94%, 97% to 103% and 90% to 102%, respectively. Mean concentrations of Zn, Fe, and Cu in human milk samples were 5.35, 0.47 and 0.83 mg L-1, respectively while these values in infant formula were ranged from 3.52-4.75 mg L-1, 3.37-4.56 mg L-1 and 0.28-0.41 mg L-1, respectively. Despite the sample complexity, the proposed method using dilution of milk samples with water was simple, rapid, effective and accurate. ICP-OES was a better method for Zn determination while FAAS was a better method for Fe determination. In the case of Cu both methods were comparable. PMID- 28621408 TI - A "Brief History" of Developmental Biology in Israel. AB - While the history of developmental biology in Israel is relatively short, its impact is far-reaching, so we wanted to present a concise perspective on the Israeli developmental biology community, past-present-future. This community has undergone a wonderful, nearly exponential growth over the last three decades. How exactly did this happen? There are approximately fifty research groups that focus on developmental biology questions in Israel today that are members of the Israel Society of Developmental Biology (IsSDB; http://issdb.org/). The community has representative groups in a plethora of model systems, such as Nematostella, C. elegans, Drosophila, sea urchin, ascidians, zebrafish, Xenopus, chick and mouse, as well as plants, representing all the major universities and their branches, which include Bar-Ilan University, Ben-Gurion University of the Negev, The Hebrew University of Jerusalem, The University of Haifa, Technion - Israel Institute of Technology, Tel Aviv University and the Weizmann Institute of Science. PMID- 28621409 TI - Hefzibah Eyal-Giladi (1925-2017): over fifty years of embryological research in Israel. AB - Hefzibah Eyal-Giladi was a creative and innovative pioneering scientist in the creation of the field of early chick embryo development. She had a sharp thinking and enthusiastic attitude, which enabled her to make a deep impression that was highly valued by the general scientific community. Notably, she was a highly successful female researcher in an era which was dominated by male scientists. Her unique personality and keen intellect enabled her to break these borders in a most successful manner. The experiments conducted by her personally, her students and her collaborators served to provide the basic knowledge and paradigms for future scientists in the field, also paving the way for discoveries in other vertebrate model systems. The experimental embryology assays she performed were "old school", examining embryos and explants at a precise morphological level of tissue interactions. In recent years, most of the experimentation in embryology has shifted to molecular and genetic levels. However, the results obtained with these technologically advanced research tools still re-confirm the fundamental findings obtained by Eyal-Giladi using "classic" experimental embryology techniques. Finally, Hefzibah Eyal-Giladi was an outstanding teacher and lecturer. For five decades, she trained and taught generations of undergraduate and graduate students in Israel, exposing them to the field of embryology and developmental biology in the most exciting and enthusiastic way. PMID- 28621410 TI - The Leo Sachs' legacy: a pioneer's journey through hematopoiesis. AB - Leo Sachs spent almost his entire scientific career in Israel, at the Weizmann Institute of Science, and became a worldwide renowned scientist for his pioneering studies in normal hematopoiesis, its breakdown in leukemia and the suppression of malignancy by inducing differentiation, thereby bypassing genetic defects that give rise to malignancy. The cell culture system he established in the early 1960s for the clonal development of normal hematopoietic cells, made it possible to discover the proteins that regulate the viability, proliferation and differentiation of different blood cell lineages, the molecular basis of normal hematopoiesis and the changes that drive leukemia. His studies established significant general concepts including: a) the value of a multi-gene cytokine network in regulating the viability, number and development of different cell types; b) the existence of alternative pathways that give flexibility to development in both normal and cancer cells; c) the response of some cancer cells to normal regulators of development; d) suppression of myeloid leukemia by inducing differentiation, bypassing malignancy-driving genetic defects; e) identification of chromosomes that control tumor suppression; f) discovering apoptosis as a major mechanism by which WT-p53 suppresses malignancy and g) the ability of hematopoietic cytokines to suppress apoptosis in both normal and leukemic cells. It is gratifying that Leo had the good fortune to witness his pioneering discoveries and ideas move from the basic science stage to effective clinical applications, augmenting normal hematopoiesis in patients with various hematopoietic deficiencies, in patients requiring hematopoietic stem cell transplantation and in the suppression of malignancy by inducing differentiation and apoptosis. PMID- 28621411 TI - Annotating the genome by DNA methylation. AB - DNA methylation plays a prominent role in setting up and stabilizing the molecular design of gene regulation and by understanding this process one gains profound insight into the underlying biology of mammals. In this article, we trace the discoveries that provided the foundations of this field, starting with the mapping of methyl groups in the genome and the experiments that helped clarify how methylation patterns are maintained through cell division. We then address the basic relationship between methyl groups and gene repression, as well as the molecular rules involved in controlling this process during development in vivo. Finally, we describe ongoing work aimed at defining the role of this modification in disease and deciphering how it may serve as a mechanism for sensing the environment. PMID- 28621412 TI - The not-so-long history of zebrafish research in Israel. AB - The zebrafish has become a model of choice in fundamental and applied life sciences and is widely used in various fields of biomedical research as a human disease model for cancer, metabolic and neurodegenerative diseases, and regenerative medicine. The transparency of the zebrafish embryo allows real-time visualization of the development and morphogenesis of practically all of its tissues and organs. Zebrafish are amenable to genetic manipulation, for which innovative genetic and molecular techniques are constantly being introduced. These include the study of gene function and regulation using gene knockdown, knockout and knock-in, as well as transgenesis and tissue-specific genetic perturbations. Complementing this genetic toolbox, the zebrafish exhibits measurable behavioral and hormonal responses already at the larval stages, providing a viable vertebrate animal model for high-throughput drug screening and chemical genetics. With the available tools of the genomic era and the abundance of disease-associated human genes yet to be explored, the zebrafish model is becoming the preferred choice in many studies. Its advantages and potential are being increasingly recognized within the Israeli scientific community, and its use as a model system for basic and applied science has expanded in Israel in recent years. Since the first zebrafish-focused laboratory was introduced at Tel Aviv University 16 years ago, seven more zebrafish-centric research groups have been established, along with more than two dozen academic research groups and three bio-medical companies that are now utilizing this model. PMID- 28621413 TI - The SUMO system in Caenorhabditis elegans development. AB - SUMO, a small ubiquitin-like modifier, is a highly conserved post translational modification and a central regulatory system in eukaryotes. Sumoylation modulates the activities of multiple proteins, mainly in the nucleus, such as transcription factors, chromatin modifiers, and proteins involved in DNA replication and repair. However, SUMO also modifies substrates in the cytoplasm, mitochondria, plasma and ER membrane. This review summarizes our current knowledge on the functions of sumoylation in C. elegans development. SUMO modification is highly reversible and several examples described here establish its function as a molecular switch during embryogenesis and postembryonic organogenesis. PMID- 28621414 TI - microRNAs in Drosophila regulate cell fate by repressing single mRNA targets. AB - Regulation of gene expression governs all aspects of the lifespan of the organism, such as embryonic development, stem cell differentiation, reproduction and aging. Among the most important regulators of these extremely complex processes are microRNAs (miRNAs), small non-coding RNAs that repress gene expression by binding to primary sequences on the mRNA of their target. Theoretically, the mere existence of a miRNA recognition sequence on a given mRNA is sufficient to generate a functional response. Since these short sequences are abundant, one miRNA can potentially bind to multiple targets, thus generating endless possible biological outcomes. However, is this really the case? Bioinformatics and molecular biology tools provide theoretical interaction predictions, but the data obtained by these methods is often too general and is impaired by false identifications. Therefore, a better understanding of the biological role of miRNAs requires mapping of the exact miRNA-mRNA interactions that occur in vivo. Drosophila melanogaster provides several unique advantages over other model organisms in the study of miRNA functional targeting. The majority of its miRNAs are evolutionarily conserved up to humans, suggesting that they regulate similar pathways across organisms. Complete genome-wide collections make Drosophila the only organism that enables constitutive and inducible gain and loss-of function manipulations of all annotated miRNAs. These powerful tools led to several groundbreaking discoveries of the role that miRNAs play in regulation of development, stem-cell function and aging, and proved that although many outcomes are possible, most Drosophila miRNAs regulate a single phenotype through downregulation of a single major mRNA target. PMID- 28621415 TI - Building functional units of movement-generation and movement-sensation in the embryo. AB - The musculoskeletal and proprioceptive sensory systems exhibit intricate crosstalk between force generation, force sensation and force transmission, all of which are critical for coordinated animal locomotion. Recent developmental studies of the musculoskeletal and proprioceptive units of the invertebrate Drosophila embryo, have revealed several common molecular and structural principles mediating the formation of each of these systems. These common principles, as well as the differences between the developmental programs of the two systems, are discussed. Interestingly, a molecular pathway triggered by the Neuregulin/Vein ligand-dependent activation of the epidermal growth factor receptor (EGFR) pathway, which upregulates the early growth response (EGR)-like transcription factor Stripe, is utilized not only by the Drosophila muscle-tendon and proprioceptive organ-ectoderm attachment, but also by their vertebrate counterparts. An additional theme that has been observed during the development of the musculoskeletal system in both invertebrates and vertebrates is the functional importance of the extracellular matrix and its adhesion receptors. The contribution of mechanical forces to proper junction formation between muscles and tendons and between the sensory cap/ligament cells and their epidermal attachment cells is discussed. The structural and genetic similarities between the musculoskeletal and the proprioceptive systems offer new perspectives as to their common developmental nature. PMID- 28621416 TI - All in one - integrating cell polarity, meiosis, mitosis and mechanical forces in early oocyte differentiation in vertebrates. AB - While the differentiation of oocytes is key for embryonic development, and its investigation is crucial for advancing our understanding of human reproduction and fertility, many fundamental questions in oogenesis have been long standing. However, recent technical advances have led to several breakthroughs mainly in mice and zebrafish. Here I review these recent findings, including regulation and organization of the germline cyst, the mechanistics of chromosomal pairing, establishment of cell polarity, and formation of a universal mRNA-protein (mRNP) granule called the Balbiani body. I discuss common themes in oogenesis from frogs, fish and mouse and compare them to findings from C. elegans and Drosophila. The zebrafish juvenile ovary is an attractive model where these individual processes can be investigated, but also revealing how they are inter coordinated in oocyte differentiation. A conserved cellular organizer was discovered in the zebrafish oocyte that seems to function at a nexus of oocyte differentiation. This organizer, termed the Meiotic Vegetal Center (MVC), is composed of the oocyte centrosome, and couples meiotic chromosomal pairing with oocyte polarization and Balbiani body formation. The MVC breaks the oocyte symmetry, is regulated by upstream mitotic division in the cyst and nucleates Balbiani body mRNPs prion-like aggregation downstream. These processes can shed new light on broad questions in biology, such as how mitosis contributes to cell polarity, and how prion aggregation which lead to neurodegenerative disease when awry, is regulated in a physiological context. Furthermore, novel cytoskeletal structures can unravel cytoplasmic mechanical functions in chromosomal pairing. Finally, together with recently developed tools, genome editing technology now enables a robust genetic analysis of these fundamental processes in the zebrafish, paving the way for a comprehensive cell and developmental view of vertebrate oogenesis. PMID- 28621417 TI - Cell fate decisions during neural crest ontogeny. AB - The neural crest (NC) originates in the central nervous system (CNS) primordium. Born as an epithelium, NC progenitors undergo an epithelial-to-mesenchymal transition that generates cellular movement away from the CNS. Mesenchymal NC progenitors then migrate through stereotypic pathways characteristic of various axial levels until homing to distinct primordia where phenotypic differentiation takes place. Being the source of most of the peripheral nervous system, pigment cells and ectomesenchyme, the embryonic NC is considered to be a multipotent population of precursors. In spite of numerous recent studies, an essential and still unsolved question is when during ontogeny do the different lineages segregate from putative homogeneous and multipotent progenitors. Evidence suggests that the premigratory NC still resident in the dorsal neural tube epithelium is composed both of multipotent as well as of fate-restricted precursors, supporting the notion of an early appearance of cellular heterogeneity. Understanding these changing states of commitment is a prerequisite for deciphering molecular mechanisms that regulate fate segregation of the embryonic NC. In this review, we present data illustrating the existence of progenitors harboring different states of specification and their emergence as a function of time and space. PMID- 28621419 TI - TAM receptor signaling in development. AB - TYRO3, AXL and MERTK comprise the TAM family of receptor protein tyrosine kinases. Activated by their ligands, protein S (PROS1) and growth-arrest-specific 6 (GAS6), they mediate numerous cellular functions throughout development and adulthood. Expressed by a myriad of cell types and tissues, they have been implicated in homeostatic regulation of the immune, nervous, vascular, bone and reproductive systems. The loss-of-function of TAM signaling in adult tissues culminates in the destruction of tissue homeostasis and diseased states, while TAM gain-of-function in various tumors promotes cancer phenotypes. Combinatorial ligand-receptor interactions may elicit different molecular and cellular responses. Many of the TAM regulatory functions are essentially developmental, taking place both during embryogenesis and postnatally. This review highlights current knowledge on the role of TAM receptors and their ligands during these developmental processes in the immune, nervous, vascular and reproductive systems. PMID- 28621420 TI - The retinal pigmented epithelium - from basic developmental biology research to translational approaches. AB - The development of the eye has been a topic of extensive investigation, from the early studies on tissue induction to more recent breakthroughs in resolving the mechanism regulating progenitor patterning and their gradual and coordinated differentiation into diverse tissue types that function together throughout life. Among the ocular tissue types, the retinal pigmented epithelium (RPE) is at the forefront of developmental biology and stem cell research. The growing interest in this lineage stems from its importance for photoreceptor function as well as from its requirement during embryogenesis for the development of the photoreceptors and the choroid. Indeed mutations in RPE genes and epigenetic changes that occur during aging are the cause of monogenic as well as multifactorial retinal diseases. Importantly, the RPE is readily generated from stem cells, and these stem cell-derived RPE cells are currently being tested in clinical trials for transplantation in cases of retinal dystrophies; they also constitute an important model to study developmental processes in vitro. This review summarizes recent advances in our understanding of RPE development and its requirement for the development of photoreceptors and choroidal vasculature. We discuss the contribution of basic findings to therapeutic applications and the future challenges in uncovering developmental processes and mimicking them ex vivo to further advance research and therapy of retinal disorders. PMID- 28621418 TI - Single cell analysis of the inner ear sensory organs. AB - The inner ear is composed of a complex mixture of cells, which together allow organisms to hear and maintain balance. The cells in the inner ear, which undergo an extraordinary process of development, have only recently begun to be studied on an individual level. As it has recently become clear that individual cells, previously considered to be of uniform character, may differ dramatically from each other, the need to study cell-to-cell variation, along with distinct transcriptional and regulatory signatures, has taken hold in the scientific community. In conjunction with high-throughput technologies, attempts are underway to dissect the inter- and intra-cellular variability of different cell types and developmental states of the inner ear from a novel perspective. Single cell analysis of the inner ear sensory organs holds the promise of providing a significant boost in building an omics network that translates into a comprehensive understanding of the mechanisms of hearing and balance. These networks may uncover critical elements for trans-differentiation, regeneration and/or reprogramming, providing entry points for therapeutics of deafness and vestibular pathologies. PMID- 28621421 TI - Roles of DSCAM in axonal decussation and fasciculation of chick spinal interneurons. AB - The ventral midline of the embryonic neural tube, the floor plate, has a profound role in guiding axons during embryonic development. Floor plate-derived guidance cues attract or repel axons, depending on the neuronal subtype and developmental stage. Netrin-1 and its receptor, Deleted in Colon Carcinoma (DCC), are the key constituents of commissurral axons guidance cues toward the floor plate. Recent studies have implicated Down Syndrome Cell Adhesion Molecule (Dscam) as an additional Netrin-1 receptor. In this study, we examined the role of Dscam in guiding defined spinal dorsal interneuron populations. In vivo knockdown and ectopic expression of Dscam were performed in the dorsal dI1, dI2 and dI3 interneurons of chick embryos, by separately increasing or decreasing Dscam expression in each of these three specific interneuronal populations. Neuron specific gain and loss of function of Dscam had no effect on the axonal trajectories of dI1-3 neurons. The commissural neurons, dI1c and dI2, crossed the midline, and the ipsilaterally projecting neurons, dI1i and dI3, projected ipsilaterally. However, the fasciculation of dI1 axons was diminished when Dscam expression was attenuated. Dscam is not required for either attraction to or repulsion from the floor plate. In contrast, Dscam is required for the fasciculation of axons, probably via homophilic interaction. PMID- 28621422 TI - A new role of the membrane-type matrix metalloproteinase 16 (MMP16/MT3-MMP) in neural crest cell migration. AB - Neural crest cells (NCCs) are a transient population of neuroectodermal originated cells that populate the dorsal neural tube (dNT), before migrating and giving rise to multiple cell lineages in the developing embryo. Prior to their migration, NCCs undergo epithelial-to-mesenchymal-transition (EMT) through which they lose cell contacts and detach from the dNT to invade their surrounding environment. Multiple signals and transcription factors have been identified to regulate these events. Yet, less is known regarding effectors that act downstream to execute the actual NCC separation and migration. Matrix metalloproteinases (MMPs) are a family of proteases that degrade the extracellular matrix as well as other pericellular proteins during processes of tissue remodeling, angiogenesis and metastasis. Previously, we and others have demonstrated the role of the gelatinases MMP2 and MMP9 during the onset of NCC migration. Several evidences link the cleavage and activation of these secreted gelatinases to the activity of membrane-type MMPs (MT-MMP), such as MMP14 and MMP16, which are tethered to plasma membrane and affect various cellular behaviors. The aim of this study was to investigate whether MMP16 acts in NCCs. Here we demonstrate the expression of MMP16 mRNA and protein in cranial NCCs in avian embryos. Knockdown of MMP16 inhibited NCC migration. This inhibition was rescued by the addition of recombinant MMP16, which was also sufficient to increase proper NCC migration. Furthermore, excess MMP16 caused enhanced NCC EMT, concomitant with degradation of dNT-related proteins, laminin and N-cadherin. Altogether, these results uncover MMP16 as a new effector participating in EMT and in the migration of NCCs. PMID- 28621423 TI - Roles of the cilium-associated gene CCDC11 in left-right patterning and in laterality disorders in humans. AB - Axial determination occurs during early stages of embryogenesis. Flaws in laterality patterning result in abnormal positioning of visceral organs, as manifested in heterotaxy syndrome, or complete left-right inversion as in situs inversus totalis. These malformations are often associated with ciliopathies, as seen in primary ciliary dyskinesia. We have recently described a novel mutation in the Coiled-Coil Domain-Containing 11 (CCDC11) gene associated with laterality disorders in a consanguineous family of Arab-Muslim origin with two affected siblings presenting with diverse phenotypes, one with heterotaxy syndrome and the other with non-primary ciliary dyskinesia situs inversus totalis. This study further characterizes the roles of CCDC11 and the implications of the identified mutation on left-right axial patterning in patient-derived cells and in the frog embryo as a model organism. We analyzed patient-derived cells and manipulated Ccdc11 levels in Xenopus laevis frog embryos. Cilia length in patient cells was longer than in controls, and CCDC11 was localized to the centriole and the actin cytoskeleton. Mutated truncated protein accumulated and was also localized to the centriole and actin cytoskeleton. In frog embryos, Ccdc11 was regulated downstream of FoxJ1, and overexpression of the full-length or truncated protein, or downregulation of the gene resulted in severe disruption of embryonic left right axial patterning. Taken together, our initial description of the deleterious mutation in CCDC11 in patients, the current results and more recent supportive studies highlight the important role of CCDC11 in axial patterning. PMID- 28621424 TI - Ocular vessel patterning in zebrafish is indirectly regulated by Hedgehog signaling. AB - The superficial ocular vasculature of the embryonic zebrafish develops in a highly stereotypic manner and hence provides a convenient model for studying molecular mechanisms that regulate vascular patterning. We have used transgenic zebrafish embryos in which all endothelial cells express enhanced Green Fluorescent Protein and small molecule inhibitors to examine the contribution of two signaling pathways, vascular endothelial growth factor (VEGF) and Hedgehog (Hh) pathways, to the development of the superficial system. We find that most, but not all vessels of the superficial system depend on VEGF signaling for their growth. Hh signaling appears to limit superficial vessel growth over the dorsal eye and is required to promote superficial vessel growth over the ventral eye. These effects of Hh signaling are indirect. Our initial analyses of factors that regulate growth and patterning of superficial ocular vessels suggest that early patterning events in the embryo during organogenesis stages could influence vascular patterning later on. By studying development of specific vascular systems it should be possible to identify new roles for signaling pathways in regulating vascular development. PMID- 28621425 TI - Epigenetic mechanism of FMR1 inactivation in Fragile X syndrome. AB - Fragile X syndrome is the most frequent cause of inherited intellectual disability. The primary molecular defect in this disease is the expansion of a CGG repeat in the 5' region of the fragile X mental retardation1 (FMR1) gene, leading to de novo methylation of the promoter and inactivation of this otherwise normal gene, but little is known about how these epigenetic changes occur during development. In order to gain insight into the nature of this process, we have used cell fusion technology to recapitulate the events that occur during early embryogenesis. These experiments suggest that the naturally occurring Fragile XFMR1 5' region undergoes inactivation post implantation in a Dicer/Ago-dependent targeted process which involves local SUV39H-mediated tri-methylation of histone H3K9. It thus appears that Fragile X syndrome may come about through inadvertent siRNA-mediated heterochromatinization. PMID- 28621426 TI - FoxD1 protein interacts with Wnt and BMP signaling to differentially pattern mesoderm and neural tissue. AB - The foxd1 gene (previously known as Brain Factor 2/BF2) is expressed during early Xenopus laevis development. At gastrula stages, foxd1 is expressed in dorsal mesoderm regions fated for muscle and notochord, while at neurula stages, foxd1 is expressed in the forebrain region. Previous studies in the neural plate showed that FoxD1 protein acts as transcriptional repressor downstream of BMP antagonism, neuralizing the embryo to control anterior neural cell fates. FoxD1 mesoderm function was not rigorously analyzed, but ectopic FoxD1 levels increased muscle marker expression in embryos. Using a FoxD1-specific antisense morpholino oligonucleotide, we knocked down endogenous FoxD1 protein activity in developing Xenopus embryos. In this present study, we show that FoxD1 is crucial for dorsal mesoderm formation. Analogous to neural tissue, FoxD1 acts downstream of BMP antagonism to induce dorsal mesoderm cell fates, such as muscle and notochord. FoxD1 is sensitive to its local signaling environment, having differential transcription factor activity in the presence or absence of Wnt or BMP signaling. FoxD1 induces posterior neural tissue in the presence of Wnt or BMP activities, but its activity is restricted to "normal" anterior neural tissue induction when BMP and Wnt activities are repressed. In dorsal mesoderm, FoxD1 interacts with Wnt signaling and BMP antagonism to induce muscle and notochord, while simultaneously repressing more anterior and ventral mesoderm cell fates. FoxD1 protein has multiple activities that are masked or released in the different germ layers as a function of the local signaling environment. PMID- 28621427 TI - ADHFe1: a novel enzyme involved in retinoic acid-dependent Hox activation. AB - Retinoic acid (RA) signaling is a central pathway regulating anterior-posterior patterning of the embryo through its targets, the Hox genes. RA is produced by two sequential oxidations from vitamin A (retinol) and this biosynthesis has to be regulated temporally, spatially and quantitatively. Mining Xenopus embryonic expression databases identified a novel component of the RA metabolic network, ADHFe1. Using Xenopus laevis embryos as our experimental system we determined the temporal and spatial pattern of AdhFe1 expression. Gain- and loss-of-function of ADHFe1 were induced to study its function and the regulation of the AdhFe1 gene by RA was studied. Expression analysis localized the ADHFe1 protein to the late Spemann's organizer, the trunk organizer. Subsequently, ADHFe1 can be detected in the prechordal mesoderm, the notochord and the lateral plate mesoderm. Manipulation of ADHFe1 levels affects the normal Hox gene expression. The effects of ADHFe1 manipulation can by rescued by increasing the levels of RA or its biosynthesis. Expression of the AdhFe1 gene is regulated by RA itself. ADHFe1 is an enzyme active already during gastrula stages and the protein is still present during neurula stages. ADHFe1 regulates the expression of the Hox genes during the early patterning of the trunk. The effect of ADHFe1 on Hox expression is mediated through regulation of RA levels. ADHFe1 probably reduces retinaldehyde to retinol thereby restricting the availability of retinaldehyde, the substrate needed by retinaldehyde dehydrogenases to produce RA making it a novel regulator of RA concentrations in the embryo and RA homeostasis. PMID- 28621428 TI - Loss of thrombospondin reveals a possible role for the extracellular matrix in chordotonal cap cell elongation. AB - In the Drosophila larva, major proprioceptive input is provided to the brain by sub-epidermal stretch receptors called chordotonal organs (ChO). Similarly to the body wall muscle that needs to be attached on both of its sides to the larval exoskeleton in order to generate movement, the sensory unit of a ChO must be stably anchored to the cuticle on both of its sides in order to sense the relative displacement of body parts. Through an RNAi screen we have identified thrombospondin (Tsp), a secreted calcium binding glycoprotein, as a critical component in the anchoring of ChOs to the cuticle. We show that the Tsp protein starts to accumulate in the extracellular matrix (ECM) surrounding the ChO attachment cells towards the end of embryogenesis and that it becomes highly concentrated at the attachment junction during larval stages. In the absence of Tsp, the ChO's accessory cells fail to form a stable junction with their epidermal attachment cells and organ integrity is not maintained. Tsp is a known player in the establishment of the myotendinous junctions in both invertebrates and vertebrates. Thus, our findings extend the known similarities between muscle attachment and ChO-attachment cells. In addition to its role in establishing the ChO attachment junctions, Tsp was found to affect ligament cell migration and cap cell elongation. Most interestingly, the Tsp protein was found to decorate the ChO cap cells along their entire length, suggesting that the elongated cap cells are supported by the ECM to which they attach via integrin-based, Tsp-dependent, adhesion plaques. The ECM enwrapping the cap cells is probably important for keeping the cap cells fasciculate and may also provide mechanical support that allows the extremely elongated cells to maintain tension. PMID- 28621429 TI - The SUMO-targeted ubiquitin ligase, Dgrn, is essential for Drosophila innate immunity. AB - The ability of metazoans to combat pathogenic infection involves both systemic and local responses to the invading pathogens. Ubiquitin and SUMO pathways molecularly regulate the response to infection, immune signaling and gene expression. Here, we report that Degringolade (Dgrn, CG10981), a SUMO-targeted ubiquitin ligase connecting the two pathways, is essential for the innate immunity response in Drosophila. dgrnDK null and heterozygous mutant adult flies are severely immune-compromised and succumb rapidly to both pathogenic bacteria and fungi infections. The sensitivity to infection stems from the inability to produce multiple anti-microbial peptides, and transcriptional analyses suggest that the overexpression of Dgrn enhances the transcriptional output of the NF ĸB related Toll and immune deficiency (IMD)-pathways. Moreover, expression of Dgrn alleviated the inhibitory impact of the cytoplasmic NF-ĸB inhibitor Cactus and the nuclear co-repressor Groucho/TLE (Gro). Additionally, we found that Dgrn is required for the local regenerative response of the mid-gut following infection. Upon oral infection, dgrn mutant flies fail to activate the Delta-Notch pathway in stem cells and enteroblasts, and are unable to regenerate and replace the damaged and dying enterocytes. Interestingly, the ubiquitin specific protease CG8334 (dUSP32/dUSP11) antagonizes Dgrn activity in the gut, and halving the dose of CG8334 restores Delta-Notch signaling and rescues the lethality observed in dgrn mutants. Collectively, our data suggest that Dgrn is essential for both systemic and local tissue response to infection. PMID- 28621431 TI - Adhesion molecule Kirrel3/Neph2 is required for the elongated shape of myocytes during skeletal muscle differentiation. AB - Kirrel/Neph proteins are evolutionarily conserved members of the immunoglobulin superfamily of adhesion proteins. Kirrel3 is the mouse orthologue of Dumbfounded (Duf), a family member that regulates myoblast pre-fusion events in Drosophila. Yet, the role of Kirrel3 in mammalian myogenesis has not been demonstrated. Experiments performed here indicate that the mouse Kirrel3 protein regulates morphological changes of myoblasts that are required for their subsequent fusion into multinucleated myotubes. We show that Kirrel3 is transiently expressed at the tips of myocytes during early myoblast differentiation and that its expression is dependent on the myogenic transcription factor, MyoD. Kirrel3 is transported in vesicles into the plasma membrane and its extracellular domain is cleaved in a proteasome-dependent manner. C-terminal deletion mutant lacking most of the intracellular domain accumulates at cellular extensions, does not undergo extracellular cleavage and induces the formation of large cell aggregates. This result suggests that the processing of the extracellular domain is regulated by the receptor's intracellular region. Knock-down of Kirrel3 in primary muscle progenitor cells (MPCs) prevented spindle shape myocyte formation, and significantly reduced their fusion with other myocytes to form multinucleated myotubes. In addition, migration of Kirrel3-deficient MPCs was randomized relative to the directed migration of control MPCs. We conclude that mouse Kirrel3 is a myobast adhesion molecule which promotes the morphological change of rounded MPC to a spindle shaped myocyte that migrates in a directed fashion and participates in the tight interactions between myocytes prior to their fusion. PMID- 28621430 TI - Disruption of the aortic wall by coelomic lining-derived mesenchymal cells accompanies the onset of aortic hematopoiesis. AB - In vertebrates, definitive hematopoietic stem cells (HSCs) first emerge in the ventral wall of the aorta in the Aorta-Gonad-Mesonephros (AGM) region of the embryo, where they differentiate from a specialized type of endothelium termed Hemogenic Endothelium (HE). While the transition from HE to hematopoietic tissue has received much experimental attention, much less is known regarding generation of HE itself. The current study investigates the emergence of the HE in the chick embryo aorta. Using the HE marker Runx1 as well as a new chicken-reactive antibody to the endothelial marker VE-Cadherin, we document the relationship between the emerging HE and surrounding tissues, particularly the coelomic epithelium (CE) and CE-derived sub-aortic mesenchyme. In addition, the fate of the CE cells was traced by electroporation of a GFP-expressing plasmid into the CE, followed by analysis using immunofluorescence and in situ hybridization. We make the novel observation that CE-derived mesenchyme transiently invades through the ventral wall of the aorta during the period of establishment of HE and just prior to the emergence of hematopoietic cell clusters in the ventral aortic wall. These observations emphasize a hitherto unappreciated dynamism in the aortic wall during the period of HE generation, and open the door to future studies regarding the role of invasive CE-derived cells during aortic hematopoiesis. PMID- 28621432 TI - Regulatory heterochronies and loose temporal scaling between sea star and sea urchin regulatory circuits. AB - It has long been argued that heterochrony, a change in relative timing of a developmental process, is a major source of evolutionary innovation. Heterochronic changes of regulatory gene activation could be the underlying molecular mechanism driving heterochronic changes through evolution. Here, we compare the temporal expression profiles of key regulatory circuits between sea urchin and sea star, representative of two classes of Echinoderms that shared a common ancestor about 500 million years ago. The morphologies of the sea urchin and sea star embryos are largely comparable, yet, differences in certain mesodermal cell types and ectodermal patterning result in distinct larval body plans. We generated high resolution temporal profiles of 17 mesodermally-, endodermally- and ectodermally-expressed regulatory genes in the sea star, Patiria miniata, and compared these to their orthologs in the Mediterranean sea urchin, Paracentrotus lividus. We found that the maternal to zygotic transition is delayed in the sea star compared to the sea urchin, in agreement with the longer cleavage stage in the sea star. Interestingly, the order of gene activation shows the highest variation in the relatively diverged mesodermal circuit, while the correlations of expression dynamics are the highest in the strongly conserved endodermal circuit. We detected loose scaling of the developmental rates of these species and observed interspecies heterochronies within all studied regulatory circuits. Thus, after 500 million years of parallel evolution, mild heterochronies between the species are frequently observed and the tight temporal scaling observed for closely related species no longer holds. PMID- 28621433 TI - Stability and reliability of error-related electromyography over the corrugator supercilii with increasing trials. AB - Electromyographic activity over the corrugator supercilii (cEMG), the primary facial muscle involved in negative emotions, is increased during the commission of errors on speeded reaction-time tasks. In the present paper, data from two previously published studies were reanalyzed to investigate the reliability and stability of error-related, correct-related, and difference cEMG across increasing numbers of trials. For a modified go/no-go and a flanker task, we found that error-related cEMG was highly stable and reliable in 14 trials, and correct-related cEMG between 56 and 82 trials, respectively. Given the typical number of trials used in studies of cognitive control, these findings suggest that many investigations of error monitoring are already sufficient to obtain acceptable error- and correct-related cEMG signals. Error-related cEMG activity is relatively easy to measure and, as such, it shows great promise for future research investigating the cognitive and affective mechanisms of error monitoring. PMID- 28621435 TI - Reduction of acrylamide content in bread crust by starch coating. AB - BACKGROUND: A technique of starch coating to reduce acrylamide content in bread crust was proposed. Bread was prepared in accordance with a conventional procedure and corn or potato starch coating was brushed on the surface of the fermented dough prior to baking. RESULTS: Corn starch coating caused a decrease in acrylamide of 66.7% and 77.1% for the outer and inner crust, respectively. The decrease caused by the potato starch coating was 68.4% and 77.4%, respectively. Starch coating reduced asparagine content significantly (43.4-82.9%; P < 0.01)in both the outer and inner crust. A lower temperature (difference of 10-20 degrees C) in combination with a higher moisture content (maximum difference of 8%) of bread crust were a result of starch coating, which effectively shortened the time span (4-8 min) over which acrylamide could form and accumulate. CONCLUSION: The present study demonstrates that starch coating could be a simple, effective and practical application for reducing acrylamide levels in bread crust without changing the texture and crust color of bread. (c) 2017 Society of Chemical Industry. PMID- 28621434 TI - EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice. AB - KEY POINTS: Rett syndrome is a neurodevelopmental disorder caused by loss-of function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. ABSTRACT: Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na+ channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons have lower levels of early endosome antigen 1 (EEA1), a protein involved in AMPA-type glutamate receptor endocytosis. In addition, expression of EEA1 in Mecp2 KO neurons reduced mEPSC amplitudes to wild-type levels, and restored synaptic scaling down of mEPSC amplitudes after 48 h blockade of GABAA R-mediated inhibition with bicuculline. The identification of a molecular deficit in HSP in Mecp2 KO neurons provides potentially novel targets of intervention for improving hippocampal function in Rett syndrome individuals. PMID- 28621436 TI - Development of a Cell-Based Gene Therapy Approach to Selectively Turn Off Bone Formation. AB - Cell and gene therapy approaches are safer when they possess a system that enables the therapy to be rapidly halted. Human mesenchymal stem cells were transduced with an adenoviral vector containing the cDNA for bone morphogenetic protein 2 (AdBMP2) to induce bone formation. To make this method safer, a system to quickly kill these virally transduced cells was designed and evaluated. Cells were encapsulated inside poly(ethylene glycol) diacrylate (PEG-Da) hydrogels that are able to shield the cells from immunological destruction. The system involves an inducible caspase-9 (iCasp9) activated using a specific chemical inducer of dimerization (CID). Delivering AdBMP2-transduced human mesenchymal stem cells encapsulated in PEG-Da hydrogel promoted ectopic ossification in vivo, and the iCasp9 system allowed direct control of the timing of apoptosis of the injected cells. The iCasp9-CID system enhances the safety of delivering AdBMP2-transduced cells, making it a more compelling therapeutic for bone repair and spine fusion. J. Cell. Biochem. 118: 3627-3634, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28621437 TI - Hepatitis A virus strains circulating during 1997-2015 in Campania, a Southern Italy region with periodic outbreaks. AB - In Italy, the incidence of hepatitis A has progressively declined over the last 30 years, though not homogeneously throughout the country. In Campania, Southern Italy, high annual incidence rates have been reported and several periodic outbreaks have occurred. To investigate the phylogenetic and epidemiologic relationships among HAV strains circulating in Campania over the period 1997 2015, 87 hepatitis A cases were investigated. The most frequent risk factor was the consumption of raw/undercooked shellfish (75/87, 86.2%). During 1997-2002 most viral strains were subtype IA (16/23, 70%); the phylogenetic pattern suggests that the incidence peaks observed in 2000-2001 had likely been caused by multiple strains. During a large 2004 outbreak, almost all viral variants were subtype IB (38/41, 93%); most of them (22/38, 58%) were recognized to be one of two main strains (differing for just a single nucleotide), the remaining sequences were strictly related variants. In 2014/2015, only IA strains were observed; two phylogenetically related but distinct strains were responsible, respectively, for a small cluster in 2014 and an outbreak in 2015. In each outbreak, several strains unrelated to those responsible for most cases were detected in a minority of patients, documenting a background of sporadic cases occurring even in the course of outbreaks; some of them proved to be identical to strains detected 11-14 years previously. Overall, the data suggest that several related and unrelated HAV strains have endemically circulated over the last 15 years in Campania, with some strains gaining epidemic transmission likely because of a local combination of multiple factors, including inadequate waste water purification and dietary habits. PMID- 28621438 TI - Moderate Alcoholic Beer Consumption: The Effects on the Lipid Profile and Insulin Sensitivity of Adult Men. AB - Beer is the most consumed alcoholic beverage in the world. The purpose was to compare the effects of consuming alcoholic beer (AB) and nonalcoholic beer (NAB) on the biochemical blood parameters. Two beers were produced under known and controlled conditions from the same raw material, NAB (0.6%, v/v) and AB with the addition of 6% grain alcohol. Fifteen healthy adult men (aged 20 to 57 y) underwent 3 treatments (30 d per treatment). In Treatment 1 (Baseline), they followed their usual diet without drinking any alcoholic beverage; in Treatment 2, they added the daily consumption of 330 mL NAB; and in Treatment 3, they added the daily consumption of 330 mL AB. It was found that the use of AB for 30 d (16 g alcohol/d) reduced the blood insulin and fasting glucose, reducing insulin resistance. These data suggest that the daily intake of 330 mL AB could statistically change the lipid profile and insulin sensitivity of adult men. The volunteers were healthy before and remained so after the intervention, with no change in their clinical status. PMID- 28621439 TI - Cloning and functional identification of moricins from the diamondback moth, Plutella xylostella (L.). AB - Antimicrobial peptides (AMPs) are small-molecule peptides that play crucial roles in insect innate immune responses. To better understand the function of AMPs in Plutella xylostella, one of the main pests of cruciferous vegetables, three full length cDNAs encoding moricins were cloned from Pl. xylostella. Two variants of the moricin named PxMor2 and PxMor3 were heterologously expressed and purified. A secondary structure analysis using circular dichroism demonstrated that the two peptides adopted an alpha-helical structure in the membrane-like environment, but in aqueous solution, they were present in random coiled conformation. Antimicrobial activity assays demonstrated that PxMor2 exhibited high activity against Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli; however, PxMor3 only demonstrated high activity against E. coli. Scanning electron microscopy and confocal laser-scanning microscopy analyses suggest that PxMors can lead to the disruption of bacterial membrane, which might be the mechanism by which PxMors inhibit bacterial growth. This study contributes to the understanding of Pl. xylostella AMPs and immune responses, and also enriches the knowledge of insect moricin. PMID- 28621440 TI - T lymphocytes dominate local leukocyte infiltration in response to intradermal injection of functionalized graphene-based nanomaterial. AB - Graphene-based nanomaterials (GBN) have many potential biomedical applications. However, information regarding their biological properties and interactions with cells and/or soluble factors within a complex tissue is limited. The objective of this study was to use the growing feather (GF) of chickens as a minimally invasive cutaneous test-site to assess and monitor leukocyte recruitment in response to intradermal GBN injection. Specifically, the dermis of 20 GFs per chicken was injected with 10 MUl of phosphate-buffered saline (PBS)-vehicle or 10 MUl of 300 MUg ml-1 oxygen-functionalized (f) GBN (6 chickens/treatment). GFs were collected before- (0) and at 0.25, 1, 2, 3, 4, 5, and 7 days post-injection and used for leukocyte-population analysis of immunofluorescently stained pulp cell suspensions or histological examination. Based on flow-cytometric cell population analysis, lymphocytes and macrophages were the major leukocyte populations infiltrating GFs in response to f-GBN presence. Compared with PBS controls, levels of T cells (gammadelta-, alphabeta-, CD4- and CD8-T cells) were greatly elevated in f-GBN-injected GFs within 6 h and remained elevated throughout the 7-day examination period. f-GBN's effects on local tissue leukocyte recruitment were not reflected in the blood, except for a higher percentage of lymphocytes on 7 days. These observations together with a visual examination of f-GBN-injected GF tissue-sections suggest a delayed-type hypersensitivity-like, inflammatory cell-mediated response to the non biodegradable f-GBN. The GF 'in vivo test-tube'system together with blood sampling provided unique insight into the time-course, qualitative, and quantitative aspects of immune system activities initiated by the presence of f GBN in a complex tissue of a living animal. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28621441 TI - Exuberant granulation tissue successfully treated with ingenol mebutate. Two cases report. PMID- 28621442 TI - Dendritic-cell-based immunotherapy evokes potent anti-tumor immune responses in CD105+ human renal cancer stem cells. AB - Cancer stem cells (CSCs) are responsible for tumor initiation, progression, and resistance to therapeutic agents; they are usually less sensitive to conventional cancer therapies, and could cause tumor relapse. An ideal therapeutic strategy would therefore be to selectively target and destroy CSCs, thereby preventing tumor relapse. The aim of the present study was to evaluate the effectiveness of dendritic cells (DCs) pulsed with antigen derived from CD105+ human renal cell carcinoma (RCC) CSCs against renal cancer cells in vitro and in vivo. We identified "stem-like" characteristics of CD105+ cells in two human RCC cell lines: A498 and SK-RC-39. Loading with cell lysates did not change the characteristics of the DCs. However, DCs loaded with lysates derived from CD105+ CSCs induced more functionally specific active T cells and specific antibodies against CSCs, and clearly depressed the tumor growth in mice. Our results could form the basis for a novel strategy to improve the efficacy of DC-based immunotherapy for human RCC. PMID- 28621444 TI - Implementation of electron-induced dissociation mass spectrometry technique for differentiation of isomeric metabolites of diclofenac. PMID- 28621443 TI - Noninvasive treatment of keloid using customized Re-188 skin patch. AB - Keloids are developed as fibrotic scar at the site of surgery or trauma and often enlarge beyond the original scar margins. Re-188 colloid coated customized patch was superficially fixed onto the lesion for 3 hrs. The same patch was reapplied on the lesion on third day for 3 hrs. The patients were followed up at 1, 3,6 and 12 months post treatment. The size and elevation of the keloid lesion was reduced after treatment. The total radiation dose from the patch (day-1 and day-3) was 100 Gy/mCi of Re-188. The radioactive patch treatment of keloids is noninvasive, painless and safe with prolonged outcome. PMID- 28621445 TI - Nutritional and Functional Bioactivity Value of Selected Azorean Macroalgae: Ulva compressa, Ulva rigida, Gelidium microdon, and Pterocladiella capillacea. AB - This study presents information on the biochemical composition (dry weight basis), nutritional aspects, and angiotensin I-converting enzyme (ACE) inhibitory properties of selected macroalgae (Ulva compressa, Ulva rigida, Gelidium microdon, and Pterocladiella capillacea) from Azores. Moisture content was very high (83.2% to 90.0% of fresh weight). Total dietary fiber (33.7% to 41.0%) that presented a good balance of both soluble and insoluble fibers (15.5% to 19.2% and 18.2% to 21.8%, respectively) was the most abundant component in these macroalgae. Protein and ash (ranged from 15.7% to 23.4% and 10.7% to 20.7%, respectively) were the 2nd most abundant components in red and green macroalgae, respectively. Moderate soluble carbohydrate contents (14.5% to 19.8%) were found in all species. Lipid contents were low (1.0% to 4.3%), particularly in Ulva species (1.0% to 1.7%), but contained higher unsaturated fatty acids (FAs) (7.5% to 32.9% and 29.6% to 69.2% of total FA for monounsaturated fatty acid and polyunsaturated fatty acid groups, respectively) than saturated fatty acid (23.3% to 46.8% of total FA) contents. All the macroalgal proteins had high digestibility in vitro (82.2% to 89.4%, relatively to sodium caseinate), contained high quantity of essential amino acids (45.3% to 58.1% of total amino acids), but in different proportions, and were rich in aspartic and glutamic acids that together account for 17.2% to 36.2% of the total amino acids. These results suggested that regular consumption of the selected macroalgae may improve human health and revealed that they can be used for producing food supplements for human and animal nutrition and/or pharmaceuticals with potential effect on the regional economy. Furthermore, the ACE-inhibitory IC50 values of 0.095 to 0.695 mg/mL for the <1 kDa protein hydrolysate fraction revealed a potential impact on hypertension disorder. PMID- 28621446 TI - The long and winding road for selective androgen receptor modulators. AB - Numerous selective androgen receptor modulators (SARMs) with differing chemical structures and nearly ideal pharmacological and pharmacokinetic properties have been developed that are well tolerated and selectively increase lean body mass in humans. However, definitive demonstration of the linkage between lean body mass and physical function in a relevant, large patient population has remained elusive for a SARM. The clinical endpoints serving as their basis of approval have shifted with time and clinical indication and are likely to continue to do so as the field matures with additional safety and efficacy data pertaining to the relationship between lean body mass and physical function, regulatory decisions with SARMs and other agents, and yet unexplored clinical indications. PMID- 28621447 TI - Metformin prevents vascular prostanoid release alterations induced by a high-fat diet in rats. AB - Perivascular adipose tissue dysfunction induced by high-fat feeding leads to alterations in the modulation of inflammation, contractile activity of the vascular smooth muscle and endothelial function, all risk factors in the development of hypertension. Metformin, an activator of AMP-activated protein kinase (AMPK), is currently the first-line drug treatment for type 2 diabetes (T2DM) and metabolic syndrome. Besides its glucose-lowering effect, there is an interest in actions of this drug with potential relevance in cardiovascular diseases. The high-fat (HF) diet is an experimental model that resembles human metabolic syndrome. We have previously reported an altered pattern of prostanoid release in mesenteric vessels in this model. The aim of this study was to analyse the effects of metformin on mesenteric vascular bed prostanoid release, adiposity index and its relation to blood pressure in Sprague-Dawley rats fed a HF diet for 8 and 12 weeks. Eight groups were used: control (C8, C1), HF diet (HF8, HF12, 50% w/w bovine fat), metformin-treated (CMf8, CMf12, 500 mg/kg/day) and metformin treated HF diet (HFMf8, HFMf12, both treatments). HF diet increased mesenteric vascular bed adiposity index (%, HF8: 1.7+/-0.1 vs C8: 0.9+/-0.04 and HF12: 1.8+/ 0.1 vs C12: 0.8+/-0.1, P<.001); systolic blood pressure (SBP, mm Hg, HF8: 145+/-6 vs C8: 118+/-4, P<.01 and HF12: 151+/-1 vs C12: 121+/-3, P<.001). We found a positive correlation between these two parameters. Moreover HF diet increased the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 (ng PR/mg of tissue, HF8: 117+/-6 vs C8: 66+/-2 and HF12: 123+/-6 vs C12: 62+/-5, P<.001) and prostaglandin (PG) F2alpha (ng/mg, HF8: 153+/-9 vs C8: 88+/-3 and HF12: 160+/-11 vs C12: 83+/-5, P<.001). We also found that this increase in the release of vasoconstrictor prostanoids positively correlates with the elevation of SBP. In addition, HF diet increases the release of PGE2 and decreases the prostacyclin (PGI2 )/TXA2 release ratio at 8 and 12 weeks of treatment compared to control groups. In the HFMf group, metformin treatment prevented all these increases in mesenteric vascular bed adiposity index (%, HFMf8: 1.3+/-0.2 vs HF8 and HFMf12: 1.3+/-0.1 vs HF12, P<.05); SBP (mm Hg, HFMf8: 127+/-2 vs HF8 and HFMf12: 132+/-1 vs HF12, P<.001); TXB2 release (ng PR/mg of tissue, HFMf8: 65+/-12 vs HF8, P<.05 and HFMf12: 53+/-3 vs HF12, P<.001) and PGF2 alpha (ng PR/mg of tissue, HFMf8: 99+/-13 vs HF8, P<.01 and HFMf12: 77+/-8 vs HF12, P<.001). Meanwhile metformin prevented the increment in PGE2 release only at 12 weeks. On the other hand, metformin improved the PGI2 /TXA2 ratio in both periods studied. In conclusion, metformin could exert beneficial effects on adipose tissue and the vascular system by improving endothelial dysfunction induced by an imbalance of vasoactive substances in mesenteric perivascular adipose tissue in this model. PMID- 28621448 TI - Mastocytosis: a case series of 107 consecutive patients. PMID- 28621449 TI - A flexible e-learning resource promoting the critical reading of scientific papers for science undergraduates. AB - An important aim of undergraduate science education is to develop student skills in reading and evaluating research papers. We have designed, developed, and implemented an on-line interactive resource entitled "Evaluating Scientific Research literature" (ESRL) aimed at students from the first 2 years of the undergraduate program. In this article, we describe the resource, then use student data collected from questionnaire surveys to evaluate the resource within 2 years of its launch. Our results add to those reported previously and indicate that ESRL can enable students to start evaluating research articles when used during their undergraduate program. We conclude maximal learning is likely to occur when the resource can be embedded in the curriculum such that students have a clearly articulated context for the resource's activities, can see their relevance in relation to assessed assignments and can be encouraged to think deeply about the activities in conversation with one another and/or with staff. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 45(6):483-490, 2017. PMID- 28621451 TI - Knockdown of a metathoracic scent gland desaturase enhances the production of (E) 4-oxo-2-hexenal and suppresses female sexual attractiveness in the plant bug Adelphocoris suturalis. AB - Insect sex pheromones (SPs) are central to mate-finding behaviour, and play an essential role in the survival and reproduction of organisms. Understanding the roles, biosynthetic pathways and evolution of insect chemical communication systems has been an exciting challenge for biologists. Compared with Lepidoptera, little is known about the mechanisms underlying pheromone biosynthesis in Hemiptera. In this study, we isolated and characterized two new desaturase-like genes, termed Asutdes1 and Asutdes2, from Adelphocoris suturalis, an important agricultural pest in China. Although the two genes encode an identical protein, Southern blot analysis revealed that they are duplicated genes. The Asutdes2 transcript is more abundant than Asutdes1 in the tissues tested, in particular the metathoracic scent gland and fat body. Silencing Asutdes expression in females by injecting double-stranded RNA (dsAsutdes) against a portion of the coding sequence shared by the two genes enhanced the production of (E)-4-oxo-2 hexenal, a component of the A. suturalis SP blend, and dramatically suppressed the sexual attractiveness of A. suturalis females. We conclude that dsAsutdes is associated with the SP biosynthetic pathway in A. suturalis. PMID- 28621452 TI - Osteogenic commitment and differentiation of human mesenchymal stem cells by low intensity pulsed ultrasound stimulation. AB - Low-intensity pulsed ultrasound (LIPUS) as an adjuvant therapy in in vitro and in vivo bone engineering has proven to be extremely useful. The present study aimed at investigating the effect of 30 mW/cm2 LIPUS stimulation on commercially available human mesenchymal stem cells (hMSCs) cultured in basal or osteogenic medium at different experimental time points (7, 14, 21 days). The hypothesis was that LIPUS would improve the osteogenic differentiation of hMSC and guarantying the maintenance of osteogenic committed fraction, as demonstrated by cell vitality and proteomic analysis. LIPUS stimulation (a) regulated the balance between osteoblast commitment and differentiation by specific networks (activations of RhoA/ROCK signaling and upregulation of Ribosome constituent/Protein metabolic process, Glycolysis/Gluconeogenesis, RNA metabolic process/Splicing and Tubulins); (b) allowed the maintenance of a few percentage of osteoblast precursors (21 days CD73+/CD90+: 6%; OCT-3/4+/NANOG+/SOX2+: 10%); (c) induced the activation of osteogenic specific pathways shown by gene expression (early: ALPL, COL1A1, late: RUNX2, BGLAP, MAPK1/6) and related protein release (COL1a1, OPN, OC), in particular in the presence of osteogenic soluble factors able to mimic bone microenvironment. To summarize, LIPUS might be able to improve the osteogenic commitment of hMSCs in vitro, and, at the same time, enhance their osteogenic differentiation. PMID- 28621453 TI - The pinhole method using an erbium: YAG laser for the treatment of papular acne scars. AB - Papular acne scars are skin-colored or hypopigmented, soft and elevated lesions of the chin and trunk. Papular scars are one of the most difficult acne scars to treat. Herein, we reported two patients with papular acne scars on the chin that were successfully treated by the pinhole method using an Erbium (ER):YAG laser. Good cosmetic results were achieved in both patients. The side effects included mild, intra-, and post-procedural pain and erythema that resolved spontaneously within 2 weeks. The pinhole method with an Er:YAG laser could potentially be used as a safe and effective treatment for papular acne scars. PMID- 28621454 TI - Adult males with haemophilia have a different macrovascular and microvascular endothelial function profile compared with healthy controls. AB - INTRODUCTION: Endothelial function has been identified as an independent predictor of cardiovascular risk in the general population. It is unclear if the haemophilia population has a different endothelial function profile compared to the healthy population. AIM: This prospective study aims to assess if there is a difference in endothelial function between haemophilia patients and healthy controls, and the impact of endothelial function on vascular outcomes in the haemophilia population. Baseline cardiovascular risk factors and endothelial function were presented. METHODS: Adult males with haemophilia A or B recruited from the British Columbia and Southern Alberta haemophilia treatment centres were matched to healthy male controls by age and cardiovascular risk factors. Macrovascular endothelial function was assessed by brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD), and microvascular endothelial function was assessed by hyperaemic velocity time integral (VTI). Multivariable linear regression was used to assess the association between haemophilia and endothelial function. RESULTS: A total of 81 patients with haemophilia and 243 controls were included. Patients with haemophilia had a similar FMD and NMD compared to controls, although haemophilia was associated with higher FMD on multivariable analysis. Haemophilia was associated with significantly lower VTI on univariate and multivariable analyses, regardless of haemophilia type and severity. CONCLUSIONS: Adult males with haemophilia appear to have lower microvascular endothelial function compared to healthy controls. Future studies to assess the impact of endothelial dysfunction on cardiovascular events in the haemophilia population are needed. PMID- 28621455 TI - Addition of Rifampicin to Bolton Broth to Inhibit Extended-Spectrum beta Lactamase-Producing Escherichia coli for the Detection of Campylobacter. AB - Exponential growth of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli in Campylobacter media has become a common problem for the detection of Campylobacter in chicken meats. We investigated the minimum inhibitory concentration of 40 ESBL-producing E. coli isolates from meats obtained from various countries against antibacterial agents in Bolton broth (cefoperazone, vancomycin, and trimethoprim). All ESBL-producing E. coli strains were resistant to cefoperazone and vancomycin, whereas 50% of them were resistant to trimethoprim and grew in Bolton broth. We found that 20 MUg/mL of rifampicin inhibited the growth of trimethoprim-resistant E. coli strains. Hence, we added 20 MUg/mL of rifampicin to Bolton broth to improve the isolation of Campylobacter from chicken carcass rinses. The isolation rate of Campylobacter was significantly higher in the modified broth (44 out of 58, 75.9%, P < 0.05) than in the normal broth (0 out of 58, 0%). Furthermore, the number of agar plates with non-Campylobacter spp. was much lower after enrichment in the modified broth (4 out of 58, 6.9%, P < 0.05) than in the normal broth (58 out of 58, 100%). PMID- 28621456 TI - Absorption, Distribution and Excretion of Four Forms of Titanium Dioxide Pigment in the Rat. AB - Titanium dioxide (TiO2 ) is a white color additive that has a long history of global approval and use in food. There is, however, considerable confusion regarding the applicability of the biological effects of novel, engineered, nano sized forms of TiO2 developed for nonpigmentary applications to the safety of oral exposure to food grade TiO2 pigment. The objective of this study was to assess the absorption, distribution, and routes of excretion in rats after oral exposure to food grade TiO2 . Four different grades of TiO2 (200 ppm) or control (0 ppm) diets were fed to rats for 7 consecutive days, followed by control diet only for 1, 24, or 72 h. Concentrations of titanium in liver, kidney and muscle were mainly below the limit of detection (<0.1 to < 0.2 mg/kg wet weight); tissue concentrations of titanium above the LOD were in the range of 0.1 to 0.3 mg/kg wet weight for all groups. Whole blood concentrations of titanium were <0.04 mg/L for all groups. Urinary excretion of titanium was equivalent to <2% daily dose/L of urine for all groups and was generally below the limit of quantification (<0.04 mg/L). Feces represented the predominant route of excretion. These results demonstrate that there is no accumulation of titanium in tissues following consumption of diets containing 200 ppm food grade TiO2 . No differences in systemic absorption of the 4 forms of TiO2 were observed indicating that the bioavailability of TiO2 is consistently low for the range of particle sizes and morphologies examined in this study. PMID- 28621457 TI - Core outcome research measures in anal cancer. PMID- 28621458 TI - What did the "Unossified zone" of the non-mammalian therapsid braincase house? AB - Most nonmammalian synapsids possess a mid-dorsal depression in the brain cavity known as the "unossified zone." It remains obscure which structures this zone contained, and, as candidates, the vermis of the cerebellum, the superior sagittal sinus, a junction of several blood vessels, the pineal gland or other midbrain structures were considered. Neutron tomography of a skull of Diictodon feliceps (Therapsida, Anomodontia) revealed some clear impressions of canals in this region of the brain cavity. Furthermore, the prootic sinus probably ran on the internal surface of the pila antotica and had a similar course in anomodonts as it has been proposed for cynodonts and Mesozoic mammals. Comparisons with the vascular systems of nonmammalian synapsids and mammals suggest that the unossified zone is best interpreted as a terminal chamber of the anterior segment of the medial head vein, which housed the junction of the superior sagittal sinus and the transverse sinuses. Consequently, the system of cranial vessels in Diictodon reveals a partial division of the medial head vein system into an anterior and a posterior segment at an early stage of synapsid evolution, which is consistent with the well-known common pattern of early ontogenetic development in amniotes. J. Morphol., 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28621459 TI - Microtubule actin crosslinking factor 1 promotes osteoblast differentiation by promoting beta-catenin/TCF1/Runx2 signaling axis. AB - Osteoblast differentiation is a multistep process delicately regulated by many factors, including cytoskeletal dynamics and signaling pathways. Microtubule actin crosslinking factor 1 (MACF1), a key cytoskeletal linker, has been shown to play key roles in signal transduction and in diverse cellular processes; however, its role in regulating osteoblast differentiation is still needed to be elucidated. To further uncover the functions and mechanisms of action of MACF1 in osteoblast differentiation, we examined effects of MACF1 knockdown (MACF1-KD) in MC3T3-E1 osteoblastic cells on their osteoblast differentiation and associated molecular mechanisms. The results showed that knockdown of MACF1 significantly suppressed mineralization of MC3T3-E1 cells, down-regulated the expression of key osteogenic genes alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and type I collagen alpha1 (Col Ialpha1). Knockdown of MACF1 dramatically reduced the nuclear translocation of beta-catenin, decreased the transcriptional activation of T cell factor 1 (TCF1), and down-regulated the expression of TCF1, lymphoid enhancer-binding factor 1 (LEF1), and Runx2, a target gene of beta catenin/TCF1. In addition, MACF1-KD increased the active level of glycogen synthase kinase-3beta (GSK-3beta), which is a key regulator for beta-catenin signal transduction. Moreover, the reduction of nuclear beta-catenin amount and decreased expression of TCF1 and Runx2 were significantly reversed in MACF1-KD cells when treated with lithium chloride, an agonist for beta-catenin by inhibiting GSK-3beta activity. Taken together, these findings suggest that knockdown of MACF1 in osteoblastic cells inhibits osteoblast differentiation through suppressing the beta-catenin/TCF1-Runx2 axis. Thus, a novel role of MACF1 in and a new mechanistic insight of osteoblast differentiation are uncovered. PMID- 28621460 TI - Older adults display diminished error processing and response in a continuous tracking task. AB - Advancing age is often accompanied by a decline in motor control that results in a decreased ability to successfully perform motor tasks. While there are multiple factors that contribute to age-related deficits in motor control, one unexplored possibility is that age-related deficits in our ability to evaluate motor output result in an increase in motor errors. In line with this, previous work from our laboratory demonstrated that motor errors evoked an error-related negativity (ERN)-a component of the human ERP associated with error evaluation originating within the human medial-frontal cortex. In the present study, we examined whether or not deficits in the medial-frontal error evaluation system contribute to age related deficits in motor control. Two groups of participants (young, old) performed a computer-based tracking task that paralleled driving while EEG data were recorded. Our results show that older adults committed more behavioral errors than young adults during performance of the tracking task. An analysis of our ERP data revealed that the amplitude of the ERN was reduced in older adults relative to young adults following motor errors. Our results make an important extension from previous work demonstrating age-related reductions in the ERN during performance of cognitive tasks. Importantly, our results imply the possibility of understanding motor deficits in older age. PMID- 28621461 TI - The Use of Eptifibatide Alone or in Combination With Heparin or Argatroban for Suspected Thrombosis in Patients With Left Ventricular Assist Devices. AB - Pump thrombosis and hemolysis in patients with left ventricular assist devices (LVADs) are associated with significant morbidity and mortality. Intensification of anticoagulation has been suggested as potential therapy, with mixed results. The aim of this study is to assess the safety and efficacy of adding eptifibatide with or without an anticoagulation agent in managing patients with LVAD presenting with hemolysis and suspected pump thrombosis. This retrospective single center study included all patients who presented with their first episode of suspected pump thrombosis and were treated with eptifibatide with or without an anticoagulant between March 1, 2011 and July 30, 2015. A total of 27 patients (23 HeartMate II, 4 HeartWare) were identified. The average age was 55 years (range 19-75) and time from implant to event averaged 513 days (range 35-1760). The average lactate dehydrogenase on presentation was 1111 and 63% of patients had power elevations. The average international normalized ratio (INR) on admission was 2.4, with INR of >=2 in 21/27 patients. All patients received eptifibatide: 10 received eptifibatide only, 9 received eptifibatide and argatroban, and 8 received eptifibatide and heparin. Warfarin was continued in 25/27 patients. Overall, 21 patients (77.8%) were successfully treated medically, 5 (18.5%) underwent pump exchange, and 1 (3.7%) died. There were no differences in outcomes or complications between the three treatment groups. Despite initial success, 12/21 patients developed repeat episodes of hemolysis at 1 year. The 1 year survival in the patients treated medically was 90% and surgically was 60%. Our experience indicates that medical therapy for hemolysis and suspected LVAD thrombosis with warfarin and eptifibatide alone or in combination with argatroban or heparin appears safe and may be effective, although the episodes of recurrent hemolysis after medical management remain high. PMID- 28621462 TI - Evidence for convergent evolution of a neocortex-like structure in a late Permian therapsid. AB - The special sensory, motor, and cognitive capabilities of mammals mainly depend upon the neocortex, which is the six-layered cover of the mammalian forebrain. The origin of the neocortex is still controversial and the current view is that larger brains with neocortex first evolved in late Triassic Mammaliaformes. Here, we report the earliest evidence of a structure analogous to the mammalian neocortex in a forerunner of mammals, the fossorial anomodont Kawingasaurus fossilis from the late Permian of Tanzania. The endocranial cavity of Kawingasaurus is almost completely ossified, which allowed a less hypothetical virtual reconstruction of the brain endocast to be generated. A parietal foramen is absent. A small pit between the cerebral hemispheres is interpreted as a pineal body. The inflated cerebral hemispheres are demarcated from each other by a median sulcus and by a possible rhinal fissure from the rest of the endocast. The encephalization quotient estimated by using the method of Eisenberg is 0.52, which is 2-3 times larger than in other nonmammalian synapsids. Another remarkable feature are the extremely ramified infraorbital canals in the snout. The shape of the brain endocast, the extremely ramified maxillary canals as well as the small frontally placed eyes suggest that special sensory adaptations to the subterranean habitat such as a well developed sense of touch and binocular vision may have driven the parallel evolution of an equivalent of the mammalian neocortex and a mammal-like lemnothalamic visual system in Kawingasaurus. The gross anatomy of the brain endocast of Kawingasaurus supports the Outgroup Hypothesis, according to which the neocortex evolved from the dorsal pallium of an amphibian-like ancestor, which receives sensory projections from the lemnothalamic pathway. The enlarged brain as well as the absence of a parietal foramen may be an indication for a higher metabolic rate of Kawingasaurus compared to other nonmammalian synapsids. PMID- 28621464 TI - Differences in excitability properties between medial gastrocnemius, tibialis anterior, and abductor pollicis brevis motor axons. AB - INTRODUCTION: Excitability properties of motor nerves to different muscles are different, but the explanation is uncertain. We characterized motor axon excitability properties to the medial gastrocnemius (MG) in 27 adults, and made comparisons with the peroneal nerve to the tibialis anterior (TA) and median nerve to the abductor pollicis brevis (APB) in 10 subjects. METHODS: Recordings of multiple excitability properties were made using threshold tracking, stimulating the nerves at the wrist or knee. RESULTS: Threshold electrotonus and superexcitability differed between nerves (APB>MG>TA axons) that may reflect differences in fast K+ conductance. APB axons had larger S2 accommodation and undershoot than TA and MG axons, indicating greater slow K+ conductance. TA axons demonstrated greater accommodation during hyperpolarizing currents than MG and APB axons, suggestive of greater inwardly rectifying current. DISCUSSION: Inherent differences in several conductances underlie nerve differences in excitability, presumably related to muscle or motoneuron properties. Muscle Nerve 57: E60-E69, 2018. PMID- 28621463 TI - Can the Apgar Score be Used for International Comparisons of Newborn Health? AB - BACKGROUND: The Apgar score has been shown to be predictive of neonatal mortality in clinical and population studies, but has not been used for international comparisons. We examined population-level distributions in Apgar scores and associations with neonatal mortality in Europe. METHODS: Aggregate data on the 5 minute Apgar score for live births and neonatal mortality rates from countries participating in the Euro-Peristat project in 2004 and 2010 were analysed. Country level associations between the Apgar score and neonatal mortality were assessed using the Spearman rank correlation coefficient. RESULTS: Twenty-three countries or regions provided data on Apgar at 5 minutes, covering 2 183 472 live births. Scores <7 ranged from 0.3% to 2.4% across countries in 2004 and 2010 and were correlated over time (rho = 0.88, P < 0.01). There were large differences in healthy baby scores: scores of 10 ranged from 8.8% to 92.7% whereas scores of 9 or 10 ranged from 72.9% to 96.8%. Countries more likely to score 10 s, as opposed to 9 s, for healthy babies had lower proportions of Apgar <7 (rho = -0.43, P = 0.04). Neonatal mortality rates were weakly correlated with Apgar score <7 (rho = -0.06, P = 0.61), but differences over time in these two indicators were correlated (rho =0.56, P = 0.02). CONCLUSIONS: Large variations in the distribution of Apgar scores likely due to national scoring practices make the Apgar score an unsuitable indicator for benchmarking newborn health across countries. However, country-level trends over time in the Apgar score may reflect real changes and merit further investigation. PMID- 28621465 TI - Structural Phase Transitions and Dielectric Switching in a Series of Organic Inorganic Hybrid Perovskites ABX3 (X=ClO4- or BF4- ). AB - A series of organic-inorganic hybrid perovskites ABX3 (A=diprotonated 1,4 diazabicyclo[2.2.2]octane or piperazine; B=Na+ or K+ ; X=ClO4- or BF4- ) has been synthesized. They feature a cubic cage-like host-guest structures of which A is the cationic guest residing in the anionic cage B8 X12 , B is the vertex of the cage with variable coordination numbers between six and twelve, and X is the bridging ligand with mono- and/or bidentate coordination modes. The extended Goldschmidt tolerance factor t is used to describe the phase stability of the compounds. Differential scanning calorimetry, variable-temperature structural analyses, and dielectric measurements reveal that order-disorder transitions of the A guest and/or X bridging ligand are supposed to be responsible for structural phase transitions and dielectric switching in the compounds. PMID- 28621466 TI - Integrative Pericyclic Cascade: An Atom Economic, Multi C-C Bond-Forming Strategy for the Construction of Molecular Complexity. AB - An all-pericyclic manifold is developed for the construction of topologically diverse, structurally complex and natural product-like polycyclic chemotypes. The manifold uses readily accessible tertiary propargyl vinyl ethers as substrates and imidazole as a catalyst to form up to two new rings, three new C-C bonds, six stereogenic centers and one transannular oxo-bridge. The manifold is efficient, scalable and instrumentally simple to perform and entails a propargyl Claisen rearrangement-[1,3]H shift, an oxa-6pi-electrocyclization, and an intramolecular Diels-Alder reaction. PMID- 28621467 TI - Critical role of CREBH-mediated induction of transforming growth factor beta2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells. AB - : Mechanisms of hepatic fibrogenesis induced by hepatitis C virus (HCV), one of the leading causes of liver fibrosis, are not fully understood. We studied transcriptional up-regulation of transforming growth factor beta (TGF-beta), especially TGF-beta2, which is mediated by activation of liver-enriched transcription factor cAMP-responsive element-binding protein, hepatocyte specific (CREBH) triggered by HCV infection and its functional significance for induction of profibrogenic phenotypes by interaction of HCV-infected cells with hepatic stellate cells (HSCs). Compared to TGF-beta1, expression of TGF-beta2 mRNA was induced faster and to a higher level upon HCV infection. Serum TGF-beta2 levels in hepatitis C patients were higher compared to those in healthy individuals and were positively correlated with hepatic fibrosis stages F0-F2. TGF-beta2 promoter activity was decreased and increased, respectively, by silencing and overexpression of CREBH. CREBH recognition sites were identified in the TGF-beta2 promoter. CREBH binding to the promoter and its increase in cells expressing HCV Core-NS2 were shown by gel mobility shift and chromatin immunoprecipitation, respectively. The active form of CREBH was detectable in HCV-infected chimeric mice with human livers and cells expressing HCV proteins. Involvement of CREBH in HCV-induced fibrogenic response was further demonstrated in the CREBH null-mutant mouse model. Fibrogenic phenotypes were assessed using co-cultures of HCV infected cells and HSCs. Expressions of fibrogenic factors and TGF-beta1 increasing in the co-cultures was prevented by TGF-beta2- or CREBH silencing. CONCLUSION: CREBH was identified as a key positive regulator of TGF-beta2 transcription in HCV-infected cells. TGF-beta2 released from infected cells potentially contributes to cross-induction of TGF-beta in an autocrine manner through its own signaling pathway, leading to an increase in fibrogenic responses in adjacent HSCs. (Hepatology 2017;66:1430-1443). PMID- 28621468 TI - Characteristics of regional bone quality in cervical vertebrae considering BMD: Determining a safe trajectory for cervical pedicle screw fixation. AB - This study aimed to report the mechanical strength and characteristics of the lateral mass and pedicle considering BMD for the safe insertion of pedicle screws in the subaxial cervical level. We evaluated BMD and Hounsfield unit (HU) values of cortical bones at the lateral mass and pedicle of C3-7 from CT images in 99 patients. Patients were divided into three groups (Group A, T-score >= -1; Group B, -2.5 < T-score < -1.0; Group C, T-score <= -2.5). The HU numbers of cortical bone in the vertebral canal (medial wall of the lateral mass; cHU), posterior wall of the transverse foramen (fHU), and medial wall, lateral wall, and trabecular area of the pedicle (mHU, lHU, and pHU, respectively) were measured on the CT images in the middle of the pedicle. A mechanical study was also performed to measure cortical bone strength using 10 fresh cadavers. The cHU and mHU values in Group C were higher than lHU and fHU in Groups A and B, and there was a wide gap between the pHU value and other areas. The penetrating force also had a close correlation with HU number. The mean penetrating force of the medial wall of the lateral mass and the posterior wall of the transverse foramen were 210.08 +/- 110.46 and 50.51 +/- 46.09 N, respectively. The cortical bones in the vertebral canal and medial wall of the pedicle were stronger than the lateral wall and the trabecular area. The cHU and mHU in the osteoporotic group were higher than fHU and pHU in the normal group. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:217-223, 2018. PMID- 28621469 TI - Solitary fibrous tumor of the breast: A case report and the review of the literature. AB - Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms. They were first described as spindle-cell tumors originating from the pleura, but they may arise in any anatomical site. SFT of the breast is an exceedingly rare clinical entity. Our literature review yielded only 21 cases reported so far. We describe a case of a SFT of the breast in a premenopausal patient who presented with a gradually enlarging palpable breast mass. Diagnostic evaluation and management are discussed along with a review of the relevant literature. There are no pathognomonic imaging findings of SFT of the breast. Complete surgical resection with clear margins is the gold standard of treatment. Thorough immunohistochemical analysis is crucial to obtain a definitive diagnosis. Although most SFTs run an indolent course, in some cases the clinical behavior can be unpredictable and a long-term follow-up for all patients is therefore mandatory. PMID- 28621470 TI - The POU homeodomain transcription factor POUM2 and broad complex isoform 2 transcription factor induced by 20-hydroxyecdysone collaboratively regulate vitellogenin gene expression and egg formation in the silkworm Bombyx mori. AB - Vitellogenin (Vg) is a source of nutrition for embryo development. Our previous study showed that the silkworm (Bombyx mori) transcription factor broad complex isoform 2 (BmBrC-Z2) regulates gene expression of the Vg gene (BmVg) by induction with 20-hydroxyecdysone (20E). However, the mechanism by which 20E regulates BmVg expression was not clarified. In this study, cell transfection experiments showed that the BmVg promoter containing the POU homeodomain transcription factor POUM2 (POUM2) and BrC-Z2 cis-response elements (CREs) showed a more significant response to 20E than that harbouring only the BrC-Z2 or POUM2 CRE. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay showed that BmPOUM2 could bind to the POUM2 CRE of the BmVg promoter. Over expression of BmPOUM2 and BmBrC-Z2 in B. mori embryo-derived cell line (BmE) could enhance the activity of the BmVg promoter carrying both the POUM2 and BrC Z2 CREs following 20E induction. Quantitative PCR and immunofluorescence histochemistry showed that the expression pattern and tissue localization of BmPOUM2 correspond to those of BmVg. Glutathione S-transferase pull-down and co immunoprecipitation assays confirmed that BmPOUM2 interacts only with BmBrC-Z2 to regulate BmVg expression. Down-regulation of BmPOUM2 in female silkworm by RNA interference significantly reduced BmVg expression, leading to abnormal egg formation. In summary, these results indicate that BmPOUM2 binds only to BmBrC-Z2 to collaboratively regulate BmVg expression by 20E induction to control vitellogenesis and egg formation in the silkworm. Moreover, these findings suggest that homeodomain protein POUM2 plays a novel role in regulating insect vitellogenesis. PMID- 28621471 TI - Tuberculosis breast and its coexistence with carcinoma breast: A retrospective analysis at a tertiary care hospital in India. PMID- 28621472 TI - The Role of Multiword Building Blocks in Explaining L1-L2 Differences. AB - Why are children better language learners than adults despite being worse at a range of other cognitive tasks? Here, we explore the role of multiword sequences in explaining L1-L2 differences in learning. In particular, we propose that children and adults differ in their reliance on such multiword units (MWUs) in learning, and that this difference affects learning strategies and outcomes, and leads to difficulty in learning certain grammatical relations. In the first part, we review recent findings that suggest that MWUs play a facilitative role in learning. We then discuss the implications of these findings for L1-L2 differences: We hypothesize that adults are both less likely to extract MWUs and less capable of benefiting from them in the process of learning. In the next section, we draw on psycholinguistic, developmental, and computational findings to support these predictions. We end with a discussion of the relation between this proposal and other accounts of L1-L2 difficulty. PMID- 28621475 TI - In Memoriam. PMID- 28621480 TI - Analogy and Abstraction. AB - A central question in human development is how young children gain knowledge so fast. We propose that analogical generalization drives much of this early learning and allows children to generate new abstractions from experience. In this paper, we review evidence for analogical generalization in both children and adults. We discuss how analogical processes interact with the child's changing knowledge base to predict the course of learning, from conservative to domain general understanding. This line of research leads to challenges to existing assumptions about learning. It shows that (a) it is not enough to consider the distribution of examples given to learners; one must consider the processes learners are applying; (b) contrary to the general assumption, maximizing variability is not always the best route for maximizing generalization and transfer. PMID- 28621481 TI - Metal-Free, Room-Temperature Oxygen-Atom Transfer in the N2 O/CO Redox Couple as Catalyzed by [Si2 Ox ].+ (x=2-5). AB - The thermal reduction of N2 O by CO mediated by the metal-free cluster cations [Si2 Ox ].+ (x=2-5) has been examined in the gas phase using Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry in conjunction with quantum chemical calculations. Three successive oxidation/reduction steps occur starting from [Si2 O2 ].+ and N2 O to form eventually [Si2 O5 ].+ ; the latter as well as the intermediate oxide cluster ions react sequentially with CO molecules to regenerate [Si2 O2 ].+ . Thus, full catalytic cycles occur at ambient conditions in the gas phase. Mechanistic aspects of these sequential redox processes have been addressed to reveal the electronic origins of these unparalleled reactions. PMID- 28621482 TI - Identification of 400 novel alleles at the HLA-A, -B, -C, -DRB1, -DQB1 loci from China Marrow Donor Program. AB - Four hundred novel human leukocyte antigen (HLA) alleles were identified in Chinese individuals: 100 HLA-A alleles, 100 HLA-B alleles, 101 HLA-C alleles, 28 HLA-DRB1 alleles and 71 HLA-DQB1 alleles. Comparing novel alleles with their most homologous allele, we found 72.73% non-synonymous nucleotide substitutions, 21.13% silent mutations, 3.90% nonsense mutations and 3.25% frameshift mutation. 352 (88%) of the 400 novel alleles are single nucleotide substitution variants when compared with their most homologous alleles and other novel alleles differ from their most similar allele by more than 1 nucleotide substitutions, such as 2, 3, 5, 6, 8 and so on. Some of the novel alleles are characterized by long deletions or insertions, for example there is 23 bp deletion in the B*58:31N allele when compared to its most homologous allele B*58:01:01:01. PMID- 28621483 TI - Glycodendrimers as Chondroitin Sulfate Mimetics: Synthesis and Binding to Growth Factor Midkine. AB - Chondroitin sulfate (CS) is a member of the glycosaminoglycan (GAG) family, a class of polysaccharides implicated in relevant biological functions. The structural complexity of these carbohydrates demands the development of simple glycomimetics as useful tools to study the biological processes in which GAGs are involved. In this work we described the synthesis of the disaccharide unit of the CS-E (GlcA-GalNAc(4,6-di-OSO3 )), in a multivalent presentation. Using a fluorescence polarization competition assay we have demonstrated that a hexavalent dendrimer of this disaccharide interact with midkine, in the low micromolar range. This result highlights the potency of these disaccharide displaying multivalent systems as interesting mimetics of longer and synthetically more complex GAG oligosaccharides. PMID- 28621484 TI - Janusarene: A Homoditopic Molecular Host. AB - A homoditopic molecular host, janusarene, is presented that has two back-to-back compactly arranged nanocavities for guest complexation. The unique two-face structural feature of janusarene allows it to bind and align various guest compounds concurrently, which include spherical pristine fullerene C60 and planar polycyclic aromatic hydrocarbons (PAHs), such as pyrene, perylene, and 9,10 dimethylanthracene. The host-guest interactions were characterized by single crystal X-ray diffraction. A pairwise encapsulation of the PAH guests by janusarene enables PAH dimers to be obtained that deliver spectroscopic properties distinct from those of PAHs dissolved in solution, or in the bulk state. A monotopic control host was also synthesized and used to characterize the host-guest complexing behavior in solution. PMID- 28621485 TI - The conundrums of human development - implications for the study of child and adolescent disorder. AB - The conundrums inherent in the study of child and adolescent development are likely never far from the minds of the readers of JCPP. The complexity of development is flagged clearly in this issue. Included papers remind us that the link between associations (here maternal depression and child internalising problems) can change over short time periods. Even when the magnitude of associations stay consistent over time (here between the home environment and depression), there may be different aetiological processes underlying these links. Going forward, we should not lose sight of the significance of small changes in study designs, whether concerning the age range of participants, stipulated reporting periods and data analysis decisions (such as combining data from different age groups). The value of longitudinal data in addressing these questions remains paramount. PMID- 28621486 TI - Editorial Perspective: The use of person-first language in scholarly writing may accentuate stigma. AB - Numerous style guides, including those issued by the American Psychological and the American Psychiatric Associations, prescribe that writers use only person first language so that nouns referring to persons (e.g. children) always precede phrases referring to characteristics (e.g. children with typical development). Person-first language is based on the premise that everyone, regardless of whether they have a disability, is a person-first, and therefore everyone should be referred to with person-first language. However, my analysis of scholarly writing suggests that person-first language is used more frequently to refer to children with disabilities than to refer to children without disabilities; person first language is more frequently used to refer to children with disabilities than adults with disabilities; and person-first language is most frequently used to refer to children with the most stigmatized disabilities. Therefore, the use of person-first language in scholarly writing may actually accentuate stigma rather than attenuate it. Recommendations are forwarded for language use that may reduce stigma. PMID- 28621487 TI - Simultaneous quantification of imatinib and its main metabolite N-demethyl imatinib in human plasma by liquid chromatography-tandem mass spectrometry and its application to therapeutic drug monitoring in patients with gastrointestinal stromal tumor. AB - The aim of this study was to improve and validate a more stable and less time consuming method based on liquid chromatography and tandem mass spectrometry (LC- MS/MS) for the quantitative measurement of imatinib and its metabolite N-demethyl imatinib (NDI) in human plasma. Separation of analytes was performed on a Waters XTerra RP18 column (50 * 2.1 mm i.d., 3.5 MUm) with a mobile phase consisting of methanol-acetonitrile-water (65:20:15, v/v/v) with 0.05% formic acid at a flow rate of 0.2 mL/min. The Quattro MicroTM triple quadruple mass spectrometer was operated in the multiple-reaction-monitoring mode via positive electrospray ionization interface using the transitions m/z 494.0 -> 394.0 for imatinib, m/z 479.6 -> 394.0 for NDI and m/z 488.2 -> 394.0 for IS. The method was linear over 0.01-10 MUg/mL for imatinib and NDI. The intra- and inter-day precisions were all <15% in terms of relative standard deviation, and the accuracy was within +/-15% in terms of relative error for both imatinib and NDI. The lower limit of quantification was identifiable and reproducible at 10 ng/mL. The method was sensitive, specific and less time-consuming and it was successfully applied in gastrointestinal stromal tumor patients treated with imatinib. PMID- 28621488 TI - Effects of Intradialytic Neuromuscular Electrical Stimulation on Strength and Muscle Architecture in Patients With Chronic Kidney Failure: Randomized Clinical Trial. AB - This study aimed to evaluate the effects of neuromuscular electrical stimulation (NMES) on muscle strength and architecture, functional capacity, and endothelial function in patients with chronic kidney failure (CKF) on hemodialysis (HD). Twenty-one patients with CKF on HD were randomized into a control group (CG; n = 10) and neuromuscular electrical stimulation group (NMESG; n = 11) who received NMES in the quadriceps muscle for 8 weeks, 3 times/week (20-34 min) during HD sessions. The muscle strength of the lower limbs was evaluated by dynamometry and sit-and-stand test (SST); muscle architecture through ultrasonography; functional capacity by the distance covered in a 6-min walk test and the endothelial function by flow-mediated dilatation technique of the brachial artery. There was an increase in the strength of the lower limbs in the NMESG compared to the CG (dynamometry: 43.28 +/- 16.94 vs. 35.84 +/- 16.89, P = 0.006; SST: 16.10 +/- 6.51 vs. 12.50 +/- 4.7, P = 0.029). There was a significant reduction in pennation angles of the right vastus lateralis (RVL) and left vastus lateralis (LVL) in the CG when compared to the NMESG (RVL: 11.93 [10.70-15.11] vs. 13.57 [11.81-15.96], P = 0.039; LVL: 11.62 [9.00-14.20] vs. 15.52 [12.86-20.02], P = 0.042). There was no change in functional capacity and in the endothelial function for CG and NMESG, respectively. In conclusion, NMES increases muscle strength and has a protective effect against muscle atrophy of the lower limbs of patients with chronic kidney failure on HD. PMID- 28621490 TI - Dissecting the benefits of long-term non-invasive ventilation in patients with distinct neuromuscular disorders. PMID- 28621489 TI - Validation and comparison of quality-of-life measures for topical 5-fluorouracil treatment: results from a randomized controlled trial. AB - BACKGROUND: Topical 5-fluorouracil (5-FU) is commonly used for high-risk patients with keratinocyte carcinoma (KC). Skindex and Skin Cancer Index (SCI) are validated instruments to measure quality of life (QoL) of patients with KC and those who have had surgical treatment of KCs. AIM: To validate Skindex and SCI for topical 5-fluorouracil (5-FU) application and to compare the two QoL instruments. METHODS: We randomized 932 veterans at high risk for developing a KC to either topical 5-FU or vehicle control cream applied to the face and ears for up to 1 month. We collected their Skindex-29 and SCI scores at baseline and follow-up visits. RESULTS: Compared with controls, 5-FU reduced QoL, measured by the Skindex symptom, Skindex function and SCI social subscales (P < 0.001, P < 0.01, P = 0.02, respectively). At 1 month, significant changes in QoL in the 5-FU group were observed in the Skindex symptom (10.1, 95% CI 0.36-12.6), Skindex function (6.0, 95% CI 4.0-8.0) and SCI social (-3.5, 95% CI -6.2 to -0.8) subscales, while the other subscales of Skindex and SCI did not show significant changes. All three Skindex subscales at 1 month correlated with patient-reported symptom score and photograph-based toxicity score, whereas social subscale was the only one of the SCI subscales that correlated with patient-reported symptom and photograph-based toxicity scores. CONCLUSIONS: Our study validated Skindex symptom, Skindex function and SCI social subscales for QoL measurement during treatment with topical 5-FU. The study could not provide evidence for construct validity of the other subscales. Skindex was more responsive than SCI in the context of 5-FU treatment. PMID- 28621491 TI - Outcome of patients older than 80 years with diffuse large B-cell lymphoma (DLBCL) treated with "standard" immunochemotherapy: A large retrospective study from 4 institutions. AB - Little information is available on the very elderly patients with diffuse large B cell lymphoma (DLBCL). We performed a retrospective analysis of 281 patients >80 years old with newly diagnosed DLBCL treated in 4 referral institutions in Switzerland and Northern Italy. Primary end points were overall survival, progression-free survival, and cause-specific survival. Systemic chemotherapy was given to 239 patients, and 119 of them received rituximab in their initial treatment. At a median follow-up of 5.5 years, 5-year progression-free survival was 26% (95% confidence interval [CI], 20-32%), 5-year overall survival was 31% (95% CI, 25-37%), and 5-year cause-specific survival was 48% (95% CI, 41-55%) for the entire cohort. Rituximab and/or anthracyclines as part of initial treatment were associated with improved outcome. Cause-specific survival in patients receiving both agents approximated 60% at 5 years. At multivariate analysis, rituximab use maintained a significant prognostic impact after controlling for age, performance status, stage, haemoglobin, and lactate dehydrogenase levels. The International Prognostic Index as well as the more recently proposed revised International Prognostic Index and National Comprehensive Cancer Center Network International Prognostic Index could discriminate patients with significantly different outcomes. Albeit very elderly and potentially frail, there may be a potential for cure in fit DLBCL patients >=80 years old. Accurate selection of patients able to tolerate proper immunochemotherapy is crucial. PMID- 28621493 TI - Bioelectronic medicine: technology targeting molecular mechanisms for therapy. PMID- 28621492 TI - Tendons and Ligaments: Connecting Developmental Biology to Musculoskeletal Disease Pathogenesis. AB - Tendons and ligaments provide connections between muscle and bone or bone and bone to enable locomotion. Damage to tendons and ligaments caused by acute or chronic injury or associated with aging and arthritis is a prevalent cause of disability. Improvements in approaches for the treatment of these conditions depend on a better understanding of tendon and ligament development, cell biology, and pathophysiology. This review focuses on recent advances in the discovery of transcription factors that control ligament and tendon cell differentiation, how cell and extracellular matrix homeostasis are altered in disease, and how this new insight can lead to novel therapeutic approaches. (c) 2017 American Society for Bone and Mineral Research. PMID- 28621494 TI - An analysis of blood donor deferrals among repeat donors. PMID- 28621495 TI - The spectrum of pre-dementia stages: cognitive profile of motoric cognitive risk syndrome and relationship with mild cognitive impairment. AB - BACKGROUND AND PURPOSE: Motoric cognitive risk (MCR) syndrome is a pre-dementia syndrome. There is little information on the cognitive profile of individuals with MCR syndrome and its overlap with mild cognitive impairment (MCI) syndrome. This study aimed to examine and compare the cognitive performance of non-demented older community dwellers with and without MCR and MCI syndromes. METHODS: A total of 291 non-demented individuals were selected from the Gait and Alzheimer Interactions Tracking study, which is a cross-sectional study. All participants were referred to a memory clinic. Individuals with and without MCR were separated into those with and without MCI. Cognitive performance was measured using the scores of the Mini Mental Status Examination, Frontal Assessment Battery, Free and Cued Selective Reminding Test, Trail Making Test part A and B, and Stroop test. RESULTS: The prevalence of MCI was 40.1% and that of MCR was 18.2%, with a higher prevalence of MCI in MCR group compared with the non-MCR group (47.2% vs. 39.5%). Individuals with MCR and MCI syndromes had poorer cognitive performance in all domains compared with those without MCR (P < 0.005), except for the ratio part III: part I of the Stroop test (P = 0.345). The association between cognitive performance and MCR syndrome was worse on the Mini Mental Status Examination score [effect size, -0.57 (95% confidence interval, -1.02 to -0.12)] and Trail Making Test part B [effect size, 0.59 (95% confidence interval, 0.14 1.04)] in individuals with MCR and MCI syndromes. CONCLUSIONS: Motoric cognitive risk syndrome is associated with low global cognitive performance. Association of MCR and MCI syndromes is characterized by a worse cognitive performance. PMID- 28621496 TI - Adrenomedullin regulates the speed of oviductal fluid flow in cattle. AB - Unidirectional flow of oviductal fluid from the ovarian to uterine side of the ampulla plays a significant role in successful pregnancy, and is produced by ciliary beating. Various systems regulate ciliary beating, such as paracrine, autocrine, and endocrine. We hypothesized that Adrenomedullin (ADM)-a peptide hormone that acts via its receptors, which are complexes of Calcitonin receptor like receptor (CRLR) and Receptor activity-modifying protein (RAMP) 2 or 3 - promotes oviductal fluid flow in the ampulla of bovine oviducts. First, we examined the expression of ADM, CRLR, RAMP2, and RAMP3 mRNAs in isolated epithelial cells throughout the estrous cycle, and the localization of ADM receptor protein constituents in the ampulla. RAMP2 expression was significantly higher in the follicular phase. Furthermore, RAMP2 protein was detected only in ciliated cells, whereas CRLR and RAMP3 were detected in all epithelial cells. The effects of ADM and an ADM antagonist on fluid-flow speed were examined using microbeads in ampullary tissue. ADM antagonist decreased bead transport speed, and this decrease was reversed by ADM. In addition, ADM recovered the bead transport speed that decreased in the absence of calcium. Overall, our results suggest that ADM contributes to the regulation of oviductal fluid flow in ampulla. PMID- 28621497 TI - Werner Reutter: A Visionary Pioneer in Molecular Glycobiology. AB - A creative pioneer: Werner Reutter (1937-2016) was a scientist who both made fundamental discoveries in glycobiology and reached out to disciplines beyond his core field. Many of his former colleagues and students will remember his desire to exchange research ideas, which ultimately contributed to the birth of new research fields. PMID- 28621499 TI - Dyslipidemia in patients with androgenetic alopecia. Statins, finasteride or both? PMID- 28621498 TI - Sustainable Production of o-Xylene from Biomass-Derived Pinacol and Acrolein. AB - o-Xylene (OX) is a large-volume commodity chemical that is conventionally produced from fossil fuels. In this study, an efficient and sustainable two-step route is used to produce OX from biomass-derived pinacol and acrolein. In the first step, the phosphotungstic acid (HPW)-catalyzed pinacol dehydration in 1 ethyl-3-methylimidazolium chloride ([emim]Cl) selectively affords 2,3 dimethylbutadiene. The high selectivity of this reaction can be ascribed to the H bonding interaction between Cl- and the hydroxy group of pinacol. The stabilization of the carbocation intermediate by the surrounding anion Cl- may be another reason for the high selectivity. Notably, the good reusability of the HPW/[emim]Cl system can reduce the waste output and production cost. In the second step, OX is selectively produced by a Diels-Alder reaction of 2,3 dimethylbutadiene and acrolein, followed by a Pd/C-catalyzed decarbonylation/aromatization cascade in a one-pot fashion. The sustainable two step process efficiently produces renewable OX in 79 % overall yield. Analogously, biomass-derived crotonaldehyde and pinacol can also serve as the feedstocks for the production of 1,2,4-trimethylbenzene. PMID- 28621500 TI - Occupational skin disease - a major health problem in Europe. PMID- 28621501 TI - Medication non-adherence: the hidden problem in clinical practice. PMID- 28621502 TI - Amniotic membrane stimulates cell migration by modulating transforming growth factor-beta signalling. AB - Keratinocyte migration is a mandatory aspect of wound healing. We have previously shown that amniotic membrane (AM) applied to chronic wounds assists healing through a process resulting in the overexpression of c-Jun at the wound's leading edge. We have also demonstrated that AM modifies the genetic programme induced by transforming growth factor-beta (TGF-beta) in chronic wounds. Here we used a scratch assay of mink lung epithelial cells (Mv1Lu) and a spontaneously immortalized human keratinocyte cell line (HaCaT) cells to examine the influence of AM application on the underlying signalling during scratch closure. AM application induced c-Jun phosphorylation at the leading edge of scratch wounds in a process dependent on MAPK and JNK signalling. Strikingly, when the TGF-beta dependent Smad-activation inhibitor SB431542 was used together with AM, migration improvement was partially restrained, whereas the addition of TGF-beta had a synergistic effect on the AM-induced cell migration. Moreover, antagonizing TGF beta with specific antibodies in both cell lines or knocking out TGF-beta receptors in Mv1Lu cells had similar effects on cell migration as using SB431542. Furthermore, we found that AM was able to attenuate TGF-beta-Smad signalling specifically at the migrating edge; AM treatment abated Smad2 and Smad3 nuclear localization in response to TGF-beta in a process dependent on mitogen-activated protein kinase kinase 1 (MEK1) activation but independent of EGF receptor or JNK activation. The involvement of Smad signalling on AM effects on HaCaT keratinocytes was further corroborated by overexpression of either Smad2 or Smad3 and the use of Smad phosphorylation-specific inhibitors, revealing a differential influence on AM-induced migration for each Smad. Thus, AM TGF-beta-Smad signalling abating is essential for optimal cell migration and wound closure. PMID- 28621503 TI - pH-Responsive Fluorescence Enhancement in Graphene Oxide-Naphthalimide Nanoconjugates: A Fluorescence Turn-On Sensor for Acetylcholine. AB - A pH-sensitive, fluorescence "turn-on" sensor based on a graphene oxide naphthalimide (GO-NI) nanoconjugate for the detection of acetylcholine (ACh) by monitoring the enzymatic activity of acetylcholinesterase (AChE) in aqueous solution is reported. These nanoconjugates were synthesized by covalently anchoring picolyl-substituted NI derivatives on the GO/reduced GO surface through a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide coupling strategy, and the morphological and photophysical properties were studied in detail. Synergistic effects of pi-pi interactions between GO and the NI chromophore, and efficient photoinduced electron- and energy-transfer processes, were responsible for the strong quenching of fluorescence of these nanoconjugates, which were perturbed under acidic pH conditions, leading to significant enhancement of fluorescence emission. This nanoconjugate was successfully employed for the efficient sensing of pH changes caused by the enzymatic activity of AChE, thereby demonstrating its utility as a fluorescence turn-on sensor for ACh in the neurophysiological range. PMID- 28621506 TI - Cover Image, Volume 175C, Number 2, June 2017. AB - The cover image, by Louise Pyle and Katherine Nathanson, is based on the Research Review A practical guide for evaluating gonadal germ cell tumor predisposition in differences of sex development, DOI: 10.1002/ajmg.c.31562. PMID- 28621507 TI - Incorporating the joint toxicity of co-applied pesticides into the ecological risk assessment process. AB - Pesticides are frequently formulated as mixtures of active ingredients. Although traditionally ecological risk assessments (ERAs) have focused on individual active ingredients, there is an ongoing effort in many jurisdictions to more formally include assessment of mixtures. The overall goal of this project was to describe an approach for conducting ERA of jointly applied pesticides. We suggest that standard testing of formulation mixtures is not warranted due to the low probability of synergy occurring at a high-enough magnitude to be measurable above experimental variability. Thus, empirical testing should focus on formulations for which there is a greater likelihood of synergy due to known toxicological interactions of the pesticide class or a priori knowledge of synergy, such as intellectual property claims. Additionally, empirical testing should focus on species that are above levels of concern and limit testing on species for which it is unlikely that synergy would significantly change the outcome of the ERA. If empirical testing is warranted, we suggest that results be compared to the concentration addition model (CA). If the empirical data deviates from the model by a factor of greater than 5, then synergy is considered likely and the ERA is based on the empirical data. Otherwise, the ERA may use CA to calculate risk quotients or be based on the most toxic active ingredient. To evaluate the approach, we reviewed formulation mixtures for which data were available. Only 3 of 24 mixture studies were found to deviate from CA by more than 5. The majority of the studies had a single component that dominated toxicity, suggesting that the ERA for these formulations will not be meaningfully different if based on the most toxic active ingredient. Overall, this approach balances risk assessment conservatism and reduces testing that would likely not result in improvement of the ERA. Integr Environ Assess Manag 2018;14:79-91. (c) 2017 SETAC. PMID- 28621508 TI - Avoidance of parasitized host by female wasps of Aphidius gifuensis (Hymenoptera: Braconidae): The role of natal rearing effects and host availability? AB - Natal rearing experience of animals may affect their behaviors, such as habitat selection and oviposition decision. As part of the overall fitness of insect parasitoids, successful host discrimination (distinguishing parasitized hosts from unparasitized hosts) is of paramount importance. In this study we examined whether and how parasitoids' natal rearing experience would affect their host discrimination ability according to host availability. We established separate colonies of Aphidius gifuensis Ashmead by continual rearing on two hosts, Sitobion avenae F. and Myzus persicae (Suzler), and quantified self superparasitism and self superparasitism versus parasitism ratio for the four combinations of parasitoid colonies and host species (S. aveane and M. persicae) at four host densities (30, 50, 100 or 150 per plant). Results showed that self superparasitism of M. persicae by A. gifuensis reared on S. avenae was significantly higher than by those reared on M. persicae, no matter whether the host densities were 30, 50, 100 or 150. Aphidius gifuensis reared on M. persicae significantly superparasitized more S. avenae than those reared on S. aveane only when host density was 30. Self superparasitism versus parasitism ratio of A. gifuensis from both colonies was always lower on natal hosts than on new hosts, and the difference was more pronounced as the host density decreased. These results suggested that natal rearing effects is important on host discrimination and oviposition decision of the parasitoid A. gifuensis. These effects promoted the parasitoid's host adaptation and made them confer greater fitness. PMID- 28621509 TI - The risk of anastomotic leakage after anterior resection: retrospective analysis of 501 rectal cancer patients operated without protective stoma. AB - BACKGROUND: The aim of this study was to verify the accuracy of the existing scoring system for the assessment of anastomotic leakage risk after anterior resection and to identify additional risk factors that were not included in this classification. METHODS: The study included 501 consecutive rectal cancer patients who underwent anterior resection without formation of protective stoma. The risk for anastomotic leakage was determined using a previously proposed scoring system based on three factors: male sex, intraoperative blood loss and level of anastomosis. RESULTS: Symptomatic leakage occurred in 12.2% (61/501) of our patients. Lower level of anastomosis (P<0.001) and longer duration of surgery (P=0.018) were identified as independent risk factors for the leakage. Anastomotic dehiscence occurred in 7.3% (24/327), 20.1% (29/144) and 26.7% (8/30) of patients at low, intermediate and high risk of leakage according to the previously proposed scoring system. No differences were found in the leakage rates of patients from the intermediate and high risk groups (20.1% vs. 26.7%, P=0.427, RR=0.755 (95% CI: 0.384-1.486). CONCLUSIONS: The new scoring system is necessary for the identification of patients at increased risk of anastomotic leakage after anterior resection. PMID- 28621510 TI - Laparoscopic cholecystectomy for acute cholecystitis: an analysis of early versus delayed cholecystectomy and predictive factors for conversion. AB - BACKGROUND: There is an increasing preference for early laparoscopic cholecystectomy (ELC) as compared to delayed LC (DLC) in the management of acute cholecystitis (AC). Conversion to open cholecystectomy (LOC) remains an important outcome. We aim to compare ELC and DLC outcomes and identify LOC predictors. METHODS: Retrospective analysis of 466 patients who underwent LC for AC from June 2010 to June 2015 was performed. Patients were divided into ELC and DLC groups, defined as LC performed within 7 days and between 4 to 24 weeks of symptom onset, respectively. Peri-operative outcomes and predictors for LOC were analyzed. RESULTS: Conversion rates were comparable [ELC, 8.6% vs. DLC, 8.0%] (P=0.867). While median operative time was longer in ELC (101.5 min [83.0-130.1]) than DLC (88.0 min [62.3-118.8]) (P<0.001), intraoperative (ELC, 1.9% vs. DLC, 3.0%; P=0.541) and postoperative morbidity (ELC, 13.5% vs. DLC, 12.5%; P=0.688) was comparable. Median total length of stay (LOS) was shorter in ELC (4 days [3-6]) than DLC (5 days [4-9]) (P<0.001). Univariate analysis showed increased age (LC, 57 [45-66] vs. LOC, 60 [56-72]; P=0.016), presence of comorbidities (LC, 69.0% vs. LOC, 87.8%; P=0.009), previous abdominal surgery (LC, 6.1% vs. LOC, 17.1%; P=0.014), fever (P=0.001), Murphy's sign (P=0.005) and lower albumin (LC, 42.0 [39.0-45.0] vs. LOC, 40.0 [36.0-43.0]; P=0.003) to be predictors for LOC. CONCLUSIONS: ELC provides shorter LOS and eliminates the risk of gallstone related morbidity while awaiting surgery. It should be advocated for patients with AC. The presence of comorbidities, increased age, previous abdominal surgery and low albumin are predictors for conversion. PMID- 28621511 TI - Pregnancy and bariatric surgery. AB - INTRODUCTION: A large number of women experience pregnancy after bariatric surgery. The purpose of this review was to understand the evidence base in this area to come up with practical, evidence-based recommendations. EVIDENCE ACQUISITION: We examined PubMed for all published articles on pregnancy in patients who have previously undergone a bariatric surgery. EVIDENCE SYNTHESIS: There is an increasing body of evidence pointing towards a beneficial effect of weight loss induced by bariatric surgery on female and male fertility prompting calls for recognition of infertility as a qualifying co-morbidity for patients between the Body Mass Index of 35.0 kg/m2 and 40.0 kg/m2. Women in childbearing age group should be routinely offered contraceptive advice after bariatric surgery and advised to avoid pregnancy until their weight has stabilized. Until more focused studies are available, the advice to wait for 12 months or 2 months after the weight loss has stabilized, whichever is latter, seems reasonable. Patients should be advised to seek clearance from their bariatric teams prior to conception and looked after by a multi-disciplinary team of women health professionals, bariatric surgeons, and dietitians during pregnancy. The main objective of care is to ensure adequate nutritional state to allow for a satisfactory weight gain and fetal growth. CONCLUSIONS: There is a relative lack of studies and complete lack of Level 1 evidence to inform practice in this area. This review summarizes current literature and makes a number of practical suggestions for routine care of these women while we develop evidence to better inform future practice. PMID- 28621512 TI - Endovascular redo aortic surgery. AB - Endovascular redo aortic operations are a challenging undertaking. Techniques for treatment date almost as far back as the original open repair itself. Risk factors for failure following aortic repair include larger abdominal aortic aneurysm necks, severe neck angulation, as well as clinical variables such as age, family history, obesity and chronic obstructive pulmonary disease. The armamentarium of endovascular treatments is vast and increasing. Aside from provisional embolization of endoleaks or deferment to open repair conversion, attention should be directed toward obtaining adequate proximal and distal sealing. This can be achieved with Palmaz stents, endoanchors, and extension with fenestrated or branched endovascular repair. Thoracic aortic coverage may be required, and revascularization of the left subclavian artery should be considered. Technical issues such as these, as well as target vessel cannulation and accommodation of the new graft within the previous implanted graft, require experience and careful planning. Distal extension can likewise resolve a failing repair, and this may require the use of internal iliac artery embolization or iliac-branch devices. Redo aortic operations are technically demanding and are carried out with increased risks. Improving technology, such as fusion imaging, should mitigate some of this risk and are recommended. PMID- 28621513 TI - Topological Insulator Bi2Se3/Si-Nanowire-Based p-n Junction Diode for High Performance Near-Infrared Photodetector. AB - Chemically derived topological insulator Bi2Se3 nanoflake/Si nanowire (SiNWs) heterojunctions were fabricated employing all eco-friendly cost-effective chemical route for the first time. X-ray diffraction studies confirmed proper phase formation of Bi2Se3 nanoflakes. The morphological features of the individual components and time-evolved hybrid structures were studied using field emission scanning electron microscope. High resolution transmission electron microscopic studies were performed to investigate the actual nature of junction whereas elemental distributions at junction, along with overall stoichiometry of the samples were analyzed using energy dispersive X-ray studies. Temperature dependent current-voltage characteristics and variation of barrier height and ideality factor was studied between 50 and 300 K. An increase in barrier height and decrease in the ideality factor were observed with increasing temperature for the sample. The rectification ratio (I+/I-) for SiNWs substrate over pristine Si substrate under dark and near-infrared (NIR) irradiation of 890 nm was found to be 3.63 and 10.44, respectively. Furthermore, opto-electrical characterizations were performed for different light power intensities and highest photo responsivity and detectivity were determined to be 934.1 A/W and 2.30 * 1013 Jones, respectively. Those values are appreciably higher than previous reports for topological insulator based devices. Thus, this work establishes a hybrid system based on topological insulator Bi2Se3 nanoflake and Si nanowire as the newest efficient candidate for advanced optoelectronic materials. PMID- 28621514 TI - In Vitro and in Vivo Analysis of Mineralized Collagen-Based Sponges Prepared by a Plasma- and Precursor-Assisted Biomimetic Process. AB - Three-dimensional (3D) porous scaffolds for supporting cell adhesion and growth play a vital role in tissue engineering applications. In the present study, three different collagen-based 3D sponges were functionalized by apatite coating. The sponges were coated with apatite on their outer and inner surfaces while retaining their interconnecting pores. To achieve this, we employed a vacuum degassing system in our plasma- and precursor-assisted biomimetic process using a supersaturated calcium phosphate solution. The resulting apatite-coated sponges (mineralized sponges) showed better cell adhesion properties in vitro for osteoblast-like MC3T3-E1 cells compared to that of uncoated sponges. The three mineralized sponges were implanted in the subcutaneous tissue of rats. Upon histological evaluation after 10 days, the mineralized sponges showed cell in growth rates that were approximately 4-fold greater than those of the untreated sponges without any notable inflammatory reactions. As these sponges are composed of clinically approved collagen-based frameworks and possess a 3D porous structure with a mineralized surface appropriate for cell adhesion and internalization, further in vitro and in vivo studies should be conducted regarding tissue engineering applications. PMID- 28621515 TI - On-Demand Capture and Release of Organic Droplets Using Surfactant-Doped Polypyrrole Surfaces. AB - In this paper, we demonstrate the controlled capture and release of dichloromethane (DCM) droplets on dodecylbenzenesulfonate-doped polypyrrole (PPy(DBS)) surfaces in an aqueous environment. The droplets captured on oxidized PPy(DBS) surfaces were released on-demand via a reduction process at ~0.9 V, with controlled release time and droplet morphology. The release time of an entire droplet (2 +/- 1 MUL) was proportional to the thickness of the PPy(DBS) coating, increasing from 11.5 to 26.3 s for thicknesses ranging from 0.6 to 5.1 MUm. The droplet-release time was also affected by the redox voltages, and among the tested redox voltages, the fastest release was achieved at -0.9/0.1 V. The PPy(DBS) surfaces with larger thicknesses were more durable for the droplet capture and release. The droplets were more rapidly released from PPy(DBS) surfaces with increased surface roughness ratios, such as 6.0 s on a micropillared surface and 10.3 s on a meshed surface, as compared to 14.6 s on the 1.8 MUm thick PPy(DBS) surfaces coated on frosted-glass substrates (i.e., with random microstructures). The release of a single droplet was achieved by increasing the underwater oleophobicity of PPy(DBS) surface via O2 plasma treatment. PMID- 28621516 TI - Proton Conductivity of Proton Exchange Membrane Synergistically Promoted by Different Functionalized Metal-Organic Frameworks. AB - In this study, two functionalized metal-organic frameworks (MOFs), UiO-66-SO3H and UiO-66-NH2, were synthesized. Then, different composite proton exchange membranes (PEMs) were prepared by single doping and codoping of these two MOFs, respectively. It was found that codoping of these two MOFs with suitable sizes was more conducive to the proton conductivity enhancement of the composite PEM. A synergistic effect between these two MOFs led to the the formation of more consecutive hydration channels in the composite PEM. It further greatly promoted the proton conductivity of the composite PEM. The proton conductivity of the codoped PEM reached up to 0.256 S/cm under 90 degrees C, 95% RH, which was ~1.17 times higher than that of the recast Nafion (0.118 S/cm). Besides, the methanol permeability of the codoped PEM was prominently decreased owing to the methanol trapping effect of the pores of these two MOFs. Meanwhile, the high water and thermal stabilities of these two MOFs were beneficial to the high proton conductivity stability of the codoped PEM under high humidity and high temperature. The proton conductivity of the codoped PEM was almost unchanged throughout 3000 min of testing under 90 degrees C, 95% RH. This work provides a valuable reference for designing different functionalized MOFs to synergistically promote the proton conductivities of PEMs. PMID- 28621517 TI - Simultaneous Measurements of Mass and Collisional Cross-Section of Single Ions with Charge Detection Mass Spectrometry. AB - The masses and mobilities of single multiply charged ions of cytochrome c, ubiquitin, myoglobin, and bovine serum albumin formed by electrospray ionization are measured using charge detection mass spectrometry (CDMS). Single ions are trapped and repeatedly measured as they oscillate inside an electrostatic ion trap with cone electrodes for up to the maximum trapping time set at 500 ms. The histograms of the many single ion oscillation frequencies have resolved peaks that correspond to the different charge states of each protein. The m/z of each ion is determined from the initial oscillation frequency histogram, and the evolution of the ion energy with time is obtained from the changing frequency. A short-time Fourier transform of the time-domain data indicates that the increase in ion frequency occurs gradually with time with occasional sudden jumps in frequency. The frequency jumps are similar for each protein and may be caused by collision-induced changes in the ion trajectory. The rate of the gradual frequency shift increases with protein mass and charge state. This gradual frequency change is due to ion energy loss from collisions with the background gas. The total energy lost by an ion is determined from the latter frequency shifts normalized to a 500 ms lifetime, and these values increase nearly linearly with measured collisional cross-sections for these protein ions. These results show that the mass and collisional cross-section of single multiply charged ions can be obtained from these CDMS measurements by using proteins with known collisional cross-sections for calibration. PMID- 28621518 TI - Photoelectrochemical Bioanalysis Platform for Cells Monitoring Based on Dual Signal Amplification Using in Situ Generation of Electron Acceptor Coupled with Heterojunction. AB - By using in situ generation of electron acceptor coupled with heterojunction as dual signal amplification, a simple photoelectrochemical (PEC) bioanalysis platform was designed. The synergic effect between the photoelectrochemical (PEC) activities of carbon nitride (C3N4) nanosheets and PbS quantum dots (QDs) achieved almost nine-fold photocurrent intensity increment compared with the C3N4 alone. After the G-quadruplex/hemin/Pt nanoparticles (NPs) with catalase-like activity toward H2O2 were introduced, oxygen was in situ generated and acted as electron donor by improving charge separation efficiency and further enhancing photocurrent response. The dually amplified signal made enough sensitivity for monitoring H2O2 released from live cells. The photocathode was prepared by the stepwise assembly of C3N4 nanosheets and PbS QDs on indium tin oxide (ITO) electrode, which was characterized by scanning electron microscope. A signal-on protocol was achieved for H2O2 detection in vitro due to the relevance of photocurrent on the concentration of H2O2. Under the optimized condition, the fabricated PEC bioanalysis platform exhibited a linear range of 10-7000 MUM with a detection limit of 1.05 MUM at S/N of 3. Besides, the bioanalysis platform displayed good selectivity against other reductive biological species. By using HepG2 cells as a model, a dual signal amplifying PEC bioanalysis platform for monitoring cells was developed. The bioanalysis platform was successfully applied to the detection of H2O2 release from live cells, which provided a novel method for cells monitoring and would have prospect in clinical assay. PMID- 28621519 TI - Mildred S. Dresselhaus (1930-2017): A Pinnacle of Scholarship. PMID- 28621520 TI - Homogeneously Sensitive Detection of Multiple DNA Glycosylases with Intrinsically Fluorescent Nucleotides. AB - DNA glycosylases are responsible for recognition and excision of the damaged bases in the base excision repair pathway, and all mammals express multiple DNA glycosylases to maintain genome stability. However, simultaneous detection of multiple DNA glycosylase still remains a great challenge. Here, we develop a rapid and sensitive fluorescent method for simultaneous detection of human 8-oxoG DNA glycosylase 1 (hOGG1) and uracil DNA glycolase (UDG) using exonuclease assisted recycling signal amplification in combination with fluorescent bases 2 aminopurine (2-AP) and pyrrolo-dC (P-dC) as the fluorophores. We design a bifunctional DNA probe modified with one 8-oxoG and five uracil bases, which can hybridize with the trigger probes to form a sandwiched DNA substrate for hOGG1 and UDG. In addition, we design 2-AP and P-dC signal probes as the hairpin structures with 2-AP and P-dC in the stems. The presence of hOGG1 and UDG may initiate the signal amplification process by the recycling lambda exonuclease digestion and generates distinct fluorescence signals, with 2-AP indicating the presence of hOGG1 and P-dC indicating the presence of UDG. This method can simultaneously detect multiple DNA glycosylases with the detection limits of 0.0035 U/mL for hOGG1 and 0.0025 U/mL for UDG, and it can even measure DNA glycosylases at the single-cell level. Moreover, this method can be applied for the measurement of enzyme kinetic parameters and the screening of DNA glycosylase inhibitors, holding great potential for further applications in biomedical research and clinical diagnosis. PMID- 28621521 TI - In Situ Live-Cell Nucleus Fluorescence Labeling with Bioinspired Fluorescent Probes. AB - Fluorescent imaging techniques for visualization of nuclear structure and function in live cells are fundamentally important for exploring major cellular events. The ideal cellular labeling method is capable of realizing label-free, in situ, real-time, and long-term nucleus labeling in live cells, which can fully obtain the nucleus-relative information and effectively alleviate negative effects of alien probes on cellular metabolism. However, current established fluorescent probes-based strategies (e.g., fluorescent proteins-, organic dyes-, fluorescent organic/inorganic nanoparticles-based imaging techniques) are unable to simultaneously realize label-free, in situ, long-term, and real-time nucleus labeling, resulting in inevitable difficulties in fully visualizing nuclear structure and function in live cells. To this end, we present a type of bioinspired fluorescent probes, which are highly efficacious for in situ and label-free tracking of nucleus in long-term and real-time manners. Typically, the bioinspired polydopamine (PDA) nanoparticles, served as fluorescent probes, can be readily synthesized in situ within live cell nucleus without any further modifications under physiological conditions (37 degrees C, pH ~7.4). Compared with other conventional nuclear dyes (e.g., propidium iodide (PI), Hoechst), superior spectroscopic properties (e.g., quantum yield of ~35.8% and high photostability) and low cytotoxicity of PDA-based probes enable long-term (e.g., 3 h) fluorescence tracking of nucleus. We also demonstrate the generality of this type of bioinspired fluorescent probes in different cell lines and complex biological samples. PMID- 28621523 TI - Mussel-Inspired Hyaluronic Acid Derivative Nanostructures for Improved Tumor Targeting and Penetration. AB - An amphiphilic hyaluronic acid-ceramide-dopamine (HACE-d) conjugate was prepared, and HACE-d-based nanoparticles (NPs) including phloretin (as an inhibitor of glucose transporter (GLUT1)) were fabricated. Mussel-inspired property of d was introduced to HACE NPs, and it may improve tumor targetability and penetration in addition to passive (based on enhanced permeability and retention effect) and active (interaction between HA and CD44 receptor) tumor targeting effects. HACE d/phloretin NPs with 279 nm mean diameter, ~0.2 polydispersity index, and -18 mV zeta potential were successfully fabricated, and a sustained drug release pattern was observed. HACE-d/phloretin NPs exhibited enhanced cellular accumulation efficiency and antiproliferation property, compared with HACE/phloretin NPs, in MDA-MB-231 cells (GLUT1 and CD44 receptor-expressed human breast adenocarcinoma cells). In a MDA-MB-231 spheroid model, HACE-d NPs group showed better tumor penetration efficiency and spheroid growth inhibitory effect rather than HACE NPs group. According to the optical imaging test in MDA-MB-231 tumor-xenografted mouse, HACE-d NPs group exhibited more selective distribution in tumor region and deeper infiltration into the inner part of tumor compared with HACE NPs group. After intravenous injection, HACE-d/phloretin NPs group also exhibited improved antitumor efficacies rather than the other experimental groups in MDA-MB-231 tumor-xenografted mouse. All these findings suggested that HACE-d/phloretin NP may be a promising tumor targetable and penetrable nanosystem for the therapy and imaging of GLUT1 and CD44 receptor-expressed cancers. PMID- 28621522 TI - Formation and Structure of Wild Type Huntingtin Exon-1 Fibrils. AB - The fact that the heritable neurodegenerative disorder Huntington's disease (HD) is autosomal dominant means that there is one wild type and one mutant allele in most HD patients. The CAG repeat expansion in the exon 1 of the protein huntingtin (HTTex1) that causes the disease leads to the formation of HTT fibrils in vitro and vivo. An important question for understanding the molecular mechanism of HD is which role wild type HTT plays for the formation, propagation, and structure of these HTT fibrils. Here we report that fibrils of mutant HTTex1 are able to seed the aggregation of wild type HTTex1 into amyloid fibrils, which in turn can seed the fibril formation of mutant HTTex1. Solid-state NMR and electron paramagnetic resonance data showed that wild type HTTex1 fibrils closely resemble the structure of mutant fibrils, with small differences indicating a less extended fibril core. These data suggest that wild type fibrils can faithfully perpetuate the structure of mutant fibrils in HD. However, wild type HTTex1 monomers have a much higher equilibrium solubility compared to mutant HTTex1, and only a small fraction incorporates into fibrils. PMID- 28621524 TI - Harnessing the Power of Nanotechnology for Enhanced Radiation Therapy. AB - Radiotherapy has emerged as one of the first lines of treatment in oncology. The past few decades have seen dramatic changes in the delivery of radiation therapy, with dose fractionation and treatment planning being the major focuses of research. Although effective, such empirical approaches are hardly optimal, and instances of patient mortality and tumor relapse are not rare. In this Perspective, we review the emerging technologies for optimization of radiosensitization, hypoxia modulation, and combinatorial therapeutic regimes for improved treatment outcomes in preclinical tumor models, with a focus on nanotechnology-mediated approaches. Such an approach is expected to open more productive avenues in the advancement of radiation therapy compared to simply modulating the radiation dose delivered to the tumor. PMID- 28621525 TI - Correction to Bond Fission and Non-Radiative Decay in Iridium(III) Complexes. PMID- 28621526 TI - Orthogonal Mass Spectrometry-Based Footprinting for Epitope Mapping and Structural Characterization: The IL-6 Receptor upon Binding of Protein Therapeutics. AB - Higher-order structure (HOS) is a crucial determinant for the biological functions and quality attributes of protein therapeutics. Mass spectrometry (MS) based protein footprinting approaches play an important role in elucidating the relationship between protein biophysical properties and structure. Here, we describe the use of a combined method including hydrogen-deuterium exchange (HDX), fast photochemical oxidation of proteins (FPOP), and site-specific carboxyl group footprinting to investigate the HOS of protein and protein complexes. The work focuses on implementing complementary solution-phase footprinting approaches that differ in time scale, specificity for protein residue side chains vs backbone as well as selectivity for different residue types to map integratively the epitope of human interleukin-6 receptor (IL-6R) for two adnectins with distinct affinities (Kd, Adnectin1 ~ 6.2 pM vs Kd, Adnectin2 ~ 46 nM). Furthermore, the study evaluates the resultant conformation/dynamic change of IL-6R. The suggested epitope, which is conserved for adnectin1 and adnectin2 binding, is a flexible loop that connects two beta strands in the cytokine-binding domain (DII) of IL-6R. We also found that adnectin1, the more strongly binding ligand, induces structural perturbations on two unstructured loops that are distally located beyond the epitope. Those changes are either attenuated or not detected for the case of adnectin2 binding. In addition to providing credibility in epitope determination, utilization of those combined approaches reveals the structural effects that can differentiate protein therapeutics with apparently similar biophysical properties. PMID- 28621527 TI - Dielectrophoretic-Assembled Single and Parallel-Aligned Ag Nanowire-ZnO-Branched Nanorod Heteronanowire Ultraviolet Photodetectors. AB - The branched hierarchical heteronanowires have been widely studied for optoelectronics application because of their unique electronic and photonic performances. Here, we successfully synthesized Ag nanowire-ZnO-branched nanorod heteronanowires based on an improved hydrothermal method. Then we fabricated single heteronanowire across a Au electrode pair with different gap widths and parallel-aligned heteronanowires on a Au interdigitated electrode with a dielectrophoresis method, indicating the flexibility and operability of the dielectrophoresis assembly method. Increased photocurrent and shortened response time could be obtained by air-annealing and Ar-plasma post-treatments. A large responsivity of 2.5 A W-1 and a linear dynamic range of 74 dB could be obtained, indicating stable responsivity for both weak and strong illumination. The excellent photoresponse performance is attributed to the structure superiority of heteronanowires. The proposed strategy of dielectrophoresis-assembled heteronanowires provides a new opportunity to design and fabricate hierarchical nanostructure photodetectors. PMID- 28621529 TI - Domino Direct Arylation and Cross-Aldol for Rapid Construction of Extended Polycyclic pi-Scaffolds. AB - Five-membered aromatic heterocycles are a ubiquitous skeleton of pi-conjugated organic compounds, and their incorporation requires synthetic protocols that are not easily industrially sustainable or scalable. Improved methodologies for their insertion into pi-scaffolds are therefore necessary. We report an efficient and scalable protocol involving a one-pot cross-Aldol direct arylation reaction protocol for the rapid construction of thiophene- and furan-based pi-extended organic materials. PMID- 28621528 TI - Unsupervised Discovery and Comparison of Structural Families Across Multiple Samples in Untargeted Metabolomics. AB - In untargeted metabolomics approaches, the inability to structurally annotate relevant features and map them to biochemical pathways is hampering the full exploitation of many metabolomics experiments. Furthermore, variable metabolic content across samples result in sparse feature matrices that are statistically hard to handle. Here, we introduce MS2LDA+ that tackles both above-mentioned problems. Previously, we presented MS2LDA, which extracts biochemically relevant molecular substructures ("Mass2Motifs") from a collection of fragmentation spectra as sets of co-occurring molecular fragments and neutral losses, thereby recognizing building blocks of metabolomics. Here, we extend MS2LDA to handle multiple metabolomics experiments in one analysis, resulting in MS2LDA+. By linking Mass2Motifs across samples, we expose the variability in prevalence of structurally related metabolite families. We validate the differential prevalence of substructures between two distinct samples groups and apply it to fecal samples. Subsequently, within one sample group of urines, we rank the Mass2Motifs based on their variance to assess whether xenobiotic-derived substructures are among the most-variant Mass2Motifs. Indeed, we could ascribe 22 out of the 30 most-variant Mass2Motifs to xenobiotic-derived substructures including paracetamol/acetaminophen mercapturate and dimethylpyrogallol. In total, we structurally characterized 101 Mass2Motifs with biochemically or chemically relevant substructures. Finally, we combined the discovered metabolite families with full scan feature intensity information to obtain insight into core metabolites present in most samples and rare metabolites present in small subsets now linked through their common substructures. We conclude that by biochemical grouping of metabolites across samples MS2LDA+ aids in structural annotation of metabolites and guides prioritization of analysis by using Mass2Motif prevalence. PMID- 28621530 TI - Tailoring the Oxygen Reduction Activity of Hemoglobin through Immobilization within Microporous Organic Polymer-Graphene Composite. AB - A facile one-pot, bottom-up approach to construct composite materials of graphene and a pyrimidine-based porous-organic polymer (PyPOP), as host for immobilizing human hemoglobin (Hb) biofunctional molecules, is reported. The graphene was selected because of its excellent electrical conductivity, while the PyPOP was utilized because of its pronounced permanent microporosity and chemical functionality. This approach enabled enclathration of the hemoglobin within the microporous composite through a ship-in-a-bottle process, where the composite of the PyPOP@G was constructed from its molecular precursors, under mild reaction conditions. The composite-enclathrated Fe-protoporphyrin-IX demonstrated electrocatalytic activity toward oxygen reduction, as a functional metallocomplex, yet with a distinct microenvironment provided by the globin protein. This approach delineates a pathway for platform microporous functional solids, where fine-tuning of functionality is facilitated by judicious choice of the active host molecules or complexes, targeting specific application. PMID- 28621531 TI - Parallels and Distinctions in FGFR, VEGFR, and EGFR Mechanisms of Transmembrane Signaling. AB - Receptor tyrosine kinase (RTK) signal transduction is essential in human skeletal, nervous, and vascular development, in homeostasis, and in disease. RTKs are activated by dimerization in the plasma membrane. The mechanisms of receptor dimerization and activation are multifaceted and complex, and unraveling them remains challenging. Most studies of RTKs have been devoted to crystallographic analysis of their isolated extracellular domain and biochemical analysis of the catalytic domain. However, the past few years have seen direct biophysical studies of (intact) RTK dimerization in native membranes lead to significant progress in our fundamental understanding of the mechanisms of their signal transduction across the plasma membrane. This perspective focuses on recent insights into the mechanisms of fibroblast growth factor receptor and vascular endothelial growth factor receptor transmembrane signaling, derived from studies of wild-type and mutant RTKs in a number of environments, including plasma membrane-derived vesicles. These insights reveal distinct steps in and factors of RTK signaling across the plasma membrane that can guide the drug discovery process for RTK targeting therapeutics. PMID- 28621532 TI - Synthesis of Luminescent Platinum(II) 2,6-Bis(N-dodecylbenzimidazol-2' yl)pyridine Foldamers and Their Supramolecular Assembly and Metallogel Formation. AB - Dinuclear alkynylplatinum(II) metallofoldamers with an oligomeric m phenyleneethynylene backbone have been designed with the incorporation of a sterically undemanding, pi-conjugated, and hydrophobic 2,6-bis(N dodecylbenzimidazol-2'-yl)pyridine pincer ligand. The complex with the optimal chain length has been found to exhibit gelation behavior via stabilization by noncovalent Pt...Pt and pi-pi stacking interactions in the hierarchical architecture constructed from the single-turn helix. The chain lengths of the complexes have been found to be a critical determinant for their gelation behavior, conformations, and morphologies. Such a gelation process has been found to undergo a cooperative assembly mechanism according to the nucleation elongation model. Their self-assembly via the Pt...Pt and pi-pi stacking interactions has been studied by 1H NMR, 2D ROESY NMR (ROESY = rotating-frame Overhauser spectroscopy), electronic absorption, and emission spectroscopy, and density functional theory calculations have provided further insights into the folded state geometry of this class of metallofoldamers. PMID- 28621533 TI - Regioselective Rh-Catalyzed Hydroformylation of 1,1,3-Trisubstituted Allenes Using BisDiazaPhos Ligand. AB - The efficient hydroformylation of 1,1,3-trisubstituted allenes is accomplished with low loadings of a Rh catalyst supported by a BisDiazaPhos (BDP) ligand. The ligand identity is key to achieving high regioselectivity, while the mild reaction conditions minimize competing isomerization and hydrogenation to produce beta,gamma-unsaturated aldehydes and their derivatives in excellent yields. PMID- 28621534 TI - Construction of an Immunized Rabbit Phage Display Library for Selecting High Activity against Bacillus thuringiensis Cry1F Toxin Single-Chain Antibodies. AB - In the present study, a Cry1F-immunized rabbit phage display library (6.96 * 108 cfu/mL) was constructed for selecting high activity of anti-Cry1F toxin single chain antibody (a single-chain variable fragment, scFv) by biopanning. A total of 16 positive monoclonal phage scFv's were obtained after 4 rounds of panning, which were identified by enzyme-linked immunosorbent assay (ELISA), polymerized chain reaction, and DNA sequencing. The most positive phage scFv (named RF4) was expressed in Escherichia coli HB2151, and a soluble protein of approximately 30 kDa was purified with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. An indirect competitive ELISA (IC-ELISA) was established on the basis of purified soluble RF4-scFv for Cry1F toxin. It indicated the 50% inhibition of the control (IC50) was 11.56 ng/mL and the detection limit (IC10) was 0.18 ng/mL and showed weak cross-reactivities for Cry1Ab (2.8%), Cry1Ac (1.3%), and Cry1B, Cry1C, Cry1Ie, and Cry2A (less than 0.1%). It was found that IC-ELISA detected Cry1F toxin spiked in rice, wheat, corn, and soil samples with good accuracy, stability, and repeatability. The recoveries were in the range of 80.2-99.6%, and the coefficients of variation were in the range of 2.5-10.0%. These results showed that IC-ELISA based on scFv from the immunized rabbit phage display library was promising for specific detection of Cry1F toxin in agroproducts and environmental samples. PMID- 28621535 TI - Effects of Frothers and Oil at Saltwater-Air Interfaces for Oil Separation: Molecular Dynamics Simulations and Experimental Measurements. AB - Separating oil from saltwater is a process relevant to some industries and may be aided by bubble and froth generation. Simulating saltwater-air interfaces adsorbed with surfactants and oil molecules can assist in understanding froth stability to improve separation. Combining with surface tension experimental measurements, in this work we employ molecular dynamics with a united-atom force field to linear alkane oil and three surfactant frothers, methyl isobutyl carbinol (MIBC), terpineol, and ethyl glycol butyl ether (EGBE), to investigate their synergistic behaviors for oil separation. The interfacial phenomena were measured for a range of frother surface coverages on saltwater. Density profiles of the hydrophilic and hydrophobic portions of the frothers show an expected orientation of alcohol groups adsorbing to the polar water. A decrease in surface tension with increasing surface coverage of MIBC and terpineol was observed and reflected in experiments where the frother concentration increased. Relations between surface coverage and bulk concentration were observed by comparing the surface tension decreases. Additionally, a range of oil surface coverages was explored when the interface has a thin layer of adsorbed frother molecules. The obtained results indicate that an increase in surface coverage of oil molecules led to an increase in surface tension for all frother types and the pair correlation functions depicted MIBC and terpineol as having higher distributions with water at closer distances than with oil. PMID- 28621536 TI - Substituent Effect on the sigma- and pi-Electron Structure of the Nitro Group and the Ring in Meta- and Para-Substituted Nitrobenzenes. AB - An application of quantum chemical modeling allowed us to investigate a substituent effect on a sigma and pi electron structure of a ring and the nitro group in a series of meta- and para-X-substituted nitrobenzene derivatives (X = NMe2, NHMe, NH2, OH, OMe, Me, H, F, Cl, CF3, CN, CHO, COMe, CONH2, COOH, NO2, and NO). The obtained pEDA and sEDA parameters (the pi- and sigma-electron structure characteristics of a given planar fragment of the system obtained by the summation of pi- and sigma-orbital occupancies, respectively) of the NO2 group and the benzene ring allowed us to reveal the impact of the substituents on their mutual relations as well as to analyze them from the viewpoint of substituent characteristics. The decisive factor for dependence of pEDA on sEDA of the ring is electronegativity of the atom linking the substituent with the ring; in subgroups an increase of sEDA is associated with a decrease of pEDA. The obtained mutual relation between pEDA(NO2) and pEDA(ring) characteristics documents strong resonance interactions for electron-donating substituents in the para position. The observed substituent effect on the sigma-electron structure of the nitro group, sEDA(NO2), is significantly greater (~1.6 times) for meta derivatives than for the para ones. PMID- 28621537 TI - Electrochemical Deposition of Conformal and Functional Layers on High Aspect Ratio Silicon Micro/Nanowires. AB - Development of new synthetic methods for the modification of nanostructures has accelerated materials design advances to furnish complex architectures. Structures based on one-dimensional (1D) silicon (Si) structures synthesized using top-down and bottom-up methods are especially prominent for diverse applications in chemistry, physics, and medicine. Yet further elaboration of these structures with distinct metal-based and polymeric materials, which could open up new opportunities, has been difficult. We present a general electrochemical method for the deposition of conformal layers of various materials onto high aspect ratio Si micro- and nanowire arrays. The electrochemical deposition of a library of coaxial layers comprising metals, metal oxides, and organic/inorganic semiconductors demonstrate the materials generality of the synthesis technique. Depositions may be performed on wire arrays with varying diameter (70 nm to 4 MUm), pitch (5 MU to 15 MU), aspect ratio (4:1 to 75:1), shape (cylindrical, conical, hourglass), resistivity (0.001 0.01 to 1-10 ohm/cm2), and substrate orientation. Anisotropic physical etching of wires with one or more coaxial shells yields 1D structures with exposed tips that can be further site-specifically modified by an electrochemical deposition approach. The electrochemical deposition methodology described herein features a wafer-scale synthesis platform for the preparation of multifunctional nanoscale devices based on a 1D Si substrate. PMID- 28621539 TI - Dual Role of H2O2 in Palladium-Catalyzed Dioxygenation of Terminal Alkenes. AB - A palladium-catalyzed, environmentally friendly dioxygenation reaction of simple alkenes has been developed that enabled rapid assembly of valuable alpha-hydroxy ketones with high atom economy. Notably, control experiments and 18O isotope labeling experiments established that H2O2 played a dominant dual role in this transformation. PMID- 28621538 TI - Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo. AB - The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD. PMID- 28621540 TI - Accurate Prediction of the Hydration Free Energies of 20 Salts through Adaptive Force Matching and the Proper Comparison with Experimental References. AB - Simple pairwise potentials for five alkali ions and four halide ions were developed by only fitting to ab initio MP2 forces with the adaptive force matching (AFM) method. Without fitting to any experimental information, the AFM models predict the hydration free energies of all 10 fluoride and chloride salts formed by these ions within 1.5% of experimental references. The predicted hydration free energies for the 10 bromide and iodide salts are within 5-6% of experimental references with the larger error likely due to the neglect of explicit treatment of polarization and charge transfer. An inconsistency in the treatment of the gas phase entropy term between experimental and theoretical approaches is discussed. A new simplified hydration free energy for the ions is reported for use as a more appropriate experimental reference for further theoretical studies. The simulations show different dipole alignments for the hydration waters of cations and anions. While hydration waters of small cations tend to align their molecular dipole toward the ion, the dipole of one of the water OH bonds is aligned with the field of an anion. PMID- 28621541 TI - Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes. AB - There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins. Here, we report that aziridines and stabilized diazo groups preferentially react with free carboxylates over thiols. Although we did not identify a warhead that potently labels K-Ras G12D, we were able to study the interactions of many electrophiles with K-Ras, as most of the electrophiles rapidly label K-Ras G12C. We characterized the resulting complexes by crystallography, hydrogen/deuterium exchange, and differential scanning fluorimetry. Our results both demonstrate the ability of a noncatalytic cysteine to react with a diverse set of electrophiles and emphasize the importance of proper spatial arrangements between a covalent inhibitor and its intended nucleophile. We hope that these results can expand the range of electrophiles and nucleophiles of use in covalent protein modulation. PMID- 28621542 TI - Bonding Properties of Aluminum Nitride at High Pressure. AB - Exploring the bonding properties and polymerization mechanism of stable polymeric nitrogen phases is the main goal of our high-pressure study. The pressure versus composition phase diagram of the Al-N system is established. In addition to the known Fm3m phase of AlN, a notable monoclinic phase with N66- anion polymeric nitrogen chains for AlN3 in the pressure range from 43 to 85 GPa is predicted. Its energy density is up to 2.75 kJ.g-1, and the weight ratio of nitrogen is nearly 61%, which make it potentially interesting for the industrial applications as a high energy density material. The high-pressure studies of atomic and electronic structures in this predicted phase reveal that the formation of N66- anion is driven by the sp2 hybridization of nitrogen atoms. The resonance effect between alternating pi-bonds and sigma-bonds in polymeric nitrogen chains are all responsible for the structural stability. Because of the electrons transfer from aluminums to polymeric nitrogen chains, there is a pseudogap in the electronic structures of AlN3. The N_p electrons form pi-type chemical bonds with the neighboring atoms, resulting in the delocalization of pi electrons and charge transfer in polymeric nitrogen chains. Furthermore, disparities of charge density distribution between nitrogen atoms in polymeric nitrogen chains are the principal reason for the metallicity. PMID- 28621544 TI - Interrogating Charge Storage on Redox Active Colloids via Combined Raman Spectroscopy and Scanning Electrochemical Microscopy. AB - Redox active colloids (RACs) are dispersible, cross-linked polymeric materials that incorporate a high concentration of redox-active motifs, making them attractive for next-generation size-exclusion redox flow batteries. In order to tap into their full potential for energy storage, it is essential to understand their internal charge mobility, capacity, and cyclability. Here we focus on using a combined suite of Raman spectroscopy and scanning electrochemical microscopy (SECM) tools for evaluating three important parameters that govern charge storage in viologen-RACs: their intraparticle redox active concentration, their reduction/oxidation mechanism, and their charge transfer rate. We addressed RACs using SECM imaging and single-particle experiments, from which the intraparticle diffusion and concentration parameters were elucidated. By using Raman spectroscopy coupled to surface interrogation SECM, we further evaluated their reversible redox properties within monolayer films of 80- and 135-nm-sized RACs. Most notably we have confirmed that the concentration and redox mechanisms are essentially unchanged when varying the RAC size. As expected, we see that larger particles inherently require longer times for electrolysis independent of the methodology used for their study. Our simulations further verify the internal concentration of RACs and suggest that their porosity enables solution redox active mediators to penetrate and titrate charge in their interior. The combined methodology presented here sets an important analytical precedent in decoupling the charge storage properties of new bulk materials for polymer batteries starting from probing low-dimensional assemblies and single particles using nano- and spectroelectrochemical approaches. PMID- 28621545 TI - Rh(III)-Catalyzed Carboamination of Propargyl Cycloalkanols with Arylamines via Csp2-H/Csp3-Csp3 Activation. AB - A Rh(III)-catalyzed carboamination of alkynyl cycloalkanols with arylamines has been developed. This transformation involves a novel Csp2-H/Csp3-Csp3 activation relay and provides an efficient approach to versatile 1,2,3-trisubstituted indoles with a broad range of functional group tolerance. PMID- 28621543 TI - Estimating Particulate Exposure from Modern Municipal Waste Incinerators in Great Britain. AB - Municipal Waste Incineration (MWI) is regulated through the European Union Directive on Industrial Emissions (IED), but there is ongoing public concern regarding potential hazards to health. Using dispersion modeling, we estimated spatial variability in PM10 concentrations arising from MWIs at postcodes (average 12 households) within 10 km of MWIs in Great Britain (GB) in 2003-2010. We also investigated change points in PM10 emissions in relation to introduction of EU Waste Incineration Directive (EU-WID) (subsequently transposed into IED) and correlations of PM10 with SO2, NOx, heavy metals, polychlorinated dibenzo-p dioxins/furan (PCDD/F), polycyclic aromatic hydrocarbon (PAH) and polychlorinated biphenyl (PCB) emissions. Yearly average modeled PM10 concentrations were 1.00 * 10-5 to 5.53 * 10-2 MUg m-3, a small contribution to ambient background levels which were typically 6.59-2.68 * 101 MUg m-3, 3-5 orders of magnitude higher. While low, concentration surfaces are likely to represent a spatial proxy of other relevant pollutants. There were statistically significant correlations between PM10 and heavy metal compounds (other heavy metals (r = 0.43, p = <0.001)), PAHs (r = 0.20, p = 0.050), and PCBs (r = 0.19, p = 0.022). No clear change points were detected following EU-WID implementation, possibly as incinerators were operating to EU-WID standards before the implementation date. Results will be used in an epidemiological analysis examining potential associations between MWIs and health outcomes. PMID- 28621546 TI - Application of a novel phyco-composite biosorbent for the biotreatment of aqueous medium polluted with manganese ions. AB - A composite phyco-biomass including four different marine macroalgae species (Chaetomorpha sp., Polysiphonia sp., Ulva sp., and Cystoseira sp.) was evaluated as a novel biosorbent for the biosorption of manganese ions from aqueous solution. The experimental studies were performed to optimize the operational factors including solution pH, biosorbent amount, initial manganese concentration, and reaction time in a batch-mode biosorption system. The removal yield of the biosorbent for manganese ions increased with increasing pH, manganese ion concentration, and reaction time, while it decreased as the biosorbent dose increased. The obtained kinetic data indicated that the removal of manganese ions by the biosorbent was best described by the pseudo-second-order model and the pore diffusion also contributed to the biosorption process. The results of isotherm and thermodynamic studies showed that the Freundlich model represented the biosorption equilibrium data well and this biotreatment system was feasible, spontaneous, and physical. The maximum manganese uptake capacity of used biosorbent was found to be 55.874 mg g-1. Finally, a single-stage batch manganese biosorption system was designed and its kinetic performance was evaluated. All these findings revealed that the prepared composite macroalgae biosorbent has a fairly good potential for the removal of manganese ions from the aqueous medium. PMID- 28621547 TI - Endophytic bacteria enhance remediation of tannery effluent in constructed wetlands vegetated with Leptochloa fusca. AB - The use of constructed wetlands (CWs) is a promising approach for the remediation of wastewater. The present study aims to develop a plant-bacteria system within CWs for the efficient remediation of tannery effluent. In a vertical-flow CW vegetated with Leptochloa fusca (Kallar grass), a consortium of three different endophytic bacteria, Pantoea stewartii ASI11, Microbacterium arborescens HU33, and Enterobacter sp. HU38, was used for bioaugmentation. CWs vegetated with only L. fusca had the potential to remediate tannery effluent, but augmentation with endophytic bacteria enhanced the growth of L. fusca while aiding in the removal of both organic and inorganic pollutants from the tannery effluent. Moreover, the bacterial augmentation decreased toxicity in the effluent as well. A higher number of chromium (Cr)-resistant bacteria were isolated from the rhizosphere and endosphere of L. fusca inoculated with the endophytes than from uninoculated plants. Due to promising bioremediation and detoxification potential of L. fusca, it is reported for the first time as a potential candidate to develop effective CWs for the remediation of polluted effluents in combination with pollutant degrading endophytic bacteria. PMID- 28621548 TI - An investigation into the mammographic appearances of missed breast cancers when recall rates are reduced. AB - OBJECTIVE: This study investigated whether certain mammographic appearances of breast cancer are missed when radiologists read at lower recall rates. METHODS: 5 radiologists read 1 identical test set of 200 mammographic (180 normal cases and 20 abnormal cases) 3 times and were requested to adhere to 3 different recall rate conditions: free recall, 15% and 10%. The radiologists were asked to mark the locations of suspicious lesions and provide a confidence rating for each decision. An independent expert radiologist identified the various types of cancers in the test set, including the presence of calcifications and the lesion location, including specific mammographic density. RESULTS: Radiologists demonstrated lower sensitivity and receiver operating characteristic area under the curve for non-specific density/asymmetric density (H = 6.27, p = 0.04 and H = 7.35, p = 0.03, respectively) and mixed features (H = 9.97, p = 0.01 and H = 6.50, p = 0.04, respectively) when reading at 15% and 10% recall rates. No significant change was observed on cancer characterized with stellate masses (H = 3.43, p = 0.18 and H = 1.23, p = 0.54, respectively) and architectural distortion (H = 0.00, p = 1.00 and H = 2.00, p = 0.37, respectively). Across all recall conditions, stellate masses were likely to be recalled (90.0%), whereas non specific densities were likely to be missed (45.6%). CONCLUSION: Cancers with a stellate mass were more easily detected and were more likely to continue to be recalled, even at lower recall rates. Cancers with non-specific density and mixed features were most likely to be missed at reduced recall rates. Advances in knowledge: Internationally, recall rates vary within screening mammography programs considerably, with a range between 1% and 15%, and very little is known about the type of breast cancer appearances found when radiologists interpret screening mammograms at these various recall rates. Therefore, understanding the lesion types and the mammographic appearances of breast cancers that are affected by readers' recall decisions should be investigated. PMID- 28621549 TI - Age-appropriate services for people diagnosed with young onset dementia (YOD): a systematic review. AB - BACKGROUND: Literature agrees that post-diagnostic services for people living with young onset dementia (YOD) need to be age-appropriate, but there is insufficient evidence of 'what works' to inform service design and delivery. OBJECTIVE: To provide an evidence base of age-appropriate services and to review the perceived effectiveness of current interventions. METHODS: We undertook a systematic review including all types of research relating to interventions for YOD. We searched PubMed, CINHAL Plus, SCOPUS, EBSCO Host EJS, Social Care Online and Google Scholar, hand-searched journals and carried out lateral searches (July October 2016). Included papers were synthesised qualitatively. Primary studies were critically appraised. RESULTS: Twenty articles (peer-reviewed [n = 10], descriptive accounts [n = 10]) discussing 195 participants (persons diagnosed with YOD [n = 94], caregivers [n = 91] and other [n = 10]) were identified for inclusion. Services enabled people with YOD to remain living at home for longer. However, service continuity was compromised by short-term project-based commissioning and ad-hoc service delivery. CONCLUSION: The evidence on the experience of living with YOD is not matched by research and the innovation needed to mitigate the impact of YOD. The inclusion of people with YOD and their caregivers in service design is critical when planning support in order to delay institutional care. PMID- 28621550 TI - The use of digital technologies to collect patient data in outcomes research. PMID- 28621551 TI - Strengthening stakeholder-engaged research and research on stakeholder engagement. AB - Stakeholder engagement is an emerging field with little evidence to inform best practices. Guidelines are needed to improve the quality of research on stakeholder engagement through more intentional planning, evaluation and reporting. We developed a preliminary framework for planning, evaluating and reporting stakeholder engagement, informed by published conceptual models and recommendations and then refined through our own stakeholder engagement experience. Our proposed exploratory framework highlights contexts and processes to be addressed in planning stakeholder engagement, and potential immediate, intermediate and long-term outcomes that warrant evaluation. We use this framework to illustrate both the minimum information needed for reporting stakeholder-engaged research and the comprehensive detail needed for reporting research on stakeholder engagement. PMID- 28621552 TI - Complete isolation of right subclavian artery supplied by the thoracic aorta and bilateral patent ductus arteriosus. AB - Disconnection of the subclavian artery from the aortic arch, defined as isolation, is a rare aortic arch anomaly. In this anomaly, loss of continuity between one subclavian artery and the aorta with persistent connection to the homocollateral pulmonary artery through a patent or remnant ductus arteriosus is present. This isolation is almost always seen on the side contralateral to the aortic arch position. Complex cardiac and genetic anomalies are frequently associated with the isolation of a subclavian artery. We report a rare case of right subclavian artery originating from right pulmonary artery with bilateral patent ductus arteriosus in an otherwise normal infant. PMID- 28621553 TI - Attitudes toward comparative effectiveness research and patient engagement among reproductive health clinicians. AB - AIM: To assess reproductive health clinicians' knowledge of and attitudes toward comparative effectiveness research (CER), patient-centered outcomes research (PCOR) and patient engagement in research. MATERIALS & METHODS: Web-based survey of reproductive health clinicians. RESULTS: Among 103 responding clinicians, familiarity with CER and PCOR was moderate (35 and 44%, respectively). Once definitions were provided, most respondents agreed with the potential positive impacts of CER and patient engagement (65-87%), the importance of PCOR (95-99%) and that their patients might be interested in engaging in research as more than subjects (93%). CONCLUSION: We found positive attitudes toward PCOR and CER, and a range of experiences with patient engagement in research. There may be untapped potential for PCOR and CER in the reproductive health field. PMID- 28621554 TI - Gut microbiota changes and chronic hepatitis C virus infection. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is a global health problem with 150 million infected people worldwide. Liver can be greatly affected by changes in gut microbiota due to increased intestinal permeability with passage of microbial antigens into the liver through the portal circulation. The concept of 'gut-liver' axis is important to understand the pathophysiology of several liver diseases. Several recent studies also revealed that an altered gut microbiota can be implicated in the pathogenesis of HCV-induced chronic liver disease (CHC). Areas covered: An overview of intestinal microflora composition, host reaction during CHC, and a description of relevant clinical trials on the use of probiotics in this field. Expert commentary: HCV patients gut microbiota composition is stable over liver disease stages. This is a unique example of gut disbiosis stability vs. NAFLD, HBV, HIV, and HCV co-infected patients. The impact of HCV infection on intestinal permeability allows gut disbiosis starting, maintenance and its proinflammatory effect until liver cirrhosis and HCC development. HCV eradication has unraveled the strong impact of gut microbiota unbalance on liver disease development with possible future implications for probiotics use to change the natural history of cirrhosis progression. PMID- 28621555 TI - SLC28A3 rs7853758 as a new biomarker of tacrolimus elimination and new-onset hypertension in Chinese liver transplantation patients. AB - AIM: The effect of SLC28A3 on tacrolimus disposition and new-onset hypertension (NOHP) after liver transplantation (LT) remains unclear. Methodology & results: A total of 169 patients in two cohorts from the China Liver Transplant Registry database were included. Rs7853758 in recipients'SLC28A3 could predict tacrolimus pharmacokinetics in two sets. The model of donors' CYP3A5 rs776746 and recipients' CYP3A4 rs2242480 could predict tacrolimus metabolism at week 1 and the model of donors' CYP3A5 rs776746, recipients' CYP3A4 rs2242480, recipients' SLC28A3 rs7853758 and hemoglobin could predict tacrolimus disposition at weeks 2, 3 and 4. Besides, recipients' SLC28A3 rs7853758 was a new risk factor of NOHP after LT. CONCLUSION: Rs7853758 in recipients' SLC28A3 has a correlation with tacrolimus pharmacokinetics and the risk of NOHP in Chinese LT patients. PMID- 28621556 TI - Exposure to Sexual Stimuli Induces Greater Discounting Leading to Increased Involvement in Cyber Delinquency Among Men. AB - People frequently encounter sexual stimuli during Internet use. Research has shown that stimuli inducing sexual motivation can lead to greater impulsivity in men, as manifested in greater temporal discounting (i.e., a tendency to prefer smaller, immediate gains to larger, future ones). Extant findings in crime research suggest that delinquents tend to focus on short-term gains while failing to adequately think through the longer-term consequences of delinquent behavior. We experimentally tested the possibility that exposure to sexual stimuli is associated with the tendency to engage in cyber delinquency among men, as a result of their overly discounting remote consequences. In Experiment 1, participants exposed to pictures of "sexy" women were more likely to discount the future and were more inclined to make cyber-delinquent choices (e.g., cyberbullying, cyber fraud, cyber theft, and illegal downloading), compared with male participants who rated the sex appeal of less sexy opposite-sex pictures. However, these relationships were not observed in female participants exposed to either highly or less sexy pictures of men. In Experiment 2, male participants exposed to sexual primes showed a greater willingness to purchase a wide range of counterfeit rather than authentic products online and experienced a higher likelihood of logging into the other person's Facebook webpage (i.e., invading online privacy). The discounting tendency mediated the link between exposure to sexual primes and the inclination to engage in cyber-delinquent behavior. These findings provide insight into a strategy for reducing men's involvement in cyber delinquency; that is, through less exposure to sexual stimuli and promotion of delayed gratification. The current results suggest that the high availability of sexual stimuli in cyberspace may be more closely associated with men's cyber delinquent behavior than previously thought. PMID- 28621557 TI - A positive association between the human tissue kallikerin gene A2233C polymorphism and blood pressure response to benazepril. AB - BACKGROUND: It is generally believed that essential hypertension is influenced by both genetic and environmental factors, as well as their interactions. Tissue kallikrein encoded by the tissue kallikrein gene (KLK1) is a key serine proteinase of kallikrein-kinin system, which is capable of generating potent vasactive peptides, kinins, by selective cleavage of the kininogen substrate. It was reported that the A2233 -> C polymorphism in KLK1 gene is associated with essential hypertension. The aim of this study was to examine whether the molecular variations of KLK1 play role in determining the therapeutic response to benazepril, an ACE inhibitor. METHODS: A total of 331 hypertensive individuals were recruited and treated with benazepril for 15 days. A variant impact of KLK1 A2233C was revealed. Chi-square analysis showed that the hypertensive subjects with the mutation genotype (AC + CC) had a higher proportion in systolic blood pressure (SBP, 88.1% vs. 79.0%, chi2 = 4.141, p = 0.042) and diastolic blood pressure (DBP, 91.1% vs. 79.2%, chi2 = 9.336, p = 0.002), respectively, to benazepril medication in good responders than in poor responders. Logistic regression analysis indicated that the hypertensive subjects with AC + CC genotype were more sensitive to the benazepril therapy in SBP (OR=1.97, 95% CI: 1.02-3.80, p = 0.044) and DBP (OR = 1.91, 95% CI: 2.69-5.16, p = 0.003), as compared with those hypertensive subjects with AA genotype. CONCLUSION: Our findings suggest that the A2233C polymorphism of KLK1 may be a marker of evaluation of hypertensive subjects' responses to angiotensin I converting enzyme inhibitors benazepril. PMID- 28621558 TI - Patient engagement in patient-centered outcomes research: challenges, facilitators and actions to strengthen the field. AB - AIM: To describe challenges to and facilitators of patient engagement to inform future strategies and suggested actions to strengthen engagement. METHODS: Interviews with 19 principal investigators of projects funded by the Patient Centered Outcomes Research Institute and with 33 patients from 18 of the 19 projects. RESULTS: Facilitators included using existing resources, having clear goals, educating patients and treating patients respectfully. Logistical challenges included extra time and work, institutional barriers and difficulty having meetings. Substantive challenges to selecting, educating and engaging patients, and incorporating feedback were also reported. CONCLUSION: To bolster the infrastructure for engagement, we suggest funders, institutions and researchers focus on resources and training for researchers and patients, networks and programs to connect stakeholders and model policies. PMID- 28621559 TI - Psychosocial risk factors: Time for action in the lifelong prevention of coronary heart disease. PMID- 28621560 TI - The risks associated with prenatal antidepressant exposure: time for a precision medicine approach. AB - INTRODUCTION: The prevalence of depression in pregnancy is over 10% and a significant proportion of pregnant women use antidepressant medication. The safety of antidepressants in pregnancy is controversial, partly due to methodological challenges. The conflicting results in the literature may, however, also be due to differences in risks between the study populations related to variations in e.g. degree of depression, type of antidepressant, and lifestyle. Areas covered: The literature on the safety of antidepressants in pregnancy is vast and thousands of papers have been published mainly in the last decades. This paper summarizes the evidence on important outcomes, including malformations, obstetric and neonatal outcomes, and long-term effects. It further describes results indicating that genetic variations in e.g. metabolism need to be taken into account. Expert opinion: Use of antidepressants during pregnancy must balance between the risks related to the underlying disease and the risks of antidepressant use. This balance needs to include information on a number of factors, including degree of depression and life-style. More data are required on how to include genetic information in the counseling. Overall, emerging evidence points to the need for a precision medicine approach to the treatment of pregnant women with depression. PMID- 28621561 TI - A patent review of two fruitful decades (1997-2016) of Isocoumarin research. AB - INTRODUCTION: Isocoumarins comprise a six-membered oxygen heterocycle (alpha pyranone) along with one aromatic ring and are known to possess interesting biological properties. During the last two decade (1997-2016), isocoumarin chemistry has attracted attention due to its biological and pharmaceutical effects viz., anticancer, anti-diabetic, antibacterial, antimalarial, and fungicidal effects. Areas covered: This review covers the patents on the therapeutic activities of natural and synthetic isocoumarins over the last two decades (1997-2016). Moreover a number of international patents related to natural and synthetic isocoumarins along with their biological effects will be presented and discussed. Although a large number of patents have been published during the period of the review, the aim of this review is to focus on those important patents specifically related to microbial diseases, cancer, malaria, and diabetes. Expert opinion: Isocoumarin and its synthetic analogs display a wide range of important pharmaceutical properties. Furthermore, isocoumarins have the potential to conjugate with other anticancer drugs which will synergistically increase the delivery and thus anticancer effects. Moreover, in order to get lead compounds, scientists should focus on the synthesis of halo and functionalized heterocyclic ring containing derivatives of isocoumarins as more potent drugs. PMID- 28621562 TI - Association between alcohol consumption trajectories and clinical profiles among women and men living with HIV. AB - BACKGROUND: Alcohol use is common among persons living with HIV (PLWH). It is unclear how alcohol consumption changes over time and if these changes are associated with clinical profiles. OBJECTIVE: We aimed to describe the association between longitudinal patterns of alcohol consumption and the clinical profiles of PLWH. METHODS: Data from the Women's Interagency HIV Study (n = 1123 women) and Multicenter AIDS Cohort Study (n = 597 men) from 2004 to 2013 were utilized. Group-based trajectory models were used to assess alcohol consumption patterns across 10 years. Generalized estimating equations were used to identify associations between clinical factors and alcohol consumption. All analyses were stratified by sex. RESULTS: Four trajectories of alcohol use were identified in women and men (women: abstinent 38%, low: 25%, moderate: 30%, heavy: 7%; men: abstinent 16%, low: 69%, moderate: 9%, heavy: 5%). The Framingham Risk Score (women: adjusted odds ratio [AOR] 1.07, 95% confidence interval [CI] 1.04-1.09), years on ART (women: AOR 1.02, CI 1.00-1.05; men: AOR 1.05, CI 1.01-1.09), suboptimal ART adherence (men: AOR 1.23, CI 1.07-1.42), and unsuppressed viral load (women: AOR 1.82, CI 1.56-2.13; men: AOR 1.36, CI 1.17-1.58) were associated with increased odds for moderate drinking. The Framingham Risk Score (women: AOR 1.10, CI 1.07-1.14; men: AOR 1.12, CI 1.06-1.20), suboptimal adherence (women: AOR 1.25, CI 1.04-1.51), and unsuppressed viral load (women: AOR 1.78, CI 1.42 2.24) were associated with increased odds for heavy drinking. CONCLUSIONS: Clinicians should consider screening patients for alcohol consumption, particularly if patients have comorbid medical conditions, suboptimal antiretroviral adherence, and/or detectable viral load. PMID- 28621563 TI - Reduced Mastication Impairs Memory Function. AB - Mastication is an indispensable oral function related to physical, mental, and social health throughout life. The elderly tend to have a masticatory dysfunction due to tooth loss and fragility in the masticatory muscles with aging, potentially resulting in impaired cognitive function. Masticatory stimulation has influence on the development of the central nervous system (CNS) as well as the growth of maxillofacial tissue in children. Although the relationship between mastication and cognitive function is potentially important in the growth period, the cellular and molecular mechanisms have not been sufficiently elucidated. Here, we show that the reduced mastication resulted in impaired spatial memory and learning function owing to the morphological change and decreased activity in the hippocampus. We used an in vivo model for reduced masticatory stimuli, in which juvenile mice were fed with powder diet and found that masticatory stimulation during the growth period positively regulated long-term spatial memory to promote cognitive function. The functional linkage between mastication and brain was validated by the decrease in neurons, neurogenesis, neuronal activity, and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. These findings taken together provide in vivo evidence for a functional linkage between mastication and cognitive function in the growth period, suggesting a need for novel therapeutic strategies in masticatory function-related cognitive dysfunction. PMID- 28621564 TI - The emerging role of anamorelin hydrochloride in the management of patients with cancer anorexia-cachexia. AB - Cancer cachexia affects many patients with advanced cancer. This multifactorial syndrome, which involves loss of muscle mass and body weight, profoundly affects patients' physical functioning and quality of life. Pharmacologic interventions that target weight loss and also improve patient-reported measures are required. Anamorelin hydrochloride is an oral ghrelin receptor agonist for the treatment of cancer anorexia-cachexia that stimulates release of growth hormone and insulin like growth factor 1, and improves food intake and body weight. Phase II and III trials have demonstrated that anamorelin increases body muscle and fat composition, and improves patient-reported appetite and quality of life. Anamorelin shows promise as an anabolic agent with benefits maintained over time, without the virilizing side effects of other anabolic medications. PMID- 28621565 TI - Light-Emitting Diode at 460 +/- 20 nm Increases the Production of IL-12 and IL-6 in Murine Dendritic Cells. AB - BACKGROUND DATA: Light emitting diode (LED) therapy has been proposed as an option for the treatment of many skin inflammatory processes. Dendritic cells (DCs) are important cells of skin that participate in the initiation and activation of skin immunity. The modulation of these cells by LED could explain much of its effects. OBJECTIVE: Thus, the aim of this study was to examine the effects of LED at 460 +/- 20 nm on cytokine production and the expression of surface markers on DCs. MATERIALS AND METHODS: DCs were obtained from mouse bone marrow-derived dendritic cells (BMDCs). The LED was applied giving a fluence of 3.3, 8.2, or 16.5 J/cm2 on BMDCs or lipopolysaccharide (LPS)-matured BMDCs. The production of cytokine was analyzed by enzyme linked immunosorbant assay (ELISA) and the expression of DC co- and stimulatory was analyzed markers by cytometry. RESULTS: LED increases IL-12p40 and IL-6 production in both nonstimulated BMDCs and LPS-matured BMDCs. The expression of MHC-II molecule was inhibited and the expression of the CD86 molecule was increased in nonstimulated BMDCs but not in LPS-matured BMDCs. The production of tumor necrosis factor alpha (TNF-alpha) and interleukin-10 (IL-10) and the expression of CD40 were not altered. CONCLUSIONS: These results demonstrate that LED stimulated cytokine production in BMDCs, suggesting a proinflammatory role in the tested conditions and maybe it can increase DC maturation. PMID- 28621566 TI - Glutamate dehydrogenase is essential to sustain neuronal oxidative energy metabolism during stimulation. AB - The enzyme glutamate dehydrogenase (GDH; Glud1) catalyzes the (reversible) oxidative deamination of glutamate to alpha-ketoglutarate accompanied by a reduction of NAD+ to NADH. GDH connects amino acid, carbohydrate, neurotransmitter and oxidative energy metabolism. Glutamine is a neurotransmitter precursor used by neurons to sustain the pool of glutamate, but glutamine is also vividly oxidized for support of energy metabolism. This study investigates the role of GDH in neuronal metabolism by employing the Cns- Glud1-/- mouse, lacking GDH in the brain (GDH KO) and metabolic mapping using 13C-labelled glutamine and glucose. We observed a severely reduced oxidative glutamine metabolism during glucose deprivation in synaptosomes and cultured neurons not expressing GDH. In contrast, in the presence of glucose, glutamine metabolism was not affected by the lack of GDH expression. Respiration fuelled by glutamate was significantly lower in brain mitochondria from GDH KO mice and synaptosomes were not able to increase their respiration upon an elevated energy demand. The role of GDH for metabolism of glutamine and the respiratory capacity underscore the importance of GDH for neurons particularly during an elevated energy demand, and it may reflect the large allosteric activation of GDH by ADP. PMID- 28621567 TI - 68Ga-radiolabeled AGuIX nanoparticles as dual-modality imaging agents for PET/MRI guided radiation therapy. AB - AIM: The aim of this study was to develop a dual-modality positron emission tomography/magnetic resonance (PET/MR) imaging probe by radiolabeling gadolinium containing AGuIX derivatives with the positron-emitter Gallium-68 (68Ga). MATERIALS & METHODS: AGuIX@NODAGA nanoparticles were labeled with 68Ga at high efficiency. Tumor accumulation in an appropriate disease model was assessed by ex vivo biodistribution and in vivo PET/MR imaging. RESULTS: 68Ga-AGuIX@NODAGA was proven to passively accumulate in U87MG human glioblastoma tumor xenografts. Metabolite assessment in serum, urine and tumor samples showed that 68Ga AGuIX@NODAGA remains unmetabolized up to at least 60 min postinjection. CONCLUSION: This study demonstrates that 68Ga-AGuIX@NODAGA can be used as a dual modality PET/MR imaging agent with passive accumulation in the diseased area, thus showing great potential for PET/MR image-guided radiation therapy. PMID- 28621568 TI - Presenting a Method to Improve Bone Quality Through Stimulation of Osteoporotic Mesenchymal Stem Cells by Low-Level Laser Therapy. AB - OBJECTIVE: This review aims to present a method to improve bone quality through stimulation of osteoporotic mesenchymal stem cells (MSCs) by low-level laser therapy (LLLT). BACKGROUND: Osteoporosis (OP) is characterized by decreased bone mass and bone strength, which results in an increased incidence of bone fractures. These fractures often lead to additional disability and mortality. Osteoporotic MSCs have reduced osteogenic differentiation when cultured in their standard differentiation media. LLLT has a biostimulatory effect on fibroblasts and osteoblasts. MSCs have the ability to generate cells of connective tissue lineages, which includes the bones. Recently, transplantation of in vitro cultured bone marrow (BM) MSCs into sites at risk for development of osteoporotic bone has resulted in improved bone structure. METHODS: Comprehensive research was performed using PubMed, and biostimulatory effect of LLLT on bony cells and MSCs were studied. RESULTS: LLLT can stimulate growth, proliferation, and differentiation of SCs in vitro and in vivo. This ability of LLLT is an essential prerequisite for performing experiments related to disease control in humans. Thus, laser-treated osteoporotic autologous BMMSCs may represent a promising therapeutic method to protect the bones in patients with OP and prevent fractures in these patients. Therefore, researchers hypothesize that transplantation of in vitro laser-treated autologous cultured osteoporotic BMMSCs that have the appropriate osteogenic phenotype into sites at risk for development of osteoporotic bone may result in improved bone structure. In this respect, investigators have successfully used LLLT to restore autologous osteoporotic MSCs in vitro. Subsequently, these cells have been differentiated into osteoblast cell lines with the use of laser treatment after which they were transplanted into osteoporotic animal models. CONCLUSIONS: This technique might improve bone quality and structure. However, additional research must be undertaken to understand the underlying mechanisms of this treatment, validate its effectiveness, and assess the feasibility for clinical application of LLLT to treat MSCs in regeneration of osteoporotic bone. PMID- 28621570 TI - Forensic science and forensic pathology: Quality standards and risks. PMID- 28621569 TI - Down-regulation of SlCyp1 in the phloem reduces auxin response and photosynthetic rate in tomato (Solanum lycopersicum) plants. AB - The tomato dgt mutant, containing a single mutation in the Cyclophilin1 (SlCyp1) gene, is auxin insensitive and exhibits a pleotropic phenotype that includes lack of lateral roots, malformed xylem structure and reduced root-to-shoot ratio. Recently, we found that the SlCyp1 protein is phloem-mobile and traffic from shoot to root to induce lateral root formation. These processes are achieved through activation of auxin-mediated developmental programs. Inhibition of the trafficked SlCyp1 activity at the target site resulted in inhibition of the auxin response, supporting the hypothesis that this protein is indeed a mobile signal. Here, we show that partial silencing of SlCyp1 in the phloem only resulted in perturbed auxin response in the roots and reduced photosynthetic and transpiration rates. The presented data suggests that expression of SlCyp1 in the phloem is essential for proper auxin response at the whole plant level. We, therefore, propose that this protein acts as a long-distance signaling molecule acting as coordinator between roots and shoot activities. PMID- 28621571 TI - Targeted nanotechnologies for cancer intervention: a patent review (2010-2016). AB - INTRODUCTION: In recent years, several active targeting nanostrategies have been patented for application in cancer theranostics. The versatility of nanostructures in terms of composition, manufacturability, functionalization, and matrix formation make them ideal for carrying large dose of bioactive contents, high density of targeting ligands on their surface, efficient delivery to the site of interest, and capable of forming multicomponent platforms. Areas covered: The patents were classified into polymeric and non-polymeric nanostructures and their applicability in addressing the targeting paradigm related to cancer intervention was explored. Specialized platforms such as nanoparticles, nanomicelles, nanocomposites, nanotubes, quantum dots, metal/silica particles, and dendrimers were cited as targeted nanostructures along with ligands such as antibody fragments, synthetic peptides, aptamers, small molecules, and folates. Here, we focused on patented targeted nanotechnological advances in recent years (2010-2016). Expert opinion: The formulation and performance prerequisites, available nanomaterial options, fabrication feasibility, and challenges and issues related with regulatory approval and patenting of cancer targeted nanocarriers are reviewed. Future research in this area should focus on clinically relevant bioactive combinations, better metastasis control, integration of imaging and theranostic techniques, predictive animal/pre-clinical models, maximal utilisation of extra- and intracellular tumor microenvironment for drug delivery, and exploring the metabolomic-, proteomic-, and genomic-based personalization of cancer nanomedicine. PMID- 28621572 TI - Changes to International Nonproprietary Names for antibody therapeutics 2017 and beyond: of mice, men and more. AB - Active pharmaceutical substances require an International Nonproprietary Name (INN) assigned by the World Health Organization (WHO) to obtain market authorization as a medicinal product. INNs are selected to represent a unique, generic name for a drug enabling unambiguous identification by stakeholders worldwide. INNs may be requested after initiating clinical development of an investigational drug. Pharmaceutical classes are indicated by a common stem or suffix. Currently, INNs for monoclonal antibody-based drugs are recognized by the suffix, -mab, preceded by a source infix such as -xi- (chimeric), -zu- (humanized) or -u- (human) designating the species from which the antibody was derived. However, many technological advances have made it increasingly difficult to accurately capture an antibody's source in its name. In 2014, the WHO and the United States Adopted Names (USAN) Council approached this challenge by implementing changes to antibody source infix definitions. Unfortunately, gaps and ambiguities in the definitions and procedures resulted in inconsistent source category assignments and widespread confusion. The Antibody Society, extensively supported by academic and industry scientists, voiced concerns leading to constructive dialog during scheduled consultations with WHO and USAN Council representatives. In June 2017, the WHO announced that use of the source infix will be discontinued for new antibody INNs effective immediately. We fully support this change as it better aligns antibody INNs with current and foreseeable future innovations in antibody therapeutics. Here we review the changes implemented. Additionally, we analyzed antibody INNs recently assigned under the previous 2014 definitions and provide recommendations for further alignment. PMID- 28621573 TI - Update on the diagnostic value and safety of stereotactic biopsy for pediatric brainstem tumors: a systematic review and meta-analysis of 735 cases. AB - OBJECTIVE Recent studies have shed light on the molecular makeup of diffuse intrinsic pontine gliomas and led to the identification of potential treatment targets for these lesions, which account for the majority of pediatric brainstem tumors (pedBSTs). Therefore, stereotactic biopsy-driven molecular characterization of pedBSTs may become an important prerequisite for the management of these fatal brain tumors. The authors conducted a systemic review and meta-analysis to precisely determine the safety and diagnostic success of stereotactic biopsy of pedBSTs. METHODS A systematic search of PubMed, EMBASE, and the Web of Science yielded 944 potentially eligible abstracts. Meta-analysis was conducted on 18 studies (including the authors' own institutional series), describing a total of 735 biopsy procedures for pedBSTs. The primary outcome measures were diagnostic success and procedure-related complications. Pooled estimates were calculated based on the Freeman-Tukey double-arcsine transformation and DerSimonian-Laird random-effects model. Heterogeneity, sensitivity, and meta-regression analyses were also conducted. RESULTS The weighted average proportions across the analyzed studies were 96.1% (95% CI 93.5% 98.1%) for diagnostic success, 6.7% (95% CI 4.2%-9.6%) for overall morbidity, 0.6% (95% CI 0.2%-1.4%) for permanent morbidity, and 0.6% (95% CI 0.2%-1.3%) for mortality. Subgroup analyses at the study level identified no significant correlation between the outcome measures and the distribution of the chosen biopsy trajectories (transfrontal vs transcerebellar), age, year of publication, or the number of biopsy procedures annually performed in each center. CONCLUSION Stereotactic biopsy of pedBSTs is safe and allows successful tissue sampling as a prerequisite for the molecular characterization and the identification of potentially druggable targets toward more individualized treatment concepts to improve the outcome for children harboring such lesions. PMID- 28621574 TI - Endovascular plug for internal carotid artery occlusion in the management of a cavernous pseudoaneurysm with bifrontal subdural empyema: technical note. AB - The authors demonstrate the use of an endovascular plug in securing a carotid artery pseudoaneurysm in an emergent setting requiring craniotomy for a concurrent subdural empyema. They describe the case of a 14-year-old boy with sinusitis and bifrontal subdural empyema who underwent transsphenoidal exploration at an outside hospital. An injury to the right cavernous segment of the ICA caused torrential epistaxis. Bleeding was successfully controlled by inflating a Foley balloon catheter within the sphenoid sinus, and the patient was transferred to the authors' institution. Emergent angiography showed a dissection of the right cavernous carotid artery, with a large pseudoaneurysm projecting into the sphenoid sinus at the site of arterial injury. The right internal carotid artery was obliterated using pushable coils distally and an endovascular plug proximally. The endovascular plug enabled the authors to successfully exclude the pseudoaneurysm from the circulation. The patient subsequently underwent an emergent bifrontal craniotomy for evacuation of a left frontotemporal subdural empyema and exenteration of both frontal sinuses. He made a complete neurological recovery. Endovascular large-vessel sacrifice, obviating the need for numerous coils and antiplatelet therapy, has a role in the setting of selected acute neurosurgical emergencies necessitating craniotomy. The endovascular plug is a useful adjunct in such circumstances as the device can be deployed rapidly, safely, and effectively. PMID- 28621575 TI - Analysis of radio-sensitization patents in China from 2006 to 2015. AB - INTRODUCTION: Radiotherapy is by means of ionizing radiation to kill tumor cells, inhibit and control the growth, metastasis and diffusion of tumor cells. During the last few decades, application of radiotherapy combined with chemotherapy and surgery are clinical mainstream treatments. However, little is known what radio sensitization agents have been patented in China and what the potential drug candidates for patents are in China. Areas covered: This reviews covers research and patent literature of the last 10 years dealing with the discovery and development of novel radio-sensitization patents in China. Expert opinion: The 94 radio-sensitization patents granted from 2006 to 2015 mainly focus on six types of products. They are: traditional Chinese medicines (TCM), synthetic compounds, combinations of synthetic compounds and TCM, biological products, medical apparatus and others. In the course of tumor treatment, radiotherapy occupies an irreplaceable position. Previously believed that due to the prevalence of hypoxic cells in solid tumors, most of the tumor exist a certain degree of radiation resistance. To find effective ways to improve the sensitivity of tumor cells to radiation therapy has become a focus in scientific research and clinical treatment. So radiation sensitivity has been proposed and widely studied. PMID- 28621576 TI - Tethering of Lsh at the Oct4 locus promotes gene repression associated with epigenetic changes. AB - Lsh is a chromatin remodeling factor that regulates DNA methylation and chromatin function in mammals. The dynamics of these chromatin changes and whether they are directly controlled by Lsh remain unclear. To understand the molecular mechanisms of Lsh chromatin controlled regulation of gene expression, we established a tethering system that recruits a Gal4-Lsh fusion protein to an engineered Oct4 locus through Gal4 binding sites in murine embryonic stem (ES) cells. We examined the molecular epigenetic events induced by Lsh binding including: histone modification, DNA methylation and chromatin accessibility to determine nucleosome occupancy before and after embryonic stem cell differentiation. Our results indicate that Lsh assists gene repression upon binding to the Oct4 promoter region. Furthermore, we detected less chromatin accessibility and reduced active histone modifications at the tethered site in undifferentiated ES, while GFP reporter gene expression and DNA methylation patterns remained unchanged at this stage. Upon differentiation, association of Lsh promotes transcriptional repression of the reporter gene accompanied by the increase of repressive histone marks and a gain of DNA methylation at distal and proximal Oct4 enhancer sites. Taken together, this approach allowed us to examine Lsh mediated epigenetic regulation as a dynamic process and revealed chromatin accessibility changes as the primary consequence of Lsh function. PMID- 28621577 TI - Fatigue-free operation of most body-powered prostheses not feasible for majority of users with trans-radial deficiency. AB - BACKGROUND: Body-powered prostheses require cable operation forces between 33 and 131 N. The accepted upper limit for fatigue-free long-duration operation is 20% of a users' maximum cable operation force. However, no information is available on users' maximum force. OBJECTIVES: To quantify users' maximum cable operation force and to relate this to the fatigue-free force range for the use of body powered prostheses. STUDY DESIGN: Experimental trial. METHODS: In total, 23 subjects with trans-radial deficiencies used a bypass prosthesis to exert maximum cable force three times during 3 s and reported discomfort or pain on a body map. Additionally, subjects' anthropometric measures were taken to relate to maximum force. RESULTS: Subjects generated forces ranging from 87 to 538 N. Of the 23 subjects, 12 generated insufficient maximum cable force to operate 8 of the 10 body-powered prostheses fatigue free. Discomfort or pain did not correlate with the magnitude of maximum force achieved by the subjects. Nine subjects indicated discomfort or pain. No relationships between anthropometry and maximal forces were found except for maximum cable forces and the affected upper-arm circumference for females. CONCLUSION: For a majority of subjects, the maximal cable force was lower than acceptable for fatigue-free prosthesis use. Discomfort or pain occurred in ~40% of the subjects, suggesting a suboptimal force transmission mechanism. Clinical relevance The physical strength of users determines whether a body-powered prosthesis is suitable for comfortable, fatigue free long-duration use on a daily basis. High cable operation forces can provoke discomfort and pain for some users, mainly in the armpit. Prediction of the users' strength by anthropometric measures might assist the choice of a suitable prosthesis. PMID- 28621578 TI - The effect of nanoparticle size on the ability to cross the blood-brain barrier: an in vivo study. AB - AIM: Our goal was to develop an efficient nanoparticle-based system that can overcome the restrictive mechanism of the blood-brain barrier (BBB) by targeting insulin receptors and would thus enable drug delivery to the brain. METHODS: Insulin-coated gold nanoparticles (INS-GNPs) were synthesized to serve as a BBB transport system. The effect of nanoparticle size (20, 50 and 70 nm) on their ability to cross the BBB was quantitatively investigated in Balb/C mice. RESULTS: The most widespread biodistribution and highest accumulation within the brain were observed using 20 nm INS-GNPs, 2 h post injection. In vivo CT imaging revealed that particles migrated to specific brain regions, which are involved in neurodegenerative and neuropsychiatric disorders. CONCLUSION: These findings promote the optimization of nanovehicles for transport of drugs through the BBB. The insulin coating of the particles enabled targeting of specific brain regions, suggesting the potential use of INS-GNPs for delivery of various treatments for brain-related disorders. PMID- 28621579 TI - Optimization of Antimicrobial Photodynamic Therapy in Biofilms by Inhibiting Efflux Pump. AB - BACKGROUND: One of the main mechanisms of microbial resistance is given by efflux pumps, which reduce the effectiveness of antimicrobials by decreasing their intracellular concentration. OBJECTIVE AND METHODS: Considering that efflux pump inhibitors are promising adjuvant molecules for antibiotics in infections, in this study, using XTT test and colony forming unit (CFU) counting, we evaluated the association between the pump inhibitor verapamil (VP) and the antimicrobial photodynamic therapy (aPDT) mediated by methylene blue (MB) in biofilms of Escherichia coli and Staphylococcus aureus to optimize the bacterial reduction. RESULTS: By applying 44 J/cm2, 215 MUg/mL of VP, and 200 MUg/mL of MB, we obtained 80% of metabolism reduction and 3.4 log10 CFU/mL decrease for E. coli. Biofilm of S. aureus presented 80% of metabolism reduction and 3.65 log10 CFU/mL decrease when 22 J/cm2, 312 MUg/mL of VP, and 200 MUg/mL of MB was used. Applying 200 MUg/mL of MB, the E. coli biofilm required a higher dose of light, while the S. aureus biofilm required a higher concentration of VP to obtain the same reduction. CONCLUSIONS: The VP optimized the efficiency of aPDT and showed no toxicity when used alone in both strains, proving that inhibiting efflux pumps in combination with aPDT has great potential for clinical application. PMID- 28621580 TI - VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016). AB - INTRODUCTION: Angiogenesis is an important component of certain normal physiological processes, but aberrant angiogenesis contributes to some pathological disorders and in particular to tumor growth. Activation of vascular endothelial growth factor receptor-2 (VEGFR-2) by vascular endothelial growth factor (VEGF) is a critical step in the signal transduction pathway that initiates tumor angiogenesis. Inhibition of angiogenesis via blocking VEGF/VEGFR 2 signaling pathway has emerged as a potential approach to anticancer therapy. Indeed, this approach has recently been clinically validated with the approvals of VEGFR-2 inhibitors. Areas covered: This review accounts for small-molecule inhibitors and antibodies of VEGFR-2 reported in the patent literature covering between January 2012 and June 2016, and their potential use as therapeutics for cancers, angiogenesis-related disorders and inflammatory diseases. Expert opinion: Despite the attractiveness of anti-angiogenic therapy by VEGF inhibition alone, several issues may limit this approach. VEGF expression levels can be elevated by numerous diverse stimuli such as the activation of other RTK signaling transduction pathway. Therefore, the development of multi-targeted tyrosine kinase inhibitors and the strategy of using these agents in conjunction with other anti-cancer agents are recent interesting therapeutic approaches that could give promising results. PMID- 28621581 TI - Self-assembling protein nanoparticles: a promising tool against lethal influenza? PMID- 28621582 TI - Assessment of pulmonary arterial compliance evaluated using harmonic oscillator kinematics. AB - We hypothesized that KPA, a harmonic oscillator kinematics-derived spring constant parameter of the pulmonary artery pressure (PAP) profile, reflects PA compliance in pediatric patients. In this prospective study of 33 children (age range = 0.5-20 years) with various cardiac diseases, we assessed the novel parameter designated as KPA calculated using the pressure phase plane and the equation KPA = (dP/dt_max)2/([Pmax - Pmin])/2)2, where dP/dt_max is the peak derivative of PAP, and Pmax - Pmin is the difference between the minimum and maximum PAP. PA compliance was also calculated using two conventional methods: systolic PA compliance (sPAC) was expressed as the stroke volume/Pmax - Pmin; and diastolic PA compliance (dPAC) was determined according to a two-element Windkessel model of PA diastolic pressure decay. In addition, data were recorded during abdominal compression to determine the influence of preload on KPA. A significant correlation was observed between KPA and sPAC (r = 0.52, P = 0.0018), but not dPAC. Significant correlations were also seen with the time constant (tau) of diastolic PAP (r = -0.51, P = 0.0026) and the pulmonary vascular resistance index (r = -0.39, P = 0.0242). No significant difference in KPA was seen between before and after abdominal compression. KPA had a higher intraclass correlation coefficient than other compliance and resistance parameters for both intra-observer and inter-observer variability (0.998 and 0.997, respectively). These results suggest that KPA can provide insight into the underlying mechanisms and facilitate the quantification of PA compliance. PMID- 28621583 TI - Effect of a Publicly Accessible Disclosure System on Food Safety Inspection Scores in Retail and Food Service Establishments. AB - The increased frequency with which people are dining out coupled with an increase in the publicity of foodborne disease outbreaks has led the public to an increased awareness of food safety issues associated with food service establishments. To accommodate consumer needs, local health departments have increasingly publicized food establishments' health inspection scores. The objective of this study was to estimate the effect of the color-coded inspection score disclosure system in place since 2006 in Columbus, OH, by controlling for several confounding factors. This study incorporated cross-sectional time series data from food safety inspections performed from the Columbus Public Health Department. An ordinary least squares regression was used to assess the effect of the new inspection regime. The introduction of the new color-coded food safety inspection disclosure system increased inspection scores for all types of establishments and for most types of inspections, although significant differences were found in the degree of improvement. Overall, scores increased significantly by 1.14 points (of 100 possible). An exception to the positive results was found for inspections in response to foodborne disease complaints. Scores for these inspections declined significantly by 10.2 points. These results should be useful for both food safety researchers and public health decision makers. PMID- 28621584 TI - Inactivation of Nondesiccated and Desiccated Cronobacter sakazakii in Reconstituted Infant Formula by Combination of Citral and Mild Heat. AB - The objective of this study was to evaluate the combined effect of citral plus mild heat on nondesiccated and desiccated Cronobacter sakazakii in reconstituted infant formula. Various concentrations of citral (0, 0.3, 0.6, and 0.9%) combined with various temperatures (25, 45, 50, and 55 degrees C) were applied to nondesiccated and desiccated cocktails of three C. sakazakii strains (approximately 6.0 log CFU mL-1) in reconstituted infant formula, and the bacterial populations were assayed periodically. The combined treatments had marked antimicrobial effects on C. sakazakii compared with the control. Desiccated cells were more susceptible to citral than were nondesiccated cells in reconstituted infant formula. These findings suggest there is a potential application of citral in combination with mild heat to control C. sakazakii during preparation of reconstituted infant formula. PMID- 28621585 TI - Inactivation of Nonpathogenic Escherichia coli, Escherichia coli O157:H7, Salmonella enterica Typhimurium, and Listeria monocytogenes in Ice Using a UVC Light-Emitting Diode. AB - Ice, widely used in the food industry, is a potential cause of food poisoning resulting from microbial contamination. Direct microbial inactivation of ice is necessary because microorganisms may have been present in the source water used to make it and/or may have been introduced due to poor hygiene during production or handling of the ice. Nonthermal and nondestructive microbial inactivation technologies are needed to control microorganisms in ice. We evaluated the applicability of a UVC light-emitting diode (UVC-LED) for microbial inactivation in ice. The effects of UV intensity and UV dose of the UVC-LED on Escherichia coli ATCC 25922 and a comparison of UVC-LED with a conventional UV lamp for effective bacterial inactivation in distilled water and ice cubes were investigated to evaluate the performance of the UVC-LED. Finally, we assessed the effects of the UVC-LED on pathogens such as E. coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes in ice cubes. The results indicated that UVC-LED effectiveness depended on the UV dose at all UV intensity conditions (0.084, 0.025, 0.013, 0.007, and 0.005 mW/cm2) in ice and that UVC-LED could more efficiently inactivate E. coli ATCC 25922 in distilled water and ice than the UV lamp. At a UV dose of 2.64 mJ/cm2, E. coli in distilled water was decreased by 0.90 log CFU/mL (UV lamp) and by more than 7.0 log CFU/mL (UVC-LED). At 15.2 mJ/cm2, E. coli in ice was decreased by 3.18 log CFU/mL (UV lamp) and by 4.45 CFU/mL (UVC-LED). Furthermore, UVC-LED irradiation reduced the viable number of pathogens by 6 to 7 log cycles at 160 mJ/cm2, although the bactericidal effect was somewhat dependent on the type of bacteria. L. monocytogenes in ice was relatively more sensitive to UVC irradiation than were E. coli O157:H7 and Salmonella Typhimurium. These results demonstrate that UVC-LED irradiation could contribute to the safety of ice in the food industry. PMID- 28621586 TI - The COOLER Code: A Novel Analytical Approach to Calculate Subcellular Energy Deposition by Internal Electron Emitters. AB - COmputation Of Local Electron Release (COOLER), a software program has been designed for dosimetry assessment at the cellular/subcellular scale, with a given distribution of administered low-energy electron-emitting radionuclides in cellular compartments, which remains a critical step in risk/benefit analysis for advancements in internal radiotherapy. The software is intended to overcome the main limitations of the medical internal radiation dose (MIRD) formalism for calculations of cellular S-values (i.e., dose to a target region in the cell per decay in a given source region), namely, the use of the continuous slowing down approximation (CSDA) and the assumption of a spherical cell geometry. To this aim, we developed an analytical approach, entrusted to a MATLAB-based program, using as input simulated data for electron spatial energy deposition directly derived from full Monte Carlo track structure calculations with PARTRAC. Results from PARTRAC calculations on electron range, stopping power and residual energy versus traveled distance curves are presented and, when useful for implementation in COOLER, analytical fit functions are given. Example configurations for cells in different culture conditions (V79 cells in suspension or adherent culture) with realistic geometrical parameters are implemented for use in the tool. Finally, cellular S-value predictions by the newly developed code are presented for different cellular geometries and activity distributions (uniform activity in the nucleus, in the entire cell or on the cell surface), validated against full Monte Carlo calculations with PARTRAC, and compared to MIRD standards, as well as results based on different track structure calculations (Geant4-DNA). The largest discrepancies between COOLER and MIRD predictions were generally found for electrons between 25 and 30 keV, where the magnitude of disagreement in S-values can vary from 50 to 100%, depending on the activity distribution. In calculations for activity distribution on the cell surface, MIRD predictions appeared to fail the most. The proposed method is suitable for Auger-cascade electrons, but can be extended to any energy of interest and to beta spectra; as an example, the 3H case is also discussed. COOLER is intended to be accessible to everyone (preclinical and clinical researchers included), and may provide important information for the selection of radionuclides, the interpretation of radiobiological or preclinical results, and the general establishment of doses in any scenario, e.g., with cultured cells in the laboratory or with therapeutic or diagnostic applications. The software will be made available for download from the DTU-Nutech website: http://www.nutech.dtu.dk/ . PMID- 28621587 TI - Treatment of severe hypertension in a 14-year-old child: Successful blood pressure control with additive administration of captopril, an angiotensin converting enzyme inhibitor, in a patient with bilateral renovascular hypertension. AB - We report a 14-year-old boy with recurrent episodes of headache caused by uncontrolled hypertension. The diagnosis of renovascular hypertension due to Takaysu arteritis (TA) was made based on an increase in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and computed tomography (CT) image of bilateral renal artery stenosis was taken. Renal scintigraphy revealed normal perfusion and function of the right kidney and severe reduction of the perfusion and function of the left kidney. Careful drug adjustments significantly improved but did not fully control the blood pressure (BP); further, angioplasty, which showed almost occlusion of the left renal artery opening and the minor narrowing of the right renal artery, failed to regain sufficient BP control. The addition of captopril, an angiotensin-converting enzyme (ACE) inhibitor, to conventional antihypertensive drugs successfully and safely lowered BP and preserved the renal function. This unique case suggested that ACE inhibitors achieved better control of BP in a patient with bilateral renal stenosis and that the patient may have hemodynamically significant stenosis caused by unilateral renal artery. PMID- 28621588 TI - Perioperative single-site veno-venous extracorporeal CO2 removal for minimally invasive giant bulla resection. AB - Giant pulmonary bullae are rare and surgical management of patients with severe emphysema and advanced chronic obstructive lung disease (COPD) presenting with giant bullae can be very challenging. Previously, perioperative, two-site, high flow, veno-venous extracorporeal membrane oxygenation (ECMO) was successfully utilized during giant bulla resection. Here we report the perioperative application of single-site, low-flow extracorporeal CO2 removal (ECCO2R) for minimally invasive thoracoscopic giant bulla resection. This approach of low flow, veno-venous ECCO2R, which is less invasive than conventional ECLS approaches, has enabled the safe performance of surgery and facilitated protective intraoperative single-lung ventilation while avoiding possible complications of aggressive mechanical ventilation. PMID- 28621589 TI - Effect of hospitalization on gastrointestinal motility and pH in dogs. AB - OBJECTIVE To determine the effect of hospitalization on gastrointestinal motility and pH in healthy dogs. DESIGN Experimental study. ANIMALS 12 healthy adult dogs. PROCEDURES A wireless motility capsule (WMC) that measured pressure, transit time, and pH within the gastrointestinal tract was administered orally to dogs in 2 phases. In the first phase, dogs received the WMC at the hospital and then returned to their home to follow their daily routine. In the second phase, dogs were hospitalized, housed individually, had abdominal radiography performed daily, and were leash exercised 4 to 6 times/d until the WMC passed in the feces. All dogs received the same diet twice per day in both phases. Data were compared between phases with the Wilcoxon signed rank test. RESULTS Data were collected from 11 dogs; 1 dog was excluded because the WMC failed to exit the stomach. Median gastric emptying time during hospitalization (71.8 hours; range, 10.7 to 163.0 hours) was significantly longer than at home (17.6 hours; range, 9.7 to 80.8 hours). Values of all other gastric, small bowel, and large bowel parameters (motility index, motility pattern, pH, and transit time) were similar between phases. No change in gastric pH was detected over the hospitalization period. High interdog variability was evident for all measured parameters. CONCLUSIONS AND CLINICAL RELEVANCE Hospitalization of dogs may result in a prolonged gastric emptying time, which could adversely affect gastric emptying of meals, transit of orally administered drugs, or assessments of underlying motility disorders. PMID- 28621590 TI - Cystoscopic diagnosis of polypoid cystitis in two pet rabbits. AB - CASE DESCRIPTION AS-year-old male Dwarf rabbit and 4-year-old female Mini-Rex rabbit were evaluated because of anorexia and urine scalding of the perineum. CLINICAL FINDINGS Abdominal radiography revealed a diffuse increase in the opacity of the urinary bladder attributable to urinary sludge. In 1 rabbit, abdominal ultrasonography revealed several mass-like lesions protruding from the mucosal surface into the lumen of the urinary bladder. Rabbits were anesthetized, and cystoscopy was performed with a rigid 2.7-mm, 30 degrees endoscope. Histologic analysis of tissue samples obtained through the cystoscope operating channel revealed findings consistent with polypoid cystitis. TREATMENT AND OUTCOME To remove the urinary sludge from each rabbit, the urinary bladder was filled with sterile saline (0.9% NaCl) solution and emptied with a gentle massage several times until the ejected fluid was transparent. Rabbits were treated with NSAIDs, antimicrobials (chosen following microbial culture of urine and antimicrobial susceptibility testing), bathing of the perineum, and a low-calcium diet. The male rabbit died of unrelated causes 18 months later; postmortem examination findings confirmed the polypoid cystitis. The female rabbit remained disease free through to last follow-up (12 months after initial evaluation). CLINICAL RELEVANCE This was the first report of polypoid cystitis in pet rabbits. Although ultrasonographic findings supported this diagnosis, a definitive diagnosis was achieved through cystoscopy and lesion biopsy. Treatments administered were intended to reduce the potential sources of irritation. Research is needed to investigate the effectiveness of the applied interventions and the association between excessive urinary calcium excretion and polyploid cystitis in rabbits. PMID- 28621592 TI - What Is Your Neurologic Diagnosis? Lipomas. PMID- 28621591 TI - Rates of intraoperative complications and conversion to laparotomy during laparoscopic ovariectomy performed by veterinary students: 161 cases (2010-2014). AB - OBJECTIVE To assess rates of intraoperative complications and conversion to laparotomy associated with supervised veterinary students performing laparoscopic ovariectomy in dogs. DESIGN Retrospective case series. ANIMALS 161 female shelter dogs for which elective laparoscopic ovariectomy had been performed by supervised senior (fourth-year) veterinary students from 2010 through 2014. PROCEDURES Medical records of all dogs were reviewed and data collected regarding duration of surgery, surgical complications and other characteristics, and whether conversion to laparotomy was required. RESULTS Laparoscopic ovariectomy was performed with a 2-cannula technique and a 10-mm vessel-sealing device for hemostasis in all dogs. A Veress needle was used for initial insufflation in 144 (89.4%) dogs; method of insufflation was not reported for the remaining 17 (10.6%) dogs. Mean +/- SD duration of surgery was 114.90 +/- 33.40 minutes. Surgical complications, all classified as minor blood loss, occurred in 24 (14.9%) dogs. These included splenic puncture during insertion of the Veress needle (n = 20 [12.4%]) and minor bleeding from the ovarian pedicle (4 [2.5%]). Splenic puncture required no intervention, and ovarian pedicle bleeding required application of the vessel-sealing device an additional time to control the bleeding. Two ovaries were dropped in the abdominal cavity at the time of removal. Both were retrieved without complication. Conversion to laparotomy was not required for any dog. All dogs were discharged from the hospital within 24 hours after surgery. CONCLUSIONS AND CLINICAL RELEVANCE Laparoscopic ovariectomy in dogs was performed safely by closely supervised novice surgeons, with only minor intraoperative complications encountered and no need for conversion to laparotomy. PMID- 28621593 TI - Pathology in Practice. Cutaneous leishmaniasis. PMID- 28621594 TI - ECG of the Month. PMID- 28621595 TI - Optimizing client and student learning from the brain's perspective. PMID- 28621596 TI - In This Issue * July 1, 2017. PMID- 28621598 TI - Leading our profession into the future: some final thoughts. PMID- 28621597 TI - Pharmacokinetics of chloramphenicol base after oral administration in adult horses. AB - OBJECTIVE To determine the pharmacokinetics of chloramphenicol base after PO administration at a dose of SO mg/kg (22.7 mg/lb) in adult horses from which food was not withheld. DESIGN Prospective crossover study. ANIMALS 5 adult mares. PROCEDURES Chloramphenicol base (SO mg/kg) was administered PO to each horse, and blood samples were collected prior to administration (0 minutes) and at 5, 10, 15, and 30 minutes and 1, 2, 4, 8, and 12 hours thereafter. Following a washout period, chloramphenicol sodium succinate (25 mg/kg [11.4 mg/lb]) was administered IV to each horse, and blood samples were collected prior to administration (0 minutes) and at 3, 5, 10, 15, 30, and 45 minutes and 1, 2, 4, and 8 hours thereafter. RESULTS In horses, plasma half-life, volume of distribution at steady state, clearance, and area under the plasma concentration-time curve for chloramphenicol after IV administration ranged from 0.65 to 1.20 hours, 0.51 to 0.78 L/kg, 0.78 to 1.22 L/h/kg, and 20.5 to 32.1 h.MUg/mL, respectively. The elimination half-life, time to maximum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve after PO administration ranged from 1.7 to 7.4 hours, 0.25 to 2.00 hours, 1.52 to 5.45 MUg/mL, and 10.3 to 21.6 h.MUg/mL, respectively. Mean +/- SD chloramphenicol bioavailability was 28 +/- 10% and terminal half-life was 2.85 +/- 1.32 hours following PO administration. CONCLUSIONS AND CLINICAL RELEVANCE Given that the maximum plasma chloramphenicol concentration in this study was lower than previously reported values, it is recommended to determine the drug's MIC for target bacteria before administration of chloramphenicol in adult horses. PMID- 28621599 TI - Comparison of ultrasonography and magnetic resonance imaging to arthroscopy for diagnosing medial meniscal lesions in dogs with cranial cruciate ligament deficiency. AB - OBJECTIVE To compare the accuracy of ultrasonography and MRI for diagnosing medial meniscal lesions in dogs with cranial cruciate ligament (CCL) deficiency. DESIGN Diagnostic test evaluation. ANIMALS 26 dogs (31 stifle joints) with CCL deficiency. PROCEDURES A single surgeon physically examined each dog and performed ultrasonography and arthroscopy of affected stifle joints to identify medial meniscal lesions. Video recordings of the arthroscopic procedure were saved and subsequently reviewed by the same surgeon and by a second surgeon working independently and blinded to results of all examinations. A radiologist blinded to results of all examinations evaluated MRI scans of the affected joints. Correct classification rate (CCR), sensitivity, and specificity of ultrasonography and MRI were calculated twice, with each of the 2 surgeons' arthroscopic assessments used as the reference standard. RESULTS Compared with arthroscopic examination by the unblinded surgeon, ultrasonography had a CCR of 90%, sensitivity of 95% (95% confidence interval [CI], 73% to 100%), and specificity of 82% (95% CI, 48% to 97%). For MRI, these values were 84%, 75% (51% to 90%), and 100% (68% to 100%), respectively. Compared with arthroscopic assessment by the blinded surgeon, ultrasonography had a CCR of 84%, sensitivity of 86% (95% CI, 64% to 96%), and specificity of 78% (95% CI, 40% to 96%). For MRI, these values were 77%, 68% (45% to 82%), and 100% (63% to 100%), respectively. CONCLUSIONS AND CLINICAL RELEVANCE These data suggested imperfect performance but clinical usefulness of both ultrasonography and MRI for diagnosing medial meniscal lesions in dogs. PMID- 28621600 TI - Pathology in Practice. Pneumonia and hepatitis associated with ascarid larval migration. PMID- 28621602 TI - Resolution of nonurine transudative pleural effusion in a cat after removal of a hydronephrotic kidney. AB - CASE DESCRIPTION A 3-year-old spayed female Bengal cat was evaluated because of a history of bilateral pleural effusion and hydronephrosis of the right kidney. CLINICAL FINDINGS Cytologic analysis of a pleural fluid sample revealed characteristics of a pure transudate with a high percentage of lymphocytes. Results of fluid biochemical testing were not consistent with urine or chyle. Serum biochemical analysis and echocardiography yielded no evidence of hypoalbuminemia or high hydrostatic pressure secondary to cardiac disease. Abdominal ultrasonography revealed hydronephrosis of the right kidney and hydroureter of the right ureter. TREATMENT AND OUTCOME Exploratory laparotomy with nephrectomy of the right kidney was performed. At the time of surgery, there was no evidence of communication between the retroperitoneal space and thoracic cavity. No other treatments were performed. No evidence of pleural fluid accumulation was detected 1 week after surgery, and no recurrence of clinical signs associated with pleural effusion was observed for > 1 year after surgery. CLINICAL RELEVANCE Transudative, or nonchylous lymphatic, pleural effusion secondary to intra-abdominal disease, but independent of a low plasma protein concentration, is uncommon in veterinary medicine. This case emphasized that urinary tract obstruction should be considered as a differential diagnosis for cats with pleural effusion when more common disorders are not identified. Even without evidence of direct communication between the abnormal kidney or retroperitoneal space and the pleural space, removal of the hydronephrotic kidney appeared curative. PMID- 28621603 TI - Letters to the Editor. PMID- 28621604 TI - What Is Your Diagnosis? Gastrointestinal pneumatosis. PMID- 28621605 TI - Anesthesia Case of the Month. PMID- 28621607 TI - Novel proteomic biomarkers for skeletal muscle diseases. PMID- 28621606 TI - Nano-targeting of mucosal addressin cell adhesion molecule-1 identifies bowel inflammation foci in murine model. AB - AIM: We investigate MAdCAM-1 as a reliable target to detect active bowel inflammation for selective noninvasive nanodiagnostics. MATERIALS & METHODS: We coupled anti-MAdCAM-1 antibodies to manganese oxide nanoparticles, and analyzed nanoconjugate biodistribution and safety in murine model of inflammatory bowel disease by imaging and histology. RESULTS: Nanoparticles were stable and nontoxic. Upon administration in colitic mice, anti-MAdCAM-1 functionalized nanoparticles preferentially localized in the inflamed bowel, whereas untargeted nanoparticles were more rapidly washed out. Nanoparticles did not induce lesions in nontarget organs. CONCLUSION: Anti-MAdCAM-1 functionalized nanoparticles detected active bowel inflammation foci, accurately following MAdCAM-1 expression pattern. These nanoconjugates could be a promising noninvasive imaging system for an early and accurate follow-up in patients affected by acute colitis. PMID- 28621608 TI - Glycosylation change of alpha-1-acid glycoprotein as a serum biomarker for hepatocellular carcinoma and cirrhosis. AB - AIM: This research is to explore the glycosylation change of alpha-1-acid glycoprotein (AGP) in hepatocellular carcinoma (HCC), cirrhosis and controls. METHODS: The affinity chromatography and lectin affinity techniques were used to separate and enrich glycosylated AGP, and combined with mass spectrometry to identify and relatively quantify the glycopeptides from AGP. RESULTS: The sialylation and fucosylation of AGP were different among HCC, cirrhosis and controls. The highly sialylated and fucosylated peptides from AGP were found in HCC and cirrhosis compared with controls. These glycopeptides showed excellent diagnostic ability to differentiate HCC from cirrhosis (area under the curve >0.9). In addition, these glycopeptides showed significantly different among four HCC stages. CONCLUSION: The sialylation and fucosylation change of AGP may serve as serum biomarker for HCC and cirrhosis. PMID- 28621609 TI - Preoperative serum TMAO level is a new prognostic marker for colorectal cancer. AB - AIM: This study is aimed to determine whether trimethylamine-N-oxide (TMAO) is a predictor of prognosis of patients with colorectal cancer. METHODS: Pretreatment TMAO serum levels were determined in 108 patients with colorectal cancer and 30 healthy controls. RESULTS: Median serum TMAO level was significantly higher in colorectal cancer patients than in healthy controls (p < 0.01). No correlation was observed between the disease-free survival and the type of chemotherapy regimen used, tumor location or lymphovascular invasion. Patients with high serum TMAO level had significantly shorter disease-free survival than patients with low serum TMAO level. Multivariate analysis showed that serum TMAO level and distant metastases were independent prognostic factors. CONCLUSION: Pretreatment serum TMAO level is identified as a new independent prognostic biomarker in patients with colorectal cancer. PMID- 28621610 TI - Gamma-glutamyltransferase activity as a surrogate biomarker of metabolic health status in young nondiabetic obese women. AB - AIM: We investigated the association of gamma-glutamyltransferase (GGT) activity with atherogenic risk factors and metabolic health status in young nondiabetic obese women. METHODS & RESULTS: In 140 obese women GGT activity was independently associated with BMI, triglyceride to high-density cholesterol ratio and homeostasis model assessment. Metabolically healthy but obese women had significantly lower GGT activity, associated with a normal insulin sensitivity, favorable lipid profile and apolipoprotein B to apolipoprotein AI ratio. GGT activity showed good diagnostic accuracy to distinguish between metabolically healthy but obese and obese women at risk (77.8% sensitivity and 60% specificity). GGT activity >17 U/l can predict atherogenic risk and insulin resistance. CONCLUSION: GGT activity may serve as a potential surrogate biomarker of atherogenic risk and metabolic health status. PMID- 28621611 TI - Plasma microRNA-19a as a potential biomarker for esophageal squamous cell carcinoma diagnosis and prognosis. AB - AIM: To investigate whether plasma miR-19a can serve as a biomarker for esophageal squamous cell carcinoma (ESCC) diagnosis and prognosis. MATERIALS & METHODS: Plasma samples from 89 ESCC, 45 benign lesion patients and 80 healthy controls were subjected to RT-qPCR analyses for miR-19a. In addition, plasma samples from 30 patients were collected before and after surgery for the same analyses. RESULTS: Plasma miR-19a was significantly increased in ESCC patients compared with healthy controls. The sensitivity of miR-19a for early stages of ESCC was 68.09%. Combination of miR-19a and cytokeratin 19 fragment 21-1 (Cyfra21 1) further improved the sensitivity to 78.70%. Moreover, plasma miR-19a level was decreased in patients after surgery. CONCLUSION: Plasma miR-19a may serve as a potential biomarker that complements Cyfra21-1 in detecting early stages of ESCC. PMID- 28621612 TI - Association of ANRIL gene polymorphisms with prostate cancer and benign prostatic hyperplasia in an Iranian population. AB - AIM: Prostate cancer and benign prostate hyperplasia (BPH) are heterogeneous disorders with high prevalence among men. The antisense noncoding RNA in the INK4 locus codes for a long noncoding RNA whose participation in cancer has been elucidated. METHOD: We analyzed rs1333045, rs4977574, rs1333048 and rs10757278 genotypes from this locus in 125 prostate cancer patients, 125 BPH patients as well as 220 normal age-matched subjects by means of tetra-primer amplification refractory mutation system PCR method. RESULTS: The rs1333045 showed no significant difference in allele or genotype frequencies between three groups. However, the other three single nucleotide polymorphisms have been shown to be associated with BPH and prostate cancer risk. CONCLUSION: Antisense noncoding RNA in the INK4 locus possibly participates in the pathogenesis of these disorders. PMID- 28621613 TI - Relationship of IL-17A and IL-17F genetic variations to cervical cancer risk: a meta-analysis. AB - AIM: We performed a meta-analysis to determine a more precise relationship of IL 17A and IL-17F polymorphisms with cervical cancer risk. MATERIALS & METHODS: PubMed, CNKI and Wan Fang databases were searched for studies on these associations using STATA version 10.0 software. RESULTS: Five studies were included. The AG and AA genotypes and A allele of IL-17A rs2275913 were correlated with an elevated risk of cervical cancer. The TT genotype and T allele of IL-17A rs3748067 and the CC genotype and C allele of IL-17F rs763780 carried a moderate risk of cervical cancer, when compared with the wild-type genotype. CONCLUSION: IL-17A and IL-17F polymorphisms therefore have the potential to act as predictive biomarkers for cervical cancer risk. PMID- 28621614 TI - Biomarkers in the accurate subclassification of non-small-cell lung carcinoma for targeted therapy: issues and prospects. PMID- 28621615 TI - Molecular determinants for cyclo-oligosaccharide-based nanoparticle-mediated effective siRNA transfection. AB - AIM: To study the structural requirements that a cyclooligosaccharide-based nanoparticle must fulfill to be an efficient siRNA transfection vector. MATERIALS & METHODS: siRNA protection from degradation by RNAses, transfection efficiency and the thermodynamic parameters of the nanoparticle/siRNA interactions were studied on pairs of amphiphilic molecules using biochemical techniques and molecular dynamics. RESULTS: The lower the siRNA solvent accessible surface area in the presence of the nanoparticle, higher the protection from RNAse-mediated degradation in the corresponding nanocomplex; a moderate nanoparticle/siRNA binding energy value further facilitates reversible complexation and binding to the target cellular mRNA. CONCLUSION: The use, in advance, of these parameters will provide a useful indication of the potential of a molecular nanoparticle as siRNA transfecting vector. PMID- 28621616 TI - Prevalence of foramen arcuale and its clinical significance: a meta-analysis of 55,985 subjects. AB - OBJECTIVE The foramen arcuale (FA) is a bony bridge located over the vertebral artery on the posterior arch of the atlas. The presence of an FA can pose a risk during neurosurgery by providing a false impression of a broader posterior arch. The aim of this study was to provide the most comprehensive investigation on the prevalence of the FA and its clinically important anatomical features. METHODS Major electronic databases were searched to identify all studies that reported relevant data on the FA and the data were pooled into a meta-analysis. RESULTS A total of 127 studies (involving 55,985 subjects) were included. The overall pooled prevalence of a complete FA was 9.1% (95% CI 8.2%-10.1%) versus an incomplete FA, which was 13.6% (95% CI 11.2%-16.2%). The complete FA was found to be most prevalent in North Americans (11.3%) and Europeans (11.2%), and least prevalent among Asians (7.5%). In males (10.4%) the complete FA was more common than in females (7.3%) but an incomplete FA was more commonly seen in females (18.5%) than in males (16.7%). In the presence of a complete FA, a contralateral FA (complete or incomplete) was found in 53.1% of cases. CONCLUSIONS Surgeons should consider the risk for the presence of an FA prior to procedures on the atlas in each patient according to sex and ethnic group. We suggest preoperative screening with computerized tomography as the gold standard for detecting the presence of an FA. PMID- 28621617 TI - Intrathoracic meningocele associated with neurofibromatosis Type 1 and a novel technique for surgical repair: case report. AB - Neurofibromatosis Type 1 (NF1) is a neurocutaneous disorder that can have associated spinal abnormalities related to both bone and dural dysplasia. Thoracic meningoceles are one spine anomaly associated with NF1, although they are a fairly uncommon pathology. Surgical techniques to treat these meningoceles, usually undertaken only when the patient is symptomatic, are targeted at decreasing the size of the protrusion and improving lung capacity. Surgical interventions discussed in the literature include shunting the pseudomeningocele, primary repair with laminectomy, thoracoscopic plication, and reinforcement of the closure with cement, muscle, or fascia. Authors here report the case of a 43 year-old woman with NF1 with worsening pulmonary function tests and in whom shunting of the pseudomeningocele failed. Subsequently, a posterolateral thoracotomy was performed. The dura mater was reconstructed and primarily closed. On this closure a Gore-Tex soft-tissue patch was placed along with polypropylene mesh and Evicel fibrin sealant, followed by titanium mesh. At the end of the procedure, a chest tube was left in place and therapeutic pneumoperitoneum was performed to decrease the dead space as the lung did not fully expand with positive-pressure ventilation. The patient's pulmonary function tests improved after the procedure. Thoracic meningoceles are uncommon and difficult pathologies to treat surgically. Although shunting is arguably the least invasive surgical option, it can fail in some patients. When it does fail, there are other options that require a multidisciplinary approach and careful attention to the dural closure and reinforcing layers. PMID- 28621619 TI - Histopathological prognostic factors of recurrence following definitive therapy for atypical and malignant meningiomas. AB - OBJECTIVE Patients with atypical and malignant (WHO Grade II and III) meningiomas have a worse prognosis than patients with benign (WHO Grade I) meningiomas. However, there is limited understanding of the pathological risk factors that affect long-term tumor control following combined treatment with surgery and radiation therapy. Here, the authors identify clinical and histopathological risk factors for the progression and/or recurrence (P/R) of high-grade meningiomas based on the largest series of patients with atypical and malignant meningiomas, as defined by the 2007 WHO classification. METHODS Patients diagnosed with WHO Grade II and III meningiomas between 2007 and 2014 per the WHO 2007 criteria and treated with both surgery and external beam radiation therapy were retrospectively reviewed for clinical and histopathological factors at the time of diagnosis and assessed for P/R outcomes at the last available follow-up. RESULTS A total of 76 patients met the inclusion criteria (66 Grade II meningiomas, 10 Grade III meningiomas). Median follow-up from the time of pathological diagnosis was 52.6 months. Three factors were found to predict P/R: Grade III histology, brain and/or bone invasion, and a Ki-67 proliferation rate at or above 3%. The crude P/R rate was 80% for patients with Grade III histology, 40% for those with brain and/or bone involvement (regardless of WHO tumor grade), and 20% for those with a proliferative index >= 3% (regardless of WHO tumor grade). The median proliferation index was significantly different between patients in whom treatment failed and those in whom it did not fail (11% and 1%, respectively). CONCLUSIONS In patients with atypical or malignant meningiomas, the presence of Grade III histology, brain and/or bone involvement, and a high mitotic index significantly predicted an increased risk of treatment failure despite combination therapy. These patients can be stratified into risk groups predicting P/R. Patients with high-risk features may benefit from more treatment and counseling than is typically offered currently. PMID- 28621618 TI - Placental imprinting variation associated with assisted reproductive technologies and subfertility. AB - Infertility affects one in 6 couples in developed nations, resulting in an increasing use of assisted reproductive technologies (ART). Both ART and subfertility appear to be linked to lower birth weight outcomes, setting infants up for poor long-term health. Prenatal growth is, in part, regulated via epigenetically-controlled imprinted genes in the placenta. Although differences in DNA methylation between ART and control infants have been found, it remains unclear whether these differences are due to the ART procedures or to the underlying parental subfertility and how these methylation differences affect imprinted gene expression. In this study, we examined the expression of 108 imprinted genes in placental tissues from infants born to subfertile parents (n = 79), matched naturally-conceived controls (n = 158), and infants conceived using in vitro fertilization (IVF, n = 18). Forty-five genes were identified as having significantly different expression between the subfertile infants and controls, whereas no significant differences were identified between the IVF and control groups. The expression of 4 genes-IGF2, NAPIL5, PAX8-AS1, and TUBGCP5-was significantly downregulated in the IVF compared with the subfertile group. Three of the 45 genes significantly dysregulated between subfertile and control placentae-GRB10, NDN, and CD44 -were found to have a significant positive correlation between expression and birth weight. Methylation levels for these 3 genes and 4 others-MKRN3, WRB, DHCR24, and CYR61-were significantly correlated with expression. Our findings indicate that epigenetic differences in placentas resulting from IVF pregnancies may be related to the underlying subfertility in parents using IVF rather than the IVF procedure itself. PMID- 28621620 TI - Deep brain stimulation for the early treatment of the minimally conscious state and vegetative state: experience in 14 patients. AB - OBJECTIVE An effective treatment of patients in a minimally conscious state (MCS) or vegetative state (VS) caused by hypoxic encephalopathy or traumatic brain injury (TBI) is not yet available. Deep brain stimulation (DBS) of the thalamic reticular nuclei has been attempted as a therapeutic procedure mainly in patients with TBI. The purpose of this study was to investigate the therapeutic use of DBS for patients in VS or MCS. METHODS Fourteen of 49 patients in VS or MCS qualified for inclusion in this study and underwent DBS. Of these 14 patients, 4 were in MCS and 10 were in VS. The etiology of VS or MCS was TBI in 4 cases and hypoxic encephalopathy due to cardiac arrest in 10. The selection criteria for DBS, evaluating the status of the cerebral cortex and thalamocortical reticular formation, included: neurological evaluation, electrophysiological evaluation, and the results of positron emission tomography (PET) and MRI examinations. The target for DBS was the centromedian-parafascicular (CM-pf) complex. The duration of follow-up ranged from 38 to 60 months. RESULTS Two MCS patients regained consciousness and regained their ability to walk, speak fluently, and live independently. One MCS patient reached the level of consciousness, but was still in a wheelchair at the time the article was written. One VS patient (who had suffered a cerebral ischemic lesion) improved to the level of consciousness and currently responds to simple commands. Three VS patients died of respiratory infection, sepsis, or cerebrovascular insult (1 of each). The other 7 patients remained without substantial improvement of consciousness. CONCLUSIONS Spontaneous recovery from MCS/VS to the level of consciousness with no or minimal need for assistance in everyday life is very rare. Therefore, if a patient in VS or MCS fulfills the selection criteria (presence of somatosensory evoked potentials from upper extremities, motor and brainstem auditory evoked potentials, with cerebral glucose metabolism affected not more than the level of hypometabolism, which is judged using PET), DBS could be a treatment option. PMID- 28621621 TI - Indications, technique, and safety profile of insular stereoelectroencephalography electrode implantation in medically intractable epilepsy. AB - OBJECTIVE Insular epilepsy is relatively rare; however, exploring the insular cortex when preoperative workup raises the suspicion of insular epilepsy is of paramount importance for accurate localization of the epileptogenic zone and achievement of seizure freedom. The authors review their clinical experience with stereoelectroencephalography (SEEG) electrode implantation in patients with medically intractable epilepsy and suspected insular involvement. METHODS A total of 198 consecutive cases in which patients underwent SEEG implantation with a total of 1556 electrodes between June 2009 and April 2013 were reviewed. The authors identified patients with suspected insular involvement based on seizure semiology, scalp EEG data, and preoperative imaging (MRI, PET, and SPECT or magnetoencephalography [MEG]). Patients with at least 1 insular electrode based on the postoperative 3D reconstruction of CT fused with the preoperative MRI were included. RESULTS One hundred thirty-five patients with suspected insular epilepsy underwent insular implantation of a total of 303 electrodes (1-6 insular electrodes per patient) with a total of 562 contacts. Two hundred sixty-eight electrodes (88.5%) were implanted orthogonally through the frontoparietal or temporal operculum (420 contacts). Thirty-five electrodes (11.5%) were implanted by means of an oblique trajectory either through a frontal or a parietal entry point (142 contacts). Nineteen patients (14.07%) had insular electrodes placed bilaterally. Twenty-three patients (17.04% of the insular implantation group and 11.6% of the whole SEEG cohort) were confirmed by SEEG to have ictal onset zones in the insula. None of the patients experienced any intracerebral hemorrhage related to the insular electrodes. After insular resection, 5 patients (33.3%) had Engel Class I outcomes, 6 patients (40%) had Engel Class II, 3 patients (20%) had Engel Class III, and 1 patient (6.66%) had Engel Class IV. CONCLUSIONS Insula exploration with stereotactically placed depth electrodes is a safe technique. Orthogonal electrodes are implanted when the hypothesis suggests opercular involvement; however, oblique electrodes allow a higher insular sampling rate. PMID- 28621622 TI - Glossopharyngeal neuralgia treated by Gamma Knife radiosurgery: safety and efficacy through long-term follow-up. AB - OBJECTIVE Glossopharyngeal neuralgia (GPN) is a rare and disabling condition. Just as for trigeminal neuralgia, Gamma Knife radiosurgery (GKRS) is increasingly proposed as a therapeutic option for GPN. The purpose of this study was to assess long-term safety and efficacy of GKRS for this indication. METHODS From 2007 to 2015, 9 patients (4 male and 5 female) underwent a total of 10 GKRS procedures. All of the patients presented with GPN that was refractory to all medical treatment, and all had a long history of pain. One patient had previously undergone surgical microvascular decompression. In 5 cases, a neurovascular conflict had been identified on MRI. For the GKRS procedure, the glossopharyngeal nerve was localized on MRI and CT under stereotactic conditions. The target was located at the glossopharyngeal meatus of the jugular foramen. The dose administered to the nerve was 80 Gy in 3 procedures and 90 Gy in the others. Follow-up was planned for 3, 6, and 12 months after the procedure and annually thereafter. RESULTS Eight patients experienced an improvement in their pain. The median length of time from GKRS to symptom improvement in this group was 7 weeks (range 2-12 months). At the first follow-up, 6 patients were pain-free (pain intensity scores of I-III, based on an adaptation of the Barrow Neurological Institute scoring system for trigeminal neuralgia), including 4 patients who were also medication-free (I). One patient had partial improvement (IV) and 2 patients had no change. The mean duration of follow-up was 46 months (range 10-90 months). At the last follow-up 6 patients remained pain-free (pain scores of I-III), including 4 patients who were pain free with no medication (I). No side effect was observed. CONCLUSIONS Because of its safety and efficacy, GKRS appears to be a useful tool for treatment of GPN, including first-line treatment. PMID- 28621623 TI - Patterns of care and outcomes in gliosarcoma: an analysis of the National Cancer Database. AB - OBJECTIVE The authors compared presenting characteristics and survival for patients with gliosarcoma (GS) and glioblastoma (GBM). Additionally, they performed a survival analysis for patients who underwent GS treatments with the hypothesis that trimodality therapy (surgery followed by radiation and chemotherapy) would be superior to nontrimodality therapy (surgery alone or surgery followed by chemotherapy or radiation). METHODS Adults diagnosed with GS and GBM between the years 2004 and 2013 were queried from the National Cancer Database. Chi-square analysis was used to compare presenting characteristics. Kaplan-Meier, Cox regression, and propensity score analyses were employed for survival analyses. RESULTS In total, data from 1102 patients with GS and 36,658 patients with GBM were analyzed. Gliosarcoma had an increased rate of gross-total resection (GTR) compared with GBM (19% vs 15%, p < 0.001). Survival was not different for patients with GBM (p = 0.068) compared with those with GS. After propensity score analysis for GS, patients receiving trimodality therapy (surgery followed by radiation and chemotherapy) had improved survival (12.9 months) compared with those not receiving trimodality therapy (5.5 months). In multivariate analysis, GTR, female sex, fewer comorbidities, trimodality therapy, and age < 65 years were associated with improved survival. There was a trend toward improved survival with MGMT promoter methylation (p = 0.117). CONCLUSIONS In this large registry study, there was no difference in survival in patients with GBM compared with GS. Among GS patients, trimodality therapy significantly improved survival compared with nontrimodality therapy. Gross-total resection also improved survival, and there was a trend toward increased survival with MGMT promoter methylation in GS. The major potential confounder in this study is that patients with poor functional status may not have received aggressive radiation or chemotherapy treatments, leading to the observed outcome. This study should be considered hypothesis-generating; however, due to its rarity, conducting a clinical trial with GS patients alone may prove difficult. PMID- 28621624 TI - Use of telomerase promoter mutations to mark specific molecular subsets with reciprocal clinical behavior in IDH mutant and IDH wild-type diffuse gliomas. AB - OBJECTIVE Recent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade. METHODS Four molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed. RESULTS TERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses. CONCLUSIONS Molecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas. PMID- 28621625 TI - Editorial. Thalamic stimulation in vegetative or minimally conscious patients. PMID- 28621626 TI - A multimodal concept for invasive diagnostics and surgery based on neuronavigated voxel-based morphometric MRI postprocessing data in previously nonlesional epilepsy. AB - OBJECTIVE Diagnosis and surgical treatment of refractory and apparent nonlesional focal epilepsy is challenging. Morphometric MRI voxel-based and other postprocessing methods can help to localize the epileptogenic zone and thereby support the planning of further invasive electroencephalography (EEG) diagnostics, and maybe resective epilepsy surgery. METHODS The authors developed an algorithm to implement regions of interest (ROI), based on postprocessed MRI data, into a neuronavigation tool. This was followed by stereotactic ROI-guided implantation of depth electrodes and ROI-navigated resective surgery. Data on diagnostic yield, histology, and seizure outcome were collected and evaluated. RESULTS Fourteen consecutive patients with apparently nonlesional epilepsy were included in this study. Reevaluation of the MR images with the help of MRI postprocessing analysis led to the identification of probable subtle lesions in 11 patients. Additional information obtained by SPECT imaging and MRI reevaluation suggested possible lesions in the remaining 3 patients. The ROI guided invasive implantation of EEG yielded interictal and ictal activity in 13 patients who were consequently referred to resective surgery. Despite the apparently negative MRI findings, focal cortical dysplasia was found in 64% of the patients (n = 9). At the last available outcome, 8 patients (57%) were completely seizure free (International League Against Epilepsy Class 1). CONCLUSIONS The results demonstrate the feasibility and usefulness of a robust and straightforward algorithm for implementation of MRI postprocessing-based targets into the neuronavigation system. This approach allowed the stereotactic implantation of a low number of depth electrodes only, which confirmed the seizure-onset hypothesis in 90% of the cases without causing any complications. Furthermore, the neuronavigated ROI-guided lesionectomy helped to perform resective surgery in this rather challenging subgroup of patients with apparent nonlesional epilepsy. PMID- 28621627 TI - Factors associated with shunt-dependent hydrocephalus after decompressive craniectomy for traumatic brain injury. AB - OBJECTIVE Posttraumatic hydrocephalus (PTH) affects 11.9%-36% of patients undergoing decompressive craniectomy (DC) and is an important cause of morbidity after traumatic brain injury (TBI). Early diagnosis and treatment of PTH can prevent further neurological compromise in patients who are recovering from TBI. There is limited data on predictors of shunting for PTH after DC for TBI. METHODS Prospectively collected data from the erythropoietin severe TBI randomized controlled trial were studied. Demographic, clinical, and imaging data were analyzed for enrolled patients who underwent a DC. All head CT scans during admission were reviewed and assessed for PTH by the Gudeman criteria or the modified Frontal Horn Index >= 33%. The presence of subdural hygromas was categorized as unilateral/bilateral hemispheric or interhemispheric. Using L1 regularized logistic regression to select variables, a multiple logistic regression model was created with ventriculoperitoneal shunting as the binary outcome. Statistical significance was set at p < 0.05. RESULTS A total of 60 patients who underwent DC were studied. Fifteen patients (25%) underwent placement of a ventriculoperitoneal shunt for PTH. The majority of patients underwent unilateral decompressive hemicraniectomy (n = 46, 77%). Seven patients (12%) underwent bifrontal DC. Unilateral and bilateral hemispheric hygromas were noted in 31 (52%) and 7 (11%) patients, respectively. Interhemispheric hygromas were observed in 19 patients (32%). The mean duration from injury to first CT scan showing hemispheric subdural hygroma and interhemispheric hygroma was 7.9 +/ 6.5 days and 14.9 +/- 11.7 days, respectively. The median duration from injury to shunt placement was 43.7 days. Multivariate analysis showed that the presence of interhemispheric hygroma (OR 63.6, p = 0.001) and younger age (OR 0.78, p = 0.009) were significantly associated with the need for a shunt after DC. CONCLUSIONS The presence of interhemispheric subdural hygromas and younger age were associated with shunt-dependent hydrocephalus after DC in patients with severe TBI. PMID- 28621628 TI - Gamma Knife surgery for clival epidural-osseous dural arteriovenous fistulas. AB - OBJECTIVE Clival epidural-osseous dural arteriovenous fistula (DAVF) is often associated with a large nidus, multiple arterial feeders, and complex venous drainage. In this study the authors report the outcomes of clival epidural osseous DAVFs treated using Gamma Knife surgery (GKS). METHODS Thirteen patients with 13 clival epidural-osseous DAVFs were treated with GKS at the authors' institution between 1993 and 2015. Patient age at the time of GKS ranged from 38 to 76 years (median 55 years). Eight DAVFs were classified as Cognard Type I, 4 as Type IIa, and 1 as Type IIa+b. The median treatment volume was 17.6 cm3 (range 6.2-40.3 cm3). The median prescribed margin dose was 16.5 Gy (range 15-18 Gy). Clinical and radiological follow-ups were performed at 6-month intervals. Patient outcomes after GKS were categorized as 1) complete improvement, 2) partial improvement, 3) stationary, and 4) progression. RESULTS All 13 patients demonstrated symptomatic improvement, and on catheter angiography 12 of the 13 patients had complete obliteration and 1 patient had partial obliteration. The median follow-up period was 26 months (range 14-186 months). The median latency period from GKS to obliteration was 21 months (range 8-186 months). There was no intracranial hemorrhage during the follow-up period, and no deaths occurred. Two adverse events were observed following treatment, and 2 patients required repeat GKS treatment with eventual complete obliteration. CONCLUSIONS Gamma Knife surgery offers a safe and effective primary or adjuvant treatment modality for complex clival epidural-osseous DAVFs. All patients in this case series demonstrated symptomatic improvement, and almost all patients attained complete obliteration. PMID- 28621629 TI - Endoscopic endonasal odontoid resection with real-time intraoperative image guided computed tomography: report of 4 cases. AB - The authors present 4 cases in which they used intraoperative CT (iCT) scanning to provide real-time image guidance during endonasal odontoid resection. While intraoperative CT has previously been used as a confirmatory test after resection, to the authors' knowledge this is the first time it has been used to provide real-time image guidance during endonasal odontoid resection. The operating room setup, as well as the advantages and pitfalls of this approach, are discussed. A mobile intraoperative CT scanner was used in conjunction with real-time craniospinal neuronavigation in 4 patients who underwent endoscopic endonasal odontoidectomy for basilar invagination. All patients underwent a successful decompression. In 3 of the 4 patients, real-time intraoperative CT image guidance was instrumental in achieving a comprehensive decompression. In 3 (75%) cases in which the right nostril was the predominant working channel, there was a tendency for asymmetrical decompression toward the right side, meaning that residual bone was seen on the left, which was subsequently removed prior to completion of the surgery. Endoscopic endonasal odontoid resection with real-time intraoperative image-guided CT scanning is feasible and provides accurate intraoperative localization of pathology, thereby increasing the chance of a complete odontoidectomy. For right-handed surgeons operating predominantly through the right nostril, special attention should be paid to the contralateral side of the resection, where there is often a tendency for residual pathology. PMID- 28621630 TI - Evaluation of surgical treatment for neuropathic pain from neuroma in patients with injured peripheral nerves. AB - OBJECTIVE Chronic neuropathic pain after peripheral nerve injury is a major clinical problem. Its management is difficult, and therapeutic approaches vary and include oral medication, neurostimulation, and surgery. The aim of this study was to assess the adequacy of surgical nerve revision in a large series of patients with long-term follow-up. METHODS The authors reviewed the charts of 231 patients (335 nerve injuries) who experienced neuropathic pain after peripheral nerve injury and underwent surgery for nerve revision at the authors' institution between 1997 and 2012. The following parameters were recorded for each patient: history, location, duration, and severity of the pain and details of nerve revision surgery. In addition, patients were invited to participate in a follow up consultation and were asked to score their pain at that time. Current medications and examination findings were also documented. RESULTS Elective surgery was the source of nerve injury for 55.4% of the patients. The lower extremity was the most commonly involved anatomical region (54.3%), followed by the lower abdomen (16.4%) and the thoracic region (13%). The mean time between the onset of injury and revision surgery was 48 months. On average, 1.3 injured nerves per patient were explored, and surgery was performed 1.2 times per patient. Each nerve underwent revision 1.1 times on average. Neuromas-in continuity and scar-tethered nerves were observed in 205 nerves (61%) and terminal neuromas were observed in 130 nerves (39%). The authors performed 186 (56%) neurolyses and 149 (44%) neuroma resections and translocations. The mean follow-up of the 127 (55%) patients who agreed to come back for a consultation was 68 months. These patients indicated an average pain decrease of 4 points in the visual analog scale (VAS) score. Pain relief greater than a 2-point decrease on the VAS, a criterion for a successful treatment according to the European Federation of Neurological Societies guidelines, was encountered in 80% of patients. Pain relief did not vary in a statistically significant way with regard to surgical technique, age and sex of the patient, affected nerve, or time between trauma and surgery. Before surgery, 76% of the patients were on a regimen of paracetamol and/or NSAIDs and 44% received opiates, while after nerve revision only 37% still required simple analgesia and 14% needed opiates. CONCLUSIONS Bearing in mind that medication achieves satisfying pain relief in only 30%-40% of patients with neuropathic pain, surgery must be considered as an effective alternative therapy. No objective criteria were shown to be factors of poor prognosis. Systematic preoperative clinical mapping of the injured nerves and diagnostic nerve blocks could improve the primary success rate of the surgery. PMID- 28621631 TI - Comparative analysis of monotherapy versus duotherapy antiseizure drug management for postoperative seizure control in patients undergoing an awake craniotomy. AB - OBJECTIVE Postoperative seizures are a common complication in patients undergoing an awake craniotomy, given the cortical manipulation during tumor resection and the electrical cortical stimulation for brain mapping. However, little evidence exists about the efficacy of postoperative seizure prophylaxis. This study aims to determine the most appropriate antiseizure drug (ASD) management regimen following an awake craniotomy. METHODS The authors performed a retrospective analysis of data pertaining to patients who underwent an awake craniotomy for brain tumor from 2007 to 2015 performed by a single surgeon. Patients were divided into 2 groups, those who received a single ASD (the monotherapy group) and those who received 2 types of ASDs (the duotherapy group). Patient demographics, symptoms, tumor characteristics, hospitalization details, and seizure outcome were evaluated. Multivariable logistic regression was used to evaluate numerous clinical variables associated with postoperative seizures. RESULTS A total of 81 patients underwent an awake craniotomy for tumor resection of an eloquent brain lesion. Preoperative baseline characteristics were comparable between the 2 groups. The postoperative seizure rate was 21.7% in the monotherapy group and 5.7% in the duotherapy group (p = 0.044). Seizure outcome at 6 months' follow-up was assessed with the Engel classification scale. The duotherapy group had a significantly higher proportion of seizure-free (Engel Class I) patients than the monotherapy group (90% vs 60%, p = 0.027). The length of stay was similar, 4.02 days in the monotherapy group and 4.51 days in the duotherapy group (p = 0.193). The 90-day readmission rate was higher for the monotherapy group (26.1% vs 8.5% in the duotherapy group, p = 0.044). Multivariate logistic regression showed that preoperative seizure history was a significant predictor for postoperative seizures following an awake craniotomy (OR 2.08, 95% CI 0.56-0.90, p < 0.001). CONCLUSIONS Patients with a preoperative seizure history may be at a higher risk for postoperative seizures following an awake craniotomy and may benefit from better postoperative seizure control with postoperative ASD duotherapy. PMID- 28621632 TI - How can nanoparticles be used in sentinel node detection? PMID- 28621633 TI - Fatigue After Liver Transplant and Combined Liver and Kidney Transplant. AB - OBJECTIVES: To date, fatigue is still poorly understood in recipients of orthotopic liver transplant and simultaneous/sequential liver and kidney transplant procedures. The present study examined the appearance of fatigue in patients who received orthotopic liver and sequential liver and kidney transplant procedures compared with the general population and the influence of various clinical and socioeconomic factors on fatigue levels. MATERIALS AND METHODS: The Multidimensional Fatigue Inventory survey was sent to all patients with a history of orthotopic liver and simultaneous/sequential liver and kidney transplant. The results were compared to data from a reference population. RESULTS: Our survey included 276 eligible patients: 256 recipients (92.7%) of orthotopic liver transplant and 20 recipients (7.3%) of simultaneous/sequential liver and kidney transplant. Significantly lower fatigue scores were found in the general population compared with both transplant groups (P < .001). There were also no significant differences between the transplant groups. Among the clinical and socioeconomic factors, history of hepatocellular carcinoma, chronic kidney disease, age, family status, and education had a significant impact on fatigue levels. CONCLUSIONS: This is the first study to compare fatigue in recipients of orthotopic liver and simultaneous/sequential liver and kidney transplant. We found that fatigue is an important but still poorly understood outcome after transplant. PMID- 28621634 TI - The Utility of Screening Colonoscopy During Kidney Transplant Evaluation. AB - OBJECTIVES: Transplant centers often recommend, but not necessarily require, screening colonoscopies for people over 50 years of age in accordance with the US Preventative Services Task Force guidelines for the general population. We sought to identify risk factors affecting colonoscopy results in renal failure patients undergoing kidney transplant evaluation. MATERIALS AND METHODS: We retrospectively examined patients undergoing kidney transplant evaluation from 2009 to 2012 (n = 469 patients). Comparisons were made between colonoscopy reports categorized as normal (no finding or hyperplastic polyp) or abnormal (adenomatous polyp or carcinoma). RESULTS: Of 469 patients who met the study criteria, 303 (64.6%) had normal colonoscopies and 166 (35.4%) had abnormal colonoscopies. Logistic regression analysis showed that male sex (odds ratio = 2.09; 95% confidence interval, 1.37-3.20; P = .001) and increasing age (odds ratio = 1.04; 95% confidence interval, 1.01-1.08; P = .019) were more likely to correspond to abnormal findings. Those with dialysis vintage (length of time on dialysis) up to 3 years (odds ratio = 2.10; 95% confidence interval, 1.09-4.06; P = .027) and hypertension as the cause of renal failure (odds ratio = 1.79; 95% confidence interval, 1.05-2.87; P = .002) had more abnormal findings. No differences in length of evaluation, rate of being listed for transplant, and rate of transplant were shown. CONCLUSIONS: The overall rate of adenomatous findings on colonoscopy was higher among patients with pretransplant end-stage renal disease than in the general population, as shown in other studies. Age, sex, dialysis vintage up to 3 years, and hypertensive renal failure were associated with adenomatous polyps of the colon in this study population. Because adenomatous polyp rates are high in patients with chronic kidney disease who are undergoing transplant evaluation and colonoscopic findings do not appear to delay transplant evaluations or listing rates, screening colonoscopies should be encouraged. PMID- 28621635 TI - Clinical Impact and Risk Factors of Portal Vein Thrombosis for Patients on Wait List for Liver Transplant. AB - OBJECTIVES: The effect of portal vein thrombosis on the progression of liver disease is controversial, with no consensus on optimal treatment. We aimed to assess how portal vein thrombosis affects wait list outcomes, identify risk factors associated with its development while on a wait list, and assess its effects on patient and graft survival. MATERIALS AND METHODS: This US-based retrospective cohort study analyzed 134 109 adult patients on wait lists for or undergoing primary orthotopic liver transplant between January 2002 and June 2014. Rate of portal vein thrombosis development, time from entry on wait list to transplant, comparisons of wait list drop-off rates between patients with versus those without portal vein thrombosis, risk factors associated with its development while on a wait list, and its effects on patient and graft survival were analyzed. RESULTS: We found that the rate of portal vein thrombosis at listing increased. Patients with the disease at listing were more likely to be removed from wait lists because of being too sick. Portal vein thrombosis at listing was an independent risk factor for being removed from a wait list. Of 63 265 patients who underwent primary orthotopic liver transplant, those with the disease were more likely to have higher Model for End-Stage Liver Disease scores and incidence of nonalcoholic steatohepatitis and diabetes mellitus. Portal vein thrombosis had a negative effect on patient and graft survival. Nonalcoholic steatohepatitis, body mass index, diabetes, and hepatocellular carcinoma were identified as risk factors for its development. CONCLUSIONS: Portal vein thrombosis represents an increasing management and outcome burden in liver transplant. Having this disease at listing and/or at time of transplant is associated with worse patient and graft survival. Nonalcoholic steatohepatitis and hepatocellular carcinoma are among the biggest risk factors for its development while on a wait list. PMID- 28621637 TI - Surgical Techniques and Procedures for Kidney Transplant Recipients With Severe Atherosclerosis. AB - OBJECTIVES: Atherosclerosis is becoming a more common problem for dialysis patients. Therefore, transplant surgeons are faced with the need to develop surgical techniques and procedures for severe atherosclerosis. This study aimed to clarify the clinical features, the usefulness of examinations, and operative procedures for kidney transplant recipients with the complication of severe atherosclerosis. MATERIALS AND METHODS: Among 220 kidney transplant candidates, 13 patients (severe atherosclerosis group) were predicted complications due to arterial calcification in the bilateral iliac arterial system using a computed tomographic scan. They were compared with the remaining 207 patients (mild atherosclerosis group) based on patient characteristics. The severe atherosclerosis group was evaluated by additional examination, anastomosis procedure of the graft artery, and patient outcome. RESULTS: The severe atherosclerosis group had significantly higher rates of mean recipient age, glycosylated hemoglobin A1c, past smoking, and administration of antithrombotics. Past vascular surgery related to atherosclerosis in the aortoiliac region had been performed in 8 patients from the severe atherosclerosis group. A three dimensional computed tomography angiography and an intraoperative periarterial echography were useful to determine the kidney transplant site. A balloon catheter effectively blocked blood flow. A polytetrafluoroethylene vascular graft was used for bypass between the graft artery and abdominal aorta. All kidney grafts of the severe atherosclerosis group were functioning well. CONCLUSIONS: Kidney transplant for patients with severe atherosclerosis can be achieved successfully by additional examinations and vascular surgical techniques. PMID- 28621638 TI - Urologic Complications After Renal Transplant: A Single-Center Experience. AB - OBJECTIVES: Urologic complications after kidney transplant are associated with significant morbidity, mortality, and prolonged hospital stay. An intervention or second surgical procedure is frequently required. Here, we report urologic complications in adult kidney recipients. MATERIALS AND METHODS: Since 2006, 171 adult kidney transplant procedures have been performed at the Gazi University Transplantation Center (Ankara, Turkey). Among these patients, there were 65 adult female (38%) and 106 adult male (62%) recipients. Donor source included 61 deceased donations (36%) and 110 living related donations (64%). The Haberal corner-saving technique was used for ureteroneocystostomy anastomosis. All recipients received a calcineurin-based triple immunosuppression regimen. All recipients also received trimethoprim/sulfamethoxazole prophylaxis for 3 months after transplant. RESULTS: In the 171 adult kidney recipients analyzed for urologic complications, mean age was 32.5 +/- 14.1 years (median: 32.5 y; range, 18-67 y); mean donor age was 41 +/- 14.2 years (median: 42 y). We focused on 3 specific urologic complications: urine leak, ureteric stenosis, and symptomatic vesicoureteral reflux. In our study group, urologic complications were encountered in 7 patients (4%), with 5 complications detected in the early period and 2 complications detected in the late period. No symptomatic vesicoureteral reflux complications were shown in this study group. Urologic complications did not result in any patient deaths or graft loss. CONCLUSIONS: In this study, the Haberal corner-saving suture technique with double J stent seemed to have a protective effect for development of urologic complications. PMID- 28621636 TI - Is Brain-Dead Donor Fluid Therapy With Colloids Associated With Better Kidney Grafts? AB - OBJECTIVES: Fluid therapy is required to maintain perfusion to donor organs. Recent reviews on the choices of fluids have emphasized the safety of using crystalloids, as opposed to fluid therapy with colloids, which has been reported to be either unequivocally or potentially harmful in a number of studies on various patient populations. We aimed to analyze whether the type of fluid administered to donors is connected with kidney transplant outcomes. MATERIALS AND METHODS: A total of 100 consecutive brain-dead multiorgan donors and their respective 181 kidney recipients were studied retrospectively. Data concerning donor fluid therapy, the characteristics of the donors and the recipients, and outcomes after kidney transplant were extracted from organ retrieval and patient records. Cases with early graft function were compared with cases with delayed graft function. RESULTS: Donors had received both crystalloids and colloids in most cases (84%). Fluid therapy with crystalloids alone was more common among the 40 recipients with delayed (30%) than in the 103 recipients with early graft function (11%) (P = .005). Donor age, time on renal replacement therapy before transplant, and donor fluid therapy with crystalloids alone were independent risk factors for delayed graft function in multivariate analysis. CONCLUSIONS: Our results suggest that donor fluid therapy including colloids could be beneficial instead of harmful compared with treatment with crystalloids alone. This finding needs to be evaluated in prospective studies. PMID- 28621639 TI - Outcome of the Double-J Stent Placement in Pediatric Kidney Transplant: A Single Center Experience. AB - OBJECTIVES: Double J stent placement at kidney transplant may reduce stenosis or leakage complication rates. However, placement may also increase risk for early urinary tract infection (ie, < 3 mo after transplant). In children, the usefulness of double J stent placement is not well defined. MATERIALS AND METHODS: We analyzed retrospective data from children who received transplants at the Gazi University Transplantation Center and Pediatric Nephrology (Ankara, Turkey) for outcomes related to double J stents. At our center, double J stent placement decision is made by the transplant surgery team during operation. Placements were routinely performed in all transplant recipients. Stent removal occurs within 6 week after transplant. RESULTS: Among 42 transplants since 2006, early urinary tract infection was seen in 7% and stenosis in 3.6% of patients, with no leakage reported. Mean stent removal time was 6 +/- 0.5 weeks. Early urinary tract infection was seen in 3 recipients with posterior urethral valve and neurogenic bladder (2 recipients) and meningoma cells and neurogenic bladder (1 recipient). All 3 recipients with early urinary tract infection received clean intermittent catheterization after transplant for adequate emptying of the bladder. In our study group, stent complications such as migration (2 patients) and hematuria (1 patient) were seen, but crusting, breakage, and stone formation were not seen. The 3 patients with urinary tract infection had neurogenic bladder types, complicating the urine outflow system. Stent placement was not a significant risk factor for early urinary tract infection and but had a protective effect. CONCLUSIONS: In our study group, we observed no risk factors for routine double J stent placement in pediatric renal transplant procedures. Stent placement was not a risk factor for early urinary tract infection. However, regardless of stent placement, when a recipient had complicated urologic outflow problems, infection became a long-term hurdle. PMID- 28621640 TI - Clinical and Biochemical Characteristics of Brain-Dead Donors as Predictors of Early- and Long-Term Renal Function After Transplant. AB - OBJECTIVES: Organs from brain-dead donors are the main source of allografts for transplant. Comparisons between living-donor and brain-dead donor kidneys show that the latter are more likely to demonstrate delayed graft function and lower long-term survival. This study aimed to assess the effects of various clinical and biochemical factors of donors on early- and long-term renal function after transplant. MATERIALS AND METHODS: We analyzed data from kidney recipients treated between 2006 and 2008 who received organs from brain-dead donors. Data from 54 donors and 89 recipients were analyzed. RESULTS: No relation was observed between donor sodium concentration and the presence of delayed graft function. Donor height was positively correlated with creatinine clearance in recipients in the 1 to 3 months after renal transplant. Donor diastolic blood pressure was negatively correlated with estimated glomerular filtration rate throughout the observation period. Donor age was negatively correlated with the allograft recipient's estimated glomerular filtration rate throughout 4 years of observation. Donor estimated glomerular filtration rate was positively correlated with that of the recipient throughout 3 years of observation. CONCLUSIONS: The results of this study indicate that various factors associated with allograft donors may influence graft function. PMID- 28621641 TI - Colistin resistance in Pseudomonas aeruginosa that is not linked to arnB. AB - PURPOSE: It is known that the arnB (or pmrH) gene encoding uridine 5'-(beta-1 threo-pentapyranosyl-4-ulose diphosphate) aminotransferase plays a critical role in colistin resistance in Pseudomonas aeruginosa through the addition of 4-amino 4-deoxy-l-arabinose (l-Ara4N) to lipid A. In this study, we attempted to obtain a colistin-resistant mutant from an arnB-deleted mutant through exposure to colistin. METHODOLOGY: We constructed an arnB deletion mutant (P5DeltaarnB :: nptIII) from a colistin-susceptible strain (P5) by allelic replacement mutagenesis, and colistin-resistant mutants were selected in vitro using P5 and P5DeltaarnB :: nptIII. The growth rate, lipid A structure, biofilm-forming activity and cell viability in diverse stressful conditions (osmotic, oxidative, acidic and heat stress) were investigated. Expression of phoP, pmrA, parR, and cprR was evaluated by qRT-PCR. RESULTS: An arnB deletion mutant was shown to develop colistin resistance through the addition of l-Ara4N to lipid A, despite a low survival rate (over 1000-fold lower than that of the wild-type strain) in the media with colistin. Two colistin-resistant mutants showed higher survival rates than colistin-susceptible strains against 5 % NaCl. In the presence of acidic and heat stress, P5DeltaarnB :: nptIII-CstR exhibited higher survival rates during conditions of 1 % HCl and 42 degrees C than the other strains. Both phoP and pmrA genes were overexpressed significantly in both colistin-resistant mutants, but parR and cprR genes were not. CONCLUSION: We revealed that colistin resistance could be developed despite arnB deletion in P. aeruginosa through the addition of l-Ara4N to lipid A, which was accompanied by diverse physiological changes. PMID- 28621642 TI - Spectrum and antibiotic resistance of uropathogens between 2004 and 2015 in a tertiary care hospital in Hungary. AB - PURPOSE: Surveillance of the bacterial spectrum and antibiotic-resistance patterns of locally occurring uropathogens is essential to serve as a basis for empirical treatment of urinary tract infections (UTIs), as antibiotic-resistance rates may vary geographically with significant differences between countries and regions, and with time. METHODOLOGY: We retrospectively analysed all urine samples taken in the department of urology in a tertiary care hospital in Hungary from January 2004 to December 2015.Results/Key findings. The five most commonly occurring bacteria were Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa and Proteus mirabilis. Resistance of Escherichia coli to ciprofloxacin increased significantly from 19 to 25 %. Although the resistance of Escherichia coli against cephalosporins showed an increasing trend, it still remained generally low. However, resistance rates of K. pneumoniae to cephalosporins were very high, reaching 60 %, due to the high rate of extended-spectrum-beta-lactamase-positive Klebsiella strains. We observed a significant increase in the rate of carbapenem-resistant Pseudomonas aeruginosa. CONCLUSION: Fluoroquinolones cannot be recommended for empirical treatment in our region. Cephalosporins can be a good empirical choice for treating Gram-negative UTIs, but should be avoided when multi-drug resistant (MDR) bacteria are suspected. Increases in the rate of carbapenem-resistant Pseudomonas aeruginosa, and in the general rate of MDR bacteria, are both a very alarming trend. We recommend practising prudent antibiotic policy, preferably using antibiotics with the narrowest possible spectrum. PMID- 28621643 TI - The clinical effectiveness of different surveillance strategies to prevent colorectal cancer in people with intermediate-grade colorectal adenomas: a retrospective cohort analysis, and psychological and economic evaluations. AB - BACKGROUND: The UK guideline recommends 3-yearly surveillance for patients with intermediate-risk (IR) adenomas. No study has examined whether or not this group has heterogeneity in surveillance needs. OBJECTIVES: To examine the effect of surveillance on colorectal cancer (CRC) incidence; assess heterogeneity in risk; and identify the optimum frequency of surveillance, the psychological impact of surveillance, and the cost-effectiveness of alternative follow-up strategies. DESIGN: Retrospective multicentre cohort study. SETTING: Routine endoscopy and pathology data from 17 UK hospitals (n = 11,944), and a screening data set comprising three pooled cohorts (n = 2352), followed up using cancer registries. SUBJECTS: Patients with IR adenoma(s) (three or four small adenomas or one or two large adenomas). PRIMARY OUTCOMES: Advanced adenoma (AA) and CRC detected at follow-up visits, and CRC incidence after baseline and first follow-up. METHODS: The effects of surveillance on long-term CRC incidence and of interval length on findings at follow-up were examined using proportional hazards and logistic regression, adjusting for patient, procedural and polyp characteristics. Lower intermediate-risk (LIR) subgroups and higher-intermediate-risk (HIR) subgroups were defined, based on predictors of CRC risk. A model-based cost-utility analysis compared 13 surveillance strategies. Between-group analyses of variance were used to test for differences in bowel cancer worry between screening outcome groups (n = 35,700). A limitation of using routine hospital data is the potential for missed examinations and underestimation of the effect of interval and surveillance. RESULTS: In the hospital data set, 168 CRCs occurred during 81,442 person-years (pys) of follow-up [206 per 100,000 pys, 95% confidence interval (CI) 177 to 240 pys]. One surveillance significantly lowered CRC incidence, both overall [hazard ratio (HR) 0.51, 95% CI 0.34 to 0.77] and in the HIR subgroup (n = 9265; HR 0.50, 95% CI 0.34 to 0.76). In the LIR subgroup (n = 2679) the benefit of surveillance was less clear (HR 0.62, 95% CI 0.16 to 2.43). Additional surveillance lowered CRC risk in the HIR subgroup by a further 15% (HR 0.36, 95% CI 0.20 to 0.62). The odds of detecting AA and CRC at first follow-up (FUV1) increased by 18% [odds ratio (OR) 1.18, 95% CI 1.12 to 1.24] and 32% (OR 1.32, 95% CI 1.20 to 1.46) per year increase in interval, respectively, and the odds of advanced neoplasia at second follow-up increased by 22% (OR 1.22, 95% CI 1.09 to 1.36), after adjustment. Detection rates of AA and CRC remained below 10% and 1%, respectively, with intervals to 3 years. In the screening data set, 32 CRCs occurred during 25,745 pys of follow-up (124 per 100,000 pys, 95% CI 88 to 176 pys). One follow-up conferred a significant 73% reduction in CRC incidence (HR 0.27, 95% CI 0.10 to 0.71). Owing to the small number of end points in this data set, no other outcome was significant. Although post-screening bowel cancer worry was higher in people who were offered surveillance, worry was due to polyp detection rather than surveillance. The economic evaluation, using data from the hospital data set, suggested that 3-yearly colonoscopic surveillance without an age cut-off would produce the greatest health gain. CONCLUSIONS: A single surveillance benefited all IR patients by lowering their CRC risk. We identified a higher-risk subgroup that benefited from further surveillance, and a lower-risk subgroup that may require only one follow-up. A surveillance interval of 3 years seems suitable for most IR patients. These findings should be validated in other studies to confirm whether or not one surveillance visit provides adequate protection for the lower-risk subgroup of intermediate-risk patients. STUDY REGISTRATION: Current Controlled Trials ISRCTN15213649. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28621644 TI - Farewell Mark. PMID- 28621645 TI - Patterns and factors of problematic marijuana use in the Canadian population: Evidence from three cross-sectional surveys. AB - OBJECTIVES: The objectives of this study are to describe marijuana use in Canada and explore factors associated with problematic use. METHODS: Data from the 2010 2012 circulations of the Canadian Alcohol and Drug Use Monitoring Survey were used to create three logistic regression models for the purposes of identifying and comparing factors associated with the degree of marijuana use, as determined via the WHO Alcohol, Smoking and Substance Abuse Involvement Screening Test (non problematic, problematic) and European Monitoring Centre for Drugs and Drug Addiction (experiential, recent, current) methods. RESULTS: Canadians aged 15-24 years are 15 times (p < 0.001) more likely to be current users than Canadians aged 65 or older, with the odds of exhibiting problematic marijuana use being 10 times (p < 0.001) greater. The odds of a male exhibiting problematic marijuana use are 2.46 times (p < 0.001) greater than for females. The odds of exhibiting problematic marijuana use are 41.0% (p = 0.031) and 53.0% (p = 0.008) greater for marijuana users with household incomes $40,000-$80,000 and less than $40,000 respectively compared to those with household income over $80,000. An earlier age of first marijuana use is associated with problematic use but not necessarily with being a current user. CONCLUSION: The majority of our findings are consistent with the literature, showing that Canadians who are: male, adolescent or young adult, smokers, heavy drinkers, other illicit drug users, and who have poorer mental health status are more likely to engage in any marijuana use, particularly higher levels of marijuana use. These findings can be used to inform the development of policy in Canada to address problematic marijuana use and prepare for its possible legalization. PMID- 28621646 TI - The contribution of excise cigarette taxes on the decline in youth smoking in Canada during the time of the Federal Tobacco Control Strategy (2002-2012). AB - OBJECTIVES: To evaluate the impact of changes in cigarette taxes on smoking for youths aged 15-18 in Canada during the time of the Federal Tobacco Control Strategy (FTCS). METHODS: We used a difference-in-differences framework and leveraged the variation in cigarette taxes across Canada and over time. We used regression models with province and year fixed effects, and individual-level and provincial-level covariates on 2002-2012 data from the Canadian Tobacco Use Monitoring Survey. RESULTS: Tax increases generally did not affect smoking outcomes. Each increase of CAD $1.00 (adjusted to year 2000 dollars) in excise cigarette taxes per package of 20 was associated with a 0.2 percentage point (95% CI: -1.8; 2.2) change in smoking prevalence, and a change of 0.3 in mean cigarettes smoked in the past week (95% CI: -1.2; 1.8). CONCLUSION: From 2002 to 2012, smoking prevalence and mean smoking frequency were in steady decline among youths in Canada. This decline, however, was evident even among provinces with stable or decreasing cigarette tax levels. Tobacco taxes have mostly increased since the 1980s, and so, tax levels were already quite high by the launch of the FTCS. Province fixed effects and common temporal changes accounted for 83.7% of the variation in smoking prevalence. We derived similar results for smoking frequency. The cumulative tax increase during our study period was at least $1.00 for only three provinces. Thus, our findings suggest that factors driving down tobacco use among youths in all provinces appear to outweigh any impact of small tax increases at already high tax levels. PMID- 28621647 TI - Timeliness and completeness of routine childhood vaccinations in children by two years of age in Alberta, Canada. AB - OBJECTIVES: Assessing timeliness and completeness of vaccine administration is important for evaluating the effectiveness of immunization programs. Few studies have reported timeliness, particularly in Canada. The objective of this study was to examine timeliness of the receipt of vaccination for each routine childhood recommended vaccine by 24 months of age among children in a community-based pregnancy cohort in Calgary, Alberta. METHODS: Survey data from a community-based pregnancy cohort in Alberta were linked to Public Health vaccination records of children (n = 2763). The proportion of children receiving early, timely, delayed, or no vaccination was calculated. A dose was considered early if it was administered before the recommended age in days as per the vaccination schedule, timely if administered at any time from start of recommended age in days to age in days when delay counts were initiated, and delayed if it was administered on or after age in days when delay counts were initiated. Series completion rates were also calculated. RESULTS: For multi-dose vaccines, over 80% of children had timely doses at 2, 4 and 6 months. By 12 months, this proportion decreased to 65% (95% CI: 63%-66%) for meningococcal conjugate group C, 61% (95% CI: 59%-62%) for measles antigen-containing vaccines and 64% (95% CI: 62%-65%) for varicella antigen-containing vaccines. At 18 months, only 55% (95% CI: 53%-56%) of the children had a timely 4th dose of diphtheria, acellular pertussis, tetanus, polio, and Haemophilus influenzae type b vaccine. Eventual series completion rate for all recommended vaccines was 77% (95% CI: 75%-79%). CONCLUSION: The timeliness and completeness of routine childhood vaccination in preschool children in this community-based pregnancy cohort is lower than provincial targets. Data on timeliness of vaccination can inform further work on barriers and enablers to vaccination in order to meet provincial targets. PMID- 28621648 TI - High vulnerability to household food insecurity in a sample of Canadian renter households in government-subsidized housing. AB - OBJECTIVES: To determine the prevalence and severity of household food insecurity and examine household material circumstances related to food insecurity in a sample of renter households in government-subsidized housing. METHODS: Cross sectional data from the 2010 Survey of Household Spending were used to determine the food insecurity status of 455 renter households living in the 10 provinces and receiving a government housing subsidy. Multivariable logistic regressions were conducted to examine the relationship between household characteristics describing material circumstances and food insecurity. RESULTS: One in two households was food insecure. Marginal, moderate and severe food insecurity affected 9.0%, 23.3% and 18.5% of households respectively. Household economic resources, as captured with after-tax income, after-rent income, or total expenditure, had an independent, inverse relationship with food insecurity. Among the other characteristics examined, more adults or children in the household, presence of a member with disability, and receipt of social assistance increased the odds of food insecurity, but receipt of social assistance lost statistical significance when controlling for total expenditure. Presence of a senior in the household was independently associated with lower odds of food insecurity. CONCLUSION: Our findings suggest that more effective income-based interventions are needed to address food insecurity among low-income households receiving government housing subsidies. A better integration of housing and income-based policies is necessary to support household food security among government subsidized renter households. PMID- 28621649 TI - A natural experimental study of the protective effect of home ownership on household food insecurity in Canada before and after a recession (2008-2009). AB - OBJECTIVES: Home ownership as opposed to renting is associated with lower rates of food insecurity, the latter being a marker of household economic deprivation associated with adverse health outcomes. It is unclear whether this relationship persists during a major economic decline, or whether different subgroups of home owners are equally protected. The 2008-2009 recession in Canada was tied to events in the United States related to inappropriate mortgage financing; the impact of the recession on food insecurity among home owners may identify policies to mitigate recessionary outcomes. METHODS: We used a before-and-after natural experimental design using data from the Canadian Community Health Survey (CCHS) cycles 2007/2008 (pre-recession) and 2009/2010 (post-recession) with information on household food insecurity, home ownership versus renting, and socio-demographics. Applying multivariable logistic regression, we examined changes in household food insecurity by housing tenure and sex over the period. RESULTS: Pre-recession, food insecurity affected 3.3% of home owners and 17.1% of renter households. Among home owners, the risk of food insecurity increased post recession by 10%, which was not statistically significant. Post-recession, and with adjustment, although renters' higher absolute risk of food insecurity persisted, male-respondent home owners experienced the highest rate of increase in food insecurity prevalence by subgroup (OR = 1.26, 95% CI: 1.06-1.50) versus renters (OR = 1.17, 95% CI: 1.05-1.29). CONCLUSION: Housing policies in Canada protected most home owners from precarity during the 2008-2009 economic recession; however, male-respondent home owners exhibited a unique economic vulnerability during this time. Implications of Canadian home ownership policies are discussed in light of differential vulnerability of home owner groups. PMID- 28621650 TI - Socio-economic status and fruit juice consumption in Canada. AB - OBJECTIVES: The role of socio-economic status (SES) in fruit juice and fruit drink consumption is not well understood in a Canadian context. This study examines the relationship between SES and Canadian fruit juice and fruit drink consumption. METHODS: The Canadian Community Health Survey (2011-2012), a cross sectional survey that employs multistage cluster sampling, provided relevant data for a sample of 103 125 Canadians, aged 12 and older, living in the 10 provinces. Household income level decile, ranked at the health region level, was used as a surrogate measure of SES. Fruit juice and fruit drink consumption data were collected via self-report in telephone/in-person interviews. Multivariable gamma regression was used to model the relationship between SES and frequency of fruit juice and fruit drink consumption, adjusting for age, sex, diabetes status, daily fruit and vegetable consumption, education level, racial identity and physical activity. RESULTS: A negative relationship was found, with a decreasing daily rate of fruit juice and fruit drink consumption associated with increasing SES. In the adjusted model, Canadians in the lowest SES category consumed fruit juice and fruit drinks at an average daily rate 1.18 times (95% CI: 1.14-1.23) that of Canadians in the highest SES category. CONCLUSION: The negative association between health region-adjusted SES and fruit juice and fruit drink consumption highlights the potentially important role of socio-economic factors at a local level. Canadian policy that aims to lower fruit juice and fruit drink consumption, and thus sugar intake, should target financial avenues (such as making fruit juice less financially attractive by lowering the cost of whole fruit and vegetables) in addition to communicating health benefits. PMID- 28621651 TI - The economic benefits of fruit and vegetable consumption in Canada. AB - OBJECTIVES: The objectives of this study were to determine the proportion of the population that meets or exceeds Canada's Food Guide (CFG) recommendations regarding the number of daily servings of fruits and vegetables (F/V), to assess trends in this proportion between 2000 and 2013, to estimate the annual economic burden attributable to inadequate F/V consumption within the context of other important risk factors, and to estimate the short- and long-term costs that could be avoided if modest improvements were made to F/V consumption in Canada. METHODS: We used a previously developed methodology based on population attributable fractions and a prevalence-based cost-of-illness approach to estimate the economic burden associated with low F/V consumption. RESULTS: Over three quarters of Canadians are not meeting CFG recommendations regarding the number of daily servings of F/V, leading to an annual economic burden of $4.39 billion. If a 1% relative increase in F/V consumption occurred annually between 2013 and 2036, the cumulative reduction in economic burden over the 23-year period would reach $8.4 billion. Consumption levels of F/V, and the resulting economic burden, varied by sex, age and province. CONCLUSION: A significant majority of Canadians are not consuming the recommended daily servings of F/V, with important consequences to their health and the Canadian economy. Programs and policies are required to encourage F/V consumption in Canada. PMID- 28621652 TI - Region-level obesity projections and an examination of its correlates in Quebec. AB - OBJECTIVES: Regional public health policy-makers frequently adopt obesity programs and objectives that have been established at global, provincial/state or national levels. However, the presence of substantial inter-regional disparities could render this practice inefficient. Studies that collectively assess obesity prevalence, temporal trends and their heterogeneity at the region level are rare, though they could be used to support better regional surveillance and planning. To address this gap, our study projected obesity prevalence time series to 2023 for 16 health regions in Quebec. We also compared the extent to which yearly rates of increase (or slope) versus cross-sectional prevalence drove regional heterogeneity and correlated with obesity-related sociodemographic and behavioural characteristics. METHODS: Projections were done using weighted compositional regression to fit and extrapolate obesity prevalence time series (1987-2012). Heterogeneity in obesity prevalence as a function of time and obesity slope were characterized using standard deviation. The correlation of region-level obesity prevalence and slope with 14 area-level obesity-related characteristics was assessed. RESULTS: Obesity prevalence is projected to increase in all regions. Region-level heterogeneity in prevalence in 2012 (sigma = 2.2%) is projected to increase to (sigma = 3.1%) by 2023. The increase in prevalence heterogeneity appeared to be driven by region-level heterogeneity in slope (beta = 0.22%-0.51%/year). Obesity-related characteristics were found to be more strongly correlated with slope than with prevalence. CONCLUSION: Large area obesity trends mask substantial and increasing region-level disparities. Obesity slope appears to drive region-level heterogeneity and correlate strongly with explanatory factors, and may represent a pertinent metric for public health monitoring. PMID- 28621653 TI - Increased mortality among Indigenous persons in a multisite cohort of people living with HIV in Canada. AB - OBJECTIVE: Compare all-cause mortality between Indigenous participants and participants of other ethnicities living with HIV initiating combination antiretroviral therapy (cART) in an interprovincial multi-site cohort. METHODS: The Canadian Observational Cohort is a collaboration of 8 cohorts of treatment naive persons with HIV initiating cART after January 1, 2000. Participants were followed from the cART initiation date until death or last viral load (VL) test date on or before December 31, 2012. Cox proportional hazard models were used to estimate the effect of ethnicity on time until death after adjusting for age, gender, injection drug use, being a man who has sex with men, hepatitis C, province of origin, baseline VL and CD4 count, year of cART initiation and class of antiretroviral medication. RESULTS: The study sample consisted of 7080 participants (497 Indigenous, 2471 Caucasian, 787 African/Caribbean/Black (ACB), 629 other, and 2696 unknown ethnicity). Most Indigenous persons were from British Columbia (BC) (83%), with smaller numbers from Ontario (13%) and Quebec (4%). During the study period, 714 (10%) participants died. The five-year survival probability was lower for Indigenous persons (0.77) than for Caucasian (0.94), ACB (0.98), other ethnicities (0.96) and unknown ethnicities (0.85) (p < 0.0001). In an adjusted proportional hazard model for which missing data were imputed, Indigenous persons were more likely to die than Caucasian participants (hazard ratio = 2.69, p < 0.0001). CONCLUSION: The mortality rate for Indigenous persons was higher than for other ethnicities and is largely reflective of the BC population. Addressing treatment challenges and identifying HIV- and non-HIV related causes for mortality among Indigenous persons is required to optimize their clinical management. PMID- 28621654 TI - Diabetes risk reduction in primary care: Evaluation of the Ontario Primary Care Diabetes Prevention Program. AB - OBJECTIVES: Lifestyle interventions can reduce type 2 diabetes risk. The Primary Care Diabetes Prevention Program (PCDPP) was implemented by the Government of Ontario to lower diabetes risk. This study first evaluated the program, and second used a validated tool to estimate a potential population impact if the program were implemented more broadly in the province. METHODS: PCDPP was implemented in six primary care settings serving communities with high mortality risk due to chronic diseases. In total, 1916 adults with prediabetes or metabolic syndrome were enrolled from January 2011 to December 2012. Body weight was the primary outcome variable, and was modeled using four time periods (i.e., baseline, 3rd, 6th and 9th month). The intervention effect was estimated using multilevel mixed-effects linear regression, and was stratified by gender and age. In the population impact analysis, a number needed to treat (NNT) for the intervention to prevent one case of diabetes and an absolute number of diabetes cases averted were estimated. RESULTS: Weight loss over 9 months was 7.5% (or 6.8 kg), with 7.4% (or 6.4 kg) in females and 8.6% (or 8.6 kg) in males. When modeled, changes in weight were all statistically significant. The models for male participants predicted, however, some gains in weight in the last 3 months of the program. Dropout rates were 26.8%, 46.8% and 63.0% at 3rd, 6th and 9th month respectively. Scaling up the program would produce an NNT of approximately 36 and would avert 6401 cases of diabetes in five years. CONCLUSION: PCDPP may represent a potentially effective tool for population-level diabetes risk reduction. PMID- 28621656 TI - Pathways to policy: Lessons learned in multisectoral collaboration for physical activity and built environment policy development from the Coalitions Linking Action and Science for Prevention (CLASP) initiative. AB - OBJECTIVES: The Canadian Partnership Against Cancer funded 12 large-scale knowledge to action cancer and chronic disease prevention projects between 2009 and 2016 through the Coalitions Linking Action and Science for Prevention (CLASP) initiative. Two projects, Healthy Canada by Design (HCBD) and Children's Mobility, Health and Happiness (CMHH), developed policies to address physical activity and the built environment through a multisectoral approach. A qualitative analysis involving a review of 183 knowledge products and 8 key informant interviews was conducted to understand what policy changes occurred, and the underlying critical success factors, through these projects. SETTING: Both projects worked at the local level to change physical activity and built environment policy in 203 sites, including municipalities and schools. Both projects brought multisectoral expertise (e.g., public health, land use planning, transportation engineering, education, etc.) together to inform the development of local healthy public policy in the areas of land use, transportation and school travel planning. INTERVENTION: Through the qualitative analysis of the knowledge products and key informant interviews, 163 policies were attributed to HCBD and CMHH work. OUTCOMES: Fourteen "pathways to policy" were identified as critical success factors facilitating and accelerating the development and implementation of physical activity and built environment policy. Of the 14 pathways to policy, 8 had a focus on multisectoral collaboration. IMPLICATIONS: The lessons learned from the CLASP experience could support enhanced multisectoral collaborations to accelerate the development and implementation of physical activity and built environment policy in new jurisdictions across Canada and internationally. PMID- 28621655 TI - Trends in the leading causes of injury mortality, Australia, Canada, and the United States, 2000-2014. AB - OBJECTIVES: The aim of this study was to highlight the differences in injury rates between populations through a descriptive epidemiological study of population-level trends in injury mortality for the high-income countries of Australia, Canada and the United States. METHODS: Mortality data were available for the US from 2000 to 2014, and for Canada and Australia from 2000 to 2012. Injury causes were defined using the International Classification of Diseases, Tenth Revision external cause codes, and were grouped into major causes. Rates were direct-method age-adjusted using the US 2000 projected population as the standard age distribution. RESULTS: US motor vehicle injury mortality rates declined from 2000 to 2014 but remained markedly higher than those of Australia or Canada. In all three countries, fall injury mortality rates increased from 2000 to 2014. US homicide mortality rates declined, but remained higher than those of Australia and Canada. While the US had the lowest suicide rate in 2000, it increased by 24% during 2000-2014, and by 2012 was about 14% higher than that in Australia and Canada. The poisoning mortality rate in the US increased dramatically from 2000 to 2014. CONCLUSION: Results show marked differences and striking similarities in injury mortality between the countries and within countries over time. The observed trends differed by injury cause category. The substantial differences in injury rates between similarly resourced populations raises important questions about the role of societal-level factors as underlying causes of the differential distribution of injury in our communities. PMID- 28621657 TI - A surgical intervention for the body politic: Generation Squeeze applies the Advocacy Coalition Framework to social determinants of health knowledge translation. AB - SETTING: The World Health Organization Commission on the Social Determinants of Health (SDoH) observes that building political will is central to all its recommendations, because governments respond to those who organize and show up. Since younger Canadians are less likely to vote or to organize in between elections, they are less effective at building political will than their older counterparts. This results in an age gap between SDoH research and government budget priorities. Whereas Global AgeWatch ranks Canada among the top countries for aging, UNICEF ranks Canada among the least generous OECD (Organisation for Economic Co-operation and Development) countries for the generations raising young children. INTERVENTION: A surgical intervention into the body politic. Guided by the "health political science" literature, the intervention builds a non-profit coalition to perform science-based, non-partisan democratic engagement to increase incentives for policy-makers to translate SDoH research about younger generations into government budget investments. OUTCOMES: All four national parties integrated policy recommendations from the intervention into their 2015 election platforms. Three referred to, or consulted with, the intervention during the election. The intervention coincided with all parties committing to the single largest annual increase in spending on families with children in over a decade. IMPLICATIONS: Since many population-level decisions are made in political venues, the concept of population health interventions should be broadened to include activities designed to mobilize SDoH science in the world of politics. Such interventions must engage with the power dynamics, values, interests and institutional factors that mediate the path by which science shapes government budgets. PMID- 28621658 TI - Zoning out methadone and rising opioid-related deaths in Ontario: Reforms and municipal government actions. AB - In this commentary, we argue that the use of amendments to bylaws by Ontario cities and municipalities to restrict where and how methadone maintenance treatment (MMT) clinics and pharmacies operate may run counter to efforts to prevent record high rates of opioid-related overdoses. As the province of Ontario seeks to reform the opioid treatment system, it is crucial to understand the structural (e.g., stigma) and treatment system organization factors that drive the actions of municipalities such as those described above. Changes that exacerbate these factors may lead to increased use of bylaws to curtail access at a time when efforts are underway to reduce alarming rates of opioid-related overdose. PMID- 28621659 TI - Reclaiming Indigenous identities: Culture as strength against suicide among Indigenous youth in Canada. AB - In Canada, Indigenous youth suicide represents one of several health disparities burdening Indigenous populations, and like many other of these disparities, can be understood as an expression of societal, historical, cultural and familial trauma. As the number of Indigenous youth who take their own lives every year in Canada continues to far exceed national averages, it appears that conventional suicide prevention efforts remain ineffective among this population. A growing body of research argues that conventional interventions, largely rooted in Western individual-level behavioural change frameworks, are culturally discordant with Indigenous paradigms. In response, some Indigenous communities are turning to cultural revitalization as a holistic community-driven response to suicide prevention and treatment. The following commentary explores the emerging evidence base for "culture as treatment" - a novel approach to suicide that emphasizes the significance of interconnectedness in healing, alongside the revitalization of traditional values to reclaim community wellness. In doing so, we seek to contribute to a changing discourse surrounding Indigenous youth suicide by acknowledging culture as strength against this national crisis. PMID- 28621660 TI - Promoting children's health: Toward a consensus statement on food literacy. AB - This consensus statement reflects the views of a diverse group of stakeholders convened to explore the concept of "food literacy" as it relates to children's health. Evidence-based conceptions of food literacy are needed in light of the term's popularity in health promotion and educational interventions designed to increase food skills and knowledge that contribute to overall health. Informed by a comprehensive scoping review that identified seven main themes of food literacy, meeting participants ranked those themes in terms of importance. Discussions highlighted two key points in conceptualizing food literacy: the need to recognize varying food skill and knowledge levels, and the need to recognize critical food contexts. From these discussions, meeting participants created two working definitions of food literacy, as well as the alternative conception of "radical food literacy". We conclude that multiple literacies in relation to food skills and knowledge are needed, and underline the importance of ongoing dialogue in this emergent area of research. PMID- 28621661 TI - Prevalence of non-food allergies among British Columbia residents from different countries of origin. PMID- 28621662 TI - Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling. AB - Lithium is widely used as a treatment for Bipolar Disorder although the molecular mechanisms that underlie its therapeutic effects are under debate. In this study, we show brain-derived neurotrophic factor (BDNF) is required for the antimanic like effects of lithium but not the antidepressant-like effects in mice. We performed whole cell patch clamp recordings of hippocampal neurons to determine the impact of lithium on synaptic transmission that may underlie the behavioral effects. Lithium produced a significant decrease in alpha-amino-3-hydroxyl-5 methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes due to postsynaptic homeostatic plasticity that was dependent on BDNF and its receptor tropomyosin receptor kinase B (TrkB). The decrease in AMPAR function was due to reduced surface expression of GluA1 subunits through dynamin-dependent endocytosis. Collectively, these findings demonstrate a requirement for BDNF in the antimanic action of lithium and identify enhanced dynamin-dependent endocytosis of AMPARs as a potential mechanism underlying the therapeutic effects of lithium. PMID- 28621663 TI - Ionotropic Receptor-dependent moist and dry cells control hygrosensation in Drosophila. AB - Insects use hygrosensation (humidity sensing) to avoid desiccation and, in vectors such as mosquitoes, to locate vertebrate hosts. Sensory neurons activated by either dry or moist air ('dry cells' and 'moist cells') have been described in many insects, but their behavioral roles and the molecular basis of their hygrosensitivity remain unclear. We recently reported that Drosophila hygrosensation relies on three Ionotropic Receptors (IRs) required for dry cell function: IR25a, IR93a and IR40a (Knecht et al., 2016). Here, we discover Drosophila moist cells and show that they require IR25a and IR93a together with IR68a, a conserved, but orphan IR. Both IR68a- and IR40a-dependent pathways drive hygrosensory behavior: each is important for dry-seeking by hydrated flies and together they underlie moist-seeking by dehydrated flies. These studies reveal that humidity sensing in Drosophila, and likely other insects, involves the combined activity of two molecularly related but neuronally distinct hygrosensing systems. PMID- 28621664 TI - Post-meiotic DNA double-strand breaks occur in Tetrahymena, and require Topoisomerase II and Spo11. AB - Based on observations of markers for DNA lesions, such as phosphorylated histone H2AX (gammaH2AX) and open DNA ends, it has been suggested that post-meiotic DNA double-strand breaks (PM-DSBs) enable chromatin remodeling during animal spermiogenesis. However, the existence of PM-DSBs is unconfirmed, and the mechanism responsible for their formation is unclear. Here, we report the first direct observation of programmed PM-DSBs via the electrophoretic separation of DSB-generated DNA fragments in the ciliate Tetrahymena thermophila. These PM-DSBs are accompanied by switching from a heterochromatic to euchromatic chromatin structure in the haploid pronucleus. Both a topoisomerase II paralog with exclusive pronuclear expression and Spo11 are prerequisites for PM-DSB induction. Reduced PM-DSB induction blocks euchromatin formation, characterized by histone H3K56 acetylation, leading to a failure in gametic nuclei production. We propose that PM-DSBs are responsible for histone replacement during the reprogramming of generative to undifferentiated progeny nuclei. PMID- 28621665 TI - Neural mechanisms of social learning in the female mouse. AB - Social interactions are often powerful drivers of learning. In female mice, mating creates a long-lasting sensory memory for the pheromones of the stud male that alters neuroendocrine responses to his chemosignals for many weeks. The cellular and synaptic correlates of pheromonal learning, however, remain unclear. We examined local circuit changes in the accessory olfactory bulb (AOB) using targeted ex vivo recordings of mating-activated neurons tagged with a fluorescent reporter. Imprinting led to striking plasticity in the intrinsic membrane excitability of projection neurons (mitral cells, MCs) that dramatically curtailed their responsiveness, suggesting a novel cellular substrate for pheromonal learning. Plasticity was selectively expressed in the MC ensembles activated by the stud male, consistent with formation of memories for specific individuals. Finally, MC excitability gained atypical activity-dependence whose slow dynamics strongly attenuated firing on timescales of several minutes. This unusual form of AOB plasticity may act to filter sustained or repetitive sensory signals. PMID- 28621666 TI - 9A structure of the COPI coat reveals that the Arf1 GTPase occupies two contrasting molecular environments. AB - COPI coated vesicles mediate trafficking within the Golgi apparatus and between the Golgi and the endoplasmic reticulum. Assembly of a COPI coated vesicle is initiated by the small GTPase Arf1 that recruits the coatomer complex to the membrane, triggering polymerization and budding. The vesicle uncoats before fusion with a target membrane. Coat components are structurally conserved between COPI and clathrin/adaptor proteins. Using cryo-electron tomography and subtomogram averaging, we determined the structure of the COPI coat assembled on membranes in vitro at 9 A resolution. We also obtained a 2.57 A resolution crystal structure of betadelta-COP. By combining these structures we built a molecular model of the coat. We additionally determined the coat structure in the presence of ArfGAP proteins that regulate coat dissociation. We found that Arf1 occupies contrasting molecular environments within the coat, leading us to hypothesize that some Arf1 molecules may regulate vesicle assembly while others regulate coat disassembly. PMID- 28621677 TI - Genome-wide methylome and chromatin interactome identify abnormal enhancer to be risk factor of breast cancer. AB - Enhancer is critical cis regulatory elements in gene expression. To understand whether and how the aberrant enhancer activation may contribute to cancer risk, the differentially methylated enhancers (eDMRs) in normal and malignant breast tissues were identified and analyzed. By incorporating genome-wide chromatin interaction, integrated analysis of eDMRs and target gene expression identified 1,272 enhancer-promoter pairs. Surprisingly, two functionally distinct groups of genes were identified in these pairs, one showing better correlation to enhancer methylation (eRGs) and the other showing better correlation to promoter methylation (pRGs), and the former group is functionally enriched with cancer related genes. Moreover, enhancer methylation based clustering of breast cancer samples is capable of discriminating basal breast cancer from other subtypes. By correlating enhancer methylation status to patient survival, 345 enhancers show the impact on the disease outcome and the majority of their target genes are important regulators of cell survival pathways including known cancer related genes. Together, these results suggest reactivation of enhancers in cancer cells has the add-on effect and contributes to cancer risk in combination. PMID- 28621693 TI - Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases: An EEG Study. AB - The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer's disease (ADMCI) and Parkinson's disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery. PMID- 28621694 TI - Ergonomics as a tool to improve the sustainability of the workforce. AB - BACKGROUND: The sustainability of the workforce is threatened due to working conditions. One of the reasons for this is an imbalance between the working conditions and the capacity of the workers. OBJECTIVE: The objective of the paper, based on a literature review, is to explore the relationship between two main concepts, beginning with sustainability, and finished with ergonomics. Based on that relationship, determine if ergonomics could be helpful to improve the sustainability of the workforce. METHODS: Literature review was based on two keywords: sustainability and ergonomics. The focus was on create a theoretical path between these two concepts. The literature review draws on 100 journal articles, books, conference proceedings, thesis and reports. RESULTS: The results of the literature review highlights that an ergonomics approach is helpful and appropriate to determine the mismatch between people capacity and system demand. In that sense, the literature review reveals that both disciplines, ergonomics and sustainability, share the same principles and that the mix of both has significant potential. However, the literature also shows a lack of empirical information that proves that potential. CONCLUSION: The review first posits that sustainability principles could be helpful to improve the working conditions, and second, that an ergonomics approach provides information related with working conditions, organizations' problems and the needs of workers that would be helpful to create a sustainability workforce. PMID- 28621695 TI - Learning challenges and sustainable development: A methodological perspective. AB - BACKGROUND: Sustainable development requires learning, but the contents of learning are often complex and ambiguous. This requires new integrated approaches from research. It is argued that investigation of people's learning challenges in every-day work is beneficial for research on sustainable development. OBJECTIVE: The aim of the paper is to describe a research method for examining learning challenges in promoting sustainable development. This method is illustrated with a case example from organic vegetable farming in Finland. METHODS: The method, based on Activity Theory, combines historical analysis with qualitative analysis of need expressions in discourse data. RESULTS: The method linking local and subjective need expressions with general historical analysis is a promising way to overcome the gap between the individual and society, so much needed in research for sustainable development. CONCLUSIONS: Dialectically informed historical frameworks have practical value as tools in collaborative negotiations and participatory designs for sustainable development. The simultaneous use of systemic and subjective perspectives allows researchers to manage the complexity of practical work activities and to avoid too simplistic presumptions about sustainable development. PMID- 28621696 TI - Professional transitions towards sustainable farming systems: The development of farmers' professional worlds. AB - BACKGROUND: While farming in France and generally in Europe is continuing to intensify, at the expense of its environmental sustainability, promising alternatives are emerging. OBJECTIVE: The processes whereby farmers change and transform their own work, to shift from an intensive mode of production to a self sufficient and autonomous one, need to be formalized if we are to further our understanding of why and how these forms of sustainable farming activity emerge. METHODS: We use the development of professional worlds theory, a systemic representation of workers' activity, whereby their experience is formalized. This can be explained as the praxis1, conceptual and axiological underpinnings form a system with the object of the action. The development of a professional world is analyzed according to the evolution of its components and the search for pragmatic coherence within it. We analyzed professional transitions towards self sufficient and autonomous mixed farming through a case study. RESULTS: Our findings showed that the transition is initiated by the discovery of the unthinkable, awareness of a discrepancy between what the farmers think and what they do, the appearance of problems, and the response to external constraints. Professional transition is a non-teleological and non-incremental process; it corresponds to a comparison with reality, and a resolution of difficulties. This process is stimulated by the use of artifacts instrumented by the farmers. CONCLUSION: New perspectives are opened up by this formalization of transitions, in terms of (i) support towards sustainable farming and (ii) the design of sustainable farming systems. PMID- 28621697 TI - Innovation, systemic appropriation and prevention in the granite mining sector: The case of humidification. AB - BACKGROUND: This research was conducted in the Brazilian granite mining sector. After epidemiological studies, it was established that professional pneumoconiosis is related to the inhalation of dust. Therefore, the Brazilian mining health and safety regulatory standard made it compulsory to provide humidification throughout the extraction and mineral treatment processes. OBJECTIVE: To develop the concept of systemic appropriation of the technological innovations that aim to protect the worker's health. Until now, appropriation has usually been presented in its individual dimensions. In this article, the focus is placed on the collective and organizational aspects of this appropriation. METHODS: Two methodological approaches were used: interviews with the different individuals involved in order to report the history of the implementation of technical devices which meet the humidification norm; and ergonomic analysis of the work of the operators who used these devices. RESULTS: The appropriation of the technical devices occurred at two distinct levels: 1) Individual, related to the direct contact of the operator with the instrument; 2) Systemic, as the effects of the innovation propagated through the system affecting interdependent tasks, adaptation of the work organization and new production strategies. CONCLUSIONS: The implementation of prevention norms require innovations which are necessarily accompanied by transformations in the companies' techniques, work and management. PMID- 28621698 TI - From the past to the future: Integrating work experience into the design process. AB - BACKGROUND: Integrating work activity issues into design process is a broadly discussed theme in ergonomics. Participation is presented as the main means for such integration. However, a late participation can limit the development of both project solutions and future work activity. OBJECTIVE: This article presents the concept of construction of experience aiming at the articulated development of future activities and project solutions. It is a non-teleological approach where the initial concepts will be transformed by the experience built up throughout the design process. METHODS: The method applied was a case study of an ergonomic participation during the design of a new laboratory complex for biotechnology research. Data was obtained through analysis of records in a simulation process using a Lego scale model and interviews with project participants. RESULTS: The simulation process allowed for developing new ways of working and generating changes in the initial design solutions, which enable workers to adopt their own developed strategies for conducting work more safely and efficiently in the future work system. CONCLUSIONS: Each project decision either opens or closes a window of opportunities for developing a future activity. Construction of experience in a non-teleological design process allows for understanding the consequences of project solutions for future work. PMID- 28621699 TI - Diagnostic value of single-source dual-energy spectral computed tomography for papillary thyroid microcarcinomas. AB - BACKGROUND: Ultrasound (US) and computed tomography (CT) are common diagnostic imaging methods for detecting and diagnosing papillary thyroid microcarcinoma (PTMC). However, single-source dual-energy spectral computed tomography (spectral CT) reduces beam hardening artefacts and optimizes contrast, which may add value in detecting PTMC. OBJECTIVE: To investigate values of applying single-source dual-energy spectral CT for diagnosing PTMCs, in comparison with high frequency ultrasound and conventional polychromatic images. METHODS: Thirty-one patients with suspected PTMC underwent contrast-enhanced dual-energy spectral CT. The images were analyzed by two experienced radiologists. Noise and contrast-noise ratio (CNR) were compared between conventional CT and spectral CT. Ultrasonography was also performed by an experienced radiologist with a 7 to 12 MHz linear array transducer. Detection and diagnostic sensitivity were determined and compared. RESULTS: Forty-six pathologically-confirmed PTMC lesions were detected in 31 patients. Spectral CT had lower noise and higher CNR than conventional CT (P < 0.05). US detected more tumors (45/46 [97.8%] than conventional CT images (40/46 [87.0%]) or spectral CT images (44/46 [95.7%]). Among them, 30 (65.2%), 36 (78.3%), and 40 (87.0%) lesions were diagnosed correctly by conventional CT, spectral CT and US, respectively. Spectral CT had higher sensitivity than conventional CT (P = 0.031). However, there was no significant difference between spectral CT and US diagnostic sensitivities (P = 0.125). CONCLUSION: Single-source dual-energy spectral CT was superior to conventional polychromatic images and similar to high frequency ultrasound in detecting and diagnosing for PTMCs. CT had advantages in detecting level VI and VII lymph nodes. Spectral CT and US provided good results for PTMC, and aid preoperative diagnosis. PMID- 28621700 TI - Impact of Parent-Targeted eHealth on Parent and Infant Health Outcomes: A Scoping Review. AB - Improved communication, education, and parental involvement in infant care have been demonstrated to enhance parental well-being and neonatal health outcomes. eHealth has the potential to increase parental presence in the neonatal intensive care unit (NICU). There has been no synthesized review on the direct impact of eHealth use on parental and neonatal health outcomes. The aim of this scoping review is to explore eHealth utilization by families of high-risk newborn infants in the NICU and/or postdischarge on health outcomes. PubMed, CINAHL, and EMBASE were searched from 1980 to October 2015 using key terms for "neonatal," "parents," "eHealth," and "patient education." Criteria of peer-reviewed empirical studies published in English, targeting parents of NICU infants regardless of diagnosis, and eHealth utilization during NICU stay or postdischarge yielded 2218 studies. Extracted data were synthesized using thematic content analysis. Ten studies met inclusion, and 5 themes emerged: usability and feasibility, parental perceived benefits, infant's hospital length of stay, knowledge uptake, and predictors of variations in use. eHealth utilization was found to be desired by parents and promotes positive change in parental experience in the NICU. Actual and perceived benefits of eHealth for parents included ease of use, higher confidence in infant care, satisfaction, and knowledge uptake. PMID- 28621701 TI - Epigenetics insights into chronic pain: DNA hypomethylation in fibromyalgia-a controlled pilot-study. AB - To evaluate changes in DNA methylation profiles in patients with fibromyalgia (FM) compared to matched healthy controls (HCs). All individuals underwent full clinical and neurophysiological assessment by cortical excitability (CE) parameters measured by transcranial magnetic stimulation. DNA from the peripheral blood of patients with FM (n = 24) and HC (n = 24) were assessed using the Illumina-HumanMethylation450 BeadChips. We identified 1610 differentially methylated positions (DMPs) in patients with FM displaying a nonrandom distribution in regions of the genome. Sixty-nine percent of DMP in FM were hypomethylated compared to HC. Differentially methylated positions were enriched in 5 genomic regions (1p34; 6p21; 10q26; 17q25; 19q13). The functional characterization of 960 genes related to DMPs revealed an enrichment for MAPK signaling pathway (n = 18 genes), regulation of actin cytoskeleton (n = 15 genes), and focal adhesion (n = 13 genes). A gene-gene interaction network enrichment analysis revealed the participation of DNA repair pathways, mitochondria-related processes, and synaptic signaling. Even though DNA was extracted from peripheral blood, this set of genes was enriched for disorders such as schizophrenia, mood disorders, bulimia, hyperphagia, and obesity. Remarkably, the hierarchical clusterization based on the methylation levels of the 1610 DMPs showed an association with neurophysiological measurements of CE in FM and HC. Fibromyalgia has a hypomethylation DNA pattern, which is enriched in genes implicated in stress response and DNA repair/free radical clearance. These changes occurred parallel to changes in CE parameters. New epigenetic insights into the pathophysiology of FM may provide the basis for the development of biomarkers of this disorder. PMID- 28621702 TI - Short-duration physical activity prevents the development of activity-induced hyperalgesia through opioid and serotoninergic mechanisms. AB - Regular physical activity prevents the development of chronic muscle pain through the modulation of central mechanisms that involve rostral ventromedial medulla (RVM). We tested if pharmacological blockade or genetic deletion of mu-opioid receptors in physically active mice modulates excitatory and inhibitory systems in the RVM in an activity-induced hyperalgesia model. We examined response frequency to mechanical stimulation of the paw, muscle withdrawal thresholds, and expression of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate receptor (p-NR1) and serotonin transporter (SERT) in the RVM. Mice that had performed 5 days of voluntary wheel running prior to the induction of the model were compared with sedentary mice. Sedentary mice showed significant increases in mechanical paw withdrawal frequency and a reduction in muscle withdrawal threshold; wheel running prevented the increase in paw withdrawal frequency. Naloxone-treated and MOR mice had increases in withdrawal frequency that were significantly greater than that in physically active control mice and similar to sedentary mice. Immunohistochemistry in the RVM showed increases in p-NR1 and SERT expression in sedentary mice 24 hours after the induction of the model. Wheel running prevented the increase in SERT, but not p-NR1. Physically active, naloxone-treated, and MOR mice showed significant increases in SERT immunoreactivity when compared with wild-type physically active control mice. Blockade of SERT in the RVM in sedentary mice reversed the activity-induced hyperalgesia of the paw and muscle. These results suggest that analgesia induced by 5 days of wheel running is mediated by mu-opioid receptors through the modulation of SERT, but not p-NR1, in RVM. PMID- 28621703 TI - Pain sensation in human osteoarthritic knee joints is strongly enhanced by diabetes mellitus. AB - The major burden of knee joint osteoarthritis (OA) is pain. Since in elder patients diabetes mellitus is an important comorbidity of OA, we explored whether the presence of diabetes mellitus has a significant influence on pain intensity at the end stage of knee OA, and we aimed to identify factors possibly related to changes of pain intensity in diabetic patients. In 23 diabetic and 47 nondiabetic patients with OA undergoing total knee arthroplasty, we assessed the pain intensity before the operation using the "Knee Injury and Osteoarthritis Outcome Score". Furthermore, synovial tissue, synovial fluid (SF), cartilage, and blood were obtained. We determined the synovitis score, the concentrations of prostaglandin E2 and interleukin-6 (IL-6) in the SF and serum, and of C-reactive protein and HbA1c and other metabolic parameters in the serum. We performed multivariate regression analyses to study the association of pain with several parameters. Diabetic patients had on average a higher Knee Injury and Osteoarthritis Outcome Score pain score than nondiabetic patients (P < 0.001). Knee joints from diabetic patients exhibited on average higher synovitis scores (P = 0.024) and higher concentrations of IL-6 in the SF (P = 0.003) than knee joints from nondiabetic patients. Multivariate regression analysis showed that patients with higher synovitis scores had more intense pain independent of all investigated confounders, and that the positive association between pain intensities and IL-6 levels was dependent on diabetes mellitus and/or synovitis. These data suggest that diabetes mellitus significantly increases pain intensity of knee OA, and that in diabetic patients higher pain intensities were determined by stronger synovitis. PMID- 28621704 TI - Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity. AB - Peripheral tissue inflammation or injury causes glutamate release from nociceptive axons, keratinocytes, and Schwann cells, resulting in thermal hypersensitivity. However, the detailed molecular mechanisms underlying glutamate induced thermal hypersensitivity are unknown. The aim of this study was to clarify the involvement of peripheral transient receptor potential (TRP) TRP vanilloid 1 (TRPV1), TRP ankyrin 1 (TRPA1), and protein kinase C epsilon (PKCepsilon) in glutamate-induced pain hypersensitivity. The amount of glutamate in the facial tissue was significantly increased 3 days after facial Complete Freund's adjuvant injection. The head-withdrawal reflex threshold to heat, cold, or mechanical stimulation was significantly decreased on day 7 after continuous glutamate or metabotropic glutamate receptor 5 (mGluR5) agonist (CHPG) injection into the facial skin compared with vehicle-injected rats, and glutamate-induced hypersensitivity was significantly recovered by mGluR5 antagonist MTEP, TRPA1 antagonist HC-030031, TRPV1 antagonist SB366791, or PKCepsilon translocation inhibitor administration into the facial skin. TRPV1 and TRPA1 were expressed in mGluR5-immunoreactive (IR) trigeminal ganglion (TG) neurons innervating the facial skin, and mGluR5-IR TG neurons expressed PKCepsilon. There was no significant difference in the number of GluR5-IR TG neurons among glutamate injected, saline-injected, and naive rats, whereas that of TRPV1- or TRPA1-IR TG neurons was significantly increased 7 days after continuous glutamate injection into the facial skin compared with vehicle injection. PKCepsilon phosphorylation in TG was significantly enhanced following glutamate injection into the facial skin. Moreover, neuronal activity of TG neurons was significantly increased following facial glutamate treatment. The present findings suggest that sensitization of TRPA1 and/or TRPV1 through mGluR5 signaling via PKCepsilon is involved in facial thermal and mechanical hypersensitivity. PMID- 28621705 TI - Hyperspectral IASI L1C Data Compression. AB - The Infrared Atmospheric Sounding Interferometer (IASI), implemented on the MetOp satellite series, represents a significant step forward in atmospheric forecast and weather understanding. The instrument provides infrared soundings of unprecedented accuracy and spectral resolution to derive humidity and atmospheric temperature profiles, as well as some of the chemical components playing a key role in climate monitoring. IASI collects rich spectral information, which results in large amounts of data (about 16 Gigabytes per day). Efficient compression techniques are requested for both transmission and storage of such huge data. This study reviews the performance of several state of the art coding standards and techniques for IASI L1C data compression. Discussion embraces lossless, near-lossless and lossy compression. Several spectral transforms, essential to achieve improved coding performance due to the high spectral redundancy inherent to IASI products, are also discussed. Illustrative results are reported for a set of 96 IASI L1C orbits acquired over a full year (4 orbits per month for each IASI-A and IASI-B from July 2013 to June 2014) . Further, this survey provides organized data and facts to assist future research and the atmospheric scientific community. PMID- 28621706 TI - NADA Ear Acupuncture: An Adjunctive Therapy to Improve and Maintain Positive Outcomes in Substance Abuse Treatment. AB - The National Acupuncture Detoxification Association protocol (NADA) is an adjunctive therapy using 1 to 5 invariant ear acupuncture/acupressure points. This is a randomized prospective study to determine if NADA plus traditional treatment enhance outcomes: quality of life, depression, anxiety and abstinence from substance abuse. There were 100 patients enrolled in the Keystone Substance Abuse Services-Winthrop University Department of Sociology and Anthropology NADA study. All patients completed Generalized Anxiety Disorder scale (GAD-7), Patient Health Questionnaire (PHQ-9), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES) prior to starting the program and at program completion. Patients self-reported alcohol, tobacco, and drug use prior to starting the program at program completion and at 3 and 6 month follow- up. Patient characteristics are predictive of completion versus non-completion when race, criminal history and initial drug test is considered. Those identified as nonwhite, (p < 0.05) and patients with positive initial drug test, (p < 0.01) were more likely to complete treatment in the NADA group. Also, among patients with criminal history a higher percentage failed to complete the program in the control group (p < 0.05). Participation in NADA positively associated with Q-LES score (p < 0.05), feeling better about oneself and improved energy (p < 0.05), likelihood of employment upon discharge (p < 0.05), and decreased alcohol use at 3 month follow up (p < 0.05) and 6-month follow-up (p < 0.01). NADA group reported less tobacco use at 6 months (p < 0.05). PMID- 28621707 TI - Antioxidant Potential and Antibacterial Efficiency of Caffeic Acid-Functionalized ZnO Nanoparticles. AB - We report a novel zinc oxide (ZnO) nanoparticle with antioxidant properties, prepared by immobilizing the antioxidant 3-(3,4-dihydroxyphenyl)-2-propenoic acid (caffeic acid, CA) on the surfaces of micro-dielectric barrier discharge (DBD) plasma-treated ZnO nanoparticles. The microstructure and physical properties of ZnO@CA nanoparticles were characterized by field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), infrared spectroscopy, and steady state spectroscopic methods. The antioxidant activity of ZnO@CA nanoparticles was evaluated using an ABTS (3-ethyl-benzothiazoline-6 sulfonic acid) radical cation decolorization assay. ZnO@CA nanoparticles exhibited robust antioxidant activity. Moreover, ZnO@CA nanoparticles showed strong antibacterial activity against Gram-positive bacteria (Staphylococcus aureus) including resistant bacteria such as methicillin-resistant S. aureus and against Gram-negative bacteria (Escherichia coli). Although Gram-negative bacteria appeared to be more resistant to ZnO@CA nanoparticles than Gram-positive bacteria, the antibacterial activity of ZnO@CA nanoparticles was dependent on particle concentration. The antioxidant and antibacterial activity of ZnO@CA may be useful for various biomedical and nanoindustrial applications. PMID- 28621708 TI - Breathing Analysis Using Thermal and Depth Imaging Camera Video Records. AB - The paper is devoted to the study of facial region temperature changes using a simple thermal imaging camera and to the comparison of their time evolution with the pectoral area motion recorded by the MS Kinect depth sensor. The goal of this research is to propose the use of video records as alternative diagnostics of breathing disorders allowing their analysis in the home environment as well. The methods proposed include (i) specific image processing algorithms for detecting facial parts with periodic temperature changes; (ii) computational intelligence tools for analysing the associated videosequences; and (iii) digital filters and spectral estimation tools for processing the depth matrices. Machine learning applied to thermal imaging camera calibration allowed the recognition of its digital information with an accuracy close to 100% for the classification of individual temperature values. The proposed detection of breathing features was used for monitoring of physical activities by the home exercise bike. The results include a decrease of breathing temperature and its frequency after a load, with mean values -0.16 degrees C/min and -0.72 bpm respectively, for the given set of experiments. The proposed methods verify that thermal and depth cameras can be used as additional tools for multimodal detection of breathing patterns. PMID- 28621709 TI - An Unobtrusive Fall Detection and Alerting System Based on Kalman Filter and Bayes Network Classifier. AB - Falls are one of the main health risks among the elderly. A fall detection system based on inertial sensors can automatically detect fall event and alert a caregiver for immediate assistance, so as to reduce injuries causing by falls. Nevertheless, most inertial sensor-based fall detection technologies have focused on the accuracy of detection while neglecting quantization noise caused by inertial sensor. In this paper, an activity model based on tri-axial acceleration and gyroscope is proposed, and the difference between activities of daily living (ADLs) and falls is analyzed. Meanwhile, a Kalman filter is proposed to preprocess the raw data so as to reduce noise. A sliding window and Bayes network classifier are introduced to develop a wearable fall detection system, which is composed of a wearable motion sensor and a smart phone. The experiment shows that the proposed system distinguishes simulated falls from ADLs with a high accuracy of 95.67%, while sensitivity and specificity are 99.0% and 95.0%, respectively. Furthermore, the smart phone can issue an alarm to caregivers so as to provide timely and accurate help for the elderly, as soon as the system detects a fall. PMID- 28621710 TI - A Recyclable Cu-MOF-74 Catalyst for the Ligand-Free O-Arylation Reaction of 4 Nitrobenzaldehyde and Phenol. AB - The activity and recyclability of Cu-MOF-74 as a catalyst was studied for the ligand-free C-O cross-coupling reaction of 4-nitrobenzaldehyde (NB) with phenol (Ph) to form 4-formyldiphenyl ether (FDE). Cu-MOF-74 is characterized by having unsaturated copper sites in a highly porous metal-organic framework. The influence of solvent, reaction temperature, NB/Ph ratio, catalyst concentration, and basic agent (type and concentration) were evaluated. High conversions were achieved at 120 degrees C, 5 mol % of catalyst, NB/Ph ratio of 1:2, DMF as solvent, and 1 equivalent of K2CO3 base. The activity of Cu-MOF-74 material was higher than other ligand-free copper catalytic systems tested in this study. This catalyst was easily separated and reused in five successive runs, achieving a remarkable performance without significant porous framework degradation. The leaching of copper species in the reaction medium was negligible. The O-arylation between NB and Ph took place only in the presence of Cu-MOF-74 material, being negligible without the solid catalyst. The catalytic advantages of using nanostructured Cu-MOF-74 catalyst were also proven. PMID- 28621711 TI - Indigenous Probiotic Lactobacillus Isolates Presenting Antibiotic like Activity against Human Pathogenic Bacteria. AB - BACKGROUND: Indigenous lactic acid bacteria are well known probiotics having antibacterial activity against potentially pathogenic bacteria. This study aims to characterize the curd lactobacilli for their probiotic potentiality and antagonistic activity against clinical bacteria. METHODS: Four curd samples were processed microbiologically for the isolation of lactic acid bacteria (LAB). The LAB strains obtained were identified by conventional methods: cultural aspect, gram-staining, biochemical and sugar fermentation tests. The probiotic properties were justified with tolerance to low-pH, bile salt and sodium chloride, and the antagonistic activity of the lactobacilli against human pathogenic bacteria (Escherichia coli, Proteus vulgaris, Acinetobacter baumannii and Salmonella enterica serovar Typhi) was assessed. Hemolytic activity and antibiotic susceptibility were determined for the lactobacilli isolates, and the cumulative probiotic potential (CPP) values were recorded. RESULT: Four lactobacilli isolates, L. animalis LMEM6, L. plantarum LMEM7, L. acidophilus LMEM8 and L. rhamnosus LMEM9, procured from the curd samples, survived in low-pH and high bile salt conditions, and showed growth inhibitory activity against the indicator bacteria by agar-well (zone diameter of inhibition; ZDIs: 13.67 +/- 0.58-29.50 +/ 2.10 mm) and agar overlay (ZDIs: 11.33 +/- 0.58-35.67 +/- 2.52 mm) methods; the average growth inhibitory activity of lactobacilli ranged 233.34 +/- 45.54-280.56 +/- 83.67 AU/mL, against the test bacterial pathogens. All the lactobacilli were non-hemolytic and sensitive to most of the test antibiotics. The CPP values of the isolated LAB were recorded as 80-100%. CONCLUSION: The curd lactobacilli procured might be used as the valid candidates of probiotics, and bio therapeutics against bacterial infection to humans. PMID- 28621712 TI - Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors. AB - Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic. PMID- 28621713 TI - GPE Promotes the Proliferation and Migration of Mouse Embryonic Neural Stem Cells and Their Progeny In Vitro. AB - This study was designed to investigate a possible role of the N-terminal tripeptide of insulin-like growth factor-1 (IGF-I), Gly-Pro-Glu (GPE), physiologically generated in neurons following IGF-I-specific cleavage, in promoting neural regeneration after an injury. Primary cultures of mouse neural stem cells (NSCs), obtained from 13.5 Days post-conception (dpc) mouse embryos, were challenged with either GPE, growth hormone (GH), or GPE + GH and the effects on cell proliferation, migration, and survival were evaluated both under basal conditions and in response to a wound healing assay. The cellular pathways activated by GPE were also investigated by using specific chemical inhibitors. The results of the study indicate that GPE treatment promotes the proliferation and the migration of neural stem cells in vitro through a mechanism that involves the activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase PI3K-Akt pathways. Intriguingly, both GPE effects and the signaling pathways activated were similar to those observed after GH treatment. Based upon the results obtained from this study, GPE, as well as GH, may be useful in promoting neural protection and/or regeneration after an injury. PMID- 28621714 TI - Acute Effect of Metformin on Postprandial Hypertriglyceridemia through Delayed Gastric Emptying. AB - Postprandial hypertriglyceridemia is a potential target for cardiovascular disease prevention in patients with diabetic dyslipidemia. Metformin has been reported to reduce plasma triglyceride concentrations in the postprandial states. However, little is known about the mechanisms underlying the triglyceride lowering effect of metformin. Here, we examined the effects of metformin on lipid metabolism after olive oil-loading in 129S mice fed a high fat diet for three weeks. Metformin administration (250 mg/kg) for one week decreased postprandial plasma triglycerides. Pre-administration (250 mg/kg) of metformin resulted in a stronger triglyceride-lowering effect (approximately 45% lower area under the curve) than post-administration. A single administration (250 mg/kg) of metformin lowered plasma postprandial triglycerides comparably to administration for one week, suggesting an acute effect of metformin on postprandial hypertriglyceridemia. To explore whole body lipid metabolism after fat-loading, stomach size, fat absorption in the intestine, and fat oxidation (13C/12C ratio in expired CO2 after administration of glyceryl-1-13C tripalmitate) were measured with and without metformin (250 mg/kg) pre-treatment. In metformin-treated mice, larger stomach size, lower fat oxidation, and no change in lipid absorption were observed. In conclusion, metformin administration before fat loading reduced postprandial hypertriglyceridemia, most likely by delaying gastric emptying. PMID- 28621715 TI - Neuropsychiatric Burden in Huntington's Disease. AB - Huntington's disease is a disorder that results in motor, cognitive, and psychiatric problems. The symptoms often take different forms and the presence of disturbances of the psychic sphere reduces patients' autonomy and quality of life, also impacting patients' social life. It is estimated that a prevalence between 33% and 76% of the main psychiatric syndromes may arise in different phases of the disease, often in atypical form, even 20 years before the onset of chorea and dementia. We present a narrative review of the literature describing the main psychopathological patterns that may be found in Huntington's disease, searching for a related article in the main database sources (Medline, ISI Web of Knowledge, Scopus, and Medscape). Psychiatric conditions were classified into two main categories: affective and nonaffective disorders/symptoms; and anxiety and neuropsychiatric features such as apathy and irritability. Though the literature is extensive, it is not always convergent, probably due to the high heterogeneity of methods used. We summarize main papers for pathology and sample size, in order to present a synoptic vision of the argument. Since the association between Huntington's disease and psychiatric symptoms was demonstrated, we argue that the prevalent and more invalidating psychiatric components should be recognized as early as possible during the disease course in order to best address psychopharmacological therapy, improve quality of life, and also reduce burden on caregivers. PMID- 28621717 TI - Poly(vinylbenzylchloride) Based Anion-Exchange Blend Membranes (AEBMs): Influence of PEG Additive on Conductivity and Stability. AB - In view of the many possible applications such as fuel cells and electrolysers, recent interest in novel anion exchange membranes (AEMs) has increased significantly. However, their low conductivity and chemical stability limits their current suitability. In this study, the synthesis and characterization of several three- and four-component anion exchange blend membranes (AEBMs) is described, where the compositions have been systematically varied to study the influence of the AEBM's composition on the anion conductivities as well as chemical and thermal stabilities under strongly alkaline conditions. It was shown that the epoxide-functionalized poly(ethylene glycol)s that were introduced into the four-component AEBMs resulted in increased conductivity as well as a marked improvement in the stability of the AEBMs in an alkaline environment. In addition, the thermal stability of the novel AEBMs was excellent showing the suitability of these membranes for several electrochemical applications. PMID- 28621716 TI - Antibacterial and Antifungal Activities of Spices. AB - Infectious diseases caused by pathogens and food poisoning caused by spoilage microorganisms are threatening human health all over the world. The efficacies of some antimicrobial agents, which are currently used to extend shelf-life and increase the safety of food products in food industry and to inhibit disease causing microorganisms in medicine, have been weakened by microbial resistance. Therefore, new antimicrobial agents that could overcome this resistance need to be discovered. Many spices-such as clove, oregano, thyme, cinnamon, and cumin possessed significant antibacterial and antifungal activities against food spoilage bacteria like Bacillus subtilis and Pseudomonas fluorescens, pathogens like Staphylococcus aureus and Vibrio parahaemolyticus, harmful fungi like Aspergillus flavus, even antibiotic resistant microorganisms such as methicillin resistant Staphylococcus aureus. Therefore, spices have a great potential to be developed as new and safe antimicrobial agents. This review summarizes scientific studies on the antibacterial and antifungal activities of several spices and their derivatives. PMID- 28621718 TI - Using Small RNA-seq Data to Detect siRNA Duplexes Induced by Plant Viruses. AB - Small interfering RNA (siRNA) duplexes are short (usually 21 to 24 bp) double stranded RNAs (dsRNAs) with several overhanging nucleotides at both 5'- and 3' ends. It has been found that siRNA duplexes bind the RNA-induced silencing complex (RISC) and cleave the sense strands with endonucleases. In this study, for the first time, we detected siRNA duplexes induced by plant viruses on a large scale using next-generation sequencing (NGS) data. In addition, we used the detected 21 nucleotide (nt) siRNA duplexes with 2 nt overhangs to construct a dataset for future data mining. The analytical results of the features in the detected siRNA duplexes were consistent with those from previous studies. The investigation of siRNA duplexes is useful for a better understanding of the RNA interference (RNAi) mechanism. It can also help to improve the virus detection based on the small RNA sequencing (sRNA-seq) technologies and to rationally design siRNAs for RNAi experiments. PMID- 28621719 TI - The Ability of Extracellular Vesicles to Induce a Pro-Inflammatory Host Response. AB - Extracellular vesicles (EVs) can modulate the host immune response, executing both pro- and anti-inflammatory effects. As EVs increasingly gain attention as potential carriers for targeted gene and drug delivery, knowledge on the effects of EVs on the host immune response is important. This review will focus on the ability of EVs to trigger a pro-inflammatory host response by activating target cells. The overall view is that EVs can augment an inflammatory response, thereby potentially contributing to organ injury. This pro-inflammatory potential of EVs may hamper its use for therapeutic drug delivery. Whether removal of EVs as a means to reduce a pro-inflammatory or pro-coagulant response during hyper inflammatory conditions is beneficial remains to be determined. Prior to any proposed therapeutic application, there is a need for further studies on the role of EVs in physiology and pathophysiology using improved detection and characterization methods to elucidate the roles of EVs in inflammatory conditions. PMID- 28621720 TI - Know Your Noodles! Assessing Variations in Sodium Content of Instant Noodles across Countries. AB - Reducing salt intake is a cost-effective public health intervention to reduce the global burden of non-communicable disease (NCDs). Ultra-processed foods contribute ~80% of dietary salt in high income countries, and are becoming prominent in low-middle income countries. Instant noodle consumption is particularly high in the Asia Pacific region. The aim of this study was to compare the sodium content of instant noodles sold worldwide to identify potential for reformulation. Analysis was undertaken for 765 instant noodle products from 10 countries using packaged food composition databases of ultra processed foods compiled by the Global Food Monitoring Group (GFMG) and national shop survey data. Sodium levels were high and variable, within and between countries. Instant noodles in China had the highest mean sodium content (1944 mg/100 g; range: 397-3678/100 g) compared to New Zealand (798 mg/100 g; range: 249-2380 mg/100 g). Average pack size ranged from 57 g (Costa Rica) to 98 g (China). The average packet contributed 35% to 95% of the World Health Organization recommended daily salt intake of <5 g. Forty-one percent of products met the Pacific Island (PICs) regional sodium targets, 37% met the South Africa 2016 targets, and 62% met the UK 2017 targets. This study emphasises a need for stronger regulation and closer monitoring to drive rigorous reformulation of salt in ultra-processed foods. PMID- 28621721 TI - Perceived Health and Nutrition Concerns as Predictors of Dietary Patterns among Polish Females Aged 13-21 Years (GEBaHealth Project). AB - Health-related concerns can often be factors influencing health-related behaviours. It remains unclear whether a high level of concerns is associated with pro-healthy or unhealthy dietary behaviours and whether any associations between nutrition-related concerns and dietary behaviours exist in a population of girls and young women. The aim of the study was to investigate the associations between perceived health and nutrition concerns and dietary patterns in a representative sample of Polish young females. Data was collected in 2012 through a cross-sectional quantitative survey within the GEBaHealth (Girls Eating Behaviours and Health) project in a group of 1107 Polish girls aged 13-21 years old. Dietary patterns were identified by Principal Component Analysis (PCA) based on dietary data collected with Food Frequency Questionnaires (FFQs). Nutrition and health concerns were assessed separately by two indices: Health Concern Index (HCI) and Nutrition Concern Index (NCI); both based on the Health Concern Scale (HCS). The associations between perceived health and nutrition concerns and each dietary pattern were investigated using logistic regression analysis. Displaying a higher level of health concerns increased the chances of adherence to the upper tertile of 'Fruit & vegetables' pattern (adjusted odds ratio [adj. ORs]: 1.46, 95% Confidence Interval [95% CI]: 1.02-2.10). Displaying a lower level of health concerns increased the chances of the adherence to the upper tertiles of 'Traditional Polish', 'Dairy & fats', 'Fruit and vegetables' and 'Fast food & sweets' patterns (adj. ORs: 1.87, 95% CI: 1.31-2.67; 1.66, 95% CI: 1.18-2.34; 1.57, 95% CI: 1.11-2.22; 1.52, 95% CI: 1.08-2.13; respectively). No significant associations were found between levels of nutrition concerns and dietary patterns in the adjusted model. We found associations between self-perceived health concerns and dietary patterns in our study sample, suggesting health concerns can be an important predictor of dietary behaviours in girls and young women. To increase the effectiveness of healthy eating, an emphasis should be laid on health, reinforced with awareness of nutrition, when advising on food-related decisions. PMID- 28621722 TI - Comparative Analysis of Genome Wide DNA Methylation Profiles for the Genic Male Sterile Cabbage Line 01-20S and Its Maintainer Line. AB - Methylation modifications play an important role in multiple biological processes. Several studies have reported altered methylation patterns in male sterile plants such as rice and wheat, but little is known about the global methylation profiles and their possible roles in the cabbage (Brassicaoleracea) male sterile line. In this study, single-base-resolution bisulfite sequencing (BS Seq) was adopted to identify the pattern and degree of cytosine methylation in the male sterile line 01-20S and its near-isogenic fertile line 01-20F. Similar methylation patterns were profiled, with some changes observed in local positions. In total, 505 differentially methylated genomic regions (DMRs) and 106 DMR-associated genes were detected. Nine genes related to pollen development were discovered and further validated by a quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Among these, four were downregulated in 01 20S. In particular, Bol039180 (an invertase/pectin methylesterase inhibitor family protein) is likely involved in pectin degradation, and might play an important role in the pollen separation defects of 01-20S. This study facilitates a better understanding of DNA methylation alterations and their possible roles in genic male sterility in cabbages. PMID- 28621723 TI - A Quantile Mapping Bias Correction Method Based on Hydroclimatic Classification of the Guiana Shield. AB - Satellite precipitation products (SPPs) provide alternative precipitation data for regions with sparse rain gauge measurements. However, SPPs are subject to different types of error that need correction. Most SPP bias correction methods use the statistical properties of the rain gauge data to adjust the corresponding SPP data. The statistical adjustment does not make it possible to correct the pixels of SPP data for which there is no rain gauge data. The solution proposed in this article is to correct the daily SPP data for the Guiana Shield using a novel two set approach, without taking into account the daily gauge data of the pixel to be corrected, but the daily gauge data from surrounding pixels. In this case, a spatial analysis must be involved. The first step defines hydroclimatic areas using a spatial classification that considers precipitation data with the same temporal distributions. The second step uses the Quantile Mapping bias correction method to correct the daily SPP data contained within each hydroclimatic area. We validate the results by comparing the corrected SPP data and daily rain gauge measurements using relative RMSE and relative bias statistical errors. The results show that analysis scale variation reduces rBIAS and rRMSE significantly. The spatial classification avoids mixing rainfall data with different temporal characteristics in each hydroclimatic area, and the defined bias correction parameters are more realistic and appropriate. This study demonstrates that hydroclimatic classification is relevant for implementing bias correction methods at the local scale. PMID- 28621724 TI - Erratum: Intake of Marine-Derived Omega-3 Polyunsaturated Fatty Acids and Mortality in Renal Transplant Recipients; Nutrients 2017, 9, 363. PMID- 28621725 TI - How Environmental Factors Affect the Production of Guanidine Alkaloids by the Mediterranean Sponge Crambe crambe. AB - Most marine sponges are known to produce a large array of low molecular-weight metabolites which have applications in the pharmaceutical industry. The production of so-called specialized metabolites may be closely related to environmental factors. In this context, assessing the contribution of factors like temperature, nutrients or light to the metabolomes of sponges provides relevant insights into their chemical ecology as well as the supply issue of natural sponge products. The sponge Crambe crambe was chosen as a model due to its high content of specialized metabolites belonging to polycyclic guanidine alkaloids (PGA). First results were obtained with field data of both wild and farmed specimens collected in two seasons and geographic areas of the North Western Mediterranean. Then, further insights into factors responsible for changes in the metabolism were gained with sponges cultivated under controlled conditions in an aquarium. Comparative metabolomics showed a clear influence of the seasons and to a lesser extent of the geography while no effect of depth or farming was observed. Interestingly, sponge farming did not limit the production of PGA, while ex situ experiments did not show significant effects of several abiotic factors on the specialized metabolome at a one-month time scale. Some hypotheses were finally proposed to explain the very limited variations of PGA in C. crambe placed under different environmental conditions. PMID- 28621727 TI - Insights into the Experiences of Treatment for An Eating Disorder in Men: A Qualitative Study of Autobiographies. AB - Eating disorders are increasingly recognized as a problem for men but help seeking is low and little is known about their treatment experiences. This paper sought to determine the treatment experiences of men who have suffered from an eating disorder using autobiographical data. Inclusion criteria were autobiographies of men who had experienced an eating disorder and sought any form of treatment for this, written in the English language, published between 1995 and 2015, and available for purchase in 2016. The search resulted in six books that were thematically analyzed. Analysis of data resulted in two broad themes (1. Positive experiences; 2. Negative experiences) with sub-themes. With regards to the first theme, factors such as concern of staff members, therapist's expertise (in treating eating disorders in men), and a collaborative treatment approach were considered favorable for treatment. In contrast to the first theme, apathy of staff members, the authors' own negative preconceptions, treatment providers being perceived as prioritizing financial concerns, perceived as incompetent and judgmental behavior of therapist(s), and time limitations of sessions were considered unfavorable treatment experiences. In this study, the perceived success of treatment depended on therapist's features and the form of treatment provided. Further research examining these is indicated. PMID- 28621726 TI - Microbiota and Probiotics in Health and HIV Infection. AB - Microbiota play a key role in various body functions, as well as in physiological, metabolic, and immunological processes, through different mechanisms such as the regulation of the development and/or functions of different types of immune cells in the intestines. Evidence indicates that alteration in the gut microbiota can influence infectious and non-infectious diseases. Bacteria that reside on the mucosal surface or within the mucus layer interact with the host immune system, thus, a healthy gut microbiota is essential for the development of mucosal immunity. In patients with human immunodeficiency virus (HIV), including those who control their disease with antiretroviral drugs (ART), the gut microbiome is very different than the microbiome of those not infected with HIV. Recent data suggests that, for these patients, dysbiosis may lead to a breakdown in the gut's immunologic activity, causing systemic bacteria diffusion and inflammation. Since in HIV-infected patients in this state, including those in ART therapy, the treatment of gastrointestinal tract disorders is frustrating, many studies are in progress to investigate the ability of probiotics to modulate epithelial barrier functions, microbiota composition, and microbial translocation. This mini-review analyzed the use of probiotics to prevent and attenuate several gastrointestinal manifestations and to improve gut associated lymphoid tissue (GALT) immunity in HIV infection. PMID- 28621729 TI - Correction: Rachel Brown and Sheila Skeaff. Nutrition Society of New Zealand Annual Conference Held in Christchurch, New Zealand, 8-9 December 2016. Nutrients 2017, 9, 348. AB - n/a. PMID- 28621728 TI - Determination of Sulfonamide Residues in Food by Capillary Zone Electrophoresis with On-Line Chemiluminescence Detection Based on an Ag(III) Complex. AB - The presence of sulfonamide (SA) residues in foods is largely due to the raising of animals with sulfonamide antibiotics added or polluted feedstuff. In this paper, a sensitive method was developed for the determination of the residues of three sulfonamides in animal-derived food; the SAs include sulfadimidine (SDD), sulfadiazine (SDZ), and sulfathiazole (STZ). The method is based on capillary zone electrophoresis (CE) with online chemiluminescence (CL) detection, using an Ag(III) complex as an oxidant. These SAs have an inhibiting effect on the Ag(III) luminol CL reaction. The electrophoretic buffer is 12.0 mM sodium borate. Under a set of optimized conditions, the linear ranges for the detections were found to be 10.0-200 ug.mL-1 for SDD and SDZ, and 2.0-50.0 ug.mL-1 for STZ. The detection limits were 2.75, 3.14, and 0.65 ug.mL-1 for SDD, SDZ, and STZ, respectively. Relative standard deviations (RSD) for the peak heights were between 2.1% and 2.8% (n = 7). The proposed method was used in the analysis of the SAs in samples from pork meat, chicken meat, and milk, showing satisfactory detection results. A reaction mechanism was also proposed for the Ag(III)-luminol-SA CL reactions. The method has potential applications for the monitoring of residue levels of the three SAs in food, providing food safety data. PMID- 28621730 TI - Hydronopylformamides: Modification of the Naturally Occurring Compound (-)-beta Pinene to Produce Insect Repellent Candidates against Blattella germanica. AB - The development of a novel repellent plays an important role in the integrated control of Blattella germanica. A series of novel hydronopylformamides derivatives were synthesized from a naturally occurring compound (-)-beta-pinene. The structures of these hydronopylformamides derivatives were characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (1H-NMR and 13C-NMR), and electron impact mass spectrometry (EI-MS). Repellency of these hydronopylformamides derivatives against Blattella germanica was evaluated by the using petri dish arena method. The results showed that four derivatives (compounds 8a, 8b, 8c and 8e) exhibited repellency against Blattella germanica at a concentration of 20 mg/mL. Compound 8a was the most active compound among these derivatives, where the repelling ratios of compound 8a against Blattella germanica were 66.10%, 50.46%, 48.26%, at concentrations of 20 mg/mL, 10 mg/mL, and 5 mg/mL, respectively. In addition, compound 8a showed better repellency than the traditional insect repellent N, N-diethyl-3 methylbenzamide (DEET), which indicated that compound 8a had a good application prospect in the prevention of Blattella germanica. This research hopes to promote the value-added utilization of (-)-beta-pinene and the development of novel German cockroach repellents. PMID- 28621731 TI - The Therapeutic Benefit of Bacterial Membrane Vesicles. AB - The therapeutic potential of extracellular vesicles from eukaryotes has gained strong interest in recent years. However, research into the therapeutic application of their bacterial counterparts, known as bacterial membrane vesicles, is only just beginning to be appreciated. Membrane vesicles (MVs) from both Gram-positive and Gram-negative bacteria offer significant advantages in therapeutic development, including large-scale, cost effective production and ease of molecular manipulation to display foreign antigens. The nanoparticle size of MVs enables their dissemination through numerous tissue types, and their natural immunogenicity and self-adjuvanting capability can be harnessed to induce both cell-mediated and humoral immunity in vaccine design. Moreover, the ability to target MVs to specific tissues through the display of surface receptors raises their potential use as targeted MV-based anti-cancer therapy. This review discusses recent advances in MV research with particular emphasis on exciting new possibilities for the application of MVs in therapeutic design. PMID- 28621732 TI - Lipid Accumulation in HepG2 Cells Is Attenuated by Strawberry Extract through AMPK Activation. AB - Regulation of lipid metabolism is essential for treatment and prevention of several chronic diseases such as obesity, diabetes, and cardiovascular diseases, which are responsible for most deaths worldwide. It has been demonstrated that the AMP-activated protein kinase (AMPK) has a direct impact on lipid metabolism by modulating several downstream-signaling components. The main objective of the present work was to evaluate the in vitro effect of a methanolic strawberry extract on AMPK and its possible repercussion on lipid metabolism in human hepatocellular carcinoma cells (HepG2). For such purpose, the lipid profile and the expression of proteins metabolically related to AMPK were determined on cells lysates. The results demonstrated that strawberry methanolic extract decreased total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglycerides levels (up to 0.50-, 0.30-, and 0.40-fold, respectively) while it stimulated the p-AMPK/AMPK expression (up to 3.06-fold), compared to the control. AMPK stimulation led to the phosphorylation and consequent inactivation of acetyl coenzyme A carboxylase (ACC) and inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the major regulators of fatty acids and cholesterol synthesis, respectively. Strawberry treatment also entailed a 4.34-, 2.37-, and 2.47-fold overexpression of LDL receptor, sirtuin 1 (Sirt1), and the peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1alpha), respectively, compared to control. The observed results were counteracted by treatment with compound C, an AMPK pharmacological inhibitor, confirming that multiple effects of strawberries on lipid metabolism are mediated by the activation of this protein. PMID- 28621733 TI - Discovery of Indeno[1,2-c]quinoline Derivatives as Potent Dual Antituberculosis and Anti-Inflammatory Agents. AB - A series of indeno[1,2-c]quinoline derivatives were designed, synthesized and evaluated for their anti-tuberculosis (anti-TB) and anti-inflammatory activities. The minimum inhibitory concentration (MIC) of the newly synthesized compound was tested against Mycobacterium tuberculosis H37RV. Among the tested compounds, (E) N'-[6-(4-hydroxypiperidin-1-yl)-11H-indeno[1,2-c]quinolin-11-ylidene]isonicotino hydrazide (12), exhibited significant activities against the growth of M. tuberculosis (MIC values of 0.96 MUg/mL) with a potency approximately equal to that of isoniazid (INH), an anti-TB drug. Important structure features were analyzed by quantitative structure-activity relationship (QSAR) analysis to give better insights into the structure determinants for predicting the anti-TB activity. The anti-inflammatory activity was induced by superoxide anion generation and neutrophil elastase (NE) release using the formyl-l-methionyl-l leucyl-l-phenylalanine (fMLF)-activated human neutrophils method. Results indicated that compound 12 demonstrated a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 values of 1.76 and 1.72 MUM, respectively. Our results indicated that compound 12 is a potential lead compound for the discovery of dual anti-TB and anti-inflammatory drug candidates. In addition, 6-[3-(hydroxymethyl)piperidin-1-yl]-9-methoxy-11H-indeno[1,2-c]quinolin 11-one (4g) showed a potent dual inhibitory effect on NE release and superoxide anion generation with IC50 values of 0.46 and 0.68 MUM, respectively, and is a potential lead compound for the discovery of anti-inflammatory drug candidates. PMID- 28621734 TI - The Roles of Spinochromes in Four Shallow Water Tropical Sea Urchins and Their Potential as Bioactive Pharmacological Agents. AB - Spinochromes are principally known to be involved in sea urchin pigmentation as well as for their potentially interesting pharmacological properties. To assess their biological role in sea urchin physiology, experiments are undertaken on crude extracts from four species and on four isolated spinochromes in order to test their antibacterial, antioxidant, inflammatory and cytotoxic activities. First, the antibacterial assays show that the use of crude extracts as representatives of antibacterial effects of spinochromes are inaccurate. The assays on purified spinochromes showed a decrease in the growth of four strains with an intensity depending on the spinochromes/bacteria system, revealing the participation of spinochromes in the defense system against microorganisms. Secondly, in the 2,2-diphenyl-1-picrylhydrazyl antioxidant assays, spinochromes show an enhanced activity compared to the positive control. This latter observation suggests their involvement in ultraviolet radiation protection. Third, spinochromes present a pro-inflammatory effect on lipopolysaccharide stimulated macrophages, highlighting their possible implication in the sea urchin immune system. Finally, cytotoxicity assays based on Trypan blue exclusion, performed in view of their possible future applications as drugs, show a weak cytotoxicity of these compounds against human cells. In conclusion, all results confirm the implication of spinochromes in sea urchin defense mechanisms against their external environment and reveal their potential for pharmacological and agronomical industries. PMID- 28621735 TI - Anti-Inflammatory and Anti-Oxidant Potential of the Root Extract and Constituents of Doronicum austriacum. AB - BACKGROUND: Doronicum austriacum Jacq., Asteraceae, is a plant which is used in traditional alpine medicine. Historical sources describe the medical use of the root, but up until now only a few studies evaluated its pharmacological properties. The evaluation of the dichloromethane extract, and its major compounds for their anti-inflammatory and anti-oxidant potential was performed in macrophages J774A.1 and C6 astrocytes. Nitric oxide (NO) and reactive oxygen species (ROS) release, as well as nitrotyrosine formation, were evaluated. Moreover, in order to evaluate the potential anti-proliferative activity, under the same experimental conditions, 3-(4,5-dimethyltiazol-2yl)-2,5-phenyl-2H tetrazolium bromide (MTT) assay was also performed. Our results indicate that Doronicum austriacum has a significant effect in inhibiting both pro-inflammatory and pro-oxidative mediators. All isolated compounds were able to significantly inhibit NO and ROS release both in macrophage and in astrocytes cells, even if the effect was more pronounced in macrophage. In particular, among the tested compounds, 6,12-dihydroxy-(-)-2S-tremetone exerted stronger activity. Both extract and single compounds did not affect cellular viability. This study provides evidence for the pharmacological anti-inflammatory and anti-oxidant potential of Doronicum austriacum extract. These effects could be due to the activity of its major constituents and subsequent identification of benzofurans as a promising compound class to combat inflammation and related diseases. PMID- 28621736 TI - A Panel of MicroRNAs as Diagnostic Biomarkers for the Identification of Prostate Cancer. AB - Prostate cancer is the most common non-cutaneous cancer among men; yet, current diagnostic methods are insufficient, and more reliable diagnostic markers need to be developed. One answer that can bridge this gap may lie in microRNAs. These small RNA molecules impact protein expression at the translational level, regulating important cellular pathways, the dysregulation of which can exert tumorigenic effects contributing to cancer. In this study, high throughput sequencing of small RNAs extracted from blood from 28 prostate cancer patients at initial stages of diagnosis and prior to treatment was used to identify microRNAs that could be utilized as diagnostic biomarkers for prostate cancer compared to 12 healthy controls. In addition, a group of four microRNAs (miR-1468-3p, miR 146a-5p, miR-1538 and miR-197-3p) was identified as normalization standards for subsequent qRT-PCR confirmation. qRT-PCR analysis corroborated microRNA sequencing results for the seven top dysregulated microRNAs. The abundance of four microRNAs (miR-127-3p, miR-204-5p, miR-329-3p and miR-487b-3p) was upregulated in blood, whereas the levels of three microRNAs (miR-32-5p, miR-20a 5p and miR-454-3p) were downregulated. Data analysis of the receiver operating curves for these selected microRNAs exhibited a better correlation with prostate cancer than PSA (prostate-specific antigen), the current gold standard for prostate cancer detection. In summary, a panel of seven microRNAs is proposed, many of which have prostate-specific targets, which may represent a significant improvement over current testing methods. PMID- 28621739 TI - Root System Water Consumption Pattern Identification on Time Series Data. AB - In agriculture, soil and meteorological sensors are used along low power networks to capture data, which allows for optimal resource usage and minimizing environmental impact. This study uses time series analysis methods for outliers' detection and pattern recognition on soil moisture sensor data to identify irrigation and consumption patterns and to improve a soil moisture prediction and irrigation system. This study compares three new algorithms with the current detection technique in the project; the results greatly decrease the number of false positives detected. The best result is obtained by the Series Strings Comparison (SSC) algorithm averaging a precision of 0.872 on the testing sets, vastly improving the current system's 0.348 precision. PMID- 28621738 TI - Integration of P-CuO Thin Sputtered Layers onto Microsensor Platforms for Gas Sensing. AB - P-type semiconducting copper oxide (CuO) thin films deposited by radio-frequency (RF) sputtering were integrated onto microsensors using classical photolithography technologies. The integration of the 50-nm-thick layer could be successfully carried out using the lift-off process. The microsensors were tested with variable thermal sequences under carbon monoxide (CO), ammonia (NH3), acetaldehyde (C2H4O), and nitrogen dioxide (NO2) which are among the main pollutant gases measured by metal-oxide (MOS) gas sensors for air quality control systems in automotive cabins. Because the microheaters were designed on a membrane, it was then possible to generate very rapid temperature variations (from room temperature to 550 degrees C in only 50 ms) and a rapid temperature cycling mode could be applied. This measurement mode allowed a significant improvement of the sensor response under 2 and 5 ppm of acetaldehyde. PMID- 28621737 TI - Comprehensive Identification of Guan-Xin-Shu-Tong Capsule via a Mass Defect and Fragment Filtering Approach by High Resolution Mass Spectrometry: In Vitro and In Vivo Study. AB - The Guan-Xin-Shu-Tong capsule (GXSTC) is a well-known traditional Chinese medicine that is used for the treatment of coronary heart disease. Despite its common use in China, basic pharmacological research on its active components is limited. A comprehensive analytical method using quadrupole-time-of-flight mass spectrometry (Q-TOF/MS), specifically with the Triple TOF 5600 platform, was developed to characterize the compounds in the GXSTC powder itself (in vitro) as well as the active components in healthy and heart disease model rats after its oral administration (in vivo). The 5600 platform was operated in both positive and negative ion modes, before the raw data were processed using the extracted ion chromatography (EIC), mass defect filtering (MDF) and fragment filtering (FF) techniques. With the aid of reference compounds for retention time and fragment ion comparisons, 18 compounds were unambiguously identified in vitro. An additional 56 other compounds were tentatively characterized using the accurate quasi-molecular ion mass and Tandem mass spectrometry (MS/MS) fragmentation pattern strategies. Among them, 30 compounds were characterized based on the MDF and FF approaches. Normal rats in addition to hyperlipidemic (HL) and acute blood stasis (ABS) model rats were given a single oral dose of GXSTC solution for subsequent blood analysis at 1 and 2 h after administration. A total of 24 prototypecomponents and 20 metabolites derived from GXSTC were differentially detected across the three animal groups, including the absence of four phase II phenolic acid metabolites in the ABS group and the presence of three diterpenoid related metabolites exclusive to the HL group. The use of reference compounds as well as the mass defect and fragment-filtering strategies were critical to identify GXSTC compounds in vitro and in vivo. This can be used for further quality control and pharmacological studies aimed at characterizing the active and potential beneficial compounds of this ancient medicine. PMID- 28621740 TI - A Multi-Disciplinary Approach to Remote Sensing through Low-Cost UAVs. AB - The use of Unmanned Aerial Vehicles (UAVs) based on remote sensing has generated low cost monitoring, since the data can be acquired quickly and easily. This paper reports the experience related to agave crop analysis with a low cost UAV. The data were processed by traditional photogrammetric flow and data extraction techniques were applied to extract new layers and separate the agave plants from weeds and other elements of the environment. Our proposal combines elements of photogrammetry, computer vision, data mining, geomatics and computer science. This fusion leads to very interesting results in agave control. This paper aims to demonstrate the potential of UAV monitoring in agave crops and the importance of information processing with reliable data flow. PMID- 28621741 TI - Iron Deficiency Anemia as a Risk Factor for Osteoporosis in Taiwan: A Nationwide Population-Based Study. AB - The cause-effect relationship between iron deficiency anemia (IDA) and osteoporosis has not been established in the general population. Thus, the current longitudinal study determined the role of IDA as a risk factor for osteoporosis by analyzing a large nationwide population-based sample. In a sample of 1,000,000 randomly sampled individuals from the 1998-2012. Taiwan National Health Insurance Research Database, patients with IDA (case group (n = 35,751)) and individuals without IDA (control group (n = 178,755)) were compared. Patients who were <20 years of age and who had pre-existing osteoporosis prior to the diagnosis of IDA were excluded. Each patient with IDA was age- and gender-matched to five individuals without IDA. The diagnoses of IDA and osteoporosis (coded using ICD-9CM) were further confirmed with blood test results and X-ray bone densitometry to ensure the accuracy of the diagnoses. Osteoporosis occurred more often among patients with IDA compared to individuals without IDA (2.27% vs. 1.32%, p < 0.001). Cox proportional hazard analysis revealed that the risk for osteoporosis was significantly higher in the case than the control group (hazard ratio (HR) = 1.74; 95% CI = 1.61-1.88) and remained similar after adjustment for covariates (adjusted HR = 1.81; 95% CI = 1.67-1.97). Compared with individuals without IDA, the risk for osteoporosis was even higher for patients with IDA who received intravenous ferrum therapy (adjusted HR = 2.21; 95% CI = 1.85-2.63). In contrast, the risk for osteoporosis was reduced for patients with IDA who received a blood transfusion (adjusted HR = 1.47; 95% CI = 1.20-1.80). As a predictor, prior IDA is a significant and independent risk factor for development of osteoporosis. PMID- 28621742 TI - High Sensitivity Refractometer Based on Reflective Smf-Small Diameter No Core Fiber Structure. AB - A high sensitivity refractive index sensor based on a single mode-small diameter no core fiber structure is proposed. In this structure, a small diameter no core fiber (SDNCF) used as a sensor probe, was fusion spliced to the end face of a traditional single mode fiber (SMF) and the end face of the SDNCF was coated with a thin film of gold to provide reflective light. The influence of SDNCF diameter and length on the refractive index sensitivity of the sensor has been investigated by both simulations and experiments, where results show that the diameter of SDNCF has significant influence. However, SDNCF length has limited influence on the sensitivity. Experimental results show that a sensitivity of 327 nm/RIU (refractive index unit) has been achieved for refractive indices ranging from 1.33 to 1.38, which agrees well with the simulated results with a sensitivity of 349.5 nm/RIU at refractive indices ranging from 1.33 to 1.38. PMID- 28621743 TI - Long-Term In-Service Monitoring and Performance Assessment of the Main Cables of Long-Span Suspension Bridges. AB - Despite the recent developments in structural health monitoring, there remain great challenges for accurately, conveniently, and economically assessing the in service performance of the main cables for long-span suspension bridges. A long term structural health monitoring technique is developed to measure the tension force with a conventional sensing technology and further provide the in-service performance assessment strategy of the main cable. The monitoring system adopts conventional vibrating strings transducers to monitor the tension forces of separate cable strands of the main cable in the anchor span. The performance evaluation of the main cable is conducted based on the collected health monitoring data: (1) the measured strand forces are used to derive the overall tension force of a main cable, which is further translated into load bearing capacity assessment using the concept of safety factor; and (2) the proposed technique can also evaluate the uniformity of tension forces from different cable strands. The assessment of uniformity of strand forces of a main cable offers critical information in terms of potential risks of partial damage and performance deterioration of the main cable. The results suggest the proposed low cost monitoring system is an option to provide approximate estimation of tension forces of main cables for suspension bridges. With the long-term monitoring data, the proposed monitoring-based evaluation methods can further provide critical information to assess the safety and serviceability performance of main cables. PMID- 28621744 TI - In Vitro Comparative Study of the Inhibitory Effects of Mangiferin and Its Aglycone Norathyriol towards UDP-Glucuronosyl Transferase (UGT) Isoforms. AB - Mangiferin (MGF), the predominant constituent of extracts of the mango plant Mangifera Indica L., has been investigated extensively because of its remarkable pharmacological effects. In vitro recombinant UGTs-catalyzed glucuronidation of 4 methylumbelliferone (4-MU) was used to investigate the inhibition of mangiferin and aglycone norathyriol towards various isoforms of UGTs in our study, which evaluated the inhibitory capacity of MGF and its aglycone norathyriol (NTR) towards UDP-glucuronosyltransferase (UGT) isoforms. Initial screening experiment showed that deglycosylation of MGF into NTR strongly increased the inhibitory effects towards almost all the tested UGT isoforms at a concentration of 100 MUM. Kinetic experiments were performed to further characterize the inhibition of UGT1A3, UGT1A7 and UGT1A9 by NTR. NTR competitively inhibited UGT1A3, UGT1A7 and UGT1A9, with an IC50 value of 8.2, 4.4, and 12.3 MUM, and a Ki value of 1.6, 2.0, and 2.8 MUM, respectively. In silico docking showed that only NTR could dock into the activity cavity of UGT1A3, UGT1A7 and UGT1A9. The binding free energy of NTR to UGT1A3, 1A7, 1A9 were -7.4, -7.9 and -4.0 kcal/mol, respectively. Based on the inhibition evaluation standard ([I]/Ki < 0.1, low possibility; 0.1 < [I]/Ki < 1, medium possibility; [I]/Ki > 1, high possibility), an in vivo herb-drug interaction between MGF/NTR and drugs mainly undergoing UGT1A3-, UGT1A7- or UGT1A9-catalyzed metabolism might occur when the plasma concentration of NTR is above 1.6, 2.0 and 2.8 MUM, respectively. PMID- 28621745 TI - System Proposal for Mass Transit Service Quality Control Based on GPS Data. AB - Quality is an essential aspect of public transport. In the case of regular public passenger transport by road, punctuality and regularity are criteria used to assess quality of service. Calculating metrics related to these criteria continuously over time and comprehensively across the entire transport network requires the handling of large amounts of data. This article describes a system for continuously and comprehensively monitoring punctuality and regularity. The system uses location data acquired continuously in the vehicles and automatically transferred for analysis. These data are processed intelligently by elements that are commonly used by transport operators: GPS-based tracking system, onboard computer and wireless networks for mobile data communications. The system was tested on a transport company, for which we measured the punctuality of one of the routes that it operates; the results are presented in this article. PMID- 28621746 TI - Biocompatibility Analyses of Al2O3-Treated Titanium Plates Tested with Osteocyte and Fibroblast Cell Lines. AB - Osseointegration of a titanium implant is still an issue in dental/orthopedic implants durable over time. The good integration of these implants is mainly due to their surface and topography. We obtained an innovative titanium surface by shooting different-in-size particles of Al2O3 against the titanium scaffolds which seems to be ideal for bone integration. To corroborate that, we used two different cell lines: MLO-Y4 (murine osteocytes) and 293 (human fibroblasts) and tested the titanium scaffolds untreated and treated (i.e., Al2O3 shot-peened titanium surfaces). Distribution, density, and expression of adhesion molecules (fibronectin and vitronectin) were evaluated under scanning electron microscope (SEM) and confocal microscope (CM). DAPI and fluorochrome-conjugated antibodies were used to highlight nuclei, fibronectin, and vitronectin, under CM; cell distribution was analyzed after gold-palladium sputtering of samples by SEM. The engineered biomaterial surfaces showed under SEM irregular morphology displaying variously-shaped spicules. Both SEM and CM observations showed better outcome in terms of cell adhesion and distribution in treated titanium surfaces with respect to the untreated ones. The results obtained clearly showed that this kind of surface-treated titanium, used to manufacture devices for dental implantology: (i) is very suitable for cell colonization, essential prerequisite for the best osseointegration, and (ii) represents an excellent solution for the development of further engineered implants with the target to obtain recovery of stable dental function over time. PMID- 28621748 TI - Identification of Onosma visianii Roots Extract and Purified Shikonin Derivatives as Potential Acaricidal Agents against Tetranychus urticae. AB - There is an increasing need for the discovery of reliable and eco-friendly pesticides and natural plant-derived products may play a crucial role as source of new active compounds. In this research, a lipophilic extract of Onosma visianii roots extract containing 12% of shikonin derivatives demonstrated significant toxicity and inhibition of oviposition against Tetranychus urticae mites. Extensive chromatographic separation allowed the isolation of 11 naphthoquinone derivatives that were identified by spectral techniques and were tested against Tetranychus urticae. All the isolated compounds presented effects against the considered mite and isobutylshikonin (1) and isovalerylshikonin (2) were the most active, being valuable model compounds for the study of new anti mite agents. PMID- 28621749 TI - Surface Acoustic Wave Sensors for Hydrogen and Deuterium Detection. AB - A delay-line-type surface acoustic wave (SAW) sensor based on a zinc oxide (ZnO) sensitive layer was developed. Two types of sensitive layers were obtained: ZnO nanowires and ZnO thin films, both deposited using laser methods (VLS-PLD and PLD, respectively) onto quartz substrates. The responses of sensors with two different nanowire lengths (300 and 600 nm) were compared with those of sensors with thin films of different thicknesses (ca. 100 and 200 nm) to different concentrations of hydrogen and deuterium. The experimental results revealed a high response at low concentrations and a rapid saturated response for nanowires, but a low response at low concentrations and a linear response to much higher gas concentrations for the thin-film-based SAW sensors. PMID- 28621747 TI - Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer's Agents: Design, Synthesis and Biological Evaluation. AB - A novel series of 6-chlorotacrine-scutellarin hybrids was designed, synthesized and the biological activity as potential anti-Alzheimer's agents was assessed. Their inhibitory activity towards human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), antioxidant activity, ability to cross the blood brain barrier (BBB) and hepatotoxic profile were evaluated in vitro. Among these compounds, hybrid K1383, bearing two methylene tether between two basic scaffolds, was found to be very potent hAChE inhibitor (IC50 = 1.63 nM). Unfortunately, none of the hybrids displayed any antioxidant activity (EC50 >= 500 MUM). Preliminary data also suggests a comparable hepatotoxic profile with 6 Cl-THA (established on a HepG2 cell line). Kinetic studies performed on hAChE with the most active compound in the study, K1383, pointed out to a mixed, non competitive enzyme inhibition. These findings were further corroborated by docking studies. PMID- 28621750 TI - Initial Alignment for SINS Based on Pseudo-Earth Frame in Polar Regions. AB - An accurate initial alignment must be required for inertial navigation system (INS). The performance of initial alignment directly affects the following navigation accuracy. However, the rapid convergence of meridians and the small horizontalcomponent of rotation of Earth make the traditional alignment methods ineffective in polar regions. In this paper, from the perspective of global inertial navigation, a novel alignment algorithm based on pseudo-Earth frame and backward process is proposed to implement the initial alignment in polar regions. Considering that an accurate coarse alignment of azimuth is difficult to obtain in polar regions, the dynamic error modeling with large azimuth misalignment angle is designed. At the end of alignment phase, the strapdown attitude matrix relative to local geographic frame is obtained without influence of position errors and cumbersome computation. As a result, it would be more convenient to access the following polar navigation system. Then, it is also expected to unify the polar alignment algorithm as much as possible, thereby further unifying the form of external reference information. Finally, semi-physical static simulation and in-motion tests with large azimuth misalignment angle assisted by unscented Kalman filter (UKF) validate the effectiveness of the proposed method. PMID- 28621751 TI - Geographic Variations in Cardiometabolic Risk Factors in Luxembourg. AB - Cardiovascular disease (CVD) and associated behavioural and metabolic risk factors constitute a major public health concern at a global level. Many reports worldwide have documented different risk profiles for populations with demographic variations. The objective of this study was to examine geographic variations in the top leading cardio metabolic and behavioural risk factors in Luxembourg, in order to provide an overall picture of CVD burden across the country. The analysis conducted was based on data from the nationwide ORISCAV-LUX survey, including 1432 subjects, aged 18-69 years. A self-reported questionnaire, physical examination and blood sampling were performed. Age and sex-adjusted risk profile maps were generated using multivariate Bayesian geo-additive regression models, based on Markov Chain Monte Carlo techniques and were used to evaluate the significance of the spatial effects on the distribution of a range of cardio metabolic risk factors, namely smoking, high body mass index (BMI), high blood pressure, high fasting plasma glucose, alcohol use, high total cholesterol, low glomerular filtration rate, and physical inactivity. Higher prevalence of smoking was observed in the northern regions, higher overweight/obesity and abdominal obesity clustered in the central belt, whereas hypertension was spotted particularly in the southern part of the country. Maps revealed that subjects residing in Luxembourg canton were significantly less likely to be hypertensive or overweight/obese, whereas they were less likely to practice physical activity of >=8000 Metabolic Equivalent of Task (MET)-min/week. These patterns were also observed at the municipality level in Luxembourg. Statistically, there were non significant spatial patterns regarding smoking, diabetes, total serum cholesterol and low glomerular filtration rate risk distribution. This comprehensive risk profile mapping showed remarkable geographic variations in cardio metabolic and behavioural risk factors. Considering the prominent burden of CVD this research provides opportunities for tailored interventions and may help to better fight against this escalating public health problem. PMID- 28621752 TI - The Impact of Service Dogs on Engagement in Occupation among Females with Mobility Impairments: A Qualitative Descriptive Study. AB - It is becoming more common for people with disabilities to procure service dogs as a form of assistive technology (AT). However, there is little qualitative research examining the impact of service dogs on engagement in valued daily activities (occupations) among persons with mobility impairments. This study used a qualitative descriptive methodology to learn about the experiences of four female service dog owners with mobility impairments, with a focus on the impact of service dog use on the performance of daily occupations and participation in social activities, and their experiences utilizing a service dog as a form of AT. Data analysis indicated that each participant's service dog made a significant impact on their everyday lives and their ability to independently perform everyday activities; however, there are also unique challenges associated with service dog ownership that must be considered when evaluating benefits of service dog partnership. Overall, the positive outcomes reported by participants indicate that service dogs can be considered a beneficial, adaptable form of AT for some persons with mobility impairments. PMID- 28621753 TI - Media Coverage of Alcohol Issues: A Critical Political Economy Framework-A Case Study from Ireland. AB - There is a growing literature on news media representations of alcohol-related issues. However, current scholarship has neglected critical political economic frameworks to interpret media coverage of alcohol. This paper presents such a framework that conceives of news organisations as corporations that share the values and interests of political and economic elites. The media are thus expected to present viewpoints that are more aligned with the alcohol industry than the scientific consensus on public health policy would warrant. The media are also expected, but to a lesser extent, to present a certain amount of support for public health perspectives because these are supported by a few socioeconomic elite groups (the medical professions, progressive politicians). The case of Ireland from 2012 to 2017 illustrates the framework empirically. Four main newspapers' coverage of the Public Health (Alcohol) Bill and related policies is examined. Results show that, overall, 44.0% of articles support public health measures and 56.0% are opposed or remain neutral. It is argued that the media are not strong proponents of public health for multiple reasons: there are more articles opposed to or neutral toward public health measures than supporting them; the number of supportive articles remains relatively small and there are still many pieces presenting drinks industry views; there are virtually no calls in the media for stronger measures; supportive coverage is partially explained by the pub owners lobby's support for minimum unit pricing; the media often downplay or ignore the negative consequences of alcohol, such as its role in accidents; many news articles normalise drinking and promote events sponsored by the industry; there is not a single Irish journalist covering alcohol issues systematically; and other policy issues that are prioritised by elites receive multiple times more media coverage than public health measures. In short, the media reflect the views of the political and economic establishment on public health measures: there is some support from the medical professions and progressive politicians, but overall, there is a clear reluctance to support strong public health strategies. One main recommendation for public health advocates to promote their perspectives is to diversify the mass media and make them less commercial in nature, as well as to engage with non-corporate, so called progressive "alternative media" outlets. PMID- 28621754 TI - Environmental, Human Health and Socio-Economic Effects of Cement Powders: The Multicriteria Analysis as Decisional Methodology. AB - The attention to sustainability-related issues has grown fast in recent decades. The experience gained with these themes reveals the importance of considering this topic in the construction industry, which represents an important sector throughout the world. This work consists on conducting a multicriteria analysis of four cement powders, with the objective of calculating and analysing the environmental, human health and socio-economic effects of their production processes. The economic, technical, environmental and safety performances of the examined powders result from official, both internal and public, documents prepared by the producers. The Analytic Hierarchy Process permitted to consider several indicators (i.e., environmental, human health related and socio-economic parameters) and to conduct comprehensive and unbiased analyses which gave the best, most sustainable cement powder. As assumed in this study, the contribution of each considered parameter to the overall sustainability has a different incidence, therefore the procedure could be used to support on-going sustainability efforts under different conditions. The results also prove that it is not appropriate to regard only one parameter to identify the 'best' cement powder, but several impact categories should be considered and analysed if there is an interest for pursuing different, often conflicting interests. PMID- 28621755 TI - Biophysical Mode-of-Action and Selectivity Analysis of Allosteric Inhibitors of Hepatitis C Virus (HCV) Polymerase. AB - Allosteric inhibitors of hepatitis C virus (HCV) non-structural protein 5B (NS5B) polymerase are effective for treatment of genotype 1, although their mode of action and potential to inhibit other isolates and genotypes are not well established. We have used biophysical techniques and a novel biosensor-based real time polymerase assay to investigate the mode-of-action and selectivity of four inhibitors against enzyme from genotypes 1b (BK and Con1) and 3a. Two thumb inhibitors (lomibuvir and filibuvir) interacted with all three NS5B variants, although the affinities for the 3a enzyme were low. Of the two tested palm inhibitors (dasabuvir and nesbuvir), only dasabuvir interacted with the 1b variant, and nesbuvir interacted with NS5B 3a. Lomibuvir, filibuvir and dasabuvir stabilized the structure of the two 1b variants, but not the 3a enzyme. The thumb compounds interfered with the interaction between the enzyme and RNA and blocked the transition from initiation to elongation. The two allosteric inhibitor types have different inhibition mechanisms. Sequence and structure analysis revealed differences in the binding sites for 1b and 3a variants, explaining the poor effect against genotype 3a NS5B. The indirect mode-of-action needs to be considered when designing allosteric compounds. The current approach provides an efficient strategy for identifying and optimizing allosteric inhibitors targeting HCV genotype 3a. PMID- 28621756 TI - p53 Expression as a Diagnostic Biomarker in Ulcerative Colitis-Associated Cancer. AB - Ulcerative colitis (UC) is defined as an idiopathic inflammatory disorder primarily involving the mucosa and submucosa of the colon. UC-associated colon cancers (also known as colitic cancers) develop through the inflammation dysplasia sequence, which is a major problem affecting the prognosis of patients with UC. It is therefore very important to detect malignancy from UC at an early stage. As precancerous lesions arising in UC, there are pathological adenomatous changes, basal cell changes, in situ anaplasia, clear cell changes, and pan cellular change. It is considered that the mutation of the p53 gene plays a crucial role, and the protein expression of p53 in dysplastic crypts may serve as a good biomarker in the early stages of UC-associated colon carcinogenesis. Immunohistochemistry for p53 is a very valuable diagnostic tool in UC-associated colon cancers. However, protein expression of p53 is not always universal, and additional methods may be required to assess p53 status in UC-associated colon cancers. PMID- 28621757 TI - Impact of Virtual Touch Quantification in Acoustic Radiation Force Impulse for Skeletal Muscle Mass Loss in Chronic Liver Diseases. AB - BACKGROUND AND AIMS: We sought to clarify the relationship between virtual touch quantification (VTQ) in acoustic radiation force impulse and skeletal muscle mass as assessed by bio-electronic impedance analysis in patients with chronic liver diseases (CLDs, n = 468, 222 males and 246 females, median age = 62 years). PATIENTS AND METHODS: Decreased skeletal muscle index (D-SMI) was defined as skeletal muscle index (SMI) <7.0 kg/m2 for males and as SMI <5.7 kg/m2 for females, according to the recommendations in current Japanese guidelines. We examined the correlation between SMI and VTQ levels and investigated factors linked to D-SMI in the univariate and multivariate analyses. The area under the receiver operating curve (AUROC) for the presence of D-SMI was also calculated. RESULTS: In patients with D-SMI, the median VTQ level was 1.64 meters/second (m/s) (range, 0.93-4.32 m/s), while in patients without D-SMI, the median VTQ level was 1.11 m/s (range, 0.67-4.09 m/s) (p < 0.0001). In the multivariate analysis, higher VTQ was found to be an independent predictor linked to the presence of D-SMI (p < 0.0001). In receiver operating characteristic analysis, body mass index had the highest AUROC (0.805), followed by age (0.721) and VTQ (0.706). CONCLUSION: VTQ levels can be useful for predicting D-SMI in patients with CLDs. PMID- 28621758 TI - Brain Magnetic Resonance Imaging (MRI) as a Potential Biomarker for Parkinson's Disease (PD). AB - Magnetic resonance imaging (MRI) has the potential to serve as a biomarker for Parkinson's disease (PD). However, the type or types of biomarker it could provide remain to be determined. At this time there is not sufficient sensitivity or specificity for MRI to serve as an early diagnostic biomarker, i.e., it is unproven in its ability to determine if a single individual is normal, has mild PD, or has some other forms of degenerative parkinsonism. However there is accumulating evidence that MRI may be useful in staging and monitoring disease progression (staging biomarker), and also possibly as a means to monitor pathophysiological aspects of disease and associated response to treatments, i.e., theranostic marker. As there are increasing numbers of manuscripts that are dedicated to diffusion- and neuromelanin-based imaging methods, this review will focus on these topics cursorily and will delve into pharmacodynamic imaging as a means to get at theranostic aspects of PD. PMID- 28621759 TI - A High-Fructose-High-Coconut Oil Diet Induces Dysregulating Expressions of Hippocampal Leptin and Stearoyl-CoA Desaturase, and Spatial Memory Deficits in Rats. AB - We investigated the effects of high-fructose-high-fat diets with different fat compositions on metabolic parameters, hippocampal-dependent cognitive function, and brain leptin (as well as stearoyl-CoA desaturase (SCD1) mRNA expressions). Thirty-two male Wistar rats were divided into 3 groups, a control group (n = 8), a high-fructose soybean oil group (37.5% of fat calories, n = 12), and a high fructose coconut oil group (37.5% of fat calories, n = 12) for 20 weeks. By the end of the study, the coconut oil group exhibited significantly higher serum fasting glucose, fructosamine, insulin, leptin, and triglyceride levels compared to those of the control and soybean oil groups. However, hippocampal leptin expression and leptin receptor mRNA levels were significantly lower, while SCD1 mRNA was significantly higher in rats fed the high-fructose-high-coconut oil diet than in rats fed the other experimental diets. In addition, the coconut oil group spent significantly less time in the target quadrant on the probe test in the Morris water maze (MWM) task. Rats fed the high-fructose-high-coconut oil diet for 20 weeks were prone to develop hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia. These metabolic consequences may contribute to hippocampal-dependent memory impairment, accompanied by a lower central leptin level, and a higher SCD1 gene expression in the brain. PMID- 28621761 TI - Production of Chitin from Penaeus vannamei By-Products to Pilot Plant Scale Using a Combination of Enzymatic and Chemical Processes and Subsequent Optimization of the Chemical Production of Chitosan by Response Surface Methodology. AB - The waste generated from shrimp processing contains valuable materials such as protein, carotenoids, and chitin. The present study describes a process at pilot plant scale to recover chitin from the cephalothorax of Penaeus vannamei using mild conditions. The application of a sequential enzymatic-acid-alkaline treatment yields 30% chitin of comparable purity to commercial sources. Effluents from the process are rich in protein and astaxanthin, and represent inputs for further by-product recovery. As a last step, chitin is deacetylated to produce chitosan; the optimal conditions are established by applying a response surface methodology (RSM). Under these conditions, deacetylation reaches 92% as determined by Proton Nuclear Magnetic Resonance (1H-NMR), and the molecular weight (Mw) of chitosan is estimated at 82 KDa by gel permeation chromatography (GPC). Chitin and chitosan microstructures are characterized by Scanning Electron Microscopy (SEM). PMID- 28621760 TI - Systematic Review and Meta-Analysis of the Association between Ambient Nitrogen Dioxide and Respiratory Disease in China. AB - Objective: This study aimed to assess the quantitative effects of short-term exposure of ambient nitrogen dioxide (NO2) on respiratory disease (RD) mortality and RD hospital admission in China through systematic review and meta-analysis. Methods: A total of 29 publications were finally selected from searches in PubMed, Web of Science, CNKI and Wanfang databases. Generic inverse variance method was used to pool effect estimates. Pooled estimates were used to represent the increased risk of RD mortality and RD hospital admission per 10 MUg/m3 increase in NO2 concentration. Results: Positive correlations were found between short-term NO2 exposure and RD in China. RD mortality and RD hospital admission respectively increased by 1.4% (95% CI: 1.1%, 1.7%) and 1.0% (95% CI: 0.5%, 1.5%) per 10 MUg/m3 increase in NO2 concentration. Differences were observed across geographic regions of China. The risk of RD mortality due to NO2 was higher in the southern region (1.7%) than in the north (0.7%). Conclusions: Evidence was found that short-term exposure to NO2 was associated with an increased risk of RD mortality and RD hospital admission in China and these risks were more pronounced in the southern regions of the country, due in part to a larger proportion of elderly persons with increased susceptibility to NO2 in the population compared with the north. PMID- 28621762 TI - The Landscape of the Emergence of Life. AB - This paper reports on the various nuances of the origins of life on Earth and highlights the latest findings in that arena as reported at the Network of Researchers on Horizontal Gene Transfer and the Last Universal Common Ancestor (NoR HGT and LUCA) which was held from the 3-4th November 2016 at the Open University, UK. Although the answers to the question of the origin of life on Earth will not be fathomable anytime soon, a wide variety of subject matter was able to be covered, ranging from examining what constitutes a LUCA, looking at viral connections and "from RNA to DNA", i.e., could DNA have been formed simultaneously with RNA, rather than RNA first and then describing the emergence of DNA from RNA. Also discussed are proteins and the origins of genomes as well as various ideas that purport to explain the origin of life here on Earth and potentially further afield elsewhere on other planets. PMID- 28621764 TI - Neuroimmunology: B cells and variant BAFF in autoimmune disease. PMID- 28621763 TI - Why Don't More Smokers Switch to Using E-Cigarettes: The Views of Confirmed Smokers. AB - Whilst e-cigarettes have been characterised by Public Health England as being around 95% less harmful than combustible tobacco products, only a minority of current smokers (around 16% within the UK) are using these devices. In this paper we report the results of an online survey of 650 smokers in contact with a smokers' rights group in the UK. A total of 91% of the smokers surveyed were smoking on a daily basis. Fifty nine percent reported having used electronic nicotine delivery systems, the majority of whom reported having used e cigarettes. Those smokers that had not used these devices principally explained this in terms of the pleasure they derived from smoking. The features smokers' liked most about e-cigarette had to do with the range of settings in which they could be used, the lack of an offensive smell associated with their use, the available flavours and the reduced level of harm. The elements which smokers liked least about e-cigarettes had to do with the vaping experience, the technology, the chemical nature of e-liquids and the complex technology that was associated with these devices. If a greater number of smokers are to be encouraged to take up e-cigarettes, it will be necessary not only to convey accurate information on the relative harm of these devices (compared to combustible tobacco products), but to ensure that they are able to be used in a wider range of settings than those within which smoking can currently occur and that the vaping experience more closely resembles the smoking experience. PMID- 28621765 TI - Epilepsy: Cannabidiol reduces seizure frequency in Dravet syndrome. PMID- 28621767 TI - Neuroimmunology: Complement is no bystander in CNS degeneration. PMID- 28621766 TI - Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. AB - Autologous haematopoietic stem cell transplantation (AHSCT) is a multistep procedure that enables destruction of the immune system and its reconstitution from haematopoietic stem cells. Originally developed for the treatment of haematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders. Results from ~20 years of research make a compelling case for selective use of AHSCT in patients with highly active multiple sclerosis (MS), and for controlled trials. Immunological studies support the notion that AHSCT causes qualitative immune resetting, and have provided insight into the mechanisms that might underlie the powerful treatment effects that last well beyond recovery of immune cell numbers. Indeed, studies have demonstrated that AHSCT can entirely suppress MS disease activity for 4-5 years in 70-80% of patients, a rate that is higher than those achieved with any other therapies for MS. Treatment-related mortality, which was 3.6% in studies before 2005, has decreased to 0.3% in studies since 2005. Current evidence indicates that the patients who are most likely to benefit from and tolerate AHSCT are young, ambulatory and have inflammatory MS activity. Clinical trials are required to rigorously test the efficacy, safety and cost-effectiveness of AHSCT against highly active MS drugs. PMID- 28621769 TI - Alzheimer disease: Sniffing out a marker of early Alzheimer disease. PMID- 28621770 TI - Epilepsy: A new guideline on sudden unexpected death in epilepsy. PMID- 28621771 TI - Repeat expansion disorders: New evidence for RNA gelation in repeat expansion disorders. PMID- 28621768 TI - Imaging and fluid biomarkers in frontotemporal dementia. AB - Frontotemporal dementia (FTD), the second most common type of presenile dementia, is a heterogeneous neurodegenerative disease characterized by progressive behavioural and/or language problems, and includes a range of clinical, genetic and pathological subtypes. The diagnostic process is hampered by this heterogeneity, and correct diagnosis is becoming increasingly important to enable future clinical trials of disease-modifying treatments. Reliable biomarkers will enable us to better discriminate between FTD and other forms of dementia and to predict disease progression in the clinical setting. Given that different underlying pathologies probably require specific pharmacological interventions, robust biomarkers are essential for the selection of patients with specific FTD subtypes. This Review emphasizes the increasing availability and potential applications of structural and functional imaging biomarkers, and cerebrospinal fluid and blood fluid biomarkers in sporadic and genetic FTD. The relevance of new MRI modalities - such as voxel-based morphometry, diffusion tensor imaging and arterial spin labelling - in the early stages of FTD is discussed, together with the ability of these modalities to classify FTD subtypes. We highlight promising new fluid biomarkers for staging and monitoring of FTD, and underline the importance of large, multicentre studies of individuals with presymptomatic FTD. Harmonization in the collection and analysis of data across different centres is crucial for the implementation of new biomarkers in clinical practice, and will become a great challenge in the next few years. PMID- 28621772 TI - High temperature spin-glass-like transition in La0.67Sr0.33MnO3 nanofibers near the Curie point. AB - The glassy transition of superparamagnetic (SPM) (r < r0) nanoparticle systems usually occurs at a very low temperature that greatly limits its application to high temperatures. In this work, we report a spin-glass-like (SGL) behavior near the Curie point (TC), i.e., T0 = 330 K, in La0.67Sr0.33MnO3 (LSMO) nanofibers (NFs) composed of nanoparticles beyond the SPM size (r ? r0), resulting in a significant increase of the glass transition temperature. This SGL transition near the TC of bulk LSMO can be explained to be the scenario of locally ordered clusters embedded in a disordered host, in which the assembly of nanoparticles has a magnetic core-shell model driven by surface spin glass. The presence of a surface spin glass of nanoparticles was proved by the Almeida-Thouless line deltaTf ? H2/3, exchange bias, and reduced saturation magnetization of the NF system. Composite dynamics were found - that is, both the SPM and the super-spin glass (SSG) behavior are found in such an NF system. The bifurcation of the zero field-cooled (ZFC) and field-cooled (FC) magnetization vs. temperature curves at the ZFC peak, and the flatness of FC magnetization involve SSG, while the frequency-dependent ac susceptibility anomaly follows the Vogel-Fulcher law that implies weak dipole interactions of the SPM model. This finding can help us to find a way to search for high temperature spin glass materials. PMID- 28621773 TI - An all-inkjet-printed flexible UV photodetector. AB - In this work, a novel concept of the all-inkjet-printed flexible photodetectors based on ZnO nanocrystals with high performance was proposed and demonstrated with emphasis on the influence of different post-treatments including UV light irradiation and high temperature annealing. The photodetectors based on UV treated ZnO nanocrystal films exhibit a responsivity and an on/off ratio as high as 0.14 A W-1 and >103, respectively, which are better than the thermally treated devices. The high performance of ZnO nanocrystal-based photodetectors originates from unique band-edge modulation among the nanoparticles, where the existence of Schottky barriers leads to a low dark current and gives rise to a fast photoelectric response. The photodetector is capable of 500 bending cycles, and almost no degradation is observed. The as-obtained all-printable devices open up the possibility of fabricating a low-cost, solution processed, flexible, and large-area integrated optoelectronic sensor circuitry for future practical applications. PMID- 28621774 TI - Mesoporous polydopamine nanoparticles with co-delivery function for overcoming multidrug resistance via synergistic chemo-photothermal therapy. AB - Theranostic agents for combined chemo-photothermal therapy have attracted intensive interest in the treatment of multi-drug resistance (MDR) in cancer therapy. However, the development of simple theranostic agents as dual hosts for both heat and a high payload of chemotherapeutic agents remains a big challenge. Herein, mesoporous polydopamine nanoparticles (MPDA) were successfully developed with properties of a high payload of DOX (up to 2000 MUg mg-1) and the drug efflux inhibitor TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), as well as strong near-infrared absorption. Particularly, DOX and TPGS were sequentially loaded in the pore space and on the external particle surface of MPDA via pi-pi stacking and hydrophobic interactions, resulting in a MPDA DOX@TPGS complex. The DOX release observably relies on the pH value and glutathione (GSH). Furthermore, it is possible to accelerate the rate of drug release by NIR irradiation. Importantly, the MPDA-DOX@TPGS complex was found to escape from endosomes after cellular uptake and release the loaded drugs into the cytosol. By TPGS mediated MDR reversal, the delivered DOX induced significant cytotoxicity to MCF-7/ADR cells. Besides, MPDA can absorb the NIR light and convert it into fatal heat to kill the cancer cells. As a consequence, the combined therapy in our system yields a synergistic effect with high therapeutic efficacy. PMID- 28621775 TI - 3D cellular invasion platforms: how do paper-based cultures stack up? AB - Cellular invasion is the gateway to metastasis, which is the leading cause of cancer-related deaths. Invasion is driven by a number of chemical and mechanical stresses that arise in the tumor microenvironment. In vitro assays are needed for the systematic study of cancer progress. To be truly predictive, these assays must generate tissue-like environments that can be experimentally controlled and manipulated. While two-dimensional (2D) monolayer cultures are easily assembled and evaluated, they lack the extracellular components needed to assess invasion. Three-dimensional (3D) cultures are better suited for invasion studies because they generate cellular phenotypes that are more representative of those found in vivo. This feature article provides an overview of four invasion platforms. We focus on paper-based cultures, an emerging 3D culture platform capable of generating tissue-like structures and quantifying cellular invasion. Paper-based cultures are as easily assembled and analyzed as monolayers, but provide an experimentally powerful platform capable of supporting: co-cultures and representative extracellular environments; experimentally controlled gradients; readouts capable of quantifying, discerning, and separating cells based on their invasiveness. With a series of examples we highlight the potential of paper-based cultures, and discuss how they stack up against other invasion platforms. PMID- 28621776 TI - Tuning Pt and Cu sites population inside functionalized UiO-67 MOF by controlling activation conditions. AB - The exceptional thermal and chemical stability of the UiO-66, -67 and -68 classes of isostructural MOFs [J. Am. Chem. Soc., 2008, 130, 13850] makes them ideal materials for functionalization purposes aimed at introducing active centres for potential application in heterogeneous catalysis. We previously demonstrated that a small fraction (up to 10%) of the linkers in the UiO-67 MOF can be replaced by bipyridine-dicarboxylate (bpydc) moieties exhibiting metal-chelating ability and enabling the grafting of Pt(ii) and Pt(iv) ions in the MOF framework [Chem. Mater., 2015, 27, 1042] upon interaction with PtCl2 or PtCl4 precursors. Herein we extend this functionalization approach in two directions. First, we show that by controlling the activation of the UiO-67-Pt we can move from a material hosting isolated Pt(ii) sites anchored to the MOF framework with Pt(ii) exhibiting two coordination vacancies (potentially interesting for C-H bond activation) to the formation of very small Pt nanoparticles hosted inside the MOF cavities (potentially interesting for hydrogenation reactions). The second direction consists of the extension of the approach to the insertion of Cu(ii), obtained via interaction with CuCl2, and exhibiting interesting redox properties. All materials have been characterized by in situ X-ray absorption spectroscopy at the Pt L3- and Cu K-edges. PMID- 28621777 TI - Polar metal-formate frameworks templated with 1,2-diaminoethane-water assemblies showing ferromagnetic and ferroelectric properties. AB - A set of five novel formate frameworks templated with assemblies comprising diprotonated 1,2-diaminoethane (DAE) and a water molecule of the formula: [NH3(CH2)2NH3]M2(HCOO)6.H2O, where M = Mg, Mn, Co, Ni, Zn, has been synthesized. Four compounds crystallize in the polar R3 space group and one in the chiral P6322 space group (Ni-analog) at room temperature. The polyammonium-water assemblies, mutually joined by hydrogen bonds, fill the cavities of the frameworks and are disordered in the three latter compounds. Additional disorder is found in the Ni-sample as the DAE2+-H2O couple is placed in a special position on the 63 screw axis. IR spectroscopy provides evidence of proton dynamic disorder within the assemblies, which turns into a static one at low temperatures. The crystals preserve their arrangement up to approximately 370 K as shown by differential calorimetric measurements and temperature-dependent IR spectroscopy. The ferroelectric nature of a representative of the family, DAEMgF, at room temperature has been confirmed by pyroelectric measurements. It has been found that the spontaneous polarization may be changed by an external electric field. The magnetic studies reveal a weak ferromagnetic behavior within 8.5-35 K for magnetically active ions: Mn, Co, and Ni. PMID- 28621778 TI - Synthesis of functionalized alkyl substituted benzoquinones by Rh-catalyzed additions of boronic acids. AB - A general synthetic route to gamma-oxo alkyl or alpha-hydroxy benzyl 2 substituted benzoquinones has been developed through a one-pot Rh-catalyzed C-C bond formation/oxidative demethylation sequence from 2,5-dimethoxy aryl boronic acids and several electron deficient alkenes or aldehydes. The process allows rapid access to functionalized benzoquinones under very mild conditions and good yields. We disclose the first example of a Rh-catalyzed 1,4-addition reaction of benzoquinonyl boronic acid to methyl vinyl ketone and other conjugate acceptors, which allows the direct synthesis of 2-(gamma-functionalized alkyl) substituted benzoquinones. PMID- 28621779 TI - The effective determination of Cd(ii) and Pb(ii) simultaneously based on an aluminum silicon carbide-reduced graphene oxide nanocomposite electrode. AB - A platform for the simultaneous determination of Cd(ii) and Pb(ii) in aqueous solution has been applied based on an aluminum silicon carbide-reduced graphene oxide nanocomposite (Al4SiC4-RGO) modified bismuth film glassy carbon electrode (GCE) using square wave anodic stripping voltammetry (SWASV) for the first time. The Al4SiC4-RGO nanocomposite electrode was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Compared with the Al4SiC4 modified GCE and bare GCE, the electrochemical performance of the Al4SiC4-RGO nanocomposite electrode is obviously enhanced resulting from the synergistic effects of Al4SiC4, RGO and bismuth film. The chemical and electrochemical parameters that exert an influence on the deposition and stripping of metal ions, such as supporting electrolytes, pH values, concentrations of Bi3+, deposition potentials and deposition times, were carefully studied. Under optimal conditions, a linear relationship exists between the currents and the concentrations of Cd(ii) and Pb(ii) in the range of 50 to 2700 MUg L-1. The limits of detection (S/N = 3) are estimated to be 1.30 MUg L-1 for Pb(ii) and 2.15 MUg L-1 for Cd(ii). Compared with the related work reported in the literature, the analytical performance in this work has a lower determination limit and a wider detection linear range. In addition, this electrode also exhibits good stability and reproducibility. These results imply that the Al4SiC4 RGO nanocomposite might be a promising candidate for practical applications in the electrochemical detection of metal ions. PMID- 28621780 TI - Structure-property relationship of blue solid state emissive phenanthroimidazole derivatives. AB - Seven new derivatives of phenanthro[9,10-d]imidazole having differenet substituents at the 1st and the 2nd positions of the phenanthroimidazole moiety were synthesized and characterized. The comparative study of their properties was performed employing thermal, optical, electrochemical and photoelectrical measurements. The properties of the newly synthesized compounds were compared with those of earlier reported derivatives of phenanthroimidazole and several interesting new findings were disclosed. Density functional theory calculations accompanied by optical spectroscopy measurements have shown the possibility of tuning the emission properties (excited-stated decay rate, fluorescence quantum yield, etc.) of phenanthro[9,10-d]imidazole derivatives via attachment of different substituents to the 1st and the 2nd positions. The most polar and bulky substituents linked to the 2nd position were found to have the greatest impact on the emissive properties of compounds causing (i) fluorescence quantum yield enhancement of dilute liquid and solid solutions (up to 97%), (ii) suppression of intramolecular torsion-induced nonradiative excited-state relaxation in rigid polymer films as well as (iii) inhibition of aggregation-promoted emission quenching in the neat films. Most of the studied compunds exhibited ambipolar charge transport character with comparable drift mobilities of holes and electrons. The highest hole and electron mobilities approaching 10-4 cm2 V-1 s-1 were observed for the derivative having a triphenylamino group at the 1st position of the imidazole ring and the phenyl group at the 2nd position. The estimated triplet energies of phenanthro[9,10-d]imidazole compounds were found to be in the range of 2.4-2.6 eV, which is sufficiently high to ensure effective energy transfer to yellow/red emitters. PMID- 28621781 TI - The relevance of structural features of cellulose and its interactions to dissolution, regeneration, gelation and plasticization phenomena. AB - Cellulose is the most abundant polymer and a very important renewable resource. Since cellulose cannot be shaped by melting, a major route for its use for novel materials, new chemical compounds and renewable energy must go via the solution state. Investigations during several decades have led to the identification of several solvents of notably different character. The mechanisms of dissolution in terms of intermolecular interactions have been discussed from early work but, even on fundamental aspects, conflicting and opposite views appear. In view of this, strategies for developing new solvent systems for various applications have remained obscure. There is for example a strong need for using forest products for higher value materials and for environmental and cost reasons to use water based solvents. Several new water-based solvents have been developed recently but there is no consensus regarding the underlying mechanisms. Here we wish to address the most important mechanisms described in the literature and confront them with experimental observations. A broadened view is helpful for improving the current picture and thus cellulose derivatives and phenomena such as fiber dissolution, swelling, regeneration, plasticization and dispersion are considered. In addition to the matter of hydrogen bonding versus hydrophobic interactions, the role of ionization as well as some applications of new knowledge gained are highlighted. PMID- 28621782 TI - Stereodivergent synthesis of all the four stereoisomers of antidepressant reboxetine. AB - Chiral amino alcohol-copper(ii) catalysts Cu-L1c and Cu-ent-L1c were utilized to promote the diastereoselective nitroaldol reactions of chiral aldehydes (S)-3 or (R)-3 with nitromethane, which respectively led to the preferential formation of certain stereoisomer for nitro diol derivatives 4. Using this catalytic protocol, all the four stereoisomers of the antidepressant reboxetine were divergently prepared. The highest overall yield of this synthetic route reached up to 30.5% from aldehyde (S)-3. PMID- 28621783 TI - Liquid-phase oxidation of alkylaromatics to aromatic ketones with molecular oxygen over a Mn-based metal-organic framework. AB - Liquid-phase oxidation of alkylaromatics with molecular O2 was examined using a microporous Mn-based metal-organic framework (Mn-MOF-74). Mn-MOF-74 consisting of trimeric Mn clusters and 2,5-dihydroxyterephthalate (dhtp) linkers exhibits superior catalytic activity with good ketone selectivity compared to conventional oxide-supported Mn catalysts without showing any lengthy induction period. Combined analyses by means of XRD, FE-SEM, N2 physisorption and Mn K-edge XAFS reveal that the superior catalytic performance is attributed to the inherently formed Mn(iii)2(dhtp) moieties embedded in the Mn-MOF-74 framework rather than structural factors associated with the MOF. The catalyst is reusable over multiple catalytic runs along with retaining its original catalytic activity due to the ability of the dhtp ligand to stabilize active Mn(iii) atoms. Owing to high activity, reusability and nontoxicity, Mn-MOF-74 can offer a simple, inexpensive and efficient protocol for the oxidation of some important alkylaromatics, such as ethylbenzene and diphenylmethane to produce the corresponding aromatic ketones. PMID- 28621784 TI - Dynamic reconfiguration of van der Waals gaps within GeTe-Sb2Te3 based superlattices. AB - Phase-change materials based on GeSbTe show unique switchable optoelectronic properties and are an important contender for next-generation non-volatile memories. Moreover, they recently received considerable scientific interest, because it is found that a vacancy ordering process is responsible for both an electronic metal-insulator transition and a structural cubic-to-trigonal transition. GeTe-Sb2Te3 based superlattices, or specifically their interfaces, provide an interesting platform for the study of GeSbTe alloys. In this work such superlattices have been grown with molecular beam epitaxy and they have been characterized extensively with transmission electron microscopy and X-ray diffraction. It is shown that the van der Waals gaps in these superlattices, which result from vacancy ordering, are mobile and reconfigure through the film using bi-layer defects and Ge diffusion upon annealing. Moreover, it is shown that for an average composition that is close to GeSb2Te4 a large portion of 9 layered van der Waals systems is formed, suggesting that still a substantial amount of random vacancies must be present within the trigonal GeSbTe layers. Overall these results illuminate the structural organization of van der Waals gaps commonly encountered in GeSbTe alloys, which are intimately related to their electronic properties and the metal-insulator transition. PMID- 28621785 TI - Three-dimensional atomic models from a single projection using Z-contrast imaging: verification by electron tomography and opportunities. AB - In order to fully exploit structure-property relations of nanomaterials, three dimensional (3D) characterization at the atomic scale is often required. In recent years, the resolution of electron tomography has reached the atomic scale. However, such tomography typically requires several projection images demanding substantial electron dose. A newly developed alternative circumvents this by counting the number of atoms across a single projection. These atom counts can be used to create an initial atomic model with which an energy minimization can be applied to obtain a relaxed 3D reconstruction of the nanoparticle. Here, we compare, at the atomic scale, this single projection reconstruction approach with tomography and find an excellent agreement. This new approach allows for the characterization of beam-sensitive materials or where the acquisition of a tilt series is impossible. As an example, the utility is illustrated by the 3D atomic scale characterization of a nanodumbbell on an in situ heating holder of limited tilt range. PMID- 28621786 TI - Alkali and alkaline earth metal salts of tetrazolone: structurally interesting and excellently thermostable. AB - Tetrazolone (5-oxotetrazole) was synthesized by a moderate strategy through three steps (addition, cyclization and catalytic hydrogenation) avoiding the unstable intermediate diazonium, as reported during the previous preparation. Alkali and alkaline earth metal salts with lithium (1), sodium (2), potassium (3), rubidium (4) caesium (5), magnesium (6), calcium (7), strontium (8) and barium (9) were prepared and fully characterized using elemental analysis, IR and NMR spectroscopy, DSC and TG analysis. All metal salts were characterized via single crystal X-ray diffraction. They crystallize in common space groups with high densities ranging from 1.479 (1) to 3.060 g cm-3 (5). Furthermore, the crystal structures of 7, 8 and 9 reveal interesting porous energetic coordination polymers with strong hydrogen bond interactions. All new salts have good thermal stabilities with decomposition temperature between 215.0 degrees C (4) and 328.2 degrees C (7), significantly higher than that of the reported nitrogen-rich salt neutral tetrazolone. The sensitivities towards impact and friction were tested using standard methods, and all the tetrazolone-based compounds investigated can be classified into insensitive. The flame test of these metal salts supports their potential use as perchlorate-free pyrotechnics or eco-friendly insensitive energetic materials. PMID- 28621787 TI - Cascade energy transfer and tunable emission from nanosheet hybrids: locating acceptor molecules through chiral doping. AB - Light harvesting donor-acceptor assemblies are indispensable to efficiently tap photons. In an attempt to improve the light harvesting efficiency of an acceptor doped assembly, we design and synthesize a donor-acceptor-donor triad which exhibits an exceptional intramolecular energy transfer with excellent efficiency. Moreover, a facile cascade energy transfer (energy funnelling) is observed in the presence of a series of second acceptors (63-91% efficiency) with tunable emission colours. Self-assembled nanosheets formed by the triad in the presence of acceptors exhibit cascade energy transfer assisted tunable emission. In addition, use of chiral acceptors induces chirality to the triad and results in the formation of chiral nanosheets along with cascade energy transfer. Here chiral induction, nanosheet formation and cascade energy transfer in the presence of chiral acceptors are used as tools to probe the intercalation of acceptor molecules in the donor scaffold. PMID- 28621788 TI - Graphene on h-BN: to align or not to align? AB - The contact strength, adhesion and friction, between graphene and an incommensurate crystalline substrate such as h-BN depends on their relative alignment angle theta. The well-established Novaco-McTague (NM) theory predicts for a monolayer graphene on a hard bulk h-BN crystal face a small spontaneous misalignment, here thetaNM ? 0.45 degrees which if realized would be relevant to a host of electronic properties besides the mechanical ones. Because experimental equilibrium is hard to achieve, we inquire theoretically about alignment or misalignment by simulations based on dependable state-of-the-art interatomic force fields. Surprisingly at first, we find compelling evidence for theta = 0, i.e., full energy-driven alignment in the equilibrium state of graphene on h-BN. Two factors drive this deviation from the NM theory. First, graphene is not flat, developing on h-BN a long-wavelength out-of-plane corrugation. Second, h-BN is not hard, releasing its contact stress by planar contractions/expansions that accompany the interface moire structure. Repeated simulations by artificially forcing graphene to keep flat, and h-BN to keep rigid, indeed yield an equilibrium misalignment similar to thetaNM as expected. Subsequent sliding simulations show that friction of graphene on h-BN, small and essentially independent of misalignments in the artificial frozen state, strongly increases in the more realistic corrugated, strain-modulated, aligned state. PMID- 28621789 TI - Display of functional proteins on supramolecular peptide nanofibrils using a split-protein strategy. AB - The display of functional proteins on self-assembled peptide nanofibrils is challenging since the steric bulk of proteins attached to simple self-assembling peptides often impedes incorporation into nanofibrils. Herein is described a split-protein strategy to tether functional proteins to preassembled peptide nanofibrils. In this strategy, a short affinity motif peptide derived from a split protein system is appended to a self-assembly motif (the amphipathic Ac (FKFE)2-NH2 peptide) to form an affinity-assembly fusion peptide. The small size of the affinity motif allows the affinity-assembly fusion peptide to be readily incorporated into peptide nanofibrils that display the affinity motif when the affinity-assembly peptide is coassembled with Ac-(FKFE)2-NH2. Introduction of the split-protein that is complementary to the affinity motif to the assembled nanofibrils results in efficient, multivalent attachment of functional proteins to the peptide nanofibrils. This strategy is demonstrated with two split-protein systems, ribonuclease S' (RNase S') and split green fluorescent protein (GFP). PMID- 28621790 TI - Molecular interactions and thermal transport in ionic liquids with carbon nanomaterials. AB - We used molecular dynamics simulation to study the effect of suspended carbon nanomaterials, nanotubes and graphene sheets, on the thermal conductivity of ionic liquids, an issue related to understanding the properties of nanofluids. One important aspect that we developed is an atomistic model of the interactions between the organic ions and carbon nanomaterials, so we did not rely on existing force fields for small organic molecules or assume simple combining rules to describe the interactions at the liquid/material interface. Instead, we used quantum calculations with a density functional suitable for non-covalent interactions to parameterize an interaction model, including van der Waals terms and also atomic partial charges on the materials. We fitted a n-m interaction potential function with n values of 9 or 10 and m values between 5 and 8, so a 12 6 Lennard-Jones function would not fit the quantum calculations. For the atoms of ionic liquids and carbon nanomaterials interacting among themselves, we adopted existing models from the literature. We studied the imidazolium ionic liquids [C4C1im][SCN], [C4C1im][N(CN)2], [C4C1im][C(CN)3] and [C4C1im][(CF3SO2)2N]. Attraction is stronger for cations (than for anions) above and below the pi system of the nanomaterials, whereas anions show stronger attraction for the hydrogenated edges. The ordering of ions around and inside (7,7) and (10,10) single-walled nanotubes, and near a stack of graphene sheets, was analysed in terms of density distribution functions. We verified that anions are found, as well as cations, in the first interfacial layer interacting with the materials, which is surprising given the interaction potential surfaces. The thermal conductivity of the ionic liquids and of composite systems containing one nanotube or one graphene stack in suspension was calculated using non-equilibrium molecular dynamics. Thermal conductivity was calculated along the axis of the nanotube and across the planes of graphene, in order to see the anisotropy. In the composite systems containing the nanotube, there is an enhancement of the overall thermal conductivity, with calculated values comparing well with experiments on nanotube suspensions, namely in terms of the order of the different ionic liquids. In the systems containing the graphene stack, the interfacial region of the ionic liquid near the surface of the material has an enhanced thermal conductivity with respect to the bulk liquid, but no significant discontinuity in the temperature profiles were observed. This is important information for models of thermal conduction in nanofluids. PMID- 28621791 TI - N-Hydroxy sulfonamides as new sulfenylating agents for the functionalization of aromatic compounds. AB - An unprecedented use of N-hydroxy sulfonamides as sulfenylating agents has been established. In the presence of catalytic amounts of iodine and N hydroxysuccinimide, N-hydroxy sulfonamides participated in sulfenylation with indoles, 7-azaindole, N-methyl pyrrole, and 2-naphthol to afford structurally diverse thioethers in moderate to excellent yields with very high regioselectivity. PMID- 28621792 TI - Ruthenium-catalyzed site-selective C-H arylation of 2-pyridones and 1 isoquinolinones. AB - An efficient Ru(ii)-catalyzed site-selective C-H arylation of 2-pyridones and 1 isoquinolinones was achieved with boronic acids by using pyridine as a directing group. The developed protocol is general and provides rapid access to an array of C6-arylated 2-pyridones and C3-arylated 1-isoquinolinones in excellent yields. These designed arylated 2-pyridones and 1-isoquinolinones can serve as key structural motifs for accessing functionalized pyridines and isoquinolines. PMID- 28621794 TI - Exploring surface landscapes with molecules: rotationally induced diffraction of H2 on LiF(001) under fast grazing incidence conditions. AB - Atomic diffraction by surfaces under fast grazing incidence conditions has been used for almost a decade to characterize surface properties with more accuracy than with more traditional atomic diffraction methods. From six-dimensional solutions of the time-dependent Schrodinger equation, we show that diffraction of H2 molecules under fast grazing incidence conditions could be even more informative for the characterization of ionic surfaces, due to the large anisotropic electrostatic interaction between the quadrupole moment of the molecule and the electric field created by the ionic crystal. Using the LiF(001) surface as a benchmark, we show that fast grazing incidence diffraction of H2 strongly depends on the initial rotational state of the molecule, while rotationally inelastic processes are irrelevant. We demonstrate that, as a result of the anisotropy of the impinging projectile, initial rotational excitation leads to an increase in intensity of high-order diffraction peaks at incidence directions that satisfy precise symmetry constraints, thus providing a more detailed information on the surface characteristics than that obtained from low order atomic diffraction peaks under fast grazing incidence conditions. As quadrupole-ion surface potentials are expected to accurately represent the interaction between H2 and any surface with a marked ionic character, our analysis should be of general applicability to any of such surfaces. Finally, we show that a density functional theory description of the molecule-ion surface potential catches the main features observed experimentally. PMID- 28621793 TI - Kinetics and mechanism of oxidation of the anti-tubercular prodrug isoniazid and its analog by iridium(iv) as models for biological redox systems. AB - A complex reaction mechanism of oxidation of the anti-tubercular prodrug isoniazid (isonicotinic hydrazide, INH) by [IrCl6]2- as a model for redox processes of such drugs in biological systems has been studied in aqueous solution as a function of pH between 0 and 8.5. Similar experiments have been performed with its isomer nicotinic hydrazide (NH). All reactions are overall second-order, first-order in [IrCl6]2- and hydrazide, and the observed second order rate constants k' have been determined as a function of pH. Spectrophotometric titrations indicate a stoichiometry of [Ir(iv)] : [hydrazide] = 4 : 1. HPLC analysis shows that the oxidation product of INH is isonicotinic acid. The derived reaction mechanism, based on rate law, time-resolved spectra and stoichiometry, involves parallel attacks by [IrCl6]2- on all four protolytic species of INH and NH as rate-determining steps, depending on pH. These steps are proposed to generate two types of hydrazyl free radicals. These radicals react further in three rapid consecutive processes, leading to the final oxidation products. Rate constants for the rate-determining steps have been determined for all protolytic species I-IV of INH and NH. They are used to calculate reactivity pH diagrams. These diagrams demonstrate that for both systems, species IV is ca. 105 times more reactive in the redox process than the predominant species III at the physiological pH of 7.4. Thus, species IV will be the main reactant, in spite of the fact that its concentration at this pH is extremely low, a fact that has not been considered in previous work. The results indicate that pH changes might be an important factor in the activation process of INH in biological systems also, and that in such systems this process most likely is more complicated than previously assumed. PMID- 28621795 TI - Machine learning for autonomous crystal structure identification. AB - We present a machine learning technique to discover and distinguish relevant ordered structures from molecular simulation snapshots or particle tracking data. Unlike other popular methods for structural identification, our technique requires no a priori description of the target structures. Instead, we use nonlinear manifold learning to infer structural relationships between particles according to the topology of their local environment. This graph-based approach yields unbiased structural information which allows us to quantify the crystalline character of particles near defects, grain boundaries, and interfaces. We demonstrate the method by classifying particles in a simulation of colloidal crystallization, and show that our method identifies structural features that are missed by standard techniques. PMID- 28621796 TI - Reply to Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry-methodological issues. PMID- 28621797 TI - A better angel of our nature: Hanna Michel "Jean" Khoury, MD (April 24, 1967-May 22, 2017). PMID- 28621798 TI - The relationship of serum adipokines with malnutrition inflammation score in haemodialysis. AB - BACKGROUND: Protein-energy wasting is a prevalent disorder in haemodialysis. Zinc alpha2-glycoprotein (ZAG) and adipose triglyceride lipase (ATGL) are novel adipokines with recognized lipolytic effects and proposed role in metabolic homoeostasis. This study was conducted to investigate the association of ZAG and ATGL concentrations with malnutrition-inflammation score (MIS) and metabolic profile of patients with haemodialysis. MATERIALS AND METHODS: Eighty-eight patients under regular haemodialysis were divided based on MIS to normal to mild wasting (NMW; n = 35) or moderate wasting (MW; n = 53) group. Anthropometric measurements along with fasting serum concentrations of ZAG, ATGL, free fatty acids (FFAs), albumin, transferrin, total iron-binding capacity (TIBC), hs-CRP, lipid profile and glucose metabolism were assessed. RESULTS: Adipose triglyceride lipase concentration was significantly higher in MW than NMW group (10.89 +/- 5.7 vs. 8.02 +/- 3.37 mIU/mL; P = 0.008). The ZAG and FFAs were not significantly different between two groups. ATGL was directly correlated with FFAs in all of the patients (r = 0.284, P = 0.007) and MW (r = 0.32, P = 0.021), and marginally in NMW (r = 0.31, P = 0.057) groups. ATGL and odds of having mild or moderate wasting were significantly correlated (OR = 1.21, P = 0.033). A positive association was observed between ATGL with TG (r = 0.31, P = 0.049) and also with transferrin and TIBC (r = 0.44, P = 0.001) only in MW group. An inverse relationship was observed between ATGL and HDL in all of the participants (r= 0.222, P = 0.04). No significant correlation was observed between ZAG and other parameters. CONCLUSIONS: The serum concentrations of ATGL, but not ZAG, were significantly higher in MW compared to NMW group. Each unit increase in ATGL concentrations was correlated with 21% increase in the odds of wasting severity. ATGL might play a role in wasting pathogenesis and metabolic profile in haemodialysis. PMID- 28621799 TI - Clinical guideline for the management of odontogenic infections in the tertiary setting. AB - BACKGROUND: Odontogenic infections are a common presentation to emergency departments of Australian hospitals. Due to the limited training in diagnosis and treatment of dental conditions, these patients can present a challenge for the medical practitioner. The objective of this study was to provide an evidence based approach to the management of odontogenic infections in adults presenting to Royal Perth Hospital. METHODS: A literature search was conducted to identify evidence-based guidelines for the management of odontogenic infections in the tertiary hospital setting. Keywords 'dental', 'infections' and 'management' were used to search PubMed, DynaMed and Embase databases. RESULTS: Recommendations were drawn from existing literature including coroner reports with respect to clinical assessment, investigations, medical and surgical management, and postoperative care. A flow chart, incorporating these recommendations, was created to allow for appropriate disposition of patients presenting with odontogenic infections to Royal Perth Hospital. CONCLUSIONS: A clinical guideline is needed to appropriately manage patients presenting with odontogenic infections. We recommend the guideline be submitted to intradepartmental committees for assessment. PMID- 28621801 TI - Effect of velaglucerase alfa enzyme replacement therapy on red blood cell properties in Gaucher disease. PMID- 28621800 TI - A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. AB - Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life-threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy-associated HLH (M-HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M-HLH may occur in up to 1% of patients with hematologic malignancies. M-HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M-HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M-HLH with optimal combinations of T lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M-HLH. Cancer 2017;123:3229-40. (c) 2017 American Cancer Society. PMID- 28621802 TI - Glypican-3: A promising biomarker for hepatocellular carcinoma diagnosis and treatment. AB - Liver cancer is the second leading cause of cancer-related deaths, and hepatocellular carcinoma (HCC) is the most common type. Therefore, molecular targets are urgently required for the early detection of HCC and the development of novel therapeutic approaches. Glypican-3 (GPC3), an oncofetal proteoglycan anchored to the cell membrane, is normally detected in the fetal liver but not in the healthy adult liver. However, in HCC patients, GPC3 is overexpressed at both the gene and protein levels, and its expression predicts a poor prognosis. Mechanistic studies have revealed that GPC3 functions in HCC progression by binding to molecules such as Wnt signaling proteins and growth factors. Moreover, GPC3 has been used as a target for molecular imaging and therapeutic intervention in HCC. To date, GPC3-targeted magnetic resonance imaging, positron emission tomography, and near-infrared imaging have been investigated for early HCC detection, and various immunotherapeutic protocols targeting GPC3 have been developed, including the use of humanized anti-GPC3 cytotoxic antibodies, treatment with peptide/DNA vaccines, immunotoxin therapies, and genetic therapies. In this review, we summarize the current knowledge regarding the structure, function, and biology of GPC3 with a focus on its clinical potential as a diagnostic molecule and a therapeutic target in HCC immunotherapy. PMID- 28621803 TI - Absent pulmonary valve syndrome - diagnosis, associations, and outcome in 71 prenatally diagnosed cases. AB - OBJECTIVE: The objective of this study was to analyze the spectrum of prenatally diagnosed absent pulmonary valve syndrome (APVS) and the outcome from diagnosis onwards. Fetuses with APVS and tetralogy of Fallot (TOF/APVS) and with APVS and intact ventricular septum (APVS/IVS) were included. METHOD: Multicenter retrospective study of the International Prenatal Cardiology Collaboration Group. Clinical and echocardiographic databases of nine referral centers were reviewed from 2012-2016. RESULTS: The cohort included 71 cases, 59 with TOF/APVS and 12 with APVS/IVS. In 18.3% of cases, diagnosis was achieved within first trimester. Association with hydrops fetalis was high within first trimester (69%). No fetus with known outcome survived after first trimester diagnosis. Karyotype anomalies occurred in 45% of cases with known karyotype. Intrauterine fetal demise occurred in 14.3%. Overall survival after initial diagnosis in the total cohort was 28.1% (28.8% TOF/APVS and 25.0% APVS/IVS). Survival to birth was 50% in TOF/APVS and 44.4% in APVS/IVS. Survival of subjects born alive beyond neonatal period was 84.6% in TOF/APVS and 100% in APVS/IVS. CONCLUSION: Diagnosis of APVS is feasible within first trimester. Outcomes remain guarded, especially if first trimester diagnosis is included into the analysis because of associated karyotypic anomalies, the presence of hydrops fetalis, and patent ductus arteriosus. (c) 2017 John Wiley & Sons, Ltd. PMID- 28621804 TI - Long-term evolution of viruses: A Janus-faced balance. AB - The popular textbook image of viruses as noxious and selfish genetic parasites greatly underestimates the beneficial contributions of viruses to the biosphere. Given the crucial dependency of viruses to reproduce in an intracellular environment, viruses that engage in excessive killing (lysis) can drive their cellular hosts to extinction and will not survive. The lytic mode of virus propagation must, therefore, be tempered and balanced by non-lytic modes of virus latency and symbiosis. Here, we review recent bioinformatics and metagenomic studies to argue that viral endogenization and domestication may be more frequent mechanisms of virus persistence than lysis. We use a triangle diagram to explain the three major virus persistence strategies that explain the global scope of virus-cell interactions including lysis, latency and virus-cell symbiosis. This paradigm can help identify novel directions in virology research where scientists could artificially gain control over switching lytic and beneficial viral lifestyles. Also see the Video Abstract: http://youtu.be/GwXWz4N8o8. PMID- 28621805 TI - Noninvasive screening test for detecting early stage lymphedema using follow-up computed tomography imaging after cancer treatment and results of treatment with lymphaticovenular anastomosis. AB - BACKGROUND: Although early detection is valuable for secondary lymphedema treatment, existing screening tests are not popular. This study aimed to propose a novel method of screening lymphedema patients based on the thickness of the subcutaneous fat measured with perioperative computed tomography (CT) and present the results from evaluation of patients who underwent those examinations was performed. METHOD: The medical records of 96 gynecological cancer patients and 189 breast cancer patients, whose lymphatic function was assessed with indocyanine green lymphography, were reviewed. In gynecological cancer patients, the perioperative temporal subcutaneous fat thickness index (T-SFTI) was calculated from presurgical and follow-up CT data, and in breast cancer patients, the postoperative crosswise subcutaneous fat thickness index (C-SFTI) was calculated. In lower extremity lymphedema patients, the effect of lymphaticovenular anastomosis (LVA) was also evaluated using T-SFTI. RESULTS: Perioperative T-SFTI was assessed in 180 lower extremities, and it was significantly higher in 46 lymphatic dysfunction limbs (1.21 +/- 0.08) than in 134 normal lymphatic function limbs (1.03 +/- 0.08), (P < .01). Postoperative C SFTI was assessed in 53 upper extremity, and it was significantly higher in 11 lymphatic dysfunction limbs (1.31 +/- 0.21) than in 42 normal lymphatic function limbs (1.01 +/- 0.06), (P < .01). In lower extremity lymphedema patients, T-SFTI improved significantly after planned conservative treatments and LVA (P = .04). CONCLUSION: Assessment of subcutaneous fat thickness using CT is useful for screening early stage lymphedema. If the efficacy of this method is validated, patients worldwide may be assessed using the same criterion. PMID- 28621806 TI - Inequalities in uptake of prenatal screening according to ethnicity and socio economic status in the four largest cities of the Netherlands (2011-2013). AB - OBJECTIVES: In the Netherlands, all women are claimed to have equal access to prenatal screening (PS). Prior research demonstrated substantial inequalities in PS uptake associated with socioeconomic status (SES) and ethnic background. The suggested pathway was a lack of intention to participate in PS among these subgroups. We studied the background of inequalities in PS participation, challenging intention heterogeneity as the single explanation. METHODS: Multivariable logistic regression analyses of the national PS registry, focusing on the four largest cities in the Netherlands (n = 4578, years 2011-2013), stratified by SES. OUTCOME MEASURES: (1) any uptake of PS (yes/no) and (2) uptake (one/two tests) for women who intended to participate in two tests. Determinants included intention, ethnicity, practice, and age. RESULTS: Of non-Western women, 85.7% were screened versus 89.7% of Western women. Intention was an important explanatory factor in all models. However, after correction for intention, ethnicity remained a significant determinant for differences in uptake. Ethnicity and SES also interacted, indicating that non-Western women in low SES areas had the lowest uptake (corrected for intention). CONCLUSIONS FOR PRACTICE: Socioeconomic status and ethnicity related inequalities in PS uptake are only partially explained by intention heterogeneity; other pathways, in particular provider-related determinants, may play a role. (c) 2017 John Wiley & Sons, Ltd. PMID- 28621807 TI - Cellular compartmentation follows rules: The Schnepf theorem, its consequences and exceptions: A biological membrane separates a plasmatic from a non-plasmatic phase. AB - Is the spatial organization of membranes and compartments within cells subjected to any rules? Cellular compartmentation differs between prokaryotic and eukaryotic life, because it is present to a high degree only in eukaryotes. In 1964, Prof. Eberhard Schnepf formulated the compartmentation rule (Schnepf theorem), which posits that a biological membrane, the main physical structure responsible for cellular compartmentation, usually separates a plasmatic form a non-plasmatic phase. Here we review and re-investigate the Schnepf theorem by applying the theorem to different cellular structures, from bacterial cells to eukaryotes with their organelles and compartments. In conclusion, we can confirm the general correctness of the Schnepf theorem, noting explicit exceptions only in special cases such as endosymbiosis and parasitism. PMID- 28621808 TI - Primary care interventions to reduce childhood obesity and sugar-sweetened beverage consumption: Food for thought for oral health professionals. AB - OBJECTIVES: Childhood obesity remains a significant threat to America's children. Health care leaders have increasingly called upon oral health professionals to integrate healthy weight promotion and enhanced sugar-sweetened beverage counseling into their professional practices. The aim of this scoping review is to examine recent evidence regarding the effectiveness of primary care childhood obesity interventions that have potential for adoption by oral health professionals. METHODS: Medine, and PubMed were searched from 2010 to 2016 for review articles and studies reporting patient outcomes or policy outcomes relevant to primary care childhood obesity interventions for children ages 2-11 years. Additional articles were accessed through relevant websites, journals, and references. Our screening criteria included interventions that could be adopted by oral health professionals. RESULTS: Forty-two articles met inclusion criteria. Effective interventions fell into four domains: family-based programs, motivational interviewing, office-based practice tools, and policy interventions. Despite strong evidence linking the consumption of sugar-sweetened beverages to childhood obesity, our review did not find evidence of primary care programs effectively targeting and reducing childhood sugary drinks. CONCLUSIONS: Effective primary care interventions for addressing childhood obesity have been identified, although only short-term effectiveness has been demonstrated. Dissemination of these practices as well as further research and advocacy are needed. Childhood obesity and poor oral health share many common risk factors. Additional research should focus on the benefits and feasibility of widespread interdisciplinary medical-oral health collaboration in addressing the two most prevalent diseases of childhood. PMID- 28621809 TI - Primary care visit use after positive fecal immunochemical test for colorectal cancer screening. AB - BACKGROUND: For some patients, positive cancer screening test results can be a stressful experience that can affect future screening compliance and increase the use of health care services unrelated to medically indicated follow-up. METHODS: Among 483,216 individuals aged 50 to 75 years who completed a fecal immunochemical test to screen for colorectal cancer at a large integrated health care setting between 2007 and 2011, the authors evaluated whether a positive test was associated with a net change in outpatient primary care visit use within the year after screening. Multivariable regression models were used to evaluate the relationship between test result group and net changes in primary care visits after fecal immunochemical testing. RESULTS: In the year after the fecal immunochemical test, use increased by 0.60 clinic visits for patients with true positive results. The absolute change in visits was largest (3.00) among individuals with positive test results who were diagnosed with colorectal cancer, but significant small increases also were found for patients treated with polypectomy and who had no neoplasia (0.36) and those with a normal examination and no polypectomy performed (0.17). Groups of patients who demonstrated an increase in net visit use compared with the true-negative group included patients with true-positive results (odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.54-1.66), and positive groups with a colorectal cancer diagnosis (OR, 7.19; 95% CI, 6.12-8.44), polypectomy/no neoplasia (OR, 1.37; 95% CI, 1.27-1.48), and normal examination/no polypectomy (OR, 1.24; 95% CI, 1.18-1.30). CONCLUSIONS: Given the large size of outreach programs, these small changes can cumulatively generate thousands of excess visits and have a substantial impact on total health care use. Therefore, these changes should be included in colorectal cancer screening cost models and their causes investigated further. Cancer 2017;123:3744 3753. (c) 2017 American Cancer Society. PMID- 28621810 TI - Adherence to Standards for Reporting Diagnostic Accuracy in Emergency Medicine Research. AB - BACKGROUND: Diagnostic tests are used frequently in the emergency department (ED) to guide clinical decision making and, hence, influence clinical outcomes. The Standards for Reporting of Diagnostic Accuracy (STARD) criteria were developed to ensure that diagnostic test studies are performed and reported to best inform clinical decision making in the ED. OBJECTIVE: The objective was to determine the extent to which diagnostic studies published in emergency medicine journals adhered to STARD 2003 criteria. METHODS: Diagnostic studies published in eight MEDLINE-listed, peer-reviewed, emergency medicine journals over a 5-year period were reviewed for compliance to STARD criteria. RESULTS: A total of 12,649 articles were screened and 114 studies were included in our study. Twenty percent of these were randomly selected for assessment using STARD 2003 criteria. Adherence to STARD 2003 reporting standards for each criteria ranged from 8.7% adherence (criteria-reporting adverse events from performing index test or reference standard) to 100% (multiple criteria). CONCLUSION: Just over half of STARD criteria are reported in more than 80% studies. As poorly reported studies may negatively impact their clinical usefulness, it is essential that studies of diagnostic test accuracy be performed and reported adequately. Future studies should assess whether studies have improved compliance with the STARD 2015 criteria amendment. PMID- 28621811 TI - Multisensory neural integration of chemical and mechanical signals. AB - Chemosensation and mechanosensation cover an enormous spectrum of processes by which animals use information from the environment to adapt their behavior. For pragmatic reasons, these sensory modalities are commonly investigated independently. Recent advances, however, have revealed numerous situations in which they function together to control animals' actions. Highlighting examples from diverse vertebrates and invertebrates, we first discuss sensory receptors and neurons that have dual roles in the detection of chemical and mechanical stimuli. Next we present cases where peripheral chemosensory and mechanosensory pathways are discrete but intimately packaged to permit coordinated reception of external cues. Finally, we consider how chemical and mechanical signals converge in central neural circuitry to enable multisensory integration. These insights demonstrate how investigation of the interplay between different sensory modalities is key to a more holistic and realistic understanding of sensory guided behaviors. PMID- 28621812 TI - TCDD induces UbcH7 expression and synphilin-1 protein degradation in the mouse ventral midbrain. AB - UbcH7 is an ubiquitin-conjugating enzyme that interacts with parkin, an E3 ligase. The UbcH7-parkin complex promotes the ubiquitination and degradation of several proteins via the 26S proteasome. Cellular accumulation of the UbcH7 parkin targets alpha-synuclein and synphilin-1 has been associated with Parkinson disease. In mouse liver, 2,3,7,8-tetrachlorodibenzo-p-dioxin, an aryl hydrocarbon receptor ligand, induces UbcH7 expression. Therefore, the aim of the present study was to determine whether 2,3,7,8-tetrachlorodibenzo-p-dioxin induces Ubch7 mRNA and UbcH7 protein expression in the mouse brain, to characterize the molecular mechanism, and the effect on synphilin-1 half-life. We found that 2,3,7,8-tetrachlorodibenzo-p-dioxin promotes the aryl hydrocarbon receptor binding to Ubch7 gene promoter as well as its transactivation, resulting in an induction of UbcH7 levels in the olfactory bulb, ventral midbrain, hippocampus, striatum, cerebral cortex, brain stem, and medulla oblongata. In parallel, 2,3,7,8-tetrachlorodibenzo-p-dioxin promoted synphilin-1 degradation in an aryl hydrocarbon receptor-dependent way. PMID- 28621813 TI - Legacy effects of drought on plant-soil feedbacks and plant-plant interactions. AB - Interactions between aboveground and belowground biota have the potential to modify ecosystem responses to climate change, yet little is known about how drought influences plant-soil feedbacks with respect to microbial mediation of plant community dynamics. We tested the hypothesis that drought modifies plant soil feedback with consequences for plant competition. We measured net pairwise plant-soil feedbacks for two grassland plant species grown in monoculture and competition in soils that had or had not been subjected to a previous drought; these were then exposed to a subsequent drought. To investigate the mechanisms involved, we assessed treatment responses of soil microbial communities and nutrient availability. We found that previous drought had a legacy effect on bacterial and fungal community composition that decreased plant growth in conspecific soils and had knock-on effects for plant competitive interactions. Moreover, plant and microbial responses to subsequent drought were dependent on a legacy effect of the previous drought on plant-soil interactions. We show that drought has lasting effects on belowground communities with consequences for plant-soil feedbacks and plant-plant interactions. This suggests that drought, which is predicted to increase in frequency with climate change, may change soil functioning and plant community composition via the modification of plant-soil feedbacks. PMID- 28621815 TI - Liquid chromatographic enantioseparation of limonene-based carbocyclic beta-amino acids on zwitterionic Cinchona alkaloid-based chiral stationary phases. AB - The eight stereoisomers of limonene-based carbocyclic beta-amino acids containing three chiral centers have been directly separated on chiral stationary phases containing Cinchona alkaloid-based zwitterionic selectors. The effects of bulk solvent composition of the mobile phase, the nature of base additives, counterion concentration, and the structure of selector on the enantiorecognition were studied. Experiments were performed at constant mobile phase composition in the temperature range 5-40 degrees C to study the effect of temperature. Thermodynamic parameters were calculated on the basis of the plots of ln alpha versus 1/T curves. The enthalpically or entropically driven enantioseparations were found to depend strongly on the structures of analyte and selector. The eight stereoisomers of limonene-based carbocyclic beta-amino acids could be differentiated as well-separated peaks in a traditional 1D chromatographic system in two runs by applying the two complementary ZWIX(+)TM and ZWIX(-)TM columns. PMID- 28621814 TI - Identification and characterization of the zebrafish glutathione S-transferase Pi 1. AB - Zebrafish has in recent years emerged as a popular vertebrate model for use in pharmacological and toxicological studies. While there have been sporadic studies on the zebrafish glutathione S-transferases (GSTs), the zebrafish GST gene superfamily still awaits to be fully elucidated. We report here the identification of 15 zebrafish cytosolic GST genes in NCBI GenBank database and the expression, purification, and enzymatic characterization of the zebrafish cytosolic GST Pi-1 (GSTP1). The cDNA encoding the zebrafish GSTP1 was cloned from a 3-month-old female zebrafish, expressed in Eschelichia coli host cells, and purified. Purified GSTP1 displayed glutathione-conjugating activity toward 1 chloro-2,4-dinitrobenzene as a representative substrate. The enzymatic characteristics of the zebrafish GSTP1, including pH-dependency, effects of metal cations, and kinetic parameters, were studied. Moreover, the expression of zebrafish GSTP1 at different developmental stages during embryogenesis, throughout larval development, onto maturity was examined. PMID- 28621816 TI - Control of a Pediatric Pulsatile Ventricular Assist Device: A Hybrid Cardiovascular Model Study. AB - The aim of this work is to study pediatric pneumatic ventricle (PVAD) performance, versus VAD rate (VADR) and native heart rate (HR) ratio Rr (VADR/HR). The study uses a hybrid model of the cardiovascular system (HCS). HCS consists of a computational part (a lumped parameter model including left and right ventricles, systemic and pulmonary arterial and venous circulation) interfaced to a physical part. This permits the connection of a VAD (15 mL PVAD). Echocardiographic and hemodynamic data of a pediatric patient (average weight 14.3 kg, HR 100 bpm, systemic pressure 75/44 mm Hg, CO 1.5 L/min) assisted apically with asynchronous PVAD were used to set up a basal condition in the model. After model tuning, the assistance was started, setting VAD parameters (ejection and filling pressures, systole duration) to completely fill and empty the PVAD. The study was conducted with constant HR and variable VADR (50-120, step 10, bpm). Experiments were repeated for two additional patients' HRs, 90 and 110 bpm and for two values of systemic arterial resistance (Ras ) and Emax . Experimental data were collected and stored on disk. Analyzed data include average left and right ventricular volumes (LVV, RVV), left ventricular flow (LVF), VAD flow (VADF), and total cardiac output (COt). Data were analyzed versus Rr. LVV and RVV are sensitive to Rr and a left ventricular unloading corresponds in general to a right ventricular loading. In the case of asynchronous assistance, frequency beats are always present and the beat rate is equal to the difference between HR and VADR. In the case of pulsatile asynchronous LVAD assistance, VADR should be chosen to minimize frequency beat effects and right ventricular loading and to maximize left ventricular unloading. PMID- 28621817 TI - Gas phase basicities of polyfunctional molecules. Part 6: Cyanides and isocyanides. AB - This paper gathers structural and thermochemical informations related to the gas phase basicity of molecules containing cyanides (nitriles) and isocyanides (isonitriles) functional groups. It constitutes the sixth part of a general review devoted to gas-phase basicities of polyfunctional compounds. A large corpus of cyanides and isocyanides molecules is examined under seven major chapters. In the first one, a rapid overview of the definitions and methods leading to gas-phase basicity, GB, proton affinity, PA, and protonation entropy, Deltap S degrees , is given. In the same chapter, several aspects of the gas phase chemistry of protonated cyanides and isocyanides are also presented. Chapters II-VI detail the protonation energetics of aliphatic, unsaturated, and heteroatom substituted (halogens, O, S, N, P) cyanides. A seventh chapter is devoted to isocyanides. Experimental data available in the literature (120 references) were reevaluated according to the presently adopted basicity scale that is the NIST database anchored to PA(NH3 ) = 853.6 kJ/mol and GB (NH3 ) = 819 kJ/mol. In this latter source, however, several erroneous values have been identified which were corrected in the present review. Structural and energetic information given by G4MP2 quantum chemistry computations on ca. 60 typical systems are presented. The present review includes the GB, PA, and Deltap S degrees values of ca. 110 cyanides and isocyanides, and, for selected examples, is completed by a set of computed heats of formation (Deltaf H degrees ) at 0 and 298 K. PMID- 28621818 TI - Healthy Futures: Engaging the oral health community in childhood obesity prevention - Conference summary and recommendations. AB - Childhood obesity is a major public health problem. An association between obesity and dental caries, the most prevalent disease of childhood, has been identified. One explanation for the association is that consumption of sugar sweetened beverages and frequent snacking on carbohydrate-rich foods are common risk factors for development of both obesity and caries. The Robert Wood Johnson Foundation (RWJF) has been at the forefront of national efforts to promote healthy weight in children. As part of these efforts, RWJF sponsored the Healthy Futures: Engaging the Oral Health Community in Childhood Obesity Prevention National Conference, held on November 3-4, 2016, at Georgetown University in Washington, DC. The aim of the conference was to increase awareness of evidence based recommendations; identify strategies; and promote collaborative efforts that oral health professionals, oral-health-related organizations, and others can employ to prevent childhood obesity. This report summarizes the findings presented at the conference and discusses their implications. The report also reviews recommendations made in the areas of research, education, and policy that resulted from the conference. PMID- 28621819 TI - Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry-methodological issues. PMID- 28621820 TI - The efficacy of Internet-based cognitive behavioral therapy for severely fatigued survivors of breast cancer compared with care as usual: A randomized controlled trial. AB - BACKGROUND: Severe fatigue is a common and distressing symptom affecting approximately one in four survivors of breast cancer. The current study examined the efficacy of Internet-based cognitive behavioral therapy (ICBT) for severe fatigue in survivors of breast cancer compared with care as usual (CAU). METHODS: The authors conducted a parallel-group randomized controlled trial. Severely fatigued, disease-free survivors of breast cancer who had completed cancer treatment at least 3 months previously were eligible. Participants were randomly allocated to ICBT or CAU using computer-generated stratified block randomization. The primary outcome of fatigue severity was assessed at baseline and after 6 months, as were the secondary outcomes of functional impairment, psychological distress, and quality of life. Statistical effects were tested with analyses of covariance (intention-to-treat analysis). RESULTS: Participants were recruited between January 2014 and March 2016 and assigned to ICBT (66 patients) or CAU (66 patients). Compared with the participants who had received CAU, those who had received ICBT reported lower fatigue scores at 6 months (mean difference [Delta], 11.5; 95% confidence interval [95% CI], 7.7-15.3) and a large effect size (Cohen d = 1.0), with the majority of patients (73%) demonstrating clinically significant improvement. ICBT also was found to lead to lower functional impairment (Delta, 297.8; 95% CI, 145.5-450.1) and psychological distress scores (Delta, 5.7; 95% CI, 3.4-7.9) and higher quality-of-life scores (Delta, 11.7; 95% CI, 5.8-17.7) compared with CAU, with medium to large effect sizes (Cohen d = 0.6 0.8). CONCLUSIONS: ICBT appears to be effective in reducing severe fatigue and related symptoms and meets the current need for easy accessible and more efficient evidence-based treatment options for severely fatigued survivors of breast cancer. Cancer 2017;123:3825-34. (c) 2017 American Cancer Society. PMID- 28621821 TI - An unusual case of dental infection by Pseudomonas aeruginosa causing a brain abscess: case report. AB - A brain abscess may result when dental infection reaches the brain through contiguous anatomic cavities such as the maxillary sinus, the ethmoid sinus and the orbital cavity. It is an important complication and should be treated aggressively. Such treatment would include the excision of the etiological factor, drainage and adjuvant antibiotic therapy. The present case concerns a 23 year old woman who presented at the General Hospital of Nova Iguacu with complaints of pain in the right side of the face and was diagnosed with acute sinusitis. Antibiotics and analgesics were prescribed to treat the disease. However, after 10 days, she returned to the emergency room, presenting with proptosis of the right eyeball, subconjunctival haemorrhage, ophthalmoplegia and intense pain in the right orbit, in addition to headaches. After computed tomography was performed, she was diagnosed with a brain abscess in the frontal lobe with the involvement of the maxillary right first molar, the maxillary sinus, the ethmoid sinus and the orbital cavity. With culturing of the secretion, the growth of Pseudomonas aeruginosa colonies was evident. Treatment consisted of a craniotomy to drain the brain abscess, a Caldwell-Luc procedure to drain the right maxillary sinus, dental extraction and aggressive antibiotic therapy. After 6 weeks, the patient was discharged with no neurological sequelae. PMID- 28621823 TI - Raw material procurement for termite fishing tools by wild chimpanzees in the Issa valley, Western Tanzania. AB - OBJECTIVES: Chimpanzee termite fishing has been studied for decades, yet the selective processes preceding the manufacture of fishing tools remain largely unexplored. We investigate raw material selection and potential evidence of forward planning in the chimpanzees of Issa valley, western Tanzania. MATERIALS AND METHODS: Using traditional archaeological methods, we surveyed the location of plants from where chimpanzees sourced raw material to manufacture termite fishing tools, relative to targeted mounds. We measured raw material abundance to test for availability and selection. Statistics included Chi-Squared, two-tailed Wilcoxon, and Kruskall-Wallace tests. RESULTS: Issa chimpanzees manufactured extraction tools only from bark, despite availability of other suitable materials (e.g., twigs), and selected particular plant species as raw material sources, which they often also exploit for food. Most plants were sourced 1-16 m away from the mound, with a maximum of 33 m. The line of sight from the targeted mound was obscured for a quarter of these plants. DISCUSSION: The exclusive use of bark tools despite availability of other suitable materials indicates a possible cultural preference. The fact that Issa chimpanzees select specific plant species and travel some distance to source them suggests some degree of selectivity and, potentially, forward planning. Our results have implications for the reconstruction of early hominin behaviors, particularly with regard to the use of perishable tools, which remain archaeologically invisible. PMID- 28621822 TI - cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjogren's syndrome. AB - To examine genes expressed specifically in labial salivary glands (LSGs) of patients with Sjogren's syndrome (SS) in comparison with those of patients with immunoglobulin (Ig)G4-related disease (IgG4-RD), and to identify the genes involved in the pathogenesis of SS. Gene expression in LSGs of SS patients, IgG4 RD patients and healthy controls (HC) was analysed by cDNA microarray. Quantitative polymerase chain reaction (qPCR) was used to validate the up regulation of differentially expressed genes (DEGs) in SS. Protein production of the validated gene in LSGs was examined by immunofluorescence (IF) assay. The association of molecular functions of the gene with the pathological conditions in SS was examined using peripheral blood lymphocytes. Among 1320 DEGs up regulated in SS, qPCR confirmed the up-regulation of NR4A2 in LSGs of SS compared with IgG4-RD. IF staining showed higher production of NR4A2 in nuclei of CD4+ T cells and interleukin (IL)-17-producing cells in LSGs of SS, compared with IgG4 RD. Over-expression of NR4A2 mRNA was observed in peripheral CD4+ T cells of SS patients, compared with HC. Nuclear NR4A2 expression in T helper type 17 (Th17) polarized CD4+ T cells determined by cellular IF was significantly higher in SS than in HC. Importazole, an inhibitor of importin-beta, inhibited nuclear transport of NR4A2 and Th17 polarization along with IL-21 expression in naive CD4+ T cells under Th17-polarizing conditions, but did not alter retinoic acid receptor-related orphan receptor C (RORC) expression. NR4A2 seems to promote Th17 polarization via increased expression and intranuclear localization in CD4+ T cells of SS patients, which could play a critical role in the pathogenesis of SS. PMID- 28621825 TI - 13th World Congress of Pediatric Dermatology, Chicago, IL, July 6-9, 2017. PMID- 28621824 TI - Design, Synthesis, and Evaluation of Novel Tyrosine-Based DNA Gyrase B Inhibitors. AB - The discovery and synthesis of new tyrosine-based inhibitors of DNA gyrase B (GyrB), which target its ATPase subunit, is reported. Twenty-four compounds were synthesized and evaluated for activity against DNA gyrase and DNA topoisomerase IV. The antibacterial properties of selected GyrB inhibitors were demonstrated by their activity against Staphylococcus aureus and Enterococcus faecalis in the low micromolar range. The most promising compounds, 8a and 13e, inhibited Escherichia coli and S. aureus GyrB with IC50 values of 40 and 30 uM. The same compound also inhibited the growth of S. aureus and E. faecalis with minimal inhibitory concentrations (MIC90 ) of 14 and 28 ug/mL, respectively. PMID- 28621826 TI - Cerebral metabolic alterations and cognitive dysfunction in children with chronic kidney disease using Magnetic Resonance Spectroscopy and Wechsler intelligence scale. AB - BACKGROUND: Many studies described Impaired intelligence, attention, memory and executive function in patients with chronic kidney disease (CKD) dialyzed and non dialyzed, but there is still lacking the early and sensitive method of detection of these deficits. The purpose of this study is to investigate relation between the brain metabolic alteration [measured by magnetic resonance spectroscopy (MRS)] and cognitive dysfunction in CKD children (detected by psychometric analysis). SUBJECTS AND METHODS: One hundred and forty patients with CKD were included [ 40 patients with stage 5 CKD on dialysis, 30 patients with stage 4 to 5 CKD without dialysis, and 70 patients with stage 1 to 3 CKD]. All patients with previous neurological disorders were excluded. Conventional MRI, MRS and psychometric assessment by using Wechsler intelligence scale for children third edition was done in all subjects. RESULTS: We found a significant negative correlation between MRS abnormalities and Wechsler IQ Test scores. But there was a significantly positive correlation between the CKD stages and MRS abnormalities in patients with CKD and negative significant correlation between CKD stages and Wechsler IQ test scores in patients with CKD. There were correlations between "the electrolyte disturbance, blood hemoglobin and hypertension" and "the CKD staging, cognitive functions IQ scores and MRS parameter changes". CONCLUSION: We concluded that both MRS and psychometric tests are sensitive methods for detection of cognitive function affection in CKD children, particularly in dialyzed group and these findings appears before the clinical diagnosis. PMID- 28621827 TI - Maize (Zea mays) consumption in the southern andes (30 degrees -31 degrees S. Lat): Stable isotope evidence (2000 BCE-1540 CE). AB - OBJECTIVES: The timing and dietary role of maize agriculture is central to archaeological discussions in the Andean region. In the semi-arid region of northern Chile (SARNC), archaeological models propose that maize was adopted during the Early Ceramic period in tandem with pottery and sedentism. Through stable isotope (SI) analyses, of bone collagen and apatite, this study assesses the timing of maize introduction, diachronic changes (2,000 BCE to 1,540 CE.), and synchronic dietary variability in the prehistoric SARNC. MATERIALS AND METHODS: Fifty-two prehistoric individuals from SARNC were analyzed for delta13 Cap , delta13 Ccol, and delta15 N. Descriptive statistics were used to characterize the results by period and location (inland and coast). Between periods (ANOVA or Kruskal-Wallis tests), and synchronic comparisons (inland vs. coast; Student's t-tests), were conducted. A SIAR model was run to further evaluate dietary changes. Dietary interpretations are based on food web data. RESULTS: Coastal groups show significant changes in the diet during the Middle (900-1,000CE; enrichment in delta13 C), and Late Intermediate periods (100 1450CE; when the Delta13 Cap-col is above 5.20/00). In the inland, significant changes in SI occurred in the Late Intermediate period (delta13 C enrichment). In the Late period, the inland diet became enriched for delta15 N. Synchronic comparisons showed coastal individuals to have higher delta15 N. DISCUSSION: The popularization of maize in the SARNC was not associated with the appearance of pottery and/or sedentism, and its role as a dietary staple was a late phenomenon (c.a. 1,000CE). The results obtained in this study show that the adoption and consumption of maize varied dramatically in the Southern Andes. PMID- 28621829 TI - Heterogeneous Sodium-Manganese Oxide Catalyzed Aerobic Oxidative Cleavage of 1,2 Diols. AB - The aerobic oxidative cleavage of 1,2-diols using a heterogeneous catalyst only based on earth-abundant metals manganese and sodium is reported for the first time. This reusable catalyst cleaves a variety of substrates into aldehydes or ketones with high selectivity. The reaction requires small catalytic loadings and is performed under mild conditions using ambient pressure O2 or air as the oxidant while producing water as the only by-product. Mechanistic investigations reveal a monodentate, two-electron oxidative fragmentation process involving a MnIV species. The eco-friendly, innocuous catalyst is compatible with a wide range of functional groups and conditions, making it highly competitive with classical reagents, such as periodic acid or lead tetraacetate, as a preferred method for activated 1,2-diols. PMID- 28621830 TI - Phytochelatin synthase OsPCS1 plays a crucial role in reducing arsenic levels in rice grains. AB - Reduction of the level of arsenic (As) in rice grains is an important challenge for agriculture. A recent study reported that the OsABCC1 transporter prevents the accumulation of As in grains by sequestering As-phytochelatin complexes into vacuoles in the upper nodes. However, how phytochelatins are provided in response to As remains unclear. Here, we show that the phytochelatin synthase OsPCS1 plays a crucial role in reducing As levels in rice grains. Using a forward genetic approach, we isolated two rice mutants (has1 and has2) in which As levels were much higher in grains but significantly lower in node I compared with the wild type. Map-based cloning identified the genes responsible as OsABCC1 in has1 and OsPCS1 in has2. The levels of As in grains and node I were similar between the two mutants, suggesting that OsABCC1 preferentially cooperates with OsPCS1 to sequester As, although rice has another phytochelatin synthase, OsPCS2. An in vitro phytochelatin synthesis assay indicated that OsPCS1 was more sensitive to activation by As than by cadmium, whereas OsPCS2 was more weakly activated by As than by cadmium. Transgenic plants highly expressing OsPCS1 showed significantly lower As levels in grains than did wild-type plants. Our results provide new knowledge of the relative contribution of rice PCS paralogs to As sequestration and suggest a good candidate tool to reduce As levels in rice grains. PMID- 28621828 TI - Progress in the synthesis and biological evaluation of lipid A and its derivatives. AB - Lipid A is one of the core structures of bacterial lipopolysaccharides (LPSs), and it is mainly responsible for the strong immunostimulatory activities of LPS through interactions with the Toll-like receptors and other molecules in the human immune system. To obtain structurally homogeneous and well-defined lipid As and its derivatives in quantities meaningful for various biological studies and applications, their chemical synthesis has become a focal point. This review has provided a survey of significant progresses made in the synthesis of lipid A, and its derivatives that carry diverse saturated and unsaturated lipids, have the phosphate group at its reducing end replaced with a more stable phosphate or carboxyl group, or lack the reducing end phosphate or both phosphate groups, as well as progresses in the synthesis of LPS analogs and other lipid A conjugates. These synthetic molecules have facilitated the elucidation of the structure activity relationships of lipid A useful for the design and development of lipid A based therapeutics, such as those utilized to treat sepsis, and other medical applications, for example the use of monophosphoryl lipid A as a carrier molecule for the study of fully synthetic self-adjuvanting conjugate vaccines. These topics are also briefly covered in the current review. PMID- 28621831 TI - A New Rat Model of Seizures Suitable for Screening Antiepileptic Electrical Stimulation Therapies. AB - The antiepileptic effects of the electrical stimulation therapies developed for patients with intractable epilepsies depend critically on the stimulation parameters, including the pulse duration, current, and frequency. Consequently, optimization of such therapies requires many animals for testing each of the stimulation parameters alone or in combination, which is costly and time consuming. This drawback could be reduced by testing several stimulation paradigms in each animal, but this requires an animal model of long-lasting seizures allowing such repetitive tests. This study was performed to validate such a model of long-lasting seizures. The present analysis was performed on electrocorticogram and intracortical signals collected from the somatosensory cortex of 11 Sprague Dawley rats. A protocol of controlled intravenous infusion of pentylenetetrazol (PTZ) was developed to induce spike-and-wave (SW) seizures and maintain stable those seizures for the whole experimental time. SW discharges were induced and maintained stable for 2 h in all rats through a two-stage infusion of PTZ. During the first stage, the SW discharges were induced by 2.5 min infusion of 10 mg/kg/min PTZ. During the second stage, the SW discharges were maintained at a stable level of frequency and power for 2 h via a 0.21 mg/kg/min PTZ infusion rate. The proposed animal model of seizures is characterized by SW discharges which remain stable for 2 h. This 2-h long time interval allows repetitive tests with different stimulation parameters in each animal, which may lead to a significant reduction of the number of animals necessary for optimizing electrical stimulation therapies developed to inhibit seizures. PMID- 28621833 TI - Multiple external cervical root resorptions after home whitening treatment: a case report. AB - Invasive multiple cervical root resorptions after vital tooth bleaching is a rare condition. The aim of this article is to present a case of multiple external cervical root resorptions (ECRR) after a misguided home whitening treatment. A 34 year old male patient presented with slight sensitivity and mobility in several teeth. Despite the manufacturer's recommendations, the patient used a 22% carbamide peroxide-based tooth bleaching gel at home for 4 days consecutively, at night, on the upper and lower arches. Clinical examination revealed gingival swelling, probing depths ranging 5-7 mm on the buccal and proximal surfaces, and grade 2 mobility of the teeth affected by ECRR. Radiographs revealed presence of ECRR in several teeth during initial examination, and development of multiple new lesions 6 months later. The teeth were subsequently extracted. Histological analysis showed multiple dentine lacunae and areas of dentine reparation. The careful use of these products can prevent sequelae such as those reported in this clinical case. As the vital bleaching has a variable success rate, patients should be informed through a consent form of the benefits and risks of tooth bleaching treatment. PMID- 28621832 TI - Break-induced replication links microsatellite expansion to complex genome rearrangements. AB - The instability of microsatellite DNA repeats is responsible for at least 40 neurodegenerative diseases. Recently, Mirkin and co-workers presented a novel mechanism for microsatellite expansions based on break-induced replication (BIR) at sites of microsatellite-induced replication stalling and fork collapse. The BIR model aims to explain single-step, large expansions of CAG/CTG trinucleotide repeats in dividing cells. BIR has been characterized extensively in Saccharomyces cerevisiae as a mechanism to repair broken DNA replication forks (single-ended DSBs) and degraded telomeric DNA. However, the structural footprints of BIR-like DSB repair have been recognized in human genomic instability and tied to the etiology of diverse developmental diseases; thus, the implications of the paper by Kim et al. (Kim JC, Harris ST, Dinter T, Shah KA, et al., Nat Struct Mol Biol 24: 55-60) extend beyond trinucleotide repeat expansion in yeast and microsatellite instability in human neurological disorders. Significantly, insight into BIR-like repair can explain certain pathways of complex genome rearrangements (CGRs) initiated at non-B form microsatellite DNA in human cancers. PMID- 28621835 TI - Exogenously applied dsRNA molecules deriving from the Zucchini yellow mosaic virus (ZYMV) genome move systemically and protect cucurbits against ZYMV. AB - Zucchini yellow mosaic virus (ZYMV) causes serious damage in a large number of cucurbits, and control measures are necessary. Transgenic cucurbits expressing parts of the ZYMV genome have been shown to be resistant to the cognate virus. A non-transgenic approach involving the exogenous application of double-stranded RNA (dsRNA) has also been shown to induce resistance in tobacco against Cucumber mosaic virus (CMV) and Tobacco mosaic virus (TMV). In the present study, dsRNA molecules derived from the helper component-proteinase (HC-Pro) and coat protein (CP) genes of the ZYMV_DE_2014 isolate were produced in vitro. On exogenous dsRNA application in cucumber, watermelon and squash plants, dsRNA HC-Pro conferred resistance of 82%, 50% and 18%, and dsRNA CP molecules of 70%, 43% and 16%, respectively. On deep sequencing analysis of ZYMV-infected watermelon, hot-spot regions for viral small interfering RNAs (vsiRNAs) in the genome of ZYMV were identified. Stem-loop reverse transcription-polymerase chain reaction (RT-PCR) detection of selected 21-nucleotide-long vsiRNAs in plants that received only dsRNA molecules suggested that the dsRNAs exogenously applied onto plants were successfully diced, thus initiating RNA silencing. dsRNA molecules were found to be progressively degraded in planta, and strongly detected by semi-quantitative RT-PCR for at least 9 days after exogenous application. Moreover, dsRNA molecules were detected in systemic tissue of watermelon and squash, showing that dsRNA is transported long distances in these plants. PMID- 28621834 TI - From intricate to integrated: Biofabrication of articulating joints. AB - Articulating joints owe their function to the specialized architecture and the complex interplay between multiple tissues including cartilage, bone and synovium. Especially the cartilage component has limited self-healing capacity and damage often leads to the onset of osteoarthritis, eventually resulting in failure of the joint as an organ. Although in its infancy, biofabrication has emerged as a promising technology to reproduce the intricate organization of the joint, thus enabling the introduction of novel surgical treatments, regenerative therapies, and new sets of tools to enhance our understanding of joint physiology and pathology. Herein, we address the current challenges to recapitulate the complexity of articulating joints and how biofabrication could overcome them. The combination of multiple materials, biological cues and cells in a layer-by-layer fashion, can assist in reproducing both the zonal organization of cartilage and the gradual transition from resilient cartilage toward the subchondral bone in biofabricated osteochondral grafts. In this way, optimal integration of engineered constructs with the natural surrounding tissues can be obtained. Mechanical characteristics, including the smoothness and low friction that are hallmarks of the articular surface, can be tuned with multi-head or hybrid printers by controlling the spatial patterning of printed structures. Moreover, biofabrication can use digital medical images as blueprints for printing patient specific implants. Finally, the current rapid advances in biofabrication hold significant potential for developing joint-on-a-chip models for personalized medicine and drug testing or even for the creation of implants that may be used to treat larger parts of the articulating joint. (c) 2017 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 35:2089-2097, 2017. PMID- 28621836 TI - Dietary advanced glycation end products modify gut microbial composition and partially increase colon permeability in rats. AB - SCOPE: The adverse impacts of dietary advanced glycation end products (AGEs) on health are currently of interest. These compounds are inevitably formed during thermal food processing and make foods less digestible because of protein cross linking. This study examined not only whether dietary AGEs alter cecal microbiota and their metabolites but also their effects on colon permeability. METHODS AND RESULTS: Sprague-Dawley rats were exposed to a high-AGEs diet (AGEs content was increased by heating food at 125 degrees C/3 h) for 6, 12, or 18 weeks. Cecal microbiota was analyzed by 16S rDNA gene sequencing. Colon permeability was assessed through histopathology, immunohistochemistry and endotoxin testing. Microbial metabolites (e.g. ammonia and short-chain fatty acids (SCFAs)) were also measured. AGEs treatment reduced the diversity and richness of the microbiota, especially saccharolytic bacteria such as Ruminococcaceae and Alloprevotella, which can produce SCFAs, whereas some putatively harmful bacteria (Desulfovibrio and Bacteroides) were increased. Protein fermentation was enhanced, supported by elevated ammonia and branched-chain fatty acid levels (p < 0.05). Additionally, the colonocytes structure changed and the expression of tight junction proteins in colon were decreased. CONCLUSION: Dietary AGEs detrimentally modulate gut microbial ecology and may partially increase colon permeability, which can adversely impact host health. PMID- 28621837 TI - Paediatric follicular thyroid carcinoma - indolent cancer with low prevalence of RAS mutations and absence of PAX8-PPARG fusion in a Japanese population. AB - AIMS: Paediatric follicular thyroid carcinomas are uncommon, and their clinicopathological features and molecular profiles are still unknown. In the present study, we aimed to investigate the clinicopathological aspects of a large series of follicular thyroid carcinomas (FTCs) in paediatric patients and to analyse the point mutations in codons 12, 13 and 61 of NRAS, HRAS and KRAS genes and the rearrangements of PAX8-PPARG. METHODS AND RESULTS: A total of 41 paediatric FTCs less than 21 years of age were enrolled into the present study. We used direct sequencing and reverse transcription-polymerase chain reaction (RT PCR) to detect RAS mutations and PAX8-PPARG fusions, respectively. The paediatric FTCs were 6:1 in a female to male ratio, with a mean tumour size of 52.7 mm. Distant metastasis was found in one case at the time of presentation. During a median follow-up time of 69 months, two cases had lung metastasis and all patients were alive. Histologically, all cases were minimally invasive FTCs and varied in growth patterns: microfollicular (39%), follicular (14.6%), solid/trabecular (6%), oncocytic (4.9%) and mixed patterns (26.8%). The mean Ki67 index was 5.7% and it was not statistically different among the growth patterns. NRAS mutations were found in five cases (12.2%) and associated significantly with small tumour size (P = 0.014). PAX8-PPARG fusion was not detected in our series. CONCLUSION: Paediatric FTCs are indolent in clinical course in spite of their large tumour size and have a distinct genetic background. RAS mutations and PAX8 PPARG fusions may not play major roles in the tumorigenesis of paediatric FTCs. PMID- 28621838 TI - The Effect of Compliant Inflow Cannulae on the Hemocompatibility of Rotary Blood Pump Circuits in an In Vitro Model. AB - Rotary blood pumps (RBPs) are used for mechanical circulatory support in heart failure patients but exhibit a reduced response to preload changes, which can lead to ventricular suction events. A passive control system, in the form of a compliant inflow cannula (IC), has been developed to mitigate suction, although this device may cause significant hemolysis. This study compared the incidence of mechanically induced hemolysis of two compliant IC designs (strutted and nonstrutted) with a rigid IC (control) in a blood circulation loop over 90 min. The nonstrutted compliant IC introduced high frequency and high amplitude oscillations in RBP inlet pressure and RBP IC resistance. These oscillations were correlated with a significant increase in plasma-free hemoglobin (pfHb) and hemolysis: pfHb increased to 2.005 +/- 0.665 g/L, while normalized index of hemolysis (NIH) and modified index of hemolysis (MIH) increased to 0.04945 +/- 0.01276 g/100 L and 4.0505 +/- 0.6589 after 90 min (P < 0.05). In contrast, the strutted compliant IC performed similar to the clinically utilized rigid IC and did not increase pfHb (0.300 +/- 0.090 and 0.320 +/- 0.171 g/L, respectively) and rate of hemolysis (NIH 0.00435 +/- 0.00155 and 0.00543 +/- 0.00371 g/100 L; MIH 0.3896 +/- 0.1749 and 0.4261 +/- 0.2792, respectively) within the RBP circuit. These data indicated that strutted, compliant ICs meet the hemocompatibility of clinically used rigid ICs while also offering a potential solution to prevent ventricular suction events. PMID- 28621839 TI - Evaluation of Hemodynamic Performance of a Combined ECLS and CRRT Circuit in Seven Positions With a Simulated Neonatal Patient. AB - As it is common for patients treated with extracorporeal life support (ECLS) to subsequently require continuous renal replacement therapy (CRRT), and neonatal patients encounter limitations due to lack of access points, inclusion of CRRT in the ECLS circuit could provide advanced treatment for this population. The objective of this study was to evaluate an alternative neonatal ECLS circuit containing either a Maquet RotaFlow centrifugal pump or Maquet HL20 roller pump with one of seven configurations of CRRT using the Prismaflex 2000 System. All ECLS circuit setups included a Quadrox-iD Pediatric diffusion membrane oxygenator, a Better Bladder, an 8-Fr arterial cannula, a 10-Fr venous cannula, and 6 feet of 1/4-inch diameter arterial and venous tubing. The circuit was primed with lactated Ringer's solution and packed human red blood cells resulting in a total priming volume of 700 mL for both the circuit and the 3-kg pseudopatient. Hemodynamic data were recorded for ECLS flow rates of 200, 400, and 600 mL/min and a CRRT flow rate of 50 mL/min. When a centrifugal pump is used, the hemodynamic performance of any combined ECLS and CRRT circuit was not significantly different than that of the circuit without CRRT, thus any configuration could potentially be used. However, introduction of CRRT to a circuit containing a roller pump does affect performance properties for some CRRT positions. The circuits with CRRT positions B and G demonstrated decreased total hemodynamic energy (THE) levels at the post-arterial cannula site, while positions D and E demonstrated increased post-arterial cannula THE levels compared to the circuit without CRRT. CRRT positions A, C, and F did not have significant changes with respect to pre-arterial cannula flow and THE levels, compared to the circuit without CRRT. Considering hemodynamic performance, for neonatal combined extracorporeal membrane oxygenation (ECMO) and CRRT circuits with both blood pumps, we recommend the use of CRRT position A due to its hemodynamic similarities to the ECMO circuit without CRRT. PMID- 28621840 TI - Association of disease-specific causes of visual impairment and 10-year mortality amongst Indigenous Australians: the Central Australian Ocular Health Study. AB - IMPORTANCE: Visual impairment significantly impairs the length and quality of life, but little is known of its impact in Indigenous Australians. BACKGROUND: To investigate the association of disease-specific causes of visual impairment with all-cause mortality. DESIGN: A retrospective cohort analysis. PARTICIPANTS: A total of 1347 Indigenous Australians aged over 40 years. METHODS: Participants visiting remote medical clinics underwent clinical examinations including visual acuity, subjective refraction and slit-lamp examination of the anterior and posterior segments. The major ocular cause of visual impairment was determined. Patients were assessed periodically in these remote clinics for the succeeding 10 years after recruitment. Mortality rates were obtained from relevant departments. MAIN OUTCOME MEASURES: All-cause 10-year mortality and its association with disease-specific causes of visual impairment. RESULTS: The all-cause mortality rate for the entire cohort was 29.3% at the 10-year completion of follow-up. Of those with visual impairment, the overall mortality rate was 44.9%. The mortality rates differed for those with visual impairment due to cataract (59.8%), diabetic retinopathy (48.4%), trachoma (46.6%), 'other' (36.2%) and refractive error (33.4%) (P < 0.0001). Only those with visual impairment from diabetic retinopathy were any more likely to die during the 10 years of follow-up when compared with those without visual impairment (HR 1.70; 95% CI, 1.00-2.87; P = 0.049). CONCLUSIONS AND RELEVANCE: Visual impairment was associated with all-cause mortality in a cohort of Indigenous Australians. However, diabetic retinopathy was the only ocular disease that significantly increased the risk of mortality. Visual impairment secondary to diabetic retinopathy may be an important predictor of mortality. PMID- 28621841 TI - Hypomethylating agent therapy use and survival in older patients with chronic myelomonocytic leukemia in the United States: A large population-based study. AB - BACKGROUND: Despite the approval of azacitidine in 2004 and the approval of decitabine in 2006 in the United States for chronic myelomonocytic leukemia (CMML), the overall survival (OS) benefit with hypomethylating agent (HMA) therapy is unclear. METHODS: Older adults (age >= 66 years) who had been diagnosed with CMML from 2001 to 2011 were selected from the Surveillance, Epidemiology, and End Results-Medicare database, and propensity score matching was used to match patients who had been diagnosed after HMA approval (2007-2011) and had received HMA treatment with patients diagnosed before HMA approval (2001 2003). Cox proportional hazards models with the matched sample were used to assess the change in OS. A second matched cohort of patients who did not receive HMA after approval and patients diagnosed before HMA approval was used to evaluate survival change attributable to other potential differences between the 2 time periods, such as improved supportive care. RESULTS: Among 1378 older adults diagnosed with CMML, the median OS was 13 months, and 18.8% received HMAs. In the primary matched analysis, with 225 HMA users diagnosed in 2007-2011 and 395 patients diagnosed in 2001-2003, the median OS times were 17 and 11 months, respectively (hazard ratio, 0.72; 95% confidence interval [CI], 0.58-0.91; P = .005). In a secondary analysis, the risk of death did not differ between 395 propensity score-matched HMA nonusers diagnosed in 2007-2011 and 484 patients diagnosed in 2001-2003 (hazard ratio, 1.09; 95% CI, 0.91-1.32; P = .34). CONCLUSIONS: Despite limited evidence, HMAs are commonly used to treat older CMML patients. The use of HMAs was associated with a 28% reduction in the risk of death in adjusted analyses. Improvements in supportive care do not appear to account for temporal improvements in OS. Cancer 2017;123:3754-3762. (c) 2017 American Cancer Society. PMID- 28621842 TI - Study on morphological characteristics and microscopic structure of medicinal organs of Pulsatilla chinensis (Bunge) Regel. AB - Modern clinical studies have found that Pulsatilla radix contains a variety of active ingredients; however, its medicinal parts and microstructure have been controversial. Based on morphological observation and microscopic identification of different structures, we chose Anhui, Henan, Jilin, and Shanxi Province to study Pulsatilla chinensis (Bunge) Regel populations. We specifically addressed different diameters and anatomical structures of different parts of underground organs. We also found that P. chinensis (Bunge) Regel had a "joint point" structure in its underground organ. Above the "joint point" is the rhizome, below the "joint point" is the root. The main medicinal organ is the rhizome. The protective tissues of the endothelial layer of P. chinensis (Bunge) Regel changed in the process of its development. The protective tissues were replaced by epidermis, cortex, endodermis, and phloem. With the secondary growth, the endothelial cells have been radial division. This study showed that morphology and microscopic identification was an important mean of medicinal material identifications, and it had the characteristics of a convenient, fast, and intuitive method to identify the composition and structural characteristics of P. chinensis (Bunge) Regel medicinal parts. PMID- 28621865 TI - A Miniature Gamma Cameraa. PMID- 28621843 TI - Metabolic reprogramming in the tumour microenvironment: a hallmark shared by cancer cells and T lymphocytes. AB - Altered metabolism is a hallmark of cancers, including shifting oxidative phosphorylation to glycolysis and up-regulating glutaminolysis to divert carbon sources into biosynthetic pathways that promote proliferation and survival. Therefore, metabolic inhibitors represent promising anti-cancer drugs. However, T cells must rapidly divide and survive in harsh microenvironments to mediate anti cancer effects. Metabolic profiles of cancer cells and activated T lymphocytes are similar, raising the risk of metabolic inhibitors impairing the immune system. Immune checkpoint blockade provides an example of how metabolism can be differentially impacted to impair cancer cells but support T cells. Implications for research with metabolic inhibitors are discussed. PMID- 28621866 TI - What Can Management Do? PMID- 28621874 TI - Preface. PMID- 28621875 TI - Retransplantation After a Failed Donation After Circulatory Determination of Death Liver Transplant: MELD Exception Priority and Second Chances. PMID- 28621876 TI - Social, health and ocular factors associated with primary open-angle glaucoma amongst Chinese Singaporeans. AB - IMPORTANCE: There is limited literature on lifestyle and health factors related to primary open-angle glaucoma amongst Asians. BACKGROUND: This study evaluated the association of primary open-angle glaucoma with smoking, health and ocular factors amongst Chinese Singaporeans. DESIGN: Case-control study. PARTICIPANTS: The study used 711 primary open-angle glaucoma patients from a Singapore hospital and 2788 population-based controls. METHODS: Subjects underwent clinical examination and completed a questionnaire with details on family history of glaucoma, comorbidities, smoking and alcohol consumption. Glaucoma cases were subclassified as normal or high-tension glaucoma according to their untreated intraocular pressures. MAIN OUTCOME MEASURES: The association of various health and lifestyle factors, with normal-tension and high-tension glaucoma was evaluated. RESULTS: Using multiple logistic regression, primary open-angle glaucoma was associated with older age (odds ratio 1.12 per year older; 95% confidence interval 1.10-1.15; P < 0.001), family history of glaucoma (odds ratio 7.86; 95% confidence interval 4.48-13.79; P < 0.001), higher intraocular pressure (odds ratio 1.75 per 1 mmHg; 95% confidence interval 1.64-1.87; P < 0.001) and thinner central corneal thickness (odds ratio 1.01; 95% confidence interval 1.01 1.02; P < 0.001). Myopes were more likely to have primary open-angle glaucoma (P < 0.001). A current smoking habit was protective against normal-tension glaucoma (odds ratio 0.30; 95% confidence interval 0.10-0.92; P = 0.035). CONCLUSIONS AND RELEVANCE: Older age, family history of glaucoma, higher intraocular pressure, thinner central corneal thickness and myopia were significantly associated with primary open-angle glaucoma amongst Chinese Singaporeans. PMID- 28621877 TI - Autoimmune hemolytic anemia in solid organ transplantation-The role of immunosuppression. AB - Hemolysis after solid organ transplantation can be caused by both immune and non immune-mediated mechanisms, and the evaluation must take into account issues distinctive to the post-transplant period. Autoimmune hemolytic anemia usually occurs within the first year and has been attributed to immunosuppressive treatment, infections, or underlying post-transplant lymphoproliferative disorder. Review of the literature revealed 59 cases with autoimmune hemolytic anemia mostly in children after liver transplantation. Almost all of the patients at the time of diagnosis received immunosuppression with tacrolimus, and first line treatment with steroids and/or intravenous immunoglobulin was ineffective for complete remission. Rituximab was used as second-line treatment especially in patients with underlying lymphoproliferative disorders whereas sirolimus showed encouraging results. PMID- 28621878 TI - Isolation and chemical characterization of agelaiatoxin8 (AvTx8) from Agelaia vicina wasp venom and its biological effects on GABA neurotransmission. AB - Arthropod venoms are sources of molecules that may be useful tools to investigate molecular mechanisms of putative new medicines and laboratory drugs. Here we show the effects of the compound agelaiatoxin-8 (AVTx8), isolated from Agelaia vicina venom, on gamma-aminobutyric acid (GABA) neurotransmission in rat brain synaptosomes. Analysis reveals that AvTx8 is composed by 14 amino acid residues with a molecular weight (MW) of 1567 Da. AvTx8 increased GABA release and inhibited GABA uptake in synaptosomes from rat cerebral cortex. AvTx8 inhibited GABA uptake and increased GABA release in the presence of Ca+ , Na+ , and K+ channel blockers, suggesting that it acts directly on GABA transporters. In addition, AvTx8 significantly decreases GABA binding in synaptic membranes from rat brain cortex, suggesting that it also modulates the activity of GABA receptors. Moreover, AvTx8 decreased GAT-1- and GAT-3-mediated GABA uptake in transfected COS-7 cells. Accordingly, we suggest that AvTx8 modulates GABA neurotransmission and might provide a novel entry point for identifying a new class of GABA-modulating neuroprotective drugs. PMID- 28621880 TI - Response to 'Letter to the Editor' regarding the article 'The seasonal importance of serum 25-hydroxyvitamin D for bone mineral density in older women'. PMID- 28621879 TI - Bactericidal peptidoglycan recognition protein induces oxidative stress in Escherichia coli through a block in respiratory chain and increase in central carbon catabolism. AB - Mammalian Peptidoglycan Recognition Proteins (PGRPs) kill both Gram-positive and Gram-negative bacteria through simultaneous induction of oxidative, thiol and metal stress responses in bacteria. However, metabolic pathways through which PGRPs induce these bactericidal stress responses are unknown. We screened Keio collection of Escherichia coli deletion mutants and revealed that deleting genes for respiratory chain flavoproteins or for tricarboxylic acid (TCA) cycle resulted in increased resistance of E. coli to PGRP killing. PGRP-induced killing depended on the production of hydrogen peroxide, which required increased supply of NADH for respiratory chain oxidoreductases from central carbon catabolism (glycolysis and TCA cycle), and was controlled by cAMP-Crp. Bactericidal PGRP induced a rapid decrease in respiration, which suggested that the main source of increased production of hydrogen peroxide was a block in respiratory chain and diversion of electrons from NADH oxidoreductases to oxygen. CpxRA two-component system was a negative regulator of PGRP-induced oxidative stress. By contrast, PGRP-induced thiol stress (depletion of thiols) and metal stress (increase in intracellular free Zn2+ through influx of extracellular Zn2+ ) were mostly independent of oxidative stress. Thus, manipulating pathways that induce oxidative, thiol and metal stress in bacteria could be a useful strategy to design new approaches to antibacterial therapy. PMID- 28621881 TI - Hodgkin lymphoma classification: Are we at a crossroads? PMID- 28621882 TI - Exercise Capacity and Functional Performance in Heart Failure Patients Supported by a Left Ventricular Assist Device at Discharge From Inpatient Rehabilitation. AB - Adequate physical and functional performance is an important prerequisite for renewed participation and integration in self-determined private and (where appropriate) professional lives following left ventricular assist device (LVAD) implantation. During cardiac rehabilitation (CR), individually adapted exercise programs aim to increase exercise capacity and functional performance. A retrospective analysis of cardiopulmonary exercise capacity and functional performance in LVAD patients at discharge from a cardiac rehabilitation program was conducted. The results from 68 LVAD patients (59 males, 9 females; 55.9 +/- 11.7 years; 47 HVAD, 2 MVAD, 15 HeartMate II, 4 HeartMate 3, and 4 different implanting centers) were included in the analysis. Exercise capacity was assessed using a cardiopulmonary exercise test on a bicycle ergometer (ramp protocol; 10 W/min). The 6-min walk test was used to determine functional performance. At discharge from CR (53 +/- 17 days after implantation), the mean peak work load achieved was 62.2 +/- 19.3 W (38% of predicted values) or 0.79 +/- 0.25 W/kg body weight. The mean cardiopulmonary exercise capacity (relative peak oxygen uptake) was 10.6 +/- 5.3 mL/kg/min (37% of predicted values). The 6-min walk distance improved significantly during CR (325 +/- 106 to 405 +/- 77 m; P < 0.01). No adverse events were documented during CR. The results show that, even following LVAD implantation, cardiopulmonary exercise capacity remains considerably restricted. In contrast, functional performance, measured by the 6-min walk distance, reaches an acceptable level. Light everyday tasks seem to be realistically surmountable for patients, making discharge from inpatient rehabilitation possible. Long-term monitoring is required in order to evaluate the situation and how it develops further. PMID- 28621883 TI - Determination of the serine palmitoyl transferase inhibitor myriocin by electrospray and Q-trap mass spectrometry. AB - Myriocin is a potent inhibitor of serine-palmitoyl-transferase, the first and rate-determining enzyme in the sphingolipids biosynthetic pathway. This study developed, validated and applied a LC-MS/MS method to measure myriocin in minute specimens of animal tissue. The chemical analog 14-OH-myriocin was used as the internal standard. The two molecules were extracted from the tissue homogenate by solid-phase extraction, separated by gradient reversed-phase liquid chromatography and measured by negative ion electrospray mass spectrometry in the triple quadrupole. Detection was accomplished by multiple reaction monitoring, employing the most representative transitions, 400@104 and 402@104 for myriocin and 14-OH-myriocin, respectively. The typical limit of detection and lower limit of quantitation of the optimized method were 0.9 pmol/mL (~0.016 pmol injected) and 2.3 pmol/mL, respectively, and the method was linear up to 250 pmol/mL range (r2 = 0.9996). The intra- and between-day repeatability afforded a coefficient of variation <=7.0%. Applications included quantification of myriocin in mouse lungs after 24 h from administration of ~4 nmol by intra-tracheal delivery. Measured levels ranged from 4.11 (median; 2.3-7.4 IQR, n = 4) to 11.7 (median; 7.6-22.7 interquartile range (IQR), n = 6) pmol/lung depending on the different formulations used. Myriocin was also measured in retinas of mice treated by intravitreal injection and ranged from 0.045 (less than the limit of detection) to 0.35 pmol/retina. PMID- 28621884 TI - Young athletes with ventricular premature beats: Continuing or not intense training and competition? AB - Isolated ventricular premature beats (VPBs) are commonly found during pre participation screening in athletes. Currently, the debate about the role of detraining in reducing the number of VPBs is still open. This study evaluated the arrhythmic risk in a population of young competitive athletes who showed VPBs during eligibility evaluation and that did not undergo detraining but continued practicing competitive sports. 3746 consecutive subjects underwent pre participation screening. Athletes who showed VPBs were selected and underwent second level evaluation (Echocardiogram, 24 hour Holter ECG and Exercise test). Athletes were re-evaluated after a follow-up period (6-48 months) while they continued practicing competitive sports. 5.3% of the whole population showed ventricular arrhythmias. 73% of the subjects showed isolated VPBs. 88% of the subjects showed monomorphic VPBs, and 12% of athletes showed polymorphic VPBs. At echocardiogram, there was not any pathology which contraindicated competitive sport activity. At 24 hour Holter ECG recording, mean number of daily VPBs was 1592+/-3217 (range 0-16678). At holter ECG follow-up (16+/-12 months), the median number of VPBs decreased from 93 (IQR 20-3065) to a new value of 72 (IQR 2-1299). Continuing competitive sport in subjects with ventricular arrhythmias even though frequent but with a low grade of complexity and without structural cardiomyopathy does not increase sudden death risk. PMID- 28621885 TI - Multiagent induction chemotherapy followed by chemoradiation is associated with improved survival in locally advanced pancreatic cancer. AB - BACKGROUND: The role of chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) is uncertain after multiple randomized clinical trials have yielded mixed results. The authors used the National Cancer Data Base (NCDB) to determine whether CRT yields a survival benefit compared with chemotherapy alone (CT). METHODS: Patients with nonmetastatic LAPC diagnosed during 2004 through 2014 were identified in the NCDB. Patients who received CT were compared with those who received CRT using chi-square analysis. Univariate and multivariate Cox regression analyses were used to compare demographic, clinical, and treatment characteristics that were predictive of survival. Propensity score matching and shared frailty analysis were done. Subgroup analyses were undertaken to examine patients who underwent pancreatectomy and cohorts of patients who received different CT or CRT regimens. RESULTS: In total, 8689 patients with LAPC were identified. CRT was associated with improved survival (median survival [MS], 13.5 months) compared with CT (MS, 10.6 months) on multivariate analysis (hazard ratio [HR], 0.80; P < .001). Induction chemotherapy before CRT (HR, 0.67; P < .001) and multiagent chemotherapy (HR, 0.72; P < .001) were also identified as independent predictors of survival compared with concurrent CRT and single-agent CT, respectively. Patients in the CRT group who received multiagent induction chemotherapy had superior MS and pancreatectomy rates (MS, 17.5 months; HR, 0.70; P < .001; pancreatectomy rate, 10%) compared with those who received multiagent CT alone (MS, 12.4 months; pancreatectomy rate, 3.3%). Patients who underwent pancreatectomy experienced improved survival (MS, 22 vs 10.6 months; HR, 0.39; P < .001). CONCLUSIONS: In this NCDB analysis, maximizing systemic chemotherapy before CRT improved survival compared with CT alone in patients with LAPC. Continued analysis of CRT in properly selected patients after maximized systemic therapy is needed. Cancer 2017;123:3816-24. (c) 2017 American Cancer Society. PMID- 28621886 TI - Review of emerging metabolomic tools and resources: 2015-2016. AB - Data processing and analysis are major bottlenecks in high-throughput metabolomic experiments. Recent advancements in data acquisition platforms are driving trends toward increasing data size (e.g., petabyte scale) and complexity (multiple omic platforms). Improvements in data analysis software and in silico methods are similarly required to effectively utilize these advancements and link the acquired data with biological interpretations. Herein, we provide an overview of recently developed and freely available metabolomic tools, algorithms, databases, and data analysis frameworks. This overview of popular tools for MS and NMR-based metabolomics is organized into the following sections: data processing, annotation, analysis, and visualization. The following overview of newly developed tools helps to better inform researchers to support the emergence of metabolomics as an integral tool for the study of biochemistry, systems biology, environmental analysis, health, and personalized medicine. PMID- 28621887 TI - Programmed death-ligand 1 testing in patients with non-small cell lung cancer: Ready for prime time? PMID- 28621888 TI - WIDE AND THICK GRAIN 1, which encodes an otubain-like protease with deubiquitination activity, influences grain size and shape in rice. AB - Grain size and shape are two crucial traits that influence grain yield and grain appearance in rice. Although several factors that affect grain size have been described in rice, the molecular mechanisms underlying the determination of grain size and shape are still elusive. In this study we report that WIDE AND THICK GRAIN 1 (WTG1) functions as an important factor determining grain size and shape in rice. The wtg1-1 mutant exhibits wide, thick, short and heavy grains and also shows an increased number of grains per panicle. WTG1 determines grain size and shape mainly by influencing cell expansion. WTG1 encodes an otubain-like protease, which shares similarity with human OTUB1. Biochemical analyses indicate that WTG1 is a functional deubiquitinating enzyme, and the mutant protein (wtg1 1) loses this deubiquitinating activity. WTG1 is expressed in developing grains and panicles, and the GFP-WTG1 fusion protein is present in the nucleus and cytoplasm. Overexpression of WTG1 results in narrow, thin, long grains due to narrow and long cells, further supporting the role of WTG1 in determining grain size and shape. Thus, our findings identify the otubain-like protease WTG1 to be an important factor that determines grain size and shape, suggesting that WTG1 has the potential to improve grain size and shape in rice. PMID- 28621889 TI - Enhanced Skin Regeneration by Herbal Extract-Coated Poly-L-Lactic Acid Nanofibrous Scaffold. AB - The wound healing process is directly related to the type of treatment. Existing methods of treatment are not responsive enough for severe wounds. The aim of this study was the potential capacity investigation of poly-L-lactic acid (PLLA) nanofibrous scaffolds coated by aloe vera gel for wound dressing applications. In this study, electrospinning method was used for preparing PLLA nanofibers, and after characterization by SEM and MTT, its influence on the wound healing process was investigated with and without aloe vera gel as a wound dressing in full thickness skin defect in mice. Band-Aids were used as a positive control and vaseline gauze as a negative control. SEM and MTT assays confirmed the nanometer size and biocompatibility of fabricated nanofibers. Macroscopic and histopathological characteristics were evaluated at the end of days 7, 12, and 17 and their results showed that the gel-coated scaffold accelerated the wound healing process compared with other groups. At the end of the experiment, it was shown that during the whole time of study, gel-coated scaffold had the highest overall repair score. Therefore, gel-coated PLLA scaffold would be an ideal construct for wound healing and skin regenerative medicine application. PMID- 28621890 TI - Reference data for BabyBody-plethysmographic measurements in Chinese neonates and infants. AB - BACKGROUND AND OBJECTIVE: Population-specific pulmonary function reference data are essential to identify the nature and severity of respiratory diseases. However, there is a lack of reference data for Chinese neonates and infants. The objective of this study was to develop reference data for tidal breathing and plethysmographic measurements for Chinese subjects during the first 2 years of life. METHODS: Data of tidal breathing and plethysmography from healthy Chinese neonates (<=28 days) and infants (1-24 months) using the Jaeger MasterScreen BabyBody were collated. All subjects were sedated for the tests. Multivariable analyses were performed to determine predictive variables for the pulmonary function parameters. Reference equations for outcomes were constructed using multilevel modelling and the LMS (lambda-mu-sigma) method was used for establishing smoothed reference percentiles. RESULTS: Four hundred and ten healthy subjects were tested. Acceptable measurements of tidal breathing analysis and plethysmography outcomes were obtained in 396 (96.6%) and 370 (90.4%) subjects, respectively. Normal reference percentiles and equations for the main parameters of tidal breathing and plethysmography were derived from test occasions of 211 neonates and 185 infants. Body weight, crown-heel length and age were significantly associated with lung function, of which length was the strongest predictor. CONCLUSION: This study provides reference data of BabyBody plethysmographic measurements for healthy Chinese subjects in their first 2 years of life. Weight and length are the strongest predictors for neonatal and infant lung function, respectively. PMID- 28621891 TI - Sugar metabolism by mutans streptococci. PMID- 28621892 TI - Regulation of energy source metabolism in streptococci. PMID- 28621894 TI - Pyogenic streptococci of Lancefield groups C and G as pathogens in man. PMID- 28621893 TI - Group A streptococcal infections in humans. PMID- 28621895 TI - Classification and overview of the genera Streptococcus and Enterococcus. PMID- 28621896 TI - Faecal streptococci as indicators of faecal contamination in water. PMID- 28621897 TI - Horizontal gene transfer and the evolution of resistance and virulence determinants in Streptococcus. PMID- 28621898 TI - Streptococci and enterococci as animal pathogens. PMID- 28621899 TI - Regulation of competence for genetic transformation in Streptococcus pneumoniae. PMID- 28621900 TI - Enterococci as emerging pathogens of humans. PMID- 28621901 TI - Biology of streptococcal capsular polysaccharides. PMID- 28621902 TI - Molecular analysis of virulence factors of Streptococcus pneumoniae. PMID- 28621903 TI - Histological assessment of beta-amyloid precursor protein immunolabelled rectal biopsies aids diagnosis of equine grass sickness. AB - BACKGROUND: An accurate, minimally invasive, ante-mortem diagnostic test for equine grass sickness (EGS) is currently lacking. Although histological examination of haematoxylin and eosin-stained rectal biopsies for chromatolytic neurons is insensitive as a diagnostic test for EGS, we hypothesised that its diagnostic accuracy could be improved by immunolabelling for beta-amyloid precursor protein (beta-APP), which has increased expression in cranial cervical ganglia (CCG) neuronal perikarya in EGS. OBJECTIVES: To develop a grading scheme for assessing the distribution and intensity of beta-APP immunoreactivity within individual rectal submucosal neurons and subsequently to determine the value of the distribution of different grades of neurons in EGS diagnosis. STUDY DESIGN: Retrospective case-control diagnostic accuracy study. METHODS: Initially, a standardised grading scheme was developed and beta-APP immunoreactivity in individual neuronal perikarya and axons was compared in sections of CCG and ileum from EGS and control horses. The grading scheme was then refined before being blindly applied to submucosal neurons in rectal biopsies derived from 21 EGS and 23 control horses. RESULTS: beta-APP immunoreactivity was increased in neuronal perikarya and axons in sections of CCG, ileum and rectum from EGS horses compared with controls. For rectal biopsies, a mean immunoreactivity grade exceeding 1.1 was 100% specific and sensitive for EGS, and the presence of at least one neuron with diffuse labelling of the entire cytoplasm (grade 3) was 95% sensitive and 100% specific for EGS. MAIN LIMITATIONS: Although the diagnostic criteria facilitated the discrimination of the EGS and control biopsies evaluated in this study, further prospective validation using a larger sample set is required. CONCLUSIONS: Histological assessment of beta-APP immunolabelled rectal biopsies is more sensitive than conventional histological examination in EGS diagnosis. Further validation is required before this technique can be advocated for use in clinical decision making. PMID- 28621904 TI - Anxiety and depression may contribute to an increased risk of death in some cancers. PMID- 28621905 TI - Expert panel issues new global cervical cancer screening guideline. PMID- 28621906 TI - Perkins P, Cooksley CD and Cox JD. Breast cancer: Is ethnicity an independent prognostic factor for survival? Cancer. 1996;78:1241-1247. PMID- 28621907 TI - Role of cleavage and polyadenylation specificity factor 100: anchoring poly(A) sites and modulating transcription termination. AB - CPSF100 is a core component of the cleavage and polyadenylation specificity factor (CPSF) complex for 3'-end formation of mRNA, but it still has no clear functional assignment. CPSF100 was reported to play a role in RNA silencing and promote flowering in Arabidopsis. However, the molecular mechanisms underlying these phenomena are not fully understood. Our genetics analyses indicate that plants with a hypomorphic mutant of CPSF100 (esp5) show defects in embryogenesis, reduced seed production or altered root morphology. To unravel this puzzle, we employed a poly(A) tag sequencing protocol and uncovered a different poly(A) profile in esp5. This transcriptome-wide analysis revealed alternative polyadenylation of thousands of genes, most of which result in transcriptional read-through in protein-coding genes. AtCPSF100 also affects poly(A) signal recognition on the far-upstream elements; in particular it prefers less U-rich sequences. Importantly, AtCPSF100 was found to exert its functions through the change of poly(A) sites on genes encoding binding proteins, such as nucleotide binding, RNA-binding and poly(U)-binding proteins. In addition, through its interaction with RNA Polymerase II C-terminal domain (CTD) and affecting the expression level of CTD phosphatase-like 3 (CPL3), AtCPSF100 is shown to potentially ensure transcriptional termination by dephosphorylation of Ser2 on the CTD. These data suggest a key role for CPSF100 in locating poly(A) sites and affecting transcription termination. PMID- 28621909 TI - Systemic therapy of ocular and cutaneous rosacea in children. AB - BACKGROUND: In paediatric rosacea, ocular symptoms are often predominant. Literature about systemic therapy of paediatric ocular rosacea is sparse, though. OBJECTIVE: Analysis of children with ocular rosacea treated systemically, particularly addressing remission and recurrence rates. METHODS: Retrospective study reviewing the medical records of children with ocular rosacea treated with systemic antibiotic therapy. Nine of 19 patients were chosen for detailed analysis. To our knowledge, this is the first study in paediatric ocular rosacea requiring systemic therapy with a larger patient group and a longer follow-up (mean follow-up = 30.2 months). RESULTS: 17 patients (89.5%) suffered from blepharitis, 15 patients (78.9%) from conjunctivitis, twelve patients (63.2%) from chalazia/styes and nine female patients (47.4%) from corneal involvement. We used erythromycin (n = 9) or roxithromycin (n = 1) in patients younger than 8 years and doxycycline (n = 8) or minocycline (n = 1) in patients older than 8 years. Seven of nine patients treated with erythromycin, one of eight patients treated with doxycycline and the patient treated with minocycline achieved a complete remission of ocular and cutaneous symptoms. Two of nine patients treated with erythromycin, seven of eight patients treated with doxycycline and the patient treated with roxithromycin achieved a partial remission. Relapses occurred in the patient treated with minocycline (cutaneous), two of eight patients treated with doxycycline (ocular and cutaneous) and one of nine patients treated with erythromycin (cutaneous). CONCLUSION: To achieve a complete remission of cutaneous and ocular rosacea, a long-term anti-inflammatory treatment of at least 6 months is necessary. The relapse rates seem to be lower than in adults especially in the patients treated with erythromycin. PMID- 28621910 TI - Allospecific Memory B Cell Responses Are Dependent on Autophagy. AB - Long-lived, donor-reactive memory B cells (Bmems) can produce alloantibodies that mediate transplant injury. Autophagy, an intrinsic mechanism of cell organelle/component recycling, is required for Bmem survival in infectious and model antigen systems, but whether autophagy affects alloreactive Bmem is unknown. We studied mice with an inducible yellow fluorescent protein (YFP) reporter expressed under the activation-induced cytidine deaminase (AID) promoter active in B cells undergoing germinal center reactions. Up to 12 months after allogeneic sensitization, splenic YFP+ B cells were predominantly IgD- IgM- IgG+ and expressed CD73, CD80, and PD-L2, consistent with Bmems. Labeled cells contained significantly more cells with autophagosomes and more autophagosomes per cell than unlabeled, naive B cells. To test for a functional link, we quantified alloantibody formation in mice with B cells conditionally deficient in the requisite autophagy gene ATG7. These experiments revealed absent B cell ATG7 (1) prevented B cell autophagy, (2) inhibited secondary alloantibody responses without altering primary alloantibody formation, and (3) diminished frequencies of alloreactive Bmems. Pharmacological autophagy inhibition with 3-methyladenine had similar effects on wild-type mice. Together with new documentation of increased autophagosomes within human Bmems, our data indicate that targeting autophagy has potential for eliminating donor-reactive Bmems in transplant recipients. PMID- 28621911 TI - Different roles of CD4, CD8 and gammadelta T-lymphocytes in naive and vaccinated chickens during Salmonella Enteritidis infection. AB - Lymphocytes represent the key antigen-specific leukocyte subpopulation. Despite their importance in mounting an immune response, an unbiased description of proteins expressed by chicken lymphocytes has not been presented. In this study, we therefore intravenously infected chickens with Salmonella Enteritidis, sorted CD4, CD8 and gammadelta T-lymphocytes from the spleen by flow cytometry and determined the proteome of each population by LC-MS/MS. CD4 T-lymphocyte characteristic proteins included ubiquitin SUMO-like domain and BAR domain containing proteins. CD8 T-lymphocyte specific proteins were characterized by purine ribonucleoside triphosphate binding and were involved in cell differentiation, cell activation and regulation of programmed cell death. gammadelta T-lymphocyte specific proteins exhibited enrichment of small GTPase of Rab type and GTP binding. Following infection, inducible proteins in CD4 lymphocytes included ribosomal proteins and downregulated proteins localized to the lysosome. CD8 T-lymphocytes induced MCM complex proteins, proteins required for DNA replication and machinery for protein processing in the endoplasmic reticulum. Proteins inducible in gammadelta T-lymphocytes belonged to immune system response, oxidative phosphorylation and the spliceosome. In this study, we predicted the likely events in lymphocyte response to systemic bacterial infection and identified proteins which can be used as markers specific for each lymphocyte subpopulation. PMID- 28621912 TI - Use of Estradiol Promotes Graft-Bone Healing in Rabbit Model of Anterior Cruciate Ligament Reconstruction With a Polyethylene Terephthalate Ligament. AB - The purpose of this study was to investigate whether the local use of estradiol after anterior cruciate ligament (ACL) reconstruction with a polyethylene terephthalate (PET) artificial ligament graft could promote graft-bone healing. A total of 45 New Zealand white rabbits underwent ACL reconstruction with a PET ligament graft. The experimental groups were administered a local estradiol injection at either a low dose after surgery or a high dose after surgery, and the control group did not receive an injection. Computed tomography (CT) scans and blood sample collection were routinely performed in all three groups. Over time, the serum estradiol levels increased in both experimental groups, and the CT images revealed a trend of a shrinking bone tunnel area in all three groups. The rabbits were randomly sacrificed at 2, 4, and 8 weeks after surgery. The load to failure and stiffness of the experimental groups were significantly higher than those of the control group at 4 and 8 weeks. The histological study identified more bone mineralization in the experimental groups at 4 weeks after surgery compared to the control group. This study showed that the use of estradiol is a promising approach in promoting graft-bone healing in rabbits undergoing ACL reconstruction with a PET ligament graft. PMID- 28621913 TI - Visible-Light-Promoted Generation of alpha-Ketoradicals from Vinyl-bromides and Molecular Oxygen: Synthesis of Indenones and Dihydroindeno[1,2-c]chromenes. AB - Ortho-alkynylated alpha-bromocinnamates can be converted by a visible-light mediated photocascade reaction with molecular oxygen into either indenones or dihydroindeno[1,2-c]chromenes. The one-step process features key photochemical steps, that is, the initial activation of vinyl bromides through energy transfer to give alpha-ketoradicals in a reaction with molecular oxygen, followed by alpha oxidation of an arene moiety by 6-pi electrocyclization, and subsequent hydroxylation by an electron-transfer process from the same photocatalyst leads to the dihydroindeno[1,2-c]chromenes. PMID- 28621914 TI - Distinguishing parathyroid and thyroid lesions on ultrasound-guided fine-needle aspiration: A correlation of clinical data, ancillary studies, and molecular analysis. AB - BACKGROUND: Differentiating parathyroid and thyroid lesions can be challenging because of considerable morphologic overlap and anatomic proximity. Therefore, the authors sought to identify characteristic morphologic patterns and useful adjunct tests to distinguish these 2 entities. METHODS: A search was conducted in the study institution database for clinically indeterminate thyroid nodules from 2000 through 2016 with an emphasis on confirmed parathyroid nodules. Pathology reports, slides, ancillary studies, molecular analysis, and clinical and radiologic data were retrieved. RESULTS: A total of 143 cases of clinically indeterminate thyroid nodules were identified; 34 of these were confirmed parathyroid nodules. Three cytologic patterns were identified: 1) oncocytic cell pattern (9 cases; 26%); 2) follicular lesion of undetermined significance like/papillary-like pattern (14 cases; 41%); and 3) nonspecific endocrine cell clusters (11 cases; 32%). Bare oval nuclei (100%), nuclear overlap (88%), crowded sheets (88%), and intracytoplasmic vacuoles (62%) were observed. Ten cases (29%) demonstrated positive immunostaining for parathyroid hormone (PTH), 7 cases (21%) demonstrated a positive PTH assay, and 9 cases (26%) had PTH detected by ThyroSeq v.2. The remaining 8 cases were morphologically either indeterminate or suggestive of parathyroid origin. The cytologic diagnosis was confirmed clinically (20 cases) or surgically (14 cases). Based on cytology alone, 8 cases initially were diagnosed as thyroid tissue and amended to parathyroid lesion after ancillary studies were performed, including 5 cases based on ThyroSeq v.2 results alone. CONCLUSIONS: Lesions with follicular lesion of undetermined significance-like or oncocytic features are prone to misdiagnosis. The current study identified distinct cytologic patterns in parathyroid lesions suggestive of parathyroid origin, which, together with PTH immunostains or assay, molecular studies, or sestamibi scans, aid in distinguishing parathyroid from thyroid lesions. Cancer Cytopathol 2017;125:674-82. (c) 2017 American Cancer Society. PMID- 28621915 TI - Wounding of Arabidopsis leaves induces indole-3-carbinol-dependent autophagy in roots of Arabidopsis thaliana. AB - In cruciferous plants insect attack or physical damage induce the synthesis of the glucosinolate breakdown product indole-3-carbinol, which plays a key role in the defense against attackers. Indole-3-carbinol also affects plant growth and development, acting as an auxin antagonist by binding to the TIR1 auxin receptor. Other potential functions of indole-3-carbinol and the underlying mechanisms in plant biology are unknown. Here we show that an indole-3-carbinol-dependent signal induces specific autophagy in root cells. Leaf treatment with exogenous indole-3-carbinol or leaf-wounding induced autophagy and inhibited auxin response in the root. This induction is lost in glucosinolate-defective mutants, indicating that the effect of indole-3-carbinol is transported in the plants. Thus, indole-3-carbinol is not only a defensive metabolite that repels insects, but is also involved in long-distance communication regulating growth and development in plants. PMID- 28621916 TI - Construction of Anterior Hemi-Corneal Equivalents Using Nontransfected Human Corneal Cells and Transplantation in Dog Models. AB - Tissue-engineered human anterior hemi-cornea (TE-aHC) is a promising equivalent for treating anterior lamellar keratopathy to surmount the severe shortage of donated corneas. This study was intended to construct a functional TE-aHC with nontransfected human corneal stromal (ntHCS) and epithelial (ntHCEP) cells using acellular porcine corneal stromata (aPCS) as a carrier scaffold, and evaluate its biological functions in a dog model. To construct a TE-aHC, ntHCS cells were injected into an aPCS scaffold and cultured for 3 days; then, ntHCEP cells were inoculated onto the Bowman's membrane of the scaffold and cultured for 5 days under air-liquid interface condition. After its morphology and histological structure were characterized, the constructed TE-aHC was transplanted into dog eyes via lamellar keratoplasty. The corneal transparency, thickness, intraocular pressure, epithelial integrity, and corneal regeneration were monitored in vivo, and the histological structure and histochemical property were examined ex vivo 360 days after surgery, respectively. The results showed that the constructed TE aHC was highly transparent and composed of a corneal epithelium of 7-8 layer ntHCEP cells and a corneal stroma of regularly aligned collagen fibers and well preserved glycosaminoglycans with sparsely distributed ntHCS cells, mimicking a normal anterior hemi-cornea (aHC). Moreover, both ntHCEP and ntHCS cells maintained positive expression of their marker and functional proteins. After transplantation into dog eyes, the constructed TE-aHC acted naturally in terms of morphology, structure and inherent property, and functioned well in maintaining corneal clarity, thickness, normal histological structure, and composition in dog models by reconstructing a normal aHC, which could be used as a promising aHC equivalent in corneal regenerative medicine and aHC disorder therapy. PMID- 28621917 TI - Molecules Designed to Contain Two Weakly Coupled Spins with a Photoswitchable Spacer. AB - Controlling the charges and spins of molecules lies at the heart of spintronics. A photoswitchable molecule consisting of two independent spins separated by a photoswitchable moiety was designed in the form of new ligand H4 L, which features a dithienylethene photochromic unit and two lateral coordinating moieties, and yields molecules with [MM???MM] topology. Compounds [M4 L2 (py)6 ] (M=Cu, 1; Co, 2; Ni, 3; Zn, 4) were prepared and studied by single-crystal X-ray diffraction (SCXRD). Different metal centers can be selectively distributed among the two chemically distinct sites of the ligand, and this enables the preparation of many double-spin systems. Heterometallic [MM'???M'M] analogues with formulas [Cu2 Ni2 L2 (py)6 ] (5), [Co2 Ni2 L2 (py)6 ] (6), [Co2 Cu2 L2 (py)6 ] (7), [Cu2 Zn2 L2 (py)6 ] (8), and [Ni2 Zn2 L2 (py)6 ] (9) were prepared and analyzed by SCXRD. Their composition was established unambiguously. All complexes exhibit two weakly interacting [MM'] moieties, some of which embody two-level quantum systems. Compounds 5 and 8 each exhibit a pair of weakly coupled S=1/2 spins that show quantum coherence in pulsed Q-band EPR spectroscopy, as required for quantum computing, with good phase memory times (TM =3.59 and 6.03 MUs at 7 K). Reversible photoswitching of all the molecules was confirmed in solution. DFT calculations on 5 indicate that the interaction between the two spins of the molecule can be switched on and off on photocyclization. PMID- 28621918 TI - Identification of Protonated Sulfone and Aromatic Carboxylic Acid Functionalities in Organic Molecules by Using Ion-Molecule Reactions Followed by Collisionally Activated Dissociation in a Linear Quadrupole Ion Trap Mass Spectrometer. AB - Gas-phase reactivity of protonated model compounds with different functional groups toward trimethoxymethylsilane (TMMS) was studied to explore the utility of this reagent in mass spectrometric identification of specific functionalities for potentially rapid characterization of drug metabolites. Only protonated analytes with a carboxylic acid, a sulfone, or a sulfonamide functionality formed diagnostic adducts that had lost a methanol molecule upon reactions with TMMS. Collisionally activated dissociation (CAD) of these methanol-eliminated adduct ions (MS3 experiments) produced characteristic fragment ions of m/z 75, 105, and 123 for sulfones, while an additional methanol elimination was observed for carboxylic acids and sulfonamides. CAD of latter products (MS4 experiments) resulted in elimination of diagnostic neutral molecules CO2 (44 Da) and C2H6O2Si (90 Da) for aromatic carboxylic acids. Both aliphatic carboxylic acids and sulfonamides yield several fragment ions in these MS4 experiments that are different from those observed for sulfones or aromatic carboxylic acids. Potential energy surfaces were calculated (at the M06-2X/6-311++G(d,p) level of theory) to explore the mechanisms of various reactions. In summary, sulfones and aromatic carboxylic acids can be differentiated from each other and also from sulfonamides and aliphatic carboxylic acids based on reactions with TMMS and one or two CAD experiments. Aliphatic carboxylic acids and sulfonamides could not be differentiated from each other. PMID- 28621919 TI - Insights on Tuning the Nanostructure of rGO Laminate Membranes for Low Pressure Osmosis Process. AB - In this research, rGO laminates were prepared by a controlled partial reduction step, aimed to avoid aggregation and tune the interlayer spacing (d) between the rGO layers. The mild reducing agent vitamin C (l-AA) and cross-linker poly(carboxylic acid)s were used to improve the stability of the assembled rGO laminate membranes. AFM was used for the first time to further investigate the statistical size distribution of spacing between rGO layers. Topographical images of the edges of the rGO layers were obtained with an AFM instrument; interlayer spacing profiles were extracted, and then the data was plotted and fitted with Gaussian curves. We confirmed that the differently sized spacing coexisted, and their size distribution was affected by the reduction degree of rGO. At greater levels of reduction, more interlayer spacing was formed in the smaller size range, while few large gaps were still present. The obtained rGO laminate composite membranes were evaluated in a low pressure osmosis process such as forward osmosis (FO). The water permeation was higher in the rGO membrane prepared with a medium reduction degree (1.2-R) than the sample prepared by higher reduction degree (2.0-R) due to well-balanced nanochannels in hydrophilic regions and hydrophobic walls for fast transport of water molecules. The solute flux of the FO membrane was inversely correlated to the reduction degree. These findings helped in developing future strategies for designing high water flux and low reverse solute flux rGO membranes that are ideal for an FO process. PMID- 28621920 TI - Hydroxide Ion Oxidation in Aqueous Solutions Using Boron-Doped Diamond Electrodes. AB - The electrochemical oxidation behavior of hydroxide ions at the surface of boron doped diamond (BDD) electrodes is presented. The hydroxide ion oxidation behavior was found to be affected by the surface conditions of the BDD electrode. Over the NaOH concentration range of 0.5-10 mM, a well-defined voltammetric wave attributed to hydroxide ion oxidation was observed at ~1.25 V versus a Ag/AgCl reference electrode when using an anodically oxidized BDD (AO-BDD) electrode, while it was observed at around ~1.15 V when a cathodically reduced BDD (CR-BDD) electrode was used. Although the hydroxide ion oxidation profiles were slightly different for the AO-BDD and CR-BDD electrodes, the peak currents was each found to have linear relationships with the NaOH concentration over the same range. PMID- 28621921 TI - Novel Polymer Aerogel toward High Dimensional Stability, Mechanical Property, and Fire Safety. AB - Inorganc silica-based aerogels, the earliest and widely used aerogels, have poorer mechanical properties than their organic substitutes, which are flammable. In this study, a novel polymeric aerogel with high strength, inherent flame retardancy, and cost-effectiveness, which is based on poly(vinyl alcohol) (PVA) cross-linked with melamine-formaldehyde (MF), was prepared under aqueous condition with an ecofriendly freeze-drying and postcuring process. Combined with the additional rigid MF network and benifited from the resulting unique infrastructure of inter-cross-linked flexible PVA segments and rigid MF segments, PVA-based aerogels exibited a significantly decreased degradation rate and sharply decreased peak heat release rate (PHRR) in cone calorimeter tests (by as much as 83%) compared with neat PVA. The polymer aerogels have a limiting oxygen index (LOI) as high as 36.5% and V-0 rating in UL-94 test. Furthermore, the aerogel samples exposured to harsh temperatures maintain their dimensions (<10% change), original mechanical strength and fire safety. Therefore, this work provides a novel stragegy for preparing pure organic polymeric aerogel materials with high mechanical strength, dimensional stability, and fire safety. PMID- 28621922 TI - Selective Organic Contacts for Methyl Ammonium Lead Iodide (MAPI) Perovskite Solar Cells: Influence of Layer Thickness on Carriers Extraction and Carriers Lifetime. AB - We have fabricated MAPI solar cells using as selective contacts PEDOT:PSS polymer for holes and PCBM-C70 fullerene derivative for electrons. The thickness of MAPI, PCBM-C70, and PEDOT:PSS layers has been varied in order to evaluate the contribution of each layer to the final device performance. We have measured the devices capacitance under illumination and the charge carrier's lifetime using photoinduced time-resolved techniques. The results show that in this kind of devices the limiting layer is the PCBM-C70 due to its relative reduced mobility compared to PEDOT:PSS that makes the control of the fullerene thickness crucial for device optimization. Moreover, capacitive measurements show differences for the devices having different PCBM-C70 layer thicknesses in contrast with the measurements on the different PEDOT:PSS thickness. These give indications about holes and electrons storage and their distribution. PMID- 28621924 TI - Revealing the Crystalline Integrity of Wafer-Scale Graphene on SiO2/Si: An Azimuthal RHEED Approach. AB - The symmetry of graphene is usually determined by a low-energy electron diffraction (LEED) method when the graphene is on the conductive substrates, but LEED cannot handle graphene transferred to SiO2/Si substrates due to the charging effect. While transmission electron microscopy can generate electron diffraction on post-transferred graphene, this method is too localized. Herein, we employed an azimuthal reflection high-energy electron diffraction (RHEED) method to construct the reciprocal space mapping and determine the symmetry of wafer-size graphene both pre- and post-transfer. In this work, single-crystalline Cu(111) films were prepared on sapphire(0001) and spinel(111) substrates with sputtering. Then the graphene was epitaxially grown on single-crystalline Cu(111) films with a low pressure chemical vapor deposition. The reciprocal space mapping using azimuthal RHEED confirmed that the graphene grown on Cu(111) films was single crystalline, no matter the form of the monolayer or multilayer structure. While the Cu(111) film grown on sapphire(0001) may occasionally consist of 60 degrees in-plane rotational twinning, the reciprocal space mapping revealed that the in plane orientation of graphene grown atop was not affected. The proposed method for checking the crystalline integrity of the post-transferred graphene sheets is an important step in the realization of the graphene as a platform to fabricate electronic and optoelectronic devices. PMID- 28621925 TI - KPIC2: An Effective Framework for Mass Spectrometry-Based Metabolomics Using Pure Ion Chromatograms. AB - Distilling accurate quantitation information on metabolites from liquid chromatography coupled with mass spectrometry (LC-MS) data sets is crucial for further statistical analysis and biomarker identification. However, it is still challenging due to the complexity of biological systems. The concept of pure ion chromatograms (PICs) is an effective way of extracting meaningful ions, but few toolboxes provide a full processing workflow for LC-MS data sets based on PICs. In this study, an integrated framework, KPIC2, has been developed for metabolomics studies, which can detect pure ions accurately, align PICs across samples, group PICs to identify isotope and potential adducts, fill missing peaks and do multivariate pattern recognition. To evaluate its performance, MM48, metabolomics quantitation, and Soybean seeds data sets have been analyzed using KPIC2, XCMS, and MZmine2. KPIC2 can extract more true ions with fewer detecting features, have good quantification ability on a metabolomics quantitation data set, and achieve satisfactory classification on a soybean seeds data set through kernel-based OPLS-DA and random forest. It is implemented in R programming language, and the software, user guide, as well as example scripts and data sets are available as an open source package at https://github.com/hcji/KPIC2 . PMID- 28621923 TI - Capture and Release of tRNA by the T-Loop Receptor in the Function of the T-Box Riboswitch. AB - In Gram-positive bacteria, the tRNA-dependent T-box riboswitch system regulates expression of amino acid biosynthetic and aminoacyl-tRNA synthetase genes through a transcription attenuation mechanism. Binding of uncharged tRNA "closes" the switch, allowing transcription read-through. Structural studies of the 100 nucleotide stem I domain reveal tRNA utilizes base pairing and stacking interactions to bind the stem, but little is known structurally about the 180 nucleotide riboswitch core (stem I, stem III, and antiterminator stem) in complex with tRNA or the mechanism of coupling of the intermolecular binding domains crucial to T-box function. Here we utilize solution structural and biophysical methods to characterize the interplay of the different riboswitch-tRNA contact points using Bacillus subtilis and Oceanobacillus iheyensis glycyl T-box and T box:tRNA constructs. The data reveal that tRNA:riboswitch core binding at equilibrium involves only Specifier-anticodon and antiterminator-acceptor stem pairing. The elbow:platform stacking interaction observed in studies of the T-box stem I domain is released after pairing between the acceptor stem and the bulge in the antiterminator helix. The results are consistent with the model of T-box riboswitch:tRNA function in which tRNA is captured by stem I of the nascent mRNA followed by stabilization of the antiterminator helix and the paused transcription complex. PMID- 28621926 TI - Mimicking the Active Sites of Organophosphorus Hydrolase on the Backbone of Graphene Oxide to Destroy Nerve Agent Simulants. AB - Recent global military events, such as the conflict in Syria, have emphasized the need to find effective strategies to rapidly destroy organophosphorus-based nerve agents. In this work, we designed active site-engineered graphene oxide (GO) via polymerization (polymer bead-GOs) as organophosphorus hydrolase (OPH) mimetic hotspots for the rapid degradation of nerve agents. This hybrid catalyst has a high total turnover frequency value of 0.65 s-1 and good stability (94.8% activity maintained after 5 cycles). Mechanism investigations suggested that the high catalytic performance could be attributed to the synergistic effect among the clusters of imidazole and the presence of - COOH groups on the GO surface and Zn2+. PMID- 28621927 TI - Hemocompatibility of Degrading Polymeric Biomaterials: Degradable Polar Hydrophobic Ionic Polyurethane versus Poly(lactic-co-glycolic) Acid. AB - The use of degradable polymers in vascular tissue regeneration has sparked the need to characterize polymer biocompatibility during degradation. While tissue compatibility has been frequently addressed, studies on polymer hemocompatibility during degradation are limited. The current study evaluated the differences in hemocompatibility (platelet response, complement activation, and coagulation cascade initiation) between as-made and hydrolyzed poly(lactic-co-glycolic) acid (PLGA) and degradable polar hydrophobic ionic polyurethane (D-PHI). Platelet activation decreased (in whole blood) and platelet adhesion decreased (in blood without leukocytes) for degraded versus as-made PLGA. D-PHI showed minimal hemocompatibility changes over degradation. Leukocytes played a major role in mediating platelet activation for samples and controls, as well as influencing platelet-polymer adhesion on the degraded materials. This study demonstrates the importance of assessing the blood compatibility of biomaterials over the course of degradation since the associated changes in surface chemistry and physical state could significantly change biomaterial hemocompatibility. PMID- 28621928 TI - Aluminum (Oxy)Hydroxide Nanosticks Synthesized in Bicontinuous Reverse Microemulsion Have Potent Vaccine Adjuvant Activity. AB - Insoluble aluminum salts such as aluminum (oxy)hydroxide are commonly used as vaccine adjuvants. Recently, there is evidence suggesting that the adjuvant activity of aluminum salt-based materials is tightly related to their physicochemical properties, including nanometer-scale size, shape with long aspect ratio, and low degree of crystallinity. Herein, for the first time, the bicontinuous reverse microemulsion (RM) technique was utilized to synthesize stick-like monodisperse aluminum (oxy)hydroxide nanoparticles with a long aspect ratio of ~10, length of ~80 nm, and low degree of crystallinity (denoted as Al nanosticks). Moreover, the relationship between the physicochemical properties of Al-nanosticks and the bicontinuous RM was discussed. Compared to the commercial Alhydrogel, which contains micrometer-scale aluminum oxyhydroxide particular aggregates with moderate degree of crystallinity, the Al-nanosticks are more effective in adsorbing and delivering antigens (e.g., ovalbumin, OVA) into antigen-presenting cells, activating inflammasomes, and potentiating OVA-specific antibody responses in a mouse model. It is concluded that the aluminum (oxy)hydroxide nanosticks synthesized in the bicontinuous RM are promising new aluminum salt-based vaccine adjuvants. PMID- 28621930 TI - In Situ Monitoring of the Deposition of Flame-Made Chemoresistive Gas-Sensing Films. AB - Flame-deposited semiconducting nanomaterials on microelectronic circuitry exhibit exceptional performance as chemoresistive gas sensors. Current manufacturing technology, however, does not monitor in situ the formation of such nanostructured films, even though this can facilitate the controlled and economic synthesis of these sensors. Here, the resistance of such growing films is measured in situ during fabrication to monitor the creation of a semiconducting nanoparticle network for gas sensors. Upon formation of that network, the film resistance drops drastically to an asymptotic value that depends largely on the film structure or morphology rather than on its thickness and size of nanoparticle building blocks. Precursor solutions of various concentrations enable the flame deposition of Sb-doped SnO2 sensing films of different morphologies, each of which exhibit a characteristic in situ resistance pattern. Low precursor concentrations (1 mM) lead to thin (ca. 0.16 MUm) films with slender columnar structures of increasing diameter (up to 25 nm) after prolonged deposition (up to 6 min) and show an oscillating in situ resistance during their fabrication. On the other extreme, high precursor concentrations (100 mM) lead to thick (up to 80 MUm) dendritic and porous films consisting of nanoparticles with relatively small primary particle diameter (around 7 nm) that remain invariant of deposition duration, which is in agreement with the stable in situ resistance. Such dendritic films exhibit a sensor recovery time that is an order of magnitude longer than that of those made at lower concentrations. The above understanding enables the rapid and economic flame synthesis of thin gas sensors consisting of minimal semiconducting nanomaterial mass possessing a tuned baseline resistance and exhibiting excellent response to ethanol vapor. PMID- 28621929 TI - Kinetic Analysis Reveals the Identity of Abeta-Metal Complex Responsible for the Initial Aggregation of Abeta in the Synapse. AB - The mechanism of Abeta aggregation in the absence of metal ions is well established, yet the role that Zn2+ and Cu2+, the two most studied metal ions, released during neurotransmission, paly in promoting Abeta aggregation in the vicinity of neuronal synapses remains elusive. Here we report the kinetics of Zn2+ binding to Abeta and Zn2+/Cu2+ binding to Abeta-Cu to form ternary complexes under near physiological conditions (nM Abeta, MUM metal ions). We find that these reactions are several orders of magnitude slower than Cu2+ binding to Abeta. Coupled reaction-diffusion simulations of the interactions of synaptically released metal ions with Abeta show that up to a third of Abeta is Cu2+-bound under repetitive metal ion release, while any other Abeta-metal complexes (including Abeta-Zn) are insignificant. We therefore conclude that Zn2+ is unlikely to play an important role in the very early stages (i.e., dimer formation) of Abeta aggregation, contrary to a widely held view in the subject. We propose that targeting the specific interactions between Cu2+ and Abeta may be a viable option in drug development efforts for early stages of AD. PMID- 28621932 TI - High Efficiency Quantum Dot Sensitized Solar Cells Based on Direct Adsorption of Quantum Dots on Photoanodes. AB - Unambiguously direct adsorption (DA) of initial oil-soluble quantum dots (QDs) on TiO2 film electrode is a convenient and simple approach in the construction of quantum dot sensitized solar cells (QDSCs). Regrettably, low QD loading amount and poor reproducibility shadow the advantages of DA route and constrain its practical application. Herein, the influence of experimental variables in DA process on QD loading amount as well as on the photovoltaic performance of the resultant QDSCs was investigated and optimized systematically, including the choice of solvent, purification of QDs, and sensitization time, as well as QD concentration. Experimental results demonstrated that it is essential to choose appropriate solvent as well as control purification cycles of original QD suspensions so as to realize satisfactory QD loading amount and ensure the high reproducibility. In addition, DA mode renders efficient electron injection from QD to TiO2, yet low QD loading amount and adverse QD agglomeration in comparison with the well-developed capping ligand induced self-assembly (CLIS) deposition approach. Mg2+ treatment on TiO2 photoanodes can promote the QD loading amount in DA mode. The optimized QDSCs based on DA mode exhibited efficiencies of 6.90% and 9.02% for CdSe and Zn-Cu-In-Se QDSCs, respectively, which were comparable to the best results based on CLIS mode (6.88% and 9.56%, respectively). PMID- 28621931 TI - Tunable Surface Repellency Maintains Stemness and Redox Capacity of Human Mesenchymal Stem Cells. AB - Human bone marrow derived mesenchymal stem cells (hMSCs) hold great promise for regenerative medicine due to their multipotent differentiation capacity and immunomodulatory capabilities. Substantial research has elucidated mechanisms by which extracellular cues regulate hMSC fate decisions, but considerably less work has addressed how material properties can be leveraged to maintain undifferentiated stem cells. Here, we show that synthetic culture substrates designed to exhibit moderate cell-repellency promote high stemness and low oxidative stress-two indicators of naive, healthy stem cells-in commercial and patient-derived hMSCs. Furthermore, the material-mediated effect on cell behavior can be tuned by altering the molar percentage (mol %) and/or chain length of poly(ethylene glycol) (PEG), the repellant block linked to hydrophobic poly(epsilon-caprolactone) (PCL) in the copolymer backbone. Nano- and angstrom scale characterization of the cell-material interface reveals that PEG interrupts the adhesive PCL domains in a chain-length-dependent manner; this prevents hMSCs from forming mature focal adhesions and subsequently promotes cell-cell adhesions that require connexin-43. This study is the first to demonstrate that intrinsic properties of synthetic materials can be tuned to regulate the stemness and redox capacity of hMSCs and provides new insight for designing highly scalable, programmable culture platforms for clinical translation. PMID- 28621933 TI - Structural Flexibility of an Inhibitor Overcomes Drug Resistance Mutations in Staphylococcus aureus FtsZ. AB - In the effort to combat antibiotic resistance, inhibitors of the essential bacterial protein FtsZ have emerged as a promising new class of compounds with clinical potential. One such FtsZ inhibitor (TXA707) is associated with potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to current standard-of-care antibiotics. However, mutations in S. aureus FtsZ (SaFtsZ) that confer resistance to TXA707 have been observed, with mutations in the Gly196 and Gly193 residues being among the most prevalent. Here, we describe structural studies of an FtsZ inhibitor, TXA6101, which retains activity against MRSA isolates that express either G196S or G193D mutant FtsZ. We present the crystal structures of TXA6101 in complex with both wild-type SaFtsZ and G196S mutant SaFtsZ, as well the crystal structure of TXA707 in complex with wild-type SaFtsZ. Comparison of the three structures reveals a molecular basis for the differential targeting abilities of TXA6101 and TXA707. The greater structural flexibility of TXA6101 relative to TXA707 enables TXA6101 to avoid steric clashes with Ser196 and Asp193. Our structures also demonstrate that the binding of TXA6101 induces previously unobserved conformational rearrangements of SaFtsZ residues in the binding pocket. In aggregate, the structures reported in this work reveal key factors for overcoming drug resistance mutations in SaFtsZ and offer a structural basis for the design of FtsZ inhibitors with enhanced antibacterial potency and reduced susceptibility to mutational resistance. PMID- 28621934 TI - TQOPEN (N,N,N',N'-Tetrakis(2-quinolylmethyl)-3-oxa-1,5-pentanediamine) Family as Heptadentate Fluorescent Cd2+ Sensors. AB - A quinoline-based heptadentate ligand, N,N,N',N'-tetrakis(2-quinolylmethyl)-3-oxa 1,5-pentanediamine (TQOPEN), exhibits a fluorescence increase (ICd/I0 = 25, phiCd = 0.017) at 428 nm upon addition of 1 equiv of Cd2+. In contrast, 1 equiv of Zn2+ induces a negligible fluorescence change due to weak interaction (IZn/I0 = 2.5, IZn/ICd = 10%). In comparison with TQOPEN, the thia and aza derivatives TQSPEN and TQNPEN exhibit improved Cd2+/Zn2+ selectivity and higher Cd2+-binding affinity, respectively. The solid-state structures of mononuclear Cd2+ and hydroxide-bridged dinuclear Zn2+ complexes of TQOPEN were elucidated by X-ray crystallography. Although the crystal structure of the TQOPEN-Cd2+ complex exhibits a six-coordinate metal center, in which one quinoline weakly interacts with the Cd center (Cd...Nquinoline = 3.303(3) A), a 1H NMR study at 233 K suggests that all quinolines interact with the Cd center to form a symmetrical seven-coordinate structure in solution. Theoretical calculations (TDDFT) support the flexible coordination environment around the Cd center, leading to intramolecular excimer formation with two quinoline moieties in the excited state. The importance of a heptadentate structure was further demonstrated by the lack of Cd2+ specificity with hexadentate ligands TriQOPEN (N,N,N'-tris(2 quinolylmethyl)-3-oxa-1,5-pentanediamine) and TQCPEN (N,N,N',N'-tetrakis(2 quinolylmethyl)-1,5-pentanediamine). PMID- 28621935 TI - Computational Implementation of Nudged Elastic Band, Rigid Rotation, and Corresponding Force Optimization. AB - The nudged elastic band (NEB) algorithm is the leading method of calculating transition states in chemical systems. However, the current literature lacks adequate guidance for users wishing to implement a key part of NEB, namely, the optimization method. Here, we provide details of this implementation for the following six gradient descent algorithms: steepest descent, quick-min Verlet, FIRE, conjugate gradient, Broyden-Fletcher-Goldfarb-Shanno (BFGS), and limited memory BFGS (LBFGS). We also construct and implement a new, accelerated backtracking line search method in concert with a partial Procrustes superimposition to improve upon existing methods. Validation is achieved through benchmark calculations of two test cases, the isomerization of CNX and BOX (where X ? {H, Li, Na}) and the study of a conformational change within an alanine dipeptide. We also make direct comparisons to the well-established codebase known as the atomic simulation environment. PMID- 28621936 TI - C-H Alkenylation of Heteroarenes: Mechanism, Rate, and Selectivity Changes Enabled by Thioether Ligands. AB - Thioether ancillary ligands have been identified that can greatly accelerate the C-H alkenylation of O-, S-, and N-heteroarenes. Kinetic data suggest thioether-Pd catalyzed reactions can be as much as 800* faster than classic ligandless systems. Furthermore, mechanistic studies revealed C-H bond cleavage as the turnover-limiting step, and that rate acceleration upon thioether coordination is correlated to a change from a neutral to a cationic pathway for this key step. The formation of a cationic, low-coordinate catalytic intermediate in these reactions may also account for unusual catalyst-controlled site selectivity wherein C-H alkenylation of five-atom heteroarenes can occur under electronic control with thioether ligands even when this necessarily involves reaction at a more hindered C-H bond. The thioether effect also enables short reaction times under mild conditions for many O-, S-, and N-heteroarenes (55 examples), including examples of late-stage drug derivatization. PMID- 28621937 TI - Surface Termination of Fe3O4(111) Films Studied by CO Adsorption Revisited. AB - Although the (111) surface of Fe3O4 (magnetite) has been investigated for more than 20 years, substantial controversy remains in the literature regarding the surface termination proposed based on structural and adsorption studies. The present article provides density functional theory results that allow to rationalize experimental results of infrared reflection-absorption spectroscopy and temperature-programmed desorption studies on CO adsorption, thus leading to a unified picture in which the Fe3O4(111) surface is terminated by a 1/4 monolayer of tetrahedrally coordinated Fe3+ ions on top of a close-packed oxygen layer as previously determined by low energy electron diffraction. However, surface defects play a crucial role in adsorption properties and may dominate chemical reactions on Fe3O4(111) when exposed to the ambient. PMID- 28621938 TI - Inhibition of Proliferation of Vascular Smooth Muscle Cells by Cucurbitanes from Momordica charantia. AB - The cucurbitaceous plant Momordica charantia L., named "bitter melon", inhabits Asia, Africa, and South America and has been used as a traditional medicine. The atypical proliferation of vascular smooth muscle cells (VSMCs) plays an important role in triggering the pathogenesis of cardiovascular diseases. Platelet-derived growth factor (PDGF) is regarded as the most powerful growth factor in promoting the intimal accumulation of VSMCs. The current study features the identification of six new cucurbitane-type triterpenoids (1-6) from the fruits of M. charantia, utilizing diverse chromatographic and spectroscopic techniques. In particular, the 2D structure of 1 was confirmed utilizing the long-range HSQMBC NMR pulse, capable of measuring heteronuclear long-range correlations (4-6JCH). The cucurbitanes were also assessed for their inhibitory activity against PDGF induced VSMC proliferation. This current study may constitute a basis for developing those chemotypes into sensible pharmacophores alleviating cardiovascular disorders. PMID- 28621939 TI - [2]Rotaxane Formation by Transition State Stabilization. AB - We report on the synthesis of [2]rotaxanes driven by stabilization of the axle forming transition state. A bifunctional macrocycle, with hydrogen bond donors at one end and acceptors at the other, is used to stabilize the charges that develop during the addition of a primary amine to a cyclic sulfate. PMID- 28621940 TI - Solvation and Proton-Coupled Electron Transfer Reduction Potential of 2NO* to 1HNO in Aqueous Solution: A Theoretical Investigation. AB - In this work, quantum mechanical calculations and Monte Carlo statistical mechanical simulations were carried out to investigate the solvation properties of HNO in aqueous solution and to evaluate the proton-coupled one electron reduction potential of 2NO to 1HNO, which is essential missing information to understand the fate of 2NO in the biological medium. Our results showed that the 1HNO molecule acts mainly as a hydrogen bond donor in aqueous solution with an average energy of -5.5 +/- 1.3 kcal/mol. The solvation free energy of 1HNO in aqueous solution, computed using three approaches based on the linear response theory, revealed that the current prediction of the hydration free energy of HNO is, at least, 2 times underestimated. We proposed two pathways for the production of HNO through reduction of NO. The first pathway is the direct reduction of NO through proton-coupled electron transfer to produce HNO, and the second path is the reduction of the radical anion HONO*-, which is involved in equilibrium with NO in aqueous solution. We have shown that both pathways are viable processes under physiological conditions, having reduction potentials of E degrees ' = 0.161 V and E degrees ' ~ 1 V for the first and second pathways, respectively. The results shows that both processes can be promoted by well-known biological reductants such as NADH, ascorbate, vitamin E (tocopherol), cysteine, and glutathione, for which the reduction potential at physiological pH is around -0.3 to -0.5 V. The computed reduction potential of NO through the radical anion HONO* can also explain the recent experimental findings on the formation of HNO through the reduction of NO, promoted by H2S, vitamin C, and aromatic alcohols. Therefore, these results contribute to shed some light into the question of whether and how HNO is produced in vivo and also for the understanding of the biochemical and physiological effects of NO. PMID- 28621941 TI - Sulawesins A-C, Furanosesterterpene Tetronic Acids That Inhibit USP7, from a Psammocinia sp. Marine Sponge. AB - Three new furanosesterterpene tetronic acids, sulawesins A-C (1-3), were isolated from a Psammocinia sp. marine sponge, along with the known compounds ircinins-1 (4) and -2 (5). Although ircinins-1 and -2 were previously isolated as (+)- or ( )-enantiomers from marine sponges, we isolated them as enantiomeric mixtures. Sulawesins A and B possess a new carbon skeleton with a 5-(furan-3-yl)-4 hydroxycyclopent-2-enone moiety and were also found to be diastereomeric mixtures of four isomers by an HPLC analysis with a chiral-phase column. Sulawesin C has a dimeric structure of ircinin-1 and is the first dimer in this family. USP7, a deubiquitinating enzyme, is an emergent target of cancer therapy, and the isolated compounds inhibited USP7 with IC50 values in the range of 2.7-4.6 MUM. PMID- 28621942 TI - Hygroscopicity of Organic Compounds as a Function of Carbon Chain Length and Carboxyl, Hydroperoxy, and Carbonyl Functional Groups. AB - The albedo and microphysical properties of clouds are controlled in part by the hygroscopicity of particles serving as cloud condensation nuclei (CCN). Hygroscopicity of complex organic mixtures in the atmosphere varies widely and remains challenging to predict. Here we present new measurements characterizing the CCN activity of pure compounds in which carbon chain length and the numbers of hydroperoxy, carboxyl, and carbonyl functional groups were systematically varied to establish the contributions of these groups to organic aerosol apparent hygroscopicity. Apparent hygroscopicity decreased with carbon chain length and increased with polar functional groups in the order carboxyl > hydroperoxy > carbonyl. Activation diameters at different supersaturations deviated from the 3/2 slope in log-log space predicted by Kohler theory, suggesting that water solubility limits CCN activity of particles composed of weakly functionalized organic compounds. Results are compared to a functional group contribution model that predicts CCN activity of organic compounds. The model performed well for most compounds but underpredicted the CCN activity of hydroperoxy groups. New best-fit hydroperoxy group/water interaction parameters were derived from the available CCN data. These results may help improve estimates of the CCN activity of ambient organic aerosols from composition data. PMID- 28621944 TI - Mechanism and Product Distribution of the O3-Initiated Degradation of (E)-2 Heptenal, (E)-2-Octenal, and (E)-2-Nonenal. AB - The O3-molecule initiated degradation of three 2-alkenals (E)-2-heptenal, (E)-2 octenal, and (E)-2-nonenal has been investigated in a 1080 L quartz-glass environmental chamber at 298 +/- 2 K and atmospheric pressure of synthetic air using in situ FTIR spectroscopy to monitor the reactants and products. The experiments were performed in the absence of an OH scavenger. The molar yields of the primary products formed were glyoxal (49 +/- 4) % and pentanal (34 +/- 3) % from the reaction of (E)-2-heptenal with O3, glyoxal (41 +/- 3) % and hexanal (39 +/- 3) % from the reaction of (E)-2-octenal with O3, and glyoxal (45 +/- 3) % and heptanal (46 +/- 3) % from the reaction of (E)-2-nonenal with O3. The residual bands in the infrared product spectra for each of the studied reactions are attributed to 2-oxoaldehyde compounds. Based on the observed products, a general mechanism for the ozonolysis reaction of long chain unsaturated aldehydes is proposed, and the results are compared with the available literature data. PMID- 28621945 TI - Concentration-Driven Selectivity of Energy Transfer Channels and Color Tunability in Ba3La(PO4)3:Tb3+, Sm3+ for Warm White LEDs. AB - Here, we report the large-scale emission color tunability in Ba3La(PO4)3:Tb3+, Sm3+ (BLPO:TS) system based on the detailed discussion on the concentration driven selectivity of energy transfer (ET) channels from Tb3+ to Sm3+. It is induced by the concentration-dependent 5D3 and 5D4 emissions of Tb3+ and the different interaction mechanisms of ET from Tb3+ to Sm3+ via 5D3 and 5D4 channels. In the diluted Tb3+ scenario, the red emission of Sm3+ is efficiently sensitized via the 5D3 channel, while in the concentrated Tb3+ case, the contribution of 5D4 channel is dominant. Therefore, by simply adjusting the doping concentrations of Tb3+ and Sm3+, the emission color of the phosphors can be tuned from green to red. In view of the phosphors with red emissions are critical to the warm white light-emitting diodes (WLEDs), an orange-red Tb3+, Sm3+ coactivated phosphor Ba3La0.90Tb0.05Sm0.05(PO4)3 (BLPO:5T5S) with good thermal and chromaticity stability and internal quantum efficiency ~67% is developed in the system. Then, a near-UV WLED (CCT ~ 4500 K, Ra ~ 81) is fabricated using this phosphor. These findings not only indicate that the orange red phosphor BLPO:5T5S is available for near-UV warm white LEDs but also deliver new insights into the ET processes in Tb3+ and Sm3+ activated phosphors. PMID- 28621943 TI - Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines. AB - Regulator of G Protein Signaling (RGS) 17 is an overexpressed promoter of cancer survival in lung and prostate tumors, the knockdown of which results in decreased tumor cell proliferation in vitro. Identification of drug-like molecules inhibiting this protein could ameliorate the RGS17's pro-tumorigenic effect. Using high-throughput screening, a chemical library containing natural products was interrogated for inhibition of the RGS17-Galphao interaction. Initial hits were verified in control and counter screens. Leads were characterized via biochemical, mass spectrometric, Western blot, microscopic, and cytotoxicity measures. Four known compounds (1-4) were identified with IC50 values ranging from high nanomolar to low micromolar. Three compounds were extensively characterized biologically, demonstrating cellular activity determined by confocal microscopy, and two compounds were assessed via ITC exhibiting high nanomolar to low micromolar dissociation constants. The compounds were found to have a cysteine-dependent mechanism of binding, verified through site-directed mutagenesis and cysteine reactivity assessment. Two compounds, sanguinarine (1) and celastrol (2), were found to be cytostatic against lung and prostate cancer cell lines and cytotoxic against prostate cancer cell lines in vitro, although the dependence of RGS17 on these phenomena remains elusive, a result that is perhaps not surprising given the multimodal cytostatic and cytotoxic activities of many natural products. PMID- 28621946 TI - The Acute Effects of Fine Particulate Matter Constituents on Blood Inflammation and Coagulation. AB - Limited evidence is available on the effects of various fine particulate matter (PM2.5) constituents on blood inflammation and coagulation. We examined the associations between 10 constituents and 10 circulating biomarkers in a panel of 28 urban residents with four repeated measurements in Shanghai, China. Based on the linear mixed-effect models, we fitted the single-constituent models, the constituent-PM2.5 joint models, and the constituent-residual models to evaluate the associations between PM2.5 constituents and eight inflammatory biomarkers (fibrinogen, C-reactive protein, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, interleukin-1b, intercellular adhesion molecule-1, P selectin, vascular cell adhesion molecule-1) and two coagulation biomarkers (plasminogen activator inhibitor-1 and soluble CD40 ligand). We found robust associations of organic carbon (OC), elemental carbon (EC), nitrate (NO3-), and ammonium (NH4+) with at least 1 of 8 inflammatory markers. On average, an interquartile range increase in the four constituents corresponded to increments of 50%, 37%, 25%, and 26% in inflammatory biomarkers, respectively. Only sulfate (SO42-) or NH4+ was robustly associated with coagulation markers (corresponding increments: 23% and 20%). Our results provided evidence that some constituents in PM2.5 (OC, EC, NO3-, SO42-, and NH4+) might play crucial roles in inducing systematic inflammation and coagulation, but their roles varied by the selected biomarkers. PMID- 28621948 TI - Insight into the Am-O Phase Equilibria: A Thermodynamic Study Coupling High Temperature XRD and CALPHAD Modeling. AB - In the frame of minor actinide transmutation, americium can be diluted in UO2 and (U, Pu)O2 fuels burned in fast neutron reactors. The first mandatory step to foresee the influence of Am on the in-reactor behavior of transmutation targets or fuel is to have fundamental knowledge of the Am-O binary system and, in particular, of the AmO2-x phase. In this study, we coupled HT-XRD (high temperature X-ray diffraction) experiments with CALPHAD thermodynamic modeling to provide new insights into the structural properties and phase equilibria in the AmO2-x-AmO1.61+x-Am2O3 domain. Because of this approach, we were able for the first time to assess the relationships between temperature, lattice parameter, and hypostoichiometry for fcc AmO2-x. We showed the presence of a hyperstoichiometric existence domain for the bcc AmO1.61+x phase and the absence of a miscibility gap in the fcc AmO2-x phase, contrary to previous representations of the phase diagram. Finally, with the new experimental data, a new CALPHAD thermodynamic model of the Am-O system was developed, and an improved version of the phase diagram is presented. PMID- 28621947 TI - Cucurbit[7]uril Enables Multi-Stimuli-Responsive Release from the Self-Assembled Hydrophobic Phase of a Metal Organic Polyhedron. AB - Mixed self-assembly of ligands 1, 2, 1,6-hexanediamine (HDA), and Pd(NO3)2 afforded Fujita-type metal organic polyhedron MOP1 (diameter ~ 8.2 nm), which is covalently functionalized with an average of 18 cucurbit[7]uril (CB[7]) units, as evidenced by 1H NMR, diffusion-ordered spectroscopy NMR, and transmission electron microscopy measurements. By virtue of the host-guest properties of CB[7], the inner cavity of MOP can be rendered hydrophobic by using octadecyl HDA (3) as guest during the self-assembly process. The hydrophobic cavity was successfully utilized to trap the hydrophobic dye Nile Red (NR) and the anticancer drug doxorubicin (DOX). The stimuli-responsive release of encapsulated NR or DOX occurs (1) upon addition of a competitive binder (e.g., adamantane ammonium (ADA)) for CB[7], (2) by a dual pH-chemical stimulus involving the protonation state change of adamantane carboxylate at pH 5.8, and (3) by a dual pH-photochemical stimulus involving photoisomerization of trans-6 to cis-6 at pH 5.8. NR is released from NR@MOP2 within HeLa cancer cells. This body of work suggests that the covalent attachment of cucurbit[n]uril to metal organic polyhedra constitutes a promising vehicle for the development of both diagnostic and therapeutic nanoparticles. PMID- 28621949 TI - Cyclotides from the Indian Medicinal Plant Viola odorata (Banafsha): Identification and Characterization. AB - Cyclotides are cyclic cystine knotted macrocyclic plant peptides that have several promising applications. This study was undertaken to detect and identify known and new cyclotides in Viola odorata, a commercially important medicinal plant, from three geographical locations in India. The number of cyclotides in the plant varied with the tissue (leaves, petioles, flowers, runners, and roots) and with geographical locations in India. Using liquid chromatography coupled to Fourier transform mass spectrometry (FTMS), 166 cyclotide-like masses were observed to display cyclotide-diagnostic mass shifts following reduction, alkylation, and digestion, and 71 of these were positively identified based on automated spectrum matching. Of the remaining 95 putative cyclotides observed, de novo peptide sequencing of three new cyclotides, namely, vodo I1 (1), vodo I2 (2), and vodo I3 (3), was carried out with tandem mass spectrometry. PMID- 28621950 TI - Direct Observation of the Symmetrical and Asymmetrical Protonation States in Molecular Crystals. AB - The symmetrical and asymmetrical protonation states are realized via the formation of intermolecular hydrogen bonds inside 9,10-bis((E)-2-(pyridin-4 yl)vinyl)anthracene (BP4VA) molecular crystals. With the protonation of H2SO4, BP4VA molecules are protonated symmetrically, while the molecules are asymmetrically protonated by introducing HCl. The different protonation states of BP4VA crystals result in various supramolecular interactions, aggregation states, and even tunable optical properties. It provides a fundamental principle to understand the effect of protonation in organic conjugated molecules and an approach to expanding the scope of organic functional materials. PMID- 28621951 TI - Bioinspired Total Synthesis and Stereochemical Revision of the Fungal Metabolite Pestalospirane B. AB - The total synthesis of both enantiomers of pestalospirane B, 2, has been achieved using a bioinspired tandem dimerization-spiroketalization reaction. Electronic circular dichroism (ECD) and X-ray analysis were used to revise the absolute stereochemistry of the natural product pestalospirane B from 3S, 3'S, 12R, 12'R to its enantiomer 3R, 3'R, 12S, 12'S. PMID- 28621952 TI - Gastrointestinal and Systemic Disposition of Diclofenac under Fasted and Fed State Conditions Supporting the Evaluation of in Vitro Predictive Tools. AB - This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e., Cataflam) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus, and the TNO gastrointestinal model equipped with the recently developed advanced gastric compartment (TIMagc). In vivo data suggested impaired drug dissolution and/or immediate precipitation in the fasted stomach, linked to the acidity of the gastric environment. Similarly, a vast presence of solid drug material in the stomach was observed under fed state conditions, which could be attributed to a marked delay in intragastric tablet disintegration after drug intake with a meal. Emptying of solid drug from the stomach into the duodenum generally resulted in rapid intestinal drug (re)dissolution in both test conditions, explaining the absence of a food effect on the extent of overall systemic exposure for diclofenac. In vitro tools were found to be capable of predicting in vivo intraluminal (and systemic) disposition of this compound, the extent of which depended on the degree to which the dynamic nature of the gastrointestinal process(es) to be investigated was simulated. PMID- 28621953 TI - Observation of Exciton Redshift-Blueshift Crossover in Monolayer WS2. AB - We report a rare atom-like interaction between excitons in monolayer WS2, measured using ultrafast absorption spectroscopy. At increasing excitation density, the exciton resonance energy exhibits a pronounced redshift followed by an anomalous blueshift. Using both material-realistic computation and phenomenological modeling, we attribute this observation to plasma effects and an attraction-repulsion crossover of the exciton-exciton interaction that mimics the Lennard-Jones potential between atoms. Our experiment demonstrates a strong analogy between excitons and atoms with respect to interparticle interaction, which holds promise to pursue the predicted liquid and crystalline phases of excitons in two-dimensional materials. PMID- 28621954 TI - van der Waals Contribution to the Relative Stability of Aqueous Zn(2+) Coordination States. AB - Many properties of aqueous cations depend on their coordination state. However, the lack of long-range order and the dynamic character of aqueous solutions make it difficult to obtain information beyond average coordination parameters. A thorough understanding of the molecular-scale environment of aqueous cations usually requires a combination of experimental and theoretical approaches. In the case of Zn2+, significant discrepancies occur among theoretical investigations based on first-principles molecular dynamics (FPMD) or free-energy calculations, although experimental data consistently point to a dominant hexaaquo-zinc complex (Zn[H2O]6)2+ in pure water. In the present study, the aqueous speciation of zinc is theoretically investigated by combining FPMD simulations and free-energy calculations based on metadynamics and umbrella-sampling strategies. The simulations are carried out within the density functional theory (DFT) framework using for the exchange-correlation functional either a standard generalized gradient approximation (GGA) or a nonlocal functional (vdw-DF2) which includes van der Waals interactions. The theoretical environment of Zn is confronted to experiment by comparing calculated and measured X-ray absorption spectra. It is shown that the inclusion of van der Waals interactions is crucial for the correct modeling of zinc aqueous speciation, whereas GGA incorrectly favors tetraaquo- (Zn[H2O]4)2+ and pentaaquo-zinc (Zn[H2O]5)2+ complexes, results obtained with the vdW-DF2 functional show that the hexaaquo-zinc complex is more stable than the tetraaquo and pentaaquo-zinc complexes by 13 and by 4 kJ mol-1, respectively. These results highlight the critical importance of even subtle interactions for the correct balance of different coordination states in aqueous solutions. However, for a given coordination state, GGA leads to a reasonable description of the geometry of the aqueous complex. PMID- 28621955 TI - Regioselective Three-Component Reaction of Pyridine N-Oxides, Acyl Chlorides, and Cyclic Ethers. AB - A novel three-component reaction of pyridine N-oxides, acyl chlorides, and cyclic ethers is described. Treatment of an electron-deficient pyridine N-oxide with an acyl chloride in the presence of a cyclic ether at 25-50 degrees C leads to a substituted pyridine as a single regioisomer in up to 58% isolated yield. Isotopic-labeling experiments and substrate scope support the reaction proceeding through a carbene intermediate. PMID- 28621956 TI - Controlled Terahertz Birefringence in Stretched Poly(lactic acid) Films Investigated by Terahertz Time-Domain Spectroscopy and Wide-Angle X-ray Scattering. AB - We report a correlation between the dielectric property and structure of stretched poly(lactic acid) (PLA) films, revealed by polarization-sensitive terahertz time-domain spectroscopy and two-dimensional (2D) wide-angle X-ray scattering (WAXS). The experiments evidence that the dielectric function of the PLA film becomes more anisotropic with increasing draw ratio (DR). This behavior is explained by a classical Lorentz oscillator model assuming polarization dependent absorption. The birefringence can be systematically altered from 0 to 0.13 by controlling DR. The combination of terahertz spectroscopy and 2D WAXS measurement reveals a clear correlation between the birefringence in the terahertz frequency domain and the degree of orientation of the PLA molecular chains. These findings imply that the birefringence is a result of the orientation of the PLA chains with anisotropic macromolecular vibration modes. Because of a good controllability of the birefringence, polymer-based materials will provide an attractive materials system for phase retarders in the terahertz frequency range. PMID- 28621957 TI - [Editor's Note: Maternity, its Value and Sense as Core of the Bioethical Debate on Surrogated Motherhood]. PMID- 28621958 TI - [Biomedical Perspective of the Surrogate Motherhood]. AB - The subrogated motherhood takes place when an embryo created by in vitro fertilization (IVF) technology is implanted in a surrogate, sometimes called a gestational mother, by means a contract with her. It can imply to natural families (woman and man) with or without infertility problems, or to monoparental or biparental families of the same sex. Concerning the origin of the gametes used in the IVF emerges different implications on the genetic relationship of the resulting child with the surrogate and the future parents. The subrogated motherhood was initially considered an option to solve infertility problems. Nevertheless this practice has become a possible and attractive option as a source of economic resources for poor women. The cases of benefit of a pregnancy without mediating a contract are exceptional and they are not properly cases of "subrogated maternity" but of "altruistic maternity" and must be considered as heterologous in vitro fertilization. In this article are analyzed the medical, genetic and bioethics aspects of this new derivation of the fertilization in vitro. As points of special attention are considered the following questions: Is it the surrogate motherhood used preferably to solve infertility problems? Is not this actually a new form of exploitation of the woman? Does not suppose an attack to the natural family? Does not suppose in addition an attack to the dignity of the human being? PMID- 28621959 TI - [Surrogate Motherhood and Woman Dignity]. AB - Motherhood by subrogation is an issue that directly affects human rights and, ultimately, human dignity. Therefore, if we want to give an adequate response to this issue, it is essential to reflect on how this practice affects the dignity and rights of the people involved in it and, more specifically, the pregnant mother. This study tries to show how in relation to the latter, maternity by subrogation directly contradicts some basic requirements of human dignity, since it reifies, instrumentalizes, convert into an object of commerce, and disregards the personal uniqueness of pregnant women. PMID- 28621960 TI - [The Reproductive Exploitation of Women and the Myth of Altruistic Surrogacy: An Overview of the Phenomenon of Gestation by Substitution]. AB - The article approaches the issue of surrogacy from a global point of view. Surrogacy is analysed from international and comparative law perspective, as well as the effects of the legalization of altruistic surrogacy in the first-world countries on vulnerable women in other parts of the world. The paper concludes extrapolating the conclusions of this analysis to the current debate about legalization of altruistic surrogacy in Spain. PMID- 28621961 TI - [Economic Dimension of Surrogacy Maternity ("Rooms For Rent")]. AB - Maternity by subrogation has an important economic dimension that, in the last years, has been even more potentiated. It is a multimillion-dollar industry that, on the other hand, takes advantage of women with low economic resources. Faced with this, there is an important criticism, carried out by different groups, that refer to this sector with such questionable terms as "uterine rental industry", "baby farms", "children's factories", etc. These criticisms are being strongly counteracted by maternity centers by subrogation. To this they dedicate enormous budgets with strategies that, based on great doses of sentimentality, manage to transmit a positive image of the process. The objective is to provide tranquility to users and to society in general. To this end they distort the ethical and legal implications of the process; in particular, deny the exploitation of women and the instrumentalization of the children that, necessarily, implies this technique. PMID- 28621962 TI - [Language Manipulation, Surrogacy, Altruism]. AB - The Newspeak propitiates a change of the sense of the words and next to the double thinking forms the picture of totalitarianism described by Orwell in 1984. The purpose of the Newspeak is to make all other forms of thought impossible. In bioethics the Newspeak is applied, not because Bioethics is a new science but by the manipulative intention. The twentieth-century political language has, according to Orwell, the intention to remove the "mental image " of what really happens. This is clear in the terms "surrogacy ". On the one hand, the mother is deprived of her child. On the other, there is no legal subrogation. As has been said the technique reduces a woman to the condition of a vessel. The excuse of gratuity does not change the exploitative relationship, since gratuitousness in the provision of women is not the altruism of all those involved in surrogacy. PMID- 28621963 TI - [Taking Altruistic Surrogacy Seriously]. AB - Since two years ago Spanish public opinion is living an intense debate on the ethical and legal aspects about surrogacy. There is a shared concern about the risks of exploitation for women related to commercial surrogacy. To get rid of them, and make possible at the same time that people who is not able to gestate could become father/mother, it has been proposed to regulate altruistic surrogacy. In order to defend this proposal it is said that there is an analogy between altruistic organ donation and altruistic surrogacy: you can help a person in need giving an organ or your ability to gestate. In this paper I confront both considerations. First, there is not a real analogy between organ donation and altruistic surrogacy. And second, if we think seriously a possible regulation for altruistic surrogacy we will find many problems with difficult or impossible solutions. PMID- 28621964 TI - [The Best Interest of the Child in the Case of Surrogate Maternity]. AB - This article claims to analyze the situation of children born by means of surrogate maternity contract since these babies are one of the most vulnerable parts of this agreement, so their rights and interests could be affected in many ways. In order to study that situation, in the first place, has been accomplished a brief analysis of the concept of the best interest of the child. Afterwards it is examined the possible violation of the best interest of the child in the cases that have already been examined by Doctrine and Jurisprudence, that is, first the case of registration of these children in the country of origin Civil Registry of the intentional parents, and, in second place, the case of maternity benefit for intentional mothers. The article concludes with a reflection about other situations in where the best interest of children can be affected , such as their right to know their biological origins or the cases of identity problems. PMID- 28621965 TI - [Ethical Dilemas in Pediatrics]. PMID- 28621967 TI - Mott Transition in a Metallic Liquid: Gutzwiller Molecular Dynamics Simulations. AB - We present a formulation of quantum molecular dynamics that includes electron correlation effects via the Gutzwiller method. Our new scheme enables the study of the dynamical behavior of atoms and molecules with strong electron interactions. The Gutzwiller approach goes beyond the conventional mean-field treatment of the intra-atomic electron repulsion and captures crucial correlation effects such as band narrowing and electron localization. We use Gutzwiller quantum molecular dynamics to investigate the Mott transition in the liquid phase of a single-band metal and uncover intriguing structural and transport properties of the atoms. PMID- 28621968 TI - Direct Lattice Shaking of Bose Condensates: Finite Momentum Superfluids. AB - We address band engineering in the presence of periodic driving by numerically shaking a lattice containing a bosonic condensate. By not restricting to simplified band structure models we are able to address arbitrary values of the shaking frequency, amplitude, and interaction strengths g. For "near-resonant" shaking frequencies with moderate g, a quantum phase transition to a finite momentum superfluid is obtained with Kibble-Zurek scaling and quantitative agreement with experiment. We use this successful calibration as a platform to support a more general investigation of the interplay between (one particle) Floquet theory and the effects associated with arbitrary g. Band crossings lead to superfluid destabilization, but where this occurs depends on g in a complicated fashion. PMID- 28621969 TI - Statistics of Fractionalized Excitations through Threshold Spectroscopy. AB - We show that neutral anyonic excitations have a signature in spectroscopic measurements of materials: The low-energy onset of spectral functions near the threshold follows universal power laws with an exponent that depends only on the statistics of the anyons. This provides a route, using experimental techniques such as neutron scattering and tunneling spectroscopy, for detecting anyonic statistics in topologically ordered states such as gapped quantum spin liquids and hypothesized fractional Chern insulators. Our calculations also explain some recent theoretical results in spin systems. PMID- 28621971 TI - Universality of the Turbulent Velocity Profile. AB - For nearly a century, the universal logarithmic law of the mean velocity profile has been a mainstay of turbulent fluid mechanics and its teaching. Yet many experiments and numerical simulations are not fit exceedingly well by it, and the question whether the logarithmic law is indeed universal keeps turning up in discussion and in writing. Large experiments have been set up in various parts of the world to confirm or deny the logarithmic law and accurately estimate von Karman's constant, the coefficient that governs it. Here, we show that the discrepancy among flows in different (circular or plane) geometries can be ascribed to the effect of the pressure gradient. When this effect is accounted for in the form of a higher-order perturbation, universal agreement emerges beyond doubt and a satisfactorily simple formulation is established. PMID- 28621966 TI - Rosenbluth Separation of the pi^{0} Electroproduction Cross Section Off the Neutron. AB - We report the first longitudinal-transverse separation of the deeply virtual exclusive pi^{0} electroproduction cross section off the neutron and coherent deuteron. The corresponding four structure functions dsigma_{L}/dt, dsigma_{T}/dt, dsigma_{LT}/dt, and dsigma_{TT}/dt are extracted as a function of the momentum transfer to the recoil system at Q^{2}=1.75 GeV^{2} and x_{B}=0.36. The ed->edpi^{0} cross sections are found compatible with the small values expected from theoretical models. The en->enpi^{0} cross sections show a dominance from the response to transversely polarized photons, and are in good agreement with calculations based on the transversity generalized parton distributions of the nucleon. By combining these results with previous measurements of pi^{0} electroproduction off the proton, we present a flavor decomposition of the u and d quark contributions to the cross section. PMID- 28621970 TI - Anomalies in the Charge Yields of Fission Fragments from the ^{238}U(n,f) Reaction. AB - Fast-neutron-induced fission of ^{238}U at an energy just above the fission threshold is studied with a novel technique which involves the coupling of a high efficiency gamma-ray spectrometer (MINIBALL) to an inverse-kinematics neutron source (LICORNE) to extract charge yields of fission fragments via gamma-gamma coincidence spectroscopy. Experimental data and fission models are compared and found to be in reasonable agreement for many nuclei; however, significant discrepancies of up to 600% are observed, particularly for isotopes of Sn and Mo. This indicates that these models significantly overestimate the standard 1 fission mode and suggests that spherical shell effects in the nascent fission fragments are less important for low-energy fast-neutron-induced fission than for thermal neutron-induced fission. This has consequences for understanding and modeling the fission process, for experimental nuclear structure studies of the most neutron-rich nuclei, for future energy applications (e.g., Generation IV reactors which use fast-neutron spectra), and for the reactor antineutrino anomaly. PMID- 28621972 TI - Warm Dense Matter Demonstrating Non-Drude Conductivity from Observations of Nonlinear Plasmon Damping. AB - We present simulations using finite-temperature density-functional-theory molecular dynamics to calculate the dynamic electrical conductivity in warm dense aluminum. The comparison between exchange-correlation functionals in the Perdew Burke-Enzerhof and Heyd-Scuseria-Enzerhof (HSE) approximation indicates evident differences in the density of states and the dc conductivity. The HSE calculations show excellent agreement with experimental Linac Coherent Light Source x-ray plasmon scattering spectra revealing plasmon damping below the widely used random phase approximation. These findings demonstrate non-Drude-like behavior of the dynamic conductivity that needs to be taken into account to determine the optical properties of warm dense matter. PMID- 28621974 TI - Continuous Matrix Product States for Quantum Fields: An Energy Minimization Algorithm. AB - The generalization of matrix product states (MPS) to continuous systems, as proposed in the breakthrough Letter of Verstraete and Cirac [Phys. Rev. Lett. 104, 190405 (2010).PRLTAO0031-900710.1103/PhysRevLett.104.190405], provides a powerful variational ansatz for the ground state of strongly interacting quantum field theories in one spatial dimension. A continuous MPS (cMPS) approximation to the ground state can be obtained by simulating a Euclidean time evolution. In this Letter we propose a cMPS optimization algorithm based instead on energy minimization by gradient methods and demonstrate its performance by applying it to the Lieb-Liniger model (an integrable model of an interacting bosonic field) directly in the thermodynamic limit. We observe a very significant computational speed-up, of more than 2 orders of magnitude, with respect to simulating a Euclidean time evolution. As a result, a much larger cMPS bond dimension D can be reached (e.g., D=256 with moderate computational resources), thus helping unlock the full potential of the cMPS representation for ground state studies. PMID- 28621975 TI - Gas Marbles: Much Stronger than Liquid Marbles. AB - Enwrapping liquid droplets with hydrophobic particles allows the manufacture of so-called "liquid marbles" [Aussillous and Quere Nature (London) 411, 924 (2001); NATUAS0028-083610.1038/35082026Mahadevan Nature (London)411, 895 (2001)NATUAS0028 083610.1038/35082164]. The recent intensive research devoted to liquid marbles is justified by their very unusual physical and chemical properties and by their potential for various applications, from microreactors to water storage, including water pollution sensors [Bormashenko Curr. Opin. Colloid Interface Sci. 16, 266 (2011)COCSFL1359-029410.1016/j.cocis.2010.12.002]. Here we demonstrate that this concept can be successfully applied for encapsulating and protecting small gas pockets within an air environment. Similarly to their liquid counterparts, those new soft-matter objects, that we call "gas marbles," can sustain external forces. We show that gas marbles are surprisingly tenfold stronger than liquid marbles and, more importantly, they can sustain both positive and negative pressure differences. This magnified strength is shown to originate from the strong cohesive nature of the shell. Those interesting properties could be exploited for imprisoning valuable or polluted gases or for designing new aerated materials. PMID- 28621976 TI - Dark Vibronic Polaritons and the Spectroscopy of Organic Microcavities. AB - Organic microcavities are photonic nanostructures that strongly confine the electromagnetic field, allowing exotic quantum regimes of light-matter interaction with disordered organic semiconductors. The unambiguous interpretation of the spectra of organic microcavities has been a long-standing challenge due to several competing effects involving electrons, vibrations, and cavity photons. Here we present a theoretical framework that is able to describe the main spectroscopic features of organic microcavities consistently. We introduce a class of light-matter excitations called dark vibronic polaritons, which strongly emit but only weakly absorb light in the same frequency region of the bare electronic transition. A successful comparison with experimental data demonstrates the applicability of our theory. The proposed microscopic understanding of organic microcavities paves the way for the development of optoelectronic devices enhanced by quantum optics. PMID- 28621977 TI - Photostrictive Two-Dimensional Materials in the Monochalcogenide Family. AB - Photostriction is predicted for group-IV monochalcogenide monolayers, two dimensional ferroelectrics with rectangular unit cells (the lattice vector a_{1} is larger than a_{2}) and an intrinsic dipole moment parallel to a_{1}. Photostriction is found to be related to the structural change induced by a screened electric polarization (i.e., a converse piezoelectric effect) in photoexcited electronic states with either p_{x} or p_{y} (in-plane) orbital symmetry that leads to a compression of a_{1} and a comparatively smaller increase of a_{2} for a reduced unit cell area. The structural change documented here is 10 times larger than that observed in BiFeO_{3}, making monochalcogenide monolayers an ultimate platform for this effect. This structural modification should be observable under experimentally feasible densities of photexcited carriers on samples that have been grown already, having a potential usefulness for light-induced, remote mechano-optoelectronic applications. PMID- 28621978 TI - Self-Similar Nanocavity Design with Ultrasmall Mode Volume for Single-Photon Nonlinearities. AB - We propose a photonic crystal nanocavity design with self-similar electromagnetic boundary conditions, achieving ultrasmall mode volume (V_{eff}). The electric energy density of a cavity mode can be maximized in the air or dielectric region, depending on the choice of boundary conditions. We illustrate the design concept with a silicon-air one-dimensional photon crystal cavity that reaches an ultrasmall mode volume of V_{eff}~7.01*10^{-5}lambda^{3} at lambda~1550 nm. We show that the extreme light concentration in our design can enable ultrastrong Kerr nonlinearities, even at the single-photon level. These features open new directions in cavity quantum electrodynamics, spectroscopy, and quantum nonlinear optics. PMID- 28621979 TI - Model of Cell Crawling Controlled by Mechanosensitive Adhesion. AB - We study the motility of model cells and biomimetic soft objects crawling over a substrate covered with adhesive linkers. The cell exerts traction forces on the substrate through the active periodic motion of molecular complexes to which the linkers bind and unbind stochastically. We first show that the diffusion coefficient of a force dipole (unable by symmetry to perform directed motion) is maximal for a finite ratio of the unbinding to binding rates, highlighting the role of adhesion kinetics on cell translocation. We next show that cells exerting more complex traction force distributions may exhibit directed motion only if the linkers are mechanosensitive, i.e., if the bonds' lifetime decreases (slip bonds) or increases (catch bonds) under stress. The average migration speed is higher in the catch-bond regime but so are the fluctuations, yielding a biased diffusive motion characterized by a Peclet number smaller than in the slip-bond regime. PMID- 28621980 TI - Converting Quasiclassical States into Arbitrary Fock State Superpositions in a Superconducting Circuit. AB - We propose and experimentally demonstrate a new method to generate arbitrary Fock state superpositions in a superconducting quantum circuit, where a qubit is dispersively coupled to a microwave cavity mode. Here, the qubit is used to conditionally modulate the probability amplitudes of the Fock state components of a coherent state to those of the desired superposition state, instead of pumping photons one by one into the cavity as in previous schemes. Our method does not require the adjustment of the qubit frequency during the cavity state preparation and is more robust to noise and accumulation of experimental errors compared to previous ones. Using the method, we experimentally generate phase eigenstates under various Hilbert-space dimensions and squeezed states, which are useful for the quantum walk and high-precision measurement. PMID- 28621981 TI - Adatom Extraction from Pristine Metal Terraces by Dissociative Oxygen Adsorption: Combined STM and Density Functional Theory Investigation of O/Ag(110). AB - The reconstruction and modification of metal surfaces upon O_{2} adsorption plays an important role in oxidation processes and in gauging their catalytic activity. Here, we show by employing scanning tunneling microscopy and the ab initio density functional theory that Ag atoms are extracted from pristine (110) terraces upon O_{2} dissociation, resulting in vacancies and in Ag-O complexes. The substrate roughening generates undercoordinated atoms and opens pathways to the Ag subsurface layer. With increasing O coverage, multiple vacancies give rise to remarkable structures. The mechanism is expected to be very general depending on the delicate interplay of energy and entropy, so that it may be active for other materials at different temperatures. PMID- 28621982 TI - Quantum Nonlinear Optics with a Germanium-Vacancy Color Center in a Nanoscale Diamond Waveguide. AB - We demonstrate a quantum nanophotonics platform based on germanium-vacancy (GeV) color centers in fiber-coupled diamond nanophotonic waveguides. We show that GeV optical transitions have a high quantum efficiency and are nearly lifetime broadened in such nanophotonic structures. These properties yield an efficient interface between waveguide photons and a single GeV center without the use of a cavity or slow-light waveguide. As a result, a single GeV center reduces waveguide transmission by 18+/-1% on resonance in a single pass. We use a nanophotonic interferometer to perform homodyne detection of GeV resonance fluorescence. By probing the photon statistics of the output field, we demonstrate that the GeV-waveguide system is nonlinear at the single-photon level. PMID- 28621984 TI - Lattice Effects on Nematic Quantum Criticality in Metals. AB - Theoretically, it is commonly held that in metals near a nematic quantum critical point the electronic excitations become incoherent on the entire "hot" Fermi surface, triggering non-Fermi-liquid behavior. However, such conclusions are based on electron-only theories, ignoring a symmetry-allowed coupling between the electronic nematic variable and a suitable crystalline lattice strain. Here, we show that including this coupling leads to entirely different conclusions because the critical fluctuations are mostly cut off by the noncritical lattice shear modes. At sufficiently low temperatures the thermodynamics remain Fermi-liquid type, while, depending on the Fermi surface geometry, either the entire Fermi surface stays cold, or at most there are hot spots. In particular, our predictions are relevant for the iron-based superconductors. PMID- 28621983 TI - Test of Special Relativity Using a Fiber Network of Optical Clocks. AB - Phase compensated optical fiber links enable high accuracy atomic clocks separated by thousands of kilometers to be compared with unprecedented statistical resolution. By searching for a daily variation of the frequency difference between four strontium optical lattice clocks in different locations throughout Europe connected by such links, we improve upon previous tests of time dilation predicted by special relativity. We obtain a constraint on the Robertson Mansouri-Sexl parameter |alpha|?1.1*10^{-8}, quantifying a violation of time dilation, thus improving by a factor of around 2 the best known constraint obtained with Ives-Stilwell type experiments, and by 2 orders of magnitude the best constraint obtained by comparing atomic clocks. This work is the first of a new generation of tests of fundamental physics using optical clocks and fiber links. As clocks improve, and as fiber links are routinely operated, we expect that the tests initiated in this Letter will improve by orders of magnitude in the near future. PMID- 28621985 TI - Quantum Secure Direct Communication with Quantum Memory. AB - Quantum communication provides an absolute security advantage, and it has been widely developed over the past 30 years. As an important branch of quantum communication, quantum secure direct communication (QSDC) promotes high security and instantaneousness in communication through directly transmitting messages over a quantum channel. The full implementation of a quantum protocol always requires the ability to control the transfer of a message effectively in the time domain; thus, it is essential to combine QSDC with quantum memory to accomplish the communication task. In this Letter, we report the experimental demonstration of QSDC with state-of-the-art atomic quantum memory for the first time in principle. We use the polarization degrees of freedom of photons as the information carrier, and the fidelity of entanglement decoding is verified as approximately 90%. Our work completes a fundamental step toward practical QSDC and demonstrates a potential application for long-distance quantum communication in a quantum network. PMID- 28621986 TI - Wigner Entropy Production Rate. AB - The characterization of irreversibility in general quantum processes is an open problem of increasing technological relevance. Yet, the tools currently available to this aim are mostly limited to the assessment of dynamics induced by equilibrium environments, a situation that often does not match the reality of experiments at the microscopic and mesoscopic scale. We propose a theory of irreversible entropy production that is suited for quantum systems exposed to general, nonequilibrium reservoirs. We illustrate our framework by addressing a set of physically relevant situations that clarify both the features and the potential of our proposal. PMID- 28621987 TI - Photoassociation of Trilobite Rydberg Molecules via Resonant Spin-Orbit Coupling. AB - We report on a novel method for the photoassociation of strongly polar trilobite Rydberg molecules. This exotic ultralong-range dimer, consisting of a ground state atom bound to the Rydberg electron via electron-neutral scattering, inherits its polar character from the admixture of high-angular-momentum electronic orbitals. The absence of low-L character hinders standard photoassociation techniques. Here, we show that for suitable principal quantum numbers the resonant coupling of the orbital motion with the nuclear spin of the perturber, mediated by electron-neutral scattering, hybridizes the trilobite molecular potential with the more conventional S-type molecular state. This provides a general path to associate trilobite molecules with large electric dipole moments, as demonstrated via high-resolution spectroscopy. We find a dipole moment of 135(45) D for the trilobite state. Our results are compared to theoretical predictions based on a Fermi model. PMID- 28621988 TI - Relaxation Decoupling in Metallic Glasses at Low Temperatures. AB - Upon cooling, glass-forming liquids experience a dynamic decoupling in the fast beta and slow alpha process, which has greatly influenced glass physics. By exploring an extremely wide temporal and temperature range, we find a surprising gradual change of the relaxation profile from a single-step to a two-step decay upon cooling in various metallic glasses. This behavior implies a decoupling of the relaxation in two different processes in a glass state: a faster one likely related to the anomalous stress-dominated microscopic dynamics, and a slower one associated with subdiffusive motion at larger scales with a broader distribution of relaxation times. PMID- 28621990 TI - Global Phase Diagram of a Three-Dimensional Dirty Topological Superconductor. AB - We investigate the phase diagram of a three-dimensional, time-reversal symmetric topological superconductor in the presence of charge impurities and random s-wave pairing. Combining complimentary field theoretic and numerical methods, we show that the quantum phase transition between two topologically distinct paired states (or thermal insulators), described by thermal Dirac semimetal, remains unaffected in the presence of sufficiently weak generic randomness. At stronger disorder, however, these two phases are separated by an intervening thermal metallic phase of diffusive Majorana fermions. We show that across the insulator insulator and metal-insulator transitions, normalized thermal conductance displays single parameter scaling, allowing us to numerically extract the critical exponents across them. The pertinence of our study in strong spin-orbit coupled, three-dimensional doped narrow gap semiconductors, such as Cu_{x}Bi_{2}Se_{3}, is discussed. PMID- 28621991 TI - New Approaches to Coding Information using Inverse Scattering Transform. AB - Remarkable mathematical properties of the integrable nonlinear Schrodinger equation (NLSE) can offer advanced solutions for the mitigation of nonlinear signal distortions in optical fiber links. Fundamental optical soliton, continuous, and discrete eigenvalues of the nonlinear spectrum have already been considered for the transmission of information in fiber-optic channels. Here, we propose to apply signal modulation to the kernel of the Gelfand-Levitan-Marchenko equations that offers the advantage of a relatively simple decoder design. First, we describe an approach based on exploiting the general N-soliton solution of the NLSE for simultaneous coding of N symbols involving 4*N coding parameters. As a specific elegant subclass of the general schemes, we introduce a soliton orthogonal frequency division multiplexing (SOFDM) method. This method is based on the choice of identical imaginary parts of the N-soliton solution eigenvalues, corresponding to equidistant soliton frequencies, making it similar to the conventional OFDM scheme, thus, allowing for the use of the efficient fast Fourier transform algorithm to recover the data. Then, we demonstrate how to use this new approach to control signal parameters in the case of the continuous spectrum. PMID- 28621992 TI - Chaotic Model for Levy Walks in Swarming Bacteria. AB - We describe a new mechanism for Levy walks, explaining the recently observed superdiffusion of swarming bacteria. The model hinges on several key physical properties of bacteria, such as an elongated cell shape, self-propulsion, and a collectively generated regular vortexlike flow. In particular, chaos and Levy walking are a consequence of group dynamics. The model explains how cells can fine-tune the geometric properties of their trajectories. Experiments confirm the spectrum of these patterns in fluorescently labeled swarming Bacillus subtilis. PMID- 28621994 TI - Nonmaximal theta_{23} Mixing at NOvA from Neutrino Decoherence. AB - In a study of a muon-neutrino disappearance at 810 km, the NOvA experiment finds flavor mixing of the atmospheric sector to deviate from maximal (sin^{2}theta_{23}=0.5) by 2.6sigma. The result is in tension with the 295-km baseline measurements of T2K, which are consistent with maximal mixing. We propose that theta_{23} is in fact maximal, and that the disagreement is a harbinger of environmentally induced decoherence. The departure from maximal mixing can be accounted for by an energy-independent decoherence of strength Gamma=(2.3+/-1.1)*10^{-23} GeV. PMID- 28621993 TI - Dark Matter Search in a Proton Beam Dump with MiniBooNE. AB - The MiniBooNE-DM Collaboration searched for vector-boson mediated production of dark matter using the Fermilab 8-GeV Booster proton beam in a dedicated run with 1.86*10^{20} protons delivered to a steel beam dump. The MiniBooNE detector, 490 m downstream, is sensitive to dark matter via elastic scattering with nucleons in the detector mineral oil. Analysis methods developed for previous MiniBooNE scattering results were employed, and several constraining data sets were simultaneously analyzed to minimize systematic errors from neutrino flux and interaction rates. No excess of events over background was observed, leading to a 90% confidence limit on the dark matter cross section parameter, Y=epsilon^{2}alpha_{D}(m_{chi}/m_{V})^{4}?10^{-8}, for alpha_{D}=0.5 and for dark matter masses of 0.01 .05). Linear regression analyses with stepwise model selection demonstrated that anterior cranial base, mandibular plane angle, and upper incisor inclination commonly have a significant effect on frontal sinus size. CONCLUSION: The frontal sinus size could be used as an indicator of harmonious anterior occlusion. There were no differences among the subgroups of each skeletal malocclusion. The anterior cranial base, facial height, and maxillary incisor inclination appear to have a significant effect on frontal sinus size. PMID- 28622000 TI - Observation of psi(3686)->e^{+}e^{-}chi_{cJ} and chi_{cJ}->e^{+}e^{-}J/psi. AB - Using 4.479*10^{8} psi(3686) events collected with the BESIII detector, we search for the decays psi(3686)->e^{+}e^{-}chi_{cJ} and chi_{cJ}->e^{+}e^{ }J/psi, where J=0, 1, 2. The decays psi(3686)->e^{+}e^{-}chi_{cJ} and chi_{cJ} >e^{+}e^{-}J/psi are observed for the first time. The measured branching fractions are B(psi(3686)->e^{+}e^{-}chi_{cJ})=(11.7+/-2.5+/-1.0)*10^{-4}, (8.6+/ 0.3+/-0.6)*10^{-4}, (6.9+/-0.5+/-0.6)*10^{-4} for J=0, 1, 2, and B(chi_{cJ} >e^{+}e^{-}J/psi)=(1.51+/-0.30+/-0.13)*10^{-4}, (3.73+/-0.09+/-0.25)*10^{-3}, (2.48+/-0.08+/-0.16)*10^{-3} for J=0, 1, 2, respectively. The ratios of the branching fractions B(psi(3686)->e^{+}e^{-}chi_{cJ})/B(psi(3686)->gammachi_{cJ}) and B(chi_{cJ}->e^{+}e^{-}J/psi)/B(chi_{cJ}->gammaJ/psi) are also reported. Also, the alpha values of helicity angular distributions of the e^{+}e^{-} pair are determined for psi(3686)->e^{+}e^{-}chi_{c1,2} and chi_{c1,2}->e^{+}e^{-}J/psi. PMID- 28622015 TI - The first whole genome sequence and pathogenicity characterization of a fowl adenovirus 4 isolated from ducks associated with inclusion body hepatitis and hydropericardium syndrome. AB - In June 2015, an infectious disease with high prevalence causing severe hydropericardium syndrome (HPS) first appeared in duck farms of northeast China. The disease showed high morbidity of 35% and mortality of 15% in a commercial duck farm with 200,000 45-day-old ducks. One strain of hypervirulent fowl adenovirus serotype 4 was identified and designated as HLJDAd15. The whole genome of the duck isolate was sequenced and found to contain the same large deletions as a genotype that has become prevalent in chickens in China recently, indicating that this disease might be transmitted from chickens to ducks. The pathogenicity of HLJDAd15 was evaluated in SPF chickens and ducks. The results showed that chickens were more susceptible to this new genotype of fowl adenovirus, and it was more difficult to infect ducks than chickens with the duck origin virus. Thus, it appears that this severe HPS in ducks is far more likely to have been transmitted from chickens to ducks than from ducks to ducks. Therefore, transmission from chickens to ducks constitutes a threat to the duck farming industry, and this transmission route is a very important consideration for the prevention and control of the new genotype of fowl adenovirus. This is the first whole genome sequence of a FAdV-4 isolated from ducks, and this information is important for understanding the molecular characteristics and evolution of aviadenoviruses. The potential risks of infection with this new hypervirulent FAdV-4 genotype in chickens and ducks urgently require an effective vaccine. PMID- 28622016 TI - Endoplasmic Reticulum Stress Is Involved in Nucleus Pulposus Degeneration and Attenuates Low pH-Induced Apoptosis of Rat Nucleus Pulposus Cells. AB - The microenvironment of degenerative intervertebral disk (IVD) is characteristic of a high concentration of lactic acid and low pH levels, whereas the underlying mechanism has not been clearly defined. Endoplasmic reticulum (ER) is the hub of interactions between environmental signals and cellular biological functions, the malfunction of which is closely involved in the pathogenesis of multiple disorders, including IVD degeneration (IVDD). This research mainly aims at exploring what role ER stress plays in the natural process of IVDD and pH-induced apoptosis of rat nucleus pulposus (NP) cells (NPCs). The IVD of Sprague-Dawley rats at different ages was stained by Hematoxylin-Eosin staining to visualize the histocytological changes during the nature process of IVDD. Immunohistochemical staining was performed to evaluate the expression of ER stress markers within normal and degenerated NP. The ER stress markers were also quantified by quantitative real-time-polymerase chain reaction (PCR) and Western blotting analysis, respectively. NPCs were exposed to the culturing media with acidity of pH 7.4, 7.0, 6.5, or 6.0 for 24-72 h, with or without the supplement of 4 phenylbutyrayte (4-PBA, the blocker of ER stress pathways). Changes in cell viability were evaluated by CCK-8 assay and neutral red assay, whereas apoptosis was stained by Annexin-V/PI staining and quantified by flow cytometry analysis. The acidity-induced changes in the expression of ER stress markers were studied by immunofluorescent staining, qRT-PCR, and Western blotting analysis. In vivo, the expression of GRP78 and XBP1 was downregulated whereas CHOP and Caspase12 were upregulated in natural degeneration. In vitro, low pH induced apoptosis of rat NPCs; prolonged exposure of acid reduced cell viability and caused upregulation of ER stress markers. 4-PBA was used to alleviate ER stress, and it promoted acid-induced apoptosis of NPCs. ER stress is involved in NP natural degeneration and attenuates low-pH-induced apoptosis of NPCs. PMID- 28622017 TI - "Less Is More" Approach for Management of Intrapleural Sepsis. PMID- 28622018 TI - Reply: "Less Is More" Approach for Management of Intrapleural Sepsis. PMID- 28622019 TI - Patient Perceptions of Illness Identity in Cancer Clinical Trial Decision-Making. AB - When patients are diagnosed with cancer, they begin to negotiate their illness identity in relation to their past and future selves, their relationships, and their group memberships. Thus, how patients view their cancer in relation to their other identities may affect how and why they make particular decisions about treatment options. Using the Communication Theory of Identity (CTI), the current study explores: (1) how and why illness identity is framed across identity layers in relation to one particular cancer treatment: participation in a cancer clinical trial (CT); and (2) how and why patients experience identity conflicts while making their treatment decisions. Semi-structured, in-depth interviews were analyzed for 46 cancer patients who were offered a CT. Results of a grounded theory analysis indicated that patients expressed separate identity frames (e.g., personal, relational, and communal), aligned identity frames (e.g., personal and communal), and identity conflicts (e.g., personal-personal). This study theoretically shows how and why patient illness identity relates to cancer treatment decision-making as well as how and why patients relate (and conflict) with the cancer communal identity frame. Practical implications include how healthcare providers and family members can support patient decision-making through awareness of and accommodating to identity shifts. PMID- 28622020 TI - The effect of direct and indirect force transmission on peri-implant bone stress a contact finite element analysis. AB - In almost all finite element (FE) studies in dentistry, virtual forces are applied directly to dentures. The purpose of this study was to develop a FE model with non-linear contact simulation using an antagonist as force transmitter and to compare this with a similar model that uses direct force transmission. Furthermore, five contact situations were created in order to examine their influence on the peri-implant bone stresses, which are relevant to the survival rate of implants. It was found that the peri-implant bone stresses were strongly influenced by the kind of force transmission and contact number. PMID- 28622021 TI - Source Credibility and E-Cigarette Attitudes: Implications for Tobacco Communication. AB - As there are many conflicting sources of e-cigarette information, research is needed to determine the impact of these sources on e-cigarette attitudes to inform future communication campaigns. Source credibility is important in shaping attitudes toward other health topics; however, no study has examined its role in influencing e-cigarette attitudes. Data from the 2015 Health Information National Trends Survey-FDA (HINTS-FDA) were utilized to assess differences in trust in different sources by e-cigarette user status and to investigate the associations between trust in sources and e-cigarette attitudes (n = 3,738). Differences in trust in sources were examined using weighted linear regression. Associations between trust in sources of e-cigarette health effects and attitudes toward e cigarettes were assessed using weighted logistic regression. Overall, e-cigarette ever users reported significantly lower trust in governmental agencies as compared to never users. Trust in e-cigarette companies was negatively associated with perceived addictiveness of e-cigarettes (AOR = 0.76, 95% CI = 0.58, 1.00), while trust in doctors/pharmacists/healthcare providers was negatively associated with harm perceptions of e-cigarettes relative to conventional cigarettes (AOR = 0.72, 95% CI = 0.55, 0.95). Trust in tobacco companies and trust in e-cigarette companies were negatively associated with absolute perceived harm of e-cigarettes (AOR = 0.70, 95% CI = 0.51, 0.95; AOR = 0.60, 95% CI = 0.46, 0.79, respectively). Results from this study indicate that the associations between trust in sources of e-cigarette health effects and e-cigarette attitudes differ both by source and specific attitude assessed. Ultimately, future campaigns should incorporate messaging to discredit industry sources of information and utilize non governmental sources to effectively influence e-cigarette attitudes. PMID- 28622022 TI - Comparison of Clinical and Radiological Results in the Arthroscopic Repair of Full-Thickness Rotator Cuff Tears With and Without the Anterior Attachment of the Rotator Cable. AB - BACKGROUND: The anterior rotator cable is critical in force transmission of the rotator cuff. However, few clinical studies have examined the correlation between the integrity of the anterior supraspinatus tendon and surgical outcomes in patients with rotator cuff tears. PURPOSE: To compare the clinical and structural outcomes of the arthroscopic repair of full-thickness rotator cuff tears with and without anterior disruption of the supraspinatus tendon. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: One hundred eighty-one shoulders available for magnetic resonance imaging (MRI) at least 6 months after arthroscopic rotator cuff repair, with a minimum 1-year follow-up, were enrolled. The anterior attachment of the rotator cable was disrupted in 113 shoulders (group A) and intact in 68 shoulders (group B). The mean age at the time of surgery in groups A and B was 59.6 and 59.2 years, respectively, and the mean follow-up period was 24.2 and 25.1 months, respectively. RESULTS: There were statistically significant differences in the preoperative tear size and pattern and muscle fatty degeneration between the 2 groups ( P = .004, P = .008, and P < .001, respectively). At final follow-up, the mean visual analog scale (VAS) for pain score during motion was 1.31 +/- 0.98 and 1.24 +/- 0.90 in groups A and B, respectively ( P = .587). The mean Constant score was 77.5 +/- 11.2 and 78.0 +/- 11.9 points in groups A and B, respectively ( P = .875). The mean University of California, Los Angeles score was 30.5 +/- 4.1 and 31.0 +/- 3.0 points in groups A and B, respectively ( P = .652). In assessing the repair integrity on postoperative MRI, the retear rate was 23.9% and 14.7% in groups A and B, respectively ( P = .029). CONCLUSION: Irrespective of involvement in the anterior attachment of the rotator cable, the mean 24-month follow-up demonstrated excellent pain relief and improvement in the ability to perform activities of daily living after arthroscopic rotator cuff repair. However, tears with anterior disruption of the rotator cable showed a significantly larger and more complex tear pattern and more advanced fatty degeneration. Additionally, the retear rate was significantly higher in patients with a tear involving the anterior attachment of the rotator cable. PMID- 28622023 TI - Ending as Intended: The Educational Effects of an Epilogue to a TV Show Episode about Bipolar Disorder. AB - Entertainment persuasion theory was applied to investigate how an epilogue to a dramatic episode with an educational subtext about bipolar disorder affected viewer processing and response. In an experiment, viewers (N = 89) were randomly assigned to watch the episode either with or without an epilogue. Exposure to the epilogue increased recognition of the subtext. It also increased counterarguing against the subtext, but only among viewers less involved with the episode's story. The epilogue decreased social distance for people with bipolar disorder and decreased their belief that bipolar disorder is not treatable. These findings speak to the utility of epilogues as a tool to both reinforce intended entertainment-education messages and to combat misinformation. This function is particularly useful for entertainment portrayals of stigmatized conditions, which are at greater risk of being misunderstood. To avoid viewer reactance, epilogues should be paired with highly involving narratives. PMID- 28621973 TI - GW170104: Observation of a 50-Solar-Mass Binary Black Hole Coalescence at Redshift 0.2. AB - We describe the observation of GW170104, a gravitational-wave signal produced by the coalescence of a pair of stellar-mass black holes. The signal was measured on January 4, 2017 at 10?11:58.6 UTC by the twin advanced detectors of the Laser Interferometer Gravitational-Wave Observatory during their second observing run, with a network signal-to-noise ratio of 13 and a false alarm rate less than 1 in 70 000 years. The inferred component black hole masses are 31.2_{ 6.0}^{+8.4}M_{?} and 19.4_{-5.9}^{+5.3}M_{?} (at the 90% credible level). The black hole spins are best constrained through measurement of the effective inspiral spin parameter, a mass-weighted combination of the spin components perpendicular to the orbital plane, chi_{eff}=-0.12_{-0.30}^{+0.21}. This result implies that spin configurations with both component spins positively aligned with the orbital angular momentum are disfavored. The source luminosity distance is 880_{-390}^{+450} Mpc corresponding to a redshift of z=0.18_{-0.07}^{+0.08}. We constrain the magnitude of modifications to the gravitational-wave dispersion relation and perform null tests of general relativity. Assuming that gravitons are dispersed in vacuum like massive particles, we bound the graviton mass to m_{g}<=7.7*10^{-23} eV/c^{2}. In all cases, we find that GW170104 is consistent with general relativity. PMID- 28622024 TI - Comparison of Radiation Exposure from Fixed Table Fluoroscopy to a Portable C-Arm During Ureteroscopy. AB - INTRODUCTION: Current treatment practices within the field of endourology require the routine use of radiation exposure to provide adequate imaging during urologic procedures. One such procedure requiring repeated radiation exposure during treatment is ureteroscopy. We set out to compare estimated fluoroscopic radiation exposures employing fixed table and portable C-arm fluoroscopy. MATERIALS AND METHODS: A cross-sectional dosimetry phantom model was placed supine on both fixed fluoroscopy and standard operating room tables. The models were then exposed to three separate 5-minute runs of fluoroscopic exposure. Metal oxide semiconductor field effect transistor dosimeters were utilized in organ-specific locations to determine specific radiation exposure dosages. Absorbed radiation was determined for each organ location for both fluoroscopy units. Organ dose volumetric corrections were performed for skin and red bone marrow, to correct for the nonirradiated portion. Organ dose rate (ODR, mGy/s) and effective dose rate (EDR, mSv/s) were calculated, with values reported as mean +/- standard deviation. RESULTS: There were found to be statistically significant elevations for both total EDR and organ-specific dose rates with the use of fixed table fluoroscopy compared with C-arm fluoroscopy. EDR was found to be 0.0240 +/- 0.0019 mSv/s for the fixed table unit and 0.0029 +/- 0.0005 mSv/s for the C-arm unit (p = 0.0024). Internal organs exposed to the most radiation during fixed table fluoroscopy included the gall bladder and stomach in comparison to C-arm fluoroscopy, which found elevated exposure in the kidneys, pancreas, and spleen. CONCLUSION: The routine use of fixed table fluoroscopy results in significantly elevated estimated organ doses and EDR when directly compared with C-arm fluoroscopy in model trials. This difference should be taken into consideration by practicing urologists when patient treatment requires the use of fluoroscopy to maintain radiation exposure as low as reasonably achievable. PMID- 28622026 TI - The Moderating Effects of Self-Esteem and Self-Efficacy on Responses to Graphic Health Warnings on Cigarette Packages: A Comparison of Smokers and Nonsmokers. AB - Do graphic pictorial health warnings (GPHWs) on cigarette packaging work better for some people than others? According to the Extended Parallel Process Model (EPPM), fear appeals should heighten positive change only if a person believes he or she is capable of change (i.e., self-efficacy). We exposed 242 smokers and 241 nonsmokers (aged 18-29) in the Republic of Korea to either a GPHW or a text-only warning in a between-subjects experiment. Results indicated that the GPHW increased intentions and motivations to quit smoking (for smokers) and intentions and motivations to not start smoking (for nonsmokers). However, these effects were moderated by self-efficacy related to quitting or not starting smoking. For smokers, a GPHW was especially effective in increasing desires and intentions to quit for people high in self-efficacy and high in self-esteem. However, for nonsmokers, a GPHW was effective only when self-efficacy was high, regardless of self-esteem level. For smokers and nonsmokers, results were mediated by heightened perceived health estimation. Implications for understanding the effectiveness of warning labels on cigarettes, for the introduction of GPHWs in the Republic of Korea, and for the Extended Parallel Process Model, are discussed. PMID- 28622025 TI - Comparison of Concussion Rates Between NCAA Division I and Division III Men's and Women's Ice Hockey Players. AB - BACKGROUND: Examinations related to divisional differences in the incidence of sports-related concussions (SRC) in collegiate ice hockey are limited. PURPOSE: To compare the epidemiologic patterns of concussion in National Collegiate Athletic Association (NCAA) ice hockey by sex and division. STUDY DESIGN: Descriptive epidemiology study. METHODS: A convenience sample of men's and women's ice hockey teams in Divisions I and III provided SRC data via the NCAA Injury Surveillance Program during the 2009-2010 to 2014-2015 academic years. Concussion counts, rates, and distributions were examined by factors including injury activity and position. Injury rate ratios (IRRs) and injury proportion ratios (IPRs) with 95% confidence intervals (CIs) were used to compare concussion rates and distributions, respectively. RESULTS: Overall, 415 concussions were reported for men's and women's ice hockey combined. The highest concussion rate was found in Division I men (0.83 per 1000 athlete-exposures [AEs]), followed by Division III women (0.78/1000 AEs), Division I women (0.65/1000 AEs), and Division III men (0.64/1000 AEs). However, the only significant IRR was that the concussion rate was higher in Division I men than Division III men (IRR = 1.29; 95% CI, 1.02-1.65). The proportion of concussions from checking was higher in men than women (28.5% vs 9.4%; IPR = 3.02; 95% CI, 1.63-5.59); however, this proportion was higher in Division I women than Division III women (18.4% vs 1.8%; IPR = 10.47; 95% CI, 1.37-79.75). The proportion of concussions sustained by goalkeepers was higher in women than men (14.2% vs 2.9%; IPR = 4.86; 95% CI, 2.19 10.77), with findings consistent within each division. CONCLUSION: Concussion rates did not vary by sex but differed by division among men. Checking-related concussions were less common in women than men overall but more common in Division I women than Division III women. Findings highlight the need to better understand the reasons underlying divisional differences within men's and women's ice hockey and the need to develop concussion prevention strategies specific to each athlete population. PMID- 28622027 TI - Communicating with Sensation Seekers: An fMRI Study of Neural Responses to Antidrug Public Service Announcements. AB - This study examined the neural basis of processing high- and low-message sensation value (MSV) antidrug public service announcements (PSAs) in high (HSS) and low sensation seekers (LSS) using fMRI. HSS more strongly engaged the salience network when processing PSAs (versus LSS), suggesting that high-MSV PSAs attracted their attention. HSS and LSS participants who engaged higher level cognitive processing regions reported that the PSAs were more convincing and believable and recalled the PSAs better immediately after testing. In contrast, HSS and LSS participants who strongly engaged visual attention regions for viewing PSAs reported lower personal relevance. These findings provide neurobiological evidence that high-MSV content is salient to HSS, a primary target group for antidrug messages, and additional cognitive processing is associated with higher perceived message effectiveness. PMID- 28622028 TI - Prefrontal Activation During Executive Tasks Emerges Over Early Childhood: Evidence From Functional Near Infrared Spectroscopy. AB - Functional Near Infrared Spectroscopy (fNIRS) is a brain imaging technique that is well-suited for use in young children, making it particularly useful for investigating the neural bases of the development of executive functions. In the present study, children (ages 4-10) underwent fNIRS while completing response inhibition and working memory tasks. While both tasks were associated with increases in oxyhemoglobin and decreases in deoxyhemoglobin, we found that strength of activation increased with age and with improvements in task performance. These findings support the relation between emerging executive functions and maturation of the prefrontal cortex. PMID- 28622030 TI - Age of Initiation and Internet Gaming Disorder: The Role of Self-Esteem. AB - The link between early initiation and problematic use has been observed for substance use disorders; however, this link has not been as clearly established for Internet gaming disorder (IGD). Available studies indicate that individuals who initiate Internet use at younger ages exhibit an increased risk for general Internet addiction. Prior research also suggests unique cognitive processes in online gaming, such that an individual's overall sense of self-worth can become contingent upon self-esteem derived from the gaming environment. The current research examines the mediational role of self-esteem variables in the relationship between age of initiation and IGD symptomatology. Data were analyzed from 1,044 adult participants (mean age = 30.90; standard deviation: 9.28; 35.0% female) recruited from Amazon Mechanical Turk who reported playing massively multiplayer online role-playing games. Age of gaming initiation is directly linked to IGD, as earlier age predicted overall IGD symptom severity (b = -0.10, 95% confidence interval [CI: -0.17, -0.03]), controlling for self-esteem factors. In addition, self-esteem factors emerged as mediators of the effect, where global self-esteem served as a protective factor (b = -0.05, 95% CI: [-0.07, -0.02]) and high gaming-contingent self-worth (GCSW; b = -0.10, 95% CI: [-0.15, -0.04]) was associated with more negative outcomes. Earlier age of gaming initiation is associated with IGD symptomatology. Although risks of screen time are often referred to in terms of physical consequences, the present study provides support regarding the inclusion of self-esteem factors in the link between early use and IGD. PMID- 28622031 TI - Time Spent on Social Network Sites and Psychological Well-Being: A Meta-Analysis. AB - This meta-analysis examines the relationship between time spent on social networking sites and psychological well-being factors, namely self-esteem, life satisfaction, loneliness, and depression. Sixty-one studies consisting of 67 independent samples involving 19,652 participants were identified. The mean correlation between time spent on social networking sites and psychological well being was low at r = -0.07. The correlations between time spent on social networking sites and positive indicators (self-esteem and life satisfaction) were close to 0, whereas those between time spent on social networking sites and negative indicators (depression and loneliness) were weak. The effects of publication outlet, site on which users spent time, scale of time spent, and participant age and gender were not significant. As most included studies used student samples, future research should be conducted to examine this relationship for adults. PMID- 28622033 TI - Adolescents' Perceptions of Popularity-Motivated Behaviors, Characteristics, and Relationships in Cyberspace and Cyber Aggression: The Role of Gender. AB - Research is increasingly revealing that adolescents utilize electronic technologies to promote and/or maintain their social standing among their peer group. Little is known about whether adolescents' perceptions of popularity motivated behaviors, characteristics, and relationships in cyberspace are associated with popularity-motivated cyber relational aggression. It is also unclear how gender might impact these associations, especially considering that adolescent girls and boys differ in regard to the type of behaviors, characteristics, and relationships they believe contribute to popularity. To this end, this study examined the potential moderating effect of gender on the association between adolescents' perceptions of popularity-motivated behaviors, characteristics, and relationships in cyberspace and their engagement in popularity-motivated cyber relational aggression over 1 year, from seventh to eighth grade. There were 217 eighth graders (51 percent female; M age = 12.13) from three middle schools in a large Midwestern city in the United States included in this research. They completed questionnaires on their popularity motivated behaviors, characteristics, and relationships in cyberspace and their perpetration of popularity-motivated cyber relational aggression during the seventh grade. One year later, they completed the perpetration of popularity motivated cyber relational aggression questionnaire. The results revealed that the association between popularity-motivated behaviors, characteristics, and relationships in cyberspace and the perpetration of popularity-motivated cyber relational aggression was stronger for girls, while such an association was not found for boys. These findings indicate the importance of considering cyberspace as an environment in which adolescents can enhance their social standing among peers from their school. PMID- 28622035 TI - Being Authentic on Facebook Has Same Health Benefits as In-Person Authentic Behavior. PMID- 28622034 TI - The Experiences of Newly Diagnosed Men Who Have Sex with Men Entering the HIV Care Cascade in Lima, Peru, 2015-2016: A Qualitative Analysis of Counselor Participant Text Message Exchanges. AB - Mobile phone technology (mHealth) is a promising tool that has been used to improve HIV care in high-risk populations worldwide. Understanding patient perspectives of newly diagnosed men who have sex with men (MSM) in Lima, Peru during linkage and engagement in the HIV care continuum can help close the gaps in care following initial HIV diagnosis and ensure retention in continuous care. From June 2015 to March 2016, as part of a randomized controlled trial, 40 MSM participants were linked to care with an mHealth intervention within 3 months of HIV diagnosis at Via Libre clinic. For 12 weeks, participants agreed to receive weekly predetermined, standardized short message service (SMS), WhatsApp(c), and/or Facebook(c) messages from an assigned HIV counselor. Text messaging was bi directional, meaning participants could also send messages to their counselor at any time. In this qualitative study, we coded and thematically analyzed 947 SMS, 918 WhatsApp, and 2,694 Facebook bi-directional messages. Mean age of participants was 29.8 years (20-50); with 70 percent reporting some post-high school education and 73 percent self-identifying as homosexual. We identified six recurring themes that emerged from the data: (a) mental health symptoms; (b) coping behaviors; (c) interpersonal support; (d) physical symptoms; (e) HIV knowledge; and (f) care coordination. Participants sent text messages describing depressive symptoms and seeking mental health services during this initial stage of HIV care. For newly diagnosed MSM entering the HIV care continuum, a bi directional mHealth intervention provided support to facilitate care while eliciting deeply personal mental and emotional states. Future interventions could benefit from using mHealth interventions as ancillary support for clinicians. PMID- 28622036 TI - Molecular Targeted Drugs and Treatment of Colorectal Cancer: Recent Progress and Future Perspectives. AB - Nowadays, colorectal cancer is the fourth most common type of tumor all over the world. When diagnosed, ~50%-60% of tumors have metastasized, thus resulting in a grim prognosis. Chemotherapy is regarded as standard treatment for patients with colorectal cancer, however, limitations of chemotherapy cannot be ignored, such as low selectivity, insufficient concentrations in tumor tissues, and systemic toxicity. Recently, six targeted drugs have been approved by the U.S. Food and Drug Administration (FDA) for treatment of metastatic colorectal cancer (mCRC), including bevacizumab, aflibercept, regorafenib, cetuximab, and panitumumab. The development of these drugs marked significant advancement in the field of mCRC therapy. The addition of biologic agents to chemotherapy has prolonged the median overall survival. Now, many investigational drugs are under clinical trials, of which programmed death (PD)-1/L1 has drawn much attention. In this review, new biologic agents under clinical trials such as MEK/MET/RAS/RAF/PD-1 inhibitors with potentials for mCRC treatment are concluded by describing targeted drugs approved by FDA, to offer new insights into global trends and future development. PMID- 28622037 TI - Inhibition of the AKT/mTOR Pathway Augments the Anticancer Effects of Sorafenib in Thyroid Cancer. AB - BACKGROUND: Sorafenib is a multikinase inhibitor that has been approved for the treatment of patients with advanced 131iodine (131I) refractory differentiated thyroid cancer (DTC). However, the progression-free survival of patients with advanced 131I refractory DTC is short, and most DTC patients eventually acquire resistance to sorafenib. Therefore, new therapeutic strategies need to be developed. MATERIALS AND METHODS: The thyroid cancer cell lines 8505C and FTC133 were treated with sorafenib in the presence or absence of BEZ235 or small interfering RNA (siRNA) directed against AKT. A CCK8 kit was used to evaluate cell viability. Protein expression levels of relevant genes were determined by Western blotting analysis, whereas messenger RNA expression levels were determined by real-time PCR analysis. Flow cytometry was performed to assess the number of apoptotic cells. RESULTS: The results indicate that sorafenib simultaneously inhibited the activities of the MAPK and PI3K/AKT/mTOR pathways in thyroid cancer cells. Treatment of 8505C and FTC133 cells with NVP-BEZ235, siRNA against AKT, or sorafenib induced tumor cell apoptosis and led to reduced tumor cell proliferation. Sorafenib in combination with PI3K/AKT/mTOR inhibition by NVP BEZ235 or AKT siRNA enhanced apoptosis and proliferation suppression. CONCLUSIONS: The evidence of this study suggests that a combinatorial approach that inhibits both the MAPK and PI3K/AKT/mTOR pathways exerts a greater antitumor effect than sorafenib alone in thyroid cancer cell lines. PMID- 28622038 TI - See Something, Say Something: Correction of Global Health Misinformation on Social Media. AB - Social media are often criticized for being a conduit for misinformation on global health issues, but may also serve as a corrective to false information. To investigate this possibility, an experiment was conducted exposing users to a simulated Facebook News Feed featuring misinformation and different correction mechanisms (one in which news stories featuring correct information were produced by an algorithm and another where the corrective news stories were posted by other Facebook users) about the Zika virus, a current global health threat. Results show that algorithmic and social corrections are equally effective in limiting misperceptions, and correction occurs for both high and low conspiracy belief individuals. Recommendations for social media campaigns to correct global health misinformation, including encouraging users to refute false or misleading health information, and providing them appropriate sources to accompany their refutation, are discussed. PMID- 28622039 TI - Determinants for craniofacial pains in children 6-8 years of age: the PANIC study. AB - OBJECTIVE: Determinants for orofacial pain, headache, morning headache and painful signs of temporomandibular disorders (TMD) were investigated in prepubertal children. MATERIAL AND METHODS: The participants were a population sample of 439 children aged 6-8 years. Craniofacial pains, eating meals and snacks, sleep bruxism, sleep quality, sleep-disordered breathing (SDB), psychological well-being, parental education and household income were assessed by questionnaires filled out by the parents. Sleep duration was assessed using a combined heart rate and movement sensor and clinical signs of TMD and dental occlusion by a dentist. The determinants of pain conditions were analyzed using logistic regression. RESULTS: Of all 439 children, 26% had experienced orofacial pain and 31% headache during the past 3 months, 17% had suffered morning headache weekly and 13% had painful signs of TMD in a clinical examination. Restless sleep was associated with increased risk of orofacial pain, the painful signs of TMD and restless sleep with increased risk of headache and restless sleep, sleep bruxism and skipping meals with increased risk of morning headache after adjustment for other independent determinants of these pain conditions. Headache was associated with increased risk for painful signs of TMD. CONCLUSIONS: Craniofacial pains are common among prepubertal children. Prepubertal children with sleep bruxism, restless sleep and skipping meals have increased likelihood of craniofacial pains. PMID- 28621989 TI - Azimuthally Differential Pion Femtoscopy in Pb-Pb Collisions at sqrt[s_{NN}]=2.76 TeV. AB - We present the first azimuthally differential measurements of the pion source size relative to the second harmonic event plane in Pb-Pb collisions at a center of-mass energy per nucleon-nucleon pair of sqrt[s_{NN}]=2.76 TeV. The measurements have been performed in the centrality range 0%-50% and for pion pair transverse momenta 0.2 0.05) were observed between the two groups concerning the expression of the studied endometrial cancer risk factor genes, or with regard to the clinical aspects evaluated. CONCLUSION: The study found no evidence that symptomatic endometrial polyps have a similar phenotype to type 1 endometrial cancer; further studies are needed in order to establish whether endometrial polyps are in fact true cancer precursors, or simply raise cancer incidence due to a detection bias. PMID- 28622041 TI - The effects of low-level laser therapy on the healing of bone defects in streptozotocin-induced diabetic rats: A histological and morphometric evaluation. AB - BACKGROUND: The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) on the healing of bone defects in rats with streptozotocin (STZ)-induced DM. METHODS: 28 male Sprague-Dawley rats were used in this study. 14 animals received a single dose of STZ intraperitoneally (65 mg/kg) to induce Type I DM, whereas others were injected only with sterile saline solution. Four weeks later, standard bone defects were created in the tibiae of rats. Surgical wounds in one group from each of the diabetic and non-diabetic animals were irradiated with diode laser for every other day for 4 weeks and they were described as DM + LLLT and CONT + LLLT groups, respectively. Remaining two groups received no laser treatment. New bone formation, osteoblast and blood vessel counts were calculated in histologic sections. RESULTS: DM group had significantly smaller bone area and lower blood vessel count when compared to DM + LLLT, CONT and CONT + LLLT groups (p < 0.05 for each). CONT and CONT + LLLT groups had significantly larger bone area than DM + LLLT group (p < 0.05 for both). CONCLUSIONS: LLLT application promoted vascularization and new bone formation in animals with DM to a limited extent, since it was unable to support the healing process up to the level of non-diabetic animals. PMID- 28622042 TI - The Relationship between the 24-hour Fluctuations in Schlemm's Canal and Intraocular Pressure: An Observational Study using High-Frequency Ultrasound Biomicroscopy. AB - PURPOSE: To assess 24-hour fluctuations in Schlemm's canal (SC) parameters (cross sectional area, perimeter) and intraocular pressure (IOP) and the relationship between these fluctuations in healthy individuals. METHODS: SC and IOP were examined in 29 participants at 2:30, 5:30, 11:30, 17:30, and 23:30 within one day. The superior, inferior, nasal, and temporal SC quadrants were evaluated using 80-MHz ultrasound biomicroscopy. RESULTS: SC parameters and IOP fluctuated significantly within 24 hours (all P < 0.05). After age, gender, axial length, and central corneal thickness were adjusted, compared with the baseline (23:30) value, the change in SC cross-sectional area was negatively associated with the change in IOP at 2:30, 5:30, 11:30, and 17:30 (beta = -0.072[-0.094, -0.049], 0.070[-0.102, -0.038], -0.046[-0.079, -0.013], and -0.033[-0.062, -0.004], respectively; P < 0.001, < 0.001, = 0.009, and = 0.028, respectively). The nasal (175.6 +/- 36.0 pixels) and inferior (174.8 +/- 36.0 pixels) SC cross-sectional areas were significantly larger than the superior area (156.2 +/- 27.1 pixels) (P = 0.018 and 0.048, respectively) at 23:30. The observable SC proportion did not change among the quadrants or measurement time points (all P > 0.05). CONCLUSIONS: SC cross-sectional area fluctuated throughout the day and was negatively associated with changes in IOP. PMID- 28622043 TI - Anterior Segment Injury by a High-Power Handheld Blue Laser Device. AB - PURPOSE: To report a case of severe anterior segment inflammation secondary to exposure to a high-power blue laser device. METHODS: Case report. RESULTS: A 14 year-old male presented with redness, pain and decreased vision in his left eye after exposure to blue laser. Examination indicated severe conjunctival injection associated with 4+ cells in the anterior chamber with fibrinous reaction. The posterior pole was normal. CONCLUSION: Blue laser devices are easily available through the Internet. These devices can cause devastating ocular injuries. National safety guidelines are required to regulate use. PMID- 28622044 TI - Effects of Notch signalling pathway on the relationship between vascular endothelial dysfunction and endothelial stromal transformation in atherosclerosis. AB - At present, with the improvement of living standards and population aging, the incidence of cardiovascular and cerebrovascular disease is on the rise and has been a serious threat to human health. Statistics show that the current death caused by cardiovascular and cerebrovascular disease has become the first cause of death has been increasing year by year. Therefore, studies on coronary heart disease and atherosclerosis (AS) have become a hot topic in clinical and basic research. In this study, the question of the effect of Notch signalling pathway on the relationship between endothelial dysfunction and endothelial stromal transformation in AS was studied in depth. Based on our results, we drew conclusions as follows. First, the Notch signalling pathway was activated in the atherosclerotic model; secondly, the Notch signalling pathway was demonstrated to enhance AS by promoting vascular endothelial dysfunction; thirdly, it was demonstrated that the Notch signalling pathway was mediated by promoting endothelial and to enhance AS; finally, we confirmed the endothelial function through the Notch signalling pathway to affect the transformation of endothelial stroma to achieve synergistic AS effect. The results of this study have a good guiding significance for the important role of Notch signalling in AS and indicate the ability to influence endothelial function and endothelial stromal transformation by intervening Notch signalling pathway and can affect the relationship between them, and thus eventually achieve the treatment of AS. PMID- 28622045 TI - Age-related characteristics of outpatients with anxiety disorders: the Leiden routine outcome monitoring study. AB - OBJECTIVE: It has been hypothesised that clinically important age-related differences between adults with anxiety disorders exist; this study aims to elucidate these differences. METHODS: We analysed data from 1950 outpatients diagnosed with DSM-IV-TR anxiety disorders treated at a Dutch hospital or affiliated mental healthcare centres. Three age-groups (young- (18-25; n = 435), mid- (26-40; n = 788) and older adult (41-65; n = 727)) were compared with regard to social demographic characteristics, diagnostic characteristics, anxiety symptom profile, general psychiatric symptom profile and generic health status, in addition, linear analyses were carried out with age as a continuous variable. RESULTS: Average age was 36.48 years (SD 11.71), 62.8% were female. Significant associations with age emerged for gender, employment, education level, living situation, observed depression, agoraphobia (AP), social phobia, aches and pains, inner tension, sleep, interpersonal sensitivity, observed hostility, physical functioning, role limitations due to physical problems, vitality and bodily pain in categorical and continuous analyses. Self reported hostility was only significant in group-wise comparisons; role limitations due to emotional problems were only significant in linear analyses (all at p < .001). CONCLUSIONS: This study identified clinically relevant differences between younger and older adult outpatients with anxiety disorders. Clinicians should take these findings into account, as they may support treatment. PMID- 28622046 TI - Online Research Club: A mentoring program for undergraduate students. PMID- 28622047 TI - Repositionable and retrievable Lotus Valve System for the treatment of bicuspid aortic stenosis: is it time to treat all valves? AB - INTRODUCTION: For a long time, a bicuspid valve has been considered a contraindication to transcatheter aortic valve implantation (TAVI) due to worse procedural results. Currently available technologies are changing the scenario, with initial experiences reporting much better results with second-generation devices. Areas covered: This review will analyze the risk and potential pitfalls of TAVI on bicuspid valves and will try ascertain how the use of a new-generation fully repositionable device, the Lotus Valve System (LVS), could improve procedural and clinical results in bicuspid anatomies. Expert commentary: The LVS offers relevant potential advantages that could be helpful in bicuspid anatomies: its mechanical controlled expansion can reduce the risk of elliptical deployment; its adaptive seal may reduce final paravalvular leak and give the possibility of checking the final result before final deployment, with the opportunity of fully resheating or repositioning, which is crucial to minimize malpositioning and abolish final residual gradients. Although limited in population, preliminary data show good outcomes with LVS on bicuspid anatomies. Future studies are to be encouraged to confirm whether this device could be considered the first choice in this challenging anatomy and whether clinical outcomes, in presence of an excellent procedural result, could be ever compared to those obtained with surgery. PMID- 28622048 TI - A randomized, double-blind, parallel-group, phase III study of shortening the dosing interval of subcutaneous tocilizumab monotherapy in patients with rheumatoid arthritis and an inadequate response to subcutaneous tocilizumab every other week: Results of the 12-week double-blind period. AB - OBJECTIVE: To determine the efficacy and safety of subcutaneous tocilizumab (TCZ SC) monotherapy every week (qw) versus every other week (q2w) in patients with rheumatoid arthritis who had an inadequate response to TCZ-SC q2w. METHODS: Adult patients in Japan with inadequate response to TCZ-SC q2w were randomized to either TCZ-SC 162 mg qw monotherapy or TCZ-SC 162 mg q2w monotherapy for 12 weeks (double-blind). The primary endpoint was the change from baseline in adjusted Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) at week 12. Efficacy, safety and pharmacokinetics were assessed. RESULTS: TCZ-SC qw was superior to TCZ-SC q2w for adjusted mean change in DAS28-ESR from baseline to week 12. The difference in the change in DAS28-ESR between TCZ-SC qw and q2w was 1.21 (95%CI: -2.13, -0.30, p = .0108). A higher proportion of patients receiving TCZ-SC qw achieved DAS28-ESR remission/low disease activity than TCZ-SC q2w. Adverse events were 71.4% and 66.7% for TCZ-SC qw and q2w, respectively; infection was the most common event with one fatal case with TCZ-SC qw. CONCLUSIONS: In patients with inadequate response to TCZ-SC q2w, shortening the dosing interval to qw improved efficacy with acceptable tolerability. Occurrence of infection for both TCZ q2w and qw is important and needs careful attention. PMID- 28622049 TI - The efficacy and safety of estriol to treat vulvovaginal atrophy in postmenopausal women: a systematic literature review. AB - OBJECTIVES: To evaluate the efficacy and safety of estriol for the treatment of vulvovaginal atrophy in postmenopausal women. METHODS: A systematic literature review was performed. We searched the following electronic databases: Medline, Cochrane, Embase, Lilacs, CINHAL and Google Scholar. The studies selected included controlled clinical trials and quasi-experimental studies. Selections were made in pairs and independently, first by title and abstract and then complete texts. RESULTS: We identified 188 studies, 22 of which met the inclusion criteria; 13 were controlled clinical trials and nine were quasi-experimental, and 1217 women were included. These studies confirmed the efficacy of local estrogens to treat symptoms of vulvovaginal atrophy with few adverse effects reported. Following treatment, serum estriol levels rose, peaking at 1 h. At the 6-month follow-up, there was no increase in serum estriol in treated women. CONCLUSIONS: The available evidence (of low and moderate quality) shows that, when administered vaginally, estriol preparations appear to be safe for women who have risk factors related to systemic estrogen therapy. PMID- 28622050 TI - Serum and Aqueous Humor Levels of Fetuin-A in Pseudoexfoliation Syndrome. AB - PURPOSE: To evaluate serum and aqueous humor levels of fetuin-A in patients with pseudoexfoliation syndrome (PEXS) in comparison with those of age- and sex matched healthy subjects. MATERIALS AND METHODS: This prospective study included 25 patients with PEXS and 25 control subjects who were undergoing cataract surgery without any systemic or ocular disease. Aqueous humor and serum fetuin-A levels were measured with enzyme-linked immunosorbent assay method. RESULTS: The mean age of the PEXS group (14 males, 11 females, n = 25) was 57.7 +/- 6.9 years, and the control group (13 males, 12 females, n = 25) was 58.1 +/- 5.7 years. There was no difference between the groups in terms of age (p = 0.77) and sex (p = 0.83). The mean serum fetuin-A level of the PEXS group did not differ from that of the control group (p = 0.53). The mean aqueous humor level of the PEXS group was significantly higher than that of the control group (p = 0.032). There were no significant correlations between aqueous humor and serum fetuin-A levels among patients with PEXS and control group (p > 0.05). CONCLUSIONS: Increased levels of fetuin-A in aqueous humor of patients with PEXS may show the local effect of fetuin-A on the anterior segment. With considering the wide range of possible biological functions of fetuin-A in the pathogenesis of PEXS, further studies are needed to clarify the clinical relevance of these findings. PMID- 28622051 TI - Time-of-day variation in sustained attentional control. AB - Sustained attention is a fundamental cognitive function underlying many activities in daily life including workplace safety, but its natural variation throughout the day is incompletely characterized. To examine time-of-day variation, we collected a large online data set (N = 6,363) with participation throughout the day and around the world on the gradual-onset continuous performance task, a sensitive measure of sustained attention. This allowed us to examine accuracy, attentional stability, and strategy. Results show that both accuracy and attentional stability peak between 9:00 and 11:00 a.m. and progressively decline throughout the day, whereas strategy is more stable. PMID- 28622052 TI - Biologic treatment eligibility for real-world patients with severe asthma: The IDEAL study. AB - OBJECTIVES: Severe asthma comprises several distinct phenotypes. Consequently, patients with severe asthma can be eligible for more than one biologic treatment targeting Th2 inflammation, such as anti-interleukin (IL)-5 and anti immunoglobulin (Ig) E. The objective of this study was to describe treatment eligibility and overlap in treatment eligibility for mepolizumab (anti-IL-5), omalizumab (anti-IgE) and reslizumab (anti-IL-5) in patients with severe asthma, who were recruited from clinical practice. METHODS: This cross-sectional, single visit, observational study in six countries enrolled patients with severe asthma (defined by American Thoracic Society/European Respiratory Society guidelines). Assessable patients were analysed as a total cohort and a sub-cohort, who were not currently receiving omalizumab. Treatment eligibility was defined according to the local prescribing information or protocol-defined inclusion/exclusion criteria. Patients currently receiving omalizumab were automatically categorised as omalizumab-eligible. RESULTS: The total cohort comprised 670 patients who met the analysis criteria, of whom 20% were eligible for mepolizumab, 31-41% were eligible for omalizumab (depending on eligibility criteria used), and 5% were eligible for reslizumab. In patients not currently receiving omalizumab (n = 502), proportions eligible for each biologic were similar (mepolizumab: 20%, reslizumab 6%) or lower (omalizumab 7-21%) than those for the total cohort. Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab (n = 101), 27-37% were omalizumab-eligible and 18% were reslizumab-eligible. CONCLUSIONS: Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab. Although there was some overlap in treatment eligibility, the patient groups eligible for treatment with anti-IL 5 or anti-IgE therapies were often distinct, emphasising the different phenotypes and endotypes in severe asthma. PMID- 28622053 TI - Importance of sandy bottoms in coral reefs to the oscillation of daily rhythms in the tropical wrasse Halichoeres trimaculatus. AB - Most wrasse species swim during the day and bury themselves in the sandy bottoms of shallow reefs at night. This study aimed to evaluate the importance of sandy bottoms to the day-active/night-inactive rhythmicity of the tropical wrasse Halichoeres trimaculatus. Actogram analysis revealed that fish were active during the photophase and inactive during the scotophase in aquariums with both sandy and bare bottoms. When fish were kept in aquariums with bare bottoms, rhythmicity was maintained under constant dark conditions (DD) but became obscured under constant light conditions (LL), suggesting that a day-active/night-inactive rhythmicity is regulated by the circadian system. Robust fluctuations in Period1 (wPer1) and Period2 (wPer2) expression were observed in the pectoral fin tissue under light-dark conditions (LD). Similar fluctuations in wPer1 expression persisted under DD. When fish were kept under LD conditions for 7 days and then DD for 20 days, the emergence of fish from the sandy bottom was delayed gradually. At the same time, the peak time of wPer1 expression under DD was retarded from 06:00 to 10:00. Although wPer2 expression was dampened under DD, it increased after exposing fish to light. These results suggest that wPer1 and wPer2 are differentially involved in the day-active/night-inactive rhythmicity, and that blocking light with a sandy bed at night and exposing fish to light during emergence in the morning play important roles in maintaining consistent activities in wrasse species. PMID- 28622054 TI - Down-regulation of liver-intestine cadherin enhances noscapine-induced apoptosis in human colon cancer cells. AB - BACKGROUND: The aim of the present study was to explore the signaling pathway of noscapine which induces apoptosis by blocking liver-intestine cadherin (CDH17) gene in colon cancer SW480 cells. METHODS: Human colon cancer SW480 cells were transfected with CDH17 interference vector and treatment with 10 umol/L noscapine. The proliferation and apoptosis of SW480 cells were detected by MTT assay and AnnexinV-FITC/PI flow cytometry kit (BD), respectively. Cell invasion were assessed by transwell assays. Apoptosis related proteins (Cyt-c, Bax, Bcl-2 and Bcl-xL) levels were evaluated by western blot. RESULTS: Compared to the noscapine group, the proliferation was decreased significantly and the apoptosis was increased significantly in SW480 cells of the siCDH17+noscapine group. Cyt-c and Bax protein levels in siCDH17+noscapine group was higher than that of the noscapine group, but Bcl-2 and Bcl-xL protein levels in siCDH17+noscapine group were lower than that of the noscapine group. Moreover, up-expression of CDH17 inhibited the efficacy of noscapine-induced apoptosis in SW480 cells. CONCLUSIONS: We inferred that down-expression of extrinsic CDH17 gene can conspicuously promote apoptosis-inducing effects of noscapine on human colon cancer SW480 cells, which is a novel strategy to improve chemotherapeutic effects on colon cancer. PMID- 28622055 TI - Factors related to uncomfortable loudness levels for patients seen in a tinnitus and hyperacusis clinic. AB - OBJECTIVES: The aims were as follows: (1) to explore patterns of uncomfortable loudness levels (ULLs) across frequency and their associated factors for patients with tinnitus and hyperacusis, and (2) to re-evaluate the criteria for diagnosing hyperacusis based on ULLs and scores for the Hyperacusis Questionnaire (HQ). DESIGN: This was a retrospective cross-sectional study. STUDY SAMPLE: 573 consecutive patients for whom ULLs had been measured were included. RESULTS: A good correspondence between the diagnosis of hyperacusis based on the across frequency average ULL for the ear with the lowest ULLs (ULLmin) and hyperacusis handicap based on HQ scores was obtained with cut-off values of ULLmin <=77 dB HL and HQ score >= 22. A regression model showed significant relationships between ULLmin and the score on the HQ and age. The mean HQ score for patients with a large interaural asymmetry in ULLs was significantly higher than for the remainder. Hyperacusis handicap was associated with strong across-frequency variations in ULLs. CONCLUSIONS: Appropriate cut-off values for diagnosing hyperacusis are ULLmin <=77 dB HL and HQ score >=22. Large interaural asymmetry and large across-frequency variations in ULLs are associated with higher HQ scores. PMID- 28622056 TI - Two-Part Predictors in Regression Models. AB - Researchers often build regression models to relate a response to a set of predictor variables. In some cases, there are predictors that apply to some participants, or to some measurement occasions, but not others. For example, a romantic partner's substance use may be a key predictor of one's own substance use. However, not all participants have a partner, and in a longitudinal study, participants may have a partner during only some occasions. This could be viewed as missing data, but of a very distinctive type: the values are not just unknown but also undefined. In this paper, we present a simple method to accommodate this situation, along with a motivating example, the algebraic justification, a simulation study, and examples on how to carry out the technique. PMID- 28622057 TI - Sending messages: How faculty influence professionalism teaching and learning. AB - BACKGROUND: Ambiguity in understanding what "professionalism" means, and uncertainty in how best to teach it, remains. This study aimed to explore experiences of senior faculty in their endeavor to develop and include professionalism within a curriculum reform (CR), and illuminate challenges encountered. METHODS: Using a qualitative case study approach, data were collected from interviews with faculty who were involved in a major CR, plus archived document analysis to provide context, and aid triangulation. Data coding and analysis were inductive, using thematic analysis to generate initial coding scheme; exploring themes in the data. RESULTS: Seventeen interviews were undertaken and approximately 90 documents were reviewed. Analysis revealed: faculty may unintentionally influence, through mixed messages and hidden meanings, the content and processes of professionalism teaching and learning. We identified several intersecting tensions related to the nature of the existing curriculum, staff knowledge, resources, and lack of clear guidance about the "what and how" to teach professionalism. CONCLUSION: This study illustrates, hidden messages and contextual factors can enable or inhibit the translation of professionalism into curricula. Those involved in implementing professionalism must be reflective, keep the "hidden curriculum" in the spotlight to consider how presuppositions and prejudices of their cultural milieu may shape curricular outcomes. PMID- 28622058 TI - Herpes Zoster Ophthalmicus with Orbital Apex Syndrome-Difference in Outcomes and Literature Review. PMID- 28622059 TI - Author's Reply: Zika Virus Infection and Ophthalmic Examination in Newborn. PMID- 28622060 TI - Parental occupations and risk for Crohn's disease in children. AB - BACKGROUND AND OBJECTIVES: Lacunae exist on the identity of specific environmental risk factors that associate with Crohn's disease (CD). We hypothesized that indirect exposures acquired via the parents' occupation may confer susceptibility. METHODS: A case-control study based on children diagnosed with CD (prior to age 20) at a tertiary care gastroenterology clinic in Montreal, Canada was carried out. Population- and hospital-based controls without IBD were selected. Information on occupations held by the parents was acquired from interview. Jobs were coded using the Canadian National Occupational Classification for Statistics. Associations were examined using logistic regression accounting for potential confounders. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated. RESULTS: A total of 466 cases and 335 controls were studied. The mean (+/-SD) age of the cases (12.4 +/- 3.2) was slightly higher than controls (10.5 +/- 4.9). Gender and ethnicity were equally distributed between the groups. Logistic regression analysis suggested that children whose fathers worked as retail salespersons/sales clerks [odds ratio (OR) 3.6, 95% confidence interval (CI) 1.2-11.1], and whose mothers worked as administrative secretaries (OR 3.2, 95% CI 1.6-6.4), were more likely to be at risk for CD. Mothers who worked as either early childhood educators (OR 2.3, 95% CI 0.85-6.2) or as clerks (OR 2.8, 95% CI 0.8-9.9) also appeared to confer risks, but these associations were statistically not significant. CONCLUSION: Parental occupations related to 'social mixing' that can potentially enhance exposure to infectious agents, appear to confer higher risk for CD in children. PMID- 28622061 TI - Formulation and in vitro evaluation of curcumin-lactoferrin conjugated nanostructures for cancerous cells. AB - Curcumin, a natural polyphenol, exhibits anti-oxidant, anti-inflammatory, anti neoplastic and chemopreventive properties. In fact, targeting of this natural anticancer agent has received a great deal of attention during the recent years. In this study, we proposed that curcumin conjugation with lactoferrin molecules may lead to a potential drug delivery system targeted toward cancerous cells through both active and passive targeting. In this regard, curcumin conjugated lactoferrin was developed via a carbodiimide-based coupling reaction and the resulting conjugates were appraised for their molecular properties as a potential targeted drug delivery system. The mean diameter of the designed nanostructure was about 165 +/- 26 nm with a PDI of 0.308 +/- 0.045. The conjugated nanostructures showed a considerably improved cytotoxicity on HCT116 cells as illustrated by MTT assay along with a higher level of cellular uptake. Cellular uptake and targeting capability of conjugated samples were further investigated by confocal microscopy and the conjugated curcumin nanostructures showed an enhanced efficacy compared to curcumin. Furthermore, flow cytometry analysis proved that early apoptosis occurred in HCT116 cell line, after 24 h incubation with conjugated curcumin. PMID- 28622062 TI - Novel Zinc Finger Protein Gene 469 (ZNF469) Variants in Advanced Keratoconus. AB - PURPOSE: Common polymorphic variants upstream of Zinc finger protein gene 469 (ZNF469) have been associated with central corneal thickness. Rare ZNF469 variants have been shown in keratoconus patients. The aim of the current study was to investigate the frequency of ZNF 469 gene variants in rapidly progressive advance keratoconus patients who underwent corneal transplant surgery by the age of 30, compared to their frequency in the normal Turkish population. METHODS: A search in a patient database was performed to identify patients with a rapidly progressive keratoconus requiring corneal transplant surgery by the age of 30 in at least one eye. Twenty-six advance keratoconus patients (study group) and 109 health subjects (control group) were included in the study. Blood samples were donated, and genomic DNA was extracted. The entire coding sequence of the ZNF469 gene including the 84 bp of the putative intron was amplified using PCR primers and analyzed using next generation sequencing (NGS). RESULTS: Fifteen single nucleotide polymorphisms previously reported and registered to the dbSNP database were detected in the study group. The allele frequencies of these polymorphisms were higher in the keratoconus group compared to the control group and to the ExAC genome database. Three new missense heterozygote variants and one new synonym variant were detected in keratoconus group. According to prediction software, the P873T and Q2188H variants were shown to be non-tolerated, whereas G3424S could be tolerated. The synonymous variant R1060R is not predicted to lead to abnormal splicing by Human Splicing Finder in silico analysis. CONCLUSION: New detected ZNF 469 P873T and Q2188H heterozygote coding variants in isolated advance keratoconus patients may be associated with the disease pathogenesis. PMID- 28622063 TI - Characteristic Profiles of Inflammatory Cytokines in the Aqueous Humor of Glaucomatous Eyes. AB - PURPOSE: To analyze cytokine profiles of the aqueous humor of eyes with primary open-angle glaucoma (POAG), neovascular glaucoma (NVG), and cataract (as controls). METHODS: A multiplex bead assay was used to measure concentrations of 27 cytokines in aqueous humor samples from 54 eyes. RESULTS: Detection rates were as follows: IL-7: NVG higher than POAG; IL-10: POAG lower than cataract or NVG; and GM-CSF: cataract higher than POAG or NVG. Concentrations were as follows: IL 8, IP-10, MCP-1, and MIP-1beta: POAG and NVG higher than cataract; IL-9: POAG lower than NVG; IL-12: POAG lower than cataract or NVG; and VEGF: NVG higher than cataract or POAG and POAG lower than cataract. Further analysis showed that IL-8, IP-10, MCP-1, and MIP-1beta were correlated with intraocular pressure and age. CONCLUSIONS: The detection rates and levels of various cytokines had different patterns in POAG and NVG patients, suggesting distinctive alterations in the microenvironment in different types of glaucoma. PMID- 28622064 TI - Re: "Comparison of Helicopter Emergency Medical Services Transport Types and Delays on Patient Outcomes at Two Level I Trauma Centers". PMID- 28622065 TI - Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues. AB - The leptin gene was transferred into the liver of streptozocin- and high fat diet induced type 2 diabetic (T2D) mice by hydrodynamic-based gene delivery. The food intake, water consumption, glucose concentration, and triglyceride and total cholesterol levels of T2D mice were significantly decreased. Meanwhile, plasma leptin was remarkably increased after gene transfer for 2, 3, 5, and 7 days, while plasma adiponectin was also significantly increased at day 2. To understand the mechanism of action of leptin on T2D mice, gene expressions related to glycometabolism and energy metabolism in the liver, epididymal adipose tissue, hypothalamus, and muscle were measured. The mRNA expression levels of adiponectin receptor 1 (ADR1), glucose transporter 4 (GLUT4), glucose-6-phosphase, and peroxisome proliferator-activated receptor gamma in the liver, leptin, adiponectin, and hormone-sensitive lipase in adipose tissue, leptin, leptin receptor, ADR1 in the hypothalamus, and ADR1, GLUT4, and insulin 1 in the gastrocnemius significantly increased. Moreover, the hepatic glycogen of the leptin-gene-treated group was significantly increased in comparison to the control group. Meanwhile, the significant decrease of forkhead box O1, adiponectin receptor 2, and peroxisome proliferator-activated receptor alpha in the liver, and agouti-related protein and proopiomelanocortin genes in the hypothalamus were also observed. In fat tissue and hypothalamus, leptin and adiponectin protein levels were also significantly increased, whereas the neuropeptide Y protein level was significantly decreased. These results indicated that the leptin gene transfer could improve the symptoms of T2D mice by regulating the leptin-hypothalamus signaling pathway and improving the insulin resistance of the peripheral tissues of T2D mice. PMID- 28622066 TI - Vascular-Associated Muc4/Vwf Co-Localization in Human Conjunctival Malignant Melanoma Specimens-Tumor Metastasis by Migration? AB - PURPOSE: To investigate whether vascular differentiation marker von Willebrand factor (vWf) and proliferation marker KI67 expression correlate with MUC4 localization around stromal tumor vascularization in human conjunctival malignant melanoma (CMM). MATERIALS AND METHODS: For the purposes of this study, we analyzed samples from human CMMs (n = 4), conjunctival compound nevi (n = 7), and samples from healthy conjunctiva (n = 7) for MUC1, 4, and 16 by immunohistochemistry. To test CMM vessel association of MUC4, we investigated the co-localization of MUC4 with vWf or KI67 in human CMM specimens (n = 10) by immunohistochemistry. Also, we investigated the MUC4 localization around vessels of healthy conjunctiva (n = 10). RESULTS: The immunohistochemical analysis demonstrated membrane-associated mucin expression in epithelia of CMM, nevi and healthy conjunctiva, whereas only MUC4 was localized perivascular in CMM tissue in this preliminary analysis. Co-staining analysis with vWf and KI67 demonstrated MUC4 localization around stromal vessels in human CMM specimens. In contrast, no MUC4 localization has been seen around healthy conjunctiva stroma vessels. CONCLUSIONS: MUC4 was detected around vWf/KI67-positive CMM stromal vascular tissue, but not around healthy conjunctival stroma vessels. Therefore, we assume that MUC4 might play a role in tumor cell migration toward vessels inducing metastasis. PMID- 28622067 TI - Opioid-Involved Overdose Among Male Afghanistan/Iraq-Era U.S. Military Veterans: A Multidimensional Perspective. AB - BACKGROUND: Mirroring nationwide trends in a broad range of U.S. populations, an alarming number of Afghanistan/Iraq-era U.S. Military veterans have experienced opioid-related overdoses. A growing body of research has examined the proximal behaviors that can precipitate an overdose; considerably less is known about more distal physiological, psychosocial and structural influences on these risk behaviors. OBJECTIVES: This study adopts a multidimensional approach to better understand opioid-related overdose among U.S. Military veterans, and seeks to explore not only the proximal behavioral precipitants of overdose events, but also the complex nexus of physiological, psychological, and sociological influences that undergird overdose events. METHODS: This qualitative examination is based on interview data from 36 male veterans who were discharged from the military after September 2001 and experienced at least one opioid-related overdose during or after military service. Participants were recruited in New York City during 2014 to share narrative accounts of their overdoses. RESULTS: Veterans' accounts indicate that background experiences, such as self-medication for social and psychological pain, trauma, social alienation and isolation, and histories of illicit drug use, precondition the more immediate factors and behaviors that precipitate overdose (including bingeing on drugs, mixing drugs, naivete about dosage, and ambivalence about life/death). CONCLUSIONS: Findings suggest the need for comprehensive drug safety and overdose education that is sensitive to veterans' physiological, psychological, and sociological conditions. A multidimensional understanding of the distal and proximal overdose risks faced by veterans and other vulnerable groups may help lay a foundation for more inclusive/holistic approaches to overdose prevention and education. PMID- 28622069 TI - Spontaneous Coronary Artery Dissection in a Woman with a Past Medical History of Subarachnoid Hemorrhage: A Case Report. AB - Spontaneous coronary artery dissection (SCAD) is an uncommon disease. We report the case of a 50 year-old woman with a past medical history of aneurysmal subarachnoid hemorrhage, presenting with acute chest pain and diffuse ST segment elevation on ECG. Coronary angiogram revealed a SCAD of the left anterior descending coronary artery. The association between cerebral aneurysms and SCAD should trigger providers concern for fibromuscular dysplasia. We hereby report on a rare and atypical case involving the relationship between fibromuscular dysplasia and SCAD. PMID- 28622068 TI - Salmonella typhimurium A1-R targeting of a chemotherapy-resistant BRAF-V600E melanoma in a patient-derived orthotopic xenograft (PDOX) model is enhanced in combination with either vemurafenib or temozolomide. AB - A metastatic melanoma obtained from the right chest wall of a patient was previously established orthotopically in the right chest wall of nude mice as a patient-derived orthotopic xenograft (PDOX) model. We previously showed that the combination of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and chemotherapy was highly effective against the melanoma PDOX. In the present study, we investigated the mechanism of the high efficacy of this combination. Two weeks after implantation, 40 PDOX mouse models were randomized into 4 groups of 10 mice each: untreated control (n = 10); treated with S. typhimurium A1-R (5 * 107 CFU/100 MUl, i.v., once a week for 2 weeks, n = 10); treated with temozolomide (TEM) (25 mg/kg, p.o. for 14 consecutive days) combined with S. typhimurium A1-R (5 * 107 CFU/100 MUl, i.v., once a week for 2 weeks, n = 10); treated with vemurafenib (VEM) (30 mg/kg, p.o., for 14 consecutive days) combined with S. typhimurium A1-R (5 * 107 CFU/100 MUl, i.v., once a week for 2 weeks) (n = 10). On day 14 from initiation, all treatments significantly inhibited tumor growth compared with untreated control (S. typhimurium A1-R: p < 0.01; TEM combined with S. typhimurium A1-R: p < 0.01; VEM combined with S. typhimurium A1 R: p < 0.01). Combination therapy with S. typhimurium A1-R was significantly more effective on tumor growth than S. typhimurium A1-R alone (with TEM: p < 0.01; with VEM: p < 0.01). Combination therapy significantly increased S. typhimurium A1-R tumor targeting alone (S. typhimurium A1-R + TEM: p < 0.01, S. typhimurium A1-R + VEM: p < 0.01), relative to S. typhimurium A1-R alone, respectively. In conclusion, chemotherapy drugs promoted targeting of S. typhimurium A1-R of melanoma, thereby enhancing efficacy against the melanoma PDOX. PMID- 28622071 TI - Survival in Out-of-hospital Rapid Sequence Intubation of Non-Traumatic Brain Pathologies. AB - INTRODUCTION: Rapid sequence intubation (RSI) is not only used in traumatic brain injuries in the out-of-hospital setting, but also for non-traumatic brain pathologies (NTBP) such as brain tumors, meningitis, encephalitis, hypoxic/anoxic brain injury, stroke, arteriovenous malformations, tumors, aneurysms, brain hemorrhage, as well as brain injury due to diabetes, seizures and toxicity, metabolic conditions, and alcohol and drug overdose. Previous research suggests that RSI is common in non-traumatic coma, but with an unknown prevalence of NTBP in those that receive RSI. If NTBP is common and if brain trauma RSI evidence is not valid for NTBP then a sizable proportion of NTBP receive this treatment without evidence of benefit. This study calculated the out-of-hospital NTBP prevalence in patients that had received RSI and explored factors that predicted survival. METHODS: A retrospective cohort study based on data collected from an ambulance service and seven hospitals based in Melbourne, Australia. Non traumatic brain pathologies were defined using ICD10-AM codes for the calculation of NTBP prevalence. Logistic regression modelled out-of-hospital predictors of survival to hospital discharge after adjustment for comorbidities. RESULTS: The seven participating hospitals treated 2,277 patients that received paramedic RSI for all illnesses and indications from January 1, 2008 to December 31, 2015, with survival data available for 1,940 (85%). Of the 1,940, 1,125 (58%) patients had at least one hospital-diagnosed NTBP. Sixty-nine percent all of NTBP survived to hospital discharge, compared to 65% for traumatic intracranial injury. Strokes were the most common and had poor survival to discharge (37%) compared to the second most common NTBP toxicity/toxic encephalopathy that had very high survival (98%). No out-of-hospital clinical intervention or prehospital time interval predicted survival. Factors that did predict survival include Glasgow Coma Scale (GCS), duration of mechanical ventilation, age, ICU length of stay, and comorbidities. CONCLUSIONS: Non-traumatic brain pathologies are seven times more prevalent than traumatic brain injuries in patients that underwent out-of hospital RSI in Victoria, Australia. Since the mechanisms through which RSI impacts mortality might differ between traumatic brain injuries and NTBP, and given that NTBP is very prevalent, it follows that the use of RSI in NTBP could be unsupported. PMID- 28622070 TI - Loop ileostomy-mediated fecal stream diversion is associated with microbial dysbiosis. AB - Loop ileostomy is an effective procedure to protect downstream intestinal anastomoses. Ileostomy reversal surgery is often performed within 12 months of formation but is associated with substantial morbidity due to severe post surgical complications. Distal ileum is deprived of enteral nutrition and rendered inactive, often becoming atrophied and fibrotic. This study aimed to investigate the microbial and morphological changes that occur in the defunctioned ileum following loop ileostomy-mediated fecal stream diversion. Functional and defunctioned ileal resection tissue was obtained at the time of loop-ileostomy closure. Intrapatient comparisons, including histological assessment of morphology and epithelial cell proliferation, were performed on paired samples using the functional limb as control. Mucosal-associated microflora was quantified via determination of 16S rRNA gene copy number using qPCR analysis. DGGE with Sanger sequencing and qPCR methods profiled microflora to genus and phylum level, respectively. Reduced villous height and proliferation confirmed atrophy of the defunctioned ileum. DGGE analysis revealed that the microflora within defunctioned ileum is less diverse and convergence between defunctioned microbiota profiles was observed. Candidate Genera, notably Clostridia and Streptococcus, reduced in relative terms in defunctioned ileum. We conclude that Ileostomy-associated nutrient deprivation results in dysbiosis and impaired intestinal renewal in the defunctioned ileum. Altered host-microbial interactions at the mucosal surface likely contribute to the deterioration in homeostasis and thus may underpin numerous postoperative complications. Strategies to sustain the microflora before reanastomosis should be investigated. PMID- 28622072 TI - New model for the interaction of IQGAP1 with CDC42 and RAC1. AB - The specific and rapid formation of protein complexes, involving IQGAP family proteins, is essential for diverse cellular processes, such as adhesion, polarization, and directional migration. Although CDC42 and RAC1, prominent members of the RHO GTPase family, have been implicated in binding to and activating IQGAP1, the exact nature of this protein-protein recognition process has remained obscure. Here, we propose a mechanistic framework model that is based on a multiple-step binding process, which is a prerequisite for the dynamic functions of IQGAP1 as a scaffolding protein and a critical mechanism in temporal regulation and integration of cellular pathways. PMID- 28622073 TI - Neighborhood Poverty and 9-1-1 Ambulance Contacts. AB - BACKGROUND: Neighborhood poverty is positively associated with frequency of 9-1-1 ambulance utilization, but it is unclear whether this association remains significant when accounting for variations in the severities and types of ambulance contacts. METHODS: We merged EMS ambulance contact records in a single California county (n = 88,027) with data from the American Community Survey at the census tract level (n = 300). Using tract as a proxy for neighborhood and negative binomial regression as an analytical tool, we predicted 16 outcomes: any ambulance contacts, ambulance contacts stratified by three intervention severities, and ambulance contacts varied by 12 primary impression categories. For each model, we estimated the incident rate ratios for 10 percentage point increases in tract-level poverty while controlling for geographic patterns in race, citizenship, gender, age, emergency department proximity, population density, and population size. RESULTS: Our study produced three major findings. First, tract-level poverty was positively associated with ambulance contacts (incident rate ratio [IRR] 1.45; 95% confidence interval [CI] 1.34 to 1.57). Second, poverty was positively associated with low severity contacts (IRR 1.48; 95% CI 1.35 to 1.61), medium severity contacts (IRR 1.38; 95% CI 1.28 to 1.49), and high severity contacts (IRR 1.40; 95% CI 1.30 to 1.51). Third, poverty was positively associated with 12 primary impression categories: abdominal (IRR 1.48; 95% CI 1.36 to 1.61), altered level of consciousness (IRR 1.37; 95% CI 1.25 to 1.50), cardiac (IRR 1.28; 95% CI 1.14 to 1.42), overdose/intoxication (IRR 1.59; 95% CI 1.40 to 1.81), pain (IRR 1.56; 95% CI 1.41 to 1.73), psych/behavioral (IRR 1.50; 95% CI 1.34 to 1.67), respiratory (IRR 1.42; 95% CI 1.29 to 1.56) seizure (IRR 1.52; 95% CI 1.38 to 1.68), stroke (IRR 1.14; 95% CI 1.01 to 1.28), syncope/near syncope (IRR 1.23; 95% CI 1.12 to 1.36), trauma (IRR 1.44; 95% CI 1.31 to 1.58), and general weakness (IRR 1.31; 95% CI 1.20 to 1.42). CONCLUSION: Our study suggests poverty is a positive, strong, and enduring predictor of ambulance contacts at the neighborhood level. The relationship between neighborhood poverty and ambulance utilization should be considered at multiple levels of EMS decision making. PMID- 28622074 TI - Disparities in Feedback Provision to Emergency Medical Services Professionals. AB - INTRODUCTION: Feedback to EMS professionals is a critical component for optimizing patient care and outcomes in the prehospital setting. There is a paucity of data concerning the feedback received by prehospital providers. OBJECTIVES: The objective of this study was to describe the prevalence of feedback received by EMS professionals in the past 30 days including the types, sources, modes, and utility of feedback. The secondary objective was to identify factors associated with receiving any feedback and, specifically, feedback regarding medical care provided. METHODS: This was a cross-sectional survey examining currently practicing nationally certified EMS patient care providers (EMT or higher) in non-military and non-tribal settings. Data were collected on provider characteristics along with feedback received. Descriptive statistics were calculated, and multivariable logistic regression models were constructed to assess the relationship between EMS provider characteristics and receiving feedback. A non-respondent survey was administered to assess for non-response bias. RESULTS: Responses from 32,314 EMS providers were received (response rate = 10.4%) with 15,766 meeting inclusion criteria. In the 30 days preceding the survey, 69.4% (n = 10,924) of respondents received at least one type of feedback with 54.7% (n = 8,592) reporting receiving medical care feedback. Multivariable logistic regression modeling indicated that higher certification level, fewer years of experience in EMS, working for a hospital-based agency, air medical service, and higher weekly call volumes were significantly associated with increased odds of having received at least one type of feedback, and specifically medical care feedback. Additionally, providing primarily medical/convalescent transport and more years of EMS experience were significantly associated with decreased odds of receiving feedback. CONCLUSION: Feedback to EMS providers is critical to improving prehospital care. In this study, nearly a third of providers did not receive any feedback in a 30-day period, and nearly half reported not receiving medical care feedback. Disparities in the frequency of feedback exist between different provider levels and service settings, while reported feedback decreased with years of experience in the profession. Future work is needed to assess the content of feedback and role in improving patient care and safety. PMID- 28622075 TI - Meaningful Interventions in Prehospital and Retrieval Medicine. PMID- 28622077 TI - A Comparative Study of the Effects of Sodium Selenite and Glutathione Mono Ethyl Ester on Aged Adipose-Derived Stem Cells: The Telomerase and Cellular Responses. AB - The proliferation and differentiation potential of adipose-derived stem cells (ADSCs) decline with aging. Moreover, Alzheimer's disease is associated with progressive decline in cholinergic neurons. The purpose of this study is to enhance the proliferation potential of aged rat ADSCs and their differentiation into cholinergic neurons. The ADSCs were collected from aged male rats cultured and treated with different concentrations of sodium selenite for 3 days or glutathione mono ethyl ester (GSH-MEE) for 1 day. Incubating the ADSCs with 27 nM sodium selenite for 3 days significantly increased the relative cell proliferation, compared with the control, without any change in the telomerase activity, the related telomerase gene expression, and the telomere length, but it does improve differentiation of the aged ADSCs to cholinergic neuron-like cells. GSH-MEE at a concentration of 2 mM for 1 day resulted in increased relative cell proliferation, but it did not change the telomerase activity, the related telomerase gene expression, the telomere length, and differentiation potential. Sodium selenite is more effective than GSH-MEE in improving the aged ADSCs' properties. However, both did not have any effect on telomerase activity. PMID- 28622078 TI - A Feasibility Study and Technical Tips for the Use of an Articulating Bipolar Vessel Sealer in da Vinci Robot-Assisted Gastrectomy. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and safety of a new articulating bipolar energy device, the EndoWrist(r) OneTM Vessel Sealer (VS), in da Vinci(r) robot-assisted gastrectomy. MATERIALS AND METHODS: Patients (n = 17) with cT1/2 gastric cancer who underwent robotic gastrectomy using the VS were prospectively enrolled in the study group (VS group). The clinicopathological outcomes, including operative time, intraoperative blood loss, amount of postoperative drainage, postoperative biochemical analysis results, and complication rates, were prospectively collected and compared with those of patients who underwent robotic gastrectomy using conventional ultrasonic shear force ([US] group, n = 52) during the same time period. RESULTS: Although the VS provided a good direction for dissection because of the articulating function, the ancillary use of conventional bipolar coagulation was occasionally needed due to the blunt, nonactive end tip of the VS. The operative time, intraoperative blood loss, postoperative drainage, and absence of complication rates did not differ between the VS and US groups, but the C-reactive protein levels on the second postoperative day (8.06 versus 11.7, P = .002) and serum albumin levels on the fifth postoperative day (3.51 versus 3.32, P = .019) were superior in the VS group. CONCLUSION: Use of the VS in robotic gastrectomy was feasible and provided good configuration in the direction of dissection. The learning process for use of the VS in the initial series was relatively rapid, resulting in comparable results between the VS and US groups. Reduced inflammation and albumin loss were identified as possible benefits of the VS. PMID- 28622076 TI - Human Induced Pluripotent Stem Cell-Derived Endothelial Cells for Three Dimensional Microphysiological Systems. AB - Microphysiological systems (MPS), or "organ-on-a-chip" platforms, aim to recapitulate in vivo physiology using small-scale in vitro tissue models of human physiology. While significant efforts have been made to create vascularized tissues, most reports utilize primary endothelial cells that hinder reproducibility. In this study, we report the use of human induced pluripotent stem cell-derived endothelial cells (iPS-ECs) in developing three-dimensional (3D) microvascular networks. We established a CDH5-mCherry reporter iPS cell line, which expresses the vascular endothelial (VE)-cadherin fused to mCherry. The iPS-ECs demonstrate physiological functions characteristic of primary endothelial cells in a series of in vitro assays, including permeability, response to shear stress, and the expression of endothelial markers (CD31, von Willibrand factor, and endothelial nitric oxide synthase). The iPS-ECs form stable, perfusable microvessels over the course of 14 days when cultured within 3D microfluidic devices. We also demonstrate that inhibition of TGF-beta signaling improves vascular network formation by the iPS-ECs. We conclude that iPS-ECs can be a source of endothelial cells in MPS providing opportunities for human disease modeling and improving the reproducibility of 3D vascular networks. PMID- 28622079 TI - Use of an Automated Mobile Phone Messaging Robot in Postoperative Patient Monitoring. AB - BACKGROUND: Mobile phone messaging software robots allow clinicians and healthcare systems to communicate with patients without the need for human intervention. The purpose of this study was to (1) describe a method for communicating with patients postoperatively outside of the traditional healthcare setting by utilizing an automated software and mobile phone messaging platform and to (2) evaluate the first week of postoperative pain and opioid use after common ambulatory hand surgery procedures. MATERIALS AND METHODS: The investigation was a prospective, multicenter investigation of patient-reported pain and opioid usage after ambulatory hand surgery. Inclusion criteria included any adult with a mobile phone capable of text messaging, who was undergoing a common ambulatory hand surgical procedure at one of three tertiary care institutions. Participants received daily, automated text messages inquiring about their pain level and how many tablets of prescription pain medication they had taken in the past 24 h. Initial 1-week response rate was assessed and compared between different patient demographics. Patient-reported pain and opioid use were also quantified for the first postoperative week. Statistical significance was set as p < 0.05. RESULTS: Forty-seven (n = 47) patients were enrolled in this investigation. Total response rate of both pain and opioid medication questions through 7 days was 88.3%. Pain trended down on a daily basis for the first postoperative week, with the highest levels of pain being reported in the first 48 h after surgery. Patients reported an average use of 15.9 +/- 14.8 tablets of prescription opioid pain medication. CONCLUSIONS: We find that a mobile phone messaging software robot allows for effective data collection of postoperative pain and pain medication use. Patients undergoing common ambulatory hand procedures utilized an average of 16 tablets of opioid medication in the first postoperative week. PMID- 28622080 TI - Differences in glucose yield of residues from among varieties of rice, wheat, and sorghum after dilute acid pretreatment. AB - Bio-refinery processes require use of the most suitable lignocellulosic biomass for enzymatic saccharification and microbial fermentation. Glucose yield from biomass solid fractions obtained after dilute sulfuric acid (1%) pretreatment (at 180 degrees C) was investigated using 14, 8, and 16 varieties of rice, wheat, and sorghum, respectively. Biomass solid fractions of each crop showed similar cellulose content. However, glucose yield after enzymatic hydrolysis (cellulase loading at 6.6 filter paper unit/g-biomass) was different among the varieties of each crop, indicating genotypic differences for rice, wheat, and sorghum. Nuclear magnetic resonance method revealed that the high residual level of lignin aromatic regions decreased glucose yield from solid fraction of sorghum. PMID- 28622081 TI - Effects of inspiratory muscle training in professional women football players: a randomized sham-controlled trial. AB - This study was conducted to determine the effects of inspiratory muscle training (IMT) on respiratory and peripheral muscles oxygenation during a maximal exercise tolerance test and on repeated-sprint ability (RSA) performance in professional women football players. Eighteen athletes were randomly assigned to one of the following groups: SHAM (n = 8) or IMT (n = 10). After a maximal incremental exercise test, all participants performed (on a different day) a time-to exhaustion (Tlim) test. Peripheral and respiratory muscles oxygenation by near infrared spectroscopy, breath-by-breath ventilatory and metabolic variables, and blood lactate concentration were measured. The RSA test was performed on a grass field. After a 6 week intervention, all athletes were reevaluated. Both groups showed increases in inspiratory muscles strength, exercise tolerance and RSA performance, however only the IMT group presented lower deoxyhemoglobin and total hemoglobin blood concentrations on intercostal muscles concomitantly to an increased oxyhemoglobin and total hemoglobin blood concentrations on vastus lateralis muscle during Tlim. In conclusion, these results may indicate the potential role of IMT to attenuate inspiratory muscles metaboreflex and consequently improve oxygen and blood supply to limb muscles during high intensity exercise, with a potential impact on inspiratory muscle strength, exercise tolerance and sprints performance in professional women football players. PMID- 28622082 TI - Comparing the Effectiveness of Fractional CO2 Laser and the Combination Therapy with Micro-Needling and Topical 10% Trichloroacetic Acid to Remove Infra-Orbital Dark Circles in Tehran Women. AB - BACKGROUND: Infra-orbital dark circles in now identified as a cosmetic problem which should be considered in treatment issue. The present study aimed to assess and compare the clinical efficiency of the combination of micro-needling and 10% trichloroacetic acid (TCA) cream as well as carbon dioxide laser in the management of infra-orbital dark circles. METHODS: This randomized clinical trial was performed on women ranged 28 to 62 years that complained of infra-orbital dark circles. The patients were randomly assigned to treat with micro-needling combined, using TCA 10% cream topically or CO2 laser. The treatment period in each group included three sessions with an interval of one month between sessions. The assessment was based on both subjective and objective methods. RESULTS: the mean of DeltaE (the difference in the intensity of darkening at infra-orbital point and other points of the face) was significantly higher in laser group than in another group in all visit sessions. The patients who treated with the laser were specified to have a higher level of satisfaction in fifth visit when compared to those who received another treatment method. CONCLUSION: Regarding clinical effectiveness and the patients' compliance, fractional CO2 laser was more preferred in the combination therapy with micro-needling and topical TCA for removing infra-orbital dark circles. PMID- 28622083 TI - The Importance of Considering Differences in Study Design in Network Meta analysis: An Application Using Anti-Tumor Necrosis Factor Drugs for Ulcerative Colitis. AB - BACKGROUND AND AIMS: Adaptive trial designs present a methodological challenge when performing network meta-analysis (NMA), as data from such adaptive trial designs differ from conventional parallel design randomized controlled trials (RCTs). We aim to illustrate the importance of considering study design when conducting an NMA. METHODS: Three NMAs comparing anti-tumor necrosis factor drugs for ulcerative colitis were compared and the analyses replicated using Bayesian NMA. The NMA comprised 3 RCTs comparing 4 treatments (adalimumab 40 mg, golimumab 50 mg, golimumab 100 mg, infliximab 5 mg/kg) and placebo. We investigated the impact of incorporating differences in the study design among the 3 RCTs and presented 3 alternative methods on how to convert outcome data derived from one form of adaptive design to more conventional parallel RCTs. RESULTS: Combining RCT results without considering variations in study design resulted in effect estimates that were biased against golimumab. In contrast, using the 3 alternative methods to convert outcome data from one form of adaptive design to a format more consistent with conventional parallel RCTs facilitated more transparent consideration of differences in study design. This approach is more likely to yield appropriate estimates of comparative efficacy when conducting an NMA, which includes treatments that use an alternative study design. CONCLUSIONS: RCTs based on adaptive study designs should not be combined with traditional parallel RCT designs in NMA. We have presented potential approaches to convert data from one form of adaptive design to more conventional parallel RCTs to facilitate transparent and less-biased comparisons. PMID- 28622084 TI - The Streptococcus suis factor H-binding protein: A key to unlocking the blood brain barrier and access the central nervous system? PMID- 28622085 TI - C-Reactive Protein as a Predictor of Difficult Laparoscopic Cholecystectomy in Patients with Acute Calculous Cholecystitis: A Multivariate Analysis. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the treatment of choice for mild and moderate acute cholecystitis. The aim of this study was to analyze the utility of C-reactive protein (CRP) as a predictor of difficult laparoscopic cholecystectomy (DLC) in patients with acute cholecystitis. MATERIALS AND METHODS: We conducted a prospective study. All patients included were treated with emergency LC. Patients were analyzed as DLC and nondifficult laparoscopic cholecystectomy (NDLC). Multiple logistic regression and receiver-operating characteristic curve analysis were employed to explore which variables were statistically significant in predicting a DLC. Two different models were analyzed. RESULTS: A total of 66 patients were included (37.9% DLC versus 62.1% NDLC). Ideal cutoff point for CRP was calculated as 11 mg/dL, with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for predicting DLC being 92% (95% CI 75-97.8), 82.9% (95% CI 68.7-91.5), 76.7%, and 94.4%, respectively. In the first model multivariate analysis, age >45 years, male sex, gallbladder wall thickness >=5 mm, and pericholecystic fluid collection were significant predictors of DLC, with an area under the curve (AUC) of 0.89. In the second model multivariate analysis, only CRP >=11 (odds ratio, OR = 17.9, P = .013) was significant predictor of presenting DLC, with an AUC of 0.96. CONCLUSIONS: Preoperative CRP with values >=11 mg/dL was associated with the highest odds (OR = 17.9) of presenting DLC in our study. This value possesses good sensitivity, specificity, PPV, and NPV for predicting DLC in our population with acute calculous cholecystitis. PMID- 28622086 TI - Naringenin Ameliorates Behavioral Dysfunction and Neurological Deficits in a d Galactose-Induced Aging Mouse Model Through Activation of PI3K/Akt/Nrf2 Pathway. AB - In this study, we evaluated the protective effects of naringenin on aging mice induced by d-galactose (d-gal). Open field test and Morris water maze test were performed to evaluate the effect of naringenin on behavioral dysfunction. Hematoxylin-eosin staining, TUNEL staining, and Nissl staining were used to estimate the effect of naringenin on neurological deficits. Furthermore, naringenin markedly activated PI3K/Akt signaling, eventually promoted the nuclear translocation of nuclear factor-erythroid 2-related factor 2, and induced the expression of heme oxygenase 1 and NAD(P)H-quinone oxidoreductase 1. Superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) assays were conducted to evaluate oxidative stress in d-gal-induced aging mice. Our finding demonstrated that naringenin was a promising agent for attenuating the aging process, and enhancing endogenous antioxidant defense capacity was a reliable strategy to delay the senescence process. PMID- 28622087 TI - Body physique and proportionality of Brazilian female artistic gymnasts. AB - This study aimed to identify physique characteristics (anthropometry, somatotype, body proportionality) of Brazilian female artistic gymnasts, and to compare them across competitive levels (sub-elite versus non-elite) within competitive age categories. Two hundred forty-nine female gymnasts (68 sub-elite; 181 non-elite) from 26 Brazilian gymnastics clubs, aged 9-20 years and split into four age categories, were sampled. Gymnasts were assessed for 16 anthropometric traits (height, weight, lengths, widths, girths, and skinfolds); somatotype was determined according to Heath-Carter method, body fat was estimated by bioimpedance, and proportionality was computed based on the z-phantom strategy. Non-elite and sub-elite gymnasts had similar values in anthropometric characteristics, however non-elite had higher fat folds in all age-categories (P < 0.01). In general, mesomorphy was the salient somatotype component in all age categories, and an increase in endomorphy, followed by a decrease in ectomorphy across age was observed. Regarding proportionality, profile similarity was found between sub-elite and non-elite within age-categories. In conclusion results suggest the presence of a typical gymnast's physical prototype across age and competitive level, which can be useful to coaches during their selection processes in clubs and regional/national teams. PMID- 28622088 TI - * Engineering Osteoinductive Biomaterials by Bioinspired Synthesis of Apatite Coatings on Collagen Hydrogels with Varied Pore Microarchitectures. AB - Biomaterial controlled osteoinduction is influenced by the porous microenvironment and the composition of incorporated calcium orthophosphate (CaPi) polymorphs, however, for the design of materials that rival the efficacies of natural grafts a systematic approach to assessing the physicochemical properties that affects cellular differentiation is needed. In this research, we introduce a bioinspired synthetic approach to the mineralization of preformed porous collagen hydrogel scaffolds with tunable apatite coatings. Initially, collagen scaffolds are mineralized with dicalcium phosphate dihydrate (DCPD) by alternate immersion in Ca2+ and HPO42- salt solutions. Utilizing classic DCPD conversion chemistry, the surface coatings are selectively transformed to apatite by immersion of the DCPD-collagen substrate in Tris buffer at pH 7.4, 37 degrees C, for 5 days. The composition and morphology of the deposited mineral coatings are characterized by XRD, SEM, and AFM. Variations in the porous microarchitecture of the collagen hydrogel substrate, pore size (9.5 +/- 5 MUm, 165 +/- 50 MUm) and pore alignment altered the morphology of the deposited apatite particles. Intrafibrillar and extrafibrillar mineralization of the collagen templates were observed for both investigated pore sizes. However, templates with aligned pores of both sizes were observed to restrict intrafibrillar mineralization resulting in the exclusive deposition of surface coatings. The osteoinductive activity of the apatite-collagen materials with varied pore microarchitectures was evaluated by in vitro culture of human mesenchymal stem cells for 28 days based on cellular proliferation, alkaline phosphatase activity, and the expression of RUNX2. The combined effects of apatite coatings, reduced pore size, and pore alignment contributed to reductions in cellular proliferation. However, the apatite mineral coating was determined to induce high levels of RUNX2 expression in the absence of additional osteoinductive agents, indicative of biomaterial-induced osteogenesis. This work establishes a versatile synthetic platform for the preparation of bone-like apatite collagen materials with osteoinductive activity. PMID- 28622089 TI - Large Animal Models of Meniscus Repair and Regeneration: A Systematic Review of the State of the Field. AB - Injury to the meniscus is common, but few viable strategies exist for its repair or regeneration. To address this, animal models have been developed to translate new treatment strategies toward the clinic. However, there is not yet a regulatory document guiding such studies. The purpose of this study was to carry out a systematic review of the literature on meniscus treatment methods and outcomes to define the state of the field. Public databases were queried by using search terms related to animal models and meniscus injury and/or repair over the years 1980-2015. Identified peer-reviewed manuscripts were screened by using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. One of nine reviewers read each manuscript and scored them based on whether the publication described a series of predefined study descriptors and outcome measures. Additional data were extracted to identify common assays used. A total of 128 full-length peer-reviewed manuscripts were identified. The number of publications increased over the time frame analyzed, with 48% focused on augmented repair. Rabbit was, by far, the most prevalent species utilized (46%), with dog (21%) and sheep (20%) being the next most common. Analysis of study descriptors revealed that most studies appropriately documented details of the animal used, the surgical approach, and defect and implant characteristics (e.g., 63% of studies identified clearly the defect size). In terms of outcome parameters, most studies carried out macroscopic (85%), histologic (90%), and healing/integration (83%) analyses of the meniscus. However, many studies did not provide further analysis beyond these fundamental measures, and less than 40% reported on the adjacent cartilage and synovium, as well as joint function. There is intense interest in the field of meniscus repair. However, given the current lack of guidance documentation in this area, preclinical animal models are not performed in a standardized fashion. The development of a "Best Practices" document would increase reproducibility and external validity of experiments, while accelerating advancements in translational research. Advancement is of paramount importance given the high prevalence of meniscal injuries and the paucity of effective repair or regenerative strategies. PMID- 28622091 TI - Differences by age and sex in the sedentary time of adults in Scotland. AB - Previous nationally-representative research in Scotland found a j-shaped relationship between age and leisure sedentary time (ST): a decrease from young to middle-age, before rising steeply in older-age. This study investigated the effects of age and sex on weekday (including work) ST for all adults and stratified by work-status, and on weekend day ST. Differences in the relative contributions of component behaviours were also investigated. Responses from 14,367 adult (>=16 years) 2012-14 Scottish Health Survey participants were analysed using linear regressions. We found no j-shaped relationship between age and weekday ST. Instead, only 16-24 year olds reported lower levels than those over 75 years (6.6 (95% CI: 6.3-6.9) compared to 7.4 (95% CI: 7.2-7.6) hours/day; p < 0001). The j-shape was only evident in the stratified analysis amongst women not in work, and for weekend day ST for all groups. For those in work, work ST accounted for 45% of weekday ST. Television/screen ST made up over half of leisure ST on weekdays and weekend days, regardless of sex, age, or work-status. These results challenge our understanding of how ST varies by age. Interventions to reduce ST should consider differences in the relative contributions of ST behaviours by age and work-status. PMID- 28622090 TI - Assembly and Function of the Bacillus anthracis S-Layer. AB - Bacillus anthracis, the anthrax agent, is a member of the Bacillus cereus sensu lato group, which includes invasive pathogens of mammals or insects as well as nonpathogenic environmental strains. The genes for anthrax pathogenesis are located on two large virulence plasmids. Similar virulence plasmids have been acquired by other B. cereus strains and enable the pathogenesis of anthrax-like diseases. Among the virulence factors of B. anthracis is the S-layer-associated protein BslA, which endows bacilli with invasive attributes for mammalian hosts. BslA surface display and function are dependent on the bacterial S-layer, whose constituents assemble by binding to the secondary cell wall polysaccharide (SCWP) via S-layer homology (SLH) domains. B. anthracis and other pathogenic B. cereus isolates harbor genes for the secretion of S-layer proteins, for S-layer assembly, and for synthesis of the SCWP. We review here recent insights into the assembly and function of the S-layer and the SCWP. PMID- 28622092 TI - Exogenous proline enhances the sensitivity of Tobacco BY-2 cells to arsenate. AB - Arsenic causes physiological and structural disorders in plants. Proline is accumulated as a compatible solute in plants under various stress conditions and mitigates stresses. Here, we investigated the effects of exogenous proline on tobacco Bright Yellow-2 (BY-2) cultured cells under [Formula: see text] stress. Arsenate did not inhibit BY-2 cell growth at 40 and 50 MUM but did it at 60 MUM. Proline at 0.5 to 10 mM did not affect the cell growth but delayed it at 20 mM. At 40 MUM [Formula: see text], neither 0.5 mM nor 1 mM proline affected the cell growth but 10 mM proline inhibited it. In the presence of [Formula: see text], 10 mM proline increased the number of Evans Blue-stained (dead) cells and decreased the number of total cells. Together, our results suggest that exogenous proline does not alleviate arsenate toxicity but enhances the sensitivity of BY-2 cells to arsenate. PMID- 28622093 TI - Suppressive effect of dengue virus envelope protein domain III on megakaryopoiesis. AB - Dengue virus (DENV) infection can cause severe, life-threatening events, and no specific treatments of DENV infection are currently approved. Although thrombocytopenia is frequently observed in dengue patients, its pathogenesis is still not fully understood. Previous studies have suggested that DENV-induced thrombocytopenia occurs through viral-replication-mediated megakaryopoiesis inhibition in the bone marrow; however, the exact mechanism for megakaryopoiesis suppression remains elusive. In this study, a reductionist approach was applied, in which C57B/6J mice were inoculated with recombinant DENV-envelope protein domain III (DENV-EIII) instead of the full viral particle. Our results demonstrated that DENV-EIII-suppressed megakaryopoiesis is similar to those observed with DENV infection. Furthermore, in agreement with our in vivo analyses, DENV-EIII sufficiently suppressed the megakaryopoiesis of progenitor cells from murine bone marrow and human cord blood in vitro. Additional analyses suggested that autophagy impairment and apoptosis are involved in DENV-EIII mediated suppression of megakaryopoiesis. These data suggest that, even without viral replication, the binding of DENV-EIII to the cell surface is sufficient to suppress megakaryopoiesis. PMID- 28622094 TI - Self-care behavior change and depression among low-income predominantly Hispanic patients in safety-net clinics. AB - This study examined whether changes in self-care behaviors during a 12-month period predicted the likelihood of screening positive for depression concurrently and prospectively among low-income Hispanic patients with diabetes. Secondary analyses were conducted with longitudinal data collected from a randomized controlled trial that had tested effectiveness of collaborative depression care. We examined whether changes in self-care behaviors observed during the 12 months after baseline predicted the likelihood of screening positive for depression at 12-, 18-, and 24-month follow-up. Self-care behaviors included healthy diet, exercise, self-blood glucose monitoring, and foot care, which were measured by a validated self-reported instrument. Logistic regression analyses indicated that patients with more frequent healthy diet during the 12 months after baseline had significantly lower likelihood of depression. Patients with more frequent exercise had a lower likelihood of screening for depression at 18- and 24-month follow-up. No significant association was found with self-blood glucose monitoring and foot care. These findings suggest the importance of integrated care that emphasizes healthy diet and exercise, together with traditional depression treatment, when helping low-income Hispanic patients with diabetes and comorbid depression. PMID- 28622095 TI - Black and White Lies: Race-Based Biases in Deception Judgments. AB - In six studies ( N = 605), participants made deception judgments about videos of Black and White targets who told truths and lies about interpersonal relationships. In Studies 1a, 1b, 1c, and 2, White participants judged that Black targets were telling the truth more often than they judged that White targets were telling the truth. This truth bias was predicted by Whites' motivation to respond without prejudice. For Black participants, however, motives to respond without prejudice did not moderate responses (Study 2). In Study 3, we found similar effects with a manipulation of the targets' apparent race. Finally, in Study 4, we used eye-tracking techniques to demonstrate that Whites' truth bias for Black targets is likely the result of late-stage correction processes: Despite ultimately judging that Black targets were telling the truth more often than White targets, Whites were faster to fixate on the on-screen "lie" response box when targets were Black than when targets were White. These systematic race based biases have important theoretical implications (e.g., for lie detection and improving intergroup communication and relations) and practical implications (e.g., for reducing racial bias in law enforcement). PMID- 28622096 TI - Practical considerations for managing Helicobacter pylori in college health. PMID- 28622097 TI - Evolution of cytokines and inflammatory biomarkers during infliximab induction therapy and the impact of inflammatory burden on primary response in patients with Crohn's disease. AB - OBJECTIVE: Primary non-response to infliximab in Crohn's disease is still incompletely understood. Our aim was to further characterize the role of inflammatory burden during infliximab induction therapy. MATERIALS AND METHODS: We studied a well-characterized cohort of 201 anti-TNF naive Crohn's disease patients treated with infliximab 5mg/kg at week 0, 2, 6 and 14 who had serum samples drawn just before every infusion. All serum samples were analyzed for CRP, albumin, TNF, IFN-gamma, IL-6, IL-8, IL-10, infliximab trough concentrations (in-house-developed ELISA) and antibodies to infliximab (HMSA, Prometheus Laboratories Inc., San Diego, CA). Primary non-response was defined as the absence of clinical improvement at week 14. RESULTS: The incidence of primary non response to infliximab was 8% (n = 16). IL-8 concentrations at baseline were higher (p = .01) and albumin at week 6 was lower in primary non-responders (p = .01) compared to responders. During induction, IFN-gamma and IL-6 concentrations decreased significantly at week 2 and week 6 in responders compared to primary non-responders (p < .05). Serum TNF increased significantly after each infliximab infusion and this increase from week 0 to week 14 was more pronounced in responders (p = .03). Multiple logistic regression identified TNF/CRP ratio at baseline as predictive for primary non-response to infliximab at week 14 (OR 2.8 (95% CI 1.4-5.5; p = .003)). CONCLUSIONS: In this intensively sampled cohort of Crohn's disease patients, we demonstrate that inflammatory burden is more determining for primary non-response than drug exposure or immunogenicity. Our findings furthermore suggest that the contribution of TNF in inflammation might be higher in primary non-response, contradicting the non-TNF-driven concept. PMID- 28622098 TI - Influence of Session Context on Physical Activity Levels Among Russian Girls During a Summer Camp. AB - PURPOSE: This study investigated the effect of summer camp session context on Russian girls' physical activity (PA). METHOD: Girls (n = 32, Mage = 10.7 years, SD = 0.6 years) from a resident summer camp taking place in the Vologda Region of Russia were exposed to 1 session context/day (i.e., free play, organized with no choice, organized with choice) on Wednesday, Thursday, and Friday for 3 weeks, with the context order counterbalanced across the 3 weeks. The organized session sport/game changed weekly. The primary outcome was accelerometer-assessed PA. Repeated-measures mixed models were used to analyze all outcome data. RESULTS: Findings showed that girls spent a greater percentage of session time (%time) in moderate-to-vigorous PA (p < .001; effect sizes between free play and organized with no choice and organized with choice, respectively = .60, .42) and moderate PA (p < .001; effect size = .57, .39) and a lower %time in light PA (p < .001; effect size = .55, .52) in organized PA contexts compared with free play. CONCLUSIONS: This study provides novel findings in a Russian setting, suggesting that a well-planned, organized camp session can elicit higher PA levels in girls, relative to a free-play session. PMID- 28622099 TI - Energy drinks and alcohol-related risk among young adults. AB - BACKGROUND: Energy drink consumption, with or without concurrent alcohol use, is common among young adults. This study sought to clarify risk for negative alcohol outcomes related to the timing of energy drink use. METHODS: The authors interviewed a community sample of 481 young adults, aged 18-25, who drank alcohol in the last month. Past-30-day energy drink use was operationalized as no-use, use without concurrent alcohol, and concurrent use of energy drinks with alcohol ("within a couple of hours"). Negative alcohol outcomes included past-30-day binge drinking, past-30-day alcohol use disorder, and drinking-related consequences. RESULTS: Just over half (50.5%) reported no use of energy drinks,18.3% reported using energy drinks without concurrent alcohol use, and 31.2% reported concurrent use of energy drinks and alcohol. Relative to those who reported concurrent use of energy drinks with alcohol, and controlling for background characteristics and frequency of alcohol consumption, those who didn't use energy drinks and those who used without concurrent alcohol use had significantly lower binge drinking, negative consequences, and rates of alcohol use disorder (P < .05 for all outcomes). There were no significant differences between the no-use and energy drink without concurrent alcohol groups on any alcohol-related measure (P > .10 for all outcomes). CONCLUSIONS: Concurrent energy drink and alcohol use is associated with increased risk for negative alcohol consequences in young adults. Clinicians providing care to young adults could consider asking patients about concurrent energy drink and alcohol use as a way to begin a conversation about risky alcohol consumption while addressing 2 substances commonly used by this population. PMID- 28622100 TI - Prevalence of substance use among middle school-aged e-cigarette users compared with cigarette smokers, nonusers, and dual users: Implications for primary prevention. AB - BACKGROUND: The objective of this study was to compare the prevalence of substance use in e-cigarette (EC)-only users with combustible cigarette (CC)-only users, dual users, and nonusers in a large sample of middle school-aged adolescents. METHODS: Population-based cross-sectional school survey conducted in 15 middle schools in 3 counties in West Virginia in the United States between October and December of 2015 (N = 6547, girls = 49.6%; response rate 84.7%). RESULTS: Approximately 4.3% of participants had used EC only, 4.5% had used CC only, and around 5.5% were dual users. Nonusers had the lowest prevalence of all 9 forms of substance use assessed in the study (i.e., chewing tobacco, any alcohol, drunkenness, marijuana, sniffing, prescription drugs, hallucinogens, synthetic marijuana, and bath salts), followed by EC and CC users. Dual users had the highest prevalence of 8 of 9 forms of substance use. Multinomial logistic regression models showed that EC-only users had significantly greater odds over nonusers of using 8 of 9 types of substances included in the study. Conversely, EC-only users had significantly lower odds of using 7 of 9 types of substances when compared with dual users. However, EC-only users did not differ from CC-only users in odds of use in any of the 9 substances included in this analysis. CONCLUSIONS: Among middle school-aged adolescents, EC-only users do not differ from CC-only users in odds for other forms of substance use. Primary prevention programs should consider EC use initiation as a pathway to greater risk of other licit and illicit substances among young adolescents. PMID- 28622102 TI - Suicide Screening Tools for use in Incarcerated Offenders: A Systematic Review. AB - Self-inflicted deaths in prisons in England and Wales, recently reported as the highest in over a decade, are a significant cause of mortality. A lack of guidelines surrounding the screening and identification of suicide risk of new prisoners along with a dearth of effective screening tools indicate the need for review. Our aims are to examine findings on the effectiveness of prison specific suicide screening tools used with adult prisoners. Papers were identified via systematic searches of databases, scanning grey literature, and reference checking. Included studies were published over the period between 2000-2016. PRISMA guidelines were followed. Studies were selected based on population - adult imprisoned offenders; intervention - suicide screening tool; comparators - participants screened vs. not screened outcome - suicide or attempted suicide. Data was extracted manually. A narrative synthesis presented the findings between different screening tools. Eight screening tools were critically appraised. Evidence suggested that the VISCI and Dutch screening tools are most effective in identifying those at risk and reducing suicide and/or self-harm behavior. Variance in methodological quality and associated factors indicate the need for further development of prospective studies to develop robust screening tools. This study is registered with PROSPERO (CRD42016035471). PMID- 28622101 TI - Hepatitis C Virus in Pakistan: Community Education Is an Effective Weapon Against the Killer. PMID- 28622103 TI - The t-test: An Influential Inferential Tool in Chaplaincy and Other Healthcare Research. AB - The t-test developed by William S. Gosset (also known as Student's t-test and the two-sample t-test) is commonly used to compare one sample mean on a measure with another sample mean on the same measure. The outcome of the t-test is used to draw inferences about how different the samples are from each other. It is probably one of the most frequently relied upon statistics in inferential research. It is easy to use: a researcher can calculate the statistic with three simple tools: paper, pen, and a calculator. A computer program can quickly calculate the t-test for large samples. The ease of use can result in the misuse of the t-test. This article discusses the development of the original t-test, basic principles of the t-test, two additional types of t-tests (the one-sample t test and the paired t-test), and recommendations about what to consider when using the t-test to draw inferences in research. PMID- 28622104 TI - Disease and injury trends among evacuees in a shelter located at the epicenter of the 2016 Kumamoto earthquakes, Japan. AB - Two huge earthquakes struck Kumamoto, Japan, in April 2016, forcing residents to evacuate. Few studies have reported early-phase disease and injury trends among evacuees following major inland earthquakes. We evaluated the trends among evacuees who visited a medical clinic in a shelter located at the epicenter of the 2016 Kumamoto earthquakes. The clinic opened on April 15, the day after the foreshock, and closed 3 weeks later. We reviewed medical charts related to 929 outpatient visits and conducted descriptive analyses. The evacuees experienced mild injuries and common diseases. The types of diseases changed weekly. Elderly people needed medical support for longer than other age groups. Future earthquakes may be inevitable, but establishing arrangements for medical needs or making precautions for infectious diseases in shelters could reduce the effects of earthquake-related health problems. PMID- 28622105 TI - Physically strenuous work during pregnancy and risk of preterm birth. AB - The aim of the study was to examine the risk of preterm birth following physically strenuous work during pregnancy. We included 343 pregnant women referred to an occupational medical clinic. Data on preterm birth and covariates were retrieved from the Danish Birth Registry. Risk estimates were computed by logistic regression using a population sample of gainfully employed women as reference (n = 345,915). The risk of preterm birth was increased in women lifting heavy loads during pregnancy (OR 1.40, 95% CI [0.88, 2.23]) but not in women with physically strenuous work (OR 0.98, 95% CI [0.66, 1.46]). The mean gestational age in the heavy-lifting group compared to the reference group was 2.4 days shorter (95% CI [0.36, 4.41]). The study challenges earlier reassuring findings as heavy-lifting pregnant women had a reduced gestational age, indicating a possibility of increased risk of preterm birth. PMID- 28622106 TI - Parent Support for Children's Physical Activity: A Qualitative Investigation of Barriers and Strategies. AB - PURPOSE: Parents play an important role in supporting children's physical activity (PA) behavior. Parent PA support is a behavior unto itself that has been examined within the framework of an adapted theory of planned behavior (TPB). The primary purpose of this research was to identify key barriers to parent PA support to understand perceptions of control in relation to parent PA support. The second purpose of this research was to identify potential strategies to enhance parent PA support via enhanced perceived behavioral control. METHOD: Focus groups were conducted with parents (N = 21) of children aged 5 to 11 years old. A deductive content analysis was employed to analyze the data guided by an adapted TPB. RESULTS: Themes related to barriers included parents' motivation, affective experiences in providing PA support, and control factors (e.g., cost, time, safety concerns, screen). Themes related to potential strategies included opportunities for participation and improved affective experiences for parents, community parenting, and self-regulatory strategies. CONCLUSION: The identification of specific barriers to parent PA support can guide the development of interventions to facilitate parent PA support. Informational, programming, and self-regulatory training interventions may be useful in enhancing parent support. PMID- 28622108 TI - Fluctuations of pol I and fibrillarin contents of the nucleoli. AB - Nucleoli are formed on the basis of ribosomal DNA (rDNA) clusters called Nucleolus Organizer Regions (NORs). Each NOR contains multiple genes coding for RNAs of the ribosomal particles. The prominent components of the nucleolar ultrastructure, fibrillar centers (FC) and dense fibrillar components (DFC), together compose FC/DFC units. These units are centers of rDNA transcription by RNA polymerase I (pol I), as well as the early processing events, in which an essential role belongs to fibrillarin. Each FC/DFC unit probably corresponds to a single transcriptionally active gene. In this work, we transfected human-derived cells with GFP-RPA43 (subunit of pol I) and RFP-fibrillarin. Following changes of the fluorescent signals in individual FC/DFC units, we found two kinds of kinetics: 1) the rapid fluctuations with periods of 2-3 min, when the pol I and fibrillarin signals oscillated in anti-phase manner, and the intensities of pol I in the neighboring FC/DFC units did not correlate. 2) fluctuations with periods of 10 to 60 min, in which pol I and fibrillarin signals measured in the same unit did not correlate, but pol I signals in the units belonging to different nucleoli were synchronized. Our data indicate that a complex pulsing activity of transcription as well as early processing is common for ribosomal genes. PMID- 28622109 TI - Farmworker and nonfarmworker Latino immigrant men in North Carolina have high levels of specific pesticide urinary metabolites. AB - This article compares detections and concentrations of specific organophosphate (OP), bis-dithiocarbamate, and pyrethroid pesticide urinary metabolites among Latino male farmworkers and nonfarmworkers in North Carolina. Data are from interviews and urine samples collected in 2012 and 2013. Farmworkers and nonfarmworkers frequently had detections for OP and pyrethroid pesticide urinary metabolites. Detection of bis-dithiocarbamate urinary metabolites was less frequent, but substantial among the nonfarmworkers. The concentrations of organophosphate, bis-dithiocarbamate, and pyrethroid pesticide urinary metabolites were high for farmworkers and nonfarmworkers compared to National Health and Nutrition Examination Survey results. Pesticide urinary metabolite detection was not associated with occupation in nonfarmworkers. Research for reducing pesticide exposure among farmworkers remains important; research is also needed to determine pesticide exposure pathways among Latino nonfarmworkers. PMID- 28622110 TI - Pavlov and Cajal: Two different pathways to a Nobel Prize. AB - Ivan Pavlov (1849-1936) and Santiago Ramon y Cajal (1852-1934) were two contemporary scientists who not only had a great impact on Russian and Spanish science but also on the international stage. Both shared several common features in their life and work, yet they followed fundamentally different paths during their training as scientists. While Pavlov received his laboratory training under the guidance of Ilya Tsion (1843-1912), Cajal did not receive any formal training within a particular laboratory nor did he have a mentor in the traditional sense, rather he was mainly self-taught, although he was supported by key figures like Maestre de San Juan (1828-1890) and Luis Simarro (1851-1921). In this article, we compare the scientific training of these two Nobel Prize laureates and the influences they received during their scientific lives. PMID- 28622111 TI - Caregiving for the Elderly Person: Discourses Embedded in the Brazilian Practical Guide for the Caregiver. AB - It is estimated that in 2025, Brazil will have the sixth largest elderly population in the world. Beyond the economic consequences of this projection, this changing demographic portends significant changes in the social realm. The aim of this study was to review and consider a range of government documents, developed during the past thirty years and directed toward elderly Brazilian citizens, to explore the ways that caregivers of older persons are positioned in daily care practices through the discourses such documents deploy. The analysis draws on Foucault's genealogical approach, and begins with a review of the historicity of policies, regulations, and legislation related to older people, followed by an analysis of the discourses embedded in the Practical Guide for the Caregiver, a document created by the Brazilian Ministry of Health to provide guidance to informal caregivers in the actual provision of care to elders. The analysis shows that throughout the Guide, caregivers are portrayed as multifaceted subjects; yet at the same time, three primary positionings for the caregiver and her or his work are emphasized: the almost-angel, the almost healthcare professional, and the almost-household professional. PMID- 28622112 TI - You Can Clinically Diagnose "Bursitis": You Probably Don't Need to Order That Ultrasound or MRI To Do It. PMID- 28622113 TI - Seafarers' perceptions of job demand: A cross-sectional study. AB - This study offers an insight regarding seafarers' perceptions of factors of psychological distress on shipboard. To identify stressors on maritime workers, a cross-sectional survey was conducted targeting a population of workers of Italian shipping companies sailing across the world. The research aimed to investigate workers' demographic and professional characteristics and the ways they influence perception of job fatigue, using an Italian version of the Karasek questionnaire. Of the involved seafarers, 80.1% returned the questionnaire, yielding a mean level of perceived job demand of 32.8 points and a mean level of perceived decision latitude of 65.5 points; 37.2% of interviewees stated having a scarce level of decision latitude. The results of the multivariate logistic regression models allowed assessment of the seafarers' characteristics related to their perception of job strain. These results confirm the need for measures that prevent stress factors in maritime workers. PMID- 28622114 TI - The role of age and setting in adolescents' first drinking experience for predicting college problem drinking. AB - OBJECTIVE: The purpose of this study was to determine the reliability of longitudinally reporting age at first drink (AFD), and to test AFD and setting of first drink (SFD) as predictors of collegiate problem drinking. PARTICIPANTS: 338 first-year college students were interviewed multiple times during their first academic year, from May 2011 through August 2012. METHODS: AFD, SFD, and problem drinking were measured using the Alcohol Use Disorders Identification Test (AUDIT) during the first year of college. Bivariate analysis and parsimonious multivariate linear regression model were conducted. RESULTS: 62% of respondents were inconsistent in reporting AFD over time. Social SFD was the strongest independent predictor for higher AUDIT scores (b = 4.74, 95% confidence interval; 1.91, 7.57; p = .002). CONCLUSIONS: Findings suggest caution should be used in relying upon using AFD as a sole predictor of problem drinking. SFD may be a complementary measure to identify students at high risk of collegiate problem drinking. PMID- 28622115 TI - PPARgamma2 C1431T Polymorphism Interacts with the Antiobesogenic Effects of Kochujang, a Korean Fermented, Soybean-Based Red Pepper Paste, in Overweight/Obese Subjects: A 12-Week, Double-Blind Randomized Clinical Trial. AB - Kochujang, a Korean fermented soybean-based red pepper paste, has been reported to have beneficial health effects. The aim of this study was to examine the antiobesity effects of Kochujang as a supplement in overweight/obese subjects according polymorphisms in the obesity-linked gene, peroxisome proliferator activator receptor gamma (PPARgamma2). Sixty overweight/obese subjects, who had body mass indexes (BMI, kg/m2) >=23 or waist/hip ratios (WHR) >=0.90 for males or >=0.85 for females, were randomly assigned to either taking 32 g/day of placebo or Kochujang for 12 weeks. Before and after the intervention, anthropometric and metabolic parameters and body fat distribution (by computed tomography) were measured. After PPARgamma2 C1431T polymorphism was analyzed by PCR-restriction fragment length polymorphism, the differences among the four groups (wild and mutant alleles in Kochujang and placebo groups) were determined. Between the Kochujang (n = 26) and placebo (n = 27) groups, there were no differences in body composition, insulin resistance, or antioxidant biomarkers before and after intervention. Compared to placebo, Kochujang significantly decreased plasma triglyceride (TG), TG/high-density lipoprotein (HDL), and dietary intakes of protein, sodium, and potassium after age, sex, and BMI were adjusted. The beneficial effects of Kochujang on lowering of TG and TG/HDL were weakened in subjects with the PPARgamma2 mutant T allele with increasing subcutaneous fat area. However, the interaction between Kochujang and the PPARgamma2 T allele improved insulin sensitivity. The obesogenic variables affected by the T mutant allele of PPARgamma2 C1431T SNP were different in overweight/obese subjects in response to Kochujang. PMID- 28622116 TI - A General Theory for "Post" Systems Biology: Iatromics and the Environtome. PMID- 28622117 TI - Periprosthetic Femoral Fractures in the Emergency Department: What the Orthopedic Surgeon Wants to Know. AB - Femoral fracture in the setting of a hip arthroplasty is an increasingly common complication encountered in the emergency department (ED). Diagnosis and management of periprosthetic fractures are complicated, and orthopedic surgeons rely on imaging findings to guide the appropriate management approach to the injury. Delay in identification and appropriate definitive management of periprosthetic fractures is associated with high morbidity and mortality. At present, the Vancouver classification system for periprosthetic hip fractures is the most common classification system used by orthopedic surgeons. It relies on three radiographic criteria-fracture location, prosthesis stability, and quality of the femoral bone stock-to characterize these fractures and to help guide management decisions. Familiarly with the Vancouver classification system allows radiologists to both recognize and communicate the most clinically relevant imaging findings to the treating orthopedic surgeon. This article reviews the imaging workup for hip pain in patients with a femoral prosthesis, risk factors for periprosthetic fracture, and the expected normal appearance of the most commonly encountered types of femoral prostheses. Fracture terminology and the Vancouver classification system are reviewed in a simplified algorithm with emphasis on the most common patterns of periprosthetic fractures, the radiologic determinants of prosthesis stability and bone quality, and the management implications of these imaging findings. Finally, multiple instructive clinical cases are used to demonstrate critical application of the classification system and to highlight the clinical implications of the imaging findings. (c)RSNA, 2017. PMID- 28622118 TI - Imaging Spectrum of Invasive Fungal and Fungal-like Infections. AB - Invasive fungal and fungal-like infections contribute to substantial morbidity and mortality in immunocompromised individuals. The incidence of these infections is increasing-largely because of rising numbers of immunocompromised patients, including those with neutropenia, human immunodeficiency virus, chronic immunosuppression, indwelling prostheses, burns, and diabetes mellitus, and those taking broad-spectrum antibiotics. Invasive fungal pathogens include primary mycotic organisms such as Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Paracoccidioides brasiliensis, which are true pathogens and inherently virulent. Secondary mycotic organisms such as Candida and Aspergillus species, Cryptococcus neoformans, Pneumocystis jirovecii, and Mucorales fungi are opportunistic, less virulent pathogens. Nocardia and Actinomyces species are gram-positive bacteria that behave like fungi in terms of their growth pattern and cause fungal-like invasive indolent infections; thus, these organisms are included in this review. Fungal and fungal-like infections can affect a variety of organ systems and include conditions such as meningitis, sinusitis, osteomyelitis, and enteritis. As awareness of these infections increases, timely diagnosis and treatment will become even more important. Imaging has a critical role in the evaluation of disease activity, therapy response, and related complications. Using an organ-based approach with computed tomography, magnetic resonance imaging, and ultrasonography to gain familiarity with the appearances of these infections enables timely and accurate diagnoses. (c)RSNA, 2017. PMID- 28622119 TI - Caffeine adsorption of montmorillonite in coffee extracts. AB - The growth in health-conscious consumers continues to drive the demand for a wide variety of decaffeinated beverages. We previously developed a new technology using montmorillonite (MMT) in selective decaffeination of tea extract. This study evaluated and compared decaffeination of coffee extract using MMT and activated carbon (AC). MMT adsorbed caffeine without significant adsorption of caffeoylquinic acids (CQAs), feruloylquinic acids (FQAs), dicaffeoylquinic acids (di-CQAs), or caffeoylquinic lactones (CQLs). AC adsorbed caffeine, chlorogenic acids (CGAs) and CQLs simultaneously. The results suggested that the adsorption selectivity for caffeine in coffee extract is higher in MMT than AC. The caffeine adsorption isotherms of MMT in coffee extract fitted well to the Langmuir adsorption model. The adsorption properties in coffee extracts from the same species were comparable, regardless of roasting level and locality of growth. Our findings suggest that MMT is a useful adsorbent in the decaffeination of a wide range of coffee extracts. PMID- 28622120 TI - Trends in Pap test practices and results: An 11-year review of the annual ACHA Pap Test and STI Survey. AB - OBJECTIVE: To conduct a trend analysis of Pap test practices, Pap test results and related women's services and guidelines of college health centers. PARTICIPANTS: College health centers who participated in the annual ACHA Pap Test and STI (sexually transmitted infection) Survey years 2004-2014 (n ranged from 127 to 181 depending on year). METHODS: Descriptive analyses are presented with ANOVAs (Analysis of Variance) and chi-square tests calculated to examine trends over time. RESULTS: The number of Pap tests significantly decreased over time; however, the percentage of normal and HSIL (high-grade squamous intraepithelial lesion) results did not vary. Availability of conventional cytology slides and cryotherapy were significantly associated with year. Over time, college health centers' guidelines related to initiation of Pap testing evolved to consistently conform to national recommendations for cervical screening. CONCLUSIONS: The results indicate most college health centers are following the current national guidelines regarding Pap testing for young adult women. PMID- 28622121 TI - Student and faculty perceptions about mandatory influenza vaccinations on a health sciences campus. AB - OBJECTIVE: To examine the perceptions among faculty and health professional students regarding mandatory vaccination policies on a health sciences campus. PARTICIPANTS: A total of 296 faculty and 244 students completed surveys during Fall 2015. METHODS: The online survey administered to individuals who received the influenza vaccine during the fall 2015 influenza vaccination clinic season included five items evaluating perceptions of employer mandatory vaccination requirements. RESULTS: Chi-square analysis indicated that although faculty and students agree mandatory vaccinations in a health care environment are appropriate, faculty are more likely than students to get vaccinated in the absence of a mandate. Additionally, a small fraction of faculty would consider employment elsewhere when facing this mandate. CONCLUSIONS: Overall, faculty and students had favorable perceptions about mandatory influenza vaccine policies. Since students were less likely to be vaccinated in the absence of a mandate, education of students should be improved to support the importance of vaccinations in a health care environment. PMID- 28622122 TI - Exploding Head Syndrome in the Epilepsy Monitoring Unit: Case Report and Literature Review. AB - Diagnosis of paroxysmal events in epilepsy patients is often made through video telemetry electroencephalography in the epilepsy monitoring unit. This case report describes the first-ever diagnosis of exploding head syndrome in a patient with longstanding epilepsy and novel nocturnal events. In this report, we describe the presentation of exploding head syndrome and its prevalence and risk factors. In addition, the prevalence of newly diagnosed sleep disorders through video-telemetry electroencephalography in the epilepsy monitoring unit is briefly reviewed. This report also illustrates the novel use of clobazam for the treatment of exploding head syndrome. PMID- 28622123 TI - Review of "Atlas of Neonatal Electroencephalography, Fourth Edition," by Eli M. Mizrahi and Richard A. Hrachovy. PMID- 28622124 TI - Waveform Window #39: Deep Brain Stimulator Artifact on EEG Recording. PMID- 28622126 TI - Review of "Pocket EMG," by Eric Wisotsky, Victor Tseng, and Dane Pohlman. PMID- 28622125 TI - Early-Onset Shapiro Syndrome Variant Treated with Pizotifen: A Case Report. AB - Shapiro Syndrome is a rare entity defined by the triad of recurrent spontaneous hypothermia, hyperhidrosis, and agenesis of the corpus callosum. Fewer than 100 cases have been reported so far and there are only few cases without a complete agenesis of corpus callosum ("Shapiro Syndrome Variant"). In this article, we report the clinical, electroencephalographic, and neuroimaging data of a patient with early-onset Shapiro Syndrome Variant. The case study describes a 4-year-old patient with episodes characterized by generalized hyperhidrosis, hypotonia, impaired consciousness, and hypothermia with onset before the first year of age. We captured an event during which the EEG showed rhythmic low- to medium-voltage theta waves without clear epileptiform activity. Brain MRI was normal and Shapiro Syndrome Variant was hypothesized. We started treatment with pizotifen, and after 2 years, the patient showed a reduction in frequency and duration of episodes. Shapiro Syndrome, although rare, should be considered in the differential diagnosis in patients with neurovegetative symptoms which suggest epileptic attacks at first. Our case is of particular interest to specialists because Shapiro SyndromeVariant is a rare syndrome and our patient had a very early onset of symptoms.In addition, we report our experience with pizotifen therapy, which produced a good response. PMID- 28622127 TI - Prevalence of Sleep-Disordered Breathing During Routine Electroencephalogram (EEG): A Hospital-Based Descriptive Study. AB - Sleep-disordered breathing (SDB) in adults is a common condition that is associated with a range of medical problems including hypertension, cardiovascular complications, and increase of seizure frequency in susceptible individuals. Polysomnography (PSG) is considered the gold standard measure in the diagnosis of SDB. This is an observational study on the frequency of SDB in adult patients referred for routine EEG. We found that routine EEG was capable of detecting moderate to severe symptoms of SDB in 14% of adult patients (95% confidence interval = 8.1-19.9%). The state of sleep during a routine EEG recording could help in assessing a SDB pattern and could provide an opportunity for further diagnostic sleep consultation if the patient has not previously reported problems with sleep or if SDB was not considered by the referring physician. This study underscores the need for a practice approach to ensure that patients suffering from SDB are properly referred to a sleep specialist. In the context of this report, some training and experience in PSG can be an added advantage for EEG technologists in the detection of SDB. PMID- 28622128 TI - Credentialing Organizations. PMID- 28622130 TI - Waveform Window #40: Stimulus-induced Rhythmic, Periodic, or Ictal Discharges (SIRPIDs). PMID- 28622129 TI - Ellen Grass Memorial Lecture: The Utility of Neurodiagnostics-It's Never Too Late to Make a Difference: Epilepsy and Seizures as a Continuum through Case Studies. PMID- 28622132 TI - ASET-CEU Quiz. PMID- 28622133 TI - Mirror Image Video Artifact: An Under-Reported Digital Video-EEG Artifact. AB - Synchronous video recording can be helpful in EEG recordings, especially in recognition of seizures and in rejection of artifacts. However, video recordings themselves are also subject to the risk of contamination by artifacts. We report a unique case in which a digital video artifact was identified, occurring during synchronous video-EEG recording, albeit independently of the EEG tracing itself. A synchronous digital video-EEG recording was performed on a 67-year-old male who presented in focal motor status epilepticus. During the initial review of the data, right-sided abnormalities on EEG apparently corresponded with (ipsilateral) right arm motor activity on video, suggesting a nonsensical anatomical localization. However, review of the patient's chart and discussion with the EEG technologist led to the recognition that the video data recorded a mirror image of the true findings of left arm motor activity. Review of the software settings led to the discovery that the video recording was inverted along the vertical axis, leading to mirror image video artifact. Recognition of this video artifact allowed for accurate interpretation of the study-that right hemispheric EEG abnormalities correlated appropriately with (contralateral) left arm twitching. Effective communication between the EEG reading physician, the treating team, and the EEG technologist is critical for recognition of such artifacts, for proper EEG interpretation, and for appropriate patient management. Mirror image video artifact affirms that bedside evaluation, astute technologists, and attentive EEG reading physicians remain important, even in the presence of video recording. PMID- 28622134 TI - Review of "Neurocritical Care, Second Edition," edited by Eelco F. M. Wijdicks, Alejandro A. Rabinstein, Sara E. Hocker, and Jennifer E. Fugate. PMID- 28622135 TI - The case for implementing the levels of prevention model: Opiate abuse on American college campuses. AB - Opiate abuse in the United States is on the rise among the college student population. This public health crisis requires immediate action from professionals and stakeholders who are committed to addressing the needs of prospective, current, and recovering opiate users using comprehensive prevention methods. Such approaches have been used to deliver primary, secondary, and tertiary intervention to alcohol and other drug users but are underutilized in the case of opiate abuse among college students in the United States. There is a definite need for involving college campus faculty, staff, students, and others in efforts to prevent opiate abuse at all levels. Our recommendations include specific strategies to address this imminent issue using an innovative application of the traditional Levels of Prevention Model. PMID- 28622136 TI - Exploring medical students' conceptions of substance use: A follow-up evaluation. AB - BACKGROUND: Despite the devastating impact of alcohol and other drug involvement and misuse within society, medical students still receive very limited exposure to these issues. The Scaife Advanced Medical Student Fellowship in Alcohol and Other Drug Dependency, offered by the Institute for Research, Education and Training in Addictions for over 10 years, offers a unique, 3-week intensive educational experience, including didactic, observation, and experiential learning in these topics to first-year medical students. The goal of this project was to evaluate the impact of the Scaife Fellowship on medical students' attitudes toward patients with alcohol and other drug involvement 1 to 5 years after completion of the experience. METHODS: Past Scaife students and individuals who applied but did not attend were located and recruited to participate in an online attitude survey. RESULTS: Results indicated that Scaife Fellowship students largely retain their sense of role security around working with patients with alcohol and other drug involvement at the follow-up time point. Although therapeutic commitment or the motivation to work with these patients decreased for drug use, the decrease was smaller than that typically noted in the literature. The group of comparison students showed lower scores on both subscales at the evaluation time point compared with Scaife students. CONCLUSIONS: A three-week experiential program significantly improved medical students' Role Security and Therapeutic Commitment toward working with patients with substance use disorders. Moreover, the positive effects gained from the program were sustained over time. PMID- 28622137 TI - Editor's Note. PMID- 28622138 TI - Cellular and plasma nitrite levels in myeloid leukemia: a pathogenetic decrease. AB - Nitric oxide (NO) has a contributory role in hemopoietic cell growth and differentiation. The effects of NO on leukemic cell growth have been predominantly studied in in vitro settings. This study was done to assess the alterations in nitrite level in myeloid leukemias. Thirty-six newly diagnosed cases of myeloid leukemia (16 AML and 20 CML) were enrolled in the study. Neutrophil precursors from the marrow aspirate and peripheral blood were separated into cell bands using the Percoll density gradient method of Borregard and Cowland. The blood plasma and marrow fluid was also collected. Nitrite (stable non-volatile end product of NO) was estimated in the cell bands, blood plasma and marrow fluid using Griess reagent. The mean nitrite level in all cell bands from peripheral blood, bone marrow, blood plasma, and marrow fluid of cases was significantly lower as compared to corresponding value in the controls. No significant difference between AML and CML was seen. On follow-up, analysis of 13 CML patients higher nitrite levels were seen (p>0.05). The significant decrease in nitrite levels in myeloid leukemia suggests a decrease in nitric oxide synthase (NOS) activity. Further work may unfold molecular targets for therapeutic role of NO modulators. PMID- 28622139 TI - Immune-regulation and -functions of eicosanoid lipid mediators. AB - Bioactive lipids regulate most physiological processes, from digestion to blood flow and from hemostasis to labor. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators. Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.g. sphingolipids, formed from sphingosine or eicosanoids, formed from arachidonic acid (AA)]. Owing to the complexity of different mediator classes and the prominent immunological roles of eicosanoids, this review will focus solely on the immune-regulation of eicosanoids. Eicosanoids do not only control key immune responses (e.g. chemotaxis, antigen presentation, phagocytosis), but they are also subject to reciprocal control by the immune system. Particularly, key immunoregulatory cytokines such as IL-4 and IFN-gamma shape the cellular eicosanoid profile, thus providing efficient feedback regulation between cytokine and eicosanoid networks. For the purpose of this review, I will first provide a short overview of the most important immunological functions of eicosanoids with a focus on prostaglandins (PGs) and leukotrienes (LTs). Second, I will summarize the current knowledge on immunological factors that regulate eicosanoid production during infection and inflammation. PMID- 28622140 TI - Reactive nitrogen species (RNS)-resistant microbes: adaptation and medical implications. AB - Nitrosative stress results from an increase in reactive nitrogen species (RNS) within the cell. Though the RNS - nitric oxide (.NO) and peroxynitrite (ONOO-) - play pivotal physiological roles, at elevated concentrations, these moieties can be poisonous to both prokaryotic and eukaryotic cells alike due to their capacity to disrupt a variety of essential biological processes. Numerous microbes are known to adapt to nitrosative stress by elaborating intricate strategies aimed at neutralizing RNS. In this review, we will discuss both the enzymatic systems dedicated to the elimination of RNS as well as the metabolic networks that are tailored to generate RNS-detoxifying metabolites - alpha-keto-acids. The latter has been demonstrated to nullify RNS via non-enzymatic decarboxylation resulting in the production of a carboxylic acid, many of which are potent signaling molecules. Furthermore, as aerobic energy production is severely impeded during nitrosative stress, alternative ATP-generating modules will be explored. To that end, a holistic understanding of the molecular adaptation to nitrosative stress, reinforces the notion that neutralization of toxicants necessitates significant metabolic reconfiguration to facilitate cell survival. As the alarming rise in antimicrobial resistant pathogens continues unabated, this review will also discuss the potential for developing therapies that target the alternative ATP generating machinery of bacteria. PMID- 28622141 TI - Analysis of structural brain MRI and multi-parameter classification for Alzheimer's disease. AB - Incorporating with machine learning technology, neuroimaging markers which extracted from structural Magnetic Resonance Images (sMRI), can help distinguish Alzheimer's Disease (AD) patients from Healthy Controls (HC). In the present study, we aim to investigate differences in atrophic regions between HC and AD and apply machine learning methods to classify these two groups. T1-weighted sMRI scans of 158 patients with AD and 145 age-matched HC were acquired from the ADNI database. Five kinds of parameters (i.e. cortical thickness, surface area, gray matter volume, curvature and sulcal depth) were obtained through the preprocessing steps. The recursive feature elimination (RFE) method for support vector machine (SVM) and leave-one-out cross validation (LOOCV) were applied to determine the optimal feature dimensions. Each kind of parameter was trained by SVM algorithm to acquire a classifier, which was used to classify HC and AD ultimately. Moreover, the ROC curves were depicted for testing the classifiers' performance and the SVM classifiers of two-dimensional spaces took the top two important features as classification features for separating HC and AD to the maximum extent. The results showed that the decreased cortical thickness and gray matter volume dramatically exhibited the trend of atrophy. The key differences between AD and HC existed in the cortical thickness and gray matter volume of the entorhinal cortex and medial orbitofrontal cortex. In terms of classification results, an optimal accuracy of 90.76% was obtained via multi-parameter combination (i.e. cortical thickness, gray matter volume and surface area). Meanwhile, the receiver operating characteristic (ROC) curves and area under the curve (AUC) were also verified multi-parameter combination could reach a better classification performance (AUC=0.94) after the SVM-RFE method. The results could be well prove that multi-parameter combination could provide more useful classified features from multivariate anatomical structure than single parameter. In addition, as cortical thickness and multi-parameter combination contained more important classified information with fewer feature dimensions after feature selection, it could be optimum to separate HC from AD to take the top two important features of them to construct SVM classifiers in two-dimensional space. The proposed work is a promising approach suggesting an important role for machine-learning based diagnostic image analysis for clinical practice. PMID- 28622142 TI - Birth weight discordance and adverse perinatal outcomes. AB - OBJECTIVE: Our purpose was to examine the association between discordant growth and perinatal mortality and morbidity among twins with careful adjustment for maternal confounding factors. STUDY DESIGN: Two cohorts with and without chorionicity data were compared using generalized estimating modeling. RESULTS: Our population-based dataset consisted of 12,656 individual twins from whom 4% (452/12,656) had>=30% growth discordance. A subgroup of this population with chorionicity information had an incidence of 7.3%>=30% growth discordance. In growth-discordant twins, perinatal mortality and morbidity were higher than concordant pairs (P<0.01). Low Apgar score and perinatal mortality were more frequent in growth-discordant twins compared with growth-concordant ones (all P<0.01). CONCLUSION: Birth weight discordance (BWD) places twins at increased risk of perinatal mortality. Growth discordance was also an independent risk factor for lower Apgar score of 5 min less than 5. PMID- 28622143 TI - Epidural analgesia at trial of labor after cesarean (TOLAC): a significant adjunct to successful vaginal birth after cesarean (VBAC). AB - INTRODUCTION: Epidural analgesia has been considered a risk factor for labor dystocia at trial of labor after cesarean (TOLAC) and uterine rupture. We evaluated the association between exposure to epidural during TOLAC and mode of delivery and maternal-neonatal outcomes. MATERIALS AND METHODS: A single center retrospective study of women that consented to TOLAC within a strict protocol between 2006 and 2013. Epidural "users" were compared to "non-users". Primary outcome was the mode of delivery: repeat in-labor cesarean or vaginal birth after cesarean (VBAC). Secondary outcomes were maternal/neonatal morbidities. Univariate/multivariate analyses for associations between epidural and mode of delivery were adjusted for significant covariates/mediators. RESULTS: Of a total of 105,471 births registered, 9464 (9.0%) were eligible for TOLAC; 7149 (75.5%) women consented to TOLAC, among which 4081 (57.1%) had epidural analgesia. The in labor cesarean rate was significantly lower for the epidural "users" 8.7% vs. "non-users" 11.8%, P<0.0001, with a parallel increased rate of instrumental delivery. Uterine rupture rates were comparable: 0.4% and 0.29%, respectively (P=0.31). The adjusted multivariate model showed that epidural "users" were more likely to experience a VBAC, odds ratio (OR) 4.58 [3.67; 5.70]; P<0.0001 with a similar rate of adverse maternal-neonatal outcomes. CONCLUSION: Epidural analgesia at TOLAC may emerge as a safe and significant adjunct for VBAC. PMID- 28622144 TI - A technological advance for 21st century obstetricians: the electronically controlled vacuum extractor. AB - OBJECTIVE: To describe an innovative electronically-controlled vacuum extractor (VE) in detail and to illustrate its performance characteristics, as observed in a laboratory study. DESIGN: Thirty simulated, vacuum-assisted deliveries. MAIN OUTCOME MEASURE(S): (1) The ability to measure in real-time of the pull applied and to sound an alert, when the traction approaches the negative pressure under the cup, to prevent its detachment. (2) The recording and printing of a graphic representation of the pull applied (vacuum delivery graph). (3) The emission of a warning signal when the 15-min time limit of continuous cup application on the fetal scalp, is reached. RESULTS: No cup detachment occurred in any of the 15 vacuum-assisted deliveries, in which traction was kept below the adhesive force of the cup [44 lb (20 kg)], except in three cases, due to loss of negative pressure. In the remaining 15 tests, in which traction was greater than the adhesive force of the cup, "pull-offs" inevitably occurred. Furthermore, upon reaching the 15-min time limit of continuous cup application on the fetal cephalic model, a warning signal was emitted, as programmed. Conclusions We demonstrated that the electronically-controlled VE, with its distinctive pull sensing handle, performs suitably for its intended purposes. The ability of the modernized device to decrease the incidence of cup detachment, secondary to the inadvertent application of excessive traction, may result in considerable safety, medico-legal and didactic advantages. PMID- 28622145 TI - Clinical analyses of 383 cases with maternal cardiac diseases. AB - AIM: To evaluate the pregnancy outcomes of women with heart disease. MATERIALS AND METHODS: In this retrospective study, 383 pregnant women with cardiac diseases were examined. The cases were classified according to the World Health Organization (WHO) classification. The distribution of the cases according to class, congenital heart diseases, mean birthweight, mean gestational week at delivery, type of delivery [cesarean section (CS) or vaginal delivery], and cardivascular events (during pregnancy and puerperium) were evaluated. RESULTS: Of the 383 patients, 25 were in Class I; 39, Class II; 255, Class II or III; 31, Class III; and 33, Class IV cardiac diseases. The neonatal birth weights were significantly lower in Class III than in Classes II, and II or III. The preterm delivery rate was higher in Class III than in the other classes. Delivery was performed by CS due to cardiac indications in the high-risk classes, however, only obstetric indications were considered in the low-risk classes. Only one case of maternal death occurred during the postpartum period, in a patient with Eisenmenger's syndrome. DISCUSSION: Cardiovascular diseases are an important cause of mortality and morbidity in pregnancy. The adverse impact of cardiovascular disorders on pregnancy outcomes should be the main concern during the management of these women. PMID- 28622146 TI - Relationship between various maternal conditions and lactic acid dehydrogenase activity in umbilical cord blood at birth. AB - BACKGROUND: Lactic acid dehydrogenase (LDH) is a valuable marker for some of the most important diseases in newborns and the plasma LDH activity in newborns correlates well with conditions such as asphyxia. If LDH should be considered as a useful tool also in obstetric care, key factors associated with maternal health before and during pregnancy which could affect umbilical cord LDH activity need to be known. The aims of this study were to explore relationships between selected maternal conditions and arterial lactic acid dehydrogenase activity (aLDH) in umbilical cord blood at delivery. METHODS: A prospective observational study was conducted at Sodersjukhuset, Stockholm, Sweden. Included in the study were 1247 deliveries, and cord blood samples from each were analyzed for aLDH. Background, delivery and neonatal data were collected from the medical records. RESULTS: Higher median values of aLDH were found (P=0.001) among women with chronic disorders not related to pregnancy but there was no increased frequency of high aLDH levels (>612 MU/L, P=0.30). No difference in aLDH was identified between infants born to women with pregnancy-related disorders compared with healthy women, neither in median values, nor in high values (>612 MU/L, P=0.95). CONCLUSION: Newborn infants born to women with non-pregnancy-related chronic disorders had a somewhat higher median value of aLDH in cord blood at delivery. The influence of common maternal conditions and diseases on umbilical cord arterial LDH levels is small compared to the increase reported in fetal distress and several other critical conditions in the newborn. PMID- 28622147 TI - Brachiocephalic Vein Perforation During Cannulation of Internal Jugular Vein: A Case Report. AB - We report a rare complication of right brachiocephalic vein perforation during ultrasound-guided cannulation of the right internal jugular vein (IJV) in a patient with a tortuous common carotid artery (CCA). We suspect that the tortuous CCA displaced the IJV, which caused misplacement of the J-tip guidewire into the subclavian vein. The stiff dilator sheath introduced over the guidewire then perforated the wall of the brachiocephalic vein, causing massive hemothorax. This was diagnosed by videothoracoscopy. Anesthesiologists should be aware of the possibility of guidewire malposition during IJV catheterization in patients with a tortuous CCA. PMID- 28622148 TI - In Response. PMID- 28622149 TI - Definitive Airway Management in the Presence of a Laryngeal Tube Supraglottic Airway: "There's More Than One Way to Skin a Cat". PMID- 28622150 TI - Intraoperative Hyperkalemia and Ventricular Arrhythmia During Parathyroidectomy: A Case Report. AB - We present a case of acute hyperkalemia and ventricular arrhythmia during parathyroidectomy in a patient with end-stage renal disease. This case highlights the under-recognized alterations in potassium homeostasis associated with parathyroidectomy and underscores the importance of preoperative optimization. PMID- 28622151 TI - Two Consecutive Preoperative Cardiac Arrests Involving Vancomycin in a Patient Presenting for Hip Disarticulation: A Case Report. AB - While an abundance of literature exists describing adverse reactions to vancomycin (eg, nausea, vomiting, red man syndrome, acute kidney injury), there is scarce evidence demonstrating vancomycin anaphylactic reactions requiring cardiopulmonary resuscitation. We report a case of a patient who had 2 separate preoperative episodes of cardiac arrest following vancomycin that occurred 4 weeks apart. Both episodes of anaphylaxis required cardiopulmonary resuscitation, which led to a successful patient outcome. We discuss identification and treatment of vancomycin-induced anaphylaxis. PMID- 28622152 TI - Use of Transnasal Humidified Rapid-Insufflation Ventilatory Exchange for Emergent Surgical Tracheostomy: A Case Report. AB - Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) is a novel airway technique that utilizes high-flow humidified nasal oxygen. It can extend apnea time and maintain oxygen saturation. Here we report the use of THRIVE in a 35-year-old man who required emergent surgical tracheostomy for a clinically relevant compromised airway secondary to acute supraglottic and glottic pathology. Intravenous sedation resulted in hypoventilation close to apnea. THRIVE maintained oxygen saturation for 40 minutes until transient desaturation developed after complete airway obstruction. PMID- 28622153 TI - Extraskeletal Osteosarcoma: Outcomes and the Role of Chemotherapy. AB - OBJECTIVES: Extraskeletal osteosarcoma (EO) is a malignant neoplasm that produces osteoid, bone, and chondroid material without direct attachment to bone or periosteum. Surgical resection is the mainstay of treatment; the role of chemotherapy is not well defined. Therefore, we evaluated the impact of chemotherapy in the survival of patients with EO. METHODS: All EO patients seen at Mayo Clinic between 1990 and 2014 were assessed. Forty-three patients were included after all archived pathology slides were reviewed to confirm the diagnosis of EO. RESULTS: Of 43 patients, 37 patients had localized disease and 6 patients had metastatic disease at diagnosis. Chemotherapy was used in 73% and 75% of patients, respectively. Chemotherapy was predominantly anthracycline based, and included platinum in 22 patients (84%).Median overall survival (OS) and progression-free survival (PFS) were 50 months (95% confidence interval, 25 99), and 21 months (95% confidence interval, 13-not reached), respectively. There was a trend towards longer OS and PFS in patients who received chemotherapy. Those who received platinum-based therapy had remarkably prolonged OS (median, 182 vs. 18 mo; 5-year, 61% vs. 0%; P=0.01) and PFS (median, not reached vs. 10 mo; 5-year, 56% vs. 0%; P=0.005). Baseline characteristics were similar in the platinum and nonplatinum group.In patients who received chemotherapy, relapse/recurrence rate was lower in the platinum-based group (41%) as opposed to the nonplatinum-based group (100%; P=0.02). In the neoadjuvant setting, the overall response rate of platinum-containing regimens was 27%. CONCLUSIONS: Our results suggest a clinical benefit when platinum-based chemotherapy is incorporated in the management of patients with EO. We plan to validate this further with an expanded multicenter analysis. PMID- 28622154 TI - Operative Treatment of 2-Part Surgical Neck Fracture of the Humerus: Intramedullary Nail Versus Locking Compression Plate With Technical Consideration. AB - OBJECTIVE: To compare the outcomes of patients who underwent either open reduction internal fixation with a locking plate and screws or closed reduction internal fixation with an antegrade intramedullary nail (IMN) for displaced surgical neck fracture of the humerus. DESIGN: Retrospective comparative study. SETTING: Single institute, Level-I academic trauma center. PATIENTS AND INTERVENTION: Sixty-nine patients with 2-part surgical neck fracture of the humerus underwent either an IMN (38 patients group A) or a locked plate fixation (31 patients group B). OUTCOMES MEASUREMENT: Pain on a visual analog scale, University of California Los Angeles (UCLA) Shoulder Score, American Shoulder and Elbow Surgeons (ASES) score, and active range of motion (ROM). RESULTS: At the 2 year follow-up, there were no significant differences in the visual analog scale pain score (1.3 in group A; 0.9 in group B), ASES score (90.2 in group A; 91.9 in group B), and UCLA Shoulder Score (30.7 in group A; 31.8 in group B) between groups. Active ROM did not differ significantly between groups. There were 3 complications in the IMN group, 1 nonunion requiring autogenous iliac crest bone graft, and 2 cases of screw loosening. CONCLUSIONS: For displaced surgical neck fractures of the humerus, both IM nailing and locked plate fixation in patients yielded satisfactory outcomes at the 2-year follow-up with no significant differences in pain or ROM between groups. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28622155 TI - TRIAD IX: Can a Patient Testimonial Safely Help Ensure Prehospital Appropriate Critical Versus End-of-Life Care? AB - OBJECTIVE: The present study sought to assess the clarity of Physician Orders for Life-Sustaining Treatment (POLST) or Living Will (LW) documents alone or in combination with a video message/testimonial (VM). METHODS: Emergency medical services (EMS) personnel responded to survey questions about the meaning of stand alone POLST and LW documents and those used in conjunction with emergent care scenarios. Personnel were randomized to receive documents only or documents with VM. Questions sought a code status for each scenario and a resuscitation decision. Code status responses were analyzed for consensus (95% response rate), resuscitation responses for correct treatment decisions. RESULTS: The survey response rate was 85%. Approximately half of emergency medical technician (EMT) respondents were EMT basic, and half EMT respondents were paramedic, with an average age of 42 years. Less than half had previous POLST/LW training averaging 2 hours. Consensus failed to be reached for stand-alone documents. For clinical scenarios, responses to POLST documents specifying do not resuscitate/comfort measures only or cardiopulmonary resuscitation/full treatment exceeded 80% for code status designation and correct resuscitation decisions. Other POLST resuscitation/treatment combinations showed more disparate responses, and most benefited from VM with changes in responses of 20% or more (P <= 0.025). Code status responses to LW-based scenarios evidenced a nonconsensus majority (79% 83%) that was significantly affected with VMs (>=12%, P <= 0.004); half evidenced large changes in resuscitation decisions (49%, P < 0.001). CONCLUSIONS: Document clarity, judged by consensus response, was rarely evidenced. video message/testimonial seems to be a helpful aid to both POLST and LWs. Standardized education and training reveal opportunities to improve patient safety to ensure patient wishes. PMID- 28622156 TI - Aerobic versus isometric handgrip exercise in hypertension: a randomized controlled trial. AB - OBJECTIVES: Aerobic dynamic exercise reduces blood pressure (BP) and is broadly recommended by current American and European hypertension guidelines. Isometric exercise is currently not recommended, since data from only a few studies are available. We compare for the first time the effects of isometric handgrip training and aerobic exercise in a randomized controlled trial. METHODS: A total of 75 hypertensive patients were randomized to one of the following 12-week programmes: Isometric handgrip training five times weekly (two contractions of 2 min at 30% of maximal power with each arm); 'Sham-handgrip training' five times weekly (two contractions of 2 min at 5% of maximal power with each arm); Aerobic exercise training of 30 min three to five times per week. All patients underwent office BP measurement, 24-h ambulatory BP measurement and noninvasive assessment of arterial compliance and systemic vascular resistance at baseline and after 12 weeks. RESULTS: Baseline epidemiological and hemodynamic characteristics did not differ between groups. Aerobic exercise led to a significant reduction of systolic 24-h BP (P = 0.025), office SBP (P = 0.03), systemic vascular resistance (P = 0.001) and small artery elasticity index (P = 0.005). There were no statistical significant changes of these parameters in the isometric exercise and the 'sham exercise' groups (P > 0.05 each). CONCLUSION: Isometric handgrip training, performed according to a typical protocol, did not reduce BP in hypertensive patients. Aerobic exercise, even as an uncontrolled and unsupervised exercise regimen, led to a significant reduction of ambulatory and office BP. PMID- 28622157 TI - Predictors of 5-year outcomes in malignant phase hypertension: the West Birmingham Malignant Hypertension Registry. AB - OBJECTIVE: Malignant hypertension represents a high-risk condition and there are scarce data on current clinical patterns of this condition. The aim of the study is to identify the clinical and demographic factors associated with poor outcome. METHODS: The data collected from 1958 to May 2016 included a total of 351 patients whose 5-year survival status was known: 221 white Caucasians (63%, age 51 +/- 13 years, 64% male), 83 African-Caribbeans (24%, 45 +/- 11 years, 61% male), and 47 South Asians (13%, 42 +/- 11 years, 74% male). RESULTS: During the 5-year follow-up 119 (34%) patients suffered a primary outcome, defined as the composite endpoint of death or dialysis. The 5-year mortality ranged from 76% in patients diagnosed before 1967 to 7% in patients diagnosed between 1997 and 2006. The independent predictors of outcome were advanced age (vs. a reference group of < 40-year-old; P = 0.01 for age at presentation 51-60 years, P < 0.001 for age > 60 years), prior use of antihypertensive medications (P = 0.002), higher serum creatinine (P = 0.006), and proteinuria (P < 0.01). Also, white Caucasian (odds ratio12.02, 95% confidence interval 1.64-88.15, P = 0.01) and African-Caribbean (odds ratio 15.55, 95% confidence interval 2.06-117.29, P = 0.008) origins were associated with higher mortality vs. South Asians. The years of the diagnosis after 1977 were significantly associated with lower composite endpoint of death or dialysis, all P < 0.01. CONCLUSION: There has been a major improvement in 5 year survival in patients with malignant hypertension over recent decades. Abnormal renal function at presentation still predicts worse outcome. South Asian ethnicity is also associated with better outcome, although mechanisms involved are yet to be established. PMID- 28622160 TI - History of Neuro-Ophthalmology in Argentina. PMID- 28622159 TI - Weeding Out the Justification for Marijuana Treatment in Patients with Developmental and Behavioral Conditions. AB - CASE: Alex is a 13-year-old adolescent with high-functioning autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD)-combined type, anxiety, and depression. He has been resistant to engaging in therapy and treatment with various medications has been unsuccessful. Alex's parents are concerned about his anxiety, isolation, oppositional behaviors, academic underachievement, truancy, and substance use. A recent altercation with his stepfather led to a police intervention and a brief removal of Alex from the home. Alex previously used alcohol and other drugs; at present, he reports that his current drug use consists of frequently smoking pot. Alex states that he uses marijuana to relieve his anxiety and does not understand why this is problematic as marijuana is now legal in his state.Kevin is a 24-year-old adult man with diagnoses of autism spectrum disorder, mild intellectual disability, and schizoaffective disorder. He has a long history of challenging and problematic behaviors including aggression toward self and others, property destruction, inappropriate sexual behaviors, elopement, emotional outbursts, anxiety, and suicidal ideation. Past diagnoses include bipolar affective disorder, depression, and intermittent explosive disorder. Kevin is notably obese and somnolent. His current medications include 8 psychotropic medications, 3 antiallergy medications, levothyroxine, and a fish oil supplement. His father reports that medications have gradually been added and dosages increased over time. Two weeks ago, his new psychiatrist initiated a trial of medical marijuana. His father hopes that the marijuana will allow Kevin's other medications to be decreased or discontinued.Linda is an 11-year-old girl with high-functioning autism spectrum disorder, anxiety, and ADHD inattentive subtype. Anxiety has been her most impairing condition, and Linda has been responding well to a treatment with cognitive behavioral therapy and a selective serotonin reuptake inhibitor. She is also working with her therapist on strategies to address her symptoms of ADHD. Linda has had no side effects from her medication and she and her family have been pleased with her progress. At a follow-up appointment, her mother brings an article from the lay press authored by a parent who claims that marijuana "saved" her autistic son. Linda's mother asks if marijuana should be considered for her daughter. PMID- 28622158 TI - General Anesthesia and Young Brain: What is New? AB - Considering that growing population of very young children is exposed to general anesthesia every year, it is of utmost importance to understand how and whether such practice may affect the development and growth of their very immature and vulnerable brains. Compelling evidence from animal studies suggests that an early exposure to general anesthesia is detrimental to normal brain development leading to structural and functional impairments of neurons and glia, and long-lasting impairments in normal emotional and cognitive development. Although the evidence from animal studies is overwhelming and confirmed across species examined from rodents to non-human primates, the evidence from human studies is inconsistent and not conclusive at present. In this review we focus on new developments in animal studies of anesthesia-induced developmental neurotoxicity and summarize recent clinical studies while focusing on outcome measures and exposure variables in terms of their utility for assessing cognitive and behavioral development in children. PMID- 28622161 TI - Antipsychotic Use Among Adult Outpatients and Venous Thromboembolic Disease: A Retrospective Cohort Study. AB - BACKGROUND: Treatment with antipsychotic (AP) agents is associated with incident thromboembolic events. However, the underpinnings of this association remain unknown. We sought to evaluate the effect of AP agents-categorized by their metabolic/sedative and hyperprolactinemia adverse effect profile-on the risk of venous thromboembolic disease during long-term follow-up. METHODS: A retrospective cohort study of adult patients initiating AP treatment for the first time was conducted. Primary outcome was defined as the time to venous thromboembolism (VTE) (either deep venous thrombosis or acute pulmonary embolism). Antipsychotic agents were categorized by their risk (high vs low) of either drug-induced (a) sedation/metabolic adverse event or (b) hyperprolactinemia. We used a propensity score-adjusted Cox proportional hazards model to control for confounding. FINDINGS: One thousand eight patients (mean age, 72.4 y) were followed for a median of 36 months. Incident VTE occurred in 6.25% of patients, corresponding to an incidence rate of 184 cases per 10,000 person-years. We found no difference in the hazard of VTE during follow-up between high- and low-risk groups (hazard ratio, 1.23 [95% confidence interval, 0.74-2.04] for drug-induced sedation/metabolic adverse event risk categories, and hazard ratio 0.81 [95% confidence interval, 0.50-1.35] for high versus low hyperprolactinemia risk). CONCLUSIONS: These results suggest that the risk of thromboembolic events in older adults who started AP treatment for the first time does not seem to be related to these drugs' risk of either sedation/metabolic adverse events or hyperprolactinemia. However, VTE remains a common problem in this subgroup of patients. PMID- 28622164 TI - Measuring Left Ventricular Size in Non-Electrocardiographic-gated Chest Computed Tomography: What Radiologists Should Know. AB - Non-electrocardiographic (ECG)-gated computed tomography (CT) of the chest is one of the most commonly performed imaging studies. Although the heart is included in every CT study, cardiac findings are commonly underreported in radiology reports. Left ventricular size is one of the most important prognostic markers in multiple cardiac diseases and can be measured on almost all non-ECG-gated multidetector chest CT studies. This review will discuss the available evidence on different measurements of left ventricular size obtained on non-ECG-gated CT of the chest. Measurement thresholds, technical issues, and potential problems are emphasized, with practical recommendations. PMID- 28622165 TI - Thoracic Imaging After Bariatric Surgery. AB - Obesity and its association with long-term health problems constitutes one of the major challenges in medicine. Though diet regulation and exercise are the primary treatment strategies, surgery is the most reliable long-term solution. Although bariatric surgical complications continue to decline, prompt recognition is essential to optimize patient outcomes. Despite their relative rarity, it is important to recognize thoracic complications, as several of these can result in severe morbidity and mortality. This article describes common bariatric surgical procedures performed, their expected postoperative appearances, and intrathoracic complications. PMID- 28622163 TI - Novel roles for mucin 1 in the kidney. AB - PURPOSE OF REVIEW: Recent studies in the kidney have revealed that the well characterized tumor antigen mucin 1 (MUC1/Muc1) also has numerous functions in the normal and injured kidney. RECENT FINDINGS: Mucin 1 is a transmembrane mucin with a robust glycan-dependent apical targeting signal and efficient recycling from endosomes. It was recently reported that the TRPV5 calcium channel is stabilized on the cell surface by galectin-dependent cross-linking to mucin 1, providing a novel mechanism for regulation of ion channels and normal electrolyte balance.Our recent studies in mice show that Muc 1 is induced after ischemia, stabilizing hypoxia-inducible factor 1 (HIF-1)alpha and beta-catenin levels, and transactivating the HIF-1 and beta-catenin protective pathways. However, prolonged induction of either pathway in the injured kidney can proceed from apparent full recovery to chronic kidney disease. A very recent report indicates that aberrant activation of mucin 1 signaling after ischemic injury in mice and humans is associated with development of chronic kidney disease and fibrosis. A frameshift mutation in MUC1 was recently identified as the genetic lesion causing medullary cystic kidney disease type 1, now appropriately renamed MUC1 Kidney Disease. SUMMARY: Studies of mucin 1 in the kidney now reveal significant functions for the extracellular mucin-like domain and signaling through the cytoplasmic tail. PMID- 28622166 TI - Quantitative Analysis of Iodine Image of Dual-energy Computed Tomography at Rest: Comparison With 99mTc-Tetrofosmin Stress-rest Single-photon Emission Computed Tomography Myocardial Perfusion Imaging as the Reference Standard. AB - PURPOSE: Dual-energy computed tomography (DECT) can be used for visual determination of iodine distribution in the myocardium (iodine image); however, the accuracy and reproducibility of the process remains debatable. Because of the low contrast-to-noise ratio of CT, we hypothesized that quantitative measurement may be more accurate for detecting myocardial ischemia. In this study, we evaluated our quantitative method by comparing it with visual analysis using Tc tetrofosmin (TF) stress-rest single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) as the reference standard. MATERIALS AND METHODS: Forty-three patients who had a significant stenosis on cardiac rest DECT and had received Tc-TF stress-rest SPECT MPI within 1 month were retrospectively analyzed. The regions of interest were set on iodine images in accordance with the American Heart Association (AHA) 17-segment model (a total of 731 segments). The regions of interest values were divided by the amount of iodine (mg) per unit weight (kg) and defined as perfusion value (perfusion value analysis). All segments were also visually analyzed and receiver operating characteristic curve analysis performed to identify the superior analysis. RESULTS: The receiver operating characteristic curve analysis showed that perfusion value analysis is significantly superior to visual analysis [the area under the curve: 0.921 (95% confidence interval, 0.860-0.981) versus 0.685 (95% confidence interval, 0.580 0.791), respectively, P<0.05], with 93.8% sensitivity, 99.1% specificity, 98.9% accuracy, 83.3% positive predictive value, and 99.7% negative predictive value (P<0.01). CONCLUSIONS: Quantitative analysis of the iodine image of rest DECT, called perfusion value analysis, is more accurate than visual analysis when compared with Tc-TF SPECT MPI as the reference standard. PMID- 28622167 TI - Statin and Its Association With Delirium in the Medical ICU. AB - OBJECTIVES: To examine the association between statin use and the risk of delirium in hospitalized patients with an admission to the medical ICU. DESIGN: Retrospective propensity-matched cohort analysis with accrual from September 1, 2012, to September 30, 2015. SETTING: Hartford Hospital, Hartford, CT. PATIENTS: An initial population of patients with an admission to a medical ICU totaling 10,216 visits were screened for delirium by means of the Confusion Assessment Method. After exclusions, a population of 6,664 was used to match statin users and nonstatin users. The propensity-matched cohort resulted in a sample of 1,475 patients receiving statin matched 1:1 with control patients not using statin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Delirium defined as a positive Confusion Assessment Method assessment was the primary end point. The prevalence of delirium was 22.3% in the unmatched cohort and 22.8% in the propensity-matched cohort. Statin use was associated with a significant decrease in the risk of delirium (odds ratio, 0.47; 95% CI, 0.38-0.56). Considering the type of statin used, atorvastatin (0.51; 0.41-0.64), pravastatin (0.40; 0.28 0.58), and simvastatin (0.33; 0.21-0.52) were all significantly associated with a reduced frequency of delirium. CONCLUSIONS: The use of statins was independently associated with a reduction in the risk of delirium in hospitalized patients. When considering types of statins used, this reduction was significant in patients using atorvastatin, pravastatin, and simvastatin. Randomized trials of various statin types in hospitalized patients prone to delirium should validate their use in protection from delirium. PMID- 28622168 TI - ICU Telemedicine: Financial Analyses of a Complex Intervention. PMID- 28622170 TI - Skin allergy. PMID- 28622171 TI - Reactions to cytostatic agents in children. AB - PURPOSE OF REVIEW: The current review will focus on drug hypersensitivity reactions to chemotherapy specifically to those drugs most used in children. We know that potentially all chemotherapeutic agents can cause infusion reactions, generally defined as adverse drug reactions. Of these, some are Type A, defined as expected and described in the characteristics of the drug and others, and Type B, defined as unexpected reactions which cannot be explained by the known toxicity profile of the drug. When an unexpected reaction occurs, drugs we can refer as hypersensitivity reactions (HSRs). Some of these (HSRs) are allergic reactions as they have an underlying immunologic mechanism. In general, the cytotoxic agents most commonly associated with HSRs are the platinum salts derivatives, taxanes, pegylated liposomal doxorubicin, L-asparaginase, procarbazine, etoposide, bleomycin, and cytarabin. RECENT FINDINGS: HSRs may also occur in children with cancer, during the treatment with chemotherapeutic drugs. The most used drugs of this group in children to cause HSRs are: carboplatin, L asparaginase, and methothrexate. The aim of this review is to summarize the incidence and the clinical features of HSRs occurring with these drugs in children. SUMMARY: The aim of this review is to summarize the incidence and the clinical features of HSRs occurring with these drugs in children. The current review will focus on the most involved drugs in children, the type of reactions, the mechanisms involved, and the best way to manage them. PMID- 28622172 TI - In Response. PMID- 28622169 TI - Molecular aspects of allergens in atopic dermatitis. AB - PURPOSE OF REVIEW: Molecular allergology uses pure, mainly recombinant and structurally defined allergen molecules and allergen-derived epitopes to study mechanisms of IgE-associated allergy, to diagnose, and even predict the development of allergic manifestations and to treat and prevent IgE-associated allergies. Atopic dermatitis, a chronic inflammatory skin disease is almost always associated with IgE sensitization to allergens. However, also non-IgE mediated pathomechanisms seem to be operative in atopic dermatitis and it is often difficult to identify the disease-causing allergens. Here we review recent work showing the usefulness of molecular allergology to study mechanisms of atopic dermatitis, for diagnosis and eventually for treatment and prevention of atopic dermatitis. RECENT FINDINGS: IgE sensitization to airborne, food-derived, microbial allergens, and autoallergens has been found to be associated with atopic dermatitis. Using defined allergen molecules and non-IgE-reactive allergen derivatives, evidence could be provided for the existence of IgE- and non-IgE mediated mechanisms of inflammation in atopic dermatitis. Furthermore, effects of epicutaneous allergen administration on systemic allergen-specific immune responses have been studied. Multi-allergen tests containing micro-arrayed allergen molecules have been shown to be useful for the identification of culprit allergens in atopic dermatitis and may improve the management of atopic dermatitis by allergen-specific immunotherapy, allergen avoidance, and IgE targeting therapies in a personalized medicine approach. SUMMARY: Molecular allergology allows for dissection of the pathomechanisms of atopic dermatitis, provides new forms of allergy diagnosis for identification of disease-causing allergens, and opens the door to new forms of management by allergen-specific and T cells-targeting or IgE-targeting interventions in a personalized medicine approach. PMID- 28622173 TI - Does Memory Consolidation by Anesthetics Relate to a Time Window of Age? PMID- 28622175 TI - Predictors, Prognosis, and Management of New Clinically Important Atrial Fibrillation After Noncardiac Surgery: A Prospective Cohort Study. AB - BACKGROUND: Despite the frequency of new clinically important atrial fibrillation (AF) after noncardiac surgery and its increased association with the risk of stroke at 30 days, there are limited data informing their prediction, association with outcomes, and management. METHODS: We used the data from the PeriOperative ISchemic Evaluation trial to determine, in patients undergoing noncardiac surgery, the association of new clinically important AF with 30-day outcomes, and to assess management of these patients. We also aimed to derive a clinical prediction rule for new clinically important AF in this population. We defined new clinically important AF as new AF that resulted in symptoms or required treatment. We recorded an electrocardiogram 6 to 12 hours postoperatively and on the 1st, 2nd, and 30th days after surgery. RESULTS: A total of 211 (2.5% [8351 patients]; 95% confidence interval, 2.2%-2.9%) patients developed new clinically important AF within 30 days of randomization (8140 did not develop new AF). AF was independently associated with an increased length of hospital stay by 6.0 days (95% confidence interval, 3.5-8.5 days) and vascular complications (eg, stroke or congestive heart failure). The usage of an oral anticoagulant at the time of hospital discharge among patients with new AF and a CHADS2 score of 0, 1, 2, 3, and >=4 was 6.9%, 10.2%, 23.0%, 9.4%, and 33.3%, respectively. Two independent predictors of patients developing new clinically important AF were identified (ie, age and surgery). The prediction rule included the following factors and assigned weights: age >=85 years (4 points), age 75 to 84 years (3 points), age 65 to 74 years (2 points), intrathoracic surgery (3 points), major vascular surgery (2 points), and intra-abdominal surgery (1 point). The incidence of new AF based on scores of 0 to 1, 2, 3 to 4, and 5 to 6 was 0.5%, 1.0%, 3.1%, and 5.3%, respectively. CONCLUSIONS: Age and surgery are independent predictors of new clinically important AF in the perioperative setting. A minority of patients developing new clinically important AF with high CHADS2 scores are discharged on an oral anticoagulant. There is a need to develop effective and safe interventions to prevent this outcome and to optimize the management of this event when it occurs. PMID- 28622176 TI - Impact of Sternotomy and Pericardial Opening in Patients With Ventricular Septal Defects: Assess Before Sawing! PMID- 28622174 TI - Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3beta/Mitochondrial Fission Pathway. AB - BACKGROUND: Growing animal evidence demonstrates that prolonged exposure to propofol during brain development induces widespread neuronal cell death, but there is little information on the role of astrocytes. Astrocytes can release neurotrophic growth factors such as brain-derived neurotrophic factor (BDNF), which can exert the protective effect on neurons in paracrine fashion. We hypothesize that during propofol anesthesia, BDNF released from developing astrocytes may not be sufficient to prevent propofol-induced neurotoxicity. METHODS: Hippocampal astrocytes and neurons isolated from neonatal Sprague Dawley rats were exposed to propofol at a clinically relevant dose of 30 MUM or dimethyl sulfoxide as control for 6 hours. Propofol-induced cell death was determined by propidium iodide (PI) staining in astrocyte-alone cultures, neuron-alone cultures, or cocultures containing either low or high density of astrocytes (1:9 or 1:1 ratio of astrocytes to neurons ratio [ANR], respectively). The astrocyte conditioned medium was collected 12 hours after propofol exposure and measured by protein array assay. BDNF concentration in astrocyte-conditioned medium was quantified using enzyme-linked immunosorbent assay. Neuron-alone cultures were treated with BDNF, tyrosine receptor kinase B inhibitor cyclotraxin-B, glycogen synthase kinase 3beta (GSK3beta) inhibitor CHIR99021, or mitochondrial fission inhibitor Mdivi-1 before propofol exposure. Western blot was performed for quantification of the level of protein kinase B and GSK3beta. Mitochondrial shape was visualized through translocase of the outer membrane 20 staining. RESULTS: Propofol increased cell death in neurons by 1.8-fold (% of PI-positive cells [PI%] = 18.6; 95% confidence interval [CI], 15.2-21.9, P < .05) but did not influence astrocyte viability. The neuronal death was attenuated by a high ANR (1:1 cocultures; fold change [FC] = 1.17, 95% CI, 0.96-1.38, P < .05), but not with a low ANR [1:9 cocultures; FC = 1.87, 95% CI, 1.48-2.26, P > .05]). Astrocytes secreted BDNF in a cell density-dependent way and propofol decreased BDNF secretion from astrocytes. Administration of BDNF, CHIR99021, or Mdivi-1 significantly attenuated the propofol-induced neuronal death and aberrant mitochondria in neuron-alone cultures (FC = 0.8, 95% CI, 0.62-0.98; FC = 1.22, 95% CI, 1.11-1.32; FC = 1.35, 95% CI, 1.16-1.54, respectively, P < .05) and the cocultures with a low ANR (1:9; FC = 0.85, 95% CI, 0.74-0.97; FC = 1.08, 95% CI, 0.84-1.32; FC = 1.25, 95% CI, 1.1-1.39, respectively, P < .05). Blocking BDNF receptor or protein kinase B activity abolished astrocyte-induced neuroprotection in the cocultures with a high ANR (1:1). CONCLUSIONS: Astrocytes attenuate propofol-induced neurotoxicity through BDNF-mediated cell survival pathway suggesting multiple neuroprotective strategies such as administration of BDNF, astrocyte-conditioned medium, decreasing mitochondrial fission, or inhibition of GSK3beta. PMID- 28622177 TI - Postoperative Respiratory Complications in Patients at Risk for Obstructive Sleep Apnea: A Single-Institution Cohort Study. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a prevalent condition that is associated with early postoperative respiratory complications (PRCs). As the majority of patients with OSA are undiagnosed, preoperative screening remains the most efficient method to identify suspected OSA. METHODS: This retrospective study was performed on patients undergoing anesthesia in a single academic medical center. We assigned OSA risk class retrospectively to all patients in the study by using the Perioperative Sleep Apnea Prediction (PSAP) score. We evaluated the relationship between PSAP categories and early postoperative invasive airway placement after adjusting for several preoperative and intraoperative factors (including surgical risk) previously associated with PRC occurrence. RESULTS: A total of 108,479 patients were included in the final analysis with an incidence of PRC was 0.3% (n = 280). High PSAP score was associated with postoperative intubation (adjusted odds ratio, 2.3; 95% confidence interval, 1.5-3.7). Several risk factors reflecting anesthetic agents, neuromuscular blocking agents, and opioids were also independently associated with early PRC. CONCLUSIONS: We report that suspected OSA based on the PSAP score is independently associated with increased risk of early PRC. Specific anesthetic agents are independently associated with early PRC, pointing to the potential for examining risk modification through these exposures in future studies. PMID- 28622178 TI - Labor Analgesia Onset With Dural Puncture Epidural Versus Traditional Epidural Using a 26-Gauge Whitacre Needle and 0.125% Bupivacaine Bolus: A Randomized Clinical Trial. AB - BACKGROUND: Lumbar epidurals (LEs) provide excellent analgesia. Combined spinal epidural and dural puncture epidural (DPE) are 2 techniques to expedite neuraxial analgesia onset. In DPE, dura is punctured but medication is not administered in the cerebrospinal fluid. Expedited analgesia onset has been demonstrated with DPE, using 0.25% bupivacaine; however, this concentration may impede an unassisted vaginal birth and is not currently used for induction and maintenance of labor analgesia. The primary goal of this study was to compare the percentage of patients who achieved adequate labor analgesia following DPE or LE with an epidural bolus of 0.125% bupivacaine. Adequate labor analgesia was defined as Visual Analog Scale (VAS) measurement <= 10 mm on a 100-mm scale during active contractions, measured 10 minutes after epidural bolus initiation. METHODS: Laboring patients were randomly assigned to receive LE or DPE. Immediately before epidural placement, subjects marked a VAS score during an active contraction and parturients with VAS < 50 mm were excluded. The epidural space was identified by a loss of resistance technique to saline (17G Tuohy needle [Arrow International, Inc, Redding, PA]). In the DPE group, dura was punctured with a 26G Whitacre needle (Arrow International, Inc). In all participants, a 19G epidural catheter (Arrow International, Inc) was inserted. An epidural bolus was then administered over 3 minutes (12 mL, 0.125% bupivacaine, 50 MUg fentanyl) followed by infusion (0.1% bupivacaine, 2 MUg/mL fentanyl). After initiation of epidural bolus (time zero), VAS measurements were collected at 2-minute intervals for up to 20 minutes. Median time to achieve adequate analgesia by treatment group was assessed by Kaplan-Meier analysis. Time to achieving adequate analgesia was evaluated using a Cox regression model. All analyses were conducted in SAS version 9.4. (SAS Institute, Cary, NC) RESULTS:: Data were analyzed from 80 participants (40 per group). Adequate analgesia at 10 minutes did not differ by neuraxial technique (DPE = 55.3% vs LE = 44.7%; P= .256). However, parturients receiving DPE had shorter median times to adequate analgesia (median [95% confidence interval], 8 minutes [6-10] vs 10 minutes [8-14]) and a 67% increase in the relative risk of achieving adequate analgesia compared to LE (relative risk = 1.67; 95% confidence interval, 1.02-2.64; P= .042). CONCLUSIONS: Although the percentage of parturients achieving adequate labor analgesia at 10 minutes after epidural bolus did not differ by technique, DPE was associated with faster time to VAS <= 10 mm compared with LE. PMID- 28622179 TI - Paucicellular Fibrointimal Proliferation Characterizes Pediatric Pulmonary Vein Stenosis: Clinicopathologic Analysis of 213 Samples From 97 Patients. AB - Pulmonary vein stenosis (PVS) is a luminal narrowing of extrapulmonary pulmonary veins. In pediatric patients, it arises following repair of congenital heart disease, particularly anomalous pulmonary venous return; in lung disease, especially prematurity; and rarely in isolation. The etiology is unknown and the course often fatal without lung transplantation. We hypothesized that systematic clinicopathologic review of pediatric PVS could provide further pathogenic insight. We included patients who underwent first resection of pulmonary venous tissue for symptomatic PVS at our pediatric referral center from 1995 to 2014. Clinical records and hematoxylin and eosin slides were reviewed. Subsets were immunostained for smooth muscle actin, Ki-67, beta-catenin, estrogen receptor, and other markers and analyzed for USP6 gene rearrangement. A total of 97 patients (57% male; median age: 6 mo) were identified. Overall, 59 (61%) had prior congenital heart disease repair, 35 involving pulmonary vein manipulation. Samples included 213 separate anatomic sites (median: 2/patient). Histologically, all showed sparsely cellular intimal expansion composed of haphazardly arranged fibroblasts with slender nuclei in myxoid matrix. This tissue merged with underlying collagen. Most samples had a variably continuous sheath of cardiomyocytes. Ancillary tests supported a reactive fibroblastic proliferation; in particular, fibroblasts showed cytoplasmic beta-catenin localization, no estrogen receptor expression, and no USP6 rearrangement. At last follow-up (mean: 2.3 y), 46% of patients had died of disease. Pediatric PVS uniformly consists of a paucicellular fibrointimal proliferation, irrespective of clinical scenario. It may be best conceived of as a form of reactive hyperplasia. As with other forms of vascular remodeling, trauma (iatrogenic or occult) is likely an inciting factor. A comprehensive understanding of the surgical pathology of PVS may further inform therapeutic strategies in this lethal disease. PMID- 28622180 TI - A Prospective Study of Loose Tissue Fragments in Non-Small Cell Lung Cancer Resection Specimens: An Alternative View to "Spread Through Air Spaces". AB - The World Health Organization Classification of Lung Tumors considers "Spread Through Air Spaces" a form of invasion in lung adenocarcinoma. The recently described spread of free-floating cell clusters during lung specimen sectioning, otherwise known as "Spread Through A Knife Surface," represents an ex vivo artifact. The purpose of this study was to prospectively investigate the presence and frequency of these free-floating tumor cell clusters in surgically resected lung cancer specimens and their possible relation to gross examination procedures. A prospective, multi-institutional study of non-small cell lung cancer resection specimen was undertaken. At prosection the first cut was made with a clean knife; the second cut was made in a parallel plane to the first. Four tissue blocks were taken from upper and lower parts of first and second cuts. Hematoxylin and eosin-stained slides were examined for displaced benign and/or malignant tissue fragments. Forty-four resection specimens were studied. The mean number of tumor clusters for blocks 1 to 4 was 0.36, 1.44, 1.86, and 1.95, respectively, and for benign fragments was 0.11, 0.11, 0.13, and 0.25, respectively. Almost all cell clusters were intra-alveolar. Comparison of tumor cell clusters in block 1 with blocks 2 to 4 was significant with P-values (Friedman test for repeated measures 0.03) 0.031, 0.02, and 0.05, respectively. Overall 93% of the loose tissue fragments could be explained by mechanical forces associated with tissue handling. While the 2015 World Health Organization Classification of Lung Tumors recognizes Spread Through Air Spaces as a form of lung cancer invasion, such is debatable and in many instances likely represents mechanical artifact, including dissemination along the prosecting knife blade. PMID- 28622181 TI - Validation of a Mitotic Index Cutoff as a Prognostic Marker in Undifferentiated Uterine Sarcomas. AB - Undifferentiated uterine sarcomas (UUS) are a heterogenous group of high-grade mesenchymal tumors. Although these tumors are highly aggressive, a subset of patients may experience long-term survival. These tumors have previously been divided morphologically into uniform and pleomorphic types. A previous study demonstrated that a mitotic index cutoff of 25 mitoses/10 high-power fields (corresponding to 11.16 mitotic figures/mm) could successfully divide tumors into 2 prognostic groups with significantly different overall survival. The goals of the current study were to (1) validate this mitotic index cutoff in an independent, multicenter cohort and (2) explore the prognostic value of the mitotic index groups in relation to other clinicopathologic variables. Cases were included from 3 independent institutions: The Norwegian Radium Hospital, The Mayo Clinic, and Skane University Hospital. A total of 40 tumors were included after central review. All cases were negative for the YWHAE-FAM22A/B and JAZF1-JJAZ1 translocations. Survival data were available on all patients. In this study, one third of patients with UUS survived beyond 5 years. The crude (unadjusted) Cox Proportional Hazards model revealed a number of parameters that significantly impacted overall survival, including mitotic index group, patient age, stage, and the presence of tumor necrosis. Classification into the uniform and pleomorphic types was not prognostic. Combining these parameters into an adjusted model revealed that only the mitotic index group and stage were prognostic. On the basis of these findings, it is proposed that UUS be subdivided into "mitogenic" and "not otherwise specified" types. PMID- 28622182 TI - Reflux-Associated Cholecystopathy: Analysis of 76 Gallbladders From Patients With Supra-Oddi Union of the Pancreatic Duct and Common Bile Duct (Pancreatobiliary Maljunction) Elucidates a Specific Diagnostic Pattern of Mucosal Hyperplasia as a Prelude to Carcinoma. AB - Pancreaticobiliary maljunction (PBM) is the anomalous union of the main pancreatic duct and common bile duct outside the Oddi-sphincter, allowing the reflux of pancreatic juice to the gallbladder. There is only limited awareness and understanding of the pathologic correlates of this condition, mostly from Japan; this entity is largely unrecognized in the West. In this study, 76 gallbladders from patients with PBM (64 from Japan; 12 from the United States) were analyzed and contrasted with 66 from non-PBM patients. These were predominantly females (54 vs. 22), mean age, 53 (range: 14 to 81). Cholelithiasis was uncommon (16% vs. 80% in non-PBM, P<0.01) whereas cholesterolosis was more common (49% vs. 29%, P=0.02) suggesting an altered chemical milieu. There was a distinctive diffuse mucosal hyperplasia (82% vs. 42%, P<0.01) with markedly elongated folds (mean: 1.1 vs. 0.7 mm, P<0.01) composed of compact villoglandular proliferation, often showing broad-based pushing into muscle, accompanied by prominent and more complex Rokitansky-Aschoff sinus formation (2.0 vs. 1.0/cm, P<0.01) at the base. At the tips, this villiform hyperplasia displayed frequent horizontal bridging of the folds (68% vs. 47%, P=0.01), bulbous dilatation (52% vs. 21%, P<0.01) as well as deposition of a peculiar amyloid-like hyaline material (56% vs. 15%, P<0.01). Despite paucity of inflammation and gallstones, findings attributed to mucosal injury were common including: pyloric gland metaplasia (70% vs. 48%, P=0.01) and intestinal metaplasia (24% vs. 6%, P<0.01). Invasive gallbladder carcinoma was present in 22 (29%) of the cases with 6 of these (27%) arising in association with intracholecystic papillary tubular neoplasm. Five cases had bile duct carcinoma at the time of cholecystectomy and 1 developed it 4 years after. In conclusion, gallbladders with patients with PBM display a distinctive pattern of mucosal hyperplasia with distinguishing features, which in constellation render it a microscopically diagnosable specific entity. We propose to refer to this entity as "reflux-associated cholecystopathy." Recognition of the pathologic characteristics of this entity is important so that investigation for, as well as treatment and prevention of, PBM associated complications (biliary tract cancers and pancreatitis) can be instituted. This group also offers a distinct model of carcinogenesis (chemical rather than inflammatory) in the gallbladder for cancer researchers to scrutinize. PMID- 28622183 TI - Cyclin D1 Is Expressed in Neoplastic Cells of Langerhans Cell Histiocytosis but Not Reactive Langerhans Cell Proliferations. AB - Langerhans cell histiocytosis (LCH) is characterized by frequent activating mutations involving the mitogen-activated protein kinase (MAPK) pathway. Therefore, downstream markers of MAPK pathway activation such as cyclin D1 may be useful as novel diagnostic markers of neoplasia in LCH. The goal of this study was to investigate cyclin D1 expression in LCH and reactive Langerhans cell accumulations using immunohistochemistry on archival tissue. All LCH cases tested (39/39) showed cyclin D1 expression in CD1a/Langerin cells. Most cases (22/39; 56%) showed strong cyclin D1 expression in the majority (>=50%) of lesional cells. Only a few cases (6/39; 15%) showed cyclin D1 expression in a small subset (<20%). Nearly all LCH cases (26/27; 96%) showed p-ERK expression by immunohistochemistry, parallel to cyclin D1 expression. CD1a Langerhans cells in all cases of florid dermatopathic lymphadenopathy and normal skin were negative for cyclin D1, as demonstrated by CD1a/cyclin D1 double staining. The majority of skin specimens (14/18; 78%) with dermatitis-related changes did not show cyclin D1 expression in the CD1a epidermal Langerhans cell aggregates. A minority (4/18; 22%) showed weak cyclin D1 staining in a small subset (5% to 10%) of CD1a Langerhans cells. We conclude that cyclin D1 is ubiquitously expressed in LCH, in keeping with the known near universal MAPK activation in this disease. Further, it is not significantly expressed in reactive Langerhans cell proliferations in lymph node or skin. Therefore, cyclin D1 immunohistochemistry may be useful in excluding non-neoplastic mimics of LCH. PMID- 28622184 TI - Does Age Influence the Efficacy of Demineralized Bone Matrix Enriched with Concentrated Bone Marrow Aspirate in Lumbar Fusions? AB - STUDY DESIGN: Retrospective study. OBJECTIVE: Evaluate the effect of age on the efficacy of allograft/demineralized bone matrix (DBM) enriched with concentrated bone marrow aspirate (BMA) in posterolateral lumbar fusions (PLFs). SUMMARY OF BACKGROUND DATA: Cell-based therapies such as concentrated BMA have been developed as a potential alternative to iliac crest bone graft (ICBG). BMA contains mesenchymal stem cells (MSCs) and growth factors that can confer osteogenic and osteoinductive potential to osteoconductive scaffolds such as DBM/allograft. To date, no studies have examined the role of age on fusion outcomes when BMA is utilized despite the well-established deleterious effects of advanced age on bone marrow and MSC potential. MATERIALS AND METHODS: Fifty-one patients that underwent PLF were divided into 3 groups. Group A (n=14) composed of patients age 65 years and older who received BMA with DBM. Group B (n=17) consisted of patients younger than 65 years of age who received BMA with DBM. Group C (n=20) composed of patients age 65 years and older who received ICBG. Fusion rates and clinical outcomes were assessed. RESULTS: Fusion was significantly lower in group A (35.7%) compared with both groups B (76.4%) and C (80%) (A vs. B, P=0.03; A vs. C, P=0.01). There were no differences in clinical outcomes among all groups except for pseudarthrosis which occurred in 28.6% of patients in group A compared with none and 5% of patients in groups B and C, respectively (A vs. B, P=0.03; A vs. C, P=0.13). CONCLUSIONS: Elderly patients undergoing PLF using DBM enriched with BMA achieved lower radiographic fusion success compared with their nonelderly counterparts and compared with elderly patients that had fusion with ICBG. This may be partly due to the effect of advanced age on MSC potential. PMID- 28622185 TI - A Comprehensive Meta-Analysis of the Adjacent Segment Parameters in Cervical Disk Arthroplasty Versus Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: This is a meta-analysis of controlled trials. OBJECTIVE: To assess the overall condition of adjacent segment of cervical disk arthroplasty (CDA) compared with anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: With the increase in CDA and ACDF, surgeons are taking more attention to adjacent segment degeneration (ASDeg) and adjacent segment disease (ASDis). There are more and more meta-analyses comparing the efficacy of CDA with ACDF, however, there are few meta-analyses referring to adjacent segment parameters, and investigators are still unable to arrive at the same conclusion. METHODS: Several important databases were searched for controlled trials comparing CDA and ACDF before February 2016 according to PRISMA guidelines. The analysis parameters included follow-up time, operative segments, cervical range of motion (ROM), adjacent segment motion, ASDeg, ASDis and adjacent segment reoperation. The risk of bias scale and Newcastle-Ottawa Scale were used to assess the papers. Subgroup analysis and sensitivity analysis were used to analyze the reason for high heterogeneity. RESULTS: Forty-one controlled trials fulfilled the inclusion criteria, including 36 English papers and 5 Chinese. The average follow-up time of all included patients was 39 months. Compared with ACDF, the rate of adjacent segment reoperation in the CDA group was significantly lower (P<0.01), and the advantage of CDA group increased with the increasing of follow-up time according to subgroup analysis. The rate of ASDeg in CDA was significantly lower than that of ACDF (P<0.01). There was no statistical difference between upper and lower ASDeg using the same surgical method (P>0.05). CDA provided a greater cervical ROM than did ACDF (P<0.01). There was a lower adjacent segment ROM and the rate of ASDis in CDA compared with ACDF (P<0.05). CONCLUSIONS: Compared with ACDF, the advantages of CDA were lower ASDeg, ASDis, adjacent segment reoperation and adjacent segment motion; and higher cervical ROM. However, there was no statistical difference between upper and lower adjacent segment ROM/ASDeg using the same surgery. PMID- 28622186 TI - A 90-day Bundled Payment for Primary Single-level Lumbar Discectomy/Decompression: What Does "Big Data" Say? AB - Episode-based bundling may become the major form of reimbursement for many elective spine procedures. As the amount for a 90-day episode of care is not known for a lumbar discectomy, we analyzed the previous reimbursements from Commercial payers (2007-Q2 2015), Medicare Advantage (2007-Q2 2015), and Medicare (2005-2012) for a primary single-level lumbar discectomy/decompression. Distribution of payments among various service providers was studied and a 90-day bundle was simulated. Depending on the payer type, the average facility costs constituted 59.7% to 73.6% of total payments, followed by surgeon's fees, which accounted for 13.7% to 18.5%. Postacute services made up 8.8% to 15.8% of the total reimbursement. Surgeries performed in the inpatient setting were significantly more expensive as compared with surgeries performed in the outpatient setting (P<0.01). The average 90-day bundle amount was estimated at $11,091, $6571, and $6239 for Commercial payers, Medicare Advantage, and Medicare, respectively. Overall, service providers in the Southern region were reimbursed the lowest from Commercial payers and Medicare, compared with other regions. Postacute services are not as major cost drivers after discectomy as after total joint arthroplasty or hip fracture repair. PMID- 28622187 TI - Radiographic and Clinical Outcomes of Anterior and Transforaminal Lumbar Interbody Fusions: A Systematic Review and Meta-analysis of Comparative Studies. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Compare the radiographic and clinical outcomes of anterior lumbar interbody fusion (ALIF) to transforaminal lumbar interbody fusion (TLIF). SUMMARY OF BACKGROUND DATA: ALIF and TLIF are 2 methods of achieving spinal arthrodesis. There are conflicting reports with no consensus on the optimal interbody technique to achieve successful radiographic and clinical outcomes. The goal of this systematic review and meta-analysis was to compare the radiographic and clinical outcomes of ALIF to TLIF. MATERIALS AND METHODS: A systematic search of multiple medical reference databases was conducted for studies comparing ALIF to TLIF. Studies that included stand-alone ALIFs were excluded. Meta-analysis was performed using the random effects model for heterogeneity. Radiographic outcome measures included segmental and overall lumbar lordosis, and fusion rates. Clinical outcomes measures included Oswestry disability index (ODI) and visual analog scale (VAS) score for back pain. RESULTS: The search yielded 7 studies totaling 811 patients (ALIF=448, TLIF=363). ALIF was superior to TLIF in restoring segmental lumbar lordosis at L4 L5 and L5-S1 (L4-L5; P=0.013, L5-S1; P<0.001). ALIF was also superior to TLIF in restoring overall lumbar lordosis (P<0.001). However, no significant differences in fusion rates were noted between both techniques [odds ratio=0.905; 95% confidence interval, 0.458-1.789; P=0.775]. In addition, ALIF and TLIF were comparable with regards to ODI and VAS scores (ODI; P=0.184, VAS; P=0.983). CONCLUSIONS: For the restoration of lumbar lordosis, ALIF is superior to TLIF. However, TLIF is comparable to ALIF with regards to fusion rate and clinical outcomes. PMID- 28622188 TI - Differences in Fundamental Sagittal Pelvic Parameters Based on Age, Sex, and Race. AB - STUDY DESIGN: This is a retrospective cohort study. OBJECTIVE: To determine whether age, sex, and race have independent effects on sagittal pelvic parameters. SUMMARY OF BACKGROUND DATA: Pelvic parameters and sagittal balance correlate with health-related quality of life and are important for patient assessment and surgical planning. Age, sex, and race are 3 unalterable patient factors that may influence pelvic morphology. METHODS: We conducted a retrospective review of consecutive adult patients who presented to our radiology practice between 2010 and 2015 and had a standing, lateral lumbosacral radiograph. Any patients without both femoral heads and L1-S1 visible on the radiograph, and any patients presenting with traumatic injury, coronal deformity, prior instrumentation, spondylolisthesis, or neoplasm of the spine were excluded. Univariate analysis determined differences in measurements among African American, white, and Hispanic races, as well as between male and female sexes. Correlation analysis between age and different measurements was also conducted. Multivariable regression was then used to determine the independent effect of age, sex, and race on pelvic parameters. RESULTS: We investigated 1801 adults (older than 18 y) and 1246 had a recorded race. There were 1165 women, 636 men, 525 whites, 404 African Americans, and 317 Hispanics. Multivariable regression demonstrated a statistically significant increase in pelvic tilt (PT), pelvic incidence (PI), and pelvic incidence-lumbar lordosis (PI-LL) with aging, and statistically significant decrease in sacral slope (SS) and LL with aging. Women had a statistically greater LL than men. African Americans had a statistically smaller PT and greater SS and PI-LL relative to whites, while Hispanics had a statistically smaller PT and PI-LL, and a statistically greater SS and LL relative to whites. CONCLUSIONS: Pelvic parameters were different between sexes, among races, and changed with age. These findings are important for patient assessment and preoperative planning to obtain optimal sagittal balance. LEVEL OF EVIDENCE: Level 3. PMID- 28622189 TI - Subsidizing the Sick: How Community Rating Works. AB - Insurance premium rates have typically been calculated using a variety of rating algorithms. Passage of the Patient Protection and Affordable Care Act mandated that all individual and small group plans must use the community rating method. This method gives the same insurance rate to all members of a community, with adjustments only being allowed based on age, geography, and tobacco use. This effectively raises rates on low-risk individuals to subsidize high-risk individuals. With President Trump and Congressional Republicans vowing to repeal the Patient Protection and Affordable Care Act, this lesser-known but controversial portion of the law may be abolished. This paper will review the various rating methods used by insurance companies in determining premiums. PMID- 28622190 TI - Are Exercise Benefits in Nonalcoholic Fatty Liver Disease Due to Increased Autophagy? PMID- 28622191 TI - Interval Walking Training for Older People: No Pain and Lots of Gain. PMID- 28622192 TI - Editorial: 'Old tools, new insights': assessment of nutritional and metabolic status. PMID- 28622193 TI - The Lifestyle Information and Intervention Preferences of Teenage and Young Adult Cancer Survivors: A Qualitative Study. AB - BACKGROUND: Little is currently known about how best to promote healthy lifestyle choices among teenage and young adult (TYA) cancer survivors. Such data gathered from a patient-centered perspective are instrumental for the development of health behavior change interventions for young people with cancer. OBJECTIVE: This study aimed to explore the lifestyle information needs of TYA cancer survivors and their preferences regarding lifestyle information and intervention delivery. Lifestyle behaviors of interest were physical activity, diet, smoking, alcohol consumption, and sun safety. METHODS: A total of 13 TYA cancer survivors (mean age, 22.9 years) participated in 10 individual interviews and 1 focus group (n = 3). Each interview and focus group followed the same semistructured interview guide, which was designed to explore young peoples' motivation behind leading a healthy lifestyle, their past experience of searching for lifestyle information, and their preferences relating to lifestyle information delivery. RESULTS: Three core themes emerged: cancer as a catalyst to lifestyle behavior change, factors influencing health behavior change, and health behavior information preferences. Social support emerged as facilitator of both health behavior change and self-efficacy. CONCLUSION: Young people with cancer want age appropriate lifestyle information on a range of topics delivered in multiple formats at various time points. IMPLICATIONS FOR PRACTICE: Health professionals working with TYA cancer survivors should address young peoples' lifestyle information needs throughout the cancer care pathway and support young people to foster the confidence to make, and sustain, positive lifestyle behavior changes. PMID- 28622194 TI - Population-based Cancer Screening: Measurement of Coordination and Continuity of Care. AB - BACKGROUND: European guidelines for the quality of screening programs for breast and colorectal cancer describe process, structure, and outcome indicators. However, none of them specifically evaluate coordination and continuity of care during the cancer screening process. OBJECTIVES: The aim of this study was to identify and adapt care quality indicators related to the coordination and continuity of the cancer screening process to assess nursing care in cancer screening programs. METHODS: The indicators proposed in this study were selected in 2 phases. The first consisted of a literature review, and the second was made by consensus of an expert group. An electronic literature search was conducted, through June 2016. From a total of 225 articles retrieved, 14 studies met inclusion criteria, and these 14 documents were delivered to the group of experts for evaluation and to propose a final list of agreed-upon indicators. RESULTS: The group of experts selected 7 indicators: adequacy and waiting time derivation of participants, delivery and availability of the report of the process, understanding professionals involved in the process, and satisfaction and understanding of participants. CONCLUSIONS: These indicators should help identify areas for improvement and measure the outcome of coordination and continuity of care. IMPLICATIONS FOR PRACTICE: The results provided a common set of indicators to evaluate the coordination and continuity of care for cancer screening and to consequently assess the contribution of nursing care in cancer screening programs. The identification and adaptation of these quality indicators will help to identify areas for improvement and measure the effect of coordination and continuity of care. PMID- 28622195 TI - Financial Toxicity Among Patients With Cancer-Where to From Here? PMID- 28622196 TI - Spinal Cord Stimulation for Cancer-Related Pain in Adults. PMID- 28622197 TI - Bilateral HPV Positive Squamous Cell Carcinoma In Situ of Conjunctiva. AB - A 45 year-old woman presented with blurred vision and irritation of the left eye. Clinical examination revealed a superior palpebral conjunctival lesion consistent with a diagnosis of papilloma. She was lost to follow up despite repeated attempts to schedule a biopsy, and presented again after an extended period with bilateral disease. Subsequent biopsy confirmed bilateral squamous cell carcinoma in situ which was human papilloma virus-16 positive by molecular testing. She declined further treatment; during the subsequent year, the lesions extended across the bulbar conjunctiva bilaterally. PMID- 28622199 TI - Antifibrotic drugs as treatment of nonidiopathic pulmonary fibrosis interstitial pneumonias: the time is now (?). AB - PURPOSE OF REVIEW: Therapeutic advances in the management of idiopathic pulmonary fibrosis (IPF) has led to improved outcomes with the use of the antifibrotic agents pirfenidone and nintedanib, with a number of randomized studies demonstrating benefits in slowing disease progression in IPF. However, treatment of other fibrosing interstitial lung diseases (ILD) remains challenging. RECENT FINDINGS: Observational and uncontrolled studies investigating pirfenidone and nintedanib in non-IPF ILDs suggest potential benefits, although the data is weak. A number of randomized controlled trials evaluating pirfenidone and nintedanib in a variety of fibrosing ILDs are currently enrolling or planned. SUMMARY: The review will discuss the rationale for use of established antifibrotic drugs approved for IPF for use in non-IPF ILD, describe supportive data from observational studies and ongoing clinical trials. PMID- 28622198 TI - Ocular sarcoidosis: new diagnostic modalities and treatment. AB - PURPOSE OF REVIEW: Ocular involvement in sarcoidosis is present in up to 80% of patients and is frequently manifested before diagnosis of the underlying systemic disease. Considering the therapeutic consequences, early diagnosis of the underlying disease is advantageous in patients presenting with ocular inflammation. There are several ocular findings suggestive of underlying sarcoidosis, such as granulomatous keratic precipitates, iris nodules, cells in the vitreous humor known as snowballs and snowbanks, and retinal periphlebitis. High suspicion is crucial for the diagnosis of sarcoidosis. This review on ocular sarcoidosis will mainly focus on new diagnostic and treatment modalities. RECENT FINDINGS: Recent studies found possible new diagnostic indicators for the diagnosis of ocular sarcoidosis which include not only serum profiles but also vitreous sample analysis. Ophthalmologic imaging techniques have improved to investigate the ocular structure in detail. Results from recent uveitis clinical trials have included sarcoidosis as an underlying cause and have reported positive results. SUMMARY: The diagnosis of ocular sarcoidosis can be challenging in some cases. High suspicion is important to diagnose ocular sarcoidosis with various laboratory and ophthalmic tools. There are many possible options for the treatment of ocular sarcoidosis including various biologic agents. PMID- 28622200 TI - Service line structure and decision-maker attention in three health systems: Implications for patient-centered care. AB - BACKGROUND: Scholars have noted a disconnect between the level at which structure is typically examined (the organization) and the level at which the relevant coordination takes place (service delivery). Accordingly, our understanding of the role structure plays in care coordination is limited. PURPOSE: In this article, we explore service line structure, with an aim of advancing our understanding of the role service line structure plays in producing coordinated, patient-centered care. We do so by giving special attention to the cognitive roots of patient-centeredness. METHODOLOGY/APPROACH: Our exploratory study relied on comparative case studies of the breast cancer service lines in three health systems. Nonprobability discriminative snowball sampling was used to identify the final sample of key informants. We employed a grounded approach to analyzing and interpreting the data. RESULTS: We found substantial variation across the three service lines in terms of their structure. We also found corresponding variation across the three case sites in terms of where informant attention was primarily focused in the process of coordinating care. Drawing on the attention-based view of the firm, our results draw a clear connection between structural characteristics and the dominant focus of attention (operational tactics, provider roles and relationships, or patient needs and engagement) in health care service lines. CONCLUSION: Our exploratory results suggest that service line structures influence attention in two ways: (a) by regulating the type and intensity of the problems facing service line participants and (b) by encouraging (or discouraging) a shared purpose around patient needs. PRACTICE IMPLICATIONS: Patient-centered attention-a precursor to coordinated, patient-centered care depends on the internal choices organizations make around service line structure. Moreover, a key task for organizational and service line leaders is to structure service lines to create a context that minimizes distractions and enables care providers to focus their attention on the needs of their patients. PMID- 28622201 TI - Improper Assessment of the Effect of Ad Libitum Drinking on Cycling Performance. PMID- 28622202 TI - Response. PMID- 28622203 TI - Crucial Points for Analysis of Ischemic Preconditioning in Sports and Exercise. PMID- 28622204 TI - Response. PMID- 28622205 TI - Effect of Excessive Coffee Consumption on the Clinical Course of a Patient With Bipolar Disorder: A Case Report and Literature Review. AB - OBJECTIVE: The aim of this study was to examine the impact of excessive caffeine consumption on therapeutic outcomes in bipolar disorder. METHODS AND RESULTS: We report on a case of a patient with bipolar disorder whose psychiatric symptoms were ameliorated with the elevation of lithium concentrations after the reduction of excessive daily coffee consumption, and we review the relevant literatures. CONCLUSIONS: Excessive coffee consumption may exacerbate the therapeutic course of bipolar disorder through its effects on the mechanisms underlying bipolar disorder itself, as well as by affecting the blood concentration of lithium. PMID- 28622206 TI - Bupropion Augmentation in a Case of Compulsive Buying Disorder. AB - BACKGROUND: Compulsive buying disorder (CBD) is a condition characterized by excessive preoccupations, impulses, and behaviors regarding buying, resulting in serious psychological, social, and financial problems. Even though it has not been included in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, "behavioral addictions" section, CBD is a hot topic in current clinical psychiatry, because of its relevant prevalence (at least 5% in adult populations) and severe effect on quality of life.The CBD shares some clinical features with substance-related and behavioral addictions, impulse control disorders, and obsessive compulsive disorder, and it is often comorbid with other psychiatric illnesses (especially depressive and anxiety disorders). The treatment of CBD is therefore difficult, and clear therapeutic guidelines are not yet available. Treating the comorbid disorders as the first-line approach, or combining drugs with different pharmacodynamic profiles, has been suggested to address this challenging condition. CASE: A 60-year-old woman affected by a severe form of CBD with comorbid major depressive disorder, resistant/intolerant to previous selective serotonin reuptake inhibitor treatments and only partially responder to mirtazapine, achieved a good clinical improvement adding bupropion. CONCLUSIONS: Combining 2 agents with different pharmacological profiles and mechanisms of action, such as bupropion and mirtazapine, could be a useful strategy in the management of complex CBD cases. PMID- 28622207 TI - Sleep Disturbance as a Precursor of Severe Regression in Kleefstra Syndrome Suggests a Need for Firm and Rapid Pharmacological Treatment. AB - Intellectual disability is frequently accompanied by psychiatric symptoms that require pharmacological interventions. Treatment guidelines often provide a general treatment approach for these symptoms in intellectual disability. However, this may not always be the best strategy, as illustrated here in Kleefstra syndrome. We present 3 patients showing severe regression after sleep disturbances. If these are treated with care as usual (eg, behavioral programs and sleep medication) deterioration is likely to follow. It is observed that rapid treatment with relatively high dosages of antipsychotics contributes to restore sleep, halt further regression, and improve daily life functioning. PMID- 28622208 TI - Duloxetine Plasma Concentrations and Its Effectiveness in the Treatment of Nonorganic Chronic Pain in the Orofacial Region. AB - OBJECTIVE: The purpose of this study was to examine the relationship between the pain-relieving effects of duloxetine and its plasma concentrations in patients with burning mouth syndrome and atypical odontalgia characterized by chronic nonorganic pain in the orofacial region. METHODS: We administered duloxetine to 77 patients diagnosed as having burning mouth syndrome or atypical odontalgia for 12 weeks. The initial dose of duloxetine was established as 20 mg/d and was increased to 40 mg/d after week 2. We evaluated pain using the visual analog scale and depressive symptoms using the Structured Interview Guide for the Hamilton Depression Rating Scale at weeks 0, 2, 4, 6, 8, 10, and 12 and measured plasma concentrations of duloxetine 12 weeks after the start of its administration. RESULTS: Visual analog scale scores were significantly lower 12 weeks after than at the start of the administration of duloxetine (paired t test, t = 6.65, P < 0.0001). We examined the relationship between the rate of decreases in visual analog scale scores and plasma concentrations of duloxetine. There was no significant linear regression or quadratic regression. CONCLUSIONS: Duloxetine significantly relieved pain in patients with chronic nonorganic pain in the orofacial region. However, no relationship was observed between its pain relieving effects and plasma concentrations. PMID- 28622209 TI - The "Forgotten" Treatment of Alcohol Withdrawal Delirium With Electroconvulsive Therapy: Successful Use in a Very Prolonged and Severe Case. AB - OBJECTIVE: Alcohol withdrawal delirium (AWD) is a notorious complication in alcohol withdrawal. Usually, the symptomatic treatment is efficacious; however, some patients show treatment resistance or a prolonged course of AWD. METHOD: We report the case of a patient with a prolonged and severest form of AWD. Even 11 weeks after admission, he received approximately 100 mg diazepam per week to manage the symptoms of withdrawal delirium. RESULTS: A treatment course of electroconvulsive therapy was initiated, which allowed a complete tapering off of benzodiazepines during electroconvulsive therapy without adverse effects. CONCLUSIONS: The reported case might contribute to alternative approaches reserved for severest forms of prolonged AWD. PMID- 28622210 TI - Serotonin Syndrome Following Combined Administration of Dopaminergic and Noradrenergic Agents in a Patient With Akinetic Mutism After Frontal Intracerebral Hemorrhage: A Case Report. AB - BACKGROUND: Serotonin syndrome (SS) is a potentially life-threatening condition that can be caused by use of proserotonergic drugs. Several studies have reported that combined administration of various medications may induce SS. We report a case of SS in a patient who was being treated with dopaminergic and noradrenergic drugs. CASE PRESENTATION: A 55-year-old man with a right frontal intracerebral hemorrhage extending to the left cerebral hemisphere presented with clinical features of akinetic mutism. Three months after onset, dopaminergic (methylphenidate, levodopa/benserazide) and noradrenergic (atomoxetine) drugs were administered to enhance his cognitive function. His cognitive function gradually improved during 8 weeks of dose escalation. One day after the dose of atomoxetine was increased from 40 mg/d to 60 mg/d, the patient developed inducible clonus, rigidity, diarrhea, tachycardia, and hyperthermia, in keeping with a diagnosis of SS. The symptoms and signs suggestive of SS resolved on the day following cessation of all dopaminergic and noradrenergic drugs. CONCLUSIONS: This case demonstrates that medications generally known as dopaminergic or noradrenergic agents could have serotonergic effects via a mechanism that is yet to be fully elucidated. The clinical manifestations of SS can be diverse, ranging from mild to severe and potentially fatal symptoms. When administering a combination of catecholaminergic agents, clinicians should carefully monitor the patient's neurologic status for unexpected adverse reactions. PMID- 28622211 TI - Aripiprazole-Related Diurnal Enuresis in Children: 2 Cases (Aripiprazole-Related Enuresis). AB - Aripiprazole is an atypical antipsychotic with dopaminergic and serotonergic effects. Enuresis as an adverse effect has been reported with aripiprazole use in children with autism spectrum disorders. Here, we report 2 cases without autism spectrum disorders who developed diurnal enuresis after starting aripiprazole and ceased after discontinuation of the medication. PMID- 28622212 TI - A Retrospective Study of Pimavanserin Use in a Movement Disorders Clinic. AB - Pimavanserin, a 5-HT2A inverse agonist, was commercially released in the United States in April 2016 for the treatment of Parkinson disease psychosis. No "naturalistic" treatment results have yet been published. Charts from the movement disorders clinic were reviewed for all patients who received this drug as treatment for psychosis associated with primary parkinsonism due to alpha synucleinopathies. Data of 10 patients with idiopathic Parkinson disease, including 1 with a long history of schizophrenia, 4 with dementia with Lewy bodies, and 1 with multiple-system atrophy, were reviewed. There were no adverse events reported. Ten patients improved and continue on the drug, whereas 5 stopped because of lack of benefit. PMID- 28622213 TI - Selective Serotonin Reuptake Inhibitor-Induced Hyponatremia: Clinical Implications and Therapeutic Alternatives. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed among the general population. Despite their benign side effect profile, these drugs can cause significant adverse effects in elderly patients, including severe hyponatremia. We report 1 case of SSRI-induced hyponatremia and review therapeutic alternatives. CASE: We present an 81-year-old male patient treated with sertraline and furosemide who presented with a recent-onset symptomatic hyponatremia. Low sodium levels persisted for more than 1 week after furosemide had been discontinued. Sertraline was then replaced with a nonserotonergic antidepressant (bupropion), leading to a full recovery. CONCLUSIONS: Although SSRIs are the first treatment option for elderly depressed patients, they should be prescribed cautiously in this population because of the risk of potentially severe adverse effects such as hyponatremia. Particularly vulnerable patients could benefit from being prescribed nonserotonergic antidepressants from the start. PMID- 28622214 TI - Acute Care Nurse Practitioners and Physician Assistants in Critical Care: Transforming Education and Practice. PMID- 28622215 TI - Influence of Gender on the Performance of Cardiopulmonary Rescue Teams: A Randomized, Prospective Simulator Study. AB - OBJECTIVES: Little is known about the influence of gender on resuscitation performance which may improve future education in resuscitation. The aim of this study was to compare female and male rescuers in regard to cardiopulmonary resuscitation and leadership performance. DESIGN: Prospective, randomized simulator study. SETTING: High-fidelity patient simulator center of the medical ICU, University Hospitals Basel (Switzerland). SUBJECTS: Two hundred sixteen volunteer medical students (108 females and 108 males) of two Swiss universities in teams of three. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data on the group and the individual level separately. The primary outcome on the group level was the hands-on time within the first 180 seconds after the onset of the cardiac arrest. Compared with male-only teams, female-only teams showed less hands-on time (mean +/- SD) (87 +/- 41 vs 109 +/- 33 s; p = 0.037) and a longer delay before the start of chest compressions (109 +/- 77 vs 70 +/- 56 s; p = 0.038). Additionally, female-only teams showed a lower leadership performance in different domains and fewer unsolicited cardiopulmonary resuscitation measures compared with male-only teams. On the individual level, which was assessed in mixed teams only, female gender was associated with a lower number of secure leadership statements (3 +/- 2 vs 5 +/- 3; p = 0.027). Results were confirmed in regression analysis adjusted for team composition. CONCLUSIONS: We found important gender differences, with female rescuers showing inferior cardiopulmonary resuscitation performance, which can partially be explained by fewer unsolicited cardiopulmonary resuscitation measures and inferior female leadership. Future education of rescuers should take gender differences into account. PMID- 28622217 TI - An Ejection Fraction Measurement for the Masses. PMID- 28622218 TI - Stress Ulcer Prophylaxis-Friend or Foe? PMID- 28622219 TI - Penalizing Readmissions After Sepsis Could Do More Harm Than Good. PMID- 28622220 TI - Hypothermia for the Treatment of Acute Respiratory Distress Syndrome? Cool It. PMID- 28622221 TI - Can the Treatment Approach of Sepsis With Balanced Crystalloid Fluids Translate Into Therapy for Acute Respiratory Distress Syndrome if Considered as "Lung Limited Sepsis"? PMID- 28622216 TI - The Clinical Picture of Severe Systemic Capillary-Leak Syndrome Episodes Requiring ICU Admission. AB - OBJECTIVE: Systemic capillary-leak syndrome is a very rare cause of recurrent hypovolemic shock. Few data are available on its clinical manifestations, laboratory findings, and outcomes of those patients requiring ICU admission. This study was undertaken to describe the clinical pictures and ICU management of severe systemic capillary-leak syndrome episodes. DESIGN, SETTING, PATIENTS: This multicenter retrospective analysis concerned patients entered in the European Clarkson's disease (EureClark) Registry and admitted to ICUs between May 1992 and February 2016. MEASUREMENTS AND MAIN RESULTS: Fifty-nine attacks occurring in 37 patients (male-to-female sex ratio, 1.05; mean +/- SD age, 51 +/- 11.4 yr) were included. Among 34 patients (91.9%) with monoclonal immunoglobulin G gammopathy, 20 (58.8%) had kappa light chains. ICU-admission hemoglobin and proteinemia were respectively median (interquartile range) 20.2 g/dL (17.9-22 g/dL) and 50 g/L (36.5-58.5 g/L). IV immunoglobulins were infused (IV immunoglobulin) during 15 episodes (25.4%). A compartment syndrome developed during 12 episodes (20.3%). Eleven (18.6%) in-ICU deaths occurred. Bivariable analyses (the 37 patients' last episodes) retained Sequential Organ-Failure Assessment score greater than 10 (odds ratio, 12.9 [95% CI, 1.2-140]; p = 0.04) and cumulated fluid-therapy volume greater than 10.7 L (odds ratio, 16.8 [1.6-180]; p = 0.02) as independent predictors of hospital mortality. CONCLUSIONS: We described the largest cohort of severe systemic capillary-leak syndrome flares requiring ICU admission. High volume fluid therapy was independently associated with poorer outcomes. IV immunoglobulin use was not associated with improved survival; hence, their use should be considered prudently and needs further evaluation in future studies. PMID- 28622222 TI - Rocky Versus Drago, Luke Versus Vader...Chest Radiograph Versus Ultrasound? PMID- 28622223 TI - Managing Safely the Complexity in Critical Care: Are Protocols for Artificial Ventilation in Pediatric Acute Respiratory Distress Syndrome Beneficial in Searching for Reliable Biomarkers? PMID- 28622224 TI - Too Much Too Soon or Too Little Too Late: The Challenge of Preventing Acinetobacter Transmissions. PMID- 28622225 TI - A Climate Change in Mechanical Ventilation? PMID- 28622226 TI - Early Electroencephalography for Neurologic Prognostication After Cardiac Arrest: More Optimization Before Generalization? PMID- 28622227 TI - Getting to Patients' Heads Through Their Hearts. PMID- 28622228 TI - A Chamber With a View: The Size of the Right Ventricle During Cardiopulmonary Resuscitation. PMID- 28622229 TI - Shields Up-Systemic Protection Provided by microRNA-21 During Sepsis? PMID- 28622230 TI - Claims-Based ICU Research: Learning From Imperfect Data. PMID- 28622231 TI - Catheter-Related Bloodstream Infection in Jugular Versus Subclavian Central Catheterization. PMID- 28622232 TI - The authors reply. PMID- 28622233 TI - Human Mesenchymal Stem/Stromal Cells From Human Umbilical Cord Ameliorate Acute Respiratory Distress Syndrome in Rats: Factors to Consider. PMID- 28622234 TI - The authors reply. PMID- 28622235 TI - Central Venous Pressure and Mean Airway Pressure Back for Outcome in Mechanically Ventilated Patients? Still More Consideration for Cardiopulmonary Interactions at the Bedside. PMID- 28622236 TI - The authors reply. PMID- 28622237 TI - There Are More Things in Heaven and Earth, Horatio, Than Are Dreamt of in Our Philosophy. PMID- 28622238 TI - The authors reply. PMID- 28622239 TI - The Whole Is Greater Than the Sum of Its Parts...? PMID- 28622240 TI - The authors reply. PMID- 28622241 TI - Greater Protein and Energy Intake for Improving Mortality in Higher Risk Critically Ill Patients: Useful or Useless? PMID- 28622242 TI - The authors reply. PMID- 28622243 TI - Fulminant or Early Severe Acute Pancreatitis Is Overlooked by Classifications of Severity. PMID- 28622244 TI - The author replies. PMID- 28622245 TI - Iodinated Contrast Medium Renal Toxicity: The Phantom Menace or Much Ado About Nothing? PMID- 28622246 TI - The authors reply. PMID- 28622247 TI - Effects of Portal Hypertension on Gadoxetic Acid-Enhanced Liver Magnetic Resonance: Diagnostic and Prognostic Implications. AB - OBJECTIVE: The aim of this study was to investigate the impact of portal hypertension (PH) on gadoxetic acid-enhanced liver magnetic resonance imaging (MRI) and assess diagnostic and prognostic implications in comparison to established imaging features of PH. MATERIALS AND METHODS: Institutional review board-approved retrospective study of 178 patients (142 men; median age, 59.4 years) with chronic liver disease undergoing MRI and hepatic venous pressure gradient (HVPG) measurement between January 2008 and April 2015. Magnetic resonance imaging was assessed for established features of PH (splenic and portal vein diameters, portosystemic collaterals, ascites) and for features on 20 minutes delayed T1-weighted gadoxetic acid-enhanced MRI, that is, relative liver enhancement (RLE), biliary contrast excretion, or portal vein hyperintensity or isointensity (ie, portal vein hyperintensity sign, PVHS). Statistics encompassed linear regression, logistic regression, and survival analysis. RESULTS: There was an inverse correlation between HVPG and RLE (r = 0.18, P < 0.0001). On univariate analysis, clinically significant PH (ie, HVPG >= 10 mm Hg, n = 109) and severe PH (ie, HVPG >= 12 mm Hg, n = 99) were associated with delayed biliary contrast excretion (n = 33) and the PVHS (n = 74) (P < 0.01 for all). Multivariate analysis demonstrated significant associations between the PVHS and severe PH (odds ratio [OR], 3.33; P = 0.008), independently of spleen size (OR, 1.26; P = 0.002), portosystemic collaterals (n = 81; OR, 5.46; P = 0.0001), and ascites (n = 88; OR, 3.24; P = 0.006). Lower RLE and the PVHS were associated with lower 3 year, transplantation-free survival (hazards ratios, 0.98 and 3.99, respectively, P = 0.002 for all), independently of the Child-Pugh and Model for End-Stage Liver Disease scores. CONCLUSIONS: The presence of the PVHS on gadoxetic acid-enhanced MRI is an independent indicator of severe PH and may enable more accurate diagnosis. This feature and decreased hepatic contrast uptake may also comprise prognostic information. PMID- 28622248 TI - Quantitative Perfusion Analysis of the Rectum Using Golden-Angle Radial Sparse Parallel Magnetic Resonance Imaging: Initial Experience and Comparison to Time Resolved Angiography With Interleaved Stochastic Trajectories. AB - OBJECTIVES: Purpose of this study was to compare the quality of perfusion maps obtained from prototypical free-breathing magnetic resonance imaging (MRI) with continuous golden-angle radial sampling and iterative reconstruction (GRASP) to conventional acquisition using time-resolved angiography with interleaved stochastic trajectories (TWIST) in patients with rectal cancer. MATERIAL AND METHODS: Forty cases were included for retrospective analysis. Twenty of the patients received routine multiparametric MRI at 3 T for rectal cancer staging, including perfusion measurement with GRASP or TWIST (10 patients for each technique, including 5 prechemoradiation and 5 postchemoradiation). Twenty patients without history of rectal disease served as control group (10 GRASP, 10 TWIST). GRASP images were reconstructed at temporal resolution of 3.45 seconds (21 spokes/frame). A voxel-by-voxel deconvolution approach was used to determine rectal plasma flow (mL/100 mL per minute). Regions of interest were placed at 3 levels within the tumor and normal rectum (lower, middle, and upper part). The quality of morphologic images, perfusion maps, and arterial input function were scored by 2 blinded radiologists. Independent t tests were applied. RESULTS: Three patients of the TWIST control group had to be excluded due to technical failure of the sequence. Significantly higher scores for the perfusion maps and arterial input functions (total cohort) were obtained using GRASP (P < 0.05). Artifacts in the perfusion maps were rated significantly lower than for TWIST (P < 0.05). In the healthy rectum cohort, the average plasma flow of normal rectal wall was 31.78 +/- 7.39 mL/100 mL per minute with GRASP, compared with 77.62 +/- 34.08 mL/100 mL per minute with TWIST, indicating much lower variance for GRASP. Plasma flow values obtained with both methods enabled distinguishing between normal rectal wall and rectal cancer, both before and after chemoradiation. Morphologic image quality was generally higher with GRASP (P < 0.01). CONCLUSIONS: GRASP perfusion imaging can distinguish between normal rectum and rectal cancers with higher image quality and less variance than TWIST. Additional morphologic assessment with high spatial resolution from the GRASP acquisition may increase the accuracy and diagnostic confidence of the examination. PMID- 28622250 TI - Nocturnal patterns. PMID- 28622249 TI - Dynamic Liver Magnetic Resonance Imaging in Free-Breathing: Feasibility of a Cartesian T1-Weighted Acquisition Technique With Compressed Sensing and Additional Self-Navigation Signal for Hard-Gated and Motion-Resolved Reconstruction. AB - OBJECTIVES: The aim of this study was to assess the feasibility of a free breathing dynamic liver imaging technique using a prototype Cartesian T1-weighted volumetric interpolated breathhold examination (VIBE) sequence with compressed sensing and simultaneous acquisition of a navigation signal for hard-gated and motion state-resolved reconstruction. MATERIALS AND METHODS: A total of 43 consecutive oncologic patients (mean age, 66 +/- 11 years; 44% female) underwent free-breathing dynamic liver imaging for the evaluation of liver metastases from colorectal cancer using a prototype Cartesian VIBE sequence (field of view, 380 * 345 mm; image matrix, 320 * 218; echo time/repetition time, 1.8/3.76 milliseconds; flip angle, 10 degrees; slice thickness, 3.0 mm; acquisition time, 188 seconds) with continuous data sampling and additionally acquired self navigation signal. Data were iteratively reconstructed using 2 different approaches: first, a hard-gated reconstruction only using data associated to the dominating motion state (CS VIBE, Compressed Sensing VIBE), and second, a motion resolved reconstruction with 6 different motion states as additional image dimension (XD VIBE, eXtended dimension VIBE). Continuous acquired data were grouped in 16 subsequent time increments with 11.57 seconds each to resolve arterial and venous contrast phases. For image quality assessment, both CS VIBE and XD VIBE were compared with the patient's last staging dynamic liver magnetic resonance imaging including a breathhold (BH) VIBE as reference standard 4.5 +/- 1.2 months before. Representative quality parameters including respiratory artifacts were evaluated for arterial and venous phase images independently, retrospectively and blindly by 3 experienced radiologists, with higher scores indicating better examination quality. To assess diagnostic accuracy, same readers evaluated the presence of metastatic lesions for XD VIBE and CS VIBE compared with reference BH examination in a second session. RESULTS: Compared with CS VIBE, XD VIBE showed significantly higher overall image quality for both arterial phase (4.2 +/- 0.6 vs 3.8 +/- 0.7, P = 0.008) and venous phase (4.7 +/- 0.4 vs 4.3 +/- 0.7, P < 0.001) imaging. There was no significant difference between XD VIBE and BH VIBE for overall image quality in the venous phase (4.7 +/ 0.4 vs 4.8 +/- 0.4, P = 0.834), whereas arterial phase images were scored slightly lower for XD VIBE (4.5 +/- 0.6 vs 4.2 +/- 0.6, P = 0.024). Both XD VIBE and BH VIBE were characterized by a very low level of respiratory artifacts with no significant difference between BH and motion-resolved free-breathing strategy (P = 0.505 for arterial phase; P = 0.496 for venous phase). Compared with CS VIBE, obvious quality improvement could be achieved for the extended XD VIBE reconstruction with significantly reduced motion artifacts for venous phase images (P = 0.007). Generally, arterial phase images were scored slightly lower compared with venous phase images when using the free-breathing protocol. Overall, 98% of all metastatic lesions were identified on XD VIBE images and 92% of all metastases were found on CS VIBE. CONCLUSIONS: Dynamic liver imaging using the proposed free-breathing Cartesian strategy is feasible in oncologic patients with excellent image quality, high respiratory motion robustness, and accurate lesion detection. Overall, XD VIBE was superior to CS VIBE in our study. PMID- 28622251 TI - Treating relapsing multiple sclerosis with dimethyl fumarate. PMID- 28622252 TI - Assessing hip pain: Could it be femoroacetabular impingement? PMID- 28622255 TI - Constipation in children: Diagnosis, treatment, and prevention. AB - Deviation from normal bowel function in the pediatric population is often a cause for concern for parents and caregivers, prompting numerous visits to a primary care provider. Constipation is a common and challenging issue in children that can have an adverse impact on their psychosocial and emotional well-being as well as quality of life. This article provides practical strategies for diagnosing, treating, and preventing constipation in children. PMID- 28622256 TI - Psoriasis & psoriatic therapies. AB - Psoriasis is a chronic inflammatory disease primarily affecting the skin. This article discusses the presentation, epidemiology, and pathogenesis of psoriasis as well as a brief consideration of psoriatic arthritis. Psoriasis treatment options include topical agents, phototherapy, conventional systemic therapies, and biologics. PMID- 28622257 TI - NCNP Spring 2017: Poster presentation winner. PMID- 28622258 TI - Tuberculosis: Still an emerging threat. AB - Primary care providers must be aggressive in their assessment and screening of tuberculosis (TB) infection, which is still a major cause of mortality and morbidity worldwide. This article highlights the overall management of TB infection including the appropriate screening, diagnosis, and treatment of both latent and active infection. PMID- 28622259 TI - Urosepsis: A simple infection turns toxic. PMID- 28622261 TI - Pelvic pain in transgender men taking testosterone: Assessing the risk of ovarian cancer. AB - Some guidelines on care for transgender men taking testosterone recommend oophorectomy to prevent ovarian cancer, while others recommend following guidelines for females. A review of the literature finds no strong evidence that transgender men are at increased risk for ovarian cancer. In transgender men taking testosterone without other risk factors, oophorectomy to prevent cancer is unnecessary. PMID- 28622262 TI - Distracted Nursing: Strategies to Teach Nursing Students About Mobile Devices. PMID- 28622263 TI - Targeting the Tactile Learner in the Classroom. PMID- 28622264 TI - Staunching the Faculty Nursing Shortage. PMID- 28622265 TI - Thinking Like a Nurse, Revisited. PMID- 28622266 TI - An Integrative Literature Review of Evidence-Based Teaching Strategies for Nurse Educators. AB - AIM: The aim of the study was to explore and describe the best available literature on evidence-based teaching strategies that can be used by nurse educators. BACKGROUND: Evidence-based teaching strategies in nursing education are fundamental to promote an in-depth understanding of information. Although some teaching strategies for nurse educators were identified, no integrative literature review was found summarizing the best teaching strategies for nurse educators. METHOD: Integrative literature review. RESULTS: Sixteen studies were included encompassing eight teaching strategies (e-learning, concept mapping, Internet-based learning, web-based learning, gaming, problem-based learning, case studies, and evidence-based learning). Of these, three (concept mapping, Internet based learning, and evidence-based learning) significantly increased student knowledge. CONCLUSION: All teaching strategies increased knowledge in some way, indicating that faculties should use a variety of teaching strategies. However, more research is needed to compare the impact of a variety of teaching strategies and the best use of different teaching strategies. PMID- 28622267 TI - The Potential of Blockchain in Education and Health Care. PMID- 28622268 TI - NLN Biennial Survey of Schools of Nursing Academic Year 2015-2016: Executive Summary. PMID- 28622271 TI - Bubble-Wiping Technique for Clearing the Condensation on Intraocular Lenses. PMID- 28622270 TI - DEXAMETHASONE INTRAVITREAL IMPLANT FOR THE TREATMENT OF RECALCITRANT MACULAR EDEMA AFTER RHEGMATOGENOUS RETINAL DETACHMENT REPAIR. AB - PURPOSE: To investigate the efficacy of the intravitreal dexamethasone implant as the treatment for recalcitrant macular edema after successful rhegmatogenous retinal detachment repair. METHODS: A retrospective review of the medical records was performed on 17 consecutive patients (17 eyes) with recalcitrant macular edema associated with rhegmatogenous retinal detachment repair who were treated with a single or multiple injections of an intravitreal dexamethasone 0.7-mg implant (Ozurdex; Allergan Inc) at two centers. Main outcomes of the study were change in logarithm of the minimum angle of resolution visual acuity, measurement of central foveal thickness, and macular cube volume as measured by spectral domain optical coherence tomography and frequency of complications. RESULTS: The mean age was 67 years (range, 51-78 years). All 17 patients received previous topical therapy and 12 of them had previous administration of intravitreal triamcinolone with persistence of macular edema. Baseline mean best-corrected visual acuity was 20/100 (logarithm of the minimum angle of resolution 0.75; range, 0.18-1.3 +/-0.37) in the affected eyes. There was a statistically significant improvement in best-corrected visual acuity at 1 month (P < 0.001) and 3 months (P = 0.01). Mean baseline central foveal thickness was 505 MUm, and mean macular cube volume was 10.62 mm. There was a statistically significant decrease in central foveal thickness and macular cube volume at 1 month (505-290 MUm, P = 0.013 and 10.62-9.13 mm, P < 0.0001) and 3 months (P = 0.01). All patients developed recurrence of macular edema at 3 months, which required retreatment. The average number of implants was 4 (range, 1-14). No adverse effects such as retinal detachment or endophthalmitis occurred. Two patients experienced an increase in intraocular pressure that was controlled with topical therapy. CONCLUSION: Macular edema that occurs in eyes after successful repair of rhegmatogenous retinal detachment can be chronic and recalcitrant, and may be successfully and safely treated with the dexamethasone intravitreal implant. PMID- 28622272 TI - NK Cell-derived Exosomes From NK Cells Previously Exposed to Neuroblastoma Cells Augment the Antitumor Activity of Cytokine-activated NK Cells. AB - Immune cell-derived exosomes can increase immunity against tumors. In contrast, tumor-derived exosomes can reduce the immunity and can change the tumor microenvironment to further develop and provide metastasis. These effects take place by an alteration in the innate and adaptive immune cell functions. In this experiment, we studied the natural killer (NK) cells' effectiveness on tumor cells after expansion and thereafter incubated it with exosomes. The exosomes were derived from 2 populations of NK cells: (1) naive NK cells and, (2) NK cells previously exposed to neuroblastoma (NB) cells. Moreover, we have studied the NB derived exosomes on NK cell function. The molecular load of the characterized exosomes (by means of nanoparticle-tracking analysis, flow cytometry, scanning electron microscopy, and western blot) from NK cells exposed to the NB cell revealed their expression of natural killer cell receptors in addition to CD56, NKG2D, and KIR2DL2 receptors. These exosomes were used to treat NK cells and thereafter administered to NB tumor cells both in vitro and in vivo. Our results showed some kind of NK cells' education by the exosomes. This education from NK cells previously exposed to NB cell-derived exosomes caused efficient and greater cytotoxicity against NB tumors, but NB-derived exosomes act as tumor promoters by providing a tumor supporting niche. Hence, this method of preparing the exosomes has a dramatic effect on activation of anti-NK cells against NB cells. PMID- 28622273 TI - Using magnetic resonance imaging to visualize the brain in chronic pain. PMID- 28622274 TI - A role for neurokinin-1 receptor neurons in the rostral ventromedial medulla in the development of chronic postthoracotomy pain. AB - Thoracotomy results in chronic postoperative pain (CPTP) in half of the cases. Earlier findings in rat models of persistent post-surgical pain suggest that spinal pathways are critical for pain onset but not its maintenance. Descending systems from the brain stem modulate nociceptive transmission in the spinal cord and contribute to persistent pain, but their role in chronic postoperative pain has not been studied. Here, we ablated pronociceptive neurokinin-1 receptor (NK 1R)-expressing neurons in the rat rostral ventromedial medulla (RVM) to identify their role in CPTP. Cells were ablated by microinjection of the neurotoxin Sar, Met(O2)-Substance P (SSP-SAP), either 2 to 3 weeks before ("Prevention" condition) or 10 days after ("Reversal" condition) thoracotomy with rib retraction. Inactive Blank-SAP was the control. Tactile hypersensitivity was defined by lowered force thresholds for nocifensive responses to von Frey filaments applied over the dorsal trunk, and pain-like behavior assessed by the Qualitative Hyperalgesia Profile; both were followed for 5 weeks after surgery. SSP-SAP injection before surgery resulted in ~95% loss of NK-1R neurons in RVM and prevented postoperative mechano-hypersensitivity. Blank-SAP was ineffective. SSP-SAP given at postoperative day 10 was equally effective in ablating NK-1R neurons but fully reversed mechano-hypersensitivity in only 3 of 9 hypersensitive rats. Fewer rats showed intense pain-like behavior, by Qualitative Hyperalgesia Profile analysis, in the Prevention than in the Control conditions, and the more intense pain behaviors declined along with SSP-SAP-induced Reversal of hypersensitivity. Neurokinin-1 receptor-expressing neurons in RVM appear essential for the development but contribute only partially to the maintenance of CPTP. PMID- 28622275 TI - Support for extended classification of pain states. PMID- 28622276 TI - Reply. PMID- 28622277 TI - Assessment of physical function: considerations in chronic pain populations. PMID- 28622278 TI - Corrigendum to: Effectiveness of psychological interventions for chronic pain on health care use and work absence: systematic review and meta-analysis, by Pike et al. PAIN 2016;157: 777-785. PMID- 28622279 TI - Hydrogen Sulfide in Exhaled Gases From Ventilated Septic Neonates and Children: A Preliminary Report. AB - OBJECTIVES: There is increasing interest in hydrogen sulfide as a marker of pathologic conditions or predictors of outcome. We speculate that as hydrogen sulfide is a diffusible molecule, if there is an increase in plasma hydrogen sulfide in sepsis, it may accumulate in the alveolar space and be detected in exhaled gas. We wished to determine whether we could detect hydrogen sulfide in exhaled gases of ventilated children and neonates and if the levels changed in sepsis. DESIGN: Prospective, observational study. SETTING: The study was conducted across three intensive care units, pediatric, neonatal and cardiac in a large tertiary children's hospital. PATIENTS: We studied ventilated children and neonates with sepsis, defined by having two or more systemic inflammatory response syndrome criteria and one organ failure or suspected infection. A control group of ventilated non-septic patients was also included. INTERVENTION: A portable gas chromatograph (OralChroma; Envin Scientific, Chester, United Kingdom) was used to measure H2S in parts per billion. MEASUREMENTS AND MAIN RESULTS: A 1-2 mL sample of expired gas was taken from the endotracheal tube and analyzed. A repeat sample was taken after 30 minutes and a further single daily sample up to a maximum of 5 days or until the patient was extubated. WBC and C reactive protein were measured around the time of gas sampling. Each group contained 20 subjects. Levels of H2S were significantly higher in septic patients (Mann Whitney U-test; p < 0.0001) and trended to control levels over five days. C reactive protein levels were also significantly raised (p < 0.001) and mirrored the decrease in H2S levels. CONCLUSION: Hydrogen sulfide can be detected in expired pulmonary gases in very low concentrations of parts per billion. Significantly higher levels are seen in septic patients compared with controls. The pattern of response was similar to that of C-reactive protein. PMID- 28622280 TI - Elevated Central Venous to Arterial CO2 Difference Is Not Associated With Poor Clinical Outcomes After Cardiac Surgery With Cardiopulmonary Bypass in Children. AB - OBJECTIVE: To investigate whether elevated central venous to arterial CO2 difference is associated with delayed extubation and prolonged ICU stay in children after cardiac surgery with cardiopulmonary bypass. DESIGN: Retrospective review of medical records. SETTING: PICU in a tertiary children's hospital. PATIENTS: Pediatric patients younger than 18 years old who underwent cardiac surgery with cardiopulmonary bypass between January 2014 and December 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 114 patients were included in this study. On ICU admission, blood samples were obtained simultaneously from an arterial line and a central venous line. There were no strong correlations between central venous to arterial CO2 difference (median, 11.1 [8.4-13] mm Hg) and other commonly used variables for the assessment of oxygen delivery including arteriovenous oxyhemoglobin saturation difference (R = 0.16) and blood lactate concentration (R = 0.02). When the patients were divided into two groups, based on the CO2 difference, the high group (difference >= 6 mm Hg; n = 103 [90%]) and the low group (difference < 6 mm Hg; n = 11 [10%]) showed no difference in the time to extubation (6 vs 5 hr, respectively; p = 0.80) or in the time to discharge from ICU (4 vs 5 d, respectively; p = 0.49). There was no mortality within 30 days of surgery. CONCLUSIONS: Elevation of central venous to arterial CO2 difference on ICU admission in children after cardiac surgery with cardiopulmonary bypass does not appear to be associated with delayed extubation or prolonged ICU stay. PMID- 28622281 TI - Effects of Baicalin on Blood Pressure and Left Ventricular Remodeling in Rats with Renovascular Hypertension. AB - BACKGROUND This study aimed to explore the effect of baicalin, which is a kind of bioactive flavonoid, on blood pressure and left ventricular remodeling in rats with renovascular hypertension. MATERIAL AND METHODS A total of 40 male Wistar rats were randomly assigned into sham-operation (n=10) and renal hypertension model groups (2-kidney-1 clip; 2K-1C, n=30). The rats in the renal hypertension model group were randomly subdivided into 2K-1C (n=13) and 2K-1C/Baicalin groups (n=14). The cardiac function indexes were determined after 4 weeks. The morphological changes in the myocardial tissue were observed using hematoxylin and eosin and Masson staining. The myocardial apoptosis was detected using the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling method, and the expression of C/EBP homologous protein and caspase-3 was monitored by Western blot. The expression of GRP78 and GRP94 in myocardial cells of rats was detected by qPCR and Western blot technology. RESULTS No significant change in blood pressure was observed in the 2K-1C/Baicalin group compared with the 2K-1C group, but the indexes of left ventricular remodeling significantly improved. Pathological myocardial fibrosis and expression of fibrosis-related factors significantly decreased in the 2K-1C/Baicalin group compared with the 2K 1C group. The expression of glucose-regulated protein (GRP)78, GRP94, CHOP, and caspase-3, and apoptosis of cardiomyocytes also decreased in the 2K-1C/Baicalin group. CONCLUSIONS Baicalin has no significant antihypertensive effect, but reduced pathological changes in the myocardium, alleviated endoplasmic reticulum stress, and reduced myocardial apoptosis, reverting left ventricular remodeling in rats with renovascular hypertension. PMID- 28622282 TI - Towards a neurobiological understanding of alexithymia. AB - Although the specialized literature on the etiology of alexithymia is controversial, neurobiological research has shown relevant advances. The aim of this review is to analyze the available evidence regarding the neurophysiological bases of alexithymia. A comprehensive review of available articles from Medline/PubMed, EBSCO and SciELO was conducted. Previously, alexithymia was linked to a reduced interhemispheric brain connection. From a childhood traumatic perspective, the right prefrontal cortex and the default mode network would experience alterations, first hypermetabolic (dopaminergic and glutamatergic dysregulation) and then hypometabolic-dissociative (serotonergic and opioid dysregulation), resulting in a distorted interoceptive and emotional awareness. Mirror neurons are the essential neurobiological substrate of theory of mind and social cognition, intrinsically linked to alexithymia, involving parietal, temporal, premotor, and cingulate cortices, and inferior frontal gyrus. Other structures involved are the amygdala (facial expression and emotional reactivity), the insula (interoception, emotional integration and empathy) and the cerebellum (limbic cerebellum and somatosensory awareness). Molecular genetics has detected polymorphisms in genes of the serotonin transporter, in the enzyme genes of dopaminergic metabolism and brain-derived neurotrophic factor, while the role of oxytocin is controversial. To sum up, we found several studies demonstrating the overwhelming evidence of a neurobiological basis underlying alexithymia; nevertheless, research is still inconclusive and must include environmental, traumatic, social, and psychological factors that contribute to the origin of the alexithymia. PMID- 28622283 TI - Are cannabinoids effective for Parkinson?s disease? AB - It is postulated cannabinoids may have benefits in Parkinson's disease. However, its actual clinical effectiveness is still discussed. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified six systematic reviews including eight studies overall, of which four were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalyzed data of primary studies included in these reviews, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded cannabinoids probably do not decrease symptoms in Parkinson?s disease or dyskinesia, and probably are associated to frequent adverse effects in patients with Parkinson?s disease. PMID- 28622284 TI - Alternative, traditional, or complementary medicine: A perspective of intercultural therapeutic adherence. PMID- 28622285 TI - What is the effectiveness of systemic corticosteroids in children with croup? AB - Systemic corticosteroids constitute standard treatment in children with acute obstructive laryngitis (croup). However, there is some uncertainty in relation with the magnitude of the benefits and risks associated with their use. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified six systematic reviews including 25 randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reananalysed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded the use of systemic corticosteroids increases the number of patients with clinical improvement at 12 hours and reduces the risk of readmission. PMID- 28622286 TI - Are cannabinoids an effective treatment for chronic non-cancer pain? AB - The use of cannabinoids has been proposed as an analgesic for different painful conditions, especially for chronic pain refractory to usual treatment. However, its real efficacy and safety remains controversial. We sought to determine whether cannabinoids are an effective treatment for chronic non-cancer pain. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified 37 systematic reviews including 41 studies overall, of which 32 were randomized trials relevant for the question of interest. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded it is not clear whether cannabinoids decrease pain in patients with chronic non-cancer pain because the certainty of available evidence is very low. On the other hand, they are associated with significant adverse effects. PMID- 28622287 TI - A niche for cyanobacteria producing chlorophyll f within a microbial mat. AB - Acquisition of additional photosynthetic pigments enables photosynthetic organisms to survive in particular niches. To reveal the ecological significance of chlorophyll (Chl) f, we investigated the distribution of Chl and cyanobacteria within two microbial mats. In a 7-mm-thick microbial mat beneath the running water of the Nakabusa hot spring, Japan, Chl f was only distributed 4.0-6.5 mm below the surface, where the intensity of far-red light (FR) was higher than that of photosynthetically active radiation (PAR). In the same mat, two ecotypes of Synechococcus and two ecotypes of Chl f-producing Leptolyngbya were detected in the upper and deeper layers, respectively. Only the Leptolyngbya strains could grow when FR was the sole light source. These results suggest that the deeper layer of the microbial mat was a habitat for Chl f-producing cyanobacteria, and Chl f enabled them to survive in a habitat with little PAR. PMID- 28622288 TI - Optimization of design and production strategies for novel adeno-associated viral display peptide libraries. AB - Libraries displaying random peptides on the surface of adeno-associated virus (AAV) are powerful tools for the generation of target-specific gene therapy vectors. However, for unknown reasons the success rate of AAV library screenings is variable and the influence of the production procedure has not been thoroughly evaluated. During library screenings, the capsid variants with the most favorable tropism are enriched over several selection rounds on a target of choice and identified by subsequent sequencing of the encapsidated viral genomes encoding the library capsids with targeting peptide insertions. Thus, a high capsid-genome correlation is crucial to obtain the correct information about the selected capsid variants. Producing AAV libraries by a two-step protocol with pseudotyped library transfer shuttles has been proposed as one way to ensure such a correlation. Here we show that AAV2 libraries produced by such a protocol via transfer shuttles display an unexpected additional bias in the amino-acid composition which confers increased heparin affinity and thus similarity to wildtype AAV2 tropism. This bias may fundamentally impair the intended use of AAV libraries, discouraging the use of transfer shuttles for the production of AAV libraries in the future. PMID- 28622291 TI - Predicting lung cancer recurrence from circulating tumour DNA. Commentary on 'Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution'. PMID- 28622290 TI - Structural basis for the regulatory interactions of proapoptotic Par-4. AB - Par-4 is a unique proapoptotic protein with the ability to induce apoptosis selectively in cancer cells. The X-ray crystal structure of the C-terminal domain of Par-4 (Par-4CC), which regulates its apoptotic function, was obtained by MAD phasing. Par-4 homodimerizes by forming a parallel coiled-coil structure. The N terminal half of Par-4CC contains the homodimerization subdomain. This structure includes a nuclear export signal (Par-4NES) sequence, which is masked upon dimerization indicating a potential mechanism for nuclear localization. The heteromeric-interaction models specifically showed that charge interaction is an important factor in the stability of heteromers of the C-terminal leucine zipper subdomain of Par-4 (Par-4LZ). These heteromer models also displayed NES masking capacity and therefore the ability to influence intracellular localization. PMID- 28622289 TI - MicroRNA-26a and -26b inhibit lens fibrosis and cataract by negatively regulating Jagged-1/Notch signaling pathway. AB - Fibrosis is a chronic process involving development and progression of multiple diseases in various organs and is responsible for almost half of all known deaths. Epithelial-mesenchymal transition (EMT) is the vital process in organ fibrosis. Lens is an elegant biological tool to investigate the fibrosis process because of its unique biological properties. Using gain- and loss-of-function assays, and different lens fibrosis models, here we demonstrated that microRNA (miR)-26a and miR-26b, members of the miR-26 family have key roles in EMT and fibrosis. They can significantly inhibit proliferation, migration, EMT of lens epithelial cells and lens fibrosis in vitro and in vivo. Interestingly, we revealed that the mechanisms of anti-EMT effects of miR-26a and -26b are via directly targeting Jagged-1 and suppressing Jagged-1/Notch signaling. Furthermore, we provided in vitro and in vivo evidence that Jagged-1/Notch signaling is activated in TGFbeta2-stimulated EMT, and blockade of Notch signaling can reverse lens epithelial cells (LECs) EMT and lens fibrosis. Given the general involvement of EMT in most fibrotic diseases, cancer metastasis and recurrence, miR-26 family and Notch pathway may have therapeutic uses in treating fibrotic diseases and cancers. PMID- 28622292 TI - The potential of erythrocytes as cellular aging models. PMID- 28622293 TI - SUMO-triggered ubiquitination of NR4A1 controls macrophage cell death. AB - Nuclear receptor NR4A1 has been implicated as a key regulator in a wide range of pathophysiological responses. As an immediate early response gene, NR4A1 can be rapidly and potently induced by a variety of stimuli. Its induction is followed by its rapid degradation, but the mechanism by which NR4A1 is degraded remains poorly understood. Here we show that nuclear receptor NR4A1 is sumoylated by SUMO2/3. Upon poly-SUMO modification, NR4A1 can be targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. The SUMO E3 ligase PIAS3 promotes SUMOylation and polyubiquitination of NR4A1, while the SUMO protease SENP1 acts to de-conjugate SUMO. We demonstrate that this pathway is important for rapid degradation of NR4A1 after induced by stress. Moreover, we identify two SUMO modification sites in NR4A1 that are critical for maintaining low levels of NR4A1 expression. Mutation of these two NR4A1 SUMO modification sites enhances the stability of NR4A1. Importantly, we show that SUMOylation is critical in controlling NR4A1 function in inflammatory cytokine signaling and controlling macrophage cell death. SUMOylation and subsequent ubiquitination on NR4A1 mitigates its inhibition of innate immune signaling, such as TNF-alpha- and IL-1beta-induced NF-kappaB activation. This mechanism of sequential SUMOylation and ubiquitination, which together control the degradation of NR4A1, could be exploited for the therapeutic treatment of diseases with NR4A1 involvement. PMID- 28622294 TI - Hepatocyte nuclear factor 1b is a novel negative regulator of white adipocyte differentiation. AB - Hepatocyte nuclear factor 1b (HNF1b) is a transcription factor belonging to the HNF family. We aimed to investigate the role of HNF1b in white adipocyte differentiation. The expression of HNF1b was reduced in white adipose tissue (WAT) of both diet-induced and genetic obese mice and decreased during the process of 3T3-L1 adipocyte differentiation. Downregulation of HNF1b enhanced 3T3 L1 adipocyte differentiation and upregulation of HNF1b inhibited this process. Upregulation of HNF1b inhibited peroxisome proliferator-activated receptor gamma (PPARgamma) and its target gene expression, while downregulation of HNF1b increased those genes expression. Overexpression of PPARgamma suppressed HNF1b upregulation-induced inhibition of adipocyte differentiation. HNF1b can directly bind with the promoter of PPARgamma in 3T3-L1 cells, which was decreased after adipogenic differentiation. HNF1b promoted apoptotic and autophagic cell death in early differentiated adipocytes through regulation of cell cycle progress and cell death-related factors, and thus inhibited the process of mitotic clonal expansion (MCE). HNF1b acted as an antioxidant regulator through regulating various antioxidant enzymes via binding with antioxidant response element. Oxidant treatment suppressed HNF1b upregulation-induced inhibition of adipocyte differentiation. Overall, our results suggest that HNF1b is a novel negative regulator of adipocyte differentiation through regulation of PPARgamma signaling, MCE and redox state. PMID- 28622295 TI - High autophagic flux guards ESC identity through coordinating autophagy machinery gene program by FOXO1. AB - Although much is known about transcriptional networks that control embryonic stem cell (ESC) self-renewal and differentiation, the metabolic regulation of ESC is less clear. Autophagy is a catabolic process that is activated under both stress and normal conditions to degrade damaged organelles and aggregated proteins, and thus plays pivotal roles in somatic and adult stem cell function. However, if and how ESCs harness autophagy to regulate stemness remains largely unknown. Recently, we have defined that autophagy is essential for mitochondrial homeostasis regulation in pluripotency acquirement and maintenance. Here we identified high autophagic flux as an essential mechanism to maintain ESC identity. We show that mouse ESCs exhibit a high autophagic flux that is maintained by coordinating expression of autophagy core molecular machinery genes through FOXO1, a forkhead family transcription factor. Tapering autophagic flux by manipulating either Atg3 or Foxo1 expression compromised ESC self-renewal, pluripotency, and differentiation that could be restored by gain of wild-type but not function-deficient Atg3 or Foxo1 mutants, respectively. Our results define a newly recognized role of autophagic flux in mouse ESC identity maintenance that links cellular catabolism to ESC fate regulation. PMID- 28622297 TI - p53-mediated suppression of BiP triggers BIK-induced apoptosis during prolonged endoplasmic reticulum stress. AB - Physiological and pathological conditions that affect the folding capacity of the endoplasmic reticulum (ER) provoke ER stress and trigger the unfolded protein response (UPR). The UPR aims to either restore the balance between newly synthesized and misfolded proteins or if the damage is severe, to trigger cell death. However, the molecular events underlying the switch between repair and cell death are not well understood. The ER-resident chaperone BiP governs the UPR by sensing misfolded proteins and thereby releasing and activating the three mediators of the UPR: PERK, IRE1 and ATF6. PERK promotes G2 cell cycle arrest and cellular repair by inducing the alternative translated p53 isoform p53DeltaN40 (p53/47), which activates 14-3-3sigma via suppression of p21CDKN1A. Here we show that prolonged ER stress promotes apoptosis via a p53-dependent inhibition of BiP expression. This leads to the release of the pro-apoptotic BH3-only BIK from BiP and activation of apoptosis. Suppression of bip mRNA translation is mediated via the specific binding of p53 to the first 346-nt of the bip mRNA and via a p53 trans-suppression domain located within the first seven N-terminal amino acids of p53DeltaN40. This work shows how p53 targets BiP to promote apoptosis during severe ER stress and further illustrates how regulation of mRNA translation has a key role in p53-mediated regulation of gene expression during the UPR. PMID- 28622296 TI - BCL-2 family: integrating stress responses at the ER to control cell demise. AB - In the last decade, the endoplasmic reticulum (ER) has emerged as a central organelle regulating the core mitochondrial apoptosis pathway. At the ER membrane, a variety of stress signals are integrated toward determining cell fate, involving a complex cross talk between key homeostatic pathways including the unfolded protein response, autophagy, calcium signaling and mitochondrial bioenergetics. In this context, key regulators of cell death of the BCL-2 and TMBIM/BI-1 family of proteins have relevant functions as stress rheostats mediated by the formation of distinct protein complexes that regulate the switch between adaptive and proapoptotic phases under stress. Here, we overview recent advances on our molecular understanding of how the apoptotic machinery integrates stress signals toward cell fate decisions upstream of the mitochondrial gateway of death. PMID- 28622298 TI - TGFbeta pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis. AB - Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-kappaB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFbeta signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFbeta type 1 receptor (Tgfbr1/Alk5) enhanced the ability of KrasG12D/+ mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFbeta and blockade of these makes tumourigenesis more efficient from this compartment. PMID- 28622299 TI - A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation. AB - Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1 transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142 fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm3 in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy. PMID- 28622300 TI - The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins. AB - Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway. The E102Q mutation in one such candidate gene, the endoplasmic reticulum (ER) chaperone Sigma receptor-1 (SigR1), has been reported to cause juvenile ALS. Although loss of SigR1 protein contributes to neurodegeneration in several ways, the molecular mechanisms underlying E102Q-SigR1-mediated neurodegeneration are still unclear. In the present study, we showed that the E102Q-SigR1 protein rapidly aggregates and accumulates in the ER and associated compartments in transfected cells, leading to structural alterations of the ER, nuclear envelope and mitochondria and to subsequent defects in proteasomal degradation and calcium homeostasis. ER defects and proteotoxic stress generated by E102Q-SigR1 aggregates further induce autophagy impairment, accumulation of stress granules and cytoplasmic aggregation of the ALS-linked RNA-binding proteins (RBPs) matrin-3, FUS, and TDP-43. Similar ultrastructural abnormalities as well as altered protein degradation and misregulated RBP homeostasis were observed in primary lymphoblastoid cells (PLCs) derived from E102Q-SigR1 fALS patients. Consistent with these findings, lumbar alpha-MNs of both sALS as well as fALS patients showed cytoplasmic matrin-3 aggregates which were not co-localized with pTDP-43 aggregates. Taken together, our results support the notion that E102Q-SigR1-mediated ALS pathogenesis comprises a synergistic mechanism of both toxic gain and loss of function involving a vicious circle of altered ER function, impaired protein homeostasis and defective RBPs. PMID- 28622302 TI - Evaluation of coagulopathy before and during induction chemotherapy for acute lymphoblastic leukaemia, including assessment of global clotting tests. PMID- 28622301 TI - Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach. PMID- 28622303 TI - Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib. AB - Bortezomib, in combination with dexamethasone (VD) or with the addition of cyclophosphamide (VCD), is highly effective in patients with amyloid light-chain (AL) amyloidosis. Currently, VCD is considered as a primary regimen for patients with AL, but it is not clear whether the addition of cyclophosphamide to VD further and significantly improves efficacy, given the substantial activity of bortezomib itself. We retrospectively compared the outcomes of 101 patients with AL amyloidosis who received VD (n=59) or VCD (n=42) in two consecutive periods. Early mortality after adjustment for Mayo stage was similar. On intent to treat, a hematologic response rate was 68% for patients treated with VD and 78% for VCD (P=0.26), while complete response+very good partial response (CR+VGPR) rate was 47.5% and 35%, respectively. Higher doses of dexamethasone or twice-weekly bortezomib were not associated with significantly higher CR+VGPR rates. Organ responses occurred in similar rates between the two groups. Median survival was similar (33 vs 36 months, P=0.45) even after adjustment for Mayo stage and dose and schedule of bortezomib and dexamethasone. In conclusion, bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of cyclophosphamide do not seem to have a profound effect on efficacy and survival. PMID- 28622304 TI - Outcomes of newly diagnosed myeloma patients requiring dialysis: renal recovery, importance of rapid response and survival benefit. PMID- 28622305 TI - The thrombopoietin/MPL axis is activated in the Gata1low mouse model of myelofibrosis and is associated with a defective RPS14 signature. AB - Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1low mutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1low mice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1low LSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice. Gata1low marrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of Gata1low mice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1low mice activation of the TPO/MPL axis was associated with a RSP14 deficiency and a discordant microarray ribosome signature (reduced RPS24, RPS26 and SBDS expression). Finally, electron microscopy revealed that Gata1low megakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1low mice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients. PMID- 28622306 TI - Changes in uninvolved immunoglobulins during induction therapy for newly diagnosed multiple myeloma. AB - Little is known about the impact of multiple myeloma (MM) treatment on uninvolved immunoglobulins (Ig). We identified 448 patients who received high-dose dexamethasone (HD-DEX), lenalidomide and dexamethasone (RD), bortezomib and dexamethasone (VD), bortezomib, cyclophosphamide and dexamethasone (VCD) or bortezomib, lenalidomide and dexamethasone (VRD) for newly diagnosed MM at our institution between 2000 and 2013, and who had available data on absolute lymphocyte count (ALC) and quantitative uninvolved Ig at baseline and at the end of four cycles of therapy. Changes in ALC and uninvolved Ig were significantly different across treatments, with VCD and HD-DEX producing reductions in uninvolved Ig, and RD, VD and VRD leading to increases in uninvolved Ig. In addition, treatment with RD, VD and VRD was independently associated with higher odds of achieving a ?25% increase in or normalization of the primary uninvolved Ig on multivariate analysis. Although achievement of a humoral response in the primary uninvolved Ig was associated with a higher odds of achieving VGPR or better after four cycles of therapy, it was not associated with improved overall survival. These data highlight the different mechanisms of action of MM drugs and point toward a possible role for the use of VCD in treating antibody-mediated autoimmune disease. PMID- 28622307 TI - Beta-atrophy in Alzheimer's disease. PMID- 28622308 TI - Response to 'Functional and anatomical outcomes of punctoplasty with Kelly punch'. PMID- 28622309 TI - Eyelid and fornix reconstruction in abortive cryptophthalmos: a single-center experience over 12 years. AB - PurposeAbortive cryptophthalmos is a rare congenital eyelid anomaly with poor prognosis for vision and cosmesis. The study aims to present its varied manifestations and surgical outcomes.Patients and methodsThe medical records of patients with abortive cryptophthalmos treated at the Oculoplastic Clinic of Beijing Tongren Hospital between January 2004 and May 2016 were reviewed. Early surgical intervention was performed when exposure keratopathy occurs. Upper eyelid and superior fornix were mainly reconstructed with sliding myocutaneous flap and scleral and amniotic grafts. Post-operative upper eyelid contour, recurrence of symblepharon, and ability to retain prosthesis were evaluated.ResultsThe study included 41 eyes of 28 patients. The median age at first presentation was 5 years (ranging from 1 month to 58 years). The majority (79%) with concurrent craniofacial abnormalities tended to be associated with more severe cryptophthalmos. Nine eyes of 9 patients had recurrence of symblepharon. Acceptable functional and cosmetic outcomes were achieved in 20 of the 24 patients receiving repair procedures during the follow-up period.ConclusionOne-stage reconstruction of eyelid and fornix with scleral and amniotic grafts is an effective strategy to correct abortive cryptophthalmos. PMID- 28622311 TI - An alternative method for upper and lower conjunctival fornix measurement. PMID- 28622310 TI - How to defuse a demographic time bomb: the way forward? PMID- 28622312 TI - Clinical features and prognostic factors of Klebsiella endophthalmitis-10-year experience in an endemic region. AB - AimsTo identify the clinical features and prognostic factors of endogenous endophthalmitis caused by Klebsiella pneumoniae.MethodsThis is a retrospective case series of all patients with Klebsiella endophthalmitis managed from January 2006 to December 2015 by Kowloon East Ophthalmic Service. Statistical analysis involved hypothesis testing on the SPSS 18.0 software (SPSS). A significance level of P<0.05 was taken.ResultsIn the 10-year period, K. pneumoniae accounted for 19 out of 39 cases of endogenous endophthalmitis (48.7%). The mean age of patients was 67.9 years. Bilateral involvement occurred in five patients (26.3%). More than half of the patients (10/19, 52.6%) had underlying diabetes mellitus. Most patients had concurrent liver abscess (18/19, 94.74%). Ten patients (52.6%) had disseminated intravascular coagulopathy. Eight patients (42.1%) were in shock. The overall mortality was 21.1% (4/19). Septic shock was associated with a significantly higher mortality (50.0 vs 0%, P=0.018). Among the 15 survivors, nine patients (60.0%) required evisceration and three patients (20.0%) had no light perception in an involved eye. Eyes with diffuse posterior involvement were less likely to have a final visual acuity of logMAR 0.30 or better than those with focal posterior involvement (4.76 vs 100% 4.76%, P=0.002). Patients with hypopyon were more likely to require evisceration (85.71 vs 25.00%, P=0.02).ConclusionsKlebsiella endophthalmitis is associated with a high incidence of diabetes mellitus and liver abscess. Prognosis remains poor. Universal ocular screening and systemic control in patients with Klebsiella sepsis are recommended. PMID- 28622313 TI - Optical coherence tomography analysis of evolution of Bruch's membrane features in angioid streaks. AB - PurposeTo describe optical coherence tomography (OCT) features in the Bruch's membrane (BM) of eyes with angioid streaks (AS) and evaluate their evolution over the follow-up.Patients and methodsPatients with AS presenting between March 2016 and September 2016 at two tertiary referral centers were consecutively recruited in this study. Eligibility criteria included prior spectral domain (SD)-OCT images, taken at least 3 months before at the same referral center, with automated eye tracking and image alignment modules. Alterations of BM were described and compared to previous scans over the follow-up. Multimodal imaging was used to identify alteration of retinal pigment epithelium (RPE) and choroid.ResultsThirty-two eyes of 16 consecutive patients with AS were included. BM undulations, mostly observed around the optic nerve head, were found in 19 (59.4%) of 32 eyes. BM breaks were found in 31 (96.9%) out of 32 eyes. Evolution of BM undulations into BM breaks was observed in 5 eyes (15.6%). Choroidal neovascularization (CNV) was observed in 12 eyes (37.5%) during follow-up, typically in areas of BM interruption.ConclusionsBM undulations, probably caused by high stretching forces exerted on the BM around the optic nerve head, seem to precede some BM breaks. BM interruptions may be a preferred way for the growth of CNV, which was identified in one-third of our cases. PMID- 28622314 TI - Development of a simple computerized torsion test to quantify subjective ocular torsion. AB - PurposeThe double Maddox-rod test (DMRT) and Lancaster red-green test (LRGT) are the most widely used tests worldwide to assess subjective ocular torsion. However, these tests require equipment and the quantified results of ocular torsion are only provided in rough values. Here we developed a novel computerized torsion test (CTT) for individual assessment of subjective ocular torsion and validated the reliability and accuracy of the test compared with those of the DMRT and LRGT.MethodsA total of 30 patients with cyclovertical strabismus and 30 controls were recruited. The CTT was designed using Microsoft Office PowerPoint. Subjects wore red-green filter spectacles and viewed gradually tilted red and cyan lines on an LCD monitor and pressed the keyboard to go through the slides, until both lines seemed parallel. All subjects underwent the CTT, DMRT, and LRGT. Intraclass correlation coefficients and Bland-Altman plots were analyzed to assess the acceptability of the CTT compared with that of the DMRT.ResultsBoth the DMRT and CTT showed no significant test-retest differences in the strabismus and control groups. The DMRT and CTT results demonstrated an acceptable agreement. The reliability of the CTT was better than that of the DMRT. The LRGT showed low sensitivity for the detection of ocular torsion compared with the DMRT (40.0%) and CTT (39.1%).ConclusionOur results suggest that the assessment of subjective ocular torsion using the CTT based on PowerPoint software is simple, reproducible, and accurate and can be applied in clinical practice. PMID- 28622315 TI - Developing a children's glaucoma passport: mapping innovations in healthcare. PMID- 28622316 TI - Corneal densitometry after photorefractive keratectomy, laser-assisted in situ keratomileusis, and small-incision lenticule extraction. AB - PurposeThe aim of this study was to gain greater insight into the corneal densitometry changes occurring as a result of refractive surgery and to compare these changes across three widely used surgical techniques, namely, photorefractive keratectomy (PRK), laser-assisted in situ keratomileusis with a femtosecond laser (LASIK-FS), or ReLEx small-incision lenticule extraction (ReLEx SMILE).Patients and methodsThree hundred and thirty-six patients (184 male and 152 female patients) participated in this study. They were split into three groups according to the refractive surgery technique they had undergone: LASIK-FS (74 patients), PRK (153 patients), and ReLEx SMILE (109 patients). All participants underwent an exhaustive eye examination both before and after surgery. Pre- and postoperative corneal densitometry was measured using an Oculus Pentacam system.ResultsThe mean postoperative total corneal densitometry values were 16.53+/-1.94 for the LASIK-FS group, 15.53+/-1.65 for PRK, and 16.10+/-1.54 for ReLEx SMILE. When corneal densitometry was analyzed for specific corneal areas, the values corresponding to the 0-2, 2-6, and 6-10 mm annuli were similar across the three surgical techniques. The only region in which differences were found was the peripheral area (P<0.05), but these variations across techniques were not statistically significant.ConclusionsCorneal densitometry can be used as an objective metric to assess corneal response to refractive surgery, and to monitor patients over time. Corneal densitometry was not negatively affected by any of the refractive surgical procedures under evaluation. PMID- 28622317 TI - Assessment of patient-reported outcome and quality of life improvement following surgery for epiphora. AB - PurposeTo assess and compare the subjective improvement in symptoms and quality of life in adult patients who underwent commonly performed oculoplastic surgical interventions to treat epiphora.Materials and methodsA prospective study was undertaken involving all adult patients undergoing dacryocystorhinostomy (DCR), lid tightening (lateral tarsal strip or lateral wedge resection), and punctoplasty surgery at our institution. We assessed severity of epiphora preoperatively using the Munk score. At 3 months postoperatively, all patients were sent postal questionnaires comprising of Munk score, 'social impact score' from validated Lac-Q questionnaire ranging from 0 (no impact) to 5 (maximal negative impact) and Glasgow Benefit Inventory (GBI) score, ranging from -100 (maximal detriment) to +100 (maximal benefit).ResultsA total of 134 questionnaires were sent with an overall response rate of 74.6%. For the purpose of data analysis, patients were divided into four groups: DCR, lid tightening, punctoplasty, and combined group (lid tightening plus punctoplasty). There was statistically significant improvement in subjective epiphora postoperatively, as assessed by Munk score (P<0.001) in all groups. The total GBI scores were +42.67 (95% CI: 33.42-51.91) for DCR, +19.65 (95% CI: 10.33-28.97) for lid tightening, +16.06 (95% CI: 2.65-29.48) for punctoplasty, and +26.53 (95% CI: 13.15-39.90) for the combined group, demonstrating a positive change in health status for all groups. There was negative correlation between total GBI and post-operative Munk scores (r=-0.58, P<0.001), and positive correlation between Lac-Q and Munk scores (r=0.65, P<0.001).ConclusionPatients derived significant improvement in symptoms and health-related quality of life benefit following all surgical interventions for epiphora. PMID- 28622318 TI - Characteristics of symptoms experienced by persons with dry eye disease while driving in China. AB - PurposeTo assess the vision-related quality of life and self-reported driving performance of patients with dry eye disease (DED).Patients and methodsThe study was performed in the eye centre of Peking University Third Hospital, China. In total, 87 dry eye patients and 42 controls were enroled, including 49 patients without any treatment (group A), 38 patients treated with artificial tears (group B) and 42 controls without DED (group C). The participants had no eye disease other than DED. Scores of a vision-related quality-of-life questionnaire (Ocular Surface Disease Index (OSDI)), a daily life-related visual function questionnaire and a questionnaire about performance during driving were collected. Data were compared among the groups and analysed.ResultsSignificant differences in all clinical characteristics and OSDI scores were found between DED patients and normal controls (P<0.05). While subjects in group A felt more uncomfortable than those in group B, the functional limitations related to dry eye were significant in all DED patients, especially for daily work and using a computer. DED was correlated with unsafe driving habits and performance, which may increase the risk of dangerous driving (P<0.01). For patients with DED, the rate of accidents and near-accidents was 10.33%, and the rate of missed targets totalled 32.17%.ConclusionsDED can lead to many inconveniences in daily life, including driving. The frequencies of unsafe driving habits and performance were increased in patients with DED. PMID- 28622319 TI - Flicker electroretinograms recorded with mydriasis-free RETeval system before and after cataract surgery. AB - PurposeThe purpose of this study is to compare the amplitudes and peak times of the flicker electroretinograms (ERGs) recorded before and after cataract surgery with the RETeval system (LKC Technologies, Gaithersburg, MD, USA) from eyes without dilation.Patients and methodsThirty-two eyes of 32 patients (77.3+/-6.5 years) that had grade 2 Emery-Little nuclear or cortical cataract without any other abnormalities were studied. Flicker ERGs were recorded with the RETeval system under mydriatic-free conditions. Skin electrodes were used to pick-up the ERGs that were elicited by white light delivered at a rate of 28.3 Hz and intensity of 2, 8, and 32 Td-s. The amplitudes and peak times of the flicker ERGs before and after cataract surgery were compared.ResultsThe mean amplitudes were significantly increased after the removal of the cataractous lenses at the three stimulus intensities (2 Td-s, P<0.0001; 8 Td-s, P<0.0001; and 32 Td-s, P<0.0001). The mean peak times of the flicker ERGs elicited by 2 and 8 Td-s were significantly shortened after the surgery (2 td-s, P<0.0001 and 8 td-s, P=0.0127) but not at 32 td-s (P=0.595).ConclusionsThese results indicate that the presence of cataracts will affect both the amplitudes and the peak times of the flicker ERGs even if the cataract is mild. In addition, the results indicate that as stimulus intensity increases, the peak times is less affected by a cataract. The clarity of the crystalline lens should be considered when interpreting the flicker ERGs recorded with the RETeval system. PMID- 28622320 TI - A novel graft option after pterygium excision: platelet-rich fibrin for conjunctivoplasty. AB - PurposeTo compare the surgical results, complications, and recurrence rates of primary pterygium excision with conjunctival autografts (CA) vs platelet-rich fibrin (PRF) grafts.Patients and methodsA total of 35 eyes of 35 patients with primary pterygium were included in the study. The patients underwent excision of pterygium followed by closure of the bare sclera by CA (group 1, n=20) vs PRF grafts (group 2, n=15). The PRF was generated from the patients' own whole-blood sample by centrifugation and pressing. The surgery times, intra/postoperative complications, recurrence rates of pterygium, and changes in visual acuity (VA) were evaluated and compared within groups.ResultsThe mean follow-up period was 14.3+/-6.5 months (6-24 months). The mean preoperative and postoperative VAs were same (20/25) (P=0.204). The mean surgery time was shorter in group 2 (22.1+/-1.9 min) compared to group 1 (33.8+/-7.8 min) (P=0.001). The recurrence was observed only in one (6.6%) case of group 2, while none of the cases showed recurrence in group 1. Graft loss was observed in 2 (10%) cases in group 1, and 1 (6.6%) case in group 2. No other intra/postoperative complications such as tear in the graft, excessive bleeding, scleral necrosis, graft necrosis, pannus formation, or symblepharon occurred in both groups.ConclusionsThis preliminary study showed encouraging results of the application of PRF for conjuntivoplasty after pterygium excision. The use of PRF in pterygium surgery is a simple, easily applicable, and a promising method with low rates of recurrence and complications. PMID- 28622321 TI - Identification of time point to best define 'sub-optimal response' following intravitreal ranibizumab therapy for diabetic macular edema based on real-life data. AB - PurposeTo determine the average time-point at which it is best to define 'sub optimal response' after ranibizumab treatment for diabetic macular edema (DME) based on the data obtained from real-life clinical practice.MethodsIn this retrospective observational study, 322 consecutive treatment naive eyes with DME were treated with three loading doses of intravitreal ranibizumab followed by re treatment based on decision of the treating physician on a case-by-case basis. The demographic data, clinic-based visual acuity measurements and central subfield thickness (CST) assessed on spectral domain optical coherence tomography (OCT) were evaluated at baseline (month 0), 1, 2, 3, 6, and 12 months.ResultsOn an average, the improvement in visual acuity and CST was first seen after the loading dose. However, the maximal response in terms of proportion of patients with improvement in visual acuity and/ or CST in this cohort was observed at 12 months. Patients who presented with low visual acuity at baseline (<37 ETDRS letters) were unlikely to attain driving vision with ranibizumab therapy.ConclusionsOn an average, a 'sub-optimal response' after ranibizumab therapy is best defined at month 12 as patients may continue to improve with treatment. PMID- 28622322 TI - The urgent need to develop emergency EYE care in the UK: the way forward? PMID- 28622323 TI - UK ophthalmology electronic medical records, databases, big data, and Robert L Johnston! PMID- 28622324 TI - Postoperative change in lateral rectus muscle insertion measured by anterior segment optical coherence tomography. AB - AimsThe aims of this study were to investigate the longitudinal change in lateral rectus (LR) muscle insertion after recession surgery, and to evaluate a relationship between insertion distance and postoperative amount of deviation.MethodsWe recruited 31 patients who underwent primary LR recession surgery with normal anterior segment structures. An AS-OCT scan of the LR muscle was performed at every visit. Data on sex, age, degree of deviation (prism diopter), and spur-LR insertion distance using AS-OCT were collected at preoperatively and postoperative months 1, 3, and 6. Spur-LR insertion was defined as the shortest distance between the insertion of the LR muscle and the scleral spur was measured using the caliper function in the AS-OCT software.ResultsThe mean distance of spur-LR insertion measured with AS-OCT was 5.5+/-0.7 mm preoperatively, and 11.1+/-0.9 mm at 1 month, 11.5+/-0.8 mm at 3 months, and 11.0+/-0.7 mm at 6 months postoperatively. There were significant differences in spur-LR insertion between postoperative 1 and 3 months, and between 3 and 6 months (generalized estimating equation, all P<0.001). The overall spur-LR insertion measurement has a significantly negative correlation with postoperative amount of deviation (Pearson's correlation, P=0.035, r= 0.218).ConclusionsAS-OCT is a useful instrument for understanding postoperative changes in EOM after tissue swelling subsides. PMID- 28622326 TI - Clinical real-world results of switching treatment from ranibizumab to aflibercept in patients with diabetic macular oedema. PMID- 28622325 TI - Fingerprick autologous blood: a novel treatment for dry eye syndrome. AB - PurposeDry eye syndrome (DES) causes significant morbidity. Trials of blood derived products in treatment of the condition show promising results. However, their production is expensive and time-consuming. We investigate fingerprick autologous blood (FAB) as an alternative low-cost, readily accessible treatment for DES.Patients and methodsProspective, non-comparative, interventional case series. In total, 29 eyes of 16 DES patients (2 males and 14 females) from two NHS sites in the United Kingdom. Patients instructed to clean a finger, prick with a blood lancet, and apply a drop of blood to the lower fornix of the affected eye(s), 4 times daily for 8 weeks then stop and review 4 weeks later. Follow-up visits occurred ~3 days, 2, 4, 8 weeks into therapy, and 4 weeks post cessation. At each visit, visual acuity, corneal staining, Schirmer's test, tear break-up time (TBUT), and ocular comfort index (OCI) were measured, and photographs taken. Results were analysed using Student's paired t-test.ResultsAt 8 weeks, there was improvement in mean Oxford corneal staining grade (3.31 to 2.07 (P<0.0001)), TBUT (5.00 to 7.80 s (P<0.05)), visual acuity (0.08 to 0.01 LogMAR equivalent (P<0.05)), and OCI score (56.03 to 39.72 (P<0.0001)). There was no statistically significant change in Schirmer's test results. Four weeks post cessation versus immediately after completion of FAB therapy, mean staining grade worsened from 2.07 to 2.86 (P<0.0001). OCI score worsened from 39.72 to 44.67 (P<0.05).ConclusionsIn our limited case series FAB appears to be a safe and effective treatment for DES. PMID- 28622327 TI - Response to: 'An alternative method for upper and lower conjunctival fornix measurement'. PMID- 28622328 TI - Second-year visual acuity outcomes of nAMD patients treated with aflibercept: data analysis from the UK Aflibercept Users Group. AB - PurposeTo audit the visual acuity (VA) outcomes achieved at the end of year two in 17 UK centres, which followed the year 1 VIEW protocol in year 1, but a variable approach in year 2 for aflibercept for neovascular macular degeneration (nAMD).Patients and methodsRetrospective data analysis, from an electronic medical record, of a consecutive series of treatment-naive nAMD patients who received aflibercept for 2 consecutive years, having followed the VIEW protocol in year one, defined as eyes having received 7 or 8 injections from baseline.ResultsThe mean number of intravitreal injections (IVI)s during year 2 was 3.7 in 1180 eyes (1083 patients). The mean baseline VA of the whole cohort was 56.3 ETDRS letters, improving to 61.3 at 1 year (+5) and 59.1 (+2.8) at the end of year 2. The mean VA letter score at the end of year 2, stratified by number of IVIs into three groups was as follows: group A, 57.3 (gain of +1.7) (44% of eyes (/=6 IVIs)). Even though there were VA gains in the three groups over the 2-years, there was a drop in VA in year one to two. Eyes that received >/=6 IVIs (group C) had a smaller reduction of VA during year 2 than those which received =7 days after pneumonectomy, whereas 100% of the control mice died within a few h and 50% of mice in the rHSA group died within 24 h after pneumonectomy. Immunohistochemical staining for hypoxia-inducible factor-1alpha showed that hepatic and renal hypoxic injuries were prominently mitigated by HbV and mRBCs. CONCLUSIONS: The oxygen-carrying performance of HbV was similar to that of mRBCs, even with impaired lung functions following pneumonectomy. HbV infusion did not interfere with the recovery from surgical injury. In the near future, HbVs could be used clinically as a substitute for the perioperative transfusion of RBCs, when or where donated RBCs are not immediately available. PMID- 28622334 TI - Sterol 14alpha-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana. AB - Amphotericin B has emerged as the therapy of choice for use against the leishmaniases. Administration of the drug in its liposomal formulation as a single injection is being promoted in a campaign to bring the leishmaniases under control. Understanding the risks and mechanisms of resistance is therefore of great importance. Here we select amphotericin B-resistant Leishmania mexicana parasites with relative ease. Metabolomic analysis demonstrated that ergosterol, the sterol known to bind the drug, is prevalent in wild-type cells, but diminished in the resistant line, where alternative sterols become prevalent. This indicates that the resistance phenotype is related to loss of drug binding. Comparing sequences of the parasites' genomes revealed a plethora of single nucleotide polymorphisms that distinguish wild-type and resistant cells, but only one of these was found to be homozygous and associated with a gene encoding an enzyme in the sterol biosynthetic pathway, sterol 14alpha-demethylase (CYP51). The mutation, N176I, is found outside of the enzyme's active site, consistent with the fact that the resistant line continues to produce the enzyme's product. Expression of wild-type sterol 14alpha-demethylase in the resistant cells caused reversion to drug sensitivity and a restoration of ergosterol synthesis, showing that the mutation is indeed responsible for resistance. The amphotericin B resistant parasites become hypersensitive to pentamidine and also agents that induce oxidative stress. This work reveals the power of combining polyomics approaches, to discover the mechanism underlying drug resistance as well as offering novel insights into the selection of resistance to amphotericin B itself. PMID- 28622335 TI - Psychotic symptoms in older people without dementia from a Brazilian community based sample: A seven years' follow-up. AB - BACKGROUND: Studies of the incidence of psychotic symptoms in elderly people at risk of dementia are scarce. This is a seven year follow up study aiming to determine the incidence of psychotic symptoms and their correlation with other clinical aspects, in particular the rate of development of cognitive impairment. METHODS: Cohort study of a community-based sample of elderly subjects. At study entry in 2004, the sample was composed of 1,125 individuals aged 60 years and older. Of this total, 547 subjects were re-evaluated in 2011 and submitted to the original study protocol. Of these, 199 showed no psychotic symptoms at phase I, while 64 already had psychotic symptoms in 2004. RESULTS: The incidence of at least one psychotic symptom in the 7 year period was 8.0% (Visual/tactile hallucinations: 4.5%; Persecutory delusions: 3.0%; Auditory hallucinations: 2.5%). Development of psychotic symptoms was associated with epilepsy (OR: 7.75 and 15.83), lower MMSE (OR: 0.72) and reported depression (OR: 6.48). A total of 57.8% of individuals with psychotic symptoms developed cognitive impairment after 7 years. Visual/tactile hallucinations were the only psychotic symptom predictive of this impairment, which was related to lower MMSE and greater functional impairment. CONCLUSIONS: The incidence of psychotic symptoms and the conversion rate to cognitive impairment was in the upper range when compared with previous reports. Visual/tactile hallucinations were the most frequent symptoms and were predictive of cognitive impairment over the 7 year period. A significant relationship was found between the incidence of psychotic symptoms and low MMSE scores, as well as clinical comorbities such as epilepsy, reported depression, diabetes and syphilis. PMID- 28622337 TI - Magnetic resonance imaging of posterolateral plica of the elbow joint: Asymptomatic vs. symptomatic subjects. AB - BACKGROUND: Magnetic resonance imaging (MRI) may be useful to diagnose a posterolateral plica syndrome of the elbow joint because this syndrome has less clear clinical features. The purposes of this study were to document mediolateral and sagittal dimensions of a posterolateral synovial fold and to determine the proportion of subjects with the posterolateral plica in asymptomatic elbows. We also aimed to determine whether the dimensions of the posterolateral synovial fold and the prevalence of the plica differ between symptomatic and asymptomatic subjects. MATERIALS AND METHODS: This retrospective review of prospectively collected data included 50 asymptomatic elbows (asymptomatic group) and 14 elbows with arthroscopically confirmed posterolateral plicae (plica group). The mediolateral and sagittal dimensions of the posterolateral synovial fold were measured. In addition, the criteria for the prevalence of posterolateral plica was determined with conventional MRI as synovial fold dimension >= 3 mm and coverage of radial head by synovial fold >= 30%. RESULTS: The plica group showed larger posterolateral synovial fold dimensions compared to the asymptomatic group. The median mediolateral and sagittal dimensions of the synovial fold in the asymptomatic group were 3.8 mm and 4.7 mm, respectively. Dimensions in the plica group were 7.0 mm and 7.4 mm, respectively. When the presence of posterolateral plica was determined using the dimension criteria, there was no difference in the prevalence of the plica between the asymptomatic and the plica group. However, using the coverage criteria, the prevalence of posterolateral elbow plica was significantly greater in the plica group than the asymptomatic group (64% vs. 18%; p < 0.001). CONCLUSIONS: The patients who underwent arthroscopic surgery for posterolateral plica syndrome had larger dimensions of the posterolateral synovial fold and higher prevalence of the posterolateral plica on conventional MRI compared to the asymptomatic subjects. PMID- 28622336 TI - A knowledge-based T2-statistic to perform pathway analysis for quantitative proteomic data. AB - Approaches to identify significant pathways from high-throughput quantitative data have been developed in recent years. Still, the analysis of proteomic data stays difficult because of limited sample size. This limitation also leads to the practice of using a competitive null as common approach; which fundamentally implies genes or proteins as independent units. The independent assumption ignores the associations among biomolecules with similar functions or cellular localization, as well as the interactions among them manifested as changes in expression ratios. Consequently, these methods often underestimate the associations among biomolecules and cause false positives in practice. Some studies incorporate the sample covariance matrix into the calculation to address this issue. However, sample covariance may not be a precise estimation if the sample size is very limited, which is usually the case for the data produced by mass spectrometry. In this study, we introduce a multivariate test under a self contained null to perform pathway analysis for quantitative proteomic data. The covariance matrix used in the test statistic is constructed by the confidence scores retrieved from the STRING database or the HitPredict database. We also design an integrating procedure to retain pathways of sufficient evidence as a pathway group. The performance of the proposed T2-statistic is demonstrated using five published experimental datasets: the T-cell activation, the cAMP/PKA signaling, the myoblast differentiation, and the effect of dasatinib on the BCR ABL pathway are proteomic datasets produced by mass spectrometry; and the protective effect of myocilin via the MAPK signaling pathway is a gene expression dataset of limited sample size. Compared with other popular statistics, the proposed T2-statistic yields more accurate descriptions in agreement with the discussion of the original publication. We implemented the T2-statistic into an R package T2GA, which is available at https://github.com/roqe/T2GA. PMID- 28622338 TI - Multi-phase simultaneous segmentation of tumor in lung 4D-CT data with context information. AB - Lung 4D computed tomography (4D-CT) plays an important role in high-precision radiotherapy because it characterizes respiratory motion, which is crucial for accurate target definition. However, the manual segmentation of a lung tumor is a heavy workload for doctors because of the large number of lung 4D-CT data slices. Meanwhile, tumor segmentation is still a notoriously challenging problem in computer-aided diagnosis. In this paper, we propose a new method based on an improved graph cut algorithm with context information constraint to find a convenient and robust approach of lung 4D-CT tumor segmentation. We combine all phases of the lung 4D-CT into a global graph, and construct a global energy function accordingly. The sub-graph is first constructed for each phase. A context cost term is enforced to achieve segmentation results in every phase by adding a context constraint between neighboring phases. A global energy function is finally constructed by combining all cost terms. The optimization is achieved by solving a max-flow/min-cut problem, which leads to simultaneous and robust segmentation of the tumor in all the lung 4D-CT phases. The effectiveness of our approach is validated through experiments on 10 different lung 4D-CT cases. The comparison with the graph cut without context constraint, the level set method and the graph cut with star shape prior demonstrates that the proposed method obtains more accurate and robust segmentation results. PMID- 28622339 TI - The Chlamydia trachomatis type III secretion substrates CT142, CT143, and CT144 are secreted into the lumen of the inclusion. AB - Chlamydia trachomatis is a human bacterial pathogen causing ocular and genital infections. It multiplies exclusively within an intracellular membrane-bound vacuole, the inclusion, and uses a type III secretion system to manipulate host cells by injecting them with bacterially-encoded effector proteins. In this work, we characterized the expression and subcellular localization in infected host cells of the C. trachomatis CT142, CT143, and CT144 proteins, which we previously showed to be type III secretion substrates. Transcriptional analyses in C. trachomatis confirmed the prediction that ct142, ct143 and ct144 are organized in an operon and revealed that their expression is likely driven by the main sigma factor, sigma66. In host cells infected by C. trachomatis, production of CT142 and CT143 could be detected by immunoblotting from 20-26 h post-infection. Immunofluorescence microscopy of infected cells revealed that from 20 h post infection CT143 appeared mostly as globular structures outside of the bacterial cells but within the lumen of the inclusion. Furthermore, immunofluorescence microscopy of cells infected by C. trachomatis strains carrying plasmids producing CT142, CT143, or CT144 under the control of the ct142 promoter and with a C-terminal double hemagglutinin (2HA) epitope tag revealed that CT142-2HA, CT143-2HA or CT144-2HA showed an identical localization to chromosomally-encoded CT143. Moreover, CT142-2HA or CT144-2HA and CT143 produced by the same bacteria co-localized in the lumen of the inclusion. Overall, these data suggest that the CT142, CT143, and CT144 type III secretion substrates are secreted into the lumen of the inclusion where they might form a protein complex. PMID- 28622341 TI - Hygienic and grooming behaviors in African and European honeybees-New damage categories in Varroa destructor. AB - Varroa destructor is an ectoparasitic pest of honeybees, and a threat to the survival of the apiculture industry. Several studies have shown that unlike European honeybees, African honeybee populations appear to be minimally affected when attacked by this mite. However, little is known about the underlying drivers contributing to survival of African honeybee populations against the mite. We hypothesized that resistant behavioral defenses are responsible for the survival of African honeybees against the ectoparasite. We tested this hypothesis by comparing grooming and hygienic behaviors in the African savannah honeybee Apis mellifera scutellata in Kenya and A. mellifera hybrids of European origin in Florida, USA against the mite. Grooming behavior was assessed by determining adult mite infestation levels, daily mite fall per colony and percentage mite damage (as an indicator of adult grooming rate), while hygienic behavior was assessed by determining the brood removal rate after freeze killing a section of the brood. Our results identified two additional undescribed damaged mite categories along with the six previously known damage categories associated with the grooming behavior of both honeybee subspecies. Adult mite infestation level was approximately three-fold higher in A. mellifera hybrids of European origin than in A. m. scutellata, however, brood removal rate, adult grooming rate and daily natural mite fall were similar in both honeybee subspecies. Unlike A. mellifera hybrids of European origin, adult grooming rate and brood removal rate did not correlate with mite infestation levels on adult worker honeybee of A. m. scutellata though they were more aggressive towards the mites than their European counterparts. Our results provide valuable insights into the tolerance mechanisms that contribute to the survival of A. m. scutellata against the mite. PMID- 28622340 TI - Antibiotic prophylaxis for surgical site infections as a risk factor for infection with Clostridium difficile. AB - OBJECTIVE: We aimed to measure the association between 2013 guideline concordant prophylactic antibiotic use prior to surgery and infection with Clostridium difficile. DESIGN: We conducted a retrospective case-control study by selecting patients who underwent a surgical procedure between January 1, 2012 and December 31, 2013. SETTING: Large urban community hospital. PATIENTS: Cases and controls were patients age 18+ years who underwent an eligible surgery (i.e., colorectal, neurosurgery, vascular/cardiac/thoracic, hysterectomy, abdominal/pelvic and orthopedic surgical procedures) within six months prior to infection diagnosis. Cases were diagnosed with C. difficile infection while controls were not. METHODS: The primary exposure was receiving (vs. not receiving) the recommended prophylactic antibiotic regimen, based on type and duration. Potential confounders included age, sex, length of hospital stay, comorbidities, type of surgery, and prior antibiotic use. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS: We enrolled 68 cases and 220 controls. The adjusted OR among surgical patients between developing C. difficile infection and not receiving the recommended prophylactic antibiotic regimen (usually receiving antimicrobial prophylaxis for more than 24 hours) was 6.7 (95% CI: 2.9-15.5). Independent risk factors for developing C. difficile infection included having severe comorbidities, receiving antibiotics within the previous 6 months, and undergoing orthopedic surgery. CONCLUSIONS: Adherence to the recommended prophylactic antibiotics among surgical patients likely reduces the probability of being case of C. difficile. Antibiotic stewardship should be a priority in strategies to decrease the morbidity, mortality, and costs associated with C. difficile infection. PMID- 28622342 TI - National survey of outcomes and practices in acute respiratory distress syndrome in Singapore. AB - INTRODUCTION: In the past 20 years, our understanding of acute respiratory distress syndrome (ARDS) management has improved, but the worldwide incidence and current outcomes are unclear. The reported incidence is highly variable, and no studies specifically characterise ARDS epidemiology in Asia. This observation study aims to determine the incidence, mortality and management practices of ARDS in a high income South East Asian country. METHODS: We conducted a prospective, population based observational study in 6 public hospitals. During a one month period, we identified all ARDS patients admitted to public hospital intensive care units (ICU) in Singapore, according to the Berlin definition. Demographic information, clinical management data and ICU outcome data was collected. RESULTS: A total of 904 adult patients were admitted to ICU during the study period and 15 patients met ARDS criteria. The unadjusted incidence of ARDS was 4.5 cases per 100,000 population, accounting for 1.25% of all ICU patients. Most patients were male (75%), Chinese (62%), had pneumonia (73%), and were admitted to a Medical ICU (56%). Management strategies varied across all ICUs. In-hospital mortality was 40% and median length of ICU stay was 7 days. CONCLUSION: The incidence of ARDS in a developed S.E Asia country is comparable to reported rates in European studies. PMID- 28622344 TI - Protecting an island nation from extreme pandemic threats: Proof-of-concept around border closure as an intervention. AB - BACKGROUND: Countries are well advised to prepare for future pandemic risks (e.g., pandemic influenza, novel emerging agents or synthetic bioweapons). These preparations do not typically include planning for complete border closure. Even though border closure may not be instituted in time, and can fail, there might still plausible chances of success for well organized island nations. OBJECTIVE: To estimate costs and benefits of complete border closure in response to new pandemic threats, at an initial proof-of-concept level. New Zealand was used as a case-study for an island country. METHODS: An Excel spreadsheet model was developed to estimate costs and benefits. Case-study specific epidemiological data was sourced from past influenza pandemics. Country-specific healthcare cost data, valuation of life, and lost tourism revenue were imputed (with lost trade also in scenario analyses). RESULTS: For a new pandemic equivalent to the 1918 influenza pandemic (albeit with half the mortality rate, "Scenario A"), it was estimated that successful border closure for 26 weeks provided a net societal benefit (e.g., of NZ$11.0 billion, USD$7.3 billion). Even in the face of a complete end to trade, a net benefit was estimated for scenarios where the mortality rate was high (e.g., at 10 times the mortality impact of "Scenario A", or 2.75% of the country's population dying) giving a net benefit of NZ$54 billion (USD$36 billion). But for some other pandemic scenarios where trade ceased, border closure resulted in a net negative societal value (e.g., for "Scenario A" times three for 26 weeks of border closure-but not for only 12 weeks of closure when it would still be beneficial). CONCLUSIONS: This "proof-of-concept" work indicates that more detailed cost-benefit analysis of border closure in very severe pandemic situations for some island nations is probably warranted, as this course of action might sometimes be worthwhile from a societal perspective. PMID- 28622343 TI - Association of Alzhemier's disease with hepatitis C among patients with bipolar disorder. AB - Associations of hepatitis C virus infection with Alzheimer's disease have not been studied among higher risk, bipolar disorder patients. This population-based case-control study investigated the risks of hepatitis C virus infection among Alzheimer's disease patients with bipolar disorder in the years preceding their Alzheimer's disease diagnosis. We used 2000-2013 data from the Longitudinal Health Insurance Database in Taiwan. Among patients with bipolar disorder, 73 were diagnosed with Alzheimer's disease (cases), who were compared with 365 individuals with bipolar disorder but without Alzheimer's disease (randomly selected controls matched on sex, age, and index year with cases). Prior claims (before the diagnosis year/index year for controls) were screened for a diagnosis of hepatitis C virus infection. Conditional logistic regression models were used for analysis. We found that 23 (31.51%) and 60 (16.44%) patients with bipolar disease were identified with a hepatitis C diagnosis among those with and without Alzheimer's disease, respectively. Compared to controls, patients with Alzheimer's disease showed 2.31-fold (95% confidence interval = 1.28-4.16) increased risk of hepatitis C infections adjusted for demographics and socio economic status. Findings suggest an association of Alzheimer's disease with a preceding diagnosis of hepatitis C infection among patients with bipolar disorder. Findings may suggest a need for increased awareness of and appropriate surveillance for Alzheimer's disease in patients with bipolar disorder diagnosed with hepatitis C infection. PMID- 28622345 TI - The infection staging and profile of genotypic distribution and drug resistance mutation among the human immunodeficiency virus-1 infected blood donors from five Chinese blood centers, 2012-2014. AB - The increasing complexity and diversity of the human immunodeficiency virus-1 (HIV-1) infections challenge the disease control and anti-retrovirus treatment in China. The infection stages and molecular characteristics of HIV-1 from infected Chinese blood donors were examined to shed light on the HIV genotype distribution and the status of drug resistance mutations (DRMs) in the changing HIV epidemic in China. Western blot (WB) confirmed HIV-1 positive plasma samples were collected from blood donors at five Chinese blood centers from April 16, 2012, through June 30, 2014. The HIV infection stages were determined using the Lag avidity assay. HIV Pol regions including whole protease and partial reverse transcriptase (RT) were amplified and sequenced to establish the profile of genotype distribution and drug resistance mutations (DRMs). Viral loads were determined using the ROCHE COBAS system. Of the 259 HIV-1 positive samples tested by the Lag-avidity assay, 23.6% (61/259) were identified as recent infections. A total of 205 amplified sequences displayed the following genotype distributions: circulating recombinant form (CRF) 07_BC (61.5%), CRF08_BC (8.3%), CRF01_AE (20%), B (6.3%), and 01B (3.9%). There was no significant difference in genotype distribution between recent and long-term infections. 31 DRMs were identified from 27 samples including four protease inhibitors (PIs) accessory DRMs, two PIs major DRMs (M46I), two nucleoside RT inhibitors DRMs (K219R and K70Q), and 23 nonnucleoside RT inhibitors DRMs. 27 samples had DRMs, yielding a drug resistance prevalence of 13.2% (27/205). Our findings provide important information for developing strategies for comprehensive HIV control and improving anti-retroviral treatment in China. PMID- 28622346 TI - Flavivirus and Filovirus EvoPrinters: New alignment tools for the comparative analysis of viral evolution. AB - BACKGROUND: Flavivirus and Filovirus infections are serious epidemic threats to human populations. Multi-genome comparative analysis of these evolving pathogens affords a view of their essential, conserved sequence elements as well as progressive evolutionary changes. While phylogenetic analysis has yielded important insights, the growing number of available genomic sequences makes comparisons between hundreds of viral strains challenging. We report here a new approach for the comparative analysis of these hemorrhagic fever viruses that can superimpose an unlimited number of one-on-one alignments to identify important features within genomes of interest. METHODOLOGY/PRINCIPAL FINDING: We have adapted EvoPrinter alignment algorithms for the rapid comparative analysis of Flavivirus or Filovirus sequences including Zika and Ebola strains. The user can input a full genome or partial viral sequence and then view either individual comparisons or generate color-coded readouts that superimpose hundreds of one-on one alignments to identify unique or shared identity SNPs that reveal ancestral relationships between strains. The user can also opt to select a database genome in order to access a library of pre-aligned genomes of either 1,094 Flaviviruses or 460 Filoviruses for rapid comparative analysis with all database entries or a select subset. Using EvoPrinter search and alignment programs, we show the following: 1) superimposing alignment data from many related strains identifies lineage identity SNPs, which enable the assessment of sublineage complexity within viral outbreaks; 2) whole-genome SNP profile screens uncover novel Dengue2 and Zika recombinant strains and their parental lineages; 3) differential SNP profiling identifies host cell A-to-I hyper-editing within Ebola and Marburg viruses, and 4) hundreds of superimposed one-on-one Ebola genome alignments highlight ultra-conserved regulatory sequences, invariant amino acid codons and evolutionarily variable protein-encoding domains within a single genome. CONCLUSIONS/SIGNIFICANCE: EvoPrinter allows for the assessment of lineage complexity within Flavivirus or Filovirus outbreaks, identification of recombinant strains, highlights sequences that have undergone host cell A-to-I editing, and identifies unique input and database SNPs within highly conserved sequences. EvoPrinter's ability to superimpose alignment data from hundreds of strains onto a single genome has allowed us to identify unique Zika virus sublineages that are currently spreading in South, Central and North America, the Caribbean, and in China. This new set of integrated alignment programs should serve as a useful addition to existing tools for the comparative analysis of these viruses. PMID- 28622347 TI - RNA-guided transcriptional activation via CRISPR/dCas9 mimics overexpression phenotypes in Arabidopsis. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR associated protein 9 (Cas9) system allows effective gene modification through RNA guided DNA targeting. The Cas9 has undergone a series of functional alterations from the original active endonuclease to partially or completely deactivated Cas9. The catalytically deactivated Cas9 (dCas9) offers a platform to regulate transcriptional expression with the addition of activator or repressor domains. We redesigned a CRISPR/Cas9 activation system by adding the p65 transactivating subunit of NF-kappa B and a heat-shock factor 1 (HSF) activation domain to dCas9 bound with the VP64 (tetramer of VP16) activation domain for application in plants. The redesigned CRISPR/Cas9 activation system was tested in Arabidopsis to increase endogenous transcriptional levels of production of anthocyanin pigment 1 (PAP1) and Arabidopsis thaliana vacuolar H+-pyrophosphatase (AVP1). The expression of PAP1 was increased two- to three-fold and the activated plants exhibited purple leaves similar to that of PAP1 overexpressors. The AVP1 gene expression was increased two- to five-fold in transgenic plants. In comparison to the wild type, AVP1 activated plants had increased leaf numbers, larger single leaf areas and improved tolerance to drought stress. The AVP1 activated plants showed similar phenotypes to AVP1 overexpressors. Therefore, the redesigned CRISPR/Cas9 activation system containing modified p65-HSF provides a simple approach for producing activated plants by upregulating endogenous transcriptional levels. PMID- 28622348 TI - Factors influencing practitioner adoption of carer-led assessment in palliative homecare: A qualitative study of the use of the Carer Support Needs Assessment Tool (CSNAT). AB - INTRODUCTION: Informal caregivers play a pivotal role in supporting patients approaching the end of life. The Carer Support Needs Assessment Tool (CSNAT) is designed to facilitate person-centred assessment and support through a process that is practitioner-facilitated, but carer-led. This study explored practitioners' experiences of implementing the CSNAT in palliative homecare. METHODS: We conducted qualitative interviews/focus groups with 20 practitioners in one UK hospice homecare service (18 nurses, two healthcare assistants) before and after the implementation of the CSNAT. Thematic analysis of the data was underpinned by framework analysis. RESULTS: Not all practitioners appreciated that using the CSNAT required a shift towards a more person-centred approach to assessment; consequently they tagged the tool onto their existing practitioner led practice. Practitioners who did use the CSNAT as intended were able to act as role models and support their colleagues in making this transition. Practitioners' comments revealed a number of contradictions: 1) Most felt that they 'already do' identify carer support needs, but feared using the CSNAT could increase their workload; 2) some worried about introducing the CSNAT 'too soon', but recognised that it was 'too late' once patients were close to the end of life; 3) whilst practitioners stated 'they were there for the family as well as the patient', care provision was overtly centred around patients. CONCLUSION: This study provides vital insights into barriers and facilitators to implementing the CSNAT as part of a person-centred approach to assessment. The findings identified the training and support required to help practitioners make this transition to this new way of working. PMID- 28622349 TI - A randomized cross-over study of the acute effects of running 5 km on glucose, insulin, metabolic rate, cortisol and Troponin T. AB - BACKGROUND: We aimed to study the impact by running 5 km, at maximal speed, on the normal variations of metabolic variables related to glucose, insulin, insulin sensitivity, cortisol, glucagon, Troponin T and metabolic rate. MATERIAL AND METHODS: Five women and 12 men 25.7+/-5.2 years of age with a body-mass-index of 22.5+/-2.3 kg/m2 where recruited to run 5 km at individual maximal speed in the morning, and to a corresponding day of rest, followed by standardized breakfast and lunch meals. Blood sampling and measurement of indirect calorimetry were done before and after meals. The participants were randomized regarding the order of the two trial-days in this cross-over study. RESULTS: Insulin and cortisol levels were higher, and insulin sensitivity was lower, on the race-day compared with the day of rest (linear mixed model: p<0.0001 for all three analyses). However, glucose levels and metabolic rate did not differ between the two trial days (p = 0.29 and p = 0.53, respectively). When analyzing specific time-points we found that glucose increased from 5.01+/-0.37 mmol/l to 6.36 +/- 1.3 mmol/l, p<0.0001, by running, while serum insulin concomitantly increased from 42+/-21 to 90+/-54 pmol/l, p<0.0001. In accordance, the QUICKI index of serum sensitivity, 1/(log10insulin+log10glucose), was lowered post-race, p<0.0001. Serum cortisol levels increased from 408+/-137 nmol/l to 644+/-171 nmol/l, p<0.0001, post-race while serum glucagon levels were unaffected. Troponin T was detectable in serum post-race in 12 out of the 17 participants and reached or surpassed the clinical reference level of 15 ng/l in three subjects. Post-race electrocardiograms displayed no pathologies. CONCLUSIONS: Relatively short running-races can apparently induce a reduction in insulin sensitivity that is not fully compensated by concomitantly increased insulin secretion intended to ensure euglycemia. Since also Troponin T was detected in plasma in a majority of the participants, our data suggest that it is possible to induce considerable metabolic stress by running merely 5 km, when striving for maximal speed. PMID- 28622350 TI - Significance of likes: Analysing passive interactions on Facebook during campaigning. AB - With more and more political candidates using social media for campaigning, researchers are looking at measuring the effectiveness of this medium. Most research, however, concentrates on the bare count of likes (or twitter mentions) in an attempt to correlate social media presence and winning. In this paper, we propose a novel method, Interaction Strength Plot (IntS) to measure the passive interactions between a candidate's posts on Facebook and the users (liking the posts). Using this method on original Malaysian General Election (MGE13) and Australian Federal Elections (AFE13) Facebook Pages (FP) campaign data, we label an FP as performing well if both the posting frequency and the likes gathered are above average. Our method shows that over 60% of the MGE13 candidates and 85% of the AFE13 candidates studied in this paper had under-performing FP. Some of these FP owners would have been identified as popular based on bare count. Thus our performance chart is a vital step forward in measuring the effectiveness of online campaigning. PMID- 28622352 TI - Volunteer trials of a novel improvised dry decontamination protocol for use during mass casualty incidents as part of the UK'S Initial Operational Response (IOR). AB - Previous studies have demonstrated that rapid evacuation, disrobing and emergency decontamination can enhance the ability of emergency services and acute hospitals to effectively manage chemically-contaminated casualties. The purpose of this human volunteer study was to further optimise such an "Initial Operational Response" by (1) identifying an appropriate method for performing improvised skin decontamination and (2) providing guidance for use by first responders and casualties. The study was performed using two readily available, absorbent materials (paper towels and incontinence pads). The decontamination effectiveness of the test materials was measured by quantifying the amount of a chemical warfare agent simulant (methyl salicylate) removed from each volunteer's forearm skin. Results from the first study demonstrated that simulant recovery was lower in all of the dry decontamination conditions when compared to matched controls, suggesting that dry decontamination serves to reduce chemical exposure. Blotting in combination with rubbing was the most effective form of decontamination. There was no difference in effectiveness between the two absorbent materials. In the following study, volunteers performed improvised dry decontamination, either with or without draft guidelines. Volunteers who received the guidance were able to carry out improvised dry decontamination more effectively, using more of the absorbent product (blue roll) to ensure that all areas of the body were decontaminated and avoiding cross-contamination of other body areas by working systematically from the head downwards. Collectively, these two studies suggest that absorbent products that are available on ambulances and in acute healthcare settings may have generic applicability for improvised dry decontamination. Wherever possible, emergency responders and healthcare workers should guide casualties through decontamination steps; in the absence of explicit guidance and instructions, improvised dry decontamination may not be performed correctly or safely. PMID- 28622351 TI - DNA extraction replicates improve diversity and compositional dissimilarity in metabarcoding of eukaryotes in marine sediments. AB - Human impact on marine benthic communities has traditionally been assessed using visible morphological traits and has focused on the macrobenthos, whereas the ecologically important organisms of the meio- and microbenthos have received less attention. DNA metabarcoding offers an alternative to this approach and enables a larger fraction of the biodiversity in marine sediments to be monitored in a cost efficient manner. Although this methodology remains poorly standardised and challenged by biases inherent to rRNA copy number variation, DNA extraction, PCR, and limitations related to taxonomic identification, it has been shown to be semi quantitative and useful for comparing taxon abundances between samples. Here, we evaluate the effect of replicating genomic DNA extraction in order to counteract small scale spatial heterogeneity and improve diversity and community structure estimates in metabarcoding-based monitoring. For this purpose, we used ten technical replicates from three different marine sediment samples. The effect of sequence depth was also assessed, and in silico pooling of DNA extraction replicates carried out in order to maintain the number of reads constant. Our analyses demonstrated that both sequencing depth and DNA extraction replicates could improve diversity estimates as well as the ability to separate samples with different characteristics. We could not identify a "sufficient" replicate number or sequence depth, where further improvements had a less significant effect. Based on these results, we consider replication an attractive alternative to directly increasing the amount of sample used for DNA extraction and strongly recommend it for future metabarcoding studies and routine assessments of sediment biodiversity. PMID- 28622353 TI - Transmission electron microscopic observation of body cuticle structures of phoretic and parasitic stages of Parasitaphelenchinae nematodes. AB - Using transmission electron microscopy, we examined the body cuticle ultrastructures of phoretic and parasitic stages of the parasitaphelenchid nematodes Bursaphelenchus xylophilus, B. conicaudatus, B. luxuriosae, B. rainulfi; an unidentified Bursaphelenchus species, and an unidentified Parasitaphelenchus species. Nematode body cuticles usually consist of three zones, a cortical zone, a median zone, and a basal zone. The phoretic stages of Bursaphelenchus spp., isolated from the tracheal systems of longhorn beetles or the elytra of bark beetles, have a thick and radially striated basal zone. In contrast, the parasitic stage of Parasitaphelenchus sp., isolated from bark beetle hemocoel, has no radial striations in the basal zone. This difference probably reflects the peculiar ecological characteristics of the phoretic stage. A well-developed basal radially striated zone, composed of very closely linked proteins, is the zone closest to the body wall muscle. Therefore, the striation is necessary for the phoretic species to be able to seek, enter, and depart from host/carrier insects, but is not essential for internal parasites in parasitaphelenchid nematodes. Phylogenetic relationships inferred from near-full length small subunit ribosomal RNA sequences suggest that the cuticle structures of parasitic species have apomorphic characters, e.g., lack of striation in the basal zone, concurrent with the evolution of insect parasitism from a phoretic life history. PMID- 28622354 TI - Awareness of knowledge and practice regarding physical activity: A population based prospective, observational study among students in Nanjing, China. AB - BACKGROUND: Physical activity (PA) promotion has proven effectiveness in preventing childhood obesity. Increasing children's health knowledge is the most frequently used approach in PA intervention programs targeting childhood obesity prevention. However, little is known about the specific association between the change in a child's knowledge awareness and their PA practice. METHODS: A one year follow-up study was conducted among primary and junior high school students in Nanjing, China. At baseline students' knowledge of healthy behavior, and their PA levels, were assessed. Students who were unaware of the association between PA and obesity were followed for one academic year. After nine-months their knowledge and PA levels were re-measured using the same validated questionnaire. Mixed effects regression models were used to estimate the relationship between awareness of knowledge about the link between PA and obesity and PA changes. RESULTS: Of the 1899 students who were unaware of the association between PA and obesity at baseline, 1859 (follow-up rate = 97.9%) were successfully followed-up. After nine months 1318 (70.9%) participants had become aware of PA-obesity association. Compared to their counterparts who remained unaware, students who became aware of the PA-obesity association were more likely to increase both the frequency (odds ratio (OR) = 1.34, 95%CI = 1.09, 1.64) and duration (OR = 1.34, 95%CI = 1.09, 1.65) of PA, after adjusting for potentially confounding variables. CONCLUSION: Becoming aware of the known link between PA and obesity led to positive behavior modification regarding PA in this cohort of Chinese students. This is of particular importance that knowledge disimination and health education may be a useful approach for population-based physical activity promotion aiming at childhood obesity prevention in China. PMID- 28622355 TI - Anesthetic action on the transmission delay between cortex and thalamus explains the beta-buzz observed under propofol anesthesia. AB - In recent years, more and more surgeries under general anesthesia have been performed with the assistance of electroencephalogram (EEG) monitors. An increase in anesthetic concentration leads to characteristic changes in the power spectra of the EEG. Although tracking the anesthetic-induced changes in EEG rhythms can be employed to estimate the depth of anesthesia, their precise underlying mechanisms are still unknown. A prominent feature in the EEG of some patients is the emergence of a strong power peak in the beta-frequency band, which moves to the alpha-frequency band while increasing the anesthetic concentration. This feature is called the beta-buzz. In the present study, we use a thalamo-cortical neural population feedback model to reproduce observed characteristic features in frontal EEG power obtained experimentally during propofol general anesthesia, such as this beta-buzz. First, we find that the spectral power peak in the alpha- and delta-frequency ranges depend on the decay rate constant of excitatory and inhibitory synapses, but the anesthetic action on synapses does not explain the beta-buzz. Moreover, considering the action of propofol on the transmission delay between cortex and thalamus, the model reveals that the beta-buzz may result from a prolongation of the transmission delay by increasing propofol concentration. A corresponding relationship between transmission delay and anesthetic blood concentration is derived. Finally, an analytical stability study demonstrates that increasing propofol concentration moves the systems resting state towards its stability threshold. PMID- 28622356 TI - Elevated C-reactive protein level during clinical remission can predict poor outcomes in patients with Crohn's disease. AB - Intestinal inflammation and mucosal damage in Crohn's disease (CD) are believed to progress even during clinical remission. We investigated the long-term prognosis of CD patients in clinical remission according to serum C-reactive protein (CRP) levels. This study included 339 CD patients in clinical remission (Crohn's disease activity index < 150) for more than 6 months between January 2008 and December 2010. Clinical outcomes were compared between patients with normal and elevated CRP levels during clinical remission. During clinical remission, 150 patients had normal CRP consistently and 189 had elevated CRP at least once. During follow-up (median, 7.9 years [interquartile range, 6.8-8.0]), the Kaplan-Meier analysis with the log-rank test showed that normal CRP group had a longer CD-related hospitalization-free survival (P = 0.007) and a longer CD related intestinal resection-free survival (P = 0.046) than elevated CRP group. In multivariate analysis, elevated CRP was significantly and independently associated with an increased risk of subsequent CD-related hospitalization (adjusted hazard ratio [aHR] 1.787, 95% confidence interval [CI]: 1.245-2.565, P = 0.002) and of subsequent CD-related intestinal resection (aHR 1.726, 95% CI: 1.003-2.969, P = 0.049). The most common reason for CD-related hospitalization was penetrating complications (35.6%). Even when CD patients are in clinical remission, elevated CRP is significantly associated with subsequent CD-related hospitalization and CD-related intestinal resection during follow-up. CD patients in clinical remission but elevated CRP should receive more careful attention and timely interventions to improve long-term outcomes. PMID- 28622357 TI - Protective effect of aplysin on liver tissue and the gut microbiota in alcohol fed rats. AB - BACKGROUND: This study investigated the protective effect of aplysin on the liver and its influence on inflammation and the gut microbiota in rats with ethanol induced liver injury. METHODS: Male Sprague-Dawley rats were randomly assigned to an alcohol-containing liquid diet, control liquid diet or treatment with aplysin for 8 weeks. Hepatic and intestinal histopathological analysis was performed, and cytokine levels and the intestinal mucosal barrier were assessed. Enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) and 16S rDNA high-throughput sequencing were performed to provide an overview of the gut microbiota composition. RESULTS: Chronic alcohol exposure caused liver damage in rats. Serum aspartate aminotransferase (AST), aminotransferase (ALT), alkaline phosphatase (ALP) and triglyceride (TG) activities in liver tissue were higher than in the control group. Alcohol administration elevated the levels of serum transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF alpha) and reduced interleukin-10 (IL-10) levels compared with those of control rats. In addition, the levels of plasma endotoxin, diamine oxidase (DAO), and fatty acid-binding protein 2 (FABP2) in the alcohol group were higher than in the control group. The results of ERIC-PCR indicated that aplysin treatment shifted the overall structure of the ethanol-disrupted gut microbiota toward that of the control group. One hundred twenty to 190 genera of bacteria were detected by high throughput sequencing. Alcohol-induced changes in the gut microbial composition were detected at the genus level. These alcohol-induced effects could be reversed with aplysin treatment. CONCLUSIONS: These results suggest that aplysin exerts a protective effect on ethanol-induced hepatic injury in rats by normalizing fecal microbiota composition and repairing intestinal barrier function. PMID- 28622358 TI - Rotavirus replication is correlated with S/G2 interphase arrest of the host cell cycle. AB - In infected cells rotavirus (RV) replicates in viroplasms, cytosolic structures that require a stabilized microtubule (MT) network for their assembly, maintenance of the structure and perinuclear localization. Therefore, we hypothesized that RV could interfere with the MT-breakdown that takes place in mitosis during cell division. Using synchronized RV-permissive cells, we show that RV infection arrests the cell cycle in S/G2 phase, thus favoring replication by improving viroplasms formation, viral protein translation, and viral assembly. The arrest in S/G2 phase is independent of the host or viral strain and relies on active RV replication. RV infection causes cyclin B1 down-regulation, consistent with blocking entry into mitosis. With the aid of chemical inhibitors, the cytoskeleton network was linked to specific signaling pathways of the RV-induced cell cycle arrest. We found that upon RV infection Eg5 kinesin was delocalized from the pericentriolar region to the viroplasms. We used a MA104-Fucci system to identify three RV proteins (NSP3, NSP5, and VP2) involved in cell cycle arrest in the S-phase. Our data indicate that there is a strong correlation between the cell cycle arrest and RV replication. PMID- 28622359 TI - Aerobic exercise protects against pressure overload-induced cardiac dysfunction and hypertrophy via beta3-AR-nNOS-NO activation. AB - Aerobic exercise confers sustainable protection against cardiac hypertrophy and heart failure (HF). Nitric oxide synthase (NOS) and nitric oxide (NO) are known to play an important role in exercise-mediated cardioprotection, but the mechanism of NOS/NO stimulation during exercise remains unclear. The aim of this study is to determine the role of beta3-adrenergic receptors (beta3-ARs), NOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of aerobic exercise. An HF model was constructed by transverse aortic constriction (TAC). Animals were treated with either moderate aerobic exercise by swimming for 9 weeks and/or the beta3-AR-specific inhibitor SR59230A at 0.1 mg/kg/hour one day after TAC operation. Myocardial fibrosis, myocyte size, plasma catecholamine (CA) level, cardiac function and geometry were assessed using Masson's trichrome staining, FITC-labeled wheat germ agglutinin staining, enzyme-linked immuno sorbent assay (ELISA) and echocardiography, respectively. Western blot analysis was performed to elucidate the expression of target proteins. The concentration of myocardial NO production was evaluated using the nitrate reductase method. Myocardial oxidative stress was assessed by detecting the concentration of myocardial super oxidative dismutase (SOD), malonyldialdehyde (MDA), and reactive oxygen species (ROS). Aerobic exercise training improved dilated left ventricular function and partially attenuated the degree of cardiac hypertrophy and fibrosis in TAC mice. Moreover, the increased expression of beta3-AR, activation of neuronal NOS (nNOS), and production of NO were detected after aerobic exercise training in TAC mice. However, selective inhibition of beta3-AR by SR59230A abolished the upregulation and activation of nNOS induced NO production. Furthermore, aerobic exercise training decreased the myocardial ROS and MDA contents and increased myocardial levels of SOD; both effects were partially attenuated by SR59230A. Our study suggested that aerobic exercise training could improve cardiac systolic function and alleviate LV chamber dilation, cardiac fibrosis and hypertrophy in HF mice. The mechanism responsible for the protective effects of aerobic exercise is associated with the activation of the beta3-AR-nNOS-NO pathway. PMID- 28622360 TI - The seroprevalence of West Nile Virus in Israel: A nationwide cross sectional study. AB - West Nile Virus (WNV) is endemic in Israel, affecting yearly 40-160 individuals. Israel is located on a central migratory path between Africa and Eurasia and most West Nile Fever (WNF) cases reported in recent years were among residents of the coastal plain. The aim of the study was to evaluate the seroprevalence of WNV among the Israeli population and to assess correlates for WNV infection. A cross sectional nationwide serologic survey was conducted using 3,145 serum samples collected by the national Israeli serum bank during 2011-2014, representing all age and population groups in Israel. Prevalence rates of WNV IgG antibodies were determined. Logistic regressions models were applied to assess the associations between demographic characteristics and WNV seropositivity. 350 samples were positive to WNV (11.1%; 95%CI: 10.0-12.3%). In the multivariable analysis, there was a significant association between seropositivity and the Arab population group vs. Jews and others (OR = 1.86, 95%CI: 1.37-2.52), the time lived in Israel [50-59 years vs. 0-9 years; OR = 10.80 (95%CI: 1.03-113.46) and >=60 years vs. 0 9 years; OR = 14.00 (1.32-148.31)] residence area] Coastal Plain, Inland Plain (Shfela) and Great Rift Valley vs. Upper Galilee; OR = 2.24 (95%CI: 1.37-3.65), OR = 2.18 (95%CI: 1.18-4.03), OR = 1.90 (95%CI: 1.10-3.30), respectively [and rural vs. urban settlement (OR = 1.65, 95%CI: 1.26-2.16). People, who reside in the Coastal Plain, Inland Plain and Great Rift Valley, should be aware of the risk of contracting WNV and reduce exposure to mosquito bites, using insect repellents, and wearing protective clothing. The Ministry of Environmental Protection should be active in reducing the mosquito population by eliminating sources of standing water, a breeding ground for mosquitoes. PMID- 28622361 TI - Prevalence, trend and risk factors for antiretroviral therapy discontinuation among HIV-infected adults in Ethiopia in 2003-2015. AB - BACKGROUND: It is well acknowledged that antiretroviral therapy (ART) discontinuation hampers the progress towards achieving the UNAIDS treatment targets that aim to treat 90% of HIV diagnosed patients and achieve viral suppression for 90% of those on treatment. Nevertheless, the magnitude, trend and risk factors for ART discontinuation have not been explored extensively. We carried out a retrospective data analysis to assess prevalence, trend and risk factors for ART discontinuation among adults in Southwest Ethiopia. METHODS: 12 years retrospective cohort analysis was performed with 4900 HIV-infected adult patients between 21 June 2003 and 15 March 2015 registered at the ART clinic at Jimma University Teaching Hospital. ART discontinuation could be loss to follow up, defaulting and/or stopping medication while remaining in care. Because data for 2003 and 2015 were incomplete, the 10 years data were used to describe trends for ART discontinuation using a line graph. We used binary logistic regression to identify factors that were correlated with ART discontinuation. To handle missing data, we applied multiple imputations assuming missing at random pattern. RESULTS: In total, 4900 adult patients enrolled on ART, of whom 1090 (22.3%) had discontinued, 954 (19.5%) had transferred out, 300 (6.1%) had died, 2517 (51.4%) were alive and on ART, and the remaining 39 (0.8%) had unknown outcome status. The trend of ART discontinuation showed an upward direction in the recent times and reached a peak, accounting for a magnitude of 10%, in 2004 and 2005. Being a female (AOR = 2.1, 95%CI: 1.7-2.8), having an immunological failure (AOR = 2.3, 1.9-8.2), having tuberculosis/HIV co-infection (AOR = 1.5, 1.1-2.1) and no previous history of HIV testing (AOR = 1.8, 1.4-2.9) were the risk factors for ART discontinuation. CONCLUSIONS: One out of five adults had discontinued from ART, and the trend of ART discontinuation increased recently. Discontinued adults were more likely to be females, tuberculosis/HIV co-infected, with immunological failure and no history of HIV testing. Therefore, it is vital to implement effective programs such as community ART distribution and linkage-case-management to enhance ART linkage and retention. PMID- 28622362 TI - The complete mitochondrial genome of Sesarmops sinensis reveals gene rearrangements and phylogenetic relationships in Brachyura. AB - Mitochondrial genome (mitogenome) is very important to understand molecular evolution and phylogenetics. Herein, in this study, the complete mitogenome of Sesarmops sinensis was reported. The mitogenome was 15,905 bp in size, and contained 13 protein-coding genes (PCGs), two ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a control region (CR). The AT skew and the GC skew are both negative in the mitogenomes of S. sinensis. The nucleotide composition of the S. sinensis mitogenome was also biased toward A + T nucleotides (75.7%). All tRNA genes displayed a typical mitochondrial tRNA cloverleaf structure, except for the trnS1 gene, which lacked a dihydroxyuridine arm. S. sinensis exhibits a novel rearrangement compared with the Pancrustacean ground pattern and other Brachyura species. Based on the 13 PCGs, the phylogenetic analysis showed that S. sinensis and Sesarma neglectum were clustered on one branch with high nodal support values, indicating that S. sinensis and S. neglectum have a sister group relationship. The group (S. sinensis + S. neglectum) was sister to (Parasesarmops tripectinis + Metopaulias depressus), suggesting that S. sinensis belongs to Grapsoidea, Sesarmidae. Phylogenetic trees based on amino acid sequences and nucleotide sequences of mitochondrial 13 PCGs using BI and ML respectively indicate that section Eubrachyura consists of four groups clearly. The resulting phylogeny supports the establishment of a separate subsection Potamoida. These four groups correspond to four subsections of Raninoida, Heterotremata, Potamoida, and Thoracotremata. PMID- 28622364 TI - IpiRId: Integrative approach for piRNA prediction using genomic and epigenomic data. AB - Many computational tools have been proposed during the two last decades for predicting piRNAs, which are molecules with important role in post transcriptional gene regulation. However, these tools are mostly based on only one feature that is generally related to the sequence. Discoveries in the domain of piRNAs are still in their beginning stages, and recent publications have shown many new properties. Here, we propose an integrative approach for piRNA prediction in which several types of genomic and epigenomic properties that can be used to characterize these molecules are examined. We reviewed and extracted a large number of piRNA features from the literature that have been observed experimentally in several species. These features are represented by different kernels, in a Multiple Kernel Learning based approach, implemented within an object-oriented framework. The obtained tool, called IpiRId, shows prediction results that attain more than 90% of accuracy on different tested species (human, mouse and fly), outperforming all existing tools. Besides, our method makes it possible to study the validity of each given feature in a given species. Finally, the developed tool is modular and easily extensible, and can be adapted for predicting other types of ncRNAs. The IpiRId software and the user-friendly web based server of our tool are now freely available to academic users at: https://evryrna.ibisc.univ-evry.fr/evryrna/. PMID- 28622363 TI - Acyloxyacyl hydrolase promotes the resolution of lipopolysaccharide-induced acute lung injury. AB - Pulmonary infection is the most common risk factor for acute lung injury (ALI). Innate immune responses induced by Microbe-Associated Molecular Pattern (MAMP) molecules are essential for lung defense but can lead to tissue injury. Little is known about how MAMP molecules are degraded in the lung or how MAMP degradation/inactivation helps prevent or ameliorate the harmful inflammation that produces ALI. Acyloxyacyl hydrolase (AOAH) is a host lipase that inactivates Gram-negative bacterial endotoxin (lipopolysaccharide, or LPS). We report here that alveolar macrophages increase AOAH expression upon exposure to LPS and that Aoah+/+ mice recover more rapidly than do Aoah-/- mice from ALI induced by nasally instilled LPS or Klebsiella pneumoniae. Aoah-/- mouse lungs had more prolonged leukocyte infiltration, greater pro- and anti-inflammatory cytokine expression, and longer-lasting alveolar barrier damage. We also describe evidence that the persistently bioactive LPS in Aoah-/- alveoli can stimulate alveolar macrophages directly and epithelial cells indirectly to produce chemoattractants that recruit neutrophils to the lung and may prevent their clearance. Distinct from the prolonged tolerance observed in LPS-exposed Aoah-/- peritoneal macrophages, alveolar macrophages that lacked AOAH maintained or increased their responses to bioactive LPS and sustained inflammation. Inactivation of LPS by AOAH is a previously unappreciated mechanism for promoting resolution of pulmonary inflammation/injury induced by Gram-negative bacterial infection. PMID- 28622365 TI - Association between socioeconomic deprivation and colorectal cancer screening outcomes: Low uptake rates among the most and least deprived people. AB - BACKGROUND: Screening with faecal occult blood tests reduces colorectal cancer related mortality; however, age, sex and socioeconomic factors affect screening outcomes and could lead to unequal mortality benefits. The aim of this study was to describe the main outcomes of the population-based Barcelona colorectal cancer screening programme (BCRCSP) by deprivation. METHODS: Retrospective study of the eligible population of the first round of the BCRCSP. Participants' postal addresses were linked with the MEDEA database to obtain the deprivation quintiles (Dq). Chi-squared tests were used to compare proportions across variables and logistic regression was used to estimate the adjusted effects of age, sex and deprivation on uptake, FIT positivity, colonoscopy adherence and advanced neoplasia detection rate. RESULTS: Overall uptake was 44.7%, higher in Dq2, 3 and 4 (OR 1.251, 1.250 and 1.276, respectively) than in the least deprived quintile (Dq 1), and lowest in Dq5 (OR 0.84). Faecal immunochemical test (FIT) positivity and the percentage of people with detectable faecal haemoglobin below the positivity threshold increased with deprivation. The advanced neoplasia detection rate was highest in Dq4. CONCLUSION: Unlike most regions where inequalities are graded along the socioeconomic continuum, inequalities in the uptake of colorectal cancer screening in Spain seem to be concentrated first in the most disadvantaged group and second in the least deprived group. The correlation of deprivation with FIT-positivity and faecal haemoglobin below the positivity threshold is worrying due to its association with colorectal cancer and overall mortality. PMID- 28622366 TI - Decomposition of recalcitrant carbon under experimental warming in boreal forest. AB - Over the long term, soil carbon (C) storage is partly determined by decomposition rate of carbon that is slow to decompose (i.e., recalcitrant C). According to thermodynamic theory, decomposition rates of recalcitrant C might differ from those of non-recalcitrant C in their sensitivities to global warming. We decomposed leaf litter in a warming experiment in Alaskan boreal forest, and measured mass loss of recalcitrant C (lignin) vs. non-recalcitrant C (cellulose, hemicellulose, and sugars) throughout 16 months. We found that these C fractions responded differently to warming. Specifically, after one year of decomposition, the ratio of recalcitrant C to non-recalcitrant C remaining in litter declined in the warmed plots compared to control. Consistent with this pattern, potential activities of enzymes targeting recalcitrant C increased with warming, relative to those targeting non-recalcitrant C. Even so, mass loss of individual C fractions showed that non-recalcitrant C is preferentially decomposed under control conditions whereas recalcitrant C losses remain unchanged between control and warmed plots. Moreover, overall mass loss was greater under control conditions. Our results imply that direct warming effects, as well as indirect warming effects (e.g. drying), may serve to maintain decomposition rates of recalcitrant C compared to non-recalcitrant C despite negative effects on overall decomposition. PMID- 28622367 TI - Role of serum ferritin level on overall survival in patients with myelodysplastic syndromes: Results of a meta-analysis of observational studies. AB - BACKGROUND: The role of serum ferritin (SF) as a prognostic factor has been analyzed in patients with myelodysplastic syndromes (MDS) who have undergone hematopoietic stem cell transplantation (HSCT), but the prognostic role of elevated SF levels is still controversial in lower risk MDS patients. Therefore, we performed a meta-analysis of all available published literature to evaluate whether elevated SF levels are associated with a worse overall survival (OS) among patients with low risk MDS. MATERIAL AND METHODS: A systematic bibliographic search of relevant studies was undertaken in accordance with guidelines for meta-analysis of observational studies in epidemiology. Electronic databases were searched through July 2016 for studies examining the level of SF as a prognostic factor in the adults affected by MDS. RESULTS: Six articles were included in the meta-analysis. A significant association between OS and SF was achieved for the threshold of SF>=1000 ng/mL, when the only study that used SF cut-off >=2000 ng/mL was not included in the meta-analysis (RR = 1.33; 95% CI = 1.06-1.67). The estimated risk was 2.58 (95% CI = 1.41-4.74) when a SF cut off>=500 ng/mL was considered. CONCLUSIONS: Our findings underlined a worse survival in patients with MDS who had higher SF levels. The association was stronger and achieved statistical significance after stratification of analyses in which we excluded cut-offs of SF level considered as outliers. These results suggest that negative impact on OS already exist at SF level >=500 ng/mL. Prospective studies, are needed to better understand this relationship and, above all, to clarify whether earlier iron chelation therapy could improve patients' OS. PMID- 28622368 TI - Minimal genetic change in Vibrio cholerae in Mozambique over time: Multilocus variable number tandem repeat analysis and whole genome sequencing. AB - Although cholera is a major public health concern in Mozambique, its transmission patterns remain unknown. We surveyed the genetic relatedness of 75 Vibrio cholerae isolates from patients at Manhica District Hospital between 2002-2012 and 3 isolates from river using multilocus variable-number tandem-repeat analysis (MLVA) and whole genome sequencing (WGS). MLVA revealed 22 genotypes in two clonal complexes and four unrelated genotypes. WGS revealed i) the presence of recombination, ii) 67 isolates descended monophyletically from a single source connected to Wave 3 of the Seventh Pandemic, and iii) four clinical isolates lacking the cholera toxin gene. This Wave 3 strain persisted for at least eight years in either an environmental reservoir or circulating within the human population. Our data raises important questions related to where these isolates persist and how identical isolates can be collected years apart despite our understanding of high change rate of MLVA loci and the V. cholerae molecular clock. PMID- 28622370 TI - Evaluation of the performance of Abbott m2000 and Roche COBAS Ampliprep/COBAS Taqman assays for HIV-1 viral load determination using dried blood spots and dried plasma spots in Kenya. AB - BACKGROUND: Routine HIV viral load testing is not widely accessible in most resource-limited settings, including Kenya. To increase access to viral load testing, alternative sample types like dried blood spots (DBS), which overcome the logistic barriers associated with plasma separation and cold chain shipment need to be considered and evaluated. The current study evaluated matched dried blood spots (DBS) and dried plasma spots (DPS) against plasma using the Abbott M 2000 (Abbott) and Roche Cobas Ampliprep/Cobas TaqMan (CAP/CTM) quantitative viral load assays in western Kenya. METHODS: Matched plasma DBS and DPS were obtained from 200 HIV-1 infected antiretroviral treatment (ART)-experienced patients attending patient support centers in Western Kenya. Standard quantitative assay performance parameters with accompanying 95% confidence intervals (CI) were assessed at the assays lower detection limit (400cps/ml for CAP/CTM and 550cps/ml for Abbott) using SAS version 9.2. Receiver operating curves (ROC) were further used to assess viral-load thresholds with best assay performance (reference assay CAP/CTM plasma). RESULTS: Using the Abbott test, the sensitivity and specificity, respectively, for DPS were (97.3%, [95%CI: 93.2-99.2] and 98.1% [95%CI: 89.7 100]) and those for DBS (93.9% [95%CI: 88.8-97.2] and 88.0% [95%CI: 82.2-92.4]). The correlation and agreement using paired plasma and DPS/DBS were strong, with r2 = 90.5 and rc = 68.1. The Bland-Altman relative percent change was 95.3 for DPS, (95%CI: 90.4-97.7) and 73.6 (95%CI: 51.6-86.5) for DBS. Using the CAP/CTM assay, the sensitivity for DBS was significantly higher compared to DPS (100.0% [95% CI: 97.6-100.0] vs. 94.7% [95%CI: 89.8-97.7]), while the specificity for DBS was lower: 4%, [95% CI: 0.4-13.7] compared to DPS: 94.0%, [95% CI: 83.5-98.7]. When compared under different clinical relevant thresholds, the accuracy for the Abbott assay was 95% at the 1000cps/ml cut-off with a sensitivity and specificity of 96.6% [95% CI 91.8-98.7] and 90.4% [95% CI 78.2-96.4] respectively. The optimum threshold was at 3000 cps/ml with an accuracy of 95.5%, sensitivity and specificity of 94.6% [95%CI 89.3-97.5] and 98.1% [95%CI 88.4-99.9]) respectively. The best threshold for CAP/CTM was at 4000 copies /mL, with 92.5% accuracy (sensitivity of 96.0% [95%CI 91.0-98.3] and specificity of 82.7% [95%CI 69.2 91.3]). CONCLUSIONS: There was similar performance between matched DBS, DPS and plasma using the Abbott test, and good correlation for matched DPS and plasma using the CAPCTM test. The findings suggest that DBS and DPS may be reliably used as alternative specimens to plasma to measure HIV-1 VL using Abbott, and DPS may be reliably used with CAP/CTM in resource-limited settings. PMID- 28622369 TI - Comparative sequence analysis reveals regulation of genes in developing schistosomula of Schistosoma mansoni exposed to host portal serum. AB - Once inside a vertebrate host after infection, individual schistosomula of the parasite Schistosoma mansoni find a new and complex environment, which requires quick adjustments for survival, such as those that allow it to avoid the innate immune response of the host. Thus, it is very important for the parasite to remain within the skin after entering the host for a period of about 3 days, at which time it can then reach the venous system, migrate to the lungs and, by the end of eighth day post-infection, it reach the portal venous system, while undergoing minimal changes in morphology. However, after just a few days in the portal blood system, the parasite experiences an extraordinary increase in biomass and significant morphological alterations. Therefore, determining the constituents of the portal venous system that may trigger these changes that causes the parasite to consolidate its development inside the vertebrate host, thus causing the disease schistosomiasis, is essential. The present work simulated the conditions found in the portal venous system of the vertebrate host by exposing schistosomula of S. mansoni to in vitro culture in the presence of portal serum of the hamster, Mesocricetus auratus. Two different incubation periods were evaluated, one of 3 hours and one of 12 hours. These time periods were used to mimic the early contact of the parasite with portal serum during the course of natural infection. As a control, parasites were incubated in presence of hamster peripheral serum, in order to compare gene expression signatures between the two conditions. The mRNA obtained from parasites cultured under both conditions were submitted to a whole transcriptome library preparation and sequenced with a next generation platform. On average, nearly 15 million reads were produced per sample and, for the purpose of gene expression quantification, only reads mapped to one location of the transcriptome were considered. After statistical analysis, we found 103 genes differentially expressed by schistosomula cultured for 3 hours and 12 hours in the presence of hamster portal serum. After the subtraction of a second list of genes, also differentially expressed between schistosomula cultured for 3 hours and 12 hours in presence of peripheral serum, a set of 58 genes was finally established. This pattern was further validated for a subset of 17 genes, by measuring gene expression through quantitative real time polymerase chain reaction (qPCR). Processes that were activated by the portal serum stimulus include response to stress, membrane transport, protein synthesis and folding/degradation, signaling, cytoskeleton arrangement, cell adhesion and nucleotide synthesis. Additionally, a smaller number of genes down-regulated under the same condition act on cholinergic signaling, inorganic cation and organic anion membrane transport, cell adhesion and cytoskeleton arrangement. Considering the role of these genes in triggering processes that allow the parasite to quickly adapt, escape the immune response of the host and start maturation into an adult worm after contact with the portal serum, this work may point to unexplored molecular targets for drug discovery and vaccine development against schistosomiasis. PMID- 28622371 TI - High tolerance to temperature and salinity change should enable scleractinian coral Platygyra acuta from marginal environments to persist under future climate change. AB - With projected changes in the marine environment under global climate change, the effects of single stressors on corals have been relatively well studied. However, more focus should be placed on the interactive effects of multiple stressors if their impacts upon corals are to be assessed more realistically. Elevation of sea surface temperature is projected under global climate change, and future increases in precipitation extremes related to the monsoon are also expected. Thus, the lowering of salinity could become a more common phenomenon and its impact on corals could be significant as extreme precipitation usually occurs during the coral spawning season. Here, we investigated the interactive effects of temperature [24, 27 (ambient), 30, 32 degrees C] and salinity [33 psu (ambient), 30, 26, 22, 18, 14 psu] on larval settlement, post-settlement survival and early growth of the dominant coral Platygyra acuta from Hong Kong, a marginal environment for coral growth. The results indicate that elevated temperatures (+3 degrees C and +5 degrees C above ambient) did not have any significant effects on larval settlement success and post-settlement survival for up to 56 days of prolonged exposure. Such thermal tolerance was markedly higher than that reported in the literature for other coral species. Moreover, there was a positive effect of these elevated temperatures in reducing the negative effects of lowered salinity (26 psu) on settlement success. The enhanced settlement success brought about by elevated temperatures, together with the high post-settlement survival recorded up to 44 and 8 days of exposure under +3 degrees C and +5 degrees C ambient respectively, resulted in the overall positive effects of elevated temperatures on recruitment success. These results suggest that projected elevation in temperature over the next century should not pose any major problem for the recruitment success of P. acuta. The combined effects of higher temperatures and lowered salinity (26 psu) could even be beneficial. Therefore, corals that are currently present in marginal environments like Hong Kong, as exemplified by the dominant P. acuta, are likely to persist in a warmer and intermittently less saline, future ocean. PMID- 28622372 TI - Vitrectomy with or without internal limiting membrane peeling for idiopathic epiretinal membrane: A meta-analysis. AB - BACKGROUND: Studies on vitrectomy with and without internal limiting membrane (ILM) peeling for idiopathic epiretinal membrane (ERM) have yielded uncertain results regarding clinical outcomes and recurrence rates. OBJECTIVE: To compare the clinical outcomes of vitrectomy with and without ILM peeling for idiopathic ERM. METHODS: Databases, including PubMed, Embase, Cochrane, Web of Science, Google Scholar, CNKI databases, FDA.gov, and ClinicalTrials.gov, published until July 2016, were searched to identify studies comparing the clinical outcomes following vitrectomy with ERM and ILM peeling and with only ERM peeling, for treating idiopathic ERM. Studies with sufficient data were selected. Pooled results were expressed as mean differences (MDs) and risk ratios (RRs) with corresponding 95% confidence intervals (CI) for vitrectomy with and without ILM peeling with regard to postoperative best corrected visual acuity (BCVA), central retinal thickness (CRT), and ERM recurrence rate. RESULTS: Eleven retrospective studies and one randomized controlled trial involving 756 eyes were identified. This demonstrated that the postoperative BCVA within 12 months was significantly better in the non-ILM peeling group (MD = 0.04, 95% CI: 0.00 to 0.08; P = 0.0460), but that the patients in the ILM peeling group had significantly better postoperative BCVA after 18 months (MD = -0.13, 95% CI: -0.23 to -0.04; P = 0.0049) than did those in the non-ILM peeling group. The non-ILM peeling group exhibited a higher reduction in postoperative CRT (MD = 51.55, 95% CI:-84.23 to 18.88; P = 0.0020) and a higher recurrence rate of ERM (RR = 0.34, 95% CI:0.16 to 0.72; P = 0.0048) than did the ILM peeling group. However, the improvement rates of BCVA (RR = 1.03, 95% CI:0.72 to 1.47; P = 0.8802) and postoperative CRTs (MD = 18.15, 95% CI:-2.29 to 38.60; P = 0.0818) were similar between the two groups. CONCLUSIONS: Vitrectomy with ILM peeling results in better visual improvement in long-term follow-ups and lower ERM recurrence rates, and vitrectomy with only ERM peeling is more efficacious in reduction of CRT than is vitrectomy with ILM peeling. PMID- 28622373 TI - A versatile and low-cost open source pipetting robot for automation of toxicological and ecotoxicological bioassays. AB - In the past decades, bioassays and whole-organism bioassay have become important tools not only in compliance testing of industrial chemicals and plant protection products, but also in the monitoring of environmental quality. With few exceptions, such test systems are discontinuous. They require exposure of the biological test material in small units, such as multiwell plates, during prolonged incubation periods, and do not allow online read-outs. It is mostly due to these shortcomings that applications in continuous monitoring of, e.g., drinking or surface water quality are largely missing. We propose the use of pipetting robots that can be used to automatically exchange samples in multiwell plates with fresh samples in a semi-static manner, as a potential solution to overcome these limitations. In this study, we developed a simple and low-cost, versatile pipetting robot constructed partly using open-source hardware that has a small footprint and can be used for online monitoring of water quality by means of an automated whole-organism bioassay. We tested its precision in automated 2 fold dilution series and used it for exposure of zebrafish embryos (Danio rerio) a common model species in ecotoxicology-to cadmium chloride and permethrin. We found that, compared to conventional static or semi-static exposure scenarios, effects of the two chemicals in zebrafish embryos generally occurred at lower concentrations, and analytically verified that the increased frequency of media exchange resulted in a greater availability of the chemical. In combination with advanced detection systems this custom-made pipetting robot has the potential to become a valuable tool in future monitoring strategies for drinking and surface water. PMID- 28622375 TI - Identification of benthic diatoms isolated from the eastern tidal flats of the Yellow Sea: Comparison between morphological and molecular approaches. AB - Benthic diatoms isolated from tidal flats in the west coast of Korea were identified through both traditional morphological method and molecular phylogenetic method for methodological comparison. For the molecular phylogenetic analyses, we sequenced the 18S rRNA and the ribulose bisphosphate carboxylase large subunit coding gene, rbcL. Further, the comparative analysis allowed for the assessment of the suitability as a genetic marker for identification of closely related benthic diatom species and as potential barcode gene. Based on the traditional morphological identification system, the 61 isolated strains were classified into 52 previously known taxa from 13 genera. However, 17 strains could not be classified as known species by morphological analyses, suggesting a hidden diversity of benthic diatoms. The Blast search on NCBI's Genebank indicated that the reference sequences for most of the species were absent for the benthic diatoms. Of the two genetic markers, the rbcL genes were more divergent than the 18S rRNA genes. Furthermore, a long branch attraction artefact was found in the 18S rRNA phylogeny. These results suggest that the rbcL gene is a more appropriate genetic marker for identification and classification of benthic diatoms. Considering their high diversity and simple shapes, and thus the difficulty associated with morphological classification of benthic diatoms, a molecular approach could provide a relatively easy and reliable classification system. However, this study suggests that more effort should be made to construct a reliable database containing polyphasic taxonomic data for diatom classification. PMID- 28622374 TI - Large-scale modulation of reconstituted Min protein patterns and gradients by defined mutations in MinE's membrane targeting sequence. AB - The E. coli MinDE oscillator is a paradigm for protein self-organization and gradient formation. Previously, we reconstituted Min protein wave patterns on flat membranes as well as gradient-forming pole-to-pole oscillations in cell shaped PDMS microcompartments. These oscillations appeared to require direct membrane interaction of the ATPase activating protein MinE. However, it remained unclear how exactly Min protein dynamics are regulated by MinE membrane binding. Here, we dissect the role of MinE's membrane targeting sequence (MTS) by reconstituting various MinE mutants in 2D and 3D geometries. We demonstrate that the MTS defines the lower limit of the concentration-dependent wavelength of Min protein patterns while restraining MinE's ability to stimulate MinD's ATPase activity. Strikingly, a markedly reduced length scale-obtainable even by single mutations-is associated with a rich variety of multistable dynamic modes in cell shaped compartments. This dramatic remodeling in response to biochemical changes reveals a remarkable trade-off between robustness and versatility of the Min oscillator. PMID- 28622376 TI - Client and facility level determinants of quality of care in family planning services in Ethiopia: Multilevel modelling. AB - INTRODUCTION: Over the last two decades, while contraceptive use has improved in Ethiopia, the contraceptive prevalence rate remains low. In addition to socio demographic and cultural factors, the quality of care in Family Planning (FP) services is an important determining factor of FP utilization. However, little research exists on the determinants of quality of care in FP services in Ethiopia. This study aims to identify the client and facility level determinants of quality of care in FP services in Ethiopia. METHODS: This study was based on the first Ethiopian Services Provision Assessment Plus (ESPA+) survey conducted in 2014. A total of 1247 clients nested in 374 health facilities were included in the analysis. Multilevel mixed-effects logistic regression modelling was conducted. The outcome variable, client satisfaction, was created using polychoric principal component analysis using eleven facets that reflect client satisfaction. RESULTS: The results showed that both client-level and facility level factors were associated with quality of care in FP services in Ethiopia. At the client-level; provision of information on potential side effects of contraceptive method (AOR = 5.22, 95% CI: 2.13-12.80), and number of history and physical assessments (AOR = 1.19, 95% CI: 1.03-1.34) were positively associated with client satisfaction, whereas waiting times of 30 minutes to two hours (AOR = 0.11, 95% CI: 0.03-0.33) was negatively associated with client satisfaction. At the facility-level; urban location (AOR = 4.61, 95% CI: 1.04-20.58), and availability of FP guidelines/protocols for providers (AOR = 4.90, 95% CI: 1.19 20.19) had positive significant effect on client satisfaction. CONCLUSION: Quality improvement programs in FP services in Ethiopia should focus on shortening waiting times and provision of information about the potential side effects of contraceptive methods. It is also important to improve health providers' skills in thorough client history taking and physical assessment. Further distribution and implementation of best practice guidelines for providers working in the FP services must be a priority. PMID- 28622377 TI - Hemostatic function to regulate perioperative bleeding in patients undergoing spinal surgery: A prospective observational study. AB - Although bleeding is a common complication of surgery, routine laboratory tests have been demonstrated to have a low ability to predict perioperative bleeding. Better understanding of hemostatic function during surgery would lead to identification of high-risk patients for bleeding. Here, we aimed to elucidate hemostatic mechanisms to determine perioperative bleeding. We prospectively enrolled 104 patients undergoing cervical spinal surgery without bleeding diathesis. Blood sampling was performed just before the operation. Volumes of perioperative blood loss were compared with the results of detailed laboratory tests assessing primary hemostasis, secondary hemostasis, and fibrinolysis. Platelet aggregations induced by several agonists correlated with each other, and only two latent factors determined inter-individual difference. Platelet aggregability independently determined perioperative bleeding. We also identified low levels of plasminogen-activator inhibitor-1 (PAI-1) and alpha2-plasmin inhibitor to be independent risk factors for intraoperative and postoperative bleeding, respectively. Most important independent factor to determine postoperative bleeding was body weight. Of note, obese patients with low levels of PAI-1 became high-risk patients for bleeding during surgery. Our data suggest that bleeding after surgical procedure may be influenced by inter-individual differences of hemostatic function including platelet function and fibrinolysis, even in the patients without bleeding diathesis. PMID- 28622378 TI - Gene modification of the acetate biosynthesis pathway in Escherichia coli and implementation of the cell recycling technology to increase L-tryptophan production. AB - The implementation of a novel cell recycling technology based on a special disk centrifuge during microbial fermentation process can continuously separate the product and harmful intermediates, while maintaining the cell viability owing to the installed cooling system. Acetate accumulation is an often encountered problem in L-tryptophan fermentation by Escherichia coli. To extend our previous studies, the current study deleted the key genes underlying acetate biosynthesis to improve l-tryptophan production. The deletion of the phosphotransacetylase (pta)-acetate kinase (ackA) pathway in a gltB (encoding glutamate synthase) mutant of E. coli TRTHB, led to the highest production of l-tryptophan (47.18 g/L) and glucose conversion rate (17.83%), with a marked reduction in acetate accumulation (1.22 g/L). This strain, TRTHBPA, was then used to investigate the effects of the cell recycling process on L-tryptophan fermentation. Four different strategies were developed concerning two issues, the volume ratio of the concentrated cell solution and clear solution and the cell recycling period. With strategy I (concentrated cell solution: clear solution, 1: 1; cell recycling within 24-30 h), L-tryptophan production and the glucose conversion rate increased to 55.12 g/L and 19.75%, respectively, 17.55% and 10.77% higher than those without the cell recycling. In addition, the biomass increased by 13.52% and the fermentation period was shortened from 40 h to 32 h. These results indicated that the cell recycling technology significantly improved L-tryptophan production by E. coli. PMID- 28622379 TI - End of life care for people with dementia: The views of health professionals, social care service managers and frontline staff on key requirements for good practice. AB - BACKGROUND: Evidence consistently shows that people with advanced dementia experience suboptimal end of life care compared to those with cancer; with increased hospitalisation, inadequate pain control and fewer palliative care interventions. Understanding the views of those service managers and frontline staff who organise and provide care is crucial in order to develop better end of life care for people with dementia. METHODS AND FINDINGS: Qualitative interviews and focus groups were conducted from 2013 to 2015 with 33 service managers and 54 staff involved in frontline care, including doctors, nurses, nursing and care home managers, service development leads, senior managers/directors, care assistants and senior care assistants/team leads. All were audio recorded and transcribed verbatim. Participants represented a diverse range of service types and occupation. Transcripts were subject to coding and thematic analysis in data meetings. Analysis of the data led to the development of seven key themes: Recognising end of life (EOL) and tools to support end of life care (EOLC), Communicating with families about EOL, Collaborative working, Continuity of care, Ensuring comfort at EOL, Supporting families, Developing and supporting staff. Each is discussed in detail and comprise individual and collective views on approaches to good end of life care for people with dementia. CONCLUSIONS: The significant challenges of providing good end of life care for people with dementia requires that different forms of expertise should be recognised and used; including the skills and knowledge of care assistants. Successfully engaging with people with dementia and family members and helping them to recognise the dying trajectory requires a supportive integration of emotional and technical expertise. The study strengthens the existing evidence base in this area and will be used with a related set of studies (on the views of other stakeholders and observations and interviews conducted in four services) to develop an evidence-based intervention. PMID- 28622380 TI - Personality traits across countries: Support for similarities rather than differences. AB - In the current climate of migration and globalization, personality characteristics of individuals from different countries have received a growing interest. Previous research has established reliable differences in personality traits across countries. The present study extends this research by examining 30 personality traits in 22 countries, based on an online survey in English with large national samples (NTotal = 130,602). The instrument used was a comprehensive, open-source measure of the Five Factor Model (FFM) (IPIP-NEO-120). We postulated that differences in personality traits between countries would be small, labeling this a Similarities Hypothesis. We found support for this in three stages. First, similarities across countries were observed for model fits for each of the five personality trait structures. Second, within-country sex differences for the five personality traits showed similar patterns across countries. Finally, the overall the contribution to personality traits from countries was less than 2%. In other words, the relationship between a country and an individual's personality traits, however interesting, are small. We conclude that the most parsimonious explanation for the current and past findings is a cross-country personality Similarities Hypothesis. PMID- 28622381 TI - Cell-free DNA release by mouse placental explants. AB - Although suggested that "fetal" cell-free DNA (cfDNA) is derived from trophoblast cells, the exact origin is unclear. The studies in this report sought to demonstrate that placental tissue releases cfDNA in parallel with cell death, that the size range of cfDNA is similar to that found in maternal plasma, and that the cfDNA fragments are able to stimulate a proinflammatory cytokine response. Placentas were harvested from near term pregnant CD-1 mice and cultured in DMEM/Ham's F12/FBS media in 8% or 21% O2. After centrifugation to remove cells and cellular debris, the cfDNA was extracted from the media and quantified by DNA spectrophotometry. The cfDNA fragments were sized using a 1.5% TAE gel. Cell death was quantified by lactate dehydrogenase assay; and tissue homogenates were used to quantify caspase activity and BAX expression. Cultured RAW-264.7 macrophage cells were used to determine IL6 stimulation by cfDNA. The cfDNA levels released in 8% O2 (placental normoxia) were not significantly different from explants cultured in 21% O2 (placental hyperoxia). The cfDNA fragments ranged in size from < 100 -< 400 bp. The cfDNA release increased when cultured with LPS, whereas it decreased with trolox (vitamin E analog). Explant release of cfDNA increased in parallel with cell death. The cfDNA release and cell death of trophoblast appears to involve components of the apoptosis signaling pathway as suggested by LPS enhancement of placental caspase activity, suppression of cfDNA release by a pan-caspase inhibitor and the trend toward increased Bax protein expression. Studies with cultured macrophage cells confirmed the ability of cfDNA to stimulate an IL6 response. In summary, these studies have confirmed the ability of placental tissue to release significant amounts of cfDNA, a phenomenon that appears to be mediated, at least in part, by apoptosis; and that the cfDNA released by the placental explants is able to stimulate a significant proinflammatory response. Thus, these studies provide support for the hypothesis that cell-free fetal DNA released by placental tissue potentially plays a mechanistically important role during the events leading to the onset of parturition. PMID- 28622382 TI - Correction: Aberrant neuronal activity-induced signaling and gene expression in a mouse model of RASopathy. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006684.]. PMID- 28622383 TI - Long-term trends in the prevalence of patients hospitalized with ischemic stroke from 1995 to 2010 in Sweden. AB - OBJECTIVE: The prevalence of stroke is expected to increase partly because of prolonged life expectancy in the general population. The objective of this study was to investigate trends in the prevalence of patients hospitalized with ischemic stroke (IS) in Sweden from 1995-2010. METHODS: The Swedish inpatient and cause-specific death registries were used to estimate the absolute numbers and prevalence of patients who were hospitalized with and survived an IS from 1995 2010. RESULTS: The overall number of IS increased from 129,418 in 1995 to 148,778 in 2010. In 1995, the prevalence of IS was 189 patients per 10,000 population. An increase in overall prevalence was observed until 2000, and then it remained stable, followed by a decline with an annual percentage change of (APC) -0.8% (95% CI -1.0 to 0.6) and with a final prevalence of 199 patients per 10,000 population in 2010. The prevalence of IS in people aged <45 years increased from 6.4 in 1995 to 7.6 patients per 10,000 population in 2010, with an APC of 2.1% (95% CI 0.9 to 3.4) from 1995-1998 and 0.7% (95% CI 0.6-0.9) from 1998-2010. Among those aged 45-54 years, the prevalence rose through the mid to late 1990s, followed by a slight decrease (APC: -0.7%, 95% CI-1.1 to -0.4) until 2006 and then remained stable with a prevalence of 43.8 patients per 10,000 population in 2010. Among >=85 years, there was a minor decrease (APC: -0.3%, 95% CI -0.5 to 0.1) in overall prevalence after 2002 from 1481 to 1453 patients per 10,000 population in 2010. CONCLUSION: The overall prevalence of IS increased until 2000, but then remained stable followed by a slight decline. However, the prevalence of IS in the young increased through the study period. The absolute number of IS survivors has markedly increased, mainly because of demographic changes. PMID- 28622384 TI - Preventability of early vs. late readmissions in an academic medical center. AB - BACKGROUND: It is unclear if the 30-day unplanned hospital readmission rate is a plausible accountability metric. OBJECTIVE: Compare preventability of hospital readmissions, between an early period [0-7 days post-discharge] and a late period [8-30 days post-discharge]. Compare causes of readmission, and frequency of markers of clinical instability 24h prior to discharge between early and late readmissions. DESIGN, SETTING, PATIENTS: 120 patient readmissions in an academic medical center between 1/1/2009-12/31/2010. MEASURES: Sum-score based on a standard algorithm that assesses preventability of each readmission based on blinded hospitalist review; average causation score for seven types of adverse events; rates of markers of clinical instability within 24h prior to discharge. RESULTS: Readmissions were significantly more preventable in the early compared to the late period [median preventability sum score 8.5 vs. 8.0, p = 0.03]. There were significantly more management errors as causative events for the readmission in the early compared to the late period [mean causation score [scale 1-6, 6 most causal] 2.0 vs. 1.5, p = 0.04], and these errors were significantly more preventable in the early compared to the late period [mean preventability score 1.9 vs 1.5, p = 0.03]. Patients readmitted in the early period were significantly more likely to have mental status changes documented 24h prior to hospital discharge than patients readmitted in the late period [12% vs. 0%, p = 0.01]. CONCLUSIONS: Readmissions occurring in the early period were significantly more preventable. Early readmissions were associated with more management errors, and mental status changes 24h prior to discharge. Seven-day readmissions may be a better accountability measure. PMID- 28622385 TI - Effect of acute predation with bacteriophage on intermicrobial aggression by Pseudomonas aeruginosa. AB - In persons with structural lung disease, particularly those with cystic fibrosis (CF), chronic airway infections cause progressive loss of lung function. CF airways can be colonized by a variety of microorganisms; the most frequently encountered bacterial and fungal pathogens are Pseudomonas aeruginosa and Aspergillus fumigatus, respectively. Co-infection with P. aeruginosa and A. fumigatus often results in a more rapid loss of lung function, indicating that interactions between these pathogens affect infection pathogenesis. There has been renewed interest in the use of viruses (bacteriophage, mycoviruses) as alternatives to antibiotics to treat these infections. In previous work, we found that filamentous Pf bacteriophage produced by P. aeruginosa directly inhibited the metabolic activity of A. fumigatus by binding to and sequestering iron. In the current study, we further examined how filamentous Pf bacteriophage affected interactions between P. aeruginosa and A. fumigatus. Here, we report that the antifungal properties of supernatants collected from P. aeruginosa cultures infected with Pf bacteriophage were substantially less inhibitory towards A. fumigatus biofilms. In particular, we found that acute infection of P. aeruginosa by Pf bacteriophage inhibited the production of the virulence factor pyoverdine. Our results raise the possibility that the reduced production of antimicrobials by P. aeruginosa infected by Pf bacteriophage may promote conditions in CF airways that allow co-infection with A. fumigatus to occur, exacerbating disease severity. Our results also highlight the importance of considering how the use of bacteriophage as therapeutic agents could affect the behavior and composition of polymicrobial communities colonizing sites of chronic infection. PMID- 28622386 TI - Alpha-defensin-dependent enhancement of enteric viral infection. AB - The small intestinal epithelium produces numerous antimicrobial peptides and proteins, including abundant enteric alpha-defensins. Although they most commonly function as potent antivirals in cell culture, enteric alpha-defensins have also been shown to enhance some viral infections in vitro. Efforts to determine the physiologic relevance of enhanced infection have been limited by the absence of a suitable cell culture system. To address this issue, here we use primary stem cell-derived small intestinal enteroids to examine the impact of naturally secreted alpha-defensins on infection by the enteric mouse pathogen, mouse adenovirus 2 (MAdV-2). MAdV-2 infection was increased when enteroids were inoculated across an alpha-defensin gradient in a manner that mimics oral infection but not when alpha-defensin levels were absent or bypassed through other routes of inoculation. This increased infection was a result of receptor independent binding of virus to the cell surface. The enteroid experiments accurately predicted increased MAdV-2 shedding in the feces of wild type mice compared to mice lacking functional alpha-defensins. Thus, our studies have shown that viral infection enhanced by enteric alpha-defensins may reflect the evolution of some viruses to utilize these host proteins to promote their own infection. PMID- 28622387 TI - Estimates and impact of lymphocyte division parameters from CFSE data using mathematical modelling. AB - Carboxyfluorescein diacetate succinimidyl ester (CFSE) labelling has been widely used to track and study cell proliferation. Here we use mathematical modelling to describe the kinetics of immune cell proliferation after an in vitro polyclonal stimulation tracked with CFSE. This approach allows us to estimate a set of key parameters, including ones related to cell death and proliferation. We develop a three-phase model that distinguishes a latency phase, accounting for non-divided cell behaviour, a resting phase and the active phase of the division process. Parameter estimates are derived from model results, and numerical simulations are then compared to the dynamics of in vitro experiments, with different biological assumptions tested. Our model allows us to compare the dynamics of CD4+ and CD8+ cells, and to highlight their kinetic differences. Finally we perform a sensitivity analysis to quantify the impact of each parameter on proliferation kinetics. Interestingly, we find that parameter sensitivity varies with time and with cell generation. Our approach can help biologists to understand cell proliferation mechanisms and to identify potential pathological division processes. PMID- 28622388 TI - Correlation of ultrasound bladder vibrometry assessment of bladder compliance with urodynamic study results. AB - PURPOSE OR OBJECTIVE: The objective of this study is to assess correlation between bladder wall mechanical properties obtained by ultrasound bladder vibrometry (UBV) and urodynamic study (UDS) measurements in a group of patients undergoing clinical UDS procedure. MATERIALS AND METHODS: Concurrent UBV and UDS were performed on 70 patients with neurogenic bladders (56 male and 14 female). Bladder wall mechanical properties measured by UBV at different filling volumes were correlated with recorded detrusor pressure (Pdet) values. Mean, median and standard deviation of correlation values were calculated and the significance of these observations was tested. RESULTS: Bladder wall mechanical properties obtained by UBV as group velocity squared and elasticity showed high correlations with Pdet measured at different volumes (median correlation 0.73, CI: 0.64-0.80 and 0.72, CI: 0.56-0.82 respectively). The correlation of group velocity squared and elasticity with Pdet were both significantly higher than 0.5. CONCLUSIONS: The results of this study suggest that UBV can closely monitor changes in bladder wall mechanical properties at different volumes in a group of patients undergoing UDS. The high correlation between UBV parameters and detrusor pressure measurements suggests that UBV can be utilized as a reliable and cost-effective tool for assessment of the bladder wall mechanical changes in a noninvasive fashion. PMID- 28622389 TI - 'Foraging' for a place to lay eggs: A genetic link between foraging behaviour and oviposition preferences. AB - Gravid female arthropods in search of egg-laying substrates embark on foraging like forays: they survey the environment assessing multiple patches, tasting each with their tarsi and proboscis, and then, if interested, they deposit an egg (or eggs). In fruit flies, Drosophila melanogaster, allelic variation in the foraging gene (for) underlies the rover/sitter foraging behaviour polymorphism. Rover flies (forR) are more active foragers (both within and between food patches) compared to sitters (fors). In nematodes, Caenorhabditis elegans, a mutation in egl-4, the ortholog of for, leads to aberrations in egg laying. Given this and the notion that females may 'forage' for a place to oviposit, we hypothesized that for may underlie egg-laying decisions in the fruit fly. Indeed, when given a choice between patches of low- and high-nutrient availability, rovers lay significantly more eggs on the low-nutrient patches than sitters and also a sitter mutant (fors2). We confirm the role of for by inducing rover-like oviposition preferences in a sitter fly using the transgenic overexpression of for-mRNA in the nervous system. PMID- 28622390 TI - Inhibiting DNA methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells. AB - Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that epigenetic therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells compared to normal tissues. In addition, treatment with clinically relevant low doses of DNMT inhibitors (that remove DNA methylation) increases expression of both antigen processing and presentation and Cancer Testis Antigens in these cell lines. We confirm that treatment with DNMT inhibitors upregulates expression of the antigen processing and presentation molecules B2M, CALR, CD58, PSMB8, PSMB9 at the RNA and protein level in a wider range of colon and ovarian cancer cell lines and treatment time points than had been described previously. In addition, we show that DNMTi treatment upregulates many Cancer Testis Antigens common to both colon and ovarian cancer. This increase of both antigens and antigen presentation by epigenetic therapy may be one mechanism to sensitize patients to immune therapies. PMID- 28622391 TI - Neuronal substrates underlying stress resilience and susceptibility in rats. AB - BACKGROUND: Stress and stressful life events have repeatedly been shown as causally related to depression. The Chronic Mild Stress rat model is a valid model of stress-induced depression. Like humans, rats display great heterogeneity in their response to stress and adversity. Hence some individuals are stress sensitive and prone to develop depression-like behaviour in response to modest stressors, while others are stress-resilient and remain essentially symptom free. OBJECTIVES: Compared to the large body of research, which describes stress induced maladaptive neurobiological changes, relatively little attention has been devoted to understand resiliency to stress. The aim of the present study was to identify changes in neuronal activity, associated with stress-resilient and stress-susceptible chronic mild stress endophenotypes, by examining c-Fos expression in 13 different brain areas. Changes in c-Fos expression have been reported as associated to stressful conditions. METHODS: Stress-induced modulation of neuronal activation patterns in response to the chronic mild stress paradigm was mapped using the immediate early gene expression c-Fos as a marker. Quantification of the c-Fos-like immunoreactivity responses was done by semi automated profile counting procedures and design-based stereology. RESULTS: Exposure to chronic mild stress significantly altered c-Fos expression in a total of 6 out of 13 investigated areas. Chronic mild stress was found to suppress the c-Fos response within the magnocellular ventral lateral geniculate nucleus of both stress subgroups. In the the lateral and ventral orbital cortices of stress resilient rats, the c-Fos like immunoreactivity response was also repressed by stress exposure. On the contrary the c-Fos response within the amygdala, medial habenula, and infralimbic cortex was increased selectively for the stress susceptible rats. CONCLUSIONS: The study was initiated to characterize neuronal substrates associated with stress-coping mechanisms. Six areas, all of which represents limbic structures, were found to be sensitive to stress exposure. The effects within these areas associate to the hedonic status of the rats. Hence, these areas might be associated to stress-coping mechanisms underlying the chronic mild stress induced segregation into stress-susceptible and stress resilient endophenotypes. PMID- 28622392 TI - Therapeutic efficacy of AAV8-mediated intrastriatal delivery of human cerebral dopamine neurotrophic factor in 6-OHDA-induced parkinsonian rat models with different disease progression. AB - Parkinson's disease (PD) is a progressive and age-associated neurodegenerative disorder. Patients at different stages of the disease course have distinguished features, mainly in the number of dopaminergic neurons. Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered neurotrophic factor, being deemed as a hopeful candidate for PD treatment. Here, we evaluated the efficacy of CDNF in protecting dopaminergic function using the 6-OHDA-induced PD rat model suffering from different levels of neuronal loss and the recombinant adeno associated virus 8 (AAV8) as a carrier for the CDNF gene. The results showed that AAV8-CDNF administration significantly improved the motor function and increased the tyrosine hydroxylase (TH) levels in PD rats with mild lesions (2 weeks post lesion), but it had limited therapeutic effects in rats with severe lesions (5 weeks post lesion). To better improve the recovery of motor function in severely lesioned PD rats, we employed a strategy using the CDNF gene along with the aromatic amino acid decarboxylase (AADC) gene. This combination therapeutic strategy indeed showed an enhanced benefit in restoring the motor function of severely lesioned PD rats by providing the neuroprotective effect of CDNF and dopamine enhancing effect of AADC as expected. This study may provide a basis for future clinical application of CDNF in PD patients at different stages and offer a new alternative strategy of joint use of CDNF and AADC for advanced PD patients in clinical trials. PMID- 28622393 TI - Giardia co-infection promotes the secretion of antimicrobial peptides beta defensin 2 and trefoil factor 3 and attenuates attaching and effacing bacteria induced intestinal disease. AB - Our understanding of polymicrobial gastrointestinal infections and their effects on host biology remains incompletely understood. Giardia duodenalis is an ubiquitous intestinal protozoan parasite infecting animals and humans. Concomitant infections with Giardia and other gastrointestinal pathogens commonly occur. In countries with poor sanitation, Giardia infection has been associated with decreased incidence of diarrheal disease and fever, and reduced serum inflammatory markers release, via mechanisms that remain obscure. This study analyzed Giardia spp. co-infections with attaching and effacing (A/E) pathogens, and assessed whether and how the presence of Giardia modulates host responses to A/E enteropathogens, and alters intestinal disease outcome. In mice infected with the A/E pathogen Citrobacter rodentium, co-infection with Giardia muris significantly attenuated weight loss, macro- and microscopic signs of colitis, bacterial colonization and translocation, while concurrently enhancing the production and secretion of antimicrobial peptides (AMPs) mouse beta-defensin 3 and trefoil factor 3 (TFF3). Co-infection of human intestinal epithelial cells (Caco-2) monolayers with G. duodenalis trophozoites and enteropathogenic Escherichia coli (EPEC) enhanced the production of the AMPs human beta-defensin 2 (HBD-2) and TFF3; this effect was inhibited with treatment of G. duodenalis with cysteine protease inhibitors. Collectively, these results suggest that Giardia infections are capable of reducing enteropathogen-induced colitis while increasing production of host AMPs. Additional studies also demonstrated that Giardia was able to directly inhibit the growth of pathogenic bacteria. These results reveal novel mechanisms whereby Giardia may protect against gastrointestinal disease induced by a co-infecting A/E enteropathogen. Our findings shed new light on how microbial-microbial interactions in the gut may protect a host during concomitant infections. PMID- 28622394 TI - Y-chromosomal analysis of Greek Cypriots reveals a primarily common pre-Ottoman paternal ancestry with Turkish Cypriots. AB - Genetics can provide invaluable information on the ancestry of the current inhabitants of Cyprus. A Y-chromosome analysis was performed to (i) determine paternal ancestry among the Greek Cypriot (GCy) community in the context of the Central and Eastern Mediterranean and the Near East; and (ii) identify genetic similarities and differences between Greek Cypriots (GCy) and Turkish Cypriots (TCy). Our haplotype-based analysis has revealed that GCy and TCy patrilineages derive primarily from a single gene pool and show very close genetic affinity (low genetic differentiation) to Calabrian Italian and Lebanese patrilineages. In terms of more recent (past millennium) ancestry, as indicated by Y-haplotype sharing, GCy and TCy share much more haplotypes between them than with any surrounding population (7-8% of total haplotypes shared), while TCy also share around 3% of haplotypes with mainland Turks, and to a lesser extent with North Africans. In terms of Y-haplogroup frequencies, again GCy and TCy show very similar distributions, with the predominant haplogroups in both being J2a-M410, E M78, and G2-P287. Overall, GCy also have a similar Y-haplogroup distribution to non-Turkic Anatolian and Southwest Caucasian populations, as well as Cretan Greeks. TCy show a slight shift towards Turkish populations, due to the presence of Eastern Eurasian (some of which of possible Ottoman origin) Y-haplogroups. Overall, the Y-chromosome analysis performed, using both Y-STR haplotype and binary Y-haplogroup data puts Cypriot in the middle of a genetic continuum stretching from the Levant to Southeast Europe and reveals that despite some differences in haplotype sharing and haplogroup structure, Greek Cypriots and Turkish Cypriots share primarily a common pre-Ottoman paternal ancestry. PMID- 28622395 TI - Optical imaging of radiation-induced metabolic changes in radiation-sensitive and resistant cancer cells. AB - Radiation resistance remains a significant problem for cancer patients, especially due to the time required to definitively determine treatment outcome. For fractionated radiation therapy, nearly 7 to 8 weeks can elapse before a tumor is deemed to be radiation-resistant. We used the optical redox ratio of FAD / ( FAD + NADH ) to identify early metabolic changes in radiation-resistant lung cancer cells. These radiation-resistant human A549 lung cancer cells were developed by exposing the parental A549 cells to repeated doses of radiation (2 Gy). Although there were no significant differences in the optical redox ratio between the parental and resistant cell lines prior to radiation, there was a significant decrease in the optical redox ratio of the radiation-resistant cells 24 h after a single radiation exposure ( p = 0.01 ). This change in the redox ratio was indicative of increased catabolism of glucose in the resistant cells after radiation and was associated with significantly greater protein content of hypoxia-inducible factor 1 ( HIF - 1 ? ), a key promoter of glycolytic metabolism. Our results demonstrate that the optical redox ratio could provide a rapid method of determining radiation resistance status based on early metabolic changes in cancer cells. PMID- 28622396 TI - Mutant Fibulin-3 Causes Proteoglycan Accumulation and Impaired Diffusion Across Bruch's Membrane. AB - Purpose: The mutation R345W in EFEMP1 (fibulin-3) causes macular degeneration. This study sought to determine whether proteoglycan content and diffusion across Bruch's membrane are altered in Efemp1ki/ki mice carrying this mutation or in Efemp1-/- mice. Methods: Proteoglycans in mouse Bruch's membranes were stained with Cupromeronic Blue (CB). Heparan sulfated proteoglycan (HSPG) and chondroitin/dermatan sulfate proteoglycan (C/DSPG) distributions were visualized following treatments with chondroitinase ABC (C-ABC) or nitrous acid. Total sulfated glycosaminoglycans (sGAGs) in Bruch's membrane/choroid (BrM/Ch) were measured with dimethylmethylene blue (DMMB). Matrix metalloprotease (MMP)-2, MMP 9, and tissue inhibitor of metalloproteinase (TIMP)-3 were examined by immunofluorescence and quantified using Image J. Molecules with different Stokes radius (Rs) were allowed simultaneously to diffuse through mouse BrM/Ch mounted in a modified Ussing chamber. Samples were quantified using gel exclusion chromatography. Results: HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired. In contrast, the proteoglycan amount in Efemp1-/- Bruch's membrane was not significantly different, but the size of proteoglycans was much larger. MMP-2, MMP-3, and TIMP 3 levels were similar to that of Efemp1+/+ mice, but they were localized diffusely in retinal pigment epithelium (RPE) cells instead of Bruch's membrane. Diffusion across Efemp1-/- Bruch's membrane was enhanced. Conclusions: Mutant fibulin-3 causes proteoglycan accumulation, reduction of MMP-2 and MMP-9, but increase of TIMP-3, and impairs diffusion across Bruch's membrane. Fibulin-3 ablation results in altered sizes of proteoglycans, altered distributions of MMP 2, MMP-9, and TIMP-3, and enhances diffusion across Bruch's membrane. PMID- 28622397 TI - Looking for the Most Suitable Orthotopic Retinoblastoma Mouse Model in Order to Characterize the Tumoral Development. AB - Purpose: Because retinoblastoma therapies have many adverse effects, new approaches must be developed and evaluated on animal models. We describe orthotopic xenograft models of retinoblastoma using different strains of mice, suitable for this purpose. Methods: Human retinoblastoma tumors were established on immunodeficient mice by subcutaneous engraftment of tumors from enucleated eyes. The orthotopic model was obtained by subretinal injections of suspension cells into the right eye of immunodeficient (Swiss-nude, severe combined immunodeficiency [SCID]) and immunocompetent mice (C57BL/6N, B6Albino). In vivo tumor growth was monitored by fundus and spectral-domain optical coherence tomography (SD-OCT) imaging and compared with histology. Results: Retinal and vitreal tumor growth was achieved both in immunocompetent and immunodeficient strains after the subretinal injection of tumor cells. The best tumor engraftment rate was obtained in the SCID mice (68.8%). No tumor growth was observed in the C57BL/6N strain. Chronic retinal detachment may occur in most strains after the subretinal injection, in particular the Swiss-nude strain, which exhibits retinal degeneration. Conclusions: The setting up of an orthotopic mouse model depends mainly on the choice of the engrafted cells (cell lines or patient-derived xenografts) but it can also depend on the xenografted mouse strain. Severe combined immunodeficiency mice (an immunodeficient strain) achieved the best tumor engraftment rate (68.8%). However, intraocular tumor growth was also satisfactory (50%) in the immunocompetent strain B6Albino, and this strain will allow to exploit the immune response after a tumor treatment. Both of these strains may therefore be recommended when setting up orthotopic retinoblastoma xenografts. PMID- 28622398 TI - Axial Length Variation Impacts on Superficial Retinal Vessel Density and Foveal Avascular Zone Area Measurements Using Optical Coherence Tomography Angiography. AB - Purpose: To evaluate the impact of image magnification correction on superficial retinal vessel density (SRVD) and foveal avascular zone area (FAZA) measurements using optical coherence tomography angiography (OCTA). Methods: Participants with healthy retinas were recruited for ocular biometry, refraction, and RTVue XR Avanti OCTA imaging with the 3 * 3-mm protocol. The foveal and parafoveal SRVD and FAZA were quantified with custom software before and after correction for magnification error using the Littman and the modified Bennett formulae. Relative changes between corrected and uncorrected SRVD and FAZA were calculated. Results: Forty subjects were enrolled and the median (range) age of the participants was 30 (18-74) years. The mean (range) spherical equivalent refractive error was 1.65 (-8.00 to +4.88) diopters and mean (range) axial length was 24.42 mm (21.27 28.85). Images from 13 eyes were excluded due to poor image quality leaving 67 for analysis. Relative changes in foveal and parafoveal SRVD and FAZA after correction ranged from -20% to +10%, -3% to +2%, and -20% to +51%, respectively. Image size correction in measurements of foveal SRVD and FAZA was greater than 5% in 51% and 74% of eyes, respectively. In contrast, 100% of eyes had less than 5% correction in measurements of parafoveal SRVD. Conclusions: Ocular biometry should be performed with OCTA to correct image magnification error induced by axial length variation. We advise caution when interpreting interocular and interindividual comparisons of SRVD and FAZA derived from OCTA without image size correction. PMID- 28622399 TI - Comparative Longterm Mortality Trends in Cancer vs. Ischemic Heart Disease in Puerto Rico. AB - OBJECTIVE: Although contemporary mortality data are important for health assessment and planning purposes, their availability lag several years. Statistical projection techniques can be employed to obtain current estimates. This study aimed to assess annual trends of mortality in Puerto Rico due to cancer and Ischemic Heart Disease (IHD), and to predict shorterm and longterm cancer and IHD mortality figures. METHODS: Age-adjusted mortality per 100,000 population projections with a 50% interval probability were calculated utilizing a Bayesian statistical approach of Age-Period-Cohort dynamic model. Multiple cause-of-death annual files for years 1994-2010 for Puerto Rico were used to calculate shortterm (2011-2012) predictions. Longterm (2013-2022) predictions were based on quinquennial data. We also calculated gender differences in rates (men-women) for each study period. RESULTS: Mortality rates for women were similar for cancer and IHD in the 1994-1998 period, but changed substantially in the projected 2018-2022 period. Cancer mortality rates declined gradually overtime, and the gender difference remained constant throughout the historical and projected trends. A consistent declining trend for IHD historical annual mortality rate was observed for both genders, with a substantial changepoint around 2004-2005 for men. The initial gender difference of 33% (80/100,00 vs. 60/100,000) in mortality rates observed between cancer and IHD in the 1994-1998 period increased to 300% (60/100,000 vs. 20/100,000) for the 2018-2022 period. CONCLUSION: The APC projection model accurately projects shortterm and longterm mortality trends for cancer and IHD in this population: The steady historical and projected cancer mortality rates contrasts with the substantial decline in IHD mortality rates, especially in men. PMID- 28622400 TI - Prevalence of Malocclusion and Distribution of Occlusal Characteristics in 13- to 18-year-old Adolescents Attending Selected High Schools in the Municipality of San Juan, PR (2012-2013). AB - OBJECTIVE: A cross-sectional study was conducted (2012-2013) to evaluate the prevalence of 1) malocclusion and 2) occlusal characteristics in 13- to 18 yearold adolescents in San Juan, Puerto Rico (PR) from selected high schools in the municipality of San Juan. METHODS: The study sample consisted of 155 adolescents. The University of Puerto Rico's IRB approved the study and consent and assent were completed for or by each participant, as applicable. A calibrated dentist performed a single-visit dental evaluation at each school. Occlusal characteristics were measured and recorded according to the criteria reported in the US National Health and Nutrition Examination Survey (NHANES III) and included overjet, overbite, anterior and posterior crossbites, incisor irregularity, maxillary midline diastema and Angle's classification. Descriptive and inferential statistical analyses were performed using SAS statistical software. RESULTS: The mean age of the study subjects was 16 (+/-1.2) years; all subjects (100%) presented at least 1 abnormal occlusal trait. The most frequent anomaly noted was maxillary malalignment (83%), followed by lower incisor irregularity and excessive overbite (79%) and excessive overjet (63%); the least common occlusal trait was open bite (1.9%). Compared by gender, no statistically significant difference was observed for any variable (p = 0.05). Seventy-three percent (73%) of the subjects presented with Class I malocclusion, 7.1% with Class II malocclusion and 19.4% with Class III malocclusion. CONCLUSION: A high prevalence of malocclusion was observed in this group of adolescents, highlighting the need to implement preventive measures to improve oral health in this population. PMID- 28622401 TI - Impact of a Pharmacist Conducted Educational Program on Human Papilloma Virus Vaccination Rates in a Low Socioeconomic Population in the City of Lares, PR. AB - OBJECTIVE: To observe whether local vaccination rates are improved by a patient and physician education program on the human papillomavirus (HPV) vaccine in Farmacia San Jose, Lares. According to the Puerto Rico Immunization Registry, the HPV vaccine is currently underutilized. METHODS: Patients within the ages of 18 and 26 years who are current patients of Farmacia San Jose were contacted by phone and approached in person at the pharmacy. Once contacted, patients were provided with educational materials and counseling regarding the risks and benefits of HPV vaccination. The primary outcome for this study is HPV vaccination rates at 4 months after starting the educational program. RESULTS: Only 79 of the 200 attempted patients who were candidates to receive the HPV vaccine were able to be reached by phone. Out of 79 patients, 24 reported they had previously been vaccinated against HPV. After all educational efforts, 4 patients (all insured by government) received vaccination against HPV at the pharmacy. In addition, 16 physicians near the pharmacy were contacted and visited by the pharmacist resident. The physicians agreed to receive educational information regarding the ACIP recommendations for their patients. CONCLUSION: Although the total number of HPV vaccination administered at the pharmacy during the study period was low, we found an individual patient counseling approach to be much more successful than attempting to coordinate group educational interventions. PMID- 28622402 TI - Prevalence of Concurrent Prescribing of ACE-Is and ARBs among Beneficiaries of Puerto Rico's Government-Sponsored Health Care Plan During 2012 and 2013. AB - OBJECTIVE: Cardiovascular conditions are the second cause of death in Puerto Rico. The individual use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) is considered the first-line therapy for the treatment of several cardiovascular-related medical conditions. However, the concurrent use of these 2 therapeutic classes of drugs is not supported by treatment guidelines. Studies have shown that their concurrent use represents a potential health risk. The research described in this paper aimed to determine the prevalence of the concurrent prescription of ACE-Is and ARBs, either separately or as a combination product, in a group of beneficiaries of the Puerto Rico Health Services Administration (ASES, by its initials in Spanish). METHODS: A 2-year cross sectional study was conducted. All pharmacy claims from the years 2012 and 2013 were provided by ASES and subsequently evaluated by the investigators to identify those involving the prescription of an ACE-I, an ARB, or a combination of drugs belonging to both therapeutic classes. Each pharmacy claim was complemented with sociodemographic and clinical data. The final dataset was analyzed at the person-month level using frequency, cumulative frequency, percentage, and cumulative percentage. RESULTS: The final sample consisted of 361,841 beneficiaries. A total of 23,598 beneficiaries were excluded because of incomplete diagnostic information. Of the beneficiaries with complete information, 36,202 out of 338,243 (10.7%) had concurrent prescriptions for ACE Is and ARBs during the study period. We excluded 1,124 beneficiaries who had a primary diagnosis of HF, resulting in a final pool of 35,078 beneficiaries (10.4%) who had prescriptions for combination products. CONCLUSION: An unacceptable pattern of ACE-I and ARB co-prescribing during the years 2012 and 2013 was observed in patients with diagnoses for which the combination is not clinically indicated. PMID- 28622403 TI - Using Network Sampling and Recruitment Data to Understand Social Structures Related to Community Health in a Population of People Who Inject Drugs in Rural Puerto Rico. AB - OBJECTIVE: This research examined the social network and recruitment patterns of a sample of people who inject drugs (PWIDs) in rural Puerto Rico, in an attempt to uncover systematic clustering and between-group social boundaries that potentially influence disease spread. METHODS: Respondent driven sampling was utilized to obtain a sample of PWID in rural Puerto Rico. Through eight initial "seeds", 317 injection drug users were recruited. Using recruitment patterns of this sample, estimates of homophily and affiliation were calculated using RDSAT. RESULTS: Analyses showed clustering within the social network of PWID in rural Puerto Rico. In particular, females showed a very high tendency to recruit male PWID, which suggests low social cohesion among female PWID. Results for (believed) HCV status at the time of interview indicate that HCV+ individuals were less likely to interact with HCV- individuals or those who were unaware of their status, and may be acting as "gatekeepers" to prevent disease spread. Individuals who participated in a substance use program were more likely to affiliate with one another. The use of speedballs was related to clustering within the network, in which individuals who injected this mixture were more likely to affiliate with other speedball users. CONCLUSION: Social clustering based on several characteristics and behaviors were found within the IDU population in rural Puerto Rico. RDS was effective in not only garnering a sample of PWID in rural Puerto Rico, but also in uncovering social clustering that can potentially influence disease spread among this population. PMID- 28622404 TI - The Use of Community Engaged Research Principles to Improve Health: Community Academic Partnerships for Research. PMID- 28622405 TI - Implementing a Randomized Controlled Trial through a Community-Academia Partnered Participatory Research: Arte con Salud Research-Informed Intervention. AB - OBJECTIVE: "Arte con Salud" is an HIV/AIDS prevention intervention tailored for Puerto Rican women who have sex with men. The intervention curriculum was refined through a community-academic collaboration between Taller Salud, the UPRCayey Campus, and the UCC-School of Medicine, subsided in 2012-13 by PRCTRC. The collaboration has been crucial to validate the impact of using art as a tool to facilitate sexual negotiation skills and safer sexual practices among adult women have sex with men participating in HIV prevention education. METHODS: This article describes the vision, valley, victory phases endured to establish a community-academia partnership based on the CPPR framework as an effective mean to implement a randomized controlled trial intervention (RCT). We also discuss the barriers, outcomes, and lessons learned from this partnership. RESULTS: Some of the identified solutions include: setting goals to secure funding, regular meetings, and the inclusion of undergraduate level students to assist in the implementation of the intervention. These solutions helped to build trust among the community and academic partners. As a result of this collaboration, a total of 86 participants were enrolled and 5 competitive research grants have been submitted. CONCLUSION: The community-academic collaboration was essential in order to build a solid research infrastructure that addresses the complexities of HIV prevention education among groups of Puerto Rican women. PMID- 28622406 TI - Building Bridges to Address Health Disparities in Puerto Rico: the "Salud para Pinones" Project. AB - Over the past several decades, Puerto Ricans have faced increased health threats from chronic diseases, particularly diabetes and hypertension. The patient provider relationship is the main platform for individual disease management, whereas the community, as an agent of change for the community's health status, has been limited in its support of individual health. Likewise, traditional research approaches within communities have placed academic researchers at the center of the process, considering their knowledge was of greater value than that of the community. In this paradigm, the academic researcher frequently owns and controls the research process. The primary aim is contributing to the scientific knowledge, but not necessarily to improve the community's health status or empower communities for social change. In contrast, the community-based participatory research (CBPR) model brings community members and leaders together with researchers in a process that supports mutual learning and empowers the community to take a leadership role in its own health and well-being. This article describes the development of the community-campus partnership between the University of Puerto Rico School of Medicine and Pinones, a semi-rural community, and the resulting CBPR project: "Salud para Pinones". This project represents a collaborative effort to understand and address the community's health needs and health disparities based on the community's participation as keystone of the process. This participatory approach represents a valuable ally in the development of long-term community-academy partnerships, thus providing opportunities to establish relevant and effective ways to translate evidence based interventions into concrete actions that impact the individual and community's wellbeing. PMID- 28622407 TI - Challenges and Lessons Learned in Implementing a Community-Academic Partnership for Drug Prevention in a Native Hawaiian Community. AB - OBJECTIVE: The broad purpose of this project is to improve health in Native Hawaiian communities through the prevention of substance use. Our community academic partnership (CAP) team developed an intervention called Puni Ke Ola for this purpose. This paper provides a brief overview of the intervention, then describes challenges and lessons learned in piloting Puni Ke Ola. METHODS: A single module of the Puni Ke Ola intervention was implemented, after which the intervention leaders (N=3) convened for a debriefing meeting. The information shared was content analyzed to identify challenges in implementation. RESULTS: Five challenges were identified: 1) timeline and schedule, 2) participant recruitment and sample size, 3) place-based intervention intensity and transportation, 4) communication, and 5) staff time and funding. CONCLUSION: Challenges were reframed as lessons learned and organized under the overarching theme of Kapu Aloha. Kapu Aloha refers to the idea that practicing aloha (love and compassion) is sacred and extends to all of our interactions. By honoring this value, our CAP team managed a number of challenges throughout the implementation process, which also has implications for future implementation. PMID- 28622408 TI - Creation of the Quebrada Arriba Community and Academic Partnership: An Effective Coalition for Addressing Health Disparities in Older Puerto Ricans. AB - OBJECTIVE: The objective of this project was to develop a community-academic coalition partnership to conduct community-based participatory research (CBPR) to address health disparities in older adults with chronic conditions living in the Quebrada Arriba community. METHODS: We used the 'Developing and Sustaining CPPR Partnerships: A Skill-Building Curriculum', to create the Quebrada Arriba Community-Academic Partnership (QACAP). We assessed the meetings effectiveness and the CBPR experiences of the coalition members in the community-academic partnership. RESULTS: The stepwise process resulted in: the development of The Coalition for the Health and Wellbeing of Older People of Quebrada Arriba; the partnership's mission and vision; the operating procedures; the formulation of the research question, and; the action plan for obtaining funding resources. The mean levels of satisfaction for each of the items of the Meeting Effectiveness Evaluation tool were 100%. The mean agreement rating scores on variables related to having a positive experience with the coalition, members' representativeness of community interest, respectful contacts between members, the coalition's vision and mission, the participation of the members in establishing the prioritized community problem, and sharing of resources between the members was 100%. CONCLUSION: The steps used to build the QACAP provided an effective structure to create the coalition and captured the results of coalition activities. Partners' time to build trust and developing a sufficient understanding of local issues, high interest of the community members, flexibility of the partners, capitalization on the partners' strengths, and the shared decision building process were key contributors of this coalition's success. PMID- 28622409 TI - Ultrasound-guided hydrodissection decreases gliding resistance of the median nerve within the carpal tunnel. AB - INTRODUCTION: The aim of this study was to assess alterations in median nerve (MN) biomechanics within the carpal tunnel resulting from ultrasound-guided hydrodissection in a cadaveric model. METHODS: Twelve fresh frozen human cadaver hands were used. MN gliding resistance was measured at baseline and posthydrodissection, by pulling the nerve proximally and then returning it to the origin. Six specimens were treated with hydrodissection, and 6 were used as controls. RESULTS: In the hydrodissection group there was a significant reduction in mean peak gliding resistance of 92.9 +/- 34.8 mN between baseline and immediately posthydrodissection (21.4% +/- 10.5%; P = 0.001). No significant reduction between baseline and the second cycle occurred in the control group: 9.6 +/- 29.8 mN (0.4% +/- 5.3%; P = 0.467). DISCUSSION: Hydrodissection can decrease the gliding resistance of the MN within the carpal tunnel, at least in wrists unaffected by carpal tunnel syndrome. A clinical trial of hydrodissection seems justified. Muscle Nerve 57: 25-32, 2018. PMID- 28622410 TI - Accuracy of deformable image registration on magnetic resonance images in digital and physical phantoms. AB - PURPOSE: Accurate deformable image registration is necessary for longitudinal studies. The error associated with commercial systems has been evaluated using computed tomography (CT). Several in-house algorithms have been evaluated for use with magnetic resonance imaging (MRI), but there is still relatively little information about MRI deformable image registration. This work presents an evaluation of two deformable image registration systems, one commercial (Velocity) and one in-house (demons-based algorithm), with MRI using two different metrics to quantify the registration error. METHODS: The registration error was analyzed with synthetic MR images. These images were generated from interpatient and intrapatient variation models trained on 28 patients. Four synthetic post-treatment images were generated for each of four synthetic pretreatment images, resulting in 16 image registrations for both the T1- and T2 weighted images. The synthetic post-treatment images were registered to their corresponding synthetic pretreatment image. The registration error was calculated between the known deformation vector field and the generated deformation vector field from the image registration system. The registration error was also analyzed using a porcine phantom with ten implanted 0.35-mm diameter gold markers. The markers were visible on CT but not MRI. CT, T1-weighted MR, and T2 weighted MR images were taken in four different positions. The markers were contoured on the CT images and rigidly registered to their corresponding MR images. The MR images were deformably registered and the distance between the projected marker location and true marker location was measured as the registration error. RESULTS: The synthetic images were evaluated only on Velocity. Root mean square errors (RMSEs) of 0.76 mm in the left-right (LR) direction, 0.76 mm in the anteroposterior (AP) direction, and 0.69 mm in the superior-inferior (SI) direction were observed for the T1-weighted MR images. RMSEs of 1.1 mm in the LR direction, 0.75 mm in the AP direction, and 0.81 mm in the SI direction were observed for the T2-weighted MR images. The porcine phantom MR images, when evaluated with Velocity, had RMSEs of 1.8, 1.5, and 2.7 mm in the LR, AP, and SI directions for the T1-weighted images and 1.3, 1.2, and 1.6 mm in the LR, AP, and SI directions for the T2-weighted images. When the porcine phantom images were evaluated with the in-house demons-based algorithm, RMSEs were 1.2, 1.5, and 2.1 mm in the LR, AP, and SI directions for the T1-weighted images and 0.81, 1.1, and 1.1 mm in the LR, AP, and SI directions for the T2 weighted images. CONCLUSIONS: The MRI registration error was low for both Velocity and the in-house demons-based algorithm according to both image evaluation methods, with all RMSEs below 3 mm. This implies that both image registration systems can be used for longitudinal studies using MRI. PMID- 28622411 TI - Using automated patch clamp electrophysiology platforms in pain-related ion channel research: insights from industry and academia. AB - : Automated patch clamp (APC) technology was first developed at the turn of the millennium. The increased throughput it afforded promised a new paradigm in ion channel recordings, offering the potential to overcome the time-consuming, low throughput bottleneck, arising from manual patch clamp investigations. This has relevance to the fast-paced development of novel therapies for chronic pain. This review highlights the advances in technology, using select examples that have facilitated APC usage in both industry and academia. It covers both first generation and the latest developments in second-generation platforms. In addition, it also provides an overview of the pain research field and how APC platforms have furthered our understanding of ion channel research and the development of pharmacological tools and therapeutics. APC platforms have much to offer to the ion channel research community, and this review highlights areas of best practice for both academia and industry. The impact of APC platforms and the prospects of ion channel research and improved therapeutics for chronic pain will be evaluated. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 28622412 TI - Textural analysis of early-phase spatiotemporal changes in contrast enhancement of breast lesions imaged with an ultrafast DCE-MRI protocol. AB - PURPOSE: New ultrafast view-sharing sequences have enabled breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to be performed at high spatial and temporal resolution. The aim of this study is to evaluate the diagnostic potential of textural features that quantify the spatiotemporal changes of the contrast-agent uptake in computer-aided diagnosis of malignant and benign breast lesions imaged with high spatial and temporal resolution DCE-MRI. METHOD: The proposed approach is based on the textural analysis quantifying the spatial variation of six dynamic features of the early-phase contrast-agent uptake of a lesion's largest cross-sectional area. The textural analysis is performed by means of the second-order gray-level co-occurrence matrix, gray level run-length matrix and gray-level difference matrix. This yields 35 textural features to quantify the spatial variation of each of the six dynamic features, providing a feature set of 210 features in total. The proposed feature set is evaluated based on receiver operating characteristic (ROC) curve analysis in a cross-validation scheme for random forests (RF) and two support vector machine classifiers, with linear and radial basis function (RBF) kernel. Evaluation is done on a dataset with 154 breast lesions (83 malignant and 71 benign) and compared to a previous approach based on 3D morphological features and the average and standard deviation of the same dynamic features over the entire lesion volume as well as their average for the smaller region of the strongest uptake rate. RESULT: The area under the ROC curve (AUC) obtained by the proposed approach with the RF classifier was 0.8997, which was significantly higher (P = 0.0198) than the performance achieved by the previous approach (AUC = 0.8704) on the same dataset. Similarly, the proposed approach obtained a significantly higher result for both SVM classifiers with RBF (P = 0.0096) and linear kernel (P = 0.0417) obtaining AUC of 0.8876 and 0.8548, respectively, compared to AUC values of previous approach of 0.8562 and 0.8311, respectively. CONCLUSION: The proposed approach based on 2D textural features quantifying spatiotemporal changes of the contrast-agent uptake significantly outperforms the previous approach based on 3D morphology and dynamic analysis in differentiating the malignant and benign breast lesions, showing its potential to aid clinical decision making. PMID- 28622413 TI - Observations from our evaluation of bodyweight changes after initiation of a biologic therapy in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). PMID- 28622414 TI - Reflectance confocal microscopic presentation of basosquamous carcinoma. PMID- 28622415 TI - Is bisphenol A an environmental obesogen? AB - Bisphenol A (BPA) is an endocrine disruptor with an oestrogenic activity that is widely produced for the manufacture of polycarbonate plastic, epoxy resin, and thermal paper. Its ubiquitous presence in the environment contributes to broad and continuous human exposure, which has been associated with deleterious health effects. Despite numerous controversial discussions and a lack of consensus about BPA's safety, growing evidence indicates that BPA exposure positively correlates with an increased risk of developing obesity. An updated analysis of the epidemiological, in vivo, and in vitro studies indicates that BPA should be considered an obesogenic environmental compound. Precisely, BPA exposure during all life stages correlates with increased body weight and/or body mass index. Developmental periods that include prenatal, infancy, and childhood appear to be critical windows with increased sensitivity to BPA effects. Finally, blood analysis and in vitro data clearly demonstrate that BPA promotes adipogenesis, lipid and glucose dysregulation, and adipose tissue inflammation, thus contributing to the pathophysiology of obesity. Future prevention efforts should now be employed to avoid BPA exposure, and more research to determine in depth the critical time windows, doses, and impact of long-term exposure of BPA is warranted in order to clarify its risk assessment. PMID- 28622416 TI - Rosacea and demodicidosis associated with gain-of-function mutation in STAT1. PMID- 28622417 TI - The anti-migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel. AB - BACKGROUND AND PURPOSE: The mechanism of the anti-migraine action of extracts of butterbur [Petasites hybridus (L.) Gaertn.] is unknown. Here, we investigated the ability of isopetasin, a major constituent of these extracts, to specifically target TRPA1 channel and to affect functional responses relevant to migraine. EXPERIMENTAL APPROACH: Single-cell calcium imaging and patch-clamp recordings in human and rodent TRPA1-expressing cells, neurogenic motor responses in rodent isolated urinary bladder, release of CGRP from mouse spinal cord in vitro and facial rubbing in mice and meningeal blood flow in rats were examined. KEY RESULTS: Isopetasin induced (i) calcium responses and currents in rat/mouse trigeminal ganglion (TG) neurons and in cells expressing the human TRPA1, (ii) substance P-mediated contractions of rat isolated urinary bladders and (iii) CGRP release from mouse dorsal spinal cord, responses that were selectively abolished by genetic deletion or pharmacological antagonism of TRPA1 channels. Pre-exposure to isopetasin produced marked desensitization of allyl isothiocyanate (AITC, TRPA1 channel agonist)- or capsaicin (TRPV1 channel agonist)-evoked currents in rat TG neurons, contractions of rat or mouse bladder and CGRP release from mouse central terminals of primary sensory neurons. Repeated intragastric administration of isopetasin attenuated mouse facial rubbing, evoked by local AITC or capsaicin, and dilation of rat meningeal arteries by acrolein or ethanol (TRPA1 and TRPV1 channel agonists respectively). CONCLUSION AND IMPLICATIONS: Activation of TRPA1 channels by isopetasin results in excitation of neuropeptide containing nociceptors, followed by marked heterologous neuronal desensitization. Such atten uation in pain and neurogenic inflammation may account for the anti migraine action of butterbur. PMID- 28622418 TI - Severe apparently isolated fetal ventriculomegaly and neurodevelopmental outcome. AB - OBJECTIVE: Our aim is to assess the neurodevelopmental outcome of children with a prenatal diagnosis of apparently isolated severe ventriculomegaly (SVM). METHOD: This is a retrospective cohort study from 1994 to 2011. We included fetuses with unilateral or bilateral ventriculomegaly equal to or greater than 15 mm at prenatal ultrasound and confirmed by magnetic resonance imaging, whose parents chose continuation of pregnancy past 22 weeks, and with no associated findings at diagnosis (i.e. no brain malformation or cerebral lesions, normal karyotype, no other congenital abnormalities by ultrasound, and negative toxoplasma, rubella, cytomegalovirus, and herpes test. Children were followed up for at least 2 years. Children were classified into three groups: normal, moderate, or severe abnormalities according to psychomotor developmental stages and/or a visual or hearing impairment and/or behavioral disorders. RESULTS: Twenty-one patients fulfilled the study criteria. SVM was diagnosed at an average gestational age of 30 weeks (range 22-37 weeks). Head circumference was >95th centile in 39% of them. The etiology of SVM was intraventricular hemorrhage in 6 (29%), stenosis of the aqueduct of Sylvius in 3 (14%), and undetermined in 12 (57%). Neurosurgery was performed in four infants, and ventriculoperitoneal shunts were inserted in three. At a mean age at last follow-up of 8.4 years, neurodevelopmental outcome was normal in 62% and moderate and severely impaired in 14% and 24% of children, respectively. There was no association between neurologic outcome and severity of ventricular dilation at prenatal imaging, gestational age at initial diagnosis of SVM, or etiology of the ventricular dilatation. CONCLUSION: The majority of children with apparently isolated SVM show normal neurodevelopmental outcome. No prenatal risk factor identify cases at higher risk for severely abnormal neurologic outcome. (c) 2017 John Wiley & Sons, Ltd. PMID- 28622420 TI - Technical Note: Comparison of megavoltage, dual-energy, and single-energy CT based MU-maps for a four-channel breast coil in PET/MRI. AB - PURPOSE: The purpose of this study was to describe and evaluate methods for calculating a megavoltage computed tomography (MVCT)-derived MR hardware attenuation map (MU-map) and dual-energy CT (DECT) for 511 keV photons. METHODS: Phantom measurements were acquired on a whole-body hybrid PET/MRI system, using a four-channel receive-only MR radiofrequency (RF) breast coil. Two acquisitions were performed: with the phantoms positioned in the four-channel RF breast coil, and without the breast coil. PET attenuation from the breast coil was corrected using three different CT-derived hardware MU-maps: (a) Single-energy CT (SECT), (b) DECT, and (c) MVCT. Each attenuation-corrected (AC) PET volume was evaluated and compared with the acquisition performed without the breast coil. RESULTS: The breast coil attenuated PET photons by 10% overall. Threshold values were applied to the SECT MU-map to reduce the effects of metal artifacts, but overcorrection occurred in more highly attenuated regions. The DECT-derived virtual monochromatic image reduced beam-hardening artifacts, but other metal artifacts remained. Despite the remaining metal artifacts in the DECT image, it led to an improvement in the more attenuated regions. The MVCT images appear to be free from metal artifacts leading to an artifact-free MU-map and a further improvement AC-PET images. CONCLUSIONS: Our MVCT-based approach for creating MU-maps for MR RF coils greatly reduces artifacts produced by metal in a SECT approach. This eliminates the need for other artifact reduction methods, including the application of a threshold of narrow beam attenuation coefficients, or disassembling hardware to remove high-Z components before imaging with a kilovoltage source. PMID- 28622419 TI - The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. AB - : Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long-term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10-center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for >=1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5-10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5-10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness >=12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender-Hepatitis B score at baseline or year 5 developed HCC. CONCLUSION: The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially >=50 years), lower platelets, and liver stiffness >=12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444-1453). PMID- 28622421 TI - How to record high-frequency oscillations in epilepsy: A practical guideline. AB - OBJECTIVE: Technology for localizing epileptogenic brain regions plays a central role in surgical planning. Recent improvements in acquisition and electrode technology have revealed that high-frequency oscillations (HFOs) within the 80 500 Hz frequency range provide the neurophysiologist with new information about the extent of the epileptogenic tissue in addition to ictal and interictal lower frequency events. Nevertheless, two decades after their discovery there remain questions about HFOs as biomarkers of epileptogenic brain and there use in clinical practice. METHODS: In this review, we provide practical, technical guidance for epileptologists and clinical researchers on recording, evaluation, and interpretation of ripples, fast ripples, and very high-frequency oscillations. RESULTS: We emphasize the importance of low noise recording to minimize artifacts. HFO analysis, either visual or with automatic detection methods, of high fidelity recordings can still be challenging because of various artifacts including muscle, movement, and filtering. Magnetoencephalography and intracranial electroencephalography (iEEG) recordings are subject to the same artifacts. SIGNIFICANCE: High-frequency oscillations are promising new biomarkers in epilepsy. This review provides interested researchers and clinicians with a review of current state of the art of recording and identification and potential challenges to clinical translation. PMID- 28622422 TI - Patient-reported outcome measures in oral lichen planus: A comprehensive review of the literature with focus on psychometric properties and interpretability. AB - OBJECTIVE: To review the range of patient-reported outcome measures (PROMs) used in clinical studies of patients with oral lichen planus (OLP) and to assess their psychometric properties and interpretability. METHODS: Literature searches were performed on MEDLINE, EMBASE and Web of Science databases (1990-September 2016) to retrieve relevant studies related to the development, psychometric testing and/or use of PROMs assessing oral symptoms, psychosocial status and quality of life in individuals with OLP. The identified PROMs were then categorised by concept measured and assessed for instrument characteristics and evidence for psychometric properties and interpretability. RESULTS: We identified a total of 41 PROMs used in clinical studies for the assessment of patient-reported outcomes in patients with OLP. There were three PROMs of oral symptoms, 30 PROMs of psychosocial status and eight PROMs of quality of life. Six instruments (Visual Analog Scale, Numerical Rating Scale, Change in Symptom Scale, Oral Health Impact Profile-14, Oral Health-related Quality of Life-UK and Chronic Oral Mucosal Disease Questionnaire) demonstrated some evidence of psychometric properties but no evidence for interpretability of their results in the OLP population. CONCLUSION: The range of PROMs used in clinical studies of patients with OLP is wide and include instruments for oral symptoms, psychosocial status and quality of life. The vast majority of these instruments have no evidence of psychometric properties and interpretability for patients with OLP. Further qualitative and validation studies are required to investigate whether these instruments are appropriate for use in this patient population. PMID- 28622423 TI - Congenital dermatofibrosarcoma protuberans clinically mimicking a melanocytic naevus treated with serial excisions. PMID- 28622424 TI - Migration of the distal catheter of the ventriculoperitoneal shunt in hydrocephalus: A Comprehensive Analytical Review from an Anatomical Perspective. AB - There have been many reports on migration of the distal catheter of the ventriculoperitoneal shunt (VPS) since this phenomenon was recognized 50 years ago. However, there have been no attempts to analyze its different patterns or to assess these patterns in terms of potential risk to patients. We comprehensively reviewed all reports of distal VPS catheter migration indexed in PubMed and identified three different anatomical patterns of migration based on catheter extension and organs involved: (1) internal, when the catheter invades any viscus inside the thoracic, abdominal, or pelvic cavity; (2) external, when the catheter penetrates through the body wall either incompletely (subcutaneously) or completely (outside the body); and (3) compound, when the catheter penetrates a hollow viscus and protrudes through a pre-existing anatomical orifice. We also analyzed the association between each migration type and several key factors. External migration occurred mostly in infants. In contrast, internal migration occurred mostly in adults. A body wall weakness was not a risk factor for catheter protrusion. Shunt duration was a critical factor in the migration pattern, as most newly-replaced shunts tended to migrate externally. Clinicians must pay close attention to cases of large bowel perforation, since they were most often associated with intracranial infections. The organ involved in compound migration could determine the route of extrusion, as the bowel was involved in all trans-anal migrations and the stomach in most trans-oral cases. Clin. Anat. 30:821-830, 2017. (c) 2017Wiley Periodicals, Inc. PMID- 28622425 TI - Adalimumab use in patients with psoriasis and hepatitis B: a case series. PMID- 28622426 TI - Experimental study on the friction effect of plastic stents for biliary stone fragmentation (with video). AB - BACKGROUND AND AIM: In patients with irretrievable or intractable bile duct stone, temporary insertion of a plastic stent (PS) followed by further endoscopic retrograde cholangiopancreatography (ERCP) or surgery has been recommended as a 'bridge' therapy. However, the exact mechanism of stone fragmentation has not been discovered. The aim of the present study was to evaluate whether PS shape can facilitate stone fragmentation. METHODS: Using a new in vitro bile flow phantom model, we compared the friction effect among three different PS groups (straight PS group, double pigtail-shaped PS group, and screw-shaped PS group) and a control group. Each group had 10 silicon tube blocks that separately contained one stone and two PS. The control group had 10 blocks each with only a stone and no PS. We carried out analysis of the friction effect by stone weight and volume changes among the groups, excluding fragmented stones. RESULTS: After 8 weeks, complete fragmentation was noted in one out of 34 cholesterol stones (2.9%) and in four out of six pigmented stones (66.7%). Fragmentation tended to be more prominent in the screw-shaped PS group than in the straight PS group, double pigtail-shaped group, and control group (volume change: -11.33%, 7.94%, 4.43%, and 2.05%, respectively, P = 0.1390; weight change: -9.30%, 0.71%, -0.10%, and -1.23%, respectively, P = 0.3553). CONCLUSION: Stone fragmentation may be induced by PS friction effect. Also, screw-shaped plastic stents may improve friction effect. These results may help guide future PS development and clinical decisions. PMID- 28622428 TI - Cutaneous pseudomyogenic (epithelioid sarcoma-like) haemangioendothelioma FOSB immunohistochemistry demonstrating the SERPINE1-FOSB fusion gene. PMID- 28622427 TI - Feasibility study of personalized peptide vaccination for hepatocellular carcinoma patients refractory to locoregional therapies. AB - Overall survival of patients with hepatocellular carcinoma (HCC) refractory to locoregional therapy is dismal, even following treatment with sorafenib, a multikinase inhibitor. To develop a more efficacious treatment, we undertook a feasibility study of personalized peptide vaccination (PPV) for HCC, in which the peptides were selected from 31 peptide candidates based on the pre-existing immunity. Twenty-six HCC patients refractory to locoregional therapies (cohort 1) and 30 patients refractory to both locoregional and systemic therapies (cohort 2) were entered into the study. There were no severe adverse events related to PPV except for one injection site reaction. At the end of the first cycle of six vaccinations, successful CTL or IgG boosting was observed in 57% or 46% of patients in cohort 1 and in 54% or 52% of patients in cohort 2, respectively. Successful IgG boosting at the end of the second cycle was observed in the majority of patients tested. Median overall survival was 18.7 months (95% confidence interval, 12.2-22.5 months) in cohort 1, and 8.5 months (95% confidence interval, 5.9-12.2 months) in cohort 2. Based on the higher rates of immune boosting and the safety profile of PPV, further clinical studies of PPV would be warranted for patients with HCC refractory to not only locoregional therapy but also both locoregional and systemic therapies. The protocol of this study was registered with the UMIN Clinical Trials Registry (UMIN000001882 and UMIN000003590). PMID- 28622429 TI - Synthesis and Antigenic Evaluation of Oligosaccharide Mimics of Vi Antigen from Salmonella typhi. AB - Salmonella typhi is responsible for typhoid fever, which is a serious health threat in developing countries. As a virulent factor of Salmonella typhi, the purified Vi polysaccharide (Vi PS) has become an effective vaccine to combat typhoid fever. The chemical synthesis can provide homogeneous and well-defined molecules for the development of Vi-based vaccines. However, the synthesis of Vi oligosaccharides in high yields and with exclusive alpha-stereoselectivities remains very challenging. In this paper, a series of Vi pseudooligosaccharides, including pseudo tetra-, hexa-, and octa-saccharides were efficiently synthesized. These oligosaccharide analogues were conjugated by carbon chain tether through olefin cross metathesis or by the 1,2,3-triazole moiety through copper (I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC). The binding affinities of these oligosaccharide mimics to anti-Vi antibodies were investigated. These results will be beneficial to the further development of Vi based oligosaccharide vaccines. PMID- 28622430 TI - Enterohaemorrhagic Escherichia coli produces outer membrane vesicles as an active defence system against antimicrobial peptide LL-37. AB - Antimicrobial peptides (AMPs) are important components of the innate immune system. Enterohaemorrhagic Escherichia coli (EHEC), a food-borne pathogen causing serious diarrheal diseases, must overcome attack by AMPs. Here, we show that resistance of EHEC against human cathelicidin LL-37, a primary AMP, was enhanced by butyrate, which has been shown to act as a stimulant for the expression of virulence genes. The increase of resistance depended on the activation of the ompT gene, which encodes the outer membrane protease OmpT for LL-37. The expression of the ompT gene was enhanced through the activation system for virulence genes. The increase in ompT expression did not result in an increase in OmpT protease in bacteria but in enhancement of the production of OmpT-loaded outer membrane vesicles (OMVs), which primarily contributed to the increase in LL 37-resistance. Furthermore, a sublethal dosage of LL-37 stimulated the production of OMVs. Finally, we showed that OMVs produced by OmpT-positive strains protect the OmpT-negative strain, which is susceptible to LL-37 by itself more efficiently than OMVs from the ompT mutant. These results indicate that EHEC enhances the secretion of OmpT-loaded OMVs in coordination with the activation of virulence genes during infection and blocks bacterial cell attack by LL-37. PMID- 28622431 TI - Loss of CDKC;2 increases both cell division and drought tolerance in Arabidopsis thaliana. AB - Drought stress is one of the abiotic stresses that limit plant growth and agricultural productivity. To further understand the mechanism of drought tolerance and identify the genes involved in this process, a genetic screen for altered drought response was conducted in Arabidopsis. One mutant with enhanced drought tolerance was isolated and named Arabidopsis drought tolerance mutant 1 (atdtm1), which has larger lateral organs, prolonged growth duration, increased relative water content and a reduced leaf stomatal density compared with the wild type. The loss of AtDTM1 increases cell division during leaf development. The phenotype is caused by the loss of a T-DNA tagged gene encoding CYCLIN-DEPENDENT KINASE C;2 (CDKC;2), which functions in the regulation of transcription by influencing the phosphorylation status of RNA polymerase II (Pol II). Here, we show that CDKC;2 affects the transcription of downstream genes such as cell cycle genes and genes involved in stomatal development, resulting in altered plant organ size as well as drought tolerance of the plant. These results reveal the crucial role of CDKC;2 in modulating both cell division and the drought response in Arabidopsis. PMID- 28622432 TI - Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma. PMID- 28622433 TI - Research on genodermatoses using novel genome-editing tools. AB - Genodermatoses comprise a clinically heterogeneous group of mostly devastating disorders affecting the skin. To date, treatment options have in general been limited to symptom relief. However, the recent technical evolution in genome editing has ushered in a new era in the development of causal therapies for rare monogenetic diseases such as genodermatoses. The present review revisits the advantages and drawbacks of engineered nuclease tools currently available: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), meganucleases, and - the most innovative - clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) nuclease 9 (CRISPR/Cas9) system. A mechanistic overview of the different modes of action of these programmable nucleases as well as their significance for causal therapy of genodermatoses is presented. Remaining limitations and challenges such as efficient delivery and off-target activity are critically discussed, highlighting both the past and future of gene therapy in dermatology. PMID- 28622435 TI - Single port laparoscopic ileocaecal resection for Crohn's disease: a multicentre comparison with multi-port laparoscopy. AB - AIM: Single port (SP) ileocaecal resection (ICR) is an established technique but there are no large studies comparing SP and multi-port (MP) laparoscopic surgery in Crohn's disease (CD). The aim of this study was to compare postoperative pain scores and analgesia requirements after SP and MP laparoscopic ICR for CD. METHOD: This was a retrospective study of patients undergoing SP or MP ICR for CD in three tertiary referral centres from February 1999 to October 2014. Baseline characteristics (age, sex, body mass index and indication for surgery) were compared. Primary end-points were postoperative pain scores, analgesia requirements and short-term postoperative outcomes. RESULTS: SP ICR (n = 101) and MP ICR (n = 156) patients were included in the study. Visual analogue scale scores were significantly lower after SP ICR on postoperative day 1 (P = 0.016) and day 2 (P = 0.04). Analgesia requirements were significantly reduced on postoperative day 2 in the SP group compared with the MP group (P = 0.007). Duration of surgery, conversion to open surgery and stoma rates were comparable between the two groups. Surgery was more complex in terms of additional procedures when MP was adopted (P = 0.001). There were no differences in postoperative complication rates, postoperative food intake, length of stay and readmissions. CONCLUSION: These data suggest that in comparison to standard laparoscopic surgery SP ICR might be less painful and patients might require less opioid analgesia. PMID- 28622434 TI - Magnetic-activated cell sorting before density gradient centrifugation improves recovery of high-quality spermatozoa. AB - Recent studies have evaluated the use of magnetic-activated cell sorting (MACS) to reduce apoptotic spermatozoa and improve sperm quality. However, the efficiency of using MACS alone, before or after sperm processing by density gradient centrifugation (DGC) has not yet been established. The purpose of this study is to determine the optimal protocol of MACS in assisted reproduction techniques (ART). Thus, we compared sperm quality obtained by DGC alone (DGC), DGC followed by MACS (DGC-MACS), MACS followed by DGC (MACS-DGC), and MACS alone (MACS), and found that the combined methods (MACS-DGC and DGC-MACS) led to retrieval of less spermatozoa with fragmented DNA compared to the single protocols. However, MACS-DGC protocol led to a significantly higher percentage of spermatozoa with progressive motility and normal morphology than DGC-MACS protocol. These findings suggest the potential clinical value of using MACS-DGC to improve sperm quality in seminal preparation for ART. PMID- 28622436 TI - Mechanistic basis for increased human gene targeting by promoterless vectors roles of homology arms and Rad54 paralogs. AB - Gene targeting by homologous recombination provides the definitive tool for analyzing gene function. Promoterless vectors, which do not possess a promoter to drive marker gene expression, confer higher targeting efficiencies than conventional vectors due to the reduced number of drug-resistant clones. We here show that gene-targeting efficiency is typically >= 25% with the use of exon trapping-type promoterless vectors in a human diploid cell line, Nalm-6. The efficiency of exon-trapping gene targeting was correlated with the level of target gene expression when a 2A peptide sequence was linked to the marker gene. Intriguingly, total arm length was not necessarily a determinant of targeting efficiency, as longer arms tend to enhance both homologous (targeted) and nonhomologous (nontargeted) integration of the vector; rather, the presence of an exon in the 5' arm led to a decreased targeting efficiency. Strikingly, loss of Rad54 did not severely affect the targeting efficiency of exon-trap vectors. Moreover, additional deletion of the Rad54 paralog Rad54B had limited impact on the high-efficiency gene targeting. These results indicate that targeted integration occurs in human cells even when both Rad54 and Rad54B are missing. These studies provide additional important insight into the contribution of various DNA repair factors on the targeting mechanics. PMID- 28622437 TI - Detection of halitosis in breath: Between the past, present, and future. AB - To develop a new generation of diagnostics for halitosis, replacing the subjective organoleptic assessment, a series of exhaled breath analyzers has been developed and assessed. All three devices rely on the assessment of exhaled volatile sulfuric compounds (VSCs), which are mainly generated in and emitted from the oral cavity, contributing to the malodor. Portable, on-site and easy to use, these devices have potential for non-invasive diagnosis of halitosis. However, global assessment of exhaled VSCs alone has two main drawbacks: (i) the absence of VSCs does not rule out halitosis; (ii) non-sulfuric volatile compounds that could be biomarkers of systemic diseases, found in up to 15% of halitosis cases, are neglected. In this article, we review and discuss progress to date in the field of oral/exhaled volatile compounds as potential non-invasive diagnostics for halitosis. We will briefly describe the generation of these compounds both from local (oral) and distal (extra-oral) sources. In addition, we debate the different analytical approaches in use and discuss the potential value of bio-inspired artificially intelligent olfaction in diagnosing and classifying oral and systemic diseases by analyzing exhaled breath. PMID- 28622438 TI - GBF1 differentially regulates CAT2 and PAD4 transcription to promote pathogen defense in Arabidopsis thaliana. AB - G-BOX BINDING FACTOR 1 (GBF1) influences light-regulated seedling development in Arabidopsis, and inhibits CATALASE 2 (CAT2) expression during senescence. CAT2 functions as a scavenger of hydrogen peroxide. The role of GBF1 in the defense response is not known. We report here that GBF1 positively influences the defense against virulent and avirulent strains of Pseudomonas syringae. The gbf1 mutants are susceptible, whereas GBF1 over-expresser transgenic plants are resistant to bacterial pathogens. GBF1 negatively regulates pathogen-induced CAT2 expression and thereby positively regulates the hypersensitive response. In addition to CAT2 promoter, GBF1 binds to the G-box-like element present in the intron of PHYTOALEXIN DEFICIENT 4 (PAD4). This association of GBF1 with PAD4 intron is enhanced upon pathogenesis. GBF1 positively regulates PAD4 transcription in an intron-dependent manner. GBF1-mediated positive regulation of PAD4 expression is also evident in gbf1 mutant and GBF1 over-expression lines. Similar to pad4 mutants, pathogen-induced camalexin and salicylic acid (SA) accumulation, and expression of SA-inducible PATHOGENESIS RELATED1 (PR1) gene are compromised in the gbf1 mutant. Exogenous application of SA rescues the loss-of-defense phenotypes of gbf1 mutant. Thus, altogether, our results demonstrate that GBF1 is an important component of the plant defense response that functions upstream of SA accumulation and, by oppositely regulating CAT2 and PAD4, promotes disease resistance in Arabidopsis. PMID- 28622439 TI - Clinical effectiveness of a Bayesian algorithm for the diagnosis and management of heparin-induced thrombocytopenia. AB - : Essentials We previously published a diagnostic algorithm for heparin-induced thrombocytopenia (HIT). In this study, we validated the algorithm in an independent large healthcare system. The accuracy was 98%, sensitivity 82% and specificity 99%. The algorithm has potential to improve accuracy and efficiency in the diagnosis of HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is a life-threatening drug reaction caused by antiplatelet factor 4/heparin (anti-PF4/H) antibodies. Commercial tests to detect these antibodies have suboptimal operating characteristics. We previously developed a diagnostic algorithm for HIT that incorporated 'four Ts' (4Ts) scoring and a stratified interpretation of an anti-PF4/H enzyme-linked immunosorbent assay (ELISA) and yielded a discriminant accuracy of 0.97 (95% confidence interval [CI], 0.93 1.00). Objectives The purpose of this study was to validate the algorithm in an independent patient population and quantitate effects that algorithm adherence could have on clinical care. Methods A retrospective cohort comprised patients who had undergone anti-PF4/H ELISA and serotonin release assay (SRA) testing in our healthcare system from 2010 to 2014. We determined the algorithm recommendation for each patient, compared recommendations with the clinical care received, and enumerated consequences of discrepancies. Operating characteristics were calculated for algorithm recommendations using SRA as the reference standard. Results Analysis was performed on 181 patients, 10 of whom were ruled in for HIT. The algorithm accurately stratified 98% of patients (95% CI, 95-99%), ruling out HIT in 158, ruling in HIT in 10 and recommending an SRA in 13 patients. Algorithm adherence would have obviated 165 SRAs and prevented 30 courses of unnecessary antithrombotic therapy for HIT. Diagnostic sensitivity was 0.82 (95% CI, 0.48-0.98), specificity 0.99 (95% CI, 0.97-1.00), PPV 0.90 (95% CI, 0.56-0.99) and NPV 0.99 (95% CI, 0.96-1.00). Conclusions An algorithm incorporating 4Ts scoring and a stratified interpretation of the anti-PF4/H ELISA has good operating characteristics and the potential to improve management of suspected HIT patients. PMID- 28622440 TI - Chemical Characterization and Biological Activities of Phenolic-Rich Fraction from Cauline Leaves of Isatis tinctoria L. (Brassicaceae) Growing in Sicily, Italy. AB - The present work focused on the evaluation of the antioxidant and cytotoxic activities of the phenolic-rich fraction (ItJ-EAF) obtained from cauline leaves collected in January from Isatis tinctoria L. (Brassicaceae) growing wild around Acireale (Sicily, Italy). The total phenolic, flavonoid, and condensed tannin contents of the fraction were determined spectrophotometrically, whereas the phenolic profile was assessed by HPLC-PDA/ESI-MS analysis. A total of 20 compounds were positively identified and twelve out of them were never previously reported in I. tinctoria leaves. The fraction exhibited good radical scavenging activity in DPPH test (IC50 = 0.6657 +/- 0.0024 mg/ml) and reducing power (3.87 +/- 0.71 ASE/ml), whereas, it neither showed chelating activity nor was able to counteract H2 O2 induced oxidative stress damage in Escherichia coli. The antiproliferative effect was evaluated in vitro on two human anaplastic thyroid carcinoma cell lines (CAL-62 and 8505C) by MTT assay. At the highest tested concentration ItJ-EAF significantly reduced (80%) the growth of CAL-62 cells. No cytotoxicity against Artemia salina was observed. It can be concluded that I. tinctoria cauline leaves represent a source of phenolic compounds which could be potentially used as chemopreventive or adjuvant agents against cancer. PMID- 28622442 TI - Muscular Basis of Whisker Torsion in Mice and Rats. AB - Whisking mammals move their whiskers in the rostrocaudal and dorsoventral directions with simultaneous rolling about their long axes (torsion). Whereas muscular control of the first two types of whisker movement was already established, the anatomic muscular substrate of the whisker torsion remains unclear. Specifically, it was not clear whether torsion is induced by asymmetrical operation of known muscles or by other largely unknown muscles. Here, we report that mystacial pads of newborn and adult rats and mice contain oblique intrinsic muscles (OMs) that connect diagonally adjacent vibrissa follicles. Each of the OMs is supplied by a cluster of motor end plates. In rows A and B, OMs connect the ventral part of the rostral follicle with the dorsal part of the caudal follicle. In rows C-E, in contrast, OMs connect the dorsal part of the rostral follicle to the ventral part of the caudal follicle. This inverse architecture is consistent with previous behavioral observations [Knutsen et al.: Neuron 59 (2008) 35-42]. In newborn mice, torsion occurred in irregular single twitches. In adult anesthetized rats, microelectrode mediated electrical stimulation of an individual OM that is coupled with two adjacent whiskers was sufficient to induce a unidirectional torsion of both whiskers. Torsional movement was associated with protracting movement, indicating that in the vibrissal system, like in the ocular system, torsional movement is mechanically coupled to horizontal and vertical movements. This study shows that torsional whisker rotation is mediated by specific OMs whose morphology and attachment sites determine rotation direction and mechanical coupling, and motor innervation determines rotation dynamics. Anat Rec, 300:1643-1653, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28622441 TI - Cardiovascular mortality among liver transplant recipients with nonalcoholic steatohepatitis in the United States-a retrospective study. AB - Nonalcoholic steatohepatitis (NASH) has become an increasingly important indication for liver transplantation (LT), and there has been a particular concern of excessive cardiovascular-related mortality in this group. Using the United Network for Organ Sharing-Standard Transplant Analysis and Research (UNOS STAR) dataset, we reviewed data on 56,995 adult transplants (January 2002 through June 2013). A total of 3,170 NASH liver-only recipients were identified and were matched with 3,012 non-NASH HCV+ and 3,159 non-NASH HCV- controls [matched 1:1 based on gender, age at LT (+/-3 years), and MELD score (+/-3)]. Cox regression analysis revealed significantly lower hazard of all-cause (HR 0.669; P < 0.0001) and cardiovascular-related mortality (HR 0.648; P < 0.0001) in the NASH compared to the non-NASH group after adjusting for diabetes, BMI, and race. Relative to the non-NASH HCV-positive group, NASH group has lower hazard of all-cause (HR 0.539; P < 0.0001) and cardiovascular-related mortality (HR 0.491; P < 0001). A lower hazard of all-cause mortality (HR 0.844; P = 0.0094) was also observed in NASH patients compared to non-NASH HCV-negative group, but cardiovascular mortality was similar (HR 0.892; P = 0.3276). LT recipients with NASH have either lower or similar risk of all-cause and cardiovascular-related mortality compared to its non-NASH counterparts after adjusting for diabetes, BMI, and race. PMID- 28622443 TI - miR-2909 regulates ISGylation system via STAT1 signalling through negative regulation of SOCS3 in prostate cancer. AB - One of the well-document strategies adopted by tumour cells for progression is to evade immune surveillance mechanisms. An understanding of the tight interaction between immunity and progression of cancer can provide novel treatment options for different malignancies including prostate cancer (PCa). Here, we have shown that AATF genome encoded miR-2909, known to play role both in immunity and cancer upregulates various interferon stimulating genes (ISGs) including ISGylation system through STAT1. Our results revealed that miR-2909 up-regulates STAT1 through negative regulation of SOCS3 and not through up-regulation of Type 1 interferon (IFN) production. It was observed that inhibition of ISGylation reduced the proliferation potential of PCa cells. Furthermore, androgens were found to negatively regulate ISGylation in LNCaP cells through androgen receptor signalling independently of miR-2909. TGF-beta mediated SMAD3 signalling was also seen to be suppressed by miR-2909 through induction of SMAD7 via enhanced STAT1 expression. Collectively, these studies suggest that miR-2909 could play a vital role in prostate carcinogenesis through modulation of ISGylation system and TGFbeta signalling via STAT1. PMID- 28622444 TI - Paraneoplastic pemphigus in two pairs of brothers. PMID- 28622445 TI - Palladium-Catalyzed Enantioselective Narasaka-Heck Reaction/Direct C-H Alkylation of Arenes: Iminoarylation of Alkenes. AB - A palladium-catalyzed reaction of gamma,delta-unsaturated oxime esters with oxadiazoles afforded dihydropyrroles in good to excellent yields through an intramolecular iminopalladation/intermolecular direct heteroarene C-H alkylation cascade. This unprecedented iminoarylation of alkenes was subsequently realized in an enantioselective manner in the presence of a chiral bidentate phosphine ligand (Synphos). PMID- 28622446 TI - Dermal melanoma arising in a congenital large plaque-type blue nevus. PMID- 28622447 TI - Does Sexual Selection Influence Ornamentation of Hemipenes in Old World Snakes? AB - In the present study, we investigated and documented the morphology of the male copulatory organs (hemipenes) in fifteen wide-ranging snake species. The species represent four families (Boidae, Colubridae, Lamprophiidae, and Viperidae) and ten genera. We applied the same preparation techniques for all species, successfully everting and expanding the organs completely. The detailed description of the general morphology of the male copulatory organs was based on 31 specimens. Our data were compared with published observations and we point out some incorrectly described details in previous investigations. We provide the first description of the hemipenial morphology for three ophidian species (Elaphe sauromates, Telescopus fallax, and Malpolon insignitus). In addition to the morphological characteristics of the hemipenes presented in the research, we propose the adoption of a standardized index describing the hemipenial proportions. The immense variation in hemipenial morphology presupposes its dynamic evolution, but we suggest that many of the significant structures observed here may have escaped previous researchers due to differing methodologies. Some of the highly ornamented morphologies that we describe are consistent with a locking mechanism during copulation. However, other morphologies may relate to the variety of mating behaviors observed. As a result, we propose that sexual selection is the major driver affecting the hemipenial ornamentation in snakes. Anat Rec, 300:1680-1694, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28622449 TI - Methods for cell volume measurement. AB - Volume is an essential characteristic of a cell, and this review describes the main methods of its measurement that have been used in the past several decades. The discussed methods include various implementations of light scattering, estimates based on one or two cell dimensions, surface scanning, fluorescence confocal and transmission slice-by-slice imaging, intracellular volume markers, displacement of extracellular solution, quantitative phase imaging, radioactive methods, and some others. Suitability of these methods to some typical samples and applications is discussed. (c) 2017 International Society for Advancement of Cytometry. PMID- 28622448 TI - Ileocaecal valve syndrome after surgery in adult patients: myth or reality? AB - AIM: The onset of symptoms after removal of the ileocaecal valve (ICV) may be perceived as an unwanted effect of surgery and induce patients to bring unnecessary litigation against surgeons. The aim of our study is to assess the real impact on the quality of life of patients whose ICV has been surgically removed, using three validated questionnaires. METHOD: In patients who had their ICV removed surgically, the Gastrointestinal Quality of life (GIQLI) questionnaire and those used by the European Organization for research and Treatment of Cancer (EORTC) were administered before and after surgery. The empirical rule effect size method was used to evaluate the clinical significance of the statistical data. RESULTS: We interviewed 225 patients. Data collected through the three questionnaires highlighted a trend towards postoperative improvement of the selected gastrointestinal symptoms compared with the baseline. The GIQLI questionnaire showed a statistically significant improvement in 'pain', 'nausea' and 'constipation' during the follow-up. Constipation appeared more frequently in patients older than 70 years compared with younger ones. The EORTC QLQ-C30 questionnaire showed a significant correlation between diarrhoea and extended right colectomy at 3 months after surgery, which was not confirmed at 6 months. The EORTC QLQ-CR29 questionnaire showed a slight deterioration of 'leakage of stools from the anal opening' at 6 months after surgery, but this symptom was not deemed clinically significant. CONCLUSION: We found that bowel functions in most patients after surgical removal of the ICV were satisfactory. Providing patients with a comprehensive and exhaustive informed consent during preoperative consultations could promote patient trust and avoid misunderstandings. PMID- 28622451 TI - Clinical Images: Ochronotic arthropathy. PMID- 28622450 TI - Large oesophageal varice screening by a sequential algorithm using a cirrhosis blood test and optionally capsule endoscopy. AB - BACKGROUND & AIMS: Large oesophageal varice (LEV) screening is recommended in cirrhosis. We performed a prospective study to improve non-invasive LEV screening. DESIGN: 287 patients with cirrhosis had upper gastrointestinal endoscopy (LEV reference), oesophageal capsule endoscopy (ECE), liver elastography and blood marker analyses. CirrhoMeter (cirrhosis blood test), the most accurate non-invasive LEV test, was segmented for cirrhosis (reference comparator) or LEV. VariScreen, a sequential and partially minimally invasive diagnostic algorithm, was developed by multivariate analysis. It uses CirrhoMeter first, then ECE if CirrhoMeter cannot rule LEV out or in, and finally endoscopy if CirrhoMeter+ECE combination remains uninformative. RESULTS: Diagnostic effectiveness rates for LEV were: cirrhosis-segmented CirrhoMeter: 14.6%, LEV segmented CirrhoMeter: 34.6%, ECE: 60.6% and VariScreen: 66.4% (P <= .001 for overall or pair comparison). The respective missed LEV rates were: 2.8%, 5.6%, 8.3% and 5.6% (P = .789). Spared endoscopy rates were, respectively: 15.6%, 36.0%, 70.6% and 69%, (P < .001 for overall or paired comparison except ECE vs VariScreen: P = .743). VariScreen spared 38% of ECE and reduced missed LEV by 87% compared to classical ECE performed in all patients. Excepting cirrhosis segmented CirrhoMeter, these spared endoscopy rates were significantly higher than that of the Baveno VI recommendation (using platelets and Fibroscan): 18.4% (P < .001). Ascites and Child-Pugh class independently predicted endoscopy sparing by VariScreen: from 86.0% in compensated Child Pugh class A to 24.1% in Child-Pugh class C with ascites. CONCLUSION: VariScreen algorithm significantly reduced the missed LEV rate with ECE by 87%, ECE use by 38% and endoscopy requirement by 69%, and even 86% in compensated cirrhosis. PMID- 28622452 TI - A Seasonal and Age-Related Study of Interstitial Cells in the Pineal Gland of Male Viscacha (Lagostomus maximus maximus). AB - The pineal gland of viscacha exhibits histophysiological variations throughout the year, with periods of maximal activity in winter and minimal activity in summer. The aim of this work is to analyze the interstitial cells (IC) in the pineal gland of male viscachas in relation to season and age. The S-100 protein, glio-fibrillary acidic protein (GFAP), and vimentin were detected in adult and immature animals by immunohistochemistry (IHC). Double-IHC was also performed. The S-100 protein was localized within both, IC nucleus and cytoplasm. GFAP was present only in the cytoplasm. Vimentin was expressed in some IC, besides endothelial cells, and perivascular spaces. In the adult males, the morphometric parameters analyzed for the S-100 protein and GFAP exhibited seasonal variations with higher values of immunopositive area percentage in winter and lower values in summer, whereas the immature ones showed the lowest values for all the adult animals studied. Colocalization of S-100 protein and GFAP was observed. The IC exhibited differential expression for the proteins studied, supporting the hypothesis of the neuroectodermal origin. The IC generate an intraglandular communication network, suggesting its participation in the glandular activity regulation processes. The results of double-IHC might indicate the presence of IC in different functional stages, probably related to the needs of the cellular microenvironment. The morphometric variations in the proteins analyzed between immature and adult viscachas probed to be more salient in the latter, suggesting a direct relationship between the expression of the S-100 protein and GFAP, and animal age. Anat Rec, 2017. (c) 2017 Wiley Periodicals Inc. Anat Rec, 300:1847 1857, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28622453 TI - Plasmablasts With a Mucosal Phenotype Contribute to Plasmacytosis in Systemic Lupus Erythematosus. AB - OBJECTIVE: To analyze the composition of known plasmacytosis in systemic lupus erythematosus (SLE) to obtain further insight into the nature of underlying mechanisms. METHODS: Plasmablasts from patients with active SLE, patients with inactive/treated SLE, and healthy controls were characterized by flow cytometry, enzyme-linked immunospot assay, and Transwell migration assays and compared to vaccination-induced plasmablasts. Serum cytokine levels were analyzed by Luminex assay, and histologic analysis of kidney biopsy specimens was performed. RESULTS: Circulating plasmablasts in SLE expressed markers of mucosal immune reactions. IgA, CCR10, and beta7 integrin were expressed by 48%, 40%, and 38% of plasmablasts, respectively, with varying coexpression patterns. Consistent with mucosal homing, some SLE plasmablasts migrated toward the mucosal chemokine CCL28 and secreted polymeric IgA. SLE plasmablasts shared phenotypic characteristics with antigen-specific plasmablasts induced by oral, but not parenteral, vaccinations. Autoreactive antibody-secreting cells of the IgG and IgA isotypes were detectable, but only the emergence of phenotypically mucosal plasmablasts was positively associated with serum interleukin-2 and platelet-derived growth factor BB levels. CONCLUSION: Our data suggest that distinct plasmablast differentiation pathways jointly contribute to peripheral plasmacytosis in SLE, i.e., a cytokine-amplified mucosal "steady-state" plasmablast response, and an autoreactive plasmablast response, representing conventional autoimmunity. Our results indicate an overly activated mucosal immune system in patients with SLE, with both immunologic and clinical implications. PMID- 28622454 TI - Treatment of Rheumatoid Arthritis With Anti-Tumor Necrosis Factor or Tocilizumab Therapy as First Biologic Agent in a Global Comparative Observational Study. AB - OBJECTIVE: To compare clinical effectiveness between tocilizumab and tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) and inadequate response to conventional synthetic disease-modifying antirheumatic drugs initiating biologic therapy. METHODS: Patients prescribed tocilizumab (intravenous) or TNFi were prospectively observed in routine clinical practice for 52 weeks across 158 sites in 26 countries. The primary observation was the change from baseline in Disease Activity Score based on 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) at week 24 using analysis of covariance for between-groups comparison. Secondary end points included Clinical Disease Activity Index (CDAI) and patient-reported outcomes at weeks 24 and 52. RESULTS: Of 1,216 patients, 35% initiated tocilizumab and 65% initiated TNFi. RA duration was shorter, and disease activity and corticosteroid use were higher in tocilizumab patients. Tocilizumab-treated patients had greater improvement in DAS28-ESR at weeks 24 and 52 (week 24 difference [95% confidence interval] in adjusted means: -0.831 [-1.086, -0.576]; P < 0.001). Change from baseline in CDAI was also greater with tocilizumab (adjusted means difference: week 24, -3.48; week 52, -4.60; both P < 0.001). Tocilizumab-treated patients had more improvement in the Health Assessment Questionnaire disability index than TNFi treated patients (P < 0.05). The cumulative probability of drug discontinuation at week 52 was lower with tocilizumab (15%) than TNFi (27%; P < 0.001, unadjusted analysis). Unadjusted frequencies (events per 100 patient-years) for tocilizumab and TNFi were 6.44 and 11.99 for serious adverse events, 1.98 and 5.03 for serious infections, and 0.74 and 0.77 for deaths, respectively. CONCLUSION: Patients initiating tocilizumab experienced greater effectiveness and drug survival than those initiating TNFi in an observational setting. PMID- 28622456 TI - Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjogren's Syndrome: Potential New Axis in Lymphoid Neogenesis. AB - OBJECTIVE: Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjogren's syndrome (SS). CCR9-expressing T helper cells have "Tfh-like" characteristics and their numbers are increased at mucosa-associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS. METHODS: Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non-SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties. RESULTS: CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non-SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin-21 (IL-21) and soluble IL-7 receptor alpha-chain (IL-7Ralpha). Furthermore, the frequency of CCR9-expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL-7Ralpha and secreted higher levels of interferon-gamma, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9-CXCR5- T helper cells. CONCLUSION: Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease. PMID- 28622457 TI - Social Role Participation and Satisfaction With Life: A Study Among Patients With Ankylosing Spondylitis and Population Controls. AB - OBJECTIVE: Participation in society of persons with chronic diseases receives increasing attention. However, little is known about which components of participation are most relevant to life satisfaction. This study examines the association between several aspects of social role participation and satisfaction with life (SWL) in patients with ankylosing spondylitis (AS) compared to population controls. METHODS: In a cross-sectional study, participants completed the Social Role Participation Questionnaire (SRPQ) and SWL scale. The SRPQ assesses several dimensions of participation (importance, satisfaction with performance, and satisfaction with time and physical difficulty) in 11 roles representing 3 domains (interpersonal relations, leisure, and work). For individuals with AS and controls, the association between role domains and SWL was examined using linear regression for each participation dimension separately, in the total and the employed population, adjusting for age, sex, education, and income. RESULTS: A total of 246 AS patients (mean +/- SD age 51 +/- 12 years, 62% males, mean +/- SD disease duration 17 +/- 12 years) and 510 controls (mean +/- SD age 42 +/- 15 years, 70% males) were included. AS patients were more frequently (extremely) dissatisfied with life (17.9% versus 8.6%; P < 0.05). In the total and the employed population, less physical difficulty and higher satisfaction with interpersonal relations and leisure were associated with higher SWL, and this was somewhat stronger in patients than in controls (P < 0.1). In employed controls, but not in employed patients, satisfaction with work was independently associated with SWL. CONCLUSION: These findings highlight the importance of supporting persons with AS in ameliorating social role participation, particularly in areas like close relationships and leisure activities, which are typically ignored when treating AS. PMID- 28622455 TI - Intestinal Metabolites Are Profoundly Altered in the Context of HLA-B27 Expression and Functionally Modulate Disease in a Rat Model of Spondyloarthritis. AB - OBJECTIVE: HLA-B27-associated spondyloarthritides are associated with an altered intestinal microbiota and bowel inflammation. We undertook this study to identify HLA-B27-dependent changes in both host and microbial metabolites in the HLA B27/beta2 -microglobulin (beta2 m)-transgenic rat and to determine whether microbiota-derived metabolites could impact disease in this major model of spondyloarthritis. METHODS: Cecal contents were collected from Fischer 344 33-3 HLA-B27/beta2 m-transgenic rats and wild-type controls at 6 weeks (before disease) and 16 weeks (with active bowel inflammation). Metabolomic profiling was performed by high-throughput gas and liquid chromatography-based mass spectrometry. HLA-B27/beta2 m-transgenic rats were treated with the microbial metabolites propionate or butyrate in drinking water for 10 weeks, and disease activity was subsequently assessed. RESULTS: Our screen identified 582 metabolites, of which more than half were significantly altered by HLA-B27 expression at 16 weeks. Both microbial and host metabolites were altered, with multiple pathways affected, including those for amino acid, carbohydrate, xenobiotic, and medium-chain fatty acid metabolism. Differences were even observed at 6 weeks, with up-regulation of histidine, tyrosine, spermidine, N acetylmuramate, and glycerate in HLA-B27/beta2 m-transgenic rats. Administration of the short-chain fatty acid propionate significantly attenuated HLA-B27 associated inflammatory disease, although this was not associated with increased FoxP3+ T cell induction or with altered expression of the immunomodulatory cytokines interleukin-10 (IL-10) or IL-33 or of the tight junction protein zonula occludens 1. HLA-B27 expression was also associated with altered host expression of messenger RNA for the microbial metabolite receptors free fatty acid receptor 2 (FFAR2), FFAR3, and niacin receptor 1. CONCLUSION: HLA-B27 expression profoundly impacts the intestinal metabolome, with changes evident in rats even at age 6 weeks. Critically, we demonstrate that a microbial metabolite, propionate, attenuates development of HLA-B27-associated inflammatory disease. These and other microbiota-derived bioactive mediators may provide novel treatment modalities in HLA-B27-associated spondyloarthritides. PMID- 28622458 TI - Bullous pemphigoid associated with silicosis. PMID- 28622459 TI - Structural plasticity among glutathione transferase Phi members: natural combination of catalytic residues confers dual biochemical activities. AB - : The glutathione transferase (GST) gene family is divided into 14 classes in photosynthetic organisms. Among them, the Phi class (GSTF) is composed of a large number of genes that are often induced in response to environmental constraints due to their ability to detoxify xenobiotics, to their peroxidase activity and to their involvement in the biosynthesis and/or transport of secondary metabolites. However, the exact functions of GSTFs from many plants including Populus trichocarpa are unknown. Here, following GSTF1 characterization, we have performed a comparative analysis of the seven other GSTFs found in poplar by systematically evaluating the biochemical and enzymatic properties of the corresponding recombinant proteins and of variants mutated for active site residues and by determining the three-dimensional structures of several representatives. Owing to the presence of a cysteine with a pKa value around 5 in their active site, GSTF3, F7, and F8 displayed a thiol transferase activity in addition to the usual glutathione transferase and peroxidase activities. From structural analyses, it appeared that these dual biochemical properties originate from the existence of a certain variability in the beta1-alpha1 loop. This allows positioning of several active site residues at proximity of the glutathione molecule, which itself remains unchanged in GSTF three-dimensional structures. These results highlight the promiscuity of some GSTFs and that changes of active site residues in some isoforms during evolution generated functional diversity by modifying their activity profile. DATABASE: Structural data are available in the PDB under the accession numbers 5EY6, 5F05, 5F06, and 5F07. PMID- 28622460 TI - Antifungal activity of tyrosol and farnesol used in combination against Candida species in the planktonic state or forming biofilms. AB - AIM: This study examined the antifungal activity of the combination of tyrosol and farnesol against Candida albicans and Candida glabrata in the planktonic state or forming biofilms. METHODS AND RESULTS: The effect of drug association against Candida planktonic cells was assessed by the fractional inhibitory concentration index. Mono- and dual-species biofilms were developed during 24 h and then treated with the compounds for 3 days, with two daily treatments of 1 min each. After, the total biomass, metabolic activity and the number of cultivable cells were quantified. Planktonic cells of the two species showed a similar susceptibility to the drug combination, however, a synergistic effect was only verified for C. glabrata. Regarding biofilm susceptibility, significant reductions in C. glabrata biomass, metabolism of C. albicans and mixed biofilms, and cultivable cells of single biofilms were verified for the drug combination, indicating an additive effect. For all other experiments, the effects were classified as indifferent. CONCLUSION: The combined use of tyrosol and farnesol was advantageous for some of the analysed parameters against Candida species. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings may contribute to the development of oral care products containing tyrosol and farnesol to combat oral infections caused by Candida species. PMID- 28622461 TI - Co-Occurrence and Characteristics of Patients With Axial Spondyloarthritis Who Meet Criteria for Fibromyalgia: Results From a UK National Register. AB - OBJECTIVE: To estimate the proportion of patients with axial spondyloarthritis (SpA) in a UK national biologics registry who met criteria for fibromyalgia (FM), and to delineate the characteristics of these patients. METHODS: Two cohorts of patients are prospectively recruited from across 83 centers in the UK for the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS). All patients are required to meet Assessment of SpondyloArthritis international Society (ASAS) criteria for axial SpA. Patients are either newly starting biologic therapy (biologics cohort) or are naive to treatment with biologic agents (non-biologics cohort) at the time of recruitment, and all patients are followed up prospectively. At recruitment and follow-up, clinical information and measurements are recorded while patients complete the 2011 research criteria for FM and assessments of the level of disease activity and work impact. RESULTS: Of the patients registered in the BSRBR-AS, 1,504 (68% male) were eligible for the current analysis, of whom 311 (20.7%) met the 2011 research criteria for FM. Prevalence of FM was similar between patients who fulfilled the modified New York criteria for AS (19.7%) and those who fulfilled ASAS imaging criteria but not the modified New York criteria (25.2%); however, among those who fulfilled only the ASAS clinical criteria, the prevalence of FM was lower (9.5%). Patients who met FM criteria reported significantly worse disease activity, function, global severity scores, and quality of life, and were more likely to have moderate or severe levels of mood disorder and clinically important fatigue. Patients who met FM criteria reported experiencing work impairment around half their working time. Meeting FM criteria was not related to elevated C-reactive protein levels or most extraspinal manifestations, but was associated with a higher likelihood of having received biologic therapy. CONCLUSION: Developing management approaches that would address the significant unmet clinical needs of the 1 in 5 patients with axial SpA who meet criteria for FM should be a research priority. PMID- 28622462 TI - Determinants of Perceived Health Nonimprovement in Early Rheumatoid Arthritis Patients With Favorable Treatment Outcomes. AB - OBJECTIVE: To explore the association between achieving favorable clinical outcomes and patients' perceived change in overall health status after 12 months of treat-to-target in patients with early rheumatoid arthritis (RA) and to identify determinants of subjective nonimprovement. METHODS: Baseline and 12 month data of patients included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study with at least a moderate response (by European League Against Rheumatism criteria) after 1 year were selected for analysis. Logistic regression analysis was used to identify factors associated with nonimproved perceived overall health status at 12 months. RESULTS: At 12 months, 75 of 210 patients (35%) did not consider their health to have improved despite having achieved favorable clinical outcomes. Relative change from baseline in pain (Wald = 20.20; P < 0.01) and fatigue (Wald = 5.58; P = 0.02) was independently associated with nonimproved perceived overall health status. The results were similar when only patients with <=1 swollen joint were analyzed. An improvement of 55% in pain measured on a visual analog scale was found to discriminate reasonably well between patients who considered their health to have improved versus patients who did not, with an area under the receiver operating characteristic curve of 0.70 (95% confidence interval 0.61-0.78). CONCLUSION: These results demonstrate that clinical improvements do not equate with improved subjective health for all patients. The association of nonimprovement with changes in pain and fatigue suggest that it might be worthwhile to monitor and address pain and fatigue in addition to and independently of disease activity in early RA. PMID- 28622463 TI - Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials. AB - OBJECTIVE: JAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK-1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors. METHODS: In two 4-week exploratory, double-blind, placebo-controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS-6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4. RESULTS: Treatment with filgotinib at 75 300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C-reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30-300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK-2 inhibition related], no effects on liver transaminases, and no increase in low-density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK-1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea. CONCLUSION: Selective inhibition of JAK-1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies. PMID- 28622465 TI - Validation of maternal and neonatal tetanus elimination in Equatorial Guinea, 2016. PMID- 28622464 TI - The impact of drugs on male fertility: a review. AB - Beside cytotoxic drugs, other drugs can impact men's fertility through various mechanisms. Via the modification of the hypothalamic-pituitary-gonadal axis hormones or by non-hormonal mechanisms, drugs may directly and indirectly induce sexual dysfunction and spermatogenesis impairment and alteration of epididymal maturation. This systematic literature review summarizes existing data about the negative impact and associations of pharmacological treatments on male fertility (excluding cytotoxic drugs), with a view to making these data more readily available for medical staff. In most cases, these effects on spermatogenesis/sperm maturation/sexual function are reversible after the discontinuation of the drug. When a reprotoxic treatment cannot be stopped and/or when the impact on semen parameters/sperm DNA is potentially irreversible (Sulfasalazine Azathioprine, Mycophenolate mofetil and Methotrexate), the cryopreservation of spermatozoa before treatment must be proposed. Deleterious impacts on fertility of drugs with very good or good level of evidence (Testosterone, Sulfasalazine, Anabolic steroids, Cyproterone acetate, Opioids, Tramadol, GhRH analogues and Sartan) are developed. PMID- 28622466 TI - Dissolved CO2 Increases Breakthrough Porosity in Natural Porous Materials. AB - When reactive fluids flow through a dissolving porous medium, conductive channels form, leading to fluid breakthrough. This phenomenon is caused by the reactive infiltration instability and is important in geologic carbon storage where the dissolution of CO2 in flowing water increases fluid acidity. Using numerical simulations with high resolution digital models of North Sea chalk, we show that the breakthrough porosity is an important indicator of dissolution pattern. Dissolution patterns reflect the balance between the demand and supply of cumulative surface. The demand is determined by the reactive fluid composition while the supply relies on the flow field and the rock's microstructure. We tested three model scenarios and found that aqueous CO2 dissolves porous media homogeneously, leading to large breakthrough porosity. In contrast, solutions without CO2 develop elongated convective channels known as wormholes, with low breakthrough porosity. These different patterns are explained by the different apparent solubility of calcite in free drift systems. Our results indicate that CO2 increases the reactive subvolume of porous media and reduces the amount of solid residual before reactive fluid can be fully channelized. Consequently, dissolved CO2 may enhance contaminant mobilization near injection wellbores, undermine the mechanical sustainability of formation rocks and increase the likelihood of buoyance driven leakage through carbonate rich caprocks. PMID- 28622467 TI - H2O Adsorption on WO3 and WO3-x (001) Surfaces. AB - The nature of the interaction of water with the WO3 surface is of crucial importance for the use of this semiconductor oxide in photocatalysis. In this work, we investigate water adsorption and dissociation on both clean and O deficient (001) WO3 surfaces by means of an accurate DFT approach. The O vacancy formation energy (computed with respect to O2) has been evaluated for all possible surface configurations, and the removal of the terminal O atom along the c axis is found to be preferred, costing about half the corresponding energy in the bulk. The presence of oxygen vacancies leads to a semiconductor to metal transition, confirming the experimental evidence of n-type conductivity in defective WO3 films. H2O preferably adsorbs on WO3 in a molecular undissociated form, due to the presence of W ions at the surface that act as Lewis acid sites. This interaction, about -1 eV per H2O molecule, is not very strong. Contrary to what is usually expected, the presence of oxygen vacancies does not significantly affect H2O adsorption. Finally, we investigated the H2O desorption from a hydroxylated surface. This suggests that the exposure of WO3 to H2 directly results in a hydroxylated surface and the corresponding H2O desorption turns out to be a very efficient mechanism to generate a reduced oxide surface, with important consequences on the electronic structure of this oxide. PMID- 28622468 TI - Theoretical Evaluation of [VIV(alpha-C3S5)3]2- as Nuclear-Spin-Sensitive Single Molecule Spin Transistor. AB - In a straightforward application of molecular nanospintronics to quantum computing, single-molecule spin transistors can be used to measure nuclear spin qubits. Conductance jumps accompany electronic spin flips at the so-called anticrossings between energy levels, which take place only at specific magnetic fields determined by the nuclear spin state. To date, the only molecular hardware employed for this technique has been the terbium(III) bis(phthalocyaninato) complex. Here we explore theoretically whether a similar behavior is expected for a highly stable molecular spin qubit, the vanadium tris-dithiolate complex [VIV(alpha-C3S5)3]2-. We consider such a molecule between two gold electrodes and determine the spin-dependent conductance. We verify that the transport channel in experimental conditions does not overlap with the occupied spin orbitals, indicating that the spin states may survive in the conduction regime. We validate the robustness of the theoretical methodology by studying two chemically related vanadium complexes and offer some criteria to guide the experiments. PMID- 28622469 TI - Free Energy Calculations of Microcin J25 Variants Binding to the FhuA Receptor. AB - Computer simulations were performed to study the antimicrobial peptide microcin J25 (MJ25), a 21-mer peptide with an unusual lasso structure and high activity against Gram-negative bacteria. MJ25 has intracellular targets. The initial step of MJ25 acquisition in bacterial cells is binding to the outer-membrane receptor FhuA. Molecular dynamics simulations were implemented to study the binding mechanism of MJ25 to FhuA and to search for important binding residues. The absolute binding free energy calculated from combined free energy perturbation and thermodynamic integration methods agrees well with experimental data. In addition, computational mutation analysis revealed that His5 is the key residue responsible for MJ25 and FhuA association. We found that the number of hydrogen bonds is essential for binding of MJ25 to FhuA. This atomistic, quantitative insight sheds light on the mechanism of action of MJ25 and may pave a path for designing active MJ25 analogues. PMID- 28622470 TI - Patterned Photonic Nitrocellulose for Pseudopaper ELISA. AB - We report an enzyme-link immunosorbent assay (ELISA) based on patterned pseudopaper that is made of photonic nitrocellulose for highly sensitive fluorescence bioanalysis. The pseudopaper is fabricated using self-assembled monodisperse SiO2 nanoparticles that are patterned on a polypropylene substrate as template. The self-assembled nanoparticles have a close-packed hexagonal (opal) structure, so the resulting nitrocellulose has a complementary (inverse opal) photonic structure. Owing to the slow-photon effect of the photonic structure, fluorescence emission for ELISA is enhanced by up to 57-fold without increasing the assay time or complexity. As the detection signal is significantly amplified, a simple smartphone camera suffices to serve as the detector for rapid and on-site analysis. As a demonstration, human IgG is quantitatively analyzed with a detection limit of 3.8 fg/mL, which is lower than that of conventional ELISA and paper-based ELISA. The consumption of sample and reagent is also reduced by 33 times compared with conventional ELISA. Therefore, the pseudopaper ELISA based on patterned photonic nitrocellulose is promising for sensitive, high throughput bioanalysis. PMID- 28622471 TI - Coacervate of Polyacrylamide and Cationic Gemini Surfactant for the Extraction of Methyl Orange from Aqueous Solution. AB - Coacervation in aqueous solution of the mixture of cationic ammonium surfactant hexamethylene-1,6-bis(dodecyldimethylammonium bromide) (12-6-12) and 10% hydrolyzed polyacrylamide (PAM) has been investigated. It was found that the 12-6 12/PAM mixture forms coacervate with a large network structure over a wide concentration range of surfactant and polyelectrolyte and shows great efficiency in the extraction of Methyl Orange (MO) from water owing to the cooperation of hydrophobic, electrostatic, and pi-cation interactions. Meanwhile, the dye joins the coacervate and strengthens the network structure of the coacervate. In particular, benefiting from partial excess of 12-6-12 molecules, the coacervate phase presents selective adsorption behavior toward anionic dye MO in the presence of cationic dye methylene blue (MB). Furthermore, the coacervate phase is utilized to modify quartz sand and melamine foam, and the coacervate-treated adsorbents can adsorb MO efficiently. Moreover, the MO-loaded adsorbents are easily regenerated with hydrochloric acid, making this an inexpensive and environmentally benign process. These findings offer a simple and effective alternative for the treatment of dye contaminated water and the recovery of dyes. PMID- 28622472 TI - Describing a Strongly Correlated Model System with Density Functional Theory. AB - The linear chain of hydrogen atoms, a basic prototype for the transition from a metal to Mott insulator, is studied with a recent density functional theory model functional for nondynamic and strong correlation. The computed cohesive energy curve for the transition agrees well with accurate literature results. The variation of the electronic structure in this transition is characterized with a density functional descriptor that yields the atomic population of effectively localized electrons. These new methods are also applied to the study of the Peierls dimerization of the stretched even-spaced Mott insulator to a chain of H2 molecules, a different insulator. The transitions among the two insulating states and the metallic state of the hydrogen chain system are depicted in a semiquantitative phase diagram. Overall, we demonstrate the capability of studying strongly correlated materials with a mean-field model at the fundamental level, in contrast to the general pessimistic view on such a feasibility. PMID- 28622473 TI - Nonculturability Might Underestimate the Occurrence of Campylobacter in Broiler Litter. AB - We investigated the contribution of litter to the occurrence of Campylobacter on three broiler farms, which were known to have low (LO) and high (HI-A and HI-B) Campylobacter prevalence. For this purpose, we collected litter samples (n = 288) during and after two rearing cycles from each farm. We evaluated the occurrence of Campylobacter (using selective enrichment and quantitative real-time polymerase chain reaction [q-PCR] analysis) in the litter samples as well as the litter's pH and moisture content. Ceca from each flock (n = 144) were harvested at slaughter age and used to quantify Campylobacter colony-forming units (CFUs). Campylobacter was only retrieved from 7 litter samples that were collected from HI-A and HI-B during the growing period, but no Campylobacter was isolated from LO farms. The q-PCR analysis detected Campylobacter in pooled litter samples from all three farms. However, in litter collected during the same rotation, Campylobacter levels were significantly higher (p < 0.05) in HI-A and HI-B litter samples in comparison to those in LO. Cecal samples from HI-A and HI-B yielded relatively high numbers of Campylobacter CFUs, which were undetectable in LO samples. Litter's pH and moisture did not affect the overall occurrence of Campylobacter in litter and ceca on any of the farms. Our data suggest that Campylobacter was generally more abundant in litter that was collected from farms with highly colonized flocks. Therefore, better approaches for assessing the occurrence of Campylobacter in litter might be warranted in order to reduce the dissemination of these pathogens on and off poultry farms. PMID- 28622474 TI - Larch Arabinogalactan Attenuates Myocardial Injury by Inhibiting Apoptotic Cascades in a Rat Model of Ischemia-Reperfusion. AB - We reported previously that supplementation with apple pectin, a dietary fiber, reduced myocardial injury in a rat model of ischemia-reperfusion. In this study, we further investigated an arabinogalactan, one of the constituent polysaccharides of pectin, to determine which domains comprising pectin were responsible for the protection. In a rat model of 30-min ischemia followed by 3-h reperfusion, supplementation with larch arabinogalactan (LAG) over 50 mg/kg/day significantly reduced infarct size. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblot analyses showed that intake of LAG blocked the steps involved in apoptotic cascades through downregulation of gelsolin gene expression at the protein (Gelsolin) level, inhibition of p38 phosphorylation in mitogen-activated protein kinase (MAPK) pathways, decreased bax/bcl-2 ratio at the protein (Bax/Bcl-2) level, which was correlated with the ratio at the mRNA level, inhibition of the conversion of Procaspase protein to Caspase-3 protein, and consequently a decrease in apoptotic cells. In addition, the intake of LAG reduced the hif1-alpha gene expression at the protein (HIF1-alpha) level. These findings suggest that arabinogalactan is an active component of pectin for reducing myocardial injury by inhibiting apoptosis in postocclusion steps, possibly indicating that arabinogalactan can be developed as a cardioprotectant to prevent myocardial injury. PMID- 28622475 TI - Racial Differences in the Association Between Maternal Antenatal Depression and Preterm Birth Risk: A Prospective Cohort Study. AB - BACKGROUND: In the United States, racial/ethnic disparities in preterm birth (PTB) are well documented, but explanations for why the disparity persists remain to be fully explored. We examined racial/ethnic differences in the association of maternal antenatal depression with PTB (<37 completed weeks of gestation) risk. METHODS: In a prospective cohort study, participants (n = 2073) included non Hispanic (NH) black, NH white, Asian, and Hispanic women who received prenatal care at a university obstetric clinic January 2004-March 2010, and delivered at the university's hospital. We obtained data from self-reported questionnaires and electronic medical records. We assessed antenatal depression using the Patient Health Questionnaire-9 and self-reported antenatal antidepressant medication use. Poisson regression models were used to estimate the association between antenatal depression and PTB risk, within strata of race/ethnicity. RESULTS: NH black (risk ratio [RR] = 1.89; 95% confidence interval [CI]: 0.94, 3.80), NH white (RR = 1.58, 95% CI: 1.04, 2.39), and Asian (RR = 2.06; 95% CI: 0.69, 6.13) women with antenatal depression were at increased risk for delivering preterm infants, compared with women without antenatal depression, although the associations were statistically significant only among NH white women. There was no evidence of an association between antenatal depression and risk of PTB among Hispanic women (RR = 0.96; 95% CI: 0.28, 3.25); p-value for interaction = 0.81. CONCLUSION: Our findings suggest race-specific associations of antenatal depression with an increased risk of delivering a preterm infant, supporting the importance of considering race/ethnicity when examining risk factors for health outcomes. PMID- 28622477 TI - An Examination of Factors Affecting the Length of Stay in a Palliative Care Center. AB - BACKGROUND: With the increase in elderly population, life-threatening chronic diseases are increasing, simultaneously increasing the need for palliative care centers (PCCs). OBJECTIVES: To evaluate the factors affecting the length of stay (LOS) and discharge of patients from a PCC. METHODS: A retrospective scan was made of the records of patients followed up in the PCC between January 2013 and March 2016. A record was made of patient age, gender, diagnosis, conditions/comorbidities, Glasgow Coma Scale, Karnofsky Performance Scale, LOS, prognosis (exitus or surviving), percutaneous endoscopic gastrostomy (PEG), tracheostomy, mechanical ventilator, nutrition (total parenteral nutrition [TPN] or enteral nutrition), and the results of cultures taken during stay in PCCs (blood, tracheal aspirate, urine, rectal swab, wound). Evaluation with regression analysis was made of the data related to factors thought to have a possible effect on the LOS in PCCs. RESULTS: Four hundred thirty-five patients were included in the study, comprising 58.6% men and 41.4% women with a mean age of 70.6 +/- 17.2 years. The LOS was 27.2 +/- 30.9 days. A total of 234 patients were discharged and 201 (46.2%) were lost to mortality in PCCs. The bacteria most isolated in cultures were Escherichia coli (28.5%) and methicillin resistant Staphylococcus aureus (MRSA) (17%). According to the results of the regression analysis, cancer, hypoxic brain, and advanced age had a negative effect on LOS and PEG, TPN, hypertension, and E. coli, Proteus, Pseudomonas, and Acinetobacter infections increased LOS. CONCLUSION: The results of this study revealed some basic factors that affect LOS in PCCs. However, there may be much variation in the data obtained with the various reasons for which this patient group is admitted to a PCC. PMID- 28622476 TI - The Effect of Transdermal Estrogen Patch Use on Cardiovascular Outcomes: A Systematic Review. AB - BACKGROUND: Vasomotor symptoms are the most commonly reported menopausal symptoms. Hormone therapy has been widely used to relieve postmenopausal symptoms. With studies suggesting an increased risk of cardiovascular events and breast cancer with oral hormone therapy use, there has been reluctance to use it. The transdermal estrogen patch provides relief from menopausal symptoms. However, there are limited data on mortality and cardiovascular outcomes, while on the transdermal estrogen patch. METHODS: An extensive search in Cochrane and PubMed databases was conducted up to February 2016. The selection criteria included healthy, peri-, and postmenopausal women between the ages of 50 and 79 and should have received transdermal estrogen therapy. The relationship between estrogen patch use and cardiovascular outcomes was analyzed. Six articles met the criteria and were included. RESULTS: We found some evidence suggestive of protective cardiovascular effects with transdermal estrogen therapy with a decrease in the risk of stroke and no increase in the risk of coronary heart disease, death, or myocardial infarction. DISCUSSION: This is one of the first systematic reviews addressing the association of transdermal estrogen patch use on cardiovascular outcomes. We found some evidence suggestive of a possible protective cardiovascular effect with transdermal estrogen therapy. Further randomized controlled studies are needed with a longer duration of follow-up, to study the cardiovascular effects of transdermal estrogen patches. PMID- 28622478 TI - Novel Nonsurgical Endoscopic Approaches for the Treatment of Obesity. AB - Globally, obesity is a leading cause of preventable death and is associated with >60 comorbid medical conditions, including 10 types of cancer that are strongly associated with body mass index. There are a number of traditional obesity treatments-for example, lifestyle management (eg, decreased caloric intake and increased expenditure), pharmacotherapy, and bariatric surgery. Recently, endoscopic approaches have emerged as a viable alternative for weight loss. Endoscopically placed intragastric balloons were introduced in the early 1980s for the treatment of medically complicated obesity but, unfortunately, had high rates of complications, such as premature deflation leading to obstruction. Despite these shortcomings, these devices have experienced a renewal, with a second generation of improved devices being approved for clinical use in 2015. In addition to the intragastric balloons, there are a number of other endoscopic approaches to weight loss that are either Food and Drug Administration approved or undergoing evaluation (aspiration therapy, duodenal jejunal bypass sleeve). The current review examines the literature available and discusses the practical clinical considerations involved. PMID- 28622479 TI - Making Use of Lasers in Periodontal Treatment: A New Gold Standard? PMID- 28622480 TI - Circadian Variation of Breast Milk Components and Implications for Care. AB - Several components of breast milk show circadian variability. It is likely that at least some of these macronutrients, hormones, and micronutrients produce circadian stimuli that enhance the well-being of breast-fed infants. Future research should determine whether high-risk infants benefit if breast milk is given during the same circadian phase as it was expressed. PMID- 28622481 TI - Hospice Visit Patterns in the Last Seven Days of Life and the Service Intensity Add-On Payment. AB - BACKGROUND: Hospice in-person visits in the last week of life are critical to ensure quality of care. In 2016, The Centers for Medicare & Medicaid Services (CMS) introduced a Service Intensity Add-on (SIA) payment for in-person routine home care (RHC) visits by a registered nurse or social worker in the last 7 days of life. OBJECTIVES: The aim of the study was to examine visit patterns in the last week of life and provide SIA payment impact estimates. DESIGN/MEASUREMENTS: Hospice data from 42 volunteer hospice programs for the 6-year period of 2005 2010 were examined. The data included information on the type and duration of visits/other care, the staff discipline, and patient demographics, diagnoses, date of death, and care setting (home, assisted living, nursing home). RESULTS: In their last week of life, 251,407 decedents received 2,818,695 visits during 1,352,638 RHC days. Forty-four percent of the decedents had at least one SIA eligible visit (in-person direct care visit by a registered nurse (RN) or social worker (SW)); 6.6% had only phone contact, and 30.4% had no hospice contact. Rates of RHC days with SIA-eligible days varied considerably across hospices (31% to 60.9%). For the 86.3% decedents with any SIA-eligible visits, average SIA payment would have been $202.5 (Median = $177.2, inter quartile range [IQR] = $108.3-$275.6), which represents a 21.6% increase over the average regular RHC payments received during the last week of life. CONCLUSIONS: The relative size of the new SIA payment introduced by CMS has the potential to increase RN/SW visits and reduce disparities in visit patterns in the last week of life. PMID- 28622482 TI - Antidiabetic Properties of an Apple/Kale Extract In Vitro, In Situ, and in Mice Fed a Western-Type Diet. AB - Type 2 diabetes mellitus (T2DM) is a common and increasingly prevalent metabolic disorder, and effective preventive strategies against this disease are needed. The aim of the present study was to evaluate the potential antidiabetic properties of a dietary apple/kale extract (AKE), which was rich in phlorizin and flavonoids, in laboratory mice. Mice were fed a control diet, a Western-type high sugar, high-fat diet (WTD), or a WTD plus AKE for 10 weeks. Body weight, food and energy intake, body composition, and blood glucose level were recorded in addition to the postprandial rise in blood glucose concentration after a single administration of glucose (oral glucose tolerance test, OGTT). Furthermore, changes in glucose-induced short-circuit current (ISC) in response to AKE and phlorizin administration were evaluated in situ in intestinal tissues with Ussing chambers. In addition, the in vitro inhibition of alpha-glucosidase by AKE was determined. The present data suggest that supplementation of an AKE to a WTD significantly improved both blood glucose levels and OGTT in mice. Furthermore, in situ uptake of glucose was significantly inhibited by AKE. Finally, we showed that AKE significantly inhibits alpha-glucosidase activity in vitro. We conclude that AKE exhibits antidiabetic properties by a dual mechanism, including the inhibition of alpha-glucosidase and sodium-dependent glucose transporter 1 (SGLT1). Thus, AKE has the potential to serve as a natural plant bioactive compound for dietary prevention strategies against T2DM. PMID- 28622483 TI - Human Milk Fortifiers Do Not Meet the Current Recommendation for Nutrients in Very Low Birth Weight Infants. AB - BACKGROUND: Use of multinutrient fortifiers is standard of care for small preterm infants fed exclusively human milk. However, adequacy of human milk fortifiers (HMFs) to meet the recommended intake for macronutrients and micronutrients is now known. MATERIALS AND METHODS: Nutrient content of human milk fortified according to manufacturer's recommendations was compared at isocaloric levels for 1 human milk-based (HMF-A), 2 bovine milk protein-based (HMF-B, HMF-C), and 2 preterm infant formulas (PTF-B, PTF-C). In addition, 4 multivitamin supplements were compared. RESULTS: At 130 kcal/kg, intake of macronutrients was similar to the recommendation, although deficient and excess intake of micronutrient occurred with all fortifiers. Four to 9 micronutrients were absent in HMF or PTF (biotin, choline, inositol, carnitine, taurine, molybdenum, iodine, selenium, or chromium). For the remainder, HMF resulted in deficient intake for 1-13 micronutrients, occurring most frequently with HMF-A. Excess micronutrients (3-15 at <50% and 1-3 at 109%-437%) occurred with all HMF and most frequently with HMF B and HMF-C. At 150 kcal/kg, deficient intake improved but generally remained below recommendation, while excess intake became exaggerated. PTF and multivitamin formulations do not fully compensate for the deficiencies and can result in extremely high micronutrient intake. CONCLUSIONS: At the recommended energy intake for very low birth weight infants, many micronutrients are absent or are present in grossly inadequate amounts, and several micronutrients are in excess. Reformulation of HMF is urgently needed since PTF or multivitamin supplement only partially corrects some deficiencies while providing some nutrients in excess. PMID- 28622484 TI - Bactericidal Effect of Er:YAG Laser-Activated Sodium Hypochlorite Irrigation Against Biofilms of Enterococcus faecalis Isolate from Canal of Root-Filled Teeth with Periapical Lesions. AB - OBJECTIVE: This study was to evaluate the bactericidal effect of Er:YAG laser activated sodium hypochlorite irrigation (Er:YAG + NaOCl) on biofilms of Enterococcus faecalis clinical isolate. BACKGROUND DATA: It was reported that Er:YAG + NaOCl had effective bactericidal effect on laboratory-adapted E. faecalis strain, while no study has reported its effect on the clinical isolate. METHODS: Eighteen E. faecalis strains were isolated from 39 root-filled teeth with periapical lesions, and their biofilm formation abilities were evaluated using the crystal violet staining method. Extracted human root canals were prepared to a 40#/.04 K3 instrument and contaminated with the E. faecalis isolate that presented the strongest biofilm formation ability for 4 weeks. The infected canals then received treatments of syringe irrigation with normal saline (NS) or NaOCl, ultrasonic activated irrigations US + NS and US + NaOCl, and Er:YAG laser activated irrigations Er:YAG + NS and Er:YAG + NaOCl. The root canals were examined using scanning electron microscopy (SEM). The bacterial reductions were evaluated using the cell count method. RESULTS: SEM results showed that biofilm like structures formed on the root canal walls after 4-week bacterial incubation. Er:YAG + NaOCl completely removed the E. faecalis biofilm from the root canal wall and made it the cleanest and most smooth surface among the treatment groups. Bacterial reductions in the treatment groups were presented in a descending order of Er:YAG + NaOCl (98.8%), US + NaOCl (98.6%) > NaOCl (94.0%) > Er:YAG + NS (91.9%) > US + NS (78.1%) > NS (51.1%) (p < 0.05). CONCLUSIONS: The Er:YAG + NaOCl showed an effective bactericidal effect on biofilms of E. faecalis isolate, which may be considered an effective protocol for root canal treatment. PMID- 28622485 TI - The Nature of Whiplash in a Compensable Environment: Injury, Disability, Rehabilitation, and Compensation Systems. AB - Synopsis Whiplash is a compensable injury in many jurisdictions, but there is considerable heterogeneity in the compensation arrangements that apply across jurisdictions, even within some countries. These compensation schemes have, however, been subject to a common set of interrelated concerns, chiefly concerning the incentives, behaviors, and outcomes that may arise when financial compensation for injuries is available to injured parties. This article provides a nontechnical overview of some of those concerns through the lens of economics: principally, insurance economics and health economics, including related subsets such as information economics and agency theory, as well as economics and the law. It notes that because it is generally infeasible to randomize the treatment (ie, compensation) via trials, analyses of observational data are necessary to discover more about the relationship between compensation and health outcomes. This poses the analytical challenge of discovering causal connections between phenomena from nonrandomized data sets. The present article calls for further research that would enable convincing causal interpretations of such relationships via the careful analysis of rich observational data sets using modern econometric methods. J Orthop Sports Phys Ther 2017;47(7):503-508. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7533. PMID- 28622486 TI - The Physiological Basis of Cervical Facet-Mediated Persistent Pain: Basic Science and Clinical Challenges. AB - Synopsis Chronic neck pain is a common condition and a primary clinical symptom of whiplash and other spinal injuries. Loading-induced neck injuries produce abnormal kinematics between the vertebrae, with the potential to injure facet joints and the afferent fibers that innervate the specific joint tissues, including the capsular ligament. Mechanoreceptive and nociceptive afferents that innervate the facet have their peripheral terminals in the capsule, cell bodies in the dorsal root ganglia, and terminal processes in the spinal cord. As such, biomechanical loading of these afferents can initiate nociceptive signaling in the peripheral and central nervous systems. Their activation depends on the local mechanical environment of the joint and encodes the neural processes that initiate pain and lead to its persistence. This commentary reviews the complex anatomical, biomechanical, and physiological consequences of facet-mediated whiplash injury and pain. The clinical presentation of facet-mediated pain is complex in its sensory and emotional components. Yet, human studies are limited in their ability to elucidate the physiological mechanisms by which abnormal facet loading leads to pain. Over the past decade, however, in vivo models of cervical facet injury that reproduce clinical pain symptoms have been developed and used to define the complicated and multifaceted electrophysiological, inflammatory, and nociceptive signaling cascades that are involved in the pathophysiology of whiplash facet pain. Integrating the whiplash-like mechanics in vivo and in vitro allows transmission of pathophysiological mechanisms across scales, with the hope of informing clinical management. Yet, despite these advances, many challenges remain. This commentary further describes and highlights such challenges. J Orthop Sports Phys Ther 2017;47(7):450-461. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7255. PMID- 28622487 TI - An Integrated Model of Chronic Whiplash-Associated Disorder. AB - Synopsis The development of persistent symptoms following whiplash injury from a motor vehicle collision is common and contributes substantially to societal and personal costs. The popular Quebec Task Force classification system of whiplash associated disorders (WADs) was meant to function as a prognostic and intervention decision aid, but its usefulness has been questioned. Emerging evidence highlights the heterogeneity of WAD by demonstrating physical and psychological impairments that are unique to those who develop persistent symptoms. These impairments are not recognized in the Quebec Task Force classification system. The purpose of this clinical commentary is to describe an integrated model that focuses on how psychological and neurobiological factors interact with, and are influenced by, existing personal and environmental factors to contribute to the development of chronic WAD. The model has been developed through more than 20 years of work in the field, consultation with experts, in depth synthesis of existing evidence, and new evidence from the authors' own research programs. A subtheme is that a point of convergence currently exists between the psychological, physiological, and social determinants of health literature that can further explain the complex presentation of WAD. The new model is proposed to orient future research toward more interdisciplinary efforts across nontraditional fields, including data scientists and consumers, to clarify the WAD condition. J Orthop Sports Phys Ther 2017;47(7):462-471. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7455. PMID- 28622488 TI - Dizziness, Unsteadiness, Visual Disturbances, and Sensorimotor Control in Traumatic Neck Pain. AB - Synopsis There is considerable evidence to support the importance of cervical afferent dysfunction in the development of dizziness, unsteadiness, visual disturbances, altered balance, and altered eye and head movement control following neck trauma, especially in those with persistent symptoms. However, there are other possible causes for these symptoms, and secondary adaptive changes should also be considered in differential diagnosis. Understanding the nature of these symptoms and differential diagnosis of their potential origin is important for rehabilitation. In addition to symptoms, the evaluation of potential impairments (altered cervical joint position and movement sense, static and dynamic balance, and ocular mobility and coordination) should become an essential part of the routine assessment of those with traumatic neck pain, including those with concomitant injuries such as concussion and vestibular or visual pathology or deficits. Once adequately assessed, appropriate tailored management should be implemented. Research to further assist differential diagnosis and to understand the most important contributing factors associated with abnormal cervical afferent input and subsequent disturbances to the sensorimotor control system, as well as the most efficacious management of such symptoms and impairments, is important for the future. J Orthop Sports Phys Ther 2017;47(7):492-502. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7052. PMID- 28622489 TI - The Role of Exercise and Patient Education in the Noninvasive Management of Whiplash. AB - Synopsis The majority of people with whiplash-associated disorder do not have neurological deficit or fracture and are therefore largely managed with nonsurgical interventions such as exercise, patient education, and behavioral based interventions. To date, clinical guidelines, systematic reviews, and the results of high-quality randomized controlled trials recommend exercise and patient education as the primary interventions for people in both acute and chronic stages after injury. However, the relatively weak evidence and small effect sizes in individual trials have led authors of some systematic reviews to reach equivocal recommendations for either exercise or patient education, and led policy makers and funders to question whether the more expensive intervention (exercise) should be funded at all. Physical therapists, one of the most commonly consulted professionals treating individuals with whiplash-associated disorder, need to look beyond the evidence for insights as to what role patient education and exercise should play in the future management of whiplash. This clinical commentary therefore will review the evidence for exercise, patient education, and behavioral-based interventions for whiplash and provide clinical insight as to the future role that exercise and patient education should play in the management of this complex condition. Possible subgroups of patients who may best respond to exercise will be explored using stratification based on impairments, treatment response, and risk/prognostic factors. J Orthop Sports Phys Ther 2017;47(7):481-491. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7138. PMID- 28622490 TI - Lawsonia intracellularis in Pigs: Progression of Lesions and Involvement of Apoptosis. AB - The purpose of this study was to follow the progression of gross and histologic lesions and apoptosis events in Lawsonia intracellularis-infected enterocytes through the course of the disease, proliferative enteropathy (PE). Thirty 5-week old pigs were divided into 2 groups: 20 challenged and 10 control animals. Groups of 3 pigs, 2 challenged and 1 control, were euthanized at 1, 3, 5, 8, 11, 15, 19, 24, 29, and 35 days after inoculation. Complete necropsies were performed with gross evaluation. Tissue samples from different sites of the gastrointestinal tract and other visceral organs were collected for routine histologic staining and for immunohistochemistry (IHC) for L. intracellularis. In addition, caspase 3, terminal deoxyuridine nick-end labeling assay, and electron microscopy were performed in ileum samples. Macroscopic and histologic lesions suggestive of PE were first detected 11 days after infection and continued through day 24. L. intracellularis antigen was first detected in the intestine by IHC on day 5 after inoculation, and the bacterium was first detected by transmission electron microscopy on day 15. Positive IHC staining for [L. intracellularis] and enterocyte proliferation, but no gross lesion, were detected on day 29. All 3 pigs euthanized on day 35 were grossly and histologically normal and IHC negative. Hyperplastic crypts in challenge pigs had more apoptotic cells on days 15, 19, and 24 postinfection ( P < .05) compared to control pigs. Our results demonstrated the progression of lesions and infection by L. intracellularis and that inhibition of enterocyte apoptosis is not involved in the pathogenesis of proliferative enteropathy. PMID- 28622491 TI - Putting the Idiopathic Back Into Porcine Idiopathic Vesicular Disease:: Setting the Record Straight on Reports of PIVD in New Zealand. PMID- 28622493 TI - The Evolving Significance and Future Relevance of the Impact Factor. PMID- 28622494 TI - Laryngeal Neuropathy in Adult Goats With Copper Deficiency. AB - The aim of this study was to elucidate the cause of a neurological syndrome characterized by stridor in adult goats with clinical signs of copper deficiency. The main clinical signs consisted of apathy, emaciation, pale mucous membranes, mucous nasal discharge, dyspnea, severe achromotrichia, diffuse alopecia, torpor, ataxia, and stridor. When the goats were forced to move, the stridor increased. In a herd of 194 Toggenburg goats, 10 adult goats with clinical signs of copper deficiency were removed from the herd and divided into 2 groups: group 1, which consisted of 4 nannies and 1 buck with stridor, and group 2, which consisted of 4 nannies and 1 buck without stridor. Group 3, used as a control, consisted of 5 adult goats from another flock without any clinical signs of disease. The mean serum copper concentrations were 1.3 +/- 0.3 MUmol/L in group 1, 8.1 +/- 1.1 MUmol/L in group 2, and 11.3 +/- 2.2 MUmol/L in group 3. The mean serum iron concentrations were 42.3 +/- 14.2 MUmol/L in group 1, 39.1 +/- 8.2 MUmol/L in group 2, and 20.6 +/- 6.1 MUmol/L in group 3. The main histological lesions in goats from group 1 were axonal degeneration of the recurrent laryngeal nerves and atrophy of the muscles of vocal folds and of the dorsal cricoarytenoid and right and left cricothyroid muscles. Goats with ataxia had neuronal degeneration and necrosis of cerebellar Purkinje cells and of the cranial cervical ganglion. We concluded that the stridor was caused by axonal degeneration of the recurrent laryngeal nerves due to the severe copper deficiency. PMID- 28622495 TI - The ACVP/STP Coalition for Veterinary Pathology Fellows Celebrates 32 New Training Positions. PMID- 28622496 TI - Equine Hoof Canker: Cell Proliferation and Morphology. AB - Hoof canker is described as progressive pododermatitis of the equine hoof with absent epidermal cornification and extensive proliferation of the dermal papillary body; however, in-depth research on the type of proliferative activity has not yet been reported. The aim of the present study was to determine cell specific proliferation patterns together with morphological analysis of hoof canker tissue. Tissues removed during surgery from 19 horses presented for treatment of canker were compared with similar postmortem tissues of healthy hooves of 10 horses. Morphological alterations visible in light microscopy were assessed semiquantitatively and graded for severity. Proliferative activity was evaluated by means of anti-PCNA (proliferative cell nuclear antigen) and anti Ki67 immunohistochemistry. Histologically, canker tissue showed 5 major morphological alterations-the presence of lacunae, vacuoles, giant cells, hemorrhage, and inflammation-not seen in control tissue. Also, there was a notable koilocytotic appearance of keratinocytes in canker tissue. Immunohistochemistry revealed increased levels of PCNA protein expression in keratinocytes and fibroblasts of canker tissue compared with control tissue. In control tissue, keratinocytes showed higher levels of Ki67 compared with canker tissue, while the dermal fibroblasts of both groups showed similar levels of Ki67, indicating similar proliferative activity of less than 3% of total dermal fibroblasts. These results demonstrate that, in contrast to previous reports, there is no evidence for increased proliferative activity of the dermal papillary body associated with hoof canker. Increased levels of PCNA protein expression and morphological alterations indicate that dysregulation of keratinocyte differentiation constitutes a key event in equine hoof canker development. PMID- 28622497 TI - Feline Panleukopenia Virus Is Not Associated With Myocarditis or Endomyocardial Restrictive Cardiomyopathy in Cats. AB - Canine parvovirus-2 (CPV-2) is nearly indistinguishable from feline panleukopenia virus (FPV) and is a well-known cause of viral myocarditis in young puppies; however, it is not known whether either FPV or CPV-2 naturally infects feline cardiomyocytes and causes myocarditis. Endomyocarditis (EMC) and left ventricular endomyocardial fibrosis (LVEF), clinically known as "endomyocardial restrictive cardiomyopathy," are important feline heart diseases suspected to have an infectious etiology. A continuum is suggested with EMC representing the acute reaction to an unknown infectious agent and LVEF the chronic manifestation of repair. The purpose of this study was to determine (1) whether there is natural parvovirus infection of the feline myocardium and (2) whether parvoviral infection is associated with feline EMC and/or LVEF. In a retrospective study, polymerase chain reaction and sequencing for the parvovirus VP1/2 gene was performed on archived heart tissue from cats with endomyocardial disease and controls. Similar methods were used prospectively on myocardial tissues from shelter-source kittens. Although 8 of 36 (22%; 95% confidence interval [CI], 11% 40%) shelter kittens had parvoviral DNA in myocardial tissue, VP1/2 DNA was not detected in 33 adult cases or 34 controls (95% CI, 0% to ~11%). These findings were confirmed by in situ hybridization: adult cats did not have detectable parvovirus DNA, although rare intranuclear signal was confirmed in 7 of 8 shelter source kittens. In kittens, parvovirus was not significantly associated with myocarditis, and in situ hybridization signal did not colocalize with inflammation. Although infection of cardiomyocytes was demonstrated in kittens, these data do not support a role for parvovirus in EMC-LVEF. PMID- 28622498 TI - Sorting Out Complex Thoughts and Messy Emotions. PMID- 28622499 TI - The Measure of a Man. AB - Moving beyond simple fitness tracking, wearable devices may soon offer opportunities for monitoring health and bring vast amounts of new data to the study of human diseases. PMID- 28622500 TI - Getting Surprising Answers to Unasked Questions. PMID- 28622501 TI - Microbiome and Longevity: Gut Microbes Send Signals to Host Mitochondria. AB - The microbiome has emerged as a major determinant of the functioning of host organisms, affecting both health and disease. Here, Han et al. use the workhorse of aging research, C. elegans, to identify specific mechanisms by which gut bacteria influence mitochondrial dynamics and aging, a first step toward analogous manipulations to modulate human aging. PMID- 28622502 TI - Just a Spoonful of Sugar Helps the Tolerance Go Up. AB - Survival of deleterious infections depends significantly on how much stress the affected organism can tolerate. In this issue, Weis et al. find that mice can survive sepsis by maintaining normoglycemia through ferritin's capacity to inactivate Fe2+ ions that otherwise induce free radicals impacting gluconeogenesis in the liver. PMID- 28622503 TI - DAMed in (Trem) 2 Steps. AB - The role of microglia in neurodegenerative diseases has been controversial. In this issue, Keren-Shaul et al. identify a unique population of disease-associated microglia (DAM) that develop in two steps and may help to restrict damage in Alzheimer and related diseases. PMID- 28622504 TI - Sex at Atomic Resolution. AB - Interspecies fertilization is rare, partly due to species separation enforced at the molecular level. In this issue, Raj et al. now reveal the crystal structures of mollusk egg coat protein, VERL, complexed with cognate sperm protein lysin. Given that VERL is structurally similar to mammalian ZP2, the mechanism elucidating species-specific gamete recognition likely exists in mammals. PMID- 28622505 TI - An Expanded View of Complex Traits: From Polygenic to Omnigenic. AB - A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease-causing variants to cluster into key pathways that drive disease etiology. But for complex traits, association signals tend to be spread across most of the genome-including near many genes without an obvious connection to disease. We propose that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liable to affect the functions of core disease related genes and that most heritability can be explained by effects on genes outside core pathways. We refer to this hypothesis as an "omnigenic" model. PMID- 28622506 TI - Dynamic RNA Modifications in Gene Expression Regulation. AB - Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6 methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information. PMID- 28622507 TI - Independent and Stochastic Action of DNA Polymerases in the Replisome. AB - It has been assumed that DNA synthesis by the leading- and lagging-strand polymerases in the replisome must be coordinated to avoid the formation of significant gaps in the nascent strands. Using real-time single-molecule analysis, we establish that leading- and lagging-strand DNA polymerases function independently within a single replisome. Although average rates of DNA synthesis on leading and lagging strands are similar, individual trajectories of both DNA polymerases display stochastically switchable rates of synthesis interspersed with distinct pauses. DNA unwinding by the replicative helicase may continue during such pauses, but a self-governing mechanism, where helicase speed is reduced by ~80%, permits recoupling of polymerase to helicase. These features imply a more dynamic, kinetically discontinuous replication process, wherein contacts within the replisome are continually broken and reformed. We conclude that the stochastic behavior of replisome components ensures complete DNA duplication without requiring coordination of leading- and lagging-strand synthesis. PAPERCLIP. PMID- 28622508 TI - SAF-A Regulates Interphase Chromosome Structure through Oligomerization with Chromatin-Associated RNAs. AB - Higher eukaryotic chromosomes are organized into topologically constrained functional domains; however, the molecular mechanisms required to sustain these complex interphase chromatin structures are unknown. A stable matrix underpinning nuclear organization was hypothesized, but the idea was abandoned as more dynamic models of chromatin behavior became prevalent. Here, we report that scaffold attachment factor A (SAF-A), originally identified as a structural nuclear protein, interacts with chromatin-associated RNAs (caRNAs) via its RGG domain to regulate human interphase chromatin structures in a transcription-dependent manner. Mechanistically, this is dependent on SAF-A's AAA+ ATPase domain, which mediates cycles of protein oligomerization with caRNAs, in response to ATP binding and hydrolysis. SAF-A oligomerization decompacts large-scale chromatin structure while SAF-A loss or monomerization promotes aberrant chromosome folding and accumulation of genome damage. Our results show that SAF-A and caRNAs form a dynamic, transcriptionally responsive chromatin mesh that organizes large-scale chromosome structures and protects the genome from instability. PMID- 28622509 TI - Antibacterial Nucleoside-Analog Inhibitor of Bacterial RNA Polymerase. AB - Drug-resistant bacterial pathogens pose an urgent public-health crisis. Here, we report the discovery, from microbial-extract screening, of a nucleoside-analog inhibitor that inhibits bacterial RNA polymerase (RNAP) and exhibits antibacterial activity against drug-resistant bacterial pathogens: pseudouridimycin (PUM). PUM is a natural product comprising a formamidinylated, N hydroxylated Gly-Gln dipeptide conjugated to 6'-amino-pseudouridine. PUM potently and selectively inhibits bacterial RNAP in vitro, inhibits bacterial growth in culture, and clears infection in a mouse model of Streptococcus pyogenes peritonitis. PUM inhibits RNAP through a binding site on RNAP (the NTP addition site) and mechanism (competition with UTP for occupancy of the NTP addition site) that differ from those of the RNAP inhibitor and current antibacterial drug rifampin (Rif). PUM exhibits additive antibacterial activity when co-administered with Rif, exhibits no cross-resistance with Rif, and exhibits a spontaneous resistance rate an order-of-magnitude lower than that of Rif. PUM is a highly promising lead for antibacterial therapy. PMID- 28622510 TI - Microbial Genetic Composition Tunes Host Longevity. AB - Homeostasis of the gut microbiota critically influences host health and aging. Developing genetically engineered probiotics holds great promise as a new therapeutic paradigm to promote healthy aging. Here, through screening 3,983 Escherichia coli mutants, we discovered that 29 bacterial genes, when deleted, increase longevity in the host Caenorhabditis elegans. A dozen of these bacterial mutants also protect the host from age-related progression of tumor growth and amyloid-beta accumulation. Mechanistically, we discovered that five bacterial mutants promote longevity through increased secretion of the polysaccharide colanic acid (CA), which regulates mitochondrial dynamics and unfolded protein response (UPRmt) in the host. Purified CA polymers are sufficient to promote longevity via ATFS-1, the host UPRmt-responsive transcription factor. Furthermore, the mitochondrial changes and longevity effects induced by CA are conserved across different species. Together, our results identified molecular targets for developing pro-longevity microbes and a bacterial metabolite acting on host mitochondria to promote longevity. PMID- 28622511 TI - Metabolic Adaptation Establishes Disease Tolerance to Sepsis. AB - Sepsis is an often lethal syndrome resulting from maladaptive immune and metabolic responses to infection, compromising host homeostasis. Disease tolerance is a defense strategy against infection that preserves host homeostasis without exerting a direct negative impact on pathogens. Here, we demonstrate that induction of the iron-sequestering ferritin H chain (FTH) in response to polymicrobial infections is critical to establish disease tolerance to sepsis. The protective effect of FTH is exerted via a mechanism that counters iron-driven oxidative inhibition of the liver glucose-6-phosphatase (G6Pase), and in doing so, sustains endogenous glucose production via liver gluconeogenesis. This is required to prevent the development of hypoglycemia that otherwise compromises disease tolerance to sepsis. FTH overexpression or ferritin administration establish disease tolerance therapeutically. In conclusion, disease tolerance to sepsis relies on a crosstalk between adaptive responses controlling iron and glucose metabolism, required to maintain blood glucose within a physiologic range compatible with host survival. PMID- 28622512 TI - Structural Basis of Egg Coat-Sperm Recognition at Fertilization. AB - Recognition between sperm and the egg surface marks the beginning of life in all sexually reproducing organisms. This fundamental biological event depends on the species-specific interaction between rapidly evolving counterpart molecules on the gametes. We report biochemical, crystallographic, and mutational studies of domain repeats 1-3 of invertebrate egg coat protein VERL and their interaction with cognate sperm protein lysin. VERL repeats fold like the functionally essential N-terminal repeat of mammalian sperm receptor ZP2, whose structure is also described here. Whereas sequence-divergent repeat 1 does not bind lysin, repeat 3 binds it non-species specifically via a high-affinity, largely hydrophobic interface. Due to its intermediate binding affinity, repeat 2 selectively interacts with lysin from the same species. Exposure of a highly positively charged surface of VERL-bound lysin suggests that complex formation both disrupts the organization of egg coat filaments and triggers their electrostatic repulsion, thereby opening a hole for sperm penetration and fusion. PMID- 28622514 TI - Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. AB - Systematic interrogation of tumor-infiltrating lymphocytes is key to the development of immunotherapies and the prediction of their clinical responses in cancers. Here, we perform deep single-cell RNA sequencing on 5,063 single T cells isolated from peripheral blood, tumor, and adjacent normal tissues from six hepatocellular carcinoma patients. The transcriptional profiles of these individual cells, coupled with assembled T cell receptor (TCR) sequences, enable us to identify 11 T cell subsets based on their molecular and functional properties and delineate their developmental trajectory. Specific subsets such as exhausted CD8+ T cells and Tregs are preferentially enriched and potentially clonally expanded in hepatocellular carcinoma (HCC), and we identified signature genes for each subset. One of the genes, layilin, is upregulated on activated CD8+ T cells and Tregs and represses the CD8+ T cell functions in vitro. This compendium of transcriptome data provides valuable insights and a rich resource for understanding the immune landscape in cancers. PMID- 28622515 TI - A Mechanogenetic Toolkit for Interrogating Cell Signaling in Space and Time. PMID- 28622516 TI - SnapShot: Phosphoregulation of Mitosis. AB - During mitosis, a cell divides its duplicated genome into two identical daughter cells. This process must occur without errors to prevent proliferative diseases (e.g., cancer). A key mechanism controlling mitosis is the precise timing of more than 32,000 phosphorylation and dephosphorylation events by a network of kinases and counterbalancing phosphatases. The identity, magnitude, and temporal regulation of these events have emerged recently, largely from advances in mass spectrometry. Here, we show phosphoevents currently believed to be key regulators of mitosis. For an animated version of this SnapShot, please see http://www.cell.com/cell/enhanced/odonoghue2. PMID- 28622517 TI - ER Stress Promotes Inflammation through Re-wIREd Macrophages in Obesity. AB - A new mechanism linking ER dysfunction to metabolic inflammation is discovered in a recent study by Shan et al. (2017), which demonstrated ER stress-induced rewiring of adipose tissue macrophage polarization by IRE1alpha activation, leading to impaired systemic glucose homeostasis. PMID- 28622518 TI - Habits of Highly Effective Biofilms: Ion Signaling. AB - How do neighboring bacterial biofilms sense and communicate with each other? In a recent paper, Liu et al. (2017) demonstrate how electrical signaling allows communication of metabolic states between adjacent B. subtilis biofilms, providing a possible generalizable mechanism for communication in multispecies biofilms with interdependent metabolism. PMID- 28622519 TI - Replication Catastrophe: When a Checkpoint Fails because of Exhaustion. AB - Proliferating cells rely on the so-called DNA replication checkpoint to ensure orderly completion of genome duplication, and its malfunction may lead to catastrophic genome disruption, including unscheduled firing of replication origins, stalling and collapse of replication forks, massive DNA breakage, and, ultimately, cell death. Despite many years of intensive research into the molecular underpinnings of the eukaryotic replication checkpoint, the mechanisms underlying the dismal consequences of its failure remain enigmatic. A recent development offers a unifying model in which the replication checkpoint guards against global exhaustion of rate-limiting replication regulators. Here we discuss how such a mechanism can prevent catastrophic genome disruption and suggest how to harness this knowledge to advance therapeutic strategies to eliminate cancer cells that inherently proliferate under increased DNA replication stress. PMID- 28622513 TI - Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. AB - Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. PMID- 28622520 TI - Innate Immune Receptors as Competitive Determinants of Cell Fate. AB - Infections can cause a multitude of stresses on the host and microbe. To detect potential infections, the mammalian immune system utilizes several families of pattern recognition receptors, which survey the intracellular and extracellular environments for microbial products. Members of each receptor family induce antimicrobial effector responses, which include inflammatory cytokine or interferon expression, downregulation of protein synthesis, or host cell death. In this review, we discuss the benefits of each of these innate immune responses. We highlight how non-infectious bacteria and viruses typically activate a single family of receptors, which results in a predictable host response. Infections with virulent pathogens, in contrast, may activate receptors from distinct families. As each receptor family may induce responses that antagonize or synergize with the activities of another family, cell fate decisions during pathogenic encounters are unpredictable. Understanding the antagonistic antimicrobial activities of the innate immune system should provide insight into how cell fate decisions are made during infections and potentially during other environmental stresses. PMID- 28622521 TI - The UPRER: Sensor and Coordinator of Organismal Homeostasis. AB - Life is stressful. Organisms are repeatedly exposed to stressors that disrupt protein homeostasis (proteostasis), resulting in protein misfolding and aggregation. To sense and respond to proteotoxic perturbations, cells have evolved compartment-specific stress responses, such as the unfolded protein response of the endoplasmic reticulum (UPRER). However, UPRER function is impaired with age, which, we propose, creates a permissive environment for protein aggregation, unresolved ER stress, and chronic inflammation. Understanding age-related changes to the UPRER will provide new avenues for therapeutic intervention in metabolic disease, neurodegeneration, and aging. PMID- 28622522 TI - The EGLN-HIF O2-Sensing System: Multiple Inputs and Feedbacks. AB - The EGLN (also called PHD) prolyl hydroxylase enzymes and their canonical targets, the HIFalpha subunits, represent the core of an ancient oxygen monitoring machinery used by metazoans. In this review, we highlight recent progress in understanding the overlapping versus specific roles of EGLN enzymes and HIF isoforms and discuss how feedback loops based on recently identified noncoding RNAs introduce additional layers of complexity to the hypoxic response. Based on novel interactions identified upstream and downstream of EGLNs, an integrated network connecting oxygen-sensing functions to metabolic and signaling pathways is gradually emerging with broad therapeutic implications. PMID- 28622523 TI - Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling. AB - Ca2+ is a ubiquitous intracellular messenger that controls diverse cellular functions but can become toxic and cause cell death. Selective control of specific targets depends on spatiotemporal patterning of the calcium signal and decoding it by multiple, tunable, and often strategically positioned Ca2+-sensing elements. Ca2+ is detected by specialized motifs on proteins that have been biochemically characterized decades ago. However, the field of Ca2+ sensing has been reenergized by recent progress in fluorescent technology, genetics, and cryo EM. These approaches exposed local Ca2+-sensing mechanisms inside organelles and at the organellar interfaces, revealed how Ca2+ binding might work to open some channels, and identified human mutations and disorders linked to a variety of Ca2+-sensing proteins. Here we attempt to place these new developments in the context of intracellular calcium homeostasis and signaling. PMID- 28622525 TI - ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. AB - In vertebrate cells, the DNA damage response is controlled by three related kinases: ATM, ATR, and DNA-PK. It has been 20 years since the cloning of ATR, the last of the three to be identified. During this time, our understanding of how these kinases regulate DNA repair and associated events has grown profoundly, although major questions remain unanswered. Here, we provide a historical perspective of their discovery and discuss their established functions in sensing and responding to genotoxic stress. We also highlight what is known regarding their structural similarities and common mechanisms of regulation, as well as emerging non-canonical roles and how our knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health. PMID- 28622526 TI - Extragastrointestinal stromal tumour of the lesser omentum: A case report and literature review. AB - INTRODUCTION: Extragastrointestinal stromal tumours (EGISTs) are very uncommon compared to their gastrointestinal counterparts. Most of them originate from the intestinal mesentery and the omentum. CASE REPORT: A 70 year-old Caucasian woman presented with a bulky abdominal mass which on laparotomy was found to originate from the lesser omentum and was completely resected. Histological examination revealed spindle cells with severe pleomorphism and high mitotic activity. Immunohistochemically, the tumour cells showed strong positivity for c-kit (CD117), DOG-1 and human haematopoietic progenitor cell antigen (CD34). An exon 11 deleterious mutation was identified and thus regular dosing of 400mg imatinib mesylate was initiated. DISCUSSION: There have been only a few previous reports of EGISTs arising in the lesser omentum. Although EGISTs seem to have morphological and immunohistochemical similarities with GISTs, their pathogenesis, incidence, genetic background and prognosis are not completely known because they are extremely rare. It is strongly believed that such tumours originate from cells, which have similar pathological characteristics and biological behaviour as the intestinal cells of Cajal. In most series of EGISTs, a female predominance, a greater size and a higher mitotic index than GISTs were observed. CONCLUSION: EGISTs are very rare mesenchymal tumours which originate from cells outside the gastrointestinal tract and tend to have a more aggressive biological behaviour than their GI counterparts. Complete surgical resection is the most effective treatment associated with the use of imatinib in the presence of adverse prognostic factors. In any case a strict follow-up is necessary due to high recurrence rates. PMID- 28622524 TI - AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. AB - AMPK is a highly conserved master regulator of metabolism, which restores energy balance during metabolic stress both at the cellular and physiological levels. The identification of numerous AMPK targets has helped explain how AMPK restores energy homeostasis. Recent advancements illustrate novel mechanisms of AMPK regulation, including changes in subcellular localization and phosphorylation by non-canonical upstream kinases. Notably, the therapeutic potential of AMPK is widely recognized and heavily pursued for treatment of metabolic diseases such as diabetes, but also obesity, inflammation, and cancer. Moreover, the recently solved crystal structure of AMPK has shed light both into how nucleotides activate AMPK and, importantly, also into the sites bound by small molecule activators, thus providing a path for improved drugs. PMID- 28622527 TI - Alzheimer's disease: The state of the art in resting-state magnetoencephalography. AB - Alzheimer's disease (AD) is accompanied by functional brain changes that can be detected in imaging studies, including electromagnetic activity recorded with magnetoencephalography (MEG). Here, we systematically review the studies that have examined resting-state MEG changes in AD and identify areas that lack scientific or clinical progress. Three levels of MEG analysis will be covered: (i) single-channel signal analysis, (ii) pairwise analyses over time series, which includes the study of interdependencies between two time series and (iii) global network analyses. We discuss the findings in the light of other functional modalities, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Overall, single-channel MEG results show consistent changes in AD that are in line with EEG studies, but the full potential of the high spatial resolution of MEG and advanced functional connectivity and network analysis has yet to be fully exploited. Adding these features to the current knowledge will potentially aid in uncovering organizational patterns of brain function in AD and thereby aid the understanding of neuronal mechanisms leading to cognitive deficits. PMID- 28622528 TI - Band-specific atypical functional connectivity pattern in childhood autism spectrum disorder. AB - OBJECTIVE: Altered brain connectivity has been theorized as a key neural underpinning of autism spectrum disorder (ASD), but recent investigations have revealed conflicting patterns of connectivity, particularly hyper-connectivity and hypo-connectivity across age groups. The application of graph theory to neuroimaging data has become an effective approach for characterizing topographical patterns of large-scale functional networks. We used a graph approach to investigate alteration of functional networks in childhood ASD. METHOD: Magnetoencephalographic signals were quantified using graph-theoretic metrics with a phase lag index (PLI) for specific bands in 24 children with autism spectrum disorder and 24 typically developing controls. RESULTS: No significant group difference of PLI was found. Regarding topological organization, enhanced and reduced small-worldness, representing the efficiency of information processing, were observed respectively in ASD children, particularly in the gamma band and delta band. CONCLUSIONS: Analyses revealed frequency-dependent atypical neural network topologies in ASD children. SIGNIFICANCE: Our findings underscore the recently proposed atypical neural network theory of ASD during childhood. Graph theory with PLI applied to magnetoencephalographic signals might be a useful approach for characterizing the frequency-specific neurophysiological bases of ASD. PMID- 28622529 TI - Automatic multimodal detection for long-term seizure documentation in epilepsy. AB - OBJECTIVE: This study investigated sensitivity and false detection rate of a multimodal automatic seizure detection algorithm and the applicability to reduced electrode montages for long-term seizure documentation in epilepsy patients. METHODS: An automatic seizure detection algorithm based on EEG, EMG, and ECG signals was developed. EEG/ECG recordings of 92 patients from two epilepsy monitoring units including 494 seizures were used to assess detection performance. EMG data were extracted by bandpass filtering of EEG signals. Sensitivity and false detection rate were evaluated for each signal modality and for reduced electrode montages. RESULTS: All focal seizures evolving to bilateral tonic-clonic (BTCS, n=50) and 89% of focal seizures (FS, n=139) were detected. Average sensitivity in temporal lobe epilepsy (TLE) patients was 94% and 74% in extratemporal lobe epilepsy (XTLE) patients. Overall detection sensitivity was 86%. Average false detection rate was 12.8 false detections in 24h (FD/24h) for TLE and 22 FD/24h in XTLE patients. Utilization of 8 frontal and temporal electrodes reduced average sensitivity from 86% to 81%. CONCLUSION: Our automatic multimodal seizure detection algorithm shows high sensitivity with full and reduced electrode montages. SIGNIFICANCE: Evaluation of different signal modalities and electrode montages paces the way for semi-automatic seizure documentation systems. PMID- 28622531 TI - Explaining transgression in respiratory rate observation methods in the emergency department: A classic grounded theory analysis. AB - BACKGROUND: Abnormal respiratory rates are one of the first indicators of clinical deterioration in emergency department(ED) patients. Despite the importance of respiratory rate observations, this vital sign is often inaccurately recorded on ED observation charts, compromising patient safety. Concurrently, there is a paucity of research reporting why this phenomenon occurs. OBJECTIVE: To develop a substantive theory explaining ED registered nurses' reasoning when they miss or misreport respiratory rate observations. DESIGN: This research project employed a classic grounded theory analysis of qualitative data. PARTICIPANTS: Seventy-nine registered nurses currently working in EDs within Australia. Data collected included detailed responses from individual interviews and open-ended responses from an online questionnaire. METHODS: Classic grounded theory (CGT) research methods were utilised, therefore coding was central to the abstraction of data and its reintegration as theory. Constant comparison synonymous with CGT methods were employed to code data. This approach facilitated the identification of the main concern of the participants and aided in the generation of theory explaining how the participants processed this issue. RESULTS: The main concern identified is that ED registered nurses do not believe that collecting an accurate respiratory rate for ALL patients at EVERY round of observations is a requirement, and yet organizational requirements often dictate that a value for the respiratory rate be included each time vital signs are collected. The theory 'Rationalising Transgression', explains how participants continually resolve this problem. The study found that despite feeling professionally conflicted, nurses often erroneously record respiratory rate observations, and then rationalise this behaviour by employing strategies that adjust the significance of the organisational requirement. These strategies include; Compensating, when nurses believe they are compensating for errant behaviour by enhancing the patient's outcome; Minimalizing, when nurses believe that the patient's outcome would be no different if they recorded an accurate respiratory rate or not and; Trivialising, a strategy that sanctions negligent behaviour and occurs when nurses 'cut corners' to get the job done. Nurses' use these strategies to titrate the level ofemotional discomfort associated with erroneous behaviour, thereby rationalising transgression CONCLUSION: This research reveals that despite continuing education regarding gold standard guidelines for respiratory rate collection, suboptimal practice continues. Ideally, to combat this transgression, a culture shift must occur regarding nurses' understanding of acceptable practice methods. Nurses must receive education in a way that permeates their understanding of the relationship between the regular collection of accurate respiratory rate observations and optimal patient outcomes. PMID- 28622530 TI - Brain network dynamics in the human articulatory loop. AB - OBJECTIVE: The articulatory loop is a fundamental component of language function, involved in the short-term buffer of auditory information followed by its vocal reproduction. We characterized the network dynamics of the human articulatory loop, using invasive recording and stimulation. METHODS: We measured high-gamma activity70-110 Hz recorded intracranially when patients with epilepsy either only listened to, or listened to and then reproduced two successive tones by humming. We also conducted network analyses, and analyzed behavioral responses to cortical stimulation. RESULTS: Presentation of the initial tone elicited high-gamma augmentation bilaterally in the superior-temporal gyrus (STG) within 40ms, and in the precentral and inferior-frontal gyri (PCG and IFG) within 160ms after sound onset. During presentation of the second tone, high-gamma augmentation was reduced in STG but enhanced in IFG. The task requiring tone reproduction further enhanced high-gamma augmentation in PCG during and after sound presentation. Event-related causality (ERC) analysis revealed dominant flows within STG immediately after sound onset, followed by reciprocal interactions involving PCG and IFG. Measurement of cortico-cortical evoked-potentials (CCEPs) confirmed connectivity between distant high-gamma sites in the articulatory loop. High frequency stimulation of precentral high-gamma sites in either hemisphere induced speech arrest, inability to control vocalization, or forced vocalization. Vocalization of tones was accompanied by high-gamma augmentation over larger extents of PCG. CONCLUSIONS: Bilateral PCG rapidly and directly receives feed forward signals from STG, and may promptly initiate motor planning including sub vocal rehearsal for short-term buffering of auditory stimuli. Enhanced high-gamma augmentation in IFG during presentation of the second tone may reflect high-order processing of the tone sequence. SIGNIFICANCE: The articulatory loop employs sustained reciprocal propagation of neural activity across a network of cortical sites with strong neurophysiological connectivity. PMID- 28622532 TI - Evaluation of ALCAM, PECAM-1 and selectin levels in intracranial meningiomas. AB - OBJECTIVES: Cell adhesion molecules play a major role in various pathological states. The aim of this study was to evaluate the tissue levels of selectins (E-, L-, and P-Selectins), activated leukocyte cell adhesion molecule (ALCAM) and platelet endothelial cell adhesion molecule-1 (PECAM-1) in intracranial meningiomas and compare with the levels in control tissues. PATIENTS AND METHODS: 20 consecutive patients who were operated on meningiomas (grade-I: 17 and grade II: 3) and 15 cerebral tissues obtained during the autopsy procedures as a resource for the healthy controls were included in this study. RESULTS: All three selectins', ALCAM and PECAM-1 levels were found to be significantly higher in meningiomas when compared with the control tissues (p<0.001, p<0.001, p<0.001, p<0.05, p<0.001), respectively. CONCLUSIONS: According to our results, the adhesion molecules were found to be higher in meningiomas suggesting that they may be involved in the pathological process of this type of brain tumors. We conceive that developing alternate therapies such as immunotherapeutic approaches against brain tumors might be amendatory in the treatment. Since this is the first study performed in meningioma type brain tumors demonstrating and comparing the levels of various adhesion molecules with control tissues, further clinical and experimental studies are needed to support our current findings with higher number of patients. PMID- 28622533 TI - Intrathecal IgM index correlates with a severe disease course in multiple sclerosis: Clinical and MRI results. AB - OBJECTIVES: Intrathecally synthesized IgM can be seen not only in the cerebrospinal fluid (CSF) in infectious and inflammatory diseases of the central nervous system, but also in that of patients with multiple sclerosis (MS). Intrathecal IgM synthesis in MS seems to be correlated with an unfavorable disease course. In one cross-sectional study, intrathecal synthesis of IgM (IgM index) was found to be correlated with cranial magnetic resonance imaging (MRI) parameters. The purpose of this study was to determine the possible relationship between the IgM index and MRI and clinical parameters. PATIENTS AND METHODS: Eighty-one patients with MS (58 female) undergoing lumbar puncture were included in the study. Fifty-one patients had a relapsing-remitting (RR) disease course, while 30 cases were secondary progressive MS (SPMS). IgM was detected in paired CSF and serum specimens using ELISA. The IgM index was calculated using the formula CSF IgM/serum IgM: CSF albumin/serum albumin. IgM indexes higher than 0.1 were considered "increased". All patients underwent brain and whole spinal cord MRI. RESULTS: The IgM index was normal in 43 of the 81 patients (53.1%) and increased in 38 (46.9%). A significant correlation was determined between the IgM index and Expanded Disability Status Scale (EDSS) (r=0.638, p=0.001). Most of the subjects with increased IgM indexes were SPMS patients, 28 having a SPMS course and 10 a RRMS course. Only two patients with SPMS courses had normal IgM indexes. EDSS scores were significantly higher in patients with increased IgM indexes (EDSS 4.3 vs EDSS 2.8, p=0.000). All patients with EDSS >3 had increased IgM indexes. All patients with IgM index values higher than 0.2 IgM had SPMS courses and EDSS >6. Time to onset of the secondary progressive phase of the disease was correlated with IgM index values (p=0.004). IgM index values were also correlated with T1 hypointense lesions (r=0.0431, p=0.008) and Gd enhancing lesions (r=0.0396, p=0.006). Patients with increased IgM indexes also had more spinal lesions (p=0.000). No relation was determined between an increased IgM index and an increased IgG index. No relation was determined with IgG oligoclonal band positivity. No correlation was also observed between IgM index and IgG index values. CONCLUSION: According to our findings, intrathecal IgM synthesis is associated with a worse long-term prognosis. It also correlates with a higher relapse rate, greater disability, and worse MRI outcomes. Early observation of increased IgM index values will be a helpful tool for clinicians in selecting patients for early immunomodulatory or immunosuppressant treatments. PMID- 28622534 TI - Increased expression of toll-like receptors 2 and 9 is associated with reduced DNA methylation in spontaneous preterm labor. AB - The cause of spontaneous preterm labor (sPTL) is not known, but it could be due to epigenetic alterations that increase the sensitivity of decidual tissue to inflammatory stimuli. We collected decidual tissue from women at term not in labor (TNL), women at term in labor (TL), and women with sPTL. Illumina Infinium HumanMethylation450 BeadChip analysis revealed significantly reduced DNA methylation for TLR-2 and TLR-9 in sPTL as compared to TL. Immunohistochemical staining documented significantly increased expression of TLR-2 and TLR-9 in decidual tissue of women with sPTL as compared to TL or TNL. TLR expression was not present in decidual cells, but localized to tissue leukocytes as revealed by staining for CD14, a macrophage antigen, and neutrophil elastase. Microarray analysis of inflammatory genes to assess innate immune response demonstrated marked increases in expression of inflammatory cytokines and chemokines in women with TL as compared to TNL. However, when sPTL was compared to TL, there was a further increase in inflammatory cytokines, and a remarkable increase in neutrophil chemokines. These results suggest that epigenetic mechanisms could play a role in increasing leukocyte infiltration, and increasing the sensitivity of decidual tissue to inflammatory stimuli that could precipitate labor prematurely. PMID- 28622536 TI - Peer review in forensic science. AB - Peer review features prominently in the forensic sciences. Drawing on recent research and studies, this article examines different types of peer review, specifically: editorial peer review; peer review by the scientific community; technical and administrative review; and verification (and replication). The article reviews the different meanings of these quite disparate activities and their utility in relation to enhancing performance and reducing error. It explains how forensic practitioners should approach and use peer review, as well as how it should be described in expert reports and oral testimony. While peer review has considerable potential, and is a key component of modern quality management systems, its actual value in most forensic science settings has yet to be determined. In consequence, forensic practitioners should reflect on why they use specific review procedures and endeavour to make their actual practices and their potential value transparent to consumers; whether investigators, lawyers, jurors or judges. Claims that review increases the validity of a scientific technique or accuracy of opinions within a particular case should be avoided until empirical evidence is available to support such assertions. PMID- 28622535 TI - Vitamin D mediates the relationship between placental cathelicidin and group B streptococcus colonization during pregnancy. AB - Vitamin D is thought to modulate innate immune responses, and recent studies have highlighted the autocrine and paracrine functions of vitamin D in the placenta. Our objective was to determine the relationship between maternal vitamin D status and placental antimicrobial peptide (AMP) expression in a group of racially and ethnically diverse pregnant adolescents. In this study, 158 pregnant adolescents were recruited from the Rochester Adolescent Maternity Program (RAMP) in Rochester, NY. Maternal serum concentrations of the vitamin D biomarkers, 25 hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D), were measured at mid-gestation (~26 weeks) and at delivery. At the placental level, vitamin D regulatory proteins (cubilin, megalin, 1alpha-hydroxylase (CYP27B1), 24 hydroxylase (CYP24A1), vitamin D receptor (VDR)) and AMPs (cathelicidin and hepcidin) were analyzed using quantitative PCR and western blot techniques. Placental CYP27B1 mRNA expression was significantly positively associated with both placental cathelicidin mRNA expression (P<0.0001) and placental hepcidin mRNA expression (P=0.002). In teens with positive recto-vaginal group B streptococcus (GBS) colonization, placental mRNA expression of cathelicidin (P=0.007), cubilin (P=0.03), and CYP27B1 (P=0.04) were significantly lower compared to those who tested negative for this infection. A mediation analysis showed that the indirect relationship between GBS colonization and placental cathelicidin mRNA expression was mediated by the placental mRNA expression of the vitamin D proteins cubilin and CYP27B1 (P=0.02). Additional research is needed to identify the role and relative contributions of placental and systemic vitamin D metabolites in relation to potentially pathogenic microorganisms which may be present during pregnancy. PMID- 28622538 TI - Current psychiatric disorders in patients with epilepsy are predicted by maltreatment experiences during childhood. AB - PURPOSE: Childhood maltreatment has been shown to be a risk factor for the development of psychiatric disorders. Although the prevalence of psychiatric disorders is high in epilepsy patients, it is unknown if childhood maltreatment experiences are elevated compared to the normal population and if early maltreatment is a risk factor for current psychiatric comorbidities in epilepsy patients. This is the main purpose of this study. METHODS: Structured interviews were used to assess current Axis I diagnoses in 120 epilepsy patients from a tertiary Epilepsy Center (34 TLE patients, 86 non-TLE patients). Childhood maltreatment in the family and peer victimization were assessed with validated questionnaires. Patients' maltreatment scores were compared with those of a representative matched control group. Logistic regression analysis was conducted to assess the potential impact of childhood maltreatment on current psychiatric comorbidity in epilepsy patients. RESULTS: Compared to a matched control group, epilepsy patients had higher emotional and sexual maltreatment scores. Patients with a current psychiatric diagnosis reported more family and peer maltreatment than patients without a psychiatric disorder. Family maltreatment scores predicted the likelihood of a current psychiatric disorder. TLE patients did not differ from non-TLE patients according to maltreatment experiences and rates of current psychiatric disorders. CONCLUSION: Our findings suggest that in epilepsy patients emotional and sexual childhood maltreatment is experienced more often than in the normal population and that early maltreatment is a general risk factor for psychiatric comorbidities in this group. PMID- 28622537 TI - Intravenous lacosamide in status epilepticus: Correlation between loading dose, serum levels, and clinical response. AB - INTRODUCTION: Intravenous lacosamide (LCM) is increasingly used in the treatment of status epilepticus (SE), but optimal loading dose and target serum levels are unclear. We analysed the correlation between LCM serum levels after intravenous loading dose and clinical response. MATERIALS AND METHODS: Retrospective study in two centres from December 2014 to May 2016 including consecutive SE patients treated with LCM, in which trough serum levels after intravenous loading dose were available. Trough levels were correlated with the loading dose and the clinical response, defined as LCM introduction terminating SE without the need of further treatment. Correlations were adjusted for other SE characteristics. RESULTS: Among 40 patients, 16 (40%) responded to LCM. LCM serum concentrations within the reference interval (10-20mg/l) were associated with loading doses of >9mg/kg (p=0.003; chi2). However, we observed no difference between LCM serum levels in responders (median 10.4mg/l) versus non-responders (median 9.5mg/l; p=0.36; U test), even after adjusting for other predictors of clinical outcome (SE severity, aetiology, and number of previous treatment). DISCUSSION: High intravenous LCM loading doses (>9mg/kg) were associated with serum levels within the reference interval, there was however no correlation with the clinical response. Prospective studies are needed to evaluate the benefit of increasing the LCM loading dose in SE. PMID- 28622539 TI - Features of amygdala in patients with mesial temporal lobe epilepsy and hippocampal sclerosis: An MRI volumetric and histopathological study. AB - OBJECTIVE: It is well-known that there is a correlation between the neuropathological grade of hippocampal sclerosis (HS) and neuroradiological atrophy of the hippocampus in mesial temporal lobe epilepsy (mTLE) patients. However, there is no strict definition or criterion regarding neuron loss and atrophy of the amygdala neighboring the hippocampus. We examined the relationship between HS and neuronal loss in the amygdala. MATERIALS AND METHODS: Nineteen mTLE patients with neuropathological proof of HS were assigned to Group A, while seven mTLE patients without HS were assigned to Group B. We used FreeSurfer software to measure amygdala volume automatically based on pre-operation magnetic resonance images. Neurons observed using Kluver-Barrera (KB) staining in resected amygdala tissue were counted. and the extent of immunostaining with stress marker antibodies was semiquantitatively evaluated. RESULTS: There was no significant difference in amygdala volume between the two groups (Group A: 1.41+/-0.24; Group B: 1.41+/-0.29cm3; p=0.98), nor in the neuron cellularity of resected amygdala specimens (Group A: 3.98+/-0.97; Group B: 3.67+/-0.67 10*-4 number of neurons/MUm2; p=0.40). However, the HSP70 level, representing acute stress against epilepsy, in Group A patients was significantly larger than that in Group B. There was no significant difference in the level of Bcl-2, which is known as a protein that inhibits cell death, between the two groups. CONCLUSIONS: Neuronal loss and volume loss in the amygdala may not necessarily follow hippocampal sclerosis. From the analysis of stress proteins, epileptic attacks are as likely to damage the amygdala as the hippocampus but do not lead to neuronal death in the amygdala. PMID- 28622540 TI - Scattering of Airy elastic sheets by a cylindrical cavity in a solid. AB - The prediction of the elastic scattering by voids (and cracks) in materials is an important process in structural health monitoring, phononic crystals, metamaterials and non-destructive evaluation/imaging to name a few examples. Earlier analytical theories and numerical computations considered the elastic scattering by voids in plane waves of infinite extent. However, current research suggesting the use of (limited-diffracting, accelerating and self-healing) Airy acoustical-sheet beams for non-destructive evaluation or imaging applications in elastic solids requires the development of an improved analytical formalism to predict the scattering efficiency used as a priori information in quantitative material characterization. Based on the definition of the time-averaged scattered power flow density, an analytical expression for the scattering efficiency of a cylindrical empty cavity (i.e., void) encased in an elastic medium is derived for compressional and normally-polarized shear-wave Airy beams. The multipole expansion method using cylindrical wave functions is utilized. Numerical computations for the scattering energy efficiency factors for compressional and shear waves illustrate the analysis with particular emphasis on the Airy beam parameters and the non-dimensional frequency, for various elastic materials surrounding the cavity. The ratio of the compressional to the shear wave speed stimulates the generation of elastic resonances, which are manifested as a series of peaks in the scattering efficiency plots. The present analysis provides an improved method for the computations of the scattering energy efficiency factors using compressional and shear-wave Airy beams in elastic materials as opposed to plane waves of infinite extent. PMID- 28622541 TI - Transmission characteristics of the S0 and A0 Lamb waves at contacting edges of plates. AB - In order to gain basic insight into the interaction between ultrasonic guided waves and structural discontinuities with contacting surfaces, the transmission characteristics of Lamb waves at contacting edges of two plates are studied experimentally. The edges of two 2.5-mm thick aluminum alloy plates are mated together to constitute a contacting interface of plates and subjected to different levels of compressive loading. The transmission measurements of the lowest-order symmetric (S0) and antisymmetric (A0) Lamb modes across the contacting interface are performed in a frequency range below the cut-off frequencies of the higher-order modes. As a result, it is found that the transmission coefficient of the S0 mode increases monotonically with the applied contact pressure, but the transmission coefficient of the A0 mode exhibits non monotonic dependence on the contact pressure and the frequency showing a local minimum. For the incidence of the S0 mode, the resonance at the contacting interface is observed as a long-time oscillation tail in the transmission waveform. The resonance frequency is found to increase with the contact pressure. The experimental results are discussed in the light of the theoretical results based on the spring-type interface model. The normal and tangential stiffnesses of the contacting interface are identified from the transmission coefficients as well as from the resonance frequency. The estimated interfacial stiffnesses increase monotonically with the contact pressure, and indicate their dependence on the frequency. Implications of the present results to the Lamb-wave based characterization of the plate contact condition are discussed briefly. PMID- 28622542 TI - On the mechanism of non-radiative decay of blue fluorescent protein chromophore: New insight from the excited-state molecular dynamics simulations and potential energy calculations. AB - A detailed theoretical investigation based on the ab initio on-the-fly surface hopping dynamics simulations and potential energy surfaces calculations has been performed to unveil the mechanism of the photoinduced non-adiabatic relaxation process of the isolated blue fluorescent protein (BFP) chromophore in gas phase. The data analysis presents that the dominant reaction coordinate of the BFP chromophore is driven by a rotation motion around the CC double bridging bond, which is in remarkable difference with a previous result which supports a Hula Twist rotation pattern. Such behavior is consistent with the double bond rotation pattern of the GFP neutral chromophore. In addition, the dynamics simulations give an estimated decay time of 1.1ps for the S1 state, which is agrees well with the experimental values measured in proteins. The present work offers a straightforward understanding for the decay mechanism of the BFP chromophore and suggestions of the photochemical properties of analogous protein chromophores. We hope the current work would be helpful for further exploration of the BFP photochemical and photophysical properties in various environments, and can provide guidance and prediction for rational design of the fluorescent proteins catering for different demands. PMID- 28622543 TI - Quantitative analysis of anti-inflammatory drugs using FTIR-ATR spectrometry. AB - Four simple, accurate, sensitive and economic Attenuated Total Reflectance Fourier Transform Infrared Spectroscopic (ATR-FTIR) methods have been developed for the quantitative estimation of some non-steroidal anti-inflammatory drugs. The first method involves the determination of Etodolac by direct measurement of the absorbance at 1716cm-1. In the second method, the second derivative of the IR spectra of Tolfenamic acid and its reported degradation product (2-chlorobenzoic acid) was used and the amplitudes were measured at 1084.27cm-1 and 1056.02cm-1 for Tolfenamic acid and 2-chlorobenzoic acid, respectively. The third method used the first derivative of the IR spectra of Bumadizone and its reported degradation product, N,N-diphenylhydrazine and the amplitudes were measured at 2874.98cm-1 and 2160.32cm-1 for Bumadizone and N,N-diphenylhydrazine, respectively. The fourth method depends on measuring the amplitude of Diacerein at 1059.18cm-1 and of rhein, its reported degradation product, at 1079.32cm-1 in their first derivative spectra. The four methods were successfully applied on the pharmaceutical formulations by extracting the active constituent in chloroform and the extract was directly measured in liquid phase mode using a specific cell. Moreover, validation of these methods was carried out following International Conference of Harmonisation (ICH) guidelines. PMID- 28622544 TI - Conformational transition of kappa-casein in micellar environment: Insight from the tryptophan fluorescence. AB - Intrinsically disordered proteins (IDPs) are under intense analysis due to their structural flexibility and importance in biological functions. Minuscule modulation in the microenvironment induces significant conformational changes in IDPs, and these non-native conformations of the IDPs often induce aggregation and cause cell death. Changes in the membrane composition often change the microenvironment, which promote conformational change and aggregation of IDPs. kappa-Casein, an important milk protein, belongs to the class of IDPs containing net negative charges. In this present work, we have studied the interaction of kappa-casein with cetyltrimethyl ammonium bromide (CTAB), a positively charged surfactant, utilizing various steady state fluorescence, time-resolved fluorescence and circular dichroism spectroscopy. Our results clearly indicate that kappa-casein undergoes at least two conformational transitions in presence of various concentrations of CTAB. The intrinsically disordered kappa-casein assumes a partially folded conformation at lower concentration of CTAB, which adopts an unstructured conformation at higher concentration of CTAB. The partially folded conformation of kappa-casein at a lower CTAB concentration might be induced by the favorable electrostatic interaction between the positively charged surfactant headgroup and net negative charges of the protein, whereas surfactant nature of CTAB is being pronounced at higher concentration of CTAB. PMID- 28622545 TI - Diagnosing psychogenic nonepileptic seizures: Video-EEG monitoring, suggestive seizure induction and diagnostic certainty. AB - Psychogenic nonepileptic seizures (PNES) can remain undiagnosed for many years, leading to unnecessary medication and delayed treatment. A recent report by the International League Against Epilepsy Nonepileptic Seizures Task Force recommends a staged approach to the diagnosis of PNES (LaFrance, et al., 2013). We aimed to investigate its practical utility, and to apply the proposed classification to evaluate the role of long-term video-EEG monitoring (VEEG) and suggestive seizure induction (SSI) in PNES workup. Using electronic medical records, 122 inpatients (mean age 36.0+/-12.9years; 68% women) who received the diagnosis of PNES at our epilepsy center during a 4.3-year time period were included. There was an 82.8% agreement between diagnostic certainty documented at discharge and that assigned retroactively using the Task Force recommendations. In a minority of cases, having used the Task Force criteria could have encouraged the clinicians to give more certain diagnoses, exemplifying the Task Force report's utility. Both VEEG and SSI were effective at supporting high level diagnostic certainty. Interestingly, about one in four patients (26.2%) had a non-diagnostic ("negative") VEEG but a positive SSI. On average, this subgroup did not have significantly shorter mean VEEG recording times than VEEG-positive patients. However, VEEG-negative/SSI-positive patients had a significantly lower habitual seizure frequency than their counterparts. This finding emphasizes the utility of SSI in ascertaining the diagnosis of PNES in patients who do not have a spontaneous habitual event during VEEG due to, for example, low seizure frequency. PMID- 28622546 TI - The semiology of febrile seizures: Focal features are frequent. AB - OBJECTIVE: To clarify the semiology of febrile seizures (FS) and to determine the frequency of FS with symptoms suggestive of focal onset. METHODS: FS symptoms in children were reported within 24h of seizure onset by the parents using a structured questionnaire consisting principally of closed-ended questions. We focused on events at seizure commencement, including changes in behavior and facial expression, and ocular and oral symptoms. We also investigated the autonomic and motor symptoms developing during seizures. The presence or absence of focal and limbic features was determined for each patient. The associations of certain focal and limbic features with patient characteristics were assessed. RESULTS: Information was obtained on FS in 106 children. Various events were recorded at seizure commencement. Behavioral changes were observed in 35 children, changes in facial expression in 53, ocular symptoms in 78, and oral symptoms in 90. In terms of events during seizures, autonomic symptoms were recognized in 78, and convulsive motor symptoms were recognized in 68 children. Focal features were evident in 81 children; 38 children had two or more such features. Limbic features were observed in 44 children, 9 of whom had two or more such features. There was no significant relationship between any patient characteristic and the numbers of focal or limbic features. SIGNIFICANCE: The semiology of FS varied widely among children, and symptoms suggestive of focal onset were frequent. FS of focal onset may be more common than is generally thought. PMID- 28622547 TI - Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy. AB - PURPOSE: A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. METHOD: From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. RESULTS: Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. CONCLUSIONS: Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions. PMID- 28622548 TI - Early bony changes associated with bisphosphonate-related osteonecrosis of the jaws in rats: A longitudinal in vivo study. AB - OBJECTIVE: To evaluate early bony changes in an animal model of Medication Related Osteonecrosis of the Jaw (MRONJ) at the side of the local trauma and at the contralateral side, comparing with a control group. Bony changes were evaluated by Microcomputed Tomography (MicroCT) at three times points: at baseline (T0), after drug administration (T1) and after dental extraction (T2). DESIGN: Two groups were compared: the experimental group in which zoledronic acid (ZA) was administered (17 rats) and the control group (13 rats). Dental extractions of the lower left first molars were performed in all animals. The left side was considered as the supposed affected area in the ZA group, and the right side was considered as the unaffected area. In these areas, the following structural microtomographic bone parameters were calculated: Bone Mineral Density (BMD), Trabecular Thickness (Tb.Th), and Bone Volume Proportion (BV/TV). The comparison of quantitative bone parameters among the different sides and experimental phases of both studied groups were performed by ANOVA-factorial. RESULTS: None of the animals of the control group developed MRONJ. In the ZA group, 76% presented bone exposure. From T0 to T1, Tb.Th and BV/TV increased, and in T2, the mean values were higher in ZA group than in the control group. BMD increased throughout the different phases of both groups. CONCLUSIONS: Structural bony changes occurred in the ZA group at both mandibular sides before the dental extraction (T1). Tb.Th and BV/TV should be further investigated as potential early bone markers of MRONJ. PMID- 28622549 TI - Immunological and epidemiological factors affecting candidiasis in HIV patients beginning antiretroviral therapy in an Asian clinic. AB - OBJECTIVES: Oropharyngeal candidiasis (OPC) is common in HIV patients beginning antiretroviral therapy (ART). Here we address the response to ART, and the roles of poor oral hygiene and defects in local innate immunity with a focus on salivary beta-defensins, as they are implicated in control of candidiasis but have not been investigated in this context. DESIGN: ART naive HIV-infected adults (n=82) with <200 CD4+ T-cells/mm3 attending clinics at Cipto Mangunkusumo Hospital, Jakarta, were examined at the commencement of ART, and 73 were re examined after 3 months. OPC was detected by clinical examination, and Candida albicans and fungal burdens were determined following culture on CHROMagar and saboroud-dextrose agar (resp). Salivary beta-defensins (-2 and -3) were quantified by ELISA. Healthy control subjects (n=40) matched the patients by age and gender. RESULTS: OPC was evident in 47 patients before ART, and associated with greater fingal burdens. No OPC was detected in healthy controls and culture positivity was rare. ART decreased the prevalence of OPC to 8/73 HIV patients re examined after 3 months, with reduced total fungal and C. albicans burdens. The incidence of OPC was independent of oral hygiene. Hyposalivation was more common in untreated HIV patients (16%) than after 3 months on ART and was rare in healthy controls. HIV patients were also more likely to have acidic saliva. Salivary beta-defensin-2 was elevated in the presence of C. albicans pseudohyphae and OPC after 3 months on ART, but beta-defensin-3 was not affected by OPC or ART. CONCLUSIONS: ART reduces the prevalence of OPC, and the total fungal and C. albicans burden. Levels of salivary beta-defensin-2 may associate with OPC in HIV patients responding to ART. PMID- 28622550 TI - Effect of gels containing chlorhexidine or epigallocatechin-3-gallate on the protein composition of the acquired enamel pellicle. AB - OBJECTIVE: This study evaluated changes in protein profile of the acquired enamel pellicle (AEP) formed in vivo, after application of gels containing chlorhexidine or EGCG and further challenge with citric acid. DESIGN: AEP was formed in 9 volunteers for 2h and then treated with one of the following gels: placebo, 400MUM EGCG or 0.012% chlorhexidine. A thin layer of gel was applied and after 1min the excess was removed. One hour after gel application, the AEP was collected from the buccal surface (upper and lower jaw) of one of the sides with filter paper dipped in 3% citric acid. On the other side, erosive challenge was performed through gentle application of 1% citric acid (pH 2.5) for 20s (using a pipette) followed by washing with deionized water. The AEP was collected as mentioned before. Proteomic analysis was performed through liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The MS/MS spectra obtained were compared with human protein databases (SWISS-PROT). Label free quantitation was done using the PLGS software. RESULTS: In total, 223 proteins were identified. After treatment with EGCG and CHX gels, proteins with potential functions to protect against caries and erosion such as PRPs, calcium bind proteins and Statherin were increased. When EGCG and CHX-treated AEPs were challenged with citric acid, there was increase in cystatins and Profilin-1. CONCLUSION: CHX- and EGCG-treated AEPs, submitted to challenge with citric acid or not, had remarkable changes in their proteomic profiles. PMID- 28622551 TI - Tips and tricks to optimize MRI protocols for cutaneous vascular anomalies. AB - Magnetic resonance imaging (MRI) serves as the principal imaging modality to diagnose and plan treatment for children with cutaneous vascular anomalies. While routine MRI protocols can lead to the correct diagnosis in the majority of cases, the imaging appearances can sometimes be nonspecific or confusing, yielding more than one possible diagnosis. This review highlights specific MRI sequence recommendations and scanning tips that can optimize the imaging protocol to increase diagnostic confidence. PMID- 28622552 TI - Fornix microalterations associated with early trauma in panic disorder. AB - BACKGROUND: It is well accepted that panic disorder (PD) is associated with early trauma, and that the limbic systems are one of the main structures involved in PD pathophysiology. However, previous studies have not addressed the relationship between early trauma and major limbic white-matter (WM) structures in PD. METHODS: Participants enrolled in the study consisted of 53 right-handed patients with PD and 21 healthy controls (HC). The Early Trauma Inventory Self Report Short Form (ETISR-SF), Anxiety Sensitivity Inventory-Revised (ASI-R), and the Albany Panic and Phobia Questionnaire (APPQ) were applied in the study. Tract based spatial statistics were used for diffusion tensor magnetic resonance imaging analysis. RESULTS: Among the patients with PD, the fractional anisotropy (FA) values of the fornix body in major limbic WM regions showed significant negative correlation with the ETISR-SF total score, while the scores of mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in the same region of fornix had significant positive correlation with those scores (p<0.05; FWE corrected). Further significant correlation was observed between these four scores and the measures of symptom severity in PD, such as that in ASI-R and APPQ in the same region. LIMITATIONS: Recall bias is possible in evaluating early trauma in the participants. CONCLUSIONS: The current study suggests a significant association of early trauma with the fornix body possibly through axons and myelin disruptions within major limbic structures in PD. A multi-centered large sample will be needed to confirm these findings. PMID- 28622553 TI - Toxic responses of cytochrome P450 sub-enzyme activities to heavy metals exposure in soil and correlation with their bioaccumulation in Eisenia fetida. AB - The dose- and time- dependent responses of cytochrome P450 (CYP) sub-enzyme activities to heavy metals in soil, and the relationships between biomarker responses and metal bioaccumulation in Eisenia fetida were evaluated. Earthworms were exposed to soils spiked with increasing doses of Cd, Cu, Pb or Zn for 21 d. Results demonstrated that EROD and CYP3A4 activities responded significantly with increasing dose and exposure duration. EROD activity significantly (P < 0.05) correlated with CYP3A4 activity exposed to Pb and Cu. The earthworm metal burdens had significant correlation with the total metal concentrations in soil (P < 0.01). The bioaccumulation factor (BAF) decreased with the increasing metal concentration in soil. The order of metal bioavailability to E. fetida was Cd > Zn > Cu > Pb. CYP3A4 activity in Pb-exposed earthworms had a significant correlation with the accumulated metal (P < 0.05). Both EROD and CYP3A4 activities in Cu-exposed worms negatively correlated with BAF (P < 0.05). Based on Discriminant Analysis (DA), CYPs activities were sensitive biomarkers of heavy metals exposure, and we also concluded that different biomarkers with multiple durations could be conducted in the eco-toxicological diagnosis of soil pollution. PMID- 28622554 TI - Evaluation of DNA damage induced by gamma radiation in gill and muscle tissues of Cyprinus carpio and their relative sensitivity. AB - The effect of radiation on the aquatic environment is of major concern in recent years. Limited data is available on the genotoxicity of gamma radiation on different tissues of aquatic organisms. Hence, the present investigation was carried out to study the DNA damage induced by gamma radiation in the gill and muscle tissues and their relative sensitivity using the comet assay in the freshwater teleost fish, common carp (Cyprinus carpio). The comet assay was optimized and validated in common carp using cyclophosphamide (CP), a reference genotoxic agent. The fish were exposed (acute) to various doses of gamma radiation (2, 4, 6, 8 and 10Gy) and samplings (gill and muscle tissue) were done at regular intervals (24, 48 and 72h) to assess the DNA damage. A significant increase in DNA damage was observed as indicated by an increase in % tail DNA for all doses of gamma radiation in both tissues. We also observed a dose-related increase and a time-dependent decrease of DNA damage. In comparison, DNA damage showed different sensitivity among the tissues at different doses. This shows that a particular dose may have different effects on different tissues which could be due to physiological factors of the particular tissue. Our study also suggests that the gills and muscle of fish are sensitive and reliable tissues for evaluating the genotoxic effects of reference and environmental agents, using the comet assay. PMID- 28622555 TI - Very sensitive electrochemical determination of diuron on glassy carbon electrode modified with reduced graphene oxide-gold nanoparticle-Nafion composite film. AB - In this work, a very sensitive electrochemical sensor based on glassy carbon electrode (GCE) modified with reduced graphene oxide-gold nanoparticles/Nafion (rGO-AuNPs/Nafion) composite film was applied to determine diuron. Synthesized GO was characterized using X-ray diffraction (XRD) and UV-visible spectroscopy. The surface morphology of the rGO-AuNPs/Nafion film was also characterized using scanning electron microscopy and electrochemical impedance spectroscopy. Cyclic voltammetry (CV) and adsorptive differential pulse voltammetry (AdDPV) were applied to investigate the electrochemical response of the diuron on the modified electrode. The electrode showed a linear response at 1.0*10-9-1.0*10-7 M and a detection limit of 0.3nM under the optimized conditions. The effect of some other species on the determination of diuron was investigated and the sensor showed good selectivity for determination of diuron. The constructed sensor was applied to determine diuron in enriched samples of orange juice, mineral and tap water which statistical t-test showed accuracy of method. Also the sensor was applied to obtain diuron content in the tea sample. The reliability of the proposed sensor was confirmed after comparing the results with those obtained using high performance liquid chromatography (HPLC) as a comparative method. PMID- 28622556 TI - Early chemical and ecotoxicological responses of the Varano lagoon (SE Italy) to a flood event. AB - The effects on coastal lagoons of floods resulting from intense rainfall need to be assessed using a multidisciplinary approach, able to describe in real time the occurrence of changes in sediment quality, anticipating risk situations. In the present study the effectiveness as pre-screening tool of the MOT-test, an innovative bioassay that uses sperm motility as endpoint, has been evaluated; its response has been compared with the sediment chemical characterization, in order to determine the effects of a flood event occurred in the Varano lagoon, a poorly anthropized Mediterranean coastal lagoon. The MOT-test effect percentages ranged from 10% to 30%, fully reflecting data from chemical analyses. Organic pollutants showed concentrations always below the critical levels. The highest metal values were found in the south-eastern area; however, only for few metals (mainly Cd), and in few sites, they reached the limits defined by the sediment quality guidelines; consistently, these sites are located in the area where a higher stressors' impact was expected and the highest MOT-test effect percentages were recorded. In conclusion, even if results exclude the occurrence of serious contamination events as a consequence of the flood, the runoff resulting from the intense rainfall event has caused a pollutant load in the lagoon, consistent with the localization of the main anthropogenic activities in the catchment area. Moreover, preliminary data indicate the validity of the approach adopted for the post-flood quality assessment, proving the usefulness of the MOT-test as early screening tool in the case of extreme events. PMID- 28622557 TI - The executive profile of children with Benign Epilepsy of Childhood with Centrotemporal Spikes and Temporal Lobe Epilepsy. AB - RATIONALE: Benign Epilepsy of Childhood with Centrotemporal Spikes (BECTS) and temporal lobe epilepsy (TLE) represent two distinct models of focal epilepsy of childhood. In both, there is evidence of executive dysfunction. The purpose of the present study was to identify particular deficits in the executive function that would distinguish children with BECTS from children with TLE. METHODS: We prospectively evaluated 19 consecutive children and adolescents with TLE with hippocampal sclerosis (HS) (57.9% male; mean 11.74years [SD 2.05]; mean IQ 95.21 [SD 15.09]), 19 with BECTS (36.8% male; mean 10.95years [SD 2.33]; mean IQ 107.40 [SD 16.01]), and 21 age and gender-matched controls (33.3% male; mean 11.86years [SD 2.25]; mean IQ 108.67 [15.05]). All participants underwent a neuropsychological assessment with a comprehensive battery for executive and attentional functions. We used ANOVA and chi-square to evaluate differences on demographic aspects among groups (BECTS, TLE-HS, and control groups). Group comparisons on continuous variables were complemented by MANOVA and Bonferroni posthoc comparisons. RESULTS: Patients with BECTS had worse performance than controls in: Matching Familiar Figures Test, time (p=0.001); Matching Familiar Figures Test, time*errors index (p<0.001); Verbal Fluency for foods (p=0.038); Trail Making Test, part B time (p=0.030); Trail Making Test, part B number of errors (p=0.030); and WCST, number of categories achieved (p=0.043). Patients with BECTS had worse performance than patients with TLE-HS on Matching Familiar Figures Test, time (p=0.004), and Matching Familiar Figures Test, time*errors index (p<0.001). Patients with TLE-HS had worse performance than controls on the following tests: Verbal Fluency for foods (p=0.004); Wisconsin Card Sorting Test, the number of categories achieved (p<0.001); and Wisconsin Card Sorting Test, the number of perseverative errors (p=0.028). Patients with TLE-HS had worse performance than patients with BECTS on Digit Backward (p=0.002); and the Wisconsin Card Sorting Test, the number of perseverative errors (p<0.001). CONCLUSIONS: Patients with TLE and BECTS present distinct cognitive profiles. Patients with TLE-HS had worse performance in mental flexibility, concept formation, and working memory compared to BECTS. Patients with BECTS had worse inhibitory control compared to children with TLE-HS. Both TLE-HS and BECTS had a higher number of errors on an inhibitory control test. However, patients with BECTS had a slower mental processing even when compared to patients with TLE-HS. Rehabilitation programs for children with epilepsy must include children with benign epilepsies and must take into account the epileptic syndrome and its particular neurocognitive phenotype. PMID- 28622558 TI - Photodynamic Therapy treatment of onychomycosis with Aluminium-Phthalocyanine Chloride nanoemulsions: A proof of concept clinical trial. AB - The conventional treatment of onychomycosis, a common fungal infection, consists in the use of local and systemic drugs for 4-6 months. This long protocol is often ineffective due to patient compliance, and usually promotes important collateral effects such as liver and kidney failure. As the alternative, Photodynamic Therapy (PDT) has been used as a noninvasive alternative local treatment for onychomycosis due to the reduction of systemic side effects, fact indicates their use for patients undergoing other systemic treatments. In the present article, we evaluated the effectiveness, as well as the safety of PDT mediated by Aluminium-Phthalocyanine Chloride, entrapped in nanoemulsions, as a drug carrier, to treat onychomycosis in a proof of concept clinical trial. To the date, this is the first published clinical trial that uses PDT mediated by nanomedicines to treat onychomycosis. As main results, we can highlight the safety of the clinical protocol and the antifungal effectiveness similar to the conventional treatments. We observed the (1) clinical cure of 60% of treated lesions; (2) the absence of local and systemic adverse effects; (3) from these clinically healed lesions, 40% were negative for fungal infection in laboratorial exams; and (4) nails that presented negative fungal culture were kept without fungal infection for at least four weeks. The innovation of this approach is the absence of collateral effects, due to the local therapeutically treatment, and the possibility to repeat the treatment without inducing fungal resistance, a fact that indicates this approach as a possible alternative protocol for onychomycosis management. PMID- 28622559 TI - Controlling sunbathing safety during the summer holidays - The solar UV campaign at Baltic Sea coast in 2015. AB - Information regarding the intensity of surface UV radiation, provided for the public, is frequently given in terms of a daily maximum UV Index (UVI), based on a prognostic model. The quality of the UV forecast depends on the accuracy of column amount of ozone and cloudiness prediction. Daily variability of UVI is needed to determine the risk of the UV overexposure during outdoor activities. Various methods of estimating the temporary UVI and the maximum duration of UV exposures (received a dose equal to minimal erythemal dose - MED), at the site of sunbathing, were compared. The UV indices were obtained during a field experiment at the Baltic Sea coast in the period from 13th to 24th July 2015. The following UVI calculation models were considered: UVI measurements by simple hand-held biometers (Silver Crest, Oregon Scientific, or more advanced Solarmeter 6.5), our smartphone models based on cloud cover observations at the site and the cloudless sky UVI forecast (available for any site for all smartphone users) or measured UVI, and the 24h weather predictions by the ensemble set of 10 models (with various cloud parameterizations). The direct UV measurements, even by a simple biometer, provided useful UVI estimates. The smartphone applications yielded a good agreement with the UV measurements. The weather prediction models for cloudless-sky conditions could provide valuable information if almost cloudless sky conditions (cloudless-sky or slightly scattered clouds) were observed at the sunbathing site. PMID- 28622560 TI - Kinetic and isotherm studies on adsorption of toxic pollutants using porous ZnO@SiO2 monolith. AB - Removal of toxic effluents (like dyes and pesticides) by cost-effective and user friendly method is needed to provide sustaining the environment for civilization. Here, low-cost mesoporous silica monolith (SiO2) and silica supported metal-oxide (ZnO@SiO2) monolith were synthesized to reduce the solemn impact of toxic effluents. Batch experiments were performed to remove Alizarin (AZ), Paradol (PD), Acid blue-113 (AB) and Rhodamine-B (RD) from aqueous solution via synthesized monoliths. The influence of various parameters (like pH, contact time, temperature and adsorbate concentration) has been optimized. The maximum adsorption capacity of ZnO@SiO2 monolith is 625, 500, 714 and 555mg/g for AZ, RD, AB, and PD respectively. The adsorption for AZ, PD, AB, and RD is spontaneous and exothermic. The adsorption process can be well described by the pseudo-second order kinetic model (high regression coefficients) and the Freundlich isotherm model (R2=0.97-0.99). PMID- 28622561 TI - Dendrite-like PtAg alloyed nanocrystals: Highly active and durable advanced electrocatalysts for oxygen reduction and ethylene glycol oxidation reactions. AB - In this work, well-defined dendrite-like PtAg alloyed nanocrystals were prepared by a facile one-pot l-hydroxyproline-assisted successive coreduction approach on a large scale, where no any template or seed involved. l-Hydroxyproline was employed as a green structuring director. The formation mechanism of the alloyed dendritic nanocrystals was investigated in details. The as-prepared frameworks exhibited boosted electrocatalytic activity, improved stability and enhanced tolerance toward oxygen reduction reaction (ORR) and ethylene glycol oxidation reaction (EGOR) in alkaline media in contrast with commercial Pt black catalyst. The developed method provides novel strategy for preparing other shape-controlled nanocatalysts with superior catalytic activity and durability. PMID- 28622562 TI - Hierarchical flower-like nickel(II) oxide microspheres with high adsorption capacity of Congo red in water. AB - Monodispersed hierarchical flower-like nickel(II) oxide (NiO) microspheres were fabricated by a facile solvothermal reaction with the assistance of ethanolamine and a subsequent calcination process. The as-synthesized samples were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, nitrogen adsorption-desorption isotherms, zeta potential measurement and Fourier transform infrared spectroscopy. Flower-like nickel(II) hydroxide microspheres with uniform diameters of approximate 6.3MUm were obtained after the solvothermal reaction. After heat treatment at 350 degrees C, the crystal phase transformed to NiO, but the hierarchical porous structure was maintained. The as-prepared microspheres exhibited outstanding performance for the adsorption of Congo red (CR), an anionic organic dye, from aqueous solution at circumneutral pH. The pseudo-second-order model can make a good description of the adsorption kinetics, while Langmuir model could well express the adsorption isotherms, with calculated maximum CR adsorption capacity of 534.8 and 384.6mgg 1, respectively, for NiO and Ni(OH)2. The adsorption mechanism of CR onto the as synthesized samples can be mainly attributed to electrostatic interaction between the positively charged sample surface and the anionic CR molecules. The as prepared NiO microspheres are a promising adsorbent for CR removal in water treatment. PMID- 28622563 TI - Graphitic carbon nitride nanosheets decorated with CuCr2O4 nanoparticles: Novel photocatalysts with high performances in visible light degradation of water pollutants. AB - In this paper, CuCr2O4 nanoparticles were decorated on the surface of g-C3N4 nanosheets (g-C3N4-NS) by a facile refluxing process. The structure, composition, morphology, optical, textural, and thermal properties were characterized by XRD, EDX, SEM, TEM, UV-vis DRS, FT-IR, XPS, PL, BET, and TGA techniques. The photocatalytic performance of g-C3N4-NS/CuCr2O4 nanocomposites was assessed by degrading RhB and MB dyes and phenol under visible-light illumination. When the loading amount of CuCr2O4 was 10 wt%, the nanocomposite exhibited the highest activity. Activity of the g-C3N4-NS/CuCr2O4 (10%) nanocomposite refluxed for 3h and calcined at 520 degrees C for 4h was almost 11.8 and 4.8 times greater than those of the bulk g-C3N4 and g-C3N4-NS photocatalysts in degradation of RhB, respectively. In the prepared nanocomposites, nanosheets of g-C3N4 act not only as CuCr2O4 support, but also as co-catalyst. The novel visible-light-active photocatalyst has considerable stability and it can be reused for five times without obvious loss of its photocatalytic activity. PMID- 28622564 TI - Visible light photocatalytic performance and mechanism of highly efficient SnS/BiOI heterojunction. AB - Novel SnS/BiOI heterostructures with excellent photocatalytic degradation of methyl orange were successfully prepared by a facile hydrothermal-coprecipitation method. The maximum methyl orange degradation activity under visible light irradiation (lambda>400nm) was found for 10wt% SnS/BiOI. The composite also showed better stability and good recyclability compared to BiOI. The energy band diagram and band offsets from X-ray photoelectron spectroscopy investigation indicated that the novel composite was a type-II heterojunction where the photogenerated electron-hole can be efficiently separated and transferred. Results from UV-vis DRS, PL-TA and photocurrent response measurement suggested that the improved photodegradation efficiency of the SnS/BiOI heterojunction was mainly attributed to enhanced light absorption capability, strong ability to generate and transfer photoexcited charge carriers and high active species formation. Additionally, radical scavenging experiments demonstrated that holes and superoxide radicals are dominant active species, whereas hydroxyl radicals are of secondary importance in this system. A plausible photocatalytic mechanism of the SnS/BiOI composite was also discussed. PMID- 28622565 TI - A shear-induced network of aligned wormlike micelles in a sugar-based molecular gel. From gelation to biocompatibility assays. AB - A new low molecular weight hydrogelator with a saccharide (lactobionic) polar head linked by azide-alkyne click chemistry was prepared in three steps. It was obtained in high purity without chromatography, by phase separation and ultrafiltration of the aqueous gel. Gelation was not obtained reproducibly by conventional heating-cooling cycles and instead was obtained by shearing the aqueous solutions, from 2 wt% to 0.25 wt%. This method of preparation favored the formation of a quite unusual network of interconnected large but thin 2D-sheets (7nm-thick) formed by the association side-by-side of long and aligned 7nm diameter wormlike micelles. It was responsible for the reproducible gelation at the macroscopic scale. A second network made of helical fibres with a 10-13nm diameter, more or less intertwined was also formed but was scarcely able to sustain a macroscopic gel on its own. The gels were analysed by TEM (Transmission Electronic Microscopy), cryo-TEM and SAXS (Small Angle X-ray Scattering). Molecular modelling was also used to highlight the possible conformations the hydrogelator can take. The gels displayed a weak and reversible transition near 20 degrees C, close to room temperature, ascribed to the wormlike micelles 2D sheets network. Heating over 30 degrees C led to the loss of the gel macroscopic integrity, but gel fragments were still observed in suspension. A second transition near 50 degrees C, ascribed to the network of helical fibres, finally dissolved completely these fragments. The gels showed thixotropic behaviour, recovering slowly their initial elastic modulus, in few hours, after injection through a needle. Stable gels were tested as scaffold for neural cell line culture, showing a reduced biocompatibility. This new gelator is a clear illustration of how controlling the pathway was critical for gel formation and how a new kind of self-assembly was obtained by shearing. PMID- 28622566 TI - Crosslinking hydroxylated reduced graphene oxide with RAFT-CTA: A nano-initiator for preparation of well-defined amino acid-based polymer nanohybrids. AB - Here, we demonstrate a novel reversible addition-fragmentation chain transfer agent (RAFT-CTA)-modified reduced graphene oxide nanosheets (CTA-rGONSs) by crosslinking rGONSs with a RAFT-CTA via esterification reaction. These nano CTA rGONSs were used to polymerize a hydrophobic amino acid-based methacrylamide (N acryloyl-l-phenylalanine methyl ester) monomer with different monomer/initiator ratios. Thermogravimetric analysis showed that the polymer-graphene composites were thermally more stable than GO itself. Mn of the polymers increased with increasing monomer/initiator ratio, while the polydispersity index decreased, indicating controlled polymerization. The composites were stable in DMF even after two months. PMID- 28622567 TI - The application of traffic-light food labelling in a worksite canteen intervention in Taiwan. AB - OBJECTIVE: This study evaluated customer attitudes, perceptions, and utilisation of a traffic-light food labelling (TFL) programme before and after the TFL was implemented in a worksite canteen in Taiwan. STUDY DESIGN: A one-arm intervention was implemented in the canteen and buffet of a research park in Taiwan. Phase 1 consisted of dissemination of information regarding the TFL, targeting the customers (June-July, 2014); phase 2 consisted of implementation of the TFL in the buffet starting in August 2014. The TFL included red, yellow and green labels, indicating 'unhealthy/stop', 'moderately unhealthy/wait' and 'healthy/go', respectively. METHODS: The evaluation was based on two independent anonymous surveys in July 2014 (in phase 1) and April 2015 (in phase 2). Customers were invited to take a survey regarding the TFL programme, the food environment in the canteen, and their lunch choices. Logistic regression models examined the changes in customers' attention and attitudes towards the labelling and their food choices between the two surveys. RESULTS: The customers reported positive attitudes towards the TFL. The proportion of customers who reported choosing foods based on the recommendations increased from 38% to 50% (P < 0.01). The proportion of the buffet customers who chose green-light entrees and red light entrees changed from 13% and 63% to 36% and 21%, respectively (P < 0.001). The availability of green-light entrees in the buffet increased as well. CONCLUSIONS: This first report of a TFL intervention in an Asian worksite suggests that TFL is acceptable and well understood by this population and may assist customers in choosing healthier items when healthier choices are available. PMID- 28622568 TI - Per-protocol investigation of a best practice exercise referral scheme. AB - OBJECTIVES: To investigate the effects of an exercise referral scheme (ERS) aligned to the UK best practice guidelines on a range of outcomes including those associated with key health concerns of the Scottish population. STUDY DESIGN: A longitudinal design with data collection at three time points (baseline, midway and post) during a 12-week ERS intervention was employed. METHODS: Health-related physical fitness was assessed through measurement of resting heart rate, blood pressure, FEV1:FEV6 (ratio of forced expiratory volume over one [FEV1] and six [FEV6] seconds), body mass and peak oxygen uptake (VO2 peak), whilst functional capacity was assessed through the five times sit to stand test. Psychosocial well being and quality of life were measured using the World Health Organization Quality of Life questionnaire (WHOQOL-BREF) and the Profile of Mood State questionnaires. Growth curve analyses were used to model each outcome variable across the three time periods. RESULTS: A range of effects were obtained with significant linear improvements in physical performance tests (P < 0.001) and psychosocial assessments (P <= 0.002). Additionally, significant quadratic effects of time were obtained for body composition variables and physical activity levels (P < 0.001) with the greatest improvements obtained between baseline and midway assessments. CONCLUSIONS: An ERS aligned to the UK best practice guidelines can positively influence a range of health outcomes including those associated with lung function and cardiovascular fitness which are prevalent medical conditions in Scotland. In addition, results indicate that ERS can positively affect outcomes related to functional capacity as well as mental well-being and perceptions of health. The findings of the study identify the need for further investigation including consideration of the initial health status of referred clients. PMID- 28622569 TI - Selective laser melting porous metallic implants with immobilized silver nanoparticles kill and prevent biofilm formation by methicillin-resistant Staphylococcus aureus. AB - Implant-associated infection and limited longevity are two major challenges that orthopedic devices need to simultaneously address. Additively manufactured porous implants have recently shown tremendous promise in improving bone regeneration and osseointegration, but, as any conventional implant, are threatened by infection. In this study, we therefore used rational design and additive manufacturing in the form of selective laser melting (SLM) to fabricate porous titanium implants with interconnected pores, resulting in a 3.75 times larger surface area than corresponding solid implants. The SLM implants were biofunctionalized by embedding silver nanoparticles in an oxide surface layer grown using plasma electrolytic oxidation (PEO) in Ca/P-based electrolytes. The PEO layer of the SLM implants released silver ions for at least 28 days. X-ray diffraction analysis detected hydroxyapatite on the SLM PEO implants but not on the corresponding solid implants. In vitro and ex vivo assays showed strong antimicrobial activity of these novel SLM PEO silver-releasing implants, without any signs of cytotoxicity. The rationally designed SLM porous implants outperformed solid implants with similar dimensions undergoing the same biofunctionalization treatment. This included four times larger amount of released silver ions, two times larger zone of inhibition, and one additional order of magnitude of reduction in numbers of CFU in an ex vivo mouse infection model. PMID- 28622570 TI - The role of premorbid personality and social cognition in suicidal behaviour in first-episode psychosis: A one-year follow-up study. AB - BACKGROUND: High suicide attempt (SA) rates have been reported in first-episode psychosis (FEP) patients, particularly during the first year after the illness onset. Despite previous studies establishing several risk factors for suicidal behaviour in FEP, premorbid personality and social cognition have not been sufficiently investigated to date. OBJECTIVE: To test whether personality traits and social cognition are associated with SAs in FEP over a 12-month follow-up. METHOD: Sixty-five FEP patients were evaluated at first contact with mental health services. The presence of SAs was recorded at six and twelve months after first presentation. Bivariate and multivariate analyses explored the influence of a range of sociodemographic and clinical variables, including premorbid personality and social cognition-related Theory of Mind (ToM) measures, on SAs. RESULTS: SAs were associated with greater severity of symptoms at first hospitalization with psychotic symptoms (OR = 2.18, 95% CI = 1.25-3.82), schizoid personality traits (OR = 1.62, 95% CI = 1.02-2.57) and impairment in a first order false belief task (OR = 4.26, 95% CI = 1.05-17.31) in the multivariate models. CONCLUSIONS: Symptom severity at illness onset, premorbid schizoid personality traits and ToM impairment emerged as predictors of SA in this FEP sample, which, if replicated, may be useful in identifying high-risk groups and implementing more targeted suicide prevention programs in FEP. PMID- 28622572 TI - Differential predictive value of PTSD symptom clusters for mental health care among Iraq and Afghanistan veterans following PTSD diagnosis. AB - OBJECTIVES: Veterans from the recent conflicts in Iraq and Afghanistan are being diagnosed with posttraumatic stress disorder (PTSD) at high rates. This study examined characteristics associated with mental health service utilization, specifically psychotherapy, through the Department of Veterans Affairs (VA), in a large cohort of Iraq and Afghanistan veterans newly diagnosed with PTSD. METHOD: This study utilized national VA administrative data from Iraq and Afghanistan veterans following an initial diagnosis of PTSD and completed a self-report measure of PTSD symptoms between Fiscal Years 2008-2012 (N=52,456; 91.7% male; 59.7% Caucasian; mean age 30.6, SD=8.3). Regression analyses examined the relation between PTSD symptom cluster severity and treatment-related variables. RESULTS: Accounting for demographic/clinical variables, PTSD symptom clusters were related to psychotherapy initiation (re-experiencing, OR=1.23; numbing, OR=1.15), combination treatment (medication and psychotherapy; re-experiencing, OR=1.13; avoidance, OR=1.07; dysphoric arousal, OR=1.06), number of psychotherapy visits (re-experiencing, IRR= 1.08; numbing, IRR=1.09), and adequate dose of therapy (e.g., 8 visits/14 weeks; re-experiencing: OR= 1.07). CONCLUSIONS: When considering treatment approaches for trauma-exposed veterans, it is important to map the severity of unique PTSD symptoms clusters; this may have implications on the selection of treatment that best fits the veterans' needs and preferences (e.g., exposure therapy versus cognitive processing therapy). PMID- 28622573 TI - The specificity of public stigma: A comparison of suicide and depression-related stigma. AB - Each year, approximately 1.3 million Americans survive a suicide attempt. While stigma has been reported by suicide attempt survivors, limited research has examined how suicide stigma may differ from the stigma of mental illness. U.S. adults (n = 440) completed an online survey in which they were randomly assigned to one of four vignettes. Vignettes depicted a target individual with either past depression, past suicide attempt, death by suicide, or no information on suicide or mental illness (control). Participants completed a general measure of stigma, a suicide-specific stigma measure, and were surveyed on the recovery potential of individuals with mental illness and suicide attempt. While the general stigma measure failed to distinguish between groups, significant differences on the suicide stigma scale (SSAS-44) emerged between participants assigned in the depression and suicide conditions, especially for stereotype and prejudice subscales. Across conditions, participants believed that recovery was more realistic for someone described as having a mental illness than it was for someone described as having attempted suicide. These findings suggest that individuals who have attempted suicide are subject to differential stigma content from those with depression. Implications are discussed for combating stigma for suicide attempt survivors. PMID- 28622571 TI - Substantiated childhood maltreatment and young adulthood cannabis use disorders: A pre-birth cohort study. AB - This study investigates the association between exposure to prospectively substantiated childhood maltreatment between 0 and 14 years of age and lifetime cannabis use, abuse and dependence reported at 21 years. Data were taken from 2526 (51.6% female) participants in the Mater Hospital-University of Queensland Study of Pregnancy, a pre-birth, prospective, cohort study. Prospectively substantiated cases of childhood maltreatment, reported to the government child protection agencies between 0 and 14 years of age, were linked to CIDI DSM-IV self-report data from the 21-year follow-up. Exposure to any childhood maltreatment, and childhood neglect in particular, predicted subsequent cannabis abuse with adjusted odds ratios (AORs) of 1.79 and 2.62, respectively. Any childhood maltreatment, physical abuse, emotional abuse and neglect predicted cannabis dependence with AORs of 2.47, 2.81, 2.44 and 2.68, respectively. The associations for an early age of onset of cannabis abuse and dependence were significant and consistent for maltreated children. In addition, frequency of maltreatment substantiations predicted cannabis abuse, dependence and an early age of onset of these disorders. The AORs for cannabis ever use without any DSM IV cannabis disorder were 1.78 for any maltreatment and 2.15 for emotional abuse. Any childhood maltreatment and neglect predicted lifetime ever cannabis use, as well as cannabis use disorder. There was little evidence for any interaction between gender and different forms of childhood maltreatment and its association with cannabis use disorders. Physical abuse, emotional abuse and neglect, as well as multiple episodes of maltreatment independently predicted cannabis use disorders. PMID- 28622574 TI - Analysis of adipose tissue immune gene expression after vaccination of rainbow trout with adjuvanted bacterins reveals an association with side effects. AB - Most existing fish vaccines are presented in the form of oil-based emulsions delivered by intraperitoneal injection. Whilst very effective they are frequently associated with inflammatory responses that can result in clinically significant side-effects often involving the adipose tissue that is in direct contact with the vaccine. To explore the potential of immune gene expression changes in the adipose tissue of fish to be markers of vaccination efficacy or development of side-effects we have studied the response to a bacterial (Aeromonas salmonicida) vaccine administered with two different adjuvants. The first adjuvant was MontanideTM ISA 763A VG, thought to induce a mostly humoral response, and the second was MontanideTM ISA 761 VG that gives a more balanced humoral and cell mediated response. Following vaccination tissue samples were collected at days 3, 14 and 28 for RTqPCR analysis. Fifty immune genes were studied with a focus on a) pro-inflammatory associated molecules and b) adaptive immune response related molecules linked with possible Th1, Th2, Th17 and T-regulatory pathways, with the expression data analysed for associations with Speilberg post-vaccination side effect scores. The results showed that the adipose tissue is a particularly sensitive and discriminatory tissue for studying adjuvant effects. A clear upregulation of many immune genes occurred in response to both vaccine groups, which persisted over time and overlapped with the appearance of visible adhesions. Our analysis revealed a relationship between adipose tissue immune function and the development of vaccine-induced adhesions giving the potential to use immune gene expression profiling in this tissue to predict the side-effects seen. PMID- 28622576 TI - Coordinating cell movements in vivo: junctional and cytoskeletal dynamics lead the way. AB - Collective cell movements drive embryonic development and tissue repair, and can cause disease. However, the mechanisms that coordinate the migration of groups of cells in vivo are unclear. Cells generate, transmit and sense mechanical forces to align their movements. Therefore, the machinery used by cells to generate force (cytoskeleton) and to transmit and sense mechanical signals (cell-cell adhesion) is critical for collective movement. Here, we review the components and organization of the cytoskeletal and cell-cell adhesive machineries, and how they are organized to promote collective cell movements in living animals. We discuss the signals that orchestrate molecular rearrangements necessary for coordinated cell motility, and we provide specific examples of movements both in the plane of the tissue (wound healing) and perpendicular to that plane (apical constriction). PMID- 28622575 TI - Protein nanoparticle vaccine based on flagellin carrier fused to influenza conserved epitopes confers full protection against influenza A virus challenge. AB - Currently marketed influenza vaccines only confer protection against matching influenza virus strains. The influenza A composition of these vaccines needs to be annually updated. Vaccines that target conserved epitopes of influenza viruses would in principle offer broad cross-protection against influenza A viruses. In our study, we investigated the specific immune responses and protective efficacy of protein nanoparticles based on fusion proteins of flagellin carrier linked to conserved influenza epitopes. We designed fusion proteins by replacing the hyperimmunogenic region of flagellin (FliC) with four tandem copies of the ectodomain of matrix protein 2 (f4M2e), H1 HA2 domain (fHApr8) or H3 HA2 domain (fHAaichi). Protein nanoparticles fabricated from these fusion proteins by using DTSSP crosslinking retained Toll-like receptor 5 agonist activity of FliC. Intranasal immunization with f4M2e, f4M2e/fHApr8 or f4M2e/fHAaichi nanoparticles induced vaccine antigen-specific humoral immune responses. It was also found that the incorporation of the H1 HA2 domain into f4M2e/fHApr8 nanoparticles boosted M2e specific antibody responses. Immunized mice were fully protected against lethal doses of virus challenge. PMID- 28622577 TI - Hyperoside inhibits lipopolysaccharide-induced inflammatory responses in microglial cells via p38 and NFkappaB pathways. AB - Hyperoside (quercetin-3-O-beta-d-galactoside) is an active compound isolated from herbs. Neuroinflammation is a key mechanism involved in neurodegenerative disorders including Parkinson's disease. In this study, we aimed to investigate the potentiality of hyperoside in inhibiting microglia-mediated neuroinflammation. BV2 microglial cells were pretreated with hyperoside and stimulated with lipopolysaccharide (LPS). The results showed that hyperoside significantly inhibited LPS-induced production of nitric oxide and pro inflammatory cytokines including IL-1beta and TNF-alpha, as well as the expression of inducible nitric oxide synthase. Similar results were observed in primary microglial cells isolated from neonatal mice. Analyses in MAPK and NFkappaB signaling combined with specific inhibitors suggested that hyperoside attenuated the LPS-induced inflammatory responses via p38 and NFkappaB pathways. Furthermore, hyperoside suppressed reactive microglia-mediated neurotoxicity as evidenced by conditioned media culture, but had no direct impact on MPP+-induced toxicity in SH-SY5Y neuroblastoma cells. Collectively, our data suggest that hyperoside may serve as a protective agent by alleviating microglia activation in disorders such as Parkinson's disease. PMID- 28622578 TI - The progression of hallux valgus in the oriental Chinese population in Hong Kong. AB - BACKGROUND: Hallux valgus is the lateral deviation of the great toe at the MTPJ that has many attributing aetiologies. This study will aim to identify whether hallux valgus progresses over time in the oriental Chinese population in Hong Kong. METHODS: Patients with acquired symptomatic hallux valgus who presented to clinic between 2008 and 2013 were included. The deformities were analysed radiologically at presentation and pre-operative and angles were measured. These angles were analysed in relation to the waiting time from presentation to surgery. RESULTS: A sample of 43 cases from 38 patients (Mean age 63 years, range 48-80 years) were included. Forty-one cases had a hallux valgus angle (HVA) >24 degrees at presentation (Mean 40.4 degrees ) and all had an intermetatarsal angle (IMA) >9 degrees . A significant difference is seen with HVA (p=0.040, t= 2.128) at presentation and pre-op but not IMA (p=0.281, t=-1.095). The average wait for surgery was 705.7days which had shown significant correlation with progression in HVA (p=0.031). No significant difference was seen between IMA and waiting time to surgery (p=0.195). DISCUSSION: The findings suggests severe hallux valgus deformity does progress over time in Hong Kong. Shorter waiting times for surgery could be beneficial to this population. Level III, retrospective comparative series. PMID- 28622579 TI - Evidence of promising biological-pharmacological activities of the sertraline based copper complex: (SerH2)2[CuCl4]. AB - In the current study the ability of copper complex to exert multiple biological activities is combined with the pharmacological action of sertraline (SerH2Cl, antidepressant drug). The hydrated and anhydrous forms of the tetrachlorocuprate(II) salts, namely (SerH2)2[CuCl4].1/2H2O and (SerH2)2[CuCl4], were synthesized and characterized by physicochemical methods. The crystal structures were determined by X-ray diffraction methods. The hydrate complex crystallizes in the monoclinic P21 space group with a=8.0807(2) A, b=36.2781(8) A, c=12.6576(3) A, beta=95.665(2) degrees , and Z=4 molecules per unit cell and the un-hydrate in P21 with a=13.8727(6) A, b=7.5090(3) A, c=18.618(1) A, beta=104.563(6) degrees , and Z=2. It has been suggested that Cu(II) ions might be critical in the development of mood disorders, showed potent biocidal activity, and also acted as analgesic adjuvant. To improve sertraline efficiency, the antidepressant and analgesic activities of the complex have been assessed in rats denoting a marked synergistic effect. Antithyroid and antimicrobial activities were also evaluated. Because depressive disorders and hyperthyroidism diseases led to an oxidative stress state, antioxidant capability has also been tested. The complex behaved as a good superoxide radical scavenger (IC50=6.3*10 6M). The ability of the complex to act as bromoperoxidase mimic was assessed. A pseudo-first order constant of k=0.157+/-0.007min-1 has been determined. The complex evidences promising biological-pharmacological activities and the albumin binding studies showed a Kb of 2.90*103M-1 showing an improvement in the uptake of sertraline by albumin at 8h incubation (time required for effective interaction of sertraline with the protein). PMID- 28622580 TI - Combating breast cancer with non-steroidal aromatase inhibitors (NSAIs): Understanding the chemico-biological interactions through comparative SAR/QSAR study. AB - It is a challenging task to design target-specific and less toxic non-steroidal aromatase inhibitors (NSAIs) though the modeling studies for designing anti aromatase molecules have been continuing for more than two decades to fight the dreaded estrogen-dependent breast cancer. In this article, different validated QSAR models are developed and analyzed to understand important physicochemical and structural parameters modulating the aromatase inhibitory activity of NSAIs. Physicochemical properties such as molar refractivity and dipole moment are found to be the most important parameters for controlling aromatase inhibition. This indicates the characteristic of bulky, complex and steric properties as well as, the flexibility of molecules is playing pivotal roles for aromatase inhibition. In many cases, hydrophobicity also plays important contribution. Regarding the structural point of view, some important indicator parameters are also found to be important for aromatase inhibitory activity. Though azole function is playing a crucial role by coordinating the heme moiety of the aromatase enzyme, the imidazole or the imidazolylmethyl ring systems may be better NSAIs than triazole, tetrazole or other azoles. The 4-pyridylmethyl group containing compounds are also found to be better NSAIs. The QSAR study, in a nutshell, provides a detailed understanding of the effectivity of NSAIs which is dependent mainly on the shape and size as well as the steric features of molecules and the heme-coordinator azole functions. These findings may open up a new horizon for designing new potential NSAIs that can be effective to reduce the mortality rate of breast cancer in future. PMID- 28622581 TI - Assessment of atherosclerotic luminal narrowing of coronary arteries based on morphometrically generated visual guides. AB - BACKGROUND AND AIMS: Determination of the degree of stenosis of atherosclerotic coronary arteries is an important part of postmortem examination of the heart, but, unfortunately, estimation of the degree of luminal narrowing can be imprecise and tends to be approximations. Visual guides can be useful to assess this, but earlier attempts to develop such guides did not employ digital technology. Using this approach, we have developed two computer-generated morphometric guides to estimate the degree of luminal narrowing of atherosclerotic coronary arteries. The first is based on symmetric or eccentric circular or crescentic narrowing of the vessel lumen and the second on either slit-like or irregularly shaped narrowing of the vessel lumens. METHODS: Using the Aperio ScanScope XT at a magnification of 20* we created digital whole-slide images of 20 representative microscopic cross sections of the left anterior descending (LAD) coronary artery, stained with either hematoxylin and eosin (H&E) or Movat's pentachrome stain. These cross sections illustrated a variety of luminal profiles and degrees of stenosis. Three representative types of images were selected and a visual guide was constructed with Adobe Photoshop CS5. Using the "Scale" and "Measurement" tools, we created a series of representations of stenosis with luminal cross sections depicting 20%, 40%, 60%, 70%, 80%, and 90% occlusion of the LAD branch. Four pathologists independently reviewed and scored the degree of atherosclerotic luminal narrowing based on our visual guides. In addition, digital technology was employed to determine the degree of narrowing by measuring the cross-sectional area of the 20 microscopic sections of the vessels, first assuming no narrowing and then comparing this to the percent of narrowing determined by precise measurement. RESULTS: Two of the observers were very experienced general autopsy pathologists, one was a first-year pathology resident on his first rotation on the autopsy service, and the fourth observer was a highly experienced cardiovascular pathologist. Interobserver reliability was assessed by determination of the intraclass correlation coefficient. The degrees of agreement for two H&E- and Movat-stained sections of the LADs from each of 10 decedents were 0.874 and 0.899, respectively, indicating strong interobserver agreement. On the average, the mean visual scores were ~8% less than the morphometric assessment (52.7 vs. 60.2), respectively. CONCLUSIONS: The visual guides that we have generated for scoring atherosclerotic luminal narrowing of coronary arteries should be helpful for a broad group of pathologists, from beginning pathology residents to experienced cardiovascular pathologists. PMID- 28622582 TI - Porous Mn doped g-C3N4 photocatalysts for enhanced synergetic degradation under visible-light illumination. AB - Photocatalytic degradation by semiconductors is an ideal way to solve the environmental problem. Here, the porous Mn doped g-C3N4 photocatalyst was synthesized by the calcination-refluxing method. The as-prepared g-C3N4 exhibits the high activity of photocatalytic degradation under visible light irradiation ( > 400nm) in the mixed system of Cr(VI) and organic pollutants. Especially, the photocatalytic activity of Cr(VI) reduction was increased from 9.5% to 76.5%, while that of Rhodamine B(RhB) degradation was enhanced from 15.3% to 88.9% after 60min irradiation. The porous Mn doped g-C3N4 still keeps the high degradation efficiency of mixed pollutants in the 7th running. Based on the computational modeling, the Mn doping and carboxyl modification affect the atomic arrangement and molecular orbital distribution of the g-C3N4 semiconductor, leading to the enhancement of photo-induced carrier separation. Additionally, the active oxygen species and intermediates in the photoreaction process were discovered by ESR measurement and UV-vis test. The RhB degradation in synergistic photocatalysis not only inhibits the reverse reaction of Cr(VI) reduction, but also validly supply the photogenerated electrons by the photosensitization effect. This work may be useful for rationally designing photocatalysts and providing illuminating insights into the photocatalytic mechanism. PMID- 28622583 TI - PVP capped silver nanocubes assisted removal of glyphosate from water-A photoluminescence study. AB - Glyphosate [N-phosphono-methylglycine (PMG)] is the most used herbicide worldwide and it has been reported very recently that Glyphosate is very harmful and can produce lots of diseases such as alzheimer and parkinson's disease, depression, cancer, infertility including genotoxic effects. As it is mostly present in stable water body and ground water system, its detection and removal is very important. Here, we have shown a fluorescence technique for the removal of glyphosate from water using chemically synthesized polyvinylpyrrolidone (PVP) silver nanocrystals. Transmission Electron Microscopy (TEM) study shows the average size of silver nanocrystals of 100nm approximately with a morphology of cubic shape. Glyphosate does not show absorption in the visible region. But both glyphosate and silver nanocrystals show strong fluorescence in the visible region. So, photoluminescence study has been successfully utilized to detect the glyphosate in water samples and on treating the glyphosate contaminated water sample with silver nanocrystals, the sample shows no emission peak of glyphosate at 458nm. Thus, this approach is a promising and very rapid method for the detection and removal of glyphosate from water samples on treatment with silver nanocubes. NMR spectra further confirms that the silver nanocrystals treated contaminated water samples are glyphosate free. PMID- 28622584 TI - STMN1 as a candidate gene associated with atypical meningioma progression. AB - OBJECTIVES: Meningiomas are the most common type of primary intracranial tumor. Atypical meningiomas are especially difficult to manage due to frequent disease recurrence. This study aimed to examine the role of stathmin (coded by the gene STMN1) as a factor in atypical meningioma recurrence. PATIENTS AND METHODS: A total of 59 sporadic atypical meningioma formalin-fixed paraffin-embedded (FFPE) samples were collected. The mRNA levels of the biomarker gene STMN1 were tested using quantitative RT-PCR. RESULTS: We observed significant up-regulation of STMN1 mRNA expression in recurrent tumors in comparison with primary tumors (p<0.05). Moreover, mRNA expression levels of STMN1 significantly correlated with Ki-67 score (r=0.93, p<0.01). Multivariate survival analyses indicated that high expression of STMN1, high Ki-67 score, and more advanced patient age at diagnosis (>60yrs) each act as independence prognostic factors for recurrence. Kaplan-Meier analysis revealed that STMN1 expression pattern could effectively predict prognosis of atypical meningioma in patients (p<0.01). CONCLUSIONS: Our study indicates for the first time that an increased risk of sporadic atypical meningioma recurrence can be found in cases with elevated expression of STMN1. These results suggest that STMN1 expression might serve as a biomarker for determining patient atypical meningioma prognosis. PMID- 28622585 TI - The fading affect bias shows positive outcomes at the general but not the individual level of analysis in the context of social media. AB - Unpleasant affect fades faster than pleasant affect (e.g., Walker, Vogl, & Thompson, 1997); this effect is referred to as the Fading Affect Bias (FAB; Walker, Skowronski, Gibbons, Vogl, & Thompson, 2003a). Research shows that the FAB is consistently related to positive/healthy outcomes at a general but not at a specific level of analysis based on event types and individual differences (e.g., Gibbons et al., 2013). Based on the positive outcomes for FAB and negative outcomes for social media (Bolton et al., 2013; Huang, 2010), the current study examined FAB in the context of social media events along with related individual differences. General positive outcomes were shown in the form of robust FAB effects across social media and non-social media events, a larger FAB for non social media events than for social media events, negative correlations of FAB with depression, anxiety, and stress as well as a positive correlation of FAB with self-esteem. However, the lack of a negative correlation between FAB and anxiety for social media events in a 3-way interaction did not show positive outcomes at a specific level of analysis. Rehearsal ratings mediated the 3-way interaction. Implications are discussed. PMID- 28622586 TI - Outerwear through the ages: evolutionary cell biology of vesicle coats. AB - Vesicular transport was key to the evolution of eukaryotes, and is essential for eukaryotic life today. All modern eukaryotes have a set of vesicle coat proteins, which couple cargo selection to vesicle budding in the secretory and endocytic pathways. Although these coats share common features (e.g. recruitment via small GTPases, beta-propeller-alpha-solenoid proteins acting as scaffolds), the relationships between them are not always clear. Structural studies on the coats themselves, comparative genomics and cell biology in diverse eukaryotes, and the recent discovery of the Asgard archaea and their 'eukaryotic signature proteins' are helping us to piece together how coats may have evolved during the prokaryote to-eukaryote transition. PMID- 28622587 TI - Statistical characterization of noise for spatial standardization of CT scans: Enabling comparison with multiple kernels and doses. AB - Computerized tomography (CT) is a widely adopted modality for analyzing directly or indirectly functional, biological and morphological processes by means of the image characteristics. However, the potential utilization of the information obtained from CT images is often limited when considering the analysis of quantitative information involving different devices, acquisition protocols or reconstruction algorithms. Although CT scanners are calibrated as a part of the imaging workflow, the calibration is circumscribed to global reference values and does not circumvent problems that are inherent to the imaging modality. One of them is the lack of noise stationarity, which makes quantitative biomarkers extracted from the images less robust and stable. Some methodologies have been proposed for the assessment of non-stationary noise in reconstructed CT scans. However, those methods focused on the non-stationarity only due to the reconstruction geometry and are mainly based on the propagation of the variance of noise throughout the whole reconstruction process. Additionally, the philosophy followed in the state-of-the-art methods is based on the reduction of noise, but not in the standardization of it. This means that, even if the noise is reduced, the statistics of the signal remain non-stationary, which is insufficient to enable comparisons between different acquisitions with different statistical characteristics. In this work, we propose a statistical characterization of noise in reconstructed CT scans that leads to a versatile statistical model that effectively characterizes different doses, reconstruction kernels, and devices. The statistical model is generalized to deal with the partial volume effect via a localized mixture model that also describes the non stationarity of noise. Finally, we propose a stabilization scheme to achieve stationary variance. The validation of the proposed methodology was performed with a physical phantom and clinical CT scans acquired with different configurations (kernels, doses, algorithms including iterative reconstruction). The results confirmed its suitability to enable comparisons with different doses, and acquisition protocols. PMID- 28622588 TI - Attachment representations and socio-emotional difficulties in alternative care: A comparison between residential, foster and family based children in Chile. AB - Attachment has been assessed in children living in alternative care (AC) settings, such as Residential Homes (RC) and Foster Care (FC). However, no study has been conducted to compare attachment styles in residential, foster and parental care conducted as usual in the same country at the same point in time. There is also a lack of studies conducted in less developed countries. Therefore, the aim of this study was to compare outcomes for children living in three different types of care in Chile. Three groups of children (N=77), living in (RC), (FC) and with biological parents (PC) were compared. Attachment styles, Indiscriminate Friendliness (IF) and socio-emotional/behavioral difficulties were assessed. Higher rates of secure attachment were observed in the RC group (36.1%) when compared to studies in RC in other countries (mean 18%). However, children in both types of AC were significantly more likely to have insecure and/or disorganized attachment styles than PC children. Higher rates of socio-emotional and behavioral problems were observed in RC (55.6%) and FC (50%) compared to PC (10%). Within type of AC, no significant differences were found, for attachment styles or for socio-emotional/behavioral difficulties, the only difference were the levels of IF, with children in RC having higher levels. As a conclusion, impact of placement in AC can vary between different countries, other factors, rather than only type of AC could better explain differences in attachment security for children. Implications for research and practices are discussed. PMID- 28622589 TI - Improving outcomes for babies and toddlers in child welfare: A model for infant mental health intervention and collaboration. AB - Children under three comprise a sizable and growing proportion of foster care placements. Very young children who enter the child welfare system experience disruptions of critical attachments that are essential to this formative stage of brain development, as well as other traumatic events, leaving them at great risk for lifelong impairments. To reverse these concerning outcomes, babies who have been removed from their homes require intensive, relationship-based interventions that promote secure attachment to a primary caregiver and holistic attention the child's developmental needs. Child welfare decision-makers must be informed of infant brain development and knowledgeable about the particular needs and circumstances of each child. This article describes a model with these features that has been developed and tested in the Bronx, New York, one of the nation's poorest urban counties with high rates of foster care. The Project utilizes evidence-based Child-Parent Psychotherapy (CPP) as its core intervention, and emphasizes collaboration and information sharing- driven by the CPP clinician- with judges, child welfare workers, attorneys and other social service and mental health providers, thereby encouraging developmentally and relationally informed case planning and permanency decisions. The model is evaluated using pre and post treatment psychosocial measures and program outcome data. Results indicate improvement in parenting interactions, positive child welfare outcomes (including increased rates of reunification, fewer returns to foster care), and improved safety and wellbeing. Results highlight the need for child welfare practices to be more closely aligned with the current science of infant brain development, and to incorporate a specialized approach to address the unique needs of infants. PMID- 28622590 TI - Can evolutionary theory explain the slow development of knowledge about the level of safety built into roads? AB - In several papers, Hauer (1988, 1989, 2000a, 2000b, 2016) has argued that the level of safety built into roads is unpremeditated, i.e. not the result of decisions based on knowledge of the safety impacts of design standards. Hauer has pointed out that the development of knowledge about the level of safety built into roads has been slow and remains incomplete even today. Based on these observations, this paper asks whether evolutionary theory can contribute to explaining the slow development of knowledge. A key proposition of evolutionary theory is that knowledge is discovered through a process of learning-by-doing; it is not necessarily produced intentionally by means of research or development. An unintentional discovery of knowledge is treacherous as far as road safety is concerned, since an apparently effective safety treatment may simply be the result of regression-to-the-mean. The importance of regression-to-the-mean was not fully understood until about 1980, and a substantial part of what was regarded as known at that time may have been based on studies not controlling for regression-to-the-mean. An attempt to provide an axiomatic foundation for designing a safe road system was made by Gunnarsson and Lindstrom (1970). This had the ambition of providing universal guidelines that would facilitate a preventive approach, rather than the reactive approach based on accident history (i.e. designing a system known to be safe, rather than reacting to events in a system of unknown safety). Three facts are notable about these principles. First, they are stated in very general terms and do not address many of the details of road design or traffic control. Second, they are not based on experience showing their effectiveness. Third, they are partial and do not address the interaction between elements of the road traffic system, in particular road user adaptation to system design. Another notable fact consistent with evolutionary theory, is that the safety margins built into various design elements have been continuously eroded by the development of bigger and faster motor vehicles, that can only be operated safely if roads are wider and straighter than they needed to be when motor vehicles were smaller and moved slower. PMID- 28622591 TI - Targeting proinflammatory cytokines, oxidative stress, TGF-beta1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity. AB - The aim of this study was to assess the possible modulatory effects of rosuvastatin and/or ubiquinone on trastuzumab (TRZ)-induced cardiotoxicity in mice. One hundred and twenty mice were divided into six equal groups as follows: control group; TRZ group; TRZ+carboxymethyl cellulose group; TRZ+rosuvastatin group; TRZ+Ubiquinone group and TRZ+rosuvastatin+Ubiquinone group. Serum creatine kinase (CK-MB), lactate dehydrogenase (LDH), troponin I and N-terminal pro-B-type natriuretic peptide (NT-pro BNP) were measured. Also, tissue malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPx), interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-beta1) and signal transducers and activators of transcription-3 (STAT-3) were determined. Also, echocardiography was performed. Parts of the heart were subjected to histopathological, immunohistochemical and electron microscopic examination. Administration of rosuvastatin and/or ubiquinone to TRZ-treated mice induced significant increase in tissue GPx, CAT and STAT-3 with significant decrease in serum CK-MB, LDH, troponin I, NT-pro BNP, tissue MDA, TGF-beta1 and IL-6 and improved the histopathological, immunohistochemical, echocardiographic and electron microscopic changes compared to the group that received TRZ alone. These changes were significant in rosuvastatin/ubiquinone combination group compared to the use of each of these drugs alone. In conclusion, rosuvastatin/ubiquinone combination may represent a new therapeutic modality to ameliorate TRZ-induced cardiotoxicity. PMID- 28622592 TI - Second generation H1 - antihistamines interaction with food and alcohol-A systematic review. AB - Histamine is a mediator of many physiological processes. It plays an important role in modulating allergy reactions and immune system responses. H1 receptor is a therapeutic target for drugs applied in allergic diseases such as allergic rhinoconjunctivitis, urticarial, or atopic dermatitis. H1-antihistamines display different chemical structures, pharmacokinetics and a potential for drug-drug and drug-food interactions. Drug-food interactions are known to reduce therapeutic effects of the medicine, as well as to induce a potent adverse drug reactions. Considering it all, a systematic review was conducted to investigate the importance of drug-food interaction for H1-antihistamine drugs. As non-sedating second generation H1-antihistamines remain to be drugs of choice in treating allergic conditions, the review has been focused on this particular class of medicines. The aim of this paper is to examine the evidence of food-drug and food alcohol interactions for second generation H1-antihistamine drugs. A systematic literature queries were performed in the following databases: Medline (via PubMed), Cochrane Library, Embase and Web of Science (all from their inception date till October 2016). The queries covered nine specific names of second generation anthistamine drugs, namely bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mizolastine, and rupatadine, in combinations with such terms as "food", "juice", "grapefruit", "fruits", "alcohol", "pharmacokinetics", and "meal". Additional publications were found by checking all the reference lists. Where none data on drug-food interaction could be found within the investigated databases, a specific drug prescribing information was used. 2326 publications were identified with the database queries. Articles were subjected to analysis by reviewing their title, abstract and full text; duplicated papers were removed. Having collected a complete set of data, a critical review was undertaken. For selected H1-antihistamines food, fruit juices or alcohol consumption may significantly impact the efficacy and safety of the therapy. This issue shall be well understood to educate patients properly, as it provides the major therapeutic element in allergic diseases. PMID- 28622593 TI - Long noncoding RNA linc00462 promotes hepatocellular carcinoma progression. AB - BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most common malignancies worldwide. In two pubic long noncoding RNA (lncRNA) profiling studies of HCC, linc00462 was consistently upregulated. We analyzed the clinical significance and biological role of linc00462 in HCC. METHODS: We performed quantitative real-time PCR analysis to determine the levels of linc00462 in HCC tissues from 49 patients. Functional analysis was performed in cell lines and in an animal model to support clinical findings. RESULTS: Our data showed that linc00462 was significantly upregulated in HCC tissues compared with matched normal tissues. The knockdown of linc00462 in HCC cells resulted in a much less aggressive oncogenic phenotype, and linc00462 downregulation contribute to the inactivation of the PI3K/AKT signaling pathway. CONCLUSIONS: linc00462 may be a potential therapeutic target in HCC. PMID- 28622594 TI - The role of apitoxin in alleviating propionic acid-induced neurobehavioral impairments in rat pups: The expression pattern of Reelin gene. AB - The efficacy of apitoxin (bee venom; BV) in ameliorating propionic acid (PPA) induced neurobehavioral impacts was studied. Sixty rat pups were enrolled in a split litter design to six groups: a control group, a PPA-treated group, a BV treated group, a BV/PPA protective group, a PPA/BV therapeutic group, and a BV/PPA/BV protective and therapeutic group. Exploratory, social, locomotor, and repetitive/stereotype-like activities were assessed and prosocial, empathy, and acquired behavior were evaluated. Levels of neurotransmitter including serotonin, dopamine, and gamma-aminobutyric acid (GABA) were determined and a quantitative analysis of Reelin gene expression was performed. PPA treatment induced several behavioral alterations, as reduced exploratory activity and social behaviors, increased repetitive/stereotypic behaviors, and hyperactivity. In addition, a marked decline of neurotransmitters and down-regulation of Reelin mRNA expression were observed. BV exhibited high efficiency in ameliorating the PPA-induced neurobehavioral alterations, particularly when applied both before and after PPA administration. Overall, the results implied that BV has merit as a candidate therapeutic treatment to alleviate PPA-induced neurobehavioral disorders. PMID- 28622596 TI - Synthesis of novel fenfuram-diarylether hybrids as potent succinate dehydrogenase inhibitors. AB - Twelve novel fenfuram-diarylether hybrids were designed, synthesized and characterized by 1H NMR and MS. Their in vitro antifungal activities were evaluated against five phytopathogenic fungi by mycelial growth inhibition method. Most compounds showed significant antifungal effect on Rhizoctonia solani and Sclerotinia sclerotiorum. Compound 1c exhibited the most potent antifungal effect on R. solani with an EC50 value of 0.242mg/L, superior to the commercial fungicide boscalid (EC50=1.758mg/L) and the lead fungicide fenfuram (EC50=7.691mg/L). Molecular docking revealed that compound 1c featured a higher affinity for succinate dehydrogenase (SDH) than fenfuram. Furthermore, it was shown that the 2-chlorophenyl group of compound 1c formed a pi-pi stacking with D/Tyr-128 and a Cl-pi interaction with B/His-249, which made compound 1c more active than fenfuram against SDH. PMID- 28622595 TI - Exogenous deoxyribonuclease has a protective effect in a mouse model of sepsis. AB - Sepsis is associated with the activation of white blood cells (WBCs) that leads to the production of extracellular traps. This process increases extracellular DNA (ecDNA) that can be recognized by the innate immune system and leads to inflammation. Previous studies have shown that by cleaving ecDNA deoxyribonuclease (DNase) prevents the antibacterial effects of extracellular traps, but also has beneficial effects in sepsis. The aim of our study was to analyze the effects of DNase on WBCs in vitro and on ecDNA in a mouse model of sepsis. Our results confirmed that DNase decreases ecDNA by 70% and prevents the antibacterial effects of WBCs in vitro. Sepsis was induced in mice by intraperitoneal injection of E. coli. DNase was subsequently administered intravenously. In comparison to untreated septic mice DNase treatment improved the survival of septic mice by 60%, reduced their weight loss as well as inflammatory markers. Increased plasma DNase activity led to ecDNA concentrations in plasma comparable with the control group. In conclusion, the study showed that intravenous DNase improves survival of septic mice by cleavage of ecDNA, especially of nuclear origin. Further mechanistic studies are needed to prove the potential of DNase in the treatment or prevention of septic complications. PMID- 28622597 TI - Investigation of RadFET response to X-ray and electron beams. AB - The irradiation response of Radiation Sensing Field Effect Transistor (RadFET), also known as MOSFET/pMOS dosimeter, to high energy X-rays and electron beams was investigated. The threshold voltages before and after irradiation were measured and the trap densities in the gate oxide and oxide/silicon interface of the RadFETs are evaluated. The RadFETs were irradiated with 6MV X-rays, and 10 and 18MeV electron beams emitted from a Linear accelerator (LINAC). Linear and non linear fits to experimental results showed that after an initial linear response up to several Gy, deviation from the linearity occurred due to electric field screening by the radiation induced oxide trapped charges. The radiation-induced fixed traps (FTs) and switching traps (STs) were analysed and the FT density was found to be higher than the ST density for all beam types and doses. The radiation response, fading characteristics, and variation of the trapped charges of the RadFETs showed similar behaviour in tests. PMID- 28622598 TI - Utilization of GEANT to calculation of production yield for 89Zr by charge particles interaction on 89Y, natZr and natSr. AB - The 89Zr, is one of the radionuclide with near-ideal properties for PET due to its suitable half-life and decay properties. The cross-section of 89Zr via 89Y(p,n)89Zr, 89Y(d,2n)89Zr, natSr(alpha,xn)89Zr and natZr(p,pxn)89Zr, were calculated by the TALYS-1.8 code to predict the optimum range of charge particle energy. The Monte Carlo code GEANT4 was used to simulate the formation of 89Zr in the target body. The simulated 89Zr yield was in good agreement with published experimental results in the optimum energy range. According to the calculations, the 89Y(p,n)89Zr was superior to the other reactions useful to medical application. PMID- 28622599 TI - Adrenergic regulation of cytoplasmic structures related to secretory processes in pig pinealocytes-an ultrastructural, quantitative study. AB - Two structures, considered as secretory in nature, are present in the pinealocytes in of the domestic pig show the presence of two structures, which are considered as secretory in nature - the dense core vesicles (DCV) and the membrane bounded (dense) bodies (MBB). The latter are extremely numerous in pig pinealocytes (they occupy 6-20% of the cytoplasm), and the number of MBB changes under different physiological and experimental conditions. Norepinephrine is the main neurotransmitter that regulates the secretion of pineal melatonin. The present study was carried out to 1) clarify whether the DCV and their source - the Golgi apparatus (GA) - as well as the MBB are controlled by norepinephrine, 2) determine the effect of adrenergic stimulation on these structures, and 3) identify the receptors involved in the regulation of these structures. The studies were performed using a static organ culture of pig pineal explants. The explants were incubated in a control medium between 08:00 and 20:00 and in a medium with 10MUM norepinephrine or alpha- or beta-adrenoceptor agonists between 20:00 and 08:00 on five consecutive days. The tissues were subsequently prepared for ultrastructural analysis. The results distinctly showed that the DCV, GA and MBB in pig pinealocytes are under adrenergic control. The stimulation of the beta adrenoceptors resulted in an increase in the numerical density of the DCV and a decrease in the relative volume of the GA in the perikarya, while the incubation with agonists of the alpha1-adrenoceptors was ineffective. The relative volume of the MBB in the perikarya significantly decreased after treatment with both beta agonists and alpha1-agonists, which suggested the involvement of two types of adrenoceptors in the regulation of these structures. PMID- 28622600 TI - Grain size quantification by optical microscopy, electron backscatter diffraction, and magnetic force microscopy. AB - Quantification of microstructure, especially grain size, in polycrystalline materials is a vital aspect to understand the structure-property relationships in these materials. In this paper, representative characterization techniques for determining the grain size, including optical microscopy (OM), electron backscatter diffraction (EBSD) in the scanning electron microscopy (SEM), and atomic force microscopy/magnetic force microscopy (AFM/MFM), are thoroughly evaluated in comparison, illustrated by rare-earth sintered Nd-Fe-B permanent magnets. Potential applications and additional information achieved by using aforementioned characterization techniques have been discussed and summarized. PMID- 28622601 TI - Immobilisation of barley aleurone layers enables parallelisation of assays and analysis of transient gene expression in single cells. AB - The barley aleurone layer is an established model system for studying phytohormone signalling, enzyme secretion and programmed cell death during seed germination. Most analyses performed on the aleurone layer are end-point assays based on cell extracts, meaning each sample is only analysed at a single time point. By immobilising barley aleurone layer tissue on polydimethylsiloxane pillars in the lid of a multiwell plate, continuous monitoring of living tissue is enabled using multiple non-destructive assays in parallel. Cell viability and menadione reducing capacity were monitored in the same aleurone layer samples over time, in the presence or absence of plant hormones and other effectors. The system is also amenable to transient gene expression by particle bombardment, with simultaneous monitoring of cell death. In conclusion, the easy to handle and efficient experimental setup developed here enables continuous monitoring of tissue samples, parallelisation of assays and single cell analysis, with potential for time course studies using any plant tissue that can be immobilised, for example leaves or epidermal peels. PMID- 28622602 TI - Assessment of the phenolic profile, antimicrobial activity and oxidative stability of transgenic Perilla frutescens L.overexpressing tocopherol methyltransferase (gamma-tmt) gene. AB - This study evaluated the effects of enhanced concentrations of alpha-tocopherol and phenolic compounds on the resistance and stability of Perilla oil in transgenic Perilla frutescens plants against various tested pathogenic bacteria by over-expressing the gamma-tmt gene. The concentration of phenolic compounds in the non-transgenic samples was 9313.198 +/- 18.887 MUg g-1 dry weight (DW), whereas the total concentration of the transgenic samples ranged from 9118.015 +/ 18.822 to 10527.612 +/- 20.411 MUg g-1 DW. The largest increases in phenolic compounds in the transgenic plants in comparison with the control plants were observed in gallic acid, pyrogallol, 5-sulfosalicylic acid, catechin, chlorogenic acid, vanillin, syringic acid, naringenin, salicylic acid, quercetin, o-coumaric acid, kaempferol, and hesperetin. o-coumaric and benzoic acid acid were the most abundant phenolic acids found in the transgenic plants. Gram-negative bacteria (Salmonella typhimurium) were the most susceptible microorganism against transgenic ethyl acetate extracts with lower measurement of minimum inhibitory concentration (MICs) (0.25 +/- 0.03 mg/ml) at an extract concentration of 2 mg/ml in dried plant material. The same extracts were more effective against gram positive bacteria (Bacillus subtilis) when compared to control plants with MICs values of 0.52 +/- 0.02 mg/ml. The suplementation of 20 MUg of alpha-tocopherol (1000 ppm) in combination with ethyl acetate extracts enhanced the antimicrobial activity against S. typhimurium and B. subtilis, compared to the non-transgenic plants. The acid value of transgenic Perilla oil improved by 91.2% and 35.54% relative to the non-transgenic control oil and commercial Perilla oil, respectively. The low acid value suggests that the oil will be less susceptible to lipase action, and more economically viable and thus, may also improve the oil quality for industrial purposes. In addition, extracts obtained from transgenic plants could be a potential source of antimicrobial agents for the treatment of bacterial infections. PMID- 28622603 TI - Probing supramolecular protein assembly using covalently attached fluorescent molecular rotors. AB - Changes in microscopic viscosity and macromolecular crowding accompany the transition of proteins from their monomeric forms into highly organised fibrillar states. Previously, we have demonstrated that viscosity sensitive fluorophores termed 'molecular rotors', when freely mixed with monomers of interest, are able to report on changes in microrheology accompanying amyloid formation, and measured an increase in rigidity of approximately three orders of magnitude during aggregation of lysozyme and insulin. Here we extend this strategy by covalently attaching molecular rotors to several proteins capable of assembly into fibrils, namely lysozyme, fibrinogen and amyloid-beta peptide (Abeta(1-42)). We demonstrate that upon covalent attachment the molecular rotors can successfully probe supramolecular assembly in vitro. Importantly, our new strategy has wider applications in cellulo and in vivo, since covalently attached molecular rotors can be successfully delivered in situ and will colocalise with the aggregating protein, for example inside live cells. This important advantage allowed us to follow the microscopic viscosity changes accompanying blood clotting and during Abeta(1-42) aggregation in live SH-SY5Y cells. Our results demonstrate that covalently attached molecular rotors are a widely applicable tool to study supramolecular protein assembly and can reveal microrheological features of aggregating protein systems both in vitro and in cellulo not observable through classical fluorescent probes operating in light switch mode. PMID- 28622604 TI - Tissue-engineered hypertrophic chondrocyte grafts enhanced long bone repair. AB - Bone has innate ability to regenerate following injury. However, large and complex fractures exceed bone's natural repair capacity and result in non-unions, requiring external intervention to facilitate regeneration. One potential treatment solution, tissue-engineered bone grafts, has been dominated by recapitulating intramembranous ossification (bone formation by osteoblasts), although most serious bone injuries heal by endochondral ossification (bone formation by remodeling of hypertrophic cartilaginous anlage). The field has demonstrated that using endochondral ossification-based strategies can lead to bone deposition. However, stem cell differentiated hypertrophic chondrocytes, the key cell type in endochondral ossification, have not been studied for long bone defect repair. With translation in mind, we created tissue-engineered grafts using human adipose stem cells (ASC), a clinically relevant stem cell source, differentiated into hypertrophic chondrocytes in decellularized bone scaffolds, and implanted these grafts into critical-size femoral defects in athymic rats. Over 12 weeks of implantation, these grafts were compared to acellular scaffolds and grafts engineered using ASC-derived osteoblasts. Grafts engineered using hypertrophic chnodrocytes recapitulated endochondral ossification, as evidenced by the expression of genes and proteins associated with bone formation. Markedly enhanced bone deposition was associated with extensive bone remodeling and the formation of bone marrow, and with the presence of pro-regenerative M2 macrophages within the hypertrophic grafts. As a result, hypertrophic chondrocyte grafts bridged 7/8 defects, as compared to only 1/8 for osteoblast grafts and 3/8 acellular scaffolds. These data suggest that ASC-derived hypertrophic chondrocytes in osteogenic scaffolds can improve long bone repair. PMID- 28622605 TI - Flexible nanofilms coated with aligned piezoelectric microfibers preserve the contractility of cardiomyocytes. AB - The use of engineered cardiac tissue for high-throughput drug screening/toxicology assessment remains largely unexplored. Here we propose a scaffold that mimics aspects of cardiac extracellular matrix while preserving the contractility of cardiomyocytes. The scaffold is based on a poly(caprolactone) (PCL) nanofilm with magnetic properties (MNF, standing for magnetic nanofilm) coated with a layer of piezoelectric (PIEZO) microfibers of poly(vinylidene fluoride-trifluoroethylene) (MNF+PIEZO). The nanofilm creates a flexible support for cell contraction and the aligned PIEZO microfibers deposited on top of the nanofilm creates conditions for cell alignment and electrical stimulation of the seeded cells. Our results indicate that MNF+PIEZO scaffold promotes rat and human cardiac cell attachment and alignment, maintains the ratio of cell populations overtime, promotes cell-cell communication and metabolic maturation, and preserves cardiomyocyte (CM) contractility for at least 12 days. The engineered cardiac construct showed high toxicity against doxorubicin, a cardiotoxic molecule, and responded to compounds that modulate CM contraction such as epinephrine, propranolol and heptanol. PMID- 28622606 TI - Dementia correlates with anticoagulation underuse in older patients with atrial fibrillation. AB - OBJECTIVES: Stroke prevention in older atrial fibrillation (AF) patients remains a challenge. This study aimed to investigate whether a dementia diagnosis is an independent correlate of lower prescription rate of oral anticoagulant treatment (OAT) in a sample of older AF patients. METHODS: Cross-sectional retrospective study. Consecutive older community-dwelling AF patients referred for a comprehensive geriatric assessment, were considered. Evaluation of physical, social and mental health, and administration of the Cumulative Illness Rating Scale (CIRS) and Barthel Index were performed. Dementia cases were ascertained by consensus of 2 experienced geriatricians. Dementia severity was assessed using the Clinical Dementia Rating scale (CDR). RESULTS: 316 AF patients (ages 74.7+/ 7.0years, 55.7% women) with high stroke risk (77.5% had a CHA2DS2VASC score >=3), low bleeding and falling risk, and no neuropsychiatric/behavioral symptoms, were included. 60.1% were prescribed with OAT. Among patients with dementia (n=86, 27.2%), 22.0% received inadequate antithrombotic prophylaxis (i.e. antiplatelet) and 38.5% no treatment. Proportion of those receiving inadequate or no prophylaxis increased at increasing CDR score. By multiple regression models, either dementia (yes vs no), OR=1.33, 95%CI=1.11-1.46, p<0.001, and dementia severity (CDR>1), OR=2.38, 95%CI=2.19-2.60, p<0.001, were associated with lack of OAT prescription independently of age, paroxysmal AF, and comorbidity burden. CONCLUSIONS: Dementia might be associated with underuse of OAT in older AF patients even in the absence of established contraindications. Future studies are needed to assess the real dimension of the problem and clinician's barriers to prescribing OAT in demented patients. PMID- 28622607 TI - Mammalian fibroblast cells avoid residual stress zone caused by nanosecond laser pulses. AB - This study investigates the effects of laser irradiation on crystalline silicon and its application in biomaterials. We used an analytical model to predict the ablation depth and pit size resulting from laser exposure of silicon samples. The temperatures generated are predicted correlate with laser power, and to result in the formation of a residual stress zone bordering the ablated groove. Different crystal orientations found in the substrate confirm that there was crystal distortion, which consequently induces these residual stress zones. Mouse embryonic fibroblasts avoid the stress areas and accumulate outside of these zones. Higher laser power results in broader residual stress zone and a larger zone of cellular exclusion. We argue that residual stress resulting from high energy laser ablation of silicon may be a promising avenue to explore as a method for patterning cell growth on these materials. PMID- 28622608 TI - A comparative study of the mechanical behaviour of thermally oxidised commercially pure titanium and zirconium. AB - The objective of this study is to compare the mechanical behaviour of thermally oxidised commercially pure titanium (CP-Ti) and commercially pure zirconium (CP Zr). For this purpose, these two bio-metals were thermally oxidised under the same condition (650 degrees C for 6h) and the oxidised specimens were characterised using various analytical and experimental techniques, including oxygen uptake analysis, layer thickness and hardness measurements, scratch tests, dry sliding friction and wear tests and tribocorrosion tests in Ringer's solution. The results show that under the present thermal oxidation condition, 4 times more oxygen is introduced into CP-Zr than into CP-Ti and the oxide layer produced on CP-Zr is nearly 6 times thicker than that on CP-Ti. Thermally oxidised CP-Zr possesses a higher hardness, a deeper hardening depth and better scratch resistance than thermally oxidised CP-Ti. Under dry sliding and tribocorrosion conditions, thermally oxidised CP-Zr also possesses much better resistance to material removal and a higher load bearing capacity than thermally oxidised CP-Ti. Thus, thermally oxidised Zr possesses much better mechanical behaviour than thermally oxidised Ti. PMID- 28622609 TI - The strategic defense of physician autonomy: State public health agencies as countervailing powers. AB - Advances in genetic testing and the aggressive marketing of genetic tests by commercial diagnostic laboratories have driven both consumer demand and the need for unbiased information about how tests should guide healthcare delivery. This paper uses the countervailing powers framework to explore the role of state public health agencies as arbiters of quality and safety, specifically through their efforts to encourage physicians to follow evidence-based recommendations for screening for hereditary cancers. Social scientists have often viewed actions by the state to regulate cost, quality, or safety as a threat to physician autonomy. This paper draws on case studies from two US states-Michigan and Connecticut-to better understand the specific role of state public health agencies, and especially whether their activities to encourage adherence to evidence-based recommendations bolster or subvert the interests of other parties in the healthcare arena. We find that lacking authority to compel provider to follow evidence-based recommendations, they improvised ways to foster compliance voluntarily, for example, by emphasizing the role of the physician as gatekeeper, thus affirming the importance of physician autonomy and clinical judgment. Both states also used public health surveillance data to make rare diseases visible and illustrate gaps between recommendations and practice. Finally, they both showed that following evidence-based recommendations could align the professional and market interests of healthcare stakeholders. Both states employed similar strategies with similar effects, despite substantial differences in the regulatory climate and organizational capacity. Taken as a whole, their activities orchestrated a countervailing response that checked the profit-seeking motives of commercial laboratories. Our findings demonstrate that rather than eroding physician autonomy, state action to monitor healthcare quality and encourage adherence to evidence-based recommendations can actually reinforce physician authority. PMID- 28622610 TI - F1174V mutation alters the ALK active conformation in response to Crizotinib in NSCLC: Insight from molecular simulations. AB - Crizotinib is an efficient antineoplastic drug for treatment of non-small cell lung carcinoma (NSCLC), which is identified as an anaplastic lymphoma kinase (ALK) inhibitor. F1174V is a recently identified acquired point mutation relating to the Crizotinib resistance in NSCLC patients. The mechanism of Crizotinib resistance relating to F1174V mutation as a non-active site mutation remains unclear. In this study, the molecular dynamic simulation was used to investigate the possible mechanisms by which F1174V mutation may affect the structure and activity of ALK kinase domain. The results suggested that F1174V mutation could cause two important secondary structure alterations, which led to the local conformational change in ALK kinase domain. This causes more positive free energy in the mutant complex in comparison with the wild-type one. In addition, our structural analyses illustrated that F1174V mutation could result in some important interactions, which represent the key characteristics of the ALK active conformation. This study provided a molecular mechanism for ALK Crizotinib resistance caused by F1174V mutation,which could facilitate designing more efficient drugs. PMID- 28622611 TI - De novo transcriptome sequencing and comparative analysis to discover genes involved in ovarian maturity in Strongylocentrotus nudus. AB - Strongylocentrotus nudus is an edible sea urchin, mainly harvested in China. Correlation studies indicated that S. nudus with larger diameter have a prolonged marketing time and better palatability owing to their precocious gonads and extended maturation process. However, the molecular mechanism underlying this phenomenon is still unknown. Here, transcriptome sequencing was applied to study the ovaries of adult S. nudus with different shell diameters to explore the possible mechanism. In this study, four independent cDNA libraries were constructed, including two from the big size urchins and two from the small ones using a HiSeqTM2500 platform. A total of 88,581 unigenes were acquired with a mean length of 1354bp, of which 66,331 (74.88%) unigenes could be annotated using six major publicly available databases. Comparative analysis revealed that 353 unigenes were differentially expressed (with log2(ratio)>=1, FDR<=0.001) between the two groups. Of these, 20 differentially expressed genes (DEGs) were selected to confirm the accuracy of RNA-seq data by quantitative real-time RT-PCR. Furthermore, gene ontology and KEGG pathway enrichment analyses were performed to find the putative genes and pathways related to ovarian maturity. Eight unigenes were identified as significant DEGs involved in reproduction related pathways; these included Mos, Cdc20, Rec8, YP30, cytochrome P450 2U1, ovoperoxidase, proteoliaisin, and rendezvin. Our research fills the gap in the studies on the S. nudus ovaries using transcriptome analysis. PMID- 28622613 TI - Dissociation of item and source memory in rhesus monkeys. AB - Source memory, or memory for the context in which a memory was formed, is a defining characteristic of human episodic memory and source memory errors are a debilitating symptom of memory dysfunction. Evidence for source memory in nonhuman primates is sparse despite considerable evidence for other types of sophisticated memory and the practical need for good models of episodic memory in nonhuman primates. A previous study showed that rhesus monkeys confused the identity of a monkey they saw with a monkey they heard, but only after an extended memory delay. This suggests that they initially remembered the source - visual or auditory - of the information but forgot the source as time passed. Here, we present a monkey model of source memory that is based on this previous study. In each trial, monkeys studied two images, one that they simply viewed and touched and the other that they classified as a bird, fish, flower, or person. In a subsequent memory test, they were required to select the image from one source but avoid the other. With training, monkeys learned to suppress responding to images from the to-be-avoided source. After longer memory intervals, monkeys continued to show reliable item memory, discriminating studied images from distractors, but made many source memory errors. Monkeys discriminated source based on study method, not study order, providing preliminary evidence that our manipulation of retention interval caused errors due to source forgetting instead of source confusion. Finally, some monkeys learned to select remembered images from either source on cue, showing that they did indeed remember both items and both sources. This paradigm potentially provides a new model to study a critical aspect of episodic memory in nonhuman primates. PMID- 28622614 TI - Desirable difficulties during the development of active inquiry skills. AB - This study explores developmental changes in the ability to ask informative questions, hypothesizing a link between the ability to update beliefs in light of evidence and the ability to ask informative questions. Five- to ten-year-old children played an iPad game asking them to identify a hidden insect. Learners could either ask about individual insects, or make a series of feature queries (e.g., "Does the hidden insect have antenna?") that could more efficiently narrow the hypothesis space. Critically, the task display either helped children integrate evidence with the hypothesis space or required them to perform this operation themselves. Our prediction was that assisting children with belief updating would help them formulate more informative queries. This assistance improved some aspects of children's active inquiry behavior; however, despite making some updating mistakes, children required to update their own beliefs asked questions that were more context-sensitive and thus informative. The results show how making a task more difficult can improve some aspects of children's active inquiry skills, thus illustrating a type of "desirable difficulty" for reasoning. PMID- 28622612 TI - Influence of age and comorbidity on prognosis and application of adjuvant chemotherapy in elderly Japanese patients with colorectal cancer: A retrospective multicentre study. AB - BACKGROUND: Adjuvant therapy for colorectal cancer (CRC) in patients aged >=75 years is supported by inadequate evidence, although such patients are increasing in number worldwide. PATIENTS AND METHODS: We assessed the influence of age and comorbidities on the prognosis of CRC in elderly patients using pooled data by the Japanese Study Group for Postoperative Follow-up of Colorectal Cancer. In total, 4598 patients (3304 with colon cancer and 1294 with rectal cancer) who underwent curative surgery from 2004 to 2006 were analysed with respect to age, Charlson comorbidity score (CS), tumour marker positivity, adjuvant therapy and prognosis. RESULTS: The number of patients aged <64, 65-74 and >75 years was 2007 (44%), 1614 (35%) and 977 (21%), respectively. Tumour location, tumour marker positivity, clinical stage, performance of adjuvant therapy, CS and overall survival (OS) were significantly different among these age groups (P < 0.0001). Among patients aged >=75 years with stage III CRC, 35% with colon cancer and 21% with rectal cancer received adjuvant therapy; these proportions were much lower than those in younger patients. Application of adjuvant therapy was dependent on the CS in patients aged <=74 years, but not in older patients. Sex, the carcinoembryonic antigen concentration and adjuvant therapy were significantly associated with OS in elderly patients with stage III CRC. CONCLUSION: Age and comorbidities worsened the OS of patients with CRC who underwent curative surgery. However, patients aged >=75 years were undertreated regardless of their CS despite the possibility of OS improvement by adjuvant therapy. PMID- 28622615 TI - Domain-general neural correlates of dependency formation: Using complex tones to simulate language. AB - There is an ongoing debate whether the P600 event-related potential component following syntactic anomalies reflects syntactic processes per se, or if it is an instance of the P300, a domain-general ERP component associated with attention and cognitive reorientation. A direct comparison of both components is challenging because of the huge discrepancy in experimental designs and stimulus choice between language and 'classic' P300 experiments. In the present study, we develop a new approach to mimic the interplay of sequential position as well as categorical and relational information in natural language syntax (word category and agreement) in a non-linguistic target detection paradigm using musical instruments. Participants were instructed to (covertly) detect target tones which were defined by instrument change and pitch rise between subsequent tones at the last two positions of four-tone sequences. We analysed the EEG using event related averaging and time-frequency decomposition. Our results show striking similarities to results obtained from linguistic experiments. We found a P300 that showed sensitivity to sequential position and a late positivity sensitive to stimulus type and position. A time-frequency decomposition revealed significant effects of sequential position on the theta band and a significant influence of stimulus type on the delta band. Our results suggest that the detection of non linguistic targets defined via complex feature conjunctions in the present study and the detection of syntactic anomalies share the same underlying processes: attentional shift and memory based matching processes that act upon multi-feature conjunctions. We discuss the results as supporting domain-general accounts of the P600 during natural language comprehension. PMID- 28622616 TI - Treatment of substance use disorders: Effects on patients with higher or lower levels of PTSD symptoms. AB - While guidelines advise integrated treatment of patients with substance use disorder (SUD) and posttraumatic stress disorder (PTSD), recent studies and reviews find no convincing evidence of different outcomes following treatment between non-trauma focused integrated programs and SUD treatment alone. In this study, we analyzed whether SUD patients with higher levels of PTSD symptoms receiving standard, non-integrated SUD treatment (N=145) differed in outcomes compared to patients with lower levels of PTSD symptoms (N=152). Patients with higher levels of PTSD symptoms showed no difference in days of substance use, but significantly more craving and psychiatric symptoms (depression, anxiety and stress) were measured at baseline. After 3 and 6months of SUD treatment, there was no difference between the groups in decreased days of substance use. After 6months of SUD treatment, depression, anxiety and stress were significantly diminished in both groups. However, those with higher levels of PTSD symptoms at the start of the SUD treatment still reported significantly higher scores on depression, anxiety and stress after 6months of SUD treatment. These findings corroborate earlier studies that SUD patients with PTSD symptoms do not necessarily have poorer addiction treatment outcomes. However, as anxiety and PTSD symptoms predict relapse, future research should note the effect of higher symptom levels on long-term SUD treatment results. Additionally, more research is needed to determine which patients need additional treatment in conjunction with or following SUD treatment. PMID- 28622617 TI - Determination and pharmacokinetics of engeletin in rat plasma by ultra-high performance liquid chromatography with tandem mass spectrometry. AB - Engeletin, a bioactive flavonoid, has attracted much attention recently by virtue of its multiple biological (anti-diabetic and anti-inflammatory) activities. Despite signifying many therapeutic applications researches indicating quantification or pharmacokinetics of engeletin in biological matrix are still lacking. Here, a simple, sensitive, accurate and reliable ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) approach for the quantification of engeletin in rat plasma was developed and fully validated for the first time. Plasma samples were processed with acetonitrile by a single step protein precipitation and the separation was achieved on a ZORBAX Eclipse Plus C18 Rapid Resolution High Definition column with a gradient acetonitrile-water mobile phase. Quantification of engeletin was carried out by electrospray ionization tandem mass spectrometry in multiple reaction monitoring (MRM) mode with negative ionization. Results revealed that the approach was linearity from 5 to 5000ng/mL (r2=0.9937) and proved to be precise (better than 12.3%) and accurate (-3.3%-5.2%). The developed approach was successfully employed to pharmacokinetic study of engeletin following peroral and intravenous administration to rats. The results of pharmacokinetics demonstrated rapid engeletin absorption (Tmax of 15min) after oral administration, extensive distribution after three different dosages and an absolute bioavailability of ~1.53%. The developed method and pharmacokinetic data can provide a meaningful basis for further studies on engeletin. PMID- 28622618 TI - Recovery and purification of limonin from pummelo [Citrus grandis] peel using water extraction, ammonium sulfate precipitation and resin adsorption. AB - Limonin is a bioactive compound that is traditionally extracted from citrus seeds using organic solvents or alkaline/metal ion solutions. In the present study, pummelo [Citrus grandis] peel was investigated for limonin preparation using a novel process consisting of water extraction, ammonium sulfate precipitation and resin adsorption. The pummelo peel was determined to have 4.7mg/g limonin, which could be extracted by water and further recovered by ammonium sulfate precipitation with a yield of 2.4mg/g, which was similar to that of traditional process using ethanol extraction and vacuumed evaporation. The precipitated limonin was purified by resin adsorption and crystallization with a purity of 96.4%. In addition, the limonin was identified via the analyses of retention time, infrared spectrum and nuclear magnetic resonance. This study indicates a novel and eco-friendly process for recovering limonin, providing a new candidate for limonin preparation. PMID- 28622619 TI - Simultaneous quantification of 25-hydroxyvitamin D3-3-sulfate and 25 hydroxyvitamin D3-3-glucuronide in human serum and plasma using liquid chromatography-tandem mass spectrometry coupled with DAPTAD-derivatization. AB - 25-hydroxyvitamin D3-3-sulfate (25-OHD3-S) and 25-hydroxyvitamin D3-3-glucuronide (25-OHD3-G) are major conjugative metabolites of vitamin D3 found in the systemic circulation and potentially important reservoirs for 25-hydroxyvitamin D3. Simultaneous and accurate quantification of these metabolites could advance assessment of the impact of vitamin D3 on health and disease. In this study, a highly sensitive and accurate liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed and validated for simultaneous quantification of 25 OHD3-S and 25-OHD3-G in human serum or plasma. Following protein precipitation, the analytes of interest were partially purified by solid-phase extraction and subjected to derivatization with 4-(4'-dimethylaminophenyl)-1,2,4-triazoline-3,5 dione (DAPTAD). Quantification of the analytes was based on multiple reaction monitoring (MRM) operated in the positive ion mode, and deuterated internal standards were used for each conjugative metabolite. Applying this method to the analysis of 25-OHD3-S and 25-OHD3-G concentrations in human serum or plasma samples achieved satisfactory reproducibility, accuracy and sensitivity. We subsequently used this method to simultaneously determine serum concentrations of the two metabolites in archived samples from a rifampin treatment study. Drug treatment had no effect on metabolite concentrations, but significantly increased the 25-OHD3-S/25-OHD3 concentration ratio (p=0.01). The availability of this new method should improve sample throughput and our ability to quantify and monitor circulating 25-OHD3-S and 25-OHD3-G concentrations. PMID- 28622620 TI - Simultaneous UHPLC-UV analysis of hydroxychloroquine, minocycline and doxycycline from serum samples for the therapeutic drug monitoring of Q fever and Whipple's disease. AB - A fast UHPLC-UV method was developed for the simultaneous analysis of Hydroxychloroquine, Minocycline and Doxycycline drugs from 100MUL of human serum samples. Serum samples were extracted by liquid-liquid extraction and injected into a phenyl hexyl reverse phase column. Compounds were separated using a mobile phase linear gradient and monitored by UV detection at 343nm. Chloroquine and Oxytetracycline were used as internal standards. Lower and upper limits of quantifications, as well as the other levels of calibration, were validated with acceptable accuracy (<15% deviation) and precision (<15% coefficient of variation) according to the European Medicines Agency guidelines. This new method enables cost and time reduction and was considered suitable for the clinical laboratory. It is the first published assay for the therapeutic drug monitoring of patients diagnosed with Q fever or Whipple's disease. PMID- 28622621 TI - Development of an ultra-fast liquid chromatography-tandem mass spectrometry method for simultaneous determination of seven flavonoids in rat plasma: Application to a comparative pharmacokinetic investigation of Ginkgo biloba extract and single pure ginkgo flavonoids after oral administration. AB - For deeper pharmacokinetic investigation and further curative application of ginkgo flavonoids, a delicate, efficient and precise UFLC-MS/MS technique for synchronous quantitation of seven flavonoids, apigenin, luteolin, naringenin, quercetin, diosmetin, kaempferol and isorhamnetin in rat plasma has been established. After mixing with the internal standard (IS) linarin, bio-samples were pretreated via ethyl acetate for liquid-liquid extraction, then isolated at 0.2ml/min flow rate on a Venusil MP C18 chromatographic column (100mm*2.1mm, 3MUm) by means of gradient elution. 0.1% formic acid-water and methanol system was used as the mobile phase. Mass spectrometric inspection was conducted on a 4000Q UFLC-MS/MS system with turbo ion spray source in patterns of negative ion and multiple reaction-monitoring (MRM). All calibration curves proved favorable linearity (R2>=0.9918) in linear ranges. Intra-day and inter-day precisions didn't exceed 14.0% for all the analytes, and the accuracy was within 6.9%. Extraction recoveries of analytes and IS were less than +/-15.0% of nominal concentrations. This method has been under thorough and firm verification for a comparative pharmacokinetic research after gavage between Ginkgo biloba extract and single pure ginkgo flavonoids. The results demonstrated that there're evident pharmacokinetic discrepancies, and possible structural influences were innovatively proposed. Generally, substitution with 3-hydroxylation, a double bond in ring C, ring B methoxylation often confer longer onset period. The existence of ring B catechol group gives rise to faster clearance. PMID- 28622622 TI - Characterization of drug load variants in a thiol linked antibody-drug conjugate using multidimensional chromatography. AB - The biological complexity associated with biotherapeutics such as antibody-drug conjugates (ADCs) requires extensive characterization to ensure product quality consistency, safety, and efficacy. ADCs generated via partial reduction of antibody interchain disulfide bonds result in a distribution of variants containing 0-8 conjugated drugs. Hydrophobic interaction chromatography (HIC) is a key analytical technique used to separate drug load variants of thiol linked ADCs and to calculate the average drug-to-antibody molar ratio (DAR). Salts present in HIC separations are not amenable to mass spectrometry (MS) detection, therefore confirmation of HIC peak identities have historically required offline fraction collection and subsequent MS analysis. We present a workflow comprised of three MS compatible two-dimensional liquid chromatography methods for higher throughput characterization of HIC peaks without manual fractionation. These methods are complementary and together provide DAR confirmation, identification of drug-load isomers, and localization of post-translational modifications to specific subunits. The results demonstrate an efficient mechanism for characterization of ADC HIC peaks and provided unique insight into differential HIC retention times based on conjugation sites and glycan structure. PMID- 28622623 TI - A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia. AB - Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100mg and 200mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10*109/L, platelet count <=400*109/L, and resolution of palpable splenomegaly, each lasting >=4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving >=12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET). PMID- 28622624 TI - Primary myelofibrosis: Older age and high JAK2V617F allele burden are associated with elevated plasma high-sensitivity C-reactive protein levels and a phenotype of progressive disease. AB - We measured plasma levels of high-sensitivity C-reactive protein (hs-CRP) in 526 subjects with primary myelofibrosis (PMF). Thirty-eight percent had an elevated hs-CRP level (>=0.3mg/dL). Elevated hs-CRP levels were associated with a progressive disease phenotype, including anemia, high white blood cell count, low platelet count, increased splenomegaly, increased risk of blast transformation, and worse survival. Age>=52years, but no other demographic characteristics, was associated with an elevated hs-CRP level in multivariable logistic regression (odds ratio [OR], 4.29; 95% CI, 2.73-6.77; P <0.001). Subjects with JAK2V617F mutation and an allele burden>=50% had an age-independent higher incidence of elevated hs-CRP level (OR=1.97; 95% CI,1.21-3.22; P=0.006) compared with a combined cohort of subjects with JAK2V617F <50% allele burden, CALR, MPL mutations, or no detectable driver mutations. Neither ASXL1 or EZH2 sub-clonal mutations, nor JAK2 46/1 haplotype or the A3669G polymorphism of glucocorticoid receptor were significantly associated with increased hs-CRP levels. Subjects with age>=52years and JAK2V617F with>=50% allele burden had a phenotype of progressive disease. Our data indicate that older age and high JAK2V617 allele burden are major determinants of inflammation in PMF, and are associated with disease progression. PMID- 28622625 TI - Cigarette smoking is associated with amplified age-related volume loss in subcortical brain regions. AB - BACKGROUND: Magnetic resonance imaging studies of cigarette smoking-related effects on human brain structure have primarily employed voxel-based morphometry, and the most consistently reported finding was smaller volumes or lower density in anterior frontal regions and the insula. Much less is known about the effects of smoking on subcortical regions. We compared smokers and non-smokers on regional subcortical volumes, and predicted that smokers demonstrate greater age related volume loss across subcortical regions than non-smokers. METHODS: Non smokers (n=43) and smokers (n=40), 22-70 years of age, completed a 4T MRI study. Bilateral total subcortical lobar white matter (WM) and subcortical nuclei volumes were quantitated via FreeSurfer. In smokers, associations between smoking severity measures and subcortical volumes were examined. RESULTS: Smokers demonstrated greater age-related volume loss than non-smokers in the bilateral subcortical lobar WM, thalamus, and cerebellar cortex, as well as in the corpus callosum and subdivisions. In smokers, higher pack-years were associated with smaller volumes of the bilateral amygdala, nucleus accumbens, total corpus callosum and subcortical WM. CONCLUSIONS: Results provide novel evidence that chronic smoking in adults is associated with accelerated age-related volume loss in subcortical WM and GM nuclei. Greater cigarette quantity/exposure was related to smaller volumes in regions that also showed greater age-related volume loss in smokers. Findings suggest smoking adversely affected the structural integrity of subcortical brain regions with increasing age and exposure. The greater age related volume loss in smokers may have implications for cortical-subcortical structural and/or functional connectivity, and response to available smoking cessation interventions. PMID- 28622626 TI - Age-related patterns in nonmedical prescription opioid use and disorder in the US population at ages 12-34 from 2002 to 2014. AB - OBJECTIVES: To estimate age-related patterns in nonmedical prescription opioid (NMPO) use in the US population and disorder among past-year users at ages 12-34 between 2002 and 2014, controlling for period and birth-cohort effects. METHODS: Data are from 13 consecutive cross-sectional National Surveys on Drug Use and Health (N=542,556). Synthetic longitudinal cohorts spanning ages 12-34 were created and an age-period-cohort analysis was implemented based on the Intrinsic Estimator algorithm. RESULTS: In every birth cohort, past-year NMPO use increases during adolescence, peaks at ages 18-21, decreases through ages 30-34; disorder among past-year users increases from ages 18-21 through 30-34. Use at ages 12-34 decreased from the 1984-87 birth cohorts to more recently-born cohorts. Peak prevalence of use at ages 18-21 has also decreased, and the rates of increase from ages 14-17 to ages 18-21 are slowing down. Disorder at ages 18-34 increased from the 1976-79 to 1992-95 cohorts, but decreased at ages 12-17 from the 1992-95 to the most recently-born 2000-02 cohorts. The years 2010-2014 were characterized by lower NMPO use but higher disorder than 2002-2009. CONCLUSIONS: Increasing NMPO disorder among users aged 18-34 warrants concern. However, declining NMPO use among 12-34 year-olds, a declining rate of increase from adolescence to early adulthood, and a suggestive decline in disorder among the most recent adolescent cohorts may forecast a potential reduction in the public health crisis associated with NMPO drugs. PMID- 28622627 TI - Changes in nonhuman primate brain function following chronic alcohol consumption in previously naive animals. AB - INTRODUCTION: Chronic alcohol abuse is associated with neurophysiological changes in brain activity; however, these changes are not well localized in humans. Non human primate models of alcohol abuse enable control over many potential confounding variables associated with human studies. The present study utilized high-resolution magnetoencephalography (MEG) to quantify the effects of chronic EtOH self-administration on resting state (RS) brain function in vervet monkeys. METHODS: Adolescent male vervet monkeys were trained to self-administer ethanol (n=7) or an isocaloric malto-dextrin solution (n=3). Following training, animals received 12 months of free access to ethanol. Animals then underwent RS magnetoencephalography (MEG) and subsequent power spectral analysis of brain activity at 32 bilateral regions of interest associated with the chronic effects of alcohol use. RESULTS: demonstrate localized changes in brain activity in chronic heavy drinkers, including reduced power in the anterior cingulate cortex, hippocampus, and amygdala as well as increased power in the right medial orbital and parietal areas. DISCUSSION: The current study is the first demonstration of whole-head MEG acquisition in vervet monkeys. Changes in brain activity were consistent with human electroencephalographic studies; however, MEG was able to extend these findings by localizing the observed changes in power to specific brain regions. These regions are consistent with those previously found to exhibit volume loss following chronic heavy alcohol use. The ability to use MEG to evaluate changes in brain activity following chronic ethanol exposure provides a potentially powerful tool to better understand both the acute and chronic effects of alcohol on brain function. PMID- 28622629 TI - Bacterial community dynamics in a cooling tower with emphasis on pathogenic bacteria and Legionella species using universal and genus-specific deep sequencing. AB - Cooling towers are the major source of outbreaks of legionellosis in Europe and worldwide. These outbreaks are mostly associated with Legionella species, primarily L. pneumophila, and its surveillance in cooling tower environments is of high relevance to public health. In this study, a combined NGS-based approach was used to study the whole bacterial community, specific waterborne and water based bacterial pathogens, especially Legionella species, targeting the 16S rRNA gene. This approach was applied to water from a cooling tower obtained by monthly sampling during two years. The studied cooling tower was an open circuit cooling tower with lamellar cooling situated in Braunschweig, Germany. A highly diverse bacterial community was observed with 808 genera including 25 potentially pathogenic taxa using universal 16S rRNA primers. Sphingomonas and Legionella were the most abundant pathogenic genera. By applying genus-specific primers for Legionella, a diverse community with 85 phylotypes, and a representative core community with substantial temporal heterogeneity was observed. A high percentage of sequences (65%) could not be affiliated to an acknowledged species. L. pneumophila was part of the core community and the most abundant Legionella species reinforcing the importance of cooling towers as its environmental reservoir. Major temperature shifts (>10 degrees C) were the key environmental factor triggering the reduction or dominance of the Legionella species in the Legionella community dynamics. In addition, interventions by chlorine dioxide had a strong impact on the Legionella community composition but not on the whole bacterial community. Overall, the presented results demonstrated the value of a combined NGS approach for the molecular monitoring and surveillance of health related pathogens in man-made freshwater systems. PMID- 28622630 TI - Temporal-spatial patterns of three types of pesticide loadings in a middle-high latitude agricultural watershed. AB - Pesticide loadings to watersheds increase during agricultural development and may vary in accordance with different crop types and seasons. High pesticide loadings can potentially result in polluted stream water. The objective of this study was to determine the pesticide loadings and concentrations of three typical pesticides (atrazine, oxadiazon, and isoprothiolane) in river water from a middle high latitude agricultural watershed in northern China. During this study, we evaluated the watershed pesticide loss patterns for two crop types over three decades. For this purpose, we integrated data from field investigations, laboratory experiments, and modeling simulations involving a distributed hydrological solute transport model (Soil and Water Assessment Tool, SWAT). SWAT was employed to compare the temporal-spatial fate and behaviors of atrazine, oxadiazon, and isoprothiolane from 1990 to 2014 in a watershed area amounting to 141.5 km2. The results showed that the three pesticides could be detected at different locations throughout the watershed, and isoprothiolane was detected at the maximum value of 1.082 MUg/L in surface runoff of paddy land. The temporal trend for the yearly loading of atrazine decreased slightly over time, but the trends for oxadiazon and isoprothiolane increased markedly over an 18-year analysis period. In regard to the pesticide concentrations in water, atrazine was associated with the largest value of nearly 1.4 MUg/L. July and August were the found to be prime periods for pesticide loss from paddy land, and the biggest monthly loss of atrazine from dryland appeared in June. Under similar usage conditions, isoprothiolane loading from paddy fields ranked as the largest one among the three types of pesticides and reached up to 17 g/ha. Limited monitoring data were useful for validating the model, which yielded valuable temporal spatial data on the fate of pesticides in this watershed. With the expansion of paddy rice cultivation, risks for pesticide contamination of water bodies will increase. The results of this study should be valuable for future exposure and risk assessments aimed at protecting the environment and human health. PMID- 28622631 TI - Equilibria model for pH variations and ion adsorption in capacitive deionization electrodes. AB - Ion adsorption and equilibrium between electrolyte and microstructure of porous electrodes are at the heart of capacitive deionization (CDI) research. Surface functional groups are among the factors which fundamentally affect adsorption characteristics of the material and hence CDI system performance in general. Current CDI-based models for surface charge are mainly based on a fixed (constant) charge density, and do not treat acid-base equilibria of electrode microstructure including so-called micropores. We here expand current models by coupling the modified Donnan (mD) model with weak electrolyte acid-base equilibria theory. In our model, surface charge density can vary based on equilibrium constants (pK's) of individual surface groups as well as micropore and electrolyte pH environments. In this initial paper, we consider this equilibrium in the absence of Faradaic reactions. The model shows the preferential adsorption of cations versus anions to surfaces with respectively acidic or basic surface functional groups. We introduce a new parameter we term "chemical charge efficiency" to quantify efficiency of salt removal due to surface functional groups. We validate our model using well controlled titration experiments for an activated carbon cloth (ACC), and quantify initial and final pH of solution after adding the ACC sample. We also leverage inductively coupled plasma mass spectrometry (ICP-MS) and ion chromatography (IC) to quantify the final background concentrations of individual ionic species. Our results show a very good agreement between experiments and model. The model is extendable to a wide variety of porous electrode systems and CDI systems with applied potential. PMID- 28622632 TI - Applying rheological analysis to better understand the mechanism of acid conditioning on activated sludge dewatering. AB - The pH value is a key parameter and affects sludge dewatering. Comprehensive understanding of the effects and mechanism of pH is important for sludge treatment process and sludge dewatering. The goal of this study was to evaluate the proposed mechanism of acid conditioning on sludge dewatering based on rheological analysis. At lower sludge pH, changes in floc structure, surface properties, and flocculation improved the performance of dewatering. Additionally, lower sludge pH caused the hydrolysis of EPS and intracellular materials, which released greater amounts of bound water. These changes resulted in altered rheological properties, weakening network strength and shrinking the linear viscoelastic regime, making the sludge system sensitive to shear. Thus, both the sludge dewatering rate and moisture reduction efficiency were improved by lowering the pH. These factors demonstrate that rheological analysis can understand the mechanism of acid conditioning on activated sludge dewatering better. PMID- 28622628 TI - Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies. AB - Immune checkpoint inhibitors (ICI) have shown great promise in a wide spectrum of adult solid and hematological malignancies, achieving objective tumor responses and prolonging survival. However, there is limited clinical success amongst pediatric patients. In this review, we summarize the current understanding of ICI and present an up-to-date overview of recent and ongoing clinical trials of ICI in pediatric malignancies. In addition, we will discuss immunologic and clinical difficulties in this young population, as well as future prospects for combination of ICI with other immune-based and conventional treatments. PMID- 28622633 TI - Generalized parameter estimation and calibration for biokinetic models using correlation and single variable optimisations: Application to sulfate reduction modelling in anaerobic digestion. AB - In this work, a generalized method for the estimation of biokinetic parameters in anaerobic digestion (AD) models is proposed. The method consists of a correlation based approach to estimate specific groups of parameters mechanistically, followed by a sensitivity-based hierarchical and sequential single parameter optimisation (SHSSPO) calibration method for the remaining groups of parameters. The method was evaluated to estimate and calibrate the parameter values for sulfate reduction processes when included into the IWA Anaerobic Digestion Model No. 1 (ADM1) and simulations were compared with experimental data from literature. Under the proposed method, a large number of biokinetic parameters, namely biomass yields, maximum specific uptake rates, and half saturation constants, can first be estimated using mechanistic correlations. This achieves a significant reduction in the number of parameters to be fitted to data. For the remaining parameters, a method is proposed based on the overall sensitivity and degree of ubiquity of each parameter to establish a hierarchy in a sequential single parameter optimisation against the experimental data. This approach aims at eliminating the uncertainty on optimality (and therefore parameter identification) associated to multivariable parameter calibration problems. The method was applied to the sulfate reduction related parameters and led to the hydrogen sulfide inhibition parameters as the only ones requiring optimisation against experimental data. Comparison of the proposed SHSSPO performance with that of multi-dimensional parameter optimisation methods shows a superior performance in terms of overall error and computation times. Also, final simulation results led to model predictions of similar, if not better, quality than those achieved by multivariable parameter optimisation methods. The experimental variables optimized for included liquid effluent concentrations of sulfur species and volatile fatty acids as well as effluent methane gas flow. Overall, the proposed parameter estimation and calibration method provides a deterministic step-by-step approach to parameter estimation that decreases identifiability uncertainty at a very low computational effort. The results obtained suggest that the method could be generically applied with similar success to other biokinetic models frequently used in wastewater treatment. PMID- 28622634 TI - Type of gonadotropin used during controlled ovarian stimulation induces differential gene expression in human cumulus cells: A randomized study. AB - BACKGROUND: The cumulus-oocyte complex plays a central role in the regulation of folliculogenesis where it is important for the maturation, reprogramming, and fertilization of oocytes. Consequently, cumulus cell gene expression profiling is being explored as a promising method for assessing oocyte competence in the near future. Through DNA microarray technology, we analyzed the potential differences in the gene expression profiles of cumulus cells from preovulatory follicles after controlled ovarian stimulation using different types of gonadotropins. METHODS: A prospective, randomized study was performed among 90 women participating in an oocyte donation program. Subjects were assigned to receive recombinant follicle-stimulating hormone (FSH), urinary FSH, or human menopausal gonadotropin (hMG). The gene expression profile in cumulus cells was analyzed according the type of gonadotropin received during ovarian stimulation. Furthermore, we also performed a gene ontology analysis to provide structural knowledge. RESULTS: Hierarchical clustering, principal component analysis, and gene enrichment analysis revealed greater differences between the urinary FSH and hMG groups compared to the rest of the pair-wise comparisons; recombinant FSH vs hMG and urinary FSH vs recombinant FSH. CONCLUSIONS: Data suggest that controlled ovarian stimulation induces specific gene expression profiles in human cumulus cells depending on the type of gonadotropin used. TRIAL REGISTRATION: Registered at clinicaltrials.gov; identifier NCT022437032. PMID- 28622635 TI - Management of parturients with Factor XI deficiency-10year case series and review of literature. AB - This is an article reviewing the management of pregnant women with factor XI (FXI) deficiency. Retrospective review of the electronic records of 67 pregnancies in 25 women with FXI deficiency over a ten-year period was undertaken. All women received care at St Mary's Tertiary Referral Obstetric/Haematology Clinic for some or all of their pregnancies. Outcome measures included antenatal complications, mode of delivery, anaesthesia provided and postpartum haemorrhage (PPH) and management required. A positive bleeding history was identified in 50% of women prior to pregnancy. Fifteen pregnancies (22%) ended in first trimester miscarriage; there was 1 termination of pregnancy. Two pregnancies were complicated by Antepartum haemorrhage. Of the remaining 51 pregnancies there were 50 live births - 2 preterm and 48 at term. There was one antenatal (34 weeks gestation) stillbirth of a growth restricted baby and one neonatal death secondary to severe prematurity (24 weeks gestation). Twenty -five babies delivered vaginally (20 spontaneous and 5 instrumental). The remaining 26 were delivered by Caesarean section (9 elective and 17 emergency). A sub-analysis of 22 operative deliveries was reviewed; this suggested that regional anaesthesia was safe in selected women with FXI deficiency - a selection that was based on FXI level/range, presence/absence of bleeding history and intended operative intervention.Solvent detergent treated Fresh Frozen Plasma (SD-FFP/Octaplas) and Tranexamic Acid (TXA) were given to those considered vulnerable -an individualised decision made by the multidisciplinary team in accordance with BCSH guidance. Primary PPH complicated 10/51 (15%) deliveries. The commonest cause of PPH was due to atony. Secondary PPH was only seen in only one case. Bleeding in women with FXI deficiency is highly variable and, whilst it does not directly correlate with Factor XI levels, provision of replacement therapy is required if FXI levels are <15 IU/dL as per BCSH guidance. Women with Factor XI levels >40 IU/dL are considered safe for regional anaesthesia following prophylactic FFP as suggested by sub group analysis. Treatment of women with rare bleeding disorders during pregnancy should be by a multidisciplinary team of specialists, to include Haematologist, Anaesthetist and Obstetrician, all of whom have an interest in bleeding disorders in pregnancy. Decisions should then be individualised, based on the presence/absence of a bleeding history and the third trimester FXI levels. Delivery does not have to be by Elective Caesarean. With appropriate care both operative vaginal delivery and regional anaesthesia can be facilitated. PMID- 28622636 TI - CRISPR-based engineering of next-generation lactic acid bacteria. AB - The advent of CRISPR-based technologies has opened new avenues for the development of next-generation food microorganisms and probiotics with enhanced functionalities. Building off two decades of functional genomics studies unraveling the genetic basis for food fermentations and host-probiotic interactions, CRISPR technologies offer a wide range of opportunities to engineer commercially-relevant Lactobacillus and Bifidobacteria. Endogenous CRISPR-Cas systems can be repurposed to enhance gene expression or provide new features to improve host colonization and promote human health. Alternatively, engineered CRISPR-Cas systems can be harnessed to genetically modify probiotics and enhance their therapeutic potential to deliver vaccines or modulate the host immune response. PMID- 28622637 TI - Children benefit differently from night- and day-time sleep in motor learning. AB - Motor skill acquisition occurs while practicing (on-line) and when asleep or awake (off-line). However, developmental questions still remain about whether children of various ages benefit similarly or differentially from night- and day time sleeping. The likely circadian effects (time-of-day) and the possible between-test-interference (order effects) associated with children's off-line motor learning are currently unknown. Therefore, this study examines the contributions of over-night sleeping and mid-day napping to procedural skill learning. One hundred and eight children were instructed to practice a finger sequence task using computer keyboards. After an equivalent 11-h interval in one of the three states (sleep, nap, wakefulness), children performed the same sequence in retention tests and a novel sequence in transfer tests. Changes in the movement time and sequence accuracy were evaluated between ages (6-7, 8-9, 10 11years) during practice, and from skill training to retrievals across three states. Results suggest that night-time sleeping and day-time napping improved the tapping speed, especially for the 6-year-olds. The circadian factor did not affect off-line motor learning in children. The interference between the two counter-balanced retrieval tests was not found for the off-line motor learning. This research offers possible evidence about the age-related motor learning characteristics in children and a potential means for enhancing developmental motor skills. The dynamics between age, experience, memory formation, and the theoretical implications of motor skill acquisition are discussed. PMID- 28622638 TI - Corrigendum to "The association of annual air pollution exposure with blood pressure among patients with sleep-disordered breathing"[Sci. Total Environ. 543 (2016) 61-66]. PMID- 28622639 TI - An investigation into the rapid removal of tetracycline using multilayered graphene-phase biochar derived from waste chicken feather. AB - This study investigated the removal of tetracycline (TC) using multilayered graphene-phase biochar (MGB) derived from waste chicken feather. MGB was produced through a two-stage carbonization and KOH-activation method. MGB was characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), Fourier transform infrared (FT-IR), Raman spectra, Zeta potential and elemental analysis. Various chemical functional groups were demonstrated on the surface of MGB. MGB was featured by a very large BET surface area of 1838m2/g. A rapid equilibrium (within 30s) and an ultrahigh removal efficiency (up to 99.65%) were obtained when MGB was used in the adsorption of TCs. The adsorption processes were temperature-dependent and the maximum adsorption capacity of MGB was 388.33mg/g at 30 degrees C. The data of adsorption isotherms and kinetics were represented well by the Langmuir and Elovich models, respectively. The chemical monolayer adsorption could play an important role in this process. Furthermore, the adsorption of MGB was tolerant with wide pH, high ionic strength and even co-existing anions. Regeneration experiments indicated the removal efficiency was still satisfied (96.61%) even after four cycles. These results have important implications for the future application of animal waste derived adsorbents in the treatment of wastewater containing antibiotic residues. PMID- 28622640 TI - Clinical course and core variability in HBV infected patients without detectable anti-HBc antibodies. AB - BACKGROUND: The presence of anti-HBc antibodies indicates direct encounter of the immune system with hepatitis B virus (HBV). OBJECTIVES: Aim of our study was to seek for anti-HBc negative but HBV replicating patients and analyze their clinical course and preconditions. STUDY DESIGN: From 1568 HBV-DNA positive patients, 29 patients (1.85%) tested negative for anti-HBc. The absence of anti HBc could be confirmed in 19 patients using an alternative assay. In 16 of 19 cases, a partial or full HBV genome analysis was performed with NGS sequencing to evaluate if specific mutations were associated with anti-HBc absence. As a control group samples from 32 matched HBV infected patients with detectable anti HBc were sequenced. RESULTS: Patients with detectable HBV-DNA and sequenced HBV core region in the confirmed absence of anti-HBc were diagnosed with acute HBV infection (n=3), HBV reactivation (n=9) and chronic hepatitis B (n=4). Most patients (12/16) were immunosuppressed: 3/16 patients had an HIV coinfection, 7/16 patients suffered from a malignant disease and 4/16 patients underwent solid organ transplantation (from which 2/4 had a malignant disease). Compared to the control cohort, HBV variants from anti-HBc negative patients showed less variability in the core region. CONCLUSIONS: In the absence of anti-HBc, HBV-DNA was most often found in immunocompromised hosts. Distinct mutations or deletions in the core region did not explain anti-HBc negativity. It would be advisable not to rely only on a single result of anti-HBc negativity to exclude HBV infection in immunocompromised hosts, but to measure anti-HBc repeatedly or with different methods. PMID- 28622641 TI - U.S. drug shortages for medications used in adult critical care (2001-2016). AB - PURPOSE: We describe trends in U.S. shortages impacting critical care drugs from 2001 to 2016. MATERIALS AND METHODS: Shortages within the scope of critical care were identified using data from the University of Utah Drug Information Services. Shortage characteristics were described using standard descriptive statistics and regression analysis. RESULTS: Of 1969 shortages reported, 1004 (51%) were for drugs used in critical care. New shortages fell from 2001 to 2004, then increased, peaking in 2011 (116). For critical care shortages, 247 (24.6%) involved drugs used for high acuity conditions. The majority of drugs on shortage were parenteral, (720; 71.7%) and 393 (39.1%) were single source drugs. Alternatives were available for 887 (88.3%) drugs, although 250 (24.9%) alternatives were impacted by shortages. Infectious disease drugs were the most common drugs on shortage, with 200 (19.9%) shortages, with a median duration of 7.7months (IQR=2.8-17.3). By the end of the study, 896 (89.2%) shortages were resolved and 108 (10.8%) remained active. The median duration for active shortages was 13.6months (IQR=5.8-58.4) while the duration for resolved shortages was 7.2months (IQR=2.8-17.3). CONCLUSIONS: Although the number of new shortages peaked in 2011 and is now declining, there remain a substantial number of active shortages impacting critical care drugs. PMID- 28622642 TI - Highly sensitive electrochemical thrombin aptasensor based on peptide-enhanced electrocatalysis of hemin/G-quadruplex and nanocomposite as nanocarrier. AB - In this work, we first conjugated a short peptide to thrombin binding aptamer (TBA) and bond hemin to the hybrid, effectively rendering hemin/G4-peptide more active over the original hemin/G4, so that a highly sensitive electrochemical thrombin (TB) aptasensor was developed based on it and PtNTs@rGO nanocomposite. It was the first report on the application of hemin/G4-peptide in electrochemical aptasensor. PtNTs@rGO with large surface area served as excellent nanocarrier for high loading of hemin/G4-peptide hybrids, resulting in the formation of hemin/G4 peptide-PtNTs@rGO bioconjugate as the secondary aptamer and further signal enhancement. The specific affinity of aptamer for target TB made the secondary aptamer go into the sensing interface, and then a noticeable current signal was obtained from hemin without additional redox mediators. Due to the collaborative electrocatalysis of hemin/G4-peptide and PtNTs toward H2O2, which was formed in situ during the process of hemin/G4-peptide-catalyzed oxidation of NADH with dissolved O2, the current intensity increased dramatically. Such an electrochemical aptasensing system could be used to detect TB with a linear range of 0.05 pM-60nM and very lower detection limit of 15fM. Notably, this method exhibited a higher sensitivity than that of many hemin/G4-based electrochemical strategies for TB detection due to the improvement of the catalytic activity of hemin/G4-peptide. The present works opened a new way for expanding the application of hemin/G4 in biological detection. With the mediator-free, proteinous enzyme-free yet high-sensitivity advantages, this electrochemical aptasensor held great promise for other biomarker detections in clinical diagnostics. PMID- 28622643 TI - Simultaneously electrochemical detection of microRNAs based on multifunctional magnetic nanoparticles probe coupling with hybridization chain reaction. AB - We report a sensor combining two distinguishable magnetic nanoprobes (DNA1/Fe3O4 NPs/Thi and DNA2/Fe3O4 NPs/Fc) with target-triggered hybridization chain reaction (HCR) strategy for the simultaneous detection of microRNA-141 (miR-141) and microRNA-21 (miR-21). In the presence of targets, the thiol-modified hairpin capture probes (HCP1 and HCP2) specifically hybridize with miR-141 and miR-21 on a gold electrode, leading to the conformation change of HCP1 and HCP2, respectively. The conformation change subsequently triggers HCR to generate plentiful bonding sequences of magnetic nanoprobes. Thus, numerous thionine (Thi) modified DNA1/Fe3O4 NPs/Thi and ferrocene carboxaldehyde (Fc-CHO) modified DNA2/Fe3O4 NPs/Fc are captured by the well-designed HCR, via DNA hybridization respectively, giving rise to the dual magnified response of currents. The increase in the electrochemical currents at different potentials of the two magnetic nanoprobes enables us to simultaneously and quantitatively detect miR 141 and miR-21. Target-triggered HCR increases the amount of captured nanoprobes due to the increasing number of bonding sequences, greatly amplifying the currents of the two magnetic nanoprobes in the presence of targets, and ultimately realizing the dual signal amplification with increased sensitivity. The sensor can be applied for detecting miRNAs in cell lysates, thus, promising to be a clinic diagnosis of cancers by means of simultaneous detection of a variety of miRNA biomarkers. PMID- 28622644 TI - Study on the occurrence of polycyclic aromatic hydrocarbons in milk and meat/fish based baby food available in Italy. AB - The study compared the profile of 14 polycyclic aromatic hydrocarbons, frequently occurred in food, in milk (N = 22) and meat/fish based (N = 18) baby foods available on the Italian market. PAH total levels, markers (Regulation EC/835/2011) and carcinogenic PAHs were determined by high- performance liquid chromatography with fluorescence detector (HPLC-FD). The average of total PAHs was 52.25 MUg kg-1 in milk and 11.82 MUg kg-1 in meat/fish based baby foods. The levels of PAH markers were higher than the permissible EU limits of 1 MUg kg-1 in 18.2% and 77.7% milk, and 5.6% and 44.4% meat/fish based baby foods. Milk based samples showed significant higher values (P < 0.05) of carcinogenic and possible carcinogenic hydrocarbons than meat/fish based products. The Margins of Exposure (MOE) value of milk based baby food samples indicated a potential concern for consumer health. Monitoring programs, and good agriculture and manufacture practices should be recommended. PMID- 28622645 TI - Statistical equivalence of prediction models of the soil sorption coefficient obtained using different log P algorithms. AB - The soil sorption coefficient normalized to the organic carbon content (Koc) is a physicochemical parameter used in environmental risk assessments and in determining the final fate of chemicals released into the environment. Several models for predicting this parameter have been proposed based on the relationship between log Koc and log P. The difficulty and cost of obtaining experimental log P values led to the development of algorithms to calculate these values, some of which are free to use. However, quantitative structure-property relationship (QSPR) studies did not detail how or why a particular algorithm was chosen. In this study, we evaluated several free algorithms for calculating log P in the modeling of log Koc, using a broad and diverse set of compounds (n = 639) that included several chemical classes. In addition, we propose the adoption of a simple test to verify if there is statistical equivalence between models obtained using different data sets. Our results showed that the ALOGPs, KOWWIN and XLOGP3 algorithms generated the best models for modeling Koc, and these models are statistically equivalent. This finding shows that it is possible to use the different algorithms without compromising statistical quality and predictive capacity. PMID- 28622647 TI - Endocrine-disrupting activity of per- and polyfluoroalkyl substances: Exploring combined approaches of ligand and structure based modeling. AB - Exposure to perfluorinated and polyfluoroalkyl substances (PFCs/PFASs), endocrine disrupting halogenated pollutants, has been linked to various diseases including thyroid toxicity in human populations across the globe. PFASs can compete with thyroxine (T4) for binding to the human thyroid hormone transport protein transthyretin (TTR) which may lead to reduce thyroid hormone levels leading to endocrine disrupting adverse effects. Environmental fate and endocrine-disrupting activity of PFASs has initiated several research projects, but the amount of experimental data available for these pollutants is limited. In this study, experimental data for T4-TTR competing potency of 24 PFASs obtained in a radioligand-binding assay were modeled using classification- and regression-based quantitative structure-activity relationship (QSAR) tools with simple molecular descriptors obtained from chemical structure of these compounds in order to identify the responsible structural features and fragments of the studied PFASs for endocrine disruption activity. Additionally, docking studies were performed employing the crystal structure complex of TTR with bound 2', 6'-difluorobiphenyl 4-carboxylic acid (PDB: 2F7I) in order to constitute the receptor model for human TTR. The results corroborate evidence for these binding interactions and indicate multiple high-affinity modes of binding. The developed in silico models therefore advance our understanding of important structural attributes of these chemicals and may provide important information for the design of future synthesis of PFASs as well as may serve as an efficient query tool for virtual screening of large PFAS databases to check their endocrine toxicity profile. PMID- 28622646 TI - Enhanced degradation of chlorpyrifos in rice (Oryza sativa L.) by five strains of endophytic bacteria and their plant growth promotional ability. AB - Endophytic bacteria reside in plant tissues, such as roots, stems, leaves and seeds. Most of them can stimulate plant growth or alleviate phytotoxicity of pollutants. There are handful species with dual functions stimulating plant growth and degrading pollutants have been reported. Five endophytic bacteria were isolated from chlorpyrifos (CP) treated rice plants and identified as Pseudomonas aeruginosa strain RRA, Bacillus megaterium strain RRB, Sphingobacterium siyangensis strain RSA, Stenotrophomonas pavanii strain RSB and Curtobacterium plantarum strain RSC according to morphological characteristics, physiological and biochemical tests, and 16S rDNA phylogeny. All of them possessed some plant growth promotional traits, including indole acetic acid and siderophore production, secretion of phosphate solubilization and 1-aminocyclopropane-1 carboxylate deaminase. The bacteria were marked with the green fluorescent protein (gfp) gene and successfully colonized into rice plants. All isolates were able to degrade CP in vitro and in vivo. The five isolates degraded more than 90% of CP in 24 h when the initial concentration was lower than 5 mg/L. CP degradation was significantly enhanced in the infested rice plants and rice grains. The final CP residual was reduced up to 80% in the infested rice grains compared to the controls. The results indicate that these isolates are promising bio-inoculants for the removal or detoxification of CP residues in rice plants and grains. PMID- 28622648 TI - Long-term sustainability of microbial-induced CaCO3 precipitation in aqueous media. AB - Microbially induced CaCO3 precipitation (MICP) via urea hydrolysis is an emerging technique for soil amelioration, building materials rehabilitation and pollutants sequestration amongst other various environmental applications. The successful application of MICP requires the sustainability of the precipitated CaCO3; to which the fate of ammonia, the main by-product of ureolysis, is potentially significante. Ammonia volatilization and biological ammonia oxidation both induce a pH decrease, which, in turn, might cause CaCO3 dissolution. To examine the potential effect of accumulated ammonia on precipitated CaCO3, we conducted a long-term MICP batch experiment, using environmental enrichment cultures of ureolytic bacteria. Here we show that CaCO3 precipitation was completed within 15 27 days, along with a rise in ammonium concentration. Following completion of ureolysis and precipitation, ammonium concentrations decreased, leading to a pH decrease. About 30 days after precipitation was completed, as much as 30% CaCO3 dissolution, was observed. A two-step model, describing urea hydrolysis followed by the removal of ammonia from the precipitation solution, predicted CaCO3 dissolution due to ammonia volatilization. We suggest that ureolytic MICP might result in ammonia volatilization, leading to significant CaCO3 dissolution. These results provide basic insights into the sustainability of ureolytic MICP and should further encourage removal of the accumulated ammonia from the treated site. PMID- 28622649 TI - Influence of surface chemistry of carbon materials on their interactions with inorganic nitrogen contaminants in soil and water. AB - Inorganic nitrogen contaminants (INC) (NH4+, NO3-, NO2-, NH3, NO, NO2, and N2O) pose a growing risk to the environment, and their remediation methods are highly sought after. Application of carbon materials (CM), such as biochar and activated carbon, to remediate INC from agricultural fields and wastewater treatment plants has gained a significant interest since past few years. Understanding the role of surface chemistry of CM in adsorption of various INC is highly critical to increase adsorption efficiency as well as to assess the long term impact of using these highly recalcitrant CM for remediation of INC. Critical reviews of adsorption studies related to INC have revealed that carbon surface chemistry (surface functional groups, pH, Eh, elemental composition, and mineral content) has significant influence on adsorption of INC. Compared to basic functional groups, oxygen containing surface functional groups have been found to be more influential for adsorption of INC. However, basic sites on carbon materials still play an important role in chemisorption of anionic INC. Apart from surface functional groups, pH, Eh and pHzpc of CM and elemental and mineral composition of its surface are important properties capable of altering INC interactions with CM. This review summarizes our current understanding of INC interactions with CM's surface through the known chemisorption mechanisms: electrostatic interaction, hydrogen bonding, electron donor-acceptor mechanism, hydrophobic and hydrophilic interaction, chemisorption aided by minerals, and interactions influenced by pH and elemental composition. Change in surface chemistry of CM in soil during aging is also discussed. PMID- 28622650 TI - The positive effect of phosphogypsum-supplemented composts on potato plant growth in the field and tuber yield. AB - The production of phosphoric acid from phosphate rock leads to an industrial by product called phosphogypsum (PG). One ton of phosphoric acid generates 5 tons of PG that is frequently stocked near the production units. Several attempts were made to test PG valorization via soil amendment because of its phosphate, sulphate and calcium content. In this study, the use of PG in composting was envisaged. Composts were produced by mixing olive oil wastes and spent coffee grounds. Two concentrations of PG, 10% (A10) and 30% (A30), were tested in composting substrate in addition to control compost without PG (AT). After 8 months of fermentation, the resulting composts were used in field experiments using nine different treatments conducted to evaluate the potential use of these PG-containing composts in potato plant (cv. Spunta) cultivation. Plants were grown in the field and the different composts (AT, A10 and A30) were added as fertilizer and compared to commercial compost and cattle manure. During the culture period, a number of physiological (dry weight, chlorophyll content, tuber yield) and biochemical parameters (antioxidant activities, mineral content, starch and protein content) were followed. Similarly, chlorophyll content was measured in plants cultivated on commercial or PG supplemented composts. An increment of 55.17% in potato yield was recorded with the use of A30 the compost. Collectively, these data reveal the positive impact of the addition of PG in composting which may be adopted as a strategy for PG valorization and its use for the production of high quality edible products. PMID- 28622651 TI - Application of electroencephalographic techniques to the study of visual impact of renewable energies. AB - Much is currently being studied on the negative visual impact associated to the installation of large wind turbines or photovoltaic farms. However, methodologies for quantitatively assessing landscape impact are scarce. In this work we used electroencephalographic (EEG) recordings to investigate the brain activity of 14 human volunteers when looking at the same landscapes with and without wind turbines, solar panels and nuclear power plants. Our results showed no significant differences for landscapes with solar power systems or without them, and the same happened for wind turbines, what was in agreement with their subjective scores. However, there were clear and significant differences when looking at landscapes with and without nuclear power plants. These differences were more pronounced around a time window of 376-407 msec and showed a clear right lateralization for the pictures containing nuclear power plants. Although more studies are still needed, these results suggest that EEG recordings can be a useful procedure for measuring visual impact. PMID- 28622652 TI - Deterioration pattern of six biodegradable, potentially low-environmental impact mulches in field conditions. AB - Polyethylene plastic mulches are widely used in agriculture due to the countless advantages they have. However, the environmental problems associated with their use have led us to look for alternative mulch materials which degrade naturally and quickly, impact the environment less and function satisfactorily. To this end, biodegradable plastics and paper mulches are being used, but aspects related to their degradation should be studied more in-depth. This work provides the deterioration pattern of six biodegradable mulch materials (i.e. vegetable starch, polylactic acid plastic films or paper mulches) in horticultural crop in the edaphoclimatic conditions of Central Spain in two situations: over the lifetime of the mulches and after being incorporated into the soil. In the first situation, the deterioration levels were evaluated by recording the puncture resistance, weight and area covered in the above-soil and the in-soil part, and after soil incorporation by the number of fragments, their surfaces and weight. In the above-soil part, biodegradable plastics experienced further deterioration, particularly with no crop, while the paper mulch remained practically intact. However, the in-soil paper experienced complete and rapid degradation. At 200 days after soil incorporation, mulch residues were scarce, with the environmental effects it entails. These findings offer practical implications regarding the type of crop. The measurement of the surface covered, rather than the weight, was shown to be a more reliable indicator of the degradation of mulches. Furthermore, visual estimation was found to underestimate the functionality of mulches in comparison to that of the measurement of the surface covered. PMID- 28622653 TI - Surfactant coupled sonic pretreatment of waste activated sludge for energetically positive biogas generation. AB - The objective of this study was to evaluate the effect of dioctyl sodium sulphosuccinate (DOSS, a surfactant) on lysis rate of sludge and specific energy required for sonic pretreatment of waste activated sludge (WAS). Different ultrasonic power levels, WAS concentrations, DOSS dosages, and specific energy levels were used to compare pretreatment efficiencies. At an optimum time of 10min with ultrasonic power level of 160W, DOSS coupled sonic pretreatment resulted in better lysis rate (24.7%) of sludge than sonic pretreatment (17.6%). Biodegradability estimation through non-linear regression modeling revealed that DOSS coupled ultrasound pretreatment of sludge showed better biodegradability with higher hydrolysis constant (about 0.25d-1) than sonic pretreatment (0.19d 1). Nearly six times less energy was required for DOSS coupled ultrasound pretreatment compared to that required for sonic pretreatment. Therefore, DOSS coupled ultrasound pretreatment makes the pretreatment process energetically positive. PMID- 28622654 TI - Continuous production of biodiesel under supercritical methyl acetate conditions: Experimental investigation and kinetic model. AB - In this study, biodiesel production by using supercritical methyl acetate in a continuous flow reactor was investigated for the first time. The aim of this study was to elucidate the reaction kinetics of biodiesel production by using supercritical methyl. Experiments were conducted at various reaction temperatures (300-400 degrees C), residence times (5-30min), oil-to-methyl acetate molar ratio of 1:40, and a fixed pressure of 20MPa. Reaction kinetics of biodiesel production with supercritical methyl acetate was determined. Finally, biodiesel yield obtained from this method was compared to that obtained with supercritical methanol, ethanol, and MTBE (methyl tertiary-butyl ether). The results showed that biodiesel yield with supercritical methyl acetate increased with temperature and time. The developed kinetic model was found to fit the experimental data well. The reactivity of supercritical methyl acetate was the lowest, followed by that of supercritical MTBE, ethanol, and methanol, under the same conditions. PMID- 28622655 TI - Effective cell trapping using PDMS microspheres in an acoustofluidic chip. AB - We present a facile particle-based cell manipulation method using acoustic radiation forces. In this work, we selected several representative particles including poly(lactic-co-glycolic acid) (PLGA) microspheres, silica-coated magnetic microbeads, polydimethylsiloxane (PDMS) microspheres and investigated the responses of these particle systems to ultrasonic standing waves (USWs) in a microfluidic chip. We show that depending on the nature (positive or negative acoustic contrast factors) of the particles, these particle systems display different alignment behaviors along the microfluidic channel under USWs. Specifically, PLGA microspheres and silica-coated magnetic microbeads are able to be aligned in the middle of the microfluidic channel, while PDMS microspheres are translocated to the side walls of the channel, which is beneficial for cell trapping and manipulation. Further results demonstrate that the functional PDMS microspheres with a negative acoustic contrast factor can be used to trap cells to the pressure antinodes in the acoustofluidic chip. Cell viability tests reveal that the ultrasonic manipulation does not exert any harmful effect to the cells. This acoustic-based particle and cell manipulation technique may hold a great promise for the development of rapid, noninvasive, continuous assays for detecting of cells and separation of biological samples. PMID- 28622656 TI - A combined experimental setup for OP and ODNMR. AB - Instrumentation for optically-pumped and optically-detected nuclear magnetic resonance (OPNMR and ODNMR) has been developed and implemented as a single experimental apparatus to study semiconductors such as GaAs and CdTe. These two measurement schemes use many of the same components for experiments. Here we describe, in two parts, the apparatus that can record such measurements and give examples of representative data. In Part 1, the radio-frequency probe and low temperature cryostat are described, including single-channel and two-channel static cryogenic probes that both incorporate a modified solenoid coil that permits better optical access. In Part 2, the optical bench is described in detail, which uses a set of experiments (magneto-photoluminescence, photoluminescence excitation, detection of polarized photoluminescence) as important input for ODNMR. We are able to portray a robust design that encompasses multiple measurement modalities, along with the ability to change many experimental parameters with ease. PMID- 28622657 TI - Patterns of multimorbidity in people with severe or profound intellectual and motor disabilities. AB - BACKGROUND: People with severe or profound intellectual and motor disabilities (SPIMD) experience multimorbidity and have complex health needs. Multimorbidity increases mortality, decreases functioning, and negatively influences quality of life. Information regarding patterns of multimorbidity in people with SPIMD may lead to proactive prevention, specifically detection and treatment of physical health problems at an early stage and prevention of secondary complications. AIM: The aim of this study was to explore patterns of multimorbidity in individuals with SPIMD. METHODS AND PROCEDURES: Data from medical records and care plans on reported physical health problems of 99 adults with SPIMD were analysed. To explore the co-occurrence of physical health problems, cross tabulations and a 5 set Venn Diagram were used. OUTCOMES AND RESULTS: The most common combination of two physical health problems comprise the most prevalent physical health problems, which included visual impairment, constipation, epilepsy, spasticity, and scoliosis. These five issues occurred as a multimorbidity combination in 37% of the participants. In 56% of the participants a multimorbidity combination of four health problems emerged, namely constipation, visual impairment, epilepsy, and spasticity. CONCLUSIONS AND IMPLICATIONS: People experiencing SPIMD have interrelated health problems. As a consequence, a broad variety of potential interactions between physical health problems and their treatments may occur. Identifying multimorbidity patterns can provide guidance for accurate monitoring of persistent health problems and, early detection of secondary complications. However, the results require confirmation with larger samples in further studies. PMID- 28622658 TI - How effectors promote beneficial interactions. AB - Beneficial microbes such as rhizobia possess effector proteins that are secreted into the host cytoplasm where they modulate host-signaling pathways. Among these effectors, type 3 secreted effectors (T3Es) of rhizobia play roles in promoting nitrogen-fixing nodule symbiosis, suppressing host defenses and directly activating symbiosis-related processes. Rhizobia use the same strategy as pathogenic bacteria to suppress host defenses such as targeting the MAPK cascade. In addition, rhizobial T3E can promote root nodule symbiosis by directly activating Nod factor signaling, which bypasses Nod factor perception. The various strategies employed by beneficial microbes to promote infection and maintain viability in the host are therefore crucial for plant endosymbiosis. PMID- 28622660 TI - Assessing the effects of the antidepressant venlafaxine to fathead minnows exposed to environmentally relevant concentrations over a full life cycle. AB - Venlafaxine is an antidepressant drug that has been detected in municipal wastewater effluents at low MUg/L concentrations. To assess the potential of this compound to affect the survival, development and reproductive capacity of fish, we exposed fathead minnow (Pimephales promelas) over a full lifecycle in a flow through system to nominal venlafaxine concentrations of 0.88, 8.8, and 88 MUg/L. Mean measured venlafaxine concentrations in these treatments were 1.0, 9.3 and 75 MUg/L. During the 167-168 d exposure, no significant changes were observed in survival, or the weights and lengths of fathead minnows. At maturity, there were no significant differences relative to controls in condition factor, liver somatic index, or secondary sex characteristics in the venlafaxine exposed male or female fish. Fathead minnows from the highest venlafaxine treatment (i.e. 88 MUg/L) produced 46% more eggs per female than control fish (p = 0.031). Egg quality, % fertilization, % hatching, and % deformities in F1 fry were unaffected by exposure of the parent fish to venlafaxine at any of the test concentrations. Venlafaxine exposure at environmentally relevant concentrations (i.e. 0.88 and 8.8 MUg/L) caused no adverse effects in fathead minnows. This study is the first to assess the potential for effects in fish exposed to the antidepressant venlafaxine over a full lifecycle. PMID- 28622659 TI - Understanding and exploiting plant beneficial microbes. AB - After a century of incremental research, technological advances, coupled with a need for sustainable crop yield increases, have reinvigorated the study of beneficial plant-microbe interactions with attention focused on how microbiomes alter plant phenotypes. We review recent advances in plant microbiome research, and describe potential applications for increasing crop productivity. The phylogenetic diversity of plant microbiomes is increasingly well characterized, and their functional diversity is becoming more accessible. Large culture collections are available for controlled experimentation, with more to come. Genetic resources are being brought to bear on questions of microbiome function. We expect that microbial amendments of varying complexities will expose rules governing beneficial plant-microbe interactions contributing to plant growth promotion and disease resistance, enabling more sustainable agriculture. PMID- 28622661 TI - Air pollution and genomic instability: The role of particulate matter in lung carcinogenesis. AB - In this review, we summarize and discuss the evidence regarding the interaction between air pollution, especially particulate matter (PM), and genomic instability. PM has been widely studied in the context of several diseases, and its role in lung carcinogenesis gained relevance due to an increase in cancer cases for which smoking does not seem to represent the main risk factor. According to epidemiological and toxicological evidence, PM acts as a carcinogenic factor in humans, inducing high rates of genomic alterations. Here, we discuss not only how PM is capable of inducing genomic instability during the carcinogenic process but also how our genetic background influences the response to the sources of damage. PMID- 28622662 TI - The chronic effects of fullereneC60-associated sediments in the midge Chironomus riparius - Responses in the first and the second generation. AB - The life cycle parameters of the benthic invertebrate Chironomus riparius make it a relevant organism for use in multi-generation chronic ecotoxicology tests. Since studies on chronic exposures with fullerene carbon nanoparticles have revealed adverse effects at lower concentration ranges, it is crucial to gain understanding of the consequences in following generations. The aims of this study were to investigate whether sediment-associated fullereneC60 impacts on C. riparius emergence and breeding, thus affecting the growth of the second generation. Larvae were exposed to fullerene-spiked sediment at concentrations of 0.5, 10 and 40 mg/kg sediment dw. Total emergence and breeding success were monitored after the first generation and the newly hatched larvae from the first generation exposure were transferred either to continuous exposure or to pristine sediment without fullerene. Findings indicate that the presence of fullerenes has major impacts on the first generation, mainly shown as delayed emergence time of females. Increased larval growth was observed in the second generation, and we conclude that the C. riparius response to fullerene exposure indicated significant signs of recovery in second-generation larval growth. The result shows the effects to be important for population dynamics, revealing delayed female emergence time, which leads to situation where adults' breeding is impaired. PMID- 28622663 TI - Sensitive immunoassay for simultaneous determination of tetrabromobisphenol A bis(2-hydroxyethyl) ether and tetrabromobisphenol A mono(hydroxyethyl) ether: An effective and reliable strategy to estimate the typical tetrabromobisphenol A derivative and byproduct in aquatic environments. AB - Tetrabromobisphenol A bis(2-hydroxyethyl) ether (TBBPA DHEE), as one of the TBBPA derivatives, is frequently applied as a flame retardant. To date, however, little evidence has been gathered regarding its environmental behavior and fate. This is mainly attributed to the lack of an analytical approach available to measure it. Mass spectrometry cannot determine levels of TBBPA DHEE. LC-MS could not ionize TBBPA DHEE to yield enough fragments, while GC-MS could not be applied for the analysis either, due to the thermal degradation of TBBPA DHEE. We here designed a novel hapten, then conjugated it with a carrier protein and produced a type of polyclonal antibody capable of recognizing TBBPA DHEE. Based on this approach, a sensitive and high-throughput indirect competitive enzyme-linked immunosorbent assay (ELISA) was established. The respective detection limit (LOD, based on 90% B/B0) and IC50 calculated from the standard curve were 0.702 and 9.868 ng/mL for TBBPA DHEE. And the established method showed good tolerance to various matrix interferents. Using our ELISA, we measured the concentrations of these substances from environmental water samples with no pretreatment other than filtration. We found the presence of TBBPA DHEE in environmental water samples collected in Jiangsu province, and the detected concentrations ranging from 1.5 to 7.7 ng/mL. Our proposed method here could be applied to completely and systematically investigate TBBPA DHEE and TBBPA MHEE concentrations in environmental samples. PMID- 28622664 TI - Mechanical Imaging of Soft Tissues With a Highly Compliant Tactile Sensing Array. AB - OBJECTIVE: The mechanical imaging of lumps in tissues via surface measurements can permit the noninvasive detection of disease-related differences in body tissues. We present and evaluate sensing techniques for the mechanical imaging of soft tissues, using a highly compliant electronic sensing array. METHODS: We developed a mechanical imaging system for capturing tissue properties during automatic- or human-guided palpation. It combines extremely compliant capacitive tactile sensors based on soft polymers and microfluidic electrodes with custom electronic data acquisition hardware, and new algorithms for enhanced tactile imaging by reference to nominal tissue responses. RESULTS: We demonstrate that the system is able to image simulated tumors (lumps), yielding accurate estimates of cross-sectional area independent of embedding depth. In addition, as a proof of concept, we show that similar tactile images can be obtained when the sensor is worn on a palpating finger. CONCLUSION: Soft capacitive sensors can accurately image lumps in soft tissue provided that care is taken to control and compensate for electrical and mechanical background signals. SIGNIFICANCE: The results underline the utility of soft electronic sensors for applications in medical imaging or clinical practices of palpation. PMID- 28622665 TI - Noninvasive In-Situ Measurement of Blood Lactate Using Microwave Sensors. AB - GOAL: This paper reports a novel electromagnetic sensor technique for real-time noninvasive monitoring of blood lactate in human subjects. METHODS: The technique was demonstrated on 34 participants who undertook a cycling regime, with rest period before and after, to produce a rising and falling lactate response curve. Sensors attached to the arm and legs of participants gathered spectral data, blood samples were measured using a Lactate Pro V2; temperature and heart rate data was also collected. RESULTS: Pointwise mutual information and neural networks are used to produce a predictive model. The model shows a good correlation between the standard invasive and novel noninvasive electromagnetic wave based blood lactate measurements, with an error of 13.4% in the range of 0 12 mmol/L. CONCLUSION: The work demonstrates that electromagnetic wave sensors are capable of determining blood lactate level without the need for invasive blood sampling. SIGNIFICANCE: Measurement of blood metabolites, such as blood lactate, in real-time and noninvasively in hospital environments will reduce the risk of infection, increase the frequency of measurement and ensure timely intervention only when necessary. In sports, such tools will enhance training of athletes, and enable more effecting training regimes to be prescribed. PMID- 28622666 TI - Real-Time Automatic Apneic Event Detection Using Nocturnal Pulse Oximetry. AB - OBJECTIVE: Nocturnal pulse oximetry has been proposed as a simpler alternative to polysomnography in diagnosing sleep apnea. However, existing techniques are limited in terms of inability to provide time information on sleep apnea occurrence. This study aimed to propose a new strategy for near real-time automatic detection of apneic events and reliable estimation of apnea-hypopnea index using nocturnal pulse oximetry. METHODS: Among 230 polysomnographic recordings with apnea-hypopnea index values ranging from 0 to 86.5 events/h, 138 (60%) and the remaining 92 recordings (40%) were categorized as training and test sets, respectively. By extracting the quantitative characteristics caused by the apneic event for the amount and duration of the change in blood oxygen saturation value, we established the criteria to determine the occurrence of apneic event. Regression modeling was used to estimate the apnea-hypopnea index from the apneic event detection results. RESULTS: The minute-by-minute apneic segment detection exhibited an average accuracy of 91.0% and an average Cohen's kappa coefficient of 0.71. Between the apnea-hypopnea index estimations and reference values, the mean absolute error was 2.30 events/h. The average accuracy of our diagnosis of sleep apnea was 96.7% for apnea-hypopnea index cutoff values of >=5, 10, 15, and 30 events/h. CONCLUSION: We developed an effective strategy to detect apneic events by using morphometric characteristics in the fluctuation of blood oxygen saturation values. SIGNIFICANCE: Our study could be potentially useful in home based multinight apneic event monitoring for purposes of therapeutic intervention and follow-up study on sleep apnea. PMID- 28622668 TI - A Bayesian Approach to Policy Recognition and State Representation Learning. AB - Learning from demonstration (LfD) is the process of building behavioral models of a task from demonstrations provided by an expert. These models can be used, e.g., for system control by generalizing the expert demonstrations to previously unencountered situations. Most LfD methods, however, make strong assumptions about the expert behavior, e.g., they assume the existence of a deterministic optimal ground truth policy or require direct monitoring of the expert's controls, which limits their practical use as part of a general system identification framework. In this work, we consider the LfD problem in a more general setting where we allow for arbitrary stochastic expert policies, without reasoning about the optimality of the demonstrations. Following a Bayesian methodology, we model the full posterior distribution of possible expert controllers that explain the provided demonstration data. Moreover, we show that our methodology can be applied in a nonparametric context to infer the complexity of the state representation used by the expert, and to learn task-appropriate partitionings of the system state space. PMID- 28622667 TI - NetVLAD: CNN Architecture for Weakly Supervised Place Recognition. AB - We tackle the problem of large scale visual place recognition, where the task is to quickly and accurately recognize the location of a given query photograph. We present the following four principal contributions. First, we develop a convolutional neural network (CNN) architecture that is trainable in an end-to end manner directly for the place recognition task. The main component of this architecture, NetVLAD, is a new generalized VLAD layer, inspired by the "Vector of Locally Aggregated Descriptors" image representation commonly used in image retrieval. The layer is readily pluggable into any CNN architecture and amenable to training via backpropagation. Second, we create a new weakly supervised ranking loss, which enables end-to-end learning of the architecture's parameters from images depicting the same places over time downloaded from Google Street View Time Machine. Third, we develop an efficient training procedure which can be applied on very large-scale weakly labelled tasks. Finally, we show that the proposed architecture and training procedure significantly outperform non-learnt image representations and off-the-shelf CNN descriptors on challenging place recognition and image retrieval benchmarks. PMID- 28622669 TI - Matching by Monotonic Tone Mapping. AB - In this paper, a novel dissimilarity measure called Matching by Monotonic Tone Mapping (MMTM) is proposed. The MMTM technique allows matching under non-linear monotonic tone mappings and can be computed efficiently when the tone mappings are approximated by piecewise constant or piecewise linear functions. The proposed method is evaluated in various template matching scenarios involving simulated and real images, and compared to other measures developed to be invariant to monotonic intensity transformations. The results show that the MMTM technique is a highly competitive alternative of conventional measures in problems where possible tone mappings are close to monotonic. PMID- 28622670 TI - Adaptive Clutter Demodulation for Non-Contrast Ultrasound Perfusion Imaging. AB - Conventional Doppler ultrasound is useful for visualizing fast blood flow in large resolvable vessels. However, frame rate and tissue clutter caused by movement of the patient or sonographer make visualizing slow flow with ultrasound difficult. Patient and sonographer motion causes spectral broadening of the clutter signal, which limits ultrasound's sensitivity to velocities greater than 5-10 mm/s for typical clinical imaging frequencies. To address this, we propose a clutter filtering technique that may increase the sensitivity of Doppler measurements to at least as low as 0.52 mm/s. The proposed technique uses plane wave imaging and an adaptive frequency and amplitude demodulation scheme to decrease the bandwidth of tissue clutter. To test the performance of the adaptive demodulation method at suppressing tissue clutter bandwidths due to sonographer hand motion alone, six volunteer subjects acquired data from a stationary phantom. Additionally, to test in vivo feasibility, arterial occlusion and muscle contraction studies were performed to assess the efficiency of the proposed filter at preserving signals from blood velocities 2 mm/s or greater at a 7.8 MHz center frequency. The hand motion study resulted in initial average bandwidths of 175 Hz (8.60mm/s), which were decreased to 10.5 Hz (0.52 mm/s) at -60 dB using our approach. The in vivo power Doppler studies resulted in 4.73 dB and 4.80 dB dynamic ranges of the blood flow with the proposed filter and 0.15 dB and 0.16 dB dynamic ranges of the blood flow with a conventional 50 Hz high-pass filter for the occlusion and contraction studies, respectively. PMID- 28622672 TI - Physiological Effects of Single- and Multi-Walled Carbon Nanotubes on Rice Seedlings. AB - In this paper, single-walled carbon nano- tubes (SWCNTs) and multi-walled carbon nano- tubes (MWCNTs) were found to accelerate leaf growth and development of rice seedlings at a low concentration (20 mg/L), accompanied with the increased chlorophyll content and net photosynthetic rate (PN). Quantitative real-time polymerase chain reaction results indicated that both SWCNTs and MWCNTs significantly increased expression of genes associated with chloroplast development and cell sizes. Further analysis revealed that the abscisic acid content decreased and the gibberellin content increased while the content of [Formula: see text] and H2O2 was slightly elevated and the activities of antioxidative enzymes (SOD, EC 1.15.1.1, and POD, EC 1.11.1.7) were differently modulated after treatment with the carbon nanotube (CNT). These results suggest a possible link between reactive oxygen species and plant hormones under CNTs treatment to promote rice seedlings growth. PMID- 28622673 TI - Exact Algorithms for Duplication-Transfer-Loss Reconciliation with Non-Binary Gene Trees. AB - Duplication-Transfer-Loss (DTL) reconciliation is a powerful method for studying gene family evolution in the presence of horizontal gene transfer. DTL reconciliation seeks to reconcile gene trees with species trees by postulating speciation, duplication, transfer, and loss events. Efficient algorithms exist for finding optimal DTL reconciliations when the gene tree is binary. In practice, however, gene trees are often non-binary due to uncertainty in the gene tree topologies, and DTL reconciliation with non-binary gene trees is known to be NP-hard. In this paper, we present the first exact algorithms for DTL reconciliation with non-binary gene trees. Specifically, we (i) show that the DTL reconciliation problem for non-binary gene trees is fixed-parameter tractable in the maximum degree of the gene tree, (ii) present an exponential-time, but in practice efficient, algorithm to track and enumerate all optimal binary resolutions of a non-binary input gene tree, and (iii) apply our algorithms to a large empirical data set of over 4700 gene trees from 100 species to study the impact of gene tree uncertainty on DTL-reconciliation and to demonstrate the applicability and utility of our algorithms. The new techniques and algorithms introduced in this paper will help biologists avoid incorrect evolutionary inferences caused by gene tree uncertainty. PMID- 28622671 TI - Low-Dose CT With a Residual Encoder-Decoder Convolutional Neural Network. AB - Given the potential risk of X-ray radiation to the patient, low-dose CT has attracted a considerable interest in the medical imaging field. Currently, the main stream low-dose CT methods include vendor-specific sinogram domain filtration and iterative reconstruction algorithms, but they need to access raw data, whose formats are not transparent to most users. Due to the difficulty of modeling the statistical characteristics in the image domain, the existing methods for directly processing reconstructed images cannot eliminate image noise very well while keeping structural details. Inspired by the idea of deep learning, here we combine the autoencoder, deconvolution network, and shortcut connections into the residual encoder-decoder convolutional neural network (RED CNN) for low-dose CT imaging. After patch-based training, the proposed RED-CNN achieves a competitive performance relative to the-state-of-art methods in both simulated and clinical cases. Especially, our method has been favorably evaluated in terms of noise suppression, structural preservation, and lesion detection. PMID- 28622674 TI - A Two-Stage Biomedical Event Trigger Detection Method Integrating Feature Selection and Word Embeddings. AB - Extracting biomedical events from biomedical literature plays an important role in the field of biomedical text mining, and the trigger detection is a key step in biomedical event extraction. We propose a two-stage method for trigger detection, which divides trigger detection into recognition stage and classification stage, and different features are selected in each stage. In the first stage, we select the features which are more suitable for recognition, and in the second stage, the features that are more helpful to classification are adopted. Furthermore, we integrate word embeddings to represent words semantically and syntactically. On the multi-level event extraction (MLEE) corpus test dataset, our method achieves an F-score of 79.75 percent, which outperforms the state-of-the-art systems. PMID- 28622675 TI - State-of-the-Art Methods for Brain Tissue Segmentation: A Review. AB - Brain tissue segmentation is one of the most sought after research areas in medical image processing. It provides detailed quantitative brain analysis for accurate disease diagnosis, detection, and classification of abnormalities. It plays an essential role in discriminating healthy tissues from lesion tissues. Therefore, accurate disease diagnosis and treatment planning depend merely on the performance of the segmentation method used. In this review, we have studied the recent advances in brain tissue segmentation methods and their state-of-the-art in neuroscience research. The review also highlights the major challenges faced during tissue segmentation of the brain. An effective comparison is made among state-of-the-art brain tissue segmentation methods. Moreover, a study of some of the validation measures to evaluate different segmentation methods is also discussed. The brain tissue segmentation, content in terms of methodologies, and experiments presented in this review are encouraging enough to attract researchers working in this field. PMID- 28622676 TI - Training DCNN by Combining Max-Margin, Max-Correlation Objectives, and Correntropy Loss for Multilabel Image Classification. AB - In this paper, we build a multilabel image classifier using a general deep convolutional neural network (DCNN). We propose a novel objective function that consists of three parts, i.e., max-margin objective, max-correlation objective, and correntropy loss. The max-margin objective explicitly enforces that the minimum score of positive labels must be larger than the maximum score of negative labels by a predefined margin, which not only improves accuracies of the multilabel classifier, but also eases the threshold determination. The max correlation objective can make the DCNN model learn a latent semantic space, which maximizes the correlations between the feature vectors of the training samples and their corresponding ground-truth label vectors projected into this space. Instead of using the traditional softmax loss, we adopt the correntropy loss from the information theory field to minimize the training errors of the DCNN model. The proposed framework can be end-to-end trained. Comprehensive experimental evaluations on Pascal VOC 2007 and MIR Flickr 25K multilabel benchmark data sets with four DCNN models, i.e., AlexNet, VGG-16, GoogLeNet, and ResNet demonstrate that the proposed objective function can remarkably improve the performance accuracies of a DCNN model for the task of multilabel image classification. PMID- 28622677 TI - Tree-Based Kernel for Graphs With Continuous Attributes. AB - The availability of graph data with node attributes that can be either discrete or real-valued is constantly increasing. While existing Kernel methods are effective techniques for dealing with graphs having discrete node labels, their adaptation to nondiscrete or continuous node attributes has been limited, mainly for computational issues. Recently, a few kernels especially tailored for this domain, and that trade predictive performance for computational efficiency, have been proposed. In this brief, we propose a graph kernel for complex and continuous nodes' attributes, whose features are tree structures extracted from specific graph visits. The kernel manages to keep the same complexity of the state-of-the-art kernels while implicitly using a larger feature space. We further present an approximated variant of the kernel, which reduces its complexity significantly. Experimental results obtained on six real-world data sets show that the kernel is the best performing one on most of them. Moreover, in most cases, the approximated version reaches comparable performances to the current state-of-the-art kernels in terms of classification accuracy while greatly shortening the running times. PMID- 28622678 TI - Robust Least-Squares Support Vector Machine With Minimization of Mean and Variance of Modeling Error. AB - The least-squares support vector machine (LS-SVM) is a popular data-driven modeling method and has been successfully applied to a wide range of applications. However, it has some disadvantages, including being ineffective at handling non-Gaussian noise as well as being sensitive to outliers. In this paper, a robust LS-SVM method is proposed and is shown to have more reliable performance when modeling a nonlinear system under conditions where Gaussian or non-Gaussian noise is present. The construction of a new objective function allows for a reduction of the mean of the modeling error as well as the minimization of its variance, and it does not constrain the mean of the modeling error to zero. This differs from the traditional LS-SVM, which uses a worst-case scenario approach in order to minimize the modeling error and constrains the mean of the modeling error to zero. In doing so, the proposed method takes the modeling error distribution information into consideration and is thus less conservative and more robust in regards to random noise. A solving method is then developed in order to determine the optimal parameters for the proposed robust LS SVM. An additional analysis indicates that the proposed LS-SVM gives a smaller weight to a large-error training sample and a larger weight to a small-error training sample, and is thus more robust than the traditional LS-SVM. The effectiveness of the proposed robust LS-SVM is demonstrated using both artificial and real life cases. PMID- 28622679 TI - Neighborhood Structural Similarity Mapping for the Classification of Masses in Mammograms. AB - In this paper, two novel feature extraction methods, using neighborhood structural similarity (NSS), are proposed for the characterization of mammographic masses as benign or malignant. Since gray-level distribution of pixels is different in benign and malignant masses, more regular and homogeneous patterns are visible in benign masses compared to malignant masses; the proposed method exploits the similarity between neighboring regions of masses by designing two new features, namely, NSS-I and NSS-II, which capture global similarity at different scales. Complementary to these global features, uniform local binary patterns are computed to enhance the classification efficiency by combining with the proposed features. The performance of the features are evaluated using the images from the mini-mammographic image analysis society (mini-MIAS) and digital database for screening mammography (DDSM) databases, where a tenfold cross validation technique is incorporated with Fisher linear discriminant analysis, after selecting the optimal set of features using stepwise logistic regression method. The best area under the receiver operating characteristic curve of 0.98 with an accuracy of is achieved with the mini-MIAS database, while the same for the DDSM database is 0.93 with accuracy . PMID- 28622680 TI - Optimized Multistable Stochastic Resonance for the Enhancement of Pituitary Microadenoma in MRI. AB - Magnetic resonance imaging (MRI) is the modality of choice as far as imaging diagnosis of pathologies in the pituitary gland is concerned. Furthermore, the advent of dynamic contrast enhanced (DCE) has enhanced the capability of this modality in detecting minute benign but endocrinologically significant tumors called microadenoma. These lesions are visible with difficulty and a low confidence level in routine MRI sequences, even after administration of intravenous gadolinium. Techniques to enhance the visualization of such foci would be an asset in improving the overall accuracy of DCE-MRI for detection of pituitary microadenomas. The present study proposes an algorithm for postprocessing DCE-MRI data using multistable stochastic resonance (MSSR) technique. Multiobjective ant lion optimization optimizes the contrast enhancement factor (CEF) and anisotropy of an image by varying the parameters associated with the dynamics of MSSR. The marked regions of interest (ROIs) are labeled as normal and microadenoma of pituitary obtained with increased level of accuracy and confidence using proposed algorithm. The increased difference between the mean intensity curves obtained using these ROIs validated the obtained subjective results. Furthermore, the proposed MSSR-based algorithm has been evaluated on standard T1 and T2 weighted BrainWeb dataset images and quantified in terms of CEF, peak signal to noise ratio (PSNR), structure similarity index measure (SSIM), and universal quality index (UQI). The obtained mean values of CEF 1.22, PSNR 27.68, SSIM 0.75, UQI 0.83 for twenty dataset images were highest among considered contrast enhancement algorithms for the comparison. PMID- 28622681 TI - A Mixed Representation-Based Multiobjective Evolutionary Algorithm for Overlapping Community Detection. AB - Designing multiobjective evolutionary algorithms (MOEAs) for community detection in complex networks has attracted much attention of researchers recently. However, most of the existing methods focus on addressing the task of nonoverlapping community detection, where each node must belong to one and only one community. In fact, communities are often overlapped with each other in many real-world networks, thus it is necessary to design overlapping community detection algorithms. To this end, this paper proposes a mixed representation based MOEA (MR-MOEA) for overlapping community detection. In MR-MOEA, a mixed individual representation scheme is proposed to fast encode and decode the overlapping divisions of complex networks. Specifically, this mixed representation consists of two parts: one represents all potential overlapping nodes and the other delegates all nonoverlapping nodes. These two parts evolve together to detect the overlapping communities of networks based on different updating strategies suggested in MR-MOEA. We verify the effectiveness of the proposed algorithm MR-MOEA on ten real-world complex networks and the experimental results demonstrate that MR-MOEA is superior over six representative algorithms for overlapping community detection. PMID- 28622682 TI - Audio Tracking in Noisy Environments by Acoustic Map and Spectral Signature. AB - A novel method is proposed for generic target tracking by audio measurements from a microphone array. To cope with noisy environments characterized by persistent and high energy interfering sources, a classification map (CM) based on spectral signatures is calculated by means of a machine learning algorithm. Next, the CM is combined with the acoustic map, describing the spatial distribution of sound energy, in order to obtain a cleaned joint map in which contributions from the disturbing sources are removed. A likelihood function is derived from this map and fed to a particle filter yielding the target location estimation on the acoustic image. The method is tested on two real environments, addressing both speaker and vehicle tracking. The comparison with a couple of trackers, relying on the acoustic map only, shows a sharp improvement in performance, paving the way to the application of audio tracking in real challenging environments. PMID- 28622699 TI - Corrections. PMID- 28622701 TI - Free Tissue Transfers for Head and Neck Reconstruction in Patients with End-Stage Renal Disease on Dialysis: Analysis of Outcomes Using the Taiwan National Health Insurance Research Database. PMID- 28622702 TI - Impact of Pregnancy on Maternal Cardiac Atria. PMID- 28622700 TI - Evidence for long-range spatiotemporal interactions in infant and adult visual cortex. AB - The development of spatiotemporal interactions giving rise to classical receptive field properties has been well studied in animal models, but little is known about the development of putative nonclassical mechanisms in any species. Here we used visual evoked potentials to study the developmental status of spatiotemporal interactions for stimuli that were biased to engage long-range spatiotemporal integration mechanisms. We compared responses to widely spaced stimuli presented either in temporal succession or at the same time. The former configuration elicits a percept of apparent motion in adults but the latter does not. Component flash responses were summed to make a linear prediction (no spatiotemporal interaction) for comparison with the measured evoked responses to sequential or simultaneous flash conditions. In adults, linear summation of the separate flash responses measured with 40% contrast stimuli predicted sequential flash responses twice as large as those measured, indicating that the response measured under apparent motion conditions is subadditive. Simultaneous-flash responses at the same spatial separation were also subadditive, but substantially less so. The subadditivity in both cases could be modeled as a simple multiplicative gain term across all electrodes and time points. In infants aged 3-8 months, responses to the stimuli used in adults were similar to their linear predictions at 40%, but the responses measured at 80% contrast resembled the subadditive responses of the adults for both sequential and simultaneous flash conditions. We interpret the developmental data as indicating that adult-like long-range spatiotemporal interactions can be demonstrated by 3-8 months, once stimulus contrast is high enough. PMID- 28622703 TI - Qualitative Determination of Human Chorionic Gonadotropin in Vaginal Washings for the Early Diagnosis of Premature Rupture of Fetal Membranes. AB - Purpose This study aimed to evaluate and validate the qualitative human chorionic gonadotropin beta subunit (beta-hCG) test of the vaginal fluid washings of pregnant women with premature rupture of fetal membranes (PROM). Methods Cross sectional study of pregnant women between gestational weeks 24 and 39 who underwent consultations in one of our institutions. They were divided into two groups: group A (pregnant women clinically diagnosed with PROM) and group B (pregnant women without loss of amniotic liquid). The patients were subjected to a vaginal fluid washing with 3 mL of saline solution, which was aspirated subsequently with the same syringe. The solution was immediately sent to the laboratory to perform the vaginal beta-hCG test with cut-off points of 10 mIU/mL (beta-hCG-10) and/or 25 mIU/mL (beta-hCG-25). Results The beta-hCG-10 test of the vaginal secretion was performed in 128 cases. The chi-squared test with Yates' correction showed a statistically significant difference between the 2 groups (p = 0.0225). The sensibility, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy parameters were 77.1%, 43.6%, 52.3%; 70.4%; and 58.6% respectively. The beta-hCG-25 test of the vaginal washing was performed in 49 cases. The analysis by Fisher's exact test showed a statistically significant difference between the groups (p = 0.0175). The sensibility, specificity, PPV, NPV, and accuracy parameters were 44.4%, 87.1%, 66.6%; 72.9%; and 71.4% respectively. Conclusions The beta-hCG-25 test showed better accuracy for the diagnosis of PROM, and can corroborate the early diagnosis of PROM because it is a simple and quick exam. PMID- 28622704 TI - Evaluation of Quality of life, Physical Activity and Nutritional Profile of Postmenopausal Women with and without Vitamin D Deficiency. AB - Introduction Vitamin D deficiency is associated with various diseases. Prevalent in Brazil, it can result from inadequate lifestyle habits. Objective To demonstrate that postmenopausal women with vitamin D deficiency have worse quality of health, expressed as worse quality of life, lower levels of physical activity, and worse nutritional profile. Methods Postmenopausal women answered questionnaires about physical activity and quality of life, provided a 24-hour food record, and had serum vitamin D levels measured. Results Among the more active women, those who perform a daily average of one hour of physical activity had vitamin D levels above 20 ng/mL (76.9%), and those, which expose themselves to sunlight, had vitamin D levels above 30 ng/mL (34.6%). Meanwhile the percentages for the women who are less physically active and less exposed to sunlight were 42.2% and 8.9% respectively. Being more active and more exposed to sunlight resulted in a lower fat percentage. Serum vitamin D levels were not correlated with quality of life. Conclusion Walking and gardening increased serum vitamin D levels and decreased the percentage of body fat. The limitations of the study prevented the impact of 25-hidroxyvitamin D on the quality of life and nutritional aspects of the women from being evaluated. PMID- 28622705 TI - PARVUS affects aluminium sensitivity by modulating the structure of glucuronoxylan in Arabidopsis thaliana. AB - Glucuronoxylan (GX), an important component of hemicellulose in the cell wall, appears to affect aluminium (Al) sensitivity in plants. To investigate the role of GX in cell-wall-localized xylan, we examined the Arabidopsis thaliana parvus mutant in detail. This mutant lacks alpha-D-glucuronic acid (GlcA) side chains in GX and has greater resistance to Al stress than wild-type (WT) plants. The parvus mutant accumulated lower levels of Al in its roots and cell walls than WT despite having cell wall pectin content and pectin methylesterase (PME) activity similar to those of WT. Our results suggest that the altered properties of hemicellulose in the mutant contribute to its decreased Al accumulation. Although we observed almost no differences in hemicellulose content between parvus and WT under control conditions, less Al was retained in parvus hemicellulose than in WT. This observation is consistent with the finding that GlcA substitutions in WT GX, but not mutant GX, were increased under Al stress. Taken together, these results suggest that the modulation of GlcA levels in GX affects Al resistance by influencing the Al binding capacity of the root cell wall in Arabidopsis. PMID- 28622706 TI - Electrical stimulation of microengineered skeletal muscle tissue: Effect of stimulus parameters on myotube contractility and maturation. AB - Skeletal muscle tissues engineered in vitro are aneural, are short in the number of fibres required to function properly and degenerate rapidly. Electrical stimulation has been widely used to compensate for such a lack of neural activity, yet the relationship between the stimulation parameters and the tissue response is subject to debate. Here we studied the effect of overnight electrical stimulation (training) on the contractility and maturity of aligned C2C12 myotubes developed on micropatterned gelatin methacryloyl (GelMA) substrates. Bipolar rectangular pulse (BRP) trains with frequency, half-duration and applied pulse train amplitudes of f = 1 Hz, ton = 0.5 ms and Vapp = {3 V, 4 V, 4.5 V}, respectively, were applied for 12 h to the myotubes formed on the microgrooved substrates. Aligned myotubes were contracting throughout the training period for Vapp >= 4 V. Immediately after training, the samples were subjected to series of BRPs with 2 <= Vapp <= 5 V and 0.2 <= ton <= 0.9 ms, during which myotube contraction dynamics were recorded. Analysis of post-training contraction revealed that only the myotubes trained at Vapp = 4 V displayed consistent and repeatable contraction profiles, showing the dynamics of myotube contractility as a function of triggering pulse voltage and current amplitudes, duration and imposed electrical energy. In addition, myotubes trained at Vapp = 4 V displayed amplified expression levels of genes pertinent to sarcomere development correlated with myotube maturation. Our findings are imperative for a better understanding of the influence of electrical pulses on the maturation of microengineered myotubes. PMID- 28622707 TI - Coordination between leaf CO2 diffusion and Rubisco properties allows maximizing photosynthetic efficiency in Limonium species. AB - High photosynthetic efficiency intrinsically demands tight coordination between traits related to CO2 diffusion capacity and leaf biochemistry. Although this coordination constitutes the basis of existing mathematical models of leaf photosynthesis, it has been barely explored among closely related species, which could reveal rapid adaptation clues in the recent past. With this aim, we characterized the photosynthetic capacity of 12 species of Limonium, possessing contrasting Rubisco catalytic properties, grown under optimal (WW) and extreme drought conditions (WD). The availability of CO2 at the site of carboxylation (Cc ) determined the photosynthetic capacity of Limonium under WD, while both diffusional and biochemical components governed the photosynthetic performance under WW. The variation in the in vivo caboxylation efficiency correlated with both the concentration of active Rubisco sites and the in vitro-based properties of Rubisco, such as the maximum carboxylase turnover rate (kcatc ) and the Michaelis-Menten constant for CO2 (Kc ). Notably, the results confirmed the hypothesis of coordination between the CO2 offer and demand functions of photosynthesis: those Limonium species with high total leaf conductance to CO2 have evolved towards increased velocity (i.e. higher kcatc ), at the penalty of lower affinity for CO2 (i.e. lower specificity factor, Sc/o ). PMID- 28622708 TI - Pharmacokinetic comparison of two phenolic acids after oral administration of Typhae pollen to normal rats and rats with acute cold blood stasis. AB - Typhae Pollen, dried pollen of Typha angustifolia L., Typha orientalis Presl or other plants of the same genus (Typhaeceae), has the effect of activating the circulation to cure blood stasis in traditional Chinese Medicine. The purpose of this study was to set up an ultra-high performance liquid chromatography method that could determine p-hydroxybenzoic acid and vanillic acid simultaneously in rat plasma, and to compare their pharmacokinetics in normal rats and rats with acute cold blood stasis, and further to investigate the influence of different dosages of oral administration. The pharmacokinetic parameters obtained showed that both of the phenolic acids had a higher bioavailability in rats with cold blood stasis than that in normal rats with a higher area under the concentration time curve and longer mean residence time, and the high dose oral administration group had a higher capacity in blood stasis rats than in normal rats. These results reminded us that changes in health condition could alter the absorption and elimination of both phenolic acids in vivo, and the pharmacokinetic study under pathological conditions provides important information for more rational drug use in clinical situations. PMID- 28622710 TI - Effect of Intravenous immunoglobulin on Th1 and Th2 lymphocytes and improvement of pregnancy outcome in recurrent pregnancy loss (RPL). AB - BACKGROUND: Women with elevated natural killer (NK) cell frequency and function during pregnancy, suffer from recurrent pregnancy loss (RPL). In the present study, the possible effect of intravenous immunoglobulin (IVIG) administration on Th1 and Th2 cell frequency, cytokine secretion, and expression of transcription factors is compared between RPL patients and control group. MATERIALS AND METHODS: Totally, 44 women with a history of RPL (32 women as treated group and 12 as control group) were enrolled in the study. The frequency of Th1 and Th2 lymphocytes, the expression of transcription factors related to these cells and the serum levels of associated cytokines were assessed by flowcytometry, real time PCR and ELISA, respectively. All, assessments were performed both before and after treatment with IVIG. RESULTS: A significant reduction in Th1 lymphocyte frequency, transcription factor expression and cytokine levels were observed in IVIG-treated group, while all the above parameters indicated a significant increase for Th2 lymphocytes. Th1/Th2 ratio decreased significantly (p value<0.0001) at the end of treatment and 28 out of 32 (87.5%) women in IVIG treated group had live birth in comparison with 5 out of 12 (41.6%) in untreated group. CONCLUSION: IVIG administration proves to be an efficient therapeutic strategy which is able to enhance the success rate of pregnancy through a shift in Th2 responses. Furthermore, IVIG presents efficacy for the treatment of reproduction failures especially in subjects with immune cell abnormalities and increased NK cell level and function. PMID- 28622709 TI - Spirulina platensis prevents hyperglycemia in rats by modulating gluconeogenesis and apoptosis via modification of oxidative stress and MAPK-pathways. AB - Spirulina platensis (SP) is a microalga with antioxidant, antidiabetic and anti inflammatory properties. The present study explored the ability and potential mechanism(s) by which SP induced glucose lowering impact in diabetic rat model. Forty rats were allocated into four groups: control; streptozotocin (STZ)-induced diabetes (STZ, 45mg/kg b.w., intraperitoneally); SP (500mg/kg b.w., orally twice weekly for 2 months) and STZ-induced diabetes+SP group. In the STZ-induced diabetic rats, SP significantly decreased (P>0.05) serum glucose, glycated hemoglobin (HbA1c), malondialdehyde (MDA) levels and significantly increased (P>0.05) serum insulin, the activity of antioxidant enzymes and normalized their mRNA gene expression. Furthermore, SP attenuates STZ-induced upregulation of the gluconeogenic enzyme pyruvate carboxylase (PC), the pro-apoptotic Bax and caspase 3 (CASP-3), tumor necrosis factor alpha (TNF-alpha) gene expression. The Western blot results revealed that, SP induced downregulation of mitogen activated protein kinase pathway (MAPK) protein expression in hepatic tissues of diabetic rats. Additionally, SP reestablished the typical histological structure of the liver and pancreas of diabetic rats. Acute toxicity study further shows that SP is relatively safe. This study demonstrates that SP is rich in antioxidant compounds and has powerful glucose lowering effect through the normalization of increased hepatic PC gene expression. Interestingly, SP induced recovery of damaged hepatocytes and pancreatic beta-cells via its anti-inflammatory, antioxidant and anti-apoptotic properties. The MAPK signaling cascade is a pivotal component of the proapoptotic signaling pathway induced by diabetes mellitus. MAPK activation may be dependent from ROS production, since SP which exhibited antioxidant activities did have a significant impact on MAPK activity. PMID- 28622711 TI - Curcumin accelerates the repair of sciatic nerve injury in rats through reducing Schwann cells apoptosis and promoting myelinization. AB - BACKGROUND: Schwann cells (SCs) play an indispensable role in the repair and regeneration of injured peripheral nerve. Curcumin can reduce SCs apoptosis, and promote the regeneration and functional recovery of injured peripheral nerves. However, the corresponding mechanisms are not clear. OBJECTIVE: The article was aimed to explore the effect and corresponding mechanisms of curcumin on the repair of sciatic nerve injury in rats. METHODS: After surgery induced sciatic nerve injury, the model rats were divided into three groups and treated with curcumin, curcumin+PD98059 and curcumin+IGF-1 respectively for 4days. The phosphorylation of Erk1/2 and Akt, and the expression of LC3-II, Beclin 1 and p62 were measured using western blotting. After treatment for 60days, myelination of the injured sciatic nerve was evaluated by MBP immunohistochemical staining and the expression of PMP22, Fibrin and S100 were determined using qRT-PCR and western blotting. In vitro, RSC96 cells were starved for 12h to induce autophagy, and received DMSO, curcumin, PD98059+curcumin, IGF-1+curcumin and BFA1 respectively. The phosphorylation of Erk1/2,Akt and the expression of LC3-II, Beclin 1, p62, PMP22, Fibrin and S100 were measured using western blotting, and the cell apoptosis was detected by flow cytometry. RESULTS: Curcumin could promote injury-induced cell autophagy, remyelination and axon regeneration in sciatic nerve of rats. In vitro, curcumin could accelerate cell autophagy through regulating autophagy related Erk1/2 and Akt pathway, prevent cell apoptosis and promote expression of PMP22 and S100, and reduced deposition of Fibrin in cultured RSC96 SCs. CONCLUSIONS: Curcumin could accelerate injured sciatic nerve repair in rats through reducing SCs apoptosis and promoting myelinization. PMID- 28622712 TI - Evaluation of the antibacterial and modulatory potential of alpha-bisabolol, beta cyclodextrin and alpha-bisabolol/beta-cyclodextrin complex. AB - The present study aimed to evaluate the antibacterial and modulatory potential of alpha-bisabolol, beta-cyclodextrin and alpha-bisabolol/beta-cyclodextrin complex. The minimum inhibitory concentration was determined through the broth microdilution technique using the bacterial strains: Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. The drugs norfloxacin, imipenem and gentamicin were used in the tests, and the compounds alpha-bisabolol and beta cyclodextrin; all the compounds were diluted in DMSO. To obtain the minimum inhibitory concentration (MIC) a serial microdilution of the substances in volumes corresponding to the sub-inhibitory concentration (MIC/8), and microdilution with the antibiotic until the penultimate well were performed. The results showed that beta-cyclodextrin did not present synergistic effects when combined with the antibiotics. It was found that alpha-bisabolol presented a synergistic effect against S. aureus, when combined with the antibiotic norfloxacin. Moreover, alpha-bisabolol presented synergism against E. coli when combined with gentamicin. The results of this study show that alpha-bisabolol presents a modulatory synergistic effect for some antibiotics, as gentamicin, and this is an interesting result against multidrug resistant bacteria (MDR). By other side, the complexation of alpha-bisabolol with beta-cyclodextrin apparently reduces the modulatory effect, maybe due the polarity enhancement of the polarity of alpha-bisabolol, affecting the interaction of this compound with the cell membrane bilayer. However, more studies are necessary to demonstrate or not these interactions. PMID- 28622713 TI - miR-142-5p promotes development of colorectal cancer through targeting SDHB and facilitating generation of aerobic glycolysis. AB - Aberrant expression of miRNAs contributes to the development of human malignancies. A recent study revealed that miR-142-5p is increased in the serum of colorectal cancer (CRC) patients compared to health people. Using starBase v2.0, we found that succinate dehydrogenase-B (SDHB) is a potential target of miR 142-5p, while SDHB is negatively correlated to cancer development through regulating energetic metabolism. Based on these information, this study further examined the expression profiles of miR-142-5p and SDHB in CRC tissues and cell lines using PCR and Western blotting. Transfection experiment and luciferase assay were performed to identify relationship between miR-142-5p and SDHB. Oxygen intake, glucose consumption and production of lactic acid were used to evaluate the influence on energetic metabolism. CRC growth and proliferation were assessed by in vitro and in vivo studies. Results showed that miR-142-5p was up-regulated in CRC, but SDHB was down-regulated. SDHB was confirmed as a target of miR-142 5p, and decreased SDHB in CRC was result from the abnormal up-regulation of miR 142-5p. Lose of SDHB by miR-142-5p inhibited oxygen intake by CRC cells, but increased glucose consumption and lactate production. These suggest miR-142-5p up regulation in CRC probably facilitates generation of aerobic glycolysis by reducing SDHB. miR-142-5p promoted proliferation and colony formation of CRC, but inhibited apoptosis. SDHB overexpression abrogated these effect of miR-142-5p, which indicates that SDHB depletion mediates tumor-promoting actions of miR-142 5p. This study added novel insight into the CRC development regulated by miR-142 5p. It may be a promising therapy target in the future molecular therapy. PMID- 28622714 TI - NiCo2S4@NiMoO4 Core-Shell Heterostructure Nanotube Arrays Grown on Ni Foam as a Binder-Free Electrode Displayed High Electrochemical Performance with High Capacity. AB - Core-shell-structured system has been proved as one of the best architecture for clean energy products owing to its inherited superiorities from both the core and the shell part, which can provide better conductivity and high surface area. Herein, a hierarchical core-shell NiCo2S4@NiMoO4 heterostructure nanotube array on Ni foam (NF) (NiCo2S4@NiMoO4/NF) has been successfully fabricated. Because of its novel heterostructure, the capacitive performance has been enhanced. A specific capacitance up to 2006 F g-1 was obtained at a current density of 5 mA cm-2, which was far higher than that of pristine NiCo2S4 nanotube arrays (about 1264 F g-1). More importantly, NiCo2S4@NiMoO4/NF and active carbon (AC) were congregated as positive electrode and negative electrode in an asymmetric supercapacitor. As-fabricated NiCo2S4@NiMoO4/NF//AC device has a good cyclic behavior with 78% capacitance retention over 2000 cycles, and exhibits a high energy density of 21.4 Wh kg-1 and power density of 58 W kg-1 at 2 mA cm-2. As displayed, the NiCo2S4@NiMoO4/NF core-shell herterostructure holds great promise for supercapacitors in energy storage. PMID- 28622715 TI - Nanotechniques Inactivate Cancer Stem Cells. AB - One of the tasks of current oncology is identification of cancer stem cells and search of therapeutic means capable of their specific inhibition. The paper presents the data on phenotype characteristics of Ehrlich carcinoma cells as convenient and easy-to-follow model of tumor growth. The evidence of cancer stem cells as a part of Ehrlich carcinoma and significance of CD44+ and CD44- subpopulations in maintaining the growth of this type of tumor were demonstrated. A high (tenfold) tumorigenic activity of the Ehrlich carcinoma CD44+ cells if compared to CD44- cells was proven. In this pair of comparison, the CD44+ cells had a higher potential of generating in peritoneal cavity of CD44high, CD44+CD24 , CD44+CD24+ cell subpopulations, highlighting the presence of cancer stem cells in a pool of CD44+ cells.In this study, the ability of synthesized hybrid nanocomplexes, comprising the nanoparticles of rare earth orthovanadates GdYVO4:Eu3+ and cholesterol to inhibit the tumor growth and to increase the survival of the animals with tumors was established. A special contribution into tumor-inhibiting effect is made by each of its components. Treatment of Ehrlich carcinoma cells with two-component hybrid complex resulted in maximum reduction in the concentration of the most tumorigenic CD44high cells with simultaneous rise in the number of CD117+ cells that decreased an intensity of tumor growth by 74.70 +/- 4.38% if compared with the control. PMID- 28622716 TI - A New Method Without Organic Solvent to Targeted Nanodrug for Enhanced Anticancer Efficacy. AB - Since the hydrophobic group is always essential to the synthesis of the drug loaded nanoparticles, a majority of the methods rely heavily on organic solvent, which may not be completely removed and might be a potential threat to the patients. In this study, we completely "green" synthesized 10 hydroxycamptothecine (HCPT) loaded, folate (FA)-modified nanoneedles (HFNDs) for highly efficient cancer therapy with high drug loading, targeting property, and imaging capability. It should be noted that no organic solvent was used in the preparation process. In vitro cell uptake study and the in vivo distribution study showed that the HFNDs, with FA on the surface, revealed an obviously targeting property and entered the HeLa cells easier than the chitosan-HCPT nanoneedles without FA modified (NDs). The cytotoxicity tests illustrated that the HFNDs possessed better killing ability to HeLa cells than the individual drug or the NDs in the same dose, indicating its good anticancer effect. The in vivo anticancer experiment further revealed the pronounced anticancer effects and the lower side effects of the HFNDs. This new method without organic solvent will lead to a promising sustained drug delivery system for cancer diagnosis and treatment. PMID- 28622717 TI - Synthesis and Electrochemical Properties of LiNi0.5Mn1.5O4 Cathode Materials with Cr3+ and F- Composite Doping for Lithium-Ion Batteries. AB - A Cr3+ and F- composite-doped LiNi0.5Mn1.5O4 cathode material was synthesized by the solid-state method, and the influence of the doping amount on the material's physical and electrochemical properties was investigated. The structure and morphology of the cathode material were characterized by XRD, SEM, TEM, and HRTEM, and the results revealed that the sample exhibited clear spinel features. No Cr3+ and F- impurity phases were found, and the spinel structure became more stable. The results of the charge/discharge tests, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) test results suggested that LiCr0.05Ni0.475Mn1.475O3.95F0.05 in which the Cr3+ and F- doping amounts were both 0.05, had the optimal electrochemical properties, with discharge rates of 0.1, 0.5, 2, 5, and 10 C and specific capacities of 134.18, 128.70, 123.62, 119.63, and 97.68 mAh g-1 , respectively. After 50 cycles at a rate of 2 C, LiCr0.05Ni0.475Mn1.475O3.95F0.05 showed extremely good cycling performance, with a discharge specific capacity of 121.02 mAh g-1 and a capacity retention rate of 97.9%. EIS test revealed that the doping clearly decreased the charge-transfer resistance. PMID- 28622718 TI - Surface Effect on Oil Transportation in Nanochannel: a Molecular Dynamics Study. AB - In this work, we investigate the dynamics mechanism of oil transportation in nanochannel using molecular dynamics simulations. It is demonstrated that the interaction between oil molecules and nanochannel has a great effect on the transportation properties of oil in nanochannel. Because of different interactions between oil molecules and channel, the center of mass (COM) displacement of oil in a 6-nm channel is over 30 times larger than that in a 2-nm channel, and the diffusion coefficient of oil molecules at the center of a 6-nm channel is almost two times more than that near the channel surface. Besides, it is found that polarity of oil molecules has the effect on impeding oil transportation, because the electrostatic interaction between polar oil molecules and channel is far larger than that between nonpolar oil molecules and channel. In addition, channel component is found to play an important role in oil transportation in nanochannel, for example, the COM displacement of oil in gold channel is very few due to great interaction between oil and gold substrate. It is also found that nano-sized roughness of channel surface greatly influences the speed and flow pattern of oil. Our findings would contribute to revealing the mechanism of oil transportation in nanochannels and therefore are very important for design of oil extraction in nanochannels. PMID- 28622719 TI - Toward TiO2 Nanofluids-Part 1: Preparation and Properties. AB - As a new generation of working fluid, nanofluid has long been regarded as a hot research topic in the past three decades. Many review papers have provided comprehensive and systematic summaries on the development and state-of-the-art of nanofluids. As of today, it is becoming increasingly difficult to provide a comprehensive review of all kinds of nanofluids owing to the huge amounts of the related literatures. And many controversies and inconsistencies in the reported arguments have been observed in various nanofluids. Meanwhile, the systematic or comprehensive reviews on a certain kind of nanofluid are insufficient. Therefore, this review focuses on the research about one of the hottest kinds viz. TiO2 nanofluid, which has captured scientists' great attention because of its interesting and comprehensive properties such as sensational dispersivity, chemical stability, and non-toxicity. Due to the preparation of nanofluids is the prerequisite and physical properties are critical factors for further applications, this first part of the review summarizes recent research on preparation, stability, and physical properties of TiO2 nanofluids. PMID- 28622720 TI - A RRAM Integrated 4T SRAM with Self-Inhibit Resistive Switching Load by Pure CMOS Logic Process. AB - This paper reports a novel full logic compatible 4T2R non-volatile static random access memory (nv-SRAM) featuring its self-inhibit data storing mechanism for in low-power/high-speed SRAM application. With compact cell area and full logic compatibility, this new nv-SRAM incorporates two STI-ReRAMs embedded inside the 4T SRAM. Data can be read/write through a cross-couple volatile structure for maintaining fast accessing speed. Data can be non-volatilely stored in new SRAM cell through a unique self-inhibit operation onto the resistive random access memory (RRAM) load, achieving zero static power during data hold. PMID- 28622721 TI - Control of Structural and Electrical Transitions of VO2 Thin Films. AB - Unstrained and defect-free VO2 single crystals undergo structural (from high temperature tetragonal to low-temperature monoclinic phase) and electronic phase transitions simultaneously. In thin films, however, in the presence of unrelaxed strains and defects, structural (Peierls) and electronic (Mott) transitions are affected differently, and are separated. In this paper, we have studied the temperature dependence of structural and electrical transitions in epitaxially grown vanadium dioxide films on (0001) sapphire substrates. These results are discussed using a combined kinetics and thermodynamics approach, where the velocity of phase transformation is controlled largely by kinetics, and the formation of intermediate phases is governed by thermodynamic considerations. We have grown (020) VO2 on (0001) sapphire with two (001) and (100) in-plane orientations rotated by 122 degrees . The (100)-oriented crystallites are fully relaxed by the paradigm of domain-matching epitaxy, whereas (001) crystallites are not relaxed and exhibit the formation of a few atomic layers of thin interfacial V2O3. We have studied the structural (Peierls) transition by temperature-dependent in situ X-ray diffraction measurements, and electronic (Mott) transition by electrical resistance measurements. A delay of 3 degrees C is found between the onset of structural (76 degrees C) and electrical (73 degrees C) transitions in the heating cycle. This temporal lag in the transition is attributed to the residual strain existing in the VO2 crystallites. With this study, we suggest that the control of structural and electrical transitions is possible by varying the transition activation barrier for atomic jumps through the strain engineering. PMID- 28622722 TI - Carbon Nanofibers Functionalized with Active Screen Plasma-Deposited Metal Nanoparticles for Electrical Energy Storage Devices. AB - Supercapacitors are energy storage devices with higher energy densities than conventional capacitors but lower than batteries or fuel cells. There is a strong interest in increasing the volumetric and gravimetric capacitance of these devices to meet the growing demands of the electrical and electronic sectors. The capacitance depends largely on the electrode material, and carbon nanofibers (CNFs) have attracted much attention because of their relatively low cost, large surface area, and good electrical conductivity as well as chemical and thermal stability. The deposition of metal nanoparticles on CNFs is a promising way to increase their surface properties and, ultimately, the capacitance of the devices. In this study, nickel and silver nanoparticles were deposited on CNFs using the active screen plasma technology. The CNFs were characterized, and their electrochemical performance was assessed in a three-electrode cell. The results show significant improvements over the untreated CNFs, particularly after functionalization with silver nanoparticles. PMID- 28622723 TI - Catalytic 1,3-Difunctionalization via Oxidative C-C Bond Activation. AB - Electronegative substituents arrayed in 1,3-relationships along saturated carbon frameworks can exert strong influence over molecular conformation due to dipole minimization effects. Simple and general methods for incorporation of such functional group relationships could thus provide a valuable tool for modulating molecular shape. Here, we describe a general strategy for the 1,3-oxidation of cyclopropanes using aryl iodine(I-III) catalysis, with emphasis on 1,3 difluorination reactions. These reactions make use of practical, commercially available reagents and can engage a variety of substituted cyclopropane substrates. Analysis of crystal and solution structures of several of the products reveal the consistent effect of 1,3-difluorides in dictating molecular conformation. The generality of the 1,3-oxidation strategy is demonstrated through the catalytic oxidative ring-opening of cyclopropanes for the synthesis of 1,3-fluoroacetoxylated products, 1,3-diols, 1,3-amino alcohols, and 1,3 diamines. PMID- 28622724 TI - Porphyrin Arch-Tapes: Synthesis, Contorted Structures, and Full Conjugation. AB - Porphyrin tapes possessing meso-meso beta-beta beta-beta triple direct linkages have been targets of extensive studies because of their fully conjugated characteristic pi-electronic networks. In this paper, we report porphyrin arch tapes that bear additional carbonyl group(s) or methylene group(s) inserted between one of the beta-beta linkage(s) of the porphyrin tapes. The carbonyl inserted porphyrin arch-tapes were efficiently synthesized by double fusion reactions of beta-to-beta carbonyl-bridged porphyrin oligomers with DDQ and Sc(OTf)3, and were converted to the methylene-bridged porphyrin arch-tapes via Luche reduction with NaBH4 and CeCl3 followed by ionic hydrogenation with HBF4.OEt2 and BH3.NEt3. While the conventional porphyrin tapes display rigid and planar structures and low solubilities, these porphyrin arch-tapes show remarkably contorted structures, flexible conformations, and improved solubilities because of the presence of the incorporated seven-membered ring(s). Interestingly, the methylene-inserted arch-tapes exhibited conjugative electronic interactions that were comparable to those of porphyrin tapes probably owing to through-space interaction in the contorted conformations. The carbonyl-inserted arch-tapes displayed distinctly larger conjugative interactions owing to an active involvement of the carbonyl group(s) in the electronic conjugation. A similar trend was observed in the nonlinear optical properties, as evidenced by their two-photon absorption cross sections. Furthermore, as a benefit of the contorted structures, these porphyrin arch-tapes can catch C60 fullerene effectively. Naturally, the electron-rich methylene-bridged arch-tapes exhibited larger association constants than the electron-deficient carbonyl-bridged arch tapes. Among these arch-tapes, a methylene-bridged syn-Ni(II) porphyrin trimer recorded the largest association constant of (1.5 +/- 0.4) * 107 M-1 in toluene at 25 degrees C. PMID- 28622725 TI - Self-Supported Biocarbon-Fiber Electrode Decorated with Molybdenum Carbide Nanoparticles for Highly Active Hydrogen-Evolution Reaction. AB - Devising and facilely synthesizing an efficient noble metal-free electrocatalyst for the acceleration of the sluggish kinetics in the hydrogen-evolution reaction (HER) is still a big challenge for electrolytic water splitting. Herein, we present a simple one-step approach for constructing self-supported biocarbon fiber cloth decorated with molybdenum carbide nanoparticles (BCF/Mo2C) electrodes by a direct annealing treatment of the Mo oxyanions loaded cotton T-shirt. The Mo2C nanoparticles not only serve as the catalytic active sites toward the HER but also enhance the hydrophilicity and conductivity of resultant electrodes. As an integrated three-dimensional HER cathode catalyst, the BCF/Mo2C exhibits outstanding electrocatalytic performance with extremely low overpotentials of 88 and 115 mV to drive a current density of 20 mA cm-2 in alkaline and acidic media, respectively. In addition, it can continuously work for 50 h with little decrease in the cathodic current density in both alkaline and acidic solutions. Even better, self-supported tungsten carbide and vanadium carbide based electrodes also can be prepared by a similar synthesis process. This work will illuminate an entirely new avenue for the preparation of various self-supported three dimensional electrodes made of transition-metal carbides for various applications. PMID- 28622726 TI - Efficient Covalent Modification of Multiwalled Carbon Nanotubes with Diazotized Dyes in Water at Room Temperature. AB - Tetrafluoroborate salts of diazotized Azure A (AA-N2+), Neutral Red (NR-N2+) and Congo Red (CR-N2+) dyes were prepared and reacted with multiwalled carbon nanotubes (MWCNTs) at room temperature, in water without any reducing agent. The as-modified MWCNTs were examined by IRATR, Raman spectroscopy, XPS, TGA, TEM, and cyclic voltammetry. The diazonium band located at ~2350 cm-1 in the diazotized dye IR spectra vanished after attachment to the nanotubes whereas the Raman D/G peak ratio slightly increased after dye covalent attachment at a high initial diazonium/CNT mass ratio. XPS measurements show the loss of F 1s from the BF4- anion together with a clear change in the high-resolution C 1s region from the modified nanotubes. Thermogravimetric analyses proved substantial mass loadings of the organic grafts leveling off at 40.5, 34.3, and 50.7 wt % for AA, NR, and CR, respectively. High-resolution TEM pictures confirmed the presence of 1.5-7-nm thick continuous amorphous layers on the nanotubes assigned to the aryl layers from the dyes. Cyclic voltammetry studies in acetonitrile (ACN) confirmed the grafting of the dyes; the latter retain their electrochemical behavior in the grafted state. The experimental results correlate remarkably well with quantum chemical calculations that indicate high binding energies between the dyes and the CNTs accounting for true covalent bonding (140-185 kJ/mol with the CNT-aryl distance <1.6 nm), though attachment by pi stacking also contributes to obtaining stable hybrids. Finally, the pH-responsive character of the robust hybrids was demonstrated by a higher degree of protonation of Neutral Red-grafted CNTs at pH 2 compared to that of the neutral aqueous medium. This work demonstrates that diazotized dyes can be employed for the surface modification of MWCNTs in a very simple and efficient manner in water and at room temperature. The hybrids could be employed for many purposes such as optically pH-responsive materials, biosensors, and optothermal composite actuators to name a few. PMID- 28622727 TI - Tetralogy of Fallot, left ventricular clot, aortic dissection: rare association. AB - Cases of uncorrected adult tetralogy of Fallot are rare and mostly manifest secondary to complications. A 30-year-old man presented with progressive breathlessness and severe chest discomfort. Echocardiography revealed tetralogy of Fallot with a left ventricular apical clot and DeBakey type I dissection of the aorta. The patient underwent successful surgical correction. The combination of preoperative complications in the setting of uncorrected tetralogy of Fallot, such as a left ventricular clot and DeBakey type I dissection of the aorta, is very rare. PMID- 28622728 TI - FESSH abstracts. PMID- 28622730 TI - Response to 2017-0288 by Kahriman et al. PMID- 28622732 TI - Cost-effectiveness of Memory Assessment Services for the diagnosis and early support of patients with dementia in England. AB - Background Policy makers in England advocate referral of patients with suspected dementia to Memory Assessment Services (MAS), but it is unclear how any improvement in patients' health-related quality of life (HRQL) compares with the associated costs. Aims To evaluate the cost-effectiveness of MAS for the diagnosis and follow-up care of patients with suspected dementia. Method We analysed observational data from 1318 patients referred to 69 MAS, and their lay carers (n = 944), who completed resource use and HRQL questionnaires at baseline, three and six months. We reported mean differences in HRQL (disease-specific DEMQOL and generic EQ-5D-3L), quality-adjusted life years (QALYs) and costs between baseline and six months after referral to MAS. We also assessed the cost effectiveness of MAS across different patient subgroups and clinic characteristics. Results Referral to MAS was associated with gains in DEMQOL (mean gain: 3.48, 95% confidence interval: 2.84 to 4.12), EQ-5D-3L (0.023, 0.008 to 0.038) and QALYs (0.006, 0.002 to 0.01). Mean total cost over six months, assuming a societal perspective, was L1899 (L1277 to L2539). This yielded a negative incremental net monetary benefit of -L1724 (-L2388 to -L1085), assuming NICE's recommended willingness-to-pay threshold (L30,000 per QALY). These base case results were relatively robust to alternative assumptions about costs and HRQL. There was some evidence that patients aged 80 or older benefitted more from referral to MAS (p < 0.01 from adjusted mean differences in net benefits) compared to younger patients. MAS with over 75 new patients a month or cost per patient less than L2500 over six months were relatively more cost-effective (p < 0.01) than MAS with fewer new monthly patients or higher cost per patient. Conclusions Diagnosis, treatment and follow-up care provided by MAS to patients with suspected dementia appears to be effective, but not cost-effective, in the six months after diagnosis. Longer term evidence is required before drawing conclusions about the cost-effectiveness of MAS. PMID- 28622733 TI - Suicide Trends According to Age, Gender, and Marital Status in South Korea. AB - The purpose of this study is to examine suicide trends in South Korea, which has one of the highest suicide rates in the world. The results show that the male suicide rate outweighs that of females, the likelihood of committing suicide increases with age, and that, in regard to marital status, nonmarried people are the most at risk. In addition, several methods of reducing suicide rates are identified: the wider use of social networks to reduce social burden, the development of a social atmosphere where aging is accepted as a natural process, and the development of protection factors within families. PMID- 28622731 TI - Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective. AB - Tissue chips are poised to deliver a paradigm shift in drug discovery. By emulating human physiology, these chips have the potential to increase the predictive power of preclinical modeling, which in turn will move the pharmaceutical industry closer to its aspiration of clinically relevant and ultimately animal-free drug discovery. Despite the tremendous science and innovation invested in these tissue chips, significant challenges remain to be addressed to enable their routine adoption into the industrial laboratory. This article describes the main steps that need to be taken and highlights key considerations in order to transform tissue chip technology from the hands of the innovators into those of the industrial scientists. Written by scientists from 13 pharmaceutical companies and partners at the National Institutes of Health, this article uniquely captures a consensus view on the progression strategy to facilitate and accelerate the adoption of this valuable technology. It concludes that success will be delivered by a partnership approach as well as a deep understanding of the context within which these chips will actually be used. Impact statement The rapid pace of scientific innovation in the tissue chip (TC) field requires a cohesive partnership between innovators and end users. Near term uptake of these human-relevant platforms will fill gaps in current capabilities for assessing important properties of disposition, efficacy and safety liabilities. Similarly, these platforms could support mechanistic studies which aim to resolve challenges later in development (e.g. assessing the human relevance of a liability identified in animal studies). Building confidence that novel capabilities of TCs can address real world challenges while they themselves are being developed will accelerate their application in the discovery and development of innovative medicines. This article outlines a strategic roadmap to unite innovators and end users thus making implementation smooth and rapid. With the collective contributions from multiple international pharmaceutical companies and partners at National Institutes of Health, this article should serve as an invaluable resource to the multi-disciplinary field of TC development. PMID- 28622734 TI - Epidemiology of multidrug-resistant Acinetobacter baumannii strains in Iran: a systematic review and meta-analysis. AB - Acinetobacter baumannii is an important opportunistic pathogen that causes major public health concern especially in hospitalized patients due to the acquisition of multidrug resistance (MDR). The aim of this study was to systematically review published data about the prevalence rate of MDR-A. baumannii (MDR-AB) from different parts of Iran and provide an overall relative frequency (RF) using meta analysis. All available national and international databanks were searched to find published studies up to June 2016. Quality of studies was assessed by STROB and PRISMA forms. Because of the significant heterogeneity observed, random effects model was used to combine the results. STATA SE version 11.2 was used for statistical analysis. Out of the 9646 results, 37 suitable articles were extracted according to inclusion and exlusion criteria. The pooled prevalence of MDR-AB was estimated 72% annually. Relative frequency of MDR-AB in different studies varied from 22.8 to 100%. Since the prevalence of MDR-AB is higher than many other countries, measures should be taken to keep the emergence and transmission of these strains to a minimum. PMID- 28622735 TI - Rifampin-Resistant Staphylococcus aureus Bacteremia in a Patient on Chronic Rifaximin. PMID- 28622736 TI - Vaxchora: A Single-Dose Oral Cholera Vaccine. AB - OBJECTIVE: To review trials evaluating the efficacy and safety of Vaxchora, a reformulated, single-dose, oral, lyophilized Vibrio cholerae CVD 103-HgR vaccine for the prevention of travel-related cholera caused by V cholerae serogroup O1. DATA SOURCES: A literature search was conducted using MEDLINE (1946 to January week 3, 2017) and EMBASE (1996 to 2017 week 3). Keywords included oral cholera vaccine, single-dose, Vaxchora, and CVD 103-HgR. Limits included human, clinical trials published in English since 2010. ClinicalTrials.gov was used as a source for unpublished data. Additional data sources were obtained through bibliographic review of selected articles. STUDY SELECTION AND DATA EXTRACTION: Studies that addressed the safety and efficacy of Vaxchora, the reformulated, single-dose oral CVD 103-HgR cholera vaccine, were selected for analysis. DATA SYNTHESIS: Approval of Vaxchora, was based on efficacy of the vaccine in human trials demonstrating 90.3% protection among those challenged with V cholerae 10 days after vaccination and in immunogenicity studies with 90% systemic vibriocidal antibody conversion at 6 months after a single-dose of vaccine. Tolerability was acceptable, with the most common adverse effects reported to be fatigue, headache, and abdominal pain. CONCLUSION: Vaxchora is the only FDA-approved, single-dose oral vaccine for the prevention of cholera caused by V cholerae serogroup O1 in adult travelers from the United States going to cholera-affected areas. Safety and efficacy has not been established in children, immunocompromised persons, and pregnant or breastfeeding women or those living in cholera-endemic areas. PMID- 28622737 TI - A Mnemonic for Pharmacists to Ensure Optimal Monitoring and Safety of Total Parenteral Nutrition: I AM FULL. AB - OBJECTIVE: To present a guideline-derived mnemonic that provides a systematic monitoring process to increase pharmacists' confidence in total parenteral nutrition (TPN) monitoring and improve safety and efficacy of TPN use. DATA SOURCES: The American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines were reviewed. Additional resources included a literature search of PubMed (1980 to May 2016) using the search terms: total parenteral nutrition, mnemonic, indications, allergy, macronutrients, micronutrients, fluid, comorbidities, labs, peripheral line, and central line. Articles (English language only) were evaluated for content, and additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: All English-language observational studies, review articles, meta analyses, guidelines, and randomized trials assessing monitoring parameters of TPN were evaluated. DATA SYNTHESIS: The ASPEN guidelines were referenced to develop key components of the mnemonic. Review articles, observational trials, meta-analyses, and randomized trials were reviewed in cases where guidelines did not adequately address these components. CONCLUSIONS: A guideline-derived mnemonic was developed to systematically and safely manage TPN therapy. The mnemonic combines 7 essential components of TPN use and monitoring: Indications, Allergies, Macro/Micro nutrients, Fluid, Underlying comorbidities, Labs, and Line type. PMID- 28622738 TI - Assessment of the Risk of Hospitalization for Heart Failure With Dipeptidyl Peptidase-4 Inhibitors, Saxagliptin, Alogliptin, and Sitagliptin in Patients With Type 2 Diabetes, Using an Alternative Measure to the Hazard Ratio. AB - BACKGROUND: Saxagliptin statistically significantly increased the risk of hospitalization for heart failure compared with placebo in the clinical trial of SAVOR-TIMI 53. Neither the reason why only saxagliptin among several dipeptidyl peptidase-4 (DPP-4) inhibitors increased the risk, nor the clinical implication of the result has been explained. OBJECTIVE: To evaluate the risk of hospitalization for heart failure associated with DPP-4 inhibitors by using an alternative measure to the hazard ratio. METHODS: We used the difference in restricted mean survival time (RMST) between DPP-4 inhibitors and placebo to evaluate the risk of cardiovascular events, including hospitalization for heart failure associated with DPP-4 inhibitors. Three randomized clinical trials with cardiovascular events as a primary end point-EXAMINE (alogliptin), SAVOR-TIMI 53 (saxagliptin), and TECOS (sitagliptin)-were reevaluated by estimating the RMSTs for the DPP-4 inhibitors and placebo based on the reconstructed individual patient data for each time-to-event outcome from publicly available information. RESULTS: The differences of RMSTs (DPP-4 inhibitors minus placebo) for hospitalization for heart failure were -4 days [-6, -2] in the SAVOR-TIMI 53 (720 days follow-up), -3 days [-9, 3] in the EXAMINE (900 days follow-up), and 1 day [ 5, 7] in the TECOS (1440 days follow-up). There were no substantial differences in the risk of other cardiovascular outcomes between DPP-4 inhibitors and placebo. CONCLUSIONS: There are no substantial clinically relevant differences in the risk of cardiovascular events, including hospitalization for heart failure, between 3 of the DPP-4 inhibitors and placebo. PMID- 28622739 TI - Impact of A Collaborative Strategy to Reduce the Inappropriate Use of Acid Suppressive Therapy in Non-Intensive Care Unit Patients. AB - BACKGROUND: Stress ulcer prophylaxis (SUP) is inappropriately prescribed in more than 30% of non-intensive care unit (ICU) patients, leading to unnecessary adverse events as well as increases in economic burden. OBJECTIVE: There was an increasing trend in the prophylactic use of acid suppressive therapy (AST) in non critically ill patients at our institution, which prompted this initiative aimed at reducing the inappropriate use of AST in non-ICU patients. METHODS: This was a retrospective interventional study that consisted of formulation of a guideline, education to the hospitalist service, and intervention by clinical pharmacists. All adult non-ICU patients admitted to the hospitalist service who were newly initiated on AST were considered for inclusion. The primary outcome was a comparison of the proportion of inpatient days with inappropriate AST. Secondary outcomes included a comparison of patients discharged on inappropriate AST and drug acquisition costs, successful pharmacy interventions, hospitalist interventions, incidence of Clostridium difficile infection (CDI) or gastrointestinal (GI) bleeding, and drug costs averted through pharmacy intervention. RESULTS: There were 61 patients in the historical group and 81 patients in the interventional group. This intervention resulted in a 31% absolute reduction in inappropriate patient days of AST and a 24% absolute reduction in patients discharged on inappropriate AST. There were 23 successful interventions. There were no cases of CDI and 1 GI bleed. This intervention resulted in an 87% reduction in drug acquisition costs per patient. CONCLUSIONS: A collaboration between clinical pharmacists and a hospitalist service can significantly reduce the inappropriate use of AST in non-ICU patients. PMID- 28622740 TI - Impact of a Pharmacist-Managed Heart Failure Postdischarge (Bridge) Clinic for Veterans. AB - BACKGROUND: Hospitals that provide early postdischarge follow-up after heart failure (HF) hospitalization tend to have lower rates of readmission. However, HF postdischarge (bridge) clinics have not been extensively evaluated. OBJECTIVE: To assess the impact of a pharmacist-managed HF bridge clinic in a veteran population. METHODS: HF patients hospitalized from November 2010 to August 2013 were identified. Retrospective chart review was conducted of 122 HF patients seen at bridge clinic compared with 122 randomly selected HF patients not seen at this clinic (usual care). Primary end point was 90-day all-cause readmission and death. Secondary outcomes were 30-day all-cause readmission and death, time to first postdischarge follow-up, first all-cause readmission. RESULTS: Bridge clinic patients were at higher baseline risk of readmission and death; other characteristics were similar. 90-day death and all-cause readmission trended lower in bridge clinic patients (adjusted hazard ratio [HR] = 0.64; 95% CI = 0.40 1.02; P = 0.06). Time to first follow-up was shorter in bridge clinic patients (11 +/- 6 vs 20 +/- 23 days; P < 0.001); time to first all-cause readmission trended longer (40 +/- 20 vs 33 +/- 25days; P = 0.11). 30-day death and all-cause readmission was significantly lower in bridge clinic patients (adjusted HR = 0.44; 95% CI = 0.22-0.88; P = 0.02). CONCLUSIONS: In veteran patients hospitalized for HF, pharmacist-managed HF bridge clinic significantly reduced the time to initial follow-up compared with usual care. Improved short-term outcomes and trend toward improvement of longer-term outcomes in bridge clinic patients was shown. PMID- 28622741 TI - Characterization of Guideline Evidence for Off-label Medication Use in the Intensive Care Unit. AB - BACKGROUND: Non-Food and Drug Administration (FDA) or off-label medication prescribing occurs commonly in the intensive care unit (ICU). Off-label medication use creates a concern for untoward adverse effects; however, this worry may be alleviated by supportive literature. OBJECTIVE: To evaluate the evidence behind off-label medication use by determining the presence of guideline support and compare graded recommendations to an online tertiary resource, DRUGDEX. METHODS: Off-label medication use was identified prospectively over 3 months in medical ICUs in 3 academic medical centers. Literature searches were conducted in PubMed and the national guideline clearinghouse website to determine the presence of guideline support. DRUGDEX was also searched for strength-of evidence ratings to serve as a comparator. RESULTS: A total of 287 off-label medication indication searches resulted in 44% (126/287) without identified evidence; 253 guidelines were identified for 56% (161/287) of indications. Of the published guidelines, 89% (226/253) supported the off-label indication. In the DRUGDEX comparison, 67% (97/144) of guideline gradings disagree with DRUGDEX, whereas 33% (47/144) of the gradings matched the online database. CONCLUSION: Because more than half of off-label medication use has the benefit of supportive guidelines recommendations and a majority of gradings are inconsistent with DRUGDEX, clinicians should consider utilizing guidelines to inform off-label medication use in the ICU. Still, there is a considerable amount of off-label medication use in the ICU that lacks supporting evidence, and use remains concerning because it may lead to inappropriate treatment and adverse events. PMID- 28622742 TI - Intravenous Ferumoxytol in Pediatric Patients With Iron Deficiency Anemia. AB - BACKGROUND: Iron deficiency anemia (IDA) is common in children. Limited data exist on the efficacy and safety of ferumoxytol in children. OBJECTIVE: To assess the efficacy of 10 mg/kg dose given over 15-60 minutes in correcting IDA and report any adverse drug reactions (ADRs). METHODS: We conducted a retrospective review of all patients who received ferumoxytol infusions for the management of IDA by the Pediatric Blood Management Program between October 2010 and March 2015. RESULTS: A total of 110 infusions were given to 54 patients. Compared with baseline preinfusion hemoglobin (Hb; 9.2 +/- 1.9 g/dL), a significant rise was seen at 1 week and 4 weeks postinfusion (11.5 +/- 1.5 and 11.8 +/- 1.7 g/dL, respectively, P < 0.001). Also, a significant rise in serum ferritin at 1 week and 4 weeks postinfusion was seen (51 +/- 71 vs 192 +/- 148 and 89 +/- 135 ng/mL, P < 0.001 and <0.035, respectively). Patients who concomitantly received erythropoietin had a significantly larger Hb rise from baseline than those who did not at 4 weeks (2.7 +/- 2.2 vs 1.6 +/- 1.1 g/dL, P < 0.017). ADRs included pruritus (n = 1), urticaria (n = 1), and multisymptom episodes (n = 3) that included shortness of breath, chest tightness, back pain, and epigastric cramping that responded to therapy with IV diphenhydramine and methylprednisolone. CONCLUSION: Ferumoxytol was effective in treating IDA in our small study. Slow infusion rate and close monitoring allowed early detection of the infrequent ADRs. PMID- 28622743 TI - Endovascular treatment for chronic lower extremity ischaemia with sub-acute deterioration. AB - OBJECTIVES: The purpose of this study is to report the efficacy of endovascular treatment for patients with sub-acute (14-day to 2-month) deterioration of chronic lower extremity ischaemia. MATERIALS AND METHODS: Between June 2013 and May 2015, 26 consecutive patients (22 men, 4 women; mean age, 68.6 years; range, 50-86 years) were treated for sub-acute deterioration of chronic lower extremity ischaemia in our hospital. All patients were treated with catheter-directed thrombolysis initially and then adjunctive percutaneous transluminal angioplasty and/or stenting was performed to correct underlying lesions. RESULTS: The 26 intra-arterial thrombolysis procedures were all performed in native lower arteries including 8 iliac, 13 femoropopliteal and 5 diffuse occlusions involving the iliac and femoropopliteal segments. Lesion length decreased from 194 mm (70 350 mm) to 92 mm (20-270 mm) after the thrombolytic procedures, and the residual lesions were corrected with percutaneous transluminal angioplasty alone in 4 (15.4%) limbs and stenting in 22 (84.6%) patients. No cross-joint stenting was seen in the 22 affected limbs that used stents. Throughout the treatment process, nine patients with intermittent claudication achieved an unrestricted walking distance, and 17 patients with rest pain or foot ulcers showed significant symptom improvement. The mean ankle-brachial index increased from 0.42 +/- 0.16 preoperatively to 0.81 +/- 0.25 postoperatively ( p < 0.01). CONCLUSION: Endovascular therapy with catheter-directed thrombolysis and percutaneous transluminal angioplasty/stenting is feasible for sub-acute deterioration of chronic lower extremity ischaemia patients with favourable midterm results. PMID- 28622744 TI - Effects of sedentary occupations on type 2 diabetes and hypertension in different ethnic groups in North West China. AB - This study investigated the effects of sedentary occupations on type 2 diabetes and hypertension in different ethnic groups in North West China. All subjects were civil servants who received health examinations in the First Affiliated Hospital of Xinjiang Medical University from October 2010 to March 2014. A total of 46,612 participants (39,120 Han, 4148 Uygur, 2098 Hui, 877 Kazak and 369 other ethnicities) completed the examination. Overall, 16.4% of the Han, 14.4% of the Uygur, 15.9% of the Hui, 20.6% of the Kazak and 16.0% of other ethnicities had hypertension. Diabetes was found in 7.6% of the Han, 8.5% of the Uygur, 9.2% of the Hui, 7.4% of the Kazak, and 3.3% of other ethnicities. There was a significant difference between men and women in the prevalence of diabetes (4.3% in women vs 9.7% in men, p < 0.001) and hypertension (9.7% in women vs 21.0% in men, p < 0.001). Our results indicate that both diabetes and hypertension are highly prevalent in individuals with sedentary occupations. PMID- 28622745 TI - Sex differences in vascular stiffness and relationship to the risk of renal functional decline in patients with type 2 diabetes. AB - BACKGROUND: Recent data suggest that the higher risk of end-stage renal disease in women compared with men is associated with waist circumference. We investigated whether vascular stiffness which is linked to visceral fat accumulation is gender specific and associated with a loss in renal function. METHODS: We studied 166 patients with type 2 diabetes at high risk of progressive renal disease. A vascular stiffness index was derived from measurement of the peripheral arterial pulse waveform using infrared finger photoplethysmography. Multiple regression analysis was used to examine the relationship between vascular stiffness and traditional clinical and biochemical renal disease risk factors. RESULTS: Women were of similar mean (standard deviation) age [61.6 (6.8) vs 60.0 (8.3) years; p = 0.444] and duration of diabetes [9.8 (7.2) vs 10.9 (8.1) years; p = 0.885] compared to men. Waist circumference was significantly associated with vascular stiffness [regression coefficient B = 0.15 (95% confidence interval: 0.06-2.24); p = 0.001]. There was a negative slope parameter for the relationship between glomerular filtration rate and vascular stiffness [ B = -0.15 (95% confidence interval: -0.22 to -0.09); p < 0.001] in women only. CONCLUSION: In this cohort, early renal functional decline in women is linked to increased vascular stiffness which may be associated with visceral fat accumulation as determined by waist circumference. PMID- 28622746 TI - Sol-gel derived lithium-releasing glass for cartilage regeneration. AB - Wnt-signalling cascade is one of the crucial pathways involved in the development and homeostasis of cartilage. Influencing this pathway can potentially contribute to improved cartilage repair or regeneration. One key molecular regulator of the Wnt pathway is the glycogen synthase kinase-3 enzyme, the inhibition of which allows initiation of the signalling pathway. This study aims to utilise a binary SiO2-Li2O sol-gel derived glass for controlled delivery of lithium, a known glycogen synthase kinase-3 antagonist. The effect of the dissolution products of the glass on chondrogenic differentiation in an in vitro 3D pellet culture model is reported. Dissolution products that contained 5 mM lithium and 3.5 mM silicon were capable of inducing chondrogenic differentiation and hyaline cartilaginous matrix formation without the presence of growth factors such as TGF-beta3. The results suggest that sol-gel derived glass has the potential to be used as a delivery vehicle for therapeutic lithium ions in cartilage regeneration applications. PMID- 28622748 TI - DNA barcoding of five species of groupers (Pisces: Serranidae) off Visakhapatnam, central eastern coast of India. AB - Grouper species of Epinephelus - E. epistictus, E. heniochus, E. latifasciatus, E. magniscuttis and E. radiatus exhibit overlapping colour pattern that often leads to misidentification in the field. Even the colour pattern of juveniles of these species in different size groups varies considerably with that of adults. DNA barcoding of these five species was carried out to reinforce our knowledge on existing taxonomic relationships derived based on morphological and biochemical genetic studies that were previously done from Indian waters. Mean interspecific genetic distance is in the range 0.079-0.164.The phylogeny tree revealed distinct clades for species that are in concurrence with previous taxonomic and allozyme electrophoretic studies carried out from central eastern coast of India. Barcode sequences generated for the first time for species E. heniochus from Indian waters for E. magniscuttis so far there are no reference sequences in GenBank. PMID- 28622747 TI - Reducing Stigma in Media Professionals: Is there Room for Improvement? Results from a Systematic Review. AB - OBJECTIVE: The mass media may increase stigma against people with mental health problems by reinforcing common stereotypes. Media professionals thus represent a target group for antistigma interventions. This paper aims to review available literature on antistigma interventions for mass media professionals, seeking to clarify what kind of interventions have been found to be effective in reducing mental health stigma among mass media professionals. METHOD: Six electronic databases (MEDLINE, PsycINFO, Embase, Cochrane Reviews Library and Cochrane Central Register of Controlled Trials, Web of Science, and Applied Social Sciences Index & Abstracts) were systematically searched through March 2017 for studies addressing antistigma interventions on mass media professionals. Results: A total of 27 studies on antistigma interventions targeted to media professionals were found. Reviewed articles were classified into 3 categories: media-monitoring projects/reporting guidelines ( n = 23), interventions for educating journalists ( n = 2), and interventions for educating journalism students ( n = 2). Overall, antistigma interventions for media professionals seem to have some effect in improving reporting style, thus providing a more balanced portrayal of people with mental health problems: the most promising interventions are contact-based educational approaches and the provision of guidelines by authoritative institutions. CONCLUSION: It should be useful to promote and disseminate contact-based educational interventions targeted to journalists and to include specific modules on mental health topics in the training curricula of journalism students. However, as research in the field suffers from several limitations, high-quality studies exploring the long-term effect of antistigma interventions for media professionals are needed. PMID- 28622749 TI - General Exercise Does Not Improve Long-Term Pain and Disability in Individuals With Whiplash-Associated Disorders: A Systematic Review. AB - Study Design Systematic review of randomized controlled trials. Background General exercise, defined as purposeful physical activity involving repetitive exercises and incorporating multiple muscle groups, is frequently used in the management of whiplash-associated disorders (WADs). Evidence supporting its efficacy is not well established. Objectives To determine whether general exercise is effective in reducing pain and disability in people with WAD. Methods Studies published in English in peer-reviewed journals between January 1990 and May 2015 were eligible if they evaluated a general exercise intervention compared with a different intervention or control. Studies were required to evaluate pain and disability at medium-term (6-14 weeks) and long-term (52 weeks) follow-ups. The mean +/- SD and sample size were recorded for follow-up scores and for change scores from baseline to follow-up. Results Of the 3 high-quality studies that were eligible for inclusion, none investigated general exercise alone. There were no clinically meaningful differences between comprehensive exercise programs, which included general exercise, and minimal intervention controls in the medium and long term. No studies directly compared general exercise with a no-treatment control. All included studies used different control interventions, preventing meta-analysis. Conclusion A lack of significant long-term improvements from general exercise interventions in individuals with WAD was identified. This finding differs from the positive benefits of general exercise for other musculoskeletal conditions. This may, in part, relate to the complexity of whiplash conditions. This may also reflect the challenge of exercise prescription in this population, where the need for sufficient intensity is balanced against the impact that exercise has on pain. Level of Evidence Therapy, level 1a. J Orthop Sports Phys Ther 2017;47(7):472-480. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7081. PMID- 28622751 TI - Clinical Prediction Models for Patients With Nontraumatic Knee Pain in Primary Care: A Systematic Review and Internal Validation Study. AB - Study Design Systematic review and validation study. Background Many prognostic models of knee pain outcomes have been developed for use in primary care. Variability among published studies with regard to patient population, outcome measures, and relevant prognostic factors hampers the generalizability and implementation of these models. Objectives To summarize existing prognostic models in patients with knee pain in a primary care setting and to develop and internally validate new summary prognostic models. Methods After a sensitive search strategy, 2 reviewers independently selected prognostic models for patients with nontraumatic knee pain and assessed the methodological quality of the included studies. All predictors of the included studies were evaluated, summarized, and classified. The predictors assessed in multiple studies of sufficient quality are presented in this review. Using data from the Musculoskeletal System Study (BAS) cohort of patients with a new episode of knee pain, recruited consecutively by Dutch general medical practitioners (n = 372), we used predictors with a strong level of evidence to develop new prognostic models for each outcome measure and internally validated these models. Results Sixteen studies were eligible for inclusion. We considered 11 studies to be of sufficient quality. None of these studies validated their models. Five predictors with strong evidence were related to function and 6 to recovery, and were used to compose 2 prognostic models for patients with knee pain at 1 year. Running these new models in another data set showed explained variances (R2) of 0.36 (function) and 0.33 (recovery). The area under the curve of the recovery model was 0.79. After internal validation, the adjusted R2 values of the models were 0.30 (function) and 0.20 (recovery), and the area under the curve was 0.73. Conclusion We developed 2 valid prognostic models for function and recovery for patients with nontraumatic knee pain, based on predictors with strong evidence. A longer duration of complaints predicted poorer function but did not adequately predict chance of recovery. Level of Evidence Prognosis, levels 1a and 1b. J Orthop Sports Phys Ther 2017;47(8):518-529. Epub 16 Jun 2017. doi:10.2519/jospt.2017.7142. PMID- 28622750 TI - Preparation and in vivo evaluation of a silicate-based composite bone cement. AB - Silicate-based cements have been developed as a class of bioactive and biodegradable bone cements owing to their good in vitro bioactivity and ability to dissolve in a simulated body fluid. Until recently, however, the in vivo evidence of their ability to support bone regeneration is still scarce. In the present study, a pilot in vivo evaluation of a silicate-based composite bone cement (CSC) was carried out in a rabbit femur defect model. The cement was composed of tricalcium silicate, 45S5 bioglass and calcium sulfate, and the self setting properties of the material were established. The in vivo bone integration and biodegradability of CSC were investigated and compared with those of bioactive glass particulates, and a calcium phosphate cement. The results showed that CSC underwent a relatively slower in vivo degradation as compared with bioactive glass and calcium phosphate cement. Histological observation demonstrated that bone contact area at the interface between the surrounding bone and CSC gradually increased with time proceeding. CSC kept its structural integrity during implantation in vivo because of its acceptable mechanical strength. These results provide evidence of effectiveness in vivo and suggest potential clinical applications of the silicate-based composite bone cements. PMID- 28622752 TI - Microvascular fluid exchange during CPB with deep hypothermia circulatory arrest or low flow. AB - OBJECTIVE: Use of deep hypothermic low-flow (DHLF) cardiopulmonary bypass (CPB) has been associated with higher fluid loading than the use of deep hypothermia circulatory arrest (DHCA). We evaluated whether these perfusion strategies influenced fluid extravasation rates and edema generation differently per operatively. MATERIALS AND METHODS: Twelve anesthetized pigs, randomly allocated to DHLF (n = 6) or DHCA (n = 6), underwent 2.5 hours CPB with cooling to 20 degrees C for 30 minutes (min), followed by 30 min arrested circulation (DHCA) or 30 min low-flow circulation (DHLF) before 90 min rewarming to normothermia. Perfusion of tissues, fluid requirements, plasma volumes, colloid osmotic pressures and total tissue water contents were recorded and fluid extravasation rates calculated. During the experiments, cerebral microdialysis was performed in both groups. RESULTS: Microvascular fluid homeostasis was similar in both groups, with no between-group differences, reflected by similar fluid extravasation rates, plasma colloid osmotic pressures and total tissue water contents. Although extravasation rates increased dramatically from 0.10 (0.11) ml/kg/min (mean with standard deviation in parentheses) and 0.16 (0.02) ml/kg/min to 1.28 (0.58) ml/kg/min and 1.06 (0.41) ml/kg/min (DHCA and DHLF, respectively) after the initiation of CPB, fluid filtrations during both cardiac arrest and low flow were modest and close to baseline values. Cerebral microdialysis indicated anaerobic metabolism and ischemic brain injury in the DHCA group. CONCLUSION: No differences in microvascular fluid exchange could be demonstrated as a direct effect of DHCA compared with DHLF. Thirty minutes of DHCA was associated with anaerobic cerebral metabolism and possible brain injury. PMID- 28622753 TI - Re-randomization tests for unplanned changes in clinical trials. AB - Despite the best efforts of investigators, problems forcing design changes can occur in clinical trials. Changes are usually relatively minor, but sometimes not. The primary endpoint or analysis may need to be revised, for example. It is common to regard any conclusion from such a tarnished trial as hypothesis generating rather than definitive. This article reviews a very useful technique, re-randomization tests, for dealing with such anomalies. Re-randomization tests remain valid for testing a strong null hypothesis that treatment has no effect on the data that led to design changes. Another way of expressing this is that the data used to inform a design change must give no information about the treatment labels. This restriction has implications for limiting the amount of information examined by a committee deciding whether to make design alterations. While nothing can eliminate the pall cast by breaches of protocol, re-randomization tests following blinded and limited data examination go a long way toward amelioration. PMID- 28622754 TI - Prevalence of non-infectious comorbidities in the HIV-positive population in Belgium: a multicenter, retrospective study. AB - OBJECTIVES: In Belgium, eleven AIDS Reference Centers (ARCs) and seven AIDS Reference Laboratories diagnose and treat HIV-positive individuals and track patients under care. As AIDS-related deaths are avoided and the HIV-positive population ages, non-infectious comorbidities (NICMs), such as cardiovascular disease, renal disease and certain cancers, play a larger role in the quality and length of patients' lives. This study aims to characterize the HIV-positive population in Belgium in terms of the prevalence of key NICMs. METHODS: We performed a retrospective study of 5787 HIV-positive patients under follow-up at four ARCs across Belgium between 1st of June 2014 and 1st of July 2016. RESULTS: The mean age of patients under follow-up was 46.7 (SD = 11.6) years, and the mean nadir CD4 count was 268.8 cells/mm3 (SD = 189.5). The prevalence of diabetes mellitus, arterial hypertension and chronic kidney disease (CKD) were 5.9, 31 and 7.8%, respectively. Cardiovascular events, defined as the occurrence of myocardial infarction, stroke or an invasive coronary procedure, occurred in 2.9% of patients. The highest age-adjusted mortality rates were observed among patients 51-55 years of age. Mortality rates were also higher among patients with CKD and patients with viremic hepatitis C virus (p < 0.05). CONCLUSIONS: Helping the aging HIV-positive population avoids premature morbidity and mortality from NICMs represents a key challenge to further improve patient outcomes. Belgium has an advanced system of HIV care and patient management; however, standardized data collection across ARCs is needed to improve knowledge sharing and to support future countrywide analyses. PMID- 28622755 TI - Cross-Sensory Correspondences: Heaviness is Dark and Low-Pitched. AB - Everyday language reveals how stimuli encoded in one sensory feature domain can possess qualities normally associated with a different domain (e.g., higher pitch sounds are bright, light in weight, sharp, and thin). Such cross-sensory associations appear to reflect crosstalk among aligned (corresponding) feature dimensions, including brightness, heaviness, and sharpness. Evidence for heaviness being one such dimension is very limited, with heaviness appearing primarily as a verbal associate of other feature contrasts (e.g., darker objects and lower pitch sounds are heavier than their opposites). Given the presumed bidirectionality of the crosstalk between corresponding dimensions, heaviness should itself induce the cross-sensory associations observed elsewhere, including with brightness and pitch. Taking care to dissociate effects arising from the size and mass of an object, this is confirmed. When hidden objects varying independently in size and mass are lifted, objects that feel heavier are judged to be darker and to make lower pitch sounds than objects feeling less heavy. These judgements track the changes in perceived heaviness induced by the size weight illusion. The potential involvement of language, natural scene statistics, and Bayesian processes in correspondences, and the effects they induce, is considered. PMID- 28622756 TI - Effects of Implied Motion and Facing Direction on Positional Preferences in Single-Object Pictures. AB - Palmer, Gardner, and Wickens studied aesthetic preferences for pictures of single objects and found a strong inward bias: Right-facing objects were preferred left of-center and left-facing objects right-of-center. They found no effect of object motion (people and cars showed the same inward bias as chairs and teapots), but the objects were not depicted as moving. Here we measured analogous inward biases with objects depicted as moving with an implied direction and speed by having participants drag-and-drop target objects into the most aesthetically pleasing position. In Experiment 1, human figures were shown diving or falling while moving forward or backward. Aesthetic biases were evident for both inward-facing and inward-moving figures, but the motion-based bias dominated so strongly that backward divers or fallers were preferred moving inward but facing outward. Experiment 2 investigated implied speed effects using images of humans, horses, and cars moving at different speeds (e.g., standing, walking, trotting, and galloping horses). Inward motion or facing biases were again present, and differences in their magnitude due to speed were evident. Unexpectedly, faster moving objects were generally preferred closer to frame center than slower moving objects. These results are discussed in terms of the combined effects of prospective, future-oriented biases, and retrospective, past-oriented biases. PMID- 28622757 TI - Stationary Objects Flashed Periodically Appear to Move During Smooth Pursuit Eye Movement. AB - We discovered that a white disc flashed twice at the same location appears to move during smooth pursuit eye tracking in the direction opposite to that of the eye movement. We called this novel phenomenon movement-induced apparent motion (MIAM). Using the method of constant stimuli, we measured the required displacement of the second appearance of the disc in the pursuit direction to null the effect during the closed-loop stage of smooth pursuit eye tracking. We observed a strong linear relationship between the points of subjective stationarity and the inter-stimuli intervals for four smooth pursuit eye movement speeds. The slopes and y-intercepts of these linear fits were well predicted by the hypothesis according to which subjects saw illusory motion from the first to the second retinal projections of the flashed disc during smooth pursuit eye movement, with no extra-retinal signal compensation. PMID- 28622758 TI - On the Ecological Validity of Computer Displays. PMID- 28622759 TI - Catching Audiovisual Interactions With a First-Person Fisherman Video Game. AB - The human brain is excellent at integrating information from different sources across multiple sensory modalities. To examine one particularly important form of multisensory interaction, we manipulated the temporal correlation between visual and auditory stimuli in a first-person fisherman video game. Subjects saw rapidly swimming fish whose size oscillated, either at 6 or 8 Hz. Subjects categorized each fish according to its rate of size oscillation, while trying to ignore a concurrent broadband sound seemingly emitted by the fish. In three experiments, categorization was faster and more accurate when the rate at which a fish oscillated in size matched the rate at which the accompanying, task-irrelevant sound was amplitude modulated. Control conditions showed that the difference between responses to matched and mismatched audiovisual signals reflected a performance gain in the matched condition, rather than a cost from the mismatched condition. The performance advantage with matched audiovisual signals was remarkably robust over changes in task demands between experiments. Performance with matched or unmatched audiovisual signals improved over successive trials at about the same rate, emblematic of perceptual learning in which visual oscillation rate becomes more discriminable with experience. Finally, analysis at the level of individual subjects' performance pointed to differences in the rates at which subjects can extract information from audiovisual stimuli. PMID- 28622761 TI - Dated tribe-wide whole chloroplast genome phylogeny indicates recurrent hybridizations within Triticeae. AB - BACKGROUND: Triticeae, the tribe of wheat grasses, harbours the cereals barley, rye and wheat and their wild relatives. Although economically important, relationships within the tribe are still not understood. We analysed the phylogeny of chloroplast lineages among nearly all monogenomic Triticeae taxa and polyploid wheat species aiming at a deeper understanding of the tribe's evolution. We used on- and off-target reads of a target-enrichment experiment followed by Illumina sequencing. RESULTS: The read data was used to assemble the plastid locus ndhF for 194 individuals and the whole chloroplast genome for 183 individuals, representing 53 Triticeae species and 15 genera. We conducted Bayesian and multispecies coalescent analyses to infer relationships and estimate divergence times of the taxa. We present the most comprehensive dated Triticeae chloroplast phylogeny and review previous hypotheses in the framework of our results. Monophyly of Triticeae chloroplasts could not be confirmed, as either Bromus or Psathyrostachys captured a chloroplast from a lineage closely related to a Bromus-Triticeae ancestor. The most recent common ancestor of Triticeae occurred approximately between ten and 19 million years ago. CONCLUSIONS: The comparison of the chloroplast phylogeny with available nuclear data in several cases revealed incongruences indicating past hybridizations. Recent events of chloroplast capture were detected as individuals grouped apart from con-specific accessions in otherwise monopyhletic groups. PMID- 28622762 TI - The dose-response relationship between tobacco smoking and the risk of lymphomas: a case-control study. AB - BACKGROUND: Previous studies have provided limited support to the association between tobacco smoking and lymphomas with weak evidence of a dose-response relationship. METHODS: We investigated the relationship between tobacco smoking and risk of non-Hodgkin lymphomas (NHL) and Hodgkin lymphomas (HL) through logistic regression spline models. Data were derived from an Italian hospital based case-control study (1999-2014), which enrolled 571 NHLs, 188 HLs, and 1004 cancer-free controls. Smoking habits and other lifestyle factors were assessed through a validated questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression, adjusting for potential confounders. RESULTS: Compared to never smokers, people smoking >=15 cigarettes/day showed increased risks of both NHL (OR = 1.42, 95% CI: 1.02, 1.97) and HL (OR = 2.47, 95% CI: 1.25, 4.87); the risk was particularly elevated for follicular NHL (OR = 2.43; 95% CI:1.31-4.51) and mixed cellularity HL (OR = 5.60, 95% CI: 1.31, 23.97). No excess risk emerged for former smokers or people smoking <15 cigarettes/day. Spline analyses showed a positive dose-response relationship with significant increases in NHL and HL risks starting from 15 and 21 cigarettes/day, respectively, with the most evident effects for follicular NHL and mixed cellularity HL. Smoking duration was significantly associated with the HL risk only (OR = 2.15, 95% CI: 1.16, 3.99). CONCLUSIONS: These findings support a role of tobacco smoking in the etiology of both NHL and HL, providing evidence of a direct association of risk with smoking intensity. PMID- 28622763 TI - Treatment decisions and mortality in HIV-positive presumptive smear-negative TB in the XpertTM MTB/RIF era: a cohort study. AB - BACKGROUND: The XpertTM MTB/RIF (XP) has a higher sensitivity than sputum smear microscopy (70% versus 35%) for TB diagnosis and has been endorsed by the WHO for TB high burden countries to increase case finding among HIV co-infected presumptive TB patients. Its impact on the diagnosis of smear-negative TB in a routine care setting is unclear. We determined the change in diagnosis, treatment and mortality of smear-negative presumptive TB with routine use of Xpert MTB/RIF (XP). METHODS: Prospective cohort study of HIV-positive smear-negative presumptive TB patients during a 12-month period after XP implementation in a well-staffed and trained integrated TB/HIV clinic in Kampala, Uganda. Prior to testing clinicians were asked to decide whether they would treat empirically prior to Xpert result; actual treatment was decided upon receipt of the XP result. We compared empirical and XP-informed treatment decisions and all-cause mortality in the first year. RESULTS: Of 411 smear-negative presumptive TB patients, 175 (43%) received an XP; their baseline characteristics did not differ. XP positivity was similar in patients with a pre-XP empirical diagnosis and those without (9/29 [17%] versus 14/142 [10%], P = 0.23). Despite XP testing high levels of empirical treatment prevailed (18%), although XP results did change who ultimately was treated for TB. When adjusted for CD4 count, empirical treatment was not associated with higher mortality compared to no or microbiologically confirmed treatment. CONCLUSIONS: XP usage was lower than expected. The lower sensitivity of XP in smear-negative HIV-positive patients led experienced clinicians to use XP as a "rule-in" rather than "rule-out" test, with the majority of patients still treated empirically. PMID- 28622764 TI - "In the mood for ageing": determinants of subjective well-being in older men and women of the population-based KORA-Age study. AB - BACKGROUND: To investigate risk factors associated with low subjective well-being (SWB) in men and women (>=65 years) separately with a special focus on emotional distress. METHODS: A cross-sectional analysis was conducted among 3602 participants (50.6% women) aged 65-90 years (mean age 72.8 years, SD +/- 5.8) from the population-based KORA-Age study conducted in 2008/2009. SWB was assessed using the WHO-5 well-being index (score range: 0 to 100). SWB was dichotomized into "low" (score <= 50) and "high" (score > 50) SWB. The association between potential risk factors and SWB was assessed by logistic regressions analyses. Population-attributable risks (PARs) were calculated. RESULTS: Low SWB was significantly higher in women than in men (23.8% versus 18.2%; p < 0.0001). The logistic regressions analyses revealed low income, physical inactivity, multimorbidity, depression, anxiety and sleeping problems to be associated with low SWB in both sexes. Living alone increased the odds of having low SWB in women, but not in men. Depression and anxiety were the strongest risk factors of low SWB among men (depression: OR: 4.19, 95% CI: 1.33-13.17, p < 0.05; anxiety: 8.45, 5.14-13.87, p < 0.0001) and women (depression: 6.83, 2.49-18.75 p < 0.05; anxiety: 7.31, 5.14-10.39, p < 0.0001). In both sexes, anxiety had the highest population-attributable risk (men: 27%, women: 41%). CONCLUSION: Our results call out for an increased focus on mental health interventions among older adults, especially for women living alone. Further research is needed to understand the paradoxical pattern of discrepant subjective well-being versus objective health in age. PMID- 28622765 TI - Unusual primary breast cancer - malignant peripheral nerve sheath tumor: a case report and review of the literature. AB - BACKGROUND: Sarcomas are a rare type of breast malignancies and malignant peripheral nerve sheath tumors of the breast are even rarer. There are no specific clinical and radiological features for the diagnosis of this tumor and histological features are also reported to be nonspecific. Therefore, immunohistochemistry is required for its diagnosis. A definitive treatment protocol is unavailable because of its rarity. CASE PRESENTATION: We report a case of a sporadic form of breast malignant peripheral nerve sheath tumor found in a 16-year-old Asian Bangladeshi girl. She experienced local recurrence and she had multiple left breast lumps four times in a very short period after repeated surgeries. However, she was later managed successfully with chemotherapy and locoregional radiotherapy. A chemotherapy protocol with ifosfamide, vincristine, and actinomycin was used and radiotherapy was given with a total dose of 50 Gy given in 25 fractions of 2 Gy by a 6 MV photon linear accelerator followed by 10 Gy boost given in 5 fractions of 2 Gy by 9 MeV electron energy. With more than 3 years of periodic follow-up, she is still well without any locoregional and metastatic recurrence. CONCLUSIONS: This report suggests proper immunohistochemical analysis whenever a breast sarcoma is found in order to find a rare histological variety. We believe that malignant peripheral nerve sheath tumor of the breast can be managed by total mastectomy followed by adjuvant chemotherapy and radiotherapy. Long-term meticulous follow-up is required to develop an optimum therapeutic strategy. PMID- 28622766 TI - Translational contributions to tissue specificity in rhythmic and constitutive gene expression. AB - BACKGROUND: The daily gene expression oscillations that underlie mammalian circadian rhythms show striking differences between tissues and involve post transcriptional regulation. Both aspects remain poorly understood. We have used ribosome profiling to explore the contribution of translation efficiency to temporal gene expression in kidney and contrasted our findings with liver data available from the same mice. RESULTS: Rhythmic translation of constantly abundant messenger RNAs (mRNAs) affects largely non-overlapping transcript sets with distinct phase clustering in the two organs. Moreover, tissue differences in translation efficiency modulate the timing and amount of protein biosynthesis from rhythmic mRNAs, consistent with organ specificity in clock output gene repertoires and rhythmicity parameters. Our comprehensive datasets provided insights into translational control beyond temporal regulation. Between tissues, many transcripts show differences in translation efficiency, which are, however, of markedly smaller scale than mRNA abundance differences. Tissue-specific changes in translation efficiency are associated with specific transcript features and, intriguingly, globally counteracted and compensated transcript abundance variations, leading to higher similarity at the level of protein biosynthesis between both tissues. CONCLUSIONS: We show that tissue specificity in rhythmic gene expression extends to the translatome and contributes to define the identities, the phases and the expression levels of rhythmic protein biosynthesis. Moreover, translational compensation of transcript abundance divergence leads to overall higher similarity at the level of protein production across organs. The unique resources provided through our study will serve to address fundamental questions of post-transcriptional control and differential gene expression in vivo. PMID- 28622768 TI - Erratum to: Social relationships, mental health and wellbeing in physical disability: a systematic review. PMID- 28622769 TI - Erratum to: Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients. PMID- 28622767 TI - Praziquantel decreases fecundity in Schistosoma mansoni adult worms that survive treatment: evidence from a laboratory life-history trade-offs selection study. AB - BACKGROUND: Mass drug administration of praziquantel is the World Health Organization's endorsed control strategy for schistosomiasis. A decade of annual treatments across sub-Saharan Africa has resulted in significant reductions of infection prevalence and intensity levels, although 'hotspots' remain. Repeated drug treatments place strong selective pressures on parasites, which may affect life-history traits that impact transmission dynamics. Understanding drug treatment responses and the evolution of such traits can help inform on how to minimise the risk of drug resistance developing, maximise sustainable control programme success, and improve diagnostic protocols. METHODS: We performed a four generation Schistosoma mansoni praziquantel selection experiment in mice and snails. We used three S. mansoni lines: a praziquantel-resistant isolate (R), a praziquantel-susceptible isolate (S), and a co-infected line (RS), under three treatment regimens: untreated, 25 mg/kg praziquantel, or 50 mg/kg praziquantel. Life-history traits, including parasite adult-worm establishment, survival, reproduction (fecundity), and associated morbidity, were recorded in mice across all four generations. Predictor variables were tested in a series of generalized linear mixed effects models to determine which factors had a significant influence on parasite life-history traits in definitive hosts under different selection regimes. RESULTS: Praziquantel pressure significantly reduced adult worm burdens across all generations and isolates, including within R-lines. However, previous drug treatment resulted in an increase in adult-worm establishment with increasing generation from P1 to F3. The highest worm numbers were in the co-infected RS line. Praziquantel treatment decreased adult-worm burden, but had a larger negative impact on the mean daily number of miracidia, a proxy for fecundity, across all three parasite isolates. CONCLUSIONS: Our predicted cost of resistance was not supported by the traits we measured within the murine host. We did not find evidence for negative adult worm density dependent effects on fecundity. In contrast, of the adult worms that survived treatment, even low doses of praziquantel significantly reduced adult-worm fecundity. Such reductions in worm fecundity post treatment suggest that egg - based measures of drug efficacy, such as Kato-Katz, may overestimate the short term effect of praziquantel on adult - worm burdens. These findings have important implications for S. mansoni transmission control, diagnostic protocols, and the potential for undetected selection toward drug resistance. PMID- 28622772 TI - Lorenz Poellinger. PMID- 28622770 TI - Intensity-modulated radiation therapy from 70Gy to 80Gy in prostate cancer: six- year outcomes and predictors of late toxicity. AB - OBJECTIVE: To report grade >=2 overall late rectal and urinary toxicities in patients (pts) with prostate cancer treated by intensity-modulated radiotherapy (IMRT) at 3 dose-levels. Identify predictors of radiation toxicity and report biochemical progression free survival (bPFS). METHODS: A total of 277 pts were treated with 70Gy (10.8%), 74Gy (63.9%) and 80 Gy (25.3%) using IMRT without pelvic irradiation were analyzed. Short or long-course androgen deprivation therapy (ADT) was allowed in 46.1% of pts. The toxicity was described using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 scale. Cox regression models addressed demographics, disease and dosimetry characteristics as potential predictors of late grade >=2 toxicity after adjusting for other modifying factors. RESULTS: The median follow-up was 77 months (range 15; 150). There was no grade >=4 toxicity. The 5-year cumulative rate of grade >=2 late rectal and urinary toxicities was 6.3% (95% CI = 3.8%; 10.3%) and 25.3% (95% CI = 19.8%; 31.8%) respectively. In multivariate analysis, only the dose (80Gy vs 74 and 70Gy) was found to increase the risk of rectal toxicity (HR = 2.96 [1.07; 8.20]). For pts receiving 74 Gy, International Prostate Symptom Score (IPSS) at baseline >=8 (HR = 2.40 [1.08; 5.35]) and dose >=73Gy delivered in more than 2% of bladder (D2%) were found to be predictors of bladder toxicity (HR = 3.29 [1.36; 7.98]). The 5-year biochemical relapse free survival was 81.0% [74.5%; 86.0%] in the entire population, 97.5% [83.5%; 99.6%] in the low risk group, 84.9% [76.7%; 90.3%] in the intermediate risk group and 66.4% [51.8%; 77.4%] in the high-risk group. D'Amico low (HR = 0.09 [0.01; 0.69]) and intermediate risk groups (HR = 0.50 [0.28; 0.88]) as well as PSA nadir >=0.2 ng/ml (HR = 1.79 [1.01; 3.21]) were predictive of biochemical relapse. CONCLUSIONS: The rate of late rectal toxicity increased with higher doses, while Dmax >=74Gy, D2% >= 73Gy for bladder wall and baseline IPSS >=8 increased late urinary toxicity. PMID- 28622773 TI - A new editorial project for Morphologie. PMID- 28622774 TI - Exam time. PMID- 28622775 TI - [Iron deficiency in childhood: recommendations of the French Pediatric Society]. PMID- 28622776 TI - [Iron and susceptibility to infections]. AB - Iron is essential for proper functioning of the host immune system as well as an essential nutrient for growth of various pathogens. Iron deficiency increases infection susceptibility, specially those due to intracellular pathogens. At the opposite, excess iron stores could increase the virulence of some pathogens. Hepcidin synthesis is increased during the acute inflammation phase; leading to decreased iron intestinal absorption and retention of the metal within macrophages. This is considered to result from a defense mechanism of the child to limit the availability of iron for extracellular pathogens. On the other hand, iron affect innate immune responses by influencing IFN-gamma or NF-kB pathways in macrophages. Consequently, iron enhances host resistance to intracellular pathogens but excess iron may alter immune system. PMID- 28622777 TI - [Iron and Neurodevelopment]. AB - In the central nervous system, iron is a cofactor of many metabolic processes and synthesis of aminergic neurotransmitters. Iron plays an major function on brain development from the prenatal period to teenage years. The blood-brain barrier modulates concentration of iron in the brain. In case of iron deficiency in the child, the negative impact on the myelinogenesis and synaptogenesis are well proven, with negative effects on psychomotor and cognitive functions. Iron supplementation has a beneficial effect, even if there is no anemia. The consequences of iron deficiency are more harmful as deficiency is early. The main mechanisms involved about iron and brain are reviewed. PMID- 28622778 TI - [Causes of iron deficiency in children]. AB - Iron deficiency and iron deficiency anemia are common conditions worldwide affecting especially children. In developing countries, iron deficiency is caused by poor iron intake and parasitic infection. Poor iron intake linked to inadequate diets, low iron intestinal absorption, chronic blood losses and increased requirements are common causes in high-income countries. PMID- 28622779 TI - [Iron in nutrition]. AB - Iron deficiency is the main nutritional disease worldwide. The multidisciplinary working group of the French Pediatric Society on iron assessed the following recommendations. Since iron is variably absorbed depending on foods, the group defined absorbed iron requirements instead of dietary iron requirements. Iron rich foods should be introduced at 4-months of age in some breast-fed infants. Between 7 and 11 month-old, formula-fed infants should drink at least 700ml per day of follow-on formula and partially or totally breast-fed infants should receive oral iron supplementation. Between 1 and 6 year-old, children should drink at least 300ml per day of growing-up milk until they become able to consume 100 to 150 grams per day of meat products. From 7 year-old, consumption of 2 portions per day of meat products is necessary in order to achieve daily iron requirements. Oral iron therapy from either increased iron-rich foods consumption or iron salts preparations is indicated when absorbed iron requirements are not achieved or when ferritin concentration is lower than age-specific limit values. PMID- 28622780 TI - [Iron metabolism]. AB - Iron is an essential trace element ensuring many functions in the body. However, excess iron can be toxic with deleterious consequences on function and tissue integrity. The understanding of the molecular and cellular mechanisms allowing iron level to be kept at physiological concentration has greatly progressed in recent years, in particular with the identification of the iron-regulatory hormone, hepcidin and its receptor ferroportin, the sole iron exporter known to date. This discovery has improved our ability to diagnose and manage iron disorders and offered new therapeutic perspectives for an important class of human diseases. However many questions remain to be answered. With the development of high-throughput techniques and the "omics" strategies (transcriptomic, proteomic, metabolomic, etc.), we should be able in the coming years to identify new iron regulatory pathways and to assign original roles for iron in normal cellular processes but also in diseases. A more complete iron regulatory network should be established with the identification of the crosstalk between intracellular and systemic iron homeostasis. PMID- 28622781 TI - [Iron requirements during the first 6 months of life]. AB - Because of the postnatal redistribution of the iron store, the term infant born after an uneventful pregnancy virtually needs no iron during its first 6 months of life. On the other hand, several factors, such as duration of gestation, gender, mother's iron status, alteration of the iron placental transfer, significantly influence the iron store at birth. Because of their reduced body store at birth and their higher demand during catch-up growth, low birth weight infants should receive an iron supplement, which should be started earlier and given at a higher dose in the more premature infants. This preventive strategy can be given as enteral supplement, preterm formula, or enriched breast milk. Finally, because of its benefits on neonatal morbidity and iron status, delayed umbilical cord clamping is recommended for preterm infants. PMID- 28622782 TI - [Prevalence of iron deficiency]. AB - Studies of prevalence in iron deficiency separate iron depletion (defined as decreased blood ferritin) and iron deficiency anemia (defined as blood decrease in both ferritin and hemoglobin). In Europe, most studies are outdated. Prevalence of iron depletion varies from 7 to 18 % and 24 to 36% in toddlers and adolescents, respectively. Prevalence of iron deficiency anemia varies from 2 to 8.5% and 7 to 10% in toddlers and adolescents. In French speaking African countries, Demography Health Surveys show that 80% of children aged 0 to 2 years are anemic, severely for 5 to 9% of them. PMID- 28622783 TI - [Biological diagnosis of iron deficiency in children]. AB - Measurement of serum ferritin (SF) is currently the laboratory test recommended for diagnosing iron deficiency. In the absence of an associated disease, a low SF value is an early and highly specific indicator of iron deficiency. The WHO criteria proposed to define depleted storage iron are 12MUg/L for children under 5 years and 15MUg/L for those over 5 years. A higher threshold of 30MUg/L is used in the presence of infection or inflammation. Iron deficiency anemia, with typical low mean corpuscular volume and mean corpuscular hemoglobin, is only present at the end stage of iron deficiency. Other diagnostic tests for iron deficiency including iron parameters (low serum iron, increased total iron binding capacity, low transferrin saturation) and erythrocyte traits (low mean corpuscular volume, increased zinc protoporphyrin) provide little additional diagnostic value over SF. In children, serum soluble transferrin receptor (sTfR) has been reported to be a sensitive indicator of iron deficiency and is relatively unaffected by inflammation. On the other hand, sTfR is directly related to extent of erythroid activity and not commonly used in clinical practice. In population surveys, approaches based on combinations of markers have been explored to improve the specificity and sensitivity of diagnostic. In addition to Hb value determination, a combination of parameters (among transferrin saturation, zinc protoporphyrin, mean corpuscular volume or serum ferritin) was generally used to assess iron deficiency. More recently sTfR/ ferritin index were evaluated, sTfR in conjunction with SF allowing to better distinguishing iron deficiency from inflammatory anemia. Also, hepcidin measurements appeared an interesting marker for diagnosing iron deficiency and identifying individuals in need of iron supplementation in populations where inflammatory or infectious diseases are frequently encountered. Reticulocyte Hb content (CHr) determination is an early parameter of iron deficiency erythropoiesis. CHr can be measured with several automated hematology analyzers and so, used for individual's iron status assessment. In addition to Hb concentration determination, individual's iron status is commonly assessed in the pediatric clinical practice by the SF measurement accompanied by the determination of C-reactive protein for detection of a simultaneous acute infection and/or inflammation. PMID- 28622784 TI - First-trimester inter- and intrafetal size discrepancies in bichorionic twins conceived by in vitro fertilization: can it predict pregnancy outcome? AB - OBJECTIVE: To evaluate the association between first-trimester inter- and intrafetal size discrepancies and pregnancy outcome, among bichorionic-biamniotic twins conceived by IVF. DESIGN: A retrospective study design was used. SETTING: Tertiary university-affiliated medical center. PATIENT(S): All women with a viable first-trimester bichorionic-biamniotic twin gestation, who conceived after IVF in 2007-2015. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The association between fetal size differences and pregnancy outcome was analyzed. Intrafetal size discordance was defined as a difference between the actual gestational age calculated by ovum pickup (OPU) date and the evaluated gestational age by crown rump length (CRL), for each twin. Intertwin size discrepancy was defined as a difference in CRL between the twins. The primary outcome was the number of live born fetuses; the secondary outcome measures were gestational age at birth, birth weight percentile, and birth weight discordancy. RESULT(S): A total of 277 women met the study criteria and were divided into three groups by outcome: 218 (78.7%) live-born twins, 41 (14.8%) live-born singleton, and 19 (6.5%) non-live-born pregnancy. Among the smaller than expected twin, the association of CRL-OPU differences with the primary outcome was significant for twin live-born delivery (-1.43 day), singleton live-born delivery (-4.12 days), and non-live-born pregnancy (-6.72 days). For the relatively larger twin, the association was significant for non-live-born pregnancy (-4.33 days) compared with any live-born delivery, either singleton (-0.95 days) or twin (-0.21 days). CONCLUSION(S): Among IVF conceived twin gestations, a CRL-OPU gap was associated with an increased risk of a negative pregnancy outcome. PMID- 28622785 TI - Comprehensive long non-coding RNA expression profiling reveals their potential roles in systemic lupus erythematosus. AB - Long non-coding RNAs can regulate gene transcription, modulate protein function, and act as competing endogenous RNA. Yet, their roles in systemic lupus erythematosus remain to be elucidated. We determined the expression profiles of lncRNAs in T cells of SLE patients and healthy controls using microarrays. Up to 1935 lncRNAs and 1977 mRNAs were differentially expressed. QRT-PCR showed downregulated uc001ykl.1 and ENST00000448942 in SLE patients. Expression of uc001ykl.1 correlated with erythrocyte sedimentation rate (ESR) and C-reactive protein, whereas ENST00000448942 level correlated with ESR and anti-Sm antibodies. Short time-series expression miner analysis revealed some lncRNAs whose expressions might correlate with disease activity of SLE patients. Coding non-coding gene coexpression analyses showed differential lncRNAs might operate via modulating expressions of their correlated, relevant mRNAs in SLE. Differential lncRNAs might also function through their ceRNAs. Our study established that the aberrant expression profiles of lncRNAs may play a role in SLE and thus warrant further investigation. PMID- 28622786 TI - Dairy cow disability weights. AB - Over the past 175 years, data related to human disease and death have progressed to a summary measure of population health, the Disability-Adjusted Life Year (DALY). As dairies have intensified there has been no equivalent measure of the impact of disease on the productive life and well-being of animals. The development of a disease-adjusted metric requires a consistent set of disability weights that reflect the relative severity of important diseases. The objective of this study was to use an international survey of dairy authorities to derive disability weights for primary disease categories recorded on dairies. National and international dairy health and management authorities were contacted through professional organizations, dairy industry publications and conferences, and industry contacts. Estimates of minimum, most likely, and maximum disability weights were derived for 12 common dairy cow diseases. Survey participants were asked to estimate the impact of each disease on overall health and milk production. Diseases were classified from 1 (minimal adverse effects) to 10 (death). The data was modelled using BetaPERT distributions to demonstrate the variation in these dynamic disease processes, and to identify the most likely aggregated disability weights for each disease classification. A single disability weight was assigned to each disease using the average of the combined medians for the minimum, most likely, and maximum severity scores. A total of 96 respondents provided estimates of disability weights. The final disability weight values resulted in the following order from least to most severe: retained placenta, diarrhea, ketosis, metritis, mastitis, milk fever, lame (hoof only), calving trauma, left displaced abomasum, pneumonia, musculoskeletal injury (leg, hip, back), and right displaced abomasum. The peaks of the probability density functions indicated that for certain disease states such as retained placenta there was a relatively narrow range of expected impact whereas other diseases elicited a wider breadth of impact. This was particularly apparent with respect to calving trauma, lameness and musculoskeletal injury, all of which could be redefined using gradients of severity or accounting for sequelae. These disability weight distributions serve as an initial step in the development of the disease-adjusted lactation (DALact) metric. They will be used to assess the time lost due to dynamic phases of dairy cow diseases and injuries. Prioritizing health interventions based on time expands the discussion of animal health to view profits and losses in light of the quality and length of life. PMID- 28622787 TI - Monitoring of the newborn dog and prediction of neonatal mortality. AB - Despite the high neonatal mortality rate in puppies, pertinent criteria for health evaluation of the newborns are not defined. This study was thus designed to measure and to characterize factors of variation of six health parameters in dog neonates, and to evaluate their value as predictors of neonatal mortality. A total of 347 purebred puppies under identical conditions of housing and management were examined within the first 8h after birth and then at Day 1. The first health evaluation included Apgar score, weight, blood glucose, lactate and beta-hydroxybutyrate concentration, rectal temperature and urine specific gravity (SG). The second evaluation at Day 1 included the same parameters, excluding Apgar score and weight. The mortality rate over the first 24h and over 21days of age was recorded. The early predictors of neonatal mortality in the dog were determined with generalized linear mixed models and receiver operating characteristic curves analyses. An Apgar score at or below 6 evaluated within the first 8h after birth was found associated with a higher risk of death during the first 24h. A reduced glucose concentration (<=92mg/dl) at Day 1 was found to be associated with higher mortality between 1 and 21days of age. Low-birth-weight puppies were characterized by both low viability (low Apgar score) and low blood glucose concentration, and thus were found indirectly at higher risk of neonatal mortality. This study promotes two low cost easy-to-use tests for health evaluation in puppies, i.e. Apgar scoring and blood glucose assay. Further investigation is necessary to establish if the strong relationship between blood glucose and neonatal survival reflects high energy requirements or other benefits from colostrum intake. PMID- 28622788 TI - A questionnaire study of associations between potential risk factors and salmonella status in Swedish dairy herds. AB - In this study associations between potential risk factors and salmonella status in Swedish dairy herds were investigated. A case-control study design was used, including existing as well as new cases. Herds were assigned a salmonella status on the basis of antibody analysis of bulk milk samples. Information on potential risk factors was collected from registry data and from farmers via a questionnaire. Univariable and multivariable logistic regression analyses were used to investigate associations between salmonella status and potential risk factors. In addition, multivariate analysis with Additive Bayesian Network (ABN) modelling was performed to improve understanding of the complex relationship between all the variables. Because of the difficulty in identifying associations between potential risk factors and infections with low prevalence and a large regional variation, exposure of potential risk factors in the high-prevalence region (Oland) were compared to exposure in other regions in Sweden. In total 483 of 996 (48%) farmers responded to the questionnaire, 69 herds had test-positive bulk milk samples. The strongest association with salmonella status was 'presence of salmonella test-positive herds <5 km' (OR 4.3, 95% CI 2.0-9.4). Associations with salmonella status were also seen between 'feeding calves residue milk only' (OR 2.4, 95% CI 1.2-4.6), 'certified organic herds' (OR 2.5, 95% CI 1.2-4.9) and 'frequently seeing signs of rodents' (OR 0.4, 95% CI 0.13-0.97). The ABN model showed associations between Oland and four of the variables: salmonella status, presence of test-positive herds <5km, shared pastures and providing protective clothing for visitors. The latter is probably a reflection of increased disease awareness in Oland. The ABN model showed associations between herd size and housing as well as several management procedures. This provides an explanation why herd size frequently has been identified as a risk factor for salmonella by other studies. The study confirms the importance of local transmission routes for salmonella, but does not identify specific components in this local spread. Therefore, it supports the use of a broad biosecurity approach in the prevention of salmonella. In Oland, some potential risk factors are more common than in other parts of Sweden. Theoretically these could contribute to the spread of salmonella, but this was not confirmed in the present study. The study also highlights the difficulty in identifying associations between potential risk factors and infections with low prevalence and large regional variation. PMID- 28622789 TI - Characterization of the epidemiology of bat-borne rabies in Chile between 2003 and 2013. AB - Rabies is a zoonotic disease of great impact to public health. According to the World Health Organization, the country of Chile is currently declared free from human rabies transmitted by dogs. An epidemiological characterization and description was conducted using rabies data from 2003 to 2013 held by the National Program for Prevention and Control of Rabies from the Ministry of Health, consisting of bats samples reported as suspect and samples taken by active surveillance (bats brain tissue). Spatial autocorrelation analysis was performed using Local Indicators of Spatial Association (LISA) statistics, particularly Moran's I index, for the detection of spatial clusters. Temporal descriptive analysis was also carried out. Nine hundred and twenty-seven positive cases were reported, presenting an average of 84 cases per year, mainly originated from passive surveillance (98.5%), whilst only 1.5% of cases were reported by active surveillance. Global positivity for the study period was 7.02% and 0.1% in passive and active surveillance respectively. Most of the cases were reported in the central zone of Chile (88.1%), followed by south zone (9.1%) and north zone (2.8%). At a regional level, Metropolitana (40.6%), Valparaiso (19.1%) and Maule (11.8%) regions reported the majority of the cases. Tadarida brasiliensis (92%) presented the majority of the cases reported, with viral variant 4 (82%) being most commonly diagnosed. Only two cases were detected in companion animals. The central zone presented a positive spatial autocorrelation (Moran's I index=0.1537, 95% CI=0.1141-0.1933; p-value=0.02); north and south zones returned non-significant results (Moran's I index=0.0517 and -0.0117, 95% CI=-0.0358-0.1392 and -0.0780-0.0546, and p-values=0.21 and 0.34 respectively). The number of rabies cases decreased between May and August (late fall and winter) and tended to increase during the hot season (December to March), confirmed with the evidence from Autocorrelation analysis and the Ljun-Box test (X2=234.85 and p-value<0.0001). Knowledge of animal rabies epidemiologic behaviour becomes relevant when designing prevention and control measures and surveillance programs. This is especially important considering the high impact to Public Health of this disease and that wildlife rabies in bats remains endemic in Chile. PMID- 28622790 TI - Early-life risk factors identified for owner-reported feline overweight and obesity at around two years of age. AB - Obesity is considered the second most common health problem in pet cats in developed countries. This study used prospective data from a longitudinal study of pet cats ('C.L.A.W.S.', www.bristol.ac.uk/vetscience/claws) to identify early life risk factors for feline overweight/obesity occurring at around two years of age. Data were collected via five owner-completed questionnaires (for cats aged two-six months, six months, 12 months, 18 months and two years respectively) completed between May 2011 and April 2015. Owner-reported body condition scores (BCS) of cats at age two years, assessed using images from the 9-point BCS system (Laflamme, 1997), were categorised into a dichotomous variable: overweight/obese (BCS 6-9) and not overweight (BCS 1-5) and used as the dependent variable. Of the 375 cats with owner-reported BCS, 25.3% were overweight or obese at two years of age. Multivariable logistic regression models were built using stepwise forward selection. To account for potential hierarchical clustering due to multi-cat households two-level random intercept models were considered but clustering had no impact on the analysis. Models were compared using Wald tests. Six factors were significantly associated with overweight/obesity at two years of age: being overweight or obese at one year of age (OR=10.6, 95%CI 4.4-25.3); owner belief that BCS 7 was the ideal weight (OR=33.2, 95%CI 8.5-129.4), or that BCS represented overweight cats but they would not be concerned if their cat were classified in this category (OR=2.7, 95%CI 1.2-6.2), at questionnaire five completion; vets advising owners that the cat should lose weight, or making no comment on their weight, between one and two years of age (OR=12.1, 95%CI 3.2 44.9 and OR=3.9, 95%CI 1.5-10.3 respectively); owners giving their cat treats when they "felt happy" with them at 18 months of age (OR=2.7, 95%CI 1.0 - 7.3); feeding >=250g wet food daily between two and six months of age (OR=2.7, 95%CI 1.2-5.9), and feeding dry food as the only or major part (>50%) of the diet at two years of age (OR=2.1, 95%CI 1.0-4.2). These findings have the potential to reduce the current high prevalence of a widespread problem by informing preventive advice, and as such improving the health and welfare of pet cats. PMID- 28622791 TI - Prevalence and associated risk factors of haemoparasites, and their effects on hematological profile in domesticated chickens in District Layyah, Punjab, Pakistan. AB - Several haemoparasites commonly infect avian species, including chicken that significantly decline productivity and ultimately lead to high mortality rate. The current study was designed to assess the prevalence and associated risk factors of haemoparasites in domesticated chickens in and around District Layyah, Punjab Province, Pakistan. For this purpose, blood samples from a total of 384 backyard chickens were collected from wing vein using sterile insulin syringe. The parasites were identified from Giemsa stained thin blood smears based on morphological features using standard keys. Results demonstrated that a total of 265 backyard chickens (69%) were infected with haemoparasites in District Layyah. According to genus-wise distribution, 31.5%, 24.4% and 13% prevalence of genera Plasmodium/Haemoproteus, Leucocytozoon and mixed species were recorded, respectively. Among associated risk factors, the prevalence was relatively higher in females, chicks, naked neck breeds, scavengers feeding patterns and chickens reared at fully open coops type. The information given in the study could be of much importance in planning of an effective haemoparasites control program at District and Provincial level. PMID- 28622792 TI - A cross-sectional field study on potential associations between feed quality measures and usage of antimicrobials in commercial mink (Neovison vison). AB - Feed quality is generally assumed to affect health status in animal production. In previous studies, the feed producer has been found to affect the occurrence of gastrointestinal disease and antimicrobial use in Mink (Neovison vison). Mink are fed with moist, freshly produced feed, based on perishable ingredients. The objective of this study was to investigate the potential effect of specific feed parameters on antimicrobial use on herd level. The study was cross-sectional, including 1472 mink herds, responsible for 97% of oral antimicrobials prescribed for Danish mink during the study period, 2012-2014. Data were obtained from the national veterinary prescription database (VetStat), Kopenhagen Fur database, and the Voluntary Feed Control (Mink producers Organization). All feed batches subject to feed control were included. A multi-variable variance analysis was carried out analysing the effect of the feed parameters total volatile nitrogen, dry matter, crude protein and fat; total bacterial count (21 degrees C), and counts of sulphite producing bacteria (21 degrees C), Clostridium spp., faecal cocci (FC) (44 degrees C), yeast, and mould; presence of Salmonella spp. and Clostridium perfringens (dichotome). Three outcome variables were applied: prescription of oral antimicrobial on herd level within time slots of 3, 5 or 7days after feeding of an included batch. Two binomial models were developed, adjusting for significant effects (p<0.0001) of Ps. aeruginosa infection, herd size, month (season) and year. Antimicrobial prescription was significantly (p<0.0001) associated with FC (all time slots, both models). A negative association (p<0.0001) with crude protein on antimicrobial prescription within a 7day slot suggested an association between low content of crude protein and antimicrobial use. The associations need to be confirmed in controlled studies, and ideally, potential causalities should be investigated. The perspective of such findings could be the development of tests for control of feed ingredients prior to use in the feed production. PMID- 28622793 TI - Comparison of bacterial culture and qPCR testing of rectal and pen floor samples as diagnostic approaches to detect enterotoxic Escherichia coli in nursery pigs. AB - : Enterotoxigenic E. coli (ETEC) are a major cause of diarrhoea in weaned pigs. The objective of this study was to evaluate the agreement at pen level among three different diagnostic approaches for the detection of ETEC in groups of nursery pigs with diarrhoea. The diagnostic approaches used were: bacterial culturing of faecal samples from three pigs (per pen) with clinical diarrhoea and subsequent testing for virulence genes in E. coli isolates; bacterial culturing of pen floor samples and subsequent testing for virulence genes in E. coli isolates; qPCR testing of pen floor samples in order to determine the quantity of F18 and F4 genes. The study was carried out in three Danish pig herds and included 31 pens with a pen-level diarrhoea prevalence of > 25%, as well as samples from 93 diarrhoeic nursery pigs from these pens. All E. coli isolates were analysed by PCR and classified as ETEC when genes for one or more adhesin factors and one or more enterotoxins were detected. RESULTS: A total of 208 E. coli colonies from pig samples and 172 E. coli colonies from pen floor samples were isolated. Haemolytic activity was detected on blood agar plates in 111 (29.2%) of the 380 colonies that were isolated. The only adhesin factor detected in this study was F18. When comparing bacterial culture or qPCR testing of pen floor samples with detection of ETEC-positive diarrhoeic pigs by culture, agreement was found in 26 (83.9%, Kappa = 0.665) and 23 (74.2%, Kappa = 0.488) of the pens, respectively. Agreement was observed between the detection of ETEC by bacterial culture and qPCR in the same pen floor sample in 26 (83.9%, Kappa = 0.679) pens. CONCLUSION: We observed an acceptable agreement for the detection of ETEC-positive diarrhoeic nursery pigs in pen samples for both bacterial culture of pen floor samples and qPCR. This study showed that both bacterial culture and qPCR testing of pen floor samples can be used as a diagnostic approach for detecting groups of ETEC-positive diarrhoeic nursery pigs. PMID- 28622794 TI - Schmallenberg virus: Predicting within-herd seroprevalence using bulk-tank milk antibody titres and exploring individual animal antibody titres using empirical distribution functions (EDF). AB - Schmallenberg virus (SBV) is transmitted by Culicoides spp. biting midges and can cause abortions and congenital malformations in ruminants and milk drop in dairy cattle. Estimating true within-herd seroprevalence is an essential component of efficient and cost-effective SBV surveillance programs. The objectives of this study were: (1) determine the correlation between bulk-tank milk (BTM)-ELISA results and within-herd seroprevalence, (2) evaluate the ability of BTM-ELISA results to predict within-herd seroprevalence and (3) explore the distributions of individual animal serology results using novel statistical methodology. BTM samples (n=24) and blood samples (n=4019) collected from all lactating cows contributing to the BTM in 26 Irish dairy herds (58-444 cows/herd) in 2014 located in a region exposed to SBV in 2012/2013, were analysed for SBV-specific antibodies using IDVet(r) ELISA kits. The correlation between BTM-ELISA results and within-herd seroprevalence was determined by calculating Pearson's correlation coefficient. Linear regression models were used to assess the ability of BTM-ELISA results to predict within-herd seroprevalence. The distributions of individual animal serology results were explored by determining the empirical distribution functions (EDF) of the individual animal serum ELISA results in each herd. EDFs were compared pairwise across herds, using the Kolmogorov-Smirnov statistical test. Herds with similar BTM-ELISA results, herds with similar within herd seroprevalence and herds with similar mean-herd serology ELISA results were stratified in order to explore their respective paired-herd EDF comparisons. Statistical significance was set at p<0.05. Twenty-two herds were BTM-ELISA positive (within-herd seroprevalence 30.6-100%) and two herds were BTM-ELISA negative (within-herd seroprevalence 10.7 and 16.2%) indicating BTM-ELISA negative herds can have seropositive animals present. BTM-ELISA results were highly correlated (r=0.807, p<0.0001) with, and predictive of (R2=0.832, p<0.0001) of within-herd seroprevalence. Predictions were most accurate for upper range BTM-ELISA antibody titres, while they were less accurate at higher and lower antibody titres. This is likely a result of the overall high within-herd seroprevalence. In herds with similar BTM-ELISA results 82% of the paired-herd EDF comparisons were significantly different. In herds with similar within-herd seroprevalence and in herds with similar mean-herd serology ELISA results, 46% and 47% of the paired-herd EDF comparisons were significantly different, respectively. These results demonstrate that BTM antibody titres are highly predictive of within-herd seroprevalence in an SBV exposed region. Furthermore, exploring the serum EDFs revealed that the variation observed in the predicted within-herd seroprevalence in the regression models is likely a result of individual animal variation in serum antibody titres in these herds. PMID- 28622795 TI - Desulfamplus magnetovallimortis gen. nov., sp. nov., a magnetotactic bacterium from a brackish desert spring able to biomineralize greigite and magnetite, that represents a novel lineage in the Desulfobacteraceae. AB - A magnetotactic bacterium, designated strain BW-1T, was isolated from a brackish spring in Death Valley National Park (California, USA) and cultivated in axenic culture. The Gram-negative cells of strain BW-1T are relatively large and rod shaped and possess a single polar flagellum (monotrichous). This strain is the first magnetotactic bacterium isolated in axenic culture capable of producing greigite and/or magnetite nanocrystals aligned in one or more chains per cell. Strain BW-1T is an obligate anaerobe that grows chemoorganoheterotrophically while reducing sulfate as a terminal electron acceptor. Optimal growth occurred at pH 7.0 and 28 degrees C with fumarate as electron donor and carbon source. Based on its genome sequence, the G+C content is 40.72mol %. Phylogenomic and phylogenetic analyses indicate that strain BW-1T belongs to the Desulfobacteraceae family within the Deltaproteobacteria class. Based on average amino acid identity, strain BW-1T can be considered as a novel species of a new genus, for which the name Desulfamplus magnetovallimortis is proposed. The type strain of D. magnetovallimortis is BW-1T (JCM 18010T-DSM 103535T). PMID- 28622797 TI - Making the best value of clinical radiology: iRefer Guidelines, 8th edition. AB - New uses of medical imaging as well as over-diagnosis and wasteful imaging have led to a 10% per annum growth in computed tomography (CT) and magnetic resonance imaging (MRI). Personalised value to the patient will be helped by referral guidelines for the best test first, adding evidence-based technical value to the investigation to answer the clinical question, thus providing allocative value to the commissioners of medical imaging. Appropriate imaging is driven by the need for effective decisions, radiation safety, and cost awareness. The eighth edition of The Royal College of Radiologists' iRefer guidelines addresses 270 common clinical settings providing imaging referral advice, particularly for primary care practitioners. There is a new section addressing asymptomatic individuals for screening and health assessment. Multiple formats, including print and web formats, will be augmented by a clinical decision support tool to bring guidance closer to referrers. Established evidence identified a reduction in requested examination numbers by typically 20%, with more recent studies showing appropriate imaging in 80-90% of cases, correctly allowing some flexibility for individual circumstances. The perceived value of referral guidance may be judged by the mandated use in the USA, the requirement for availability in Europe, and the wish by many elsewhere to avail their patients of best imaging practice. PMID- 28622796 TI - Cardiac magnetic resonance indices reflecting pulmonary regurgitation burden after tetralogy of Fallot repair. AB - AIM: To investigate cardiac magnetic resonance (CMR)-derived parameters to determine a convenient index reflecting the degree of pulmonary regurgitation (PR) after Tetralogy of Fallot (TOF) repair. MATERIALS AND METHODS: Sixty-three patients (age at CMR study, 23.6 [10.2-34.7] years, 55.6% male) underwent CMR after TOF repair. PR was quantified using ventricular stroke volume difference and phase-contrast mapping of the main pulmonary artery flow. In both approaches, the PRV index (PRVI) and the PR fraction (PRF) were calculated and correlated to the right ventricle end-diastolic volume index (RVEDVI) and the right ventricle end-systolic volume index (RVESVI). RESULTS: No statistically significant difference was observed between the PR volumes and the PRF measured by the stroke volume difference or the phase-contrast method. The PRVI was better correlated to RVEDVI and RVESVI than the PRF. CONCLUSION: The PRVI exhibits more correlation to the RVEDVI than PRF. Thus, it could be a preferable parameter to reflect the PR burden. PMID- 28622798 TI - Singapore Malaria Network Meeting (SingMalNet) 2016. PMID- 28622799 TI - Quantitative NMR analysis of intra- and extracellular metabolism of mammalian cells: A tutorial. AB - Metabolomics analysis of body fluids as well as cells is depended on many factors. While several well-accepted standard operating procedures for the analysis of body fluids are available, the NMR based quantitative analysis of cellular metabolites is less well standardized. Experimental designs depend on the cell type, the quenching protocol and the applied post-acquisition workflow. Here, we provide a tutorial for the quantitative description of the metabolic phenotype of mammalian cells using NMR spectroscopy. We discuss all key steps of the process, starting from the selection of the appropriate culture medium, quenching techniques to arrest metabolism in a reproducible manner, the extraction of the intracellular components and the profiling of the culture medium. NMR data acquisition and methods for both qualitative and quantitative analysis are also provided. The suggested methods cover experiments for adherent cells and cells in suspension. We ultimately describe the application of the discussed workflow to a thyroid cancer cell line. Although this tutorial focuses on mammalian cells, the given guidelines and procedures may be adjusted for the analysis of other cell types. PMID- 28622800 TI - Analysis of stable isotope assisted metabolomics data acquired by GC-MS. AB - Stable isotope assisted metabolomics (SIAM) measures the abundance levels of metabolites in a particular pathway using stable isotope tracers (e.g., 13C, 18O and/or 15N). We report a method termed signature ion approach for analysis of SIAM data acquired on a GC-MS system equipped with an electron ionization (EI) ion source. The signature ion is a fragment ion in EI mass spectrum of a derivatized metabolite that contains all atoms of the underivatized metabolite, except the hydrogen atoms lost during derivatization. In this approach, GC-MS data of metabolite standards were used to recognize the signature ion from the EI mass spectra acquired from stable isotope labeled samples, and a linear regression model was used to deconvolute the intensity of overlapping isotopologues. A mixture score function was also employed for cross-sample chromatographic peak list alignment to recognize the chromatographic peaks generated by the same metabolite in different samples, by simultaneously evaluating the similarity of retention time and EI mass spectrum of two chromatographic peaks. Analysis of a mixture of 16 13C-labeled and 16 unlabeled amino acids showed that the signature ion approach accurately identified and quantified all isotopologues. Analysis of polar metabolite extracts from cells respectively fed with uniform 13C-glucose and 13C-glutamine further demonstrated that this method can also be used to analyze the complex data acquired from biological samples. PMID- 28622801 TI - Rapid determination of nitrate in vegetables by gas chromatography mass spectrometry. AB - In this study we present a novel isotope dilution gas chromatography method for the determination of nitrate in vegetables. The analyte was extracted in water at 70?C and mixed with 15N isotopically enriched nitrate internal standard. The sample was centrifuged and the supernatant reacted with sulfamic acid for removal of nitrite, and with triethyloxonium tetrafluoroborate for converting nitrate into volatile EtONO2. This simple aqueous chemistry allowed for separation of analyte from sample matrix in the form of a gaseous derivative which could be sampled in the headspace before GC-MS analysis. This key-feature of the method made possible the collection of clean chromatograms within an elution time of only 1.8 min. Detection of EtONO2 could be performed using electron impact ionization with a standard GC-MS setup. The method was optimized and validated for the analysis of nitrate in fresh vegetables in the 10-10,000 MUg/g range with a detection limit of 2 MUg/g. Due to the use of primary isotope dilution quantitation, traceable results of high-precision were attained. PMID- 28622802 TI - Rapid multiplex DNA amplification on an inexpensive microdevice for human identification via short tandem repeat analysis. AB - Forensic DNA analysis requires several steps, including DNA extraction, PCR amplification, and separation of PCR fragments. Intuitively, there are numerous situations where it would be beneficial to speed up the overall DNA analysis process; in this work, we focus on the most time-consuming component in the analysis pipeline, namely the polymerase chain reaction (PCR). Primers were specially designed to target 10 human genomic loci, all yielding amplicons shorter than 350 bases, for ease of downstream integration with on-board microchip electrophoresis. Primer concentrations were adjusted specifically for microdevice amplification, resulting in well-balanced short tandem repeat (STR) profiles. Furthermore, studies were performed to push the limits of the DNA polymerase to achieve rapid, multiplexed PCR on various substrates, including transparent and black polyethylene terephthalate (Pe), and with two distinct adhesives, toner and heat sensitive adhesive (HSA). Rapid STR-based multiplexed PCR amplification is demonstrated in 15 min on a Pe microdevice using a custom built system for fluid flow control and thermocycling for the full 10-plex, and in 10 min for a smaller multiplex consisting of six core CODIS loci plus Amelogenin with amplicons shorter than 200bp. Lastly, preliminary studies indicate the capability of this PCR microdevice platform to be integrated with both upstream DNA extraction, and downstream microchip electrophoresis. This, coupled to the use of reagents that are compatible with lyophilization (lyo compatible) for PCR, represents the potential for a fully integrated rotationally driven microdevice for complete forensic DNA analysis. PMID- 28622803 TI - Lab on paper chip integrated with Si@GNRs for electroanalysis of diazepam. AB - We describe herein the fabrication of an electrochemical microfluidic paper based device (EMUPAD) for the detection of diazepam, a sedative, anxiety-relieving and muscle-relaxing drug. To achieve it, silica coated gold nanorods (Si@GNRs) were synthesized and drop casted on an electrochemical microfluidic paper based device (EMUPAD) for the detection of diazepam. The synthesized composites were characterized by recording its images in scanning electron microscope (SEM) and transmission electron microscope (TEM). The experimental results confirmed that Si@GNRs had good electrocatalytic activity towards diazepam. The modified paper based electrode showed a stable electrochemical response for diazepam in the concentration range of 3.5 nM to 3.5 mM. EMUPAD offers many advantageous features such as facile approach, economical and have potential for commercialization. Si@GNRs modified EMUPAD was also employed for determination of diazepam in spiked human urine samples. Reported facile lab paper approach integrated with Si@GNRs could be well applied for the determination of serum metabolites. PMID- 28622804 TI - G-quadruplex based Exo III-assisted signal amplification aptasensor for the colorimetric detection of adenosine. AB - Adenosine is an endogenous nucleotide pivotally involved in nucleic acid and energy metabolism. Its excessive existence may indicate tumorigenesis, typically lung cancer. Encouraged by its significance as the clinical biomarker, sensitive assay methods towards adenosine have been popularized, with high cost and tedious procedures as the inevitable defects. Herein, we report a label-free aptamer based exonuclease III (Exo III) amplification colorimetric aptasensor for the highly sensitive and cost-effective detection of adenosine. The strategy employed two unlabeled hairpin DNA oligonucleotides (HP1 and HP2), where HP1 contained the aptamer towards adenosine and HP2 embedded the guanine-rich sequence (GRS). In the presence of adenosine, hairpin HP1 could form specific binding with adenosine and trigger the unfolding of HP1's hairpin structure. The resulting adenosine-HP1 complex could hybridize with HP2, generating the Exo III recognition site. After Exo III-assisted degradation, the GRS was released from HP2, and the adenosine HP1 was released back to the solution to combine another HP2, inducing the cycling amplification. After multiple circulations, the released ample GRSs were induced to form G-quadruplex, further catalyzing the oxidation of TMB, yielding a color change which was finally mirrored in the absorbance change. On the contrary, the absence of adenosine failed to unfold HP1, remaining color unchanged eventually. Thanks to the amplification strategy, the limit of detection was lowered to 17 nM with a broad linear range from 50 nM to 6 MUM. The proposed method was successfully applied to the detection of adenosine in biological samples and satisfying recoveries were acquired. PMID- 28622805 TI - Nanomolar sensitive colorimetric assay for Mn2+ using cysteic acid-capped silver nanoparticles and theoretical investigation of its sensing mechanism. AB - A new facile, rapid, sensitive and selective colorimetric assay is proposed for the determination of manganese ions (Mn2+) utilizing cysteic acid (CA)-capped silver nanoparticles (CA-AgNPs) as colorimetric probes. The CA-AgNPs were prepared by reducing AgNO3 with NaBH4 in the presence of CA as the capping ligand. The presence of Mn2+ induces the quick aggregation of CA-AgNPs, associated with notable color changes of the CA-AgNPs solution from yellow to dark green. The Mn2+ can form a coordinated structure with CA capping on the AgNPs and leads to formation of large particles aggregation. We also used density functional theory (DFT) to calculate the change of the Gibbs free energy (DeltaG) of the interactions between the CA-AgNPs and various metal ions, which shows that CA-AgNPs have high specificity for Mn2+. The high sensitivity and selectivity for Mn2+ were achieved and the detection limit is as low as 5 nM. Furthermore, the proposed method was successfully applied in detecting Mn2+ in a rat model of focal ischemia and the results indicate that our proposed method has great potential for practical applications. PMID- 28622806 TI - Graphitic carbon nitride supported platinum nanocomposites for rapid and sensitive colorimetric detection of mercury ions. AB - In this study, graphitic carbon nitride supported platinum nanocomposites (g C3N4/PtNPs) have been synthesized for the first time by an ultrasonic-assisted chemical reduction method. By using g-C3N4 as the stabilizer, Pt ions could be reduced to PtNPs by NaBH4 and uniformly deposited on the surface of g-C3N4. The resulting g-C3N4/PtNPs exhibited enhanced catalytic activity for the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) compared to that of g-C3N4 or PtNPs alone. After interaction with Hg2+, the catalytic activity of g-C3N4/PtNPs was effectively inhibited due to the formation of HgPt amalgam. On the basis of this effect, a novel label free colorimetric sensor has been developed for sensitive detection of Hg2+ through the g-C3N4/PtNPs mediated catalytic reaction. A detection limit as low as 1.23 nM was achieved. This assay also exhibited excellent selectivity toward Hg2+ over other metal ions. In addition, it was successfully applied to the determination of Hg2+ in real water samples. In view of the advantages, such as simple operation, cost-effective, rapid response and naked-eye observation, the developed colorimetric sensor hold great potential for the detection of toxic Hg2+ in environmental and biological samples. PMID- 28622808 TI - Characterizing and predicting rates of delirium across general hospital settings. AB - OBJECTIVE: To better understand variation in reported rates of delirium, this study characterized delirium occurrence rate by department of service and primary admitting diagnosis. METHOD: Nine consecutive years (2005-2013) of general hospital admissions (N=831,348) were identified across two academic medical centers using electronic health records. The primary admitting diagnosis and the treating clinical department were used to calculate occurrence rates of a previously published delirium definition composed of billing codes and natural language processing of discharge summaries. RESULTS: Delirium rates varied significantly across both admitting diagnosis group (X210=12786, p<0.001) and department of care (X26=12106, p<0.001). In both cases obstetrical admissions showed the lowest incidences of delirium (86/109764; 0.08%) and neurological admissions the greatest (2851/25450; 11.2%). Although the rate of delirium varied across the two hospitals the relative rates within departments (r=0.96, p<0.001) and diagnostic categories (r=0.98, p<0.001) were consistent across the two institutions. CONCLUSIONS: The frequency of delirium varies significantly across admitting diagnosis and hospital department. Both admitting diagnosis and department of care are even stronger predictors of risk than age; as such, simple risk stratification may offer avenues for targeted prevention and treatment efforts. PMID- 28622809 TI - Racial and ethnic differences in mental healthcare utilization consistent with potentially effective care: The role of patient preferences. AB - OBJECTIVE: Ethnic minorities are less likely than Whites to initiate and continue mental healthcare. Minorities also prefer non-medical approaches to address mental health issues. We evaluated sector-type as a modifier of the association of race/ethnicity with service utilization for mental health. We hypothesized that minorities utilize non-mental health sectors at rates consistent with guidelines and similar to Whites. METHODS: We examined data from the Collaborative Psychiatric Epidemiologic Studies (CPES) (n=3803). We used logistic regression to assess the association of race/ethnicity with utilization consistent with potentially effective care across sectors-psychiatry, medical, non-medical mental health, human services, and spiritual. RESULTS: Asians [OR: 0.56 CI: 0.39, 0.82] and Blacks [OR: 0.74 CI: 0.60, 0.92] had lower odds of having >=1 visit compared to Whites. Blacks also had lower odds of >=4 [OR: 0.66 CI: 0.50, 0.87] and >=12 visits [OR: 0.58 CI: 0.41, 0.83]. Sector-type modified these associations. Compared to Whites, Asians [OR: 0.49 CI: 0.30, 0.82] and Blacks [OR: 0.71 CI: 0.54, 0.94] had lower odds of >=1 visit to the medical sector. Asians had lower odds of seeing psychiatrists for >=8 visits [OR: 0.15 CI: 0.04, 0.54] and >=12 visits [OR: 0.21 CI: 0.06, 0.77]. Asians and Blacks demonstrated similar utilization to Whites in non-medical mental health and spiritual settings. CONCLUSION: Racial/ethnic differences in utilization consistent with treatment guidelines are ameliorated in sectors preferred by minorities. PMID- 28622807 TI - The comparison of the effects of a novel hydrogel compound and traditional hyaluronate following micro-fracture procedure in a rat full-thickness chondral defect model. AB - PURPOSE: The aim of this experimental study was to investigate the impact of HA CS-NAG compound (hyaluronate, sodium chondroitin sulfate, N-acetyl-d-glucosamine) on the quality of repair tissue after micro-fracture and to compare it with HA (hyaluronat), in a rat full-thickness chondral defect model. METHODS: Full thickness chondral defects were created in a non-weight bearing area by using a handle 2.7-mm drill bit, in the right knees of 33 Sprague-Dawley rats. Each specimen then underwent micro-fracture using a needle. Two weeks after surgery, 3 groups were randomly formed among the rats (n = 33). In Group 1, 0.2 mL of sterile saline solution (0.9%) was injected. In Group 2, 0.2 mL HA with a mean molecular weight of 1.2 Mda was injected. In Group 3, 0.2 mL of HA-CS-NAG compound (hyaluronate, sodium chondroitin sulfate, N-acetyl-d-glucosamine) was injected. The injections were applied on the 14th, the 21st and the 28th postoperative days. All rats were sacrificed on the 42nd postoperative day. Histological analysis of the repair tissue was performed for each specimen by two blinded observers using Wakitani scoring system. RESULTS: There was significantly improved repair tissue in both Group 3 and Group 2 when compared with Group 1. Group 3 showed statistically significant improvement in terms of 'cell morphology' and 'integration of donor with host' when compared to Group 2 (p < 0.001). CONCLUSION: Intra-articular injection of HA-CS-NAG compound after micro fracture results in significantly improved repair tissue in rats' chondral defects when compared to HA regarding the donor integration and cell morphology. PMID- 28622810 TI - Exploratory examination of the utility of demoralization as a diagnostic specifier for adjustment disorder and major depression. AB - OBJECTIVE: Demoralization, a state of lowered morale and poor coping, has a prevalence of 13-18% among patients with advanced cancer. We surveyed clinicians' perspectives of the utility of "with demoralization" as a diagnostic specifier for adjustment and depressive disorders. METHOD: Using comparative clinical vignettes in a field survey, clinicians from a range of disciplines were asked their perception of the utility of diagnosis and treatment options. Response frequencies were compared using Cochran's Q and McNemar's tests, with sensitivity and specificity rated against expert rankings of diagnosis. Analysis of variance and paired t-tests examined significant differences in ratings of utility. RESULTS: Vignettes were assessed by 280 clinicians; 77% supported utility of the category 'adjustment disorder with demoralization' compared to 33% supporting 'adjustment disorder with anxiety' (McNemar test, p<0.001), while 83% supported the utility of 'with demoralization' for major depressive episode, matching 83% perceiving utility for 'with melancholia.' Sensitivity and specificity ratings were 77% and 94% for adjustment disorder with demoralization and 83% and 91% for major depression with demoralization. CONCLUSION: Clinicians perceived the specifier 'with demoralization' to deepen diagnostic understanding, treatment choice, and ability to communicate with clinicians and patients, particularly for the category of adjustment disorder with demoralization. PMID- 28622812 TI - Clozapine induced gastrointestinal hypomotility: A potentially life threatening adverse event. A review of the literature. AB - OBJECTIVE: The haematological and cardiac complications of clozapine have been well documented. Recent evidence from pharmacovigilance databases suggests that gastrointestinal (GI) complications are the leading cause of clozapine related deaths. This review aims to describe clinical features along with preventative and treatment options. METHOD: A review of MEDLINE via PubMed searching for all articles published up to February of 2016. Inclusion criteria were articles that provided clinical or epidemiological information relating to the diagnosis, outcome, management or pathophysiology of clozapine related gastrointestinal disorders in humans. RESULTS: Three large case series were identified with 104 cases, 20 of these reported clinical details. A further 52 cases reports were included. Median age was 40, with 79% being male, mean daily clozapine dose was 453 mg. Mortality was 38% with survivors being younger (39 vs. 42), on lower daily doses (400 mg vs. 532 mg), more likely to be female (32% vs. 6%). Four patients were re-challenged with clozapine following CIGH, two suffered a recurrence. CONCLUSION: Risk factors for CIGH appear to be older age, male gender, patients in the first four months of treatment, co-prescription of constipating agents, higher daily dose of clozapine, and previous CIGH. Risk factors for death were older age and male gender. Patients receiving clozapine should be counselled about the dangers of constipation and to report new GI symptoms. Once severe CIGH has occurred clozapine should be halted and reviewed with bowel symptoms managed promptly. Re-challenging with clozapine may present substantial risks due to the severity of CIGH and a paucity of evidence. From the available evidence a treatment strategy has been proposed. Further prospective data regarding CIGH are needed to allow a better assessment of the scale of the problem with the development and testing of treatment strategies. PMID- 28622811 TI - Development and preliminary performance of a risk factor screen to predict posttraumatic psychological disorder after trauma exposure. AB - OBJECTIVE: We examined data from a prospective study of risk factors that increase vulnerability or resilience, exacerbate distress, or foster recovery to determine whether risk factors accurately predict which individuals will later have high posttraumatic (PT) symptom levels and whether brief measures of risk factors also accurately predict later symptom elevations. METHOD: Using data from 129 adults exposed to traumatic injury of self or a loved one, we conducted receiver operating characteristic (ROC) analyses of 14 risk factors assessed by full-length measures, determined optimal cutoff scores, and calculated predictive performance for the nine that were most predictive. For five risk factors, we identified sets of items that accounted for 90% of variance in total scores and calculated predictive performance for sets of brief risk measures. RESULTS: A set of nine risk factors assessed by full measures identified 89% of those who later had elevated PT symptoms (sensitivity) and 78% of those who did not (specificity). A set of four brief risk factor measures assessed soon after injury identified 86% of those who later had elevated PT symptoms and 72% of those who did not. CONCLUSIONS: Use of sets of brief risk factor measures shows promise of accurate prediction of PT psychological disorder and probable PTSD or depression. Replication of predictive accuracy is needed in a new and larger sample. PMID- 28622813 TI - Evaluation of drug use and medication compliance in adolescents admitted to a psychiatric facility from the pediatric emergency department. AB - OBJECTIVES: Knowledge of drug use and medication compliance during mental health evaluation can help guide evaluation and treatment. The objective was to evaluate drug use and medication compliance in a pediatric emergency department (PED) psychiatric population by comparing medical history, standard urine drug screen (EIA), and expanded urine drug screen (HPLC-MS/MS). METHODS: A prospective cohort study of admitted psychiatric patients >=13years and <=18years in a tertiary-care children's hospital psychiatric ED from January 31, 2013 through April 16, 2014. RESULTS: 100 patients in our PED were enrolled. Marijuana was the most commonly admitted and detected substance; 43% had co-ingestions. HPLC-MS/MS revealed 36 additional substance exposures than identified by history. All substances detected by EIA were also detected by HPLC-MS/MS. Combination of history and HPLC MS/MS revealed the most substances used. HPLC-MS/MS identified antidepressants in 76% of patients prescribed a detectable antidepressant. CONCLUSION: Marijuana use was greater than nicotine use and was associated with concomitant polysubstance abuse. A combination of history and HPLC-MS/MS was the most thorough in obtaining history of drug use. Almost a quarter of patients did not have their prescribed antidepressant detected by HPLC-MS/MS. A rapid, affordable expanded drug screen should replace the more standard limited drug screen particularly for patients who are refractory to treatment. PMID- 28622814 TI - Identifying, treating, and advocating for human trafficking victims: A key role for psychiatric inpatient units. PMID- 28622815 TI - Effects of a brief ED-based alcohol and violence intervention on depressive symptoms. AB - OBJECTIVE: Depressive symptoms frequently co-exist in adolescents with alcohol use and peer violence. This paper's purpose was to examine the secondary effects of a brief alcohol-and-violence-focused ED intervention on depressive symptoms. METHOD: Adolescents (ages 14-18) presenting to an ED for any reason, reporting past year alcohol use and aggression, were enrolled in a randomized control trial (control, therapist-delivered brief intervention [TBI], or computer-delivered brief intervention [CBI]). Depressive symptoms were measured at baseline, 3, 6, and 12months using a modified 10-item Center for Epidemiological Studies Depression Scale (CESD-10). Poisson regression was used (adjusting for baseline age, gender, and depressive symptoms) to compare depressive symptoms at follow up. RESULTS: Among 659 participants, higher baseline depressive symptoms, female gender, and age>=16 were associated with higher depressive symptoms over time. At 3months, CBI and TBI groups had significantly lower CESD-10 scores than the control group; at 6months, intervention and control groups did not differ; at 12months, only CBI had a significantly lower CESD-10 score than control. CONCLUSIONS: A single-session brief ED-based intervention focused on alcohol use and violence also reduces depressive symptoms among at-risk youth. Findings also point to the potential efficacy of using technology in future depression interventions. PMID- 28622816 TI - The association between posttraumatic stress symptoms, depression, and length of hospital stay following traumatic injury. AB - OBJECTIVE: The present study examined the relationship between posttraumatic stress symptoms (PTSS) and depression symptoms with hospital outcome measures to explore how psychiatric factors relate to hospital length of stay (LOS). METHOD: Participants were adults admitted to a large Level I Trauma Center for longer than 24h. Depression was assessed at hospitalization using the Patient Health Questionnaire (PHQ-8), and PTSS was measured by the Primary Care PTSD Screen (PC PTSD). Hospital outcome information was collected from the hospital's trauma registry. Pearson correlations were performed. RESULTS: 460 participants (mean age=44years, SD=16.8; 65.4% male) completed the study. Baseline PTSS and depression were significantly correlated with longer hospital LOS while controlling for demographics and injury severity (p=0.026; p=0.023). Both PTSS positive and depression-positive groups had an average increased hospital LOS of two days. CONCLUSIONS: A significant proportion of individuals who are admitted to the hospital following trauma may be at risk for depression and PTSS, which may then increase hospital LOS. As national attention turns to reducing healthcare costs, early screenings and interventions may aid in minimizing psychiatric symptoms in trauma patients, in turn reducing the cost and outcomes associated with total hospital LOS. PMID- 28622817 TI - Prevalence and risk factors for postoperative delirium in total joint arthroplasty patients: A prospective study. AB - BACKGROUND: The aim of this prospective study was to investigate the incidence and clinical features of delirium after total joint arthroplasty, and to establish the potential risk factors for postoperative delirium. METHODS: A total of 212 consecutive patients undergoing hip or knee arthroplasty, who met the inclusion and exclusive criteria were enrolled. The general characteristics, preoperative and postoperative hematological variables were documented respectively. According to the presence of delirium, all patients were divided into the delirium group and non-delirium group. Univariate and multivariate logistic regression were performed to identify the possible predictors for postoperative delirium. RESULTS: At a minimum of 6months of follow-up, 35 patients were observed with postoperative delirium at an estimated total incidence of 16.5%. The incidence of delirium was statistically higher in hip arthroplasty (22.8%) than that in knee arthroplasty (7.1%). The multivariate regression analysis identified older age (OR=1.590, P=0.023), a history of stroke (OR=190.23, P=0.036), preoperative PaO2 (OR=1.277, P=0.018) and equivalent fentanyl dose (OR=1.010, P=0.012) as the predictive factors for postoperative delirium after total joint arthroplasty. CONCLUSIONS: The incidence of postoperative delirium after total joint arthroplasty is higher than expected. Based on our findings, we suggest that the surgeons should focus on those patients who have these risk factors and ensure the appropriate management to avoid postoperative delirium. PMID- 28622818 TI - Use of a smartphone application to screen for depression and suicide in South Korea. AB - OBJECTIVE: This is a cross-sectional study using a free depression and suicide screening smartphone application, which contains the data from the Center for Epidemiological Studies-Depression (CES-D) and a Suicide Behaviors Questionnaire Revised (SBQ-R). METHOD: The free application was downloaded worldwide from Apple's App Store and Android Market, and the participants who downloaded the application were actively measured. RESULTS: The subjects totaled 208,683 men and women. 72.6% of the subjects were females, and 81.4% of the subjects were aged between 10 and 29years. In total, 25.7% of the participants were recorded CES-D positive, and there were differences among the groups based on sex (chi2=1065.82, p<0.001), age (chi2=1420.75, p<0.001), and psychiatric history (chi2=1502.21, p<0.001). The highest score of CES-D, 40.69+/-15.79 and that of SBQ-R, 13.68+/ 4.97 was reported by the participants with a history of schizophrenia. The characteristics associated with suicide were as follows: depression (OR 8.92, 95% CI: 8.71-9.13), female (OR 1.39, 95% CI: 1.36-1.43), 30-49 age group (OR 2.51, 95% CI: 2.29-2.72), 50 or older age group (OR 1.48, 95% CI: 1.35-1.61), and psychiatric history (OR 1.98, 95% CI: 1.89-2.06). CONCLUSION: The smartphone application may be a useful tool for screening depression and suicide. PMID- 28622819 TI - Systematic and organizational issues implicated in post-hospitalization suicides of medically hospitalized patients: A study of root-cause analysis reports. AB - OBJECTIVE: Medical hospitalization is a high risk period for suicide. It is important to understand system-level factors that may be associated with suicide after a medical hospitalization. METHOD: Retrospective study of root-cause analysis (RCA) reports of suicide occurring within three months of Veterans Administration (VA) medical hospitalization, 2002-2015. We collected patient and system-level factors to characterize events. RESULTS: There were 96 RCA reports pertaining to suicide within three months of medical hospitalization. A total of 168 root causes for suicide were identified and fell into three major themes including: management of known suicide risk (N=73, 43%), decision making to monitor suicide risk (N=48, 29%), and patient engagement in treatment (N=47, 28%). RCA reports raised concerns that medical teams did not provide mental health treatment when indicated and lacked a standardized process for assessing psychological well-being in patients with a serious medical illness. In 25 cases, patients declined recommended treatment and in 15 cases, patients left against medical advice (AMA). CONCLUSIONS: Challenges with patient engagement in treatment and lack of standardized processes for assessing and managing suicide risk may play an important role in suicide risk after medical hospitalization. Additional high quality studies are needed to confirm our findings. PMID- 28622820 TI - Diabetes quality of care and outcomes: Comparison of individuals with and without schizophrenia. AB - OBJECTIVE: Individuals with schizophrenia are more likely to develop diabetes than individuals without schizophrenia. The objective of this study was to determine the quality of diabetes care and diabetes-related health outcomes among individuals with and without schizophrenia. METHOD: We conducted a retrospective cohort study. As of April 1, 2011, we identified all individuals with diabetes in Ontario with and without a diagnosis of schizophrenia. The main outcomes were quality of diabetes care (guideline-concordant testing for HbA1c, lipid testing, eye exams) and diabetes-related Emergency Department (ED) visits and hospitalizations between April 1, 2011 and March 31, 2013. We compared quality of care and diabetes outcomes among those with and without schizophrenia, adjusting for demographic, illness severity, and health service utilization variables. RESULTS: We identified 1,131,375 individuals with diabetes, among whom 25,628 (2.3%) had schizophrenia. Schizophrenia was associated with reduced likelihood of optimal diabetes care (all 3 of HbA1c, lipid testing, and eye exams) (adjusted OR (95% CI): 0.64 (0.61-0.67)) and increased likelihood of diabetes-related ED visits (adjusted OR (95% CI): 1.34 (1.28-1.41)) and hospitalizations (adjusted OR (95% CI): 1.36 (1.28-1.43)). CONCLUSION: Individuals with diabetes and schizophrenia have lower rates of recommended testing and higher rates of diabetes-related hospital visits than those with diabetes but without schizophrenia. Research is needed to understand patient, provider, and system factors underlying these disparities and test related interventions to close the gaps in quality of care. PMID- 28622821 TI - The therapeutic discharge: An approach to dealing with deceptive patients. AB - OBJECTIVE: Patients with factitious disorder or malingering behaviors pose particular problems in acute care settings. We sought to describe a manner to effectively discharge these patients and keep further harm, iatrogenic or otherwise, from being inflicted. METHOD: Once an indication has been identified, the therapeutic discharge can be carried out in a stepwise fashion, resulting in a safe discharge. We outlined how to prepare for, and execute, the therapeutic discharge, along with preemptive consideration of complications that may arise. RESULTS: Consequences for the patient, physicians, and larger healthcare system are considered. CONCLUSION: The therapeutic discharge is a safe and effective procedure for patients with deception syndromes in acute care settings. Carrying it out is a necessary element of psychiatric residency and psychosomatic medicine fellowship training. PMID- 28622822 TI - The high price of depression: Family members' health conditions and health care costs. AB - OBJECTIVE: To compare the health conditions and health care costs of family members of patients diagnosed with a Major Depressive Disorder (MDD) to family members of patients without an MDD diagnosis. METHODS: Using electronic health record data, we identified family members (n=201,914) of adult index patients (n=92,399) diagnosed with MDD between 2009 and 2014 and family members (n=187,011) of matched patients without MDD. Diagnoses, health care utilization and costs were extracted for each family member. Logistic regression and multivariate models were used to compare diagnosed health conditions, health services cost, and utilization of MDD and non-MDD family members. Analyses covered the 5years before and after the index patient's MDD diagnosis. RESULTS: MDD family members were more likely than non-MDD family members to be diagnosed with mood disorders, anxiety, substance use disorder, and numerous other conditions. MDD family members had higher health care costs than non-MDD family members in every period analyzed, with the highest difference being in the year before the index patient's MDD diagnosis. CONCLUSIONS: Family members of patients with MDD are more likely to have a number of health conditions compared to non MDD family members, and to have higher health care cost and utilization. PMID- 28622823 TI - Does behavioral health integration improve primary care providers' perceptions of health-care system functioning and their own knowledge? AB - OBJECTIVE: To examine the impact of behavioral health integration (BHI) on primary care providers' (PCPs') (1) perceptions of behavioral health (BH)-primary care (PC) system functioning and (2) perceptions of their own knowledge regarding how to manage, triage, and access help in caring for patients with mental health conditions and substance use disorders. METHODS: We implemented BHI based on evidence-based models consisting of seven elements: (1)Screening for mental health and substance use disorders, (2)Training of PC teams, (3)Integration of BH providers into PC teams, (4)Roll-out of unlicensed mental health care managers and establishment of a BH registry, (5)Psychiatry consult service, (6)Site-based BHI meetings, and (7)Site self assessments. The intervention was rolled out in early integration sites during two years and late integration sites during the subsequent two years. In this observational pre-post study, we administered an anonymous online survey annually to PCPs; 381 PCPs at 11 primary care clinics participated. RESULTS: The proportion of PCPs with high perceived BH-PC systems functioning scores quadrupled from 14% to 55% (p<0.0001) and high perceived knowledge scores increased from 63 to 85% (p<0.001). Larger increases were demonstrated in early integration sites during the first two years and in late integration sites during the latter two years of the survey. Adjusting for participant and site level characteristics did not change these outcomes. CONCLUSIONS: BHI improves PCP perceptions of BH-PC system functioning and perceptions of knowledge. PMID- 28622824 TI - Toxicological assessment of nano and micron-sized tungsten oxide after 28days repeated oral administration to Wistar rats. AB - Tungsten oxide (WO3) nanoparticles (NPs) are being used in various applications. However, the health consequences of WO3 NPs exposure have not been explored extensively. Hence, the goal of this study was to evaluate the toxicity of WO3 NPs and their microparticles (MPs) after 28days repeated oral administration in Wistar rats. The particles were characterised by transmission electron microscopy (TEM), dynamic light scattering (DLS), laser Doppler velocimetry (LDV), Brunner Emmett-Teller (BET), X- ray diffraction (XRD), and inductively coupled plasma optical emission spectrometer (ICP-OES). Genotoxicity was determined using comet assay in blood and liver and micronucleus test in bone marrow. Biochemical parameters such as aspartate aminotransferase and alanine aminotransferase in serum and reduced glutathione content, catalase and lipid peroxidation in liver tissue were determined. Histopathological changes in tissues were documented. Biodistribution of tungsten (W) in rat's blood, urine, feces and tissues were analysed. The mean size of WO3 NPs and MPs by TEM was 52+/-2.97nm, and 5.73+/ 7.58MUm and morphology were spherical in both the particles. DLS of NPs was 195.6nm. XRD and BET data of WO3 NPs and MPs showed a hexagonal and tetragonal crystal structure and surface area of 19.33 and 15.15(m2/g), respectively. The results revealed a significant increase in DNA damage and micronuclei, a difference in biochemical levels and histopathological alterations after exposure to 1000mg/kg dose of WO3 NPs. W biodistribution was detected in all the tissues in a dose and organ-dependent manner in both the particles. The highest amount of W was found in the liver and lowest in the brain of the treated rats. The tested NPs were found to have little toxicity hazard. PMID- 28622825 TI - Mutagenicity of omega-3 fatty acid peroxidation products in the Ames test. AB - Polyunsaturated fatty acids (PUFA) represent one of the main building blocks of cellular membranes and their varying composition impacts lifespan as well as susceptibility to cancer and other degenerative diseases. Increased intake of omega-3 PUFA is taught to compensate for the abundance of omega-6 PUFA in modern human diet and prevent cardiocirculatory diseases. However, highly unsaturated PUFA of marine and seed origin easily oxidize to aldehydic products which form DNA adducts. With increased PUFA consumption it is prudent to re-evaluate omega-3 PUFA safety and the genotoxic hazards of their metabolites. We have used the standard Ames test to examine the mutagenicity of 2 hexenals derived from lipid peroxidation of the common omega-3 PUFA in human diet and tissues. Both 4 hydroxyhexenal and 2-hexenal derived from the omega-3 docosahexaenoic and alpha linolenic acid, respectively, induced base substitutions in the TA104 and TA100 Ames strains in a dose dependent manner. Their mutagenicity was dependent on the Y-family DNA polymerase RI and they did not induce other types of mutations such as the -2 and -1 frameshifts in the TA98 and TA97 strains. Our results expand previous findings about the mutagenicity of related omega-3 peroxidation product 4-oxohexenal and raise alert that overuse of omega-3 rich oils may have adverse effect on genome stability. PMID- 28622826 TI - GSTP1 and XRCC1 polymorphisms and DNA damage in agricultural workers exposed to pesticides. AB - Pesticide exposure may be associated with increased risk of genotoxicity and carcinogenesis. These risks may be affected by polymorphisms of genes for glutathione transferase-dependent metabolism of pesticides and for DNA repair. We studied the prevalence of GSTP1 and XRCC1 polymorphisms and their possible correlation with DNA damage following prolonged pesticide exposure. DNA damage was estimated by the comet assay in peripheral blood samples from 51 pesticide exposed workers and 50 controls. GSTP1 (105) and XRCC1 (399 and 194) genotypes were identified by restriction fragment length analysis. Individuals carrying theGSTP1 Ile-Ile or XRCC1399 Arg-Arg genotypes showed greater DNA damage than observed for other alleles. PMID- 28622827 TI - Copaifera multijuga oleoresin and its constituent diterpene (-)-copalic acid: Genotoxicity and chemoprevention study. AB - Copaiba oleoresins are used in alternative medicine as anti-inflammatory, antitumoral, and antimicrobial treatments. (-)-Copalic acid (CA) is the major diterpene found in exudates from Copaifera species. We have examined the genotoxicity and the chemopreventive potential of Copaifera multijuga oleoresin (CM) and CA. Genotoxicity assessment was examined with the peripheral blood micronucleus test and the comet assay (male Swiss mouse hepatocytes). In the chemoprevention study, we evaluated the effects of CM and CA on the formation of 1,2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) in male Wistar rat colon. Neither agent caused a significant increase in micronucleus frequency relative to controls, but the highest CM dose tested (400mg/kg b.w.) caused DNA damage in the comet assay. Both agents significantly reduced the frequency of DMH induced ACF. Both CM and CA suppressed ACF formation and may have a protective effect against colon carcinogenesis. PMID- 28622828 TI - The index of ideality of correlation: A criterion of predictive potential of QSPR/QSAR models? AB - The index of ideality of correlation (IIC) is a new criterion of the predictive potential of quantitative structure-property/activity relationships (QSPRs/QSARs). This IIC is calculated with using of the correlation coefficient between experimental and calculated values of endpoint for the calibration set, with taking into account the positive and negative dispersions between experimental and calculated values. The mutagenicity is well-known important characteristic of substances from ecological point of view. Consequently, the estimation of the IIC for mutagenicity is well motivated. It is confirmed that the utilization of this criterion significantly improves the predictive potential of QSAR models of mutagenicity. The new criterion can be used for other endpoints. PMID- 28622829 TI - Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea. AB - Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. PMID- 28622830 TI - Corrigendum to "Involvement of autophagy in connexin 40 reduction in the late phase of traumatic brain injury in rats" [Brain Res. Bull. 131 (2017) 100-106]. PMID- 28622831 TI - Impact of Postoperative Radiotherapy in Men with Persistently Elevated Prostate specific Antigen After Radical Prostatectomy for Prostate Cancer: A Long-term Survival Analysis. AB - BACKGROUND: Prostate cancer (PCa) patients with prostate-specific antigen (PSA) persistence after radical prostatectomy (RP) are at increased risk of mortality, although the natural history of these men is heterogeneous and the optimal management has not been established. OBJECTIVE: To develop a model to predict cancer-specific mortality (CSM) and to test the impact of radiotherapy (RT) on survival in this setting. DESIGN, SETTING, AND PARTICIPANTS: We identified 496 patients treated with RP and lymph node dissection at two referral centers between 1994 and 2014 who had PSA persistence, defined as a PSA level between 0.1 and 2 ng/ml at 6-8 wk after RP. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: A multivariable model predicting CSM was developed. We assessed whether the impact of postoperative PSA levels on survival differed according to baseline CSM risk. The nonparametric curve fitting method was then used to explore the relationship between baseline CSM risk and 10-yr CSM rates according to postoperative RT. RESULTS AND LIMITATIONS: Median follow-up for survivors was 110 mo. Overall, 49 patients experienced CSM. The 10-yr CSM-free survival was 88%. Pathologic grade group and pathologic stage were independent predictors of CSM (all p=0.01). The association between CSM-free survival and PSA at 6-8 wk differed by the baseline CSM risk, whereby the effect of increasing PSA was evident only in patients with a CSM risk of >=10%. Postoperative RT was beneficial when the predicted risk of CSM was >=30% (p=0.001 by an interaction test). Our study is limited by its retrospective design. CONCLUSIONS: Increasing PSA levels should be considered as predictors of mortality exclusively in men with worse pathologic characteristics. Postoperative RT in this setting was associated with a survival benefit in patients with a CSM risk of >=30%. Conversely, individuals with a CSM risk of <30% should be initially managed expectantly. PATIENT SUMMARY: Not all patients with prostate-specific antigen persistence have a poor prognosis. Pathologic characteristics should be used to estimate the risk of cancer-specific mortality in these individuals and to identify patients who could benefit from postoperative radiotherapy. PMID- 28622832 TI - Management of war-related vascular wounds in French role 3 hospital during the Afghan campaign. AB - OBJECTIVES: To describe the management of war-related vascular injuries in the Kabul French military hospital. METHODS: From January 2009 to April 2013, in the Kabul French military hospital, we prospectively included all patients presenting with war-related vascular injuries. We collected the following data: site, type, and mechanism of vascular injury, associated trauma, type of vascular repair, amputation rate and complications. RESULTS: Out of the 922 soldiers admitted for emergency surgical care, we recorded 45 (5%) patients presenting with vascular injuries: 30 (67%) gunshot-related, 11 (24%) explosive device-related, and 4 (9%) due to road traffic accident. The majority of injuries (93%) involved limbs. Vascular injuries were associated with fractures in 71% of cases. Twelve (26.7%) had an early amputation performed before evacuation. Twenty (44.4%) patients underwent fasciotomy and three (6.6%) sustained a compartment syndrome. CONCLUSIONS: This was the first French reported series of war-related vascular injuries during the last decade's major conflicts. The majority of injuries occurred in the limbs. Autologous vein graft remains the treatment of choice for arterial repair. Functional severity of these injuries justifies specific training for military surgeons. PMID- 28622833 TI - Biomechanical evaluation of the tension band wiring principle. A comparison between two different techniques for transverse patella fracture fixation. AB - PURPOSE: The aim of this study was to investigate the validity of the dynamic compression principle of tension band wiring in two techniques for patella fracture treatment. METHODS: Twelve human cadaveric knees with simulated transverse patella fractures were assigned to two groups for treatment with tension band wiring using either Kirschner (K-) wires or cannulated screws. Biomechanical testing was performed over three knee movement cycles between 90 degrees flexion and 0 degrees full extension. Pressure distribution in the fracture gap and fracture site displacement were evaluated at the 3rd cycle in 15 degrees steps, namely 90 degrees -75 degrees -60 degrees -45 degrees -30 degrees -15 degrees -0 degrees extension phase and 0 degrees -15 degrees -30 degrees -45 degrees -60 degrees -75 degrees -90 degrees flexion phase. RESULTS: Mean anterior / posterior interfragmentary pressure in the groups with K-wires and cannulated screws ranged within 0.16-0.40MPa / 0.12-0.35MPa and 0.37-0.59MPa / 0.10-0.30MPa, respectively. These changes remained non-significant for both groups and loading phases (P>=0.171). Mean anterior / posterior fracture site displacement for K-wires and cannulated screws ranged within -0.01-0.53mm / 0.11 0.74mm and 0.11-0.55mm / -0.10-0.50mm, respectively. Anterior displacement remained without significant changes for both groups and loading phases (P>=0.112). However, posterior displacement underwent a significant increase in the course of knee extension for K-wires (P<=0.047), but not for cannulated screws (P>=0.202). Significantly smaller displacement at the posterior fracture site was detected in the group with cannulated screws compared to K-wires at 60 degrees and 75 degrees extension phase (P<=0.017), as well as at 45 degrees , 60 degrees and 75 degrees flexion phase (P<=0.018). The critical value of 2mm displacement at the posterior fracture site was not reached for any specimen and fixation technique. Knee extension was accompanied by synchronous increase in quadriceps pulling force. CONCLUSIONS: Tension band wiring fulfills from a biomechanical perspective the requirements for sufficient stability of transverse patella fracture fixation. It should, however, rather be considered as a static fixation principle than a dynamic one. Tension band wiring with cannulated screws was found advantageous over Kirschner wires in terms of interfragmentary movements at the posterior fracture site. PMID- 28622834 TI - Morbid obesity and functional status as predictors of surgical complication after renal transplantation. AB - BACKGROUND: This study evaluated the impact of body mass index (BMI) and patient functional status on the risk for surgical complications after kidney transplant. METHODS: This retrospective cohort study of adult kidney transplant recipients grouped patients by baseline Karnofsky status (low function <= 70%) and further stratified by morbid obesity (BMI >= 35 kg/m2) to assess surgical complication risk. RESULTS: 736 patients were included with surgical complications occurring in 25%. Logistic regression analysis with interaction terms demonstrated that morbid obesity and low functional status conditionally impact risk with an OR of 2.8 [95% CI (1.1-7.3)]. Within the functional status cohort, BMI >=35 kg/m2 was associated with increased risk of surgical complication, superficial wound infection, and DGF. Independent predictors for surgical complications included diabetes and morbid obesity with low functional status. There was no significant difference in graft loss or death across the cohorts. CONCLUSIONS: While neither morbid obesity nor poor functional status alone predicts increased complications, the combined presence is associated with significant increase in risk for surgical complications after renal transplantation. PMID- 28622835 TI - Percutaneous drainage for giant pyogenic liver abscess-does size matter? PMID- 28622836 TI - Safety assessment of the use of ultrasonic energy in the proximity of the recurrent laryngeal nerve in a porcine model. AB - BACKGROUND: Advanced bipolar and ultrasonic energy have demonstrated reduction of operating time and blood loss in thyroidectomy. However, these devices generate heat and thermal dispersion that may damage adjacent structures such as the recurrent laryngeal nerve (RLN). This study was designed to evaluate the safety profile of the Harmonic Focus+(r) (HF+) device through the evaluation of thermal injury to the RLN using different algorithms of distance and time with state of the art technology. METHODS: 25 Vietnamese pigs underwent activation of HF+ in the proximity of their RLN. They were divided into 4 groups according to activation distance (3 mm, 2 mm, 1 mm and on the RLN). Time of activation, time between tones of the ultrasonic generator, changes in the electromyographic signal using continuous nerve neuromonitoring, vocal fold mobility assessed by direct laryngoscopy and histological thermal damaged were evaluated. RESULTS: None of the pigs had loss of signal in the electromyography during the procedure; only one pig had isolated transient decrease in amplitude and one increase in latency. One pig had transient vocal fold paresis in the group with activation on the nerve. Evaluation of the nerves by histology and immunohistochemistry did not show significant changes attributed to thermal injury. CONCLUSIONS: The use of ultrasonic energy close to the RLN is safe, provided that activation time does not exceed the necessary time to safely transect the tissue. PMID- 28622837 TI - Risk assessment of the blunt trauma victim: The role of the quick Sequential Organ Failure Assessment Score (qSOFA). AB - BACKGROUND: A number or risk assessment tools are used in trauma victims. Because of its simplicity, we examined the ability of the recently described quick Sequential Organ Failure Assessment Score (qSOFA) to predict outcomes in blunt trauma patients presenting to the Emergency Department. METHODS: We queried the trauma registry at a Level 1 Trauma Center for all adult blunt trauma admissions between 1/1/10 and 9/30/15. qSOFA scores were the sum of binary scores for 3 variables (RR >= 22, SBP<=100 mmHg, and GCS<=13). RESULTS: There were 7064 admissions (5664 admissions had qSOFA = 0, 1164 had qSOFA = 1, 223 had qSOFA = 2, and 13 had qSOFA = 3). Higher qSOFA scores were associated with greater injury severity, increased ICU admission, and higher complication rates. qSOFA scores were associated with in-hospital mortality (1.7% with qSOFA = 0; 8.7% with qSOFA = 1; 22.4% with qSOFA = 2; 23.1% with qSOFA = 3; p < 0.001). On multivariate analysis, qSOFA score was an independent predictor of mortality. CONCLUSIONS: qSOFA scores are directly associated with adverse outcomes in blunt trauma victims. PMID- 28622838 TI - Do patients requiring a multivisceral resection for rectal cancer have worse oncologic outcomes than patients undergoing only abdominoperineal resection? AB - INTRODUCTION: Abdominoperineal Resection (APR) remains an important option for patients with advanced rectal cancer though some may require multivisceral resection (MVR) in addition to APR. We hypothesized that oncological outcomes would be worse with MVR. METHODS: A retrospective review from 2006 to 2015 of 161 patients undergoing APR or MVR for rectal cancer, of whom 118 underwent curative APR or APR with MVR. Perioperative, oncologic and survival metrics were evaluated. RESULTS: There were 82 patients who underwent APR and 36 who underwent MVR. Surgical approach and incidence of complications were similar (All P > 0.05). There was 1 local recurrence in each of the APR and MVR groups at a mean follow-up of 34 and 32 months, respectively. Distant recurrences occurred in 3 APR patients and 4 MVR patients. CONCLUSIONS: APR and APR with MVR can be performed with comparable morbidity and oncologic outcomes. PMID- 28622840 TI - Systematic review of randomized controlled trials on the role of coaching in surgery to improve learner outcomes. AB - BACKGROUND: Surgical coaching, with the goal of improving operative performance, has been introduced into residency and fellowship programs. This is the first systematic review on surgical coaching limited to randomized controlled trials. The objective of this review is to synthesize the existing evidence that addresses the following question: "What are the effects of surgical coaching to improve learner outcomes?" METHODS: A comprehensive literature search was performed through the following databases: MEDLINE, EMBASE, ERIC, and Cochrane Central Register of Controlled Trials. The methodological quality of the selected randomized controlled trials was evaluated using the Cochrane Collaboration tool for assessing risk of bias. RESULTS: Five randomized controlled trials were included in our final analysis. All five RCTs showed improvement in technical surgical performance after coaching. Two studies provided further evidence that skills were retained and one described the high satisfaction of learners. The risk of bias was low in 3 trials. CONCLUSIONS: Surgical coaching is associated with high learner satisfaction and improvements of skills and knowledge. The current evidence for surgical coaching programs is overwhelmingly positive. PMID- 28622839 TI - Water lavage as an adjunct to cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). AB - BACKGROUND: Water lavage (WL) during gastrointestinal cancer surgery has osmotically mediated lytic effects on tumor cells. We investigated the safety and efficacy of WL with CRS-HIPEC. METHODS: This is a retrospective review, 1/2003 7/2014, of a single institution experience with CRS-HIPEC comparing patients who had WL (WL+) to those who did not (WL-). RESULTS: Of 157 CRS-HIPECs, 16 (10.2%) were WL+. WL+ had more PCI scores >20 compared to WL- (56.3% vs 19.4%, respectively, p = 0.003); however, the completeness of cytoreduction (CC) was similar. There were no differences in hospital length of stay or post-operative complications. The average POD 1 sodium (Na) level was statistically lower in the WL+ group (133.6 +/- 2.5 vs 135.5 +/- 3.2 mEq/L, p = 0.023); however, the average Na at discharge for each group was 140 mEq/L. There were no differences in 3-year OS (3WL+:0.63 vs WL-:0.68, p = 0.97) or RFS (WL+:0.32 vs WL-:0.39, p = 0.47). A subset analysis for patients with PCI >20 showed no difference between groups. CONCLUSIONS: WL offers a low cost, safe and theoretically efficacious method of tumor cell lysis for peritoneal malignancy. PMID- 28622841 TI - Do online prognostication tools represent a valid alternative to genomic profiling in the context of adjuvant treatment of early breast cancer? A systematic review of the literature. AB - INTRODUCTION: Decision-making regarding adjuvant chemotherapy has been based on clinical and pathological features. However, such decisions are seldom consistent. Web-based predictive models have been developed using data from cancer registries to help determine the need for adjuvant therapy. More recently, with the recognition of the heterogenous nature of breast cancer, genomic assays have been developed to aid in the therapeutic decision-making. METHODS: We have carried out a comprehensive literature review regarding online prognostication tools and genomic assays to assess whether online tools could be used as valid alternatives to genomic profiling in decision-making regarding adjuvant therapy in early breast cancer. RESULTS AND CONCLUSIONS: Breast cancer has been recently recognized as a heterogenous disease based on variations in molecular characteristics. Online tools are valuable in guiding adjuvant treatment, especially in resource constrained countries. However, in the era of personalized therapy, molecular profiling appears to be superior in predicting clinical outcome and guiding therapy. PMID- 28622842 TI - Two-stage knee arthrodesis with a modular intramedullary nail due to septic failure of revision total knee arthroplasty with extensor mechanism deficiency. AB - BACKGROUND: Periprosthetic joint infection is a serious complication and reconstruction after failed revision total knee arthroplasty with significant bone loss and compromised soft-tissues can be challenging. Objective of this study was to assess clinical and functional results, implant survival and infection recurrence rates in patients treated with two-stage arthrodesis after failed revision TKA with extensor mechanism deficiencies due to PJI, and to identify the factors that affect outcomes after surgery. METHODS: Thirty seven patients with PJI treated within a two-stage exchange and reimplantation of an arthrodesis nail between 2008 and 2014 were included. Systemic and local risk factors were graded preoperatively according to McPherson et al. All patients were treated according to a structured treatment algorithm. Clinical and functional evaluation was performed using the Oxford Knee Score and the Visual Analogue Scale. RESULTS: Thirty two of 37 patients (86.5%) were graded as free of infection. Five patients (13.5%) had recurrent infection after arthrodesis with the need of revision surgery. Mean leg-length discrepancy was 2.2cm. The mean VAS for pain was three, the mean Oxford Knee Score was 38+/-9. Total implant survival at a 74month follow-up was 74.3% (95% CI: 45.4 to 91.1%), as determined by Kaplan Meier survival curves. Local McPherson Score, as well as number of revisions was found to be of significant influence to the survival rate. CONCLUSIONS: Septic failure of revision knee arthroplasty can be effectively treated with two-stage arthrodesis using a modular intramedullary nail, providing a stable and painless limb with satisfactory functional results and acceptable infection eradication rates. PMID- 28622843 TI - Fatal pulmonary embolism following elective total knee replacement using aspirin in multi-modal prophylaxis - A 12year study. AB - BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) has issued guidelines on which thromboprophylaxis regimens are suitable following lower limb arthroplasty. Aspirin is not a recommended agent despite being accepted in orthopaedic guidelines elsewhere. We assessed the incidence of fatal pulmonary embolism (PE) and all-cause mortality following elective primary total knee replacement (TKR) with a standardised multi-modal prophylaxis regime in a large teaching district general hospital. METHODS: We utilised a prospective audit database to identify those that had died within 42 and 90days postoperatively. Data from April 2000 to 2012 were analysed for 42 and 90day mortality rates. There were a total of 8277 elective primary TKR performed over the 12year period. The multi-modal prophylaxis regimen used unless contraindicated for all patients included 75mg aspirin once daily for four weeks. Case note review ascertained the causes of death. Where a patient had been referred to the coroner, they were contacted for post mortem results. RESULTS: The mortality rates at 42 and 90days were 0.36 and 0.46%. There was one fatal PE within 42days of surgery (0.01%) who was taking enoxaparin because of aspirin intolerance. Two fatal PE's occurred at 48 and 57days post-operatively (0.02%). The leading cause of death was myocardial infarction (0.13%). CONCLUSIONS: Fatal PE following elective TKR with a multi-modal prophylaxis regime is a very rare cause of mortality. PMID- 28622845 TI - Black Truffle, a Hermaphrodite with Forced Unisexual Behaviour. AB - The life cycle of the black truffle (Tuber melanosporum) includes a mating before sporulation: although the species is hermaphroditic, mating turns out to involve parents with very different features, that mostly behave as male or female only, suggesting that this species undergoes forced dioecism. PMID- 28622844 TI - Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery. AB - Bacteria are capable of performing a number of biotransformations that may activate or deactivate xenobiotics. Recent efforts have utilized metabolomics techniques to study the fate of small-molecule antibacterials within the targeted organism. Examples involving Mycobacterium tuberculosis are reviewed and analyzed with regard to the insights they provide as to both activation and deactivation of the antibacterial. The studies, in particular, shed light on biosynthetic transformations performed by M. tuberculosis while suggesting avenues for the evolution of chemical tools, highlighting potential areas for drug discovery, and mechanisms of approved drugs. A two-pronged approach investigating the metabolism of antibacterials within both the host and bacterium is outlined and will be of value to both the chemical biology and drug discovery fields. PMID- 28622846 TI - Comparison between resident and caged mussels: Polycyclic aromatic hydrocarbon accumulation and biological response. AB - The aim of this study was to compare the capability of "passive" and "active" biomonitoring to determine the environmental pressure. For this purpose, PAHs content and several biological responses in resident and caged mussels (Mytilus galloprovincialis) at five sampling sites (Rijeka Bay, Adriatic Sea) were analsed. Resident mussels were found better in reflecting the level of PAH loads at particular sites while only caged mussels could detect input of HMW PAHs. When data of each investigated parameter were compared separately, the majority of differences between resident and caged mussels' results were site-specific. Integration of biological response patterns expressed as Index of Biological Response (IBR) resulted with different sampling sites ranking for resident and caged mussels. Multiple Factor Analysis (MFA) based on integration of tissue PAH concentration and biological response revealed resident mussels as more powerful for detection of environmental pressure. The use of resident mussels is recommended as appropriate and less costly approach for monitoring the effect of pollution. PMID- 28622847 TI - Historic scale and persistence of drill cuttings impacts on North Sea benthos. AB - Despite its long history of hydrocarbon exploitation, the United Kingdom lacks scientific protocols to monitor ecological impacts of drill cuttings (mixtures between rocky material excavated from wells and drilling mud). The present study used the UK Benthos industry database to apply standardised variance partitioning and measure the scale and persistence of these effects at 19 sites across the UK sector of the North Sea. Generally, effects were limited to within 1 km from the platform, but two platforms historically drilled with oil-based mud were impacted up to 1.2 km away. Impacts persisted for at least 6-8 years in the northern and central North Sea, but were undetectable in the south where cuttings piles do not accumulate. This study underpins new recommendations to implement regional, phase based approaches to drill cuttings monitoring, and to apply a precautionary approach in considering decommissioning options that will minimise disturbance to cuttings piles. PMID- 28622848 TI - Average male and female virtual dummy model (BioRID and EvaRID) simulations with two seat concepts in the Euro NCAP low severity rear impact test configuration. AB - Soft tissue neck injuries, also referred to as whiplash injuries, which can lead to long term suffering accounts for more than 60% of the cost of all injuries leading to permanent medical impairment for the insurance companies, with respect to injuries sustained in vehicle crashes. These injuries are sustained in all impact directions, however they are most common in rear impacts. Injury statistics have since the mid-1960s consistently shown that females are subject to a higher risk of sustaining this type of injury than males, on average twice the risk of injury. Furthermore, some recently developed anti-whiplash systems have revealed they provide less protection for females than males. The protection of both males and females should be addresses equally when designing and evaluating vehicle safety systems to ensure maximum safety for everyone. This is currently not the case. The norm for crash test dummies representing humans in crash test laboratories is an average male. The female part of the population is not represented in tests performed by consumer information organisations such as NCAP or in regulatory tests due to the absence of a physical dummy representing an average female. Recently, the world first virtual model of an average female crash test dummy was developed. In this study, simulations were run with both this model and an average male dummy model, seated in a simplified model of a vehicle seat. The results of the simulations were compared to earlier published results from simulations run in the same test set-up with a vehicle concepts seat. The three crash pulse severities of the Euro NCAP low severity rear impact test were applied. The motion of the neck, head and upper torso were analysed in addition to the accelerations and the Neck Injury Criterion (NIC). Furthermore, the response of the virtual models was compared to the response of volunteers as well as the average male model, to that of the response of a physical dummy model. Simulations with the virtual male and female dummy models revealed differences in dynamic response related to the crash severity, as well as between the two dummies in the two different seat models. For the comparison of the response of the virtual models to the response of the volunteers and the physical dummy model, the peak angular motion of the first thoracic vertebra as found in the volunteer tests and mimicked by the physical dummy were not of the same magnitude in the virtual models. The results of the study highlight the need for an extended test matrix that includes an average female dummy model to evaluate the level of occupant protection different seats provide in vehicle crashes. This would provide developers with an additional tool to ensure that both male and female occupants receive satisfactory protection and promote seat concepts that provide the best possible protection for the whole adult population. This study shows that using the mathematical models available today can provide insights suitable for future testing. PMID- 28622849 TI - The Sampling Brain. PMID- 28622850 TI - Infection of porcine precision cut intestinal slices by transmissible gastroenteritis coronavirus demonstrates the importance of the spike protein for enterotropism of different virus strains. AB - TGEV is a coronavirus that is still widely spread in pig farming. On molecular level this virus has been studied in detail. However, studying TGEV infection within the complexity of the porcine intestinal epithelium reveals difficulties due to limiting infection models. Here we established a new ex vivo model to analyze the enterotropism of TGEV in porcine intestinal tissue. Precision cut intestinal slices (PCIS) were produced and ATP level was measured to proof vitality of the slices. ATP measurements and HE staining revealed living tissue in culture for up to 24h. PCIS were infected with three different TGEV strains. TGEV PUR 46-MAD is a commonly used TGEV strain that is known to be attenuated. TGEV Miller was passaged in piglets several times to reveal high infection. Finally, TGEV GFP is a recombinant strain that obtained its main body from TGEV PUR 46-MAD, but its spike protein from TGEV PUR-C11 that showed high mortality in piglets in vivo. Our results were in complete consensus of these statements. TGEV Miller mildly and TGEV GFP extensively infected the cells in the jejunum based on the amount of positive stained epithelial cells. However, for TGEV PUR 46-MAD no nucleocapsid protein was detected in the epithelial cells of the tissue. This shows that differences in TGEV strains and their infectious potential are highly dependent on their S protein. PMID- 28622851 TI - Prevalence and zoonotic risks of Trichophyton mentagrophytes and Cheyletiella spp. in guinea pigs and rabbits in Dutch pet shops. AB - Young rabbits and guinea pigs are often purchased as pets for children and may be infected with zoonotic skin infections. To assess the risk of acquiring such an infection from rabbits or guinea pigs, this study investigated the prevalence of the fungus Trichophyton mentagrophytes and the fur mite Cheyletiella parasitovorax in asymptomatic rabbits and guinea pigs in Dutch pet shops. In 91 pet shops a total of 213 rabbits and 179 guinea pigs were sampled using the Mackenzie technique and cultured. Clean cultures were examined microscopically and a PCR was performed on at least one sample from each pet shop. All animals were investigated for fur mite using a flea comb, a magnifying glass and white paper. From the fur of 3.8% (8/213) of the rabbits and 16.8% (30/179) of the guinea pigs, T. mentagrophytes was isolated. From 1 guinea pig (0,6%) Chrysosporium keratinophilum was isolated. Dermatophyte-positive rabbits and guinea pigs originated from 5.6% (5/90) and 27.3% (24/88) of the investigated pet shops, respectively. Fur mites were not found. Pet shops can play an important role in preventing transmission of zoonotic ringworm infections (dermatophytosis) and educating their customers. Specific preventive measures such as routine screening examinations and (prophylactic) treatment of rabbits and guinea pigs are recommended next to regular hygiene when handling animals. PMID- 28622852 TI - Efficacy of E2 glycoprotein fused to porcine CD154 as a novel chimeric subunit vaccine to prevent classical swine fever virus vertical transmission in pregnant sows. AB - Here we evaluated the effect of double vaccination with a novel subunit marker vaccine candidate based in the CSFV E2 glycoprotein fused to the porcine CD154 to prevent CSFV vertical transmission. A lentivirus-based gene delivery system was used to obtain a stable recombinant HEK 293 cell line for the expression of E2 fused to porcine CD154 molecule. Six pregnant sows were distributed in two groups and at 64days of gestation animals numbered 1-4 (group 1) were vaccinated via intramuscular inoculation with 50MUg of E2-CD154 subunit vaccine. Animals from group 2 (numbered 5 and 6, control animals) were injected with PBS. Seventeen days later sows from group 1 were boosted with the same vaccine dose. Twenty seven days after the first immunization, the sows were challenged with a virulent CSFV Margarita strain and clinical signs were registered. Samples were collected during the experiment and at necropsy to evaluate immune response and virological protection. Between 14 and 18days after challenge, the sows were euthanized, the foetuses were obtained and samples of sera and tissues were collected. E2-CD154 vaccinated animals remained clinically healthy until the end of the study; also, no adverse reaction was shown after vaccination. An effective boost effect in the neutralizing antibody response after the second immunization and viral challenge was observed and support the virological protection detected in these animals after vaccination. Protection against CSFV vertical transmission was found in the 100% of serums samples from foetus of vaccinated sows. Only two out of 208 samples (0.96%) were positive with Ct value about 36 corresponding to one tonsil and one thymus, which may be non-infective viral particles. Besides, its DIVA potential and protection from vertical transmission, the novel CSFV E2 bound to CD154 subunit vaccine, is a promising alternative to the live-attenuated vaccine for developing countries. PMID- 28622853 TI - Preexisting Salmonella-specific immunity interferes with the subsequent development of immune responses against the Salmonella strains delivering H9N2 hemagglutinin. AB - Recombinant Salmonella strains expressing foreign heterologous antigens have been extensively studied as promising live vaccine delivery vehicles. In this study, we constructed attenuated smooth (S-HA) and rough (R-HA) Salmonella strains expressing hemagglutinin (HA) of H9N2, a low pathogenic avian influenza A virus. We then investigated the HA-specific immune responses following oral immunization with either S-HA or R-HA strain in chicken model. We further examined the effects of the preexisting anti-Salmonella immunity on the subsequent elicitation of the HA and the Salmonella ompA specific immune responses. Our results showed that primary immunization with either the S-HA or the R-HA strain elicited comparable HA-specific immune responses and the responses were significantly (p<0.05) higher compared to the Salmonella vector control. When chickens were pre-immunized with the smooth Salmonella carrier alone and then vaccinated with either S-HA or R-HA strain 3, 6 and 9 weeks later, respectively, significant reductions were seen for HA-specific immune responses at week 6, a point which corresponded to the peak of the primary Salmonella-specific antibody responses. No reductions were seen at week 3 and 9, albeit, the HA-specific immune responses were boosted at week 9, a point which corresponded to the lowest primary Salmonella-specific antibody responses. The ompA recall responses remain refractory at week 3 and 6 following deliberate immunization with the carrier strain, but were significantly (p<0.05) increased at week 9 post-primary immunization. We conclude that preexisting anti Salmonella immunity inhibits antigen-specific immune responses and this effect could be avoided by carefully selecting the time point when carrier-specific immune responses are relatively low. PMID- 28622854 TI - Linear DNA vaccine prepared by large-scale PCR provides protective immunity against H1N1 influenza virus infection in mice. AB - Linear DNA vaccines provide effective vaccination. However, their application is limited by high cost and small scale of the conventional polymerase chain reaction (PCR) generally used to obtain sufficient amounts of DNA effective against epidemic diseases. In this study, a two-step, large-scale PCR was established using a low-cost DNA polymerase, RKOD, expressed in Pichia pastoris. Two linear DNA vaccines encoding influenza H1N1 hemagglutinin (HA) 1, LEC-HA, and PTO-LEC-HA (with phosphorothioate-modified primers), were produced by the two step PCR. Protective effects of the vaccines were evaluated in a mouse model. BALB/c mice were immunized three times with the vaccines or a control DNA fragment. All immunized animals were challenged by intranasal administration of a lethal dose of influenza H1N1 virus 2 weeks after the last immunization. Sera of the immunized animals were tested for the presence of HA-specific antibodies, and the total IFN-gamma responses induced by linear DNA vaccines were measured. The results showed that the DNA vaccines but not the control DNA induced strong antibody and IFN-gamma responses. Additionally, the PTO-LEC-HA vaccine effectively protected the mice against the lethal homologous mouse-adapted virus, with a survival rate of 100% versus 70% in the LEC-HA-vaccinated group, showing that the PTO-LEC-HA vaccine was more effective than LEC-HA. In conclusion, the results indicated that the linear H1N1 HA-coding DNA vaccines induced significant immune responses and protected mice against a lethal virus challenge. Thus, the low-cost, two-step, large-scale PCR can be considered a potential tool for rapid manufacturing of linear DNA vaccines against emerging infectious diseases. PMID- 28622855 TI - B cell cross-epitope of Propionibacterium acnes and Actinobacillus pleuropneumonia selected by phage display library can efficiently protect from Actinobacillus pleuropneumonia infection. AB - Contagious porcine pleuropneumonia (CPP), caused by Actinobacillus pleuropneumoniae (APP), is a highly transmissible and fatal respiratory illness that causes tremendous economic losses for the pig breeding industry worldwide. Propionibacterium acnes (PA) has a strong cross-reaction with anti-APP1 and anti APP5 serum and can efficiently prevent APP infection, which was fortuitously found in researching the differential gene between the different APP serotypes. There seems to be some natural cross-protection between PA and APP. To identify the common epitope, the phage display library of a PA whole genome was constructed, whose size is 105. The DNA sequence of the positive clone was determined after three rounds of biopanning, and ten common protein types were identified and the epitope was predicted by computer software. Six peptide epitopes were selected and synthesized for further analysis. Among these epitopes, Ba1, Bb5 and C1 could bind to anti-PA serum and anti-APP1 serum and vice versa. Furthermore, the IgG and IL-4 levels and CD4+/CD8+ T cell ratios in the Ba1, Bb5 and C1 groups were significantly higher than that in the control group, indicating that the epitopes could trigger an immune response, which was mainly humoral immunity. Moreover, Ba1 and Bb5 equally protected 80% of mice from a fatal dose of APP1 infection compared with the control group. Mice could resist APP1 and APP5 challenge after being treated with the combination of Ba1 and Bb5, with survival rates of 80% and 90%, respectively. These findings suggest that the PA epitope confers antigenicity and can heterologously resist to the APP infection. This finding provides a novel strategy for preventing APP infection. PMID- 28622856 TI - Survey for selected pathogens in wild pigs (Sus scrofa) from Guam, Marianna Islands, USA. AB - Pigs (Sus scrofa) were introduced to Guam in the 1600's and are now present in high densities throughout the island. Wild pigs are reservoirs for pathogens of concern to domestic animals and humans. Exposure to porcine parvovirus, transmissible gastroenteritis, and Leptospira interrogans has been documented in domestic swine but data from wild pigs are lacking. The close proximity of humans, domestic animals, and wild pigs, combined with the liberal hunting of wild pigs, results in frequent opportunities for pathogen transmission. From February-March 2015, blood, tissue and ectoparasite samples were collected from 47 wild pigs. Serologic testing found exposure to Brucella spp. (2%), Toxoplasma gondii (11%), porcine reproductive and respiratory syndrome (PRRS) virus (13%), porcine circovirus type 2 (36%), pseudorabies virus (64%), Actinobacillus pleuropneumoniae (93%), Lawsonia intracellularis (93%), and porcine parvovirus (94%). Eleven (24%) samples had low titers (1:100) to Leptospira interrogans serovars Bratislava (n=6), Icterohaemorrhagiae (n=6), Pomona (n=2), and Hardjo (n=1). Kidney samples from nine pigs with Leptospira antibodies were negative for Leptospira antigens. Numerous pigs had Metastrongylus lungworms and three had Stephanurus dentatus. Lice (Hematopinus suis) and ticks (Amblyomma breviscutatum) were also detected. No antibodies to Influenza A viruses were detected. In contrast to the previous domestic swine survey, we found evidence of numerous pathogens in wild pigs including new reports of pseudorabies virus, PRRS virus, Brucella, and Leptospira in pigs on Guam. These findings highlight that domestic swine-wild pig interactions should be prevented and precautions are needed when handling wild pigs to minimize the risk of pathogen transmission. PMID- 28622857 TI - Streptococcus suis serotype 9 strain GZ0565 contains a type VII secretion system putative substrate EsxA that contributes to bacterial virulence and a vanZ-like gene that confers resistance to teicoplanin and dalbavancin in Streptococcus agalactiae. AB - Streptococcus suis (SS), an important pathogen for pigs, is not only considered as a zoonotic agent for humans, but is also recognized as a major reservoir of antimicrobial resistance contributing to the spread of resistance genes to other pathogenic Streptococcus species. In addition to serotype 2 (SS2), serotype 9 (SS9) is another prevalent serotype isolated from diseased pigs. Although many SS strains have been sequenced, the complete genome of a non-SS2 virulent strain has been unavailable to date. Here, we report the complete genome of GZ0565, a virulent strain of SS9, isolated from a pig with meningitis. Comparative genomic analysis revealed five new putative virulence or antimicrobial resistance associated genes in strain GZ0565 but not in SS2 virulent strains. These five genes encode a putative triacylglycerol lipase, a TipAS antibiotic-recognition domain protein, a putative TetR family transcriptional repressor, a protein containing a LPXTG domain and a G5 domain, and a type VII secretion system (T7SS) putative substrate (EsxA), respectively. Western blot analysis showed that strain GZ0565 can secrete EsxA. We generated an esxA deletion mutant and showed that EsxA contributes to SS virulence in a mouse infection model. Additionally, the antibiotic resistance gene vanZSS was identified and expression of vanZSS conferred resistance to teicoplanin and dalbavancin in Streptococcus agalactiae. We believe this is the first experimental demonstration of the existence of the T7SS putative substrate EsxA and its contribution to bacterial virulence in SS. Together, our results contribute to further understanding of the virulence and antimicrobial resistance characteristics of SS. PMID- 28622858 TI - A novel avian retrovirus associated with lymphocytoma isolated from a local Chinese flock induced significantly reduced growth and immune suppression in SPF chickens. AB - Avian Leukosis Viruses (ALVs) are associated with neoplasias, immune suppression and reduced performance in chicken flocks. In the present study, a naturally occurring recombinant strain of ALV (FJ15HT0) was isolated from an infected flock of Chinese "Hetian" chickens, and was subsequently identified as an exogenous ALV by immuno-fluorescence assay (IFA), PCR and following entire proviral DNA nucleotide sequencing. This isolate is revealed as a novel recombinant virus, lacking viral oncogenes, with the gp85 (93.4%) of subgroup B, the U3 (92.1%) and R (95.2%) region of subgroup J, the U5 (93.8%) region and 5'UTR (95.7%) of subgroup C, as well as the gp37 (90.6%) and 3' (92.2%) of ALV-E. The simulative congenital infection with this isolate in SPF chickens resulted in significant weight loss (P<0.05) and a significant reduction in the humoral immune response to the live NDV vaccine (P<0.05), but not to the inactive AIV-H5 vaccine (P>0.05). Foci of lymphocytomas were observed in tissues of congenitally infected chickens at 11 weeks post-hatch, demonstrating the acute oncogenicity of the isolate. PMID- 28622859 TI - Multilocus sequence analysis reveals extensive genetic variety within Tenacibaculum spp. associated with ulcers in sea-farmed fish in Norway. AB - Skin ulcer development in sea-reared salmonids, commonly associated with Tenacibaculum spp., is a significant fish welfare- and economical problem in Norwegian aquaculture. A collection of 89 Tenacibaculum isolates was subjected to multilocus sequence analysis (MLSA). The isolates were retrieved from outbreaks of clinical disease in farms spread along the Norwegian coast line from seven different fish species over a period of 19 years. MLSA analysis reveals considerable genetic diversity, but allows identification of four main clades. One clade encompasses isolates belonging to the species T. dicentrarchi, whereas three clades encompass bacteria that likely represent novel, as yet undescribed species. The study identified T. maritimum in lumpsucker, T. ovolyticum in halibut, and has extended the host and geographic range for T. soleae, isolated from wrasse. The overall lack of clonality and host specificity, with some indication of geographical range restriction argue for local epidemics involving multiple strains. The diversity of Tenacibaculum isolates from fish displaying ulcerative disease may complicate vaccine development. PMID- 28622860 TI - Immunogenicity of T7 bacteriophage nanoparticles displaying G-H loop of foot-and mouth disease virus (FMDV). AB - Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals that causes severe economic losses worldwide. The G-H loop of the FMDV VP1 structural protein is the major neutralizing antigenic site. However, a fully protective G-H loop peptide vaccine requires the addition of promiscuous Th sites from a source outside VP1. Thus, we demonstrated the potential of T7 bacteriophage based nanoparticles displaying a genetically fused G-H loop peptide (T7-GH) as a FMDV vaccine candidate. Recombinant T7-GH phage was constructed by inserting the G-H loop coding region into the T7 Select 415-1b vector. Purified T7-GH phage nanoparticles were analyzed by SDS-PAGE, Western blot and Dot-ELISA. Pigs seronegative for FMDV exposure were immunized with T7-GH nanoparticles along with the adjuvant Montanide ISA206, and two commercially available FMDV vaccines (InactVac and PepVac). Humoral and cellular immune responses, as well as protection against virulent homologous virus challenge were assessed following single dose immunization. Pigs immunized T7-GH developed comparable anti-VP1 antibody titers to PepVac, although lower LPBE titers than was induced by InactVac. Antigen specific lymphocyte proliferation was detected in T7-GH group similar to that of PepVac group, however, weaker than InactVac group. Pigs immunized with T7-GH developed a neutralizing antibody response stronger than PepVac, but weaker than InactVac. Furthermore, 80% (4/5) of T7-GH immunized pigs were protected from challenge with virulent homologous virus. These findings demonstrate that the T7-GH phage nanoparticles were effective in eliciting antigen specific immune responses in pigs, highlighting the value of such an approach in the research and development of FMDV vaccines. PMID- 28622861 TI - Antimicrobial susceptibility and genotyping of Staphylococcus aureus isolates collected between 1986 and 2015 from ovine mastitis. AB - In this research, 330 Staphylococcus aureus isolates, collected in Sardinia (Italy) in the period 1986-2015 from clinical ovine mastitis and used for the preparation of inactivated autogenous vaccines, were analyzed. Susceptibility to 12 antimicrobial agents was tested by disk diffusion, according to CLSI recommendations. Resistance genes were detected by PCR assays. The most of isolates (85.2%) were susceptible to all antimicrobials tested, suggesting that did not exist change of resistance over time. Two isolates were multidrug resistant (MDR), one of them (isolate 1496) showed resistance to seven antibiotics including oxacillin and erythromycin. This MRSA harboured SCCmec type IV and the erm(C) gene. Isolates were characterized by spa typing and MLST. Isolates belonged to 29 spa types: t1773 (n=186), t2678 (n=53), t7754 (n=14), t1532 (n=5), t524 (n=5) and t6060 (n=4) were the most frequent spa types found in Sardinia. The majority of ovine isolates (t1773, t7754 and t1532) was grouped in MLST CC130 (n=205) followed by CC133 (n=57). MRSA 1496 was classified as t3896, ST1 and CC1, a clonal complex common in human and also reported in cattle and pig. This study suggests that the CC130/ST700/t1773 is the prevalent S. aureus lineage associated with ovine mastitis in Sardinia. PMID- 28622862 TI - Identification of Lawsonia intracellularis putative hemolysin protein A and characterization of its immunoreactivity. AB - Despite the recent global increase in fatal endemic outbreaks of proliferative enteropathy (PE) caused by the obligate intracellular bacterium Lawsonia intracelluralis (LI) in the swine industry, development of effective prevention strategies or immunodiagnostic tests has been delayed due to the difficulty of cultivating this pathogen in vitro. Although several genetic analyses have been performed at the level of gene transcription after the complete genome sequence of LI was made available, the mechanism of LI infection and virulence genes remain unidentified. In the present study, we assessed the antigenic features of the LI0004 protein, which we putatively defined as Lawsonia hemolysin A (LhlyA), by employing bioinformatics tools and in vivo and in vitro protein-based molecular assays. The amino acid sequence of LhlyA showed approximately 60% homology to the hemolysin-like proteins of Bilophila wadsworthia and Desulfovibrio piger. Presence of computationally predicted linear antigenic B cell epitopes on the LhlyA protein was demonstrated by immunoblotting; a band with a molecular mass corresponding to the predicted size of the protein was strongly recognized by sera collected from artificially infected mice. Further, in an in vivo cytotoxicity assay, no splenomegaly was observed in mice inoculated with purified LhlyA. Collectively, the data presented here suggest that the LhlyA protein is a highly immuno-reactive antigen of L. intracellullaris and can potentially be used to develop effective protection strategies against PE. PMID- 28622863 TI - Down-regulating heat shock protein 27 is involved in porcine epidemic diarrhea virus escaping from host antiviral mechanism. AB - Porcine epidemic diarrhea virus (PEDV), is the etiological agent of porcine epidemic diarrhea virus (PED), causes high mortality with severe vomiting, diarrhea, and dehydration in swine farms. In this study, the PEDV strain 85-7 could be proliferated effectively in MARC-145 cells, and caused a distinct inhibition of the expression of interferon-beta (IFN-beta, encoded by IFNB1), which suggested that a full understanding how this virus manipulates the host immune responses is critical in the fight against the spread of PEDV. We found that, the infection of PEDV strain 85-7 significantly downregulated HSP27 production in MARC-145 cells, and overexpression of HSP27 (encoded by HSPB1) decreased the virus titer by about 28-fold. Further study revealed that HSP27 could significantly activate the NF-kappaB phosphorylation, and thus increase the mRNA level of IFNB1 and downstream interferon-stimulated genes (ISGs) in MARC-145 cells. Indeed, treatment with IFN-beta and the ISGs, including murine myxovirus resistance 1 and 2 (Mx1 and Mx2), showed direct anti-PEDV activity. Notably, the antiviral activity and transcription of the antiviral effectors induced by overexpression of HSP27 could be counteracted by the knockdown of IFNB1 via RNA interference, indicating that HSP27 was an upstream regulator of the intracellular antiviral effect against PEDV infection. This study is the first to link HSP27 to PEDV replication via the innate immunity response, which contributed to further clarify the mechanism of PEDV infection and the development of novel antiviral therapies. PMID- 28622864 TI - Isolation and characterization of Avibacterium paragallinarum with different nicotinamide adenine dinucleotide requirements. AB - Twenty field isolates of Avibacterium paragallinarum were obtained from chickens in South Korea during 2011-2015. The isolates were identified by a HPG-2 PCR assay specific for A. paragallinarum and by biochemical tests. Growth requirements, Page serovars, carbohydrate fermentation patterns, and antimicrobial susceptibility were also examined. Most isolates (16/20) showed the typical requirement for nicotinamide adenine dinucleotide (NAD) and an enriched CO2 atmosphere for growth. One isolate needed increased levels of NAD and serum for good growth. Three isolates showed NAD-independent growth on blood agar under aerobic conditions. In terms of carbohydrate fermentation patterns, three biochemical biovars were recognized; these varied with respect to acid production from maltose and D-xylose. The 16 typical NAD-dependent isolates were serovar A while the variants, both NAD-independent isolates and the isolate with increased NAD dependency were non-typeable. All isolates were sensitive to amoxicillin clavulanic acid, ceftiofur, gentamicin, and spectinomycin. High rates of resistance, including intermediate resistance, to lincomycin (100%), cloxacillin (75%), and erythromycin (70%) were observed. The four variant strains (the three NAD-independent isolates and the isolate showing unusual growth requirements) were more resistant to antibiotics than the typical NAD-dependent strains. The finding of NAD-independent forms of A. paragallinarum extends the known distribution of this form, previously only reported in South Africa, Mexico and Peru. There is clearly a need for increased caution in the diagnosis and, possibly, the control of infectious coryza. PMID- 28622865 TI - PA-X protein decreases replication and pathogenicity of swine influenza virus in cultured cells and mouse models. AB - Swine influenza viruses have been circulating in pigs throughout world and might be potential threats to human health. PA-X protein is a newly discovered protein produced from the PA gene by ribosomal frameshifting and the effects of PA-X on the 1918 H1N1, the pandemic 2009 H1N1, the highly pathogenic avian H5N1 and the avian H9N2 influenza viruses have been reported. However, the role of PA-X in the pathogenesis of swine influenza virus is still unknown. In this study, we rescued the H1N1 wild-type (WT) classical swine influenza virus (A/Swine/Guangdong/1/2011 (H1N1)) and H1N1 PA-X deficient virus containing mutations at the frameshift motif, and compared their replication properties and pathogenicity of swine influenza virus in vitro and in vivo. Our results show that the expression of PA X inhibits virus replication and polymerase activity in cultured cells and decreases virulence in mouse models. Therefore, our study demonstrates that PA-X protein acts as a negative virulence regulator for classical H1N1 swine influenza virus and decreases virulence by inhibiting viral replication and polymerase activity, deepening our understanding of the pathogenesis of swine influenza virus. PMID- 28622866 TI - Pathology and genetic findings in a rare case of Mycobacterium caprae infection in a sow. AB - Bovine tuberculosis, a reemerging zoonosis in diverse ecological scenarios, has been reported in the autochthonous Nebrodi black pig breed population used for meat production in Italy. During a routine abattoir inspection in 2013, 24 of 299 carcasses (8%) of Nebrodi black pigs presented tuberculosis-like lesions at pathologic examination. Mycobacterium bovis was isolated from 23 animals and M. caprae from a 3-year-old sow. The sow showed severe diffuse lesions involving the visceral organs, right coxofemoral joint, and mammary glands. Isolation of M. caprae from mammary glands is uncommon, with only one other case involving a sow reported so far; however, Mycobacteria infection of the mammary glands may be transmitted from lactating sows to piglets, contributing to the spread and maintenance of bovine tuberculosis in swine. Genotyping analysis showed M. caprae spoligotype SB0866 and profile 4,1,5,4,4,11,4,2,4,3,8,7 MIRU-VNTR (mycobacterial interspersed repetitive units-variable number of tandem repeats). The worldwide prevalence of this spoligotype is very low. The finding of severe, diffuse tuberculous lesions strongly suggests that Nebrodi black pigs are susceptible for Mycobacterium spp. and that they might act as a distributor for these microorganisms. Since natural ecosystems with multiple contacts among different livestock species and wild animals are very common in Mediterranean regions, current surveillance and eradication plans for bovine tuberculosis will need to be extended to other potential reservoir species in regions where extensive and traditional breeding systems are operated. PMID- 28622867 TI - Evaluation of the involvement of mice (Mus musculus) in the epidemiology of porcine proliferative enteropathy. AB - The aim of this study was to evaluate the fecal-oral transmission of L. intracellularis between mice and pigs. The study was divided into two parts. The first part aimed to determine whether mice could be infected by feces from pigs that are experimentally infected with L. intracellularis. Thirty-four Swiss mice received L. intracellularis PCR-positive feces from experimentally infected pigs (M1) for four consecutive days. Twelve other mice received swine negative feces (M2). Pools of mice feces were collected on alternating days post-exposure (dpe). The second part of the study aimed to test whether pigs could be infected when exposed to L. intracellularis PCR-positive feces from experimentally infected mice. Twelve 5-week-old pigs received feed mixed with L. intracellularis PCR positive mice feces (P1), while the other two pigs received PCR-negative mice feces (P2) for four consecutive days. In the first study, the amount of L. intracellularis provided to M1 boxes per day was between 106 and 108. Mice shed, an average of 104 bacterial units every collection day. Three mice from M1 were positive for L. intracellularis by immunohistochemistry (IHC) at the end of the study. In the second part of the study, pigs in P1 received an average of 105 bacterial units per day. Ten pigs were infected by L. intracellularis based on positive qPCR and/or immunohistochemistry and serology results. These pigs shed an average of 104L. intracellularis/g of feces. Mice and pigs experimentally infected with L. intracellularis can infect each other, therefore, rodents should be considered players in the epidemiology of this disease in pig farms. PMID- 28622868 TI - Vaccination against porcine reproductive and respiratory syndrome virus (PRRSV) reduces the magnitude and duration of viremia following challenge with a virulent heterologous field strain. AB - Forty PRRS-negative, three week-old weaned pigs were randomized into two groups in separate rooms and inoculated with a modified live PRRS vaccine (Fostera(r) PRRS) or control (PBS). Four weeks after vaccination pigs were rehoused in a single room and challenged intranasally and intramuscularly with virulent PRRSV strain NADC20. Timed serum samples were collected and titrated for PRRS virus and anti-PRRS virus antibodies. The study concluded when >=80% of the pigs in the control group were determined to be virus negative (27days post-challenge). Mean duration of viremia was significantly lower (p=0.0327) for vaccinated pigs compared to non-vaccinated pigs. A significant reduction (p<=0.0053) in mean post challenge viremia titer was seen in vaccinates compared to non-vaccinates from days 8 through 22 post-challenge. At the individual pig level, no pigs in the vaccinated group had detectible PRRSV in serum at the end of the study (27days post-challenge), while 15% of non-vaccinated pigs remained positive for virus. PMID- 28622869 TI - Brucella lipopolysaccharide reinforced Salmonella delivering Brucella immunogens protects mice against virulent challenge. AB - Intracellular pathogen Salmonella exhibits natural infection broadly analogous to Brucella, this phenomenon makes Salmonella a pragmatic choice for an anti Brucella vaccine delivery platform. In this study we developed and formulated a combination of four attenuated Salmonella Typhimurium live vector strains delivering heterologous Brucella antigens (rBs), namely lumazine synthase, proline racemase subunit A, lipoprotein outer membrane protein-19, and Cu-Zn superoxide dismutase. With an aim to develop a cross-protecting vaccine, Brucella pan-species conserved rBs were selected. The present study compared the efficacy of smooth and rough variants of Salmonella delivery vector and also evaluated the inclusion of purified Brucella lipopolysaccharide (LPS) in the formulation. Immunization of SPF-BALB/c mice with the vaccine combinations significantly (P<=0.05) reduced splenic wild-type Brucella abortus 544 colonization as compared to non-immunized mice as well as Salmonella only immunized mice. Increased induction of Brucella specific-IgG, sIgA production, and antigen-specific splenocyte proliferative responses were observed in the mice immunized with the formulations as compared to naive or vector only immunized mice. Modulatory effects of rB and LPS on production of interleukin (IL)-4, IL-12, and interferon gamma were detected in splenocytes of mice immunized with the formulation. Rough Salmonella variant in combination with LPS could further enhance the efficacy of the delivery when applied intraperitoneally. Taken together, it is compelling that Brucella LPS-augmented Salmonella vector delivering immunogenic Brucella proteins may be more suitable than the current non-ideal live Brucella abortus vaccine. The vaccine system also provides a basis for the development of cross protecting vaccine capable of preventing multispecies brucellosis. PMID- 28622870 TI - Molecular characterization of feline panleukopenia virus isolated from mink and its pathogenesis in mink. AB - Six feline panleukopenia viruses (FPV) were detected in the intestinal samples from the 176 mink collected in China during 2015 to 2016, named MEV-SD1, MEV-SD2, MEV-SD3, MEV-SD4, MEV-SD5 and MEV-SD6. The VP2 genes of the isolates shared 98.9% 100% identity with the reference sequences. The substitution of residue V300A in VP2 protein differentiates the isolates from the reference MEVs, and A300 is a characteristic of FPV. Furthermore, phylogenetic analysis of VP2 genes indicated that the six isolates were clustered into the same branch of all the reference FPVs. The NS1 genes of the isolates shared 98.2%-100% identity with the reference sequences. The NS1 genes of the six isolates and the three reference FPVs formed one unique evolutionary branch. To clarify the pathogenicity of the isolates, animal experiments were performed on healthy mink, using MEV-SD1. As a result, the morbidity of the inoculated animals was 100% and the mortality was as high as 38.9%. It was implied that the FPV infection caused a high morbidity and mortality in mink and the inoculation dose had an effect on pathogenicity of MEV SD1 in mink. PMID- 28622871 TI - A spike-specific whole-porcine antibody isolated from a porcine B cell that neutralizes both genogroup 1 and 2 PEDV strains. AB - Porcine epidemic diarrhea (PED), caused by an alpha coronavirus, is a highly contagious disease and causes high morbidity and mortality in suckling piglets. Isolating PEDV neutralizing antibodies from porcine B cells is critical to elucidate the development of PEDV neutralizing antibodies and the protective mechanism of PEDV infection. Here, we described the isolation of a PEDV neutralizing antibody from the B cell of a vaccinated pig. The antibody, named PC10, was demonstrated to target the conformational epitope of PEDV spike protein, specifically bind to the infected cells of PEDV genogroup 1 and 2 strains, and potently neutralize PEDV infection. PC10 neutralized PEDV infection through interfering with the viral life stages after cellular attachment instead of blocking the attachment of PEDV to cells. These results suggest that PC10 could be a promising candidate for passive protection and inform PEDV vaccine design because of its specificity and substantial neutralization potency. PMID- 28622872 TI - Processes of local alcohol policy-making in England: Does the theory of policy transfer provide useful insights into public health decision-making? AB - BACKGROUND AND AIMS: Recent years have seen a rise in new and innovative policies to reduce alcohol consumption and related harm in England, which can be implemented by local, as opposed to national, policy-makers. The aim of this paper is to explore the processes that underpin the adoption of these alcohol policies within local authorities. In particular, it aims to assess whether the concept of policy transfer (i.e. a process through which knowledge about policies in one place is used in the development of policies in another time or place) provides a useful model for understanding local alcohol policy-making. METHODS: Qualitative data generated through in-depth interviews and focus groups from five case study sites across England were used to explore stakeholder experiences of alcohol policy transfer between local authorities. The purposive sample of policy actors included representatives from the police, trading standards, public health, licensing, and commissioning. Thematic analysis was used inductively to identify key features in the data. RESULTS: Themes from the policy transfer literature identified in the data were: policy copying, emulating, hybridization, and inspiration. Participants described a multitude of ways in which learning was shared between places, ranging from formal academic evaluation to opportunistic conversations in informal settings. Participants also described facilitators and constraints to policy transfer, such as the historical policy context and the local cultural, economic, and bureaucratic context, which influenced whether or not a policy that was perceived to work in one place might be transferred successfully to another context. CONCLUSIONS: Theories of policy transfer provide a promising framework for characterising processes of local alcohol policy-making in England, extending beyond debates regarding evidence-informed policy to account for a much wider range of considerations. Applying a policy transfer lens enables us to move beyond simple (but still important) questions of what is supported by 'robust' research evidence by paying greater attention to how policy making is carried out in practice and the multiple methods by which policies diffuse across jurisdictions. PMID- 28622873 TI - Novel FREM1 mutations are associated with severe hydrocephalus and shortened limbs in a prenatal case. PMID- 28622874 TI - Saved by its back : An amazing story of uterine rupture ! PMID- 28622876 TI - Cultivating Competencies for Value-Based Care. PMID- 28622875 TI - Does the Severity of Overactive Bladder Symptoms Correlate With Risk for Female Sexual Dysfunction? AB - BACKGROUND: Several studies have associated overactive bladder (OAB) with female sexual dysfunction (FSD); however, there are no reports using a quantitative approach to measure OAB severity and to relate OAB to the risk of FSD. AIM: To evaluate women with OAB and to correlate the severity of their urinary symptoms with their sexual function. METHODS: This cross-sectional study included 267 women older than 18 years with untreated OAB. All subjects completed the International Consultation on Incontinence Questionnaire Overactive Bladder (ICIQ OAB) and the Female Sexual Function Index (FSFI). OUTCOMES: Linear regression was used to analyze the association between variables and the numeric FSFI score, and categorical FSFI scores were analyzed using logistic regression. Spearman rank correlation coefficient was used to assess the correlation between ICIQ-OAB results and the different FSFI domains. The significance level was 5%. RESULTS: Subjects' mean age was 50.2 +/- 11.9 years. Most women were married, had at least three children, and were postmenopausal (54.3%). Mean FSFI total score was 19.2 +/- 9.8. For menopausal status, 65.6% of premenopausal women had a risk for FSD vs 86.2% of postmenopausal women. Mean ICIQ-OAB score was 10 +/- 3.17. Postmenopausal women had the following risk factors statistically associated with sexual dysfunction: age, ICIQ score, and marital status. For these women, greater OAB severity, especially those with urgency and/or urge incontinence, was associated with worse scores in the arousal, lubrication, orgasm, and sexual pain domains. However, there was no statistically significant association for premenopausal women. CLINICAL IMPLICATIONS: Health professionals have to pay attention to OAB in women because of the greater risk for FSD in these patients. STRENGTHS AND LIMITATIONS: The strength was using a quantitative approach to measure OAB severity in a larger population. Limitations include a convenience sample with no power calculation; exclusion of women who did not have sexual intercourse in the past month; unmeasured distress caused by sexual disorders; and the impossibility of establishing causality between OAB and sexual dysfunction. CONCLUSION: Women with OAB frequently have a risk for sexual dysfunction. In the postmenopausal group, women with scores indicating severe OAB had worse sexual function, mainly in the arousal, lubrication, orgasm, pain, and total domains. Juliato CRT, Melotti IGR, Junior LCS, et al. Does the Severity of Overactive Bladder Symptoms Correlate With Risk for Female Sexual Dysfunction? J Sex Med 2017;14:904-909. PMID- 28622877 TI - Author Reply. PMID- 28622878 TI - Editorial Comment. PMID- 28622879 TI - Editorial Comment. PMID- 28622880 TI - MALDI imaging. PMID- 28622881 TI - Discovery of beta-d-2'-deoxy-2'-dichlorouridine nucleotide prodrugs as potent inhibitors of hepatitis C virus replication. AB - Discovery of sofosbuvir has radically changed hepatitis C treatment and nucleoside/tide NS5B inhibitors are now viewed as one of the key components in combination therapies with other direct-acting antiviral agents. As part of our program to identify new nucleoside inhibitors of HCV replication, we now wish to report on the discovery of beta-d-2'-deoxy-2'-dichlorouridine nucleotide prodrugs as potent inhibitors of HCV replication. Although, cytidine analogues have long been recognized to be metabolized to both cytidine and uridine triphosphates through the action of cytidine deaminase, uridine analogues are generally believed to produce exclusively uridine triphosphate. Detailed investigation of the intracellular metabolism of our newly discovered uridine prodrugs, as well as of sofosbuvir, has now revealed the formation of both uridine and cytidine triphosphates. This occurs, not only in vitro in cell lines, but also in vivo upon oral dosing to dogs. PMID- 28622882 TI - Stent migration during EUS-guided hepaticogastrostomy in a patient with massive ascites: Troubleshooting using additional EUS-guided antegrade stenting. AB - EUS-guided hepaticogastrostomy (EUS-HGS) is useful for treating obstructive jaundice. However, stent migration may sometimes occur both during and after the procedure. This report describes a patient with pancreatic cancer and massive ascites who underwent EUS-HGS combined with EUS-guided antegrade stenting (EUS AS), with additional EUS-AS playing a role in troubleshooting for stent migration during EUS-HGS. PMID- 28622883 TI - Health-related quality of life of Palestinian refugees inside and outside camps in Jordan. AB - BACKGROUND: Jordan hosts more Palestinian refugees than any country in the world. Conditions under which people in a community live influence their health-related quality of life (HRQOL). PURPOSE: The purpose of this descriptive comparative cross-sectional study was to compare HRQOL of Palestinian refugees in Jordan who live inside camps with those who live outside camps. METHODS: Participants, recruited from inside the Baqa'a camp (n = 86) and the surrounding Abu Nsair community (n = 91), completed the World Health Organization Quality of Life Brief questionnaire. FINDINGS: There were disparities in education and social relations and environment HRQOL related to income and residency, but not gender, among refugees. CONCLUSION: Refugees living inside camps, particularly if poorer, fared worse than refugees living outside camps. Enhanced programs and policies may be needed to improve HRQOL, education, and socioeconomics for camp refugees. Nursing's perspective on refugee health could make an important contribution to humanitarian efforts and health diplomacy. PMID- 28622884 TI - The effect of caloric restriction on the forelimb skeletal muscle fibers of the hypertrophic myostatin null mice. AB - Skeletal muscle mass loss has a broad impact on body performance and physical activity. Muscle wasting occurs due to genetic mutation as in muscular dystrophy, age-related muscle loss (sarcopenia) as well as in chronic wasting disorders as in cancer cachexia. Food restriction reduces muscle mass underpinned by increased muscle protein break down. However the influence of dietary restriction on the morphometry and phenotype of forelimb muscles in a genetically modified myostatin null mice are not fully characterized. The effect of a five week dietary limitation on five anatomically and structurally different forelimb muscles was examined. C57/BL6 wild type (Mstn+/+) and myostatin null (Mstn-/-) mice were either given a standard rodent normal daily diet ad libitum (ND) or 60% food restriction (FR) for a 5 week period. M. triceps brachii Caput laterale (T.lateral), M. triceps brachii Caput longum (T.long), M. triceps brachii Caput mediale (T.medial), M. extensor carpi ulnaris (ECU) and M. flexor carpi ulnaris (FCU) were dissected, weighted and processed for immunohistochemistry. Muscle mass, fibers cross sectional areas (CSA) and myosin heavy chain types IIB, IIX, IIA and type I were analyzed. We provide evidence that caloric restriction results in muscle specific weight reduction with the fast myofibers being more prone to atrophy. We show that slow fibers are less liable to dietary restriction induced muscle atrophy. The effect of dietary restriction was more pronounced in Mstn-/- muscles to implicate the oxidative fibers compared to Mstn+/+. Furthermore, peripherally located myofibers are more susceptible to dietary induced reduction compared to deep fibers. We additionally report that dietary restriction alters the glycolytic phenotype of the Mstn-/- into the oxidative form in a muscle dependent manner. In summary our study shows that calorie restriction alters muscle fiber profile of forelimb muscles of Myostatin null mice. PMID- 28622885 TI - The impact of prophylactic external carotid artery ligation on postoperative bleeding after transoral robotic surgery (TORS) for oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Transoral robotic-assisted surgery (TORS) is increasingly utilized in the treatment of oropharyngeal squamous cell carcinoma (OPSCC). Postoperative bleeding is a significant and potentially fatal complication of TORS. Prophylactic ligation of ipsilateral external carotid artery (ECA) branches is a recognized strategy to reduce postoperative bleeding risk. We examined the incidence and sequelae of postoperative oropharyngeal bleeding with and without routine ECA ligation. METHODS: OPSCC patients treated with TORS between 2010 and 2015 with minimum 30days follow up were included. Clinicopathological data, operative details, and postoperative course were abstracted for analysis. Cases of postoperative bleeding were classified as Minor, Intermediate, Major, and Severe. The incidence and severity of bleeding was compared between patients treated with and without prophylactic ECA ligation. RESULTS: Bleeding after TORS was documented in 13/201 (6.5%) patients. The majority of bleeding episodes were observed among anticoagulated or previously radiated patients. By surgeon preference, 52 patients had prophylactic ECA ligation during neck dissection while the remaining 149 patients did not. There was no significant difference in overall incidence of postoperative bleeding between patients with prophylactic ECA ligation (3/52, 5.8%) and patients without (10/149, 6.7%) [p=0.53]. However, severe bleeding complications (4, 2.0%) were only observed in patients without prophylactic ligation. CONCLUSION: A small but meaningful risk of bleeding after TORS for OPSCC exists, particularly among anticoagulated or previously radiated patients. Prophylactic ECA ligation did not significantly impact the overall incidence of postoperative bleeding but may reduce the risk of severe (life threatening) bleeding. PMID- 28622886 TI - Five-year outcomes of an oropharynx-directed treatment approach for unknown primary of the head and neck. AB - PURPOSE: Squamous cell carcinoma of unknown primary (SCCHNUP) is commonly treated with comprehensive radiation to the laryngopharynx and bilateral necks. In 1998, we established a departmental policy to treat SCCHNUP with radiation directed to the oropharynx and bilateral neck. METHODS: From 1998-2011, 60 patients were treated - N1: 18%, N2: 75% and N3: 7%. 82% underwent neck dissection. 55% received IMRT and 62% underwent concurrent chemoradiotherapy. RESULTS: At median follow-up of 54months, 5 patients failed regionally and 4 emerged with a primary (tongue base, hypopharynx and thoracic esophagus). Five-year rates of regional control, primary emergence, distant metastasis, disease-free survival and overall survival were 90%, 10%, 20%, 72% and 79%, respectively. The 5year rate of primary emergence in a non-oropharynx site was 3%. CONCLUSION: This is the first demonstration that an oropharynx-directed approach yields low rates of primary emergence in SCCHNUP with excellent oncologic outcomes. PMID- 28622887 TI - Genetic etiology of oral cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. It accounts for 2.5% of all new cancer cases and 1.9% of all cancer deaths annually. More than 90% of oral cancers (occurring in the mouth, lip, and tongue) are oral squamous cell carcinoma. The incidence rate of oral cancer varies widely throughout the world, with an evident prevalence in South Asian countries. This high incidence occurs in correlation with oral cancer-associated behaviors such as alcohol, tobacco use. Researchers have reported that these behaviors lead to genetic variations in tumor suppressor genes (APC, p53), proto oncogenes (Myc), oncogene (Ras) and genes controlling normal cellular processes (EIF3E, GSTM1). Processes such as segregation of chromosomes, genomic copy number, loss of heterozygosity, telomere stabilities, regulations of cell-cycle checkpoints, DNA damage repairs and defects in notch signaling pathways are involved in causing oral cancer. In order to develop preventive and therapeutic options, it is necessary to comprehend the basic molecular mechanisms forcing oral tumorigenesis. This review examines, in detail, the mechanisms of genetic alteration which are considered to be responsible for the initiation of oral cancer. PMID- 28622888 TI - Validation of the pathological classification of lymph node metastasis for head and neck tumors according to the 8th edition of the TNM Classification of Malignant Tumors. AB - OBJECTIVES: One of the main changes in the 8th edition of the TNM Classification for head and neck tumors is the inclusion of extracapsular spread (ECS) as a criterion for evaluating the regional extension, both clinical (cN) and pathological (pN). The objective of our study is to evaluate the prognostic capacity derived from the inclusion of the ECS in the pathological classification of head and neck squamous cell carcinoma (HNSCC) patients treated with a neck dissection, as established by the 8th edition TNM Classification. MATERIALS AND METHODS: Retrospective study of 1188 patients with HNSCC treated with a neck dissection between1990 and 2013. RESULTS: There were lymph node metastasis in 50.1% of the neck dissections. The pathological record revealed ECS in 50.5% of the positive neck dissections. The implementation of the changes of the 8th edition TNM classification produced the upstaging of 20.9% of the patients classified as pN1 with the 7th edition TNM classification to pN2a and the upstaging of 58.4% of the patients classified as pN2 with the 7th edition TNM classification to pN3b. We conducted an objective comparison of the quality of both classifications. The 8th TNM classification edition achieved better results regarding both the discrimination in cause-specific survival between pN categories and in the distribution in the number of cases between categories than the 7th edition TNM classification. CONCLUSION: The inclusion of ECS in the pathological classification (pN) of the neck nodes improves the prognostic capacity of the 8th TNM Classification edition. PMID- 28622889 TI - Turning the tide: Clinical utility of PD-L1 expression in squamous cell carcinoma of the head and neck. AB - The use of cytotoxic and/or targeted agents is the gold standard in first- and second-line treatment of metastatic head and neck cancer. Currently the focus of oncologic research is shifting to the implementation of immune checkpoint inhibitor regimens. Many trials are being performed evaluating the survival benefit of various PD-1/PD-L1 blocking antibodies in both solid and haematological malignancies. Also, evaluation of the predictive value of PD-L1 expression on tumour cells and immune cells is being explored. We first review the current knowledge and possible pitfalls for PD-L1 expression in squamous cell carcinoma of the head and neck. Next, we provide an update on the therapeutic use of PD-1/PD-L1 blocking antibodies as treatment modality for patients with squamous cell carcinoma of the head and neck and we assess the predictive value of tumour PD-L1 positivity. Finally, we elaborate on other promising predictive biomarkers of interest in this patient population. PMID- 28622890 TI - Evaluation of type-specific antibodies to high risk-human papillomavirus (HPV) proteins in patients with oropharyngeal cancer. AB - OBJECTIVES: High risk human papillomavirus (HR-HPV) infection leads to a subgroup of oropharyngeal cancer (OPSCC) characterized by improved treatment response. However an universally accepted definition of an HR-HPV-attributable cancer is lacking. METHODS: Detailed, type-specific HPV antibody responses were analyzed by multiplex serology in HR-HPV-attributable OPSCC patients, defined by p16INK4A overexpression and HR-HPV DNA detection by PCR amplification and sequencing. RESULTS: Fifty patients were prospectively enrolled. 26/50 (52%) tumor samples were positive for both p16INK4A expression and HR-HPV DNA (22 HPV16, 4 HPV33). Seropositivity was present in 26/26 HPV-attributable OPSCC and one p16INK4A positive/HPV DNA-negative case. The sensitivity and specificity to diagnose an HR HPV-attributable tumor was 100% and 96%, respectively for anti-E6 reactivity, 82% and 100%, respectively for anti-E2 reactivity, and clearly lower for anti-E7, anti-E1, anti-E4 and anti-L1-reactivity. 3yr-overall (OS) and disease specific survival (DSS) was higher in patients with HR-HPV-attributable tumors (OS 88% vs 64%, p=0.02; DSS 90% vs 80%, p=0.07) and seropositive patients (OS 88% vs 62%, p=0.01; DSS 92% vs 78%, p=0.05) than HR-HPV-negative or seronegative patients. CONCLUSIONS: Detection of HR-HPV type-specific antibodies highly correlated with HPV-attributable OPSCC and was associated with better survival. HR-HPV antibodies are promising diagnostic, prognostic and potentially screening markers in HR-HPV attributable OPSCC. PMID- 28622891 TI - Functional and cosmetic outcomes of robot-assisted neck dissection by a postauricular facelift approach for head and neck cancer. AB - OBJECTIVES: The purpose of this study was to compare the functional and cosmetic outcomes of robot-assisted neck dissection with those of conventional neck dissection. MATERIALS AND METHODS: We prospectively analyzed 113 patients with head and neck cancer who underwent unilateral neck dissection by a robot-assisted postauricular facelift approach (38 patients) or conventional trans-cervical approach (75 patients). Postoperative functional outcomes such as edema, sensory loss, pain, and fibrosis in the neck, and limitations of neck and shoulder motion, and cosmetic satisfaction scored by questionnaire were evaluated serially up to 1year postoperatively, and compared between the two groups. RESULTS: There were differences at baseline clinicopathologic characteristics including age, T classification and stage between the two groups. The mean score of neck edema was lower in the robotic group than that of the conventional group at 1day and 3days postoperatively, and sensory loss was also lower in the robotic group at 1day, 3days and 1week postoperatively (P<0.05). The postoperative cosmetic satisfaction were significantly higher in the robotic group than the conventional group at 1month, 3, 6, and 12months postoperatively. Transient marginal nerve palsy was higher in the robotic group than the conventional group (P=0.043). CONCLUSION: Postoperative neck edema and sensory loss were lower in the robotic group in the early postoperative period although its clinical significance is not clear. Cosmetic satisfaction was superior in the robotic group. PMID- 28622892 TI - A phase II trial of induction NAB-paclitaxel and cisplatin followed by concurrent chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma. AB - OBJECTIVES: Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) was designed to avoid solvent-related toxicities, and improve anti-tumor efficacy via increasing paclitaxel's intratumoral concentration and its uptake by tumor cells. This trial aimed to determine the safety and efficacy of induction NAB-paclitaxel combined with cisplatin followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC). PATIENTS AND METHODS: Patients with stage III-IVb NPC received NAB-paclitaxel (260mg/m2) combined with cisplatin (80mg/m2) intravenously on days 1 and 22, followed by cisplatin (80mg/m2) on days 43 and 64, concomitant with intensity-modulated radiation therapy. This trial is registered with the Chinese Clinical Trials Registry, number ChiCTR-ONC-12002615. RESULTS: From July 2010 to November 2013, 36 eligible patients with nonmetastatic stage III-IVb NPC were enrolled. The objective response rates were 97.2% (eight complete responses [CRs] and 27 partial responses [PRs]) and 100% (30 CRs and six PRs) after two cycles of induction chemotherapy (ICT) and CCRT, respectively. With a median follow-up time of 45months, the estimated 3-year progression-free survival and cancer-specific survival were 86.1% (95% confidence interval [CI], 69.8-99.8%) and 91.7% (95% CI, 68.9-100.0%), respectively. The most frequent grade 3-4 toxicities were neutropenia (8.6%) and nausea (8.6%) after ICT and thrombocytopenia (34.3%) and leukopenia (28.6%) after CCRT. CONCLUSION: NAB-paclitaxel combined with cisplatin as an ICT regimen showed encouraging anti-tumor effects and manageable toxicities in LA-NPC. Further randomized controlled trials in phase III of NAB-paclitaxel in patients with LA-NPC are warranted. PMID- 28622893 TI - Outcomes of middle fossa craniotomy for the repair of superior semicircular canal dehiscence. AB - Superior semicircular canal dehiscence (SSCD) is a rare defect of the arcuate eminence that causes an abnormal connection between the superior semicircular canal and middle cranial fossa. Patients often present with a variety of auditory and vestibular symptoms. Trigger avoidance is the initial strategy, but surgery may be necessary in debilitating cases. We retrospectively reviewed SSCD patients undergoing repair via a middle fossa craniotomy between March 2011 and September 2015. Forty-nine patients undergoing 58 surgeries were identified. Autophony was the most common symptom at presentation (n=44; 90%). Mean follow-up was 10.9months, with 100% of patients reporting resolution of at least one symptom. Aural fullness was the most commonly resolved symptom following surgical repair (n=19/22; 86%). Hearing loss (n=11/25; 44%) and tinnitus (n=11/38; 29%) were the most common symptoms to persist following surgery. The most common symptom to develop after surgery was disequilibrium (n=4/18; 22%). Upon comparing the overall pre-operative and post-operative groups, the number of patients with autophony (p<0.0001), aural fullness (p=0.0006), hearing loss (p=0.0119), disequilibrium (p=0.0002), sound- and pressure-induced vertigo (p<0.0001), and tinnitus (p<0.0001) were significantly different. Improved clinical outcomes were demonstrated in patients undergoing SSCD repair through a middle cranial fossa approach. The most common presenting symptom (autophony) was also most likely to resolve after surgery. Hearing loss is less amenable to surgical correction. Disequilibrium developed in a small number of patients after repair. PMID- 28622894 TI - Impact of stimulus-related factors and hearing impairment on listening effort as indicated by pupil dilation. AB - Previous research has reported effects of masker type and signal-to-noise ratio (SNR) on listening effort, as indicated by the peak pupil dilation (PPD) relative to baseline during speech recognition. At about 50% correct sentence recognition performance, increasing SNRs generally results in declining PPDs, indicating reduced effort. However, the decline in PPD over SNRs has been observed to be less pronounced for hearing-impaired (HI) compared to normal-hearing (NH) listeners. The presence of a competing talker during speech recognition generally resulted in larger PPDs as compared to the presence of a fluctuating or stationary background noise. The aim of the present study was to examine the interplay between hearing-status, a broad range of SNRs corresponding to sentence recognition performance varying from 0 to 100% correct, and different masker types (stationary noise and single-talker masker) on the PPD during speech perception. Twenty-five HI and 32 age-matched NH participants listened to sentences across a broad range of SNRs, masked with speech from a single talker ( 25 dB to +15 dB SNR) or with stationary noise (-12 dB to +16 dB). Correct sentence recognition scores and pupil responses were recorded during stimulus presentation. With a stationary masker, NH listeners show maximum PPD across a relatively narrow range of low SNRs, while HI listeners show relatively large PPD across a wide range of ecological SNRs. With the single-talker masker, maximum PPD was observed in the mid-range of SNRs around 50% correct sentence recognition performance, while smaller PPDs were observed at lower and higher SNRs. Mixed model ANOVAs revealed significant interactions between hearing-status and SNR on the PPD for both masker types. Our data show a different pattern of PPDs across SNRs between groups, which indicates that listening and the allocation of effort during listening in daily life environments may be different for NH and HI listeners. PMID- 28622895 TI - Cutting-edge approaches to unwrapping the mysteries of sleep. PMID- 28622896 TI - Biomechanical Modeling of Spine Flexibility and Its Relationship to Spinal Range of Motion and Idiopathic Scoliosis. AB - STUDY DESIGN: Cross-sectional. OBJECTIVE: To examine the relationships between spine morphology, spine flexibility, and idiopathic scoliosis. BACKGROUND: Girls have a higher incidence of clinically significant scoliosis than boys, along with smaller vertebrae and greater flexibility. Based on biomechanical modeling, we hypothesized that smaller vertebral width relative to intervertebral disc (IVD) height would be associated with both greater lateral flexibility of the spine and with idiopathic scoliosis. METHODS: Magnetic resonance imaging was used to measure IVD height, vertebral width, and paraspinous musculature in 22 girls with mild and moderate idiopathic scoliosis and 29 girls without scoliosis ages 9-13 years. Clinical measurement of maximum lateral bending was also performed in the girls without scoliosis. A simple biomechanical model was used to estimate bending angle from the ratio of IVD height to vertebral half-width for L1-L4. The average ratio (Ravg) and calculated total bending angle (alphatot) for L1-L4 were compared to the clinical measurements of lateral bending flexibility in the control group. These measures were also compared between the scoliosis and control groups. RESULTS: There was a significant positive relationship between clinical flexibility and both Ravg (p = .041) and alphatot (p = .042) adjusting for skeletal age, height, body mass index, and paraspinous muscle area as covariates. The ratio was significantly higher (Ravg = 0.45 vs. 0.38, p < .0001) and the bending angle was significantly greater (alphatot = 107 degrees vs. 89 degrees , p < .0001) for girls with scoliosis compared with controls. CONCLUSION: These results suggest that differences in spine morphology and corresponding changes in spine flexibility may be related to idiopathic scoliosis. If these relationships can be corroborated in larger prospective studies, these easily measured morphologic traits may contribute to a better understanding of the etiology of idiopathic scoliosis and an improved ability to predict scoliosis progression. LEVEL OF EVIDENCE: Level III. PMID- 28622898 TI - Trends in Attendance at Scoliosis Research Society Annual Meetings (SRS AM) and International Meeting on Advanced Spine Techniques (IMAST): Location, Location, Location. AB - STUDY DESIGN: Descriptive, respective. OBJECTIVE: Although overall membership in Scoliosis Research Society (SRS) has grown over the years, we were curious to see the effects of changing event venue location and timing on conference attendance. SUMMARY OF BACKGROUND DATA: Every year, the SRS hosts two major meetings: the Annual Meeting (SRS AM) in the autumn, and the International Meeting on Advanced Spine Techniques (IMAST) in the summer. Sites have alternated from within and outside North America. Often, these meetings have also overlapped with several holidays in certain countries. METHODS: This was an observational study of attendance from past SRS AM and IMAST meetings. Fourteen years of AM and 8 years of IMAST data were made available from the SRS. Participation based on delegate type and countries were tallied. Details from the 10 most represented nations and host nations per year were also tallied, and their national holidays were reviewed for overlaps with the AM. RESULTS: Membership in AM and IMAST increased from 820 in 2003 to 1,323 in 2016. Attendance at the AM has increased, whereas attendance at IMAST has declined, even after adjusting for membership size. Trends in participation were highly influenced by location. Participation by attendees from the host continent, and especially the host country, is generally high. The negative impact of distant meetings is profoundly seen with North Americans, whereas the positive impact of a nearby meeting was mostly clearly demonstrated by South Americans. Although SRS AM overlapped with holidays in China, Japan, or Korea nearly 50% of the time, this did not influence participation by delegates from these countries. CONCLUSION: Participation in the AM is highly influenced by location. Although North Americans represented the largest constituency, their presence was not needed to drive total attendance and was not sufficient to turn around the downturn in IMAST attendance. Choice of location can encourage the participation of delegates from the host and neighboring nations; through strategic selection of location, a balance can be reached between participation and global representation. PMID- 28622897 TI - The Efficacy of Local Autologous Bone Dust: A Systematic Review. AB - STUDY DESIGN: A systematic review of bone dust as an autologous bone graft to encourage osseous fusion. OBJECTIVE: To identify and review studies that report on the therapeutic potential of bone dust. The research question was structured as follows: populations-animal and human sources of bone dust harvested using burrs; interventions-autologous bone dust compared with other clinically utilized bone graft options; outcomes assessed-(1) in vitro cell viability, cell differentiation, and osteogenic potential and (2) clinical efficacy in the form of fusion rates as assessed using plain radiographs; study designs-in vitro, preclinical in vivo and clinical studies investigating the therapeutic potential of bone dust, harvested by burring, are included in this systematic review. SUMMARY OF BACKGROUND DATA: Little is known about the efficacy of bone dust, generated during burring of local bone in spine surgery, as a bone graft to encourage osseous union. METHODS: A systematic search was conducted in Medline, PubMed, OVID, Scopus, and Cochrane library. The following key words were used: bone dust, bone burring, bone paste, bone pate. RESULTS: A total of 285 studies were reviewed. Fourteen articles were identified as relevant for inclusion in this systematic review. Current evidence suggests that bone dust retains osteogenic properties, but limited information is available regarding the osteoinductive potential of bone dust. CONCLUSION: Bone dust represents a free source of autologous bone, which can be easily collected during the time of surgery and used as an augment to aid osseous fusion. Further research is required to evaluate the osteoinductive potential of bone dust. The retained growth factors in bone dust may potentially induce local osteoprogenitor cells to proliferate and mineralize to form new bone. PMID- 28622899 TI - A Novel Method for Estimating Three-Dimensional Apical Vertebral Rotation Using Two-Dimensional Coronal Cobb Angle and Thoracic Kyphosis. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVES: To use a large cohort of three-dimensional (3D) spinal reconstructions to create a simple mathematical formula capable of estimating 3D apical vertebral rotation (AVR) based on the correlation with routinely obtained two-dimensional (2D) measurements of scoliosis. SUMMARY OF BACKGROUND DATA: Quantification of vertebral rotation in AIS using 2-dimensional (2D) imaging is inherently challenging as the axial plane cannot be directly visualized. METHODS: A database of 279 3D spinal reconstructions was queried for patients with thoracic major adolescent idiopathic scoliosis (AIS). 2D thoracic Cobb angle, T5-T12 thoracic kyphosis, pelvic incidence, sacral slope, and pelvic tilt were recorded. 3D AVR was calculated for each patient from 3D reconstructions. Patients were divided into development (n = 186) and validation (n = 93) cohorts. Within the development cohort, univariate analysis was performed between 2D measurements and 3D AVR with significance set at p < .05 for inclusion in multivariate analysis. In multivariate analysis, significance was set at p < .01 for inclusion in the final model. Model performance was tested in development and validation cohorts. RESULTS: Only 2D thoracic Cobb and T5-T12 thoracic kyphosis had significance in univariate (p < .05) and multivariate analyses (p < .01), meriting inclusion in the final model. 3D AVR ( degrees ) = 0.26*(T5-T12 kyphosis) + 0.34*(coronal Cobb) - 5.38. In the development cohort, the model performed well (R = 0.739, r2 = 0.54). In testing with the validation cohort, the model proved generalizability (R = 0.703) and had a mean absolute error <5 degrees . CONCLUSIONS: This model is capable of estimating 3D AVR given 2D thoracic Cobb and T5-T12 kyphosis. The accuracy of this method is comparable to previously reported methods of 2D axial rotation measurement. However, this model provides 3D axial rotation and requires no physical instruments, non-standard measurements, or software programs. Such a model is valuable for both routine evaluation of AIS and operative preparation. LEVEL OF EVIDENCE: Level II, diagnostic. PMID- 28622900 TI - The Risk of Curve Progression and Surgery in African Americans With Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: Retrospective clinical cohort study. OBJECTIVE: To determine if certain risk factors (age, curve magnitude, skeletal maturity, gender, and curve pattern) traditionally associated with curve progression and surgical intervention in the general population apply equally to African Americans. SUMMARY OF BACKGROUND DATA: Currently, information is limited on the role that a patient's race plays in the risk of curve progression of adolescent idiopathic scoliosis (AIS), and existing studies have conflicting results. METHODS: Retrospective search of records identified patients who were African American, had been diagnosed with AIS, had a major curve Cobb angle of 10 degrees or more, and had at least two clinical visits with spinal radiographs at least 90 days apart to determine the risk factors for surgical treatment, and 2 years apart to determine the risk factors for curve progression. Patients with a medical condition likely to cause scoliosis were excluded. RESULTS: Of 738 African American patients with AIS, 223 were assessed for surgical risk factors, and 72 were assessed for curve progression risk factors. Fifty-six (29.17%) had progression of the major coronal curve, and 38 (17.04%) underwent surgery. Age at presentation and curve magnitude at presentation were significant risk factors for surgical intervention. Curve magnitude at presentation was a significant risk factor for curve progression. No significant relationships were found for gender or curve type as they relate to surgical intervention or curve progression. CONCLUSION: Age and curve magnitude at presentation were significantly associated with surgery, as is true in other scoliosis populations. Curve magnitude at presentation was associated with curve progression. In contrast to studies in other populations, however, no significant association was observed between curve progression and age at presentation, curve type, or gender, or between surgery and curve type or gender. LEVEL OF EVIDENCE: Level III, prognostic cohort study. PMID- 28622901 TI - Tridimensional Analysis of Rotatory Subluxation and Sagittal Spinopelvic Alignment in the Setting of Adult Spinal Deformity. AB - STUDY DESIGN: Retrospective single-center. OBJECTIVE: To investigate rotatory subluxation (RS) in adult spinal deformity (ASD) with three-dimensional (3D) stereoradiographic images and analyze relationships between RS, transverse plane parameters, spinopelvic parameters, and clinical outcomes. BACKGROUND: Recent research has demonstrated that sagittal plane malalignment and listhesis correlate with ASD patient-reported outcomes. However, there is still a lack of knowledge regarding the clinical impact of 3D evaluation and rotatory subluxation. Recent developments in stereoradiography allow clinicians to obtain full-body standing radiographs with low-dose radiation and 3D reconstruction. METHODS: One hundred thirty lumbar ASD patients underwent full-spine biplanar radiographs (EOS Imaging, Paris, France). Clinical outcomes were recorded. Using sterEOS software, spinopelvic parameters and lateral listhesis were measured. 3D transverse plane parameters included apical axial vertebral rotation, axial intervertebral rotation (AIR), and torsion index (sum of AIR in the curve). ASD patients were divided in three groups: AIR <5 degrees , 5 degrees < AIR <10 degrees , AIR >10 degrees . Groups were compared with respect to radiographic and clinical data. Correlations were performed between the transverse and sagittal plane parameters and clinical outcomes. RESULTS: Patients with AIR >10 degrees were significantly older, with larger Cobb angle (39.5 degrees ) and greater sagittal plane deformity (pelvic incidence-lumbar lordosis mismatch 11.7 degrees and pelvic tilt 22.6 degrees ). The AIR >10 degrees group had significantly greater apical vertebra axial rotation apex (24.8 degrees ), torsion index (45 degrees ), and upper-level AIR (21.5 degrees ) than the two other groups. Overall, 27% of AIR patients did not have two-dimensional (2D) lateral listhesis. Patients with AIR >10 degrees had significantly worse Oswestry Disability Index and more low back pain. CONCLUSION: For patients in which lateral listhesis was unreadable in 2D imaging, rotatory subluxation was revealed using stereoradiography and at an earlier disease stage. Moreover, different 3D transverse plane parameters are related to different patient-reported outcomes. Therefore, axial rotation can be considered in evaluation of lumbar degenerative scoliosis severity and prognosis. LEVEL OF EVIDENCE: Level III. PMID- 28622902 TI - A Critical Analysis of Sagittal Plane Deformity Correction With Minimally Invasive Adult Spinal Deformity Surgery: A 2-Year Follow-Up Study. AB - INTRODUCTION: Sagittal plane realignment is important to achieve desirable clinical outcomes after adult spinal deformity (ASD) surgery. This study evaluates the impact of minimally invasive (MIS) techniques on sagittal plane alignment and clinical outcomes in ASD patients. METHODS: A retrospective, multi center review of ASD patients (age >=18 years, and with one of the following: coronal Cobb >=20 degrees , sagittal vertical axis [SVA] >5 cm, and/or pelvic tilt >25 degrees ), MIS surgery, and four or more levels instrumented. Patients were stratified by baseline SRS-Schwab global alignment modifier (GAM) into three groups: 0 (SVA <4 cm), + (SVA 4-9.5 cm), or ++ (SVA >9.5 cm). Radiographic and clinical outcomes measures were analyzed with a minimum of 2-year follow-up. RESULTS: A total of 96 ASD patients were identified, and 63 met the study's inclusion criteria of circumferential MIS or posterior MIS only, with four or more levels instrumented (n: Group 0 = 37, Group + = 15, and Group ++ = 11). Group 0 was younger than ++ (56.8 vs. 69.6 years), with a higher proportion of females than Group + or ++ (83.8% vs. 66.7% and 54.5%, respectively). Baseline HRQoL was similar. Postoperatively, Groups 0 and + had improved Oswestry Disability Index (ODI) and numeric rating scale (NRS) back and leg scores. Group ++ only had improvement in NRS scores. At the latest follow-up, Groups 0 and ++ had similar sagittal measurements except for PT (21.6 vs. 23.6, p = .009). The + group had improvement in PI-LL (24.2 to 17; p = .015) and LL (30.9 to 38.3; p = .013). Eight of 27 (21.6%) Group 0 patients deteriorated (4 to Group +, 4 to Group ++). Three of 15 (20.0%) Group + patients deteriorated to Group ++, and 3 improved to Group 0. Six of 11 (54.5%) Group ++ patients improved (3 to Group + and 3 to Group 0). CONCLUSIONS: MIS techniques successfully stabilized ASD patients with Group 0 and + deformities and improved HRQoL. This study suggests that severe sagittal imbalance is not adequately treated with MIS approaches. PMID- 28622903 TI - Cell Saver for Adult Spinal Deformity Surgery Reduces Cost. AB - STUDY DESIGN: Retrospective cohort. OBJECTIVES: To determine if the use of cell saver reduces overall blood costs in adult spinal deformity (ASD) surgery. SUMMARY OF BACKGROUND DATA: Recent studies have questioned the clinical value of cell saver during spine procedures. METHODS: ASD patients enrolled in a prospective, multicenter surgical database who had complete preoperative and surgical data were identified. Patients were stratified into (1) cell saver available during surgery, but no intraoperative autologous infusion (No Infusion group), or (2) cell saver available and received autologous infusion (Infusion group). RESULTS: There were 427 patients in the Infusion group and 153 in the No infusion group. Patients in both groups had similar demographics. Mean autologous infusion volume was 698 mL. The Infusion group had a higher percentage of EBL relative to the estimated blood volume (42.2%) than the No Infusion group (19.6%, p < .000). Allogeneic transfusion was more common in the Infusion group (255/427, 60%) than the No Infusion group (67/153, 44%, p = .001). The number of allogeneic blood units transfused was also higher in the Infusion group (2.4) than the No Infusion group (1.7, p = .009). Total blood costs ranged from $396 to $2,146 in the No Infusion group and from $1,262 to $5,088 in the Infusion group. If the cost of cell saver blood was transformed into costs of allogeneic blood, total blood costs for the Infusion group would range from $840 to $5,418. Thus, cell saver use yielded a mean cost savings ranging from $330 to $422 (allogeneic blood averted). Linear regression showed that after an EBL of 614 mL, cell saver becomes cost-efficient. CONCLUSION: Compared to transfusing allogeneic blood, cell saver autologous infusion did not reduce the proportion or the volume of allogeneic transfusion for patients undergoing surgery for adult spinal deformity. The use of cell saver becomes cost-efficient above an EBL of 614 mL, producing a cost savings of $330 to $422. LEVEL OF EVIDENCE: Level III. PMID- 28622904 TI - Radiographic Outcomes of Shilla Growth Guidance System and Traditional Growing Rods Through Definitive Treatment. AB - STUDY DESIGN: Retrospective review of a multicenter database. OBJECTIVES: To compare the radiographic outcomes of patients who had undergone the Shilla Growth Guidance System (SGGS) and traditional growing rod (GR) treatment for management of early-onset scoliosis (EOS) through definitive treatment. SUMMARY OF BACKGROUND DATA: The efficacy of surgical treatment of EOS can only be determined after definitive treatment has been completed. We wanted to review our experience with the SGGS and GR for management of EOS through definitive treatment. METHODS: Patients who had surgical treatment with SGGS or GR and had undergone definitive treatment were included. The patients were matched by age, preoperative curve magnitude, and diagnosis. The study population consisted of 36 patients (18 in each group) whose mean age at initial surgery was as follows: SGGS, 7.9 years; and GR, 7.7 years (not significant [NS]). Length of follow-up after initial surgery was 6.1 years for SGGS and 7.4 years for GR (NS). Definitive treatment was posterior spinal fusion (15 SGGS, 17 GR), implant removal (3 SGGS), or completion of lengthenings (1 GR). RESULTS: The preoperative curve was 61 degrees for SGGS and 65 degrees for GR (NS). After index surgery, the major curve decreased to 24 degrees (-37 degrees) for SGGS and 38 (-27 degrees) for GR (p < .05). At last follow-up, the major curve was 34 degrees (44%) for SGGS and 36 degrees (45%) for GR (NS). The initial T1-T12 length for SGGS was 188 mm and for GR, 181 mm; at last follow-up, SGGS was 234 mm (46 mm increase) and GR was 233 mm (52 mm increase) (NS). CONCLUSION: Our analysis shows the final radiographic outcomes (and changes) and complications (implant-related and infection) between the SGGS and GR groups were not statistically different. The main difference between the two groups was the threefold difference in overall surgeries. PMID- 28622905 TI - Discovery of novel somatostatin receptor subtype 5 (SSTR5) antagonists: Pharmacological studies and design to improve pharmacokinetic profiles and human Ether-a-go-go-related gene (hERG) inhibition. AB - Somatostatin (SST) is a peptide hormone comprising 14 or 28 amino acids that inhibits endocrine and exocrine secretion via five distinct G-protein-coupled receptors (SSTR1-5). SSTR5 has an important role in inhibiting the secretion of pancreatic and gastrointestinal hormones (e.g., insulin, GLP-1, PYY) through the binding of SSTs; hence, SSTR5 antagonists are expected to be novel anti-diabetic drugs. In the course of our lead generation program of SSTR5 antagonists, we have discovered a novel spiroazetidine derivative 3a. However, pharmacological evaluation of 3a revealed that it had to be administered at a high dose (100mg/kg) to show a persistent glucose-lowering effect in an oral glucose tolerance test (OGTT). We therefore initiated an optimization study based on 3a aimed at improving the antagonistic activity and mean residence time (MRT), resulting in the identification of 2-cyclopropyl-5-methoxybiphenyl derivative 3k. However, 3k did not show a sufficient persistent glucose-lowering effect in an OGTT; moreover, hERG inhibition was observed. Hence, further optimization study of the biphenyl moiety of compound 3k, focused on improving the pharmacokinetic (PK) profile and hERG inhibition, was conducted. Consequently, the introduction of a chlorine atom at the 6-position on the biphenyl moiety addressed a putative metabolic soft spot and increased the dihedral angle of the biphenyl moiety, leading to the discovery of 3p with an improved PK profile and hERG inhibition. Furthermore, 3p successfully exhibited a persistent glucose-lowering effect in an OGTT at a dose of 3mg/kg. PMID- 28622906 TI - Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors. AB - The PARP-2 selective inhibitor is important for clarifying specific roles of PARP 2 in the pathophysiological process and developing desired drugs with reduced off target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC50=467nM, PARP-2 IC50=11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program. PMID- 28622907 TI - Synthesis, biological evaluation and molecular modeling of imidazo[1,2-a]pyridine derivatives as potent antitubulin agents. AB - Two series of novel 5,7-diarylimidazo[1,2-a]pyridine-8-carbonitrile derivatives (3a-3q and 7a-7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h-7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC50 values in double-digit nanomolar degree. Optimization toward these compounds led to the discovery of a promising lead 7e, which showed noteworthy potency with IC50 value ranging from 0.01 to 3.2uM superior to CA-4 and Crolibulin. Importantly, immunofluorescence staining and colchcine competitive binding assay revealed that microtubule dynamics was disrupted by 7e by binding at the colchicine site of tubulin. Moreover, molecular docking studies suggested the binding of this mimic at colchcine-binding site is similar to Crolibulin, as was in conformity with the observed SARs for these compounds. PMID- 28622908 TI - Small Cell Lung Cancer. Methodology and Preliminary Results of the SMALL CELL Study. AB - INTRODUCTION: Small cell lung cancer (SCLC) is the most aggressive histologic type of lung cancer, and accounts for approximately 10%-15% of all cases. Few studies have analyzed the effect of residential radon. Our aim is to determine the risk factors of SCLC. METHODS: We designed a multicenter, hospital-based case control study with the participation of 11 hospitals in 4 autonomous communities. RESULTS: Results of the first 113 cases have been analyzed, 63 of which included residential radon measurements. Median age at diagnosis was 63 years; 11% of cases were younger than 50 years of age; 22% were women; 57% had extended disease; and 95% were smokers or former smokers. Median residential radon concentration was 128Bq/m3. Concentrations higher than 400Bq/m3 were found in 8% of cases. The only remarkable difference by gender was the percentage of never smokers, which was higher in women compared to men (P<.001). Radon concentration was higher in patients with stageIV disease (non-significant difference) and in individuals diagnosed at 63 years of age or older (P=.032). CONCLUSIONS: A high percentage of SCLC cases are diagnosed early and there is a predominance of disseminated disease at diagnosis. Residential radon seems to play an important role on the onset of this disease, with some cases having very high indoor radon concentrations. PMID- 28622909 TI - Biomechanical evaluation of a novel pedicle screw-based interspinous spacer: A finite element analysis. AB - Interspinous spacers have been designed to provide a minimally invasive surgical technique for patients with lumbar spinal stenosis or foraminal stenosis. A novel pedicle screw-based interspinous spacer has been developed in this study, and the aim of this finite element experiment was to investigate the biomechanical differences between the pedicle screw-based interspinous spacer (M-rod system) and the typical interspinous spacer (Coflex-FTM). A validated finite element model of an intact lumbar spine was used to analyze the insertions of the Coflex FTM, titanium alloy M-rod (M-Ti), and polyetheretherketone M-rod (M-PEEK), independently. The range of motion (ROM) between each vertebrae, stiffness of the implanted level, the peak stress at the intervertebral discs, and the contact forces on spinous process were analyzed. Of all three devices, the Coflex-FTM provided the largest restrictions in extension, flexion and lateral bending. For intervertebral disc, the peak stress at the implanted segment decreased by 81% in the Coflex-FTM, 60.2% in the M-Ti and 46.7% in the M-PEEK when compared to the intact model. For the adjacent segments, while the Coflex-FTM caused considerable increases in the ROM and disc stress, the M-PEEK only had small changes. PMID- 28622910 TI - The link between morphology and complement in ocular disease. AB - The complement system is a vital component of the immune-priveliged human eye that is always active at a low-grade level, preventing harmful intraocular injuries caused by accumulation of turnover products and controlling pathogens to preserve eye homeostasis and vision. The complement system is a double-edged sword that is essential for protection but may also become harmful and contribute to eye pathology. Here, we review the evidence for the involvement of complement system dysregulation in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica, highlighting the relationship between morphogical changes and complement system protein expression and regulation in these diseases. The potential benefits of complement inhibition in age-related macular degeneration, glaucoma, uveitis, and neuromyelitis optica are abundant, as are those of further research to improve our understanding of complement-mediated injury in these diseases. PMID- 28622911 TI - Demyelination, strokes, and eculizumab: Lessons from the congenital CD59 gene mutations. AB - Neurological symptoms of patients with p.Cys89Tyr mutation in the CD59 gene include recurrent peripheral neuropathy resembling Guillain-Barre syndrome, characterized by sensory-motor demyelinating neuropathy with secondary axonal damage and moderate enhancement of the nerve roots on spine MRI, together with recurrent strokes and retinal involvement. Three additional mutations in CD59, leading to loss of function, have been described, and overall, 12/12 (100%) of patients with any mutation presented with neurological symptoms; 11/12 (92%) patients presented with recurrent peripheral neuropathy, 6/12 (50%) with recurrent strokes, and 1/12 (8%) with retinal involvement. We review the possible thrombophilic profile associated with the mutations. In these patients, excessive intravascular hemolysis saturates scavenger mechanisms resulting in free hemoglobin in plasma that irreversibly reacts with nitric oxide to form nitrate and methemoglobin, leading to arterial thrombosis. CD59 loss of function is also one of the major thrombophilic mechanisms in patients with paroxysmal nocturnal hemoglobinuria. We then describe the relationship with demyelination. The lack of CD59 allows uncontrolled complement amplification following low-level spontaneous , viral-, or post viral-induced complement activation, resulting in severe demyelination in the peripheral nervous system. It is interesting, and certainly encouraging, that after 3 years, following 4 patients with Cys89Tyr mutations who are treated with eculizumab, no strokes occurred and non-permanent neurological insults underwent resolution without any new neurological exacerbations. PMID- 28622912 TI - Clinical approaches to the development of a neuroprotective therapy for PD. AB - The development of a neuroprotective or disease-modifying therapy is the major unmet need in the management of Parkinson's Disease (PD) and the goal of much clinical and scientific research. However, despite enormous efforts and expense, no disease-modifying therapy for PD has been approved to date. Historically attempts to define such a therapy have been limited by confounding symptomatic/pharmacologic effects of the study intervention and the lack of a clear and well-defined regulatory and clinical development pathway that leads to a disease-modifying indication. Further, the costs of the development program average 1 billion dollars with a duration of 10 to 13years. As a consequence, many pharmaceutical companies are reluctant to test novel therapies despite the recent scientific advances and promising candidate targets and approaches. In the present review we describe previous studies aimed at defining a disease-modifying drug and discuss their limitations. We also consider some of the modern approaches and trial design for drug development that will hopefully pave the way toward identifying and gaining regulatory approval for a disease-modifying therapy in a relatively efficient and cost-effective manner. PMID- 28622915 TI - Turkish validity and reliability of Eustachian tube dysfunction questionnaire-7. AB - INTRODUCTION: During clinical evaluations, in order to interpret patients' complaints caused by Eustachian tube dysfunction and to monitor the success of the treatment, standardized and disease-related scales are necessary. OBJECTIVE: The aim of this study was to investigate the validity and reliability of the Turkish version of Eustachian tube dysfunction questionnaire-7. METHODS: Forty patients diagnosed with Eustachian tube dysfunction and 40 healthy individuals were enrolled for the study. After language validation of the Eustachian tube dysfunction questionnaire-7 for Turkish, a scale was completed by the both Eustachian tube dysfunction and control groups. Two weeks after the first evaluation, 15 of the cases filled out the scale again without any treatment intervention. Known-groups method was used in validity analysis. Floor-ceiling effect, test-retest method, item-total score correlation and internal consistency analysis were used in reliability analyses. RESULTS: Cronbach's alpha coefficient was 0.714 for the entire questionnaire. The test-retest reliability coefficient for the total scale was determined as 0.792, indicating correlation between the two questionnaires completed by the same patient over time. In the Eustachian tube dysfunction group, total and each item scores were found significantly higher than the control group (p<0.001). CONCLUSION: The Turkish version of Eustachian tube dysfunction questionnaire-7 was found to be highly valid and reliable. This scale is recommended to use for screening of Eustachian tube dysfunction and evaluating treatment outcome. PMID- 28622914 TI - Association of Resistance Exercise, Independent of and Combined With Aerobic Exercise, With the Incidence of Metabolic Syndrome. AB - OBJECTIVE: To determine the association of resistance exercise, independent of and combined with aerobic exercise, with the risk of development of metabolic syndrome (MetS). PATIENTS AND METHODS: The study cohort included adults (mean +/- SD age, 46+/-9.5 years) who received comprehensive medical examinations at the Cooper Clinic in Dallas, Texas, between January 1, 1987, and December, 31, 2006. Exercise was assessed by self-reported frequency and minutes per week of resistance and aerobic exercise and meeting the US Physical Activity Guidelines (resistance exercise >=2 d/wk; aerobic exercise >=500 metabolic equivalent min/wk) at baseline. The incidence of MetS was based on the National Cholesterol Education Program Adult Treatment Panel III criteria. We used Cox regression to generate hazard ratios (HRs) and 95% CIs. RESULTS: Among 7418 participants, 1147 (15%) had development of MetS during a median follow-up of 4 years (maximum, 19 years; minimum, 0.1 year). Meeting the resistance exercise guidelines was associated with a 17% lower risk of MetS (HR, 0.83; 95% CI, 0.73-0.96; P=.009) after adjusting for potential confounders and aerobic exercise. Further, less than 1 hour of weekly resistance exercise was associated with 29% lower risk of development of MetS (HR, 0.71; 95% CI, 0.56-0.89; P=.003) compared with no resistance exercise. However, larger amounts of resistance exercise did not provide further benefits. Individuals meeting both recommended resistance and aerobic exercise guidelines had a 25% lower risk of development of MetS (HR, 0.75; 95% CI, 0.63-0.89; P<.001) compared with meeting neither guideline. CONCLUSION: Participating in resistance exercise, even less than 1 hour per week, was associated with a lower risk of development of MetS, independent of aerobic exercise. Health professionals should recommend that patients perform resistance exercise along with aerobic exercise to reduce MetS. PMID- 28622916 TI - Osteogenic potential of platelet-rich plasma in dental stem-cell cultures. AB - The purpose of this study was to analyse the potential of platelet-rich plasma (PRP) culture media to induce osteogenic differentiation of periodontal ligament stem cells and dental pulp stem cells compared with four other methods of culture. Both types of cell were collected from 35 healthy patients and cultured in five different media (Dulbecco's modified eagle's medium (DMEM); DMEM and melatonin; DMEM and PRP; DMEM and ascorbic acid 200MUmol; DMEM and l-ascorbate 2 phosphate 50MUmol). Cells were characterised by flow cytometry. Alizarin Red stain, alkaline phosphatase stain, and the expression of collagen type 1 (Col-1), runt-related transcription factor (RUNX2), osteoprotegerin, and osteopontin (quantified by qRT-PCR) were used to detect the osteogenic profile in each culture. Flow cytometry showed that both types of stem cell were a homogeneous mixture of CD90(+), CD105(+), STRO-1(+), CD34 (-), and CD45 (-) cells. Dental pulp stem cells that were cultured with PRP showed the best osteogenic profile (RUNX2 p=0.0002; osteoprotegerin p=0.001). The group of these stem cells that showed the best osteogenic profile was also cultured with PRP (osteoprotegerin p=0.001). Medium five (with l-ascorbate 2-phosphate 50MUmol added) showed an increase in all osteogenic markers for periodontal ligament stem cells after PRP, while the best culture conditions for osteogenic expression of dental pulp stem cells after PRP was in medium four (ascorbic acid 200MUmol added). These results suggested that culture in PRP induces osteogenic differentiation of both types of stem cell, modulating molecular pathways to promote bony formation. PMID- 28622917 TI - New Beginnings: Mitochondrial Renewal by Massive Mitochondrial Fusion. AB - Massive mitochondrial fusion (MMF) in germinating arabidopsis seeds, together with earlier studies, suggests a significant role for MMF in the life cycle of flowering plants. MMF is likely to facilitate nucleoid transmission, mitochondrial DNA (mtDNA) recombination, and the homogenization of mitochondrial components, thus providing a type of quality control for mitochondrial populations in new generations. PMID- 28622918 TI - Angiosperm Plant Desiccation Tolerance: Hints from Transcriptomics and Genome Sequencing. AB - Desiccation tolerance (DT) in angiosperms is present in the small group of resurrection plants and in seeds. DT requires the presence of protective proteins, specific carbohydrates, restructuring of membrane lipids, and regulatory mechanisms directing a dedicated gene expression program. Many components are common to resurrection plants and seeds; however, some are specific for resurrection plants. Understanding how each component contributes to DT is challenging. Recent transcriptome analyses and genome sequencing indicate that increased expression is essential of genes encoding protective components, recently evolved, species-specific genes and non-protein-coding RNAs. Modification and reshuffling of existing cis-regulatory promoter elements seems to play a role in the rewiring of regulatory networks required for increased expression of DT-related genes in resurrection species. PMID- 28622913 TI - Targeting urate to reduce oxidative stress in Parkinson disease. AB - Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants. Urate, the main antioxidant found in plasma as well as the end product of purine metabolism in humans, has emerged as a promising potential neuroprotectant with advantages that distinguish it from previously tested antioxidant agents. Uniquely, higher urate levels in plasma or cerebrospinal fluid (CSF) have been linked to both a lower risk of developing PD and to a slower rate of its subsequent progression in numerous large prospective epidemiological and clinical cohorts. Laboratory evidence that urate confers neuroprotection in cellular and animal models of PD, possibly via the Nrf2 antioxidant response pathway, further strengthened its candidacy for rapid clinical translation. An early phase trial of the urate precursor inosine demonstrated its capacity to safely produce well tolerated, long-term elevation of plasma and CSF urate in early PD, supporting a phase 3 trial now underway to determine whether oral inosine dosed to elevate urate to concentrations predictive of favorable prognosis in PD slows clinical decline in people with recently diagnosed, dopamine transporter-deficient PD. PMID- 28622919 TI - Diet of Arbuscular Mycorrhizal Fungi: Bread and Butter? AB - Most plants entertain mutualistic interactions known as arbuscular mycorrhiza (AM) with soil fungi (Glomeromycota) which provide them with mineral nutrients in exchange for reduced carbon from the plant. Mycorrhizal roots represent strong carbon sinks in which hexoses are transferred from the plant host to the fungus. However, most of the carbon in AM fungi is stored in the form of lipids. The absence of the type I fatty acid synthase (FAS-I) complex from the AM fungal model species Rhizophagus irregularis suggests that lipids may also have a role in nutrition of the fungal partner. This hypothesis is supported by the concerted induction of host genes involved in lipid metabolism. We explore the possible roles of lipids in the light of recent literature on AM symbiosis. PMID- 28622921 TI - Accurate prediction of coronary and cerebrovascular events: Adding small pieces to an emerging puzzle. PMID- 28622920 TI - Post-9/11 sarcoidosis in WTC-exposed firefighters and emergency medical service workers. AB - INTRODUCTION: The World Trade Center (WTC) disaster released a huge quantity and variety of toxicants into the environment. To-date, studies from each of the three major cohorts of WTC-exposed workers have suggested "greater than expected" numbers of post-9/11 cases in some workers. We undertook this study to estimate the incidence of post-9/11 sarcoidosis in ~13,000 male firefighters and EMS workers enrolled in The Fire Department of the City of New York (FDNY) WTC Health Program; to compare FDNY incidence to rates from unexposed, demographically similar men in the Rochester Epidemiology Project (REP); and, to examine rates by level of WTC exposure. METHODS: We calculated incidence of sarcoidosis diagnosed from 9/12/2001 to 9/11/2015, and generated expected sex- and age-specific rates based on REP rates. Standardized incidence ratios (SIR) based on REP rates, and 95% confidence intervals (95% CI) were estimated. Two sensitivity analyses limited cases to those with intra-thoracic symptoms or biopsy confirmation. RESULTS: We identified 68 post-9/11 cases in the FDNY cohort. Overall, FDNY rates were significantly higher than expected rates (SIR = 2.8; 95% CI = 2.2, 3.6). Including only symptomatic cases, the SIR decreased (SIR = 2.2; 95% CI = 1.5, 3.0), but remained significantly elevated. SIRs ranged from 2.7 (95% CI = 2.0, 3.5) in the lower WTC exposure group to 4.2 (95% CI = 1.9, 8.0) in the most highly exposed. CONCLUSIONS: We found excess incident post-9/11 sarcoidosis in WTC-exposed workers. Continued surveillance, particularly of those most highly exposed, is necessary to identify those with sarcoidosis and to follow them for possible adverse effects including functional impairments and organ damage. PMID- 28622922 TI - Cross-sectional human study of soft tissue chin (STC) thickness in adult patients in relation to sex, facial pattern and skeletal class. AB - PURPOSE: The aim of this study was to study the relations between the soft tissue chin (STC) and sex, skeletal class, and facial pattern; and to describe the shape and behavior of the STC. METHODS: 385 non-growing patients were selected, 206 women and 179 men, with a mean age of 28.8 years (SD 4.2). Patients were divided into groups by skeletal class (class I, II or III) and facial pattern (brachyfacial, mesofacial or dolichofacial). STC thicknesses were measured at pogonion (Pg), soft pogonion (Pg'), gnathion (Gn), soft gnathion (Gn'), menton (Me) and soft menton (Me') in the CBCTs. RESULTS: Sexual dimorphism was observed at Pg-Pg' and Me-Me'. STC thickness was not related to skeletal class but related to facial pattern. Pg-Pg' and Me-Me' measurements showed significant differences to the combination of skeletal class/facial pattern. STC thickness was not homogenous in terms of shape and behavior. CONCLUSIONS: The results provide evidence of a strong but complex relationship between sex, facial pattern, skeletal class and STC thickness; for this reason, each patient must be evaluated individually before undergoing orthodontics or orthognathic surgery involving the mandible and the mandibular symphysis. PMID- 28622923 TI - Consistent C3 plant habitat of hominins during 400-300 ka at the Longyadong Cave site (Luonan Basin, central China) revealed by stable carbon isotope analyses of loess deposits. AB - The proportions of woody and grassland taxa in terrestrial ecosystems played an important role in the origin and evolution of early Palaeolithic hominins. However the influence of ecosystem changes on hominin behavior and adaptations in Asia has not been studied in detail. Hominins have exploited the Luonan Basin in the Eastern Qinling Mountains, central China, since the early Paleolithic. Dated sites, consisting of alternating loess and soil deposits with in situ artefacts, are common in the region, and provide a detailed record of Early to Middle Pleistocene hominin environments. Here, we present the results of measurements of the stable carbon isotopic composition of soil organic matter (delta13CSOM) in the loess-paleosol sequences from the Longyadong Cave site. Our analyses of delta13CSOM show that for at least 400 ka the Longyadong Cave site and its surroundings were dominated by C3 woody plants, whereas the nearby Liuwan site was dominated by C4 and C3 mixed grassland or woody grassland vegetation. These findings demonstrate that between 400 and 300 ka in the Luonan Basin, hominins occupied a habitat consisting of a mosaic of grassland and woodland/forest. Although the vegetation of the region changed in response to the glacial interglacial climatic cycles, patches of woody vegetation in landscapes such as at Longyadong Cave site persisted continuously. Such environments seem to be have been favored by hominins living in the Luonan Basin, possibly because they provided a diverse range of food resources during both glacial and interglacial intervals of the Middle Pleistocene, when most of northern China was experiencing an increasing trend of drying and cooling and steppe environments were expanding. Thus, the Luonan Basin would have served as a refugium for hominin occupation in China during the Middle Pleistocene. PMID- 28622924 TI - Functional associations between support use and forelimb shape in strepsirrhines and their relevance to inferring locomotor behavior in early primates. AB - The evolution of primates is intimately linked to their initial invasion of an arboreal environment. However, moving and foraging in this milieu creates significant mechanical challenges related to the presence of substrates differing in their size and orientation. It is widely assumed that primates are behaviorally and anatomically adapted to movement on specific substrates, but few explicit tests of this relationship in an evolutionary context have been conducted. Without direct tests of form-function relationships in living primates it is impossible to reliably infer behavior in fossil taxa. In this study, we test a hypothesis of co-variation between forelimb morphology and the type of substrates used by strepsirrhines. If associations between anatomy and substrate use exist, these can then be applied to better understand limb anatomy of extinct primates. The co-variation between each forelimb long bone and the type of substrate used was studied in a phylogenetic context. Our results show that despite the presence of significant phylogenetic signal for each long bone of the forelimb, clear support use associations are present. A strong co-variation was found between the type of substrate used and the shape of the radius, with and without taking phylogeny into account, whereas co-variation was significant for the ulna only when taking phylogeny into account. Species that use a thin branch milieu show radii that are gracile and straight and have a distal articular shape that allows for a wide range of movements. In contrast, extant species that commonly use large supports show a relatively robust and curved radius with an increased surface area available for forearm and hand muscles in pronated posture. These results, especially for the radius, support the idea that strepsirrhine primates exhibit specific skeletal adaptations associated with the supports that they habitually move on. With these robust associations in hand it will be possible to explore the same variables in extinct early primates and primate relatives and thus improve the reliability of inferences concerning substrate use in early primates. PMID- 28622925 TI - Subsistence strategies during the Late Pleistocene in the southern Cape of South Africa: Comparing the Still Bay of Blombos Cave with the Howiesons Poort of Klipdrift Shelter. AB - The Still Bay (SB) and Howiesons Poort (HP) were two significant techno-complexes in the Middle Stone Age and key periods in the expression of behavioral complexity. In this study, we compare the recently excavated fauna from the SB layers at Blombos Cave (BBC) with that from the HP levels at Klipdrift Shelter (KDS) in the southern Cape of South Africa. We consider our findings in the framework of recent models for early human subsistence behavior. In particular, we link our study with models involving resource intensification to examine whether foraging strategies in the HP were more or less intensive than those in the SB. Based on our criteria used to assess intensification-the exploitation of low-ranked prey, the processing of low-utility elements, transport decisions, and occupational intensity-intensive subsistence strategies are more evident at KDS than BBC. Our results suggest that low-ranked elements were processed more heavily and diet breath was broader at KDS than at BBC. However, foraging ranges may have been more extensive at BBC than at KDS. Taphonomic data also suggests that the SB at BBC was a low-intensity, sporadically occupied period in contrast to the high-intensity occupations during the HP at KDS. We argue that this may be related to differences in mobility and residential patterns between these techno complexes. PMID- 28622926 TI - Hominid visitation of the Moravian Karst during the Middle-Upper Paleolithic transition: New results from Pod Hradem Cave (Czech Republic). AB - In 1956-1958, excavations of Pod Hradem Cave in Moravia (eastern Czech Republic) revealed evidence for human activity during the Middle-Upper Paleolithic transition. This spanned 25,050-44,800 cal BP and contained artefacts attributed to the Aurignacian and Szeletian cultures, including those made from porcelanite (rarely used at Moravian Paleolithic sites). Coarse grained excavation techniques and major inversions in radiocarbon dates meant that site chronology could not be established adequately. This paper documents re-excavation of Pod Hradem in 2011 2012. A comprehensive AMS dating program using ultrafiltration and ABOx-SC pre treatments provides new insights into human occupation at Pod Hradem Cave. Fine grained excavation reveals sedimentary units spanning approximately 20,000 years of the Early Upper Paleolithic and late Middle Paleolithic periods, thus making it the first archaeological cave site in the Czech Republic with such a sedimentary and archaeological record. Recent excavation confirms infrequent human visitation, including during the Early Aurignacian by people who brought with them portable art objects that have no parallel in the Czech Republic. Raw material diversity of lithics suggests long-distance imports and ephemeral visits by highly mobile populations throughout the EUP period. PMID- 28622927 TI - Evolution of the hominin knee and ankle. AB - The dispersal of the genus Homo out of Africa approximately 1.8 million years ago (Ma) has been understood within the context of changes in diet, behavior, and bipedal locomotor efficiency. While various morphological characteristics of the knee and ankle joints are considered part of a suite of traits indicative of, and functionally related to, habitual bipedal walking, the timing and phylogenetic details of these morphological changes remain unclear. To evaluate the timing of knee and ankle joint evolution, we apply geometric morphometric methods to three dimensional digital models of the proximal and distal tibiae of fossil hominins, Holocene Homo sapiens, and extant great apes. Two sets of landmarks and curve semilandmarks were defined on each specimen. Because some fossils were incomplete, digital reconstructions were carried out independently to estimate missing landmarks and semilandmarks. Group shape variation was evaluated through shape-and form-space principal component analysis and fossil specimens were projected to assess variation in the morphological space computed from the extant comparative sample. We show that a derived proximal tibia (knee) similar to that seen in living H. sapiens evolved with early Homo at ~2 Ma. In contrast, derived characteristics in the distal tibia appear later, probably with the arrival of Homo erectus. These results suggest a dissociation of the morphologies of the proximal and distal tibia, perhaps indicative of divergent functional demands and, consequently, selective pressures at these joints. It appears that longer distance dispersals that delivered the Dmanisi hominins to Georgia by 1.8 Ma and H. erectus to east-southeast Asia by 1.6 Ma were facilitated by the evolution of a morphologically derived knee complex comparable to that of recent humans and an ankle that was morphologically primitive. This research sets the foundation for additional paleontological, developmental, and functional research to better understand the mechanisms underlying the evolution of bipedalism. PMID- 28622928 TI - Dental development and age at death of the holotype of Anapithecus hernyaki (RUD 9) using synchrotron virtual histology. AB - The chronology of dental development and life history of primitive catarrhines provides a crucial comparative framework for understanding the evolution of hominoids and Old World monkeys. Among the extinct groups of catarrhines are the pliopithecoids, with no known descendants. Anapithecus hernyaki is a medium-size stem catarrhine known from Austria, Hungary and Germany around 10 Ma, and represents a terminal lineage of a clade predating the divergence of hominoids and cercopithecoids, probably more than 30 Ma. In a previous study, Anapithecus was characterized as having fast dental development. Here, we used non destructive propagation phase contrast synchrotron micro-tomography to image several dental microstructural features in the mixed mandibular dentition of RUD 9, the holotype of A. hernyaki. We estimate its age at death to be 1.9 years and describe the pattern, sequence and timing of tooth mineralization. Our results do not support any simplistic correlation between body mass and striae periodicity, since RUD 9 has a 3-day periodicity, which was previously thought unlikely based on body mass estimates in Anapithecus. We demonstrate that the teeth in RUD 9 grew even faster and initiated even earlier in development than suggested previously. Permanent first molars and the canine initiated 49 and 38 days prenatally, respectively. These results contribute to a better understanding of dental development in Anapithecus and may provide a window into the dental development of the last common ancestor of hominoids and cercopithecoids. PMID- 28622929 TI - Catarrhine hallucal metatarsals from the early Miocene site of Songhor, Kenya. AB - Songhor is an early Miocene fossil locality in Kenya known for its diverse primate assemblage that includes catarrhine species belonging to the genera Kalepithecus, Limnopithecus, Dendropithecus, Rangwapithecus, and Proconsul. Expeditions to Songhor since the 1930s have recovered unassociated catarrhine postcranial remains from both the fore- and hindlimbs, including multiple elements from the feet. In this study, we describe KNM-SO 31233, a complete left hallucal metatarsal (Mt1), along with several other fragmentary Mt1 specimens (KNM-SO 1080, 5129, 5141, 22235). These fossils were compared to extant catarrhines and platyrrhines, as well as available fossil Miocene catarrhine Mt1s. Morphometric data were obtained from 3D surface renderings and subjected to a number of analyses to assess their phenetic affinity with the comparative sample, make predictions of body mass, and to infer their functional morphology. The size and shape of the Songhor Mt1s are diverse, exhibiting a large robust morph (KNM-SO 5141) similar in size but not in shape to extant African apes, medium-sized morphs (KNM-SO 1080, 5129 and 22235), and a smaller, slender one (KNM-SO 31233) that has a shape resembling arboreal quadrupedal leaping monkeys and suspensory atelines and hylobatids. KNM-SO 31233 is unlike other known fossil Mt1s, and in general, none of the Songhor Mt1s resembled any single extant anthropoid clade or species. The morpho-functional diversity of Songhor Mt1s is consistent with an extensive morphological and phylogenetic catarrhine diversity in the early part of the Miocene epoch. PMID- 28622930 TI - The palaeoenvironment of the middle Miocene pliopithecid locality in Damiao, Inner Mongolia, China. AB - Damiao, Inner Mongolia, has three main fossil horizons representing the early, middle, and late Miocene. The middle Miocene locality DM01 is the only primate locality from the region and also represents the latest occurrence of pliopithecoids in northern China. The presence of pliopithecoid primates in central Asia after the middle Miocene climatic optimum seems to contradict the general trend of strengthening climatic zonality and increasing aridity. To investigate this enigma, we employ faunal similarity, ecometrics, and stable isotope analysis. Our results support previous inferences concerning the presence of locally humid environments within the increasingly arid surroundings that characterized central Asia. Hypsodonty, estimated mean annual precipitation (MAP), local sedimentology, and large mammal fossils suggest more humid and possibly more forested and wooded environments for the DM01 locality. We compared our results with the adjacent fossil-rich middle Miocene Tunggur localities. However, the small mammal fauna and isotope data are consistent with a mosaic of forest and grassland environment for all Damiao localities. Based on our results, Tunggur may have been too seasonal or not sufficiently humid for pliopithecids. This is supported by the higher mean hypsodonty and lower estimated MAP estimates, as well as slightly higher delta13C values. We suggest that DM01, the driest known Asian pliopithecid locality, may have been a more humid refugium within a generally drier regional context. PMID- 28622931 TI - Three-dimensional morphometrics of thoracic vertebrae in Neandertals and the fossil evidence from El Sidron (Asturias, Northern Spain). AB - Well preserved thoracic vertebrae of Neandertals are rare. However, such fossils are important as their three-dimensional (3D) spatial configuration can contribute to the understanding of the size and shape of the thoracic spine and the entire thorax. This is because the vertebral body and transverse processes provide the articulation and attachment sites for the ribs. Dorsal orientation of the transverse processes relative to the vertebral body also rotates the attached ribs in a way that could affect thorax width. Previous research indicates possible evidence for greater dorsal orientation of the transverse processes and small vertebral body heights in Neandertals, but their 3D vertebral structure has not yet been addressed. Here we present 15 new vertebral remains from the El Sidron Neandertals (Asturias, Northern Spain) and used 3D geometric morphometrics to address the above issues by comparing two particularly well preserved El Sidron remains (SD-1619, SD-1641) with thoracic vertebrae from other Neandertals and a sample of anatomically modern humans. Centroid sizes of El Sidron vertebrae are within the human range. Neandertals have larger T1 and probably also T2. The El Sidron vertebrae are similar in 3D shape to those of other Neandertals, which differ from Homo sapiens particularly in central-lower regions (T6-T10) of the thoracic spine. Differences include more dorsally and cranially oriented transverse processes, less caudally oriented spinous processes, and vertebral bodies that are anteroposteriorly and craniocaudally short. The results fit with current reconstructions of Neandertal thorax morphology. PMID- 28622932 TI - An evolutionary medicine perspective on Neandertal extinction. AB - The Eurasian sympatry of Neandertals and anatomically modern humans - beginning at least 45,000 years ago and possibly lasting for more than 5000 years - has sparked immense anthropological interest into the factors that potentially contributed to Neandertal extinction. Among many different hypotheses, the "differential pathogen resistance" extinction model posits that Neandertals were disproportionately affected by exposure to novel infectious diseases that were transmitted during the period of spatiotemporal sympatry with modern humans. Comparisons of new archaic hominin paleogenome sequences with modern human genomes have confirmed a history of genetic admixture - and thus direct contact - between humans and Neandertals. Analyses of these data have also shown that Neandertal nuclear genome genetic diversity was likely considerably lower than that of the Eurasian anatomically modern humans with whom they came into contact, perhaps leaving Neandertal innate immune systems relatively more susceptible to novel pathogens. In this study, we compared levels of genetic diversity in genes for which genetic variation is hypothesized to benefit pathogen defense among Neandertals and African, European, and Asian modern humans, using available exome sequencing data (three individuals, or six chromosomes, per population). We observed that Neandertals had only 31-39% as many nonsynonymous (amino acid changing) polymorphisms across 73 innate immune system genes compared to modern human populations. We also found that Neandertal genetic diversity was relatively low in an unbiased set of balancing selection candidate genes for primates, those genes with the highest 1% genetic diversity genome-wide in non-human hominoids (apes). In contrast, Neandertals had similar or higher levels of genetic diversity than humans in 12 major histocompatibility complex (MHC) genes. Thus, while Neandertals may have been relatively more susceptible to some novel pathogens and differential pathogen resistance could be considered as one potential contributing factor in their extinction, the expectations of this model are not universally met. PMID- 28622934 TI - Selection to outsmart the germs: The evolution of disease recognition and social cognition. AB - The emergence of providing care to diseased conspecifics must have been a turning point during the evolution of hominin sociality. On a population level, care may have minimized the costs of socially transmitted diseases at a time of increasing social complexity, although individual care-givers probably incurred increased transmission risks. We propose that care-giving likely originated within kin networks, where the costs may have been balanced by fitness increases obtained through caring for ill kin. We test a novel hypothesis of hominin cognitive evolution in which disease may have selected for the cognitive ability to recognize when a conspecific is infected. Because diseases may produce symptoms that are likely detectable via the perceptual-cognitive pathways integral to social cognition, we suggest that disease recognition and social cognition may have evolved together. Using agent-based modeling, we test 1) under what conditions disease can select for increasing disease recognition and care-giving among kin, 2) whether providing care produces greater selection for cognition than an avoidance strategy, and 3) whether care-giving alters the progression of the disease through the population. The greatest selection was produced by diseases with lower risks to the care-giver and prevalences low enough not to disrupt the kin networks. When care-giving and avoidance strategies were compared, only care-giving reduced the severity of the disease outbreaks and subsequent population crashes. The greatest selection for increased cognitive abilities occurred early in the model runs when the outbreaks and population crashes were most severe. Therefore, over the course of human evolution, repeated introductions of novel diseases into naive populations could have produced sustained selection for increased disease recognition and care-giving behavior, leading to the evolution of increased cognition, social complexity, and, eventually, medical care in humans. Finally, we lay out predictions derived from our disease recognition hypothesis that we encourage paleoanthropologists, bioarchaeologists, primatologists, and paleogeneticists to test. PMID- 28622933 TI - Evaluating the potential for tactical hunting in the Middle Stone Age: Insights from a bonebed of the extinct bovid, Rusingoryx atopocranion. AB - The foraging behaviors of Middle Stone Age (MSA) early modern humans have largely been based on evidence from well-stratified cave sites in South Africa. Whereas these sites have provided an abundance of data for behavioral reconstruction that are unmatched elsewhere in Africa, they are unlikely to preserve evidence of the diversity of foraging strategies employed by MSA hunters who lived in a variety of ecological and landscape settings across the African continent. Here we describe the results of recent excavations at the open-air site of Bovid Hill at Wakondo, Rusinga Island, Kenya, which yielded 24 in situ MSA artifacts within an assemblage of bones comprised exclusively of the extinct alcelaphin bovid Rusingoryx atopocranion. The excavated faunal assemblage is characterized by a prime-age-dominated mortality profile and includes cut-marked specimens and an associated MSA Levallois blade-based artifact industry recovered from a channel deposit dated to 68 +/- 5 ka by optically stimulated luminescence. Taphonomic, geologic, and faunal evidence points to mass exploitation of Rusingoryx by humans at Bovid Hill, which likely represents an initial processing site that was altered post-depositionally by fluvial processes. This site highlights the importance of rivers and streams for mass procurement in an open and seasonal landscape, and provides important new insights into MSA behavioral variability with respect to environmental conditions, site function, and tactical foraging strategies in eastern Africa. Bovid Hill thus joins a growing number of MSA and Middle Paleolithic localities that are suggestive of tactical hunting behaviors and mass capture of gregarious ungulate prey. PMID- 28622935 TI - How to review a paper: suggestions from the editors of Surgery and the Journal of Surgical Research. PMID- 28622936 TI - Acoustic radiation force control: Pulsating spherical carriers. AB - The interaction between harmonic plane progressive acoustic beams and a pulsating spherical radiator is studied. The acoustic radiation force function exerted on the spherical body is derived as a function of the incident wave pressure and the monopole vibration characteristics (i.e., amplitude and phase) of the body. Two distinct strategies are presented in order to alter the radiation force effects (i.e., pushing and pulling states) by changing its magnitude and direction. In the first strategy, an incident wave field with known amplitude and phase is considered. It is analytically shown that the zero- radiation force state (i.e., radiation force function cancellation) is achievable for specific pulsation characteristics belong to a frequency-dependent straight line equation in the plane of real-imaginary components (i.e., Nyquist Plane) of prescribed surface displacement. It is illustrated that these characteristic lines divide the mentioned displacement plane into two regions of positive (i.e., pushing) and negative (i.e., pulling) radiation forces. In the second strategy, the zero, negative and positive states of radiation force are obtained through adjusting the incident wave field characteristics (i.e., amplitude and phase) which insonifies the radiator with prescribed pulsation characteristics. It is proved that zero radiation force state occurs for incident wave pressure characteristics belong to specific frequency-dependent circles in Nyquist plane of incident wave pressure. These characteristic circles divide the Nyquist plane into two distinct regions corresponding to positive (out of circles) and negative (in the circles) values of radiation force function. It is analytically shown that the maximum amplitude of negative radiation force is exactly equal to the amplitude of the (positive) radiation force exerted upon the sphere in the passive state, by the same incident field. The developed concepts are much more deepened by considering the required power supply for distinct cases of zero, negative and positive radiation force states along with the frequency dependent asymmetry index. In addition, considering the effect of phase difference between the incident wave field and the pulsating object, and its possible variation with respect to spatial position of object, some practical points about the spatial average of generated radiation force, the optimal state of operation, the stability of zero radiation force states and the possibly of precise motion control are discussed. This work would extend the novel concept of smart carriers to and may be helpful for robust single-beam acoustic handling techniques. Furthermore, the shown capability of precise motion control may be considered as a new way toward smart acoustic driven micro-mechanisms and micro-machines. PMID- 28622938 TI - American Palaeontology and the reception of Darwinism. PMID- 28622937 TI - Antibodies under pressure: A Small-Angle X-ray Scattering study of Immunoglobulin G under high hydrostatic pressure. AB - In the present work two subclasses of the human antibody Immunoglobulin G (IgG) have been investigated by Small-Angle X-ray Scattering under high hydrostatic pressures up to 5kbar. It is shown that IgG adopts a symmetric T-shape in solution which differs significantly from available crystal structures. Moreover, high-pressure experiments verify the high stability of the IgG molecule. It is not unfolded by hydrostatic pressures of up to 5kbar but a slight increase of the radius of gyration was observed at elevated pressures. PMID- 28622939 TI - Social preferences for prioritizing the treatment of severely ill patients: The relevance of severity, expected benefit, past health and lifetime health. AB - The study examined the preferences of a sample of the Australian public and health professionals regarding the relative importance of four different criteria for prioritizing between patients: the severity of the condition, the size of the benefit from the intervention, past health losses and expected lifetime health. A discussion-group methodology was adopted to elicit social preferences. This allowed participants time to consider all of the alternatives fully, to seek clarification of the task, and to engage in open debate about the issues raised. Participants traded-off cost-effectiveness for priority to the more severely ill. They placed less importance on past health and the lifetime allocation of health in deciding priority for treatment, and more importance on improving the condition of those who will be left more severely ill or disabled in the absence of treatment. The results pose a challenge to studies reporting support for the "fair innings argument". They also support the Norwegian government's decision not to pursue a life-time health loss criterion as recommended by the Norheim Commission. The study question is important given current debate both in the health economics literature and at the policy level in several jurisdictions. PMID- 28622940 TI - Feasibility of performing non-contrast magnetic resonance angiography in pregnant subjects with familial aortopathies. AB - BACKGROUND: Pregnancy is associated with an increased risk of aortic pathology. We sought to assess the feasibility of performing non-contrast 3D steady-state free-precession (SSFP) magnetic resonance angiography (MRA) in pregnant subjects with inherited aortopathy. METHODS: Fifteen pregnant subjects (age 27+/-4yr) with positive genotyping for aortopathy (Marfan, Loeys-Dietz, Ehlers-Danlos) and/or a family history of aortic dissection underwent non-contrast 3D-SSFP MRA at 1.5T (Avanto, Siemens Healthcare, Erlangen, Germany) using a modified ECG-triggered orientated in a sagittal-oblique plane with a respiratory navigator at the diaphragmatic level (mean acquisition time 4.1+/-1.9min). Imaging was performed during the mid-trimester (21+/-5weeks). Image analysis was performed off-line using Cvi42 software (Circle Cardiovascular Imaging, Calgary, Canada). An assessment of image quality (score 0-3) was made before performing inner edge to inner edge measurements of the thoracic aorta at 7 levels from the multiplanar reconstructions by two independent blinded observers. RESULTS: Non-contrast 3D MRA was successfully acquired in all 15 subjects. Image quality was deemed excellent in 87% (13/15) of cases after a mean acquisition time of 4.1+/-1.9min. There was a high level of agreement for aortic measurements, with low intra- and inter-observer variability (ICC ranges; 0.95-0.99 and 0.92-0.98, respectively). All pregnancies reached term (>=37/40) with a mean gestation at delivery of 38.0+/-0.5weeks. The mode of delivery was vaginal in 9 out of 15 subjects (60%). CONCLUSIONS: Non-contrast SSFP MRA imaging provides a quick and reproducible method of assessing the thoracic aorta in pregnancy. PMID- 28622942 TI - Arterial Hypertension after Coarctation-Repair in Long-term Follow-up (CoAFU): Predictive Value of Clinical Variables. PMID- 28622941 TI - Pre-hospital ticagrelor in ST-segment elevation myocardial infarction in the French ATLANTIC population. AB - BACKGROUND: ATLANTIC was a randomized study comparing pre- and in-hospital treatment with a ticagrelor loading dose (LD) in ongoing ST-segment elevation myocardial infarction (STEMI). We sought to compare patient characteristics and clinical outcomes in France with other countries participating in ATLANTIC. METHODS: The population comprised 1862 patients, 660 (35.4%) from France and 1202 from 12 other countries. The main endpoints were reperfusion (>=70% ST-segment elevation resolution) and TIMI flow grade 3 before (co-primary endpoints) and after percutaneous coronary intervention (PCI). Other endpoints included a composite ischaemic endpoint (death/myocardial infarction/stroke/urgent revascularization/definite stent thrombosis) and bleeding events at 30days. RESULTS: In France, median times from first LD to angiography and between first and second LDs were 49 and 35min, respectively, and were similar to other countries. French patients were younger (mean 58.7 vs 61.9years, p<0.0001) and characterized by a higher rate of radial access (89.9% vs 54.8%, p<0.0001), more frequent use of pre-hospital glycoprotein (GP) IIb/IIIa inhibitors (14.1% vs 3.1%, p<0.0001) and intravenous enoxaparin (57.3% vs 10.1%, p<0.0001). In France, as in other countries, the co-primary endpoints did not differ between the two randomization groups. The composite ischaemic endpoint was numerically lower in France (3.3% vs 5.1%, p=0.07), with a lower mortality (1.4% vs 3.3%, p=0.01). PLATO major bleeding was numerically less frequent in France (1.8% vs 3.2%, p=0.07). CONCLUSIONS: The French population appears to have better outcomes than the rest of the study population, and seems related to differences in demographics and management characteristics. TRIAL REGISTRY: ClinicalTrials.gov (NCT01347580). PMID- 28622943 TI - Cardiac rehabilitation costs. AB - BACKGROUND: Despite the clinical benefits of cardiac rehabilitation (CR) and its cost-effectiveness, it is not widely received. Arguably, capacity could be greatly increased if lower-cost models were implemented. The aims of this review were to describe: the costs associated with CR delivery, approaches to reduce these costs, and associated implications. METHODS: Upon finalizing the PICO statement, information scientists were enlisted to develop the search strategy of MEDLINE, Embase, CDSR, Google Scholar and Scopus. Citations identified were considered for inclusion by the first author. Extracted cost data were summarized in tabular format and qualitatively synthesized. RESULTS: There is wide variability in the cost of CR delivery around the world, and patients pay out-of pocket for some or all of services in 55% of countries. Supervised CR costs in high-income countries ranged from PPP$294 (Purchasing Power Parity; 2016 United States Dollars) in the United Kingdom to PPP$12,409 in Italy, and in middle income countries ranged from PPP$146 in Venezuela to PPP$1095 in Brazil. Costs relate to facilities, personnel, and session dose. Delivering CR using information and communication technology (mean cost PPP$753/patient/program), lowering the dose and using lower-cost personnel and equipment are important strategies to consider in containing costs, however few explicitly low-cost models are available in the literature. CONCLUSION: More research is needed regarding the costs to deliver CR in community settings, the cost-effectiveness of CR in most countries, and the economic impact of return-to-work with CR participation. A low-cost model of CR should be standardized and tested for efficacy across multiple healthcare systems. PMID- 28622945 TI - Safety of intracoronary provocative testing for the diagnosis of coronary artery spasm. AB - AIMS: Systematic review of literature to evaluate safety of intracoronary (i.c.) pharmacologic testing with acetylcholine (ACh), or ergonovine (ERGO), to induce coronary artery spasm. METHODS AND RESULTS: Review of all relevant publications using MEDLINE and EMBASE databases yielded 10 publications, totalling 9,444 patients. Prevalence of provoked spasm varied from 2.3% to 54.7% of patients tested in the selected studies. The wide variability in prevalence was due to heterogeneity of study populations and provocation protocols. No deaths were reported. Overall occurrence of major (0.8%) and minor (4.7%) complications for i.c. pharmacologic testing was low. Compared to ERGO, ACh showed significantly higher rate of major (1.09% vs 0.15%; p<0.001) and minor complications (5.87% vs 2.36%; p<0.001). CONCLUSION: Provocative testing with i.c. ACh or ERGO are safe and can facilitate the diagnosis of inducible coronary artery spasm during diagnostic coronary angiography. These tests should be part of the routine armamentarium of interventional cardiologists. PMID- 28622944 TI - Effect of ascending aortic dimension on acute procedural success following self expanding transcatheter aortic valve replacement: A multicenter retrospective analysis. AB - AIMS: Self-expanding (SE) valves are characterized with long stent frame design and the radial force of the device exists both in the inflow and outflow level. Therefore, we hypothesized that device success of SE-valves may be influenced by ascending aortic dimensions (AAD). The aim of this study was to determine the influence of AAD on acute device success rates following SE transcatheter aortic valve replacement (TAVR). METHODS & RESULTS: In 4 centers in the United States and Asia, 214 consecutive patients underwent SE-TAVR. Outcomes were assessed in line with Valve Academic Research Consortium criteria. AAD was defined as the sum of the short and long axis aortic diameter divided by 2. Overall, device success rate was 85.0%. Multivariate analysis revealed that increased AAD (Odds ratio 1.27) and % oversizing (Odds ratio 0.88) were found to be independent predictors of unsuccessful device implantation. The c-statistic of the model for device success was area under the curve 0.79, sensitivity 81.3% and specificity 44.0%. Co-existence of several risk factors was associated with an exponential fall to 64.2% in device success rate. For a large AAD, however, optimally oversized SE valves (threshold 16.2%) resulted with high device success rates compared to suboptimal oversizing (88.6% vs. 64.2%, p=0.005). CONCLUSIONS: Larger AAD and smaller degrees of oversizing were confirmed to be the most relevant predictors of unsuccessful device implantation following SE-valve implantations. Optimal oversizing of great significance was noted, particularly that with a large AAD. PMID- 28622946 TI - Estimation of myocardial flow reserve utilizing an ultrafast cardiac SPECT: Comparison with coronary angiography, fractional flow reserve, and the SYNTAX score. AB - BACKGROUND: Quantitative assessment of myocardial flow reserve (MFR) by single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is challenging but may facilitate evaluation of multi-vessel coronary artery disease (CAD). METHODS: We enrolled 153 patients with suspected or known CAD, referred for pharmacological stress MPI. They underwent a 99mTc-perfusion stress/rest SPECT with an ultrafast cadmium-zinc-telluride (CZT) camera. Dynamic data were acquired and time-activity curves fitted to a 1-tissue compartment analysis with input function. K1 was assigned for stress and rest data. The MFR index (MFRi) was calculated as K1 stress/K1 at-rest. The findings were validated by invasive coronary angiography in 69 consecutive patients. RESULTS: The global MFRi was 1.46 (1.16-1.76), 1.33 (1.12-1.54), and 1.18 (1.01-1.35), for 1-vessel disease (VD), 2-VD, and 3-VD, respectively. In the 3-VD, global MFRi was lower than that in 0-VD (1.63 [1.22-2.04], P<0.0001) and 1-VD (P=0.003). Multivariate logistic regression analysis for 3-VD showed significant associations with smoking history (odds ratio [OR]: 4.4 [0.4-8.4]), left ventricular ejection fraction (OR: 61.6 [57.5-66.0]), and global MFRi (OR: 119.6 [111.5-127.7], P=0.002). A cut-off value of 1.3 yielded 93.3% sensitivity and 75.9% specificity for diagnosing 3-VD. Fractional flow reserve positively correlated with regional MFRi (r=0.62, P=0.008), and the SYNTAX score correlated negatively with global MFRi (r=0.567, P=0.0003). CONCLUSION: We developed and validated a clinically available method for MFR quantification by dynamic 99mTc-perfusion SPECT utilizing a CZT camera, which improves the detectability of multi-vessel CAD. PMID- 28622947 TI - Discontinuation and non-publication of clinical trials in cardiovascular medicine. AB - BACKGROUND: Appropriate dissemination of clinical data is crucial for minimising bias. Despite this, high rates of study discontinuation and non-publication have been reported among clinical trials. Cardiovascular medicine receives a substantial proportion of academic funding; however, predictors of non publication among cardiovascular trials are not well-established. METHODS: The National Clinical Trials database was searched for cardiovascular trials completed between January 2010 and January 2014. Associated publications were identified in Medline or Embase. Relevant variables were extracted and subject to chi-squared and logistic regression to identify predictors of discontinuation and non-publication. RESULTS: After reviewing 2035 trials, 431 trials were included, of which 82.1% (n=354; 119,233 participants) were completed. Among completed trials, 70.3% (n=249; 99,095 participants) were published. Industry funding was associated with increased likelihood of non-publication (odds ratio [OR] 2.84; 95% confidence interval [CI] 1.47-5.51; P=0.002), while non-randomised studies were more likely to remain unpublished than randomised counterparts. Industry funded studies were over three times more likely to be discontinued than those sponsored by academic institutions (OR 3.89; CI 1.54-9.83; P=0.004). Trials studying heart failure and atrial fibrillation were more likely to be discontinued compared to trials studying coronary artery disease (OR 2.83; CI 1.23-6.51; and OR 3.10; CI 1.21-7.96, respectively). Of the total 135,714 participants, 25,565 were recruited into unpublished studies. CONCLUSIONS: Discontinuation and non-publication of cardiovascular trials are common, resulting in data from thousands of participants remaining unpublished. Funding source and randomisation are strong predictors of non-publication, while sponsor type, phase and blinding status are key predictors of discontinuation. PMID- 28622948 TI - High level of beta-(1,3)-d-glucan antigenaemia in cystic fibrosis in the absence of invasive fungal disease. AB - beta-(1,3)-d-glucan (BDG) is used to rule out invasive fungal disease (IFD) but its usefulness in cystic fibrosis (CF) has not been evaluated. We measured serum BDG in CF patients with no clinical suspicion of IFD. Samples from 46 adult CF patients during a stable period and during pulmonary exacerbation were tested. The association of BDG with clinical variables was analyzed. Three hundred and three non-CF patients with suspected IFD were used as comparators. Both samples were negative in 52% of CF patients, whereas 67% of comparators had only negative results (P=0.08). CF patients with pancreatic insufficiency and CF-related diabetes had fewer negative results (P<0.05 for both). Negative results were more common in older CF patients (P<0.05). Use of antibiotics, presence of fungi in sputum and CF liver disease did not impact BDG levels. In conclusion, patients with CF experience significant BDG antigenaemia in the absence of IFD. PMID- 28622949 TI - Changed epidemiology during intra and interhospital spread of high-risk clones of vanA-containing Enterococcus in Brazilian hospitals. AB - We report changes in the molecular epidemiology of vanA-containing Enterococcus during the intra and interhospital spread of high-risk clones, in Southeastern Brazil. While VRE faecalis predominated during 1998 to 2006, a reversal has been observed in the last years, where VRE faecium belonging to ST114, ST203, ST412, ST478 and ST858 have become endemic. PMID- 28622950 TI - Glycaemic control and hypoglycaemia with insulin glargine 300U/mL versus insulin glargine 100U/mL in insulin-naive people with type 2 diabetes: 12-month results from the EDITION 3 trial. AB - AIM: To explore if efficacy and safety findings for insulin glargine 300U/mL (Gla 300) versus insulin glargine 100U/mL (Gla-100), observed over 6 months in insulin naive people with type 2 diabetes, are maintained after 12 months. METHODS: EDITION 3 was a phase 3a, randomized, multicentre, open-label, parallel-group, treat-to-target study of once-daily Gla-300 versus Gla-100 (target fasting self monitored plasma glucose, 4.4-5.6mmol/L [80-100mg/dL]). Participants completing the initial 6-month treatment phase continued their previously allocated basal insulin. RESULTS: Of 878 participants randomized, 337/439 (77%) and 314/439 (72%) assigned to Gla-300 and Gla-100, respectively, completed 12 months of treatment. Improved glycaemic control was sustained until 12 months in both treatment groups, with similar reductions in HbA1c from baseline to month 12 (difference: 0.08 [95% confidence interval (CI): -0.23 to 0.07] % or -0.9 [-2.5 to 0.8] mmol/mol). Relative risk of experiencing>=1 confirmed (<=3.9mmol/L [<=70mg/dL]) or severe hypoglycaemic event with Gla-300 versus Gla-100 was 0.86 (95% CI: 0.69 to 1.07) at night and 0.92 (0.82 to 1.03) at any time of day. For events with a glycaemic threshold of<3.0mmol/L (<54mg/dL) these numbers were 0.76 (0.49 to 1.19) and 0.66 (0.50 to 0.88). A similar pattern was seen for documented symptomatic events. No between-group differences in adverse events were identified. CONCLUSION: Over 12 months, Gla-300 treatment was as effective as Gla 100 in reducing HbA1c in insulin-naive people with type 2 diabetes, with lower overall risk of hypoglycaemia at the<3.0mmol/L threshold. PMID- 28622951 TI - Population Approach to Efavirenz Therapy. AB - Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor commonly used as first-line therapy in the treatment of human immunodeficiency virus (HIV), with a narrow therapeutic range and a high between-subject variability which can lead to central nervous system toxicity or therapeutic failure. To characterize the sources of variability and better predict EFV steady-state plasma concentrations, a population pharmacokinetic model was developed from 96 HIV positive individuals, using a nonlinear mixed-effect method with Monolix(r) software. A one-compartment with first-order absorption and elimination model adequately described the data. To explain between-subject variability, demographic characteristics, biochemical parameters, hepatitis C virus-HIV coinfection, and genetic polymorphisms were tested. A combination of the single nucleotide polymorphisms rs2279343 and rs3745274, both in the CYP2B6 gene, were the only covariates influencing clearance, included in the final model. Oral clearance was estimated to be 19.6 L/h, 14.15 L/h, and 6.08 L/h for wild-type, heterozygous mutated and homozygous mutated individuals, respectively. These results are in accordance with the current knowledge of EFV metabolism and also suggest that in homozygous mutated individuals, a dose adjustment is necessary. Hepatitis C virus-HIV coinfection does not seem to be a predictive indicator of EFV pharmacokinetic disposition. PMID- 28622952 TI - Preventing major gastrointestinal bleeding in elderly patients. PMID- 28622953 TI - The need for a complex systems model of evidence for public health. PMID- 28622954 TI - Department of Error. PMID- 28622955 TI - Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study. AB - BACKGROUND: Lifelong antiplatelet treatment is recommended after ischaemic vascular events, on the basis of trials done mainly in patients younger than 75 years. Upper gastrointestinal bleeding is a serious complication, but had low case fatality in trials of aspirin and is not generally thought to cause long term disability. Consequently, although co-prescription of proton-pump inhibitors (PPIs) reduces upper gastrointestinal bleeds by 70-90%, uptake is low and guidelines are conflicting. We aimed to assess the risk, time course, and outcomes of bleeding on antiplatelet treatment for secondary prevention in patients of all ages. METHODS: We did a prospective population-based cohort study in patients with a first transient ischaemic attack, ischaemic stroke, or myocardial infarction treated with antiplatelet drugs (mainly aspirin based, without routine PPI use) after the event in the Oxford Vascular Study from 2002 to 2012, with follow-up until 2013. We determined type, severity, outcome (disability or death), and time course of bleeding requiring medical attention by face-to-face follow-up for 10 years. We estimated age-specific numbers needed to treat (NNT) to prevent upper gastrointestinal bleeding with routine PPI co prescription on the basis of Kaplan-Meier risk estimates and relative risk reduction estimates from previous trials. FINDINGS: 3166 patients (1582 [50%] aged >=75 years) had 405 first bleeding events (n=218 gastrointestinal, n=45 intracranial, and n=142 other) during 13 509 patient-years of follow-up. Of the 314 patients (78%) with bleeds admitted to hospital, 117 (37%) were missed by administrative coding. Risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age (>=75 years hazard ratio [HR] 3.10, 95% CI 2.27-4.24; p<0.0001), particularly for fatal bleeds (5.53, 2.65-11.54; p<0.0001), and was sustained during long-term follow-up. The same was true of major upper gastrointestinal bleeds (>=75 years HR 4.13, 2.60-6.57; p<0.0001), particularly if disabling or fatal (10.26, 4.37-24.13; p<0.0001). At age 75 years or older, major upper gastrointestinal bleeds were mostly disabling or fatal (45 [62%] of 73 patients vs 101 [47%] of 213 patients with recurrent ischaemic stroke), and outnumbered disabling or fatal intracerebral haemorrhage (n=45 vs n=18), with an absolute risk of 9.15 (95% CI 6.67-12.24) per 1000 patient-years. The estimated NNT for routine PPI use to prevent one disabling or fatal upper gastrointestinal bleed over 5 years fell from 338 for individuals younger than 65 years, to 25 for individuals aged 85 years or older. INTERPRETATION: In patients receiving aspirin based antiplatelet treatment without routine PPI use, the long-term risk of major bleeding is higher and more sustained in older patients in practice than in the younger patients in previous trials, with a substantial risk of disabling or fatal upper gastrointestinal bleeding. Given that half of the major bleeds in patients aged 75 years or older were upper gastrointestinal, the estimated NNT for routine PPI use to prevent such bleeds is low, and co-prescription should be encouraged. FUNDING: Wellcome Trust, Wolfson Foundation, British Heart Foundation, Dunhill Medical Trust, National Institute of Health Research (NIHR), and the NIHR Oxford Biomedical Research Centre. PMID- 28622956 TI - Obesity, Visceral Adipose Tissue, and Cognitive Function in Childhood. AB - OBJECTIVES: To evaluate the effects of a 9-month physical activity intervention on changes in adiposity and cognitive control based on pretrial weight status (ie, healthy weight vs obese) in children. STUDY DESIGN: Participants included obese (n = 77) and matched healthy-weight (n = 77) preadolescents (8-9 years) who participated in a 9-month physical activity randomized controlled trial. Cognitive function was assessed with an inhibitory control task (modified flanker task). RESULTS: After the 9-month physical activity intervention, participants exhibited a reduction in adiposity. In contrast, children in the waitlist-control condition, particularly children identified as obese pretrial, gained visceral adipose tissue (P= .008). Changes in visceral adipose tissue were related to changes in cognitive performance, such that the degree of reduction in visceral adipose tissue directly related to greater gains in inhibitory control, particularly among obese intervention participants (CI -0.14, -0.04; P= .001). CONCLUSIONS: Participation in a daily physical activity program not only reduces adiposity but also improves children's cognitive function as demonstrated by an inhibitory control task. Furthermore, these findings reveal that the benefits of physical activity to improvements in cognitive function are particularly evident among children who are obese. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01334359 and NCT01619826. PMID- 28622957 TI - Real-Time Polymerase Chain Reaction-Based Detection of Bordetella pertussis in Mexican Infants and Their Contacts: A 3-Year Multicenter Study. AB - OBJECTIVES: To evaluate the usefulness of real-time polymerase chain reaction (RT PCR) as a diagnostic method for the detection of Bordetella pertussis in hospitalized patients aged <1 year with a clinical diagnosis of whooping cough, as well as to identify the role of household contacts as a source of infection. STUDY DESIGN: This was a prospective, multicenter study of infants aged <1 year who were hospitalized with symptoms suggestive of whooping cough. Nasopharyngeal samples were obtained for culture and RT-PCR testing. The clinical and epidemiologic characteristics and outcomes were analyzed. B pertussis detection and symptoms in household contacts of patients diagnosed with pertussis were studied. RESULTS: A total of 286 patients were included; of these, 67.1% had B pertussis and 4.5% had Bordetella spp. Complications occurred in 20% of patients, and the mortality rate was 6.7%. Of 434 contacts studied, 111 were mothers of study infants, representing the most frequently B pertussis-infected group and the main symptomatic contact. CONCLUSION: The use of RT-PCR permits improved detection and diagnosis of pertussis and a better understanding of the epidemiology of sources of infection. The complications and mortality rate of pertussis continue to be high. Household contacts are confirmed as a frequent source of infection of B pertussis in young children. PMID- 28622958 TI - Metabolic Syndrome in Long-Term Survivors of Hematopoietic Stem-Cell Transplantation. AB - Since its introduction more than 50 years ago, hematopoietic stem-cell transplantation (HSCT) has transformed from an inescapably fatal procedure to one where cure from malignant and other nonmalignant hematologic diseases is becoming increasingly common. Nevertheless, longevity is not entirely restored. New causes of mortality have emerged; of particular importance is that of increased cardiovascular disease (CVD), related to metabolic syndrome and its components. Controversy exists over whether the metabolic abnormalities induced are a direct effect of HSCT itself or a consequence of other therapies involved. Analysis of the mechanisms that promote the changes in metabolic components will give insight into future HSCT therapy as well as CVD pathogenesis and prevention. PMID- 28622960 TI - Treatment of Peripheral T-Cell Lymphoma in Community Settings. AB - BACKGROUND: Peripheral T-cell lymphomas (PTCLs) represent a rare and heterogeneous group of malignancies that do not have consensus treatment recommendations. Strategies extrapolated from B-cell lymphoma have met with limited efficacy, although T-cell-specific salvage therapies have been recently developed. METHODS: To determine treatment patterns and associated outcomes in PTCL not otherwise specified (PTCL-NOS), anaplastic large T-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL), a retrospective analysis was undertaken at a large US community oncology network among patients treated between January 2010 and April 2015. RESULTS: Among 93 patients (44 PTCL-NOS, 30 ALCL, 19 AITL), 23 unique treatments were used in 66 first-line patients and 12 unique second-line treatments were used in 24 relapsed/refractory patients. First line CHOP and CHOP-like regimens were used in 74% of patients, providing 4-year overall survival (OS) outcomes of 34% (95% confidence interval [CI], 14%-83%) in patients without transplant consolidation (82% in ALCL, 37% in PTCL-NOS, and 0% in AITL). Upfront stem cell transplantation trended toward improved 4-year progression-free survival 77% (95% CI, 54%-100%) versus 34% (95% CI, 14%-80%); (P = .08; hazard ratio [HR] 0.29) with 4-year OS 77% (95% CI, 54%-100%) versus 34% (P = .22; HR 0.41). Brentuximab was the most common second-line therapy, with multiple additional regimens used in sequence (up to 5 salvage regimens) in many. CONCLUSIONS: The significant variability in treatments used for PTCL emphasizes the lack of consensus therapy in this rarer lymphoma and calls for additional organized prospective and registry studies to evaluate comparative effectiveness. PMID- 28622959 TI - A Phase I/II Trial of Panobinostat in Combination With Lenalidomide in Patients With Relapsed or Refractory Hodgkin Lymphoma. AB - BACKGROUND: Lenalidomide and panobinostat have shown single-agent efficacy of 14% to 50% and 27% to 58%, respectively, in Hodgkin lymphoma (HL). This phase I/II study was conducted to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide combined with panobinostat in relapsed/refractory HL. PATIENTS AND METHODS: In the phase I trial, previously treated patients with classical or lymphocyte-predominant HL received escalating doses of lenalidomide on days 1 to 21 and panobinostat 3 times a week (TIW) every 28 days. Dose limiting toxicity (DLT) was defined during cycle 1. When the MTD was determined, a phase II study was conducted to determine overall response (OR). RESULTS: Twenty-four patients enrolled; 11 in the phase I and 13 in phase II portions. No DLTs were observed but 2 patients who received 25 mg lenalidomide and 20 mg panobinostat experienced neutropenia and thrombocytopenia > 14 days in cycle 2, leading to selection of 25 mg lenalidomide on days 1 to 21 and 15 mg panobinostat TIW for the phase II dose. In all 24 patients, Grade 3 to 4 toxicities consisted of neutropenia (58%), thrombocytopenia (42%), lymphopenia (25%), and febrile neutropenia (25%). OR was 16.7% (2 complete response [CR] and 2 partial response). One patient with CR had lymphocyte-predominant HL and received 22 cycles. Median progression-free survival and overall survival were 3.8 and 16.4 months, respectively. CONCLUSION: Although the combination of panobinostat and lenalidomide appears safe in patients with relapsed/refractory HL, the limited efficacy and significant rates of neutropenia and febrile neutropenia observed do not support further evaluation of this combination in HL. PMID- 28622961 TI - ZOHe: A Prospective Study of the Use of Biosimilar Filgrastim Zarzio in Clinical Practice in Patients Treated With Chemotherapy for Lymphoid Malignancies. AB - BACKGROUND: The ZOHe study was a prospective, observational, multicenter study in France to assess use of biosimilar filgrastim Zarzio in routine clinical practice in patients undergoing neutropenia-inducing chemotherapy. PATIENTS AND METHODS: Patients >= 18 years undergoing chemotherapy for a malignant disease and with a first prescription for Zarzio were enrolled in 2 cohorts: solid tumor (1174 patients) or hematological malignancy (633 patients); the latter is reported here. Analyses primarily described the prescription and use of Zarzio in current practice, and included identification of factors linked to prescription for primary prophylaxis, comparison of use in relation to European Organisation for the Research and Treatment of Cancer (EORTC) guidelines, and estimation of chemotherapy dose intensity maintenance in patients given Zarzio. RESULTS: Use of Zarzio in clinical practice was relatively standardized and followed label indication in 96.7% of the analysis population (633 patients). Most patients had >= 2 EORTC patient-related risk factors for febrile neutropenia (FN). Chemotherapy dose intensity was maintained in 85.2% of evaluable patients and 89.6% of patients with non-Hodgkin lymphoma receiving R-CHOP (rituximab cyclophosphamide/doxorubicin/vincristine/prednisone). The safety profile of Zarzio was confirmed. CONCLUSIONS: In routine clinical practice in France, Zarzio is mostly used as primary prophylaxis for chemotherapy-induced neutropenia in patients with hematological malignancies. Patient-related risk factors appear to have more weight in clinicians' decisions to give Zarzio than the FN risk category of the chemotherapy regimen alone in real-world practice. PMID- 28622962 TI - Synergistic structures from magnetic freeze casting with surface magnetized alumina particles and platelets. AB - Magnetic freeze casting utilizes the freezing of water, a low magnetic field and surface magnetized materials to make multi-axis strengthened porous scaffolds. A much greater magnetic moment was measured for larger magnetized alumina platelets compared with smaller particles, which indicated that more platelet aggregation occurred within slurries. This led to more lamellar wall alignment along the magnetic field direction during magnetic freeze casting at 75 mT. Slurries with varying ratios of magnetized particles to platelets (0:1, 1:3, 1:1, 3:1, 7:1, 1:0) produced porous scaffolds with different structural features and degrees of lamellar wall alignment. The greatest mechanical enhancement in the magnetic field direction was identified in the synergistic condition with the highest particle to platelet ratio (7:1). Magnetic freeze casting with varying ratios of magnetized anisotropic and isotropic alumina provided insights about how heterogeneous morphologies aggregate within lamellar walls that impact mechanical properties. Fabrication of strengthened scaffolds with multi-axis aligned porosity was achieved without introducing different solid materials, freezing agents or additives. Resemblance of 7:1 particle to platelet scaffold microstructure to wood light-frame house construction is framed in the context of assembly inspiration being derived from both natural and synthetic sources. PMID- 28622963 TI - Commentary on "Characteristics of cadmium uptake and membrane transport in roots of intact wheat (Triticum aestivum L.) seedlings" reported by Lian-Zhen Li, Chen Tu, Willie J.G.M. Peijnenburg, Yong-Ming Luo. PMID- 28622964 TI - Grand paternal inheritance of X-linked myotubular myopathy due to mosaicism, and identification of necklace fibers in an asymptomatic male. AB - X-linked recessive myotubular myopathy (XLMTM) is a disorder associated with mutations in the myotubularin gene (MTM1) that usually affects boys, with transmission of the mutated allele from the mother. Here we describe a family with unexpected grand paternal transmission of a novel mutation in MTM1 (c.646_648dupGTT; p.Val216dup) identified in a severely affected infant boy with a centronuclear myopathy. We confirmed the carrier status of the mother, but surprisingly we found that her father was a carrier of the mutated MTM1 gene together with wild-type MTM1. A muscle biopsy from the grandfather revealed occasional typical necklace fibers with internalized nucleus, which is typically found in MTM1-associated myopathies. Further analysis of the grandfather revealed equal amounts of DNA with the wild-type sequence and DNA with the c.646_648dupGTT variant in five different tissues examined. In the presence of a normal karyotype (46,XY) in the grandfather and no evidence of intragenic duplication of MTM1, the result was interpreted as postzygotic mosaicism and the mutation had probably occurred at the first mitosis of the zygote. This study demonstrates the importance of considering the possibility of paternal transmission in families with severe X-linked disorders. The muscle biopsy with the finding of typical necklace fibers was important to further establish the pathogenicity of the novel MTM1 mutation. PMID- 28622965 TI - Tumour-Derived Human Growth Hormone As a Therapeutic Target in Oncology. AB - The growth hormone (GH) and insulin-like growth factor-1 (IGF1) axis is the key regulator of longitudinal growth, promoting postnatal bone and muscle growth. The available data suggest that GH expression by tumour cells is associated with the aetiology and progression of various cancers such as endometrial, breast, liver, prostate, and colon cancer. Accordingly there has been increased interest in targeting GH-mediated signal transduction in a therapeutic setting. Because GH has endocrine, autocrine, and paracrine actions, therapeutic strategies will need to take into account systemic and local functions. Activation of related hormone receptors and crosstalk with other signalling pathways are also key considerations. PMID- 28622966 TI - Immunohistochemical expression analysis of leucine-rich PPR-motif-containing protein (LRPPRC), a candidate colorectal cancer biomarker identified by shotgun proteomics using iTRAQ. AB - BACKGROUND: Colorectal cancer (CRC) is the fourth most frequent cause of cancer deaths in the world. Novel biomarkers for the diagnosis, prognosis, and treatment of CRC are required to improve the clinical strategy. METHODS: We applied shotgun proteomics using isobaric tags for relative and absolute quantitation (iTRAQ) to identify novel biomarkers of CRC, and then we detected leucine-rich PPR-motif containing protein (LRPPRC) expression in 83 normal colorectal tissues and 133 CRC tissues by immunohistochemistry. RESULTS: A total of 570 proteins were identified using iTRAQ. We validated the expression of LRPPRC protein by immunohistochemical analysis of the 77 proteins that showed expression changes in the cancer tissues >1.5-fold the levels in the normal tissues. The expression levels of LRPPRC were significantly higher in CRC tissues than those in normal colorectal tissues, and the expression levels were related with tumor differentiation and especially high in moderately differentiated CRC tissues. CONCLUSION: We identified a novel, differentially expressed protein, LRPPRC, which has the potential to serve as a molecular target for diagnosis and/or prognosis of CRC. PMID- 28622967 TI - New markers of urinary tract infection. AB - Urinary tract infection (UTI) is the most common bacterial infection independent of age. It is also one of the most common causes of hospitalizations for infections among elderly people and the most common indication for antibiotic prescriptions in primary care. Both diagnostics and management of lower and upper urinary tract infections provide challenges in clinical practice due to their high prevalence and recurrence, and worldwide increase of antibiotic resistance. The clinical symptoms of UTI are often uncharacteristic or asymptomatic. The accurate diagnosis and early treatment are crucial due to risk of septicaemia and long-term consequences. Currently the diagnosis of urinary tract infection is based on the presence of clinical symptoms in combination with the results of nitrite strip test indicating the presence of bacteria in urine and semi quantitative measurement of white blood cells count in urine. Although urine culture is the gold standard in UTI diagnostics it is both time-consuming and costly. Searching for novel biomarkers of UTI has attracted much attention in recent years. The article reviews several promising serum and urine biomarkers of UTI such as leukocyte esterase, C-reactive protein, procalcitonin, interleukins, elastase alpha (1)-proteinase inhibitor, lactofferin, secretory immunoglobulin A, heparin-binding protein, xanthine oxidase, myeloperoxidase, soluble triggering receptor expressed on myeloid cells-1, alpha-1 microglobulin (alpha1Mg) and tetrazolium nitroblue test (TNB). PMID- 28622968 TI - The beneficial effect of extracorporeal shockwave myocardial revascularization: Two years of follow-up. AB - OBJECTIVES: Despite the advancements achieved by revascularization technique and pharmacological therapies, the number of patients with refractory angina (RA) is still high, carrying together a poor prognosis. Experimental data and small clinical studies suggest that the use of extracorporeal shockwave myocardial revascularization (ESMR) might improve symptoms of angina in patients with RA. The aim of our study is to evaluate the efficacy of cardiac shock wave therapy in a long term follow-up of patients with coronary artery disease (CAD) otherwise not suitable for revascularization. METHODS: We performed a prospective study enrolling patients with RA despite optimal medical therapy and without indication for further PCI or CABG. Characteristics such as angina class scores (CCS class score), nitroglycerin consumption and hospitalization were compared at baseline and 1, 6 and 12months after ESMR therapy. RESULTS: We enroll 72 patients with a mean age of 74.6+/-14.7years. We treated 440 echocardiographical segments of ischemical myocardium. During the longest published follow-up (2.88+/-1.65years, range 0.63-6.11) there was a significant reduction of medium CCS class score (from 2.78+/-0.67 to 1.44+/-0.6; p=0.0002), nitroglycerin consumption (67% vs 21%; p<0.001) and hospitalization rate (40% vs 18%; p<0.03). CONCLUSION: Our study confirms the beneficial effect of ESMR therapy on cardiac symptoms and the possibility to reduce hospitalizations in patients with refractory angina also in a long term follow up. It supports a role for ESMR as a non-invasive therapeutic option for patients with RA. PMID- 28622969 TI - Probability of Undiagnosed Obstructive Sleep Apnea Does Not Correlate With Adverse Pulmonary Events nor Length of Stay in Hip and Knee Arthroplasty Using Intrathecal Opioid. AB - BACKGROUND: Recent emphasis on bundled payments and outcomes tracking has increased the focus on preoperative optimization in patients undergoing elective lower extremity arthroplasty. Since patients with obstructive sleep apnea (OSA) have an increased risk of adverse perioperative pulmonary events, screening for undiagnosed OSA is sometimes included as part of preoperative risk assessment. However, there are limited data regarding quantification of OSA risk in lower extremity arthroplasty patients, and little is known about the utility of quantitative OSA screening and the risk of pulmonary complications in hip and knee arthroplasty patients who receive intrathecal morphine anesthetic. METHODS: A retrospective review of 990 patients at a tertiary care, urban academic medical center who underwent lower extremity arthroplasty with a multimodal pain regimen including intrathecal morphine anesthesia, comparing the rate of pulmonary complications and length of stay between patients previously diagnosed with OSA and those identified as low, moderate, and high risk of undiagnosed OSA established by screening with the STOP-BANG questionnaire in the preoperative setting. RESULTS: Using logistic regression and adjusting for age, gender, and body mass index, the results suggested the rate of complications was not different across the sleep apnea risk groups (P = .4024). In addition, linear regression suggested length of stay did not differ significantly by sleep apnea risk group (P = .2823). CONCLUSION: In patients receiving intrathecal morphine as part of a multimodal pain regimen undergoing hip or knee arthroplasty, neither risk of adverse pulmonary events nor length of stay appeared to correlate with preoperative risk of undiagnosed OSA. PMID- 28622970 TI - Congener-specific determination of ultratrace levels of chlorinated and brominated polycyclic aromatic hydrocarbons in atmosphere and industrial stack gas by isotopic dilution gas chromatography/high resolution mass spectrometry method. AB - Isotopic dilution gas chromatography combined with high resolution mass spectrometry (GC/HRMS) has overwhelming advantages with respect to the accuracy of congener-specific ultratrace analysis of complex persistent organic pollutants (POPs) in environmental matrices. However, an isotopic dilution GC/HRMS method for analysis of chlorinated and brominated polycyclic aromatic hydrocarbons (Cl PAHs and Br-PAHs) using 13C-labelled congeners as internal standards has not been established. In this study, a method for identification and quantification of 38 congeners of Cl-PAHs and Br-PAHs in atmosphere and stack gas samples from waste incinerators was developed using the isotopic dilution GC/HRMS technique. The instrumental detection limits of the GC/HRMS method ranged from 0.2pg to 1.8pg for Cl-PAH congeners, and 0.7pg to 2.7pg for Br-PAH congeners, which were about three orders of magnitude lower than those of the GC/quadrupole MS method. This new method developed was also the first to enable determination of Cl-PAH and Br PAH homologs comprising congeners with the same molecular skeleton and chlorine or bromine substitution numbers. Among the detected congeners, seven Cl-PAH congeners and thirteen Br-PAH congeners that were abundant in the atmosphere and stack gases released from waste incinerators were firstly detected in real samples and reported using the established isotopic dilution GC/HRMS method. The developed isotopic dilution GC/HRMS is significant and needed for better studying the environmental behavior and health risk of Cl-PAHs and Br-PAHs. PMID- 28622971 TI - Utilization patterns of extracorporeal membrane oxygenation in neonates in the United States 1997-2012. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) remains one of the most intensive therapies for newborns in the United States. However, there is limited information on resource utilization for neonates receiving ECMO. METHODS: We conducted a retrospective data analysis of the Kids' Inpatient Database from 1997 to 2012. Bivariate and multivariate analysis was completed to identify predictors of LOS, hospital costs and mortality. Cardiac and non-cardiac diagnoses of neonates receiving ECMO were also included in the bivariate and multivariable analysis. RESULTS: Of the 5151 ECMO cases, survival to discharge was 62%. 22% had a principal cardiac diagnosis. After adjusting for covariates, increased mortality was associated with treatment in the midwest compared to the northeast region (aOR=2.0, p<0.01) and decreased among neonates with a non-cardiac diagnosis (aOR=0.4, p<0.01). Living in midwest was associated with longer LOS by 13days and increased hospital costs by 63,000 dollars (p<0.01). When stratified by non-cardiac diagnoses, infants with a diagnosis of congenital diaphragmatic hernia was associated with increased mortality (2.3, p<0.01) and longer LOS (25, p<0.01) and increased costs (11,100, p<0.01). CONCLUSION: Neonates who received ECMO in certain regions of the United States were associated with poorer survival outcomes as well as increased LOS and hospital costs. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level III. PMID- 28622972 TI - A patient led, international study of long term outcomes of esophageal atresia: EAT 1. AB - INTRODUCTION: Long term outcomes of esophageal atresia (OA) are poorly understood. The Federation of Esophageal Atresia and Tracheo-Esophageal Fistula support groups (EAT), a collaboration of patient support groups aimed to define patient reported long term outcomes and quality of life (QoL) in a large international cohort of OA patients. METHODS: Questionnaires were designed focusing on patient/parent reported outcomes including surgical history, current symptomatology and quality of life. Members of support groups within EAT were invited to complete questionnaires electronically via SurveyMonkey(r). RESULTS: 1100 patients from 25 countries responded to the questionnaire and 928 were analyzed. 80% had type C anatomy, 19% type A and 1% type E. Patient ages were <5 years (42%), 5-10 years (26%), 11-17 years (16%) and 18 years and older (16%). 49% of all patients reported previous dilatations which was similar across age groups. Reflux symptoms affected 58% of patients and persisted into adulthood. Dysphagia also persisted in the adult population with 50% reporting sometimes or often getting food stuck. Reflux was significantly more frequent in 'long gap' versus 'standard gap' patients (p<0.005). Respiratory symptoms and chest infections decreased in frequency with age. In children median SDS for height was -0.41 (IQR -1.4 to 0.67) and that for weight was -0.63 (-1.6 to 0.67). BMI in adults was 21.5. Quality of life was described as significantly affected by OA in 18% of patients while 25% reported no effect on QoL. CONCLUSIONS: These results highlight the significant long term morbidity suffered by OA patients as children and into adulthood and suggest the need for quality transitional care. The patient designed and reported nature of the study gives a unique perspective to the results and emphasizes the benefits of collaboration. PMID- 28622973 TI - Maternal programming of sex-specific responses to predator odor stress in adult rats. AB - Prenatal stress mediated through the mother can lead to long-term adaptations in stress-related phenotypes in offspring. This study tested the long-lasting effect of prenatal exposure to predator odor, an ethologically relevant and psychogenic stressor, in the second half of pregnancy. As adults, the offspring of predator odor-exposed mothers showed increased anxiety-like behaviors in commonly used laboratory tasks assessing novelty-induced anxiety, increased defensive behavior in males and increased ACTH stress reactivity in females in response to predator odor. Female offspring from predator odor-exposed dams showed increased transcript abundance of glucocorticoid receptor (NR3C1) on the day of birth and FK506 binding protein 5 (FKBP5) in adulthood in the amygdala. The increase in FKBP5 expression was associated with decreased DNA methylation in Fkbp5 intron V. These results indicate a sex-specific response to maternal programming by prenatal predator odor exposure and a potential epigenetic mechanism linking these responses with modifications of the stress axis in females. These results are in accordance with the mismatch hypothesis stating that an animal's response to cues within its life history reflects environmental conditions anticipated during important developmental periods and should be adaptive when these conditions are concurring. PMID- 28622974 TI - Survey of the adherence to the consensus of gastroesophageal reflux disease before and after the implementation course. AB - BACKGROUND/PURPOSE: The prevalence of Gastroesophageal reflux disease (GERD) is increasing worldwide, including Asia. Although several consensus reports have been published, little is known regarding the adherence of the physicians on the consensus of GERD. We aimed to survey the agreements and adherence of physicians to the Taiwan GERD consensus before and after the continual medical education (CME) courses. METHODS: Two-hundred and twenty-seven physicians, including 81 fellows of gastroenterology, 135 qualified gastroenterologists, and 11 non gastroenterologist attending physicians were invited to the CME course. Their agreements and adherence to the statements before and after the CME course were assessed by the pre-defined questionnaire with the aid of electronic keypads. The adherence rate before and after the CME course were compared by the McNemar test to indicate the changes in their willingness to follow the statements in clinical practice. RESULTS: The rates of agreement of the 227 participating physicians were uniformly greater than 80% for all of the 22 statements. However, the adherence rates were lower than 80% in 16 statements before the CME intervention. The adherence rates were significantly (p < 0.05) increased in 15 of these 16 statements after the CME intervention. The adherence rate can be improved to greater than 80% for those statements with high level of evidence. CONCLUSION: Although physicians agreed with the statements, the pre-CME survey disclosed limited adherence rates to the statements. The education intervention through the CME courses can improve the adherence of consensus statement, especially for those with higher level of evidence. PMID- 28622975 TI - Implicit versus explicit attitude to doping: Which better predicts athletes' vigilance towards unintentional doping? AB - OBJECTIVES: This preliminary study examined whether implicit doping attitude, explicit doping attitude, or both, predicted athletes' vigilance towards unintentional doping. DESIGN: A cross-sectional correlational design. METHODS: Australian athletes (N=143;Mage=18.13, SD=4.63) completed measures of implicit doping attitude (brief single-category implicit association test), explicit doping attitude (Performance Enhancement Attitude Scale), avoidance of unintentional doping (Self-Reported Treatment Adherence Scale), and behavioural vigilance task of unintentional doping (reading the ingredients of an unfamiliar food product). RESULTS: Positive implicit doping attitude and explicit doping attitude were negatively related to athletes' likelihood of reading the ingredients table of an unfamiliar food product, and positively related to athletes' vigilance towards unintentional doping. Neither attitude measures predicted avoidance of unintentional doping. Overall, the magnitude of associations by implicit doping attitude appeared to be stronger than that of explicit doping attitude. CONCLUSIONS: Athletes with positive implicit and explicit doping attitudes were less likely to read the ingredients table of an unknown food product, but were more likely to be aware of the possible presence of banned substances in a certain food product. Implicit doping attitude appeared to explain athletes' behavioural response to the avoidance of unintentional doping beyond variance explained by explicit doping attitude. PMID- 28622976 TI - Differential binding of the HIV-1 envelope to phosphatidylserine receptors. AB - Prior work has shown that the HIV-1 envelope of the human immunodeficiency virus (HIV) interacts directly with T-cell immunoglobulin mucin (TIM) family proteins. Herein, we demonstrate that HIV-1 envelope glycoproteins from varying HIV-1 clades bind differentially to TIM proteins and functionally similar proteins acting as phosphatidylserine (PtdSer) receptors. Using enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) technology, we show that lysate containing HIV-1 envelope and recombinant HIV-1 envelope glycoproteins bind TIM-4 and advanced glycosylation end product-specific receptor (AGER). The complex binding of HIV-1 UG21 gp140 to TIM-4 or AGER suggests a biphasic interaction with these proteins. PMID- 28622977 TI - Evolution of the alpha2-adrenoreceptors in vertebrates: ADRA2D is absent in mammals and crocodiles. AB - Evolutionary studies of genes that have been functionally characterized and whose variation has been associated with pathological conditions represent an opportunity to understand the genetic basis of pathologies. alpha2 Adrenoreceptors (ADRA2) are a class of G protein-coupled receptors that regulate several physiological processes including blood pressure, platelet aggregation, insulin secretion, lipolysis, and neurotransmitter release. This gene family has been extensively studied from a molecular/physiological perspective, yet much less is known about its evolutionary history. Accordingly, the goal of this study was to investigate the evolutionary history of alpha2-adrenoreceptors (ADRA2) in vertebrates. Our results show that in addition to the three well-recognized alpha2-adrenoreceptor genes (ADRA2A, ADRA2B and ADRA2C), we recovered a clade that corresponds to the fourth member of the alpha2-adrenoreceptor gene family (ADRA2D). We also recovered a clade that possesses two ADRA2 sequences found in two lamprey species. Furthermore, our results show that mammals and crocodiles are characterized by possessing three alpha2-adrenoreceptor genes, whereas all other vertebrate groups possess the full repertoire of alpha2-adrenoreceptor genes. Among vertebrates ADRA2D seems to be a dispensable gene, as it was lost two independent times during the evolutionary history of the group. Additionally, we found that most examined species possess the most common alleles described for humans; however, there are cases in which non-human mammals possess the alternative variant. Finally, transcript abundance profiles revealed that during the early evolutionary history of gnathostomes, the expression of ADRA2D in different taxonomic groups became specialized to different tissues, but in the ancestor of sarcopterygians this specialization would have been lost. PMID- 28622978 TI - The evolution and nomenclature of GnRH-type and corazonin-type neuropeptide signaling systems. AB - Gonadotropin-releasing hormone (GnRH) was first discovered in mammals on account of its effect in triggering pituitary release of gonadotropins and the importance of this discovery was recognized forty years ago in the award of the 1977 Nobel Prize for Physiology or Medicine. Investigation of the evolution of GnRH revealed that GnRH-type signaling systems occur throughout the chordates, including agnathans (e.g. lampreys) and urochordates (e.g. sea squirts). Furthermore, the discovery that adipokinetic hormone (AKH) is the ligand for a GnRH-type receptor in the arthropod Drosophila melanogaster provided evidence of the antiquity of GnRH-type signaling. However, the occurrence of other AKH-like peptides in arthropods, which include corazonin and AKH/corazonin-related peptide (ACP), has complicated efforts to reconstruct the evolutionary history of this family of related neuropeptides. Genome/transcriptome sequencing has revealed that both GnRH-type receptors and corazonin-type receptors occur in lophotrochozoan protostomes (annelids, mollusks) and in deuterostomian invertebrates (cephalochordates, hemichordates, echinoderms). Furthermore, peptides that act as ligands for GnRH-type and corazonin-type receptors have been identified in mollusks. However, what has been lacking is experimental evidence that distinct GnRH-type and corazonin-type peptide-receptor signaling pathways occur in deuterostomes. Importantly, we recently reported the identification of two neuropeptides that act as ligands for either a GnRH-type receptor or a corazonin type receptor in an echinoderm species - the common European starfish Asterias rubens. Discovery of distinct GnRH-type and corazonin-type signaling pathways in this deuterostomian invertebrate has demonstrated for the first time that the evolutionarily origin of these paralogous systems can be traced to the common ancestor of protostomes and deuterostomes. Furthermore, lineage-specific losses of corazonin signaling (in vertebrates, urochordates and nematodes) and duplication of the GnRH signaling system in arthropods (giving rise to the AKH and ACP signaling systems) and quadruplication of the GnRH signaling system in vertebrates (followed by lineage-specific losses or duplications) accounts for the phylogenetic distribution of GnRH/corazonin-type peptide-receptor pathways in extant animals. Informed by these new insights, here we review the history of research on the evolution of GnRH/corazonin-type neuropeptide signaling. Furthermore, we propose a standardized nomenclature for GnRH/corazonin-type neuropeptides wherein peptides are either named "GnRH" or "corazonin", with the exception of the paralogous GnRH-type peptides that have arisen by gene duplication in the arthropod lineage and which are referred to as "AKH" (or red pigment concentrating hormone, "RCPH", in crustaceans) and "ACP". PMID- 28622979 TI - Whole-genome sequencing for identification of the source in hospital-acquired Legionnaires' disease. AB - Acquisition of Legionnaires' disease is a serious complication of hospitalization. Rapid determination of whether or not the infection is caused by strains of Legionella pneumophila in the hospital environment is crucial to avoid further cases. This study investigated the use of whole-genome sequencing to identify the source of infection in hospital-acquired Legionnaires' disease. Phylogenetic analyses showed close relatedness between one patient isolate and a strain found in hospital water, confirming suspicion of nosocomial infection. It was found that whole-genome sequencing can be a useful tool in the investigation of hospital-acquired Legionnaires' disease. PMID- 28622980 TI - How do hospital respiratory clinicians perceive antimicrobial stewardship (AMS)? A qualitative study highlighting barriers to AMS in respiratory medicine. AB - BACKGROUND: Suboptimal antibiotic use in respiratory infections is widespread in hospital medicine and primary care. Antimicrobial stewardship (AMS) teams within hospitals, commonly led by infectious diseases physicians, are frequently charged with optimizing the use of respiratory antibiotics, but there is limited information on what drives antibiotic use in this area of clinical medicine, or on how AMS is perceived. AIM: To explore the perceptions of hospital respiratory clinicians on AMS in respiratory medicine. METHODS: In-depth interviews were conducted with 28 clinicians (13 doctors and 15 nurses) from two hospitals in Australia. Data were analysed thematically using the framework approach. FINDINGS: Four key barriers to the integration of AMS processes within respiratory medicine, from the participants' perspectives, were identified: CONCLUSIONS: AMS processes are introduced in hospitals with established social structures and knowledge bases. This study found that AMS in respiratory medicine challenges and conflicts with many of these dynamics. If the influence of these dynamics is not considered, AMS processes may not be effective in containing antibiotic use in hospital respiratory medicine. PMID- 28622981 TI - Progress of succinic acid production from renewable resources: Metabolic and fermentative strategies. AB - Succinic acid is a four-carbon dicarboxylic acid, which has attracted much interest due to its abroad usage as a precursor of many industrially important chemicals in the food, chemicals, and pharmaceutical industries. Facing the shortage of crude oil supply and demand of sustainable development, biological production of succinic acid from renewable resources has become a topic of worldwide interest. In recent decades, robust producing strain selection, metabolic engineering of model strains, and process optimization for succinic acid production have been developed. This review provides an overview of succinic acid producers and cultivation technology, highlight some of the successful metabolic engineering approaches. PMID- 28622982 TI - Comparison of the VITEK 2 antifungal susceptibility system with Etest using clinical isolates of Candida species. AB - BACKGROUND: Candida species are part of the normal human microbiota. However, in recent years, nosocomial bloodstream Candida infections have emerged as a significant problem ranking the fourth common cause of fungemia in intensive care units. Although microdilution methods are the ones recommended for susceptibility testing, they are difficult to undertake in the clinical practice. Thus, an automated commercially available test is ideal. AIMS: To compare minimum inhibitory concentrations (MICs) obtained with the recently introduced Vitek 2 yeast susceptibility system card (AST-YS01) with Etest. METHODS: 263 clinical Candida isolates representing six species were included in the study. Categorical agreements (CA) were assessed as described elsewhere. RESULTS: Irrespective of the Candida species tested, the overall CA between Vitek 2 and Etest ranged between 66.7% and 100%. In general, Etest yielded lower MICs than Vitek 2. For Candida albicans, the CA between Vitek 2 and Etest was >95% for amphotericin B, voriconazole and flucytosine, but only 89% for fluconazole. With respect to Candida glabrata, the CA was between 97% and 100%. The major errors were with Candida krusei and flucytosine and Candida kefyr and amphotericin B. Candida tropicalis susceptibility for fluconazole by Vitek 2 reported more SDD and resistant strains than Etest. Candida parapsilosis showed 100% CA against all the four antifungals tested. No very major errors were detected between the two methods. CONCLUSIONS: Vitek 2 provided comparable results to Etest with quick turnaround for the testing of Candida species susceptibilities. PMID- 28622984 TI - Revision reverse total shoulder arthroplasty in a patient with preoperative deltoid insufficiency: a case report. PMID- 28622983 TI - The Effect of a Comprehensive Care Transition Model on Cost and Utilization for Medically Complex Children With Cerebral Palsy. AB - INTRODUCTION: Our aim was to evaluate cost and acute care utilization related to an organized approach to care coordination and transitional care after major acute care hospitalization for children with medical complexities, including cerebral palsy. METHODS: A retrospective cohort of 32 patients from Ranken Jordan Pediatric Bridge Hospital (RJPBH) who received the Care Beyond the Bedside model was compared with 151 patients receiving standard care elsewhere across Missouri. Claims data (2007-2012) were obtained from MoHealthNet, Missouri's Medicaid program, for all children with moderate to severe cerebral palsy (defined using approximated Gross Motor Function Classification System levels) who had at least one hospital visit during the study period (N = 183). Risk-adjusted linear and Poisson regression models were used to analyze per-member-per-month costs and three indicators of acute care utilization (emergency department visits, readmissions, and inpatient days). RESULTS: RJPBH patients were associated with statistically significant reductions in per-member-per-month costs (-21%), hospital readmissions (-66%), and inpatient days (-57%). DISCUSSION: RJPBH's enhanced interprofessional medical home-like model, including intense care coordination, psychosocial therapy, family and caregiver empowerment, and transitional care, may be keys to reducing cost and unnecessary hospital use for children with medical complexities with cerebral palsy who receive Medicaid. PMID- 28622985 TI - Dependency distance distribution - from the perspective of genre variation: Comment on "Dependency distance: a new perspective on syntactic patterns in natural languages" by Haitao Liu et al. PMID- 28622986 TI - Top-down and bottom-up: Front to back: Comment on "Move me, astonish me... delight my eyes and brain: The Vienna Integrated Model of top-down and bottom-up processes in Art Perception (VIMAP) and corresponding affective, evaluative, and neurophysiological correlates" by Matthew Pelowski et al. PMID- 28622987 TI - Bioremediation using Gracilaria lemaneiformis to manage the nitrogen and phosphorous balance in an integrated multi-trophic aquaculture system in Yantian Bay, China. AB - To reduce negative environmental impacts from human aquaculture activities, the red alga Gracilaria lemaneiformis was co-cultured with the fish Pseudosciaena crocea in an integrated multi-trophic aquaculture (IMTA) system for 35d in Yantian Bay. The eutrophication index value decreased from 14.5 to 8.4 after seaweeds were co-cultured in cage farming areas, which indicated that the eutrophic water column in Yantian Bay could be mediated by IMTA. Total DIN and DIP of the tidal input and output were 9.23kg, 0.19kg and 11.08kg, and 0.27kg, respectively. Total 5.24kg of dissolved N and 0.81kg of dissolved P were released from IMTA system. These results indicate that G. lemaneiformis co-cultured in IMTA system could not completely remove all excess nutrients. In theory, at least 324.48kg of seaweed seedlings would be required to balance excess nutrients generated from fish cages. PMID- 28622989 TI - Rare earth elements mobility processes in an AMD-affected estuary: Huelva Estuary (SW Spain). AB - Huelva Estuary is a transition zone where REE-rich acidic waters interact with saline-alkaline seawater. This mixing process influences the geochemical and mineralogical characteristics of particulate and dissolved fractions. The Tinto River has >11,000MUgL-1 dissolved REE (pH=1.66), whereas seawater only reaches 8.75.10-2MUgL-1 dissolved REE (pH=7.87). REE-normalized patterns in "pH<6 solutions" are parallel and show similarities, diminishing their concentration as pH increases. Sequential extraction performed on the generated precipitates of mixed solutions indicates that most REE are associated to the residual phase. In a second order, REE are associated with soluble salts at pH3 and 3.5 whereas in sediments generated at pH4 and 5, they are distributed in salts (1 degrees extraction), poorly crystallized Fe-bearing minerals (schwertmannite, 3 degrees extraction) and well crystallized Fe-bearing minerals (goethite - hematite, 4 degrees extraction). Finally, precipitated REE are highest at pH6 newly formed minerals with a release to solution in higher pH. PMID- 28622988 TI - Organotins and new antifouling biocides in water and sediments from three Korean Special Management Sea Areas following ten years of tributyltin regulation: Contamination profiles and risk assessment. AB - A simultaneous monitoring study on organotins (butyltins and phenyltins) and most frequently used alternative antifouling biocides (Irgarol 1051, Diuron, Sea-Nine 211 and M1) in water and sediments (n=44) collected from three Special Management Sea Areas operated by Korean government. The lower concentration of butyltins (BTs) than that of new antifouling biocides (NEW) was found in water but the significant greater concentration of BTs than that of NEW was still found in sediments. The tributyltin (TBT) levels in water exceeded the chronic criterion to protect seawater aquatic life at several sites. Even ten years after the ban of the use of TBT-based antifouling paint, the concentrations of TBT, Diuron and Irgarol 1051 in sediments from shipyards exceeded global sediment quality guidelines and potentially poses adverse risks on marine organisms and extremely high concentration of TBT up to 2304ng/g was found for a sediment collected at a shipyard. PMID- 28622990 TI - Displacement effects of heavy human use on coral reef predators within the Molokini Marine Life Conservation District. AB - The impact of marine ecotourism on reef predators is poorly understood and there is growing concern that overcrowding in Marine Protected Areas (MPAs) may disturb the species that these areas were established to protect. To improve our understanding of this issue, we used acoustic telemetry to examine the relationship between human activity at the Molokini Marine Life Conservation District (MLCD) and the habitat use of five reef-associated predators (Caranx melampygus, Caranx ignobilis, Triaenodon obesus, Carcharhinus amblyrhynchos, and Aprion virscens). During peak hours of human use, there was a negative relationship (R2=0.77, P<0.001) between the presence of bluefin trevally (Caranx melampygus) and vessels in subzone A. No other species showed strong evidence of this relationship. However, our results suggest that during this time, the natural ecosystem function that the reserve was established to protect may be compromised and overcrowding should be considered when managing MPAs. PMID- 28622991 TI - Transcription of ribogenesis genes in fish gonads: Applications in the identification of stages of oogenesis and in environmental monitoring of intersex condition. AB - One of the best described effects of environmental xenoestrogens in fish is the generation of intersex gonads in males. Considering 5S rRNA a marker of the presence of oocytes, a 5S/18S rRNA index was calculated in 296 thicklip grey mullets (Chelon labrosus) from polluted environments. In addition, qPCR analysis of transcription factors gtf3a and ubtf1, related respectively to 5S and 18S rRNA synthesis, was conducted along female-oogenesis. 5S/18S rRNA index identified sex with a threshold value of 0.4521 separating males from females. Histological analysis identified 38 intersex individuals. Intersex severity and 5S/18S rRNA indexes were correlated. 5S/18S rRNA index identified ovarian developmental stage with high 5S rRNA levels during early oogenesis and 18S rRNA relative values increasing towards maturation. gtf3a and ubtf1 transcription levels followed the pattern of 5S rRNA accumulation. Thus, ribogenesis genes provide easy/quantitative methods to molecularly identify the sex, female gametogenic stage and intersex severity in mullets. PMID- 28622992 TI - Assessment of the anthropogenic influx of metallic pollutants in the Sefidrud delta, Gilan Province, Iran. AB - Understanding the anthropogenic effects on the Sefidrud delta, the concentration of six metals (Cr, Co, Cu, Ni, Pb and Zn) was measured in two sites included the old Sefidrud delta (Amirabad, 23 samples) and the new Sefidrud delta (Kiashahr, 24 samples). Geoaccumulation Index (Igeo), Enrichment Factor (EF), Contamination Factor (CF) and Pollution Load Index (PLI) were used to determine the metal pollution in all sediment samples. Although the EF, Igeo, CF and PLI results in the old delta indicate no significant pollution, sediment samples in the new delta show a considerable pollution. Since the sediment source and the lithology of the Sefidrud River drainage basin did not change in the past 500years, the metal pollution in the new delta must be from anthropogenic sources. PMID- 28622993 TI - Polycyclic aromatic hydrocarbons (PAHs) in traditionally harvested bivalves in northern British Columbia, Canada. AB - Butter clams, blue mussels, and Nuttall's cockle are important traditional food of the Gitga'at First Nation in Canada. Samples were collected and analyzed for polycyclic aromatic hydrocarbon (PAH) from the Gitga'at harvest sites from 2006 to 2015 to: 1) establish baseline conditions; 2) determine the likely source; 3) understand species specific response to spills; and 4) evaluate health risk associated with consumption. Baseline lipid normalized-total PAH in mussels was 2.36 (+/-2.86, 95%CI) MUg/g in mussels, 3.26(+/-4.14) MUg/g in clams and 3.98 (+/ 4.98) MUg/g in cockles. PAHs varied according to proximity to point sources and became less petrogenic through time. Concentrations of PAHs were elevated in all three species following diesel spills but returned to baseline levels within 5months. However, Gitga'at harvesters avoided bivalves from spill-affected habitats for several years because of their detection of reduced quality and palatability, highlighting the importance of incorporating local knowledge into future monitoring programs. PMID- 28622994 TI - Ultrasound-assisted acid hydrolysis of cellulose to chemical building blocks: Application to furfural synthesis. AB - In this work, the use of ultrasound energy for the production of furanic platforms from cellulose was investigated and the synthesis of furfural was demonstrated. Several systems were evaluated, as ultrasound bath, cup horn and probe, in order to investigate microcrystalline cellulose conversion using simply a diluted acid solution and ultrasound. Several acid mixtures were evaluated for hydrolysis, as diluted solutions of HNO3, H2SO4, HCl and H2C2O4. The influence of the following parameters in the ultrasound-assisted acid hydrolysis (UAAH) were studied: sonication temperature (30 to 70 degrees C) and ultrasound amplitude (30 to 70% for a cup horn system) for 4 to 8molL-1 HNO3 solutions. For each evaluated condition, the products were identified by ultra-performance liquid chromatography with high-resolution time-of-flight mass spectrometry (UPLC-ToF MS), which provide accurate information regarding the products obtained from biomass conversion. The furfural structure was confirmed by nuclear magnetic resonance (1H and 13C NMR) spectroscopy. In addition, cellulosic residues from hydrolysis reaction were characterized using scanning electron microscopy (SEM), which contributed for a better understanding of physical-chemical effects caused by ultrasound. After process optimization, a 4molL-1 HNO3 solution, sonicated for 60min at 30 degrees C in a cup horn system at 50% of amplitude, lead to 78% of conversion to furfural. This mild temperature condition combined to the use of a diluted acid solution represents an important contribution for the selective production of chemical building blocks using ultrasound energy. PMID- 28622996 TI - Ayahuasca intoxication. PMID- 28622995 TI - Syphilis epidemics: a descriptive study of patients diagnosed in a tertiary hospital between 2011 and 2015. AB - BACKGROUND AND OBJECTIVE: In the last decade, the incidence of syphilis has increased in our health area. Our objective is to describe the epidemiological and clinical characteristics of patients diagnosed with syphilis at our centre and their relationship with HIV. PATIENTS AND METHODS: The clinical and epidemiological variables of patients diagnosed with syphilis in a third-level hospital over a period of 4.5 years, as well as their HIV status, were analysed through a descriptive study. RESULTS: There was a significant increase in the incidence of syphilis in the period 2011-2015. We included 220 patients, 98% men (94% MSM). 62% were HIV+ and 89% came in early/infectious stages of the disease. 7% were concomitantly diagnosed with HIV. There was a high number of sexual partners and frequent use of drugs associated with sexual activity (46%). CONCLUSIONS: The incidence of syphilis has increased in our centre in the last 2 years. The most affected group is MSM, with high HIV prevalence and risk behaviours for STI acquisition. PMID- 28622997 TI - Effect of pharmacist intervention on improving antidepressant medication adherence and depression symptomology: A systematic review and meta-analysis. AB - BACKGROUND: Depression is a widespread disease with effective pharmacological treatments, but low medication adherence. Pharmacists play a key role in supporting medication adherence in patients with depression given their accessibility to patients. PURPOSE: The aim of this review was to systematically evaluate the impact of pharmacist interventions on adherence to antidepressants and clinical symptomology among adult outpatients with depressive disorders. METHODS: A systematic review of controlled trials (both randomized and non randomized) was conducted. Studies were obtained through a search of PubMed, Academic Search Premier, and Cochrane Library databases. Studies which included a pharmacist intervention to improve medication adherence in outpatients age 17 and above with a depressive disorder diagnosis and antidepressant treatment were included. Twelve publications met inclusion criteria, representing a total of 15,087 subjects: 1379 (9%) intervention and 13,708 (91%) control. RESULTS: The interventions in each selected publication included some level of in-person counseling and education to promote antidepressant adherence. The pooled odds ratio for medication adherence at 6 months was 2.50 (95% CI 1.62 to 3.86). There were no significant differences noted in subgroup meta-analyses except study location (US, Middle East or Europe) and setting. Only one of the identified studies reported statistically significant impacts of the pharmacist intervention on patient depression symptoms. CONCLUSIONS: The findings suggest that pharmacist interventions can enhance patient adherence to antidepressant medication in adult outpatients. However, this review failed to demonstrate a positive effect of these interventions on clinical symptoms. Additional longitudinal research is recommended to investigate the multidimensional relationships between pharmacist interventions, patient adherence, and clinical outcomes. ARTICLE SYNOPSIS: Pharmacists play a key role in supporting medication adherence in patients with depression given their accessibility to patients. The purpose of this review was to systematically evaluate the impact of pharmacist interventions on adherence to antidepressants and clinical symptomology among adult outpatients with depressive disorders. A systematic review of randomized and non-randomized controlled trials was conducted of the twelve studies which met inclusion criteria. The findings suggest that pharmacist interventions can enhance patient adherence to antidepressant medication in adult outpatients. However, this review failed to demonstrate a positive effect of these interventions on clinical symptoms. PMID- 28622998 TI - Editorial overview: Viral pathogenesis: Strategies for virus survival - Acute versus persistent infections. PMID- 28622999 TI - Editorial overview: Preventive and therapeutic vaccines: Vaccination against viral disease - current advances and challenges. PMID- 28623000 TI - Medical ozone promotes Nrf2 phosphorylation reducing oxidative stress and pro inflammatory cytokines in multiple sclerosis patients. AB - Oxidative stress and inflammation play key roles in the pathogenesis of Multiple sclerosis (MS). Different drugs have been used in the clinical practice, however, there is not a completely effective treatment. Due to its potential therapeutic action, medical ozone represents a promising approach for neurodegenerative disorders. The aim of the present study was to address the role of ozone therapy on the cellular redox state in MS patients. Ozone (20MUg/ml) was administered three times per week during a month by rectal insufflation. The effect of ozone therapy on biomarkers of oxidative stress and inflammation was addressed by spectrophotometric and immunoenzymatic assays. Furthermore, we investigated the action of ozone on CK2 expression and Nrf2 phosphorylation by western blotting analysis. Medical ozone significantly improved (P < 0.05) the activity of antioxidant enzymes and increased the levels of cellular reduced glutathione. In accordance, a significant reduction (P < 0.05) of oxidative damage on lipids and proteins was observed in ozone-treated patients. As well, the levels of pro inflammatory cytokines TNFalpha and IL-1beta were lower after ozone treatment. Ozone therapy incremented the CK2 expression together with Nrf2 phosphorylation in mononuclear cells of MS patients. These findings suggest that ozone's antioxidant and anti-inflammatory effects might be partially associated with an induction of Nrf2 phosphorylation and activation. These results provide new insights on the molecular events modulated by ozone, and pointed out ozone therapy as a potential therapeutic alternative for MS patients. PMID- 28623001 TI - A concealed observational study of infection control and safe injection practices in Jordanian governmental hospitals. AB - BACKGROUND: The recognized international organizations on infection prevention recommend using an observational method as the gold standard procedure for assessing health care professional's compliance with standard infection control practices. However, observational studies are rarely used in Jordanian infection control studies. This study aimed to evaluate injection practices among nurses working in Jordanian governmental hospitals. METHODS: A cross-sectional concealed observational design is used for this study. A convenience sampling technique was used to recruit a sample of nurses working in governmental hospitals in Jordan. Participants were unaware of the time and observer during the observation episode. RESULTS: A total of 384 nurses from 9 different hospitals participated in the study. A total of 835 injections events were observed, of which 73.9% were performed without handwashing, 64.5% without gloving, and 27.5% were followed by needle recapping. Handwashing rate was the lowest (18.9%) when injections were performed by beginner nurses. Subcutaneous injections were associated with the lowest rate (26.7%) of postinjection handwashing compared with other routes. CONCLUSIONS: This study demonstrates the need for focused and effective infection control educational programs in Jordanian hospitals. Future studies should consider exploring the whole infection control practices related to waste disposal and the roles of the infection control nurse in this process in Jordanian hospitals. PMID- 28623002 TI - Quantitative assessment of interactions between hospitalized patients and portable medical equipment and other fomites. AB - In an observational study, we demonstrated that hospitalized patients frequently had direct or indirect interactions with medical equipment and other fomites that are shared among patients, and these items were often contaminated with health care-associated pathogens. There is a need for protocols to ensure routine cleaning of shared portable equipment. PMID- 28623003 TI - Serum procalcitonin levels as a diagnostic marker for septic arthritis: A meta analysis. AB - BACKGROUND: The aim of this study was to assess the value of serum procalcitonin (PCT) levels as a diagnostic marker for septic arthritis (SA) via meta-analysis. METHODS: We searched PubMed, Embase and the Cochrane Library, as well as the reference lists of relevant articles, for studies published up to May 21, 2015 and did not impose language restrictions. We selected original studies reporting the usefulness of PCT or C-reactive protein (CRP) as a diagnostic marker for SA. We summarized test performance characteristics with the use of forest plots, hierarchical summary receiver operating characteristic curves, and bivariate random effects models. Prespecified subgroup analyses and meta-regression analyses were also performed. RESULTS: This meta-analysis comprised 10 studies including 838 patients. The overall sensitivity of serum PCT levels for the diagnosis of SA in these studies was 0.54 (95% CI, 0.41-0.66), and the specificity of PCT was 0.95 (95% CI, 0.87-0.98). The positive likelihood ratio (LR) was 10.97 (95% CI, 4.65-25.89); the negative LR was 0.49 (95% CI, 0.38 0.62); and the area under ROC curve (AUROC) was 0.82 (95% CI, 0.78-0.85). Six studies also examined the usefulness of CRP levels as a marker for the diagnosis of SA. The sensitivity and specificity of CRP were 0.45 (95% CI, 0.35-0.55) and 0.079 (95% CI, 0.0.021-0.25), respectively, and the positive LR, negative LR and AUROC curve were 0.48 (95% CI, 0.39-0.61), 6.79 (95% CI, 2.04-23.81), and 0.30 (95% CI, 0.26-0.34), respectively. CONCLUSION: PCT is more valuable than CRP for distinguishing SA from non-SA. PMID- 28623005 TI - Pre-oxygenation: Implications in emergency airway management. AB - Transient oxygen desaturation during emergency department intubation is an event with potentially devastating consequences. Pre-oxygenation is an important means of increasing a patient's oxygen reserve and duration of safe apnea prior to intubation. In the emergent setting, important modifications to pre-oxygenation techniques need to be considered to best manage critically ill patients. In this review, we discuss recent updates in pre-oxygenation techniques and evaluate the evidence supporting both commonly used and newly emerging techniques for pre oxygenation, assessing nature and level of illness, the best delivery method of oxygen, using delayed sequence intubation in patients who cannot tolerate non invasive pre-oxygenation and using apneic oxygenation via nasal cannula and non rebreather mask during intubation. PMID- 28623004 TI - Variable methodological quality and use found in systematic reviews referenced in STEMI clinical practice guidelines. AB - BACKGROUND: The objective of this study was to assess the methodological quality and clarity of reporting of the systematic reviews (SRs) supporting clinical practice guideline (CPG) recommendations in the management of ST-elevation myocardial infarction (STEMI) across international CPGs. METHODS: We searched 13 guideline clearinghouses including the National Guideline Clearinghouse and Guidelines International Network (GIN). To meet inclusion criteria CPGs must be pertinent to the management of STEMI, endorsed by a governing body or national organization, and written in English. We retrieved SRs from the reference sections using a combination of keywords and hand searching. Two investigators scored eligible SRs using AMSTAR and PRISMA. RESULTS: We included four CPGs. We extracted 71 unique SRs. These SRs received AMSTAR scores ranging from 1 (low) to 9 (high) on an 11-point scale. All CPGs consistently underperformed in areas including disclosure of funding sources, risk of bias, and publication bias according to AMSTAR. PRISMA checklist completeness ranged from 44% to 96%. The PRISMA scores indicated that SRs did not provide a full search strategy, study protocol and registration, assessment of publication bias or report funding sources. Only one SR was referenced in all four CPGs. All CPGs omitted a large subset of available SRs cited by other guidelines. CONCLUSIONS: Our study demonstrates the variable quality of SRs used to establish recommendations within guidelines included in our sample. Although guideline developers have acknowledged this variability, it remains a significant finding that needs to be addressed further. FUNDING: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. PMID- 28623006 TI - A longevity study with enhancer substances (selegiline, BPAP) detected an unknown tumor-manifestation-suppressing regulation in rat brain. AB - AIMS: First proof to show that (-)-deprenyl/selegiline (DEP), the first selective inhibitor of MAO-B, later identified as the first beta-phenylethylamine (PEA) derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)-1 (1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived presently known most potent, selective, synthetic enhancer substance, are specific markers of unknown enhancer-sensitive brain regulations. MAIN METHODS: Longevity study disclosing the operation of tumor-manifestation-suppressing (TMS) regulation in rat brain. Immonohistochemical identification of a fibromyxosarcoma in rats. Experiments with human medulloblastoma cell lines. Analysis of the mechanism of action of enhancer substances. KEY FINDINGS: Whereas 20/40 saline treated rats manifested a fibromyxosarcoma, in groups of rats treated with 0.001mg/kg DEP: 15/40 rats; with 0.1mg/kg DEP: 11/40 rats (P<0.01); with 0.0001mg/kg BPAP: 8/40 rats (P<0.001); with 0.05mg/kg BPAP: 7/40 rats (P<0.01) manifested the tumor. Experiments with human medulloblastoma cell lines, HTB-186 (Daoy); UW-228-2, showed that BPAP was devoid of direct cytotoxic effect on tumor cells, and did not alter the direct cytotoxic effectiveness of temozolomide, cisplatin, etoposide, or vincristine. Interaction with distinct sites on vesicular monoamine-transporter-2 (VMAT2) is the main mechanism of action of the enhancer substances which clarifies the highly characteristic bi-modal, bell shaped concentration-effect curves of DEP and BPAP. SIGNIFICANCE: Considering of the safeness of the enhancer substances and the finding that DEP and BPAP, specific markers of unknown enhancer sensitive brain regulations, detected the operation of an enhancer-sensitive TMS-regulation in rat brain, it seems reasonable to test in humans low dose DEP or BPAP treatment against the spreading of a malignant tumor. PMID- 28623007 TI - Gene networks in neurodegenerative disorders. AB - Three neurodegenerative diseases [Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD)] have many characteristics like pathological mechanisms and genes. In this sense some researchers postulate that these diseases share the same alterations and that one alteration in a specific protein triggers one of these diseases. Analyses of gene expression may shed more light on how to discover pathways, pathologic mechanisms associated with the disease, biomarkers and potential therapeutic targets. In this review, we analyze four microarrays related to three neurodegenerative diseases. We will systematically examine seven genes (CHN1, MDH1, PCP4, RTN1, SLC14A1, SNAP25 and VSNL1) that are altered in the three neurodegenerative diseases. A network was built and used to identify pathways, miRNA and drugs associated with ALS, AD and PD using Cytoscape software an interaction network based on the protein interactions of these genes. The most important affected pathway is PI3K-Akt signalling. Thirteen microRNAs (miRNA-19B1, miRNA-107, miRNA-124-1, miRNA-124-2, miRNA-9-2, miRNA-29A, miRNA-9-3, miRNA-328, miRNA-19B2, miRNA-29B2, miRNA-124-3, miRNA-15A and miRNA-9-1) and four drugs (Estradiol, Acetaminophen, Resveratrol and Progesterone) for new possible treatments were identified. PMID- 28623008 TI - Yucca schidigera can promote rabbit growth, fecundity, affect the release of hormones in vivo and in vitro, induce pathological changes in liver, and reduce ovarian resistance to benzene. AB - This study evaluated the effect of Yucca schidigera (YS) extract on the physiological, reproductive, and endocrine indexes of New Zealand White rabbit does. Six-week-old rabbit does were fed a standard diet (control group) or a diet enriched with 5 or 20g of Y powder extract per 100-kg feed mixture for 350days. The does were artificially inseminated after induction of superovulation. Weight gain; conception and kindling rate; viability of pups and mothers; histopathological state of liver and muscle; plasma levels of progesterone (P4), oxytocin (OT), and prostaglandin F (PGF); and the release of P4, insulin-like growth factor I (IGF-I), OT, and PGF by isolated ovarian fragments and their response to the addition of benzene were analyzed. YS extract supplementation promoted weight gain and induced histopathological changes in the liver (creased vacuolization and occurrence of fuchsinophile inclusions in hepatocytes, liver fibrosis, hyperemia, occurrence of Kupffer cells, signs of necrosis and inflammation). YS consumption was not associated with changes in muscle (occurrence of fuchsinophile inclusions and signs of atrophy, interstitial edema, and inflammation), although Y2 increased muscle vascularization. YS supplementation increased conception and kindling rates but did not affect viability of pups or adult animals. Moreover, it enhanced plasma OT and PGF levels; plasma P4 concentration was increased by low-dose YS, but decreased by high-dose YS. Cultured ovarian fragments isolated from YS-fed does released more P4 and PGF and less IGF-I than ovarian fragments of control animals. However, YS supplementation did not affect ovarian OT release. Benzene alone did not influence the release of hormones by ovaries of control does. YS supplementation induced the inhibitory effect of benzene on the release of PGF, but not on other ovarian hormones. Collectively, these results suggest that dietary supplementation of YS extract can stimulate rabbit performance (growth and fecundity), which may be due to the promotion of P4, OT, and PGF release. It could, however, induce some pathological changes in the liver and reduce resistance of ovaries to the environmental contaminant benzene. PMID- 28623010 TI - [Influence of the working conditions on sickness absence due to common diseases]. AB - OBJECTIVE: To estimate the importance of the working environment in sickness absence, as well as to show possible relationships with clinical-work variables. DESIGN: A descriptive observational study. SITE: Medical Inspection of an Andalusian province. PARTICIPANTS: A total of 1016 workers on certified sick leave due to a common illness. MAIN MEASUREMENTS: A self-report questionnaire was used to collect demographic data, profession, activity, risk assessment, and perceived occupational cause, on patients who voluntarily gave their consent when they were reviewed during 2015. The illness that caused certified sickness absences was verified in the computerised medical records. Using criteria applied by experts, the role of working conditions in each episode of certified sick leave was assessed. Bivariate and multivariate analyses were performed to determine any relationships between the variables. RESULTS: An inadequate work environment was found in 17.1% of the sickness processes. Health and hospitality services activities have a significant association with working conditions as a cause of sick leave (P<.001). With respect to diagnosis, anxiety-depressive disorders (P<.01) and low back pain (P<.05) were associated with working conditions. The factors related to certified sickness absence and work environment were: residence (OR=0.34, 0.21-0.6), normal/higher education (OR=1.7, 1.2-2.4), (OR=2.0 1.3-3.1), large companies (OR=1.97, 1.3-2.9), and job (OR=2.7, 1.6-3, 2). CONCLUSIONS: Sickness absence is affected by factors related to the work environment. Specific preventive actions for workers at their workplace could reduce work related diseases classified as a common illness. PMID- 28623009 TI - ? AB - OBJECTIVE: The aim of the study was to evaluate whether the neuropsychiatric symptoms interfere with cognitive impairment detection in primary care and to describe which of them generate more confusion. DESIGN: Descriptive and observational study. LOCATION: Mobile psychiatric unit in collaboration with primary healthcare centers in Barcelona. PARTICIPANTS: A total of 104 patients over 65years referred to mobile psychiatric unit from primary healthcare clinicians suspecting mental disease. MAIN MEASUREMENTS: All patients received a DSM-IV-TR diagnosis. We included in the study the Mini Mental State Examination (MMSE), Neuropsichiatric Inventory, Severe Psychiatric Illness scale, Global Assessment of Functioning, Clinical Global Impression and Word Health Organisation Dissability Assessment Schedule. RESULTS: 55.8% of patients referred from primary care had altered MMSE score. Neuropsychiatric symptoms more frequently associated with suspected cognitive impairment were delusions, hallucinations, agitation, disinhibition, irritability and purposeless motor behavior. CONCLUSIONS: When psychiatric symptoms of Severe Mental Disorder (SMD) are detected in elderly individuals with no history of SMD, cognitive impairment should be suspected and a screening test be done. PMID- 28623011 TI - [Recommendations for the use of rapid diagnosis techniques in respiratory infections in primary care]. AB - Respiratory tract infections rank first as causes of adult and paediatric infectious morbidity in primary care in Spain. These infections are usually self limiting and are mainly caused by viruses. However, a high percentage of unnecessary antibiotic prescription is reported. Point-of-care tests are biomedical tests, which can be used near the patient, without interference of a laboratory. The use of these tests, many of which have been recently developed, is rapidly increasing in general practice. Notwithstanding, we must mull over whether they always contribute to an effective and high-quality diagnostic process by primary care clinicians. We present a set of criteria that can be used by clinicians and discuss the pros and cons of the instruments available for the management of respiratory tract infections and how to use them appropriately. PMID- 28623012 TI - P wave peak time; a novel electrocardiographic parameter in the assessment of coronary no-reflow. AB - OBJECTIVES: Coronary no-reflow (NR) following primary percutaneous coronary intervention (pPCI) is associated with worsened prognosis in patients with ST segment elevation myocardial infarction (STEMI). Despite rapid developments in cardiovascular area; there are limited data regarding prediction of NR before pPCI. P wave duration and dispersion (PWD, PWDIS, respectively) have been studied in STEMI patients and found to be associated with reperfusion success; however none of them has been found to predict NR before PCI. In our study we aimed to evaluate whether PWD, PWDIS and a novel parameter P wave peak time (PWPT) could predict NR development in STEMI patients. METHOD: Fifty six patients who were admitted with anterior STEMI constituted study populations. The diagnosis and treatment of STEMI was made on the basis of current guidelines. P wave parameters including PWD, PWDIS and PWPT were calculated from electrocardiograms that were obtained on admission and 60 min after pPCI. RESULTS: Patients were divided into two groups according to the development of NR. We observed that PWPT that were obtained from D2 (PWPTD2) and V1 (PWPTV1) leads were longer in NR group than reflow group. There were significant correlations between PWPT and reperfusion parameters regarding percent of ST segment resolution, peak CKMB level and TIMI frame count of infarct related artery. Preprocedural PWPTD2 was found to be an independent predictor of NR development. CONCLUSION: In our study we observed that PWPT could be a useful parameter in the assessment of reperfusion success and prediction of NR development. PMID- 28623013 TI - Low QRS Voltage on Presenting Electrocardiogram Predicts Multi-vessel Disease in Anterior ST-segment Elevation Myocardial Infarction. AB - BACKGROUND: Low QRS voltage was reported to predict adverse outcomes in acute myocardial infarction in the pre-thrombolytic era. However, the association between low voltage and angiographic findings has not been fully addressed. METHODS: We performed a retrospective analysis of patients with anterior ST segment elevation myocardial infarction (STEMI). Low QRS voltage was defined as either peak to peak QRS complex voltage <1.0mV in all precordial leads or <0.5mV in all limb leads. RESULTS: Among 190 patients, 37 patients (19%) had low voltage. Patients with low voltage had a higher rate of multi-vessel disease (MVD) (76% vs. 52%, p=0.01). Patients with low voltage were more likely to undergo coronary artery bypass grafting (CABG) during admission (11% vs. 2%, p=0.028). Low voltage was an independent predictor for MVD (OR 2.50; 95% CI 1.12 to 6.03; p=0.032). CONCLUSION: Low QRS voltage was associated with MVD and in hospital CABG in anterior STEMI. PMID- 28623014 TI - Electrocardiographic risk stratification of asymptomatic population without cardiovascular disease: Should we add the QRS-T angle? PMID- 28623015 TI - Inadvertent left ventricular pacing and perforation by a temporary pacemaker. AB - Myocardial perforation by pacemaker electrode is a very serious complication. Usually, the pacemaker electrode perforates the right ventricle, but rarely the left ventricular myocardium. We describe an 82-year-old female patient who presented with left ventricular pacing after temporary pacemaker implantation and was diagnosed with myocardial perforation. Emergency thoracotomy showed that the exact position of the cardiac perforation was close to the left ventricular apex. Perforation of the left ventricular free wall by an electrode sometimes progresses slowly. We should be alert to the possibility of left ventricular perforation, in which case, immediate surgery is the best option. PMID- 28623016 TI - The Relationship between neutrophil-to-lymphocyte ratio and fragmented QRS in acute STEMI patients treated with primary PCI. AB - BACKGROUND: No study so far investigated fragmented QRS (fQRS) and neutrophil-to lymphocyte ratio (NLR) together in ST segment elevation myocardial infarction (STEMI). OBJECTIVE: To investigate the relationship between NLR and fQRS, and determine the prognostic significance of the combined use of these two parameters in STEMI. METHODS: We included 368 patients with first acute STEMI who successfully revascularized with primary percutaneous coronary intervention. RESULTS: Patients with fQRS had significantly higher NLR, and in-hospital mortality rate compared to patients with no-fQRS. The best cut-off value of NLR to predict mortality was 5.47. Patients with NLR>=5.47 had a higher frequency of fQRS and in-hospital mortality rate. Multivariate analysis showed that NLR was an independent predictor of the presence of fQRS (OR: 1.095, 95% CI: 1.039-1.153, P=0.001). When patients were stratified by fQRS and cut-off value of NLR, in hospital mortality gradually increased (P<0.001). CONCLUSION: NLR is independently associated with the presence of fQRS in STEMI patients. Combined use of both parameters provides additional prognostic contribution for identifying patients at higher cardiac risk. PMID- 28623017 TI - Electrocardiogeriatrics: ECG in advanced age. AB - The electrocardiogram (ECG) presents substantial changes associated with aging. In fact, the likelihood of having a "normal" ECG decreases with age. The most common findings are left ventricular hypertrophy pattern, leftward axis deviation and QRS widening. Interatrial block (IAB) is frequently present, mainly partial IAB. Atrial fibrillation prevalence raises from 6-7% in those aged 65-74years to 13-17% in those >75years. PMID- 28623018 TI - Spiked helmet sign after percutaneous left stellate ganglion ablation in a patient with long QT syndrome. AB - "Spiked helmet" is a type of ST elevation, which is generally observed in critically ill patients and associated with very poor prognosis. Here we present a case of previously undiagnosed long QT syndrome admitted with polymorphic ventricular tachycardia (PMVT) unresponsive to pharmacological treatment and developed "spiked helmet" sign after left percutaneous stellate ganglion ablation. PMID- 28623019 TI - Exogenous addition of H2 for an in situ biogas upgrading through biological reduction of carbon dioxide into methane. AB - Biological reduction of CO2 into CH4 by exogenous addition of H2 is a promising technology for upgrading biogas into higher CH4 content. The aim of this work was to study the feasibility of exogenous H2 addition for an in situ biogas upgrading through biological conversion of the biogas CO2 into CH4. Moreover, this study employed systematic study with isotope analysis for providing comprehensive evidence on the underlying pathways of CH4 production and upstream processes. Batch reactors were inoculated with digestate originating from a full-scale biogas plant and fed once with maize leaf substrate. Periodic addition of H2 into the headspace resulted in a completely consumption of CO2 and a concomitant increase in CH4 content up to 89%. The microbial community and isotope analysis shows an enrichment of hydrogenotrophic Methanobacterium and the key role of hydrogenotrophic methanogenesis for biogas upgrading to higher CH4 content. Excess H2 was also supplied to evaluate its effect on overall process performance. The results show that excess H2 addition resulted in accumulation of H2, depletion of CO2 and inhibition of the degradation of acetate and other volatile fatty acids (VFA). A systematic isotope analysis revealed that excess H2 supply led to an increase in dissolved H2 to the level that thermodynamically inhibit the degradation of VFA and stimulate homo-acetogens for production of acetate from CO2 and H2. The inhibition was a temporary effect and acetate degradation resumed when the excess H2 was removed as well as in the presence of stoichiometric amount of H2 and CO2. This inhibition mechanism underlines the importance of carefully regulating the H2 addition rate and gas retention time to the CO2 production rate, H2-uptake rate and growth of hydrogenotrophic methanogens in order to achieve higher CH4 content without the accumulation of acetate and other VFA. PMID- 28623020 TI - Two-step gasification of cattle manure for hydrogen-rich gas production: Effect of biochar preparation temperature and gasification temperature. AB - Two-step gasification process was proposed to dispose cattle manure for hydrogen rich gas production. The effect of temperature on product distribution and biochar properties were first studied in the pyrolysis-carbonization process. The steam gasification of biochar derived from different pyrolysis-carbonization temperatures was then performed at 750 degrees C and 850 degrees C. The biochar from the pyrolysis-carbonization temperatures of 500 degrees C had high carbon content and low volatiles content. According to the results of gasification stage, the pyrolysis-carbonization temperature of 500 degrees C and the gasification temperature of 850 degrees C were identified as the suitable conditions for hydrogen production. We obtained 1.61m3/kg of syngas production, 0.93m3/kg of hydrogen yield and 57.58% of hydrogen concentration. This study shows that two-step gasification is an efficient waste-to-hydrogen energy process. PMID- 28623021 TI - Improving the circular economy via hydrothermal processing of high-density waste plastics. AB - Rising environmental concerns on climate changes are causing an increasing attention on circular economies. The plastic economy, in particular, is in focus due to the accelerating consumption of plastics, mainly derived from virgin feedstock, combined with the lack of plastic recycling strategies. This work presents a novel outlook on the potential of using supercritical hydrothermal processing of waste plastic fractions for tertiary recycling. The study investigates hydrothermal processing of nine different, high-density types of plastics into original resin monomers and other value-added chemical compounds. The outlook presents conversion yields, carbon balances, and chemical details on the products obtained. It is found that all the investigated resins are prone to hydrothermal treatment, and that high yields of monomers and high value compounds (up to nearly 100%), suitable for chemicals and fuels applications, can be obtained. For instance, for polycarbonate, styrene-butadiene, poly(lactic acid), poly(ethylene terephthalate), and poly(butylene terephthalate), original monomeric compounds can be reclaimed for manufacturing new resins. The promising results presented demonstrate that hydrothermal processing of high-density plastics is a prospective technology for increasing the circularity of the plastic economy. PMID- 28623022 TI - Heterogeneity of zeolite combined with biochar properties as a function of sewage sludge composting and production of nutrient-rich compost. AB - In the present study, biochar combined with a higher dosage of zeolite (Z) and biochar (B) alone were applied as additives for dewatered fresh sewage sludge (DFSS) composting using 130-L working volume lab-scale reactors. We first observed that the addition of a mixture of B and Z to DFSS equivalent to 12%B+10% (Z-1), 15% (Z-2) and 30% (Z-3) zeolite (dry weight basis) worked synergistically as an amendment and increased the composting efficiency compared with a treatment of 12%B alone amended and a control without any amendment. In a composting reactor, the addition of B+Z may serve as a novel approach for improving DFSS composting and the quality of the end product in terms of the temperature, water holding capacity, CO2 emissions, electrical conductivity, water-soluble and total macro-nutrient content and phytotoxicity. The results indicated that during the thermophilic phase, dissolved organic carbon, NH4+-N and NO3--N increased drastically in all biochar amended treatments, whereas considerably low water soluble nutrients were observed in the control treatment throughout and at the end of the composting. Furthermore, the maturity parameters and dissolved organic carbon (DOC) indicated that compost with 12%B+15%Z became more mature and humified within 35days of DFSS composting, with the maturity parameters, such as CO2 evolution and the concentration of NH4+-N in the compost, being within the permissible limits of organic farming in contrast to the control. Furthermore, at the end of composting, the addition of higher dosage of biochar (12%) alone and 12% B+Z lowered the pH by 7.15 to 7.86 and the electrical conductivity by 2.65 to 2.95mScm-1 as compared to the control, while increased the concentrations of water-soluble nutrients (gkg-1) including available phosphorus, sodium and potassium. In addition, greenhouse experiments demonstrated that the treatment of 150kgha-1 biochar combined with zeolite and that of 12%B alone improved the yield of Chinese cabbage (Brassica rapa chinensis L.). The highest dry weight biomass (1.41+/-0.12g/pot) was obtained with 12%B+15%Z amended compost. Therefore, 12%B+15%Z can be potentially applied as an amendment to improve DFSS composting. PMID- 28623023 TI - Pyrolysis reaction models of waste tires: Application of Master-Plots method for energy conversion via devolatilization. AB - Land applied disposal of waste tires has far-reaching environmental, economic, and human health consequences. Pyrolysis represents a potential waste management solution, whereby the solid carbonaceous residue is heated in the absence of oxygen to produce liquid and gaseous fuels, and a solid char. The design of an efficient conversion unit requires information on the reaction kinetics of pyrolysis. This work is the first to probe the appropriate reaction model of waste tire pyrolysis. The average activation energy of pyrolysis was determined via iso-conversional methods over a mass fraction conversion range between 0.20 and 0.80 to be 162.8+/-23.2kJmol-1. Using the Master Plots method, a reaction order of three was found to be the most suitable model to describe the pyrolytic decomposition. This suggests that the chemical reactions themselves (cracking, depolymerization, etc.), not diffusion or boundary layer interactions common with carbonaceous biomasses, are the rate-limiting steps in the pyrolytic decomposition of waste tires. PMID- 28623024 TI - Functional diversity of aquatic ciliates. AB - This paper first reviews the concept of functional diversity in general terms and then applies it to free-living aquatic ciliates. Ciliates are extremely versatile organisms and display an enormous functional diversity as key elements of pelagic food webs, acting as predators of bacteria, algae, other protists and even some metazoans. Planktonic ciliates are important food for zooplankton, and mixotrophic and functionally autotrophic species may significantly contribute to primary production in the ocean and in lakes. The co-occurrence of many ciliate species in seemingly homogenous environments indicates a wide range of their ecological niches. Variation in space and time may foster co-occurrence and prevent violating the competitive exclusion principle among ciliates using the same resources. Considering that many ciliates may be dormant and/or rare in many habitats, ciliate species diversity must be higher than can be deduced from simple sampling techniques; molecular methods of identification clearly point to this hidden diversity. From a functional point of view, the question is how much of this diversity represents redundancy. A key challenge for future research is to link the ecophysiological performance of naturally co-occurring ciliates to their functional genes. To this end, more experimental research is needed with with functionally different species. PMID- 28623025 TI - Identification of elemental weight fraction and mass density of humanoid tissue equivalent materials using dual energy computed tomography. AB - The purpose of this study was to obtain the fraction by weight of the elemental composition and mass density of a humanoid tissue phantom that includes lung tissue, soft tissue, and bone tissue, by using dual energy computed tomography (DECT). The fraction by weight and the mass density for tissue-equivalent materials were calculated by means of a least-squares method with a linear attenuation coefficient, using monochromatic photon energies of 10-140keV, as obtained from DECT. The accuracy of calculated values for the fractions by weight of H (hydrogen), C (carbon), N (nitrogen), and O (oxygen) as verified by comparing the values with those that were analyzed using the combustion technique. The fraction by weight for other elements was confirmed by comparing with the analyzed values by means of energy dispersive photon spectroscopy. The calculated mass densities for each tissue were compared with those that were obtained by dividing the weight by volume. The calculated values of the fraction by weight that were obtained by means of DECT had differences of 1.9%, 9.2%, 6.6%, 7.8%, 0.8%, and 0.2% at a maximum for H, C, N, O, P (phosphorus), and Ca (calcium), respectively, from the reference values analyzed by the combustion technique and energy dispersive photon spectroscopy. The difference in the mass density for tissue was 0.011g/cm3 at a maximum. This study demonstrated the fraction by weight and the mass density of the humanoid tissue-equivalent materials that were calculated by means of DECT were expected high accuracy. PMID- 28623026 TI - Vaccination resilience: Building and sustaining confidence in and demand for vaccination. PMID- 28623027 TI - ADE and dengue vaccination. AB - The vaccine against Dengue virus (DENV), Dengvaxia(r) (CYD), produced by Sanofi Pasteur, has been registered by several national regulatory agencies; nevertheless, the performance and security of this vaccine have been challenged in a series of recent papers. In this work, we intend to contribute to the debate by analyzing the concept of an enhancing vaccine, presenting objections to the epidemiological model base of the concept and, likewise, presenting data that contradict that concept. PMID- 28623028 TI - Impact and cost-effectiveness of rotavirus vaccination in Bangladesh. AB - INTRODUCTION: Diarrheal disease is a leading cause of child mortality globally, and rotavirus is responsible for more than a third of those deaths. Despite substantial decreases, the number of rotavirus deaths in children under five was 215,000 per year in 2013. Of these deaths, approximately 41% occurred in Asia and 3% of those in Bangladesh. While Bangladesh has yet to introduce rotavirus vaccination, the country applied for Gavi support and plans to introduce it in 2018. This analysis evaluates the impact and cost-effectiveness of rotavirus vaccination in Bangladesh and provides estimates of the costs of the vaccination program to help inform decision-makers and international partners. METHODS: This analysis used Pan American Health Organization's TRIVAC model (version 2.0) to examine nationwide introduction of two-dose rotavirus vaccination in 2017, compared to no vaccination. Three mortality scenarios (low, high, and midpoint) were assessed. Benefits and costs were examined from the societal perspective over ten successive birth cohorts with a 3% discount rate. Model inputs were locally acquired and complemented by internationally validated estimates. RESULTS: Over ten years, rotavirus vaccination would prevent 4000 deaths, nearly 500,000 hospitalizations and 3 million outpatient visits in the base scenario. With a Gavi subsidy, cost/disability adjusted life year (DALY) ratios ranged from $58/DALY to $142/DALY averted. Without a Gavi subsidy and a vaccine price of $2.19 per dose, cost/DALY ratios ranged from $615/DALY to $1514/DALY averted. CONCLUSION: The discounted cost per DALY averted was less than the GDP per capita for nearly all scenarios considered, indicating that a routine rotavirus vaccination program is highly likely to be cost-effective. Even in a low mortality setting with no Gavi subsidy, rotavirus vaccination would be cost effective. These estimates exclude the herd immunity benefits of vaccination, so represent a conservative estimate of the cost-effectiveness of rotavirus vaccination in Bangladesh. PMID- 28623029 TI - Efficacy of PLGA microparticle-encapsulated formalin-killed Aeromonas hydrophila cells as a single-shot vaccine against A. hydrophila infection. AB - Control and prevention of disease is a high priority in aquaculture, and vaccination is important to prevent outbreaks. Here, poly(d,l-lactide-co-glycolic acid) (PLGA) microparticles (MPs) approximately 36MUm in diameter were used to encapsulate and deliver Aeromonas hydrophila formalin-killed cells (FKC) as an antigen, and the innate and adaptive immune responses of cyprinid loaches and common carp were assessed following vaccination. The antigen was confirmed to be well encapsulated by scanning electron microscopy analysis of PLGA MP sections. Blood and head kidney specimens were collected and analyzed for bacterial agglutination activity and relative mRNA expression of immune-related genes (IL 1beta, IL-10, TNF-alpha, lysozyme C, TGF-beta, and IgM) at 2, 4, 6, and 8weeks post vaccination (wpv). For both fish species, the curve of antibody titer over time was shallower in the PLGA group than the FKC group. These titers in loaches and carp were very similar in the two vaccination groups until 8 and 6 wpv, respectively, but differences were subsequently noted in both species until the end of experiment. Loaches and carp were then challenged with A. hydrophila at 12 and 20 wpv, and 10 and 14 wpv, respectively, and relative survival rates were calculated. For both species, the PLGA groups demonstrated higher survival rates at all time points. Relative expression of IL-1beta and TNF-alpha mRNA was significantly upregulated in the PLGA group at 2 and 4 wpv. Moreover, PLGA-MP vaccination increased relative mRNA levels of lysozyme C and IgM, which were significantly higher than those observed with FKC treatment at 2 wpv and 4, 6, and 8 wpv, respectively. In conclusion, PLGA-MP vaccines have the potential to induce longer and more potent immune responses than FKCs alone, and protect both cyprinid loaches and common carp with greater efficiency. PMID- 28623031 TI - [Pulmonary hypertension screening in systemic sclerosis: The best strategy remains to be defined]. PMID- 28623030 TI - Immunogenicity of mumps virus vaccine candidates matching circulating genotypes in the United States and China. AB - Mumps virus (MuV) causes acute infection in humans with characteristic swelling of the parotid gland. While vaccination has greatly reduced the incidence of MuV infection, there have been multiple large outbreaks of mumps virus (MuV) in highly vaccinated populations. The most common vaccine strain, Jeryl Lynn, belongs to genotype A, which is no longer a circulating genotype. We have developed two vaccine candidates that match the circulating genotypes in the United States (genotype G) and China (genotype F). We found that there was a significant decrease in the ability of the Jeryl Lynn vaccine to produce neutralizing antibody responses to non-matched viruses, when compared to either of our vaccine candidates. Our data suggests that an updated vaccine may allow for better immunity against the circulating MuV genotypes G and F. PMID- 28623032 TI - [Smoking cessation in pregnancy]. PMID- 28623033 TI - Anti-inflammatory profile of paricalcitol in kidney transplant recipients. AB - BACKGROUND AND OBJECTIVES: Paricalcitol, a selective vitamin D receptor activator, is used to treat secondary hyperparathyroidism in kidney transplant patients. Experimental and clinical studies in non-transplant kidney disease patients have found this molecule to have anti-inflammatory properties. In this exploratory study, we evaluated the anti-inflammatory profile of paricalcitol in kidney-transplant recipients. METHODS: Thirty one kidney transplant recipients with secondary hyperparathyroidism completed 3 months of treatment with oral paricalcitol (1MUg/day). Serum concentrations and gene expression levels of inflammatory cytokines in peripheral blood mononuclear cells were analysed at the beginning and end of the study. RESULTS: Paricalcitol significantly decreased parathyroid hormone levels with no changes in calcium and phosphorous. It also reduced serum concentrations of interleukin (IL)-6 and tumour necrosis factor alpha (TNF-alpha) by 29% (P<0.05) and 9.5% (P<0.05) compared to baseline, respectively. Furthermore, gene expression levels of IL-6 and TNF-alpha in peripheral blood mononuclear cells decreased by 14.1% (P<0.001) and 34.1% (P<0.001), respectively. The ratios between pro-inflammatory cytokines (TNF-alpha and IL-6) and anti-inflammatory cytokines (IL-10), both regarding serum concentrations and gene expression, also experienced a significant reduction. CONCLUSIONS: Paricalcitol administration to kidney transplant recipients has been found to have beneficial effects on inflammation, which may be associated with potential clinical benefits. PMID- 28623035 TI - Prevalence and risk factors associated with peripheral arterial disease in an adult population from Colombia. AB - BACKGROUND: Cardiovascular diseases (CVD) are the most important cause of mortality in Latin America, while peripheral arterial disease (PAD) is the third leading cause of atherosclerotic cardiovascular morbidity. OBJECTIVE: To establish the prevalence of PAD and the distribution of traditional CVD risk factors in a population from the Department of Cauca, Colombia. METHODS: A cross sectional study was conducted on a total of 10,000 subjects aged >=40 years, from 36 municipalities. An ankle-brachial index (ABI) <= 0.9 in either leg was used as diagnostic criterion of PAD. RESULTS: Overall PAD prevalence was 4.4% (4.7% females vs. 4.0% males), with diabetes being the most prevalent risk factor (23%). Among individuals self-reporting a history of acute myocardial infarction or stroke, PAD prevalence was 31.0% and 8.1%, respectively. After adjusting for potential confounders, PAD was significantly associated with hypertension (OR 4.6; 95% CI; 3.42-6.20), diabetes (4.3; 3.17-5.75), dyslipidaemia (3.1; 2.50 3.88), obesity (1.8; 1.37-2.30), and cigarette smoking (1.6; 1.26-1.94). Analysis for the interaction of risk factors showed that diabetes, dyslipidaemia, and obesity accounted for 13.2 times the risk for PAD (6.9-25.4), and when adding hypertension to the model, the risk effect was the highest (17.2; 8.4-35.1). CONCLUSIONS: Hypertension, diabetes, dyslipidaemia, and obesity, but not smoking were strong predictors of PAD. ABI measurement should be routinely performed as a screening test in intermediate and high-risk patients for CVD prevention. This could lead to an early intervention and follow-up on populations at risk, thus, contributing to improve strategies for reducing CVD burden. PMID- 28623036 TI - [Arrhythmogenic right ventricular cardiomyopathy/dysplasia. Literature review and case report]. AB - Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited autosomal dominant disease, with an estimated prevalence of 1:2,500 to 1:5,000, being higher in males (3:1). It is characterised histologically by the substitution of cardiomyocytes for fibrous-adipose tissue, which predisposes to ventricular arrhythmias, right ventricular failure, and sudden cardiac death. The main aim of treatment is to reduce the risk of sudden death and improve the quality of life of patients. The case is presented of a 23 year old woman whose clinical symptoms started with palpitations, chest pain with physical activity, syncope, and headache, 6 years ago during her first pregnancy. Due to an increase in symptomatology, a stress test was performed, during which she collapsed with a sustained monomorphic ventricular tachycardia. A cardiac magnetic resonance scan showed dilation, an increase in trabeculae, and decreased function of the right ventricle. A 3-dimensional mapping and ablation was performed, and during the isoproterenol infusion test, a polymorphic ventricular flutter was generated that required electrical cardioversion. The decision was made to implant a dual chamber cardioverter defibrillator and perform stellate ganglion ablation as secondary prevention. After her discharge, the patient re-consulted many times due to discharges of the device associated with palpitations. A comprehensive review of the patient's medical records was performed, finding characteristics that may suggest arrhythmogenic right ventricular dysplasia. The Task Force criteria was applied, concluding that, as she met more than 2 major criteria, the patient had a definitive diagnosis of this disease. PMID- 28623034 TI - New NMR tools for protein structure and function: Spin tags for dynamic nuclear polarization solid state NMR. AB - Magic angle spinning solid state NMR studies of biological macromolecules [1-3] have enabled exciting studies of membrane proteins [4,5], amyloid fibrils [6], viruses, and large macromolecular assemblies [7]. Dynamic nuclear polarization (DNP) provides a means to enhance detection sensitivity for NMR, particularly for solid state NMR, with many recent biological applications and considerable contemporary efforts towards elaboration and optimization of the DNP experiment. This review explores precedents and innovations in biological DNP experiments, especially highlighting novel chemical biology approaches to introduce the radicals that serve as a source of polarization in DNP experiments. PMID- 28623038 TI - Perfusion kinetics in human brain tumor with DCE-MRI derived model and CFD analysis. AB - Cancer is one of the leading causes of death all over the world. Among the strategies that are used for cancer treatment, the effectiveness of chemotherapy is often hindered by factors such as irregular and non-uniform uptake of drugs inside tumor. Thus, accurate prediction of drug transport and deposition inside tumor is crucial for increasing the effectiveness of chemotherapeutic treatment. In this study, a computational model of human brain tumor is developed that incorporates dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) data into a voxelized porous media model. The model takes into account realistic transport and perfusion kinetics parameters together with realistic heterogeneous tumor vasculature and accurate arterial input function (AIF), which makes it patient specific. The computational results for interstitial fluid pressure (IFP), interstitial fluid velocity (IFV) and tracer concentration show good agreement with the experimental results. The computational model can be extended further for predicting the deposition of chemotherapeutic drugs in tumor environment as well as selection of the best chemotherapeutic drug for a specific patient. PMID- 28623037 TI - Muscle recruitment and coordination with an ankle exoskeleton. AB - Exoskeletons have the potential to assist and augment human performance. Understanding how users adapt their movement and neuromuscular control in response to external assistance is important to inform the design of these devices. The aim of this research was to evaluate changes in muscle recruitment and coordination for ten unimpaired individuals walking with an ankle exoskeleton. We evaluated changes in the activity of individual muscles, cocontraction levels, and synergistic patterns of muscle coordination with increasing exoskeleton work and torque. Participants were able to selectively reduce activity of the ankle plantarflexors with increasing exoskeleton assistance. Increasing exoskeleton net work resulted in greater reductions in muscle activity than increasing exoskeleton torque. Patterns of muscle coordination were not restricted or constrained to synergistic patterns observed during unassisted walking. While three synergies could describe nearly 95% of the variance in electromyography data during unassisted walking, these same synergies could describe only 85-90% of the variance in muscle activity while walking with the exoskeleton. Synergies calculated with the exoskeleton demonstrated greater changes in synergy weights with increasing exoskeleton work versus greater changes in synergy activations with increasing exoskeleton torque. These results support the theory that unimpaired individuals do not exclusively use central pattern generators or other low-level building blocks to coordinate muscle activity, especially when learning a new task or adapting to external assistance, and demonstrate the potential for using exoskeletons to modulate muscle recruitment and coordination patterns for rehabilitation or performance. PMID- 28623039 TI - The Acoustic Characteristics of the Voice in Cochlear-Implanted Children: A Longitudinal Study. AB - OBJECTIVE: The purpose of this study was to characterize changes in the voice and vowel articulation of prelingually deaf children after cochlear implantation. METHODS: In this study, the patient group included 30 prelingually deaf children who underwent unilateral cochlear implantation at 4-6 years of age. The control group included normally hearing children of the same age. All deaf children had follow-ups before cochlear implantation and at 1, 3, 6, 12, and 24 months after implantation. The acoustic parameters, aerodynamic parameters, and vowel formants were measured in the patient group and compared with those of the control group. RESULTS: All acoustic parameters, aerodynamic parameters, and vowel formants differed significantly between normally hearing children and prelingually deaf children. For prelingually deaf children, all of the above parameters gradually decreased after cochlear implantation. Furthermore, the acoustic parameters Jitter and Shimmer were significantly reduced as early as 6 months, whereas the fundamental frequency, the standard deviation of fundamental frequency, estimated subglottal pressure, aF1, iF2, and uF2 were significantly altered 12 months after implantation. However, statistically significant differences in these parameters were not observed between 12 and 24 months after cochlear implantation. CONCLUSION: After cochlear implantation, prelingually deaf children established auditory feedback and improved voice control and vowel production. PMID- 28623040 TI - [Neuro-ophthalmological conditions: Study of the clinical care pathway]. AB - INTRODUCTION: Neuro-ophthalmologic conditions require specialized multidisciplinary management, both medical and surgical, for patients affected by visual loss due to nervous system disease. The primary goal of this study is to define the specificity of neuro-ophthalmology within the realm of visual health. The secondary goal is to review clinical care pathways by studying the organization of management, in terms of accessibility to care and personalization of the care pathway. PATIENTS AND METHODS: A field study was carried out from February to June 2015, within the ophthalmology service of the Pitie-Salpetriere University Medical Center in Paris. A 30-minute interview with the patient before or after his or her neuro-ophthalmology consultation was performed, so as to describe the clinical care pathway. The medical records of interviewed patients were also analyzed. RESULTS: Seventeen care pathways (10 women and 7 men) were reviewed. The mean age at appearance of visual involvement was 44.5 years (+/-8.4 years). If we exclude 3 patients over 66 years and retired, 35.71% were active, 35.71% were disabled, and 28.57% were on sick leave. Ten patients (58.82%) met the criteria for admission to long-term care. The first step had been carried out by local private practitioners. The first physician seen was the general medicine physician (59%), then the private ophthalmologist on an emergency basis (17%). On average, patients went through 8 steps during their care pathway (from 6 to 10 steps) and 14 medical departments were involved. The study showed collaboration with the other services of the University Hospital Department of Vision and Disabilities (notably with the Fondation Rothschild, the Quinze-Vingts National Ophthalmology Hospital and the Fondation Sainte-Marie). In addition to rehabilitation services, health care professionals participating in the outpatient care of the patients included an orthoptist (11.7%), a psychologist (11.7%), and an optician specializing in low vision for visual aids. And finally, patient support groups, AFM-Telethon (myasthenia) and the ARIBa Association (visual disability) were solicited by 2 patients for their involvement. A disturbance in activities of daily living leading to disabilities with psychological repercussions was noted by a number of patients. The most frequent complaints involve mobility (29.41%) and reading (23.52%). In total, 77% of patients state that their well-being has been affected and they are disturbed by the progression of their disease. DISCUSSION AND CONCLUSIONS: The review of the clinical care pathway of patients affected by neuro-ophthalmological conditions shows that these pathologies are, on the one hand, often poorly understood, and on the other hand complex, leading to an often significant number of steps for the patient. This also emphasizes the necessity of a care network, specialized and structured to improve the efficiency of this management. Finally, these results demonstrate the existence of a very frequent disability, which may affect all aspects of the patients' lives, highlighting the importance of rehabilitation services and individuals participating in the follow-up of these patients beyond their acute care. PMID- 28623041 TI - [Corneal dystrophies]. AB - Degenerative or hereditary corneal diseases are sometimes difficult to discriminate. Corneal dystrophies affect approximately 0.09 % of the population. They are identified by the IC3D classification based on their phenotype, genotype and evidence gathered for their diagnosis. Practically, the ophthalmologist manages functional symptoms, such as recurrent erosions, visual loss and amblyopia, photophobia, foreign body sensation, and sometimes pain and aesthetic concerns. Medical treatments consist of drops to promote healing, ointments, hyperosmotic agents and bandage contact lenses. Less invasive surgical treatments are used as second line therapy (phototherapeutic keratectomy, lamellar keratectomy). More invasive procedures may eventually be utilized (lamellar or penetrating keratoplasty). Anterior lamellar or endothelial keratoplasty are now preferred to penetrating keratoplasty, although the latter still remains the only possible option in some cases. Some rare dystrophies require coordinated and comprehensive medical care. PMID- 28623042 TI - Corneocyte lipid envelope (CLE), the key structure for skin barrier function and ichthyosis pathogenesis. AB - Research on the genetic abnormalities and pathogenetic processes of ichthyoses has progressed remarkably, and many causative genes and molecules have been identified in ichthyoses and ichthyosis syndromes. Most of the genes/molecules causative of ichthyosis are associated with the barrier function of the stratum corneum, and defects in the skin barrier play important roles in the pathogenesis of various ichthyosis phenotypes. It has been elucidated that, of the ichthyosis causative genes, ABCA12, ALOXE3, ALOX12B, CYP4F22, CERS3, ABHD5, PNPLA1 and ELOVL4 work in the formation of the corneocyte lipid envelope (CLE), a structure that is essential to sound skin barrier function. The CLE mostly consists of ultra-long-chain (ULC) ceramides derived from ULC-acylceramide (EOS; a combination of esterified omega-hydroxy fatty acids and sphingosines). In this review, I shed light on the synthesis, metabolism and transport of epidermal ceramides, especially on ULC-acylceramide and the processes of CLE formation. In addition, I summarize the pathogeneses of various ichthyoses and ichthyosis syndromes from the aspects of abnormal synthesis of ULC-acylceramide and malformation of the CLE. Investigations on the pathomechanisms of ichthyoses have provided novel knowledge on the synthesis and metabolism of ceramides in the epidermis. Conversely, research on the dynamics of epidermal ceramides has contributed to the elucidation of the pathogenesis of ichthyoses. Advances in our understanding of the biology of epidermal lipids and the disease pathogeneses of ichthyoses and ichthyosis syndromes promise to provide clues for the development of effective therapies for ichthyosis patients in the near future. PMID- 28623043 TI - Nasal airway evaluation in obstructive sleep apnoea patients: volumetric tomography and endoscopic findings. AB - Obstructive sleep apnoea (OSA) results from the recurrent collapse of the upper airway during sleep. Nasal abnormalities influence the stability of the pharynx. The aim of this study was to evaluate the volumetric and anatomical changes of the nasal cavity in patients with OSA. The Nasal Obstruction Symptom Evaluation (NOSE) scale was used to grade nasal obstruction. Sleep-related breathing disorders were evaluated by polysomnography. The nasal airway volume was obtained from computed tomography scans through volumetric reconstruction of the nasal airway. Alterations to the nasal anatomy were identified by nasal fibre-optic endoscopy. Ninety-four patient charts were analyzed. The final sample comprised 32 patients with severe OSA, 16 with moderate OSA, 23 with mild OSA, and 20 without OSA. Three groups were established based on nasal obstruction and OSA. The groups were compared for nasal airway volume (P=0.464) and body mass index (P=0.001). The presence of nasal septum deviation and inferior turbinate hypertrophy were related to the NOSE score (P=0.05 for both), apnoea-hypopnoea index (P=0.03 and P=0.05, respectively), and nasal airway volume (P=0.71 and P=0.78, respectively). In this nasal airway evaluation of OSA patients, the presence of sites of obstruction was correlated with the severity of OSA; this was not the case for the evaluation of the nasal airway volume dimensions. PMID- 28623044 TI - Corrigendum to "Can a surgery-first orthognathic approach reduce the total treatment time?" [Int. J. Oral Maxillofac. Surg. 46 (2017) 473-482]. PMID- 28623045 TI - The risk of malignancy among biologic-naive pediatric psoriasis patients: A retrospective cohort study in a US claims database. AB - BACKGROUND: Little published literature exists regarding malignancy risk in pediatric psoriasis patients. OBJECTIVE: To compare malignancy risk in biologic naive pediatric psoriasis patients with a matched pediatric population without psoriasis. METHODS: This retrospective cohort study used IMS LifeLink Health Plan Claims data covering 1998-2008. Cancer incidence was compared with the US Surveillance, Epidemiology, and End Results (SEER) data using standardized incidence ratios (SIR), and between cohorts using Cox models. RESULTS: Among 9045 pediatric psoriasis patients and 77,206 comparators, 18 probable or highly probable cancers were identified. Pediatric psoriasis patients had a nonsignificantly lower incidence than comparators (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.05-3.54). The HR increased to 1.67 (95% CI 0.54-5.18) when cancer diagnosed during the first 90 days of follow-up was included. The pediatric psoriasis cohort had a significantly increased lymphoma rate compared with SEER (SIR 5.42, 95% CI 1.62-12.94), but no significant increase relative to the comparator cohort. LIMITATIONS: Misclassification of disease and outcome might have occurred with patients in the claims database. CONCLUSION: Patients with pediatric psoriasis showed no significant increase in overall cancer risk compared with those without psoriasis. A potential increased risk for lymphoma was observed when compared with the general population. PMID- 28623046 TI - Real-world burden of comorbidities in US patients with psoriasis. AB - BACKGROUND: Understanding background comorbidity rates in psoriasis can provide perspective for adverse events associated with new therapies. OBJECTIVE: We sought to assess the extent of comorbidities in psoriasis patients by use of the Truven Health Analytics MarketScan database. METHODS: MarketScan, comprising commercial claims representative of a large US-insured population, had 1.22 million patients with >=1 claim with a psoriasis diagnosis between January 1, 2008, and December 31, 2014. Patients >=18 years of age who had >=2 health claims in any diagnosis field for psoriasis (International Classification of Diseases, 9th Revision, Clinical Modification 696.1) with a psoriasis diagnosis (index) date between July 1, 2008, and June 30, 2014, were included to allow follow-up observation time. RESULTS: Prevalence and incidence of 24 comorbidities were assessed in 469,097 psoriasis patients; the most common comorbidities were hyperlipidemia (45.64% and 30.83%, respectively), hypertension (42.19% and 24.19%), depression (17.91% and 12.68%), type 2 diabetes mellitus (17.45% and 8.44%), and obesity (14.38% and 11.57%). LIMITATIONS: A limitation of the study was that only a certain insured population was represented. CONCLUSIONS: Comorbidity rates align with those described in the literature and support the concept that psoriasis patients have high rates of cardiometabolic comorbidities. This analysis highlights the potential utility of very large insurance databases for determining comorbidity prevalence in psoriasis, which may aid health care providers in managing psoriasis. PMID- 28623047 TI - Use of a PACS-Based Tool for Improving Communications With Referring Physicians. PMID- 28623048 TI - Decreasing Utilization of Inferior Vena Cava Filters in Post-FDA Warning Era: Insights From 2005 to 2014 Nationwide Inpatient Sample. AB - BACKGROUND: To determine the impact, if any, of the 2010 FDA safety communication on the rate of inferior vena cava filter (IVCF) placement over time. METHODS: The Nationwide Inpatient Sample was interrogated for the most recent years preceding and after the FDA safety communication-from 2005 to 2014. IVCF placements and associated diagnoses were identified using corresponding International Classification of Diseases, version nine codes. Trends in number of IVCF placement were evaluated in aggregate and by associated diagnoses, both of which were further stratified by hospital geographic cluster, hospital teaching status, and patient demographics. Generalized linear regression models were used to determine statistical significance of trends over time. RESULTS: IVCF placements steadily increased between 2005 and 2010 (100,434 in 2005 versus 129,614 in 2010, growth rate 5.81%). Aggregate IVCF placements subsequently declined between 2010 and 2014 (96,005 in 2014, decline rate -6.48%). IVCF placements peaked in 2010, the year of the FDA advisory. The proportion of filter placements for therapeutic indication of venous thromboembolism increased significantly during the study period (69.8% in 2005 versus 80.4% in 2014, P < .001). Neither trend varied significantly by patient demographics or hospital characteristics. CONCLUSIONS: IVCF placements have declined significantly since 2010, when the FDA advisory was released. The proportion of IVCFs placed in patients with venous thromboembolism, as opposed to prophylactic indications, is increasing. PMID- 28623049 TI - A Resident- and Fellow-Driven Review Course to Prepare Trainees for the ABR Core Examination. PMID- 28623050 TI - The Clash of Organizational Cultures. PMID- 28623051 TI - Decision proposals in the family conference. AB - OBJECTIVES: To explore how clinicians make decision proposals about life sustaining treatments and to determine if certain decision proposals are more likely to lead surrogates to align with or resist the proposal. METHODS: We audio recorded 36 family conferences between clinicians and surrogates and analyzed the interactions using conversation analysis (a qualitative method) and event sequence analysis (a quantitative method). RESULTS: The transitional probability of a proposal that incorporates the patient's previously described preferences leading to alignment with the proposal was .76. The odds ratio of an aligning response in the presence of this proposal was 8.27 (95% CI 2.21, 30.97). The transitional probability of a proposal that asserts the healthcare team is going to do or not do a treatment leading to resistance was .70. The odds ratio of a resisting response in the presence of this proposal was 8.4 (95% CI 1.83, 38.53). CONCLUSIONS: There is evidence to suggest that incorporating the patient's previously described preferences into a decision proposal leads to surrogates' alignment to those proposals. PRACTICE IMPLICATIONS: These results strengthen the need for clinicians to engage with surrogates in shared decision making to determine the best treatment decision for the patient. PMID- 28623053 TI - LGBT healthcare disparities: What progress have we made? AB - Nearly fifteen years have passed since this author's publication which examined the depth of education and training for medical students and practicing physicians specific to clinical competence in the care of lesbian and gay patients in the United States. Since then, there has been an explosion of research gains which have shed a steady light on the needs and disparities of lesbian and gay healthcare. This rich literature base has expanded to include bisexual and transgender (LGBT) healthcare in peer-reviewed journals. Despite these research gains underscoring a call for action, there continues to be a dearth of cultural competency education and training for healthcare professionals focused on clinical assessment and treatment of LGBT patients. This article will focus exclusively on the current status of medical and nursing education and training specific to clinical competence for LGBT healthcare. We are long overdue in closing the clinical competency gap in medical and nursing education to reduce the healthcare disparities within the LGBT community. PMID- 28623052 TI - How physicians draw satisfaction and overcome barriers in their practices: "It sustains me". AB - OBJECTIVE: Major reorganizations of medical practice today challenge physicians' ability to deliver compassionate care. We sought to understand how physicians who completed an intensive faculty development program in medical humanism sustain their humanistic practices. METHODS: Program completers from 8 U.S. medical schools wrote reflections in answer to two open-ended questions addressing their personal motivations and the barriers that impeded their humanistic practice and teaching. Reflections were qualitatively analyzed using the constant comparative method. RESULTS: Sixty-eight physicians (74% response rate) submitted reflections. Motivating factors included: 1) identification with humanistic values; 2) providing care that they or their family would want; 3) connecting to patients; 4) passing on values through role modelling; 5) being in the moment. Inhibiting factors included: 1) time, 2) stress, 3) culture, and 4) episodic burnout. CONCLUSIONS: Determination to live by one's values, embedded within a strong professional identity, allowed study participants to alleviate, but not resolve, the barriers. Collaborative action to address organizational impediments was endorsed but found to be lacking. PRACTICE IMPLICATIONS: Fostering fully mature professional development among physicians will require new skills and opportunities that reinforce time-honored values while simultaneously partnering with others to nurture, sustain and improve patient care by addressing system issues. PMID- 28623054 TI - Detection of yellow fever virus genomes from four imported cases in China. AB - Yellow fever virus (YFV), as the first proven human-pathogenic virus, is still a major public health problem with a dramatic upsurge in recent years. This is a report on four imported cases of yellow fever virus into China identified by whole genome sequencing. Phylogenetic analysis was performed and the results showed that these four viruses were highly homologous with Angola 71 strains (AY968064). In addition, effective mutations of amino acids were not observed in the E protein domain of four viruses, thus confirming the effectiveness of the YFV-17D vaccine (X03700). Although there is low risk of local transmission in most part of China, the increasing public health risk of YF caused by international exchange should not be ignored. PMID- 28623055 TI - Prevalence of adiposity and its association with sleep duration, quality, and timing among 9-12-year-old children in Guangzhou, China. AB - BACKGROUND: Short sleep duration has been reported to be associated with obesity in children, but findings are not consistent. Since few studies have examined the relationship between more complex sleep characteristics and obesity, we examined the association between adiposity and self-reported sleep duration, bedtime, and sleep quality in 9-12-year-old Chinese children using multilevel mixed models. METHODS: 5518 children aged 9-12 years were recruited from 29 randomly selected primary schools in Guangzhou, China in 2014. Standardized questionnaires were used to obtain data to estimate sleep duration on typical weekdays and weekends. Sleep quality data were collected using the Children's Sleep Habits Questionnaire (CSHQ). Trained researchers undertook measurements of weight, height, and waist circumference (WC) for all participating children. Body mass index (BMI) z-scores were derived using the World Health Organization (WHO) child growth reference, and children were classified as overweight or obese using +1 and +2 SD as cut offs, respectively. Percentage body fat (BF%) was calculated using bioelectrical impedance. RESULTS: Longer sleep duration was inversely associated with BMI z score (beta = -0.16, p < 0.05), WC (beta = -1.11, p < 0.05) and later bedtime was associated with higher BMI z-score (beta = 0.03, p < 0.05), WC (beta = 1.72, p < 0.001), and BF% (beta = 0.15, p < 0.05) in multivariable multilevel mixed models, after adjustment for age, gender, physical activity, parental education level, and average monthly income. No association was seen between sleep quality and adiposity. CONCLUSION: Shorter sleep duration and later bedtime are associated with higher adiposity indices in early adolescents from southern China. PMID- 28623056 TI - The prevalence and risk factor control associated with noncommunicable diseases in China, Japan, and Korea. AB - BACKGROUND: Noncommunicable disease (NCD) has become the leading cause of mortality and disease burden worldwide. METHODS: A cross-sectional survey was carried out to investigate the prevalence of NCDs and risk factor control on dietary behaviors and dietary intake in China, Japan, and Korea. RESULTS: There were significant differences among the three countries on the prevalence of hypertension (24.5% in China, 17.6% in Korea, and 15.2% in Japan), diabetes (8.9% in China, 5.7% in Korea, and 4.8% in Japan), hyperlipidemia (13.1% in China, 9.2% in Korea, and 6.9% in Japan), and angina pectoris (3.6% in China, 1.7% in Korea, and 1.5% in Japan). The prevalence rate of hypertension, diabetes, hyperlipidemia, and angina pectoris was highest in China and lowest in Japan. However, 82.2%, 48.4%, and 64.4% of Chinese, Koreans, and Japanese presented good dietary behavior, respectively. Multivariable logistic regression analysis found that sex, age, and marital status were predictors of good dietary behavior. In addition, in comparison with subjects without hypertension, diabetes, or hyperlipidemia, subjects with hypertension, diabetes, or hyperlipidemia significantly improved their dietary behaviors and controlled their intake of salt, sugar, and oil. CONCLUSIONS: The prevalence of NCDs and trends in major modifiable risk factor control in China, Korea, and Japan remain troubling. Public efforts to introduce healthy lifestyle changes and systematic NCDs prevention programs are necessary to reduce the epidemic of NCDs in these three Asian countries. PMID- 28623057 TI - Clinical outcomes of endoscopic submucosal dissection for colorectal tumors: a large multicenter retrospective study from the Hiroshima GI Endoscopy Research Group. AB - BACKGROUND AND AIMS: Although advanced high-volume centers have reported good outcomes of colorectal endoscopic submucosal dissection (ESD), a limited number of highly skilled experts in specialized institutions performed these procedures. We undertook a retrospective multicenter survey, which included nonspecialized hospitals, to investigate the clinical outcomes of colorectal ESD. METHODS: We recruited 1233 consecutive patients with 1259 colorectal tumors resected by ESD at 12 institutions. We evaluated the en bloc resection rate, histologic complete resection rate, curative (R0) resection rate, adverse events, and the long-term prognoses, including local recurrence, metachronous tumor development, and survival rate. RESULTS: The en bloc, histologic complete, and R0 resection rates were 92.6%, 87.4%, and 83.7%, respectively. The delayed bleeding, intraoperative perforation, and delayed perforation rates were 3.7%, 3.4%, and .4%, respectively. The long-term outcomes analysis included 1091 patients (88.4%). Local recurrences occurred in 1.7%, and metachronous tumors (>5 mm) developed in 11.0% of the patients. The 3- and 5-year overall survival rates were 95.1% and 92.3%, respectively. The number of colonic tumors, severe submucosal fibrosis, and en bloc resection rates were significantly higher in the high-volume centers (Group H) than those in the low-volume centers (Group L). The average tumor size in Group H was significantly larger than that in Group L. CONCLUSIONS: Colorectal ESDs are feasible, have acceptable adverse event risks, and favorable long-term prognoses. (Clinical trial registration number: UMIN000016197.). PMID- 28623058 TI - Supraclavicular schwannoma mimicking a lymphadenopathy in a lung cancer patient: PET/CT findings. PMID- 28623059 TI - Piloting a global mentorship initiative to support African emergency nurses. PMID- 28623060 TI - Amniotic Band Syndrome With Pseudoarthrosis of Tibia and Fibula: A Case Report. AB - Constriction of the lower limb by a congenital amniotic band has been proposed to explain the development of pseudoarthrosis of the tibia and fibula. We report a case of amniotic band syndrome in a preterm female infant with pseudoarthrosis of the tibia and fibula. She was born at 29 weeks of gestation with congenital amniotic bands and was noted to have a severely edematous left foot distal to the constricting band with rudimentary digits. The skin was pink and well perfused with palpable pulses. Radiography demonstrated pseudoarthrosis of the tibia and fibula. The limb deformities were managed with splints, positioning, and physiotherapy. She underwent Z-plasty with soft tissue release on the left lower leg on day 7 of life. At 36 weeks of postmenstrual age, a repeat radiograph showed markedly improved growth of the tibia and fibula with mature new bone formation, which avoided the need for further surgical intervention. During the follow-up period, she underwent left Syme's amputation at 18 months. At 29 months of age, the child was able to walk and run without support. The findings from our case confirm the potential for bone growth in patients with amniotic band syndrome, once the constricting band has been released. Simple release of the constriction band with Z-plasty resulted in growth of mature bone, replacing the pseudoarthrosis and, hence, the patient did not require surgical amputation. Thus, one should be cautious when deciding on surgical amputation, even in the presence of pseudoarthrosis, especially in preterm infants. Early limb-preserving surgery with release of the constricting band with an intention to salvage the limb appears appropriate. PMID- 28623061 TI - Comparison of Extraosseous Talotarsal Stabilization Implants in a Stage II Adult Acquired Flatfoot Model: A Finite Element Analysis. AB - Subtalar arthroereisis has been proved to be an efficient method for correcting flexible adult flatfoot. However, the optimal sinus tarsi implant is still debated and yet to be determined. In the present study, we compared the biomechanical effects of type I and II sinus tarsi implants in stage II adult acquired flatfoot deformity (AAFD). First, a finite element model of stage II AAFD was established in which virtual surgery of subtalar arthroereisis was simulated. The indexes of plantar stress distribution, peak von Mises of the medial and lateral columns, strain of the medial ligaments and plantar fascia, arch height, talo-first metatarsal angle, calcaneus pitch angle, talonavicular coverage angle, and hindfoot valgus angle were all compared and analyzed. The results of the present study have validated the stage II AAFD finite element model by comparing the simulation results with the same parameters measured from weightbearing radiographs in the midstance phase. All the indexes showed that both types of arthroereisis can lower the plantar pressure and the strain of the medial ligaments that support the medial longitudinal arch and can shift the load of the medial column to the lateral column. They can also help to correct the deformity and restore the arch. However, the type II sinus tarsi implant design exhibited a more obvious effect than that of type I. PMID- 28623063 TI - Low dose out-of-field radiotherapy, part 2: Calculating the mean photon energy values for the out-of-field photon energy spectrum from scattered radiation using Monte Carlo methods. AB - PURPOSE: During radiotherapy, leakage from the machine head and collimator expose patients to out-of-field irradiation doses, which may cause secondary cancers. To quantify the risks of secondary cancers due to out-of-field doses, it is first necessary to measure these doses. Since most dosimeters are energy-dependent, it is essential to first determine the type of photon energy spectrum in the out-of field area. The aim of this study was to determine the mean photon energy values for the out-of-field photon energy spectrum for a 6 MV photon beam using the GEANT 4-Monte Carlo method. MATERIAL AND METHODS: A specially-designed large water phantom was simulated with a static field at gantry 0 degrees . The source to-surface distance was 92cm for an open field size of 10*10cm2. The photon energy spectra were calculated at five unique positions (at depths of 0.5, 1.6, 4, 6, 8, and 10cm) along the central beam axis and at six different off-axis distances. RESULTS: Monte Carlo simulations showed that mean radiation energy levels drop rapidly beyond the edge of the 6 MV photon beam field: at a distance of 10cm, the mean energy level is close to 0.3MeV versus 1.5MeV at the central beam axis. In some cases, the energy level actually increased even as the distance from the field edge increased: at a depth of 1.6cm and 15cm off-axis, the mean energy level was 0.205MeV versus 0.252MeV at 20cm off-axis. CONCLUSION: The out-of-field energy spectra and dose distribution data obtained in this study with Monte Carlo methods can be used to calibrate dosimeters to measure out-of field radiation from 6MV photons. PMID- 28623062 TI - Salvage of the Foot for Recurrent Malignant Peripheral Nerve Sheath Tumor. AB - Malignant peripheral nerve sheath tumors are rare soft tissue tumors accounting for 3% to 10% of all soft tissue tumors. They are strongly related to neurofibromatosis type 1, an autosomal dominant disease, and are characterized by aggressive biologic behavior, high local recurrence rates, and frequent metastases. Although the major nerves of the lower extremities are a common location of these tumors, scarce cases have been reported of malignant peripheral nerve sheath tumors involving the interdigital nerves of the foot. We report the case of a patient with non-neurofibromatosis type 1 and a recurrent malignant peripheral nerve sheath tumor of the first interdigital nerve of the foot treated successfully with limb salvage surgery with wide resection margins and reconstruction with an autogenous fibula graft. PMID- 28623064 TI - To Screen or Not to Screen? Examining the Arguments Against Screening for Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia, with a lifetime risk of one in four of developing AF over the age of 40 years. Around 40% of patients are asymptomatic, which is of concern as AF is a major risk factor for stroke. Early detection and appropriate management reduces stroke risk by two thirds. Atrial fibrillation screening is now recommended in international guidelines, but there are some common arguments against screening. Overall, to be of value any screening program must fulfil the World Health Organization (WHO) Wilson and Jungner criteria for screening programs. In this paper we address the common arguments, and determine if AF screening fulfils the WHO criteria. PMID- 28623065 TI - Upper limb neurodynamic test 1 in patients with clinical diagnosis of carpal tunnel syndrome: A diagnostic accuracy study. AB - STUDY DESIGN: Diagnostic accuracy. INTRODUCTION: Upper limb neurodynamic test 1 (ULNT1) is used to evaluate the mechanical sensitivity especially in the peripheral nerves of the upper limbs. The reproduction of typical symptoms in the affected hand improves the estimation of the probability of carpal tunnel syndrome (CTS). However the test has not been evaluated sufficiently to determine its real usefulness. In the present study the diagnostic accuracy of ULNT1 as a clinical test for CTS was determined. METHODS: We used the ULNT1 as the index test and nerve conduction as the reference standard. 120 subjects, (240 hands), with a medical diagnosis of CTS were evaluated. The study population was a consecutive series of participants. Sensitivity, specificity, positive and negative predictive values, accuracy, and positive likelihood ratio were calculated. RESULTS: ULNT1 was found to have a sensitivity of 93 % and a specificity of 6.67 %. The positive likelihood ratio was 1.04 and the negative likelihood ratio was 1.00. The positive predictive value was 86.9 % and the negative predictive value was 12.5%. DISCUSSION: Acute or relatively mild CTS cases may not be accurately identified through nerve conduction tests. The findings of this study coincide with other studies in the finding that ULNT1 has a significant diagnostic and clinical screening value for CTS in people at-risk, or with upper limb symptoms. CONCLUSION(S): This research suggests the use of ULNT1 as a screening test for CTS, followed by tests that are more specific. LEVEL OF EVIDENCE: III-2. PMID- 28623066 TI - Association of posterior semicircular canal hypofunction on video-head-impulse testing with other vestibulo-cochlear deficits. AB - OBJECTIVES: The video-head-impulse test (vHIT) provides a functional assessment of all six semicircular canals (SCC). Occasionally isolated loss of the posterior canal(s) (ILPC) is diagnosed, though this finding is poorly characterized. Here we assessed how accurate that diagnosis is by measuring the co-occurrence of abnormalities on caloric irrigation, vestibular-evoked myogenic-potentials and audiometry. METHODS: We identified 52 patients with ILPC (unilateral=40, bilateral=12). We determined vHIT-gains and saccade-amplitudes and correlated vHIT-findings with other vestibulo-cochlear tests. RESULTS: The most frequent diagnoses were history of vestibular neuritis (13/52), Meniere's disease (12/52) and vertigo/dizziness of unclear origin (13/52). Unilateral ILPC on vHIT was accompanied by a deficient horizontal canal on calorics, saccular and/or utricular deficits ipsilesionally in 33/40 (83%), while ipsilesional hearing-loss was noted in 24/40 (60%). Involvement of other sensors was highest for vestibular schwannoma (100%) and history of vestibular neuritis (92%). Bilateral deficits in >=1 vestibulo-cochlear sensor(s) were noted in 2/12 cases with bilateral ILPC. CONCLUSIONS: >80% of patients with unilateral ILPC had additional deficits of other parts of the vestibular organ, while this rate was <=20% for patients with bilateral ILPC. SIGNIFICANCE: Dizzy patients should receive testing of the posterior canals and if abnormalities are observed, additional vestibulo-cochlear testing should be obtained. PMID- 28623067 TI - A Case Report of Abnormal Fracture Healing as Detected With High-Resolution Peripheral Quantitative Computed Tomography. PMID- 28623068 TI - Corrigendum to "Comparative study of therapeutic response to baclofen vs tolperisone in spasticity" [Biomed. Pharmacother. 87 (2017) 628-635]. PMID- 28623069 TI - Neonatal hypoglycemia: A wide range of electroclinical manifestations and seizure outcomes. AB - PURPOSE: We examined the various types of epilepsy in children with neonatal hypoglycemia in order to define electroclinical and prognostic features of these patients. METHOD: We retrospectively reviewed the medical records of patients with a history of symptomatic neonatal hypoglycaemia who have been followed at Gazi University Hospital Pediatric Neurology Department between 2006 and 2015. Patients with perinatal asphyxia were excluded. Details of each patient's perinatal history, neurological outcome, epilepsy details, seizure outcome and EEG and brain MRI findings were reviewed. RESULTS: Fourty five patients (range 6 mo-15 y) with a history of symptomatic neonatal hypoglycaemia were included the study. Epilepsy developed in 36 patients and 23 of them had intractable epilepsy. All patients had occipital brain injury. CONCLUSION: We observed that most of the patients, either manifesting focal or generalized seizures, further develop intractable epilepsy. This finding establishes neonatal hypoglycemia as a possible cause to be considered in any case of intractable epilepsy. PMID- 28623070 TI - Commentary on "Inherited DNA-repair gene mutations in men with metastatic prostate cancer". Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, Garofalo A, Gulati R, Carreira S, Eeles R, Elemento O, Rubin MA, Robinson D, Lonigro R, Hussain M, Chinnaiyan A, Vinson J, Filipenko J, Garraway L, Taplin ME, AlDubayan S, Han GC, Beightol M, Morrissey C, Nghiem B, Cheng HH, Montgomery B, Walsh T, Casadei S, Berger M, Zhang L, Zehir A, Vijai J, Scher HI, Sawyers C, Schultz N, Kantoff PW, Solit D, Robson M, Van Allen EM, Offit K, de Bono J, Nelson PS. N Engl J Med. 2016;375(5):443-53. AB - BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. RESULTS: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). CONCLUSIONS: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. PMID- 28623071 TI - Overall survival in Swedish patients with renal cell carcinoma treated in the period 2002 to 2012: Update of the RENCOMP study with subgroup analysis of the synchronous metastatic and elderly populations. AB - BACKGROUND: This retrospective study investigated overall survival (OS) and factors influencing OS in Swedish patients with metastatic renal cell carcinoma (mRCC) during the pre- (2002-2005), early (2006-2008), and late (2009-2012) targeted therapy (TT) era. METHODS: Three national Swedish registries identified patients with mRCC. Median OS was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards regression. Subgroup analysis was conducted for patients with synchronous metastases (M1) and the elderly (aged>=75y). RESULTS: A total of 4,217 patients with mRCC were identified, including 1,533 patients with M1 and 1,275 elderly patients. For patients with mRCC diagnosed in 2002 to 2005, 2006 to 2008, and 2009 to 2012, median OS was 10.0, 13.0, and 18.0 months. Similarly, median OS improved in the M1 and elderly populations. Elderly patients were less likely to be prescribed TT (>=75 vs.<75y): 18.3 vs. 63.5% (in 2006-2008) and 28.6% vs. 55.9% (in 2009-2012). Diagnosis of mRCC in 2009 to 2012, nephrectomy and TT prescription were associated with improved OS in the total mRCC, M1, and elderly populations. CONCLUSION: This real-world study showed continued significant improvement in mRCC OS during the late TT era, including in M1 and elderly populations. TT should be considered for all patients with mRCC based on tolerability, regardless of age. PMID- 28623072 TI - Commentary on "Integrative clinical genomics of advanced prostate cancer". Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM.Cell. 21 May 2015;161(5):1215-1228. AB - Toward development of a precision medicine framework for metastatic, castration resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R spondin, BRAF/RAF1, APC, beta-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. A total of 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could affect treatment decisions for these affected individuals. PMID- 28623073 TI - Commentary on "Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer". Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery B. Eur Urol. Jun 2016;69(6):992-5. AB - Understanding the molecular underpinnings of sensitivity to specific therapies will advance the goal of precision medicine in prostate cancer (PCa). We identified 3 patients with metastatic castration-resistant PCa (mCRPC) who achieved an exceptional response to platinum chemotherapy (not first-line treatment for PCa), despite disease progression on prior standard therapies. Using targeted next-generation sequencing on the primary and metastatic tumors, we found that all 3 patients had biallelic inactivation of BRCA2, a tumor suppressor gene critical for homologous DNA repair. Notably, 2 had germline BRCA2 mutations, including a patient without compelling family history who was diagnosed at age 66 year. The third patient had somatic BRCA2 homozygous copy loss. Biallelic BRCA2 inactivation in mCRPC warrants further exploration as a predictive biomarker for sensitivity to platinum chemotherapy. PMID- 28623074 TI - Geographic variability in gestational weight gain: a multilevel population-based study of women having term births in Florida (2005-2012). AB - PURPOSE: We examined the extent of geographic variability in gestational weight gain (GWG), identified areas where women have suboptimal GWG, and evaluated whether individual- and area-level factors account for such variability. METHODS: We conducted a population-based cohort study including 1,385,574 women delivering term, singleton, and live births in Florida. We used a Bayesian, structured additive regression with a spatial function to analyze data from Florida's birth certificates (2005-2012) and ZIP code tabulation areas (ZCTAs; 2010 Census). RESULTS: The prevalence of insufficient (7.7%-42.9%) and excessive (17.1%-82.4%) GWG varied widely within Florida. Geographic variability was not explained by risk factors under study. Clusters in Orlando, Tampa, and Miami exhibited increased likelihood of insufficient GWG, whereas clusters in the Northwest of Florida exhibited increased likelihood of excessive GWG. CONCLUSIONS: We identified areas in Florida with high likelihood of suboptimal GWG that policy makers should prioritize in the implementation of programs for optimizing GWG. PMID- 28623075 TI - Thioflavin T fluorescence to analyse amyloid formation kinetics: Measurement frequency as a factor explaining irreproducibility. AB - The most frequent method to monitor amyloid formation relies on the fluorescence of thioflavin T (ThT). The present study reports a novel factor of irreproducibility in ThT kinetic assays performed in microplate. Discrepancies among kinetics of amyloid assembly, performed under quiescent conditions, were associated with the frequency of fluorescence measurement. Evaluating self assembly of the islet amyloid polypeptide at short intervals hastened its fibrillization. This observation was confirmed by transmission electron microscopy, circular dichroism spectroscopy and 8-anilino-1-naphthalenesulfonic acid fluorescence. This effect, attributed to agitation during microplate displacements between fluorescence measurements, reinforces the importance of a better standardization in amyloid formation assays. PMID- 28623076 TI - [Staphylococcus aureus epidural abscess following epidural catheter placement in a patient suffering from psoriasis]. PMID- 28623077 TI - [Viral triumvirate]. PMID- 28623078 TI - Arthroscopic Treatment of Femoroacetabular Impingement in Adolescents Provides Clinically Significant Outcome Improvement. AB - PURPOSE: To define minimal clinically important difference (MCID) and substantial clinical benefit (SCB) for adolescents undergoing arthroscopic femoroacetabular impingement (FAI) surgery. METHODS: A prospective institutional hip preservation registry was reviewed to identify hip arthroscopies performed for FAI. Patients with pre-existing hip conditions such as slipped capital femoral epiphysis and Legg-Calve-Perthese were excluded. Included patients were 18 years and younger. The modified Harris Hip Score (mHHS), the Hip Outcome Score (HOS), and the international Hip Outcome Tool (iHOT-33) were administered as part of the registry. MCID was calculated using a distribution-based method, and SCB was calculated using a physical function anchor question. Receiver operating characteristic analysis with area under the curve (AUC) was used for psychometric analyses. RESULTS: Forty-seven adolescents were identified. The majority of patients were female (n = 32, 68.1%) with a mean age of 16.5 (+/-1.1) years. The MCID (% achieving) for the mHHS, HOS activities of daily living (ADL), HOS Sport, and iHOT-33 was 9.5 (85%), 9.8 (79%), 12.1 (85%), and 10.7 (94%), respectively. Ninety-two percent of adolescents reported some form of improved hip physical ability on the anchor question. The following 1-year absolute outcome scores were significantly representative of an SCB state on the mHHS, HOS ADL, HOS Sport, and mHHS, respectively (AUC): 93.5 (0.79), 98.5 (0.84), 96.9 (0.81), and 85.9 (0.76). CONCLUSIONS: Adolescents undergoing arthroscopic FAI surgery achieve clinically significant outcome improvement. We found that the vast majority of adolescents achieve MCID on hip-specific patient-reported outcome tools. However, although adolescents readily achieve MCID, a considerable improvement in postoperative outcome score is often needed to perceive a substantial benefit (SCB). The available hip outcome tools may be subject to ceiling effects for measuring clinically significant outcome improvement in adolescents. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28623079 TI - Restoration of Articular Geometry Using Current Graft Options for Large Glenoid Bone Defects in Anterior Shoulder Instability. AB - PURPOSE: The purpose of this cadaveric study was to compare standard and modified coracoid transfer procedures, bicortical and tricortical iliac crest autografts, and tibial plafond and glenoid allografts with respect to glenoid surface curvature restoration. METHODS: Computed tomography scans of 8 cadaveric shoulders were acquired in 9 conditions: (1) intact, (2) 25% width defect, (3) classic Latarjet, (4) modified congruent-arc Latarjet, (5) tricortical iliac crest inner table, (6) outer table, (7) bicortical iliac crest, (8) distal tibia, and (9) glenoid allograft. Outcome measures included articular surface area, width, depth, axial and coronal radius of curvature, and subchondral articular step-off, analyzed in bone and soft-tissue window. RESULTS: Reconstruction of the articular surface area was optimal with the glenoid allograft (99.4%), classic Latarjet (97.4%), and iliac crest bicortical graft (93.2%). Depth was best restored by the congruent-arc Latarjet (101.0%), tibial (98.9%), and glenoid (95.3%) allografts. Axial curvature was closely matched by the glenoid allograft (97.5%), classic Latarjet (108.7%), and iliac bicortical graft (91.2%). Coronal curvature was most accurately restored by the glenoid allograft (102.6%), the tibial allograft (115.0%), and the classic Latarjet (55.9%). The articular step off was smallest using the glenoid allograft. CONCLUSIONS: Overall, glenoid allografts most accurately restored articular geometry. Alternative grafts provided restoration of some parameters but not others. Classic Latarjet performed well in axial and coronal curvature on average but exhibited large variability. Tibial allograft produced the poorest results in axial curvature, despite excellent coronal curvature reconstruction. The congruent-arc Latarjet did not restore the axial curvature accurately and overcorrected coronal curvature. Graft geometry must be weighed against availability, morbidity, and the role of additional stabilizers. CLINICAL RELEVANCE: Accurate graft morphology may help prevent postoperative osteoarthritis. Grafts differ significantly regarding geometric parameters. The findings of this study will help surgeons select the most appropriate graft for glenoid reconstruction. PMID- 28623080 TI - Increased constitutive nitric oxide production by whole body periodic acceleration ameliorates alterations in cardiomyocytes associated with utrophin/dystrophin deficiency. AB - Duchenne Muscular Dystrophy (DMD) cardiomyopathy is a progressive lethal disease caused by the lack of the dystrophin protein in the heart. The most widely used animal model of DMD is the dystrophin-deficient mdx mouse; however, these mice exhibit a mild dystrophic phenotype with heart failure only late in life. In contrast, mice deficient for both dystrophin and utrophin (mdx/utrn-/-, or dKO) can be used to model severe DMD cardiomyopathy where pathophysiological indicators of heart failure are detectable by 8-10weeks of age. Nitric oxide (NO) is an important signaling molecule involved in vital functions of regulating rhythm, contractility, and microcirculation of the heart, and constitutive NO production affects the function of proteins involved in excitation-contraction coupling. In this study, we explored the efficacy of enhancing NO production as a therapeutic strategy for treating DMD cardiomyopathy using the dKO mouse model of DMD. Specifically, NO production was induced via whole body periodic acceleration (pGz), a novel non-pharmacologic intervention which enhances NO synthase (NOS) activity through sinusoidal motion of the body in a headward-footward direction, introducing pulsatile shear stress to the vascular endothelium and cardiomyocyte plasma membrane. Male dKO mice were randomized at 8weeks of age to receive daily pGz (480cpm, Gz+/-3.0m/s2, 1h/d) for 4weeks or no treatment, and a separate age matched group of WT animals (pGz-treated and untreated) served as non-diseased controls. At the conclusion of the protocol, cardiomyocytes from untreated dKO animals had, respectively, 4.3-fold and 3.5-fold higher diastolic resting concentration of Ca2+ ([Ca2+]d) and Na+ ([Na+]d) compared to WT, while pGz treatment significantly reduced these levels. For dKO cardiomyocytes, pGz treatment also improved the depressed contractile function, decreased oxidative stress, blunted the elevation in calpain activity, and mitigated the abnormal increase in [Ca2+]d upon mechanical stress. These improvements culminated in a significant reduction in circulating cardiac troponin T (cTnT) and an extension of the median lifespan of dKO mice from 16 to 31weeks. Treatment with L-NAME (NOS inhibitor) significantly decreased overall lifespan and abolished the cardioprotective properties elicited by pGz. Our results provide evidence that enhancement of NO synthesis by pGz can ameliorate cellular dysfunction in dKO cardiomyocytes and may represent a novel therapeutic intervention in DMD cardiomyopathy patients. PMID- 28623081 TI - Multimorbidity: A Review of the Complexity of Mental Health Issues in Bariatric Surgery Candidates Informed by Canadian Data. AB - BACKGROUND: Multimorbidity is significant for obesity and mental health issues. As a consequence, mental illness is overrepresented in patients seeking bariatric surgery. This review addresses that overlap, with a focus on Canadian data. CONCLUSION: The healthcare system in Canada is unique, but issues related to prevalence of mental health in patients seeking bariatric surgery are similar to those in studies conducted in other countries. Although data on suicide are lacking, Canadian data have shown similar rates of self-harm behaviours and linkages between psychopathology and weight regain after surgery. Geographic issues that make it difficult for individuals to attend regular follow-up appointments have encouraged the use of e-health tools to engage patients and ensure access to follow-up care, which may provide unique opportunities going forward. Additional work is needed to inform best practices in the Canadian system, but in keeping with other data, the consistent message from Canada is that appropriate evaluation and aftercare are essential components of a well informed bariatric program. PMID- 28623083 TI - Editorial Commentary: Atrial fibrillation: Challenges and opportunities. PMID- 28623082 TI - Diabetes mellitus mortality in Spanish cities: Trends and geographical inequalities. AB - AIM: To analyze the geographical pattern of diabetes mellitus (DM) mortality and its association with socioeconomic factors in 26 Spanish cities. METHODS: We conducted an ecological study of DM mortality trends with two cross-sectional cuts (1996-2001; 2002-2007) using census tract (CT) as the unit of analysis. Smoothed standardized mortality rates (sSMR) were calculated using Bayesian models, and a socioeconomic deprivation score was calculated for each CT. RESULTS: In total, 27,757 deaths by DM were recorded, with higher mortality rates observed in men and in the period 1996-2001. For men, a significant association between CT deprivation score and DM mortality was observed in 6 cities in the first study period and in 7 cities in the second period. The highest relative risk was observed in Pamplona (RR, 5.13; 95% credible interval (95%CI), 1.32 15.16). For women, a significant association between CT deprivation score and DM mortality was observed in 13 cities in the first period and 8 in the second. The strongest association was observed in San Sebastian (RR, 3.44; 95%CI, 1.25-7.36). DM mortality remained stable in the majority of cities, although a marked decrease was observed in some cities, including Madrid (RR, 0.67 and 0.64 for men and women, respectively). CONCLUSIONS: Our findings demonstrate clear inequalities in DM mortality in Spain. These inequalities remained constant over time are were more marked in women. Detection of high-risk areas is crucial for the implementation of specific interventions. PMID- 28623085 TI - Variability of treatment planning of seed implantation: A Japanese multicenter simulation study. AB - PURPOSE: This multicenter study was conducted to evaluate the current variability of treatment planning of seed implantation in Japanese centers and the feasibility of two virtual trials. METHODS AND MATERIALS: Two types of contour data were sent to 12 radiation oncologists with a request letter that asked them to make treatment plans on the data in the same manner as in their own practice. Five of the 12 radiation oncologists were asked to participate in the two virtual trials in which the D90 (dose to the hottest 90% of prostate volume) was 1) required to be set at just 180 Gy and 2) increased as much as possible without violating other limitations. RESULTS: A relatively high dose with a small deviation was irradiated to the prostate in Japanese centers (mean D90 = 188 Gy; SD = 10 Gy). In the virtual trials, all five physicians could achieve 180 Gy for the D90 with a very small deviation, although the urethral dose showed relatively large deviations. Dose escalation without increase of urethral dose or V150 was difficult, although the rectum could be spared by most of the physicians. CONCLUSION: Our study showed a relatively high dose with a small deviation was prescribed to the prostate in Japanese centers. Consolidated protocols such as D90 = 180 Gy could be available for future trials. Meanwhile, our study suggested that some cautions might be needed for urethral dose and the V150, even when a relatively low D90 was requested. PMID- 28623087 TI - Highly Multiplex Real-Time PCR-Based Screening for Blood-Borne Pathogens on an OpenArray Platform. AB - Molecular diagnostics are increasingly used in the blood bank industry. A device that can combine simultaneous detection of multiple targets with the flexibility of inclusion of emerging pathogens is desirable for testing blood products. A highly multiplexed blood-borne pathogen panel (BBPP) using dual-label probe chemistry (TaqMan assays) was developed for simultaneous detection and discrimination of 17 viral pathogens in human plasma samples and 13 bacterial and protozoan pathogens in human blood samples on the OpenArray platform. The custom BBPP OpenArray plate was tested for specificity and analytical sensitivity with purified nucleic acids from each pathogen and with pathogen-spiked human blood and plasma samples. The results of analytical validation of known samples yielded decision trees for identification of coded samples: pathogens spiked in human plasma or whole blood. Results from coded samples demonstrated no false positives among the plasma or whole blood specimens. Samples not detected were at the lower limit of the detectible range or qualified for retesting as indeterminate. Further demonstration of the performance of the BBPP OpenArray was achieved with clinical samples from a blood donor testing organization. Ninety-five percent of virus-positive samples were correctly identified. These results show that a high throughput OpenArray PCR platform can be expanded and adapted for higher discrimination and newly emerging agents, enabling consideration for development as a next-generation device for testing blood products. PMID- 28623084 TI - Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs. A complex interaction of genetics, environment, and hormones leads to immune dysregulation and breakdown of tolerance to self-antigens, resulting in autoantibody production, inflammation, and destruction of end organs. Emerging evidence on the role of these factors has increased our knowledge of this complex disease, guiding therapeutic strategies and identifying putative biomarkers. Recent findings include the characterization of genetic/epigenetic factors linked to SLE, as well as cellular effectors. Novel observations have provided an improved understanding of the contribution of tissue-specific factors and associated damage, T and B lymphocytes, as well as innate immune cell subsets and their corresponding abnormalities. The intricate web of involved factors and pathways dictates the adoption of tailored therapeutic approaches to conquer this disease. PMID- 28623086 TI - The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells. AB - Host defense requires the specification of CD4+ helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-gamma (IFN gamma). IFN-gamma, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-gamma production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-gamma aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling. PMID- 28623088 TI - Patient reported activities after reverse total shoulder arthroplasty in rotator cuff arthropathy patients. AB - INTRODUCTION AND OBJECTIVE: Reverse total shoulder arthroplasty in rotator cuff arthropathy patients, improves anteversion and abduction, but not rotational, outcomes. The main aim of this study is to determine its repercussions on daily life activities in our patients. MATERIAL AND METHODS: Between 2009 and 2011 we implanted 210 shoulder arthroplasties, 126 of them were reverse total shoulder arthroplasty in a rotator cuff arthropathy context. About 88% were women, with a mean age at time of surgery of 81 years, 95% were retired. The mean follow up was 53 months. The Constant scale, Visual Analogue Scale, Charlson Comorbidity Index, range of motion were measured for each patient and whether they could manage 40 daily life activities by means of a new questionnaire, classifying them according toshoulder functional demand. RESULTS AND DISCUSSION: Mean normalized by sex and age Constant value was 81.2%. Mean Visual Analogue Scale and Charlson Index were 3.56 and 1.69 respectively. Improvement in anteversion and abduction, not in rotational range of motion. Limitation was found in low and high functional demand activities in 20% and 51% respectively, especially those which involved internal rotation. CONCLUSION: Reverse total shoulder arthroplasty treatment for RCA in the elderly, achieves adequate pain management and good functional outcomes. Nevertheless, an important risk of DLA limitation must be accepted in those which involve internal rotation or shoulder high functional demand. PMID- 28623089 TI - Optimal intrathecal hyperbaric bupivacaine dose with opioids for cesarean delivery: a prospective double-blinded randomized trial. AB - BACKGROUND: Single-shot spinal anesthesia is commonly used for cesarean delivery. Achieving adequate anesthesia throughout surgery needs to be balanced with associated complications. We investigated the optimal dose of intrathecal hyperbaric bupivacaine, co-administered with opioids, for anesthesia for cesarean delivery. METHODS: This prospective, randomized, double-blinded, dose-ranging trial included parturients scheduled to undergo cesarean delivery under spinal anesthesia. An epidural catheter was first inserted at the T11-12 vertebral interspace, followed by spinal anesthesia at the L2-3 or L3-4 vertebral interspace. Subjects were randomly assigned to one of seven doses of intrathecal hyperbaric bupivacaine 0.5% (6, 7, 8, 9, 10, 11 or 12mg), with added 15MUg fentanyl and 75MUg morphine. Successful induction of anesthesia (successind) was defined as achievement of bilateral sensory loss to cold at the T6 dermatome or higher, within 10 minutes. Successful maintenance of anesthesia (successmain) was defined by no epidural supplementation within 60 minutes of intrathecal injection. The effective doses for 50% (ED50) and 95% (ED95) of patients were estimated using logistic regression analysis. RESULTS: The ED50 and ED95 for successmain were 6.0mg (95% CI: 4.5 to 7.5mg) and 12.6mg (95% CI: 7.9 to 17.2mg), respectively. The incidence of respiratory discomfort and maternal satisfaction scores did not differ significantly between dose groups. Phenylephrine dose and nausea/vomiting incidence increased with increasing doses of bupivacaine. CONCLUSION: Under study conditions, our results suggest that 12.6mg of intrathecal bupivacaine, administered with fentanyl and morphine, is required to achieve adequate intraoperative analgesia without the need for epidural supplemention. PMID- 28623090 TI - More perfect - in reply. PMID- 28623093 TI - The role of SMARCAL1 in replication fork stability and telomere maintenance. AB - SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1), also known as HARP, is an ATP-dependent annealing helicase that stabilizes replication forks during DNA damage. Mutations in this gene are the cause of Schimke immune-osseous dysplasia (SIOD), an autosomal recessive disorder characterized by T-cell immunodeficiency and growth dysfunctions. In this review, we summarize the main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress. PMID- 28623091 TI - DNA repair and systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with no known cure that affects at least five million people worldwide. Monozygotic twin concordance and familial aggregation studies strongly suggest that lupus results from genetic predisposition along with environmental exposures including UV light. The majority of the common risk alleles associated with genetic predisposition to SLE map to genes associated with the immune system. However, evidence is emerging that implicates a role for aberrant DNA repair in the development of lupus. Here we summarize our current knowledge of the potential association of lupus with mutations in DNA repair genes. We also discuss how defective or aberrant DNA repair could lead to the development of lupus. PMID- 28623095 TI - Chasing the elusive cerebral autoregulation curve in pursuit of intraoperative brain protection. PMID- 28623094 TI - Structural and functional relationships of FAN1. AB - FANCD2/FANCI-associated nuclease (FAN1) is a 5' flap structure-specific endonuclease and 5' to 3' exonuclease. This nuclease can resolve interstrand cross-links (ICLs) independently of the Fanconi anemia (FA) pathway and controls the progression of stalled replication forks in an FA-dependent manner, thereby maintaining chromosomal stability. Several FAN1 mutations are observed in various cancers and degenerative diseases. Recently, several crystal structures of the FAN1-DNA complexes have been reported, and to date, these represent the only structures for a DNA bound ICL-repair nuclease. Puzzlingly, human FAN1 forms two different quaternary structures with different DNA binding modes, and based on these structures, two ICL-repair mechanisms have been proposed. In one mechanism, monomeric FAN1 recognizes the 5' flap terminal phosphate via a basic pocket and successively cleaves at every third nucleotide of the DNA substrates. In the other mechanism, dimeric FAN1 scans, latches, and unwinds the postnick duplex of the substrate DNA to direct the scissile phosphodiester group to the active site. In this review, we discuss the structures, function, and proposed mechanisms of FAN1 nuclease, and provide the insights into its role in ICL repair and in processing of stalled replication forks. PMID- 28623096 TI - How long will my repair last, doctor? Additional data on the durability of mitral valve repair. PMID- 28623092 TI - CtIP/Ctp1/Sae2, molecular form fit for function. AB - Vertebrate CtIP, and its fission yeast (Ctp1), budding yeast (Sae2) and plant (Com1) orthologs have emerged as key regulatory molecules in cellular responses to DNA double strand breaks (DSBs). By modulating the nucleolytic 5'-3' resection activity of the Mre11/Rad50/Nbs1 (MRN) DSB repair processing and signaling complex, CtIP/Ctp1/Sae2/Com1 is integral to the channeling of DNA double strand breaks through DSB repair by homologous recombination (HR). Nearly two decades since its discovery, emerging new data are defining the molecular underpinnings for CtIP DSB repair regulatory activities. CtIP homologs are largely intrinsically unstructured proteins comprised of expanded regions of low complexity sequence, rather than defined folded domains typical of DNA damage metabolizing enzymes and nucleases. A compact structurally conserved N-terminus forms a functionally critical tetrameric helical dimer of dimers (THDD) region that bridges CtIP oligomers, and is flexibly appended to a conserved C-terminal Sae2-homology DNA binding and DSB repair pathway choice regulatory hub which influences nucleolytic activities of the MRN core nuclease complex. The emerging evidence from structural, biophysical, and biological studies converges on CtIP having functional roles in DSB repair that include: 1) dynamic DNA strand coordination through direct DNA binding and DNA bridging activities, 2) MRN nuclease complex cofactor functions that direct MRN endonucleolytic cleavage of protein-blocked DSB ends and 3) acting as a protein binding hub targeted by the cell cycle regulatory apparatus, which influences CtIP expression and activity via layers of post-translational modifications, protein-protein interactions and DNA binding. PMID- 28623097 TI - On sinuses and vortices. PMID- 28623098 TI - Acquired inhibition of microRNA-124 protects against spinal cord ischemia reperfusion injury partially through a mitophagy-dependent pathway. AB - OBJECTIVE: Mitophagy results in selective clearance of damaged mitochondria. We investigated whether mitophagy was involved in the neuroprotection by inhibiting microRNA (miRNA)-124 on ischemic spinal cords. METHODS: Inhibition of miRNA-124 was conducted by intrathecal injection of lentivirus vectors containing antagomiR 124. Spinal cord ischemia was induced in rats by crossclamping the descending aorta just distal to the left subclavian artery for 14 minutes. Hind-limb motor function was assessed with the motor deficit index (MDI). Lumbar spinal cords were harvested for ultrastructural, histologic examinations, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling staining. Mitophagy was evaluated by expressions of beclin-1 and LC3-II in mitochondria. Expressions of inhibitory member of the apoptosis-stimulating proteins of p53 family, p53, beclin-1, LC3-II, and miRNA-124 were measured by Western blot and quantitative real-time polymerase chain reaction. Mitophagy was inhibited by the antagonist of 3-methyladenine. RESULTS: Compared with control animals, antagomiR 124 significantly inhibited expressions of miRNA-124 (P < .01) and p53 (P < .05) and enhanced expressions of inhibitory member of the apoptosis-stimulating proteins of p53 family, becline-1 and LC3-II (P < .01, respectively) in spinal cords. MDI at 6, 12, 24, and 48 hours after reperfusion were markedly lower in antagomiR-124 group (P < .01, vs control group, respectively). More motor neurons and less apoptotic cells were detected in lumbar spinal cords of antagomiR-124 group (P < .01 vs control group). Administration of 3-methyladenine completely abolished enhancements of mitochondrial becline-1 and LC3-II by antagomiR-124 (P < .01 vs antagomiR-124 group) and partially inhibited effects of antagomiR-124 on MDI, number of motor neurons, and apoptotic cells (P < .01 or < .05 vs control group and antagomiR-124 group, respectively). CONCLUSIONS: Inhibition of miRNA 124 exerts neuroprotection on spinal cords against ischemia-reperfusion injury, possibly by induction of mitophagy and antiapoptotic effects. PMID- 28623099 TI - Consensus statement on definitions and nomenclature for robotic thoracic surgery. AB - OBJECTIVES: Robotic thoracic operations are increasing, and new robotic systems are imminent. A definition of what constitutes a robotic thoracic operation and a nomenclature to detail the technique used is needed to accurately compare outcomes. METHODS: The American Association of Thoracic Surgeons Guideline Committee appointed an expert consensus writing committee to construct definitions and nomenclature for robotic thoracic surgery. A PubMed search was generated and after vetting and review of the literature a consensus statement was reached. RESULTS: The proposed definition is: "A robotic thoracic operation is a minimally invasive surgical procedure that does not spread, lift or remove any part of the chest or abdominal wall and is characterized by: the surgeon and the assistant's vision of the operative field is via a monitor only and the patient's tissue is manipulated by robotic instruments that follow a slave like mimic of human hands or thoughts via a computerized system." In addition, a flexible nomenclature is proposed that should be applicable to current and future robotic systems that details the number of robotic arms used, the types of ports and/or incisions made, the use of insufflation, and the operation performed. CONCLUSIONS: The American Association of Thoracic Surgeons writing committee proposes a definition and nomenclature for robotic thoracic surgery. Definitions are needed to ensure that future studies accurately compare results and outcomes and nomenclatures allow surgeons and scientists from diverse countries and cultures to use the same language to allow accurate communication. PMID- 28623100 TI - "The more things change...": The challenges ahead. PMID- 28623101 TI - A good chimney requires a good sweep. PMID- 28623102 TI - The enemy of good is better. PMID- 28623103 TI - What does it take to seal the deal? PMID- 28623105 TI - Transfer of the lateral antebrachial cutaneous nerve to the dorsal branch of the ulnar nerve without nerve graft in case of lower brachial plexus injuries: Anatomical and feasibility study. AB - In the context of lower (C8-T1) brachial plexus injury, transfer of the lateral antebrachial cutaneous nerve (LABCN) to the dorsal branch of the ulnar nerve (DBUN) with an interposed sural nerve graft has been proposed to restore sensitivity on the ulnar side of the hand. The purpose of this study was to assess the feasibility of performing this transfer directly - without interposition of a nerve graft - by intraneural dissection of the DBUN. An anatomical study was performed with 20 upper limbs from adult human cadavers. The LABCN and the DBUN were dissected. The LABCN emerged from the lateral side of the biceps brachii muscle at an average of 2.6+/-0.4cm from the interepicondylar line and was 13.5+/-2.6cm long, on average. The DBUN arose from the ulnar nerve 8.2+/ 1.6cm from the styloid process of the ulna. The maximum length of DBUN intraneural dissection relative to the ulnar nerve was 7.5+/-2.1cm, on average. The LABCN could be transferred to the DBUN in a tension-free manner with end-to end suturing. Intraneural dissection of the DBUN allows LABCN nerve transfer without interposition of a graft. PMID- 28623104 TI - Zearalenone adsorption capacity of lactic acid bacteria isolated from pigs. AB - The ability to adsorb zearalenone by five strain of lactic acid bacteria was evaluated: four strains of Lactobacillus spp. isolated from pig rectal swabs and one commercial strain (Lactobacillus rhamnosus). Several factors affecting the adsorption capacity were evaluated in order to improve the adsorption of the mycotoxin by bacteria. The stability of the zearalenone-bacteria complex was analyzed. In every case, bacterial adsorption capacity was higher than 40.0%. The strain showing the highest adsorption (68.2%) was selected for the following steps of this research. The adsorption percentages obtained after processing 6.5 and 7.5mL MRS broth were 57.40%+3.53 and 64.46%+0.76, respectively. The stability of zearalenone-bacteria complex was evaluated by successively rinsing. In the first rinsing step 42.26%+0.414 was still bound. In the second rinsing step 25.12%+0.664 was still bound, whereas 15.82%+0.675 remained in the pellet after the third rinse. Results obtained demonstrated that Lactic Acid Bacteria has capacity to adsorb zearalenone. Finally adsorption was increased using a higher volume of initial broth. These results could be used to design a new lyophilized powder for detoxification, using lactic acid bacteria as potential zearalenone adsorbents. PMID- 28623106 TI - The role of physiotherapy in patients undergoing pulmonary surgery for lung cancer. A literature review. AB - This review aims to appraise the role of physiotherapy care in patients submitted to pulmonary surgery, in preoperative, perioperative, and postoperative phases. Pulmonary surgery is the gold standard treatment for patients with lung cancer if it is completely resectable. However, the major impairments and complications induced by surgery are well known. Physiotherapy has been regularly used both in the preparation of the surgical candidates; in their functional recovery in the immediate postoperative period, and in the medium/long term but there is a lack of concise evidence-based recommendations. Therefore, the aim of this review is to appraise the literature about the role of physiotherapy interventions in patients undergoing lung surgery for lung cancer, in preoperative, perioperative, postoperative and maintenance stages, to the recovery and well-being, regardless of the extent of surgical approach. In conclusion, physiotherapy programs should be individually designed, and the goals established according to surgery timings, and according to each subject's needs. It can also be concluded that in the preoperative phase, the main goals are to avoid postoperative pulmonary complications and reduce the length of hospital stay, and the therapeutic targets are respiratory muscle training, bronchial hygiene and exercise training. For the perioperative period, breathing exercises for pulmonary expansion and bronchial hygiene, as well as early mobilization and deambulation, postural correction and shoulder range of motion activities, should be added. Finally, it can be concluded that in the postoperative phase exercise training should be maintained, and adoption of healthy life-style behaviours must be encouraged. PMID- 28623107 TI - Speech-in-noise perception in unilateral hearing loss: Relation to pure-tone thresholds and brainstem plasticity. AB - We investigated speech recognition in noise in subjects with mild to profound levels of unilateral hearing loss. Thirty-five adults were evaluated using an adaptive signal-to-noise ratio (SNR50) sentence recognition threshold test in three spatial configurations. The results revealed a significant correlation between pure-tone average audiometric thresholds in the poorer ear and SNR thresholds in the two conditions where speech and noise were spatially separated: dichotic - with speech presented to the poorer ear and reverse dichotic - with speech presented to the better ear. This first result suggested that standard pure-tone air-conduction thresholds can be a reliable predictor of speech recognition in noise for binaural conditions. However, a subgroup of 14 subjects was found to have poorer-than-expected speech recognition scores, especially in the reverse dichotic listening condition. In this subgroup 9 subjects had been diagnosed with vestibular schwannoma at stage III or IV likely affecting the lower brainstem function. These subjects showed SNR thresholds in the reverse dichotic condition on average 4dB poorer (higher) than for the other 21 normally performing subjects. For the 7 of 9 subjects whose vestibular schwannoma was removed, the deficit was no longer apparent on average 5 months following the surgical procedure. These results suggest that following unilateral hearing loss the capacity to use monaural spectral information is supported by the lower brainstem. PMID- 28623108 TI - Acting, seeing, and conscious awareness. AB - We argue that there is a relation between the judgements that 'I did it' and 'I saw it'. Both are statements are about the individual, not just the world. We show that the dorsal prefrontal cortex is activated both when human subjects judge that they are the agents of their actions and when they judge that they are confident that they have seen a masked visual stimulus. Macaque monkeys have also been taught to report whether they have or have not seen visual stimuli and cells can be found in the dorsal prefrontal cortex that distinguish between 'seen' and 'not seen'. The judgement is abstract in that it applies largely irrespective of the nature and location of the stimulus. We suggest that the reason why the prefrontal cortex is involved is that it evolved in primates, adapted by searching for fruit and leaves and using their hands to retrieve them. There is cell activity in the dorsal prefrontal cortex that relates to eye movements, covert attention and visual search; activity that relates to learning abstract rules; and activity that relates to the planning of the hand movements that are appropriate. We propose that this is the reason why this area is involved in making judgements about both agency and visual detection. PMID- 28623109 TI - Serotype distribution of Streptococcus pneumoniae isolated from adult respiratory tract infections in nationwide Japanese surveillances from 2006 to 2014. AB - BACKGROUND AND OBJECTIVE: Reports on the efficacy of pneumococcal conjugate vaccines (PCVs) have been received from many countries. However, in countries where the 7-valent PCV (PCV7) and 13-valent PCV (PCV13) were introduced, overall coverage of the serotypes by the vaccine gradually decreased due to pneumococcal serotype replacement. The aim of this study is to assess the distribution of pneumococcal serotypes and to also provide basic data on adult respiratory infection in Japan. METHODS: We analyzed 1086 Streptococcus pneumoniae strains that had been isolated from respiratory tract infection specimens in adult patients from 2006 to 2014. Capsular typing was performed by the Quellung reaction and multiplex PCR. RESULTS: Among all 1086 strains, serotype 3 was the most common and was identified in 160 strains (14.7%), followed by serotypes 19F, 6B, 19A and 23F. From 2006-10 to 2012-14, the coverage rate of PCV7 tended to gradually decrease. Particularly, serotypes 6B and 19F of penicillin non susceptible strains decreased. On the other hand, serotypes 19A and 15A of penicillin non-susceptible strains increased. However, coverage by PCV13 of penicillin-resistant S. pneumoniae (PRSP) (penicillin G minimum inhibitory concentration >=2 MUg/mL) remained high (88.7% [2006-10], 88.0% [2012-14]). CONCLUSIONS: In Japan, PCV13 vaccination of adults became available from June 2014. Our study demonstrated that most PRSP (88.0%) still remain covered by PCV13. At present, the introduction of PCV13 in adult clinical practice seems to be highly significant. However, there is a possibility that the distribution has been changing, and careful screening should be continued in the future. PMID- 28623110 TI - Pertussis without apparent cough in a disabled girl with a tracheostomy. AB - Pertussis is characterized by intense, prolonged coughing in children often followed by a distinctive whooping sound on inspiration. However, the clinical manifestations and natural course of pertussis in disabled children are largely unknown. We experienced a case of pertussis in a disabled girl who had previously undergone a tracheostomy and laryngotracheal separation. She presented with increased tracheal secretions and required hospitalization but did not develop a cough. Pertussis was suspected from the sputum Gram stain, which revealed numerous, short gram-negative rods that did not grow on chocolate agar. A nucleic acid amplification test was positive for Bordetella pertussis and the patient improved on azithromycin. Pertussis may present without its cardinal symptoms in disabled children. PMID- 28623111 TI - Reversal of ABCB1 mediated efflux by imatinib and nilotinib in cells expressing various transporter levels. AB - Recently, it has been suggested that imatinib (IM) and nilotinib (NIL) could be studied beyond their original application, as inhibitors of the drug efflux pump ABCB1 (P-glycoprotein, MDR1). Since the reversal of ABCB1-mediated resistance has never been successfully demonstrated in the clinic, we addressed the question of whether IM and NIL may actually serve as efficient inhibitors of ABCB1. Here we define an efficient inhibitor as a compound that achieves full (90-100%) reversal of drug efflux at a concentration that does not exhibit significant off-target toxicity in vitro. In this study, human leukemia K562 cells expressing various levels of ABCB1 were used. We observed that cells expressing higher ABCB1 levels required higher concentrations of IM and NIL to achieve full reversal of drug efflux. Among the well-known ABCB1 inhibitors, a similar effect was found for cyclosporin A (CsA) but not for zosuquidar. IM was efficient only in cells with the low and moderate ABCB1 expression at high concentrations that were cytotoxic in the absence of Bcr-Abl. In contrast, NIL was as efficient an inhibitor of ABCB1 as CsA. Low and moderate expression levels of ABCB1 could be efficiently inhibited by NIL concentrations without cytotoxic effects in the absence of Bcr Abl. However, high expression levels of ABCB1 required higher NIL concentrations with off-target cytotoxic effects. In conclusion, application of NIL, but not of IM, in clinics is promising, however, only in cells with low ABCB1 expression levels. We hypothesize that some patients may benefit from an inhibitor exhibiting an ABCB1 expression-dependent effect. PMID- 28623112 TI - Protective and prophylactic effects of chlorogenic acid on aluminum-induced acute hepatotoxicity and hematotoxicity in mice. AB - The possible health impact of the exposures to Al from environment would be inevitable for humans. Using chelating agents and natural antioxidants against Al induced biotoxicity become a natural and modern way to prevent the adverse effects of Al in people. This study was undertaken to determine the effectiveness of chlorogenic acid (CGA, 5-O-caffeoylquinic acid) in preventing aluminum chloride (AlCl3) induced hepatotoxicity and hematotoxicity in mice. Control, Al treated (a single injection of 25 mg Al3+/kg, i.p.), Al + CGA (2 h after, a single dose of 100 mg/kg, i.p.), CGA + Al (administered to mice daily for 5 days at 30 mg/kg before Al-treatment) and group of CGA per se (administered to mice daily for 5 days at 30 mg/kg) were used. The levels of Al in liver and blood, the activities of transaminases in serum and osmotic fragility were increased by comparison with the control, while the activities of superoxide dismutase and catalase decreased significantly in the Al-treated group. However, treating mice with CGA at either dosing regimens, post- or pre- Al administration alleviate Al oxidative damaging effects, stabilize cell membrane, prevent hepatocyte apoptosis. CGA supplementation may be favorable to avoid Al-induced hematotoxicity and hepatotoxicity for humans. PMID- 28623113 TI - Does Robotic Surgical Simulator Performance Correlate With Surgical Skill? AB - OBJECTIVE: To assess the relationship between robotic surgical simulation performance and the real-life surgical skill of attending surgeons. We hypothesized that simulation performance would not correlate with real-life robotic surgical skill in attending surgeons. DESIGN: In 2013, Birkmeyer et al. demonstrated an association between laparoscopic surgical performance as determined by expert review of video clips and surgical outcomes. Using that model of expert review, we studied the relationship between robotic simulator performance and real-life surgical skill. Ten attending robotic surgeons performed 4 tasks on the da Vinci Skills Simulator (Camera Targeting 1, Ring Walk 3, Suture Sponge 3, and Energy Dissection 3). Two video clips of a robotic assisted operation were then recorded for each surgeon. Three expert robotic surgeons reviewed the recordings and rated surgical technique using the Global Evaluative Assessment of Robotic Skills. SETTING: University of Virginia; Charlottesville, VA; tertiary hospital PARTICIPANTS: All attending surgeons who perform robotic-assisted surgery at our institution were enrolled and completed the study. RESULTS: The surgeons had a median of 7.25 years of robotic surgical experience with a median of 91 cases (ranging: 20-346 cases) in the last 4 years. Median scores for each simulator task were 87.5%, 39.0%, 77.5%, and 81.5%. Using Pearson's correlation, scores for each of the individual tasks correlated poorly with expert review of intraoperative performance. There was also no correlation (r = -0.0304) between overall simulation score (mean: 70.7 +/- 9.6%) and expert video ratings (mean: 3.66 +/- 0.32 points). CONCLUSIONS: There was no correlation between attending surgeons' simulator performance and expert ratings of intraoperative videos based on the Global Evaluative Assessment of Robotic Skills scale. Although novice surgeons may put considerable effort into training on robotic simulators, performance on a simulator may not correlate with attending robotic surgical performance. Development of simulation exercises that guide novice surgeons toward expert performance is needed. PMID- 28623114 TI - Characterizing the Relationship Between Surgical Resident and Faculty Perceptions of Autonomy in the Operating Room. AB - OBJECTIVE: Characterize the concordance among faculty and resident perceptions of surgical case complexity, resident technical performance, and autonomy in a diverse sample of general surgery procedures using case-specific evaluations. DESIGN: A prospective study was conducted in which a faculty surgeon and surgical resident independently completed a postoperative assessment examining case complexity, resident operative performance (Milestone assessment) and autonomy (Zwisch model). Pearson correlation coefficients (r) reaching statistical significance (p < 0.05) were further classified as moderate (r >= 0.40), strong (r >= 0.60), or very strong (r >= 0.80). SETTING: This study was conducted in the General Surgery Residency Program at an academic tertiary care facility (Geisinger Medical Center, Danville, PA). PARTICIPANTS: Participants included 6 faculty surgeons, in addition to 5 postgraduate year (PGY) 1, 6 midlevel (PGY 2 3), and 4 chief (PGY 4-5) residents. RESULTS: In total, 75 surgical cases were analyzed. Midlevel residents accounted for the highest number of cases (35, 46.6%). Overall, faculty and resident perceptions of case complexity demonstrated a strong correlation (r = 0.76, p < 0.0001). Technical performance scores were also strongly correlated (r = 0.66, p < 0.0001), whereas perceptions of autonomy demonstrated a moderate correlation (r = 0.56, p < 0.0001). Subgroup analysis revealed very strong correlations among faculty perceptions of case complexity and the perceptions of PGY 1 (r = 0.80, p < 0.0001) and chief residents (r = 0.82, p < 0.0001). All other intergroup correlations were strong with 2 notable exceptions as follows: midlevel and chief residents failed to correlate with faculty perceptions of autonomy and operative performance, respectively. CONCLUSIONS: General surgery residents generally demonstrated high correlations with faculty perceptions of case complexity, technical performance, and operative autonomy. This generalized accord supports the use of the Milestone and Zwisch assessments in residency programs. However, discordance among perceptions of midlevel resident autonomy and chief resident operative performance suggests that these trainees may need more direct communication from the faculty. PMID- 28623115 TI - Association of Cerebral Venous Thrombosis and Intracranial Hypotension: Review of 3 Cases. AB - Cerebral venous thrombosis is a rare complication of intracranial hypotension. We describe 3 cases in which this phenomenon occurred, as a result of a lumbar puncture or due to a spontaneous cerebrospinal fluid leak. We emphasize the importance of early detection of the intracranial hypotension syndrome, the most common clinical manifestation being orthostatic headache. It is not an innocent condition as it is associated with other potential complications such as subdural hygroma/hematoma, cranial nerve palsies, cerebellar tonsillar descent, and even brainstem manifestations. Any change in the typical features of the syndrome should lead to further investigation. Repeat cerebral imaging is important in that situation, including ruling out cerebral venous thrombosis. PMID- 28623116 TI - Comparison of the Prevalence of Ruptured and Unruptured Cerebral Aneurysms in a Poor Urban Minority Population. AB - BACKGROUND: Most ruptured cerebral aneurysms are small (<7 mm). Evidence suggests low rupture rates for such lesions (<1% per year). Population studies demonstrate a prevalence rate of 3.2%. This study simultaneously estimates the prevalence of aneurysms in a single geographic population while reporting the observed rate of aneurysmal subarachnoid hemorrhage (aSAH) in the same geographic region composed of a poor urban minority demographic. METHODS: This is an institutional review board-approved, Health Insurance Portability and Accountability Act of 1996 compliant retrospective study performed between 2005 and 2011 at a single center. Part 1 used the electronic medical record to identify all patients with a magnetic resonance angiography demonstrating a cerebral aneurysm. Part 2 used the electronic medical record to identify all patients from the same geographic area presenting with aSAH during the study period. RESULTS: A total of 11,160 subjects had a magnetic resonance angiography from the study area. In this group, 422 intradural cerebral aneurysms were incidentally discovered. Ninety-one percent were less than 10 mm (mean 5.49, standard deviation 4.6). Twenty-one percent were aneurysms of the anterior communicating artery complex. Fourteen percent were of posterior communicating artery origin. A total of 237 patients had aSAH. Ninety two percent of the aneurysms were less than 10 mm (mean 6 mm, standard deviation 3.2 mm). Both groups were composed of poor urban minority patients. CONCLUSIONS: The observed annual rate of rupture of small anterior circulation aneurysms in this study was .06%-.15% per year. The extrapolated population prevalence of such aneurysms (4.0%-1.5%) may explain the observed rate of rupture of these small aneurysms in a poor urban minority population. PMID- 28623117 TI - Open Heart Surgery Does Not Increase the Incidence of Ipsilateral Ischemic Stroke in Patients with Asymptomatic Severe Carotid Stenosis. AB - BACKGROUND AND PURPOSE: We evaluated the incidence of perioperative stroke following the institution's 2007 practice change of discontinuing combined carotid endarterectomy and open heart surgery (OHS) for patients with severe carotid stenosis. METHODS: In this retrospective cohort study, we compared 113 patients undergoing coronary artery bypass grafting, aortic valve replacement, or both from 2007 to 2011 with data collected from 2001 to 2006 from a similar group of patients. Our aim was to assess whether the practice change led to a greater incidence of stroke. RESULTS: A total of 7350 consecutive patients undergoing OHS during the specified time period were screened. Of these, 3030 had OHS between 2007 and 2011 but none were combined with carotid artery surgery (new cohort). The remaining 4320 had OHS before 2007 and 44 had combined procedures (old cohort). Of patients undergoing OHS during the 10-year period of observation, 230 had severe (>80%) carotid stenosis. In the old cohort (before 2007), carotid stenosis was associated with perioperative stroke in 2.5% of cases. None of the 113 patients having cardiac procedures after 2007 received combined carotid artery surgery; only 1 of these patients harboring severe carotid stenosis had an ischemic stroke (.9%) during the perioperative period. The difference in stroke incidence between the 2 cohorts was statistically significant (P = .002). CONCLUSION: The incidence of stroke in patients with severe carotid artery stenosis undergoing OHS was lower after combined surgery was discontinued. Combined carotid and OHS itself seems to be an important risk factor for stroke. PMID- 28623118 TI - Derivation and Validation of a Clinical Prediction Scale for Isolated Distal Deep Venous Thrombosis in Patients after Acute Ischemic Stroke. AB - BACKGROUND: Isolated distal deep venous thrombosis (IDDVT) is a common complication after ischemic stroke. However, there is a paucity of evidence regarding the clinical features and risk factors of IDDVT in patients with acute ischemic stroke. This study aimed to establish and validate a clinical prediction scale of IDDVT at an early stage of ischemic stroke development. METHODS: We retrospectively studied consecutive patients with stroke admitted to our neurology department between January and December 2016. Selected clinical variables were assessed by multivariable logistic regression to determine the independent risk factors for IDDVT. A prediction scale was developed and verified by the receiver operating characteristic curve. RESULTS: A total of 671 patients with ischemic stroke were included in the study, with 450 patients allocated into the derivation group and 221 patients into the validation group. A substantial proportion (22.1%) of patients developed IDDVT. A 16-point prediction scale (female gender = 2, older age [>=60 years] = 3, atrial fibrillation = 2, acute infection = 2, active cancer = 5, and higher [>=2.6 mmol/L] level of low-density lipoprotein = 2) derived from a multivariable logistic regression model was highly predictive of 10-day risk of IDDVT in both the validation group (c statistic = .70, 95% confidence interval [CI], .63-0.78, P < .0001) and the derivation group (c statistic = .68, 95% CI, .63-0.74, P < .0001). CONCLUSIONS: This prediction scale may help to identify patients with ischemic stroke who are at a higher risk of developing IDDVT. PMID- 28623119 TI - The Cost-Effectiveness of a Stroke Unit in Providing Enhanced Patient Outcomes in an Australian Teaching Hospital. AB - BACKGROUND: Stroke is one of the leading causes of disability and mortality. Patients who receive organized inpatient care in a stroke unit (SU) have better clinical outcomes. However, evidence on the cost analysis of an SU is lacking. The objective of this study was to assess the performance and analyze the cost effectiveness of an SU. METHODS: A retrospective observational study was conducted comparing the acute stroke patient care in a 6-month period before and after the establishment of an acute SU at Calvary Hospital in 2013-2014. RESULTS: There were 103 patients included in the pre-SU period, as compared to 186 patients in the post-SU period. In the pre- and post-SU groups, 54 and 87 patients, respectively, had ischemic stroke, with significant trends in improved morbidity and mortality in the post-SU group (P = .01). The average length of stay (LOS) for patients was reduced from 9.7 days to 4.6 days in the post-SU group (P = .001). There was a reduction of cost per admission from $6382 Australian dollars (AUD) with conventional ward care as compared to $6061 (AUD) with SU care. CONCLUSION: This study confirmed that the establishment of an SU not only improves treatment outcomes but also shortens LOS, thereby achieving cost-effectiveness. PMID- 28623120 TI - Association between Ischemic Stroke and Erdheim-Chester Disease: A Case Report and Review of Literature. AB - Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by a xanthogranulomatous infiltration of tissues by spumous histiocytes. Neurological involvement is frequent, but ischemic strokes have been exceptionally described. We report the case of a 68-year-old woman who presented with an acute ischemic stroke associated with a multisystemic disorder including insipidus diabetes, infiltration of the aorta and the carotid arteries, perirenal infiltration, aortitis, and lytic bone lesions. The surgical biopsy of a lumbar vertebra revealed an infiltration of spumous macrophages consistent with ECD. Many ischemic symptoms can occur in ECD. Ischemic strokes, infrequently reported, might be caused by perivascular infiltration and adventitial fibrosis of the supra-aortic trunks or intracranial arteries. PMID- 28623121 TI - Radiomics-based Assessment of Radiation-induced Lung Injury After Stereotactic Body Radiotherapy. AB - BACKGROUND: Over 50% of patients who receive stereotactic body radiotherapy (SBRT) develop radiographic evidence of radiation-induced lung injury. Radiomics is an emerging approach that extracts quantitative features from image data, which may provide greater value and a better understanding of pulmonary toxicity than conventional approaches. We aimed to investigate the potential of computed tomography-based radiomics in characterizing post-SBRT lung injury. METHODS: A total of 48 diagnostic thoracic computed tomography scans (acquired prior to SBRT and at 3, 6, and 9 months post-SBRT) from 14 patients were analyzed. Nine radiomic features (ie, 7 gray level co-occurrence matrix [GLCM] texture features and 2 first-order features) were investigated. The ability of radiomic features to distinguish radiation oncologist-defined moderate/severe lung injury from none/mild lung injury was assessed using logistic regression and area under the receiver operating characteristic curve (AUC). Moreover, dose-response curves (DRCs) for radiomic feature changes were determined as a function of time to investigate whether there was a significant dose-response relationship. RESULTS: The GLCM features (logistic regression P-value range, 0.012-0.262; AUC range, 0.643-0.750) outperformed the first-order features (P-value range, 0.100-0.990; AUC range, 0.543-0.661) in distinguishing lung injury severity levels. Eight of 9 radiomic features demonstrated a significant dose-response relationship at 3, 6, and 9 months post-SBRT. Although not statistically significant, the GLCM features showed clear separations between the 3- or 6-month DRC and the 9-month DRC. CONCLUSION: Radiomic features significantly correlated with radiation oncologist scored post-SBRT lung injury and showed a significant dose-response relationship, suggesting the potential for radiomics to provide a quantitative, objective measurement of post-SBRT lung injury. PMID- 28623123 TI - Screening mutations in drug-resistant Mycobacterium tuberculosis strains in Yunnan, China. AB - Drug-resistant tuberculosis (DR-TB), especially multidrug-resistant tuberculosis (MDR-TB), is a serious medical and societal problem in China. The purpose of this study was to evaluate the mutation characteristics of drug-resistant Mycobacterium tuberculosis (M. tuberculosis) isolates in Yunnan, China. Drug susceptibility testing (DST) was performed in 523 clinical M. tuberculosis isolates. Six drug resistance genes (katG, inhA, rpoB, rpsL, embB, and pncA) were selected to screen for mutations. In total, 54 clinical M. tuberculosis strains were identified as drug-resistant by DST, including 18 single drug-resistant (SDR) strains and 36 multidrug-resistant (MDR) strains. Twenty-four types of mutations in five genes (excluding the inhA gene) were screened in forty-one strains. Six novel mutations were identified in this study, including three missense mutations (p.S302R in katG, p.D78G in embB, and p.M1I in pncA), two frameshift mutations (408 ins A and 538-580 del in pncA), and one mutation in a control region (-6 C>T located upstream of rpsL). The mutation frequencies in the hotspot mutation regions in the katG, rpoB, rpsL, embB, and pncA genes were 92.5%, 44.4%, 54.2%, 52.6%, and 37.5%, respectively. The mutation spectra and frequencies seemed somewhat unique in the Yunnan DR-TB strains. PMID- 28623122 TI - A Randomized Phase II Study Comparing Nivolumab With Carboplatin-Pemetrexed for Patients With EGFR Mutation-Positive Nonsquamous Non-Small-Cell Lung Cancer Who Acquire Resistance to Tyrosine Kinase Inhibitors Not Due to a Secondary T790M Mutation: Rationale and Protocol Design for the WJOG8515L Study. AB - Antibodies to programmed cell death-1 (PD-1), such as nivolumab, have shown promising clinical activity in patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy appears to be less pronounced in patients with such tumors harboring epidermal growth factor receptor gene (EGFR) mutations. Recent findings suggest that patients with EGFR mutation-positive NSCLC who develop resistance to tyrosine kinase inhibitors (TKIs) due to mechanisms other than acquisition of the secondary T790M mutation of EGFR are more likely to benefit from nivolumab treatment, possibly as a result of a higher level of expression of the PD-1 ligand PD-L1, than are patients who are T790M-positive. The WJOG8515L study (UMIN ID: 000021133) is a randomized phase II trial to compare nivolumab with the combination of carboplatin and pemetrexed in patients with EGFR mutation positive nonsquamous NSCLC who have developed resistance to EGFR-TKIs due to mechanisms other than T790M. Eligible patients are those with stage IV or recurrent EGFR mutation-positive NSCLC who experience disease progression after therapy with more than 1 EGFR-TKI, including gefitinib, erlotinib, or afatinib; they must show no evidence of the T790M mutation on analysis of a tumor biopsy specimen obtained after progression on such EGFR-TKI therapy, or, if T790M is detected, they must again experience progression on subsequent treatment with a third-generation EGFR-TKI. The primary endpoint is progression-free survival (PFS), and secondary end points include overall survival (OS), objective response rate, duration of response, safety, and OS and PFS according to PD-L1 expression level. Recruitment started in May 2016 and is ongoing. PMID- 28623124 TI - Development and implementation of the compensation plan for pharmacy services in Alberta, Canada. AB - OBJECTIVE: To describe experiences with development and implementation of a compensation plan for pharmacy services delivered by pharmacists in community pharmacies. SETTING: Community pharmacy practice in Alberta, Canada. PRACTICE DESCRIPTION: Pharmacists in Alberta have one of the most progressive scopes of practice in North America. They have authority to prescribe drugs independently, administer drugs by injection, access electronic health records, and order laboratory tests. PRACTICE INNOVATION: A publicly funded compensation plan for pharmacy services was implemented in 2012. Principles that guided development of the compensation plan aimed to 1) ensure payment for pharmacy services, 2) support pharmacists in using their full scope of practice, 3) enable the development of long-term relationships with patients, 4) facilitate expansion of services delivered by pharmacists, and 5) provide access to pharmacy services for all eligible Albertans. Services covered by the compensation plan include care planning, prescribing, and administering drugs by injection. EVALUATION: The guiding principles were used to evaluate experiences with the compensation plan. RESULTS: Claims for pharmacy services covered by the compensation plan increased from 30,000 per month in July 2012 to 170,000 per month in March 2016. From September 2015 to August 2016, 1226 pharmacies submitted claims for services provided by 3901 pharmacists. The number of pharmacists with authorization to prescribe and administer injections continued to increase following implementation of the plan. CONCLUSION: Alberta's experiences with the development and implementation of the compensation plan will be of interest to jurisdictions considering implementation of remunerated pharmacy services. The potential impact of the plan on health and economic outcomes, in addition to the value of the services as perceived by the public, patients, pharmacists, and other health care providers, should also be explored. PMID- 28623125 TI - Chronic intermittent hypoxia induces liver fibrosis in mice with diet-induced obesity via TLR4/MyD88/MAPK/NF-kB signaling pathways. AB - Obstructive sleep apnea (OSA) is associated with nonalcoholic fatty liver disease (NAFLD), and causes chronic intermittent hypoxia (CIH) during sleep. Inflammation is associated with the development of metabolic complications induced by CIH. Research suggests that innate immune mechanisms are involved in the pro inflammatory pathways of liver fibrosis. The purpose of this study was to investigate whether innate immune responses induce liver fibrosis, and to evaluate mechanisms underlying hepatic inflammation related to CIH in a murine diet-induced obesity (DIO) model. Inflammatory and oxidative stress markers, TLR4, MyD88, Toll/interleukin-1-receptor-domain-containing adaptor-inducing interferon-beta (TRIF), I-kappaB, NF-kappaB, p38 MAPK, c-JNK, and ERK activation, were measured in the serum and liver. As a result, alpha1(I)-collagen mRNA was significantly higher in DIO mice exposed to CIH than in the control groups. CIH mice exhibited liver fibrosis and significantly higher protein expression of TLR4, MyD88, phosphorylated (phospho-) I-kappaB, and phospho-ERK1/2 activation in the liver, and higher expression of NF-kappaB than that in the controls. TRIF, p38 MAPK, and JNK activation did not differ significantly between groups. We conclude that CIH in DIO mice leads to liver fibrosis via TLR4/MyD88/MAPK/NF-kB signaling pathways. PMID- 28623126 TI - Crystal structure of tRNAHis guanylyltransferase from Saccharomyces cerevisiae. AB - tRNA maturation involves several steps, including processing, splicing, CCA addition, and posttranscriptional modifications. tRNAHis guanylyltransferase (Thg1) is the only enzyme known to catalyze templated nucleotide addition in the 3'-5' direction, unlike other DNA and RNA polymerases. For a better understanding of its unique catalytic mechanism at the molecular level, we determined the crystal structure of GTP-bound Thg1 from Saccharomyces cerevisiae at the maximum resolution of 3.0 A. The structure revealed the enzyme to have a tetrameric conformation that is well conserved among different species, and the GTP molecule was clearly bound at the active site, coordinating with two magnesium ions. In addition, two flexible protomers at the potential binding site (PBS) for tRNAHis were observed. We suggest that the PBS of the tetramer could also be one of the sites for interaction with partner proteins. PMID- 28623127 TI - The inhibition of NLRP3 signaling attenuates liver injury in an alpha galactosylceramide-induced hepatitis model. AB - Inflammasomes are involved in innate immune responses. Several NOD-Like receptors (NLRs) participate in the formation of inflammasomes. NACHT, LRR and PYD domains containing protein 3 (NALP3) belongs to the NLR family and recognizes adenosine triphosphate (ATP), crystals, and Reactive Oxygen Species (ROS). This study examined the effect of inflammasomes on alpha-galactosylceramide (GalCer)-induced liver injury using NALP3-knockout (KO) mice. GalCer administration induced inflammasome activation and IL-1beta-maturation. In NALP3-KO mice treated with GalCer, serum ALT levels were significantly reduced compared with those in GalCer treated WT mice. Histological examination revealed decreased necrosis in NALP3-KO mice compared with WT mice, consistent with ALT levels. Expression of proinflammatory cytokines (such as IL-6, and TNF-alpha) and chemokines was also significantly suppressed in NALP3-KO mice. Moreover, flow cytometry analysis revealed fewer infiltrating immune cells in the livers of GalCer-treated NALP3-KO mice. Inportantly, the frequency of MDSCs (CD11b+Gr-1int cells), which suppress the immune response, was significantly increased in GalCer-treated NALP3-KO mice. In conclusion, NALP3 inhibition attenuated liver injury in GalCer-induced hepatitis. The inhibition of NALP3 signaling coused be a therapeutic target in immune-mediated liver injury. PMID- 28623128 TI - Targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin squamous cell carcinoma cell growth in vitro and in vivo. AB - Abnormal activation of PI3K-AKT-mTOR signaling is detected in human skin squamous cell carcinoma (SCC). LY3023414 is a novel, potent, and orally bio-available PI3K AKT-mTOR inhibitor. Its activity against human skin SCC cells was tested. We demonstrated that LY3023414 was cytotoxic when added to established (A431 line) and primary (patient-derived) human skin SCC cells. LY3023414 induced G0/1-S arrest and inhibited proliferation of skin SCC cells. Moreover, LY3023414 induced activation of caspase-3/-9 and apoptosis in skin SCC cells. Intriguingly, LY3023414 was yet non-cytotoxic nor pro-apoptotic to normal human skin cells (melanocytes, keratinocytes and fibroblasts). At the molecular level, LY3023414 blocked PI3K-AKT-mTOR activation in skin SCC cells, as it dephosphorylated PI3K AKT-mTOR substrates: P85, AKT and S6K1. In vivo studies showed that oral administration of LY3023414 at well-tolerated doses inhibited A431 xenograft tumor growth in severe combined immunodeficiency (SCID) mice. AKT-mTOR activation in LY3023414-treated tumors was also largely inhibited. Together, these results suggest that targeting PI3K-AKT-mTOR by LY3023414 inhibits human skin SCC cell growth in vitro and in vivo, establishing the rationale for further clinical testing. PMID- 28623129 TI - Increased expression of microRNA-31-5p inhibits cell proliferation, migration, and invasion via regulating Sp1 transcription factor in HepG2 hepatocellular carcinoma cell line. AB - Accumulating evidence has suggested that microRNA-31-5p (miR-31-5p) is dysfunctional in hepatocellular carcinoma (HCC). However, the molecular mechanism of HCC remains unclear. In this study, we investigated the role of miR-31-5p in tumor formation and development of HCC. The expression of miR-31-5p was detected in HCC tissues, corresponding adjacent tissues, normal liver tissues, and HCC cell lines. miR-31-5p mimics and an inhibitor were transfected into HepG2 cells to assess the effects of miR-31-5p on cell proliferation, apoptosis, cell cycle, migration, and invasion assays. Western blotting was used to detect the expression of Sp1 transcription factor (SP1), cyclin D1, and survivin in transfected HCC cells and control cells. The expression of miR-31-5p was significantly decreased in HCC cells and HCC tissues. Overexpression of miR-31-5p inhibited HCC cell growth, migration, and invasion. Overexpression of miR-31-5p reduced the expression of SP1 and cyclin D1, and knockdown of SP1 decreased cyclin D1 expression. The dual luciferase assay showed that miR-31-5p directly targeted SP1 in HepG2. Together, the results suggested that miR-31-5p acted as a tumor suppressor to regulate SP1, and that miR-31-5p could be used as a therapeutic target for the treatment of HCC. PMID- 28623130 TI - Leukotriene signaling via ALOX5 and cysteinyl leukotriene receptor 1 is dispensable for in vitro growth of CD34+CD38- stem and progenitor cells in chronic myeloid leukemia. AB - Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein in chronic myeloid leukemia (CML) are remarkably effective inducing deep molecular remission in most patients. However, they are less effective to eradicate the leukemic stem cells (LSC), resulting in disease persistence. Therefore, there is great need to develop novel therapeutic strategies to specifically target the LSC. In an experimental mouse CML model system, the leukotriene pathway, and specifically, the expression ALOX5, encoding 5-lipoxygenase (5-LO), has been reported as a critical regulator of the LSC. Based on these results, the 5-LO inhibitor zileuton has been introduced in clinical trials as a therapeutic option to target the LSC although its effect on primary human CML LSC has not been studied. We have here by using multiplex single cell PCR analyzed the expression of the mediators of the leukotriene pathway in bone marrow (BM) BCR-ABL+CD34+CD38- cells at diagnosis, and found low or undetectable expression of ALOX5. In line with this, zileuton did not exert significant overall growth inhibition in the long term culture-initiating cell (LTC-IC) and colony (CFU-C) assays of BM CD34+CD38- cells from 7 CML patients. The majority of the single leukemic BCR-ABL+CD34+CD38- cells expressed cysteinyl leukotriene receptors CYSLT1 and CYSLT2. However, montelukast, an inhibitor of CYSLT1, also failed to significantly suppress CFU-C and LTC-IC growth. These findings indicate that targeting ALOX5 or CYSLT1 signaling with leukotriene antagonists, introduced into the clinical practice primarily as prophylaxis and treatment for asthma, may not be a promising pharmacological strategy to eradicate persisting LSC in CML patients. PMID- 28623132 TI - Generation and characterization of mouse knockout for glyoxalase 1. AB - Glyoxalase 1 (Glo1) is the first enzyme involved in glutathione-dependent detoxification of methylglyoxal, eventually generating d-lactate by the second enzyme glyoxalase 2 (Glo2). An accumulation of intracellular glyoxal and methylglyoxal leads to protein malfunction and mutation via formation of the advanced glycation end products (AGEs). Studies on mouse behavior suggest that methylglyoxal has anxiolytic properties. In this report, we generated and characterized a mouse knockout for Glo1. The knockout mice were viable without a pronounced phenotypic defect. Increased level of AGEs in Glo1 knockout mice was detected by immunoblotting with anti-MGH1 in liver homogenate, but not in brain. Alterations in behavior were observed in open field, light-dark transition, and tail suspension test. Open field data indicate increased exploration for novel environment and entry/stay in center zone in Glo1 knockout mice. In addition, increased light-dark transition and immobility was observed in the knockout mice. These data indicate that Glo1 knockout reduces anxiety-like behavior, but increases depression-like behavior. PMID- 28623131 TI - FGF21 regulates melanogenesis in alpaca melanocytes via ERK1/2-mediated MITF downregulation. AB - Fibroblast growth factor 21 (FGF21) is known as a metabolic regulator to regulate the metabolism of glucose and lipids. However, the underlying mechanism of FGF21 on melanin synthesis remains unknown. Therefore, the current study investigates the effect of FGF21 on melanogenesis in alpaca melanocytes. We transfected the FGF21 into alpaca melanocytes, then detected the melanin contents, protein and mRNA levels of pigmentation-related genes in order to determine the melanogenesis regulating pathway of FGF21. The results showed that FGF21 overexpression suppressed melanogenesis and decreased the expression of the major target genes termed microphthalmia-associated transcription factor (MITF) and its downstream genes, including tyrosinase (TYR) and tyrosinase-related protein 2 (TRP2). However FGF21 increased the expression of phospho-extracellular signal-regulated kinase (p-Erk1/2). In contrast, FGF21-siRNA, a small interference RNA mediating FGF21 silencing, abolished the inhibition of melanogenesis. Altogether, FGF21 may decrease melanogenesis in alpaca melanocytes via ERK activation and subsequent MITF downregulation, which is then followed by the suppression of melanogenic enzymes and melanin production. PMID- 28623134 TI - Dysfunction in diurnal synaptic responses and social behavior abnormalities in cathepsin S-deficient mice. AB - The expression of cathepsin S (CatS), a microglia-specific lysosomal cysteine protease in the brain, is regulated by the intrinsic microglial circadian clock. We herein report that the diurnal variation of evoked synaptic responses of cortical neurons disappeared in cathepsin S-deficient (CatS-/-) mice. The dendritic spine density of the cortical neurons was significantly reduced by incubation with a recombinant CatS. Furthermore, CatS-/- mice exhibited impaired social interaction and social novelty recognition in the three-chamber test. These findings indicate that the circadian clock-regulated secretion of CatS from microglia is involved in the diurnal variation of synaptic responses and dendritic spine density through the proteolytic modification of perisynaptic ECM molecules. Therefore, a dysfunction of the diurnal synaptic responses due to CatS deficiency may lead to social behavior abnormalities. PMID- 28623133 TI - Prostaglandin D2 enhances lipid accumulation through suppression of lipolysis via DP2 (CRTH2) receptors in adipocytes. AB - Prostaglandin (PG) D2 enhanced lipid accumulation in adipocytes. However, its molecular mechanism remains unclear. In this study, we investigated the regulatory mechanisms of PGD2-elevated lipid accumulation in mouse adipocytic 3T3 L1 cells. The Gi-coupled DP2 (CRTH2) receptors (DP2R), one of the two-types of PGD2 receptors were dominantly expressed in adipocytes. A DP2R antagonist, CAY10595, but not DP1 receptor antagonist, BWA868C cleared the PGD2-elevated intracellular triglyceride level. While, a DP2R agonist, 15R-15-methyl PGD2 (15R) increased the mRNA levels of the adipogenic and lipogenic genes, and decreased the glycerol release level. In addition, the forskolin-mediated increase of cAMP dependent protein kinase A (PKA) activity and phosphorylation of hormone sensitive lipase (HSL) was repressed by the co-treatment with 15R. Moreover, the lipolysis was enhanced in the adipocyte-differentiated DP2R gene-knockout mouse embryonic fibroblasts. These results indicate that PGD2 suppressed the lipolysis by repression of the cAMP-PKA-HSL axis through DP2R in adipocytes. PMID- 28623135 TI - Serum long non coding RNA MALAT-1 protected by exosomes is up-regulated and promotes cell proliferation and migration in non-small cell lung cancer. AB - Circulating lncRNAs have been defined as a novel biomarker for non-small cell lung cancer (NSCLC), MALAT-1 was first identified lncRNA that was related to lung cancer metastasis. However, the relationship between exosomal lncRNAs and the diagnosis and prognosis of NSCLC was poorly understood. The aim of this study is to evaluate the clinical significance of serum exosomal MALAT-1 as a biomarker in the metastasis of NSCLC. In this study, we firstly isolated the exosomes from healthy subjects and NSCLC patients. Then we measured the expression levels of MALAT-1 contained in exosomes, and found that exosomal MALAT-1 was highly expressed in NSCLC patients, more importantly, the levels of exosomal MALAT-1 were positively associated with tumor stage and lymphatic metastasis. In addition, we decreased MALAT-1 expression by short hairpin RNA and conducted a series of assays including MTT, cell cycle, colony formation, wound-healing scratch and Annexin/V PI by flow cytometry in human lung cancer cell lines. These in vitro studies demonstrated that serum exosome-derived long noncoding RNA MALAT 1 promoted the tumor growth and migration, and prevented tumor cells from apoptosis in lung cancer cell lines. Taken together, this study shed a light on utilizing MALAT-1 in exosomes as a non-invasive serum-based tumor biomarker for diagnosis and prognosis of NSCLC. PMID- 28623136 TI - Arabidopsis inositol polyphosphate kinase AtIpk2beta is phosphorylated by CPK4 and positively modulates ABA signaling. AB - Arabidopsis inositol polyphosphate kinase 2beta (AtIpk2beta) has multiple functions in plant development and in responding to abiotic stress. Although some related clues suggested a potential role of AtIpk2beta in ABA signaling, the defined evidence was still lack. Here we discovered that a key ABA signaling component calcium-dependent protein kinase 4 (CPK4) can interact with AtIpk2beta under ABA treated conditions through affinity purification and mass spectrometry detection. The interaction between CPK4 and AtIpk2beta were further confirmed by yeast two hybrid and bimolecular fluorescence complementation assays. Expression of AtIpk2beta also can be rapidly induced by ABA. In addition, we found that CPK4 can phosphorylate AtIpk2beta in vitro and identified five novel phosphorylation sites of AtIpk2beta by CPK4 kinase, including Tyr46, Ser48, Ser51, Thr128, Ser147. Overexpression of AtIpk2beta in Arabidopsis was more sensitive to ABA in seed germination, primary root inhibition, ABA-responsive gene expression than wild type plants, whereas knockout mutant atipk2beta exhibited no significant difference. The AtIpk2beta variants containing Tyr46, Thr128, Ser147 mutated to Ala cannot complement the yeast mutant ipk2 growth in high temperature, suggesting that those three amino acid residues are critical for AtIpk2beta. These findings provide insight into the modulation of ABA signaling by AtIpk2beta. PMID- 28623137 TI - Azomethines, isoxazole, N-substituted pyrazoles and pyrimidine containing curcumin derivatives: Urease inhibition and molecular modeling studies. AB - Curcumin has shown large number of pharmacological properties against different phenotypes of various disease models. Different synthetic routes have been employed to develop its various derivatives for diverse biological functions. In this study, curcumin derived azomethine, isoxazole, pyrimidines and N-substituted pyrazoles were synthesized to investigate their urease enzyme inhibition. The structures of newly synthesized compounds were described by IR, MS, 1H NMR and 13C NMR spectral data. Urease enzyme inhibition was evaluated through in vitro assays in which compound 8b was found to be the most potent (IC50 = 2.44 +/- 0.07 MUM) among the tested compounds. The compounds with diazine ring system except the 4d showed better urease inhibition (IC50 = 11.43 +/- 0.21-19.63 +/- 0.28 MUM) than the standard urease inhibitor thiourea (IC50 = 22.61 +/- 0.23 MUM). Similarly enzyme kinetics data revealed that compounds 3c-3e and 8b were competitive inhibitors with Ki values of 20.0, 19.87, 20.23 and 19.11 MUM respectively while the compounds 4b, 4c and 4e were mixed type of inhibitors with Ki values 6.72, 19.69 and 6.72 MUM respectively. Molecular docking studies were also performed to identify the plausible binding modes of the most active compounds. PMID- 28623138 TI - HP1alpha is highly expressed in glioma cells and facilitates cell proliferation and survival. AB - Epigenetic alteration plays critical roles in gliomagenesis by regulating gene expression through modifications of Histones and DNA. Trimethylation of H3K9, an essential repressed transcription mark, and one of its methyltransferase, SUV39H1, are implicated in glioma pathogenesis and progression. We find that the protein level of HP1alpha, a reader of H3K9me3 is elevated in cultured glioma cell lines and glioma tissues. H3K9me3 is also upregulated. Depletion of HP1alpha and SUV39H1 weakens glioma cell proliferation capacity and results in apoptosis of cells. Furthermore, we find that HP1alpha and H3K9me3 are enriched in the FAS and PUMA promoters, which suggests that upregulated HP1alpha and H3K9me3 contribute to cell survival by suppressing apoptotic activators. These data suggests that up-regulated HP1alpha and H3K9me3 in glioma cells are functionally associated with glioma pathogenesis and progression and may serve as novel biomarkers for diagnostic and therapeutic targeting of brain tumors. PMID- 28623139 TI - The co-expression of Neogenin with SOX2 in hippocampal neurons. AB - Dementia has been shown to be closely related with neuronal degeneration and/or a decrease in the activity of neural stem cells in many brain regions, including the hippocampus. It has been recently established that Neogenin is involved in the cell fate determination by regulating Oct3/4, SOX and Nanog, notable embryonic cell markers, expressions in pre-implantation mouse embryos. Further, Neogenin expression at both mRNA and protein levels is manifest in many brain regions in mice, but it remains unclear whether Neogenin expression is prerequisite for the maintenance of neural stem cells, particularly, playing a critical role in the hippocampus, a brain region known to be involved in memory generation and consolidation. Here, we provide evidence that supports that Neogenin is implicated in the maintenance of neural stem cells in the hippocampus by enhancing PCNA expressions. We have performed RT-PCR analysis, Western blotting, and immunohistochemistry with fetal rat brain tissues at E18 for Neogenin mRNA and protein profiling. Neuronal cells obtained from the hippocampus were subjected to FACS analysis for the identification of Neogenin-positive and/or neuronal stem cell marker-positive cells. Western blotting results showed that Neogenin expression was higher in the hippocampal region compared to the cortical region. FACS analysis results indicated that a significant population of fetal rat neuronal cells exhibiting Neogenin expression also displayed SOX2 expression, implying co-expression of Neogenin and SOX2 in the hippocampus. Next, we investigated the role of Neogenin through gain- and loss-of-function studies with cultured rat hippocampal neurons. Neogenin down-regulation by small hairpin RNAs led to a dramatic decrease in SOX2 expression while its up-regulation by overexpression caused an increase in PCNA expression, a cell proliferation marker, compared with none-transfected cells. From this study, we propose a model whereby Neogenin could maintain neural stem cell population and control cell proliferation. PMID- 28623140 TI - The isoforms of alpha-actin and myosin affect the Ca2+ regulation of the actin myosin interaction in the heart. AB - Myocardium of mammals contains a wide range of isoforms of proteins that provides contractile function of the heart. These are two isoforms of ventricular and two of atrial myosin, alpha- and beta-tropomyosin, and two isoforms of alpha-actin: cardiac and skeletal. We believe that the difference in the amino acid sequence of alpha-actin can affect the calcium regulation of the actin-myosin interaction. To test this hypothesis, we investigated effects of the isoforms of alpha-actin, cardiac and skeletal, and the isoforms of cardiac myosin on the calcium regulation of the actin-myosin interaction in an in vitro motility assay using reconstructed regulated thin filaments. The results show that isoforms of alpha actin and the ratio of alpha/beta-chains of Tpm differently affect the calcium regulation of the actin-myosin interaction in myocardium in dependence on cardiac myosin isoforms. PMID- 28623141 TI - Sirtuin 7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4. AB - Sirtuin 7 (SIRT7) is an NAD+-dependent deacetylase/deacylase, but only a limited number of SIRT7 substrates have been identified. Recently, we found that Sirt7 knockout mice are resistant to high-fat diet-induced fatty liver, and that SIRT7 positively regulates the protein level of TR4, a nuclear receptor involved in lipid metabolism, by inhibiting the CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex. However, the mechanism by which SIRT7 inhibits the E3 ubiquitin ligase complex was not identified. Here, we demonstrate that SIRT7 binds directly to DDB1 and deacetylates DDB1 at Lys1121. K1121R-DDB1 (a deacetylation-mimicking mutant) displayed reduced binding with DCAF1. The expression of TR4 protein and TR4 target genes, including Cd36, Cidea, Cidec and Pparg1, was increased in K1121R DDB1-overexpressing Hepa1-6 cells compared to WT-DDB1-overexpressing cells. Our results indicate that the SIRT7-mediated deacetylation of K1121 attenuates the activity of the CUL4B/DDB1/DCAF1 E3 ubiquitin ligase complex by reducing binding between DDB1 and DCAF1, leading to the increased expression of TR4. PMID- 28623142 TI - Complication of newborn circumcision: Meatal stenosis or meatal web? AB - INTRODUCTION: Meatal stenosis (MS) is a known complication of newborn circumcision. Symptoms are usually masked in young kids with a diaper. Deflation of urinary stream, dysuria, urinary frequency, and incontinence are the most common reported symptoms. Diagnosis of MS is still controversial. A narrow pinpoint urethral meatus is the current accepted diagnostic criteria. OBJECTIVE: In our practice, we observed that our cases do not overlap to the classic definition and presentation of MS. In this study, we presented our cases and aimed to share our observations. MATERIALS AND METHODS: Records of children who had meatoplasty between 2014 with 2016 were analyzed retrospectively. Only children with MS who had had newborn circumcision performed in our clinic were included in the study. Over 500 newborn circumcisions are performed per year in our clinic using the Gomco Clamp technique. Age at diagnosis, presenting complaints, penile anomalies including urethral meatus configuration, urinary symptoms, operation methods, and postoperative follow-up were gathered. RESULTS: A total of 13 boys who were circumcised in the newborn period had undergone meatoplasty with the diagnosis of MS. The mean age at the time of meatoplasty was 52.5 +/- 17.9 (range 37-93 months). All children were examined before and during the circumcision. There were no associated penile anomalies, including MS. The only presenting complaint was upward deflation of urinary stream instead of other lower urinary tract symptoms. Although the appearance of the meatus was pinpoint in all cases (Figure); it was easy to calibrate with an 8-10 Fr feeding tube. There was no stenosis, but a ventral web was detected. Meatoplasty with removal of this web was performed under general anesthesia. Two sutures were applied at 5 and 7 o'clock with 7/0 PDS. Mean postoperative follow-up time was 16.9 +/- 7.5 months. Children were pleased with direction of urinary stream. DISCUSSION: Both the diagnosis and morphological definition of MS have some controversies. To our knowledge, there is no similar reported study with pinpoint appearance and normal calibration of the meatus. There was no stenosis in any of them. Unlike classical MS presentations, upward deflation of urinary stream resulting from ventral web was a single presenting complaint. CONCLUSIONS: Upward deflation of urinary stream can develop after neonatal circumcision because of a meatal web without stenosis, and can be cured easily with meatoplasty. Instead of 'meatal stenosis', 'meatal web' may be a more appropriate term to explain the pathology in these patients. PMID- 28623143 TI - Changes in Physical Activity and Sedentary Behavior During Cardiac Rehabilitation. AB - OBJECTIVE: To objectively measure changes in both moderate-to-vigorous physical activity (MVPA) and sedentary behavior (SB) during and after standard cardiac rehabilitation (CR). DESIGN: Prospective cohort study. SETTING: Outpatient CR center. PARTICIPANTS: Patients (N=135) with acute coronary syndrome (ACS) who completed CR. INTERVENTIONS: Multidisciplinary CR according to current guidelines. MAIN OUTCOME MEASURES: The proportion of time spent in MVPA and SB was objectively measured with an accelerometer. The distribution of time in MVPA and SB was also determined (eg, average length of time periods spent in MVPA and SB). All measurements were obtained before CR, after CR, and at 1-year follow-up. RESULTS: Patients' time in MVPA during waking hours increased by .65% (~5min) during CR (P=.002) and remained increased at 1-year follow-up (P=.037). The MVPA distribution did not change. During CR, time spent in SB decreased by 2.49% (~22min; P<.001), and SB time became more fragmented with more breaks and shorter SB periods (P<.001). These SB improvements were maintained at 1-year follow-up (P<.001). CONCLUSIONS: Patients with ACS achieved a small improvement in MVPA time during CR, but MVPA distribution remained unchanged. More substantial improvements occurred for SB time and distribution. However, by the end of CR, patients still spent relatively little time in MVPA and a long time in SB, which is known to be detrimental to cardiovascular health. Although CR programs have the potential to improve physical behavior, our findings highlight the need to develop adjusted CR targets that address the amount and distribution of MVPA and SB. PMID- 28623144 TI - Cardiovascular Stress During Inpatient Spinal Cord Injury Rehabilitation. AB - OBJECTIVES: (1) To measure the amount of cardiovascular stress, self-reported physical activity, and accelerometry-measured physical activity by individuals with spinal cord injury (SCI) during physical therapy (PT) and occupational therapy (OT); and (2) to investigate the relations between these measures. DESIGN: Observational study. SETTING: Two inpatient SCI rehabilitation centers. PARTICIPANTS: Patients with SCI (N=87) were recruited from consecutive admissions to rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Heart rate was recorded by a Holter monitor, whereas physical activity was captured by self-report (Physical Activity Recall Assessment for People with SCI questionnaire) and real-time wrist accelerometry during a total of 334 PT and OT inpatient sessions. Differences between individuals with paraplegia and tetraplegia were assessed via Mann-Whitney U tests. Spearman correlations were used to explore the relation between measurements of physical activity and heart rate. RESULTS: Time spent at a heart rate within a cardiovascular training zone (>=40% heart rate reserve) was low and did not exceed a median of 5 minutes. In contrast, individuals reported at least 60 minutes of higher-intensity time during therapy. There was a low but statistically significant correlation between all measures. CONCLUSIONS: The cardiovascular stress incurred by individuals with SCI during inpatient PT and OT sessions is low and not sufficient to obtain a cardiovascular training effect to optimize their neurologic, cardiovascular, or musculoskeletal health; this represents a lost opportunity to maximize rehabilitation. Self-reported minutes of higher-intensity physical activity do not reflect actual time spent at a higher intensity measured objectively via a heart rate monitor. PMID- 28623145 TI - Global burden of pertussis: signs of hope but need for accurate data. PMID- 28623146 TI - An update of the global burden of pertussis in children younger than 5 years: a modelling study. AB - BACKGROUND: Since the publication in 2003 of a model to estimate the disease burden of pertussis, new evidence of the protective effect of incomplete pertussis vaccination against severe pertussis has been reported. We revised the model to provide new estimates of regional and global pertussis cases and deaths for children younger than 5 years. METHODS: We developed a revised model with data from 2014 to estimate pertussis cases and deaths. Pertussis cases were defined according to the WHO clinical case definition, as a coughing illness lasting at least 2 weeks with paroxysms of coughing, inspiratory whooping, or post-tussive vomiting. We used UN population estimates and WHO and UNICEF data on national pertussis immunisation coverage. Estimates were made for vaccine effectiveness against pertussis cases and deaths for one, two, and three doses of vaccination, probability of infection in low and high coverage countries, and case fatality ratios in low and high mortality countries in two age groups: infants younger than 1 year and children aged 1-4 years. We did sensitivity analyses with a range of input parameters to assess the effect of uncertainty of the input parameters on the model outputs. FINDINGS: We estimated that there were 24.1 million pertussis cases and 160 700 deaths from pertussis in children younger than 5 years in 2014, with the African region contributing the largest proportions (7.8 million [33%] cases and 92 500 [58%] deaths). 5.1 million (21%) estimated pertussis cases and 85 900 (53%) estimated deaths were in infants younger than 1 year. In the sensitivity analyses, the estimated number of cases ranged from 7 million to 40 million and deaths from 38 000 to 670 000. INTERPRETATION: Our estimates suggest that, compared with the 1999 estimates published in 2003 (30.6 million pertussis cases and 390 000 deaths from pertussis in children younger than 5 years), the numbers of cases and deaths of pertussis have fallen substantially. Model sensitivity emphasised the importance of better surveillance to improve country-level decision making and pertussis control. FUNDING: None. PMID- 28623147 TI - Neuregulin-1 protects mouse cerebellum against oxidative stress and neuroinflammation. AB - Cerebellum undergoes degenerative changes in neurodegenerative diseases. Two main factors including oxidative stress and neuroinflammation mediate neurodegeneration. Neuregulin-1 (Nrg1) has been implicated in many neurodegenerative diseases, while the underlying mechanisms are unknown. We hypothesized that Nrg1 prevents oxidative stress and neuroinflammation in neurodegeneration. We found a positive correlation between Nrg1 protein levels and ErbB4 and ErbB2 receptor phosphorylation in microarrays of normal human cerebellar tissue. In addition, Nrg1 was also co-localized with pErbB4 and pErbB2. Primary mouse cerebellar granule neurons (CGNs) were treated with H2O2 or LPS combined with recombinant Nrg1beta (rNrg1beta). Western blot analysis and immunofluorescence revealed that H2O2 and LPS-induced neuronal toxicity down regulated the activation of ErbB receptors and Akt1, and the ratio of Bcl2/Bax, which was reversed by rNrg1beta. In vivo studies showed that LPS-induced neuroinflammation in mouse cerebellum down-regulated pErbB4, pErbB2, pAkt1/Akt1 and Bcl2/Bax levels, whereas rNrg1beta treatment reversed the changes. Immunohistochemistry and Western blot analysis showed that rNrg1beta alleviates neuroinflammation by reducing the number of microglial cells and astrocytes and the expression of IL1beta. Our results indicate that Nrg1 protects against oxidative stress and neuroinflammation in mouse cerebellum, suggesting potential therapeutic application in neuroinflammation associated with neurodegenerative diseases. PMID- 28623148 TI - Male sexual enhancement after methoprene treatment in Anastrepha fraterculus (Diptera: Tephritidae): A sustained response that does not fade away after sexual maturation. AB - The juvenile hormone (JH) of insects triggers physiological changes related to reproduction in adults of both sexes. Methoprene is a sesquiterpene with some effects that are analogous to those of JH. Treatments with methoprene accelerate sexual maturation in males of the South American fruit fly Anastrepha fraterculus, giving young males a mating advantage over non-treated males of the same age. Here, we evaluated the effects of methoprene treatment on A. fraterculus males after the sexual maturation phase and tested whether this compound provides a long-term mating advantage. Moreover, we took the first step to unravel the mechanisms that underlie male sexual enhancement. We treated males 1day or 8days after adult emergence and compared mate choice between recently matured (young) females and females that had been mature for ca. 10days (aged females). We also addressed methoprene treatment effects on male sexual signalling. We found that methoprene treatment enhanced male sexual competitiveness even after the sexual maturation phase, and the effect did not decrease until males were older than 20days. However, when methoprene treatment was carried out close to sexual maturity, the mating enhancement was no longer observed, suggesting a non-immediate effect and excluding the possibility that methoprene acts as a pheromonal compound. Young and aged females tended to mate more frequently with treated-males. This might indicate that in a context of sexual selection, the potential benefits associated with reproductive success would be similar for females of both ages. Treated males released larger amounts of pheromonal compounds than non-treated males, but their courtship behaviour was not altered to the same extent, suggesting that methoprene treatment may accelerate differently the components of male courtship. We discuss potential benefits of using methoprene to increase the efficiency of the sterile insect technique, which is an environmentally safe method to control this important South American fruit pest. PMID- 28623150 TI - Another Impairment in Older Age: What Does Osteosarcopenic Obesity Syndrome Mean for Middle-Aged and Older Women? PMID- 28623149 TI - Subtle effect of Xenos vesparum (Xenidae, Strepsiptera) on the reproductive apparatus of its male host: Parasite or parasitoid? AB - Parasitic castration is an adaptive strategy where parasites usurp the hosts' reproductive physiology to complete their life cycle. The alterations in the host traits vary in their magnitude, from subtle changes in the host morpho-physiology and behaviour to the production of complex aberrant phenotypes, which often depend on the host gender. The strepsipteran macroparasite Xenos vesparum induces dramatic behavioural and physiological changes in its female host, the paper wasp Polistes dominula, while its effect on the male phenotype is largely unknown. In this study we investigated how a single X. vesparum parasite influences the functional morphology of P. dominula male reproductive apparatus. We performed morphometry and ultrastructure characterization of corpora allata, testes, seminal vesicles and accessory glands in parasitized and unparasitized males, and also in young and old males to control for the effect of age on the natural deterioration of these organs. Our results show that age significantly affects the development of male reproductive apparatus. A low parasite load - one parasite per host is the common prevalence in the field - has only a marginal impact on the reproductive morphology of P. dominula males, affecting quantitatively but not qualitatively the protein content of male accessory glands. Thus, in male P. dominula wasps, X. vesparum appears to behave as a true "parasite", in clear opposition to the role of "parasitoid" that it takes in female hosts where castration causes the reproductive death. PMID- 28623151 TI - Cognitive Performance across 3 Frailty Phenotypes: Toledo Study for Healthy Aging. AB - INTRODUCTION: Frailty is a strong predictor of adverse health events, but its impact on cognitive function is poorly understood. AIM: To assess cognitive performance in frailty and to identify the frailty stage where cognitive impairment begins. METHODS: Data were taken from 2044 people aged >=65 years without cognitive impairment selected from the Toledo Study for Healthy Aging, a population-based cohort of older adults. Frailty status was assessed by 3 different scales: Frailty Phenotype (FP), Frailty Trait Scale (FTS), and Frailty Index (FI). Neuropsychological assessments of different cognitive domains included the Mini-Mental State Examination, Short and Long-Term Memory Recalling Test, the Boston Naming Test, Verbal Fluency Test, Digit Span Forward, Go/No-go Test, Luria Orders Test, Clock Drawing Test, and Serial Word Learning Test. The relationships between the score of the scales and frailty status (robust, prefrail, and frail for FP and quartiles for FTS and FI) were analyzed using multivariate linear regression models including age, sex, and educative level as possible confounders. RESULTS: Participants classified as the worst degree of frailty (frail in FP and fourth quartile of FTS and FI) presented more cognitive domains affected and to a higher extent than moderate frail (prefrail and second quartile and third quartile of FTS and FI) and robust (and first quartile of FTS and FI) participants. CONCLUSIONS: Cognitive performance progressively declined across the frailty state, regardless of the instrument used to assess frailty. In prefrail participants, cognitive impairment may be an early marker of frailty dependent cerebral involvement and could be already subject to interventions aimed at reducing the transition to frailty. PMID- 28623152 TI - Singapore Healthy Older People Everyday (HOPE) Study: Prevalence of Frailty and Associated Factors in Older Adults. AB - BACKGROUND: In the context of a rapidly ageing population, Singapore is anticipating a rise in multimorbidity, disability, and dependency, which are driven by physical frailty. Healthy Older People Everyday (HOPE) is an epidemiologic population-based study on community-dwelling older adults aged 65 years and older in Singapore. OBJECTIVE: To investigate the prevalence of frail and prefrail states and their association with polypharmacy, multimorbidity, cognitive and functional status, and perceived health status among community dwelling older adults in Singapore. METHODS: Participants for HOPE were older adults aged 65 years and older recruited from a cohort study on the northwest region of Singapore. Analysis was performed on data collected from a combination of interviewer-administered questionnaires (including FRAIL scale, EQ-5D, Mini Mental State Examination, Barthel index, and Lawton IADL scale), clinical assessments, and physical measurements (including hand grip strength and Timed-Up and-Go [TUG] test). RESULTS: A total of 1051 older adults (mean age 71.2 years) completed the study. More than half (57.2%) were female. The prevalence of frailty and prefrailty was 6.2% and 37%, respectively. Frailty was associated with older age, female gender, Indian (instead of Chinese) ethnicity, multimorbidity, polypharmacy, cognitive and functional impairment, weaker hand grip strength, longer TUG times, and poor perceived health status. Those with underlying cognitive impairment and frailty were at greater risk of adverse health outcome. CONCLUSION: Frailty is a complex health state with multiple domains and dimensions. In our study in a multiethnic Asian population, we identified nonmodifiable factors and modifiable risk factors (multimorbidity, polypharmacy, cognitive and functional impairment) that were associated with frailty. Interventions will have to be multipronged and will require a collaborated effort in order to effect change and improve the health span in rapidly ageing populations. PMID- 28623154 TI - Standardizing Protection of Patients' Rights From POLST to MOELI (Medical Orders for End-of-Life Intervention). PMID- 28623153 TI - Cognitive Status of Older Adults on Admission to a Skilled Nursing Facility According to a Hospital Discharge Diagnosis of Dementia. AB - OBJECTIVE: Describe the cognitive status on admission to a skilled nursing facility (SNF) according to a hospital discharge diagnosis of dementia in a national sample of Medicare beneficiaries. DESIGN: Retrospective cohort design. SETTING: SNFs in the United States. PARTICIPANTS: Medicare-fee-for-service beneficiaries newly admitted to an SNF within 3 days of discharge from an acute hospital during 2013-2014 (n = 1,885,015). MEASUREMENTS: Beneficiaries with a discharge diagnosis of dementia were identified using ICD-9 CM codes from the Medicare Provider Analysis and Review (MedPAR) Part A file. Cognitive status at SNF admission was classified as cognitively intact, mildly impaired, moderately impaired, or severely impaired according to the Cognitive Function Scale using items in the Minimum Data Set 3.0. RESULTS: For beneficiaries with a discharge diagnosis of dementia (n = 252,970), 17.9% were classified as cognitively intact, 25.8% were mildly impaired, and 56.3% were moderately or severely impaired on SNF admission. Approximately 65% of beneficiaries without a hospital diagnosis of dementia were cognitively intact on admission to an SNF, whereas 13.1% were classified as moderately or severely impaired. CONCLUSION: Medicare beneficiaries with a hospital diagnosis of dementia are often classified as cognitively intact or mildly impaired on admission to an SNF. These findings provide evidence that a hospital diagnosis of dementia might not always reflect cognitive status on admission to an SNF. PMID- 28623155 TI - Care Toward the End of Life in Older Populations and Its Implementation Facilitators and Barriers: A Scoping Review. AB - PURPOSE: To inform health system improvements for care of elderly populations approaching the end of life (EOL) by identifying important elements of care and implementation barriers and facilitators. DESIGN: A scoping review was carried out to identify key themes in EOL care. Articles were identified from MEDLINE, the Cochrane Library, organizational websites, and internet searches. Eligible publications included reviews, reports, and policy documents published between 2005 and 2016. Initially, eligible documents included reviews or reports concerning effective or important models or components of EOL care in older populations, and evidence was thematically synthesized. Later, other documents were identified to contextualize implementation issues. RESULTS: Thematic synthesis using 35 reports identified key features in EOL care: (1) enabling policies and environments; (2) care pathways and models; (3) assessment and prognostication; (4) advance care planning and advance directives; (5) palliative and hospice care; (6) integrated and multidisciplinary care; (7) effective communication; (8) staff training and experience; (9) emotional and spiritual support; (10) personalized care; and (11) resources. Barriers in implementing EOL care include fragmented services, poor communication, difficult prognostication, difficulty in accepting prognosis, and the curative focus in medical care. CONCLUSIONS: Quality EOL care for older populations requires many core components but the local context and implementation issues may ultimately determine if these elements can be incorporated into the system to improve care. Changes at the macro-level (system/national), meso-level (organizational), and micro-level (individual) will be required to successfully implement service changes to provide holistic and person-centered EOL care for elderly populations. PMID- 28623156 TI - Trends in Influenza and Pneumococcal Vaccination Among US Nursing Home Residents, 2006-2014. AB - BACKGROUND: Institutionalized adults are at increased risk of morbidity and mortality from influenza and pneumococcal infection. Influenza and pneumococcal vaccination have been shown to be effective in reducing hospitalization and deaths due to pneumonia and influenza in this population. OBJECTIVE: To assess trends in influenza vaccination coverage among US nursing home residents from the 2005-2006 through 2014-2015 influenza seasons and trends in pneumococcal vaccination coverage from 2006 to 2014 among US nursing home residents, by state and demographic characteristics. METHODS: Data were analyzed from the Centers for Medicare and Medicaid Services' (CMS's) Minimum Data Set (MDS). Influenza and pneumococcal vaccination status were assessed for all residents of CMS-certified nursing homes using data reported to the MDS by all certified facilities. RESULTS: Influenza vaccination coverage increased from 71.4% in the 2005-2006 influenza season to 75.7% in the 2014-2015 influenza season and pneumococcal vaccination coverage increased from 67.4% in 2006 to 78.4% in 2014. Vaccination coverage varied by state, with influenza vaccination coverage ranging from 50.0% to 89.7% in the 2014-2015 influenza season and pneumococcal vaccination coverage ranging from 55.0% to 89.7% in 2014. Non-Hispanic black and Hispanic residents had lower coverage compared with non-Hispanic white residents for both vaccines, and these differences persisted over time. CONCLUSION: Influenza and pneumococcal vaccination among US nursing home residents remains suboptimal. Nursing home staff can employ strategies such as provider reminders and standing orders to facilitate offering vaccination to all residents along with culturally appropriate vaccine promotion to increase vaccination coverage among this vulnerable population. PMID- 28623158 TI - The Disaster Evacuation or Shelter-in-Place Decision: Who Will Decide? PMID- 28623157 TI - Mortality and Antipsychotic Drug Use in Elderly Patients With Parkinson Disease in Nursing Homes. AB - OBJECTIVES: To evaluate mortality rate in elderly and very elderly (>=85 years) residents with Parkinson disease (PD) in nursing homes (NHs) with and without antipsychotic drugs. DESIGN: Cross-sectional study. PARTICIPANTS: All residents with PD from the 6275 NH residents participating in the Impact d'une demarche QUAlite sur l'evolution des pratiques et le declin fonctionnel des Residents en Etablissement d'hebergement pour personnes agees dependantes (IQUARE) study. SETTING: A total of 175 NHs in Midi-Pyrenees region, South-Western France. EXPOSURE: Patients with PD taking antipsychotic drugs. OUTCOME MEASUREMENTS: All cause mortality between baseline and 18 months. STATISTICAL METHODS: Logistic regression was used to explore baseline characteristics associated with mortality rate and with antipsychotic use at 18 months. RESULTS: At baseline, among 452 residents with PD, 72 (15.9%) received at least 1 antipsychotic drug. Mortality rates at 18 months in residents with PD with and without antipsychotic use were similar (34.3% and 38.2%, respectively, P = .58). Among factors associated with mortality, a statistically significant increase in mortality rate was found in very old residents (>=85 years of age) [odds ratio (OR) 2.0; 95% confidence interval (CI) 1.3-3.1] or in those with chronic pulmonary disease (OR 3.6; 95% CI 1.5-8.5). Among residents >=85 years of age, we also found a statistically significant increase in mortality rate in individuals with arterial hypertension (OR 2.8; 95% CI 1.3-5.8). Moreover, a statistically significant increase in prescription of antipsychotic drugs was found in residents who tried to elope (OR 3.8; 95% CI 1.4-10.7) and in those with severe psychiatric diseases (excluding depression) (OR 7.5; 95% CI 4.1-13.6). CONCLUSIONS: In this study investigating factors associated with mortality in old and very old residents with PD in NHs, no significant association was observed with the use of antipsychotics. However, our study suggests that age (>=85 years) or chronic pulmonary disease could be associated with mortality among patients with PD, as well as arterial hypertension in very old patients (>=85 years of age). PMID- 28623159 TI - Epigenetic Biomarkers and Cardiovascular Disease: Circulating MicroRNAs. AB - MicroRNAs (miRNAs) are a class of small noncoding RNA (20-25 nucleotides) involved in gene regulation. In recent years, miRNAs have emerged as a key epigenetic mechanism in the development and physiology of the cardiovascular system. These molecular species regulate basic functions in virtually all cell types, and are therefore directly associated with the pathophysiology of a large number of cardiovascular diseases. Since their relatively recent discovery in extracellular fluids, miRNAs have been studied as potential biomarkers of disease. A wide array of studies have proposed miRNAs as circulating biomarkers of different cardiovascular pathologies (eg, myocardial infarction, coronary heart disease, and heart failure, among others), which may have superior physicochemical and biochemical properties than the conventional protein indicators currently used in clinical practice. In the present review, we provide a brief introduction to the field of miRNAs, paying special attention to their potential clinical application. This includes their possible role as new diagnostic or prognostic biomarkers in cardiovascular disease. PMID- 28623160 TI - Basic Concepts in Molecular Biology Related to Genetics and Epigenetics. AB - The observation that "one size does not fit all" for the prevention and treatment of cardiovascular disease, among other diseases, has driven the concept of precision medicine. The goal of precision medicine is to provide the best targeted interventions tailored to an individual's genome. The human genome is composed of billions of sequence arrangements containing a code that controls how genes are expressed. This code depends on other nonstatic regulators that surround the DNA and constitute the epigenome. Moreover, environmental factors also play an important role in this complex regulation. This review provides a general perspective on the basic concepts of molecular biology related to genetics and epigenetics and a glossary of key terms. Several examples are given of polymorphisms and genetic risk scores related to cardiovascular risk. Likewise, an overview is presented of the main epigenetic regulators, including DNA methylation, methylcytosine-phosphate-guanine-binding proteins, histone modifications, other histone regulations, micro-RNA effects, and additional emerging regulators. One of the greatest challenges is to understand how environmental factors (diet, physical activity, smoking, etc.) could alter the epigenome, resulting in healthy or unhealthy cardiovascular phenotypes. We discuss some gene-environment interactions and provide a methodological overview. PMID- 28623161 TI - The Genetics of Ischemic Heart Disease: From Current Knowledge to Clinical Implications. AB - Ischemic heart disease continues to cause high morbidity and mortality. Its prevalence is expected to increase due to population aging, and its prevention is a major goal of health policies. The risk of developing ischemic heart disease is related to a complex interplay between genetic, environmental, and lifestyle factors. In the last decade, considerable progress has been made in knowledge of the genetic architecture of this disease. This narrative review provides an overview of current knowledge of the genetics of ischemic heart disease and of its translation to clinical practice: identification of new therapeutic targets, assessment of the causal relationship between biomarkers and disease, improved risk prediction, and identification of responders and nonresponders to specific drugs (pharmacogenomics). PMID- 28623162 TI - What do we know about neurogenic bladder prevalence and management in developing countries and emerging regions of the world? AB - OBJECTIVE: To summarize information on Neurogenic Bladder (NB) epidemiology, management and access to patient treatment in developing countries and emerging regions of the world in order to propose future interventions and help governmental as well as non-governmental organizations design their action plans. METHODS: Different search methods were used to gather the maximum available data. They included strategic searches; reference checks; grey literature searches (reports, working papers, government documents, civil society information); contacting professional societies, registries, and authors; requesting unpublished data from organizations; and browsing related websites and journals. RESULTS: The incidence and prevalence rates of NB in developing countries are difficult to establish because epidemiological reports are few and far between. The frequency of bladder dysfunction in neurologically impaired populations can be approximately estimated in some of these countries. Similar information paucity affects diagnostic and therapeutic approaches to NB patients living in less-developed regions of the world. The assessment and management of NB seems to vary markedly between countries, and care of patients from emerging regions of the world is often inadequate. CONCLUSION: Strong concerted efforts are needed on the part of international scientific societies, non-governmental organizations and local governments to work together to change the prognosis for these patients and to improve their quality of life. PMID- 28623163 TI - Factors Associated with School Lunch Consumption: Reverse Recess and School "Brunch". AB - BACKGROUND: While school foods have become healthier under the Healthy, Hunger Free Kids Act, research suggests there is still substantial food waste in cafeterias. It is therefore necessary to study factors that can impact food consumption, including holding recess before lunch ("reverse recess") and starting lunch periods very early or very late. OBJECTIVE: This study examined the association between the timing of recess (pre-lunch vs post-lunch recess), the timing of the lunch period, and food consumed by students at lunch. DESIGN: We conducted a secondary data analysis from a repeated cross-sectional design. PARTICIPANTS/SETTING: An 8-week plate waste study examining 20,183 trays of food was conducted in New Orleans, LA, in 2014. The study involved 1,036 fourth- and fifth-grade students from eight public schools. MAIN OUTCOME MEASURES: We measured percent of entrees, fruit, vegetables, and milk consumed by students at lunch. STATISTICAL ANALYSES PERFORMED: We used mixed-model analyses, controlling for student sex, grade, and the timing of the lunch period, and examined the association between reverse recess and student lunch consumption. Mixed-model analyses controlling for student sex, grade, and recess status examined whether the timing of the lunch period was associated with student lunch consumption. RESULTS: On average, students with reverse recess consumed 5.1% more of their fruit than students with post-lunch recess (P=0.009), but there were no significant differences in entrees, vegetables, or milk intake. Compared to students with "midday" lunch periods, on average students with "early" lunch periods consumed 5.8% less of their entrees (P<0.001) and 4.5% less of their milk (P=0.047). Students with "late" lunch periods consumed 13.8% less of their entrees (P<0.001) and 15.9% less of their fruit (P<0.001). CONCLUSIONS: Reverse recess was associated with increased fruit consumption. "Early" lunch periods were associated with decreased entree and milk consumption, and "late" lunch periods were associated with decreased entree and fruit consumption. Additional research is recommended to determine whether these associations are causal. PMID- 28623164 TI - Thick corneas, large pupils, and a giant problem. AB - An 87-year-old woman presented 1 month after uneventful cataract surgery with ipsilateral corneal edema. She was diagnosed with pseudophakic bullous keratopathy and scheduled for endothelial transplantation. A few days later, however, she presented with bilateral corneal edema, dilated pupils, and further reduction of visual acuity. Neuro-ophthalmic evaluation disclosed a bilateral ocular ischemic syndrome causing complete visual loss. Temporal artery biopsy was consistent with giant cell arteritis. Corneal decompensation should be considered as a rare presentation of giant cell arteritis, a diagnosis that ophthalmologists should suspect in any case of unilateral or bilateral ocular ischemic syndrome. PMID- 28623165 TI - Ocular effects of Zika virus-a review. AB - Zika virus was considered an innocent pathogen while restricted to the African and Asian population; however, after reaching the Americas in March 2015, it became a global threat. Despite usually causing mild or no symptoms in infected adults, Zika virus displays a different behavior toward fetuses. When infected during gestation, fetuses have their immature neural cells killed by the virus and consequently have devastating findings at birth. In the past year the drastic effects of Zika virus infection in newborns include neurological, ophthalmological, audiological, and skeletal abnormalities. These findings represent a new entity called congenital Zika syndrome. We summarize the ocular findings of congenital Zika Syndrome, as well as the current understanding of the illness, systemic manifestations, laboratory investigation, differential diagnosis, prophylaxis, and treatment for this disorder. PMID- 28623167 TI - The ketogenic diet affects the social behavior of young male rats. AB - The positive effects of the ketogenic diet (KD) on social behavior have been recently reported in patients and rodent models of autism spectrum disorder (ASD). Given the beneficial effects of the KD on epilepsy, mitochondrial function, carbohydrate metabolism, and inflammation, treatment based on the KD has the potential to reduce some of the ASD-associated symptoms, including abnormal social interactions. It is not known whether the KD influences sociability by reducing the pathological processes underlying ASD or through some independent mechanism. The aim of the present study was to evaluate the influence of the KD on the social behavior of rats. Four-week-old Long-Evans males were treated with the KD for 4 subsequent weeks. Afterwards, behavioral tests were performed in order to evaluate sociability, locomotor activity, working memory, and anxiety-related behaviors. Additionally we performed the social interaction test in animals that were receiving beta-hydroxybutyrate or acetone. We have observed that rats fed with the KD showed increased social exploration in three different experimental settings. We did not observe any changes in the level of social interactions in animals treated with exogenous ketone bodies. The results did not show any difference in mobility or anxiety-related behaviors or working memory between the animals fed with the KD or standard rodent chow. In conclusion, we showed that the KD affects the social behavior of wild-type young adult male rats, which was not associated with other behavioral changes. PMID- 28623168 TI - Access to nicotine in drinking water reduces weight gain without changing caloric intake on high fat diet in male C57BL/6J mice. AB - Nicotine and tobacco use is associated with lower body weight, and many smokers report concerns about weight. In animal studies, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Previous studies have used standardized nicotine doses, however, in this study, male and female mice had free access to nicotine drinking water for 30 days while fed either a high fat diet (HFD) or chow, allowing animals to titrate their nicotine intake. In male mice, HFD increased body weight and caloric intake. Nicotine attenuated this effect and decreased weight gain per calorie consumed without affecting overall caloric intake or acute locomotion, suggesting metabolic changes. Nicotine did not decrease weight in chow-fed animals. In contrast, the same paradigm did not result in significant differences in weight gain in female animals, but did alter corticosterone levels and locomotion, indicating sex differences in the response to HFD and nicotine. We measured levels of mRNAs encoding nicotinic acetylcholine receptor subunits, uncoupling proteins (UCP) 1-3, and neuropeptides involved in energy balance in adipose tissues and the arcuate nucleus of the hypothalamus (ARC). HFD and nicotine regulated UCP levels in adipose tissues and ARC from female, but not male, mice. Regulation of agouti-related peptide, neuropeptide-Y, melanin-concentrating hormone, and cocaine- and amphetamine-regulated transcript in ARC varied with diet and nicotine in a sex-dependent manner. These data demonstrate that chronic consumption of nicotine moderates the effect of HFD in male mice by changing metabolism rather than food intake, and identify a differential effect on female mice. PMID- 28623166 TI - Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia. AB - Signaling networks that regulate cellular proliferation often involve complex interactions between several signaling pathways. In this manuscript we review the crosstalk between the Casein Kinase II (CK2) and Glycogen Synthase Kinase-3 (GSK 3) pathways that plays a critical role in the regulation of cellular proliferation in leukemia. Both CK2 and GSK-3 are potential targets for anti leukemia treatment. Previously published data suggest that CK2 and GSK-3 act synergistically to promote the phosphatidylinositol-3 kinase (PI3K) pathway via phosphorylation of PTEN. More recent data demonstrate another mechanism through which CK2 promotes the PI3K pathway - via transcriptional regulation of PI3K pathway genes by the newly-discovered CK2-Ikaros axis. Together, these data suggest that the CK2 and GSK-3 pathways regulate AKT/PI3K signaling in leukemia via two complementary mechanisms: a) direct phosphorylation of PTEN and b) transcriptional regulation of PI3K-promoting genes. Functional interactions between CK2, Ikaros and GSK3 define a novel signaling network that regulates proliferation of leukemia cells. This regulatory network involves both direct posttranslational modifications (by CK and GSK-3) and transcriptional regulation (via CK2-mediated phosphorylation of Ikaros). This information provides a basis for the development of targeted therapy for leukemia. PMID- 28623170 TI - Nicotinic acetylcholine receptor inhibitors derived from snake and snail venoms. AB - The nicotinic acetylcholine receptor (nAChR) represents the prototype of ligand gated ion channels. It is vital for neuromuscular transmission and an important regulator of neurotransmission. A variety of toxic compounds derived from diverse species target this receptor and have been of elemental importance in basic and applied research. They enabled milestone discoveries in pharmacology and biochemistry ranging from the original formulation of the receptor concept, the first isolation and structural analysis of a receptor protein (the nAChR) to the identification, localization, and differentiation of its diverse subtypes and their validation as a target for therapeutic intervention. Among the venom derived compounds, alpha-neurotoxins and alpha-conotoxins provide the largest families and still represent indispensable pharmacological tools. Application of modified alpha-neurotoxins provided substantial structural and functional details of the nAChR long before high resolution structures were available. alpha bungarotoxin represents not only a standard pharmacological tool and label in nAChR research but also for unrelated proteins tagged with a minimal alpha bungarotoxin binding motif. A major advantage of alpha-conotoxins is their smaller size, as well as superior selectivity for diverse nAChR subtypes that allows their development into ligands with optimized pharmacological and chemical properties and potentially novel drugs. In the following, these two groups of nAChR antagonists will be described focusing on their respective roles in the structural and functional characterization of nAChRs and their development into research tools. In addition, we provide a comparative overview of the diverse alpha-conotoxin selectivities that can serve as a practical guide for both structure activity studies and subtype classification. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.' PMID- 28623169 TI - Mutation of the inhibitory ethanol site in GABAA rho1 receptors promotes tolerance to ethanol-induced motor incoordination. AB - Genes encoding the rho1/2 subunits of GABAA receptors have been associated with alcohol (ethanol) dependence in humans, and rho1 was also shown to regulate some of the behavioral effects of ethanol in animal models. Ethanol inhibits GABA mediated responses in wild-type (WT) rho1, but not rho1(T6'Y) mutant receptors expressed in Xenopus laevis oocytes, indicating the presence of an inhibitory site for ethanol in the second transmembrane helix. In this study, we found that rho1(T6'Y) receptors expressed in oocytes display overall normal responses to GABA, the endogenous GABA modulator (zinc), and partial agonists (beta-alanine and taurine). We generated rho1 (T6'Y) knockin (KI) mice using CRISPR/Cas9 to test the behavioral importance of the inhibitory actions of ethanol on this receptor. Both rho1 KI and knockout (KO) mice showed faster recovery from acute ethanol-induced motor incoordination compared to WT mice. Both KI and KO mutant strains also showed increased tolerance to motor impairment produced by ethanol. The KI mice did not differ from WT mice in other behavioral actions, including ethanol intake and preference, conditioned taste aversion to ethanol, and duration of ethanol-induced loss of righting reflex. WT and KI mice did not differ in levels of rho1 or rho2 mRNA in cerebellum or in ethanol clearance. Our findings indicate that the inhibitory site for ethanol in GABAA rho1 receptors regulates acute functional tolerance to moderate ethanol intoxication. We note that low sensitivity to alcohol intoxication has been linked to risk for development of alcohol dependence in humans. PMID- 28623171 TI - Broad analgesic activity of a novel, selective M1 agonist. AB - Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors. However, upon introduction of a novel pharmacologic mechanism, it is prudent to ensure that no new off-target activities have arisen, particularly within the context of in vivo experiments. Reported here, is the in vitro and in vivo characterization of a novel M1 agonist tool compound, PPBI, and demonstrations that the primary biological effects of PPBI are mediated through M1. PPBI reverses d-amphetamine locomotor activity, but fails to do so in transgenic mice that do not express M1. PPBI also reverses a natural deficit in a rat cognition model at a level of exposure which also activates cortical circuitry. Most notably, PPBI is analgesic in a variety of rat and mouse models and the analgesic effect of PPBI is reversed by an M1-preferring antagonist and an M1-selective toxin. Finally, the pharmacokinetic/pharmacodynamic measures of PPBI are compared across multiple endpoints which highlights that activity in models of psychosis and pain require higher exposures than that required in the cognition model. PMID- 28623172 TI - The Armadillo Factor: Lepromatous Leprosy. PMID- 28623173 TI - Outcomes of Transcatheter and Surgical Aortic Valve Replacement in Patients on Maintenance Dialysis. AB - BACKGROUND: The introduction of transcatheter aortic valve replacement (TAVR) expanded definitive therapy of aortic stenosis to many high-risk patients, but it has not been fully evaluated in the dialysis population. We aimed to evaluate the current trend and in-hospital outcome of surgical aortic valve replacement (SAVR) and TAVR in the dialysis population. METHODS: Severe aortic stenosis patients on maintenance dialysis who underwent SAVR or TAVR in the Nationwide Inpatient Sample database from January 1, 2005, through December 31, 2014, were included in our comparative analysis. The trends of SAVR and TAVR were assessed. In-hospital mortality, rates of major adverse events, hospital length of stay, cost of care, and intermediate care facility utilization were compared between the 2 groups using both unadjusted and propensity-matched data. RESULTS: Utilization of aortic valve replacement in dialysis patients increased 3-fold; a total of 2531 dialysis patients who underwent either SAVR (n = 2264) or TAVR (n = 267) between 2005 and 2014 were identified. Propensity score matching yielded 197 matched pairs. After matching, a 2-fold increase in in-hospital mortality was found with SAVR compared with TAVR (13.7% vs 6.1%, P = .021). Patients who underwent TAVR had more permanent pacemaker implantation (13.2% vs 5.6%, P = .012) but less blood transfusion (43.7% vs 56.8%, P = .02). Rates of other key morbidities were similar. Hospital length of stay (19 +/- 16 vs 11 +/- 11 days, P <.001) and non home discharges (44.7% vs 31.5%, P = .002) were significantly higher with SAVR. Cost of hospitalization was 25% less with TAVR. CONCLUSION: In patients on maintenance dialysis, TAVR is associated with lower hospital mortality, resource utilization, and cost in comparison with SAVR. PMID- 28623174 TI - Sex Differences in the Management and 5-Year Outcome of Young Patients (<55 Years) with Acute Coronary Syndromes. AB - BACKGROUND: Young women are usually protected against coronary artery disease due to hormonal and risk-factor profile. Previous studies have suggested poorer outcome in women hospitalized with acute coronary syndrome as compared with men. However, when adjusted for age and other risk factors, this difference does not remain significant. We compared the risk profile and outcome between young (<=55 years) women and men admitted with acute coronary syndrome. METHODS: We analyzed clinical characteristics, management strategies, and outcomes of men and women <=55 years of age enrolled in the biennial Acute Coronary Syndrome Israeli Surveys between 2000 and 2013. RESULTS: Among 11,536 patients enrolled, 3949 (34%) were <=55 years old (407 women, 3542 men). Women were slightly older (48.9 +/- 5.7 vs 48.3 +/- 5.5, P = .007) and suffered more from diabetes (34% vs 24%) and hypertension (47% vs 37%, P <.001 for both). Rates of prior myocardial infarction were high in both sexes (18% vs 21%). Women presented less often with ST-elevation myocardial infarction (50% vs 57%, P = .007) and with typical chest pain (73% vs 80%, P = .004), and had higher rates of Global Registry of Acute Coronary Events (GRACE) score >=140 (19% vs 12%, P = .007). After adjustment for GRACE score, diabetes, and enrollment year, women had a lower likelihood to undergo coronary angiography during hospitalization (odds ratio 0.6, P = .007). Female sex was independently associated with higher risk of in-hospital mortality (hazard ratio [HR] 4.1; 95% confidence interval [CI], 1.15-14.0), 30-day major adverse cardiac and cerebral events (HR 2.1; 95% CI, 1.31-3.36), and 5-year mortality (HR 1.96; 95% CI, 1.3-2.8). CONCLUSIONS: Young women admitted with acute coronary syndrome are a unique high-risk group that presents a diagnostic challenge for clinicians. Women receive less invasive therapy during hospitalization and have worse in-hospital and long-term outcomes. PMID- 28623175 TI - Elevated High-Density Lipoprotein Cholesterol Is Associated with Hyponatremia in Hypertensive Patients. AB - BACKGROUND: Recently, the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive lowering of systolic blood pressure is beneficial, but is associated with more adverse events. Hyponatremia was notably more frequent in the intensive treatment group. Investigating its risk factors is crucial for preventing this complication. Our objective in this study was to identify risk factors for hyponatremia in the adult population. METHODS: We investigated the baseline demographic, clinical, and laboratory data from the 9361 participants of SPRINT to identify the best predictors of hyponatremia (serum sodium <=130 mEq/L), and adverse events, which could be attributed to hyponatremia, using machine learning and multivariable Cox proportional hazards models. We confirmed our results in the independent National Health and Nutrition Examination Survey (NHANES) cohort between the years 2005 and 2010 (16,501 participants). RESULTS: Elevated baseline high-density lipoprotein cholesterol (HDL-C) was a strong predictor of future hyponatremia. Multivariable Cox regression showed hyponatremia events to be significantly increased for SPRINT participants with baseline HDL-C levels in the highest quintile (hazard ratio [HR] 2.8; 95% confidence interval [CI], 2.2-3.7; P <.001), and were also associated with treatment-related serious adverse events (HR 1.6; 95% CI, 1.3-2.1; P <.001). We confirmed the association between HDL-C and hyponatremia in the NHANES cohort (HR 2.5; 95% CI, 1.7-3.7; P <.001). CONCLUSIONS: Elevated HDL-C (>=62 mg/dL) is a risk factor for hyponatremia. Thus, hypertensive patients with elevated HDL-C should be closely monitored for hyponatremia when treated for hypertension. PMID- 28623176 TI - Duration of Dual Antiplatelet Therapy in Patients with an Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention. AB - BACKGROUND: The recent American Heart Association/American College of Cardiology guidelines on duration of dual antiplatelet therapy (DAPT) recommend DAPT for 1 year in patients presenting with an acute coronary syndrome, with a Class IIb recommendation for continuation. We aim to assess the evidence for these recommendations using a meta-analytic approach. METHODS: We searched electronic databases for randomized trials comparing short-term (<=6 months) vs 12-month vs extended (>12 months) DAPT in patients with an acute coronary syndrome undergoing percutaneous coronary intervention. We evaluated all-cause mortality, cardiovascular mortality, myocardial infarction, stent thrombosis, and major bleeding. A random-effects model was used to calculate pooled relative risk (RR) and 95% confidence intervals (CI). RESULTS: We included 8 trials comprising 12,917 patients with an acute coronary syndrome; 5 trials compared short-term vs 12-month/extended DAPT, whereas 3 trials compared 12-month vs extended DAPT. There was no significant difference in cardiovascular mortality (RR 1.04; 95% CI, 0.67-1.60), myocardial infarction (RR 1.08; 95% CI, 0.79-1.47), or major bleeding (RR 0.91; 95% CI, 0.49-1.69) between short-term and 12-month/extended DAPT. However, compared with extended DAPT, 12-month DAPT showed significantly higher risk of myocardial infarction (RR 2.00; 95% CI, 1.47-2.73), but reduced risk of major bleeding (RR 0.58; 95% CI, 0.34-0.98). All-cause mortality was found to be similar between 12-month and extended DAPT. CONCLUSIONS: In acute coronary syndrome, short-term DAPT may be reasonable for some patients, whereas extended DAPT may be appropriate in select others. An individualized approach is needed, taking into account the competing risks of bleeding and ischemic events. PMID- 28623177 TI - Delay in Diagnosis of Celiac Disease in Patients Without Gastrointestinal Complaints. AB - PURPOSE: The purpose of our study is to investigate the delay in diagnosis of patients with biopsy-proven celiac disease in those who present with gastrointestinal complaints vs nongastrointestinal complaints at our tertiary care center. Celiac disease is an autoimmune disorder that affects approximately 1% of the population worldwide. Celiac disease can have variable clinical presentations; it can be characterized by predominately gastrointestinal symptoms, or it may present without any gastrointestinal symptoms. METHODS: We retrospectively reviewed the charts of 687 adult patients who carried the diagnosis of celiac disease. Patients included had biopsy-proven celiac disease and were categorized based on presence or absence of gastrointestinal symptoms prior to their diagnosis. RESULTS: There were 101 patients with biopsy-proven celiac disease that met inclusion criteria. Fifty-two patients presented with gastrointestinal symptoms and 49 had nongastrointestinal complaints. Results from Mann-Whitney statistical analysis showed a median delay in diagnosis of 2.3 months for the gastrointestinal symptoms group and 42 months for the nongastrointestinal group (P <.001); 43.2% of patients with nongastrointestinal symptoms had abnormal thyroid-stimulating hormone, as opposed to 15.5% in the gastrointestinal symptom group (P = .004). Of patients with nongastrointestinal symptoms, 69.4% had anemia, compared with 11.5% of the gastrointestinal symptom group (P <.001). The majority of patients in the nongastrointestinal symptom group, 68%, were noted to have abnormal bone density scans, compared with 41% in the gastrointestinal symptom group. No sex differences were noted on chi-squared analysis between the 2 groups (P = .997). CONCLUSIONS: Although there is growing awareness of celiac disease, the delay in diagnosis for patients without gastrointestinal symptoms remains prolonged, with an average delay of 3.5 years. PMID- 28623178 TI - Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation. AB - Ozone-induced systemic effects are modulated through activation of the neuro hormonal stress response pathway. Adrenal demedullation (DEMED) or bilateral total adrenalectomy (ADREX) inhibits systemic and pulmonary effects of acute ozone exposure. To understand the influence of adrenal-derived stress hormones in mediating ozone-induced lung injury/inflammation, we assessed global gene expression (mRNA sequencing) and selected proteins in lung tissues from male Wistar-Kyoto rats that underwent DEMED, ADREX, or sham surgery (SHAM) prior to their exposure to air or ozone (1ppm), 4h/day for 1 or 2days. Ozone exposure significantly changed the expression of over 2300 genes in lungs of SHAM rats, and these changes were markedly reduced in DEMED and ADREX rats. SHAM surgery but not DEMED or ADREX resulted in activation of multiple ozone-responsive pathways, including glucocorticoid, acute phase response, NRF2, and PI3K-AKT. Predicted targets from sequencing data showed a similarity between transcriptional changes induced by ozone and adrenergic and steroidal modulation of effects in SHAM but not ADREX rats. Ozone-induced increases in lung Il6 in SHAM rats coincided with neutrophilic inflammation, but were diminished in DEMED and ADREX rats. Although ozone exposure in SHAM rats did not significantly alter mRNA expression of Ifngamma and Il-4, the IL-4 protein and ratio of IL-4 to IFNgamma (IL-4/IFNgamma) proteins increased suggesting a tendency for a Th2 response. This did not occur in ADREX and DEMED rats. We demonstrate that ozone-induced lung injury and neutrophilic inflammation require the presence of circulating epinephrine and corticosterone, which transcriptionally regulates signaling mechanisms involved in this response. PMID- 28623179 TI - Modulation of TGF-beta/Smad and ERK signaling pathways mediates the anti-fibrotic effect of mirtazapine in mice. AB - Serotonin (5-HT) has been implicated as a key driver of liver fibrosis, acting via 5-HT2 receptor activation in the hepatic stellate cells. The current study was conducted to investigate the effects of mirtazapine, a 5-HT2A antagonist, in a mouse model of liver fibrosis. Mice received thioacetamide (TAA, 150mg/kg/biweekly, ip) for nine successive weeks for induction of liver fibrosis. Administration of mirtazapine significantly improved the plasma aminotransferases, reduced hepatic 5-HT concentration and ameliorated TAA-induced liver fibrosis, as demonstrated by reduced portal blood pressure, liver procollagen I content and alpha alpha smooth muscle actin expression. Moreover, hepatic collagen deposition was markedly decreased in mirtazapine-treated mice as evaluated by Masson's trichrome staining. Mirtazapine provided an antifibrotic environment by decreasing the liver content of transforming growth factor-beta1 (TGF-beta1), and protein kinase C as well as the expression of phosphorylated Smad3 (p-Smad) and phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2). Additionally, oxidative stress was largely mitigated by mirtazapine as manifested by decreased liver lipid peroxidation and NADPH oxidase 1 along with glutathione replenishment. The current study indicates that mirtazapine suppressed 5-HT-mediated TGF-beta1/Smad3 and ERK1/2 signaling pathways as well as oxidative stress that contribute to the progression of liver fibrosis. PMID- 28623180 TI - Behavioral screening of the LOPAC1280 library in zebrafish embryos. AB - Spontaneous activity represents an early, primitive form of motor activity within zebrafish embryos, providing a potential readout for identification of neuroactive compounds. However, despite use as an endpoint in chemical screens around the world, the predictive power and limitations of assays relying on spontaneous activity remain unclear. Using an improved high-content screening assay that increased throughput from 384 to 3072 wells per week, we screened a well-characterized library of 1280 pharmacologically active compounds (LOPAC1280) - 612 of which target neurotransmission - to identify which targets are detected using spontaneous activity as a readout. Results from this screen revealed that (1) 8% of the LOPAC1280 library was biologically active; (2) spontaneous activity was affected by compounds spanning a broad array of targets; (3) only 4% of compounds targeting neurotransmission impacted spontaneous activity; and (4) hypoactivity was observed for 100% of hits detected, including those that exhibit opposing mechanisms of action for the same target. Therefore, while this assay was able to rapidly identify potent neuroactive chemicals, these data suggest that spontaneous activity may lack the ability to discriminate modes of action for compounds interfering with neurotransmission, an issue that may be due to systemic uptake following waterborne exposure, persistent control variation, and/or interference with non-neurotransmission-related mechanisms. PMID- 28623181 TI - Allele-level HLA matching for umbilical cord blood transplantation for non malignant diseases in children: a retrospective analysis. AB - BACKGROUND: The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation. METHODS: We retrospectively studied 1199 paediatric donor recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model. FINDINGS: Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1.55, 95% CI 1.08-2.21, p=0.018), three (2.04, 1.44-2.89, p=0.0001), and four or more alleles (3.15, 2.16 4.58, p<0.0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1.18, 95% CI 0.80-1.72, p=0.39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1.40, 95% CI 1.13-1.74, p=0.0020), reduced intensity compared with myeloablative conditioning regimens (HR 1.36, 1.10-1.68, p=0.0041), transplantation of units with total nucleated cell dose of more than 21 * 107 cells per kg compared with 21 * 107 cells per kg or less (HR 1.47, 1.11-1.95, p=0.0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1.64, 1.31-2.04, p<0.0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality. INTERPRETATION: These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1. FUNDING: National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services Health Resources and Services Administration; and US Department of Navy. PMID- 28623182 TI - MyGeneFriends: A Social Network Linking Genes, Genetic Diseases, and Researchers. AB - BACKGROUND: The constant and massive increase of biological data offers unprecedented opportunities to decipher the function and evolution of genes and their roles in human diseases. However, the multiplicity of sources and flow of data mean that efficient access to useful information and knowledge production has become a major challenge. This challenge can be addressed by taking inspiration from Web 2.0 and particularly social networks, which are at the forefront of big data exploration and human-data interaction. OBJECTIVE: MyGeneFriends is a Web platform inspired by social networks, devoted to genetic disease analysis, and organized around three types of proactive agents: genes, humans, and genetic diseases. The aim of this study was to improve exploration and exploitation of biological, postgenomic era big data. METHODS: MyGeneFriends leverages conventions popularized by top social networks (Facebook, LinkedIn, etc), such as networks of friends, profile pages, friendship recommendations, affinity scores, news feeds, content recommendation, and data visualization. RESULTS: MyGeneFriends provides simple and intuitive interactions with data through evaluation and visualization of connections (friendships) between genes, humans, and diseases. The platform suggests new friends and publications and allows agents to follow the activity of their friends. It dynamically personalizes information depending on the user's specific interests and provides an efficient way to share information with collaborators. Furthermore, the user's behavior itself generates new information that constitutes an added value integrated in the network, which can be used to discover new connections between biological agents. CONCLUSIONS: We have developed MyGeneFriends, a Web platform leveraging conventions from popular social networks to redefine the relationship between humans and biological big data and improve human processing of biomedical data. MyGeneFriends is available at lbgi.fr/mygenefriends. PMID- 28623183 TI - Phone-Based Interventions in Adolescent Psychiatry: A Perspective and Proof of Concept Pilot Study With a Focus on Depression and Autism. AB - BACKGROUND: Telemedicine has emerged as an innovative platform to diagnose and treat psychiatric disorders in a cost-effective fashion. Previous studies have laid the functional framework for monitoring and treating child psychiatric disorders electronically using videoconferencing, mobile phones (smartphones), and Web-based apps. However, phone call and text message (short message service, SMS) interventions in adolescent psychiatry are less studied than other electronic platforms. Further investigations on the development of these interventions are needed. OBJECTIVE: The aim of this paper was to explore the utility of text message interventions in adolescent psychiatry and describe a user feedback-driven iterative design process for text message systems. METHODS: We developed automated text message interventions using a platform for both depression (EpxDepression) and autism spectrum disorder (ASD; EpxAutism) and conducted 2 pilot studies for each intervention (N=3 and N=6, respectively). The interventions were prescribed by and accessible to the patients' healthcare providers. EpxDepression and EpxAutism utilized an automated system to triage patients into 1 of 3 risk categories based on their text responses and alerted providers directly via phone and an online interface when patients met provider specified risk criteria. Rapid text-based feedback from participants and interviews with providers allowed for quick iterative cycles to improve interventions. RESULTS: Patients using EpxDepression had high weekly response rates (100% over 2 to 4 months), but exhibited message fatigue with daily prompts with mean (SD) overall response rates of 66.3% (21.6%) and 64.7% (8.2%) for mood and sleep questionnaires, respectively. In contrast, parents using EpxAutism displayed both high weekly and overall response rates (100% and 85%, respectively, over 1 to 4 months) that did not decay significantly with time. Monthly participant feedback surveys for EpxDepression (7 surveys) and EpxAutism (18 surveys) preliminarily indicated that for both interventions, daily messages constituted the "perfect amount" of contact and that EpxAutism, but not EpxDepression, improved patient communication with providers. Notably, EpxDepression detected thoughts of self-harm in patients before their case managers or caregivers were aware of such ideation. CONCLUSIONS: Text-message interventions in adolescent psychiatry can provide a cost-effective and engaging method to track symptoms, behavior, and ideation over time. Following the collection of pilot data and feedback from providers and patients, larger studies are already underway to validate the clinical utility of EpxDepression and EpxAutism. TRIAL REGISTRATION: Clinicaltrials.gov NCT03002311; https://clinicaltrials.gov/ct2/show/NCT03002311 (Archived by WebCite at http://www.webcitation.org/6qQtlCIS0). PMID- 28623184 TI - Scaling Up Psychological Treatments: A Countrywide Test of the Online Training of Therapists. AB - BACKGROUND: A major barrier to the widespread dissemination of psychological treatments is the way that therapists are trained. The current method is not scalable. OBJECTIVE: Our objective was to conduct a proof-of-concept study of Web centered training, a scalable online method for training therapists. METHODS: The Irish Health Service Executive identified mental health professionals across the country whom it wanted to be trained in a specific psychological treatment for eating disorders. These therapists were given access to a Web-centered training program in transdiagnostic cognitive behavior therapy for eating disorders. The training was accompanied by a scalable form of support consisting of brief encouraging telephone calls from a nonspecialist. The trainee therapists completed a validated measure of therapist competence before and after the training. RESULTS: Of 102 therapists who embarked upon the training program, 86 (84.3%) completed it. There was a substantial increase in their competence scores following the training (mean difference 5.84, 95% Cl -6.62 to -5.05; P<.001) with 42.5% (34/80) scoring above a predetermined cut-point indicative of a good level of competence. CONCLUSIONS: Web-centered training proved feasible and acceptable and resulted in a marked increase in therapist competence scores. If these findings are replicated, Web-centered training would provide a means of simultaneously training large numbers of geographically dispersed trainees at low cost, thereby overcoming a major obstacle to the widespread dissemination of psychological treatments. PMID- 28623185 TI - A Web-Based Data Collection Platform for Multisite Randomized Behavioral Intervention Trials: Development, Key Software Features, and Results of a User Survey. AB - BACKGROUND: Meticulous tracking of study data must begin early in the study recruitment phase and must account for regulatory compliance, minimize missing data, and provide high information integrity and/or reduction of errors. In behavioral intervention trials, participants typically complete several study procedures at different time points. Among HIV-infected patients, behavioral interventions can favorably affect health outcomes. In order to empower newly diagnosed HIV positive individuals to learn skills to enhance retention in HIV care, we developed the behavioral health intervention Integrating ENGagement and Adherence Goals upon Entry (iENGAGE) funded by the National Institute of Allergy and Infectious Diseases (NIAID), where we deployed an in-clinic behavioral health intervention in 4 urban HIV outpatient clinics in the United States. To scale our intervention strategy homogenously across sites, we developed software that would function as a behavioral sciences research platform. OBJECTIVE: This manuscript aimed to: (1) describe the design and implementation of a Web-based software application to facilitate deployment of a multisite behavioral science intervention; and (2) report on results of a survey to capture end-user perspectives of the impact of this platform on the conduct of a behavioral intervention trial. METHODS: In order to support the implementation of the NIAID funded trial iENGAGE, we developed software to deploy a 4-site behavioral intervention for new clinic patients with HIV/AIDS. We integrated the study coordinator into the informatics team to participate in the software development process. Here, we report the key software features and the results of the 25-item survey to evaluate user perspectives on research and intervention activities specific to the iENGAGE trial (N=13). RESULTS: The key features addressed are study enrollment, participant randomization, real-time data collection, facilitation of longitudinal workflow, reporting, and reusability. We found 100% user agreement (13/13) that participation in the database design and/or testing phase made it easier to understand user roles and responsibilities and recommended participation of research teams in developing databases for future studies. Users acknowledged ease of use, color flags, longitudinal work flow, and data storage in one location as the most useful features of the software platform and issues related to saving participant forms, security restrictions, and worklist layout as least useful features. CONCLUSIONS: The successful development of the iENGAGE behavioral science research platform validated an approach of early and continuous involvement of the study team in design development. In addition, we recommend post-hoc collection of data from users as this led to important insights on how to enhance future software and inform standard clinical practices. TRIAL REGISTRATION: Clinicaltrials.gov NCT01900236; (https://clinicaltrials.gov/ct2/show/NCT01900236 (Archived by WebCite at http://www.webcitation.org/6qAa8ld7v). PMID- 28623186 TI - Assessment of Active Video Gaming Using Adapted Controllers by Individuals With Physical Disabilities: A Protocol. AB - BACKGROUND: Individuals with disabilities are typically more sedentary and less fit compared to their peers without disabilities. Furthermore, engaging in physical activity can be extremely challenging due to physical impairments associated with disability and fewer opportunities to participate. One option for increasing physical activity is playing active video games (AVG), a category of video games that requires much more body movement for successful play than conventional push-button or joystick actions. However, many current AVGs are inaccessible or offer limited play options for individuals who are unable to stand, have balance issues, poor motor control, or cannot use their lower body to perform game activities. Making AVGs accessible to people with disabilities offers an innovative approach to overcoming various barriers to participation in physical activity. OBJECTIVE: Our aim was to compare the effect of off-the-shelf and adapted game controllers on quality of game play, enjoyment, and energy expenditure during active video gaming in persons with physical disabilities, specifically those with mobility impairments (ie, unable to stand, balance issues, poor motor control, unable to use lower extremity for gameplay). The gaming controllers to be evaluated include off-the-shelf and adapted versions of the Wii Fit balance board and gaming mat. METHODS: Participants (10-60 years old) came to the laboratory a total of three times. During the first visit, participants completed a functional assessment and became familiar with the equipment and games to be played. For the functional assessment, participants performed 18 functional movement tasks from the International Classification of Functioning, Disability, and Health. They also answered a series of questions from the Patient Reported Outcomes Measurement Information System and Quality of Life in Neurological Conditions measurement tools, to provide a personal perspective regarding their own functional ability. For Visit 2, metabolic data were collected during an initial 20-minute baseline, followed by 40 minutes of game play. The controller (balance board or gaming mat) played was randomly selected. A set of games was played for 10 minutes, followed by 5 minutes of rest, and then another set of games was played for 10 minutes, followed by rest. Quality of game play was observed and documented for each set. During rest, the participant completed questions regarding enjoyment. Following the same procedures, the participant then played the two sets of games using the other version (off-the-shelf or adapted) of the controller. The entire procedure was repeated during Visit 3 with the controller that was not played. RESULTS: Enrollment began in February 2016 and ended in September 2016. Study results will be reported in late 2017. CONCLUSIONS: We hypothesized that the adapted versions of the Wii Fit balance board and gaming mat would produce greater quality of game play, enjoyment, and energy expenditure in persons with mobility impairments compared to off-the-shelf versions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02994199; https://clinicaltrials.gov/ct2/show/NCT02994199 (Archived by WebCite at http://www.webcitation.org/6qpPszPJ7). PMID- 28623189 TI - The "Anthropocene": neglects, misconceptions, and possible futures: The term "Anthropocene" is often erroneously used, as it is not formally defined yet. PMID- 28623188 TI - Gli1-induced deubiquitinase USP48 aids glioblastoma tumorigenesis by stabilizing Gli1. AB - Aberrant activation of the Hedgehog (Hh) signaling pathway drives the tumorigenesis of multiple cancers. In this study, we screened a panel of deubiquitinases that may regulate the Hh pathway. We find that deubiquitinase USP48 activates Gli-dependent transcription by stabilizing Gli1 protein. Mechanistically, USP48 interacts with Gli1 and cleaves its ubiquitin off directly. In glioblastoma cells, knockdown of USP48 inhibits cell proliferation and the expression of Gli1's downstream targets, which leads to repressed glioblastoma tumorigenesis. Importantly, USP48's effect on cell proliferation and tumorigenesis depends to some extent on Gli1. In addition, we find that the Sonic Hedgehog (SHH) pathway induces USP48 expression through Gli1-mediated transcriptional activation, which forms thus a positive feedback loop to regulate Hh signaling. In human glioblastoma specimens, the expression levels of USP48 and Gli1 proteins are clinically relevant, and high expression of USP48 correlates with glioma malignancy. In summary, our study reveals that the USP48-Gli1 regulatory axis is critical for glioma cell proliferation and glioblastoma tumorigenesis. PMID- 28623187 TI - Control of box C/D snoRNP assembly by N6-methylation of adenine. AB - N6-methyladenine is the most widespread mRNA modification. A subset of human box C/D snoRNA species have target GAC sequences that lead to formation of N6 methyladenine at a key trans Hoogsteen-sugar A.G base pair, of which half are methylated in vivo The GAC target is conserved only in those that are methylated. Methylation prevents binding of the 15.5-kDa protein and the induced folding of the RNA Thus, the assembly of the box C/D snoRNP could in principle be regulated by RNA methylation at its critical first stage. Crystallography reveals that N6 methylation of adenine prevents the formation of trans Hoogsteen-sugar A.G base pairs, explaining why the box C/D RNA cannot adopt its kinked conformation. More generally, our data indicate that sheared A.G base pairs (but not Watson-Crick base pairs) are more susceptible to disruption by N6mA methylation and are therefore possible regulatory sites. The human signal recognition particle RNA and many related Alu retrotransposon RNA species are also methylated at N6 of an adenine that forms a sheared base pair with guanine and mediates a key tertiary interaction. PMID- 28623190 TI - Primary tuberculosis of cystic duct lymph node. AB - Tuberculosis (TC) is very common and significant cause of morbidity and mortality worldwide. Isolated cystic duct lymph node TC cases without involvement of gallbladder are exceedingly rare. It is difficult to diagnose preoperatively because of lack of characteristic signs and symptoms of TC. We report a man aged 45 years who presented with right upper abdominal pain since 1week. It was associated with nausea and postprandial fullness. There was no evidence of jaundice and lymphadenopathy. Abdominal examination showed moderate right upper quadrant tenderness with positive Murphy's sign and splenomegaly but no signs of peritonism. Abdomen ultrasound revealed sludge in gallbladder, dilated pancreatic duct, coarse exotexture of liver, splenomegaly and no lymphadenopathy. He underwent laparoscopic cholecystectomy; histological report showed chronic caseating granulomatous lymphadenitis with Langhans type of giant cells in lymph node near cystic duct with chronic cholecystitis of gallbladder. Standard antituberculosis therapy was given for 12 months. PMID- 28623191 TI - Renal capillary haemangioma associated with renal cell carcinoma and polycythaemia in acquired cystic disease. AB - Capillary haemangiomas are relatively common tumours, typically occurring in the subcutaneous tissue during childhood. However, visceral occurrence is very rare. These tumours make up a subset of vascular lesions that have previously, although rarely, been described in case reports in association with the kidney. Here we review the literature and describe a capillary haemangioma occurring in the renal hilum found to be coexistent with end-stage renal disease, renal cell carcinoma and polycythaemia. To our knowledge, this is the first case report to describe the occurrence of this tumour in the renal hilum in association with this constitution of renal pathologies. PMID- 28623193 TI - Hunt will ask chancellor to consider lifting NHS pay cap. PMID- 28623192 TI - Ultrasound B scan: a simple tool to simplify the diagnosis. PMID- 28623194 TI - Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3zeta-binding sites reveals key differences between MAP2c and its homolog Tau. PMID- 28623195 TI - Cytokine-induced paracrystals prolong the activity of signal transducers and activators of transcription (STAT) and provide a model for the regulation of protein solubility by small ubiquitin-like modifier (SUMO). PMID- 28623196 TI - Origin single-stranded DNA releases Sld3 protein from the Mcm2-7 complex, allowing the GINS tetramer to bind the Mcm2-7 complex. PMID- 28623197 TI - The replication initiation protein Sld3/Treslin orchestrates the assembly of the replication fork helicase during S phase. PMID- 28623201 TI - Scotland takes a step closer to reversing its tail docking ban. PMID- 28623198 TI - The Dbf4-Cdc7 kinase promotes Mcm2-7 ring opening to allow for single-stranded DNA extrusion and helicase assembly. PMID- 28623202 TI - Gove becomes environment secretary. PMID- 28623204 TI - Are hunting dogs spreading bovine TB? PMID- 28623206 TI - Animal establishments: what might the new licensing legislation look like? PMID- 28623209 TI - Five dogs stolen each day in the UK, with Staffies the most stolen breed. PMID- 28623207 TI - 'It's now time to make CCTV in abattoirs compulsory'. PMID- 28623213 TI - Is marbofloxacin a good candidate for treating pigs in Europe? PMID- 28623217 TI - Official controls in slaughterhouses. PMID- 28623218 TI - Official controls in slaughterhouses. PMID- 28623220 TI - Engagement between vets and sheep farmers. PMID- 28623221 TI - Holly leaf ingestion causing pharyngeal obstruction in lambs. PMID- 28623223 TI - Inspired by the Army. AB - Claire Scott likes to meet people with similar interests - people who like keeping fit, being outside and laughing loudly. Being an Army Reservist offers her this chance. PMID- 28623222 TI - Colin Berkeley Bewsher. AB - A mixed practitioner who enjoyed many sports. An 'inspirational, supportive and caring boss', and described by friends as a true gentleman. PMID- 28623224 TI - Ten-minute chat. AB - Claire explains more about what being an Army Reservist means. PMID- 28623225 TI - High peripheral temperatures in king penguins while resting at sea: thermoregulation versus fat deposition. AB - Marine endotherms living in cold water face an energetically challenging situation. Unless properly insulated, these animals will lose heat rapidly. The field metabolic rate of king penguins at sea is about twice that on land. However, when at sea, their metabolic rate is higher during extended resting periods at the surface than during foraging, when birds descend to great depth in pursuit of their prey. This is most likely explained by differences in thermal status. During foraging, peripheral vasoconstriction leads to a hypothermic shell, which is rewarmed during extended resting bouts at the surface. Maintaining peripheral perfusion during rest in cold water, however, will greatly increase heat loss and, therefore, thermoregulatory costs. Two hypotheses have been proposed to explain the maintenance of a normothermic shell during surface rest: (1) to help the unloading of N2 accumulated during diving; and (2) to allow the storage of fat in subcutaneous tissue, following the digestion of food. We tested the latter hypothesis by maintaining king penguins within a shallow seawater tank, while we recorded tissue temperature at four distinct sites. When king penguins were released into the tank during the day, their body temperature immediately declined. However, during the night, periodic rewarming of abdominal and peripheral tissues occurred, mimicking temperature patterns observed in the wild. Body temperatures, particularly in the flank, also depended on body condition and were higher in 'lean' birds (after 10 days of fasting) than in 'fat' birds. While not explicitly tested, our observation that nocturnal rewarming persists in the absence of diving activity during the day does not support the N2 unloading hypothesis. Rather, differences in temperature changes throughout the day and night, and the effect of body condition/mass supports the hypothesis that tissue perfusion during rest is required for nutritional needs. PMID- 28623227 TI - Our job. PMID- 28623226 TI - Entraining to the polar day: circadian rhythms in arctic ground squirrels. AB - Circadian systems are principally entrained to 24 h light-dark cycles, but this cue is seasonally absent in polar environments. Although some resident polar vertebrates have weak circadian clocks and are seasonally arrhythmic, the arctic ground squirrel (AGS) maintains daily rhythms of physiology and behavior throughout the summer, which includes 6 weeks of constant daylight. Here, we show that persistent daily rhythms in AGS are maintained through a circadian system that readily entrains to the polar day yet remains insensitive to entrainment by rapid light-dark transitions, which AGS generate naturally as a consequence of their semi-fossorial behavior. Additionally, AGS do not show 'jet lag', the slow realignment of circadian rhythms induced by the inertia of an intrinsically stable master circadian clock in the suprachiasmatic nucleus (SCN). We suggest this is due to the low expression of arginine vasopressin in the SCN of AGS, as vasopressin is associated with inter-neuronal coupling and robust rhythmicity. PMID- 28623228 TI - Half of salaried and locum GPs are stressed, BMA survey finds. PMID- 28623229 TI - Zebrafish Znfl1 proteins control the expression of hoxb1b gene in the posterior neuroectoderm by acting upstream of pou5f3 and sall4 genes. AB - Transcription factors play crucial roles in patterning posterior neuroectoderm. Previously, zinc finger transcription factor znfl1 was reported to be expressed in the posterior neuroectoderm of zebrafish embryos. However, its roles remain unknown. Here, we report that there are 13 copies of znfl1 in the zebrafish genome, and all the paralogues share highly identical protein sequences and cDNA sequences. When znfl1s are knocked down using a morpholino to inhibit their translation or dCas9-Eve to inhibit their transcription, the zebrafish gastrula displays reduced expression of hoxb1b, the marker gene for the posterior neuroectoderm. Further analyses reveal that diminishing znfl1s produces the decreased expressions of pou5f3, whereas overexpression of pou5f3 effectively rescues the reduced expression of hoxb1b in the posterior neuroectoderm. Additionally, knocking down znfl1s causes the reduced expression of sall4, a direct regulator of pou5f3, in the posterior neuroectoderm, and overexpression of sall4 rescues the expression of pou5f3 in the knockdown embryos. In contrast, knocking down either pou5f3 or sall4 does not affect the expressions of znfl1s Taken together, our results demonstrate that zebrafish znfl1s control the expression of hoxb1b in the posterior neuroectoderm by acting upstream of pou5f3 and sall4. PMID- 28623230 TI - Flexible-body motions of calmodulin and the farnesylated hypervariable region yield a high-affinity interaction enabling K-Ras4B membrane extraction. AB - In calmodulin (CaM)-rich environments, oncogenic KRAS plays a critical role in adenocarcinomas by promoting PI3K/Akt signaling. We previously proposed that at elevated calcium levels in cancer, CaM recruits PI3Kalpha to the membrane and extracts K-Ras4B from the membrane, organizing a K-Ras4B-CaM-PI3Kalpha ternary complex. CaM can thereby replace a missing receptor-tyrosine kinase signal to fully activate PI3Kalpha. Recent experimental data show that CaM selectively promotes K-Ras signaling but not of N-Ras or H-Ras. How CaM specifically targets K-Ras and how it extracts it from the membrane in KRAS-driven cancer is unclear. Obtaining detailed structural information for a CaM-K-Ras complex is still challenging. Here, using molecular dynamics simulations and fluorescence experiments, we observed that CaM preferentially binds unfolded K-Ras4B hypervariable regions (HVRs) and not alpha-helical HVRs. The interaction involved all three CaM domains including the central linker and both lobes. CaM specifically targeted the highly polybasic anchor region of the K-Ras4B HVR that stably wraps around CaM's acidic linker. The docking of the farnesyl group to the hydrophobic pockets located at both CaM lobes further enhanced CaM-HVR complex stability. Both CaM and K-Ras4B HVR are highly flexible molecules, suggesting that their interactions permit highly dynamic flexible-body motions. We, therefore, anticipate that the flexible-body interaction is required to extract K Ras4B from the membrane, as conformational plasticity enables CaM to orient efficiently to the polybasic HVR anchor, which is partially diffused into the liquid-phase membrane. Our structural model of the CaM-K-Ras4B HVR association provides plausible clues to CaM's regulatory action in PI3Kalpha activation involving the ternary complex in cell proliferation signaling by oncogenic K-Ras. PMID- 28623231 TI - Cry6Aa1, a Bacillus thuringiensis nematocidal and insecticidal toxin, forms pores in planar lipid bilayers at extremely low concentrations and without the need of proteolytic processing. AB - Cry6Aa1 is a Bacillus thuringiensis (Bt) toxin active against nematodes and corn rootworm insects. Its 3D molecular structure, which has been recently elucidated, is unique among those known for other Bt toxins. Typical three-domain Bt toxins permeabilize receptor-free planar lipid bilayers (PLBs) by forming pores at doses in the 1-50 MUg/ml range. Solubilization and proteolytic activation are necessary steps for PLB permeabilization. In contrast to other Bt toxins, Cry6Aa1 formed pores in receptor-free bilayers at doses as low as 200 pg/ml in a wide range of pH (5.5-9.5) and without the need of protease treatment. When Cry6Aa1 was preincubated with Western corn rootworm (WCRW) midgut juice or trypsin, 100 fg/ml of the toxin was sufficient to form pores in PLBs. The overall biophysical properties of the pores were similar for all three forms of the toxin (native, midgut juice- and trypsin-treated), with conductances ranging from 28 to 689 pS, except for their ionic selectivity, which was slightly cationic for the native and midgut juice-treated Cry6Aa1, whereas dual selectivity (to cations or anions) was observed for the pores formed by the trypsin-treated toxin. Enrichment of PLBs with WCRW midgut brush-border membrane material resulted in a 2000-fold reduction of the amount of native Cry6Aa1 required to form pores and affected the biophysical properties of both the native and trypsin-treated forms of the toxin. These results indicate that, although Cry6Aa1 forms pores, the molecular determinants of its mode of action are significantly different from those reported for other Bt toxins. PMID- 28623232 TI - The RING finger- and PDZ domain-containing protein PDZRN3 controls localization of the Mg2+ regulator claudin-16 in renal tube epithelial cells. AB - Ion exchange in the renal tubules is fundamental to the maintenance of physiological ion levels. Claudin-16 (CLDN16) regulates the paracellular reabsorption of Mg2+ in the thick ascending limb of Henle's loop in the kidney, with dephosphorylation of CLDN16 increasing its intracellular distribution and decreasing paracellular Mg2+ permeability. CLDN16 is located in the tight junctions, but the mechanism regulating its localization is unclear. Using yeast two-hybrid systems, we found that CLDN16 binds to PDZRN3, a protein containing both RING-finger and PDZ domains. We also observed that the carboxyl terminus of the cytoplasmic CLDN16 region was required for PDZRN3 binding. PZDRN3 was mainly distributed in the cytosol of rat kidney cells and upon cell treatment with the protein kinase A inhibitor H-89, colocalized with CLDN16. H-89 also increased mono-ubiquitination and the association of CLDN16 with PDZRN3. Mono ubiquitination levels of a K275A mutant were lower, and its association with PDZRN3 was reduced compared with wild-type (WT) CLDN16 and a K261A mutant, indicating that Lys-275 is the major ubiquitination site. An S217A mutant, a dephosphorylated form of CLDN16, localized to the cytosol along with PDZRN3 and the endosomal marker Rab7. PDZRN3 siRNA increased cell-surface localization of WT CLDN16 in H-89-treated cells or containing the S217A mutant and also suppressed CLDN16 endocytosis. Of note, H-89 decreased paracellular Mg2+ flux in WT CLDN16 cells, and PDZRN3 siRNA increased Mg2+ flux in the H-89-treated WT CLDN16 and S217A mutant cells. These results suggest that PDZRN3 mediates endocytosis of dephosphorylated CLDN16 and represents an important component of the CLDN16 trafficking machinery in the kidney. PMID- 28623233 TI - Structural and functional analyses of pyroglutamate-amyloid-beta-specific antibodies as a basis for Alzheimer immunotherapy. AB - Alzheimer disease is associated with deposition of the amyloidogenic peptide Abeta in the brain. Passive immunization using Abeta-specific antibodies has been demonstrated to reduce amyloid deposition both in vitro and in vivo Because N terminally truncated pyroglutamate (pE)-modified Abeta species (AbetapE3) exhibit enhanced aggregation potential and propensity to form toxic oligomers, they represent particularly attractive targets for antibody therapy. Here we present three separate monoclonal antibodies that specifically recognize AbetapE3 with affinities of 1-10 nm and inhibit AbetapE3 fibril formation in vitro. In vivo application of one of these resulted in improved memory in AbetapE3 oligomer treated mice. Crystal structures of Fab-AbetapE3 complexes revealed two distinct binding modes for the peptide. Juxtaposition of pyroglutamate pE3 and the F4 side chain (the "pEF head") confers a pronounced bulky hydrophobic nature to the AbetapE3 N terminus that might explain the enhanced aggregation properties of the modified peptide. The deep burial of the pEF head by two of the antibodies explains their high target specificity and low cross-reactivity, making them promising candidates for the development of clinical antibodies. PMID- 28623235 TI - Jeffrey Tate. PMID- 28623236 TI - Authors' reply to Rishniw. PMID- 28623234 TI - A ciliary opsin in the brain of a marine annelid zooplankton is ultraviolet sensitive, and the sensitivity is tuned by a single amino acid residue. AB - Ciliary opsins were classically thought to function only in vertebrates for vision, but they have also been identified recently in invertebrates for non visual photoreception. Larvae of the annelid Platynereis dumerilii are used as a zooplankton model, and this zooplankton species possesses a "vertebrate-type" ciliary opsin (named c-opsin) in the brain. Platynereis c-opsin is suggested to relay light signals for melatonin production and circadian behaviors. Thus, the spectral and biochemical characteristics of this c-opsin would be directly related to non-visual photoreception in this zooplankton model. Here we demonstrate that the c-opsin can sense UV to activate intracellular signaling cascades and that it can directly bind exogenous all-trans-retinal. These results suggest that this c-opsin regulates circadian signaling in a UV-dependent manner and that it does not require a supply of 11-cis-retinal for photoreception. Avoidance of damaging UV irradiation is a major cause of large-scale daily zooplankton movement, and the observed capability of the c-opsin to transmit UV signals and bind all-trans-retinal is ideally suited for sensing UV radiation in the brain, which presumably lacks enzymes producing 11-cis-retinal. Mutagenesis analyses indicated that a unique amino acid residue (Lys-94) is responsible for c opsin-mediated UV sensing in the Platynereis brain. We therefore propose that acquisition of the lysine residue in the c-opsin would be a critical event in the evolution of Platynereis to enable detection of ambient UV light. In summary, our findings indicate that the c-opsin possesses spectral and biochemical properties suitable for UV sensing by the zooplankton model. PMID- 28623237 TI - NICE approves trastuzumab emtansine after deal with drug company. PMID- 28623238 TI - A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms. AB - Matrix metalloproteinase 9 (MMP-9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype-based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Gottingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP-9 rs20544 C/T single nucleotide polymorphism (SNP) located in the 3'untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP-9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP-9 3'UTR We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP-9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis-related locomotor hyperactivity in Mmp 9 heterozygous mice. We propose a novel mechanism that involves MMP-9-dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP-9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients. PMID- 28623239 TI - (CCUG)n RNA toxicity in a Drosophila model of myotonic dystrophy type 2 (DM2) activates apoptosis. AB - The myotonic dystrophies are prototypic toxic RNA gain-of-function diseases. Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are caused by different unstable, noncoding microsatellite repeat expansions - (CTG)DM1 in DMPK and (CCTG)DM2 in CNBP Although transcription of mutant repeats into (CUG)DM1 or (CCUG)DM2 appears to be necessary and sufficient to cause disease, their pathomechanisms remain incompletely understood. To study the mechanisms of (CCUG)DM2 toxicity and develop a convenient model for drug screening, we generated a transgenic DM2 model in the fruit fly Drosophila melanogaster with (CCUG)n repeats of variable length (n=16 and 106). Expression of noncoding (CCUG)106, but not (CCUG)16, in muscle and retinal cells led to the formation of ribonuclear foci and mis-splicing of genes implicated in DM pathology. Mis splicing could be rescued by co-expression of human MBNL1, but not by CUGBP1 (CELF1) complementation. Flies with (CCUG)106 displayed strong disruption of external eye morphology and of the underlying retina. Furthermore, expression of (CCUG)106 in developing retinae caused a strong apoptotic response. Inhibition of apoptosis rescued the retinal disruption in (CCUG)106 flies. Finally, we tested two chemical compounds that have shown therapeutic potential in DM1 models. Whereas treatment of (CCUG)106 flies with pentamidine had no effect, treatment with a PKR inhibitor blocked both the formation of RNA foci and apoptosis in retinae of (CCUG)106 flies. Our data indicate that expression of expanded (CCUG)DM2 repeats is toxic, causing inappropriate cell death in affected fly eyes. Our Drosophila DM2 model might provide a convenient tool for in vivo drug screening. PMID- 28623241 TI - Suppressing mTORC1 on the lysosome. PMID- 28623242 TI - OH MYeloid! Immune cells wreaking havoc on brain homeostasis. PMID- 28623243 TI - Metaplastic breast carcinoma with chondroid differentiation: a rare variant of infiltrative carcinoma in a 38-year-old woman. AB - Metaplastic breast carcinoma (MBC) is a rare type of invasive breast carcinoma, and chondroid differentiation is even rarer. Here we report a case of MBC with extensive chondroid differentiation in a 38-year-old woman who presented with a lump in her left breast. Ultrasound findings were most compatible with those of giant fibroadenoma. A histopathological examination revealed a malignant lesion comprising neoplastic epithelial cells arranged in solid nests, with large areas of chondroid differentiation. Neoplastic chondroid cells exhibited a positive reaction for S-100, patchy positive reaction for pan-cytokeratin (AE1/AE3) and negative reaction for epithelial membrane antigen. Both carcinomatous and chondroid cells exhibited p53 overexpression. Sentinel lymph node biopsy revealed no tumorous involvement. PMID- 28623240 TI - Adipose tissue: between the extremes. AB - Adipose tissue represents a critical component in healthy energy homeostasis. It fulfills important roles in whole-body lipid handling, serves as the body's major energy storage compartment and insulation barrier, and secretes numerous endocrine mediators such as adipokines or lipokines. As a consequence, dysfunction of these processes in adipose tissue compartments is tightly linked to severe metabolic disorders, including obesity, metabolic syndrome, lipodystrophy, and cachexia. While numerous studies have addressed causes and consequences of obesity-related adipose tissue hypertrophy and hyperplasia for health, critical pathways and mechanisms in (involuntary) adipose tissue loss as well as its systemic metabolic consequences are far less understood. In this review, we discuss the current understanding of conditions of adipose tissue wasting and review microenvironmental determinants of adipocyte (dys)function in related pathophysiologies. PMID- 28623244 TI - It's a cod! Finding Nemo (impacted fishbone) in the emergency department. AB - A 23-year-old woman presented to the emergency department (ED) with a sensation of a 'fish bone' stuck in her throat after eating cod. On physical examination, while she reported an uncomfortable sensation in her throat, no airway compromise was evident. Clinical examination, including ear, nose and throat (ENT) and oropharyngeal assessment, was unremarkable. A linear opacity consistent with a fishbone was visualised on a soft tissue lateral neck X-ray anterior to the vertebral body of C4-6. One attempt to visualise the fishbone on direct laryngoscopy failed in the ED. The fishbone was later removed the next day via direct visualisation with a flexible endoscope in the operating theatre by the ENT surgical team. The patient's recovery was uneventful. PMID- 28623245 TI - "Perception v production" of asparagus odour in urine needs to be determined in a controlled study. PMID- 28623248 TI - Dieulafoy's Lesion of the Anal Canal: A Rare Cause of Lower Gastrointestinal Bleeding. AB - BACKGROUND Dieulafoy's lesion of the anal canal is an uncommon cause of lower gastrointestinal bleeding due to rupture of a submucosal artery. This could be an under-recognized cause of hemorrhagic shock in rare cases. CASE REPORT We present 2 cases admitted with bleeding per rectum and hemorrhagic shock, and both were diagnosed as Dieulafoy's lesion of the anal canal on sigmoidoscopy. One case was treated surgically and the second was managed endoscopically. CONCLUSIONS Dieulafoy's lesion of the anal canal can be a source of massive lower gastrointestinal bleeding. Initial anoscopy or sigmoidoscopy might miss such a lesion. Proper visualization helps not only the diagnosis, but also the provision of therapeutic intervention in the same setting. PMID- 28623247 TI - Evaluation of Serological Indicators and Glomerular Filtration Rate Equations in Chinese Cancer Patients. AB - BACKGROUND The performance of estimated glomerular filtration rate (eGFR) have been proved to vary according to the races of the target population. The eGFR equations have not been validated in the Chinese cancer population received chemotherapy. Meanwhile, serum cystatin C (CysC), urea, beta2 microglobulin (beta2-MG), and creatinine (SCr) were also evaluated in a cohort of Chinese cancer patients. MATERIAL AND METHODS A total of 1000 cancer patients undergoing combination chemotherapy and 108 healthy volunteers were included in this study, and their renal function parameters were evaluated. The eGFR values were compared with reference GFR (rGFR) according to correlation, consistency, precision, and accuracy. Receiver operating characteristic (ROC) curves were used to evaluate the discriminating ability of the GFR equations and serological indicators of renal function. RESULTS (1) The equations contained CysC had the same varying tendency as rGFR in relation to the chemotherapeutic cycle. (2) eGFRscr+cysc and eGFRChinese scr+cysc worked better than the other equations, as indicated by a stronger correlation, less bias, improved precision, higher accuracy, and greater AUC. (3) CysC was more sensitive than the other serological indicators for identifying early renal injury. (4) Each parameter showed different characteristics in subgroups of Chinese cancer patients. CONCLUSIONS CysC was the most sensitive marker for early renal injury. Among the 8 most commonly used eGFR equations, the combination equation eGFRscr+cysc and eGFRChinese scr+cysc exhibited the best performance in the assessment of the renal function of Chinese cancer patients. PMID- 28623249 TI - Sequential self-assembly of DNA functionalized droplets. AB - Complex structures and devices, both natural and manmade, are often constructed sequentially. From crystallization to embryogenesis, a nucleus or seed is formed and built upon. Sequential assembly allows for initiation, signaling, and logical programming, which are necessary for making enclosed, hierarchical structures. Although biology relies on such schemes, they have not been available in materials science. Here, we demonstrate programmed sequential self-assembly of DNA functionalized emulsions. The droplets are initially inert because the grafted DNA strands are pre-hybridized in pairs. Active strands on initiator droplets then displace one of the paired strands and thus release its complement, which in turn activates the next droplet in the sequence, akin to living polymerization. Our strategy provides time and logic control during the self assembly process, and offers a new perspective on the synthesis of materials.Natural complex systems are often constructed by sequential assembly but this is not readily available for synthetic systems. Here, the authors program the sequential self-assembly of DNA functionalized emulsions by altering the DNA grafted strands. PMID- 28623250 TI - ADAMTS-7 is associated with a high-risk plaque phenotype in human atherosclerosis. AB - Several large-scale genome-wide association studies have identified single nucleotide polymorphisms in the genomic region of A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats (ADAMTS)-7 and associations to coronary artery disease. Experimental studies have provided evidence for a functional role of ADAMTS-7 in both injury-induced vascular neointima formation and development of atherosclerotic lesions. However, whether ADAMTS-7 is associated with a specific plaque phenotype in humans has not been investigated. Carotid plaques (n = 206) from patients with and without cerebrovascular symptoms were analyzed for expression of ADAMTS-7 by immunohistochemistry and correlated to components associated with plaque vulnerability. Plaques from symptomatic patients showed increased levels of ADAMTS-7 compared with lesions from asymptomatic patients. High levels of ADAMTS-7 correlated with high levels of CD68-staining and lipid content, but with low smooth muscle cell and collagen content, which together are characteristics of a vulnerable plaque phenotype. ADAMTS-7 levels above median were associated with increased risk for postoperative cardiovascular events. Our data show that ADAMTS-7 is associated with a vulnerable plaque phenotype in human carotid lesions. These data support previous observations of a potential proatherogenic role of ADAMTS-7. PMID- 28623251 TI - Highly functional T-cell receptor repertoires are abundant in stem memory T cells and highly shared among individuals. AB - To expand our knowledge of the ontogeny of the T-cell receptor (TCR) repertoire of antigen-specific T-cell subsets, we combined next-generation deep sequencing and single-cell multiplex clonotype analysis to evaluate the diversity and frequency of paired TCRs, their functions and whether clonotypic TCRs are shared among different individuals. Using an HLA-A*02-restricted cytomegalovirus (CMV) pp65-derived immunogenic peptide, we found that the more dominant pp65-specific TCR clonotypes in the blood of healthy donors have higher binding affinities for the CMV peptide and arise from clonotypes that are highly shared among individuals. Interestingly, these highly shared HLA-A*02-restricted CMV-specific TCRs were detected in a CMV-seronegative individual as well as in HLA-A*02 negative donors albeit at lower frequency. More intriguingly, these shared TCR clonotypes were abundant in the stem memory T-cell subset, and TCR diversity of the stem memory T-cell repertoire was significantly lower than in the central memory and effector memory T-cell repertoires. These results suggest that the stem memory T-cell subset may serve as a reservoir of highly shared and highly functional memory T-cells. PMID- 28623252 TI - Natural variation in Arabidopsis thaliana Cd responses and the detection of quantitative trait loci affecting Cd tolerance. AB - Metal tolerance is often a result of metal storage or distribution. Thus, with the goal of advancing the molecular understanding of such metal homeostatic mechanisms, natural variation of metal tolerance in Arabidopsis thaliana was investigated. Substantial variation exists in tolerance of excess copper (Cu), zinc (Zn) and cadmium (Cd). Two accessions, Col-0 and Bur-0, and a recombinant inbred line (RIL) population derived from these parents were chosen for further analysis of Cd and Zn tolerance variation, which is evident at different plant ages in various experimental systems and appears to be genetically linked. Three QTLs, explaining in total nearly 50% of the variation in Cd tolerance, were mapped. The one obvious candidate gene in the mapped intervals, HMA3, is unlikely to contribute to the variation. In order to identify additional candidate genes the Cd responses of Col-0 and Bur-0 were compared at the transcriptome level. The sustained common Cd response of the two accessions was dominated by processes implicated in plant pathogen defense. Accession-specific differences suggested a more efficient activation of acclimative responses as underlying the higher Cd tolerance of Bur-0. The second hypothesis derived from the physiological characterization of the accessions is a reduced Cd accumulation in Bur-0. PMID- 28623253 TI - C-C Chemokine Ligand-5 is critical for facilitating macrophage infiltration in the early phase of liver ischemia/reperfusion injury. AB - CCL5/RANTES, a chemoattractant for myeloid cells, is induced by hepatic ischemia/reperfusion injury (IRI). The roles of CCL5 in hepatic IRI were carried out by means of CCL5 immunodepletion, antagonistic competition by Met-CCL5, and treatment with recombinant murine CCL5 (rmCCL5). Depletion or inhibition of CCL5 reduced severity of hepatic IRI, whereas rmCCL5 treatment aggravated liver IRI as manifested in elevated serum alanine aminotransferase (ALT) and tissue myeloperoxidase (MPO) levels. Moreover, IRI severity was reduced in CCL5-knockout (CCL5-KO) mice versus wildtype (WT) mice, with drops in serum ALT level, intrahepatic MPO activity, and histological pathology. Bone marrow transplantion (BMT) studies show that myeloid cells and tissue cells are both required for CCL5 aggravated hepatic IRI. The profile of liver-infiltrating leukocyte subsets after hepatic reperfusion identified CD11b+ cells as the only compartment significantly reduced in CCL5-KO mice versus WT controls at early reperfusion phase. The role of CCL5 recruiting CD11b+ cells in early reperfusion was validated by in vitro transwell migration assay of murine primary macrophages (broadly characterized by their CD11b expression) in response to liver lysates after early reperfusion. Taken together, our results demonstrate a sequence of early events elicited by CCL5 chemoattracting macrophage that result in inflammatory aggravation of hepatic IRI. PMID- 28623254 TI - High-throughput mass spectrometry analysis revealed a role for glucosamine in potentiating recovery following desiccation stress in Chironomus. AB - Desiccation tolerance is an essential survival trait, especially in tropical aquatic organisms that are vulnerable to severe challenges posed by hydroperiodicity patterns in their habitats, characterized by dehydration rehydration cycles. Here, we report a novel role for glucosamine as a desiccation stress-responsive metabolite in the underexplored tropical aquatic midge, Chironomus ramosus. Using high- throughput liquid chromatography quadrupole time of-flight mass spectrometry (LC-QToF-MS) analysis, biochemical assays and gene expression studies, we confirmed that glucosamine was essential during the recovery phase in C. ramosus larvae. Additionally, we demonstrated that trehalose, a known stress-protectant was crucial during desiccation but did not offer any advantage to the larvae during recovery. Based on our findings, we emphasise on the collaborative interplay of glucosamine and trehalose in conferring overall resilience to desiccation stress and propose the involvement of the trehalose-chitin metabolic interface in insects as one of the stress management strategies to potentiate recovery post desiccation through recruitment of glucosamine. PMID- 28623255 TI - Quantitative modelling of hip fracture trends in 14 European countries: testing variations of a shared reversal over time. AB - Qualitative similarities between hip fracture trends in different countries suggests variations of the same epidemic. We tested a single statistical shape to describe time trends in Europe, while allowing for country-level variability. Using data from 14 countries, we modelled incidence rates over time using linear mixed-effects models, including the fixed effects of calendar year and age. Random effects were tested to quantify country-level variability in background rates, timing of trend reversal and tempo of reversal. Mixture models were applied to identify clusters of countries defined by common behavioural features. A quadratic function of time, with random effects for background rates and timing of trend reversal, adjusted well to the observed data. Predicted trend reversal occurred on average in 1999 in women (peak incidence about 600 per 100 000) and 2000 in men (about 300 per 100 000). Mixture modelling of country-level effects suggested three clusters for women and two for men. In both sexes, Scandinavia showed higher rates but earlier trend reversals, whereas later trend reversals but lower peak incidences were found in Southern Europe and most of Central Europe. Our finding of a similar overall reversal pattern suggests that different countries show variations of a shared hip fracture epidemic. PMID- 28623257 TI - No-scanning 3D measurement method using ultrafast dimensional conversion with a chirped optical frequency comb. AB - A simultaneously high-precision, wide-range, and ultrafast time-resolution one shot 3D shape measurement method is presented. Simultaneous times of flight from multiple positions to a target encoded in a chirped optical frequency comb can be obtained from spectral interferometry. We experimentally demonstrate a one-shot imaging profile measurement of a known step height of 480 um with um-level accuracy. We further demonstrate the extension of the dynamic range by measuring in one shot a large step height of 3 m while maintaining high accuracy using the accurate pulse-to-pulse separation of the optical frequency comb. The proposed method with its large dynamic range and measurement versatility can be applied to a broad range of applications, including microscopic structures, objects with large size or aspect ratio, and ultrafast time-resolved imaging. This study provides a powerful and versatile tool for 3D measurement, where various ranges of measurement performances can be tailored to demand. PMID- 28623256 TI - LNA/DNA mixmer-based antisense oligonucleotides correct alternative splicing of the SMN2 gene and restore SMN protein expression in type 1 SMA fibroblasts. AB - Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting motor neurons, and is currently the most frequent genetic cause of infant mortality. SMA is caused by a loss-of-function mutation in the survival motor neuron 1 (SMN1) gene. SMN2 is an SMN1 paralogue, but cannot compensate for the loss of SMN1 since exon 7 in SMN2 mRNA is excluded (spliced out) due to a single C-to-T nucleotide transition in the exon 7. One of the most promising strategies to treat SMA is antisense oligonucleotide (AON)-mediated therapy. AONs are utilized to block intronic splicing silencer number 1 (ISS-N1) on intron 7 of SMN2, which causes exon 7 inclusion of the mRNA and the recovery of the expression of functional SMN protein from the endogenous SMN2 gene. We developed novel locked nucleic acid (LNA)-based antisense oligonucleotides (LNA/DNA mixmers), which efficiently induce exon 7 inclusion in SMN2 and restore the SMN protein production in SMA patient fibroblasts. The mixmers are highly specific to the targeted sequence, and showed significantly higher efficacy than an all-LNA oligonucleotide with the equivalent sequence. These data suggest that use of LNA/DNA mixmer-based AONs may be an attractive therapeutic strategy to treat SMA. PMID- 28623258 TI - Chromatin organization regulates viral egress dynamics. AB - Various types of DNA viruses are known to elicit the formation of a large nuclear viral replication compartment and marginalization of the cell chromatin. We used three-dimensional soft x-ray tomography, confocal and electron microscopy, combined with numerical modelling of capsid diffusion to analyse the molecular organization of chromatin in herpes simplex virus 1 infection and its effect on the transport of progeny viral capsids to the nuclear envelope. Our data showed that the formation of the viral replication compartment at late infection resulted in the enrichment of heterochromatin in the nuclear periphery accompanied by the compaction of chromatin. Random walk modelling of herpes simplex virus 1-sized particles in a three-dimensional soft x-ray tomography reconstruction of an infected cell nucleus demonstrated that the peripheral, compacted chromatin restricts viral capsid diffusion, but due to interchromatin channels capsids are able to reach the nuclear envelope, the site of their nuclear egress. PMID- 28623259 TI - MicroRNA-34a Encapsulated in Hyaluronic Acid Nanoparticles Induces Epigenetic Changes with Altered Mitochondrial Bioenergetics and Apoptosis in Non-Small-Cell Lung Cancer Cells. AB - Therapies targeting epigenetic changes for cancer treatment are in Phase I/II trials; however, all of these target only nuclear DNA. Emerging evidence suggests presence of methylation marks on mitochondrial DNA (mtDNA); but their contribution in cancer is unidentified. Expression of genes encoded on mtDNA are altered in cancer cells, along with increased glycolytic flux. Such glycolytic flux and elevated reactive oxygen species is supported by increased antioxidant; glutathione. MicroRNA-34a can translocate to mitochondria, mediate downstream apoptotic effects of tumor suppressor P53, and inhibit the antioxidant response element Nrf-2, resulting in depleted glutathione levels. Based on such strong rationale, we encapsulated microRNA-34a in our well-established Hyaluronic-Acid nanoparticles and delivered to cisplatin-sensitive and cisplatin-resistant A549 lung adenocarcinoma cells. Successful delivery and uptake in cells resulted in altered ATP levels, decreased glycolytic flux, Nrf-2 and glutathione levels, ultimately resulting in caspase-3 activation and apoptosis. Most important were the concurrent underlying molecular changes in epigenetic status of D-loop on the mtDNA and transcription of mtDNA-encoded genes. Although preliminary, we provide a novel therapeutic approach in form of altered mitochondrial bioenergetics and redox status of cancer cells with underlying changes in epigenetic status of mtDNA that can subsequently results in induction of cancer cell apoptosis. PMID- 28623260 TI - Qualifying a eukaryotic cell-free system for fluorescence based GPCR analyses. AB - Membrane proteins are key elements in cell-mediated processes. In particular, G protein-coupled receptors (GPCRs) have attracted increasing interest since they affect cellular signaling. Furthermore, mutations in GPCRs can cause acquired and inheritable diseases. Up to date, there still exist a number of GPCRs that has not been structurally and functionally analyzed due to difficulties in cell-based membrane protein production. A promising approach for membrane protein synthesis and analysis has emerged during the last years and is known as cell-free protein synthesis (CFPS). Here, we describe a simply portable method to synthesize GPCRs and analyze their ligand-binding properties without the requirement of additional supplements such as liposomes or nanodiscs. This method is based on eukaryotic cell lysates containing translocationally active endogenous endoplasmic reticulum derived microsomes where the insertion of GPCRs into biologically active membranes is supported. In this study we present CFPS in combination with fast fluorescence-based screening methods to determine the localization, orientation and ligand-binding properties of the endothelin B (ET-B) receptor upon expression in an insect-based cell-free system. To determine the functionality of the cell free synthesized ET-B receptor, we analyzed the binding of its ligand endothelin 1 (ET-1) in a qualitative fluorescence-based assay and in a quantitative radioligand binding assay. PMID- 28623261 TI - Epitaxially stabilized thin films of epsilon-Fe2O3 (001) grown on YSZ (100). AB - Epsilon ferrite (epsilon-Fe2O3) is a metastable phase of iron(III) oxide, intermediate between maghemite and hematite. It has recently attracted interest because of its magnetocrystalline anisotropy, which distinguishes it from the other polymorphs, and results in a gigantic coercive field and a natural ferromagnetic resonance frequency in the THz range. Moreover, it possesses a polar crystal structure, making it a potential ferroelectric, hence a potential multiferroic. Due to the need of size confinement to stabilize the metastable phase, epsilon-Fe2O3 has been synthesized mainly as nanoparticles. However, to favor integration in devices, and take advantage of its unique functional properties, synthesis as epitaxial thin films is desirable. In this paper, we report the growth of epsilon-Fe2O3 as epitaxial thin films on (100)-oriented yttrium-stabilized zirconia substrates. Structural characterization outlined the formation of multiple in-plane twins, with two different epitaxial relations to the substrate. Transmission electron microscopy showed how such twins develop in a pillar-like structure from the interface to the surface. Magnetic characterization confirmed the high magnetocrystalline anisotropy of our film and revealed the presence of a secondary phase which was identified as the well-known magnetite. Finally, angular analysis of the magnetic properties revealed how the presence of twins impacts their azimuthal dependence. PMID- 28623262 TI - Optofluidic device for the quantification of circulating tumor cells in breast cancer. AB - Metastatic cancer patients require a continuous monitoring during the sequential treatment cycles to carefully evaluate their disease evolution. Repetition of biopsies is very invasive and not always feasible. Herein, we design and demonstrate a 3D-flow focusing microfluidic device, where all optics are integrated into the chip, for the fluorescence quantification of CTCs in real samples. To test the chip performance, two cell membrane targets, the epithelial cell adhesion molecule, EpCAM, and the receptor tyrosine-protein kinase, HER2, are selected. The efficiency of the platform is demonstrated on cell lines and in a variety of healthy donors and metastatic-breast cancer patients. PMID- 28623263 TI - Probing spermiogenesis: a digital strategy for mouse acrosome classification. AB - Classification of morphological features in biological samples is usually performed by a trained eye but the increasing amount of available digital images calls for semi-automatic classification techniques. Here we explore this possibility in the context of acrosome morphological analysis during spermiogenesis. Our method combines feature extraction from three dimensional reconstruction of confocal images with principal component analysis and machine learning. The method could be particularly useful in cases where the amount of data does not allow for a direct inspection by trained eye. PMID- 28623264 TI - Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7. AB - The 2525 amino acid SMRT corepressor is an intrinsically disordered hub protein responsible for binding and coordinating the activities of multiple transcription factors and chromatin modifying enzymes. Here we have studied its interaction with HDAC7, a class IIa deacetylase that interacts with the corepressor complex together with the highly active class I deacetylase HDAC3. The binding site of class IIa deacetylases was previously mapped to an approximate 500 amino acid region of SMRT, with recent implication of short glycine-serine-isoleucine (GSI) containing motifs. In order to characterize the interaction in detail, we applied a random library screening approach within this region and obtained a range of stable, soluble SMRT fragments. In agreement with an absence of predicted structural domains, these were characterized as intrinsically disordered by NMR spectroscopy. We identified one of them, comprising residues 1255-1452, as interacting with HDAC7 with micromolar affinity. The binding site was mapped in detail by NMR and confirmed by truncation and alanine mutagenesis. Complementing this with mutational analysis of HDAC7, we show that HDAC7, via its surface zinc ion binding site, binds to a 28 residue stretch in SMRT comprising a GSI motif followed by an alpha helix. PMID- 28623265 TI - Long Sleep Duration Is an Independent Risk Factor for Incident Atrial Fibrillation in a Chinese Population: A Prospective Cohort Study. AB - There is limited information on the relation between sleep duration and incident atrial fibrillation. We aimed to investigate this association in a Chinese population using cohort data from a study in Kailuan. The analysis included 87,693 participants (age range, 18-98 years) free of atrial fibrillation at the baseline survey. Participants were divided into three categories according to self-reported sleep duration: <=6.0 hours, 7 hours (ref), >=8.0 hours. Atrial fibrillation diagnosis was made on a standard 12-lead electrocardiogram and via self-reported history. Cox proportional hazards models were used to calculate hazard ratio (HR) and confidence interval (CI) for atrial fibrillation, according to sleep duration. During median follow-up of 7.89 (range, 6.36-8.57) years, 322 cases of atrial fibrillation had occurred. Using 7 hours of sleep as the reference group, multivariable adjusted HRs (95% CI) for atrial fibrillation were 1.07 (0.75-1.53), 1.0 (ref), and 1.50 (1.07-2.10), from lowest to highest category of sleep duration. Secondary analysis showed no evidence of interactions between sleep duration and sex and snoring on the risk of incident atrial fibrillation (p = 0.75/0.25). We conclude long sleep duration may be a potential predictor/marker for incident atrial fibrillation. PMID- 28623266 TI - Design of a Peripheral Building Block for H-Bonded Dendritic Frameworks and Analysis of the Void Space in the Bulk Dendrimers. AB - Three dendrimers, (t-Bu-G 2 N) 2 , CC(t-Bu-G 1 N) 3 and (t-Bu-G 1 N) 2 , with 3,5 di-tert-butyl amidobenzene as a common peripheral moiety were prepared in 64-83% yields and characterized. The bulk solids had high BET surface areas of 136-138 m2/g, which were similar for the three dendrimers in spite of their different molecular weight (ranging from 1791 to 2890). It was concluded that the peripheral amide groups do not imbed in the interstitial space of neighbouring dendrimer molecules but rather build a supramolecular architecture through strong intermolecular H-bonds. This mode of assembly generates voids in the bulk dendrimers responsible for sorption properties. The X-ray crystal structure analysis of a compound representing the peripheral moiety of the dendrimers and the FT-IR and powder-XRD data for (t-Bu-G 1 N) 2 suggest the proposed supramolecular structure. The isosteric heats of CO2 sorption (Q st) for (t-Bu-G 2 N) 2 were significantly higher than those for the other two dendrimers, which is consistent with the formation of a different type of voids within the interstitial space of the molecule. It is suggested that the interstitial void space can be designed and tuned to adjust its properties to a particular task, such as the separation of gases or a catalytic reaction facilitated by the dendrimer. PMID- 28623267 TI - A new paradigm for antiangiogenic therapy through controlled release of bevacizumab from PLGA nanoparticles. AB - Monoclonal antibodies have deserved a remarkable interest for more than 40 years as a vital tool for the treatment of various diseases. Still, there is a raising interest to develop advanced monoclonal antibody delivery systems able to tailor pharmacokinetics. Bevacizumab is a humanized immunoglobulin IgG1 used in antiangiogenic therapies due to its capacity to inhibit the interaction between vascular endothelial growth factor and its receptor. However, bevacizumab-based antiangiogenic therapy is not always effective due to poor treatment compliance associated to multiples administrations and drug resistance. In this work, we show a promising strategy of encapsulating bevacizumab to protect and deliver it, in a controlled manner, increasing the time between administrations and formulation shelf-life. Nanoencapsulation of bevacizumab represents a significant advance for selective antiangiogenic therapies since extracellular, cell surface and intracellular targets can be reached. The present study shows that bevacizumab-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles does not impair its native-like structure after encapsulation and fully retain the bioactivity, making this nanosystem a new paradigm for the improvement of angiogenic therapy. PMID- 28623268 TI - Ascorbate induces apoptosis in melanoma cells by suppressing Clusterin expression. AB - Pharmacological levels of ascorbate have long been suggested as a potential treatment of cancer. However, we observed that EC50 of ascorbate was at a similar level for cultured healthy melanocytes and melanoma cells, suggesting a limit of pharmacological ascorbate in treating cancer. Loss of 5-hydroxymethylcytosine (5 hmC) is an epigenetic hallmark of cancer and ascorbate promotes 5 hmC generation by serving as a cofactor for TET methylcytosine dioxygenases. Our previous work demonstrated that ascorbate treatment at physiological level (100 MUM) increased 5 hmC content in melanoma cells toward the level of healthy melanocytes. Here we show that 100 uM of ascorbate induced apoptosis in A2058 melanoma cells. RNA-seq analysis revealed that expression of the Clusterin (CLU) gene, which is related to apoptosis, was downregulated by ascorbate. The suppression of CLU was verified at transcript level in different melanoma cell lines, and at protein level in A2058 cells. The anti-apoptotic cytoplasmic CLU was decreased, while the pro apoptotic nuclear CLU was largely maintained, after ascorbate treatment. These changes in CLU subcellular localization were also associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, this study establishes an impending therapeutic role of physiological ascorbate to potentiate apoptosis in melanoma. PMID- 28623269 TI - Theory of Inverse Edelstein Effect of The Surface States of A Topological Insulator. AB - The surface states of three-dimensional topological insulators possess the unique property of spin-momentum interlocking. This property gives rise to the interesting inverse Edelstein effect (IEE), in which an applied spin bias MU is converted to a measurable charge voltage difference V. We develop a semiclassical theory for the IEE of the surface states of Bi2Se3 thin films, which is applicable from the ballistic regime to diffusive regime. We find that the efficiency of the spin-charge conversion, defined as gamma = V/MU, exhibits a universal dependence on the ratio between sample size and electron mean free path. The efficiency increases from gamma = pi/4 in the ballistic limit to gamma = pi in the diffusive limit, suggesting that sufficient strength of impurity scattering is favorable for the IEE. PMID- 28623270 TI - Behavioural and physiological responses to prey-related cues reflect higher competitiveness of invasive vs. native ladybirds. AB - Understanding the traits that might be linked with biological invasions represents a great challenge for preventing non-target effects on local biodiversity. In predatory insects, the ability to exploit habitats for oviposition and the physiological response to prey availability differs between species. Those species that respond more readily to environmental changes may confer to their offspring a competitive advantage over other species. Here, we tested the hypothesis that the invasive Harmonia axyridis (Coleoptera: Coccinellidae) makes better use of information from a plant-prey (Vicia faba - Aphis fabae) system compared to the native Oenopia conglobata. Y-tube olfactometer bioassays revealed that both species used olfactory cues from the system, but H. axyridis exhibited a more complete response. This species was also attracted by plants previously infested by aphids, indicating the capacity to exploit volatile synomones induced in plants by aphid attack. Oocyte resorption was investigated when different olfactory stimuli were provided under prey shortage and the readiness of new oogenesis was measured when prey was available again. H. axyridis exhibited higher plasticity in oogenesis related to the presence/absence of plant-aphid volatiles. Our results support the hypothesis that H. axyridis is more reactive than O. conglobata to olfactory cues from the plant-prey system. PMID- 28623271 TI - Decoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons. AB - Accumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent. PMID- 28623272 TI - Exosomes derived from palmitic acid-treated hepatocytes induce fibrotic activation of hepatic stellate cells. AB - Non-alcoholic fatty liver disease (NAFLD) is a dominant cause of chronic liver disease, but the exact mechanism of progression from simple steatosis to nonalcoholic steatohepatitis (NASH) remains unknown. Here, we investigated the role of exosomes in NAFLD progression. Exosomes were isolated from a human hepatoma cell line treated with palmitic acid (PA) and their miRNA profiles examined by microarray. The human hepatic stellate cell (HSC) line (LX-2) was then treated with exosome isolated from hepatocytes. Compared with controls, PA treated hepatocytes displayed significantly increased CD36 and exosome production. The microarray analysis showed there to be distinctive miRNA expression patterns between exosomes from vehicle- and PA-treated hepatocytes. When LX-2 cells were cultured with exosomes from PA-treated hepatocytes, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with exosomes from vehicle-treated hepatocytes. In conclusion, PA treatment enhanced the production of exosomes in these hepatocytes and changed their exosomal miRNA profile. Moreover, exosomes derived from PA-treated hepatocytes caused an increase in the expression levels of fibrotic genes in HSCs. Therefore, exosomes may have important roles in the crosstalk between hepatocytes and HSCs in the progression from simple steatosis to NASH. PMID- 28623273 TI - Arabidopsis Transporter ABCG37/PDR9 contributes primarily highly oxygenated Coumarins to Root Exudation. AB - The chemical composition of root exudates strongly impacts the interactions of plants with microorganisms in the rhizosphere and the efficiency of nutrient acquisition. Exudation of metabolites is in part mediated by ATP-binding cassette (ABC) transporters. In order to assess the contribution of individual ABC transporters to root exudation, we performed an LC-MS based non-targeted metabolite profiling of semi-polar metabolites accumulating in root exudates of Arabidopsis thaliana plants and mutants deficient in the expression of ABCG36 (PDR8/PEN3), ABCG37 (PDR9) or both transporters. Comparison of the metabolite profiles indicated distinct roles for each ABC transporter in root exudation. Thymidine exudation could be attributed to ABCG36 function, whereas coumarin exudation was strongly reduced only in ABCG37 deficient plants. However, coumarin exudation was compromised in abcg37 mutants only with respect to certain metabolites of this substance class. The specificity of ABCG37 for individual coumarins was further verified by a targeted LC-MS based coumarin profiling method. The response to iron deficiency, which is known to strongly induce coumarin exudation, was also investigated. In either treatment, the distribution of individual coumarins between roots and exudates in the investigated genotypes suggested the involvement of ABCG37 in the exudation specifically of highly oxygenated rather than monohydroxylated coumarins. PMID- 28623274 TI - Reduction in chromosome mobility accompanies nuclear organization during early embryogenesis in Caenorhabditis elegans. AB - In differentiated cells, chromosomes are packed inside the cell nucleus in an organised fashion. In contrast, little is known about how chromosomes are packed in undifferentiated cells and how nuclear organization changes during development. To assess changes in nuclear organization during the earliest stages of development, we quantified the mobility of a pair of homologous chromosomal loci in the interphase nuclei of Caenorhabditis elegans embryos. The distribution of distances between homologous loci was consistent with a random distribution up to the 8-cell stage but not at later stages. The mobility of the loci was significantly reduced from the 2-cell to the 48-cell stage. Nuclear foci corresponding to epigenetic marks as well as heterochromatin and the nucleolus also appeared around the 8-cell stage. We propose that the earliest global transformation in nuclear organization occurs at the 8-cell stage during C. elegans embryogenesis. PMID- 28623275 TI - Influences of temperature and salinity on physicochemical properties and toxicity of zinc oxide nanoparticles to the marine diatom Thalassiosira pseudonana. AB - Climate change is predicted to result in rising average temperature of seawater with more extreme thermal events, and frequent rainfalls in some coastal regions. It is imperative to understand how naturally mediated changes in temperature and salinity can modulate toxicity of chemical contaminants to marine life. Thus, this study investigated combined effects of temperature and salinity on toxicity of zinc oxide nanoparticles (ZnO-NPs) to the marine diatom Thalassiosira pseudonana. Because ZnO-NPs formed larger aggregations and released less zinc ions (Zn2+) at greater temperature and salinity, toxicity of ZnO-NPs to T. pseudonana was less at 25 degrees C than at 10 degrees C and less at 32 than 12 PSU. However, toxicity of ZnO-NPs was significantly greater at 30 degrees C, since T. pseudonana was near its upper thermal limit. Three test compounds, ZnO, ZnO-NPs and ZnSO4, displayed different toxic potencies and resulted in different profiles of expression of genes in T. pseudonana. This indicated that ZnO-NPs caused toxicity via different pathways compared to ZnSO4. Mechanisms of toxic action of the three compounds were also dependent on temperature and salinity. These results provide insights into molecular mechanisms underlying the responses of the diatom to ZnO-NPs and Zn2+ under various regimes of temperature and salinity. PMID- 28623276 TI - Gag-protease coevolution analyses define novel structural surfaces in the HIV-1 matrix and capsid involved in resistance to Protease Inhibitors. AB - Despite the major role of Gag in establishing resistance of HIV-1 to protease inhibitors (PIs), very limited data are available on the total contribution of Gag residues to resistance to PIs. To identify in detail Gag residues and structural interfaces associated with the development of HIV-1 resistance to PIs, we traced viral evolution under the pressure of PIs using Gag-protease single genome sequencing and coevolution analysis of protein sequences in 4 patients treated with PIs over a 9-year period. We identified a total of 38 Gag residues correlated with the protease, 32 of which were outside Gag cleavage sites. These residues were distributed in 23 Gag-protease groups of coevolution, with the viral matrix and the capsid represented in 87% and 52% of the groups. In addition, we uncovered the distribution of Gag correlated residues in specific protein surfaces of the inner face of the viral matrix and at the Cyclophilin A binding loop of the capsid. In summary, our findings suggest a tight interdependency between Gag structural proteins and the protease during the development of resistance of HIV-1 to PIs. PMID- 28623278 TI - Highly conductive nano-sized Magneli phases titanium oxide (TiOx). AB - Despite the strong recent revival of Magneli phase TiOx as a promising conductive material, synthesis of Magneli phase TiOx nanoparticles has been a challenge because of the heavy sintering nature of TiO2 at elevated temperatures. We have successfully synthesized chain-structured Magneli phases TiOx with diameters under 30 nm using a thermal-induced plasma process. The synthesized nanoparticles consisted of a mixture of several Magneli phases. A post-synthesis heat-treatment was performed to reduce the electrical resistivity without changing the particle morphology. The resistivity of the heat-treated particle was as low as 0.04 Omega.cm, with a specific surface area of 52.9 m2 g-1. The effects of heat treatment on changes in the crystal structure and their correlation with the electron conductivity are discussed based on transmission electron microscopy images, X-ray diffraction spectra, and X-ray adsorption fine structure spectra. Electrochemical characterization using cyclic voltammetry and potentiodynamic scan shows a remarkable electrochemical stability in a strongly oxidizing environment. PMID- 28623277 TI - In Vivo Quantification of Placental Insufficiency by BOLD MRI: A Human Study. AB - Fetal health is critically dependent on placental function, especially placental transport of oxygen from mother to fetus. When fetal growth is compromised, placental insufficiency must be distinguished from modest genetic growth potential. If placental insufficiency is present, the physician must trade off the risk of prolonged fetal exposure to placental insufficiency against the risks of preterm delivery. Current ultrasound methods to evaluate the placenta are indirect and insensitive. We propose to use Blood-Oxygenation-Level-Dependent (BOLD) MRI with maternal hyperoxia to quantitatively assess mismatch in placental function in seven monozygotic twin pairs naturally matched for genetic growth potential. In-utero BOLD MRI time series were acquired at 29 to 34 weeks gestational age. Maps of oxygen Time-To-Plateau (TTP) were obtained in the placentas by voxel-wise fitting of the time series. Fetal brain and liver volumes were measured based on structural MR images. After delivery, birth weights were obtained and placental pathological evaluations were performed. Mean placental TTP negatively correlated with fetal liver and brain volumes at the time of MRI as well as with birth weights. Mean placental TTP positively correlated with placental pathology. This study demonstrates the potential of BOLD MRI with maternal hyperoxia to quantify regional placental function in vivo. PMID- 28623279 TI - Divergent Regulation of Actin Dynamics and Megakaryoblastic Leukemia-1 and -2 (Mkl1/2) by cAMP in Endothelial and Smooth Muscle Cells. AB - Proliferation and migration of vascular smooth muscle cells (VSMCs) or endothelial cell (ECs) promote or inhibit, respectively, restenosis after angioplasty, vein graft intimal thickening and atherogenesis. Here we investigated the effects of cAMP-induced cytoskeletal remodelling on the serum response factor (SRF) co-factors Megakaryoblastic Leukemia-1 and -2 (MKL1 and MKL2) and their role in controlling VSMC and EC proliferation and migration. Elevation of cAMP using forskolin, dibutyryl-cAMP (db-cAMP), BAY60-6583 or Cicaprost induced rapid cytoskeleton remodelling and inhibited proliferation and migration in VSMCs but not EC. Furthermore, elevated cAMP inhibited mitogen induced nuclear-translocation of MKL1 and MKL2 in VSMCs but not ECs. Forskolin also significantly inhibited serum response factor (SRF)-dependent reporter gene (SRE-LUC) activity and mRNA expression of pro-proliferative and pro-migratory MKL1/2 target genes in VSMCs but not in ECs. In ECs, MKL1 was constitutively nuclear and MKL2 cytoplasmic, irrespective of mitogens or cAMP. Pharmacological or siRNA inhibition of MKL1 significantly inhibited the proliferation and migration of VSMC and EC. Our new data identifies and important contribution of MKL1/2 to explaining the strikingly different response of VSMCs and ECs to cAMP elevation. Elucidation of these pathways promises to identify targets for specific inhibition of VSMC migration and proliferation. PMID- 28623280 TI - EV-3, an endogenous human erythropoietin isoform with distinct functional relevance. AB - Generation of multiple mRNAs by alternative splicing is well known in the group of cytokines and has recently been reported for the human erythropoietin (EPO) gene. Here, we focus on the alternatively spliced EPO transcript characterized by deletion of exon 3 (hEPODelta3). We show co-regulation of EPO and hEPODelta3 in human diseased tissue. The expression of hEPODelta3 in various human samples was low under normal conditions, and distinctly increased in pathological states. Concomitant up-regulation of hEPODelta3 and EPO in response to hypoxic conditions was also observed in HepG2 cell cultures. Using LC-ESI-MS/MS, we provide first evidence for the existence of hEPODelta3 derived protein EV-3 in human serum from healthy donors. Contrary to EPO, recombinant EV-3 did not promote early erythroid progenitors in cultures of human CD34+ haematopoietic stem cells. Repeated intraperitoneal administration of EV-3 in mice did not affect the haematocrit. Similar to EPO, EV-3 acted anti-apoptotic in rat hippocampal neurons exposed to oxygen-glucose deprivation. Employing the touch-screen paradigm of long-term visual discrimination learning, we obtained first in vivo evidence of beneficial effects of EV-3 on cognition. This is the first report on the presence of a naturally occurring EPO protein isoform in human serum sharing non-erythropoietic functions with EPO. PMID- 28623281 TI - Tamm plasmon modes on semi-infinite metallodielectric superlattices. AB - We analyze the fundamental properties of optical waves referred to as Tamm plasmon modes (TPMs) which are tied to the interface of a semi-infinite two-phase metallodielectric superlattice with an arbitrary homogeneous capping medium. Such modes offer new ways of achieving high electromagnetic field localization and spontaneous emission enhancement in the vicinity of the interface in conjunction with absorption loss management, which is crucial for future applications. The homointerface, formed when the capping medium has the same permittivity as one of the superlattice constituents, is found to support a TPM whose dispersion overlaps the single-interface surface plasmon polariton (SPP) dispersion but which has a cut off at the topological transition point. In contrast, a heterointerface formed for an arbitrary capping medium, is found to support multiple TPMs whose origin can be traced by considering the interaction between a single-interface SPP and the homointerface TPM burried under the top layer of the superlattice. By carrying out a systematic comparison between TPMs and single interface SPPs, we find that the deviations are most pronounced in the vicinity of the transition frequency for superlattices in which dielectric layers are thicker than metallic ones. PMID- 28623282 TI - A Nationwide Study of Severe and Protracted Diarrhoea in Patients with Primary Immunodeficiency Diseases. AB - Diarrhoea lasting longer than 14 days and failing to respond to conventional management is defined as severe and protracted diarrhoea (SD). In this study, we investigated the prevalence, pathogens and prognosis of SD in primary immunodeficiency diseases (PIDs). Among 246 patients with predominantly paediatric-onset PIDs from 2003-2015, 21 [Btk (six), IL2RG (four), WASP, CD40L, gp91 (three each), gp47, RAG2 (one each)] and five [CVID (four), SCID (one)] without identified mutations had SD before prophylactic treatment. Detectable pathogens included pseudomonas, salmonella (six each), E. coli, cytomegalovirus, coxsackie virus and cryptosporidium (one each), all of whom improved after a mean 17 days of antibiotics and/or IVIG treatment. Seven (7/26; 27.0%) patients died [respiratory failure (four), lymphoma, sepsis and intracranial haemorrhage (one each)]. The patients with WAS, CGD and CD40L and SD had a higher mortality rate than those without. Another five males with mutant XIAP, STAT1, FOXP3 (one each) and STAT3 (two) had undetectable-pathogenic refractory diarrhoea (RD) that persisted >21 days despite aggressive antibiotic/steroid treatment and directly resulted in mortality. For the patients with RD without anti-inflammatory optimization, those with mutant XIAP and FOXP3 died of Crohn's-like colitis and electrolyte exhaustion in awaiting transplantation, while transplantation cured the STAT1 patient. PMID- 28623283 TI - Dosage compensation in the process of inactivation/reactivation during both germ cell development and early embryogenesis in mouse. AB - Ohno proposed that dosage compensation in mammals evolved as a two-step mechanism involving X-inactivation and X-upregulation. While X-inactivation is well characterized, it remains to further analysis whether upregulation of the single activated X chromosome in mammals occurs. We obtained RNA-seq data, including single-cell RNA-seq data, from cells undergoing inactivation/reactivation in both germ cell development and early embryogenesis stages in mouse and calculated the X: A ratio from the gene expression. Our results showed that the X: A ratio is always 1, regardless of the number of X chromosomes being transcribed for expressed genes. Furthermore, the single-cell RNA-seq data across individual cells of mouse preimplantation embryos of mixed backgrounds indicated that strain specific SNPs could be used to distinguish transcription from maternal and paternal chromosomes and further showed that when the paternal was inactivated, the average gene dosage of the active maternal X chromosome was increased to restore the balance between the X chromosome and autosomes. In conclusion, our analysis of RNA-seq data (particularly single-cell RNA-seq) from cells undergoing the process of inactivation/reactivation provides direct evidence that the average gene dosage of the single active X chromosome is upregulated to achieve a similar level to that of two active X chromosomes and autosomes present in two copies. PMID- 28623284 TI - Spatio-Temporal Steering for Testing Nonclassical Correlations in Quantum Networks. AB - We introduce the concept of spatio-temporal steering (STS), which reduces, in special cases, to Einstein-Podolsky-Rosen steering and the recently-introduced temporal steering. We describe two measures of this effect referred to as the STS weight and robustness. We suggest that these STS measures enable a new way to assess nonclassical correlations in an open quantum network, such as quantum transport through nano-structures or excitation transfer in a complex biological system. As one of our examples, we apply STS to check nonclassical correlations among sites in a photosynthetic pigment-protein complex in the Fenna-Matthews Olson model. PMID- 28623285 TI - Structure of the human TRiC/CCT Subunit 5 associated with hereditary sensory neuropathy. AB - The human chaperonin TRiC consists of eight non-identical subunits, and its protein-folding activity is critical for cellular health. Misfolded proteins are associated with many human diseases, such as amyloid diseases, cancer, and neuropathies, making TRiC a potential therapeutic target. A detailed structural understanding of its ATP-dependent folding mechanism and substrate recognition is therefore of great importance. Of particular health-related interest is the mutation Histidine 147 to Arginine (H147R) in human TRiC subunit 5 (CCT5), which has been associated with hereditary sensory neuropathy. In this paper, we describe the crystal structures of CCT5 and the CCT5-H147R mutant, which provide important structural information for this vital protein-folding machine in humans. This first X-ray crystallographic study of a single human CCT subunit in the context of a hexadecameric complex can be expanded in the future to the other 7 subunits that form the TRiC complex. PMID- 28623286 TI - Trait choice profoundly affected the ecological conclusions drawn from functional diversity measures. AB - Although trait choice is crucial to quantify functional diversity appropriately, the quantitative methods for it are rarely compared and discussed. Meanwhile, very little is known about how trait choice affects ecological conclusions drawn from functional diversity measures. We presented the four methods of trait selection as alternatives to the ordination axis-based method, which directly identify a subset of key traits to represent the main variation of all the traits. To evaluate their performance, we compared the closeness of association obtained by different methods between species richness and functional diversity indices (FAD, FD, Q, FDis) in the six ecosystems. The evaluation was also benchmarked against the results obtained by calculating the possible indices using all the trait combinations (the complete search method). We found that the trait selection methods were potential alternatives to axis-based method to gain a mechanistic understanding of functional responses and effects of traits, while these methods as well as the axis-based method possibly use mismatched information to interpret the investigated ecosystem properties. Trait choice profoundly affected the ecological conclusions drawn from functional diversity measures. The complete search method should be used to assess the rationale of different trait choice methods and the quality of the calculated indices. PMID- 28623287 TI - Heritability and responses to high fat diet of plasma lipidomics in a twin study. AB - Lipidomics have a great potential as clinical tool for monitoring metabolic changes in health and disease. Nevertheless hardly anything is known about the heritability of lipids. Therefore, it is necessary to clarify how and how much we can affect these progresses in individuals. In our interventional twin study (46 healthy, non-obese twin pairs) we investigated the lipid profile in plasma samples after switching from a low fat diet to an isocaloric high fat diet (HFD) to characterize the metabolic adaptation. Additionally we used the ACE model for Additive genetics, Common and unique Environment as well as linear mixed modelling to analyse the heritability of lipids. The heritability of lipids varied between 0-62% and applied to lipid species rather than to lipid classes. Phospholipids showed the highest inheritance. In addition, sex, body mass index (BMI) and age were important modifiers. The lipid profile changed already after one week of HFD and diverged further after 5 weeks of additional HFD. Basal concentrations of specific lipids within phospholipids are strongly inherited and are likely to be associated with heritable disease risks. BMI, sex and age were major modifiers. Nutrition strongly alters specific lipid classes, and has to be controlled in clinical association studies. PMID- 28623288 TI - Seabirds supply nitrogen to reef-building corals on remote Pacific islets. AB - Seabirds concentrate nutrients from large marine areas on their nesting islands playing an important ecological role in nutrient transfer between marine and terrestrial ecosystems. Here we investigate the role of guano on corals reefs across scales by analyzing the stable nitrogen isotopic (delta15N) values of the scleractinian coral Pocillopora damicornis on fringing reefs around two Pacific remote islets with large seabird colonies. Marine stations closest to the seabird colonies had higher nitrate + nitrite concentrations compared to more distant stations. Coral and zooxanthellae delta15N values were also higher at these sites, suggesting that guano-derived nitrogen is assimilated into corals and contributes to their nitrogen requirements. The spatial extent of guano influence was however restricted to a local scale. Our results demonstrate that seabird derived nutrients not only spread across the terrestrial ecosystem, but also affect components of the adjacent marine ecosystem. Further studies are now needed to assess if this nutrient input has a positive or negative effect for corals. Such studies on remote islets also open fresh perspectives to understand how nutrients affect coral reefs isolated from other anthropogenic stressors. PMID- 28623289 TI - 3D Super-Resolution Optical Profiling Using Microsphere Enhanced Mirau Interferometry. AB - We present quantitative three dimensional images of grooves on a writable Blu-ray Disc based on a single objective Mirau type interferometric microscope, enhanced with a microsphere which is considered as a photonic nanojet source. Along the optical axis the resolution of this microsphere assisted interferometry system is a few nanometers while the lateral resolution is around 112 nm. To understand the physical phenomena involved in this kind of imaging we have modelled the interaction between the photonic jet and the complex disc surface. Agreement between simulation and experimental results is demonstrated. We underline that although the ability of the microsphere to generate a photonic nanojet does not alone explain the resolution of the interferometer, the nanojet can be used to try to understand the imaging process. To partly explain the lateral super resolution, the potential role of coherence is illustrated. The presented modality may have a large impact on many fields from bio-medicine to nanotechnology. PMID- 28623290 TI - TCRP1 transcriptionally regulated by c-Myc confers cancer chemoresistance in tongue and lung cancer. AB - Previously, we cloned a new gene termed 'tongue cancer resistance-associated protein 1' (TCRP1), which modulates tumorigenesis, enhances cisplatin (cDDP) resistance in cancers, and may be a potential target for reversing drug resistance. However, the mechanisms for regulating TCRP1 expression remain unclear. Herein, we combined bioinformatics analysis with luciferase reporter assay and ChIP assay to determine that c-Myc could directly bind to TCRP1 promoter to upregulate its expression. TCRP1 upregulation in multidrug resistant tongue cancer cells (Tca8113/PYM) and cisplatin-resistant A549 lung cancer cells (A549/DDP) was accompanied by c-Myc upregulation, compared to respective parental cells. In tongue and lung cancer cells, siRNA-mediated knockdown of c-Myc led to decrease TCRP1 expression, whereas overexpression c-Myc did the opposite. Moreover, TCRP1 knockdown attenuated chemoresistance resulting from c-Myc overexpression, but TCRP1 overexpression impaired the effect of c-Myc knockdown on chemosensitivity. Additionally, in both human tongue and lung cancer tissues, c-Myc protein expression positively correlated with TCRP1 protein expression and these protein levels were associated with worse prognosis for patients. Combined, these findings suggest that c-Myc could transcriptionally regulate TCRP1 in cell lines and clinical samples and identified the c-Myc-TCRP1 axis as a negative biomarker of prognosis in tongue and lung cancers. PMID- 28623291 TI - Crystal structure of the DNA-binding domain of Myelin-gene Regulatory Factor. AB - Myelin-gene Regulatory Factor (MyRF) is one of the master transcription factors controlling myelin formation and development in oligodendrocytes which is crucial for the powerful brain functions. The N-terminal of MyRF, which contains a proline-rich region and a DNA binding domain (DBD), is auto-cleaved from the ER membrane, and then enters the nucleus to participate in transcription regulation of the myelin genes. Here we report the crystal structure of MyRF DBD. It shows an Ig-fold like architecture which consists of two antiparallel beta-sheets with 7 main strands, packing against each other, forming a beta-sandwich. Compared to its homolog, Ndt80, MyRF has a smaller and less complex DBD lacking the helices and the big loops outside the core. Structural alignment reveals that MyRF DBD possess less interaction sites with DNA than Ndt80 and may bind only at the major groove of DNA. Moreover, the structure reveals a trimeric assembly, agreeing with the previous report that MyRF DBD functions as a trimer. The mutant that we designed based on the structure disturbed trimer formation, but didn't affect the auto-cleavage reaction. It demonstrates that the activation of self-cleavage reaction of MyRF is independent of the presence of its N-terminal DBD homotrimer. The structure reported here will help to understand the molecular mechanism underlying the important roles of MyRF in myelin formation and development. PMID- 28623292 TI - Structural and Biochemical Characterization of Poly-ADP-ribose Polymerase from Trypanosoma brucei. AB - Trypanosoma brucei is a unicellular parasite responsible for African trypanosomiasis or sleeping sickness. It contains a single PARP enzyme opposed to many higher eukaryotes, which have numerous PARPs. PARPs are responsible for a post-translational modification, ADP-ribosylation, regulating a multitude of cellular events. T. brucei PARP, like human PARPs-1-3, is activated by DNA binding and it potentially functions in DNA repair processes. Here we characterized activation requirements, structure and subcellular localization of T. brucei PARP. T. brucei PARP was found to be selectively activated by 5' phosphorylated and 3' phosphorylated DNA breaks. Importantly, the N-terminal region is responsible for high-affinity DNA-binding and required for DNA dependent enzymatic activation. This module is also required for nuclear localization of the protein in response to oxidative stress. Solution structures of activating and non-activating PARP-DNA complexes were determined with small angle X-ray scattering revealing distinct differences in their DNA-binding modes. PMID- 28623293 TI - Intricate disorder in defect fluorite/pyrochlore: a concord of chemistry and crystallography. AB - Intuitively scientists accept that order can emerge from disorder and a significant amount of effort has been devoted over many years to demonstrate this. In metallic alloys and oxides, disorder at the atomic scale is the result of occupation at equivalent atomic positions by different atoms which leads to the material exhibiting a fully random or modulated scattering pattern. This arrangement has a substantial influence on the material's properties, for example ionic conductivity. However it is generally accepted that oxides, such as defect fluorite as used for nuclear waste immobilization matrices and fuel cells, are the result of disorder at the atomic scale. To investigate how order at the atomic scale induces disorder at a larger scale length, we have applied different techniques to study the atomic composition of a homogeneous La 2 Zr 2 O 7 pyrochlore, a textbook example of such a structure. Here we demonstrate that a pyrochlore, which is considered to be defect fluorite, is the result of intricate disorder due to a random distribution of fully ordered nano-domains. Our investigation provides new insight into the order disorder transformations in complex materials with regards to domain formation, resulting in a concord of chemistry with crystallography illustrating that order can induce disorder. PMID- 28623294 TI - H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes. AB - Hydrogen sulfide (H2S), a cardioprotective gas, is endogenously produced from homocysteine by cystathionine beta synthase (CBS) and cystathionine gamma lyase (CSE) enzymes. However, effect of H2S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesize that homocysteine and H2S regulate CBS and CSE expressions in a dose dependent manner in cardiomyocytes, and CBS deficiency induces cardiac CSE expression. To test the hypothesis, we treated murine atrial HL1 cardiomyocytes with increasing doses of homocysteine or Na2S/GYY4137, a H2S donor, and measured the levels of CBS and CSE. We found that homocysteine upregulates CSE but downregulates CBS whereas Na2S/GYY4137 downregulates CSE but upregulates CBS in a dose-dependent manner. Moreover, the Na2S-treatment downregulates specificity protein-1 (SP1), an inducer for CSE, and upregulates miR-133a that targets SP1 and inhibits cardiomyocytes hypertrophy. Conversely, in the homocysteine-treated cardiomyocytes, CBS and miR-133a were downregulated and hypertrophy was induced. In vivo studies using CBS+/-, a model for hyperhomocysteinemia, and sibling CBS+/+ control mice revealed that deficiency of CBS upregulates cardiac CSE, plausibly by inducing SP1. In conclusion, we revealed a novel mechanism for H2S mediated regulation of homocysteine metabolism in cardiomyocytes, and a negative feedback regulation between CBS and CSE in the heart. PMID- 28623295 TI - Optimal angle of magnetic field for magnetic bubblecade motion. AB - Unidirectional motion of magnetic structures such as the magnetic domain and domain walls is a key concept underlying next-generation memory and logic devices. As a potential candidate of such unidirectional motion, it has been recently demonstrated that the magnetic bubblecade-the coherent unidirectional motion of magnetic bubbles-can be generated by applying an alternating magnetic field. Here we report the optimal configuration of applied magnetic field for the magnetic bubblecade. The tilted alternating magnetic field induces asymmetric expansion and shrinkage of the magnetic bubbles under the influence of the Dzyaloshinskii-Moriya interaction, resulting in continuous shift of the bubbles in time. By examining the magnetic bubblecade in Pt/Co/Pt films, we find that the bubblecade speed is sensitive to the tilt angle with a maximum at an angle, which can be explained well by a simple analytical form within the context of the domain-wall creep theory. A simplified analytic formula for the angle for maximum speed is then given as a function of the amplitude of the alternating magnetic field. The present results provide a useful guideline of optimal design for magnetic bubblecade memory and logic devices. PMID- 28623296 TI - Iodine-125 Brachytherapy Prophylaxis after Radiofrequency Ablation Cannot Benefit Patients in High Risk of Locoregional Hepatocellular Carcinoma Recurrence. AB - This study evaluated if iodine-125 brachytherapy prophylaxis after radiofrequency ablation (RFA) prolongs time to recurrence (TTR) and overall survival (OS) of patients in high risk of locoregional hepatocellular carcinoma (HCC) recurrence. 116 patients with total tumor necrosis after RFA were divided into iodine-125 brachytherapy prophylaxis treatment group and control group. The primary endpoint was TTR, and secondary endpoints were OS and treatment-related adverse events. There were no significant differences among the baseline characteristics of two subgroups patients. The mean iodine-125 particles were 29.8 (26.59 +/- 12.51 mCi) per patient. The mean follow-up was 25 months, and mean TTR of treatment and control groups were 21.7 and 15.9 months (P = 0.733); mean OS of two subgroups were 41.7 and 40.9 months (P = 0.316). There were no significant differences of 1 , 2-, 3-, 4-and 5-years TTR and OS and patients' immunity pre- and 1 month post treatment. Extrahepatic metastasis was found to have a statistically significant influence on TTR, and AFP, extrahepatic metastasis were found to have a statistically significant influence on OS by multivariate analysis. There was no major complications and procedure related death. Iodine-125 brachytherapy prophylaxis after RFA can't improve TTR and OS of HCC patients who were in high risk of locoregional tumor recurrence. PMID- 28623297 TI - Dynamical amplification of magnetoresistances and Hall currents up to the THz regime. AB - Spin-orbit-related effects offer a highly promising route for reading and writing information in magnetic units of future devices. These phenomena rely not only on the static magnetization orientation but also on its dynamics to achieve fast switchings that can reach the THz range. In this work, we consider Co/Pt and Fe/W bilayers to show that accounting for the phase difference between different processes is crucial to the correct description of the dynamical currents. By tuning each system towards its ferromagnetic resonance, we reveal that dynamical spin Hall angles can non-trivially change sign and be boosted by over 500%, reaching giant values. We demonstrate that charge and spin pumping mechanisms can greatly magnify or dwindle the currents flowing through the system, influencing all kinds of magnetoresistive and Hall effects, thus impacting also dc and second harmonic experimental measurements. PMID- 28623298 TI - Constraint-based modeling identifies new putative targets to fight colistin resistant A. baumannii infections. AB - Acinetobacter baumannii is a clinical threat to human health, causing major infection outbreaks worldwide. As new drugs against Gram-negative bacteria do not seem to be forthcoming, and due to the microbial capability of acquiring multi resistance, there is an urgent need for novel therapeutic targets. Here we have derived a list of new potential targets by means of metabolic reconstruction and modelling of A. baumannii ATCC 19606. By integrating constraint-based modelling with gene expression data, we simulated microbial growth in normal and stressful conditions (i.e. following antibiotic exposure). This allowed us to describe the metabolic reprogramming that occurs in this bacterium when treated with colistin (the currently adopted last-line treatment) and identify a set of genes that are primary targets for developing new drugs against A. baumannii, including colistin resistant strains. It can be anticipated that the metabolic model presented herein will represent a solid and reliable resource for the future treatment of A. baumannii infections. PMID- 28623299 TI - Integrated optical waveguide-based fluorescent immunosensor for fast and sensitive detection of microcystin-LR in lakes: Optimization and Analysis. AB - Nowadays, biosensor technologies which can detect various contaminants in water quickly and cost-effectively are in great demand. Herein, we report an integrated channel waveguide-based fluorescent immunosensor with the ability to detect a maximum of 32 contaminants rapidly and simultaneously. In particular, we use waveguide tapers to improve the efficiency of excitation and collection of fluorescent signals in the presence of fluorophore photobleaching in a solid surface bioassay. Under the optimized waveguide geometry, this is the first demonstration of using such a type of waveguide immunosensor for the detection of microcystin-LR (MC-LR) in lake water. The waveguide chip was activated by (3 Mercaptopropyl) trimethoxysilane/N-(4-maleimidobutyryloxy) succinimide (MTS/GMBS) for immobilization of BSA-MC-LR conjugate, which was confirmed to have uniform monolayer distribution by atomic force microscopy. All real lake samples, even those containing MC-LR in the sub-microgram per liter range (e.g. 0.5 MUg/L), could be determined by the immunosensor with recovery rates between 84% and 108%, confirming its application potential in the measurement of MC-LR in real water samples. PMID- 28623300 TI - Improving Photocatalytic Performance from Bi2WO6@MoS2/graphene Hybrids via Gradual Charge Transferred Pathway. AB - The charge transfer from the main catalyst to the cocatalyst is a key factor to enhance catalytic activity for photocatalytic nanocomposite materials. In order to enhance the charge transfer between Bi2WO6 and graphene, we inlet MoS2 as a "stepping-stone" into Bi2WO6 and graphene. Here, we report an effective strategy to synthesize ternary Bi2WO6@MoS2/graphene nanocomposite photocatalyst by a facile two-step hydrothermal method, which is afforded by assembling two cocatalysts, graphene and MoS2, into the Bi2WO6 matrix with a nanoparticle morphology as a visible light harvester. Compared with Bi2WO6/graphene, Bi2WO6/MoS2 and pure Bi2WO6, the Bi2WO6@MoS2/graphene ternary composites exhibit superior photocatalytic activity owing to an enhanced charge carrier separation via gradual charge transferred pathway. This work indicates a promising cocatalyst strategy for designing a more efficient graphene based semiconductor photocatalyst toward degradation of organic pollutants. PMID- 28623301 TI - Designing a molecular magnetic button based on 4d and 5d transition-metal phthalocyanines. AB - The field of molecular spintronics exploits the properties of organic molecules possessing a magnetic moment, either native in the form of radicals or induced by the insertion of transition metal magnetic ions. To realize logic or storage molecular spin-tronics devices, molecules with stable different magnetic states should be deposited on a substrate, and switching between the states controllably achieved. By means of a first-principles calculations, we have devised a functional molecule exhibiting different magnetic states upon structural changes induced by current injection. We investigate the prototypical case of non-planar M-Phthalocyanine (MPc), where M is a transition-metal ion belonging to the 4d and 5d series. We find that for ZrPc and HfPc deposited on a graphene decorated Ni(111) substrate, two different structural conformations could be stabilized, for which the molecules attain different magnetic states depending on the position of the M ion - whether above the Pc or between the Pc and the substrate , acting therefore as molecular magnetic button. Our work indicates an intuitive way to engineer a magnetic molecular switch with tailored properties, starting from the knowledge of the basic atomic properties of elements and surfaces. PMID- 28623302 TI - Insecticide susceptibility of Anopheles mosquitoes changes in response to variations in the larval environment. AB - Insecticide resistance threatens the success achieved through vector control in reducing the burden of malaria. An understanding of insecticide resistance mechanisms would help to develop novel tools and strategies to restore the efficacy of insecticides. Although we have substantially improved our understanding of the genetic basis of insecticide resistance over the last decade, we still know little of how environmental variations influence the mosquito phenotype. Here, we measured how variations in larval rearing conditions change the insecticide susceptibility phenotype of adult Anopheles mosquitoes. Anopheles gambiae and A. stephensi larvae were bred under different combinations of temperature, population density and nutrition, and the emerging adults were exposed to permethrin. Mosquitoes bred under different conditions showed considerable changes in mortality rates and body weight, with nutrition being the major factor. Weight is a strong predictor of insecticide susceptibility and bigger mosquitoes are more likely to survive insecticide treatment. The changes can be substantial, such that the same mosquito colony may be considered fully susceptible or highly resistant when judged by World Health Organization discriminatory concentrations. The results shown here emphasise the importance of the environmental background in developing insecticide resistance phenotypes, and caution for the interpretation of data generated by insecticide susceptibility assays. PMID- 28623303 TI - XtracTB Assay, a Mycobacterium tuberculosis molecular screening test with sensitivity approaching culture. AB - Nucleic acid amplification tests are increasingly used to diagnose tuberculosis (TB) due to their speed and sensitivity compared to sputum smear microscopy. However, these tests fail to equal culture's sensitivity with sputum smear microscopy negative specimens and therefore cannot be used to rule out TB disease. For molecular tests to match culture's sensitivity, they must detect <=10 genomic copies of Mycobacterium tuberculosis (MTB) DNA, the limit of detection of culture, process >=1 ml of sputum ensuring sufficient number of MTB are in the reaction, and efficiently remove sputum associated inhibitors from this large sample. Here we report the preliminary characterization of XtracTB Assay, a MTB testing protocol designed for inclusion in either an integrated point-of-care platform or a high throughput automated central laboratory system. The test combines DNA sequence specific sample prep to reduce the co-extraction of qPCR inhibitors with the amplification of two MTB specific loci (IS6110 and senX3-regX3) to increase test sensitivity and minimize the likelihood of false negatives. The analytical sensitivity of the XtracTB Assay was 5 genomic copies/ml of sputum rivaling that of culture. Furthermore, 142 valid test results yield clinical sensitivity of 94.9% (95% CI: 90.1-99.9) and specificity of 100% (95% CI: 90.0-100.0). PMID- 28623304 TI - Identification of transcripts with short stuORFs as targets for DENR*MCTS1 dependent translation in human cells. AB - The non-canonical initiation factors DENR and MCTS1 have been linked to cancer and autism. We recently showed in Drosophila that DENR and MCTS1 regulate translation re-initiation on transcripts containing upstream Open Reading Frames (uORFs) with strong Kozak sequences (stuORFs). Due to the medical relevance of DENR and MCTS1, it is worthwhile identifying the transcripts in human cells that depend on DENR and MCTS1 for their translation. We show here that in humans, as in Drosophila, transcripts with short stuORFs require DENR and MCTS1 for their optimal expression. In contrast to Drosophila, however, the dependence on stuORF length in human cells is very strong, so that only transcripts with very short stuORFs coding for 1 amino acid are dependent on DENR and MCTS1. This identifies circa 100 genes as putative DENR and MCTS1 translational targets. These genes are enriched for neuronal genes and G protein-coupled receptors. The identification of DENR and MCTS1 target transcripts will serve as a basis for future studies aimed at understanding the mechanistic involvement of DENR and MCTS1 in cancer and autism. PMID- 28623305 TI - Enhanced Optical Properties of ZnO and CeO2-coated ZnO Nanostructures Achieved Via Spherical Nanoshells Growth On A Polystyrene Template. AB - In this paper, ZnO, CeO2 and CeO2-coated ZnO nanostructures were synthesised by simple and efficient low temperature wet chemical methods on Si (100) and quartz substrates. The ZnO films were prepared by a drop coating deposition method. This was then combined with a thin layer of the redox active material CeO2 to form CeO2-coated ZnO films. Spherical ZnO nanoshell structures and CeO2-coated ZnO nanoshells have been prepared using polystyrene (PS) sphere monolayer templates. The structural properties and morphologies of the nanostructures were analysed by x-ray diffraction (XRD) and scanning electron microscopy (SEM). The nanostructure compositions are studied in more detail using secondary ion mass spectroscopy (SIMS). The optical properties of the nanostructures were measured using ultraviolet-visible (UV-Vis) absorption spectroscopy in order to ascertain the effects of the nanoshell structures and the whispering gallery modes associated with these structures on the optical properties of the deposits. Our data show UV and visible light absorption was very significantly enhanced due to this nanostructuring. PMID- 28623306 TI - Diversity of endophytic mycobiota of tropical tree Tectona grandis Linn.f.: Spatiotemporal and tissue type effects. AB - Fungal endophytes were isolated from leaf, bark and stem of Tectona grandis Linn.f. sampled at four geographical locations in winter, summer and monsoon seasons. The recovered 5089 isolates were assigned to 45 distinct morphotypes based on morphology. The sequences of the internal transcribed spacers (ITS) of the nrDNA of some morphotypes were identical, but morphological differences were strong enough to consider these morphotypes as separate species. Forty-three morphotypes were assigned to ascomycotina and two to basidiomycotina. Ascomycotina was the predominating group with 99.7% of total isolates followed by basidiomycotina with only 0.3% of total isolates. Diaporthe (Phomopsis) species dominated the communities independently on tissue type, location or season. More than 60% of the examined tissue pieces were colonized by members of this species complex. While these endophytes are ubiquitous others were tissue or location specific. Tissue type had the strongest effect on the species evenness of the endophytic assemblage followed by geographical location and season. However, Shannon-Wiener index (H') significantly (p <= 0.001) varied with all three factors i.e. season, location and tissue type. Leaves supported the highest diversity across all the seasons and locations. In conclusion, all the three factors together determined the structure of endophytic mycobiota assemblage of T. grandis. PMID- 28623307 TI - Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice. AB - Co-infection with hepatitis B (HBV) and D virus (HDV) is associated with the most severe course of liver disease. Interferon represents the only treatment currently approved. However, knowledge about the impact of interferons on HDV in human hepatocytes is scant. Aim was to assess the effect of pegylated interferon alpha (peg-IFNalpha) and lambda (peg-IFNlambda), compared to the HBV-polymerase inhibitor entecavir (ETV) on all HDV infection markers using human liver chimeric mice and novel HDV strand-specific qRT-PCR and RNA in situ hybridization assays, which enable intrahepatic detection of HDV RNA species. Peg-IFNalpha and peg IFNlambda reduced HDV viremia (1.4 log and 1.2 log, respectively) and serum HBsAg levels (0.9-log and 0.4-log, respectively). Intrahepatic quantification of genomic and antigenomic HDV RNAs revealed a median ratio of 22:1 in untreated mice, resembling levels determined in HBV/HDV infected patients. Both IFNs greatly reduced intrahepatic levels of genomic and antigenomic HDV RNA, increasing the amounts of HDAg- and antigenomic RNA-negative hepatocytes. ETV mediated suppression of HBV replication (2.1-log) did not significantly affect HBsAg levels, HDV productivity and/or release. In humanized mice lacking adaptive immunity, IFNs but not ETV suppressed HDV. Viremia decrease reflected the intrahepatic reduction of all HDV markers, including the antigenomic template, suggesting that intracellular HDV clearance is achievable. PMID- 28623308 TI - Improved Growth Patterns in Cystic Fibrosis Mice after Loss of Histone Deacetylase 6. AB - Growth failure in cystic fibrosis (CF) patients has been well-documented and shown to correlate with poorer disease outcomes. This observation is also true in CF animal models, including mouse, pig, rat, and ferret. The etiology underlying growth deficits is unknown, and our previous work demonstrated reduced tubulin acetylation in CF cell models and tissue that is correctable by inhibition of histone deacetylase-6 (HDAC6). Here, we hypothesize that loss of HDAC6 will improve growth phenotype in a CF mouse model. Hdac6 knockout mice were crossed with F508del (CF) mice to generate F508del/Hdac6 (CF/HDA) mice. Growth, fat deposits, survival, and bioelectric measurements were analyzed. CF/HDA mice displayed improvements in length and weight with no correction of CFTR function. Mechanistically, Igf1 levels likely account for increased length and improvements in fertility. Weight gain is attributed to increased fat deposits potentially mediated by increased adipocyte differentiation. CF-related growth deficits can be improved via inhibition of HDAC6, further implicating it as a potential therapeutic target for CF. PMID- 28623310 TI - One-Pot Synthesis of GeAs Ultrafine Particles from Coal Fly Ash by Vacuum Dynamic Flash Reduction and Inert Gas Condensation. AB - Ge-monopnictides (GeAs) plays critical role in high-tech industry, especially in the field of advanced optical devices and infrared. As a secondary material, coal fly ash could be further recycled to retrieve germanium and prepare GeAs material with high added values. Hence, the aim of this paper is to propose a one-pot synthesis that uses vacuum flash reduction and inert-gas consolidation method to prepare GeAs ultrafine particles. Germanium in coal fly ash can be successfully recycled; simultaneously, GeAs ultrafine particles were prepared. Separation principle and feasibility of this process was discussed. Temperature, carrier gas flow rate and system pressure were the major factors on formation, morphology and distribution of particle size of GeAs ultrafine particles. A three steps synthetic mechanism was clarified, namely, thermal rupture of coal fly ash and release of GeO2 and As2O3, the gas-solid phase reaction of GeO2, As2O3 and coke to generate metallic Ge and As in vacuum flash reduction. Meantime, GeAs were produced in the gas phase reaction. Finally, GeAs ultrafine particles were obtained by carrier gas condensation. In short, this research developed a practical and environment-friendly one-pot synthesis to recycle germanium in coal fly ash and prepare GeAs ultrafine particles with high added values. PMID- 28623309 TI - Fibronectin promotes directional persistence in fibroblast migration through interactions with both its cell-binding and heparin-binding domains. AB - The precise mechanisms through which insoluble, cell-adhesive ligands induce and regulate directional cell migration remain obscure. We recently demonstrated that elevated surface density of physically adsorbed plasma fibronectin (FN) promotes high directional persistence in fibroblast migration. While cell-FN association through integrins alpha5beta1 and alphavbeta3 was necessary, substrates that selectively engaged these integrins did not support the phenotype. We here show that high directional persistence necessitates a combination of the cell-binding and C-terminal heparin-binding domains of FN, but does not require the engagement of syndecan-4 or integrin alpha4beta1. FN treatment with various fixation agents indicated that associated changes in fibroblast motility were due to biochemical changes, rather than alterations in its physical state. The nature of the coating determined the ability of fibroblasts to assemble endogenous or exogenous FN, while FN fibrillogenesis played a minor, but significant, role in regulating directionality. Interestingly, knockdown of cellular FN abolished cell motility altogether, demonstrating a requirement for intracellular processes in enabling fibroblast migration on FN. Lastly, kinase inhibition experiments revealed that regulation of cell speed and directional persistence are decoupled. Hence, we have identified factors that render full-length FN a promoter of directional migration and discuss the possible, relevant mechanisms. PMID- 28623311 TI - Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis. AB - The genetic etiology and the contribution of rare genetic variation in multiple sclerosis (MS) has not yet been elucidated. Although familial forms of MS have been described, no convincing rare and penetrant variants have been reported to date. We aimed to characterize the contribution of rare genetic variation in familial and sporadic MS and have identified a family with two sibs affected by concomitant MS and malignant melanoma (MM). We performed whole exome sequencing in this primary family and 38 multiplex MS families and 44 sporadic MS cases and performed transcriptional and immunologic assessment of the identified variants. We identified a potentially causative homozygous missense variant in NLRP1 gene (Gly587Ser) in the primary family. Further possibly pathogenic NLRP1 variants were identified in the expanded cohort of patients. Stimulation of peripheral blood mononuclear cells from MS patients with putatively pathogenic NLRP1 variants showed an increase in IL-1B gene expression and active cytokine IL-1beta production, as well as global activation of NLRP1-driven immunologic pathways. We report a novel familial association of MS and MM, and propose a possible underlying genetic basis in NLRP1 gene. Furthermore, we provide initial evidence of the broader implications of NLRP1-related pathway dysfunction in MS. PMID- 28623312 TI - Recovery of the first full-length genome sequence of a parapoxvirus directly from a clinical sample. AB - We recovered the first full-length poxvirus genome, including the terminal hairpin region, directly from complex clinical material using a combination of second generation short read and third generation nanopore sequencing technologies. The complete viral genome sequence was directly recovered from a skin lesion of a grey seal thereby preventing sequence changes due to in vitro passaging of the virus. Subsequent analysis of the proteins encoded by this virus identified genes specific for skin adaptation and pathogenesis of parapoxviruses. These data warrant the classification of seal parapoxvirus, tentatively designated SePPV, as a new species within the genus Parapoxvirus. PMID- 28623313 TI - Inhibition of Calpains Protects Mn-Induced Neurotransmitter release disorders in Synaptosomes from Mice: Involvement of SNARE Complex and Synaptic Vesicle Fusion. AB - Overexposure to manganese (Mn) could disrupt neurotransmitter release via influencing the formation of SNARE complex, but the underlying mechanisms are still unclear. A previous study demonstrated that SNAP-25 is one of substrate of calpains. The current study investigated whether calpains were involved in Mn induced disorder of SNARE complex. After mice were treated with Mn for 24 days, Mn deposition increased significantly in basal nuclei in Mn-treated and calpeptin pre-treated groups. Behaviorally, less time spent in the center of the area and decreased average velocity significantly in an open field test after 24 days of Mn exposure. With the increase in MnCl2 dosage, intracellular Ca2+ increased significantly, but pretreatment with calpeptin caused a dose-dependent decrease in calpains activity. There were fragments of N-terminal of SNAP-25 protein appearance in Mn-treated groups, but it is decreased with pretreatment of calpeptin. FM1-43-labeled synaptic vesicles also provided evidence that the treatment with Mn resulted in increasing first and then decreasing, which was consistent with Glu release and the 80 kDa protein levels of SNARE complexes. In summary, Mn induced the disorder of neurotransmitter release through influencing the formation of SNARE complex via cleaving SNAP-25 by overactivation of calpains in vivo. PMID- 28623314 TI - Comparative transcriptomic and proteomic analyses provide insights into the key genes involved in high-altitude adaptation in the Tibetan pig. AB - Tibetan pigs that inhabit the Tibetan Plateau exhibit striking phenotypic and physiological differences from lowland pigs, and have adapted well to extreme conditions. However, the mechanisms involved in regulating gene expression at high altitude in these animals are not fully understood. In this study, we obtained transcriptomic and proteomic data from the heart tissues of Tibetan and Yorkshire pigs raised in the highlands (TH and YH) and lowlands (TL and YL) via RNA-seq and iTRAQ (isobaric tags for relative and absolute quantitation) analyses, respectively. Comparative analyses of TH vs. YH, TH vs.TL, TL vs. YL, and YH vs. YL yielded 299, 169, 242, and 368 differentially expressed genes (DEGs), and 473, 297, 394, and 297 differentially expressed proteins (DEPs), respectively. By functional annotation of these DEGs and DEPs, genes that were enriched in the HIF-1 signaling pathway (NPPA, ERK2, ENO3, and EGLN3), VEGF signaling pathway (ERK2, A2M, FGF1, CTGF, and DPP4), and hypoxia-related processes (CRYAB, EGLN3, TGFB2, DPP4, and ACE) were identified as important candidate genes for high-altitude adaptation in the Tibetan pig. This study enhances our understanding of the molecular mechanisms involved in hypoxic adaptation in pigs, and furthers our understanding of human hypoxic diseases. PMID- 28623315 TI - Avalanche of entanglement and correlations at quantum phase transitions. AB - We study the ground-state entanglement in the quantum Ising model with nearest neighbor ferromagnetic coupling J and find a sequential increase of entanglement depth d with growing J. This entanglement avalanche starts with two-point entanglement, as measured by the concurrence, and continues via the three-tangle and four-tangle, until finally, deep in the ferromagnetic phase for J = infinity, arriving at a pure L-partite (GHZ type) entanglement of all L spins. Comparison with the two, three, and four-point correlations reveals a similar sequence and shows strong ties to the above entanglement measures for small J. However, we also find a partial inversion of the hierarchy, where the four-point correlation exceeds the three- and two-point correlations, well before the critical point is reached. Qualitatively similar behavior is also found for the Bose-Hubbard model, suggesting that this is a general feature of a quantum phase transition. This should be taken into account in the approximations starting from a mean-field limit. PMID- 28623316 TI - Revealing protein networks and gene-drug connectivity in cancer from direct information. AB - The connection between genetic variation and drug response has long been explored to facilitate the optimization and personalization of cancer therapy. Crucial to the identification of drug response related genetic features is the ability to separate indirect correlations from direct correlations across abundant datasets with large number of variables. Here we analyzed proteomic and pharmacogenomic data in cancer tissues and cell lines using a global statistical model connecting protein pairs, genes and anti-cancer drugs. We estimated this model using direct coupling analysis (DCA), a powerful statistical inference method that has been successfully applied to protein sequence data to extract evolutionary signals that provide insights on protein structure, folding and interactions. We used Direct Information (DI) as a metric of connectivity between proteins as well as gene-drug pairs. We were able to infer important interactions observed in cancer related pathways from proteomic data and predict potential connectivities in cancer networks. We also identified known and potential connections for anti cancer drugs and gene mutations using DI in pharmacogenomic data. Our findings suggest that gene-drug connections predicted with direct couplings can be used as a reliable guide to cancer therapy and expand our understanding of the effects of gene alterations on drug efficacies. PMID- 28623317 TI - Prediction of lncRNA-protein interactions using HeteSim scores based on heterogeneous networks. AB - Massive studies have indicated that long non-coding RNAs (lncRNAs) are critical for the regulation of cellular biological processes by binding with RNA-related proteins. However, only a few experimentally supported lncRNA-protein associations have been reported. Existing network-based methods are typically focused on intrinsic features of lncRNA and protein but ignore the information implicit in the topologies of biological networks associated with lncRNAs. Considering the limitations in previous methods, we propose PLPIHS, an effective computational method for Predicting lncRNA-Protein Interactions using HeteSim Scores. PLPIHS uses the HeteSim measure to calculate the relatedness score for each lncRNA-protein pair in the heterogeneous network, which consists of lncRNA lncRNA similarity network, lncRNA-protein association network and protein-protein interaction network. An SVM classifier to predict lncRNA-protein interactions is built with the HeteSim scores. The results show that PLPIHS performs significantly better than the existing state-of-the-art approaches and achieves an AUC score of 0.97 in the leave-one-out validation test. We also compare the performances of networks with different connectivity density and find that PLPIHS performs well across all the networks. Furthermore, we use the proposed method to identify the related proteins for lncRNA MALAT1. Highly-ranked proteins are verified by the biological studies and demonstrate the effectiveness of our method. PMID- 28623318 TI - ZipA and FtsA* stabilize FtsZ-GDP miniring structures. AB - The cytokinetic division ring of Escherichia coli comprises filaments of FtsZ tethered to the membrane by FtsA and ZipA. Previous results suggested that ZipA is a Z-ring stabilizer, since in vitro experiments it is shown that ZipA enhanced FtsZ assembly and caused the filaments to bundles. However, this function of ZipA has been challenged by recent studies. First, ZipA-induced FtsZ bundling was not significant at pH greater than 7. Second, some FtsA mutants, such as FtsA* were able to bypass the need of ZipA. We reinvestigated the interaction of FtsZ with ZipA in vitro. We found that ZipA not only stabilized and bundled straight filaments of FtsZ-GTP, but also stabilized the highly curved filaments and miniring structures formed by FtsZ-GDP. FtsA* had a similar stabilization of FtsZ GDP minirings. Our results suggest that ZipA and FtsA* may contribute to constriction by stabilizing this miniring conformation. PMID- 28623319 TI - Fast Projection Matching for X-ray Tomography. AB - X-ray 3D tomographic techniques are powerful tools for investigating the morphology and internal structures of specimens. A common strategy for obtaining 3D tomography is to capture a series of 2D projections from different X-ray illumination angles of specimens mounted on a finely calibrated rotational stage. However, the reconstruction quality of 3D tomography relies on the precision and stability of the rotational stage, i.e. the accurate alignment of the 2D projections in the correct three-dimensional positions. This is a crucial problem for nano-tomographic techniques due to the non-negligible mechanical imperfection of the rotational stages at the nanometer level which significantly degrades the spatial resolution of reconstructed 3-D tomography. Even when using an X-ray micro-CT with a highly stabilized rotational stage, thermal effects caused by the CT system are not negligible and may cause sample drift. Here, we propose a markerless image auto-alignment algorithm based on an iterative method. This algorithm reduces the traditional projection matching method into two simplified matching problems and it is much faster and more reliable than traditional methods. This algorithm can greatly decrease hardware requirements for both nano tomography and data processing and can be easily applied to other tomographic techniques, such as X-ray micro-CT and electron tomography. PMID- 28623320 TI - Postprandial metabolic response of breast-fed infants and infants fed lactose free vs regular infant formula: A randomized controlled trial. AB - Lactose intolerance is a major concern driving the growth of lactose-free foods including lactose-free infant formula. It is unknown what the metabolic consequence is of consumption of a formula where lactose has been replaced with corn syrup solids (CSS). Here, a randomized double-blinded intervention study was conducted where exclusively formula-fed infants were fed formula containing either lactose or CSS-based infant formula and compared with an equal number of exclusively breast-fed infants. Plasma metabolites and insulin were measured at baseline, 15, 30, 60, 90 and 120 min after feeding. Differences in plasma metabolite profiles for formula-fed infants included a rapid increase in circulating amino acids, creatinine and urea compared with breast-fed infants. At 120 min post-feeding, insulin was significantly elevated in formula-fed compared with breast-fed infants. Infants fed lactose-based formula had the highest levels of glucose at 120 min, and leucine, isoleucine, valine and proline at 90 and 120 min, whereas infants fed CSS-based formula had the lowest levels of non esterified fatty acids at all time points, and glucose at 120 min. Overall, these differences highlight that changes in infant formula composition impact infant metabolism, and show that metabolomics is a powerful tool to help with development of improved infant formulas. PMID- 28623322 TI - Design of Non-Deterministic Quasi-random Nanophotonic Structures Using Fourier Space Representations. AB - Despite their seemingly random appearances in the real space, quasi-random nanophotonic structures exhibit distinct structural correlations and have been widely utilized for effective photon management. However, current design approaches mainly rely on the deterministic representations consisting two dimensional (2D) discretized patterns in the real space. They fail to capture the inherent non-deterministic characteristic of the quasi-random structures and inevitably result in a large design dimensionality. Here, we report a new design approach that employs the one-dimensional (1D) spectral density function (SDF) as the unique representation of non-deterministic quasi-random structures in the Fourier space with greatly reduced design dimensionality. One 1D SDF representation can be used to generate infinite sets of real space structures in 2D with equally optimized performance, which was further validated experimentally using light-trapping structures in a thin film absorber as a model system. The optimized non-deterministic quasi-random nanostructures improve the broadband absorption by 225% over the unpatterned cell. PMID- 28623321 TI - Dysbiosis in chronic periodontitis: Key microbial players and interactions with the human host. AB - Periodontitis is an extremely prevalent disease worldwide and is driven by complex dysbiotic microbiota. Here we analyzed the transcriptional activity of the periodontal pocket microbiota from all domains of life as well as the human host in health and chronic periodontitis. Bacteria showed strong enrichment of 18 KEGG functional modules in chronic periodontitis, including bacterial chemotaxis, flagellar assembly, type III secretion system, type III CRISPR-Cas system, and two component system proteins. Upregulation of these functions was driven by the red-complex pathogens and candidate pathogens, e.g. Filifactor alocis, Prevotella intermedia, Fretibacterium fastidiosum and Selenomonas sputigena. Nine virulence factors were strongly up-regulated, among them the arginine deiminase arcA from Porphyromonas gingivalis and Mycoplasma arginini. Viruses and archaea accounted for about 0.1% and 0.22% of total putative mRNA reads, respectively, and a protozoan, Entamoeba gingivalis, was highly enriched in periodontitis. Fourteen human transcripts were enriched in periodontitis, including a gene for a ferric iron binding protein, indicating competition with the microbiota for iron, and genes associated with cancer, namely nucleolar phosphoprotein B23, ankyrin-repeat domain 30B-like protein and beta-enolase. The data provide evidence on the level of gene expression in vivo for the potentially severe impact of the dysbiotic microbiota on human health. PMID- 28623323 TI - RUFY3 interaction with FOXK1 promotes invasion and metastasis in colorectal cancer. AB - RUFY3 is highly expressed in brain tissue and has a role in neuronal development. Transcriptional factor FOXK1 is involved in cell growth and metabolism. We knew that RUFY3 or FOXK1 has been correlated with the malignant of tumor cells. However, the role of these molecules in colorectal cancer (CRC) progression remains unknown. We investigated the protein expression levels by Western blot, immunofluorescence and immunohistochemistry analyses. The migration and invasive abilities of CRC cells were assessed using shRNA-mediated inhibition in vitro and in vivo. We showed that RUFY3 expression was up-regulated in CRC compared with its expression in a normal human colon cell line (FHC). RUFY3 suppression inhibited anchorage independent cell tumorigenesis. RUFY3 induced elevated expression of eight major oncogenes. Moreover, RUFY3 physically interacts with FOXK1 in CRC. A positive correlation was observed between the expression patterns of RUFY3 and FOXK1. Furthermore, RUFY3 and FOXK1 expression were correlated with tumor progression and represented significant predictors of overall survival in CRC patients. SiRNA-mediated repression of FOXK1 in RUFY3-overexpressing cells reversed the epithelial-mesenchymal transition (EMT) and metastatic phenotypes. In vivo, FOXK1 promoted RUFY3-mediated metastasis via orthotopic implantation. These findings suggest that the RUFY3-FOXK1 axis might promote the development and progression of human CRC. PMID- 28623324 TI - Rapid discrimination of human oesophageal squamous cell carcinoma by mass spectrometry based on differences in amino acid metabolism. AB - Oesophageal cancer (OC) is associated with high morbidity and mortality, and surgery is the most effective approach to treat it. In order to reduce surgical risks and duration of surgery, we explored a new strategy to determine tumour margins in surgery. In this study, we included 128 cancerous and 128 noncancerous database entries obtained from 32 human patients. Using internal extractive electrospray ionization-MS, in positive ion detection mode, the relative abundances of m/z 104.13, m/z 116.10, m/z 132.13, and m/z 175.13 were higher in cancer tissue while the relative abundances of m/z 82.99, m/z 133.11, m/z 147.08, m/z 154.06, and m/z 188.05 were higher in normal tissue. Using partial least squares analysis, the mass spectra of cancer samples was discriminated from those of normal tissues, and the discriminatory ions were obtained from loading plots. Dimethylglycine(m/z 104), proline(m/z 116), isoleucine(m/z 132), asparagine(m/z 133), glutamine(m/z 147), and arginine(m/z 175) were identified by collision induced dissociation experiments. Using the ROC curve analysis, we verified the validity of six amino acids for the identification of tumour tissue. Further investigations of tissue amino acids may allow us to better understand the underlying mechanisms involved in OC and develop novel means to identify tumour tissue during operation. PMID- 28623325 TI - Fluorescence Lifetime Imaging Microscopy, a Novel Diagnostic Tool for Metastatic Cell Detection in the Cerebrospinal Fluid of Children with Medulloblastoma. AB - In pediatric brain tumours, dissemination of malignant cells within the central nervous system confers poor prognosis and determines treatment intensity, but is often undetectable by imaging or cytology. This study describes the use of fluorescence lifetime (FLT) imaging microscopy (FLIM), a novel diagnostic tool, for detection of metastatic spread. The study group included 15 children with medulloblastoma and 2 with atypical teratoid/rhabdoid tumour. Cells extracted from the tumour and the cerebrospinal fluid (CSF) 2 weeks postoperatively and repeatedly during chemo/radiotherapy were subjected to nuclear staining followed by FLT measurement and cytological study. Control CSF samples were collected from patients with infectious/inflammatory disease attending the same hospital. Median FLT was prolonged in tumour cells (4.27 +/- 0.28 ns; P < 2.2*10-16) and CSF metastatic cells obtained before chemo/radiotherapy (6.28 +/- 0.22 ns; P < 2.2*10 16); normal in inflammatory control cells (2.6 +/- 0.04 ns) and cells from children without metastasis before chemo/radiotherapy (2.62 +/- 0.23 ns; P = 0.858) and following treatment (2.62 +/- 0.21 ns; P = 0.053); and short in CSF metastatic cells obtained after chemo/radiotherapy (2.40 +/- 0.2 ns; P < 2.2*10 16). FLIM is a simple test that can potentially identify CSF spread of brain tumours. FLT changes in accordance with treatment, with significant prolonged median values in tumours and metastases. More accurate detection of metastatic cells may guide personalised treatment and improve the therapeutic outcome. PMID- 28623326 TI - Sialic acid linkage differentiation of glycopeptides using capillary electrophoresis - electrospray ionization - mass spectrometry. AB - Sialylation is a glycosylation feature that occurs in different linkages at the non-reducing end of a glycan moiety, the linkage isomers are often differentially associated with various biological processes. Due to very similar physico chemical properties, the separation of isomeric sialylated glycopeptides remains challenging but of utmost importance in the biomedicine and biotechnology, including biomarker discovery, glyco-engineering and biopharmaceutical characterization. This study presents the implementation of a high-resolution separation platform based on capillary electrophoresis - mass spectrometry (CE MS) allowing for the selective analysis of alpha2,3- and alpha2,6-sialylated glycopeptides. These differentially linked glycopeptides showed an identical fragmentation pattern (collision induced dissociation) but different electrophoretic mobilities, allowing for baseline separation of the different linkages without the need for an extensive sample preparation. The different migration behavior between the two moieties was found to correlate with differences in pKa values. Using a novel methodology adapted from the so-called internal standard CE approach, a relative difference of 3.4.10-2 in pKa unit was determined. This approach was applied for the analysis of tryptic glycopeptides of prostate specific antigen, which shows highly complex and heterogeneous glycosylation. The developed platform therefore appears attractive for the identification of differentially linked sialic acids that may be related to pathological conditions. PMID- 28623328 TI - Platelet-rich plasma induces post-natal maturation of immature articular cartilage and correlates with LOXL1 activation. AB - Platelet-rich plasma (PRP) is used to stimulate the repair of acute and chronic cartilage damage even though there is no definitive evidence of how this is achieved. Chondrocytes in injured and diseased situations frequently re-express phenotypic biomarkers of immature cartilage so tissue maturation is a potential pathway for restoration of normal structure and function. We used an in vitro model of growth factor-induced maturation to perform a comparative study in order to determine whether PRP can also induce this specific form of remodeling that is characterised by increased cellular proliferation and tissue stiffness. Gene expression patterns specific for maturation were mimicked in PRP treated cartilage, with chondromodulin, collagen types II/X downregulated, deiodinase II and netrin-1 upregulated. PRP increased cartilage surface cell density 1.5-fold (P < 0.05), confirmed by bromodeoxyuridine incorporation and proportionate increases in proliferating cell nuclear antigen gene expression. Atomic force microscopy analysis of PRP and growth factor treated cartilage gave a 5-fold increase in stiffness correlating with a 10-fold upregulation of lysyl oxidase like-1 gene expression (P < 0.001). These data show PRP induces key aspects of post-natal maturation in immature cartilage and provides the basis to evaluate a new biological rationale for its activity when used clinically to initiate joint repair. PMID- 28623327 TI - Exendin-4 attenuates blast traumatic brain injury induced cognitive impairments, losses of synaptophysin and in vitro TBI-induced hippocampal cellular degeneration. AB - Mild blast traumatic brain injury (B-TBI) induced lasting cognitive impairments in novel object recognition and less severe deficits in Y-maze behaviors. B-TBI significantly reduced the levels of synaptophysin (SYP) protein staining in cortical (CTX) and hippocampal (HIPP) tissues. Treatment with exendin-4 (Ex-4) delivered by subcutaneous micro-osmotic pumps 48 hours prior to or 2 hours immediately after B-TBI prevented the induction of both cognitive deficits and B TBI induced changes in SYP staining. The effects of a series of biaxial stretch injuries (BSI) on a neuronal derived cell line, HT22 cells, were assessed in an in vitro model of TBI. Biaxial stretch damage induced shrunken neurites and cell death. Treatment of HT22 cultures with Ex-4 (25 to 100 nM), prior to injury, attenuated the cytotoxic effects of BSI and preserved neurite length similar to sham treated cells. These data imply that treatment with Ex-4 may represent a viable option for the management of secondary events triggered by blast-induced, mild traumatic brain injury that is commonly observed in militarized zones. PMID- 28623329 TI - Factors controlling the mechanical properties degradation and permeability of coal subjected to liquid nitrogen freeze-thaw. AB - Freeze-thaw induced fracturing coal by liquid nitrogen (LN2) injection exerts a significant positive effect on the fracture permeability enhancement of the coal reservoir. To evaluate the different freeze-thaw variables which modify the mechanical properties of treated coals, the effects of freezing time, number of freeze-thaw cycles, and the moisture content of coal were studied using combined uniaxial compression and acoustic emission testing systems. Freezing the samples with LN2 for increasing amounts of time degraded the strength of coal within a certain limit. Comparison to freezing time, freeze-thaw cycling caused much more damage to the coal strength. The third variable studied, freeze-thaw damage resulting from high moisture content, was restricted by the coal's moisture saturation limit. Based on the experimental results, equations describing the amount of damage caused by each of the different freeze-thaw variables were empirically regressed. Additionally, by using the ultrasonic wave detection method and fractal dimension analyses, how freeze-thaw induced fractures in the coal was quantitatively analyzed. The results also showed that the velocity of ultrasonic waves had a negative correlation with coal permeability, and the freeze-thaw cycles significantly augment the permeability of frozen-thawed coal masses. PMID- 28623330 TI - Assessing Spatial and Temporal Patterns of Observed Ground-level Ozone in China. AB - Elevated ground-level ozone (O3), which is an important aspect of air quality related to public health, has been causing increasing concern. This study investigated the spatiotemporal distribution of ground-level O3 concentrations in China using a dataset from the Chinese national air quality monitoring network during 2013-2015. This research analyzed the diurnal, monthly and yearly variation of O3 concentrations in both sparsely and densely populated regions. In particular, 6 major Chinese cities were selected to allow a discussion of variations in O3 levels in detail, Beijing, Chengdu, Guangzhou, Lanzhou, Shanghai, and Urumchi, located on both sides of the Heihe-Tengchong line. Data showed that the nationwide 3-year MDA8 of ground-level O3 was 80.26 MUg/m3. Ground-level O3 concentrations exhibited monthly variability peaking in summer and reaching the lowest levels in winter. The diurnal cycle reached a minimum in morning and peaked in the afternoon. Yearly average O3 MDA8 concentrations in Beijing, Chengdu, Lanzhou, and Shanghai in 2015 increased 12%, 25%, 34%, 22%, respectively, when compared with those in 2013. Compared with World Health Organization O3 guidelines, Beijing, Chengdu, Guangzhou, and Shanghai suffered O3 pollution in excess of the 8-hour O3 standard for more than 30% of the days in 2013 to 2015. PMID- 28623331 TI - Clinical Efficacy and Post-Treatment Seromarkers Associated with the Risk of Hepatocellular Carcinoma among Chronic Hepatitis C Patients. AB - This follow-up study enrolled chronic hepatitis C patients to evaluate the treatment efficacy and to identify post-treatment seromarkers associated with risk of hepatocellular carcinoma (HCC) among patients with a sustained virological response (SVR) or nonsustained virological response (NSVR). A total of 4639 patients who received pegylated interferon and ribavirin during 2004-2013 were followed until December 2014. HCC was confirmed through health examinations and data linkage with a national database. A total of 233 HCC cases were reported after 26,163 person-years of follow-up, indicating an incidence of 8.9 per 1000 person-years: 6.9 for SVR and 21.6 for NSVR per 1000 person-years. The associated risk of HCC in patients with SVR was 0.37 (0.22-0.63) for those without cirrhosis and 0.54 (0.31-0.92) for those with cirrhosis compared with their respective counterparts with NSVR. Among patients with SVR, advanced age, male gender, cirrhosis, decreased platelet count, and increased aspartate aminotransferase and alpha-fetoprotein levels were associated with HCC (p < 0.001). The treatment of chronic hepatitis C patients before they developed cirrhosis showed a higher efficacy than did the treatment of those who had already developed cirrhosis. Patients with SVR may still have a risk of HCC and need to be regularly monitored. PMID- 28623333 TI - Relation between the Co-O bond lengths and the spin state of Co in layered Cobaltates: a high-pressure study. AB - The pressure-response of the Co-O bond lengths and the spin state of Co ions in a hybrid 3d-5d solid-state oxide Sr2Co0.5Ir0.5O4 with a layered K2NiF4-type structure was studied by using hard X-ray absorption and emission spectroscopies. The Co-K and the Ir-L 3 X-ray absorption spectra demonstrate that the Ir5+ and the Co3+ valence states at ambient conditions are not affected by pressure. The Co Kbeta emission spectra, on the other hand, revealed a gradual spin state transition of Co3+ ions from a high-spin (S = 2) state at ambient pressure to a complete low-spin state (S = 0) at 40 GPa without crossing the intermediate spin state (S = 1). This can be well understood from our calculated phase diagram in which we consider the energies of the low spin, intermediate spin and high spin states of Co3+ ions as a function of the anisotropic distortion of the octahedral local coordination in the layered oxide. We infer that a short in-plane Co-O bond length (<1.90 A) as well as a very large ratio of Co-Oapex/Co-Oin-plane is needed to stabilize the IS Co3+, a situation which is rarely met in reality. PMID- 28623332 TI - Interaction of the Antimicrobial Peptide Aurein 1.2 and Charged Lipid Bilayer. AB - Aurein 1.2 is a potent antimicrobial peptide secreted by frog Litoria aurea. As a short membrane-active peptide with only 13 amino acids in sequence, it has been found to be residing on the surface of lipid bilayer and permeabilizing bacterial membranes at high concentration. However, the detail at the molecular level is largely unknown. In this study, we investigated the action of Aurein 1.2 in charged lipid bilayers composed of DMPC/DMPG. Oriented Circular Dichroism results showed that the peptide was on the surface of lipid bilayer regardless of the charged lipid ratio. Only at a very high peptide-to-lipid ratio (~1/10), the peptide became perpendicular to the bilayer, however no pore was detected by neutron in-plane scattering. To further understand how it interacted with charged lipid bilayers, we employed Small Angle Neutron Scattering to probe lipid distribution across bilayer leaflets in lipid vesicles. The results showed that Aurein 1.2 interacted strongly with negatively charged DMPG, causing strong asymmetry in lipid bilayer. At high concentration, while the vesicles were intact, we found additional structure feature on the bilayer. Our study provides a glimpse into how Aurein 1.2 disturbs anionic lipid-containing membranes without pore formation. PMID- 28623334 TI - Novel complex of HAT protein TIP60 and nuclear receptor PXR promotes cell migration and adhesion. AB - PXR is a member of nuclear receptor superfamily and a well-characterized mediator of xenobiotic metabolism. The classical mode of PXR activation involves its binding to appropriate ligand and subsequent heterodimerization with its partner RXR. However, various factors such as post-translational modifications and crosstalk with different cellular factors may also regulate the functional dynamics and behavior of PXR. In the present study, we have identified that TIP60, an essential lysine acetyltransferase protein interacts with unliganded PXR and together this complex promotes cell migration & adhesion. TIP60 utilizes its NR Box to interact with LBD region of PXR and acetylates PXR at lysine 170 to induce its intranuclear reorganization. Also, RXR is not required for TIP60-PXR complex formation and this complex does not induce ligand-dependent PXR target gene transactivation. Interestingly, we observed that PXR augments the catalytic activity of TIP60 for histones. This is the first report demonstrating the exclusive interaction of TIP60 with PXR and uncovers a potential role for the TIP60-PXR complex in cell migration and adhesion. PMID- 28623335 TI - Complex neuroanatomy in the rostrum of the Isle of Wight theropod Neovenator salerii. AB - The discovery of large, complex, internal canals within the rostra of fossil reptiles has been linked with an enhanced tactile function utilised in an aquatic context, so far in pliosaurids, the Cretaceous theropod Spinosaurus, and the related spinosaurid Baryonyx. Here, we report the presence of a complex network of large, laterally situated, anastomosing channels, discovered via micro-focus computed tomography (MUCT), in the premaxilla and maxilla of Neovenator, a mid sized allosauroid theropod from the Early Cretaceous of the UK. We identify these channels as neurovascular canals, that include parts of the trigeminal nerve; many branches of this complex terminate on the external surfaces of the premaxilla and maxilla where they are associated with foramina. Neovenator is universally regarded as a 'typical' terrestrial, predatory theropod, and there are no indications that it was aquatic, amphibious, or unusual with respect to the ecology or behaviour predicted for allosauroids. Accordingly, we propose that enlarged neurovascular facial canals shouldn't be used to exclusively support a model of aquatic foraging in theropods and argue instead that an enhanced degree of facial sensitivity may have been linked with any number of alternative behavioural adaptations, among them defleshing behaviour, nest selection/maintenance or social interaction. PMID- 28623336 TI - Molecular Identification of Multiple Antibiotic Resistant Fish Pathogenic Enterococcus faecalis and their Control by Medicinal Herbs. AB - The opportunistic fish pathogen, Enterococcus faecalis has been reported to cause mass mortality in several fish species in different countries. The objectives of this study were to (i) identify E. faecalis from the diseased fishes through molecular techniques; (ii) assess the antibiotic susceptibility profile of E. faecalis isolates; and (iii) control disease in tilapia fish by treatment with medicinal plant extracts. A total of 48 isolates were phenotypically identified as Enterococcus species from tilapia, stinging catfish and walking catfish cultivated in several fish farms in Gazipur. Ten randomly selected isolates were identified as E. faecalis by 16S rRNA gene sequencing. Artificial infection revealed that most of the isolates caused moderate to high mortality in fishes with characteristic disease symptoms. These isolates exhibited resistance to multiple antibiotics in vitro. Bioassay revealed that organic extracts of Tamarindus indica and Emblica officinalis leaves, Allium sativum bulb, and Syzygium aromaticum bud inhibited the growth of E. faecalis. Methanol extracts of A. sativum and methanol and acetone extracts of S. aromaticum significantly reduced the mortality of fish artificially infected with E. faecalis as both preventive and therapeutic agents. This is the first report on molecular identification, and herbal control of fish pathogenic E. faecalis in Bangladesh. PMID- 28623337 TI - Impact of Module-X2 and Carbohydrate Binding Module-3 on the catalytic activity of associated glycoside hydrolases towards plant biomass. AB - Cellulolytic enzymes capable of hydrolyzing plant biomass are secreted by microbial cells specifically in response to the carbon substrate present in the environment. These enzymes consist of a catalytic domain, generally appended to one or more non-catalytic Carbohydrate Binding Module (CBM), which enhances their activity towards recalcitrant biomass. In the present study, the genome of a cellulolytic microbe Paenibacillus polymyxa A18 was annotated for the presence of CBMs and analyzed their expression in response to the plant biomass and model polysaccharides Avicel, CMC and xylan using quantitative PCR. A gene that encodes X2-CBM3 was found to be maximally induced in response to the biomass and crystalline substrate Avicel. Association of X2-CBM3 with xyloglucanase and endoglucanase led to up to 4.6-fold increase in activity towards insoluble substrates. In the substrate binding study, module X2 showed a higher affinity towards biomass and phosphoric acid swollen cellulose, whereas CBM3 showed a higher affinity towards Avicel. Further structural modeling of X2 also indicated its potential role in substrate binding. Our findings highlighted the role of module X2 along with CBM3 in assisting the enzyme catalysis of agricultural residue and paved the way to engineer glycoside hydrolases for superior activity. PMID- 28623339 TI - Machine Learning and Network Analysis of Molecular Dynamics Trajectories Reveal Two Chains of Red/Ox-specific Residue Interactions in Human Protein Disulfide Isomerase. AB - The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening closing structure variations are highlighted on projected free energy landscapes. Then, important structural features that exhibit considerable differences in dynamics of redox states are extracted by statistical machine learning methods. Mapping the structural variations to time series of residue interaction networks also provides a holistic representation of the dynamical redox differences. With emphasizing on persistent long-lasting interactions, an approach is proposed that compiled these time series networks to a single dynamic residue interaction network (DRIN). Differential comparison of DRIN in oxidized and reduced states reveals chains of residue interactions that represent potential allosteric paths between catalytic and ligand binding sites of hPDI. PMID- 28623338 TI - High-resolution imaging of a cell-attached nanointerface using a gold nanoparticle two-dimensional sheet. AB - This paper proposes a simple, effective, non-scanning method for the visualization of a cell-attached nanointerface. The method uses localized surface plasmon resonance (LSPR) excited homogeneously on a two-dimensional (2D) self assembled gold-nanoparticle sheet. The LSPR of the gold-nanoparticle sheet provides high-contrast interfacial images due to the confined light within a region a few tens of nanometers from the particles and the enhancement of fluorescence. Test experiments on rat basophilic leukemia (RBL-2H3) cells with fluorescence-labeled actin filaments revealed high axial and lateral resolution even under a regular epifluorescence microscope, which produced higher quality images than those captured under a total internal reflection fluorescence (TIRF) microscope. This non-scanning-type, high-resolution imaging method will be an effective tool for monitoring interfacial phenomena that exhibit relatively rapid reaction kinetics in various cellular and molecular dynamics. PMID- 28623340 TI - Adenovirus-mediated suppression of hypothalamic glucokinase affects feeding behavior. AB - Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic beta cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART and orexigenic AgRP and NPY neuropeptides were altered in GK knockdown animals. Similarly, food intake, meal duration, frequency of eating events and the cumulative eating time were increased, whereas the intervals between meals were decreased in GK knockdown rats, suggesting a decrease in satiety. Thus, GK expression in the ventricular cells appears to play an important role in feeding behavior. PMID- 28623341 TI - Metabolic fingerprinting of bacteria by fluorescence lifetime imaging microscopy. AB - Bacterial populations exhibit a range of metabolic states influenced by their environment, intra- and interspecies interactions. The identification of bacterial metabolic states and transitions between them in their native environment promises to elucidate community behavior and stochastic processes, such as antibiotic resistance acquisition. In this work, we employ two-photon fluorescence lifetime imaging microscopy (FLIM) to create a metabolic fingerprint of individual bacteria and populations. FLIM of autofluorescent reduced nicotinamide adenine dinucleotide (phosphate), NAD(P)H, has been previously exploited for label-free metabolic imaging of mammalian cells. However, NAD(P)H FLIM has not been established as a metabolic proxy in bacteria. Applying the phasor approach, we create FLIM-phasor maps of Escherichia coli, Salmonella enterica serovar Typhimurium, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus epidermidis at the single cell and population levels. The bacterial phasor is sensitive to environmental conditions such as antibiotic exposure and growth phase, suggesting that observed shifts in the phasor are representative of metabolic changes within the cells. The FLIM-phasor approach represents a powerful, non-invasive imaging technique to study bacterial metabolism in situ and could provide unique insights into bacterial community behavior, pathology and antibiotic resistance with sub-cellular resolution. PMID- 28623342 TI - Hif-1alpha Knockdown Reduces Glycolytic Metabolism and Induces Cell Death of Human Synovial Fibroblasts Under Normoxic Conditions. AB - Increased glycolysis and HIF-1alpha activity are characteristics of cells under hypoxic or inflammatory conditions. Besides, in normal O2 environments, elevated rates of glycolysis support critical cellular mechanisms such as cell survival. The purpose of this study was to analyze the contribution of HIF-1alpha to the energy metabolism and survival of human synovial fibroblasts (SF) under normoxic conditions. HIF-1alpha was silenced using lentiviral vectors or small-interfering RNA (siRNA) duplexes. Expression analysis by qRT-PCR and western blot of known HIF-1alpha target genes in hypoxia demonstrated the presence of functional HIF 1alpha in normoxic SF and confirmed the glycolytic enzyme glyceraldehyde-3 phosphate dehydrogenase (GAPDH) as a HIF-1alpha target even in normoxia. HIF 1alpha silencing induced apoptotic cell death in cultured SF and, similarly, treatment with glycolytic, but not with OXPHOS inhibitors, induced SF death. Finally, in vivo HIF-1alpha targeting by siRNA showed a significant reduction in the viability of human SF engrafted into a murine air pouch. Our results demonstrate that SF are highly dependent on glycolytic metabolism and that HIF 1alpha plays a regulatory role in glycolysis even under aerobic conditions. Local targeting of HIF-1alpha provides a feasible strategy to reduce SF hyperplasia in chronic arthritic diseases. PMID- 28623343 TI - Data-driven nanomechanical sensing: specific information extraction from a complex system. AB - Smells are known to be composed of thousands of chemicals with various concentrations, and thus, the extraction of specific information from such a complex system is still challenging. Herein, we report for the first time that the nanomechanical sensing combined with machine learning realizes the specific information extraction, e.g. alcohol content quantification as a proof-of concept, from the smells of liquors. A newly developed nanomechanical sensor platform, a Membrane-type Surface stress Sensor (MSS), was utilized. Each MSS channel was coated with functional nanoparticles, covering diverse analytes. The smells of 35 liquid samples including water, teas, liquors, and water/EtOH mixtures were measured using the functionalized MSS array. We selected characteristic features from the measured responses and kernel ridge regression was used to predict the alcohol content of the samples, resulting in successful alcohol content quantification. Moreover, the present approach provided a guideline to improve the quantification accuracy; hydrophobic coating materials worked more effectively than hydrophilic ones. On the basis of the guideline, we experimentally demonstrated that additional materials, such as hydrophobic polymers, led to much better prediction accuracy. The applicability of this data driven nanomechanical sensing is not limited to the alcohol content quantification but to various fields including food, security, environment, and medicine. PMID- 28623344 TI - An essential role of PI3K in the control of West Nile virus infection. AB - The phosphatidyl-inositol-3 kinases (PI3K) pathway regulates a variety of cellular processes, including cell proliferation, RNA processing, protein translation, autophagy, apoptosis and antiviral immunity. Many viruses depend on PI3K signaling for replication. However, its role in flaviviral infection has not been clearly defined. Here we report that PI3K signaling is critical for the control of West Nile virus (WNV) infection by regulating type I IFN (IFN-I) response. Inhibition of PI3K activity by 3-methyl adenine (3-MA), Wortmannin (WM) and LY294002 (LY) increased viral titers by 3-16 folds in primary mouse macrophages, embryonic fibroblasts and human cell lines. Both 3-MA and LY repressed IFN-I mRNA and protein expression significantly. Surprisingly, WM enhanced the mRNA expression of IFN-I and TNF-alpha, and TNF-alpha protein production modestly, while dramatically decreased the secreted IFN-I. Further studies showed that the catalytic subunit p110delta of class I PI3K played a role in induction of antiviral immune responses. Lastly translocation of interferon regulatory factor 7(IRF7) from the cytosol to the nuclei was effectively blocked in the presence of PI3K inhibitors. Our results clearly define an antiviral role of PI3K by modulating immune responses and demonstrate differential mode of action of three PI3K inhibitors on IFN-I. PMID- 28623345 TI - Fabrication of modified hydrogenated castor oil/GPTMS-ZnO composites and effect on UV resistance of leather. AB - Leather products are made from the natural skin collagen fibers. It is vulnerable to the environmental factor such as solar ultraviolet irradiation in the using process. Therefore anti-UV performance is a very important quality, particularly for chrome-free leather. ZnO is a well-known UV absorber commonly used in the cosmetic industry. We have investigated its potential to increase the anti-UV performance of chrome-free leather. Modified hydrogenated castor oil/GPTMS-ZnO (MHCO/ GPTMS-ZnO) composites were prepared using spherical ZnO nanoparticles, hydrogenated castor oil, maleic anhydride and sodium bisulfite. MHCO/GPTMS-ZnO composites have better anti-UV ability and stability. MHCO/GPTMS-ZnO composites were applied to the leather processing. The treated samples were exposed to artificial sunlight. Anti-yellowing tests showed that MHCO/GPTMS-ZnO composites significantly improved anti-UV performance of leather. PMID- 28623346 TI - Early-onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman-Steiner and Roifman syndromes. AB - Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research. PMID- 28623347 TI - Updating the Phylogenetic Dating of New Caledonian Biodiversity with a Meta analysis of the Available Evidence. AB - For a long time, New Caledonia was considered a continental island, a fragment of Gondwana harbouring old clades that originated by vicariance and so were thought to be locally ancient. Recent molecular phylogenetic studies dating diversification and geological data indicating important events of submergence during the Paleocene and Eocene (until 37 Ma) brought evidence to dismiss this old hypothesis. In spite of this, some authors still insist on the idea of a local permanence of a Gondwanan biota, justifying this assumption through a complex scenario of survival by hopping to and from nearby and now-vanished islands. Based on a comprehensive review of the literature, we found 40 studies dating regional clades of diverse organisms and we used them to test the hypothesis that New Caledonian and inclusive Pacific island clades are older than 37 Ma. The results of this meta-analysis provide strong evidence for refuting the hypothesis of a Gondwanan refuge with a biota that originated by vicariance. Only a few inclusive Pacific clades (6 out of 40) were older than the oldest existing island. We suggest that these clades could have extinct members either on vanished islands or nearby continents, emphasizing the role of dispersal and extinction in shaping the present-day biota. PMID- 28623348 TI - A Unified Framework for Complex Networks with Degree Trichotomy Based on Markov Chains. AB - This paper establishes a Markov chain model as a unified framework for describing the evolution processes in complex networks. The unique feature of the proposed model is its capability in addressing the formation mechanism that can reflect the "trichotomy" observed in degree distributions, based on which closed-form solutions can be derived. Important special cases of the proposed unified framework are those classical models, including Poisson, Exponential, Power-law distributed networks. Both simulation and experimental results demonstrate a good match of the proposed model with real datasets, showing its superiority over the classical models. Implications of the model to various applications including citation analysis, online social networks, and vehicular networks design, are also discussed in the paper. PMID- 28623349 TI - Human bipedalism and body-mass index. AB - Body-mass index, abbreviated as BMI and given by M/H 2 with the mass M and the height H, has been widely used as a useful proxy to measure a general health status of a human individual. We generalise BMI in the form of M/H p and pursue to answer the question of the value of p for populations of animal species including human. We compare values of p for several different datasets for human populations with the ones obtained for other animal populations of fish, whales, and land mammals. All animal populations but humans analyzed in our work are shown to have p ~ 3 unanimously. In contrast, human populations are different: As young infants grow to become toddlers and keep growing, the sudden change of p is observed at about one year after birth. Infants younger than one year old exhibit significantly larger value of p than two, while children between one and five years old show p ~ 2, sharply different from other animal species. The observation implies the importance of the upright posture of human individuals. We also propose a simple mechanical model for a human body and suggest that standing and walking upright should put a clear division between bipedal human (p ~ 2) and other animals (p ~ 3). PMID- 28623350 TI - Multiplexed Spliced-Leader Sequencing: A high-throughput, selective method for RNA-seq in Trypanosomatids. AB - High throughput sequencing techniques are poorly adapted for in vivo studies of parasites, which require prior in vitro culturing and purification. Trypanosomatids, a group of kinetoplastid protozoans, possess a distinctive feature in their transcriptional mechanism whereby a specific Spliced Leader (SL) sequence is added to the 5'end of each mRNA by trans-splicing. This allows to discriminate Trypansomatid RNA from mammalian RNA and forms the basis of our new multiplexed protocol for high-throughput, selective RNA-sequencing called SL-seq. We provided a proof-of-concept of SL-seq in Leishmania donovani, the main causative agent of visceral leishmaniasis in humans, and successfully applied the method to sequence Leishmania mRNA directly from infected macrophages and from highly diluted mixes with human RNA. mRNA profiles obtained with SL-seq corresponded largely to those obtained from conventional poly-A tail purification methods, indicating both enumerate the same mRNA pool. However, SL-seq offers additional advantages, including lower sequencing depth requirements, fast and simple library prep and high resolution splice site detection. SL-seq is therefore ideal for fast and massive parallel sequencing of parasite transcriptomes directly from host tissues. Since SLs are also present in Nematodes, Cnidaria and primitive chordates, this method could also have high potential for transcriptomics studies in other organisms. PMID- 28623351 TI - Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap. AB - Angiopoietin-1 (Angpt1) is a glycoprotein ligand important for maintaining the vascular system. It signals via a receptor tyrosine kinase expressed on the surface on endothelial cells, Tie2. This receptor can undergo regulated ectodomain cleavage that releases the ligand-binding domain (sTie2) into the circulation. The concentration of sTie2 is increased in a range of conditions, including peripheral arterial disease and myocardial infarction, where it has been suggested to bind and block Angpt1 resulting in vascular dysfunction. Here we use a joint mathematical modelling and experimental approach to assess the potential impact of sTie2 on the ability of Angpt1 to signal. We find that the concentrations of sTie2 relative to Angpt1 required to suppress signalling by the ligand are more than ten-fold higher than those ever seen in normal or disease conditions. In contrast to the endogenous sTie2, an engineered form of sTie2, which presents dimeric ligand binding sites, inhibits Angpt1 signalling at seventy-fold lower concentrations. While loss of Tie2 ectodomain can suppress Angpt1 signalling locally in the cells in which the receptor is lost, our study shows that the resulting increase in circulating sTie2 is unlikely to affect Angpt1 activity elsewhere in the body. PMID- 28623352 TI - Effect of sliding friction in harmonic oscillators. AB - Sliding friction is ubiquitous in nature as are harmonic oscillators. However, when treating harmonic oscillators the effect of sliding friction is often neglected. Here, we propose a simple analytical model to include both viscous and sliding friction in common harmonic oscillator equations, allowing to separate these different types of dissipation. To compare this model with experimental data, a nanometric vibration was imposed on a quartz tuning fork, while an atomic force microscope tip was used to disturb its motion. We analyzed tuning fork resonance and 'ring down' experimental curves and for each case calculated the amount of sliding friction and of viscous damping, finding an agreement between the two different experiments and the model proposed. PMID- 28623353 TI - The efficacy and toxicities of intensive induction chemotherapy followed by concurrent chemoradiotherapy in nasopharyngeal carcinoma patients with N3 disease. AB - To assess the feasibility, efficacy and safety of 4 cycles of induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CRT) in nasopharyngeal carcinoma (NPC) patients with N3 disease. ICT consisting of paclitaxel (135 mg/m2) and nedaplatin (80 mg/m2) given every 3 weeks for 4 cycles followed by cisplatin-based CRT was planned. 22 patients completed 4 cycles of TP regimen ICT and the CRT according to the protocol. After 4 cycles of ICT, the ORR of the primary site was 100% (CR 22.7%, PR 77.3%), and that of the cervical lymph nodes was 95.5% (CR 27.3%, PR 68.2%). After the completion of CRT, the ORR of the primary site was 100% (CR 81.8%, PR 18.2%), and that of the cervical lymph nodes also reached 100% (CR 86.4%, PR 3.6%). The main hematological adverse events were grade 1 to 2 (G1/G2) neutropenia/anemia without febrile neutropenia. The most frequent toxicities during CRT were G1/G2 neutropenia, asthenia, oropharyngeal mucositis and skin injury. The median follow-up time was 46.5 (14 to 75) months. The 3-year PFS, DMFS, LRFS and OS were 81.8%, 81.8%, 100%, and 90.9%, respectively. The results suggest that intensive ICT followed by CRT in NPC patients with N3 disease is effective and well tolerated. PMID- 28623354 TI - Tomographic Particle Image Velocimetry using Smartphones and Colored Shadows. AB - We demonstrate the viability of using four low-cost smartphone cameras to perform Tomographic PIV. We use colored shadows to imprint two or three different time steps on the same image. The back-lighting is accomplished with three sets of differently-colored pulsed LEDs. Each set of Red, Green & Blue LEDs is shone on a diffuser screen facing each of the cameras. We thereby record the RGB-colored shadows of opaque suspended particles, rather than the conventionally used scattered light. We subsequently separate the RGB color channels, to represent the separate times, with preprocessing to minimize noise and cross-talk. We use commercially available Tomo-PIV software for the calibration, 3-D particle reconstruction and particle-field correlations, to obtain all three velocity components in a volume. Acceleration estimations can be done thanks to the triple pulse illumination. Our test flow is a vortex ring produced by forcing flow through a circular orifice, using a flexible membrane, which is driven by a pressurized air pulse. Our system is compared to a commercial stereoscopic PIV system for error estimations. We believe this proof of concept experiment will make this technique available for education, industry and scientists for a fraction of the hardware cost needed for traditional Tomo-PIV. PMID- 28623355 TI - Epigenetic and antitumor effects of platinum(IV)-octanoato conjugates. AB - We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values are approximately two orders of magnitude lower than those of clinically used cisplatin or Pt(IV) derivatives with biologically inactive axial ligands). Importantly, Pt(IV)diOA overcomes resistance to cisplatin, is significantly more potent than its branched Pt(IV) valproato isomer and exhibits promising in vivo antitumor activity. The potency of Pt(IV)diOA is a consequence of several factors including enhanced cellular accumulation correlating with enhanced DNA platination and cytotoxicity. Pt(IV)diOA induces DNA hypermethylation and reduces mitochondrial membrane potential in cancer cells at levels markedly lower than the IC50 value of free OA suggesting the synergistic action of platinum and OA moieties. Collectively, the remarkable antitumor effects of Pt(IV)diOA are a consequence of the enhanced cellular uptake which makes it possible to simultaneously accumulate high levels of both cisplatin and OA in cells. The simultaneous dual action of cisplatin and OA by different mechanisms in tumor cells may result in a markedly enhanced and unique antitumor effects of Pt(IV) prodrugs. PMID- 28623356 TI - High-Risk Human Papillomavirus E7 Alters Host DNA Methylome and Represses HLA-E Expression in Human Keratinocytes. AB - Human papillomavirus (HPV) infection distinctly alters methylation patterns in HPV-associated cancer. We have recently reported that HPV E7-dependent promoter hypermethylation leads to downregulation of the chemokine CXCL14 and suppression of antitumor immune responses. To investigate the extent of gene expression dysregulated by HPV E7-induced DNA methylation, we analyzed parallel global gene expression and DNA methylation using normal immortalized keratinocyte lines, NIKS, NIKS-16, NIKS-18, and NIKS-16?E7. We show that expression of the MHC class I genes is downregulated in HPV-positive keratinocytes in an E7-dependent manner. Methylome analysis revealed hypermethylation at a distal CpG island (CGI) near the HLA-E gene in NIKS-16 cells compared to either NIKS cells or NIKS-16?E7 cells, which lack E7 expression. The HLA-E CGI functions as an active promoter element which is dramatically repressed by DNA methylation. HLA-E protein expression on cell surface is downregulated by high-risk HPV16 and HPV18 E7 expression, but not by low-risk HPV6 and HPV11 E7 expression. Conversely, demethylation at the HLA-E CGI restores HLA-E protein expression in HPV-positive keratinocytes. Because HLA-E plays an important role in antiviral immunity by regulating natural killer and CD8+ T cells, epigenetic downregulation of HLA-E by high-risk HPV E7 may contribute to virus-induced immune evasion during HPV persistence. PMID- 28623357 TI - Adiponectin regulates BMSC osteogenic differentiation and osteogenesis through the Wnt/beta-catenin pathway. AB - Recent studies have demonstrated the stimulatory effects of adiponectin on bone formation, but the mechanism underlying these effects remains unclear. The Wnt/beta-catenin pathway, one of the most important pathways in osteogenesis, has rarely been associated with the osteogenic effects of adiponectin in previous studies. The present study was designed to investigate the effects of adiponectin on bone mesenchymal stem cell (BMSC) osteogenic differentiation and bone formation through the Wnt/beta-catenin pathway. We detected adiponectin receptor expression in BMSCs, constructed a recombinant adenovirus containing the human adiponectin gene, and then used the adenovirus to transfect BMSCs in vitro or injected the adenovirus into bone defect areas in animal models. Wnt/beta-catenin pathway and osteogenesis were detected by real-time PCR, western blotting, immunofluorescence, HE staining and micro-CT. In both our in vivo and in vitro experiments, we detected higher gene and protein expression levels of the Wnt/beta-catenin pathway-related factors beta-catenin and cyclinD1 in adiponectin transgenic BMSCs and rats. Similar results were noted regarding the gene and protein expression levels of osteogenesis-related genes. In addition, more new bone formation was observed in the adiponectin-treated groups. Our results indicate that adiponectin could facilitate BMSC osteogenic differentiation and osteogenesis, and the Wnt/beta-catenin pathway was involved in the osteogenic effect of adiponectin. PMID- 28623358 TI - The role of PTEN - HCV core interaction in hepatitis C virus replication. AB - Hepatitis C virus (HCV) infection leads to severe liver diseases including hepatocellular carcinoma (HCC). Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumour suppressor, is frequently mutated or deleted in HCC tumors. PTEN has previously been demonstrated to inhibit HCV secretion. In this study, we determined the effects of PTEN on the other steps in HCV life cycle, including entry, translation, and replication. We showed that PTEN inhibits HCV entry through its lipid phosphatase activity. PTEN has no effect on HCV RNA translation. PTEN decreases HCV replication and the protein phosphatase activity of PTEN is essential for this function. PTEN interacts with the HCV core protein and requires R50 in domain I of HCV core and PTEN residues 1-185 for this interaction. This interaction is required for PTEN-mediated inhibition of HCV replication. This gives rise to a reduction in PTEN levels and intracellular lipid abundance, which may in turn regulate HCV replication. HCV core domain I protein increases the lipid phosphatase activity of PTEN in an in vitro assay, suggesting that HCV infection can also regulate PTEN. Taken together, our results demonstrated an important regulatory role of PTEN in the HCV life cycle. PMID- 28623359 TI - Allosteric modulatory effects of SRI-20041 and SRI-30827 on cocaine and HIV-1 Tat protein binding to human dopamine transporter. AB - Dopamine transporter (DAT) is the target of cocaine and HIV-1 transactivator of transcription (Tat) protein. Identifying allosteric modulatory molecules with potential attenuation of cocaine and Tat binding to DAT are of great scientific and clinical interest. We demonstrated that tyrosine 470 and 88 act as functional recognition residues in human DAT (hDAT) for Tat-induced inhibition of DA transport and transporter conformational transitions. Here we investigated the allosteric modulatory effects of two allosteric ligands, SRI-20041 and SRI-30827 on cocaine binding on wild type (WT) hDAT, Y470 H and Y 88 F mutants. Effect of SRI-30827 on Tat-induced inhibition of [3H]WIN35,428 binding was also determined. Compared to a competitive DAT inhibitor indatraline, both SRI-compounds displayed a similar decrease (30%) in IC50 for inhibition of [3H]DA uptake by cocaine in WT hDAT. The addition of SRI-20041 or SRI-30827 following cocaine slowed the dissociation rate of [3H]WIN35,428 binding in WT hDAT relative to cocaine alone. Moreover, Y470H and Y88F hDAT potentiate the inhibitory effect of cocaine on DA uptake and attenuate the effects of SRI-compounds on cocaine-mediated dissociation rate. SRI-30827 attenuated Tat-induced inhibition of [3H]WIN35,428 binding. These observations demonstrate that tyrosine 470 and 88 are critical for allosteric modulatory effects of SRI-compounds on the interaction of cocaine with hDAT. PMID- 28623360 TI - Endothelial Cell-derived Extracellular Vesicles Size-dependently Exert Procoagulant Activity Detected by Thromboelastometry. AB - Endothelial cells (ECs) are major modulators of hemostasis by expressing and releasing pro- and anticoagulant mediators into the circulation. Previous studies showed that cultured ECs release procoagulant mediators into cell culture supernatants as evidenced by the reduction of viscoelastic clotting time. This effect was reversed with an anti-tissue factor antibody. Here, we aimed to investigate whether tissue factor (TF) was released by endothelial-derived extracellular vesicles (EVs) and which portion of the released vesicles displays the most prominent procoagulant properties. After stimulation of ECs with tumor necrosis factor-alpha (TNF-alpha) the supernatants of EC cultures were subjected to differential centrifugation steps to collect larger and smaller EVs which were then characterised by nanoparticle tracking analysis (NTA) and flow cytometry. Mixed with fresh human blood and analysed by thromboelastometry EVs exerted a significant procoagulant stimulus, which could be partly reversed by addition of an anti-TF antibody. Moreover, TF activity was confirmed in the centrifuged fractions. In summary, our results provide evidence of the procoagulant potential of smaller and larger endothelial-derived EV fractions detected by thromboelastometry. The observed effect is most likely due to the release of TF bearing EVs of different dimensions, which are released upon TNF-alpha stimulation of endothelial cell cultures. PMID- 28623361 TI - Burden of sleep disturbances and associated risk factors: A cross-sectional survey among HIV-infected persons on antiretroviral therapy across China. AB - This study evaluated the prevalence and factors associated with sleep disturbance in a large cohort of HIV-infected patients across China. A cross-sectional study was conducted among HIV-infected patients on antiretroviral therapy at 20 AIDS clinics. The Pittsburgh Sleep Quality Index was self-administered by subjects. Socio-demographic characteristics, medical history and HIV-related clinical data were collected. 4103 patients had complete data for analysis. Sleep disturbances were observed in 43.1% of patients. Associated factors in multivariable analysis included psychological factors: anxiety (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.44-4.00; P < 0.001), depression (OR, 2.09; 95% CI, 1.70-2.57; P < 0.001), and both anxiety and depression (OR, 5.90; 95% CI, 4.86-7.16; P < 0.001); sociodemographic factors: MSM (OR, 1.26; 95% CI, 1.04-1.52; P = 0.018), being single (OR, 1.45; 95%CI 1.21-1.74; P < 0.001), higher education (OR, 1.25; 95% CI, 1.03-1.53; P = 0.025) ; and clinical factors: suboptimal adherence (OR,1.51; 95% CI,1.23-1.85; P < 0.001), regimen-switching (OR, 1.94; 95% CI, 1.12 3.35; P = 0.018), and antidepressant use (OR, 1.98; 95% CI, 1.47-2.67; P = 0.044). Prevalence of sleep disturbance is high in this large Chinese cohort. Associated factors appear related to psychological and social-demographic factors. Health workers may consider routinely assessing sleep disturbances among HIV-infected patients, especially in the first three months after HIV diagnosis, and referring for mental health services, which may positively impact adherence to treatment. PMID- 28623363 TI - Machine learning workflow to enhance predictions of Adverse Drug Reactions (ADRs) through drug-gene interactions: application to drugs for cutaneous diseases. AB - Adverse drug reactions (ADRs) pose critical public health issues, affecting over 6% of hospitalized patients. While knowledge of potential drug-drug interactions (DDI) is necessary to prevent ADR, the rapid pace of drug discovery makes it challenging to maintain a strong insight into DDIs. In this study, we present a novel literature-mining framework for enhancing the predictions of DDIs and ADR types by integrating drug-gene interactions (DGIs). The ADR types were adapted from a DDI corpus, including i) adverse effect; ii) effect at molecular level; iii) effect related to pharmacokinetics; and iv) DDIs without known ADRs. By using random forest classifier our approach achieves an F-score of 0.87 across the ADRs classification using only the DDI features. We then enhanced the performance of the classifier by including DGIs (F-score = 0.90), and applied the classification model trained with the DDI corpus to identify the drugs that might interact with the drugs for cutaneous diseases. We successfully predict previously known ADRs for drugs prescribed to cutaneous diseases, and are also able to identify promising new ADRs. PMID- 28623362 TI - Super-resolution microscopy with very large working distance by means of distributed aperture illumination. AB - The limits of conventional light microscopy ("Abbe-Limit") depend critically on the numerical aperture (NA) of the objective lens. Imaging at large working distances or a large field-of-view typically requires low NA objectives, thereby reducing the optical resolution to the multi micrometer range. Based on numerical simulations of the intensity field distribution, we present an illumination concept for a super-resolution microscope which allows a three dimensional (3D) optical resolution around 150 nm for working distances up to the centimeter regime. In principle, the system allows great flexibility, because the illumination concept can be used to approximate the point-spread-function of conventional microscope optics, with the additional benefit of a customizable pupil function. Compared with the Abbe-limit using an objective lens with such a large working distance, a volume resolution enhancement potential in the order of 104 is estimated. PMID- 28623364 TI - Distribution and kinetics of the Kv1.3-blocking peptide HsTX1[R14A] in experimental rats. AB - The peptide HsTX1[R14A] is a potent and selective blocker of the voltage-gated potassium channel Kv1.3, which is a highly promising target for the treatment of autoimmune diseases and other conditions. In order to assess the biodistribution of this peptide, it was conjugated with NOTA and radiolabelled with copper-64. [64Cu]Cu-NOTA-HsTX1[R14A] was synthesised in high radiochemical purity and yield. The radiotracer was evaluated in vitro and in vivo. The biodistribution and PET studies after intravenous and subcutaneous injections showed similar patterns and kinetics. The hydrophilic peptide was rapidly distributed, showed low accumulation in most of the organs and tissues, and demonstrated high molecular stability in vitro and in vivo. The most prominent accumulation occurred in the epiphyseal plates of trabecular bones. The high stability and bioavailability, low normal-tissue uptake of [64Cu]Cu-NOTA-HsTX1[R14A], and accumulation in regions of up-regulated Kv channels both in vitro and in vivo demonstrate that HsTX1[R14A] represents a valuable lead for conditions treatable by blockade of the voltage-gated potassium channel Kv1.3. The pharmacokinetics shows that both intravenous and subcutaneous applications are viable routes for the delivery of this potent peptide. PMID- 28623365 TI - Preparation of core-shell structure KClO4@Al/CuO Nanoenergetic material and enhancement of thermal behavior. AB - In this paper, a solvent/non-solvent synthetic approach has been utilized in preparing a new nanoenergetic material KClO4@Al/CuO by coating Al/CuO nanocomposites particles with a layer of nanoscale oxidizer KClO4. The coating process and mechanism are discussed. The composites of Al/CuO are uniformly mixed by mechanical ball milling process and CuO acts as a catalytic metallic oxide. The ternary mixtures KClO4@Al/CuO were characterized by X-ray diffraction (XRD) and the results reveal that after ball-milling and chemical synthesis process, the phase compositions haven't changed. Scan electron microscopy (SEM) images show that these energetic nanocomposites consist of small clusters of Al/CuO that are in intimate contact with a continuous and clear-cut KClO4 layer (100-400 nm). In a Scanning transmission electron microscopy (STEM) elemental map, high K/Cl intensity on the perimeter of the nanoparticles and high Cu/Al content in the interior powerfully demonstrated the KClO4@Al/CuO core-shell nanostructure. Electrical ignition experiments and pressure cell test prove that these nanoenergetic composites are more sensitive to ignition with much higher burning rate than traditional formulations (conventional counterparts). To quantify the enhancement of thermal behavior, Thermogravimetry (TG) and Differential scanning calorimetry (DSC) were performed and the results show that the burning rate of these energetic nanocomposites nearly tripled. PMID- 28623366 TI - A novel imaging method for correlating 2D light microscopic data and 3D volume data based on block-face imaging. AB - We have developed an imaging method designated as correlative light microscopy and block-face imaging (CoMBI), which contributes to improve the reliability of morphological analyses. This method can collect both the frozen sections and serial block-face images in a single specimen. The frozen section can be used for conventional light microscopic analysis to obtain 2-dimensional (2D) anatomical and molecular information, while serial block-face images can be used as 3 dimensional (3D) volume data for anatomical analysis. Thus, the sections maintain positional information in the specimen, and allows the correlation of 2D microscopic data and 3D volume data in a single specimen. The subjects can vary in size and type, and can cover most specimens encountered in biology. In addition, the required system for our method is characterized by cost effectiveness. Here, we demonstrated the utility of CoMBI using specimens ranging in size from several millimeters to several centimeters, i.e., mouse embryos, human brainstem samples, and stag beetle larvae, and present successful correlation between the 2D light microscopic images and 3D volume data in a single specimen. PMID- 28623367 TI - Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative. AB - The increased incidence of antibiotic resistant 'superbugs' has amplified the use of broad spectrum antibiotics worldwide. An unintended consequence of antimicrobial treatment is disruption of the gastrointestinal microbiota, resulting in susceptibility to opportunistic pathogens, such as Clostridium difficile. Paradoxically, treatment of C. difficile infections (CDI) also involves antibiotic use, leaving patients susceptible to re-infection. This serious health threat has led to an urgent call for the development of new therapeutics to reduce or replace the use of antibiotics to treat bacterial infections. To address this need, we have developed colostrum-derived antibodies for the prevention and treatment of CDI. Pregnant cows were immunised to generate hyperimmune bovine colostrum (HBC) containing antibodies that target essential C. difficile virulence components, specifically, spores, vegetative cells and toxin B (TcdB). Mouse infection and relapse models were used to compare the capacity of HBC to prevent or treat primary CDI as well as prevent recurrence. Administration of TcdB-specific colostrum alone, or in combination with spore or vegetative cell targeted colostrum, prevents and treats C. difficile disease in mice and reduces disease recurrence by 67%. C. difficile-specific colostrum should be re considered as an immunotherapeutic for the prevention or treatment of primary or recurrent CDI. PMID- 28623368 TI - Regulation of sub-compartmental targeting and folding properties of the Prion like protein Shadoo. AB - Shadoo (Sho), a member of prion protein family, has been shown to prevent embryonic lethality in Prnp 0/0 mice and to be reduced in the brains of rodents with terminal prion diseases. Sho can also affect PrP structural dynamics and can increase the prion conversion into its misfolded isoform (PrPSc), which is amyloidogenic and strictly related to expression, intracellular localization and association of PrPC to lipid rafts. We reasoned that if Sho possesses a natural tendency to convert to amyloid-like forms in vitro, it should be able to exhibit "prion-like" properties, such as PK-resistance and aggregation state, also in live cells. We tested this hypothesis, by different approaches in neuronal cells, finding that Sho shows folding properties partially dependent on lipid rafts integrity whose alteration, as well as proteasomal block, regulated generation of intermediate Sho isoforms and exacerbated its misfolding. Moreover, a 18 kDa isoform of Sho, likely bearing the signal peptide, was targeted to mitochondria by interacting with the molecular chaperone TRAP1 which, in turn controlled Sho dual targeting to ER or mitochondria. Our studies contribute to understand the role of molecular chaperones and of PrP-related folding intermediates in "prion like" conversion. PMID- 28623369 TI - Looking beyond the imaging plane: 3D needle tracking with a linear array ultrasound probe. AB - Ultrasound is well suited for guiding many minimally invasive procedures, but its use is often precluded by the poor visibility of medical devices. When devices are not visible, they can damage critical structures, with life-threatening complications. Here, we developed the first ultrasound probe that comprises both focused and unfocused transducer elements to provide both 2D B-mode ultrasound imaging and 3D ultrasonic needle tracking. A fibre-optic hydrophone was integrated into a needle to receive Golay-coded transmissions from the probe and these data were processed to obtain tracking images of the needle tip. The measured tracking accuracy in water was better than 0.4 mm in all dimensions. To demonstrate the clinical potential of this system, insertions were performed into the spine and the uterine cavity, in swine and pregnant ovine models in vivo. In both models, the SNR ranged from 13 to 38 at depths of 22 to 38 mm, at out-of plane distances of 1 to 15 mm, and at insertion angles of 33 to 42 degrees relative to the probe surface normal. This novel ultrasound imaging/tracking probe has strong potential to improve procedural outcomes by providing 3D needle tip locations that are co-registered to ultrasound images, while maintaining compatibility with current clinical workflow. PMID- 28623370 TI - Rho-kinase inhibitor Y-27632 and hypoxia synergistically enhance chondrocytic phenotype and modify S100 protein profiles in human chondrosarcoma cells. AB - Articular chondrocytes are slowly dividing cells that tend to lose their cell type-specific phenotype and ability to produce structurally and functionally correct cartilage tissue when cultured. Thus, culture conditions, which enhance the maintenance of chondrocyte phenotype would be very useful for cartilage research. Here we show that Rho-kinase inhibition by Y-27632 under hypoxic conditions efficiently maintains and even enhances chondrocyte-specific extracellular matrix production by chondrocytic cells. The effects of long-term Y 27632 exposure to human chondrosarcoma 2/8 cell phenotype maintenance and extracellular matrix production were studied at normoxia and at a 5% low oxygen atmosphere. Y-27632 treatment at normoxia induced ACAN and COL2A1 gene up regulation and a minor increase of sulfated glycosaminoglycans (sGAGs), while type II collagen expression was not significantly up-regulated. A further increase in expression of ACAN and COL2A1 was achieved with Y-27632 treatment and hypoxia. The production of sGAGs increased by 65.8%, and ELISA analysis revealed a 6-fold up-regulation of type II collagen. Y-27632 also induced the up regulation of S100-A1 and S100-B proteins and modified the expression of several other S100 protein family members, such as S100-A4, S100-A6, S100-A13 and S100 A16. The up-regulation of S100-A1 and S100-B proteins is suggested to enhance the chondrocytic phenotype of these cells. PMID- 28623371 TI - Chemosensory sensitivity reflects reproductive status in the ant Harpegnathos saltator. AB - Insects communicate with pheromones using sensitive antennal sensilla. Although trace amounts of pheromones can be detected by many insects, context-dependent increased costs of high sensitivity might lead to plasticity in sensillum responsiveness. We have functionally characterized basiconic sensilla of the ant Harpegnathos saltator for responses to general odors in comparison to cuticular hydrocarbons which can act as fertility signals emitted by the principal reproductive(s) of a colony to inhibit reproduction by worker colony members. When released from inhibition workers may become reproductive gamergates. We observed plasticity in olfactory sensitivity after transition to reproductive status with significant reductions in electrophysiological responses to several long-chained cuticular hydrocarbons. Although gamergates lived on average five times longer than non-reproductive workers, the shift to reproductive status rather than age differences matched the pattern of changes in olfactory sensitivity. Decreasing sensillum responsiveness to cuticular hydrocarbons could potentially reduce mutually inhibitory or self-inhibitory effects on gamergate reproduction. PMID- 28623372 TI - Towards Printable Natural Dielectric Cloaks via Inverse Scattering Techniques. AB - The synthesis of non-magnetic 2D dielectric cloaks as proper solutions of an inverse scattering problem is addressed in this paper. Adopting the relevant integral formulation governing the scattering phenomena, analytic and numerical approaches are exploited to provide new insights on how frequency and direction of arrival of the incoming wave may influence the cloaking mechanism in terms of permittivity distribution within the cover region. In quasi-static (subwavelength) regime a solution is analytically derived in terms of homogeneous artificial dielectric cover with epsilon < epsilon 0, which is found to be a necessary and sufficient condition for achieving omnidirectional cloaking. On the other hand, beyond quasi-static regime, the cloaking problem is addressed as an optimization task looking for only natural dielectric coatings with epsilon > epsilon 0 able to hide the object for a given number of directions of the incident field. Simulated results confirm the validity of both analytic and numerical methodologies and allow to estimate effective bandwidths both in terms of frequency range and direction of arrival of the impinging field. PMID- 28623373 TI - Metabolic and evolutionary patterns in the extremely acidophilic archaeon Ferroplasma acidiphilum YT. AB - Ferroplasmaceae represent ubiquitous iron-oxidising extreme acidophiles with a number of unique physiological traits. In a genome-based study of Ferroplasma acidiphilum YT, the only species of the genus Ferroplasma with a validly published name, we assessed its central metabolism and genome stability during a long-term cultivation experiment. Consistently with physiology, the genome analysis points to F. acidiphilum YT having an obligate peptidolytic oligotrophic lifestyle alongside with anaplerotic carbon assimilation. This narrow trophic specialisation abridges the sugar uptake, although all genes for glycolysis and gluconeogenesis, including bifunctional unidirectional fructose 1,6-bisphosphate aldolase/phosphatase, have been identified. Pyruvate and 2-oxoglutarate dehydrogenases are substituted by 'ancient' CoA-dependent pyruvate and alpha ketoglutarate ferredoxin oxidoreductases. In the lab culture, after ~550 generations, the strain exhibited the mutation rate of >=1.3 * 10-8 single nucleotide substitutions per site per generation, which is among the highest values recorded for unicellular organisms. All but one base substitutions were G:C to A:T, their distribution between coding and non-coding regions and synonymous-to-non-synonymous mutation ratios suggest the neutral drift being a prevalent mode in genome evolution in the lab culture. Mutations in nature seem to occur with lower frequencies, as suggested by a remarkable genomic conservation in F. acidiphilum YT variants from geographically distant populations. PMID- 28623374 TI - Nucleotide based covalent inhibitors of KRas can only be efficient in vivo if they bind reversibly with GTP-like affinity. AB - Simple reversible competitive inhibition of nucleotide binding of GTP to Ras family GTPases has long been recognized as an unlikely approach to manipulating the activity of such proteins for experimental or therapeutic purposes. This is due to the high affinity of GTP to GTPases coupled with high cellular GTP concentrations, but also to problems of specificity for the highly conserved binding sites in GTPases. A recent approach suggested that these problems might be overcome by using GDP derivatives that can undergo a covalent reaction with disease specific mutants, in particular addressing inhibition of KRasG12C using GDP equipped with an electrophilic group at the beta-phosphate. We show here that a major drawback to this approach is a loss of reversible affinity of such beta modified derivatives for Ras of at least 104 compared to GTP and GDP. With the help of a thorough kinetic characterization, we show that this leads to covalent reaction times that are too slow to make the compounds attractive for intracellular use, but that generation of a hypothetical reactive GDP derivative that retains the high reversible affinity of GDP/GTP to Ras might be a viable alternative. PMID- 28623377 TI - Collision and composite tumors; radiologic and pathologic correlation. AB - The terms composite and collision tumors have been used interchangeably throughout radiological literature. Both composite and collision tumors involve two morphologically and immunohistochemically distinct neoplasms coexisting within a single organ. However, collision tumors lack the histological cellular intermingling seen in composite tumors. Composite tumors often arise from a common driver mutation that induces a divergent histology from a common neoplastic source while collision tumors may arise from coincidental neoplastic change. The purpose of this review is to provide an overview of abdominal composite and collision tumors by discussing hallmark radiographic and pathological presentations of rare hepatic, renal, and adrenal case studies. A better understanding of the presentation of each lesion is imperative for proper recognition, diagnosis, and management of these unique tumor presentations. PMID- 28623375 TI - Skin Immunity. AB - Skin is the largest organ of the body with a complex network of multitude of cell types that perform plastic and dynamic cellular communication to maintain several vital processes such as inflammation, immune response including induction of tolerance and disease prevention, wound healing, and angiogenesis. Of paramount importance are immunological functions of the skin that protect from harmful exposure coming from external and internal environments. Awareness of skin immunity can provide a better comprehension of inflammation, autoimmunity, cancer, graft-versus-host disease, vaccination, and immunotherapy approaches. This paper will update on what we currently know about immune sentinels contributing to skin immunity. PMID- 28623376 TI - EANM/EARL harmonization strategies in PET quantification: from daily practice to multicentre oncological studies. AB - Quantitative positron emission tomography/computed tomography (PET/CT) can be used as diagnostic or prognostic tools (i.e. single measurement) or for therapy monitoring (i.e. longitudinal studies) in multicentre studies. Use of quantitative parameters, such as standardized uptake values (SUVs), metabolic active tumor volumes (MATVs) or total lesion glycolysis (TLG), in a multicenter setting requires that these parameters be comparable among patients and sites, regardless of the PET/CT system used. This review describes the motivations and the methodologies for quantitative PET/CT performance harmonization with emphasis on the EANM Research Ltd. (EARL) Fluorodeoxyglucose (FDG) PET/CT accreditation program, one of the international harmonization programs aiming at using FDG PET as a quantitative imaging biomarker. In addition, future accreditation initiatives will be discussed. The validation of the EARL accreditation program to harmonize SUVs and MATVs is described in a wide range of tumor types, with focus on therapy assessment using either the European Organization for Research and Treatment of Cancer (EORTC) criteria or PET Evaluation Response Criteria in Solid Tumors (PERCIST), as well as liver-based scales such as the Deauville score. Finally, also presented in this paper are the results from a survey across 51 EARL-accredited centers reporting how the program was implemented and its impact on daily routine and in clinical trials, harmonization of new metrics such as MATV and heterogeneity features. PMID- 28623378 TI - Carotid Stenting in Neuroradiology : A Short Journey from the Past to Current Debates. AB - After a period of stagnation due to negative results of randomized trials for patients with symptomatic stenosis, the relevance of carotid artery stenting (CAS) is increasing again. CAS has become an important and evidence-based part of interventional stroke treatment. Our ability to manage acute recanalization of carotid occlusions and other niche indications properly led some skeptical neurologists to trust in carotid intervention for elective cases as well. The evolution of CAS from initial euphoria to more realistic views under consideration of trial results and guidelines is reviewed. Quality assurance in Germany proves that CAS complication rates within the carotid endarterectomy (CEA) quality criteria are feasible even with higher proportions of high-risk patients. Recent trial results showed that long-term efficacy of CAS or CEA are not significantly different. Other than in symptomatic stenoses, acute complication rates of both means treatment does not differ in asymptomatic patients, where medical therapy becomes increasingly competitive. Technical issues of CAS like the cell design of stents or the usefulness of embolic protection are still under discussion. We will see whether CAS results will further improve over time. Standardized techniques, proper training, and patient selection are important for acute and elective cases. PMID- 28623380 TI - [Contaminants in food - successes, challenges and trends]. PMID- 28623379 TI - Cathelicidin-deficient mice exhibit increased survival and upregulation of key inflammatory response genes following cecal ligation and puncture. AB - : Antimicrobial peptides possess a myriad of molecular properties including bacterial killing and the regulation of many aspects of innate immunity. Cathelicidins are a group of antimicrobial peptides widely investigated by the scientific community. Many studies have focused on the bactericidal and pro inflammatory roles of cathelicidins. Because the role of endogenous cathelicidin expression remains obscure in deep-seated systemic infections, we induced sepsis in cathelicidin knockout and wild-type (WT) mice by cecal ligation and puncture, performing transcriptome screening by DNA microarray in conjunction with other immunologic assays. Cathelicidin-deficient mice showed increased survival compared to WT mice in this established experimental model of polymicrobial sepsis, in association with upregulation of certain key inflammatory response genes. Therefore, cathelicidins can exert both pro- and anti-inflammatory activities depending on the disease and cellular context. KEY MESSAGES: The role of cathelicidin in a CLP model is investigated using cathelicidin-KO mice. Cathelicidin-KO mice show an enhanced immune response and improved survival rates. An anti-inflammatory effect of cathelicidin is likely to be detrimental for CLP. Cathelicidin-KO mice show upregulation of genes associated with increased plasma levels of pro-inflammatory Ils. Cathelicidins appear to have both pro- and anti-inflammatory properties. PMID- 28623381 TI - [The use of prescription drugs with dependence potential in Germany : A prospective analysis of prescriptions in the public healthcare system between 2006 and 2010]. AB - BACKGROUND: In Germany, about 1.4 to 2.6 million people are dependent on prescription drugs, mainly benzodiazepine derivatives and opioid analgesics. Despite this large number of affected people, studies on prescription behaviour and drug intake are scarce. There are particularly few empirical findings available with regard to elderly people age 65 and over who are disproportionally affected by prescription drug abuse. METHODS: The North German Pharmacy Computing Centre (Norddeutsches Apothekenrechenzentrum, NARZ) collects the prescription data of about 11 million citizens and covers over 80% of drug pharmacies in North Germany. Based on the data from NARZ, we evaluate person-related prescriptions of benzodiazepines, Z-drugs and opioid analgesics. By means of incremental calculations, we determine the prevalence of prescription drug use, the long-term intake, the average daily dose of these medications and present this information as a five-year trend (2006-2010). RESULTS: In 2006, 10.6% of the members of public healthcare system were prescribed at least one of the medications under study. This proportion hardly changed within the five-year span. The share of patients with benzodiazepine prescription steadily decreased from 2006 (5.5%) to 2010 (5.1%), especially among elderly people. While the prevalence of Z-drug prescriptions remained the same at about 1%, there was a slight increase in prescriptions of opioid analgesics with 5.4% in 2006 to 5.7% in 2010. The proportion of patients with long-term prescriptions decreased with regard to benzodiazepines (from 17.0 to 12.8%) and Z-drugs (from 24.3 to 21.2%), but increased for opioid analgesics (from 19.2 to 21.2%). CONCLUSION: The analytical method used in this study is an innovative epidemiological approach to evaluate person-related register data over the course of several years. Establishing a monitoring system of prescription drugs with potential for dependence may allow for a quicker identification of trends and initiation of appropriate measures. PMID- 28623382 TI - Carbon and hydrogen isotope fractionation during aerobic biodegradation of quinoline and 3-methylquinoline. AB - Compound-specific isotope analysis has been used extensively to investigate the biodegradation of various organic pollutants. To date, little isotope fractionation information is available for the biodegradation of quinolinic compounds. In this study, we report on the carbon and hydrogen isotope fractionation during quinoline and 3-methylquinoline aerobic microbial degradation by a Comamonas sp. strain Q10. Degradation of quinoline and 3 methylquinoline was accompanied by isotope fractionation. Large hydrogen and small carbon isotope fractionation was observed for quinoline while minor carbon and hydrogen isotope fractionation effects occurred for 3-methylquinoline. Bulk carbon and hydrogen enrichment factors (epsilon bulk) for quinoline biodegradation were -1.2 +/- 0.1 and -38 +/- 10/00, respectively, while -0.7 +/- 0.1 and -5 +/- 10/00 for 3-methylquinoline, respectively. This reveals a potential advantage for employing quinoline as the model compound and hydrogen isotope analysis for assessing aerobic biodegradation of quinolinic compounds. The apparent kinetic isotope effects (AKIEC) values of carbon were 1.008 +/- 0.0005 for quinoline and 1.0048 +/- 0.0005 for 3-methylquinoline while AKIEH values of hydrogen of 1.264 +/- 0.011 for quinoline and 1.0356 +/- 0.0103 for 3 methylquinoline were obtained. The combined evaluation of carbon and hydrogen isotope fractionation yields Lambda values (Lambda = Deltadelta2H/Deltadelta13C ~ epsilonHbulk/epsilonCbulk) of 29 +/- 2 for quinoline and 8 +/- 2 for 3 methylquinoline. The results indicate that the substrate specificity may have a significant influence on the isotope fractionation for the biodegradation of quinolinic compounds. The substrate-specific isotope enrichment factors would be important for assessing the behavior and fate of quinolinic compounds in the environment. PMID- 28623383 TI - Ethnopharmacological uses, phytochemistry, biological activities, and biotechnological applications of Eclipta prostrata. AB - Eclipta prostrata belongs to a family of medicinal plants (Asteraceae) and plays a role in the treatment of several diseases, including infectious hepatitis, snake venom poisoning, gastritis, and respiratory diseases such as a cough and asthma. A number of compounds, including thiophene derivatives, steroids, triterpenes, flavonoids, polyacetylenes, polypeptides, and coumestans, have been isolated from E. prostrata. The plant functional compounds can act as reducing agent in the field of nanoparticle synthesis. The extracts of E. prostrata are widely used for green biosynthesis of various metal and metal oxide nanoparticles, nanoparticles, which showed a potential for pharmaceutical, biotechnological, and biomedical applications. Establishment of a efficient in vitro regeneration and genetic transformation method of E. prostrata is a vital prerequisite for application of biotechnology in order to improve secondary metabolite yields. The present mini-review discusses its pharmacological profile, chemical constituents, biotechnological, and ethnomedical uses, mainly focusing on antimyotoxic, antihemorrhagic, antiproliferative, antioxidant, antitumor, antihyperglycemic, antidementia, antimicrobial, antihyperlipidemic, antivenom, anti-HIV, and larvicidal activities, so that the pharmaceutical potential of the plant can be better evaluated. The mini review, providing up-to-date phytochemical and other information on E. prostrata, will serve a reference for further studies. PMID- 28623384 TI - The Role of Cardiopulmonary Exercise Testing for Decision Making in Patients with Repaired Tetralogy of Fallot. AB - Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. As a result of the surgical strategies employed at the time of initial repair, chronic pulmonary regurgitation (PR) is prevalent in this population. Despite sustained research efforts, patient selection and timing of pulmonary valve replacement (PVR) to address PR in young asymptomatic patients with repaired tetralogy of Fallot (rToF) remain a fundamental but as yet unanswered question in the field of congenital heart disease. The ability of the heart to compensate for the chronic volume overload imposed by PR is critical in the evaluation of the risks and benefits of PVR. The difficulty in clarifying the functional impact of PR on the cardiovascular capacity may be in part responsible for the uncertainty surrounding the timing of PVR. Cardiopulmonary exercise testing (CPET) may be used to assess abnormal cardiovascular response to increased physiologic demands. However, its use as a tool for risk stratification in asymptomatic adolescents and young adults with rToF is still ill-defined. In this paper, we review the role of CPET as a potentially valuable adjunct to current risk stratification strategies with a focus on asymptomatic rToF adolescents and young adults being considered for PVR. The role of maximal and submaximal exercise measurements to identify young patients with a decreased or borderline low peak VO2 resulting from impaired ventricular function is explored. Current knowledge gaps and research perspectives are highlighted. PMID- 28623386 TI - The antipsychotic agent quetiapine is increasingly not used as such: dispensed prescriptions in Norway 2004-2015. AB - PURPOSE: The antipsychotic agent quetiapine was introduced in Norway in 2003. We have assessed changes in dispensed prescriptions, including dosing, of quetiapine in Norway from 2004 to 2015. METHODS: Data on the sales of antipsychotics and antidepressants were drawn from the Norwegian Prescription Database. A total of 47,474 outpatients filled 195,622 prescriptions of quetiapine. Reimbursement codes, use of antipsychotics or antidepressants 12 months prior to the first prescription of quetiapine and estimated mean volume used measured as defined daily doses (DDDs) per day were used as proxies for diagnoses. We conducted a regression analysis with DDD per day as a function of possible explanatory variables. RESULTS: The number of users filling at least two prescriptions of quetiapine per year increased from 584 in 2004 to 8506 in 2015 and the mean dose declined from 1.58 DDD per day (SD 8.00) to 0.48 DDD per day (SD 2.27). The latter is much lower than recommended for treatment of psychoses. In 2015, 60.1% of the 8506 quetiapine users did not seek reimbursement for the treatment of a major psychiatric disorder and only 2.6% of the patients were prescribed 1 DDD or more per day and reimbursed in accordance with the drug's primary indication, psychosis. A reported diagnosis of psychosis was not associated with higher quetiapine doses. CONCLUSIONS: In 2015, the pattern of quetiapine dispensing in Norway most likely reflects predominant off-label use. This is unsettling considering poorly documented effects in non-psychotic disorders, profound side effects, significant toxicity and growing concern regarding abuse. PMID- 28623385 TI - Juvenile social isolation affects maternal care in rats: involvement of allopregnanolone. AB - RATIONALE: Social isolation of rats immediately after weaning is thought to represent an animal model of anxiety-like disorders. Socially isolated virgin females showed a significant decrease in allopregnanolone levels, associated with increased anxiety-related behavior compared with group-housed rats. OBJECTIVES: The present study investigates whether post-weaning social isolation affects maternal behavior and assesses neuroactive steroid levels in adult female rats during pregnancy and postpartum. RESULTS: Socially isolated dams displayed a reduction in the frequency of arched back nursing (ABN) behavior compared to group-housed dams. In addition, both total and active nursing were lower in socially isolated dams compared to group-housed dams. Compared to virgin females, pregnancy increases allopregnanolone levels in group-housed as well as isolated dams and such increase was greater in the latter group. Compared to pregnancy levels, allopregnanolone levels decreased after delivery and this decrease was more pronounced in isolated than group-housed dams. Moreover, the fluctuations in plasma corticosterone levels that occur in late pregnancy and during lactation follow a different pattern in socially isolated vs. group-housed rats. CONCLUSIONS: The present results show that social isolation in female rats decreases maternal behavior; this effect is associated with lower allopregnanolone concentrations at postpartum, which may account, at least in part, for the poor maternal care observed in socially isolated dams. In support of this conclusion is the finding that finasteride-treated dams, which display a decrease in plasma allopregnanolone levels, also showed a marked reduction in maternal care, suggesting that allopregnanolone may contribute to the quality of maternal care. PMID- 28623388 TI - Lateral diffusion and signaling of receptor for advanced glycation end-products (RAGE): a receptor involved in chronic inflammation. AB - Membrane diffusion is one of the key mechanisms in the cellular function of receptors. The signaling of receptors for advanced glycation end-products (RAGE) has been extensively studied in the context of several pathological conditions, however, very little is known about RAGE diffusion. To fill this gap, RAGE lateral diffusion is probed in native, cholesterol-depleted, and cytoskeleton altered cellular conditions. In native GM07373 cellular conditions, RAGE has a 90% mobile fraction and an average diffusion coefficient of 0.3 MUm2/s. When depolymerization of the actin cytoskeleton is inhibited with the small molecule jasplakinolide (Jsp), the RAGE mobile fraction and diffusion coefficient decrease by 22 and 37%, respectively. In contrast, depolymerizing the filamentous actin cytoskeleton using the small molecule cytochalasin D (CD) does not alter the RAGE diffusion properties. There is a 70 and 50% decrease in phosphorylation of extracellular signal-regulated kinase (p-ERK) when the actin cytoskeleton is disrupted by CD or Jsp, respectively, in RAGE-expressing GM07373 cells. Disrupting the actin cytoskeleton in GM07373 cells that do not express detectable amounts of RAGE results in no change in p-ERK. Cholesterol depletion results in no statistically significant change in the diffusion properties of RAGE or p-ERK. This work presents a strong link between the actin cytoskeleton and RAGE diffusion and downstream signaling, and serves to further our understanding of the factors influencing RAGE lateral diffusion. PMID- 28623387 TI - Retinal vascular geometry and 6 year incidence and progression of diabetic retinopathy. AB - AIMS/HYPOTHESIS: We aimed to examine prospectively the association between a range of retinal vascular geometric variables measured from retinal photographs and the 6 year incidence and progression of diabetic retinopathy. METHODS: We conducted a prospective, population-based cohort study of Asian Malay individuals aged 40-80 years at baseline (n = 3280) who returned for a 6 year follow-up. Retinal vascular geometric variables (tortuosity, branching, fractal dimension, calibre) were measured from baseline retinal photographs using a computer assisted program (Singapore I Vessel Assessment). Diabetic retinopathy was graded from baseline and follow-up photographs using the modified Airlie House classification system. Incidence of diabetic retinopathy was defined as a severity of >=15 at follow-up among those without diabetic retinopathy at baseline. Incidence of referable diabetic retinopathy was defined as moderate or severe non-proliferative diabetic retinopathy, proliferative diabetic retinopathy or diabetic macular oedema at follow-up in participants who had had no or mild non-proliferative diabetic retinopathy at baseline. Progression of diabetic retinopathy was defined as an increase in severity of >=2 steps at follow-up. Log binomial models with an expectation-maximisation algorithm were used to estimate RR adjusting for age, sex, diabetes duration, HbA1c level, BP, BMI, estimated GFR and total and HDL-cholesterol at baseline. RESULTS: A total of 427 individuals with diabetes participated in the baseline and 6 year follow-up examinations. Of these, 19.2%, 7.57% and 19.2% developed incidence of diabetic retinopathy, incidence of referable diabetic retinopathy and diabetic retinopathy progression, respectively. After multivariate adjustment, greater arteriolar simple tortuosity (mean RR [95% CI], 1.34 [1.04, 1.74]), larger venular branching angle (RR 1.26 [1.00, 1.59]) and larger venular branching coefficient (RR 1.26 [1.03, 1.56]) were associated with incidence of diabetic retinopathy. Greater arteriolar simple tortuosity (RR 1.82 [1.32, 2.52]), larger venular branching coefficient (RR 1.46 [1.03, 2.07]), higher arteriolar fractal dimension (RR 1.59 [1.08, 2.36]) and larger arteriolar calibre (RR 1.83 [1.15, 2.90]) were associated with incidence of referable diabetic retinopathy. Greater arteriolar simple tortuosity (RR 1.34 [1.12, 1.61]) was associated with diabetic retinopathy progression. Addition of retinal vascular variables improved discrimination (C-statistic 0.796 vs 0.733, p = 0.031) and overall reclassification (net reclassification improvement 18.8%, p = 0.025) of any diabetic retinopathy risk beyond established risk factors. CONCLUSIONS/INTERPRETATION: Retinal vascular geometry measured from fundus photographs predicted the incidence and progression of diabetic retinopathy in adults with diabetes, beyond established risk factors. PMID- 28623389 TI - Moving higher and higher: imitators' movements are sensitive to observed trajectories regardless of action rationality. AB - Humans sometimes perform actions which, at least superficially, appear suboptimal to the goal they are trying to achieve. Despite being able to identify these irrational actions from an early age, humans display a curious tendency to copy them. The current study recorded participants' movements during an established imitation task and manipulated the rationality of the observed action in two ways. Participants observed videos of a model point to a series of targets with either a low, high or 'superhigh' trajectory either in the presence or absence of obstacles between her targets. The participants' task was to watch which targets the model pointed to and then point to the same targets on the table in front of them. There were no obstacles between the participants' targets. Firstly, we found that the peak height of participants' movements between their targets was sensitive to the height of the model's movements, even in the 'superhigh' condition where the model's action was rated as irrational. Secondly, participants showed obstacle priming-the peak height of participants' movements was higher after having observed the model move over obstacles to reach her targets, compared to when there were no obstacles between her targets. This suggests that participants code the environment of co-actors into their own motor programs, even when this compromises the efficiency of their own movements. We discuss the implications of our findings in terms of theories of imitation and obstacle priming. PMID- 28623390 TI - Disturbed cervical proprioception affects perception of spatial orientation while in motion. AB - The proprioceptive, visual and vestibular sensory systems interact to maintain dynamic stability during movement. The relative importance and interplay between these sensory systems is still not fully understood. Increased knowledge about spatial perception and postural orientation would provide better understanding of balance disorders, and their rehabilitation. Displacement of the body in space was recorded in 16 healthy subjects performing a sequence of stepping-in-place tests without any visual or auditory cues. Spatial displacement and orientation in space were determined by calculating two parameters, "Moved distance (sagittal + lateral displacement)" and "Rotation". During the stepping-in-place tests vibration were applied in a randomized order on four different cervical muscles, and the effects were compared between muscles and to a non-vibration baseline condition. During the tests a forward displacement ("Moved distance") was found to be the normal behavior, with various degrees of longitudinal rotation ("Rotation"). The moved distance was significantly larger when the vibration was applied on the dorsal muscles (916 mm) relative to on ventral muscles (715 mm) (p = 0.003) and the rate of displacement was significantly larger for dorsal muscles (36.5 mm/s) relative to ventral (28.7 mm/s) vs (p = 0.002). When vibration was applied on the left-sided muscles, 16 degrees rotation to the right was induced (p = 0.005), whereas no significant rotation direction was induced with right sided vibration (3 degrees ). The rate of rotation was significantly larger for vibration applied on ventral muscles (0.44 degrees /s) relative to on dorsal (0.33 degrees /s) (p = 0.019). The results highlight the influence of cervical proprioception on the internal spatial orientation, and subsequent for postural control. PMID- 28623391 TI - Survey of High-Affinity H2-Oxidizing Bacteria in Soil Reveals Their Vast Diversity Yet Underrepresentation in Genomic Databases. AB - While high-affinity H2-oxidizing bacteria (HA-HOB) serve as the main sink of atmospheric H2, the ecology of this specialist functional group is rather unknown due to its recent discovery. The main purpose of our study is to provide the first extensive survey of HA-HOB in farmland, larch, and poplar soils exposed to 0.5 and 10,000 ppmv H2. Using qPCR and qRT-PCR assays along with PCR amplicon high-throughput sequencing of hhyL gene encoding for the large subunit of high affinity [NiFe]-hydrogenases (HAH), we found that hhyL gene expression ratio explained better variation in measured H2 oxidation rates than HA-HOB species richness. Carbon, nitrogen, pH, and bacterial species richness appeared as the most important drivers of HA-HOB community structure. Our study also highlights the need to cultivate HA-HOB due to the huge gap in current genomic databases. PMID- 28623392 TI - MHC class I diversity in chimpanzees and bonobos. AB - Major histocompatibility complex (MHC) class I genes are critically involved in the defense against intracellular pathogens. MHC diversity comparisons among samples of closely related taxa may reveal traces of past or ongoing selective processes. The bonobo and chimpanzee are the closest living evolutionary relatives of humans and last shared a common ancestor some 1 mya. However, little is known concerning MHC class I diversity in bonobos or in central chimpanzees, the most numerous and genetically diverse chimpanzee subspecies. Here, we used a long-read sequencing technology (PacBio) to sequence the classical MHC class I genes A, B, C, and A-like in 20 and 30 wild-born bonobos and chimpanzees, respectively, with a main focus on central chimpanzees to assess and compare diversity in those two species. We describe in total 21 and 42 novel coding region sequences for the two species, respectively. In addition, we found evidence for a reduced MHC class I diversity in bonobos as compared to central chimpanzees as well as to western chimpanzees and humans. The reduced bonobo MHC class I diversity may be the result of a selective process in their evolutionary past since their split from chimpanzees. PMID- 28623394 TI - Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes. AB - Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 * 108/kg and 4.3 * 106/kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes. PMID- 28623395 TI - In Burkitt lymphoma patients who relapse after induction with a short-intensive chemoimmunotherapy protocol, aggressive salvage chemotherapy therapy is ineffective: a single-center retrospective study. PMID- 28623393 TI - Limited MHC class I intron 2 repertoire variation in bonobos. AB - Common chimpanzees (Pan troglodytes) experienced a selective sweep, probably caused by a SIV-like virus, which targeted their MHC class I repertoire. Based on MHC class I intron 2 data analyses, this selective sweep took place about 2-3 million years ago. As a consequence, common chimpanzees have a skewed MHC class I repertoire that is enriched for allotypes that are able to recognise conserved regions of the SIV proteome. The bonobo (Pan paniscus) shared an ancestor with common chimpanzees approximately 1.5 to 2 million years ago. To investigate whether the signature of this selective sweep is also detectable in bonobos, the MHC class I gene repertoire of two bonobo panels comprising in total 29 animals was investigated by Sanger sequencing. We identified 14 Papa-A, 20 Papa-B and 11 Papa-C alleles, of which eight, five and eight alleles, respectively, have not been reported previously. Within this pool of MHC class I variation, we recovered only 2 Papa-A, 3 Papa-B and 6 Papa-C intron 2 sequences. As compared to humans, bonobos appear to have an even more diminished MHC class I intron 2 lineage repertoire than common chimpanzees. This supports the notion that the selective sweep may have predated the speciation of common chimpanzees and bonobos. The further reduction of the MHC class I intron 2 lineage repertoire observed in bonobos as compared to the common chimpanzee may be explained by a founding effect or other subsequent selective processes. PMID- 28623396 TI - Assessment of the circulating cell-free DNA marker association with diagnosis and prognostic prediction in patients with lymphoma: a single-center experience. AB - Circulating cell-free DNA (ccfDNA) has been shown to be associated with the clinical characteristics and prognosis of cancer patients. Our objective was to assess whether the concentration and integrity index of ccfDNA in plasma may be useful for diagnosing and monitoring the progression of patients with lymphoma. We included plasma samples from 174 lymphoma patients and 80 healthy individuals. The total concentration of ccfDNA was determined using a fluorometry method, and the DNA integrity index (DII), which is the ratio of longer to shorter DNA fragments, for the APP gene was detected using real-time quantitative PCR. The median levels of the ccfDNA concentration and the DII in patients with lymphoma were significantly higher than those in controls (both P < 0.0001). Increases in the ccfDNA concentration and the DII were associated with advanced stage disease, elevated lactate dehydrogenase levels, and a higher prognosis score. In patients with diffuse large B cell lymphoma (DLBCL), high levels of ccfDNA (both concentration and the DII) showed an inferior 2-year progression-free survival (PFS) (P = 0.001; P < 0.0001, respectively). Our study provides quantitative and qualitative evidence in favor of using ccfDNA analysis in lymphoma patients for diagnostic and prognostic assessments. PMID- 28623397 TI - Different effects of gamma-linolenic acid (GLA) supplementation on plasma and red blood cell phospholipid fatty acid composition and calcium oxalate kidney stone risk factors in healthy subjects from two race groups with different risk profiles pose questions about the GLA-arachidonic acid-oxaluria metabolic pathway: pilot study. AB - Fatty acid (FA) composition of phospholipids in plasma and red blood cells (RBC) can influence calciuria, oxaluria and renal stone formation. In this regard, the ratio of arachidonic acid (AA) and its precursor linoleic acid (LA) appears to be important. Administration of gamma-linolenic acid (GLA) has been shown to increase the concentration of dihomo-gamma linoleic acid (DGLA) relative to AA indicating that it may attenuate biosynthesis of the latter. Such effects have not been investigated in race groups having difference stone occurrence rates. Black (B) and white (W) healthy males ingested capsules containing linoleic acid (LA) and GLA, for 30 days. Plasma and RBC total phospholipid (TPL) FA profiles, serum and 24 h urine biomarkers of hypercalciuria and urinary stone risk factors were determined on days 0 and 30. Data were tested for statistical significance using GraphPadInstat version 3.02. Concentration and percentage content of DGLA in plasma TPL increased in W but not in B. Arachidonic acid (AA) did not change in either group. There was no change in calcium excretion in either group but oxalate and citrate excretion increased in W. We suggest that elongation of GLA to DGLA may occur more rapidly than desaturation of DGLA to AA in W and that depressed activity of the enzyme elongase may occur in B. Calciuric and citraturic effects may be dependent on the quantity of LA or on the mass ratio of LA/GLA in the FA supplement. Questions about the mooted DGLA-AA-oxaluria pathway arise. We speculate that there exists a potential for using GLA as a conservative treatment for hypocitraturia. The observation of different responses in B and W indicates that such differences may play a role in stone formation and prevention. PMID- 28623398 TI - Endothelial vascular markers in coronary surgery. AB - Coronary heart disease is associated with high morbidity and mortality. Endothelial dysfunction in affected patients is linked to long-term atherosclerotic disease progression and cardiovascular event rates. The present paper reports on changes in the levels of endothelial progenitor cells (VEGFR2/CD133/CD34), essential for endothelial repair, and of endothelial microvesicles (CD31/annexin V) as indicators of endothelial lesion, in patients undergoing coronary bypass surgery with respect both to baseline levels and to counts in healthy subjects. In an observational descriptive study, 31 patients scheduled for coronary revascularization surgery were compared with those of 25 healthy controls. In a subsequent longitudinal study, patients undergoing surgery were monitored at 5 timepoints up until 48 h after surgery. Endothelial progenitor cell (VEGFR2/CD133/CD34) and endothelial microvesicle (CD31/annexin V) levels were quantified by flow cytometry. Baseline endothelial progenitor cell counts in coronary patients were significantly lower than those of healthy controls (p < 0.001); however, after surgery, levels rose steadily over all 5 timepoints to 48 h with statistically significant differences (p < 0.001) between intra-operative and 48 h after surgery (T5). Endothelial microvesicle levels were significantly higher in coronary patients prior to surgery than in healthy controls (p < 0.001), and despite declining at 48 h remained significantly higher than those of controls (p < 0.001). Coronary surgery has had a positive impact on the endothelium in the patients, prompting a decrease in signs of endothelial dysfunction and a considerable improvement in the endothelial repair mechanisms involved in angiogenesis, playing an important role in the inflammatory response and the remodelling process of ischemic myocardium in postoperative period. PMID- 28623399 TI - Endothelial dysfunction in rectal cancer patients chronically exposed to ionizing radiation. AB - We sought to identify the features of endothelial function in rectal cancer patients who were exposed to chronic ionizing radiation from a nuclear test site in Kazakhstan. We examined 146 individuals, 76 of whom were rectal cancer patients. The existence of a complex of disturbances of the endothelium and hemostasis systems in patients vs non-patients was revealed. Endothelial dysfunction was expressed as an increase of nitric oxide (NO) production along with decreases in vasodilatation function, and increased levels of von Willebrand factor in blood, along with an increase in the number of circulating endotheliocytes. Significant correlations between indicators of endothelial function and vascular-platelet hemostasis were observed. These changes and their interrelations were expressed more strongly in the patients who lived in the contaminated area around the nuclear test site. Such patients could have an increased risk of thrombosis and other complications after the treatment of a malignant neoplasm. PMID- 28623400 TI - A novel eyelid motion monitor. AB - BACKGROUND: Eyelid motion analysis can provide important information about ophthalmic, neurologic, and systemic diseases. Routine assessment of eyelid function is currently based mainly on clinical examination estimating Levator Function and static palpebral fissure measurements. Most clinical tools developed to date are cumbersome expensive and difficult to operate. Currently there is no widely available, affordable device providing user friendly precision based evaluation of eyelid kinematics. Our goal is to develop a novel device for evaluation of eyelid kinematics providing rapid defined diagnosis of diseases involving eyelid movement. METHODS: A real-time prototype eyelid motion monitoring system was designed based on magnetic field sensors detecting movement of a tiny magnet located on the upper eyelid. Motion is recorded and analyzed using specially developed hardware and software, respectively, enabling both real time and off-line data presentation. The Eyelid Motion Monitor correlates between blinking characteristics of eyelid movement and the output voltages produced by the system. Blink detection is defined as peak in voltage, caused by eyelid closure or opening. The device was tested on 20 healthy volunteers with normal clinical blinking patterns. RESULTS: The Eyelid Motion Monitor succeeded in detecting full blink motion. The system easily extracts different parameters of eyelid kinetics. CONCLUSIONS: An inexpensive prototype novel device was developed for monitoring and analyzing eyelid motion characteristics, including the inter blink interval, eye closing/opening duration and entire blink duration. The device should allow early objective non- invasive diagnosis and follow-up of disease progression. It could be of great potential value in many ophthalmic, neurologic, and systemic diseases. PMID- 28623401 TI - Biomarkers in the assessment of oral mucositis in head and neck cancer patients: a systematic review and meta-analysis. AB - PURPOSE: The aim of this study was to evaluate the capability of biomarkers to predict the risk of oral mucositis in head and neck cancer patients, as well as to assess the correlation between these biomarkers and the severity of mucositis. METHODS: The search was performed at LILACS, PubMed, Science Direct, Scopus, and Web of Science. A search of the gray literature was performed on Google Scholar, OpenGrey, and ProQuest. The methodological quality of the included studies was assessed using the Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) tool, and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system. RESULTS: After a two-step selection process, 26 studies met the eligibility criteria. In total, 27 biomarkers were evaluated, and the most frequent were the epidermal growth factor (EGF), C-reactive protein (CRP), genetic polymorphisms, tumor necrosis factor alpha (TNF-alpha), and erythrocyte sedimentation rate (ESR). The meta-analysis showed an expression of polymorphisms in XRCC1 (32.66%), XRCC3 (31.00%), and RAD51 (39.16%) genes, as well as an expression of protein biomarkers (39.57%), in patients with an increased risk of developing oral mucositis. CONCLUSIONS: Dosing biomarkers before starting radiation therapy may be a promising method to predict the risk of developing mucositis and allow radiosensitive patients to have a customized treatment. Although there is currently limited evidence to confirm the putative implementation of serum and salivary biomarkers to assess the correlation between them and the severity of mucositis, this current review provides new research directions. PMID- 28623402 TI - The impact of breast cancer treatments on sleep quality 1 year after cancer diagnosis. AB - PURPOSE: The increasing number of women living longer with potential side effects of breast cancer treatment highlights the need of a comprehensive assessment of its burden. Therefore, we aimed to quantify the relation between different breast cancer treatments and sleep quality 1 year after diagnosis. METHODS: A cohort of 502 newly diagnosed breast cancer patients was prospectively followed. Sleep quality was evaluated with the Pittsburgh Sleep Quality Index (PSQI), at baseline and at the 1-year follow-up. Odds ratios (OR) were computed to quantify the association between patient characteristics and poor sleep quality (PSQI score >5) at baseline, and relative risks (RR) were computed for the association between treatments and the occurrence of poor sleep quality at 1 year. RESULTS: A total of 60.2% of the patients had poor sleep quality before breast cancer treatments, especially those with anxiety [OR = 2.86, 95% confidence interval (95%CI) 1.92 to 4.27] or depression (OR = 5.25, 95%CI 2.01 to 13.67). Radiotherapy increased the risk of poor sleep quality at 1 year (RR = 3.71, 95%CI 1.15 to 11.96, for a cumulative dose >50 Gy) and there was a tendency for a higher risk in those submitted to chemotherapy, although not statistically significant. CONCLUSIONS: Our study shows that sleep disturbances are frequent before cancer treatment and confirms their co-occurrence with other medical conditions, such as anxiety and depression. Different breast cancer treatments increase the risk of impaired sleep quality, therefore contributing to the global disability associated with cancer treatments. PMID- 28623404 TI - Action-effects enhance explicit sequential learning. AB - Different studies have shown that action-effect associations seem to enhance implicit learning of motor sequences. In a recent study (Haider et al., Conscious Cognit 26:145-161, 2014), we found indications that action-effect learning might play a special role in acquiring explicit knowledge within an implicit learning situation. The current study aims at directly manipulating the action-effect contingencies in a Serial Reaction Time Task and examining its impact on explicit sequence knowledge. For this purpose, we created a situation in which the participants' responses led to a melodic tone sequence. For one group, these effect tones were contingently bound to the sequential responses and immediately followed the key press; for the second group, the tones were delayed by 400 ms. For a third group, the tones also followed the response immediately and resulted in the same melody but were not contingently bound to the responses. A fourth control group received no effect tones at all. Only the group that experienced contingent effect tones that directly followed the response showed an increase in explicit sequence knowledge. The results are discussed in terms of the multi modal structure of action-effect associations and the ideomotor principle of action control. PMID- 28623403 TI - Diffusion tensor imaging can predict surgical outcomes of patients with cervical compression myelopathy. AB - PURPOSE: The aim of this study was to assess the potential role of diffusion tensor imaging (DTI) as a predictor of surgical outcomes in patients with cervical compressive myelopathy (CCM). Surgical decompression is often recommended for symptomatic CCM. It is important to know the prognosis of surgical outcomes and to recommend appropriate timing for surgery. METHODS: We enrolled 26 patients with CCM who underwent surgery. The Japanese Orthopaedic Association (JOA) score for cervical myelopathy was evaluated before and 6 months after surgery. Surgical outcomes were regarded as good if there was a change in JOA score of three points or more, or the recovery rate of JOA score was 50% or more. The patients were examined using a 3.0 T magnetic resonance system before surgery. Measured diffusion parameters were fractional anisotropy (FA) and mean diffusivity (MD). The correlations between DTI parameters and surgical outcomes were analyzed. RESULTS: Both change and recovery rate of JOA score moderately correlated with FA. Furthermore, the area under the receiver-operator characteristic curve based on FA for prognostic precision of surgical outcomes indicates that FA is a good predictive factor. The cut-off values of FA for predicting good surgical outcomes evaluated by change and recovery rate of JOA score were 0.65 and 0.57, respectively. Neither change nor recovery rate of JOA score correlated with MD. CONCLUSIONS: FA in spinal cord DTI can moderately predict surgical outcomes. DTI can serve as a supplementary tool for decision making to guide surgical intervention in patients with CCM. PMID- 28623405 TI - Genome dynamics and evolution of codon usage patterns in shrimp viruses. AB - We analysed the genomes and codon usage patterns of seven small (DNA and RNA) shrimp viruses. Effective number of codon (ENC) values indicated moderate (35 < ENC < 50) codon usage bias in shrimp viruses. Correlation analysis between GC compositions at non-synonymous codon and synonymous codon positions (GC1, 2 and GC3) as well as GC3 versus ENC curves indicated varying influences of mutational pressure on codon usage. The presence of deoptimized codons and host-antagonistic codon usage trends in shrimp viruses suggested the adaptation of a slow replication strategy by these viruses to avoid host defences. Low CpG frequencies indicated that shrimp viruses have evolved with underrepresentation of CpGs to avoid the host's immune response. PMID- 28623406 TI - Nucleoside analogue 2'-C-methylcytidine inhibits hepatitis E virus replication but antagonizes ribavirin. AB - Hepatitis E virus (HEV) infection has emerged as a global health issue, but no approved medication is available. The nucleoside analogue 2'-C-methylcytidine (2CMC), a viral polymerase inhibitor, has been shown to inhibit infection with a variety of viruses, including hepatitis C virus (HCV). Here, we report that 2CMC significantly inhibits the replication of HEV in a subgenomic replication model and in a system using a full-length infectious virus. Importantly, long-term treatment with 2CMC did not result in a loss of antiviral potency, indicating a high barrier to drug resistance development. However, the combination of 2CMC with ribavirin, an off-label treatment for HEV, exerts antagonistic effects. Our results indicate that 2CMC serves as a potential antiviral drug against HEV infection. PMID- 28623407 TI - Diagnosis and phylogenetic analysis of a multifocal cutaneous orf virus with mixed bacterial infection outbreak in goats in Fujian province, China. AB - Outbreaks of orf virus on goat farms are common in China. In this study, we investigated a severe multifocal cutaneous orf virus outbreak with a correlative mixed bacterial infection which persisted for up to 6 months, and which had a high morbidity (93.7%) and mortality (15%) among kids in a herd of crossbreed goats in Fujian province in China. The disease was diagnosed as an orf virus (ORFV XD strain) infection associating with Streptococcus pluranimalium and Staphylococcus, identified using standard virological and bacteriological techniques. Multiple sequence alignments and phylogenetic analyses of the whole ORFV 011 (B2L), 059 (F1L), 032 and 080 genes revealed that the even though the virus phylogeny was clustered in branches of conventional orf virus strains, it nonetheless evidenced high variation within this subset. Furthermore, the sequences from the ORFV 080 gene allowed us to distinguish between the different strains at a higher resolution and these observations afforded us a comparative view of the ORFV 080 gene. This is the first report describing an outbreak of severe multifocal cutaneous orf virus with associated bacterial infection in China. PMID- 28623408 TI - Plexiform neurofibroma causing an ossifying subperiosteal haematoma: a rare case in the tibia of an 11-year-old girl. AB - Ossifying subperiosteal haematoma is an exceedingly rare manifestation of Neurofibromatosis type 1 (NF-1). We report an interesting case of plexiform neurofibroma causing a rapidly growing tibial mass as a result of subperiosteal haemorrhage, in an 11-year-old girl with previously undiagnosed NF-1. This reflects a precursor of the more mature periosteal ossification seen in cases traditionally termed "subperiosteal cysts". A previously well young girl was referred by her general practitioner with an increasingly large, mildly tender, soft lump on the anterior aspect of her right tibia. Plain radiographs demonstrated soft tissue thickening overlying the anterior tibia, without appreciable periosteal ossification. Magnetic resonance imaging (MRI) illustrated a single central fluid-fluid level and periosteal elevation with saucerisation of the anterior tibial cortex and mild surrounding oedema. Histopathology revealed a large plexiform neurofibroma. Interestingly, this was associated with haemorrhagic change and a peripheral rim of florid reactive new bone formation. This unusual presentation was discussed at a multidisciplinary bone and soft tissue tumour meeting, where in combination with the clinical history of cafe au lait spots and positive family history, a consensus diagnosis of NF-1 was made. To date, there have only been limited case reports of this rare pathological process. In summary, this case report accounts an acute presentation of this rare osseous manifestation of NF-1, being the first to clearly demonstrate a timeline of subperiosteal haematoma with subsequent subperiosteal bone proliferation. The clinical reasoning and radiological features for such a presentation are also described. PMID- 28623409 TI - Evaluation of bone viability in patients after girdlestone arthroplasty: comparison of bone SPECT/CT and MRI. AB - PURPOSE: To test the diagnostic performance of bone SPECT/CT and MRI for the evaluation of bone viability in patients after girdlestone-arthroplasty with histopathology used as gold standard. MATERIALS AND METHODS: In this cross sectional study, patients after girdlestone-arthroplasty were imaged with single photon-emission-computed-tomography/computed-tomography (SPECT/CT) bone-scans using 99mTc-DPD. Additionally, 1.5 T MRI was performed with turbo-inversion recovery-magnitude (TIRM), contrast-enhanced T1-fat sat (FS) and T1-mapping. All imaging was performed within 24 h prior to revision total-hip-arthroplasty in patients with a girdlestone-arthroplasty. In each patient, four standardized bone tissue-biopsies (14 patients) were taken intraoperatively at the remaining acetabulum superior/inferior and trochanter major/minor. Histopathological evaluation of bone samples regarding bone viability was used as gold standard. RESULTS: A total of 56 bone-segments were analysed and classified as vital (n = 39) or nonvital (n = 17) by histopathology. Mineral/late-phase SPECT/CT showed a high sensitivity (90%) and specificity (94%) to distinguish viable and nonviable bone tissue. TIRM (sensitivity 87%, specificity 88%) and contrast-enhanced T1-FS (sensitivity 90%, specificity 88%) also achieved a high sensitivity and specificity. T1-mapping achieved the lowest values (sensitivity 82%, specificity 82%). False positive results in SPECT/CT and MRI resulted from small bone fragments close to metal artefacts. CONCLUSIONS: Both bone SPECT/CT and MRI allow a reliable differentiation between viable and nonviable bone tissue in patients after girdlestone arthroplasty. The findings of this study could also be relevant for the evaluation of bone viability in the context of avascular bone necrosis. PMID- 28623411 TI - "I am not afraid of death"-a survey on preferences concerning neurosurgical interventions among patients over 75 years. AB - INTRODUCTION: Treatment decisions in elderly patients with traumatic brain injury (TBI) are mainly determined by trauma severity and patient age. The aim of this study was to explore personal preferences of potential patients regarding life prolonging neurosurgical interventions by interviewing ambulatory, autonomous elderly people. METHODS: One hundred consecutive patients older than 75 years frequenting the outpatient clinic of the Department of Neurosurgery were interviewed about their attitudes regarding the hypothetical case of an 81-year old patient with TBI and a space-occupying acute subdural hematoma (aSDH) using a 21-point questionnaire. RESULTS: Fifty-one percent of the consulted persons declined life-prolonging surgical measures. If surgery was associated with physical disability, 68% of the people wished no surgery. In case of cognitive impairment after surgery, 91% were against any surgical intervention. The majority feared being a burden to relatives (76%) and becoming unable to master an independent life (75%). Four-fifths of the interviewed patients (82%) were not afraid of death. CONCLUSIONS: The majority of elderly patients only consent to surgical measures if no relevant disabilities are involved and if they can return to their previous life. These findings need consideration in case of life threatening neurosurgical emergencies as well as in the surgical treatment of elderly patients in general. PMID- 28623412 TI - Long-term follow-up after endoscopic trans-sphenoidal surgery or initial observation in clivus chordomas. AB - BACKGROUND: Resection of clivus chordomas through extensive skull base approaches is associated with high mortality and morbidity even in experienced hands. We report our experience with endoscopic trans-sphenoidal surgery, or a "wait-and scan" strategy in selected patients. METHOD: Ten patients were diagnosed with clivus chordomas during an 8-year period. Six patients underwent primary treatment with endoscopic trans-sphenoidal surgery, followed by adjuvant proton beam therapy in three of these patients. Four patients with minor symptoms were followed-up untreated. Mean follow-up was 91 months. RESULTS: Of the six patients operated on, total or gross total resection was achieved in four, partial resection in one and biopsy was taken in one. Preoperative cranial neuropathies resolved in three out of five patients, and no new cranial nerve palsies were encountered. Postoperative cerebrospinal fluid leak occurred in one patient. Four patients were initially followed-up without any treatment, and three of these have remained stable without tumour progression for a mean of 94 months. Due to a slow, though progressive growth of tumour, one patient was operated on after 80 months of initial observation. CONCLUSIONS: The natural course of clivus chordomas has yet to be defined. The endoscopic trans-sphenoidal approach is a valid, minimally invasive alternative for the treatment of clival chordomas, and in selected patients a "wait and scan" strategy can be considered. Our long-term results show low mortality and good functional outcome. An endonasal endoscopic trans-sphenoidal approach should be a principal part of the armamentarium of surgeons treating clivus chordomas. PMID- 28623413 TI - Comment to: "Management and outcome of gastrointestinal bleeding in patients taking oral anticoagulants or antiplatelet drugs". PMID- 28623414 TI - Tenodesis is not superior to tenotomy in the treatment of the long head of biceps tendon lesions. AB - PURPOSE: To compare the effectiveness of tenodesis and tenotomy in the treatment of long head of the biceps tendon (LHBT) lesions. The null hypothesis was that there is no difference in functional scores between the tenotomy and tenodesis groups. METHODS: A total of 69 patients with a combined supraspinatus tear and LHBT lesion aged over 40 years entered this prospective comparative study and were randomly assigned to the arthroscopic LHB tenotomy or tenodesis group. Fifty five patients (31 in the tenotomy group and 24 in the tenodesis group) were available for the 6- and 24-month post-operative evaluations. RESULTS: There were no statistically significant differences in post-operative Constant and Murley score, quality of life, pain, and strengths between groups. Higher rates of Popeye's sign were noted 6 and 24 months post-operatively in the tenotomy group compared to tenodesis. CONCLUSIONS: Although tenotomy is affected by a higher incidence of cosmetic deformity, there is no superiority of arthroscopic tenodesis over tenotomy in the treatment of LHBT lesion as a concomitant procedure to an arthroscopic repair of the supraspinatus tendon in terms of functional outcomes, quality of life, pain, and strength measured 6 and 24 months post-operatively. LEVEL OF EVIDENCE: I. PMID- 28623416 TI - Identifying intestinal malrotation on magnetic resonance examinations ordered for unrelated indications. AB - BACKGROUND: Anatomical imaging findings indicating normal bowel rotation can be identified on cross-sectional imaging, including magnetic resonance imaging (MRI) performed for non-related indications. OBJECTIVE: The goal of our study was to assess whether non-targeted MRI can accurately assess intestinal malrotation. MATERIALS AND METHODS: Four anatomical landmarks were assessed on MRIs of the chest, spine or abdomen performed from January 2006 to June 2014, on patients who also had upper gastrointestinal series (UGI) performed within 10 years of the MRI date: 1) retroperitoneal duodenum, 2) left upper quadrant duodenojejunal junction, 3) superior mesenteric artery to the left of the superior mesenteric vein, and 4) right lower quadrant cecum. Two attending radiologists, one pediatric and one abdominal radiologist, independently reviewed the MR images. The pediatric radiologist reviewed images from UGI (considered the gold standard) to determine the intestinal rotation for each case. Validation of the criteria was performed on new patients imaged through January 2016. RESULTS: The original cohort included 109 MRIs (15 chest, 41 spine and 53 abdomen) done on 109 patients (42% males, mean age: 10.2 years). If each of the 4 anatomical questions were answered "yes" (4-YES), specificity was 100% for each radiologist and malrotation was appropriately excluded. Using the 4-YES criteria, the pediatric radiologist excluded malrotation in 71 patients (65%) and the abdominal radiologist excluded it in 65 (60%), with concurrence for 57 patients. Validation of the 4-YES criteria in 23 new patients appropriately proved the 4-YES rule, with neither labeling the one new malrotation case 4-YES. CONCLUSION: If a radiologist can confidently answer "yes" to the four questions evaluated in this study, then intestinal rotation can be safely considered normal. Normal bowel rotation should be commented upon in MRI reports when these four anatomical locations are imaged, thus helping patients avoid unnecessary UGI and radiation exposure. PMID- 28623415 TI - A stand-alone lateral condyle-elevating trochlear osteotomy leads to high residual instability but no excessive increase in patellofemoral osteoarthritis at 12-year follow-up. AB - PURPOSE AND HYPOTHESIS: Trochlear osteotomy is a rarely performed procedure, only indicated in selected cases. Due to its nature, it can potentially lead to cartilage damage and subsequent early osteoarthritis. Satisfactory short-term results from lateral condyle-elevating osteotomy have previously been reported. The long-term effects of this procedure on clinical outcomes, patellar stability and radiological osteoarthritis are reported here. METHODS: Sixteen patients (19 knees) with patellar instability due to trochlear dysplasia were included. An isolated lateral condyle-elevating trochlear osteotomy was performed between 1995 and 2002. All patients were re-examined at a minimum of 12-year follow-up. Three patients were lost to follow-up, and one patient underwent a patellofemoral arthroplasty 3 years post-operatively due to progressive osteoarthritis. Complete follow-up was therefore available in 12 patients (15 knees). Recurrent instability, VAS pain, WOMAC, Lysholm and Kujala scores were used as outcome measures. Radiological osteoarthritis was recorded using the Iwano and the Kellgren-Lawrence classifications. A repeated-measures ANOVA was used to test for repeated measures (pre-operative, 2-year and final follow-up), and Spearman's correlation coefficient for relationships between osteoarthritis and functional scores. RESULTS: At final follow-up, VAS pain showed a non-significant improvement from 52 to 25, and the median Kujala score was 78. Median Lysholm (54 71, p = 0.021) and WOMAC (78-96, p = 0.021) scores improved from the pre operative assessment to final follow-up. There was no significant difference observed between clinical scores at the 2-year and final follow-up. Residual patellar instability was reported in four out of 15 knees. Three knees showed no patellofemoral osteoarthritis, eight knees had grade 1 and four knees grade 2. No correlation between VAS pain, Lysholm, WOMAC or Kujala scores and osteoarthritis could be identified (n.s.). CONCLUSION: A stand-alone lateral condyle-elevating trochleoplasty results in the significant improvement of most clinical scores; however, when performed as a stand-alone procedure, it leads to a high percentage of residual instability. In contrast to general belief, the development of patellofemoral osteoarthritis at 12-year follow-up did not exceed the findings from other trochleoplasty case series. LEVEL OF EVIDENCE: Case series with no comparison group, Level IV. PMID- 28623417 TI - A validated clinical MRI injury scoring system in neonatal hypoxic-ischemic encephalopathy. AB - BACKGROUND: Deep nuclear gray matter injury in neonatal hypoxic-ischemic encephalopathy (HIE) is associated with worse neurodevelopmental outcomes. We previously published a qualitative MRI injury scoring system utilizing serial T1 weighted, T2-weighted and diffusion-weighted imaging (DWI), weighted for deep nuclear gray matter injury. OBJECTIVES: To establish the validity of the MRI scoring system with neurodevelopmental outcome at 18-24 months. MATERIALS AND METHODS: MRI scans from neonates with moderate to severe HIE treated with therapeutic hypothermia were evaluated. Signal abnormality was scored on T1 weighted, T2-weighted and DWI sequences and assessed using an established system in five regions: (a) subcortical: caudate nucleus, globus pallidus and putamen, thalamus and the posterior limb of the internal capsule; (b) white matter; (c) cortex, (d) cerebellum and (e) brainstem. MRI injury was graded as none, mild, moderate or severe. Inter-rater reliability was tested on a subset of scans by two independent and blinded neuroradiologists. Surviving infants underwent the Bayley Scales of Infant and Toddler Development-III (Bayley-III) at 18-24 months. Data were analyzed using univariate and multivariate linear and logistic regression. RESULTS: Fifty-seven eligible neonates underwent at least one MRI scan in the first 2 weeks of life. Mean postnatal age at scan 1 was 4+/-2 days in 50/57 (88%) neonates and 48/54 (89%) surviving infants underwent scan 2 at 10+/-2 days. In 54/57 (95%) survivors, higher MRI injury grades were significantly associated with worse outcomes in the cognitive, motor and language domains of the Bayley-III. CONCLUSION: A qualitative MRI injury scoring system weighted for deep nuclear gray matter injury is a significant predictor of neurodevelopmental outcome at 18-24 months in neonates with HIE. PMID- 28623418 TI - Women's persistent depressive and perinatal grief symptoms following a miscarriage: the role of childlessness and satisfaction with healthcare services. AB - The objectives of this cross-sectional study were to determine whether depressive and perinatal grief symptoms vary according to time since miscarriage and to test whether childlessness and satisfaction with healthcare services influence symptom duration. A total of 245 women who had experienced a miscarriage answered a self report questionnaire, indicating the date of their miscarriage and assessing their present level of depressive and perinatal grief symptoms. They also provided sociodemographic characteristics and indicated their level of satisfaction with healthcare services. One-way analyses of variance indicated that women who had miscarried within the past 6 months reported higher scores for depressive symptoms than did women who had miscarried between 7 and 12 months ago and more than 2 years ago. However, when controlling for childlessness and satisfaction with healthcare services, those differences became respectively marginal and non-significant, indicating that depressive symptoms are similar across time for more than 2 years after the loss. Regarding perinatal grief, results revealed that symptoms significantly decreased across time only for women with children and women who were satisfied with healthcare services. For childless women and those dissatisfied with healthcare services, perinatal grief symptoms did not vary according to time since miscarriage. Results suggest that, particularly for women who are childless and/or dissatisfied with healthcare services, depressive and perinatal grief symptoms persist long after a miscarriage. These results highlight the importance of paying particular attention to more vulnerable women and of improving healthcare services post miscarriage. PMID- 28623419 TI - Droxidopa for symptomatic neurogenic orthostatic hypotension: what can we learn? PMID- 28623420 TI - Managing supine hypertension in a patient with non-diabetic autonomic neuropathy receiving droxidopa for neurogenic orthostatic hypotension. PMID- 28623421 TI - Comparison of dual-energy CT, ultrasound and surface measurement for assessing tophus dissolution during rapid urate debulking. AB - Tophaceous gout is painful and impairs quality of life. The optimal modality for assessing tophus resolution in response to urate-lowering treatment remains poorly defined. Using pegloticase as a model system for resolving tophi, we compared multiple imaging and physical diagnostic strategies for assessing tophus resolution. A 32-year-old subject with chronic refractory tophaceous gout was enrolled and received 6 months of pegloticase treatment. Measurements of tophi using vernier calipers (monthly), photographs and musculoskeletal ultrasound (MSK US; every 3 months), and dual-energy CT (DECT) were compared. Pegloticase persistently lowered the patient's sUA to <0.5 mg/dl. After 6 months, caliper measurements revealed 73, 60, and 61% reductions of three index tophi, while MSK US revealed 47, 65, and 48% reductions. In contrast, DECT revealed 100% resolution of monosodium urate deposition in all three index tophi, and resolution or improvement of all other tophi identified. On caliper and MSK-US measurement, index tophus size fluctuated, with some lesions enlarging before ultimately contracting. Correlation between assessment modalities during tophus resolution may be poor. DECT identifies urate deposits invisible to physical exam and reveals that some urate deposits completely resolve even as their physically/sonographically measurable lesions persist. Recognition of urate resorption during the urate-lowering process may be confounded by fluctuating lesion volumes during initial tophus breakdown. While DECT was superior for identifying total (including occult) urate deposition, and assessing volume of deposits, other modalities may permit better assessment of non-urate tophus components. PMID- 28623422 TI - Effects of omega-3 on matrix metalloproteinase-9, myoblast transplantation and satellite cell activation in dystrophin-deficient muscle fibers. AB - In Duchenne muscular dystrophy (DMD), lack of dystrophin leads to progressive muscle degeneration, with DMD patients suffering from cardiorespiratory failure. Cell therapy is an alternative to life-long corticoid therapy. Satellite cells, the stem cells of skeletal muscles, do not completely compensate for the muscle damage in dystrophic muscles. Elevated levels of proinflammatory and profibrotic factors, such as metalloproteinase 9 (MMP-9), impair muscle regeneration, leading to extensive fibrosis and poor results with myoblast transplantation therapies. Omega-3 is an anti-inflammatory drug that protects against muscle degeneration in the mdx mouse model of DMD. In the present study, we test our hypothesis that omega-3 affects MMP-9 and thereby benefits muscle regeneration and myoblast transplantation in the mdx mouse. We observe that omega-3 reduces MMP-9 gene expression and improves myoblast engraftment, satellite cell activation, and muscle regeneration by mechanisms involving, at least in part, the regulation of macrophages, as shown here with the fluorescence-activated cell sorting technique. The present study demonstrates the benefits of omega-3 on satellite cell survival and muscle regeneration, further supporting its use in clinical trials and cell therapies in DMD. PMID- 28623423 TI - CXCL10 suppression of hem- and lymph-angiogenesis in inflamed corneas through MMP13. AB - Though not present in the normal adult cornea, both hem- and lymph-angiogenesis can be induced in this tissue after an inflammatory, infectious, or traumatic insult. We previously showed that the chemokine CXCL10 plays a key role in eradicating invading Candida (C.) albicans in C57BL6 mouse corneas. However, even after the clearance of pathogens, infection-induced inflammation and angiogenesis continue to progress in the cornea. The aim of this study is define the role of CXCL10 as a major angiostatic factor in modulating cornea angiogenesis in B6 mouse corneas under pathogenic conditions. We showed that epithelial expression of CXCL10, driven by AAV9 vector, suppressed both infection- and inflammation induced hem and lymph angiogenesis, whereas the neutralization of CXCL10 as well as its receptor CXCR3 greatly promoted these processes. The inhibitory effect of CXCL10 was unrelated to its antimicrobial activity, but through the suppression of the expression of many angiogenic factors, including VEGFa and c, and MMP-13 in vivo. Inhibition of MMP13 but not TIMPs, attenuated suture-induced neovascularization but had no effects on CXCL10 expression. Strikingly, topical application of CXCL10 post-C. albicans infection effectively blocked both hem- and lymph-angiogenesis and preserved the integrity of sensory nerves in the cornea. Taken together, CXCL10 has strong inhibitory effects on neovascularization, whereas MMP13 is required for neovascularization in C. albicans-infected corneas and the local application of CXCL10 or MMP13 inhibitors, alone or as adjuvant therapy, may target hem- and lymph-angiogenesis in the inflamed corneas. PMID- 28623424 TI - Does air pollution trigger suicide? A case-crossover analysis of suicide deaths over the life span. AB - In addition to underlying health disorders and socio-economic or community factors, air pollution may trigger suicide mortality. This study evaluates the association between short-term variation in air pollution and 10 years of suicide mortality in Belgium. In a bidirectional time-stratified case-crossover design, 20,533 suicide deaths registered between January 1st 2002 and December 31st 2011 were matched by temperature with control days from the same month and year. We used municipality-level air pollution [particulate matter (PM10) and O3 concentrations] data and meteorology data. We applied conditional logistic regression models adjusted for duration of sunshine and day of the week to obtain odds ratios (OR) and their 95% CI for an increase of 10 ug/m3 in pollutant concentrations over different lag periods (lag 0, 0-1, 0-2, 0-3, 0-4, 0-5, and 0 6 days). Effect modification by season and age was investigated by including interaction terms. We observed significant associations of PM10 and O3 with suicide during summer (OR ranging from 1.02 to 1.07, p-values <0.05). For O3, significant associations were also observed during spring and autumn. Age significantly modified the associations with PM10, with statistically significant associations observed only among 5-14 year old children (lag 0-6: OR = 1.45; 95% CI: 1.03-2.04) and >=85 years old (e.g. lag 0-4: OR = 1.17; 95% CI: 1.06-1.29). Recent increases in outdoor air pollutants such as PM10 or O3 can trigger suicide, particularly during warm periods, even at concentrations below the European thresholds. Furthermore, PM10 may have strong trigger effects among children and elderly population. PMID- 28623425 TI - Effects of a 20-week high-intensity strength and sprint training program on tibial bone structure and strength in middle-aged and older male sprint athletes: a randomized controlled trial. AB - : This randomized, controlled, high-intensity strength and sprint training trial in middle-aged and older male sprint athletes showed significant improvements in mid-tibial structure and strength. The study reveals the adaptability of aging bone, suggesting that through a novel, intensive training stimulus it is possible to strengthen bones during aging. INTRODUCTION: High-load, high-speed and impact type exercise may be an efficient way of improving bone strength even in old age. We evaluated the effects of combined strength and sprint training on indices of bone health in competitive masters athletes, who serve as a group of older people who are likely to be able to participate in vigorous exercise of this kind. METHODS: Seventy-two men (age 40-85) were randomized into an experimental (EX, n = 40) and a control (CTRL, n = 32) group. EX participated in a 20-week program combining heavy and explosive strength exercises with sprint training. CTRL maintained their usual, run-based sprint training schedules. Bone structural, strength and densitometric parameters were assessed by peripheral QCT at the distal tibia and tibial midshaft. RESULTS: The intervention had no effects on distal tibia bone traits. At the mid-tibia, the mean difference in the change in cortical thickness (ThCO) in EX compared to CTRL was 2.0% (p = 0.007). The changes in structure and strength were more pronounced in the most compliant athletes (training adherence >75%). Compared to CTRL, total and cortical cross sectional area, ThCO, and the area and density-weighted moments of inertia for the direction of the smallest flexural rigidity (I minA , I minD ) increased in EX by 1.6-3.2% (p = 0.023-0.006). Polar mass distribution analysis revealed increased BMC at the anteromedial site, whereas vBMD decreased (p = 0.035-0.043). CONCLUSIONS: Intensive strength and sprint training improves mid-tibia structure and strength in middle-aged and older male sprint athletes, suggesting that in the presence of high-intensity loading exercise, the adaptability of the bone structure is maintained during aging. PMID- 28623426 TI - Comparative physical mapping of 18S rDNA in the karyotypes of six leafcutter ant species of the genera Atta and Acromyrmex (Formicidae: Myrmicinae). AB - Leafcutter ants of the Atta and Acromyrmex genera are important plagues in different cultures. Cytogenetic data on chromosome number, morphology, and chromosomal banding pattern are only available for 17 species of leafcutter ants. Molecular cytogenetic data for the detection of ribosomal genes by the FISH technique are scarce, and only 15 Neotropical ant species have been studied. This study aimed to physically map the 18S ribosomal RNA genes (rDNA) of six leafcutter ants belonging to the genera Atta and Acromyrmex using FISH. The results were compared with data on the fluorochrome CMA3 currently available for these species. All analyzed species presented the 18S rDNA on one pair of chromosomes. In Acromyrmex subterraneus molestans and Ac. aspersus, FISH signals were observed in the terminal region of the short arm of the largest subtelocentric pair, while in Atta bisphaerica, A. laevigata, and A. sexdens, FISH signals were observed in the interstitial region of the long arm of the fourth metacentric pair. In Acromyrmex striatus, 18S rDNA was located in the interstitial region of the second metacentric pair. The karyotypic formula for Ac. aspersus was 2n = 38 (8m + 10sm + 16st + 4a), representing the first report in this species. The observed 18S rDNA regions in A. laevigata, A. sexdens, A. bisphaerica, Ac. aspersus, and Ac. subterraneus molestans corresponded to the CMA3+ bands, while in Ac. striatus, several GC-rich bands and one pair of 18S rDNA bands were observed. No differential bands were visible using the DAPI fluorochrome. Karyotype uniformity with previously studied Atta spp. was also observed at the level of molecular cytogenetics using 18S rDNA FISH. A difference in the size of the chromosomal pair carrying the 18S rDNA gene was observed in Ac. striatus (2n = 22) and Atta spp. (2n = 22) highlighting the dissimilarity between these species. The results from the present study contribute to the description of 18S rDNA clusters in Neotropical ants. PMID- 28623427 TI - Blood concentrations of lead, cadmium, mercury and their association with biomarkers of DNA oxidative damage in preschool children living in an e-waste recycling area. AB - Reactive oxygen species (ROS)-induced DNA damage occurs in heavy metal exposure, but the simultaneous effect on DNA repair is unknown. We investigated the influence of co-exposure of lead (Pb), cadmium (Cd), and mercury (Hg) on 8 hydroxydeoxyguanosine (8-OHdG) and human repair enzyme 8-oxoguanine DNA glycosylase (hOGG1) mRNA levels in exposed children to evaluate the imbalance of DNA damage and repair. Children within the age range of 3-6 years from a primitive electronic waste (e-waste) recycling town were chosen as participants to represent a heavy metal-exposed population. 8-OHdG in the children's urine was assessed for heavy metal-induced oxidative effects, and the hOGG1 mRNA level in their blood represented the DNA repair ability of the children. Among the children surveyed, 88.14% (104/118) had a blood Pb level >5 MUg/dL, 22.03% (26/118) had a blood Cd level >1 MUg/dL, and 62.11% (59/95) had a blood Hg level >10 MUg/dL. Having an e-waste workshop near the house was a risk factor contributing to high blood Pb (r s = 0.273, p < 0.01), while Cd and Hg exposure could have come from other contaminant sources. Preschool children of fathers who had a college or university education had significantly lower 8-OHdG levels (median 242.76 ng/g creatinine, range 154.62-407.79 ng/g creatinine) than did children of fathers who had less education (p = 0.035). However, we did not observe a significant difference in the mRNA expression levels of hOGG1 between the different variables. Compared with children having low lead exposure (quartile 1), the children with high Pb exposure (quartiles 2, 3, and 4) had significantly higher 8-OHdG levels (beta Q2 = 0.362, 95% CI 0.111-0.542; beta Q3 = 0.347, 95% CI 0.103-0.531; beta Q4 = 0.314, 95% CI 0.087-0.557). Associations between blood Hg levels and 8-OHdG were less apparent. Compared with low levels of blood Hg (quartile 1), elevated blood Hg levels (quartile 2) were associated with higher 8-OHdG levels (beta Q2 = 0.236, 95% CI 0.039-0.406). Compared with children having low lead exposure (quartile 1), the children with high Pb exposure (quartiles 2, 3, and 4) had significantly higher 8-OHdG levels. PMID- 28623428 TI - Quantitative Measurement of PARD3 Copy Number Variations in Human Neural Tube Defects. AB - Although more than 200 genes are known to be related to neural tube defects (NTDs), the exact molecular basis is still unclear. Evaluating the contribution of copy number variation (CNV) might be a priority because CNV involves changes in the copy number of large segments of DNA, leading to phenotypic traits and disease susceptibility. Recent studies have documented that the polarity protein partitioning defective 3 homolog (Pard3) plays an essential role in the process of neural tube closure. The aim of this study was to assess the role of PARD3 CNVs in the etiology of human NTDs. Relative quantitative PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were used to quantitative measurement of CNVs in 25 PARD3 exons in 202 NTD cases and 231 controls from a region of China with a high prevalence of NTDs. The results showed that microduplications ranging from 3 to 4 were evident in coding Exon 21 and Exon 25 in both case and control groups. A novel heterozygous microdeletion spanning 444 bp of Exon 14 was identified in two cases of anencephaly and is absent from all controls analyzed. Expression analyses indicated that this heterozygotic microdeletion showed no tissue specificity and led to defective expression of PARD3. Our study provides further evidence implicating PARD3 in the etiology of NTDs. PMID- 28623429 TI - BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. AB - Brain-derived neurotrophic factor (BDNF) is one of the most widely distributed and extensively studied neurotrophins in the mammalian brain. Among its prominent functions, one can mention control of neuronal and glial development, neuroprotection, and modulation of both short- and long-lasting synaptic interactions, which are critical for cognition and memory. A wide spectrum of processes are controlled by BDNF, and the sometimes contradictory effects of its action can be explained based on its specific pattern of synthesis, comprising several intermediate biologically active isoforms that bind to different types of receptor, triggering several signaling pathways. The functions of BDNF must be discussed in close relation to the stage of brain development, the different cellular components of nervous tissue, as well as the molecular mechanisms of signal transduction activated under physiological and pathological conditions. In this review, we briefly summarize the current state of knowledge regarding the impact of BDNF on regulation of neurophysiological processes. The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted. PMID- 28623430 TI - A Phase I/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1104). AB - PURPOSE: Suberoylanilide hydroxamic acid (SAHA; vorinostat), a small molecule inhibitor of histone deacetylase, attenuates signaling pathways known to confer trastuzumab resistance. A combination of SAHA and trastuzumab may be a promising strategy to improve the efficacy of trastuzumab against breast cancer. In this Phase I/II study, we evaluated the toxicity and response rate after treatment with SAHA and trastuzumab in patients with HER2-overexpressing metastatic breast cancer with trastuzumab-resistant progressive disease. METHODS: In Phase I, the SAHA dose was modified in cohorts of 3-6 patients to find the dose level at which 0 or 1 patients experienced a dose-limiting toxicity (DLT) during the first cycle of therapy. In the Phase II study, response to the recommended dose identified in Phase I was based on the response evaluation criteria in solid tumors. Overall survival and time to progression were also evaluated. RESULTS: The recommended dose was determined to be 200 mg twice a day on days 1-14 and IV trastuzumab 6 mg/kg on day 1 of a 21-day cycle (n = 6). The Phase II study (n = 10) was terminated when the pre-planned efficacy evaluation found that none of the patients in the primary analysis set responded to combination SAHA and trastuzumab treatment. CONCLUSIONS: In patients with HER2-positive metastatic breast cancer who had relapsed or progressed during trastuzumab therapy, we observed no DLTs with SAHA 200 mg twice daily combined with trastuzumab; however, there was insufficient statistical evidence that adding SAHA reversed trastuzumab resistance in these patients. PMID- 28623432 TI - Identification and expression analysis of CYS-A1, CYS-C1, NIT4 genes in rice seedlings exposed to cyanide. AB - Involvement of genes (CYS-A1, CYS-C1 and NIT4) encoded with cysteine synthase, beta-cyanoalanine synthase, nitrilase and cyanide metabolisms are evident in Arabidopsis. In the present study, identifications of CYS-A1, CYS-C1 and NIT4, predictions of conserved motifs, and constructions of phylogenetic relationships, based on their amino acid sequences in rice, were conducted. In order to elucidate the transcriptional responses of these cyanide-degrading genes, two candidate homologues were selected for each gene to test their expression changes upon exposure to exogenous KCN in rice seedlings using RT-PCR. Results showed that all selected candidate homologous genes were differentially expressed at different exposure points in roots and shoots of rice seedlings, suggesting their distinct roles during cyanide assimilation. Both candidate homologues for CYS-A1 constantly exhibited more abundant transcripts in comparison to control. However, only one candidate homologue for CYS-C1 and NIT4 showed a remarkable up regulation during KCN exposure. Analysis of both tissue and solution cyanide indicated that rice seedlings were quickly able to metabolize exogenous KCN with minor accumulation in plant tissues. In conclusion, significant up-regulation of CYS-A1 suggested that the endogenous pool of cysteine catalyzed by cysteine synthase does not restrict the conversion of exogenous KCN into cyanoalanine through the beta-cyanoalanine pathway. However, insufficient responses of the transcription level of NIT4 suggested that NIT enzyme may be a limiting factor for cyanoalanine assimilation by rice seedlings. PMID- 28623431 TI - Effect of chronic arsenic exposure under environmental conditions on bioaccumulation, oxidative stress, and antioxidant enzymatic defenses in wild trout Salmo trutta (Pisces, Teleostei). AB - The present study evaluates the relation between chronic arsenic (As) exposure in the natural distribution area of wild brown trout (Salmo trutta), oxidative stress and antioxidant enzymatic defenses. Two rivers of the same watershed were evaluated to highlight the correlation between As accumulation and the resulting stress: (i) the Presa River, which has high chronic As levels (2281.66 ug/L) due to past mining activity, and (ii) the Bravona River (control river). This metalloid was measured in main fish tissues (gills, kidney, liver, muscle, gonads and fins) and water. As organotropism in S. trutta was kidney > liver > gill > fin > gonad > muscle. The HepatoSomatic Index (HSI) and somatic condition (CF) were used to compare fish population conditions from both sites. Arsenic can be absorbed by the gills and can induce oxidative stress and disturb antioxidant defenses. The aim of this study was to evaluate oxidative stress response by measuring malondialdehyde (MDA) content, as a marker of lipid peroxidation, and antioxidant enzymatic defenses (Superoxide dismutase (SOD), catalase CAT, glutathione peroxidase (GPx) and glutathione S-transferase (GST)), in the main tissues of control and exposed trout. The highest MDA content was found in the kidney and liver of exposed trout. SOD and CAT activities in exposed livers and kidneys were considerably increased while a significant rise of GPx activity was observed only in the liver. GST activity was found to be significantly induced in the liver of exposed trout. The results demonstrate that arsenic bioaccumulation can induce lipid peroxidation and substantial modifications in antioxidant enzymatic defenses in main wild trout tissues. PMID- 28623433 TI - Comparison of the effect of honey and mefenamic acid on the severity of pain in women with primary dysmenorrhea. AB - BACKGROUND AND OBJECTIVE: Primary dysmenorrhea starts simultaneously with menstruation or before it and usually continues for 48-72 h. As a prevalence disorder, it affects about 80-97% of women in the reproductive age. The conventional treatment modalities of primary dysmenorrhea are associated with complications and side effects. In addition, there is a lack of knowledge of the effect of honey on the treatment of primary dysmenorrhea. The objective of this study is to investigate the effect of honey on the severity of pain in women with dysmenorrhea. METHODS: A randomized crossover clinical trial was conducted on 56 female students. Subjects were randomly assigned to two groups. Groups I and II received honey and mefenamic acid in the 'first treatment period', respectively. In the 'second treatment period', the intervention methods were reversed between the groups. Samples recorded the severity of pain during the first 3 days of menstruation. RESULTS: There were no significant differences in the most severe level of pain in the first and second months of the first treatment period, and the first and second months of the second treatment period between the groups. CONCLUSIONS: Honey and the mefenamic acid capsules led to the same amount of pain relief in women with primary dysmenorrhea. Honey is suggested to be used for pain relief due to its lower side effects and pharmacological complications. PMID- 28623434 TI - [Cost analysis as a tool for assessing the efficacy of intensive care units]. AB - BACKGROUND: The German "Hospital Structure Act" intends to align the state hospital planning on quality criteria. Within this process cost-utility analyses (CUAs) shall be used to assess the efficacy of medical care. To be objective, CUAs of intensive care units (ICUs) require standardization (adjustment) of costs. The present study analyzed the extent to which treatment costs are related to patient-specific baseline variables (such as type and severity of the primary disease). METHODS: From 2000-2004, a bottom-up procedure was used to quantify total costs on 14 ICUs in nine German university hospitals. Results were combined with demographic data, and data indicating type (ICD-10 codes) and severity (ICU scoring systems) of the primary disease at ICU admission. Various statistical models were tested to identify that which best described the associations between baseline variables and costs. RESULTS: In all, 3803 critically ill patients could be examined. The median of treatment costs per patient was 3199 ? (IQR 1768-6659 ?). No model allowed an acceptably precise adjustment of costs; the estimated mean absolute prognostic error was at least 3860 ? (mean relative prognostic error 66%), when we tested an Extreme Gradient Boosting Model. CONCLUSION: Instruments which are currently available (cost adjustment based on patient specific baseline variables) do not allow a standardization of costs, and an objective CUA of ICUs. Factors unknown at baseline may cause a large portion of treatment costs. PMID- 28623435 TI - The brain behaves as a muscle? AB - It is known that lactate accumulates in the skeletal muscle during intense anaerobic exercise but is rapidly cleared from the muscles when they resume aerobic metabolism; however, at least some lactate reaches the blood stream. It has been observed that during maximal exercise, blood lactate increases with transport of the blood to the brain. This could be interpreted as a mechanism to protect against possible "central fatigue" in times of maximal activity during the course of which the lactate would preserve the functionality of the primary cortical motor and sensory areas, even at the expense of the efficiency of the other structures. In this way, the role of lactate, both at the muscular level and in the CNS, appears to shift from being responsible for fatigue to protector from fatigue, which represents a real transition similar to that of how the image of Mr. Hyde changes to that of Dr. Jekyll. PMID- 28623436 TI - High-dose-rate brachytherapy as salvage modality for locally recurrent prostate cancer after definitive radiotherapy : A systematic review. AB - PURPOSE: To review the current status of interstitial high-dose-rate brachytherapy as a salvage modality (sHDR BRT) for locally recurrent prostate cancer after definitive radiotherapy (RT). MATERIALS AND METHODS: A literature search was performed in PubMed using "high-dose-rate, brachytherapy, prostate cancer, salvage" as search terms. In all, 51 search results published between 2000 and 2016 were identified. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control (BC) and toxicity scores. RESULTS: Eleven publications reported clinical outcome and toxicity with follow-up ranging from 4-191 months. A variety of dose and fractionation schedules were described, including 19.0 Gy in 2 fractions up to 42.0 Gy in 6 fractions. The 5-year BC ranged from 18-77%. Late grade 3 genitourinary and gastrointestinal toxicity was 0-32% and 0-5.1%, respectively. CONCLUSIONS: sHDR BRT appears as safe and effective salvage modality for the reirradiation of locally recurrent prostate cancer after definitive RT. PMID- 28623438 TI - Perspective. PMID- 28623437 TI - Root-derived bicarbonate assimilation in response to variable water deficit in Camptotheca acuminate seedlings. AB - Water deficit is one of the key factors that limits the carbon (C) assimilation and productivity of plants. The effect of variable water deficit on recently root derived bicarbonate assimilation in Camptotheca acuminate seedlings was investigated. Three-month-old seedlings were subjected to three water regimes, well-watered (WW), moderate stress (MS), and severe stress (SS) induced by polyethyleneglycol, in conjunction with relatively high (H) and low (L) natural 13C-abundance of NaHCO3-labeled treatments in hydroponics for 14 days. The delta13C of the newly expanded leaves in H were generally more enriched in heavy isotopes than were those in L, indicative of the involvement of bicarbonate in aboveground tissues. The C isotope fractionation of newly expanded leaves relative to air (?13Cair-leaves) ranged from 17.78 to 21.780/00 among the treatments. The ?13Cair-leaves under the MS and SS treatments in H were both more negative than was that in L. A linear regression between Ci/Ca and ?13Cair-leaves in both L and H were different from the theoretical regression. On the basis of the two end-member mixing model, the proportion of fixed CO2 supplied from bicarbonate contributing to the total photosynthetically inorganic C assimilation were 10.34, 20.05 and 16.60% under the WW, MS, and SS treatments, respectively. These results indicated that the increase in water deficit decreased the atmospheric CO2 gain but triggered a compensatory use of bicarbonate in C. acuminate seedlings. PMID- 28623439 TI - Proposing a Health Humanities Minor: Some Lessons. AB - For those interested in developing baccalaureate programs in health humanities, this essay draws on our experience of developing a minor in health humanities to share insights on what to expect, strategies that work well, and how to deal with obstacles. These insights range from how to explain the concept of health humanities to stakeholders (faculty, administrators, and community partners) to how to decide where to house a health humanities program. We share our insights in a way that promises to translate well to different institutional contexts. That said, this paper is more relevant for institutional contexts where budgets are stressed and, consequently, proposals to invest in humanities programs are a difficult sell. This paper is divided into sections addressing how to (a) earn institutional support, (b) gain campus buy-in, (c) identify benefits of the proposed program, (d) decide where to house the program, (e) calculate program cost, and (f) secure external funding. We conclude with some final reflections on the current status of our program and why we are committed to health humanities education. PMID- 28623441 TI - Perspective. PMID- 28623440 TI - The Impact of Baccalaureate Medical Humanities on Subsequent Medical Training and Practice: A Physician-Educator's Perspective. AB - This reflective essay is an attempt to organize trends in feedback I have observed during ten years of coursework, conversations, and correspondence with former students associated with the Medical Humanities Program at Baylor University. Over the years, recurrent themes arise when speaking with alumni about whether and how their medical humanities experience intersects with their current training. I have identified five particular domains in which baccalaureate medical humanities training affects students' subsequent healthcare professions training and practice: context and complementarity, clinical relevance, reflective practice, professional preparedness and vocational calling. I created an instrument of open-ended questions for each of these categories and posted it to social media with an invitation for alumni to respond. This informal survey was conceived as an exploratory exercise with the intent to help generate a foundation for more formal qualitative research in these five domains. In this essay, I offer my own reflections together with those of former students on the impact of baccalaureate-level medical humanities training in order to illustrate the benefits in each domain for subsequent healthcare training and practice. The need for qualitative research that explores the impact of baccalaureate medical humanities merits collaboration between multiple centers of investigation across many disciplines, and across the divide between premedical and medical educators. PMID- 28623443 TI - Autolyse the cell in order to save it? Inducing, then blocking, autolysis as a strategy for delaying cell death in the probiotic Lactobacillus reuteri. AB - OBJECTIVE: To examine whether choline and its derivatives can be used to preserve viable cells of Lactobacillus reuteri in autolytic models. RESULTS: A phosphate induced autolytic model in de Man, Rogosa and Sharpe medium (MRS) was used. Viable cell counts were determined by plated on MRS-agar. Choline and hemicholinium-3 (HC-3) significantly blocked autolysis of L. reuteri at 360 mM and 4 mM, respectively. Viable cell counts corroborated these observations. Importantly, autolytically induced cells treated with choline and hemicholinium-3 were significantly more viable then even non-induced cells. Over-production of a known autolytic protein, spirosin, was not attenuated in the presence of choline and hemicholinium-3. CONCLUSION: Inducing autolysis and then blocking it with choline and its analogs is a promising approach for retaining the viability of L. reuteri cells. PMID- 28623442 TI - Counseling interventions delivered in women with breast cancer to improve health related quality of life: a systematic review. AB - BACKGROUND: Higher survival rates for breast cancer patients have led to concerns in dealing with short- and long-term side effects. The most common complications are impairment of shoulder functions, pain, lymphedema, and dysesthesia of the injured arm; psychological consequences concern: emotional distress, anxiety, and depression, thereby, deeply impacting/affecting daily living activity, and health related quality of life. OBJECTIVE: To perform a systematic review for assessing the efficacy or effectiveness of interventions aiming at improving health-related quality of life, return to daily activity, and correct lifestyles among breast cancer patients. METHODS: A literature search was conducted in December 2016 using the databases PubMed and Scopus. Search terms included: (counseling) AND (breast cancer) AND (quality of life). Articles on counseling interventions to improve quality of life, physical and psychological outcomes were included. RESULTS: Thirty-five articles met the inclusion criteria. The interventions were grouped in five main areas: concerning lifestyle counseling interventions, related to combined interventions (physical activity and nutritional counseling), physical therapy, peer counseling, multidisciplinary approach, included psychological, psycho-educational interventions, and cognitive-behavior therapy (CBT). Exercise counseling as well as physical therapy are effective to improve shoulder mobility, healing wounds, and limb strength. Psychological therapies such as psychoeducation and CBT may help to realize a social and psychological rehabilitation. CONCLUSION: A multidisciplinary approach can help in sustaining and restoring impaired physical, psychosocial, and occupational outcomes of breast cancer patients. PMID- 28623444 TI - An overview and comparison of a recombinant antigen-binding fragment and an antigen-binding fragment from a monoclonal antibody against wogonin glucuronide. AB - Wogonin glucuronide (wogonin 7-O-beta-D-glucuronide, Wgn) is widely recognized as a constituent of Scutellariae radix, which is used in Kampo medicines. Wgn has been used for both pharmacological (antifebrile uses and in detoxification) and research purposes. A recombinant antigen-binding fragment (rFab) and an antigen binding fragment from a monoclonal antibody (mFab) against Wgn were constructed and used in an indirect competitive enzyme-linked immunosorbent assay (icELISA) in this study. The rFab and mFab against Wgn showed both activity and recognition against Wgn. The developed icELISA was validated as a quantitative analytical method to detect Wgn by testing both its utility and its reliability using multiple concentrations of Wgn from S. radix. This approach provides a more economic method to analyze and purify Kampo medicines. PMID- 28623445 TI - Laparoscopic Sleeve Gastrectomy Resolves Low GHRP-2-Stimulated Growth Hormone Levels in Obese Patients. AB - Because growth hormone (GH) secretion is reportedly decreased in obese patients, we examined not only the factors associated with the decreased GH secretion but also GH response to the GH-releasing peptide (GHRP)-2-load test before and after laparoscopic gastrectomy (LSG). The study comprised 28 individuals aged 19-65 years [mean body mass index (BMI), 39.4 +/- 9.4 kg/m2]. In the univariate analysis, GH secretion peaks correlated negatively with BMI (r = -0.59, p = 0.001), visceral adipose tissue (r = -0.47, p = 0.005), and subcutaneous adipose tissue (r = -0.40, p = 0.04). In the two obese patients, the response to the GHRP 2-load test markedly improved by weight loss 12 months after LSG. In conclusion, GH secretion was decreased in obese patients and improved by LSG. PMID- 28623446 TI - Laparoscopic Sleeve Gastrectomy: Investigation of Fundus Wall Thickness and Staple Height-an Observational Cohort Study : Fundus Wall Thickness and Leaks. AB - BACKGROUND: Staple line leakage is a well-known complication after laparoscopic sleeve gastrectomy (LSG). Gastric wall thickness and the staple height may be determining factors for the occurrence of insufficiencies. To investigate this problem, an observational cohort study was carried out. Investigation concentrated on the gastroesophageal junction close to the angle of His, since this area is at highest risk for a leakage. METHODS: Fundus wall thickness of 141 specimens after LSG was measured by light microscopy at a predetermined location by a blinded pathologist. Furthermore, fundus wall thickness was compared with demographic data, clinical outcome, and the rate of insufficiencies. RESULTS: One hundred forty-one patients, 38 male and 103 female undergoing LSG, between January 2014 and July 2015 were included in the study. Male gender was associated with thicker gastric fundus wall. Overall leak rate was 2.1% (3/141). Median wall thickness of the 3 patients with detected leaks in the study group was thinner compared to the non-leak group (2810 vs. 3249 MUm, respectively). DISCUSSION/CONCLUSION: Only male gender correlated with higher wall thickness of the fundus. The fact that all three patients who developed a leak were female, and the fundus of female patients as well as those of the leak group was thinner, indicates that wall thickness may have an impact on the rate of staple line leakage. Further studies with larger patient cohorts are needed. PMID- 28623447 TI - New Approaches to Gastroesophageal Reflux Disease. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is the most common gastrointestinal disorder of the esophagus. It is a chronic, progressive disorder that presents most typically with heartburn and regurgitation and atypically with chest pain, dysphagia, chronic cough, globus, or sore throat. The mainstay for diagnosis and characterization of the disorder is esophagoduodenoscopy (EGD), high-resolution esophageal manometry, and symptom-associated ambulatory esophageal pH impedance monitoring. Additional studies that can be useful in certain clinical presentations include gastric scintigraphy and oral contrast upper gastrointestinal radiographic series. DISCUSSION: Refractory GERD can be surgically managed with various techniques. In obese individuals, laparoscopic Roux-en-Y gastric bypass should be considered due to significant symptom improvement and lower incidence of recurrent symptoms with weight loss. Otherwise, laparoscopic Nissen fundoplication is the preferred surgical technique for treatment of this disease with concomitant hiatal hernia repair when present for either procedure. The short-term risks associated with these procedures include esophageal or gastric injury, pneumothorax, wound infection, and dysphagia. Emerging techniques for treatment of this disease include the Linx Reflux Management System, EndoStim LES Stimulation System, Esophyx(r) and MUSETM endoscopic fundoplication devices, and the Stretta endoscopic ablation system. Outcomes after surgical management of refractory GERD are highly dependent on adherence to strict surgical indications and appropriate patient-specific procedure selection. PMID- 28623448 TI - Comparison between chemoselection and definitive radiotherapy in patients with cervical esophageal squamous cell carcinoma. AB - BACKGROUD: Laryngeal preservation is an important consideration when treating cervical esophageal cancers (CECs) such as laryngeal cancer. The standard treatment for CEC allowing laryngeal preservation is chemoradiotherapy. However, in cases of laryngeal cancer, chemoselection has also been applied as a treatment strategy that promotes larynx preservation. This strategy involves assigning the appropriate radical treatment according to the primary tumor's response to induction chemotherapy. Since there have been no studies of the application of chemoselection in CEC cases, the present study compared the results, including laryngeal preservation rates, obtained upon applying chemoselection and chemoradiotherapy to CEC. STUDY DESIGN: This was a retrospective cohort study of cervical esophageal squamous cell carcinoma patients treated using chemoselection or chemoradiotherapy at Aichi Cancer Center Hospital between January 2000 and March 2013. A total of 42 patients were enrolled. RESULTS: The 2-year overall survival and laryngeal preservation rates for the chemoselection group versus the primary radiotherapy group were 65.1 and 57.3 versus 40 and 83.3%, respectively (P = 0.017 and P = 0.122, respectively). The 2-year locoregional control rates for the chemoselection and primary radiotherapy groups were 68 and 25%, respectively (P = 0.045). CONCLUSION: The chemoselection group achieved favorable results. Therefore, chemoselection can be applied as a treatment strategy for CEC. PMID- 28623449 TI - Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity. AB - PURPOSE: Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear. METHODS: We studied the metabolism of and tolerance to mercaptopurine in murine knockout models of Tpmt, Mrp4, and both genes simultaneously. RESULTS: Upon mercaptopurine treatment, Tpmt -/- Mrp4 -/- mice had the highest concentration of bone marrow thioguanine nucleotides (8.5 pmol/5 * 106 cells, P = 7.8 * 10-4 compared with 2.7 pmol/5 * 106 cells in wild-types), followed by those with Mrp4 or Tpmt deficiency alone (6.1 and 4.3 pmol/5 * 106 cells, respectively). Mrp4-deficient mice accumulated higher concentrations of methylmercaptopurine metabolites compared with wild-type (76.5 vs. 23.2 pmol/5 * 106 cells, P = 0.027). Mice exposed to a clinically relevant mercaptopurine dosing regimen displayed differences in toxicity and survival among the genotypes. The double knock-out of both genes experienced greater toxicity and shorter survival compared to the single knockout of either Tpmt (P = 1.7 * 10-6) or Mrp4 (P = 7.4 * 10-10). CONCLUSIONS: We showed that both Tpmt and Mrp4 influence mercaptopurine disposition and toxicity. PMID- 28623450 TI - The relationship between excitement symptom severity and extrastriatal dopamine D2/3 receptor availability in patients with schizophrenia: a high-resolution PET study with [18F]fallypride. AB - The purpose of this study was to investigate the relationship between specific symptom severity and D2/3 receptor availability in extrastriatal regions in outpatients with schizophrenia to shed light on the role of extrastriatal dopaminergic neurotransmission in the pathophysiology of symptoms of schizophrenia. Sixteen schizophrenia patients receiving relatively low-dose maintenance atypical antipsychotics and seventeen healthy controls underwent 3 Tesla magnetic resonance imaging and high-resolution positron emission tomography with [18F]fallypride. For D2/3 receptor availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model. The BPND values were lower in patients on antipsychotic treatment than in controls across all regions with large effect sizes (1.03 1.42). The regions with the largest effect size were the substantia nigra, amygdala, and insula. Symptoms of schizophrenia were assessed using a five-factor model of the Positive and Negative Syndrome Scale (PANSS). The region of interest based analysis showed that PANSS excitement factor score had a significant positive correlation with the [18F]fallypride BPND in the insula. The equivalent dose of antipsychotics was not significantly correlated with PANSS factor scores or regional BPND values. The voxel-based analysis also revealed a significant positive association between the PANSS excitement factor and the [18F]fallypride BPND in the insula. The present study revealed a significant association between excitement symptom severity and D2/3 receptor availability in the insula in schizophrenia, suggesting a possible important role of D2/3 receptor-mediated neurotransmission in the insula and related limbic system in the pathophysiology of this specific symptom cluster. PMID- 28623451 TI - Neighborhood Inequalities in Hepatitis C Mortality: Spatial and Temporal Patterns and Associated Factors. AB - Deaths attributable to hepatitis C (HCV) infection are increasing in the USA even as highly effective treatments become available. Neighborhood-level inequalities create barriers to care and treatment for many vulnerable populations. We seek to characterize citywide trends in HCV mortality rates over time and identify and describe neighborhoods in New York City (NYC) with disproportionately high rates and associated factors. We used a multiple cause of death (MCOD) definition for HCV mortality. Cases identified between January 1, 2006, and December 31, 2014, were geocoded to NYC census tracts (CT). We calculated age-adjusted HCV mortality rates and identified spatial clustering using a local Moran's I test. Temporal trends were analyzed using joinpoint regression. A multistep global and local Poisson modeling approach was used to test for neighborhood associations with sociodemographic indicators. During the study period, 3697 HCV-related deaths occurred in NYC, with an average annual percent increase of 2.6% (p = 0.02). The HCV mortality rates ranged from 0 to 373.6 per 100,000 by CT, and cluster analysis identified significant clustering of HCV mortality (I = 0.23). Regression identified positive associations between HCV mortality and the proportion of non-Hispanic black or Hispanic residents, neighborhood poverty, education, and non-English-speaking households. Local regression estimates identified spatially varying patterns in these associations. The rates of HCV mortality in NYC are increasing and vary by neighborhood. HCV mortality is associated with many indicators of geographic inequality. Results identified neighborhoods in greatest need for place-based interventions to address social determinants that may perpetuate inequalities in HCV mortality. PMID- 28623452 TI - Enhanced visualization of the retinal vasculature using depth information in OCT. AB - Retinal vessel tree extraction is a crucial step for analyzing the microcirculation, a frequently needed process in the study of relevant diseases. To date, this has normally been done by using 2D image capture paradigms, offering a restricted visualization of the real layout of the retinal vasculature. In this work, we propose a new approach that automatically segments and reconstructs the 3D retinal vessel tree by combining near-infrared reflectance retinography information with Optical Coherence Tomography (OCT) sections. Our proposal identifies the vessels, estimates their calibers, and obtains the depth at all the positions of the entire vessel tree, thereby enabling the reconstruction of the 3D layout of the complete arteriovenous tree for subsequent analysis. The method was tested using 991 OCT images combined with their corresponding near-infrared reflectance retinography. The different stages of the methodology were validated using the opinion of an expert as a reference. The tests offered accurate results, showing coherent reconstructions of the 3D vasculature that can be analyzed in the diagnosis of relevant diseases affecting the retinal microcirculation, such as hypertension or diabetes, among others. PMID- 28623454 TI - [Erratum to: Hybrid operating rooms versus conventional operating rooms : Economic comparisons in vascular surgery using the example of endovascular aneurysm repair]. PMID- 28623453 TI - Introducing a Novel Media to Improve the Recovery of Culturable Bacteria from the Fish Parasite Anisakis spp. larvae (Nematoda: Anisakidae). AB - This paper describes a cultivation method to increase the recovery of bacteria from the marine muscle-invading parasitic nematode larvae of Anisakis spp. These larvae hold a high and complex population of accumulated bacteria, originating from seawater, crustaceans, fish, and marine mammals, all involved in the lifecycle of Anisakis. Two in-house agars based on fish juice prepared by either mechanical or enzymatic degradation of the fish tissue, were made. The Anisakis larvae were homogenised prior to cultivation on the in-house fish juice agars and the bacterial numbers and diversity were compared to those obtained applying the commercially available Marine Agar and Iron Agar Lyngby. Bacterial colonies of unique appearance were subcultured and identified by 16S rRNA gene sequencing. Totally three of twenty identified taxa were found on the in-house fish juice agars only. Fish juice agar prepared enzymatically would be the best supplementary agar, as this agar gave significantly higher heterotrophic plate counts, compared to mechanical preparation. The enzymatically prepared fish juice gave more suitable agar quality, was more resource efficient, and had apparently increased nutrient density and availability. PMID- 28623455 TI - [Single incision laparoscopy : Current status]. AB - BACKGROUND: Since the introduction of single incision laparoscopy (SIL), there has been disagreement among professional societies regarding a general recommendation for the use of this minimally invasive method. OBJECTIVES: Determination of evidence-based advantages of SIL compared to multiport laparoscopy (MPL). MATERIALS AND METHODS: Description of recent technical developments and evaluation of prospective randomized clinical trials and valid meta-analyses with regard to organ-specific procedures. In addition, an expert opinion is provided based on 4209 SIL interventions. RESULTS: SIL is nowadays applied in all fields of general and visceral surgery. Due to the initial enthusiasm, methodologically weak studies were often published in the literature. Any beneficial effect of SIL on reduced perioperative morbidity is not clearly confirmed, yet. A better cosmetic outcome is either obvious (in SIL liver resections) or nearly unverifiable (in SIL cholecystectomies). CONCLUSION: SIL has proven feasible and safe after getting through the learning curve. Scientific evidence is currently insufficient to justify SIL without reservation in particular without the individual technical experience of the surgeon. PMID- 28623456 TI - Pertussis and Rotavirus Vaccines - Controversies and Solutions. AB - Pertussis and rotavirus vaccines have been the subject of several controversies over the years. In this paper the authors discuss facts and myths behind these controversies and also suggest solutions to overcome some limitations of these vaccines. The whole-cell pertussis vaccine (wPV) came into disrepute due to the associated adverse reactions, resulting in its replacement by acellular pertussis vaccine (aPV) in industrialized nations in 1990s. Although wPV is known to have more side effects; but they are usually minor. Whole-cell pertussis containing vaccine is being used safely in the National Immunization programme in India from many years. Another controversy erupted during 2009-2010, when there were reports of resurgence of pertussis cases among adolescents and adults, from developed nations. Present literature review raises doubts about long term protection offered by aPV, when compared with wPV. In spite of prevailing controversy, acellular pertussis containing vaccines should be acceptable, if timely delivery of primary and booster doses is ensured; including vaccination of adolescents and pregnant women. Initial rotavirus vaccine was withdrawn from the market because of increased risk of intussusception. Although three new generation rotavirus vaccines are currently available for use in India, but doubts about their efficacy, long term protection and safety still exists. Present literature review found them to be safe and moderately efficacious because of reasonable good cross protection. Even a moderately efficacious vaccine like rotavirus vaccine could significantly improve the outcome if disease burden is high. Therefore, it is being included in National Immunization Programme of India. PMID- 28623457 TI - Undernutrition in Pediatric Malignancy. PMID- 28623458 TI - Risk Factors for Bronchial Asthma in School Going Children. PMID- 28623459 TI - Blockade of CD112R and TIGIT signaling sensitizes human natural killer cell functions. AB - Trastuzumab is the first-line drug to treat breast cancer with high Her2 expression. However, many cancers failed to respond, largely due to their resistance to NK cell-triggered antibody-dependent cellular cytotoxicity (ADCC). Poliovirus receptor (PVR)-like molecules are known to be important for lymphocyte functions. We found that all PVR-like receptors are expressed on human NK cells, and only TIGIT is preferentially expressed on the CD16+ NK cell subset. Disrupting the interactions of PVR-like receptors with their ligands on cancer cells regulates NK cell activity. More importantly, TIGIT is upregulated upon NK cell activation via ADCC. Blockade of TIGIT or CD112R, separately or together, enhances trastuzumab-triggered antitumor response by human NK cells. Thus, our findings suggest that PVR-like receptors regulate NK cell functions and can be targeted for improving trastuzumab therapy for breast cancer. PMID- 28623462 TI - In Silico Investigations of Chemical Constituents of Clerodendrum colebrookianum in the Anti-Hypertensive Drug Targets: ROCK, ACE, and PDE5. AB - Understanding the molecular mode of action of natural product is a key step for developing drugs from them. In this regard, this study is aimed to understand the molecular-level interactions of chemical constituents of Clerodendrum colebrookianum Walp., with anti-hypertensive drug targets using computational approaches. The plant has ethno-medicinal importance for the treatment of hypertension and reported to show activity against anti-hypertensive drug targets Rho-associated coiled-coil protein kinase (ROCK), angiotensin-converting enzyme, and phosphodiesterase 5 (PDE5). Docking studies showed that three chemical constituents (acteoside, martinoside, and osmanthuside beta6) out of 21 reported from the plant to interact with the anti-hypertensive drug targets with good glide score. In addition, they formed H-bond interactions with the key residues Met156/Met157 of ROCK I/ROCK II and Gln817 of PDE5. Further, molecular dynamics (MD) simulation of protein-ligand complexes suggest that H-bond interactions between acteoside/osmanthuside beta6 and Met156/Met157 (ROCK I/ROCK II), acteoside and Gln817 (PDE5) were stable. The present investigation suggests that the anti-hypertensive activity of the plant is due to the interaction of acteoside and osmanthuside beta6 with ROCK and PDE5 drug targets. The identified molecular mode of binding of the plant constituents could help to design new drugs to treat hypertension. PMID- 28623461 TI - Neuropsychological Test Administration by Videoconference: A Systematic Review and Meta-Analysis. AB - The purpose of the current systematic review and meta-analysis was to assess the effect of videoconference administration on adult neurocognitive tests. We investigated whether the scores acquired during a videoconference administration were different from those acquired during on-site administration. Relevant counterbalanced crossover studies were identified according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twelve studies met criteria for analysis. Included samples consisted of healthy adults as well as those with psychiatric or neurocognitive disorders, with mean ages ranging from 34 to 88 years. Heterogenous data precluded the interpretation of a summary effect for videoconference administration. Studies including particpants with a mean age of 65-75, as well as studies that utilized a high speed network connection, indicated consistent performance across videoconference and on-site conditions, however studies with older participants and slower connections were more variable. Subgroup analyses indicated that videoconference scores for untimed tasks and those allowing for repetition fell 1/10th of a standard deviation below on-site scores. Test specific analyses indicated that verbally-mediated tasks including digit span, verbal fluency, and list learning were not affected by videoconference administration. Scores for the Boston Naming Test fell 1/10th of a standard deviation below on-site scores. Heterogenous data precluded meaningful interpretation of tasks with a motor component. The administration of verbally-mediated tasks by qualified professionals using existing norms was supported, and the use of visually-dependent tasks may also be considered. Variability in previous studies indicates a need for further investigation of motor-dependent tasks. We recommend the development of clinical best practices for conducting neuropsychological assessments via videoconference, and advocate for reimbursement structures that allow consumers to benefit from the increased access, convenience, and cost-savings that remote assessment provides. PMID- 28623460 TI - Spreading of Pathology in Alzheimer's Disease. AB - The senile plaques (SPs) and neurofibrillary tangles (NFTs) are the two major pathological hallmarks of AD, which are composed of beta-amyloid protein and Tau protein. So the beta-amyloid protein (Abeta) and Tau oligomers (oTau) are the majority in the pathology of AD. Recently, the spreading of Abeta and oTau in the brain of AD patients has received heated value. In this review, we summarize recent research progress and aim to figure out the spreading mechanism of Abeta and Tau in AD via introduction of the formation, release, uptake, diffusion between different brain regions, and the propagation principle of Abeta and Tau. Although the mechanisms of the spreading pathology in AD are still not very clear, increasing discoveries confirm that Abeta and oTau could transmit from one neuron to another along the anatomical connected synapses. Meanwhile, a mass of studies also report that they have a totally opposite hierarchical spatiotemporal pattern of spreading in cerebral areas. In addition, Tau proteins might mediate Abeta toxicity in the brain, and they might have synergistic roles with each other. So some therapies have emerged, such as inhibiting the release, preventing the oligomerization, and blocking the uptake. This review would be helpful to comprehend the mechanism of transmission in AD and provide a new way to the targeted therapy. PMID- 28623463 TI - Hypotonicity-induced cell swelling activates TRPA1. AB - Hypotonic solutions can cause painful sensations in nasal and ocular mucosa through molecular mechanisms that are not entirely understood. We clarified the ability of human TRPA1 (hTRPA1) to respond to physical stimulus, and evaluated the response of hTRPA1 to cell swelling under hypotonic conditions. Using a Ca2+ imaging method, we found that modulation of AITC-induced hTRPA1 activity occurred under hypotonic conditions. Moreover, cell swelling in hypotonic conditions evoked single-channel activation of hTRPA1 in a cell-attached mode when the patch pipette was attached after cell swelling under hypotonic conditions, but not before swelling. Single-channel currents activated by cell swelling were also inhibited by a known hTRPA1 blocker. Since pre-application of thapsigargin or pretreatment with the calcium chelator BAPTA did not affect the single-channel activation induced by cell swelling, changes in intracellular calcium concentrations are likely not related to hTRPA1 activation induced by physical stimuli. PMID- 28623464 TI - Estimating an exchange rate between the EQ-5D-3L and ASCOT. AB - BACKGROUND: The aim was to estimate an exchange rate between EQ-5D-3L and the Adult Social Care Outcome Tool (ASCOT) using preference-based mapping via common time trade-off (TTO) valuations. EQ-5D and ASCOT are useful for examining cost effectiveness within the health and social care sectors, respectively, but there is a policy need to understand overall benefits and compare across sectors to assess relative value for money. Standard statistical mapping is unsuitable since it relies on conceptual overlap of the measures but EQ-5D and ASCOT have different conceptualisations of quality of life. METHODS: We use a preference based mapping approach to estimate the exchange rate using common TTO valuations for both measures. A sample of health states from each measure was valued using TTO by 200 members of the UK adult general population. Regression analyses are used to generate separate equations between EQ-5D-3L and ASCOT values using their original value set and TTO values elicited here. These are solved as simultaneous equations to estimate the relationship between EQ-5D-3L and ASCOT. RESULTS: The relationship for moving from ASCOT to EQ-5D-3L is a linear transformation with an intercept of -0.0488 and gradient of 0.978. This enables QALY gains generated by ASCOT and EQ-5D to be compared across different interventions. CONCLUSIONS: This paper estimated an exchange rate between ASCOT and EQ-5D-3L using a preference based mapping approach that does not compromise the descriptive systems of the two measures. This contributes to the development of preference-based mapping through the use of TTO as the common metric used to estimate the exchange rate between measures. PMID- 28623465 TI - Tooth brushing motion patterns with manual and powered toothbrushes-a randomised video observation study. AB - INTRODUCTION: Systematic reviews have shown that powered toothbrushes (PTs) are more effective than manual toothbrushes (MTs), but with only minor effect sizes. Whether PTs are used adequately, however, has not been investigated so far. The aim of the present study was therefore to analyse motion habits with PT in comparison to MT toothbrushes by video observation. MATERIALS AND METHODS: One hundred subjects were enrolled in this observational trial and brushed their teeth in randomised order with a MT and PT while being video-filmed, resulting in 95 analysable sets of recordings. Parameters of interest were brushing duration (s; median (min;max)), type of brushing strokes, area of brushing, changes between areas (n; median (min;max)) and brushing sequence. RESULTS: Brushing duration was 145 s (60;354) and 135 s (48;271) for PT and MT, respectively (p <= 0.001). Subjects brushed vestibular surfaces completely, but reached oral surfaces to a much lesser extent, regardless of the toothbrush type. With both toothbrushes, subjects moved frequently between areas (MT 35 (14;79); PT 33 (14;85); n.s.) and brushed predominantly with circling and horizontal strokes; with the PT, 50.5% of the subjects spent only <10% of the brushing duration with passive brushing (positioning the brush head on the teeth with <=2 movements/s). CONCLUSIONS: Intra-individual motion patterns were similar with both MT and PT, and most subjects persisted in their habitual motion patterns regardless of the toothbrush type. CLINICAL RELEVANCE: The use of PT and MT may need intensive training and supervision from oral hygiene educators in order to help subjects taking full advantage from these devices. PMID- 28623467 TI - Reducing Anxiety and Improving Academic Performance Through a Biofeedback Relaxation Training Program. AB - The aim of this study was to analyze the influence of a biofeedback relaxation training program on anxiety and academic performance. The program consisted of five biofeedback sessions coupled with three training activities focused on deep breathing, guided imagery, and muscle relaxation. The participants were second year psychology undergraduates from the University of the Basque Country (UPV/EHU, northern Spain). The experimental group comprised 152 students (M age = 19.6, SD = 0.74; 74% women) and the control group 81 students (M age = 19.4, SD = 0.92; 71% women). Results showed that after participating in the program, students in the experimental group had lower levels of anxiety and increased academic performance. Furthermore, they scored lower on anxiety and higher on academic performance in comparison with the control subjects. This suggests that the inclusion of biofeedback training programs in educational contexts could be a way of reducing anxiety and improving academic performance. It may also deepen our understanding of the dynamic interplay between psychophysiological, cognitive, and emotional processes. PMID- 28623466 TI - Increases in circulating amino acids with in-feed antibiotics correlated with gene expression of intestinal amino acid transporters in piglets. AB - In-feed antibiotics have been commonly used to promote the growth performance of piglets. The antibiotics can increase protein utilization, but the underlying mechanism is largely unknown. The present study investigated the effects of in feed antibiotics on intestinal AA transporters and receptors to test the hypothesis that the alteration of circulating AA profiles may be concomitant with the change of intestinal AA transporters and receptors. Sixteen litters of piglets at day 7 started to receive creep feed with (Antibiotic) or without (Control) antibiotic. Piglets were weaned at day 23 after birth, and fed the same diets until day 42. In-feed antibiotics did not affect the BW of 23-day-old (P = 0.248), or 42-day-old piglets (P = 0.089), but increased the weight gain to feed ratio from day 23 to 42 (P = 0.020). At day 42 after birth, antibiotic treatment increased the concentrations of most AAs in serum (P < 0.05), and decreased the concentrations of most AAs in jejunal and ileal digesta. Antibiotics upregulated (P < 0.05) the mRNA expression levels for jejunal AAs transporters (CAT1, EAAC1, ASCT2, y+LAT1), peptide transporters (PepT1), and Na+-K+-ATPase (ATP1A1), and ileal AA transporters (ASCT2, y+LAT1, b0,+AT, and B0AT1), and ATP1A1. The antibiotics also upregulated the mRNA expression of jejunal AAs receptors T1R3 and CaSR, and ileal T1R3. Protein expression levels for jejunal AA transporters (EAAC1, b0,+AT, and ASCT2) and PepT1 were also upregulated. Correlation analysis revealed that the alterations of AA profiles in serum after the in-feed antibiotics were correlated with the upregulations of mRNA expression levels for key AA transporters and receptors in the small intestine. In conclusion, the in feed antibiotics increased serum level of most AAs and decreased most AAs in the small intestine. These changes correlated with the upregulations of mRNA expression levels for key AA transporters and receptors in the small intestine. The findings provide further insights into the mechanism of in-feed antibiotics, which may provide new framework for designing alternatives to antibiotics in animal feed in the future. PMID- 28623468 TI - [Intracranial pressure monitoring in polytrauma patients with traumatic brain injury]. AB - BACKGROUND: The monitoring of intracranial pressure (ICP) represents a cornerstone in the intensive care of patients with traumatic brain injury (TBI) and the industry provides various technical solutions to this end. Decompressive craniectomy can be an option if conservative measures fail to reduce excessive ICP. OBJECTIVE: To examine the pathophysiology of ICP in trauma, the management of polytrauma involving TBI, and the indications for decompressive craniectomy; and to compare the different monitoring systems and their complications. MATERIAL AND METHODS: A retrospective analysis of TBI patients between 2010 and 2016 was performed. Relevant publications are discussed, particularly those relating to the indications for monitoring and its influence on polytrauma management. RESULTS: Between 2010 and 2016, 106 patients with closed TBI and a mean age of 65.9 years received a total of 120 ICP monitors, most of which were parenchyma devices (111/120), followed by intraventricular catheters (8/120), and one combined system (1/120). Of these patients, 27.4% had sustained polytrauma, whilst 33% regularly used anticoagulants. ICP monitors were removed after 8.5 days on an average and the mean ICU stay was 20 days. Probe insertion was combined with craniectomy in 69.8% patients. Probe-related complications, most commonly involving malfunction, were seen in 6.6%. The duration of monitoring was significantly related to polytrauma (p <= 0.001) and age <60 (p = 0.03). ICU stay was also significantly related to polytrauma (p = 0.02) and monitoring complications (p <= 0.001). Mortality was related to anticoagulant medication (p = 0.01) and age <60 (p = 0.03). CONCLUSIONS: ICP monitoring is one of the most important tools in TBI treatment. The course and outcome of these severe injuries is affected by polytrauma, age, and the use of anticoagulants. PMID- 28623469 TI - Association between giant cell arteritis and thyroid dysfunction in a "real life" population. AB - PURPOSE: Giant cell arteritis is a systemic autoimmune disorder which involves inflammation of medium to large vessels. The association between giant cell arteritis and autoimmune thyroid disorders has been investigated numerous times in the literature with inconsistent results. Our objective was to evaluate whether a genuine association exists between giant cell arteritis and thyroid dysfunction, which is often due to immune-mediated thyroid disease. METHODS: Utilizing the medical database of Clalit Health Services, we compared the proportion of hypo and hyperthyroidisim between patients with giant cell arteritis and age-matched and gender-matched controls in a cross-sectional study. Univariate analysis was performed using Chi-square and student t-test and a multivariate analysis was performed using a logistic regression model. RESULTS: Five thousand six hundred and sixty three giant cell arteritis patients and 23,308 age-matched and gender-matched controls were included in the study. The proportion of hypothyroidism amongst giant cell arteritis patients was increased in comparison with controls (18.2 vs. 6.91%, respectively, p-value < 0.001), as was hyperthyroidism (2.56 and 1.19% respectively, p-value < 0.001). Giant cell arteritis demonstrated an independent association with hypothyroidism on multivariate analysis (Odd Ratios 1.297, 95% Confidence Intervals 1.19-1.42), yet not with hyperthyroidism. CONCLUSIONS: Giant cell arteritis patients have a higher proportion of hypothyroidism in comparison with matched controls. Physicians treating giant cell arteritis patients should consider screening for thyroid dysfunction on a regular basis. PMID- 28623470 TI - Reconstruction of AAOS type III and IV acetabular defects with the Ganz reinforcement ring: high failure in pelvic discontinuity. AB - BACKGROUND: Large acetabular defects and pelvic discontinuity represent complex problems in revision total hip arthroplasty. This study aimed to investigate whether reconstruction with the Ganz reinforcement ring would provide durable function in large acetabular defects. PATIENTS AND METHODS: 46 hips (45 patients, 19 male, 26 female, mean age 68 years) with AAOS type III and IV defects undergoing acetabular revision with the Ganz reinforcement ring were evaluated at a mean follow-up of 74 months (24-161 months). Fourteen patients died during follow-up. All surviving patients were available for clinical assessment and radiographic studies. Radiographs were evaluated for bone healing and component loosening. A Cox-regression model was performed to identify factors influencing survival of the Ganz-ring. RESULTS: In the group of AAOS III defects, 3 of 26 acetabular reconstructions failed, all due to aseptic loosening. In pelvic discontinuity (AAOS IV), 9 of 20 hips failed due to aseptic loosening (n = 4), deep infection (n = 3), and non-union of the pelvic ring (n = 2). With acetabular revision for any reason as an endpoint, the estimated Kaplan-Meier 5-year survival was 86% in type III defects and 57% in type IV defects, respectively. The presence of pelvic discontinuity was identified as the only independent predictive factor for failure of the Ganz ring acetabular reconstruction (AAOS III vs. IV, Hazard ratio: 0.217, 95%, Confidence interval: 0.054-0.880, p = 0.032). CONCLUSION: The Ganz reinforcement ring remains a favorable implant for combined segmental and cavitary defects. However, defects with pelvic discontinuity demonstrate high failure rates. The indications should therefore be narrowed to acetabular defects not associated with pelvic discontinuity. PMID- 28623471 TI - The effect of intravenous lidocaine infusion on bispectral index during major abdominal surgery. AB - Intraoperative lidocaine infusion has become widely accepted as an adjunct to general anesthesia where its use has been associated with opioid-sparing and enhanced recovery. The aims of this study were to determine whether or not intravenous (IV) lidocaine infusion (a) has an anesthetic sparing effect during major colorectal procedures and (b) if it also affects level of hypnosis as measured by bispectral index (BIS). Twenty-five patients undergoing laparotomy for resection of colorectal tumours were randomized to receive either IV lidocaine (1.5 mg kg-1 bolus then 1 mg kg-1 per hour) or an equivalent volume of normal saline commenced after intravenous induction of general anesthesia. Anesthesia was maintained with volatile anesthetic agent combined with intermittent IV fentanyl titrated to hemodynamic stability. Minimum alveolar concentration (MAC) of volatile was calculated using an age-adjusted algorithm (corrected MAC). BIS values were recorded throughout; however, treating anesthesiologists were blinded to BIS values and hence they were not used to guide depth of anesthesia. No other regional anesthesia techniques were used. During the maintenance phase of anesthesia, corrected MAC of volatile agent was lower (1.0 versus 1.1, p = 0.003); whereas BIS values were higher (45 versus 39, p < 0.001) in patients who received lidocaine versus placebo. No differences in mean arterial pressure (80 versus 80 mmHg, p = 0.796) or total fentanyl dose (538 versus 444 mcg, p = 0.24) were observed between the two groups. Heart rate was slightly higher in patients who received lidocaine versus placebo (67 versus 64 bpm, p = 0.001). Lidocaine infusion resulted in mean plasma levels of 1.7 mcg ml 1 (1.3-2.0 mcg ml-1, 95% CI). Our results support an anesthetic sparing effect of lidocaine infusion indicated by lower MAC requirements. Higher BIS values in the lidocaine versus placebo group may indicate that levels of hypnosis were not equivalent. Alternatively, BIS may not be a sensitive indicator of synergistic interactions between local anesthetic and volatile agent. Our results advocate a cautious approach to titration of general anesthesia when combined with lidocaine infusion. PMID- 28623472 TI - Failure to replace a CO2-absorber due to shifted metal pins: a potential source of hazard to patients. PMID- 28623473 TI - Increasing the Bile Acid Sequestration Performance of Cationic Hydrogels by Using an Advanced/Controlled Polymerization Technique. AB - PURPOSE: To investigate the influence of the polymerization technique and the content of hydroxyl groups on the performance of new bile acid sequestrants based on PAMPMTA-co-PHEA (PAMPTMA: poly((3-acrylamidopropyl)trimethylammonium chloride); PHEA: poly(2-hydroxyethyl acrylate)) hydrogels. METHODS: PAMPMTA-co PHEA hydrogels were prepared using either free radical polymerization or supplemental activator and reducing agent atom transfer radical polymerization. The chemical structure and composition of the hydrogels was confirmed by both FTIR and ssNMR. The binding of sodium cholate as the model bile salt was evaluated in simulated intestinal fluid using HPLC. The degradation of the polymers was evaluated in vitro in solutions mimicking the gastrointestinal tract environment. RESULTS: The binding showed that an increase of the amount of HEA in the hydrogel lead to a decrease of the binding capacity. In addition, it was demonstrated for the first time that the hydrogels produced by SARA ATRP presented a higher binding capacity than similar ones produced by FRP. Finally, it was observed that copolymers of PAMPTMA-co-PHEA showed no sign of degradation in solutions mimicking both the stomach and the intestine environment. CONCLUSIONS: The use of an advanced polymerization technique, such as the SARA ATRP, could be beneficial for the preparation of BAS with enhanced performance. PMID- 28623474 TI - Epithelial Fluid Transport is Due to Electro-osmosis (80%), Plus Osmosis (20%). AB - Epithelial fluid transport, an important physiological process shrouded in a long standing enigma, may finally be moving closer to a solution. We propose that, for the corneal endothelium, relative proportions for the driving forces for fluid transport are 80% of paracellular electro-osmosis, and 20% classical transcellular osmosis. These operate in a cyclical process with a period of 9.2 s, which is dictated by the decrease and exhaustion of cellular Na+. Paracellular electro-osmosis is sketched here, and partially discussed as much as the subject still allows; transcellular osmosis is presented at length. PMID- 28623475 TI - T1 mapping in cardiac MRI. AB - Quantitative myocardial and blood T1 have recently achieved clinical utility in numerous pathologies, as they provide non-invasive tissue characterization with the potential to replace invasive biopsy. Native T1 time (no contrast agent), changes with myocardial extracellular water (edema, focal or diffuse fibrosis), fat, iron, and amyloid protein content. After contrast, the extracellular volume fraction (ECV) estimates the size of the extracellular space and identifies interstitial disease. Spatially resolved quantification of these biomarkers (so called T1 mapping and ECV mapping) are steadily becoming diagnostic and prognostically useful tests for several heart muscle diseases, influencing clinical decision-making with a pending second consensus statement due mid-2017. This review outlines the physics involved in estimating T1 times and summarizes the disease-specific clinical and research impacts of T1 and ECV to date. We conclude by highlighting some of the remaining challenges such as their community wide delivery, quality control, and standardization for clinical practice. PMID- 28623476 TI - Early onset renal cell carcinoma in an adolescent girl with germline FLCN exon 5 deletion. AB - Birt-Hogg-Dube (BHD) disease is an autosomal dominant cancer syndrome characterized by benign skin tumors, renal cancer and spontaneous pneumothorax and is caused by mutations in the Folliculin (FLCN) gene. Benign skin tumors and pneumothorax occur in the majority of patients affected by BHD syndrome, but only 30-45% of them develop renal cell carcinoma (RCC) with a median age of diagnosis at 48. The earliest onset of RCC in a BHD patient has been reported at age 20. Here we report a case of a 14 year-old patient with germline FLCN mutation leading to an early-onset bulky RCC that could not be classified strictly according to existing histological types. Germline genetic testing revealed a deletion at FLCN exon 5. The father of the patient was identified as the asymptomatic carrier. We report the youngest patient with BHD-related RCC. This early onset presentation supports genetic testing of at-risk patients and initiation of imaging surveillance for RCC in early adolescence. In addition, future studies are necessary to understand the determinants of reduced penetrance in BHD disease. PMID- 28623477 TI - Use of the BOADICEA Web Application in clinical practice: appraisals by clinicians from various countries. AB - The 'BOADICEA' Web Application (BWA) used to assess breast cancer risk, is currently being further developed, to integrate additional genetic and non genetic factors. We surveyed clinicians' perceived acceptability of the existing BWA v3. An online survey was conducted through the BOADICEA website, and the British, Dutch, French and Swedish genetics societies. Cross-sectional data from 443 participants who provided at least 50% responses were analysed. Respondents varied in age and, clinical seniority, but mainly comprised women (77%) and genetics professionals (82%). Some expressed negative opinions about the scientific validity of BOADICEA (9%) and BWA v3 risk presentations (7-9%). Data entry time (62%), clinical utility (22%) and ease of communicating BWA v3 risks (13-17%) received additional negative appraisals. In multivariate analyses, controlling for gender and country, data entry time was perceived as longer by genetic counsellors than clinical geneticists (p < 0.05). Respondents who (1) considered hormonal BC risk factors as more important (p < 0.01), and (2) communicated numerical risk estimates more frequently (p < 0.001), judged BWA v3 of lower clinical utility. Respondents who carried out less frequent clinical activity (p < 0.01) and respondents with '11 to 15 years' seniority (p < 0.01) had less favourable opinions of BWA v3 risk presentations. Seniority of '6 to 10 years' (p < 0.05) and more frequent numerical risk communication (p < 0.05) were associated with higher fear of communicating the BWA v3 risks to patients. The level of genetics training did not affect opinions. Further development of BWA should consider technological, genetics service delivery and training initiatives. PMID- 28623478 TI - Feature fusion for lung nodule classification. AB - PURPOSE: This article examines feature-based nodule description for the purpose of nodule classification in chest computed tomography scanning. METHODS: Three features based on (i) Gabor filter, (ii) multi-resolution local binary pattern (LBP) texture features and (iii) signed distance fused with LBP which generates a combinational shape and texture feature are utilized to provide feature descriptors of malignant and benign nodules and non-nodule regions of interest. Support vector machines (SVMs) and k-nearest neighbor (kNN) classifiers in serial and two-tier cascade frameworks are optimized and analyzed for optimal classification results of nodules. RESULTS: A total of 1191 nodule and non-nodule samples from the Lung Image Data Consortium database is used for analysis. Classification using SVM and kNN classifiers is examined. The classification results from the two-tier cascade SVM using Gabor features showed overall better results for identifying non-nodules, malignant and benign nodules with average area under the receiver operating characteristics (AUC-ROC) curves of 0.99 and average f1-score of 0.975 over the two tiers. CONCLUSION: In the results, higher overall AUCs and f1-scores were obtained for the non-nodules cases using any of the three features, showing the greatest distinguishability over nodules (benign/malignant). SVM and kNN classifiers were used for benign, malignant and non-nodule classification, where Gabor proved to be the most effective of the features for classification. The cascaded framework showed the greatest distinguishability between benign and malignant nodules. PMID- 28623480 TI - The current debate on cost burden by human exposure to endocrine disrupting chemicals. PMID- 28623479 TI - Fast calibration of electromagnetically tracked oblique-viewing rigid endoscopes. AB - PURPOSE: The oblique-viewing (i.e., angled) rigid endoscope is a commonly used tool in conventional endoscopic surgeries. The relative rotation between its two moveable parts, the telescope and the camera head, creates a rotation offset between the actual and the projection of an object in the camera image. A calibration method tailored to compensate such offset is needed. METHODS: We developed a fast calibration method for oblique-viewing rigid endoscopes suitable for clinical use. In contrast to prior approaches based on optical tracking, we used electromagnetic (EM) tracking as the external tracking hardware to improve compactness and practicality. Two EM sensors were mounted on the telescope and the camera head, respectively, with considerations to minimize EM tracking errors. Single-image calibration was incorporated into the method, and a sterilizable plate, laser-marked with the calibration pattern, was also developed. Furthermore, we proposed a general algorithm to estimate the rotation center in the camera image. Formulas for updating the camera matrix in terms of clockwise and counterclockwise rotations were also developed. RESULTS: The proposed calibration method was validated using a conventional [Formula: see text], 5-mm laparoscope. Freehand calibrations were performed using the proposed method, and the calibration time averaged 2 min and 8 s. The calibration accuracy was evaluated in a simulated clinical setting with several surgical tools present in the magnetic field of EM tracking. The root-mean-square re-projection error averaged 4.9 pixel (range 2.4-8.5 pixel, with image resolution of [Formula: see text] for rotation angles ranged from [Formula: see text] to [Formula: see text]. CONCLUSIONS: We developed a method for fast and accurate calibration of oblique viewing rigid endoscopes. The method was also designed to be performed in the operating room and will therefore support clinical translation of many emerging endoscopic computer-assisted surgical systems. PMID- 28623481 TI - Erratum to: Homogeneous pancreatic cancer spheroids mimic growth pattern of circulating tumor cell clusters and macrometastases: displaying heterogeneity and crater-like structure on inner layer. PMID- 28623482 TI - Cost-effectiveness analysis of a non-contrast screening MRI protocol for vestibular schwannoma in patients with asymmetric sensorineural hearing loss. AB - PURPOSE: We aimed to determine if a non-contrast screening MRI is cost-effective compared to a full MRI protocol with contrast for the evaluation of vestibular schwannomas. METHODS: A decision tree was constructed to evaluate full MRI and screening MRI strategies for patients with asymmetric sensorineural hearing loss. If a patient were to have a positive screening MRI, s/he received a full MRI. Vestibular schwannoma prevalence, MRI specificity and sensitivity, and gadolinium anaphylaxis incidence were obtained through literature review. Institutional charge data were obtained using representative patient cohorts. One-way and probabilistic sensitivity analyses were completed to determine CE model threshold points for MRI performance characteristics and charges. RESULTS: The mean charge for a full MRI with contrast was significantly higher than a screening MRI ($4089 +/- 1086 versus $2872 +/- 741; p < 0.05). The screening MRI protocol was more cost-effective than a full MRI protocol with a willingness-to-pay from $0 to 20,000 USD. Sensitivity analyses determined that the screening protocol dominated when the screening MRI charge was less than $4678, and the imaging specificity exceeded 78.2%. The screening MRI protocol also dominated when vestibular schwannoma prevalence was varied between 0 and 1000 in 10,000 people. CONCLUSION: A screening MRI protocol is more cost-effective than a full MRI with contrast in the diagnostic evaluation of a vestibular schwannoma. A screening MRI likely also confers benefits of shorter exam time and no contrast use. Further investigation is needed to confirm the relative performance of screening protocols for vestibular schwannomas. PMID- 28623484 TI - Identification of Mycobacterium Species by MALDI-TOF Mass Spectrometry. AB - Matrix-assisted laser desorption ionization - time-of-flight (MALDI-TOF) mass spectrometry enables to identify microorganisms by comparison of the protein content with reference spectra in the database. The aim of this study was to evaluate the efficacy of phenotypic identification of mycobacteria by MALDI-TOF mass spectrometry in laboratory practice. Seventy five isolates of mycobacteria were identified by molecular and phenotypic method, and the results were compared by MALDI-TOF. For MALDI-TOF, material was processed according to the Bruker Daltonics protocol and Mycobacterial Library database version 2.0, with 313 reference mycobacteria spectra. All except one of the 72 isolates agreed with regard to the species and genus by both methods. Forty three isolates were identified as the M. tuberculosis complex by MALDI-TOF. Thirty one isolates of nontuberculous mycobacteria were consistently identified by both methods to the species level. We conclude that MALDI-TOF mass spectrometry is an accurate method of bacterial identification. Simplicity, speed, and economic availability of the method makes it suitable for mycobacteria identification in a routine laboratory. PMID- 28623483 TI - Normal appearing white matter permeability: a marker of inflammation and information processing speed deficit among relapsing remitting multiple sclerosis patients. AB - PURPOSE: Blood-brain barrier breakdown (BBBB) occurs in relapsing remitting multiple sclerosis (RRMS). Relative recirculation (rR), a BBBB surrogate, may show inflammation undetectable by gadolinium. We compared normal appearing white matter (NAWM) rR in patients with and without disability measured with Symbol Digit Modalities Test and the Expanded Disability Status Scale (EDSS). METHODS: Thirty-nine RRMS patients were prospectively recruited and classified as impaired or non-impaired based on the SDMT and EDSS threshold >=3. Significant demographic, MRI structural and regional rR characteristics were advanced into multivariate analysis to assess the association with impairment of cognition and EDSS. Bonferroni corrected p < 0.025 was applied to demographic and rR group comparisons; p < 0.05 was used in the final multivariate logistic regression. RESULTS: rR was higher in NAWM (p = 0.012), NAGM (p = 0.004), and basal ganglia (p = 0.007) in cognitively impaired versus non-impaired patients. The difference between NAWM and T2HL rR was significant in cognitively non-impaired patients and approximated that of T2HL in impairment (0.084 vs. 0.075, p = 0.008; 0.118 vs. 0.101, p = 0.091, respectively). After adjusting for confounders, rR elevation for NAWM (OR 1.777; 95% CI 1.068-2.956; p = 0.026), NAGM (OR 2.138; 1.100-4.157; p = 0.025), and basal ganglia (OR 2.192; 1.120-4.289; p = 0.022) remained significantly predictive of cognitive impairment. NAWM area under the curve (AUC) for cognitive impairment was 0.783. No significant group differences or associations were seen for rR and EDSS impairment. No NAGM and cortical lesion rR difference was present within any of the impaired or non-impaired groups. CONCLUSION: rR elevation in NAWM, NAGM, and basal ganglia appears sensitive to cognitive impairment but not EDSS. PMID- 28623485 TI - Is scaffold hopping a reliable indicator for the ability of computational methods to identify structurally diverse active compounds? AB - Computational scaffold hopping aims to identify core structure replacements in active compounds. To evaluate scaffold hopping potential from a principal point of view, regardless of the computational methods that are applied, a global analysis of conventional scaffolds in analog series from compound activity classes was carried out. The majority of analog series was found to contain multiple scaffolds, thus enabling the detection of intra-series scaffold hops among closely related compounds. More than 1000 activity classes were found to contain increasing proportions of multi-scaffold analog series. Thus, using such activity classes for scaffold hopping analysis is likely to overestimate the scaffold hopping (core structure replacement) potential of computational methods, due to an abundance of artificial scaffold hops that are possible within analog series. PMID- 28623486 TI - GalaxyDock BP2 score: a hybrid scoring function for accurate protein-ligand docking. AB - Protein-ligand docking is a useful tool for providing atomic-level understanding of protein functions in nature and design principles for artificial ligands or proteins with desired properties. The ability to identify the true binding pose of a ligand to a target protein among numerous possible candidate poses is an essential requirement for successful protein-ligand docking. Many previously developed docking scoring functions were trained to reproduce experimental binding affinities and were also used for scoring binding poses. However, in this study, we developed a new docking scoring function, called GalaxyDock BP2 Score, by directly training the scoring power of binding poses. This function is a hybrid of physics-based, empirical, and knowledge-based score terms that are balanced to strengthen the advantages of each component. The performance of the new scoring function exhibits significant improvement over existing scoring functions in decoy pose discrimination tests. In addition, when the score is used with the GalaxyDock2 protein-ligand docking program, it outperformed other state of-the-art docking programs in docking tests on the Astex diverse set, the Cross2009 benchmark set, and the Astex non-native set. GalaxyDock BP2 Score and GalaxyDock2 with this score are freely available at http://galaxy.seoklab.org/softwares/galaxydock.html . PMID- 28623487 TI - Multiple receptor-ligand based pharmacophore modeling and molecular docking to screen the selective inhibitors of matrix metalloproteinase-9 from natural products. AB - Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors. The reliability of pharmacophore model is validated based on the two different decoy sets and relevant experimental data. The virtual screening, combining pharmacophore model with molecular docking, is performed to identify the selective MMP-9 inhibitors from a database of natural products. The four novel MMP-9 inhibitors of natural products, NP-000686, NP 001752, NP-014331, and NP-015905, are found; one of them, NP-000686, is used to perform the experiment of in vitro bioassay inhibiting MMP-9, and the IC50 value was estimated to be only 13.4 uM, showing the strongly inhibitory activity of NP 000686 against MMP-9, which suggests that our screening results should be reliable. The binding modes of screened inhibitors with MMP-9 active sites were discussed. In addition, the ADMET properties and physicochemical properties of screened four compounds were assessed. The found MMP-9 inhibitors of natural products could serve as the lead compounds for designing the new MMP-9 inhibitors by carrying out structural modifications in the future. PMID- 28623488 TI - Vasculitis for the internist: focus on ANCA-associated vasculitis. AB - Vasculitides comprise several diseases affecting vessels of different sizes, mainly arteries, but also capillaries and veins. Antineutrophil cytoplasm antibody-associated vasculitides (AAVs) belong to the systemic necrotizing small vessel vasculitis group that comprises granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Internists often see AAV patients, and although their outcomes are usually good, the disease can be responsible for morbidity and mortality. Herein, after reviewing the literature, we concentrate on selected aspects important for the internist, including classification, diagnostic dilemmas, treatment novelties, and follow-up. PMID- 28623490 TI - Enzymatic saccharification of pretreated rice straw by cellulases from Aspergillus niger BK01. AB - Alkali-assisted acid pretreated rice straw was saccharified using cellulase from Aspergillus niger BK01. The cellulase production by the fungus was enhanced by parametric optimization using solid-state fermentation conditions. Maximum cellulase production (12.0 U/gds of carboxymethyl cellulase, CMCase) was achieved in 96 h, using 6.0% substrate concentration, 7.5% inoculum concentration, 1:2 solid to liquid ratio, at pH 5.5, and temperature 28 degrees C, by supplementation of the fermentation medium with 0.1% carboxymethylcellulose and 0.1% ammonium nitrate. Characterization of crude cellulases showed that highest CMCase activity was observed at pH 4.8 and temperature 40 degrees C. The CMCase was stable from pH 4.8-5.5 and at a temperature range of 35-50 degrees C. The pretreated biomass was subjected to hydrolysis with the fungal cellulases. The saccharification optimization studies showed that 2% (v/v) enzyme concentration and hydrolysis time of 2.5 h were optimum for maximum yield, i.e, 23.78% sugars and 35.96% saccharification value. PMID- 28623491 TI - An efficient process for the transformation of betulin to betulinic acid by a strain of Bacillus megaterium. AB - Betulinic acid as a derivative of betulin is widely reported for its anti-HIV and antitumor activities. Betulin has three most significant positions, i.e., primary hydroxyl group at position C-28, secondary hydroxyl group at position C-3, and alkene moiety at position C-20, where chemical modifications were performed to yield pharmacologically more active derivatives. Bioconversion optimization was performed for the enhancement in the percentage of conversion using statistical approach by opting temperature, pH and betulin concentration as independent variables. Three hundred fifty isolates were screened from natural sources under selective medium containing up to 3 g/l of betulin for their tolerance and bioconversion efficiency. Isolate KD235 was found to grow in 3 g/l betulin with 23.34 +/- 0.57 g/l biomass and 0.67 +/- 0.06 g/l betulinic acid production. New isolate KD235 was characterized by molecular analysis and named as Bacillus megaterium KD235. Molecular characterization of a potentially active isolate for the transformation of betulin to betulinic acid was suggested as isolate Bacillus megaterium KD235. Maximum bioconversion (22 +/- 1.5%) was found at optimized conditions, i.e., pH 6.5, temperature 30 degrees C and at 3 g/l betulin. Validations of experiments as ~11% more bioconversion i.e., 1 +/- 0.1 g/l betulinic acid were obtained using 5 l lab fermenter as compared to shake flask. PMID- 28623492 TI - Recombinant 20.8-kDa protein of Mycobacterium avium subsp. paratuberculosis-based sero-diagnosis of paratuberculosis. AB - Johne's disease or paratuberculosis is a chronic infectious enteric disease of ruminants caused by the intracellular pathogen. The control of the Johne's disease is hampered by lack of specific diagnostic tests. In this study, we have cloned and expressed the N-terminal region of the locus tag Map 1637c encoding 20.8-kDa (r20.8) protein of Mycobacterium avium subsp. paratuberculosis. The recombinant protein r20.8 was expressed in high levels in Escherichia coli. The protein r20.8 was purified by single-step chromatography using Ni-NTA agarose. The protein r20.8 was reacted with anti-r20.8 antibodies as well as cattle sera infected with Map on Western blot. ELISA using well-characterized sera (both positive and negative; n = 60 each) Map-infected and non-infected cattle, respectively, yielded a sensitivity of 73.3% and a specificity of 98.3%. The 20.8 kDa protein expressed in the present study will prove useful as reagent in diagnostic test. PMID- 28623489 TI - Comparing the Intracarotid Amobarbital Test and Functional MRI for the Presurgical Evaluation of Language in Epilepsy. AB - Surgery is the treatment of choice for drug-resistant temporal lobe epilepsy (TLE). However, such surgery frequently causes deficits in language function, especially if performed on the dominant hemisphere. In recent years, the intracarotid amobarbital test (IAT) has been gradually replaced by functional magnetic resonance imaging (fMRI) in the preoperative identification of language areas to estimate the risk of postoperative language decline. In this paper, we review the neural substrates for language processing, how language impairment can result both from TLE itself and from surgical attempts to treat it. Subsequently, we discuss the strengths and limitations of, and current indications for fMRI and IAT during the preoperative workup, both by discussion of the studies that have evaluated them individually and through meta-analysis of data from 31 studies deemed eligible for analysis. Electrocortical stimulation mapping (ESM) is also discussed, as is the usefulness of the novel technique of resting-state fMRI. Finally, surgical techniques designed to avoid or reduce language decline in patients at risk are explored. PMID- 28623493 TI - Bioremediation of palm industry wastes using vermicomposting technology: its environmental application as green fertilizer. AB - Several technologies are being applied for treatment of palm oil mill wastes. Among them, the biological treatments (vermicomposting) have widely been recognized as one of the most efficient and eco-friendly methods for converting organic waste materials into valuable products. The present study focuses on vermicomposting of acidic palm oil mill effluent (POME) mixed with the palm pressed fibre (PPF) which are found difficult to decompose in the environment. The industrial waste (POME) was vermicomposted using Lumbricus rubellus under laboratory conditions for a period of 45 days. A significant improvement in nitrogen, phosphorus, and potassium content was monitored during vermicomposting process. In addition, the decline in C:N ratio of vermicompost (up to 17.20 +/- 0.60) reflects the degree of stabilization of POME-PPF mixture. Different percentages of the vermicompost extract obtained from POME-PPF mixture were also examined for the germination of mung bean (Vigna radiata) seed. The results showed that 75% vermicompost extract demonstrated better performance for the seed germination. On the basis of significant findings, POME-PPF mixture can be successfully used as a feeding material for the earthworms, while on the other hand, it can also be used as a cost-effective fertilizer for the germination and the proper growth of mung bean. PMID- 28623494 TI - The effects of pesticides on morphology, viability, and germination of Blackberry (Rubus glaucus Benth.) and Tree tomato (Solanum betaceum Cav.) pollen grains. AB - The objective of this study was to determine the effect of application of pesticides on morphology, viability, and germination of pollen grains of Blackberry (Rubus glaucus Benth.) and Tree tomato (Solanum betaceum Cav.). The study was performed at Patate, Tungurahua province, Ecuador and was divided into two phases. Phase one dedicated to the study of morphology, viability, and identification of nutrient solution for better germination of pollen grains and phase two for the analysis of the effect of conventional, organic, and biological pesticides on pollen grain germination and pollen tube length. To study pollen morphology, pollens were extracted by hand pressure and was analyzed by optical and electron microscopy. The viable pollen grains were identified by staining with 1% acetocarmine. Even though Tree tomato and Blackberry pollen grains are morphologically similar, their exine shapes differ. We observed four times increase in pollen germination rate when suspended in nutrient solution (Sucrose with Boric acid) than control (water). Pollen grains under nutrient solution were subjected to different groups of pesticides for the period of 2, 4, and 6 h. With respect to pesticide affect, the Blackberry pollen grain germination followed the following order: Lecaniceb > Beauveb > Metazeb => Myceb > Control. However, the effect on Tree tomato pollen grains was as follows: Lecaniceb > Myceb > Cantus > Bacillus thuringiensis > Kripton > Control. As per as pollen grain germination is concerned, we observed that the chemical pesticides are more harmful than other pesticides. So, it is necessary to perform screening test for different pesticides and their effect on pollen grain germination before applying to the fields. PMID- 28623495 TI - Whence we came, whither we go? PMID- 28623497 TI - [Psychiatric emergencies]. AB - Psychiatric emergencies present a frequent and interdisciplinary challenge. Clinical diagnosis and management are complicated by the acuity, and the patient's compliance is often limited by the illness. Psychiatric emergencies include states of acute agitation, suicidality, delirium, stupor, and drug induced emergencies. Sometimes interventions such as conversational contact, responding empathically to patients, or "talking down" are sufficient. If pharmacotherapy is necessary, benzodiazepines and antipsychotic drugs are the primary agents of choice. PMID- 28623496 TI - Association between flow skewness and aortic dilatation in patients with aortic stenosis. AB - We investigated association between hemodynamic characteristics and aortic dilatation in patients with severe aortic stenosis (AS). Eighty patients with severe AS (mean age, 67.2 +/- 12.5 years) who underwent multi-detector computed tomography and phase-contrast magnetic resonance imaging at the ascending aorta were retrospectively analyzed. Patients with an ascending aorta diameter >4 cm had a significantly higher forward flow rate at systole (28.5 +/- 6.0 vs. 36.2 +/ 8.6 L min, P < 0.001), and retrograde flow rate at systole (11.3 +/- 4.2 vs. 18.8 +/- 5.8 L min, P < 0.001), fractional reverse ratio (a ratio of retrograde flow rate to forward flow rate; 34.1 +/- 11.9% vs. 43.5 +/- 18.0%, P = 0.014), flow skewness Rskewness (a ratio of sum of forward and retrograde systole flow to net systole flow rate; 2.4 +/- 0.7 vs. 3.2 +/- 1.0, P < 0.001). The presence of bicuspid aortic valve (BAV; odds ratio [OR] 72.01, 95% confidence interval [CI] 10.57-490.46, P < 0.001), Left ventricular mass index (LVMI; OR 1.02 /g/m2; CI 1.00-1.04, P = 0.043) and Rskewness (OR 5.6 per 1, 95% CI 1.8-17.1, P = 0.001) were associated with aortic dilatation. BAV, LVMI, and increased Rskewness in the ascending aorta are associated with aortic dilatation in patients with AS. PMID- 28623498 TI - Minimal barcode distance between two water mite species from Madeira Island: a cautionary tale. AB - In this work, we compare morphological and molecular data in their ability to distinguish between species of water mites (Acari, Prostigmata, Hydrachnidia). We have focused on the two species of the genus Lebertia inhabiting the island of Madeira. While traditional morphological traits were initially sufficient to distinguish between these two species, the molecular data were more dependable on the kind of analysis carried out. Single arbitrary genetic distance (e.g. a K2P distance below 2%) may lead to the conclusion that the specimens under study belong to the same species. Analysing the same specimens with the coalescent model has proved the evolutionary independence of both Lebertia clades in Madeira. Furthermore, multi-rate Poisson Tree Process analysis confirmed both lineages as independent species. Our results agree with previous studies warning of the dangers of rigid species delimitation based on arbitrary molecular distances. In addition, the importance of different molecular data approaches for correct species delimitation in water mites is highlighted. PMID- 28623499 TI - Precise mathematics yet hazy predictions: Can validated risk indices help improve patient selection for major elective surgery? PMID- 28623500 TI - Contribution of the nasal passage to face mask ventilation: a prospective blinded randomized crossover trial. AB - BACKGROUND: Previous studies have shown that the nasal passage plays an important role in manual face mask ventilation, but this has yet to be quantitatively assessed. We conducted a prospective randomized crossover clinical trial to compare the change in pressure-controlled face mask tidal volume with and without nasal airway occlusion. METHOD: Female patients undergoing elective surgery under general anesthesia served as study subjects. Patients were randomly assigned to face mask ventilation beginning either with or without nasal passage occlusion (achieved with a swimmer's nose clip), followed by removal or application of the nose clip, respectively. After standardized induction of general anesthesia and muscle paralysis, a tight-fitting face mask was applied to each patient, and tidal volume was measured by the anesthesia machine during pressure-controlled ventilation (10, 15, 20 cm H2O; 8 breaths.min-1; inspiratory:expiratory ratio 1:2). RESULTS: The median [interquartile range] tidal volume was lower with vs without nasal passage occlusion at 10 cm H2O inspiratory pressure (100 [55-134] mL vs 300 [230-328] mL, respectively; median difference (MD), 200 mL; 95% confidence interval (CI), 157 to 229; P < 0.001), 15 cm H2O inspiratory pressure (190 [120-230] mL vs 520 [420-593] mL, respectively; MD, 340 mL; 95% CI, 257 to 395; P < 0.001), and 20 cm H2O inspiratory pressure (270 [215-390] mL vs 790 [713 823] mL, respectively; MD, 520 mL; 95% CI, 390 to 582; P < 0.001). CONCLUSION: Nasal passage obstruction considerably reduces tidal volume achieved during face mask ventilation. In some patients, it may be advantageous to relieve nasal airway obstruction for effective face mask ventilation. TRIAL REGISTRATION: UMIN Clinical Trials Registry, number UMIN000022184. Registered 2 May 2016. PMID- 28623501 TI - We must ask relevant questions and answer with meaningful outcomes. PMID- 28623502 TI - Molecular and morphological evidence for nine species in North American Australapatemon (Sudarikov, 1959): a phylogeny expansion with description of the zygocercous Australapatemon mclaughlini n. sp. AB - Zygocercous (aggregating) cercarial larvae were recently discovered emerging from a physid snail during a molecular survey of cercariae from molluscs in lakes in central Alberta, Canada. This manuscript delves into the characterization of these cercariae through morphological and molecular techniques and provides the first genetic information for a zygocercous larval trematode. Analyses of cytochrome c oxidase I of mitochondrial DNA and two partial regions of nuclear ribosomal DNA sequences revealed the zygocercous cercariae to belong to the genus Australapatemon Sudarikov, 1959. Further analyses of sequences of Australapatemon burti (Miller, 1923), from cercariae and adults collected from across North America, indicate a complex of nine genetically-distinct lineages within this species, a surprising level of diversity. The zygocercous cercariae, along with adult worms collected from ducks in Manitoba, Canada, and from Mexico, represent one of these lineages, and are herein described as Australapatemon mclaughlini n. sp. Seven lineages cannot yet be identified, but one is tentatively identified as Australapatemon burti. PMID- 28623503 TI - Investigating the Suitability of Carbon Nanotube Reinforced Polymer in Transcatheter Valve Applications. AB - The current delivery size of transcatheter aortic valves, limited by the thickness of their pericardial leaflets, correlates with a high prevalence of major vascular complications. Polyurethane valves can be developed to a fraction of the thickness of pericardial valves through the addition of carbon nanotubes to reinforce their leaflets. This study investigates the suitability of a novel carbon nanotube reinforced leaflet to reduce the delivery profile of transcatheter aortic valves. Carbon nanotube polyurethane composites were developed with thicknesses of 50 MUm and their mechanical properties were determined in relation to various environmental effects. The composites demonstrated improvements to the material stiffness, particularly at increasing strain rates compared to the neat polymer. However, increasing nanotube concentrations significantly decreased the fatigue life of the composites. Key findings highlighted a potential for carbon nanotube reinforcement in valve replacement which experience very high strain rates during the cardiac cycle. Further testing is needed to achieve a strong nanotube-matrix interface which will prolong the cyclic fatigue life and further strengthen tensile properties. Testing on the durability and haemocompatibility of these composite heart valves are ongoing. PMID- 28623504 TI - Biosorption of chromium (VI) from aqueous solutions and ANN modelling. AB - The use of sustainable, green and biodegradable natural wastes for Cr(VI) detoxification from the contaminated wastewater is considered as a challenging issue. The present research is aimed to assess the effectiveness of seven different natural biomaterials, such as jackfruit leaf, mango leaf, onion peel, garlic peel, bamboo leaf, acid treated rubber leaf and coconut shell powder, for Cr(VI) eradication from aqueous solution by biosorption process. Characterizations were conducted using SEM, BET and FTIR spectroscopy. The effects of operating parameters, viz., pH, initial Cr(VI) ion concentration, adsorbent dosages, contact time and temperature on metal removal efficiency, were studied. The biosorption mechanism was described by the pseudo-second-order model and Langmuir isotherm model. The biosorption process was exothermic, spontaneous and chemical (except garlic peel) in nature. The sequence of adsorption capacity was mango leaf > jackfruit leaf > acid treated rubber leaf > onion peel > bamboo leaf > garlic peel > coconut shell with maximum Langmuir adsorption capacity of 35.7 mg g-1 for mango leaf. The treated effluent can be reused. Desorption study suggested effective reuse of the adsorbents up to three cycles, and safe disposal method of the used adsorbents suggested biodegradability and sustainability of the process by reapplication of the spent adsorbent and ultimately leading towards zero wastages. The performances of the adsorbents were verified with wastewater from electroplating industry. The scale-up study reported for industrial applications. ANN modelling using multilayer perception with gradient descent (GD) and Levenberg-Marquart (LM) algorithm had been successfully used for prediction of Cr(VI) removal efficiency. The study explores the undiscovered potential of the natural waste materials for sustainable existence of small and medium sector industries, especially in the third world countries by protecting the environment by eco-innovation. PMID- 28623505 TI - Assessment of arsenic content in soil, rice grains and groundwater and associated health risks in human population from Ropar wetland, India, and its vicinity. AB - In the present study, potential health risks posed to human population from Ropar wetland and its vicinity, by consumption of inorganic arsenic (i-As) via arsenic contaminated rice grains and groundwater, were assessed. Total arsenic (t-As) in soil and rice grains were found in the range of 0.06-0.11 mg/kg and 0.03-0.33 mg/kg, respectively, on dry weight basis. Total arsenic in groundwater was in the range of 2.31-15.91 MUg/L. i-As was calculated from t-As using relevant conversion factors. Rice plants were found to be arsenic accumulators as bioconcentration factor (BCF) was observed to be >1 in 75% of rice grain samples. Further, correlation analysis revealed that arsenic accumulation in rice grains decreased with increase in the electrical conductivity of soil. One-way ANOVA, cluster analysis and principal component analysis indicated that both geogenic and anthropogenic sources affected t-As in soil and groundwater. Hazard index and total cancer risk estimated for individuals from the study area were above the USEPA limits of 1.00 and 1.00 * 10-6, respectively. Kruskal-Wallis H test indicated that groundwater intake posed significantly higher health risk than rice grain consumption (chi 2(1) = 17.280, p = 0.00003). PMID- 28623506 TI - Bio-transfer factors and temporal variation of heavy metals in different sexes of three species of edible brackish water fish. AB - This article discusses bioaccumulation and temporal variation of heavy metals in three edible lagoon fish species with references to gender. Cd and As were undetected in the three fish species (i.e., below the method detection limits of 1 MUg Cd/kg wet weight and 2 MUg As/kg wet weight) irrespective of the periods, and Cd was undetected in the water too (i.e., below the detection limit of 0.0003 mg/L). Except for Zn (which was mainly available as Zn2+ in the water), Pb was present largely as low labile metal-chloride complexes and As as HAsO42- as per Visual MINTEQ, version 3.1. Bio-transfer factors of Sn (which was also undetected in the water; below the detection limit of 0.05 mg/L), Hg, Pb, and Zn were <1 in both sexes, justifying that bioaccumulation was largely attributed to food rather than uptake from the water. Metal accumulation patterns differed drastically between the fish species. Arius maculatus (a carnivore) exhibited higher Zn, Hg, and Sn accumulations during the drier periods (June-September) compared with Mugil cephalus (a detritivore/herbivore) and Etroplus suratensis (an omnivore). Pb was detected only in A. maculatus (July-August) possibly due to biomagnification. Zn was present in higher levels in all species (irrespective of sex) compared with the other metals, but levels were below admissible limits. However, the relationship between temporal variation of Zn and gender in all species was insignificant. In M. cephalus, the temporal variation of Sn and Hg between the sexes was also insignificant. Female A. maculatus and E. suratensis showed higher Hg concentrations, while males showed higher Sn concentrations. Temporal variation patterns of Pb were unclear. PMID- 28623507 TI - Physiological characteristics of Plantago major under SO2 exposure as affected by foliar iron spray. AB - Sulfur dioxide (SO2) is considered as a main air pollutant in industrialized areas that can damage vegetation. In the present study, we investigated how exposure to SO2 and foliar application of iron (Fe) would affect certain physiological characteristics of Plantago major. The plant seedlings exposed or unexposed to SO2 (3900 MUg m-3) were non-supplemented or supplemented with Fe (3 g L-1) as foliar spray. Plants were exposed to SO2 for 6 weeks in 100 * 70 * 70 cm chambers. Fumigation of plants with SO2 was performed for 3 h daily for 3 days per week (alternate day). Lower leaf Fe concentration in the plants exposed to SO2 at no added Fe treatment was accompanied with incidence of chlorosis symptoms and reduced chlorophyll concentration. No visible chlorotic symptoms were observed on the SO2-exposed plants supplied with Fe that accumulated higher Fe in their leaves. Both at with and without added Fe treatments, catalase (CAT) and peroxidase (POD) activity was higher in the plants fumigated with SO2 in comparison with those non-fumigated with SO2. Foliar application of Fe was also effective in increasing activity of antioxidant enzymes CAT and POD. Exposure to SO2 led to reduced cellulose but enhanced lignin content of plant leaf cell wall. The results obtained showed that foliar application of Fe was effective in reducing the effects of exposure to SO2 on cell wall composition. In contrast to SO2, application of Fe increased cellulose while decreased lignin content of the leaf cell wall. This might be due to reduced oxidative stress induced by SO2 in plants supplied with Fe compared with those unsupplied with Fe. PMID- 28623508 TI - Clinical Pharmacokinetic Characteristics of Cebranopadol, a Novel First-in-Class Analgesic. AB - BACKGROUND AND OBJECTIVES: Cebranopadol is a novel first-in-class analgesic acting as a nociceptin/orphanin FQ peptide and opioid peptide receptor agonist with central analgesic activity. It is currently in clinical development for the treatment of chronic pain conditions. This trial focuses on the clinical pharmacokinetic (PK) properties of cebranopadol after oral single- and multiple dose administration. METHODS: The basic PK properties of cebranopadol were assessed by means of noncompartmental methods in six phase I clinical trials in healthy subjects and patients. A population PK analysis included two further phase I and six phase II clinical trials. RESULTS: After oral administration of the immediate-release (IR) formulation, cebranopadol is characterized by a late time to reach maximum plasma concentration [C max] (4-6 h), a long half-value duration [HVD] (14-15 h), and a terminal phase half-life in the range of 62-96 h. After multiple once-daily dosing in patients, an operational half-life (the dosing interval resulting in an accumulation factor [AF] of 2) of 24 h was found to be the relevant factor to describe the multiple-dose PKs of cebranopadol. The time to reach steady state was approximately 2 weeks, the AF was approximately 2, and peak-trough fluctuation (PTF) was low (70-80%). Dose proportionality at steady state was shown for a broad dose range of cebranopadol 200-1600 ug. A two compartment disposition model with two lagged transition compartments and a first order elimination process best describes cebranopadol data in healthy subjects and patients after single- and multiple-dose administration. CONCLUSIONS: Cebranopadol formulated as an IR product can be used as a once-daily formulation; it reaches C max after only 4-6 h, and has a long HVD and a low PTF. Therefore, from a PK perspective, cebranopadol is an attractive treatment option for patients with chronic pain. PMID- 28623511 TI - 36th Meeting of the Pediatric Section of the German Society of Trauma Surgery (DGU). PMID- 28623509 TI - Telomerase and drug resistance in cancer. AB - It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gene expression. However, association of those mechanisms, i.e., drug resistance and telomerase alterations, is not fully understood yet. We review the current theories on the aspect of the role of telomerase in cancer cells resistance to therapy. We believe that revealing/unravelling this correlation might significantly contribute to an increased efficiency of cancer cells elimination, especially the most difficult ones, i.e., drug resistant. PMID- 28623512 TI - Phosphatidylethanolamine targeting for cell death imaging in early treatment response evaluation and disease diagnosis. AB - Phosphatidylethanolamine (PE) is one of the most abundant phospholipids in mammalian plasma membranes. In healthy cells, PE resides predominantly in the inner leaflet of the cell membrane. In dead or dying cells on the other hand, PE is externalized to the outer leaflet of the plasma membrane. The exposure of PE on the cell surface has therefore become an attractive target for the molecular imaging of cell death using single-photon emission computed tomography (SPECT) and positron emission tomography (PET). This has motivated the development of PE specific probes to measure cell death in vitro and non-invasively in vivo. In this review, we highlight the biological roles of PE on cell membranes, and PE exposure as a biomarker of cell death in disease processes, along with the use of PE-binding molecular probes to target PE for the characterization of cell death on a cellular and tissue level. We specifically emphasize the preclinical applications of radiolabeled duramycin for the non-invasive imaging of cell death in animal models of disease and in tumors after therapy. In addition, we discuss the clinical relevance, limitations and future perspectives of this imaging approach of cell death. PMID- 28623513 TI - The spine instability neoplastic score (SINS) in the assessment of response to radiotherapy for bone metastases. AB - BACKGROUND: Vertebral metastases are often causing pain and spine instability. Radiotherapy is of significant benefit for painful spine metastases but the response can be very variable. The spine instability neoplastic score (SINS) is a recent classification system for diagnosis of spinal instability caused by vertebral metastases. We analysed the degree of pain relief, the need of drug therapy and the imaging features and the SINS before and after radiotherapy. In particular, we investigated the possible correlation of spine instability defined by pre-treatment SINS with pretreatment pain and with response to radiotherapy. MATERIAL/METHODS: This study included 121 patients with spine metastases treated with palliative 3D conformal radiotherapy. Pain "at rest" and "breakthrough pain", need for drug therapy in terms of "anti-inflammatory", "weak opioid", "strong opioid", imaging studies and SINS were assessed before and after radiotherapy. Statistical analysis was performed by the correlation coefficient of Spearman and Kruskal-Wallis test. RESULTS: Pain relief after radiotherapy was observed in 50.4 and 57.8% of patients in terms of pain at rest and breakthrough pain, respectively. The correlation between pain before radiotherapy and SINS was not statistically significant for both pain at rest (p = 0.4) and breakthrough pain (p = 0.49). The correlation between pain response after radiotherapy and SINS was statistically significant for both pain at rest (p = 0.007) and breakthrough pain (p = 0.047). DISCUSSION/CONCLUSION: The degree of instability, classified according to SINS, resulted to be predictive factor for pain response after radiotherapy. SINS might become a valid tool to identify those patients who can benefit the most from radiotherapy. PMID- 28623516 TI - Erratum to: A Simple Analytical Approximation to an Inhomogeneously-Broadened Dispersion Spectrum. Application to Absorption-Dispersion Admixtures. PMID- 28623514 TI - The potential roles of bacteria to improve radiation treatment outcome. AB - Many combined therapies have been proposed to enhance radiotherapy outcome, but they have several limitations. As a new feasible strategy, combination of radiotherapy with bacteria showed a significant positive impact on the tumor treatment and metastasis inhibition. Although probiotic bacteria and radiotherapy alone can be effective in the treatment of different cancers, the combination of these two therapies seems to enhance therapeutic outcome and is cost-effective. Bacterial cells can act as therapeutic/gene/drug delivery vehicles as well as theranostic agents. In this communication, we reviewed current evidences, studies, suggestions, and future-based directions on combination of radiotherapy and bacteria. In another sections, an overview on tumor hypoxia, bacteria in cancer therapy, and combination of radiotherapy and bacteria is presented. A brief overview on trials and animal studies which used bacteria to protect normal tissues against radiotherapy-induced complications is also included. PMID- 28623515 TI - Pancreatic ductal adenocarcinoma: metastatic disease. AB - The treatment of choice of metastatic PADC is systemic chemotherapy. In the last decade, there have been significant advances in this area. New combination poli chemotherapy schemes have shown a significant increase in overall survival and progression-free survival without impairing quality of life. In addition, the value of second-line chemotherapy treatment has consolidated and a new concept called "therapeutic sequencing" has also emerged. The aim of this article is to review the different therapeutic options in metastatic PDAC based on patient's characteristics. PMID- 28623510 TI - The implication of neuronimmunoendocrine (NIE) modulatory network in the pathophysiologic process of Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder implicitly marked by the substantia nigra dopaminergic neuron degeneration and explicitly characterized by the motor and non-motor symptom complexes. Apart from the nigrostriatal dopamine depletion, the immune and endocrine study findings are also frequently reported, which, in fact, have helped to broaden the symptom spectrum and better explain the pathogenesis and progression of PD. Nevertheless, based on the neural, immune, and endocrine findings presented above, it is still difficult to fully recapitulate the pathophysiologic process of PD. Therefore, here, in this review, we have proposed the neuroimmunoendocrine (NIE) modulatory network in PD, aiming to achieve a more comprehensive interpretation of the pathogenesis and progression of this disease. As a matter of fact, in addition to the classical motor symptoms, NIE modulatory network can also underlie the non motor symptoms such as gastrointestinal, neuropsychiatric, circadian rhythm, and sleep disorders in PD. Moreover, the dopamine (DA)-melatonin imbalance in the retino-diencephalic/mesencephalic-pineal axis also provides an alternative explanation for the motor complications in the process of DA replacement therapy. In conclusion, the NIE network can be expected to deepen our understanding and facilitate the multi-dimensional management and therapy of PD in future clinical practice. PMID- 28623517 TI - Nerve root anomalies: making sense of a complicated literature. AB - INTRODUCTION: Nerve root anomalies (NRAs) are a set of well-described congenital irregularities for which several classification systems have been devised over the years. CONCLUSION: This comprehensive review examines the anatomy and characteristics of NRAs; their surgical, radiographic, and cadaveric prevalence rates; clinical and radiographic presentations; and surgical management. In addition, the top 5 NRA classification systems are presented and related. PMID- 28623518 TI - Primary intraventricular osteosarcoma in a 3-year-old boy: report of a case and review of literature. AB - INTRODUCTION: Extraskeletal osteosarcoma (ExOS) is a rare and well-known entity. Three to 4% of ExOSs occur in the head and neck region but anecdotally in the central nervous system (CNS). Primary intracranial osteosarcoma (PIOS) can originate from the skull, brain parenchyma, or meninges. CASE PRESENTATION: A 3 year-old boy with history of head trauma 2 weeks before admission is presented harboring an ExOS in the left temporoparietal region. He was operated with the impression of intraventricular meningioma but turned to be a PIOS without any sources in his skeleton. Tumor recurred after 5 months and patient died in 2 weeks with tumor seeding to the brain stem. CONCLUSION: This case is reported to show failure of surgery as the only treatment for these tumors, highlighting the need for more aggressive treatment. PMID- 28623519 TI - PHACE syndrome and cerebral cavernous malformations: association or simply microhemorrhages? PMID- 28623520 TI - Prediction of intracranial hypertension through noninvasive intracranial pressure waveform analysis in pediatric hydrocephalus. AB - PURPOSE: The purpose of this study is to evaluate a noninvasive device to assess intracranial pressure wave form in children with hydrocephalus. METHODS: A prospective and non-experimental descriptive-analytic study was performed. Fifty six patients were enrolled in this study. They were divided in four groups: group A, children with clinically compensated hydrocephalus; B, surgically treated hydrocephalus; C, patients with acute intracranial hypertension due to hydrocephalus; and D, children without neurological disease (control). Data were collected through the installation of an extracranial deformation sensor, coupled to the children's scalp, which allowed registration of noninvasive intracranial pressure curves. Parameters obtained were analyzed: P2/P1 ratio, "classification P1 and P2 and P1 slope. RESULTS: P2/P1 index and "classification of P1 and P2" had a sensitivity of 80% and specificity of 100% for predicting intracranial hypertension. "P1 slope" presented no statistical difference. CONCLUSION: This study showed a useful and noninvasive method for monitoring intracranial pressure, which was able to indicate the intracranial hypertension in children with hydrocephalus and, thus, should be further investigated for clinical applications. PMID- 28623521 TI - Exploring for the optimal structural design for the 3D-printing technology for cranial reconstruction: a biomechanical and histological study comparison of solid vs. porous structure. AB - PURPOSE: Cranioplasty for recovering skull defects carries the risk for a number of complications. Various materials are used, including autologous bone graft, metallic materials, and non-metallic materials, each of which has advantages and disadvantages. If the use of autologous bone is not feasible, those artificial materials also have constraints in the case of complex anatomy and/or irregular defects. MATERIAL AND METHODS: This study used metal 3D-printing technology to overcome these existing drawbacks and analyze the clinical and mechanical performance requirements. To find an optimal structure that satisfied the structural and mechanical stability requirements, we evaluated biomechanical stability using finite element analysis (FEA) and mechanical testing. To ensure clinical applicability, the model was subjected to histological evaluation. Each specimen was implanted in the femur of a rabbit and was evaluated using histological measurements and push-out test. RESULTS AND CONCLUSION: We believe that our data will provide the basis for future applications of a variety of unit structures and further clinical trials and research, as well as the direction for the study of other patient-specific implants. PMID- 28623523 TI - Erratum to: Overview of Skeletal Repair (Fracture Healing and Its Assessment). PMID- 28623522 TI - H3 K27M mutations are extremely rare in posterior fossa group A ependymoma. AB - BACKGROUND: Mutations in the tail of histone H3 (K27M) are frequently found in pediatric midline high-grade glioma's but have rarely been reported in other malignancies. Recently, recurrent somatic nucleotide variants in histone H3 (H3 K27M) have been reported in group A posterior fossa ependymoma (EPN_PFA), an entity previously described to have no recurrent mutations. However, the true incidence of H3 K27M mutations in EPN_PFA is unknown. METHODS: In order to discern the frequency of K27M mutations in histone H3 in EPN_PFA, we analyzed 151 EPN_PFA previously profiled with genome-wide methylation arrays using a validated droplet digital PCR assay. RESULTS: We identified only 1 case out of 151 EPN_PFA harboring the K27M mutation indicating that histone mutations are extremely rare in EPN_PFA. Morphologically, this single mutated case is clearly consistent with an ependymoma, and the presence of the K27M mutation was confirmed using immunohistochemistry. DISCUSSION: K27M mutations are extremely rare in EPN_PFA. Routine evaluation of K27M mutations in EPN_PFA is of limited utility, and is unlikely to have any bearing on prognosis and/or future risk stratification. PMID- 28623524 TI - Does a laparoscopic approach attenuate the body weight loss and lean body mass loss observed in open distal gastrectomy for gastric cancer? a single-institution exploratory analysis of the JCOG 0912 phase III trial. AB - BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer may prevent the loss of body weight and lean body mass resulting from reduced surgical stress in comparison to open distal gastrectomy (ODG). A multicenter phase III trial conducted by the Japan Clinical Oncology Group (JCOG0912 trial) was performed to confirm the non-inferiority of LADG to ODG for stage I gastric cancer in terms of relapse-free survival. METHODS: This study was performed as a single-institution exploratory analysis using the data of the patients from our hospital who were enrolled in the JCOG0912 phase III trial. Body weight and lean body mass were evaluated using a bioelectrical impedance analyzer within 1 week before and at 1 week, 1 month, and 3 months after surgery. RESULTS: One-hundred six patients were randomized to undergo ODG (54 patients) or LADG (51 patients). Body weight loss at 1 week, 1 month, and 3 months was -3.0%, -4.9%, and -5.4%, respectively, in the ODG group and -2.7%, -4.3%, and -5.7%, respectively, in the LADG group; the differences were not statistically significant (p = 0.330, 0.166, and 0.656, respectively). Lean body mass loss at 1 week, 1 month, and 3 months was -2.8%, -4.1%, and -2.3%, respectively, in the ODG group and -2.7%, -2.9%, and -3.0%, respectively, in the LADG group; the differences were not statistically significant (p = 0.610, 0.413, and 0.925, respectively). CONCLUSIONS: The laparoscopic approach did not attenuate the loss of body weight and lean body mass in comparison to patients who underwent open distal gastrectomy for gastric cancer. PMID- 28623525 TI - Comparison of CZT SPECT and conventional SPECT for assessment of contractile function, mechanical synchrony and myocardial scar in patients with heart failure. AB - AIM: The aim of this study was to compare CZT-SPECT (CZT SPECT) to conventional SPECT (C-SPECT) in the assessment of left ventricular myocardial scar, contractile function, and mechanical synchrony in patients with heart failure (HF). METHODS: Fifty-nine patients with HF who were referred for myocardial perfusion/metabolism imaging were enrolled. All patients underwent resting 99mTc MIBI gated myocardial perfusion imaging using a CZT SPECT camera and a C-SPECT camera, respectively, and 18F-FDG PET myocardial metabolism imaging within three days. Summed rest score (SRS) and total perfusion defect (TPD) (as indices of perfusion abnormality), left ventricular (LV), end diastolic volume (EDV), end systolic volume (ESV), and ejection fraction (EF) (as indices of LV systolic function), and histogram band width (BW) and standard deviation (SD) (as indices of mechanical synchrony) were analyzed by automated software while the perfusion/metabolism patterns were analyzed visually. RESULTS: There was a good correlation between CZT SPECT and C-SPECT for SRS and TPD. CZT SPECT tended to underestimate SRS and TPD compared to C-SPECT. CZT-SPECT and C-SPECT showed excellent agreement in assessing the perfusion/metabolism pattern though a small proportion of normal segments (6.6%) identified by CZT/PET exhibited mismatch pattern on C-SPECT/PET. CZT SPECT also showed excellent correlation with C-SPECT in measuring EDV, ESV, and EF. Finally, BW and SD measured by CZT SPECT correlated well with C-SPECT but CZT SPECT tended to overestimate BW and SD compared to C-SPECT. CONCLUSION: CZT SPECT provided comparable data to C-SPECT for measuring LV scar, function and synchrony at a considerable reduction in imaging time. CZT SPECT holds a promise for comprehensive evaluation of myocardial performance in patients with HF. PMID- 28623526 TI - Benefit-risk trade-offs for treatment decisions in moderate-to-severe rheumatoid arthritis: focus on the patient perspective. AB - Given the increasing number of available treatments for rheumatoid arthritis (RA) with varying efficacy and safety profiles, it is critical to understand the level of trade-offs that patients are willing to make between benefits and risks. Adult patients with moderate to severe RA were invited to participate in a discrete choice experiment that solicited their preferences for hypothetical RA treatments. Each participant was presented with 14 choice cards asking about their preference between two hypothetical RA treatments with varying levels of efficacy, adverse events, and process-related attributes. A multivariable logistic regression model assessed the association between the attributes and the patient's decision and risk-increases were calculated. 510 eligible patients with moderate to severe RA completed the study. The average age of the participants was 56.4 years, 64.7% were female, and 45.1% received biologic agents. To achieve a 50% improvement in physical function, patients were willing to accept risk increases of 91.1, 4.7, and 18.4% for abnormal laboratory results, cancer, and serious infection, respectively. Similarly, to achieve a 50% reduction in RA related pain, patients were willing to accept risk-increases of 70.6, 3.7, and 14.2% for each AE. Moreover, patients were willing to trade risk-increases of 42.0, 2.2, and 8.5% for each AE to obtain a 50% reduction in the number of swollen joints. Patients with moderate to severe RA are willing to accept increased treatment risks to achieve improved physical function and disease control. These attributes are helpful to clinicians to make informed treatment choices. PMID- 28623527 TI - Updating the Evidence of the Interaction Between Clopidogrel and CYP2C19 Inhibiting Selective Serotonin Reuptake Inhibitors: A Cohort Study and Meta Analysis. AB - INTRODUCTION: We previously found that patients who initiate clopidogrel while treated with a cytochrome P450 (CYP) 2C19-inhibiting selective serotonin reuptake inhibitor (SSRI) have a higher risk of subsequent ischemic events than patients treated with other SSRIs. It is not known whether initiating an inhibiting SSRI while treated with clopidogrel will also increase risk of ischemic events. OBJECTIVE: The aim of this study was to assess clinical outcomes following initiation of a CYP2C19-inhibiting SSRI versus initiation of other SSRIs among patients treated with clopidogrel and to update existing evidence on the clinical impact of clopidogrel-SSRI interaction. METHODS: Using five US databases (1998 2013), we conducted a cohort study of clopidogrel initiators who encountered treatment with SSRI during their clopidogrel therapy. Patients were matched by propensity score (PS) and followed for as long as they were exposed to both clopidogrel and index SSRI group. Outcomes were a composite ischemic event (myocardial infarction, ischemic stroke, or a revascularization procedure, whichever came first) and a composite major bleeding event (gastrointestinal bleed or hemorrhagic stroke, whichever came first). Results were combined via random-effects meta-analysis with previous evidence from subjects initiating clopidogrel while on SSRI therapy. RESULTS: The PS-matched cohort comprised 2346 clopidogrel users starting CYP2C19-inhibiting SSRI therapy and 16,115 starting other SSRIs (mean age 61 years; 59% female). Compared with those treated with a non-inhibiting SSRI, the hazard ratio (HR) for patients treated with a CYP2C19 inhibiting SSRI was 1.07 (95% confidence interval [CI] 0.82-1.40) for the ischemic outcome and 1.00 (95% CI 0.42-2.36) for bleeding. The pooled estimates were 1.11 (95% CI 1.01-1.22) for ischemic events and 0.80 (95% CI 0.55-1.18) for bleeding. CONCLUSIONS: We observed similar estimates of association between the two studies. The updated evidence still indicates a small decrease in clopidogrel effectiveness associated with concomitant exposure to clopidogrel and CYP2C19 inhibiting SSRIs. PMID- 28623528 TI - Time for a standardized clinical assessment for narcolepsy with obstructive sleep apnea. PMID- 28623530 TI - Participation of Tumor-Associated Myeloid Cells in Progression of Amelanotic Melanoma (RMM Tumor Line) in F344 Rats, with Particular Reference to MHC Class II and CD163-Expressing Cells. AB - Tumor progression is often influenced by infiltration of myeloid cells; depending on the M1- or M2-like activation status, these cells may have either inhibitory or promoting effects on tumor growth. We investigated the properties of tumor associated myeloid cells in a previously established homotransplantable amelanotic melanoma (RMM tumor line) in F344 rats. RMM tumor nodules were allowed to reach the sizes of 0.5, 1, 2 and 3 cm, respectively. Immunohistochemistry and flow cytometry was performed for macrophage markers CD68 and CD163, and for the antigen-presenting cell marker, MHC class II. Although no significant change was observed in the number of CD68+ and CD163+ macrophages during RMM progression, the number of MHC class II+ antigen-presenting cells was reduced in 3 cm nodules. Real-time RT-PCR of laser microdissection samples obtained from RMM regions rich in MHC class II+ cells demonstrated high expressions of M1-like factors: IFN gamma, GM-CSF and IL-12a. Furthermore, fluorescence-activated cell sorting, followed by real-time RT-PCR for CD11b+ MHC class II+ (myeloid antigen-presenting cells), CD11b+ CD163+ (M2 type myeloid cells), CD11b+ CD80+ (M1 type myeloid cells) and CD11b+ CD11c+ (dendritic cells) cells was performed. Based on the levels of inflammation- and tumor progression-related factors, MHC class II+ antigen-presenting cells showed polarization towards M1, while CD163+ macrophages, towards M2. CD80+ and CD11c+ myeloid cells did not show clear functional polarization. Our results provide novel information on tumor associated myeloid cells in amelanotic melanoma, and may become useful in further research on melanoma immunity. PMID- 28623529 TI - Ameliorative effect of omega-3 on spermatogenesis, testicular antioxidant status and preimplantation embryo development in streptozotocin-induced diabetes in rats. AB - PURPOSE: The present study was done to determine the ameliorative effect of polyunsaturated fatty acid omega-3 against experimental diabetes-induced damages on testicular tissue, sperm parameters and preimplantation embryo development in rat model. METHODS: Thirty-two mature male rats were divided into two control and test groups. The experimental diabetes (50 mg kg-1 streptozotocin, ip) was induced in test group and subdivided into non-treated diabetic, 300 and 600 mg kg 1 omega-3-treated (orally by gavage) groups. The rats in control group received 0.5 ml saline using intra-gastric gavage. Following 45 days, general histopathological changes, serum level of testosterone, inhibin B, glucose, and sperm parameters, testicular total antioxidant capacity (TAC) and malondialdehyde (MDA) content were analyzed. The mitochondria-dependent apoptosis was investigated by assessing the Bcl-2 and caspase-3 expression as well as DNA fragmentation. Finally, the in vitro fertilization (IVF) potential was examined by evaluating preimplantation embryo developing. RESULTS: The omega-3 significantly ameliorated the diabetes-induced histological damages, diminished serum level of glucose, testicular MDA content, and enhanced the serum testosterone, inhibin B and testicular TAC. The animals in omega-3-treated groups exhibited a significant (p < 0.05) up-regulation in Bcl-2, as well as remarkable (p < 0.05) down-regulation in caspase-3 expression compared to non-treated diabetic rats. Moreover, the omega-3 maintained DNA integrity, improved sperm quality as well as preimplantation embryo development. CONCLUSION: Our data showed that the omega-3 (especially at 600 mg kg-1 dose level) effectively ameliorates the experimental diabetes-induced infertility in rats by up regulating the testicular endocrine and antioxidant statuses, preventing mitochondria-dependent apoptosis pathway and potentially improving the sperm quality. PMID- 28623531 TI - Elevated Serum Beta-D-Glucan with Pseudomonas, Aspergillus, and a Partially Acid Fast Organism in Respiratory Cultures: A Case of Hickam's Dictum Over Occam's Razor. AB - We describe a case of a man with ectopic Cushing's syndrome, elevated serum beta D-glucan, and respiratory cultures with Pseudomonas, Aspergillus, and a partially acid-fast organism. Our case highlights challenges in diagnosis and management of coinfection in an immunocompromised host. PMID- 28623532 TI - Rhizopus homothallicus Causing Invasive Infections: Series of Three Cases from a Single Centre in North India. AB - Mucormycoses are opportunistic fungal infections with a high mortality rate. Rhizopus oryzae is the most common agent implicated in human infections. Although R. homothallicus has been previously reported to be a cause of pulmonary mucormycosis, it is the first time that we are reporting as a causative agent of rhino-orbital and cutaneous mucormycosis. PMID- 28623533 TI - Erratum to: Giovanni Verga (1879-1923), author of a pioneering treatise on pituitary surgery: the foundations of this new field in Europe in the early 1900s. PMID- 28623534 TI - Acquired Immunity in Chronic Rhinosinusitis. AB - Chronic rhinosinusitis (CRS) is a prevalent disease that is associated with significant costs and quality of life impairments. Currently, patients are classified into subgroups based on clinical characteristics, most often the presence or absence of nasal polyps. However, despite medical and surgical treatment, many of these patients continue to have symptoms. Recent efforts have focused on gaining a more complete understanding of the inflammatory mechanisms that drive pathogenesis in CRS, and it is becoming clear that the inflammatory processes in CRS are quite complex. As our understanding of these complex phenotypes improves, it may become possible to classify patients into endotypes based on unique inflammatory patterns within the sinus mucosa. This information may also lead to the identification of appropriate targeted therapies for different endotypes. This review will discuss our current understanding of endotypes in CRS along with the unique adaptive immune responses that may contribute to these different endotypes and, finally, some potential targeted therapeutics for the next generation of CRS treatment strategies. PMID- 28623535 TI - Nanotechnologies for In Vitro IgE Testing. AB - PURPOSE OF REVIEW: This review discusses the recent advances in the development of IgE antibody assays based on nanotechnologies. IgE blood testing is an important part of the diagnostic workup of IgE-mediated hypersentivity. We also address the challenges in moving from an academic proof-of-concept to a product routinely used by allergy experts. RECENT FINDINGS: Several nanotechnologies have been applied to the field of IgE testing: nanoparticles are used either as a support to capture analytes or as a detection tool to enhance the measurement signal. Nanofluidics allows to reduce assay time by enhancing molecular interaction. Nanotechnologies bring forth new methods for in vitro IgE testing. Substantial advantages such as lower sample volume, shorter assay time, simplified procedures, and lower analytic sensitivity, without affecting test precision and accuracy, can be achieved thanks to nanotechnologies. PMID- 28623536 TI - Comparison of fungicidal properties of non-thermal plasma produced by corona discharge and dielectric barrier discharge. AB - The inactivation of four micromycete species by action of non-thermal plasma was followed. Two sources of plasma were compared, namely, positive corona discharge and dielectric barrier discharge. The corona discharge appeared as suitable for fungal spore inactivation in water suspension, whereas the barrier discharge inactivated spores on the surface of cultivation agar. Cladosporium sphaerospermum was the most sensitive, being inactivated within 10 min of exposure to plasma, whereas Aspergillus oryzae displayed decrease in viable cell count only, the complete inactivation was not achieved even after 40 min of exposure. Intermediate sensitivity was found for Alternaria sp. and Byssochlamys nivea. The significant delay of growth was observed for all fungi after exposure to sublethal dose of plasma, but we failed to express this effect quantitatively. PMID- 28623537 TI - Durability of Silicone Airway Stents in the Management of Benign Central Airway Obstruction. AB - PURPOSE: The literature is devoid of a comprehensive analysis of silicone airway stenting for benign central airway obstruction (BCAO). With the largest series in the literature to date, we aim to demonstrate the safety profile, pattern of re intervention, and duration of silicone airway stents. METHODS: An institutional database was used to identify patients with BCAO who underwent rigid bronchoscopy with dilation and silicone stent placement between 2002 and 2015 at Rush University Medical Center. RESULTS: During the study period, 243 stents were utilized in 63 patients with BCAO. Pure tracheal stenosis was encountered in 71% (45/63), pure tracheomalacia in 11% (7/63), and a hybrid of both in 17% (11/63). Median freedom from re-intervention was 104 (IQR 167) days. Most common indications for re-intervention include mucus accumulation (60%; 131/220), migration (28%; 62/220), and intubation (8%; 18/220). The most common diameters of stent placed were 12 mm (94/220) and 14 mm (96/220). The most common lengths utilized were 30 mm (60/220) and 40 mm (77/220). Duration was not effected by stent size when placed for discrete stenosis. However, 14 mm stents outperformed 12 mm when tracheomalacia was present (157 vs. 37 days; p = 0.005). Patients with a hybrid stenosis fared better when longer stents were used (60 mm stents outlasted 40 mm stents 173 vs. 56 days; p = 0.05). CONCLUSION: Rigid bronchoscopy with silicone airway stenting is a safe and effective option for the management of benign central airway obstruction. Our results highlight several strategies to improve stent duration. PMID- 28623538 TI - Clinically Promising Biomarkers in Cystic Fibrosis Pulmonary Exacerbations. AB - Cystic fibrosis is a complex genetic disease hallmarked by repetitive infectious exacerbations that leads to destruction of airway architecture, acute on chronic inflammatory changes, and deterioration in lung function. Predicting an exacerbation may help preempt some of these changes by the initiation of swift antibiotic and anti-inflammatory therapy. A search for biomarkers that could predict exacerbations or help guide duration of antibiotic therapy is being aggressively sought. In this review, we discuss the most recent and promising biomarkers that hopefully will assist in the future management of the CF patient. PMID- 28623539 TI - Pneumothorax After Transbronchial Biopsy in Pulmonary Fibrosis: Lessons from the Multicenter COMET Trial. AB - PURPOSE: Some patients with diffuse interstitial lung disease (ILD) undergo bronchoscopy with transbronchial biopsy (TBB) as part of their diagnostic evaluation. It is unclear what the incidence and risk factors for pneumothorax (PTX) following TBB are in this patient population. METHODS: Ninety-seven subjects with pulmonary fibrosis who underwent a research bronchoscopy with TBB as part of the multicenter correlating outcomes with biochemical markers to estimate time-progression in idiopathic pulmonary fibrosis (COMET) trial were retrospectively reviewed. We compared subjects who developed a PTX during research bronchoscopy with TBB versus those who did not. RESULTS: Seven patients (7.2%) experienced a PTX during research bronchoscopy with TBB. Subjects who experienced PTX during TBB had significantly lower DLCO percent predicted (29 +/- 8 vs. 45 +/- 15, P = 0.006) and had lower resting room air saturation of peripheral oxygen (SPO2) on 6-min walk testing (91 +/- 10 vs. 95 +/- 3, P = 0.02). No differences between groups were found with respect to age, gender, race, BMI, HRCT characteristics, or the number of transbronchial biopsies performed. CONCLUSION: The incidence of PTX following research bronchoscopy with TBB in patients with pulmonary fibrosis was found to be 7.2% in this study. Patients who developed a pneumothorax had greater impairments in gas exchange at baseline evidenced by a lower DLCO % predicted and a lower resting room air SPO2 compared with subjects without PTX as a complication. PMID- 28623540 TI - Identification of surgical patients at high risk of OSAS using the Berlin Questionnaire to detect potential high risk of adverse respiratory events in post anesthesia care unit. AB - Obstructive sleep apnea syndrome (OSAS) increases the risk of post-surgery complications. This study uses Berlin Questionnaire (BQ) to identify Chinese adult surgical patients who are at a high risk of OSAS and to determine if the BQ could be used to detect potential high risk of adverse respiratory events in the post anesthesia care unit (PACU). Results indicated that only 11.4% of the patients were considered at a high risk of OSAS. Age and body mass index are the key factors for the risk of OSAS prevalence in China and also gender specific. Furthermore, the incidence of adverse respiratory events in the PACU was higher in patients with high risk of OSAS than others (6.8% vs. 0.9%, P < 0.001). They also stayed longer than others in the PACU (95 +/- 28 min vs. 62 +/- 19 min, P < 0.001). Age, high risk for OSAS, and smoking were independent risk factors for the occurrence of adverse respiratory events in the PACU. The BQ may be adopted as a screening tool for anesthesiologists in China to identify patients who are at high risk of OSAS and determine the potential risk of developing postoperative respiratory complications in the PACU. PMID- 28623541 TI - Multistage analysis method for detection of effective herb prescription from clinical data. AB - Determining effective traditional Chinese medicine (TCM) treatments for specific disease conditions or particular patient groups is a difficult issue that necessitates investigation because of the complicated personalized manifestations in real-world patients and the individualized combination therapies prescribed in clinical settings. In this study, a multistage analysis method that integrates propensity case matching, complex network analysis, and herb set enrichment analysis was proposed to identify effective herb prescriptions for particular diseases (e.g., insomnia). First, propensity case matching was applied to match clinical cases. Then, core network extraction and herb set enrichment were combined to detect core effective herb prescriptions. Effectiveness-based mutual information was used to detect strong herb-symptom relationships. This method was applied on a TCM clinical data set with 955 patients collected from well-designed observational studies. Results revealed that groups of herb prescriptions with higher effectiveness rates (76.9% vs. 42.8% for matched samples; 94.2% vs. 84.9% for all samples) compared with the original prescriptions were found. Particular patient groups with symptom manifestations were also identified to help investigate the indications of the effective herb prescriptions. PMID- 28623543 TI - The challenge and promise of rare disease diagnosis in China. PMID- 28623542 TI - Identification of differentially expressed miRNAs associated with chronic kidney disease-mineral bone disorder. AB - The purpose of this study is to characterize a meta-signature of differentially expressed mRNA in chronic kidney disease (CKD) to predict putative microRNA (miRNA) in CKD-mineral bone disorder (CKD-MBD) and confirm the changes in these genes and miRNA expression under uremic conditions by using a cell culture system. PubMed searches using MeSH terms and keywords related to CKD, uremia, and mRNA arrays were conducted. Through a computational analysis, a meta-signature that characterizes the significant intersection of differentially expressed mRNA and expected miRNAs associated with CKD-MBD was determined. Additionally, changes in gene and miRNA expressions under uremic conditions were confirmed with human Saos-2 osteoblast-like cells. A statistically significant mRNA meta-signature of upregulated and downregulated mRNA levels was identified. Furthermore, miRNA expression profiles were inferred, and computational analyses were performed with the imputed microRNA regulation based on weighted ranked expression and putative microRNA targets (IMRE) method to identify miRNAs associated with CKD occurrence. TLR4 and miR-146b levels were significantly associated with CKD-MBD. TLR4 levels were significantly downregulated, whereas primiR- 146b and miR-146b were upregulated in the presence of uremic toxins in human Saos-2 osteoblast-like cells. Differentially expressed miRNAs associated with CKD-MBD were identified through a computational analysis, and changes in gene and miRNA expressions were confirmed with an in vitro cell culture system. PMID- 28623544 TI - Clinical feature and waveform in infantile nystagmus syndrome in children with FRMD7 gene mutations. AB - Infant nystagmus sydrome presents as involuntary eye movement disorder and can affect seriously ocular function. We performed a retrospective study of clinical data and FRMD7 genetic test results in 12 cases of infantile nystagmus syndrome to correlate waveform, stereopsis, and visual acuity. The patients (age 6.40+/ 2.67 years) had FRMD7 mutations as follows: missense in eight cases, shear in two cases, frameshift in one case, and non-frameshift in one case. Horizontal jerk waveform was observed in six cases, versus horizontal pendulum in five cases and dual jerk in one case. The uncorrected visual acuity (24 eyes) was 0.21+/-0.12, compared with a corrected visual acuity (24 eyes) of 0.32+/-0.14. All patients had simultaneous perception, versus fusion function in 10 cases (83.33%) and stereoscopic vision in seven cases (58.33%) using the synoptophore. Eleven cases (91.67%) detected the stereo fly, compared with five cases (41.67%) for stereoscopic circles and seven cases (58.33%) for stereoscopic animals by Titmus test. Stereoscopic vision using the synoptophore did not correlate with the frequency, amplitude, or intensity of nystagmus or with corrected binocular visual acuity. The infantile nystagmus syndrome with FRMD7 mutations in our cases was caused primarily de novo and missense mutations. Visual acuity and binocular visual function were significant impaired, and the waveform was generally horizontal jerk. Also, an infrared videonystagmogram can record the frequency, amplitude, and intensity of nystagmus accurately. PMID- 28623545 TI - Analysis of genotypes and phenotypes in Chinese children with tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with serious clinical presentations, an autosomal dominant genetic disorder involving multiple organs and systems. We retrospectively investigated the clinical manifestations and genotypes of 20 Chinese children with TSC to enable informed diagnostic and surveillance recommendations in China. A retrospective analysis of clinical manifestations in 20 children (7.00+/-5.30 years old) with TSC was conducted. A genetic testing of the genes TSC1 and TSC2 was performed in 14 children.The earliest manifestations of TSC were skin lesions (80% of patients) and seizures (75%). Fourteen of the children presented with retinal hamartomas, and 2 of these underwent eye enucleation at other hospitals through misdiagnosis. On magnetic resonance imaging, 18 children exhibited subependymal nodules, and 16 ones showed cortical nodules. 5 cases of non-renal hamartomas, 5 cases of multiple renal cysts, and 5 cases of cardiac rhabdomyomas were observed. The genotyping of TSC1 and TSC2 in 14 children revealed 11 with mutations in TSC2, 2 with mutations in TSC1, and no mutations of either gene in one patient. Eight of these observed mutations are reported here in for the first time. The illness presentations of the TSC2-mutated patients were more severe than that of patients carrying TSC1 mutations.There were differences in the mutations of TSC genes in Chinese children from those reported in other countries. The described clinical characteristics and genotyping will help pediatric neurologists to understand, diagnosis, and treat TSC. PMID- 28623546 TI - Targeting sphingosine-1-phosphate signaling for cancer therapy. AB - Sphingosine-1-phosphate (S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival, cell proliferation, cell migration, angiogenesis and many other cellular processes. S1P either activates S1P receptors (S1PR1-5) through "inside-out signaling" or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1P signaling and its pathogenic roles in diseases as well as in developing modulators of S1P signaling, including S1P agonists, S1P antagonists and sphingosine kinase (SphK) inhibitors. Ceramide and S1P have been defined as reciprocal regulators of cell fate, and S1P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1P signaling in cancer development (particularly in inflammation- associated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1P signaling in cancer treatment. PMID- 28623547 TI - Profile of Dr. Xu Zhang. PMID- 28623548 TI - Genetic dissection for zinc deficiency tolerance in rice using bi-parental mapping and association analysis. AB - KEY MESSAGE: Zinc deficiency is a widespread soil constraint in rice production. Here, we present QTL/candidate genes associated with Zn deficiency tolerance identified through bi-parental QTL mapping and genome-wide association analysis. Zinc (Zn) deficiency is a widespread soil constraint in rice production. Despite several physiological studies elucidating Zn deficiency tolerance mechanisms, little is known about genetic factors conferring tolerance. To identify QTL associated with root development, biomass accumulation, and grain yield under Zn deficiency, we combined bi-parental QTL mapping in a population of 200 backcross inbred (BC1F6) lines and genome-wide association analysis using 247 k SNP markers across 140 accessions of an indica diversity panel. Three QTLs for Zn deficiency tolerance on chromosomes 3, 6, and 12 co-localized in both approaches and the association analysis detected two additional strong QTL on chromosomes 1 and 9 not present in the bi-parental population. Based on haplotype analysis of the indica panel, biomass consistently increased due to the minor 'tolerance' haplotypes, which had frequencies between 13 and 34%. By utilizing the previous transcript data collected from the same Zn-deficient field, we identified one putative candidate gene within the chromosome 6-QTL, which was associated with all traits in both analyses. Gene Os06g44220 was barely expressed under +Zn conditions but strongly upregulated in both root and shoot under stress and consistently more so in the tolerant genotype. Os06g44220 is an uncharacterized gene with expression previously detected only under salinity stress. Four SNP alterations within the promoter region distinguish the two alleles identified and a genotype tolerant to Zn deficiency shares the same allele as salinity tolerant varieties, lending support to the hypothesis that this gene may confer tolerance to both stresses. PMID- 28623549 TI - Elevated Circulating PCSK9 Concentrations Predict Subclinical Atherosclerotic Changes in Low Risk Obese and Non-Obese Patients. AB - INTRODUCTION: Many studies have highlighted the important role of PCSK9 in the development of cardiometabolic changes and its possible function as a biomarker of myocardial infarction or ischemic heart disease. This study aimed to determine the relationship between circulating PCSK9 levels and subclinical vascular changes in the group of low risk patients without manifest cardiovascular diseases. METHODS: In this study, 120 healthy patients, free of manifest cardiovascular diseases, diabetes mellitus, and without lipid-lowering therapy, were divided into three groups based on BMI: normal weight (N = 50), overweight (N = 30), and obese (N = 40). Biochemical parameters, including basic lipid and non-lipid ones, were analyzed. PCSK9 levels were measured by ELISA, vascular changes were quantified by carotid ultrasound (carotid artery intima-media thickness, cIMT), and arterial stiffness parameters (pulse wave velocity, PWV; augmentation index, AI; stiffness parameter, beta) were measured by an echo tracking method. RESULTS: Plasma levels of PCSK9 significantly increased in obese (172.78 +/- 51.67 ng/mL) in comparison with overweight (120.14 +/- 37.64, p < 0.001) and normal weight groups (114.92 +/- 35.87, p < 0.001). Differences between the overweight and normal weight groups were not significant (p = 0.85). The level of PCSK9 significantly correlated with values of BMI (p < 0.001, r = 0.38). In addition to increase in laboratory parameters associated with moderate metabolic changes, significant increase in cIMT and parameters of vascular changes (beta, AI, PWV) were detected in groups with elevated BMI. Significant positive linear correlation of PCSK9 concentrations and cIMT (p < 0.001, r = 0.39), PWV (p < 0.001, r = 0.31), and beta (p < 0.001, r = 0.3) were found. In multivariable regression analysis after adjusting for gender, age, BMI, and LDL, the impact of PCSK9 on cIMT, beta, and PWV remained significant (p = 0.006, 0.03, and 0.002, respectively). CONCLUSION: PCSK9 plasma levels significantly correlated with subclinical vascular changes and their values were significantly elevated in obese subjects. We assume that PCSK9 could be used as a predictor of early vascular involvement, prior to the existence of manifest atherosclerosis. These results also highlight the role of anti-PCSK9 treatment in primary prevention. PMID- 28623550 TI - Antibiotic susceptibility profiles among Campylobacter isolates obtained from international travelers between 2007 and 2014. AB - Campylobacter infection is a common cause of diarrhea among international travelers. We studied antibiotic resistance patterns among Campylobacter isolates obtained from international travelers according to travel destination. Three collections of isolates obtained from international travelers between 2007 and 2014 (Institute of Tropical Medicine, the "Laboratoire Hospitalier Universitaire de Bruxelles "and the Belgian National Reference Centre for Campylobacter) were used. Isolates were tested for minimal inhibitory concentration (MIC) values (E test macromethod) for fluoroquinolones, macrolides, tetracyclines, amoxicillin clavulanic acid, and meropenem. Single isolates from 261 travelers were available; median (IQR) age was 25.4 (4-42) years, 85.8% were symptomatic (information for 224 patients available). Overall resistance to ciprofloxacin was 60.9%, ranging from 50.8% in Africa to 75.0% in Asia. Resistance to erythromycin was 4.6%, with the highest rate observed for Southern Asia (15.2%, seven isolates, six of them recovered from patients returning from India). A total of 126 isolates (48.3%) were resistant to tetracycline. No resistance to amoxicillin clavulanic acid or meropenem was detected. Ciprofloxacin resistance tended to increase over time (53.9% in 2007 versus 72.2% in 2014), erythromycin resistance remained stable (median annual resistance 4.2%). Most (86.2%) ciprofloxacin resistant isolates had MIC values >=32 mg/l, and all erythromycin-resistant isolates had MIC values >=256 mg/l. Co-resistance to ciprofloxacin and erythromycin was observed in 11 (4.2%) isolates, seven of which came from Southern Asia. Among all regions of travel, more than half of Campylobacter isolates were resistant to ciprofloxacin. Overall resistance to erythromycin was below 5% but reached 15.2% in Southern Asia. PMID- 28623551 TI - Which Patients Will Benefit from a Switch in Therapy from Premixed Insulin to Insulin Glargine plus Oral Antidiabetic Drugs? Further Analysis of the Lantus Registry Study. AB - INTRODUCTION: This subgroup analysis of data from the 16-week Lantus Registry Study in China investigated the characteristics of patients with type 2 diabetes mellitus (T2DM) associated with clinical benefits of transitioning therapy from premixed insulin to insulin glargine (100 U/ml) plus oral antidiabetic drugs (OADs). METHODS: The modified intention-to-treat population of the Lantus Registry Study, comprising 1847 patients with T2DM, were included in the current subgroup analyses. Enrolled patients were divided into subgroups based on efficacy variables of endpoint glycated hemoglobin (HbA1c), endpoint fasting plasma glucose (FPG), and change in HbA1c from baseline. The baseline characteristics of those who did and did not achieve HbA1c <7.0% were compared, as were those with improvement, no change, or deterioration in HbA1c. Characteristics of patients who were unable to achieve HbA1c <7.0%, further grouped according to whether or not they achieved FPG <=6.1 mmol/L, were also compared. Logistic regression analysis was used to identify factors associated with achieving HbA1c <7.0%. RESULTS: Comparison between subgroups demonstrated that patients with endpoint HbA1c <7.0% were significantly younger, with a shorter duration of diabetes and lower baseline FPG, HbA1c, body mass index, and dose of premixed insulin than patients with endpoint HbA1c >=7.0%. Logistic regression analysis revealed a negative correlation between baseline age, HbA1c, FPG, and duration of diabetes with achieving HbA1c <7.0%. When stratified according to change in HbA1c, the improvement group was younger, with higher baseline HbA1c and a greater number of patients with duration of diabetes <=5 years. Three-quarters of patients unable to achieve HbA1c <7.0% also failed to reach FPG <=6.1 mmol/L. CONCLUSION: Younger patients with a shorter duration of diabetes and lower HbA1c, FPG, and premixed insulin dose following a switch in treatment to insulin glargine (100 U/ml) plus OADs from premixed insulin have greater potential to achieve HbA1c <7.0%. Poorly controlled patients with higher baseline HbA1c are most likely to experience an improvement in HbA1c following the switch in therapy. The majority of patients unable to achieve HbA1c <7.0% also failed to reach FPG <=6.1 mmol/L, highlighting the importance of adequate titration of insulin glargine to achieve adequate FPG control, which can enable achievement of target HbA1c. FUNDING: Sanofi. PMID- 28623552 TI - Pioglitazone and the Risk of Bladder Cancer: A Meta-Analysis. AB - : People with type 2 diabetes are at increased risk of bladder cancer. Pioglitazone is said to increase it further, although published evidence is mixed. We conducted a meta-analysis to determine if any link between the use of pioglitazone and an increased risk of bladder cancer can be found. A comprehensive literature search was conducted through electronic databases as well as registries for data of clinical trials to identify studies that investigate the effect of pioglitazone on bladder cancer in diabetic patients. We used the risk ratio (RR) and the hazard ratio (HR) provided by the studies to illustrate the risk of occurrence of bladder cancer in the experimental group compared to that in the control group. Fourteen studies using RR and 12 studies using HR were included in the analysis. The overall RR was 1.13 with 95% CI (0.96 1.33) with low heterogeneity among the studies using RR, suggesting that no connection exists between use of pioglitazone and the risk of bladder malignancy. The summary HR was 1.07 (0.96-1.18) allowing us to affirm that there is no link between long-term use of pioglitazone and bladder cancer. Our results support the hypothesis of no difference in the incidence of bladder cancer among the pioglitazone group and the nonuser group. Our conclusion is that the explanation of hypothetically increased risk of bladder malignancy should be attributed to other factors. FUNDING: Tchaikapharma High Quality Medicines Inc. PMID- 28623553 TI - Kaposi's disease in an HIV positive child, with probable contamination from his grandmother. AB - Kaposi's disease in children with HIV is rarely reported in everyday practice. This is a case study of cutaneous Kaposi's disease revealing HIV in a 5-year-old child with polymorphic eruption of papules and nodules on the face, trunk, back, and limbs. Histopathological examination confirmed the diagnosis of Kaposi's disease. The child's HIV serology was positive with a CD4 count of 240/mm3, normochromic and normocytic anemia, and a hemoglobin level at 8.5 g/dl. It was found that the child, after early weaning from his HIV-negative mother, had repeatedly suckled his healthy grandmother, who had no skin lesions but was HIV1 positive. Both grandmother and child were referred for treatment in their locality. The case is noteworthy for the way in which the HIV1 virus infected the child during weaning and then being suckled by his grandmother. The child already had an initial dental flare that could have injured his grandmother. Thus, in our case, there is a contamination by HIV1 virus most likely from the grandmother and contamination by the HHV8 virus, source unidentified as a technical plateau was reached. PMID- 28623554 TI - [Obesity, high blood pressure, hypercholesterolaemia, and untreated diabetes in HIV-infected and HIV-uninfected Adults in Mbuji-Mayi (Democratic republic of congo)]. AB - Little is known about the major cardiovascular risk factors in HIV-infected as compared to the HIV-uninfected patients in the Democratic Republic of Congo (DR Congo). We determined the prevalence of hypertension, obesity (BMI >= 30 kg/m2), total cholesterol > 200 mg/dl, HDLcholesterol &<= 40 mg/dl, and glycemia > 126 mg/dl. We also calculated the average and/or median of total cholesterol, HDL cholesterol, and glycemia among HIV-infected and HIV-uninfected patients.We conducted a cross-sectional study that enrolled 592 HIV-uninfected and 445 HIV infected patients of whom 425 (95.5%) were on first-line antiretroviral therapy based on stavudine-lamivudine-nevirapine. Clinical and laboratory data of the patients were collected. The results were analyzed by chi-square, t-student, and Wilcoxon rank sum tests. 11.5% of HIV-infected patients had an average blood pressure suggesting hypertension versus 10.6% of HIV-uninfected (P = 0.751). But in absolute value, HIVinfected patients had a median of diastolic blood pressure of 90 mmHg versus 85 mmHg of HIV-uninfected (P < 0.001). 4.04% of HIV-infected patients had a BMI suggesting obesity versus 6.08% of HIV-uninfected patients (P = 0.187). For fasting glucose: 2.50% of HIV-infected patients versus 4.20% of HIV uninfected patients had a serum fasting glucose suggesting diabetes (P<0.176). 11.9% of HIV-infected patients had a total cholesterol greater than 200 mg/dl versus 7.4% of HIVuninfected patients (P=0.019). For HDL-cholesterol: 36.40% of HIV-infected patients had a serum fasting <= 40 mg/dl versus 15.70% of HIV uninfected patients (P < 0.001). HIV-infected patients had a median fasting total cholesterol higher (140 mg/ dl) thanHIV-uninfected patients (133mg/dl) [P=0.015].HIVuninfected patients had a median fasting HDL-cholesterol higher (58.5 mg/dl) than HIV-infected patients (49 mg/dl) [P < 0.001]. HIV-infected women were more likely to have a higher mean of total cholesterol: 147.70 #x00B1; 52.09 mg/dl versus 135.72 ± 48.23 mg/dl for the HIV-infected men (P = 0.014) and of HDL-cholesterol: 55.80 +/- 30.77 mg/dl versus 48.24 +/- 28.57mg/dl for the HIV-infected men (P = 0.008). In this study population, prevalence of hypertension was elevated in HIVinfected versus HIV-uninfected patients. Being HIV positive on first-line antiretroviral therapy based on stavudine-lamivudine nevirapine was associated with high prevalence of total cholesterol > 200 mg/dl and HDL-cholesterol <= 40 mg/dl. Proactive screening and prompt management of dyslipidemia and hypertension in this population should be a priority. PMID- 28623555 TI - Goldenhar syndrome: current perspectives. AB - BACKGROUND: Progress in medical branches that has taken place since the first child with Goldenhare syndrome (GS) had been described in 1952 by Maurice Goldenhar, facilitated better understanding of this congenital defect. It also gave new perspectives and the opportunity to achieve satisfactory treatment results, mainly due to development of surgical techniques. DATA SOURCES: Based on the literature and own experience, we discussed the phenotype of presentation of GS, ethiopathogenesis, genetic counselling and treatment with particular emphasis on surgery correction of hemifacial microsomia. RESULTS: The spectrum of GS abnormalities ranges from mild to severe ones and include patients with barely noticeable facial asymmetry to very pronounced facial defect with more or less severe abnormalities of internal organs and/or skeleton. It is characterized most commonly by impaired development of eyes, ears, lips, tongue, palate, mandible, maxilla, zygomatic and orbital structures and deformations of the teeth structures. Ethiopathogenesis is multifactorial and dependent on genetic and environmental factors but there are still many unknowns about the syndrome which should be revealed. CONCLUSIONS: Patients with GS due to a large variety of abnormalities and different severity of symptoms pose a challenge for clinicians. All of this necessitate an individual approach to each single patient and involvement a team of specialists in treatment planning. It is a complex, long lasting, multidisciplinary process and should be divided into stages, according to patient's age, as well as the extent and severity of observed abnormalities. Neonatologists and pediatricians are involved in care of these patients from the onset. PMID- 28623556 TI - Characteristics and clinical role of bronchoscopy in diagnosis of childhood endobronchial tuberculosis. AB - BACKGROUND: Endobronchial tuberculosis (EBTB) is the most frequent complication of primary pulmonary tuberculosis (PTB) in children. The aim of the study was to analyze characteristics and clinical role of bronchoscopy in diagnosis of childhood EBTB. METHODS: A retrospective, descriptive study was undertaken in 157 children with EBTB undergone flexible bronchoscopy (FB) between January 2006 and June 2014. RESULTS: The median age of the enrolled patients was 3.4 years, with 73.2% of patients under five years old. The most common subtype was tumorous type (145/157, 92.4%). If only involved bronchus were considered, the common affected sites were right middle lobe bronchus (49/228, 21.5%), left upper lobe bronchus (41/228, 18.0%), right upper lobe bronchus (41/228, 18.0%), right main bronchus (35/228, 15.4%), respectively. Children younger than five years old were at higher risk to have multiple endobronchial lesions (P=0.044), with an odds ratio of 2.313 (95% confidence interval: 1.009-5.299). Before the bronchoscopy, only 16 (10.2%) patients were highly suspected of EBTB, while the others were diagnosed as PTB without EBTB (69.4%), or misdiagnosed as pneumonia or foreign body aspiration (20.4%) on admission. CONCLUSIONS: The patients under five years old are at high risk to progress to EBTB and have multiple endobronchial lesions. The most frequent subtype of EBTB in children is tumorous type. The lesions are seen in the right bronchial system more frequently. FB should be performed to detect the endobronchial lesions in suspected patients as soon as possible. PMID- 28623557 TI - Proving Value in Radiology: Experience Developing and Implementing a Shareable Open Source Registry Platform Driven by Radiology Workflow. AB - Numerous initiatives are in place to support value based care in radiology including decision support using appropriateness criteria, quality metrics like radiation dose monitoring, and efforts to improve the quality of the radiology report for consumption by referring providers. These initiatives are largely data driven. Organizations can choose to purchase proprietary registry systems, pay for software as a service solution, or deploy/build their own registry systems. Traditionally, registries are created for a single purpose like radiation dosage or specific disease tracking like diabetes registry. This results in a fragmented view of the patient, and increases overhead to maintain such single purpose registry system by requiring an alternative data entry workflow and additional infrastructure to host and maintain multiple registries for different clinical needs. This complexity is magnified in the health care enterprise whereby radiology systems usually are run parallel to other clinical systems due to the different clinical workflow for radiologists. In the new era of value based care where data needs are increasing with demand for a shorter turnaround time to provide data that can be used for information and decision making, there is a critical gap to develop registries that are more adapt to the radiology workflow with minimal overhead on resources for maintenance and setup. We share our experience of developing and implementing an open source registry system for quality improvement and research in our academic institution that is driven by our radiology workflow. PMID- 28623558 TI - A Method to Recognize Anatomical Site and Image Acquisition View in X-ray Images. AB - A method was developed to recognize anatomical site and image acquisition view automatically in 2D X-ray images that are used in image-guided radiation therapy. The purpose is to enable site and view dependent automation and optimization in the image processing tasks including 2D-2D image registration, 2D image contrast enhancement, and independent treatment site confirmation. The X-ray images for 180 patients of six disease sites (the brain, head-neck, breast, lung, abdomen, and pelvis) were included in this study with 30 patients each site and two images of orthogonal views each patient. A hierarchical multiclass recognition model was developed to recognize general site first and then specific site. Each node of the hierarchical model recognized the images using a feature extraction step based on principal component analysis followed by a binary classification step based on support vector machine. Given two images in known orthogonal views, the site recognition model achieved a 99% average F1 score across the six sites. If the views were unknown in the images, the average F1 score was 97%. If only one image was taken either with or without view information, the average F1 score was 94%. The accuracy of the site-specific view recognition models was 100%. PMID- 28623559 TI - IFN-beta-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis. AB - Dermatomyositis (DM) is an autoimmune disease associated with enhanced type I interferon (IFN) signalling in skeletal muscle, but the mechanisms underlying muscle dysfunction and inflammation perpetuation remain unknown. Transcriptomic analysis of early untreated DM muscles revealed that the main cluster of down regulated genes was mitochondria-related. Histochemical, electron microscopy, and in situ oxygraphy analysis showed mitochondrial abnormalities, including increased reactive oxygen species (ROS) production and decreased respiration, which was correlated with low exercise capacities and a type I IFN signature. Moreover, IFN-beta induced ROS production in human myotubes was found to contribute to mitochondrial malfunctions. Importantly, the ROS scavenger N-acetyl cysteine (NAC) prevented mitochondrial dysfunctions, type I IFN-stimulated transcript levels, inflammatory cell infiltrate, and muscle weakness in an experimental autoimmune myositis mouse model. Thus, these data highlight a central role of mitochondria and ROS in DM. Mitochondrial dysfunctions, mediated by IFN-beta induced-ROS, contribute to poor exercise capacity. In addition, mitochondrial dysfunctions increase ROS production that drive type I IFN inducible gene expression and muscle inflammation, and may thus self-sustain the disease. Given that current DM treatments only induce partial recovery and expose to serious adverse events (including muscular toxicity), protecting mitochondria from dysfunctions may open new therapeutic avenues for DM. PMID- 28623560 TI - Zebra chip disease enhances respiration and oxidative stress of potato tubers (Solanum tuberosum L.). AB - MAIN CONCLUSION: The physiological phenotype of potato tubers afflicted by zebra chip disease is characterized by increased oxidative stress metabolism and upregulation of systems for its mitigation. Starch catabolism and extensive buildup of reducing sugars render potatoes infected with zebra chip (ZC) pathogen (Candidatus Liberibacter solanacearum) unsuitable for fresh market and processing into chips/fries. Here we show that the disease inflicts considerable oxidative stress, which likely constitutes a substantial sink for metabolic energy, resulting in increased respiration rate of afflicted tubers. In contrast to healthy tubers, tissue from diseased tubers had greater ability to reduce 2,3,5 triphenyl-tetrazolium chloride to formazan, indicating enhanced dehydrogenase activity, probable disease-induced changes in cellular redox potential, and increased respiratory activity. The respiration rate of diseased tubers (cv. Atlantic) was 2.4-fold higher than healthy tubers and this correlated with increased activities of glucose-6-phosphate and 6-phosphogluconate dehydrogenases, key enzymes responsible for synthesis of cytosolic reducing equivalents. Wound-induced NADPH oxidase activity was greater for ZC than healthy tubers, but the resulting superoxide was rapidly catabolized by higher superoxide dismutase activity in ZC tubers. Peroxidase, catalase, glutathione reductase and ascorbate free radical reductase activities were also higher in diseased tubers, as was malondialdehyde, a biomarker of peroxidative damage and oxidative stress. Upregulation of the glutathione-ascorbate pathway is a direct response to (and indicator of) oxidative stress, which consumes reducing equivalents (NADPH) to catabolize reactive oxygen species and maintain cellular redox homeostasis. ZC disease substantially altered the oxidative metabolism of tubers, resulting in a physiological phenotype defined by metabolic changes directed toward mitigating oxidative stress. Paradoxically, the increased respiration rate of ZC tubers, which fuels the metabolic pathways responsible for attenuating oxidative stress, likely also contributes to oxidative stress. PMID- 28623561 TI - Variation in cucumber (Cucumis sativus L.) fruit size and shape results from multiple components acting pre-anthesis and post-pollination. AB - MAIN CONCLUSION: Morphological, QTL, and gene expression analyses indicate variation in cucumber fruit size and shape results from orientation, timing, and extent of cell division and expansion, and suggest candidate gene factors. Variation in cucumber (Cucumis sativus L.) fruit size and shape is highly quantitative, implicating interplay of multiple components. Recent studies have identified numerous fruit size and shape quantitative trait loci (QTL); however, underlying factors remain to be determined. We examined ovary and fruit development of two sequenced cucumber genotypes with extreme differences in fruit size and shape, Chinese Long '9930' (CL9930), and pickling type 'Gy14'. Differences were observed in several independent factors that can influence size and shape: ovule number, rate and period of cell division in longitudinal and cross section in ovaries and fruit, timing and rate of fruit expansion in length and diameter, and cell shape. Level and timing of expression of select fruit growth stage marker genes and candidate fruit size gene homologs associated with cucumber fruit size and shape QTL were examined from 5-day pre-anthesis to 20-day post-pollination. Our results indicate that variation in fruit size and shape results from differences in cell number and shape in longitudinal and cross section, driven in turn by differences in orientation, timing, and duration of cell division and expansion, both pre- and post-anthesis, and suggest candidate genes contributing to determination of cucumber fruit size and shape. PMID- 28623562 TI - Physical rupture of the xylem in developing sweet cherry fruit causes progressive decline in xylem sap inflow rate. AB - MAIN CONCLUSION: Xylem flow is progressively shut down during maturation beginning with minor veins at the stylar end and progressing to major veins and finally to bundles at the stem end. This study investigates the functionality of the xylem vascular system in developing sweet cherry fruit (Prunus avium L.). The tracers acid fuchsin and gadoteric acid were fed to the pedicel of detached fruit. The tracer distribution was studied using light microscopy and magnetic resonance imaging. The vasculature of the sweet cherry comprises five major bundles. Three of these supply the flesh; two enter the pit to supply the ovules. All vascular bundles branch into major and minor veins that interconnect via numerous anastomoses. The flow in the xylem as indexed by the tracer distribution decreases continuously during development. The decrease is first evident at the stylar (distal) end of the fruit during pit hardening and progresses basipetally towards the pedicel (proximal) end of the fruit at maturity. That growth strains are the cause of the decreased conductance is indicated by: elastic strain relaxation after tissue excision, the presence of ruptured vessels in vivo, the presence of intrafascicular cavities, and the absence of tyloses. PMID- 28623563 TI - Taxonomy and identification of bacteria associated with acute oak decline. AB - Acute oak decline (AOD) is a relatively newly described disorder affecting native oak species in Britain. Symptomatic trees are characterised by stem bleeds from vertical fissures, necrotic lesions in the live tissue beneath and larval galleries of the two spotted oak buprestid (Agrilus biguttatus). Several abiotic and biotic factors can be responsible for tree death, however the tissue necrosis and stem weeping is thought to be caused by a combination of bacterial species. Following investigations of the current episode of AOD which began in 2008, numerous strains belonging to several different bacteria in the family Enterobacteriaceae have been consistently isolated from symptomatic tissue. The majority of these enterobacteria were found to be novel species, subspecies and even genera, which have now been formally classified. The most frequently isolated species from symptomatic oak are Gibbsiella quercinecans, Brenneria goodwinii and Rahnella victoriana. Identification of these bacteria is difficult due to similarities in colony morphology, phenotypic profile and 16S rRNA gene sequences. Current identification relies heavily on gyrB gene amplification and sequencing, which is time consuming and laborious. However, newer techniques based on detection of single nucleotide polymorphisms show greater promise for rapid and reliable identification of the bacteria associated with AOD. PMID- 28623564 TI - An NADPH-dependent Lactobacillus composti short-chain dehydrogenase/reductase: characterization and application to (R)-1-phenylethanol synthesis. AB - A new anti-Prelog short-chain dehydrogenase/reductase (SDR) encoding gene lcsdr was cloned from Lactobacillus composti DSM 18527, and heterologously expressed in Escherichia coli. LcSDR is nicotinamide adenine dinucleotide phosphate (NADPH) dependent and has a molecular weight of approximately 30 kDa. The optimal pH and temperature were 6.5 and 30 degrees C, respectively. The maximal reaction rate Vmax was 133.9 U mg-1; the Michaelis-Menten constant K m of LcSDR were 0.345 mM for acetophenone (1a), and 0.085 mM for NADPH. Through introducing an EsGDH catalyzed NADPH regeneration system, a biocatalytic process for (R)-1 phenylethanol ((R)-1b) was developed with outstanding time-space yield. Under the optimized conditions, 50 g l-1 1a was converted to (R)-1b in 2 h with a yield of 93.8%, enantiomeric excess of product (e.e.p) above 99% and space-time yield of 562.8 g l-1 d-1. PMID- 28623565 TI - The novel oleaginous bacterium Sphingomonas sp. EGY1 DSM 29616: a value added platform for renewable biodiesel. AB - Oleaginous microorganisms are regarded as efficient, renewable cell factories for lipid biosynthesis, a biodiesel precursor, to overwhelm the cosmopolitan energy crisis with affordable investment capital costs. Present research highlights production and characterization of lipids by a newly isolated oleaginous bacterium, Sphingomonas sp. EGY1 DSM 29616 through an eco-friendly approach. Only sweet whey [42.1% (v/v)] in tap water was efficiently used as a growth medium and lipid production medium to encourage cell growth and trigger lipid accumulation simultaneously. Cultivation of Sphingomonas sp. EGY1 DSM 29616 in shake flasks resulted in the accumulation of 8.5 g L-1 lipids inside the cells after 36 h at 30 degrees C. Triglycerides of C16:C18 saturated and unsaturated fatty acids showed a similar pattern to tripalmitin or triolein; deduced from gas chromatography (GC), thin layer chromatography (TLC), and Matrix-assisted laser desorption/ionization time-of-flight-mass spectra analysis (MALDI-TOF-MS) analyses. Batch cultivation 2.5 L in a laboratory scale fermenter led to 13.8 g L 1 accumulated lipids after 34 h at 30 degrees C. Present data would underpin the potential of Sphingomonas sp. EGY1 DSM 29616 as a novel renewable cell factory for biosynthesis of biodiesel. PMID- 28623566 TI - Clinical and molecular genetic features of cerebrotendinous xanthomatosis patients in Chinese families. AB - Cerebrotendinous xanthomatosis (CTX) is a lipid-storage disease caused by mutations in CYP27A1. Current publications of Chinese CTX were mainly based on case reports. Here we investigated the clinical manifestations, genetic features in Chinese CTX patients. The clinical materials of 4 Chinese CTX pedigrees were collected. The genetic testing was done by polymerase chain reaction plus Sanger sequencing. The features of Chinese CTX patients reported previously were also reviewed. Three novel mutations of p.Arg513Cys, c.1477-2A > C in family 1 and p.Arg188Stop in family 4 (NM 000784.3) in CYP27A1 were found. The probands in our study manifested cerebellar ataxia, tendon xanthoma and spastic paresis in family 1 and 4, tendon xanthoma plus spastic paraparesis in family 2, asymptomatic tendon xanthoma in family 3. Three known mutations of p.Arg137Gln, p.Arg127Trp and p.Arg405Gln were found respectively in Family 2, 3 and 4. For the Chinese patients reviewed, the most common findings were xanthomatosis (100%), pyramidal signs (100%), cerebellar ataxia (66.7%), cognitive impairment (66.7%), cataracts (50.0%), and peripheral neuropathy (33.3%). Chronic diarrhea was infrequently seen (5.6%). No mutation was found associated with any given clinical features. We identified 3 novel mutations in CYP27A1. In Chinese CTX patients, xanthomatosis was the most common symptom while cataracts and chronic diarrhea were less frequent. The special features in Chinese CTX patients might caused by the lack of serum cholestanol test and should be confirmed in larger number of patients in the future. PMID- 28623567 TI - Molecular Identification and Comparative Evaluation of Tropical Marine Microalgae for Biodiesel Production. AB - Marine microalgae have emerged as important feedstock for liquid biofuel production. The identification of lipid-rich native microalgal species with high growth rate and optimal fatty acid profile and biodiesel properties is the most challenging step in microalgae-based biodiesel production. In this study, attempts have been made to bio-prospect the biodiesel production potential of marine and brackish water microalgal isolates from the west coast of India. A total of 14 microalgal species were isolated, identified using specific molecular markers and based on the lipid content; seven species with total lipid content above 20% of dry cell weight were selected for assessing biodiesel production potential in terms of lipid and biomass productivities, nile red fluorescence, fatty acid profile and biodiesel properties. On comparative analysis, the diatoms were proven to be promising based on the overall desirable properties for biodiesel production. The most potential strain Navicula phyllepta MACC8 with a total lipid content of 26.54 % of dry weight of biomass, the highest growth rate (0.58 day-1) and lipid and biomass productivities of 114 and 431 mgL-1 day-1, respectively, was rich in fatty acids mainly of C16:0, C16:1 and C18:0 in the neutral lipid fraction, the most favoured fatty acids for ideal biodiesel properties. The biodiesel properties met the requirements of fuel quality standards based on empirical estimation. The marine diatoms hold a great promise as feedstock for large-scale biodiesel production along with valuable by-products in a biorefinery perspective, after augmenting lipid and biomass production through biochemical and genetic engineering approaches. PMID- 28623568 TI - Evaluation of venous thromboembolism prophylaxis in a major hospital in a developing country. AB - : Background Venous thromboembolism is the most common preventable cause of hospital death. Despite that, there is still a large gap between what we know about venous thromboembolism prophylaxis and what is happening in current practice. Objective To evaluate VTE prophylaxis in Al-Basheer hospital and assess the extent of agreement of physicians' practice with the guidelines. Setting Al Basheer governmental hospital in Jordan between January 2016 and June 2016. Method In this cross-sectional observational study, patients were randomly selected from medical and surgical wards. The need for venous thromboembolism prophylaxis was assessed according to the American College of Chest Physicians guideline (9th edition) for men and non-pregnant women, and the Royal College of Obstetricians and Gynecologists guidelines for pregnant women. MAIN OUTCOME MEASURE: rate of agreement of venous thromboembolism prophylaxis with the guidelines. Results The total number of patients was 1030, Patients in the medical wards constituted most of the participants. The rate of concordance with the guidelines was 718/1030 (69.7%) in the total number of patients When the patients were divided into groups: those that required venous thromboembolism prophylaxis and those that did not, the rate of agreement with guidelines in the subgroup that needed prophylaxis 160/456 (35.1%) was lower than the rate in the subgroup that did not need prophylaxis 558/574 (97.2%), p value <0.001. Conclusion venous thromboembolism prophylaxis in Al-Basheer hospital is not appropriate and underused, this might be attributed to the absence of an institutional guideline. PMID- 28623569 TI - Estimating the Population Size of Female Sex Worker Population in Tehran, Iran: Application of Direct Capture-Recapture Method. AB - There is no reliable estimate of the size of female sex workers (FSWs). This study aimed to estimate the size of FSWs in south of Tehran, Iran in 2016 using direct capture-recapture method. In the capture phase, the hangouts of FSWs were mapped as their meeting places. FSWs who agreed to participate in the study tagged with a T-shirt. The recapture phase was implemented at the same places tagging FSWs with a blue bracelet. The total estimated size of FSWs was 690 (95% CI 633, 747). About 89.43% of FSWs experienced sexual intercourse prior to age 20. The prevalence of human immunodeficiency virus infection among FSWs was 4.60%. The estimated population size of FSWs was much more than our expectation. This issue must be the focus of special attention for planning prevention strategies. However, alternative estimates require to estimating the number FSWs, reliably. PMID- 28623571 TI - Erratum to: Co-spray Drying with HPMC as a Platform to Improve Direct Compaction Properties of Various Tablet Fillers. PMID- 28623570 TI - Enhanced recovery protocols in total joint arthroplasty: a review of the literature and their implementation. AB - BACKGROUND: During recent years, there has been an exponential demand for joint arthroplasty, which has coincided with the global economic recession. In response, the management of patients following arthroplasty is continuously evolving, with the average inpatient length of stay decreasing from weeks to days, and more recently, we have witnessed the development of "outpatient arthroplasty" as a novel concept which aims to address the high volume of patients. The reduction in length of stay has been made possible via implementation of "enhanced recovery programmes" encompassing each stage of the patient journey. Such programmes have aimed to maximise efficiency, whilst maintaining patient satisfaction and achieving exceptional functional outcomes. OBJECTIVE: We have undertaken a thorough review the literature in relation to enhanced recovery programmes (ERPs) and the research that has underpinned individual elements of enhanced recovery. A literature search of enhanced recovery protocols was carried out using PubMed, Cochrane, Embase and OVID. No language restrictions were imposed on the search. REVIEW: ERPs represent a multifactorial framework which may be subdivided into several phases. Pre operative education programmes, outpatient consultation, pre-anaesthetic assessment, pre-procedural physiotherapy, day-of-surgery admission, pre-operative medications, type of anaesthesia, blood loss reduction protocols, multimodal analgesia delivery, day-of-surgery mobilisation, thromboembolic prophylaxis and ongoing rehabilitation are essential in enhanced recovery. CONCLUSION: These successful strategies have streamlined the patient pathway of arthroplasty surgery in a cost-effective manner, whilst reducing length of hospital stay and maintaining patient outcomes. Further studies are required to appropriately quantify the impact of individual variables and development of an internationally agreed ERP. PMID- 28623572 TI - Nutritional (Fe, Mn, Ni, and Cr) and growth responses of rice plant affected by perennial application of two bio-solids. AB - Trace toxic elements often restrict the land application of different bio-solids in agriculture. In order to evaluate the separate influence of the municipal solid waste compost (MSW), sewage sludge (SS) and combined application with inorganic fertilizers (chemical fertilizer (CF)) on nutritional (Fe, Mn, Ni, and Cr) and growth responses of rice plant, a research was conducted on paddy soil from 2013 to 2015. Obtained results showed that SS levels were superior to MSW in most studied traits. The maximum chlorophyll content (46.52), plant height (162.6 cm), biomass (23.33 t ha-1), soil available Fe (206.26 ppm), Ni concentration in the root (14.41 ppm) and shoots (3.16 ppm), Cr concentration in the root (12.43 ppm) and grain (3.65 ppm), and Mn concentration in grain (66.938 ppm) belonged to SS levels, specially enriched 40 t ha-1, when it was added to the soil for three continuous years. The highest 1000-grain weight (29.89 g), yield (6.86 t ha-1), harvest index (48.17%), and soil available Mn (712.7 ppm), Fe, and Ni concentration in grain (107.92 and 8.79 ppm, respectively) were recorded in 3 years of applying the enriched 40 t ha-1 MSW. Accumulation of Ni in grain in critical levels and negative effects of CF treatments on toxic element entry to soil and plant were two important findings of this research that need management. PMID- 28623573 TI - Bisphenol A exposure assessment from olive oil consumption. AB - The use of bisphenol A (BPA) in packaging has grown over the past 50 years despite concerns of its migration into packaged food and beverages, resulting in human exposure. Many studies have reported tumorigenic effects and endocrine alterations associated with BPA in animal models. This study aims at assessing human exposure to BPA from olive oil. A total of 27 olive oil samples were collected from mills and local villagers in the Hasbaya District, a major olive oil harvesting region in Lebanon. Information on storage conditions was also collected. BPA was extracted and quantified by HPLC. Results showed significantly higher BPA levels in olive oil samples stored in plastic vs. non-plastic packaging (mean = 333 vs. 150 MUg/kg, p value = 0.006), samples with a plastic storage duration of >1 year compared to those with a storage duration of <1 year (mean = 452 vs. 288 MUg/kg, p value = 0.008), and oil samples sourced from locals compared to oil mills (mean = 376 vs. 228 MUg/kg, p value = 0.022). Statistically significant higher BPA levels remained for samples stored in plastic vs. non plastic packaging in the bootstrap multivariable linear regression (B = 121.56, 95% CI 53.44-194.39, p value = 0.009). This is the first report on BPA levels in Mediterranean olive oil. The estimated exposure was 1.38% of the EFSA tolerable daily intake, hence there are no concerns about potential health risks from olive oil consumption. PMID- 28623575 TI - From Genes to Networks: Characterizing Gene-Regulatory Interactions in Plants. AB - Plants, like other eukaryotes, have evolved complex mechanisms to coordinate gene expression during development, environmental response, and cellular homeostasis. Transcription factors (TFs), accompanied by basic cofactors and posttranscriptional regulators, are key players in gene-regulatory networks (GRNs). The coordinated control of gene activity is achieved by the interplay of these factors and by physical interactions between TFs and DNA. Here, we will briefly outline recent technological progress made to elucidate GRNs in plants. We will focus on techniques that allow us to characterize physical interactions in GRNs in plants and to analyze their regulatory consequences. Targeted manipulation allows us to test the relevance of specific gene-regulatory interactions. The combination of genome-wide experimental approaches with mathematical modeling allows us to get deeper insights into key-regulatory interactions and combinatorial control of important processes in plants. PMID- 28623574 TI - The bactericidal effect of simultaneous titanium oxide on common hospital bacteria. AB - Bacteria prevalence has increased in health centers and hospitals. Infection control can decrease the number of bacteria. Bacteria cause 90% of nosocomial infections and fungi, viruses, or protozoa are less involved. Bacteria control can decrease the number of diseases. The Simultaneous titanium oxide (SMTiO) is a new method of disinfection. This process degrades bacteria by producing hydroxyl radical. The present study was conducted with the aim of analyzing the bactericidal effect of simultaneous titanium oxide on common hospital bacteria. In this study, SMTiO system was placed under a laminar hood. Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Citrobacter freundii were selected as common hospital bacteria. Treatment operations were conducted at the bacteria concentration 106 cells/mL and the exposure times of 1 to 48 h. Then, the bacteria colonies were counted and removal rate calculated separately each of the bacteria. Finally, data analysis was conducted by using one-way ANOVA. Results showed that E. coli and C. freundii had the highest removal rate (40%) and the lowest removal (14%), respectively. Results confirmed that SMTiO can degrade Gram-positive and Gram-negative bacteria, but its effects were lower on Gram-positive bacteria. Results showed that removal efficiency increased gradually during exposure periods. We recommend that future studies should analyze the structure of bacteria after the treatment with SMTiO. PMID- 28623576 TI - Inducible Promoter Systems for Gene Perturbation Experiments in Arabidopsis. AB - Assessing molecular changes that occur through altering a gene's activity is often hampered by difficulties that arise due to the typically static nature of the introduced perturbation. This is especially problematic when investigating molecular events at specific stages and/or in certain tissues or organs during Arabidopsis development. To circumvent these issues, we have employed chemically inducible artificial microRNAs (amiRNAs) for the specific knockdown of developmental regulators. For our own research, we have combined this gene perturbation approach with a floral induction system, which allows the simultaneous induction of a large number of flowers on the inflorescence of a single plant, and the ability to knock down a gene's activity at any given stage of development. To enable the plant community to avail of the full benefits of these systems, we describe, in this chapter, strategies for amiRNA-mediated gene perturbations and address some common problems that can be encountered when generating inducible amiRNA constructs, growing these plants, and collecting floral buds for analysis. PMID- 28623577 TI - Cell Type-Specific Gene Expression Profiling Using Fluorescence-Activated Nuclear Sorting. AB - Fluorescence-activated cell sorting (FACS) is a powerful method for the analysis of cell type-specific transcriptome profiles, DNA or histone modifications, and chemical compounds. In plants, it has been employed mainly with root and shoot tissue in combination with cell wall digestion on cellular and nuclear content. However, many tissues are recalcitrant to cell separation and are therefore not readily accessible for FACS analysis. Here, we lay out a detailed protocol for the generation of transcriptional profiles from fluorescently labeled nuclei. The protocol described in this chapter has been used successfully to generate a transcriptional map of the early Arabidopsis thaliana embryo. PMID- 28623578 TI - Characterization of Cell-Type-Specific DNA Binding Sites of Plant Transcription Factors Using Chromatin Immunoprecipitation. AB - The generation of diverse cell types in multicellular organisms often requires the activity of cell-type-specific transcription factors. Understanding where these transcription factors bind in controlling specific cellular programs is critical. However, probing these cell-type-specific factors in vivo with standard chromatin immunoprecipitation (ChIP) assays remains a challenge. We have developed an optimized ChIP assay termed Maximized Objects for Better Enrichment (MOBE)-ChIP, which improves ChIP sensitivity and allows the detection of cell type-specific signals at a genome-wide scale. Here, I describe the procedure for implementing this method for the study of plant transcription factors. Besides being useful for cell-type-specific studies, MOBE-ChIP can also be employed as a general strategy for enhancing ChIP signals. PMID- 28623579 TI - Yeast One- and Two-Hybrid High-Throughput Screenings Using Arrayed Libraries. AB - Since their original description more than 25 years ago, the yeast one- and two hybrid systems (Y1H/Y2H) have been used by many laboratories to detect DNA protein (Y1H) and protein-protein interactions (Y2H). These systems use yeast cells (Saccharomyces cerevisiae) as a eukaryotic "test tube" and are amenable for most labs in the world. The development of highly efficient cloning methods has fostered the generation of large collections of open reading frames (ORFs) for several organisms that have been used for yeast screenings. Here, we describe a simple mating based method for high-throughput screenings of arrayed ORF libraries with DNA (Y1H) or protein (Y2H) baits not requiring robotics. One person can easily carry out this protocol in approximately 10 h of labor spread over 5 days. It can also be scaled down to test one-to-one (few) interactions, scaled up (i.e., robotization) and is compatible with several library formats (i.e., 96, 384-well microtiter plates). PMID- 28623580 TI - SELEX-Seq: A Method to Determine DNA Binding Specificities of Plant Transcription Factors. AB - Systematic evolution of ligands by exponential enrichment (SELEX) is a method that allows isolating specific nucleotide sequences that interact with a DNA binding protein of choice. By using a transcription factor (TF) and a randomized pool of double-stranded DNA, this technique can be used to characterize TF DNA binding specificities and affinities. The method is based on protein-DNA complex immunoprecipitation with protein-specific antibodies and subsequent DNA selection and amplification. Application of massively parallel sequencing (-seq) at each cycle of SELEX allows determining the relative affinities to any DNA sequence for any transcription factor or TF complex. The resulting TF DNA binding motifs can be used to predict potential DNA binding sites in genomes and thereby direct target genes of TFs. PMID- 28623581 TI - Analysis of a Plant Transcriptional Regulatory Network Using Transient Expression Systems. AB - In plant biology, transient expression systems have become valuable approaches used routinely to rapidly study protein expression, subcellular localization, protein-protein interactions, and transcriptional activity prior to in vivo studies. When studying transcriptional regulation, luciferase reporter assays offer a sensitive readout for assaying promoter behavior in response to different regulators or environmental contexts and to confirm and assess the functional relevance of predicted binding sites in target promoters. This chapter aims to provide detailed methods for using luciferase reporter system as a rapid, efficient, and versatile assay to analyze transcriptional regulation of target genes by transcriptional regulators. We describe a series of optimized transient expression systems consisting of Arabidopsis thaliana protoplasts, infiltrated Nicotiana benthamiana leaves, and human HeLa cells to study the transcriptional regulations of two well-characterized transcriptional regulators SCARECROW (SCR) and SHORT-ROOT (SHR) on one of their targets, CYCLIN D6 (CYCD6).Here, we illustrate similarities and differences in outcomes when using different systems. The plant-based systems revealed that the SCR-SHR complex enhances CYCD6 transcription, while analysis in HeLa cells showed that the complex is not sufficient to strongly induce CYCD6 transcription, suggesting that additional, plant-specific regulators are required for full activation. These results highlight the importance of the system and suggest that including heterologous systems, such as HeLa cells, can provide a more comprehensive analysis of a complex gene regulatory network. PMID- 28623582 TI - Analysis of In Vivo Chromatin and Protein Interactions of Arabidopsis Transcript Elongation Factors. AB - A central step to elucidate the function of proteins commonly comprises the analysis of their molecular interactions in vivo. For nuclear regulatory proteins this involves determining protein-protein interactions as well as mapping of chromatin binding sites. Here, we present two protocols to identify protein protein and chromatin interactions of transcript elongation factors (TEFs) in Arabidopsis. The first protocol (Subheading 3.1) describes protein affinity purification coupled to mass spectrometry (AP-MS) that utilizes suspension cultured cells as experimental system. This approach provides an unbiased view of proteins interacting with epitope-tagged TEFs. The second protocol (Subheading 3.2) depicts details about a chromatin immunoprecipitation (ChIP) procedure to characterize genomic binding sites of TEFs. These methods should be valuable tools for the analysis of a broad variety of nuclear proteins. PMID- 28623583 TI - Characterization of Mediator Complex and its Associated Proteins from Rice. AB - The Mediator complex is a multi-protein complex that acts as a molecular bridge conveying transcriptional messages from the cis element-bound transcription factor to the RNA Polymerase II machinery. It is found in all eukaryotes including members of the plant kingdom. Increasing number of reports from plants regarding different Mediator subunits involved in a multitude of processes spanning from plant development to environmental interactions have firmly established it as a central hub of plant regulatory networks. Routine isolation of Mediator complex in a particular species is a necessity because of many reasons. First, composition of the Mediator complex varies from species to species. Second, the composition of the Mediator complex in a particular species is not static under all developmental and environmental conditions. Besides this, at times, Mediator complex is used in in vitro transcription systems. Rice, a staple food crop of the world, is used as a model monocot crop. Realizing the need of a reliable protocol for the isolation of Mediator complex from plants, we describe here the isolation of Mediator complex from rice. PMID- 28623584 TI - DNase I SIM: A Simplified In-Nucleus Method for DNase I Hypersensitive Site Sequencing. AB - Identifying cis-regulatory elements is critical in understanding the direct and indirect interactions that occur within gene regulatory networks. Current approaches include DNase-seq, a technique that combines sensitivity to the nonspecific endonuclease DNase I with high-throughput sequencing to identify regions of regulatory DNA on a genome-wide scale. Yet, challenges still remain in processing recalcitrant tissues that have low DNA content. Here, we describe DNase I SIM (for Simplified In-nucleus Method), a protocol that simplifies and facilitates generation of DNase-seq libraries from plant tissues for high resolution mapping of DNase I hypersensitive sites. By removing steps requiring the use of gel agarose plugs in DNase-seq, DNase I SIM reduces the time required to perform the protocol by at least 2 days, while also making possible the processing of difficult plant tissues including plant roots. PMID- 28623585 TI - In Situ Hi-C Library Preparation for Plants to Study Their Three-Dimensional Chromatin Interactions on a Genome-Wide Scale. AB - The spatial organization of the genome in the nucleus is critical for many cellular processes. It has been broadly accepted that the packing of chromatin inside the nucleus is not random, but structured at several hierarchical levels. The Hi-C method combines Chromatin Conformation Capture and high-throughput sequencing, which allows interrogating genome-wide chromatin interactions. Depending on the sequencing depth, chromatin packing patterns derived from Hi-C experiments can be viewed on a chromosomal scale or at a local genic level. Here, I describe a protocol of plant in situ Hi-C library preparation, which covers procedures starting from tissue fixation to library amplification. PMID- 28623586 TI - Multiplexed Transcriptional Activation or Repression in Plants Using CRISPR-dCas9 Based Systems. AB - Novel tools and methods for regulating in vivo plant gene expression are quickly gaining popularity and utility due to recent advances in CRISPR-dCas9 chimeric effector regulators, otherwise known as CRISPR artificial transcription factors (CRISPR-ATFs). These tools are especially useful for studying gene function and interaction within various regulatory networks. First generation CRISPR-ATFs are nuclease-deactivated (dCas9) CRISPR systems where dCas9 proteins are fused to known transcriptional activator domains (VP64) or repressor domains (SRDX). When multiple chimeric dCas9-effector fusions are guided to gene regulatory regions via CRISPR gRNAs, they can modulate expression of transcript levels in planta. The protocol presented here provides a detailed procedure for activating AtPAP1 and repressing AtCSTF64 in Arabidopsis thaliana. This protocol makes use of our plant CRISPR toolbox to streamline the assembly and cloning of multiplex CRISPR Cas9 transcriptional regulatory constructs. PMID- 28623587 TI - Generation of dTALEs and Libraries of Synthetic TALE-Activated Promoters for Engineering of Gene Regulatory Networks in Plants. AB - Transcription factors with programmable DNA-binding specificity constitute valuable tools for the design of orthogonal gene regulatory networks for synthetic biology. Transcription activator-like effectors (TALEs), as natural transcription regulators, were used to design, build, and test libraries of synthetic TALE-activated promoters (STAPs) that show a broad range of expression levels in plants. In this chapter, we present protocols for the construction of artificial TALEs and corresponding STAPs. PMID- 28623588 TI - Design of Knowledge Bases for Plant Gene Regulatory Networks. AB - Developing a knowledge base that contains all the information necessary for the researcher studying gene regulation in a particular organism can be accomplished in four stages. This begins with defining the data scope. We describe here the necessary information and resources, and outline the methods for obtaining data. The second stage consists of designing the schema, which involves defining the entire arrangement of the database in a systematic plan. The third stage is the implementation, defined by actualization of the database by using software according to a predefined schema. The final stage is development, where the database is made available to users in a web-accessible system. The result is a knowledgebase that integrates all the information pertaining to gene regulation, and which is easily expandable and transferable. PMID- 28623589 TI - AraNet: A Network Biology Server for Arabidopsis thaliana and Other Non-Model Plant Species. AB - Functional gene networks link genes based on their functional relatedness, which is inferred from various complementary biological datasets. Gene networks comprising vast amounts of data can be used to predict which genes are associated with complex traits. Decades of studies in plant biology using the model organism Arabidopsis thaliana have generated large amounts of information, enabling the development of a system-level molecular network. AraNet (currently version 2) is a genome-scale functional gene network for Arabidopsis thaliana, constructed by integrating 19 types of genomics data and can be explored through a web-server (http://www.inetbio.org/aranet) to identify candidate genes for traits of interest. AraNet provides two alternative search paths for users to identify candidate genes and functions. The web server also exploits ortholog relationships between plant species and projects the genes of 28 other plant species (as of April, 2016) into the network of Arabidopsis genes. This allows researchers to use AraNet to predict genes/functions of not only Arabidopsis but also other non-model plants by expanding the functional knowledge of Arabidopsis. Here, we present a detailed description of how to search the AraNet network and interpret the search results to study plant gene functions and their associations with complex phenotypes. PMID- 28623590 TI - Integration of Genome-Wide TF Binding and Gene Expression Data to Characterize Gene Regulatory Networks in Plant Development. AB - Key transcription factors (TFs) controlling the morphogenesis of flowers and leaves have been identified in the model plant Arabidopsis thaliana. Recent genome-wide approaches based on chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq) enable systematic identification of genome-wide TF binding sites (TFBSs) of these regulators. Here, we describe a computational pipeline for analyzing ChIP-seq data to identify TFBSs and to characterize gene regulatory networks (GRNs) with applications to the regulatory studies of flower development. In particular, we provide step-by-step instructions on how to download, analyze, visualize, and integrate genome-wide data in order to construct GRNs for beginners of bioinformatics. The practical guide presented here is ready to apply to other similar ChIP-seq datasets to characterize GRNs of interest. PMID- 28623591 TI - Predicting Transcription Factor Binding Sites and Their Cognate Transcription Factors Using Gene Expression Data. AB - A transcription factor (TF) is a DNA binding protein that targets specific binding-sites (TFBSs) to regulate the transcript levels of its downstream genes. Thus, identifying the TF-TFBS pairs is a pivotal step in understanding the function of TFs and the regulatory network in an organism. Here, we describe two methods for predicting the TFBS of a given TF and for predicting the cognate TF of a given TFBS from a set of strongly co-expressed genes, using time-course transcriptome data of maize developing leaves. PMID- 28623592 TI - Computational Approaches to Study Gene Regulatory Networks. AB - The goal of the gene regulatory network (GRN) inference is to determine the interactions between genes given heterogeneous data capturing spatiotemporal gene expression. Since transcription underlines all cellular processes, the inference of GRN is the first step in deciphering the determinants of the dynamics of biological systems. Here, we first describe the generic steps of the inference approaches that rely on similarity measures and group the similarity measures based on the computational methodology used. For each group of similarity measures, we not only review the existing approaches but also describe specifically the detailed steps of the existing state-of-the-art algorithms. PMID- 28623593 TI - Boolean Dynamic Modeling Approaches to Study Plant Gene Regulatory Networks: Integration, Validation, and Prediction. AB - Mathematical models based on dynamical systems theory are well-suited tools for the integration of available molecular experimental data into coherent frameworks in order to propose hypotheses about the cooperative regulatory mechanisms driving developmental processes. Computational analysis of the proposed models using well-established methods enables testing the hypotheses by contrasting predictions with observations. Within such framework, Boolean gene regulatory network dynamical models have been extensively used in modeling plant development. Boolean models are simple and intuitively appealing, ideal tools for collaborative efforts between theorists and experimentalists. In this chapter we present protocols used in our group for the study of diverse plant developmental processes. We focus on conceptual clarity and practical implementation, providing directions to the corresponding technical literature. PMID- 28623594 TI - ODE-Based Modeling of Complex Regulatory Circuits. AB - Transcriptional regulatory circuits are often complex, consisting of many components and regulatory interactions. Mathematical modeling is an important tool for understanding the behavior of these circuits, and identifying gaps in our understanding of gene regulation. Ordinary differential equations (ODEs) are a commonly used formalism for constructing mathematical models of complex regulatory networks. Here, I outline the steps involved in developing, parameterizing, and testing an ODE model of a gene regulatory network. PMID- 28623595 TI - Inferring Gene Regulatory Networks in the Arabidopsis Root Using a Dynamic Bayesian Network Approach. AB - Gene regulatory network (GRN) models have been shown to predict and represent interactions among sets of genes. Here, we first show the basic steps to implement a simple but computationally efficient algorithm to infer GRNs based on dynamic Bayesian networks (DBNs), and we then explain how to approximate DBN based GRN models with continuous models. In addition, we show a MATLAB implementation of the key steps of this method, which we use to infer an Arabidopsis root GRN. PMID- 28623596 TI - Impact of Residency Training Level on the Surgical Quality Following General Surgery Procedures. AB - OBJECTIVE: To investigate the safety of surgical performance by residents of different training level performing common general surgical procedures. METHODS: Data were consecutively collected from all patients undergoing general surgical procedures such as laparoscopic cholecystectomy, laparoscopic appendectomy, inguinal, femoral and umbilical hernia repair from 2005 to 2011 at the Department of Surgery of the University Hospital of Zurich, Switzerland. The operating surgeons were grouped into junior residents, senior residents and consultants. The comprehensive complication index (CCI) representing the overall number and severity of all postoperative complications served as primary safety endpoint. A multivariable linear regression analysis was used to analyze differences between groups. Additionally, we focused on the impact of senior residents assisting junior residents on postoperative outcome comparing to consultants. RESULTS: During the observed time, 2715 patients underwent a general surgical procedure. In 1114 times, a senior resident operated and in 669 procedures junior residents performed the surgery. The overall postoperative morbidity quantified by the CCI was for consultants 5.0 (SD 10.7), for senior residents 3.5 (8.2) and for junior residents 3.6 (8.3). After adjusting for possible confounders, no difference between groups concerning the postoperative complications was detected. There is also no difference in postoperative complications detectable if junior residents were assisted by consultants then if assisted by senior residents. DISCUSSION: Patient safety is ensured in general surgery when performed by surgical junior residents. Senior residents are able to adopt the role of the teaching surgeon in charge without compromising patients' safety. PMID- 28623597 TI - Acute Appendicitis: Still a Surgical Disease? Results from a Propensity Score Based Outcome Analysis of Conservative Versus Surgical Management from a Prospective Database. AB - OBJECTIVE: The aim of the present study was to compare the outcomes of conservative versus surgical treatment for acute appendicitis. BACKGROUND: Although acute appendicitis is a common disease, great debate exists regarding the appropriate management of patients. Conservative treatment has shown positive results in several RCTs, eliciting questions about indications to surgery, therapeutic appropriateness and ethical conduct. METHODS: Data were prospectively collected; a Propensity Score-based matching method was implemented in order to reduce bias arising from characteristics of the patients; a proportion of patients (69 in total) were excluded to obtain two comparable groups of study (1a). Main outcomes of the study were: failure rate, in-hospital length of stay (at first admission and cumulative), post-discharge absence from work. Within the medical group, failure was defined as the necessity for appendectomy after conservative treatment, while it was identified with complications and negative appendectomy within the surgical group (Failure 1). In parallel, an additional definition of failure was proposed (Failure 2) and excluded negative appendectomy from the reasons for failure within the surgical group (5b). RESULTS: The failure rate for the conservative treatment resulted to be inferior, as compared to the surgical treatment (16.5 vs. 28.4%, OR 0.523 p = 0.019), considering negative appendectomy as a reason for failure. When excluding negative appendectomy from the definition of failure, medical and surgical treatment appeared to perform equally (failure rate: 16.5 vs. 18.3%, OR 1.014 p = 0.965). Patients managed conservatively showed to have a shorter length of stay at first admission than the patients who underwent appendectomy (3.11 vs. 4.11 days, beta = -0.628 days, p < 0.0001). A lower number of lost work days after discharge resulted from a conservative approach (6 vs. 14.64 days, beta = -8.7 days, p < 0.0001). CONCLUSIONS: Considering each outcome as part of a wide-angle analysis, the conservative management of acute appendicitis resulted to be safe and effective in the selected group of patients. In terms of failure rate, the medical treatment resulted to perform as effectively as surgical treatment, if negative appendectomy was excluded from failure, or better, when negative appendectomy was included in the definition of failure. A diminished length of stay during the first admission and a reduced number of lost work days were evident with a conservative approach. The comparison between medical and surgical treatment for acute appendicitis requires a change in perspective, from a spare 'effectiveness analysis' to a more thorough 'appropriateness analysis': in the present study, the conservative treatment showed to address the clinical requirements in terms of therapeutic appropriateness. Although acute appendicitis is considered a 'surgical disease', increasing evidence supports the effectiveness and safety of a conservative approach for selected groups of patients. PMID- 28623598 TI - Cost-Effectiveness of Two Decision Strategies for Shunt Use During Carotid Endarterectomy. AB - BACKGROUND: Arterial shunting during carotid endarterectomy (CEA) is essential in some patients because of insufficient cerebral perfusion during cross-clamping. However, the optimal diagnostic modality identifying these patients is still debated. None of the currently used modalities has been proved superior to another. The aim of this study was to assess the cost-effectiveness of two modalities, stump pressure measurement (SPM) versus electroencephalography (EEG) combined with transcranial Doppler (TCD) during CEA. METHODS: Two retrospective cohorts of consecutive patients undergoing CEA with different intraoperative neuromonitoring strategies (SPM vs. EEG/TCD) were analyzed. Clinical data were collected from patient hospital records. Primary clinical outcome was in-hospital stroke or death. Total admission costs were calculated based on volumes of healthcare resources. Analyses of effects and costs were adjusted for clinical differences between patients by means of a propensity score, and cost effectiveness was estimated. RESULTS: A total of 503 (239 SPM; 264 EEG/TCD) patients were included, of whom 19 sustained a stroke or died during admission (3.3 vs. 4.2%, respectively, adjusted risk difference 1.3% (95% CI -2.3-4.8%)). Median total costs were ?4946 (IQR 4424-6173) in the SPM group versus ?7447 (IQR 6890-8675) in the EEG/TCD group. Costs for neurophysiologic assessments were the main determinant for the difference. CONCLUSIONS: Given the evidence provided by this small retrospective study, SPM would be the favored strategy for intraoperative neuromonitoring if cost-effectiveness was taken into account when deciding which strategy to adopt. PMID- 28623599 TI - Energetics and reactivity of small beryllium deuterides. AB - Enthalpies and free energies of reaction for small neutral and charged beryllium deuterides BeD, BeD2, and BeD3 that have been calculated are reported for a temperature range of 0 K to 1000 K. We discuss probable dissociation channels and possible ways of producing BeD by localizing the relevant transition states and by calculating corresponding rate constants. BeD and BeD+ are found to be the most stable ones among the considered compounds. BeD2 and [Formula: see text] are more likely to decompose into Be0,+ + D2 than into BeD0,+ + D. The metastable BeD3 and [Formula: see text] predominantly decompose into BeD0,+ + D2. In light of our results on the reaction energetics, we can interpret the pathways for production of BeD via BeD2 and BeD3 intermediates observed in molecular dynamics simulations. PMID- 28623600 TI - Stability of rolled-up GaAs nanotubes. AB - This work presents a theoretical study of gallium arsenide (GaAs) nanotubes obtained from the (100), (110) and (111) crystal planes of zincblende structure in order to evaluate the electronic properties. The DFT/B3LYP/6-31G method was used to predict structures and stabilities. It was found that nanotubes from the (110) crystal plane tended to be the most stable. The results for average diameter and bond length obtained for optimized nanotube geometries show that nanotubes constructed from the (100) plane have a hyperbolic format, while (110) or (111) nanotubes have a conical format. This difference in relation to geometry introduces regions with different charge concentrations along the tube. From the calculated values for the gap it follows that increasing the number of atoms per layer causes a displacement of the frontier orbitals with a reduction in the gap, yielding characteristics of a semiconductor material. PMID- 28623601 TI - Is the hydrophobic core a universal structural element in proteins? AB - The hydrophobic core, when subjected to analysis based on the fuzzy oil drop model, appears to be a universal structural component of proteins irrespective of their secondary, supersecondary, and tertiary conformations. A study has been performed on a set of nonhomologous proteins representing a variety of CATH categories. The presence of a well-ordered hydrophobic core has been confirmed in each case, regardless of the protein's biological function, chain length or source organism. In light of fuzzy oil drop (FOD) analysis, various supersecondary forms seem to share a common structural factor in the form of a hydrophobic core, emerging either as part of the whole protein or a specific domain. The variable status of individual folds with respect to the FOD model reflects their propensity for conformational changes, frequently associated with biological function. Such flexibility is expressed as variable stability of the hydrophobic core, along with specific encoding of potential conformational changes which depend on the properties of helices and beta-folds. PMID- 28623602 TI - Protein requirements of collared peccary (Pecari tajacu). AB - A nitrogen (N) balance digestion trial was conducted to determine the protein requirement of collared peccaries (Pecari tajacu). In a 4 * 4 Latin square design, four captive adult male peccaries were fed four isoenergy diets containing four different levels of N (11.7, 16.3, 22.8, and 26.7 g N/kg of dry matter-DM). After 15 days of adaptation, a total collection of feces and urine was carried out for five consecutive days. Regression analyses between N intake and N in feces and urine allowed to calculate the metabolic fecal nitrogen (MFN = 2.3 g N/kg of dry matter intake-DMI) and daily endogenous urinary N (EUN = 185 mg N/kg0.75). Likewise, by regression analyses between consumption of nitrogen and the nitrogen balance (NB = N ingested - N excreted, mg N/kg0.75), a daily requirement of 514 mg N/kg0.75 was calculated. Therefore, if food intake is unrestricted, collared peccaries require a minimum in their diet of about 5.4% crude protein on DM basis. These values are almost as low as those found for browsing and frugivorous wild ruminants, which reinforce the proposition that peccaries' digestive physiology is nearer to that of domestic and wild ruminants than domestic pigs. This relatively low protein requirement of collared peccary and its great ability to digest protein reveal the relevance of the forestomach for the species on nitrogen/protein metabolism and allow the use of diets with lower crude protein levels than the commercial ones used for the domestic pig, which reduces feed costs. PMID- 28623603 TI - Endocrine surgery: an update. PMID- 28623604 TI - Craniospinal irradiation for treatment of metastatic pediatric low-grade glioma. AB - Patients with disseminated pediatric low-grade glioma (LGG) initially treated with chemotherapy frequently experience disease progression, with 5-year event free survival (EFS) of <20% and 10-year overall survival (OS) of approximately 70%. This study aimed to describe outcomes of metastatic pediatric LGG treated with craniospinal irradiation (CSI). A retrospective study was performed of all patients with metastatic pediatric LGG treated with CSI at a single institution. EFS was defined as survival without disease progression or secondary high-grade glioma. Dates were counted from the first day of irradiation. We identified 12 eligible patients; all had histologically confirmed LGG. Metastatic disease was present at initial presentation in 9 patients. The median age at CSI was 9.3 years. The 5-year EFS and OS were 71% (95% CI 33.7-89.5) and 70% (95% CI 32.9 89.2), respectively. No deaths were observed among the patients who underwent subtotal resection (STR) before radiotherapy, whereas 3 patients who had undergone biopsy died (OS log-rank P = 0.01). EFS may be longer among patients who underwent STR before RT (EFS log-rank P = 0.03), with a hazard ratio for biopsy of 8.4 (vs. STR; 95% CI 0.8-84.0, P = 0.07). No patient experienced acute toxicity of grade 3 or higher. Patients with metastatic pediatric LGG treated with CSI experienced longer EFS than historical cohorts treated with chemotherapy alone, with similar OS. CSI may be considered in the management of metastatic pediatric LGG, particularly in older children experiencing progression after chemotherapy. PMID- 28623605 TI - Cathepsin C Aggravates Neuroinflammation Involved in Disturbances of Behaviour and Neurochemistry in Acute and Chronic Stress-Induced Murine Model of Depression. AB - Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0.5 mg/kg) and 6-week unpredictable chronic mild stress (UCMS) exposure to establish acute and chronic stress-induced depression model. We examined and compared the behavioural and proinflammatory cytokine alterations in serum and depression targeted brain areas of Cat C differentially expressed mice in stress, as well as indoleamine 2,3-dioxygenase (IDO) and 5-hydroxytryptamine (5HT) levels in brain. The results showed that Cat C overexpression (Cat C OE) promoted peripheral and central inflammatory response with significantly increased TNFalpha, IL-1beta and IL-6 in serum, hippocampus and prefrontal cortex, and resultant upregulation of IDO and downregulation of 5HT expression in brain, and thereby aggravated depression-like behaviours accessed by open field test, forced swim test and tail suspension test. In contrast, Cat C knockdown (Cat C KD) partially prevented inflammation, which may help alleviate the symptoms of depression in mice. To the best of our knowledge, we are the first to demonstrate that Cat C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression. PMID- 28623606 TI - MARCKS is Necessary for Oligodendrocyte Precursor Cell Maturation. AB - Oligodendrocyte precursor cell (OPC) development into myelinated oligodendrocytes demands vigorous membrane addition. Since myristoylated alanine-rich C-kinase substrate (MARCKS) reportedly contributes to Ras-associated protein (Rab)-10 associated vesicle insertion into neuronal membranes, we investigated the role of MARCKS in OPC maturation. We found that either knockdown of MARCKS or interruption of its interaction with Rab10 would cause a decrease of the cell membrane area during OPC development. Enhanced MARCKS phosphorylation by Nogo66 or myelin debris treatment inhibited OPC maturation, while its dephosphorylation by protein phosphatase 2 A activator D-erythro-sphingosine promoted OPC development in the presence of myelin debris. Our results demonstrated that MARCKS is involved in OPC maturation by interacting with Rab10. PMID- 28623607 TI - Presenilin-1 Targeted Morpholino Induces Cognitive Deficits, Increased Brain Abeta1-42 and Decreased Synaptic Marker PSD-95 in Zebrafish Larvae. AB - Presenilins are transmembrane proteases required for the proteolytic cleavage of Notch and also act as the catalytic core of the gamma-secretase complex, which is responsible for the final cleavage of the amyloid precursor protein into Amyloid beta (Abeta) peptides of varying lengths. Presenilin-1 gene (psen1) mutations are the main cause of early-onset autosomal-dominant Familial Alzheimer Disease. Elucidating the roles of Presenilin-1 and other hallmark proteins involved in Alzheimer's disease is crucial for understanding the disease etiology and underlying molecular mechanisms. In our study, we used a morpholino antisense nucleotide that targets exon 8 splicing site of psen1 resulting in a dominant negative protein previously validated to investigate behavioral and molecular effects in 5 days post fertilization (dpf) zebrafish larvae. Morphants showed specific cognitive deficits in two optomotor tasks and morphological phenotypes similar to those induced by suppression of Notch signaling pathway. They also had increased mRNA levels of neurog1 at 5 dpf, confirming the potential interaction of Presenilin-1 and Notch in our model. We also evaluated levels of apoptotic markers including p53, PAR-4, Caspase-8 and bax-alpha and found only bax-a decreased at 5dpf. Western Blot analysis showed an increase in Abeta1-42 and a decrease in the selective post-synaptic marker PSD-95 at 5 dpf. Our data demonstrates that psen1 splicing interference induces phenotypes that resemble early-stage AD, including cognitive deficit, Abeta1-42 accumulation and synaptic reduction, reinforcing the potential contribution of zebrafish larvae to studies of human brain diseases. PMID- 28623608 TI - Gambling and the Reasoned Action Model: Predicting Past Behavior, Intentions, and Future Behavior. AB - Gambling is a serious concern for society because it is highly addictive and is associated with a myriad of negative outcomes. The current study applied the Reasoned Action Model (RAM) to understand and predict gambling intentions and behavior. Although prior studies have taken a reasoned action approach to understand gambling, no prior study has fully applied the RAM or used the RAM to predict future gambling. Across two studies the RAM was used to predict intentions to gamble, past gambling behavior, and future gambling behavior. In study 1 the model significantly predicted intentions and past behavior in both a college student and Amazon Mechanical Turk sample. In study 2 the model predicted future gambling behavior, measured 2 weeks after initial measurement of the RAM constructs. This study stands as the first to show the utility of the RAM in predicting future gambling behavior. Across both studies, attitudes and perceived normative pressure were the strongest predictors of intentions to gamble. These findings provide increased understanding of gambling and inform the development of gambling interventions based on the RAM. PMID- 28623609 TI - Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms. AB - Direct oral anticoagulants (DOACs) have been approved to treat and prevent thrombotic events. However, they are not yet labeled for use in patients with active cancers. Myeloproliferative neoplasms (MPNs) are clonal chronic disorders with a high incidence of thrombotic events, for which low-dose aspirin (LDA) is the standard drug treatment. We analyzed efficacy and safety of DOACs prescription in patients treated for MPNs. An MPN database, the OBENE registry, was established at our institution. We collected biological and clinical data from diagnosis to last follow-up for every patient included in this study. Thrombotic and hemorrhagic events and hematologic evolutions were categorized as major events in the database. Of the 760 MPN patients in the OBENE registry, 25 (3.3%) were treated with a DOAC. Median follow-up duration was 2.1 years (0.12 4.3 years). The reasons for prescribing DOACs were atrial fibrillation and thrombotic events for 13 and 12 patients, respectively. We only observed one thrombotic event (4%) and three major hemorrhagic events (12%). A case-control study did not detect a significant difference in thrombotic or hemorrhagic events in patients treated with LDA and DOACs. These preliminary results suggest that DOACs may be highly efficient and safe for use in MPN patients. PMID- 28623610 TI - A Singular Role of IK1 Promoting the Development of Cardiac Automaticity during Cardiomyocyte Differentiation by IK1 -Induced Activation of Pacemaker Current. AB - The inward rectifier potassium current (IK1) is generally thought to suppress cardiac automaticity by hyperpolarizing membrane potential (MP). We recently observed that IK1 could promote the spontaneously-firing automaticity induced by upregulation of pacemaker funny current (If) in adult ventricular cardiomyocytes (CMs). However, the intriguing ability of IK1 to activate If and thereby promote automaticity has not been explored. In this study, we combined mathematical and experimental assays and found that only IK1 and If, at a proper-ratio of densities, were sufficient to generate rhythmic MP-oscillations even in unexcitable cells (i.e. HEK293T cells and undifferentiated mouse embryonic stem cells [ESCs]). We termed this effect IK1-induced If activation. Consistent with previous findings, our electrophysiological recordings observed that around 50% of mouse (m) and human (h) ESC-differentiated CMs could spontaneously fire action potentials (APs). We found that spontaneously-firing ESC-CMs displayed more hyperpolarized maximum diastolic potential and more outward IK1 current than quiescent-yet-excitable m/hESC-CMs. Rather than classical depolarization pacing, quiescent mESC-CMs were able to fire APs spontaneously with an electrode-injected small outward-current that hyperpolarizes MP. The automaticity to spontaneously fire APs was also promoted in quiescent hESC-CMs by an IK1-specific agonist zacopride. In addition, we found that the number of spontaneously-firing m/hESC CMs was significantly decreased when If was acutely upregulated by Ad-CGI-HCN infection. Our study reveals a novel role of IK1 promoting the development of cardiac automaticity in m/hESC-CMs through a mechanism of IK1-induced If activation and demonstrates a synergistic interaction between IK1 and If that regulates cardiac automaticity. PMID- 28623611 TI - Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation. AB - Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model. Beginning from day 100, mice were treated with deferiprone (DFP), a ferric chelator that is able to cross the blood-brain barrier and is currently used in clinics as treatment for hemosiderosis. Our paradigm resulted in an impairment of the learning abilities in the rotarod task and the novel object recognition test. DFP treatment significantly improved the performance in both tasks. Although this was not accompanied by alterations in aSyn aggregation, our results support DFP as possible therapeutic option in PD. PMID- 28623612 TI - Challenges in longitudinal exposure-response modeling of data from complex study designs: a case study of modeling CDAI score for ustekinumab in patients with Crohn's disease. AB - Informative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn's disease, where a commonly used composite endpoint Crohn's Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and other response driven dose adjustments. This manuscript illustrates the complexities of exposure-response modeling of such composite endpoint data through a latent-variable based Indirect Response model framework for CDAI scores using data from three phase III trials of ustekinumab in patients with moderate-to-severe Crohn's Disease. Visual predictive check was used to evaluate model performance. Potential impacts of the study design on model development and evaluation of the E-R relationship in the induction and maintenance phases of treatment are discussed. Certain biases appeared difficult to overcome, and an autocorrelated residual error model was found to provide improvement. PMID- 28623614 TI - AbobotulinumtoxinA: A Review in Pediatric Lower Limb Spasticity. AB - AbobotulinumtoxinA (Dysport(r)) is currently the only botulinum toxin A formulation approved by the US FDA for the treatment of lower limb spasticity in pediatric patients aged >=2 years. Intramuscular abobotulinumtoxinA was approved based on the results of a pivotal phase 3 trial in children with lower limb spasticity due to cerebral palsy. In this trial, a single treatment cycle with abobotulinumtoxinA 10-15 U/kg/leg injected into the gastrocnemius and soleus muscles significantly improved ankle plantar flexor muscle tone (primary endpoint), with abobotulinumtoxinA recipients showing a significant response to treatment relative to placebo. AbobotulinumtoxinA treatment also improved spasticity grade. The improvements in muscle tone and spasticity were associated with an improved ability to attain functional goals. Clinical benefits of abobotulinumtoxinA treatment lasted for 16-22 weeks in most patients, and were maintained with multiple treatment cycles during 1 year in an open-label extension study. AbobotulinumtoxinA was generally well tolerated, with a relatively low incidence of treatment-related adverse events. In summary, abobotulinumtoxinA is an effective and generally well tolerated treatment option for children with lower limb spasticity. PMID- 28623615 TI - Use of Antipsychotic Drugs by Elderly Primary Care Patients and the Effects of Medication Reviews: A Cross-Sectional Study in Sweden. AB - BACKGROUND: Antipsychotics form a class of drugs that should be used with caution among elderly people because of a high risk of adverse events. Despite the risks and modest effects, their use is estimated to be high, especially in nursing homes. OBJECTIVE: The aim was to explore the effects of medication reviews on antipsychotic drug use for elderly primary care patients and describe the extent of, and reasons for, the prescription of antipsychotics. METHODS: In this cross sectional study in primary care in Skane, Sweden, patients aged >=75 years living in nursing homes or in their own homes with home care were included. The effects of medication reviews were documented, as were the use of antipsychotics and the differences in characteristics between patients receiving or not receiving antipsychotics. RESULTS: A total of 1683 patients aged 87.6 (+/-5.7) years were included in the analysis. Medication reviews reduced the use of antipsychotics by 23% (p < 0.001) in this study. Of the 206 patients using antipsychotics, 43% (n = 93) had an approved indication, while for 15% (n = 32) the indication was not given. Antipsychotic drug use was more common with increasing number of drugs (p = 0.001), and in nursing home residents (p < 0.01). It was also more frequent in patients with cognitive impairment, depressive symptoms or sleeping problems. CONCLUSION: The use of antipsychotic drugs is high in elderly patients in nursing homes. They are often given for indications that are not officially approved or are poorly documented. Medication reviews appear to offer one useful strategy for reducing excessive use of these drugs. PMID- 28623613 TI - Assessment of Metabolic Flexibility by Means of Measuring Blood Lactate, Fat, and Carbohydrate Oxidation Responses to Exercise in Professional Endurance Athletes and Less-Fit Individuals. AB - BACKGROUND: Increased muscle mitochondrial mass is characteristic of elite professional endurance athletes (PAs), whereas increased blood lactate levels (lactatemia) at the same absolute submaximal exercise intensities and decreased mitochondrial oxidative capacity are characteristics of individuals with low aerobic power. In contrast to PAs, patients with metabolic syndrome (MtS) are characterized by a decreased capacity to oxidize lipids and by early transition from fat to carbohydrate oxidation (FATox/CHOox), as well as elevated blood lactate concentration [La-] as exercise power output (PO) increases, a condition termed 'metabolic inflexibility'. OBJECTIVE: The aim of this study was to assess metabolic flexibility across populations with different metabolic characteristics. METHODS: We used indirect calorimetry and [La-] measurements to study the metabolic responses to exercise in PAs, moderately active individuals (MAs), and MtS individuals. RESULTS: FATox was significantly higher in PAs than MAs and patients with MtS (p < 0.01), while [La-] was significantly lower in PAs compared with MAs and patients with MtS. FATox and [La-] were inversely correlated in all three groups (PA: r = -0.97, p < 0.01; MA: r = -0.98, p < 0.01; MtS: r = -0.92, p < 0.01). The correlation between FATox and [La-] for all data points corresponding to all populations studied was r = -0.76 (p < 0.01). CONCLUSIONS: Blood lactate accumulation is negatively correlated with FATox and positively correlated with CHOox during exercise across populations with widely ranging metabolic capabilities. Because both lactate and fatty acids are mitochondrial substrates, we believe that measurements of [La-] and FATox rate during exercise provide an indirect method to assess metabolic flexibility and oxidative capacity across individuals of widely different metabolic capabilities. PMID- 28623616 TI - Cyclosporine A-Mediated IL-6 Expression Promotes Neural Induction in Pluripotent Stem Cells. AB - Differentiation of pluripotent stem cells (PSCs) to neural lineages has gathered huge attention in both basic research and regenerative medicine. The major hurdle lies in the efficiency of differentiation and identification of small molecules that facilitate neurogenesis would partly circumvent this limitation. The small molecule Cyclosporine A (CsA), a commonly used immunosuppressive drug, has been shown to enhance in vivo neurogenesis. To extend the information to in vitro neurogenesis, we examined the effect of CsA on neural differentiation of PSCs. We found CsA to increase the expression of neural progenitor genes during early neural differentiation. Gene silencing approach revealed CsA-mediated neural induction to be dependent on blocking the Ca2+-activated phosphatase calcineurin (Cn) signaling. Similar observation with FK506, an independent inhibitor of Cn, further strengthened the necessity of blocking Cn for enhanced neurogenesis. Surprisingly, mechanistic insight revealed Cn-inhibition dependent upregulation of IL-6 protein to be necessary for CsA-mediated neurogenesis. Together, these findings provide a comprehensive understanding of the role of CsA in neurogenesis, thus suggesting a method for obtaining large numbers of neural progenitors from PSCs for possible transplantation. PMID- 28623617 TI - Decrease in Adult Neurogenesis and Neuroinflammation Are Involved in Spatial Memory Impairment in the Streptozotocin-Induced Model of Sporadic Alzheimer's Disease in Rats. AB - Early impairments in cerebral glucose metabolism and insulin signaling pathways may participate in the pathogenesis of the sporadic form of Alzheimer's disease (sAD). Intracerebroventricular (ICV) injections of low doses of streptozotocin (STZ) are used to mimic sAD and study these alterations in rodents. Streptozotocin causes impairments in insulin signaling and has been reported to trigger several alterations in the brain, such as oxidative stress, neuroinflammation, and dysfunctions in adult neurogenesis, which may be involved in cognitive decline and are features of human AD. The aim of the present study was to assess the influence of neuroinflammation on the process of adult neurogenesis and consequent cognitive deficits in the STZ-ICV model of sAD in Wistar rats. Streptozotocin caused an acute and persistent neuroinflammatory response, reflected by reactive microgliosis and astrogliosis in periventricular areas and the dorsal hippocampus, accompanied by a marked reduction of the proliferation of neural stem cells in the dentate gyrus of the hippocampus and subventricular zone. Streptozotocin also reduced the survival, differentiation, and maturation of newborn neurons, resulting in impairments in short-term and long-term spatial memory. These results support the hypothesis that neuroinflammation has a detrimental effect on neurogenesis, and both neuroinflammation and impairments in neurogenesis contribute to cognitive deficits in the STZ-ICV model of sAD. PMID- 28623618 TI - Endothelin-1 Decreases Excitability of the Dorsal Root Ganglion Neurons via ETB Receptor. AB - Endothelin-1 (ET-1) has been demonstrated to be a pro-nociceptive as well as an anti-nociceptive agent. However, underlying molecular mechanisms for these pain modulatory actions remain unclear. In the present study, we evaluated the ability of ET-1 to alter the nociceptor excitability using a patch clamp technique in acutely dissociated rat dorsal root ganglion (DRG) neurons. ET-1 produced an increase in threshold current to evoke an action potential (I threshold) and hyperpolarization of resting membrane potential (RMP) indicating decreased excitability of DRG neurons. I threshold increased from 0.25 +/- 0.08 to 0.33 +/- 0.07 nA and hyperpolarized RMP from -57.51 +/- 1.70 to -67.41 +/- 2.92 mV by ET-1 (100 nM). The hyperpolarizing effect of ET-1 appears to be orchestrated via modulation of membrane conductances, namely voltage-gated sodium current (I Na) and outward transient potassium current (I KT). ET-1, 30 and 100 nM, decreased the peak I Na by 41.3 +/- 6.8 and 74 +/- 15.2%, respectively. Additionally, ET-1 (100 nM) significantly potentiated the transient component (I KT) of the potassium currents. ET-1-induced effects were largely attenuated by BQ-788, a selective ETBR blocker. However, a selective ETAR blocker BQ-123 did not alter the effects of ET-1. A selective ETBR agonist, IRL-1620, mimicked the effect of ET-1 on I Na in a concentration-dependent manner (IC50 159.5 +/- 92.6 MUM). In conclusion, our results demonstrate that ET-1 hyperpolarizes nociceptors by blocking I Na and potentiating I KT through selective activation of ETBR, which may represent one of the underlying mechanisms for reported anti-nociceptive effects of ET-1. PMID- 28623619 TI - Development of Chinese medicine research in Hong Kong, China in last decade. PMID- 28623620 TI - Chinese medicine practice and research in Hong Kong, China: Current status and future direction. PMID- 28623621 TI - Development of integrative medicine in Hong Kong, China. PMID- 28623622 TI - Retrospect and prospect of higher education in Chinese medicine in Hong Kong, China. PMID- 28623623 TI - Self-reported race and ethnicity of US biobank participants compared to the US Census. AB - Precision medicine envisions a future of effective diagnosis, treatment, and prevention grounded in precise understandings of the genetic and environmental determinants of disease. Given that the original genome-wide association studies represented a predominately European White population, and that diversity in genomic studies must account for genetic variation both within and across racial categories, new research studies are at a heightened risk for inadequate representation. Currently biological samples are being made available for sequencing in biobanks across the USA, but the diversity of those samples is unknown. The aims of this study were to describe the types of recruitment and enrollment materials used by US biobanks and the diversity of the samples contained within their collection. Biobank websites and brochures were evaluated for reading level, health literacy, and factors known to encourage the recruitment of minorities, such as showing pictures of diverse populations. Biobank managers were surveyed by mail on the methods and materials used for enrollment, recruitment, consent, and the self-reported race/ethnicity of biobank participants. From 51 US biobanks (68% response rate), recruitment and enrollment materials were in English only, and most of the websites and brochures exceeded a fifth-grade reading level. When compared to the 2015 US Census, self-reported race/ethnicity of participants was not significantly different for Whites (61%) and blacks (13%). The percentages were significantly lower for Hispanics and Latinos (18 vs. 7%, p = 0.00) and Hawaiian/Pacific Islanders (0.2 vs. 0.01%; p = 0.01) and higher for Asians (13 vs. 5%, p = 0.01). Materials for recruitment predominantly in English may limit participation by underrepresented populations. PMID- 28623624 TI - Effect of Parenting and Peer Stressors on Cognitive Vulnerability and Risk for Depression among Youth. AB - Parenting behaviors influence clinical depression among youth, but little is known about the developmental processes that may account for this association. This study investigated whether parenting is associated with the onset of clinical depression and depressive symptoms through negative cognitive style, particularly under conditions of high exposure to stressors, in a community sample of children and adolescents (N = 275; 59% girls). Observational methods were used to assess positive and negative parenting during a laboratory social evaluative stressor task. Depressive symptoms and clinical depressive episodes were repeatedly assessed over an 18-month prospective follow-up period. Results supported a conditional indirect effect in which low levels of observed positive parenting during a youth stressor task were indirectly associated with an increased likelihood of experiencing an episode of depression and worsening depressive symptoms over the course of the study through youth negative cognitive style, but only for youth who also experienced a high number of peer stressors. These findings elucidate mechanisms through which problematic parenting may contribute to risk for the development of clinical depression during the transition into and across adolescence. Implications for depression interventions are discussed. PMID- 28623625 TI - Switching Between Reference Biologics and Biosimilars for the Treatment of Rheumatology, Gastroenterology, and Dermatology Inflammatory Conditions: Considerations for the Clinician. AB - PURPOSE OF REVIEW: Biosimilars of the reference biologic therapeutics infliximab, etanercept, adalimumab, and rituximab are entering the market. Clinical and real world data on the effects of reference -> biosimilar switching are limited. This review was carried out to assess the current body of switching data. RECENT FINDINGS: Fifty-three switching studies were identified. Infliximab publications covered CT-P13 (25 studies), SB2 (1), infliximab NK (1), and unspecified infliximab biosimilars (2). Etanercept publications covered SB4 (2) and GP2015 (2). Adalimumab publications covered ABP 501 (2) and SB5 (1). Rituximab publications covered CT-P10 (1). Efficacy and safety data generally showed no differences between patients who switched treatments versus those who did not. No differences were seen pre- and post-switch. Immunogenicity data were presented in 19/37 (51%) studies. Additional data from switching studies of these therapies are still required, as is continuing pharma-covigilance. Switching should remain a case-by-case clinical decision made by the physician and patient on an individual basis supported by scientific evidence. PMID- 28623626 TI - Patient-specific simulation: a new avenue to be explored. PMID- 28623627 TI - Clozapine-Induced Gastrointestinal Hypomotility: A 22-Year Bi-National Pharmacovigilance Study of Serious or Fatal 'Slow Gut' Reactions, and Comparison with International Drug Safety Advice. AB - INTRODUCTION: Clozapine is the preferred antipsychotic for treatment-resistant schizophrenia, but has significant adverse effects, including gastrointestinal hypomotility or 'slow gut', which may result in severe constipation, ileus, bowel obstruction, and even death. These gastrointestinal effects remain inadequately recognized. METHODS: We reviewed all reports of serious clozapine-induced gastrointestinal hypomotility (CIGH) submitted to the Australian Therapeutic Goods Administration and New Zealand Pharmacovigilance Centre between 1992 and 2013. We extracted relevant demographic, clinical, and outcome data and derived a numerator from clozapine registries. We examined whether clozapine drug safety information in Australia, New Zealand, the US, and the UK was adequate and consistent with pharmacoepidemiologic evidence. RESULTS: A total of 43,132 people commenced clozapine over the study period. 160 were reported as having serious gastrointestinal hypomotility with clozapine the suspected cause (37/10,000 clozapine users). Of these, 66.3% were male, age range was 17-76 years, clozapine dose range 25-1000 mg/day (mean 439 mg/day) and median duration of clozapine treatment 2.5 years. Few had received laxatives. At least 29 patients died (7/10,000 clozapine users), a reported case fatality rate of 18%. The CIGH prevalence, while similar to other smaller studies, differs significantly from clozapine prescribing information issued by regulators and pharmaceutical companies, none of which mention CIGH, and which report serious gastrointestinal complications at rates of <1/10,000, almost a 40-fold difference. CONCLUSION: This is the largest study to date of serious CIGH. The reported prevalence of serious CIGH was 37/10,000, a likely underestimation of true prevalence. Current prescribing guidelines provide inadequate information on CIGH. This may be contributing to poor awareness and high associated morbidity and mortality. It is time regulators and manufacturers update their guidance. PMID- 28623628 TI - Does Patient Preference Measurement in Decision Aids Improve Decisional Conflict? A Randomized Trial in Men with Prostate Cancer. AB - BACKGROUND: Shared decision making (SDM) has been advocated as an approach to medical decision making that can improve decisional quality. Decision aids are tools that facilitate SDM in the context of limited physician time; however, many decision aids do not incorporate preference measurement. OBJECTIVES: We aim to understand whether adding preference measurement to a standard patient educational intervention improves decisional quality and is feasible in a busy clinical setting. METHODS: Men with incident localized prostate cancer (n = 122) were recruited from the Greater Los Angeles Veterans Affairs (VA) Medical Center urology clinic, Olive View UCLA Medical Center, and Harbor UCLA Medical Center from January 2011 to May 2015 and randomized to education with a brochure about prostate cancer treatment or software-based preference assessment in addition to the brochure. Men undergoing preference assessment received a report detailing the relative strength of their preferences for treatment outcomes used in review with their doctor. Participants completed instruments measuring decisional conflict, knowledge, SDM, and patient satisfaction with care before and/or after their cancer consultation. RESULTS: Baseline knowledge scores were low (mean 62%). The baseline mean total score on the Decisional Conflict Scale was 2.3 (+/ 0.9), signifying moderate decisional conflict. Men undergoing preference assessment had a significantly larger decrease in decisional conflict total score (p = 0.023) and the Perceived Effective Decision Making subscale (p = 0.003) post consult compared with those receiving education only. Improvements in satisfaction with care, SDM, and knowledge were similar between groups. CONCLUSIONS: Individual-level preference assessment is feasible in the clinic setting. Patients with prostate cancer who undergo preference assessment are more certain about their treatment decisions and report decreased levels of decisional conflict when making these decisions. PMID- 28623630 TI - Persistency of artificial aeration at hypertrophic Lake Tuusulanjarvi: A sociohistorical analysis. AB - With present-day scientific evidence challenging the efficiency of artificial aeration as an effective restoration method for eutrophicated lakes, our sociohistorical investigation traces the reasons for the persistent support for this method in Finland, where about one hundred lakes are subject to this treatment. Our study employed the concepts of technological path and aeration frame to analyze the extensive restoration and aeration history of the hypertrophic Tuusulanjarvi in southern Finland. Continuously aerated since 1972, it has the longest history of aeration in Finland. Qualitative analysis of documentary and archival sources revealed that the longstanding preference for aeration in the context of increasing scientific controversy was based on its functional versatility and seemingly unproblematic applicability in regard to shifting emphasis and goal setting of restoration. Additionally, the stability of the aeration frame has been supported by the practical and emotional attachment of local residents to lake restoration, particularly aeration, and finally the problems and contradicting interests related to alternative restoration methods. PMID- 28623629 TI - Predicting EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) Utilities from Older People's Quality of Life Brief Questionnaire (OPQoL-Brief) Scores. AB - BACKGROUND AND OBJECTIVE: Economic evaluation of healthcare treatment and services targeted at older people requires measurement of utility-based quality of-life outcomes but it is not always possible to collect such outcome data. It may, however, be possible to estimate these outcomes using non-utility measures of quality of life where the latter have been collected. The objective of this study was to develop a regression-based algorithm to map a non-utility-based outcome, the Older People's Quality of Life brief questionnaire (OPQoL-brief), onto a utility-based outcome, the EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L). METHODS: The estimation sample comprised 330 community-based Australian older people (>65 years), while the validation sample consisted of 293 older people from a separate study. Six regression techniques were employed to estimate utilities from OPQoL-brief. The predictive accuracy of 54 regression models (six regression techniques * nine model specifications) was assessed using six criteria: mean absolute error (MAE), root mean squared error (RMSE), correlation, distribution of predicted utilities, distribution of residuals, and proportion of predictions with absolute errors <0.05. RESULTS: The 54 regression models predicted EQ-5D-5L utilities that performed differently when assessed by the six criteria. However, best results were obtained from an ordinary least squares (OLS) model where all 13 OPQoL-brief items were included as continuous variables (OLS 4). RMSE and MAE estimates for this model (0.2201 and 0.1638, respectively) were within the range of published estimates. CONCLUSIONS: It is possible to predict valid utilities from OPQoL-brief using regression methods. We recommend OLS model (4) for this exercise. PMID- 28623631 TI - Effect of in vitro enzymatic degradation on 3D printed poly(epsilon-caprolactone) scaffolds: morphological, chemical and mechanical properties. AB - BACKGROUND: In recent years, the tissue engineering (TE) field has significantly benefited from advanced techniques such as additive manufacturing (AM), for the design of customized 3D scaffolds with the aim of guided tissue repair. Among the wide range of materials available to biomanufacture 3D scaffolds, poly(epsilon caprolactone) (PCL) clearly arises as the synthetic polymer with the greatest potential, due to its unique properties - namely, biocompatibility, biodegradability, thermal and chemical stability and processability. This study aimed for the first time to investigate the effect of pore geometry on the in vitro enzymatic chain cleavage mechanism of PCL scaffolds manufactured by the AM extrusion process. METHODS: Methods: Morphological properties of 3D printed PCL scaffolds before and after degradation were evaluated using Scanning Electron Microscopy (SEM) and micro-computed tomography (MU-CT). Differential Scanning Calorimetry (DSC) was employed to determine possible variations in the crystallinity of the scaffolds during the degradation period. The molecular weight was assessed using Size Exclusion Chromatography (SEC) while the mechanical properties were investigated under static compression conditions. RESULTS: Morphological results suggested a uniform reduction of filament diameter, while increasing the scaffolds' porosity. DSC analysis revealed and increment in the crystallinity degree while the molecular weight, evaluated through SEC, remained almost constant during the incubation period (25 days). Mechanical analysis highlighted a decrease in the compressive modulus and maximum stress over time, probably related to the significant weight loss of the scaffolds. CONCLUSIONS: All of these results suggest that PCL scaffolds undergo enzymatic degradation through a surface erosion mechanism, which leads to significant variations in mechanical, physical and chemical properties, but which has little influence on pore geometry. PMID- 28623632 TI - Thermal conductivity of different colored compomers. AB - BACKGROUND: Compomers are mostly used in primary dentition. The thermal conductivity properties of traditional or colored compomers have not been investigated in detail so far. The aim of this in vitro study was to assess and compare the thermal conductivities of traditional and colored compomers. METHOD: Two sets of compomers - namely, Twinky Star (available in berry, lemon, green, silver, blue, pink, gold and orange shades) and Dyract Extra (available in B1, A3 and A2 shades) - were included in this study. All of the traditional and colored compomers were applied to standard molds and polymerized according to the manufacturers' instructions. Three samples were prepared from each compomer. Measurements were conducted using a heat conduction test setup, and the coefficient of heat conductivity was calculated for each material. The heat conductivity coefficients were statistically analyzed using Kruskal-Wallis and Duncan tests. Uncertainty analysis was also performed on the calculated coefficients of heat conductivity. RESULTS: Statistically significant differences were found (p<0.05) between the thermal conductivity properties of the traditional and colored compomers examined. Among all of the tested compomers, the silver shade compomer exhibited the highest coefficient of heat conductivity (p<0.05), while the berry shade exhibited the lowest coefficient (p<0.05). Uncertainty analyses revealed that 6 out of 11 samples showed significant differences. CONCLUSIONS: The silver shade compomer should be avoided in deep cavities. The material properties could be improved for colored compomers. PMID- 28623633 TI - Biodegradable intramedullary nails reinforced with carbon and alginate fibers: In vitro and in vivo biocompatibility. AB - BACKGROUND: Commonly, intramedullary nails are made of nondegradable materials, and hence they need to be removed once the bone fracture is healed. We propose a novel composite material consisting of poly-L-lactide matrix modified with carbon and alginate fibers to be used for biodegradable intramedullary fixation. The aim of this study was to make in vitro and in vivo biocompatibility assessments. METHODS: In the in vitro conditions, biocompatibility of biomaterials was compared using normal human osteoblasts. After 3 and 7 days, cytotoxicity, viability and proliferation tests were performed, as well as cell morphology and adhesion observations. In the in vivo experiments, Californian rabbits (approx. 9 months old) were used. The composite nails and controls (Kirschner wires) were used for fixation of distal femoral osteotomy. The evaluation was made on the basis of clinical observations, radiographs taken after 2, 4, 6 and 8 weeks post implantation, and macroscopic and histological observations. RESULTS: Cell tests indicated that both modifiers had a positive influence on cell viability. Biodegradable composite nails led to bony union when used for fixation of distal diaphysis osteotomy in rabbits. Histological analysis showed that the initial focal necrosis should be fully compensated for by the osteoblast proliferation and trabeculae formation. CONCLUSIONS: Both in vitro and in vivo tests confirmed biocompatibility and potential applicability of novel biodegradable intramedullary nails modified with long carbon and alginate fibers for osteosynthesis of bone epiphysis. PMID- 28623634 TI - Perfusion bias in the apparent diffusion coefficient measurements of diffusion weighted magnetic resonance imaging. PMID- 28623635 TI - Italian cultural adaptation of the Memorial Anxiety for Prostate Cancer scale for the population of men on active surveillance. AB - PURPOSE: The Memorial Anxiety Scale for Prostate Cancer (MAX-PC) is a self-report questionnaire that was developed in English to assess prostate cancer (PCa) related anxiety. The aim of this study was to perform a cultural adaptation for the tool to be used in a population of Italian men on active surveillance (AS). METHODS: A total of 222 patients with localized PCa who were recruited for the Prostate Cancer Research International: Active Surveillance (PRIAS) protocol completed the MAX-PC. Psychometric analysis was performed to assess reliability indexes. A Spearman rank correlation was used to test the association between MAX PC scales and other questionnaires and was used for longitudinal analysis. RESULTS: Cronbach coefficients and item to total correlation demonstrated good internal consistency. Some items related to the repetition of the PSA test showed a large floor effect and thus were poorly effective in measuring anxiety for PSA testing in patients on AS. Confirmatory factor analysis partly failed to reproduce the structure of the original version. A modified version of MAX-PC, excluding the items with a large floor effect, was thus considered for AS patients. Factor analysis on this version demonstrated considerable consistency with the presence of 3 subscales: anxiety related to PCa, anxiety related to PSA testing, and anxiety related to the fear of tumor progression. Longitudinal analysis showed an acceptable validity over time. The MAX-PC was correlated with the anxious preoccupation subscale of the Mini-Mental Adjustment to Cancer scale. CONCLUSIONS: A slightly modified version of the MAX-PC was developed for use in Italian men on AS. This instrument appears to be a valid and reliable tool that measures anxiety in men with PCa who are enrolled in AS programs. PMID- 28623636 TI - Eleven-year management of prostate cancer patients on active surveillance: what have we learned? AB - PURPOSE: To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification. METHODS: In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage <=T2a, initial prostate specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) <=3 + 3 (both protocols); <=25% positive cores with a maximum core length containing cancer <=50% (SAINT); and <=2 positive cores and PSA density <0.2 ng/mL/cm3 (PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model. RESULTS: A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001). CONCLUSIONS: Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology. PMID- 28623637 TI - Pure small cell recurrent prostate cancer developing syndrome of inappropriate antidiuretic hormone secretion. AB - PURPOSE: Pure small cell neuroendocrine carcinoma of the prostate is a rare entity characterized by a poor prognosis due to early metastatic spread as well as resistance to treatment. Considering its increasing occurrence, clinicians should be aware of its aggressive behavior, the relevance of an early diagnosis, and proper management. METHODS: A 71-year-old man treated with brachytherapy for localized low-risk prostate cancer developed widespread disease 7 years later with a prostate-specific antigen-negative neuroendocrine small cell phenotype. He was also diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH) soon after starting chemotherapy. RESULTS: A substantial radiologic and clinical response to chemotherapy was observed and the paraneoplastic SIADH was successfully treated with oral vaptan therapy. CONCLUSIONS: Secondary small cell prostate carcinoma is an underestimated entity with high sensitivity to chemotherapy, although a standard treatment has not yet been defined. Moreover, oral vaptans demonstrated prompt efficacy and simple management in correcting SIADH-related hyponatremia. PMID- 28623638 TI - Urokinase-containing locking solution in the prevention of dialysis catheter dysfunction: a double blind randomized controlled trial. AB - INTRODUCTION: The prophylactic use of recombinant tissue plasminogen activator once weekly reduces the incidence rate of tunneled cuffed catheter (TCC) malfunction and bacteremia as compared to the exclusive use of heparin as locking solution. Restricting the use of prophylactic thrombolytic agents to patients with a history of thrombotic TCC malfunction could be more cost effective. We conduct a multicenter, double-blind, randomized controlled trial and test the hypothesis that weekly use of urokinase lock will reduce the incidence of thrombotic malfunction by 50% in prevalent hemodialysis patients with a history of thrombotic malfunction. METHODS: Patients with a history of at least two separate TCC thrombotic dysfunctions treated with urokinase lock during the 6 months preceding inclusion are recruited in eight Belgian dialysis units. Patients are randomized in two groups: the control group receiving TaurolockTM HEP500 (heparin 500 IU/mL, taurolidine, citrate 4%) after each hemodialysis session and the treatment group receiving Taurolock-U 25,000 (urokinase 25,000, taurolidine, citrate 4%) once a week and the standard Taurolock-HEP500 at the end of the two others sessions. The primary outcome is the incidence rate of TCC thrombotic dysfunction defined by the use of urokinase. The secondary outcomes are the incidence rate of TCC removal and systemic thrombolysis. For the study, both patients and healthcare staff are blinded to treatment allocation. CONCLUSIONS: The present trial is the first to investigate the effect of Taurolock-U 25,000 catheter lock once a week as secondary prevention in hemodialysis patients with the highest risk of TCC-related thrombotic dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02036255. PMID- 28623639 TI - Anemia after continuous-flow left ventricular assist device implantation: characteristics and implications. AB - BACKGROUND: Anemia is common in patients with heart failure and is associated with adverse outcomes. Management of anemia in CF-LVAD patients is not well studied. Our purpose is to characterize and identify the etiology of anemia in CF LVAD patients. Secondary objectives are to describe the effect of CF-LVAD on pre existing anemia and assess its impact after CF-LVAD support. METHODS: Cross sectional study from January to July 2015 of ambulatory patients supported with a CF-LVAD for at least 6-months that presented with hemoglobin <12 g/dL and no recent gastrointestinal bleeding. Patients were classified as iron-deficient and non-iron-deficient and compared. Additionally, a retrospective analysis of 116 consecutive patients who underwent CF-LVAD from 2008 to 2013 with reported hemoglobin at 6 months as outpatients were divided into anemic or non-anemic and compared. RESULTS: In our cross-sectional cohort, iron deficiency was the most common cause of anemia. Notably, 49% of the iron-deficient patients were already on iron supplementation. In our retrospective cohort, 59% of the patients were anemic after 6 months of support. Anemic patients were older, had lower albumin, higher brain natriuretic peptide (BNP), worse renal function and New York Heart Association (NYHA) class. Anemia had a HR of 3.16 (95%CI 1.38-7.26) to predict a composite of 1-year death and HF readmissions, as well as HF-readmissions alone. CONCLUSIONS: The most common cause of anemia in our study was iron-deficiency; almost half of the patients were iron deficient despite treatment, suggesting that oral iron may not be sufficient to reverse anemia. Anemia regardless of etiology was associated with adverse outcomes. PMID- 28623640 TI - Creating a bioartificial kidney. PMID- 28623641 TI - Clinical expectations for the new bioactive treatments: greater well-being or longer survival? PMID- 28623642 TI - Particle spallation in a microfluidic blood processing device: the problem of using peristaltic pumps and silicon-based microfilters. AB - Peristaltic pumps rely on constant compression of elastomeric tubing from which particles may be shed, a phenomenon known as spallation. We studied spallated particles on microfluidic filtration devices with photolithographically prepared micron-level pore fields. Filtration of ultra-pure water through these pores was analyzed using either the usual peristaltic pump or a reciprocating pair of syringe pumps. Using syringe pumps, transmembrane pressure (TMP) values during filtration at 2.5 cm3/min revealed steady filtration for over 80 minutes at 2.3 mmHg. Using the peristaltic pump, TMP was never stable, increasing to approximately 11 mmHg during the first 10 minutes. Pore plugging was the culprit, evidenced by post-perfusion microphotography. PMID- 28623643 TI - Transplanted fibroblasts proliferate in host bronchial tissue and enhance bronchial anastomotic healing in a rodent model. AB - INTRODUCTION: Healing of airway anastomoses after preoperative irradiation can be a significant clinical problem. The augmentation of bronchial anastomoses with a fibroblast-seeded human acellular dermis (hAD) was shown to be beneficial, although the underlying mechanism remained unclear. Therefore, in this study we investigated the fate of the fibroblasts transplanted to the scaffold covering the anastomosis. MATERIAL AND METHODS: 32 Fisher rats underwent surgical anastomosis of the left main bronchus. In a 2 * 2 factorial design, they were randomized to receive preoperative irradiation of 20 Gy and augmentation of the anastomosis with a fibroblast-seeded transplant. Fibroblasts from subcutaneous fat of Fischer-344 rat were transduced retrovirally with tdTomato for cell tracking. After 7 and 14 days, animals were sacrificed and cell concentration of transplanted and nontransplanted fibroblasts in the hAD as well as in the bronchial tissue was measured using RT-PCR. RESULTS: Migration of transplanted fibroblasts from dermis to bronchus were demonstrated in both groups, irradiated and nonirradiated. In the irradiated groups, there was a cell count of 7 * 104 +/ 1 * 104 tomato+-fibroblasts in the bronchial tissue at day 7, rising to 1 * 105 +/- 1 * 104 on day 14 (p <0.0001). Tomato+-cell concentration in hAD increased from 6 * 103 +/- 1 * 103 at day 7 to 6 * 104 +/- 1 * 104 at day 14 (p <0.0001). In the nonirradiated groups, tomato+-cell concentration in bronchus was 4 * 103 +/- 1 * 103 on day 7 and 4 * 103 +/- 1 * 103 at day 14. In the hAD tomato+ cell concentration rising from 1 * 104 +/- 1 * 103 at day 7 to 2 * 104 +/- 3 * 103 cells at day 14 (p = 0.0028). CONCLUSIONS: Transplanted fibroblasts in the irradiated groups proliferate and migrate into the irradiated host bronchial tissue, but not in the nonirradiated groups. PMID- 28623644 TI - Increased AAA-TOB3 correlates with lymph node metastasis and advanced stage of lung adenocarcinoma. AB - BACKGROUND: This study was to investigate the differential mitochondrial protein expressions in human lung adenocarcinoma and provide preliminary data for further exploration of the carcinogenic mechanism. METHODS: Total proteins of A549 and 16HBE mitochondria were extracted through 2D polyacrylamide gel electrophoresis (2-DE). The differential mitochondria proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and were further confirmed by Western blot, immunoelectron microscopy and immunohistochemistry (IHC) in A549 cells as well as lung adenocarcinoma tissues. RESULTS: A total of 41 differentially expressed protein spots were found in A549 mitochondria. Of them, 15 proteins were highly expressed and 26 proteins were lowly expressed in the mitochondria of A549 (by more than 1.5 times). Among the 15 more highly expressed proteins, AAA-TOB3 (by more than 3 times) was highly expressed in the mitochondria of A549 compared with the 16HBE, by LC-MS/MS identification. High electron density and clear circular colloidal gold-marked AAA-TOB3 particles were observed in the A549 cells via immunoelectron microscopy. Besides, AAA-TOB3 was confirmed to be elevated in lung adenocarcinoma by Western blot and IHC. Moreover, increased AAA-TOB3 correlated with lymph node metastasis and advanced stage of lung adenocarcinoma (p<0.05). CONCLUSIONS: AAA-TOB3 was highly expressed in lung adenocarcinoma, and the up-regulation of AAA-TOB3 correlated with lymph node metastasis and advanced stage of lung adenocarcinoma, which suggested that it could serve as a potential molecular marker for lung adenocarcinoma. PMID- 28623645 TI - PSMB5 is associated with proliferation and drug resistance in triple-negative breast cancer. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by advanced disease stage and poor prognosis. Moreover, due to the lack of therapeutic markers, TNBC patients can't benefit fully from currently available targeted therapies. METHODS: To fully understand the molecular basis of TNBC, we used gene set enrichment analysis (GSEA) to screen out the most altered functional module in TNBC, from publicly available microarray data and studied the association of the candidate gene with TNBC development. RESULTS: We found that the proteasome was significantly activated in TNBC. As compared with other breast cancer subtypes and normal tissue, proteasome subunit beta 5 (PSMB5), the key regulator of proteasome function, was overexpressed in TNBC tissue and predictive of poor prognosis. Moreover, we also found that PSMB5 knockdown induced TNBC apoptosis and significantly enhanced cancer cell sensitivity to the chemotherapeutic agents bortezomib and paclitaxel. CONCLUSIONS: Our results suggest a potential role for PSMB5 as a biomarker and therapeutic target for TNBC. PMID- 28623646 TI - Prognostic and clinicopathological significance of CCAT2 in Chinese patients with various tumors. AB - BACKGROUND: Colon cancer-associated transcript 2 (CCAT2) as a long noncoding RNA (lncRNA) is overexpressed and plays a significant prognostic role in patients with tumors. The present study aimed to comprehensively evaluate the clinical value of CCAT2 in the Chinese population, as a potential prognostic marker in multiple cancers. METHODS: A systematic search of eligible studies was conducted in the PubMed, Web of Science, Cochrane Library, Wanfang and the China National Knowledge Infrastructure databases as of March 31, 2017. Approximately 1,711 tumor patients from 16 eligible studies were selected. Analyses of the pooled data were performed, and the odds ratio (OR) or hazard ratio (HR) and the 95% confidence interval (95% CI) were calculated and summarized to evaluate the strength of this association using a fixed- or random-effects model. RESULTS: Overall analyses showed that increased CCAT2 expression was associated with a higher risk of lymph node metastasis (LNM), an increased potential for distant metastasis (DM) and higher clinical stage (p<0.001 for LNM, p = 0.001 for DM, p<0.001 for clinical stage). HR and the 95% CI for overall survival (OS) were assessed to pool the effect size using a fixed-effects model. A significant association was observed between increased CCAT2 expression and poor OS (pooled HR = 1.91, 95% CI, 1.63-2.22, p<0.001). CONCLUSIONS: These results indicate that CCAT2 is a biomarker to predict tumor progression and a potential prognostic marker in multiple cancers. Additional well-designed clinical studies are needed to validate these findings. PMID- 28623647 TI - Expression of mTOR in Primary Pterygium and its Correlation with alpha-Smooth Muscle Actin. AB - PURPOSE: Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that has been shown to affect many cellular functions, such as cell growth, proliferation, and metabolism. However, there has been minimal focus on the expression of mTOR in pterygium. The purpose of this study was to investigate the expression of mTOR and the correlation between the levels of mTOR and alpha smooth muscle actin (alpha-SMA, a marker of transdifferentiation) in pterygium. METHODS: Primary pterygium samples from 28 patients and normal conjunctival samples from 16 patients were surgically removed and analyzed. The expression levels of mTOR and alpha-SMA in the excised specimens were assessed using immunohistochemistry and Western blotting. Furthermore, correlations between the mTOR and alpha-SMA expression levels were studied. RESULTS: The expression of mTOR and alpha-SMA was significantly higher in the pterygium tissues than in normal conjunctiva tissues. A significant positive correlation was detected between the number of mTOR-immunopositive fibroblasts and the number of alpha-SMA immunopositive fibroblasts (rho = 0.463, p = 0.0078). Additionally, mTOR expression was significantly correlated with alpha-SMA expression (rho = 0.269, p = 0.031) in pterygium. CONCLUSIONS: There was an increased expression of mTOR in pterygium samples compared to that in normal conjunctival tissues, with a positive correlation with alpha-SMA expression. These findings might be involved in the pathogenesis of pterygium. PMID- 28623648 TI - Systemic chemotherapy in muscle invasive and metastatic bladder cancer: present and future. AB - Bladder cancer is the most frequent among the urothelial tumors, and it is responsible for about 2% of all cancer mortality worldwide. The mainstay of chemotherapy treatment, both for muscle-invasive and metastatic disease, is cisplatin-based regimens. In recent years, ground-breaking results have been achieved with immunotherapy, which have led to important breakthroughs in the bladder cancer treatment scenario, with the approval of several new agents. New insights derive from a greater characterization of the tumor genome, which could lead to developing new therapies, more personalized, in the near future. PMID- 28623649 TI - Allium stent for the treatment of a malignant ureteral stenosis: A paradigmatic case. AB - OBJECTIVE: The aim of this study was to present a paradigmatic case where the new generation Allium URS stent was the optimal choice to treat a malignant ureteral stenosis. METHODS: We describe in detail all the steps of our surgery, performed on a 69-year-old patient with left hydronephrosis caused by lumbo-aortic nodal metastases compressing the ureter. The patient was intolerant to double-J stent due to strong irritative urinary symptoms. Allium URS stent was positioned under fluoroscopy in replacement of pre-existing double-J stent. RESULTS: Our approach was successful and irritative urinary symptoms disappeared. At 6 months, the Allium URS was correctly positioned and no hydronephrosis was detected on ultrasound. The stent can be left in place for a maximum of 3 years. CONCLUSIONS: In complicated scenarios of chronic ureteral stenosis, the new-generation Allium URS can be an interesting option to treat the obstruction while sparing the patient the irritative urinary symptoms and periodic replacements typical of a double-J stent. PMID- 28623650 TI - The incidence of dissociated liners in 4,751 consecutive total hip arthroplasties using Pinnacle polyethylene acetabular liners. AB - INTRODUCTION: Acetabular liner dissociation is a complication exclusive to modular designs. We present a single surgeon series of 8 polyethylene liner dissociations with the Pinnacle Acetabular System (DePuy Orthopaedics) from over 4,750 cases. We also present a review of the literature and data from the UK National Joint Registry (NJR) on dissociation in total hip arthroplasty (THA). METHODS: The Pinnacle Acetabular System has been used exclusively by the senior author since April 2003, and to date 5,882 have been implanted (837 ceramic liners, 4,751 polyethylene liners (1,606 Enduron/3,145 Marathon) and 294 metal liners). We reviewed all cases of liner dissociation from this cohort to determine an overall incidence with polyethylene liners, identify associated risk factors, and report the outcome following revision surgery. RESULTS: Our incidence of this complication is 8 out of 4,751 cases (0.17%). Review of these cases and the literature suggests that femoral neck impingement against the polyethylene liner and/or edge loading may produce fatigue failure of the locking mechanism and subsequent dissociation. CONCLUSIONS: Ensuring correct liner seating/locking, minimising impingement, achieving appropriate component version and avoiding radiographic cup inclinations >50 degrees should minimise the risk of liner dissociation. Any new noise or squeaking from a polyethylene liner should undergo radiographic investigation to exclude dissociation. We recommend managing late cases of liner dissociation with revision of the acetabular shell if the cup orientation could be improved or if there is any damage to the liner locking groove, to reduce the risk of recurrence. PMID- 28623651 TI - An investigation of support services available by Internet searching to families impacted by a parent's cancer. AB - OBJECTIVE: Throughout a parent's cancer diagnosis and treatment, families are likely to turn to the Internet to find social, emotional, and informational support services. It is important that professionals understand the content and availability of support discoverable through Web searches. This study identified and described Web-based information regarding support services offered to families when a parent has cancer. METHODS: Predefined key search terms were searched across 2 public Web browsers for a period of 3 months. Web-based information of support services (n = 25) was abstracted, and their key criteria examined. RESULTS: Of services offering face-to-face support (n = 22), more were founded by persons impacted by cancer (n = 10) (patients, parents, and offspring) than professionals (n = 4). Services offered online were created by health organisations and universities (n = 3). It appeared several service programs were delivered by volunteers, support staff, or facilitators, rather than registered health professionals or those with professional qualifications. Few services supported young children (under 5 years) or the parents themselves. CONCLUSION: Support services for families affected by a parent's cancer is relatively difficult to find through Web searches. Ambiguity around staff qualifications or evidence-base of support may hinder layperson engagement. Services offering face to-face support were often founded by those directly affected by cancer; conversely, services founded by persons with assumable expertise (health organisation and university staff) were limited to online support. Such findings highlight a possible discrepancy in consumer and provider priorities and have implications for current understandings of psychosocial support needs and service development for families affected by a parent's cancer. PMID- 28623652 TI - Micro Thin-Layer Chromatography Fingerprints of Selected Basil Species and Their Chemometric Analysis. AB - The dried aerial parts of 12 plants of Ocimum spp. were extracted with the Soxhlet apparatus using dichloromethane and methanol as solvents. A micro-TLC system with silica and a normal-phase solvent system (propan-2-ol-n-heptane formic acid) was used for the chemometric analysis of 12 selected basil methanolic extracts. Some indices of similarity (Pearson's correlation coefficient, determination coefficient, congruence coefficient, and Euclidean, Manhattan (city-block), Chebyshev, and Hausdorff distances) were calculated on the basis of thin-layer chromatograms using ImageJ software. Principal component analysis was also performed. The method allowed the comparison of the analyzed extracts and confirmed the identities of two selected unknown plants. PMID- 28623653 TI - Miniaturized Temperature-Controlled Planar Chromatography (Micro-TLC) as a Versatile Technique for Fast Screening of Micropollutants and Biomarkers Derived from Surface Water Ecosystems and During Technological Processes of Wastewater Treatment. AB - There is increasing interest in the development of simple analytical systems enabling the fast screening of target components in complex samples. A number of newly invented protocols are based on quasi separation techniques involving microfluidic paper-based analytical devices and/or micro total analysis systems. Under such conditions, the quantification of target components can be performed mainly due to selective detection. The main goal of this paper is to demonstrate that miniaturized planar chromatography has the capability to work as an efficient separation and quantification tool for the analysis of multiple targets within complex environmental samples isolated and concentrated using an optimized SPE method. In particular, we analyzed various samples collected from surface water ecosystems (lakes, rivers, and the Baltic Sea of Middle Pomerania in the northern part of Poland) in different seasons, as well as samples collected during key wastewater technological processes (originating from the "Jamno" wastewater treatment plant in Koszalin, Poland). We documented that the multiple detection of chromatographic spots on RP-18W microplates-under visible light, fluorescence, and fluorescence quenching conditions, and using the visualization reagent phosphomolybdic acid-enables fast and robust sample classification. The presented data reveal that the proposed micro-TLC system is useful, inexpensive, and can be considered as a complementary method for the fast control of treated sewage water discharged by a municipal wastewater treatment plant, particularly for the detection of low-molecular mass micropollutants with polarity ranging from estetrol to progesterone, as well as chlorophyll-related dyes. Due to the low consumption of mobile phases composed of water-alcohol binary mixtures (less than 1 mL/run for the simultaneous separation of up to nine samples), this method can be considered an environmentally friendly and green chemistry analytical tool. The described analytical protocol can be complementary to those involving classical column chromatography (HPLC) or various planar microfluidic devices. PMID- 28623654 TI - Value Assignment of Vitamin D Metabolites in Vitamin D Standardization Program Serum Samples. AB - Assay variability has been cited as an obstacle to establishing optimal vitamin D exposure. As part of the Vitamin D Standardization Program (VDSP) effort to standardize the measurement of total 25-hydroxyvitamin D [25(OH)D], the value assignment of total 25(OH)D in 50 single-donor serum samples was performed using two isotope-dilution LC with tandem MS methods. Both methods are recognized as reference measurement procedures (RMPs) by the Joint Committee for Traceability in Laboratory Medicine. These samples and their assigned values serve as the foundation for several aspects of the VDSP. To our knowledge, this is the first time that two RMPs have been used to assign 25(OH)D values to such a large number of serum samples. PMID- 28623655 TI - The Thin-Layer Microchromatography (MUTLC) and TLC-FID Technique as a New Methodology in the Study of Lubricating Oils. AB - This paper concerns the possibility of using TLC coupled with a flame ionization detector (FID) and micro-TLC (MUTLC) as precursors for microfluidized devices of analytical techniques to identify and determine the presence and content of the petroleum/vegetable oil base in the lubricating oils applied in cutting devices (chainsaws). This research is related to the problem of ensuring, in compliance with the requirements of environmental protection, a sufficient level of biodegradability of lubricating oils emitted to the environment during operation of equipment lubricated with these oils. Such oils include those mainly used in cutting devices and emitted in the form of a mist into the environment during the operation of those devices. When oil components are eco-toxic, contamination of the environment occurs. New methodologies for the identification and determination of the petroleum oil base, which is very difficult to biodegrade, as well as the easily biodegradable ingredients of vegetable origin in the lubricating oils, are presented. The described procedures indicate in an indisputable way whether the oil contains the oil base originating from crude oil and whether it contains adequate enriching additives. The procedures also allow the assessment of the content of particular groups of constituents (MUTLC) or the determination of the group composition (TLC-FID). PMID- 28623656 TI - Quantum Dots as Components of Electrochemical Sensing Platforms for the Detection of Environmental and Food Pollutants: a Review. AB - The determination of organic and inorganic environmental and food pollutants is a key matter of concern in analytical chemistry due to their effects as a serious threat to human health. Focusing on this issue, several methodologies involving the use of nanostructured electrochemical platforms have been recently reported in the literature. Among these methods, those employing the use of quantum dots (QDs) stand out because of features such as signal amplification, good reproducibility and selectivity, and the possibility for multiplexed detection, and because they preserve the outstanding characteristics of electrochemical methodologies with respect to simplicity, ease-of-use, and cost-effective instrumentation. This review describes recent electrochemical strategies, in which design QDs play a key role, for the determination of pollutants in food and environmental samples. The particular role of QDs in the reported methodologies, their preparation, and the electrochemical platform design, as well as the advantages that QDs provide in the analysis of target analytes, are critically discussed. PMID- 28623657 TI - Aptamer-Magnetic Bead Quantum Dot Sandwich Assays for Foodborne Pathogen Detection: Pros, Cons, and Lessons Learned. AB - DNA and RNA aptamers have been extensively investigated as potential competitors for antibodies for a variety of applications including food safety testing. Ultrasensitive fluorescence detection of foodborne pathogenic bacteria as low as 1-10 cells/mL has been achieved using aptamers coupled to quantum dots in clear pristine buffers for environmental sample detection. Quantum dots offer other advantages, including single UV or blue light source multiplex (multicolored) detection. However, quantum dots can exhibit decreased fluorescence in some food matrixes and even completely fail to fluoresce in some fatty matrixes, as documented in this report. Given the need to detect substances in complex food matrixes (and from data reported elsewhere), aptamer-magnetic bead pull-down methods followed by enzymatic/fluorometric- or PCR-based detection methods may be more robust methods for testing in foods or enrichment cultures. Other lessons learned, including the initial choice of aptamer targets to enhance assay specificity, are also discussed. PMID- 28623660 TI - The Method of Coating Fe3O4 with Carbon Nanoparticles to Modify Biological Properties of Oxide Measured in Vitro. AB - The coating of nanoparticles on materials for medical application [e.g., the coating of Fe3O4 nanopowder (IONP) with a carbon nanolayer] serves to protect and modify the selected biological, physical, and chemical properties of the coated material. Increases in chemical stability, changes in biocompatibility, and a modified surface structure are examples of the effects caused by the formation of carbon coatings. In the current study, Fe3O4 nanoparticles were coated with a carbon nanolayer (IONP@C) in a plasmochemical reactor (using radio-frequency plasma-enhanced chemical vapor deposition methods) under various experimental conditions. Based on data from X-ray diffraction, Raman, and IR spectroscopy, the best processing parameters were determined in order to produce a carbon coating that would not change the structure of the IONP. The materials with the best cover, i.e., a uniform carbon nanolayer, were used in cytotoxic tests to investigate their biological properties using the human HepG2 hepatocarcinoma cell line and chicken embryo red blood cells as an in vitro model. The obtained results proved the low cytotoxicity of Fe3O4 micropowder and IONP in contrast to IONP@C, which reduced cell viability, increased hemolysis, and generally was more toxic than bare Fe3O4. PMID- 28623661 TI - Graphene Nanolayers as a New Method for Bacterial Biofilm Prevention: Preliminary Results. AB - Biofilms are microbial communities of surface-attached cells embedded in a self produced extracellular matrix. They have been found to play a role in a wide variety of infections, including catheter-related urinary tract and bloodstream infections, and, therefore remain a significant source of morbidity and mortality among the world's population. Recently, much attention has been devoted to the prevention of biofilm formation on implant surfaces. Nanomaterials such as graphene, characterized by antibacterial activity and low toxicity to human cells, are promising candidates for biomedical applications. This study investigates the antibacterial efficiency of graphene and specially produced graphene decorated with silver nanoparticles, obtained by one of the methods of printed electronics (spray-coating system). These methods are not only economical, but also enable the printing of layers of various thicknesses on different types of materials, including flexible and nonplanar substrates. The aim of the study was to reveal the ability of graphene and graphene-nanosilver layers to prevent the formation of Staphylococcus epidermidis biofilm on the surface of a Foley catheter. PMID- 28623662 TI - Advances in the Analysis of Water and Wastewater Samples Using Various Sensing Protocols and Microfluidic Devices Based on PAD and MUTAS Systems. AB - The main goal of this review is to summarize practical approaches concerning the application of microfluidic systems for the analysis of various biomarkers and pollutants, as well as microbes, in water and wastewater matrixes. This problem involves multidisciplinary expertise combining research knowledge from various areas, including wet chemistry, biochemistry, physical chemistry, molecular biology, genetics, signal processing, microelectronics material science, and separation science. It has been documented that fairly primitive but fast and inexpensive screening methods involving paper-based analytical devices (PADs) and micro total analytical systems (MUTAS) can be considered as serious alternatives to their more advanced counterparts such as GC, HPLC, and capillary electrophoresis coupled to various sophisticated detectors (e.g., multiwavelength spectrophotometers such as UV-Vis/DAD and mass spectrometers). The main advantage of PAD- and MUTAS-driven technology is that such sensing devices may work under on-site and real-time conditions and measure a number of physical parameters and chemical factors simultaneously. Moreover, hybrid miniaturized analytical systems may combine sensing and data acquisition modules with common mobile phones and electronic devices working with global positioning systems and communicating through the Internet. PMID- 28623663 TI - Structural mechanism of ATP-independent transcription initiation by RNA polymerase I. AB - Transcription initiation by RNA Polymerase I (Pol I) depends on the Core Factor (CF) complex to recognize the upstream promoter and assemble into a Pre Initiation Complex (PIC). Here, we solve a structure of Saccharomyces cerevisiae Pol I-CF-DNA to 3.8 A resolution using single-particle cryo-electron microscopy. The structure reveals a bipartite architecture of Core Factor and its recognition of the promoter from -27 to -16. Core Factor's intrinsic mobility correlates well with different conformational states of the Pol I cleft, in addition to the stabilization of either Rrn7 N-terminal domain near Pol I wall or the tandem winged helix domain of A49 at a partially overlapping location. Comparison of the three states in this study with the Pol II system suggests that a ratchet motion of the Core Factor-DNA sub-complex at upstream facilitates promoter melting in an ATP-independent manner, distinct from a DNA translocase actively threading the downstream DNA in the Pol II PIC. PMID- 28623664 TI - Mechanosensory neurons control the timing of spinal microcircuit selection during locomotion. AB - Despite numerous physiological studies about reflexes in the spinal cord, the contribution of mechanosensory feedback to active locomotion and the nature of underlying spinal circuits remains elusive. Here we investigate how mechanosensory feedback shapes active locomotion in a genetic model organism exhibiting simple locomotion-the zebrafish larva. We show that mechanosensory feedback enhances the recruitment of motor pools during active locomotion. Furthermore, we demonstrate that inputs from mechanosensory neurons increase locomotor speed by prolonging fast swimming at the expense of slow swimming during stereotyped acoustic escape responses. This effect could be mediated by distinct mechanosensory neurons. In the spinal cord, we show that connections compatible with monosynaptic inputs from mechanosensory Rohon-Beard neurons onto ipsilateral V2a interneurons selectively recruited at high speed can contribute to the observed enhancement of speed. Altogether, our study reveals the basic principles and a circuit diagram enabling speed modulation by mechanosensory feedback in the vertebrate spinal cord. PMID- 28623665 TI - Position paper on olfactory dysfunction. AB - BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field. PMID- 28623666 TI - SOX2 regulates acinar cell development in the salivary gland. AB - Acinar cells play an essential role in the secretory function of exocrine organs. Despite this requirement, how acinar cells are generated during organogenesis is unclear. Using the acini-ductal network of the developing human and murine salivary gland, we demonstrate an unexpected role for SOX2 and parasympathetic nerves in generating the acinar lineage that has broad implications for epithelial morphogenesis. Despite SOX2 being expressed by progenitors that give rise to both acinar and duct cells, genetic ablation of SOX2 results in a failure to establish acini but not ducts. Furthermore, we show that SOX2 targets acinar specific genes and is essential for the survival of acinar but not ductal cells. Finally, we illustrate an unexpected and novel role for peripheral nerves in the creation of acini throughout development via regulation of SOX2. Thus, SOX2 is a master regulator of the acinar cell lineage essential to the establishment of a functional organ. PMID- 28623668 TI - Impact of PCI Appropriateness in the Long-Term Outcomes of Consecutive Patients Treated With Second-Generation Drug-Eluting Stents. AB - BACKGROUND: Appropriate use criteria (AUC) for coronary revascularization were developed to deliver high-quality care; however, the prognostic impact of these criteria remains unclear. We sought to assess the outcomes of patients treated with second-generation drug-eluting stent (DES) classified according to the updated American College of Cardiology Foundation/American Heart Association/Society for Cardiac Angiography and Intervention AUC for percutaneous coronary intervention (PCI). METHODS: Between January 2012 and December 2013, a total of 1108 consecutive patients treated only with second-generation DES were categorized according to the AUC in three groups, using the new proposed terminology: appropriate ("A"); uncertain ("U"); and inappropriate ("I"). Major adverse cardiac event (MACE, defined as cardiac death, non-fatal myocardial infarction, and ischemia-driven target-lesion revascularization) and stent thrombosis up to 3 years were compared. RESULTS: PCI was categorized as A in 33.8%, U in 46.8%, and I in 19.4% of all cases. PCI-A patients had a higher prevalence of acute coronary syndromes, while PCI-I involved the treatment of more diabetics and patients with stable coronary disease. There were no differences in procedural complications among the three groups, with comparable rates of in-hospital MACE (9.3% for A vs 9.0% for U vs 7.0% for I; P=.70) and 2 year MACE (13.9% for A vs 9.0% for U vs 8.6% for I; P=.40). In the multivariable analysis, AUC classification was not associated with adverse outcomes. CONCLUSIONS: In this contemporary cohort of patients treated with second generation DES implantation, AUC did not impact 3-year clinical follow-up. PMID- 28623669 TI - Outcomes After Successful Percutaneous Coronary Intervention of Calcified Lesions Using Rotational Atherectomy, Cutting-Balloon Angioplasty, or Balloon-Only Angioplasty Before Drug-Eluting Stent Implantation. AB - OBJECTIVES: To report adverse event rates after rotational atherectomy (RA) with contemporary drug-eluting stent (DES) implantation and compare RA to cutting balloon (CB) angioplasty and balloon-only angioplasty (BA) in the all-comers ADAPT-DES trial. BACKGROUND: Percutaneous coronary intervention (PCI) of calcified lesions is increasingly common and is associated with a high risk of adverse events. RA can ablate calcified plaque and facilitate stent delivery; however, in conjunction with first-generation DES, RA was not superior to BA alone in regard to adverse events. METHODS: ADAPT-DES enrolled 8582 patients who underwent successful PCI with DES, of whom 2644 had calcified target lesions and were included in this study. Among these patients, 1610 had exclusively second generation DESs implanted. We present Kaplan-Meier rates for the primary endpoint of target-vessel failure (TVF; defined as death, myocardial infarction, or target vessel revascularization) as well as its components, for patients who had RA, CB, or BA. RESULTS: Among the 2644 patients, RA and CB were used in 150 patients (5.7%) and 53 patients (2.0%), respectively. TVF occurred in 20.8% of the RA patients, 24.1% of the CB patients, and 17.9% of the BA patients over the 2-year study period (P=.41) and was primarily driven by target-vessel revascularization (13.8%, 11.4%, and 10.2%, respectively). RA patients with acute coronary syndromes had nominally higher 2-year TVF rates than RA patients with stable coronary artery disease. CONCLUSION: TVF is common after contemporary DES-PCI of calcified lesions, independent of the technique used to prepare the vessel for stent implantation. Better treatment strategies are needed. PMID- 28623667 TI - The genome and phenome of the green alga Chloroidium sp. UTEX 3007 reveal adaptive traits for desert acclimatization. AB - To investigate the phenomic and genomic traits that allow green algae to survive in deserts, we characterized a ubiquitous species, Chloroidium sp. UTEX 3007, which we isolated from multiple locations in the United Arab Emirates (UAE). Metabolomic analyses of Chloroidium sp. UTEX 3007 indicated that the alga accumulates a broad range of carbon sources, including several desiccation tolerance-promoting sugars and unusually large stores of palmitate. Growth assays revealed capacities to grow in salinities from zero to 60 g/L and to grow heterotrophically on >40 distinct carbon sources. Assembly and annotation of genomic reads yielded a 52.5 Mbp genome with 8153 functionally annotated genes. Comparison with other sequenced green algae revealed unique protein families involved in osmotic stress tolerance and saccharide metabolism that support phenomic studies. Our results reveal the robust and flexible biology utilized by a green alga to successfully inhabit a desert coastline. PMID- 28623670 TI - Feasibility and Safety of Right and Left Heart Catheterization Via an Antecubital Fossa Vein and the Radial Artery in Patients With Heart Failure. AB - OBJECTIVES: Heart failure is the leading cause of hospitalization among patients older than 65 years of age. A significant proportion of patients require heart catheterization for diagnostic, therapeutic, and prognostic purposes. To determine the feasibility and safety of full arm-arm catheterization access, we aimed to compare this approach with other established catheterization approaches. METHODS AND RESULTS: In this retrospective cohort study, a total of 493 consecutive patients with heart failure requiring right and left heart catheterization were studied and analyzed. Subsequently, all patients were divided into three groups based on the catheterization approach used: arm-arm, hybrid femoral-arm, and femoral-femoral access. The three groups did not significantly differ in their baseline clinical, demographic, or risk factor characteristics. The full arm-arm catheterization procedures were significantly longer when compared with hybrid femoral-arm and femoral-femoral approach (73 min vs 68 min vs 67 min, respectively; P=.04), but remarkably provided significantly less fluoroscopy radiation dose (40,337 +/- 64,799 cG/cm2 vs 62,270 +/- 120,420 cG/cm2 vs 156077 +/- 566495 cG/cm2, respectively; P=.04). Procedural complications were rare and occurred in 0.9% of the arm-arm group, 4.8% of the femoral-arm group, and 3.3% of the femoral-femoral group (P=.45). Finally, in arm arm patients, a significantly earlier ambulation was achieved compared with the others groups (P=.02). CONCLUSION: Full arm-arm access for bilateral heart catheterization in patients with heart failure proved to be a safe and feasible approach, and was associated with lower radiation burden and early ambulation time when compared with hybrid arm-leg and full femoral catheterization approaches. PMID- 28623671 TI - Feasibility of Diffusion Tensor Imaging for Assessing Functional Recovery in Rats with Olfactory Ensheathing Cell Transplantation After Contusive Spinal Cord Injury (SCI). AB - BACKGROUND Olfactory ensheathing cell transplantation is a promising treatment for spinal cord injury. Diffusion tensor imaging has been applied to assess various kinds of spinal cord injury. However, it has rarely been used to evaluate the beneficial effects of olfactory ensheathing cell transplantation. This study aimed to explore the feasibility of diffusion tensor imaging in the evaluation of functional recovery in rats with olfactory ensheathing cell transplantation after contusive spinal cord injury. MATERIAL AND METHODS Immunofluorescence staining was performed to determine the purity of olfactory ensheathing cells. Rats received cell transplantation at week 1 after injury. Basso, Beattie, and Bresnahan score was used to assess the functional recovery. Magnetic resonance imaging was applied weekly, including diffusion tensor imaging. Diffusion tensor tractography was reconstructed to visualize the repair process. RESULTS The results showed that olfactory ensheathing cell transplantation increased the functional and histological recovery and restrained the secondary injury process after the initial spinal cord injury. The fractional anisotropy values in rats with cell transplantation were significantly higher than those in the control group, while the apparent diffusion coefficient values were significantly lower. Basso, Beattie, and Bresnahan score was positively and linearly correlated with fractional anisotropy value, and it was negatively and linearly correlated with apparent diffusion coefficient value. CONCLUSIONS These findings suggest that diffusion tensor imaging parameters are sensitive biomarker indices for olfactory ensheathing cell transplantation interventions, and diffusion tensor imaging scan can reflect the functional recovery promoted by the olfactory ensheathing cell transplantation after contusive spinal cord injury. PMID- 28623672 TI - Craniosynostosis - Recognition, clinical characteristics, and treatment. AB - Craniosynostosis is a developmental craniofacial anomaly, resulting in impairment of brain development and abnormally shaped skull. The main cause of craniosynostosis is premature closure of one or more cranial sutures. It usually occurs as an isolated condition, but may also be associated with other malformations as part of complex syndromes. When left untreated, craniosynostosis can cause serious complications, such as developmental delay, facial abnormality, sensory, respiratory and neurological dysfunction, anomalies affecting the eye, and psychological disturbances. Thus, early diagnosis, expert surgical techniques, postoperative care, and adequate follow-up are of vital importance in treating craniosynostosis. PMID- 28623674 TI - Cathepsin K in Lymphangioleiomyomatosis: LAM Cell-Fibroblast Interactions Enhance Protease Activity by Extracellular Acidification. AB - Lymphangioleiomyomatosis (LAM) is a rare disease in which LAM cells and fibroblasts form lung nodules and it is hypothesized that LAM nodule-derived proteases cause cyst formation and tissue damage. On protease gene expression profiling in whole lung tissue, cathepsin K gene expression was 40-fold overexpressed in LAM compared with control lung tissue (P <= 0.0001). Immunohistochemistry confirmed cathepsin K protein was expressed in LAM but not control lungs. Cathepsin K gene expression and protein and protease activity were detected in LAM-associated fibroblasts but not the LAM cell line 621-101. In lung nodules, cathepsin K immunoreactivity predominantly co-localized with LAM associated fibroblasts. In vitro, fibroblast extracellular cathepsin K activity was minimal at pH 7.5 but significantly enhanced at pH 7 and 6. 621-101 cells reduced extracellular pH with acidification dependent on 621-101 mechanistic target of rapamycin activity and net hydrogen ion exporters, particularly sodium bicarbonate co-transporters and carbonic anhydrases, which were also expressed in LAM lung tissue. In LAM cell-fibroblast co-cultures, acidification paralleled cathepsin K activity, and both were reduced by sodium bicarbonate co-transporter (P <= 0.0001) and carbonic anhydrase inhibitors (P = 0.0021). Our findings suggest that cathepsin K activity is dependent on LAM cell-fibroblast interactions, and inhibitors of extracellular acidification may be potential therapies for LAM. PMID- 28623673 TI - A prominent lactate peak as a potential key magnetic resonance spectroscopy (MRS) feature of progressive multifocal leukoencephalopathy (PML): Spectrum pattern observed in three patients. AB - Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal, opportunistic infection, associated with demyelinating process. PML is caused by John Cunningham (JC) polyomavirus, and predominantly affects patients with human immunodeficiency virus (HIV) infection or other immunocompromised patients. The purpose of this study was to determine the role of magnetic resonance spectroscopy (MRS) in establishing the diagnosis of PML. MRS with long and short echo time was performed in two patients with PML associated with HIV infection and in one PML patient associated with chronic lymphocytic leukemia. The most prominent peak on the obtained spectra was for lactate; it showed 2-3 times higher concentration of lactate compared to choline, almost 4-6 times higher lactate concentration compared to creatine, and 4-11 times higher lactate in comparison to N-acetylaspartate concentration. Similar spectrum pattern was observed in all patients. To the best of our knowledge, this is a new finding that might be useful in early diagnosis of PML. Nevertheless, further confirmation of our results is needed, since we analyzed the spectrum pattern only in three patients. Overall, our results could help in early detection of PML, especially in non-HIV patients, and thus prevent the fatal outcome of the disease. MRS could also be useful in detecting "tumefactive" demyelinating lesions in PML patients, associated with immune reconstitution inflammatory syndrome, to avoid misdiagnosis of neoplasm. PMID- 28623675 TI - Development of a prototype immunochromatographic test for rapid diagnosis of respiratory adenovirus infection. AB - Human adenoviruses comprise an important group of etiologic agents that are responsible for various diseases in adults and children, such as respiratory, ocular, gastroenteric, and urinary infections. In immunocompromised and organ transplanted individuals, these agents can cause generalized infections. Rapid diagnostic methods for detecting these infectious agents are not widely available. The aim of this work was to produce monoclonal and polyclonal anti adenovirus antibodies to be used in a rapid diagnostic test for respiratory infections. Adenovirus hexons were satisfactorily purified by ultracentrifugation and chromatography. After virus purification, anti-hexon monoclonal antibodies were produced and characterized, following classical methods. Antibodies were specific for adenoviruses 2, 3, 5, and 41. The proposed immunochromatographic test was standardized using colloidal gold. The standardization of the rapid test was sufficient to detect adenovirus antigens (in nasopharyngeal lavage samples) with sensitivity of 100% and specificity of 85% when compared to direct immunofluorescence. The immunochromatographic assay prototype was sufficiently sensitive to detect B (3), C (2 and 5), and F (41) adenovirus samples. Although based on preliminary data, the test demonstrated the same performance as direct immunofluorescence, but with the advantage of being a point-of-care test. Further studies are still needed to confirm its effectiveness in clinical practice. PMID- 28623676 TI - Unrecognized pediatric and adult family members of children with acute brucellosis. AB - BACKGROUND AND AIM: Brucellosis is an infectious, contagious and zoonotic disease that occurs worldwide. The family members of an index case of brucellosis may be especially susceptible, due to sharing the same source of infection and similar risk factors for brucellosis. In this study, we propose to screen pediatric and adult family members of brucellosis index cases for detecting additional unrecognized infected family members. MATERIALS AND METHODS: 114 family members of 41 pediatric patients with brucellosis were evaluated. All family members completed a brief questionnaire and were tested by a standard tube agglutination test (STA). RESULTS: The majority of family members (n=96, 84.2%) were children. Among the 114 family members, 42 (36.8%) were seropositive, and 15 (35.7%) were symptomatic. The majority of the symptomatic seropositive family members (n=12, 80%) had STA titers (>=1:640) higher than asymptomatic seropositive family members (n=9, 33%; p=0.004). CONCLUSION: The routine screening of both pediatric and adult family members of index cases is a priority in endemic areas. Using this screening approach, unrecognized family members who are seropositive for brucellosis will be identified earlier and be able to receive prompt treatment. PMID- 28623677 TI - Incidence of cognitively defined late-onset Alzheimer's dementia subgroups from a prospective cohort study. AB - INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia. METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with >= APOE epsilon4 allele, more extensive Alzheimer's-related neuropathology, and higher proportions with other Alzheimer's dementia genetic risk variants. DISCUSSION: A cognitive subgrouping strategy may identify biologically distinct subsets of people with Alzheimer's dementia. PMID- 28623678 TI - The acculturation, language and learning experiences of international nursing students: Implications for nursing education. AB - BACKGROUND: International or foreign students are those who enrol in universities outside their country of citizenship. They face many challenges acculturating to and learning in a new country and education system, particularly if they study in an additional language. OBJECTIVES: This qualitative inquiry aimed to explore the learning and acculturating experiences of international nursing students to identify opportunities for teaching innovation to optimise the experiences and learning of international nursing students. METHODS: Undergraduate and postgraduate international nursing students were recruited from one campus of an Australian university to take part in semi-structured interviews. A purposive and theoretically saturated sample of 17 students was obtained. Interviews were audio recorded and field notes and interview data were thematically analysed. RESULTS: Expressing myself and Finding my place were the two major themes identified from the international student data. International nursing students identified that it took them longer to study in comparison with domestic students and that stress negatively influenced communication, particularly in the clinical setting. Additionally international nursing students identified the need to find supportive opportunities to speak English to develop proficiency. Clinical placement presented the opportunity to speak English and raised the risk of being identified as lacking language proficiency or being clinically unsafe. Initially, international nursing students felt isolated and it was some time before they found their feet. In this time, they experienced otherness and discrimination. CONCLUSIONS: International nursing students need a safe place to learn so they can adjust and thrive in the university learning community. Faculty and clinical educators must be culturally competent; they need to understand international nursing students' needs and be willing and able to advocate for and create an equitable environment that is appropriate for international nursing students' learning. PMID- 28623679 TI - As a Specialty, Where Do We Go From Here? PMID- 28623680 TI - What Are the Incidence and Factors Associated With Implant Fracture? AB - PURPOSE: Implant fracture is a serious complication, which leads to treatment failure. The purpose of this study is to estimate the incidence of implant fractures and identify factors associated with them. MATERIALS AND METHODS: In this retrospective cohort study, the sample was derived from 2 implant centers. The predictors were grouped into the following categories: demographic, location of implant, physical characteristic of implant, implant-abutment connection, type of prosthesis, type of retention, and outcome variable (time to implant fracture). The Kaplan-Meier test was used to estimate implant survival. A Cox regression model was applied to evaluate the time-to-event effect of variables on implant fracture. RESULTS: Of 18,700 implants, 37 (0.002%) had fractures. The 1- and 5-year risk of implant fracture was 0.38 per 1,000 and 1.46 per 1,000, respectively. Implant fractures more often occurred in the premolar and molar area (94.6%) than in the anterior of the jaws. The Pearson correlation test did not show any correlation between age, implant diameter, or implant length and time of fracture (P > .05). Analysis of the data by the log-rank test showed a significant difference for survival between cemented and screw-retained crowns (P = .001). The Cox regression model showed a hazard ratio of 0.23 for tapered implants versus cylindrical fixtures and for screw-retained crowns (hazard ratio, 296.54) versus cemented crowns. CONCLUSIONS: According to this study, conical implants and screw-retained prostheses may have lower survival rates due to implant fracture. PMID- 28623681 TI - Soft Tissue Changes Measured With Three-Dimensional Software Provides New Insights for Surgical Predictions. AB - PURPOSE: Although computer-aided craniofacial reconstructions allow for simulation of hard tissue changes, the prediction of the final soft tissue facial changes remains a challenge. The purpose of the present study was to evaluate the 3-dimensional (3D) soft tissue changes in patients undergoing 2-jaw orthognathic surgery. PATIENTS AND METHODS: For the present retrospective cohort study, 40 consecutive patients (11 men and 29 women; mean age 23.5 +/- 4.9 years) who had undergone 2-jaw orthognathic surgery were selected. We obtained the medical and dental records from 3 weeks before surgery and 6 months after surgery. We used image processing software to segment, superimpose, and quantify the hard and soft tissue displacements in 3 dimensions before and after surgery at 15 paired locations. The soft tissue and hard tissue changes were determined through quantification of homologous landmark displacements between the preoperative and postoperative computed tomography data. We measured the 3D soft and hard tissue changes and the anteroposterior, inferosuperior, and transverse components of the changes. We quantified the ratios between the soft and hard tissue changes, tested Pearson's correlation between these changes, and developed a predictive regression equation for the observations at each location. RESULTS: We found that soft tissue movement followed the hard tissue movement, with a correlation nearly equal to 0.9 (range 0.85 to 0.98), suggesting that in general the soft tissues of the maxillary and mandibular landmarks are affected similarly by the skeletal movements. The anteroposterior component of the soft tissue 3D displacements followed the hard tissue movement with a ratio greater than 0.9 and with high correlation (r > 0.9) in the mandible. CONCLUSION: The results of the present study provide surgeons with a ratio of hard to soft tissue change and the strength of the correlations, which will allow for more accurate 3D predictions for both midline and lateral structures in bimaxillary orthognathic surgical cases. In addition, predictive equations for various landmarks were developed and can be used in computer-based prediction programs to aid in treatment planning of soft tissue changes. PMID- 28623682 TI - Osteonecrosis of the Jaw in a Patient Presenting With Post-Transplantation Lymphoproliferative Disorder Treated With Rituximab: A Case Report. AB - Osteonecrosis of the jaw (ONJ) is a rare but potentially severe condition that can be induced by specific treatments. We report the case of a 69-year-old male kidney transplant recipient who presented with ONJ 5 years after transplantation. The patient presented with ulcerations of the oral mucosa related to post transplantation lymphoproliferative disorder, which was treated with rituximab. Subsequently, ONJ developed. Although rituximab treatment cannot be firmly established as the cause of this condition, similar cases of ONJ have been reported after treatment with this monoclonal antibody. This case raises a potential link between rituximab treatment and ONJ and prompts further studies to investigate the potential impact of rituximab on bone angiogenesis. PMID- 28623683 TI - The Effects of Unilateral Alloplastic Temporomandibular Joint Replacement on the Opposite-Side Natural Joint: A Finite-Element Analysis. AB - PURPOSE: The purpose of this study was to evaluate the stress distribution on the temporomandibular joint (TMJ) prosthesis and contralateral natural TMJ with finite-element analysis. MATERIALS AND METHODS: A TMJ implant was used to create a 3-dimensional model with a computer. This model was integrated with a mandible model created with a computer by use of computed tomography images, similar to a real TMJ replacement procedure. Masticatory loads were applied to the model. The loads transmitted to the TMJ prosthesis and contralateral healthy joint were evaluated by means of finite-element analysis. RESULTS: In the model without the TMJ prosthesis, maximum von Mises stress was 252.697 N/mm2 at the condyle and 5.418 N/mm2 at the disc. In the model with the unilateral TMJ prosthesis, maximum stress at the joint prosthesis was 792.681 N/mm2. In the contralateral natural joint, maximum stress was 268.908 N/mm2 at the condyle and 8.357 N/mm2 at the disc. CONCLUSIONS: In the TMJ model with the unilateral total TMJ prosthesis, increased stress values were observed at the disc and condyle of the contralateral natural TMJ. PMID- 28623684 TI - Chimeric Reverse Temporal Muscle and Pericranial Flap for Double-Layer Closure of Deep Facial Defects. AB - PURPOSE: Volumetric or multiplane defects of the upper and midface remain a challenge for reconstruction because of limited regional flap options. In this study, the authors harvested the reverse temporalis muscle flap and pericranial flap (RTMP flap) based on the same vascular pedicle, the superficial temporal artery, in a chimeric manner to obtain double-layer closure of deep facial defects. MATERIALS AND METHODS: This study was a prospective case series performed in the Department of Plastic Surgery of Ataturk University (Erzurum, Turkey). The outcomes, including flap survival, postoperative complications, reconstructive success, esthetic appearance, and donor site morbidity, were clinically evaluated. RESULTS: Fourteen patients (10 male and 4 female) with deep defects of the middle third of the face underwent reconstruction using the chimeric RTMP flap. All chimeric RTMP flaps survived without postoperative complications. All defects were successfully repaired and covered with chimeric RTMP flaps. Patients were satisfied with the esthetic results. CONCLUSION: The chimeric RTMP flap is a good reconstruction option and can be used safely for moderate to large 3-dimensional defects of the middle and upper face. Smooth and durable coverage over the bulky muscle flap used to fill the volume defect and a larger flap for larger volume defects can be obtained by including the pericranial segment of the chimeric RTMP flap. PMID- 28623685 TI - Two-Stage Ridge Split at Narrow Alveolar Mandibular Bone Ridges. AB - PURPOSE: When the bone ridge is corticalized, the displacement of the buccal plate may result in an unintentional malfracture. The aim of this study was to report the results of a 2-stage atrophic alveolar ridge expansion performed with a sonic-air surgical instrument. MATERIALS AND METHODS: In this retrospective cohort study, the atrophic distal segments of the mandible were treated by a split-thickness flap approach and application of an alveolar ridge expansion performed in 2 surgical phases. A sonic-air surgical instrument was used. In the first surgical procedure, only basal corticotomies on the buccal plate were performed. In the second stage, sagittal and vertical osteotomies were added, aiming to facilitate the displacement of the buccal bone plate. Subsequently, implants were installed into the created space between the buccal and lingual plates. No bone substitutes were used. The width of the displaced buccal bone wall and the gaps that occurred mesially and distally to the implant were measured at the time of implant installation. Cone beam computed tomography scans were taken before the first and after the second surgical procedures, and the width of the alveolar crest at both observations and the width of the residual mesial and distal gaps after implant installation were measured. RESULTS: We included 10 patients (6 women and 4 men; aged 37 to 69 years) in the study, and 15 implants were installed in expanded narrow ridges. Clinically, the mean width of the buccal bone wall was 1.2 +/- 0.2 mm and the gaps ranged between 2.8 and 3.2 mm. On the radiographic assessments, the mean initial width of the alveolar bone crest measured 4.1 +/- 0.5 mm, reaching 6.8 +/- 0.9 mm after ridge expansion (P < .01). CONCLUSIONS: The use of a modified edentulous ridge expansion in 2 stages allowed the installation of implants in narrow and corticalized alveolar ridges. We suggest that this technique is especially applicable in the distal segments of the mandible because of the low invasiveness, low risk of buccal plate fractures, reduced morbidity, and reduced costs. PMID- 28623686 TI - Temporomandibular Prosthetic Joint Infections Associated With Propionibacterium acnes: A Case Series, and a Review of the Literature. AB - PURPOSE: The orthopedic literature has shown an increasing incidence of prosthetic joint infections (PJIs) associated with Propionibacterium acnes (P acnes). These infections present serious diagnostic and management challenges to the treating surgeons. In this review, the authors report on cases of P acnes related temporomandibular joint (TMJ) PJIs that have been diagnosed and treated at their institution. MATERIALS AND METHODS: After approval by the institutional review board, information was obtained through a retrospective chart review. Records were retrieved from clinic visits from January 1, 2010 through January 1, 2015 using appropriate International Classification of Diseases, Ninth Revision codes. Data extracted included patient demographics, prostheses details, prosthetic infection history, interventions, diagnostic procedures, and culture processing methods. RESULTS: Of the 7 patients who met the search criteria, 4 (1 with bilateral prostheses) had cultures positive for P acnes. For the 5 TMJ PJIs with cultures positive for P acnes, tissue cultures were obtained in the operating room and processed using mass spectrometry. Symptoms identified in these 4 patients were vague and included pain and intermittent swelling; clinical and radiographic findings were nonspecific. Treatment regimens included oral and parenteral antibiotics and operative interventions. CONCLUSIONS: In this case series, the authors report on the management of 4 cases of P acnes-related TMJ PJI. When patients with TMJ prostheses report vague symptoms of swelling and pain that do not fit the typical infection scenario, the surgeon should consider P acnes as a source of infection. Additional case series and retrospective reviews will be necessary before developing prospective trials that could aid in the prevention and management of this infection. PMID- 28623687 TI - Microcalcifications in stone-obstructed human submandibular gland are associated with apoptosis and cell proliferation. AB - OBJECTIVE: Human submandibular gland (SMG) stones are associated with inflammation, fibrosis and microcalcifications in the surrounding tissues. However, there is little information about the accompanying cell injury-repair process, apoptosis, and cell proliferation. The purpose of this study was to investigate such an association and its clinical significance. DESIGN OF STUDY: Mid-gland paraffin sections of human SMGs ("stone glands") and normal SMGs ("non stone glands") were subjected to stains for general histology (hematoxylin and eosin), fibrosis (Masson's trichrome), and calcification (alizarin red) and to immunohistochemistry for proliferative activity (Ki-67), and apoptosis (Caspase 3). Tissues were assessed for areas of inflammation, calcium deposition, and fibrosis, and for cycling and apoptotic cells. RESULTS: Acini were atrophic and proportionately fewer in lobules with fibrosis in stone glands. Additionally, stone glands had intraluminal calcifications (microliths) in scattered excretory and striated ducts and blood vessel walls. Areas of inflammation and fibrosis were small and uncommon, and calcifications were not seen in non-stone glands. Proliferating and apoptotic cells were common in the main duct of stone glands where ciliated and mucous cell hyperplasia and stratified squamous metaplasia had occurred, uncommon in the main duct of non-stone glands, and uncommon in all other parenchymal elements of both stone and non-stone glands. CONCLUSION: Stone obstruction in the main excretory ducts of SMG resulted in progressive depletion of acini from proximal to distal lobules via calcification, inflammation, fibrosis, and parenchymal cell atrophy, apoptosis and proliferation. Interlobular duct microliths contributed to this depletion by further provoking intralobular inflammation, fibrosis, and acinar atrophy. PMID- 28623688 TI - Exposure to sublethal concentrations of Co3O4 and Mn2O3 nanoparticles induced elevated metal body burden in Daphnia magna. AB - Despite the significant progress made in ecotoxicological research on nanoparticles (NPs), there is still very limited information available regarding the biological effects of certain types of NPs such as Co3O4 and Mn2O3. Only a couple of studies provide data on their impact on aquatic organisms whereas, alarmingly, these NPs have been proposed to have high toxicity potential. In addition, more data are needed to determine whether the adverse effects the metal NPs induce on aquatic organisms are rather due to their chemical or particulate nature. To address these open questions, the (sub)lethal effects of Co and Mn NPs in parallel with the respective soluble metal salts on Daphnia magna were studied. The aims of the current study were to i) assess the acute toxicity of Co3O4 and Mn2O3 NPs (primary size 10-30nm) to D. magna, ii) evaluate whether the acute NP exposure at sublethal concentrations influences D. magna post-exposure feeding behaviour and iii) quantify D. magna metal body burden after exposure and after the post-exposure feeding to estimate the potential of trophic transfer of metals. Flow cytometry and total reflection X-ray fluorescence spectroscopy were applied for feeding and metal body burden evaluations, respectively. CuO NPs (primary size 22-25nm) that are very toxic to D. magna were included in the study as a positive control. Since the release of metal ions is an important possibility for toxicity of metal NPs, soluble Co-, Mn- and Cu-salts were analysed in parallel. The solubilisation of Co3O4 NPs in the OECD202 assay conditions was 0.1% and Mn2O3 NPs 35%. Mn2O3 NPs also produced reactive oxygen species in abiotic conditions. However Co3O4 and Mn2O3 NPs were not acutely toxic to D. magna (48h EC50>100mg metal/L) at OECD202 assay conditions. The 48h EC50 values of soluble Co- and Mn-salts were 3.2mgCo/L and 41mgMn/L, respectively. Post-exposure feeding behaviour after 48h exposure to sublethal concentrations (<=10mg/L) of Co3O4 and Mn2O3 NPs differed from that of the unexposed (control) D. magna only at the highest exposure concentrations but was comparable to the feeding behaviour of the respective metal salt-exposed organisms. Upon 48h exposure, dose-dependent increase of D. magna total metal body burden in case of both the NPs and the soluble salts was observed. After 48h post-exposure feeding with algae C. reinhardtii (depuration): D. magna body burden remained elevated (up to 760-fold compared to the control organism) only in case of the NPs. This may indicate potential for trophic transfer of NPs/heavy metals and thus hazard for freshwater ecosystem. PMID- 28623689 TI - Stage specific effects of soluble copper and copper oxide nanoparticles during sea urchin embryo development and their relation to intracellular copper uptake. AB - The effects of exposure to either soluble copper (copper sulfate) or copper oxide nanoparticles (nano-CuO) during specific early developmental stages of sea urchin embryos were analyzed. Soluble copper caused significant malformations in embryos (skeletal malformations, delayed development or gut malformations) when present at any given stage, while cleavage stage was the most sensitive to nano-CuO exposure causing skeletal malformations and decreased total antioxidant capacity. The stage specificity was linked to higher endocytic activity during the first hours of development that leads to higher accumulation of copper in specific cells critical for development. Results indicate that nano-CuO results in higher accumulation of copper inside of embryos and this intracellular copper is more persistent as compared to soluble copper. The possible implications later in development are discussed. PMID- 28623690 TI - Candidate cytochrome P450 genes for ethoxyresorufin O-deethylase activity in oyster Crassostrea gigas. AB - Vertebrate cytochrome P450 1 (CYP1) enzymes metabolize endogenous and xenobiotic compounds and usually demonstrate a substrate-inducible response. Ethoxyresorufin O-deethylase activity (EROD) is a common method to quantify CYP1 enzymes activity in these organisms. Despite the absence of this gene family in protostomes, CYP1 like genes were identified in several species, even though no evolutionary relationship has been established with the vertebrate CYP1 family. In the present study, EROD activity was evaluated in microsomal fraction of gills, digestive gland and mantle of Crassostrea gigas. Enzyme activity was quantified in gills, although no activity was detected in digestive gland and mantle. EROD kinetic characterization in gills using typical Michaelis-Menten equation demonstrated an apparent Km of 1.15MUM and Vmax of 229.2 fmol.min-1mg.protein -1. EROD activity was analyzed in the presence of CYP1 inhibitors, ellipticine (ELP), furafylline (FRF), clotrimazole (CTZ), alpha-naphthoflavone (ANF), and the non-ionic surfactant Triton X-100. CTZ inhibited EROD activity in all tested concentrations while Triton X-100 (0.5mM) caused 16% inhibition. Transcript levels of four CYP1 like genes were determined in gills, digestive gland and mantle. In general, CYP1 like genes showed higher transcript levels in gills compared to other tissues. The transcript levels of CYP1-like 1 and 2, analyzed together, positively correlated with EROD activity observed in gills, suggesting the possible involvement of these two gene products in EROD activity in this tissue. Homology models of translated CYP1-like 1 and 2 were generated based on human CYP1A1 structure and were similar to the general canonical cytochrome P450 fold. Molecular docking analysis showed that the two putative oyster CYP1-like structures have the potential to metabolize 7-ethoxyresorufin (7-ER), although the contribution of other CYP1-like genes needs to be investigated. Proteins encoded by CYP1-like 1 and 2 genes are plausible candidates for EROD activity observed in gills of C. gigas. PMID- 28623691 TI - Quantification of fenestrations in liver sinusoidal endothelial cells by atomic force microscopy. AB - Liver sinusoidal endothelial cells present unique morphology characterized by the presence of transmembrane pores called fenestrations. The size and number of fenestrations in live cells change dynamically in response to variety of chemical and physical factors. Although scanning electron microscopy is a well-established method for investigation of fixed liver sinusoidal endothelial cells morphology, atomic force microscopy is the interesting alternative providing detailed 3D topographical information. Moreover, simple sample preparation, only by wet fixation, minimizing sample preparation artifacts enable high-resolution atomic force microscopy-based measurements. In this work, we apply imaging methods based on atomic force microscopy, to describe characteristic features of glutaraldehyde fixed primary murine liver sinusoidal endothelial cells, namely: mean fenestration diameter, porosity, and fenestrations frequency. We also investigate the effect of different tip apex radius on evaluation of single fenestration diameter. By quantitative description of fenestrations, we demonstrate that atomic force microscopy became a well competing tool for nondestructive quantitative investigation of the liver sinusoidal endothelial cell morphology. PMID- 28623692 TI - Formulation and characterization of monodisperse O/W emulsions encapsulating astaxanthin extracts using microchannel emulsification: Insights of formulation and stability evaluation. AB - The study used straight-through microchannel emulsification (MCE) to encapsulate different extracts of astaxanthin (AXT) in oil-in-water (O/W) emulsion droplets. We used silicon microchannel plates (WMS 11-1) containing 13,752 discrete 10*104MUm microslots, connected to a circular microhole with a diameter of 10MUm. Two different AXT extracts (AstaReal (AR) and Zenthin(r) (ZR)) based upon concentration and without purification was used as encapsulants in the dispersed phase, while different emulsifiers (1% (w/w) SDS, ML-750, MO-7S, Na-Cs and ML) with different stabilizing mechanisms were used as the continuous phase. The MCE was conducted at a dispersed phase flow rate of 1mLh-1. Successful emulsification was conducted with a Sauter mean diameter of 35-37MUm and relative span factor <0.25. The emulsification was highly depended on the type of emulsifiers and the extract type used during emulsification. Better droplet productivity was achieved with AR extract with 1% (w/w) ML-750 as the optimized emulsifier in Milli-Q Water. The O/W emulsion droplets remained stable at 25 degrees C with encapsulation efficiency of over 98% during 15days of storage period. PMID- 28623693 TI - Control of human skin wettability using the pH of anionic surfactant solution treatments. AB - The outermost layer of human skin, or stratum corneum, acts as a protective barrier between underlying living tissue and the external environment. The wettability of this tissue layer can influence spreading of chemicals and the adhesion of pathogenic microorganisms. We show in this article that the wettability of isolated human stratum corneum can be controlled through treatment with solutions of the anionic surfactant, sodium lauryl sulfate, buffered to different pH values. Relative to control treatments with the buffer solution alone, surfactant solution treatments under acidic conditions cause delipidated stratum corneum to become more hydrophobic. In contrast, alkaline conditions cause the stratum corneum to become more hydrophilic; irrespective of lipid composition. This transition is consistent with a reorientation of bound surfactants at the tissue interface. Under acidic conditions, electrostatic binding of negatively charged surfactant head groups with positively charged keratin in the stratum corneum would increase tissue hydrophobicity due to the exposed hydrophobic tails. However, a hydrophobic based attraction of the apolar surfactant tails to the stratum corneum surface under alkaline conditions would leave the hydrophilic surfactant head groups exposed, causing increased tissue hydrophilicity. Changes in wettability with pH become diminished when lipids ordinarily found in stratum corneum are present, suggesting the lipids partially inhibit surfactant binding. Profilometry studies of the tissue topography highlight that surfactant induced changes in stratum corneum surface roughness cannot account for the observed changes in wettability. PMID- 28623694 TI - Monitoring of nanoclay-protein adsorption isotherms via fluorescence techniques. AB - The investigation of nanoparticles and their interaction with bio-macromolecules have become an important issue; the widely discussed protein corona around nanoparticles and their biological fate in general have drawn particular attention. Here, we focus on nanoclay dispersions and the use of solvatochromic fluorescent dyes (Dansyl and Coumarin 153) for monitoring the interaction with two model proteins, bovine serum albumin and beta-lactoglobulin. On one hand, these dyes are poorly emissive in water, but experience a boost in their fluorescence when adsorbed into the hydrophobic domains of proteins. On the other hand, (nano)clays and clay minerals have previously been investigated in terms of their individual protein adsorption isotherms and their usefulness for the solubilization of water-insoluble dyes into an aqueous environment. In the following, we have combined all three individual parts (nanoclay, fluorophore and protein) in dispersions in a wide range of concentration ratios to systematically study the various adsorption processes via fluorescence techniques. In order to clarify the extent of dye diffusion and adsorption-desorption equilibria in the investigations, nanoclay hybrids with an adsorbed dye (Coumarin 153) and a covalently conjugated dye (Dansyl) were compared. The results suggest that the fluorescence progression of protein titration curves correlate with the amount of protein adsorbed, matching their reported adsorption isotherms on hectorite clays. Furthermore, experimental data on the protein monolayer formation around the nanoclays could be extracted due to only minor alterations of the dispersions' optical quality and transparency. In this manner, a fluorescence based monitor for the formation of the globular protein layer around the nanoclay was realized. PMID- 28623695 TI - Injectable, cytocompatible, elastic, free radical scavenging and electroconductive hydrogel for cardiac cell encapsulation. AB - The injectable electroconductive hydrogels are desirable for the regenerative therapy of electroresponsive tissues like heart. With the present electroconductive hydrogels, the issues of cytotoxicity, biodegradability, and diffusion of the conductive element and poor water solubility limit their applications. Here, electroconductive injectable single component hydrogels, PANIE-P/PEGDA and PANIS-P/PEGDA, are prepared with fumarate-co-PEG-co-sebacate comacromer conjugated with non-sulfonated/sulfonated polyaniline and PEGDA. These hydrogels have maximum electrical conductivity of 0.351+/-0.043*10-3Scm-1 and 0.550+/-0.016*10-3Scm-1, which is comparable to the native myocardium. The hydrogels with 50% comacromer concentration coded as PE50P and PS50P retain 82.48% and 84.08% water on equilibrium swelling respectively. The hydrogels have required a porous surface for cell growth and proliferation. PS50P hydrogel has stiffness of 442kPa with elastic characteristics. The hydrogel is compatible with L929 fibroblast and H9c2 cardiomyoblast cells. PS50P hydrogel has better free radical scavenging property and protective effect over cells under oxidative stress. The hydrogel retains encapsulated cardiomyoblast cells with 98% viability under static long-term in vitro culture. Briefly, the PS50P hydrogel is electroconductive, free radical scavenging and mechanically suitable for cardiac regenerative therapy. PMID- 28623697 TI - Tunable synthesis of the polar modified hyper-cross-linked resins and application to the adsorption. AB - The polar modified hyper-cross-linked resins were synthesized by the suspension polymerization and Friedel-Crafts alkylation reaction, and the effect of the feeding amount of the monomers (N-vinylimidazole and p-vinylbenzyl chloride) on the porosity and polarity were clarified. As the feeding amount of p-vinylbenzyl chloride decreased from 75% to 50% (w/w), the Brunauer-Emmett-Teller surface area of the resins lowered from 1306 to 436 m2/g, and the pore size distribution showed a large population of pores in micropores stretching to a higher percentage of mesopores. As the feeding amount of N-vinylimidazole increased from 5% to 30% (w/w), the nitrogen content of the resins rose from 0.005% to 3.06% (w/w), and the contact angle decreased from 97+/-4.2 degrees to 28+/-2.0 degrees . As a result, the porosity and polarity of the resins could be accurately tuned by adjusting the feeding amount of the monomers, and the different porosity and polarity of these resins endowed them with selective adsorption to benzoic acid and Rhodamine B. PMID- 28623696 TI - Optimizing purification process of MIM-I-BAR domain by introducing atomic force microscope and dynamics simulations. AB - MIM (missing in metastasis) is a member of I-BAR (inverse BAR) domain protein family, which functions as a putative metastasis suppressor. However, methods of gaining high purity MIM-I-BAR protein are barely reported. Here, by optimizing the purification process including changing the conditions of cell lysate and protein elution, we successfully purified MIM protein. The purity of the obtained protein was up to ~90%. High-resolution atomic force microscope (AFM) provides more visual images, ensuring that we can observe the microenvironment around the target protein, as well as the conformations of the purification products following each purification process. MIM protein with two different sizes were observed on mica surface with AFM. Combining with molecular dynamics simulations, these molecules were revealed as MIM monomer and dimer. Furthermore, our study attaches importance to the usage of imidazole with suitable concentrations during the affinity chromatography process, as well as the removal of excessive imidazole after the affinity chromatography process. All these results indicate that the method described here was successful in purifying MIM protein and maintaining their natural properties, and is supposed to be used to purify other proteins with low solubility. PMID- 28623698 TI - Single-component solid lipid nanocarriers prepared with ultra-long chain amphiphilic lipids. AB - HYPOTHESIS: Synthetic sugar alcohol mono-behenates with high melting points, surface activity and resistance to enzymatic lipolysis, are expected to form stable single-component solid lipid nanocarriers (SC-SLNs). The preparation methods and the polar head group of the molecules should affect the size and drug encapsulation efficiency. EXPERIMENTS: SC-SLNs of sugar alcohol mono-behenates with varied polar heads were prepared using emulsification-diffusion method and melting-probe sonication method. Model lipophilic drug fenofibrate was formulated into nanocarriers. The drug release was assessed using the lipolysis model. The structure and drug distribution of the nanocarriers were studied using AFM and TEM. FINDINGS: Both the polar head group of the molecules and the preparation methods affect the particle size and size distribution. Nanocarriers prepared with sorbitol mono-behenates showed the smallest mean size (~100nm with PdI of 0.26). In addition, they displayed high entrapment efficiency of fenofibrate (95%) and long term drug release. Nanocarriers prepared by emulsification diffusion method entrapped fenofibrate into lipid bilayers. In contrast, Nanocarriers prepared by melting-probe sonication method had a micelle structure with fenofibrate incorporated into a lipid monolayer. This study provides an insight into the systematic development of novel amphiphilic lipids for solid lipid-based drug delivery system. PMID- 28623699 TI - The effect of the protein corona on the interaction between nanoparticles and lipid bilayers. AB - HYPOTHESIS: It is known that nanoparticles (NPs) in a biological fluid are immediately coated by a protein corona (PC), composed of a hard (strongly bounded) and a soft (loosely associated) layers, which represents the real nano interface interacting with the cellular membrane in vivo. In this regard, supported lipid bilayers (SLB) have extensively been used as relevant model systems for elucidating the interaction between biomembranes and NPs. Herein we show how the presence of a PC on the NP surface changes the interaction between NPs and lipid bilayers with particular care on the effects induced by the NPs on the bilayer structure. EXPERIMENTS: In the present work we combined Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D) and Neutron Reflectometry (NR) experimental techniques to elucidate how the NP-membrane interaction is modulated by the presence of proteins in the environment and their effect on the lipid bilayer. FINDINGS: Our study showed that the NP-membrane interaction is significantly affected by the presence of proteins and in particular we observed an important role of the soft corona in this phenomenon. PMID- 28623700 TI - Heat release at the wetting front during capillary filling of cellulosic micro substrates. AB - Spontaneous imbibition in cellulosic materials is an expanding field of research due to the direct applicability in paper-based microfluidics. Here, we show experimentally, using simultaneous thermal and optical imaging that the temperature at the wetting front during capillary filling of paper is temporarily increased, even if the imbibed fluid and the cellulosic substrate are initially at isothermal conditions. Several liquids and two types of filter paper, characterised by scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis, were investigated demonstrating a significant temperature rise at the wetting front that cannot be neglected form the process. The temperature rise is found to be related to the energetics of imbibition compounds, including acid base contributions, that result in electrostatic attractions as the liquid molecules are adhered on the fiber surfaces upon capillary contact. PMID- 28623701 TI - Transition temperature of poly(methyl methacrylate) determined by time-of-flight secondary ion mass spectrometry and contact angle measurements. AB - The surface chain conformations of poly(methyl methacrylate) (PMMA) at different temperatures were extensively studied by time-of-flight secondary ion mass spectrometry (ToF-SIMS). Similar to our previous experimental studies on polystyrene (PS) and poly(2, 3, 4, 5, 6-pentafluorostyrene) (5FPS), a transition temperature (TT) could be identified through the principal component analysis (PCA) of the ToF-SIMS spectra obtained from the PMMA samples annealed at different temperatures. Interestingly, our results show that the TT depended on molecular weight and was about 50-60C below the bulk glass transition temperature (Tg) and therefore could possibly be related to the surface glass transition temperature (TgS). These results were confirmed by contact angle measurements. ToF-SIMS results showed higher peak intensities of several low-mass oxygen containing positive ions, hydrocarbon positive ions and OCH3- negative ion at higher temperatures, which can be interpreted by a higher surface concentration of methoxy groups at the surface. PMID- 28623702 TI - Adsorption of ionic surfactants at microscopic air-water interfaces using the micropipette interfacial area-expansion method: Measurement of the diffusion coefficient and renormalization of the mean ionic activity for SDS. AB - The dynamic adsorption of ionic surfactants at air-water interfaces have been less-well studied than that of the simpler non-ionics since experimental limitations on dynamic surface tension (DST) measurements create inconsistencies in their kinetic analysis. Using our newly designed "Micropipette interfacial area-expansion method", we have measured and evaluated both equilibrium and dynamic adsorption of a well-known anionic surfactant, sodium dodecyl sulphate (SDS), in the absence or presence of 100mM NaCl. Our focus was to determine if and to what extent the inclusion of a new correction parameter for the "ideal ionic activity", A+/-i, can renormalize both equilibrium and dynamic surface tension measurements and provide better estimates of the diffusion coefficient of ionic surfactants in aqueous media obtained from electroneutral models, namely extended Frumkin isotherm and Ward-Tordai adsorption models. We found that the estimated value of the new parameter, A+/-i=0.29, is key to obtain the diffusion coefficient D=5.3+/-0.3*10-6cm2/s for SDS, in excellent agreement with the literature. These new technique and analyses can now be applied to study the interfacial adsorption of a range of both ionic and non-ionic surface-active molecules, including the potentially slower-diffusing polymers and biological materials like lipids, peptides, and proteins. PMID- 28623704 TI - Graphene-poly(nickel complex) as novel electrochromic nanocomposite for the fabrication of a robust solid-state device. AB - An electrochromic nanocomposite based on a nickel-salen polymeric film - poly[Ni(3-Mesalen)], Mesalen=N,N'-bis(3-methylsalicylideneiminate) - and graphene nanoplatelets (GFNPs) with enhanced electrochromic stability was successfully prepared by anodic electropolymerization. Although the electrochemical processes typical of the polymer film were not changed by the presence of graphene, higher electroactive surface coverages could be obtained for nanocomposite films, which suggest the incorporation of GFNPs into the polymeric network. The nanocomposite showed multi-electrochromic behavior, with color changes between yellow (reduced state) and green (oxidized state). The inclusion of GFNPs into the poly[Ni(3 Mesalen)] structure accelerates the switching process, with the response time for green coloration decreasing by 50.7% and for yellow coloration by 60.0%, for films prepared with 30 electropolymerization cycles. In terms of electrochemical stability, after 10,000 electrochemical cycles the loss of charge was 7% for the graphene nanocomposite. The nanocomposite film was used as electrochromic material to assemble a flexible solid-state electrochromic device (ECD), which exhibited an outstanding electrochemical stability - only 3% of charge loss after 15days of continuous activity. PMID- 28623703 TI - Praseodymium sorption on Laminaria digitata algal beads and foams. AB - Algal (Laminaria digitata) beads and algal foams have been prepared by a new synthesis mode and the sorbents were tested for praseodymium sorption in batch and fixed-bed like systems (recirculation or one-pass modes), respectively. Metal binding occurs through ion-exchange with Ca(II) ions used for ionotropic gelation of alginate contained in the algal biomass and eventually with protons. Sorption isotherms at pH 4 are described by the Langmuir and the Sips equations with maximum sorption capacities close to 110-120mgPrg-1. Uptake kinetics are fitted by the pseudo-second order reaction rate equation for both beads and foams; in the case of beads the Crank equation also gives good fit of experimental data. Metal is successfully desorbed using 2M HCl/0.05M CaCl2 solutions and the sorbent can be efficiently re-used for a minimum of 5 cycles with negligible decrease in sorption/desorption properties and appreciable concentrating effect (around 8-10 times the initial metal concentration). Tested in continuous mode, the algal foam shows typical breakthrough curves that are fitted by the Yan method; desorption is also efficient and allows under the best conditions to achieve a concentration factor close to 8. PMID- 28623705 TI - Counter-ion transport number and membrane potential in working membrane systems. AB - In this work we use the general space-charge (SC) theory for a combined transport model of fluid and ion through cylindrical nanopores to derive equations for the membrane potential and counter-ion transport numbers. We discuss this approach for ion exchange membranes assuming aqueous domains as interconnected network of cylindrical pores. The transport number calculations from the SC theory are compared with the corresponding ones from the uniform potential (UP) and Teorell Meyer-Sievers (TMS) models in the case of both zero and non-zero concentration gradient across the membrane and with an applied current density. By using this approach we suggest the optimal conditions for performing membrane potential experiments (i.e. choice of electrolyte and concentration difference) depending on an easily accessible membrane property, namely the volumetric charge density. We also theoretically describe a novel dynamic method to determine in a single experiment the membrane potential and membrane conductivity. To exemplify the use of the dynamic method we report the calculations based on typical operating conditions of the reverse electrodialysis process. The numerical results are presented in terms of the electrical potential difference versus the average pore radius and charge density. The resulting map is a useful tool for a rational design of an effective membrane morphology for a specific electrochemical application. PMID- 28623706 TI - Primary inferior vena cava smooth muscle tumor with diffuse bizarre giant nuclei and low mitotic rate: a nomenclatural conundrum. AB - A male patient with obstructive jaundice was found to have an incidental nodule within the inferior vena cava (IVC), below the level of the renal vein, on abdominal imaging. At the time of the Whipple's procedure for pancreatic adenocarcinoma, the IVC mass measuring 3.4*2.7*2.2 cm was also removed. Histologically, the lesion was well circumscribed, composed focally of spindle shaped cells with cigar-shaped nuclei reminiscent of smooth muscle and a dominant pervasive, pleomorphic, bizarre giant cell component. Two mitoses per 10 high power fields were identified in the most mitotically active area of the entire tumor, with the vast majority of the tumor being mitotically inert. Additionally, no evidence of coagulative necrosis was noted. The bizarre giant cells had multi- and polylobated configurations, and several were replete with nuclear pseudoinclusions. Both the spindle cell and pleomorphic components displayed strong immunoreactivity for all smooth muscle markers. This lesion conformed morphologically to a smooth muscle tumor with bizarre nuclei or so-called symplastic/bizarre leiomyoma, as encountered in the uterus. However, current thinking based on location in the IVC and the presence of any mitotic activity with cellular atypia makes this lesion a leiomyosarcoma. Perhaps more pragmatic terminology would be smooth muscle tumor with bizarre nuclei and low malignant potential since the limited number of cases described thus far appear to have a more indolent course. PMID- 28623707 TI - The role of PON-1, GR, IL-18, and OxLDL in depression with and without posttraumatic stress disorder. AB - BACKGROUND: Both oxidative stress markers and inflammatory markers are important when diagnosing depression. Oxidative stress occurs due to an imbalance between free radical generation and antioxidant potential. Both adenosine triphosphate and reactive oxygen/nitrogen species are released during oxidative phosphorylation. When neuroinflammation and free radical production are increased, oxidative stress occurs and causes damage to all major cellular macromolecules. The aim of the study was to compare the concentrations of paraoxonase-1 (PON-1), glutathione reductase (GR), interleukin-18 (IL-18), and oxidized low-density lipoproteins (OxLDL) in depressed patients with and without posttraumatic stress disorder (PTSD), and PTSD alone. METHODS: The number of participants was 460, including 230 males and 230 females. Each study group involved 60 subjects (30 males and 30 females). These were patients with mild depression (MD), moderate depression (MOD), severe depression (SeD), MD and PTSD (MD+PTSD), MOD and PTSD (MOD+PTSD), SeD and PTSD (SeD+PTSD), and with PTSD alone. The control group comprised 40 individuals (20 males and 20 females). At 7:00 a.m. all patients had blood samples collected to determine serum PON-1, GR, IL 18, and OxLDL concentrations using the ELISA test. RESULTS: Depression became more severe as GR, IL-18 and OxLDL concentrations increased and PON-1 concentrations decreased. CONCLUSION: All studied parameters can be considered markers of chronic stress in the above cases. They can be useful when making an early diagnosis and evaluating disease severity. Changes in the concentration levels of GR, IL-18, PON-1, and OxLDL may constitute a biological response to oxidative stress typical of depression. PMID- 28623708 TI - Isobolographic analysis of the cutaneous antinociceptive interaction between bupivacaine co-injected with serotonin in rats. AB - BACKGROUND: The aim of this experiment was to investigate a long-lasting local anesthetic bupivacaine combined with serotonin at inducing cutaneous antinociception. METHODS: The skin antinociception, characterized by an inhibition of the cutaneous trunci muscle reflex (CTMR) following the pinprick on the dorsal skin of rats, was evaluated. The cutaneous antinociceptive effects of bupivacaine alone, serotonin alone, or bupivacaine co-injected with serotonin in a dose-dependent fashion were constructed, while the drug-drug interactions were evaluated by isobologram. RESULTS: Subcutaneous serotonin, as well as the local anesthetic bupivacaine provoked dose-related cutaneous antinociception. On an equipotent basis (50% effective dose [ED50]), the relative potency was bupivacaine (0.43 [0.37-0.50] MUmol)>serotonin (1.27 [1.15-1.40] MUmol) (p<0.01). At the equi-anesthetic doses (ED75, ED50 and ED25), the duration of bupivacaine was similar to that of serotonin at producing cutaneous antinociceptive effects. Co-administration of bupivacaine and serotonin displayed a synergistic antinociception. CONCLUSIONS: The preclinical data demonstrated that serotonin is less potent in eliciting cutaneous antinociceptive effects but has the similar duration of action, compared with bupivacaine. We also found a more significant depth of the sensory block with bupivacaine+serotonin than bupivacaine alone. PMID- 28623710 TI - Application of standard cell cultures and 3D in vitro tissue models as an effective tool in drug design and development. AB - Cell culture systems are essential tools used in a wide range of biomedical and clinical studies. Two dimensional cell culture models (2D) provide basic information on cytotoxicity, penetration and accumulation of drugs in cells and they are of outmost importance when selecting new compounds of the desired biopharmaceutical properties as candidates for novel drugs. The improvement over 2D growing cells are three dimensional (3D) tissue models that mimic in vivo conditions and the functions of living tissue more accurately. These models reduce the cost of drug development, enable more efficient drug screening, minimise failure rate in medicine discovery and eliminate animal use during experiments. The article provides an overview of 2D cell cultures and 3D tissue models - their properties, basic procedures, conditions of culturing and applications. PMID- 28623709 TI - The mechanism of neuroprotective action of natural compounds. AB - Disturbance of cerebral redox homeostasis is the primary cause of human neurodegenerative disorders, such as Parkinson's disease or Alzheimer's disease. Well known experimental research demonstrates that oxidative stress is a main cause of cell death. A high concentration of reactive oxygen and nitrogen species leads to damage of a lot of proteins, lipids and also DNA. Synthetic compounds used for the treatment in the neurodegenerative diseases failed to meet the hopes they had raised and often exhibit a number of side effects. Therefore, in recent years interest in natural compounds derived from plants appears to be on the rise. This review describes a few natural compounds (1MeTIQ, resveratrol, curcumin, vitamin C and Gingko biloba) which revealed neuroprotective potential both in experimental studies and clinical trials. 1MeTIQ has a privileged position because, as opposed to the remaining compounds, it is an endogenous amine synthesized in human and animal brain. Based on evidence from research, it seems that a common protective mechanism for all the above-mentioned natural compounds relies on their ability to inhibit or even scavenge the excess of free radicals generated in oxidative and neurotoxin-induced processes in nerve cells of the brain. However, it was demonstrated that further different molecular processes connected with neurotoxicity (e.g. the inhibition of mitochondrial complex I, activation of caspase-3, apoptosis) follow later and are initiated by the reactive oxygen species. What is more, these natural compounds are able to inhibit further stages of apoptosis triggered by neurotoxins in the brain. PMID- 28623711 TI - Contribution of dopaminergic and noradrenergic systems in the antinociceptive effect of alpha-(phenylalanyl) acetophenone. AB - BACKGROUND: This study evaluated the antinociceptive action of alpha (phenylalanyl) acetophenone (PSAP) in mice. METHODS: Evaluated whether the serotonergic, adrenergic and dopaminergic systems are involved in PSAP antinociceptive activity. PSAP was administered intragastrically (ig) 30min prior to formalin or glutamate test and compared with a standard drug, meloxicam (10mg/kg, ig). RESULTS: The treatment with PSAP (10-50mg/kg) caused inhibition in the neurogenic phase and reduced the paw oedema caused by intraplantar (ipl) injection of formalin. PSAP (1-50mg/kg) decreased the nociceptive response in the inflammatory phase of the formalin test and in licking behaviour triggered by glutamate at doses of 0.1-50mg/kg. The antinociceptive effect of PSAP (1mg/kg) was abolished when the animals were pre-treated with prazosin (alpha1-adrenergic antagonist receptor, 0.15mg/kg, intraperitoneally, ip), yohimbine (alpha2 adrenergic antagonist receptor, 1mg/kg, ip) and sulpiride (D2/D3 dopamine antagonist, 5mg/kg, ip). The antinociceptive effect of PSAP (1mg/kg) was not abolished by WAY100635 (5-HT1A-selective serotoninergic antagonist, 0.7mg/kg, ip), ketanserin (selective antagonist of serotonergic 5-HT2A/2C, 0.3mg/kg, ip), ondansetron (5-HT3 selective serotoninergic antagonist, 0.5mg/kg, ip) or SCH23390 (D1 dopamine receptor antagonist, 0.05mg/kg, ip) in the glutamate test. No changes in locomotor activity were observed in the animals treated with PSAP and/or antagonists in the open field test. CONCLUSION: These results showed the antinociceptive action of PSAP in formalin and glutamate tests and the involvement of the dopaminergic and adrenergic systems in its antinociceptive activity. PMID- 28623712 TI - Deoxypodophyllotoxin induces cytoprotective autophagy against apoptosis via inhibition of PI3K/AKT/mTOR pathway in osteosarcoma U2OS cells. AB - BACKGROUND: A natural compound deoxypodophyllotoxin (DPT) possesses potent anti proliferative and anti-tumor properties on several cancer types. It triggers cell cycle arrest followed by apoptosis through various cellular processes. However, it is limited to the action mechanism of DPT-mediated cell death modes via apoptosis and autophagy. METHODS: Cell viability assay, morphological changes, annexin-V/propidium iodide (PI) assay, reactive oxygen species (ROS), acridine orange staining, and Western blot analyses were evaluated. RESULTS: We demonstrated that DPT induced both apoptosis and autophagy via production of mitochondrial reactive oxygen species (ROS). DPT suppressed the PI3K/AKT/mTOR signaling cascades to lead autophagy process, resulting from conversion of light chain 3-I (LC3-I) into LC3-II and acidic vesicular organelles (AVOs) formation. Even if DPT-induced ROS were occurred in both apoptosis and autophagy, inhibition of ROS generation enhanced cell viability. Otherwise, 3-methyladeine (3-MA) impeding on autophagy accelerated an apoptotic response caused by DPT. Therefore, these findings suggest that DPT triggers cytoprotective autophagy against cytotoxic apoptosis. CONCLUSION: Autophagy is required for cell survival by inhibition of apoptosis through down-regulation of PI3K/AKT/mTOR pathway against DPT-induced apoptosis in U2OS cells. PMID- 28623713 TI - Indirect sinusoidal vibrations induces an acute increase in explosive strength. AB - The purpose of this study was to examine the acute effect of indirect vibration on neuromuscular responses and fatigue resistance (electromyographic activity - EMG and force) during isometric exercise. Nineteen healthy men (age=22.4+/ 2.7years; body mass=76.4+/-12.9kg, height=175+/-6.7cm) performed isometric elbow flexion exercises in three experimental treatments: only isometric exercise (control - CON); isometric exercise with the addition of sinusoidal vibrations (SVE1; frequency=20Hz, displacement=3.55+/-0.54mm); and isometric exercise with the addition of sinusoidal vibrations with frequency variation (SVE2; frequency=20+/-3Hz, displacement=3.6+/-0.8mm). The peak of the rate of EMG rise (RER) and the root mean square of biceps brachii during the first 200ms (RMS200bic) were significantly higher in SVE1 (RMS200bic, 25.57+/-11.70%MVC; RER, 266.91+/-130.16%MVCs-1) than CON (RMS200bic, 19.31+/-8.19%MVC; RER, 169.15+/ 65.98%MVCs-1). Regarding force, in SVE1, compared to CON, significant increases were observed in peak of rate of force development (CON, 643.96+/-192.57N/s; SVE1, 845.54+/-292.84N/s), rate of force development in the first 200ms (CON, 382.92+/-138,63N/s; SVE1, 501.09+/-147.46N/s), and impulse in 200ms (CON, 8.56+/ 3.56Ns; SVE1, 11.67+/-4.45Ns). The addition of indirect sinusoidal vibrations during exercise induced increases in the rate of force development (explosive strength), without affecting the peak force (maximal strength) and the ability to sustain strength production. PMID- 28623714 TI - Can the co-dependence of the immune system and angiogenesis facilitate pharmacological targeting of tumours? AB - Tumours elicit a number of mechanisms to induce a reprogramming of innate and adaptive immune cells to their advantage, inducing a pro-angiogenic phenotype. Investigation of these events is now leading to the identification of specific myeloid and lymphoid cell-targeted therapies, as well as of unexplored off-target activities of clinically relevant chemotherapeutic and metabolic drugs. It is also leading to an enhanced understanding of the interplay between angiogenesis and the immune system, and the value of novel co-targeting approaches using both immunotherapy and anti-angiogenic therapy. Here, we review recently identified mechanisms and potential pharmacological approaches targeting the crosstalk between cancer cells and the host immune system, providing an overview on novel therapeutic opportunities linking immuno-oncology and anti-angiogenic therapy. PMID- 28623715 TI - Diosgenin glucoside provides neuroprotection by regulating microglial M1 polarization. AB - The selective suppression of inflammatory factors in activated microglia, rather than totally inhibiting their activation, might be an effective means of slowing the progression of certain neurodegenerative diseases. Diosgenin glucoside (Dios) is a saponin compound extracted from Tritulus terrestris L. We found that Dios suppressed the synthesis of molecules that promote inflammation (M1 markers, such as NO, IL-6, and TNF-alpha) in rat microglia and BV-2 cells induced with lipopolysaccharides (LPS). In contrast, Dios had no effects on the cellular production of anti-inflammatory factors (M2 markers, such as IL-10, IL-1Ralpha and CD206) in LPS and IL-4 treated microglia. Dios repressed IkappaB-alpha, ERK MAPK and p38 MAPK phosphorylation, but did not affect JNK in LPS-activated microglia. We also found that conditioned medium obtained from cultures of BV-2 cells incubated with Dios plus LPS was markedly less neurotoxic than conditioned medium obtained from cultures of BV-2 cells incubated with LPS alone. In conclusion, this study demonstrated that Dios can selectively suppress the production/expression of pro-inflammatory M1 markers by activated microglia, without affecting M2 markers, and might provide neuroprotection by regulating microglial M1 polarization. Our results suggest that Dios can be used in treatment of various neuroinflammatory diseases mediated by microglia. PMID- 28623716 TI - Aldose reductase inhibitors attenuate beta-amyloid-induced TNF-alpha production in microlgia via ROS-PKC-mediated NF-kappaB and MAPK pathways. AB - Microglia-mediated neuroinflammation is a key risk factor to the development of Alzheimer' disease (AD). Aldose reductase (AR) has been found to be widely involved in inflammation-related diseases; however, whether aldose reductase inhibitors (ARIs) could be used to treat neuroinflammation is rarely reported. This study aims to evaluate the anti-neuroinflammatory effects of two major ARIs of Sorbinil (Sor) and Zopolrestat (Zol) in beta-amyloid protein (Abeta)-induced microglia (BV-2). We find that Sor and Zol significantly inhibit TNF-alpha, IL 1beta, IL-6 production from microglia in response to Abeta stimulation. Mechanism study showed that Sor and Zol decreased the production of intracellular ROS which resulted in an effective inhibition on the phosphorylation of several protein kinase C (PKC) isoforms including PKCalpha/beta, delta, zeta/lambda and mu. Moreover, Sor and Zol inactivated PCK-associated IKKbeta-IkappaB-NF-kappaB and mitogen-activated protein kinase (JNK, p38, ERK) inflammation pathways. In summary, our findings suggest that Sor and Zol could inhibit Abeta-induced neuroinflammation by regulating ROS/PKC-dependent NF-kappaB and MAPK signaling pathways, indicating that ARIs could be promising agents for treating inflammation-related neurodegenerative diseases such as AD. PMID- 28623717 TI - Baicalein exerts anti-neuroinflammatory effects to protect against rotenone induced brain injury in rats. AB - Baicalein, a major bioactive flavone constituent isolated from Scutellaria baicalensis Georgi, has been shown to be neuroprotective in several Parkinson's disease (PD) animal models. Since neuroinflammation has been known to play a critical role in the pathogenesis of PD, potential explanation for the neuroprotective action of anti-PD compounds involves among others reduced inflammation. Our study investigated that one of the mechanisms of protection afforded by baicalein in rotenone-induced parkinsonian rats was associated with anti-inflammatory action and explored its underlying mechanism in vivo and in vitro. The results showed that baicalein treatment improved motor impairments, attenuated brain damage, suppressed the production of proinflammatory cytokines (tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6)), modulated the astrocytes and microglia activation, and blocked the activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signals in rotenone-induced rats of PD. Furthermore, treatment of baicalein prominently suppressed the generation of nitric oxide (NO) and the expression of inducible NO synthase (iNOS) protein by blocking LPS-induced IkappaBalpha phosphorylation and NF-kappaB translocation, and downregulated the Toll-like receptor 4 (TLR4) which functions in the upstream of NF-kappaB signal in the activated BV2 microglia. In conclusion, our studies suggest that baicalein may be effective in the treatment of PD through anti-neuroinflammation. PMID- 28623718 TI - Transcranial direct current stimulation (tDCS) reveals a dissociation between SNARC and MARC effects: Implication for the polarity correspondence account. AB - The concept of stimulus response compatibility (SRC) refers to the existence of a privileged association between a specific stimulus feature and a specific response feature. Two examples of SRC are the Spatial Numerical Association of Response Codes (SNARC) and the Markedness Association of Response Codes (MARC) effects. According to the polarity correspondence principle, these two SRC effects occur because of a match between the most salient dimensions of stimulus and response. Specifically, the SNARC effect would be caused by a match between right-sided responses and large numbers, while a match between right-sided responses and even numbers would give rise to the MARC effect. The aim of the present study was to test the validity of the polarity correspondence principle in explaining these two SRC effects. To this end, we applied transcranial direct current stimulation (tDCS) over left and right posterior parietal cortex (PPC), which is thought to be the neural basis of salience processing, during a parity judgement task. Results showed that cathodal tDCS over the PPC significantly reduced the MARC effect but did not affect the SNARC effect, suggesting a dissociation between the two effects. That is, the MARC would rely on a salience processing mechanism, whereas the SNARC would not. Despite this interpretation is in need of further experimental confirmations (i.e., testing different tasks or using different tDCS montages), our results suggest that the polarity correspondence principle can be a plausible explanation only for the MARC effect but not for the SNARC effect. PMID- 28623719 TI - The CRISPR-Cas app goes viral. AB - If biology laboratories were smartphones, CRISPR-Cas would be the leading app. Nowadays, technology users rely on apps to communicate, get directions, entertain, and more. Likewise, many life scientists now rely on CRISPR-Cas systems to study the interactions between microbes and their viruses, to track strains as well as to modify and modulate genomes. Considering their high level of polymorphism, CRISPR arrays can increase the resolution of a microbial typing scheme. As dynamic systems, they allow the identification and the tracking of specific sequences, which is highly valuable for epidemiological studies. As a defense mechanism, they offer an opportunity to generate virus-resistant strains or even to construct strains refractory to the acquisition of specific genes. And last but not least, as customizable and transferable tools, CRISPR-Cas systems are particularly promising to fight multi-drug resistant bacteria through the engineering of phages. PMID- 28623720 TI - Next-generation precision antimicrobials: towards personalized treatment of infectious diseases. AB - Antibiotics started to be used almost 90 years ago to eradicate life-threatening infections. The urgency of the problem required rapid, broad-spectrum elimination of infectious agents. Since their initial discovery, these antimicrobials have saved millions of lives. However, they are not exempt from side effects, which include the indiscriminate disruption of the beneficial microbiota. Recent technological advances have enabled the development of antimicrobials that can selectively target a gene, a cellular process, or a microbe of choice. These strategies bring us a step closer to developing personalized therapies that exclusively remove disease-causing infectious agents. Here, we advocate the preservation of our beneficial microbes and provide an overview of promising alternatives to broad-spectrum antimicrobials. Specifically, we emphasize nucleic acid and peptide-based systems as a foundation for next-generation alternatives to antibiotics that do not challenge our microbiota and may help to mitigate the spread of resistance. PMID- 28623721 TI - Macrophage phenotypic mechanomodulation of enhancing bone regeneration by superparamagnetic scaffold upon magnetization. AB - Macrophages are involved in all phases of scaffold induced tissue regeneration, orchestrating the transition from an inflammatory to regenerative phenotype to guide all other cell types to complete the wound healing process when a tissue defect advances beyond the critical size. Therefore, harnessing macrophages by scaffolds is important for facilitating tissue regeneration in situ. In this work we utilized the superparamagnetic scaffold upon magnetization as a mechanostimulation platform to apply forces directly to macrophages grown in the scaffold, aiming to figure out whether the functions of macrophages related to bone tissue regeneration can be mechanomodulated and to elucidate the underlying mechanisms. We showed the first evidence that upon magnetization the interaction of superparamagnetic scaffolds to macrophages drove them to polarize towards an M2-like phenotype by inhibiting TLR2/4 activation and enhancing VEGFR2 activation, thereby inhibiting secretion of the pro-inflammatory cytokines IL 1beta, TNF-alpha and MCP-1, as well as the osteoclast differentiation cytokines MMP-9 and TRAP, and up-regulating VEGF and PDGF. The conditioned media enhanced the osteogenesis of osteoblasts and the angiogenesis of endothelial cells. PMID- 28623722 TI - Recent advances in synthetic biology for engineering isoprenoid production in yeast. AB - Isoprenoids (terpenes/terpenoids) have many useful industrial applications, but are often not produced at industrially viable level in their natural sources. Synthetic biology approaches have been used extensively to reconstruct metabolic pathways in tractable microbial hosts such as yeast and re-engineer pathways and networks to increase yields. Here we review recent advances in this field, focusing on central carbon metabolism engineering to increase precursor supply, re-directing carbon flux for production of C10, C15, or C20 isoprenoids, and chemical decoration of high value diterpenoids (C20). We also overview other novel synthetic biology strategies that have potential utility in yeast isoprenoid pathway engineering. Finally, we address the question of what is required in the future to move the field forwards. PMID- 28623723 TI - DFT/B3LYP calculations, in vitro cytotoxicity and antioxidant activities of steroidal pyrimidines and their interaction with HSA using molecular docking and multispectroscopic techniques. AB - As a part of our continuing program on the synthesis of steroidal heterocycles, it has been prepared a series of novel steroidal pyrimidine derivatives 4-6via TMSCl, steroidal ketones (1c-3c), urea and benzaldehyde. The systems presented here, are novel scaffolds and have not been described before at 6th position of steroidal-6-one (1c-3c). Structural assignment of newly synthesized compounds was performed by DFT/B3LYP calculations as well as spectral and analytical data. The interactions of compounds (4-6) with HSA were studied by fluorescence spectroscopy, DLS, CD and molecular docking, under imitated physiological conditions. The antitumor activity has been tested in vitro against three cancer cell lines MDA-MB231 (breast carcinoma), HeLa (human cervical carcinoma), HepG2 (hepatic carcinoma) and one non-cancer normal cell lines, PBMCs (peripheral blood mononuclear cell) by MTT assay. In addition, in vitro antioxidant activity and apoptosis assay of the synthesized compounds (4-6) have also been investigated. PMID- 28623724 TI - Sub-lethal pharmaceutical hazard tracking in adult zebrafish using untargeted LC MS environmental metabolomics. AB - Antibiotics in the aquatic environment are dispersed through anthropogenic activities at low concentrations. Despite their sub lethal concentration, these biologically active compounds may still have adverse effects to non-target species. This study examined the response of adult zebrafish to 0.1mg/L concentration of clarithromycin, florfenicol, sulfamethazine, and their mixture using environmental metabolomics. Embryo and larvae of the fish were also used to assess fish embryo acute toxicity and behavior tests respectively. The fish embryo toxicity test did not show any inhibition of growth and development of the embryos after 96h of exposure to the antibiotics. Changes in swimming activity were seen in 5-dpf larvae which is believed to be correlated with the length of exposure to the compounds. Meanwhile, environmental metabolomics revealed diverse metabolites and pathways that were affected after 72h of exposure of the adult fish to sub-lethal concentration of the compounds. We found that even at low concentration of the antibiotics, behavioral and metabolic effects were still observed despite the lack of visible morphological changes. Further studies involving other aquatic organisms and bioactive compounds are encouraged to strengthen the findings presented in this novel research. PMID- 28623725 TI - A new route to the stable capture and final immobilization of radioactive cesium. AB - Radioactive Cs released from damaged fuel materials in the event of nuclear accidents must be controlled to prevent the spreading of hazardous Cs into the environment. This study describes a simple and novel process to safely manage Cs gas by capturing it within ceramic filters and converting it into monolithic waste forms. The results of Cs trapping tests showed that CsAlSiO4 was a reaction product of gas-solid reactions between Cs gas and our ceramic filters. Monolithic waste forms were readily prepared from the Cs-trapping filters by the addition of a glass frit followed by thermal treatment at 1000 degrees C for 3h. Major findings revealed that the Cs-trapping filters could be added up to 50wt% to form durable monoliths. In 30-50wt% of waste fraction, CsAlSiO4 was completely converted to pollucite (CsAlSi2O6), which is a potential phase for radioactive Cs due to its excellent thermal and chemical stability. A static leaching test for 28 d confirmed the excellent chemical resistance of the pollucite structure, with a Cs leaching rate as low as 7.21*10-5gm-2/d. This simple scheme of waste processing promises a new route for radioactive Cs immobilization by synthesizing pollucite-based monoliths. PMID- 28623726 TI - Diagnostic causal reasoning with verbal information. AB - In diagnostic causal reasoning, the goal is to infer the probability of causes from one or multiple observed effects. Typically, studies investigating such tasks provide subjects with precise quantitative information regarding the strength of the relations between causes and effects or sample data from which the relevant quantities can be learned. By contrast, we sought to examine people's inferences when causal information is communicated through qualitative, rather vague verbal expressions (e.g., "X occasionally causes A"). We conducted three experiments using a sequential diagnostic inference task, where multiple pieces of evidence were obtained one after the other. Quantitative predictions of different probabilistic models were derived using the numerical equivalents of the verbal terms, taken from an unrelated study with different subjects. We present a novel Bayesian model that allows for incorporating the temporal weighting of information in sequential diagnostic reasoning, which can be used to model both primacy and recency effects. On the basis of 19,848 judgments from 292 subjects, we found a remarkably close correspondence between the diagnostic inferences made by subjects who received only verbal information and those of a matched control group to whom information was presented numerically. Whether information was conveyed through verbal terms or numerical estimates, diagnostic judgments closely resembled the posterior probabilities entailed by the causes' prior probabilities and the effects' likelihoods. We observed interindividual differences regarding the temporal weighting of evidence in sequential diagnostic reasoning. Our work provides pathways for investigating judgment and decision making with verbal information within a computational modeling framework. PMID- 28623727 TI - Current clinical magnetoencephalography practice across Europe: Are we closer to use MEG as an established clinical tool? AB - PURPOSE: This comprehensive survey aims at characterizing the current clinical use of magnetoencephalography (MEG) across European MEG centres. METHODS: Forty four MEG centres across Europe were contacted in May 2015 via personalized e-mail to contribute to survey. The web-based survey was available on-line for 1 month and the MEG centres that did not respond were further contacted to maximize participation. RESULTS: Among the 57% of responders, 12 centres from 10 different countries reported to use MEG for clinical applications. A total of 524 MEG investigations were performed in 2014 for the pre-surgical evaluation of epilepsy, while in the same period 244 MEG investigations were performed for pre surgical functional brain mapping. Seven MEG centres located in different European countries performed >=50 MEG investigations for epilepsy mapping in 2014, both in children and adults. In those centres, time from patient preparation to MEG data reporting tends to be lower than those investigating a lower annual number of patients. CONCLUSION: This survey demonstrates that there is in Europe an increasing and widespread expertise in the field of clinical MEG. These findings should serve as a basis to harmonize clinical MEG procedures and promote the clinical added value of MEG across Europe. MEG should now be considered in Europe as a mature clinical neurophysiological technique that should be used routinely in two specific clinical indications, i.e, the pre surgical evaluation of refractory focal epilepsy and functional brain mapping. PMID- 28623728 TI - Epilepsy surgery in patients older than 50 years: Effectiveness, safety, and predictors of outcome. AB - PURPOSE: Surgery is an effective treatment for drug resistant focal epilepsy. Predictors of seizure outcome have been extensively addressed in the general population but similar data on older patients are still lacking. The aim of this study is to evaluate effectiveness and safety of surgery for patients over 50 years and to investigate variables associated to seizure outcome. METHODS: We performed a single center retrospective study including 50 patients over 50 years treated surgically for drug resistant focal epilepsy between 1997 and 2014. We analyzed the rate of success of seizure control, the association of several clinical variables with seizure outcome and the rate of surgery-related complications. We also investigated the impact of surgery on the patients' cognitive performances and mood profile. RESULTS: At last follow-up 78% of our patients were seizure-free, similar to patients younger than 50 years operated on in the same period (p=1). The rate of surgery-related complications was 10%, higher compared to younger patients (p<0.0001). Pre-surgical daily seizure frequency (p=0.0040) and the histological diagnosis of LEAT (p=0.0233) were associated to a poorer seizure outcome. No significant differences were evidenced between pre- and postoperative neuropsychological profiles. A slight, not statistically significant improvement of the mood profile was observed postoperatively. CONCLUSION: Our results suggest that surgery is an effective treatment option also for older epileptic patients, although it is burdened by a higher surgical risk as compared to younger patients. The availability of predictors of outcome also for these patients may be helpful for pre-surgical counseling. PMID- 28623729 TI - Host-microbiota interactions in Caenorhabditis elegans and their significance. AB - As a useful genetic model, C. elegans can facilitate investigation of the genetic underpinnings of host-microbiota interactions. However, decades of feeding it with Escherichia coli left a gap in our understanding of its interactions with microbes, hindering such use. This is changing, with recent studies characterizing the gut microbiota of worms in their natural habitats, comparing them to those in their environment, and evaluating the significance of gut and environmental commensals. This work defined a shared core gut microbiota significantly influenced by host genetics, and unraveled bacterial contributions to life history traits. Establishing C. elegans as a new model of host-microbiota interactions will benefit from existing knowledge about bacterial modulation of worm physiology, and could draw mechanistic insights from characterized interactions between parasitic nematodes and their symbionts. PMID- 28623730 TI - Quantitative microscopy based on single-molecule fluorescence. AB - Quantitative microscopy is needed to understand reactions or phenomena carried out by biological molecules such as enzymes, receptors, and membrane-localized proteins. Counting the biomolecules of interest in single organelles or cellular compartments is critical in these approaches. In this brief perspective, we focus on the development of quantitative fluorescence microscopies that measure the precise copy numbers of proteins in cellular organelles or purified samples. We introduce recent improvements in quantitative microscopies to overcome undercounting or overcounting errors in certain conditions. We conclude by discussing biological applications. PMID- 28623732 TI - Safety and acceptability of transcranial direct current stimulation for the acute treatment of major depressive episodes: Analysis of individual patient data. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation modality that has been increasingly used for major depressive disorder (MDD) treatment. Although studies in healthy volunteers showed that the technique is well-tolerated, tDCS safety and acceptability have not been sufficiently explored in patients with MDD. METHODS: We collected individual patient data from 6 randomized clinical trials that had been previously identified in a systematic review and meta-analysis. Primary outcomes were safety (rate of adverse events) and acceptability (rate of dropouts). Secondary outcomes were clinical, demographic and treatment predictors of the primary outcomes. RESULTS: Dropout rates between active (8.8%) and sham (12%) groups were not significantly different (OR= 0.7, p=0.38). Adverse event rates between active (73.5%) and sham (68.3%) groups were not significantly different (OR= 1.4, p= 0.23). Higher current densities were associated with lower adverse event rates. LIMITATIONS: Dropout reasons were not systematically reported and adverse events were not collected using questionnaires standardized across studies. CONCLUSIONS: Active tDCS is as acceptable and safe as sham tDCS, as found in randomized clinical trials of MDD. PMID- 28623731 TI - New Cu(II) complexes with pyrazolyl derived Schiff base ligands: Synthesis and biological evaluation. AB - Since the discovery of cisplatin there has been a continuous pursuit for new metallodrugs showing higher efficacies and lower side effects. In this work, new copper(II) complexes (C1-C6) of Schiff bases derived from pyrazolyl were developed. Through condensation of 5-methyl-1H-pyrazole-3-carbohydrazide with different aromatic aldehydes - pyridoxal, salicylaldehyde, 3-methoxy-2 hydroxybenzaldehyde, 3-ethoxy-2-hydroxybenzaldehyde and 2-hydroxynaphthene-1 carbaldehyde - a set of new pyrazole based "ONO" tridentate Schiff bases were obtained in moderate to good yields - L1-L6, as well as their Cu(II)-complexes. All compounds were characterized by analytical techniques and their molecular formulae established. The antioxidant potential of all compounds was tested, yielding low activity in most cases, with the exception of L1 and C5. The Cu(II) complexes were tested for their aqueous stability, and for their interaction with biological molecules, namely DNA and HSA (human serum albumin), through fluorescence quenching experiments (and electrophoresis for DNA). With the exception of C3, all the synthesized complexes were able to interact with DNA and HSA. Their cytotoxic activity against two cancer cell lines (MCF7 - breast and PC3 - prostate) was also evaluated. Complexes C5 and C6, with larger aromatic systems, showed much higher cytotoxicity (in the low MUM range), than C1-C4, as well as IC50 values much lower than cisplatin. For C6 the results suggest that the mechanisms of cell death do not seem to be mediated by apoptosis, through caspases 3/7 activation, but by involving membrane potential and imbalance in physiological elements such as P, K and Ca. PMID- 28623733 TI - A novel immune-related gene HDD1 of silkworm Bombyx mori is involved in bacterial response. AB - Insects have evolved an effective immune system to respond to various challenges. In this study, a novel immune-related gene, called BmHDD1, was first charactered in silkworm, Bombyx mori. BmHDD1 contained an ORF of 837bp and encoding a deduced protein of 278 amino acids. BmHDD1 was specifically expressed in hemocytes, and highly expressed at the molting and metamorphosis stages under normal physiological conditions. Our results suggested that BmHDD1 was mainly generated by hemocytes and secreted into hemolymph. Our results also showed that the expression level of BmHDD1 was significantly increased after 20E injection, which indicated that BmHDD1 might be regulated by ecdysone. More importantly, BmHDD1 was dramatically induced after injected with different types of PAMPs or bacteria, either in hemocytes or fat body. Those results suggested that BmHDD1 plays a role in developing and immunity system in silkworm, Bombyx mori. PMID- 28623734 TI - Ig-seq: Deep sequencing of the variable region of Atlantic salmon IgM heavy chain transcripts. AB - Immunoglobulin M plays a key role in systemic protection of Atlantic salmon against pathogens. Until recent, studies have focused on antigen-specific antibodies and little is known about the IgM repertoire: its size, developmental changes and responses to antigens. We report the development of deep sequencing protocol to characterize the repertoire of IgM heavy chain variable region. Its structure and changes were examined at the early stages of life and after infection with virus of cardiac myopathy. Clonotypes are identified by the V and J gene segments and amino acid sequences of CDR3, which determine the contribution of the heavy chain to the antigen binding properties. A major fraction of transcripts are functional while the rest are either sterile (transcribed from noncoding parts of Ig loci) or include stop codons. Despite marked difference in frequencies of combinations of V and J genes, the size of repertoire is large. The IgM diversity steadily increases after hatch followed with temporal reduction during smoltification and recovery after seawater transfer. Most clonotypes are present only in one fish. However multiple transcripts in uninfected fish are produced exclusively from a small fraction of shared clonotypes. While only 4.7% of clonotypes are detected in three and more fish, they comprise 35% of transcripts. Increased frequencies of most abundant clonotypes were detected in the head kidney and blood at ten weeks after viral infection and all were shared. Occurrence of the same clonotypes in multiple individuals can be explained with either their simple structure or exposure to common antigens. Complexity of CDR3 assessed by contents of non complementary nucleotides is slightly lower in shared clonotypes but difference is small. High nucleotide diversity of CDR3 with identical amino acid sequences suggests selection. PMID- 28623735 TI - Biochemical and structural characterization of Penicillium purpurogenum alpha-D galactosidase: Binding of galactose to an alternative pocket may explain enzyme inhibition. AB - The fungus Penicillium purpurogenum degrades plant cell walls by the action of cellulolytic, xylanolytic and pectinolytic enzymes. The alpha-D-galactosidase is one of the enzymes which may act on pectin degradation. This enzyme has several biotechnological and medical applications. The aim of this work was to better understand the molecular mechanism of alpha-D-galactosidase from P. purpurogenum (GALP1). For this purpose, a gene coding for the enzyme was identified from the fungal genome and heterologously expressed in Pichia pastoris. The enzyme belongs to glycosyl hydrolase family 27. The protein of 435 amino acids has an optimum pH and temperature for activity of 5.0 and 50 degrees C, respectively. The KM for p nitrophenyl-alpha-D-galactopyranoside (GalalphapNP) is 0.138 mM. The enzyme is inhibited by GalalphapNP at concentrations higher than 1 mM, and by the product galactose. A kinetic analysis of product inhibition shows that it is of mixed type, suggesting the presence of an additional binding site in the enzyme. To confirm this hypothesis, a structural model for GALP1 was built by comparative modelling methodology, which was validated and refined by molecular dynamics simulation. The data suggest that galactose may bind to an enzyme alternative pocket promoting structural changes of the active site, thus explaining its inhibitory effect. In silico site-directed mutagenesis experiments highlighted key residues involved in the maintenance of the alternative binding site, and their mutations for Ala predict the formation of proteins which should not be inhibited by galactose. The availability of an alpha-galactosidase with different kinetic properties to the existent proteins may be of interest for biotechnological applications. PMID- 28623736 TI - Glycerol mycolates from synthetic mycolic acids. AB - R- and S-Glycerol mycolates derived from single synthetic alpha-, keto- and methoxy-mycolic acids are described. PMID- 28623737 TI - Rumpictuside A: Unusual 9,10-anthraquinone glucoside from Rumex pictus Forssk. AB - A new 8-ionized hydroxylated 9,10-anthraquinone namely, 1-hydroxy-3-methyl-9,10 anthraquinone-6-O-beta-D-glucopyranoside-8-olate (Rumpictuside A, 1) along with five known flavonoids, apigenin 7-O-beta-D-glucoside (2), vitexin (3), quercetin 3-O-beta-D-glucouronide (4), orientin (5), and isorientin (6) were isolated from Rumex pictus. The structures of isolated compounds were identified by the extensive spectroscopic techniques such as, UV, FT-IR, 1D, 2D NMR and HR-FAB-ESI MS. The ionized hydroxyl group in the new anthraquinone (1) was rarely found for anthraquinone glycosides isolated from natural sources. All the isolated compounds were found inactive against influenza A virus infection. Compounds 2-6 exhibited significant antioxidant activity against DPPH and ABTS+. The alcoholic extract exhibited moderate activity while the new anthraquinone 1 showed the lowest activity against both assays. PMID- 28623738 TI - Iridoids from the roots of Valeriana jatamansi Jones. AB - Five iridoids, named as chlorovaltrate P-T, together with six known analogues, (4beta,8beta)-8-methoxy-3-methoxy-10-methylene-2,9-dioxatricyclo[4.3.1.03,7]decan 4-ol, chlorovaltrate A, (1R,3R,5R,7S,8R,9S)-3,8-epoxy-1-O-ethyl-5 hydroxyvalechlorine, 8-methoxy-4-acetoxy-3-chlormethyl-10-methylen-2,9-dioxa tricyclo[4.3.1.03,7]decan, (1S,3R,5R,7S,8R,9S)-3,8-epoxy-1-O-ethyl-5 hydroxyvalechlorine, (1R,3R,5R,7S,8R,9S)-3,8-epoxy-1-O-methyl-5 hydroxyvalechlorine were isolated from the roots of Valeriana jatamansi (syn. Valeriana wallichii). Their structures were elucidated by extensive analysis of 1D, 2D NMR and HRESIMS spectroscopic. The absolute configuration of chlorovaltrate P-T were established by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. 3,8-epoxy iridoids exhibited weak cytotoxicity against the lung adenocarcinoma (A 549) and gastric carcinoma cells (SGC 7901). Some also showed moderate neuroprotective effects against CoCl2-induced neuronal cell death in PC12 cells. PMID- 28623739 TI - High-density lipoprotein cholesterol levels are associated with coronary severity but not with outcomes in new-onset patients with stable coronary artery disease. AB - BACKGROUND AND AIMS: The atheroprotective role of high-density lipoprotein cholesterol (HDL-C) levels in coronary artery disease (CAD) remains controversial. This study sought to reappraise the value of HDL-C in predicting the severity and outcomes of new-onset patients with stable CAD in Chinese populations. METHODS: A total of 4205 new-onset patients with stable CAD who received coronary angiography were enrolled to analyze the relation of HDL-C to coronary severity and major adverse cardiovascular events (MACEs). Coronary severity was evaluated by Gensini scoring system. The MACEs included all-cause death, non-fatal myocardial infarction, stroke, unplanned revascularization and hospitalized unstable angina. RESULTS: Significantly, HDL-C levels were negatively associated with coronary severity (p < 0.001). During an average of 27.32-month follow-up, 341 (8.12%) MACEs occurred. There was no significant difference of HDL-C levels between events group and non-events group. Furthermore, both Kaplan-Meier and Cox regression analyses found no relationship between HDL-C and cardiovascular outcomes (p > 0.05). CONCLUSIONS: Plasma HDL-C levels appeared to be a predicator for coronary severity, but it is not associated with clinical outcomes in new-onset, Chinese patients with stable CAD. PMID- 28623740 TI - Detection of atherosclerotic cardiovascular disease influences the perceived need for aggressive lipid management. AB - BACKGROUND AND AIMS: Overt atherosclerotic cardiovascular disease (ASCVD) warrants aggressive lipid lowering. Imaging for ambiguous symptoms suggesting ischemia or for clarification of CV risk in asymptomatic individuals often uncovers previously unknown ASCVD. Guidelines do not provide clear recommendations for aggressive lipid lowering in such cases. We explored physicians' perception, as influenced by tests that detect ASCVD, regarding appropriateness of getting to lipid goals and for theoretically accessing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i). METHODS: A questionnaire was developed including cases of low to high CV risk, chronic kidney disease (CKD) or type 2 diabetes mellitus (T2DM). Each case was considered with or without angina symptoms and, in turn, whether testing identified previously unknown advanced, early/subclinical or no ASCVD. Synthesis of responses was facilitated by using a scale for perceived appropriateness from 1 (lowest) to 9 (highest). RESULTS: Getting to goal and, if not achieved by statins and/or ezetimibe, accessing PCSK9i was considered appropriate in patients with T2DM with preclinical or advanced ASCVD, patients with moderate or high CV risk and advanced ASCVD, patients with CKD or low CV risk with angina symptoms and advanced ASCVD. For most of the remaining cases adding PCSK9i was considered only possibly appropriate. CONCLUSIONS: Physicians' perception of appropriateness for achieving lipid goals, including access to PCSK9i, is markedly influenced by detection of previously unknown ASCVD. Since these commonly encountered scenarios do not clearly meet current indications for PCSK9i, our data identify pressing areas requiring further research. PMID- 28623741 TI - Oxidized LDL activated eosinophil polarize macrophage phenotype from M2 to M1 through activation of CD36 scavenger receptor. AB - BACKGROUND AND AIMS: Inflammation, particularly innate immunity, plays an important role in cardiovascular diseases. The aim of this study was to investigate whether atherogenic determinants such as oxidized LDL modulate the phenotype of eosinophils. METHODS: Cultured eosinophils were treated with oxidized LDL and the expression of selective inflammatory and anti-inflammatory cytokines was determined. In addition, the eosinophil receptor and signaling that mediate these events were identified. RESULTS: Treatment of cultured eosinophils with oxidized LDL (Ox-LDL) specifically induced the expression of IFNalpha and IFNbeta without affecting expression of other proinflammatory cytokines, such as TNFalpha, IL-1beta, and IL-6. In macrophages, Ox-LDL downregulated expression of both IFNalpha and IFNbeta, suggesting that the effect of Ox-LDL on the expression of type I interferons is specific to eosinophils. Furthermore, we noted that eosinophils constitutively expressed IL-4 and IL-13, and Ox-LDL markedly downregulated their expression. Analysis of Ox-LDL signaling revealed that eosinophils constitutively expressed SRB2, CD36, and CD68 scavenger receptors, and Ox-LDL markedly induced the expression of CD36. Further analysis of CD36 signaling by siRNA and neutralizing antibodies showed that the induction of type I IFN by Ox-LDL is mediated by CD36 signaling whereas downregulation of IL-4 is independent of CD36 activation. We further showed that peritoneal macrophages treated with condition medium collected from Ox-LDL treated eosinophils markedly induced the expression of M1 markers such as iNOS, IL6, SOSC3 and TNFalpha whereas the condition medium from non-treated eosinophils significantly induced expression of M2 markers like ARG1 and CCL24. CONCLUSIONS: Our data suggest that an atherogenic condition could activate eosinophils and modulate the phenotype of macrophages (from M2 to M1 phenotype), in part, through the CD36 receptor signaling. PMID- 28623742 TI - Effect of intensive LDL cholesterol lowering with PCSK9 monoclonal antibodies on tendon xanthoma regression in familial hypercholesterolemia. AB - BACKGROUND AND AIMS: The effect of LDLc lowering with PCSK9 antibodies on tendon xanthomas (TX) is unknown. METHODS: TX was measured in 24 heterozygous familial hypercholesterolemia (HeFH) cases and in 24 HeFH controls with or without PCSK9 inhibitors for at least one year. RESULTS: Exposure to PCSK9 inhibitors in cases was 2.96 +/- 1.33 years. LDLc decreased 80.8 +/- 7.66% in cases and 56.9 +/- 11.1% in controls. There was a decrease in maximum (-5.03%) and mean (-5.32%) TX in cases but not in controls (+3.97%, +3.16, respectively, p = 0.01). PCSK9 inhibitor treatment was independently associated with TX reduction. CONCLUSION: Addition of a PCSK9 inhibitor to statin and ezetimibe resulted in a greater decrease in LDLc and TX after 3 years of treatment. PMID- 28623743 TI - Repeated measurements of serum concentrations of TNF-alpha, interleukin-6 and interleukin-10 in the evaluation of internal carotid artery stenosis progression. AB - BACKGROUND AND AIMS: The inflammatory process (with TNFalpha, interleukin-6 and interleukin-10 involvement) plays a key role in the development, progression and destabilization of atherosclerotic plaques. The aim of this study was to assess the importance of double-checked measurements of TNFalpha, interleukin-6 (IL-6) and interleukin-10 (Il-10) serum levels in patients with internal carotid artery (ICA) stenosis to determine the dynamics of changes in the stenosis degree and in the ultrasound plaque morphology. METHODS: The study included 65 patients with ICA stenosis. Ultrasound of the carotid arteries was performed during qualification and every 3 months to identify any progression of stenosis degree and dynamics of changes in plaque morphology. Serum concentrations of TNF-alpha, IL-6 and IL-10 were measured during qualification and at month 6 of the study. Calculations considered cytokine concentrations and their indices determined as relative differences of cytokine levels assessed in the first and in second tests. RESULTS: Patients with increasing degree of ICA stenosis had higher indices of IL-6 and IL-10 than patients without any increase in the stenosis degree. In patients with unfavorable dynamics of changes in plaque morphology, significantly higher levels of interleukin-6 were found in the second test; these patients had higher indices of IL-6 and IL-10 than patients with favorable dynamics of atherosclerotic plaque morphology on ultrasound. CONCLUSIONS: Long term trends in serum concentrations of IL-6 and IL-10 in patients with ICA stenosis allow to predict the progression of the degree of stenosis and the unfavorable change of atherosclerotic plaque morphology. PMID- 28623744 TI - Obtaining sparse distributions in 2D inverse problems. AB - The mathematics of inverse problems has relevance across numerous estimation problems in science and engineering. L1 regularization has attracted recent attention in reconstructing the system properties in the case of sparse inverse problems; i.e., when the true property sought is not adequately described by a continuous distribution, in particular in Compressed Sensing image reconstruction. In this work, we focus on the application of L1 regularization to a class of inverse problems; relaxation-relaxation, T1-T2, and diffusion relaxation, D-T2, correlation experiments in NMR, which have found widespread applications in a number of areas including probing surface interactions in catalysis and characterizing fluid composition and pore structures in rocks. We introduce a robust algorithm for solving the L1 regularization problem and provide a guide to implementing it, including the choice of the amount of regularization used and the assignment of error estimates. We then show experimentally that L1 regularization has significant advantages over both the Non-Negative Least Squares (NNLS) algorithm and Tikhonov regularization. It is shown that the L1 regularization algorithm stably recovers a distribution at a signal to noise ratio<20 and that it resolves relaxation time constants and diffusion coefficients differing by as little as 10%. The enhanced resolving capability is used to measure the inter and intra particle concentrations of a mixture of hexane and dodecane present within porous silica beads immersed within a bulk liquid phase; neither NNLS nor Tikhonov regularization are able to provide this resolution. This experimental study shows that the approach enables discrimination between different chemical species when direct spectroscopic discrimination is impossible, and hence measurement of chemical composition within porous media, such as catalysts or rocks, is possible while still being stable to high levels of noise. PMID- 28623745 TI - A new air quality monitoring and early warning system: Air quality assessment and air pollutant concentration prediction. AB - Air pollution in many countries is worsening with industrialization and urbanization, resulting in climate change and affecting people's health, thus, making the work of policymakers more difficult. It is therefore both urgent and necessary to establish amore scientific air quality monitoring and early warning system to evaluate the degree of air pollution objectively, and predict pollutant concentrations accurately. However, the integration of air quality assessment and air pollutant concentration prediction to establish an air quality system is not common. In this paper, we propose a new air quality monitoring and early warning system, including an assessment module and forecasting module. In the air quality assessment module, fuzzy comprehensive evaluation is used to determine the main pollutants and evaluate the degree of air pollution more scientifically. In the air pollutant concentration prediction module, a novel hybridization model combining complementary ensemble empirical mode decomposition, a modified cuckoo search and differential evolution algorithm, and an Elman neural network, is proposed to improve the forecasting accuracy of six main air pollutant concentrations. To verify the effectiveness of this system, pollutant data for two cities in China are used. The result of the fuzzy comprehensive evaluation shows that the major air pollutants in Xi'an and Jinan are PM10 and PM2.5 respectively, and that the air quality of Xi'an is better than that of Jinan. The forecasting results indicate that the proposed hybrid model is remarkably superior to all benchmark models on account of its higher prediction accuracy and stability. PMID- 28623746 TI - Electrokinetic - Enhanced ryegrass cultures in soils polluted with organic and inorganic compounds. AB - The effect of electric fields on seed germination and development of ryegrass (Lolium perenne L.) was studied in clean and contaminated soil with heavy metals and/or PAHs. The application of 0.2 DCV/cm in clean soil near ryegrass seeds enhanced the germination by 75%. The presence of contaminants in soil hindered the germination and growing of ryegrass. However, the application of DC electric field favored the germination and growing of plants compensating the negative effects of the contaminants. The electrode material in anodes has a decisive influence in the germination and growing of ryegrass. Stable anode materials have to be used to avoid the release of toxic ions in the soil that affect the development of the plant. Graphite anodes are very appropriate because they are inexpensive and does not generate toxic effects on plants. The electro phytoremediation of mixed contaminated soil with ryegrass showed very promising results, especially AC electric fields. The tests with AC current showed the highest biomass production in a treatment of 1 month. The more biomass production the more removal of heavy metals and PAHs from soil. PMID- 28623747 TI - Results of a national survey of high-frequency fish consumers in the United States. AB - Exposure to contaminants in fish may be associated with adverse health outcomes even as fish consumption is generally considered beneficial. Risk assessments conducted to support regulatory analyses rely on quantitative fish consumption estimates. Here we report the results of a national survey of high-frequency fish consumers (n = 2099) based on a survey population statistically representative of ~17.6 million U.S. individuals consuming three or more fish meals per week. The survey was conducted during 2013 using an on-line survey instrument. Total fish consumption averaged 111g/day from market, restaurant and self-caught sources. Depending on the season, the incidence of individuals reporting consumption of self-caught species ranged between 10-12% of our high-frequency fish consuming demographic, averaging approximately 30g/day and comprising 23% of total fish consumption from all sources of fish. Recreational or self-caught consumption rates vary regionally and are poorly understood, particularly for high-frequency consumers, making it difficult to support national-scale assessments. A divergence between sport-fishing and harvesting of fish as a food-staple is apparent in survey results given differences in consumption patterns with income and education. Highest consumption rates were reported for low income respondents more likely to harvest fish as a food staple. By contrast, the incidence of self caught fish consumption was higher with income and education although overall consumption rates were lower. Regional differences were evident, with respondents from the East-South Central and New England regions reporting lowest consumption rates from self-caught fish on the order of 12-16g/day and those from Mountain, Pacific and Mid-Atlantic regions reporting highest rates ranging from 44 to 59g/day. Respondent-specific consumption rates together with national-level data on fish tissue concentrations of PCBs, MeHg, and PFOS suggest that 10-58% of respondents reporting self-caught fish consumption are exposed to concentrations of these contaminants that exceed threshold levels for health effects based on a target hazard index of one, representing 2.3M to 19M individuals. The results of this nationwide survey of high-frequency fish consumers highlights regional and demographic differences in self-caught and total fish consumption useful for policy analysis with implications for distributional differences in potential health impacts in the context of both contaminant exposures as well as protective effects. PMID- 28623748 TI - Occupant thorax response variations due to arm position and restraint systems in side impact crash scenarios. AB - Recent epidemiological studies have identified that thoracic side airbags may vary in efficacy to reduce injury severity in side impact crash scenarios, while previous experimental and epidemiological studies have presented contrasting results. This study aimed to quantify the variations in occupant response in side impact conditions using a human body computational model integrated with a full vehicle model. The model was analyzed for a Moving Deformable Barrier side impact at 61km/h to assess two pre-crash arm positions, the incorporation of a seatbelt, and a thorax air bag on thorax response. The occupant response was evaluated using chest compression, the viscous criterion and thoracic spinal curvature. The arm position accounted for largest changes in the thorax response (106%) compared to the presence of the airbag and seatbelt systems (75%). It was also noted that the results were dependant on the method and location of thorax response measurement and this should be investigated further. Assessment using lateral displacement of the thoracic spine correlated positively with chest compression and Viscous Criterion, with the benefit of evaluating whole thorax response and provides a useful metric to compare occupant response for different side impact safety systems. The thoracic side airbag was found to increase the chest compression for the driving arm position (+70%), and reduced the injury metrics for the vertical arm position (-17%). This study demonstrated the importance of occupant arm position on variability in thoracic response, and provides insight for future design and optimization of side impact safety systems. PMID- 28623749 TI - Evaluating the Safety In Numbers effect for pedestrians at urban intersections. AB - Assessment of collision risk between pedestrians and automobiles offers a powerful and informative tool in urban planning applications, and can be leveraged to inform proper placement of improvements and treatment projects to improve pedestrian safety. Such assessment can be performed using existing datasets of crashes, pedestrian counts, and automobile traffic flows to identify intersections or corridors characterized by elevated collision risks to pedestrians. The Safety In Numbers phenomenon, which refers to the observable effect that pedestrian safety is positively correlated with increased pedestrian traffic in a given area (i.e. that the individual per-pedestrian risk of a collision decreases with additional pedestrians), is a readily observed phenomenon that has been studied previously, though its directional causality is not yet known. A sample of 488 intersections in Minneapolis were analyzed, and statistically-significant log-linear relationships between pedestrian traffic flows and the per-pedestrian crash risk were found, indicating the Safety In Numbers effect. Potential planning applications of this analysis framework towards improving pedestrian safety in urban environments are discussed. PMID- 28623750 TI - LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy. AB - AIMS: LCZ696, a novel angiotensin receptor neprilysin inhibitor, is effective in treating heart failure patients. Doxorubicin (DOX) is an effective antitumor medication but the cardiotoxicity limited its clinical use. In this study, we aimed to determine the effect of LCZ696 on DOX-induced cardiomyopathy in mice and in vitro and to explore related mechanisms focusing on fission protein dynamin related protein 1 (Drp1). METHODS AND RESULTS: In human study, we found that myocardial fission protein Drp1 expression and its ser 616 phosphorylation were significantly increased in dilated cardiomyopathy (DCM) patients. Male Balb/c mice and H9c2 cardiomyocytes were randomized into three groups: saline, DOX, DOX plus LCZ696. Reduced cardiac function, mitochondrial morphology disturbance, reduced activity of mitochondrial respiration complex I and lowered adenosine triphosphate (ATP) content were detected post DOX stimulation in mice, which could be significantly improved by LCZ696. Fission protein Drp1 and its ser 616 phosphorylation were also increased post DOX and which could be reduced by LCZ696. In vitro, increased cardiomyocyte apoptosis, Drp1 ser 616 phosphorylation post DOX stimulation could be significantly attenuated by LCZ696 or Drp1 specific inhibitor Midivi-1. Furthermore, over-expression of Drp1 abrogated the protection effect of LCZ696 against DOX-induced cardiotoxicity in H9c2 cells. CONCLUSION: The protective effect of LCZ696 against DOX-induced cardiac dysfunction is at least partly associated with alleviating Drp1-mediated mitochondrial dysfunction. PMID- 28623751 TI - Epilepsy and stigmatization in Turkey. AB - Patients with epilepsy experience stigmatization quite often. Studies investigating stigmatization perceived by patients with epilepsy in Turkey are limited in number. In this study, we aimed to understand the relationship between stigmatization and psychopathology and also to identify the effects of stigmatization on the quality of life in epilepsy. Patients completed a socio demographical data form and epilepsy information form. They were evaluated in terms of psychiatric diagnosis using SCID I and they were asked to complete SCL 90 R, Epilepsy Stigmatization Scale and SF 36. The percentages of patients who did and did not report perception of stigmatization were similar in the study group. Depression was the most common diagnosis followed by anxiety disorder. In comparison to patients who did not feel stigmatized, patients who reported perceived stigmatization had a higher frequency of generalized tonic clonic seizures and injuries during seizures and more frequently missed taking their medication. They also showed higher rates of both suicide attempts and psychopathology as evidenced by a higher rate of psychiatric diagnosis and higher score in all the subscales of SCL 90. With regard to their quality of life they were observed to be more disabled in the physical functioning, general health perception, vitality, social role functioning and mental health dimensions. A logistic regression analysis revealed that stigmatization was best predicted by three variables: history of suicide attempts, receiving a psychiatric diagnosis and higher score in SCL90PST. Our study has shown that psychopathology is a more significant predictor of stigmatization than the other variables related with seizure control. PMID- 28623752 TI - Process evaluation of a multi-component self-management intervention for adults with epilepsy (ZMILE study). AB - BACKGROUND: People with epilepsy need to monitor and manage their symptoms. They, as well as their relatives, have to deal with the psychological burden, reflected in a reduced quality of life. Support in self-management can be of importance. We have developed a multi-component self-management intervention for patients and their relatives (MCI). This eight-week group intervention is conducted by nurse practitioners and consists of six two-hour sessions. The main components are: 1) providing self-management education, 2) stimulating proactive coping and goal setting and 3) facilitating peer and social support. This study is a process evaluation to establish the feasibility, fidelity and acceptability of the intervention by assessing performance according to protocol, attendance and adherence, and the opinion of patients, relatives and facilitators about the intervention. METHOD: Study population consists of 52 patients with epilepsy living in the community (e.g. at home), 37 relatives and six facilitators. In this prospective mixed methods study, data were gathered using questionnaires for patients and relatives, registration forms for facilitators and by carrying out semi-structured group interviews with patients, relatives and facilitators. RESULTS: Patients and relatives attended a mean of 5.2 sessions. Forty-seven (90%) patients and 32 (86.5%) relatives attended at least five sessions. The mean group size was 8.1 (SD=1.3; range 6-10). All elements of the intervention were offered to participants, except for one e-Health tool which was only available at the start of the study. Overall, the sessions were considered useful by patients, their relatives and facilitators. The participation of a relative (social support) and sharing ideas and feelings about having epilepsy with peers (peer support) were rated as important aspects. CONCLUSION: This process evaluation revealed that the MCI was largely performed according to protocol, attendance rate was high, and participants and facilitators had, on the whole, a favourable opinion about the MCI, and would recommend it to others with epilepsy and their relatives. Overall, the adherence of patients and relatives was high. The MCI is considered feasible according to patients, relatives and facilitators. Implementation is recommended if the intervention proves to be effective. PMID- 28623753 TI - Precuneal epilepsy: Clinical features and surgical outcome. AB - OBJECTIVE: The precuneus is a complex and highly connected structure located in the medial portion of the superior parietal lobule. The clinical presentation of precuneal epilepsy is poorly characterized, mostly because these patients have seldom been distinguished from those with other types of parietal lobe epilepsy. The present study aims to improve the understanding of precuneal epilepsy by detailing its clinical features and surgical outcomes. METHODS: Six previously unreported cases of drug-resistant precuneal epilepsy investigated between 2002 and 2014 were retrospectively studied. Seizure focus was confirmed by presence of a lesion, intracranial monitoring, or post-operative seizure control when applicable. RESULTS: Seizures arising from the precuneus have heterogeneous presentations, including body movement sensation, visual auras, eye movements, vestibular manifestations, and complex motor behaviors. Two patients with an anterior precuneus lesion described body movement sensations whereas two others with a posterior precuneus lesion experienced visual symptoms. Two of the five patients who underwent epilepsy surgery achieved good seizure control (Engel IA). One patient underwent gamma knife surgery with an Engel IV outcome. Surgical complications included contralateral visual field impairment, limb hypoesthesia and hemispatial neglect. One patient developed late-onset epilepsia partialis continua from a Rolandic subdural grid-related contusion. SIGNIFICANCE: In absence of a clear precuneal epileptogenic lesion, recognition of a precuneal focus is challenging. Magnetoencephalography may sometimes localize the generator but invasive EEG remains in well-selected cases necessary to identify the seizure focus. Surgical failures may be explained by the widespread connectivity of the precuneus with distant and adjacent structures. Different ictal manifestations of precuneal epilepsy in this series provide a clinical correlate to the described functional subdivisions of the precuneus. PMID- 28623754 TI - Quality of life, mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group. AB - OBJECTIVE: Brain tumor-related epilepsy (BTRE) is often drug resistant and patients can be forced to take polytherapy that can adversely affect their quality of life (QoL). Lacosamide (LCM) is a new antiepileptic drug (AED) used as adjunctive therapy in patients with partial seizures with or without secondary generalization, with a favorable pharmacokinetic profile that seems to be effective and well tolerated. Therefore it represents a possible therapeutic choice for patients with BTRE. We propose a prospective study with a historical control group to evaluate the effect of LCM as add-on therapy on seizure control and quality of life in patients with BTRE. This study has been designed to test the superiority of Lacosamide over Levetiracetam as an add-on. We compared a prospective cohort of 25 patients treated with Lacosamide with a historical control group (n=19) treated with Levetiracetam as an add-on. METHODS: We recruited 25 adult patients (M 18, F 7; mean age 41.9) affected by BTRE with uncontrolled partial-onset seizures treated with AED polytherapy. We added LCM as an add-on. Patients were evaluated at baseline, after 3months and at 6months. This population has been compared with a historical control group of 19 BTRE adult patients (M 13, F 6; median age 48.0, range: 28-70) with uncontrolled partial-onset seizures treated with LEV as add-on. The patients underwent QoL, mood and adverse events tests (Adverse Event Profile-AEP) and evaluation of seizure frequency. RESULTS: Twelve patients had high grade gliomas, and thirteen had low grade gliomas. During follow-up, thirteen patients underwent chemotherapy, three radiotherapy and five patients had disease progression. Nine patients had simple partial seizures, eight had complex partial seizures, and eight had secondary generalized seizures. Fifteen patients were in monotherapy and ten in polytherapy with AEDs. LCM was added up to reach the maximum dosage of 400mg/die (mean final dose 300mg/die). Four patients dropped out due to poor compliance and 1 for inefficacy. In the historical control group treated with LEV (mean final dose 2000mg/die) 12 patients had high-grade gliomas, and 7 had low grade gliomas. Thirteen patients were in monotherapy and 6 in polytherapy with AEDs. In the 22 patients evaluable of 25 patients treated with LCM, we observed at final follow-up 7 patients seizure free, 12 with a significant reduction of seizures>=50%, 2 stable and 1 patient with number of seizures increased. Mean seizure frequency at baseline compared with baseline period: the mean number of seizures significantly decreased from baseline (9.4) to final follow-up (1.2) (P=0.005). The Responder Rate was 86.4%. Comparing responder rate of 22 evaluable patients with LCM with responder rate of 19 patients with LEV we didn't observe significant differences (p=0.31). In our patients treated with LCM we didn't observe significant difference at 3 and 6months in QoL tests results; we observe a significant reduction in the mean score of Karnofsky Performance Status (KPS) and Barthel Index (BI) between baseline and 6months of follow-up (KPS p=0.003; BI p=0.007). No clinical side effects were observed. CONCLUSION: Comparing the LCM with the historical group treated with LEV in add-on, we observed that LCM seems to have a higher clinical efficacy than LEV. In our patients, we did not observe any significant changes in QoL tests, indicating stability in all quality of life domains explored, despite the objective worsening in their functional status. Although this is a small series with a relatively short follow-up, our data indicates that LCM in add-on in patients with BTRE appears to be as effective as LEV in add-on, without impact on mood and quality of life. PMID- 28623755 TI - Effects of adjunctive lacosamide on mood and quality of life in patients with epilepsy. AB - We examined the effects of adjunctive lacosamide (LCM) on mood and quality of life (QOL) in adult patients with partial-onset seizures in a prospective, controlled, single-blind study. Patients in whom LCM was added to their AED regimen for clinical indications comprised the LCM group (n=18), while the control group (n=32) comprised patients on >=2 AEDs with anticipated stable dosing for the duration of the study. Profile of Mood States (POMS) and QOLIE-89 were used to assess mood and QOL at enrollment and 12-16weeks later. Adherence to LCM was measured electronically with the Medication Event Monitoring System (MEMS) and using a self-report measure. There were no significant between-group differences in age, AED load, side-effects (A-B Neurotoxicity Scale), MoCA mental status, or seizure-related factors. LCM adherence (measured by MEMS) was 70.7%. There was a significant decrease in negative mood states in the LCM group (estimated marginal mean at baseline=49.4, at follow-up=29.7; p=0.02), after controlling for seizure freedom. Based on previously reported benchmarks, clinically significant change on the POMS occurred in 7 (38%) LCM patients. The effect of LCM on the overall QOL was not significant (p=0.078). Correlation between POMS Total Mood Distress and Emotional-Wellbeing on the QOLIE-89 was significant (r=-0.783; p=0.01). These results suggest that LCM may have a favorable impact on mood. PMID- 28623756 TI - Longitudinal investigation into implicit stigma of epilepsy among Japanese medical students before and after mass media coverage of car accidents associated with people with epilepsy. AB - OBJECTIVE: Public attitudes and stigma toward epilepsy may limit patient motivation for treatment and participation in social activities. Stigma research requiring individuals to report personal beliefs is useful but is subject to social desirability bias. Self-reporting methods often do not capture implicit attitudes; therefore, in this study, implicit stigma was measured using the implicit association test (IAT), which is a word sorting task to minimize this bias. Recently, in Japan, several serious car accidents caused by people with epilepsy (PWE) resulted in pedestrian fatalities. Traffic accidents involving PWE have been reported extensively and repeatedly in the media since 2011. The present study aimed to examine differences in implicit stigma toward epilepsy among medical students in 2010, 2013, and 2016. METHODS: We recruited 41 medical students in 2010, 44 medical students in 2013 and 42 medical students in 2016. We investigated the strength of conceptual associations between the words "Epilepsy" or "Hypertension", and "Safety" or "Danger" in the IAT. RESULTS: The association between the words "Epilepsy" and "Danger" was stronger in 2013 compared with that in 2010; however, the association was weaker in 2016 compared with that in 2013. There was no significant difference between 2010 and 2016. CONCLUSION: The change in IAT results between 2010 and 2013 might be due to the traffic accident involving PWE in Japan. However, the result in 2016 might indicate that the implicit attitudes toward epilepsy were improved to the same level as those in 2010. PMID- 28623757 TI - Heterotopic mesenteric and abdominal wall ossification - Two case reports in one institution. AB - INTRODUCTION: Heterotopic ossification occurs when bone develops in tissues which usually don't undergo ossification. Heterotopic mesenteric ossification, also known as intra-abdominal myositis ossificans, is a rare and benign form of ossification, usually related with previous abdominal surgery or trauma. PRESENTATION OF CASES: We report two cases of heterotopic ossification both after multiple abdominal surgeries, with intraoperative findings of mesenteric and abdominal wall ossification. Histopathology revealed metaplastic bone deposition, without evidence of atypia or malignancy. DISCUSSION: This rare entity shares clinical and pathological characteristics of myositis ossificans. It is important to consider the differential diagnosis with sarcomas. In the cases described, the patients were proposed for elective surgery and this pathology was as an incidental finding. CONCLUSION: The simultaneous presence of mesenteric and abdominal wall ossification in both patients makes these cases even rarer. PMID- 28623758 TI - A massive hepatic tumor demonstrating hepatocellular, cholangiocarcinoma and neuroendocrine lineages: A case report and review of the literature. AB - INTRODUCTION: Mixed hepatocellular and cholangiocarcinoma tumors (MHCC) are described in the literature, as are the more rare mixed adenoneuroendocrine carcinomas (MANC) of hepatobiliary origin. Only two cases of tumors with characteristics of all three histologies/phenotypes have been previously described in one Chinese study. PRESENTATION OF CASE: Herein we report clinical, microscopic and molecular features of a 25cm mixed hepatic tumor with hepatocellular, cholangiocarcinoma and neuroendocrine differentiation arising in an otherwise healthy 19-year-old North American Caucasian male without any identifiable risk factors. DISCUSSION: The patient underwent multimodality imaging and the tumor was biopsied preoperatively, and it was initially interpreted to be hepatocellular carcinoma fibrolamellar type. A left trisegmentectomy with lymphadenectomy was performed and the tumor was definitively diagnosed based on the surgically resected specimen. Integrated microscopic and molecular features defined the differing biological aggressiveness of growth pattern components. Cases in the literature of MHCC and rare cases of MANC have largely undergone aggressive surgical resection as well, however the majority of studies on mixed hepatic tumors to date reflect Eastern patient cohorts and populations with underlying liver disease, thereby limiting extrapolation on management or outcomes in this case. CONCLUSION: This is one of the only reports of a hepatic tumor arising from hepatocellular carcinoma, cholangiocarcinoma and neuroendocrine lineages. Increased awareness of this tumor type may optimize improve future management. PMID- 28623759 TI - Associations between suicidal behavior and childhood abuse and neglect: A meta analysis. AB - BACKGROUND: Relationships of some types of childhood maltreatment and suicidal behavior remain controversial and inconclusive. METHODS: Medline, Embase, PsycINFO and Cochrane library were searched for eligible studies, and the results were synthesized in meta-analyses. RESULTS: childhood maltreatment was associated positively with suicidal behavior in the total population and maltreatment subgroups. Emotional abuse had the strongest effect (OR =2.33, SMD =0.660, P<0.001). Subgroup analyses showed that the effects of childhood abuse (OR =1.55, SMD =0.523) and neglect (OR =1.25, SMD =0.31) were significant. According to the analysis of dichotomous outcomes, childhood maltreatment was associated positively with suicidal behavior in men and women (women: OR =4.84, P<0.001; men: OR =1.03, P<0.001). Among populations, childhood maltreatment had the strongest effect on suicidal behavior in the general population (OR =3.78, P<0.001). However, the analysis of continuous outcomes showed that the effect was strongest in patients with chronic schizophrenia (SMD =0.89, P<0.001). In addition, childhood maltreatment was associated positively with suicide attempt (OR =1.11, SMD =0.48, P<0.001), but not with suicidal ideation. LIMITATIONS: Some subgroup samples were not sufficiently large. CONCLUSIONS: Childhood maltreatment increases the risk of suicidal behavior. Emotional abuse had the strongest effect among the five types of maltreatment. The risk of suicidal behavior is higher in the general population, women, and individuals with chronic schizophrenia who have histories of childhood maltreatment. PMID- 28623760 TI - Gait dynamics in Pisa syndrome and Camptocormia: The role of stride length and hip kinematics. AB - This is an observational cross-sectional study evaluating gait dynamics in patients with Parkinson's Disease (PD) and severe postural deformities, PD without axial deviations and healthy subjects. Ten PS individuals with Pisa syndrome (PS) and nine subjects with Camptocormia (CC) performed 3-D Gait Analysis and were evaluated with walking and balance scales. Correlations with clinical and functional scales were investigated. Spatio-temporal and kinematic data were compared to ten PD subjects without postural deformities (PP) and ten healthy matched individuals (CG). Data obtained showed decreased walking velocity, stride and step length in PP, PS and CC groups compared to controls. The correlation analysis showed that stride and step length were associated with reduced functional abilities and disease severity in PS and CC groups. Kinematic data revealed marked reduction in range of movements (ROMs) at all lower extremity joints in PS group. While, in CC group the main differences were pronounced in hip and knee joints. PS and CC groups presented a more pronounced reduction in hip articular excursion compared to PP subjects, revealing an increased hip flexion pattern during gait cycle. Moreover, the increased hip and knee flexion pattern adversely affected functional performance during walking tests. Results obtained provide evidence that step length, along with stride length, can be proposed as simple and clear indicators of disease severity and reduced functional abilities. The reduction of ROMs at hip joint represented an important mechanism contributing to decreased walking velocity, balance impairment and reduced gait performance in PD patients with postural deformities. PMID- 28623761 TI - The added value of the CSF cleft on ADC in distinguishing extra-axial from intra axial tumors. AB - We investigated whether the CSF cleft sign on ADC maps is beneficial for differentiating extra-axial tumors from intra-axial tumors. Seventy-seven intracranial tumor patients were reviewed. Visual grades of CSF cleft sign on T2WI and ADC were compared. The diagnostic performance of CSF cleft sign using ADC plus T2WI was compared with that using T2WI alone. A CSF cleft was more easily visualized on ADC (P<0.01). The diagnostic performance of CSF cleft sign significantly increased in accuracy of 85.7 to 96.1% (P<0.01) when ADC and T2WI were used together. PMID- 28623762 TI - Cortisol stress response in post-traumatic stress disorder, panic disorder, and major depressive disorder patients. AB - BACKGROUND: Previous research has focussed extensively on the distinction of HPA axis functioning between patient groups and healthy volunteers, with relatively little emphasis on a direct comparison of patient groups. The current study's aim was to analyse differences in the cortisol stress response as a function of primary diagnosis of panic disorder (PD), post-traumatic stress disorder (PTSD), and major depressive disorder (MDD). METHODS: A total of n=30 PD (mean age+/-SD: 36.07+/-12.56), n=23 PTSD (41.22+/-10.17), n=18 MDD patients (39.00+/-14.93) and n=47 healthy control (HC) individuals (35.51+/-13.15) participated in this study. All the study participants were female. The Trier Social Stress Test (TSST) was used for reliable laboratory stress induction. Blood sampling accompanied the TSST for cortisol and ACTH assessment. Panic-related, PTSD-specific questionnaires and the Beck Depression Inventory II were handed out for the characterisation of the study groups. Repeated measure ANCOVAs were conducted to test for main effects of time or group and for interaction effects. Regression analyses were conducted to take comorbid depression into account. RESULTS: 26.7% of the PD patients, 43.5% of the PTSD patients, 72.2% of the MDD patients and 80.6% of the HC participants showed a cortisol stress response upon the TSST. ANCOVA revealed a cortisol hypo-responsiveness both in PD and PTSD patients, while no significant group differences were seen in the ACTH concentrations. Additional analyses showed no impact of comorbid depressiveness on the cortisol stress response. MDD patients did not differ in the hormonal stress response neither compared to the HC participants nor to the PD and PTSD patients. CONCLUSION: Our main findings provide evidence of a dissociation between the cortisol and ACTH concentrations in response to the TSST in PTSD and in PD patients, independent of comorbid depression. Our results further support overall research findings of a cortisol hypo-responsiveness in PD patients. A hypo response pattern was also seen in the PTSD patients agreeing with previous finding on the cortisol stress reactivity following TSST stress induction in these patients. Patients with a primary MDD diagnosis showed descriptively higher cortisol concentrations compared to the anxiety patients, and lower cortisol concentrations as the healthy individuals. The limitations of the study and implications for future studies will be discussed. PMID- 28623763 TI - Saturated high-fat feeding independent of obesity alters hypothalamus-pituitary adrenal axis function but not anxiety-like behaviour. AB - Overconsumption of dietary fat can elicit impairments in emotional processes and the response to stress. While excess dietary lipids have been shown to alter hypothalamus-pituitary-adrenal (HPA) axis function and promote anxiety-like behaviour, it is not known if such changes rely on elevated body weight and if these effects are specific to the type of dietary fat. The objective of this study was to investigate the effect of a saturated and a monounsaturated high-fat diet (HFD) on HPA axis function and anxiety-like behaviour in rats. Biochemical, metabolic and behavioural responses were evaluated following eight weeks on one of three diets: (1) a monounsaturated HFD (50%kcal olive oil), (2) a saturated HFD (50%kcal palm oil), or (3) a control low-fat diet. Weight gain was similar across the three diets while visceral fat mass was elevated by the two HFDs. The saturated HFD had specific actions to increase peak plasma levels of corticosterone and tumour-necrosis-factor-alpha and suppress mRNA expression of glucocorticoid and mineralocorticoid receptors, corticotropin-releasing hormone and 11beta-hydroxysteroid dehydrogenase-1 in the paraventricular nucleus of the hypothalamus. Both HFDs enhanced the corticosterone-suppressing response to dexamethasone administration without affecting the physiological response to a restraint stress and failed to increase anxiety-like behaviour as measured in the elevated-plus maze and open field tests. These findings demonstrate that prolonged intake of saturated fat, without added weight gain, increases CORT and modulates central HPA feedback processes. That saturated HFD failed to affect anxiety-like behaviour can suggest that the anxiogenic effects of prolonged high fat feeding may rely on more pronounced metabolic dysfunction. PMID- 28623764 TI - Children's diurnal cortisol responses to negative events at school and home. AB - This study examined the within-and between-person associations between daily negative events - peer problems, academic problems and interparental conflict - and diurnal cortisol in school-age children. Salivary cortisol levels were assessed four times per day (at wakeup, 30min later, just before dinner and at bedtime) on eight days in 47 youths ages 8-13 years old (60% female; M age=11.28, SD=1.50). The relative contributions of within- and between-person variances in each stressor were estimated in models predicting same-day diurnal cortisol slope, same-day bedtime cortisol, and next morning wakeup cortisol. Children who reported more peer problems on average showed flatter slopes of cortisol decline from wakeup to bedtime. However, children secreted more cortisol at wakeup following days when they had reported more peer or academic problems than usual. Interparental conflict was not significantly associated with diurnal cortisol. Findings from this study extend our understanding of short-term cortisol responses to naturally occurring problems in daily life, and help to differentiate these daily processes from the cumulative effects of chronic stress. PMID- 28623765 TI - Is there a relationship between adverse childhood experiences and problem drinking behaviors? Findings from a population-based sample. AB - OBJECTIVES: The study investigated the relationships between adverse childhood experiences (ACEs) and heavy and binge drinking, stratified by gender. STUDY DESIGN: Population-based cross-sectional study. METHODS: Data were retrieved from 2012 Behavioral Risk Factor Surveillance System. Over 39,000 individuals from five states were included in the study. Multiple logistic regression models were used to analyze the weighted data to determine factors associated with heavy and binge drinking for men and women. Each model included ACEs and controlled for sociodemographic variables, depression and smoking status. Bonferroni method was used to correct multiple comparisons. RESULTS: Only a few relationships between ACEs and problem drinking were observed. Among men, living with a drug abuser as a child was significantly associated with both heavy and binge drinking compared to men who did not reside with a drug abuser as a child. Childhood verbal abuse was linked with men's binge drinking compared to men who were not verbally abused as children. Among women, none of the nine ACEs examined in the study were associated with their heavy drinking. Only one ACE, verbal abuse, was found to be correlated with binge drinking, compared to women who did not experience childhood verbal abuse. In addition, we did not find the hypothesized, step-wise, graded relationship between the number of ACEs and heavy and binge drinking. However, the risk of heavy drinking was greater if the individual was exposed to four or more childhood adversities among both men and women. CONCLUSION: Study hypotheses were only partially supported. Future studies should unpack the interplay among gender, socio-economic status, ACEs, and problem alcohol consumption. PMID- 28623766 TI - The long-term effects of using telehomecare technology on functional health literacy: results from a randomized trial. AB - OBJECTIVES: The association between the use of telehomecare technology and functional health literacy is rather unexplored in the current literature. This relationship could prove important in the future management of chronic diseases, as technology has become a more integrated part of modern healthcare systems. Therefore, the purpose of this study was to explore how the use of telehomecare technology affects the level of functional health literacy over a period of 10 months. STUDY DESIGN: Randomized controlled trial. METHODS: Our sample comprised 116 patients diagnosed with chronic obstructive pulmonary disease. A face-to-face interview and an objective test of functional health literacy were conducted with each patient at baseline and again at follow-up after 10 months. Twenty-six patients were lost to follow-up and thus, providing a total of 47 chronic obstructive pulmonary disease patients in the intervention group and 43 in the control group for this follow-up study. The level of functional health literacy was assessed with the Danish Test of Functional Health Literacy in Adults. The difference from baseline to follow-up, in both the functional health literacy score and the mean response time to the entire Danish Test of Functional Health Literacy in Adults (TOFHLA), was tested for statistical significance between the intervention group and the control group. RESULTS: A significant increase in functional health literacy is observed in both the groups from baseline to follow up, but there is no statistical difference between groups (P-value = 0.62). CONCLUSIONS: A significant increase in the functional health literacy score was observed in both groups, but the findings of this present study provide no information on what causes the increase, so further research is needed to explore the increase in functional health literacy score more thoroughly and establish if the use of telehomecare technology is a part of the explanation. PMID- 28623767 TI - An examination of the roles of glutamate and sex in latent inhibition: Relevance to the glutamate hypothesis of schizophrenia? AB - The present study examined the effects of the glutamate receptor antagonist MK 801, the glutamate receptor agonist N-methyl-D-aspartate (NMDA), and sexual dimorphism on latent inhibition to elucidate the glutamate hypothesis of schizophrenia. During the pre-exposure phase, 56 male and 65 female Wistar rats were intracerebroventricularly administered normal saline, MK-801 or NMDA, in the left ventricle and then exposed to a passive avoidance box (or a different context) in three trials over 3 days. Then, all of the rats were placed in the light compartment of the passive avoidance box and were allowed to enter the dark compartment, where they each received a footshock (1mA, 2s) in five trials over 5 days. Injections of the glutamate drugs NMDA and MK-801 did not affect latent inhibition. Sexual dimorphism did not occur in latent inhibition. The present data on the male rats indicated that the glutamate system did not affect latent inhibition, indicating that the glutamate system was not like the dopamine system in terms of mediating the positive symptoms of schizophrenia. The glutamate system might be involved in the negative and cognitive symptoms of schizophrenia. The results may provide information for novel treatments of the negative and cognitive symptoms of schizophrenia. PMID- 28623768 TI - General Health Questionnaire-12 validity in Colombia and factorial equivalence between clinical and nonclinical participants. AB - The General Health Questionnaire - 12 (GHQ-12) is a widely used screening self report for emotional disorders among adults. However, there is little evidence concerning the validity of the GHQ-12 in Colombia and its factorial invariance between nonclinical and clinical samples. Accordingly, the current study aims to explore the GHQ-12 validity in Colombian nonclinical and clinical samples. The GHQ-12 was administered to a total of 1641 participants, including a sample of undergraduates, one of general population, and a clinical sample. The internal consistency of the GHQ-12 across samples was good (overall alpha of .90). The one factor model showed a good fit to the data and was considered theoretically more coherent than the two-factor model with positive and negative items loading in separate factors. Metric and scalar invariance were observed across nonclinical and clinical samples. The GHQ-12 scores were strongly and positively related to emotional symptoms and experiential avoidance, and negatively related to life satisfaction. According to the receiver operating characteristic (ROC) curves, a threshold score of 11/12 was optimal to identify emotional disorders. In conclusion, the GHQ-12 is a valid screening self-report in Colombia that provides scores that can be compared across clinical and nonclinical participants. PMID- 28623769 TI - The promotive effects of peer support and active coping on the relationship between bullying victimization and depression among chinese boarding students. AB - We examined the relationship between bully victimization experience and depression in rural adolescents and analyzed the moderating roles of peer support and active coping in male and female students. The sample comprised N=755 adolescents (376 females) with a mean age of 13.52 years. Through structural model and multi-group analysis, the results indicated: (1) a significant gender difference on the positive association between bullying victimization and depression; (2) peer support had a directly negative effect on depression among all boarding adolescents; and (3) significant moderating effect of active coping on the association between victimization and depression, without significant gender difference. We discuss enhancing active coping and peer support as a prevention strategy to reduce adverse mental health outcomes in adolescents due to bullying victimization. PMID- 28623770 TI - Energy efficiency increase of NQR spectrometer transmitter at pulse resonance excitation with noise signals. AB - The specific feature of NQR is expansion of spectral lines which is caused not only by dipole-dipole interaction of nuclei, but also by local field nonuniformity caused by the defects and deformation in crystal matrix. Considerable line expansion, which is typical of crystals, requires in pulsed NQR method the optimization of pulse shape and the reserve of transmitter power output. Parametric computer identification was used to study a dependence of parameters of the energy spectra of the output signal of pulsed NQR spectrometer transmitter on the duration of excitation pulses with sine and noise occupation. The energy efficiency of a linear amplifier was calculated and experimental investigations of its temperature conditions were carried out. The energy efficient broadband transmitter was proposed that can be used in portable setups for the pursuance of research in the field of pulsed NQR spectroscopy, for instance when studying isotopes with quadrupole moments 14N, 35Cl, 63Cu, 69Ga, 71Ga, 113In, 115In and others. PMID- 28623771 TI - Liquid electrode plasma-optical emission spectrometry combined with solid-phase preconcentration for on-site analysis of lead. AB - A relatively rapid and precise method is presented for the determination of lead in aqueous matrix. The method consists of analyte quantitation using the liquid electrode plasma-optical emission spectrometry (LEP-OES) coupled with selective separation/preconcentration by solid-phase extraction (SPE). The impact of operating variables on the retention of lead in SPEs such as pH, flow rate of the sample solution; type, volume, flow rate of the eluent; and matrix effects were investigated. Selective SPE-separation/preconcentration minimized the interfering effect due to manganese in solution and limitations in lead-detection in low concentration samples by LEP-OES. The LEP-OES operating parameters such as the electrical conductivity of sample solution; applied voltage; on-time, off-time, pulse count for applied voltage; number of measurements; and matrix effects have also been optimized to obtain a distinct peak for the lead at lambdamax=405.8nm. The limit of detection (3sigma) and the limit of quantification (10sigma) for lead determination using the technique were found as 1.9 and 6.5ng mL-1, respectively. The precision, as relative standard deviation, was lower than 5% at 0.1MUg mL-1 Pb, and the preconcentration factor was found to be 187. The proposed method was applied to the analysis of lead contents in the natural aqueous matrix (recovery rate:>95%). The method accuracy was verified using certified reference material of wastewaters: SPS-WW1 and ERM-CA713. The results from LEP-OES were in good agreement with inductively coupled plasma optical emission spectrometry measurements of the same samples. The application of the method is rapid (<=5min, without preconcentration) with a reliable detection limit at trace levels. PMID- 28623772 TI - Development and validation of a highly sensitive LC-ESI-MS/MS method for estimation of IIIM-MCD-211, a novel nitrofuranyl methyl piperazine derivative with potential activity against tuberculosis: Application to drug development. AB - In the present study, a simple, sensitive, specific and rapid liquid chromatography (LC) tandem mass spectrometry (MS/MS) method was developed and validated according to the Food and Drug Administration (FDA) guidelines for estimation of IIIM-MCD-211 (a potent oral candidate with promising action against tuberculosis) in mice plasma using carbamazepine as internal standard (IS). Bioanalytical method consisted of one step protein precipitation for sample preparation followed by quantitation in LC-MS/MS using positive electrospray ionization technique (ESI) operating in multiple reaction monitoring (MRM) mode. Elution was achieved in gradient mode on High Resolution Chromolith RP-18e column with mobile phase comprised of acetonitrile and 0.1% (v/v) formic acid in water at the flow rate of 0.4mL/min. Precursor to product ion transitions (m/z 344.5/218.4 and m/z 237.3/194.2) were used to measure analyte and IS, respectively. All validation parameters were well within the limit of acceptance criteria. The method was successfully applied to assess the pharmacokinetics of the candidate in mice following oral (10mg/kg) and intravenous (IV; 2.5mg/kg) administration. It was also effectively used to quantitate metabolic stability of the compound in mouse liver microsomes (MLM) and human liver microsomes (HLM) followed by its in-vitro-in-vivo extrapolation. PMID- 28623773 TI - Genetic determinants of response to fibroblast growth factor receptor inhibitors in solid tumours. PMID- 28623774 TI - Discrepancy in BRAF status among patients with metastatic malignant melanoma: A meta-analysis. AB - The incidence of malignant melanoma is growing rapidly. Approximately half of the cases are BRAF mutated, making treatment with kinase inhibitors a (MEK and BRAF inhibitors) preferred choice in the advanced setting. The vast majority of these patients will benefit from the treatment. It is therefore of vital importance that the BRAF analysis is reliable and reflects the true nature of the tumour. Intraindividual tumour BRAF heterogeneity may exist, and changes of BRAF status over time might occur. We reviewed the literature by searching the PubMed database and 630 potentially relevant studies were identified. Thereafter, studies that investigated intralesional heterogeneity only, studies with <=10 patients and studies that did not include adequate data to calculate discrepancy rates were excluded. Twenty-two studies met our inclusion criteria and were included in the meta-analysis. The pooled discrepancy rate between primary and metastatic lesions was 13.4% (95% confidence interval [CI]: 9.2-18.2%) while it was 7.3% (95% CI: 3.3-12.6) between two metastatic lesions. The number of patients whose tumoural BRAF status was changed from mutation to wild type and from wild type to mutation, respectively, was comparable. We conclude that a clinically meaningful discrepancy rate in BRAF status both between primary metastatic and metastatic-metastatic melanoma lesions exists. Our results support the polyclonal model of melanomas in which subclones with different BRAF status co-exist in the same melanoma lesion. In addition, the results indicate a need for biopsy of a metastatic lesion for subsequent BRAF analysis when treatment with kinase inhibitors is considered. PMID- 28623775 TI - Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. AB - Cancer immunotherapy is now established as a powerful way to treat cancer. The recent clinical success of immune checkpoint blockade (antagonists of CTLA-4, PD 1 and PD-L1) highlights both the universal power of treating the immune system across tumour types and the unique features of cancer immunotherapy. Immune related adverse events, atypical clinical response patterns, durable responses, and clear overall survival benefit distinguish cancer immunotherapy from cytotoxic cancer therapy. Combination immunotherapies that transform non responders to responders are under rapid development. Current challenges facing the field include incorporating immunotherapy into adjuvant and neoadjuvant cancer therapy, refining dose, schedule and duration of treatment and developing novel surrogate endpoints that accurately capture overall survival benefit early in treatment. As the field rapidly evolves, we must prioritise the development of biomarkers to guide the use of immunotherapies in the most appropriate patients. Immunotherapy is already transforming cancer from a death sentence to a chronic disease for some patients. By making smart, evidence-based decisions in developing next generation immunotherapies, cancer should become an imminently treatable, curable and even preventable disease. PMID- 28623776 TI - Case series of patients treated with the oral fluoropyrimidine S-1 after capecitabine-induced coronary artery vasospasm. PMID- 28623777 TI - Method for lateral force calibration in atomic force microscope using MEMS microforce sensor. AB - In this paper we present a simple and direct method for the lateral force calibration constant determination. Our procedure does not require any knowledge about material or geometrical parameters of an investigated cantilever. We apply a commercially available microforce sensor with advanced electronics for direct measurement of the friction force applied by the cantilever's tip to a flat surface of the microforce sensor measuring beam. Due to the third law of dynamics, the friction force of the equal value tilts the AFM cantilever. Therefore, torsional (lateral force) signal is compared with the signal from the microforce sensor and the lateral force calibration constant is determined. The method is easy to perform and could be widely used for the lateral force calibration constant determination in many types of atomic force microscopes. PMID- 28623778 TI - Are there signature limits in early theory of mind? AB - Current theory-of-mind research faces the challenge of reconciling two sets of seemingly incompatible findings: Whereas children come to solve explicit verbal false belief (FB) tasks from around 4years of age, recent studies with various less explicit measures such as looking time, anticipatory looking, and spontaneous behavior suggest that even infants can succeed on some FB tasks. In response to this tension, two-systems theories propose to distinguish between an early-developing system, tracking simple forms of mental states, and a later developing system, based on fully developed concepts of belief and other propositional attitudes. One prediction of such theories is that the early developing system has signature limits concerning aspectuality. We tested this prediction in two experiments. The first experiment showed (in line with previous findings) that 2- and 3-year-olds take into account a protagonist's true or false belief about the location of an object in their active helping behavior. In contrast, toddlers' helping behavior did not differentiate between true and false belief conditions when the protagonist's belief essentially involved aspectuality. Experiment 2 replicated these findings with a more stringent method designed to rule out more parsimonious explanations. Taken together, the current findings are compatible with the possibility that early theory-of-mind reasoning is subject to signature limits as predicted by the two-systems account. PMID- 28623779 TI - The honest truth about deception: Demographic, cognitive, and neural correlates of child repeated deceptive behavior. AB - This study examined situational, psychological, and neurobiological factors associated with deceptive behavior in 8-year-old children. By assessing deception in low- and high-risk conditions, we differentiated between children displaying some dishonesty and children who deceived repeatedly, and we assessed the correlates of deception in 163 children. A large majority of the children were deceptive in the low-risk condition (n=121, 74.2%), but most children refrained from deception when at risk for getting caught (69 of 121). Using an aggregate score, children who continued deceiving could be discriminated from other children based on gender, lower age, lower IQ, less effortful control, and lower educated mothers. Compared with honest children and high-risk deceivers, low-risk deceivers differed on an aggregate score, suggesting that they were more likely to be girls and to come from higher income families. Compared with the other children, high-risk deceivers showed decreased activation in the bilateral anterior cingulate cortex (ACC) and right frontal pole during the low-risk condition, suggesting decreased engagement in conflict monitoring and error detection during opportunities for deception. In high-risk deceivers, high-risk deception was associated with increased bilateral ACC and right paracingulate gyrus activation compared with low-risk deception. High-risk deceivers may require a higher level of risk to engage the ACC to the same degree as low-risk deceivers or honest children. Our results suggest that deceptive behavior in children seems to be largely dependent on the estimated likelihood of getting caught. High-risk deceivers form a distinct group with different cognitive and neurobiological characteristics compared with honest children and low-risk deceivers. PMID- 28623780 TI - Preschoolers' disclosures of child sexual abuse: Examining corroborated cases from Swedish courts. AB - Young victims of child sexual abuse can - for a range of developmental, motivational and contextual reasons - have difficulties disclosing their experiences. In the present study, corroborated court cases concerning 57 preschoolers' disclosures of sexual abuse were examined using qualitative and quantitative methodologies. Together, the cases involved 53 girls and 4 boys between 2-6 years (M=4.2, SD=1.2) during the (first) incident of abuse. The children were between 3-7 years (M=5.3, SD=1.2) during their police interview. Analyses showed that many children could provide at least one central detail about the abuse to; i) informal disclosure recipients, and ii) during their police interview. However, the time up until their first disclosure was often delayed. A range of barriers for disclosing were observed in the court cases, and many young victims were assessed as reluctant during their police interview. Repeated sessions, direct questions, and other reassurances could at times facilitate the disclosure process. Other suggestions on actions and future research that may help young child abuse victims are discussed. PMID- 28623781 TI - Inhibition activities of catechol diether based non-nucleoside inhibitors against the HIV reverse transcriptase variants: Insights from molecular docking and ONIOM calculations. AB - The therapeutic effectiveness of the catechol diether analogs against both the wild-type and drug-resistant reverse transcriptase (RT) mutants of HIV strains are investigated by performing molecular docking and hybrid ONIOM calculations. The docking protocol has been used to predict the binding modes of the non nucleoside inhibitors inside the active site cavity of the viral enzymes. For each enzyme-inhibitor adduct, the predicted docked poses are assessed by employing different scoring function based programs. However, the docking protocol fails to explain satisfactorily the antiviral activities of the drug molecules. Two-layered ONIOM calculations have been carried out to compute the relative binding affinities of the catechol diether derivatives to the binding pockets of RT variants. The binding efficacies of the inhibitors are significantly suppressed by the Y181C and K103N mutations, as revealed by the computed interaction energies at the ONIOM [B3LYP/6-31G(d,p):PM6] level of theory. Deformation energies for each bound ligand conformer are also estimated. The nature of interactions between the drug molecules and the active site residues are analyzed from the reduced density gradient (RDG) isosurfaces. The simulated ECD spectra support the conformational adaption upon inhibitor binding in the binding pockets of HIV strains. PMID- 28623782 TI - Factors responsible for the aggregation behavior of hydrophobic polyelectrolyte PEA in aqueous solution studied by molecular dynamics simulations. AB - Self-association (i.e. interchain aggregation) behavior of atactic poly(ethacrylic acid) PEA in dilute aqueous solution as function of degree-of neutralization by Na+ counter-ions (i.e. charge fraction f) was investigated by molecular dynamics simulations. Aggregation is found to occur in the range 0<=f<=0.7 in agreement with experimental results compared at specified polymer concentration Cp=0.36mol/l in dilute solution. The macromolecular solution was characterized and analysed for radius-of-gyration, torsion angle distribution, inter and intra-molecular hydrogen bonds, radial distribution functions of intermolecular and inter-atomic pairs, inter-chain contacts and solvation enthalpy. The PEA chains form aggregate through attractive inter-chain interaction via hydrogen bonding, in the range f<0.7, in agreement with experimental observation. The numbers of inter-chain contacts decreases with f. A critical structural transition occurs at f=0.7, observed via simulations for the first time, in Rg as well as inter-chain H-bonds. The inter-chain distance increases with f due to repulsive interactions between COO- groups on the chains. PEA-PEA electrostatic interactions dominant solvation enthalpy. The PEA solvation enthalpy becomes increasingly favorable with increase in f. The transition enthalpy change, in going from uncharged (acid) state to fully charged state (f=1) is unfavorable towards aggregate formation. PMID- 28623783 TI - Scoparone attenuates hepatic stellate cell activation through inhibiting TGF beta/Smad signaling pathway. AB - Activation of hepatic stellate cells (HSCs) plays a critical role in liver fibrosis. Scoparone, a major constituent isolated from Artemisia capillaris, was reported to possess hepatoprotective effect. However, the role of scoparone in liver fibrosis remains unknown. In the present study, we investigated the effects of scoparone on liver fibrosis in HSCs. Our results demonstrated that scoparoene inhibited the proliferation of HSCs exposed to transforming growth factor (TGF) beta1. In addition, scoparoene significantly suppressed TGF-beta1-induced the expression of alpha-smooth muscle actin (alpha-SMA) and collagen I in HSC-T6 cells, as well as attenuated the expression of NADPH oxidase (NOX) isoforms expression and ROS production in TGF-beta1-stimialted HSC-T6 cells. Mechanistically, scoparoene suppressed the phosphorylation level of Smad3 in TGF beta1-stimialted HSC-T6 cells. In conclusion, these findings showed that scoparone significantly inhibited the proliferation and activation of HSCs through the inactivation of TGF-beta/Smad signaling pathway. These data provide that scoparone may have potential to treat liver fibrosis. PMID- 28623784 TI - Antihypertensive and vasodilator effects of methanolic extract of Inula viscosa: Biological evaluation and POM analysis of cynarin, chlorogenic acid as potential hypertensive. AB - BACKGROUND: Inula viscosa L. (Asteraceae) is a medicinal plant widely used as a folk medicine in oriental Morocco, to treat hypertension. The antihypertensive effect of the methanolic extract obtained from I. viscosa leaves was evaluated in hypertensive L-NAME rats. Systolic blood pressure (SBP) was measured using a non invasive indirect tail-cuff plethysmographic method. Four groups of rats were used: a control group; a hypertensive group treated with L-NAME (32mg/kg/day); a positive control group treated with L-NAME plus enalapril (15mg/kg/day) as a reference antihypertensive agent; and a group treated with L-NAME plus MeOH extract (40mg/kg/day). METHODS: Treatment with L-NAME alone caused a progressive increase in SBP. After 4 weeks, the value of SBP reached 160+/-2mmHg which shows the installation of hypertension. Enalapril prevented the increase in SBP, which remained normal at 123+/-1mmHg after 4 weeks of treatment. The administration of MeOH-extract along with L-NAME prevented the increase in SBP as well, which remained constant at 115+/-1mmHg after 4 weeks of treatment. In ex-vivo models, MeOH-extract produced a relaxation of pre-contracted ring aorta (54 +/- 2% of relaxation at 3g/L). But, when the rings were denuded, MeOH-extract failed to relax pre-contracted rings of aorta. Phytochemical study of I. viscosa MeOH extract revealed the presence of phenolic compounds, such as cynarin and chlorogenic acid. RESULTS: The present results suggest that I. viscosa MeOH extract has an antihypertensive, predominantly mediated by an endothelium dependent vasodilatory effect. Cynarin and chlorogenic acid, which have a strong vasorelaxant effect may be involved in the antihypertensive effect of the plant extract. The bioinformatic POM analysis confirms the therapeutic potential of cynarin and chlorogenic acids as inhibitors of various biotargets. Based on the results, the coordination of these phytochemicals with calcium and transition metals should be studied, for better scope at antihypertensive drug development. PMID- 28623785 TI - In vitro studies on nobiletin isolated from citrus plants and the bioactive metabolites, inhibitory action against gelatinase enzymatic activity and the molecular mechanisms in human retinal Muller cell line. AB - Diabetic retinopathy (DR) is the most common cause of vision loss in patients with diabetes mellitus. Despite the presence of effective therapy, DR is still a significant health burden. A recent research suggests that matrix metalloproteinases (MMPs) could be promising targets, which exert multiple actions on early- and late-stage pathogenesis of DR. Among the MMP family, gelatinases (MMP-2 and MMP-9) act as potent proinflammatory, proangiogenic, and pro-apoptotic factors. Therefore, the pharmacological inhibitory effect of gelatinases on retinal MMP-producing cells may be useful in the treatment or prevention of DR. Nobiletin isolated from citrus plants is a multi-functional polymethoxylated flavone, which exerts biological effects including inhibitory action against MMP activity in several cancer cells. In the present study, we demonstrated that nobiletin isolated from citrus plants attenuated MMP-9 enzymatic activity through the suppression of transcription for MMP-9 gene expression and augmentation of TIMP-1 production in retinal Muller cells. Nobiletin regulated MMP-9 gene expression and TIMP-1 by inhibiting the PI3K/Akt signaling pathway. In addition, we observed the augmentation of inhibitory action against MMP-9 enzymatic activity by 4'-demethylated nobiletin, which is a major metabolite of nobiletin. We believe that the enhancement of inhibitory action against MMP-9 enzymatic activity by 4'-demethylated nobiletin is through the dual inhibition on Erk1/2 and Akt phosphorylation. The structure-activity relationship analysis revealed that, for the enhancement of inhibitory action against MMP-9 enzymatic activity, demethylation at position 4' in B-ring was a key structural modification in Muller cells, which are an important source of MMPs found in vitreous fluid and retinal tissues in retinal proliferative diseases. These results suggested that nobiletin, derived from a natural source, may serve as a novel MMP inhibitor with minimal side effects, and lead compound for the design of more efficacious drugs. PMID- 28623786 TI - Proteolytic processed form of CXCL12 abolishes migration and induces apoptosis in neural stem cells in vitro. AB - The subventricular zone (SVZ) of the adult mammalian brain hosts full potential neural stem cells (NSCs). NSCs are able to respond to extracellular signals in the brain, amplifying the pool of progenitor cells and giving rise to neuroblasts that show ability to migrate towards an injury site. These signals can come from vascular system, cerebrospinal fluid, glial cells, or projections of neurons in adjoining regions. CXCL12, a chemokine secreted after brain injury, reaches the SVZ in a gradient manner and drives neuroblasts towards the lesion area. Among many other molecules, matrix metalloproteinase 2 and 9 (MMP-2/9) are also released during brain injury. MMP-2/9 can cleave CXCL12 generating a new molecule, CXCL12(5-67), and its effects on NSCs viability is not well described. Here we produced recombinant CXCL12 and CXCL12(5-67) and evaluated their effect in murine adult NSCs migration and survival in vitro. We showed CXCL12(5-67) does not promote NSCs migration, but does induce cell death. The NSC death induced by CXCL12(5-67) involves caspases 9 and 3/7 activation, implying the intrinsic apoptotic pathway in this phenomenon. Our evidences in vitro make CXCL12(5-67) and its receptor potential candidates for brain injuries and neurodegeneration studies. PMID- 28623787 TI - Simultaneous determination of BTEX and their metabolites using solid-phase microextraction followed by HPLC or GC/MS: An application in teeth as environmental biomarkers. AB - Applications of benzene, toluene, ethylbenzene, and o-, m-, and p-xylenes (BTEX) release them into the environment exposing living organism. These endocrine disruptors are toxic, highly volatile and easily absorbed by the lungs and can cause adverse consequences for the human health as neurological diseases and cancer. A method for the analysis of BTEX and its metabolites (phenols and aromatic acids) in teeth is presented. The method consists in a one-step simple extraction procedure from spiked tooth using NaOH solution followed by SPME-HPLC or HS-SPME-GC/MS determination. Optimization of both, spiking procedure and extraction step of these analytes from tooth, was carried out. Two fibers CAR/PDMS for BTEX and PA for BTEX metabolites were used for the SPME and variables were optimized for analytes at 30 degrees C using spiked solutions. The optimized adsorption times were 30, 75 and 30min and desorption times were 10, 40 and 30min for BTEX, phenols and aromatic acids, respectively. Linearity for SPME HPLC method was established using spiked solutions with both, BTEX and metabolites, at 2.5, 5.0, 10.0, 25.0MUg/mL. The obtained results indicated a good linearity (r2 above 0.994) for all analytes. Triplicate analyses were performed with RSD lower than 15%. LODs were in the range 0.2-33.3ng/mL for SPME-HPLC and 0.06-0.09pg/mL for HS-SPME-GC/MS methods in spiking solutions. Once the method was optimized, bovine teeth were used as biological matrix model for the tuning of spiking and extraction steps. Optimal adsorption and desorption times were 4h for both procedures. Micrograms per tooth gram of BTEX and phenols were quantified in ten human teeth and aromatic acids were not identified. The developed method for BTEX and metabolites analyses using SPME-HPLC or HS-SPME GC/MS shows good precision, linearity and sensitivity. The method was successfully applied in human teeth as environmental biomarker of BTEX and metabolites. PMID- 28623788 TI - SSRIs antidepressants in marine mussels from Atlantic coastal areas and human risk assessment. AB - Selective serotonin reuptake inhibitors (SSRIs) are among the most prescribed antidepressants nation and worldwide. Their presence in the aquatic environment is known, causing growing pressures in heavily populated coastal areas. For instance, disruption of invertebrate endocrine systems has been described. Since discrete seawater sampling may not be suitable to evaluate such environmental risk, we aimed to assess SSRIs and metabolites in wild Mytilus galloprovincialis, and assess risk to human health. A total of 1225 mussels were sampled during one year along the Portuguese Atlantic coast. Each freeze-dried pool of 25 specimens was analyzed, in duplicate, by solid phase extraction (SPE) and liquid chromatography with tandem mass spectrometry (LC-MSn). Approximately 70% of the samples were contaminated with at least one, and up to 4 from the 7 targeted compounds. The cumulative SSRIs and metabolites content in mussels ranged between 3.17 and 33.93ngg-1 dry weight, in a mean level of 14.68+/-9.69ngg-1. Norfluoxetine was the most recurring SSRI and the one with the highest mean concentration, 13.52ngg-1. Although some differences were found between different sampling periods and locations, those were not statistically significant (p>0.05) and no correlation was found between wet weight and mean contamination levels. Regarding risk to human health following consumption of these filter-feeders, when considering the average sample contamination of positive samples and the average Portuguese and European consumption, the ratio between the estimated daily intake (EDI) and the acceptable daily intake (ADI) ranged from 0.45 to 5.50%, and from 1.60 to 19.41%, respectively. Therefore, although the resultant risk is lower for the Portuguese consumer than for the average EU consumer, apparently, no appreciable risk to human health is expected. PMID- 28623789 TI - Linking Pan-European data to the local scale for decision making for global change and water scarcity within water resources planning and management. AB - This study focuses on a novel type of methodology which connects Pan-European data to the local scale in the field of water resources management. This methodology is proposed to improve and facilitate the decision making within the planning and management of water resources, taking into account climate change and its expected impacts. Our main point of interest is focused on the assessment of the predictability of extreme events and their possible effects, specifically droughts and water scarcity. Consequently, the Jucar River Basin was selected as the case study, due to the ongoing water scarcity problems and the last drought episodes suffered in the Mediterranean region. In order to study these possible impacts, we developed a modeling chain divided into four steps, they are: i) data collection, ii) analysis of available data, iii) models calibration and iv) climate impact analysis. Over previous steps, we used climate data from 15 different regional climate models (RCMs) belonging to the three different Representative Concentration Pathways (RCPs) coming from a hydrological model across all of Europe called E-HYPE. The data were bias corrected and used to obtain statistical results of the availability of water resources for the future (horizon 2039) and in form of indicators. This was performed through a hydrological (EVALHID), stochastic (MASHWIN) and risk management (SIMRISK) models, all of which were specifically calibrated for this basin. The results show that the availability of water resources is much more enthusiastic than in the current situation, indicating the possibility that climate change, which was predicted to occur in the future has already happened in the Jucar River Basin. It seems that the so called "Effect 80", an important decrease in water resources for the last three decades, is not well contemplated in the initial data. PMID- 28623790 TI - Effect of topsoil removal and selective countermeasures on radiocesium accumulation in rice plants in Fukushima paddy field. AB - A wide area of paddy fields was contaminated by radiocesium derived from the Fukushima nuclear accident. Implement of agricultural countermeasures is one of the principle methods to reduce the contamination of rice plants. In this study, the effect of topsoil removal measure and fertilizer application on radiocesium uptake by rice plants was investigated over a four-year period. Some other available countermeasures carried out after the Fukushima nuclear accident were also summarized. The results indicate that the effect of topsoil removal measure on the accumulation of radiocesium in rice plants was effective, but the concentration ratio of radiocesium activity concentration between rice plant and soil increased. This may be correlated with the radiocesium imported from irrigation water and relatively high exchangeable radiocesium proportion of plowing soil in the topsoil removal paddy. We summarized four year's data to further confirm that potassium and nitrogen fertilizers had an opposite effect on the accumulation of radiocesium in rice plants. Increasing potassium and reducing nitrogen fertilizer conditions tended to inhibit the radiocesium uptake by rice plants. Moreover, of all the available countermeasures applied in the paddy fields, the most effective countermeasure was the application of phlogopite. However, further analyses are required to confirm the effectiveness of application of phlogopite considering the limited available information. PMID- 28623791 TI - Exposure profile of volatile organic compounds receptor associated with paints consumption. AB - Epidemiologic studies regarding solvent-based paints (SBPs) containing VOCs have demonstrated a strong correlation between chronic and acute adverse health effects and the SBPs. Therefore, new environmentally friendly paints as substitutes containing less or none VOCs have been rapidly developed in research for future sustainable use. However, a few studies focusing on penetration and exposure condition of the substitute have been reported duo to the complexity and inaccessibility of painting industry. Surveys specifically looking at the present status of exposure condition were conducted to ascertain the popularization of water-based paints (WBPs) which concluded that markers of SBPs were detected in all 134 samples indicating bad industrial penetration. VOCs exposure concentrations of painters ranged from 3.8 to 18.2mg/m3 for WBPs, 3.5*103 to 14.8*103mg/m3 for SBPs, respectively. The negative correlation between ambient concentration and breathing zone concentration suggested the former was incapable of representing the actual exposure concentration. The real-time concentration was proved to be closely associated with the activity patterns while the mean concentration level was found mostly dependent on the paint types. Authentic inhalation dose ranged from 7.68 to 15.84mg (WBPs) and 3.84 to 15.59g (SBPs), respectively, for occupational painters (work 8h per day) and the total inhalation dose was estimated through a new conception. The findings suggested that WBPs could significantly reduce VOCs emission and occupational exposure. PMID- 28623792 TI - Variations in microbial community and ciprofloxacin removal in rhizospheric soils between two cultivars of Brassica parachinensis L. AB - Ciprofloxacin (CIP) is one of most used quinolone antibiotics detected frequently in agricultural soils and vegetables. In the present study, variations in microbial community and CIP removal in rhizospheric soils between two cultivars of Brassica parachinensis L. that accumulate higher and lower CIP (Sijiu and Cutai, respectively) were investigated under CIP stress (0mg/kg in CK, 2.94mg/kg in T1, and 67.11mg/kg in T2). The removal rates of CIP in rhizospheric soils of cultivar Sijiu were higher than those of cultivar Cutai, with a significant difference in T2 (48.7%>39.4%, P<0.05). The pyrosequencing of 16S rRNA and ITS gene indicated that the microbial diversity and community structure in rhizospheric soils of the two cultivars varied significantly. Spirochaeta and Trichosporon might be associated with CIP degradation, and higher relative abundances of Trichosporon in rhizoshperic soils of cultivar Sijiu might be responsible for higher CIP removal. Fourteen bacterial genera and ten fungal genera were screened as potential biomarkers for CIP removal process. The community level physiological profiling in rhizospheric soils of the two cultivars under CIP stress differed significantly, and more C substrates that favored CIP removal were observed in rhizoshperic soils of cultivar Sijiu. Our results demonstrate that variations in microbial community and the utilization of C substrates played important roles in differring the CIP removal in rhizospheric soils between the two cultivars. PMID- 28623793 TI - Tributyl phosphate impairs the urea cycle and alters liver pathology and metabolism in mice after short-term exposure based on a metabonomics study. AB - As a newly emerging environmental contaminant, tributyl phosphate (TBP) is of increasing concern because of the environmental problems it can cause. Studies have suggested that TBP induces hepatocellular adenomas and has malignant potential for hepatocellular carcinoma. However, the mechanisms of its adverse effects are unclear. In this study, metabonomic techniques were used to identify differential endogenous metabolites, draw network metabolic pathways and conduct network analysis to elucidate the underlying mechanisms involved in TBP induced pathological changes of the liver. The metabonomics study showed that TBP altered endogenous metabolites in the plasma and liver. The number of categories of endogenous metabolites with a VIP >1 were 14 in plasma and 20 in liver. The results also showed that TBP impaired urea synthesis in the liver. In addition, results of both in vitro and in vivo experiments indicated that TBP activated nuclear receptor CAR and inhibited CYP3a11 and CYP2b10 activities in the liver of mice after short-term exposure. These effects may be the underlying causes leading to TBP induced hepatocellular adenomas. This study combined metabonomics and other technical methods to clarify the mechanism of TBP-induced liver tumorigenesis from a new perspective. PMID- 28623794 TI - New thermodynamic entropy calculation based approach towards quantifying the impact of eutrophication on water environment. AB - Although the eutrophication phenomenon has been studied for a long time, there are still no quantifiable parameters available for a comprehensive assessment of its impacts on the water environment. As contamination alters the thermodynamic equilibrium of a water system to a state of imbalance, a novel method was proposed, in this study, for its quantitative evaluation. Based on thermodynamic analyses of the algal growth process, the proposed method targeted, both theoretically and experimentally, the typical algae species encountered in the water environment. By calculating the molar enthalpy of algae biomass production, the heat energy dissipated in the photosynthetic process was firstly evaluated. The associated entropy production (DeltaS) in the aquatic system could be then obtained. For six algae strains of distinct molecular formulae, the heat energy consumed for the production of a unit algal biomass was found to proportionate to the mass of nitrogen (N) or phosphorus (P) uptake through photosynthesis. A proportionality relationship between DeltaS and the algal biomass with a coefficient circa 44kJ/g was obtained. By the principle of energy conservation, the heat energy consumed in the process of algae biomass production is stored in the algal biomass. Furthermore, by measuring the heat of combustion of mature algae of Microcystis flos-aquae, Anabaena flos-aquae, and Chlorella vulgaris, the proportionality relationships between the heat energy and the N and P contents were validated experimentally at 90% and 85% confidence levels, respectively. As the discharge of excess N and P from domestic wastewater treatment plants is usually the main cause of eutrophication, the proposed impact assessment approach estimates that for a receiving water body, the DeltaS due to a unit mass of N and P discharge is 268.9kJ/K and 1870.1kJ/K, respectively. Consequently, P discharge control would be more important for environmental water protection. PMID- 28623795 TI - Transport of road salt contamination in karst aquifers and soils over multiple timescales. AB - Road deicing has caused widespread environmental Na+ and Cl- release for decades, yet the transport and retention of these contaminants in karst aquifers and soils are poorly understood. We examined the transport dynamics of Na+ and Cl- from road salt in shallow groundwater during flooding and over seasonal timescales by intensively monitoring an urban and a rural karst spring over approximately 2 years. Furthermore, we used a 20-year dataset for the rural spring to determine how salt retention affected long-term geochemical trends in the shallow groundwater. Salt transport was governed by hydrologic pathways through karst aquifers: during winter and early spring floods, flow through preferential pathways rapidly transported salty meltwater or stormwater over hours to days, while the remaining salt-contaminated water moved diffusely through the rock matrix on timescales of months to years. Flood hydrograph separations revealed that event water constituted 61.2% of stormflow on average at the urban spring, leading to more extreme variability in salt concentrations during flooding and throughout the year. This variability indicates that baseflow contributions to urban streams overlying karst aquifers with preferential flowpaths are likely less effective at buffering salt concentrations. In contrast, salt concentrations were less variable in the baseflow-dominated rural spring (28.7% event water). Furthermore, salt was episodically released from soils to shallow groundwater throughout the year during first flush events. A Cl- mass balance indicates that Cl- applied during previous winters persists within the springs' recharge basins for more than a year, raising baseline concentrations as road salt is introduced faster than it can be flushed from the basin. Inter-annual salt retention by soils or slow groundwater movement likely caused significant Cl- and specific conductivity (SpC) increases at the rural spring from 1996 to 2016. Accumulation of salt in shallow groundwater can elevate baseflow concentrations in surface waters, where it threatens aquatic organisms. PMID- 28623796 TI - Cadmium exposure on tissue-specific cadmium accumulation and alteration of hemoglobin expression in the 4th-instar larvae of Propsilocerus akamusi (Tokunaga) under laboratory conditions. AB - The expression of hemoglobin (Hb) genes has considerable potential as a biomarker for environmental monitoring in Chironomus. However, no sequence information is available regarding Hb genes in Propsilocerus akamusi (Tokunaga), thus the change in Hb mRNA gene expression caused by environmental pollutants remains unknown. In this study, we cloned two Hb gene fragments (PaHbV and PaHbVII) from P. akamusi, analyzed the expression patterns of the PaHbV and PaHbVII transcripts in different tissues using Real-Time quantitative PCR (RT-qPCR), and also measured the Cd levels in different tissues exposed to a sublethal concentration. The results showed significantly increased Cd concentrations and tissue-specific Cd distribution patterns in all of the tissues tested, including the hemolymph, during all time courses. A model describing the roles of specific tissues in Cd uptake and accumulation dynamics was also determined. The Malpighian tubules, gut, and epidermis were the primary sites of Cd accumulation, whereas the hemolymph was the temporary target organ of Cd accumulation, with the Cd being transferred to other internal tissues via the hemolymph. The relative mRNA expression profiles of PaHbV and PaHbVII indicated that their expression levels differed across the different tissues, indicating a tissue-specific response. Our results suggested a reverse effect between Hb expression and Cd accumulation during long-term Cd exposure in comparison with previous studies. The expressions of Hb genes in P. akamusi could be developed as biomarkers for assessing the general health conditions of freshwater ecosystems. PMID- 28623797 TI - Phenotypic defects in newborn Gammarus fossarum (Amphipoda) following embryonic exposure to fenoxycarb. AB - During morphogenesis numerous morphogenetic factors ensure the production of a target phenotype. By disrupting these processes, a toxic exposure during this period could cause an increase of phenotypic defects. In the present study, embryos of the freshwater amphipod Gammarus fossarum were exposed throughout the embryogenesis to increasing concentrations of fenoxycarb (0, 0.5ugL-1, 5ugL-1 and 50ugL-1), a growth regulator insecticide analog of the insect juvenile hormone. In addition, to identify morphogenesis' sensitive period, embryos were exposed during either early or late embryonic development to 5ugL-1 of fenoxycarb. In newborn individuals from exposed embryos, three phenotypes were investigated: i) eye pigmentation, ii) length of the antenna and gnathopod of both left and right sides and iii) midgut tissue state. Developmental homeostasis was assessed by measuring fluctuating asymmetry and inter-individual variance of both the antenna and gnathopod. Exposure to 5ugL-1 and 50ugL-1 fenoxycarb throughout the embryonic development induced a delayed hatching and altered appendages size. Moreover, exposure to 5ugL-1 throughout the embryogenesis and during the gastrulation phase impaired eye pigmentation, while exposure to 50ugL-1 resulted in increased tissue damages of the midgut. No significant increase of fluctuating asymmetry was observed in exposed individuals, neither for the antenna nor for the gnathopod. These results demonstrate that fenoxycarb can alter embryonic development of G. fossarum without disrupting developmental homeostasis. PMID- 28623798 TI - Monitoring the ecotoxicity of gamma-Al2O3 and Ni/gamma-Al2O3 nanomaterials by means of a battery of bioassays. AB - The increasing application of nanoparticles (NPs) to a variety of new technologies has become a matter of concern due to the potential toxicity of these materials. Many questions about the fate of NPs in the environment and the subsequent impact on ecosystems need to be answered. The aim of this work was to evaluate the ecotoxicity of two alumina-based nanoceramics, gamma-Al2O3 (NC) and Ni/ gamma-Al2O3 (NiNC) by means of three different standardized tests: Biochemical Oxygen Demand (BOD5), bioassay with luminescent bacteria (Vibrio fischeri; Microtox), and bioassay on amphibian larvae (Rhinella arenarum) (AMPHITOX). BOD5 values of a very biodegradable mixture (glucose/glutamic acid) decreased with the addition of NiNC(43.8%) and NC (31.6%) with respect to control samples (52.9%). Microtox test results indicated that NiNC presents higher toxicity than NC, with EC50s values of 16.1% and 29.9% respectively; a reduced toxicity was observed, however, in presence of organic matter, thus obtaining EC50s of 37.8% and 19.4%. The results of AMPHITOX test showed a significant increase in the toxicity of both substances over time, the NiNC toxicity being greater than that of NC. The values of 96h-LC50 and 504h-LC50 determined for NiNC were 1.58 and 0.83mg/L, respectively, and 14.5 and 10.5mg/L for NC samples. Amphibian larvae exhibited collapsed cavities, edema, axial flexures, and behavioral alterations as hyperkinesia and reduced movements. These results evidence the vulnerability of wildlife to xenobiotics and the need to develop specific standardized ecotoxicity tests in order to help environmental sustainability and natural species conservation. PMID- 28623799 TI - Assessment of species-specific and temporal variations of major, trace and rare earth elements in vineyard ambient using moss bags. AB - Since the methodological parameters of moss bag biomonitoring have rarely been investigated for the application in agricultural areas, two mosses, Sphagnum girgensohnii (a species of the most recommended biomonitoring genus) and Hypnum cupressiforme (commonly available), were verified in a vineyard ambient. The moss bags were exposed along transects in six vineyard parcels during the grapevine season (March-September 2015). To select an appropriate period for the reliable 'signal' of the element enrichment in the mosses, the bags were simultaneously exposed during five periods (3 * 2 months, 1 * 4 months, and 1 * 6 months). Assuming that vineyard is susceptible to contamination originated from different agricultural treatments, a wide range of elements (41) were determined in the moss and topsoil samples. The mosses were significantly enriched by the elements during the 2-month bag exposure which gradually increasing up to 6 months, but Cu and Ni exhibited the noticeable fluctuations during the grapevine season. However, the 6-month exposure of moss bags could be recommended for comparative studies among different vineyards because it reflects the ambient pollution comprising unpredictable treatments of grapevine applied during the whole season. Although higher element concentrations were determined in S. girgensohnii than H. cupressiforme, both species reflected the spatio-temporal changes in the ambient element content. Moreover, the significant correlation of the element (Cr, Cu, Sb, and Ti) concentrations between the mosses, and the same pairs of the elements correlated within the species, imply the comparable use of S. girgensohnii and H. cupressiforme in the vineyard (agricultural) ambient. Finally, both the moss bags and the soil analyses suggest that vineyard represents a dominant diffuse pollution source of As, Cr, Cu, Ni, Fe, and V. PMID- 28623800 TI - Inpatient geriatric care in Sweden-Important factors from an inter-disciplinary team perspective. AB - The purpose of this study was to describe factors of importance for the quality of inpatient geriatric care from an inter-disciplinary team perspective, an area that has not been previously studied to our knowledge. The study design was qualitative descriptive with data being collected from focus-group interviews with members of geriatric care teams. The data collection was conducted at a Swedish university hospital with 69 beds for geriatric care. It comprised five group interviews with a total of 32 staff members, including representatives of all the seven professions working with geriatric care. Data was analysed using qualitative content analysis and a thematic framework approach. Three main themes were identified as being perceived as characterising important factors essential for quality geriatric care: Interactive assessment processes, A holistic care approach, and Proactive non-hierarchical interaction. Aspects of Time and Goal Orientation were additionally running like common threads through these themes and informed them. Accessibility, open communication, and staff continuity were experienced as prerequisites for well-functioning teamwork. Including patients and relatives in care planning and implementation was seen as essential for good care, but was at risk due to budget cuts that imposed shortened hospital stays. To meet the care demands of the growing population of older frail people, more specialised team-based care according to the concept of Comprehensive Geriatric Assessment - which is possibly best provided by older-friendly hospitals - appears as a constructive solution for reaching high degrees of both staff and patient satisfaction in geriatric care. More research is needed in this area. PMID- 28623801 TI - DNA analysis of root canal-filled teeth. AB - Teeth are markedly useful as samples for DNA analysis; however, intact teeth are not always available. This study examined the possibility of identifying autosomal and Y-chromosome short tandem repeat (STR) types in samples from 34 teeth (15 intact and 19 root canal filled) that had been preserved for 10-33years after dental extraction. The aim was to explore the feasibility of individual identification by DNA analysis of samples obtained from highly decomposed and skeletonized corpses. Only one out of 24 autosomal STR loci was not identified in two of the 15 intact teeth, whereas all 23 loci of the Y chromosome STR were detected. One or two autosomal STR loci remained unidentified in eight of the 19 root-filled teeth, and four or five of the 23 Y STR loci were undetected in three cases. However, the types were identified in about 20 loci in all samples, and the composition of the root canal filling material did not appear to interfere with the PCR. This study demonstrates that the storage period of the teeth had no influence on our results indicating that root canal filled teeth can be used for DNA analysis. PMID- 28623802 TI - Developmental toxicity of glycine-coated silica nanoparticles in embryonic zebrafish. AB - Nanoparticle (NP) surface coatings are known to influence the toxicity of engineered nanomaterials. This work examines the effect of glycine functionalization on silica NPs and investigates changes in viability and developmental defects in the organs of zebrafish embryos upon exposure. Silica NPs and glycine-functionalized silica NPs are synthesized and characterized. Exposure of zebrafish embryos to glycine-silica NPs affects the mortality percentage in a similar manner to soluble glycine. Developmental defects are observed in embryos exposed to soluble glycine, glycine-silica NPs, or silica NPs in comparison with the unexposed embryos. The damage is localized in the brain, heart, and liver of zebrafish embryos. These observations suggest a complex mechanism of toxicity, with glycine maintaining its toxic activity even when covalently bound on silica surface. Our results illustrate that surface modification of non-lethal particles can create different toxicity outcomes in the organs of exposed zebrafish embryos. PMID- 28623803 TI - Oxidative status in relation to metal pollution and calcium availability in pied flycatcher nestlings - A calcium manipulation experiment. AB - Metal exposure can produce oxidative stress by disrupting the prooxidant/antioxidant balance. It has been suggested that calcium (Ca) may provide protection against metal toxicity in the organism. The objective of this study is to explore the effects of Ca availability and metal pollution on oxidative stress biomarkers in pied flycatcher (Ficedula hypoleuca) nestlings. For this purpose, we performed a Ca-supplementation experiment with birds inhabiting a Ca-poor and metal-polluted area in SW Finland. An array of oxidative stress biomarkers (GSH, GSH:GSSG ratio, GPx, GST, CAT, SOD, lipid peroxidation and protein carbonylation) was measured in red blood cells. The effects of antioxidant molecules and oxidative damage on nestling size, growth, fledging success and fledgling number were evaluated. We observed an up-regulation of GST activity and increased protein carbonyl content in the polluted zone, probably related to a combination of higher metal exposure and reduced food quantity and quality in this area. As expected, birds from the unpolluted zone showed higher GSH:GSSG ratio but, unexpectedly, also showed signs of higher lipid peroxidation (not statistically significant, p = 0.056), both responses likely being related with the lower Ca availability. Our study suggests that different measures of oxidative damage are affected by different factors: while damage to proteins was the target of metal exposure/food limitation, poor Ca availability may enhance damage to lipids in growing birds. The intercorrelations found between Ca in plasma, metal exposure and the different oxidative stress biomarkers show that the antioxidant defense is finely regulated to cope with increased oxidative challenges. Finally, our results suggest that the antioxidant status during early development, conditioned by environmental pollution and Ca availability, is one factor affecting nestling survival and fledgling number. PMID- 28623804 TI - Evaluating the effectiveness of a programme for improving the participation and academic success of an underrepresented minority group in New Zealand. AB - Pacific peoples are a minority under-represented ethnic group in higher education in New Zealand. This article explores the effectiveness of a specific programme, which sought to improve outcomes of Pacific students in the tertiary environment. The aim of the evaluation was to determine the effectiveness of an intervention programme (2013-2015) to increase the participation and academic success of Pacific students in the first year in Health Sciences. The study found the academic results of Pacific students who participated in the intervention programme were significantly better compared to those who did not. The findings inform future research, suggesting that, when assessing the effectiveness of a programme, it is useful to explore the performance of the whole cohort separately to those who declared intention or interest to attend the programme. Strategies to support participation of each of these groups are likely to be different. Having a standardised approach when comparing groups will adjust for any confounding factors or prior differences. This will allow a more accurate assessment of the effectiveness of the programme being evaluated. This paper presents the importance of a robust approach to the delivery and evaluation of intervention programmes for improving outcomes for underrepresented students in the tertiary environment. PMID- 28623805 TI - Heroin and pharmaceutical opioid overdose events: Emergency medical response characteristics. AB - BACKGROUND: Emergency Medical Services (EMS) data may provide insight into opioid overdose incidence, clinical characteristics, and medical response. This analysis describes patient characteristics, clinical features, and EMS response to opioid overdoses, comparing heroin and pharmaceutical opioid (PO) overdoses, using a structured opioid overdose case criteria definition. METHODS: A case series study was conducted. EMS medical staff screened cases for possible overdoses and study staff categorized the likelihood of opioid overdose. Medical form data were abstracted. Patient characteristics, clinical presentation, and medical response to heroin and PO-involved overdoses were compared with bi-variate test statistics. RESULTS: We identified 229 definite or probable opioid overdose cases over six months: heroin in 98 (43%) cases (10 also involved PO), PO without heroin in 85 (37%) cases, and 46 (20%) that could not be categorized and were excluded from analyses. Heroin overdose patients were younger than PO (median age 33 v 41 (p<0.05)), more often male (80% v 61% (p=<0.01)), intubated less (8% v 22%, p<0.01) and more likely to be administered naloxone (72% v 51%, p<0.01). No significant differences were found between heroin and PO overdoses for initial respiratory rate, Glasgow Coma Scale score, or co-ingestants, but heroin users were more likely to have miotic pupils (p<0.01). CONCLUSIONS: While heroin and PO events presented similarly, heroin-involved cases were more likely to receive naloxone and less likely to be intubated. Standardized case definitions and data documentation could aid opioid overdose surveillance as well as provide data for measuring the impact of professional and lay interventions. PMID- 28623806 TI - Prevalence and correlates of light and non-daily smoking in Brazil: Results from a nationwide representative survey. AB - BACKGROUND: The research of light (<=10 cigarettes per day) and non-daily smokers in developing countries including Brazil is scarce despite the high prevalence of these groups among smokers and health risks associated to low-level smoking. OBJECTIVE: To describe health and smoking characteristics of Brazilian adult light and non-daily smokers. METHODS: We analyzed data from the 2013 Brazilian National Health Research survey (n=48,282). RESULTS: The prevalence of current manufactured cigarette smoking in the total sample was 12.4%. Among these smokers, 12.8% were non-daily smokers (NDS), 47.4% were light smokers (LS) and 39.8% were moderate/heavy smokers (MHS). Bivariate analysis showed that non-daily smoking was associated with higher odds of poor self-rated health, binge drinking and lung diseases compared to never smokers (ORs=1.2; 5.9 and 1.9). Light smoking was associated with higher odds of poor self-rated health, binge drinking, depression, use of sleeping pills and lung diseases (ORs=1.3; 4.3; 1.4; 1.2 and 2.0). After controlling for sex and age, non-daily smoking was associated with lung disease (OR=2.2) and light smoking with depression and lung diseases (ORs=1.3 and 1.8). Smoking levels were associated with living with same-level smokers in bivariate and multivariate analyses. CONCLUSION: A large proportion of smokers in Brazil are light and non-daily smokers, carrying substantial health risks related to tobacco use. Longitudinal research is needed to provide further evidence of associations found in this study. Public health policies must take the different smoking patterns into consideration to effectively target all smokers and reduce the harmful consequences of tobacco worldwide. PMID- 28623808 TI - Role of polyphenols and polyphenol-rich foods in the modulation of PON1 activity and expression. AB - Paraoxonase 1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme involved in the protection of low-density lipoprotein and HDLs against lipid peroxidation. Several studies documented the capacity of polyphenols to stimulate PON1 transcription activation. The objective of the present review is to provide the main evidence about the role and the potential mechanism of action of polyphenols and polyphenol-rich foods in the modulation of PON1 gene expression and activity. A total of 76 in vitro and in vivo studies were included in the review. Overall, while evidence obtained in vitro is limited to quercetin and resveratrol, those deriving from animal models seem more convincing for a wide range of polyphenols but only at pharmacological doses. Evidence from human studies is promising but deserves more substantiation about the role of polyphenol-rich foods in the regulation of PON1 activity and expression. Research focused on the understanding of the structure-activity relationship of polyphenols with PON1 and on the mechanisms at the base of PON1 modulation is warranted. Well-designed human intervention studies are encouraged to corroborate the findings of polyphenols also at physiological doses. PMID- 28623807 TI - HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens. AB - BACKGROUND: HIV-1 infection and drug abuse are frequently co-morbid and their association greatly increases the severity of HIV-1-induced neuropathology. While nucleus accumbens (NAcc) function is severely perturbed by drugs of abuse, little is known about how HIV-1 infection affects NAcc. METHODS: We used calcium and voltage imaging to investigate the effect of HIV-1 trans-activator of transcription (Tat) on rat NAcc. Based on previous neuronal studies, we hypothesized that Tat modulates intracellular Ca2+ homeostasis of NAcc neurons. RESULTS: We provide evidence that Tat triggers a Ca2+ signaling cascade in NAcc medium spiny neurons (MSN) expressing D1-like dopamine receptors leading to neuronal depolarization. Firstly, Tat induced inositol 1,4,5-trisphsophate (IP3) receptor-mediated Ca2+ release from endoplasmic reticulum, followed by Ca2+ and Na+ influx via transient receptor potential canonical channels. The influx of cations depolarizes the membrane promoting additional Ca2+ entry through voltage gated P/Q-type Ca2+ channels and opening of tetrodotoxin-sensitive Na+ channels. By activating this mechanism, Tat elicits a feed-forward depolarization increasing the excitability of D1-phosphatidylinositol-linked NAcc MSN. We previously found that cocaine targets NAcc neurons directly (independent of the inhibition of dopamine transporter) only when IP3-generating mechanisms are concomitantly initiated. When tested here, cocaine produced a dose-dependent potentiation of the effect of Tat on cytosolic Ca2+. CONCLUSION: We describe for the first time a HIV-1 Tat-triggered Ca2+ signaling in MSN of NAcc involving TRPC and depolarization and a potentiation of the effect of Tat by cocaine, which may be relevant for the reward axis in cocaine-abusing HIV-1-positive patients. PMID- 28623809 TI - Dual-target screening of bioactive components from traditional Chinese medicines by hollow fiber-based ligand fishing combined with liquid chromatography-mass spectrometry. AB - A novel strategy was developed for dual-target screening of bioactive components from traditional Chinese medicines (TCMs). This strategy was based on the use of low-cost microporous hollow fibers filled with target enzymes as baits to "fish out" the ligands in TCM extracts, followed by identification of the ligands dissociated from the target-ligand complexes by liquid chromatography-mass spectrometry. Ganjiang Huangqin Huanglian Renshen Decoction (GHHRD), a classical TCM prescription for diabetes treatment, was chosen as a model sample to evaluate the feasibility of the proposed strategy. Three bioactive components were successfully screened out from GHHRD. Coptisine was identified as the ligand of alpha-glucosidase and baicalin as the ligand of angiotensin-converting enzyme (ACE). Berberine was found to be a dual inhibitor of alpha-glucosidase and ACE. The results were further verified by enzyme inhibitory assay and molecular docking simulation. The study suggested that our developed strategy would be a powerful tool for screening bioactive components from multi-component and multi target TCMs. PMID- 28623810 TI - Platelet granule release is associated with reactive oxygen species generation during platelet storage: A direct link between platelet pro-inflammatory and oxidation states. AB - BACKGROUND: Upon platelet stimulation with agonists, reactive oxygen species (ROS) generation enhances platelet activation and granule release. Whether ROS generation during platelet storage could be directly correlated with the expression of proinflammatory molecules and granule release has been investigated in this study. MATERIAL AND METHOD: PRP-platelet concentrates were subjected to flowcytometry analysis to assess the expression of platelet activation marker, P selectin and CD40L during storage. Intracellular ROS generation was also detected in platelet by flowcytometry using dihydrorhodamine (DHR) 123. Through the dual staining, ROS production was analyzed in either P-selectin positive or negative populations. RESULTS: ROS formation in platelet population was significantly increased by either TRAP (a potent agonist that induces granule release) or PMA (a classic inducer of ROS generation), while the effects of each agonists on P selectin expression and ROS generation in platelets were comparable. Platelet storage was also associated with the increasing levels of ROS (day 0 vs. day 5; p<0.001) while this increasing pattern was directly correlated with the either expressed P-selectin or CD40L. In addition, in 5 day-stored platelets, samples with ROS levels above 40% showed significantly higher levels of P-selectin and CD40L expression. P-selectin negative population of platelet did not show significant amount of ROS. CONCLUSION: Our data demonstrated decreased levels of important platelet pro-inflammatory molecules in stored platelets with lower levels of intraplatelet ROS. However, whether quenching of ROS generation during platelet storage can attenuate adverse transfusion reactions raised by platelet pro-inflammatory status is required to be further studied. PMID- 28623811 TI - Residential exposure to pesticides as risk factor for childhood and young adult brain tumors: A systematic review and meta-analysis. AB - BACKGROUND: Accumulating evidence suggests a positive association between exposure to non-agricultural pesticides and childhood brain tumors (CBT). OBJECTIVE: (1) To conduct a systematic review and meta-analysis of published studies on the association between residential/household/domestic exposure to pesticides and childhood brain tumors. (2) To clarify variables that could impact the results. METHODS: Publications in English were identified from a MEDLINE search through 28 February 2017 and from the reference list of identified publications. Risk estimates were extracted from 18 case-control studies published between 1979 and 2016 and study quality assessments were performed. Summary odds ratios (mOR) were calculated according to fixed and random-effect meta-analysis models. Separate analyses were conducted after stratification for study quality, critical exposure period, exposure location, specific exposures, pesticide category, application methods, type of pest treated, type of CBT, child's age at diagnosis and geographic location. RESULTS: Statistically significant associations were observed with CBT after combining all studies (mOR: 1.26; 95% CI: 1.13-1.40) without evidence of inconsistency between study results or publication bias. Specifically, increased risks were observed for several groupings and more particularly for gliomas and exposure involving insecticides. Statistical significance was also reached for high quality studies, for all exposure periods, for indoor exposure and, more particularly, during the prenatal period for all stratifications involving insecticides (except for outdoor use), for pet treatments, for flea/tick treatment, for studies from USA/Canada and studies from Europe (borderline) as well as for data from studies including children of up to 10years at diagnosis and of up to 15years. CONCLUSIONS: Our findings support an association between residential exposure to pesticides and childhood brain tumors. Although causality cannot be established, these results add to the evidence leading to recommend limiting residential use of pesticides and to support public health policies serving this objective. PMID- 28623812 TI - Discovery of non-spherical heterogeneous radiocesium-bearing particles not derived from Unit 1 of the Fukushima Dai-ichi Nuclear Power Plant, in residences five years after the accident. AB - Non-spherical heterogeneous radiocesium-bearing particles were found on masks worn during cleaning work in residences near the Fukushima Dai-ichi Nuclear Power Plant (FDNPP), from which residents had evacuated. Three slightly larger (6.6-12 MUm) non-spherical radiocesium-bearing particles were found in a residence in Futaba Town, a straight distance of 2.11 km west-northwest from the FDNPP. These were collected on October 25, 2016, 5 years and 7 months after the Fukushima Dai ichi nuclear disaster and were presumed to originate from the Plant's Unit 2 based on the measured radioactivity ratio of 134Cs/137Cs. The main elemental composition was similar to particles already reported in other studies. However, this is the first time that such particles had a clearly heterogeneous distribution. PMID- 28623813 TI - Association between altered physical activity and neurocognitive function among people with schizophrenia: A minimum 6-months' follow-up study. AB - BACKGROUND: The long-term benefits of physical activity on neurocognitive function among patients with schizophrenia, specifically among inpatients, remain unclear. This preliminary study, with a minimum of 6-months' follow-up, examined alterations in physical activity and neurocognitive function in both inpatients and outpatients with schizophrenia. METHODS: Symptoms and neurocognitive function were assessed at 2 intervals using the Positive and Negative Symptom Scale and Cognitrax, respectively. After each testing period, participants wore an accelerometer for 1week to measure their levels and duration of physical activity. After the 6-months' follow-up (average duration, 235.9+/-36.2days), participants were divided into 2 groups based on either increased or decreased activity, as compared with baseline: increased-activity and decreased-activity groups. RESULTS: Of the 29 initially enrolled participants, 25 (mean age, 56.8+/ 11.8years) completed the follow-up. Reaction times in the increased-activity group in daily activity (n=10) improved as compared with the decreased-activity group (n=15). Moreover, cognitive flexibility and executive function improved in the increased-activity group in steps (n=7) compared with the decreased-activity group (n=18). Finally, there was no association between the duration of moderate or vigorous exercise and neurocognitive function. CONCLUSIONS: Together, our results suggest that increased daily activity and walking, but not high intensity activity, are associated with improved neurocognitive function in patients with schizophrenia. PMID- 28623814 TI - Synthesis, antimicrobial, antiquorum-sensing and antitumor activities of new benzimidazole analogs. AB - New benzimidazole analogs were prepared and tested for antimicrobial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85, Staphylococcus aureus ATCC 29213, Candida albicans and Aspergillus fumigatus 293. Results indicated that compound 10 has potent and broad spectrum antimicrobial activity. In addition, 4b and 5c showed eminent antimicrobial efficacy toward B. cereus, S. aureus, C. albicans and A. fumigatus. Furthermore, 12 and 14 demonstrated interesting antifungal activity toward C. albicans. Antiquorum-sensing efficacy of the new compounds toward Chromobacterium violacium ATCC 12472 was also examined. In vitro antitumor screening of the new benzimidazoles toward HepG2, HCT-116 and MCF-7 cancer cell lines demonstrated that 4b and 5b,c are the most potent analogs toward all tested cell lines. The three potent in vitro antitumor analogs were further assessed for in vivo antitumor activity toward EAC in mice, and in vitro cytotoxicity toward W138 normal cell line. Results revealed that 4b has the highest in vivo activity, and that the three tested analogs are less cytotoxic than 5-FU toward W138 normal cell line. The most active antimicrobial and antitumor analogs were examined for DNA-binding affinity, whereas 4b and 5c displayed the highest affinity. The in silico studies illustrated that all of the new benzimidazoles meet the optimal requirements for good oral absorption and bioavailability. Moreover, in silico toxicity assessment has been reported. PMID- 28623815 TI - Colorimetric sensor array for protein discrimination based on different DNA chain length-dependent gold nanoparticles aggregation. AB - A facile colorimetric sensor array for detection of proteins was demonstrated using DNA as nonspecific receptors. We found that different proteins could trigger the DNA-protected gold nanoparticles (AuNPs) to show different aggregation behaviors in the presence of salt with high concentrations along with various color changes. As a proof-of-concept application, a multi-protein discrimination array was fabricated with two ssDNA strands (15A and 30A bases) as a receptor array. The combinatorial colorimetric response of this sensor array can be analyzed by linear discriminant analysis (LDA) and hierarchical cluster analysis (HCA). 12 proteins have been well distinguished with the naked eye at the 50nM level. The proteins in human serum have also been discriminated. Furthermore, the accuracies of discrimination of the similar mixtures of proteins and unknown samples were all 100%. PMID- 28623816 TI - Siderophore coated magnetic iron nanoparticles: Rational designing of water soluble nanobiosensor for visualizing Al3+ in live organism. AB - This article aims to establish the judicious use of iron-binding chemistry of microbial chelators in order to functionalize the surface of iron nanoparticles to develop non-toxic nanobiosensor. Anchoring a simple siderophore 2,3 dihydroxybenzoylglycine (H3L), which bears catechol and carboxyl functionalities in tandem, on to the surface of Fe3O4 nanoparticles has developed a unique nanobiosensor HL-FeNPs which showed highly selective and sensitive detection of Al3+ in 100% water at physiological pH. The biosensor HL-FeNPs, with 20nM limit of detection, behaves reversibly and instantly. In-vivo bio-imaging in live brine shrimp Artemia confirmed that HL-FeNPs could be used as fluorescent biomarker for Al3+ in live whole organisms. Magnetic nature of the nanosensor enabled HL-FeNPs to remove excess Al3+ by using external magnet. To our knowledge, the possibility of microbial chelator in the practical development of Al3+ selective nanobiosensor is unprecedented. PMID- 28623817 TI - Development of a simple and convenient cell-based electrochemical biosensor for evaluating the individual and combined toxicity of DON, ZEN, and AFB1. AB - A simple and convenient cell-based electrochemical biosensor was developed to assess the individual and combined toxicity of deoxynivalenol (DON), zearalenone (ZEN), and Aflatoxin B1 (AFB1) on Hep G2 cells. The sensor was modified in succession with AuNPs (gold nanoparticles), cysteamine, and laminin. The cells interacting with laminin formed tight cell-to-electrode contacts, and collagen was used to maintain cell adhesion and viability. Electrochemical impedance spectroscopy (EIS) was developed to evaluate mycotoxin toxicity. Experimental results show that DON, ZEN, and AFB1 caused a significant decrease in cell viability in a dose dependent manner. The EIS value decreased with concentrations of DON, ZEN, and AFB1 in the range of 0.01-20, 0.1-50, and 0.1-3.5MUg/mL, and IC50 obtained using the developed method was 48.5, 59.0, and 3.10MUg/mL, respectively. A synergistic effect was observed between DON and ZEN, an additive effect was observed between DON and AFB1, and an antagonism effect was found in the binary mixtures of ZEN and AFB1 and ternary mixtures. These results were confirmed via CCK-8 assay. Utilizing SEM, we found that cells treated with mycotoxins caused significant changes in cell morphology, thus lessening cell adsorption and impedance reduction. Biological assay indicated that EIS patterns correlated with [Ca2+]i concentrations and apoptosis and necrotic cells ratios, thus effecting electrochemical signals. This method is simpler, more convenient, sensitive, and has a quicker response rate than most conventional cytotoxicity evaluation methods. PMID- 28623818 TI - The rule of five should not impede anti-parasitic drug development. AB - The "rule of 5" has become a mainstay of decision-making in the pharmaceutical industry as well as in nonindustrial (academic and institutional) drug development. However the authors of the original paper never intended for "double cutoffs" to preclude development of new drug leads for parasitic diseases. PMID- 28623819 TI - The texture, structure and nutrient availability of artificial soil on cut slopes restored with OSSS - Influence of restoration time. AB - Outside soil spray seeding (OSSS) is widely used to restore cut slopes in southwest of China, and artificial soil is often sprayed onto cut slopes to establish a soil layer for revegetation. The stability of artificial soil layer and its supply of water and nutrients for plants is crucial for successful restoration. To evaluate the long-term effectiveness of OSSS, the texture, structure and nutrient availability of artificial soil were studied, various soil samples were obtained from three cut slopes with different restoration time (restored with OSSS in 1996, 2003 and 2007 respectively) and one natural developed slope (NS). The properties measured including soil particle size distribution (PSD), texture, fractal dimension of PSD (Dm), the bias (CS) and peak convex (CE) coefficients of aggregate size distribution, structure failure rate, bulk density, moisture, pH, soil organic carbon (SOC), calcium carbonate content, Available nitrogen (NA), Available phosphorus (PA), and Available potassium (KA). The results showed that different restoration time resulted in significant differences in soil PSD, Dm, CS, CE, structure failure rate, bulk density, moisture, pH, NA, and KA. And these properties improved with increasing restoration age. However, there is still a huge disparity in soil texture, structure, and the availability of nutrients and moisture between the cut slopes and NS over a restoration period of up to 17 years, and this is caused by the little fine particles and the lack of slow release fertilizers and organic fertilizers in the artificial soil, resulting in poorer soil structure stability, retention and availability of moisture and nutrients on the cut slopes. Overall, the OSSS technique shows a long-term effectiveness in southwest of China, but there is still room for improvement. PMID- 28623820 TI - Spectral selectivity model for light transmission by the intermediate filaments in Muller cells. AB - Presently we continue our studies of the quantum mechanism of light energy transmission in the form of excitons by axisymmetric nanostructures with electrically conductive walls. Using our theoretical model, we analyzed the light energy transmission by biopolymers forming optical channels within retinal Muller cells. There are specialized intermediate filaments (IF) 10-18nm in diameter, built of electrically conductive polypeptides. Presently, we analyzed the spectral selectivity of these nanostructures. We found that their transmission spectrum depends on their diameter and wall thickness. We also considered the classical approach, comparing the results with those predicted by the quantum mechanism. We performed experimental measurements on model quantum waveguides, made of rectangular nanometer-thick chromium (Cr) tracks. The optical spectrum of such waveguides varied with their thickness. We compared the experimental absorption/transmission spectra with those predicted by our model, with good agreement between the two. We report that the observed spectra may be explained by the same mechanisms as operating in metal nanolayers. Both the models and the experiment show that Cr nanotracks have high light transmission efficiency in a narrow spectral range, with the spectral maximum dependent on the layer thickness. Therefore, a set of intermediate filaments with different geometries may provide light transmission over the entire visible spectrum with a very high (~90%) efficiency. Thus, we believe that high contrast and visual resolution in daylight are provided by the quantum mechanism of energy transfer in the form of excitons, whereas the ultimate retinal sensitivity of the night vision is provided by the classical mechanism of photons transmitted by the Muller cell light-guides. PMID- 28623821 TI - Green biosynthesis of magnetic iron oxide (Fe3O4) nanoparticles using the aqueous extracts of food processing wastes under photo-catalyzed condition and investigation of their antimicrobial and antioxidant activity. AB - In this study, a simple, rapid, and eco-friendly green method was introduced to synthesize magnetite iron oxide nanoparticles (Fe3O4 NPs) using the aqueous extracts of two food processing wastes, namely silky hairs of corn (Zea mays L.) and outer leaves of Chinese cabbage (Brassica rapa L. subsp. pekinensis). The boiled solutions of silky hairs (MH) and outer leaves of Chinese cabbage (CCP) were used to synthesize Fe3O4 NPs under photo exposed condition. The MH-FeNPs and CCP-FeNPs synthesized via green route were characterized by UV-Vis spectroscopy, field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDX), Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), differential thermogravimetric (TG/DTG) analysis, and vibrating sample magnetometer (VSM) analysis. The UV-Visible spectra displayed two absorption bands at 325nm and 375mm for the MH-FeNPs, and 325mm and 365mm for the CCP-FeNPs, respectively. The estimated absolute crystallite sizes of the MH FeNPs and CCP-FeNPs were calculated to be 84.81 and 48.91nm, respectively. VSM analysis revealed that both FeNPs were superparamagnetic in nature. Both FeNPs mixed with kanamycin and rifampicin displayed positive synergistic antibacterial activity against pathogenic foodborne bacteria (9.36-24.42mm inhibition zones), and those mixed with amphotericin b also exerted synergistic anticandidal activity against five different pathogenic Candida species (9.81-17.68mm inhibition zones). Both FeNPs exhibited strong antioxidant activities; therefore, all the properties of the green synthesized MH-FeNPs and CCP-FeNPs using food processing wastes could be beneficial for their potential applications in various fields such as drug delivery, antibacterial and anticandidal drugs, and biomedical fields. PMID- 28623822 TI - A novel photosensitization treatment for the inactivation of fungal spores and cells mediated by curcumin. AB - The global concerns regarding the emergence of fungicide-resistant strains and the impact of the excessive use of fungicidal practises on our health, food, and environment have increased, leading to a demand for alternative clean green technologies as treatments. Photosensitization is a treatment that utilises a photosensitiser, light and oxygen to cause cell damage to microorganisms. The effect of photosensitization mediated by curcumin on Aspergillus niger, Aspergillus flavus, Penicillium griseofulvum, Penicillium chrysogenum, Fusarium oxysporum, Candida albicans and Zygosaccharomyces bailii was investigated using three methods. The viability of spores/cells suspended in aqueous buffer using different concentrations of curcumin solution (100-1000MUM) and light dose (0, 24, 48, 72 and 96J/cm2) were determined. Spraying curcumin solution on inoculated surfaces of agar plates followed by irradiation and soaking spores/cells in curcumin solution prior to irradiation was also investigated. In aqueous mixtures, photosensitised spores/cells of F. oxysporum and C. albicans were inhibited at all light doses and curcumin concentrations, while inactivation of A. niger, A. flavus P. griseofulvum, P. chrysogenum and Z. bailii were highly significant (P<0.001) reduced by 99%, 88.9%, 78%, 99.7% and 99.2% respectively. On the surface of agar plates, spores/cells exposed to a light dose of 360J/cm2 sprayed with curcumin at 800MUM showed complete inhibition for A. niger, F. oxysporum, C. albicans and Z. bailii, while A. flavus P. griseofulvum, and P. chrysogenum reduced by 75%, 80.4% and 88.5% respectively. Soaking spores/cells with curcumin solution prior to irradiation did not have a significant effect on the percentage reduction. These observations suggest that a novel photosensitization mediated curcumin treatment is effective against fungal spores/cells and the variation of percentage reduction was dependent on curcumin concentration, light dosage and fungal species. PMID- 28623825 TI - Application of static fatigue testing to the behavior of absorbable sutures. AB - Absorbable sutures, since their conception, have become the dominant method for surgical wound closure and are constantly being improved. However, despite their years of service, not all aspects of their performance are fully understood. In particular, suture absorption is usually characterized by immersing the suture in a model in vitro environment under zero stress followed by measurement of the residual tensile strength as a function of immersion time. When in use, absorbable sutures are exposed to mechanical stress, which may affect the absorption rate; however, this phenomenon has not been adequately studied. The present work reports results of static fatigue tests in which the suture material is subjected to a mechanical load while immersed in a controlled environment and the time to fracture is measured as a function of the applied load. This approach is proved a viable method for obtaining a more detailed evaluation of absorbable suture performance. PMID- 28623824 TI - Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress. AB - Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0mmol/kg/day) or standard chow for two weeks prior to 30min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1beta, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury. PMID- 28623823 TI - A randomized placebo-controlled trial of N-acetylcysteine for cannabis use disorder in adults. AB - BACKGROUND: Cannabis use disorder (CUD) is a prevalent and impairing condition, and established psychosocial treatments convey limited efficacy. In light of recent findings supporting the efficacy of N-acetylcysteine (NAC) for CUD in adolescents, the objective of this trial was to evaluate its efficacy in adults. METHODS: In a 12-week double-blind randomized placebo-controlled trial, treatment seeking adults ages 18-50 with CUD (N=302), enrolled across six National Drug Abuse Treatment Clinical Trials Network-affiliated clinical sites, were randomized in a 1:1 ratio to a 12-week course of NAC 1200mg (n=153) or placebo (n=149) twice daily. All participants received contingency management (CM) and medical management. The primary efficacy measure was the odds of negative urine cannabinoid tests during treatment, compared between NAC and placebo participants. RESULTS: There was not statistically significant evidence that the NAC and placebo groups differed in cannabis abstinence (odds ratio=1.00, 95% confidence interval 0.63-1.59, p=0.984). Overall, 22.3% of urine cannabinoid tests in the NAC group were negative, compared with 22.4% in the placebo group. Many participants were medication non-adherent; exploratory analysis within medication-adherent subgroups revealed no significant differential abstinence outcomes by treatment group. CONCLUSIONS: In contrast with prior findings in adolescents, there is no evidence that NAC 1200mg twice daily plus CM is differentially efficacious for CUD in adults when compared to placebo plus CM. This discrepant finding between adolescents and adults with CUD may have been influenced by differences in development, cannabis use profiles, responses to embedded behavioral treatment, medication adherence, and other factors. PMID- 28623826 TI - Mechanical characterization via nanoindentation of the woven bone developed during bone transport. AB - Nanoindentation has been used successfully in the determination of the mechanical properties of bone. Its application in fracture healing provides information on the evolution of material properties of the woven bone during regeneration process. However, this technique has not been applied in assessing the mechanical properties of woven bone during distraction osteogenesis. Therefore, the aim of this work is to evaluate the spatial and temporal variations of the elastic modulus of the woven bone generated during the bone transport process. Callus samples were harvested from intervened animals at different time points during the bone transport process (35, 50, 79, 98, 161 and 525 days after surgery) for nanoindentation measurements. Results clearly showed that the mean elastic modulus of the woven bone increased during the bone transport process reaching 77% of value for cortical bone after 525 days (from 7GPa 35 days after surgery to 14GPa 525 days after surgery approximately). Woven bone generated during bone transport seems to present similar evolution of elastic modulus with time as values reported for fracture healing. Furthermore, different spatial variations of elastic modulus within the callus were found for different stages of the process. PMID- 28623827 TI - Changes in aquatic microbial responses to C-substrates with stream water and sediment quality related to land use pressures. AB - The degradation of aquatic ecosystems by multiply-acting stressors is a key threat requiring new approaches to identify impairment processes and restoration targets. Heterotrophic respiration of C-substrates can be an integrative indicator of how aquatic ecosystems respond to pollution. We utilised sixteen C substrates (simple metabolites to dissolved organic matter (DOM)) to characterise substrate induced respiration (SIR) for sediments from sixteen NE Scotland streams covering a range of land use-related pollution pressures. Pollution explanatory variables were as assessed from GIS-derived land cover areas, dissolved water chemistry (N, P, base cations and trace elements) and sediment trace metals (by aqua-regia digest). Large inter-site variation in dissolved and sediment chemical concentrations was strongly significantly correlated with land cover: dissolved N, Ca, Mg, K, Na positively with agriculture and urban, negatively with semi-natural land areas; sediment As, Ba, Co, Zn with agriculture, Cu, Pb, Zn with urban areas. Simple linear regression modelling was used to explore the influences across land cover, dissolved and sediment chemistry with C-substrate responses, both individually and using principal components-derived SIR 'fingerprints'. The data supported the hypothesis that pollution pressures altered water and sediment quality, in turn affecting sediment microbes and their respiration responses to a range of C-substrates, especially discriminating the DOM respiration. Since headwater DOM is a dominant pool of C driving ecosystem processes downstream then any loss of ability to utilise DOM should be further explored in terms of possible connections to pollution processes. PMID- 28623828 TI - PCDD/F-isomers signature - Effect of metal chlorides and oxides. AB - A recent paper presented the results from de novo tests, involving 11 distinct catalytic systems (oxides and chlorides of Cd, Cr, Cu, Ni, and Zn, as well as a blank sample). Their PCDD and PCDF formation activity was shown. This paper further assesses their isomer signature, with special emphasis on those congeners associated with chlorophenol precursor routes, and on 2,3,7,8- and 1,9 substituted congeners. Each metal catalyst generates a significantly different signature, also affected by the presence or absence of oxygen in the reaction atmosphere. Oxide and chloride catalysts supply distinctive signatures, suggesting singly weighted pathways. Quite a large number of data was handled, so that throughout this analysis special attention was given to testing and developing an appropriate methodology, allowing appropriate correlation analysis and statistical data treatment. The large tables resulting relate to the 11 catalytic systems, studied at 3 levels of oxygen concentration, with 94 PCDD/F congeners considered individually. They constitute an extensive reference data bank for confronting novel experimental data with this vast data set. PMID- 28623829 TI - Criteria for assessing the ecological risk of nonylphenol for aquatic life in Chinese surface fresh water. AB - The typical environmental endocrine disruptor nonylphenol is becoming an increasingly common pollutant in both fresh and salt water; it compromises the growth and development of many aquatic organisms. As yet, water quality criteria with respect to nonylphenol pollution have not been established in China. Here, the predicted "no effect concentration" of nonylphenol was derived from an analysis of species sensitivity distribution covering a range of species mainly native to China, as a means of quantifying the ecological risk of nonylphenol in surface fresh water. The resulting model, based on the log-logistic distribution, proved to be robust; the minimum sample sizes required for generating a stable estimate of HC5 were 12 for acute toxicity and 13 for chronic toxicity. The criteria maximum concentration and criteria continuous concentration were, respectively 18.49 MUg L-1 and 1.85 MUg L-1. Among the 24 sites surveyed, two were associated with a high ecological risk (risk quotient >1) and 12 with a moderate ecological risk (risk quotient >0.1). The potentially affected fraction ranged from 0.008% to 24.600%. The analysis provides a theoretical basis for both short- and long-term risk assessments with respect to nonylphenol, and also a means to quantify the risk to aquatic ecosystems. PMID- 28623830 TI - Identification, characteristics and human exposure assessments of triclosan, bisphenol-A, and four commonly used organic UV filters in indoor dust collected from Shanghai, China. AB - Indoor dust is a very significant medium to understand human exposure of emerging contaminants. A novel and robust analytical method to measure the amounts of six personal care products (PCPs) (triclosan, bisphenol-A and four commonly used organic ultraviolet (UV) filters) simultaneously in indoor dust is developed in this paper. Target analytes were extracted using accelerated solvent extraction. After sample cleanup by solid-phase extraction (SPE), the extracts were derivatized and analyzed using gas chromatography-tandem mass spectrometry. The method detection limits achieves 0.16-0.62 pg g-1 (except for 4-methylbenzylidene camphor with 3800 pg g-1). The method was successfully applied to the analysis of 110 indoor dust samples from Shanghai, China. Results showed that the PCPs were found in most of the samples analyzed. The concentrations of the most analytes are relatively lower than those reported in USA, Japan, and European countries. The median concentration of octocrylene (OC) (1170.4 ng g-1) was found to be nearly 5-10 times higher than those of other analytes. The significantly higher concentration of ?PCPs was observed in indoor dusts from residences than from offices (P < 0.05). The human exposure was analyzed by calculate the estimated daily intakes (EDI) of PCPs through dust ingestion for various age groups. The EDI of the target analytes for infants ranged from 0.85 to 6.18 ng kg-1 -bw day-1 and 0.07-0.49 ng kg-1 -bw day-1 for adults, respectively. This is the first study to report the doses of human exposure to UV filters in China. PMID- 28623831 TI - Tracking historical mobility behavior and sources of lead in the 59-year sediment core from the Huaihe River using lead isotopic compositions. AB - A historical perspective of past 59 years (1955-2014) for contamination and isotopic composition of Pb in sediment core system of the Huaihe River, Huainan City, Anhui Province of China is presented. Detailed investigation regarding changes in Pb sources, enrichment factor, sequential extraction and isotopic analysis revealed that high Pb concentrations were detected along the core, especially during the first two decades (1955-1974). Large variations in Pb isotopic compositions were observed, with 206Pb/207Pb and 208Pb/207Pb values ranging from 1.1504-1.1694, and 2.0817-2.1380, respectively. Diverse Pb sources were identified for sediment contamination over the time. Among anthropogenic sources, metallurgic dust and leaded petrol were on top during 1955-1974, especially when the Great Leap Forward Movement (1958-1960) was in progress in China, the time numerous small industries were established without wastewater treatment facility. However, coal and coal combustion were recognized as the primary sources of Pb emissions for the recent four decades (1974-2014) due to tremendous increase of coal consumption for power and heat generation. Unleaded vehicle exhaust, waste incineration and industrial emission were also sources of Pb during the years 1974-2014. Our estimates based on geochemical and lead isotopic approaches have shown that anthropogenic Pb contributions varied from 4.35 to 92.01%, and 13.28-99.06%, respectively. Assessment of lead speciation indicated an overwhelming presence of reducible fraction (Fe-Mn hydro-(oxides)) in the sediment core, except during 1995-1997, which was thought to be affected by water pollution accidents caused by heavy rainfall. PMID- 28623832 TI - A review on in situ phytoremediation of mine tailings. AB - Mine tailings are detrimental to natural plant growth due to their physicochemical characteristics, such as high pH, high salinity, low water retention capacity, high heavy metal concentrations, and deficiencies in soil organic matter and fertility. Thus, the remediation of mine tailings has become a key issue in environmental science and engineering. Phytoremediation, an in situ cost-effective technology, is emerging as the most promising remediation method for mine tailings by introducing tolerant plant species. It is particularly effective in dealing with large-area mine tailings with shallow contamination of organic, nutrient and metal pollutants. In this review, the background, concepts and applications of phytoremediation are comprehensively discussed. Furthermore, proper amendments used to improve the physical, chemical and biological properties of mine tailings are systematically reviewed and compared. Emphasis is placed on the types and characteristics of tolerant plants and their role in phytoremediation. Moreover, the role of microorganisms and their mechanism in phytoremediation are also discussed in-depth. PMID- 28623833 TI - Organic dye removal by MnO2 and Ag micromotors under various ambient conditions: The comparison between two abatement mechanisms. AB - MnO2- and Ag- based micromotors were developed recently as new types of micromotors with the advantage of low costs and have been utilized to treat environmental pollutants. However, knowledge about the effects of ambient conditions on the performance of them is still lacking. In this article, the influences of pH, electrolytes and surfactant on the treatment of organic dye (with methylene blue as the representative) by the commercial MnO2 and Ag micromotors with H2O2 as the fuel were studied. In the motion visualization experiments, besides the routine types of trajectories, the circular motion of micromotors around the already formed bubbles was observed for the first time. In the pollutant removal experiments, two abatement mechanisms (catalytic degradation and adsorptive bubble separation) were studied. The decolorization efficiency for MnO2 due to catalytic degradation increased with the increasing pH, which disagreed with previous studies in which no H2O2 was added. The inhibitory effects of the tested electrolytes were in the order: CaCl2>NaNO3>NaCl. Surfactant can increase the decolorization efficiency only under highly alkaline conditions. For Ag, decolorization only occurs with the existence of surfactant at high pH values (pH = 11.4) indicating that the dominant mechanism is adsorptive bubble separation. PMID- 28623834 TI - Nitrate formation during ozonation as a surrogate parameter for abatement of micropollutants and the N-nitrosodimethylamine (NDMA) formation potential. AB - In this study, nitrate formation from ammonium and/or dissolved organic nitrogen (DON) was investigated as a novel surrogate parameter to evaluate the abatement of micropollutants during ozonation of synthetic waters containing natural organic matter (NOM) isolates, a natural water and secondary wastewater effluents. Nitrate formation during ozonation was compared to the changes in UV absorbance at 254 nm (UVA254) including the effect of pH. For low specific ozone doses UVA254 was abated more efficiently than nitrate was formed. This is due to a relatively slow rate-limiting step for nitrate formation from the reaction between ozone and a proposed nitrogen-containing intermediate. This reaction cannot compete with the fast reactions between ozone and UV-absorbing moieties (e.g., activated aromatic compounds). To further test the kinetics of nitrate formation, two possible intermediates formed during ozonation of DON were tested. At pH 7, nitrate was formed during ozonation of acetone oxime and methyl nitroacetate with second-order rate constants of 256.7 +/- 4.7 M-1 s-1 and 149.5 +/- 5.8 M-1 s-1, respectively. The abatement of the selected micropollutants (i.e., 17alpha-ethinylestradiol (EE2), carbamazepine (CBZ), bezafibrate (BZF), ibuprofen (IBU), and p-chlorobenzoic acid (pCBA)) was investigated for specific ozone doses <=1.53 mgO3/mgDOC and its efficiency depended strongly on the reactivity of the selected compounds with ozone. The relative abatement of micropollutants (i.e., EE2 and CBZ) with high ozone reactivity showed linear relationships with nitrate formation. The abatement of micropollutants with intermediate-low ozone reactivity (BZF, IBU, and pCBA) followed one- and two phase behaviors relative to nitrate formation during ozonation of water samples containing high and low concentrations of nitrate-forming DON, respectively. During ozonation of a wastewater sample, the N-nitrosodimethylamine formation potential (NDMA-FP) during chloramination decreased with increasing specific ozone doses. A good correlation was obtained between NDMA-FP abatement and nitrate formation. Therefore, nitrate formation after pre-ozonation may be a useful parameter to estimate the reduction of the NDMA-FP during post chloramination. Overall, the results of this study suggest that nitrate formation (possibly in combination with UVA254 abatement) during ozonation of DON containing waters may be a good surrogate for assessing the abatement of micropollutants and the NDMA-FP. PMID- 28623835 TI - Life cycle assessment of treatment and handling options for a highly saline brine extracted from a potential CO2 storage site. AB - Carbon dioxide (CO2) injection in deep saline aquifers is a promising option for CO2 geological sequestration. However, brine extraction may be necessary to control the anticipated increase in reservoir pressure resulting from CO2 injection. The extracted brines usually have elevated concentrations of total dissolved solids (TDS) and other contaminants and require proper handling or treatment. Different options for the handling or treatment of a high-TDS brine extracted from a potential CO2 sequestration site (Mt. Simon Sandstone, Illinois, USA) are evaluated here through a life cycle assessment (LCA) study. The objective of this LCA study is to evaluate the environmental impact (EI) of various treatment or disposal options, namely, deep well disposal (Case 1); near zero liquid discharge (ZLD) treatment followed by disposal of salt and brine by products (Case 2); and near-ZLD treatment assuming beneficial use of the treatment by-products (Case 3). Results indicate that energy use is the dominant factor determining the overall EI. Because of the high energy consumption, desalination of the pretreated brine (Cases 2 and 3) results in the highest EI. Consequently, the overall EI of desalination cases falls mainly into two EI categories: global warming potential and resources-fossil fuels. Deep well disposal has the least EI when the EI of brine injection into deep formations is not included. The overall freshwater consumption associated with different life cycle stages of the selected disposal or treatment options is 0.6-1.8 m3 of freshwater for every 1.0 m3 of brine input. The freshwater consumption balance is 0.6 m3 for every 1.0 m3 of brine input for Case 3 when desalination by-products are utilized for beneficial uses. PMID- 28623836 TI - Sequential matched analysis of racial disparities in breast cancer hospitalization outcomes among African American and White patients. AB - BACKGROUND: The purpose of this study is to determine if racial disparities in inpatient outcomes persist among hospitalized patients comparing African American and White breast cancer patients matched on demographics, presentation and treatment. METHODS: A total of 136,211 African American and White breast cancer patients from the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS) database, matched on demographics alone, demographics and presentation or demographics, presentation and treatment were studied. Conditional logistic regression was conducted to evaluate post-surgical complications, length of stay and in-hospital mortality outcomes. Analysis was further stratified by age (<=65 years and >65years) to evaluate whether disparities were larger in younger or older patients. All analysis was conducted using SAS 9.3. RESULTS: White women had significantly shorter hospital length of stay when matched on demographics (beta=-0.87, p-value=<0.0001), demographics and presentation (beta=-0.63, p-value=<0.0001), and demographics, presentation and treatment (beta=-0.51, p-value=<0.0001) compared with African Americans. White women also had lower odds of mortality compared with African American women when matched on demographics (OR: 0.72, 95% CI: 0.65-0.79), demographics and presentation (OR: 0.77, 95% CI: 0.71-0.85), or matched on demographics, presentation and treatment (OR: 0.80, 95% CI: 0.73-0.88). The racial difference observed in length of stay and mortality was larger in the age group <=65 years compared with >65years CONCLUSION: African American women experienced higher odds of inpatient mortality and longer length of stay compared with White women even after accounting for differences in demographics, presentation and treatment characteristics. PMID- 28623837 TI - Abnormal asymmetry in benign epilepsy with unilateral and bilateral centrotemporal spikes: A combined fMRI and DTI study. AB - Benign epilepsy with centrotemporal spikes (BECTS) is the most common idiopathic focal childhood epilepsy associated with either unilateral or bilateral epileptic discharge. Asymmetry as an important characteristic of the human brain is beneficial for brain functions. However, little is known about on asymmetry of BECTS patients with different epileptic spikes pattern. In the present study, we investigated functional and structural asymmetries in unilateral spikes BECTS (U_BECTS) patients and bilateral spikes BECTS (B_BECTS) patients using resting state functional magnetic resonance images and diffusion tensor imaging. Compared with the controls, we observed a decreased voxel-mirrored interhemispheric functional connectivity (FC) in primary sensorimotor cortex (SM1) in U_BECTS and B_BECTS groups, and reduced fractional anisotropy (FA) values of the corpus callosum (CC) connecting bilateral SM1 were also observed in B_BECTS group. Further region-based FC map analysis of SM1 demonstrated increased functional asymmetry with ipsilateral hemisphere, contralateral hemisphere and the whole brain in U_BECTS and increased functional asymmetry with the contralateral hemisphere and the whole brain in B_BECTS groups. The correlation between functional asymmetry of SM1 and intelligence quotient scores was found in the U_BECTS group. The altered asymmetries of the SM1 further indicated the important role of SM1 in the pathophysiology of the BECTS. Furthermore, the B_BECTS group also showed abnormal voxel-mirrored interhemispheric FC in the temporal pole, the lobule IX of the cerebellum, the caudate and the occipital cortex relative to the controls. Altogether, our findings provide additional insight into the neuronal mechanism of BECTS with different epileptic spikes pattern and cognitive impairments with BECTS patients. PMID- 28623838 TI - Economic analysis of an epilepsy outreach model of care in a university hospital setting. AB - The prevalence of epilepsy in people with intellectual disability is higher than in the general population and prevalence rates increase with increasing levels of disability. Prevalence rates of epilepsy are highest among those living in residential care. The healthcare needs of people with intellectual disability and epilepsy are complex and deserve special consideration in terms of healthcare provision and access to specialist epilepsy clinics, which are usually held in acute hospital campuses. This patient population is at risk of suboptimal care because of significant difficulties accessing specialist epilepsy care which is typically delivered in the environs of acute hospitals. In 2014, the epilepsy service at Cork University Hospital established an Epilepsy Outreach Service providing regular, ambulatory outpatient follow up at residential care facilities in Cork city and county in an effort to improve access to care, reduce the burden and expense of patient and carer travel to hospital outpatient appointments, and to provide a dedicated specialist phone service for epilepsy related queries in order to reduce emergency room visits when possible. We present the findings of an economic analysis of the outreach service model of care compared to the traditional hospital outpatient service and demonstrate significant cost savings and improved access to care with this model. Ideally these cost savings should be used to develop novel ways to enhance epilepsy care for persons with disability. We propose that this model of care can be more suitable for persons with disability living in residential care who are at risk of losing access to specialist epilepsy care. PMID- 28623839 TI - Expression profiles of genes for mitochondrial respiratory energy-dissipating systems and antioxidant enzymes in wheat leaves during de-etiolation. AB - Mitochondrial respiratory components participate in the maintenance of chloroplast functional activity. This study investigates the effects 48h de etiolation of spring wheat seedlings (Triticum aestivum L., var. Irgina) on the expression of genes that encode energy-dissipating respiratory components and antioxidant enzymes under continuous light conditions. The expression of AOX1a following the prolonged darkness exhibited a pattern indicating a prominent dependence on light. The expression of other respiratory genes, including NDA2, NDB2, and UCP1b, increased during de-etiolation and dark-to-light transition; however, changes in the expression of these genes occurred later than those in AOX1a expression. A high expression of NDA1 was detected after 12h of de etiolation. The suppression of AOX1a, NDA2, NDB2, and UCP1b was observed 24h after de-etiolation when the photosynthetic apparatus and its defence systems against excess light were completely developed. The expression patterns of the respiratory genes and several genes encoding antioxidant enzymes (MnSOD, Cu ZnSOD, t-APX, GR, and GRX) were quite similar. Our data indicate that the induction of nuclear genes encoding respiratory and antioxidant enzymes allow the plants to control reactive oxygen species (ROS) production and avoid oxidative stress during de-etiolation. PMID- 28623840 TI - On the spectral properties of methyl and methoxy derivatives of 1,3-diphenyl-1H pyrazolo[3,4-b]quinoxalines: Experiment and DFT/TDDFT calculations. AB - Paper reports the synthesis and spectroscopic studies of two novel 1,3-diphenyl pyrazoloquinoxaline (PQX) derivatives with 6-substituted methyl (MePQX) or methoxy (MeOPQX) side groups. The optical absorption and fluorescence emission spectra are recorded in solvents of different polarity. Other photophysical constants, such as the fluorescence lifetime and quantum yield, radiationless and radiative rate constants, electronic transition dipole moments, give complete characterization of MePQX and MeOPQX dyes as materials for potential luminescence or electroluminescence applications. Measured optical absorption and fluorescence emission spectra are compared with the results of quantum-chemical analysis using density functional theory (DFT/TDDFT) methods based on hybrid and long range corrected (LRC) exchange-correlation (xc) functionals in combination with solvation self consistent reaction field model. Comparing to conventional hybrid xc-functionals, the DFT/TDDFT calculations using LRC xc-functionals yield considerably more accurate description of optical absorption and fluorescence emission spectra. The best description of the absorption-emission circle provides the model assuming that optical absorption takes place from preferably flat or weakly twisted molecular conformations in the ground state, as particularly is suggested by the geometrical DFT optimization, whereas the fluorescence emission would be expected from more twisted molecular conformations in the excited state. PMID- 28623841 TI - Development of a HPLC method for determination of four UV filters in sunscreen and its application to skin penetration studies. AB - This study describes the development, validation and application of a high performance liquid chromatography (HPLC) method for the simultaneous determination of the in vitro skin penetration profile of four UV filters on porcine skin. Experiments were carried out on a gel-cream formulation containing the following UV filters: diethylamino hydroxybenzoyl hexyl benzoate (DHHB), bis ethylhexyloxyphenol methoxyphenyl triazine (BEMT), methylene bis-benzotriazolyl tetramethylbutylphenol (MBBT) and ethylhexyl triazone (EHT). The HPLC method demonstrated suitable selectivity, linearity (10.0-50.0 MUg/mL), precision, accuracy and recovery from porcine skin and sunscreen formulation. The in vitro skin penetration profile was evaluated using Franz vertical diffusion cells for 24 h after application on porcine ear skin. None of the UV filters penetrated the porcine skin. Most of them stayed on the skin surface (>90%) and only BEMT, EHT and DHHB reached the dermis plus epidermis layer. These results are in agreement with previous results in the literature. Therefore, the analytical method was useful to evaluate the in vitro skin penetration of the UV filters and may help the development of safer and effective sunscreen products. PMID- 28623842 TI - What Are They Thinking? A National Study of Stability and Change in Divorce Ideation. AB - This study reports on a nationally representative sample of married individuals ages 25-50 (N = 3,000) surveyed twice (1 year apart) to investigate the phenomenon of divorce ideation, or what people are thinking when they are thinking about divorce. Twenty-eight percent of respondents had thought their marriage was in serious trouble in the past but not recently. Another 25% had thoughts about divorce in the last 6 months. Latent Class Analysis revealed three distinct groups among those thinking about divorce at Time 1: soft thinkers (49%), long-term-serious thinkers (45%), and conflicted thinkers (6%). Yet, divorce ideation was not static; 31% of Time 1 thinkers were not thinking about it 1 year later (and 36% of nonthinkers at Time 1 were thinking about it 1 year later). Also, Latent Transition Analysis revealed 49% of Time 1 long-term-serious thinkers, 56% of soft thinkers, and 51% of conflicted thinkers had shifted groups at Time 2, mostly in the direction of less and softer thinking about divorce. Overall, divorce ideation is common but dynamic, and it is not necessarily an indication of imminent marital dissolution. PMID- 28623843 TI - Proposal for long-term protocols after Psoriasis Area and Severity Index clear with initial biologic therapy: Happily ever after with or without biologics in psoriasis therapy. PMID- 28623844 TI - LC-MS/MS characterization, anti-inflammatory effects and antioxidant activities of polyphenols from different tissues of Korean Petasites japonicus (Meowi). AB - The Korean Petasites japonicus is a perennial plant used in folk medicine as a remedy for many diseases and popularly consumed as spring greens. Ten polyphenols were characterized from the leaves, stems and roots of this plant via high performance liquid chromatography-tandem mass spectrometry. Individual polyphenols were quantified for the first time using calibration curves of six structurally related external standards. Validation data indicated that coefficients of determinations (R2 ) were >=0.9702 for all standards. Recoveries measured at 50 and 100 mg/L were 80.0-91.9 and 80.3-105.3%, respectively. Precisions at these two concentration levels were 0.7-6.1 and 1.1-5.5%, respectively. The total number of identified components was largest for the leaves and smallest for the stems. The leaf and root polyphenolic extracts showed anti-inflammatory effects by inducing LPS-activated COX-2 and iNOS protein levels in mouse macrophage RAW 264.7 cells. The antioxidant capacity of the polyphenols, when evaluated for DPPH (alpha,alpha-diphenyl-beta-picrylhydrazyl)? , ABTS+ [2-2' azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] and superoxide radical scavenging activities, and in ferric reducing ability of plasma (FRAP) assays, was highest in the leaf and lowest in the stem. This trend suggests that the antioxidant capacities depend primarily on polyphenol concentration in each tissue. The current findings suggest that polyphenols derived from P. japonicas tissues could have potential as functional health foods. PMID- 28623845 TI - Direct C2-Functionalization of Indoles Triggered by the Generation of Iminium Species from Indole and Sulfonium Salt. AB - An indole core bearing a functional group on the C2 position is often found as a key structure in biologically active natural products and pharmaceuticals. Here, we report direct C2-functionalization of indoles triggered by the formation of an iminium species generated from indole and a sulfonium reagent. The reaction proceeded under very mild conditions to give the corresponding C2-substituted indole derivatives in good to high yields. PMID- 28623846 TI - SonoCAD: a software to solve the dilemma of the prenatal diagnosis of fetal syndromes. AB - OBJECTIVE: The aim of this work is to develop an efficient, user-friendly, time saving computer software program specified with prenatal diagnosis, based solely on ultrasound findings provided by the sonographer. MATERIALS AND METHOD: Sonographyic computer-assisted diagnosis (SonoCAD) program was developed in four phases. Phase I: data gathering phase. Phase II: the software development phase in which the source code of the software was developed. Phase III: system testing phase that was divided into two steps: alpha testing phase, in which 20 syndromic scenarios were supplied to the software and the beta testing phase, in which the performance of SonoCAD was compared with the performance of the already established web site phenotip.com launched in 2014. Phase IV: the refining phase. RESULTS: In 92% of the syndromes provided, SonoCAD was capable of providing the correct diagnosis, while only in 53.3% of the syndromes phenotip.com was capable of providing the correct diagnosis. DISCUSSION AND CONCLUSION: Sonographyic computer-assisted diagnosis is an efficient, properly functioning, time-saving software that could be utilized by all who are involved in prenatal diagnosis. SonoCAD was found to be more efficient and more accurate in generating a correct diagnosis when compared with the already available website phenotip.com having the same functionality. (c) 2017 John Wiley & Sons, Ltd. PMID- 28623847 TI - Toxicity after post-prostatectomy image-guided intensity-modulated radiotherapy using Australian guidelines. AB - INTRODUCTION: We evaluated single institution toxicity outcomes after post prostatectomy radiotherapy (PPRT) via image-guided intensity-modulated radiation therapy (IG-IMRT) with implanted fiducial markers following national eviQ guidelines, for which late toxicity outcomes have not been published. METHODS: Prospectively collected toxicity data were retrospectively reviewed for 293 men who underwent 64-66 Gy IG-IMRT to the prostate bed between 2007 and 2015. RESULTS: Median follow-up after PPRT was 39 months. Baseline grade >=2 genitourinary (GU), gastrointestinal (GI) and sexual toxicities were 20.5%, 2.7% and 43.7%, respectively, reflecting ongoing toxicity after radical prostatectomy. Incidence of new (compared to baseline) acute grade >=2 GU and GI toxicity was 5.8% and 10.6%, respectively. New late grade >=2 GU, GI and sexual toxicity occurred in 19.1%, 4.7% and 20.2%, respectively. However, many patients also experienced improvements in toxicities. For this reason, prevalence of grade >=2 GU, GI and sexual toxicities 4 years after PPRT was similar to or lower than baseline (21.7%, 2.6% and 17.4%, respectively). There were no grade >=4 toxicities. CONCLUSIONS: Post-prostatectomy IG-IMRT using Australian contouring guidelines appears to have tolerable acute and late toxicity. The 4-year prevalence of grade >=2 GU and GI toxicity was virtually unchanged compared to baseline, and sexual toxicity improved over baseline. This should reassure radiation oncologists following these guidelines. Late toxicity rates of surgery and PPRT are higher than following definitive IG-IMRT, and this should be taken into account if patients are considering surgery and likely to require PPRT. PMID- 28623848 TI - Very brief physician advice and supplemental proactive telephone calls to promote smoking reduction and cessation in Chinese male smokers with no intention to quit: a randomized trial. AB - BACKGROUND AND AIMS: There is inconsistent evidence that behavioural support to promote smoking reduction is effective at increasing smoking cessation. We examined the effectiveness of brief physician advice together with four very brief telephone calls in promoting smoking cessation among Chinese men via reduction compared with equivalent advice on diet and exercise. DESIGN: A two group pragmatic randomized controlled trial. PARTICIPANTS AND SETTING: Male patients attending the Endocrinology and Acupuncture out-patient clinics of a general hospital in Beijing, China. INTERVENTION AND COMPARATORS: Physicians advised participants allocated to the smoking-reduction intervention (SRI, n = 181) group to reduce smoking to at least half of their current consumption within 1 month at baseline. At follow-up, a telephone counsellor repeated this advice if the participant had not reduced their cigarette consumption. Participants who had reduced consumption were encouraged to quit smoking. Physicians gave participants in the exercise and diet advice (EDA, n = 188) control group brief advice about physical activity and healthy diet at baseline, and a telephone counsellor reinforced this at each follow-up interview. Both groups had one face-to-face interview at baseline plus five telephone interviews and interventions (approximately 1 minute each) at 1 week and 1-, 3-, 6- and 12-month follow-up. MEASUREMENTS: The primary outcome was self-reported 6-month prolonged abstinence rate at 12-month follow-up interview. FINDINGS: By intention-to-treat, the self reported 6-month prolonged abstinence rate at 12-month follow-up in the SRI groups (19 quitters, 15.7%) was higher, but not significantly, than the EDA control group (10 quitters, 7.8%), and the adjusted odds ratio (OR) and 95% confidence interval (CI) was 2.26 (0.97-5.26), P = 0.062. The self-reported 7-day point prevalence quit rate (secondary outcome) in the SRI group was significantly higher than the control group at each follow-up interview (at 12-month follow-up: 13.3 versus 6.9%, OR (95% CI) = 2.09 (1.01, 4.34), P = 0.049). CONCLUSIONS: A very brief, proactive and low-cost smoking-reduction intervention without medications for Chinese male smokers with no intention to quit appears to increase smoking abstinence. PMID- 28623850 TI - Arabidopsis TOR signaling is essential for sugar-regulated callus formation. AB - Dedifferentiation is a remarkable process that produces pluripotent stem cells from differentiated somatic cells to ensure developmental plasticity. Plants have evolved the ability of cellular dedifferentiation, and signaling cascades related to auxin and cytokinin-dependent callus formation have been extensively investigated. However, the molecular mechanism underlying sugar-dependent callus formation remains unknown. Here, we show that sugar-dependent callus formation is mainly regulated by the TOR-E2Fa module in Arabidopsis. Sugar-activated TOR kinase phosphorylates and stabilizes E2Fa proteins to transcriptionally activate S-phase genes during callus formation. In parallel, E2Fa is transcriptionally regulated by the ARF-LBD transcription cascade. Multi-layered regulation of E2Fa by sugar and auxin is likely to shape balanced cellular dedifferentiation capability in Arabidopsis. PMID- 28623849 TI - Population Pharmacokinetics/Pharmacodynamics of 3,4-Diaminopyridine Free Base in Patients With Lambert-Eaton Myasthenia. AB - Lambert-Eaton myasthenia (LEM) is a rare autoimmune disorder associated with debilitating muscle weakness. There are limited treatment options and 3,4 diaminopyridine (3,4-DAP) free base is an investigational orphan drug used to treat LEM-related weakness. We performed a population pharmacokinetic/pharmacodynamic (PK/PD) analysis using 3,4-DAP and metabolite concentrations collected from a phase II study in patients with LEM. The Triple Timed Up & Go (3TUG) assessment, which measures lower extremity weakness, was the primary outcome measure. A total of 1,270 PK samples (49 patients) and 1,091 3TUG data points (32 randomized patients) were included in the PK/PD analysis. A two compartment and one-compartment model for parent and metabolite, respectively, described the PK data well. Body weight and serum creatinine partially explained the variability in clearance for the final PK model. A fractional inhibitory maximum effect (Emax ) model characterized the exposure-response relationship well. The PK/PD model was applied to identify a suggested dosing approach for 3,4 DAP free base. PMID- 28623851 TI - Quantification of beta-eudesmol in rat plasma using LC-MS/MS and its application to a pharmacokinetic study. AB - A sensitive and specific LC-MS/MS assay for determination of beta-eudesmol in rat plasma was developed and validated. After liquid-liquid extraction with ethyl ether, the analyte and IS were separated on a Capcell Pak C18 column (50 * 2.0 mm, 5 MUm) by isocratic elution with acetonitrile-water-formic acid (77.5:22.5:0.1, v/v/v) as the mobile phase at a flow rate of 0.4 mL/min. An ESI source was applied and operated in positive ion mode; a selected reaction monitoring scan was used for quantification by monitoring the precursor-product ion transitions of m/z 245.1 -> 163.1 for beta-eudesmol and m/z 273.4 -> 81.2 for IS. Good linearity was observed in the concentration range of 3-900 ng/mL for beta-eudesmol in rat plasma. Intra- and inter-day precision and accuracy were both within +/-14.3%. This method was applied for pharmacokinetic studies after intravenous bolus of 2.0 mg/kg or intragastric administration of 50 mg/kg beta eudesmol in rats. PMID- 28623852 TI - Frusemide aids diagnostic interpretation of 68 Ga-PSMA positron emission tomography/CT in men with prostate cancer. AB - INTRODUCTION: 68 Ga-PSMA positron emission tomography-computed tomography (PET/CT) is useful for both staging and assessment of biochemical relapse in men with prostate cancer. Renal excretion of 68 Ga-PSMA can lead to difficulties in scan interpretation, particularly in the pelvis. We evaluated if intravenous Frusemide at the time of 68 Ga-PSMA injection reduces excreted activity artefact and improves diagnostic certainty. METHODS: Sixty-two men with prostate cancer undergoing clinically indicated 68 Ga-PSMA PET/CT were prospectively included, 30 men receiving Frusemide at the time of radiotracer injection. Clinical information and reasons for the scan were documented. Intensity of excreted activity was assessed semi quantitatively for each patient (SUV max). PET/CT images were interpreted by two experienced readers for image quality, and presence/absence of PSMA-positive disease. RESULTS: Twenty-nine percent (18/62) were staging scans, and 71% (44/62) re-staging. PSMA-positive findings were identified in 95% (59/62). Staging scans had PSMA-positive findings within the prostate in 100% (18/18) and re-staging scans, 50% (22/44) in the prostate fossa, 64% (28/44) in lymph nodes and 21% (9/44) in viscera and bone. Administration of Frusemide had a significant impact on intensity of excreted activity in the ureters and bladder. Impaired image quality was noted in 33% (10/30) of men not given Frusemide, compared to only 3% (1/32) in men given Frusemide (P = 0.002). Reporter confidence on the presence/absence of PSMA avid disease in the prostate fossa improved from 63% (19/30) without Frusemide, to 91% (29/32) with Frusemide (P < 0.015). CONCLUSION: Intravenous Frusemide given with 68 Ga-PSMA reduces excretion artefact, and improves diagnostic certainty. Frusemide should be considered for all 68 Ga-PSMA PET/CT imaging protocols. PMID- 28623854 TI - Successful treatment of tufted angioma with low-dose electron beam radiation therapy: Report of two cases. PMID- 28623853 TI - The validity of DSM-5 severity specifiers for anorexia nervosa, bulimia nervosa, and binge-eating disorder. AB - OBJECTIVE: The DSM-5 includes severity specifiers (i.e., mild, moderate, severe, extreme) for anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED), which are determined by weight status (AN) and frequencies of binge-eating episodes (BED) or inappropriate compensatory behaviors (BN). Given limited data regarding the validity of eating disorder (ED) severity specifiers, this study examined the concurrent and predictive validity of severity specifiers in AN, BN, and BED. METHOD: Adults with AN (n = 109), BN (n = 76), and BED (n = 216) were identified from previous datasets. Concurrent validity was assessed by measures of ED psychopathology, depression, anxiety, quality of life, and physical health. Predictive validity was assessed by ED symptoms at the end of the treatment in BN and BED. RESULTS: Severity categories did not differ in baseline validators, though the mild AN group evidenced greater ED symptoms compared to the severe group. In BN, greater severity was related to greater end of treatment binge-eating and compensatory behaviors, and lower likelihood of abstinence; however, in BED, greater severity was related to lower ED symptoms at the end of the treatment. DISCUSSION: Results demonstrated limited support for the validity of DSM-5 severity specifiers. Future research is warranted to explore additional validators and possible alternative indicators of severity in EDs. PMID- 28623855 TI - Authentic feminist? Authenticity and feminist identity in teenage feminists' talk. AB - This article explores how young people's feminist identities take shape in conjunction with a contemporary ideal of personal authenticity: to know and to express the 'real me'. Drawing from interviews with 18 teenagers living in Auckland, New Zealand, we examine a novel convergence of authenticity and feminism in participants' identity talk. For social psychologists interested in identity and politics, this convergence is intriguing: individualizing values such as authenticity are generally associated with disengagement with structural critique and with a repudiation of politicized and activist identities. Rather than seeking to categorize authentic feminism as an instance of either 'good/collective' or 'bad/individualized' feminist politics, we use discourse analysis to examine how the identity position of authentic feminist was constructed and to explore implications for feminist politics. On one hand, interviewees mobilized authentic feminism to affirm their commitment to normative liberal values of authenticity and self-expression. At the same time, the position of authentic feminist appeared to authorize risky feminist identifications and to justify counter-normative feelings, desires, and actions. To conclude, we explore how encountering others' intolerance of authentic feminism exposed interviewees to the limits of authenticity discourse, propelling some towards new understandings of the social world and their space for action within it. PMID- 28623856 TI - Antimicrobial susceptibility and phylogenetic analysis of Propionibacterium acnes isolated from acne patients in Japan between 2013 and 2015. AB - The prevalence of antimicrobial-resistant Propionibacterium acnes strains isolated from acne patients has been increasing in Japan. Here, to estimate the current resistance rate, we tested antimicrobial susceptibility among P. acnes from acne patients having visited a specialized dermatology clinic between 2013 and 2015. Rates of resistance to macrolides and clindamycin were 44.3 (31/70) and 38.6% (27/70), respectively. erm(X), which confers high-level clindamycin resistance (minimum inhibitory concentration >=256 MUg/mL), was detected in six isolates, whereas no resistance determinants were identified in eight strains showing high-level resistance to clindamycin. Using single-locus sequence typing, the P. acnes isolates were classified into five clades (A, E, F, H and K), with all high-level clindamycin-resistant strains lacking known clindamycin resistance determinants being grouped together (in clade F). P. acnes isolates from patients previously treated with macrolides and clindamycin showed a macrolide resistance rate (55.3%) significantly higher than that of those from patients not having received these treatments (21.7%, P < 0.05). Furthermore, strains of clade F, which were very rarely isolated from healthy individuals, were more frequently recovered from patients with severe acne (40.0%) than those with mild acne (23.3%). Our data showed an increase in macrolide-resistant P. acnes prevalence in Japan due to the use of antimicrobial agents for acne treatment. Furthermore, we identified strains of specific phylogenetic groups frequently associated with severe acne patients. PMID- 28623857 TI - Vincristine-induced neuropathy in pediatric patients with acute lymphoblastic leukemia in Oman: Frequent autonomic and more severe cranial nerve involvement. AB - BACKGROUND: Vincristine (VCR) induced peripheral neuropathy is a common complication in children with acute lymphoblastic leukemia (ALL). PROCEDURES: A retrospective data analysis over an interval of 10 years (2006-2016) of all children with ALL seen at Sultan Qaboos University Hospital was carried out. Electronic medical records of eligible patients were reviewed. Patients with clinical evidence of neuropathy and abnormal nerve conduction studies (NCSs) were included in the study. RESULTS: Nineteen (nine females and 10 males) out of 103 pediatric patients developed VCR-related neuropathy, and their age ranged between 2.5 and 14 years. Symptoms started after 2-11 doses of VCR. All 19 patients had documented peripheral neuropathy on NCSs. The autonomic nervous system and cranial nerves affection was relatively common in our patients; two presented with bradycardia, two patients with unexplained tachycardia, and five had abdominal pain and constipation, complicated by typhlitis in two patients. One patient developed unilateral hearing loss. Two patients developed severe life threatening cranial nerve involvement with bilateral ptosis and recurrent laryngeal nerve involvement presented as vocal cord paralysis, hoarseness of voice, frequent chocking, and aspiration episodes. CONCLUSIONS: Peripheral neuropathy was the commonest form of VCR-related neuropathy. Autonomic neuropathy was relatively common in our patients. Cranial neuropathy is a serious side effect of VCR that can be severe, involving multiple cranial nerves and needs prompt recognition and management. Concomitant administration of pyridoxine and pyridostigmine does not seem to protect against further neurological damage in some patients. PMID- 28623858 TI - Roles of ST2, IL-33 and BNP in predicting major adverse cardiovascular events in acute myocardial infarction after percutaneous coronary intervention. AB - This study investigated roles of serum ST2, IL-33 and BNP in predicting major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Blood samples were collected from the included AMI patients (n = 180) who underwent PCI. All patients were divided into the MACEs and MACEs-free groups. Enzyme-linked immunosorbent assay was performed to measure serum levels of ST2, IL-33 and BNP. Severity of coronary artery lesion was evaluated by Gensini score. Pearson correlation analysis was used. A receiver operating characteristics curve was drawn to evaluate the potential roles of ST2, IL-33 and BNP in predicting MACEs, and Kaplan-Meier curve to analyse the 1-year overall survival rate. Logistic regression analysis was conducted to analyse the independent risk factors for MACEs. Compared with the MACEs-free group, the serum levels of ST2, IL-33 and BNP were significantly higher in the MACEs group. Serum levels of ST2, IL-33 and BNP were positively correlated with each other and positively correlated with Gensini score. The area under curves of ST2, IL-33 and BNP, respectively, were 0.872, 0.675 and 0.902. The relative sensitivity and specificity were, respectively, 76.27% and 85.92%, 69.49% and 58.68%, as well as, 96.61% and 77.69%. Serum levels of ST2, IL-33 and BNP were independent risk factors for MACEs. The 1-year overall survival rate was higher in AMI patients with lower serum levels of ST2, IL-33 and BNP. In conclusion, serum levels of ST2, IL-33 and BNP have potential value in predicting MACEs in AMI patients undergoing PCI. PMID- 28623860 TI - Radiotherapy-induced basal cell carcinoma in irradiated and surrounding areas in relation to exposure dose of radiation. PMID- 28623861 TI - Level of acceptance of islet cell and kidney xenotransplants by personnel of hospitals with and without experience in clinical xenotransplantation. AB - BACKGROUND: Recently, significant progress in both safety and efficacy has been achieved in the field of xenotransplantation, as exemplified by results from the first clinical trials of porcine islet transplantation. It would be of interest to learn whether the attitude of the clinical staff involved in such trials changes as the trials are carried out in their own hospital. METHODS: One hundred and four clinical staff members from the Eva Peron Hospital of San Martin (Buenos Aires, Argentina) where clinical trials of islet xenotransplantation have been performed and 92 similar staff members from the Diego Thompson Hospital (Buenos Aires, Argentina) where no such xenotransplantation has been carried out participated in the study. Data were collected anonymously using questionnaires. RESULTS: Statistically significant differences between the acceptance of xenotransplantation by clinical personnel in a hospital that had carried out clinical xenotransplantation trials were observed when compared with the acceptance of a similar staff from the hospital that had not carried out such trials. CONCLUSION: This study shows that involvement in clinical xenotransplantation trials significantly changes the attitude of the clinical staff towards this technology and suggests that better information given to the society may increase acceptance of the xenotransplantation. PMID- 28623862 TI - Stimuli-Responsive Metal-Organic Framework (MOF) with Chemo-Switchable Properties for Colorimetric Detection of CHCl3. AB - The ligands 3,6-di(pyridin-4-yl)-1,4-dihydro-1,2,4,5-tetrazine (H2 DPT), as a pillar spacer, and 4,4'-oxybis(benzoic acid) (H2 OBA), as a dicarboxylate linker, have been used to develop a dihydrotetrazine-functionalized pillared metal organic framework (MOF), [Zn(OBA)(H2 DPT)0.5 ]?DMF (TMU-34), as a functionally convertible stimuli-responsive MOF-based sensor. Sonochemically synthesized TMU 34 powder has been employed in the sensing of volatile organic compounds (VOCs). The results show that TMU-34 can act as a solid-state, naked-eye visual chemosensor for the detection of chloroform in the liquid and gas phases. TMU-34, as a chemo-switchable MOF with rapid response, undergoes a significant color change from yellow to pink through reversible dynamic conversion of dihydrotetrazine into tetrazine upon exposure to chloroform in the presence of other VOCs. Whereas other colorimetric MOF-based sensors show a wide range of color changes in the presence of different analytes, TMU-34 undergoes a color change only in the presence of chloroform. A mechanism for the observed color change is proposed on the basis of UV/Vis and 1 H NMR spectroscopic studies. These observations reveal that TMU-34 represents one of the most promising candidates for the highly selective and sensitive detection of chloroform. PMID- 28623859 TI - Self-reported cognitive scales in a US National Survey: reliability, validity, and preliminary evidence for associations with alcohol and drug use. AB - AIMS: To evaluate relationships between measures of cognitive functioning and alcohol or drug use among adults (>= 18 years) in the US general population. DESIGN: Two cognitive scales were created based on dimensionality and reliability of self-reported Executive Function Index items. Relationships between the two scales and validators were evaluated. Associations between the cognitive scales and past-year frequency of alcohol or drug use were estimated with adjusted odds ratios (aOR). SETTING: United States, using the 2012-13 National Epidemiologic Survey on Alcohol and Related Conditions-III, a nationally representative adult sample selected by multi-stage probability sampling. PARTICIPANTS: 36 085 respondents. MEASUREMENTS: Past-year substance use outcome variables categorized binge drinking, marijuana, cocaine, opioid, sedative/tranquilizer and stimulant use as frequent (at least weekly to daily), infrequent (any to two to three times/month) or no use, assessed by the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Key predictors were the two cognitive scales. Construct validators included education and functional impairment. Covariates included age, gender, income and race/ethnicity. FINDINGS: Nine cognitive items fitted a two-factor model (comparative fit index = 0.973): attention (five items) and executive functioning (four items). Both scales were associated positively with higher education (Ps < 0.001) and negatively with functional impairment (Ps < 0.001), demonstrating construct validity. Poorer attention was associated with frequent and infrequent binge drinking and use of drugs [aOR range = 1.07 (binge drinking) to 1.72 (stimulants), Ps <= 0.01]. Poorer executive functioning was associated with frequent binge drinking and use of drugs [aOR range = 1.22 (binge drinking) to 2.03 (cocaine), Ps < 0.001] and infrequent use of all drugs [aOR range = 1.19 (marijuana) to 1.63 (cocaine), Ps < 0.001]. CONCLUSIONS: Impairments in attention and executive functioning are positively associated with substance use in the US general population. PMID- 28623863 TI - Linear immunoglobulin A/G bullous dermatosis associated with ulcerative colitis. AB - Linear immunoglobulin (Ig)A/G bullous dermatosis (LAGBD) is an autoimmune bullous disease characterized by formation of subepidermal blisters and linear deposition of IgA and IgG antibodies along the basement membrane zone (BMZ). The association between linear IgA bullous dermatosis and ulcerative colitis (UC) is well recognized, but reports of UC-associated LAGBD are lacking. We have reported a 24 year-old man suffering from LAGBD associated with UC, which occurred before exacerbations of skin rash. A skin biopsy indicated a subepidermal blister with an infiltration of primarily neutrophils and eosinophils in the dermis. Direct immunofluorescence (IF) studies showed a linear deposition of IgA, IgG and C3c. Indirect IF of human skin revealed IgA and IgG anti-BMZ autoantibodies. Indirect IF of 1 M NaCl-split human skin demonstrated reactivity of IgA and IgG antibodies at the epidermal side. Immunoblotting showed that IgG antibodies reacted to the BP180 NC16a domain and 120-kDa linear IgA dermatosis-1, and enzyme-linked immunoassay detected IgG anti-BP230 antibodies. Administration of prednisolone and diaminodiphenyl sulfone (DDS) via the p.o. route improved skin lesions and bowel conditions. These results suggest that the bowel inflammation observed in UC may have a causative effect of initiation of the immune response to the skin and development of the bullous skin lesions in LAGBD. A combination of DDS and corticosteroid could be a recommended therapeutic option for patients with LAGBD with UC. PMID- 28623864 TI - A highly sensitive LC-MS/MS method for simultaneous determination of glycyrrhizin and its active metabolite glycyrrhetinic acid: Application to a human pharmacokinetic study after oral administration. AB - A highly sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneous determination of glycyrrhizin (GL) and its active metabolite, glycyrrhetinic acid (GA), from human plasma was validated and applied to a human pharmacokinetic study. The analytes were extracted from human plasma using an Oasis MAX cartridge and chromatographic separation was performed on an Inertsil ODS-3 column. The detection was performed using an API 4000 mass spectrometer operating in the positive electrospray ionization mode. Selected ion monitoring transitions of m/z 823 -> 453 for GL and m/z 471 -> 149 for GA were obtained. The response was a linear function of concentration over the ranges of 0.5-200 ng/mL for GL and 2-800 ng/mL for GA (both R2 > 0.998). Using this method, the pharmacokinetics of GL after single oral administration of a clinical dose (75 mg) to six healthy male Japanese volunteers were evaluated. GL was detected in the plasma of all subjects and the average peak concentration was 24.8 +/- 12.0 ng/mL. In contrast, peak concentration of GA was 200.3 +/- 60.3 ng/mL, i.e. ~8-fold higher than that of GL. This is the first report clarifying pharmacokinetic profiles of GL and GA simultaneously at a therapeutic oral dose of a GL preparation. PMID- 28623865 TI - Deriving low-risk gambling limits from longitudinal data collected in two independent Canadian studies. AB - AIMS: To derive low-risk gambling limits using the method developed by Currie et al. (2006) applied to longitudinal data. DESIGN: Secondary analysis of data from the Quinte Longitudinal Study (n = 3054) and Leisure, Lifestyle and Lifecycle Project (n = 809), two independently conducted cohort studies of the natural progression of gambling in Canadian adults. SETTING: Community-dwelling adults in Southeastern Ontario and Alberta, Canada. PARTICIPANTS: A total of 3863 adults (50% male; median age = 44) who reported gambling in the past year. MEASUREMENTS: Gambling behaviours (typical monthly frequency, total expenditure and percentage of income spent on gambling) and harm (experiencing two or more consequences of gambling in the past 12 months) were assessed with the Canadian Problem Gambling Index. FINDINGS: The dose-response relationship was comparable in both studies for frequency of gambling (days per month), total expenditure and percentage of household income spent on gambling (area under the curve values ranged from 0.66 to 0.74). Based on the optimal sensitivity and specificity values, the low-risk gambling cut-offs were eight times per month, $75CAN total per month and 1.7% of income spent on gambling. Gamblers who exceeded any of these limits at time 1 were approximately four times more likely to report harm at time 2 [95% confidence interval (CI) = 2.9-6.6]. CONCLUSIONS: Longitudinal data in Canada suggest low-risk gambling thresholds of eight times per month, $75CAN total per month and 1.7% of income spent on gambling, all of which are higher than previously derived limits from cross-sectional data. Gamblers who exceed any of the three low-risk limits are four times more likely to experience future harm than those who do not. PMID- 28623866 TI - Exploration of Spinel LiCrTiO4 as Cathode Material for Rechargeable Mg-Li Hybrid Batteries. AB - Mg-Li hybrid batteries have attracted wide interest in recent years because of their potential safety as well as their cost benefit and high volumetric capacity. However, slow kinetic properties strongly hinder their commercial application. In this study, we have prepared spinel LiCrTiO4 by a solid-state reaction and have conducted a comprehensive study aimed at improving the performance of Mg-Li hybrid batteries by optimizing the dual-salt electrolyte. LiCrTiO4 has been found to show reversible discharge/charge capacities of 178 and 169 mA h g-1 in electrolytes of 1 m LiCl and 0.3 m APC (all-phenyl-complex), respectively. When the concentration of APC was increased to 0.4 m, LiCrTiO4 showed a high capacity retention of 95 % after 30 cycles. In addition, no phase transition could be observed for an LiCrTiO4 electrode in a dual-salt system, suggesting high electrochemical reversibility. Ex situ EDX and SEM studies have indicated that only Li+ ions are inserted into the cathode side, while Mg2+ ions are reversibly deposited on the surface of Mg metal without dendrite-like growth, indicative of good safety of the Mg-Li hybrid batteries. PMID- 28623867 TI - A validated UHPLC-MS/MS method for the measurement of riluzole in plasma and myocardial tissue samples. AB - Through blocking the cardiac persistent sodium current, riluzole has the potential to prevent myocardial damage post cardiac bypass surgery. A sensitive UHPLC-MS/MS method was developed and validated for quantitation of riluzole and 5 methoxypsoralen in human plasma and myocardial tissue homogenate using a liquid liquid extraction with dichloromethane. The chromatographic separation was achieved using Shimadzu Shim-pack XR-ODS III, 2.0 * 50 mm, 1.6 MUm column with a gradient mobile phase comprising methanol and ammonium acetate buffer pH 3.6 in purified water. The analyte and internal standard were separated within 3.5 min. Riluzole quantitation was achieved using the mass transitions of 235-138 for riluzole and 217-156 for 5-methoxypsoralen. The method was linear for riluzole plasma concentrations from 0.2 to 500 ng/mL and myocardial tissue homogenate concentrations from 0.2 to 100 ng/mL. The method developed was successfully applied to a clinical study for patients receiving riluzole while undergoing cardiac bypass surgery. PMID- 28623869 TI - Changing predictions, stable recognition: Children's representations of downward incline motion. AB - Various studies to-date have demonstrated children hold ill-conceived expressed beliefs about the physical world such as that one ball will fall faster than another because it is heavier. At the same time, they also demonstrate accurate recognition of dynamic events. How these representations relate is still unresolved. This study examined 5- to 11-year-olds' (N = 130) predictions and recognition of motion down inclines. Predictions were typically in error, matching previous work, but children largely recognized correct events as correct and rejected incorrect ones. The results also demonstrate while predictions change with increasing age, recognition shows signs of stability. The findings provide further support for a hybrid model of object representations and argue in favour of stable core cognition existing alongside developmental changes. Statement of contribution What is already known on this subject? Children's predictions of physical events show limitations in accuracy Their recognition of such events suggests children may use different knowledge sources in their reasoning What the present study adds? Predictions fluctuate more strongly than recognition, suggesting stable core cognition But recognition also shows some fluctuation, arguing for a hybrid model of knowledge representation. PMID- 28623870 TI - Probing the Role of a Non-Thermal Plasma (NTP) in the Hybrid NTP Catalytic Oxidation of Methane. AB - Three recurring hypotheses are often used to explain the effect of non-thermal plasmas (NTPs) on NTP catalytic hybrid reactions; namely, modification or heating of the catalyst or creation of new reaction pathways by plasma-produced species. NTP-assisted methane (CH4 ) oxidation over Pd/Al2 O3 was investigated by direct monitoring of the X-ray absorption fine structure of the catalyst, coupled with end-of-pipe mass spectrometry. This in situ study revealed that the catalyst did not undergo any significant structural changes under NTP conditions. However, the NTP did lead to an increase in the temperature of the Pd nanoparticles; although this temperature rise was insufficient to activate the thermal CH4 oxidation reaction. The contribution of a lower activation barrier alternative reaction pathway involving the formation of CH3 (g) from electron impact reactions is proposed. PMID- 28623868 TI - Ozone-induced foliar damage and release of stress volatiles is highly dependent on stomatal openness and priming by low-level ozone exposure in Phaseolus vulgaris. AB - Acute ozone exposure triggers major emissions of volatile organic compounds (VOCs), but quantitatively, it is unclear how different ozone doses alter the start and the total amount of these emissions, and the induction rate of different stress volatiles. It is also unclear whether priming (i.e. pre-exposure to lower O3 concentrations) can modify the magnitude and kinetics of volatile emissions. We investigated photosynthetic characteristics and VOC emissions in Phaseolus vulgaris following acute ozone exposure (600 nmol mol-1 for 30 min) under illumination and in darkness and after priming with 200 nmol mol-1 O3 for 30 min. Methanol and lipoxygenase (LOX) pathway product emissions were induced rapidly, followed by moderate emissions of methyl salicylate (MeSA). Stomatal conductance prior to acute exposure was lower in darkness and after low O3 priming than in light and without priming. After low O3 priming, no MeSA and lower LOX emissions were detected under acute exposure. Overall, maximum emission rates and the total amount of emitted LOX products and methanol were quantitatively correlated with total stomatal ozone uptake. These results indicate that different stress volatiles scale differently with ozone dose and highlight the key role of stomatal conductance in controlling ozone uptake, leaf injury and volatile release. PMID- 28623871 TI - Simple computing of the viscosity of water-dioxane mixtures, according to a fluctuating SPC/E-Ih interstitial model. AB - In this contribution, we propose a new simple and fast computing approach to model liquid water and water-1,4 dioxane mixture, which is intermediate between molecular dynamics calculation and lattice fluid H-bonding theory in which water molecules are arranged according to a fluctuating hexagonal Ih network. It generalizes the interstitial mixture models of Samoilov and Pauling by increasing the number of spatial configurations into the space of phases due to the addition of rotations and vibrations of the molecules around their equilibrium positions. The potential energy landscape is determined by the generalization of the Madelung's approach to the molecular water network using simple point charge model (SPC/E partial charges). This approach allows useful predictions as the possibility of incorporation of a molecule of dioxane in the water Ih -network or how some cooperative dynamic jumps (site - hole) of water molecules, contribute to lower Eyring's activation energies and thus to facilitate the viscous flow. (c) 2017 Wiley Periodicals, Inc. PMID- 28623872 TI - Uptake in sympathetic ganglia on 68 Ga-PSMA-HBED PET/CT: A potential pitfall in scan interpretation. AB - INTRODUCTION: The aim of this study was to assess the frequency of PSMA-HBED uptake in coeliac and stellate ganglia in patients presenting for PSMA-HBED PET/CT scan. METHODS: Prostate-specific membrane antigen-HBED PET/CT scans of 100 consecutive patients were analysed. Coeliac and stellate ganglia were identified by their anatomical location. PSMA-HBED uptake in these ganglia was recorded as either present or absent. If present, the SUVmax value for each ganglion was measured and compared to SUVmax of mediastinal blood pool. RESULTS: Of the 100 patients, 45 had PSMA-HBED uptake in the right coeliac ganglion and 81 had PSMA HBED uptake in the left coeliac ganglion. The mean SUVmax for the right coeliac ganglion was 2.6 (range 1.2-4.0) and for the left, 2.7 (range 1.2-6.5). An SUVmax 1.5 times greater than that of mediastinal blood pool activity was found in 25 of right and 47 of left coeliac ganglia. Stellate ganglion uptake of PSMA-HBED was identified in 54 of right and 74 of left stellate ganglia. The mean SUVmax for the right and left stellate ganglia were 2.2 (range 1.6-3.6) and 2.4 (range 1.4 4.2) respectively. An SUVmax 1.5 times greater than that of mediastinal blood pool activity was found in 12 of right and 32 of left coeliac ganglia. CONCLUSION: Uptake in coeliac and stellate ganglia is a frequent finding on PSMA HBED PET/CT imaging. Often this uptake can be sufficiently high to cause potential diagnostic confusion. It is important to be aware of this physiologic uptake to avoid incorrect diagnosis of metastatic prostate carcinoma. PMID- 28623873 TI - Cardiac regulatory mechanisms: new concepts and challenges. PMID- 28623874 TI - Lansoprazole-sulfide, pharmacokinetics of this promising anti-tuberculous agent. AB - Lansoprazole (LPZ) is a commercially available proton-pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis. It was also reported that a 300 mg kg-1 oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg-1 oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL-1 , respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti-TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti-TB compound. PMID- 28623875 TI - Chemiluminescent enzyme immunoassay failed to detect anti-desmoglein 3 antibodies in a case of pemphigus vulgaris. PMID- 28623876 TI - Developmental history and application of CRISPR in human disease. AB - Genome-editing tools are programmable artificial nucleases, mainly including zinc finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeat (CRISPR). By recognizing and cleaving specific DNA sequences, genome-editing tools make it possible to generate site-specific DNA double-strand breaks (DSBs) in the genome. DSBs will then be repaired by either error-prone nonhomologous end joining or high-fidelity homologous recombination mechanisms. Through these two different mechanisms, endogenous genes can be knocked out or precisely repaired/modified. Rapid developments in genome-editing tools, especially CRISPR, have revolutionized human disease models generation, for example, various zebrafish, mouse, rat, pig, monkey and human cell lines have been constructed. Here, we review the developmental history of CRISPR and its application in studies of human diseases. In addition, we also briefly discussed the therapeutic application of CRISPR in the near future. PMID- 28623877 TI - 5-aminosalicylic acid agents for prevention of recurrent diverticulitis: A systematic review and meta-analysis. AB - BACKGROUND AND AIM: Prevalence of colonic diverticulosis is increasing worldwide with age, and up to 25% of patients who have colonic diverticulosis might experience diverticulitis. However, a definitive approach of preventing recurrent diverticulitis remains unknown. 5-aminosalicylic acid (5-ASA) agents are anti inflammatory agents and have been used to prevent recurrent diverticulitis, and there have been some randomized clinical trials (RCTs). However, the efficacy results for secondary prevention in uncomplicated diverticulitis differed across studies. Our aim was to clarify the efficacy and safety of 5-ASA agents in the prevention of recurrent diverticulitis. METHODS: We searched MEDLINE, EMBASE, Web of Science, and the Cochrane library with no language restrictions. Two reviewers independently assessed and selected RCTs. The data were pooled using a random effect model and were presented in the pooled risk ratio (RR) and 95% confidence interval (CI). Cochrane's Q and I-squared statistics were used to assess heterogeneity. The protocol was registered at PROSPERO. RESULTS: Seven articles with eight RCTs from 329 potentially relevant articles were included. 5-ASA agents were not superior to controls in preventing recurrent diverticulitis (RR 0.86, 95% CI 0.63 to 1.17, I2 = 60%) and the incidence of adverse events was not different between 5-ASA agents and controls (RR 0.97, 95% CI 0.84 to 1.11, I2 = 45%). However, some included studies were few in number of participants and substantial risk of bias. CONCLUSIONS: 5-aminosalicylic acid agents were not associated with prevention of recurrent diverticulitis. PMID- 28623878 TI - In vivo characterisation of a therapeutically relevant self-assembling 18 F labelled beta-sheet forming peptide and its hydrogel using positron emission tomography. AB - Positron emission tomography (PET) and fluorescence labelling have been used to assess the pharmacokinetics, biodistribution and eventual fate of a hydrogel forming nonapeptide, FEFKFEFKK (F9), in healthy mice, using 18 F-labelled and fluorescein isothiocyanate (FITC)-labelled F9 analogues. F9 was site-specifically radiolabelled with 2-[18 F]fluoro-3-pyridinecarboxaldehyde ([18 F]FPCA) via oxime bond formation. [18 F]FPCA-F9 in vivo fate was evaluated both as a solution, following intravenous administration, and as a hydrogel when subcutaneously injected. The behaviour of FITC-F9 hydrogel was assessed following subcutaneous injection. [18 F]FPCA-F9 demonstrated high plasma stability and primarily renal excretion; [18 F]FPCA-F9 when in solution and injected into the bloodstream displayed prompt bladder uptake (53.4 +/- 16.6 SUV at 20 minutes postinjection) and rapid renal excretion, whereas [18 F]FPCA-F9 hydrogel, formed by co-assembly of [18 F]FPCA-F9 monomer with unfunctionalised F9 peptide and injected subcutaneously, showed gradual bladder accumulation of hydrogel fragments (3.8 +/ 0.4 SUV at 20 minutes postinjection), resulting in slower renal excretion. Gradual disaggregation of the F9 hydrogel from the site of injection was monitored using FITC-F9 hydrogel in healthy mice (60 +/- 3 over 96 hours), indicating a biological half-life between 1 and 4 days. The in vivo characterisation of F9, both as a gel and a solution, highlights its potential as a biomaterial. PMID- 28623879 TI - Successful epithelialization of perianal infantile hemangioma, presenting as intractable ulcers, with application of protective colostomy powder. PMID- 28623881 TI - Cardiac tamponade associated with delayed ascending aortic perforation after blunt chest trauma: a case report. AB - BACKGROUND: Cardiac tamponade due to aortic injury after blunt trauma is a rare and potentially fatal injury. Most aortic injuries caused by blunt trauma present as aortic dissection or rupture of the aortic isthmus. Several cases of delayed aortic injury have been reported. However, all of these injuries were observed in the descending aorta because they had been caused by a posterior rib fracture. CASE PRESENTATION: We report the first case of cardiac tamponade associated with delayed ascending aortic perforation 2 weeks after blunt trauma. The patient was an 81-year-old man. CONCLUSION: In cases of blunt chest trauma, delayed ascending aortic injury causing cardiac tamponade is possible associated with various causes such as direct injury by fractured rib or delayed aortic perforation of initial blunt injury. PMID- 28623880 TI - Associations between anhedonia and marijuana use escalation across mid adolescence. AB - BACKGROUND AND AIMS: Anhedonia-a transdiagnostic psychopathological trait indicative of inability to experience pleasure-could lead to and result from adolescent marijuana use, yet this notion has not been tested. This study aimed to estimate the association of: (1) anhedonia at age 14 with rate of change in marijuana use over an 18-month follow-up, and (2) marijuana use at age 14 with rate of change in anhedonia over follow-up. Secondary aims were to test whether gender, baseline marijuana use history and peer marijuana use moderated these associations. DESIGN: Observational longitudinal cohort repeated-measures design, with baseline (age 14 years), 6-month, 12-month and 18-month follow-up assessments. SETTINGS: Ten public high schools in Los Angeles, CA, USA, 2013-15. PARTICIPANTS: Students [n = 3394; 53.5% female, mean (standard deviation) age at baseline = 14.1 (0.42)]. MEASUREMENTS: Self-report level of anhedonia on the Snaith-Hamilton Pleasure Scale and frequency of marijuana use in the past 30 days. FINDINGS: Parallel process latent growth curve models adjusting for confounders showed that baseline anhedonia level was associated positively with the rate of increase in marijuana use frequency across follow-ups [beta, 95% confidence interval (CI) = 0.115 (0.022, 0.252), P = 0.03]. Baseline marijuana use frequency was not related significantly to the rate of change in anhedonia across follow-ups [beta, 95% CI = -0.015 (-0.350, 0.321), P = 0.93]. The association of baseline anhedonia with faster marijuana use escalation was amplified among adolescents with (versus without) friends who used marijuana at baseline [beta, 95% CI = 0.179 (0.043, 0.334) versus 0.064 (-0.071, 0.187), interaction P = 0.04], but did not differ by gender or baseline ever marijuana use. CONCLUSIONS: In mid-adolescence, anhedonia is associated with subsequent marijuana use escalation, but marijuana use escalation does not appear to be associated with subsequent anhedonia. PMID- 28623882 TI - Peripheral venous catheter-related bloodstream infection is associated with severe complications and potential death: a retrospective observational study. AB - BACKGROUND: The purpose of this study was to identify the clinical characteristics and outcomes of peripheral vascular catheter-related bloodstream infections (PVC-BSIs) and determine the risk of severe complications or death. METHODS: We performed a retrospective observational study from June 2010 to April 2015 at two regional university-affiliated hospitals in Tokyo. We studied the clinical manifestations, underlying diseases, laboratory results, treatment methods, recurrence rates, and complications in 62 hospitalized patients diagnosed with PVC-BSIs by positive blood cultures. RESULTS: The median time from admission to bacteremia was 17 days (range, 3-142 days) and that from catheter insertion to bacteremia diagnosis was 6 days (range, 2-15 days). Catheter insertion sites were in the arm in 48 (77.4%) patients, in the foot in 3 (4.8%) patients, and in an unrecorded location in 11 (17.7%) patients. Additionally, the causative pathogens were Gram-positive microorganisms in 58.0% of cases, Gram negative microorganisms in 35.8% of cases, Candida spp. in 6.2% of cases, and polymicrobials in 25.8% of cases. Eight (12.9%) patients died within 30 days of their blood culture becoming positive. Patients who died of PVC-BSIs had a higher proportion of Staphylococcus aureus infection than patients who survived (odds ratio, 8.33; p = 0.004). CONCLUSIONS: PVC-BSIs are a significant cause of health care-associated infection. We observed cases of severe PVC-BSI requiring intensive and long-term care along with lengthy durations of antibiotic treatment due to hematogenous complications, and some patients died. For patients with PVC BSIs, S. aureus bacteremia remains a major problem that may influence the prognosis. PMID- 28623883 TI - No consistent effect of plant species richness on resistance to simulated climate change for above- or below-ground processes in managed grasslands. AB - BACKGROUND: Species richness affects processes and functions in many ecosystems. Since management of temperate grasslands is directly affecting species composition and richness, it can indirectly govern how systems respond to fluctuations in environmental conditions. Our aim in this study was to investigate whether species richness in managed grasslands can buffer the effects of drought and warming manipulations and hence increase the resistance to climate change. We established 45 plots in three regions across Germany, each with three different management regimes (pasture, meadow and mown pasture). We manipulated spring warming using open-top chambers and summer drought using rain-out shelters for 4 weeks. RESULTS: Measurements of species richness, above- and below-ground biomass and soil carbon and nitrogen concentrations showed significant but inconsistent differences among regions, managements and manipulations. We detected a three-way interaction between species richness, management and region, indicating that our study design was sensitive enough to detect even intricate effects. CONCLUSIONS: We could not detect a pervasive effect of species richness on biomass differences between treatments and controls, indicating that a combination of spring warming and summer drought effects on grassland systems are not consistently moderated by species richness. We attribute this to the relatively high number of species even at low richness levels, which already provides the complementarity required for positive biodiversity-ecosystem functioning relationships. A review of the literature also indicates that climate manipulations largely fail to show richness-buffering, while natural experiments do, suggesting that such manipulations are milder than reality or incur treatment artefacts. PMID- 28623884 TI - Mitochondrial RNA processing in absence of tRNA punctuations in octocorals. AB - BACKGROUND: Mitogenome diversity is staggering among early branching animals with respect to size, gene density, content and order, and number of tRNA genes, especially in cnidarians. This last point is of special interest as tRNA cleavage drives the maturation of mitochondrial mRNAs and is a primary mechanism for mt RNA processing in animals. Mitochondrial RNA processing in non-bilaterian metazoans, some of which possess a single tRNA gene in their mitogenomes, is essentially unstudied despite its importance in understanding the evolution of mitochondrial transcription in animals. RESULTS: We characterized the mature mitochondrial mRNA transcripts in a species of the octocoral genus Sinularia (Alcyoniidae: Octocorallia), and defined precise boundaries of transcription units using different molecular methods. Most mt-mRNAs were polycistronic units containing two or three genes and 5' and/or 3' untranslated regions of varied length. The octocoral specific, mtDNA-encoded mismatch repair gene, the mtMutS, was found to undergo alternative polyadenylation, and exhibited differential expression of alternate transcripts suggesting a unique regulatory mechanism for this gene. In addition, a long noncoding RNA complementary to the ATP6 gene (lncATP6) potentially involved in antisense regulation was detected. CONCLUSIONS: Mt-mRNA processing in octocorals possessing a single mt-tRNA is complex. Considering the variety of mitogenome arrangements known in cnidarians, and in general among non-bilaterian metazoans, our findings provide a first glimpse into the complex mtDNA transcription, mt-mRNA processing, and regulation among early branching animals and represent a first step towards understanding its functional and evolutionary implications. PMID- 28623885 TI - Monitoring the electric activity of the diaphragm during noninvasive positive pressure ventilation: a case report. AB - BACKGROUND: In patients with post-extubation respiratory distress, delayed reintubation may worsen clinical outcomes. Objective measures of extubation failure at the bedside are lacking, therefore clinical parameters are currently used to guide the need of reintubation. Electrical activity of the diaphragm (EAdi) provides clinicians with valuable, objective information about respiratory drive and could be used to monitor respiratory effort. CASE PRESENTATION: We describe the case of a patient with Chronic Obstructive Pulmonary Disease (COPD), from whom we recorded EAdi during four different ventilatory conditions: 1) invasive mechanical ventilation, 2) spontaneous breathing trial (SBT), 3) unassisted spontaneous breathing, and 4) Noninvasive Positive Pressure Ventilation (NPPV). The patient had been intubated due to an exacerbation of COPD, and after four days of mechanical ventilation, she passed the SBT and was extubated. Clinical signs of respiratory distress were present immediately after extubation, and EAdi increased compared to values obtained during mechanical ventilation. As we started NPPV, EAdi decreased substantially, indicating muscle unloading promoted by NPPV, and we used the EAdi signal to monitor respiratory effort during NPPV. Over the next three days, she was on NPPV for most of the time, with short periods of spontaneous breathing. EAdi remained considerably lower during NPPV than during spontaneous breathing, until the third day, when the difference was no longer clinically significant. She was then weaned from NPPV and discharged from the ICU a few days later. CONCLUSION: EAdi monitoring during NPPV provides an objective parameter of respiratory drive and respiratory muscle unloading and may be a useful tool to guide post-extubation ventilatory support. Clinical studies with continuous EAdi monitoring are necessary to clarify the meaning of its absolute values and changes over time. PMID- 28623886 TI - EPSILON-CP: using deep learning to combine information from multiple sources for protein contact prediction. AB - BACKGROUND: Accurately predicted contacts allow to compute the 3D structure of a protein. Since the solution space of native residue-residue contact pairs is very large, it is necessary to leverage information to identify relevant regions of the solution space, i.e. correct contacts. Every additional source of information can contribute to narrowing down candidate regions. Therefore, recent methods combined evolutionary and sequence-based information as well as evolutionary and physicochemical information. We develop a new contact predictor (EPSILON-CP) that goes beyond current methods by combining evolutionary, physicochemical, and sequence-based information. The problems resulting from the increased dimensionality and complexity of the learning problem are combated with a careful feature analysis, which results in a drastically reduced feature set. The different information sources are combined using deep neural networks. RESULTS: On 21 hard CASP11 FM targets, EPSILON-CP achieves a mean precision of 35.7% for top- L/10 predicted long-range contacts, which is 11% better than the CASP11 winning version of MetaPSICOV. The improvement on 1.5L is 17%. Furthermore, in this study we find that the amino acid composition, a commonly used feature, is rendered ineffective in the context of meta approaches. The size of the refined feature set decreased by 75%, enabling a significant increase in training data for machine learning, contributing significantly to the observed improvements. CONCLUSIONS: Exploiting as much and diverse information as possible is key to accurate contact prediction. Simply merging the information introduces new challenges. Our study suggests that critical feature analysis can improve the performance of contact prediction methods that combine multiple information sources. EPSILON-CP is available as a webservice: http://compbio.robotics.tu berlin.de/epsilon/. PMID- 28623887 TI - Association between the ERCC1 polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer: a meta-analysis. AB - BACKGROUND: Ovarian cancer is a prominent public health problem which affects people all around the world. Platinum-based chemotherapy is a common treatment for ovarian cancer, however, the effectiveness of chemotherapy varies from patient to patient. The excision repair cross complementation group 1 (ERCC1) protein may mediate chemotherapy resistance. A meta-analysis was conducted to explore whether platinum-based chemotherapy effectiveness could be attributed to the ERCC1 C19007T polymorphisms. METHODS: Seven major databases (EMBASE, Web of Science, Pubmed, Springer Link, Chinese National Knowledge Infrastructure (CNKI), EBSCO and Science Direct databases) were searched for eligible studies. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the results. RESULTS: In this meta-analysis, 1169 subjects (425 non-responders and 744 responders) from 8 studies were included. The overall OR (C vs. T alleles) using random model was 1.07 (95% CI 0.75-1.52, P = 0.7), which was not statistically significant. Moreover, there was no significant difference in the analysis by race. CONCLUSION: There is no association between the ERCC1 C19007T polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer. The polymorphism did not have a significant impact on platinum-based chemotherapy in non-responders and responders. PMID- 28623888 TI - Ub-ISAP: a streamlined UNIX pipeline for mining unique viral vector integration sites from next generation sequencing data. AB - BACKGROUND: The analysis of viral vector genomic integration sites is an important component in assessing the safety and efficiency of patient treatment using gene therapy. Alongside this clinical application, integration site identification is a key step in the genetic mapping of viral elements in mutagenesis screens that aim to elucidate gene function. RESULTS: We have developed a UNIX-based vector integration site analysis pipeline (Ub-ISAP) that utilises a UNIX-based workflow for automated integration site identification and annotation of both single and paired-end sequencing reads. Reads that contain viral sequences of interest are selected and aligned to the host genome, and unique integration sites are then classified as transcription start site proximal, intragenic or intergenic. CONCLUSION: Ub-ISAP provides a reliable and efficient pipeline to generate large datasets for assessing the safety and efficiency of integrating vectors in clinical settings, with broader applications in cancer research. Ub-ISAP is available as an open source software package at https://sourceforge.net/projects/ub-isap/ . PMID- 28623889 TI - Surgical accuracy, function, and quality of life of simultaneous versus staged bilateral Total hip Arthroplasty in patients with Osteonecrosis of the femoral head. AB - BACKGROUND: The optimal surgical option for patients requiring bilateral hip replacement remains controversial. The purpose of this study was to compare surgical accuracy; functional outcome and health-related quality of life; and prosthetic-related complications and revision surgery of a simultaneous bilateral total hip arthroplasty (THA) with those of a staged bilateral THA with an interval between procedures <12 months. METHODS: A total of 123 unselected consecutive patients (mean age, 43.3 years) who underwent bilateral THAs for osteonecrosis of the femoral head (ONFH) with a minimum follow-up of two years (mean, 60.2 months) were studied retrospectively; 63 simultaneous procedures served as a test group and 60 staged procedures served as a control group. RESULTS: The mean postoperative leg-length discrepancy (LLD) and the percentage of patients who had an LLD >3 mm were significantly lower in the simultaneous group (P < 0.001 and P = 0.001, respectively). A higher number of cups within the safe zones, a higher correction rate, and a lower failure rate for the cup placement in the second-operated hip were also identified in the simultaneous group. The mean Harris hip score, EuroQol-5D index, and EuroQol-visual analogue scale score were all better in the simultaneous group at the latest follow-up (P < 0.001, in all comparisons). We found that the simultaneous procedure was associated with a lower incidence of postoperative prosthetic-related complications and revision surgery. CONCLUSIONS: We suggest that bilateral ONFH could be treated with a simultaneous THA rather than a staged THA to achieve a better surgical outcome. PMID- 28623890 TI - Survey of maternal sleep practices in late pregnancy in a multi-ethnic sample in South Auckland, New Zealand. AB - BACKGROUND: The Auckland Stillbirth study demonstrated a two-fold increased risk of late stillbirth for women who did not go to sleep on their left side. Two further studies have confirmed an increased risk of late stillbirth with supine sleep position. As sleep position is modifiable, we surveyed self-reported late pregnancy sleep position, knowledge about sleep position, and views about changing going-to-sleep position. METHODS: Participants in this 2014 survey were pregnant women (n = 377) in their third trimester from South Auckland, New Zealand, a multi-ethnic and predominantly low socio-economic population. An ethnically-representative sample was obtained using random sampling. Multivariable logistic regression was performed to identify factors independently associated with non-left sided going-to-sleep position in late pregnancy. RESULTS: Respondents were 28 to 42 weeks' gestation. Reported going-to-sleep position in the last week was left side (30%), right side (22%), supine (3%), either side (39%) and other (6%). Two thirds (68%) reported they had received advice about sleep position. Non-left sleepers were asked if they would be able to change to their left side if it was better for their baby; 87% reported they would have little or no difficulty changing. Women who reported a non-left going to-sleep position were more likely to be of Maori (aOR 2.64 95% CI 1.23-5.66) or Pacific (aOR 2.91 95% CI 1.46-5.78) ethnicity; had a lower body mass index (BMI) (aOR 0.93 95% CI 0.89-0.96); and were less likely to sleep on the left-hand side of the bed (aOR 3.29 95% CI 2.03-5.32). CONCLUSIONS: Maternal going-to-sleep position in the last week was side-lying in 91% of participants. The majority had received advice to sleep on their side or avoid supine sleep position. Sleeping on the left-hand side of the bed was associated with going-to-sleep on the left side. Most non-left sleepers reported their sleeping position could be modified to the left side suggesting a public health intervention about sleep position is likely to be feasible in other multi-ethnic communities. PMID- 28623891 TI - Systolic blood pressure variability in patients with early severe sepsis or septic shock: a prospective cohort study. AB - BACKGROUND: Severe sepsis and septic shock are often lethal syndromes, in which the autonomic nervous system may fail to maintain adequate blood pressure. Heart rate variability has been associated with outcomes in sepsis. Whether systolic blood pressure (SBP) variability is associated with clinical outcomes in septic patients is unknown. The propose of this study is to determine whether variability in SBP correlates with vasopressor independence and mortality among septic patients. METHODS: We prospectively studied patients with severe sepsis or septic shock, admitted to an intensive care unit (ICU) with an arterial catheter. We analyzed SBP variability on the first 5-min window immediately following ICU admission. We performed principal component analysis of multidimensional complexity, and used the first principal component (PC1) as input for Firth logistic regression, controlling for mean systolic pressure (SBP) in the primary analyses, and Acute Physiology and Chronic Health Evaluation (APACHE) II score or NEE dose in the ancillary analyses. Prespecified outcomes were vasopressor independence at 24 h (primary), and 28-day mortality (secondary). RESULTS: We studied 51 patients, 51% of whom achieved vasopressor independence at 24 h. Ten percent died at 28 days. PC1 represented 26% of the variance in complexity measures. PC1 was not associated with vasopressor independence on Firth logistic regression (OR 1.04; 95% CI: 0.93-1.16; p = 0.54), but was associated with 28-day mortality (OR 1.16, 95% CI: 1.01-1.35, p = 0.040). CONCLUSIONS: Early SBP variability appears to be associated with 28-day mortality in patients with severe sepsis and septic shock. PMID- 28623892 TI - Improving transitions in acute stroke patients discharged to home: the Michigan stroke transitions trial (MISTT) protocol. AB - BACKGROUND: For some stroke patients and caregivers, navigating the transition between hospital discharge and returning home is associated with substantial psychosocial and health-related challenges. Currently, no evidence-based standard of care exists that addresses the concerns of stroke patients and caregivers during the transition period. Objectives of the Michigan Stroke Transitions Trial (MISTT) are to test the impact of a social worker home-based case management program, as well as an online information and support resource, on patient and caregiver outcomes after returning home. METHODS: The Michigan Stroke Transitions Trial is a randomized, pragmatic, open (un-blinded), 3-group parallel designed superiority trial conducted in 3 Michigan hospitals. Eligible participants are adult acute stroke patients discharged home directly or within 4 weeks of being discharged to a rehabilitation facility. The patient's primary caregiver is also invited to participate. Patients are randomized on the day they return home using a randomized block design. Consented patients discharged to a rehabilitation facility who do not go home within 4 weeks are dropped from the study. The 2 study interventions begin within a week of returning home and conclude 3 months later. The 3-group design compares usual care to either a home-based social worker stroke case management (SWSCM) program, or a combination of the SWSCM program plus access to an online information and support resource (MISTT website). Outcomes data are collected at 7-days and 90-days by trained telephone interviewers. Primary patient outcomes include the PROMIS global 10 score (a generic Quality of Life scale), and the Patient Activation Measure (PAM). Caregiver outcomes include the Bakas Caregiving Outcomes Scale. Final analysis will be based on 214 randomized acute stroke patients. To accommodate subjects excluded due to prolonged rehabilitation stays, as well as those lost-to-follow up, up to 315 patients will be consented. DISCUSSION: The MISTT study will determine if a home-based case management program designed around the needs and preferences of stroke patients and caregivers, alone or in combination with a patient-centered online information and support resource can improve stroke survivor and caregiver outcomes 3 months after returning home. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02653170 (Protocol ID: 135457). Registered April 9, 2015. PMID- 28623893 TI - Evolutionary origin of type IV classical cadherins in arthropods. AB - BACKGROUND: Classical cadherins are a metazoan-specific family of homophilic cell cell adhesion molecules that regulate morphogenesis. Type I and type IV cadherins in this family function at adherens junctions in the major epithelial tissues of vertebrates and insects, respectively, but they have distinct, relatively simple domain organizations that are thought to have evolved by independent reductive changes from an ancestral type III cadherin, which is larger than derived paralogs and has a complicated domain organization. Although both type III and type IV cadherins have been identified in hexapods and branchiopods, the process by which the type IV cadherin evolved is still largely unclear. RESULTS: Through an analysis of arthropod genome sequences, we found that the only classical cadherin encoded in chelicerate genomes was the type III cadherin and that the two type III cadherin genes found in the spider Parasteatoda tepidariorum genome exhibited a complex yet ancestral exon-intron organization in arthropods. Genomic and transcriptomic data from branchiopod, copepod, isopod, amphipod, and decapod crustaceans led us to redefine the type IV cadherin category, which we separated into type IVa and type IVb, which displayed a similar domain organization, except type IVb cadherins have a larger number of extracellular cadherin (EC) domains than do type IVa cadherins (nine versus seven). We also showed that type IVa cadherin genes occurred in the hexapod, branchiopod, and copepod genomes whereas only type IVb cadherin genes were present in malacostracans. Furthermore, comparative characterization of the type IVb cadherins suggested that the presence of two extra EC domains in their N-terminal regions represented primitive characteristics. In addition, we identified an evolutionary loss of two highly conserved cysteine residues among the type IVa cadherins of insects. CONCLUSIONS: We provide a genomic perspective of the evolution of classical cadherins among bilaterians, with a focus on the Arthropoda, and suggest that following the divergence of early arthropods, the precursor of the insect type IV cadherin evolved through stepwise reductive changes from the ancestral type III state. In addition, the complementary distributions of polarized genomic characters related to type IVa/IVb cadherins may have implications for our interpretations of pancrustacean phylogeny. PMID- 28623894 TI - 'Doing the right thing': factors influencing GP prescribing of antidepressants and prescribed doses. AB - BACKGROUND: Antidepressant prescribing continues to increase, with 5-16% of adults receiving antidepressants annually. Total prescribing growth is due in part to increased long-term use, greater selective serotonin re-uptake inhibitor (SSRI) use and the use of higher SSRI doses. Evidence does not support routine use of higher SSRI doses for depression treatment, and factors influencing the use of such doses are not well known. The aim of this study was to explore factors influencing GPs' use of antidepressants and their doses to treat depression. METHODS: Semi-structured interviews with a purposive sample of 28 practising GPs; sampled by antidepressant prescribing volume, practice size and deprivation level. A topic guide drawing on past literature was used with enough flexibility to allow additional themes to emerge. Interviews were audio-recorded and transcribed verbatim. Framework analysis was employed. Constant comparison and disconfirmation were carried out across transcripts, with data collection being interspersed with analysis by three researchers. The thematic framework was then systematically applied to the data and conceptualised into an overarching explanatory model. RESULTS: Depression treatment involved ethical and professional imperatives of 'doing the right thing' for individuals by striving to achieve the 'right care fit'. This involved medicalised and non-medicalised patient-centred approaches. Factors influencing antidepressant prescribing and doses varied over time from first presentation, to antidepressant initiation and longer-term treatment. When faced with distressed patients showing symptoms of moderate to severe depression GPs were confident prescribing SSRIs which they considered as safe and effective medicines, and ethically and professionally appropriate. Many GPs were unaware that higher doses lacked greater efficacy and onset of action occurred within 1-2 weeks, preferring to wait 8-12 weeks before increasing or switching. Ongoing pressures to maintain prescribing (e.g. fear of depression recurrence), few perceived continuation problems (e.g. lack of safety concerns) and lack of proactive medication review (e.g. patients only present in crisis), all combine to further drive antidepressant prescribing growth over time. CONCLUSIONS: GPs strive to 'do the right thing' to help people. Antidepressants are only a single facet of depression treatment. However, increased awareness of drug limitations and regular proactive reviews may help optimise care. PMID- 28623895 TI - Effects of home-based exercise on pre-dialysis chronic kidney disease patients: a randomized pilot and feasibility trial. AB - BACKGROUND: Only a few research is available on the effects of home-based exercise training on pre-dialysis chronic kidney disease (CKD) patients. Therefore, we aimed to elucidate the effect of home-based exercise therapy on kidney function and arm and leg muscle strength in pre-dialysis CKD patients. METHODS: Thirty-six male stage 3-4 pre-dialysis CKD patients (age, 68.7 +/- 6.8 years; estimated glomerular filtration rate (eGFR), 39.0 +/- 11.6 ml/min/1.73 m2) who were being treated as outpatients were included. The subjects were randomly assigned to an exercise intervention group (Ex group: 18) and a control group (C group: 18). The Ex group wore accelerometer pedometers and were instructed to perform home-based aerobic and resistance exercises, such as brisk walking for 30 min per day, for 12 months. The C group subjects wore accelerometer pedometers but received no exercise therapy guidance; the number of steps covered during normal daily activities was recorded for the C group. The outcome measures were changes in kidney function and handgrip and knee extension muscle strength. Values at the baseline (T1) and 12 months later (T2) were compared. RESULTS: There were no significant differences in baseline characteristics between the two groups; however, the C group was more physically active than the Ex group. Eight subjects dropped out, and 28 subjects (14 in each group) were included in the final analysis. Physical activity increased significantly only in the Ex group. Grip strength (F = 7.0, p = 0.01) and knee extension muscle strength (F = 14.3, p < 0.01) were found to improve only in the Ex group. Further, the changes in eGFR were not significantly different between the two groups (F = 0.01, p = 0.93). CONCLUSIONS: Home-based exercise therapy for pre-dialysis CKD patients was feasible and improved arm and leg muscle strength without affecting kidney function. TRIAL REGISTRATION: UMIN Clinical Trials Registry ( UMIN000005091 ). Registered 2/15/2011. PMID- 28623896 TI - With a little help from my friends: cooperation can accelerate the rate of adaptive valley crossing. AB - BACKGROUND: Natural selection favors changes that lead to genotypes possessing high fitness. A conflict arises when several mutations are required for adaptation, but each mutation is separately deleterious. The process of a population evolving from a genotype encoding for a local fitness maximum to a higher fitness genotype is termed an adaptive peak shift. RESULTS: Here we suggest cooperative behavior as a factor that can facilitate adaptive peak shifts. We model cooperation in a public goods scenario, wherein each individual contributes resources that are later equally redistributed among all cooperating individuals. We use mathematical modeling and stochastic simulations to study the effect of cooperation on peak shifts in both panmictic and structured populations. Our results show that cooperation can substantially affect the rate of complex adaptation. Furthermore, we show that cooperation increases the population diversity throughout the peak shift process, thus increasing the robustness of the population to sudden environmental changes. CONCLUSIONS: We provide a new explanation to adaptive valley crossing in natural populations and suggest that the long term evolution of a species depends on its social behavior. PMID- 28623897 TI - Altered somatosensory profile according to quantitative sensory testing in patients with degenerative lumbar spine disorders scheduled for surgery. AB - BACKGROUND: Somatosensory profiling in affected and non-affected body regions can strengthen our insight regarding the underlying pain mechanisms, which can be valuable in treatment decision making and to improve outcomes, in patients with degenerative lumbar spine disorders pre-surgery. The aim was to describe somatosensory profiles in patients with degenerative lumbar spine disorders, to identify the proportion with altered somatosensory profile, and to analyze demographic characteristics, self-reported function, pain, and health pre- and 3 months post-surgery. METHODS: In this prospective cohort study in a Spine Clinic, 105 patients scheduled for surgery for spinal stenosis, disc herniation, degenerative disc disease, or spondylolisthesis were consecutively recruited. Exclusion criteria were; indication for acute surgery or previous surgery at the same spinal level or severe grade of pathology. Quantitative sensory testing (QST) and self-reported function, pain, and health was measured pre- and 3 months post-surgery. The somatosensory profile included cold detection threshold, warmth detection threshold, cold pain threshold, heat pain threshold and pressure pain threshold in affected and non-affected body regions. RESULTS: On a group level, the patients' somatosensory profiles were within the 95% confidence interval (CI) from normative reference data means. On an individual level, an altered somatosensory profile was defined as having two or more body regions (including a non-affected region) with QST values outside of normal ranges for reference data. The 23 patients (22%) with altered somatosensory profiles, with mostly loss of function, were older (P = 0.031), more often female (P = 0.005), had higher back and leg pain (P = 0.016, 0.020), lower mental health component summary score (SF 36 MCS) (P = 0.004) and larger pain distribution (P = 0.047), compared to others in the cohort. Post-surgery there was a tendency to worse pain, function and health in the group with altered somatosensory profile pre-surgery. CONCLUSIONS: On a group level, patients with degenerative lumbar spine disorders scheduled for surgery were within normal range for the QST measurements compared to reference values. On an individual level, an altered somatosensory profile outside of normal range in both affected and non-affected body regions occurred in 22% of patients, which may indicate disturbed somatosensory function. Those patients had mostly loss of sensory function and had worse self-reported outcome pre-surgery, compared to the rest of the cohort. Future prospective studies are needed to further examine whether these dimensions can be useful in predicting post-surgery outcome and guide need of additional treatments. PMID- 28623898 TI - Early-life gut microbial colonization shapes Th1/Th2 balance in asthma model in BALB/c mice. AB - BACKGROUND: We aimed to investigate the effect of early-life diverse microbial exposures on gut microbial colonization in an OVA-induced asthma model in BALB/c mice. METHODS: BALB/c mice were divided into 4 groups: A, offsprings were kept in a SPF environment during fetal, lactation, and childhood periods; B, offsprings were kept in the SPF environment during fetal and lactation periods, and kept in the general environment during childhood; C, offsprings were kept in the SPF environment only during fetal period, and then kept in the general environment; and D, offsprings were kept in the general environment during whole periods. The diversity of intestinal flora was analyzed using denaturing gradient gel electrophoresis. Mice were sensitized with OVA to establish an animal model of asthma. Then asthma-related inflammatory cytokines and histological analysis were performed. RESULTS: The diversity of intestinal microflora in group D was significantly higher than groups A, B and C at three days and three weeks after birth, and the diversity of intestinal microflora in groups C and D were significantly higher than groups A and B at five weeks after birth. The pathologic scores of OVA-induced asthmatic mice in group D were significantly lower than group A, and serum IFN-gamma levels and the IFN-gamma/IL-4 ratio in group D were significantly higher than group A. CONCLUSIONS: Exposure to diverse microbial environments in early life affects gut microbial colonization in BALB/c mice. The diversity of the intestinal flora in early life may prevent airway inflammation in asthma via regulating the Th1/Th2 balance. PMID- 28623899 TI - Renin-angiotensin system blockers and residual kidney function loss in patients initiating peritoneal dialysis: an observational cohort study. AB - BACKGROUND: Although angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) have been shown to preserve residual kidney function in a select group of Asian patients undergoing continuous ambulatory peritoneal dialysis (PD) in two small randomized clinical trials, the effectiveness of these drugs has yet to be demonstrated in a more diverse population of patients with multiple comorbid conditions. We investigated the association between ACEI/ARB use and development of recorded anuria in a cohort of patients initiating PD in the U.S. METHODS: We conducted a retrospective observational cohort study using the US Renal Data System and electronic health records data from a large national dialysis provider. We identified adult patients who initiated PD from 2007 to 2011. Only patients who participated in the federal prescription drug benefit program, Medicare Part D, for the first 90 days of dialysis were included. Patients who filled a prescription for an ACEI or ARB during those 90 days were considered users. We applied Cox proportional hazards models to an inverse probability of treatment-weighted (IPTW) cohort to estimate the hazard ratio (HR) for anuria (24-h urine volume < 200 ml) in ACEI/ARB users vs. non-users. RESULTS: Among 886 patients, 389 (44%) used an ACEI/ARB. Almost a third of these patients were black or Hispanic, and more than a quarter had comorbidities that would have excluded them from the randomized clinical trials of ACEI/ARB. Two hundred eighty patients reached anuria over 840 person-years of follow-up, for a composite event rate of 33 events per 100 person years. We found no clear association between ACEI/ARB use and progression to anuria [HR: 0.86, 95% CI: 0.73-1.02]. CONCLUSIONS: ACEI/ARB use is common in patients initiating PD in the U.S. but was not associated with a lower risk of anuria. Residual confounding by unmeasured variables is an important limitation of this observational study. Still, these findings suggest that pragmatic clinical trials are warranted to test the effectiveness of ACEI/ARB in slowing the decline of residual kidney function in a diverse population of peritoneal dialysis patients with multiple comorbid conditions. PMID- 28623900 TI - Characterization of MicroRNA-200 pathway in ovarian cancer and serous intraepithelial carcinoma of fallopian tube. AB - BACKGROUND: Ovarian cancer is the leading cause of death among gynecologic diseases in Western countries. We have previously identified a miR-200-E-cadherin axis that plays an important role in ovarian inclusion cyst formation and tumor invasion. The purpose of this study was to determine if the miR-200 pathway is involved in the early stages of ovarian cancer pathogenesis by studying the expression levels of the pathway components in a panel of clinical ovarian tissues, and fallopian tube tissues harboring serous tubal intraepithelial carcinomas (STICs), a suggested precursor lesion for high-grade serous tumors. METHODS: RNA prepared from ovarian and fallopian tube epithelial and stromal fibroblasts was subjected to quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) to determine the expression of miR-200 families, target and effector genes and analyzed for clinical association. The effects of exogenous miR-200 on marker expression in normal cells were determined by qRT-PCR and fluorescence imaging after transfection of miR-200 precursors. RESULTS: Ovarian epithelial tumor cells showed concurrent up-regulation of miR 200, down-regulation of the four target genes (ZEB1, ZEB2, TGFbeta1 and TGFbeta2), and up-regulation of effector genes that were negatively regulated by the target genes. STIC tumor cells showed a similar trend of expression patterns, although the effects did not reach significance because of small sample sizes. Transfection of synthetic miR-200 precursors into normal ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells confirmed reduced expression of the target genes and elevated levels of the effector genes CDH1, CRB3 and EpCAM in both normal OSE and FTE cells. However, only FTE cells had a specific induction of CA125 after miR-200 precursor transfection. CONCLUSIONS: The activation of the miR-200 pathway may be an early event that renders the OSE and FTE cells more susceptible to oncogenic mutations and histologic differentiation. As high-grade serous ovarian carcinomas (HGSOC) usually express high levels of CA125, the induction of CA125 expression in FTE cells by miR-200 precursor transfection is consistent with the notion that HGSOC has an origin in the distal fallopian tube. PMID- 28623902 TI - Prevalence and treatment of atherogenic dyslipidemia in the primary prevention of cardiovascular disease in Europe: EURIKA, a cross-sectional observational study. AB - BACKGROUND: Atherogenic dyslipidemia is associated with poor cardiovascular outcomes, yet markers of this condition are often ignored in clinical practice. Here, we address a clear evidence gap by assessing the prevalence and treatment of two markers of atherogenic dyslipidemia: elevated triglyceride levels and low levels of high-density lipoprotein cholesterol. METHODS: This cross-sectional observational study assessed the prevalence of two atherogenic dyslipidemia markers, high triglyceride levels and low high-density lipoprotein cholesterol levels, in the study population from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA; N = 7641; of whom 51.6% were female and 95.6% were White/Caucasian). The EURIKA population included European patients, aged at least 50 years with at least one cardiovascular risk factor but no history of cardiovascular disease. RESULTS: Over 20% of patients from the EURIKA population have either triglyceride or high-density lipoprotein cholesterol levels characteristic of atherogenic dyslipidemia. Furthermore, the proportions of patients with one of these markers were higher in subpopulations with type 2 diabetes mellitus or those already calculated to be at high risk of cardiovascular disease. Approximately 55% of the EURIKA population who have markers of atherogenic dyslipidemia are not receiving lipid-lowering therapy. CONCLUSIONS: A considerable proportion of patients with at least one major cardiovascular risk factor in the primary cardiovascular disease prevention setting have markers of atherogenic dyslipidemia. The majority of these patients are not receiving optimal treatment, as specified in international guidelines, and thus their risk of developing cardiovascular disease is possibly underestimated. TRIAL REGISTRATION: The present study is registered with ClinicalTrials.gov (ID: NCT00882336). PMID- 28623903 TI - Religious coping methods predict depression and quality of life among end-stage renal disease patients undergoing hemodialysis: a cross-sectional study. AB - BACKGROUND: Poor quality of life (QOL) and a high prevalence of depression have been identified among end-stage renal disease (ESRD) patients undergoing hemodialysis (HD). We aimed to evaluate the associations between religious/spiritual (R/S) coping methods and both QOL and depression among ESRD patients undergoing hemodialysis (HD). METHODS: The sample included 161 ESRD patients over 18 years of age who had been undergoing HD for more than 3 months. R/S coping methods were assessed using the Religious Coping Questionnaire (RCOPE). The RCOPE generates scores (from 1 to 5) for positive and negative R/S coping methods. The higher the score, the more frequent the use of that coping method. Depression was evaluated using the 20-item version of the Center for Epidemiologic Studies Depression Scale (CES-D). Scores on the CES-D range from 0 to 60. A cutoff of 18 was used to define depression. QOL was evaluated using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36); this survey was used to generate scores for the eight dimensions of QOL, which can vary from 0 (worst) to 100 (best). RESULTS: We identified a depression prevalence of 27.3%. Positive R/S coping scores were higher among non-depressed than depressed patients (2.98 vs. 2.77; p = 0.037). Positive R/S coping scores were negatively correlated with depression scores (r = -0.200; p = 0.012) and were an independent protective factor for depression (OR = 0.13; CI 95% = 0.02-0.91; p = 0.039). Regarding QOL, a positive correlation was identified between positive R/S coping scores and scores related to general health (r = 0.171; p = 0.030) and vitality (r = 0.183; p = 0.019), and an inverse correlation was identified between negative R/S coping scores and scores in the social functioning (r = -0.191; p = 0.015) and mental health (r = -0.214; p = 0.006) dimensions. In addition, positive R/S coping scores were an independent predictor of higher scores in the bodily pain (beta = 14.401; p = 0.048) and vitality (beta = 12.580; p = 0.022) dimensions. In contrast, negative R/S coping scores independently predicted lower social functioning scores (beta = -21.158; p = 0.017). CONCLUSIONS: Our results provide further evidence suggesting that R/S coping methods may be associated with QOL and depression among HD patients. In our opinion, the use of religious resources should be encouraged among HD patients, and psycho-spiritual interventions should be attempted to target religious struggles (negative R/S coping) in patients undergoing HD. PMID- 28623901 TI - Biomarker correlation network in colorectal carcinoma by tumor anatomic location. AB - BACKGROUND: Colorectal carcinoma evolves through a multitude of molecular events including somatic mutations, epigenetic alterations, and aberrant protein expression, influenced by host immune reactions. One way to interrogate the complex carcinogenic process and interactions between aberrant events is to model a biomarker correlation network. Such a network analysis integrates multidimensional tumor biomarker data to identify key molecular events and pathways that are central to an underlying biological process. Due to embryological, physiological, and microbial differences, proximal and distal colorectal cancers have distinct sets of molecular pathological signatures. Given these differences, we hypothesized that a biomarker correlation network might vary by tumor location. RESULTS: We performed network analyses of 54 biomarkers, including major mutational events, microsatellite instability (MSI), epigenetic features, protein expression status, and immune reactions using data from 1380 colorectal cancer cases: 690 cases with proximal colon cancer and 690 cases with distal colorectal cancer matched by age and sex. Edges were defined by statistically significant correlations between biomarkers using Spearman correlation analyses. We found that the proximal colon cancer network formed a denser network (total number of edges, n = 173) than the distal colorectal cancer network (n = 95) (P < 0.0001 in permutation tests). The value of the average clustering coefficient was 0.50 in the proximal colon cancer network and 0.30 in the distal colorectal cancer network, indicating the greater clustering tendency of the proximal colon cancer network. In particular, MSI was a key hub, highly connected with other biomarkers in proximal colon cancer, but not in distal colorectal cancer. Among patients with non-MSI-high cancer, BRAF mutation status emerged as a distinct marker with higher connectivity in the network of proximal colon cancer, but not in distal colorectal cancer. CONCLUSION: In proximal colon cancer, tumor biomarkers tended to be correlated with each other, and MSI and BRAF mutation functioned as key molecular characteristics during the carcinogenesis. Our findings highlight the importance of considering multiple correlated pathways for therapeutic targets especially in proximal colon cancer. PMID- 28623904 TI - Impact of preconceptional micronutrient supplementation on maternal mental health during pregnancy and postpartum: results from a randomized controlled trial in Vietnam. AB - BACKGROUND: Micronutrient malnutrition has been associated with maternal depressive symptoms (MDS), but little is known about the effects of preconceptional micronutrient supplementation. This paper examined the effects of preconceptional micronutrient supplementation on MDS during pregnancy and postpartum. METHODS: We used data from a double-blind controlled trial (PRECONCEPT) in which 5011 Vietnamese women were randomized to receive weekly supplements containing either a) multiple micronutrients (MM) b) iron and folic acid (IFA) or c) folic acid (FA) until conception (n = 1813). Maternal mental health was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline (preconception), and the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy and 3 months postpartum. Elevated MDS was defined as EPDS score >= 4. All group comparisons were done using ANOVA or chi-square tests of proportions intention to treat and per protocol analyses (women consumed supplements >=26 weeks before conception). We also conducted stratified analyses by preconception CES-D scores, underweight, or anemia status using generalized linear models. RESULTS: Baseline CES-D scores were similar across treatment groups. The proportion of women experiencing elevated MDS was 11.3, 8.1 and 4.9% at first, second and third trimesters of pregnancy, respectively, and 3.6% at 3 mo postpartum. Mean EPDS scores at first (1.5 +/- 2.7), second (1.1 +/- 2.4), and third trimester of pregnancy (0.7 +/- 2.0) and early postpartum (0.6 +/- 1.8) were low and did not differ by treatment group. However, among women in the highest tertile of CES-D scores at preconception, mean EPDS scores in the first and second trimesters of pregnancy were lower in the MM and IFA groups compared to FA only (P < 0.05). CONCLUSIONS: Weekly preconceptional micronutrient supplements containing iron did not improve depression measures relative to folic acid alone among all women, but may have benefitted women who were at risk for depression. TRIAL REGISTRATION: The trial was registered retrospectively at ClinicalTrials.Gov as NCT01665378 on August 13, 2012. PMID- 28623905 TI - Educational standards for training paramedics in ultrasound: a scoping review. AB - BACKGROUND: Paramedic-performed out-of-hospital ultrasound is a novel skill that has gained popularity in some services in recent years. In this setting point-of care ultrasound (POCUS) can provide additional information that can assist with management and guide transport to the most appropriate facility. We sought to explore the different educational approaches used for training paramedics in ultrasound in the out-of-hospital setting. METHODS: Ovid MEDLINE, EMBASE, EBM Reviews, The Cochrane Library, CINAHL plus, The Monash University Research Repository and the British Thesis Library were searched from the 1st of January 1990 to the 6th of April 2016. Google Scholar was searched and reference lists of relevant papers were examined to identify additional studies. Articles were included if they reported on out-of-hospital and POCUS educational approaches for paramedics. RESULTS: A total of 2002 unique articles were identified of which 18 articles met the inclusion criteria. Most articles reported combined cohorts of emergency providers with varying years of experience though most operators were POCUS naive. The most common clinical assessment for which paramedic POCUS curricula was described was the focused assessment sonography for trauma (FAST) examination. Education programs varied from two-minutes to two-days with all studies including both didactic and practical training. CONCLUSION: Education programs for POCUS for paramedics vary considerably, and do not appear to align with qualification level or clinical experience. Further research investigating education and subsequent clinical application of POCUS by paramedics is required, as well as prospective, outcome based studies in order to measure the clinical utility of out-of-hospital POCUS. PMID- 28623906 TI - Correlations between inflammatory cytokines, muscle damage markers and acute postoperative pain following primary total knee arthroplasty. AB - BACKGROUND: Despite the success of total knee arthroplasty (TKA) in reducing knee pain and improving functional disability, the management of acute postoperative pain is still unsatisfactory. This study was aimed to quantitatively analyze the possible correlations between inflammatory cytokines, muscle damage markers and acute postoperative pain following primary TKA. METHODS: Patients scheduled for unilateral primary TKA were consecutively included, the serial changes of the numerical rating scale (NRS) at rest (NRSR) and at walking (NRSW), serum inflammatory cytokines and muscle damage markers were assessed before surgery (T0) and at postoperative day 1, 2, 3 and 5 (T1-T4, respectively); while pain disability questionnaire (PDQ) and synovial fluid inflammatory cytokines were evaluated at T0. The correlations between inflammatory cytokines, muscle damage markers and pain scores were examined, and Bonferroni correction was applied for multiple comparisons. RESULTS: Ninety six patients were included for serum markers and pain evaluations at T0-T4, while 54 (56.25%) for synovial fluid cytokines at T0. The NRSR at T1 and T2 were positively correlated with preoperative NRSW, while the NRSW at T1 to T4 were positively correlated with preoperative NRSR, NRSW and PDQ (all p < 0.05). The NRSR was positively correlated with serum PGE2, IL-6, and CK at T1; the NRSW was positively correlated with serum CRP at T1, with PGE2 and IL-6 at T1 to T3, with CK at T2 and T4, and with Mb and LDH at T1 to T4 (all p < 0.003). Meanwhile, positive correlations were observed between preoperative NRSW and synovial fluid PGE2, IL 6, IL-8, or TNF-alpha, as well as between PDQ and PGE2 (all p < 0.003), but no associations between postoperative pain scores and preoperative synovial fluid cytokines was found (all p >= 0.003). Additionally, the NRSR at T1 and T2, and NRSW at T1 to T4 were positively correlated with body mass index (all p < 0.05). CONCLUSIONS: Serum inflammatory cytokines and muscle damage markers are positively correlated with acute postoperative pain following primary TKA, and the key cytokines (CRP, PGE2, and IL-6) and markers (Mb, CK and LDH) may serve as the targets for developing novel analgesic strategies. PMID- 28623907 TI - DNA methylation dysregulations in rheumatic heart valve disease. AB - BACKGROUND: The epigenetic changes underlying the development of rheumatic heart valve disease (RHVD) remain incompletely understood. Limited evidence suggests that abnormal DNA methylation might be involved in the pathogenesis of RHVD. In the present study, we evaluated the DNA methylation dysregulations from myocardial tissue in RHVD patients systematically. METHODS: Right atrial myocardial tissue obtained from rheumatic valvular patients who had undergone valve replacements surgery (n = 73) and were compared to healthy controls (n = 4). the promoter methylation level of Intercellular adhesion molecule-1 (ICAM-1) gene and its correlation with ICAM-1 mRNA expression level, the global DNA methylation level and its correlation with age and mRNA expression level of DNA methyltransferase (DNMT) genes were detected. RESULTS: The ICAM-1 mRNA expression was increased (healthy control vs. NHYA III, 0.70 +/- 0.19 vs. 4.38 +/- 3.19, p = 0.011; NYHA IIvs. NHYA III, 2.60 +/- 1.99 vs. 4.38 +/- 3.19, p = 0.008) and the ICAM-1 gene was hypomethylated in RHVD patients (healthy controls vs. NYHA II, 0.120 +/- 0.011 vs. 0.076 +/- 0.057, p = 0.039; healthy control vs. NHYA III, 0.120 +/- 0.011 vs. 0.041 +/- 0.022, p < 0.001; NYHA IIvs. NHYA III, 0.076 +/- 0.057 vs. 0.041 +/- 0.022, p < 0.001). Meanwhile, The ICAM-1 mRNA expression level has negative correlation with the mean methylation level in the promoter region of ICAM-1 gene (r = -0.459, p < 0.001). The global DNA methylation levels was significantly increased in RHVD patients than in healthy controls (healthy control vs. NHYA III, 0.77 +/- 0.28 vs. 2.09 +/- 1.20, p = 0.017; NYHA IIvs. NHYA III, 1.57 +/- 0.78 vs. 2.09 +/- 1.20, p = 0.040) and had positive correlation with age (r = 0.326, p = 0.005), especially for older age group (>= 60 years). DNMT1 likely plays an essential role in the DNA dysregulations in RHVD patients. CONCLUSIONS: Our analysis revealed that DNA methylation dysregulations may be relevant in the pathogenesis of RHVD. PMID- 28623908 TI - Programmed death-ligand 1 (PD-L1) is expressed in a significant number of the uterine cervical carcinomas. AB - BACKGROUND: The programmed death-1/programmed death-ligand-1 (PD-1/PD-L1) immune regulatory axis has emerged as a promising new target for cancer therapeutics, with lasting responses seen in the treatment of metastatic renal and lung carcinomas, as well as melanomas. As tumor surface expression of PD-L1 has been found to correlate with objective responses to anti-PD-L1 immunotherapies, we investigated the expression of PD-L1 in human cervical tumors and provide an adopted scoring system for the systematic evaluation of PD-L1 staining. METHODS: Immunohistochemical staining for PD-L1 expression was performed on a tissue microarray of 101 normal and neoplastic cervical tissues. Neoplastic cores were divided into three groups: squamous cell carcinoma, adenosquamous carcinoma, and endocervical adenocarcinoma. PD-L1 expression was scored based on an adopted scoring system accounting to percentage and intensity of positivity, and results provided alongside available clinical and demographic data. RESULTS: Overall, PD L1 was positive in 32 of 93 (34.4%) cervical carcinomas. Subcategorically, PD-L1 was positive in 28 of 74 (37.8%) squamous cell carcinomas, two of seven (28.6%) adenosquamous carcinomas, and two of 12 (16.7%) endocervical adenocarcinomas. It was negative in six benign cervical tissues. CONCLUSIONS: This study shows a significant expression of PD-L1 in 34.4% of cervical carcinomas and no expression of PD-L1 in benign cervical tissues. These findings suggest a role for further investigation of anti-PD-L1/PD-1 immunotherapies in the treatment of PD-L1 positive cervical tumors. In addition, our adopted scoring system will facilitate more systematic correlations between tumor reactivity and response to treatment. PMID- 28623909 TI - A systematic review and narrative synthesis of group self-management interventions for adults with epilepsy. AB - BACKGROUND: Epilepsy is a serious and costly long-term condition that negatively affects quality of life, especially if seizures persist on medication. Studies show that people with epilepsy (PWE) want to learn more about the condition and some educational self-management courses have been trialled internationally. The objectives of this review were to evaluate research and summarise results on group self-management interventions for PWE. METHODS: We searched Medline and PsycINFO for results published in English between 1995 and 2015. Only studies evaluating face-to-face, group interventions for adults with epilepsy were included. Heterogeneity in study outcomes prevented the carrying out of a meta analysis; however, a Cochrane style review was undertaken. RESULTS: We found eleven studies, nine of which were randomised controlled trials. There were variable standards of methodological reporting with some risk of bias. Seven of the studies used quality of life as an outcome, with four finding statistically significant improvements in mean total score. Two found an improvement in outcome subscales. One study included some additional semi-qualitative data. CONCLUSIONS: We identified promising trends in the trials reviewed. In particular, there were significant improvements in quality of life scales and seizure frequency in many of the interventions. However, considerable heterogeneity of interventions and outcomes made comparison between the studies difficult. Courses that included psychological interventions and others that had a high number of sessions showed more effect than short educational courses. Furthermore, the evidence was predominantly from pilot studies with small sample sizes and short follow-up duration. Further research is needed to better evaluate the role of group self management interventions in outpatient epilepsy management. PMID- 28623911 TI - Moderate mental illness as a predictor of chronic disease prevention and screening. AB - BACKGROUND: Primary care plays a pivotal role in the provision of both mental health care and chronic disease prevention and screening (CDPS). Unfortunately, moderate mental illness (MMI) is associated with poorer general health outcomes. Part of this burden of illness may be due to reduced CDPS uptake. The Building on the Existing Tools to Improve Chronic Disease Prevention in Primary Care (BETTER) trial recruited 777 participants ages 40-65 from 32 family practice panels, of whom 135 (18.2%) had elevated GAD scores, 118 (16.4%) had elevated PHQ scores, and 264 (34.0%) had electronic medical record (EMR)-documented MMI. We hypothesized that patients with screen-positive or chart-documented MMI are 1) eligible for more CDPS actions, and 2) able to complete a lower proportion of CDPS actions than patients unaffected by MMI. METHODS: This study was a secondary analysis of data from the BETTER trial. Participants were stratified by both EMR documented MMI and screen-positive evidence of MMI (using the General Anxiety Disorders (GAD-7) and Patient Health Questionnaire (PHQ-9) instruments for anxiety and depression screening, respectively). The primary outcome was the proportion of CDPS actions for which the patient was eligible completed at follow up, using a composite index. RESULTS: After adjusting for age, gender, and social support, patients with evidence of MMI had a lower composite index than patients without evidence of MMI (p < 0.05). The lower composite index is primarily due to higher eligibility for CDPS at baseline; ability to complete CDPS was not statistically different. CONCLUSIONS: Patients affected by MMI are eligible for more CDPS actions than their unaffected counterparts. Although they are able to complete a similar number of CDPS actions, they are not able to eliminate their baseline CDPS gap. Primary care teams need to be aware of this increased CDPS eligibility for patients with MMI and ensure best practices in CDPS supports are available to this patient population. Further study is needed to determine the ideal suite of targeted supports. PMID- 28623910 TI - Pilot study using 3D-longitudinal strain computation in a multi-parametric approach for best selecting responders to cardiac resynchronization therapy. AB - BACKGROUND: Almost all attempts to improve patient selection for cardiac resynchronization therapy (CRT) using echo-derived indices have failed so far. We sought to assess: the performance of homemade software for the automatic quantification of integral 3D regional longitudinal strain curves exploring left ventricular (LV) mechanics and the potential value of this tool to predict CRT response. METHODS: Forty-eight heart failure patients in sinus rhythm, referred for CRT-implantation (mean age: 65 years; LV-ejection fraction: 26%; QRS duration: 160 milliseconds) were prospectively explored. Thirty-four patients (71%) had positive responses, defined as an LV end-systolic volume decrease >=15% at 6-months. 3D-longitudinal strain curves were exported for analysis using custom-made algorithms. The integrals of the longitudinal strain signals (I L,peak) were automatically measured and calculated for all 17 LV-segments. RESULTS: The standard deviation of longitudinal strain peak (SDI L,peak ) for all 17 LV-segments was greater in CRT responders than non-responders (1.18% s-1 [0.96; 1.35] versus 0.83% s-1 [0.55; 0.99], p = 0.007). The optimal cut-off value of SDI L,peak to predict response was 1.037%.s-1. In the 18-patients without septal flash, SDI L,peak was significantly higher in the CRT-responders. CONCLUSIONS: This new automatic software for analyzing 3D longitudinal strain curves is avoiding previous limitations of imaging techniques for assessing dyssynchrony and then its value will have to be tested in a large group of patients. PMID- 28623912 TI - Role of epigenetics-microRNA axis in drug resistance of multiple myeloma. AB - Despite administration of novel therapies, multiple myeloma (MM) remains incurable with resistance to drugs leading to relapse in most patients. Thus, it is critical to understand the detailed mechanisms underlying the drug resistance of MM and develop more effective therapeutic strategies. Genetic abnormalities are well known to play a central role in MM pathogenesis and therapy resistance; however, epigenetic aberrations mainly affecting the patterns of DNA methylation/histone modifications of genes (especially tumor suppressors) and miRNAs have also been shown to be involved. Importantly, while epigenetic silencing of miRNAs in MM is well documented, some epigenetic markers are known to be direct targets of miRNAs particularly the recently described "epimiRNAs". Drugs targeting epigenetic modifiers (e.g., HDACs, EZH2) can sensitize MM resistant cells to anti-myeloma drugs and reversibility of epigenetic changes makes these drugs promising therapeutic agents. Therefore, combination of miRNA mimics with inhibitors of epigenetic modifiers would be a more potent therapeutic strategy in MM patients in relapse or refractory to treatments. In this review, we will discuss the findings of recent investigations on epigenetics/miRNA regulatory axis in development of drug resistance in MM and highlight possible approaches for therapeutic applications of such interaction. PMID- 28623913 TI - Aggressive natural killer cell leukemia or extranodal NK/T cell lymphoma? a case with nasal involvement. AB - BACKGROUND: Aggressive natural killer cell leukemia/lymphoma (ANKL) is a rare and highly aggressive NK cell neoplasm with a short clinical course and poor prognosis and is often misdiagnosed and confused with NK/T cell lymphoma (NKTL), which has a very different prognosis. Here, we present a case with nasal and bone marrow involvement, provide a literature review and make a differential diagnosis. CASE PRESENTATION: A 41-year-old male presented nasal congestion pharyngalgia, palatal perforation, high fever and multiorgan dysfunction. Our diagnosis primarily relied on clinical features, the morphology and immunophenotype of the neoplastic cells and imaging studies. Characteristic large granular lymphocytes with azurophilic granules were visible in the bone marrow smears. In addition, the neoplastic cells expressed a typical immunophenotype, and the T cell receptor gamma (TCR-gamma) gene rearrangement analysis and presence of Epstein-Barr virus (EBV) were negative. The patient's symptoms and signs were temporarily relieved after chemotherapy treatment, but after a short time, he underwent a rapid clinical decline and died 8 weeks later after admission due to multiorgan function failure. CONCLUSION: Our case demonstrates that to avoid a misdiagnosis, bone marrow analyses and other examinations should be performed early when a patient initially presents nasal lesions and other systemic symptoms. To the best of our knowledge, this may be the first reported case of ANKL with sternal tenderness. PMID- 28623914 TI - Synaptonemal complex protein 3 is associated with lymphangiogenesis in non-small cell lung cancer patients with lymph node metastasis. AB - BACKGROUND: The interaction of vascular endothelial growth factor-C (VEGF-C)/VEGF D/VEGF receptor-3 is considered to be a major driver of lymphangiogenesis, however the mechanism of this process remains unclear. We aimed to investigate the possible lymphangiogenic significance of synaptonemal complex protein 3 (SCP3) in non-small cell lung cancer (NSCLC). METHODS: The expression of SCP3, VEGF-C, and VEGF-D were measured and examined a correlation between SCP3 and VEGF C or VEGF-D in various human lung cancer cell lines. Subsequently, we assessed SCP3, VEGF-A, VEGF-B, VEGF-C, and VEGF-D expression in archival tumor tissues from 89 NSCLC patients with lymph node (LN) metastasis by combined immunohistochemistry with quantitative digital image analysis. RESULTS: Positive correlations between SCP3 and VEGF-C expression (R 2 = 0.743) and VEGF-D expression (R 2 = 0.932) were detected in various human lung cancer cell lines. The high expression of SCP3, VEGF-A, VEGF-B, VEGF-C, and VEGF-D were detected in 24 (27.0%), 22 (24.7%), 27 (30.3%), 27 (30.3%), and 24 cases (27.0%), respectively. Notably, SCP3 positively correlated with VEGF-C and VEGF-D expression (for both, P < 0.001) and negatively correlated with VEGF-A and VEGF-B expression (P = 0.029 and P = 0.026, respectively). In multivariate analysis of patients with LN metastasis, SCP3 expression predicted worse overall survival (hazard ratio = 1.86, P = 0.008). CONCLUSIONS: SCP3 is associated with lymphangiogenesis and provides insight into the SCP3-VEGF-C/VEGF-D axis based cancer therapy strategy. PMID- 28623916 TI - Using record linkage to validate notification and laboratory data for a more accurate assessment of notifiable infectious diseases. AB - BACKGROUND: Infectious disease burden is commonly assessed using notification data. Using retrospective record linkage in Western Australia, we described how well notification data captures laboratory detections of influenza, pertussis and invasive pneumococcal disease (IPD). METHODS: We linked data from the Western Australian Notifiable Infectious Diseases Database (WANIDD) and the PathWest Laboratory Database (PathWest) pertaining to the Triple I birth cohort, born in Western Australia in 1996-2012. These were combined to calculate the number of unique cases captured in each dataset alone or in both datasets. To assess the impact of under-ascertainment, we compared incidence rates calculated using WANIDD data alone and using combined data. RESULTS: Overall, there were 5550 influenza, 513 IPD (2001-2012) and 4434 pertussis cases (2000-2012). Approximately 2% of pertussis and IPD cases and 7% of influenza cases were solely recorded in PathWest. Notification of influenza and pertussis cases to WANIDD improved over time. Overall incidence rates of influenza in children aged <5 years using both datasets was 10% higher than using WANIDD data alone (IRR = 1.1, 95% CI = 1.1-1.2). CONCLUSIONS: This is the first time WANIDD data have been validated against routinely collected laboratory data. We anticipated all cases would be captured in WANIDD but found additional laboratory-confirmed cases that were not notified. Studies investigating pathogen-specific infectious disease would benefit from using multiple data sources. PMID- 28623915 TI - Safety pharmacology and subchronic toxicity of jinqing granules in rats. AB - BACKGROUND: Jinqing granules which are made of a mixture extract that contains Radix Tinosporae and Canarii fructus in proportions according to a longstanding formula have a good effect on the prevention and treatment of gastric ulcer disease. It has not been through safety through systematic toxicological studies, however. To provide basis for clinical application, we performed safety pharmacology and subchronic toxicity experiments in specific pathogen-free Sprague-Dawley rats. RESULTS: In safety pharmacology experiments, Jinqing granules had no evident adverse effects on the central nervous, cardiovascular, or respiratory systems. In subchronic toxicity study, 2-8 g/kg of Jinqing granules induced no evident adverse effects on Clinical signs, body weight changes, food and water intake, death daily, indicators of urine, hematological assay, serum biochemistry, organ coefficient and histopathological examination. However, the 16 g/kg dose was associated with slightly slowed weight growth, decreased number of sperm in seminiferous tubules and increased values of serum aspartate aminotransferase and bilirubin. During the 30-day feeding test, 3 rats that received the 16 g/kg dose died, but the deaths were most likely due to trauma of oral gavage, not to drug toxicity. CONCLUSION: Jinqing granules given to Sprague-Dawley rats orally for 30 days at a dose of 8 g/kg or less appears safe, but higher doses were not proven safe. The significance of these observations with respect to animal usage of Jinqing granules deserves thorough investigation. PMID- 28623917 TI - The dynamic changes of interferon lambdas related genes and proteins in JAK/STAT pathway in both acute and chronic HIV-1 infected patients. AB - BACKGROUND: Host immune responses during acute HIV-1 infection can influence the viral setpoint, which is a predictor of disease progression. Interferon (IFN) lambdas are newly classified type III interferons, which use JAK-STAT pathway. Currently, the dynamics of IFN-lambdas related genes and proteins expression in the signaling pathway have not been well elaborated, especially in acute HIV-1 infected patients. OBJECTIVES: To evaluate the dynamic changes of IFN-lambdas related genes and proteins in JAK/STAT pathway in acute HIV-1-infected patients, and analyze their correlation with CD4 T cell counts and HIV-1 viral loads. STUDY DESIGN: Real-time PCR and flow cytometry methods were used to evaluate the dynamic changes of IFN-lambdas related genes and proteins in JAK/STAT pathway in both acute and chronic HIV-1-infected patients. RESULTS: The IFN-alpha receptors (R), IFN-gamma R, IFN-lambdas R and STAT1 mRNA and protein levels increased in acute HIV-1-infected patients (p < 0.01), in addition, Mx1 mRNA levels in acute HIV-1-infected patients are higher than those in HIV-negative subjects. IFN lambdas R and IFN-alpha R mRNA levels are inversely correlated with CD4+ T-cell counts, but are positively correlated with viral loads. CONCLUSIONS: The dynamic changes of IFNs related genes in JAK-STAT pathway in acute HIV-1 infection will deepen our understanding of the roles of IFN-lambdas in HIV pathogenesis. PMID- 28623918 TI - Effects of herbal medicine for dysmenorrhea treatment on accompanied acne vulgaris: a study protocol for a randomized controlled trial. AB - BACKGROUND: The incidence of preadolescent acne among women is increasing. Acne deteriorates the quality of life; conventional treatment options are limited and have not been effective against acne, particularly acne associated with menstruation. Despite evidence that acne associated with menstruation abnormalities naturally improves when menstruation recovers to normal, there have only been few studies on the effects of dysmenorrhea treatment on acne. Therefore we designed this study to assess the effects of gyejibokryung-hwan (GBH) and dangguijagyag-san (DJS), which are widely used in dysmenorrhea treatment, on acne associated with menstruation cycle. METHODS: This is a protocol for a randomized, double-blind, parallel-group, placebo-controlled and multicenter trial. One hundred and sixteen participants with dysmenorrhea accompanied by acne vulgaris will be recruited at three centers and randomized into two groups, the herbal treatment group and placebo group. The participants will receive GBH or DJS based on pattern identification or placebo granules thrice daily for 8 weeks, with an 8 week follow up. The primary outcome will be the mean percentage change in the count of inflammatory acne lesions. The secondary outcomes would be based on dysmenorrhea numeric rating scale, verbal multidimensional scoring system for dysmenorrhea, acne numeric rating scale, investigator's static global assessment scale of facial acne vulgaris, and safety testing. Adverse events will also be reported. DISCUSSION: The effects of GBH or DJS used in dysmenorrhea treatment on acne associated with the menstrual cycle will be evaluated. The findings of this trial will provide evidence regarding the effect of herbal medicine in improving acne vulgaris associated with menstruation in women. TRIAL REGISTRATION: Korean Clinical Trial Registry ( http://cris.nih.go.kr ; registration number: KCT0002259). Date of registration: March 10, 2017. PMID- 28623919 TI - Effects of Karela (Bitter Melon; Momordica charantia) on genes of lipids and carbohydrates metabolism in experimental hypercholesterolemia: biochemical, molecular and histopathological study. AB - BACKGROUND: Hypercholesterolemia is a serious diseases associated with type-2 diabetes, atherosclerosis, cardiovascular disorders and liver diseases. Humans seek for safe herbal medication such as karela (Momordica charantia/bitter melon) to treat such disorders to avoid side effect of pharmacotherapies widely used. METHODS: Forty male Wistar rats were divided into four equal groups; control group with free access to food and water, cholesterol administered group (40 mg/kg BW orally); karela administered group (5 g /kg BW orally) and mixture of cholesterol and karela. The treatments continued for 10 weeks. Karela was given for hypercholesterolemic rats after 6 weeks of cholesterol administration. Serum, liver and epididymal adipose tissues were taken for biochemical, histopathological and genetic assessments. RESULTS: Hypercholesterolemia induced a decrease in serum superoxide dismutase (SOD), catalase, reduced glutathione (GSH) and an increase in malondialdehyde (MDA) levels that were ameliorated by karela administration. Hypercholesterolemia up regulated antioxidants mRNA expression and altered the expression of carbohydrate metabolism genes. In parallel, hypercholesterolemic groups showed significant changes in the expression of PPAR-alpha and gamma, lipolysis, lipogenesis and cholesterol metabolism such as carnitine palmitoyltransferase-1 (CPT-1). Acyl CoA oxidase (ACO), fatty acids synthase (FAS), sterol responsible element binding protein-1c (SREBP1c), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) and cholesterol 7alpha-hydroxylase (CYP7A1) at hepatic and adipose tissue levels. Interestingly, Karela ameliorated all altered genes confirming its hypocholesterolemic effect. Histopathological and immunohistochemical findings revealed that hypercholesterolemia induced hepatic tissue changes compared with control. These changes include cholesterol clefts, necrosis, karyolysis and sever congestion of portal blood vessel. Caspase-3 immunoreactivity showed positive expression in hepatic cells of hypercholesterolemic rats compared to control. All were counteracted and normalized after Karela administration to hypercholesterolemic group. CONCLUSION: Current findings confirmed that karela is a potential supplement useful in treatment of hypercholesterolemia and its associated disorders and is good for human health. PMID- 28623920 TI - Ketamine-induced apoptosis in the mouse cerebral cortex follows similar characteristic of physiological apoptosis and can be regulated by neuronal activity. AB - The effects of general anesthetics on inducing neuronal apoptosis during early brain development are well-documented. However, since physiological apoptosis also occurs during this developmental window, it is important to determine whether anesthesia-induced apoptosis targets the same cell population as physiological apoptosis or different cell types altogether. To provide an adequate plane of surgery, ketamine was co-administered with dexmedetomidine. The apoptotic neurons in the mouse primary somatosensory cortex (S1) were quantitated by immunohistochemistry. To explore the effect of neural activity on ketamine induced apoptosis, the approaches of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and an environmental enrichment (EE) were performed. Ketamine-induced apoptosis in S1 is most prominent at postnatal days 5 and 7 (P5 P7), and becomes insignificant by P12. Physiological and ketamine-induced apoptosis follow similar developmental patterns, mostly comprised of layer V pyramidal neurons at P5 and shifting to mostly layer II to IV GABAergic neurons by P9. Changes in neuronal activity induced by the DREADD system bidirectionally regulated the pattern of ketamine-induced apoptosis, with reduced activity inducing increased apoptosis and shifting the lamination pattern to a more immature form. Importantly, rearing mice in an EE significantly reduced the magnitude of ketamine-induced apoptosis and shifted its developmental pattern to a more mature form. Together, these results demonstrate that lamination pattern and cell-type dependent vulnerability to ketamine-induced apoptosis follow the physiological apoptosis pattern and are age- and activity-dependent. Naturally elevating neuronal activity is a possible method for reducing the adverse effects of general anesthesia. PMID- 28623921 TI - Genome-wide analysis of codon usage bias in Bovine Coronavirus. AB - BACKGROUND: Bovine coronavirus (BCoV) belong to the genus Betacoronavirus of the family Coronaviridae. BCoV are widespread around the world and cause enteric or respiratory infections among cattle, leading to important economic losses to the beef and dairy industry worldwide. To study the relation of codon usage among viruses and their hosts is essential to understand host-pathogen interaction, evasion from host's immune system and evolution. METHODS: We performed a comprehensive analysis of codon usage and composition of BCoV. RESULTS: The global codon usage among BCoV strains is similar. Significant differences of codon preferences in BCoV genes in relation to codon usage of Bos taurus host genes were found. Most of the highly frequent codons are U-ending. G + C compositional constraint and dinucleotide composition also plays a role in the overall pattern of BCoV codon usage. CONCLUSIONS: The results of these studies revealed that mutational bias is a leading force shaping codon usage in this virus. Additionally, relative dinucleotide frequencies, geographical distribution, and evolutionary processes also influenced the codon usage pattern. PMID- 28623922 TI - Use of simulation-based medical training in Swiss pediatric hospitals: a national survey. AB - BACKGROUND: Simulation-based medical training (SBMT) is a powerful tool for continuing medical education. In contrast to the Anglo-Saxon medical education community, up until recently, SBMT was scarce in continental Europe's pediatric health care education: In 2009, only 3 Swiss pediatric health care institutions used SBMT. The Swiss catalogue of objectives in Pediatrics does not acknowledge SBMT. The aim of this survey is to describe and analyze the current state of SBMT in Swiss pediatric hospitals and health care departments. METHODS: A survey was carried out with medical education representatives of every institution. SBMT was defined as any kind of training with a mannequin excluding national and/or international standardized courses. The survey reference day was May 31st 2015. RESULTS: Thirty Swiss pediatric hospitals and health care departments answered our survey (response rate 96.8%) with 66.6% (20 out of 30) offering SBMT. Four of the 20 hospitals offering SMBT had two independently operating training simulation units, resulting in 24 educational units as the basis for our SBMT analysis. More than 90% of the educational units offering SBMT (22 out of 24 units) were conducting in-situ training and 62.5% (15 out of 24) were using high technology mannequins. Technical skills, communication and leadership ranked among the top training priorities. All institutions catered to inter-professional participants. The vast majority conducted training that was neither embedded within a larger educational curriculum (19 out of 24: 79.2%) nor evaluated (16 out of 24: 66.6%) by its participants. Only 5 institutions (20.8%) extended their training to at least two thirds of their hospital staff. CONCLUSIONS: Two thirds of the Swiss pediatric hospitals and health care departments are offering SBMT. Swiss pediatric SBMT is inter-professional, mainly in-situ based, covering technical as well as non-technical skills, and often employing high-technology mannequins. The absence of a systematic approach and reaching only a small number of healthcare employees were identified as shortcomings that need to be addressed. PMID- 28623923 TI - Making HIV testing work at the point of care in South Africa: a qualitative study of diagnostic practices. AB - BACKGROUND: Point of care testing promises to reduce delays in diagnosing and initiating treatment for infectious diseases such as Human Immuno-deficiency Virus (HIV). In South Africa, decentralized HIV testing with rapid tests offers important lessons for point of care testing programs. Yet, little is known about the strategies of providers and clients to make HIV testing successful in settings short of equipment, human resources and space. We aimed at examining these strategies. METHODS: This paper is based on a larger qualitative study of diagnostic practices across major diseases and actors in homes, clinics, communities, hospitals and laboratories in South Africa. We conducted 101 semi structured interviews and 7 focus group discussions with doctors, nurses, community health workers, patients, laboratory technicians, policymakers, hospital managers and manufacturers between September 2012 and June 2013 in Durban, Cape Town and Eastern Cape. The topics explored included diagnostic processes and challenges, understanding of diagnosis, and visions of ideal tests. For this paper, the data on HIV testing processes in clinics, communities and hospitals was used. RESULTS: Strategies to make HIV testing work at point of care involve overcoming constraints in equipment, spaces, human resources and workload and actively managing diagnostic processes. We grouped these strategies into subthemes: maintaining relationships, adapting testing guidelines and practices to stock-outs, to physical space, and to different clients, turning the test into a tool to reach another aim and turning the testing process into a tool to enhance adherence. These adaptive strategies are locally negotiated solutions, often ad-hoc, depending on personal commitment, relationships, human resources, physical space and referral systems. In the process, testing is redefined and repurposed. Not all of these repurposing acts are successful in ensuring a timely diagnosis. Some lead to disruptions, unnecessary testing or delays with at times unclear implications for quality of diagnosis. CONCLUSION: Tests shape relationships, professional roles and practices of users at point of care. At the same time, testing processes are dynamic and test results and processes take on new meanings for clients and providers. These insights are crucial for understanding the contexts within which diagnostic devices and policies need to function. PMID- 28623924 TI - In vitro physiological and antibacterial characterization of ZnO nanoparticle composites in simulated porcine gastric and enteric fluids. AB - BACKGROUND: Diarrhea in piglets is one of the main causes of animal death after weaning; zinc oxide (ZnO) has been used in high doses for the control of this sickness. The aim of this study was to determine the physicochemical properties of ZnO nanoparticles synthesized and immobilized on a chitosan/alginate (CH/SA) complex and investigate the antimicrobial activity and in vitro release profile of zinc (Zn2+) from these new compounds. The ZnO nanoparticles composites were prepared and combined with CH/SA or CH/SA and sodium tripolyphosphate (TPP). The structure and morphology of the composites were analyzed by characterization methods such as X-ray diffraction, FTIR spectroscopy, thermogravimetric analysis, atomic absorption spectrophotometry and scanning electron microscopy. RESULTS: The crystallite size of ZnO nano was 17 nm and the novel ZnO composites were effective in protecting ZnO in simulated gastric fluid, where Zn2+ reached a concentration six-fold higher than the levels obtained with the unprotected commercial-zinc oxide. In addition, the novel composites suggest effective antimicrobial activity against Escherichia coli and Staphylococcus aureus. CONCLUSIONS: The results described herein suggest that the novel nano composites may work as an alternative product for pig feeding as verified by the in vitro assays, and may also contribute to lower the zinc released in the environment by fecal excretion in animals waste. PMID- 28623925 TI - Human jugular vein collapse in the upright posture: implications for postural intracranial pressure regulation. AB - BACKGROUND: Intracranial pressure (ICP) is directly related to cranial dural venous pressure (P dural ). In the upright posture, P dural is affected by the collapse of the internal jugular veins (IJVs) but this regulation of the venous pressure has not been fully understood. A potential biomechanical description of this regulation involves a transmission of surrounding atmospheric pressure to the internal venous pressure of the collapsed IJVs. This can be accomplished if hydrostatic effects are cancelled by the viscous losses in these collapsed veins, resulting in specific IJV cross-sectional areas that can be predicted from flow velocity and vessel inclination. METHODS: We evaluated this potential mechanism in vivo by comparing predicted area to measured IJV area in healthy subjects. Seventeen healthy volunteers (age 45 +/- 9 years) were examined using ultrasound to assess IJV area and flow velocity. Ultrasound measurements were performed in supine and sitting positions. RESULTS: IJV area was 94.5 mm2 in supine and decreased to 6.5 +/- 5.1 mm2 in sitting position, which agreed with the predicted IJV area of 8.7 +/- 5.2 mm2 (equivalence limit +/-5 mm2, one-sided t tests, p = 0.03, 33 IJVs). CONCLUSIONS: The agreement between predicted and measured IJV area in sitting supports the occurrence of a hydrostatic-viscous pressure balance in the IJVs, which would result in a constant pressure segment in these collapsed veins, corresponding to a zero transmural pressure. This balance could thus serve as the mechanism by which collapse of the IJVs regulates P dural and consequently ICP in the upright posture. PMID- 28623926 TI - Perennial transmission of malaria in the low altitude areas of Baringo County, Kenya. AB - BACKGROUND: Malaria causes the greatest public health burden in sub-Saharan Africa where high mortality occurs mainly in children under 5 years of age. Traditionally, malaria has been reported mainly in the lowlands endemic regions of western Kenya, while the highlands of the Rift Valley have been relatively free except for the sporadic epidemics in some areas. Baringo County is located in the Kenyan highlands. The county generally experiences seasonal transmission of malaria. A few hotspots which experience continuous malaria transmission in the county do however exist. The objective of this study was to assess malaria infection status and identify areas with continuous transmissions with a view to mapping out probable transmission hot spots useful in mounting focused interventions within the county. METHODS: Systematic sampling was employed to identify 1668 primary school pupils from fifteen primary schools located in 4 ecological zones (lowland, midland, highland and riverine) of three sub-counties of Baringo. Finger prick blood sampling was done every 4 months (during the dry season in February/March, after the long rains in June/July and short rains in November 2015). Malaria occurrence was tested using rapid diagnostic test kit (CareStart HRP-2 Pf). Microscopic examination was done on all RDT positive and 10% of negative cases. RESULTS: A total of 268 (16.1%), out of 1668 pupils tested positive for Plasmodium falciparum by RDT; 78% had a single episode, 16.8% had 2 episodes, 4.9% had 3 episodes and 0.4% had 4 episodes. The riverine zone had the highest malaria cases (23.2%) followed by lowlands (0.9%). No malaria cases were detected in the midland zone while highland zone recorded only few cases during the third follow up. Up to 10.7% of malaria cases were reported in the dry season, 2.9% during the long rains and 5.7% in short rains season. CONCLUSIONS: Malaria infection was prevalent in Baringo County and was mainly restricted to the riverine zone where transmission is continuous throughout the year. High malaria prevalence occurred in the dry season compared to the wet season. Even though malaria transmission is relatively low compared to endemic regions of Kenya, there is a need for continued monitoring of transmission dynamics under changing climatic conditions as well as establishing expanded malaria control strategies especially within the riverine zone which would include an integrated mosquito control and chemotherapy for infected individuals. PMID- 28623927 TI - Caffeoylquinic acid derivatives rich extract from Gnaphalium pensylvanicum willd. Ameliorates hyperuricemia and acute gouty arthritis in animal model. AB - BACKGROUND: The Gnaphalium pensylvanicum willd. is used in China as a folk medicine to treat anti-inflammatory, cough and rheumatism arthritis. The aim of this study was to evaluate the potential of the extract of G. pensylvanicum to treat hyperuricemia and acute gouty arthritis in animal model. METHODS: G. pensylvanicum extract was evaluated in an experimental model with potassium oxonate (PO) induced hyperuricemia in mice which was used to evaluate anti hyperuricemia activity and xanthine oxidase (XO) inhibition. Therapies for acute gouty arthritis was also investigated on monosodium urate (MSU) crystal induced paw edema model. RESULTS: G. pensylvanicum extract showed activity in reducing serum uric acid (Sur) through effect renal glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1) and urate transporter 1 (URAT1) mainly and inhibited XO activity in vivo of mice with PO induced hyperuricemia. The extract of G. pensylvanicum also showed significant anti-inflammatory activity and reduced the paw swelling on MSU crystal-induced paw edema model. Meanwhile, 13 caffeoylquinic acid derivatives and 1 flavone were identified by UPLC-ESI-MS/MS as the main active component of G. pensylvanicum. CONCLUSIONS: The extract of G. pensylvanicum showed significant effect on evaluated models and therefore may be active agents for the treatment of hyperuricemia and acute gouty arthritis. PMID- 28623928 TI - The effects of beliefs about AIDS-related death on quality of life in Chinese married couples with both husband and wife infected with HIV: examining congruence using the actor-partner interdependence model. AB - BACKGROUND: This cross-sectional study examined the actor and partner effects of beliefs about AIDS-related death on quality of life in Chinese married couples in which both were living with HIV. METHODS: A total of 49 married couples in central China who were both infected with HIV completed measures to assess their beliefs about AIDS-related death and quality of life. RESULTS: In the actor partner interdependence model, the husband-wife dyad showed congruence in their beliefs about AIDS-related death (r = .40) and quality of life-mental health summary (r = .31), respectively, within the couple. Both actor and partner effects of beliefs about AIDS-related death on the quality of life-mental health summary, rather than the quality of life-physical health summary, were significant within the husband-wife dyad. CONCLUSIONS: Our findings indicate the dyadic interdependence of beliefs about AIDS-related death and the quality of life-mental health summary in married couples. Psychosocial interventions that target a reduction of negative death beliefs and enhancement of well-being in the context of HIV should treat the couple as a unit. PMID- 28623929 TI - The potential regulatory mechanisms of the gonadotropin-releasing hormone in gonadotropin transcriptions identified with bioinformatics analyses. AB - BACKGROUND: The regulation of gonadotropin synthesis and release by gonadotropin releasing hormone (GnRH) plays an essential role in the neuroendocrine control of reproduction. However, the mechanisms underlying gonadotropin regulation by GnRH pulse frequency and amplitude are still ambiguous. This study aimed to explore the molecular mechanisms and biological pathways associated with gonadotropin synthesis by GnRH pulse frequencies and amplitudes. METHODS: Using GSE63251 datasets downloaded from the Gene Expression Omnibus (GEO), differentially expressed genes (DEGs) were screened by comparing the RNA expression from the GnRH pulse group, the GnRH tonic group and the control group. Pathway enrichment analyses of DEGs was performed, followed by protein-protein interaction (PPI) network construction. Furthermore, sub-network modules were constructed by ClusterONE and GO function and pathways analysed by DAVID. In addition, the relationship between the metabolic pathways and the GnRH pathway was verified in vitro. RESULTS: In total, 531 common DEGs were identified in GnRH groups, including 290 up-regulated and 241 down-regulated genes. DEGs predominantly enriched in 16 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including 11 up-regulated pathways (signallingsignallingmetabolic pathways, signallingand GnRH signalling pathway) and 5 down-regulated pathways (type II diabetes mellitus). Moreover, FBJ osteosarcoma oncogene (FOS) and jun proto-oncogene (JUN) had higher connectivity degrees in the PPI network. Three modules in the PPI were identified with ClusterONE. The genes in module 1 were significantly enriched in five pathways, including signallingthe insulin resistance and GnRH signalling pathway. The genes in modules 2 and 3 were mainly enriched in metabolic pathways and steroid hormone biosynthesis, respectively. Finally, knockdown leptin receptor (LEPR) and insulin receptor (INSR) reversed the GnRH-modulated metabolic related-gene expression. CONCLUSIONS: The present study revealed the involvement of GnRH in the regulation of gonadotropin biosynthesis and metabolism in the maintenance of reproduction, achieved by bioinformatics analyses. This, indicates that the GnRH signalling pathway played a central linkings role in reproductive function and metabolic balance. In addition, the present study identified the difference response between GnRH pulse and GnRH tone, indicated that abnormal GnRH pulse and amplitude may cause disease, which may provide an improved understanding of the GnRH pathway and a new insight for disease diagnosis and treatment. PMID- 28623930 TI - Systematic assessment of advanced respiratory physiology: precision medicine entering real-life ICU? PMID- 28623931 TI - Retinal involvement in sepsis: from the eye of the patient to the eye of the beholder. PMID- 28623933 TI - Transferring research from a university to the United Kingdom National Health Service: the implications for impact. AB - The aim of this article is to inform readers of the author's reflections on the experience of transferring university-based research into the commercial sector, and of the processes and strategies employed when preparing for impact in so doing. Concepts for the transfer are illustrated by the author's reflection on aspects that arose during the birthing and subsequent start-up of a university spin-off, Pathways2Wellbeing, a form of reflection-on-action. This is the vehicle for the adaption required to transfer research into the delivery of a specialised clinic in the United Kingdom National Health Service for people with medically unexplained, persistent, bodily symptoms such as fibromyalgia, chronic fatigue and chronic pain. It is hoped that the article will provide readers with an insight into how knowledge transfer can take place through engagement with stakeholders to create an exchange of knowledges to result in impact on health service policy for service users, despite the challenges, and the enablers that facilitated this process. The reflections on the process of knowledge transfer and the implications for impact are underpinned by relevant theory. PMID- 28623932 TI - Impact of glycemic control on aortic stiffness, left ventricular mass and diastolic longitudinal function in type 2 diabetes mellitus. AB - BACKGROUND: Poor glycemic control is associated with impaired left ventricular (LV) diastolic function in patients with type 2 diabetes mellitus (T2DM). Inappropriate LV mass increase and accelerated aortic stiffening were suggested to participate on deterioration of diastolic function. The present study investigated the inter-relationships between glycemic control, early diastolic and systolic longitudinal velocity of mitral annulus, LV mass and aortic stiffness in T2DM patients free of cardiovascular disease and with preserved LV ejection fraction, and compared them with those observed in healthy volunteers of similar age and sex distribution. METHODS: 125 T2DM patients and 101 healthy volunteers underwent noninvasive measurement of systolic (s') and early diastolic (e') velocities of mitral annulus, LV mass, carotid-femoral pulse wave velocity (cfPWV) and local carotid blood pressure (BP). RESULTS: Forty-four (35.2%) T2DM patients had e' velocity lower than that expected for age (against 7.9% in healthy volunteers; P < 0.0001), 34 (27.2%) had cfPWV higher than that expected for age and mean BP (against 5.9% in healthy volunteers; P < 0.0001), and 71 (56.8%) had LV mass higher than that expected for body size and stroke work (against 17.6% in healthy volunteers; P < 0.0001). Carotid systolic BP was higher in T2DM patients (124 +/- 14 vs 111 +/- 11 mmHg; P < 0.0001). In multivariate analysis, e' velocity was independently related to age, carotid BP and s' velocity in healthy volunteers, and to male sex, age, carotid BP, heart rate and LV mass in T2DM. Glycosylated hemoglobin (HbA1c) was independently related to cfPWV and LV mass in T2DM patients. T2DM patients with HbA1c >=6.5% (N = 85) had higher cfPWV (P < 0.05), central BP (P = 0.01), prevalence of LV hypertrophy (P = 0.01) and lower e' and s' velocity (P = 0.001 and <0.05, respectively) as compared to those with HbA1c <6.5%. CONCLUSIONS: One-third of T2DM patients with preserved LV ejection fraction has sign of subclinical LV diastolic dysfunction. HbA1c levels are positively associated with LV mass and aortic stiffness, both of which show a negative independent impact on early diastolic velocity e', the latter through an increase in afterload. T2DM patients with suboptimal glycemic control (HbA1c >= 6.5%) have lower diastolic and systolic LV longitudinal performance, together with increased aortic stiffness and a higher prevalence of LV hypertrophy. PMID- 28623934 TI - Serological and virological surveillance of avian influenza virus in domestic ducks of the north-east region of Bangladesh. AB - BACKGROUND: Wild waterfowl are considered as the natural reservoir for avian influenza (AI) viruses. Bangladesh has been experiencing highly pathogenic avian influenza (HPAI) outbreaks since 2007, mostly in chickens and occasionally in ducks. Ducks play an important role in the persistence and genetic recombination of AI viruses. This paper presents the results of serological and virological monitoring of AI in domestic ducks in 2013 in the north-east region of Bangladesh. RESULTS: A total of 871 and 662 serum samples and 909 and 302 pairs of cloacal and oropharyngeal swabs from domestic ducks of Mymensingh and Sylhet division, respectively, were analysed. Antibodies to type A influenza virus were detected by blocking ELISA in 60.73 and 47.73% serum samples of Mymensingh and Sylhet division, respectively. On haemagglutination-inhibition (HI) test 17.5% of ELISA positive serum samples were found to be seropositive to H5 avian influenza virus. Five cloacal swabs and one oropharyngeal swab were positive for M gene of type A influenza virus by real time RT-PCR (rRT-PCR), but all of them were negative for H5 influenza virus. Three of the six viruses were successfully characterized as H1N5, H2N5 and H7N5 subtype of AI virus, the other three remained uncharacterized. On sequencing and phylogenetic analysis the HA and NA genes were found to be of Eurasian avian lineage. The H7 virus had cleavage site motif of low pathogenic virus. CONCLUSIONS: Low pathogenic avian influenza viruses were detected from apparently healthy domestic ducks. A small proportion of domestic ducks were found seropositive to H5 AI virus. PMID- 28623935 TI - Variation in susceptibility of different breeds of sheep to Mycobacterium avium subspecies paratuberculosis following experimental inoculation. AB - Exposure to Mycobacterium avium subspecies paratuberculosis (MAP) does not always lead to Johne's disease. Understanding differences in disease susceptibility of individual animals is a key aspect to controlling mycobacterial diseases. This study was designed to examine the susceptibility or resistance of various breeds of sheep to MAP infection. Merino, Suffolk first cross Merino, Border Leicester, and Poll Dorset sheep were orally inoculated with MAP and monitored for 14 months. Clinical disease occurred more frequently in the Merino (42%) and Suffolk first cross Merino (36%) compared to the Border Leicester (12%) and Poll Dorset (11%) breeds. Infection risk, as determined by culture of gut and associated lymphoid tissues, ranged from 75% for the Suffolk first cross Merino to 47% for the Poll Dorset sheep. Significant differences were identified in the site in the intestines of the most severe histopathological lesions and the immune responses to infection between the breeds. However, there was no difference in faecal MAP shedding by clinical cases between breeds. All breeds tested were susceptible to MAP infection, as determined by infection and clinical disease development, although there were differences in the proportions of diseased animals between the breeds. Poll Dorset and Border Leicester sheep were more resilient to MAP infection but there was evidence that more animals could have developed disease if given more time. These findings provide evidence of potential differential disease susceptibility between breeds, further our understanding of disease pathogenesis and risks of disease spread, and may have an influence on control programs for paratuberculosis. PMID- 28623936 TI - Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders. AB - Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care. Many of the therapeutic advances require invasive procedures but some progress in slowing the disease has been found and more options can be expected in the future. We also review the literature on children with disease/conditions other than NCL for the non invasive use, safety, and tolerability of a lipid-lowering drug, gemfibrozil, as a potential treatment for NCLs. Gemfibrozil has shown efficacy in an animal model of NCL known as CLN2 (late infantile classic juvenile) and has been shown to be safe for lowering lipids in children. Among the 200 non-NCL children found in the published literature who were treated with gemfibrozil for NCL-related problems, only 3 experienced adverse events, including 2 with muscle pain and 1 with localized linear IgA bullous dermatitis. We conclude that gemfibrozil is safe for long-term use in children, causes minimal adverse events, is well tolerated, and may delay the progression of NCLs. Gemfibrozil may potentially be an alternative to more invasive therapeutic approaches currently under investigation and has the potential to be used in combination with other therapeutic approaches. PMID- 28623937 TI - The association of lipid metabolism relative gene polymorphisms and ischemic stroke in Han and Uighur population of Xinjiang. AB - BACKGROUND: The present study is aimed to evaluate difference of lipid metabolism related gene single nucleotide polymorphisms (SNPs) with ischemic stroke (IS) in Han and Uighur population of Xinjiang, China. METHODS: Four hundred eight patients with ischemic stroke and 347 unrelated healthy individuals of age and sex matched were genotyped for Apolipoprotein A5 (ApoA5), lipoprotein lipase (LPL), Cholesteryl ester transfer protein (CETP) and low-density lipoprotein receptor (LDL-R) genes. Their mutation difference was analyzed by SNaP shot techniques. GeneMapper4.1 SPSS20.0 software was used for data management and analysis. Using a single locus analysis, the distribution difference of genotype loci in ischemic stroke cases and controls were detected to assess the genetic risk factors of ischemic stroke. RESULTS: Significance differences of genotype distribution in ischemic stroke cases and controls were observed in LDLR rs688 in Han and Uighur population in recessive model from analysis of single gene locus. It also was found that dramatic difference of triglyceride (TG) of LPL rs328 and systolic blood pressure in CETP rs708277 of total population. In binary logistic regression analysis of total studied population, ischemic stroke was observed significantly associated with LDLR rs688 both addictive model (TT/CC, adjusted OR = 1.47, 95% CI = 1.04-2.07) and recessive model (TT/CT + CC, adjusted Odds ratio (OR) = 2.66, 95% Confidence Interval (CI) = 1.37-5.14). In Han population, ischemic stroke was observed significantly associated with rs688 both in addictive model (TT/CC, adjusted OR = 3.27, 95% CI = 1.06-10.05). In Uighur population, no significant association was found between gene polymorphisms and the risk of ischemic stroke. Combined analysis of multiple gene and loci, interaction effects of LDLR rs688 C/T, ApoA5 rs662799 A/G and CETP rs708272 C/T denoted a significant influence on IS susceptibility. CONCLUSION: Single nucleotide polymorphisms of lipid metabolism relative gene were significantly associated with the morbidity of ischemic stroke in Han population. The interaction effects of rs688 C/T with ApoA5 rs662799 A/G and CETP rs708272 C/T promoted the occurrence of IS. PMID- 28623938 TI - Transcriptome modulation by hydrocortisone in severe burn shock: ancillary analysis of a prospective randomized trial. AB - BACKGROUND: Despite shortening vasopressor use in shock, hydrocortisone administration remains controversial, with potential harm to the immune system. Few studies have assessed the impact of hydrocortisone on the transcriptional response in shock, and we are lacking data on burn shock. Our objective was to assess the hydrocortisone-induced transcriptional modulation in severe burn shock, particularly modulation of the immune response. METHODS: We collected whole blood samples during a randomized controlled trial assessing the efficacy of hydrocortisone administration in burn shock. Using whole genome microarrays, we first compared burn patients (n = 32) from the placebo group to healthy volunteers to describe the transcriptional modulation induced by burn shock over the first week. Then we compared burn patients randomized for either hydrocortisone administration or placebo, to assess hydrocortisone-induced modulation. RESULTS: Study groups were similar in terms of severity and major outcomes, but shock duration was significantly reduced in the hydrocortisone group. Many genes (n = 1687) were differentially expressed between burn patients and healthy volunteers, with 85% of them exhibiting a profound and persistent modulation over seven days. Interestingly, we showed that hydrocortisone enhanced the shock-associated repression of adaptive, but also innate immunity. CONCLUSIONS: We found that the initial host response to burn shock encompasses wide and persistent modulation of gene expression, with profound modulation of pathways associated with metabolism and immunity. Importantly, hydrocortisone administration may worsen the immunosuppression associated with severe injury. These data should be taken into account in the risk ratio of hydrocortisone administration in patients with inflammatory shock. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00149123 . Registered on 6 September 2005. PMID- 28623939 TI - On-line plasma lactate concentration monitoring in critically ill patients. PMID- 28623940 TI - Clonorchis sinensis lysophospholipase A upregulates IL-25 expression in macrophages as a potential pathway to liver fibrosis. AB - BACKGROUND: Liver fibrosis is an excessive wound-healing reaction that requires the participation of inflammatory cells and hepatic stellate cells (HSCs). The pathogenesis of liver fibrosis caused by viruses and alcohol has been well characterized, but the molecular mechanisms underlying liver fibrosis induced by the liver fluke Clonorchis sinensis are poorly understood. Lysophospholipase A (LysoPLA), which deacylates lysophospholipids, plays a critical role in mediating the virulence and pathogenesis of parasites and fungi; however, the roles of C. sinensis lysophospholipase A (CsLysoPLA) in C. sinensis-induced liver fibrosis remain unknown. METHODS: A mouse macrophage cell line (RAW264.7) was cultured and treated with CsLysoPLA. IL-25 and members of its associated signaling pathway were detected by performing quantitative real-time PCR, Western blotting and immunofluorescent staining. A human hepatic stellate cell line (LX-2) was cultured and exposed to IL-25. LX-2 cell activation markers were examined via quantitative real-time PCR, Western blotting and immunofluorescent staining. Migration was analyzed in transwell plates. RESULTS: Treating RAW264.7 cells with CsLysoPLA significantly induced IL-25 expression. Elevated PKA, B-Raf, and ERK1/2 mRNA levels and phosphorylated B-Raf and ERK1/2 were detected in CsLysoPLA stimulated RAW264.7 cells. The PKA inhibitor H-89 weakened B-Raf and ERK1/2 phosphorylation whereas the AKT activator SC79 attenuated ERK1/2 phosphorylation in RAW264.7 cells. Both H-89 and SC79 inhibited CsLysoPLA-induced IL-25 upregulation. In addition, stimulation of LX-2 cells with IL-25 upregulated the expression of mesenchymal cell markers, including alpha-smooth muscle actin (alpha-SMA) and collagen type I (Collagen-I), and promoted cell migration. CONCLUSIONS: CsLysoPLA activates HSCs by upregulating IL-25 in macrophages through the PKA-dependent B-Raf/ERK1/2 pathway and potentially promotes hepatic fibrosis during C. sinensis infection. PMID- 28623942 TI - The palisade cartilage tympanoplasty technique: a systematic review and meta analysis. AB - BACKGROUND: Tympanoplasty is a common procedure performed by Otolaryngologists. Many types of autologous grafts have been used with variations of techniques with varying results. This is the first systematic review of the literature and meta analysis with the aim to evaluate the effectiveness of one of the techniques which is gaining popularity, the palisade cartilage tympanoplasty. PubMed, EMBASE, and Cochrane databases were searched for "palisade", "cartilage", "tympanoplasty", "perforation" and their synonyms. In total, 199 articles reporting results of palisade cartilage tympanoplasty were identified. Five articles satisfied the following inclusion criteria: adult patients, minimum 6 months follow-up, hearing and surgical outcomes reported. Studies with patients undergoing combined mastoidectomy, ossicular chain reconstruction, and/or other middle ear surgery were excluded. Perforation closure, rate of complications, and post-operative pure-tone average change were extracted for pooled analysis. Study failure and complication proportions that were used to generate odds ratios were pooled. Fixed effects and random effects weightings were generated. The resulting pooled odds ratios are reported. Palisade cartilage tympanoplasty has an overall take rate of 96% at beyond 6 months and has similar odds of complications compared to temporalis fascia (OR 0.89, 95% CI 0.62, 1.30). The air-bone gap closure is statistically similar to reported results from temporalis fascia tympanoplasty. CONCLUSIONS: Cartilage palisade tympanoplasty offers excellent graft take rates and good postoperative hearing outcomes for perforations of various sizes and for both primary and revision cases. This technique has predictable, long-term results with low complication rates, similar to temporalis fascia tympanoplasty. PMID- 28623941 TI - Development of a program theory for shared decision-making: a realist review protocol. AB - BACKGROUND: The practicality of applying evidence to healthcare systems with the aim of implementing change is an ongoing challenge for practitioners, policy makers, and academics. Shared decision- making (SDM), a method of medical decision-making that allows a balanced relationship between patients, physicians, and other key players in the medical decision process, is purported to improve patient and system outcomes. Despite the oft-mentioned benefits, there are gaps in the current literature between theory and implementation that would benefit from a realist approach given the value of this methodology to analyze complex interventions. In this protocol, we outline a study that will explore: "In which situations, how, why, and for whom does SDM between patients and health care providers contribute to improved decision making?" METHODS: A seven step iterative process will be described including preliminary theory development, establishment of a search strategy, selection and appraisal of literature, data extraction, analysis and synthesis of extracted results from literature, and formation of a revised program theory with the input of patients, physicians, nurse navigators, and policy makers from a stakeholder session. DISCUSSION: The goal of the realist review will be to identify and refine a program theory for SDM through the identification of mechanisms which shape the characteristics of when, how, and why SDM will, and will not, work. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017062609. PMID- 28623943 TI - Does metabolic syndrome predict surgical complications? A protocol for a systematic review and meta-analysis. AB - BACKGROUND: Metabolic syndrome (MetS) is defined by an accumulation of risk factors that include cardiovascular disease, diabetes, chronic high blood pressure, obesity, and hypercholesterolaemia which results in an increased risk of developing serious chronic diseases. MetS is widespread as it is estimated to affect up to 30% of the global population. For people with MetS who undergo surgery, an emerging body of literature points to significantly poorer postoperative outcomes compared with non-affected populations. Surgical patients with MetS are at significantly higher risk of a range of adverse outcomes including death, morbid cardiovascular events, coma, stroke, renal failure, myocardial infarction, and surgical site infections. Increased complication rates result in prolonged hospital stays, a greater need for post-hospitalisation care, and reduced effectiveness of surgical interventions. METHODS/DESIGN: We will search the following electronic bibliographic databases: MEDLINE, EMBASE, ScienceDirect, and CINAHL, and the reference lists of included articles. We will also search for unpublished literature. Two authors will screen titles and abstract information independently and select studies according to established inclusion and exclusion criteria. Data will be extracted by the study investigators using Review Manager 5 and will include information on demographics, incidence, prevalence, and outcome variables. Subgroup analysis and sensitivity analysis will be performed to assess the heterogeneity of included studies. Meta-analysis will also be carried out if appropriate study groups are identified. A descriptive narrative for statistical data will also be provided to highlight findings of the systematic review and meta-analysis. DISCUSSION: This study will report and summarise adverse outcomes among adult patients with MetS undergoing surgery across a range of surgical specialties. Developing insights into outcomes of this population of interest is necessary to develop guidelines towards better management of surgical patients with metabolic syndrome. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016051071. PMID- 28623944 TI - The effect of combining manual therapy with exercise for mild chronic obstructive pulmonary disease: study protocol for a randomised controlled trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of disability and hospital admission. Current management strategies have not been successful in altering the loss of lung function typically seen as the disease progresses. A recent systematic review into the use of spinal manipulative therapy (SMT) in the management of COPD concluded that there was low level evidence to support the view that a combination of SMT and exercise had the potential to improve lung function more than exercise alone in people with moderate to severe COPD. The aim of this study is to investigate whether the combination of exercise and manual therapy (MT) that includes SMT produces sustainable improvements in lung function and exercise capacity in people with mild COPD. METHODS/DESIGN: The study is a randomised controlled trial of 202 people with stable mild COPD. The cohort will be divided into two equal groups matched at baseline. The first group will receive a standardised exercise program. The second group will receive MT that includes SMT plus the same standardised exercise program. Exercise will be administered a total of 36 times over an 18-week period, while MT will be administered in conjunction with exercise a total of 15 times over a 6-week period. The primary outcome measure is lung function (forced expiratory volume in the 1st second: FEV1 and forced vital capacity: FVC). The secondary outcome measures are the 6-minute walking test (6MWT), quality of life questionnaire (St George's Respiratory Questionnaire: SGRQ), anxiety and depression levels (Hospital Anxiety and Depression Scale: HADS), frequency of exacerbations, chest wall expansion measurements (tape measurements) and systemic inflammatory biomarker levels. Outcome measurements will be taken by blinded assessors on seven occasions over a 48-week period. Adverse event data will also be gathered at the beginning of each intervention session. DISCUSSION: This randomised controlled trial is designed to investigate whether the combination of MT and exercise delivers any additional benefits to people with mild COPD compared to exercise alone. The study is designed in response to recommendations from a recent systematic review calling for more research into the effect of MT in the management of COPD. TRIAL REGISTRATION: ANZCTRN, 12614000766617 . Registered on 18 July 2014. PMID- 28623946 TI - Antiarrhythmic drugs in out-of-hospital cardiac arrest: is there a place for potassium chloride? PMID- 28623945 TI - Mir-155 is overexpressed in systemic sclerosis fibroblasts and is required for NLRP3 inflammasome-mediated collagen synthesis during fibrosis. AB - BACKGROUND: Despite the important role that microRNAs (miRNAs) play in immunity and inflammation, their involvement in systemic sclerosis (SSc) remains poorly characterized. miRNA-155 (miR-155) plays a role in pulmonary fibrosis and its expression can be induced with interleukin (IL)-1beta. SSc fibroblasts have activated inflammasomes that are integrally involved in mediating the myofibroblast phenotype. In light of this, we investigated whether miR-155 played a role in SSc and if its expression was dependent on inflammasome activation. METHODS: miR-155 expression was confirmed in SSc dermal and lung fibroblasts by quantitative polymerase chain reaction (PCR). Wild-type and NLRP3-deficient murine fibroblasts were utilized to explore the regulation of miR-155 during inflammasome activation. miR-155-deficient fibroblasts and retroviral transductions with a miR-155 expression or control vectors were used to understand the contribution of miR-155 in fibrosis. RESULTS: miR-155 was significantly increased and the highest expressing miRNA in SSc lung fibroblasts. Its expression was dependent on inflammasome activation as miR-155 expression could be blocked when inflammasome signaling was inhibited. In the absence of miR 155, inflammasome-mediated collagen synthesis could not be induced but was restored when miR-155 was expressed in miR-155-deficient fibroblasts. CONCLUSIONS: miR-155 is upregulated in SSc. These results suggest that the inflammasome promotes the expression of miR-155 and that miR-155 is a critical miRNA that drives fibrosis. PMID- 28623947 TI - Effects of digital Cognitive Behavioural Therapy for Insomnia on cognitive function: study protocol for a randomised controlled trial. AB - BACKGROUND: The daytime effects of insomnia pose a significant burden to patients and drive treatment seeking. In addition to subjective deficits, meta-analytic data show that patients experience reliable objective impairments across several cognitive domains. While Cognitive Behavioural Therapy for Insomnia (CBT-I) is an effective and scalable treatment, we know little about its impact upon cognitive function. Trials of CBT-I have typically used proxy measures for cognitive functioning, such as fatigue or work performance scales, and no study has assessed self-reported impairment in cognitive function as a primary outcome. Moreover, only a small number of studies have assessed objective cognitive performance, pre-to-post CBT-I, with mixed results. This study specifically aims to (1) investigate the impact of CBT-I on cognitive functioning, assessed through both self-reported impairment and objective performance measures, and (2) examine whether change in sleep mediates this impact. METHODS/DESIGN: We propose a randomised controlled trial of 404 community participants meeting criteria for Insomnia Disorder. In the DISCO trial (D efining the I mpact of improved S leep on CO gnitive function (DISCO)) participants will be randomised to digital automated CBT-I delivered by a web and/or mobile platform (in addition to treatment as usual (TAU)) or to a wait-list control (in addition to TAU). Online assessments will take place at 0 (baseline), 10 (post-treatment), and 24 (follow up) weeks. At week 25, all participants allocated to the wait-list group will be offered digital CBT-I, at which point the controlled element of the trial will be complete. The primary outcome is self-reported cognitive impairment at post treatment (10 weeks). Secondary outcomes include objective cognitive performance, insomnia severity, sleepiness, fatigue, and self-reported cognitive failures and emotional distress. All main analyses will be carried out on completion of follow up assessments and will be based on the intention-to-treat principle. Further analyses will determine to what extent observed changes in self-reported cognitive impairment and objective cognitive performance are mediated by changes in sleep. The trial is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) based at Oxford University Hospitals NHS Trust and University of Oxford, and by the NIHR Oxford Health BRC. DISCUSSION: This study will be the first large-scale examination of the impact of digital CBT-I on self-reported cognitive impairment and objective cognitive performance. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN89237370 . Registered on 17 October 2016. PMID- 28623948 TI - One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond. AB - BACKGROUND: Hyperhomocysteinemia is a risk factor for cognitive decline and dementia, including Alzheimer disease (AD). Homocysteine (Hcy) is a sulfur containing amino acid and metabolite of the methionine pathway. The interrelated methionine, purine, and thymidylate cycles constitute the one-carbon metabolism that plays a critical role in the synthesis of DNA, neurotransmitters, phospholipids, and myelin. In this study, we tested the hypothesis that one carbon metabolites beyond Hcy are relevant to cognitive function and cerebrospinal fluid (CSF) measures of AD pathology in older adults. METHODS: Cross-sectional analysis was performed on matched CSF and plasma collected from 120 older community-dwelling adults with (n = 72) or without (n = 48) cognitive impairment. Liquid chromatography-mass spectrometry was performed to quantify one carbon metabolites and their cofactors. Least absolute shrinkage and selection operator (LASSO) regression was initially applied to clinical and biomarker measures that generate the highest diagnostic accuracy of a priori-defined cognitive impairment (Clinical Dementia Rating-based) and AD pathology (i.e., CSF tau phosphorylated at threonine 181 [p-tau181]/beta-Amyloid 1-42 peptide chain [Abeta1-42] >0.0779) to establish a reference benchmark. Two other LASSO determined models were generated that included the one-carbon metabolites in CSF and then plasma. Correlations of CSF and plasma one-carbon metabolites with CSF amyloid and tau were explored. LASSO-determined models were stratified by apolipoprotein E (APOE) epsilon4 carrier status. RESULTS: The diagnostic accuracy of cognitive impairment for the reference model was 80.8% and included age, years of education, Abeta1-42, tau, and p-tau181. A model including CSF cystathionine, methionine, S-adenosyl-L-homocysteine (SAH), S-adenosylmethionine (SAM), serine, cysteine, and 5-methyltetrahydrofolate (5-MTHF) improved the diagnostic accuracy to 87.4%. A second model derived from plasma included cystathionine, glycine, methionine, SAH, SAM, serine, cysteine, and Hcy and reached a diagnostic accuracy of 87.5%. CSF SAH and 5-MTHF were associated with CSF tau and p-tau181. Plasma one-carbon metabolites were able to diagnose subjects with a positive CSF profile of AD pathology in APOE epsilon4 carriers. CONCLUSIONS: We observed significant improvements in the prediction of cognitive impairment by adding one-carbon metabolites. This is partially explained by associations with CSF tau and p tau181, suggesting a role for one-carbon metabolism in the aggregation of tau and neuronal injury. These metabolites may be particularly critical in APOE epsilon4 carriers. PMID- 28623949 TI - Hemoglobin concentrations and RBC transfusion thresholds in patients with acute brain injury: an international survey. AB - BACKGROUND: The optimal hemoglobin (Hb) threshold at which to initiate red blood cell (RBC) transfusion in patients with acute brain injury is unknown. The aim of this survey was to investigate RBC transfusion practices used with these patients. METHODS: We conducted a web-based survey within various societies of critical care medicine for intensive care unit (ICU) physicians who currently manage patients with primary acute brain injury. RESULTS: A total of 868 responses were obtained from around the world, half of which (n = 485) were from European centers; 204 (24%) respondents had a specific certificate in neurocritical care, and most were specialists in anesthesiology or intensive care and had less than 15 years of practice experience. Four hundred sixty-six respondents (54%) said they used an Hb threshold of 7-8 g/dl to initiate RBC transfusion after acute brain injury, although half of these respondents used a different threshold (closer to 9 g/dl) in patients with traumatic brain injury, subarachnoid hemorrhage, or ischemic stroke. Systemic and cerebral factors were reported as influencing the need for higher Hb thresholds. Most respondents agreed that a randomized clinical trial was needed to compare two different Hb thresholds for RBC transfusion, particularly in patients with traumatic brain injury, subarachnoid hemorrhage, and ischemic stroke. CONCLUSIONS: The Hb threshold used for RBC transfusion after acute brain injury was less than 8 g/dl in half of the ICU clinicians who responded to our survey. However, more than 50% of these physicians used higher Hb thresholds in certain conditions. PMID- 28623950 TI - Work outcome in yet undiagnosed patients with non-radiographic axial spondyloarthritis and ankylosing spondylitis; results of a cross-sectional study among patients with chronic low back pain. AB - BACKGROUND: To understand the impact of yet undiagnosed non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) on work outcomes in a cohort of patients with long-lasting chronic low back pain (CLBP). METHODS: Data were used from a primary care CLBP cohort that was established to understand the prevalence of nr-axSpA and AS. Clinical characteristics comprised measures of back pain (visual analogue scale), inflammation (C-reactive protein) and physical functioning (Roland Morris Disability Questionnaire (RMDQ)). Worker outcomes comprised a question on employment and the Work Productivity and Activity Impairment (WPAI) questionnaire, distinguishing absenteeism, presenteeism, and overall work impairment in those employed and activity impairment in all patients. For each disease subgroup, employment ratio compared to the general population was assessed by indirect standardization. Factors associated with work productivity were explored by zero inflated negative binomial (ZINB) regression models. RESULTS: Patients with CLBP (n = 579) were included (41% male, mean age 36 years), of whom 71 (12%) were identified as having nr-axSpA and 24 (4%) as having AS. The standardized employment ratios were 0.89 (95% CI 0.84-0.94), 0.97 (95% CI 0.85-1.09) and 0.81 (95% CI 0.56-1.06) for patients with CLBP, nr-axSpA and AS, respectively. Scores for the WPAI subdomains were not significantly different between patients with CLBP, nr-axSpA or AS. The ZINB models showed significant associations between visual analog scale (VAS) score for pain and RMDQ and work productivity. CONCLUSION: The impact of yet undiagnosed nr-axSpA and AS on patients' work outcomes was substantial but was not significantly different from those of patients with long-standing CLBP. Variables significantly associated with reduced work productivity were VAS for pain and RMDQ score. PMID- 28623951 TI - Progressive respiratory distress in a 42-year-old HIV-positive woman with systemic lupus erythematosus. AB - BACKGROUND: Identifying and treating the cause of pulmonary symptoms in HIV patients with underlying systemic lupus erythematosus (SLE) can be very challenging. Delays in diagnosing active SLE in HIV patients can lead to significant morbidity and even mortality. We report the case of an HIV-positive woman with SLE who presented with severe respiratory distress. CASE PRESENTATION: A 42-year-old HIV-positive woman presented with a 7-month history of anorexia, progressive dyspnoea, and a productive cough. She had been put on treatment for pulmonary tuberculosis and pneumocystis jiroveci pneumonia for several months by the referring hospital without any significant improvement in her symptoms. Her initial laboratory investigations showed highly elevated d-dimer test results but confirmatory investigations for pulmonary embolism proved otherwise. An autoimmune screen revealed highly positive antinuclear antibody and anti-double stranded DNA tests, and she responded very well to SLE treatment. CONCLUSIONS: Our case represents a situation where two diseases with antagonizing pathways of disease pathogenesis occur concurrently in the same patient. SLE is usually not among the differential diagnoses in HIV patients with respiratory distress. Management of patients with both SLE and HIV is also very challenging because improvement in one condition can lead to worsening of the other. Despite opportunistic infections being the likely cause of pulmonary symptoms in HIV patients, clinicians are encouraged to have a high index of suspicion for autoimmune interstitial lung disease in these patients. PMID- 28623952 TI - Spontaneous cecal perforation in a 40-year-old pregnant woman treated by primary repair and omental patch: a case report. AB - BACKGROUND: Spontaneous colonic perforations are scarce, and cecal perforations even more so. Preoperative diagnosis of the latter in a pregnant woman is particularly difficult because of physiologic changes and restrictions on some diagnostic imaging techniques, such as X-rays. Furthermore, management of these patients is a big challenge. CASE PRESENTATION: We present a case of a spontaneous cecal perforation in a 40-year-old pregnant black woman in the Regional Hospital of Bafoussam in Cameroon. The results of clinical examination and ultrasonography on admission were in line with acute generalized peritonitis in a woman at 20 weeks of a viable pregnancy, indicating an urgent laparotomy. Operative findings were a 1 * 1-cm perforation on a distended cecum with minimal fecal contamination. The treatment consisted of excision of the edges, primary suture of the perforation, and omentoplasty. The recovery of the patient was uneventful. CONCLUSIONS: The management of spontaneous cecal perforation in a pregnant woman was a big challenge. The perforation was repaired by primary suture and omentoplasty. Further studies comparing this approach with right hemicolectomy are recommended. PMID- 28623953 TI - Early versus late initiation of renal replacement therapy impacts mortality in patients with acute kidney injury post cardiac surgery: a meta-analysis. AB - BACKGROUND: Acute kidney injury (AKI) is a common clinical complication of cardiac surgery and increases mortality and hospitalization. We aimed to explore and perform an updated meta-analysis of qualitative and quantitative evaluations of the relationship between early renal replacement therapy (RRT) and mortality. METHODS: We searched the Chinese Biomedical Database, the Cochrane Library, EMBASE, Global Health, MEDLINE and PubMed. RESULTS: Fifteen studies (five randomized controlled trials (RCTs), one prospective cohort and nine retrospective cohorts) including 1479 patients were identified for detailed evaluation. The meta-analysis suggested that early RRT initiation reduced 28-day mortality (odds ratio (OR) 0.36; 95% confidence interval (CI) 0.23 to 0.57; I 2 60%), and shortened intensive care unit (ICU) length of stay (LOS) (mean difference (MD) -2.50; 95% CI -3.53 to -1.47; I 2 88%) and hospital LOS (MD 0.69; 95% CI -1.13 to -0.25; I 2 88%), and also reduced the duration of RRT (MD 1.18; 95% CI -2.26 to -0.11; I 2 69%), especially when RRT was initiated early within 12 hours (OR 0.23; 95% CI 0.08 to 0.63; I 2 73%) and within 24 hours (OR 0.52; 95% CI 0.28 to 0.95; I 2 58%) in patients with AKI after cardiac surgery. CONCLUSIONS: Early RRT initiation decreased 28-day mortality, especially when it was started within 24 hours after cardiac surgery in patients with AKI. PMID- 28623954 TI - Efficacy and safety of alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid-lowering therapy or the lowest strength of statin: ODYSSEY NIPPON study design and rationale. AB - BACKGROUND: Statins are generally well-tolerated and serious side effects are infrequent, but some patients experience adverse events and reduce their statin dose or discontinue treatment altogether. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), which can produce substantial and sustained reductions of low-density lipoprotein cholesterol (LDL-C). METHODS: The randomized, double-blind, placebo controlled, parallel-group, phase 3 ODYSSEY NIPPON study will explore alirocumab 150 mg every 4 weeks (Q4W) in 163 Japanese patients with hypercholesterolemia who are on the lowest-strength dose of atorvastatin (5 mg/day) or are receiving a non statin lipid-lowering therapy (LLT) (fenofibrate, bezafibrate, ezetimibe, or diet therapy alone). Hypercholesterolemia is defined as LDL-C >= 100 mg/dL (2.6 mmol/L) in patients with heterozygous familial hypercholesterolemia or non familial hypercholesterolemia with a history of documented coronary heart disease, or >=120 mg/dL (3.1 mmol/L) in patients with non-familial hypercholesterolemia classified as primary prevention category III (i.e. high risk patients). During the 12-week double-blind treatment period, patients will be randomized (1:1:1) to receive alirocumab subcutaneously (SC) 150 mg Q4W alternating with placebo for alirocumab Q4W, or alirocumab 150 mg SC every 2 weeks (Q2W), or SC placebo Q2W. The primary efficacy endpoint is the percentage change in calculated LDL-C from baseline to week 12. The long-term safety and tolerability of alirocumab will also be investigated. DISCUSSION: The ODYSSEY NIPPON study will provide insights into the efficacy and safety of alirocumab 150 mg Q4W or 150 mg Q2W among Japanese patients with hypercholesterolemia who are on the lowest-strength dose of atorvastatin, or are receiving a non-statin LLT (including diet therapy alone). TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02584504. PMID- 28623956 TI - Differential protein expression in chicken macrophages and heterophils in vivo following infection with Salmonella Enteritidis. AB - In this study we compared the proteomes of macrophages and heterophils isolated from the spleen 4 days after intravenous infection of chickens with Salmonella Enteritidis. Heterophils were characterized by expression of MMP9, MRP126, LECT2, CATHL1, CATHL2, CATHL3, LYG2, LYZ and RSFR. Macrophages specifically expressed receptor proteins, e.g. MRC1L, LRP1, LGALS1, LRPAP1 and a DMBT1L. Following infection, heterophils decreased ALB and FN1, and released MMP9 to enable their translocation to the site of infection. In addition, the endoplasmic reticulum proteins increased in heterophils which resulted in the release of granular proteins. Since transcription of genes encoding granular proteins did not decrease, these genes remained continuously transcribed and translated even after initial degranulation. Macrophages increased amounts of fatty acid elongation pathway proteins, lysosomal and phagosomal proteins. Macrophages were less responsive to acute infection than heterophils and an increase in proteins like CATHL1, CATHL2, RSFR, LECT2 and GAL1 in the absence of any change in their expression at RNA level could even be explained by capturing these proteins from the external environment into which these could have been released by heterophils. PMID- 28623955 TI - Precision medicine in breast cancer: reality or utopia? AB - Many cancers, including breast cancer, have demonstrated prognosis and support advantages thanks to the discovery of targeted therapies. The advent of these new approaches marked the rise of precision medicine, which leads to improve the diagnosis, prognosis and treatment of cancer. Precision medicine takes into account the molecular and biological specificities of the patient and their tumors that will influence the treatment determined by physicians. This new era of medicine is accessible through molecular genetics platforms, the development of high-speed sequencers and means of analysis of these data. Despite the spectacular results in the treatment of cancers including breast cancer, described in this review, not all patients however can benefit from this new strategy. This seems to be related to the many genetic mutations, which may be different from one patient to another or within the same patient. It comes to give new impetus to the research-both from a technological and biological point of view-to make the hope of precision medicine accessible to all. PMID- 28623957 TI - Developing a mathematical model for the evaluation of the potential impact of a partially efficacious vaccine on the transmission dynamics of Schistosoma mansoni in human communities. AB - BACKGROUND: There is currently no vaccine available to protect humans against infection with the schistosome digenean parasites, although candidate formulations for Schistosoma mansoni are under trial in animal models, including rodents and primates. Current strategies for the control of infection are based on mass drug administration (MDA) targeted at school-aged children of age 5 to 14 years. This approach is unlikely to eliminate exposure to infection except in settings with very low levels of transmission. METHODS: A deterministic mathematical model for the transmission dynamics of the parasite is described and employed to investigate community level outcomes. The model is defined to encompass two different delivery strategies for the vaccination of the population, namely, infant (cohort) and mass vaccination. However, in this paper the focus is on vaccination delivered in a cohort immunisation programme where infants are immunised within the first year of life before acquiring infection. An analysis of the parasite's transmission dynamics following the administration of a partially protective vaccine is presented. The vaccine acts on parasite mortality, fecundity or/and establishment. RESULTS: A vaccine with an efficacy of over 60% can interrupt transmission in low and moderate transmission settings. In higher transmission intensity areas, greater efficacy or higher infant vaccination coverage is required. Candidate vaccines that act either on parasite mortality, fecundity or establishment within the human host, can be similarly effective. In all cases, however, the duration of protection is important. The community level impact of vaccines with all modes of action, declines if vaccine protection is of a very short duration. However, durations of protection of 5-10 years or more are sufficient, with high coverage and efficacy levels, to halt transmission. The time taken to break transmission may be 18 years or more after the start of the cohort vaccination, depending on the intensity of the transmission in a defined location. CONCLUSIONS: The analyses provide support for the proposition that even a partially efficacious vaccine could be of great value in reducing the burden of schistosome infections in endemic regions and hopefully could provide a template for the elimination of parasite transmission. PMID- 28623960 TI - Preface. PMID- 28623958 TI - Knockdown of subunit 3 of the COP9 signalosome inhibits C2C12 myoblast differentiation via NF-KappaB signaling pathway. AB - BACKGROUND: The COP9 signalosome (CSN) is a conserved protein complex composed of 8 subunits designated CSN1-CSN8. CSN3 represents the third subunit of the CSN and maintains the integrity of the complex. CSN3 binds to the striated muscle specific beta1D integrin tail, and its subcellular localization is altered in differentiated skeletal muscle cells. However, the role of CSN3 in skeletal muscle differentiation is unknown. The main goal of this study was to identify whether CSN3 participates in myoblast differentiation and the signalling mechanisms involved using C2C12 cells as a skeletal muscle cell model. METHODS: Small-hairpin (shRNA) was used to knockdown CSN3 in C2C12 cells. Differentiation was evaluated by immunostaining and confocal microscopy. Markers of differentiation, NF-kappaB signaling and CSN subunits expression, were assessed by immunoblotting and/or immunostaining. Cell proliferation was analysed by cell counting, flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Data were analyzed by one or two-way analysis of variance (ANOVA) followed by post-hoc testing. RESULTS: Transduction of C2C12 cells with two distinct CSN3 shRNAs led to the production of two cells lines expressing 7% of CSN3 protein (shCSN3-Low) and 43% of CSN3 protein (CSN3 Med) compared to controls. Knockdown of CSN3 was accompanied by destabilization of several CSN subunits and increased nuclear NF-kappaB localization. shCSN3-Med cells expressed less myogenin and formed shorter and thinner myotubes. In contrast, the shCSN3-Low cells expressed higher levels of myogenin prior and during the differentiation and remained mononucleated throughout the differentiation period. Both CSN3 knockdown cell lines failed to express sarcomeric myosin heavy chain (MHC) protein during differentiation. The fusion index was significantly higher in control cells than in shCSN3-Med cells, whereas shCSN3-Low cells showed no cell fusion. Interestingly, CSN3 knockdown cells exhibited a significantly slower growth rate relative to the control cells. Cell cycle analysis revealed that CSN3 knockdowns delayed in S phase and had increased levels of nuclear p21/Cip1 and p27/Kip1. CONCLUSIONS: This study clarifies the first step toward unrevealing the CSN3/CSN-mediated pathways that controls C2C12 differentiation and proliferation. Further in vivo characterization of CSN/CSN3 may lead to the discovery of novel therapeutic target of skeletal muscle diseases such as muscular dystrophies. PMID- 28623961 TI - Histone modifications for chromatin dynamics and cellular plasticity. PMID- 28623959 TI - The impact of Wolbachia infection on the rate of vertical transmission of dengue virus in Brazilian Aedes aegypti. AB - BACKGROUND: Wolbachia pipientis is a common endosymbiotic bacterium of arthropods that strongly inhibits dengue virus (DENV) infection and transmission in the primary vector, the mosquito Aedes aegypti. For that reason, Wolbachia-infected Ae. aegypti are currently being released into the field as part of a novel strategy to reduce DENV transmission. However, there is evidence that DENV can be transmitted vertically from mother to progeny, and this may help the virus persist in nature in the absence of regular human transmission. The effect of Wolbachia infection on this process had not previously been examined. RESULTS: We challenged Ae. aegypti with different Brazilian DENV isolates either by oral feeding or intrathoracic injection to ensure disseminated infection. We examined the effect of Wolbachia infection on the prevalence of DENV infection, and viral load in the ovaries. For orally infected mosquitoes, Wolbachia decreased the prevalence of infection by 71.29%, but there was no such effect when the virus was injected. Interestingly, regardless of the method of infection, Wolbachia infection strongly reduced DENV load in the ovaries. We then looked at the effect of Wolbachia on vertical transmission, where we observed only very low rates of vertical transmission. There was a trend towards lower rates in the presence of Wolbachia, with overall maximum likelihood estimate of infection rates of 5.04 per 1000 larvae for mosquitoes without Wolbachia, and 1.93 per 1000 larvae for Wolbachia-infected mosquitoes, after DENV injection. However, this effect was not statistically significant. CONCLUSIONS: Our data support the idea that vertical transmission of DENV is rare in nature, even in the absence of Wolbachia. Indeed, we observed that vertical transmission rates were low even when the midgut barrier was bypassed, which might help to explain why we only observed a trend towards lower vertical transmission rates in the presence of Wolbachia. Nevertheless, the low prevalence of disseminated DENV infection and lower DENV load in the ovaries supports the hypothesis that the presence of Wolbachia in Ae. aegypti would have an effect on the vertical transmission of DENV in the field. PMID- 28623962 TI - Editorial. PMID- 28623963 TI - [The pathologist, urologist's air traffic controller]. PMID- 28623964 TI - Editorial to EEMDS, Krakow, 2015. PMID- 28623965 TI - Preface. PMID- 28623966 TI - Relative amount of telomeric sequences in terminal villi does not differ between normal term placentas and placentas from patients with well-controlled type 1 diabetes mellitus. AB - We applied qPCR to compare relative telomere length in terminal villi microdissected from term control placentas and placentas of patients suffering from type 1 diabetes. Significant differences were not found in the relative T/S ratios between placental groups or between the diabetic placentas affected and those not affected with chorangiosis. We hypothesize that there is no relationship between decreased placental proliferative ability in maternal diabetes type 1 and telomere shortening. PMID- 28623967 TI - When is peripartum hysterectomy an unethical procedure? PMID- 28623968 TI - Oxygen and tissue culture affect placental gene expression. AB - INTRODUCTION: Placental explant culture is an important model for studying placental development and functions. We investigated the differences in placental gene expression in response to tissue culture, atmospheric and physiologic oxygen concentrations. METHODS: Placental explants were collected from normal term (38 39 weeks of gestation) placentae with no previous uterine contractile activity. Placental transcriptomic expressions were evaluated with GeneChip(r) Human Genome U133 Plus 2.0 arrays (Affymetrix). RESULTS: We uncovered sub-sets of genes that regulate response to stress, induction of apoptosis programmed cell death, mis regulation of cell growth, proliferation, cell morphogenesis, tissue viability, and protection from apoptosis in cultured placental explants. We also identified a sub-set of genes with highly unstable pattern of expression after exposure to tissue culture. Tissue culture irrespective of oxygen concentration induced dichotomous increase in significant gene expression and increased enrichment of significant pathways and transcription factor targets (TFTs) including HIF1A. The effect was exacerbated by culture at atmospheric oxygen concentration, where further up-regulation of TFTs including PPARA, CEBPD, HOXA9 and down-regulated TFTs such as JUND/FOS suggest intrinsic heightened key biological and metabolic mechanisms such as glucose use, lipid biosynthesis, protein metabolism; apoptosis, inflammatory responses; and diminished trophoblast proliferation, differentiation, invasion, regeneration, and viability. DISCUSSION: These findings demonstrate that gene expression patterns differ between pre-culture and cultured explants, and the gene expression of explants cultured at atmospheric oxygen concentration favours stressed, pro-inflammatory and increased apoptotic transcriptomic response. PMID- 28623969 TI - Altered gene expression in human placenta after suspected preterm labour. AB - INTRODUCTION: Suspected preterm labour occurs in around 9% of pregnancies. However, almost two-thirds of women admitted for threatened preterm labour ultimately deliver at term and are considered risk-free for fetal development. METHODS: We examined placental and umbilical cord blood samples from preterm or term deliveries after threatened preterm labour as well as term deliveries without threatened preterm labour. We quantitatively analysed the mRNA expression of inflammatory markers (IL6, IFNgamma, and TNFalpha) and modulators of angiogenesis (FGF2, PGF, VEGFA, VEGFB, and VEGFR1). RESULTS: A total of 132 deliveries were analysed. Preterm delivery and term delivery after suspected preterm labour groups showed similar increases in TNFalpha expression compared with the term delivery control group in umbilical cord blood samples. Placental samples from preterm and term deliveries after suspected preterm labour exhibited significantly increased expression of TNFalpha and IL6 and decreased expression of IFNgamma. Suspected preterm labour was also associated with altered expression of angiogenic factors, although not all differences reached statistical significance. DISCUSSION: We found gene expression patterns indicative of inflammation in human placentas after suspected preterm labour regardless of whether the deliveries occurred preterm or at term. Similarly, a trend towards altered expression of angiogeneic factors was not limited to preterm birth. These findings suggest that the biological mechanisms underlying threatened preterm labour affect pregnancies independently of gestational age at birth. PMID- 28623970 TI - Localization of the placental BCRP/ABCG2 transporter to lipid rafts: Role for cholesterol in mediating efflux activity. AB - INTRODUCTION: The breast cancer resistance protein (BCRP/ABCG2) is an efflux transporter in the placental barrier. By transporting chemicals from the fetal to the maternal circulation, BCRP limits fetal exposure to a range of drugs, toxicants, and endobiotics such as bile acids and hormones. The purpose of the present studies was to 1) determine whether BCRP localizes to highly-ordered, cholesterol-rich lipid raft microdomains in placenta microvillous membranes, and 2) determine the impact of cholesterol on BCRP-mediated placental transport in vitro. METHODS: BCRP expression was analyzed in lipid rafts isolated from placentas from healthy, term pregnancies and BeWo trophoblasts by density gradient ultracentrifugation. BeWo cells were also tested for their ability to efflux BCRP substrates after treatment with the cholesterol sequestrant methyl beta-cyclodextrin (MbetaCD, 5 mM, 1 h) or the cholesterol synthesis inhibitor pravastatin (200 MUM, 48 h). RESULTS AND DISCUSSION: BCRP was found to co localize with lipid raft proteins in detergent-resistant, lipid raft-containing fractions from placental microvillous membranes and BeWo cells. Treatment of BeWo cells with MbetaCD redistributed BCRP protein into higher density non-lipid raft fractions. Repletion of the cells with cholesterol restored BCRP localization to lipid raft-containing fractions. Treatment of BeWo cells with MbetaCD or pravastatin increased cellular retention of two BCRP substrates, the fluorescent dye Hoechst 33342 and the mycotoxin zearalenone. Repletion with cholesterol restored BCRP transporter activity. Taken together, these data demonstrate that cholesterol may play a critical role in the post-translational regulation of BCRP in placental lipid rafts. PMID- 28623971 TI - Remodelling of the bovine placenta: Comprehensive morphological and histomorphological characterization at the late embryonic and early accelerated fetal growth stages. AB - INTRODUCTION: Placental function impacts growth and development with lifelong consequences for performance and health. We provide novel insights into placental development in bovine, an important agricultural species and biomedical model. METHODS: Concepti with defined genetics and sex were recovered from nulliparous dams managed under standardized conditions to study placental gross morphological and histomorphological parameters at the late embryo (Day48) and early accelerated fetal growth (Day153) stages. RESULTS: Placentome number increased 3 fold between Day48 and Day153. Placental barrier thickness was thinner, and volume of placental components, and surface areas and densities were higher at Day153 than Day48. We confirmed two placentome types, flat and convex. At Day48, there were more convex than flat placentomes, and convex placentomes had a lower proportion of maternal connective tissue (P < 0.01). However, this was reversed at Day153, where convex placentomes were lower in number and had greater volume of placental components (P < 0.01- P < 0.001) and greater surface area (P < 0.001) than flat placentomes. Importantly, embryo (r = 0.50) and fetal (r = 0.30) weight correlated with total number of convex but not flat placentomes. DISCUSSION: Extensive remodelling of the placenta increases capacity for nutrient exchange to support rapidly increasing embryo-fetal weight from Day48 to Day153. The cellular composition of convex placentomes, and exclusive relationships between convex placentome number and embryo-fetal weight, provide strong evidence for these placentomes as drivers of prenatal growth. The difference in proportion of maternal connective tissue between placentome types at Day48 suggests that this tissue plays a role in determining placentome shape, further highlighting the importance of early placental development. PMID- 28623972 TI - Placentation in the colugos Cynocephalus volans and Galeopterus variegatus (Dermoptera) and the transition from labyrinthine to villous placentation in primates. AB - INTRODUCTION: Phylogenetics and genomics place colugos as the sister group to primates. Therefore their placentation is of interest in an evolutionary perspective. Previous accounts are fragmentary, not readily accessible and sometimes contradictory. METHODS: We have examined archival material covering the early development of fetal membranes and placenta, the fate of the yolk sac and definitive placentation. RESULTS: Initially the trophoblast extended over a rather broad but shallow area, enclosing maternal blood spaces. After expansion of the exocoelom it became covered by somatic mesoderm. The mature chorioallantoic placenta was haemochorial and characterized by a labyrinth with markedly dilated maternal blood spaces. Blood vessels appeared in the splanchnopleure early in development and later extended to the yolk sac, but we found no evidence of a choriovitelline placenta at any stage of gestation. There was, however, an extensive paraplacenta. CONCLUSIONS: A choriovitelline placenta is not formed early in gestation nor is it present at term. Early in development invasive trophoblast spreads laterally to form a trophoblastic plate. We found evidence to support the idea that the colugo placenta is intermediate between the labyrinthine placenta of rodents and the trabecular type of Neotropical primates. PMID- 28623973 TI - Dynamic maternal and fetal Notch activity and expression in placentation. AB - INTRODUCTION: Murine placentation requires trophoblast Notch2, while the Notch ligand, JAGGED1, is reduced in invasive trophoblasts from women with preeclampsia. However, the placental cells with active Notch signaling and expression of other Notch proteins and ligands in placentation have yet to be defined. We sought to identify endothelial cell and trophoblast subtypes with canonical Notch signaling in the decidua and placenta and correlate this to expression of Notch proteins and ligands. METHODS: Notch reporter transgenic mice were used to define canonical Notch activity and immunofluorescence staining performed to characterize expression of Notch1, 2, 3, 4 and ligands, Delta-like 4 (Dll4) and Jagged1 (Jag1) during early placentation and in the mature placenta. RESULTS: Notch signaling is active in maternal and fetal endothelial cells and trophoblasts during early placentation and in the mature placenta. Dll4, Jag1, Notch1, and Notch4 are expressed in maternal vasculature in the decidua. Dll4, Jag1 and Notch1 are expressed in fetal vasculature in the labyrinth. Dll4, Notch2 and Notch4 are co-expressed in the ectoplacental cone. Notch2 and Notch4 are expressed in parietal-trophoblast giant cells and junctional zone trophoblasts with active canonical Notch signaling and in labyrinthine syncytiotrophoblasts and sinusoidal-trophoblast giant cells. DISCUSSION: Canonical Notch activity and distinct expression patterns for Notch proteins and ligands was evident in endothelium and trophoblasts, suggesting Notch1, Notch2, Notch4, Dll4, and Jag1 have distinct and overlapping functions in placentation. Characterization of Notch signaling defects in existing mouse models of preeclampsia may shed light on the role of Notch in developing the preeclampsia phenotype. PMID- 28623974 TI - Increased placental phospholipase A2 gene expression and free F2-isoprostane levels in response to oxidative stress in preeclampsia. AB - Vasoactive eicosanoids such as thromboxane (TX) A2 and F2-isoprostanes (F2-isoPs) were shown to be increased in the preeclamptic placenta. Only one of the 64 possible isomers of F2-isoPs derived from the oxidation of arachidonic acid was investigated in the placenta so far. F2-isoPs are released from membrane phospholipids by phospholipases A2 (PLA2) and were shown to act on the TXA2 receptor (TBXA2R). However, the PLA2 deregulated in preeclampsia (PE) remains to be determined. In this study, we analyzed the concentrations of six isomers of F2 isoPs; 8-iso-PGF2alpha, 8-iso-15(R)-PGF2alpha, 15(R)-PGF2alpha, iPF2alpha-IV, iPF2alpha-VI, 5-iPF2alpha-VI and the concentrations of the stable metabolites of TXA2, TXB2, by high performance liquid chromatography coupled with tandem mass spectrometry in placentas of PE (n = 17) and normotensive (n = 15) pregnancies according to the biopsy site: peri-insertion or periphery. In the same biopsies, relative mRNA expression of PLA2G2A, PLA2G4A, PLA2G5, PLA2G7, the PLA2 receptor (PLA2R1), the TXA2 synthase and TBXAR2 were measured by quantitative RT-PCR. We observed similar concentrations of total F2-isoP isomers between groups whereas higher concentrations (>40%) of free F2-isoP were observed for all isomers (p <= 0.033) in PE than normotensive controls. As expected, we also observed higher placental concentrations of TXB2 in PE (p = 0.005). Interestingly, we concomitantly found higher mRNA expression of secretory PLA2G2A (p = 0.010), PLA2G5 (p = 0.038) and TBXA2R (p = 0.023) in PE than normotensive placentas. In sum, deregulated PLA2 could potentially be implicated in freeing F2-isoP which could participate in local hypertension observed in the PE placenta through the TX pathway. PMID- 28623975 TI - Mitochondrial DNA content and methylation in fetal cord blood of pregnancies with placental insufficiency. AB - INTRODUCTION: Intrauterine growth restriction (IUGR) and preeclampsia (PE) are pregnancy disorders characterized by placental insufficiency with oxygen/nutrient restriction and oxidative stress, all influencing mitochondria functionality and number. Moreover, IUGR and PE fetuses are predisposed to diseases later in life, and this might occur through epigenetic alterations. Here we analyze content and methylation of mitochondrial DNA (mtDNA), for the first time in IUGR and PE singleton fetuses, to identify possible alterations in mtDNA levels and/or epigenetic control of mitochondrial loci relevant to replication (D-loop) and functionality (mt-TF/RNR1: protein synthesis, mt-CO1: respiratory chain complex). METHODS: We studied 35 term and 8 preterm control, 31 IUGR, 17 PE/IUGR and 17 PE human singleton pregnancies with elective cesarean delivery. Fetal cord blood was collected and evaluated for biochemical parameters. Extracted DNA was subjected to Real-time PCR to assess mtDNA content and analyzed for D-loop, mt-TF/RNR1 and mt-CO1 methylation by bisulfite conversion and pyrosequencing. RESULTS: mtDNA levels were increased in all pathologic groups compared to controls. Mitochondrial loci showed very low methylation levels in all samples; D-loop methylation was further decreased in the most severe cases and associated to umbilical vein pO2. mt-CO1 methylation levels inversely correlated to mtDNA content. DISCUSSION: Increased mtDNA levels in IUGR, PE/IUGR and PE cord blood may denote a fetal response to placental insufficiency. Hypomethylation of D loop, mt-TF/RNR1 and mt-CO1 loci confirms their relevance in pregnancy. PMID- 28623976 TI - ADAM28 localizes to HLA-G+ trophoblasts and promotes column cell outgrowth. AB - INTRODUCTION: Trophoblast progenitor cell differentiation towards the extravillous trophoblast (EVT) lineage initiates within proximal regions of anchoring columns of first trimester placental villi. While molecular processes controlling the initial stages of progenitor cell differentiation along the EVT pathway have been described, much remains unknown about factors important in distal column cell differentiation into invasive EVTs. ADAMs are proteases that regulate growth factor signaling, cell-matrix adhesion, and matrix proteolysis, and thus impact many processes relevant in placentation. Global gene expression studies identified the ADAM subtype, ADAM28, to be highly expressed in EVT-like trophoblasts, suggesting that it may play a role in EVT function. This study aims to test the functional importance of ADAM28 in column cell outgrowth and maintenance. METHODS: ADAM28 mRNA levels and protein localization were determined by qPCR and immunofluorescence microscopy analyses in purified placental villi cell populations and tissues. ADAM28 function in trophoblast column outgrowth was examined using ADAM28-targetting siRNAs in Matrigel-imbedded placental explant cultures. RESULTS: Within placental villi, ADAM28 mRNA levels were highest in HLA G+ column trophoblasts, and consistent with this, ADAM28 was preferentially localized to HLA-G+ trophoblasts within distal anchoring columns and decidual tissue. siRNA-directed loss of ADAM28 impaired trophoblast column outgrowth and resulted in increased apoptosis in matrix-invading trophoblasts. DISCUSSION: Our findings suggest that ADAM28 promotes column outgrowth by providing survival cues within anchoring column cells. This study also provides insight into a possible role for ADAM28 in driving differentiation of column trophoblasts into invasive HLA-G+ EVT subsets. PMID- 28623977 TI - Loss of selenocysteine insertion sequence binding protein 2 suppresses the proliferation, migration/invasion and hormone secretion of human trophoblast cells via the PI3K/Akt and ERK signaling pathway. AB - INTRODUCTION: Selenocysteine insertion binding protein 2 (SECISBP2) plays a vital role in selenocysteine incorporation into selenoprotein in many creatures. However, the impact of SECISBP2 in development of trophoblast cells remains unclear. The aim of this study was to investigate the roles of SECISBP2 in human trophoblast cells and the underlying molecular mechanism. METHODS: Low-expression of SECISBP2 in trophoblast cells was achieved by transfection with siRNAs. Then protein levels of selenoproteins and MDA content were performed to evaluate the levels of oxidative stress. CCK-8 assays, transwell chamber assay and wound healing assay were used to assess the trophoblast proliferation, migration/invasion. Production of beta-hCG and progesterone was quantified to estimate the effect of SECISBP2 on hormone secretion. The underlying mechanisms were also examined in two trophoblast cell lines. RESULTS: Knockdown of SECISBP2 clearly reduced the levels of some selenoproteins, including GPx1, SelK, Dio2 (p < 0.05). On the contrary, the levels of oxidative stress presented as MDA content markedly increased in two cell lines (p < 0.05). In addition, proliferative, migratory and invasive abilities of trophoblast cells were significantly suppressed when SECISBP2 was partially deleted (p < 0.05). Furthermore, silencing SECISBP2 reduced the expression of beta-hCG at mRNA and protein levels (p < 0.05), and inhibited the production of progesterone (p < 0.01). The PI3K/Akt and ERK signaling pathway were found to involve in the progress (p < 0.05). DISCUSSION: Our results suggest that the decreased SECISBP2 impaired trophoblast proliferation, migration/invasion and hormone secretion through inactivation of the PI3K/Akt and ERK signaling pathway may provide an insight into the preeclampsia and miscarriage induced by selenium deficiency. PMID- 28623978 TI - Gestational diabetes affects fetal autophagy. AB - Autophagy is a catabolic process involved in the preservation of energy homeostasis and its dysregulation has been implicated in the development of metabolic disorders, including diabetes mellitus. Gestational diabetes mellitus represents a risk for fetal morbidity and mortality. The present study focuses on the autophagy process in human diabetic placenta and fetal pancreas, compared with controls. Analysis of the autophagy markers LC3, Beclin-1 and p62 suggests an impairment of the autophagy process in diabetic placentas. Results indicate an association between gestational diabetes and autophagy, emphasizing the importance of unravelling the mechanisms regulating this relationship. PMID- 28623979 TI - Placental glucose transporter (GLUT)-1 is down-regulated in preeclampsia. AB - INTRODUCTION: Transplacental fetal glucose supply is predominantly regulated by glucose transporter-1 (GLUT1). Altered expression and/or function of GLUT1 may affect the intrauterine environment, which could compromise fetal development and may contribute to fetal programming. To date it is unknown whether placental GLUT1 is affected by preeclampsia, which is often associated with intrauterine growth restriction (IUGR). We addressed the hypothesis that preeclampsia leads to decreased expression and function of placental GLUT1. METHODS: Placentae were obtained following normal pregnancy and from pregnancies affected by preeclampsia. Washed villous tissue fragments were used to prepare syncytial microvillous (MVM) and basal plasma membranes (BM) microvesicles. GLUT1 protein and mRNA expression was assessed by western blot analysis and qPCR using Fast SYBR Green. A radio-labeled glucose up-take assay using placenta-derived syncytial microvesicles was used to analyze GLUT1 function. RESULTS: GLUT1 protein expression was significantly down-regulated in (apical) MVM of the syncytiotrophoblast in preeclampsia (n = 6) compared to controls (n = 6) (0.40 +/ 0.04 versus 1.00 +/- 0.06, arbitrary units, P < 0.001, Student's t-test), while GLUT1 mRNA expression did not show a significant difference. In addition, the functional assay in syncytial microvesicles showed a significantly decreased glucose transport activity in preeclampsia (61.78 +/- 6.48%, P < 0.05) compared to controls. BM GLUT1 protein expression was unchanged and glucose up-take into BM microvesicles showed no differences between the preeclampsia and control groups. DISCUSSION: Our study shows for the first time that in preeclampsia placental GLUT1 expression and function are down-regulated at the apical plasma membrane of the syncytiotrophoblast. Further studies are needed to assess whether these changes occur also in vivo and contribute to the development of IUGR in preeclampsia. PMID- 28623980 TI - Moving toward more appropriate care for women with pelvic, labial, or perineal venous disease. PMID- 28623981 TI - Characteristics of provoked deep venous thrombosis in a tertiary care center. AB - OBJECTIVE: Provoked deep venous thrombosis (DVT) is precipitated by a specific event. This paper compares the characteristics of provoked DVT in patients with transient risk (TR) factors and patients with continuous risk (CR) factors. METHODS: A retrospective review of records of all consecutive patients diagnosed with DVT between January 2013 and August 2014 was performed. Patients with provoked DVT were included in the TR group if the provoking event resolved in 2 weeks and they did not have ongoing risk of thrombosis. Patients in the CR group had a provoked DVT with ongoing risk of thrombosis due to individual factors deemed to be ongoing risks of thrombosis, such as cancer, hypercoagulable disorder, and prolonged immobilization. Demographics, risk factors, association with pulmonary embolism (PE) and its severity, risk of recurrent venous thromboembolism (VTE), and mortality were compared between the two groups. RESULTS: A total of 838 patients were diagnosed with DVT, and 50.7% (425) were provoked. There were 127 (29.9%) patients with TR and 298 (70.1%) with CR. TR patients were younger (60.4 +/- 16.3 vs 65.9 +/- 16.0; P = .001). TR was more likely to be provoked by surgery (70.9% vs 55.4%; P = .003), whereas CR was more likely to be provoked by immobilization (21.5% vs 12.6%; P = .032). CR patients were affected by cancer (48.7%) and hypercoagulable disorders (4.4%). TR patients were more likely to have calf DVTs (36.2% vs 26.2%; P = .047). There was a trend toward lower association with PE on presentation in TR (17.3% vs 21.1%; P = .072), but that did not reach statistical significance. However, TR factors were more likely to be associated with low-risk PE compared with CR factors (30.2% vs 54.6%; P = .040). After mean follow-up of 7.2 months, CR had higher risk of recurrent VTE (14.0% vs 6.8%; P = .045) and mortality (23.5% vs 7.1%; P < .0001). CONCLUSIONS: Provoked DVT with CR factors affects older patients and is associated with high recurrence of VTE and mortality compared with provoked DVT with TR factors. PMID- 28623982 TI - Clinical characteristics and prognostic features of intravenous leiomyomatosis with inferior vena cava or intracardiac extension. AB - OBJECTIVE: The aim of this study was to explore the clinical characteristics and prognostic features of intravenous leiomyomatosis (IVL) with inferior vena cava extension (IVCE) or intracardiac extension (ICE). METHODS: A retrospective analysis was conducted of the clinical data of 38 patients with pathologically diagnosed IVL with IVCE or ICE. RESULTS: The mean age of the patients was 44.05 +/- 6.31 years. Twenty-two patients (57.9%) had a history of uterine leiomyoma. Nine patients (23.7%) had a history of IVL without IVCE or ICE. The most common symptoms were chest tightness (seven patients), lower limb swelling (five patients), palpitation (four patients), dizziness (two patients), and abdominal distention (two patients). Preoperative diagnoses were achieved in 28 patients (73.7%); 23 patients (60.5%) underwent one-stage surgery, whereas 15 (39.5%) underwent two-stage surgery. Eighteen patients (72%) received postoperative antiestrogen hormone therapy. Regular follow-up was available in 30 patients, with a median follow-up time of 12.0 months; 15 patients (50.0%) showed evidence of recurrence. Factors such as postoperative antiestrogen hormone therapy (9/20 compared with 6/10; P = .601), duration of postoperative hormonal therapy (10/15 in >6 months compared with 5/15 in <=6 months; P = .862), and heart involvement (10/22 compared with 5/8; P = .669) were not significantly associated with recurrence. CONCLUSIONS: IVL with IVCE or ICE is a rare disease with nonspecific manifestations. Surgery is the primary treatment. The postoperative recurrence rate is high, and postoperative antiestrogen hormone therapy is not significantly correlated with recurrence. PMID- 28623983 TI - Clinical presentation of women with pelvic source varicose veins in the perineum as a first step in the development of a disease-specific patient assessment tool. AB - OBJECTIVE: Pelvic venous incompetence can cause symptomatic varicose veins in the perineum, buttock, and thigh. Presentation, symptom severity, and response to treatment of pelvic source varicose veins are not well defined. Currently available tools to measure the severity of lower extremity venous disease and its effects on quality of life may be inadequate to assess disease severity in these patients. The purpose of this study was to evaluate the histories, demographics, and clinical presentations of women with pelvic source varicose veins and to compare these data to a population of women with nonpelvic source varicose veins. METHODS: A total of 72 female patients with symptomatic pelvic source varicose veins were prospectively followed up. Age, weight, height, parity, and birth weights of offspring were recorded. Both pelvic source varicose veins and saphenous incompetence were identified by duplex ultrasound. Patients were queried as to their primary symptoms, activities that made their symptoms worse, and time when their symptoms were most prominent. Severity of disease was objectively evaluated using the revised Venous Clinical Severity Score (rVCSS) and 10-point numeric pain rating scale (NPRS). RESULTS: Compared with women without a pelvic source of varicose veins (N = 1163), patients with pelvic source varicose veins were younger (mean, 44.6 +/- 8.6 vs 52.6 +/- 12.9 years; P < .001), had lower body mass index (mean, 21.9 +/- 2.8 vs 25.8 +/- 6.2; P < .001), and had larger babies than the U.S. population mean (mean, 3656 +/- 450 g vs 3389 +/- 466 g; P < .001). The most common symptoms were aching (68%), throbbing (47%), and heaviness (35%). In premenopausal patients, 70% noted that symptoms were worst during menses. NPRS score varied from 0 to 8 (mean, 4.9). The correlation between rVCSS (mean 5.6 +/- 1.9) and NPRS was small (r = 0.26; P = .03). There was a modest correlation between older age and lower NPRS scores (r = -0.39; P < .001). CONCLUSIONS: Women with pelvic source varicose veins are a unique subset of patients. They are younger and thinner than those with nonpelvic source varicose veins, have larger infants than the general U.S. population, and have an inverse correlation between age and pain. As the majority of premenopausal patients have increased symptoms during menses, this may be due to hormonal influence. As it is poorly associated with patient-reported discomfort, the rVCSS is a poor tool for evaluating pelvic source varicose veins. A disease specific tool for the evaluation of pelvic source varicose veins is critically needed, and this study is a first step in that endeavor. PMID- 28623984 TI - Routine extended follow-up surveillance of iliac vein stents for iliocaval venous obstruction may not be warranted. AB - OBJECTIVE: The purpose of this study was to evaluate outcomes of iliac vein stents placed for iliocaval venous obstruction (ICVO) and to determine if routine follow-up surveillance is warranted on the basis of timing of stent failure. METHODS: All patients who underwent iliac vein stenting from 2003 to 2015 were identified from a prospectively maintained registry. Demographics of the patients, venous risk factors, prior venous interventions, indications, imaging, anatomic location of the ICVO, operative findings, procedural success, complications, and clinical follow-up were recorded. Clinical and ultrasound surveillance was performed at first postoperative follow-up and at routine subsequent intervals. Continuous data were analyzed with Student t-tests or Mann Whitney U test, and frequency data were analyzed with chi2 analysis or Fisher exact test. Primary patency was analyzed using Kaplan-Meier survival analysis. RESULTS: Seventy-four limbs in 70 patients who underwent iliac vein stenting for ICVO were identified; 36 limbs (48.6%) were stented for nonthrombotic venous compression (stent-VC), and 38 limbs (51.4%) were stented for venous thrombosis (stent-VT). Twenty-seven limbs (71.1%) of the stent-VT group were treated for acute venous thrombosis requiring lysis followed by stenting for underlying venous lesions. The median number of follow-up visits for the stent-VC and stent VT groups was two (interquartile range [IQR], 1-4) and two (IQR, 1-3), whereas the mean length of follow-up was 19.6 +/- 29.5 months and 19.8 +/- 26.5 months (P = .972), respectively. During the first 6 months, one limb (2.8% [n = 36]) in the stent-VC group occluded, whereas 13.2% (5/38) of the limbs in the stent-VT group occluded. In the stent-VT group, 57% of limbs (4 of 7) with acute venous thrombosis requiring thrombolytic therapy had limb occlusion at >6 months (median, 18.1 months; IQR, 16.6-30.1). Overall patency rates for the stent-VC and stent-VT groups were 97.2% (1/36) and 73.7% (10/38) at 36 months (standard error, <=10%; P = .001), respectively. CONCLUSIONS: Iliac vein stents placed for nonthrombotic iliac vein compression had statistically higher patency than those placed for venous thrombosis, with few stent failures, all occurring within 6 months. Iliac vein stents placed for venous thrombosis continued with stent failure after 6 months and may benefit from extended surveillance. PMID- 28623985 TI - Invited commentary. PMID- 28623986 TI - Double prepuncture as a valuable adjunctive technique for complex endovenous ablation. AB - OBJECTIVE: The objective of this study was to characterize the technique and to report the results of double prepuncture used during complex radiofrequency ablation (RFA) in cases of treating multiple incompetent veins or encountering focal obstruction to catheter advancement. METHODS: A double prepuncture technique was applied in patients requiring endovascular ablation of multiple veins and patients with great saphenous vein cannulation failure. We treated 13 limbs in 12 patients during a 24-month period with RFA in which the double prepuncture technique was used. Clinical history, operative reports, outcomes, and follow-up were reviewed. RESULTS: RFA was performed with the double puncture technique on, collectively, 10 great saphenous veins, 5 small saphenous veins, and 5 anterior accessory saphenous veins. Mean preoperative Clinical, Etiology, Anatomy, and Pathophysiology score was 4.38 +/- 1.6. Three limbs required prepuncture because of difficulty in advancing the catheter cephalad through tortuosity and focal obstruction after failure with techniques such as a guidewire, a guide catheter, and manual compression with ultrasound guidance. Ten limbs received planned double prepuncture for multiple adjacent incompetent veins, for which venipuncture and cannulation of the second target vein would be difficult after tumescent application to the first vein. Postoperative ultrasound demonstrated successful closure of all target veins in which the double prepuncture technique was used. One patient had a deep venous thrombosis (7.7%) that resolved without complications. CONCLUSIONS: Double prepuncture is a useful technical adjunct both for simultaneous endovenous ablation of multiple adjacent incompetent veins and when catheter passage is impeded. This technique aids in efficient and successful application of endovenous ablation to complex venous anatomy. PMID- 28623987 TI - Invited commentary. PMID- 28623988 TI - Rivaroxaban for thrombosis prophylaxis in endovenous laser ablation with and without phlebectomy. AB - OBJECTIVE: Endovenous heat-induced thrombosis (EHIT) is a well-described complication of endovenous laser ablation (EVLA). We report our centers' experience on the efficacy (EHIT level >=2 according to the Kabnick classification) and safety (observed major and minor bleeding events) of rivaroxaban for EHIT prophylaxis in EVLA with and without concomitant phlebectomy. METHODS: Demographic, procedural, and outcome data of all patients with EVLA of the great, accessory, or small saphenous vein and EHIT prophylaxis with 10 mg/d rivaroxaban between 2012 and 2014 were reviewed and analyzed in this investigator-initiated multicenter retrospective observational single-arm study. RESULTS: During a median (interquartile range) follow-up duration of 51 (41-68) days, complete vein occlusion was achieved in 98.4% of 438 EVLA procedures in 306 patients. One patient had an EHIT level 2 (0.2%; 95% confidence interval, 0.006% 1.3%). No major bleedings (0%; 95% confidence interval, 0.0%-0.8%) and six minor bleedings (1.4%; 95% confidence interval, 0.5%-3%) were observed. CONCLUSIONS: Rivaroxaban (10 mg/d) for 5 to 10 days seems to be an efficacious and safe alternative for EHIT prophylaxis in EVLA with or without phlebectomy. PMID- 28623989 TI - Invited commentary. PMID- 28623991 TI - Invited commentary. PMID- 28623990 TI - Incidence of venous leg ulcer healing and recurrence after treatment with endovenous laser ablation. AB - BACKGROUND: The Effect of Surgery and Compression on Healing and Recurrence (ESCHAR) trial previously reported that patients with venous leg ulcers treated with saphenous stripping experienced a significantly reduced incidence of ulcer recurrence compared with patients treated with compression therapy. Most patients with leg ulcers and saphenous insufficiency are currently treated with endovenous thermal ablation (EVTA), but little information is available on the long-term results after EVTA in Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) clinical class 5 (C5) and class 6 (C6) patients. METHODS: We retrospectively reviewed all CEAP C5 or C6 patients treated with EVTA to define the incidence of ulcer healing and recurrence. Patients with active ulcers were managed weekly in a comprehensive wound center until healed. After healing, patients were treated with compression stockings and returned at 6-month intervals for follow-up. Time to healing and time to ulcer recurrence were determined by Kaplan-Meier survival analysis. Risk factors were assessed to determine their association with ulcer recurrence. RESULTS: EVTA of the great saphenous vein (n = 146), small saphenous vein (n = 20), or both (n = 7) was performed on 173 limbs with active (n = 72) or healed (n = 101) ulcers. Deep venous insufficiency was present in 54 cases (31.2%). Concomitant phlebectomy was performed in 59 limbs (34%). Median follow up time was 25.2 months after EVTA. Venous ulcers healed after EVTA in 57% of cases at 3 months, 74% at 6 months, and 78% at 12 months. Ulcers recurred in 9% of patients at 1 year after EVTA, 20% at 2 years, and 29% at 3 years of follow up. Ulcers recurred significantly more often in patients with deep venous insufficiency and in patients who did not undergo phlebectomy of associated varicose veins at the time of EVTA. CONCLUSIONS: Ulcers recurred in a minority of CEAP clinical C5 and C6 patients after EVTA of the saphenous veins. Ulcer recurrence was less frequent in patients without concomitant deep venous reflux and in those treated with phlebectomy of varicose veins at the time of EVTA. We suggest consideration of phlebectomy at the time of EVTA for patients with C5 and C6 venous insufficiency, particularly in those with isolated superficial venous insufficiency. PMID- 28623992 TI - Near-infrared fluorescence lymphatic imaging of Klippel-Trenaunay syndrome. AB - The relationship between lymphatic and venous malformations in Klippel-Trenaunay syndrome is difficult to assess. Herein the authors describe near-infrared fluorescence lymphatic imaging to assess the lymphatics of a subject with a large port-wine stain and right leg edema. Although lymphatic vessels in the medial, affected knee appeared dilated and perhaps tortuous, no definitive abnormal lymphatic pooling or propulsion was observed. The lymphatics in the affected limb were well defined but less numerous than in the contralateral limb, and active, contractile function was observed in all vessels. As demonstrated, near-infrared fluorescence lymphatic imaging enables the clinical assessment of lymphatics in lymphovenous malformations. PMID- 28623993 TI - Management of refractory chylous ascites with peritoneovenous shunts. AB - OBJECTIVE: The purpose of this study was to define outcome of treatments of refractory chylous ascites using peritoneovenous shunts (PVSs). METHODS: Clinical data of patients with refractory chylous ascites treated with PVSs between 1992 and 2015 were retrospectively reviewed. The primary end point was clinical benefit, defined as cured, improved, or poor results; secondary end points were complications and reinterventions. RESULTS: Seventeen patients (eight female [47%]; median age, 47 years [range, 19-78 years]) with refractory chylous ascites were studied. This group represented 6% of 284 patients treated for chylous ascites during the study period. The etiology was primary lymphangiectasia in 10 patients (59%) and secondary chylous ascites due to previous surgery, lymphatic obstruction with associated portal hypertension, or malignant tumor in 7 (41%). Eleven patients were treated with LeVeen shunts and six with Denver shunts. Thirty-day mortality, morbidity, and reintervention rates were 5.9%, 18%, and 12%, respectively. Reintervention rate at 6 months was 9.1% with LeVeen shunt, significantly lower than 100% with Denver shunt (P = .001). During a mean follow up of 5.1 years (range, 17 days-22.7 years), 7 of 11 patients with LeVeen shunt and all 6 patients with Denver shunt required shunt replacement. Median duration of patency was 215 days (range, 2 days-9.0 years) of a total of 25 LeVeen shunts placed in 11 patients and 44 days (range, 6-91 days) of 20 Denver shunts placed in 6 patients. At last follow-up, patency of the LeVeen shunt was 36% (4/11); symptoms improved in 64% of the patients (7/11). Patency rate of Denver shunts was 33% (2/6), and symptoms improved in 33% (2/6). CONCLUSIONS: Treatment of refractory chylous ascites continues to be a major challenge. The only currently available PVS, the Denver shunt, had a median patency period of <2 months; it required frequent replacements and resulted in intermittent short-term clinical benefit in one-third of the patients. Improvements in technology to design new shunts, to develop new therapies, or to adopt new techniques to treat chylous ascites are urgently needed. PMID- 28623994 TI - Placement of tunneled cuffed vascular catheter through superior vena cava puncture. AB - OBJECTIVE: The purpose of this study was to assess the feasibility and safety of placement of tunneled cuffed catheters through direct percutaneous puncture of the superior vena cava (SVC) in patients with occluded right and left innominate veins. METHODS: This was a retrospective review of all patients with right and left innominate vein occlusions who underwent tunneled catheter placement with direct SVC puncture between January 2012 and December 2014. Under fluoroscopic guidance with the patient in a supine position, a 5F catheter was placed at the distal end of the SVC through the femoral vein, iliac vein, or hepatic vein. This catheter was used as a fluoroscopic target for the puncture. Following the guidance of fluoroscopy, the puncture needle and sheath were placed through a transcutaneous route with the insertion site 0.5 to 1.0 cm lateral-inferior to the clavicle head of the sternocleidomastoid, with the pathway inferior (caudal) to the clavicle, which allowed access of the guidewire and placement of a tunneled central venous catheter. RESULTS: The procedure succeeded in all 16 patients. During follow-up (mean, 12 months; range, 3-36 months), access failure due to thrombosis was observed in one patient. The remaining continued to function well until the end of the follow-up period or until the death of the patient (n = 3). No pneumothorax occurred. The most common complication was mediastinal hematoma after puncture failure in five patients. The diameter of the maximum hematoma was 2.2 cm, and all resolved spontaneously. CONCLUSIONS: In patients with central vein occlusion and exhaustion of conventional insertion sites, a tunneled central venous catheter can be safely placed through SVC puncture by the transcutaneous route. PMID- 28623996 TI - Functional polymorphism rs1024611 in the MCP1 gene is associated with the risk of varicose veins of lower extremities. AB - OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) is a chemokine responsible for monocyte, basophil, and T-lymphocyte attraction. Polymorphism rs1024611 located in the regulatory region of the MCP1 gene has previously been shown to be associated with increased MCP-1 production. In our study, we aimed to examine the association of rs1024611 with the risk of primary varicose veins (PVVs) of lower extremities. METHODS: The case group comprised 470 patients with PVVs, and the control group included 269 individuals without a history of chronic venous disease. All cases and controls were ethnic Russians. Genotypes were determined by real-time polymerase chain reaction allelic discrimination. Association was studied by logistic regression analysis. RESULTS: We revealed the association of genotype G/G with the increased risk of PVVs (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.02-3.44; P = .04). In the subgroup analysis, association was revealed only in patients with C2 Clinical, Etiology, Anatomy, and Pathophysiology class (allele G: OR, 1.62 [95% CI, 1.13-2.33; P = .008]; genotype G/G: OR, 3.22 [95% CI, 1.43-7.27; P = .005]), in patients with age at onset of PVVs before 30 years (allele G: OR, 1.41 [95% CI, 1.08-1.85; P = .01]; genotype G/G: OR, 2.35 [95% CI, 1.22-4.55; P = .01]), and in patients who declared no family history (allele G: OR, 1.46 [95% CI, 1.02-2.09; P = .04]; genotype G/G: OR, 2.50 [95% CI, 1.11-5.63; P = .03]). CONCLUSIONS: Our results provide evidence for MCP-1 involvement in the development of PVVs and indicate that inflammation could be implicated in the pathogenesis of this condition. PMID- 28623997 TI - A rare case of idiopathic bilateral ovarian vein thrombosis. AB - Ovarian vein thrombosis (OVT) is a rare medical disorder most often diagnosed in the peripartum period and maybe associated with other risk factors for thrombosis. Rarely, OVT is considered idiopathic. It occurs in the right ovarian vein alone in two-thirds of patients. In this report, we present a case of idiopathic and bilateral OVT in a 35-year-old woman who presented with 2-day history of left flank pain. Duplex ultrasound imaging and computed tomography confirmed the diagnosis. Oral anticoagulation achieved a favorable outcome. PMID- 28623995 TI - Rationale, design, and methodology of the observational INSIGHTS-SVT study on the current state of care and outcomes of patients with superficial vein thrombosis. AB - OBJECTIVE: Superficial vein thrombosis (SVT) is a common disease in clinical practice. In terms of pathophysiology and outcomes, the condition is related to venous thromboembolism, bearing a potential for severe thromboembolic complications if it is not treated adequately. A wide range of treatment approaches (including oral and injectable anticoagulants, pain medication, nondrug therapy including compression therapy, and no treatment at all) are applied in clinical practice, but there is sparse information about selection of patients for therapies, current treatment pathways, and drug use as well as outcomes. The INvestigating SIGnificant Health TrendS in the management of Superficial Vein Thrombosis (INSIGHTS-SVT) study aims to close this gap by collecting representative data on the current treatment of SVT. METHODS: The observational prospective study of about 1200 patients is carried out by up to 120 clinical and office-based physicians who regularly treat patients with SVT and are capable of conducting appropriate compression ultrasound diagnostics, such as vascular physicians, phlebologists, internists, vascular surgeons, and general practitioners. Patients are eligible for inclusion if they have ultrasound-confirmed acute, isolated SVT of the lower extremities. Documentation about the characteristics of the patients, diagnostics, comorbidities, and medical and nonmedical treatment is collected at baseline, at 10 +/- 3 days or at approximately 45 days (depending on treatment), at approximately 3 months, and at approximately 12 months. Patients are requested to fill in quality of life questionnaires (on pain, Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms [VEINES-QOL/Sym], EuroQol-5 Dimension 5-Level [EQ-5D 5L]) at baseline and at approximately 3 months. Interventions are not stipulated by the trial protocol. RESULTS: The primary efficacy outcome is the incidence of venous thromboembolism at 3 months; the primary safety outcome is the combined incidence of major and clinically relevant bleeding events at 3 months. As quality measures, plausibility checks at data entry, queries based on statistical analyses that focus on outliers and distribution of values, monitoring visits, and adjudication procedures will be applied. CONCLUSIONS: This large study is expected to provide a comprehensive picture of patients with SVT under clinical practice conditions in Germany. PMID- 28623998 TI - Ruptured common femoral vein pseudoaneurysm from a common femoral arteriovenous fistula presenting as lower extremity steal after radiofrequency ablation of the great saphenous vein. AB - Radiofrequency ablation of the superficial venous systems has become one of the mainstays of minimally invasive approaches to varicose veins and chronic venous insufficiency. These procedures have high rates of success with scarce complications. This case report highlights a patient with a common femoral arteriovenous fistula presenting with lower extremity steal after radiofrequency ablation treatment of the great saphenous vein. During operative repair of the arteriovenous fistula, a pseudoaneurysm of the common femoral vein ruptured. We review the current literature and highlight the importance of expanding the scope of complications that can occur from seemingly straightforward minimally invasive venous procedures. Informed consent was obtained for publication of this report. PMID- 28623999 TI - Dilation of inferior vena cava and iliac veins in elite athlete. PMID- 28624001 TI - Diagnosis and management of the venous malformations of Klippel-Trenaunay syndrome. AB - OBJECTIVE: A dearth of information exists in the literature regarding current practice in the management of Klippel-Trenaunay syndrome (KTS), a rare condition. We review and describe the etiology, diagnosis, and treatment of KTS. METHODS: Relevant data were synthesized from a Medline review using a combination of the keyterms "Klippel" and "Trenaunay." The majority of hits described singular case reports and were subsequently excluded. The remaining papers were then reviewed and included on the basis of the quality of evidence and the authors' discretion. CONCLUSIONS: KTS is characterized by a clinical triad of extremity varicosities, cutaneous vascular malformations, and hypertrophy of soft tissues and long bones. The diagnosis is clinically supplemented with magnetic resonance imaging and computed tomography. Although this syndrome is associated with significant comorbidities, such as pain, edema, ulcerations, and pruritus, it is rarely the cause of death. The backbone of treatment is nonoperative in nature but should be supplemented with minimally invasive, endovascular, and rarely open surgical procedures for refractory cases. PMID- 28624000 TI - Aneurysms of the azygos vein. AB - OBJECTIVE: Azygos vein aneurysms (AVAs) are uncommon and infrequently diagnosed. When confronted with a patient presenting with an AVA, physicians can rely on only a few case reports after an extensive literature search. To date, no guideline, no rule, and no review on the optimal treatment strategy for these patients exist. METHODS: A PubMed and MEDLINE database search for papers and case reports describing AVA was performed. Cases from our own institutions were also reviewed. RESULTS: The literature search identified 57 published case reports that were reviewed for inclusion. Of those published cases, etiologic factors can be classified into idiopathic, acquired, and traumatic causes. Most AVAs are limited to the azygos arch, a congenital anatomic weak point. Clinical symptoms generally remain nonspecific. Computed or magnetic resonance tomography scans are effective diagnostic tools, although the optimal therapeutic plan remains unclear. Complications include rupture, thromboembolism, mediastinal mass effects, and pulmonary artery hypertension. CONCLUSIONS: Conservative treatment along with oral anticoagulation may be reasonable for some AVAs, but to date, there is no clear guideline or evidence-based threshold for surgical or interventional therapy. In review of the existing data and from our clinical and scientific knowledge, interventional or surgical treatment should strongly be considered in cases with clinical symptoms, pulmonary embolism or pulmonary arterial hypertension, thrombus formation within the AVA in patients with oral anticoagulation or for patients with a contraindication to oral anticoagulants, considerable increase in diameter or compression of adjacent structures, saccular AVA, or an underlying connective tissue disease. The most common procedure is surgical ligation of the AVA, although endovascular occlusion of the aneurysms is becoming more frequent. PMID- 28624002 TI - Pathophysiology of venous ulceration. AB - Our understanding of the pathophysiologic process of venous ulceration has dramatically increased during the past two decades because of dedicated, venous specific basic science research. Currently, the mechanisms regulating venous ulceration are a combination of macroscopic and microscopic pathologic processes. Macroscopic alterations refer to pathologic processes related to varicose vein formation, vein wall architecture, and cellular abnormalities that impair venous function. These processes are primarily caused by genetic factors that lead to the destruction of normal vein wall architecture and venous hypertension. Venous hypertension causes a chronic inflammatory response that over time can cause venous ulceration. The inciting inflammatory injury is chronic extravasation of macromolecules and red blood cell degradation products and iron overload. Chronic inflammation causes white blood cell extravasation into the dermis with secretion of numerous proinflammatory cytokines. These cytokines transform the phenotype of fibroblasts to a contractile phenotype that increases tension in the dermis. In addition, iron overload keeps macrophages in an M1 phenotype, which leads to tissue destruction instead of dermal repair. Current surgical and medical therapies are primarily directed at eliminating venous hypertension and promoting venous ulcer wound healing. Despite advances in our understanding of venous ulcer formation and healing, ulcers still take an average of 6 months to heal, and ulcer recurrence rates at 5 years are >58%. To improve the care of patients with venous ulcers, we need to further our understanding of the underlying pathologic events that lead to ulcer formation, prevent healing, and decrease ulcer-free recurrence intervals. PMID- 28624003 TI - There is still time to avoid the 4% CMS payment penalty. PMID- 28624004 TI - Correction. PMID- 28624005 TI - Differentiation between cholangiocarcinoma and hepatocellular carcinoma with target sign on diffusion-weighted imaging and hepatobiliary phase gadoxetic acid enhanced MR imaging: Classification tree analysis applying capsule and septum. AB - OBJECTIVES: To assess the usefulness of classification tree analysis (CTA) for discrimination of hepatocellular carcinoma (HCC) with target sign on hepatobiliary phase (HBP) and/or diffusion-weighted image (DWI) from intrahepatic cholangiocarcinoma (ICC). METHODS: This retrospective study was approved by the institutional review board. From among the 811 patients with histopathologically proven 79 ICCs and 732 HCCs, 69 patients with 69 (87.3%) ICCs and 115 patients with 115 HCCs (15.7%) including 25 scirrhous HCCs and 10 HCCs with central scar that showed the target sign either on HBP or on DWI were included. Two radiologists evaluated the presence of capsule, septum, and arterial enhancement pattern on MR imaging. Capsule, septum, arterial enhancement pattern, and target sign on HBP or DWI were used to classify the tumors using CTA. RESULTS: On CTA, capsule was the initial predictor for assessing the probability of tumors being HCC. The CTA model demonstrated a sensitivity of 86.1%, specificity of 76.8%, and accuracy of 82.6% for discriminating between ICCs and HCCs. In 115 HCCs, only 16 (13.9%) tumors were misclassified as high probability of ICC, and 64.0% (16/25) scirrhous HCCs and 90.0% (9/10) HCCs with central scar were correctly classified as high probability of HCC. CONCLUSIONS: Target sign either on HBP or on DWI was shown in 87.3% (69/79) of ICCs and 15.7% (115/732) of HCCs. The CTA applying capsule and septum may be useful for guiding correct diagnosis of atypical HCCs with the target sign from ICCs. PMID- 28624006 TI - Multi-parametric (mp) MRI for the diagnosis of abdominal wall desmoid tumors. AB - INTRODUCTION: Desmoid tumors are benign myofibroblastic neoplasms, originating from the muscle aponeurosis and classified as deep fibromatoses. The aim of this study was to evaluate the utility of multi-parametric (mp)-MRI for the diagnosis of abdominal wall desmoid tumor (awdt). MATERIAL AND METHODS: This Institutional review board approved retrospective study compared 10 patients (mean age+/-SD; 38.2+/-13years; 9 females and 1 male) with awdt to 14 subjects (mean age+/-SD; 45.6+/-14.7years; 9 females and 5 males) with non-desmoid abdominal wall tumors (ndawt). All included subjects underwent mp-MRI, which included conventional, diffusion weighted and dynamic contrast-enhanced (DCE) MRI. Two blinded experienced fellowship trained radiologists (MK and SR) evaluated each lesion characteristics qualitatively and quantitatively which included margin, homogeneity, T2W/T1W signal intensity (SI), T2 dark strands, and fascial tail together with measurements of apparent diffusion coefficient (ADC) and semi quantitative DCE analysis. Inter-observer agreement was assessed using Cohen's kappa and data were compared between groups using independent sample t-tests and Chi-square tests. RESULTS: No significant differences in age or gender appeared between groups. On qualitative analysis, T2 dark strands were identified in 90% by both radiologist (K=0.82) of awdt, while fascial tail was identified in 70% by radiologist 1 and 80% by second radiologist (k=0.91) of awdt; however no other lesions showed these findings. Other subjective imaging findings did not significantly differ between groups with moderate-to-strong agreements (k=0.7 1.0). On quantitative measurements, diffusion imaging awdt lesions showed higher mean ADC value compared to other lesions, although it did not reached at the level of significance. While on DCE MRI, all awdt lesions showed type 1 (progressive) DCE curve, however no significant difference was observed between groups. CONCLUSIONS: T2 dark strands and fascial tail are characteristic features of awdt, whereas other subjective/qualitative findings are not useful. Quantitative findings such as ADC measurements and DCE curve analysis may have additional value to differentiate awdt from ndawt, but will require further analysis. PMID- 28624007 TI - Cardiac MRI left ventricular global function index and quantitative late gadolinium enhancement in unrecognized myocardial infarction. AB - PURPOSE: To compare left ventricular global function index (LVGFI) and quantitative late gadolinium enhancement (LGE) in patients with unrecognized myocardial infarction (UMI), recognized myocardial infarction (RMI) and without myocardial infarction (MI). MATERIAL AND METHODS: Under waiver of the Institutional Review Board 235 patients (age 63.5+/-10.5years, 57 female) were retrospectively evaluated. All patients had undergone cardiac MRI at 1.5T for symptoms of CAD. 67 patients (29%) had suffered a known RMI before. Functional imaging and full-intensity late gadolinium enhancement (LGE) imaging were evaluated for LVGFI and quantitative LGE mass. RESULTS: Of 168 patients without history of RMI, 48 patients (29%) had UMI, 120 patients had no MI. LVGFI was lower in RMI patients (34+/-8% [range 16;52]), and UMI patients (35+/-8% [range 10;51]), compared to patients with no MI (38+/-7% [range 16;55]) respectively and similar between RMI and UMI patients. RMI patients had full-intensity LGE in 11+/ 6% of left ventricular myocardial mass (LVMM). UMI patients had LGE in 9+/-5% of LVMM. RMI patients had significantly more LGE than UMI patients (p=0.0096). CONCLUSION: LGE quantification is effective to assess infarction scar size in RMI and UMI patients. LVGFI provides information on cardiac function and morphology but does not allow for a reliable differentiation between patients with and without history of MI, due small differences and wide overlap of LVGFI values for all three patient groups. This may be a reason why LVGFI is not applied in clinical routine. PMID- 28624008 TI - A systematic review of yttrium-90 radioembolization for unresectable liver metastases of melanoma. AB - PURPOSE: To assess the effectiveness of yttrium-90 (90Y) radioembolization in the treatment of unresectable liver metastases of melanoma. METHODS: PubMed and EMBASE were systemically searched for all English language studies related to 90Y radioembolization for unresectable liver metastases of melanoma, including clinical trials, observational studies, and abstracts from conferences, published between January 1991 and March 2016. RESULTS: A total of 12 reports (7 observational studies and 5 abstracts from conferences) involving 255 patients were included in the analysis. The primary sites of melanoma were cutaneous (n=22; 8.6%), ocular (n=197; 77.3%), rectal (n=3; 1.2%), and unknown (n=33; 12.9%). The median disease control rate at 3 months was 73.6% (range, 58.3% 88.9%). Among the 207 patients for whom tumor response at 3 months was reported, complete response was seen in 1.0% (2/207), partial response was seen in 19.3% (40/207), stable disease was seen in 46.9% (97/207), and progressive disease was seen in 32.9% (68/207). The median survival was 10 months (range, 7-13.4 months), and the median 1-year survival rate was 34.6% (range, 23%-80%). Complications of 90Y radioembolization were reported in 13 cases. The most common side effects were fatigue (median, 36.1%), abdominal pain (median, 17.8%), and nausea (median, 15.0%). CONCLUSIONS: 90Y radioembolization is a promising alternative therapy for the treatment of unresectable liver metastases of melanoma, with encouraging effects on disease control and survival. Some complications can occur, and side effects are frequent but mild. PMID- 28624009 TI - Measuring hepatic functional reserve using T1 mapping of Gd-EOB-DTPA enhanced 3T MR imaging: A preliminary study comparing with 99mTc GSA scintigraphy and signal intensity based parameters. AB - PURPOSE: To determine the utility of liver T1-mapping on gadolinium-ethoxybenzyl diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance (MR) imaging for the measurement of liver functional reserve compared with the signal intensity (SI) based parameters, technetium-99m-galactosyl serum albumin (99mTc-GSA) scintigraphy and indocyanine green (ICG) clearance. MATERIALS AND METHODS: This retrospective study included 111 patients (Child-Pugh-A 90; -B 21) performed with both Gd-EOB-DTPA enhanced liver MR imaging and 99mTc-GSA (76 patients with ICG). Receiver operating characteristic (ROC) curve analysis was performed to compare diagnostic performances of T1-relaxation-time parameters [pre-(T1pre) and post-contrast (T1hb) Gd-EOB-DTPA], SI based parameters [relative enhancement (RE), liver-to-muscle-ratio (LMR), liver-to-spleen-ratio (LSR)] and 99mTc-GSA scintigraphy blood clearance index (HH15)] for Child-Pugh classification. Pearson's correlation was used for comparisons among T1 relaxation-time parameters, SI-based parameters, HH15 and ICG. RESULTS: A significant difference was obtained for Child-Pugh classification with T1hb, DeltaT1, all SI based parameters and HH15. T1hb had the highest AUC followed by RE, LMR, LSR, DeltaT1, HH15 and T1pre. The correlation coefficients with HH15 were T1pre 0.22, T1hb 0.53, DeltaT1 -0.38 of T1 relaxation parameters; RE -0.44, LMR -0.45, LSR -0.43 of SI-based parameters. T1hb was highest for correlation with HH15. The correlation coefficients with ICG were T1pre 0.29, T1hb 0.64, DeltaT1 -0.42 of T1 relaxation parameters; RE -0.50, LMR -0.61, LSR -0.58 of SI based parameters; 0.64 of HH15. Both T1hb and HH15 were highest for correlation with ICG. CONCLUSION: T1 relaxation time at post-contrast of Gd-EOB-DTPA (T1hb) was strongly correlated with ICG clearance and moderately correlated HH15 with 99mTc-GSA. T1hb has the potential to provide robust parameter of liver functional reserve. PMID- 28624010 TI - Lupus mastitis as a first manifestation of systemic disease: About two cases with a review of the literature. AB - Lupus mastitis is an uncommon manifestation of systemic lupus erythematosus (SLE) that affects the subcutaneous fat in the breast, much like lupus panniculitis, but additionally involves the mammary gland. We report on two women for whom lupus mastitis was the initial manifestation of SLE and provide a literature review of 34 additional cases reported in the Anglo-Saxon and French literature since 1971, making this the largest review to date. Lupus mastitis (LM) can manifest clinically as subcutaneous masses that may be painful, or may present cutaneous involvement such as thickening and discolouration. The radiologic manifestations of LM are broad and include calcifications, masses and asymmetries. Most often, excluding malignancy requires percutaneous biopsy, with histologic findings that are virtually pathognomonic for SLE. Thus, surgery is avoided and medical management can begin, antimalarial drugs and corticosteroids in most cases. PMID- 28624011 TI - Peroneal tendon pathology: Pre- and post-operative high resolution US and MR imaging. AB - Peroneal tendon pathology is an important cause of lateral ankle pain and instability. Typical peroneal tendon disorders include tendinitis, tenosynovitis, partial and full thickness tendon tears, peroneal retinacular injuries, and tendon subluxations and dislocations. Surgery is usually indicated when conservative treatment fails. Familiarity with the peroneal tendon surgeries and expected postoperative imaging findings is essential for accurate assessment and to avoid diagnostic pitfalls. Cross-sectional imaging, especially ultrasound and MRI provide accurate pre-operative and post-operative evaluation of the peroneal tendon pathology. In this review article, the normal anatomy, clinical presentation, imaging features, pitfalls and commonly performed surgical treatments for peroneal tendon abnormalities will be reviewed. The role of dynamic ultrasound and kinematic MRI for the evaluation of peroneal tendons will be discussed. Normal and abnormal postsurgical imaging appearances will be illustrated. PMID- 28624012 TI - Differentiation of small intrahepatic mass-forming cholangiocarcinoma from small liver abscess by dual source dual-energy CT quantitative parameters. AB - PURPOSE: To investigate the use of dual source dual-energy CT (DECT) quantitative parameters compared with the use of conventional CT for differentiating small (<=3cm) intrahepatic mass-forming cholangiocarcinoma (IMCC) from small liver abscess (LA) during the portal venous phase (PVP). MATERIAL AND METHODS: In this institutional review board-approved, retrospective study, 64 patients with IMCCs and 52 patients with LAs who were imaged in PVP using dual-energy mode were included retrospectively. A radiologist drew circular regions of interest in the lesion on the virtual monochromatic images (VMI), color-coded iodine overlay images, and linear blending images with a linear blending ratio of 0.3 to obtain CT value, its standard deviation, slope (k) of spectral curve and normalized iodine concentration (NIC). Two radiologists assessed lesion type on the basis of qualitative CT imaging features. RESULTS: CT values on VMI at 50-130keV (20keV interval), k, and NIC values were significantly higher in IMCCs than in LAs (p<0.0001). The best single parameter for differentiating IMCC from LA was CT value at 90keV, with sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 89.1%, 86.5%, 87.9%, 89.1%, and 86.5%, respectively. The best combination of parameters was CT value at 90keV, k, and NIC, with values of 87.5%, 84.6%, 83.6%, 87.5%, and 84.6%, respectively. Compared with CT value at linear blending images, CT value at 90keV showed greater sensitivity (89.1% vs 60.9%, p<0.0001) and similar specificity (86.5% vs 84.6%, p=1.0000), and combined CT value at 90keV, k, and NIC showed greater sensitivity (87.5% vs 60.9%, p<0.0001) and similar specificity (84.6% vs 84.6%, p=1.0000). Compared with qualitative analysis, CT value at 90keV showed greater sensitivity (89.1% vs 65.6%, p=0.0059) and specificity (86.5% vs 69.2%, p=0.0352), and combined CT value at 90keV, k, and NIC showed greater sensitivity (87.5% vs 65.6%, p=0.0094) and similar specificity (84.6% vs 69.2%, p >0.05). CONCLUSION: Quantitative analysis of dual source dual-energy CT quantitative parameters showed greater accuracy than quantitative and qualitative analyses of conventional CT for differentiating small IMCCs from small LAs on single PVP scan. PMID- 28624013 TI - Femoral torsion assessment with MRI in children: Should we use the bony or cartilaginous contours? AB - OBJECTIVE: To assess whether the use of cartilaginous contours at the femoral condyles instead of bony contours significantly changes femoral torsion measurements in children. MATERIALS AND METHODS: Femoral torsion was measured in 32 girls (mean age 10.1 years+/-2.3 standard deviation) and 42 boys (10.9 years+/ 2.5) on axial magnetic resonance (MR) images by two independent readers (R1,R2). The femoral condyle angle was measured using each the cartilaginous and bony contours of the distal femur. Cartilage thickness at femoral condyles was assessed. Intraclass-correlation-coefficient (ICC) and Pearson's correlation were used for statistical analysis. RESULTS: Mean difference between cartilaginous and bony femoral torsion in girls was -1.1 degrees +/-1.75 (range, -5.4 degrees to 3.1 degrees ) for R1 and -1.64 degrees +/-1.67 (-6.3 degrees to 2.1 degrees ) for R2, in boys -1.5 degrees +/-1.87 (-8.4 degrees to 1.1 degrees ) for R1 and 2.28 degrees +/-1.48 (-4.3 degrees to 9.7 degrees ) for R2. Weak-to-moderate correlations between difference of cartilaginous-versus-bony measurements and cartilage thickness (r=-0.15 to -0.55, P<0.001-0.46) or age (r=-0.33 to 0.46, P<0.001-0.006) were found for both genders. Intermethod-ICC for cartilaginous versus bony femoral torsion measurements was 0.99/0.99 for R1/R2 in girls, and 0.99/0.98 in boys. CONCLUSION: There is only a small difference when measuring femoral torsion through cartilaginous versus bony contours, and no major difference in this between boys and girls. PMID- 28624014 TI - Can routine chest radiography be used to diagnose mild COPD? A nested case control study. AB - OBJECTIVES: To determine whether mild stage chronic obstructive pulmonary disease (COPD) can be detected on chest radiography without substantial overdiagnosis. METHODS: A retrospective nested case-control study (case:control, 1:1) was performed in 783 patients scheduled for cardiothoracic surgery who underwent both spirometry and a chest radiograph preoperative. Diagnostic accuracy of chest radiography for diagnosing mild COPD was investigated using objective measurements and overall appearance specific for COPD on chest radiography. Inter observer variability was investigated and variables with a kappa >0.40 as well as baseline characteristics were used to make a diagnostic model which was aimed at achieving a high positive predictive value (PPV). RESULTS: Twenty percent (155/783) had COPD. The PPV of overall appearance specific for COPD alone was low (37-55%). Factors in the diagnostic model were age, type of surgery, gender, distance of the right diaphragm apex to the first rib, retrosternal space, sternodiaphragmatic angle, maximum height right diaphragm (lateral view) and subjective impression of COPD (using both views). The model resulted in a PPV of 100%, negative predictive value (NPV) of 82%, sensitivity of 10% and specificity of 100% with an area under the curve of 0.811. CONCLUSIONS: Detection of mild COPD without substantial overdiagnosis was not feasible on chest radiographs in our cohort. PMID- 28624015 TI - Imaging modalities in the diagnosis of pancreatic adenocarcinoma: A systematic review and meta-analysis of sensitivity, specificity and diagnostic accuracy. AB - BACKGROUND: Pancreatic cancer, primarily pancreatic ductal adenocarcinoma (PDAC), accounts for 2.4% of cancer diagnoses and 5.8% of cancer death annually. Early diagnoses can improve 5-year survival in PDAC. The aim of this systematic review was to determine the sensitivity, specificity and diagnostic accuracy values for MRI, CT, PET&PET/CT, EUS and transabdominal ultrasound (TAUS) in the diagnosis of PDAC. METHODS: A systematic review was undertaken to identify studies reporting sensitivity, specificity and/or diagnostic accuracy for the diagnosis of PDAC with MRI, CT, PET, EUS or TAUS. Proportional meta-analysis was performed for each modality. RESULTS: A total of 5399 patients, 3567 with PDAC, from 52 studies were included. The sensitivity, specificity and diagnostic accuracy were 93% (95% CI=88-96), 89% (95% CI=82-94) and 90% (95% CI=86-94) for MRI; 90% (95% CI=87-93), 87% (95% CI=79-93) and 89% (95% CI=85-93) for CT; 89% (95% CI=85-93), 70% (95% CI=54-84) and 84% (95% CI=79-89) for PET; 91% (95% CI=87-94), 86% (95% CI=81-91) and 89% (95% CI=87-92) for EUS; and 88% (95% CI=86-90), 94% (95% CI=87-98) and 91% (95% C=87-93) for TAUS. CONCLUSION: This review concludes all modalities, except for PET, are equivalent within 95% confidence intervals for the diagnosis of PDAC. PMID- 28624016 TI - Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes. AB - OBJECTIVE: Patellofemoral cartilage changes have been evaluated in knee trauma and osteoarthritis; however, little is known about changes in patellar and trochlear cartilage thickness, T2 relaxation-time and subchondral bone plate area (tAB) during growth. Our prospective study aimed to explore longitudinal change in patellofemoral cartilage thickness, T2 and tAB in adolescent athletes, and to compare these data with those of mature (i.e., adult) athletes. MATERIALS AND METHODS: 20 adolescent (age 16+/-1years) and 20 mature (46+/-5years) volleyball players were studied over 2-years (10 men and 10 women each group). 1.5T MRI 3D VIBE and multi-echo spin-echo sequences were acquired at baseline and 2-year follow-up. Using manual segmentation and 3D reconstruction, longitudinal changes in patellar and trochlear cartilage thickness, patellar cartilage T2 (mono exponential decay curve with five echoes [9.7-67.9ms]), and patellar and trochlear tAB were determined. RESULTS: The annual increase in both patellar and trochlear cartilage thickness was 0.8% (95% confidence interval [CI] 0.6, 1.0) and 0.6% (0.3, 0.9), for adolescent males and females respectively; the longitudinal gain in patellar and trochlear tAB was 1.3% (1.1, 1.5) and 0.5% (0.2, 0.8), and 1.6% (1.1, 2.2) and 0.8% (0.3, 0.7) for adolescent males and females, respectively (no significant between-sex differences). Mature athletes showed smaller gains in tAB, and loss of <1% of cartilage thickness annually. While no significant sex-differences existed in adolescent patellar T2 changes, mature males gained significantly greater T2 than mature females (p=0.002-0.013). CONCLUSIONS: Patellar and trochlear cartilage thickness and tAB were observed to increase in young athletes in late adolescence, without significant differences between sexes. Mature athletes displayed patellar cartilage loss (and T2 increases in mature males), potentially reflecting degenerative changes. PMID- 28624017 TI - Association of pharmacokinetic and metabolic parameters derived using simultaneous PET/MRI: Initial findings and impact on response evaluation in breast cancer. AB - PURPOSE: To study relationships among pharmacokinetic and 18F-fluorodeoxyglucose (18F-FDG) PET parameters obtained through simultaneous PET/MRI in breast cancer patients and evaluate their combined potential for response evaluation. METHODS: The study included 41 breast cancer patients for correlation study and 9 patients (pre and post therapy) for response evaluation. All patients underwent simultaneous PET/MRI with dedicated breast imaging. Pharmacokinetic parameters and PET parameters for tumor were derived using an in- house developed and vendor provided softwares respectively. Relationships between SUV and pharmacokinetic parameters and clinical as well as histopathologic parameters were evaluated using Spearman correlation analysis. Response to chemotherapy was derived as percentage reduction in size and in parameters post therapy. RESULTS: Significant correlations were observed between SUVmean, max, peak, TLG with Ktrans (rho=0.446, 0.417, 0.491, 0.430; p<=0.01); with Kep(rho=0.303, rho=0.315, rho=0.319; p<=0.05); and with iAUC(rho=0.401, rho=0.410, rho=0.379; p<=0.05, p<=0.01). The ratio of ve/iAUC showed significant negative correlation to SUVmean, max, peak and TLG (rho=0.420, 0.446, 0.443, 0.426; p<=0.01). Ability of SUV as well as pharmacokinetic parameters to predict response to therapy matched the RECIST criteria in 9 out of 11 lesions in 9 patients. Maximum post therapy quantitative reduction was observed in SUVpeak, TLG and Ktrans. CONCLUSION: Simultaneous PET/MRI enables illustration of close interactions between glucose metabolism and pharmacokinetic parameters in breast cancer patients and potential of their simultaneity in response assessment to therapy. PMID- 28624018 TI - Difference in the craniocaudal gradient of the maximum pixel value change rate between chronic obstructive pulmonary disease patients and normal subjects using sub-mGy dynamic chest radiography with a flat panel detector system. AB - OBJECTIVES: To compare the craniocaudal gradients of the maximum pixel value change rate (MPCR) during tidal breathing between chronic obstructive pulmonary disease (COPD) patients and normal subjects using dynamic chest radiography. MATERIALS AND METHODS: This prospective study was approved by the institutional review board and all participants provided written informed consent. Forty-three COPD patients (mean age, 71.6+/-8.7 years) and 47 normal subjects (non-smoker healthy volunteers) (mean age, 54.8+/-9.8 years) underwent sequential chest radiographs during tidal breathing in a standing position using dynamic chest radiography with a flat panel detector system. We evaluated the craniocaudal gradient of MPCR. The results were analyzed using an unpaired t-test and the Tukey-Kramer method. RESULTS: The craniocaudal gradients of MPCR in COPD patients were significantly lower than those in normal subjects (right inspiratory phase, 75.5+/-48.1 vs. 108.9+/-42.0s-1cm-1, P<0.001; right expiratory phase, 66.4+/-40.6 vs. 89.8+/-31.6s-1cm-1, P=0.003; left inspiratory phase, 75.5+/-48.2 vs. 108.2+/ 47.2s-1cm-1, P=0.002; left expiratory phase, 60.9+/-38.2 vs. 84.3+/-29.5s-1cm-1, P=0.002). No significant differences in height, weight, or BMI were observed between COPD and normal groups. In the sub-analysis, the gradients in severe COPD patients (global initiative for chronic obstructive lung disease [GOLD] 3 or 4, n=26) were significantly lower than those in mild COPD patients (GOLD 1 or 2, n=17) for both right and left inspiratory/expiratory phases (all P<=0.005). CONCLUSIONS: A decrease of the craniocaudal gradient of MPCR was observed in COPD patients. The craniocaudal gradient was lower in severe COPD patients than in mild COPD patients. PMID- 28624019 TI - Scapholunate dissociation; diagnostics made easy. AB - Scapholunate dissociation (SLD) is a form of carpal instability, caused by rupture of the scapholunate ligament (SLL) the secondary stabiliser of the scapholunate (SL) compartment. SLD can cause osteoarthritis of the wrist. Recently a study was published that shows cineradiography to be an excellent radiological imaging technique for diagnosing SLD at a tertiary centre for hand and wrist surgery [1]. As the quality of these results can be influenced by the expertise of the operator and observer of the cineradiographic studies, the aim of this study was to determine if these results were reproducible at a secondary centre for hand and wrist surgery with less expertise in wrist cineradiography. All cineradiographic studies carried out during a 10-year period were obtained. All patients who underwent the gold standard procedure (arthroscopy/arthrotomy) after cineradiography were included, a total of 50 patients. The diagnostic accuracy of detecting SLD by both cineradiography and conventional radiography was calculated. Cineradiography had a high diagnostic accuracy, while the accuracy for conventional radiography was average. When all wrists with an SL distance >=3mm were excluded (static SLD), diagnostic accuracy for conventional radiography dropped even lower, while accuracy for cineradiography remained high. These results are comparable with published accuracy rates and show that cineradiography has a high diagnostic value for detecting SLD and do not seem to be influenced by the operator or observer of the cineradiographic studies. PMID- 28624020 TI - A new method to reduce false positive results in breast MRI by evaluation of multiple spectral regions in proton MR-spectroscopy. AB - OBJECTIVES: To investigate whether the evaluation of multiple spectral regions can increase the diagnostic performance of 1H-MRS of the breast and reduce false positive findings. METHODS: 93 patients (mean age 56 years, range 23-79) undergoing breast MRI for routine clinical indications on a 1.5T scanner were eligible for this IRB-approved prospective study. Suspicious enhancing lesions >=8mm underwent single-voxel point-resolved 1H-MRS (PRESS, TR=2000ms, TE=272ms). Histology showed 69 malignant and 24 benign lesions. The Signal-to-Noise ratio of choline, olefinic acids and the water-to-methylene ratio were measured. The area under the ROC-curve (AUC) was used to evaluate single measurements. Combined diagnostic accuracy was explored using a 10-fold cross-validated Chi-squared automatic interaction detection (CHAID) analysis. Inter-reader agreement was evaluated in a subset of patients. RESULTS: A significant AUC for differentiation between benign and malignant lesions was identified for choline (0.733, P=0.001), olefinic acids (0.769, P=0.0001) and water-to-methylene ratio (0.704, P=0.003). All three variables were included in a classification algorithm using CHAID methodology. Using this classification, 70.8% (17/24) false positive diagnoses in benign lesions would have been avoided. Inter-reader agreement was almost perfect. CONCLUSIONS: The combined evaluation of multiple spectral regions can increase the diagnostic performance of 1H-MRS and potentially reduce false positive findings. PMID- 28624021 TI - Assessment of treatment response after lung stereotactic body radiotherapy using diffusion weighted magnetic resonance imaging and positron emission tomography: A pilot study. AB - BACKGROUND AND PURPOSE: There is no early predictor of treatment response after lung stereotactic body radiotherapy (SBRT). We conducted this pilot study to evaluate whether serial diffusion weighted magnetic resonance imaging (DW-MRI) or positron emission tomography (PET) could predict response after SBRT. MATERIAL AND METHODS: Early stage non-small cell lung cancer patients who received SBRT were eligible. DW-MRI and PET were undertaken pretreatment and every 3 months after SBRT in the first year. Patients with <1year of follow-up were excluded from the analysis. The apparent diffusion coefficient (ADC) value and maximum standardized uptake value (SUVmax) of tumors were measured and compared between groups with or without local recurrence (LR). RESULTS: Fifteen patients were enrolled and the data of 14 patients were analyzed. The median ADC value was significantly lower in patients with LR (n=3) than in those without LR (n=11) at 3 and 6 months (1.11 vs. 1.54 and 0.98 vs. 1.69 [*10-3mm2/s]; p=0.039 and 0.012, respectively) while there was no significant difference pretreatment and at 9 and 12 months after treatment. No significant difference was observed in the SUVmax at any time point. CONCLUSIONS: DW-MRI could be an early predictor of treatment response after lung SBRT. PMID- 28624022 TI - Whole liver CT texture analysis to predict the development of colorectal liver metastases-A multicentre study. AB - OBJECTIVES: CT texture analysis has shown promise to differentiate colorectal cancer patients with/without hepatic metastases. AIM: To investigate whether whole-liver CT texture analysis can also predict the development of colorectal liver metastases. MATERIAL AND METHODS: Retrospective multicentre study (n=165). Three subgroups were assessed: patients [A] without metastases (n=57), [B] with synchronous metastases (n=54) and [C] who developed metastases within <=24 months (n=54). Whole-liver texture analysis was performed on primary staging CT. Mean grey-level intensity, entropy and uniformity were derived with different filters (sigma0.5-2.5). Univariable logistic regression (group A vs. B) identified potentially predictive parameters, which were tested in multivariable analyses to predict development of metastases (group A vs. C), including subgroup analyses for early (<=6 months), intermediate (7-12 months) and late (13-24 months) metastases. RESULTS: Univariable analysis identified uniformity (sigma0.5), sex, tumour site, nodal stage and carcinoembryonic antigen as potential predictors. Uniformity remained a significant predictor in multivariable analysis to predict early metastases (OR 0.56). None of the parameters could predict intermediate/late metastases. CONCLUSIONS: Whole-liver CT-texture analysis has potential to predict patients at risk of developing early liver metastases <=6 months, but is not robust enough to identify patients at risk of developing metastases at later stage. PMID- 28624024 TI - Differentiation between acute and chronic myocardial infarction by means of texture analysis of late gadolinium enhancement and cine cardiac magnetic resonance imaging. AB - The purpose of this study was to differentiate acute from chronic myocardial infarction using machine learning techniques and texture features extracted from cardiac magnetic resonance imaging (MRI). The study group comprised 22 cases with acute myocardial infarction (AMI) and 22 cases with chronic myocardial infarction (CMI). Cine and late gadolinium enhancement (LGE) MRI were analyzed independently to differentiate AMI from CMI. A total of 279 texture features were extracted from predefined regions of interest (ROIs): the infarcted area on LGE MRI, and the entire myocardium on cine MRI. Classification performance was evaluated by a nested cross-validation approach combining a feature selection technique with three predictive models: random forest, support vector machine (SVM) with Gaussian Kernel, and SVM with polynomial kernel. The polynomial SVM yielded the best classification performance. Receiver operating characteristic curves provided area-under-the-curve (AUC) (mean+/-standard deviation) of 0.86+/-0.06 on LGE MRI using 72 features; AMI sensitivity=0.81+/-0.08 and specificity=0.84+/ 0.09. On cine MRI, AUC=0.82+/-0.06 using 75 features; AMI sensitivity=0.79+/-0.10 and specificity=0.80+/-0.10. We concluded that texture analysis can be used for differentiation of AMI from CMI on cardiac LGE MRI, and also on standard cine sequences in which the infarction is visually imperceptible in most cases. PMID- 28624023 TI - Enhanced radiation damage caused by iodinated contrast agents during CT examination. AB - OBJECTIVE: To access the effect of iodinate contrast agent (ICA) on DNA double stand breaks (DSBs) in human peripheral blood lymphocytes during computed tomography (CT) examinations. MATERIALS AND METHODS: This present study was approved by the institutional ethics committee; written informed patient consent was obtained from 70 patients. A total of 48 patients underwent computed tomography urography (CTU), in which only one time CT scanning was examined after injecting ICA, and 22 patients received unenhanced whole abdominal CT, among them 10 patients were selected to get ICA injection immediately after irradiation. Blood samples were taken from all patients prior to and immediately after CT scan, as well as 8min after the injection of ICA. The lymphocytes in these blood samples were separated by using density-gradient centrifugation, fixed and immunostained with gammaH2AX antibody. The average number of phosphorylated histone H2AX (gammaH2AX) foci per lymphocyte was counted under a fluorescence microscopy. Differences in the number of gammaH2AX-foci were statistically analyzed using independent sample t test and one way ANOVA. RESULT: The three patient groups had no significant differences in the baseline foci numbers(P>0.05). The gammaH2AX-focus levels increased in both groups after CT scan. Patients who underwent CTU examinations had a greater DSBs level (mean+/ standard error of mean, 0.945+/-0.184 foci per cell) than those who received unenhanced whole abdominal CT scan (mean+/-standard error of mean, 0.700+/-0.112 foci per cell), increasing by about 37.9%; The ICA injected before CT scan itself had an effect on the DSBs, which increased DSBs level by approximately 90.3% (0.059+/-0.018vs 0.031+/-0.025, P<0.05), but no significant difference was found if added after irradiation, increasing DSBs level only by 3.2% approximately (0.711+/-0.091vs 0.689+/-0.108, P=0.499). CONCLUSION: The iodinated contrast agent itself can lead to an increase in the level of DSBs as assessed with gammaH2AX foci formation, and the application of ICA can amplify DNA damage induced by diagnostic x-ray procedures such as whole abdominal CT. PMID- 28624025 TI - Quantitative computed tomography texture analysis for estimating histological subtypes of thymic epithelial tumors. AB - OBJECTIVES: To investigate whether high-risk thymic epithelial tumor (TET) (HTET) can be differentiated from low-risk TET (LTET) using computed tomography (CT) quantitative texture analysis. MATERIALS AND METHODS: The data of 39 patients (mean age, 58.6+/-14.1 years) (39 unenhanced CT (UECT) and 33 contrast-enhanced CT (CECT)) who underwent thymectomy for TET were retrospectively analyzed. A region of interest was placed to include the entire TET within the slice at its maximum diameter. Texture analysis was performed for images with or without a Laplacian of Gaussian filter (with various spatial scaling factors [SSFs]). Two radiologists evaluated the visual heterogeneity of TET using a 3-point scale. RESULTS: The mean in the unfiltered image (mean0u) and entropy in the filtered image (SSF: 6mm) (entropy6u) for UECT, and the mean in the unfiltered image (mean0c) for CECT were significant parameters for differentiating between HTET and LTET as determined by logistic regression analysis. The area under the receiver operating characteristics curve (AUC) for differentiating HTET from LTET using mean0u, entropy6u, and mean0c was 0.75, 0.76, and 0.89, respectively. And the combination of mean0u and entropy6u allowed AUC of 0.87. Entropy6u provided a higher diagnostic performance compared with visual heterogeneity analysis (p<=0.018). CONCLUSION: Using CT quantitative texture analysis, HTET can be differentiated from LTET with a high diagnostic performance. PMID- 28624026 TI - The prediction of the treatment response of cervical nodes using intravoxel incoherent motion diffusion-weighted imaging. AB - PURPOSE: To investigate the predictive role of Intravoxel Incoherent Motion Diffusion-Weighted Imaging (IVIM-DWI) parameters on cervical nodal response to chemo-radiotherapy (CRT) of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Patients with pathologically confirmed HNSCC were included in the present prospective study, having at least one positive cervical lymph node (LN). They received concomitant CRT and underwent three serial IVIM-DWI investigations: before, at mid-treatment and after treatment completion. Tissue diffusion coefficient D, perfusion-related diffusion coefficient D* and perfusion fraction f were calculated by a bi-exponential fit. The two-sided Mann-Whitney rank test was used to compare the imaging parameters of patients with regional failure (RF) and regional control (RC). A p value lower than 0.05 was considered to be statistically significant. RESULTS: Thirty-four patients were accrued. Twenty-four out of 34 LN (70.6%) showed persistent RC after a median follow-up time of 27.6 months (range: 12.0-50.2 months), while ten cases of RF (29.4%) were confirmed with a median time of 6.8 months (range: 1.5-19.5 months). Patients with RC showed significantly lower pre-treatment D values compared to the RF patients (p=0.038). At mid-treatment, the patients with RF showed significantly higher D values (p=0.025), and exhibited larger percent reductions in f and the product D**f from the baseline (p=0.008 and <0.001, respectively). No additional information was provided by the examination at the end of treatment. CONCLUSION: Pre-treatment and mid-treatment IVIM-DWI showed potential for prediction of treatment response of cervical LN in HNSCC patients. PMID- 28624027 TI - Racial disparities in treatment and survival of hepatocellular carcinoma in native Americans and Hispanics. AB - BACKGROUND: We investigated if there were any differences in disease presentation and survival between the 3 major ethnicities in New Mexico; non-Hispanic whites (NHW), native Americans (NA), and Hispanics (H). METHODS: A retrospective analysis of patients with hepatocellular carcinoma treated at our institution between 2000 and 2014 was performed. Overall survival was analyzed using the Kaplan-Meier and Cox regression models. RESULTS: We identified 326 patients; 106 (32.5%) NHW, 183 (56.1%) H, and 37 (11.4%) NA. No difference in disease stage, resectability, rate of offering surgery, or chemotherapy was found. Advanced cirrhosis was more common in H and NA than NHW (P = .01). NA had a higher incidence of nonviral hepatocellular carcinoma (P = .0009). NHW were more likely to receive transarterial chemoembolization/radiofrequency than NA or H (P = .04). Median survivals for NA, NHW, H were 24, 14, and 11 months, respectively, (P = .01). CONCLUSIONS: Although there was no difference in disease stage or resectability, NA and H had more advanced cirrhosis and were less likely to undergo transarterial chemoembolization and/or radiofrequency than NHW. NA had the best survival, whereas H had the worst survival. PMID- 28624028 TI - Impact of long-acting local anesthesia on clinical and financial outcomes in laparoscopic colorectal surgery. AB - BACKGROUND: Our objective was to assess clinical and financial outcomes with long acting liposomal bupicavaine (LB) in laparoscopic colorectal surgery. METHODS: Patients that received local infiltration with LB were strictly matched to a control group, and compared for postoperative pain, opioid use, length of stay (LOS), hospital costs, and complication, readmission, and reoperation rates. RESULTS: A total of 70 patients were evaluated in each cohort. Operative times and conversion rates were similar. LB patients had lower post-anesthesia care unit pain scores (P = .001) and used less opioids through postoperative day 3 (day 0 P < .01; day 1 P = .03; day 2 P = .02; day 3 P < .01). Daily pain scores were comparable. LB had shorter LOS (mean 2.96 vs 3.93 days; P = .003) and trended toward lower readmission, complication, and reoperation rates. Total costs/patient were $746 less with LB, a savings of $52,200 across the cohort. CONCLUSIONS: Using local wound infiltration with LB, opioid use, LOS, and costs were improved after laparoscopic colorectal surgery. The additional medication cost was overshadowed by the overall cost benefits. Incorporating LB into a multimodal pain regiment had a benefit on patient outcomes and health care utilization. PMID- 28624029 TI - Effect of complications on oncologic outcomes after pancreaticoduodenectomy for pancreatic cancer. AB - BACKGROUND: Although adjuvant therapy (AT) is a necessary component of multimodality therapy for pancreatic ductal adenocarcinoma (PDAC), its application can be hindered by post-pancreaticoduodenectomy (PD) complications. The primary aim of this study was to evaluate the impact of post-PD complications on AT utilization and overall survival (OS). METHODS: Patients undergoing PD without neoadjuvant therapy for stages I-III PDAC at a single institution (2007 2015) were evaluated. Ninety-day postoperative major complications (PMCs) were defined as grade >=3. Records were linked to the Kentucky Cancer Registry for AT/OS data. Early AT was given <8 wk; late 8-16 wk. Initiation >16 wk was not considered to be AT. Complication effects on AT timing/utilization and OS were evaluated. RESULTS: Of 93 consecutive patients treated with surgery upfront with AT data, 64 (69%) received AT (41 [44%] early; 23 [25%] late). There were 32 patients (34%) with low-grade complications and 24 (26%) with PMC. With PMC, only six of 24 patients (25%) received early AT and 13 of 24 (54%) received any (early/late) AT versus 35 of 69 (51%) early AT and 51 of 69 (74%) any AT without PMC. PMCs were associated with worse median OS (7.1 versus 24.6 mo, without PMC, P < 0.001). Independent predictors of OS included AT (hazard ratio [HR]: 0.48), tumor >2 cm (HR: 3.39), node-positivity (HR: 2.16), and PMC (HR: 3.69, all P < 0.02). CONCLUSIONS: Independent of AT utilization and biologic factors, PMC negatively impacted OS in patients treated with surgery first. These data suggest that strategies to decrease PMC and treatment sequencing alternatives to increase multimodality therapy rates may improve oncologic outcomes for PDAC. PMID- 28624030 TI - Emergency department length of stay in critical nonoperative trauma. AB - BACKGROUND: Prolonged emergency department (ED) stays correlate with negative outcomes in critically ill nontrauma patients. This study sought to determine the effect of ED length of stay (LOS) on trauma patients. MATERIALS AND METHODS: Two hundred forty-one trauma patients requiring direct intensive care unit (ICU) admission were identified. Patients requiring immediate operative intervention were excluded. Odds ratios (ORs) of outcomes for patients transferred to ICU in <=90 min were compared with patients transferred in >90 min, adjusting for Injury Severity Score (ISS). RESULTS: One hundred two of 241 patients (42%) were transferred to the ICU in <=90 min. Increased ED LOS was associated with decreased complications (OR 0.545, 95% confidence interval 0.312-0.952). Although the result was not statistically significant, patients with an ISS >15 were less likely to have long ED stays (OR 0.725, 95% CI 0.407-1.290). No significant difference was seen in mortality. No difference in duration of intubation was observed for patients intubated in the ED versus the ICU. For the subgroup with ISS <=15, there was a significant decrease in ICU LOS for patients who remained in the ED >90 min (5.5 d versus 2.7 d, P = 0.02). No other differences in LOS were identified. CONCLUSIONS: In a mature trauma center with standardized activation protocols and focused resource allocation in the ED trauma bay, trauma activation and subsequent management appear to mitigate the negative effects of prolonged ED LOS seen in other critically ill populations. PMID- 28624031 TI - Lung transplantation with lungs from older donors: an analysis of survival in elderly recipients. AB - BACKGROUND: The average ages of lung transplant (LTx) recipients and donors are increasing. With older recipients considered to be especially at high risk of posttransplant mortality, we sought to determine whether the use of allografts from older donors affects survival among older patients undergoing LTx. METHODS: The United Network for Organ Sharing registry was used to identify patients aged 65-80 y receiving a first-time LTx between 1987 and 2013. Survival analysis examined implications of a donor-recipient age difference >10 y using Cox proportional hazards regression. RESULTS: The cohort selected for analysis included 3227 elderly LTx recipients, of whom 263 (8.15%) had donors within 10 y of their age at transplantation. Univariate Cox models found no differences with LTx involving donors at least 10 y younger than the recipient with respect to overall survival (hazard ratio = 0.979; 95% confidence interval [CI] = 0.807 1.188; P = 0.831) or conditional survival past 1 y (hazard ratio = 1.067; 95% CI = 0.819-1.391; P = 0.629) relative to LTx involving donors within 10 y of an elderly recipient's age. These findings were substantiated in multivariate analysis adjusting for potential confounders. CONCLUSIONS: In elderly LTx recipients aged 65-80 y at transplantation, intermediate-term survival was not influenced by donor age. For the viable elderly LTx candidate, a carefully selected older donor should be considered to increase donor availability. PMID- 28624033 TI - House staff-led interdisciplinary morbidity and mortality conference promotes systematic improvement. AB - BACKGROUND: Improvements in patient safety are critical to improving clinical outcomes. We present a resident-led interdisciplinary morbidity and mortality (M&M) conference utilizing postconference task forces to identify unique system issues, classify key contributors to interdisciplinary complications, and implement systems solutions. The conference also served to facilitate resident involvement in quality improvement projects. MATERIALS AND METHODS: Members of the UNC Housestaff Council designed and implemented a hospital-wide M&M conference. Cases involving two or more service lines and resulting from systematic failures were selected for presentation by an interdisciplinary group of residents involved in the patient's care. Postconference task forces addressed problems and developed initiatives to improve care. RESULTS: Of the 15 cases presented, 60% were attributable to an error in judgment, 26% to an error in diagnosis, and 13% to an error in technique. Communication (67%), coordination/care utilization (47%), poor process/workflow (40%), and inadequate training (33%) were the main associated contributing factors. Poor communication contributed to all complications resulting from an error in judgment. Inadequate training and poor workflow were the most common contributing factors with an error in technique. Poor utilization of care and inadequate processes were most common with an error in diagnosis. Postconference task forces identified system based improvement projects in 73% (11 of 15) of cases with 82% (9 of 11) of projects successfully implemented or in process. CONCLUSIONS: House staff-led interdisciplinary M&M conference utilizing postconference task forces is an ideal setting to identify unique system issues and implement system-based improvement strategies. PMID- 28624032 TI - Epidural analgesia for traumatic rib fractures is associated with worse outcomes: a matched analysis. AB - BACKGROUND: The optimal method of pain control for patients with traumatic rib fractures is unknown. The aim of this study was to determine the effect of epidural analgesia on respiratory complications and in-hospital mortality in patients with rib fractures. METHODS: Adult patients at a level I trauma center with >=1 rib fracture from blunt trauma were included (2004-2013). Those with a blunt-penetrating mechanism, traumatic brain injury, or underwent a laparotomy or thoracotomy were excluded. Patients who were treated with epidural analgesia (EPI) were compared with those were not treated with epidural analgesia (NEPI) using coarsened exact matching. Primary outcomes were respiratory complications (pneumonia, deep vein thrombosis/pulmonary embolus, and respiratory failure) and 30-d in-hospital mortality. Secondary outcomes were total hospital and intensive care unit length of stay, and duration of ventilator support. RESULTS: About 1360 patients (EPI: 329 and NEPI: 1031) met inclusion criteria (mean age: 54.2 y; standard deviation [SD]: 19.7; 68% male). The mean number of rib fractures was 4.8 (SD: 3.3; 21% bilateral) with a high total burden of injury (mean Injury Severity Score: 19.9 [SD: 8.9]). The overall incidence of respiratory complications was 13% and mortality was 4%. After matching, 204 EPI patients were compared with 204 NEPI patients, with no differences in baseline characteristics. EPI patients experienced more respiratory complications (19% versus 10%, P = 0.009), but no differences in 30-d mortality (5% versus 2%, P = 0.159), duration of mechanical ventilation (EPI: 148 h [SD: 167] versus NEPI: 117 h [SD: 187], P = 0.434), or duration of intensive care unit length of stay (6.5 d [SD: 7.6] versus 5.8 d [SD: 9.1], P = 0.626). Hospital stay was higher in the EPI group (16.6 d [SD: 19.6] vs 12.7 d [SD: 15.2], P = 0.026). CONCLUSIONS: Epidural analgesia is associated with increased respiratory complications without providing mortality benefit after traumatic rib fractures. Alternate analgesic strategies should be investigated to treat these severely injured patients. PMID- 28624034 TI - Factors influencing failure to rescue after pancreaticoduodenectomy: a National Surgical Quality Improvement Project Perspective. AB - BACKGROUND: Failure to rescue is the concept of death after a complication, and it is an important factor driving variation in mortality rates after pancreatic surgery. The purpose of this study was to conduct a retrospective review of a large, multi-institutional data set to describe patient-level risk factors for failure to rescue in greater detail. METHODS: From the American College of Surgeons National Surgical Quality Improvement Program participant use file, 14,557 patients who underwent pancreaticoduodenectomy were identified. Of these, 4514 experienced at least one complication and were therefore at risk for failure to rescue. Multivariable logistic regression models to identify factors independently associated with failure to rescue. RESULTS: Age, American Society of Anesthesiologists class, ascites and/or varices, and disseminated malignancy were significant independent risk factors for failure to rescue. Participation of a resident was associated with reduced odds of failure to rescue. Patients who experienced an initial complication and then accumulated additional complications were more common in the failure to rescue group (68.6% versus 31.3%, P < 0.001). CONCLUSIONS: Accumulation of complications after pancreaticoduodenectomy is a significant risk factor for failure to rescue. Pancreatic surgery quality improvement programs should continue developing strategies to identify and intervene on post-pancreatectomy complications, especially in high-risk patients. PMID- 28624035 TI - Racial disparities in length-of-stay persist even with no postoperative complications. AB - BACKGROUND: To determine the contribution of race to postoperative length-of-stay in elective colorectal surgery without complications. METHODS: The 2012-2013 National Surgical Quality Improvement Program Colectomy-Targeted Database was queried for patients undergoing elective colorectal surgery without complications. After stratifying by race, univariate/bivariate comparisons were made. On adjusted comparison, predictors of postoperative length-of-stay were identified along with incident rate ratios and Least Squares Means for predicted length-of-stays. RESULTS: Of 28,480 elective colorectal surgeries, 19,898 patients had no postoperative complications. Patients stratified to white (84%), black (8%), Hispanic (3%), and Asian (3%). Overall mean postoperative length-of stay was 4.8 d, with black patients having the longest at 5.3 d (P < 0.05). After covariate adjustment, black race increased postoperative length-of-stay by 9%, 7%, and 6% compared to white, Hispanic, and Asian patients, respectively (P < 0.05). No statistical difference existed in postoperative length-of-stay for Hispanic and Asian patients versus white patients. Adjusted postoperative length of-stay was 5.1 d for black patients compared to 4.7, 4.8, and 4.8 d for white, Hispanic, and Asian patients, respectively (P < 0.05). CONCLUSIONS: Black patients have significantly longer postoperative length-of-stay after elective colorectal surgery even if no postoperative complications occur. Further studies are needed to understand the mechanism(s) for these disparities. PMID- 28624036 TI - Firearm injuries due to legal intervention in children and adolescents: a national analysis. AB - BACKGROUND: Firearm injuries related to legal intervention have come under scrutiny because of recent events. METHODS: The Kids' Inpatient Database (1997 2012) was searched for firearm injuries due to legal interventions (International Classification of Diseases, ninth revision, Clinical Modification E970) requiring inpatient admission in children aged <20 y. Cases were weighted to provide national estimates. The Brady Campaign criteria were used to identify lenient versus strict gun law states. RESULTS: Overall, 275 cases were identified, with a 7.5% mortality rate. Incidence peaked at 1.0 per 100,000 admissions in 2006, significantly increased from a low 0.2 per 100,000 admissions in 1997, P < 0.001. Patients were predominantly male (97%). African Americans (44%) represented the largest racial group, followed by Hispanics (30%) and Caucasians (20%). Mean age was 17.5 +/- 2.08 y. Patients were insured by Medicaid (33%) or a private payer (24%); the remainder (43%) was uninsured. Admissions most frequently occurred at urban teaching hospitals (81%). Cases occurred most frequently in the Southern United States (44%), followed by the Western United States (35%). Most patients presented to non-children's hospitals (97%). Mean hospital admission cost was 27,507 +/- 40,197 USD, whereas mean charges amounted to 75,905 +/- 116,622 USD. Cases mostly occurred in lenient (56%) gun law states, whereas the remainder occurred in strict (41%) and neutral (3%) states. When analyzed by race, Caucasians (16%) had a significantly higher mortality rate when compared with African Americans (5%), P = 0.03. CONCLUSIONS: An analysis of this very specific injury mechanism demonstrates important findings, which are difficult to collect from conventional data sources. Future research will contribute to the objective analysis of this politically charged subject. PMID- 28624037 TI - Trauma care in a multiethnic population: effects of being undocumented. AB - BACKGROUND: Epidemiologic studies have shown that undocumented immigrants (UIs) display characteristics of having a low socioeconomic status and are primarily of ethnic minorities. These social determinants of health are known to be associated with diminished health care access and poor clinical outcomes. We therefore investigated the impact of documentation status on the clinical outcomes of patients with traumatic injuries. MATERIALS AND METHODS: We conducted a retrospective review of the trauma registry at our safety net institution for all adult patients who were admitted from 2010 to 2014. UIs were identified by the absence of a valid social security number within their medical records. Multivariate regression analysis was used to determine the impact of documentation status on in-hospital mortality, length of stay (LOS), and the odds of rehab placement. RESULTS: 4924 trauma patients met the study criteria, of which 1050 (21.3%) were UIs. There was no significant difference in mortality rates between the two populations. Multivariate regression analyses revealed a longer average LOS and a decreased likelihood for placement in an in-patient rehabilitation facility following hospitalization for UIs, even after accounting for insurance, age, injury severity, and other possible confounders known to affect these outcomes. CONCLUSIONS: There was no association between in-hospital mortality and documentation status; however, UIs had a longer average LOS and were less likely to be placed into rehab following their hospitalization. A longer LOS and a decreased likelihood for rehabilitation placement suggest that disparities in trauma care exist for UIs, putting them at risk for worse clinical and functional outcomes. PMID- 28624038 TI - Impact of blood products on platelet function in patients with traumatic injuries: a translational study. AB - BACKGROUND: Reductions in platelet (PLT) count and function are associated with poor outcomes in trauma patients. We proposed to determine if patients expected to receive blood products have a decrease in PLT function higher than expected based on the reduction in PLT count, and if the reduction in function could be associated with the donor plasma/supernatant received. METHODS: PLT count and function were measured on admission to the emergency department and intensive care unit in severely injured patients expected to receive a transfusion. PLT function was measured by Multiplate aggregometry in response to five agonists. Function was corrected for alterations in count. In vitro studies were conducted in the blood of normal subjects to assess the effect of dilutions with AB donor plasma on PLT function. RESULTS: Forty-six patients were enrolled, with 87% requiring a transfusion. Median Injury Severity Score was 23 (13, 29) and mortality 15%. PLT count and function were decreased from emergency department to intensive care unit admission by 25% and 58%, respectively. Decreases in function persisted after adjustment for count. Patients requiring large volumes of blood products had reductions in function that were disproportionately greater. Reductions in PLT function were greatest after transfusion of PLTs. In in vitro studies with a 30% dilution by autologous plasma caused a relational reduction in function, whereas allogenic plasma resulted in greater decreases that were highly variable between donors. CONCLUSIONS: Within hours of injury a decrease in both PLT count and function occurs, that is aggravated with the administration of blood products, with transfusion of PLTs showing the greatest effect. The effect on PLT function of allogenic transfused plasma appears to be highly donor related. PMID- 28624039 TI - The total number of prelaryngeal and pretracheal lymph node metastases: is it a reliable predictor of contralateral central lymph node metastasis in papillary thyroid carcinoma? AB - BACKGROUND: Central lymph node (CLN) metastasis in papillary thyroid carcinoma (PTC) is common and being able to predict CLN metastasis helps surgeons determine individualized therapy. However, the relationship between contralateral CLN metastasis and the total number of positive lymph nodes (LNs) in the combined prelaryngeal and pretracheal region remains unclear. This study aimed to investigate whether the total number of positive LNs in the combined prelaryngeal and pretracheal region has clinical significance as a predictor for contralateral CLN metastasis. METHODS: We prospectively enrolled 153 consecutive patients with unifocal PTC >1.0 cm without ultrasonographic evidence of nodal metastasis who underwent total thyroidectomy and prophylactic bilateral CLN dissection from July 2011-May 2013. Patients were divided into three groups according to the total number of positive LNs in the combined prelaryngeal and pretracheal region. RESULTS: Rates of metastasis to ipsilateral and contralateral central compartments in PTC >1.0 cm were 84.3% and 24.2%, respectively. Multivariate analysis showed that >=3 positive LNs in the combined prelaryngeal and pretracheal region were an independent predictive factor of contralateral CLN metastasis (P < 0.001; odds ratio, 8.585). After a mean follow-up of 24.1 mo, none of these patients had a recurrence in the central or lateral compartment. CONCLUSIONS: Occult metastasis is highly prevalent in the ipsilateral central neck of patients with PTC >1.0 cm, and the total number of prelaryngeal and pretracheal LNs metastases may be a useful indicator to predict contralateral CLN metastasis in patients with unifocal PTC. PMID- 28624040 TI - Hyperglycemia attenuates receptor activator of NF-kappaB ligand-induced macrophage activation by suppressing insulin signaling. AB - BACKGROUND: Although male gender, aging, hypertension, dyslipidemia, and smoking are common risk factors for abdominal aortic aneurysm, diabetes mellitus is an independent negative risk factor. In aneurysm tissue, matrix metalloproteinases (MMPs) expressed by activated macrophages degrades extracellular matrix proteins. In our previous experimental study, we demonstrated that the aneurysmal formation and macrophage activity were suppressed by inhibiting mimicking hyperglycemia (HG) through upregulation of glucose-sensing nuclear receptor, Nr1h2. Here in this study, we focused on the role of HG-induced altered glucose uptake on macrophage activation. METHODS: RAW264.7 murine macrophage cells were pretreated in cultures containing HG (HG group, 15.5 mM) or normal glucose (NG) concentrations (NG group, 5.5 mM) for 7 d. The culture medium was then changed in both groups to NG conditions, and the cells were stimulated with recombinant murine soluble receptor activator of NF-kappaB ligand (sRANKL). Macrophage activation was confirmed by tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: Compared with the NG group, MMP-9 expression in the HG group was significantly suppressed. Glucose uptake was increased in the NG group but not in the HG group during macrophage activation. To determine the mechanism of activation, we studied the expression and distribution of glucose transporters (Gluts) in the macrophages. Although Glut expression was unaffected by glucose pretreatment, membrane translocation of Glut-1 was significantly enhanced in macrophages in the NG group but not in the HG group during activation. Insulin receptor and insulin receptor substrate-1 (IRS-1) messenger RNA, known stimulate to membrane translocation of Gluts, were both decreased by the HG condition but not by the NG condition. CONCLUSIONS: HG pretreatment suppressed the macrophage activation. sRANKL increased macrophage glucose uptake at NG concentrations, which was impaired by HG pretreatment through the inhibition of Glut1 membrane translocation and the insulin receptor and IRS-1 gene transcription. These data suggest that HG suppressed macrophage activation, through attenuation of glucose uptake via the suppression of the membrane translocation of Glut1 and insulin signaling. PMID- 28624041 TI - Effects of replacing saline solution during surgery for colon cancer in Korea. AB - BACKGROUND: Surgical site infections are often linked to contamination of saline solution by the patient's organs, doctors' and nurses' hands, or surgical instruments. Scrub nurses also use the saline solution to soften sutures or moisturize gauze. Therefore, we performed a randomized study of Korean clean contaminated surgeries for colon cancer to evaluate whether replacing saline solution affected the level of contamination. MATERIALS AND METHODS: In the control group (n = 26), normal saline was not replaced during surgery. In the experimental group (n = 26), normal saline and bowl were replaced after colon lesions were removed. RESULTS: We found that replacing the saline solution during surgery significantly lowered the number of colony-forming units in the solution (t = -5.18, P < 0.001). CONCLUSIONS: Therefore, we suggest that nurses replace the saline solution after removing the contaminated organs and that this replace be performed in clinical settings in Korea. PMID- 28624042 TI - Wound management and outcome of 595 electrical burns in a major burn center. AB - BACKGROUND: Electrical burns are important causes of trauma worldwide. This study aims to analyze the clinical characteristics, wound management, and outcome of electric burns. METHODS: This retrospective study was performed at the Institute of Burn Research of the Third Military Medical University during 2013-2015. Data including the demographics, injury patterns, wound treatment, and outcomes were collected and analyzed. RESULTS: A total of 595 electrical burn patients (93.8% males) were included. The average age was 37.3 +/- 14.6 y, and most patients (73.5%) were aged 19~50 years. Most patients (67.2%) were injured in work-related circumstances. The mean total body surface area was 8.8 +/- 11.8% and most wounds (63.5%) were full-thickness burns. Operation times of high-voltage burns and current burns were higher than those of low-voltage burns and arc burns, respectively. Of the 375 operated patients, 83.2% (n = 312) underwent skin autografting and 49.3% (n = 185) required skin flap coverage. Common types of skin flaps were adjacent (50.3%), random (42.2%), and pedicle (35.7%). Amputation was performed in 107 cases (18.0%) and concentrated on the hands (43.9%) and upper limbs (39.3%). The mean length of stay was 42.9 +/- 46.3 d and only one death occurred (0.2%). Current burns and higher numbers of operations were major risk factors for amputation and length of stay, respectively. CONCLUSIONS: Electrical burns mainly affected adult males with occupational exposures in China. Skin autografts and various skin flaps were commonly used for electric burn wound management. More standardized and effective strategies of treatment and prevention are still needed to decrease amputation rates. PMID- 28624043 TI - Composition of the cellular infiltrate in patients with simple and complex appendicitis. AB - BACKGROUND: It is now well established that there are two types of appendicitis: simple (nonperforating) and complex (perforating). This study evaluates differences in the composition of the immune cellular infiltrate in children with simple and complex appendicitis. MATERIALS AND METHODS: A total of 47 consecutive children undergoing appendectomy for acute appendicitis between January 2011 and December 2012 were included. Intraoperative criteria were used to identify patients with either simple or complex appendicitis and were confirmed histopathologically. Immune histochemical techniques were used to identify immune cell markers in the appendiceal specimens. Digital imaging analysis was performed using Image J. RESULTS: In the specimens of patients with complex appendicitis, significantly more myeloperoxidase positive cells (neutrophils) (8.7% versus 1.2%, P < 0.001) were detected compared to patients with a simple appendicitis. In contrast, fewer CD8+ T cells (0.4% versus 1.3%, P = 0.016), CD20 + cells (2.9% versus 9.0%, P = 0.027), and CD21 + cells (0.2% versus 0.6%, P = 0.028) were present in tissue from patients with complex compared to simple appendicitis. CONCLUSIONS: The increase in proinflammatory innate cells and decrease of adaptive cells in patients with complex appendicitis suggest potential aggravating processes in complex appendicitis. Further research into the underlying mechanisms may identify novel biomarkers to be able to differentiate simple and complex appendicitis. PMID- 28624044 TI - Predictors of a histopathologic diagnosis of complicated appendicitis. AB - BACKGROUND: Despite its utilization, the intraoperative (IO) assessment of complicated appendicitis (CA) is subjective. The histopathologic (HP) diagnosis should be the gold standard in identifying patients with CA; however, it is not immediately available to guide postoperative management. The objective of this study was to identify predictors of an HP diagnosis of CA. MATERIALS AND METHODS: A retrospective review of all patients who underwent appendectomy at our institution from 2011-2013 was conducted. CA was defined by perforation or abscess on pathology report. Predictors of an HP diagnosis of CA were evaluated using a multivariable regression model. RESULTS: A total of 239 of 1066 patients had CA based on IO assessment, whereas 143 of 239 patients (60%) had CA on HP and IO assessment. On multivariable analysis, an IO diagnosis of CA was associated with an HP diagnosis of CA (odds ratio [OR]: 10.92; 95% confidence interval [CI]: 7.19-16.58). Other risk factors were age (OR: 1.28; 95% CI: 1.09-1.49), number of days of pain (OR: 1.20; 95% CI: 1.07-1.37), increased heart rate (OR: 1.14; 95% CI: 1.02-1.26), appendix size (OR: 1.09; 95% CI: 1.03-1.16), and an appendicolith (OR: 1.74; 95% CI: 1.12-2.71) on preoperative CT imaging. CONCLUSIONS: In addition to age, increased heart rate, pain duration, appendix size and appendicolith, the IO assessment is also associated with an HP diagnosis of CA; however, 40% of patients were incorrectly classified. Using these predictors with improved IO grading may achieve more accurate diagnosis of CA. PMID- 28624045 TI - A comparison of a homemade central line simulator to commercial models. AB - BACKGROUND: Simulation is quickly becoming vital to resident education, but commercially available central line models are costly and little information exists to evaluate their realism. This study compared an inexpensive homemade simulator to three commercially available simulators and rated model characteristics. MATERIALS AND METHODS: Seventeen physicians, all having placed >50 lines in their lifetime, completed blinded central line insertions on three commercial and one homemade model (made of silicone, tubing, and a pressurized pump system). Participants rated each model on the realism of its ultrasound image, cannulation feel, manometry, and overall. They then ranked the models based on the same variables. Rankings were assessed with Friedman's and post hoc Conover's tests, using alphas 0.05 and 0.008 (Bonferroni corrected), respectively. RESULTS: The models significantly differed (P < 0.0004) in rankings across all dimensions. The homemade model was ranked best on ultrasound image, manometry measurement, cannulation feel, and overall quality by 71%, 67%, 53%, and 77% of raters, respectively. It was found to be statistically superior to the second rated model in all (P < 0.003) except cannulation feel (P = 0.134). Ultrasound image and manometry measurement received the lowest ratings across all models, indicating less realistic simulation. The cost of the homemade model was $400 compared to $1000-$8000 for commercial models. CONCLUSIONS: Our data suggest that an inexpensive, homemade central line model is as good or better than commercially available models. Areas for potential improvement within models include the ultrasound image and ability to appropriately measure manometry of accessed vessels. PMID- 28624046 TI - Failure to rescue following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) can significantly improve the survival in selected patients with peritoneal carcinomatosis. This study aims to identify perioperative patient characteristics predictive of failure to rescue (FTR), mortality following postoperative complications from CRS/HIPEC. METHODS: Patients suffering a complication following CRS/HIPEC between 2005 and 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program data set. FTR was defined as 30-d mortality in the setting of a complication. Patients who suffered FTR were compared against those who survived a complication (non FTR). Predictors of FTR were identified using a multivariable logistic regression model. RESULTS: A total of 915 eligible CRS/HIPEC cases were identified. In all, 382 patients (42%) developed >=1 postoperative complication, and 88 patients (10%) suffered >=1 major complication. Seventeen patients died following a complication, amounting to an FTR rate of 4%. FTR patients were more likely than non-FTR patients to have dependent functional status (18% versus 2%, P = 0.01), have American Society of Anesthesiologists (ASA) class 4 status (29% versus 8%, P = 0.01), develop >=3 complications (65% versus 24%, P < 0.01), and suffer a major complication (94% versus 20%, P < 0.01). The following were independently associated with FTR: ASA class 4 (odds ratio [OR]: 13.4, 95% confidence interval [CI], 1.2-146.8) and major complications (OR: 66.0, 95% CI, 8.4-516.6). CONCLUSIONS: ASA class 4, major morbidity, and likely dependent functional status are independent predictors of FTR following CRS/HIPEC to treat peritoneal carcinomatosis. Therefore, ASA class 4 and dependent functional status should be considered as contraindications for CRS/HIPEC and only offered in highly selective cases. PMID- 28624047 TI - Viscoelastic monitoring in pediatric trauma: a survey of pediatric trauma society members. AB - BACKGROUND: Viscoelastic monitoring (VEM), including thromboelastography (TEG) and rotational thromboelastometry (ROTEM) in the setting of goal-directed hemostatic resuscitation has been shown to improve outcomes in adult trauma. The American College of Surgeons (ACS) Committee on Trauma recommends that "thromboelastography should be available at level I and level II trauma centers". The purpose of this study is to determine the current availability and utilization of VEM in pediatric trauma. METHODS: After IRB and Pediatric Trauma Society (PTS) approval, a survey was administered to the current members of the PTS via Survey Monkey. The survey collected demographic information, hospital and trauma program type, volume of trauma admissions, and use and/or availability of VEM for pediatric trauma patients. RESULTS: We received 107 responses representing 77 unique hospitals. Survey respondents were: 61% physicians, 29% nurses, 6% trauma program managers, and 4% nurse practitioners/physician assistants. Over half of providers worked in a free standing children's hospital. Seventy-seven percent of respondents were from hospitals that had >200 trauma admissions/year, 42% were providers at ACS level 1 pediatric trauma centers, and 62% practiced at state level 1 designated centers. VEM was available to 63% of providers, but only 31% employed VEM in pediatric trauma patients. For those who had no VEM available, over 73% would utilize this technology if it was available. Seventy-one percent of providers continue to rely on conventional coagulation assays to monitor coagulopathy in pediatric trauma patients after admission. CONCLUSIONS: While a growing body of evidence demonstrates the benefit of viscoelastic hemostatic assays in management of adult traumatic injuries, VEM during active resuscitation is infrequently used by pediatric trauma providers, even when the technology is readily available. This represents a timely and unique opportunity for quality improvement in pediatric trauma. PMID- 28624048 TI - Comparison of two different types of oxidized regenerated cellulose for partial breast defects. AB - BACKGROUND: A defect after partial mastectomy, sometimes, is hard to be filled with patient's own breast tissue. Two different types of oxidized regenerated cellulose (ORC) for filling of partial defects in small-sized breasts were compared with respect to clinicopathologic factors and outcomes. METHODS: A total of 45 patients with breast cancer underwent conventional partial mastectomy with insertion of an ORC filling material. The two filling materials used were a hemostasis-purposed ORC and adhesion barrier-purposed ORC. Clinical factors were compared between these two ORC materials. Both the surgeon and patient assessed the cosmetic outcomes using the Harvard/NSABP/RTOG Breast Cosmesis Grading Scale. RESULTS: Partial mastectomy with filling material insertion technique was not inferior to partial mastectomy-only technique in many clinical aspects. And most of the clinicopathologic factors showed no significant difference between the two groups. However, the mean operation time was significantly shorter in the hemostasis-purposed ORC group (P = 0.027). In addition, the infection rate was significantly higher in the adhesion barrier-purposed ORC group (P = 0.040). CONCLUSIONS: Reconstructive surgery using a hemostasis-purposed ORC was associated with a shorter operation time and lower incidence of postoperative infection than that using an adhesion barrier-purposed ORC. However, both types of ORC were feasible as filling compounds for partial defects of the breast. PMID- 28624049 TI - Failure to operate on resectable gastric cancer: implications for policy changes and regionalization. AB - BACKGROUND: A significant proportion of patients never receive curative-intent surgery for resectable gastric cancer (GC). The primary aims of this study were to identify disparities and targetable risk factors associated with failure to operate in the context of national trends in surgical rates for resectable GC. METHODS: The National Cancer Database was used to identify patients with resectable GC (adenocarcinoma, clinical stage IA-IIIC, 2004-2013). Multivariate modeling was used to identify predictors of resection and to analyze the impact of surgery on overall survival (OS). RESULTS: Of 46,970 patients with resectable GC, 18,085 (39%) did not receive an appropriate operation. Among unresected patients, 69% had no comorbidities. Failure to resect was associated with reduced median OS (44.4 versus 11.8 mo, hazard ratio [HR]: 2.09, P < 0.001). In the multivariate analysis, the most critical factors affecting OS were resection (HR: 2.09) and stage (reference IA; HR range: 1.16-3.50, stage IB-IIIC). Variables independently associated with no surgery included insurance other than private or Medicare (odds ratio [OR]: 1.60/1.54), nonacademic/nonresearch hospital (OR: 1.16), non-Asian race (OR: 1.72), male (OR: 1.19), older age (OR: 1.04), Charlson Deyo score >1 (OR: 1.17), residing in areas with median income <$48,000 (OR: 1.23), small urban populations <20,000 (OR: 1.41), and stage (reference IA; OR range: 1.36-3.79, stage IB-IIIC, P < 0.001). CONCLUSIONS: Over one-third of patients with resectable GC fail to receive surgery. Suitable insurance coverage and treatment facility are the most salient (and only modifiable) risk factors for omitting surgery. To mitigate national disparities in surgical care, policymakers should consider improving insurance coverage in underserved areas and regionalization of gastric cancer care. PMID- 28624050 TI - Impact of hospital volume on outcomes for laparoscopic adhesiolysis for small bowel obstruction. AB - BACKGROUND: Volume-to-outcome data have been studied in several complex surgical procedures, demonstrating improved outcomes at higher volume centers. Laparoscopic lysis of adhesions (LLOA) for small bowel obstruction (SBO) may result in better outcomes, but there is no information on the learning curve for this potentially complex case. This study evaluates the effect of institutional procedural volume on length of stay (LOS), outcomes, and costs in LLOA for SBOs. MATERIALS AND METHODS: The Nationwide Inpatient Sample data set between 2000 and 2013 was queried for discharges for a diagnosis of SBO involving LLOA in adult patients. Patients with intra-abdominal malignancy and evidence of any other major surgical procedure during hospitalization were excluded. The procedural volume per hospital was calculated over the period, and high-volume hospitals were designated as those performing greater than five LLOA per year. Patient characteristics were described by hospital volume status using stratified cluster sampling tabulation and linear regression methods. LOS, total charges, and costs were reported as means with standard deviation and median values. P < 0.05 was considered significant. RESULTS: A total of 9111 discharges were selected, which was representative of 43,567 weighted discharges nationally between 2000 and 2013. Over the study period, there has been a 450% increase in the number of LLOA performed. High-volume hospitals had significantly shorter LOS (mean: 4.92 +/- standard error (SE) 0.13 d; median: 3.6) compared to low-volume hospitals (mean: 5.68 +/- 0.06 d; median: 4.5). In multivariate analysis, high-volume status was associated with a decreased LOS of 0.72 d (P < 0.0001) as compared to low-volume status. Other significant predictors for decreased LOS included decreased age, decreased comorbidity, and the absence of small bowel resection. There was no significant association between volume status and total charges in multivariate or univariate models, but high-volume hospitals were associated with lower costs in multivariate models by approximately $984 (P = 0.017). CONCLUSIONS: This study demonstrates that high hospital volume was associated with decreased LOS for LLOA in SBO. Although volume was not associated with differences in total charges, there was a small decrease in hospital costs. PMID- 28624051 TI - Persistent injury-associated anemia: the role of the bone marrow microenvironment. AB - BACKGROUND: The regulation of erythropoiesis involves hematopoietic progenitor cells, bone marrow stroma, and the microenvironment. Following severe injury, a hypercatecholamine state develops that is associated with increased mobilization of hematopoietic progenitor cells to peripheral blood and decreased growth of bone marrow erythroid progenitor cells that manifests clinically as a persistent injury-associated anemia. Changes within the bone marrow microenvironment influence the development of erythroid progenitor cells. Therefore, we sought to determine the effects of lung contusion, hemorrhagic shock, and chronic stress on the hematopoietic cytokine response. MATERIALS AND METHODS: Bone marrow was obtained from male Sprague-Dawley rats (n = 6/group) killed 7 d after lung contusion followed by hemorrhagic shock (LCHS) or LCHS followed by daily chronic restraint stress (LCHS/CS). End point polymerase chain reaction was performed for interleukin-1beta, interleukin-10, stem cell factor, transforming growth factor beta, high-mobility group box-1 (HMGB-1), and B-cell lymphoma-extra large. RESULTS: Seven days following LCHS and LCHS/CS, bone marrow expression of prohematopoietic cytokines (interleukin-1beta, interleukin-10, stem cell factor, and transforming growth factor-beta) was significantly decreased, and bone marrow expression of HMGB-1 was significantly increased. B-cell lymphoma-extra large bone marrow expression was not affected by LCHS or LCHS/CS (naive: 44 +/- 12, LCHS: 44 +/- 12, LCHS/CS: 37 +/- 1, all P > 0.05). CONCLUSIONS: The bone marrow microenvironment was significantly altered following severe trauma in a rodent model. Prohematopoietic cytokines were downregulated, and the proinflammatory cytokine HMGB-1 had increased bone marrow expression. Modulation of the bone marrow microenvironment may represent a therapeutic strategy following severe trauma to alleviate persistent injury-associated anemia. PMID- 28624052 TI - Association between surgical patient satisfaction and nonmodifiable factors. AB - BACKGROUND: Patient satisfaction surveys are an important tool in measuring physician performance. We hypothesized that nonmodifiable factors would be associated with surgical outpatient satisfaction scores. METHODS: Press Ganey Consumer Assessment of Health Providers and Systems outpatient satisfaction scores from completed surveys (18,373) at an academic department of surgery were reviewed. Data were collected on patient factors, provider specialty, practice setting, and first visit status. Patients were divided into groups based on satisfaction scores-completely satisfied (score = 100) or less satisfied (score <=99). Generalized estimating equation logistic regression analysis was performed to identify factors predictive of patient satisfaction. RESULTS: Patients less likely to be completely satisfied were younger (odds ratio [OR] 0.54; confidence interval [CI] 0.43-0.69, P < 0.001 for 18-29 y versus >80 y) and were more likely to be seeing their surgeon for the first time (OR 0.84; CI 0.78-0.89, P < 0.001 for first versus return patients). Compared with patients seen at hospital subspecialty clinics, patients were more likely to be satisfied if seen at a cancer center clinic (OR 1.22; CI 1.13-1.32, P < 0.001) or a community ambulatory clinic (OR 1.30; CI 1.18-1.43, P < 0.001). There was no difference in satisfaction among patients seen in General Surgery, Plastic Surgery, or Otolaryngology Clinics. Patients were less likely to be satisfied when seen in Urology (OR 0.82; CI 0.75-0.91, P < 0.001) and Vascular Surgery (OR 0.75; CI 0.62 0.92, P = 0.006) clinics compared with General Surgery Clinics. CONCLUSIONS: Using satisfaction scores to evaluate providers should take into account nonmodifiable factors of the underlying patient population, the specialty of the provider, and the practice setting of the visit. PMID- 28624053 TI - Radiologic evaluation of vasculobiliary anatomy in the umbilical fissure. AB - BACKGROUND: Preoperative evaluation of vasculobiliary anatomy in the umbilical fissure (U-point) is pivotal for perihilar cholangiocarcinoma (PCCA) applied to right-sided hepatectomy. The purpose of our study was to review the vasculobiliary anatomy in the U-point using three-dimensional (3D) reconstruction technique, to investigate the diagnostic ability of 2D scans to evaluate anatomic variations, and to discuss its surgical implications. METHODS: A retrospective study of 159 patients with Bismuth type I, II, and IIIa PCCA, who received surgery at our institution from November 2012 to September 2016, was conducted. Anatomic structures were assessed using multidetector computed tomography (MDCT) by one hepatobiliary surgeon, whereas 3D images were reconstructed by an independent radiologist. Normal confluence pattern of left biliary system was defined as the left medial segmental bile duct (B4) joining the common trunk of segment II (B2) and segment III (B3) ducts, whereas aberrant confluence patterns were classified into 3 types: type I, triple confluence of B2, B3, and B4; type II, B2 draining into the common trunk of B3 and B4; type III, other patterns. Surgical anatomy of B4 was classified into the central, peripheral, and combined type according to its relation to the hepatic confluence. The lengths from the bile duct branch of Spiegel's lobe (B1l) to the orifice of B4 and the junction of B2 and B3 were measured on 3D images. The anatomy of left hepatic artery (LHA) was classified according to different origins and the spatial relationship related to the U-point. RESULTS: 3D reconstruction revealed that normal confluence pattern of left biliary system was observed in 71.1% (113/159) of all patients, and variant patterns were type I in 11.9% (19/159), type II in 12.6% (20/159), and type III in 4.4% (7/159). The length from B1l to the junction of B2 and B3 was 12.1 +/- 3.1 mm in type I variation, which was significantly shorter than that in normal configuration (30.0 +/- 6.8 mm, P < 0.001) but significantly longer than that in type II variation (9.6 +/- 3.4 mm, P = 0.019). Surgical anatomy of B4: the peripheral type was most commonly seen (74.2%, 118/159), followed by central type (15.7%, 25/159) and combined type (10.1%, 16/159). The distance between the B1l and B4 was 8.4 +/- 2.4 mm in central and combined type, which was significantly shorter than that in peripheral type (14.5 +/- 4.1 mm, P < 0.001). A replaced or accessory LHA from the left gastric artery was present in 6 (3.8%) and 9 (5.7%) patients, respectively. LHA running along the left caudal position of U-point was present in 143 cases (89.9%), along the right cranial position of U-point in nine cases (5.7 %), and combined position in seven cases (4.4%). Interobserver agreement of two imaging modalities was almost perfect in biliary confluence pattern (kappa = 0.90; 95% confidence interval: 0.79-1.00), substantial in surgical anatomy of B4 (kappa = 0.74; 95% confidence interval: 0.62-0.86), and perfect in LHA (kappa = 1.00). CONCLUSIONS: Thoroughly understanding the imaging characters of surgical anatomy in the U-point may be benefit for preoperative evaluation of PCCA by successive review of 2D images alone, whereas 3D reconstruction technique allows detailed hepatic anatomy and individualized surgical planning for advanced cases. PMID- 28624054 TI - Diverticulitis and Crohn's disease have distinct but overlapping tumor necrosis superfamily 15 haplotypes. AB - BACKGROUND: Diverticulitis (DD) and Crohn's disease (CD) have overlapping features including bowel structuring, inflammation, and infection. Tumor necrosis superfamily 15 (TNFSF15) is an immunoregulatory, anti-angiogenic gene. CD has been previously associated with a haplotype of five TNFSF15 single-nucleotide polymorphism alleles: rs3810936 (G allele), rs6478108 (A), rs6478109 (G), rs7848647 (G), and rs7869487 (A). We aimed to determine the TNFSF15 risk haplotype for DD versus controls with a subgroup analysis of youthful DD patients (aged <=55 y) versus older controls (aged >=55 y). METHODS: A total of 148 diverticulitis patients (90 aged <=55 y) and 200 controls (87 aged >=55 y) were genotyped using our custom-designed Illumina Veracode microarray chip. Genotypes from rs3810936, rs6478108, rs6478109, rs7848647, rs7869487 and two additional TNFSF15 single nucleotide polymorphisms, rs3810936 and rs11554257, were analyzed. PHASE version 2.1, R with HaploStats and the Broad Institute's Haploview program were used for statistics and imputed haplotype frequency. Permutation corrected for multiple comparisons. RESULTS: The CD GAGGA haplotype was significantly associated with diverticulitis (P = 0.03) in the all DD versus all controls comparison. A second haplotype, rs6478108 (A), rs6478109 (G), rs7869487 (A), and rs4263839 (G), was also associated with DD in this cohort (P = 0.025). A third haplotype rs6478108 (A), rs6478109 (G), rs7848647 (G) and rs7869487 (A), rs4263839 (G) was demonstrated in the DD < 55 versus controls >55 comparison (P = 0.045). CONCLUSIONS: Distinct but overlapping TNFSF15 haplotypes were demonstrated in diverticulitis patients versus healthy controls when compared with the known Crohn's risk haplotype suggesting similar but distinct genetic predispositions. This study strengthens the role for a genetic predisposition to diverticulitis that involves the TNFSF15 gene. PMID- 28624055 TI - Sevoflurane preconditioning protects from posttransplant injury in mouse lung transplantation. AB - BACKGROUND: Although sevoflurane (Sevo) had been shown to ameliorate posttransplant injury in various organs, data available are inconsistent, particularly in the context of lung transplantation (Tx). We here investigated if preconditioning by Sevo can protect from posttransplant injury regarding both, primary graft dysfunction (PGD) and acute rejection (AR) after experimental lung Tx, thereby focusing on two important clinical outcome parameters. MATERIALS AND METHODS: Three experimental approaches were used: (1) BALB/c mice were preconditioned for 2 h with Sevo or a fentanyl cocktail (Control; n = 10); (2) syngeneic (Syn) mouse lung Tx (C57BL/6) with a Sevo-preconditioned graft followed by 18 h storage to mimic PGD (Syn-Tx, n = 12) versus controls (fentanyl cocktail); and (3) allogeneic (Allo) Tx (BALB/c, donor; C57BL/6, recipient) to mimic AR (Allo-Tx, n = 12) versus controls (fentanyl cocktail). Syn-Tx grafts were harvested on Day 1, Allo-Tx grafts on Day 3 and analyzed for histology, immunohistochemistry, blood gas analysis, and inflammatory cytokines (enzyme linked immunosorbent assay or reverse transcription polymerase chain reaction). RESULTS: Evaluating the preconditioning effect of Sevo only showed significantly better oxygenation (P = 0.03) and a tendency toward lower levels of lung tissue messenger RNA for tumor necrosis factor-alpha. In Syn-Tx recipients, the Sevo group had histologically a tendency toward an attenuation of PGD and showed significantly lower levels of interleukin 6 (P = 0.01) in plasma, but higher levels of interleukin 10 (P < 0.01) in lungs. Allo-Tx grafts in Sevo Tx recipients showed attenuated AR with histologically significantly lower rejection scores (P = 0.03), fewer classical macrophages (F4/80+; P < 0.01), but more anti inflammatory activated macrophages (M2, CD206+; P < 0.01). Functionally, the Sevo group had a tendency toward improved oxygenation. CONCLUSIONS: We demonstrated that Sevo preconditioning has protective effects on lung transplants in both, PGD and AR. The observed amelioration may be attributed to suppressed inflammatory cytokines during PGD and the induction of alternatively activated macrophages during AR. These promising data could set the base for using Sevo preconditioning in donor lungs for a human trial. PMID- 28624056 TI - Evaluating the efficacy of different types of stem cells in preserving gut barrier function in necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants. Increased intestinal permeability is central to NEC development. We have shown that stem cells (SCs) can reduce the incidence and severity of NEC. Our current goal was to investigate the efficacy of four different types of SC in preservation of gut barrier function during NEC. MATERIALS AND METHODS: We compared (1) amniotic fluid-derived mesenchymal SC, (2) bone marrow-derived mesenchymal SC, (3) amniotic fluid-derived neural SC, and (4) enteric neural SC. Premature rat pups received an intraperitoneal injection of 2 * 106 SC or phosphate-buffered saline only and were then subjected to experimental NEC. Control pups were breastfed and not subjected to NEC. After 48 h, animals received a single enteral dose of fluorescein isothiocyanate -labeled dextran (FD70), were sacrificed 4 h later, and serum FD70 concentrations determined. RESULTS: Compared to breastfed, unstressed pups with intact gut barrier function and normal intestinal permeability (serum FD70 concentration 2.22 +/- 0.271 MUg/mL), untreated pups exposed to NEC had impaired barrier function with significantly increased permeability (18.6 +/- 4.25 MUg/mL, P = 0.047). Pups exposed to NEC but treated with SC had significantly reduced intestinal permeability: Amniotic fluid-derived mesenchymal SC (9.45 +/- 1.36 MUg/mL, P = 0.017), bone marrow-derived mesenchymal SC (6.73 +/- 2.74 MUg/mL, P = 0.049), amniotic fluid-derived neural SC (8.052 +/- 1.31 MUg/mL, P = 0.0496), and enteric neural SC (6.60 +/- 1.46 MUg/mL, P = 0.033). CONCLUSIONS: SCs improve gut barrier function in experimental NEC. Although all four types of SC reduce permeability equivalently, SC derived from amniotic fluid may be preferable due to availability at delivery and ease of culture, potentially enhancing clinical translation. PMID- 28624057 TI - Surveillance strategies in the follow-up of melanoma patients: too much or not enough? AB - BACKGROUND: After appropriate initial therapy for patients with stage II-III melanoma, there is no consensus regarding surveillance. Thus, follow-up is highly variable among institutions and individual providers. The National Comprehensive Cancer Network recommends routine clinical examination and consideration of imaging for stage IIB-IIIC every 3-12 mo with no distinction between stages. Detection of recurrence is important as novel systemic therapies and surgical resection of recurrence may provide survival benefits. METHODS: We retrospectively reviewed 369 patients with stage II and III melanoma treated at Ohio State University from 2009-2015, who underwent surgery as primary therapy. Two hundred forty-seven patients who were followed for a minimum of 6 mo after surgical resection to achieve no evidence of disease status (NED) were included in this analysis. One hundred twenty-two were lost to follow-up after surgery and were excluded. RESULTS: The rate of recurrence for stage IIA/IIB patients was 11% (14/125). Eleven of the 14 (79%) recurrences were detected by clinical symptoms or physical examination. Thirty-nine percent (49/125) of stage IIA or IIB patients were followed by clinical examination only, whereas 61% (76/125) were followed with at least two serial chest x-rays. The median time to first chest x ray after NED status was 4.7 mo (n = 76), median time to second chest x-ray after NED status was 12.7 mo (n = 76), and 66% (50/76) continued to have additional serial chest x-rays. At median follow-up of 35 mo for the 125 patients with stage IIA/IIB, there was no difference in survival between those followed clinically (95% [95% CI: 0.88-0.99]) versus those followed with at least two serial x-rays (96% [95% CI: 0.89-0.98]). For stage IIC/IIIA-C patients, recurrence was detected in 23% (28/122) at median follow-up 31.2 mo. Fifty percent of recurrences were detected by imaging in asymptomatic patients, whereas 50% (14/28) had recurrence detected on imaging associated clinical findings. Eighty-seven percent (106/122) of stage IIC/IIIA-C patients were followed with at least two serial whole body positron emission tomography/computed tomography (CT) scans or whole body CT scans plus brain magnetic resonance imaging; median time between NED status and second scan was 10.3 mo. Of stage IIC/IIIA-C patients with recurrence, 57% (16/28) went on to surgical resection of the recurrence, whereas 11 (39%) patients received B-RAF inhibitor therapy, immune blockade therapy, or combination therapy. CONCLUSIONS: For stage IIA and IIB melanoma, surveillance chest x-rays did not improve survival compared to physical examination alone. However, for stage IIC and IIIA-C melanoma, where the recurrence rates are higher, routine whole body imaging detected 50% of recurrences leading to additional surgery and/or treatment with novel systemic therapies for the majority of patients. Detection of melanoma recurrence is important and specific substage should be used to stratify risk and define appropriate follow-up. PMID- 28624059 TI - Exploring regional variability in utilization of antireflux surgery in children. AB - BACKGROUND: There is significant variation surrounding the indications, surgical approaches, and outcomes for children undergoing antireflux procedures (ARPs) resulting in geographic variation of care. Our purpose was to quantify this geographic variation in the utilization of ARPs in children. METHODS: A cross sectional analysis of the 2009 Kid's Inpatient Database was performed to identify patients with gastroesophageal reflux disease or associated diagnoses. Regional surgical utilization rates were determined, and a mixed effects model was used to identify factors associated with the use of ARPs. RESULTS: Of the 148,959 patients with a diagnosis of interest, 4848 (3.3%) underwent an ARP with 2376 (49%) undergoing a laparoscopic procedure. The Northeast (2.0%) and Midwest (2.2%) had the lowest overall utilization of surgery, compared with the South (3.3%) and West (3.4%). After adjustment for age, case-mix, and surgical approach, variation persisted with the West and the South demonstrating almost two times the odds of undergoing an ARP compared with the Northeast. Surgical utilization rates are independent of state-level volume with some of the highest case volume states having surgical utilization rates below the national rate. In the West, the use of laparoscopy correlated with overall utilization of surgery, whereas surgical approach was not correlated with ARP use in the South. CONCLUSIONS: Significant regional variation in ARP utilization exists that cannot be explained entirely by differences in patient age, race/ethnicity, case-mix, and surgical approach. In order to decrease variation in care, further research is warranted to establish consensus guidelines regarding indications for the use ARPs for children. PMID- 28624058 TI - Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis. AB - BACKGROUND: No treatment is available to reverse injury associated with traumatic brain injury (TBI). Progenitor cell therapies show promise in both preclinical and clinical studies. We conducted a meta-analysis of preclinical studies using progenitor cells to treat TBI. METHODS: EMBASE, MEDLINE, Cochrane Review, Biosis, and Google Scholar were searched for articles using prespecified search strategies. Studies meeting inclusion criteria underwent data extraction. Analysis was performed using Review Manager 5.3 according to a fixed-effects model, and all studies underwent quality scoring. RESULTS: Of 430 abstracts identified, 38 met inclusion criteria and underwent analysis. Average quality score was 4.32 of 8 possible points. No study achieved a perfect score. Lesion volume (LV) and neurologic severity score (NSS) outcomes favored cell treatment with standard mean difference (SMD) of 0.86 (95% CI: 0.64-1.09) and 1.36 (95% CI: 1.11-1.60), respectively. Rotarod and Morris water maze outcomes also favored treatment with improvements in SMD of 0.34 (95% CI: 0.02-0.65) and 0.46 (95% CI: 0.17-74), respectively. Although LV and NSS were robust to publication bias assessments, rotarod and Morris water maze tests were not. Heterogeneity (I2) ranged from 74%-85% among the analyses, indicating a high amount of heterogeneity among studies. Precision as a function of quality score showed a statistically significant increase in the size of the confidence interval as quality improved. CONCLUSIONS: Our meta-analysis study reveals an overall positive effect of progenitor cell therapies on LV and NSS with a trend toward improved motor function and spatial learning in different TBI animal models. PMID- 28624060 TI - Speed dating for mentors: a novel approach to mentor/mentee pairing in surgical residency. AB - BACKGROUND: Resident-resident mentoring offers significant benefits. Previous works have shown that the quality of the mentorship pairing is important, but techniques of pairing have seldom been described. We describe a system for mentor mentee pairing that we call "Speed Dating for Mentors" (SDM). METHODS: The SDM activity took place in an academic general surgery residency program in the Northeast. Senior residents met with junior residents (JR) in 90-second intervals. On completion of interviews, residents documented their top three choices-this was used to create senior-junior resident pairings. A cross sectional Likert survey was conducted with univariate analysis of satisfaction with the SDM event. RESULTS: Forty-two surgical residents participated in SDM-23 junior residents and 19 senior residents-resulting in 23 mentor-mentee pairings. Fourteen pairs were generated, where both mentor and mentee were among top three choices, seven pairings generated where either/or was a top three choice, and two pairings were assigned; six pairs were assigned for nonattendees. A total of 36 surveys were completed-28 (78%) respondents participated in SDM compared to eight (22%) who did not. Eighty-five percent of respondents who attended were "satisfied" or "very satisfied" with their pairing compared to only 12% of nonattendees (P = 0.001). CONCLUSIONS: "Speed dating" is a novel approach to forming mentorship pairings and identifying mentors/mentees with similar interests. Residents who attended the event were satisfied with the event and with the outcome of their mentor/mentee pairing. Further investigations are warranted to determine what effects resident mentoring has on resident performance, stress levels, and well-being. PMID- 28624061 TI - New noncontact sensor for detecting pulmonary tumors during video-assisted thoracic surgery. AB - BACKGROUND: Small pulmonary tumors are difficult to localize during video assisted thoracic surgery (VATS) because of lack of direct tissue contact. However, in partial lung resection, tumor localization is quite important. The aim of this study was to evaluate the safety and feasibility of a new noncontact sensor for detecting pulmonary nodules during VATS using human and porcine models. METHODS: The sensor, based on the principle of phase differences, comprises an air nozzle for producing air pulse jets and an optical fiber sensor to measure phase differences and visualize object stiffness. For in vivo assessment, we developed a porcine model by inserting plastic balls mimicking tumors into the pig lungs after thoracotomy and then scanned the lungs. The sensor sensitivity was evaluated by measuring the ratio of the depth of the ball from the lung surface to the ball diameter (D/S). For the ex vivo human model, partially resected lung tissue with tumors was obtained from six patients and then scanned. RESULTS: In the porcine model, 32 of 37 (86.5%), 70 of 94 (74.5%), and 60 of 100 (60.0%) tumors were detected in the categories D/S <= 1, 1 < D/S <= 2, and D/S > 2, respectively. Sensor safety was confirmed with an air jet at pressures between 0.05 and 0.15 MPa directed onto the lung surface; all the examined lungs including the pleura remained intact microscopically. In six patients, all nodules were successfully detected. CONCLUSIONS: Our noncontact sensor is a safe and feasible tool for detecting small pulmonary tumors during VATS. PMID- 28624062 TI - Diosmetin protects against ischemia/reperfusion-induced acute kidney injury in mice. AB - BACKGROUND: Renal ischemia/reperfusion (I/R)-induced acute kidney injury remains to be a troublesome condition in clinical practice. Although the exact molecular mechanisms underlying renal I/R injury are incompletely understood, the deleterious progress of renal I/R injury involves inflammation, apoptosis, and oxidative stress. Diosmetin is a member of the flavonoid glycosides family, which suppresses the inflammatory response and cellular apoptosis and enhances antioxidant activity. The purpose of this study was to investigate the protective effect of diosmetin on I/R-induced renal injury in mice. METHODS: Thirty BALB/c mice were randomly divided into five groups. Four groups of mice received diosmetin (0.25, 0.5, and 1 mg/kg) or vehicle (I/R group) before ischemia. Another group received vehicle without ischemia to serve as a negative control (sham-operated group). Twenty-four hours after reperfusion, serum and renal tissues were harvested to evaluate renal function and histopathologic features. In addition, the expression of inflammation-related proteins, apoptotic molecules, and antioxidant enzymes was analyzed. RESULTS: Compared with sham mice, the I/R group significantly exacerbated renal function and renal tube architecture and increased the inflammatory response and renal tubule apoptosis. Nevertheless, pretreatment with diosmetin reversed these changes. In addition, diosmetin treatment resulted in a marked increase in antioxidant protein expression compared with I/R mice. CONCLUSIONS: The renoprotective effects of diosmetin involved suppression of the nuclear factor-kappaB and mitochondrial apoptosis pathways, as well as activation of the nuclear factor erythroid 2 related factor 2/heme oxygenase-1 pathway. Diosmetin has significant potential as a therapeutic intervention to ameliorate renal injury after renal I/R. PMID- 28624063 TI - Acceptance of adjuvant chemotherapy recommendations in early-stage hormone positive breast cancer. AB - BACKGROUND: The role of systemic chemotherapy in early-stage, estrogen receptor (ER)-positive, and Her2-negative breast cancer remains an area of active investigation. The decision to recommend chemotherapy is multifactorial, and some patients decline recommended chemotherapy. We sought to identify patient factors leading to refusal of adjuvant therapy. MATERIALS AND METHODS: Data were collected from National Comprehensive Cancer Network Outcomes database and used to identify patients with primary, unilateral, T1-T2, N0, ER+, Her2-disease diagnosed from 2005-2011. Patient and clinical characteristics were analyzed for associations with physician recommendation for chemotherapy and patient acceptance of chemotherapy. A logistic regression model was used to identify patient and tumor characteristics associated with recommendation for and acceptance of chemotherapy. RESULTS: A total of 329 patients were identified. Chemotherapy was recommended in 191 patients (58.1%) and not in 138 (41.9%). Young age (odds ratio [OR]: 3.9, 95% confidence interval [CI]: 1.2-12.7), large tumor size (6.69, 95% CI: 3.31-13.5), and high Oncotype DX scores (11.2, 95% CI: 4.5-27.9) were more likely to receive a recommendation. About 71 patients (37.1%) refused chemotherapy. Patients younger than age 50 (20.9, 95% CI: 2.5-172.0), larger tumor size (3.4, 95% CI: 1.3-8.7), Oncotype DX score > 31 (31.3, 95% CI: 3.3-295.0), privately insured (8.2, 95% CI: 1.9-34.7), and Hispanic ethnicity (5.2, 95% CI: 1.6-16.8) were more likely to accept chemotherapy. CONCLUSIONS: Physician recommendations for adjuvant chemotherapy for early-stage ER + breast cancer varied by commonly considered factors. Patient acceptance varied by similar factors but was also influenced by race and insurance status. This may be explained by cultural or social factors not well understood or not overcome by physician guidance. PMID- 28624064 TI - Assessing written communication during interhospital transfers of emergency general surgery patients. AB - BACKGROUND: Poor communication causes fragmented care. Studies of transitions of care within a hospital and on discharge suggest significant communication deficits. Communication during transfers between hospitals has not been well studied. We assessed the written communication provided during interhospital transfers of emergency general surgery patients. We hypothesized that patients are transferred with incomplete documentation from referring facilities. METHODS: We performed a retrospective review of written communication provided during interhospital transfers to our emergency department (ED) from referring EDs for emergency general surgical evaluation between January 1, 2014 and January 1, 2016. Elements of written communication were abstracted from referring facility documents scanned into the medical record using a standardized abstraction protocol. Descriptive statistics summarized the information communicated. RESULTS: A total of 129 patients met inclusion criteria. 87.6% (n = 113) of charts contained referring hospital documents. 42.5% (n = 48) were missing history and physicals. Diagnoses were missing in 9.7% (n = 11). Ninety-one computed tomography scans were performed; among 70 with reads, final reads were absent for 70.0% (n = 49). 45 ultrasounds and x-rays were performed; among 27 with reads, final reads were missing for 80.0% (n = 36). Reasons for transfer were missing in 18.6% (n = 21). Referring hospital physicians outside the ED were consulted in 32.7% (n = 37); consultants' notes were absent in 89.2% (n = 33). In 12.4% (n = 14), referring documents arrived after the patient's ED arrival and were not part of the original documentation provided. CONCLUSIONS: This study documents that information important to patient care is often missing in the written communication provided during interhospital transfers. This gap affords a foundation for standardizing provider communication during interhospital transfers. PMID- 28624065 TI - Trends in open and endoscopic carpal tunnel release utilization in the Medicare patient population. AB - BACKGROUND: Surgical management of carpal tunnel syndrome (CTS) is performed with an open or endoscopic approach. Current literature suggests that the endoscopic approach is associated with higher costs and a steeper learning curve. This study evaluated the billing and utilization trends of both approaches. METHODS: A retrospective review of a Medicare database within the PearlDiver Supercomputer (Warsaw, IN) was performed for patients undergoing open carpal tunnel release (OCTR) or endoscopic carpal tunnel release (ECTR) from 2005-2012. Annual utilization, charges, reimbursement, demographic data, and compound annual growth rate (CAGR) were evaluated. RESULTS: Our query returned 1,500,603 carpal tunnel syndrome patients, of which 507,924 (33.8%) and 68,768 (4.6%) were surgically managed with OCTR and ECTR respectively (remainder treated conservatively). Compound annual growth rate was significantly higher in ECTR (5%) than OCTR (0.9%; P < 0.001). Average charges were higher in OCTR ($3820) than ECTR ($2952), whereas reimbursements were higher in ECTR (mean $1643) than OCTR (mean $1312). Both were performed most commonly in the age range of 65-69 y, females, and southern geographic region. CONCLUSIONS: ECTR is growing faster than OCTR in the Medicare population. Contrary to previous literature, our study shows that ECTR had lower charges and reimbursed at a higher rate than OCTR. PMID- 28624066 TI - Complexity of medical decision-making in care provided by surgeons through patient portals. AB - BACKGROUND: Patient portals are online applications that allow patients to interact with healthcare organizations and view information. Portal messages exchanged between patients and providers contain diverse types of communications, including delivery of medical care. The types of communications and complexity of medical decision-making in portal messages sent to surgeons have not been studied. MATERIALS AND METHODS: We obtained all message threads initiated by patients and exchanged with surgical providers through the Vanderbilt University Medical Center patient portal from June 1 to December 31, 2014. Five hundred randomly selected messages were manually analyzed by two research team members to determine the types of communication (i.e., informational, medical, logistical, or social), whether medical care was delivered, and complexity of medical decision-making as defined for outpatient billing in each message thread. RESULTS: A total of 9408 message threads were sent to 401 surgical providers during the study period. In the 500 threads selected for detailed analysis, 1293 distinct issues were communicated, with an average of 2.6 issues per thread. Medical needs were communicated in 453 message threads (90.6%). Further, 339 message threads (67.8%) contained medical decision-making. Overall complexity of medical decision-making was straightforward in 210 messages (62%), low in 102 messages (30%), and moderate in 27 messages (8%). No highly complex decisions were made over portal messaging. CONCLUSIONS: Through patient portal messages, surgeons deliver substantial medical care with varied levels of medical complexity. Models for compensation of online care must be developed as consumer and surgeon adoption of these technologies increases. PMID- 28624067 TI - Letter to the Editor: Hydrophobic interactions in the caseins: Challenging their dismissal by Holt et al. (2013). PMID- 28624068 TI - Letter to the Editor: A response to Horne and Lucey (2017). PMID- 28624069 TI - Corrigendum to "Factors affecting milking speed in Murciano-Granadina breed goats" (J. Dairy Sci. 99:10102-10108). PMID- 28624070 TI - Corrigendum to "Determination of ultra-low milk fat content using dual-wavelength ultraviolet spectroscopy" (J. Dairy Sci. 99:9652-9658). PMID- 28624071 TI - Corrigendum to "Genetic parameters for lactose and its correlation with other milk production traits and fitness traits in pasture-based production systems" (J. Dairy Sci. 100:3754-3766). PMID- 28624072 TI - Violent events on the road: Risk perception of traffic-related and non traffic related situations. AB - This study aimed at identifying and comparing subjective risk perception regarding two different violent situations in urban roads: traffic accidents (i.e. crashes) and robberies. A robbery consists of subtracting something from someone, while seriously threatening the victim, or using violence. Robberies can be perpetrated either with or without the use of a weapon. This study was carried out in the city of Uberlandia, a medium size city in the state of Minas Gerais, south-east Brazil. A total of 383 people was interviewed at home in two boroughs of Uberlandia, using a questionnaire divided in five parts: a) personal information; b) description of crash involvement; c) description of robbery involvement; d) the chance of being involved in a crash and in a robbery within the next three years; e) willingness to pay for more safety in traffic or for more security against robberies; f) what causes more damage or harm to society, crashes or robberies. Descriptive figures are shown for the sample which reported 1.44 crashes/person. More than half of those involved in crashes (56%) were injured and 75% of these needed hospital care. There were 1.15 robberies/person. Only 7% of those involved in robberies were injured, none of them hospitalized. During robberies, 57.3% of the respondents were threatened with weapons. Car drivers were more subject to crashes (40%) and pedestrians were more subject to robberies (78%). Risk perception of being involved in a robbery within the next three years and when on the streets of the local borough is higher than crash risk perception. Respondents thought of dying in 25.5% of the crashes and in 46.3% of the robberies. A large group (63.7% of the sample) declared the willingness to pay for more personal security rather than for more traffic safety. Statistical analysis is presented in an attempt to study the relationship between variables. As expected, the respondents' subjective risk perception appears to contradict objective risk. Instinctively, interviewees might perceive robberies as a greater threat than crashes, perhaps reflecting lightly on the latter. In countries with high crash and violent incident statistics such results could be used to orientate traffic safety policies, education and campaigns, concentrating on the outcomes of crashes. PMID- 28624073 TI - Predicting extension of cracks to the root from the dimensions in the crown: A preliminary in vitro study. AB - BACKGROUND: In this study, the authors investigated whether extension of a tooth crack into the root can be predicted by the appearance of the crack in the crown in vitro. METHODS: The authors obtained 22 cracked teeth from 22 patients who underwent extraction, and they scanned the teeth using microcomputed tomography. The length and width of the crack on the occlusal surface (LOS and WOS, respectively) and the length of the crack on the proximal surface (LCPS) were measured on 3-dimensional reconstruction images. The pulp chamber roof was penetrated and removed. A crack line visible under the microscope only on the access cavity wall rather than extending to the bottom of the pulp chamber was termed a "nonroot crack." A crack seen at the bottom of the pulp chamber or root wall was termed a "root crack." The authors analyzed the data using Pearson correlation coefficients and receiver operating characteristic curves. RESULTS: There was a significant correlation between the LOS and LCPS (correlation coefficient, 0.782; P < .001) and between the WOS and LCPS (correlation coefficient, 0.651; P < .05). The LCPS increased by 1.195 millimeters for every 1 mm increase in the LOS. The area under the receiver operating characteristic curve was 0.839 (95% confidence interval, 0.659 to 1.000) for LOS and 0.760 (95% confidence interval, 0.557 to 0.964) for WOS. CONCLUSIONS: The extent of a crown crack may indicate how far the crack extends to the root. Both the LOS and WOS may be valuable for assessing whether a crack involves the root, although the LOS seems to be more useful. PRACTICAL IMPLICATIONS: The dimensions of a crack in a crown provide a helpful approach for predicting the depth of the crack and its likely prognosis. PMID- 28624074 TI - Evaluating quality of dental care among patients with diabetes: Adaptation and testing of a dental quality measure in electronic health records. AB - BACKGROUND: Patients with diabetes are at increased risk of developing oral complications, and annual dental examinations are an endorsed preventive strategy. The authors evaluated the feasibility and validity of implementing an automated electronic health record (EHR)-based dental quality measure to determine whether patients with diabetes received such evaluations. METHODS: The authors selected a Dental Quality Alliance measure developed for claims data and adapted the specifications for EHRs. Automated queries identified patients with diabetes across 4 dental institutions, and the authors manually reviewed a subsample of charts to evaluate query performance. After assessing the initial EHR measure, the authors defined and tested a revised EHR measure to capture better the oral care received by patients with diabetes. RESULTS: In the initial and revised measures, the authors used EHR automated queries to identify 12,960 and 13,221 patients with diabetes, respectively, in the reporting year. Variations in the measure scores across sites were greater with the initial measure (range, 36.4-71.3%) than with the revised measure (range, 78.8-88.1%). The automated query performed well (93% or higher) for sensitivity, specificity, and positive and negative predictive values for both measures. CONCLUSIONS: The results suggest that an automated EHR-based query can be used successfully to measure the quality of oral health care delivered to patients with diabetes. The authors also found that using the rich data available in EHRs may help estimate the quality of care better than can relying on claims data. PRACTICAL IMPLICATIONS: Detailed clinical patient-level data in dental EHRs may be useful to dentists in evaluating the quality of dental care provided to patients with diabetes. PMID- 28624075 TI - Eosinophilia, pruritic exanthema and digital necrosis. PMID- 28624076 TI - Development of the digestive system. PMID- 28624077 TI - Water - Only a simple molecule? PMID- 28624078 TI - Effect of added ingredients on water status and physico-chemical properties of tomato sauce. AB - Different ingredients (guar, xanthan, carboxy methyl cellulose, locust bean gums, potato fiber, milk, potato and soy proteins) were added to tomato sauce to investigate their effect on its physico-chemical properties. The products were characterized in terms of colour, rheological properties (Bostwick consistency, flow behavior and consistency coefficient), water status (water activity, moisture content) and molecular mobility by 1H Nuclear Magnetic Resonance (NMR). Water activity was significantly decreased only by the addition of potato fiber. Xanthan, locust bean, guar and carboxy methyl cellulose significantly enhanced Bostwick consistency and consistency coefficient. Type of ingredient and concentration significantly affected 1H NMR mobility indicators. Principal component analysis (PCA) indicated that only 1H NMR mobility parameters were able to differentiate the effect of milk protein, xanthan and potato fiber on tomato sauce properties. The information collected in this work provides information to intelligently modulate tomato sauce attributes and tailor its properties for specific applications. PMID- 28624080 TI - Impact of the homogenization process on the structure and antioxidant properties of chitosan-lignin composite films. AB - This work investigated the impact of two homogenization treatments, High Shear (HS) and High Pressure (HP), on the structure and antioxidant activity of chitosan-lignin bio-composite films. Laser light scattering analysis revealed that smaller lignin particles were obtained after HP processing, around 0.6MUm, compared to HS treatment, between 2.5 and 5MUm. Moreover, these particles were more homogeneously distributed in the chitosan film matrix after HP process, while some aggregates remained after HS treatment, as highlighted by two-photon microscopy. The surface hydrophobicity of the composite films, as measured by water contact angle, increased after the two homogenization treatments. Finally, the antioxidant activity of the composite films was determined using the DPPH. assay. No significant difference in the radical scavenging activity was noticeable, neither after HS nor HP processing. However, a migration of lignin residues from the film to the extraction medium was noticed, particularly for HP process. PMID- 28624079 TI - Effect of the state of water and relative humidity on ageing of PLA films. AB - Various types of food are now commercialized in packaging materials based on poly(lactic acid) (PLA) due to its eco-friendly nature. However, one of the main limitations related to PLA is its reactivity with water. For food applications, it is of critical importance to better understand the hydrolysis of PLA driven by water molecules either in liquid or in vapour state. This work focuses on the modifications of PLA induced by water when simulating contact with semi-dry foods (aw~0.5), high moisture foods (aw~1) and liquid foods (aw~1). This study undoubtedly shows that both the chemical potential of water and its physical state influence the hydrolytic degradation of PLA films. From a practical point of view, PLA packaging is very well suited for semi-dry foods, but is highly sensitive to high moisture and liquid foods. PMID- 28624081 TI - pH-dependent complexation of lysozyme with low methoxyl (LM) pectin. AB - In order to understand the effect of pH on the formation of electrostatic complexes between lysozyme and low methoxyl (LM) pectin, mixtures were prepared at a fixed lysozyme concentration (0.714g.L-1) by progressive addition of LM pectin (from 0 to 4g.L-1). Turbidity analysis allowed to determine specific conditions of pH and lysozyme/LM pectin ratio for optimal complex aggregation. The intrinsic fluorescence enhancement observed upon binding of LM pectin to lysozyme was correlated with the formation of intermolecular aggregates. Conversely, the intrinsic fluorescence decrease observed at higher LM pectin amounts was correlated with the dissociation of intermolecular aggregates. UV absorption spectroscopy showed modifications in lysozyme conformation during both the aggregation phase and the dissociation phase. The role of electrostatic interactions in the formation of lysozyme/LM pectin complexes is discussed in relation to the overall structure and the charge density profile of the two biopolymers. PMID- 28624082 TI - The influence of carrier material on some physical and structural properties of carrot juice microcapsules. AB - This study investigates the effect of carrier type on the physical and structural properties of microcapsules of pure carrot juice. Low-crystallised maltodextrin (MD), gum arabic (GA), mixtures of MD and GA (1:1; 2:1; 3:1) and whey protein isolate (WPI) were used as carriers. Microencapsulation was carried out in a spray-drier at inlet air temperature of 160 degrees C. Powders were investigated for dry matter, water activity, diameter, carotene content and hygroscopicity. In addition, differential scanning calorimetry (DSC) and time domain nuclear magnetic resonance (TD-NMR) were applied to analyse microcapsules glass transition temperature (Tg). Carrot powders with GA used as a carrier material resulted in better carotenoids retention and higher stability of powders in terms of higher Tg, lower aw and good hygroscopic properties. However, all powders showed a low aw (below 0.26) and high dry matter content (98-99%) indicating a good potential for protection of microencapsulated carotenoids during the storage. PMID- 28624083 TI - Effect of the type of brewing water on the chemical composition, sensory quality and antioxidant capacity of Chinese teas. AB - The physicochemical characteristics, sensory quality, and antioxidant activity of tea infusions prepared with purified water (PW), mineral water (MW), mountain spring water (MSW), and tap water (TW) from Hangzhou were investigated. The results showed that the taste quality, catechin concentration, and antioxidant capacity of green, oolong, and black tea infusions prepared using MW and TW were significantly lower than those prepared using PW. Extraction of catechins and caffeine was reduced with high-conductivity water, while high pH influenced the stability of catechins. PW and MSW were more suitable for brewing green and oolong teas, while MSW, with low pH and moderate ion concentration, was the most suitable water for brewing black tea. Lowering the pH of mineral water partially improved the taste quality and increased the concentration of catechins in the infusions. These results aid selection of the most appropriate water for brewing Chinese teas. PMID- 28624084 TI - Water diffusion to assess meat microstructure. AB - In the quest for setting up rapid methods to evaluate water retention ability of meat microstructures, time domain nuclear magnetic resonance (TD-NMR) has gained a prominent role, due to the possibility to observe water located outside the myofibrils, easily lost upon storage or cooking. Diffusion weighted signals could be used to monitor the shape and dimension of the pores in which water is confined, thus boosting the information offered by TD-NMR. The work outlines a parsimonious model to describe relative abundance and diffusion coefficient of intra and extra myofibrillar water populations, exchange rate between them, diameter of the myofibrillar cells. To test our model, we registered diffusion and T2 weighted NMR signals at 20MHz on fresh meat from pectoralis major muscle of 100days old female turkey. We then purposely altered water distribution and myofibrils shape by means of freezing. The model predicted nicely the consequences of the imposed modifications. PMID- 28624085 TI - Multi-scale NMR and MRI approaches to characterize starchy products. AB - This review deals with the use of Nuclear Magnetic Resonance techniques to monitor the behavior of starch as well as the migration and distribution of water during the processing or storage of starchy matrices. The aim is to emphasize the potentials of NMR techniques for the quantitative characterization of water transfers in starch-water systems on different length scales. Relaxation and self diffusion experiments using low-field NMR spectrometry provided important information on the relationship between water dynamics and the microscopic organization of starch granules at various temperatures and water contents. Some works dealt with the botanical origin of starch but also the impact of possible additives. Indeed, the investigation on model starch-based systems was recently expanded to more complex real systems, including dough, bread, cakes, spaghetti and lasagna. Two-dimensional (2D) cross correlation methods have also been developed to elucidate chemical and diffusional proton exchange phenomena, and to improve the interpretation of results obtained in 1D. Finally, magnetic resonance micro-imaging methods were developed to study or to quantify water intake into starch-based matrices. PMID- 28624086 TI - RH-temperature phase diagrams of hydrate forming deliquescent crystalline ingredients. AB - Several common deliquescent crystalline food ingredients (including glucose and citric acid) are capable of forming crystal hydrate structures. The propensity of such crystals to hydrate/dehydrate or deliquesce is dependent on the environmental temperature and relative humidity (RH). As an anhydrous crystal converts to a crystal hydrate, water molecules internalize into the crystal structure resulting in different physical properties. Deliquescence is a solid-to solution phase transformation. RH-temperature phase diagrams of the food ingredients alpha-d-glucose and citric acid, along with sodium sulfate, were produced using established and newly developed methods. Each phase diagram included hydrate and anhydrate deliquescence boundaries, the anhydrate-hydrate phase boundary, and the peritectic temperature (above which the hydrate was no longer stable). This is the first report of RH-temperature phase diagrams of glucose and citric acid, information which is beneficial for selecting storage and processing conditions to promote or avoid hydrate formation or loss and/or deliquescence. PMID- 28624087 TI - Using complexation for the microencapsulation of nisin in biopolymer matrices by spray-drying. AB - The aim of this study is to investigate the potential of complexation to encapsulate nisin (5g/L concentration) using spray-drying technique and to evaluate how complexation with pectin or alginate (2g/L concentration) can preserve nisin structure and antimicrobial activity. Spray-drying of nisin-low methoxyl pectin or nisin-alginate electrostatic complexes has led to the microencapsulation of the peptide in different networks that were highly influenced by the polysaccharide type. Turbidity and particle size measurements indicated that while spray-drying promoted the aggregation of nisin-pectin complexes, it favored the dissociation of nisin-alginate aggregates to form individual complexes. Structural changes of nisin induced by complexation with pectin or alginate and spray-drying were studied by using UV-Vis absorption and fluorescence spectroscopy. The results showed that complexation with pectin or alginate preserved nisin structure as well as its antimicrobial activity during spray-drying. PMID- 28624088 TI - Nootkatone encapsulation by cyclodextrins: Effect on water solubility and photostability. AB - Nootkatone (NO) is a sesquiterpenoid volatile flavor, used in foods, cosmetics and pharmaceuticals, possessing also insect repellent activity. Its application is limited because of its low aqueous solubility and stability; this could be resolved by encapsulation in cyclodextrins (CDs). This study evaluated the encapsulation of NO by CDs using phase solubility studies, Isothermal Titration Calorimetry, Nuclear Magnetic Resonance spectroscopy and molecular modeling. Solid CD/NO inclusion complex was prepared and characterized for encapsulation efficiency and loading capacity using UV-Visible. Thermal properties were investigated by thermogravimetric-differential thermal analysis and release studies were performed using multiple headspace extraction. Formation constants (Kf) proved the formation of stable inclusion complexes. NO aqueous solubility, photo- and thermal stability were enhanced and the release could be insured from solid complex in aqueous solution. This suggests that CDs are promising carrier to improve NO properties and, consequently, to enlarge its use in foods, cosmetics, pharmaceuticals and agrochemicals preparations. PMID- 28624089 TI - Moisture evaluation of beta-cyclodextrin/fish oils complexes by thermal analyses: A data review on common barbel (Barbus barbus L.), Pontic shad (Alosa immaculata Bennett), European wels catfish (Silurus glanis L.), and common bleak (Alburnus alburnus L.) living in Danube river. AB - The moisture content of beta-cyclodextrin/Danube fish oils complexes (common barbel, Pontic shad, European wels catfish, common bleak) was evaluated by thermal methods. Saturated and monounsaturated fatty acids were the most concentrated in fish oils (25.3-30.8% and 36.1-45.0%). omega-3 And omega-6 fatty acids were identified in low concentrations of 2.8-12.1% and 4.1-7.1%. The moisture content was significantly lowered after beta-CD complexation, as revealed by thermogravimetric (TG) analysis (13.3% for beta-CD, 2.5-6.5% for complexes). These results are consistent with the differential scanning calorimetry (DSC) data for the peaks corresponding to dissociation of water (calorimetric effect of 536Jg-1 for beta-cyclodextrin and 304-422.5Jg-1 for complexes). Furthermore, both TG and DSC results support the formation of inclusion complexes. This is the first study on the nanoencapsulation of Danube fish oils in beta-cyclodextrin. PMID- 28624090 TI - Influence of different drying methods on the physicochemical properties of red beetroot (Beta vulgaris L. var. Cylindra). AB - There is an increased interest in preserving fruits and vegetables by drying. The novelty of this study consists in the combination of the following three drying methods: free convection (at 50, 60, and 70 degrees C), forced convection at 40 degrees C and 315W microwave power. The aim of this study was to investigate the effects of the drying conditions on red beetroot (Beta vulgaris L.) in terms of betalain variance, and polyphenol, microstructure changes (SEM). A strong thermal shock, provided by convection at 60 degrees followed by microwave wattage 315W/9min, leads to a better preservation of bioactive compounds content (0.631+/ 0.0042mg/g of betacyanin and 0.795+/-0.0019mg/g betaxanthin) when compared to convection at 50, 60 and 70 degrees C. The results showed that combined drying methods led to a significant preservation of the phytochemical content as compared to the traditional methods. PMID- 28624091 TI - Study of biopolymer mobility and water dynamics in wheat bran using time-domain 1H NMR relaxometry. AB - In this study, the molecular mobility of water and biopolymers in coarse, ground, and pericarp-enriched (PE) wheat bran and refined flour was investigated using time-domain proton nuclear magnetic resonance relaxometry, and related to their hydration properties. Several specific proton populations were present in the bran samples but not in flour. These populations were mainly assigned to protons of bran-related compounds such as arabinoxylan, cellulose, and lipids. All bran samples showed similar proton distributions at a 44% moisture level, although the chemical composition of coarse/ground bran and PE bran differed. When bran was further moistened up to 80%, an additional, more mobile water peak was noticed in coarse and PE bran, but not in ground bran. This can be explained by the fact that coarse and PE bran hold more weakly bound water than ground bran, which is most probably water entrapped in between bran particles. PMID- 28624092 TI - Study on the effects of wheat bran incorporation on water mobility and biopolymer behavior during bread making and storage using time-domain 1H NMR relaxometry. AB - Water binding is suggested to be key in the deleterious effect of wheat bran on bread quality. This study investigates water mobility and biopolymer behavior during bran-rich bread making and storage, using 1H NMR. Coarse, ground, and pericarp-enriched bran were incorporated in bread dough, and their impact on freshly baked and stored bread properties was assessed. Compared to wheat flour control dough, bran incorporation resulted in a progressive immobilization of water during dough resting, which could be linked to changes in evolution of dough height during fermentation and oven rise. This, together with modified starch gelatinization behavior upon baking, can be related with the inferior quality of bran-rich breads. The impact was most pronounced with pericarp enriched bran. Textural quality during storage was less affected for coarse or ground bran-rich bread compared to wheat flour bread, which could be principally attributed to retardation of amylopectin retrogradation in the presence of bran. PMID- 28624093 TI - Osmotic dehydration of organic kiwifruit pre-treated by pulsed electric fields and monitored by NMR. AB - Osmotic dehydration (OD) is a widely used preservation technique that consists in the reduction in food water activity by the immersion of the biological tissue in hypertonic solutions. The aim of this work was to analyze the effect of pulsed electric fields (PEF) in mass transfer as a pre-treatment of the OD using NMR. In this sense, PEF pre-treatments were done using three different voltages (100, 250 and 400V/cm) and 60 number of pulse. The OD of kiwifruit was carried out in 61.5% of sucrose solution at 25 degrees C, for a contact period from 0 to 120min. The water distribution into the cellular tissue was studied by NMR relaxometry. In conclusion, NMR is an excellent technique for quantifying water molecules according to their interactions in the fruit tissue, obtaining the adsorbed water and opening the possibility to apply the BET model to fit the adsorbed isotherm over the whole range of water activity. PMID- 28624094 TI - The impact of pulsed electric fields and ultrasound on water distribution and loss in mushrooms stalks. AB - Pulsed electric fields (PEF) and ultrasound (US) are promising innovative technologies with the potential to increase mass transfer when combined with further processes which in turn can provide potential benefits in the recovery of valuable compounds from food by-products. To provide evidence of the mechanism of mass transfer enhancement, the present study assessed the impact of PEF and US treatments, applied individually and in combination, at low and high temperatures, on the tissue microstructure of mushroom stalks. Different indices such as quantitative water redistribution, water loss and qualitative release of compounds were evaluated. The combination of these physical methods demonstrated that PEF redistributed a greater proportion of intracellular water into extracellular spaces than US. However, the application of high temperature treatments alone showed an even greater proportion of intracellular water migration compared to PEF. When PEF was combined with US at low temperatures the difference was not significant. PMID- 28624095 TI - Fontan Circulation over Time. AB - The unique, unphysiological Fontan circulation is associated with an impaired functional status of the patients that is suggested to deteriorate over time. Unfortunately, previous studies did not integrate both pulmonary and cardiac determinants of functional status. In addition, a comparison with the natural decrease in exercise capacity in healthy subjects (in both children and adults) is lacking. This single-center study aims to investigate the functional status in a cohort of Fontan patients in relation to time since Fontan completion and to identify its determinants, including cardiac characteristics and pulmonary characteristics. Eighty-five consecutive Fontan patients >=10 years who performed adequate cardiopulmonary exercise testing (respiratory exchange ratio >1.01) were included. Mean time since Fontan completion was 15 +/- 9 years (range 2 to 37 years). New York Heart Association functional class was I in 36 patients (42%), II in 41 patients (48%), and III in 8 patients (9%). Peak oxygen uptake during exercise (VO2 index) was 25.7 +/- 7.9 ml/min/m2 (58 +/- 14% of predicted). New York Heart Association functional class and peak VO2 index both correlated with time since the Fontan operation; however, peak VO2 as percentage of predicted (VO2(pred)) did not. In multivariate analyses, peak VO2(pred) was independently associated with maximum heart rate, oxygen pulse at peak exercise, and forced expiratory volume in 1 second (R2 = 0.579) but not with cardiac output in rest. In conclusion, the present data suggest that functional status in Fontan patients is impaired already shortly after Fontan completion, whereas its subsequent deterioration seems to follow the natural decline of aging. Furthermore, functional status in Fontan patients correlates with pulmonary function and cardiac functional parameters during exercise but not with conventional cardiac measurements at rest. PMID- 28624097 TI - Serum Zonulin, Gut Permeability, and the Pathogenesis of Autism Spectrum Disorders: Cause, Effect, or an Epiphenomenon? PMID- 28624096 TI - A Multiregional, Randomized Evaluation of the Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients With Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol. AB - This phase 3, multiregional, randomized, double-blind, placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin +/- other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein (LDL-C) goal (as per the National Cholesterol Education Program Adult Treatment Panel III guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of statin +/- other lipid-modifying therapies and with LDL-C >=70 to <115, >=100 to <145, >=130, or >=160 mg/dl for very high, high, moderate, or low CHD risk or at LDL-C goal (per CHD risk category) with HDL-C <=40 mg/dl were randomized in a ratio of 1:1 to anacetrapib 100 mg (n = 290) or placebo (n = 293) for 24 weeks, followed by a 12-week off-drug phase. The co-primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib. Treatment with anacetrapib reduced LDL-C (BQ) by 37% (95% confidence interval -42.5, -31.0) and increased HDL-C by 118% (95% confidence interval 110.6, 125.7) relative to placebo (p <0.001 for both). Anacetrapib also reduced non-HDL-C, apolipoprotein B, and lipoprotein a and increased apolipoprotein AI versus placebo (p <0.001 for all). There were no clinically meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes, creatine kinase, blood pressure, electrolytes, or adjudicated cardiovascular events. Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low HDL-C. PMID- 28624098 TI - Utility of Neurovascular Imaging in Acute Neonatal Arterial Ischemic Stroke. AB - OBJECTIVE: To evaluate the prevalence of magnetic resonance angiography (MRA) findings and clinically characterize neonates with arterial ischemic stroke (AIS) who have abnormal or variable vasculature. STUDY DESIGN: This was a single center, retrospective study of patients with neonatal stroke from 1991 to 2012. We reviewed charts and neuroimaging, including MRA, in neonates with AIS. Clinical data of patients with MRA findings were compared with the control group of neonates with AIS and a normal MRA. RESULTS: We identified 142 cases of neonatal AIS, of which 81 patients had magnetic resonance imaging and MRA. Among the neonates with arterial neuroimaging, 29 had arterial findings (for a prevalence rate of 20%-35%). The majority of the findings were stenotic or hypoplastic branches. Two patients had presumed carotid artery dissection. Low Apgar scores and the presence of sepsis were significantly (P <.05) more common in neonates with MRA findings. CONCLUSION: The prevalence of arterial abnormalities or variations in neonatal AIS has been underestimated because neurovascular imaging is often not performed. We recommend an MRA for neonates with AIS, particularly those who have low Apgar scores and/or sepsis, to rule out a vasculopathy that may warrant therapeutic intervention. PMID- 28624100 TI - Liver failure and liver transplantation. PMID- 28624101 TI - Reversal of liver fibrosis: From fiction to reality. AB - In chronic liver diseases, an ongoing hepatocellular injury together with inflammatory reaction results in activation of hepatic stellate cells (HSCs) and increased deposition of extracellular matrix (ECM) termed as liver fibrosis. It can progress to cirrhosis that is characterized by parenchymal and vascular architectural changes together with the presence of regenerative nodules. Even at late stage, liver fibrosis is reversible and the underlying mechanisms include a switch in the inflammatory environment, elimination or regression of activated HSCs and degradation of ECM. While animal models have been indispensable for our understanding of liver fibrosis, they possess several important limitations and need to be further refined. A better insight into the liver fibrogenesis resulted in a large number of clinical trials aiming at reversing liver fibrosis, particularly in patients with non-alcoholic steatohepatitis. Collectively, the current developments demonstrate that reversal of liver fibrosis is turning from fiction to reality. PMID- 28624102 TI - Hepatitis E virus: A potential threat for patients with liver disease and liver transplantation. AB - Immunocompromised patients are at risk of acquiring acute hepatitis E virus infection (HEV), leading to chronicity. Chronic HEV infection is associated with persistent viraemia, raised transaminase activity, histological features associated with chronic hepatitis and evidence of rapid development of cirrhosis. Extrahepatic manifestations have been associated with HEV. Most frequently reported are neurological disorders with predominantly involvement of the peripheral nervous system. In patients using immunosuppressive drugs antibody production is often delayed and HEV RNA detection is superior to serology to detect infection. Therapeutic options for chronic HEV includes tapering immunosuppressive and secondly ribavirin, pegylated interferon alpha (PEG-IFN). Present recommendation is to treat chronic HEV patients for 3 months, asses serum HEV RNA and stool HEV RNA and stop therapy if both are undetectable. Studies are required to determine which other antiviral agents than ribavirin and (PEG-)IFN are of clinical utility in treating HEV in the minority of patients who do not respond to ribavirin. PMID- 28624099 TI - Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention. AB - Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide. Strategies to improve their treatment and prevention are global priorities and major focus of World Health Organization's joint prevention programs. Emerging evidence suggests that modifiable risk factors including diet, sedentary lifestyle, obesity and tobacco use are central to the pathogenesis of both diseases and are reflected in common genetic, cellular, and signaling mechanisms. Understanding this important biological overlap is critical and may help identify novel therapeutic and preventative strategies for both disorders. In this review, we will discuss the shared genetic and molecular factors central to CVD and cancer and how the strategies commonly used for the prevention of atherosclerotic vascular disease can be applied to cancer prevention. PMID- 28624103 TI - From organoids to organs: Bioengineering liver grafts from hepatic stem cells and matrix. AB - Due to the complex function and structure of the liver, resourceful solutions for treating end-stage liver disease are required. Currently, liver transplantation is the only curative therapeutic option. However, due to a worldwide donor shortage, researchers have been looking in other fields for alternative sources of transplantable liver tissue. Recent advances in our understanding of liver physiology, stem cell and matrix biology, have accelerated tissue engineering research. Most notable is the discovery of a culture system to grow liver-like organoids from human hepatic stem cells. The extensive expansion capacity of these stem cells has contributed greatly to the availability of hepatocyte-like cells for tissue engineering. In addition, new techniques are explored to obtain biological liver scaffolds from full size donor organs. This review summarizes these state-of-art techniques which may lay the groundwork towards re-creating transplantable tissue from autologous or allogenic stem cells in the coming decade. PMID- 28624104 TI - Acute kidney injury after liver transplantation: Recent insights and future perspectives. AB - Acute kidney injury (AKI) is a common postoperative complication after liver transplantation (LT). The occurrence of postoperative AKI after LT (Post-LT AKI) is associated with inferior patient and graft outcomes. Post-LT AKI is multifactorial in origin and has been related to the severity of liver disease, pre-LT renal dysfunction, graft quality, perioperative events and toxicity of immunosuppressive therapy. Furthermore it is thought that hepatic ischaemia reperfusion injury might be a driving force in the aetiology of post-LT AKI. Novel biomarkers for AKI are emerging and can be useful for early identification and characterization of AKI. There is a clear need for strategies aimed at preventing or treating post-LT AKI. Several pharmacological and non pharmacological interventions have been studied, but so far failed to show any benefit in the prevention of post-LT AKI. Further studies are needed to develop and evaluate new interventions aimed at preventing post-LT AKI and improve patient outcomes. PMID- 28624105 TI - Hypo- and normothermic perfusion of the liver: Which way to go? AB - The demand of donor livers for transplantation exceeds the supply. In an attempt to maximize the number of potentially usable donor livers, several centers are exploring the role of machine perfusion. This review provides an update on machine perfusion strategies and basic concepts, based on current clinical issues, and discuss challenges, including currently used biomarkers for assessing the quality and viability of perfused organs. The potential benefits of machine perfusion on immunogenicity and the consequences on post-operative immunosuppression management are discussed. PMID- 28624106 TI - Alcohol use and smoking after liver transplantation; complications and prevention. AB - The last thirty years have been very prosperous in the field of liver transplantation (LT), with great advances in organ conservation, surgical techniques, peri-operative management and long-term immunosuppression, resulting in improved patient and graft survival rates as well as quality of life. However, substance addiction after LT, namely alcohol and tobacco, results in short term morbidity together with medium and long-term mortality. The main consequences can be vascular (increased risk of hepatic artery thrombosis in smokers), hepatic (recurrent alcoholic cirrhosis in alcohol relapsers) and oncological (increased risk of malignancy in patients consuming tobacco and/or alcohol after LT). This issue has thus drawn attention in the field of LT research. The management of these two at-risk behaviors addictions need the implication of hepatologists and addiction specialists, before and after LT. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, give practical tools for identification of high risk patients and treatment options. PMID- 28624107 TI - Recurrence of primary sclerosing cholangitis, primary biliary cholangitis and auto-immune hepatitis after liver transplantation. AB - Liver transplantation is a well-accepted treatment for decompensated chronic liver disease due to primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and auto-immune hepatitis (AIH). Survival after liver transplantation is generally good with 1 and 5-year survival rates around 90% and 70-85%. After transplantation, however, these diseases recur in 8.6-27% (rPSC), 10.9-42.3% (rPBC) and 7-42% (rAIH), and this poses significant challenges in terms of management and graft outcome in these patients. In this review we discuss the incidence, clinical presentation, challenges in diagnosis, reported risk factors and impact on post-transplant outcomes of recurrence of PSC, PBC and AIH after liver transplantation. We also discuss some of the limitations of current investigations and formulate idea's for future research objectives. PMID- 28624108 TI - Modification of immunosuppressive therapy as risk factor for complications after liver transplantation. AB - Management of complications post-liver transplantation (LT) includes immunosuppressive manipulations with the aim to reduce the overall burden of immunologic suppression and compensate for renal, cardiovascular, metabolic toxicities, and for the increased oncologic risk. Two approaches can be implemented to reduce immunosuppression-related adverse events: upfront schedules tailored to the pretransplant individual patient's risk profile versus downstream modifications in the event of immunosuppression-related complications. Upfront strategies are supported by evidence originating from prospective randomized trials and consist of triple/quadruple schedules whereby calcineurin inhibitors (CNI)-exposure is reduced with combination of anti-CD25 monoclonal antibodies, antimetabolites and corticosteroids. Quadruple regimens allow for staggering of CNI introduction and higher renal function in the early term, but their superiority in the long term has not yet been established. A more recent upfront schedule contemplates early (4 weeks) introduction of mammalian target of rapamycin inhibitor (mTORi) everolimus and allows for reduction of CNI up to 4 years posttransplantation. Incorporation of mTORi has the potential to prolong time to recurrence for patients with hepatocellular carcinoma. However, as suggested by the available evidence, downstream immunosuppressive manipulations are more frequently adopted in clinical practice. These encompass CNI replacement and immunosuppression withdrawal. Switching CNI to mTORi monotherapy is the option most commonly adopted to relieve renal function and compensate for posttransplant malignancies. Its impact is dependent on interval from transplantation and underlying severity of renal impairment. Introduction of mTORi is associated with longer overall survival for patients with extrahepatic posttransplant malignancies, but results are awaited for recurrences of hepatocellular carcinoma. Immunosuppression withdrawal seems feasible (70%) in very long term survivors (>10 years), but is not associated with reversal of immunosuppression-related complications. Awaiting novel immunosuppressive drug categories, integration of upfront strategies with the aim to reduce CNI-exposure and a low threshold for adjustment in the posttransplant course are both advisable to improve long-term outcomes of LT. PMID- 28624109 TI - The use of old donors in liver transplantation. AB - The process of ageing has an impact on the entire human body including the organ systems. In transplantation, professionals are daily faced with risk assessment of suitable donor offers , whether to accept a liver graft for a specific recipient. In this context, livers from elderly donors are more frequently accepted for transplantation, to increase the donor pool and compensate the high waiting list mortality. In the current practice it is not unusual to accept 60 year old donor livers for transplantation, as the donor demographics have significantly changed over the years. However, controversy exists regarding the use of livers from donors above 70 or 80 years, particular in combination with other risk factors, e.g. liver steatosis, warm ischaemia or long cold storage. This review focuses first on the impact of ageing on liver morphology and function. Second, we will highlight outcome after transplantation from elderly donors. Finally, we describe further risk factors and donor-recipient selection under the scope of old donor organs and include our institutional experience and policy. PMID- 28624110 TI - Interferon-free antiviral therapy for chronic hepatitis C among patients in the liver transplant setting. AB - Chronic hepatitis C (HCV) infection remains a major public health problem with many infected individuals worldwide. The revolutionary discovery of highly effective direct-acting antivirals (DAAs) makes chronic HCV infection a curable disease, even in patients with advanced liver disease. Liver function may improve shortly after initiation of antiviral therapy in patients on the waiting list and could even obviate the need for transplantation. However, whether these short term benefits also result in a favorable prognosis on the long-term remains to be seen and this fuels the discussion whether DAAs should be used prior to liver transplantation in all patients. Following liver transplantation, DAA treatment is also highly effective so that postponing antiviral treatment to the post transplant setting may be better for certain patients. Furthermore, the discussion whether HCV positive organ donors should be used now viral eradication is achieved in almost all patients has regained interest. PMID- 28624111 TI - Biliary complications after liver transplantation; recent developments in etiology, diagnosis and endoscopic treatment. AB - Biliary complications are considered to be the Achilles' heel of liver transplantation. The most common complications are leaks and bile duct strictures. Strictures can arise at the level of the anastomosis (anastomotic strictures; AS) or at other locations in the biliary tree (non-anastomotic strictures; NAS). Endoscopic treatment via endoscopic retrograde cholangiopancreatography (ERCP) is considered to be the preferred therapy for these complications. This review will focus on the diagnostic modalities, new insights in etiology of biliary complications and outcomes after different endoscopic therapies, in both deceased donor transplantation and living-donor liver transplantations. Advances in recent therapies, such as the use of self expendable metal stents (SEMS) and endoscopic therapy for patients with a bilio digestive anastomosis will be discussed. PMID- 28624113 TI - PI controller design for indirect vector controlled induction motor: A decoupling approach. AB - Decoupling of the stator currents is important for smoother torque response of indirect vector controlled induction motors. Typically, feedforward decoupling is used to take care of current coupling that requires exact knowledge of motor parameters, additional circuitry and signal processing. In this paper, a method is proposed to design the regulating proportional-integral gains that minimize coupling without any requirement of the additional decoupler. The variation of the coupling terms for change in load torque is considered as the performance measure. An iterative linear matrix inequality based Hinfinity control design approach is used to obtain the controller gains. A comparison between the feedforward and the proposed decoupling schemes is presented through simulation and experimental results. The results show that the proposed scheme is simple yet effective even without additional block or burden on signal processing. PMID- 28624112 TI - Opposing Roles of Rapid Dopamine Signaling Across the Rostral-Caudal Axis of the Nucleus Accumbens Shell in Drug-Induced Negative Affect. AB - BACKGROUND: Negative reinforcement theories of drug addiction posit that addicts use drugs to alleviate negative mood states. In a preclinical model developed in our laboratory, rats exhibit negative affect to a normally rewarding taste cue when it predicts impending but delayed cocaine. The emergence of this state is accompanied by a reduction in dopamine concentration in the rostral nucleus accumbens shell. However, the rostral and caudal regions of the shell have been implicated in promoting opposing appetitive and aversive states, respectively. Here, we tested whether dopamine transmission along the rostral-caudal axis of the shell plays differential roles in the emergence of drug-induced negative affect. METHODS: In TH::Cre rats, the dopaminergic pathways from the ventral tegmental area to the rostral and caudal regions of the shell were optogenetically stimulated during intraoral delivery of a taste cue signaling delayed cocaine. Affective responses to the taste cue were measured using taste reactivity, and optical self-stimulation of the rostral and caudal shells was also examined. RESULTS: Optical stimulation of the rostral shell during tastant infusion prevented the emergence of negative affect, but activation of the caudal shell exacerbated aversive responses. These effects endured in the absence of optical stimulation, and the degree of negative affect in our model predicted self-stimulation responding. CONCLUSIONS: These findings reveal unprecedented, pronounced, and opposing roles of rapid dopamine signaling across the rostral caudal axis of the nucleus accumbens in the control of drug-induced negative affect, a hallmark of continued drug seeking and use in human addicts. PMID- 28624114 TI - Higher prevalence of chronic endometritis in women with endometriosis: a possible etiopathogenetic link. AB - OBJECTIVE: To evaluate the association between endometriosis end chronic endometritis (CE) diagnosed by hysteroscopy, conventional histology, and immunohistochemistry. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): Women with and without endometriosis who have undergone hysterectomy. INTERVENTION(S): Retrospective evaluation of 78 women who have undergone hysterectomy and were affected by endometriosis and 78 women without endometriosis. MAIN OUTCOME MEASURE(S): CE diagnosed based on conventional histology and immunohistochemistry with anti-syndecan-1 antibodies to identify CD138 cells. RESULT(S): The prevalence of CE was statistically significantly higher in the women with endometriosis as compared with the women who did not have endometriosis (33 of 78, 42.3% vs. 12 of 78, 15.4% according to hysteroscopy; and 30 of 78, 38.5% vs. 11 of 78, 14.1% according to histology). The women were divided into two groups, 115 patients without CE and 41 patients with CE. With univariate analysis, parity was associated with a lower risk for CE, and endometriosis was associated with a statistically significantly elevated risk of CE. Using multivariate analysis, parity continued to be associated with a lower incidence of CE, whereas endometriosis was associated with a 2.7 fold higher risk. CONCLUSION(S): The diagnosis of CE is more frequent in women with endometriosis. Although no etiologic relationships between CE and endometriosis can be established, this study suggests that CE should be considered and if necessary ruled out in women with endometriosis, particularly if they have abnormal uterine bleeding. Identification and appropriate treatment of CE may avoid unnecessary surgery. PMID- 28624115 TI - Evaluation of amnion in creation of neovagina in women with Mayer-Rokitansky Kuster-Hauser syndrome. AB - OBJECTIVE: To assess the outcome of amnion vaginoplasty in cases of vaginal agenesis due to Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome managed at the authors' institution. DESIGN: Retrospective study. SETTING: Tertiary care hospital. PATIENT(S): Fifty women with MRKH who underwent neovaginoplasty. INTERVENTION(S): Modified McIndoe's vaginoplasty was done in all the patients, using human amnion graft. MAIN OUTCOME MEASURE(S): Functional status assessed by Female Sexual Function Index, anatomic status (length and width of neovagina), and epithelialization of vagina. RESULT(S): Mean (+/-SD) vaginal length after surgery was 8.2 +/- 1 cm. Mean vaginal length at 6-month follow-up in sexually active patients was significantly longer as compared with the patients who were not sexually active after surgery (8.4 +/- 1.04 cm vs. 6.6 +/- 2.4 cm). Mean Female Sexual Function Index score was 30.8 +/- 2.1. Vaginal biopsy showed complete epithelialization of vaginal mucosa. CONCLUSION(S): In a developing nation like India, McIndoe's method with amnion graft seems to be a promising option owing to its low cost, easy availability, and safety, ease of the procedure not requiring any special instrument, physiologic outcome with respect to epithelialization of the vagina without hair growth, and satisfying functional outcome. PMID- 28624116 TI - Variability in magnesium content in Arctic echinoderm skeletons. AB - In this study, 235 measurements of magnesium concentration in echinoderm's skeletons were compiled, including 30 species and 216 specimens collected from northern and western Barents Sea. We aimed to reveal the scale of Mg variation in the skeletons of Arctic echinoderms. Furthermore, we attempted to examine whether the Mg concentration in echinoderm skeletons is determined primarily by biological factors or is a passive result of environmental influences. We found that the Mg concentration in echinoderm skeletons was characteristic for particular echinoderm classes or was even species-specific. The highest Mg contents were observed in asteroids, followed by ophiuroids, crinoids, and holothuroids, with the lowest values in echinoids. These results strongly imply that biological factors play an important role in controlling the incorporation of Mg into the skeletons of the studied individuals. PMID- 28624118 TI - Decreasing Patient Stress and Physician/Medical Workforce Burnout Through Health Care Environments: Uncovering the Serious Leisure Perspective at Mayo Clinic's Campus in Rochester, Minnesota. AB - Health care environments are places of high stress for both patients and medical professionals. Although organizational efforts of workload and efficiency are often implemented to decrease both patient and physician/medical workforce stress, what is often overlooked is how leisure opportunities and programs located in day-to-day experiences and in physically built environments can increase both patient and medical staff enjoyment and pleasure, thus lowering patient stress and physician/medical staff burnout. Combining historical research on the leisure pursuits of Drs William J. Mayo and Charles H. Mayo, literature on leisure, stress, and burnout, and a case study methodology of Mayo Clinic's campus in Rochester, Minnesota, the purpose of this study was to describe how the Serious Leisure Perspective (SLP) exists at Mayo Clinic and contributes to relieving stress among patients and preventing burnout among physicians. PMID- 28624117 TI - A case of pacemaker "malfunction". Should I intervene? AB - A 53year old lady was noted to have persistent bradycardia in the recovery unit shortly after a dual chamber permanent pacemaker (PPM) was implanted. The patient was asymptomatic. The pacemaker was implanted for symptomatic intermittent complete heart block. She had surgical closure of an atrial septal defect three decades earlier and a previous tricuspid valve replacement with concomitant biatrial cryomaze procedure for paroxysmal atrial fibrillation. PMID- 28624120 TI - Histologic features of chronic cutaneous lupus erythematosus of the scalp using horizontal sectioning: Emphasis on follicular findings. AB - BACKGROUND: Chronic cutaneous lupus erythematosus (CCLE) often affects the scalp resulting in scarring alopecia. While histopathologic findings of CCLE have been well described, there is little written on the morphologic changes to the hair follicles in this condition. OBJECTIVE: We aim to determine the histopathologic findings of hair follicles in CCLE of the scalp. METHODS: We conducted a retrospective study of 33 transversely sectioned skin biopsy specimens of CCLE of the scalp at the Skin Pathology Laboratory at Boston University between April 2005 and March 2015. RESULTS: New findings include basaloid follicular epithelium lacking hair follicles at deep levels, follicular miniaturization, increased catagen/telogen hair follicles, and pigment casts. Two histopathologic patterns could be discerned, an alopecia areatalike pattern and a lichen planopilarislike pattern. LIMITATIONS: Generalizability of a single-center experience may be limited. CONCLUSION: Follicular findings in CCLE of the scalp are reported. We hypothesize that the basaloid aggregates are remnants of hair follicles that are no longer actively cycling. PMID- 28624119 TI - Skin-infiltrating, interleukin-22-producing T cells differentiate pediatric psoriasis from adult psoriasis. AB - BACKGROUND: Evidence from adult psoriasis studies implicates an imbalance between regulatory and effector T cells, particularly TH-17-producing T cells, in the pathogenesis of psoriasis. Little is known about the immunopathology of psoriasis in children. OBJECTIVE: We sought to functionally characterize the inflammatory cell profiles of psoriatic plaques from pediatric patients and compare them with healthy, age-matched controls and adult psoriasis patients. METHODS: Skin samples from pediatric psoriasis patients and healthy controls were analyzed by multiparameter flow cytometry to determine the dominant immune cell subsets present and cytokines produced. RESULTS: Lesional tissue from pediatric psoriasis patients had significantly increased interleukin (IL) 22 derived from CD4+ and CD8+ cells compared with the tissues from healthy pediatric controls and adult psoriasis patients. Tissue from pediatric psoriasis patients had significantly less elevation of IL-17 derived from CD4+ and CD8+ cells compared with the tissue from adult psoriasis patients. In contrast with the lesions from adult patients, lesional skin in pediatric patients with psoriasis did not have increases in regulatory T cells. LIMITATIONS: This is a pilot study, thus the sample size is small. CONCLUSION: Significant differences in IL-17 and IL-22 expression were observed in the pediatric psoriasis patients compared with pediatric healthy controls and adult psoriasis patients. IL-22 might be relevant in the pathogenesis of pediatric psoriasis and represents a potential treatment target unique to pediatric psoriasis. PMID- 28624121 TI - Leptin-like immunoreactivity in the central nervous system, digestive organs, and gonads of the giant freshwater prawn, Macrobrachium rosenbergii. AB - Leptin, a highly conserved adipocyte-derived hormone, plays important roles in a variety of physiological processes, including the control of fat storage and metabolic status which are linked to food intake, energy homeostasis, and reproduction in all vertebrates. In the present study, we hypothesize that leptin is also present in various organs of the fresh water prawns, Macrobrachium rosenbergii. The existence and distribution of a leptin-like peptide in prawn tissues were verified by using Western blotting (WB) and immunohistochemical detection (ID) using primary antibody against human leptin. With WB, a leptin like peptide, having a molecular weight of 15kDa, was detected in the brain, thoracic ganglia, abdominal ganglia, parts of the gastro-intestinal tract, hepatopancreas, adipocytes and gonads. By ID, leptin immunoreactivity (leptin-ir) was detected in the brain, thoracic ganglia and intersegmental commissural nerve fibers of abdominal ganglia. In the gastrointestinal tract, there was intense leptin-ir in the apical part of the epithelial cells of the cardiac and pyloric parts of the stomach. In the midgut and hindgut, the leptin-ir was detected in epithelial cells and basal cells located near the basal lamina of the epithelium. In addition, there was leptin-ir in the Restzellen cells in the hepatopancreas which produce digestive enzymes. In the ovary, the strong intensity of a leptin ir was detected in the cytoplasm of middle to late stage oocytes, whereas no positive staining was detected in follicular cells. An intense leptin-ir was detected in spermatocytes and sustentacular cells in the seminiferous tubules in the testes of small and orange claw males. Taken together, the detection of the leptin-ir in several organs implicates the existence of a leptin-like peptide in various organs of the freshwater prawn; and like in vertebrates this peptide may be an important hormonal factor in controlling feeding and reproductive process. PMID- 28624122 TI - Glucagon-like peptide-1 and insulin synergistically activate vagal afferent neurons. AB - Intestinal glucagon-like peptide-1 (GLP-1) and pancreatic insulin, released postprandially, commonly regulate glucose metabolism. Recent clinical experience indicates that the GLP-1R agonist and insulin in combination, compared to insulin alone, results in better glycemic and weight controls in type 2 diabetic patients. These observations suggest possible interactive effect of these hormones. These hormones, in addition to peripherally controlling glycemia, exert central regulation of food intake and glucose metabolism, the effect at least partly mediated by signaling to the brain via the vagal afferents. However, whether the vagal afferents are involved in the interactive effects of GLP-1 and insulin remains unknown. The present study explored possible cooperative effect of GLP-1 and insulin on vagal afferent neurons isolated from nodose ganglion (NG) of mice, while monitoring the neuronal activity by measuring cytosolic Ca2+ concentration ([Ca2+]i) with fura-2. GLP-1 at 10-8M increased [Ca2+]i in 8-11% of single NG neurons. GLP-1-induced [Ca2+]i increases were inhibited by GLP-1 receptor antagonist exendin (9-39). Majority (92%) of GLP-1-responseive NG neurons also responded to 10-7M insulin with [Ca2+]i increases. Both GLP-1 and insulin at lower concentration of 10-9M induced [Ca2+]i increases with smaller amplitude in lesser NG neuron population (4-7%). These hormones at 10-9M in combination recruited the unresponsive neurons to [Ca2+]i increases, and induced [Ca2+]i increases with greater amplitude in the responsive neurons. The results demonstrate that GLP-1 and insulin synergistically and additively activate vagal afferent neurons. This interaction may be linked to the postprandial functions mediated commonly by GLP-1 and insulin and in the beneficial outcome of the therapy with GLP-1 receptor agonist and insulin in combination. PMID- 28624123 TI - Population Pharmacokinetic/Pharmacodynamics Modeling of Ibutilide in Chinese Healthy Volunteers and Patients With Atrial Fibrillation (AF) and/or Atrial Flutter (AFL). AB - PURPOSE: The goal of this study was to develop a population pharmacokinetic (PK) and PK/pharmacodynamics (PD) model for ibutilide, to evaluate the time course of its effect on QT interval in Chinese. METHODS: The population PK and PK/PD model were developed using data from 40 Chinese healthy volunteers using nonlinear mixed-effects modeling, and the final population PK/PD model was applied on 100 patients with atrial fibrillation (AF) and/or atrial flutter (AFL). FINDINGS: The PK parameters of ibutilide were best described by a 3-compartment model with first-order elimination. No statistically significant covariate was found for each PK model parameter. Individualized QT interval correction, by heart rate, was performed by a power model, and the circadian rhythm of QT intervals was described by 2 mixed-effect cosine functions. The QT interval data of ibutilide was well characterized by a sigmoid Emax model (E(C)=Emaxgamma*Cgamma/(EC50gamma+Cgamma)) with an effect compartment. The final PK/PD model was used to estimate individual parameters of patient data and found good predictions compared with healthy volunteers; AF and/or AFL patients had lower Emax and higher EC50. IMPLICATIONS: A population PK and PK/PD model for ibutilide in healthy volunteers was developed and could well capture ibutilide's PK/PD characteristics. The final PK/PD model was applied on patients with AF and/or AFL successfully. PMID- 28624124 TI - Erratum to 'Choosing wisely: The top 5 list of recommendations from the Italian Panel of the National Guidelines for the Management of Acute Pharyngitis in Children' Clin Ther. 2017;39:646--649. PMID- 28624125 TI - Do protons have a role in the treatment of locally advanced NSCLC with radiotherapy? PMID- 28624126 TI - Racial and ethnic disparities in U.S. breastfeeding and implications for maternal and child health outcomes. AB - Marked racial and ethnic disparities exist in infant feeding in the United States. Based on a review of recent literature, this article examines current discrepancies between the 2020 Healthy People breastfeeding goals and current breastfeeding rates among women from different ethnic groups in the United States. We discuss maternal and child health outcomes associated with breastfeeding, and we review potential causes of racial and ethnic disparities in breastfeeding outcomes in the United States, especially among non-Hispanic Black, American Indian/Alaska Native, and Hispanic/Latina populations. We conclude with an overview of best practices in interventions aimed to increase U.S. breastfeeding rates, such as adoption of the baby friendly hospital initiative (BHFI) and programs that utilize peer counseling strategies to increase breastfeeding promotion and support. PMID- 28624127 TI - Surgical personalities, surgical burnout, and surgical happiness. PMID- 28624128 TI - Facilitating aging in place: A qualitative study of practical problems preventing people with dementia from living at home. AB - Although the majority of people with dementia wish to age in place, they are particularly susceptible to nursing home admission. Nurses can play an important role in detecting practical problems people with dementia and their informal caregivers are facing and in advising them on various ways to manage these problems at home. Six focus group interviews (n = 43) with formal and informal caregivers and experts in the field of assistive technology were conducted to gain insight into the most important practical problems preventing people with dementia from living at home. Problems within three domains were consistently described as most important: informal caregiver/social network-related problems (e.g. high load of care responsibility), safety-related problems (e.g. fall risk, wandering), and decreased self-reliance (e.g. problems regarding self-care, lack of day structure). To facilitate aging in place and/or to delay institutionalization, nurses in community-based dementia care should focus on assessing problems within those three domains and offer potential solutions. PMID- 28624129 TI - Testing the reliability and validity of a Transition Map for older adults in long term care settings. AB - Mapping individual patterns of decline in older adults may aid coordinating long term aged care. This study developed a new scale (Transition Maps) to summarise the overall care pathway for long term aged care residents, in a simplified manner incorporating mapping concepts. Transition Maps were developed using mixed methods in two phases, and based on expert opinion, literature review, and input from aged care health professionals. Four professions (primary physician, nurse, allied health, lifestyle services) generated 147 Transition Maps for 38 residents living in a long term care. Preliminary construct validity and inter-rated reliability were evaluated. Results showed that Inter-rater reliability of agreement with the overall care pathway for each resident was kappa = 0.492. Consensus was lowest between nurse care managers and primary physicians (kappa = 0.384), and highest between nurse managers and Lifestyle Services (kappa = 0.77). Preliminary testing of the Transition Map scale provides initial support of construct validity and inter-rater reliability and provides some evidence that Transition Maps can improve the coordination of long term aged care. PMID- 28624130 TI - Assessing the hydrogeochemical processes affecting groundwater pollution in arid areas using an integration of geochemical equilibrium and multivariate statistical techniques. AB - Rapid economic expansion poses serious problems for groundwater resources in arid areas, which typically have high rates of groundwater depletion. In this study, integration of hydrochemical investigations involving chemical and statistical analyses are conducted to assess the factors controlling hydrochemistry and potential pollution in an arid region. Fifty-four groundwater samples were collected from the Dhurma aquifer in Saudi Arabia, and twenty-one physicochemical variables were examined for each sample. Spatial patterns of salinity and nitrate were mapped using fitted variograms. The nitrate spatial distribution shows that nitrate pollution is a persistent problem affecting a wide area of the aquifer. The hydrochemical investigations and cluster analysis reveal four significant clusters of groundwater zones. Five main factors were extracted, which explain >77% of the total data variance. These factors indicated that the chemical characteristics of the groundwater were influenced by rock-water interactions and anthropogenic factors. The identified clusters and factors were validated with hydrochemical investigations. The geogenic factors include the dissolution of various minerals (calcite, aragonite, gypsum, anhydrite, halite and fluorite) and ion exchange processes. The anthropogenic factors include the impact of irrigation return flows and the application of potassium, nitrate, and phosphate fertilizers. Over time, these anthropogenic factors will most likely contribute to further declines in groundwater quality. PMID- 28624131 TI - Studying Arterial Stiffness Using High-Frequency Ultrasound in Mice with Alzheimer Disease. AB - Alzheimer disease (AD) is an irreversible, progressive brain disorder that causes slow loss of memory and thinking skills, normally leading to death in 3-9 y. The etiology of AD is not fully understood but is widely believed to be induced by the production and deposition of amyloid-beta peptide in the brain. Recently, a correlation was discovered between amyloid-beta deposition and atherosclerosis in the cerebral arteries of postmortem brains, indicating that amyloid-beta promotes atherogenesis and that in turn atherosclerosis promotes brain amyloid-beta accumulation. However, a direct measurement of arterial stiffness for AD is lacking. In the present study, the pulse wave velocity (PWV) of the carotid artery was measured non-invasively in young (3-mo-old) and middle-aged (9-mo-old) wild-type (WT) and modeled AD mice to obtain quantitative data of arterial stiffness by using a 35-MHz high-frequency dual-element transducer. Experimental results show that the PWVs were 1.6 +/- 0.5 m/s for young and 2.4 +/- 0.4 m/s for middle-aged WT mice and 1.7 +/- 0.4 m/s for young and 3.2 +/- 0.6 m/s for middle aged AD mice. Middle-aged groups had higher PWVs (p < 0.0001), which were more pronounced in the AD mice (p < 0.001). The differences in PWVs were not caused by arterial lumen diameter, wall thickness or contents of elastin or collagen. These results imply that AD increases the stiffness of the carotid artery and introduce ultrasound as a potential tool for AD research and diagnosis. PMID- 28624132 TI - Schizogony and gametogony of oocyst-deficient T-263 strain of Toxoplasma gondii. AB - Oocysts are important stage for the spread of Toxoplasma gondii because they are environmentally resistant. Among all hosts of T. gondii, only felids can excrete oocysts. Cats that have excreted T. gondii oocysts after primary infection develop immunity to re-excretion of oocysts, and this immunity appears to be long lasting. It would be desirable to have a non-infectious vaccine for the prevention of T. gondii infection in cats and to understand mechanism of immunity to excretion of oocysts. An initial step will be to indentify stage/stages of the parasite for induction of immunity. A chemically-induced mutant of T. gondii, T 263, is immunogenic but lacks the capacity to form oocysts in cats. Cats fed live bradyzoites of T-263 do not excrete oocysts after challenge with oocyst producing strains. However, it is not known at what stage of the parasite development the oocyst formation is halted. Here, four cats were fed live tissue cysts of the T 263 strain and examined for enteroepithelial stages and oocyst production. Two cats were administered methyl prednisolone aceatate (20mg/kg) once intramuscularly and these cats were euthanized 5 and 7days post inoculation. No oocysts but immature and mature schizonts (types D and E), male, and female gamonts were detected in two cats euthanized. The remaining two cats did not excrete oocysts examined 3-14days post inoculation, but both seroconverted and developed antibody titers of 1:400 tested by the modification agglutination test, indicating exposure to the inocula. The results demonstrate that the T-263 strain is defective in oocyst formation and the observations should help future studies in identification of genes/factors responsible for oocyst formation in the intestine of cats. PMID- 28624133 TI - [The use of administrative health databases in infectious disease epidemiology and public health]. AB - BACKGROUND: The public health burden resulting from infectious diseases requires efforts in surveillance and evaluation of health care. The use of administrative health databases (AHD) and in particular the French national health insurance database (SNIIRAM) is an opportunity to improve knowledge in this field. The SNIIRAM data network (REDSIAM) workshop dedicated to infectious diseases conducted a narrative literature review of studies using French AHD. From the results, benefits and limits of these new tools in the field of infectious diseases are presented. METHODS: Publications identified by the members of the workgroup were collected using an analytical framework that documented the pathology of interest, the aim of the study, the goal of the developed algorithm, the kind of data, the study period, and the presence of an evaluation or a discussion of the performance of the performed algorithm. RESULTS: Fifty-five articles were identified. A majority focused on the field of vaccination coverage and joint infections. Excluding vaccine coverage field, the aim of 28 studies was epidemiological surveillance. Twenty-six studies used hospital databases exclusively, 18 used ambulatory databases exclusively and 4 used both. Validation or discussion of the performed algorithm was present in 18 studies. CONCLUSIONS: The literature review confirmed the interest of the French AHD in the infectious diseases field. The AHD are additional tools of the existing surveillance systems and their use will probably be more frequent in the coming years given their advantage and reliability. However, incoming users need to be assisted. Thus, the workgroup will contribute to a reasonable use of AHD and support future developments. PMID- 28624134 TI - Efficacy of response-guided directly observed pegylated interferon and self administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study. AB - BACKGROUND: There are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. METHODS: ACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). RESULTS: Among 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. CONCLUSION: This study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response. PMID- 28624135 TI - Effectiveness of vitamin K2 on osteoporosis in adults with cerebral palsy. AB - BACKGROUND: Osteoporosis can lead to spontaneous fractures in adults with cerebral palsy (CP). Undercarboxylated osteocalcin (ucOC) is a useful marker for vitamin K insufficiency in osteoporosis. The primary objective of this study was to determine the effect of vitamin K2 on bone mineral density (BMD) in adults with CP and vitamin K insufficiency. METHODS: Sixteen adults, median age of 56years, with CP and osteoporosis in whom the serum ucOC concentration exceeded 4.5ng/mL were included. All patients received 45mg of vitamin K2 per day. BMD was measured and presented as a percentage of the young adult mean (%YAM). Serum levels of ucOC and BMD were measured at baseline and after 6 and 12months. RESULTS: Serum levels of ucOC decreased from 7.8ng/mL (range, 4.9-32) at baseline to 3.9ng/mL (range, 1.9-6.8) after 6months (P=0.001). BMD increased from 59%YAM (range, 45-67) at baseline to 68%YAM (range, 50-79) after 12months (P=0.003). CONCLUSIONS: Vitamin K2 had a positive effect on BMD in osteoporotic adults with CP and high serum concentrations of ucOC, and might be useful as a first line treatment for osteoporotic adults with CP and vitamin K insufficiency. PMID- 28624136 TI - Effect of ABO blood type on the outcomes of patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors. AB - OBJECTIVES: To assess the effect of blood type on survival outcomes and adverse events (AEs) in patients treated with tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Patients who received TKIs as first-line therapy for mRCC between 2008 and 2015 at our hospital were included in the study (n = 136). Patients were divided into 2 groups based on their blood type as O and non-O. Survival outcomes and AEs were compared according to blood type. Cox regression models were used for univariate and multivariate survival analyses. RESULTS: Of the 136 patients, 34 (25%) and 102 (75%) had O and non-O blood types, respectively. Blood type O was associated with an increased number of disease sites. There were no differences between the 2 groups with respect to other baseline characteristics. The progression-free survival in patients with O and non-O blood types was 12.1 and 11.6 months, respectively; the overall survival was 34.4 and 24.8 months, respectively. On univariate and multivariate analyses, the ABO blood type was not a significant prognostic factor for progression-free survival or overall survival. Furthermore, the incidences of serious AEs were similar in the 2 blood groups. CONCLUSIONS: ABO blood type was not associated with survival outcomes or incidences of serious AEs in mRCC patients treated with TKIs. However, blood type O may be associated with an increased number of disease sites. PMID- 28624137 TI - Effect of TLR ligands co-encapsulated with multiepitopic antigen in nanoliposomes targeted to human DCs via Fc receptor for cancer vaccines. AB - Nanoliposomes (NLs) hold promise as new highly specific nanomedicine for anti tumor vaccines, since they could be targeted to specific receptors on dendritic cell (DC) to induce maturation and activation and increase the anti-tumor immune response. Here we studied a NLs formulation targeted or not to FcR (the receptor for the IgG Fc fragment) for the treatment of androgen-responsive prostate cancer. Luteinizing-hormone-releasing hormone (LHRH) peptide (B- and T-cell epitopes), in tandem with a tetanus toxoid T-helper epitope (830-844 region) and several TLR (Toll-Like Receptor) ligands as adjuvants were co-encapsulated. Specific uptake in vitro of LHRH-TT liposomes targeted to the FcRs of human DCs was enhanced. DC maturation/activation, cytokine production and lymphocyte activation were consistently higher in targeted than non-targeted liposomes. Similar increase was observed as more adjuvants were administrated. Targeting to specific receptor and co-encapsulation of several TLR adjuvants are essential factors for the immune response in peptide based liposome vaccine. PMID- 28624138 TI - Serum NCAM levels and cognitive deficits in first episode schizophrenia patients versus health controls. AB - BACKGROUND: Neural cell adhesion molecule (NCAM) is a glycoprotein and plays an important role in cell-cell adhesion, neural migration, neurite outgrowth, synaptic plasticity and brain development. We investigated the relationship between the serum NCAM concentration and cognitive deficit in first episode drug naive schizophrenia (FES) patients. METHODS: Thirty FES patients and thirty healthy controls were recruited for this study. Psychiatric symptoms were assessed by the positive and negative syndrome scale (PANSS). Cognitive functions were assessed by measurement and treatment research to improve cognition in schizophrenia (MATRICS) and consensus cognitive battery (MCCB). Serum levels of NCAM were determined by ELISA. RESULTS: Schizophrenia patients had decreased serum NCAM concentrations than controls (-30%, p<0.001). Cognitive scores were significantly lower in FES patients than healthy controls (-34%, p<0.001). The NCAM concentrations were positively correlated with the total scores of MCCB (r=0.438, p=0.003). Multiple regression analysis confirmed that serum NCAM concentration was an independent contributor to MCCB total Scores. CONCLUSIONS: There were a close relationship between the serum NCAM concentrations and cognitive deficits in FES patients. Since NCAM has an important role in neurodevelopmental processes, these results support the neurodevelopmental dysfunction hypothesis of schizophrenia and suggest that an altered NCAM may be one of the risk factors for schizophrenia including cognitive deficits. PMID- 28624139 TI - Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation. AB - BACKGROUND: Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts. METHODS: After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts. RESULTS: We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R2 > 0.99, p < 10-6), as well as across manual and automated platforms (slope = 0.80, R2 = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001). CONCLUSIONS: The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation. PMID- 28624140 TI - Minor Nonintracranial Hemorrhage and Poor Prognosis among Stroke Patients Undergoing Intravenous Thrombolysis. AB - BACKGROUND: Whether nonintracranial hemorrhage (NICH) associated with intravenous thrombolysis (IVT) is a predictor of intracranial hemorrhage (ICH) and poor prognosis is ambiguous. We sought to analyze the rate of NICH and the relationship between NICH and poor outcome in the ischemic stroke population undergoing IVT. METHODS: This is a single-center, hospital-based prospective study. All ischemic stroke patients undergoing IVT between December 2015 and November 2016 were included. NICH was defined according to the criteria of the Bleeding Academic Research Consortium (BARC). ICH associated with IVT was defined based on the European Cooperative Acute Stroke Study II definition. On the basis of the modified Rankin Scale (mRS), 90-day outcome was divided into favorable outcome (mRS score 0-1) versus unfavorable outcome (mRS score 2-6) and independency (mRS score 0-2) versus dependency and death (mRS score 3-6). RESULTS: A total of 212 patients undergoing IVT were included in the analysis. Forty-five NICH events were reported in 42 patients (19.8%). Older age was independently associated with NICH (P = .049, odds ratio [OR] = .97, 95% confidence interval [CI] .94-1.0). Neither NICH with BARC class 1 or higher (P = .56, OR = .61, 95% CI .11-3.24) nor NICH with BARC class 2 or higher (P = .87, OR = 1.19, 95% CI .14-10.23) was associated with ICH. NICH with BARC class 1 or higher was not associated with unfavorable outcome (P = .67, OR = 1.17, 95% CI .56-2.45) and dependence and death (P = .47, OR = .72, 95% CI .30-1.75), neither was NICH with BARC class 2 or higher (P = .97, OR = 1.02, 95% CI .46-2.27 and P = .30, OR = .59, 95% CI .22-1.62). CONCLUSIONS: NICH was common among ischemic stroke populations receiving IVT. NICH with BARC class 2 or lower was not associated with ICH and poor outcome. PMID- 28624141 TI - Serial imaging and SWAN sequence of developmental venous anomaly thrombosis with hematoma: Diagnosis and follow-up. AB - Developmental venous anomalies (DVAs) are usually asymptomatic. We report a case of DVA thrombosis with recurrent tiny frontal hematoma in a 24-year-old man. The contribution of T2-GRE and SWAN sequences are discussed. Follow-up attested complete recanalization after anticoagulation. PMID- 28624142 TI - Anti-diabetic xanthones from the bark of Garcinia xanthochymus. AB - An ethyl acetate extract the bark of Garcinia xanthochymus exhibited strong inhibition towards alpha-glucosidase and PTP1B with IC50 values of 0.3+/ 0.1MUg/mL and 2.3+/-0.4MUg/mL, respectively. Chemical constituents of the extract were therefore examined, and two new compounds, xanthochymusxanthones A (1) and B (2), along with ten known xanthones (3-12), were isolated. Their structures were determined using spectroscopic methods, mainly 1D and 2D NMR. Inhibitory activity of the isolated compounds was then tested, and subelliptenone F (12) showed significant effect towards alpha-glucosidase with IC50 value of 4.1+/-0.3MUM (compared with acarbose, IC50=900.0+/-3.0MUM) whilst xanthochymusxanthone B (2) exhibited remarkable activity towards PTP1B with IC50 value of 8.0+/-0.6MUM (compared with RK682, IC50=4.4+/-0.3MUM). PMID- 28624143 TI - A small-molecule screen identifies the antitrypanosomal agent suramin and analogues NF023 and NF449 as inhibitors of STAT5a/b. AB - The transcription factor STAT5a is a potential target for tumor therapy. We present a fluorescence polarization-based, high-throughput screen of chemical libraries containing natural products and known bioactive molecules, for the identification of small-molecule inhibitors of the STAT5a SH2 domain. This screen identified suramin, a drug used to treat African trypanosomiasis, and its analogues NF023 and NF449 as inhibitors of the SH2 domains of STAT5a/b. Our data extend the known in vitro targets of suramin and analogues to include members of the STAT protein family. PMID- 28624144 TI - [Feasibility of outpatient laparoscopic sacrocolpopexy surgery: A pilot study]. AB - OBJECTIVE: To evaluate the feasibility of outpatient laparoscopic sacrocolpopexy surgery. METHODS: A prospective analysis was carried out in one center from May 2014 to July 2015. The main outcome was the success of day care, meaning no hospitalization, consultation to a doctor or emergency during the first 48h following the surgery. Patients requiring laparoscopic sacrocolpopexy with eligibility for day care were included. The patients were not included if they didn't match to the administrative or medical criteria of ambulatory, or if they refused ambulatory surgery. The postoperative consultation was 1 month after surgery, the satisfaction was assessed by phone call two months after surgery. RESULTS: We included 14 patients during the study. One patient stayed the night (7.1%). The median operative time of the surgery was 95minutes (70-168minutes), no complication occurred. Ten patients of 13 (76.9%) were very satisfied or satisfied of day care. CONCLUSION: With 71% of satisfaction and only one patient who stayed the night, outpatient laparoscopic sacrocolpopexy surgery seems to be feasible. LEVEL OF EVIDENCE: 4. PMID- 28624145 TI - Self-induction in Photosensitive Children With Dravet Syndrome. PMID- 28624146 TI - The impact of the BLUE protocol ultrasonography on the time taken to treat acute respiratory distress in the ED. PMID- 28624147 TI - Characteristics and outcome among 14,933 adult cases of in-hospital cardiac arrest: A nationwide study with the emphasis on gender and age. AB - AIM: To investigate characteristics and outcome among patients suffering in hospital cardiac arrest (IHCA) with the emphasis on gender and age. METHODS: Using the Swedish Register of Cardiopulmonary Resuscitation, we analyzed associations between gender, age and co-morbidities, etiology, management, 30-day survival and cerebral function among survivors in 14,933 cases of IHCA. Age was divided into three ordered categories: young (18-49years), middle-aged (50 64years) and older (65years and above). Comparisons between men and women were age adjusted. RESULTS: The mean age was 72.7years and women were significantly older than men. Renal dysfunction was the most prevalent co-morbidity. Myocardial infarction/ischemia was the most common condition preceding IHCA, with men having 27% higher odds of having MI as the underlying etiology. A shockable rhythm was found in 31.8% of patients, with men having 52% higher odds of being found in VT/VF. After adjusting for various confounders, it was found that men had a 10% lower chance than women of surviving to 30days. Older individuals were managed less aggressively than younger patients. Increasing age was associated with lower 30-day survival but not with poorer cerebral function among survivors. CONCLUSION: When adjusting for various confounders, it was found that men had a 10% lower chance than women of surviving to 30days after in-hospital cardiac arrest. Older individuals were managed less aggressively than younger patients, despite a lower chance of survival. Higher age was, however, not associated with poorer cerebral function among survivors. PMID- 28624148 TI - Multiple myeloma presenting as acute pancreatitis. AB - A 36 year old male presented to the emergency department with severe epigastric pain, nausea, vomiting without hematemesis, diarrhea and anorexia. He presented with respiratory distress, shock and fever at the emergency. He was intubated and shifted to the intensive care unit with the diagnosis of acute pancreatitis with hypercalcemia and an elevated amylase and lipase's well as thrombocytopenia and elevated creatinine. CT scan of abdomen was done which showed lytic bone lesions in the spine and necrosis of the pancrease. He was evaluated for multiple myeloma and it was confirmed in a bone marrow biopsy. Multiple myeloma usually is seen in patients aged more than 60 yrs. The typical presentation of multiple myeloma is anemia, back pain, and an elevated sedimentation rate. Patients with multiple myeloma have hypercalcemia but it's rarely manifested as acute pancreatitis. This case shows a rare presentation of multiple myeloma as acute pancreatitis in a younger adult. PMID- 28624150 TI - Importance of optimizing chromatographic conditions and mass spectrometric parameters for supercritical fluid chromatography/mass spectrometry. AB - Supercritical fluid chromatography/mass spectrometry (SFC/MS) has great potential in high-throughput and the simultaneous analysis of a wide variety of compounds, and it has been widely used in recent years. The use of MS for detection provides the advantages of high sensitivity and high selectivity. However, the sensitivity of MS detection depends on the chromatographic conditions and MS parameters. Thus, optimization of MS parameters corresponding to the SFC condition is mandatory for maximizing performance when connecting SFC to MS. The aim of this study was to reveal a way to decide the optimum composition of the mobile phase and the flow rate of the make-up solvent for MS detection in a wide range of compounds. Additionally, we also showed the basic concept for determination of the optimum values of the MS parameters focusing on the MS detection sensitivity in SFC/MS analysis. To verify the versatility of these findings, a total of 441 pesticides with a wide polarity range (logPow from -4.21 to 7.70) and pKa (acidic, neutral and basic). In this study, a new SFC-MS interface was used, which can transfer the entire volume of eluate into the MS by directly coupling the SFC with the MS. This enabled us to compare the sensitivity or optimum MS parameters for MS detection between LC/MS and SFC/MS for the same sample volume introduced into the MS. As a result, it was found that the optimum values of some MS parameters were completely different from those of LC/MS, and that SFC/MS specific optimization of the analytical conditions is required. Lastly, we evaluated the sensitivity of SFC/MS using fully optimized analytical conditions. As a result, we confirmed that SFC/MS showed much higher sensitivity than LC/MS when the analytical conditions were fully optimized for SFC/MS; and the high sensitivity also increase the number of the compounds that can be detected with good repeatability in real sample analysis. This result indicates that SFC/MS has potential for practical use in the multiresidue analysis of a wide range of compounds that requires high sensitivity. PMID- 28624149 TI - Brain function and structure and risk for incident diabetes: The Atherosclerosis Risk in Communities Study. AB - INTRODUCTION: Diabetes is prospectively associated with cognitive decline. Whether lower cognitive function and worse brain structure are prospectively associated with incident diabetes is unclear. METHODS: We analyzed data for 10,133 individuals with cognitive function testing (1990-1992) and 1212 individuals with brain magnetic resonance imaging (1993-1994) from the Atherosclerosis Risk in Communities cohort. We estimated hazard ratios for incident diabetes through 2014 after adjustment for traditional diabetes risk factors and cohort attrition. RESULTS: Higher level of baseline cognitive function was associated with lower risk for diabetes (per 1 standard deviation, hazard ratio = 0.94; 95% confidence interval = 0.90, 0.98). This association did not persist after accounting for baseline glucose level, case ascertainment methods, and cohort attrition. No association was observed between any brain magnetic resonance imaging measure and incident diabetes. DISCUSSION: This is one of the first studies to prospectively evaluate the association between both cognitive function and brain structure and the incidence of diabetes. PMID- 28624151 TI - Pixel-by-pixel correction of retention time shifts in chromatograms from comprehensive two-dimensional gas chromatography coupled to high resolution time of-flight mass spectrometry. AB - A pixel-by-pixel method for correcting retention time (RT) shifts in whole chromatograms from comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry (GC*GC-HRTOFMS) is introduced. A previously developed robust algorithm for correcting RT shifts was extended to high-resolution mass-spectral data. The performance of the new method in terms of decreasing RT shifts and peak volume changes was tested on GC*GC-HRTOFMS data. The RT shift correction algorithm, using linear interpolation for the 1st dimension and Sibson natural neighbor interpolation for the 2nd dimension, performed well for systematically shifted data acquired using two different temperature programs in terms of decreasing RT differences and alterations to the peak volumes and mass spectra. A modified RT shift correction algorithm, using Sibson natural neighbor for both dimensions, performed better for RT shifts caused by column damage, for which the original interpolation method did not appropriately correct RT shifts. Although further investigation would be required for more types of severe shifts, this study shows that the developed method is useful for correcting RT shifts with GC*GC-HRTOFMS. PMID- 28624152 TI - Simultaneous determination of 14 disinfection by-products in meat products using microwave-assisted extraction and static headspace coupled to gas chromatography mass spectrometry. AB - This paper described the first analytical method to simultaneously determine 14 disinfection by-products (DBPs) in meat products using microwave-assisted extraction (MAE) and static headspace (SHS) followed by gas chromatography-mass spectrometry (GC-MS). The DBPs included were 4 trihalomethanes, 7 haloacetic acids, 2 haloacetonitriles and trichloronitromethane, which are commonly formed as a consequence of the disinfection process of water. The combination of the MAE and SHS techniques allows meat samples to be analysed in two sequential steps into the same HS vial in spite of the sample's complexity. Detection limits were obtained within the range of 0.06-0.70ng/g, and the average relative standard deviation was 7.4%. Recoveries throughout the whole process were between 86 and 95%. The SHS-GC-MS method was applied to determine DBPs in meat products with different industrial processing which could be contaminated through contact with disinfectants and/or treated water employed in the factory either for washing or for the cooking of meat. Up to 5 DBPs were found at ng/g levels in about 36% of the samples analysed, cooked ham being the most contaminated meat product because of the brine solutions employed in its manufacturing process. PMID- 28624154 TI - Lymphedema following gynecological cancer: Results from a prospective, longitudinal cohort study on prevalence, incidence and risk factors. AB - OBJECTIVE: Cancer-related lymphedema is a debilitating condition that adversely influences function, health and quality of life. The purpose of this study was to assess the prevalence, incidence, and risk factors of lower-limb lymphedema pre- through to 24months post-surgery for gynecological cancer. METHODS: A clinic based sample of women (n=408) with gynecological cancer participated in a prospective, longitudinal study (2008-2011) using self-reported measures (swelling in one or both legs) and objectively measured lymphedema (bioimpedance spectroscopy) at baseline (pre-surgery), six weeks-three months, 6-12months, and 15-24months post-surgery. RESULTS: At pre-surgery, 15% of women self-reported lymphedema and 27% had measurable evidence of lymphedema. By 24months post surgery, incidence of new self-reported or measured lymphedema was 45% and 37%, respectively. Three-quarters of these new cases presented by 12-months post treatment. While lymphedema was transient for some women, 60% had persistent lymphedema. More extensive lymph node dissection, receipt of chemotherapy and radiation therapy, increasing body mass index, insufficient levels of physical activity, diagnosis of vulvar/vaginal cancer and presence of pre-treatment lymphedema were identified as potential risk factors (p<0.05). CONCLUSION: Findings support the need for integration of pre-surgical assessment, and prospective, post-treatment surveillance of lymphedema into gynecological cancer care. Future research exploring the role of maintaining healthy body weight, regular physical activity and education about early detection of lymphedema to improve gynecological cancer survivorship is warranted. PMID- 28624155 TI - Current understanding of the pathophysiology of chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a unique form of pulmonary hypertension arising from fibrotic obliteration of major pulmonary arteries. Pro-thrombotic states, large clot burden and impaired dissolution are believed to contribute to the occurrence and progression of thrombosis after an acute pulmonary embolic event. Recent data utilizing several models have facilitated the understanding of clot resolution. This review summarizes current knowledge on pathophysiological mechanisms of major vessel occlusion in CTEPH. PMID- 28624153 TI - Impact of ascites volume on clinical outcomes in ovarian cancer: A cohort study. AB - OBJECTIVES: To investigate the impact of ascites volume on ovarian cancer outcomes. METHODS: Clinicopathologic features of a cohort of patients with ovarian cancer were obtained from a curated database at a single institution. Progression free survival (PFS) and overall survival (OS) were recorded. Ascites volume at primary surgery was dichotomized at 2000mL and comparisons for high and low volume ascites were made. Additionally, to elucidate interactions between ascites and ovarian tumor progression, we evaluated the effect of intraperitoneal administrations of murine cell-free ascites versus saline in a syngeneic mouse model of epithelial ovarian cancer. RESULTS: Out of 685 patients identified, 58% had ascites present at the time of initial surgery. Considering the volume of ascites continuously, each liter of ascites was associated with shorter PFS (HR=1.12, 95% CI: 1.07-1.17) and OS (HR=1.12, 95%CI: 1.07-1.17). Patients with ascites greater than the median of 2000mL had significantly shorter PFS (14.5months vs. 22.7months; p<0.001) and OS (27.7months vs. 42.9months; p<0.001). After adjusting for stage, presence of ascites was inversely associated with ability to achieve optimal cytoreductive surgery. Consistent with these correlative results in patients, intraperitoneal administrations of murine cell free ascites accelerated ovarian cancer progression in mice. CONCLUSIONS: The volume of ascites at initial diagnosis of ovarian cancer correlated with worse PFS and OS. The effect of large volume on prognosis is likely to be in part related to reduced likelihood for complete resection of tumor (R0). If these findings are confirmed in independent studies, consideration should be made to add the presence of large volume ascites at diagnosis to the staging criteria for ovarian cancer. PMID- 28624156 TI - A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women Under the Age of 50 Years. AB - BACKGROUND: Despite significant advances in breast imaging, the ability to detect breast cancer (BC) remains a challenge. To address the unmet needs of the current BC detection paradigm, 2 prospective clinical trials were conducted to develop a blood-based combinatorial proteomic biomarker assay (Videssa Breast) to accurately detect BC and reduce false positives (FPs) from suspicious imaging findings. PATIENTS AND METHODS: Provista-001 and Provista-002 (cohort one) enrolled Breast Imaging Reporting and Data System 3 or 4 women aged under 50 years. Serum was evaluated for 11 serum protein biomarkers and 33 tumor associated autoantibodies. Individual biomarker expression, demographics, and clinical characteristics data from Provista-001 were combined to develop a logistic regression model to detect BC. The performance was tested using Provista 002 cohort one (validation set). RESULTS: The training model had a sensitivity and specificity of 92.3% and 85.3% (BC prevalence, 7.7%), respectively. In the validation set (BC prevalence, 2.9%), the sensitivity and specificity were 66.7% and 81.5%, respectively. The negative predictive value was high in both sets (99.3% and 98.8%, respectively). Videssa Breast performance in the combined training and validation set was 99.1% negative predictive value, 87.5% sensitivity, 83.8% specificity, and 25.2% positive predictive value (BC prevalence, 5.87%). Overall, imaging resulted in 341 participants receiving follow-up procedures to detect 30 cancers (90.6% FP rate). Videssa Breast would have recommended 111 participants for follow-up, a 67% reduction in FPs (P < .00001). CONCLUSIONS: Videssa Breast can effectively detect BC when used in conjunction with imaging and can substantially reduce unnecessary medical procedures, as well as provide assurance to women that they likely do not have BC. PMID- 28624157 TI - Endoscopic ultrasound-guided fine-needle aspiration and cytology for differentiating benign from malignant lymph nodes. AB - BACKGROUND AND STUDY AIMS: Intra-abdominal and mediastinal lymphadenopathy are often difficult to diagnose, particularly in the absence of a primary lesion. Endosonography (EUS)-guided fine-needle aspiration and cytology (FNAC) has provided an easy and safe access to these lymph nodes, sparing the use of invasive and costly interventions. The main aim of this study is to assess the specificity, sensitivity, and predictive value of EUS-guided FNAC in the diagnosis of benign and malignant lymph nodes. In addition, the study aims to determine significant EUS features that could help in predicting lymph node malignancy. PATIENTS AND METHODS: This prospective study included 142 patients with intra-abdominal or intrathoracic lymphadenopathy who were referred for EUS guided FNAC because of inaccessibility by other imaging modalities. Ninety (63.3%) patients were found to have malignant lymph nodes, and 52 (36.6%) had lymphadenopathy of benign nature. RESULTS: EUS-guided FNAC had a sensitivity and specificity of 92% and 100% respectively. It had positive and negative predictive values of 100% and 88% for malignancy, respectively. By logistic regression analysis, EUS features and shortest diameter were found to be potential predictors of malignancy with p-value of <0.0001. CONCLUSION: EUS-guided FNAC is a powerful modality in the diagnosis of benign and malignant lymph nodes. Additional complementary EUS features could be added to this technique for definitive diagnosis. PMID- 28624158 TI - Novel use of fully covered self-expandable metal stent for drainage of perirectal abscess. A case series. PMID- 28624159 TI - From the Laboratory to the Field: Updating Capacity Building in Medical Entomology. AB - Training and innovation in the field of medical entomology are essential to mitigate the burden of vector-borne diseases globally. However, there is a shortage of medical entomologists worldwide, and there are large discrepancies in capacity building in this field. In this article, we discuss the current situation, what is needed from the medical entomologist of today, and how we can bridge this gap. PMID- 28624161 TI - Clinical follow-up of the first SF-1 insufficient female patient. AB - OBJECTIVE: Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency. We describe the follow-up of a 46, XX affected woman with a SF-1 mutation and by comparing our case with the known manifestations reported in the literature, we try to further elucidate the function of SF-1 in the ovary. RESULTS: During infancy, adrenal insufficiency was the only clinical sign of the loss-of-function as ovarian development and function seemed normal. To date, this young woman aged 16.5 years shows normal growth, normal BMI and psychomotor development, has a normal puberty and regular menstruation. CONCLUSION: This report shows one, to date uniquely described, phenotypic variant of SF-1 mutation in a 46, XX affected person with adrenocortical insufficiency but no ovarian dysfunction nor disturbance of pubertal development. To follow the natural history of SF-1 mutation in a 46, XX individual will further shed light on its role in the ovarian function and thus will help to counsel affected patients in future. PMID- 28624160 TI - Association of apolipoprotein A5 gene variants with metabolic syndrome in Tunisian population. AB - AIM OF THE STUDY: APOA5 has been linked to metabolic syndrome (MetS) or its traits in several populations. In North Africa, only the Moroccan population was investigated. Our aim is to assess the association between APOA5 gene polymorphisms with the susceptibility to MetS and its components in the Tunisian population. MATERIALS AND METHODS: A total of 594 participants from the Tunisian population were genotyped for two polymorphisms rs3135506 and rs651821 located in APOA5 gene using KASPar technology. Statistical analyses were performed using R software. RESULTS: The SNP rs651821 increased the risk of MetS under the dominant model (OR=1.91 [1.17-3.12], P=0.008) whereas the variant rs3135506 was not associated with MetS. After stratification of the cohort following the sex, only the variant rs651821 showed a significant association with MetS among the women group. The influence of the geographic origin of the studied population on the genotype distribution of APOA5 variants showed that the variant rs651821 was significantly associated with MetS only for the Northern population. The association analyses of the variants rs651821 and rs3135506 with different quantitative traits of MetS showed a significant association only between the variant rs3135506 and triglycerides levels. CONCLUSION: This is the first study reporting the association of APOA5 gene variants with MetS in Tunisia. Our study emphasizes the role of APOA5 variants in the regulation of the triglycerides blood levels. Further studies are needed to confirm the clinical relevance of these associations and to better understand the physiopathology of the MetS. PMID- 28624162 TI - Stuck between a rock and a hard place: ILD + NSCLC = LIM. PMID- 28624163 TI - Simultaneous, congenital, mucocoele of the Blandin-Nuhn glands and teratoma of the tongue: early management and follow up at one year. AB - Mucocoele of the Blandin-Nuhn glands and teratomas of the tongue are rare in newborn babies. We present what is to our knowledge the first documented case of both at the same time, and describe management and follow up over 12 months after the birth. Prenatal diagnosis defined the treatment plan during delivery to establish an airway for the baby promptly. A normal delivery is possible if the cyst is anterior, and can be punctured during delivery. Delayed excision reduces the possibility of oedema and obstruction of the airway, ensures complete resection, avoids recurrence, and confirms the diagnosis. Mucocoeles are classified as extravasation or retention types; our observation supports the hypothesis of a "malformative type". A long follow-up is essential to monitor macroglossia, open bite, and the development of the mandible. PMID- 28624164 TI - Three-dimensional scanning electron microscopy of maxillofacial biomaterials. PMID- 28624165 TI - Inspiring a career in oral and maxillofacial surgery: a first-degree medical student's perspective. PMID- 28624166 TI - Retrograde Thyroidectomy for preservation of the External Branch of the Superior Laryngeal Nerve: A case series. AB - BACKGROUND: The external branch of the Superior Laryngeal nerve (EBSLN) is at high risk of injury in surgery for large multinodular goitre (MNG) since the upper pole is high in the neck, well cephalad to the EBSLN. We present a technique of drawing the lobe caudally by retrograde thyroidectomy in order to minimize nerve injury. DESIGN & METHOD: All patients having surgery for benign MNG were included. Cases with previous thyroid surgery, malignant and toxic disease were excluded. The thyroid lobe was mobilized from its inferior aspect and capsular dissection performed cephalad with bipolar or ligasure cautery, lifting the gland off the trachea while separating it from the parathyroids and branches of the inferior thyroid vessels. The ligament of Berry is divided and the entire lobe freed, attached only by the superior pedicle which is drawn caudally well below the EBSLN prior to ligation. Patients were followed for voice change at 24 hours, 7 days and 3 months. RESULTS: Ninety-one consecutive lobectomies were done in 60 patients, 31 bilateral. Forty-four (73%) patients had voice change at 24h, 10 (11%) at 7days and 1 at 3 months. The patient with persistent voice change complained of change in tone but not volume; vocal cords were normal on indirect laryngoscopy. CONCLUSION: Retrograde thyroidectomy is recommended for large MNG where the EBSLN lies well below the upper pole; it minimizes risk to the nerve. PMID- 28624167 TI - Longitudinal Vision-Related Quality of Life for Patients with Noninfectious Uveitis Treated with Fluocinolone Acetonide Implant or Systemic Corticosteroid Therapy. AB - PURPOSE: To evaluate longitudinal vision-related quality of life (VRQoL) in patients with noninfectious uveitis. DESIGN: Cohort study using randomized controlled trial data. PARTICIPANTS: Patients with active or recently active intermediate uveitis, posterior uveitis, or panuveitis enrolled in the Multicenter Steroid Treatment Trial and Follow-up Study. METHODS: Data from the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) for the first 3 years after randomization were evaluated semiannually. Analyses were stratified by assigned treatment (129 implants vs. 126 systemic therapies) because of substantial differences in the trajectories of VRQoL. The impact of baseline measurements of visual function (visual acuity and visual field), demographics, and disease characteristics was assessed using generalized estimating equations. MAIN OUTCOME MEASURES: Primary outcome was the NEI-VFQ-25 composite score over 3 years after randomization. RESULTS: Individuals in both treatment groups showed similar improvement in NEI-VFQ-25 scores after 3 years of follow-up (implant: 11.9 points; 95% confidence interval [CI], 8.6-15.2; P < 0.001; systemic: 9.0 points; 95% CI, 5.6-12.3; P < 0.001; P = 0.21 for interaction). Individuals in the implant group showed a substantial improvement during the first 6 months followed by stable scores, whereas individuals in the systemic group showed a steady improvement over the course of follow-up. Worse initial visual acuity and visual fields were associated with lower initial NEI VFQ-25 scores for both treatment groups. In the systemic group, these differences were maintained throughout follow-up. In the implant group, individuals with initial visual acuity worse than 20/40 showed additional improvement in NEI-VFQ 25 score to come within -7 points (95% CI, -15.0 to 0.9) of those with visual acuity 20/40 or better initially, a clinically meaningful but not statistically significant difference (P = 0.081). Results based on sensitivity analyses showed similar patterns. CONCLUSIONS: Both treatment groups demonstrated significant improvements in NEI-VFQ-25 scores; however, the improvement was immediate for the implant group as opposed to gradual for the systemic group. Poorer visual function was associated significantly with initial differences in NEI-VFQ-25 scores. However, only individuals in the implant group with poor visual acuity were able to overcome their initial deficits by the end of 3 years. PMID- 28624168 TI - Antibiotic Prescription Fills for Acute Conjunctivitis among Enrollees in a Large United States Managed Care Network. AB - PURPOSE: Antibiotics are seldom necessary to treat acute conjunctivitis. We assessed how frequently patients with newly diagnosed acute conjunctivitis fill prescriptions for topical antibiotics and factors associated with antibiotic prescription fills. DESIGN: Retrospective, observational cohort study. PARTICIPANTS: A total of 340 372 enrollees in a large nationwide United States managed care network with newly diagnosed acute conjunctivitis, from 2001 through 2014. METHODS: We identified all enrollees newly diagnosed with acute conjunctivitis, calculating the proportion filling 1 or more topical antibiotic prescription within 14 days of initial diagnosis. Multivariate logistic regression assessed sociodemographic, medical, and other factors associated with antibiotic prescription fills for acute conjunctivitis. Geographic variation in prescription fills also was studied. MAIN OUTCOME MEASURES: Odds ratios (ORs) with 95% confidence intervals (CIs) for filling an antibiotic prescription for acute conjunctivitis. RESULTS: Among 340 372 enrollees with acute conjunctivitis, 198 462 (58%) filled >=1 topical antibiotic prescriptions; 38 774 filled prescriptions for antibiotic-corticosteroid combination products. Compared with whites, blacks (OR, 0.89; 95% CI, 0.86-0.92) and Latinos (OR, 0.83; 95% CI, 0.81 0.86) had lower odds of filling antibiotic prescriptions. More affluent and educated enrollees had higher odds of filling antibiotic prescriptions compared with those with lesser affluence and education (P < 0.01 for all). Compared with persons initially diagnosed with acute conjunctivitis by ophthalmologists, enrollees had considerably higher odds of antibiotic prescription fills if first diagnosed by an optometrist (OR, 1.26; 95% CI, 1.21-1.31), urgent care physician (OR, 3.29; 95% CI, 3.17-3.41), internist (OR, 2.79; 95% CI, 2.69-2.90), pediatrician (OR, 2.27; 95% CI, 2.13-2.43), or family practitioner (OR, 2.46; 95% CI, 2.37-2.55). Antibiotic prescription fills did not differ for persons with versus without risk factors for development of serious infections, such as contact lens wearers (P = 0.21) or patients with human immunodeficiency virus infection or AIDS (P = 0.60). CONCLUSIONS: Nearly 60% of enrollees in this managed care network filled antibiotic prescriptions for acute conjunctivitis, and 1 of every 5 antibiotic users filled prescriptions for antibiotic corticosteroids, which are contraindicated for acute conjunctivitis. These potentially harmful practices may prolong infection duration, may promote antibiotic resistance, and increase costs. Filling antibiotic prescriptions seems to be driven more by sociodemographic factors and type of provider diagnosing the enrollee than by medical indication. PMID- 28624169 TI - Change in Optic Nerve After Intracranial Pressure Reduction in Children. PMID- 28624170 TI - Predictors of visit-to-visit blood pressure variability in patients with hypertension: an analysis of trials with an amlodipine treatment arm. AB - We conducted a post hoc analysis of blood pressure (BP) data from long-term antihypertensive trials to identify predictors of visit-to-visit BP variability (BPV). BPV was defined as the within-subject coefficient of variation in systolic BP from week 12 onward. BP data from the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis, NY92011, and R-0510 trials were pooled and dichotomized into top 25th and bottom 75th percentiles because of positive skew. Significant (P < .001) predictors of BPV within the top 25th percentile were identified using logistic regression. The baseline characteristics of the pooled cohort (n = 47,558) were similar between patients who received amlodipine (n = 17,499) versus other antihypertensive drugs (n = 29,491). BPV in the top 25th percentile was lower with amlodipine versus other treatments (13.7 +/- 3.2 vs. 14.3 +/- 3.5), with single-study analyses of Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis all showing BPV was the lowest with amlodipine. Baseline diastolic BP, estimated glomerular filtration rate, and smoking were predictors of BPV, with significant two-way interactions between smoking and both age and body mass index and between systolic BP or diastolic BP and being randomized to treatment other than amlodipine. In conclusion, analysis of BPV required transformation of BP data. After transformation, a number of baseline variables and combinations of variables were predictors of BPV. PMID- 28624171 TI - Race and sex differences in ambulatory blood pressure measures among HIV+ adults. AB - Ambulatory blood pressure monitoring (ABPM) can identify phenotypes that cannot be measured in the clinic. Determining race and sex disparities in ABPM measures among HIV+ individuals may improve strategies to diagnose and treat hypertension in this high-risk population. We compared ABPM measures between 24 African American and 25 white HIV+ adults (36 men and 13 women). Awake systolic blood pressure (SBP) and diastolic blood pressure (DBP) were similar in African Americans and whites. After multivariable adjustment, sleep SBP and DBP were 9.7 mm Hg (95% confidence interval [95% CI]: 4.7, 14.8) and 8.4 mm Hg (95% CI: 4.3, 12.5) higher, respectively, among African-Americans compared with whites. After multivariable adjustment, SBP and DBP dipping ratios were 5.2% (95% CI: 1.7%, 8.7%) and 6.1% (95% CI 2.0%, 10.3%) smaller among African-Americans compared with whites. After multivariable adjustment, awake and sleep SBP and DBP were higher in men compared to women. There was no difference in SBP or DBP dipping ratios comparing men and women. The prevalence of awake masked hypertension was 42% in men versus 17% in women, and the prevalence of sleep masked hypertension was 57% among African-Americans versus 18% among whites. These data suggest that ABPM measures differ by race and sex in HIV+ adults. PMID- 28624172 TI - Development of an imaging mitigation strategy for patient enrolment in the tanezumab nerve growth factor inhibitor (NGF-ab) program with a focus on eligibility assessment. AB - OBJECTIVE: Nerve growth factor antibodies (NGF-ab) have shown promising analgesic efficacy. Aim was to describe reader training efforts and present reliability data focusing on radiographic eligibility in the tanezumab program. METHODS: A multi-step process was used for reader calibration and reliability testing. First, a reference standard set of cases was created and diagnostic performance was evaluated. A second exercise focused on agreement of ordinal assessment (Kellgren-Lawrence grading) of radiographic osteoarthritis. Subsequently, 11 readers were trained and read a test set of 100 cases focused on eligibility assessments. Additional reliability testing and calibration of five core readers assessing eligibility of 30 cases was performed 3 and 6 months after study start. RESULTS: Sensitivity for the reference standard readings ranged from 0.50 to 0.90 and specificity from 0.40 to 0.83. Overall agreement for Kellgren-Lawrence grading ranged from 71.4% to 82.9%. For the 11 reader exercise, in 76% of cases at least 8 of 11 readers agreed on eligibility status. For the reliability testing 3 months after study start, in 80.0% of cases at least 4 of 5 readers agreed on eligibility with a kappa = 0.43 (95% CI: 0.32-0.54). For the reliability testing after 6 months, in 83.3% of cases at least 4 of 5 readers agreed on eligibility with a kappa = 0.52 (95% CI: 0.41-0.63). CONCLUSIONS: After intense efforts spent in the development of an imaging program for an NGF-ab clinical program, the achieved reliability for eligibility assessment is substantial but not perfect. Ongoing efforts of calibration prior to including additional readers to the program and during study conduct between current readers will be needed to ensure agreement on potential adverse events and radiographic disease severity. PMID- 28624173 TI - High-resolution manometry compared with the University of California, Los Angeles Scleroderma Clinical Trials Consortium GIT 2.0 in Systemic Sclerosis. AB - OBJECTIVES: To study esophageal high resolution manometry (HRM) in systemic sclerosis (SSc) patients and the correlation of findings to The University of California, Los Angeles Scleroderma Clinical Trials Consortium gastrointestinal tract 2.0 (UCLA SCTC_GIT 2.0). METHODS: Forty SSc patients were administered to the UCLA SCTC GIT 2.0. Patients underwent HRM study (Solar GI MMS). HRM data were compared with 15 healthy volunteers. RESULTS: Forty patients with mean age 46 +/- 7 years and disease duration 9.3 +/- 7 years reported upper (85.7%), lower GI symptoms (75%), while 5% reported no symptoms. Mean +/- SD scores of UCLA SCTC_GIT 2.0 items were as follows: reflux 1.2 +/- 0.8, distention 1.6 +/- 1.2, fecal soiling 0.3 +/- 0.9, diarrhea 0.8 +/- 1, social 1 +/- 1, emotional 1 +/- 1.1, constipation 0.5 +/- 0.9, and total GIT score 0.9 +/- 0.6. Lower esophageal sphincter (LES) pressure and distal esophageal amplitude were significantly lower in SSc patients than controls. Main manometric findings were decreased LES resting pressure (40%) and aperistalsis (40%). Regression analyses showed distal esophageal amplitude and LES resting pressure negatively correlated with reflux score (r = -0.64; p = 0.001 and r = -0.46; p = 0.019, respectively), and total GIT score (r = -0.54; p = 0.007 and r = -0.42; p = 0.03, respectively). LES resting pressure had negative correlations with diarrhea score (r = -0.062; p = 0.002). CONCLUSIONS: Decreased distal esophageal amplitude encountered as hypoperistalsis or even aperistalsis was associated with increased reflux and GIT scores (negatively correlated) UCLA SCTC_GIT 2.0 questionnaires. The GIT2.0 is easy to use and can serve as an indicator that further testing of the GI tract, including the esophagus, is indicated. PMID- 28624174 TI - The Performance Gap for Residents in Transfer of Intracorporeal Suturing Skills From Box Trainer to Operating Room. AB - OBJECTIVE: Training on laparoscopic box trainer (BT) improves suturing skills in the operating room (OR). Optimal laboratory training should provide trainees with an adequate level of skills that can be transferred to the OR with no decline in performances. This study aimed to compare OR intracorporeal suturing performances of residents who trained with a fundamentals of laparoscopic surgery (FLS) BT vs. those of experienced laparoscopists. DESIGN: This was a prospective observational study. Residents received training with an FLS BT over a period of 4 months. Their performances with the BT and in the OR were then compared with those of experienced senior surgeons. OR assessment took place during a laparoscopic myomectomy. Performance evaluation was based on time taken and 2 validated qualitative assessment tools (GOALS and the Moorthy checklist). SETTINGS: One academic tertiary care center, La Conception Hospital, Assistance Publique Hopitaux de Marseille, Marseille, France, was involved. PARTICIPANTS: Twelve gynecology residents and 6 experienced laparoscopic surgeons. RESULTS: Following the FLS training period, performances of residents with the BT were equivalent to those of the experienced surgeons. When tested in the OR, the trained residents performed more slowly than experienced surgeons (279.75 vs. 159.75s; p = 0.001), and they obtained lower qualitative outcomes in terms of GOALS (13 vs. 16.75; p = 0.002) and checklist (18.25 vs. 21; p = 0.049). Transfer from the BT to the OR revealed an increase in time taken that was significantly higher for the trained residents' group than for the experienced group (137s vs. 49s; p < 0.001). CONCLUSION: A performance gap emerged between trained residents and experienced surgeons when transferring from the BT to the OR. Finding an intermediate training platform between the BT and independently suturing in the OR is hence warranted. PMID- 28624175 TI - Prospective study comparing laparoscopic and open radical cystectomy: Surgical and oncological results. AB - INTRODUCTION: Laparoscopic radical cystectomy with lymphadenectomy and urinary diversion is an increasingly widespread operation. Studies are needed to support the oncological effectiveness and safety of this minimally invasive approach. PATIENTS AND METHODS: A nonrandomised, comparative prospective study between open radical cystectomy (ORC) and laparoscopic radical cystectomy (LRC) was conducted in a university hospital. The main objective was to compare cancer-specific survival. The secondary objective was to compare the surgical results and complications according to the Clavien-Dindo scale. RESULTS: We treated 156 patients with high-grade invasive bladder cancer with either ORC (n=70) or LRC (n=86). The mean follow-up was 33.5+/-23.8 (range 12-96) months. The mean age was 66.9+9.4 years, and the male to female ratio was 19:1. Both groups were equivalent in age, stage, positive lymph nodes, in situ carcinoma, preoperative obstructive uropathy, adjuvant chemotherapy and type of urinary diversion. There were no differences between the groups in terms of cancer-specific survival (log rank; P=.71). The histopathology stage was the only independent variable that predicted the prognosis. The hospital stay (P=.01) and operative transfusion rates (P=.002) were less for LRC. The duration of the surgery was greater for LRC (P<.001). There were no differences in the total complications rate (p=.62) or major complications (P=.69). The risk of evisceration (P=.02), surgical wound infection (P=.005) and pneumonia (P=.017) was greater for ORC. The risk of rectal lesion (P=.017) and urethrorectal fistulae (P=.065) was greater for LRC. CONCLUSION: LRC is an equivalent treatment to ORC in terms of oncological efficacy and is advantageous in terms of transfusion rates and hospital stays but not in terms of operating room time and overall safety. Studies are needed to better define the specific safety profile for each approach. PMID- 28624176 TI - Moderate enhancement in tissue permeability by preclinical focused ultrasound. PMID- 28624177 TI - Autophagy can alleviate severe burn-induced damage to the intestinal tract in mice. AB - BACKGROUND: The present study was designed to examine the effect of autophagy and apoptosis on intestinal injury in mice after severe burns. METHODS: Kunming mice were subjected to third degree burns over 30% of the total body surface area. Damage to the intestine was assessed by examining changes in intestinal mucosal morphology, enzyme-linked immunosorbent assay of serum d-lactate, diamine oxidase, lipopolysaccharide, interleukin-6, and tumor necrosis factor alpha (marker of intestinal damage), hematoxylin and eosin staining, and Western blotting under 4 experimental conditions: control group, burn only (burn group), burn and administration of rapamycin to stimulate intestinal autophagy (rapamycin group), or burn and administration of 3-methyladenine to inhibit intestinal autophagy (3-methyladenine group). RESULTS: At day 1 postburn, the expression levels of light chain 3 II, beclin-1, and cleaved caspase-3 were significantly greater in all 3 groups of mice subjected to the burn injury than in the control group 1 day postburn; while the levels of light chain 3 II and beclin-1 were significantly greater and those of cleaved caspase-3 were significantly less in the rapamycin group than in the burn group. In contrast, light chain 3 II and beclin-1 levels were significantly less and those of cleaved caspase-3 significantly greater in the 3-methyladenine group. All 3 groups subjected to burn injury showed significantly increased levels of d-lactate, diamine oxidase, lipopolysaccharide, interleukin-6, and tumor necrosis factor alpha. Of the 3 groups, the rapamycin group exhibited the least observed levels, the 3 methyladenine group the greatest, and the burn group intermediate. Pathologic sections of the intestinal tissue showed that all 3 burn groups exhibited severe intestinal mucosal damage at 1 day postburn. The condition of the 3-methyladenine treatment group was worse than that of the rapamycin treatment group, but better than that of the burn group. CONCLUSION: Intestinal autophagy is activated in response to intestinal apoptosis after severe burns and may alleviate burn induced intestinal injury. PMID- 28624178 TI - Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review. AB - BACKGROUND: Liver transplantation to treat neuroendocrine tumors, especially in the setting of diffuse liver involvement not amenable to operative resection remains controversial. We sought to perform a systematic review of the current literature to summarize data on patients undergoing liver transplantation with neuroendocrine tumors liver metastases as the indication. METHODS: A systematic review was conducted in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Eligible studies were identified using 3 distinct databases through March 2017: Medline (PubMed), ClinicalTrials.gov, and Cochrane library, Cochrane Central Register of Controlled Trials using a search algorithm: "(neuroendocrine or NET) and transplantation and liver." RESULTS: From the 1,216 records retrieved, 64 studies were eligible. Overall, 4 studies presented data from registries, namely the European Liver Transplant Registry and the United Network for Organ Transplantation/Organ Procurement and Transplantation Network databases, 3 were multicenter studies. The largest cohort of data on patients undergoing liver transplantation for neuroendocrine tumors liver metastasis indication were from single center studies comprising a total of 279 patients. Pancreas was the primary tumor site for most patients followed by the ileum. Several studies reported that more than half of patients presented with synchronous disease (55.9% and 57.7%); in contrast, metachronous neuroendocrine tumors liver metastasis ranged from 17.7% to 38.7%. Overall, recurrence after liver transplantation ranged from 31.3% to 56.8%. Reported 1-, 3-, and 5-year overall survival was 89%, 69%, and 63%, respectively. Several prognostic factors associated with worse long-term survival including transplantation >50% liver tumor involvement, high Ki67, as well as a pancreatic neuroendocrine tumors versus gastrointestinal neuroendocrine tumors tumor location. CONCLUSION: Liver transplantation may provide a survival benefit among patients with diffuse neuroendocrine tumors metastases to the liver. However, due to high recurrence rates, strict selection of patients is critical. Due to the scarcity of available grafts and the lack of level 1 evidence, the recommendations to endorse liver transplantation for extensive liver neuroendocrine tumors metastases warrants ongoing deliberations. PMID- 28624179 TI - Smoke-free policies in psychiatric hospitals need resources. PMID- 28624180 TI - Effect of implementation of a smoke-free policy on physical violence in a psychiatric inpatient setting: an interrupted time series analysis. AB - BACKGROUND: Smoke-free policies are important to protect health and reduce health inequalities. A major barrier to policy implementation in psychiatric hospitals is staff concern that physical violence will increase. We aimed to assess the effect of implementing a comprehensive smoke-free policy on rates of physical assaults in a large UK mental health organisation. METHODS: We did an interrupted time series analysis of incident reports of physical assault 30 months before and 12 months after the implementation of the policy in the inpatient wards of South London and Maudsley National Health Service Foundation Trust, London, UK. We used a quasi-Poisson generalised additive mixed model to model the monthly incidence of physical assaults as a function of several explanatory variables. FINDINGS: 4550 physical assaults took place between April 1, 2012, and Sept 30, 2015; 225 (4.9%) of which were smoking-related. After adjustment for temporal and seasonal trends and key confounders (sex, age, schizophrenia or related disorders, or having been sectioned under the Mental Health Act), there was a 39% reduction in the number of physical assaults per month after the policy introduction compared with beforehand (incidence rate ratio 0.61, 95% CI 0.53-0.70; p<0.0001). INTERPRETATION: Introduction of a comprehensive smoke-free policy appeared to reduce the incidence of physical assaults. Adequately resourced smoke-free policies could be part of broader violence reduction strategies in psychiatric settings. FUNDING: National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care South London (King's College Hospital NHS Foundation Trust). PMID- 28624181 TI - Corrigendum to "Prolonged chewing at lunch decreases later snack intake" [Appetite 62 (1 March 2013) 91-95]. PMID- 28624182 TI - Oral Appliances for the Management of OSA: An Updated Review of the Literature. AB - Oral appliances (OAs) are becoming increasingly recognized not only as an alternative to but also possibly as an adjunct treatment modality for OSA. Compared with CPAP, the gold standard therapy, OAs are less efficacious but are more accepted and tolerated by patients, which, in turn, may lead to a comparable level of therapeutic effectiveness. Different OA designs currently exist, and more are constantly emerging. Additionally, state-of-the-art technologies are being used in the fabrication of many; however, all the currently available OAs employ the same mechanism of action by targeting the anatomical component involved in the pathogenesis of the disease. Furthermore, the scope of use of OAs is expanding to include patients who are edentulous. For patients with OAs, the dentist is a member of an interdisciplinary team managing OSA, and constant communication and follow-up with the sleep physician and other team members is necessary for disease management. PMID- 28624184 TI - 31P MAS NMR spectroscopy with 93Nb decoupling and DFT calculations: A structural characterization of defects in a niobium-phosphate phase. AB - The present study has investigated the structure of four niobium phosphates compounds using 31P MAS NMR spectroscopy. Niobium 93Nb decoupling, applied during 31P NMR acquisition led to a resolution enhancement by a factor of 2-3, which allowed distinguish phosphorous sites separated by 1 ppm or less. The assignment of 31P spectra has been completed by use of first-principles calculations derived from the original XRD structures. One of the compounds, Na3.04Nb7P4O29, contains a sodium vacancy, clearly revealed in the 31P MAS spectrum obtained with 93Nb decoupling. A series of structural models were proposed to account for the sodium distribution in the structure of Na3.04Nb7P4O29 and the assignment was possible using DFT calculation and a statistical analysis of the NMR parameters. PMID- 28624183 TI - The neuroprotective effect of perampanel in lithium-pilocarpine rat seizure model. AB - PURPOSE: Status epilepticus (SE) causes irreversible neurodegeneration if not terminated quickly. Perampanel (PER), a potent AMPA receptor antagonist, has previously been shown to terminate seizures in the lithium-pilocarpine SE model. In the present study, we assessed whether PER would also prevent neuronal damage in this model. METHODS: SE was induced in rats using lithium chloride and pilocarpine. Initiation of SE was defined as continuous seizures that exhibited as rearing accompanied by bilateral forelimb clonus (Racine score 4). Either PER (0.6, 2, or 6mg/kg) or diazepam (DZP, 10mg/kg) was administered intravenously 30min after SE initiation. Histopathological samples from treated and seizure naive rats were taken one week after treatment and then stained with an anti neuronal nuclei (NeuN) antibody. The sections were analyzed by using a pixel counting algorithm to quantify the amount of staining in the CA1 subregion of the hippocampus, piriform cortex (Pir), and mediodorsal thalamic nucleus (MD). RESULTS: DZP administration did not suppress seizures or the degeneration of neurons in the examined areas. Seizures were terminated in 100% of rats treated with 6mg/kg PER (n=8) and in 47% (7/15) of rats treated with 2mg/kg PER, and neurons in the analyzed areas of these animals were preserved to the level seen in naive rats. In the eight animals in which 2mg/kg PER did not terminate the seizures, neuronal loss was partially attenuated in CA1 and Pir, and neurons were fully preserved in MD. Treatment with 0.6mg/kg PER did not terminate the seizures or significantly preserve neurons. The anti-seizure effect of PER correlated well with the degree of neuroprotection in each analyzed area. CONCLUSIONS: PER exhibited a strong neuroprotective effect in a drug-refractory SE model, and this effect was correlated with its attenuation of seizure. PMID- 28624185 TI - The Formation of Nanoparticles between Small Interfering RNA and Amphipathic Cell Penetrating Peptides. AB - Cell-penetrating peptides (CPPs) are delivery vectors widely used to aid the transport of biologically active cargoes to intracellular targets. These cargoes include small interfering RNAs (siRNA) that are not naturally internalized by cells. Elucidating the complexities behind the formation of CPP and cargo complexes is crucial for understanding the processes related to their delivery. In this study, we used modified analogs of the CPP transportan10 and investigated the binding properties of these CPPs to siRNA, the formation parameters of the CPP/siRNA complexes, and their stabiliy to enzymatic degradation. We conclude that the pH dependent change of the net charge of the CPP may very well be the key factor leading to the high delivery efficiency and the optimal binding strength between CPPs to siRNAs, while the hydrophobicity, secondary structure of the CPP, and the positions of the positive charges are responsible for the stability of the CPP/siRNA particles. Also, CPPs with distinct hydrophobic and hydrophilic regions may assemble into nanoparticles that could be described as core-shell formulations. PMID- 28624186 TI - GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells. AB - Pompe disease is a metabolic myopathy caused by deficiency of the acid alpha glucosidase (GAA) enzyme and results in progressive wasting of skeletal muscle cells. The c.-32-13T>G (IVS1) GAA variant promotes exon 2 skipping during pre mRNA splicing and is the most common variant for the childhood/adult disease form. We previously identified antisense oligonucleotides (AONs) that promoted GAA exon 2 inclusion in patient-derived fibroblasts. It was unknown how these AONs would affect GAA splicing in skeletal muscle cells. To test this, we expanded induced pluripotent stem cell (iPSC)-derived myogenic progenitors and differentiated these to multinucleated myotubes. AONs restored splicing in myotubes to a similar extent as in fibroblasts, suggesting that they act by modulating the action of shared splicing regulators. AONs targeted the putative polypyrimidine tract of a cryptic splice acceptor site that was part of a pseudo exon in GAA intron 1. Blocking of the cryptic splice donor of the pseudo exon with AONs likewise promoted GAA exon 2 inclusion. The simultaneous blocking of the cryptic acceptor and cryptic donor sites restored the majority of canonical splicing and alleviated GAA enzyme deficiency. These results highlight the relevance of cryptic splicing in human disease and its potential as therapeutic target for splicing modulation using AONs. PMID- 28624187 TI - Correction of the Exon 2 Duplication in DMD Myoblasts by a Single CRISPR/Cas9 System. AB - Exonic duplications account for 10%-15% of all mutations in Duchenne muscular dystrophy (DMD), a severe hereditary neuromuscular disorder. We report a CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9-based strategy to correct the most frequent (exon 2) duplication in the DMD gene by targeted deletion, and tested the efficacy of such an approach in patient-derived myogenic cells. We demonstrate restoration of wild-type dystrophin expression at transcriptional and protein level in myotubes derived from genome-edited myoblasts in the absence of selection. Removal of the duplicated exon was achieved by the use of only one guide RNA (gRNA) directed against an intronic duplicated region, thereby increasing editing efficiency and reducing the risk of off-target effects. This study opens a novel therapeutic perspective for patients carrying disease-causing duplications. PMID- 28624188 TI - A Novel Single-Strand RNAi Therapeutic Agent Targeting the (Pro)renin Receptor Suppresses Ocular Inflammation. AB - The receptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to the (pro)renin receptor [(P)RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling. Here we revealed significant upregulation of prorenin and soluble (P)RR levels in the vitreous fluid of patients with uveitis compared to non inflammatory controls, together with a positive correlation between these RAPS components and monocyte chemotactic protein-1 among several upregulated cytokines. Moreover, we developed a novel single-strand RNAi agent, proline modified short hairpin RNA directed against human and mouse (P)RR [(P)RR-PshRNA], and we determined its safety and efficacy in vitro and in vivo. Application of (P)RR-PshRNA in mice caused significant amelioration of acute (uveitic) and chronic (diabetic) models of ocular inflammation with no apparent adverse effects. Our findings demonstrate the significant implication of RAPS in the pathogenesis of human uveitis and the potential usefulness of (P)RR-PshRNA as a therapeutic agent to reduce ocular inflammation. PMID- 28624189 TI - Mir30c Is Involved in Diabetic Cardiomyopathy through Regulation of Cardiac Autophagy via BECN1. AB - Multiple factors have been shown to promote the progression of diabetic cardiomyopathy. A link has previously been found between Mir30 and autophagy in cancer cells and in the heart, but the role of Mir30 in diabetic heart has not been studied. Using in vitro and in vivo approaches, we found that the depletion of Mir30c and induction of BECN1 enhanced autophagy in diabetic (db/db) hearts and in cardiomyocytes treated with the fatty acid palmitate. We verified that Mir30c repressed BECN1 expression by direct binding to the BECN1 3' UTRs. Mir30c overexpression inhibited the induction of BECN1 and subsequent autophagy in diabetic hearts and improved cardiac function and structure in diabetic mice. However, these effects were abrogated by BECN1 overexpression. Similarly, Mir30c knockdown resulted in increased BECN1 levels and autophagic flux, aggravating cardiac abnormalities. We also show that SP1, an important transcriptional factor in energy metabolism regulation, is a key upstream activator of Mir30c that binds the promoter region of Mir30c. Our findings indicate that downregulation of Mir30c and subsequent activation of BECN1 promotes autophagy, contributing to the pathogenesis of diabetic cardiomyopathy. This observation suggests a theoretical ground for developing microRNA-based therapeutics against diabetic cardiomyopathy by inhibiting autophagy. PMID- 28624190 TI - Expression of Herpes Simplex Virus Thymidine Kinase/Ganciclovir by RNA Trans Splicing Induces Selective Killing of HIV-Producing Cells. AB - Antiviral strategies targeting hijacked cellular processes are less easily evaded by the virus than viral targets. If selective for viral functions, they can have a high therapeutic index. We used RNA trans-splicing to deliver the herpes simplex virus thymidine kinase-ganciclovir (HSV-tk/GCV) cell suicide system into HIV-producing cells. Using an extensive in silico bioinformatics and RNA structural analysis approach, ten HIV RNA trans-splicing constructs were designed targeting eight different HIV splice donor or acceptor sites and were tested in cells expressing HIV. Trans-spliced mRNAs were identified in HIV-expressing cells using qRT-PCR with successful detection of fusion RNA transcripts between HIV RNA and the HSV-tk RNA transcripts from six of ten candidate RNA trans-splicing constructs. Conventional PCR and Sanger sequencing confirmed RNA trans-splicing junctions. Measuring cell viability in the presence or absence of GCV expression of HSV-tk by RNA trans-splicing led to selective killing of HIV-producing cells using either 3' exon replacement or 5' exon replacement in the presence of GCV. Five constructs targeting four HIV splice donor and acceptor sites, D4, A5, A7, and A8, involved in regulating the generation of multiple HIV RNA transcripts proved to be effective for trans-splicing mediated selective killing of HIV infected cells, within which individual constructs targeting D4 and A8 were the most efficient. PMID- 28624191 TI - iRNA-PseColl: Identifying the Occurrence Sites of Different RNA Modifications by Incorporating Collective Effects of Nucleotides into PseKNC. AB - There are many different types of RNA modifications, which are essential for numerous biological processes. Knowledge about the occurrence sites of RNA modifications in its sequence is a key for in-depth understanding of their biological functions and mechanism. Unfortunately, it is both time-consuming and laborious to determine these sites purely by experiments alone. Although some computational methods were developed in this regard, each one could only be used to deal with some type of modification individually. To our knowledge, no method has thus far been developed that can identify the occurrence sites for several different types of RNA modifications with one seamless package or platform. To address such a challenge, a novel platform called "iRNA-PseColl" has been developed. It was formed by incorporating both the individual and collective features of the sequence elements into the general pseudo K-tuple nucleotide composition (PseKNC) of RNA via the chemicophysical properties and density distribution of its constituent nucleotides. Rigorous cross-validations have indicated that the anticipated success rates achieved by the proposed platform are quite high. To maximize the convenience for most experimental biologists, the platform's web-server has been provided at http://lin.uestc.edu.cn/server/iRNA PseColl along with a step-by-step user guide that will allow users to easily achieve their desired results without the need to go through the mathematical details involved in this paper. PMID- 28624193 TI - MiR-375 and Doxorubicin Co-delivered by Liposomes for Combination Therapy of Hepatocellular Carcinoma. AB - Doxorubicin (DOX) is one of the most frequently used anti-cancer drugs and the front line option for hepatocellular carcinoma (HCC) treatment. However, the clinical applications of DOX are restricted largely due to its toxicity and chemoresistance. Here, we report that miR-375 and DOX were co-delivered by liposomes (named L-miR-375/DOX-NPs) for combination therapy of HCC and drug resistance reversion of DOX. In vitro, L-miR-375/DOX-NPs could deliver DOX and miR-375 efficiently and simultaneously into HCC cells and ensure the successful release of mature miR-375 and DOX. Then, the released miR-375 suppressed the malignant hallmarks of HCC by significantly decreasing the expression of AEG-1, YAP1, and ATG7, while the released DOX evidently accelerated cell apoptosis and blocked cycle at a G2/M stage by activating the P53/Bax/Bcl-2, caspase-3, and P JNK, P-P38 pathway. Furthermore, miR-375 dramatically inhibited drug resistance of DOX by reducing the expression of multidrug resistance gene 1 (MDR1). In vivo, L-miR-375/DOX-NPs exhibited enhanced anti-tumor efficiency in xenograft HCC mouse models with mild adverse effects compared with doxorubicin or miR-375 alone. In conclusion, our research demonstrated that L-miR-375/DOX-NPs had significant synergetic anti-tumor effects and added values in overcoming drug resistance, which may represent a promising approach for the therapy of HCC. PMID- 28624192 TI - Stimuli-Responsive Mesoporous Silica NPs as Non-viral Dual siRNA/Chemotherapy Carriers for Triple Negative Breast Cancer. AB - Triple negative breast cancer (TNBC) is the most aggressive and lethal subtype of breast cancer. It is associated with a very poor prognosis and intrinsically resistant to several conventional and targeted chemotherapy agents and has a 5 year survival rate of less than 25%. Because the treatment options for TNBC are very limited and not efficient enough for achieving minimum desired goals, shifting toward a new generation of anti-cancer agents appears to be very critical. Among recent alternative approaches being proposed, small interfering RNA (siRNA) gene therapy can potently suppress Bcl-2 proto-oncogene and p glycoprotein gene expression, the most important chemotherapy resistance inducers in TNBC. When resensitized, primarily ineffective chemotherapy drugs turn back into valuable sources for further intensive chemotherapy. Regrettably, siRNA's poor stability, rapid clearance in the circulatory system, and poor cellular uptake mostly hampers the beneficial outcomes of siRNA therapy. Considering these drawbacks, dual siRNA/chemotherapy drug encapsulation in targeted delivery vehicles, especially mesoporous silica nanoparticles (MSNs) appears to be the most reasonable solution. The literature is full of reports of successful treatments of multi-drug-resistant cancer cells by administration of dual drug/siRNA-loaded MSNs. Here we tried to answer the question of whether application of a similar approach with identical delivery devices in TNBC is rational. PMID- 28624194 TI - Sustained Inhibition of HBV Replication In Vivo after Systemic Injection of AAVs Encoding Artificial Antiviral Primary MicroRNAs. AB - Chronic infection with hepatitis B virus (HBV) remains a problem of global significance and improving available treatment is important to prevent life threatening complications arising in persistently infected individuals. HBV is susceptible to silencing by exogenous artificial intermediates of the RNA interference (RNAi) pathway. However, toxicity of Pol III cassettes and short duration of silencing by effectors of the RNAi pathway may limit anti-HBV therapeutic utility. To advance RNAi-based HBV gene silencing, mono- and trimeric artificial primary microRNAs (pri-miRs) derived from pri-miR-31 were placed under control of the liver-specific modified murine transthyretin promoter. The sequences, which target the X sequence of HBV, were incorporated into recombinant hepatotropic self-complementary adeno-associated viruses (scAAVs). Systemic intravenous injection of the vectors into HBV transgenic mice at a dose of 1 * 1011 per animal effected significant suppression of markers of HBV replication for at least 32 weeks. The pri-miRs were processed according to the intended design, and intrahepatic antiviral guide sequences were detectable for 40 weeks after the injection. There was no evidence of toxicity, and innate immunostimulation was not detectable following the injections. This efficacy is an improvement on previously reported RNAi-based inhibition of HBV replication and is important to clinical translation of the technology. PMID- 28624195 TI - Fluorinated Nucleotide Modifications Modulate Allele Selectivity of SNP-Targeting Antisense Oligonucleotides. AB - Antisense oligonucleotides (ASOs) have the potential to discriminate between subtle RNA mismatches such as SNPs. Certain mismatches, however, allow ASOs to bind at physiological conditions and result in RNA cleavage mediated by RNase H. We showed that replacing DNA nucleotides in the gap region of an ASO with other chemical modification can improve allele selectivity. Herein, we systematically substitute every position in the gap region of an ASO targeting huntingtin gene (HTT) with fluorinated nucleotides. Potency is determined in cell culture against mutant HTT (mtHTT) and wild-type HTT (wtHTT) mRNA and RNase H cleavage intensities, and patterns are investigated. This study profiled five different fluorinated nucleotides and showed them to have predictable, site-specific effects on RNase H cleavage, and the cleavage patterns were rationalized from a published X-ray structure of human RNase H1. The results herein can be used as a guide for future projects where ASO discrimination of SNPs is important. PMID- 28624196 TI - Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. AB - The most common dominantly inherited ataxia, spinocerebellar ataxia type 3 (SCA3), is an incurable neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene that encodes an abnormally long polyglutamine tract in the disease protein, ATXN3. Mice lacking ATXN3 are phenotypically normal; hence, disease gene suppression offers a compelling approach to slow the neurodegenerative cascade in SCA3. Here we tested antisense oligonucleotides (ASOs) that target human ATXN3 in two complementary mouse models of SCA3: yeast artificial chromosome (YAC) MJD-Q84.2 (Q84) mice expressing the full-length human ATXN3 gene and cytomegalovirus (CMV) MJD-Q135 (Q135) mice expressing a human ATXN3 cDNA. Intracerebroventricular injection of ASOs resulted in widespread delivery to the most vulnerable brain regions in SCA3. In treated Q84 mice, three of five tested ASOs reduced disease protein levels by >50% in the diencephalon, cerebellum, and cervical spinal cord. Two ASOs also significantly reduced mutant ATXN3 in the mouse forebrain and resulted in no signs of astrogliosis or microgliosis. In Q135 mice expressing a single ATXN3 isoform via a cDNA transgene, ASOs did not result in similar robust ATXN3 silencing. Our results indicate that ASOs targeting full-length human ATXN3 would likely be well tolerated and could lead to a preventative therapy for SCA3. PMID- 28624197 TI - CRISPR/Cas9: Transcending the Reality of Genome Editing. AB - With the expansion of the microbiology field of research, a new genome editing tool arises from the biology of bacteria that holds the promise of achieving precise modifications in the genome with a simplicity and versatility that surpasses previous genome editing methods. This new technique, commonly named CRISPR/Cas9, led to a rapid expansion of the biomedical field; more specifically, cancer characterization and modeling have benefitted greatly from the genome editing capabilities of CRISPR/Cas9. In this paper, we briefly summarize recent improvements in CRISPR/Cas9 design meant to overcome the limitations that have arisen from the nuclease activity of Cas9 and the influence of this technology in cancer research. In addition, we present challenges that might impede the clinical applicability of CRISPR/Cas9 for cancer therapy and highlight future directions for designing CRISPR/Cas9 delivery systems that might prove useful for cancer therapeutics. PMID- 28624198 TI - Emerging Roles of circRNA Related to the Mechanical Stress in Human Cartilage Degradation of Osteoarthritis. AB - Circular RNAs (circRNAs) are involved in the development of various diseases; however, knowledge on circRNAs in osteoarthritis (OA) is limited. This study aims to identify circRNA expression in different regions affected by OA and to explore the function of mechanical stress-related circRNAs (circRNAs-MSR) in cartilage. Bioinformatics was employed to predict the interaction of circRNAs and mRNAs in the cartilage. Loss-of-function experiments for circRNAs-MSR were performed in vitro. A total of 104 circRNAs were differentially expressed in damaged versus intact cartilage. Of these circRNAs, 44 and 60 were upregulated and downregulated, respectively, in the damaged tissue. circRNA-MSR expression increased under mechanical stress in chondrocytes. circRNAs-MSR were silenced using small interfering RNA, and knockdown of circRNAs-MSR could suppress tumor necrosis factor alpha (TNF-alpha) expression and increase extracellular matrix (ECM) formation. Our results demonstrated that circRNAs-MSR regulated TNF-alpha expression and participated in the chondrocyte ECM degradation process. We propose that the inhibition of circRNAs-MSR could inhibit the degradation of chondrocyte ECM and knockdown of circRNAs-MSR could be a potential therapeutic target for OA. PMID- 28624199 TI - Engineering Next-Generation BET-Independent MLV Vectors for Safer Gene Therapy. AB - Retroviral vectors have shown their curative potential in clinical trials correcting monogenetic disorders. However, therapeutic benefits were compromised due to vector-induced dysregulation of cellular genes and leukemia development in a subset of patients. Bromodomain and extraterminal domain (BET) proteins act as cellular cofactors that tether the murine leukemia virus (MLV) pre-integration complex to host chromatin via interaction with the MLV integrase (IN) and thereby define the typical gammaretroviral integration distribution. We engineered next generation BET-independent (Bin) MLV vectors to retarget their integration to regions where they are less likely to dysregulate nearby genes. We mutated MLV IN to uncouple BET protein interaction and fused it with chromatin-binding peptides. The addition of the CBX1 chromodomain to MLV INW390A efficiently targeted integration away from gene regulatory elements. The retargeted vector produced at high titers and efficiently transduced CD34+ hematopoietic stem cells, while fewer colonies were detected in a serial colony-forming assay, a surrogate test for genotoxicity. Our findings underscore the potential of the engineered vectors to reduce the risk of insertional mutagenesis without compromising transduction efficiency. Ultimately, combined with other safety features in vector design, next-generation BinMLV vectors can improve the safety of gammaretroviral vectors for gene therapy. PMID- 28624200 TI - Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA. AB - Lipid nanoparticles (LNPs) have been used to successfully deliver small interfering RNAs (siRNAs) to target cells in both preclinical and clinical studies and currently are the leading systems for in vivo delivery. Here, we propose the use of an ordinary differential equation (ODE)-based model as a tool for optimizing LNP-mediated delivery of siRNAs. As a first step, we have used a combination of experimental and computational approaches to develop and validate a mathematical model that captures the critical features for efficient siRNA-LNP delivery in vitro. This model accurately predicts mRNA knockdown resulting from novel combinations of siRNAs and LNPs in vitro. As demonstrated, this model can be effectively used as a screening tool to select the most efficacious LNPs, which can then further be evaluated in vivo. The model serves as a starting point for the future development of next generation models capable of capturing the additional complexity of in vivo delivery. PMID- 28624201 TI - Broad-Spectrum Inhibition of Respiratory Virus Infection by MicroRNA Mimics Targeting p38 MAPK Signaling. AB - The majority of antiviral therapeutics target conserved viral proteins, however, this approach confers selective pressure on the virus and increases the probability of antiviral drug resistance. An alternative therapeutic strategy is to target the host-encoded factors that are required for virus infection, thus minimizing the opportunity for viral mutations that escape drug activity. MicroRNAs (miRNAs) are small noncoding RNAs that play diverse roles in normal and disease biology, and they generally operate through the post-transcriptional regulation of mRNA targets. We have previously identified cellular miRNAs that have antiviral activity against a broad range of herpesvirus infections, and here we extend the antiviral profile of a number of these miRNAs against influenza and respiratory syncytial virus. From these screening experiments, we identified broad-spectrum antiviral miRNAs that caused >75% viral suppression in all strains tested, and we examined their mechanism of action using reverse-phase protein array analysis. Targets of lead candidates, miR-124, miR-24, and miR-744, were identified within the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and this work identified MAPK-activated protein kinase 2 as a broad spectrum antiviral target required for both influenza and respiratory syncytial virus (RSV) infection. PMID- 28624203 TI - Exosome Mediated Delivery of miR-124 Promotes Neurogenesis after Ischemia. AB - The intrinsic ability of neurogenesis after stroke has been proven weak, which results in insufficient repair of injury in the nerve system. Recent studies suggest multiple microRNAs (miRNAs) are involved in the neuroremodeling process. Targeted miRNAs delivery for amplification of neurogenesis is promising in promoting the prognosis after ischemia. Here, we showed that modified exosomes, with rabies virus glycoprotein (RVG) fused to exosomal protein lysosome associated membrane glycoprotein 2b (Lamp2b), could efficiently deliver miR-124 to the infarct site. Systemic administration of RVG-exosomes loaded with miR-124 promoted cortical neural progenitors to obtain neuronal identity and protect against ischemic injury by robust cortical neurogenesis. Our study suggests that RVG-exosomes can be utilized therapeutically for the targeted delivery of gene drugs to the brain, thus having great potential for clinical applications. PMID- 28624204 TI - CRISPR/Cas9-Directed Reassignment of the GATA1 Initiation Codon in K562 Cells to Recapitulate AML in Down Syndrome. AB - Using a CRISPR/Cas9 system, we have reengineered a translational start site in the GATA1 gene in K562 cells. This mutation accounts largely for the onset of myeloid leukemia in Down syndrome (ML-DS). For this reengineering, we utilized CRISPR/Cas9 to generate mammalian cell lines that express truncated versions of the Gata1s protein similar to that seen in ML-DS, as determined by analyzing specific genetic alterations resulting from CRISPR/Cas9 cleavage. During this work, 73 cell lines were clonally expanded, with allelic variance analyzed. Using Tracking of Indels by DEcomposition (TIDE) and Sanger sequencing, we defined the DNA sequence and variations within each allele. We found significant heterogeneity between alleles in the same clonally expanded cell, as well as among alleles from other clonal expansions. Our data demonstrate and highlight the importance of the randomness of resection promoted by non-homologous end joining after CRISPR/Cas9 cleavage in cells undergoing genetic reengineering. Such heterogeneity must be fully characterized to predict altered functionality inside target tissues and to accurately interpret the associated phenotype. Our data suggest that in cases where the objective is to rearrange specific nucleotides to redirect gene expression in human cells, it is imperative to analyze genetic composition at the individual allelic level. PMID- 28624202 TI - 2L-piRNA: A Two-Layer Ensemble Classifier for Identifying Piwi-Interacting RNAs and Their Function. AB - Involved with important cellular or gene functions and implicated with many kinds of cancers, piRNAs, or piwi-interacting RNAs, are of small non-coding RNA with around 19-33 nt in length. Given a small non-coding RNA molecule, can we predict whether it is of piRNA according to its sequence information alone? Furthermore, there are two types of piRNA: one has the function of instructing target mRNA deadenylation, and the other does not. Can we discriminate one from the other? With the avalanche of RNA sequences emerging in the postgenomic age, it is urgent to address the two problems for both basic research and drug development. Unfortunately, to the best of our knowledge, so far no computational methods whatsoever could be used to deal with the second problem, let alone deal with the two problems together. Here, by incorporating the physicochemical properties of nucleotides into the pseudo K-tuple nucleotide composition (PseKNC), we proposed a powerful predictor called 2L-piRNA. It is a two-layer ensemble classifier, in which the first layer is for identifying whether a query RNA molecule is piRNA or non-piRNA, and the second layer for identifying whether a piRNA is with or without the function of instructing target mRNA deadenylation. Rigorous cross validations have indicated that the success rates achieved by the proposed predictor are quite high. For the convenience of most biologists and drug development scientists, the web server for 2L-piRNA has been established at http://bioinformatics.hitsz.edu.cn/2L-piRNA/, by which users can easily get their desired results without the need to go through the mathematical details. PMID- 28624205 TI - ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis. AB - Human bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human bladder urothelial carcinoma and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse invasive BC. Knockdown of ATG7 resulted in a significant inhibitory effect on tumorigenic growth of human BC cells both in vitro and in vivo by promoting p27 expression and inducing cell cycle arrest at G2/M phase. We further demonstrated that knockdown of ATG7 upregulated FOXO1 (forkhead box protein O 1) expression, which specifically promoted p27 transcription. Moreover, mechanistic studies revealed that inhibition of ATG7 stabilized ETS2 mRNA and, in turn, reduced miR-196b transcription and expression of miR-196b, which was able to bind to the 3' UTR of FOXO1 mRNA, consequently stabilizing FOXO1 mRNA and finally promoting p27 transcription and attenuating BC tumorigenic growth. The identification of the ATG7/FOXO1/p27 mechanism for promoting BC cell growth provides significant insights into understanding the nature of BC tumorigenesis. Together with our most recent discovery of the crucial role of ATG7 in promoting BC invasion, it raises the potential for developing an ATG7-based specific therapeutic strategy for treatment of human BC patients. PMID- 28624206 TI - CRISPR/Cas9-Mediated Genome Editing Corrects Dystrophin Mutation in Skeletal Muscle Stem Cells in a Mouse Model of Muscle Dystrophy. AB - Muscle stem cells (MuSCs) hold great therapeutic potential for muscle genetic disorders, such as Duchenne muscular dystrophy (DMD). The CRISP/Cas9-based genome editing is a promising technology for correcting genetic alterations in mutant genes. In this study, we used fibrin-gel culture system to selectively expand MuSCs from crude skeletal muscle cells of mdx mice, a mouse model of DMD. By CRISP/Cas9-based genome editing, we corrected the dystrophin mutation in expanded MuSCs and restored the skeletal muscle dystrophin expression upon transplantation in mdx mice. Our studies established a reliable and feasible platform for gene correction in MuSCs by genome editing, thus greatly advancing tissue stem cell based therapies for DMD and other muscle disorders. PMID- 28624209 TI - MicroRNA-146a-5p Limits Elevated TGF-beta Signal during Cell Senescence. PMID- 28624208 TI - Safe and Efficient Silencing with a Pol II, but Not a Pol lII, Promoter Expressing an Artificial miRNA Targeting Human Huntingtin. AB - Huntington's disease is a devastating, incurable neurodegenerative disease affecting up to 12 per 100,000 patients worldwide. The disease is caused by a mutation in the Huntingtin (Htt) gene. There is interest in reducing mutant Huntingtin by targeting it at the mRNA level, but the maximum tolerable dose and long-term effects of such a treatment are unknown. Using a self-complementary AAV9 vector, we delivered a mir-155-based artificial miRNA under the control of the chicken beta-actin or human U6 promoter. In mouse brain, the artificial miRNA reduced the human huntingtin mRNA by 50%. The U6, but not the CbetaA promoter, produced the artificial miRNA at supraphysiologic levels. Embedding the antisense strand in a U6-mir-30 scaffold reduced expression of the antisense strand but increased the sense strand. In mice treated with scAAV9-U6-mir-155-HTT or scAAV9 CbetaA-mir-155-HTT, activated microglia were present around the injection site 1 month post-injection. Six months post-injection, mice treated with scAAV9-CbetaA mir-155-HTT were indistinguishable from controls. Those that received scAAV9-U6 mir-155-HTT showed behavioral abnormalities and striatal damage. In conclusion, miRNA backbone and promoter can be used together to modulate expression levels and strand selection of artificial miRNAs, and in brain, the CbetaA promoter can provide an effective and safe dose of a human huntingtin miRNA. PMID- 28624207 TI - Identification of Novel Fibrosis Modifiers by In Vivo siRNA Silencing. AB - Fibrotic diseases contribute to 45% of deaths in the industrialized world, and therefore a better understanding of the pathophysiological mechanisms underlying tissue fibrosis is sorely needed. We aimed to identify novel modifiers of tissue fibrosis expressed by myofibroblasts and their progenitors in their disease microenvironment through RNA silencing in vivo. We leveraged novel biology, targeting genes upregulated during liver and kidney fibrosis in this cell lineage, and employed small interfering RNA (siRNA)-formulated lipid nanoparticles technology to silence these genes in carbon-tetrachloride-induced liver fibrosis in mice. We identified five genes, Egr2, Atp1a2, Fkbp10, Fstl1, and Has2, which modified fibrogenesis based on their silencing, resulting in reduced Col1a1 mRNA levels and collagen accumulation in the liver. These genes fell into different groups based on the effects of their silencing on a transcriptional mini-array and histological outcomes. Silencing of Egr2 had the broadest effects in vivo and also reduced fibrogenic gene expression in a human fibroblast cell line. Prior to our study, Egr2, Atp1a2, and Fkbp10 had not been functionally validated in fibrosis in vivo. Thus, our results provide a major advance over the existing knowledge of fibrogenic pathways. Our study is the first example of a targeted siRNA assay to identify novel fibrosis modifiers in vivo. PMID- 28624210 TI - Low-Dose Gene Therapy for Murine PKU Using Episomal Naked DNA Vectors Expressing PAH from Its Endogenous Liver Promoter. AB - Limited duration of transgene expression, insertional mutagenesis, and size limitations for transgene cassettes pose challenges and risk factors for many gene therapy vectors. Here, we report on physiological expression of liver phenylalanine hydroxylase (PAH) by delivery of naked DNA/minicircle (MC)-based vectors for correction of homozygous enu2 mice, a model of human phenylketonuria (PKU). Because MC vectors lack a defined size limit, we constructed a MC vector expressing a codon-optimized murine Pah cDNA that includes a truncated intron and is under the transcriptional control of a 3.6-kb native Pah promoter/enhancer sequence. This vector, delivered via hydrodynamic injection, yielded therapeutic liver PAH activity and sustained correction of blood phenylalanine comparable to viral or synthetic liver promoters. Therapeutic efficacy was seen with vector copy numbers of <1 vector genome per diploid hepatocyte genome and was achieved at a vector dose that was significantly lowered. Partial hepatectomy and subsequent liver regeneration was associated with >95% loss of vector genomes and PAH activity in liver, demonstrating that MC vectors had not integrated into the liver genome. In conclusion, MC vectors, which do not have a defined size limitation, offer a favorable safety profile for hepatic gene therapy due to their non-integration in combination with native promoters. PMID- 28624211 TI - Translation of Angiotensin-Converting Enzyme 2 upon Liver- and Lung-Targeted Delivery of Optimized Chemically Modified mRNA. AB - Changes in lifestyle and environmental conditions give rise to an increasing prevalence of liver and lung fibrosis, and both have a poor prognosis. Promising results have been reported for recombinant angiotensin-converting enzyme 2 (ACE2) protein administration in experimental liver and lung fibrosis. However, the full potential of ACE2 may be achieved by localized translation of a membrane-anchored form. For this purpose, we advanced the latest RNA technology for liver- and lung targeted ACE2 translation. We demonstrated in vitro that transfection with ACE2 chemically modified messenger RNA (cmRNA) leads to robust translation of fully matured, membrane-anchored ACE2 protein. In a second step, we designed eight modified ACE2 cmRNA sequences and identified a lead sequence for in vivo application. Finally, formulation of this ACE2 cmRNA in tailor-made lipidoid nanoparticles and in lipid nanoparticles led to liver- and lung-targeted translation of significant amounts of ACE2 protein, respectively. In summary, we provide evidence that RNA transcript therapy (RTT) is a promising approach for ACE2-based treatment of liver and lung fibrosis to be tested in fibrotic disease models. PMID- 28624212 TI - Light-Triggerable Liposomes for Enhanced Endolysosomal Escape and Gene Silencing in PC12 Cells. AB - Liposomes are an effective gene and/or drug delivery system, widely used in biomedical applications including gene therapy and chemotherapy. Here, we designed a photo-responsive liposome (lipVP) loaded with a photosensitizer verteporfin (VP). This photosensitizer is clinically approved for photodynamic therapy (PDT). LipVP was employed as a DNA carrier for pituitary adenylyl cyclase activating polypeptide (PACAP) receptor 1 (PAC1R) gene knockdown in PC12 cells. This has been done by incorporating PAC1R antisense oligonucleotides inside the lipVP cavity. Cells that have taken up the lipVP were exposed to light from a UV light source. As a result of this exposure, reactive oxygen species (ROS) were generated from VP, destabilizing the endolysosomal membranes and enhancing the liposomal release of antisense DNA into the cytoplasm. Endolysosomal escape of DNA was documented at different time points based on quantitative analysis of colocalization between fluorescently labeled DNA and endosomes and lysosomes. The released antisense oligonucleotides were found to silence PAC1R mRNA. The efficiency of this photo-induced gene silencing was demonstrated by a 74% +/- 5% decrease in PAC1R fluorescence intensity. Following the light-induced DNA transfer into cells, cell differentiation with exposure to two kinds of PACAP peptides was observed to determine the cell phenotypic change after PAC1R gene knockdown. PMID- 28624213 TI - CRISPR/Cas9-loxP-Mediated Gene Editing as a Novel Site-Specific Genetic Manipulation Tool. AB - Cre-loxP, as one of the site-specific genetic manipulation tools, offers a method to study the spatial and temporal regulation of gene expression/inactivation in order to decipher gene function. CRISPR/Cas9-mediated targeted genome engineering technologies are sparking a new revolution in biological research. Whether the traditional site-specific genetic manipulation tool and CRISPR/Cas9 could be combined to create a novel genetic tool for highly specific gene editing is not clear. Here, we successfully generated a CRISPR/Cas9-loxP system to perform gene editing in human cells, providing the proof of principle that these two technologies can be used together for the first time. We also showed that distinct non-homologous end-joining (NHEJ) patterns from CRISPR/Cas9-mediated gene editing of the targeting sequence locates at the level of plasmids (episomal) and chromosomes. Specially, the CRISPR/Cas9-mediated NHEJ pattern in the nuclear genome favors deletions (64%-68% at the human AAVS1 locus versus 4% 28% plasmid DNA). CRISPR/Cas9-loxP, a novel site-specific genetic manipulation tool, offers a platform for the dissection of gene function and molecular insights into DNA-repair pathways. PMID- 28624214 TI - Further Characterization of the Bifunctional HIV Entry Inhibitor sCD4-FIT45. AB - HIV entry into target cells is a highly sequential and time-sensitive process. In recent years, potent HIV Env-targeting antibodies, such as VRC01, have been identified. However, antibodies bind only to a single epitope, and mutations that confer resistance to antibody-mediated inhibition of HIV entry have been detected. In contrast, HIV cannot escape from binding to soluble CD4 (sCD4) without a fitness disadvantage. sCD4 has the unique ability to induce conformational changes within the HIV envelope glycoproteins (Env) that allow fusion inhibitors to bind. We have previously linked sCD4 to the fusion inhibitor FIT45 (sCD4-FIT45) and examined delivery of the bifunctional entry inhibitor via gene therapy. Here, we extend our studies and analyze the ability of sCD4-FIT45 to inhibit HIV Env-mediated cell fusion and HIV entry of several primary isolates. sCD4-FIT45 inhibited both cell fusion and HIV entry with remarkable antiviral activity. The mean 50% inhibitory concentrations (IC50) for sCD4-FIT45 were <0.2 MUg/mL in both assays. Importantly, inhibition by sCD4-FIT45 was more potent than by VRC01, sCD4, or the previously described bifunctional protein sCD4 scFv17b. In contrast to sCD4, sCD4-FIT45 as well as VRC01 and sCD4-scFv17b did not mediate cell fusion between HIV Env+ and CD4-CCR5+ cells. The results presented here provide further evidence for the testing of sCD4-FIT45 and development of bifunctional proteins based on the sCD4-fusion inhibitor architecture. PMID- 28624215 TI - Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis. AB - Peritoneal fibrosis is a major complication in peritoneal dialysis (PD) patients, which leads to dialysis discontinuation. Periostin, increased by transforming growth factor beta1 (TGF-beta1) stimulation, induces the expression of extracellular matrix (ECM) genes. Aberrant periostin expression has been demonstrated to be associated with PD-related peritoneal fibrosis. Therefore, the effect of periostin inhibition by an aptamer-based inhibitor on peritoneal fibrosis was evaluated. In vitro, TGF-beta1 treatment upregulated periostin, fibronectin, alpha-smooth muscle actin (alpha-SMA), and Snail expression and reduced E-cadherin expression in human peritoneal mesothelial cells (HPMCs). Periostin small interfering RNA (siRNA) treatment ameliorated the TGF-beta1 induced periostin, fibronectin, alpha-SMA, and Snail expression and restored E cadherin expression in HPMCs. Similarly, the periostin-binding DNA aptamer (PA) also attenuated fibronectin, alpha-SMA, and Snail upregulation and E-cadherin downregulation in TGF-beta1-stimulated HPMCs. In mice treated with PD solution for 4 weeks, the expression of periostin, fibronectin, alpha-SMA, and Snail was significantly increased in the peritoneum, whereas E-cadherin expression was significantly decreased. The thickness of the submesothelial layer and the intensity of Masson's trichrome staining in the PD group were significantly increased compared to the untreated group. These changes were significantly abrogated by the intraperitoneal administration of PA. These findings suggest that PA can be a potential therapeutic strategy for peritoneal fibrosis in PD patients. PMID- 28624216 TI - Gold Nanoparticles for BCR-ABL1 Gene Silencing: Improving Tyrosine Kinase Inhibitor Efficacy in Chronic Myeloid Leukemia. AB - Introduction of tyrosine kinase inhibitors for chronic myeloid leukemia treatment is associated with a 63% probability of maintaining a complete cytogenetic response, meaning that over 30% patients require an alternative methodology to overcome resistance, tolerance, or side effects. Considering the potential of nanotechnology in cancer treatment and the benefits of a combined therapy with imatinib, a nanoconjugate was designed to achieve BCR-ABL1 gene silencing. Gold nanoparticles were functionalized with a single-stranded DNA oligonucleotide that selectively targets the e14a2 BCR-ABL1 transcript expressed by K562 cells. This gold (Au)-nanoconjugate showed great efficacy in gene silencing that induced a significant increase in cell death. Variation of BCL-2 and BAX protein expression, an increase of caspase-3 activity, and apoptotic bodies in cells treated with the nanoconjugate demonstrate its aptitude for inducing apoptosis on K562 BCR-ABL1-expressing cells. Moreover, the combination of the silencing Au nanoconjugate with imatinib prompted a decrease of imatinib IC50. This Au nanoconjugate was also capable of inducing the loss of viability of imatinib resistant K562 cells. This strategy shows that combination of Au-nanoconjugate and imatinib make K562 cells more vulnerable to chemotherapy and that the Au nanoconjugate alone may overcome imatinib-resistance mechanisms, thus providing an effective treatment for chronic myeloid leukemia patients who exhibit drug tolerance. PMID- 28624217 TI - Efficacy of Postnatal In Vivo Nonsense Suppression Therapy in a Pax6 Mouse Model of Aniridia. AB - Nonsense mutations leading to premature stop codons are common occurring in approximately 12% of all human genetic diseases. Thus, pharmacological nonsense mutation suppression strategies would be beneficial to a large number of patients if the drugs could be targeted to the affected tissues at the appropriate time. Here, we used nonsense suppression to manipulate Pax6 dosage at different developmental times in the eye of the small eye (Pax6Sey/+; G194X) mouse model of aniridia. Efficacy was assessed by functional assays for visual capacity, including electroretinography and optokinetic tracking (OKT), in addition to histological and biochemical studies. Malformation defects in the Pax6Sey/+ postnatal eye responded to topically delivered nonsense suppression in a dose- and time-dependent manner. Elevated levels of Mmp9, a direct downstream target of Pax6 in the cornea, were observed with the different treatment regimens. The lens capsule was particularly sensitive to Pax6 dosage, revealing a potential new role for Pax6 in lens capsule maintenance and development. The remarkable capacity of malformed ocular tissue to respond postnatally to Pax6 dosage in vivo demonstrates that the use of nonsense suppression could be a valuable therapeutic approach for blinding diseases caused by nonsense mutations. PMID- 28624219 TI - CRISPR/Cas9-Mediated Three Nucleotide Insertion Corrects a Deletion Mutation in MRP1/ABCC1 and Restores Its Proper Folding and Function. AB - A three-nucleotide deletion in cystic fibrosis transmembrane conductance regulator/ATP-binding cassette transporter C7 (CFTR/ABCC7) resulting in the absence of phenylalanine at 508 leads to mis-fold of the mutated protein and causes cystic fibrosis. We have used a comparable three-nucleotide deletion mutant in another ABCC family member, multidrug resistance-associated protein (MRP1)/ABCC1, to determine whether CRISPR-Cas9-mediated recombination can safely and efficiently knock in three-nucleotide to correct the mutation. We have found that the rate of homology-directed recombination mediated by guideRNA (gRNA) complementary to the deletion mutant is significantly higher than the one mediated by gRNA complementary to the wild-type (WT) donor. In addition, the rate of homology-directed recombination mediated by gRNA complementary to the WT donor is significantly higher than that of gRNAs complementary to the 5' or 3' side of the deletion mutant. Interestingly, the frequency of mutations introduced by gRNA complementary to the deletion mutant is significantly higher than with gRNA complementary to WT donor. However, combination of gRNAs complementary to both WT donor and deletion mutant decreased the rate of homology-directed recombination, but did not significantly decrease the mutation rate introduced by this system. Thus, the data presented here provide guidance for designing of gRNA and donor DNA to do genome editing, especially to correct the mutations with three mismatched nucleotides, such as three-nucleotide deletion or insertion. PMID- 28624218 TI - Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non viral Gene Therapy for Leber's Congenital Amaurosis. AB - Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber's congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC). All-trans-retinylamine, which binds to interphotoreceptor retinoid-binding protein (IRBP), was incorporated into the nanoparticles via a polyethylene glycol (PEG) spacer for targeted delivery of pDNA into the retinal pigmented epithelium. The targeted ECO/pDNA nanoparticles provided high GFP expression in the RPE of 1-month-old Rpe65-/- mice after subretinal injection. Such mice also exhibited a significant increase in electroretinographic activity, and this therapeutic effect continued for at least 120 days. A safety study in wild-type BALB/c mice indicated no irreversible retinal damage following subretinal injection of these targeted nanoparticles. All-trans-retinylamine-modified ECO/pDNA nanoparticles provide a promising non viral platform for safe and effective treatment of RPE-specific monogenic eye diseases such as LCA2. PMID- 28624220 TI - Tat-haFGF14-154 Upregulates ADAM10 to Attenuate the Alzheimer Phenotype of APP/PS1 Mice through the PI3K-CREB-IRE1alpha/XBP1 Pathway. AB - Acid fibroblast growth factor (aFGF) has shown neuroprotection in Alzheimer's disease (AD) models in previous studies, yet its mechanism is still uncertain. Here we report that the efficacy of Tat-haFGF14-154 is markedly increased when loaded cationic liposomes for intranasal delivery are intranasally administered to APP/PS1 mice. Our results demonstrated that liposomal Tat-haFGF14-154 treatment significantly ameliorated behavioral deficits, relieved brain Abeta burden, and increased the expression and activity of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the brain. Tat-haFGF14 154 antagonized Abeta1-42-induced cell death and structural damage in rat primary neurons in an ADAM10-dependent manner, which, in turn, was promoted by the activation of XBP1 splicing and modulated by the PI3K-CREB pathway. Both knockdown of ADAM10 and inhibition of PI3K (LY294002) negated Tat-haFGF14-154 rescue. Thus, Tat-haFGF14-154 activates the IRE1alpha/XBP1 pathway of the unfolded protein response (UPR) against the endoplasmic reticulum (ER) stress induced by Abeta, and, subsequently, the nuclear translocation of spliced XBP1 (XBP1s) promotes transcription of ADAM10. These results highlight the important role of ADAM10 and its activation through the PI3K-CREB-IRE1alpha/XBP1 pathway as a key factor in the mechanism of neuroprotection for Tat-haFGF14-154. PMID- 28624221 TI - miR-1290 Is a Biomarker in DNA-Mismatch-Repair-Deficient Colon Cancer and Promotes Resistance to 5-Fluorouracil by Directly Targeting hMSH2. AB - 5-Fluorouracil (5FU)-based adjuvant therapy is the first-line therapy for treating stage II and III colon cancer after surgery. However, its therapeutic efficacy is limited because of chemoresistance, especially in deficient mismatch repair (dMMR) colon cancer. Here, we first used laser capture microdissection to obtain purified cells from four dMMR and four proficient mismatch repair (pMMR) colon cancer tissues. Second, microRNA (miRNA) microarray chips were used to identify miRNAs that are differentially expressed between these two classes of tumors. Third, we analyzed their differential expression by qRT-PCR in a panel of 5-FU-resistant colon cancer cell lines. We identified that miR-1290 was one of the most upregulated miRNAs in both dMMR colon cancer tissues and 5-FU-resistant cells. We also found that miR-1290 was positively correlated with dMMR status and predicted poor prognosis in stage II and III colon cancer patients who received 5 FU-based chemotherapy. Furthermore, we demonstrated that inhibition of the expression of miR-1290 enhanced sensitivity to 5-FU treatment in vitro and in tumor xenografts in vivo by direct targeting hMSH2. Our study indicates that miR 1290 may become a promising biomarker of dMMR colon cancer and predicts the prognosis of stage II and III patients who receive 5-FU-based adjuvant therapy. PMID- 28624222 TI - Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice. AB - Myotonic dystrophy type 1 (DM1), a dominant hereditary muscular dystrophy, is caused by an abnormal expansion of a (CTG)n trinucleotide repeat in the 3' UTR of the human dystrophia myotonica protein kinase (DMPK) gene. As a consequence, mutant transcripts containing expanded CUG repeats are retained in nuclear foci and alter the function of splicing regulatory factors members of the MBNL and CELF families, resulting in alternative splicing misregulation of specific transcripts in affected DM1 tissues. In the present study, we treated DMSXL mice systemically with a 2'-4'-constrained, ethyl-modified (ISIS 486178) antisense oligonucleotide (ASO) targeted to the 3' UTR of the DMPK gene, which led to a 70% reduction in CUGexp RNA abundance and foci in different skeletal muscles and a 30% reduction in the heart. Furthermore, treatment with ISIS 486178 ASO improved body weight, muscle strength, and muscle histology, whereas no overt toxicity was detected. This is evidence that the reduction of CUGexp RNA improves muscle strength in DM1, suggesting that muscle weakness in DM1 patients may be improved following elimination of toxic RNAs. PMID- 28624223 TI - Evaluation of MYBPC3 trans-Splicing and Gene Replacement as Therapeutic Options in Human iPSC-Derived Cardiomyocytes. AB - Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans-splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Here we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from an HCM patient carrying a heterozygous c.1358 1359insC MYBPC3 mutation and from a healthy donor. HCM hiPSC-CMs exhibited ~50% lower MYBPC3 mRNA and cMyBP-C protein levels than control, no truncated cMyBP-C, larger cell size, and altered gene expression, thus reproducing human HCM features. We evaluated RNA trans-splicing and gene replacement after transducing hiPSC-CMs with adeno-associated virus. trans-splicing with 5' or 3' pre-trans splicing molecules represented ~1% of total MYBPC3 transcripts in healthy hiPSC CMs. In contrast, gene replacement with the full-length MYBPC3 cDNA resulted in ~2.5-fold higher MYBPC3 mRNA levels in HCM and control hiPSC-CMs. This restored the cMyBP-C level to 81% of the control level, suppressed hypertrophy, and partially restored gene expression to control level in HCM cells. This study provides evidence for (1) the feasibility of trans-splicing, although with low efficiency, and (2) efficient gene replacement in hiPSC-CMs with a MYBPC3 mutation. PMID- 28624224 TI - Optimizing the DNA Donor Template for Homology-Directed Repair of Double-Strand Breaks. AB - The CRISPR-Cas (clustered regularly interspaced short palindromic repeats associated proteins) technology enables rapid and precise genome editing at any desired genomic position in almost all cells and organisms. In this study, we analyzed the impact of different repair templates on the frequency of homology directed repair (HDR) and non-homologous end joining (NHEJ). We used a stable HEK293 cell line expressing the traffic light reporter (TLR-3) system to quantify HDR and NHEJ events following transfection with Cas9, eight different guide RNAs, and a 1,000 bp donor template generated either as circular plasmid, as linearized plasmid with long 3' or 5' backbone overhang, or as PCR product. The sequence to be corrected was either centrally located (RS55), with a shorter 5' homologous region (RS37), or with a shorter 3' homologous region (RS73). Guide RNAs targeting the transcriptionally active strand (T5, T7) showed significantly higher NHEJ frequencies compared with guide RNAs targeting the transcriptionally inactive strand. HDR activity was highest when using the linearized plasmid with the short 5' backbone overhang and the RS37 design. The results demonstrate the importance of the design of the guide RNA and template DNA on the frequency of DNA repair events and, ultimately, on the outcome of treatment approaches using HDR. PMID- 28624225 TI - Inhibition of Mef2a Enhances Neovascularization via Post-transcriptional Regulation of 14q32 MicroRNAs miR-329 and miR-494. AB - Improving the efficacy of neovascularization is a promising strategy to restore perfusion of ischemic tissues in patients with peripheral arterial disease. The 14q32 microRNA cluster is highly involved in neovascularization. The Mef2a transcription factor has been shown to induce transcription of the microRNAs within this cluster. We inhibited expression of Mef2a using gene-silencing oligonucleotides (GSOs) in an in vivo hind limb ischemia model. Treatment with GSO-Mef2a clearly improved blood flow recovery within 3 days (44% recovery versus 25% recovery in control) and persisted until 14 days after ischemia induction (80% recovery versus 60% recovery in control). Animals treated with GSO-Mef2a showed increased arteriogenesis and angiogenesis in the relevant muscle tissues. Inhibition of Mef2a decreased expression of 14q32 microRNAs miR-329 (p = 0.026) and miR-494 (trend, p = 0.06), but not of other 14q32 microRNAs, nor of 14q32 microRNA precursors. Because Mef2a did not influence 14q32 microRNA transcription, we hypothesized it functions as an RNA-binding protein that influences processing of 14q32 microRNA miR-329 and miR-494. Mef2A immunoprecipitation followed by RNA isolation and rt/qPCR confirmed direct binding of MEF2A to pri-miR-494, supporting this hypothesis. Our study demonstrates a novel function for Mef2a in post-ischemic neovascularization via post-transcriptional regulation of 14q32 microRNAs miR-329 and miR-494. PMID- 28624226 TI - Transcriptome-wide Investigation of mRNA/circRNA in miR-184 and Its r.57c > u Mutant Type Treatment of Human Lens Epithelial Cells. AB - m-miR-184 (mutant miR-184, r.57c > u) appears in familial hereditary ocular diseases, including keratoconus, cataracts, EDICT (endothelial dystrophy, iris hypoplasia, congenital cataract, and stromal thinning) syndrome, severe keratoconus, and non-ectatic corneal thinning. The biological function of m-miR 184 in these ocular diseases remains unclear. With the emergence of high throughput sequencing, it is now possible to discover many different biological components simultaneously. Using two different RNA libraries, we sequenced the complete transcriptome of HLE cells treated with miR-184, m-miR-184, and a negative control. Data were integrated in an effort to identify any novel gene affected by m-miR-184. Notably, we concluded that ALDH5A1 and GABRA3 were disordered by m-miR-184, which might lead to ocular disease. Moreover, circRNA (circular RNA) expression was highy random across miR-184, m-miR-184, and negative control treatment groups. The sequences of the circRNAs did reveal a particularly high level of ALU sequences. In summary, we provide a new avenue for understanding the role of m-miR-184 in ocular diseases. PMID- 28624227 TI - Efficient SMN Rescue following Subcutaneous Tricyclo-DNA Antisense Oligonucleotide Treatment. AB - Spinal muscular atrophy (SMA) is a recessive disease caused by mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), whose absence dramatically affects the survival of motor neurons. In humans, the severity of the disease is lessened by the presence of a gene copy, SMN2. SMN2 differs from SMN1 by a C-to-T transition in exon 7, which modifies pre-mRNA splicing and prevents successful SMN synthesis. Splice-switching approaches using antisense oligonucleotides (AONs) have already been shown to correct this SMN2 gene transition, providing a therapeutic avenue for SMA. However, AON administration to the CNS presents additional hurdles. In this study, we show that systemic delivery of tricyclo-DNA (tcDNA) AONs in a type III SMA mouse augments retention of exon 7 in SMN2 mRNA both in peripheral organs and the CNS. Mild type III SMA mice were selected as opposed to the severe type I model in order to test tcDNA efficacy and their ability to enter the CNS after maturation of the blood brain barrier (BBB). Furthermore, subcutaneous treatment significantly improved the necrosis phenotype and respiratory function. In summary, our data support that tcDNA oligomers effectively cross the blood-brain barrier and offer a promising systemic alternative for treating SMA. PMID- 28624228 TI - Antisense Oligonucleotides Promote Exon Inclusion and Correct the Common c.-32 13T>G GAA Splicing Variant in Pompe Disease. AB - The most common variant causing Pompe disease is c.-32-13T>G (IVS1) in the acid alpha-glucosidase (GAA) gene, which weakens the splice acceptor of GAA exon 2 and induces partial and complete exon 2 skipping. It also allows a low level of leaky wild-type splicing, leading to a childhood/adult phenotype. We hypothesized that cis-acting splicing motifs may exist that could be blocked using antisense oligonucleotides (AONs) to promote exon inclusion. To test this, a screen was performed in patient-derived primary fibroblasts using a tiling array of U7 small nuclear RNA (snRNA)-based AONs. This resulted in the identification of a splicing regulatory element in GAA intron 1. We designed phosphorodiamidate morpholino oligomer-based AONs to this element, and these promoted exon 2 inclusion and enhanced GAA enzyme activity to levels above the disease threshold. These results indicate that the common IVS1 GAA splicing variant in Pompe disease is subject to negative regulation, and inhibition of a splicing regulatory element using AONs is able to restore canonical GAA splicing and endogenous GAA enzyme activity. PMID- 28624229 TI - A novel laparoscopic transcystic approach using an ultrathin choledochoscope and holmium laser lithotripsy in the management of cholecystocholedocholithiasis: An appraisal of their safety and efficacy. AB - BACKGROUND: Although laparoscopic transcystic common bile duct exploration (LTCBDE) is the preferred approach for CBD stone clearance, the success rate can vary between 55% and 85%. This study evaluated if ultrathin choledochoscope and holmium laser lithotripsy could improve the success rate of LTCBDE. METHODS: Records of 126 patients (average age, 46.1 +/- 13.8 years) with cholecystocholedocholithiasis treated with laparoscopic cholecystectomy (LC) and LTCBDE were retrospectively reviewed. RESULTS: LC+LTCBDE was performed successfully in 118 of 126 patients, with a surgical success rate of 93.7%. An ultrathin choledochoscope was used in 75 (63.5%) patients, and holmium lithotripsy was performed in 38 (32.2%) patients. The stone clearance rate was 99.2% (117/118). No significant complications occurred. One hundred (84.7%) patients had excellent and 13 (11%) had good outcomes for an overall success rate (excellent plus good) of 95.7%. CONCLUSION: Ultrathin choledochoscope and holmium laser lithotripsy can improve the surgical outcomes of LC+LTCBDE with minimal complications. PMID- 28624230 TI - The correlation between fundamental characteristics and first-time performance in laparoscopic tasks. AB - BACKGROUND: The ability of characteristics to predict first time performance in laparoscopic tasks is not well described. Videogame experience predicts positive performance in laparoscopic experiences but its mechanism and confounding association with aptitude remains to be elucidated. This study sought to evaluate for innate predictors of laparoscopic performance in surgically naive individuals with minimal videogame exposure. METHODS: Participants with no prior laparoscopic exposure and minimal videogaming experience were recruited consecutively from preclinical years at a medical university. Participants completed four visuospatial, one psychomotor aptitude test and an electronic survey, followed by four laparoscopic tasks on a validated Virtual Reality simulator (LAP MentorTM). RESULTS: Twenty eligible individuals participated with a mean age of 20.8 (+/ 3.8) years. Significant intra-aptitude performance correlations were present amongst 75% of the visuospatial tests. These visuospatial aptitudes correlated significantly with multiple laparoscopic task metrics: number of movements of a dominant instrument (rs >= -0.46), accuracy rate of clip placement (rs >= 0.50) and time taken (rs >= -0.47) (p < 0.05). Musical Instrument experience predicted higher average speed of instruments (rs >= 0.47) (p < 0.05). Participant's revised competitive index level predicted lower proficiency in laparoscopic metrics including: pathlength, economy and number of movements of dominant instrument (rs >= 0.46) (p < 0.05). CONCLUSION: Multiple visuospatial aptitudes and innate competitive level influenced baseline laparoscopic performances across several tasks in surgically naive individuals. PMID- 28624233 TI - [A new therapeutic era in sickle cell disease]. PMID- 28624231 TI - Is a Chest Radiograph Required After Removal of Chest Tubes in Children? AB - Our objective was to determine the clinical value of obtaining a chest radiograph after removal of a chest tube. We conducted a retrospective chart review of pediatric general surgical patients with a chest tube in place after a thoracic procedure over a 3-year time period. Postremoval films were considered to be of value if they led to a change in clinical management. Of 468 patients who had a thoracic procedure, 281 patients had a chest tube and a postremoval film. In 263 patients (93.6%) there was no change in the postremoval film result compared with baseline. Only two patients (0.7%) required an intervention based on symptoms, not based on the postremoval film. Eliminating routine postremoval radiographs after chest tube removal in pediatric patients will lessen radiation exposure and provide cost savings with no adverse impact on outcome. PMID- 28624234 TI - [An unusual cause of low back pain]. PMID- 28624235 TI - The effect of oxytocin on human-directed social behaviour in dogs (Canis familiaris). AB - The oxytocin system has recently received increasing attention due to its effect on complex human behaviours. In parallel to this, over the past couple of decades, the human-analogue social behaviour of dogs has been intensively studied. Combining these two lines of research (e.g. studying the relationship between dog social behaviour and the oxytocin system) is a promising new research area. The present paper reviews the existing literature on how oxytocin is related to different aspects of human-directed social behaviour in dogs. PMID- 28624236 TI - Regulation of the proprotein convertases expression and activity during regenerative angiogenesis: Role of hypoxia-inducible factor (HIF). AB - Proprotein convertases (PCs) are involved in various physiological and pathological processes ranging from embryogenesis to carcinogenesis. Here, using the zebrafish fin regeneration model, we report induced expression of furin and PC5 but not PACE4 and PC7 during fin regeneration that is associated with increased PC activity. Stabilization of HIF by cobalt chloride (CoCl2) further increases these processes. The use of the general PC-inhibitor decanoyl-RVKR cholromethyl ketone (CMK) inhibited control and CoCl2-induced PC activity. CoCl2 inhibits embryonic zebrafish ZF4 cell proliferation and caudal fin regeneration that is associated with the expression of the anti-proliferative genes P21, P16, PC3 and P53 in ZF4 cells and in non-regenerating stump tissues. In contrast, during fin regeneration, HIF stabilization failed to promote the expression of these anti-proliferative genes and maintained high expression of cyclin D. Further analysis revealed that CoCl2 maintained the formation of immature regenerating vasculature that was associated with amplified expression of OCT4 and various angiogenic factors reported to be PC substrates and/or downstream effectors. These findings revealed that while furin and PC5 expression/activity and their substrates/effectors are regulated during fin regeneration, HIF stabilization by CoCl2 has the potential to modulate these processes and impact on the regenerative process and vessels organization. PMID- 28624237 TI - Identification of syntaxin 4 as an essential factor for the hepatitis C virus life cycle. AB - Although there is evidence that multivesicular bodies (MVBs) are involved in the release of hepatitis C virus (HCV), many aspects of HCV release are still not fully understood. The amount of alpha-taxilin that prevents SNARE (soluble N ethylmaleimidesensitive factor attachment protein receptor) complex formation by binding to free syntaxin 4 is reduced in HCV-positive cells. Therefore, it was analyzed whether the t-SNARE protein syntaxin 4 which mediates vesicles fusion is involved in the HCV life cycle. HCV-positive cells possess an increased amount of syntaxin 4 protein, although the amount of syntaxin 4-specific transcripts is decreased in HCV-positive Huh7.5 cells and in HCV-infected primary human hepatocytes. In HCV-positive cells a significant longer half-life of syntaxin 4 was found that overcompensates for the decreased expression and leads to the elevated level of syntaxin 4. Overexpression of syntaxin 4 reduces the intracellular amount of infectious viral particles by facilitating viral release, while silencing of syntaxin 4 expression using specific siRNAs inhibits the release of HCV particles and so leads to an increase in the intracellular amount of infectious viral particles. This indicates that HCV uses a SNARE-dependent pathway for viral release. Confocal immunofluorescence microscopy revealed a colocalization of syntaxin 4 with a MVB-specific marker, exosomes and HCV core, which suggests a fraction of syntaxin 4 is associated with exosomes loaded with HCV. Altogether, it is assumed that syntaxin 4 is a novel essential cellular factor for the release of HCV. PMID- 28624238 TI - Non-IMF mandibular fracture reduction techniques: A review of the literature. AB - BACKGROUND: Intermaxillary fixation (IMF) techniques are commonly used in mandibular fracture treatment to reduce bone fragments and re-establish normal occlusion. However, non-IMF reduction techniques such as repositioning forceps may be preferable due to their quick yet adequate reduction. The purpose of this paper is to assess which non-IMF reduction techniques and reduction forceps are available for fracture reduction in the mandible. METHODS: A systematic search was performed in the databases of Pubmed and EMBASE. The search was updated until February 2016 and no initial date and language preference was set. RESULTS: 14 articles were selected for this review, among them ten articles related to reduction forceps and four articles describing other techniques. Thus, modification and design of reduction forceps and other reduction techniques are qualitatively described. CONCLUSION: Few designs of repositioning forceps have been proposed in the literature. Quick and adequate reduction of fractures seems possible with non-IMF techniques resulting in anatomic repositioning and shorter operation time, especially in cases with good interfragmentary stability. Further development and clinical testing of reduction forceps is necessary to establish their future role in maxillofacial fracture treatment. PMID- 28624239 TI - Functional Outcome and Healing of Large and Massive Rotator Cuff Tears Repaired With a Load-Sharing Rip-Stop Construct. AB - PURPOSE: To prospectively review functional outcomes and healing rates of large and massive rotator cuff tears repaired with a load-sharing rip-stop (LSRS) technique. METHODS: Twenty-one consecutive patients underwent arthroscopic rotator cuff repair with an LSRS construct between January and December 2014. Seventeen patients with a minimum of 2 years' follow-up were included. Four patients did not complete clinical evaluations and functional outcome scores at a minimum of 2 years' follow-up and were lost to follow-up. Ultrasound imaging was used to assess for rotator cuff healing at a minimum of 6 months postoperatively. Range of motion, strength, and functional outcome scores were evaluated at final follow-up. RESULTS: Mean active forward elevation improved from 109 degrees preoperatively to 153 degrees postoperatively, and mean supraspinatus strength improved by 1 strength grade, from 3.5 preoperatively to 4.4 postoperatively. When we compared preoperative and postoperative values, the American Shoulder and Elbow Surgeons score improved from 40.8 to 89.5, the Single Assessment Numeric Evaluation score improved from 32.8 to 83.1, the Simple Shoulder Test score improved from 3.8 to 10.3, and the pain score on a visual analog scale decreased from 4.8 to 0.8 (P < .001). Of 17 patients, 13 (82%) were satisfied with their outcomes. Ultrasound evaluation 6 months after surgery showed complete healing in 53%, partial healing in 29%, and no healing in 18%. CONCLUSIONS: The LSRS construct showed satisfactory functional outcomes with reasonable healing rates in an otherwise challenging subset of rotator cuff tears. This construct may be an alternative for tears not amenable to double-row repair. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28624240 TI - Bipolar Bone Loss in Patients With Anterior Shoulder Dislocation: A Comparison of Adolescents Versus Adult Patients. AB - PURPOSE: To compare bipolar bone loss by evaluating the degree of glenoid bone loss, Hill-Sachs lesion size, and glenoid track in adolescents and adults with shoulder dislocations. METHODS: We performed a retrospective review between 2012 and 2016 of surgical and nonsurgical patients with a history of anterior shoulder dislocations (primary or recurrent) who underwent magnetic resonance imaging of the affected shoulder. The exclusion criteria included multidirectional instability, prior surgery, and posterior dislocation. Patients were grouped into 2 groups: adolescents (aged 10-19 years) and adults (aged >=20 years). The groups were compared regarding measures of glenoid bone loss (best-fit circle technique) and Hill-Sachs lesion size (medial margin of rotator cuff footprint to medial margin of Hill-Sachs lesion). If the medial margin of a Hill-Sachs lesion was within the glenoid track, it was defined as on track; if it was more medial than the glenoid track, it was defined as off track. RESULTS: We identified 45 adolescents (mean age, 16.1 years) and 30 adults (mean age, 28.9 years) with anterior shoulder dislocations. There was no significant difference in percentage of bone loss between adolescents (mean, 8.4%) and adults (mean, 9.9%; P = .23). There was no significant difference in Hill-Sachs lesion size between adolescents (mean, 12.7 mm) and adults (mean, 9.9 mm; P = .12). There were 12 patients with off-track lesions. Off-track lesions were present in 11 of 45 adolescents (24.4%) and 1 of 30 adults (3.3%). Adolescents had an increased risk of having an off track lesion (odds ratio, 9.38; 95% confidence interval, 1.14-77.1). A subgroup analysis identified multiple dislocations as an independent risk factor for an off-track lesion (odds ratio, 4.15; 95% confidence interval, 0.85-20.23). CONCLUSIONS: This study shows that adolescence and a history of multiple dislocations are independent risk factors for a greater likelihood of glenoid off track lesions. The findings support the use of bipolar assessment of shoulder dislocators, especially in adolescents and multiple dislocators. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28624241 TI - Continuous-flow synthesis using a column reactor packed with heterogeneous catalysts: A convenient production of nitroolefins by using amino-functionalized silicagel. AB - A continuous-flow synthesis of beta-nitroolefins by using heterogeneous base catalysts has been developed. Although the use of an excess amount of nitro-donor such as nitromethane is required in conventional methods, nearly equimolar amounts of nitro-donors and carbonyl compounds are sufficient for high-yielding production of nitroolefins. Catalysts for this flow protocol are inexpensive and abundant, and high durability and high productivity were also realized by using an appropriate second support. PMID- 28624242 TI - Facile access to modified and functionalized PNAs through Ugi-based solid phase oligomerization. AB - Peptide nucleic acids (PNAs) derivatized with functional molecules are increasingly used in diverse biosupramolecular applications. PNAs have proven to be highly tolerant to modifications and different applications benefit from the use of modified PNAs, in particular modifications at the gamma position. Herein we report simple protocols to access modified PNAs from iterative Ugi couplings which allow modular modifications at the alpha, beta or gamma position of the PNA backbone from simple starting materials. We demonstrate the utility of the method with the synthesis of several bioactive small molecules (a peptide ligand, a kinase inhibitor and a glycan)-PNA conjugates. PMID- 28624243 TI - Glutathione production from mannan-based bioresource by mannanase/mannosidase expressing Saccharomyces cerevisiae. AB - This work aims to produce glutathione directly from mannan-based bioresources using engineered Saccharomyces cerevisiae. Mannan proved to be a valuable carbon source for glutathione production by this organism. Mannan-hydrolyzing S. cerevisiae was developed by heterologous expression of mannanase/mannosidase on its cell surface. This strain efficiently produced glutathione from mannose polysaccharide, beta-1,4-mannan. Furthermore, it produced glutathione from locust bean gum (LBG), a highly dense and inexpensive mannan-based bioresource, as sole carbon source. Glutathione productivity from LBG was enhanced by engineering the glutathione metabolism of mannan-hydrolyzing S. cerevisiae. Expression of extracellular mannanase/mannosidase protein combined with intracellular metabolic engineering is potentially applicable to the efficient, environmentally friendly bioproduction of targeted products from mannan-based bioresources. PMID- 28624244 TI - Evolutionary engineering of salt-resistant Chlamydomonas sp. strains reveals salinity stress-activated starch-to-lipid biosynthesis switching. AB - The aim of this study was to improve biomass production of the green microalga Chlamydomonas sp. JSC4 under high salinity conditions. For this purpose, heavy ion beam-coupled mutagenesis and evolutionary engineering were performed using JSC4 as the parent strain. After long-term and continuous cultivation with high salinity, salt-resistant strains that grow well even in the presence of 7% sea salt were successfully obtained. Transcriptional analysis revealed inactivation of starch-to-lipid biosynthesis switching, which resulted in delayed starch degradation and decreased lipid content in the salt-resistant strains. Cellular aggregation and hypertrophy during high salinity were relieved in these strains, indicating strong resistance to salt stress. These results suggest that high salinity stress, not the salinity condition itself, is important for activating lipid accumulation mechanisms in microalgae. PMID- 28624245 TI - A biorefinery for Nannochloropsis: Induction, harvesting, and extraction of EPA rich oil and high-value protein. AB - Microalgae have been studied as biofactories for almost four decades. Yet, even until today, many aspects of microalgae farming and processing are still considered exploratory because of the uniqueness of each microalgal species. Thus, it is important to develop the entire process of microalgae farming: from culturing to harvesting, and down to extracting the desired high-value products. Based on its rapid growth and high oil productivities, Nannochloropsis sp. is of particular interest to many industries for the production of high-value oil containing omega-3 fatty acids, specifically eicosapentaenoic acid (EPA), but also several other products. This review compares the various techniques for induction, harvesting, and extraction of EPA-rich oil and high-value protein explored by academia and industry to develop a multi-product Nannochloropsis biorefinery. Knowledge gaps and opportunities are discussed for culturing and inducing fatty acid biosynthesis, biomass harvesting, and extracting EPA-rich oil and high-value protein from the biomass of Nannochloropsis sp. PMID- 28624246 TI - UV-C irradiation accelerates neutral lipid synthesis in the marine oleaginous diatom Fistulifera solaris. AB - This study investigated the induction of oil synthesis in the oleaginous diatom, Fistulifera solaris, following irradiation with small doses of UV-C. A rapid induction of oil accumulation was confirmed within 6h following UV-C radiation of the diatom cells, with increases in cell oil body volumes after 24h of approximately 4- to 6-fold from the initial volume. Reactive oxygen species (ROS), which can be generated by a UV-C-mediated reaction, were detected in irradiated cells and the correlation between ROS generation and oil accumulation was confirmed. The smallest UV-C intensity required for oil induction in the cells was 10mJ/cm2. Based on the ideal biodiesel profile, the most suitable FAME composition was obtained when UV255 was used to irradiate the cells. The UV-C radiation method is therefore a solution for shortening the oil accumulation period and improving biodiesel productivity. PMID- 28624247 TI - Production of l-alanyl-l-glutamine by recycling E. coli expressing alpha-amino acid ester acyltransferase. AB - In this study, the optimum induction and reaction conditions, and fermentation process of producing Ala-Gln by E. coli Origami 2 overexpressing alpha-amino acid ester acyltransferase (OPA) were investigated. Besides, the Ala-Gln synthesis by OPA achieved the maximum molar yield of 94.7% and productivity of 1.89g/L/min due to the extremely high enzyme activity. On this basis, repeated-cycle batch fermentation to produce Ala-Gln indicated that OPA could maintain high Ala-Gln yields and enzyme stabilities after several cell recycling. Consequently, the cost-efficient and environmentally friendly approach for Ala-Gln production by recycling OPA makes a great contribution to further industrial-scale applications. PMID- 28624248 TI - Retinopathy diabetic screening by non-mydriatic retinography: concordance between primary care physicians, nurses and ophthalmologists. AB - AIM: To compare the evaluation of retinographies by a teleophthalmology nurse and primary care physicians (PCP) with an ophthalmologist referral hospital (gold standard). METHODS: Cross-sectional study on a random sample of 337 patients on the teleophthalmology programme from January 2010 to January 2015. We analyzed the diagnostic evaluation (whether or not it presented findings of RD) and the therapeutic assessment (whether or not referral to the opthalmology department was needed) which were conducted independently on the sample retinographies by the PCP, a nurse and an ophthalmologist (gold standard). Reliability and concordance between the gold standard and the PCP and the nurse were checked and the statistical analyses were supported using SPSSv.23.00 software and diagnostic test reliability calculators (EPIDAT 4.1). RESULTS: In the diagnosis of RD, the nurse presented: sensitivity (S): 0.96; specificity (Sp): 0.89; PPV: 0.58; NPV: 0.99; Kappa index: 0.67 and PCP: S: 0.98; Sp: 0.99; PPV: 0.96; NPV: 0.99; Kappa index: 0.96. In the referral to ophthalmology assessed by the nurse: S: 0.83; Sp: 0.83; PPV: 0.51; NPV: 0.96; Kappa Index: 0.53 and PCP: S: 0.62; Sp: 0.76; PPV: 0.36; NPV: 0.90; Kappa index: 0.29. CONCLUSIONS: A nursing teleophthalmology programme could perform population screening for RD with the same quality as PCP. This would increase coverage, in addition to providing better use of resources by avoiding intermediate patient appointments through PCP and increased health savings. PMID- 28624249 TI - The Role of 3-D Heart Models in Planning and Executing Interventional Procedures. AB - Percutaneous interventions aimed at addressing congenital and structural heart disease are simultaneously becoming more common and more complex as time progresses. An increasing number of heart defects that had previously required open heart surgery can now be successfully addressed in the cardiac catheterization laboratory. Adequate preprocedural preparation for these novel, complex procedures is critical to ensure their success. Diagnostic data can be collected before the intervention and displayed in multiple formats during the procedure. Advanced cardiac imaging, including cardiac magnetic resonance and cardiac computed tomography form the basis of this preparatory information. Novel methods of displaying these images are becoming more widespread and more useful, including 3-D printed models, 3-D digital models displayed on a virtual or augmented reality system and 3-D digital models overlaid onto a fluoroscopy system. In this review we summarize these state-of-the-art technologies and how they are able to help interventional cardiologists push the boundaries of what is possible in the cardiac catheterization laboratory. PMID- 28624250 TI - Reply to Lee and colleagues-Viral posterior uveitis. PMID- 28624251 TI - Involvement of apoptosis signal-regulating kinase-1 in house dust mite-induced allergic asthma in mice. PMID- 28624252 TI - Successful long-term prophylaxis with human plasma-derived C1 inhibitor in planning and carrying out pregnancy. PMID- 28624253 TI - Constructing an Inflammatory Bowel Disease Patient-Centered Medical Home. PMID- 28624254 TI - [Of corkscrews and barcodes]. PMID- 28624255 TI - [Psoriatic patients: Analysis of patients dissatisfied with their management]. AB - BACKGROUND: The French are frequently regarded as grouchy. In a recent study, we observed a high proportion of patients initially consulting for psoriasis because they were dissatisfied with their previous therapy. We analyzed the characteristics of these patients. PATIENTS AND METHODS: This was a cross sectional multicenter study in 40 centers belonging to the ResoPso (psoriasis treatment network) multicenter study group, with consecutive inclusions over a period of 11months in 2014. All adults (age>18 years) consulting for the first time for psoriasis at a center were included in the study. RESULTS: Among patients, 1205 were included, of whom 249 (20.3%) were consulting because of their dissatisfaction with treatment. In the univariate analysis, these patients were younger (P=0.02) and presented psoriasis that had begun earlier in life (P<0.0001). It consisted mostly of generalized plaque psoriasis (P=0.047) and more severe forms of psoriasis (PASI and/or DLQI score>10, P<0.02). There were fewer cases of psoriatic arthritis (P=0.01). The "dissatisfied" patients reported significantly more frequent use of topical treatments (P<0.0001) and alternative medicines (P=0.02), and more infrequent use of biologics (P=0.006) as well as longer treatment periods (P=0.0005). They consulted at hospitals (P=0.01) and had previously seen more GPs and dermatologists (P<=0.0008). There was no impact of gender on the dissatisfaction profile by either comorbidities (metabolic, blood pressure, alcohol and tobacco consumption, and depression), or socio-economic data. In the multivariate analysis, DLQI>10 (P=0.01; 95% CI: 1.01-1.07) and longer duration of care (P=0.004; 95% CI: 1.23-2.99) were associated with dissatisfaction. CONCLUSION: Twenty percent of our psoriatic patients seem dissatisfied with their treatment. It is difficult to draw a specific demographic and socioeconomic profile of dissatisfied patients. Only disease severity and possibly inadequate treatment at the initial consultation are associated with patient dissatisfaction. Explanations related to the individual patients and doctors may be proposed. Finally, while the French may be considered grouchy, the frequency of patient dissatisfaction seen in our study does not appear to be any greater than that observed in other countries. PMID- 28624256 TI - Extensive ulcerated lesions in a patient with cutaneous myeloid sarcoma responded to twice-daily fludarabine and cytarabine regimen. PMID- 28624257 TI - Moderate exercise training decreases inflammation in transgenic sickle cell mice. AB - Chronic systemic inflammation is a pathophysiological feature of sickle cell disease (SCD). Considering that regular exercise exerts multiple beneficial health effects including anti-inflammatory actions, we investigated whether a treadmill training program could minimize the inflammatory state in transgenic sickle cell (SS) mice. To test this hypothesis, SS mice were subjected to a treadmill training protocol of 1h/day, 5days a week for 8weeks. Exercise training increased the percent of venous oxyhemoglobin and sharply decreased the percent of carboxyhemoglobin suggesting that exercise training may limit the proportion of erythrocytes that were deoxygenated in the venous circulation. Exercise training attenuated systemic inflammation as attested by a significant drop in white blood cell (WBC) count and plasma Th1/Th2 cytokine ratio. There was reduction in interleukin-1beta and endothelin-1 mRNA expression in trained sickle mice. The spleen/body mass ratio was significantly decreased in trained sickle mice and there was a strong correlation between the magnitude of congestion and the relative spleen mass in all animals (trained and untrained). We conclude that moderate intensity exercise training, without any noticeable complications, may be associated with limited baseline blood deoxygenation and inflammation in sickle cell mice, and reduce sequestration of sickle erythrocytes/congestion in the spleen. PMID- 28624258 TI - Incentivizing healthy eating in children: An investigation of the "ripple" and "temporal" effects of a reward-based intervention. AB - Although previous studies have established the effectiveness of using small reward-based incentives in inducing the choice and consumption of healthier foods among children, little is known about their impact outside of experimental settings or their effectiveness over time when administered daily. This paper presents the results of a field experiment conducted to provide insight on these matters. The study employs a removed treatment within-subject design and was conducted at a summer program catering to low-income children between the ages of 5 and 12. The month long experiment-wherein participants were offered a small prize for choosing a fruit cup for dessert after lunch in lieu of cookies involved 23 children between the ages of 5 and 8. Corroborating existing studies, the introduction of small reward-based incentives in this context was found to induce large increases in the number of children choosing the healthy dessert options after lunch, but disaggregating the results by week and day suggests that their impact diminished over time. Attempts to ascertain their effect outside of experimental settings did not indicate that the introduction of rewards had any adverse effects, but also did not provide definitive conclusions. PMID- 28624259 TI - Body talk, weight status, and pathological eating behavior in romantic relationships. AB - This study examined whether engagement in body talk would interact with weight status (body mass index; BMI) to predict pathological eating behaviors among romantically involved adults. Adults (N = 137, females = 86.86%, average age = 23.50) involved in a romantic relationship were recruited to complete an online survey about their body image, dietary behaviors, and engagement in body talk. Results indicated that engagement in negative body talk was directly related to higher pathological eating (i.e., drive for thinness, dieting, and bulimia symptoms). Positive body talk, on the other hand, had a significant interaction effect with BMI to predict pathological eating. For individuals with a high BMI, high engagement in positive body talk was associated with increased drive for thinness, dieting, and bulimia symptoms. However, for those with a low BMI, high engagement in positive body talk was protective against pathological eating. These findings suggest that while negative body talk is harmful in general, positive body talk is uniquely problematic for individuals of a higher weight status. PMID- 28624260 TI - Development and validation of subscales to assess perceived support for self management of mood or emotional problems: Results from a randomized trial. AB - OBJECTIVES: To validate 2 new patient-reported measures of self-management support from health professionals for mood and emotional problems. METHODS: The sample comprised primary care patients with chronic physical conditions and co morbid depressive symptoms enrolled in a randomized trial of telephone coaching of a depression self-care intervention (n=120). At 6-month follow-up, patients completed 2 subscales with respect to support for self-management of their chronic physical condition(s): 1) Self-Management Information (SMInfo-Phys); and 2) Care Plan (CP-Phys) and equivalent subscales adapted to assess self-management support for mood and emotional problems: SMInfo-Mood and CP-Mood. Subscale scoring was assessed with Item Response Theory (IRT) analysis. Convergent validity of the mood subscales was assessed. The sensitivity of the mood and physical condition subscales to mental health interventions was assessed with generalized estimating equations (GEE). RESULTS: The mood subscales were associated with relevant measures of perceived unmet mental health needs. Both SMInfo-Mood and CP-Mood were sensitive to the coaching intervention; CP-Mood was also sensitive to receipt of depression treatment outside the trial. CONCLUSION: This study provides preliminary evidence for the validity of the 2 new subscales. PRACTICE IMPLICATIONS: The subscales may be used to assess perceived health professional support for self-management of mood and emotional problems. PMID- 28624261 TI - Dutch health websites and their ability to inform people with low health literacy. AB - OBJECTIVE: To evaluate whether Dutch online health information (OHI) generally reflects message elements that support information processing and understanding among people with low health literacy. METHODS: We content-analyzed one hundred Dutch webpages about Ebola, fibromyalgia, ALS, losing weight, borderline personality disorder, hemorrhoids, ADD, bladder infection, shingles, and chicken pox. The codebook covered the following domains: images and videos, readability level, Suitability Assessment of Materials (SAM), advertising, interactive features, and reliability cues. RESULTS: Thirty-seven webpages contained informative images that visualized the text. Twelve webpages incorporated videos, six of which were animations. Readability varied widely, but 79.2% of the texts exceeded the recommended B1 level. Half of the webpages had inadequate SAM scores; five were classified as superior. Interactive features were infrequently used. Many webpages included only a few elements that help users evaluate the reliability of OHI. Four presented a quality label. CONCLUSION: Over a wide range of health-related topics, Dutch OHI does not generally contain message elements that improve information processing among people with low health literacy. PRACTICE IMPLICATIONS: Communication professionals should make better use of digital message features. Videos, narration, and interactivity are scarcely used but can be valuable for people with low health literacy. PMID- 28624263 TI - Corrections. PMID- 28624262 TI - Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity. AB - Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off-target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ). These DBZ-loaded NPs support rapid cellular internalization and inhibit Notch signaling in adipocytes. Importantly, focal injection of these NPs into the inguinal white adipose tissue depots of diet-induced obese mice results in localized NP retention and browning of adipocytes, consequently improving the glucose homeostasis and attenuating body weight gain of the treated mice. These findings offer new avenues to develop a potential therapeutic strategy for clinical treatment of obesity and its associated metabolic syndrome. PMID- 28624264 TI - Profiling of cytosolic and mitochondrial H2O2 production using the H2O2-sensitive protein HyPer in LPS-induced microglia cells. AB - Dysregulation of the production of pro-inflammatory mediators in microglia exacerbates the pathologic process of neurodegenerative disease. ROS actively affect microglia activation by regulating transcription factors that control the expression of pro-inflammatory genes. However, accurate information regarding the function of ROS in different subcellular organelles has not yet been established. Here, we analyzed the pattern of cytosolic and mitochondrial H2O2 formation in LPS-activated BV-2 microglia using the H2O2-sensitive protein HyPer targeted to specific subcellular compartments. Our results show that from an early time, cytosolic H2O2 started increasing constantly, whereas mitochondrial H2O2 rapidly increased later. In addition, we found that MAPK affected cytosolic H2O2, but not mitochondrial H2O2. Consequently, our study provides the basic information about subcellular H2O2 generation in activated microglia, and a useful tool for investigating molecular targets that can modulate neuroinflammatory responses. PMID- 28624265 TI - The neuroscience of understanding the emotions of others. AB - We cannot help but impute emotions to the behaviors of others, and constantly infer not only what others are feeling, but also why they feel that way. The comprehension of other people's emotional states is computationally complex and difficult, requiring the flexible, context-sensitive deployment of cognitive operations that encompass rapid orienting to, and recognition of, emotionally salient cues; classification of emotions into culturally-learned categories; and using an abstract theory of mind to reason about what caused the emotion, what future actions the person might be planning, and what we should do next in response. This review summarizes what neuroscience data - primarily functional neuroimaging data - has so far taught us about the cognitive architecture enabling emotion understanding in its various forms. PMID- 28624266 TI - [Trochanteric under gluteus lift or bodylift, technique for massive trochanteric lipodystrophy: About 11 cases]. AB - INTRODUCTION: There is a growing demand for weight loss sequelae. Some women have a particular morphology with a major trochanteric excess that warrants specific treatment. MATERIALS AND METHODS: On the basis of the technique published in 1964 by Pitanguy, the authors suggest a lift of the external face of the thigh with the scar redrawing the lower part of the buttock, from the gluteal fold to the inguinal region by crossing the trochanteric region. Eleven cases of major trochanteric excess after slimming are presented. In 4 cases, the trochanteric excess is solely treated by trochanteric under gluteus lift. In 7 cases, it is associated with abdominoplasty to perform a trochanteric under gluteus bodylifting. RESULTS: Complications and results are presented. The trochanterian excess is reduced, the buttock is harmonious and the patients satisfied. DISCUSSION: Modifications are made to the much criticized technique of Pitanguy. The lipectomy replaces the monobloc resection, the scar is verticalized on the trochanter to join the abdominoplasty scar. This technique is an alternative to the vertical trochanteric resection associated with classic bodylift. CONCLUSION: The trochanteric under gluteus lift is an elegant solution for treating large trochanteric excess. It is adaptable. It can become bodylifting TSF in the cases of great slimming. PMID- 28624267 TI - Endoscopic robot-assisted C7 nerve root retrophalangeal transfer from the contralateral healthy side: A cadaver feasibility study. AB - Controlateral C7 nerve root transfer in brachial plexus palsy requires a nerve graft and large incisions. This study investigated the feasibility of transferring the right C7 to the left C7 nerve root, without a graft, via a minimally invasive retropharyngeal approach. After installation of 6 trocars of 1cm diameter in the supraclavicular space, a Da Vinci SI(r) robot was placed. After locating the right brachial plexus, the C7 root was sectioned flush with the clavicle, transferred behind the pharynx and sutured to the left C7 root severed at the foramen level. The duration of the procedure was 2h40min. No technical difficulties were encountered. The hypothesis of this work was verified since it was possible to carry out a transfer of the right C7 root on the left C7 root by direct retropharyngeal suture without graft and by a minimally invasive technique. PMID- 28624268 TI - [Female-to-male transgender chest reconstruction: A retrospective study of patient satisfaction]. AB - BACKGROUND: Mammaplasty in gender reassignment surgery is often poorly understood, due to a lack of information about this condition and its therapy. The aim of this work was to evaluate patient satisfaction following bilateral mastectomy for female-to-male gender reassignment. METHODS: We contacted 22 patients who underwent mammaplasty for female-to-male gender reassignment between January 2012 and March 2013 in our university hospital. Patients were sent postal questionnaires. A modified Q-breast questionnaire adapted for gender reassignment surgery enabled us to objectively evaluate patient aesthetic and psychological satisfaction. An overall score superior to 320 was considered as very satisfied for the patient. RESULTS: A total of 73% of the patients answered the questionnaire. The mean score was 332/378. This score corresponded to "very satisfied" on our questionnaire. The psychological score was 54.5/60. CONCLUSION: This study showed that a real benefit was obtained in terms of patient quality of life and self-confidence. The high level of patient satisfaction confirmed that gender reassignment mastectomy is a useful and valid procedure, which enables these patients to reclaim their place in society. It can only be considered if it is within the framework of structures that ensure comprehensive and pluridisciplinary treatment for the patient. PMID- 28624269 TI - [Technical information: The 'so called' Camille Bernard lower lip reconstruction: An eponymous confusion clarified]. AB - The use of eponyms honours those who have contributed to the development of medicine and facilitates communication between colleagues. Eponyms are based on historical knowledge to know who was the first to use a given technique. In the previous century, two different operative procedures have been attached to the 'so called' Bernard lower lip reconstruction. This historical literature on lip reconstruction with a focus on the years 1853-1855 elucidates the roles of Bernard, Saeman, Desgranges and Burow, and gives suggestions for eponyms that do justice to the innovating surgeons Bernard, Burow and Desgranges. PMID- 28624270 TI - Implementation and evaluation of a 'Navigator' role to improve emergency department throughput. AB - BACKGROUND: Emergency department overcrowding impacts patients, staff, and quality of care, and there is government pressure to optimize throughput and reduce waiting times. One solution for improving patient flow is the emerging 'navigator' role: a nurse that supports staff in care delivery; facilitating efficient and timely patient movement through the emergency department. METHODS: A 20-week project was implemented to evaluate an emergency department nurse navigator role. A controlled trial was used. The navigator worked on a week-on week-off basis, eight hours per day, seven days per week. Time-based and cost associated outcomes were compared. RESULTS: Data from nearly 20,000 presentations during the trial period were analysed. All outcomes were improved during the ten weeks the Navigator was working. A slight improvement in National Emergency Access Target compliance was shown, with an average of 4.5min per presentation saved. The labour cost associated with the time saved was estimated to be $170,000. CONCLUSIONS: The results from this study indicate that for a relatively small investment, complementary nursing roles such as the navigator can impact emergency department patient flow. However, further studies are required to determine optimisation of the role. RELEVANCE TO PRACTICE: This study provides rigorous evidence of the effects of a nurse navigator role on emergency department throughput. Whilst positive outcomes were demonstrated, suggesting a whole-of-system benefit, the magnitude of effect on a per-presentation basis was relatively small. Further studies are required to demonstrate the clinical relevance of such roles. PMID- 28624271 TI - Coagulase-negative staphylococci species affect biofilm formation of other coagulase-negative and coagulase-positive staphylococci. AB - Coagulase-negative staphylococci (CNS) are considered to be commensal bacteria in humans and animals, but are now also recognized as etiological agents in several infections, including bovine mastitis. Biofilm formation appears to be an important factor in CNS pathogenicity. Furthermore, some researchers have proposed that CNS colonization of the intramammary environment has a protective effect against other pathogens. The mechanisms behind the protective effect of CNS have yet to be characterized. The aim of this study was to evaluate the effect of CNS isolates with a weak-biofilm phenotype on the biofilm formation of other staphylococcal isolates. We selected 10 CNS with a weak-biofilm phenotype and 30 staphylococcal isolates with a strong-biofilm phenotype for this study. We measured biofilm production by individual isolates using a standard polystyrene microtiter plate assay and compared the findings with biofilm produced in mixed cultures. We confirmed the results using confocal microscopy and a microfluidic system with low shear force. Four of the CNS isolates with a weak-biofilm phenotype (Staphylococcus chromogenes C and E and Staphylococcus simulans F and H) significantly reduced biofilm formation in approximately 80% of the staphylococcal species tested, including coagulase-positive Staphylococcus aureus. The 4 Staph. chromogenes and Staph. simulans isolates were also able to disperse pre-established biofilms, but to a lesser extent. We also performed a deferred antagonism assay and recorded the number of colony-forming units in the mixed-biofilm assays on differential or selective agar plates. Overall, CNS with a weak-biofilm phenotype did not inhibit the growth of isolates with a strong biofilm phenotype. These results suggest that some CNS isolates can negatively affect the ability of other staphylococcal isolates and species to form biofilms via a mechanism that does not involve growth inhibition. PMID- 28624272 TI - Effects of partial replacement of corn grain with lactose in calf starters on ruminal fermentation and growth performance. AB - The objective of this study was to evaluate effects of partial replacement of dry ground corn with lactose in calf starters on dry matter intake, growth rate, ruminal pH, and volatile fatty acid profile. Sixty Holstein bull calves were raised on a high plane of nutrition program until 55 d of age. Calves were fed texturized calf starters containing 30.1% steam-flaked grains and lactose at 0 (control), 5, or 10% (n = 20 for each treatment) on a dry matter basis. All calves were fed treatment calf starters ad libitum from d 7 and kleingrass hay from d 35. Ruminal pH was measured continuously immediately after weaning (d 55 62) for 15 calves (n = 5 per treatment), and 3 wk after weaning (d 77 to 80) for the other 45 calves (n = 15 per treatment). Dry matter intake, growth performance, and ruminal pH variables were not affected by treatment. However, according to Spearman's correlation coefficient (rs) analyses, lactose intake was positively correlated with dairy minimum ruminal pH (rs = 0.306) for the data collected from d 77 to 80. Similarly, hay intake was not affected by treatment, but positively correlated with daily mean (rs = 0.338) and maximum ruminal pH (rs = 0.408) and negatively correlated with duration pH <5.8 (rs = -0.329) and area pH <5.8 (rs = -0.325), indicating that the variation in hay intake among animals might have masked treatment effects on ruminal pH. Ruminal molar ratio of acetate was higher (45.2 vs. 40.6%), and that of propionate was lower in 10% lactose than control (35.3 vs. 40.2%) for ruminal fluid collected on d 80; however, molar ratio of butyrate was not affected by treatment. These results indicate that lactose inclusion in calf starters up to 10% of dry matter might not affect dry matter intake and growth performance of calves, but that greater lactose and hay intake might be associated with higher ruminal pH. PMID- 28624273 TI - Temporal and spatial water use on irrigated and nonirrigated pasture-based dairy farms. AB - Robust information for water use on pasture-based dairy farms is critical to farmers' attempts to use water more efficiently and the improved allocation of freshwater resources to dairy farmers. To quantify the water requirements of dairy farms across regions in a practicable manner, it will be necessary to develop predictive models. The objectives of this study were to compare water use on a group of irrigated and nonirrigated farms, validate existing water use models using the data measured on the group of nonirrigated farms, and modify the model so that it can be used to predict water use on irrigated dairy farms. Water use data were collected on a group of irrigated dairy farms located in the Canterbury, New Zealand, region with the largest area under irrigation. The nonirrigated farms were located in the Manawatu region. The amount of water used for irrigation was almost 52-fold greater than the amount of all other forms of water use combined. There were large differences in measured milking parlor water use, stock drinking water, and leakage rates between the irrigated and nonirrigated farms. As expected, stock drinking water was lower on irrigated dairy farms. Irrigation lowers the dry matter percentage of pasture, ensuring that the amount of water ingested from pasture remains high throughout the year, thereby reducing the demand for drinking water. Leakage rates were different between the 2 groups of farms; 47% of stock drinking water was lost as leakage on nonirrigated farms, whereas leakage on the irrigated farms equated to only 13% of stock drinking water. These differences in leakage were thought to be related to regional differences rather than differences in irrigated versus nonirrigated farms. Existing models developed to predict milking parlor, corrected stock drinking water, and total water use on nonirrigated pasture-based dairy farms in a previous related study were tested on the data measured in the present research. As expected, these models performed well for nonirrigated dairy farms but provided poor predictive power for irrigated farms. Partial least squares regression models were developed specifically to simulate corrected stock drinking water, milking parlor water, and total water use on irrigated dairy farms. PMID- 28624274 TI - Effect of nutritional immunomodulation and heat stress during the dry period on subsequent performance of cows. AB - Heat stress in dairy cows during the dry period impairs milk yield in the next lactation. Feeding OmniGen-AF (OG; Phibro Animal Health Corp., Teaneck, NJ) to lactating cows during heat stress may increase dry matter intake (DMI) and lowers respiration rate (RR) and rectal temperature (RT), but the effects in dry cows are not known. We hypothesized that OG supplementation before, during, and after the dry period (approximately 160 d total) would overcome the effects of heat stress and improve cow performance in the next lactation. Cows were randomly assigned to OG or control (placebo) treatments for the last 60 d in milk (DIM), based on mature-equivalent milk yield in the previous lactation. Cows were dried off 45 d before expected calving and randomly assigned to heat stress (HT) or cooling (CL) treatments. Thus, cows received dietary supplementation during late lactation before they were exposed to either CL or HT. After dry-off, treatment groups included heat stress with placebo (HT, only shade, 56 g/d of placebo, n = 17), HT with OG supplementation (HTOG, 56 g/d of OG, n = 19), cooling with placebo (CL, shade, fans, and soakers, 56 g/d of placebo, n = 16), and CL with OG supplementation (CLOG, 56 g/d of OG, n = 11). After parturition, all cows were kept under the same CL system and management, and all cows continued to receive OG or control treatment until 60 DIM. Cooling cows during the dry period reduced afternoon RT (CL vs. HT; 38.9 +/- 0.05 vs. 39.3 +/- 0.05 degrees C) and RR (CL vs. HT; 45 +/- 1.6 vs. 77 +/- 1.6 breaths/min). Respiration rate was also decreased by OG supplementation under HT conditions (HTOG vs. HT; 69.7 +/- 1.6 vs. 77.2 +/- 1.6 breaths/min). An interaction was observed between OG supplementation and HT; HTOG cows tended to have lower morning RT compared with HT cows. During the dry period, OG reduced DMI relative to control cows. Birth weight was greater in calves from CL cows (CL vs. HT; 40.6 +/- 1.09 vs. 38.7 +/- 1.09 kg). No differences were detected among treatments in hematocrit, total protein, and body condition score. Cows offered CLOG, CL, and HTOG treatments had greater body weight during the dry period (794.9 +/- 17.9, 746.8 +/- 16.7, and 762.9 +/- 14.9 kg, respectively) than HT cows (720 +/- 16.2 kg). Gestation length was approximately 4 d longer for CL cows compared with HT cows. Cows offered CLOG, CL, and HTOG treatments produced more milk (41.3 +/- 1.6, 40.7 +/- 1.6, and 40.5 +/- 1.6 kg/d, respectively) than HT treatment (35.9 +/- 1.6 kg/d). Body weight after parturition and DMI were evaluated up to 60 DIM and averaged 661.5 +/- 15.8 and 19.4 +/- 0.7 kg/d, respectively, with no differences observed among treatments. These results confirm that exposure of dry cows to heat stress negatively affects milk yield in the subsequent lactation. Active cooling of dry cows and OG supplementation can reduce the negative effects of heat stress in the dry period on subsequent performance. PMID- 28624275 TI - Nuclear receptor subfamily 1 group H member 2 (LXRB) is the predominant liver X receptor subtype regulating transcription of 2 major lipogenic genes in goat primary mammary epithelial cells. AB - In ruminants, recent research has identified a crucial role for liver X receptors (LXR) in regulating lipid metabolism in mammary cells. However, the differences between LXR subtypes in regulating ruminant lipid metabolism are unknown. We used overexpression and knockdown of LXRA and LXRB in goat primary mammary epithelial cells to distinguish subtype-specific regulation of sterol regulatory element binding protein 1c (SREBP1c) and fatty acid synthase (FASN) mRNA expression and their promoter activity. Incubation with siRNA targeting LXR decreased expression of LXRA and LXRB. Knockdown of LXRA and LXRB in cells incubated with dimethyl sulfoxide (DMSO, control) had no effect on the expression of SREBP1c or FASN. Knockdown of LXRB in cells incubated with LXR ligand T0901317 (T09) led to decreased expression of FASN, but not SREBP1c. Overexpression of LXRB plus T09 dramatically upregulated SREBP1c and FASN to levels higher than overexpression of LXRA with T09. Luciferase reporter assays in cells with site-directed mutagenesis of LXR response elements (LXRE; LXRE1 from -286 to -251 bp or LXRE2 from -235 to 219 bp) revealed that the SREBP1c promoter with the wild type or either LXRE mutation in cells supplemented with T09 decreased markedly only when LXRB was knocked down. Knockdown of LXRA and LXRB had no effect on the SREBP1c promoter when cells had a double LXRE mutation. Overexpression of LXRA only in cells incubated with T09 increased the activity of the SREBP1c promoter with the wild type and the LXRE2 mutation. In contrast, compared with each control group, overexpression of LXRB dramatically increased SREBP1c promoter activity, regardless of LXRE mutation. Furthermore, in cells stimulated with T09, knockdown of either LXRA or LXRB did not alter wild-type FASN promoter activity. Knockdown of LXRA increased wild-type and LXRE-site-mutated (LXRE from -677 to -662 bp) FASN promoter activity. Overexpression of LXRB increased wild-type and LXRE-site mutated FASN promoter activity regardless of treatment with DMSO or T09, but overexpression of LXRA altered LXRE-site-mutated FASN promoter activity only in cells treated with DMSO. Increased activation of SREBP1c or FASN promoters containing LXRE mutations after overexpression of LXRB suggested that LXRB activates endogenous SREBP1c, which can then bind to the promoter of SREBP1c via an auto-loop circuit regulatory mechanism. Collectively, these results highlight an important role for LXRB in the transcriptional regulation of SREBP1c and FASN in goat mammary epithelial cells. Activation of this nuclear receptor controls lipogenesis via different mechanisms. PMID- 28624276 TI - Cow and environmental factors associated with protein fractions and free amino acids predicted using mid-infrared spectroscopy in bovine milk. AB - The objective of the present study was to identify the factors associated with both the protein composition and free amino acid (FAA) composition of bovine milk predicted using mid-infrared spectroscopy. Milk samples were available from 7 research herds and 69 commercial herds. The spectral data from the research herds comprised 94,286 separate morning and evening milk samples; the spectral data from the commercial herds comprised 40,260 milk samples representing a composite sample of both the morning and evening milkings. Mid-infrared spectroscopy prediction models developed in a previous study were applied to all spectra. Factors associated with the predicted protein and FAA composition were quantified using linear mixed models. Factors considered in the model included the fixed effects of calendar month of the test, milking time (i.e., morning, evening, or both combined), parity (1, 2, 3, 4, 5, and >=6), stage of lactation, the interaction between parity and stage of lactation, breed proportion of the cow (Friesian, Jersey, Norwegian Red, Montbeliarde, and other), and both the general heterosis and recombination coefficients of the cow. Contemporary group as well as both within- and across-lactation permanent environmental effects were included in all models as random effects. Total proteins (i.e., total casein, CN; total whey; and total beta-lactoglobulin) and protein fractions (with the exception of alpha-lactalbumin) decreased postcalving until 36 to 65 days in milk and increased thereafter. After adjusting the statistical model for differences in crude protein content and milk yield separately, irrespective of stage of lactation, younger animals produced more total proteins (i.e., total CN, total whey, and total beta-lactoglobulin) as well as more total FAA, Glu, and Asp than their older contemporaries. The concentration of all protein fractions (except beta-CN) in milk was greatest in the evening milk, even after adjusting for differences in the crude protein content of the milk. Relative to a purebred Holstein cow, Jersey cows, on average, produced a greater concentration of all CN fractions but less total FAA, Glu, Gly, Asp, and Val in milk. Relative to their respective purebred parental average, first-cross cows produced more total CN and more beta-CN. Results from the present study indicate that many cow-level factors, as well as other factors, are associated with protein composition and FAA composition of bovine milk. PMID- 28624277 TI - Technical note: At-line prediction of mineral composition of fresh cheeses using near-infrared technologies. AB - Milk and dairy products are important sources of macro- and trace elements for human health. However, fresh cheeses usually have a lower mineral content than other cheeses, and this makes mineral prediction more difficult. Although mineral prediction in several food matrices using infrared spectroscopy has been reported in the literature, very little information is available for cheeses. The present study was aimed at developing near-infrared reflectance (NIR, 866-2,530 nm) and transmittance (NIT, 850-1,050 nm) spectroscopy models to predict the major mineral content of fresh cheeses. We analyzed samples of mozzarella (n = 130) and Stracchino (n = 118) using reference methods and NIR and NIT spectroscopy. We developed prediction models using partial least squares regression analysis, and subjected them to cross- and external validation. Average Na content was 0.15 and 0.22 g/100 g for mozzarella and Stracchino, respectively. The NIR and NIT spectroscopy performed similarly, with few exceptions. Nevertheless, none of the prediction models was accurate enough to replace the current reference analysis. The most accurate prediction model was for the Na content of mozzarella cheese using NIT spectroscopy (coefficient of determination of external validation = 0.75). We obtained the same accuracy of prediction for P in Stracchino cheese with both NIR and NIT spectroscopy. Our results confirmed that mineral content is difficult to predict using NIT and NIR spectroscopy. PMID- 28624278 TI - Estimation of prevalence and incidence of subclinical mastitis in a large population of Brazilian dairy herds. AB - The objectives of this study were to estimate the prevalence and incidence of subclinical mastitis (SM) in a large population of Brazilian dairy herds and to describe how these indices changed over time. A data set comprising individual cow somatic cell counts (SCC) from 18,316 test days (TD) of 1,809 herds that participated in a Dairy Herd Improvement Association (DHIA) program between January 2011 and May 2015 was available for analysis. Only tests that had >=10 lactating cows and that were performed at 30 +/- 10-d intervals were used for analysis. The final data set included 8,285 TD from 517 herds located in 5 regions of the country. Prevalence (%) of SM was defined as the number of cows with SCC >=200,000 cells/mL divided by the total number of tested cows on a given TD. The incidence of SM was defined as the number of cows whose SCC increased from <200,000 to >=200,000 cells/mL over 2 consecutive TD divided by the sum of each cow's days at risk during this interval, expressed as new cases per cow month at risk. Prevalence and incidence of SM were compared among years, regions, herd size categories, and frequency of DHIA testing during the study period. The overall mean prevalence and incidence of SM including all tests performed during the study period was 46.4% and 0.17 new cases per cow month at risk, respectively. The prevalence of SM varied little from 2011 to 2015, and an increasing trend was observed over the years. Prevalence was lower in herds that performed >=60 DHIA tests during the study period than in those that performed fewer tests and was not different among regions or herd size categories. Incidence of SM varied little over the years and was not different among the regions studied. Prevalence and incidence of SM in the 517 herds studied were high and did not improve over the years. These trends were observed across all herd size categories and regions studied. Producers who had more DHIA tests performed per herd during the study period had lower prevalence of SM. Results of this study highlight the need to establish large-scale milk quality programs in Brazil. PMID- 28624279 TI - The use of national-level data to describe trends in intramammary antimicrobial usage on Irish dairy farms from 2003 to 2015. AB - In this study, we used national-level data to describe trends in on-farm intramammary antimicrobial usage in Ireland from 2003 to 2015. We calculated actual sales of intramammary tubes and the quantity of active substance sold, by year, product type [lactation or dry cow therapy (DCT)], antimicrobial group, World Health Organization antimicrobial classification, and from 2009 to 2015, prescribing route. We also estimated on-farm usage of lactation and dry cow intramammary antimicrobials using defined daily dose (DDDvet) and defined course dose (DCDvet) calculations, and dry cow coverage. Sales of tubes of antimicrobial for DCT have increased, and the estimated national dry cow coverage in 2015 was 1,022 DCDvet per 1,000 cows per year. An increase has also occurred in sales of teat sealant (2015 sales: 66.7 tubes with teat sealant for every 100 tubes with antimicrobial for DCT). In contrast, the number of tubes of antimicrobial sold for lactation use has decreased to 1,398 DDDvet and 466 DCDvet per 1,000 animals per year. Sales in intramammary tubes with at least one critically important antimicrobial (CIA) have either risen since 2007 (DCT) or fallen (lactation therapy). Increases were observed in both the number of dry cow and lactation tubes containing CIA considered of highest priority for human health. Differences between prescribing routes with respect to CIA usage were observed. This study provides detailed insight into on-farm usage of intramammary antimicrobials in Ireland. It demonstrates positive national progress but also highlights areas for review. In particular, blanket dry cow treatment in Ireland should be reconsidered. It is not possible to investigate farm-level variation in antimicrobial usage from national sales data. In several countries, measurement and benchmarking have been critical to progress in reducing antimicrobial usage in farm animal production. Central collation of data on farm-level antimicrobial use is also needed in Ireland to allow objective measurement and benchmarking of on-farm usage. More generally, standardized indicators to quantify antimicrobial usage in farm animals are urgently needed to allow country-level comparisons. PMID- 28624280 TI - Technical note: Evaluation of endogenous control gene expression in bovine neutrophils by reverse-transcription quantitative PCR using microfluidics gene expression arrays. AB - Reverse-transcription quantitative-PCR (RT-qPCR) is commonly used for assessing the cellular response to changes in physiologic and pathologic conditions. The selection of stable endogenous control genes is an important step of any RT-qPCR study, as expression can vary depending on the experimental environment. Our objective was to identify endogenous control genes in circulating neutrophils isolated from cows during the peripartum period. To do this, we used microfluidics gene expression arrays (Fluidigm, San Francisco, CA) for RT-qPCR analysis. Selection of the endogenous control genes was based on previous research investigating gene expression in neutrophils. The selected genes included ACTB, B2M, G6PD, GAPDH, GCH1, GOLGA5, OSBPL2, PGK1, RPL13A, RPL19, RPS9, SDHA, SMUG1, SNRPA, TBP, UXT, and YWHAZ. Four genes (GAPDH, GOLGA5, PGK1, and UXT) did not provide satisfactory quantification results using the selected method and were therefore excluded from the analyses. The suitability of the remaining 13 genes for use as endogenous control genes was assessed using geNorm and Normfinder. The gene pair with the greatest stability using geNorm was RPL13A and RPL19, whereas Normfinder ranked RPL19 and YWHAZ as the most stable pair. The 2 genes deemed most suitable for the experimental design were RPL19 and YWHAZ, which were selected for subsequent gene expression analysis. This study highlights that genes used as endogenous controls for relative quantification should be assessed on an experimental basis, even if the genes have been used in previous research. PMID- 28624281 TI - Short communication: Genetic parameters for milk protein composition predicted using mid-infrared spectroscopy in the French Montbeliarde, Normande, and Holstein dairy cattle breeds. AB - Genetic parameters for the major milk proteins were estimated in the 3 main French dairy cattle breeds (i.e. Montbeliarde, Normande, and Holstein) as part of the PhenoFinlait program. The 6 major milk protein contents as well as the total protein content (PC) were estimated from mid-infrared spectrometry on 133,592 test-day milk samples from 20,434 cows in first lactation. Lactation means, expressed as a percentage of milk (protein contents) or of protein (protein fractions), were analyzed with an animal mixed model including fixed environmental effects (herd, year * month of calving, and spectrometer) and a random genetic effect. Genetic parameter estimates were very consistent across breeds. Heritability estimates (h2) were generally higher for protein fractions than for protein contents. They were moderate to high for alphaS1-casein, alphaS2 casein, beta-casein, kappa-casein, and alpha-lactalbumin (0.25 < h2 < 0.72). In each breed, beta-lactoglobulin was the most heritable trait (0.61 < h2 < 0.86). Genetic correlations (rg) varied depending on how the percentage was expressed. The PC was strongly positively correlated with protein contents but almost genetically independent from protein fractions. Protein fractions were generally in opposition, except between kappa-casein and alpha-lactalbumin (0.39 < rg < 0.46) and kappa-casein and alphaS2-casein (0.36 < rg < 0.49). Between protein contents, rg estimates were positive, with highest values found between caseins (0.83 < rg < 0.98). In the 3 breeds, beta-lactoglobulin was negatively correlated with caseins (-0.75 < rg < -0.08), in particular with kappa-casein (-0.75 < rg < 0.55). These results, obtained from a large panel of cows of the 3 main French dairy cattle breeds, show that routinely collected mid-infrared spectra could be used to modify milk protein composition by selection. PMID- 28624282 TI - Effect of endoplasmic reticulum stress on metabolic and stress signaling and kidney-specific functions in Madin-Darby bovine kidney cells. AB - Recent studies demonstrated induction of endoplasmic reticulum (ER) stress in tissues of cows after parturition, but knowledge about the effect of ER stress on important cellular processes, such as critical signaling and metabolic pathways, in cattle is scarce. Thus, the present study aimed to investigate the effect of ER stress induction on nuclear factor-kappaB (NF-kappaB), nuclear factor E2 related factor 2 (Nrf2), and sterol regulatory element-binding protein (SREBF1) pathway in Madin-Darby bovine kidney (MDBK) cells, a widely used in vitro model in ruminant research. To consider the kidney origin of MDBK cells, the effect on renal distal tubular cell-specific functions, such as transport processes and regulation of 1,25(OH)2D3 levels, was also studied. Treatment of MDBK cells with 2 different ER stress inducers, thapsigargin (TG) and tunicamycin (TM), strongly induced ER stress as evident from induction of ER stress target genes, increased phosphorylation of PKR-like ER kinase, and enhanced splicing of X-box binding protein 1. The TM decreased the protein concentration of NF-kappaB p50 and the mRNA levels of the NF-kappaB target genes. Likewise, TG decreased the mRNA concentration of tumor necrosis factor and tended to decrease NF-kappaB p50 protein and mRNA levels of NF-kappaB target genes. The mRNA levels of most of the Nrf2 target genes investigated were reduced by TG and TM in MDBK cells. Both ER stress inducers reduced the mRNA levels of SREBF1 and its target genes in MDBK cells. Interestingly, TG decreased, but TM increased the mRNA level of the Ca2+ binding protein calbindin 1, whereas the mRNA level of the plasma membrane Ca2+ transporting ATPase 1 remained unchained. The mRNA level of the cytochrome P450 component 24A1 involved in 1alpha-hydroxylation of 25(OH)D3 was strongly elevated, whereas the mRNA level of the cytochrome P450 component 27A1 catalyzing the breakdown of 1,25(OH)2D3 was markedly reduced by both ER stress inducers. The concentration of 1,25(OH)2D3 in the supernatant of MDBK cells was increased by approximately 15% by both TG and TM. The present study indicates that under conditions of ER stress, critical signaling pathways, such as NF-kappaB, Nrf2, and SREBF1, are inhibited, whereas the formation of 1,25(OH)2D3 is stimulated in bovine MDBK cells. Future studies are necessary to clarify the physiological relevance of these findings. PMID- 28624283 TI - Effect of pasture versus indoor feeding systems on quality characteristics, nutritional composition, and sensory and volatile properties of full-fat Cheddar cheese. AB - The purpose of this study was to investigate the effects of pasture-based versus indoor total mixed ration (TMR) feeding systems on the chemical composition, quality characteristics, and sensory properties of full-fat Cheddar cheeses. Fifty-four multiparous and primiparous Friesian cows were divided into 3 groups (n = 18) for an entire lactation. Group 1 was housed indoors and fed a TMR diet of grass silage, maize silage, and concentrates; group 2 was maintained outdoors on perennial ryegrass only pasture (GRS); and group 3 was maintained outdoors on perennial ryegrass/white clover pasture (CLV). Full-fat Cheddar cheeses were manufactured in triplicate at pilot scale from each feeding system in September 2015 and were examined over a 270-d ripening period at 8 degrees C. Pasture derived feeding systems were shown to produce Cheddar cheeses yellower in color than that of TMR, which was positively correlated with increased cheese beta carotene content. Feeding system had a significant effect on the fatty acid composition of the cheeses. The nutritional composition of Cheddar cheese was improved through pasture-based feeding systems, with significantly lower thrombogenicity index scores and a greater than 2-fold increase in the concentration of vaccenic acid and the bioactive conjugated linoleic acid C18:2 cis-9,trans-11, whereas TMR-derived cheeses had significantly higher palmitic acid content. Fatty acid profiling of cheeses coupled with multivariate analysis showed clear separation of Cheddar cheeses derived from pasture-based diets (GRS or CLV) from that of a TMR system. Such alterations in the fatty acid profile resulted in pasture-derived cheeses having reduced hardness scores at room temperature. Feeding system and ripening time had a significant effect on the volatile profile of the Cheddar cheeses. Pasture-derived Cheddar cheeses had significantly higher concentrations of the hydrocarbon toluene, whereas TMR derived cheese had significantly higher concentration of 2,3-butanediol. Ripening period resulted in significant alterations to cheese volatile profiles, with increases in acid-, alcohol-, aldehyde-, ester-, and terpene-based volatile compounds. This study has demonstrated the benefits of pasture-derived feeding systems for production of Cheddar cheeses with enhanced nutritional and rheological quality compared with a TMR feeding system. PMID- 28624284 TI - Comparing the effect of homogenization and heat processing on the properties and in vitro digestion of milk from organic and conventional dairy herds. AB - We compared the effects of homogenization and heat processing on the chemical and in vitro digestion traits of milk from organic and conventional herds. Raw milk from organic (>50% of dry matter intake from pasture) and conventional (no access to pasture) farms were adjusted to commercial whole and nonfat milk fat standards, and processed with or without homogenization, and with high temperature-short-time or UHT pasteurization. The milk then underwent in vitro gastrointestinal digestion. Comparison of milk from organic and conventional herds showed that the milks responded to processing in similar ways. General composition was the same among the whole milk samples and among the nonfat milk samples. Protein profiles were similar, with intact caseins and whey proteins predominant and only minor amounts of peptides. Whole milk samples from grazing cows contained higher levels of alpha-linolenic (C18:3), vaccenic (C18:1 trans), and conjugated linoleic acids, and lower levels of palmitic (C16:0) and stearic (C18:0) acids than samples from nongrazing cows. Processing had no effect on conjugated linoleic acid and linolenic acid levels in milk, although homogenization resulted in higher levels of C8 to C14 saturated fatty acids. Of the 9 volatile compounds evaluated, milk from grazing cows contained lower levels of 2-butanone than milk from nongrazing cows, and milk from both farms showed spikes for heptanal in UHT samples and spikes for butanoic, octanoic, nonanoic, and N-decanoic acids in homogenized samples. At the start of in vitro digestion, nonfat raw and pasteurized milk samples formed the largest acid clots, and organic milk clots were larger than conventional milk clots; UHT whole milk formed the smallest clots. Milk digests from grazing cows had lower levels of free fatty acids than digests from nongrazing cows. In vitro proteolysis was similar in milk from both farms and resulted in 85 to 95% digestibility. Overall, milk from organic/grass-fed and conventional herds responded in similar ways to typical homogenization and heat processing used in United States dairy plants and showed only minor differences in chemical traits and in vitro digestion. Findings from this research enhance our knowledge of the effect of processing on the quality traits and digestibility of milk from organic/pasture-fed and confined conventional herds and will help health-conscious consumers make informed decisions about dairy selections. PMID- 28624285 TI - Short communication: beta-Lactam resistance and vancomycin heteroresistance in Staphylococcus spp. isolated from bovine subclinical mastitis. AB - The use of antimicrobial agents has led to the emergence of resistant bacterial strains over a relatively short period. Furthermore, Staphylococcus spp. can produce beta-lactamase, which explains the survival of these strains in a focus of infection despite the use of a beta-lactam antibiotic. The aim of this study was to evaluate the resistance of Staphylococcus spp. isolated from bovine subclinical mastitis to oxacillin and vancomycin (by minimum inhibitory concentration) and to detect vancomycin heteroresistance by a screening method. We also evaluated beta-lactamase production and resistance due to hyperproduction of this enzyme and investigated the mecA and mecC genes and performed staphylococcal cassette chromosome mec typing. For this purpose, 181 Staphylococcus spp. isolated from mastitis subclinical bovine were analyzed. Using the phenotypic method, 33 (18.2%) of Staphylococcus spp. were resistant to oxacillin. In contrast, all isolates were susceptible to vancomycin, and heteroresistance was detected by the screening method in 13 isolates. Production of beta-lactamase was observed in 174 (96%) of the Staphylococcus spp. isolates. The mecA gene was detected in 8 isolates, all of them belonging to the species Staphylococcus epidermidis, and staphylococcal cassette chromosome mec typing revealed the presence of type I and type IV isolates. PMID- 28624286 TI - Genomic evaluation of age at first calving. AB - From their time of birth until their first lactation, dairy heifers incur management, health, and feed expenses while not producing milk. Much effort has been made to estimate optimal ages of first calving (AFC) for cows to reduce these costs, which can be as high as $2.50 per day, and ensure that animals are productive earlier in life. To identify AFC for 3 dairy cattle breeds (Holstein, Jersey, and Brown Swiss) that maximizes production, we retrieved phenotypic records for more than 14 million cows calving between 1997 and 2015 from the US national dairy database. The mean AFC for Holstein and Jersey has decreased by 2.4 and 2.7 mo, respectively, since 2006. When comparing the association of AFC with production and fertility traits, we found that decreased AFC was correlated with greater fertility and higher milk yield for all but the earliest group (18 to 20 mo). We also identified an unfavorable correlation of lower AFC with increasing stillbirth rates in Holstein (0.047 least squares means compared with a baseline of 24 mo) and Brown Swiss (0.062 least squares means). Finally, we identified favorable genetic correlations of lower AFC with lifetime net merit, heifer conception rate, cow conception rate, and daughter pregnancy rate in Holstein and Jersey cattle, and favorable correlations for net merit and heifer conception rate in Brown Swiss. To maximize lifetime production and reduce the effects of AFC on stillbirth, the AFC that maximizes production for Holstein and Brown Swiss is 21 to 22 mo, and for Jersey it is 20 to 21 mo. However, the effect of AFC on stillbirth reduces the benefits of calving at very young ages. Calculated genomic predicted transmitting ability for AFC showed an improvement in reliability of 20 percentage points in genomic young bulls compared with parent averages in Holstein, suggesting that genomic testing can improve selection for this trait. PMID- 28624287 TI - Variants in the 3' untranslated region of the ovine acetyl-coenzyme A acyltransferase 2 gene are associated with dairy traits and exhibit differential allelic expression. AB - The acetyl-CoA acyltransferase 2 (ACAA2) gene encodes an enzyme of the thiolase family that is involved in mitochondrial fatty acid elongation and degradation by catalyzing the last step of the respective beta-oxidation pathway. The increased energy needs for gluconeogenesis and triglyceride synthesis during lactation are met primarily by increased fatty acid oxidation. Therefore, the ACAA2 enzyme plays an important role in the supply of energy and carbon substrates for lactation and may thus affect milk production traits. This study investigated the association of the ACAA2 gene with important sheep traits and the putative functional involvement of this gene in dairy traits. A single nucleotide substitution, a T to C transition located in the 3' untranslated region of the ACAA2 gene, was used in mixed model association analysis with milk yield, milk protein yield and percentage, milk fat yield and percentage, and litter size at birth. The single nucleotide polymorphism was significantly associated with total lactation production and milk protein percentage, with respective additive effects of 6.81 +/- 2.95 kg and -0.05 +/- 0.02%. Additionally, a significant dominance effect of 0.46 +/- 0.21 kg was detected for milk fat yield. Homozygous TT and heterozygous CT animals exhibited higher milk yield compared with homozygous CC animals, whereas the latter exhibited increased milk protein percentage. Expression analysis from age-, lactation-, and parity-matched female sheep showed that mRNA expression of the ACAA2 gene from TT animals was 2.8- and 11.8-fold higher in liver and mammary gland, respectively. In addition, by developing an allelic expression imbalance assay, it was estimated that the T allele was expressed at an average of 18% more compared with the C allele in the udder of randomly selected ewes. We demonstrated for the first time that the variants in the 3' untranslated region of the ovine ACAA2 gene are differentially expressed in homozygous ewes of each allele and exhibit allelic expression imbalance within heterozygotes in a tissue-specific manner, supporting the existence of cis-regulatory DNA variation in the ovine ACAA2 gene. This is the first study reporting differential allelic imbalance expression of a candidate gene associated with milk production traits in dairy sheep. PMID- 28624288 TI - Short communication: Behavioral evaluation of the analgesic effect of flunixin meglumine in lame dairy cows. AB - The objective of this study was to evaluate the effect of flunixin meglumine treatment on lameness pain in dairy cows. Twenty-four lactating Holstein cows were enrolled in the study based on visual observation of abnormal locomotion. The primary measurement endpoint was weight-shifting between the rear limbs. Weight-shifting was calculated as the standard deviation of the weight borne on the rear limbs over a 15 min period; this value correlates directly with lameness pain in dairy cows. After collecting baseline weight-bearing data, we randomly assigned cows to 1 of 2 treatment groups: 2.2 mg/kg body weight flunixin meglumine (2 mL/45 kg) or an equivalent volume of isotonic sterile saline solution. Weight-bearing data were collected from each cow at 2, 6, 12, and 24 h after a single intravenous drug treatment. Mean locomotion scores over the 2 d before treatment were 2.38/5 in the flunixin-treated group and 2.43/5 in the saline-treated control group; these values were not significantly different. Weight-shifting values were also not significantly different on either pretreatment day. Cows treated with flunixin meglumine showed significantly less weight-shifting between the rear limbs at 6, 12, and 24 h after treatment compared with saline-treated controls, providing evidence that flunixin meglumine alleviates lameness-associated pain. PMID- 28624289 TI - The effect of child, family and environmental factors on the participation of young children with disabilities. AB - BACKGROUND: While participation is essential to a child's health and well-being, little is known about participation patterns of young children with disabilities. OBJECTIVE: This study described the participation of children with disabilities under age 6, and examined the extent to which the child's factors (i.e., age, complexity of child's condition), family factors (i.e., general family functioning, income) and environmental factors (i.e., environmental helpfulness) affect participation dimensions (frequency, involvement, desire for change) in three different settings: home, daycare/preschool and community. METHODS: Cross sectional design was employed. Parents (n = 90) of children aged 1.4-6 years old (mean = 4.15, SD = 1.03) with disabilities completed the French Young Children's Participation and Environment Measure (YC-PEM) and Family Assessment Device. Descriptive statistics and multiple linear regressions were performed to describe participation patterns and identify the significant explanatory factors in each setting. RESULTS: Participation restriction, based on frequency of activities, was primarily observed in the community setting. Environmental helpfulness (resources, supports) consistently explained participation levels for at least one of the dimensions across all settings, whereas contribution of the child's factors was less evident. Family functioning had a significant effect when examining participation involvement in the community and desire for change in the home setting and, in combination with environmental helpfulness, explained 18% and 21% of the variance respectively. CONCLUSION: This study emphasizes the role of the environment in supporting participation of young children with disabilities. Findings can re-direct practitioners' attention towards modifying the environment as a primary target of intervention aimed at promoting health through participation. PMID- 28624290 TI - Feasibility of reducing differences in estimated doses in nuclear medicine between a patient-specific and a reference phantom. AB - The feasibility of reducing the differences between patient-specific internal doses and doses estimated using reference phantoms was evaluated. Relatively simple adjustments to a polygon-surface ICRP adult male reference phantom were applied to fit selected individual dimensions using the software Rhinoceros(r)4.0. We tested this approach on two patient-specific phantoms: the biggest and the smallest phantoms from the Helmholtz Zentrum Munchen library. These phantoms have unrelated anatomy and large differences in body-mass-index. Three models approximating each patient's anatomy were considered: the voxel and the polygon-surface ICRP adult male reference phantoms and the adjusted polygon surface reference phantom. The Specific Absorbed Fractions (SAFs) for internal photon and electron sources were calculated with the Monte Carlo code EGSnrc. Employing the time-integrated activity coefficients of a radiopharmaceutical (S) 4-(3-18F-fluoropropyl)-l-glutamic acid and the calculated SAFs, organ absorbed dose coefficients were computed following the formalism promulgated by the Committee on Medical Internal Radiation Dose. We compared the absorbed-dose coefficients between each patient-specific phantom and other models considered with emphasis on the cross-fire component. The corresponding differences for most organs were notably lower for the adjusted reference models compared to the case when reference models were employed. Overall, the proposed approach provided reliable dose estimates for both tested patient-specific models despite the pronounced differences in their anatomy. To capture the full range of inter individual anatomic variability more patient-specific phantoms are required. The results of this test study suggest a feasibility of estimating patient-specific doses within a relative uncertainty of 25% or less using adjusted reference models, when only simple phantom scaling is applied. PMID- 28624291 TI - Vascular lysyl oxidase over-expression alters extracellular matrix structure and induces oxidative stress. AB - INTRODUCTION: Lysyl oxidase (LOX) participates in the assembly of collagen and elastin fibres. The impact of vascular LOX over-expression on extracellular matrix (ECM) structure and its contribution to oxidative stress has been analysed. METHODS: Studies were conducted on mice over-expressing LOX (Tg), specifically in smooth muscle cells (VSMC). Gene expression was assessed by real time PCR analysis. Sirius Red staining, H2O2 production and NADPH oxidase activity were analysed in different vascular beds. The size and number of fenestra of the internal elastic lamina were determined by confocal microscopy. RESULTS: LOX activity was up-regulated in VSMC of transgenic mice compared with cells from control animals. At the same time, transgenic cells deposited more organised elastin fibres and their supernatants induced a stronger collagen assembly in in vitro assays. Vascular collagen cross-linking was also higher in Tg mice, which showed a decrease in the size of fenestrae and an enhanced expression of Fibulin-5. Interestingly, higher H2O2 production and NADPH oxidase activity was detected in the vascular wall from transgenic mice. The H2O2 scavenger catalase attenuated the stronger deposition of mature elastin fibres induced by LOX transgenesis. CONCLUSIONS: LOX over-expression in VSMC was associated with a change in the structure of collagen and elastin fibres. LOX could constitute a novel source of oxidative stress that might participate in elastin changes and contribute to vascular remodelling. PMID- 28624293 TI - Soft tissue sarcomas of the forearm, wrist and hand. AB - Soft tissue sarcoma of the forearm, wrist and hand are rare. Their benign appearance leads often to primary inadequate treatment. Due to the complex anatomy of the hand and forearm, they are challenging to treat. The two goals are to obtain wide resection of the primary tumor while preserving function. Limb sparing surgery is now the cornerstone for the treatment of most sarcomas of the forearm, hand and wrist. To achieve optimal oncological and functional outcomes, the surgical excision should be associated with early reconstructive procedures and a multidisciplinary meeting to define the treatment strategy including adjuvant medical treatments. This article outlines the current principles and presents the results of the treatment of soft tissue sarcomas with emphasis on to particularities related to their forearm, wrist and hand location. PMID- 28624292 TI - The use of non-prescription medicines during lactation: A qualitative study of community pharmacists' attitudes and perspectives. AB - BACKGROUND: Community pharmacists play a significant role in the provision of non prescription medicines. There is evidence that women self-medicate and use non prescription medicines whilst breastfeeding. Studies have demonstrated that breastfeeding women are likely to seek advice from pharmacists, presenting a unique opportunity for pharmacists to provide on-going support of these women especially in relation to the appropriate use of non-prescription medicines. OBJECTIVES: This study aimed to explore community pharmacists' attitudes and perspectives towards the use of non-prescription medicines during breastfeeding. METHODS: This exploratory study was conducted through semi-structured interviews with 30 community pharmacists in Western Australia, between July and September 2013. Transcribed data were analysed using descriptive and qualitative approaches. NVivo(r) Version 10.0 was used to organise qualitative data and quotations to facilitate thematic analysis. RESULTS: Four major themes emerged. Despite the positive attitudes and favourable perceived knowledge level, participants often found themselves in a dilemma when required to make clinical recommendations especially in situations where there was a therapeutic need for treatment but clear guidelines or evidence to suggest safety of the medicines or treatment in lactation was absent. Despite the popularity of complementary medicines, participants felt more confident in providing advice in relation to conventional over complementary medicines. Whilst medication safety is within the field of expertise of pharmacists, the absence of information and safety data was seen as a major challenge and barrier to enable pharmacists to confidently provide evidence-based recommendations. CONCLUSIONS: This study has enhanced our understanding of the attitudes and perspectives of community pharmacists towards the use of non-prescription, including complementary medicines, during breastfeeding. Future studies are warranted to confirm the safety of commonly used or requested medicines in breastfeeding. University training and continuing education for pharmacists should include the latest information available regarding the use of both conventional and complementary medicines throughout lactation. PMID- 28624294 TI - Decision aids for patients considering total joint replacement: a cost effectiveness analysis alongside a randomised controlled trial. AB - BACKGROUND: Shared decision-making (SDM) is a key priority to improve patient centred care, and can play an important role in helping patients decide whether to undergo total joint arthroplasty (TJA). Patient decision aids can support SDM; however, they may incur an upfront cost. We aimed to estimate the health and economic effects of patient decision aids for TJA. METHODS: A cost-effectiveness analysis of a randomised controlled trial (RCT) with 2-year follow-up. 343 patients were recruited from two orthopedic screening clinics in Ottawa, Canada. Patients were randomized to either a patient decision aid plus surgeon preference report (decision aid) or usual care. Primary outcomes were costs (in 2014 CAD$), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER). Costs were calculated by multiplying self-reported resource use by unit costs. QALYs were calculated by mapping the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) to EuroQol 5-Dimension (EQ-5D) health utilities. Costs and QALYs were discounted at 5%. Multiple imputation was used to handle missing data, and bootstrapping was used to estimate uncertainty. RESULTS: The sample comprised 167 intervention and 167 control group patients. The decision aid arm had fewer surgeries over the 2-year period thereby incurring a negative incremental cost of -$560 (95% CI: -$1358 to $426) per patient while providing 0.05 (95% CI: -0.04 to 0.13) additional QALYs per patient. Consequently, the decision aid arm was dominant. CONCLUSION: The use of a patient decision aid was associated with fewer health care costs, while producing similar health outcomes. CLINICAL TRIAL REGISTRATION NUMBER: CT00911638 (clinicaltrials.gov). PMID- 28624295 TI - Molecular characterization of Sarcocystis spp. in intestine mucosal scrapings and fecal samples of Pampas fox (Lycalopex gymnocercus). AB - Sarcocystis spp. are obligatory intracellular protozoan parasites which can infect humans and animals. Most of Sarcocystis species were identified based on the detection of muscle cysts in different intermediate hosts (IH). Regarding to natural infection in definitive host, there are few reports which have reached to determining species of Sarcocystis. The present work was aimed to studying the occurrence of Sarcocystis spp. (oocysts and sporocysts) in mucosal scrapings of small intestine and fecal samples of one the most abundant wild canids from South America, Lycalopex gymnocercus (Pampas fox), and to identify the Sarcocystis spp. using molecular tools. A total of 131 free-living L. gymnocercus were sampled in rural areas located in several departments from Buenos Aires province, Argentina. Fecal samples from all the animals and 33 small intestines were analyzed. Fecal and mucosal scrapings samples were analyzed by sugar flotation method and once oocysts or sporocysts were detected, sedimentation was performed and DNA extracted with a commercial kit. A PCR was conducted using primers targeting a fragment of the 18S rRNA gene and the amplicons were purified and sequenced. Of the total Pampas foxes analyzed, 23 (17.6%) had Sarcocystis spp. oocysts/sporocysts in fecal and/or mucosal samples. Sarcocystis spp. sporocysts were detected in 13.0% (17/131) of fecal samples and in 39.4% (13/33) of mucosal samples by the initial sugar flotation. Twenty one L. gymnocercus samples were processed by DNA extraction and PCR. Molecular identification of Sarcocystis spp. infection was successfully achieved in 14 foxes and was distributed as follows: 4.6% S. cruzi (6/131), 3.8% Sarcocystis spp. using birds as IH (S. albifronsi and S. anasi among others, 5/131), 0.8% S. tenella (1/131) and 1.5% (2/131) with low homology (97%) with S. miescheriana. In one fecal sample with spherical oocysts, the sequencing results showed a 100% sequence identity with Hammondia heydorni. The results show that the mucosal scrapings are the eligible sample to identify prevalence and to proceed with species identification. Lycalopex gymnocercus is suggested as definitive host for S. cruzi, S. tenella and probably various Sarcocystis spp. using birds as intermediate hosts as well as for H. heydorni. PMID- 28624297 TI - Aptasensors for quantitative detection of Salmonella Typhimurium. AB - Salmonella is one of the most frequent causes of food borne infectious disease. Among nearly 2500 documented serotypes are reported, Salmonella Typhimurium is the number one serotype associated with salmonellosis worldwide. Many different methods have been developed for the detection and quantification of S. typhimurium. Most of these assays are usually expensive, time consuming and require difficult sample preparation steps. Therefore, it is necessary to develop rapid, robust, cost-effective and sensitive alternative detection methods. In the last years, aptasensors, used for detection of S. typhimurium in different samples. In this review, recent advances and applications of aptasensors for the detection and quantification of S. typhimurium in details have been summarized. PMID- 28624296 TI - A refined DNA methylation detection method using MspJI coupled quantitative PCR. AB - DNA methylation is a highly conserved epigenetic modification with critical roles ranging from protection against phage infection in bacteria to the regulation of gene expression in mammals. DNA methylation at specific sequences can be measured by using methylation dependent or sensitive restriction enzymes coupled to semi- or quantitative PCR (MD-qPCR). This study reports a refined MD-qPCR method for detecting gain or loss of DNA methylation at specific sites through the specific use of MspJI or HpaII, respectively. By employing varying concentrations of DNA with methylation ranging from 0 to 100%, our data provide evidence that compared to HpaII, MspJI increases the sensitivity and accuracy of detecting relative DNA methylation gains by MD-qPCR. We also show that the MspJI-coupled MD-qPCR can accurately determine the percent gain in DNA methylation at the Sall4 enhancer and is more sensitive than HpaII in detecting relative gains in DNA methylation at the Oct4 proximal enhancer during embryonic stem cell (ESC) differentiation. The high specificity and sensitivity of this targeted approach increases its potential as a diagnostic tool to detect relatively smaller gains in DNA methylation at specific sites from limited amounts of sample. PMID- 28624298 TI - Processes and experiences of Portugal's international recruitment scheme of Colombian physicians: Did it work? AB - The Portuguese Ministry of Health performed five international recruitment rounds of Latin American physicians due to the need for physicians in certain geographic areas of the country and in some specialties, as a temporary solution to shortages. Among these recruitments is that of Colombian physicians in 2011 that was the largest of the five groups. This paper presents an evaluation of the international recruitment procedure of Colombian physicians based on the criteria of procedural outcomes and health system outcomes. The methodology used is qualitative, based on semi-structured interviews with key informants and Colombian physicians recruited in Portugal and also on documentary analysis of secondary sources. International recruitment of Colombian physicians coincided with a period of political change and severe economic crisis in Portugal that caused some problems in the course of this recruitment, mainly family reunification in the later group of Colombian physicians and non-compliance of the salary originally agreed upon. Furthermore, due to the continuous resignations of Colombian physicians throughout the 3-year contract, procedural outcomes and health system outcomes of this international recruitment were not fulfilled and therefore the expected results to meet the temporary needs for medical personnel in some areas of the country were not accomplished. PMID- 28624299 TI - Systemic large B-cell non-Hodgkin lymphoma presenting as a massive hemorrhagic intracerebral mass. PMID- 28624300 TI - Evaluating current and recent fellows' perceptions on the interventional radiology residency: Results of a United States survey. AB - PURPOSE: To evaluate current and recent interventional radiology (IR) fellows' perceptions on the new integrated IR residency. MATERIALS AND METHODS: An anonymous, web-based survey was distributed to 82 current and recent IR fellows across the Unites States. The survey contained 15 questions, most of which were based on a five-point Likert scale. The survey was open for a three-week period in September 2015. The results were analyzed by two trainees and three IR attending physicians. RESULTS: Sixty-four current or recent former IR fellows completed the survey (response rate 78%). Of these 18% decided to pursue a career in IR by the end of their third year of medical school. A majority believed that the integrated IR residency will be an improved IR training pathway (62%). Based on current medical school curricula, 74% either disagreed or strongly disagreed that IR residency applicants will be ready to select such a pathway by the end of their third year of medical school. CONCLUSIONS: Most current and recent IR fellows surveyed chose IR during their final year of medical school or during residency. Most respondents believe that the integrated IR residency will be an improved IR training pathway. PMID- 28624301 TI - Ultrasound Elastography With Imaging: Overcoming Emerging Technology Reimbursement Challenges. PMID- 28624302 TI - Implementation of Machine-Based Protocols to Standardize Performance of Diagnostic Ultrasound in a Six-Hospital System. PMID- 28624303 TI - The Importance of Brand Name. PMID- 28624304 TI - The $100,000 vaccine challenge: Another method of promoting anti-vaccination pseudoscience. PMID- 28624305 TI - Durability of immunogenicity and strain coverage of MenBvac, a meningococcal vaccine based on outer membrane vesicles: Lessons of the Normandy campaign. AB - OBJECTIVES: MenBvac(r) is an outer membrane vesicle (OMV)-based meningococcal vaccine. From 2006 to 2012, it was used to control a clonal B outbreak in Normandy (France). We aimed to analyse the durability of the response against the epidemic strain and coverage beyond the vaccine strain. These data should help to optimize the use of OMV-containing vaccines, such as the new 4CMenB/Bexsero(r) recombinant vaccine. METHODS: Serum bactericidal activity (SBA) was measured in two cohorts of children who received their first dose of MenBvac(r) at 1-5years of age and accepted to provide a blood sample either one or four years after a 2+1+1 schedule. All sera were tested against the outbreak strain. Sera from responder subjects were also tested against 12 additional B or C strains which were chosen to entirely, partially, or not at all match the two variable regions (VR1 and VR2) of the PorA vaccine strain. RESULTS: Only 47.9% and 31.3% of subjects showed an SBA titre consistent with protection one and four years, respectively, after the last boost. Protective SBA titres were observed in all sera against B or C strains that entirely matched P1.7,16, and was high (75-100%) for all but one strain that partially matched VR1 or VR2. Extrapolating our data to the OMV component of 4CMenB/Bexsero(r) suggests that 14.5% of the current B strains would be covered based on PorA matching to the OMV component of 4CMenB/Bexsero(r) (regardless of the coverage of the three other vaccine components). CONCLUSIONS: Our data confirm that OMV-based vaccines elicit short lasting SBA titres and may require repeated booster injections. However, strain coverage may be greater than expected. PMID- 28624306 TI - Preclinical assessment of safety of maternal vaccination against respiratory syncytial virus (RSV) in cotton rats. AB - Maternal immunization directed to control RSV infection in newborns and infants is an appealing vaccination strategy currently under development. In this work we have modeled maternal vaccination against RSV in cotton rats (CR) to answer two fundamental questions on maternal vaccine safety. We tested (i), whether a known, unsafe RSV vaccine (i.e., FI-RSV Lot 100 vaccine) induces vaccine enhanced disease in the presence of passively transferred, RSV maternal immunity, and (ii) whether the same FI-RSV vaccine could induce vaccine enhanced disease in CR litters when used to immunize their RSV-primed mothers. Our data show that FI-RSV immunization of pups with subsequent RSV infection results in vaccine-enhanced disease independent of whether the pups were born to RSV-seropositive or RSV seronegative mothers, and that FI-RSV immunization of RSV-seropositive mothers does not present a health risk to either the mother or the infant. Our study also raises a novel concern regarding infant immunization, namely that "safe" RSV vaccines (e.g., live RSV administered intramuscularly) may induce vaccine enhanced disease in RSV-infected pups born to seropositive mothers. Finally, we describe for the first time a sharp decrease in RSV neutralizing antibody titers in immunized seropositive CR at the time of delivery. This decline may reflect maternal immune suppression, potentially pinpointing a window of increased vulnerability to RSV infection that could be alleviated by effective immunization of expectant mothers. PMID- 28624308 TI - Efficient heterologous expression, functional characterization and molecular modeling of annular seabream digestive phospholipase A2. AB - Here we report the cDNA cloning of a phospholipase A2 (PLA2) from five Sparidae species. The deduced amino acid sequences show high similarity with pancreatic PLA2. In addition, a phylogenetic tree derived from alignment of various available sequences revealed that Sparidae PLA2 are closer to avian PLA2 group IB than to mammals' ones. In order to understand the structure-function relationships of these enzymes, we report here the recombinant expression in E.coli, the refolding and characterization of His-tagged annular seabream PLA2 (AsPLA2). A single Ni-affinity chromatography step was used to obtain a highly purified recombinant AsPLA2 with a molecular mass of 15kDa as attested by gel electrophoresis and MALDI-TOF mass spectrometry data. The enzyme has a specific activity of 400U.mg-1 measured on phosphatidylcholine at pH 8.5 and 50 degrees C. The enzyme high thermo-activity and thermo-stability make it a potential candidate in various biological applications. The 3D structure models of these enzymes were compared with structures of phylogenetically related pancreatic PLA2. By following these models and utilizing molecular dynamics simulations, the resistance of the AsPLA2 at high temperatures was explained. Using the monomolecular film technique, AsPLA2 was found to be active on various phospholipids spread at the air/water interface at a surface pressure between 12 and 25dyncm-1. Interestingly, this enzyme was shown to be mostly active on dilauroyl-phosphatidylglycerol monolayers and this behavior was confirmed by molecular docking and dynamics simulations analysis. The discovery of a thermo active new member of Sparidae PLA2, provides new insights on structure-activity relationships of fish PLA2. PMID- 28624309 TI - Letter to the editor re: "Glasgow prognostic score is a prognosis predictor for patients with endometrial cancer" [M. Saijo et al./European Journal of Obstetrics & Gynecology and Reproductive Biology 210 (2017) 355-359]. PMID- 28624307 TI - Safety and immune response to a challenge dose of hepatitis B vaccine in healthy children primed 10years earlier with hexavalent vaccines in a 3, 5, 11-month schedule: An open-label, controlled, multicentre trial in Italy. AB - BACKGROUND AND AIMS: The strategy of vaccinating infants to prevent hepatitis B virus infection in adolescence or adulthood requires durable immunity. This study investigated responses to a challenge dose of monovalent hepatitis B vaccine in children primed with three doses of either Hexavac(r) or Infanrix hexa(r) 10years earlier during infancy. METHODS: This open-label, controlled, multicentre study conducted in Italy, enrolled 751 healthy pre-adolescents (aged 11-13years) who were given either Hexavac (n=409) or Infanrix hexa (n=342) at 3, 5 and 11months of life. All participants received a challenge dose of a monovalent hepatitis B vaccine (HBVaxPro(r) 5ug). The concentrations of antibodies to hepatitis B surface antigen (anti-HBs) were measured before and 1month after the challenge dose. The analysis was descriptive and no formal hypothesis was tested. RESULTS: One month post-challenge, 331 participants in the Hexavac cohort [83.6%, 95% CI: 79.6; 87.1] and 324 in the Infanrix hexa cohort [96.4%, 95% CI: 93.8; 98.1] had anti-HBs concentrations >=10mIU/mL. Before the challenge dose, an anti-HBs concentration of >=10mIU/mL was found in 94 children in the Hexavac cohort [23.9%, 95% CI: 19.7; 28.4] and in 232 children in the Infanrix hexa cohort [69%, 95% CI: 63.8; 74.0]. Among children with a pre-challenge anti-HBs concentration of <10mIU/mL, 236 [78.7%, 95% CI: 73.6; 83.2] in the Hexavac cohort and 92 [88.5%, 95% CI: 80.7; 93.9] in the Infanrix hexa cohort achieved protective anti HBs antibody concentrations. No evidence of active hepatitis B disease was observed in either group, and the HBVaxPro challenge dose was well tolerated. CONCLUSIONS: These data confirm that immune memory persists in a high percentage of children (>80%) at least 10years after a two-dose primary and booster vaccination schedule with a hexavalent vaccine (Hexavac or Infanrix hexa). TRIAL REGISTRATION: EudraCT Number: 2013-001602-28; clinicaltrials.gov: NCT02012998. PMID- 28624310 TI - Novel ultrasound finding of a fetus with Hirschsprung's disease: A caliber change sign. PMID- 28624311 TI - Stroke after pregnancy disorders. PMID- 28624312 TI - Non-lens-based surgical techniques for presbyopia correction. AB - INTRODUCTION: Presbyopia is the most prevalent refractive error. With a progressive aging population, its surgical correction is an important challenge for the ophthalmology community, as well as the millions of patients who suffer from it, and who are increasingly demanding alternatives to its correction with glasses or contact lenses. MATERIAL AND METHODS: A review is presented with a synthesised discussion on the pathophysiological theories of presbyopia and an updated and analytical description of the non-lens involvement surgical techniques used to treat presbyopia. RESULTS: Corneal procedures include various types of corneal implants and photo-ablative techniques that generate a multifocal cornea, or monovision. Scleral procedures exert a traction on supralenticular sclera that supposedly would improve the amplitude of accommodation. CONCLUSIONS: None of the techniques are able to completely eliminate the need for near -vision glasses, but many of them manage to improve the refractive status of the patients. More studies with rigorous and standardised methods and longer follow-up are needed to evaluate the changes in the near vision of the patients, in order to corroborate the real and practical usefulness of many of these techniques. PMID- 28624313 TI - Eplerenone, a new treatment for an old problem: Retinitis pigmentosa with recalcitrant macular edema. AB - CASE REPORT: The case involves a 35-year-old man, with a history of retinitis pigmentosa, who presented with a bilateral cystoid macular oedema associated with bilateral epiretinal membrane, which was resistant to treatment with oral acetazolamide and intravitreal bevacizumab. The treatment with oral eplerenone was able to improve the visual acuity and macular thickness of this patient. DISCUSSION: A variety of treatments have been proposed for the management of cystoid macular oedema, associated with retinitis pigmentosa, with variable results. The treatment with oral eplerenone might be a good option for the control of this condition. PMID- 28624314 TI - Anatomical and refractive outcomes in patients with treated retinopathy of prematurity. AB - OBJECTIVE: To describe the anatomical and refractive outcomes after treatment with intravitreal bevacizumab or laser in a patient cohort with retinopathy of prematurity (ROP). METHODS: A multicentre, prospective, and observational study was performed on patients with ROP treated at Hospital Roberto del Rio. Those patients with less than 6months of follow-up were excluded. Cases with posterior zone II, zone I ROP, and aggressive posterior ROP (AP-ROP) were treated with intravitreal bevacizumab. All other patients were treated with laser. Follow-up was performed every 3 months, and included fondo evaluation, refraction, and Teller tests. RESULTS: The treated group included 144 eyes of 72 patients, of whom 49 were treated with laser and 23 with intravitreal bevacizumab. One (1.4%) patient from the laser group progressed to stage 4b retinal detachment and required bilateral vitrectomy. Of the remainder, 45 cases had type 1 ROP, 16 had threshold disease, and 11 had AP-ROP. The median of gestational age was 26 weeks (range 23-30), and median of birth weight was 800g (range 405-1350). Median follow-up was 10 months (range 6-8). The Teller test median was 3.2 cycles/cm (range 0.32-13). There were 16 (22%) cases with a myopic refraction of -6 D or more. The sphere median was -1.75 D (range -16.00 to +3.50 D) and the cylindrical median was 0.00 (range -4.5 to +1.5 D). Anatomical success was achieved in 71 (98.6%) of patients. CONCLUSION: Treatment with laser or intravitreal bevacizumab is a highly successful primary treatment for ROP. Anatomical success can be achieved in most cases. Treated patients develop frequent and severe refractive defects, which should be corrected. Vision outcome, measured using the Teller preferential test, shows good results. PMID- 28624315 TI - Coexisting Vocal Fold Polyps and Sulcus Vocalis: Coincidence or Coexistence? Characteristics of 14 Patients. AB - OBJECTIVE: The study aimed (1) to evaluate the prevalence of sulcus vocalis (SV) coexisting with vocal fold polyp (SV-VFP), and (2) to determine the effect of their coexistence on voice quality. STUDY DESIGN: This is a retrospective cohort study in a tertiary referral center. METHODS: The medical records of all patients who underwent micro direct laryngoscopy due to VFPs between January 2013 and April 2015 were reviewed. Patients with SV-VFP were identified and data of their demographics, medical history, habits, preoperative and intraoperative laryngeal findings, and pre- and postoperative GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) score, and compared with the data of patients with solitary VFPs (S-VFPs). RESULTS: Eighty-nine patients were diagnosed with VFPs, 14 (15.7%) of whom were diagnosed with SV-VFPs. Patients with SV-VFPs had significantly lower incidence of concurrent leukoplakia (P = 0.01), higher incidence of contralateral vocal fold lesions (P = 0.04), increased voice roughness score postoperatively (P = 0.01) on the GRBAS score, and had a lower rate of cigarette smoking (P = 0.02) compared with patients with S-VFPs. CONCLUSIONS: The possibility of a hidden SV should be considered when detecting VFPs, particularly in patients with contralateral vocal fold lesions and without cigarette smoking history. Because the group of patients with SV-VFP presented with unique features, we suspect that the coexistence of VFPs and SVs is not incidental and that SVs may contribute to the formation of VFPs, possibly by alternating glottic airflow. PMID- 28624316 TI - Reversal learning in C58 mice: Modeling higher order repetitive behavior. AB - Restricted, repetitive behaviors are diagnostic for autism and prevalent in other neurodevelopmental disorders. These behaviors cluster as repetitive sensory-motor behaviors and behaviors reflecting resistance to change. The C58 mouse strain is a promising model for these behaviors as it emits high rates of aberrant repetitive sensory-motor behaviors. The purpose of the present study was to extend characterization of the C58 model to resistance to change. This was done by comparing C58 to C57BL/6 mice on a reversal learning task under either a 100% or 80%/20% probabilistic reinforcement schedule. In addition, the effect of environmental enrichment on performance of this task was assessed as this rearing condition markedly reduces repetitive sensory-motor behavior in C58 mice. Little difference was observed between C58 and control mice under a 100% schedule of reinforcement. The 80%/20% probabilistic schedule of reinforcement generated substantial strain differences, however. Importantly, no strain difference was observed in acquisition, but C58 mice were markedly impaired in their ability to reverse their pattern of responding from the previously high density reinforcement side. Environmental enrichment did not impact acquisition under the probabilistic reinforcement schedule, but enriched C58 mice performed significantly better than standard housed C58 mice in reversal learning. Thus, C58 mice exhibit behaviors that reflect both repetitive sensory motor behaviors as well as behavior that reflects resistance to change. Moreover, both clusters of repetitive behavior were attenuated by environmental enrichment. Such findings, along with the reported social deficits in C58 mice, increase the translational value of this mouse model to autism. PMID- 28624319 TI - The Efficacy of Lenvatinib and Everolimus in Chromophobe-type Non-Clear-Cell Renal Cell Carcinoma: A Case Report and Literature Review. PMID- 28624318 TI - Differential urinary metabolites related with the severity of major depressive disorder. AB - Major depressive disorder (MDD) is a common mental disorder that affects a person's general health. However, there is still no objective laboratory test for diagnosing MDD. Here, an integrated analysis of data from our previous studies was performed to identify the differential metabolites in the urine of moderate and severe MDD patients. A dual platform approach (NMR spectroscopy and GC-MS) was used. Consequently, 14 and 22 differential metabolites responsible for separating moderate and severe MDD patients, respectively, from their respective healthy controls (HCs) were identified. Meanwhile, the moderate MDD-specific panel (N-Methylnicotinamide, Acetone, Choline, Citrate, vanillic acid and azelaic acid) and severe MDD-specific panel (indoxyl sulphate, Taurine, Citrate, 3 hydroxyphenylacetic acid, palmitic acid and Lactate) could discriminate moderate and severe MDD patients, respectively, from their respective HCs with high accuracy. Moreover, the differential metabolites in severe MDD were significantly involved in three metabolic pathways and some biofunctions. These results showed that there were divergent urinary metabolic phenotypes in moderate and severe MDD patients, and the identified potential urinary biomarkers might be useful for future developing objective diagnostic tests for MDD diagnosis. Our results could also be helpful for researchers to study the pathogenesis of MDD. PMID- 28624317 TI - Modulatory effects of Ampicillin/Sulbactam on glial glutamate transporters and metabotropic glutamate receptor 1 as well as reinstatement to cocaine-seeking behavior. AB - Glutamatergic system has an important role in cocaine-seeking behavior. Studies have reported that chronic exposure to cocaine induces downregulation of glutamate transporter-1 (GLT-1) and cystine/glutamate exchanger (xCT) in the central reward brain regions. Ceftriaxone, a beta-lactam antibiotic, restored GLT 1 expression and consequently reduced cue-induced reinstatement of cocaine seeking behavior. In this study, we investigated the reinstatement to cocaine (20mg/kg, i.p.) seeking behavior using a conditioned place preference (CPP) paradigm in male alcohol-preferring (P) rats. In addition, we investigated the effects of Ampicillin/Sulbactam (AMP/SUL) (200mg/kg, i.p.), a beta-lactam antibiotic, on cocaine-induced reinstatement. We also investigated the effects of AMP/SUL on the expression of glial glutamate transporters and metabotropic glutamate receptor 1 (mGluR1) in the nucleus accumbens (NAc) core and shell and the dorsomedial prefrontal cortex (dmPFC). We found that AMP/SUL treatment reduced cocaine-triggered reinstatement. This effect was associated with a decrease in locomotor activity. Moreover, GLT-1 and xCT were downregulated in the NAc core and shell, but not in the dmPFC, following cocaine-primed reinstatement. However, cocaine exposure increased the expression of mGluR1 in the NAc core, but not in the NAc shell or dmPFC. Importantly, AMP/SUL treatment normalized GLT-1 and xCT expression in the NAc core and shell; however, the drug normalized mGluR1 expression in the NAc core only. Additionally, AMP/SUL increased the expression of GLT-1 and xCT in the dmPFC as compared to the water naive group. These findings demonstrated that glial glutamate transporters and mGluR1 in the mesocorticolimbic area could be potential therapeutic targets for the attenuation of reinstatement to cocaine-seeking behavior. PMID- 28624320 TI - Prognostic Value of the VHL, HIF-1alpha, and VEGF Signaling Pathway and Associated MAPK (ERK1/2 and ERK5) Pathways in Clear-Cell Renal Cell Carcinoma. A Long-Term Study. AB - BACKGROUND: The prognostic value of molecular markers in renal cell carcinoma has been investigated in several studies. Although their value is still not confirmed, various proteins are important. We describe the effect on long-term survival of the status of the von Hippel-Lindau (VHL) hypoxia-inducible factor 1 alpha (HIF1-alpha) signaling pathway as well as associated mitogen-activated protein kinase (extracellular signal-regulated kinase [ERK]1/2 and ERK5). PATIENTS AND METHODS: A prospective, longitudinal cohort study was conducted with 50 patients diagnosed with clear-cell renal cell carcinoma to analyze VHL mutations and hypermethylation as well as VHL, HIF1-alpha, vascular endothelial growth factor (VEGF), ERK1/2, and ERK5 protein expression. Overall survival (OS), disease-specific survival (DSS), and progression- or recurrence-free survival (PFS) were analyzed using the Kaplan-Meier method. Mantel-Haenszel was used for comparisons, and Cox proportional risk models were also constructed. RESULTS: Follow-up was 66.9 months. There were 23 (46.0%) deaths, of which 17 (73.9%) were caused by the tumor. Mean periods were 85.6 months for OS and 94.3 months for DSS. A total of 22 (44.0%) patients showed progression (PFS, 78.1 months). VHL expression (P = .045) and > 10% of HIF1-alpha expression (P = .034) were associated with greater OS. DSS was greater in patients without VHL methylation (P = .012), with > 10% HIF1-alpha expression (P = .037), or with ERK5 protein underexpression. Greater PFS was associated with absence of VHL methylation (P = .045), presence of VHL expression (P < .0001), HIF1-alpha expression > 10% (P = .04), and ERK5 protein underexpression (P = .011). The presence of VHL mutation and/or methylation and VEGF expression had no prognostic value. Fuhrman nuclear grade and Tumor, Node, Metastases (TNM) stage were the only variables that remained in the Cox model. CONCLUSION: The HIF1-alpha and ERK5 pathway has prognostic value. Patients with no VHL or HIF1-alpha expression and ERK5 overexpression had a worse course of disease. VHL or VEGF status had no prognostic value. Only TNM stage and Fuhrman nuclear grade remained in the Cox model and, therefore, are still essential in prognostic biomarker panels. PMID- 28624321 TI - Does any association exist between Chronic Obstructive Pulmonary Disease and Erectile Dysfunction? The DECODED study. AB - INTRODUCTION: Erectile dysfunction (ED) is the inability to achieve or maintain an erection for satisfactory sexual activity. Recent studies have shown an association between ED and chronic obstructive pulmonary disease (COPD). However, this issue is often ignored. We aimed to evaluate the ED prevalence in COPD patients and its risk factors and to study the impact of dyspnea in sexual activity. METHODS: Cross-sectional study that included sexually active male patients with COPD. The International Index of Erectile Function (IIEF-5) questionnaire evaluated ED and the Respiratory Experiences with Sexuality Profile (RESP) was used to evaluate the impact of dyspnea on sexual activity. Risk factors for mild-moderate or moderate ED were determined using logistic regression. RESULTS: 84 patients were consecutively assessed for eligibility, 67 were included (median age: 65 years, 13% never-smokers). Twenty two percent had COPD 2011-GOLD A; 22% GOLD B, 14% GOLD C and 42% GOLD D. Fifty-eight patients (87%) had some degree of ED: 26 (45%) mild, 20 (34%) mild-moderate and 12 (21%) moderate ED. ED occurred in all GOLD stages of COPD, mainly in GOLD B and D stages. Higher CAT score was independently associated to mild-moderate/moderate ED. Most patients (85%) reported dyspnea during their sexual activity but 72% had never talked about it with their physician. CONCLUSIONS: ED is highly prevalent among COPD patients and it is more severe in patients with higher CAT scores. Dyspnea affects their sexual activity but this is not a topic often discussed between patients and doctors, something which needs to be improved. PMID- 28624322 TI - Assessing pragmatic communication in children with Down syndrome. AB - PURPOSE: Successful communication depends on language content, language form, and language use (pragmatics). Children with Down syndrome (DS) experience communication difficulties, however little is known about their pragmatic profile, particularly during early school years. The purpose of the present study was to explore the nature of pragmatic communication in children with DS. METHOD: Twenty-nine six-year-old children with DS were assessed, in the areas of 1) initiation, 2) scripted language, 3) understanding context and 4) nonverbal communication, as reported by children's parents via the Children's Communication Checklist-2 (Bishop, 2003). Additionally, the relationships between pragmatics and measures of vocabulary, nonverbal mental ability and social functioning were explored. RESULTS: Children with DS were impaired relative to norms from typically developing children in all areas of pragmatics. A profile of relative strengths and weaknesses was found in the children with DS; the area of nonverbal communication was significantly stronger, while the area of understanding context was significantly poorer, relative to the other areas of pragmatics assessed in these children. Relationships between areas of pragmatics and other linguistic areas, as well as aspects of vocabulary and social functioning were observed. CONCLUSIONS: By the age of six children with DS experience significantly impaired pragmatic communication, with a clear profile of relative strengths and weaknesses. The study highlights the need to teach children with DS pragmatic skills as a component of communication, alongside language content and form. PMID- 28624323 TI - Postreceptor Neuronal Loss in Intermediate Age-related Macular Degeneration. AB - PURPOSE: To investigate the relationship between ganglion cell complex (GCC) thickness and photoreceptor alterations in eyes with intermediate age-related macular degeneration (AMD). DESIGN: Retrospective case-control study. METHODS: We collected data from 68 eyes with intermediate AMD from 68 patients with spectral domain optical coherence tomography (SDOCT) imaging. A control group of 50 eyes from 50 healthy subjects was included for comparison. Our main outcome measures for comparison between groups were (1) the average and minimum GCC thickness and (2) the "normalized" reflectivity of the ellipsoid zone (EZ) en face image. RESULTS: The average and minimum GCC thicknesses were thinner in AMD patients (69.54 +/- 9.30 MUm and 63.22 +/- 14.11 MUm, respectively) than in healthy controls (78.57 +/- 6.28 MUm and 76.28 +/- 6.85 MUm, P < .0001 and P < .0001, respectively). Agreement was found to be excellent in the "normalized" EZ reflectivity assessment (intraclass correlation coefficient = 0.986, coefficient of variation = 1.11). The EZ "normalized" reflectivity was 0.67 +/- 0.11 in controls and 0.61 +/- 0.09 in the AMD group (P = .006). In univariate analysis, EZ "normalized" reflectivity was found to have a significant direct relationship with average (P < .0001) and minimum (P < .0001) GCC thickness in AMD patients, but not in controls (P = .852 and P = .892, respectively). CONCLUSIONS: Eyes with intermediate AMD exhibit GCC thinning, as well as a reduced EZ "normalized" reflectivity, and these parameters are correlated. This study supports the concept of postreceptor retinal neuronal loss as a contributor to retinal thinning in intermediate AMD. PMID- 28624324 TI - Risk Factors for Rapid Glaucoma Disease Progression. AB - PURPOSE: To determine the intraocular and systemic risk factor differences between a cohort of rapid glaucoma disease progressors and nonrapid disease progressors. DESIGN: Retrospective case-control study. METHODS: Setting: Five private ophthalmology clinics. STUDY POPULATION: Forty-eight rapidly progressing eyes (progression >=1 dB mean deviation [MD]/year) and 486 non-rapidly progressing eyes (progression <1 dB MD/year). Patients were eligible if they had a diagnosis of glaucoma from their ophthalmologist and if they had greater than or equal to 5 Humphrey visual fields (24-2) conducted. Patients were excluded if their sequential visual fields showed an improvement in MD or if they had greater than 5 dB MD variation in between visits. Patients with obvious neurologic fields were excluded. OBSERVATION PROCEDURE: Clinical and demographic data (age, sex, central corneal thickness [CCT], intraocular pressure [IOP], refraction, medications), as well as medical, surgical, and ocular histories, were collected. MAIN OUTCOME MEASURES: Risk factor differences between the cohorts were measured using the independent t test, Wald chi2, and binomial regression analysis. RESULTS: Rapid progressors were older, had significantly lower CCT and baseline IOPs, and were more likely to have pseudoexfoliation, disc haemorrhages, ocular medication changes, and IOP-lowering surgery. They also had significantly higher rates of cardiovascular disease and hypotension. Subjects with cardiovascular disease were 2.33 times more likely to develop rapidly progressive glaucoma disease despite significantly lower mean and baseline IOPs. CONCLUSION: Cardiovascular disease is an important risk factor for rapid glaucoma disease progression irrespective of IOP control. PMID- 28624325 TI - Treat-and-Extend Therapy Using Aflibercept for Neovascular Age-related Macular Degeneration: A Prospective Clinical Trial. AB - PURPOSE: To determine the efficacy and durability of aflibercept used in a treat and-extend (TAE) regimen for neovascular age-related macular degeneration (NVAMD). DESIGN: Multicenter, prospective, open label, noncomparative, interventional study. METHODS: Forty eyes of 40 patients with treatment-naive NVAMD were managed with a TAE regimen of intravitreal aflibercept. The main endpoints were the change in mean and median best-corrected visual acuity from baseline at years 1 and 2. Other endpoints included mean number of annual injections and treatment intervals. RESULTS: Thirty-five (87.5%) and 31 patients (77.5%) completed year 1 and year 2, respectively. The mean letter gain was 7.2 (P < .001) and 2.4 (P = .269) letters at 1 and 2 years, respectively, from a mean baseline of 58.9 letters (20/63 Snellen equivalent). The median visual gain was 11.5 and 7.5 letters at 1 and 2 years, respectively, from a median baseline of 59.0 letters (20/63 Snellen equivalent). The mean number of injections was 8.0 and 6.5 during the first and second year, respectively. Twelve-week or longer treatment intervals were used in 35% and 38% of patients during the first- and second-year time points, respectively. CONCLUSION: Intravitreal aflibercept TAE therapy led to significant visual improvement in eyes with NVAMD at 1 year, with some loss in the visual gains at the end of year 2 that was not related to loss of exudative control. TAE therapy with aflibercept is a rational strategy to reduce treatments and clinic evaluations over 2 years with satisfactory outcomes. PMID- 28624326 TI - Randomized Trial on Illuminated-Microcatheter Circumferential Trabeculotomy Versus Conventional Trabeculotomy in Congenital Glaucoma. AB - PURPOSE: To compare 1-year outcomes of illuminated microcatheter-assisted circumferential trabeculotomy (IMCT) vs conventional partial trabeculotomy (CPT) for primary congenital glaucoma (PCG). DESIGN: Randomized clinical trial. METHODS: Forty eyes of 31 patients with unilateral or bilateral primary congenital glaucoma aged less than 2 years were randomized to undergo IMCT (20 eyes) or CPT (20 eyes). Primary outcome measure was intraocular pressure (IOP) reduction. The success criterion was defined as IOP <= 12 mm Hg without and with antiglaucoma medications (absolute success and qualified success, respectively). RESULTS: The mean age of our study population was 8.35 +/- 1.2 months. The mean preoperative IOP was 24.70 +/- 3.90 mm Hg in the IMCT group and 24.60 +/- 3.31 mm Hg in the CPT group. Both groups were comparable with respect to preoperative IOP, corneal clarity, corneal diameter, vertical cup-to-disc ratio, and refractive error. In the IMCT group, 360-degree cannulation was achieved in 80% (16/20) of eyes. For the IMCT group and CPT groups, respectively, the absolute success rates were 80% (16/20) and 60% (12/20) (P < .001) and qualified success rates were 90% (18/20) and 70% (14/20) (P < .001). Both procedures produced a statistically significant reduction in IOP, and eyes undergoing IMCT achieved a lower IOP than CPT group eyes at 12 months follow-up (9.5 +/- 2.4 mm Hg and 11.7 +/- 2.1 mm Hg, respectively, P < .001). CONCLUSION: In primary congential glaucoma, illuminated microcatheter-assisted 360-degree circumferential trabeculotomy performed better than conventional partial trabeculotomy at 1 year follow-up and resulted in significantly lower IOP measurements. PMID- 28624327 TI - Many tocopherols, one vitamin E. AB - Four tocopherols are available in nature and are absorbed with the diet, but only one RRR-alpha-tocopherol satisfies the criteria of being a vitamin. The biological activity of the different tocopherols studied in the rat by the resorption-gestation test has been inconsistently extrapolated to human beings where the tocopherols have no influence on a successful pregnancy. Diminution of RRR-alpha-tocopherol intake results in diseases characterized by ataxia, whose pathogenetic mechanism, despite vigorous claims, has not been clarified. The calculation of the Daily Reference Intake (DRI), necessary to prevent disease, is based on an obsolete test, the peroxide-induced erythrocyte hemolysis, called the gold standard, but of highly questioned validity. If many epidemiological studies have given positive results, showing prevention by high vitamin E containing diets of cardiovascular events, neurodegenerative disease, macular degeneration and cancer, the clinical confirmatory intervention studies were mostly negative. On the positive side, besides preventing vitamin E deficiency diseases, vitamin E has shown efficacy as anti-inflammatory and immune boosting compound. It has also shown some efficacy in protecting against nonalcoholic hepato-steatosis. At a molecular level, vitamin E and some of its metabolites have shown capacity of regulating cell signaling and modulating gene transcription. PMID- 28624328 TI - Adenosine - from molecular mechanisms to pathophysiology. PMID- 28624329 TI - The Bebig Valencia-type skin applicators: Dosimetric study and implementation of a dosimetric hybrid technique. AB - PURPOSE: To determine the relative dose rate distribution in water for the Bebig 20 mm and 30 mm skin applicators and report results in a form suitable for potential clinical use. Results for both skin applicators are also provided in the form of a hybrid Task Group 43 (TG-43) dosimetry technique. Furthermore, the radiation leakage around both skin applicators from the radiation protection point of view and the impact of the geometrical source position uncertainties are studied and reported. METHODS AND MATERIALS: Monte Carlo simulations were performed using the MCNP 6.1 general purpose code, which was benchmarked against published dosimetry data for the Bebig Ir2.A85-2 high-dose-rate iridium-192 source, as well as the dosimetry data for the two Elekta skin applicators. Both Bebig skin applicators were modeled, and the dose rate distributions in a water phantom were calculated. The dosimetric quantities derived according to a hybrid TG-43 dosimetry technique are provided with their corresponding uncertainty values. The air kerma rate in air was simulated in the vicinity of each skin applicator to assess the radiation leakage. RESULTS AND CONCLUSIONS: Results from the Monte Carlo simulations of both skin applicators are presented in the form of figures and relative dose rate tables, and additionally with the aid of the quantities defined in the hybrid TG-43 dosimetry technique and their corresponding uncertainty values. Their output factors, flatness, and penumbra values were found comparable to the Elekta skin applicators. The radiation shielding was evaluated to be adequate. The effect of potential uncertainties in source positioning on dosimetry should be investigated as part of applicator commissioning. PMID- 28624330 TI - Minimally invasive mitral valve annuloplasty confers a long-term survival benefit compared with state-of-the-art treatment in heart failure with functional mitral regurgitation. AB - BACKGROUND: Clinical impact of the minimally invasive surgical mitral valve annuloplasty (MVA) of functional mitral regurgitation (FMR) in systolic heart failure on top of the state-of-the-art standards of care remains controversial. Therefore, we aimed to compare clinical outcomes of isolated MVA using the mini invasive videothoracoscopic approach versus the state-of-the-art (CON=conservative) treatment in patients with chronic systolic heart failure and symptomatic FMR. METHODS: The study population consisted of 379 patients (age 68.9+/-11.0years, 62.8% males) with left ventricular (LV) systolic dysfunction, symptomatic FMR and previous heart failure hospitalization. A total of 167 patients underwent undersized MVA and 212 patients were treated conservatively. A concomitant MAZE was performed in 53 (31.7%) patients. RESULTS: In the MVA group, the periprocedural and the 30-day mortality were 1.2% and 4.8%, respectively. During the median follow-up of 7.1years (IQR 3.5-9.8years) a total of 74 (44.3%) and 138 (65.1%) died in the MVA and the CON group, respectively (p<0.001). The lowest mortality was observed in MVA combined with MAZE (22.6%; p<0.01). In Cox regression analysis, age, MVA with MAZE emerged as independent predictors of both all-cause mortality and rehospitalizations for heart failure (all p<0.05). MVA was associated with significantly greater symptomatic improvement and reduction of FMR than the conservative treatment (both p<0.001). Reverse LV remodeling was observed only in the MVA combined with MAZE group (p<0.01). CONCLUSIONS: In patients with symptomatic FMR, minimally invasive MVA, in particular in combination with MAZE, confers an independent long-term survival benefit compared with the state-of-the-art treatment. PMID- 28624331 TI - Long-term detection of atrial fibrillation with insertable cardiac monitors in a real-world cryptogenic stroke population. AB - BACKGROUND: The long-term incidence of atrial fibrillation (AF) in cryptogenic stroke (CS) patients has been explored in carefully controlled clinical trials but real-world data are limited. We investigated the two-year incidence of AF in real-world clinical practice among a large cohort of patients with an insertable cardiac monitor (ICM) placed for AF detection following CS. METHODS: Patients in the de-identified Medtronic DiscoveryTM Link database who received an ICM (Reveal LINQTM) for the purpose of AF detection following CS were included and monitored for up to 2years. All detected AF episodes (>=2min) were adjudicated. We quantified the AF detection rate using Kaplan-Meier survival estimates, analyzed the median time to initial detection of AF, and simulated the ability of various intermittent monitoring strategies to detect AF. RESULTS: A total of 1247 patients (65.3+/-13.0years, 53% male) were included and followed for 579+/ 222days. AF episodes (n=4183) were detected in 238 patients, resulting in an AF detection rate of 21.5% at 2years. The median time to AF detection was 112 [IQR 35-293] days. Intermittent monitoring for AF detection was inferior to continuous ICM monitoring with sensitivities ranging from 2.9% (annual 24-hour Holter) to 29.9% (quarterly 7-day Holters), p<0.001. CONCLUSIONS: AF episodes were detected via continuous monitoring with ICMs in approximately 1 of every 5 CS patients within 2years of follow-up. The vast majority of patients with AF would not have been detected with conventional external ambulatory monitors. ICMs should therefore be considered in the evaluation of CS patients. PMID- 28624332 TI - Comparison of magnetic resonance feature tracking with CSPAMM HARP for the assessment of global and regional layer specific strain. AB - PURPOSE: Layer specific strain assessment is increasingly being employed clinically. Cardiac magnetic resonance (MR) Feature Tracking (FT) is considered to be an adequate alternative for strain assessment. The aim of this study is to investigate the feasibility of FT derived layer specific strain assessment. METHODS: CSPAMM and SSFP-Cine sequences were acquired in 38 individuals (19 patients with HFpEF, 19 controls) in identical midventricular short-axis locations. Global endocardial-, midmyocardial-, epicardial- peak systolic circumferential strain (PSCS) and regional epicardial PSCS were calculated and intra- as well inter-observer variability were assessed. RESULTS: FT derived global epicardial and endocardial PSCS (7.9+/-2.3%; -19.6+/-4.9%) were significantly lower than tagging derived global epicardial and endocardial PSCS ( 13.2+/-2.8%; -32.3+/-5.9%) (each p<0.001), while FT derived endocardial PSCS and tagging derived midmyocardial PSCS showed a strong correlation (r=0.71) and no significant differences. Global intra- and inter-observer variability of FT derived endocardial PSCS circumferential measures were acceptable (coefficient of variation 6.5% and 5.7%) while reproducibility of epicardial PSCS (coefficient of variation 16.8% and 18.1%) was poor. CONCLUSION: The FT algorithm allows for reliable assessment of midmyocardial strain, while underestimating epicardial and endocardial strain and delivering less reproducible results than the gold standard of tagging. PMID- 28624333 TI - L-theanine prevent quinolinic acid induced motor deficit and striatal neurotoxicity: Reduction in oxido-nitrosative stress and restoration of striatal neurotransmitters level. AB - L-theanine has been documented to possess anti-oxidant, anti-inflammatory and neuroprotective potential in various animal models of neurological disorders. The present study was anticipated to investigate the effect of L-theanine against quinolinic acid induced motor deficits, oxido-nitrosative stress, neuro inflammation and neurotransmitters alteration in rats. Rats were stereotaxically injected QA (200nmol/2ul saline; intrastriatal); bilaterally on 0 day and L theanine (25 & 50mg/kg; p.o.) was administered for 21 days starting from day 1 of QA injection. Either, L-NAME (10mg/kg; i.p.), a nitric oxide synthase inhibitor and L-arginine (50mg/kg; i.p.), a nitric oxide synthase precursor were administered with L-theanine in respective groups. Behavioral observations were evaluated on weekly basis using rota-rod, grip strength, narrow beam walking and open field test. QA treatment induces significant alteration in body weight, motor coordination, oxidative defense, pro-inflammatory cytokines and striatal neurotransmitters level. L-theanine treatment alone, at both the tested doses, significantly attenuated QA induced alterations. In addition, treatment of L theanine with L-NAME significantly enhances the protective effect of L-theanine whereas treatment of L-theanine with L-arginine significantly ameliorated the protective effect of L-theanine. The protective effect of L-theanine is attributed to its anti-oxidant, anti-inflammatory and modulatory effect on nitric oxide pathway and neurotransmitters level in striatum. This suggests use of L theanine in the clinical settings of HD. PMID- 28624334 TI - Seasonality and autoimmune diseases: The contribution of the four seasons to the mosaic of autoimmunity. AB - Autoimmune diseases (ADs) are a heterogeneous groups of diseases that occur as a results of loss of tolerance to self antigens. While the etiopathogeneis remain obscure, different environmental factors were suggested to have a role in the development of autoimmunity, including infections, low vitamin D levels, UV radiation, and melatonin. Interestingly, such factors possess seasonal variation patterns that could influence disease development, severity and progression. Vitamin D levels which reach a nadir during late winter and early spring is correlated with increased disease activity, clinical severity as well as relapse rates in several disease entities including multiple sclerosis (MS), non cutaneous flares of systemic lupus erythematosus (SLE), psoriasis, and rheumatoid arthritis (RA). Additionally, immunomodulatory actions of melatonin secretion ameliorate the severity of several ADs including MS and SLE. Melatonin levels are lowest during spring, a finding that correlates with the highest exacerbation rates of MS. Further, melatonin is postulated to be involved in the etiopathogenesis of inflammatory bowel diseases (IBD) through it influence on adhesion molecule and therefore transcription factor expression. Moreover, infections can mount to ADs through pro-inflammatory cytokine release and human antigen mimicry. Seasonal patterns of infectious diseases are correlated with the onset and exacerbation of ADs. During the winter, increased incidence of Epstein Barr virus (EBV) infectious are associated with MS and SLE flares/onset respectively. In addition, higher Rotavirus infections during the winter precedes type 1 diabetes mellitus onset (T1DM). Moreover, Escherichia coli (E. coli) infection prior to primary biliary cirrhosis (PBC) and T1DM disease onset subsequent to Coxachievirus infections are seen to occur during late summer, a finding that correlate with infectious agents' pattern of seasonality. In this review, the effects of seasonality on the onset, relapses and activity of various ADs were discussed. Consideration of seasonal variation patterns of ADs can possibly provide clues to diseases pathogenesis and lead to development of new approaches in treatment and preventative care. PMID- 28624336 TI - A framework for evaluating the accessibility of raw materials from end-of-life products and the Earth's crust. AB - An increasing number of geochemically scarce metallic raw materials are entering into our lives via new technologies. A reversal of this trend is not foreseeable, leading to concerns regarding the security of their supply. However, the evaluation of raw material supply is currently hampered by inconsistent use of fundamental terminologies and incomplete assessment criteria. In this paper, we aim to establish a consistent framework for evaluating raw material supply from both anthropogenic and geological sources. A method for concept extraction was applied to evaluate systematically the use of fundamental terms in the evaluation of raw material supply. The results have shown that 'availability' is commonly used in raw material supply evaluations, whilst other researchers suggest that raw material supply should be evaluated based on 'accessibility'. It was revealed that 'accessibility' actually comprises two aspects: 'availability' and 'approachability'. Raw material 'approachability' has not previously been explicitly addressed at a system level. A novel, consistent framework for evaluating raw material supply was therefore developed. To demonstrate the application of the established framework, we evaluated the raw material supply of four rare earth element case studies. Three case studies are End-of-Life products (the anthroposphere) from Switzerland: (i) phosphors in fluorescent lamps, (i) permanent magnets in the drive motors of electric cars and (iii) fibre optic cable. The fourth case study source is the Earth's crust (the geosphere): Mount Weld deposit in Australia. The framework comprises a comprehensive evaluation of six components relating to raw material mining and processing: their geological knowledge, eligibility, technology, economic, societal and environmental impacts. Our results show that metals are not considered to be fully accessible in any of the case studies due to a lack of necessary technologies and potential societal and environmental impacts. The framework presented here can serve as a starting point for the development of an evaluation framework for raw material accessibility at an early project development stage. PMID- 28624335 TI - Neuropathologic features of TOMM40 '523 variant on late-life cognitive decline. AB - INTRODUCTION: The study investigated the role of neuropathologies in the relationship between TOMM40 '523 genotype and late-life cognitive decline. METHODS: Participants were community-dwelling older persons who had annual cognitive assessments and brain autopsies after death. Genotyping used DNA from peripheral blood or postmortem brain tissue. Linear mixed models assessed the extent to which the association of '523 genotype with cognitive decline is attributable to neuropathologies. RESULTS: Relative to epsilon3/epsilon3 homozygotes with '523-S/VL or '523-VL/VL genotype, both '523-L carriers and epsilon3/epsilon3 homozygotes with '523-S/S genotype had faster cognitive decline. The association of '523-L with cognitive decline was attenuated and no longer significant after controlling for Alzheimer's and other neuropathologies. By contrast, the association of '523-S/S was unchanged. DISCUSSION: There are two distinct TOMM40 '523 signals in relation to late-life cognitive decline. One signal primarily acts through AD and other common neuropathologies, whereas the other operates through a different mechanism. PMID- 28624337 TI - Mobilization of prolonged mechanical ventilation patients: An integrative review. AB - Mobilization of mechanical ventilation patients has broadened to include patients requiring prolonged mechanical ventilation (PMV). A previous systematic review outlined methodological flaws in the literature. The purpose of this integrative review is to evaluate existing publications to determine if mobilization interventions in PMV patients improve physical function, weaning rates, pulmonary mechanics, and hospital outcomes. An electronicsearch covering 2005-2016, included five bibliographic databases: CINHAL, PubMed, PEDro, EMBASE, and Web of Science. Key terms: PMV, mobilization, therapy, and rehabilitation. Eight research studies were identified; 3 RCT's, 3 medical records reviews, 1 prospective cohort, and 1 undefined prospective interventional. Improvements in functional status, shorter duration of mechanical ventilation and hospitalization, decreased mortality, and superior 1-year survival rates in mobilized PMV patients were reported. Persistent methodological limitations impair the ability to determine if these outcomes were the result of improvements in pulmonary mechanics, overall functional status, or a combination of both. PMID- 28624338 TI - Heart transplant centers with multidisciplinary team show a higher level of chronic illness management - Findings from the International BRIGHT Study. AB - OBJECTIVES: The objectives of this study were to: (1) explore the proportion of HTx centers that have a multidisciplinary team and (2) assess the relationship between multidisciplinarity and the level of chronic illness management (CIM). BACKGROUND: The International Society for Heart and Lung Transplantation (ISHLT) recommends a multidisciplinary approach in heart transplant (HTx) follow-up care but little is known regarding the proportion of HTx centers that meet this recommendation and the impact on patient care. HTx centers with a multidisciplinary team may offer higher levels of CIM, a care model that has the potential to improve outcomes after HTx. METHODS: We conducted a secondary analysis of the BRIGHT study, a cross-sectional study in 11 countries. Multidisciplinarity in the 36 HTx centers was assessed through HTx director reports and was defined as having a team that was composed of physician(s), nurse(s), and another healthcare professional (either a social worker, psychiatrist, psychologist, pharmacist, dietician, physical therapist, or occupational therapist). CIM was assessed with the Patient Assessment of Chronic Illness Care (PACIC). Multiple linear regression assessed the relationship between multidisciplinarity and the level of CIM. RESULTS: Twenty-nine (80.6%) of the HTx centers had a multidisciplinary team. Furthermore, multidisciplinarity was significantly associated with higher levels of CIM (beta = 5.2, P = 0.042). CONCLUSION: Majority of the HTx centers follows the ISHLT recommendation for a multidisciplinary approach. Multidisciplinarity was associated with CIM and point toward a structural factor that needs to be in place for moving toward CIM. PMID- 28624339 TI - Structural Parameters of the Proximal Femur by 3-Dimensional Dual-Energy X-ray Absorptiometry Software: Comparison With Quantitative Computed Tomography. AB - Structural parameters of the proximal femur evaluate the strength of the bone and its susceptibility to fracture. These parameters are computed from dual-energy X ray absorptiometry (DXA) or from quantitative computed tomography (QCT). The 3 dimensional (3D)-DXA software solution provides 3D models of the proximal femur shape and bone density from anteroposterior DXA scans. In this paper, we present and evaluate a new approach to compute structural parameters using 3D-DXA software. A cohort of 60 study subjects (60.9 +/- 14.7 yr) with DXA and QCT examinations was collected. 3D femoral models obtained by QCT and 3D-DXA software were aligned using rigid registration techniques for comparison purposes. Geometric, cross-sectional, and volumetric structural parameters were computed at the narrow neck, intertrochanteric, and lower shaft regions for both QCT and 3D DXA models. The accuracy of 3D-DXA structural parameters was evaluated in comparison with QCT. Correlation coefficients (r) between geometric parameters computed by QCT and 3D-DXA software were 0.86 for the femoral neck axis length and 0.71 for the femoral neck shaft angle. Correlation coefficients ranged from 0.86 to 0.96 for the cross-sectional parameters and from 0.84 to 0.97 for the volumetric structural parameters. Our study demonstrated that accurate estimates of structural parameters for the femur can be obtained from 3D-DXA models. This provides clinicians with 3D indexes related to the femoral strength from routine anteroposterior DXA scans, which could potentially improve osteoporosis management and fracture prevention. PMID- 28624341 TI - Extranodal lymphoma arising within the maxillary alveolus: a case report. AB - OBJECTIVE: Extranodal lymphomas affecting the head and neck arise infrequently within the bones of the jaws. This is a report of a symptom-free patient whose general dentist detected a radiolucency as an incidental finding on conventional radiography. STUDY DESIGN: The conventional radiography of lesions in the maxilla displayed "floating teeth" indicative of malignancy. This case was then imaged by cone beam computed tomography (CBCT), multidetector computed tomography (MDCT), and magnetic resonance imaging (MRI). The lymphoma grew rapidly in less than a week between the MDCT and the MRI. All the above cross-sectional modalities elicited a provisional diagnosis of a squamous cell carcinoma (SCC). CONCLUSIONS: Evaluation of the extent of the lesion and its encroachment on adjacent structures is limited by conventional radiography. Nevertheless, conventional radiography can display features that are suggestive of malignant disease. Although cross-sectional imaging of lesions within the anatomically-complex maxilla has generally taken the form of MDCT and MRI, CBCT has a role. In hindsight, the absence of central necrosis should have directed the inclusion of "extranodal lymphoma arising within the maxillary alveolus" in the provisional diagnosis. PMID- 28624340 TI - Effects of Teriparatide, Denosumab, or Both on Spine Trabecular Microarchitecture in DATA-Switch: a Randomized Controlled Trial. AB - In postmenopausal women, 2 yr of combined teriparatide and denosumab increases bone mineral density more than either drug alone, and switching from either combination or teriparatide to denosumab for an additional 2 yr further increases bone mineral density. Conversely, switching from denosumab to teriparatide results in transient bone loss. The effects of these interventions on spine microarchitecture are unknown. In the DATA and DATA-Switch studies, 94 postmenopausal osteoporotic women were randomized to receive 24 mo of teriparatide (20 ug daily), denosumab (60 mg every 6 mo), or both. Then, women originally assigned to 24 mo of teriparatide received 24 mo of denosumab, whereas subjects originally randomized to 24 mo of denosumab received 24 mo of teriparatide. Subjects who received both drugs received an additional 24 mo of denosumab alone. Spine trabecular bone score (TBS, a gray-level textural assessment of bone microarchitecture) was measured blinded from treatment groups using images from 2-dimensional dual-energy X-ray absorptiometry spine scans at 0, 12, 24, 30, 36, and 48 mo in 65 women who had posterior-anterior spine dual energy X-ray absorptiometry images suitable for TBS analysis. After 24 mo, TBS increased by 2.7 +/- 4.7% in the teriparatide group (p = 0.009 vs baseline), by 1.8 +/- 5.0% in the denosumab group (p = 0.118 vs baseline), and by 4.5 +/- 6.7% in the combination group (p = 0.017 vs baseline), with no significant between group differences. In the 6 mo after the treatments were switched (months 24-30), TBS continued to increase in the combination-to-denosumab and teriparatide-to denosumab groups but decreased by -1.1 +/- 4.0% in the denosumab-to-teriparatide group (p < 0.05 vs other groups). After 48 mo, compared to month 0, TBS increased by 5.1 +/- 5.8% in the teriparatide-to-denosumab group, by 3.6 +/- 4.2% in the denosumab-to-teriparatide group, and by 6.1 +/- 4.7% in the combination-to denosumab group (p < 0.001 vs baseline for all groups, p = not significant for between-group differences). Switching from teriparatide to denosumab also increased spine TBS. Conversely, switching from denosumab to teriparatide transiently degraded spine trabecular microarchitecture, the clinical consequences of which require further study. PMID- 28624343 TI - 'Money for nothing'. The role of robotic-assisted laparoscopy for the treatment of endometriosis. AB - Despite higher costs for robotic-assisted laparoscopy (RAL) than standard laparoscopy (SL), RAL treatment of endometriosis is performed without established indications. PubMed/MEDLINE was searched for 'robotic surgery' and 'endometriosis' or 'gynaecological benign disease' from January 2000 to December 2016. Full-length studies in English reporting original data were considered. Among 178 articles retrieved, 17 were eligible: 11 non-comparative (RAL only) and six comparative (RAL versus SL). Non-comparative studies included 445 patients. Mean operating time, blood loss and hospital stay were 226 min, 168 ml and 4 days. Major complications and laparotomy conversions were 3.1% and 1.3%. Eight studies reported pain improvement at 15-month follow-up. Comparative studies were all retrospective; 749 women underwent RAL and 705 SL. Operating time was longer for RAL in five studies. Major complications and laparotomy conversions for RAL and SL were 1.5% versus 0.3% and 0.3% versus 0.5%. One study reported pain reduction for RAL at 6-month follow-up. RAL treatment of endometriosis did not provide benefits over SL, overall and among subgroups of women with severe endometriosis, peritoneal endometriosis and obesity. Available evidence is low quality, and data regarding long-term pain relief and pregnancy rates are lacking. RAL treatment of endometriosis should be performed only within controlled studies. PMID- 28624344 TI - Effect of obesity and its related metabolic factors on serum anti-Mullerian hormone concentrations in women with and without polycystic ovaries. AB - The relationship between serum anti-Mullerian hormone (AMH) levels, body mass index (BMI) and related metabolic factors were investigated in women with polycystic ovary syndrome (PCOS). A total of 691 women aged between 18 and 35 years, referred to the Department of Gynaecological Endocrinology at the University Hospital of Lille between 2009 and 2014 were included: 137 controls and 554 women with PCOS. Mean serum AMH levels were slightly but significantly lower in women with PCOS who were overweight or obese (BMI >=25) compared with women of normal weight (BMI <25) (P < 0.05). No such difference was found in the control group. After bivariate analysis, no significant correlation was found between BMI and AMH in controls. In the PCOS group, this relationship was significant (P = 0.0001) but weak (r = -0.177). Stepwise multiple regression analysis yielded a significant model, including five variables (follicle count, serum androstenedione, BMI, serum LH and FSH) explaining 38.6%, 3.4%, 1.4%, 0.7% and 1.4% of the total serum AMH variance, respectively. No effect of metabolic status was found on serum AMH levels in controls, but a significant, albeit weak, negative independent correlation was found between AMH and BMI in women with PCOS. PMID- 28624345 TI - Lamprey neural crest migration is Snail-dependent and occurs without a differential shift in cadherin expression. AB - The acquisition of neural crest cells was a key step in the origin of the vertebrate body plan. An outstanding question is how neural crest cells acquired their ability to undergo an epithelial-mesenchymal transition (EMT) and migrate extensively throughout the vertebrate embryo. We tested if differential regulation of classical cadherins-a highly conserved feature of neural crest EMT and migration in jawed vertebrates-mediates these cellular behaviors in lamprey, a basal jawless vertebrate. Lamprey has single copies of the type I and type II classical cadherins (CadIA and CadIIA). CadIIA is expressed in premigratory neural crest, and requires the transcription factor Snail for proper expression, yet CadIA is never expressed in the neural tube during neural crest development, suggesting that differential regulation of classical cadherin expression is not required to initiate neural crest migration in basal vertebrates. We hypothesize that neural crest cells evolved by retention of regulatory programs linking distinct mesenchymal and multipotency properties, and emigrated from the neural tube without differentially regulating type I/type II cadherins. Our results point to the coupling of mesenchymal state and multipotency as a key event facilitating the origin of migratory neural crest cells. PMID- 28624346 TI - Theta burst magnetic stimulation over the pre-supplementary motor area improves motor inhibition. AB - BACKGROUND: Stopping an ongoing motor response or resolving conflict induced by conflicting stimuli are associated with activation of a right-lateralized network of inferior frontal gyrus (IFG), pre-supplementary motor area (pre-SMA) and subthalamic nucleus (STN). However, the roles of the right IFG and pre-SMA in stopping a movement and in conflict resolution remain unclear. We used continuous theta burst stimulation (cTBS) to examine the involvement of the right IFG and pre-SMA in inhibition and conflict resolution using the conditional stop signal task. METHODS: We measured stop signal reaction time (SSRT, measure of reactive inhibition), response delay effect (RDE, measure of proactive action restraint) and conflict induced slowing (CIS, measure of conflict resolution). RESULTS: Stimulation over the pre-SMA resulted in significantly shorter SSRTs (improved inhibition) compared to sham cTBS. This effect was not observed for CIS, RDE, or any other measures. cTBS over the right IFG had no effect on SSRT, CIS, RDE or on any other measure. CONCLUSIONS: The improvement of SSRT with cTBS over the pre SMA suggests its critical contribution to stopping ongoing movements. PMID- 28624347 TI - Reply. PMID- 28624348 TI - Epithelial perviousness in allergic airways disease. PMID- 28624349 TI - Allergy testing in predicting outcome of open food challenge to peanut. PMID- 28624350 TI - Reply. PMID- 28624351 TI - Inhibitory effect of vitamin B3 against glycation and reactive oxygen species production in HSA: An in vitro approach. AB - Hyperglycaemia is a key factor for the formation of advanced glycated endproducts (AGEs). Inhibition of glycation may play key role in minimizing the diabetes related complications. We have tried to explore the glucose and methyl glyoxal mediated glycation and antiglycation activity of niacin using human serum albumin as model protein. Protein was incubated with glucose for 28 days at physiological temperature to achieve glycation. Antiglycation activity was evaluated by assessing free lysine, carbonyl content, AGE specific fluorescence. Molecular docking and isothermal titration calorimetry was deployed to study the interaction of niacin with HSA and get a detailed insight of binding site and thermodynamics of interaction. Niacin reduced the glycation significantly which was evident from the estimation of free lysine and carbonyl content. Niacin binds with HSA in a spontaneous manner with the binding constant in the range of 104 M 1. Niacin also prevented the loss in secondary structure induced by glycation. Reactive oxygen species were also effectively quenched by niacin leading to protection from DNA damage. Niacin was found to be located at Sudlow's site I with binding energy of 5.3 kcal/mol. These results clearly highlight the antiglycation activity of niacin and its potential in preventing disease progression in diabetes. PMID- 28624352 TI - Pressure effects on alpha-synuclein amyloid fibrils: An experimental investigation on their dissociation and reversible nature. AB - alpha-synuclein amyloid fibrils are found in surviving neurons of Parkinson's disease affected patients, but the role they play in the disease development is still under debate. A growing number of evidences points to soluble oligomers as the major cytotoxic species, while insoluble fibrillar aggregates could even play a protection role. In this work, we investigate alpha-synuclein fibrils dissociation induced at high pressure by means of Small Angle X-ray Scattering and Fourier Transform Infrared Spectroscopy. Fibrils were produced from wild type alpha-synuclein and two familial mutants, A30P and A53T. Our results enlighten the different reversible nature of alpha-synuclein fibrils fragmentation at high pressure and suggest water excluded volumes presence in the fibrils core. Wild type and A30P species stabilized at high pressure are highly amyloidogenic and quickly re-associate into fibrils upon decompression, while A53T species shows a partial reversibility of the process likely due to the presence of an intermediate oligomeric state stabilized at high pressure. The amyloid fibrils dissociation process is here suggested to be associated to a negative activation volume, supporting the notion that alpha-synuclein fibrils are in a high-volume and high-compressibility state and hinting at the presence of a hydration mediated activated state from which dissociation occurs. PMID- 28624353 TI - Expression of hypoxia inducible factor 1alpha and antioxidant enzymes: Superoxide dismutases-1 and -2 in ischemic porcine endometrium. AB - The aim of this study was to determine how 60-min ischemia changes the expression of hypoxia inducible factor 1alpha (HIF-1alpha) and superoxide dismutases (SOD)-1 and -2 in selected regions of porcine uterine horns. The results showed that 60 min ischemia of the porcine uterus conducted at the mid-secretory estrous phase caused decreased HIF-1alpha and increased SOD-2 gene expression. Higher expression of SOD-2 suggests that this enzyme may play an important role in the suppression of HIF-1alpha accumulation in an ischemic endometrium. PMID- 28624354 TI - School reintegration of pediatric burn survivors: An integrative literature review. AB - BACKGROUND: The school is an essential context for children's social interaction with peers and to develop academic skills. Therefore, a fast reintegration can help children with burns to normalize their life. Thus, school reintegration is an important outcome after burns. The aim of this review was to systematically synthesize the literature addressing school reintegration programs of pediatric burns survivors. METHODS: Five electronic databases were searched independently by two reviewers. The search yielded 13 eligible publications. A qualitative content analysis was conducted. RESULTS: The two themes identified centered around (1) the roles, obstacles, and support for the different stakeholders (i.e., the child, parents and teacher) and (2) the contents of the school reintegration programs in which subthemes such as purpose, planning, essential elements, team, and effect were distinguished. The results show that return to school should start as soon as the child is admitted to the hospital and the program should acknowledge the different stakeholders' needs and tailor the program to these needs. CONCLUSION: The review emphasizes the necessity of an integrated school reintegration program empowering both the child, the parents and the teachers and tailored to the child's specific situation. Furthermore, it offers recommendations for further improvement of the field. PMID- 28624355 TI - 3-NP-induced Huntington's-like disease impairs Nrf2 activation without loss of cardiac function in aged rats. AB - Cardiovascular diseases (CVDs) are one of the leading causes of death in patients over 60years with Huntington's disease (HD). Here, we investigated if age-related oxidative stress (OS) is a relevant factor to develop cardiac damage in an in vivo model of striatal neurodegeneration induced by 3-nitropropionic acid (3-NP). We also evaluated the potential effect of tert-butylhydroquinone (tBHQ) to increase the Nrf2-regulated antioxidant response in hearts from adult and aged rats intoxicated with 3-NP. Our results showed that 3-NP-treatment did not induce cardiac dysfunction, neither in adult nor in aged rats. However, at the cellular level, adult animals showed higher susceptibility to 3-NP-induced damage than aged rats, which suggest that chronic oxidative stress ongoing during aging might have induced an hormetic response that probably prevented from further 3-NP damage. We also found that the oxidative unbalance concurs with unresponsiveness of the Nrf2-mediated antioxidant response in old animals. PMID- 28624356 TI - Vascular ageing: Underlying mechanisms and clinical implications. AB - Epidemiological studies have shown that ageing is a major non-reversible risk factor for cardiovascular disease. Vascular ageing starts early in life and is characterized by a gradual change of vascular structure and function resulting in increased arterial stiffening. At the present review we discuss the role of the most important molecular pathways involved in vascular ageing, their association with arterial stiffening and possible novel therapeutic targets that may delay this otherwise irreversible degenerating process. Specifically, we discuss the role of oxidative stress, telomere shortening, and ubiquitin proteasome system in endothelial cell senescence and dysfunction in vascular inflammation and in arterial stiffening. Further, we summarize the most important molecular mechanisms regulating vascular ageing including sirtuin 1, telomerase, klotho, JunD, and amyloid beta 1-40 peptide. PMID- 28624357 TI - An estimation of the average residence times and onshore-offshore diffusivities of beached microplastics based on the population decay of tagged meso- and macrolitter. AB - Residence times of microplastics were estimated based on the dependence of meso- and macrolitter residence times on their upward terminal velocities (UTVs) in the ocean obtained by one- and two-year mark-recapture experiments conducted on Wadahama Beach, Nii-jima Island, Japan. A significant linear relationship between the residence time and UTV was found in the velocity range of about 0.3-0.9ms-1, while there was no significant difference between the residence times obtained in the velocity range of about 0.9-1.4ms-1. This dependence on the UTV would reflect the uprush-backwash response of the target items to swash waves on the beach. By extrapolating the linear relationship down to the velocity range of microplastics, the residence times of microplastics and the 1D onshore-offshore diffusion coefficients were inferred, and are one to two orders of magnitude greater than the coefficients of the macroplastics. PMID- 28624358 TI - Environmental drivers of heterogeneity in the trophic-functional structure of protozoan communities during an annual cycle in a coastal ecosystem. AB - Trophic-functional groupings are an important biological trait to summarize community structure in functional space. The heterogeneity of the tropic functional pattern of protozoan communities and its environmental drivers were studied in coastal waters of the Yellow Sea during a 1-year cycle. Samples were collected using the glass slide method at four stations within a water pollution gradient. A second-stage matrix-based analysis was used to summarize spatial variation in the annual pattern of the functional structure. A clustering analysis revealed significant variability in the trophic-functional pattern among the four stations during the 1-year cycle. The heterogeneity in the trophic functional pattern of the communities was significantly related to changes in environmental variables, particularly ammonium-nitrogen and nitrates, alone or in combination with dissolved oxygen. These results suggest that the heterogeneity in annual patterns of protozoan trophic-functional structure may reflect water quality status in coastal ecosystems. PMID- 28624359 TI - New challenges in multimodal workout of locally advanced breast cancer. AB - The term "locally advanced breast cancer" (LABC) encompasses a heterogeneous group of breast neoplasms that represent an extremely variable percentage of newly diagnosed breast cancers (4-90%, depending of world regions). These cancers may have different clinical and biological characteristics that can be managed by primary surgery or neoadjuvant integrated treatments. In this paper we review the updated guidelines and discuss most recently reported evidence related to LABC multidisciplinary workout, in order to maximize results of combined systemic therapies, modern surgical procedures and radiotherapy. PMID- 28624360 TI - Association between arterial access site and anticoagulation strategy on major bleeding and mortality: A historical cohort analysis in the Veteran population. AB - BACKGROUND: Studies have shown reduction in major bleeding with trans-radial intervention (TRI) compared with trans-femoral intervention (TFI), and with use of bivalirudin compared with heparin+glycoprotein IIb/IIIa inhibitors (GPI). We compared major bleeding, mortality and the interaction between arterial access site and the anticoagulant used for PCI in Veterans. METHODS: A retrospective cohort of 1192 consecutive patients who underwent PCI at a VA hospital between 2006 and 2012 was divided into TFI-heparin (n=192), TFI-bivalirudin (n=272), TRI heparin (n=274) and TRI-bivalirudin (n=454) groups. Primary outcomes were in hospital major bleeding, in-hospital and 1-year all-cause mortality. Secondary outcomes were in-hospital MI, in-hospital and 1-year MACE and net adverse cardiovascular events (NACE - composite of major bleeding+MACE). RESULTS: Femoral access was associated with a significantly increased risk of major bleeding compared with radial access (OR 11.87, p<0.001). Correspondingly, radial access was protective against major bleeding compared with femoral access (OR 0.128, p<0.01), but did not lower mortality or MACE by itself. Severe anemia was the only predictor of in-hospital all-cause mortality (OR=27.62, p<0.008). Presence of anemia and age>70 predicted 1-year mortality, whereas major bleeding and anemia predicted 1-year MACE. An interaction was noted between anticoagulant and access site, such that heparin showed significantly greater major bleeding in the femoral group compared with the radial group. Bivalirudin resulted in similar risk of bleeding, regardless of access site. There was a synergistic interaction between radial access and heparin (HR 0.38, p<0.05), but not radial access and bivalirudin, on reduction in 1-year NACE. CONCLUSION: Radial access for PCI is associated with reduction in major bleeding, but does not have an effect on in patient or 1-year MACE and mortality. Major bleeding is associated with poor short and intermediate term outcomes. In addition, anemia is strongly associated with increased in-patient and 1-year mortality. There is a differential effect of heparin but not bivalirudin on major bleeding, depending on the access site. There is no synergism between radial access and bivalirudin in lowering the composite outcome of MACE and major bleeding at 1year. PMID- 28624362 TI - Pulvis Fellis Suis extract attenuates ovalbumin-induced airway inflammation in murine model of asthma. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pulvis Fellis Suis (PFS), named with "Zhu Danfen" in China, has been extensively used for the therapy of enteritis, acute pharyngitis, whooping cough and asthma in folk medicine. Although PFS shows anti inflammatory activities, its effect on airway inflammation in asthma has not been studied. AIM OF THE STUDY: To explore the protective effect of PFS ethanol extract against airway inflammation in asthmatic mice. MATERIALS AND METHODS: Allergic asthma in mice was sensitized and challenged by OVA. Mice were administered in oral with PFS daily at doses of 100, 200 and 400mg/kg on days 21 27. Inflammatory cell counts and classification in bronchoalveolar lavage fluid (BALF) were analyzed. Histopathological evaluation of the lung tissue was performed by hematoxylin and eosin (H&E) and periodic acid-schiff (PAS) staining. The IgE level in serum was measured by using enzyme-linked immunoassay (ELISA). ELISA was also used to detect the levels of Th1/Th2 cytokine and eotaxin in BALF. RESULTS: Histological results revealed that PFS could ameliorate OVA-induced histological changes by attenuating inflammatory cell infiltration, mucus hypersecretion and goblet cell hyperplasia in the lung. Treatment with different doses of PFS significantly decreased the elevated inflammatory cell numbers in BALF and IgE production in serum. PFS treatment reduced the production of Th2 cytokine IL-4, IL-5, IL-13, and promoted Th1 cytokine IFN-gamma production in BALF. In addition, PFS also decreased the levels of eotaxin and TNF-alpha in BALF. CONCLUSIONS: These findings suggest that PFS has a markedly anti inflammatory effect on OVA-induced allergic asthma in mice, and could be a promising protective agent recommended for allergic asthma patients. PMID- 28624361 TI - Low intensity rTMS has sex-dependent effects on the local response of glia following a penetrating cortical stab injury. AB - Repetitive transcranial magnetic stimulation (rTMS), a non-invasive form of brain stimulation, has shown experimental and clinical efficacy in a range of neuromodulatory models, even when delivered at low intensity (i.e. subthreshold for action potential generation). After central nervous system (CNS) injury, studies suggest that reactive astrocytes and microglia can have detrimental but also beneficial effects; thus modulating glial activity, for example through application of rTMS, could potentially be a useful therapeutic tool following neurotrauma. Immunohistochemistry was used to measure the effect of low intensity rTMS (LI-rTMS) on GFAP (astrocyte), IBA1 (microglial), and CS56 (proteoglycan) expression in a unilateral penetrating cortical stab injury model of glial scarring in young adult and aged male and female C57BL6/J mice. Mice received contralateral low frequency, ipsilateral low frequency, ipsilateral high frequency or sham LI-rTMS (4-5mT intensity), for two weeks following injury. There was no significant difference in the overall volume of tissue containing GFAP positive (+) astrocytes, IBA1+ microglia, or proteoglycan expression, between sham and LI-rTMS-treated mice of all ages and sex. Importantly however, the density of GFAP+ astrocytes and IBA1+ microglia immediately adjacent to the injury was significantly reduced following ipsilateral low and high frequency stimulation in adult and aged females (p<=0.05), but was significantly increased in adult and aged males (p<=0.05). LI-rTMS effects were generally of greater magnitude in aged mice compared to young adult mice. These results suggest that sex differences need to be factored into therapeutic rTMS protocols. In particular, more work analyzing frequency and intensity specific effects, especially in relation to age and sex, is required to determine how rTMS can best be used to modify glial reactivity and phenotype following neurotrauma. PMID- 28624363 TI - Brazilian red propolis effects on peritoneal macrophage activity: Nitric oxide, cell viability, pro-inflammatory cytokines and gene expression. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has been used in folk medicine since ancient times and it presented inhibitory effect on neutrophil recruitment previously. However, its effect on macrophage obtained from mice remains unclear. AIM OF THE STUDY: To demonstrate BRP effects on LPS activated peritoneal macrophage. MATERIALS AND METHODS: Peritoneal macrophages, obtained from C57BL6 mice and activated with LPS, were treated with 50-80ug/mL of crude extract of Brazilian red propolis (BRP) during 48h. Cell viability, levels of NO, 20 cytokines and expression of 360 genes were evaluated. RESULTS: BRP 60ug/mL reduced NO production by 65% without affecting the cell viability and decreased production IL1alpha, IL1beta, IL4, IL6, IL12p40, Il12p70, IL13, MCP1 and GM-CSF. Molecular mechanism beyond the anti-inflammatory activity may be due to BRP effects on decreasing expression of Mmp7, Egfr, Adm, Gata3, Wnt2b, Txn1, Herpud1, Axin2, Car9, Id1, Vegfa, Hes1, Hes5, Icam1, Wnt3a, Pcna, Wnt5a, Tnfsf10, Ccl5, Il1b, Akt1, Mapk1, Noxa1 and Cdkn1b and increasing expression of Cav1, Wnt6, Calm1, Tnf, Rb1, Socs3 and Dab2. CONCLUSIONS: Therefore, BRP has anti inflammatory effects on macrophage activity by reducing NO levels and diminished release and expression of pro-inflammatory cytokine and genes, respectively. PMID- 28624364 TI - Decision-making in Swiss home-like childbirth: A grounded theory study. AB - BACKGROUND: Decision-making in midwifery, including a claim for shared decision making between midwives and women, is of major significance for the health of mother and child. Midwives have little information about how to share decision making responsibilities with women, especially when complications arise during birth. AIM: To increase understanding of decision-making in complex home-like birth settings by exploring midwives' and women's perspectives and to develop a dynamic model integrating participatory processes for making shared decisions. METHODS: The study, based on grounded theory methodology, analysed 20 interviews of midwives and 20 women who had experienced complications in home-like births. FINDINGS: The central phenomenon that arose from the data was "defining/redefining decision as a joint commitment to healthy childbirth". The sub-indicators that make up this phenomenon were safety, responsibility, mutual and personal commitments. These sub-indicators were also identified to influence temporal conditions of decision-making and to apply different strategies for shared decision-making. Women adopted strategies such as delegating a decision, making the midwife's decision her own, challenging a decision or taking a decision driven by the dynamics of childbirth. Midwives employed strategies such as remaining indecisive, approving a woman's decision, making an informed decision or taking the necessary decision. DISCUSSION AND CONCLUSION: To respond to recommendations for shared responsibility for care, midwives need to strengthen their shared decision-making skills. The visual model of decision making in childbirth derived from the data provides a framework for transferring clinical reasoning into practice. PMID- 28624365 TI - O-GlcNAcylation of amyloid-beta precursor protein at threonine 576 residue regulates trafficking and processing. AB - The pathological hallmark of Alzheimer's disease (AD) is associated with the accumulation of amyloid-beta (Abeta) derived from proteolytic processing of amyloid-beta precursor protein (APP). APP undergoes post-translational modification including N- and O-glycosylation. O-GlcNAcylation is a novel type of O-glycosylation, mediated by O-GlcNAc transferase attaching O-beta-N acetylglucosamine (O-GlcNAc) to serine/threonine residues of the target proteins. O-GlcNAc is removed by O-GlcNAcase. We have previously reported that increasing O GlcNAcylated APP using the O-GlcNAcase inhibitor, PUGNAc, increases its trafficking rate to the plasma membrane and decreases its endocytosis rate, resulting in decreased Abeta production. However, O-GlcNAc modification sites in APP are unknown. In this study, we mutated three predicted O-GlcNAc modification threonine residues of APP into alanines (T291A, T292A, and T576A) and expressed them in HeLa cells. These APP mutants showed reduced O-GlcNAcylation levels, indicating that these sites were endogenously O-GlcNAcylated. Thr 576 was the major O-GlcNAcylation site when cell was treated with PUGNAc. We also showed that the effects of PUGNAc on APP trafficking to the plasma membrane and Abeta production were prevented in the T576A mutant. These results implicate Thr 576 as the major O-GlcNAcylation site in APP and indicate that O-GlcNAcylation of this residue regulates its trafficking and processing. Thus, specific O-GlcNAcylation of APP at Thr 576 may be a novel and promising drug target for AD therapeutics. PMID- 28624366 TI - Nanoscale dose deposition in cell structures under X-ray irradiation treatment assisted with nanoparticles: An analytical approach to the relative biological effectiveness. AB - In this study, an analytical model for the assessment of the modification of cell culture survival under ionizing radiation assisted with nanoparticles (NPs) is presented. The model starts from the radial dose deposition around a single NP, which is used to describe the dose deposition in a cell structure with embedded NPs and, in turn, to evaluate the number of lesions formed by ionizing radiation. The model is applied to the calculation of relative biological effectiveness values for cells exposed to 0.5mg/g of uniformly dispersed NPs with a radius of 10nm made of Fe, I, Gd, Hf, Pt and Au and irradiated with X-rays of energies 20keV higher than the element K-shell binding energy. PMID- 28624367 TI - Evidence for revision of the evaluated half-life of 207Bi. AB - The National Institute of Standards and Technology (NIST) compared the measured full-energy peak efficiency obtained from a large set of sources to that of a 207Bi source obtained using three different half-life values. The values of the half-life used for this comparison are published in the Decay Data Evaluation Project (32.9 +/- 1.4) years and the Evaluated Nuclear Structure Data File (31.55 +/- 0.04) years, and in a recent NIST publication (31.20 +/- 0.05) years (or (11395 +/- 18) days). PMID- 28624368 TI - Conservation of BMP2/4 expression patterns within the clade Branchiostoma (amphioxus): Resolving interspecific discrepancies. AB - In 2016, Kaji et al. concluded that the amphioxus mouth has the quality of a coelomoduct and is, therefore, not homologous to the oral opening of any other animal. They studied a Japanese population of Branchiostoma japonicum and based their conclusion, in part, on the larval expression of BMP2/4 in cells that reportedly joined the rim of the forming mouth. They did not detect transcription of that gene in any other tissues in the anterior region of the larva. Their results were almost the inverse of findings for B. floridae by Panopoulou et al. (1998), who detected BMP2/4 expression in several anterior tissues, but not in cells intimately associated with the nascent mouth. To resolve this discrepancy, we have studied BMP2/4 in a Chinese population of B. japonicum as well as in an additional species, the European B. lanceolatum. In both species, larval expression of BMP2/4 closely resembles the pattern previously reported for B. floridae-that is, transcription is undetectable in tissues juxtaposed to the forming mouth, but is seen in several other anterior structures (most conspicuously in the lining of the rostral coelom and the club-shaped gland). In sum, we could not repeat the BMP2/4 expression pattern of Kaji et al. (2016) even in the same species, and their findings for this gene, at least, cannot be counted as a support for their hypothesis for a coelomoduct mouth. PMID- 28624369 TI - Controlled drug release through regulated biodegradation of poly(lactic acid) using inorganic salts. AB - Biodegradation rate of poly(lactic acid) (PLA) has been regulated, both increase and decrease with respect to the biodegradation of pure PLA, by embedding meager amount of inorganic salts in polymer matrix. Biodegradation is performed in enzyme medium on suspension and film and the extent of biodegradation is measured through spectroscopic technique which is also verified by weight loss measurement. Media pH has been controlled using trace amount of inorganic salt which eventually control the biodegradation of PLA. High performance liquid chromatography confirms the hydrolytic degradation of PLA to its monomer/oligomer. Induced pH by metal salts show maximum degradation at alkaline range (with calcium salt) while inhibition is observed in acidic medium (with iron salt). The pH of media changes the conformation of enzyme which in turn regulate the rate of biodegradation. Thermal degradation and increment of modulus indicate improvement in thermo-mechanical properties of PLA in presence of inorganic salts. Functional stability of enzyme with metal salts corresponding to acidic and alkaline pH has been established through a model to explain the conformational changes of the active sites of enzyme at varying pH influencing the rate of hydrolysis leading to regulated biodegradation of PLA. The tuned biodegradation has been applied for the controlled release of drug from the polymer matrix (both sustained and enhanced cumulative release as compared to pure polymer). The cell proliferation and adhesion are influenced by the acidic and basic nature of polymeric material tuned by two different inorganic salts showing better adhesion and proliferation in calcium based composite and, therefore, suggest biological use of these composites in biomedical applications. PMID- 28624370 TI - Leptin, Orexin, Peptide YY and Ghrelin Associated with Relapse During Smoking Cessation. PMID- 28624371 TI - Histone ubiquitination in the DNA damage response. AB - DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays a crucial role. Recent findings suggest an integrated model for DNA repair regulation through site-specific histone ubiquitination and crosstalk to other posttranslational modifications. Here we discuss how site-specific histone ubiquitination is achieved on a molecular level and how different multi-protein complexes work together to integrate different histone ubiquitination states. We propose a model where site-specific H2A ubiquitination organizes the spatio temporal recruitment of DNA repair factors which will ultimately contribute to DNA repair pathway choice between homologous recombination and non-homologous end joining. PMID- 28624372 TI - Taming Tricky DSBs: ATM on duty. AB - Ataxia Telangiectasia Mutated (ATM) has been known for decades as the main kinase mediating the DNA Double-Strand Break Response (DDR). Extensive studies have revealed its dual role in locally promoting detection and repair of DSBs as well as in activating global DNA damage checkpoints. However, recent studies pinpoint additional unanticipated functions for ATM in modifying both the local chromatin landscape and the global chromosome organization, more particularly at persistent breaks. Given the emergence of a novel and unexpected class of DSBs prevalently arising in transcriptionally active genes and intrinsically difficult to repair, a specific role of ATM at refractory DSBs could be an important and so far overlooked feature of Ataxia Telangiectasia (A-T) a severe disorder associated with ATM mutations. PMID- 28624373 TI - Acute tubulointerstitial nephritis in an HLA-B27-positive patient with axial spondyloarthritis being treated with adalimumab. AB - Antagonists of tumor necrosis factor-alpha (ATNF) are used for the treatment of multiple diseases such as psoriatic arthritis, Crohn's disease, ankylosing spondylitis and juvenile idiopathic arthritis, usually, when they are refractory to first-line treatment1. The use of ATNF has been associated with the induction of autoimmune diseases such as systemic lupus erythematosus-like disease, vasculitis, sarcoidosis-like diseases and, recently, acute granulomatous tubulointerstitial nephritis. We report a case of acute nongranulomatous tubulointerstitial nephritis in an HLA-B27-positive patient with axial spondyloarthritis and Crohn's disease being treated with adalimumab. PMID- 28624374 TI - Rheumatoid arthritis and ocular myasthenia gravis: Effectiveness of rituximab in the management of these two diseases. PMID- 28624375 TI - Non-Hodgkin's lymphoma and atypical neck pain: A case report. AB - Neck pain is a common reason for seeking medical attention. It affects at least 15% of the labor force and up to 40% of individuals whose occupation is hazardous. On the other hand, primary bone lymphoma is a very rare disease (less than 1% of all malignant bone tumors), and the relationship between the 2 has rarely been mentioned. We report the case of a patient who had a 1-month history of neck pain. The main symptom was pain on palpation of C2-C6 cervical spinous processes and contracture of the trapezius muscle that did not cease with conventional treatment. Imaging studies indicated an abnormality. He underwent surgery and the results of vertebral biopsy were compatible with diffuse large B cell lymphoma. He was treated with radiotherapy with a good outcome. PMID- 28624376 TI - Orthorexia Nervosa and Eating Disorder Symptoms in Registered Dietitian Nutritionists in the United States. AB - BACKGROUND: Registered dietitian nutritionists are trained to identify optimal food choices for clients based on medical state and lifestyle. Orthorexia nervosa (ON) is a proposed disorder related to obsessions about eating healthfully. Eating disorders (EDs) are serious mental illnesses with symptoms related to eating, body image, and self-esteem. Both ON and EDs are more common among RDNs than the general population. OBJECTIVE: This study examined the prevalence of ON and EDs in RDNs in the United States and, among this sample, assessed whether the presence of ON symptoms related to symptoms of EDs, including weight, shape, eating, and restraint. DESIGN: A cross-sectional design compared responses for participants after dividing into three groups: those scoring at-risk for ON, those with a current or past ED, and a comparison group. PARTICIPANTS: A sample of 2,500 RDNs were invited to complete surveys electronically; 636 responses were received. MAIN OUTCOME MEASURES: Scores on the Orthorexia Nervosa Questionnaire (ORTO-15) and Eating Disorder Examination Questionnaire (EDE-Q) determined prevalence of ON and EDs. Differences in these measures, and body mass index were compared among the three groups. STATISTICAL ANALYSES: Analysis of variance and chi2 analyses were used to compare the groups. RESULTS: For the entire sample, scores on the ORTO-15 suggested 49.5% were at risk for ON, and scores on the EDE Q suggested 12.9% were at risk for an ED, with 8.2% of RDNs self-disclosing treatment for an ED. Both the group disclosing ED treatment and the group at risk for ON had a lower mean body mass index, lower scores on the ORTO-15, and higher scores on the EDE-Q and all its subscales than the comparison group. CONCLUSIONS: Clarifying the relationship between ON and EDs is warranted because ON symptoms appear to be associated not only with disturbances in eating, but also with elevated shape and weight concerns. PMID- 28624377 TI - Evaluation of a biomimetic 3D substrate based on the Human Elastin-like Polypeptides (HELPs) model system for elastolytic activity detection. AB - Elastin is a fibrous protein that confers elasticity to tissues such as skin, arteries and lung. It is extensively cross-linked, highly hydrophobic and insoluble. Nevertheless, elastin can be hydrolysed by bacterial proteases in infectious diseases, resulting in more or less severe tissue damage. Thus, development of substrates able to reliably and specifically detect pathogen secreted elastolytic activity is needed to improve the in vitro evaluation of the injury that bacterial proteases may provoke. In this work, two human biomimetic elastin polypeptides, HELP and HELP1, as well as the matrices derived from HELP, have been probed as substrates for elastolytic activity detection. Thirty strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients were analyzed in parallel with standard substrates, to detect proteolytic and elastolytic activity. Results point to the HELP-based 3D matrix as an interesting biomimetic model of elastin to assess bacterial elastolytic activity in vitro. Moreover, this model substrate enables to further elucidate the mechanism underlying elastin degradation at molecular level, as well as to develop biomimetic material based devices responsive to external stimuli. PMID- 28624378 TI - Glucose triggered enhanced solubilisation, release and cytotoxicity of poorly water soluble anti-cancer drugs fromT1307 micelles. AB - Tetronic(r) 1307 (here after written as T1307) is a hydrophilic ethylene oxide propylene oxide (EO-PO) star block copolymer with long EO chains (Total MW- 18000 and 70% EO). Although biocompatible, its use as a nanocarrier is restricted owing to its high critical micelle concentration (CMC) and temperature (CMT). We examined if the addition of glucose, a common pharmaceutical ingredient promotes micellization. Scattering and thermal studies show formation of stable unimodal micelles and cloud point (CP) decreased linearly. The solubilization of anticancer drugs viz. curcumin (CN) and quercetin (QN) demonstrates improved controlled release kinetics and cytotoxicity. On the whole, modulation in micellar behaviour by glucose opens enchanting possibility of using T1307 micelles as nanoreservoirs. PMID- 28624379 TI - Heart in a Heart. PMID- 28624380 TI - Plasma Phospholipids and Sphingolipids Identify Stent Restenosis After Percutaneous Coronary Intervention. AB - OBJECTIVES: The aim of this study was to evaluate the diagnostic utility of plasma metabolomic biomarkers for in-stent restenosis (ISR). BACKGROUND: ISR remains an issue for patients after percutaneous coronary intervention. Identification of biomarkers to predict ISR could be invaluable for patient care. METHODS: Next-generation metabolomic profiling was performed in the discovery phase from the plasma of 400 patients undergoing percutaneous coronary intervention. In the validation phase, targeted analysis was conducted using stable isotope dilution-multiple reaction monitoring mass spectrometry in another independent group of 500 participants. RESULTS: A set of 6 plasma metabolites was discovered and validated for the diagnosis of ISR as early as 1 month after percutaneous coronary intervention. This biomarker panel classified patients with ISR and control subjects with sensitivity of 91% and specificity of 90% in the discovery phase. The diagnostic accuracy in the independent validation phase was 90% (95% confidence interval: 87% to 100%). The defined 6 metabolites all belong to sphingolipid and phospholipid metabolism, including phosphatidylcholine diacyl C36:0, phosphatidylcholine diacyl C34:2, phosphatidylinositol diacyl C36:4, phosphatidic acid C34:1, ceramide, and sphingomyelin diacyl 18:1/20:1. These biomarkers play essential roles in cell signaling that regulates the proliferation and migration of vascular smooth muscle cells. CONCLUSIONS: Next generation metabolomics demonstrates powerful diagnostic value in estimating ISR related metabolic disturbance. The defined plasma biomarkers provide better early diagnostic value compared with conventional imaging techniques. PMID- 28624381 TI - In-Scaffold Neovascularization 24 Months After Bioresorbable Vascular Scaffold Implantation in a Patient With ST-Segment Elevation Myocardial Infarction. PMID- 28624382 TI - A Small Molecule Solution to the Vexing Problem of Restenosis: Predicting Restenosis. PMID- 28624383 TI - Noninfective Transcatheter Pulmonary Valve Thrombosis: A Rare Cause of Post Implantation Pulmonary Valve Obstruction. PMID- 28624384 TI - A Giant Coronary Artery Aneurysm Treated Using Multiple Overlapping Covered Stents. PMID- 28624385 TI - Arteriovenous Radial Fistula: A Rare and Delayed Complication of Coronary Angiography. PMID- 28624386 TI - Economic disparities and survival from critical illness. PMID- 28624387 TI - Aptamer-based proteomic profiling for prognostication in pulmonary arterial hypertension. PMID- 28624390 TI - Nkx2.5 enhances the efficacy of mesenchymal stem cells transplantation in treatment heart failure in rats. AB - AIMS: The aim of this study is to determine whether Nkx2.5 transfection of transplanted bone marrow mesenchymal stem cells (MSCs) improves the efficacy of treatment of adriamycin-induced heart failure in a rat model. MAIN METHODS: Nkx2.5 was transfected in MSCs by lentiviral vector transduction. The expressions of Nkx2.5 and cardiac specific genes in MSCs and Nkx2.5 transfected mesenchymal stem cells (MSCs-Nkx2.5) were analyzed with quantitative real-time PCR and Western blot in vitro. Heart failure models of rats were induced by adriamycin and were then randomly divided into 3 groups: injected saline, MSCs or MSCs Nkx2.5 via the femoral vein respectively. Four weeks after injection, the cardiac function, expressions of cardiac specific gene, fibrosis formation and collagen volume fraction in the myocardium as well as the expressions of GATA4 and MEF2 in rats were analyzed with echocardiography, immunohistochemistry, Masson staining, quantitative real-time PCR and Western blot, respectively. KEY FINDINGS: Nkx2.5 enhanced cardiac specific gene expressions including alpha-MHC, TNI, CKMB, connexin-43 in MSCs-Nkx2.5 in vitro. Both MSCs and MSCs-Nkx2.5 improved cardiac function, promoted the differentiation of transplanted MSCs into cardiomyocyte like cells, decreased fibrosis formation and collagen volume fraction in the myocardium, as well as increased the expressions of GATA4 and MEF2 in adriamycin induced rat heart failure models. Moreover, the effect was much more remarkable in MSCs-Nkx2.5 than in MSCs group. SIGNIFICANCE: This study has found that Nkx2.5 enhances the efficacy of MSCs transplantation in treatment adriamycin-induced heart failure in rats. Nkx2.5 transfected to transplanted MSCs provides a potential effective approach to heart failure. PMID- 28624389 TI - Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study. AB - BACKGROUND: Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification. METHODS: In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint. FINDINGS: 20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2.5 years' follow up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0.83 (for REVEAL risk score, 95% CI 0.77-0.89; p<0.0001) to 0.91 (for panel and REVEAL 0.87-0.96; p<0.0001) and improving reclassification indices without detriment to calibration. Poor survival was preceded by an adverse change in panel score in paired samples from 43 incident patients with pulmonary arterial hypertension in cohort 3 (p=0.0133). The protein panel was validated in 93 patients with idiopathic or heritable pulmonary arterial hypertension in cohort 4, with 4.4 years' follow-up and improved risk estimates, providing complementary information to the clinical risk equation. INTERPRETATION: A combination of nine circulating proteins identifies patients with pulmonary arterial hypertension with a high risk of mortality, independent of existing clinical assessments, and might have a use in clinical management and the evaluation of new therapies. FUNDING: National Institute for Health Research, Wellcome Trust, British Heart Foundation, Assistance Publique-Hopitaux de Paris, Inserm, Universite Paris-Sud, and Agence Nationale de la Recherche. PMID- 28624391 TI - Efficacy of melatonin, IL-25 and siIL-17B in tumorigenesis-associated properties of breast cancer cell lines. AB - Mammary tumorigenesis can be modulated by melatonin, which has oncostatic action mediated by multiple mechanisms, including the inhibition of the activity of transcription factors such as NF-kappaB and modulation of interleukins (ILs) expression. IL-25 is an active cytokine that induces apoptosis in tumor cells due to differential expression of its receptor (IL-17RB). IL-17B competes with IL-25 for binding to IL-17RB in tumor cells, promoting tumorigenesis. This study purpose is to address the possibility of engaging IL-25/IL-17RB signaling to enhance the effect of melatonin on breast cancer cells. Breast cancer cell lines were cultured monolayers and 3D structures and treated with melatonin, IL-25, siIL-17B, each alone or in combination. Cell viability, gene and protein expression of caspase-3, cleaved caspase-3 and VEGF-A were performed by qPCR and immunofluorescence. In addition, an apoptosis membrane array was performed in metastatic cells. Treatments with melatonin and IL-25 significantly reduced tumor cells viability at 1mM and 1ng/mL, respectively, but did not alter cell viability of a non-tumorigenic epithelial cell line (MCF-10A). All treatments, alone and combined, significantly increased cleaved caspase-3 in tumor cells grown as monolayers and 3D structures (p<0.05). Semi-quantitative analysis of apoptosis pathway proteins showed an increase of CYTO-C, DR6, IGFBP-3, IGFBP-5, IGFPB-6, IGF-1, IGF-1R, Livin, P21, P53, TNFRII, XIAP and hTRA proteins and reduction of caspase-3 (p<0.05) after melatonin treatment. All treatments reduced VEGF-A protein expression in tumor cells (p<0.05). Our results suggest therapeutic potential, with oncostatic effectiveness, pro-apoptotic and anti-angiogenic properties for melatonin and IL-25-driven signaling in breast cancer cells. PMID- 28624392 TI - Role of fractalkine/CX3CR1 signaling pathway in the recovery of neurological function after early ischemic stroke in a rat model. AB - This study aims to explore the role of fractalkine/CX3C chemokine receptor 1 (CX3CR1) signaling pathway in the recovery of neurological functioning after an early ischemic stroke in rats. After establishment of permanent middle cerebral artery occlusion (pMCAO) models, 50 rats were divided into blank, sham, model, positive control and CX3CR1 inhibitor groups. Neurological impairment, walking and grip abilities, and cortical and hippocampal infarctions were evaluated by Zea Longa scoring criterion, beam-walking assay and grip strength test, and diffusion-weighted magnetic resonance imaging. qRT-PCR and Western blotting were performed to detect mRNA and protein expressions. ELISA was conducted to measure concentration of sFractalkine (sFkn), interleukin-1beta (IL-1beta) and TNF-alpha. The recovery rate of neurological functioning impairment and reduced walking and grip abilities was faster in the positive control and CX3CR1 inhibitor groups than the model group. The model, positive control and CX3CR1 inhibitor groups showed increased mRNA and protein expression of chemokine C-X3-C motif ligand 1 (CX3CL1) and CX3CR1, concentration of sFkn, IL-1beta and TNF-alpha, and size of cortical and cerebral infarctions while decreased expression of NGF and BDNF compared with the blank and sham groups. Compared with the model group, the mRNA and protein expression of CX3CL1 and CX3CR1, concentration of sFkn, IL-1beta and TNF-alpha, and size of cortical and cerebral infarctions decreased while expression of NGF and BDNF increased in the positive control and CX3CR1 inhibitor groups. Thus, the study suggests that inhibition of fractalkine/CX3CR1 signaling pathway promotes the recovery of neurological functioning after the occurrence of an early ischemic stroke. PMID- 28624393 TI - Endosymbiosis: The feeling is not mutual. AB - Endosymbiosis is an idea that provided a remarkable amount of explanatory power about the origins of eukaryotic organelles. But it also promoted a number of assumptions that have also been influential, but are less well-examined. Here we look at two of these to see whether or not they fit current evidence. The assumption we first address is that endosymbiotic relationships such as nutritional symbioses and eukaryotic organelles are mutualisms. We argue instead that they are more one-sided associations that can be regarded as context dependent power struggles like any other ecological interaction. The second assumption is that during endosymbiotic interactions (such as the origin of organelles), the host genomes will acquire a great many genes from endosymbionts that assume functions in host systems (as opposed to the well-documented genes whose products are simply targeted back to the endosymbiont or organelle). The idea that these genes exist in large numbers has been influential in a number of hypotheses about organelle evolution and distribution, but in the most carefully examined systems no such mass migration of genes is evident. Overall, we argue that both the nature and impact of endosymbiosis need to be constantly re evaluated to fully understand what roles it really plays in both cell biology and evolution. PMID- 28624394 TI - Reduced foraging investment as an adaptation to patchy food sources: A phasic army ant simulation. AB - Colonies of several ant species within the subfamily Dorylinae alternate stereotypical discrete phases of foraging and reproduction. Such phasic cycles are thought to be adaptive because they minimize the amount of foraging and the related costs, and at the same time enhance the colony-level ability to rely on patchily distributed food sources. In order to investigate these hypotheses, we use here a simple computational approach to study the population dynamics of two species of virtual ant colonies that differ quantitatively in their foraging investment. One species, which we refer to as "phasic", forages only half of the time, mirroring the phasic activity of some army ants; the other "non-phasic" species forages instead all the time. We show that, when foraging costs are relatively high, populations of phasic colonies grow on average faster than non phasic populations, outcompeting them in mixed populations. Interestingly, such tendency becomes more consistent as food becomes more difficult to find but locally abundant. According to our results, reducing the foraging investment, for example by adopting a phasic lifestyle, can result in a reproductive advantage, but only in specific conditions. We thus suggest phasic colony cycles to have emerged together with the doryline specialization in feeding on the brood of other eusocial insects, a resource that is hard to obtain but highly abundant if available. PMID- 28624395 TI - Statin Trials, Cardiovascular Events, and Coronary Artery Calcification: Implications for a Trial-Based Approach to Statin Therapy in MESA. AB - OBJECTIVES: This study sought to determine whether coronary artery calcium (CAC) could be used to optimize statin allocation among individuals for whom trial based evidence supports efficacy of statin therapy. BACKGROUND: Recently, allocation of statins was proposed for primary prevention of atherosclerotic cardiovascular disease (ASCVD) based on proven efficacy from randomized controlled trials (RCTs) of statin therapy, a so-called trial-based approach. METHODS: The study used data from MESA (Multi-Ethnic Study of Atherosclerosis) with 5,600 men and women, 45 to 84 years of age, and free of clinical ASCVD, lipid-lowering therapy, or missing information for risk factors at baseline examination. RESULTS: During 10 years' follow-up, 354 ASCVD and 219 hard coronary heart disease (CHD) events occurred. Based on enrollment criteria for 7 RCTs of statin therapy in primary prevention, 73% of MESA participants (91% of those >55 years of age) were eligible for statin therapy according to a trial-based approach. Among those individuals, CAC = 0 was common (44%) and was associated with low rates of ASCVD and CHD (3.9 and 1.7, respectively, per 1,000 person years). There was a graded increase in event rates with increasing CAC score, and in individuals with CAC >100 (27% of participants) the rates of ASCVD and CHD were 18.9 and 12.7, respectively. Consequently, the estimated number needed to treat (NNT) in 10 years to prevent 1 event varied greatly according to CAC score. For ASCVD events, the NNT was 87 for CAC = 0 and 19 for CAC >100. For CHD events, the NNT was 197 for CAC = 0 and 28 for CAC >100. CONCLUSIONS: Most MESA participants qualified for trial-based primary prevention with statins. Among the individuals for whom trial-based evidence supports efficacy of statin therapy, CAC = 0 and CAC >100 were common and associated with low and high cardiovascular risks, respectively. This information may guide shared decision making aimed at targeting evidence-based statins to those who are likely to benefit the most. PMID- 28624397 TI - How to Mend a Broken Heart? PMID- 28624396 TI - Hybrid Magnetic Resonance Imaging and Positron Emission Tomography With Fluorodeoxyglucose to Diagnose Active Cardiac Sarcoidosis. AB - OBJECTIVES: The purpose of this study was to explore the diagnostic usefulness of hybrid cardiac magnetic resonance (CMR) and positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) for active cardiac sarcoidosis. BACKGROUND: Active cardiac sarcoidosis (aCS) is underdiagnosed and has a high mortality. METHODS: Patients with clinical suspicion of aCS underwent hybrid CMR/PET with late gadolinium enhancement (LGE) and FDG to assess the pattern of injury and disease activity, respectively. Patients were categorized visually as magnetic resonance (MR)+PET+ (characteristic LGE aligning exactly with increased FDG uptake), MR+PET- (characteristic LGE but no increased FDG), MR-PET- (neither characteristic LGE nor increased FDG), and MR-PET+ (increased FDG uptake in absence of characteristic LGE) and further characterized as aCS+ (MR+PET+) or aCS (MR+PET-, MR-PET-, MR-PET+). FDG uptake was quantified using maximum target-to normal-myocardium ratio and the net uptake rate (Ki) from dynamic Patlak analysis. Receiver-operating characteristic methods were used to identify imaging biomarkers for aCS. FDG PET was assessed using computed tomography/PET in 19 control subjects with healthy myocardium. RESULTS: A total of 25 patients (12 males; 54.9 +/- 9.8 years of age) were recruited prospectively; 8 were MR+PET+, suggestive of aCS; 1 was MR+PET-, consistent with inactive cardiac sarcoidosis; and 8 were MR-PET-, with no imaging evidence of cardiac sarcoidosis. Eight patients were MR-PET+ (6 with global myocardial FDG uptake, 2 with focal-on diffuse uptake); they demonstrated distinct Ki values and hyperintense maximum standardized uptake value compared with MR+PET+ patients. Similar hyperintense patterns of global (n = 9) and focal-on-diffuse (n = 2) FDG uptake were also observed in control patients, suggesting physiological myocardial uptake. Maximum target-to-normal-myocardium ratio values were higher in the aCS+ group (p < 0.001), demonstrating an area under the curve of 0.98 on receiver-operating characteristic analysis for the detection of aCS, with an optimal maximum target to-normal myocardium ratio threshold of 1.2 (Youden index: 0.94). CONCLUSIONS: CMR/PET imaging holds major promise for the diagnosis of aCS, providing incremental information about both the pattern of injury and disease activity in a single scan. (In Vivo Molecular Imaging [MRI] of Atherothrombotic Lesions; NCT01418313). PMID- 28624399 TI - Updating Algorithms for Predicting Pre-Test Likelihood of Coronary Artery Disease: A Cure for Inappropriate Testing? PMID- 28624398 TI - Prognostic Significance of Remote Myocardium Alterations Assessed by Quantitative Noncontrast T1 Mapping in ST-Segment Elevation Myocardial Infarction. AB - OBJECTIVES: This study assessed the prognostic significance of remote zone native T1 alterations for the prediction of clinical events in a population with ST segment elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention (PPCI) and compared it with conventional markers of infarct severity. BACKGROUND: The exact role and incremental prognostic relevance of remote myocardium native T1 mapping alterations assessed by cardiac magnetic resonance (CMR) after STEMI remains unclear. METHODS: We included 255 consecutive patients with STEMI who were reperfused within 12 h after symptom onset. CMR core laboratory analysis was performed to assess left ventricular (LV) function, standard infarct characteristics, and native T1 values of the remote, noninfarcted myocardium. The primary endpoint was a composite of death, reinfarction, and new congestive heart failure within 6 months (major adverse cardiac events [MACE]). RESULTS: Patients with increased remote zone native T1 values (>1,129 ms) had significantly larger infarcts (p = 0.012), less myocardial salvage (p = 0.002), and more pronounced LV dysfunction (p = 0.011). In multivariable analysis, remote zone native T1 was independently associated with MACE after adjusting for clinical risk factors (p = 0.001) or other CMR variables (p = 0.007). In C-statistics, native T1 of remote myocardium provided incremental prognostic information beyond clinical risk factors, LV ejection fraction, and other markers of infarct severity (all p < 0.05). The addition of remote zone native T1 to a model of prognostic CMR parameters (ejection fraction, infarct size, and myocardial salvage index) led to net reclassification improvement of 0.82 (95% confidence interval: 0.46 to 1.17; p < 0.001) and to an integrated discrimination improvement of 0.07 (95% confidence interval: 0.02 to 0.13; p = 0.01). CONCLUSIONS: In STEMI patients treated by PPCI, evaluation of remote zone alterations by quantitative noncontrast T1 mapping provided independent and incremental prognostic information in addition to clinical risk factors and traditional CMR outcome markers. Remote zone alterations may thus represent a novel therapeutic target and a useful parameter for optimized risk stratification. (Effect of Conditioning on Myocardial Damage in STEMI [LIPSIA COND]; NCT02158468). PMID- 28624400 TI - Left Ventricular Geometry Determines Prognosis and Reverse J-Shaped Relation Between Blood Pressure and Mortality in Ischemic Stroke Patients. AB - OBJECTIVES: This study sought to investigate the prognostic significance of left ventricular (LV) mass and geometry in ischemic stroke survivors, as well as the LV geometry-specific differences in the blood pressure-mortality relationship. BACKGROUND: LV mass and geometry are well-known prognostic factors in various populations; however, there are no data on their role in ischemic stroke patients. METHODS: We prospectively recruited 2,328 consecutive patients admitted with acute ischemic stroke to our institute between 2002 and 2010. Of these, 2,069 patients were analyzed in whom echocardiographic data were available to assess LV mass and geometry. RESULTS: All-cause mortality was significantly greater in patients with concentric hypertrophy (adjusted hazard ratio [HR]: 1.417; 95% confidence interval [CI]: 1.045 to 1.920) and concentric remodeling (HR: 1.540; 95% CI: 1.115 to 2.127) but nonsignificantly in those with eccentric hypertrophy (HR: 1.388; 95% CI: 0.996 to 1.935) compared with normal geometry in multivariate analyses. Relative wall thickness was a significant predictor of all cause mortality (HR: 1.149 per 0.1-U increase in relative wall thickness; 95% CI: 1.021 to 1.307), whereas LV mass index was not (HR: 1.003 per 1 g/m2 increase in LV mass index; 95% CI: 0.999 to 1.007). Similar results were observed with cardiovascular mortality. In multivariable fractional polynomials, patients with altered LV geometry showed reverse J-curve relationships between acute-phase systolic blood pressure and all-cause or cardiovascular mortality, with the highest risks in the lower extremes, whereas those with normal geometry did not. CONCLUSIONS: Echocardiographic assessment of LV geometry provided independent and additive prognostic information in ischemic stroke patients. A reverse J-shaped relation of mortality with blood pressure was found in patients with abnormal LV geometry. PMID- 28624401 TI - The External Validity of Prediction Models for the Diagnosis of Obstructive Coronary Artery Disease in Patients With Stable Chest Pain: Insights From the PROMISE Trial. AB - OBJECTIVES: This study sought to externally validate prediction models for the presence of obstructive coronary artery disease (CAD). BACKGROUND: A better assessment of the probability of CAD may improve the identification of patients who benefit from noninvasive testing. METHODS: Stable chest pain patients from the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial with computed tomography angiography (CTA) or invasive coronary angiography (ICA) were included. The authors assumed that patients with CTA showing 0% stenosis and a coronary artery calcium (CAC) score of 0 were free of obstructive CAD (>=50% stenosis) on ICA, and they multiply imputed missing ICA results based on clinical variables and CTA results. Predicted CAD probabilities were calculated using published coefficients for 3 models: basic model (age, sex, chest pain type), clinical model (basic model + diabetes, hypertension, dyslipidemia, and smoking), and clinical + CAC score model. The authors assessed discrimination and calibration, and compared published effects with observed predictor effects. RESULTS: In 3,468 patients (1,805 women; mean 60 years of age; 779 [23%] with obstructive CAD on CTA), the models demonstrated moderate-good discrimination, with C-statistics of 0.69 (95% confidence interval [CI]: 0.67 to 0.72), 0.72 (95% CI: 0.69 to 0.74), and 0.86 (95% CI: 0.85 to 0.88) for the basic, clinical, and clinical + CAC score models, respectively. Calibration was satisfactory although typical chest pain and diabetes were less predictive and CAC score was more predictive than was suggested by the models. Among the 31% of patients for whom the clinical model predicted a low (<=10%) probability of CAD, actual prevalence was 7%; among the 48% for whom the clinical + CAC score model predicted a low probability the observed prevalence was 2%. In 2 sensitivity analyses excluding imputed data, similar results were obtained using CTA as the outcome, whereas in those who underwent ICA the models significantly underestimated CAD probability. CONCLUSIONS: Existing clinical prediction models can identify patients with a low probability of obstructive CAD. Obstructive CAD on ICA was imputed for 61% of patients; hence, further validation is necessary. PMID- 28624403 TI - Incorporating Coronary Artery Calcium Into Global Risk Scoring. PMID- 28624402 TI - Development and Validation of a Simple-to-Use Nomogram for Predicting 5-, 10-, and 15-Year Survival in Asymptomatic Adults Undergoing Coronary Artery Calcium Scoring. AB - OBJECTIVES: The purpose of this study was to develop and validate a simple-to-use nomogram for prediction of 5-, 10-, and 15-year survival among asymptomatic adults. BACKGROUND: Simple-to-use prognostication tools that incorporate robust methods such as coronary artery calcium scoring (CACS) for predicting near-, intermediate- and long-term mortality are warranted. METHODS: In a consecutive series of 9,715 persons (mean age: 53.4 +/- 10.5 years; 59.3% male) undergoing CACS, we developed a nomogram using Cox proportional hazards regression modeling that included: age, sex, smoking, hypertension, dyslipidemia, diabetes, family history of coronary artery disease, and CACS. We developed a prognostic index (PI) summing the number of risk points corresponding to weighted covariates, which was used to configure the nomogram. Validation of the nomogram was assessed by discrimination and calibration applied to a separate cohort of 7,824 adults who also underwent CACS. RESULTS: A total of 936 and 294 deaths occurred in the derivation and validation sets at a median follow-up of 14.6 years (interquartile range: 13.7 to 15.5 years) and 9.4 years (interquartile range: 6.8 to 11.5 years), respectively. The developed model effectively predicted 5-, 10-, and 15 year probability of survival. The PI displayed high discrimination in the derivation and validation sets (C-index 0.74 and 0.76, respectively), indicating suitable external performance of our nomogram model. The predicted and actual estimates of survival in each dataset according to PI quartiles were similar (though not identical), demonstrating improved model calibration. CONCLUSIONS: A simple-to-use nomogram effectively predicts 5-, 10- and 15-year survival for asymptomatic adults undergoing screening for cardiac risk factors. This nomogram may be considered for use in clinical care. PMID- 28624404 TI - Accuracy of J-CTO Score Derived From Computed Tomography Versus Angiography to Predict Successful Percutaneous Coronary Intervention. AB - OBJECTIVES: The aim of this study was to compare the ability of conventional versus computed tomography angiography (CTA) to predict procedural success and 30 min wire crossing rates in percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions. BACKGROUND: Coronary CTA can be used to assess the morphology of CTO lesions. METHODS: We examined 205 consecutive patients (218 CTO lesions) who underwent coronary CTA pre-PCI. The J-CTO (Multicenter CTO Registry of Japan) score (the sum of the following 5 binary parameters: blunt proximal cap, calcification, bending >45 degrees , and length of occluded segment >20 mm plus previously failed PCI attempt) was calculated using both CTA and conventional coronary angiography and compared. RESULTS: The median patient age was 69 years (interquartile range: 62 to 75 years), 82.4% were male, and a retrograde approach was attempted in 72 (33.0%) cases. The procedural success rate of the CTO-PCI procedures was 82.6%, and 29.4% of cases achieved 30-min wire crossing. The areas under the curve of the CTA-derived J-CTO score for predicting procedural success and 30-min wire crossing were significantly greater than those derived from conventional angiography (0.855 vs. 0.698; p < 0.001 for procedural success and 0.812 vs. 0.692; p < 0.001, for 30-min wire crossing). In addition, the areas under the curve of CTA-derived evaluations of calcification, bending, and occlusion length were significantly higher than those of derived from angiography for predicting procedural success. CONCLUSIONS: The CTA-derived J-CTO score was a more useful predictor of both procedural success and 30-min wire crossing than the J-CTO score derived from conventional angiography. PMID- 28624405 TI - Coronary Computed Tomographic Angiography Can Predict Chronic Total Occlusion Recanalization Success: Where Do We Go From Here? PMID- 28624406 TI - Global Longitudinal Strain in Asymptomatic Chronic Aortic Regurgitation: The Missing Piece for the Watchful Waiting Puzzle? PMID- 28624407 TI - Left Ventricular Geometry, Blood Pressure, Arterial Hemodynamics, and Mortality After Ischemic Stroke. PMID- 28624408 TI - Native T1 Mapping and Extracellular Volume Mapping for the Assessment of Diffuse Myocardial Fibrosis in Dilated Cardiomyopathy. AB - OBJECTIVES: The purpose of this study was to examine the histological correlation of native myocardial T1 and extracellular volume fraction (ECV) measurement at 3 T for the assessment of diffuse pathological changes in the myocardial tissue, including myocardial fibrosis and extracellular space in dilated cardiomyopathy (DCM). BACKGROUND: Cardiac magnetic resonance T1 techniques allow the quantification of diffuse myocardial fibrosis. However, there are no definitive head-to-head studies of native T1 versus ECV for the detection, quantification, and characterization of pathological changes in the myocardial tissue in DCM by using histological samples for confirmation. METHODS: A total of 36 subjects with DCM (31 men, mean age 56 +/- 16 years) underwent pre- and post-contrast T1 mapping as well as late gadolinium enhancement (LGE) cardiac magnetic resonance at 3-T. Biopsy samples were used for the quantification of collagen volume fraction using picrosirius red staining and an extracellular space component from hematoxylin and eosin-stained myocardium. RESULTS: Nonischemic LGE was observed in 14 of 36 patients. Although patients with LGE had significantly greater biopsy proven collagen volume fraction than those without LGE (21 +/- 12% vs. 11 +/- 8%; p < 0.01), there was substantial overlap of collagen volume fraction values between patients with and without LGE. Both native T1 value and ECV were similarly and significantly associated with biopsy-proven collagen volume fraction (r = 0.77 and r = 0.66, respectively; p < 0.05). Furthermore, ECV had a strong correlation with the biopsy-proven extracellular space component (r = 0.86), whereas native T1 had only a moderate correlation (r = 0.55). Interobserver and intraobserver reproducibility for native T1 and ECV were 0.89, 0.95, 0.96, and 0.98, respectively. CONCLUSIONS: Native T1 exhibited comparable ability as ECV measurement in the detection and quantification of histological collagen volume fraction, with high reproducibility, and therefore diffuse myocardial fibrosis in DCM may be reliably assessed by native T1 mapping without the administration of gadolinium contrast agent. In addition, cardiac magnetic resonance-derived ECV showed excellent agreement with histological extracellular space. PMID- 28624409 TI - Emergence of Integrated Cardiac Magnetic Resonance/Positron Emission Tomography Imaging as the Preferred Imaging Modality in Cardiac Sarcoidosis. PMID- 28624410 TI - Using Trial Eligibility to Personalize Statin Therapy Appears No More Accurate Than a Coin Flip in Determining High-Risk Status. PMID- 28624411 TI - Incremental Prognostic Utility of Left Ventricular Global Longitudinal Strain in Asymptomatic Patients With Significant Chronic Aortic Regurgitation and Preserved Left Ventricular Ejection Fraction. AB - OBJECTIVES: This study sought to examine the prognostic utility of left ventricular (LV) global longitudinal strain (GLS) in asymptomatic patients with >=III+ aortic regurgitation (AR), an indexed LV end-systolic dimension of <2.5 cm/m2, and preserved left ventricular ejection fraction (LVEF). BACKGROUND: Management of asymptomatic patients with severe chronic AR and preserved LVEF is challenging and is typically based on LV dimensions. METHODS: We studied 1,063 such patients (age 53 +/- 16 years; 77% men) seen between 2003 and 2010 (excluding those with symptoms, obstructive coronary artery disease, acute AR/dissection, aortic/mitral stenosis, more than moderate mitral regurgitation, and previous cardiac surgery). Society of Thoracic Surgeons (STS) score was calculated. The primary endpoint was mortality. Average resting LV-GLS was measured offline on 2-, 3-, and 4-chamber views using Velocity Vector Imaging (Siemens, Malvern, Pennsylvania). RESULTS: Mean STS score, LVEF, LV-GLS, and right ventricular systolic pressure were 4.4 +/- 5.0%, 57.0 +/- 4.0%, -19.5 +/- 0.2%, and 31.0 +/- 9.0 mm Hg, respectively. In total, 671 patients (63%) underwent aortic valve surgery at a median of 42 days after the initial evaluation. At 6.8 +/- 3.0 years, 146 patients (14%) had died. On multivariable Cox survival analysis, LV-GLS (hazard ratio [HR]: 1.11), STS score (HR: 1.51), indexed LV end-systolic dimension (HR: 0.50), right ventricular systolic pressure (HR: 1.33), and aortic valve surgery (HR: 0.35) were associated with longer term mortality (all p < 0.001). Sequential addition of LV-GLS and aortic valve surgery improved the C-statistic for longer term mortality for the clinical model (STS score + right ventricular systolic pressure + indexed LV end-systolic dimension) from 0.61 (95% confidence interval [CI]: 0.51 to 0.72) to 0.67 (95% CI: 0.54 to 0.87) and to 0.77 (95% CI: 0.63 to 0.90), respectively (p < 0.001 for both). A significantly higher proportion (log-rank p = 0.01) of patients with LV-GLS worse than median (-19.5%) died versus those with an LV-GLS better than median (86 of 513 [17%] vs. 60 of 550 [11%]). The risk of death at 5 years significantly increased with an LV-GLS of worse than -19%. CONCLUSIONS: In asymptomatic patients with >=III+ chronic AR and preserved LVEF, worsening LV-GLS was associated with longer term mortality, providing incremental prognostic value and improved reclassification. PMID- 28624388 TI - Geo-economic variations in epidemiology, patterns of care, and outcomes in patients with acute respiratory distress syndrome: insights from the LUNG SAFE prospective cohort study. AB - BACKGROUND: Little information is available about the geo-economic variations in demographics, management, and outcomes of patients with acute respiratory distress syndrome (ARDS). We aimed to characterise the effect of these geo economic variations in patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE). METHODS: LUNG SAFE was done during 4 consecutive weeks in winter, 2014, in a convenience sample of 459 intensive-care units in 50 countries across six continents. Inclusion criteria were admission to a participating intensive-care unit (including transfers) within the enrolment window and receipt of invasive or non-invasive ventilation. One of the trial's secondary aims was to characterise variations in the demographics, management, and outcome of patients with ARDS. We used the 2016 World Bank countries classification to define three major geo economic groupings, namely European high-income countries (Europe-High), high income countries in the rest of the world (rWORLD-High), and middle-income countries (Middle). We compared patient outcomes across these three groupings. LUNG SAFE is registered with ClinicalTrials.gov, number NCT02010073. FINDINGS: Of the 2813 patients enrolled in LUNG SAFE who fulfilled ARDS criteria on day 1 or 2, 1521 (54%) were recruited from Europe-High, 746 (27%) from rWORLD-High, and 546 (19%) from Middle countries. We noted significant geographical variations in demographics, risk factors for ARDS, and comorbid diseases. The proportion of patients with severe ARDS or with ratios of the partial pressure of arterial oxygen (PaO2) to the fractional concentration of oxygen in inspired air (FiO2) less than 150 was significantly lower in rWORLD-High countries than in the two other regions. Use of prone positioning and neuromuscular blockade was significantly more common in Europe-High countries than in the other two regions. Adjusted duration of invasive mechanical ventilation and length of stay in the intensive-care unit were significantly shorter in patients in rWORLD-High countries than in Europe-High or Middle countries. High gross national income per person was associated with increased survival in ARDS; hospital survival was significantly lower in Middle countries than in Europe-High or rWORLD-High countries. INTERPRETATION: Important geo-economic differences exist in the severity, clinician recognition, and management of ARDS, and in patients' outcomes. Income per person and outcomes in ARDS are independently associated. FUNDING: European Society of Intensive Care Medicine, St Michael's Hospital, University of Milan-Bicocca. PMID- 28624412 TI - Mild hypothermia protects hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury by improving lysosomal function and autophagic flux. AB - Mild hypothermia has been proven to be useful to treat brain ischemia/reperfusion injury. However, the underlying mechanisms have not yet been fully elucidated. The present study was undertaken to determine whether mild hypothermia protects hippocampal neurons against oxygen-glucose deprivation/reperfusion(OGD/R)-induced injury via improving lysosomal function and autophagic flux. The results showed that OGD/R induced the occurrence of autophagy, while the acidic environment inside the lysosomes was altered. The autophagic flux assay with RFP-GFP tf-LC3 was impeded in hippocampal neurons after OGD/R. Mild hypothermia recovered the lysosomal acidic fluorescence and the lysosomal marker protein expression of LAMP2, which decreased after OGD/R.Furthermore, we found that mild hypothermia up regulated autophagic flux and promoted the fusion of autophagosomes and lysosomes in hippocampal neurons following OGD/R injury, but could be reversed by treatment with chloroquine, which acts as a lysosome inhibitor. We also found that mild hypothermia improved mitochondrial autophagy in hippocampal neurons following OGD/R injury. Finally,we found that chloroquine blocked the protective effects of mild hypothermia against OGD/R-induced cell death and injury. Taken together, the present study indicates that mild hypothermia protects hippocampal neurons against OGD/R-induced injury by improving lysosomal function and autophagic flux. PMID- 28624413 TI - SRSF3-regulated miR-132/212 controls cell migration and invasion by targeting YAP1. AB - Although SRSF3 (Serine/arginine-rich splicing factor 3) plays a significant role in various biological processes, many of its functions still remain unclear. More particularly, little is known about SRSF3's involvement in the regulation of miRNA. In this report, we found that invasive and migratory abilities were inhibited in SRSF3-silenced U2OS and HeLa cells. We also found that a knockdown of SRSF3 results in a decreased expression level of REST (RE1-silencing transcription factor). The silencing of REST increased the expression of primary miR-132/212 as well as their mature forms. In particular, miR-132-3p and miR-212 3p possess an identical seed sequences and a common target gene. Overexpression of miR-132-3p and miR-212-3p suppressed the expression of YAP1 (Yes-associated protein 1) by directly binding to the 3?UTR of its mRNA. CCND1 (Cyclin D1), which acts downstream of YAP1, was downregulated in both miR-132-3p and miR-212-3p overexpressed cells, in correlation with diminished YAP1 levels. Taken together, our results reveal that SRSF3 controls the expression of the miR-132/212 cluster through regulating REST expression, and that the REST-elicited alteration of miRNA expression is implicated in enabling the migratory and invasive abilities of cancer cells. PMID- 28624416 TI - Influence of a Small Amount of Glycerol on the Trehalose Bioprotective Action Analyzed In Situ During Freeze-Drying of Lyzozyme Formulations by Micro-Raman Spectroscopy. AB - Micro-Raman spectroscopy gives the original opportunity to monitor simultaneously the operating process and the protein structure from in situ investigations along the 3 stages of the freeze-drying (FD) process. This opportunity was used for determining how a small amount of glycerol enhances the bioprotective efficiency of trehalose during FD of lysozyme formulations. Three lysozyme formulations were analyzed: lysozyme dissolved in D2O (wt% 1:9), in trehalose-D2O mixture (wt% 1:1:8), and in the trehalose-glycerol-D2O mixture (wt% 1:1:0.17:7.93). Raman mapping performed during each stage of the FD process has provided important information about the preferential interaction between water, trehalose, and lysozyme in relation to the protein stability. It was found that the addition of a small amount of glycerol had a plasticizing effect on the glassy trehalose water matrix during the primary drying stage and then reduced the bioprotective effect of trehalose. By contrast, during the secondary drying stage, glycerol significantly enhanced the stabilizing effect of trehalose in the same sample, by replacing water-trehalose H-bonds with stronger glycerol-trehalose H-bonds and stiffening the amorphous trehalose matrix. The action of glycerol is also related to its capability to prevent aggregation of trehalose, making the structure of the frozen product more homogeneous, by changing the hydrogen-bond networks in the liquid formulation before the freezing stage. PMID- 28624414 TI - Corneal kindled C57BL/6 mice exhibit saturated dentate gyrus long-term potentiation and associated memory deficits in the absence of overt neuron loss. AB - Memory deficits have a significant impact on the quality of life of patients with epilepsy and currently no effective treatments exist to mitigate this comorbidity. While these cognitive comorbidities can be associated with varying degrees of hippocampal cell death and hippocampal sclerosis, more subtle changes in hippocampal physiology independent of cell loss may underlie memory dysfunction in many epilepsy patients. Accordingly, animal models of epilepsy or epileptic processes exhibiting memory deficits in the absence of cell loss could facilitate novel therapy discovery. Mouse corneal kindling is a cost-effective and non-invasive model of focal to bilateral tonic-clonic seizures that may exhibit memory deficits in the absence of cell loss. Therefore, we tested the hypothesis that corneal kindled C57BL/6 mice exhibit spatial pattern processing and memory deficits in a task reliant on DG function and that these impairments would be concurrent with physiological remodeling of the DG as opposed to overt neuron loss. Following corneal kindling, C57BL/6 mice exhibited deficits in a DG associated spatial memory test - the metric task. Compatible with this finding, we also discovered saturated, and subsequently impaired, LTP of excitatory synaptic transmission at the perforant path to DGC synapse. This saturation of LTP was consistent with evidence suggesting that perforant path to DGC synapses in kindled mice had previously experienced LTP-like changes to their synaptic weights: increased postsynaptic depolarizations in response to equivalent presynaptic input and significantly larger amplitude AMPA receptor mediated spontaneous EPSCs. Additionally, there was evidence for kindling-induced changes in the intrinsic excitability of DGCs: reduced threshold to population spikes under extracellular recording conditions and significantly increased membrane resistances observed in DGCs. Importantly, quantitative immunohistochemical analysis revealed hippocampal astrogliosis in the absence of overt neuron loss. These changes in spatial pattern processing and memory deficits in corneal kindled mice represent a novel model of seizure-induced cognitive dysfunction associated with pathophysiological remodeling of excitatory synaptic transmission and granule cell excitability in the absence of overt cell loss. PMID- 28624415 TI - Aging rather than aneuploidy affects monoamine neurotransmitters in brain regions of Down syndrome mouse models. AB - Altered concentrations of monoamine neurotransmitters and metabolites have been repeatedly found in people with Down syndrome (DS, trisomy 21). Because of the limited availability of human post-mortem tissue, DS mouse models are of great interest to study these changes and the underlying neurobiological mechanisms. Although previous studies have shown the potential of Ts65Dn mice - the most widely used mouse model of DS - to model noradrenergic changes, a comprehensive monoaminergic characterization in multiple brain regions has not been performed so far. Here, we used RP-HPLC with electrochemical detection to quantify (nor)adrenergic (NA, adrenaline and MHPG), dopaminergic (DA, HVA and DOPAC), and serotonergic compounds (tryptophan, 5-HT and 5-HIAA) in ten regionally dissected brain regions of Ts65Dn mice, as well as in Dp1Tyb mice - a novel DS mouse model. Comparing young adult aneuploid mice (2.5-5.5months) with their euploid WT littermates did not reveal generalized monoaminergic dysregulation, indicating that the genetic overload in these mice barely affected the absolute concentrations at this age. Moreover, we studied the effect of aging in Ts65Dn mice: comparing aged animals (12-13months) with their younger counterparts revealed a large number of significant changes. In general, the (nor)adrenergic system appeared to be reduced, while serotonergic compounds were increased with aging. Dopaminergic alterations were less consistent. These overall patterns appeared to be relatively similar for Ts65Dn and WT mice, though more observed changes were regarded significant for WT mice. Similar human post-mortem studies are necessary to validate the monoaminergic construct validity of the Ts65Dn and Dp1Typ mouse models. PMID- 28624417 TI - Pharmaceutical Film Coating Catalog for Spectral Domain Optical Coherence Tomography. AB - Optical coherence tomography (OCT) has recently been demonstrated to measure the film coating thickness of pharmaceutical tablets and pellets directly. The results enable the analysis of inter- and intra-tablet coating variability at an off-line and in-line setting. To date, only a few coating formulations have been tried and there is very little information on the applicability of OCT to other coatings. As it is well documented that optical methods including OCT are prone to scattering leading to limited penetration, some pharmaceutical coatings may not be measurable altogether. This study presents OCT measurements of 22 different common coatings for the assessment of OCT applicability. PMID- 28624418 TI - Influence of Dissolution Media and Presence of Alcohol on the In Vitro Performance of Pharmaceutical Products Containing an Insoluble Drug. AB - The purpose of this investigation is to determine how the dissolution media may influence the release rate of an insoluble drug in in vitro conditions. Some oral dosage forms containing ibuprofen, a molecule that shows pH-dependent solubility, are tested. They are evaluated in different media to simulate the gastrointestinal transit at paddle rotation speeds of 50 and 100 rpm. Moreover, the potential effect of different ethanol concentrations on drug release is tested. The dissolution profiles of the tablets show a similar behavior in water (pH 1.0) and phosphate buffer (pH 4.5) where the 2 doses are not completely dissolved. The soft capsules show a different behavior: a certain amount of ibuprofen, which is in solution inside the capsule, reprecipitates in water and in the pH 4.5 buffer. Instead, ibuprofen dissolves rapidly in the pH 6.8 buffer from all the formulations. In the water-ethanol solutions, the dissolution curves show a valuable increase in the drug dissolved at higher ethanol concentrations. PMID- 28624419 TI - Thermo-Optical Protein Characterization for Straightforward Preformulation Development. AB - The determination of protein unfolding and aggregation characteristics during preformulation is of major significance for the development of biopharmaceuticals. The aim of this study was to investigate the feasibility of a new immobilization- and label-free thermo-optical approach as an orthogonal method for material and time-saving early formulation and drugability screenings. In the experimental setup used, changes in the intrinsic tryptophan fluorescence of the protein were measured during IR laser-induced heating of the samples. This temperature increase leads to characteristic fluorescence changes over time, which can be attributed to separable effects of protein unfolding, aggregation, and precipitation, depending on the stability of the respective formulation. The obtained signals were compared with data from forced degradation and thermal stability measurements and correlated well both with the aggregation propensity and with the reversibility of unfolding in different formulations. These results, gathered with only 4-MUL sample volume and 150 s measurement time per formulation, demonstrate potential for general applicability in rapid candidate and formulation selections. PMID- 28624420 TI - Biophysical Characterization and Thermal Stability of Pneumococcal Histidine Triad Protein D in the Presence of Zinc and Manganese. AB - The pneumococcal histidine triad protein D (PhtD) is believed to play a central role in pneumococcal metal ion homeostasis and has been proposed as a promising vaccine candidate against pneumococcal disease. To investigate for potential stabilizers, a panel of physiologically relevant metals was screened using the thermal shift assay and it was found that only Zn2+ and Mn2+ were able to increase PhtD melting temperature. Differential scanning calorimetry analysis revealed a sequential unfolding of PhtD and the presence of at least 3 independent folding domains that can be stabilized by Zn2+ and Mn2+. UV spectroscopy and fluorescence quenching studies showed significant Zn2+-induced tertiary structure changes in PhtD characterized by decreased accessibility of inner tryptophan residues to the aqueous solvent. Isothermal titration calorimetry data show no apparent binding to Mn2+ but revealed a Zn2+:PhtD exothermic interaction stoichiometry of 3:1 with strong enthalpic contribution, suggesting that 3 of the 5 histidine triads are accessible binding sites for Zn2+. Only Zn+2, but not Mn+2, was able to increase the thermal stability of PhtD in the presence of aluminum hydroxide adjuvant, making it a promising stabilizer excipient candidate in vaccine products containing PhtD. PMID- 28624421 TI - Spatial synchrony and harvesting in fluctuating populations:Relaxing the small noise assumption. AB - In spatio-temporal population dynamic models, the most important concept, in addition to mean and variance of local density fluctuations, is the spatial scale of fluctuations in density expressed by studying the spatial autocovariance function. Analytical formulas for this scale in models with local density regulation, dispersal and spatially autocorrelated noise, are rather simple when based on asymptotic theory giving linear models in the limit as the environmental variance approaches zero. The accuracy of these analytical small noise approximations has, however, not been investigated theoretically. Here, we work out improved approximations for the scale as well the spatial autocorrelation function using non-linear logistic local dynamics and going to the next order of approximation with respect to the environmental variance. Generally, it turns out that the asymptotic results are remarkably accurate under moderate fluctuations in density but may be inaccurate for very large fluctuations. For populations with small dispersal capacity, the main error comes from the fact that the logistic dynamics is non-linear, and this error is partly wiped out as dispersal increases. Proportional harvesting has a large effect on the dynamics in spatial as well as non-spatial models, increasing population fluctuations and their spatial scale. The optimal harvesting rate with respect to expected yield per time unit, however, is only to a small extent affected by the magnitude of population fluctuations unless these are very large, so that asymptotic results are applicable over a large range of population fluctuations. PMID- 28624422 TI - Endovascular Proximal Forearm Arteriovenous Fistula for Hemodialysis Access: Results of the Prospective, Multicenter Novel Endovascular Access Trial (NEAT). AB - BACKGROUND: Hemodialysis arteriovenous fistulas (AVFs) are suboptimally used primarily due to problems with maturation, early thrombosis, and patient nonacceptance. An endovascular approach to fistula creation without open surgery offers another hemodialysis vascular access option. STUDY DESIGN: Prospective, single-arm, multicenter study (Novel Endovascular Access Trial [NEAT]). SETTINGS & PARTICIPANTS: Consecutive adult non-dialysis-dependent and dialysis-dependent patients referred for vascular access creation at 9 centers in Canada, Australia, and New Zealand. INTERVENTION: Using catheter-based endovascular technology and radiofrequency energy, an anastomosis was created between target vessels, resulting in an endovascular AVF (endoAVF). OUTCOMES: Safety, efficacy, functional usability, and patency end points. MEASUREMENTS: Safety as percentage of device-related serious adverse events; efficacy as percentage of endoAVFs physiologically suitable (brachial artery flow >= 500mL/min, vein diameter >= 4mm) for dialysis within 3 months; functional usability of endoAVFs to provide prescribed dialysis via 2-needle cannulation; primary and cumulative endoAVF patencies per standardized definitions. RESULTS: 80 patients were enrolled (20 roll-in and 60 participants in the full analysis set; the latter are reported). EndoAVFs were created in 98% of participants; 8% had a serious procedure-related adverse event (2% device related). 87% were physiologically suitable for dialysis (eg, mean brachial artery flow, 918mL/min; endoAVF vein diameter, 5.2mm [cephalic vein]). EndoAVF functional usability was 64% in participants who received dialysis. 12-month primary and cumulative patencies were 69% and 84%, respectively. LIMITATIONS: Due to the unique anatomy and vessels used to create endoAVFs, this was a single-arm study without a surgical comparator. CONCLUSIONS: An endoAVF can be reliably created using a radiofrequency magnetic catheter-based system, without open surgery and with minimal complications. The endoAVF can be successfully used for hemodialysis and demonstrated high 12-month cumulative patencies. It may be a viable alternative option for achieving AVFs for hemodialysis patients in need of vascular access. PMID- 28624423 TI - 2-Methylpyridine-1-ium-1-sulfonate from Allium hirtifolium: An anti-angiogenic compound which inhibits growth of MCF-7 and MDA-MB-231 cells through cell cycle arrest and apoptosis induction. AB - Natural products have well been recognized as sources of drugs in cancer treatment. Some medicinal plants contain the constituents with potent anti angiogenic and anti-cancer effects, which have offered great hopes of being used as drugs for treating various cancers. The present study aims at identifying the anti-angiogenic effects of 2-Methylpyridine-1-ium-1-sulfonate (MPS) isolated from the ethyl acetate extract (EA) of Persian shallot (Allium hirtifolium). In a concentration-dependent manner, the MPS was able to inhibit endothelial cell migration and angiogenesis in both in vivo and in vitro assays, and also significantly suppressed proliferation of MCF-7 and MDA-MB-231 human breast cancer cell lines. Additionally, treatment with MPS showed a significant reduction in the vascular endothelial growth factor (VEGF) secretion level and production/activity of matrix metalloproteinases (MMP-2 and MMP-9) in the studied cells. The flow cytometry analysis indicated that MPS suppressed growth of MCF-7 and MDA-MB-231 cells at G0/G1 and S phases, respectively. Our results indicated that the induction of cell cycle arrest was correlated with the obvious changes in expression of p21, p27 and p53. According to the DNA fragmentation assay, MPS caused apoptosis in both cell lines, which confirms the results obtained with the growth assay. Moreover, the compound-mediated apoptosis accompanied with the increase in the Bax/Bcl-2 ratio and caspase-3 and -9 activities. Molecular docking results indicated that the MPS compound can surprisingly bind to VEGF and VEGF receptors and interacts with their critical amino acids. Finally, compounds with anticancer inhibitory activity (e.g. MPS) are abundant in nature and can be obtained from several sources. So, our data can be clinically developed for treating angiogenesis and cancer significantly. PMID- 28624424 TI - Fusaric acid (FA) protects heart failure induced by isoproterenol (ISP) in mice through fibrosis prevention via TGF-beta1/SMADs and PI3K/AKT signaling pathways. AB - Fusaric acid (FA) is a novel compound derived from a class of nicotinic acid derivatives, exhibiting activity against cancers. However, its role in regulating cardiac injury is limited. Our study was aimed to investigate the role and the underlying molecular mechanism of FA in heart fibrosis and hypertrophy. Isoproterenol (ISP) was used to induce cardiac fibrosis and hypertrophy in vitro and in vivo. FA administration ameliorated hypertrophy by reducing atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and beta -myosin heavy chain (beta-MHC) in vitro and in vivo. Additionally, FA reduced collagen accumulation and fibrosis-related signals, including alpha- smooth muscle actin (alpha-SMA), Collagen type I and Collagen type III. Transforming growth factor beta1 (TGF-beta1)/SMADs and mitogen-activated protein kinases (MAPKs), including p38, extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), signalling pathways were highly activated for ISP induction, which were prevented due to FA administration. Further, FA suppressed ISP-induced PI3K/AKT activity in a dose dependent manner. Of note, FA-reduced MAPKs phosphorylation was associated with phosphoinositide 3-Kinase (PI3K)/Protein kinase B (AKT) activity caused by ISP. However, PI3K/AKT activation showed no effects on TGF beta1/SMADs expression in FA-treated cells after ISP exposure. Together, FA might be an effective candidate agent for preventing cardiac fibrosis by modulating TGF beta1/SMADs and PI3K/AKT signalling pathways. PMID- 28624425 TI - Antiobesity, antioxidant and hepatoprotective effects of Diallyl trisulphide (DATS) alone or in combination with Orlistat on HFD induced obese rats. AB - The increasing rate of obesity in the past years has become a worldwide concern and it causes many diseases. Even though, Orlistat, a synthetic anti-obesity drug approved by FDA, it causes severe side effects. DATS, a natural product from garlic have gained attention in many biological activities. The aim of the study is to determine the impact of Dially trisulpide (DATS) and its combination with Orlistat therapy on obese animals. 30 male Wistar rats (150-180g) were assigned into 5 groups (n=6). Group 1 rats received normal diet and Group 2 fed with high fat diet (HFD) for 14 weeks. Group 3-5 animals fed with HFD for 8 weeks, after that respective drugs were given simultaneously along with HFD for 6 weeks; Group 3: HFD+Orlistat; Group 4: HFD+DATS; Group 5: HFD+Orlistat+DATS. Before and after drug treatment, body weight was measured and blood was collected for assessment of lipid and liver function profiles. After end of the treatment 14 weeks, liver and adipose tissues were collected for antioxidants determination and histological observations. The significantly (p<0.05) increased body weight, serum glucose, total cholesterol, triglycerides, LDL-cholesterol were observed while significantly (p<0.05) decreased HDL-cholesterol and liver function parameters in HFD induced rats when compared to control group. The significantly (p<0.05) decreased activities of SOD, CAT, GPx and GSH levels were observed while significantly (p<0.05) increased LPO in both the tissues of HFD treated group when compared to control. Histopathological changes were observed in both the liver and adipose tissue of HFD treated group. The DATS and its combination with orlistat supplementation restored all the parameters significantly (p<0.05) especially liver function parameters and also retrieved histopathological changes when compared to orlistat alone. DATS and its combination with Orlistat had great effect than Orlistat alone. PMID- 28624426 TI - Saponins extracted from Dioscorea collettii rhizomes regulate the expression of urate transporters in chronic hyperuricemia rats. AB - OBJECTIVE: The current study aimed to investigate whether the saponins, bioactive component of effects of D. collettii, could reduce the serum uric acid level in a hyperuricemic mouse via regulation of urate transporters. METHODS: Chronic hyperuricemia model was established by combine administration of adenine (100mg/kg) and ethambutol (250mg/kg). In the model group, the serum uric acid (SUA), urine uric acid (UUA) volume, and 24-h UUA values increased significantly, while the uric acid clearance rate (CUr) and creatinine clearance rate (CCr) values decreased. Further, the model groups showed significantly lower expression of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) and significantly higher expression of renal tubular urate transporter 1 (URAT1), glucose transporter 9 (GLUT9) and URAT1 mRNA than the normal control group. RESULTS: Saponins administration was found to have a dose-dependent effect, as evidenced by the increase in the 24-h UUA, CUr and CCr values; the decrease in SUA; the decrease in the renal expression of URAT1 mRNA and URAT1 and GLUT9 proteins; and the increase in the renal expression of the OAT1 and OAT3 proteins. CONCLUSION: The saponins extracted from D. collettii rhizomes had an obvious anti hyperuricemic effect through downregulation of the URAT1 mRNA and the URAT1 and GLUT9 proteins and upregulation of the OAT1 and OAT3 proteins. PMID- 28624427 TI - A case grafted with polyglycolic acid sheets and fibrin glue for protection after temporary resection of a metastatic cervical skin tumor. AB - The aim of this case report was to evaluate the usefulness of a grafting with polyglycolic acid sheet and a fibrin glue spray (PGA sheet grafting) after resection of a cervical skin tumor. A 61-year-old woman presented with left cervical skin tumor resistance to chemo-radiotherapy. She had been undergoing multimodal therapy for ovarian serous papillary adenocarcinoma for the previous six years. Although she had a poor general condition and a cervical skin tumor of 9cm in diameter, which was painful and easy bleeding, had offensive smell, she hoped to return to her job. Under local anesthesia, resection was performed, and PGA sheet grafting were used to shield the skin defect. After resection, she was relieved from pain, and could stay home without daily wound treatment. One and half months after resection, the wound was almost epithelialized. The PGA sheets consist of soft, elastic, nonwoven fabric made of PGA. In recent years, PGA sheet grafting has been widely used in the reconstruction and was chosen to shield the skin defect for this case. PGA sheet grafting after resection of cervical skin tumor can be an acceptable method for palliative care to relieve pain, bleeding, offensive smell, and ugly appearance. PMID- 28624428 TI - Undifferentiated sarcoma of the sphenoid sinus. AB - Paranasal sinuses sarcomas are rare and no treatments have been established. We report a young-adult case of sphenoid sinus sarcoma treated by carbon-ion radiotherapy. The patient presented with progressive left-sided visual impairment. A tumor was then identified and partial resection by transnasal approach was performed. The resected mass showed typical morphology of mesenchymal tumor, and morphological and molecular analyses ruled out a predominant-differentiation phenotype. The pathological diagnosis was undifferentiated sarcoma. The residual lesion was treated with carbon-ion radiotherapy, and tumor progression was absent for one year. The patient died of the tumor regrowth 20 months after initial diagnosis. Although this case had a poorer outcome compared with cases of the more-common sarcoma types, our experience suggested that carbon-ion radiotherapy is potentially beneficial in unresectable undifferentiated sarcomas cases of sphenoid sinus. PMID- 28624429 TI - Squamous cell carcinoma of the retromolar trigone: Treatment outcomes. AB - OBJECTIVE: Squamous cell carcinoma (SCC) of the retromolar trigone is uncommon, accounting for 1.4% of all oral cancer cases in Japan. Few studies have examined the optimal treatment for this cancer. The aim of this study was to evaluate the outcome of treatment for primary SCC of the retromolar area. METHODS: We retrospectively analyzed the outcome and prognosis of 45 patients (38 men, 7 women) with SCC of the retromolar trigone who underwent treatment in our department between July 1992 and March 2011. RESULTS: Mean age was 62.4 years. Clinical stages were: stage I (n=4, 8.9%); stage II (n=10, 22.2%); stage III (n=5, 11.1%); and stage IVa (n=26, 57.8%). Surgical resection was performed in all patients and 6 patients also received postoperative radiotherapy. Reconstructive surgery using free flaps was performed in 38 patients; postoperative complications occurred in 5 of these patients. The 3-year local control rate was 80%, and the 3-year over all survival rates for stage I, II, III, and IV disease were 100%, 80%, 40%, and 49.2%, respectively. Cause of death was the original disease in 23 cases and other diseases in 2 cases. The most common cause of death from the original disease was cervical lymph node metastasis. CONCLUSION: The presence of cervical lymph node metastasis was a negative prognostic factor. Marginal mandibulectomy may be selected for patients without distinct bone-marrow infiltration. PMID- 28624430 TI - Comparative assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical parameters, safety and lessons for future studies. AB - With the emergence of novel biotherapeutic formats and immunostimulatory biotherapeutics in cancer immunotherapy, an understanding of immune-complex (IC) mediated hypersensitivity reactions in toxicology studies - and their differentiation from pharmacology - remains key to the preclinical evaluation of these drugs. In this review we provide an in-depth evaluation and comparison of case examples where IC-mediated hypersensitivity reactions were observed in cynomolgus monkeys. We provide details of the parameters evaluated in each study to substantiate and guide the interpretation of these findings. Five study cases (1 therapeutic protein, 4 monoclonal antibodies) are discussed for which effects ranged from minor to fatal. Common characteristics are the high incidence of clinical signs, detectable antidrug antibodies, and accelerated drug clearance up to virtual loss of exposure. In our experience, measurement of cytokine levels in vivo and detection of complement (split products) were supportive markers in situations where coagulopathy was suspected to play a role in the observed effects. Recommendations are outlined to prepare for root-cause analysis of suspected hypersensitivity reactions. Overall, a thorough analysis of the findings has helped to start clinical trials despite major findings. The hypersensitivity reactions with our human(ized) immunoglobulins have not proven to be predictive for humans. PMID- 28624431 TI - Quantitative estimation of motor fluctuations in Parkinson's disease. AB - OBJECTIVES: To provide a quantitative estimation of motor fluctuations in PD through a 12-h Waking-day Motor Assessment (WDMA) and to develop new WDMA-based tools, the Motor Fluctuation Indices. METHODS: Two independent samples of PD patients (exploratory population N = 51, testing population N = 109) were examined. Patients underwent a WDMA using the Unified Parkinson's Disease Rating Scale (UPDRS) and were classified as either having or not having motor fluctuations. To quantify motor fluctuations, the Worsening Index (WI), the Mean Fluctuation Index (MFI) and the Coefficient of Variation (CV) were computed. The optimal cut-off for each index distinguishing patients with or without fluctuations was calculated on the exploratory population. Cut-offs' accuracy was then verified in the testing population. RESULTS: Optimal cut-off scores to differentiate stable patients from fluctuating ones were 8.3 for WI, 5 for MFI and 12.9 for CV. Sensitivity and a specificity were 91.2% (95%CI: 85.9 to 96.5) and 87.8% (95%CI: 81.7 to 93.9) for WI; 75% (95%CI: 66.9 to 83.1) and 90.2% (95%CI: 84.7 to 95.8) for MFI; 69.1% (95%CI: 60.4 to 77.8) and 95.1% (95%CI: 91.1 to 99.2) for CV. Patients with a larger magnitude of fluctuation had higher values for all three indices, whereas patients with multiple daily fluctuations presented only higher WI values. CONCLUSIONS: WDMA-derived Motor Fluctuation Indices may represent reliable tools for evaluating and quantifying the severity of motor fluctuations in PD patients. Even if WDMA is a time-consuming procedure, the detection of Motor Fluctuation Indices could be helpful in assessing therapeutic efficacy on motor fluctuations. PMID- 28624432 TI - Zinc transporter 3 (ZnT3) and vesicular zinc in central nervous system function. AB - Zinc transporter 3 (ZnT3) is the sole mechanism responsible for concentrating zinc ions within synaptic vesicles in a subset of the brain's glutamatergic neurons. This vesicular zinc can then be released into the synaptic cleft in an activity-dependent fashion, where it can exert many signaling functions. This review provides a comprehensive discussion of the localization and function of ZnT3 and vesicular zinc in the central nervous system. We begin by reviewing the fundamentals of zinc homeostasis and transport, and the discovery of ZnT3. We then focus on four main topics. I) The anatomy of the zincergic system, including its development and its modulation through experience-dependent plasticity. II) The role of zinc in intracellular signaling, with a focus on how zinc affects neurotransmitter receptors and synaptic plasticity. III) The behavioural characterization of the ZnT3 KO mouse, which lacks ZnT3 and, therefore, vesicular zinc. IV) The roles of ZnT3 and vesicular zinc in health and disease. PMID- 28624433 TI - The "highs and lows" of the human brain on dopaminergics: Evidence from neuropharmacology. AB - Rewards are appetitive events that elicit approach. Ground-breaking findings from neurophysiological experiments in animals, alongside neuropharmacology and neuroimaging research in human samples have identified dopamine as the main neurochemical messenger of global reward processing in the brain. However, dopamine's contribution to the different components of reward processing remains to be precisely defined. To facilitate the informed design and interpretation of reward studies in humans, we have systematically reviewed all existing human pharmacological studies investigating how drug manipulation of the dopamine system affects reward-related behaviour and its neural correlates. Pharmacological experiments in humans face methodological challenges in terms of the: 1) specificity and safety of the available drugs for administration in humans, 2) uncertainties about pre- or post-synaptic modes of action, and 3) possible interactions with inter-individual neuropsychological or genotypic variables. In order to circumvent some of these limitations, future research should rely on the combination of different levels of observation, in integrative pharmaco-genetics-neurobehavioral approaches, to more completely characterize dopamine's role in both general and modality-specific processing of reward. PMID- 28624434 TI - Brain glucose metabolism: Role of Wnt signaling in the metabolic impairment in Alzheimer's disease. AB - The brain is an organ that has a high demand for glucose. In the brain, glucose is predominantly used in energy production, with almost 70% of the energy used by neurons. The importance of the energy requirement in neurons is clearly demonstrated by the fact that all neurodegenerative disorders exhibit a critical metabolic impairment that includes decreased glucose uptake/utilization and decreased mitochondrial activity, with a consequent diminution in ATP production. In fact, in Alzheimer's disease, the measurement of the general metabolic rate of the brain has been reported to be an accurate tool for diagnosis. Additionally, the administration of metabolic activators such as insulin/glucagon-like peptide 1 can improve memory/learning performance. Despite the importance of energy metabolism in the brain, little is known about the cellular pathways involved in the regulation of this process. Several reports postulate a role for Wnt signaling as a general metabolic regulator. Thus, in the present review, we discuss the antecedents that support the relationship between Wnt signaling and energy metabolism in the Alzheimer's disease. PMID- 28624435 TI - Revisiting the flip side: Long-term depression of synaptic efficacy in the hippocampus. AB - Synaptic plasticity is widely regarded as a putative biological substrate for learning and memory processes. While both decreases and increases in synaptic strength are seen as playing a role in learning and memory, long-term depression (LTD) of synaptic efficacy has received far less attention than its counterpart long-term potentiation (LTP). Never-the-less, LTD at synapses can play an important role in increasing computational flexibility in neural networks. In addition, like learning and memory processes, the magnitude of LTD can be modulated by factors that include stress and sex hormones, neurotrophic support, learning environments, and age. Examining how these factors modulate hippocampal LTD can provide the means to better elucidate the molecular underpinnings of learning and memory processes. This is in turn will enhance our appreciation of how both increases and decreases in synaptic plasticity can play a role in different neurodevelopmental and neurodegenerative conditions. PMID- 28624436 TI - Zonisamide inhibits monoamine oxidase and enhances motor performance and social activity. AB - Zonisamide (ZNS) is an effective drug for not only motor symptoms but also non motor symptoms in Parkinson's disease. However, the actions of ZNS as an anti Parkinsonian drug are not well understood. To clarify the actions of ZNS in vivo, we administered ZNS to mice and examined the effects on neurotransmitter metabolism and behaviors, focusing on motor and non-motor symptoms. Administration of ZNS decreased dopamine (DA) turnover in various brain regions, including the striatum. In behavioral tests, ZNS enhanced locomotor activity and novelty seeking in the open field test, light-dark transition test, and the social interaction test. Consistent with these results of DA metabolism in ZNS treated mice, monoamine oxidase activity was significantly inhibited by ZNS in primary neurons and astrocytes. Collectively, these data suggest that ZNS inhibits monoamine oxidase activity and decreases DA turnover, which increases locomotor activity and novelty seeking in mice. ZNS is potentially useful to improve not only motor symptoms but also neuropsychiatric non-motor symptoms such as apathy in PD. PMID- 28624437 TI - The plasma membrane: Penultimate regulator of ADAM sheddase function. AB - BACKGROUND: ADAM10 and ADAM17 are the best characterized members of the ADAM (A Disintegrin and Metalloproteinase) - family of transmembrane proteases. Both are involved diverse physiological and pathophysiological processes. ADAMs are known to be regulated by posttranslational mechanisms. However, emerging evidence indicates that the plasma membrane with its unique dynamic properties may additionally play an important role in controlling sheddase function. SCOPE OF REVIEW: Membrane events that could contribute to regulation of ADAM-function are summarized. MAJOR CONCLUSIONS: Surface expression of peptidolytic activity should be differentiated from ADAM-sheddase function since the latter additionally requires that the protease finds its substrate in the lipid bilayer. We propose that this is achieved through horizontal and vertical reorganization of membrane nanoarchitecture coordinately occurring at the sites of sheddase activation. Reshuffling of nanodomains thereby guides traffic of enzyme and substrate to each other. For ADAM17 phosphatidylserine exposure is required to then induce its shedding function. GENERAL SIGNIFICANCE: The novel concept that physicochemical properties of the lipid bilayer govern the action of ADAM-proteases may be extendable to other functional proteins that act at the cell surface. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. PMID- 28624438 TI - The metalloproteinase ADAM10: A useful therapeutic target? AB - Proteolytic cleavage represents a unique and irreversible posttranslational event regulating the function and half-life of many intracellular and extracellular proteins. The metalloproteinase ADAM10 has raised attention since it cleaves an increasing number of protein substrates close to the extracellular membrane leaflet. This "ectodomain shedding" regulates the turnover of a number of transmembrane proteins involved in cell adhesion and receptor signaling. It can initiate intramembrane proteolysis followed by nuclear transport and signaling of the cytoplasmic domain. ADAM10 has also been implicated in human disorders ranging from neurodegeneration to dysfunction of the immune system and cancer. Targeting proteases for therapeutic purposes remains a challenge since these enzymes including ADAM10 have a wide range of substrates. Accelerating or inhibiting a specific protease activity is in most cases associated with unwanted side effects and a therapeutic useful window of application has to be carefully defined. A better understanding of the regulatory mechanisms controlling the expression, subcellular localization and activity of ADAM10 will likely uncover suitable drug targets which will allow a more specific and fine-tuned modulation of its proteolytic activity. PMID- 28624439 TI - Signal peptide peptidase and SPP-like proteases - Possible therapeutic targets? AB - Signal peptide peptidase (SPP) and the four homologous SPP-like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 are GxGD-type intramembrane-cleaving proteases (I CLIPs). In addition to divergent subcellular localisations, distinct differences in the mechanistic properties and substrate requirements of individual family members have been unravelled. SPP/SPPL proteases employ a catalytic mechanism related to that of the gamma-secretase complex. Nevertheless, differential targeting of SPP/SPPL proteases and gamma-secretase by inhibitors has been demonstrated. Furthermore, also within the SPP/SPPL family significant differences in the sensitivity to currently available inhibitory compounds have been reported. Though far from complete, our knowledge on pathophysiological functions of SPP/SPPL proteases, in particular based on studies in mice, has been significantly increased over the last years. Based on this, inhibition of distinct SPP/SPPL proteases has been proposed as a novel therapeutic concept e.g. for the treatment of autoimmunity and viral or protozoal infections, as we will discuss in this review. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. PMID- 28624440 TI - BAG3 promotes proliferation of ovarian cancer cells via post-transcriptional regulation of Skp2 expression. AB - Bcl-2 associated athanogene 3 (BAG3) contains a modular structure, through which BAG3 interacts with a wide range of proteins, thereby affording its capacity to regulate multifaceted biological processes. BAG3 is often highly expressed and functions as a pro-survival factor in many cancers. However, the oncogenic potential of BAG3 remains not fully understood. The cell cycle regulator, S-phase kinase associated protein 2 (Skp2) is increased in various cancers and plays an important role in tumorigenesis. The current study demonstrated that BAG3 promoted proliferation of ovarian cancer cells via upregulation of Skp2. BAG3 stabilized Skp2 mRNA via its 3'-untranslated region (UTR). The current study demonstrated that BAG3 interacted with Skp2 mRNA. In addition, miR-21-5p suppressed Skp2 expression, which was compromised by forced BAG3 expression. These results indicated that at least some oncogenic functions of BAG3 were mediated through posttranscriptional regulation of Skp2 via antagonizing suppressive action of miR-21-5p in ovarian cancer cells. PMID- 28624441 TI - Hsp90 inhibitor geldanamycin attenuates the cytotoxicity of sunitinib in cardiomyocytes via inhibition of the autophagy pathway. AB - Sunitinib malate (sunitinib) is an orally available, multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Although sunitinib is effective for the treatment of patients with gastrointestinal stromal tumor, advanced renal cell carcinoma, or pancreatic neuroendocrine tumor, adverse cardiac events associated with sunitinib administration have been reported. Here, we examined the effect of geldanamycin, an inhibitor of heat shock protein (Hsp) 90, on sunitinib-induced cytotoxicity in cardiomyocytes. First, we found that treatment with geldanamycin or other Hsp90 inhibitors (tanespimycin, ganetespib, or BIIB021) significantly attenuated sunitinib-induced cytotoxicity in rat H9c2 cardiomyocytes, suggesting a drug-class effect of Hsp90 inhibitors. We then examined the mechanisms underlying sunitinib-induced cytotoxicity and found that sunitinib induced autophagy in H9c2 cells and that pretreatment with geldanamycin inhibited the induction of autophagy by promoting degradation of the autophagy related proteins Atg7, Beclin-1, and ULK1. Pharmacological assessment with autophagy inhibitors confirmed that geldanamycin attenuated the cytotoxicity of sunitinib by interfering with autophagy. In addition, we found that the molecular chaperone Hsp70, which is induced by geldanamycin, was not involved in the attenuation of sunitinib-induced cytotoxicity. Finally, to provide more clinically relevant data, we confirmed that geldanamycin attenuated sunitinib induced cytotoxicity in human induced pluripotent stem cell-derived cardiomyocytes. Together, these data suggest that geldanamycin attenuates sunitinib-induced cytotoxicity in cardiomyocytes by inhibiting the autophagy pathway. Thus, the further investigation of combination or sequential treatment with an Hsp90 inhibitor and sunitinib is warranted as a potential strategy of attenuating the cardiotoxicity associated with sunitinib administration in the clinical setting. PMID- 28624443 TI - Inhibitory effect of trans-caryophyllene (TC) on leukocyte-endothelial attachment. AB - trans-Caryophyllene (TC) is a major component found in the essential oils of many spices and foods/medicinal plants. It is a natural sesquiterpene and has been the subject of numerous studies. However, the effects of TC on vascular inflammation remain unknown. In this study, we reported that TC treatment in human umbilical vein endothelial cells (HUVECs) prevented attachment of monocytic leukemia cell line THP-1 cells to endothelial cells. In addition, in vivo results indicate that TC inhibited macrophage infiltration to the aortic surface and reduced total serum levels of cholesterol and triglycerides. Importantly, administration of TC could inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1) both in vitro and in vivo. Notably, our data indicate that the inhibitory effects of TC on the expression of VCAM-1 are mediated by the JAK2/STAT1/IRF-1 pathway. TC is a specific agonist of the type 2 cannabinoid receptor (CB2R). Importantly, we further verified that the inhibitory effects of TC on the expression of IRF-1 and VCAM-1 are dependent on activation of CB2R. Inhibition of CB2R by either specific inhibitors or RNA interference abolished the inhibitory effects of TC on the expression of IRF-1 and VCAM-1. Our results suggest that TC might have a capacity to suppress the development of atherosclerosis. PMID- 28624442 TI - Loss of fructose-1,6-bisphosphatase induces glycolysis and promotes apoptosis resistance of cancer stem-like cells: an important role in hexavalent chromium induced carcinogenesis. AB - Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI) transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance. BEAS-2B-Cr-CSC are metabolic inactive as evidenced by reductions in oxygen consumption, glucose uptake, ATP production, and lactate production. Most importantly, BEAS-2B-Cr-CSC are more tumorigenic with high levels of cell self renewal genes, Notch1 and p21. Further study has found that fructose-1,6 bisphosphatase (FBP1), an rate-limiting enzyme driving glyconeogenesis, was lost in BEAS-2B-Cr-CSC. Forced expression of FBP1 in BEAS-2B-Cr-CSC restored ROS generation, resulting in increased apoptosis, leading to inhibition of tumorigenesis. In summary, the present study suggests that loss of FBP1 is a critical event in tumorigenesis of Cr(VI)-transformed cells. PMID- 28624444 TI - Distribution, lipid-bilayer affinity and kinetics of the metabolic effects of dinoseb in the liver. AB - Dinoseb is a highly toxic pesticide of the dinitrophenol group. Its use has been restricted, but it can still be found in soils and waters in addition to being a component of related pesticides that, after ingestion by humans or animals, can originate the compound by enzymatic hydrolysis. As most dinitrophenols, dinoseb uncouples oxidative phosphorylation. In this study, distribution, lipid bilayer affinity and kinetics of the metabolic effects of dinoseb were investigated, using mainly the isolated perfused rat liver, but also isolated mitochondria and molecular dynamics simulations. Dinoseb presented high affinity for the hydrophobic region of the lipid bilayers, with a partition coefficient of 3.75*104 between the hydrophobic and hydrophilic phases. Due to this high affinity for the cellular membranes dinoseb underwent flow-limited distribution in the liver. Transformation was slow but uptake into the liver space was very pronounced. For an extracellular concentration of 10MUM, the equilibrium intracellular concentration was equal to 438.7MUM. In general dinoseb stimulated catabolism and inhibited anabolism. Half-maximal stimulation of oxygen uptake in the whole liver occurred at concentrations (2.8-5.8MUM) at least ten times above those in isolated mitochondria (0.28MUM). Gluconeogenesis and ureagenesis were half-maximally inhibited at concentrations between 3.04 and 5.97MUM. The ATP levels were diminished, but differently in livers from fed and fasted rats. Dinoseb disrupts metabolism in a complex way at concentrations well above its uncoupling action in isolated mitochondria, but still at concentrations that are low enough to be dangerous to animals and humans even at sub-lethal doses. PMID- 28624445 TI - Prevalence and Predictors of Chronic Pain in Pregnancy and Postpartum. AB - OBJECTIVE: A clinically relevant number of patients report pain 1 year after vaginal delivery or Caesarean delivery. Study objectives were to identify the incidence of peripartum pain; determine whether pre-existing pain, pregnancy pain, or pain 2 weeks postpartum predicts pain at 3 months; and to identify whether delivery mode, epidural analgesia use, or delivery complications predict non-genito-pelvic pain postpartum. METHODS: Primiparous women at 30 to 36 weeks GA with an uncomplicated singleton pregnancy were recruited from a large perinatal clinic. Participants completed questionnaires on sociodemographics and non-genito-pelvic pain. Questionnaires were completed in the perinatal clinic and then electronically 2 weeks and 3 months postpartum. RESULTS: Of the 133 women included, 50 patients (38%) had a chronic pain condition or pain prior to pregnancy, whereas 73 patients (55%) reported pain in pregnancy. Pain was present 2 weeks postpartum in 57 patients (43%) and 3 months postpartum in 33 patients (25%). Patients with pre-existing pain were more likely to experience pain 2 weeks postpartum (P = 0.006), and patients with pain 2 weeks postpartum were more likely to have pain 3 months postpartum (P = 0.005). Women who had a Caesarean delivery (P < 0.001) were more likely to have non-genito-pelvic pain at 2 weeks but not 3 months postpartum. CONCLUSIONS: Women with pain 2 weeks postpartum were significantly more likely to have pain at 3 months. Further investigation is required to determine whether pre-existing pain, pain in pregnancy, or pain at 2 weeks postpartum can adequately predict the likelihood of chronic pain. PMID- 28624446 TI - Low Rates of Aspirin Use for the Prevention of Preeclampsia. PMID- 28624447 TI - Enhanced First Trimester Screening for Trisomy 21 with Contingent Cell-Free Fetal DNA: A Comparative Performance and Cost Analysis. AB - OBJECTIVE: Prenatal screening for trisomy 21 is a standard of care. Emerging cell free fetal DNA (cffDNA) technologies can improve screening performance, but they are expensive. This study was conducted to propose a contingent screening model that would incorporate cffDNA technology, would remain affordable, and could be applied equitably in a publically funded system. METHODS: Using performance and cost parameters from published literature, four prenatal screening strategies were compared. Scenario 1 modelled integrated prenatal screening (first trimester nuchal translucency and biochemical markers from both the first and second trimesters) with no cffDNA. Scenarios 2 and 3 modelled first trimester combined screening (FTS) and "enhanced FTS" (adding serum placental growth factor and alpha fetoprotein to FTS), respectively, with contingent cffDNA following a positive result. Scenario 4 modelled cffDNA as the primary screening test. RESULTS: Scenario 1 provides a known detection rate (DR) of 88%, with a false positive rate (FPR) of 3.3%. Scenarios 2 and 3 result in a DR of 94% and overall FPR of 0.59% and 0.33%, respectively, comparable to the DR of 96% and FPR of 0.1% with primary cffDNA (assuming the published test failure rate of 3%). The total cost, cost per woman screened, and cost per case of trisomy 21 detected were lower with scenario 3 (enhanced FTS with contingent cffDNA) compared with primary cffDNA or scenario 2 (FTS with contingent cffDNA). CONCLUSION: Enhanced FTS with contingent cffDNA following a positive result provides a similar performance to that of primary cffDNA at a substantially lower cost. PMID- 28624448 TI - Identification of functional hypoxia inducible factor response elements in the human lysyl oxidase gene promoter. AB - Human lysyl oxidase (LOX) is a hypoxia-responsive gene whose product catalyzes collagen crosslinking and is thought to be important in cancer metastasis and osteoarthritis. We previously demonstrated that LOX was upregulated by hypoxia inducible factor 2 (HIF-2) more strongly than hypoxia inducible 1 (HIF-1). Here, we further investigated the response of the LOX gene and LOX promoter to HIFs. LOX mRNA, measured by real time reverse transcriptase-PCR, was strongly up regulated (almost 40-fold), by transfection of HEK-293T cells with a plasmid encoding the HIF-2alpha subunit of HIF-2, but only three-fold by a plasmid encoding HIF-1alpha. LOX protein was detectable by Western blot of cells transfected with HIF-2alpha, but not with HIF-1alpha. Analysis of a 1487 bp promoter sequence upstream of the human LOX gene revealed 9 potential hypoxia response elements (HREs). Promoter truncation allowed the mapping of two previously unidentified functional HREs, called here HRE8 and HRE7; -455 to -451 and -382 to -386 bp, respectively, upstream of the start codon for LOX. Removal or mutation of these HREs led to a substantial reduction in both HIF-1alpha and HIF-2alpha responsiveness. Also, expression of LOX was significantly inhibited by a small molecule specific HIF-2 inhibitor. In conclusion, LOX is highly responsive to HIF-2alpha and this is largely mediated by two previously unidentified HREs. These observations enhance our understanding of the regulation of this important gene involved in cancer and osteoarthritis, and suggest that these conditions may be targeted by HIF-2 inhibitors. PMID- 28624449 TI - Intratumoral injection of IFN-beta induces chemokine production in melanoma and augments the therapeutic efficacy of anti-PD-L1 mAb. AB - Despite recent advances in treatment for melanoma patients through using immune checkpoint inhibitors, these monotherapies have limitations and additional treatments have been explored. Type I IFNs have been used to treat melanoma and possess immunomodulatory effects including enhancement of T-cell infiltration. T cell plays a critical role in immune checkpoint therapies via restoration of effector functions and tumor infiltration by T-cells predicts longer survival in a variety of cancer types. Moreover, tumor-infiltrating T-cells are associated with the expression of chemokines such as CCL5 and CXCR3 ligands in tumor tissues. We therefore investigated whether intratumoral injection of IFN-beta induces the expression of CCL5 and CXCR3 ligands in melanoma cells and has additional antitumor effects when combined with anti-PD-L1 mAb treatment. IFN beta treatment enhanced CD8+ T-cell infiltration into tumors and CCL5 and CXCR3 ligand expression. In vivo studies using a mouse model showed that monotherapy with IFN-beta, but not with anti-PD-L1 mAb, inhibited tumor growth in comparison to control. However, the therapeutic efficacy of IFN-beta was significantly enhanced by the addition of anti-PD-L1 mAb. This antitumor response of combination therapy was abrogated by anti-CD8 mAb and IFN-beta augmented the neoantigen-specific T-cell response of anti-PD-L1 mAb. Our findings suggest that IFN-beta induces the expression of CCL5 and CXCR3 ligands in melanoma, which could play a role in T-cell recruitment, and enhances the efficacy of anti-PD-L1 mAb treatment in a CD8-dependent manner. PMID- 28624450 TI - beta-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer. AB - Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). beta-elemene has therapeutic effects against several cancers, however, it remains unknown whether beta-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of beta-elemene on macrophages to elucidate a novel mechanism of beta-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by beta-elemene. Moreover, beta elemene regulated the polarization of macrophages from M2 to M1. beta-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate beta-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. PMID- 28624451 TI - Rapamycin protects against paraquat-induced pulmonary fibrosis: Activation of Nrf2 signaling pathway. AB - Paraquat (PQ) is a widely used herbicide indeveloping countries worldwide, and pulmonary fibrosis is one of the most typical features of PQ poisoning. The molecular mechanism of PQ toxicity especially how to treat PQ-induced pulmonary fibrosis is still largely unknown. In animal model of pulmonary fibrosis, we used HE staining, western blotting assay and Real-time PCR assay to analyze the effects of rapamycin on the PQ-induced epithelial mesenchymal transition (EMT). We found that PQ induced the pulmonary fibrosis using HE staining and Masson's staining, and up-regulated the activity of HYP and the mRNA expressions of Collagen I and III (COL-1and COL-3) in pulmonary tissues. We also found that rapamycin down-regulated the mesenchymal cell marker Vimentin and up-regulated the epithelial cell marker E-cadherin both in mRNA and protein levels compared with PQ group. And the EMT associated transcription factor Snail was decreased by rapamycin treatment compared with PQ group. And PQ decreased the Nrf2 expression both in mRNA and protein levels, and rapamycin inhibited these effects of PQ. SFN, a activator of Nrf2, could inhibit the EMT and the expression of Snail. And knockdowon of Nrf2 could abolish the inhibitory effects of rapamycin of PQ induced EMT. In conclusion, rapamycin protects against paraquat-induced pulmonary fibrosis by activation of Nrf2 signaling pathway. PMID- 28624452 TI - Fortunellin protects against high fructose-induced diabetic heart injury in mice by suppressing inflammation and oxidative stress via AMPK/Nrf-2 pathway regulation. AB - Inflammation and oxidative stress contribute to the progression of diabetic cardiomyopathy (DCM). The study was first designed to calculate the role of an anti-inflammatory and anti-oxidant Fortunellin (For) in high fructose-induced cardiac injury in diabetic mice. Fortunellin was found to be none of toxicity to mice and cells using various assays. High fructose was used to induce mice with diabetes. The heart histopathological changes and cardiac function were measured. Fortunellin significantly attenuated the score of histopathological alterations and alleviated heart function, accompanied with reduced inflammation and oxidative stress. The pro-inflammatory cytokines and the expression of p-IkappaB kinase alpha (IKKalpha), p-IkappaBalpha, and p-nuclear factor-kappaB (NF-kappaB) were dramatically reduced by Fortunellin, while superoxide dismutase (SOD), catalase (CAT), heme oxygenase-1 (HO-1) and p-AMP-activated protein kinase (AMPK) were significantly enhanced. Moreover, in H9C2 cells with nuclear factor erythroid 2-related factor 2 (Nrf2) knock-down abolished the prevention of Fortunellin against cardiac injury, proved by elevated inflammatory response and oxidative stress. Suppression of p-AMPK reduced the level of Nrf2 and HO-1 induced by Fortunellin, eliminating the protective role of Fortunellin. For the first time, our study suggested that Fortunellin protected against fructose induced inflammation and oxidative stress by enhancing AMPK/Nrf2 pathway in diabetic mice and cardiomyocytes with fructose treatment. PMID- 28624453 TI - Folic acid attenuates cobalt chloride-induced PGE2 production in HUVECs via the NO/HIF-1alpha/COX-2 pathway. AB - Prostaglandin E2 (PGE2), an important lipid inflammatory mediator involved in the progression of vascular diseases, can be induced by hypoxia in many cell types. While folic acid has been shown to protect against inflammation in THP-1 cells during hypoxia and hypoxia-induced endothelial cell injury, whether it might do so by attenuating PGE2 production remains unclear. To investigate this we constructed a hypoxia-induced injury model by treating human umbilical vein endothelial cells (HUVECs) with cobalt chloride (CoCl2), which mimics the effects of hypoxia. In CoCl2-treated HUVECs, folic acid significantly attenuated PGE2 production and increased vasoprotective nitric oxide (NO) content. Folic acid also decreased cyclooxygenase-2 (COX-2) and hypoxia-inducible factor 1-alpha (HIF 1alpha) expression and altered endothelial nitric oxide synthase (eNOS) signaling by increasing p-eNOS(Ser1177) and decreasing p-eNOS(Thr495) in a dose-dependent manner. Further investigation of the pathway demonstrated that treatment with 2 Methoxyestradiol (2-MeOE2) and celecoxib both decreased CoCl2-induced COX-2 expression but only 2-MeOE2 decreased HIF-1alpha expression. The ability of folic acid to down-regulate HIF-1alpha and COX-2 protein levels was dramatically abrogated by L-NAME treatment, which also decreased eNOS mRNA and NO production. The NO donor sodium nitroprusside also dose-dependently down-regulated HIF-1alpha and COX-2 protein levels. Overall, these findings suggest a novel application for folic acid in attenuating CoCl2-induced PGE2 production in HUVECs via regulation of the NO/HIF-1alpha/COX-2 pathway. PMID- 28624454 TI - WITHDRAWN: Ameloblast-like characteristics of human Hertwig's epithelial rest of Malassez/epithelial rest of Malassez cells via interaction with stem cells from human exfoliated deciduous teeth. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 28624455 TI - Cellular localization of ATBF1 protein and its functional implication in breast epithelial cells. AB - ATBF1, a large transcription factor, was normally localized in nuclei, and its mislocalization to cytoplasm was reported in multiple cancers. However, localization of ATBF1 in breast epithelial cells and its potential functions were unknown. Here, we investigated ATBF1 localization via immunofluorescence staining in different kinds of breast epithelial cells. In MCF10A cells and normal mice mammary gland tissues, ATBF1 was mainly localized in nuclei. Knockdown of ATBF1 expression in MCF10A cells by siRNA promoted cell proliferation. Moreover, ATBF1 was co-localized with chromosome during mitosis, indicating its potential function in mitosis. In an estrogen receptor (ER)-positive breast cancer cell line (MCF7), estrogen induced ATBF1 translocation from cytoplasm to nuclei in an ER dependent pathway. In ER-negative cells (Hs578T and MDA-MB-231), ATBF1 was co localized with GM130 in cytoplasm, indicating ATBF1 localization was associated with protein modification in golgi body. The results were beneficial for intensive investigation of ATBF1's function with different cellular localization in breast cancer. PMID- 28624456 TI - In vitro evidences of epithelial to mesenchymal transition in low cell-density cultured human fetal hepatocytes. AB - Culturing fetal hepatocytes in high cell-density allowed stabilization of the hepatocyte phenotype up to 8 weeks, including the maintenance of liver-specific functions. On the other hand, when cultured at low cell-density, fetal hepatocytes underwent morphological modifications and acquired fibroblastic morphology. Since a switch from E-cadherin to vimentin expression accompanied these changes, we hypothesized the occurrence of epithelial-to-mesenchymal transition when fetal hepatocytes were cultured at low cell-density. Changes in gene expressionsuch as up-regulation of fibrosis-related geneswere also observed, suggesting that the low cell-density culture system promoted the acquisition of a profibrotic phenotype in cultured hepatocytes. The origin of fibrogenic cells in the liver is not well known, and the role of hepatocytes as a source of fibrogenic cells is controversial. Therefore, we hypothesized that hepatocytes undergoing epithelial-to-mesenchymal transition could have a central role in liver fibrosis as a source of fibrogenic cells. To conclude, the high cell density culture system could be a useful model for in vitro studies requiring long-term cultures of hepatocytes, such as the development of pharmaceutical drugs and mechanisms of viral infections. The low cell-density culture system may provide additional insights into the origin of fibrogenic cells in the liver, thus contributing to the development of novel therapeutic approaches. PMID- 28624457 TI - Effect of calcium carbonate particle shape on phagocytosis and pro-inflammatory response in differentiated THP-1 macrophages. AB - Phagocytosis is a physiological process used by immune cells such as macrophages to actively ingest and destroy foreign pathogens and particles. It is the cellular process that leads to the failure of drug delivery carriers because the drug carriers are cleared by immune cells before reaching their target. Therefore, clarifying the mechanism of particle phagocytosis would have a significant implication for both fundamental understanding and biomedical engineering. As far as we know, the effect of particle shape on biological response has not been fully investigated. In the present study, we investigated the particle shape-dependent cellular uptake and biological response of differentiated THP-1 macrophages by using calcium carbonate (CaCO3)-based particles as a model. Transmission electron microscopy analysis revealed that the high uptake of needle-shaped CaCO3 particles by THP-1 macrophages because of their high phagocytic activity. In addition, the THP-1 macrophages exposed to needle-shaped CaCO3 accumulated a large amount of calcium in the intracellular matrix. The enhanced release of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) by the THP-1 macrophages suggested that the needle-shaped CaCO3 particles trigger a pro-inflammatory response. In contrast, no pro-inflammatory response was induced in undifferentiated THP-1 monocytes exposed to either needle or cuboidal-shaped CaCO3 particles, probably because of their low phagocytic activity. We also found that phosphate-coated particles efficiently repressed cellular uptake and the resulting pro-inflammatory response in both THP-1 macrophages and primary peritoneal macrophages. Our results indicate that the pro inflammatory response of macrophages upon exposure to CaCO3 particles is shape- and surface property-dependent, and is mediated by the intracellular accumulation of calcium ions released from phagocytosed CaCO3 particles. PMID- 28624458 TI - DNA hypomethylation circuit of mouse rDNA repeats in the germ cell lineage. AB - DNA methylation is dynamically reprogrammed at two developmental periods, in primordial germ cells and pre-implantation embryos, via distinct phases of DNA demethylation and de novo methylation. Here we show that ribosomal DNA (rDNA) promoters are hypomethylated in sperm and oocytes; this hypomethyaltion was maintained during pre-implantation development. A DNA methylation analysis of embryonic and extra-embryonic cells on embryonic day 7.5 (E7.5) revealed that the rDNA promoter was slightly methylated in embryonic and extra-embryonic regions. Intriguingly, this hypomethylated status was observed throughout germ cell development on E13.5 and E18.5. In contrast, fetal somatic cells in gonad and liver acquired methylation on E13.5, which was maintained in adult tissues. These findings indicate a unique rDNA methylation signature in the germ cell lineage. PMID- 28624459 TI - Overexpression of a bacterial mercury transporter MerT in Arabidopsis enhances mercury tolerance. AB - The phytoremediation by using of green plants in the removal of environmental pollutant is an environment friendly, green technology that is cost effective and energetically inexpensive. By using Agrobacterium-mediated gene transfer, we generated transgenic Arabidopsis plants ectopically expressing mercuric transport protein gene (merT) from Pseudomonas alcaligenes. Compared with wild-type (WT) plants, overexpressing PamerT in Arabidopsis enhanced the tolerance to HgCl2. Further results showed that the enhanced total activities or corresponding transcripts of antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and guaiacol peroxidase (POD) were observed in transgenic Arabidopsis under HgCl2 stress. These results were confirmed by the alleviation of oxidative damage, as indicated by the decrease of thiobarbituric acid reactive substances (TBARS) contents and reactive oxygen species (ROS) accumulation. In addition, localization analysis of PaMerT in Arabidopsis protoplast showed that it is likely to be associated with vacuole. In all, PamerT increased mercury (Hg) tolerance in transgenic Arabidopsis, and decreased production of Hg-induced ROS, thereby protecting plants from oxidative damage. The present study has provided further evidence that bacterial MerT plays an important role in the plant tolerance to HgCl2 and in reducing the production of ROS induced by HgCl2. PMID- 28624460 TI - Identification of KX2-391 as an inhibitor of HBV transcription by a recombinant HBV-based screening assay. AB - Antiviral therapies for chronic hepatitis B virus (HBV) infection that are currently applicable for clinical use are limited to nucleos(t)ide analogs targeting HBV polymerase activity and pegylated interferon alpha (PEG-IFN). Towards establishing an effective therapy for HBV related diseases, it is important to develop a new anti-HBV agent that suppresses and eradicates HBV. This study used recombinant HBV encoding NanoLuc to screen anti-HBV compounds from 1827 US Food and Drug Administration approved compounds and identified several compounds that suppressed HBV infection. Among them, KX2-391, a non-ATP competitive inhibitor of SRC kinase and tubulin polymerization, was identified as a lead candidate for an anti-HBV drug. Treatment of sodium taurocholate cotransporting polypeptide (NTCP) transduced-HepG2 (HepG2-NTCP) or primary human hepatocytes with KX2-391 suppressed HBV replication in a dose-dependent manner. The anti-HBV activity of KX2-391 appeared not to depend on SRC kinase activity because siRNA for SRC mRNA did not impair the HBV infection/replication. The anti HBV activity of KX2-391 depended on the inhibitory effect of tubulin polymerization similar to other tubulin polymerization inhibitors, some of which were shown to inhibit HBV replication. KX2-391 inhibited HBV transcription driven by a HBV precore promoter in an HBV X protein-independent manner but did not inhibit the activity of HBV-S1, -S2, -X or cytomegalovirus promoters. Treatment with KX2-391 reduced the expression of several various factors including hepatocyte nuclear factor-4a. PMID- 28624462 TI - Evaluation on antiviral activity of coumarin derivatives against spring viraemia of carp virus in epithelioma papulosum cyprini cells. AB - As one of the most serious pathogens in the freshwater aquatic environment, spring viraemia of carp virus (SVCV) induces a high mortality rate in several cyprinid fishes. In this study, we designed and synthesized a total of 44 coumarin derivatives to evaluate the anti-SVCV activity. By comparing the inhibitory concentration at half-maximal activity (IC50), two imidazole coumarins (B4 and C2) were selected, with maximum inhibitory rates on SVCV more than 90%. Mechanistically, B4 or C2 did not affect viral adhesion and delivery from endosomes to the cytosol. Further, B4 and C2 could decline the apoptosis in SVCV infected cells and the viral activated caspase-3, 8, 9 activities. Other results showed that SVCV induced the cytoskeletal structure to be a circumferential ring of microtubules near the nucleus, with occurring a disrupted microfilament organization. In comparison, cytoskeleton structure in drug-treated cells kept complete. In addition, the cellular microstructure in drug treatments showed no significant change; while SVCV-infected cells were seriously shrunk, and observed typical apoptotic features including cell shrinkage, volume reduction and cell blebbing. More importantly, B4 and C2 enhanced anti-oxidative enzyme gene expression and triggered the Nrf-2 pathway to keep balance of intracellular redox state. Therefore, the use of two imidazole coumarins (B4 and C2) could be a viable way of preventing and controlling SVCV infection. PMID- 28624461 TI - Emetine inhibits replication of RNA and DNA viruses without generating drug resistant virus variants. AB - At a noncytotoxic concentration, emetine was found to inhibit replication of DNA viruses [buffalopoxvirus (BPXV) and bovine herpesvirus 1 (BHV-1)] as well as RNA viruses [peste des petits ruminants virus (PPRV) and Newcastle disease virus (NDV)]. Using the time-of-addition and virus step-specific assays, we showed that emetine treatment resulted in reduced synthesis of viral RNA (PPRV and NDV) and DNA (BPXV and BHV-1) as well as inhibiting viral entry (NDV and BHV-1). In addition, emetine treatment also resulted in decreased synthesis of viral proteins. In a cell free endogenous viral polymerase assay, emetine was found to significantly inhibit replication of NDV, but not BPXV genome, suggesting that besides directly inhibiting specific viral polymerases, emetine may also target other factors essentially required for efficient replication of the viral genome. Moreover, emetine was found to significantly inhibit BPXV-induced pock lesions on chorioallantoic membrane (CAM) along with associated mortality of embryonated chicken eggs. At a lethal dose 50 (LD50) of 126.49 ng/egg and at an effective concentration 50 (EC50) of 3.03 ng/egg, the therapeutic index of the emetine against BPXV was determined to be 41.74. Emetine was also found to significantly delay NDV-induced mortality in chicken embryos associated with reduced viral titers. Further, emetine-resistant mutants were not observed upon long-term (P = 25) sequential passage of BPXV and NDV in cell culture. Collectively, we have extended the effective antiviral activity of emetine against diverse groups of DNA and RNA viruses and propose that emetine could provide significant therapeutic value against some of these viruses without inducing an antiviral drug-resistant phenotype. PMID- 28624463 TI - Insights from genotype-phenotype correlations by novel SPEG mutations causing centronuclear myopathy. AB - Centronuclear myopathies (CNM) are a clinically and genetically heterogeneous group of congenital myopathies, defined histologically by increased number of fibres with centrally located nuclei, and type I fibre predominance in muscle biopsy. Myotubular myopathy, the X-linked form of CNM caused by mutations in the phosphoinositide phosphatase MTM1, is histologically characteristic since muscle fibres resemble myotubes. Here we present two unrelated patients with CNM and typical myotubular fibres in the muscle biopsy caused by mutations in striated muscle preferentially expressed protein kinase (SPEG). Next generation sequencing revealed novel biallelic homozygous mutations in SPEG in both cases. Patient 1 showed the c.1627_1628insA (p.Thr544Aspfs*48) mutation and patient 2 the c.9586C>T (p.Arg3196*) mutation. The clinical phenotype was distinctive in the two patients since patient 2 developed a dilated cardiomyopathy with milder myopathy features, while patient 1 showed only myopathic features without cardiac involvement. These findings expand the genotype-phenotype correlations after the initial report. Additionally, we describe whole body muscle MRI of patient 2 and we argue on the different SPEG isoforms in skeletal muscle and heart as the possible explanation leading to variable phenotypes of SPEG mutations. PMID- 28624465 TI - Muscle pathology in Vici syndrome-A case study with a novel mutation in EPG5 and a summary of the literature. AB - Vici syndrome is a disorder characterized by myopathy, cardiomyopathy, agenesis of the corpus callosum, immunodeficiency, cataracts, hypopigmentation, microcephaly, gross developmental delay and failure to thrive. It is caused by mutations in EPG5, which encodes a protein involved in the autophagy pathway. Although myopathy is part of the syndrome, few publications have described the muscle pathology. We present a detailed morphological analysis in a boy with Vici syndrome due to a novel homozygous one-base deletion in EPG5 (c.784delA), and we review the histopathological findings from previous reports. Muscle biopsy was performed at three months of age and demonstrated small vacuolated fibers, frequently with internal nuclei, and expressing developmental and fast myosin isoforms. There was an increase in acid phosphatase activity in the small fibers, which also showed LAMP-2 upregulation, glycogen accumulation and contained numerous p62-positive inclusions and some lipid droplets. Electron microscopy demonstrated hypoplastic fibers with massive glycogen accumulation and extensive disorganization of the myofibrils. This study expands the muscle pathological features of Vici syndrome and demonstrates a pattern of vacuolar myopathy with glycogen storage and immature, hypoplastic and atrophic muscle fibers. Increased lysosomes and accumulation of p62 are in line with a disturbance of the autophagic pathway as an essential part of the pathogenesis. PMID- 28624464 TI - Complex phenotypes associated with STIM1 mutations in both coiled coil and EF hand domains. AB - Dominant mutations in STIM1 are a cause of three allelic conditions: tubular aggregate myopathy, Stormorken syndrome (a complex phenotype including myopathy, hyposplenism, hypocalcaemia and bleeding diathesis), and a platelet dysfunction disorder, York platelet syndrome. Previous reports have suggested a genotype phenotype correlation with mutations in the N-terminal EF-hand domain associated with tubular aggregate myopathy, and a common mutation at p.R304W in a coiled coil domain associated with Stormorken syndrome. In this study individuals with STIM1 variants were identified by exome sequencing or STIM1 direct sequencing, and assessed for neuromuscular, haematological and biochemical evidence of the allelic disorders of STIM1. STIM1 mutations were investigated by fibroblast calcium imaging and 3D modelling. Six individuals with STIM1 mutations, including two novel mutations (c.262A>G (p.S88G) and c.911G>A (p.R304Q)), were identified. Extra-neuromuscular symptoms including thrombocytopenia, platelet dysfunction, hypocalcaemia or hyposplenism were present in 5/6 patients with mutations in both the EF-hand and CC domains. 3/6 patients had psychiatric disorders, not previously reported in STIM1 disease. Review of published STIM1 patients (n = 49) confirmed that neuromuscular symptoms are present in most patients. We conclude that the phenotype associated with activating STIM1 mutations frequently includes extra-neuromuscular features such as hypocalcaemia, hypo-/asplenia and platelet dysfunction regardless of mutation domain. PMID- 28624466 TI - Resectable Clinical N2 Non-Small Cell Lung Cancer; What Is the Optimal Treatment Strategy? An Update by the British Thoracic Society Lung Cancer Specialist Advisory Group. AB - Patients and clinicians are faced with uncertainty as to the optimal treatment strategy for potentially resectable NSCLC in which there is clinical evidence of involvement of the ipsilateral mediastinum. Randomized controlled trials and meta analyses have failed to demonstrate superiority of one bimodality strategy over another (chemotherapy plus surgery versus chemotherapy plus radiotherapy). One trial of trimodality treatment with chemotherapy, radiotherapy, and surgery demonstrated an improvement in progression-free, but not overall, survival versus chemotherapy and radiotherapy. There are a number of limitations to the data in this complex and heterogenous patient group. No randomized controlled trial has specifically studied patients with single-station N2 disease versus multistation N2 disease. When discussing treatment for fit patients with potentially resectable cN2 NSCLC, lung cancer teams should consider trimodality treatment with chemotherapy, radiotherapy, and surgery or bimodality treatment with chemotherapy and either surgery or radiotherapy. We advocate that all patients see both a thoracic surgeon and the oncology team to discuss these different approaches. PMID- 28624467 TI - Comprehensive Analysis of EGFR-Mutant Abundance and Its Effect on Efficacy of EGFR TKIs in Advanced NSCLC with EGFR Mutations. AB - INTRODUCTION: A qualitative detection method for EGFR mutations is not sufficient to guide precise targeted therapy in clinical practice. The aim of this study was to explore the relationship between the abundance of EGFR mutations and efficacy of EGFR tyrosine kinase inhibitors (TKIs). METHODS: We used the amplification refractory mutation system (ARMS) method optimized with competitive blockers and specific mutation quantitation (ARMS+) to quantitatively evaluate the abundance of EGFR mutations in 201 patients with advanced NSCLC. A cutoff value of the abundance of EGFR mutations was determined by receiver operating characteristic analysis in a training group and validated in a validation group. RESULTS: The abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of 19DEL was significantly higher than that of L858R, with cutoff values for 19DEL and L858R of 4.9% and 9.5%, respectively. The median progression-free survival in the high group was significantly longer than that in the low group (19DEL, 15.0 versus 2.0 months [p < 0.001] and L858R, 12.3 versus 2.0 months [p < 0.001]) in the training set. Similar results were also observed in the validation set. Nine of 13 patients harboring T790M mutation achieved a partial response to EGFR TKIs. Most (seven of nine) were identified to have a low abundance of T790M mutation. The abundance of EGFR mutations appeared to be more significantly associated with the copy number of EGFR mutations from circulating tumor DNA in 19DEL group. CONCLUSION: The abundance of EGFR activating mutation by ARMS+ was significantly associated with objective response to EGFR TKIs. The abundance of EGFRT790M mutation may have an adverse impact on progression-free survival rather than on objective response rate in patients with advanced EGFR-mutant NSCLC treated with EGFR TKIs. PMID- 28624468 TI - Fish mass immunization against virus with recombinant "spiny" bacterins. AB - Bacterins obtained from recombinant bacteria displaying heterologous antigens in its surface coded by prokaryotic rather than eukaryotic expression plasmids (here called "spiny" bacterins or spinycterins), have been used to increase fish immunogenicity of recombinant viral protein fragments. To explore their immunogenicity, five bacterial-specific membrane anchor-motifs characterized in the literature (Nmistic, Mistic, NTD, YAIN and YBEL) were genetically fused to the immunorelevant cystein-free 117 amino acid fragment II from the ORF149 of cyprinid herpes virus 3 (frgIICyHV3). The fusion of anchor-motifs to the N terminus of frgIICyHV3 enriched expression in E.coli outer membranes as demonstrated by ELISA, immunofluorescence and flow cytometry of formaldehyde fixed recombinant bacteria (spinycterins). Unconventional low-intensity ultrasound inducing mucosal micropores in a reversible non-harmful manner was used before carp or zebrafish immersion on spinycterin suspensions as a practical delivery alternative to fish-to-fish injection. After ELISA screening for anti frgIICyHV3-specific antibodies of spinycterin-immunized fish plasma, the YBEL constructs were identified as the most immunogenic in both carp and zebrafish, correlating with one of the best expressed recombinant proteins as demonstrated by Western blot and surface enriched as demonstrated by ELISA and flow cytometry. The use of prokaryotic expression plasmids to express viral immunorelevant protein fragments in traditionally used fish vaccination bacterins should reduce the environmental concerns raised by DNA vaccination based on eukaryotic expression plasmids. Therefore, spinycterins may be a useful alternative to develop safer fish viral vaccines and mass vaccination methods. PMID- 28624469 TI - Effects of protein sources on growth, immunity and antioxidant capacity of juvenile pearl oyster Pinctada fucata martensii. AB - In this study, we formulated five diets, namely, P1, P2, P3, P4 and P5, with Chlorella sp. powder, Spirulina platensis powder, yeast powder, soybean meal and corn gluten, respectively, as major protein sources. A feeding experiment was designed to evaluate the effects of formulated diets on the growth performance, immunity and antioxidant and biomineralization capacity of juvenile pearl oyster (Pinctada fucata martensii). In the experiments, the five groups were separately fed with P1, P2, P3, P4 and P5 diets. After 45 days of feeding, pearl oysters fed on P1, P2, P3 and P4 diets showed significantly higher absolute growth rate and protease and amylase activities than those fed on P5 diet (P < 0.05). Moreover, pearl oysters fed on P1, P2, P3 and P4 diets exhibited significantly higher activities of alkaline phosphatase (AKP), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) (P < 0.05). Significantly higher expression levels of SOD, GPx, CAT, heat shock protein (HSP) 70, HSP90, nacrein, pif177 and pearlin mRNA were observed in pearl oysters fed on P1, P2, P3 and P4 diets relative to those fed on P5 (P < 0.05). Results suggested the suitability of Chlorella sp. powder, S. platensis powder, yeast powder and soybean meal as protein sources for development of formulated diets for pearl oyster P. f. martensii. PMID- 28624470 TI - Molecular cloning and expression analysis of CCL25 and its receptor CCR9s from Epinephelus coioides post Cryptocaryon irritans infection. AB - Among other functions, CCL25/CCR9 has an important role in regulating the trafficking of developing T cells in the thymus, and in homing memory T cells to the small intestine. The function of this chemokine-receptor complex is not well studied in fish. We identified a CCL25-like (EcCCL25, 108 aa) and two CCR9-like sequences (EcCCR9aa 373 aa; and EcCCR9b, 375 aa) from a transcriptome database of orange-spotted grouper (Epinephelus coioides). EcCCL25, EcCCR9a, and EcCCR9b shared conserved structural features with homologs from mammals and from other fish, and a consistent relationship with phylogenetic trees and sequence identities. In healthy grouper, EcCCL25, EcCCR9a, and EcCCR9b were highly expressed in the thymus, and the gills, were expressed at lower levels in the stomach, and had different expression levels in other tissues. After infection with Cryptocaryon irritans, EcCCL25 expression was up-regulated at early time points in the spleen and head kidney, and in the skin, and gills at later time points; EcCCR9a expression was increased in the gill, spleen, and head kidney. After infection with C. irritans, EcCCR9b expression was reduced in all tissues tested. These results suggested that grouper CCL25/CCR9a complex may be involved in host defense against C. irritans infection. PMID- 28624471 TI - Vitamin E antagonizes ozone-induced asthma exacerbation in Balb/c mice through the Nrf2 pathway. AB - Millions of people are regularly exposed to ozone, a gas known to contribute significantly to worsening the symptoms of patients with asthma. However, the mechanisms underlying these ozone exacerbation effects are not fully understood. In this study, we examined the exacerbation effect of ozone in OVA-induced asthma mice and tried to demonstrate the protective mechanism of vitamin E (VE). An asthma mouse model was established, and used to identify the exacerbating effects of ozone by assessing cytokine and serum immunoglobulin concentrations, airway leukocyte infiltration, histopathological changes in lung tissues, and airway hyper-responsiveness. We then determined the amount of reactive oxygen species (ROS) accumulated, the extent to which VE induced ROS elimination, and examined the antagonistic effects of VE on the ozone-induced exacerbating effects. This study showed that 1-ppm ozone exposure could exacerbate OVA-induced asthma in mice. More importantly we found that ozone induced oxidative stress in asthmatic airways may lead to the inhibition of Nuclear factor-erythroid 2-related factor 2 (Nrf2), and may subsequently induce even more exaggerated oxidative stress associated with asthma exacerbation. Through VE induced Nrf2 activation and the subsequent increase in Nrf2 target protein expression, this study suggests a novel mechanism for alleviating ozone exacerbated asthma symptoms. PMID- 28624472 TI - Nonclinical safety of astilbin: A 4-week oral toxicity study in rats with genotoxicity, chromosomal aberration, and mammalian micronucleus tests. AB - Astilbin is an active flavonoid compound isolated from Rhizoma Smilacis Glabrae. It has been widely used as an anti-hepatic, anti-arthritic, and anti-renal injury agent. However, its safety has not yet been established. The objective of this study was to evaluate 4-week repeated oral toxicity and genotoxicity of astilbin. We examined oral toxicity in Sprague-Dawley rats after daily oral administration of astilbin at 50, 150, and 500 mg/kg for 4 weeks. Negative control animals received the same volume of the solvent. Astilbin administration did not lead to death, body weight gain, food consumption, or adverse events. There were no significant differences in toxicity between the astilbin and control group; we observed no toxic effects on hematological or urinalysis parameters, biochemical values, organ weight, or histopathological findings. We assessed the genotoxicity of astilbin with the Ames test (TA97a, TA98, TA100, TA102, and TA1535), chromosomal aberration assay (using Chinese hamster ovary cells), and mammalian micronucleus test (in mice). We found no genotoxicity in any tested strains. The no-observed-adverse-effect level (NOAEL) for astilbin in the 4-week repeated oral toxicity study in rats was greater than 500 mg/kg body weight/day, regardless of gender. Results also suggested that astilbin does not have genotoxicity potential. PMID- 28624474 TI - "Exposure to the insecticides permethrin and malathion induces leukemia and lymphoma-associated gene aberrations in vitro". AB - Epidemiological studies have associated the exposure to permethrin and malathion with increased risk of leukemia and lymphoma. The aim of this study was to evaluate whether in vitro exposure to permethrin and malathion induces aberrations in genes involved in the etiology of these hematological malignancies. Genetic abnormalities in the IGH, KMT2A (MLL), ETV6 and RUNX1 genes, and aneuploidy induced by the in vitro exposure to permethrin and malathion (200MUM, 24h), were analyzed by FISH in peripheral blood mononuclear cells (PBMCs). The gene fusions IGH-BCL2, KMT2A-AFF1 and ETV6-RUNX1 were further analyzed with nested RT-PCR in PBMCs, and in K562 cells exposed to acute and chronic treatments (0.1MUM, 24h or every third day for two weeks) of insecticides. FISH analysis revealed that permethrin induces aneuploidy and structural alterations in IGH and KMT2A genes, and malathion induces breaks in KMT2A. RT-PCR detected ETV6-RUNX1 fusion in PBMCs acutely exposed to permethrin. Permethrin also induced ETV6-RUNX1 and IGH-BCL2 fusions in K562 cells, and malathion induced KMT2A-AFF1 and ETV6-RUNX1 fusions. Overall, we identified that both insecticides induce breaks and fusions in the studied genes, and permethrin induces aneuploidy. This study presents evidence of damage in cancer genes caused by these insecticides. PMID- 28624473 TI - Antibody blood-brain barrier efflux is modulated by glycan modification. AB - BACKGROUND: Drug delivery to the brain is a major roadblock to treatment of Alzheimer's disease. Recent results of the PRIME study indicate that increasing brain penetration of antibody drugs improves Alzheimer's treatment outcomes. New approaches are needed to better accomplish this goal. Based on prior evidence, the hypothesis that glycan modification alters antibody blood-brain barrier permeability was tested here. METHODS: The blood-brain barrier permeability coefficient Pe of different glycosylated states of anti-amyloid IgG was measured using in vitro models of brain microvascular endothelial cells. Monoclonal antibodies 4G8, with sialic acid, and 6E10, lacking sialic acid, were studied. The amount of sialic acid was determined using quantitative and semi-quantitative surface plasmon resonance methods. RESULTS: Influx of IgG was not saturable and was largely insensitive to IgG species and glycosylation state. By contrast, efflux of 4G8 efflux was significantly lower than both albumin controls and 6E10. Removal of alpha2,6-linked sialic acid group present on 12% of 4G8 completely restored efflux to that of 6E10 but increasing the alpha2,6-sialylated fraction to 15% resulted in no change. Removal of the Fc glycan from 4G8 partially restored efflux. Alternate sialic acid groups with alpha2,3 and alpha2,8 linkages, nor on the Fc glycan, were not detected at significant levels on either 4G8 or 6E10. CONCLUSIONS: These results support a model in which surface sialylated 4G8 inhibits its own efflux and that of asialylated 4G8. GENERAL SIGNIFICANCE: Glycan modification has the potential to increase antibody drug penetration into the brain through efflux inhibition. PMID- 28624475 TI - Oxidoreductases on their way to industrial biotransformations. AB - Fungi produce heme-containing peroxidases and peroxygenases, flavin-containing oxidases and dehydrogenases, and different copper-containing oxidoreductases involved in the biodegradation of lignin and other recalcitrant compounds. Heme peroxidases comprise the classical ligninolytic peroxidases and the new dye decolorizing peroxidases, while heme peroxygenases belong to a still largely unexplored superfamily of heme-thiolate proteins. Nevertheless, basidiomycete unspecific peroxygenases have the highest biotechnological interest due to their ability to catalyze a variety of regio- and stereo-selective monooxygenation reactions with H2O2 as the source of oxygen and final electron acceptor. Flavo oxidases are involved in both lignin and cellulose decay generating H2O2 that activates peroxidases and generates hydroxyl radical. The group of copper oxidoreductases also includes other H2O2 generating enzymes - copper-radical oxidases - together with classical laccases that are the oxidoreductases with the largest number of reported applications to date. However, the recently described lytic polysaccharide monooxygenases have attracted the highest attention among copper oxidoreductases, since they are capable of oxidatively breaking down crystalline cellulose, the disintegration of which is still a major bottleneck in lignocellulose biorefineries, along with lignin degradation. Interestingly, some flavin-containing dehydrogenases also play a key role in cellulose breakdown by directly/indirectly "fueling" electrons for polysaccharide monooxygenase activation. Many of the above oxidoreductases have been engineered, combining rational and computational design with directed evolution, to attain the selectivity, catalytic efficiency and stability properties required for their industrial utilization. Indeed, using ad hoc software and current computational capabilities, it is now possible to predict substrate access to the active site in biophysical simulations, and electron transfer efficiency in biochemical simulations, reducing in orders of magnitude the time of experimental work in oxidoreductase screening and engineering. What has been set out above is illustrated by a series of remarkable oxyfunctionalization and oxidation reactions developed in the frame of an intersectorial and multidisciplinary European RTD project. The optimized reactions include enzymatic synthesis of 1 naphthol, 25-hydroxyvitamin D3, drug metabolites, furandicarboxylic acid, indigo and other dyes, and conductive polyaniline, terminal oxygenation of alkanes, biomass delignification and lignin oxidation, among others. These successful case stories demonstrate the unexploited potential of oxidoreductases in medium and large-scale biotransformations. PMID- 28624476 TI - Measuring Immune Response to Commonly Used Vaccinations in Adult Recipients of Allogeneic Hematopoietic Cell Transplantation. AB - Recipients of hematopoietic cell transplantation (HCT) are at risk for potentially preventable infectious complications because of defects in humoral and cell-mediated immunity. Studies of vaccine immunogenicity in HCT recipients have shown that antibody response rates depend on age, type of vaccine, and presence or absence of graft-versus-host disease. However, few large-scale studies have assessed the immune response to vaccination in HCT recipients. Additionally, HCT recipients have much higher rates of potentially preventable infections compared with the general population even after vaccination. This review evaluates the available studies and our view on the measurement of specific antibody titers, definition of an immune response, and durability of response in HCT recipients in both inactivated and live attenuated vaccines. PMID- 28624478 TI - Nanomedicine-based combination anticancer therapy between nucleic acids and small molecular drugs. AB - Anticancer therapy has always been a vital challenge for the development of nanomedicine. Repeated single therapeutic agent may lead to undesirable and severe side effects, unbearable toxicity and multidrug resistance due to complex nature of tumor. Nanomedicine-based combination anticancer therapy can synergistically improve antitumor outcomes through multiple-target therapy, decreasing the dose of each therapeutic agent and reducing side effects. There are versatile combinational anticancer strategies such as chemotherapeutic combination, nucleic acid-based co-delivery, intrinsic sensitive and extrinsic stimulus combinational patterns. Based on these combination strategies, various nanocarriers and drug delivery systems were engineered to carry out the efficient co-delivery of combined therapeutic agents for combination anticancer therapy. This review focused on illustrating nanomedicine-based combination anticancer therapy between nucleic acids and small-molecular drugs for synergistically improving anticancer efficacy. PMID- 28624480 TI - Evaluation of thoracic vertebrae rotation in patients with pectus excavatum. AB - PURPOSE: The aim of our study was to evaluate thoracic vertebrae rotation in patients with pectus excavatum. Moreover, we wanted to assess the prevalence, the severity and relationship between pectus excavatum and adolescent idiopathic scoliosis (AIS). METHODS: We performed retrospective analysis of 82 preoperative chest CT in children with pectus excavatum performed between January 2008 and December 2011. For each patient Haller Index and Cobb angle was measured. To evaluate the severity of thoracic scoliosis we measured vertebral rotation for Th8 and for vertebra at the level of highest chest deformation using Aaro Dahlborn method. RESULTS: From the group of 54 patients with pectus excavatum enrolled in the study AIS was diagnosed in 8 patients (14,81%). In patients with symmetric deformation, Th8 rotation was found in 21 patients; the rotation of the apical vertebra was found in 20 patients. In patients with asymmetric deformation Th8 rotation was found in 10 patients; the rotation of the apical vertebra was found in 8 patients. CONCLUSIONS: 1. We have confirmed the higher prevalence of pectus excavatum in boys; 2. We have found a significant relationship between pectus excavatum and adolescent idiopathic scoliosis; 3. We have shown that deformation of the anterior chest wall enforces rotation of the thoracic spine; 4. We haven't found the relationship between the severity of the chest deformity (HI measured) and severity of AIS (Cobb angle measured); 5. We have shown a significant association between HI measured and rotation of thoracic vertebra at the level of highest chest deformation (apical vertebra) in symmetric pectus excavatum. LEVEL OF EVIDENCE: Level IV, Diagnostic study. PMID- 28624477 TI - Nanoformulations for combination or cascade anticancer therapy. AB - Nanoparticle drug formulations have been extensively investigated, developed, and in some cases, approved by the Food and Drug Administration (FDA). Synergistic combinations of drugs having distinct tumor-inhibiting mechanisms and non overlapping toxicity can circumvent the issue of treatment resistance and may be essential for effective anti-cancer therapy. At the same time, co-delivery of a combined regimen by a single nanocarrier presents a challenge due to differences in solubility, molecular weight, functional groups and encapsulation conditions between the two drugs. This review discusses cellular and microenvironment mechanisms behind treatment resistance and nanotechnology-based solutions for effective anti-cancer therapy. Co-loading or cascade delivery of multiple drugs using of polymeric nanoparticles, polymer-drug conjugates and lipid nanoparticles will be discussed along with lipid-coated drug nanoparticles developed by our lab and perspectives on combination therapy. PMID- 28624479 TI - Food restriction-induced changes in motivation differ with stages of the estrous cycle and are closely linked to RFamide-related peptide-3 but not kisspeptin in Syrian hamsters. AB - We tested the hypothesis that the effects of food restriction on behavioral motivation are mediated by one or both of the RFamide peptides, RFamide-related peptide-3 (RFRP-3) and kisspeptin (Kp) in female Syrian hamsters (Mesocricetus auratus). Female hamsters fed ad libitum and given a choice between food and adult male hamsters are highly motivated to visit males instead of food on all four days of the estrous cycle, but after 8days of mild food restriction (75% of ad libitum intake) they shift their preference toward food every day of the estrous cycle until the day of estrus, when they shift their preference back toward the males. In support of a role for RFRP-3 in these behavioral changes, the preference for food and the activation of RFRP-3-immunoreactive (Ir) cells in the dorsomedial hypothalamus (DMH) showed the same estrous cycle pattern in food restricted females, but no association was observed between behavior and the activation of Kp cells in the hypothalamic arcuate nucleus or preoptic area. Next, we tested the hypothesis that food-restriction-induced activation of RFRP-3 Ir cells is modulated by high levels of ovarian steroids at the time of estrus. In support of this idea, on nonestrous days, mild food restriction increased activation of RFRP-3-Ir cells, but failed to do so on the day of estrus even though this level of food restriction did not significantly decrease circulating concentrations of estradiol or progesterone. Furthermore, in ovariectomized females, food-restriction-induced increases in activation of RFRP-3-Ir cells were blocked by systemic treatment with progesterone alone, estradiol plus progesterone, but not estradiol alone. Central infusion with RFRP-3 in ad libitum fed females significantly decreased sexual motivation and produced significant increases in 90-minute food hoarding, in support of the hypothesis that elevated central levels of RFRP-3 are sufficient to create the shift in behavioral motivation in females fed ad libitum. Together, these results are consistent with the hypothesis that high levels of ingestive motivation are promoted during the nonfertile phase of the estrous cycle by elevated activation of RFRP-3-Ir cells, and RFRP-3-Ir cellular activation is modulated by ovarian steroids around the time of estrus, thereby diverting attention away from food and increasing sexual motivation. PMID- 28624481 TI - miR-34a overexpression predicts poor prognostic outcome in colorectal adenocarcinoma, independently of clinicopathological factors with established prognostic value. AB - OBJECTIVES: MicroRNA-34a (miR-34a) is regulated by TP53 and, in response, downregulates the expression of a gamut of protein-coding genes, including apoptosis regulators, transcription factors, cyclins, and cyclin-dependent kinases. Its upregulation initiates a reprogramming of gene expression and promotes apoptosis. The purpose of this study was the investigation of the potential clinical significance of miR-34a as a molecular prognostic biomarker in colorectal adenocarcinoma using an in-house real-time quantitative PCR (qPCR) methodology. DESIGN AND METHODS: Total RNA was extracted from 113 primary colorectal adenocarcinoma specimens and 61 paired non-cancerous colorectal tissue samples. After polyadenylation and reverse transcription, miR-34a molecules were determined using qPCR based on SYBR Green chemistry. Calculations were performed using the comparative CT method. Finally, extensive biostatistical analysis was performed. RESULTS: miR-34a expression does not significantly differ between colorectal adenocarcinoma tissue specimens and adjacent non-cancerous mucosae. However, miR-34a expression increases progressively as colorectal adenocarcinoma loses its differentiation, being highest in grade III tumors (P=0.010). Moreover, miR-34a expression is a potential unfavorable prognostic biomarker in colorectal adenocarcinoma, predicting poor disease-free and overall survival (P=0.002 and P=0.019, respectively), independently of classical clinicopathological parameters. Most importantly, miR-34a expression stratifies patients without local (N0) and/or distant metastasis (M0) at the time of diagnosis into two groups with substantially different prognosis (P=0.013 and P=0.002, respectively). CONCLUSIONS: High miR-34a levels in colorectal adenocarcinoma predict a rather increased risk for disease recurrence and poor overall survival, particularly in patients at an early TNM stage. The unfavorable prognostic potential of miR-34a expression is independent of established prognostic features of colorectal adenocarcinoma. PMID- 28624482 TI - NMR quantification of trimethylamine-N-oxide in human serum and plasma in the clinical laboratory setting. AB - BACKGROUND AND OBJECTIVES: Trimethylamine-N-oxide (TMAO) produced by gut microbiota metabolism of dietary choline and carnitine has been shown to be associated with increased risk of cardiovascular disease (CVD) and to provide incremental clinical prognostic utility beyond traditional risk factors for assessing a patient's CVD risk. The aim of this study was to develop an automated nuclear magnetic resonance (NMR) spectroscopy assay for quantification of TMAO concentration in serum and plasma using a high-throughput NMR clinical analyzer. METHODS: Key steps in assay development included: (i) shifting the TMAO analyte peak to a less crowded region of the spectrum with a pH buffer/reagent, (ii) attenuating the broad protein background signal in the spectrum and (iii) using a non-negative least squares algorithm for peak deconvolution. Assay performance was evaluated according to Clinical and Laboratory Standards Institute guidelines. A method comparison study was performed to compare TMAO concentrations quantified by NMR and mass spectrometry (MS). RESULTS: The within run and within-lab imprecision ranged from 4.3 to 14.5%. Under the acquisition method employed, the NMR assay had a limit of blank, detection and quantitation of 1.6, 3.0 and 3.3MUM, respectively. Linearity was demonstrated within the reportable range of 3.3 to 3000MUM. TMAO measurements using the NMR assay, which involves minimal sample preparation, compared well with values obtained with the MS-based assay (R2=0.98). CONCLUSIONS: The NMR based assay provides a simple and accurate measurement of circulating TMAO levels amenable to the high-throughput demands of the clinical chemistry laboratory. Moreover, assay performance enables the levels of TMAO to be quantified in serum or plasma at clinically actionable concentrations for the assessment of cardiovascular disease risks and individualized dietary monitoring. PMID- 28624483 TI - Biomarker Profiles of Acute Heart Failure Patients With a Mid-Range Ejection Fraction. AB - OBJECTIVES: In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare them with patients with a reduced (heart failure with a reduced ejection fraction [HFrEF]) and preserved (heart failure with a preserved ejection fraction [HFpEF]) ejection fraction. BACKGROUND: Limited data are available on biomarker profiles in acute HFmrEF. METHODS: A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 h in 843 acute heart failure patients from the PROTECT trial. HFpEF was defined as left ventricular ejection fraction (LVEF) of >=50% (n = 108), HFrEF as LVEF of <40% (n = 607), and HFmrEF as LVEF of 40% to 49% (n = 128). RESULTS: Hemoglobin and brain natriuretic peptide levels (300 pg/ml [HFpEF]; 397 pg/ml [HFmrEF]; 521 pg/ml [HFrEF]; ptrend <0.001) showed an upward trend with decreasing LVEF. Network analysis showed that in HFrEF interactions between biomarkers were mostly related to cardiac stretch, whereas in HFpEF, biomarker interactions were mostly related to inflammation. In HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. In HFpEF and HFmrEF (but not in HFrEF), remodeling markers at admission and changes in levels of inflammatory markers across the first 24 h were predictive for all-cause mortality and rehospitalization at 60 days (pinteraction <0.05). CONCLUSIONS: Biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch and in HFpEF related to inflammation. Patients with HFmrEF showed an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers. (PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; NCT00328692). PMID- 28624484 TI - Progression to Stage D Heart Failure Among Outpatients With Stage C Heart Failure and Reduced Ejection Fraction. AB - OBJECTIVES: This study sought to estimate the rate of progression to Stage D heart failure (HF) among outpatients with Stage C HF and to identify risk factors for progression. BACKGROUND: The pool of patients who may be candidates for advanced HF therapies is growing. METHODS: We estimated 3-year progression to clinically determined Stage D HF and competing mortality among 964 outpatients with Stage C heart failure with reduced ejection fraction (HFrEF), where ejection fraction is <=40%. RESULTS: The mean age of patients was 62 +/- 15 years; 35% were women; 47% were white; 46% were black, and 7% were of other races; median baseline ejection fraction was 28% (25th to 75th percentile: 20% to 35%); and 47% had ischemic heart disease. After 3.0 years (25th to 75th percentile: 1.7 to 3.2 years), 112 patients progressed to Stage D (3-year incidence: 12.2%; 95% confidence interval [CI]: 10.2% to 14.6%; annualized: 4.5%; 95% CI: 3.8% to 5.5%), and 116 patients died before progression (3-year competing mortality: 12.9%; annualized: 4.7%; 95% CI: 3.9% to 5.6%). By 3 years, 25.1% of patients (95% CI: 22.2% to 28.1%) had either progressed to Stage D or died (annualized: 9.2%; 95% CI: 8.1% to 10.5%). Annualized progression rates were higher in black versus white patients (6.3% vs. 2.7%, respectively; p < 0.001), nonischemic versus ischemic patients (6.1% vs. 2.9%, respectively; p < 0.001), and in New York Heart Association functional class III to IV versus I to II patients (7.5% vs. 1.9%, respectively; p < 0.001) but were similar for men and women (4.7% vs. 4.2%, respectively; p = 0.53). Lower ejection fraction and blood pressure, renal and hepatic dysfunction, and chronic lung disease rates were additional predictors of progression. Predictors of competing mortality were different from those of disease progression. CONCLUSIONS: Among patients with Stage C HFrEF receiving care in a referral center, 4.5% progressed to Stage D HF each year, with earlier progression among black and nonischemic patients. These findings have implications for healthcare planning and resource allocation for these patients. PMID- 28624485 TI - Time to Take the Failure Out of Heart Failure: The Importance of Optimism. PMID- 28624487 TI - The Changing Landscape of Atrial Fibrillation: Time to Target Heart Failure Prevention. PMID- 28624486 TI - Modifiable Risk Factors for Incident Heart Failure in Atrial Fibrillation. AB - OBJECTIVES: This study sought to identify modifiable risk factors and estimate the impact of risk factor modification on heart failure (HF) risk in women with new-onset atrial fibrillation (AF). BACKGROUND: Incident HF is the most common nonfatal event in patients with AF, although strategies for HF prevention are lacking. METHODS: We assessed 34,736 participants in the Women's Health Study who were free of prevalent cardiovascular disease at baseline. Cox models with time varying assessment of risk factors after AF diagnosis were used to identify significant modifiable risk factors for incident HF. RESULTS: Over a median follow-up of 20.6 years, 1,495 women developed AF without prevalent HF. In multivariable models, new-onset AF was associated with an increased risk of HF (hazard ratio [HR]: 9.03; 95% confidence interval [CI]: 7.52 to 10.85). Once women with AF developed HF, all-cause (HR: 1.83; 95% CI: 1.37 to 2.45) and cardiovascular mortality (HR: 2.87; 95% CI: 1.70 to 4.85) increased. In time updated, multivariable models accounting for changes in risk factors after AF diagnosis, systolic blood pressure >120 mm Hg, body mass index >=30 kg/m2, current tobacco use, and diabetes mellitus were each associated with incident HF. The combination of these 4 modifiable risk factors accounted for an estimated 62% (95% CI: 23% to 83%) of the population-attributable risk of HF. Compared with women with 3 or 4 risk factors, those who maintained or achieved optimal risk factor control had a progressive decreased risk of HF (HR for 2 risk factors: 0.60; 95% CI: 0.37 to 0.95; 1 risk factor: 0.40; 95% CI: 0.25 to 0.63; and 0 risk factors: 0.14; 95% CI: 0.07 to 0.29). CONCLUSIONS: In women with new-onset AF, modifiable risk factors including obesity, hypertension, smoking, and diabetes accounted for the majority of the population risk of HF. Optimal levels of modifiable risk factors were associated with decreased HF risk. Prospective assessment of risk factor modification at the time of AF diagnosis may warrant future investigation. PMID- 28624488 TI - Association between HLA-DQB1 alleles and susceptibility to coronary artery disease in Southern Han Chinese. AB - Accumulated evidence indicates that polymorphisms in human leukocyte antigens (HLA) are associated with susceptibility to coronary artery disease (CAD). However, whether HLA-DQB1 alleles are correlated with susceptibility to CAD is unclear. In this study, significantly lower frequencies of the allele groups (DQB1*03:01:01G and DQB1*05:03:01G) and the genotypes (DQB1*03:01:01G/DQB1*03:01:01G and DQB1*03:01:01G/DQB1*05:03:01G) were observed in the CAD group compared with that in the controls. However, notably higher frequencies of DQB1*04:01:01G and genotype DQB1*05:01:01G/DQB1*03:01:01G were observed in the CAD patients than in the controls. Further analysis in subgroups showed that DQB1*03:01:01G was present at a significantly lower frequency in both female and male CAD patients compared with the corresponding controls; however, DQB1*04:01:01G was overtly high only in male CAD patients. CAD patients with diabetes showed a negative association with DQB1*03:01:01G and DQB1*05:03:01G and a positive association with DQB1*04:01:01G, DQB1*03:02:01G and DQB1*03:03:02G. Results of logistic regression analysis indicated that DQB1*03:01:01G and DQB1*05:03:01G were significantly associated with reduced susceptibility to CAD, but DQB1*04:01:01G, DQB1*03:02:01G and DQB1*03:03:02G had no correlation with CAD. Together, these findings indicate that CAD in Southern Han Chinese is negatively associated with HLA-DQB1*03:01:01G and DQB1*05:03:01G, and males with HLA-DQB1*04:01:01G are likely to have high risk for CAD. PMID- 28624489 TI - Association of genetic polymorphisms of macrophage inhibitory factor (MIF) and B cell activating factor (BAFF) with the detection of donor specific antibodies in kidney allograft recipients. AB - The posttransplant development of donor specific antibodies (DSA) initiates the antibody mediated rejection (AMR), which is associated with the increased rate of graft loss. One of the characteristics of AMR is the infiltration of innate immune system including macrophages, monocytes, neutrophils or NK cells. Macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) are well known cytokines that are associated with the activation of the innate immune system which can damage kidney allograft. In this article, the association of the genetic polymorphisms of MIF and BAFF with the development of DSA including Class I and II in kidney transplant patients is investigated. A total of 231 renal transplant patients between 2008 and 2012 at St. Vincent Medical Center, CA were studied in a retrospective study design. DSA were determined by Luminex technology, and single nucleotide polymorphisms (SNP) of MIF and BAFF were determined by the real time PCR based on 5' nuclease allelic discrimination assay. The genetic polymorphisms of MIF rs1007888 (C/T) was associated with increased risk of positive DSA detection (p=0.04) after transplantation, and consistently significant after 1year (p=0.016). Furthermore, the presence of C allele were associated with the increased risk of Class I DSA detection (OR 1.816, CI 1.141-2.889, p=0.011). Also, genetic polymorphisms of BAFF rs12583006 were associated with the increased risk of Class II DSA detection (p=0.033). In conclusion, the genetic polymorphisms of MIF and BAFF may increase the risk of posttransplant development of DSA. This result suggests the association between the development of posttransplant DSA and the activation of innate immune system. PMID- 28624490 TI - Bioenergetics dysfunction, mitochondrial permeability transition pore opening and lipid peroxidation induced by hydrogen sulfide as relevant pathomechanisms underlying the neurological dysfunction characteristic of ethylmalonic encephalopathy. AB - Hydrogen sulfide (sulfide) accumulates at high levels in brain of patients with ethylmalonic encephalopathy (EE). In the present study, we evaluated whether sulfide could disturb energy and redox homeostasis, and induce mitochondrial permeability transition (mPT) pore opening in rat brain aiming to better clarify the neuropathophysiology of EE. Sulfide decreased the activities of citrate synthase and aconitase in rat cerebral cortex mitochondria, and of creatine kinase (CK) in rat cerebral cortex, striatum and hippocampus supernatants. Glutathione prevented sulfide-induced CK activity decrease in the cerebral cortex. Sulfide also diminished mitochondrial respiration in cerebral cortex homogenates, and dissipated mitochondrial membrane potential (DeltaPsim) and induced swelling in the presence of calcium in brain mitochondria. Alterations in DeltaPsim and swelling caused by sulfide were prevented by the combination of ADP and cyclosporine A, and by ruthenium red, indicating the involvement of mPT in these effects. Furthermore, sulfide increased the levels of malondialdehyde in cerebral cortex supernatants, which was prevented by resveratrol and attenuated by glutathione, and of thiol groups in a medium devoid of brain samples. Finally, we verified that sulfide did not alter cell viability and DCFH oxidation in cerebral cortex slices, primary cortical astrocyte cultures and SH-SY5Y cells. Our data provide evidence that bioenergetics disturbance and lipid peroxidation along with mPT pore opening are involved in the pathophysiology of brain damage observed in EE. PMID- 28624491 TI - The first report of cathepsin A gene in a teleost (rock bream, Oplegnathus fasciatus): An investigation of immune functions upon infection with several pathogens. AB - We isolated and characterised a cDNA encoding the lysosomal protective protein (serine protease) cathepsin A (CTSA) from rock bream (Oplegnathus fasciatus). The full-length rock bream CTSA (RbCTSA) cDNA (1814 bp) contains an open reading frame of 1419 bp that encodes 472 amino acids. Alignment of multiple CTSA protein sequences revealed that the active site serine and histidine residues were well conserved among the other CTSA sequences. RbCTSA is highly expressed in the peripheral blood leukocytes, kidney, spleen, liver, intestine, gill, heart, brain, stomach, and eye. RbCTSA expression was also examined in several tissues, including whole kidneys and spleens, under bacterial and viral challenge. In general, all of the examined tissues that were infected with Edwardsiella tarda, Streptococcus iniae, or red sea bream iridovirus (RSIV) exhibited significant upregulation of RbCTSA expression compared to the controls. Our results reveal that RbCTSA may be involved in the immune responses of rock bream. PMID- 28624492 TI - Cortical function and corticomotoneuronal adaptation in monomelic amyotrophy. AB - OBJECTIVE: To evaluate corticomotoneuronal integrity in monomelic amyotrophy using threshold tracking transcranial magnetic stimulation (TT-TMS). METHODS: Cortical excitability studies were prospectively performed in 8 monomelic amyotrophy patients and compared to 21 early-onset amyotrophic lateral sclerosis (ALS) patients and 40 healthy controls. Motor evoked potentials responses were recorded over abductor pollicis brevis. RESULTS: Maximal motor evoked potential (MEP/CMAP ratio) was significantly increased in monomelic amyotrophy compared with controls (monomelic amyotrophy 51.2+/-12.4%; control 22.7+/-2.1%, p=0.04). Averaged short-interval intracortical inhibition (SICI, ISI 1-7ms) in monomelic amyotrophy patients was similar to controls (monomelic amyotrophy 9.6+/-2.1%; control 10.0+/-0.9%, p=0.98). However, it was significantly reduced in early onset ALS in comparison with monomelic amyotrophy patients (monomelic amyotrophy 9.6+/-2.1%; ALS 2.3+/-1.7%, p<0.001). Averaged SICI is a good parameter (area under the curve 0.79, p=0.02) to discriminate between monomelic amyotrophy and early-onset ALS patients. CONCLUSIONS: TT-TMS technique has identified normal cortical function in monomelic amyotrophy, a feature that distinguishes it from early-onset ALS. The greater corticomotoneuronal projections to spinal motoneurons may represent central nervous system adaptive change in monomelic amyotrophy. SIGNIFICANCE: Corticomotoneuronal dysfunction does not drive the lower motor neurone loss presented in monomelic amyotrophy. PMID- 28624494 TI - Antibacterial activity and phospholipid recognition of the recombinant defensin J1-1 from Capsicum genus. AB - The gene of the four disulfide-bridged defensin J1-1 from Capsicum was cloned into the expression vector pQE30 containing a 6His-tag as fusion protein. This construct was transfected into Origami strain of Escherichia coli and expressed after induction with isopropyl thiogalactoside (IPTG). The level of expression was 4 mg/L of culture medium, and the His-tagged recombinant defensin (HisXarJ1 1) was expressed exclusively into inclusion bodies. After solubilization, HisXarJ1-1 was purified by affinity and hydrophobic interaction chromatography. The reverse-phase HPLC profile of the HisXarJ1-1 product obtained from the affinity chromatography step showed single main peptide fraction of molecular masses of 7050.6 Da and after treatment with DTT a single fraction of 7, 042.6 Da corresponding to the reduced peptide was observed. An in vitro folding step of the HisXarJ1-1 generated a distinct profile of oxidized forms of the peptide this oxidized peptide was capable of binding phosphatidic acid in vitro. Possible dimer and oligomer of HisXarJ1-1 were visible in gel electrophoresis and immunodetected with anti-His antibodies. Pure recombinant defensin HisXarJ1-1 exhibited antibacterial activity against Pseudomonas aeruginosa. PMID- 28624493 TI - Expression of the C-terminal domain of human apolipoprotein A-I using a chimeric apolipoprotein. AB - Human apolipoprotein A-I (apoA-I) is the most abundant protein in high-density lipoprotein, an anti-atherogenic lipid-protein complex responsible for reverse cholesterol transport. The protein is composed of an N-terminal helix bundle domain, and a small C-terminal (CT) domain. To facilitate study of CT-apoA-I, a novel strategy was employed to produce this small domain in a bacterial expression system. A protein construct was designed of insect apolipophorin III (apoLp-III) and residues 179-243 of apoA-I, with a unique methionine residue positioned between the two proteins and an N-terminal His-tag to facilitate purification. The chimera was expressed in E. coli, purified by Ni-affinity chromatography, and cleaved by cyanogen bromide. SDS-PAGE revealed the presence of three proteins with masses of 7 kDa (CT-apoA-I), 18 kDa (apoLp-III), and a minor 26 kDa band of uncleaved chimera. The digest was reloaded on the Ni affinity column to bind apoLp-III and uncleaved chimera, while CT-apoA-I was washed from the column and collected. Alternatively, CT-apoA-I was isolated from the digest by reversed-phase HPLC. CT-apoA-I was alpha-helical, highly effective in solubilizing phospholipid vesicles and disaggregating LPS micelles. However, CT-apoA-I was less active compared to full-length apoA-I in protecting lipolyzed low density lipoproteins from aggregating, and disrupting phosphatidylglycerol bilayer vesicles. Thus the novel expression system produced mg quantities of functional CT-apoA-I, facilitating structural and functional studies of this critical domain of apoA-I. PMID- 28624495 TI - Comparison of ultrasound- and electrostimulation-guided nerve blocks of brachial plexus in dogs. AB - OBJECTIVE: To compare the effectiveness of ultrasound- and electrostimulation guided nerve blocks of the brachial plexus and to determine whether ultrasound guidance is feasible in conscious dogs. STUDY DESIGN: Blinded, crossover, experimental study. ANIMALS: Six clinically healthy adult Beagle dogs. METHODS: The nerves of the brachial plexus of the right thoracic limb were blocked under ultrasound guidance (UNB) in conscious dogs and under electrostimulation guidance (ENB) in anesthetized dogs with bupivacaine (0.4 mL kg-1, 0.25%). Saline (0.4 mL kg-1) was injected in control animals. Sensory nerve blockade was evaluated by scoring cutaneous sensation in targeted nerves. Motor nerve blockade was evaluated based on weight bearing, conscious proprioception and withdrawal reflex scores. Times to execute the technique in UNB and ENB were compared using t tests (p < 0.05). Scores for sensory and motor nerve blockades in each treatment were compared with scores before treatment and with control treatment scores using nonparametric repeated-measures two-way analysis of variance. Time to onset and duration of sensory nerve block were assessed using scores for four sensory nerve functions. A successful sensory nerve block was defined by decreases in scores for these functions. Success rates of nerve blocks were compared among treatments using McNemar's test. RESULTS: In UNB and ENB, onset times of sensory nerve blocks were 1 hour and 1.5 hours, respectively. Onset times of motor nerve blocks were 0.5 hour in both treatments. In UNB and ENB, durations of sensory nerve block were 3 hours and 0.5 hour, respectively, and durations of motor nerve block were 7.5 hours and 6.5 hours, respectively. Success rates did not differ between the techniques. CONCLUSIONS AND CLINICAL RELEVANCE: The UNB brachial plexus block had a shorter onset time and longer duration than ENB. UNB can be performed in conscious dogs or those under mild sedation. PMID- 28624496 TI - Effect of fentanyl on the induction dose and minimum infusion rate of propofol preventing movement in dogs. AB - OBJECTIVE: To determine the effect of fentanyl on the induction dose of propofol and minimum infusion rate required to prevent movement in response to noxious stimulation (MIRNM) in dogs. STUDY DESIGN: Crossover experimental design. ANIMALS: Six healthy, adult intact male Beagle dogs, mean+/-standard deviation 12.6+/-0.4 kg. METHODS: Dogs were administered 0.9% saline (treatment P), fentanyl (5 MUg kg-1) (treatment PLDF) or fentanyl (10 MUg kg-1) (treatment PHDF) intravenously over 5 minutes. Five minutes later, anesthesia was induced with propofol (2 mg kg-1, followed by 1 mg kg-1 every 15 seconds to achieve intubation) and maintained for 90 minutes by constant rate infusions (CRIs) of propofol alone or with fentanyl: P, propofol (0.5 mg kg-1 minute-1); PLDF, propofol (0.35 mg kg-1 minute-1) and fentanyl (0.1 MUg kg-1 minute-1); PHDF, propofol (0.3 mg kg-1 minute-1) and fentanyl (0.2 MUg kg-1 minute-1). Propofol CRI was increased or decreased based on the response to stimulation (50 V, 50 Hz, 10 mA), with 20 minutes between adjustments. Data were analyzed using a mixed model anova and presented as mean+/-standard error. RESULTS: ropofol induction doses were 6.16+/-0.31, 3.67+/-0.21 and 3.33+/-0.42 mg kg-1 for P, PLDF and PHDF, respectively. Doses for PLDF and PHDF were significantly decreased from P (p<0.05) but not different between treatments. Propofol MIRNM was 0.60+/-0.04, 0.29+/-0.02 and 0.22+/-0.02 mg kg-1 minute-1 for P, PLDF and PHDF, respectively. MIRNM in PLDF and PHDF was significantly decreased from P. MIRNM in PLDF and PHDF were not different, but their respective percent decreases of 51+/-3 and 63+/-2% differed (p=0.035). CONCLUSIONS AND CLINICAL RELEVANCE: Fentanyl, at the doses studied, caused statistically significant and clinically important decreases in the propofol induction dose and MIRNM. PMID- 28624498 TI - Impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris at 6months follow-up. AB - BACKGROUND: We explored the impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris (SAP) at 6months follow-up. METHODS: From May 2015 to April 2016, a total of 746 patients with SAP were divided to high glycemic variability group (H group) (n=261) and low glycemic variability group (L group) (n=485). The primary end point was incidence of periprocedural myocardial infarction and MACE at 6months follow-up. RESULTS: The occurrence of periprocedural myocardial infarction occurred in 18.8% of patients in H group and in 12.4% in L group (P=0.03). The incidence of MACE at 6months follow-up was 9.6% in H group and 4.5% in L group (P=0.01). Multivariable analysis suggested that high glycemic variability conferred a 53% risk increment of 6months follow-up MACE (odds ratio 2.13, 95% confidence interval 1.85-5.38; P=0.01). CONCLUSIONS: The trial shows that higher blood glucose variability was correlated with higher incidence of periprocedural myocardial infarction and MACE at 6months follow-up. PMID- 28624499 TI - Evaluation of whole exome sequencing by targeted gene sequencing and Sanger sequencing. AB - BACKGROUND: Targeted gene sequencing (TGS) and whole exome sequencing (WES) are being used in clinical testing in laboratories. We compared the performances of TGS and WES using the same DNA samples. METHODS: DNA was extracted from 10 endometrial tumor tissue specimens. Sequencing were performed with an Illumina HiSeq 2000. We randomly selected variants to confirm through Sanger sequencing or mutant-enriched PCR with Sanger sequencing. RESULTS: We found that the variants identified in both TGS and WES were true positives (47/47), regardless of the sequencing depth. Most variants found in TGS only were true positives (34/40), and most of the variants found by WES only were false positives (8/18). From these results, we suggest that the sequencing depth may not play important role in the accuracy of NGS-based methods. After analysis, we found that WES had a sensitivity of 72.70%, specificity of 96.27%, precision of 99.44%, and accuracy of 75.03%. CONCLUSIONS: The results of NGS-based methods must currently be validated, especially for important reported variants regardless of the methods used, and for the use of WES in cancers a higher false negative rate must be considered. More sensitive methods should be used to confirm the NGS results in uneven cancer tissues. PMID- 28624500 TI - Phoenixin-14 concentrations are increased in association with luteinizing hormone and nesfatin-1 concentrations in women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is commonly characterized by obesity, insulin resistance (IR), hyperandrogenemia and hirsutism. Following the reported relationship between phoenixin-14 and gonadotropin production in rat hypothalamic-pituitary-gonadal axis, the present study was designed to investigate the circulating concentrations of phoenixin-14 and their associations with the concentrations of sex hormones including luteinizing hormone (LH), follicular stimulating hormone (FSH), estradiol (E2), progesterone (P4) and total testosterone (TT) in PCOS patients. METHODS: A total of 41 women with diagnosed PCOS using Rotterdam criteria and 37 healthy individuals were enrolled in the study. RESULTS: Serum phoenixin-14 concentration in PCOS patients (n=41) was 0.515+/-0.044ng/ml, significantly higher than that in healthy controls (0.289+/ 0.046ng/ml, n=37). PCOS patients had higher serum LH, dehydroepiandrosterone and fasting blood glucose concentrations, and higher index of homeostasis model of assessment-IR than those in healthy women. Correlation analysis showed significantly positive correlations of phoenixin-14 with LH, FSH, TT, P4, BMI and nesfatin-1 concentrations, and significantly negative correlations with E2 and serum insulin (FSI) concentrations, respectively. CONCLUSIONS: Compared to control women, PCOS patients had significantly increased serum phoenixin-14, LH and androgen concentrations. The positive correlations of phoenixin-14 concentrations with LH and TT concentrations suggest a possible role of phoenixin 14 in the development of PCOS. PMID- 28624497 TI - New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer. AB - The Hedgehog signaling network regulates organogenesis, cell fate, proliferation, survival, and stem cell self-renewal in many mammalian tissues. Aberrant activation of the Hedgehog signaling network is present in ~25% of all cancers, including breast. Altered expression of Hedgehog network genes in the mammary gland can elicit phenotypes at many stages of development. However, synthesizing a cohesive mechanistic model of signaling at different stages of development has been difficult. Emerging data suggest that this difficulty is due, in part, to non-canonical and tissue compartment-specific (i.e., epithelial, versus stromal, versus systemic) functions of Hedgehog network components. With respect to systemic functions, Hedgehog network genes regulate development of endocrine organs that impinge on mammary gland development extrinsically. These new observations offer insight into previously conflicting data, and have bearing on the potential for anti-Hedgehog therapeutics in the treatment of breast cancer. PMID- 28624502 TI - A lower dose of intravitreal bevacizumab effectively treats retinopathy of prematurity. PMID- 28624501 TI - New biomarkers for diagnosis and management of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting young women. Even though the definition of PCOS has changed over the years, all diagnostic criteria include two or more of the following: oligomenorrhea/oligoovulation/anovulation, androgen excess and polycystic ovaries (PCO). Traditional method of assessing the ovarian morphology has been transvaginal pelvic ultrasound. Recent studies support that serum anti-Mullerian hormone (AMH) levels correlate with the number of ovarian follicles and cysts. Hence, measurement of AMH is adequate to make the diagnosis. Traditionally, hyperandrogenemia has been assessed by measuring total-testosterone. The literature stresses the importance of sex hormone binding globulin (SHBG) measurements and bioavailable-testosterone and free-testosterone calculations, because insulin resistance decreases SHBG, lowers total-testosterone, and leads to under-estimation of bioavailable- and free-testosterone. Since 50-60% of PCOS patients have metabolic syndrome, assessment of metabolic risk is also necessary. It is important to diagnose insulin resistance before development of glucose intolerance and diabetes. This requires measurements of not only plasma glucose but also insulin concentrations. Determination of HgBA1 can be informative as well. This review aims to present an accurate and cost-effective approach to diagnosis and management of PCOS. PMID- 28624503 TI - Pulled-in-two syndrome: a multicenter survey of risk factors, management and outcomes. PMID- 28624504 TI - Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways. AB - Brain inflammaging is increasingly considered as contributing to age-related cognitive loss and neurodegeneration. Despite intensive research in multiple models, no clinically effective pharmacological treatment has been found yet. Here, in the mouse model of brain senescence SAMP8, we tested the effects of proinsulin, a promising neuroprotective agent that was previously proven to be effective in mouse models of retinal neurodegeneration. Proinsulin is the precursor of the hormone insulin but also upholds developmental physiological effects, particularly as a survival factor for neural cells. Adeno-associated viral vectors of serotype 1 bearing the human proinsulin gene were administered intramuscularly to obtain a sustained release of proinsulin into the blood stream, which was able to reach the target area of the hippocampus. SAMP8 mice and the control strain SAMR1 were treated at 1 month of age. At 6 months, behavioral testing exhibited cognitive loss in SAMP8 mice treated with the null vector. Remarkably, the cognitive performance achieved in spatial and recognition tasks by SAMP8 mice treated with proinsulin was similar to that of SAMR1 mice. In the hippocampus, proinsulin induced the activation of neuroprotective pathways and the downstream signaling cascade, leading to the decrease of neuroinflammatory markers. Furthermore, the decrease of astrocyte reactivity was a central effect, as demonstrated in the connectome network of changes induced by proinsulin. Therefore, the neuroprotective effects of human proinsulin unveil a new pharmacological potential therapy in the fight against cognitive loss in the elderly. PMID- 28624505 TI - Deficiency in EP4 Receptor-Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease. AB - Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-alpha, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor-associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20+/- onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20+/-EPRAP+/+ and J20+/-EPRAP-/- mice. EPRAP deficiency reversed the reduced anxiety of J20+/- mice but did not affect hyperactivity. No differences in spatial memory were observed between J20+/-EPRAP+/+ and J20+/-EPRAP-/- mice. In comparison with J20+/-EPRAP+/+, J20+/-EPRAP-/- mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-alpha mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-beta 40 or 42 in the cortex and hippocampus. J20+/-EPRAP-/- mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20+/-EPRAP+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD. PMID- 28624506 TI - Cellular gauge symmetry and the Li organization principle: General considerations. AB - Based on novel topological considerations, we postulate a gauge symmetry for living cells and proceed to interpret it from a consistent Eastern perspective: the li organization principle. In our framework, the reference system is the living cell, equipped with general symmetries and energetic constraints standing for the intertwined biochemical, metabolic and signaling pathways that allow the global homeostasis of the system. Environmental stimuli stand for forces able to locally break the symmetry of metabolic/signaling pathways, while the species specific DNA is the gauge field that restores the global homeostasis after external perturbations. We apply the Borsuk-Ulam Theorem (BUT) to operationalize a methodology in terms of topology/gauge fields and subsequently inquire about the evolution from inorganic to organic structures and to the prokaryotic and eukaryotic modes of organization. We converge on the strategic role that second messengers have played regarding the emergence of a unitary gauge field with profound evolutionary implications. A new avenue for a deeper investigation of biological complexity looms. Philosophically, we might be reminded of the duality between two essential concepts proposed by the great Chinese synthesizer Zhu Xi (in the XIII Century). On the one side the li organization principle, equivalent to the dynamic interplay between symmetry and information; and on the other side the qi principle, equivalent to the energy participating in the process-both always interlinked with each other. In contemporary terms, it would mean the required interconnection between information and energy, and the necessity to revise essential principles of information philosophy. PMID- 28624507 TI - Effect of pyridostigmine on in vivo and in vitro respiratory muscle of mdx mice. AB - The current work was conducted to verify the contribution of neuromuscular transmission defects at the neuromuscular junction to Duchenne Muscular Dystrophy disease progression and respiratory dysfunction. We tested pyridostigmine and pyridostigmine encapsulated in liposomes (liposomal PYR), an acetylcholinesterase inhibitor to improve muscular contraction on respiratory muscle function in mdx mice at different ages. We evaluated in vivo with the whole-body plethysmography, the ventilatory response to hypercapnia, and measured in vitro diaphragm strength in each group. Compared to C57BL10 mice, only 17 and 22 month-old mdx presented blunted ventilatory response, under normocapnia and hypercapnia. Free pyridostigmine (1mg/kg) was toxic to mdx mice, unlike liposomal PYR, which did not show any side effect, confirming that the encapsulation in liposomes is effective in reducing the toxic effects of this drug. Treatment with liposomal PYR, either acute or chronic, did not show any beneficial effect on respiratory function of this DMD experimental model. The encapsulation in liposomes is effective to abolish toxic effects of drugs. PMID- 28624508 TI - Epidemiological profile of cutaneous larva migrans in travelers returning to France between 2003 and 2015. AB - BACKGROUND: Cutaneous larva migrans (CLM) is caused by the penetration and migration of canine or feline hookworm larvae into the skin, and frequently affects travelers from high-income countries returning from tropical and sub tropical areas. Unfortunately, this pathology is neglected due to poor understanding among both physicians and travelers. This study describes the profile of cases reported in Marseille, France. PATIENTS AND METHODS: A retrospective study was performed in two specialized hospitals between 2003 and 2015. Data on socio-demographics, clinical aspects and treatment were collected. Diagnosis was based on travel history and symptoms. RESULTS: Forty-three patients with a diagnosis of CLM were recorded in this study. They were aged between 14 and 70 and 51% were male. They were infected while visiting the Americas (37%), Africa (33%), Asia (28%) and (in the case of one patient) Portugal. The mean timescale for diagnosis was 41 days. Track lesions associated with pruritus in the lower limbs were the most common symptoms. Nine had a history of super infection. Sixteen patients received treatment prior to referral including six who were administered antiparasitic drugs. A one-day treatment with ivermectin, administered at our facility, resulted, in most instances, in a favorable outcome. CONCLUSION: This study reports 43 cases of CLM acquired mainly in Africa, Asia and the Americas but also, for the first time, CLM acquired during travel to Portugal. The data show the need for increased awareness of CLM prevention and treatment in order to optimize pre-travel advice and case management. Travelers need to understand how CLM is transmitted and the need to avoid contact with soil and sand contaminated by dogs and cats. In particular, footwear and sun chairs should be used on beaches. PMID- 28624509 TI - Travellers' Malaria - Horizons 202X. PMID- 28624510 TI - Single neonatal status epilepticus does not impair cognitive function in rats. PMID- 28624511 TI - Cluster reduction in patients in a pilot treatment trial for psychogenic nonepileptic seizures. AB - INTRODUCTION: The present study examined seizure clusters as a primary outcome in patients receiving treatment for PNES. Cluster reduction is examined longitudinally using frequency threshold and statistical definitions of seizure cluster for patients. Possible risk factors for clustering will be examined along with clustering as a risk factor for poorer secondary outcomes. METHODS: Participants were from a pilot randomized treatment trial for PNES where they received cognitive behavioral therapy-informed psychotherapy (CBT-ip), sertraline, combination therapy, or treatment as usual. Seizure data are from patients' seizure dairies. RESULTS: Cluster reduction was observed for those receiving CBT-ip or combination treatment using all definitions of daily clusters and weekly clusters. No risk factors of clustering were observed. Those who were identified as having clusters during the trial had poorer secondary outcomes on several measures at baseline relative to those who were not identified as having clusters. DISCUSSION: This is the first study known to the authors to not only examined seizure clusters as a primary outcome for those with PNES, but also the first study to suggest that CBT-ip and combination therapy may be effective in reducing the frequency of clusters. PMID- 28624512 TI - Epidemiological investigation and risk factors of Echinococcus granulosus in yaks (Bos grunniens), Tibetan pigs and Tibetans on Qinghai Tibetan plateau. AB - Echinococcus granulosus (E. granulosus) is a diverse zoonotic parasite and causes Cystic echinococcosis (CE) disease in humans and livestock. However, scare information is available about the epidemic situation of E. granulosus infection in yaks, Tibetan pigs and native Tibetans on the Qinghai Tibetan plateau. Therefore, a study was carried out to find prevalence and risk factors of E. granulosus in yaks, Tibetan pigs and Tibetans. Serum samples from yaks (1371), Tibetan pigs (454) and Tibetans (600) were collected and assessed by commercial ELISA kits. Multivariable logistic regression model was performed to find the variables possibly associated with exposure of E. granulosus infection in yaks, Tibetan pigs and Tibetan. The overall prevalence of E. granulosus in yaks was 6.49%. In different regions, the prevalence were ranged from 3.43% to 11.79%. In male and female yaks, the prevalence was 5.67% and 7.04%, respectively. In different ages, the prevalence were ranged from 2.20% to 10.9%. While, in different years, the prevalence was 3.61% in 2014, 9.66% in 2015, and 6.33% in 2016. According to the conditional stepwise logistic regression, three factors (region, age and year) were demonstrated to be risk factors influencing the prevalence of E. granulosus in yaks significantly (P<0.05). A total 33/454 of Tibetan pigs were positive for E. granulosus with the distribution of 5.47, 5.70 and 13.27% prevalence in Gongbo'gvamda, Mainling, and Nyingchi region, respectively. In male and female Tibetan pigs, the prevalence was 7.12% and 7.49% respectively, while region was considered as a significant (P<0.05) risk factor influencing the E. granulosus infection in Tibetan pigs. The total prevalence of E. granulosus infection in Tibetans was 1.83%, while in male and female Tibetans, the prevalence was 1.41% and 2.21%, respectively. In different ages, the prevalence were ranged from 0 to 3.21%. In Tibetans contacting animals or not was 2.41% and 0.54% respectively, and breeding dogs or not was 3.0% and 1.09%, respectively. Risk factors (gender age, contact animal and breed dog) were not significant (P>0.05). The present results reported the prevalence and associated risk factors of E. granulosus in yaks, Tibetan pigs and native Tibetans. These findings could have important epidemiological significance and a direct influence on the remote plateau. PMID- 28624513 TI - Biodiversity of Simulium metallicum sensu lato (Diptera: Simuliidae), a complex of Neotropical vectors associated with human onchocerciasis. AB - The polytene chromosomes of 130 larvae of the Neotropical Simulium metallicum complex from Brazil, Costa Rica, and Ecuador revealed five cytoforms, including three ('M', 'N', and 'O') that are new and two ('B' and 'J') that represent range extensions of up to 850km. The discovery of three new cytoforms brings the total number in the complex to 17. Cytoforms 'B', 'J', and 'N' are reproductively isolated from one another, and their species status is corroborated by morphological evidence. None of the three new cytoforms is known from current or historical onchocerciasis foci, although 'M' inhabits the periphery of the former Ecuadorian Santiago onchocerciasis focus a mere 30km to the west. The number of fixed chromosomal differences, as many as 24, separating some members of the S. metallicum complex far exceeds that known between members of any other simuliid species complex. Two distinct groupings can be diagnosed within the S. metallicum complex, based on at least eight fixed chromosomal rearrangements and structural characters in the larval stage. Consequently, a recommendation is made to recognize the S. horacioi complex and the S. metallicum complex sensu stricto. Recognition of two separate complexes provides potential phylogenetic content with predictive power for understanding biological phenomena such as vector potential. PMID- 28624514 TI - Bromodomain-containing proteins in prostate cancer. AB - Several oncogenic factors have been involved in prostate cancer progression. However, therapeutic approaches still focus on suppression of androgen receptor (AR) signaling. In fact, whereas the full-length AR incorporates a ligand-binding domain, which has become a drug target for competitive inhibitors, other transcription factors often do not have tractable binding pockets that aid drug development. Consequently drug development efforts have turned to transcription co-regulators, often chromatin-modifying enzymes or factors that bind to epigenetic modifications to chromatin. Bromodomain (BRD)-containing proteins fall into the latter category and significant progress has been made in developing small molecule inhibitors that target a particular subgroup of BRD-containing proteins known as the Bromodomain and extra-terminal (BET) family proteins. These inhibitors have proven particularly effective in inactivating c-Myc in lymphoma but more recently members of the BET family have also been identified as AR interacting proteins raising the prospect of using these inhibitors as an alternative strategy for targeting AR-driven cancers. In this review we will provide an overview of BRD-containing proteins and the potential for exploiting them as biomarkers and drug targets in prostate cancer. PMID- 28624516 TI - Pleistocene range shifts, refugia and the origin of widespread species in western Palaearctic water beetles. AB - Quaternary glacial cycles drove major shifts in both the extent and location of the geographical ranges of many organisms. During glacial maxima, large areas of central and northern Europe were inhospitable to temperate species, and these areas are generally assumed to have been recolonized during interglacials by range expansions from Mediterranean refugia. An alternative is that this recolonization was from non-Mediterranean refugia, in central Europe or western Asia, but data on the origin of widespread central and north European species remain fragmentary, especially for insects. We studied three widely distributed lineages of freshwater beetles (the Platambus maculatus complex, the Hydraena gracilis complex, and the genus Oreodytes), all restricted to running waters and including both narrowly distributed southern endemics and widespread European species, some with distributions spanning the Palearctic. Our main goal was to determine the role of the Pleistocene glaciations in shaping the diversification and current distribution of these lineages. We sequenced four mitochondrial and two nuclear genes in populations drawn from across the ranges of these taxa, and used Bayesian probabilities and Maximum Likelihood to reconstruct their phylogenetic relationships, age and geographical origin. Our results suggest that all extant species in these groups are of Pleistocene origin. In the H. gracilis complex, the widespread European H. gracilis has experienced a rapid, recent range expansion from northern Anatolia, to occupy almost the whole of Europe. However, in the other two groups widespread central and northern European taxa appear to originate from central Asia, rather than the Mediterranean. These widespread species of eastern origin typically have peripherally isolated forms in the southern Mediterranean peninsulas, which may be remnants of earlier expansion-diversification cycles or result from incipient isolation of populations during the most recent Holocene expansion. The accumulation of narrow endemics of such lineages in the Mediterranean may result from successive cycles of range expansion, with subsequent speciation (and local extinction in glaciated areas) through multiple Pleistocene climatic cycles. PMID- 28624515 TI - Development of selective androgen receptor modulators (SARMs). AB - The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits. PMID- 28624517 TI - Intra-accumbal blockade of endocannabinoid CB1 receptors impairs learning but not retention of conditioned relief. AB - Humans and animals are able to associate an environmental cue with the feeling of relief from an aversive event, a phenomenon called relief learning. Relief from an aversive event is rewarding and a relief-associated cue later induces an attenuation of the startle magnitude or approach behavior. Previous studies demonstrated that the nucleus accumbens is essential for relief learning. Here, we asked whether accumbal cannabinoid type 1 (CB1) receptors are involved in relief learning. In rats, we injected the CB1 receptor antagonist/inverse agonist SR141716A (rimonabant) directly into the nucleus accumbens at different time points during a relief learning experiment. SR141716A injections immediately before the conditioning inhibited relief learning. However, SR141716A injected immediately before the retention test was not effective when conditioning was without treatment. These findings indicate that accumbal CB1 receptors play an important role in the plasticity processes underlying relief learning. PMID- 28624518 TI - Role of gut microbiota against calcium oxalate. AB - Nephrolithiasis is a condition marked by the presence or formation of stones in kidneys. Several factors contribute to kidney stones development such as environmental conditions, type of dietary intake, gender and gastrointestinal flora. Most of the kidney stones are composed of calcium phosphate and calcium oxalate, which enter in to the body through diet. Both sources of oxalates become dangerous when normal flora of gastrointestinal tract is disturbed. Oxalobacter and Lactobacillus species exist symbiotically in the human gut and prevent stone formation by altering some biochemical pathways through production of specific enzymes which help in the degradation of oxalate salts. Both Oxalobacter and Lactobacillus have potential probiotic characteristics for the prevention of kidney stone formation and this avenue should be further explored. PMID- 28624519 TI - iTRAQ-based quantitative proteomics analysis of molecular mechanisms associated with Bombyx mori (Lepidoptera) larval midgut response to BmNPV in susceptible and near-isogenic strains. AB - : Bombyx mori nucleopolyhedrovirus (BmNPV) has been identified as a major pathogen responsible for severe economic loss. Most silkworm strains are susceptible to BmNPV, with only a few highly resistant strains thus far identified. Here we investigated the molecular basis of silkworm resistance to BmNPV using susceptible (the recurrent parent P50) and resistant (near-isogenic line BC9) strains and a combination of iTRAQ-based quantitative proteomics, reverse-transcription quantitative PCR and Western blotting. By comparing the proteomes of infected and non-infected P50 and BC9 silkworms, we identified 793 differentially expressed proteins (DEPs). By gene ontology and KEGG enrichment analyses, we found that these DEPs are preferentially involved in metabolism, catalytic activity, amino sugar and nucleotide sugar metabolism and carbon metabolism. 114 (14.38%) DEPs were associated with the cytoskeleton, immune response, apoptosis, ubiquitination, translation, ion transport, endocytosis and endopeptidase activity. After removing the genetic background and individual immune stress response proteins, we identified 84 DEPs were found that are potentially involved in resistance to BmNPV. Further studies showed that a serine protease was down-regulated in P50 and up-regulated in BC9 after BmNPV infection. Taken together, these results provide insights into the molecular mechanism of silkworm response to BmNPV. BIOLOGICAL SIGNIFICANCE: Bombyx mori nucleopolyhedrovirus (BmNPV) is highly pathogenic, causing serious losses in sericulture every year. However, the molecular mechanisms of BmNPV infection and host defence remain unclear. Here we combined quantitative proteomic, bioinformatics, RT-qPCR and Western blotting analyses and found that BmNPV invasion causes complex protein alterations in the larval midgut, and that these changes are related to cytoskeleton, immune response, apoptosis, ubiquitination, translation, ion transport, endocytosis and endopeptidase activity. Five important differentially expression proteins were validation by independent approaches. These finding will help address the molecular mechanisms of silkworm resistance to BmNPV and provide a molecular target for resisting BmNPV. PMID- 28624521 TI - Semanticized autobiographical memory and the default - executive coupling hypothesis of aging. AB - As we age, the architecture of cognition undergoes a fundamental transition. Fluid intellectual abilities decline while crystalized abilities remain stable or increase. This shift has a profound impact across myriad cognitive and functional domains, yet the neural mechanisms remain under-specified. We have proposed that greater connectivity between the default network and executive control regions in lateral prefrontal cortex may underlie this shift, as older adults increasingly rely upon accumulated knowledge to support goal-directed behavior. Here we provide direct evidence for this mechanism within the domain of autobiographical memory. In a large sample of healthy adult participants (n = 103 Young; n = 80 Old) the strength of default - executive coupling reliably predicted more semanticized, or knowledge-based, recollection of autobiographical memories in the older adult cohort. The findings are consistent with the default - executive coupling hypothesis of aging and identify this shift in network dynamics as a candidate neural mechanism associated with crystalized cognition in later life that may signal adaptive capacity in the context of declining fluid cognitive abilities. PMID- 28624520 TI - Dissecting the chloroplast proteome of chickpea (Cicer arietinum L.) provides new insights into classical and non-classical functions. AB - : Chloroplast, the energy organelle unique to plant cells, is a dynamic entity which integrates an array of metabolic pathways and serves as first level for energy conversion for the entire ecological hierarchy. Increasing amount of sequence data and evolution of mass spectrometric approaches has opened up new avenues for opportune exploration of the global proteome of this organelle. In our study, we aimed at generation of a comprehensive catalogue of chloroplast proteins in a grain legume, chickpea and provided a reference proteome map. To accurately assign the identified proteins, purity of chloroplast-enriched fraction was stringently monitored by multiple chemical and immunological indexes, besides pigment and enzyme analyses. The proteome analysis led to the identification of 2451 proteins, including 27 isoforms, which include predicted and novel chloroplast constituents. The identified proteins were validated through their sequence analysis. Extensive sequence based localization prediction revealed more than 50% proteins to be chloroplast resident by at least two different algorithms. Chromosomal distribution of identified proteins across nuclear and chloroplast genome unveiled the presence of 55 chloroplast encoded gene. In depth comparison of our dataset with the non-redundant set of chloroplast proteins identified so far across other species revealed novel as well as overlapping candidates. BIOLOGICAL SIGNIFICANCE: Pulses add large amount of nitrogen to the soil and has very low water footprint and therefore, contributes to fortification of sustainable agriculture. Chickpea is one of the earliest cultivated legumes and serves as an energy and protein source for humans and animals. Chloroplasts are the unique organelles which conduct photosynthesis. Investigation on chloroplast proteome is of particular significance, especially to plant biologists, as it would allow a better understanding of chloroplast function in plants. Generation of a saturated proteome map would not only validate the proteome inventory from its genome sequencing, but also serve as a comprehensive catalogue for future studies. We identified 2451 proteins, encoded by both the nuclear as well as chloroplast genomes, presumably involved in multivariate metabolic processes. The chloroplast deduced proteome and putative chloroplast proteins identified in this study would provide a foundation for future investigation of the expression and function of the chloroplast proteins of chickpea in specific and other crops species in general. PMID- 28624522 TI - Decision-related factors in pupil old/new effects: Attention, response execution, and false memory. AB - In this study, we investigate the effects of decision-related factors on recognition memory in pupil old/new paradigms. In Experiment 1, we used an old/new paradigm with words and pseudowords and participants made lexical decisions during recognition rather than old/new decisions. Importantly, participants were instructed to focus on the nonword-likeness of presented items, not their word-likeness. We obtained no old/new effects. In Experiment 2, participants discriminated old from new words and old from new pseudowords during recognition, and they did so as quickly as possible. We found old/new effects for both words and pseudowords. In Experiment 3, we used materials and an old/new design known to elicit a large number of incorrect responses. For false alarms ("old" response for new word), we found larger pupils than for correctly classified new items, starting at the point at which response execution was allowed (2750ms post stimulus onset). In contrast, pupil size for misses ("new" response for old word) was statistically indistinguishable from pupil size in correct rejections. Taken together, our data suggest that pupil old/new effects result more from the intentional use of memory than from its automatic use. PMID- 28624523 TI - Association of interleukin-22 polymorphisms with the colon cancer: A case-control study. AB - INTRODUCTION: Interleukin-22 (IL-22), an IL-10 family cytokine produced by T cells and innate lymphoid cells, is implicated in inflammation and tumorigenesis. In this study, we aimed to investigate the association of IL-22 polymorphisms with the colon cancer in a Chinese population. MATERIALS AND METHODS: Five hundred forty colon cancer cases and 540 healthy controls were recruited in the case-control study. The fluorogenic 5' exonuclease assays were used for genotype analysis of three common polymorphisms (-429C/T, +1046T/A and +1995A/C) of the IL 22 gene. RESULTS: Colon cancer cases had a significantly higher frequency of IL 22-429 TT genotype [odds ratio (OR)=1.69, 95% confidence interval (CI)=1.24, 2.30; P=0.001] and -429T allele (OR=1.35, 95% CI=1.14, 1.60; P=0.001) than healthy controls. The findings are still emphatic by the Bonferroni correction (P<0.017). When stratifying by the differentiation of colon cancer, we found that colon cancer cases with poor differentiation had a significantly higher frequency of IL-22-429 TT genotype (OR=1.45, 95% CI=1.02, 2.07; P=0.04). When stratifying by the tumor location, tumor size, growth pattern and TNM stage of colon cancer, we found no statistical association. The IL-22 +1046T/A and IL-22 +1995A/C gene polymorphisms were not associated with colon cancer. CONCLUSION: Our findings suggested that the IL-22 -429C/T gene polymorphisms might be associated with colon cancer. PMID- 28624524 TI - A direct comparison of porcine (StratticeTM) and bovine (SurgimendTM) acellular dermal matrices in implant-based immediate breast reconstruction. AB - INTRODUCTION: Acellular dermal matrix (ADM) assisted implant-based breast reconstruction (IBBR) has grown in popularity over traditional submuscular techniques. Numerous human, bovine or porcine derived ADMs are available with the type used varying considerably worldwide. Yet, comparative evidence for the efficacy of different ADMs particularly xenogenic is limited. This study directly compares early outcomes of porcine (StratticeTM) and bovine (SurgimendTM) ADMs in IBBR. METHOD: Retrospective study of sequential experience of immediate IBBR using Strattice or Surgimend ADM. Data was collected for patients undergoing ADM assisted IBBR after prophylactic or therapeutic mastectomy in Cambridge (October 2011-March 2016). Patient demographics, adjuvant and neoadjuvant therapies, operative details, postoperative management and outcomes were analysed. KEY RESULTS: Total of 81 patients underwent IBBR with ADM; 38 bilateral and 43 unilateral (n = 119 breasts). Strattice was used in 30 breasts (25%) and Surgimend in 89 (75%). Analysis of patient specific variables showed statistical significance only for higher mastectomy weight in the Strattice group (367.1 +/- 159.3 g versus 296.3 +/- 133.4 g; P = 0.0379). Strattice was associated with higher rates of skin erythema post-operatively (16.7% versus 4.5%; P = 0.044). Analysed per woman or per breast, there was no statistically significant difference in rates of haematoma, infection, wound dehiscence, skin necrosis or seroma, although there was a trend towards more complications with Strattice. CONCLUSION: This study found significantly higher rates of skin erythema and a trend towards higher complication rates with Strattice in IBBR. Randomised controlled trials comparing different ADM outcomes are needed to inform best practice. PMID- 28624525 TI - Regulation of hepatic abcb4 and cyp3a65 gene expression and multidrug/multixenobiotic resistance (MDR/MXR) functional activity in the model teleost, Danio rerio (zebrafish). AB - Multidrug/multixenobiotic resistance (MDR/MXR) confers resistance to a diverse range of potentially toxic pharmaceuticals and environmental contaminants through a cellular response that involves the coordinated induction and activity of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) and the Phase I metabolizing enzyme cytochrome P450 3A (CYP3A). In mammals, ligand-mediated pregnane X receptor (PXR) transcriptional activity regulates the induction of P gp and CYP3A; however, this mechanism has not been well-characterized in piscine species. Zebrafish (Danio rerio) treated with the Pxr agonist pregnenolone 16alpha-carbonitrile (PCN) showed decreased P-gp (zebrafish Abcb4) and CYP3A (zebrafish Cyp3a65) mRNA levels after 48h exposure; however, treatment with PCN also resulted in increased hepatic MDR/MXR functional activity (i.e. increased Rhodamine 123 efflux) in vivo. Consistent with mammalian-like MDR/MXR regulated by PXR, the PCN-mediated modulation of hepatic Abcb4 and Cyp3a65 mRNA levels and MDR/MXR functional activity was attenuated by co-treatment with PCN and the mammalian PXR antagonist, ketoconazole (KTC). These results provide evidence that zebrafish Pxr may play a role in MDR/MXR through transcriptional regulation of abcb4 and cyp3a65 gene expression. PMID- 28624526 TI - Postoperative Urinary Retention is an Independent Predictor of Short-Term and Long-Term Future Bladder Outlet Procedure in Men. AB - PURPOSE: Postoperative urinary retention is a common complication across surgical specialties. To our knowledge no literature to date has examined postoperative urinary retention as a predictor of long-term receipt of surgery for bladder outlet obstruction. MATERIALS AND METHODS: We retrospectively reviewed the records of inpatients who underwent nonurological surgery in California between 2008 and 2010. Postoperative urinary retention during the index admission was identified, as was receipt of a bladder outlet procedure (transurethral prostate resection, prostate photoselective vaporization or suprapubic prostatectomy) at a subsequent encounter. Patients were matched using propensity scoring of demographics, comorbidities and surgery type. Adjusted Kaplan-Meier analysis was performed to determine the cumulative incidence of subsequent bladder outlet procedures by patient group, including group 1-age 60 years or greater and postoperative urinary retention, group 2-age 60 years or greater and no postoperative urinary retention, group 3-age less than 60 years and postoperative urinary retention, and group 4-age less than 60 years and no postoperative urinary retention. RESULTS: Of 769,141 eligible male patients postoperative urinary retention developed in 8,051 (1.1%). Following hospital discharge 1,855 patients (0.24%) underwent a bladder outlet procedure. Those treated with a bladder outlet procedure were significantly more likely to have experienced postoperative urinary retention during the index admission (6.3% vs 1.0%, p <0.001). On matched analysis the bladder outlet procedure rate at 3 years was 7.1%, 2.2%, 0.8% and 0.0% in groups 1, 2, 3 and 4, respectively. CONCLUSIONS: In men 60 years old or older postoperative urinary retention identified those with an increased incidence of bladder outlet procedures within 3 years. Men younger than 60 years had a low rate of subsequent bladder outlet procedures regardless of a postoperative urinary retention diagnosis. PMID- 28624527 TI - Significantly altered expression of miR-511-3p and its target AKT3 has negative prognostic value in human prostate cancer. AB - PURPOSE: In this study, we assessed the expression and functions of microRNA-511 3p (miR-511-3p) in human prostate cancer (CaP). METHODS: Gene expressions of miR 511-3p in CaP cells and human CaP tumors were assessed by qPCR. In VCaP and PC3 cells, miR-511-3p was overexpressed by lentivirus. The functions of miR-511-3p upregulation in regulating in vitro cancer proliferation, migration and in vivo cancer growth were assessed by MTT, transwell and transplantation assays, respectively. Downstream target gene of miR-511-3p, AKT3, was verified by dual luciferase activity and qPCR assays. AKT3 was then overexpressed in miR-511-3p upregulated CaP cells to assess its functions in miR-511-3p-mediated cancer regulation. RESULTS: MiR-511-3p is significantly downregulated in CaP cell lines, and human CaP tumors. MiR-511-3p was further downregulated in T3/T4-staged CaP tumors and closely correlated with shorter overall survival among CaP patients. In VCaP and PC3 cells, lentiviral-induced miR-511-3p upregulation was acting as a tumor suppressor by inhibiting in vitro cancer proliferation, migration and in vivo transplantation. Human AKT3 gene was confirmed to be the downstream target of miR-511-3p in CaP. In miR-511-3p-upregulated VCaP and PC3 cells, forced overexpression of AKT3 reversed the tumor suppressive effects of miR-511-3p in CaP. CONCLUSION: MiR-511-3p may serve as a prognostic factor and tumor suppressor in CaP, very likely through inverse regulation of its downstream target gene of AKT3. PMID- 28624528 TI - Derivation of an occupational exposure level for manganese in welding fumes. AB - Exposure to high levels of manganese (Mn) in occupational settings is known to lead to adverse neurological effects. Since Mn is an essential nutrient, there are mechanisms that maintain its homeostatic control in the body, and there is some level of Mn in air that does not perturb Mn homeostasis. However, the Mn exposure concentrations at which no adverse effects are expected in occupational settings vary considerably across regulatory agencies. We set out to derive a Mn Occupational Exposure Level (OEL) for welders based on a review of studies that evaluated Mn exposure concentrations from welding fumes and: (1) neurological effects in welders; (2) levels of Mn in the brains of welders (via pallidal index [PI] estimated from magnetic resonance imaging [MRI]); (3) other biomarkers of Mn exposure in welders (i.e., blood and urine); and (4) Mn brain concentrations, PI, and corresponding neurological effects in non-human primates. Our analysis suggests uncertainty in quantifying dose-response associations for Mn from many of the occupational welding studies. The few welding studies that adequately estimate exposure suggest a possible OEL of 100-140MUg/m3 for respirable Mn. This range is consistent with other epidemiology studies, studies of biomarkers of Mn exposure in welders, and with studies in non-human primates, though future studies could provide a stronger basis for deriving a Mn occupational guideline for welders. PMID- 28624529 TI - Cyclopamine sensitizes TRAIL-resistant gastric cancer cells to TRAIL-induced apoptosis via endoplasmic reticulum stress-mediated increase of death receptor 5 and survivin degradation. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the most effective cancer treatments owing to its ability to selectively kill cancer cells, without affecting normal cells. However, it has been reported that several gastric cancer cells show resistance to TRAIL because of a scarcity of death receptor 5 (DR5) expressed on the cell surface. In this study, we show that cyclopamine sensitizes gastric cancer cells to TRAIL-induced apoptosis by elevating the expression of DR5. Interestingly, survivin hampers the existence of DR5 protein under normal conditions and cyclopamine decreases the expression of survivin, thus acting as a TRAIL sensitizer. Mechanistically, cyclopamine induces endoplasmic reticulum (ER) stress via reactive oxygen species (ROS) and CHOP, the last protein of the ER stress pathway and it regulates the proteasome degradation of survivin. Taken together, our results indicate that cyclopamine can be used for combination therapy in TRAIL-resistant gastric cancer cells. PMID- 28624530 TI - The emerging role of Wnt signaling dysregulation in the understanding and modification of age-associated diseases. AB - Wnt signaling is a highly conserved pathway that participates in multiple aspects of cellular function during development and in adults. In particular, this pathway has been implicated in cell fate determination, proliferation and cell polarity establishment. In the brain, it contributes to synapse formation, axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. The expression and distribution of Wnt components in different organs vary with age, which may have important implications for preserving tissue homeostasis. The dysregulation of Wnt signaling has been implicated in age associated diseases, such as cancer and some neurodegenerative conditions. This is a relevant research topic, as an important research avenue for therapeutic targeting of the Wnt pathway in regenerative medicine has recently been opened. In this review, we discuss the recent findings on the regulation of Wnt components during aging, particularly in brain functioning, and the implications of Wnt signaling in age-related diseases. PMID- 28624531 TI - The short- to mid-term symptom prevalence of dumping syndrome after primary gastric-bypass surgery and its impact on health-related quality of life. AB - BACKGROUND: Early and late dumping are complications of gastric bypass surgery. Early dumping occurs within an hour after eating, when the emptying of food into the small intestine triggers rapid fluid shifts into the intestinal lumen and the release of gastrointestinal hormones, resulting in gastrointestinal and vasomotor symptoms. Late dumping occurs between 1 and 3 hours after carbohydrate ingestion and is caused by an exaggerated insulin release, resulting in hypoglycemia. Almost no data are currently available on the prevalence of early and late dumping or their impact on health-related quality of life (QoL). OBJECTIVES: To study the prevalence of early and late dumping in a large population of patients having undergone a primary Roux-en-Y gastric bypass (RYGB) and its effect on QoL. SETTING: Cross-sectional study at a single bariatric department in the Medical Center Leeuwarden, The Netherlands between 2008 and 2011. METHODS: In 2013, this descriptive cohort study approached by email or post all patients who underwent a primary RYGB in the setting between 2008 and 2011 in one hospital. These patients were asked to fill in standardized questionnaires measuring their QoL (RAND-36), anxiety and depression (HADS), fatigue (MFI-20) and any disease specific indicators of early and late dumping syndrome. RESULTS: The questionnaire was completed and returned by 351 of 613 patients (57.1%) and 121 nonobese volunteers. Participants were mostly female (80%), aged 42 (40-54 years), with an excess weight loss of 76.8% [IQR 61-95] after RYGB surgery 2.3 [ IQR 1.6-3.4] years earlier. Self-reported complaints of moderate to severe intensity suggestive of early and late dumping were present in 18.8% and 11.7% of patients, respectively. Patients with early and late dumping demonstrated significantly lower scores on the RAND-36 and HADS compared with patients without dumping. No differences were seen in the MFI-20 scores between patients with or without early and late dumping. CONCLUSION: In this descriptive cohort, self-reported complaints suggestive of early and late dumping of moderate-to-severe intensity were, respectively, 18.8% and 11.7% in a cohort after primary gastric bypass surgery. These complaints were associated with markedly reduced health-related QoL. PMID- 28624532 TI - Prospectively validated preoperative prediction of weight and co-morbidity resolution in individual patients comparing five bariatric operations. PMID- 28624533 TI - Management of duodenal carcinoid tumors in the setting of morbid obesity. PMID- 28624535 TI - ATP-free biosynthesis of a high-energy phosphate metabolite fructose 1,6 diphosphate by in vitro metabolic engineering. AB - Fructose 1,6-diphosphate (FDP) is a widely used medicine and is also a precursor of two important three-carbon phosphates - glyceraldehyde 3-phosphate (GA3P) and dihydroxyacetone phosphate (DHAP) for the biosynthesis of numerous fine chemicals. An in vitro synthetic cofactor-free enzymatic pathway comprised of four hyperthermophilic enzymes was designed to produce FDP from starch and pyrophosphate. All of four hyperthermophilic enzymes (i.e., alpha-glucan phosphorylase from Thermotaga maritima, phosphoglucomutase from Thermococcus kodakarensis, glucose 6-phosphate isomerase from Thermus thermophilus, and pyrophosphate phosphofructokinase from T. maritima) were overexpressed in E. coli BL21(DE3) and purified by simple heat precipitation. The optimal pH and temperature of one-pot biosynthesis were 7.2 and 70 degrees C, respectively. The optimal enzyme ratios of alphaGP, PGM, PGI and PFK were 2:2:1:2 in terms of units. Via step-wise addition of new substrates, up to 125 +/- 4.6mM FDP was synthesized after 7-h reaction. This de novo ATP-free enzymatic pathway comprised of all hyperthermophilic enzymes could drastically decrease the manufacturing costs of FDP and its derivatives GA3P and DHAP, better than those catalyzed by ATP-regeneration cascade biocatalysis, the use of mesophilic enzymes, whole cell lysates, and microbial cell factories. PMID- 28624534 TI - Glutaminase C overexpression in the brain induces learning deficits, synaptic dysfunctions, and neuroinflammation in mice. AB - Glutaminolysis, a metabolic process that converts glutamine to glutamate, is particularly important for the central nervous system since glutamate is the major transmitter of excitatory synapses. Glutaminase is the mitochondrial enzyme that catalyzes the first step of glutaminolysis. Two genes encode at least four isoforms of glutaminase in humans. Gls1 gene encodes isoforms kidney-type glutaminase (KGA) and glutaminase C (GAC) through alternative splicing, whereas Gls2 gene encodes liver-type glutaminase isoforms. KGA and GAC have been associated with several neurological diseases. However, it remains unclear whether changes in their expressions can directly cause brain abnormalities. Using a transgenic approach, we generated mice that overexpressed GAC in the brain. The resulting transgenic mice had severe impairments in spatial and fear learning compared with littermate controls. The learning deficits were consistent with diminished hippocampal long-term potentiation in the hippocampal slices of the GAC transgenic mice. Furthermore, we found increases in astrocyte and microglia markers, inflammatory factors, and a decrease in synapse marker synaptophysin, suggesting neuroinflammation and synaptic changes in the GAC transgenic mouse brains. In conclusion, these findings provide the first evidence that GAC overexpression in the brain has deleterious effects on learning and synaptic integrity in vivo. PMID- 28624536 TI - MicroRNA-dependent regulation of metamorphosis and identification of microRNAs in the red flour beetle, Tribolium castaneum. AB - To date, although some microRNAs (miRNAs) have been discovered in the holometabolism insect Tribolium castaneum, large numbers of miRNAs still require investigation. Knocking down Dicer-1 (Dcr-1) and Argonaute-1 (Ago-1) in late larvae impaired miRNA synthesis, affected the juvenile hormone pathway by up regulating Methoprene-tolerant (Met) and Kruppel-homolog1 (Kr-h1) transcript levels, and resulted in a series of defects in T. castaneum development and metamorphosis. Thus, high-throughput Illumina/Solexa sequencing was performed with a mixed sample of eight key developmental stages of T. castaneum. In total, 1154 unique miRNAs were discovered containing 274 conserved miRNAs belong to 68 miRNA families, 108 known candidate miRNAs and 772 novel miRNAs. Genome locus analysis showed that miRNA clusters are more abundant in T. castaneum than other species. The results indicated that RNAi of Dcr-1 and Ago-1 in T. castaneum resulted in miRNA-induced metamorphosis defects. Furthermore, large numbers of novel miRNAs were discovered in T. castaneum and localized to T. castaneum genome loci. PMID- 28624537 TI - Visualizing RNA granule transport and translation in living neurons. AB - In polarized cells, such as neurons, the synthesis of an mRNA does not ensure its proper cellular expression. Most mature transcripts require the association with RNA-binding proteins, resulting in the formation of RNA granules, which are then transported within the cytoplasm along the cytoskeleton and delivered to their proper subcellular locations, where they can be locally translated. Here we review current microscopy methods that have been developed to visualize RNA granule formation, transport and translation at the single cell level with a special emphasis on the MS2 and SunTag systems. They include the labeling of mRNAs and RNA-binding proteins in living cells or even the detection of newly synthesized proteins in situ. PMID- 28624539 TI - Polarization resolved second harmonic microscopy. AB - Second harmonic (SH) microscopy has proven to be a powerful imaging modality over the past years due to its intrinsic advantages as a multiphoton process with endogenous contrast specificity, which allows pinhole-less optical sectioning, non-invasive observation, deep tissue penetration, and the possibility of easier signal detection at visible wavelengths. Depending on the relative orientation between the polarization of the incoming light and the second-order susceptibility of non-centrosymmetric structures, SH microscopy provides the unique capacity to probe the absolute molecular structure of a broad variety of biological tissues without the necessity for additional labeling. In addition, SH microscopy, when working with polarimetry, provides clear and in-depth insights on the details of molecular orientation and structural symmetry. In this review, the working principles of the polarization resolving techniques and the corresponding implements of SH microscopy are elucidated, with focus on Stokes vector based polarimetry. An overview of the advancements on SH anisotropy measurements are also presented. Specifically, the recent progresses on the following three topics in polarization resolved SH microscopy will be elucidated, which include Stokes vector resolving for imaging molecular structure and orientation, 3-D structural chirality by SH circular dichroism, and correlation with fluorescence lifetime imaging (FLIM) for in vivo wound healing diagnosis. The potentials and challenges for future researches in exploring complex biological tissues are also discussed. PMID- 28624538 TI - Analysis of mRNA deadenylation by multi-protein complexes. AB - Poly(A) tails are found at the 3' end of almost every eukaryotic mRNA and are important for the stability of mRNAs and their translation into proteins. Thus, removal of the poly(A) tail, a process called deadenylation, is critical for regulation of gene expression. Most deadenylation enzymes are components of large multi-protein complexes. Here, we describe an in vitro deadenylation assay developed to study the exonucleolytic activities of the multi-protein Ccr4-Not and Pan2-Pan3 complexes. We discuss how this assay can be used with short synthetic RNAs, as well as longer RNA substrates generated using in vitro transcription. Importantly, quantitation of the reactions allows detailed analyses of deadenylation in the presence and absence of accessory factors, leading to new insights into targeted mRNA decay. PMID- 28624540 TI - Cross-beta polymerization and hydrogel formation by low-complexity sequence proteins. AB - Low-complexity (LC) sequences, typically believed to be incapable of assuming structural order, are abundant constituents of the proteomes of all eukaryotic organisms. These sequences have emerged as critical components for formation of meso-scaled, sub-cellular organelles not invested by surrounding membranes, exemplified by RNA granules. We have observed that LC domains of many RNA binding proteins known to be constituents of RNA granules readily form labile cross-beta polymers under physiological conditions. Several lines of experimentation have shown that formation of labile, cross-beta polymers assembled from LC domain monomers is important for formation of RNA granules. Among the various experiments we have carried out, hydrogel binding assays have evolved as a versatile technique allowing a reliable means of assessing polymer formation and the binding of heterotypic cellular components integral to the formation of RNA granules. This article presents methods allowing for the production of hydrogel droplets composed of LC domain polymers. We further describe methods allowing straightforward assessment for binding of test LC domains to hydrogel droplets by fluorescence microscopy. PMID- 28624541 TI - High Prevalence and Clinical/Sociodemographic Correlates of Miscarriages Among Flight Attendants. AB - BACKGROUND: There are many occupational health hazards associated with long hours of air travel, including cosmic radiation exposure, circadian rhythm disruptions, prior and secondhand smoke exposure, for flight attendants who flew before smoking bans were initiated in the 1990s. Previous studies in flight attendants have found increased incidence of breast cancer and melanoma. However, there is little information on the relationship of airline travel and reproductive health in flight attendants. Secondhand smoke exposure has numerous negative health effects, such as increased cardiac events and respiratory infections, but its effect on reproductive health is not known. This study seeks to examine the role of secondhand smoke exposure on the miscarriage rate in flight attendants who flew before the smoking ban. METHODS: Flight attendants who flew before the smoking ban and participating in a study of health effects of secondhand smoke were asked to complete a reproductive health survey. We compared miscarriage rates of flight attendants to the general population using 2010 data from the Centers for Disease Control and Prevention. RESULTS: In our cohort of 145 female flight attendants exposed to secondhand smoke, there were 45 miscarriages (26%), compared with a 17.1% rate in the Centers for Disease Control and Prevention report (P = .002). There was no difference in secondhand smoke exposure between the flight attendants with miscarriage and the group without miscarriage (P = .93). CONCLUSIONS: This study found an increased incidence of miscarriage in flight attendants, which was unrelated to secondhand smoke exposure. Other factors, such as circadian rhythm disruption and radiation, may be related to these reproductive health findings and require further investigation. PMID- 28624542 TI - Outcome and Clinical Significance of Immunophenotypic Markers Expressed in Different Treatment Protocols of Pediatric Patients With T-ALL in Developing Countries. AB - BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) accounts for about 15% of pediatric ALL. With wider use of intensive chemotherapy, the prognosis for childhood T-ALL has improved. Further gains in treatment outcome will likely require methods to identify patients who continue to fail on contemporary protocols. This study aimed to evaluate pediatric patients with T-ALL at 2 different Arabic cancer centers regarding their clinicopathologic, immunophenotypic, and cytogenetic features and outcome. PATIENTS AND METHODS: This retrospective study included all children with T-ALL treated between 2003 and 2013 at 2 oncology centers in the Middle East. Patients were divided into (group I) treated with Berlin-Frankfurt-Munster (BFM)-90 treatment protocol between February 2003 and June 2007 and (group II) includes all patients treated thereafter by the Total Therapy Study XIII protocol for high-risk ALL. RESULTS: This study included 103 patients with a median age of 8.9 years. The male to female ratio was 2.6:1. The median initial white blood cell count was 123 * 109/L. Central nervous system leukemia was detected in 15%. The early T-cell precursor (ETP)-ALL phenotype was found in 16.5%. The 5-year overall survival was 20.7% +/- 67.5% and 72.9% +/- 5.7% (P < .01); the 5-year disease-free survival was 47.1% +/- 13.8% and 77.3% +/- 6.0% (P = .023); and the 5-year event-free survival was 28.6% +/- 12.1% and 71.1% +/- 6.2% (P = .003) for group I and II, respectively. CONCLUSION: The outcome of patients with T-ALL significantly improved in patients who received the treatment protocol of ALL with high-risk criteria. This protocol eliminates the bad outcomes effect of several clinical and immunophenotypic markers. Patient with the ETP-ALL phenotype had a nonsignificant inferior outcome compared with the non-ETP-ALL group. PMID- 28624543 TI - Impact of Health Care Insurance Status on Treatment Outcomes of Acute Myeloid Leukemia. AB - INTRODUCTION: Insurance status has been found to influence treatment outcomes in various solid tumors. Limited data with conflicting results are available in patients with acute myeloid leukemia (AML). We examined the impact of health insurance at diagnosis on AML treatment outcomes. PATIENTS AND METHODS: All consecutive adult patients (>= 18 years of age) diagnosed with AML between 2002 and 2011 and followed through August 2013 were included. Survival estimates were calculated by Kaplan-Meier survival curves. Logistic regression and multivariate Cox proportional hazards methods were used to explore the influence of multiple baseline covariates on treatment outcomes. RESULTS: A total of 217 patients with complete medical records were identified. Of these, 161 patients had complete cytogenetic/molecular data for risk stratification and were included in the final efficacy analyses. Most patients (45.8%) were publicly insured, 36.3% were privately insured, and 17.3% were uninsured. No significant association was found between insurance source and cytogenetic/molecular risk status. Transplantation information was available for 157 patients, with no significant association found between transplant receipt and insurance source. After adjustment for age, cytogenetic/molecular risk, and transplant receipt, we found no statistically significant association between the insurance source and either event-free or overall survival. CONCLUSION: Insurance source at diagnosis has no impact on AML treatment outcomes. The consistency of our results with some, but not all, studies is probably driven primarily by access-to-care eligibility requirements among different states. Further efforts to better understand such disparities are warranted. PMID- 28624544 TI - CRISPR-GE: A Convenient Software Toolkit for CRISPR-Based Genome Editing. PMID- 28624545 TI - Speedy Grass Stomata: Emerging Molecular and Evolutionary Features. PMID- 28624546 TI - Understanding Maize Biology for Better Crop Improvement. PMID- 28624547 TI - Regioselective monoalkylation of 17beta-estradiol for the synthesis of cytotoxic estrogens. AB - The regioselective synthesis of estrogens and their derivatives continues to be of interest. Most reported syntheses require multistep protocols associated with poor overall yield and lack of regioselectivity. New preparative protocols are still desired. Herein, 11 2-alkylated 17beta-estradiol analogs were synthesized in a highly regioselective manner. The products were obtained using a convenient, one pot and high-yielding protocol. The anti-proliferative activity of the compounds was tested in human T-cell leukemia (CEM), human cervix carcinoma (HeLa) and human dermal microvascular endothelial (HMEC-1) cells. PMID- 28624548 TI - Glucocorticoids and gut bacteria: "The GALF Hypothesis" in the metagenomic era. AB - A new concept is emerging in biomedical sciences: the gut microbiota is a virtual 'organ' with endocrine function. Here, we explore the literature pertaining to the role of gut microbial metabolism of endogenous adrenocorticosteroids as a contributing factor in the etiology of essential hypertension. A body of literature demonstrates that bacterial products of glucocorticoid metabolism are absorbed into the portal circulation, and pass through the kidney before excretion into urine. Apparent mineralocorticoid excess (AME) syndrome patients were found to have congenital mutations resulting in non-functional renal 11beta hydroxysteroid dehydrogenase-2 (11beta-HSD2) and severe hypertension often lethal in childhood. 11beta-HSD2 acts as a "guardian" enzyme protecting the mineralocorticoid receptor from excess cortisol, preventing sodium and water retention in the normotensive state. Licorice root, whose active ingredient, glycerrhetinic acid (GA), inhibits renal 11beta-HSD2, and thereby causes hypertension in some individuals. Bacterially derived glucocorticoid metabolites may cause hypertension in some patients by a similar mechanism. Parallel observations in gut microbiology coupled with screening of endogenous steroids as inhibitors of 11beta-HSD2 have implicated particular gut bacteria in essential hypertension through the production of glycerrhetinic acid-like factors (GALFs). A protective role of GALFs produced by gut bacteria in the etiology of colorectal cancer is also explored. PMID- 28624549 TI - Evaluation of a new trilocus sequence-based multiplex-PCR to detect major Acinetobacter baumannii clonal complexes circulating in Brazil. AB - Dissemination of carbapenem-resistant Acinetobacter baumannii (CRAB) is mainly due to the spread of clonal lineages, particularly those included into the clonal complexes (CC) CC1, CC2, CC15, CC25, and CC79. We evaluated the usefulness of a recently modified PCR-based trilocus sequence-based typing (m3LST) in comparison with the standard multilocus sequence typing (MSLT) of 7 housekeeping genes as per the Institute Pasteur Scheme to assign the clonal complexes in CRAB. A collection of 78 CRAB isolated from 67 different Brazilian health institutions was submitted to both methodologies, and concordance rate was calculated. The collection studied included mainly isolates belonging to endemic Brazilian Clonal Complexes (CC1, CC15, CC25 and CC79, n=72, 92.3%) but also singletons sequence types (ST) with low prevalence in the country (ST107, ST113, ST188, ST317, ST584, ST733, n=6; 7.7%). The m3LST correctly assigned all the isolates into the main CC responsible for the CRAB dissemination in Brazil. All the singletons ST were not misidentified as prevalent lineages. The PCR-based m3LST is a powerful tool to investigate molecular epidemiology of A. baumannii representative of prevalent Brazilian clonal complexes 1, 15, 25 and 79. PMID- 28624550 TI - Comparative genome analysis of fish pathogen Flavobacterium columnare reveals extensive sequence diversity within the species. AB - Flavobacterium columnare is one of the deadliest fish pathogens causing devastating mortality in various freshwater fish species globally. To gain an insight into bacterial genomic contents and structures, comparative genome analyses were performed using the reference and newly sequenced genomes of F. columnare including genomovar I, II and I/II strains isolated from Thailand, Europe and the USA. Bacterial genomes varied in size from 3.09 to 3.39Mb (2714 to 3101 CDSs). The pan-genome analysis revealed open pan-genome nature of F. columnare strains, which possessed at least 4953 genes and tended to increase progressively with the addition of a new genome. Genomic islands (GIs) present in bacterial genomes were diverse, in which 65% (39 out of 60) of possible GIs were strain-specific. A CRISPR/cas investigation indicated at least two different CRISPR systems with varied spacer profiles. On the other hand, putative virulence genes, including those related to gliding motility, type IX secretion system (T9SS), outer membrane proteins (Omp), were equally distributed among F. columnare strains. The MLSA scheme categorized bacterial strains into nine different sequence types (ST 9-17). Phylogenetic analyses based on either 16S rRNA, MLSA and concatenated SNPs of core genome revealed the diversity of F. columnare strains. DNA homology analysis indicated that the estimated digital DNA DNA hybridization (dDDH) between strains of genomovar I and II can be as low as 42.6%, while the three uniquely tilapia-originated strains from Thailand (1214, NK01 and 1215) were clearly dissimilar to other F. columnare strains as the dDDH values were only 27.7-30.4%. Collectively, this extensive diversity among bacterial strains suggested that species designation of F. columnare would potentially require re-emendation. PMID- 28624551 TI - Accumulation of porphyrins in Propionibacterium acnes by 5-aminolevulinic acid and its esters. AB - We have investigated the accumulation of porphyrins in Propionibacterium acnes (P.acnes) by 5-aminolevulinic acid hydrochloride (ALA) and its esters, ALA methyl ester hydrochloride (mALA), ALA octyl ester hydrochloride (oALA), and ALA benzyl ester hydrochloride (bALA). From the fluorescence spectra of porphyrins accumulated in P.acnes, the order of porphyrin accumulation is as follows: ALA?mALA~bALA>oALA (~0). Moreover, the PDT efficacy is reduced in the order of ALA>mALA~bALA>oALA (~without additives). These results confirm that ALA is superior to ALA esters in accumulating porphyrins in P.acnes. PMID- 28624552 TI - "Watering Can" Ureterocele Puncture Technique Leads to Decreased Rates of De Novo Vesicoureteral Reflux and Subsequent Surgery With Durable Results. AB - OBJECTIVE: To assess the outcomes of "watering can" ureterocele puncture (WCP), a technique previously associated with decreased incidence of de novo vesicoureteral reflux (VUR), as a durable option for management of ureteroceles and to determine the need for subsequent surgery for VUR following watering can puncture. MATERIALS AND METHODS: We retrospectively reviewed records of 55 consecutive endoscopic ureterocele procedures performed at our institution from 1999 to 2015. The WCP was performed using a holmium laser fiber to make 10-20 puncture holes through the ureterocele. Follow-up data were collected on infection, de novo VUR in the affected renal moiety and the need for further treatment and surgery. RESULTS: Of 55 patients who underwent endoscopic ureterocele management, 34 underwent WCP and 21 patients underwent either incision or puncture. Median follow-up was 3.4 and 2.8 years in the incision and puncture groups, respectively. Both groups had similar rates of ureterocele decompression (88% vs 90%; P >.05) and improvement in hydronephrosis (82% vs 81%; P >.05). The WCP group had a significantly decreased rate of de novo VUR (32% vs 67%; P <.05) and of subsequent surgery due to de novo VUR (38% vs 71%; P <.05). The average grade of de novo VUR was lower in the WCP group (1.4 vs 2.8; P <.05). CONCLUSION: Our study shows that the endoscopic WCP successfully decompresses the obstructing ureterocele and results in a decreased incidence of de novo VUR and ultimately in fewer invasive procedures for the patient. This update demonstrates the durable outcomes of this novel technique. PMID- 28624553 TI - Comparison of the Effect of Naftopidil 75 mg and Tamsulosin 0.2 mg on the Bladder Storage Symptom With Benign Prostatic Hyperplasia: Prospective, Multi institutional Study. AB - OBJECTIVE: To compare the efficacies of naftopidil and tamsulosin in terms of reducing storage symptoms in patients with benign prostatic hyperplasia. MATERIALS AND METHODS: This prospective randomized study was performed at 10 centers. Ninety-four patients that had been taking tamsulosin for more than 8 weeks, but had an Overactive Bladder Symptom Score (OABSS) of greater than 3 points, were initially enrolled. After a 1-week washout period, patients were divided into 2 groups. Forty-five patients were treated with tamsulosin 0.2 mg daily, and 49 patients were treated with naftopidil 75 mg daily for 8 weeks. Total International Prostate Symptoms Score (IPSS), storage symptom scores, nocturia times, OABSS, maximal flow rates (Qmax), and postvoid residual volumes were checked before and after the 8-week treatment period. RESULTS: Mean patient ages in the tamsulosin and naftopidil groups were 64.8 and 66.0 years, respectively. Baseline characteristics were not significantly different. In the tamsulosin group, mean total IPSS decreased from 19.1 to 15.1 after the 8-week treated period (P = .001), and in the naftopidil group, mean total IPSS decreased from 16.9 to 13.1 (P = .001). Mean storage symptom scores were reduced in the tamsulosin and naftopidil groups from 8.0 to 6.6 (P = .002) and from 7.6 to 6.1 (P = .001), respectively. Mean nocturia times in the naftopidil groups decreased significantly from 2.5 to 1.9 (P = .001), and mean OABSSs were reduced from 7.7 to 6.0 (P = .001) and from 7.4 to 6.0 (P = .001), respectively. CONCLUSION: Total IPSS, storage symptom scores, nocturia times, and OABSS were significantly reduced by naftopidil and tamsulosin. Moreover, the naftopidil group showed better improvements in nocturia than the tamsulosin group. PMID- 28624555 TI - Sacral Neuromodulation Device Heating During Lumbar and Pelvic Magnetic Resonance Imaging-a Phantom Study. AB - OBJECTIVE: To evaluate radiofrequency-induced temperature rises associated with performing lumbar and pelvic magnetic resonance imaging (MRI) studies with an implanted sacral neuromodulation device using a phantom model. MATERIALS AND METHODS: An accepted phantom model of radiofrequency-induced heating in human tissue was used to measure the temperature rise in the stimulator lead electrodes and impulse generator under the conditions used during routine clinical lumbar and pelvic MRIs in a 1.5Tesla MRI scanner. Testing configurations included an intact device (tined lead connected to generator), an intact lead, and a lead fragment (model of lead fracture). Variations in the position of the phantom relative to the scanner were also tested. RESULTS: During testing with the intact device or the lead fragment no significant heating was detected. In contrast, the isolated intact lead model showed heating up to 5 degrees C. CONCLUSION: These tests provide preliminary evidence that the risk of heating is low for clinical lumbar and pelvic MRI at 1.5-Tesla with an intact sacral neuromodulation device system and with a fractured lead. However, there is a significant temperature change in the intact lead model. PMID- 28624554 TI - Outcomes of Urethroplasty to Treat Urethral Strictures Arising From Artificial Urinary Sphincter Erosions and Rates of Subsequent Device Replacement. AB - OBJECTIVE: To evaluate the success of urethroplasty for urethral strictures arising after erosion of an artificial urinary sphincter (AUS) and rates of subsequent AUS replacement. PATIENTS AND METHODS: From 2009-2016, we identified patients from the Trauma and Urologic Reconstruction Network of Surgeons and several other centers. We included patients with urethral strictures arising from AUS erosion undergoing urethroplasty with or without subsequent AUS replacement. We retrospectively reviewed patient demographics, history, stricture characteristics, and outcomes. Variables in patients with and without complications after AUS replacement were compared using chi-square test, independent samples t test, and Mann-Whitney U test when appropriate. RESULTS: Thirty-one men were identified with the inclusion criteria. Radical prostatectomy was the etiology of incontinence in 87% of the patients, and 29% had radiation therapy. Anastomotic (28) and buccal graft substitution (3) urethroplasty were performed. Follow-up cystoscopy was done in 28 patients (median 4.5 months, interquartile range [IQR]: 3-8) showing no urethral stricture recurrences. Median overall follow-up was 22.0 months (IQR: 15-38). In 27 men (87%), AUS was replaced at median of 6.0 months (IQR: 4-7) after urethroplasty. In 25 patients with >3 months of follow-up after AUS replacement, urethral complications requiring AUS revision or removal occurred in 9 patients (36%) and included subcuff atrophy (3) and erosion (6). Mean length of stricture was higher in patients who developed a complication after urethroplasty and AUS replacement (2.2 vs. 1.5 cm, P = .04). CONCLUSION: In patients with urethral stricture after AUS erosion, urethroplasty is successful. However, AUS replacement after urethroplasty has a high erosion rate even in the short-term. PMID- 28624556 TI - A 64-bp sequence containing the GAAGA motif is essential for CaMV-35S promoter methylation in gentian. AB - This study investigated sequence specificity and perenniality of DNA methylation in the cauliflower mosaic virus (CaMV) 35S promoter of transgenic gentian (Gentiana triflora*G. scabra) plants. Unlike conventional transgene silencing models, 35S promoter hypermethylation in gentian is species-specific and occurs irrespective of the T-DNA copy number and genomic location. Modified 35S promoters were introduced into gentian, and single-copy transgenic lines were selected for methylation analysis. Modified 35S promoter lacking a core (-90) region [35S(Deltacore)] in gentian conferred hypermethylation and high levels of de novo methylation of the CpHpH/CpCpG sites in the 35S enhancer regions (-298 to -241 and -148 to -85). Therefore, promoter transcription may not be an absolute requirement for the methylation machinery. In vitro, de novo methylation persisted for more than eight years. In another modified 35S promoter, two "GAAGA" motifs (-268 to -264 and -135 to -131) were replaced by "GTTCA" in the two highly de novo methylated regions. It did not support hypermethylation and showed transgene expression. A 64-bp fragment of the 35S enhancer region (-148 to -85) was introduced into gentian and the resultant transgenic lines analyzed. The 64-bp region exhibited hypermethylation at the CpG/CpWpG sites, but the CpHpH/CpCpG methylation frequency was lower than those of the unmodified 35S- and 35S(Deltacore) promoters. Nevertheless, a distinct CpHpH/CpCpG methylation peak was found in the 64-bp region of all single-copy transgenic lines. These results suggest that the 64-bp region may contain an element required for 35S methylation but insufficient for high de novo methylation compared with those in the unmodified 35S and 35S(Deltacore) promoters. PMID- 28624557 TI - Arthroscopic lateral retinacular release, medial retinacular plication and partial medial tibial tubercle transfer for recurrent patellar dislocation. AB - OBJECTIVE: To assess the efficacy of a therapeutic protocol composed of arthroscopic lateral retinacular release, medial retinacular plication, and partial medial tibial tuberosity transfer for patients with recurrent patellar dislocation. METHOD: 71 patients, 11 males and 60 females and a total of 77 knees, with recurrent dislocation of the patella were enrolled between 1998 and 2012. The average age of the patients was 19.5 years and 67 of them had previous knee trauma history. Tibial tubercle avulsion fractures were all surgically treated without complications like dysplasia in the femoral trochlear groove or valgus deformity. The Q angle, sulcus angle, patella-femoral trochlear congruence angle and lateral patellofemoral angle were measured on X-ray, while tibial tubercle-trochlear groove (TT-TG) distance was measure on CT scans, before the arthroscopic operation. RESULT: 69 patients were followed-up for 2-16 years (average of 7.2 years), while 2 patients were lost during follow-up. Among the patients with follow-up, one patient had recurrent patella dislocation two months after the operation. Q angle decreased from 13.2 degrees to 9.2 degrees in male patients (P < 0.05) and from 21.0 degrees to 15.4 degrees in female patients (P < 0.05). On average, the patella-femoral trochlear congruence angle decreased from 24.2 +/- 6.8 degrees to -2.1 +/- 5.8 degrees (P < 0.05) and the lateral patellofemoral angle increased from -2.0 +/- 5.2 degrees to 10.9 +/- 4.0 degrees (P < 0.05). TT-TG distance decreased from 19.8 +/- 2.1 mm to 13.6 +/- 1.8 mm (P < 0.01). Mean Lysholm score increased from 45.6 +/- 4.8 to 92.3 +/- 10.8 (P < 0.05) and, IKDC score increased from 48.3 +/- 6.8 to 94.3 +/- 8.4 (P < 0.05). CONCLUSION: As evidenced by minimal trauma and markedly improved knee joint function, the proposed therapeutic protocol demonstrated clear benefits for patients with recurrent patella dislocation. PMID- 28624559 TI - Hereditary factors are unlikely behind unusual pattern of early - Onset colorectal cancer in Egyptians: A study of family history and pathology features in Egyptians with large bowel cancer (cross-sectional study). AB - BACKGROUND: Colorectal cancer in Egypt has a higher incidence in young patients compared to western countries, where the disease is more prevalent in the old age group. This difference has been attributed to higher incidence of hereditary cancers in young Egyptian patients. The aim of this study is to compare the family history criteria and pathology features of tumors in young (<=40 years) and old (>40 years) Egyptian patients with adenocarcinoma of the colon and rectum. MATERIALS AND METHODS: This is the analysis of our prospectively collected data on the pathology features of tumors in 313 consecutive patients (133 young, 180 old) with colorectal cancer presenting to the Department of Surgery within an eight-year period. A detailed family history was obtained from 258 patients (112 young, 146 old). RESULTS: 41 young and 48 old patients reported family history of cancer, the difference was not statistically significant. Ten young patients (9%) reported a family history of colorectal cancer in a first degree relative (3 fitting into Amsterdam criteria, 7 fitting into less strict criteria) which was not significantly different from the old age group. The pathologic features of tumors in both groups resembled sporadic rather than hereditary cancer and there was no significant difference between groups in tumor location, degree of differentiation, mucin production, synchronous and metachronous colorectal tumors or polyps and grossly stricturing or ulcerating tumors. Extracolonic tumors developed in one young and two old patients. CONCLUSION: The characteristics of large bowel cancer in young Egyptian patients do not differ significantly from those in older patients. Despite the high incidence of large bowel cancer in young Egyptian patients, family history and pathologic features of tumors do not support a hereditary origin of colorectal cancer in this age group in Egypt. PMID- 28624558 TI - Safety and feasibility of electrochemotherapy in patients with unresectable colorectal liver metastases: A pilot study. AB - BACKGROUND AND OBJECTIVES: Electrochemotherapy is a novel ablation technique combining chemotherapeutic agents with reversible cell membrane electroporation. Previous experiences have shown its efficacy for cutaneous tumors. Its application for deep-seated malignancies is under investigation. We performed a prospective, pilot study to evaluate the feasibility, safety, and efficacy of intraoperative electrochemotherapy for otherwise unresectable colorectal liver metastases. METHODS: Electrochemotherapy with bleomycin was combined with open liver resection and performed with linear or hexagonal needle electrodes according to an individualized pretreatment plan. The primary endpoints were: feasibility, as ratio of completed to planned treatments; safety, and efficacy, as per response assessed at 30 days with MRI and according to RECIST. The secondary endpoint was overall and progression-free survival at month 6. RESULTS: A total of 9 colorectal liver metastases were treated in 5 patients with 20 electrode applications. No intraoperative complications were observed. At day 30, complete response was 55.5% and stable disease 45.5%. All (5) patients reached a 6 months overall survival, and 4 out of 5 patients had 6 months progression free survival. CONCLUSIONS: Electrochemotherapy is a feasible and safe adjunct to open surgery for treatment of unresectable colorectal liver metastases. Larger studies and longer follow-ups are favored to better define its role in the treatment of secondary liver malignancies. PMID- 28624560 TI - Intracranial Hypotension Following Traumatic Brain Injury: A Diagnostic and Therapeutic Challenge. AB - BACKGROUND: Intracranial hypotension (IH) is a recognized cause of coma; however, the diagnosis is often challenging, especially in patients with superimposed traumatic brain injury. CASE DESCRIPTION: A 67-year-old woman became comatose following evacuation of bilateral acute subdural hematomas with concurrent respiratory failure. Imaging and intraparenchymal intracranial pressure monitoring confirmed secondary IH. She was managed with an epidural blood patch and a 72-hour period in the Trendelenburg position guided by intracranial pressure monitoring and clinical assessment. She subsequently made an excellent neurologic recovery from an initial Glasgow Coma Scale score of 3 to a score of 15. CONCLUSIONS: Secondary IH can easily be missed in patients who have sustained a primary brain injury. In patients with a poor neurologic recovery, clinicians should rule out secondary IH as a potential cause, as immediate treatment can lead to profound clinical improvement. PMID- 28624562 TI - Impact of Gradient Number and Voxel Size on Diffusion Tensor Imaging Tractography for Resective Brain Surgery. AB - OBJECTIVE: To explore quantitatively and qualitatively how the number of gradient directions (NGD) and spatial resolution (SR) affect diffusion tensor imaging (DTI) tractography in patients planned for brain tumor surgery, using routine clinical magnetic resonance imaging protocols. METHODS: Of 67 patients with intracerebral lesions who had 2 different DTI scans, 3 DTI series were reconstructed to compare the effects of NGD and SR. Tractographies for 4 clinically relevant tracts (corticospinal tract, superior longitudinal fasciculus, optic radiation, and inferior fronto-occipital fasciculus) were constructed with a probabilistic tracking algorithm and automated region of interest placement and compared for 3 quantitative measurements: tract volume, median fiber density, and mean fractional anisotropy, using linear mixed-effects models. The mean tractography volume and intersubject reliability were visually compared across scanning protocols, to assess the clinical relevance of the quantitative differences. RESULTS: Both NGD and SR significantly influenced tract volume, median fiber density, and mean fractional anisotropy, but not to the same extent. In particular, higher NGD increased tract volume and median fiber density. More importantly, these effects further increased when tracts were affected by disease. The effects were tract specific, but not dependent on threshold. The superior longitudinal fasciculus and inferior fronto-occipital fasciculus showed the most significant differences. Qualitative assessment showed larger tract volumes given a fixed confidence level, and better intersubject reliability for the higher NGD protocol. SR in the range we considered seemed less relevant than NGD. CONCLUSIONS: This study indicates that, under time constraints of clinical imaging, a higher number of diffusion gradients is more important than spatial resolution for superior DTI probabilistic tractography in patients undergoing brain tumor surgery. PMID- 28624561 TI - Safety, Utility, and Clinical Results of Continuous Intraoperative Electrophysiologic Monitoring in 1.5T iMRI-Guided Surgery. AB - OBJECTIVE: To show that the combined use of intraoperative high-field MRI (iMRI) and electrophysiologic monitoring (IOM) is feasible, safe, and beneficial for patients. METHODS: The setup, surgical, imaging, and clinical results of 110 patients with eloquent intracranial lesions with the combined use of 1.5T iMRI and IOM were analyzed. RESULTS: 187 iMRI scans were performed with IOM needles in place, resulting in a total experience of using >4000 electrodes in the iMRI. No complication (ferromagnetic or relevant heating/burning of skin) was caused by the combined use of both technologies. Surgically induced severe postoperative sensorimotor deficits were seen in 11.8%. The surgeon's estimation of a "complete resection" proved to be true postoperatively in 90.3%. If the resection was stopped due to worsening of IOM, postoperative MRI revealed residual disease to be located in direct vicinity of eloquence in 27 of 28 cases, but not in other parts of the resection cavity. Of these patients, only 7% (2 of 28) had relevant new deficits after 3 months. In 82 patients (74.5%), the resection was continued after the iMRI scan, whereas in only 18 patients (16.4%) the resection was already completed at this point. CONCLUSION: The combined use of IOM and 1.5T iMRI is feasible and safe. The complementary use of both technologies might result in more radical resections at comparable surgically induced neurologic deficits. If available and indicated, the combined use of IOM and iMRI should be performed on a routine basis. PMID- 28624563 TI - Long-Term Volume Reduction Effects of Endovascular Embolization for Intracranial Meningioma: Preliminary Experience of 5 Cases. AB - BACKGROUND: Preoperative endovascular embolization of intracranial meningiomas denatures the tumor tissue, reduces intraoperative blood loss, and facilitates surgical removal. However, as most meningiomas are surgically removed within a few days after embolization, the effect of long-term volume reduction of the tumor due to the endovascular embolization remains unknown. METHODS: Five patients with intracranial meningioma underwent endovascular embolization between January 2006 and December 2014 and were followed without surgical resection for >14 days. The reduction in tumor and peritumoral edema volumes on sequential head magnetic resonance imaging, along with the clinical symptoms, were retrospectively reviewed. RESULTS: All the tumors indicated a 10%-30% volume reduction 30 days after embolization, which continued thereafter; no meningioma regrowth was observed for >90 days in 2 of 5 cases. Moreover, the peritumoral edema volume was reduced by 30%-70% at 30 days after embolization, and no subsequent increase was observed for >60 days in 4 of 5 cases. The neurologic symptoms related to the tumor mass effect improved after embolization. CONCLUSIONS: Endovascular embolization of intracranial meningiomas with n-butyl cyanoacrylate reduced the tumor and peritumoral edema volumes by 10%-30% and 30% 70%, respectively, within 30 days. Volume and edema reduction effect of embolization may last longer than expected, beyond the timing when most meningiomas are resected after embolization. In this study, we described our preliminary results of the volume reduction of intracranial meningiomas that were embolized using n-butyl cyanoacrylate and monitored without any surgical resection for >14 days. We believe that our study makes a significant contribution to the literature because we showed that volume and edema reduction effect of embolization may last longer than expected, beyond the timing when most meningiomas are resected after embolization. PMID- 28624564 TI - Structural Allograft versus Autograft for Instrumented Atlantoaxial Fusions in Pediatric Patients: Radiologic and Clinical Outcomes in Series of 32 Patients. AB - BACKGROUND: Allograft with wire techniques showed a low fusion rate in pediatric atlantoaxial fusions (AAFs) in early studies. Using allograft in pediatric AAFs with screw/rod constructs has not been reported. Thus we compared the fusion rate and clinical outcomes in pediatric patients who underwent AAFs with screw/rod constructs using either a structural autograft or allograft. METHODS: Pediatric patients (aged <=12 years) who underwent AAFs between 2007 and 2015 were retrospectively evaluated. Patients were divided into 2 groups (allograft or autograft). Clinical and radiographic results were collected from hospital records and compared. RESULTS: A total of 32 patients were included (18 allograft, 14 autograft). There were no significant group differences in age, sex, weight, diagnosis, or duration of follow-up. A similar fusion rate was achieved (allograft: 94%, 17/18; autograft: 100%, 14/14); however, the average fusion time was 3 months longer in the allograft group. Blood loss was significantly lower in the allograft group (68 +/- 8.5 mL) than the autograft group (116 +/- 12.5 mL). Operating time and length of hospitalization were slightly (nonsignificantly) shorter for the allograft group. A significantly higher overall incidence of surgery-related complications was seen in the autograft group, including a 16.7% (2/14) rate of donor-site-related complications. CONCLUSIONS: The use of allograft for AAF was safe and efficacious when combined with rigid screw/rod constructs in pediatric patients, with a similar fusion rate to autografts and an acceptable complication rate. Furthermore, blood loss was less when using allograft and donor-site morbidity was eliminated; however, the fusion time was increased. PMID- 28624565 TI - A Case of Laterally Extended High-Positioned Chordoma Treated Using the High Cervical Retropharyngeal Approach. AB - BACKGROUND: Several surgical approaches for the treatment of pathologies of the craniovertebral junction (CVJ) and high cervical regions have been reported. For the best postoperative results, selection of a surgical route to treat such pathologies should be based on a complete understanding of the approach. CASE DESCRIPTION: A 64-year-old woman presented with a 5-year history of motor and sensory disturbances in her right upper extremity. Cervical magnetic resonance imaging (MRI) showed a slightly enhanced mass at the C2-C4 level. Sagittal T2 weighted MRI revealed a hyperintense dumbbell-shaped mass involving a damaged C3 vertebral body. We performed a 2-stage operation to achieve gross total removal of the tumor. In the first operation, a posterior approach was used to remove the intracanalicular tumor, achieve spinal cord decompression, and establish a histological diagnosis of the tumor (subsequently diagnosed as a chordoma). In the second operation, gross total removal of the chordoma was achieved via the anterior high cervical retropharyngeal approach. We used iliac bone and titanium plates for the bony fusion. CONCLUSIONS: Our results indicate that the high cervical retropharyngeal approach is a reasonable option for pathologies located in the anterior or anterolateral portions of high cervical regions. This approach is an alternative to the transoral approach to the ventral CVJ and high cervical regions. PMID- 28624566 TI - Four-Dimensional Phase Contrast Magnetic Resonance Imaging Protocol Optimization Using Patient-Specific 3-Dimensional Printed Replicas for In Vivo Imaging Before and After Flow Diverter Placement. AB - OBJECTIVE: Hemodynamics in cerebral aneurysms are currently investigated toward clinical efficacy using nonstandardized computational simulation techniques. At the same time, flow patterns and velocities are accessible by 4-dimensional phase contrast magnetic resonance imaging (4D pcMRI). Complexity of protocol design and imaging duration has limited the use of this technique in clinical imaging. A new approach is presented to overcome these limitations. METHODS: Three-dimensional (3D) replicas of 2 cerebral aneurysms were fabricated by fused deposition prototyping (3D printing) and imaged using 4D pcMRI while connected to a magnetic resonance imaging-compatible continuous flow loop. Acquisition parameters were optimized with imaging times not to exceed 10 minutes. Six patients harboring cerebral aneurysms with sizes ranging from 4.7 to 13.8 mm were imaged with the optimized 4D pcMRI protocol. After treatment with the pipeline embolization device (PED), 4D pcMRI examinations were repeated in 3 patients. RESULTS: In all cases, major flow patterns were visualized well; smaller aneurysms posed a challenge because of limited spatial resolution, whereas larger aneurysms contained regions of low velocity resulting in limited contrast in the flow sensitive images. After PED placement, ordered aneurysmal flow was disrupted and intra-aneurysmal velocity was reduced on average by 24.5% (range, 12.9-31.5%). Exploratory statistical analysis yielded a positive significant correlation (P < 0.01) between changes in inflow velocity and posttreatment intra-aneurysmal flow velocity. CONCLUSIONS: 4D pcMRI flow imaging in cerebral aneurysms within a time frame suitable for clinical imaging applications is feasible with optimized acquisition parameters, thereby enabling quantification of intra-aneurysmal flow changes after flow diverter device treatment. PMID- 28624567 TI - Results of Operative Treatment of Brachial Plexus Injury Resulting from Shoulder Dislocation: A Study with A Long-Term Follow-Up. AB - BACKGROUND: Injury to the infraclavicular brachial plexus is an uncommon but serious complication of shoulder dislocation. This work aims to determine the effectiveness of operative treatment in patients with this type of injury. METHODS: Thirty-three patients (26 men and 7 women; mean age, 45 years and 3 months) treated operatively for brachial plexus injury resulting from shoulder dislocation between the years 2000 and 2013 were included in this retrospective case series. Motor function of affected limbs was assessed pre- and postoperatively with the use of the British Medical Research Council (BMRC) scale. Sensory function in the areas innervated by ulnar and median nerves was evaluated with the BMRC scale modified by Omer and Dellon and in the remaining areas with the Highet classification. Follow-up lasted 2-10 years (mean, 5.1 years). RESULTS: Good postoperative recovery of nerve function was observed in 100% of musculocutaneous, 93.3% of radial, 66.7% of median, 64% of axillary, and 50% of ulnar nerve injuries. No recovery was observed in 5.6% of median, 6.7% of radial, 10% of ulnar, and 20% of axillary nerve injuries. Injury to a single nerve was associated with worse treatment outcome than multiple nerve injury. CONCLUSIONS: Obtaining improvement in peripheral nerve function after injury resulting from shoulder dislocation may require operative intervention. The type of surgical procedure depends on intraoperative findings: sural nerve grafting in cases of neural elements' disruption, internal neurolysis when intraneural fibrosis is observed, and external neurolysis in the remaining cases. The outcomes of surgical treatment are good, and the risk of intra- and postoperative complications is low. PMID- 28624568 TI - Towards a mechanistic understanding of core promoter recognition from cryo-EM studies of human TFIID. AB - TFIID is a critical component of the eukaryotic transcription pre-initiation complex (PIC) required for the recruitment of RNA Pol II to the start site of protein-coding genes. Within the PIC, TFIID's role is to recognize and bind core promoter sequences and recruit the rest of the PIC components. Due to its size and its conformational complexity, TFIID poses a serious challenge for structural characterization. The small amounts of purified TFIID that can be obtained by present methods of purification from endogenous sources has limited structural studies to cryo-EM visualization, which requires very small amounts of sample. Previous cryo-EM studies have shed light on how the extreme conformational flexibility of TFIID is involved in core promoter DNA binding. Recent progress in cryo-EM methodology has facilitated a parallel progress in the study of human TFIID, leading to an improvement in resolution and the identification of the structural elements in the complex directly involved in DNA interaction. While many questions remain unanswered, the present structural knowledge of human TFIID suggests a mechanism for the sequential engagement with different core promoter sequences and how it could be influenced by regulatory factors. PMID- 28624569 TI - Readers, writers and erasers of N6-methylated adenosine modification. AB - N6-methyladenosine (m6A) as the most prevalent internal modification in mammalian RNAs has been increasingly realized as an important reversible mark that participates in various biological processes and cancer pathogenesis. In this review, we discuss the catalytic mechanisms of MT-A70 domain family proteins for mediating adenosine N6-methylation, the removal of this RNA mark by members of ALKB homologue domain family proteins, and the recognition of these m6A-modified RNAs by YTH domain family proteins. Our discussions focus on the recent advances in our understandings of the structural and functional properties of N6 methyladenosine methyltransferases, demethylases and reader proteins. Overall, we aim to mechanistically explain the reversible and dynamic nature of this unique RNA internal modification that contributes to the complexity of RNA-mediated gene regulation, and inspire new studies in epitranscriptomics. PMID- 28624570 TI - Effects of intrauterine contraception on the vaginal microbiota. AB - OBJECTIVES: There have been conflicting reports of altered vaginal microbiota and infection susceptibility associated with contraception use. The objectives of this study were to determine if intrauterine contraception altered the vaginal microbiota and to compare the effects of a copper intrauterine device (Cu-IUD) and a levonorgestrel intrauterine system (LNG-IUS) on the vaginal microbiota. STUDY DESIGN: DNA was isolated from the vaginal swab samples of 76 women using Cu IUD (n=36) or LNG-IUS (n=40) collected prior to insertion of intrauterine contraception (baseline) and at 6 months. A third swab from approximately 12 months following insertion was available for 69 (Cu-IUD, n=33; LNG-IUS, n=36) of these women. The V4 region of the bacterial 16S rRNA-encoding gene was amplified from the vaginal swab DNA and sequenced. The 16S rRNA gene sequences were processed and analyzed using the software package mothur to compare the structure and dynamics of the vaginal bacterial communities. RESULTS: The vaginal microbiota from individuals in this study clustered into 3 major vaginal bacterial community types: one dominated by Lactobacillus iners, one dominated by Lactobacillus crispatus and one community type that was not dominated by a single Lactobacillus species. Changes in the vaginal bacterial community composition were not associated with the use of Cu-IUD or LNG-IUS. Additionally, we did not observe a clear difference in vaginal microbiota stability with Cu-IUD versus LNG IUS use. CONCLUSIONS: Although the vaginal microbiota can be highly dynamic, alterations in the community associated with the use of intrauterine contraception (Cu-IUD or LNG-IUS) were not detected over 12 months. IMPLICATIONS: We found no evidence that intrauterine contraception (Cu-IUD or LNG-IUS) altered the vaginal microbiota composition. Therefore, the use of intrauterine contraception is unlikely to shift the composition of the vaginal microbiota such that infection susceptibility is altered. PMID- 28624571 TI - Age-related changes of cortical excitability and connectivity in healthy humans: non-invasive evaluation of sensorimotor network by means of TMS-EEG. AB - The sensorimotor cortical system undergoes structural and functional changes across its lifespan. Some of these changes are physiological and parallel the normal aging process, while others might represent pathophysiological mechanisms underlying neurodegenerative disorders. In the last years, the study of possible age-related modifications in brain sensorimotor functional characteristics has been the focus of several research projects. Here we have used the transcranial magnetic stimulation (TMS)-electroencephalography (EEG) navigated co-registration to investigate the influence of physiological aging on the excitability and connectivity of the human sensorimotor cortical system. To this end, we compared the TMS-evoked EEG potentials (TEPs) collected after stimulating the dominant primary motor cortex (M1) in healthy young subjects (mean age 24.5years) with those collected in healthy older adults (mean age 67.6years). We have shown that, after stimulation of the left motor cortex, TEPs are significantly affected by physiological aging. This phenomenon has a clear spatio-temporal specificity and we speculate that normal aging per se leads to some changes in the excitability of specific cortical neural assemblies whereas other alterations could reflect compensatory mechanisms to such changes. PMID- 28624572 TI - Role of beta-catenin and endocannabinoids in the nucleus accumbens in extinction in rats exposed to shock and reminders. AB - The response to a traumatic experience may be rapid recovery or development of psychopathology such as post-traumatic stress disorder (PTSD). Impaired extinction of fear memories is thought to contribute to the development of the persistent trauma memories and avoidance. The Wnt/beta-catenin pathway and the endocannabinoid system appear to play significant roles in anxiety and depressive symptoms. Here we examined the involvement of beta-catenin in the nucleus accumbens (NAc) in extinction in rats exposed to the shock and reminders model of PTSD. We found that increased beta-catenin levels in the NAc were correlated with facilitated extinction kinetics in rats exposed to shock and reminders, suggesting that increased levels of NAc beta-catenin are associated with a resilient response to the stressor. Furthermore, downregulating beta-catenin expression in the NAc in shocked rats using sulindac (0.0178, 0.178mg/side) impaired extinction whereas upregulating the Wnt/beta-catenin pathway using LiCl (2ug/side) facilitated extinction. Exposure to shock and reminders resulted in attenuated levels of the endocannabinoid N-arachidonylethanolamine (AEA) in the NAc; the cannabinoid CB1/2 receptor agonist WIN55,212-2 (5ug/side) microinjected into the NAc facilitated extinction in shocked rats. Importantly, the facilitating effect of WIN55,212-2 on extinction was blocked by co-administration of sulindac in doses that downregulated beta-catenin levels. Taken together, the results suggest that beta-catenin in the NAc may serve as a protective buffer against the effects of severe stress, and that inhibiting this system in the NAc may prevent the therapeutic effects of cannabinoids against stress-related disorders. PMID- 28624573 TI - Plasticity of intrinsic firing response gain in principal hippocampal neurons following pilocarpine-induced status epilepticus. AB - OBJECTIVE: In experimental models of temporal lobe epilepsy (TLE), brain neurons manifest multiple changes in intrinsic excitability that contribute to neuronal network hyperexcitability. We have investigated whether the intrinsic firing response gain, quantified by the slope of the function relating the number of evoked spikes (Ns) to input excitatory current intensity (I), is modified in principal rat hippocampal neurons in the pilocarpine-status epilepticus (SE) model of TLE. METHODS: Intracellular recordings were made in CA3 and CA1 pyramidal cells (PCs) and dentate granule cells (GCs) in acute hippocampal slices obtained 7-36days after pilocarpine-SE. Firing response gains were determined empirically from Ns/I relationships and compared to other measured neuronal properties. RESULTS: The firing response gain in all three types of principal neurons, particularly in CA3 PCs, was markedly multiplied following pilocarpine SE. Analyses of persistent changes in active and passive properties of CA3 PCs suggested that this increase is multifactorial in origin, the major factors being a reduction in amplitude of the slow afterhyperpolarization and an increase in the fraction of bursting neurons. SIGNIFICANCE: Here we show that pilocarpine-SE causes multiplication of the firing response gain in the three principal neurons in the hippocampal trisynaptic pathway. This alteration undoubtedly would contribute to hippocampal hyperexcitability in SE-induced TLE. PMID- 28624574 TI - Evidence for a pharmacokinetic interaction between eslicarbazepine and rosuvastatin: Potential effects on xenobiotic transporters. AB - INTRODUCTION: Patients with partial-onset seizures and comorbid cardiovascular disease may concomitantly receive eslicarbazepine acetate (ESL), an antiepileptic drug, and rosuvastatin, an HMG-CoA reductase inhibitor. This study evaluated the effect of multiple-dose ESL on the pharmacokinetic (PK) parameters of a single dose of rosuvastatin in healthy subjects. METHODS: This was a Phase I, single center, fixed-sequence, open-label study. Healthy subjects received two treatments, in sequence. Treatment A: a single 40mg oral dose of rosuvastatin on Day 1, followed by a washout period (Days 1-4); treatment B: titration of ESL (400-800mg once daily) on Days 5-18, followed by ESL 1200mg once daily on Days 19 35, with a single dose of rosuvastatin (40mg) on Day 32. Subjects then entered a 2-week follow-up period. Plasma concentrations of rosuvastatin were quantified for PK analyses. Safety and tolerability were assessed throughout the study. RESULTS: Thirty-three healthy subjects were enrolled and 30 completed the study. Mean rosuvastatin (standard deviation) t1/2 was similar when rosuvastatin was used concomitantly with ESL and when it was used alone (26.5 [16.3]h, and 22.4 [9.5]h, respectively). The geometric least squares mean ratios (90% confidence intervals) of rosuvastatin exposure levels between rosuvastatin used concomitantly with ESL and rosuvastatin used alone were as follows: Cmax, 64.0% (55.9-73.3%); AUC(0-infinity), 63.0% (57.1-69.4%); and AUC(0-last), 60.9% (55.2 67.1%). Concomitant use of ESL and rosuvastatin was generally well tolerated. CONCLUSIONS: Rosuvastatin exposure was 36-39% lower with steady-state administration of ESL, potentially due to reduced oral bioavailability of rosuvastatin. Consequently, when rosuvastatin is used with ESL, a rosuvastatin dose adjustment may be necessary if a clinically significant change in lipids is noted. PMID- 28624575 TI - Intestinal Fungal Dysbiosis Is Associated With Visceral Hypersensitivity in Patients With Irritable Bowel Syndrome and Rats. AB - BACKGROUND & AIMS: Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in the activation of nociceptive sensory pathways, but there have been few studies of the role of the mycobiome (the fungal microbiome) in the development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity. METHODS: We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long-Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble beta-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen-associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1. RESULTS: alpha diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non handled mycobiome) restored hypersensitivity to distension. Administration of soluble beta-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate beta-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine. CONCLUSIONS: In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble beta-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity. PMID- 28624576 TI - Agreement Between Magnetic Resonance Imaging Proton Density Fat Fraction Measurements and Pathologist-Assigned Steatosis Grades of Liver Biopsies From Adults With Nonalcoholic Steatohepatitis. AB - BACKGROUND & AIMS: We assessed the diagnostic performance of magnetic resonance imaging (MRI) proton density fat fraction (PDFF) in grading hepatic steatosis and change in hepatic steatosis in adults with nonalcoholic steatohepatitis (NASH) in a multi-center study, using central histology as reference. METHODS: We collected data from 113 adults with NASH participating in a multi-center, randomized, double-masked, placebo-controlled, phase 2b trial to compare the efficacy cross sectionally and longitudinally of obeticholic acid vs placebo. Hepatic steatosis was assessed at baseline and after 72 weeks of obeticholic acid or placebo by liver biopsy and MRI (scanners from different manufacturers, at 1.5T or 3T). We compared steatosis estimates by PDFF vs histology. Histologic steatosis grade was scored in consensus by a pathology committee. Cross-validated receiver operating characteristic (ROC) analyses were performed. RESULTS: At baseline, 34% of subjects had steatosis grade 0 or 1, 39% had steatosis grade 2, and 27% had steatosis grade 3; corresponding mean PDFF values were 9.8%+/-3.7%, 18.1%+/-4.3%, and 30.1%+/-8.1%. PDFF classified steatosis grade 0-1 vs 2-3 with an area under the ROC curve (AUROC) of 0.95 (95% CI, 0.91-0.98), and grade 0-2 vs grade 3 steatosis with an AUROC of 0.96 (95% CI, 0.93-0.99). PDFF cut-off values at 90% specificity were 16.3% for grades 2-3 and 21.7% for grade 3, with corresponding sensitivities of 83% and 84%. After 72 weeks' of obeticholic vs placebo, 42% of subjects had a reduced steatosis grade (mean reduction in PDFF from baseline of 7.4%+/-8.7%), 49% had no change in steatosis grade (mean increase in PDFF from baseline of 0.3%+/-6.3%), and 9% had an increased steatosis grade (mean increase in PDFF from baseline of 7.7%+/-6.0%). PDFF change identified subjects with reduced steatosis grade with an AUROC of 0.81 (95% CI, 0.71-0.91) and increased steatosis grade with an AUROC of 0.81 (95% CI, 0.63-0.99). A PDFF reduction of 5.15% identified subjects with reduced steatosis grade with 90% specificity and 58% sensitivity, whereas a PDFF increase of 5.6% identified those with increased steatosis grade with 90% specificity and 57% sensitivity. CONCLUSIONS: Based on data from a phase 2 randomized controlled trial of adults with NASH, PDFF estimated by MRI scanners of different field strength and at different sites, accurately classifies grades and changes in hepatic steatosis when histologic analysis of biopsies is used as a reference. PMID- 28624577 TI - Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. AB - BACKGROUND & AIMS: Agents that induce an immune response against tumors by altering T-cell regulation have increased survival times of patients with advanced-stage tumors, such as melanoma or lung cancer. We aimed to characterize molecular features of immune cells that infiltrate hepatocellular carcinomas (HCCs) to determine whether these types of agents might be effective against liver tumors. METHODS: We analyzed HCC samples from 956 patients. We separated gene expression profiles from tumor, stromal, and immune cells using a non negative matrix factorization algorithm. We then analyzed the gene expression pattern of inflammatory cells in HCC tumor samples. We correlated expression patterns with the presence of immune cell infiltrates and immune regulatory molecules, determined by pathology and immunohistochemical analyses, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Using data from 190 tumors in the Cancer Genome Atlas, we correlated immune cell gene expression profiles with numbers of chromosomal aberrations (based on single-nucleotide polymorphism array) and mutations (exome sequence data). RESULTS: We found approximately 25% of HCCs to have markers of an inflammatory response, with high expression levels of the CD274 molecule (programmed death-ligand 1) and programmed cell death 1, markers of cytolytic activity, and fewer chromosomal aberrations. We called this group of tumors the Immune class. It contained 2 subtypes, characterized by markers of an adaptive T cell response or exhausted immune response. The exhausted immune response subclass expressed many genes regulated by transforming growth factor beta 1 that mediate immunosuppression. We did not observe any differences in numbers of mutations or expression of tumor antigens between the immune-specific class and other HCCs. CONCLUSIONS: In an analysis of HCC samples from 956 patients, we found almost 25% to express markers of an inflammatory response. We identified 2 subclasses, characterized by adaptive or exhausted immune responses. These findings indicate that some HCCs might be susceptible to therapeutic agents designed to block the regulatory pathways in T cells, such as programmed death ligand 1, programmed cell death 1, or transforming growth factor beta 1 inhibitors. PMID- 28624578 TI - Accuracy in Diagnosis of Celiac Disease Without Biopsies in Clinical Practice. AB - BACKGROUND & AIMS: The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. METHODS: We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. RESULTS: Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61-99.99); the PPV was 100.00 (95% CI, 98.68-100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67-99.96) to 100.00 (95% CI, 99.23-100.00). CONCLUSIONS: Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555. PMID- 28624580 TI - Proton Pump Inhibitors Decrease Phlebotomy Need in HFE Hemochromatosis: Double Blind Randomized Placebo-Controlled Trial. AB - Phlebotomy constitutes the established treatment for HFE-related hemochromatosis. Retrospective studies have suggested proton pump inhibitors (PPIs) reduce the need for phlebotomy in this population. We conducted a randomized controlled trial to prove this. Thirty p.C282Y homozygous patients were randomly allocated to PPI (pantoprazole 40 mg/day) or placebo for 12 months. Phlebotomies were performed when serum ferritin was > 100 MUg/L. Phlebotomy need turned out to be significantly lower in patients taking PPI (P = .0052). PPI treatment significantly reduces the need for phlebotomies in p.C282Y homozygous patients. In view of the known long-term safety profile of PPI, they can be a valuable addition to standard therapy. Clinicaltrials.gov: NCT01524757. PMID- 28624579 TI - Epigenome-Wide Association Study Identifies Methylation Sites Associated With Liver Enzymes and Hepatic Steatosis. AB - BACKGROUND & AIMS: Epigenetic mechanisms might be involved in the regulation of liver enzyme level. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of liver enzymes and hepatic steatosis. METHODS: We conducted an epigenome-wide association study in whole blood for liver enzyme levels, including gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), among a discovery set of 731 participants of the Rotterdam Study and sought replication in a non overlapping sample of 719 individuals. Significant DNA methylation changes were further analyzed to evaluate their relation with hepatic steatosis. Expression levels of the top identified gene were measured in 9 human liver cell lines and compared with expression profiles of its potential targets associated with lipid traits. The candidate gene was subsequently knocked down in human hepatoma cells using lentiviral vectors expressing small hairpin RNAs. RESULTS: Eight probes annotated to SLC7A11, SLC1A5, SLC43A1, PHGDH, PSORS1C1, SREBF1, ANKS3 were associated with GGT and 1 probe annotated to SLC7A11 was associated with ALT after Bonferroni correction (1.0 * 10-7). No probe was identified for AST levels. Four probes for GGT levels including cg06690548 (SLC7A11), cg11376147 (SLC43A1), cg22304262 (SLC1A5), and cg14476101 (PHGDH), and 1 for ALT cg06690548 (SLC7A11) were replicated. DNA methylation at SLC7A11 was associated with reduced risk of hepatic steatosis in participants (odds ratio, 0.69; 95% CI= 0.55-0.93; P value: 2.7 * 10-3). In functional experiments, SLC7A11 was highly expressed in human liver cells; its expression is positively correlated with expression of a panel of lipid-associated genes, indicating a role of SLC7A11 in lipid metabolism. CONCLUSIONS: Our results provide new insights into epigenetic mechanisms associated with markers of liver function and hepatic steatosis, laying the groundwork for future diagnostic and therapeutic applications. PMID- 28624581 TI - Polygenic risk for depression and the neural correlates of working memory in healthy subjects. AB - INTRODUCTION: Major depressive disorder (MDD) patients show impairments of cognitive functioning such as working memory (WM), and furthermore alterations during WM-fMRI tasks especially in frontal and parietal brain regions. The calculation of a polygenic risk score (PRS) can be used to describe the genetic influence on MDD, hence imaging genetic studies aspire to combine both genetics and neuroimaging data to identify the influence of genetic factors on brain functioning. We aimed to detect the effect of MDD-PRS on brain activation during a WM task measured with fMRI and expect healthy individuals with a higher PRS to be more resembling to MDD patients. METHOD: In total, n=137 (80 men, 57 women, aged 34.5, SD=10.4years) healthy subjects performed a WM n-back task [0-back (baseline), 2-back and 3-back condition] in a 3T-MRI-tomograph. The sample was genotyped using the Infinium PsychArray BeadChip and a polygenic risk score was calculated for MDD using PGC MDD GWAS results. RESULTS: A lower MDD risk score was associated with increased activation in the bilateral middle occipital gyri (MOG), the bilateral middle frontal gyri (MFG) and the right precentral gyrus (PCG) during the 2-back vs. baseline condition. Moreover, a lower PRS was associated with increased brain activation during the 3-back vs. baseline condition in the bilateral cerebellum, the right MFG and the left inferior parietal lobule. A higher polygenic risk score was associated with hyperactivation in brain regions comprising the right MFG and the right supplementary motor area during the 3-back vs. 2-back condition. DISCUSSION: The results suggest that part of the WM-related brain activation patterns might be explained by genetic variants captured by the MDD-PRS. Furthermore we were able to detect MDD-associated activation patterns in healthy individuals depending on the MDD-PRS and the task complexity. Additional gene loci could contribute to these task-dependent brain activation patterns. PMID- 28624582 TI - Further replication of the synergistic interaction between LPHN3 and the NTAD gene cluster on ADHD and its clinical course throughout adulthood. AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder. Despite the high heritability, the unraveling of specific genetic factors related to ADHD is hampered by its considerable genetic complexity. Recent evidence suggests that gene-gene interactions can explain part of this complexity. We examined the impact of strongly supported interaction effects between the LPHN3 gene and the NTAD gene cluster (NCAM1-TTC12-ANKK1-DRD2) in a 7-year follow-up of a clinical sample of adults with ADHD, addressing associations with susceptibility, symptomatology and stability of diagnosis. The sample comprises 548 adults with ADHD and 643 controls. Entropy-based analysis indicated a potential interaction between the LPHN3-rs6551665 and TTC12-rs2303380 SNPs influencing ADHD symptom counts. Further analyses revealed significant interaction effects on ADHD total symptoms (p=0.002), and with hyperactivity/impulsivity symptom counts (p=0.005). In the group composed by predominantly hyperactive/impulsive and combined presentation, the presence of LPHN3-rs6551665 G allele was related to increased ADHD risk only in individuals carrying the TTC12-rs2303380 AA genotype (p=0.026). Also, the same allelic constellation is involved in maintenance of ADHD in a predominantly hyperactive/impulsive or combined presentation after a 7-year follow-up (p=0.008). These observations reinforce and replicate previous evidence suggesting that an interaction effect between the LPHN3 gene and the NTAD cluster may have a role in the genetic substrate associated to ADHD also in adults. Moreover, it is possible that the interactions between LPHN3 and NTAD are specific factors contributing to the development of an ADHD phenotype with increased hyperactivity/impulsivity that is maintained throughout adulthood. PMID- 28624583 TI - Pre-adolescent and adolescent mice are less sensitive to the effects of acute nicotine on extinction and spontaneous recovery. AB - Adolescence is a period of high risk for the initiation of nicotine product usage and exposure to traumatic events. In parallel, nicotine exposure has been found to age-dependently modulate acquisition of contextual fear memories; however, it is unknown if adolescent nicotine exposure alters extinction of fear related memories. Age-related differences in sensitivity to the effects of nicotine on fear extinction could increase or decrease susceptibility to anxiety disorders. In this study, we examined the effects of acute nicotine administration on extinction and spontaneous recovery of contextual fear memories in pre-adolescent (PND 23), late adolescent (PND 38), and adult (PND 53) C57B6/J mice. Mice were first trained in a background contextual fear conditioning paradigm and given an intraperitoneal injection of one of four doses of nicotine (0.045, 0.09, 0.18, or 0.36mg/kg, freebase) prior to subsequent extinction or spontaneous recovery sessions. Results indicated that all acute nicotine doses impaired extinction of contextual fear in adult mice. Late adolescent mice exhibited impaired extinction of contextual fear only following higher doses of acute nicotine, and extinction of contextual fear was unaffected by acute nicotine exposure in pre-adolescent mice. Finally, acute nicotine exposure enhanced spontaneous recovery of fear memory, but only in adult mice. Overall, our results suggest that younger mice were less sensitive to nicotine's impairing effects on extinction of contextual fear and to nicotine's enhancing effects on spontaneous recovery of contextual fear memory. PMID- 28624584 TI - Antibody-dependent NK cell degranulation as a marker for assessing antibody dependent cytotoxicity against pandemic 2009 influenza A(H1N1) infection in human plasma and influenza-vaccinated transchromosomic bovine intravenous immunoglobulin therapy. AB - This study describes an antibody-dependent NK cell degranulation assay, as a biomarker to assess antibody-dependent cellular cytotoxicity (ADCC) response in influenza plasma and for antibody therapies against influenza infection. The concentration of neutralizing antibodies (NAbs) against the hemagglutinin receptor of influenza viruses is a current determinant in protection against infection, particularly following receipt of the seasonal influenza vaccine. However, this is a limited assessment of protection, because: (i) NAb titers that incur full protection vary; and (ii) NAb titers do not account for the entire breadth of antibody responses against viral infection. Previous reports have indicated that antibodies that prime ADCC play a vital role in controlling influenza infections, and thus should be quantified for assessing protection against influenza. This report demonstrates a non-radioactive assay that assesses NK cell activation as a marker of ADCC, in which NK cells interact with opsonized viral antigen expressed on the surface of infected Raji target cells resulting in effector cell degranulation (surrogate CD107a expression). A positive correlation was determined between HAI titers and sustained NK cell activation, although NK cell activation was seen in plasma samples with HAI titers below 40 and varied amongst samples with high HAI titers. Furthermore, sustained NK cell degranulation was determined for influenza-vaccinated transchromosomic bovine intravenous immunoglobulin, indicating the potential utility of this therapy for influenza treatment. We conclude that this assay is reproducible and relevant. PMID- 28624585 TI - Contributions of the lateral habenula to circadian timekeeping. AB - Over the past 20years, substantive research has firmly implicated the lateral habenula in myriad neural processes including addiction, depression, and sleep. More recently, evidence has emerged suggesting that the lateral habenula is a component of the brain's intrinsic daily or circadian timekeeping system. This system centers on the master circadian pacemaker in the suprachiasmatic nuclei of the hypothalamus that is synchronized to the external world through environmental light information received directly from the eye. Rhythmic clock gene expression in suprachiasmatic neurons drives variation in their electrical activity enabling communication of temporal information, and the organization of circadian rhythms in downstream targets. Here, we review the evidence implicating the lateral habenula as part of an extended neural circadian system. We consider findings suggesting that the lateral habenula is a recipient of circadian signals from the suprachiasmatic nuclei as well as light information from the eye. Further we examine the proposition that the lateral habenula itself expresses intrinsic clock gene and neuronal rhythms. We then speculate on how circadian information communicated from the lateral habenula could influence activity and function in downstream targets such as the ventral tegmental area and raphe nuclei. PMID- 28624587 TI - The lateral habenula and alcohol: Role of glutamate and M-type potassium channels. AB - Alcohol use disorder (AUD) or alcoholism is a chronic relapsing disorder. Our knowledge of alcoholism hinges on our understanding of its effects on the brain. This review will center on the effects of alcohol in the lateral habenula (LHb), an epithalamic structure that connects the forebrain with the midbrain and encodes aversive signaling. Like many addictive drugs, alcohol has both rewarding and aversive properties. While alcohol's euphoric property is believed to be important for the initiation of drinking, increasing evidence suggests that alcohol's negative affect plays a critical role in excessive drinking and alcohol dependence. During withdrawal and abstinence, alcoholics often experience anxiety and depressions, both of which have been implicated in relapse drinking. This review focuses on the recent accumulation of knowledge about the effects of acute and chronic alcohol exposure on the activity of and synaptic transmissions on LHb neurons, as well as the effects of manipulation of LHb function on alcohol consumption and related behaviors. Recent evidence highlights a critical role for the LHb in AUD and related psychiatric ailments. Multidisciplinary work in animals collectively suggests that LHb function and activity, including M-type potassium channels and glutamatergic transmission are altered by acute and repeated chronic alcohol exposure. We will also discuss how functional, pharmacological, and chemogenetic manipulation of the LHb affects ethanol drinking and psychiatric disorders occurring in animals withdrawn from chronic alcohol exposure. Conceivable mechanisms behind these effects and their potential as targets for therapies will also be discussed. PMID- 28624588 TI - Segmented regression analysis of interrupted time series data to assess outcomes of a South American road traffic alcohol policy change. AB - BACKGROUND: In Chile, a new law introduced in March 2012 decreased the legal blood alcohol concentration (BAC) limit for driving while impaired from 1 to 0.8 g/l and the legal BAC limit for driving under the influence of alcohol from 0.5 to 0.3 g/l. The goal is to assess the impact of this new law on mortality and morbidity outcomes in Chile. METHODS: A review of national databases in Chile was conducted from January 2003 to December 2014. Segmented regression analysis of interrupted time series was used for analyzing the data. In a series of multivariable linear regression models, the change in intercept and slope in the monthly incidence rate of traffic deaths and injuries and association with alcohol per 100,000 inhabitants was estimated from pre-intervention to postintervention, while controlling for secular changes. In nested regression models, potential confounding seasonal effects were accounted for. All analyses were performed at a two-sided significance level of 0.05. RESULTS: Immediate level drops in all the monthly rates were observed after the law from the end of the prelaw period in the majority of models and in all the de-seasonalized models, although statistical significance was reached only in the model for injures related to alcohol. After the law, the estimated monthly rate dropped abruptly by -0.869 for injuries related to alcohol and by -0.859 adjusting for seasonality (P < 0.001). Regarding the postlaw long-term trends, it was evidenced a steeper decreasing trend after the law in the models for deaths related to alcohol, although these differences were not statistically significant. CONCLUSIONS: A strong evidence of a reduction in traffic injuries related to alcohol was found following the law in Chile. Although insufficient evidence was found of a statistically significant effect for the beneficial effects seen on deaths and overall injuries, potential clinically important effects cannot be ruled out. PMID- 28624589 TI - Dependency distance: A new perspective on syntactic patterns in natural languages. AB - Dependency distance, measured by the linear distance between two syntactically related words in a sentence, is generally held as an important index of memory burden and an indicator of syntactic difficulty. Since this constraint of memory is common for all human beings, there may well be a universal preference for dependency distance minimization (DDM) for the sake of reducing memory burden. This human-driven language universal is supported by big data analyses of various corpora that consistently report shorter overall dependency distance in natural languages than in artificial random languages and long-tailed distributions featuring a majority of short dependencies and a minority of long ones. Human languages, as complex systems, seem to have evolved to come up with diverse syntactic patterns under the universal pressure for dependency distance minimization. However, there always exist a small number of long-distance dependencies in natural languages, which may reflect some other biological or functional constraints. Language system may adapt itself to these sporadic long distance dependencies. It is these universal constraints that have shaped such a rich diversity of syntactic patterns in human languages. PMID- 28624586 TI - Modeling the development of drug addiction in male and female animals. AB - An increasing emphasis has been placed on the development and use of animal models of addiction that capture defining features of human drug addiction, including escalation/binge drug use, enhanced motivation for the drug, preference for the drug over other reward options, use despite negative consequences, and enhanced drug-seeking/relapse vulnerability. The need to examine behavior in both males and females has also become apparent given evidence demonstrating that the addiction process occurs differently in males and females. This review discusses the procedures that are used to model features of addiction in animals, as well as factors that influence their development. Individual differences are also discussed, with a particular focus on sex differences. While no one procedure consistently produces all characteristics, different models have been developed to focus on certain characteristics. A history of escalating/binge patterns of use appears to be critical for producing other features characteristic of addiction, including an enhanced motivation for the drug, enhanced drug seeking, and use despite negative consequences. These characteristics tend to emerge over abstinence, and appear to increase rather than decrease in magnitude over time. In females, these characteristics develop sooner during abstinence and/or following less drug exposure as compared to males, and for psychostimulant addiction, may require estradiol. Although preference for the drug over other reward options has been demonstrated in non-human primates, it has been more difficult to establish in rats. Future research is needed to define the parameters that optimally induce each of these features of addiction in the majority of animals. Such models are essential for advancing our understanding of human drug addiction and its treatment in men and women. PMID- 28624590 TI - Maleic acid assisted improvement of metal chelation and antioxidant metabolism confers chromium tolerance in Brassica juncea L. AB - Chromium (Cr) is a highly toxic environmental pollutant that negatively affects plant growth and development. Thus, remediating Cr from soil or increasing plant tolerance against Cr stress is urgent. Organic acids are recognized as agents of phytoremediation and as exogenous protectants, but using maleic acid (MA) to attain these results has not yet been studied. Therefore, our study investigated the effects of MA on Cr uptake and mitigation of Cr toxicity. We treated 8-d-old Indian mustard (Brassica juncea L.) seedlings with Cr (0.15mM and 0.3mM K2CrO4, 5 days) alone and in combination with MA (0.25mM) in a semi-hydroponic medium. Under Cr stress, plants accumulated Cr in both the roots and shoots in a dose dependent manner, where the roots showed higher accumulation. Chromium stress reduced the growth and biomass of the Indian mustard plants by reducing water status and photosynthetic pigments, and increased oxidative damage due to generation of toxic reactive oxygen species (ROS) and methylglyoxal (MG). Chromium stress also interfered with the function of the antioxidant defense and glyoxalase systems. However, using MA in the Cr-stressed plants further increased Cr uptake in the roots, but it slightly reduced the translocation of Cr from the roots to the shoots at a lower dose of Cr and significantly at a higher dose. Moreover, MA also increased the other non-protein thiols (NPTs) containing phytochelatin (PC) content of the seedlings, which reduced Cr toxicity. Supplementing the stressed plants with MA upregulated the non-enzymatic antioxidants (ascorbate, AsA; glutathione, GSH); the activities of the enzymatic antioxidants including ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), glutathione reductase (GR), glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase (CAT); and the enzymes of the glyoxalase system including glyoxalase I (Gly I) and glyoxalase II (Gly II); and finally reduced oxidative damage and increased the chlorophyll content and water status as well the growth and biomass of the plants. Our findings suggested two potential uses of MA: first, enhancing phytoremediation, principally phytostabilization and second, working as an exogenous protectant to enhance Cr tolerance. PMID- 28624591 TI - Safe limit of arsenic in soil in relation to dietary exposure of arsenicosis patients from Malda district, West Bengal- A case study. AB - Safe limit of arsenic in soil in relation to dietary exposure of arsenicosis patients was established in Malda district of West Bengal. Out of 182 participants examined, 80 (43.9%) participants showed clinical features of arsenicosis, characterized by arsenical skin lesion (pigmentation and keratosis), while 102 participants did not have any such lesion (control). Experimental results of the twenty eight soils (own field) of the participants showed the mean Olsen extractable and total arsenic concentration of 0.206 and 6.70mgkg-1, respectively. Arsenic concentration in rice grain ranged from 2.00 to 1260MUgkg-1 with the mean value of 146MUgkg-1. The hazard quotient (HQ) for intake of As by human through consumption of rice varied from 0.03 to 3.52. HQ exceeds 1.0 for drinking water and rice grain grown in the study area in many cases. As high as 77.6% variation in As content in rice grain could be explained by the solubility free ion activity model. Toxic limit of extractable As in soil for rice in relation to soil properties and human health hazard, associated with consumption of rice grain by human, was established. For example, the permissible limit of Olsen extractable As in soil would be 0.43mgkg-1 for rice cultivation, if soil pH and organic carbon content were 7.5% and 0.50%, respectively. However, the critical limit of Olsen extractable As in soil would be 0.54mgkg-1, if soil pH and organic carbon were 8.5% and 0.75%, respectively. The conceptual framework of fixing the toxic limit of arsenic in soils with respect to soil properties and human health under modeling-framework was established. PMID- 28624593 TI - Double sequential defibrillation therapy for out-of-hospital cardiac arrests: The London experience. AB - BACKGROUND: Despite advances in treatment for out-of-hospital cardiac arrest (OHCA), a subgroup of patients remain in refractory ventricular fibrillation (RVF) during resuscitation. Recent evidence suggests that double sequential defibrillation (DSD), where two shocks are delivered to the patient in quick succession, may provide an effective therapy for RVF. This study describes the characteristics and survival outcomes of OHCA patients treated by ambulance clinicians using a local DSD protocol in an attempt to resolve RVF. METHODS: This is a retrospective, observational analysis of patients who received DSD by the London Ambulance Service from 1st July 2015 to 31st December 2016. A comparator group of patients who received more than six consecutive standard shocks (not DSD) for persistent VF was also identified. Outcomes included pre-hospital return of spontaneous circulation (ROSC), ROSC sustained to hospital, and survival to hospital discharge. DSD patients who survived to hospital discharge are reported in further detail. RESULTS: During the 18-month study period, 45 patients were treated with DSD: a third obtained a pre-hospital ROSC and 7% survived to hospital discharge. We observed similar ROSC and survival rates amongst those who received standard defibrillation only. CONCLUSION: Our observational study did not find any clear benefit of DSD use by EMS in the treatment of RVF. However, we find that 3 patients, who were treated with DSD following unsuccessful single shocks, had their VF terminated. Prospective randomised clinical trials are urgently needed to investigate the potential value of DSD in the pre-hospital setting. PMID- 28624592 TI - Post-anoxic quantitative MRI changes may predict emergence from coma and functional outcomes at discharge. AB - BACKGROUND: Traditional predictors of neurological prognosis after cardiac arrest are unreliable after targeted temperature management. Absence of pupillary reflexes remains a reliable predictor of poor outcome. Diffusion-weighted imaging has emerged as a potential predictor of recovery, and here we compare imaging characteristics to pupillary exam. METHODS: We identified 69 patients who had MRIs within seven days of arrest and used a semi-automated algorithm to perform quantitative volumetric analysis of apparent diffusion coefficient (ADC) sequences at various thresholds. Area under receiver operating characteristic curves (ROC-AUC) were estimated to compare predictive values of quantitative MRI with pupillary exam at days 3, 5 and 7 post-arrest, for persistence of coma and functional outcomes at discharge. Cerebral Performance Category scores of 3-4 were considered poor outcome. RESULTS: Excluding patients where life support was withdrawn, >=2.8% diffusion restriction of the entire brain at an ADC of <=650*10 6m2/s was 100% specific and 68% sensitive for failure to wake up from coma before discharge. The ROC-AUC of ADC changes at <=450*10-6mm2/s and <=650*10-6mm2/s were significantly superior in predicting failure to wake up from coma compared to bilateral absence of pupillary reflexes. Among survivors, >0.01% of diffusion restriction of the entire brain at an ADC <=450*10-6m2/s was 100% specific and 46% sensitive for poor functional outcome at discharge. The ROC curve predicting poor functional outcome at ADC <=450*10-6mm2/s had an AUC of 0.737 (0.574-0.899, p=0.04). CONCLUSION: Post-anoxic diffusion changes using quantitative brain MRI may aid in predicting persistent coma and poor functional outcomes at hospital discharge. PMID- 28624594 TI - Variability in the initiation of resuscitation attempts by emergency medical services personnel during out-of-hospital cardiac arrest. AB - BACKGROUND: Some patients with out-of-hospital cardiac arrest (OHCA) assessed by emergency medical services (EMS) do not receive attempts at resuscitation on the basis of perceived futility. AIMS: 1) To measure variability in the initiation of resuscitation attempts in EMS-assessed OHCA patients across EMS agencies, 2) to evaluate the association between selected EMS agency characteristics and the proportion of patients receiving resuscitation attempts, and 3) to evaluate the association between proportion receiving resuscitation attempts and survival. METHODS: A retrospective cohort study using data from 129 EMS agencies participating in the Resuscitation Outcomes Consortium (ROC) epidemiologic registry (EPISTRY) - Cardiac Arrest from 12/01/2005 to 12/31/2010. We included non-traumatic OHCA patients assessed by EMS. RESULTS: We included 86,912 OHCA patients. Overall, 54.8% had resuscitation attempted by EMS providers, varying from 23.9% to 100% (p=<0.001) across EMS agencies. The proportion of patients receiving a resuscitation attempt was 7.87% less (95% CI 3.73-12.0) among agencies with longer average response intervals (>=6min) compared with shorter average response intervals (<6min) and 16.9% less (95% CI 11.9-21.9) among agencies with higher levels of advanced life support (ALS) availability (>=50% of available units) compared with lower levels of ALS availability (<50% of available units). There was a moderate positive correlation between the proportion of patients with resuscitation attempts and survival to hospital discharge (r=0.54, p<0.001). CONCLUSIONS: The proportion of patients with OHCA who receive resuscitation attempts is variable across EMS agencies and is associated with EMS response interval, ALS unit availability and geographic region. On average, survival was higher among EMS agencies more likely to initiate resuscitation. PMID- 28624595 TI - Atypical perceptual processing of faces in developmental dyslexia. AB - Developmental Dyslexia (DD) is often attributed to phonological processing deficits. Recent evidence, however, indicates the need for a more general explanatory framework to account for DD's range of deficits. The current study examined the specificity versus domain generality of DD by comparing the recognition and discrimination of three visual categories (faces and words with cars as control stimuli) in typical and dyslexic readers. Relative to controls, not only did dyslexic individuals perform more poorly on word recognition, but they also matched faces more slowly, especially when the faces differed in viewpoint, and discriminated between similar faces (but not cars) more poorly. Additionally, dyslexics showed reduced hemispheric lateralization for words and faces. These results reveal that DD affects both word and face, but not car, processing, implicating a partial domain general basis of DD. We offer a theoretical proposal to account for the multifaceted findings and suggestions for further, longitudinal studies. PMID- 28624596 TI - Repeated co-treatment with antidepressants and risperidone increases BDNF mRNA and protein levels in rats. AB - BACKGROUND: Recently, several clinical studies have suggested a beneficial effect of a combination of antidepressants (ADs) with antipsychotic drugs in drug resistant depression. Moreover, preclinical and clinical studies indicated a role of brain-derived neurotrophic factor (BDNF) in the pathology of depression, as well as in the mechanism of action of ADs. METHODS: In the present study, we investigated the effect of repeated administration of ADs, escitalopram, fluoxetine or mirtazapine and a low dose of risperidone (an atypical antipsychotic drug) given separately or in combination, on the mRNA and protein levels of BDNF or cAMP response element binding (p-CREB) in the hippocampus and frontal cortex of male Wistar rats. ADs were given repeatedly (once daily for 14 days), separately or in combination with a low dose of risperidone. The tissue for biochemical assays was dissected 24h after the last dose of ADs. RESULTS: The obtained results showed that repeated co-treatment with an inactive dose of risperidone and escitalopram or mirtazapine but not fluoxetine increased the BDNF mRNA expression in the hippocampus and frontal cortex. Moreover, combined treatment with an inactive dose risperidone and escitalopram elevated the protein levels of p-CREB in the frontal cortex. While, co-treatment with risperidone and fluoxetine or mirtazapine increased the protein levels of BDNF and p-CREB in both examined regions of the brain. CONCLUSIONS: Our present findings suggest that enhancement levels of BDNF may be essential for the therapeutic effect of co treatment with ADs and a low dose risperidone in patients with drug-resistant depression. PMID- 28624597 TI - Suppressive effect of kamebakaurin on acetaminophen-induced hepatotoxicity by inhibiting lipid peroxidation and inflammatory response in mice. AB - BACKGROUND: Kamebakaurin (KA) is an ent-kaurane diterpenoid known to have anti inflammatory potential. In the current study, we investigated whether pretreatment with KA could ameliorate acetaminophen (APAP)-induced hepatotoxicity by inhibiting the anti-inflammatory response in mice. METHODS: Seven-week-old C57BL/6J mice were orally administered KA or olive oil emulsion for seven days. Twenty-four hours after the last KA or olive oil administration, the mice were intraperitoneally injected with 400mg/kg APAP or saline under feed deprived condition. The mice from each group were euthanized and bled for plasma analysis 24h after the injection. RESULT: APAP increased plasma levels of hepatic injury markers (i.e., alanine aminotransferase and aspartate aminotransferase), lipid peroxidation, and pro-inflammatory cytokines. Pretreatment with KA reduced the magnitude of APAP-induced increases in plasma levels of hepatic injury markers, lipid peroxidation, and inflammatory response. In addition, KA exhibited antioxidant capacity in a dose-dependent manner, with slight reactive oxygen species scavenging activity. CONCLUSION: Our results indicate that KA has the ability to protect the liver from APAP-induced hepatotoxicity, presumably by both inhibiting the inflammatory response and oxidative stress. PMID- 28624598 TI - Inhibition of LPS induced pro-inflammatory responses in RAW 264.7 macrophage cells by PVP-coated naringenin nanoparticle via down regulation of NF kappaB/P38MAPK mediated stress signaling. AB - BACKGROUND: Naringenin (NAR) was found to display strong pharmacological properties. Since the clinical relevance of NAR is limited by its low bioavailability, we effectively synthesized and characterized a novel PVP-coated NAR nanoparticle (NAR NP) to enhance the therapeutic efficacy of NAR. The present study was designed to investigate the effects of NAR NP on lipopolysaccharide (LPS) induced inflammatory response in RAW 264.7 macrophage cells. METHODS: In vitro cell culture studies of LPS stimulated RAW 264.7 macrophage cells were used as experimental model. RESULTS: Cytotoxicity studies revealed that NAR NP is safe even at maximum tested concentration of 200MUg/ml. Initial dose fixation study in LPS induced RAW 264.7 cells, revealed the minimum optimal concentration required for anti inflammatory effect as 25MUg/ml. mRNA expression studies showed that NAR NP significantly down regulated the expressions of NF-kappaB and P38MAPK, which is paralleled with the inhibition of the nuclear translocation of NF-kappaB. This in turn led to the blockade of iNOS and COX-2, thereby inhibiting the production of nitric oxide and pro inflammatory cytokines such as TNF-alpha, IL-6, MCP-1 and IL-1beta. NAR NP was found to be more efficient, when compared with NAR. CONCLUSIONS: Anti-inflammatory effects of NAR NP may be allocated to the down regulation of COX -2 and iNOS via the suppression of NF-kappaB and MAPK signaling pathway in RAW 264.7 macrophages. The data suggests that NAR NP can be used as a potent candidate for the treatments of inflammatory diseases by exploiting the nanoscale properties and targeting efficacy. PMID- 28624599 TI - Biodegradable hydrogel derived from cellulose acetate and EDTA as a reduction substrate of leaching NPK compound fertilizer and water retention in soil. AB - To study the behavior of a biodegradable hydrogel derived from cellulose acetate and ethylenediaminetetraacetic dianhydride (EDTAD), as a reduction substrate of NPK fertilizer in soil. The biodegradable hydrogel (HEDTA) was prepared from cellulose acetate (CA) with a degree substitution (DS) 2.5 by esterification crosslinking with EDTAD catalyzed by triethylamine. We systematically investigated the performance of the HEDTA in the reducing NPK (Ammonium, phosphate and potassium) fertilizer leaching. We also compare the percentage of leaching between the HEDTA and commercial fertilizers. To characterize the esterification and crosslinking between CA and EDTAD, FTIR spectroscopy and thermogravimetric analysis (DTG) were employed. The biodegradation experiments were carried out in simulated soil (23% of sand, 23% of cattle manure, 23% of soil and 31% of water) and the HEDTA was tested in the eucalyptus planting during the dry season in the Sao Paulo state, Brazil. The HEDTA was able to reduce the leaching of fertilizers and improve the performance of eucalyptus seedlings and reduced the mortality of the seedlings. The HEDTA showed to be an excellent substrate for slow release and water-retention in soil, reducer of the fertilizers leaching, in addition being nontoxic, biodegradable in the soil and environmentally-friendly. PMID- 28624600 TI - Molecular imaging in nanomedicine - A developmental tool and a clinical necessity. AB - The development of nanomedicines presents the potential to deliver more potent drugs targeted more specifically to the site(s) of disease than is currently achievable. While encouraging results have been achieved, including at the clinical level, significant challenges and opportunities for development remain, both in terms of further developing the technology and in understanding the underlying biology. Given the lessons learned regarding variations in nanomedicine delivery to different tumor types and between different patients with the same tumor type, this is an area of drug development that, rather than simply benefiting from a patient-specific approach, actually demands it. The only way that this distribution information can be obtained is through imaging, and this requires labeling of the nanomedicine to enable detection outside the body. In this review, we describe recent advances in the labeling of nanomedicines, how imaging studies are guiding nanomedicine development, and the role of imaging in the future development of nanomedicines. PMID- 28624601 TI - The Manchester Fly Facility: Implementing an objective-driven long-term science communication initiative. AB - Science communication is increasingly important for scientists, although research, teaching and administration activities tend to eat up our time already, and budgets for science communication are usually low. It appears impossible to combine all these tasks and, in addition, to develop engagement activities to a quality and impact that would make the efforts worth their while. Here we argue that these challenges are easier addressed when centering science communication initiatives on a long-term vision with a view to eventually forming outreach networks where the load can be shared whilst being driven to higher momentum. As one example, we explain the science communication initiative of the Manchester Fly Facility. It aims to promote public awareness of research using the model organism Drosophila, which is a timely, economic and most efficient experimental strategy to drive discovery processes in the biomedical sciences and must have a firm place in the portfolios of funding organisations. Although this initiative by the Manchester Fly Facility is sustained on a low budget, its long-term vision has allowed gradual development into a multifaceted initiative: (1) targeting university students via resources and strategies for the advanced training in fly genetics; (2) targeting the general public via science fairs, educational YouTube videos, school visits, teacher seminars and the droso4schools project; (3) disseminating and marketing strategies and resources to the public as well as fellow scientists via dedicated websites, blogs, journal articles, conference presentations and workshops - with a view to gradually forming networks of drosophilists that will have a greater potential to drive the science communication objective to momentum and impact. Here we explain the rationales and implementation strategies for our various science communication activities - which are similarly applicable to other model animals and other areas of academic science - and share our experiences and resources to provide ideas and readily available means to those who are actively engaging or intend to do so. PMID- 28624602 TI - The mediating effects of depressive symptoms and sleep quality on the relationship between the non-medical use of prescription drugs and suicidal behaviors among Chinese adolescents. AB - BACKGROUND: The nature of the relationship between the non-medical use of prescription drugs (NMUPD) and suicide has not been clearly elucidated. Some studies have suggested that the relationship between substance use and suicidal ideation may be spurious and could be explained by other variables. METHODS: A school-based cross-sectional study was performed in Guangzhou. A total of 5853 students completed questionnaires and were included in the study. NMUPD, alcohol use, illicit drug use, depressive symptoms, sleep quality, and suicidal behaviors were assessed. The mediating effects of depressive symptoms and sleep quality on the relationship between NMUPD and suicidal behaviors were examined using a structural equation model. RESULTS: In the simple model without mediation, a positive relationship between NMUPD and suicidal behaviors in adolescents was found, which was independent of effects from the use of other substances. Both depressive symptoms and sleep quality were significant mediators of this relationship. CONCLUSION: Public health and educational professionals should survey depressive symptoms and sleep quality and provide interventions when managing suicidal behaviors among adolescents engaging in NMUPD. PMID- 28624603 TI - An intensive assessment of alcohol use and emergency department utilization in homeless alcohol-dependent adults. AB - BACKGROUND: Excessive alcohol use among the homeless may contribute to their high rates of emergency department use. Survey-based studies have provided some information on the relation between alcohol and emergency department use among the homeless. METHODS: This study used an intensive schedule of random breath collections and self-report assessments to examine the relation between emergency department utilization and alcohol use in homeless alcohol-dependent adults. Data were from homeless alcohol-dependent adults (N=116) who were participating in a therapeutic workplace that provided job-skills training every weekday for 26 weeks. Breath-sample collections and assessments of self-reported alcohol use were scheduled each week, an average of twice per week per participant, at random times between 9:00 A.M. and 5:00 P.M. Participants received $35 for each breath sample collected. Self-reports of emergency department use were assessed throughout the study. RESULTS: Thirty-four percent of participants reported attending an emergency department and reported an average of 2.2 emergency department visits (range 1-10 visits). Alcohol intoxication was the most common reason for emergency department use. Participants who used the emergency department had significantly more alcohol-positive breath samples and more self reported heavy alcohol use than participants who did not use the emergency department. CONCLUSIONS: This study provided a rare intensive assessment of alcohol and emergency department use in homeless alcohol-dependent adults over an extended period. Emergency department use was high and was significantly related to indices of alcohol use. PMID- 28624604 TI - User characteristics and effect profile of Butane Hash Oil: An extremely high potency cannabis concentrate. AB - BACKGROUND: Recent reports suggest an increase in use of extremely potent cannabis concentrates such as Butane Hash Oil (BHO) in some developed countries. The aims of this study were to examine the characteristics of BHO users and the effect profiles of BHO. DESIGN: Anonymous online survey in over 20 countries in 2014 and 2015. Participants aged 18 years or older were recruited through onward promotion and online social networks. The overall sample size was 181,870. In this sample, 46% (N=83,867) reported using some form of cannabis in the past year, and 3% reported BHO use (n=5922). MEASUREMENTS: Participants reported their use of 7 types of cannabis in the past 12 months, the source of their cannabis, reasons for use, use of other illegal substances, and lifetime diagnosis for depression, anxiety and psychosis. Participants were asked to rate subjective effects of BHO and high potency herbal cannabis. FINDINGS: Participants who reported a lifetime diagnosis of depression (OR=1.15, p=0.003), anxiety (OR=1.72, p<0.001), and a larger number of substance use (OR=1.29, p<0.001) were more likely to use BHO than only using high potency herbal cannabis. BHO users also reported stronger negative effects and less positive effects when using BHO than high potency herbal cannabis (p<0.001) CONCLUSION: Mental health problems and other illicit drug use were associated with use of BHO. BHO was reported to have stronger negative and weaker positive effects than high potency herbal cannabis. PMID- 28624605 TI - Transplacental exposure to environmental carcinogens: Association with childhood cancer risks and the role of modulating factors. AB - Biological responses to carcinogens from environmental exposure during adulthood are modulated over years or decades. Conversely, during transplacental exposure, the effects on the human foetus change within weeks, intertwining with developmental mechanisms: even short periods of transplacental exposure may be imprinted in the organism for a lifetime. The pathways leading to childhood and juvenile cancers, such as leukaemias, neuroblastoma/brain tumours, hepatoblastoma, and Willm's tumour involve prenatally-induced genomic, epigenomic and/or non-genomic effects caused by xenobiotics. Pregnant women most often live in complex environmental settings that cause transplacental exposure of the foetus to xenobiotic mixtures. Mother-child biomonitoring should integrate the analysis of chemicals/radiation present in the living and workplace environment with relevant risk modulators related to life style. The interdisciplinary approach for transplacental cancer risk assessment in high-pressure areas should be based on an integrated model for mother-child exposure estimation via profiling the exposure level by water quality analysis, usage of emission grids, and land use maps. PMID- 28624606 TI - Identifying individual male reproductive consistency in Drosophila melanogaster: The importance of controlling female behaviour. AB - Work on the repeatability of reproductive behaviour has mainly focused on the consistency of female preferences. We characterised the consistency of individual male Drosophila melanogaster reproductive behaviour in two experiments. In the first experiment, we allowed males to interact with a pair of live females that differed in body size. We then controlled female behaviour in a second experiment by examining the courtship behaviour of individual males interacting with a pair of decapitated females that varied in body size. In both experiments, we examined the consistency of individual male reproductive behaviour across two repeated trials on the same day. Males did not exhibit a courtship preference for the larger female in either experiment, but, in experiment 1, males did exhibit post copulatory choice by copulating for longer durations with the large female, and males that mated with the same type of female in both trials exhibited repeatable behaviour. In general, we found weak evidence of consistent male courtship behaviour in the presence of behaving females. However, when female behaviour was controlled in experiment 2, we found that male courtship behaviour was highly repeatable. These results indicate that individual male D. melanogaster exhibit consistent reproductive behaviour and demonstrate the importance of controlling female behaviour when attempting to characterise the repeatability of male reproductive behaviour. PMID- 28624607 TI - Obese asthmatic patients have decreased surfactant protein A levels: Mechanisms and implications. AB - BACKGROUND: Eosinophils are prominent in some patients with asthma and are increased in the submucosa in a subgroup of obese patients with asthma (OAs). Surfactant protein A (SP-A) modulates host responses to infectious and environmental insults. OBJECTIVE: We sought to determine whether SP-A levels are altered in OAs compared with a control group and to determine the implications of these alterations in SP-A levels in asthmatic patients. METHODS: Bronchoalveolar lavage fluid from 23 lean, 12 overweight, and 20 obese subjects were examined for SP-A. Mouse tracheal epithelial cells grown at an air-liquid interface were used for mechanistic studies. SP-A-/- mice were challenged in allergen models, and exogenous SP-A therapy was given after the last challenge. Eosinophils were visualized and quantitated in lung parenchyma by means of immunostaining. RESULTS: Significantly less SP-A (P = .002) was detected in samples from OAs compared with those from control subjects. A univariable regression model found SP-A levels were significantly negatively correlated with body mass index (r = 0.33, P = .014), whereas multivariable modeling demonstrated that the correlation depended both on asthma status (P = .017) and the interaction of asthma and body mass index (P = .008). Addition of exogenous TNF-alpha to mouse tracheal epithelial cells was sufficient to attenuate SP-A and eotaxin secretion. Allergen challenged SP-A-/- mice that received SP-A therapy had significantly less tissue eosinophilia compared with mice receiving vehicle. CONCLUSIONS: SP-A functions as an important mediator in resolving tissue and lavage fluid eosinophilia in allergic mouse models. Decreased levels of SP-A in OAs, which could be due to increased local TNF-alpha levels, might lead to impaired eosinophil resolution and could contribute to the eosinophilic asthma phenotype. PMID- 28624609 TI - Human mast cells as antigen-presenting cells: When is this role important in vivo? PMID- 28624610 TI - Anti-FcgammaRIIB mAb suppresses murine IgG-dependent anaphylaxis by Fc domain targeting of FcgammaRIII. AB - BACKGROUND: The inhibitory receptor FcgammaRIIB is expressed on human and murine bone marrow-derived cells and limits inflammation by suppressing signaling through stimulatory receptors. OBJECTIVE: We sought to evaluate the effects of K9.361, a mouse IgG2a alloantibody to mouse FcgammaRIIB, on murine anaphylaxis. METHODS: Wild-type and FcgammaR-deficient mice were used to study anaphylaxis, which was induced by injection of 2.4G2 (rat IgG2b mAb that binds both FcgammaRIIB and the stimulatory receptor FcgammaRIII), by actively immunizing IgE deficient mice and then challenging with the immunizing antigen, and by passive immunization with IgG or IgE anti-2,4,6-trinitrophenyl mAb, followed by injection of 2,4,6-trinitrophenyl-ovalbumin. Pretreatment with K9.361 was assessed for its ability to influence anaphylaxis. RESULTS: Unexpectedly, K9.361 injection induced mild anaphylaxis, which was both FcgammaRIIB and FcgammaRIII dependent and greatly enhanced by beta-adrenergic blockade. K9.361 injection also decreased expression of stimulatory Fcgamma receptors, especially FcgammaRIII, and strongly suppressed IgG-mediated anaphylaxis without strongly affecting IgE-mediated anaphylaxis. The F(ab')2 fragment of K9.361 did not induce anaphylaxis, even after beta-adrenergic blockade, and did not deplete FcgammaRIII or suppress IgG mediated anaphylaxis but prevented intact K9.361-induced anaphylaxis without diminishing intact K9.36 suppression of IgG-mediated anaphylaxis. CONCLUSION: Cross-linking FcgammaRIIB to stimulatory FcgammaRs through the Fc domains of an anti-FcgammaRIIB mAb induces and then suppresses IgG-mediated anaphylaxis without affecting IgE-mediated anaphylaxis. Because IgG- and IgE-mediated anaphylaxis can be mediated by the same cell types, this suggests that desensitization acts at the receptor rather than cellular level. Sequential treatment with the F(ab')2 fragment of anti-FcgammaRIIB mAb followed by intact anti-FcgammaRIIB safely prevents IgG-mediated anaphylaxis. PMID- 28624608 TI - Obesity's effect on asthma extends to diagnostic criteria. AB - BACKGROUND: The use of inflammatory biomarkers to delineate the type of lung inflammation present in asthmatic subjects is increasingly common. However, the effect of obesity on these markers is unknown. OBJECTIVES: We aimed to determine the effect of obesity on conventional markers of inflammation in asthmatic subjects. METHODS: We performed secondary analysis of data from 652 subjects previously enrolled in 2 Asthma Clinical Research Network trials. We performed linear correlations between biomarkers and logistic regression analysis to determine the predictive value of IgE levels, blood eosinophil counts, and fraction of exhaled nitric oxide values in relationship to sputum eosinophil counts (>2%), as well as to determine whether cut points existed that would maximize the sensitivity and specificity for predicting sputum eosinophilia in the 3 weight groups. RESULTS: Overall, statistically significant but relatively weak correlations were observed among all 4 markers of inflammation. Within obese subjects, the only significant correlation found was between IgE levels and blood eosinophil counts (r = 0.33, P < .001); furthermore, all other correlations between inflammatory markers were approximately 0, including correlations with sputum eosinophil counts. In addition, the predictive value of each biomarker alone or in combination was poor in obese subjects. In fact, in obese subjects none of the biomarkers of inflammation significantly predicted the presence of high sputum eosinophil counts. Obese asthmatic subjects have lower cut points for IgE levels (268 IU), fraction of exhaled nitric oxide values (14.5 ppb), and blood eosinophil counts (96 cells/MUL) than all other groups. CONCLUSIONS: In obese asthmatic subjects conventional biomarkers of inflammation are poorly predictive of eosinophilic airway inflammation. As such, biomarkers currently used to delineate eosinophilic inflammation in asthmatic subjects should be approached with caution in these subjects. PMID- 28624611 TI - The future of allergy/immunology: Promising young investigators. PMID- 28624612 TI - Human mast cells present antigen to autologous CD4+ T cells. AB - BACKGROUND: Mast cells (MCs), the primary effector cell of the atopic response, participate in immune defense at host/environment interfaces, yet the mechanisms by which they interact with CD4+ T cells has been controversial. OBJECTIVE: We used in situ-matured primary human MCs and matched CD4+ T cells to diligently assess the ability of MCs to act as antigen-presenting cells. METHODS: We examined mature human skin-derived MCs using flow cytometry for expression of antigen-presenting molecules, for their ability to stimulate CD4+ T cells to express CD25 and proliferate when exposed to superantigen or to cytomegalovirus (CMV) antigen using matched T cells and MCs from CMV-seropositive or CMV seronegative donors, and for antigen uptake. Subcellular localization of antigen, HLA molecules, and tryptase was analyzed by using structured illumination microscopy. RESULTS: Our data show that IFN-gamma induces HLA class II, HLA-DM, CD80, and CD40 expression on MCs, whereas MCs take up soluble and particulate antigens in an IFN-gamma-independent manner. IFN-gamma-primed MCs guide activation of T cells by Staphylococcus aureus superantigen and, when preincubated with CMV antigens, induce a recall CD4+ TH1 proliferation response only in CMV-seropositive donors. MCs co-opt their secretory granules for antigen processing and presentation. Consequently, MC degranulation increases surface delivery of HLA class II/peptide, further enhancing stimulation of T-cell proliferation. CONCLUSIONS: IFN-gamma primes human MCs to activate T cells through superantigen and to present CMV antigen to TH1 cells, co-opting MC secretory granules for antigen processing and presentation and creating a feed forward loop of T-cell-MC cross-activation. PMID- 28624613 TI - Nitroimidazole-refractory giardiasis: a growing problem requiring rational solutions. AB - BACKGROUND: Giardia intestinalis is microaerophilic diarrhoea-causing protozoan common in countries with suboptimal sanitation. Standard treatment is with nitroimidazoles, but a growing number of refractory cases is being reported. Treatment failure has become increasingly prevalent in travellers who contract giardiasis in Asia. Clinicians are increasingly falling back on second-line and less well-known drugs to treat giardiasis. AIMS: To review nitroimidazole refractory G. intestinalis infection, examine the current efficacy of standard therapeutic agents, consider potential resistance mechanisms which could cause treatment failure and describe the practical aspects of managing this emerging clinical problem. SOURCES: A PubMed search was conducted using combinations of the following terms: refractory, Giardia, giardiasis, resistance and treatment. Articles on the pharmacotherapy, drug resistance mechanisms and use of alternative agents in nitroimidazole-refractory giardiasis were reviewed. CONTENT: We review the standard drugs for giardiasis, including their efficacy in initial treatment, mode of action and documented in vitro and in vivo drug resistance. We assess the efficacy of alternative drugs in nitroimidazole refractory disease. Existing data suggest a potential advantage of combination treatment. IMPLICATIONS: An optimal treatment strategy for refractory giardiasis has still to be determined, so there is no standard treatment regimen for nitroimidazole-refractory giardiasis. Further work on drug resistance mechanisms and the use of drug combinations in this condition is a priority. PMID- 28624614 TI - Gene Transfer Agent Promotes Evolvability within the Fittest Subpopulation of a Bacterial Pathogen. AB - The Bartonella gene transfer agent (BaGTA) is an archetypical example for domestication of a phage-derived element to permit high-frequency genetic exchange in bacterial populations. Here we used multiplexed transposon sequencing (TnSeq) and single-cell reporters to globally define the core components and transfer dynamics of BaGTA. Our systems-level analysis has identified inner- and outer-circle components of the BaGTA system, including 55 regulatory components, as well as an additional 74 and 107 components mediating donor transfer and recipient uptake functions. We show that the stringent response signal guanosine tetraphosphate (ppGpp) restricts BaGTA induction to a subset of fast-growing cells, whereas BaGTA particle uptake depends on a functional Tol-Pal trans envelope complex that mediates outer-membrane invagination upon cell division. Our findings suggest that Bartonella evolved an efficient strategy to promote genetic exchange within the fittest subpopulation while disfavoring exchange of deleterious genetic information, thereby facilitating genome integrity and rapid host adaptation. PMID- 28624615 TI - Cell-Size-Dependent Transcription of FLC and Its Antisense Long Non-coding RNA COOLAIR Explain Cell-to-Cell Expression Variation. AB - Single-cell quantification of transcription kinetics and variability promotes a mechanistic understanding of gene regulation. Here, using single-molecule RNA fluorescence in situ hybridization and mathematical modeling, we dissect cellular RNA dynamics for Arabidopsis FLOWERING LOCUS C (FLC). FLC expression quantitatively determines flowering time and is regulated by antisense (COOLAIR) transcription. In cells without observable COOLAIR expression, we quantify FLC transcription initiation, elongation, intron processing, and lariat degradation, as well as mRNA release from the locus and degradation. In these heterogeneously sized cells, FLC mRNA number increases linearly with cell size, resulting in a large cell-to-cell variability in transcript level. This variation is accounted for by cell-size-dependent, Poissonian FLC mRNA production, but not by large transcriptional bursts. In COOLAIR-expressing cells, however, antisense transcription increases with cell size and contributes to FLC transcription decreasing with cell size. Our analysis therefore reveals an unexpected role for antisense transcription in modulating the scaling of transcription with cell size. PMID- 28624616 TI - Age-related plasticity of the axon initial segment of cortical pyramidal cells in marmoset monkeys. AB - Structural plasticity of the axon initial segment (AIS), the site of action potential initiation, is observed as part of the normal early development of the cortex, as well as in association with injury and disease. Here, we show that structural AIS plasticity also occurs with normal aging in adult marmosets. Immunohistochemical techniques were used to reveal the extent of the AIS of layer 2/3A pyramidal cells in 8 neocortical areas. We found that the AIS length varied significantly between areas in young adult (2-3 years old) marmosets, with neurons in frontal area 14C having the longest AIS, and those in the primary visual cortex the shortest. Similar interareal differences were observed in aged (12-14 year old) monkeys, but the AIS was significantly shortened in many areas, relative to the corresponding length in young adults. Shortening of the AIS is likely to represent a compensatory response to changes in the excitation inhibition balance, associated with the loss of GABAergic interneurons in the aged cortex. PMID- 28624617 TI - Core-shell iron oxide-layered double hydroxide: High electrochemical sensing performance of H2O2 biomarker in live cancer cells with plasma therapeutics. AB - In this work, we develop a new type of multifunctional core-shell nanomaterial by controllable integration of CuAl layered double hydroxides (LDHs) over the surface of iron oxides (Fe3O4) nanospheres (NSs) to fabricate (Fe3O4@CuAl NSs) hybrid material with interior tunability of LDH phase and explore its practical application in ultrasensitive detection of emerging biomarker, i.e., H2O2 as cancer diagnostic probe. In addition, atmospheric pressure plasmas (APPs) have also been used as potential therapeutic approach for cancer treatment. Due to the synergistic combination of p-type semiconductive channels of LDHs with multi functional properties, unique morphology and abundant surface active sites, the Fe3O4@CuAl NSs modified electrode exhibited attractive electrocatalytic activity towards H2O2 reduction. Under the optimized conditions, the proposed biosensor demonstrated striking electrochemical sensing performances to H2O2 including linear range as broad as 8 orders of magnitude, low real detection limit of 1nM (S/N = 3), high sensitivity, good reproducibility and long-term stability. Arising from the superb efficiency, the electrochemical biosensor has been used for in vitro determination of H2O2 concentrations in human urine and serum samples prior to and following the intake of coffee, and real-time monitoring of H2O2 efflux from different cancer cell lines in normal state and after plasma treatment. We believe that this novel nano-platform of structurally integrated core-shell nanohybrid materials combined with APPs will enhance diagnostic as well as therapeutic window for cancer diseases. PMID- 28624618 TI - A sample-to-answer, real-time convective polymerase chain reaction system for point-of-care diagnostics. AB - Timely and accurate molecular diagnostics at the point-of-care (POC) level is critical to global health. To this end, we propose a handheld convective-flow real-time polymerase chain reaction (PCR) system capable of direct sample-to answer genetic analysis for the first time. Such a system mainly consists of a magnetic bead-assisted photothermolysis sample preparation, a closed-loop convective PCR reactor, and a wireless video camera-based real-time fluorescence detection. The sample preparation exploits the dual functionality of vancomycin modified magnetic beads (VMBs) for bacteria enrichment and photothermal conversion, enabling cell pre-concentration and lysis to be finished in less than 3min. On the presented system, convective thermocycling is driven by a single heater thermal gradient, and its amplification is monitored in real-time, with an analysis speed of less than 25min, a dynamic linear range from 106 to 101 copies/uL and a detection sensitivity of as little as 1 copies/uL. Additionally, the proposed PCR system is self-contained with a control electronics, pocket-size and battery-powered, providing a low-cost genetic analysis in a portable format. Therefore, we believe that this integrated system may become a potential candidate for fast, accurate and affordable POC molecular diagnostics. PMID- 28624619 TI - Quorum sensing signals enhance the electrochemical activity and energy recovery of mixed-culture electroactive biofilms. AB - The impacts of exogenous or endogenous quorum sensing (QS) signaling molecules on mixed-culture electroactive biofilms (EABs), especially extracellular polymeric substances (EPS) and exoelectrogens using direct electron transfer mechanism inside EABs are poorly understood. This research focuses on the influence of acylhomoserine lactones (AHLs), the most common QS signaling molecules for gram negative bacteria, on mixed-culture EABs. Results indicated that both exogenous and endogenous AHLs played the role as regulators to improve the electrochemical activities of EABs. The energy recovery of MFCs increased from 20.5% +/- 3.9% to 28.3% +/- 4.1% with endogenous AHLs and further rose to 36.2% +/- 5.1% with exogenous AHLs, and the start-up period of MFCs shortened from 13 days to 10 days with endogenous AHLs and further reduced to 4 days in the presence of exogenous AHLs. The influences of exogenous and endogenous AHLs were non-instantaneous. They improved some intrinsic properties, i.e. the electrode-associated biomass, the biofilm compactness and the ratio of live/dead cells to obtain superior EABs. Meanwhile, both endogenous and exogenous AHLs increased the concentration and redox activities of EPS. Besides, endogenous AHLs enhanced the diversity of EPS components. Noteworthily, the relative abundance of Geoboacter sp. which is the typical microbe using direct electron transfer mechanism is raised by exogenous AHLs, though so far neither known chemical QS-related gene nor protein has been reported in this genus. These findings will increase the current understanding of QS in EABs and open up an opportunity for regulating mixed-culture MFCs via QS. PMID- 28624620 TI - AgBr nanoparticles/3D nitrogen-doped graphene hydrogel for fabricating all-solid state luminol-electrochemiluminescence Escherichia coli aptasensors. AB - It is necessary to develop rapid, simple and accurate detection method for Escherichia coli (E. coli) due to its widely distributed pathogenic bacteria. Herein, we prepared AgBr nanoparticles (NPs) anchored 3D nitrogen-doped graphene hydrogel (3DNGH) nanocomposites with an exceptionally large accessible surface by a simple hydrothermal approach. The as-prepared 3DNGH porous nanocomposite not only showed better conductivity than that of 3D graphene due to introducing nitrogen element into graphene framework, but also provided a high loading volume for immobilizing luminol. Meanwhile the anchored AgBr NPs served as the catalyst can effectively enhance the ECL behavior of luminol. And the resulting luminol/AgBr/3DNGH exhibited more excellent ECL performances, which was about 2, 3, 8 times enhanced respectively, comparing to luminol/AgBr/3DGH, luminol/3DNGH and luminol/AgBr/2DNG. Further, the multifunctional nanoarchitecture was used as the all-solid-state ECL platform for fabricating Escherichia coli aptasensors via glutaraldehyde as crosslinking agent between amine-functionalized E. coli aptamer and luminol/AgBr/3DNGH. Based on the steric hindrance mechanism that E.coli can significantly decrease the ECL intensity, the proposed aptasensor displayed a linear response for E.coli in the range from 0.5 to 500 cfu/mL with an extremely low detection limit of 0.17 cfu/mL (S/N). In addition, this ECL aptasensor possessed great advantages including the simple operation process, low-cost and sensitivity, which provided a promising approach for the E.coli detection in biomedical, food detection and environmental analysis. PMID- 28624621 TI - Innate immune system capabilities of the Asian citrus psyllid, Diaphorina citri. AB - Citrus production worldwide is currently threatened by Huanglongbing, or citrus greening disease. The associated pathogen, Candidatus Liberibacter asiaticus (CLas), is transmitted by the Asian citrus psyllid, Diaphorina citri. Annotation of the D. citri genome revealed a reduced innate immune system lacking a number of antimicrobial peptides and the Imd pathway associated with defense against Gram-negative bacteria. We characterized this apparent immune reduction in survival assays in which D. citri were exposed to Gram-negative or Gram-positive bacteria. D. citri experienced significant mortality when exposed to Serratia marcescens (Gram-negative) through oral ingestion or by septic injury. Escherichia coli (Gram-negative) also caused significant D. citri mortality, but only when inoculated at high concentrations through oral ingestion or by septic injury. Neither Micrococcus luteus (Gram-positive) or Bacillus subtilis (Gram positive) caused significant mortality as compared to controls in any experiment. E. coli titers increased rapidly following exposure, while M. luteus titer remained stable for 72 h. We demonstrate that D. citri is capable of defending against E. coli, a Gram-negative bacterium, despite lacking the Imd defense pathway. The tolerance of D. citri to M. luteus infection, yet inability to effectively clear infections, presents questions to efficacy of D. citri immune response to effectively clear Gram-positive infections. PMID- 28624622 TI - Preclinical anti-cancer activity and multiple mechanisms of action of a cationic silver complex bearing N-heterocyclic carbene ligands. AB - Organometallic complexes offer the prospect of targeting multiple pathways that are important in cancer biology. Here, the preclinical activity and mechanism(s) of action of a silver-bis(N-heterocyclic carbine) complex (Ag8) were evaluated. Ag8 induced DNA damage via several mechanisms including topoisomerase I/II and thioredoxin reductase inhibition and induction of reactive oxygen species. DNA damage induction was consistent with cytotoxicity observed against proliferating cells and Ag8 induced cell death by apoptosis. Ag8 also inhibited DNA repair enzyme PARP1, showed preferential activity against cisplatin resistant A2780 cells and potentiated the activity of temozolomide. Ag8 was substantially less active against non-proliferating non-cancer cells and selectively inhibited glycolysis in cancer cells. Ag8 also induced significant anti-tumour effects against cells implanted intraperitoneally in hollow fibres but lacked activity against hollow fibres implanted subcutaneously. Thus, Ag8 targets multiple pathways of importance in cancer biology, is less active against non-cancer cells and shows activity in vivo in a loco-regional setting. PMID- 28624623 TI - Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. AB - Both mitochondrial morphology and the level of cytosolic calcium [Ca2+]c are actively changed and play critical roles in a number of malignancies. However, whether communications existed between these two processes to ingeniously control the malignant phenotype are far from clear. We investigated the reciprocal regulation between mitochondrial fission and cytosolic calcium signaling in human hepatocellular carcinoma (HCC) cells. Furthermore, the underlying molecular mechanisms and the synergistic effect on autophagy were explored. Our results showed that mitochondrial fission increased the [Ca2+]c and calcium oscillation in HCC cells. We further found that mitochondrial fission-mediated calcium signaling was dependent on ROS-activated NF-kappaB pathways, which facilitated the expression of STIM1 and subsequent store-operated calciumentry. Additionally, we also demonstrated that increase in [Ca2+]c promoted mitochondrial fission by up-regulating expression of Drp1 and FIS1 via transcription factors NFATC2 and c Myc, respectively. Moreover, the positive feedback loop significantly promoted HCC cell global autophagy by Ca2+/CAMKK/AMPK pathway. Our data demonstrate a positive feedback loop between mitochondrial fission and cytosolic calcium signaling and their promoting role in autophagy of HCC cells, which provides evidence for this loop as a potential drug target in tumor treatment. PMID- 28624624 TI - Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer. AB - Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal-related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy. PMID- 28624625 TI - A formalin-fixed paraffin-embedded (FFPE)-based prognostic signature to predict metastasis in clinically low risk stage I/II microsatellite stable colorectal cancer. AB - Approximately 20% early-stage (I/II) colorectal cancer (CRC) patients develop metastases despite curative surgery. We aim to develop a formalin-fixed and paraffin-embedded (FFPE)-based predictor of metastases in early-stage, clinically defined low risk, microsatellite-stable (MSS) CRC patients. We considered genome wide mRNA and miRNA expression and mutation status of 20 genes assayed in 150 fresh-frozen tumours with known metastasis status. We selected 193 genes for further analysis using NanoString nCounter arrays on corresponding FFPE tumours. Neither mutation status nor miRNA expression improved the estimated prediction. The final predictor, ColoMet19, based on the top 19 genes' mRNA levels trained by Random Forest machine-learning strategy, had an estimated positive-predictive value (PPV) of 0.66. We tested ColoMet19 on an independent test-set of 131 tumours and obtained a population-adjusted PPV of 0.67 indicating that early stage CRC patients who tested positive have a 67% risk of developing metastases, substantially higher than the metastasis risk of 40% for node-positive (Stage III) patients who are generally treated with chemotherapy. Predicted-positive patients also had poorer metastasis-free survival (hazard ratios [HR] = 1.92, design-set; HR = 2.05, test-set). Thus, early-stage CRC patients who test positive may be considered for adjuvant therapy after surgery. PMID- 28624626 TI - Alternative Polyadenylation Patterns for Novel Gene Discovery and Classification in Cancer. AB - Certain aspects of diagnosis, prognosis, and treatment of cancer patients are still important challenges to be addressed. Therefore, we propose a pipeline to uncover patterns of alternative polyadenylation (APA), a hidden complexity in cancer transcriptomes, to further accelerate efforts to discover novel cancer genes and pathways. Here, we analyzed expression data for 1045 cancer patients and found a significant shift in usage of poly(A) signals in common tumor types (breast, colon, lung, prostate, gastric, and ovarian) compared to normal tissues. Using machine-learning techniques, we further defined specific subsets of APA events to efficiently classify cancer types. Furthermore, APA patterns were associated with altered protein levels in patients, revealed by antibody-based profiling data, suggesting functional significance. Overall, our study offers a computational approach for use of APA in novel gene discovery and classification in common tumor types, with important implications in basic research, biomarker discovery, and precision medicine approaches. PMID- 28624627 TI - Histopathological and proteomic responses in male Chinese rare minnow (Gobiocypris rarus) indicate hepatotoxicity following benzotriazole exposure. AB - Benzotriazole (BT) and its associated derivatives are used ubiquitously in industrial processes, and can be detected in indoor temperature coolants and in chemicals designed to inhibit corrosion. This chemical has been widely detected in aquatic environments and shows some degree of environmental persistence. Evidence has shown that BT exposure can negatively affect endocrine systems and can result in neurotoxicity in fish. However, no study has examined whether this chemical exhibits hepatotoxicity in fish, and if so, what are the underlying mechanism associated with the damage. To address this knowledge gap, we measured the liver proteome of adult male Chinese rare minnow (Gobiocypris rarus) exposed to either 0.05, 0.5, or 5 mg/L BT for 28 days. Overall, 17 proteins were induced and 9 were reduced in abundance following BT treatment (ratio > 1.5, p < 0.05). Pathway analysis revealed that cellular processes affected by BT included xenobiotic clearance, oxidative stress response, apoptosis, and translation. Moreover, transcripts related to these toxic pathways were also significantly affected by BT. In addition, rare minnows exposed to BT showed signs of hypertrophy of hepatocytes, nuclei pyknosis, and higher levels of cellular vacuolization compared to the controls, thus these early proteomic responses in the liver may be related to pathology (i.e. adverse outcome pathway). Our data demonstrate that BT dysregulates molecular responses in the liver and tissue pathology indicative of damage. This study provides new insight into BT hepatotoxicity in Chinese rare minnow. PMID- 28624628 TI - Time-dependent inhibitory effects of Tris(1, 3-dichloro-2-propyl) phosphate on growth and transcription of genes involved in the GH/IGF axis, but not the HPT axis, in female zebrafish. AB - Growth curves were used to determine sensitive exposure windows for evaluation of developmental toxicity of chemicals to zebrafish. Dose- and time-dependent effects on body mass, body length and expression of genes involved in the growth hormone/insulin-like growth factor (GH/IGF) axis and the hypothalamic-pituitary thyroid (HPT) axis were examined after exposure to environmentally relevant concentrations of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP). Based on growth curves, zebrafish grew most rapidly between 60 and 90 days post fertilization (dpf). Exposure to environmentally relevant concentrations of TDCIPP significantly decreased body mass and body length and down-regulated expression of several genes involved in the GH/IGF axis of female zebrafish, but no such effects were observed in male zebrafish. Exposure to TDCIPP did not change concentrations of thyroid hormones or expression of genes along the HPT axis in female and male zebrafish. These results suggest that growth stages of zebrafish between 60 and 90 dpf might be most appropriate for evaluation of developmental toxicity of chemicals, and down-regulation of genes involved in the GH/IGF axis, but not the HPT axis, might be responsible for the observed growth inhibition in females exposed to TDCIPP. PMID- 28624629 TI - Zinc oxide nanoparticle exposure triggers different gene expression patterns in maize shoots and roots. AB - The potential impacts of environmentally accumulated zinc oxide nanoparticles (nZnOs) on plant growth have not been well studied. A transcriptome profile analysis of maize exposed to nZnOs showed that the genes in the shoots and roots responded differently. Although the number of differentially expressed genes (DEGs) in the roots was greater than that in the shoots, the number of up- or down-regulated genes in both the shoots and roots was similar. The enrichment of gene ontology (GO) terms was also significantly different in the shoots and roots. The "nitrogen compound metabolism" and "cellular component" terms were specifically and highly up-regulated in the nZnO-exposed roots, whereas the categories "cellular metabolic process", "primary metabolic process" and "secondary metabolic process" were down-regulated in the exposed roots only. Our results revealed the DEG response patterns in maize shoots and roots after nZnO exposure. PMID- 28624630 TI - The dynamic links between carbon dioxide (CO2) emissions, health spending and GDP growth: A case study for 51 countries. AB - This document investigated the causal relationship between carbon dioxide (CO2) emissions, health spending and GDP growth for 51 countries (divided into three groups of countries: low-income countries; group of countries with lower and upper middle income; group of middle income countries) covering the annual period 1995-2013. Dynamic simultaneous-equations models and generalized method of moments (GMM) are used to investigate this relationship. The main results provide evidence of a causal relationship between the three variables. The empirical results show that there is a bidirectional causality between CO2 emissions and GDP per capita, between health spending and economic growth for the three groups of estimates. The results also indicate that there is a unidirectional causality from CO2 emissions to health spending, except low income group countries. We found that health plays an important role in GDP per capita; it limits its effect on a growing deterioration in the quality of the environment. PMID- 28624631 TI - Re: In defence of high hand-hygiene compliance rates. PMID- 28624632 TI - Healthcare workers' knowledge, attitudes and practices relating to Ebola virus disease. PMID- 28624633 TI - From flamingo dance to (desirable) drug discovery: a nature-inspired approach. AB - The therapeutic effects of drugs are well known to result from their interaction with multiple intracellular targets. Accordingly, the pharma industry is currently moving from a reductionist approach based on a 'one-target fixation' to a holistic multitarget approach. However, many drug discovery practices are still procedural abstractions resulting from the attempt to understand and address the action of biologically active compounds while preventing adverse effects. Here, we discuss how drug discovery can benefit from the principles of evolutionary biology and report two real-life case studies. We do so by focusing on the desirability principle, and its many features and applications, such as machine learning-based multicriteria virtual screening. PMID- 28624635 TI - Identification and interaction of multiple stressors in central European lowland rivers. AB - Interactions of multiple stressors in lotic systems have received growing interest and have been analysed in a growing number of studies using experiment and survey data. In this study, we present a protocol to identify, display and analyse stressors of rivers and their interactions (additive, synergistic or antagonistic). We used a dataset of 125 samples of central European lowland rivers comprising hydromorphological, physico-chemical and land use stressor and pressure variables as well as benthic macroinvertebrate traits as biological response variables. To identify and visualise multiple stressor combinations jointly operating in the data set, we applied social network analysis. The main co-occurring stressor combination was fine sediment accumulation (hydromorphological stress) and enhanced phosphorus concentration (nutrient stress). Agricultural (cropland) and urban land use were identified as the main large scale environmental pressures. Stressor interactions were analysed using generalised linear regression modelling (GLM) including pairwise interaction terms. Altogether, 14 macroinvertebrate response variables were tested on six stressor combinations and revealed predominantly additive effects (80% of all significant models with absolute standardised effect sizes >0.1). Significant antagonistic and synergistic interactions occurred in almost 20% of the models. Fine sediment stress was more influential and frequent than nutrient stress. The methodology presented here is standardisable and thus could help inform practitioners in aquatic ecosystem monitoring about prominent combinations of multiple stressors and their interactions. Yet, further understanding of the mechanisms behind the biological responses is required to be able to derive appropriate guidance for management. This applies to rather complex stressors and pressures, such as land use, for which more detailed data (e.g. nutrient concentrations, fine sediment entry, pesticide pollution) is often missing. PMID- 28624634 TI - Impact of upgrading wastewater treatment plant on the removal of typical methyl, oxygenated, chlorinated and parent polycyclic aromatic hydrocarbons. AB - Wastewater treatment plant (WWTP) secondary effluent is a main source for polycyclic aromatic hydrocarbons (PAHs) and their derivatives (SPAHs) to wastewater receiving rivers in Beijing. The treatment technologies are being upgraded in the WWTPs as the tertiary treatment. To assess the improvement of the removal efficiencies of PAHs and SPAHs after the treatment upgrading, we investigated 16 PAHs and 4 types of SPAHs in the secondary and tertiary treatment process in 5 major WWTPs. Most of the parent PAHs, methyl PAHs, oxygenated PAHs and chlorinated PAHs were detected in the influent, secondary and tertiary effluent. The concentrations of SigmaSPAHs (61ng/L-529ng/L) were similar to SigmaPAHs (89ng/L-474ng/L), indicating that SPAHs should not be ignored when studying the PAH contamination. SigmaPAHs and SigmaSPAHs were largely removed by the secondary treatment (45%-82%) and less by the tertiary treatment (0%-24%). The removal efficiencies were lower in the secondary and tertiary treatment in WWTPs than in the lab-scale experiment conducted previously, probably a result of the association of PAHs and SPAHs with dissolved organic matters (DOMs) in wastewater. DOMs might be a limiting factor for the removal of PAHs and SPAHs in WWTPs. The estimated yearly loadings of the total PAHs and SPAHs decreased only 21% in the tertiary effluent compared with the secondary effluent in WWTP1 and 9% in WWTP3. Therefore, the upgrading of WWTPs did not efficiently improve the removal of PAHs and SPAHs. DOMs should be further considered for improving the removal of PAHs, SPAHs and similar contaminants in WWTPs. PMID- 28624636 TI - Water geochemistry of shallow lakes from the southeastern Pampa plain, Argentina and their implications on mollusk shells preservation. AB - A seasonal sampling of sediments, column and interstitial water for physico chemical analysis were performed in littoral and open water areas in three freshwater shallow lakes (Nahuel Ruca, Las Mostazas and Los Carpinchos) from Southeastern Pampa plain, Argentina. The main objective of the present study is to evaluate how the characteristics of the depositional environments could be affecting mollusk shell preservation. These lakes are very shallow (2m) and are characterized by an extensive littoral area, dominated by the emergent macrophyte Schoenoplectus californicus, which forms a complete ring around the lake, and an open water area, in general free of vegetation. Five samples of sediments in each compartment were extracted for analysis of pH, moisture, organic matter and carbonates content using a gravity corer, while five samples from column and interstitial water were extracted for chemical analysis (pH, conductivity, major ions, minor ions and hardness). Besides, calcite and aragonite saturation indices and the redox potential were calculated for each lake. The results show the significant impact of water chemistry and redox conditions on the preservation potential of freshwater mollusk and consequently in the quality of paleonvironmental reconstruction based on the biological record from the study region. The higher concentration of organic matter and lower pH registered in the littoral area, mainly during warm months (autumn and summer), suggest worst environments for mollusk preservation, compared to open waters. Moreover, water geochemistry analysis showed aragonite and calcite indices near equilibrium or slightly subsaturated in interstitial water associated with more acid pHs, while column water is strongly oversaturated related to alkaline pHs. These results suggest that carbonate remains within sediments will be subject to dissolution affecting negatively their preservation potential. However, mollusk shells in contact with the column water are not expected to be dissolved. PMID- 28624637 TI - Developing a new Bayesian Risk Index for risk evaluation of soil contamination. AB - Industrial and agricultural activities heavily constrain soil quality. Potentially Toxic Elements (PTEs) are a threat to public health and the environment alike. In this regard, the identification of areas that require remediation is crucial. In the herein research a geochemical dataset (230 samples) comprising 14 elements (Cu, Pb, Zn, Ag, Ni, Mn, Fe, As, Cd, V, Cr, Ti, Al and S) was gathered throughout eight different zones distinguished by their main activity, namely, recreational, agriculture/livestock and heavy industry in the Aviles Estuary (North of Spain). Then a stratified systematic sampling method was used at short, medium, and long distances from each zone to obtain a representative picture of the total variability of the selected attributes. The information was then combined in four risk classes (Low, Moderate, High, Remediation) following reference values from several sediment quality guidelines (SQGs). A Bayesian analysis, inferred for each zone, allowed the characterization of PTEs correlations, the unsupervised learning network technique proving to be the best fit. Based on the Bayesian network structure obtained, Pb, As and Mn were selected as key contamination parameters. For these 3 elements, the conditional probability obtained was allocated to each observed point, and a simple, direct index (Bayesian Risk Index-BRI) was constructed as a linear rating of the pre-defined risk classes weighted by the previously obtained probability. Finally, the BRI underwent geostatistical modeling. One hundred Sequential Gaussian Simulations (SGS) were computed. The Mean Image and the Standard Deviation maps were obtained, allowing the definition of High/Low risk clusters (Local G clustering) and the computation of spatial uncertainty. High-risk clusters are mainly distributed within the area with the highest altitude (agriculture/livestock) showing an associated low spatial uncertainty, clearly indicating the need for remediation. Atmospheric emissions, mainly derived from the metallurgical industry, contribute to soil contamination by PTEs. PMID- 28624638 TI - The fate of spirotetramat and dissipation metabolites in Apiaceae and Brassicaceae leaf-root and soil system under greenhouse conditions estimated by modified QuEChERS/LC-MS/MS. AB - The aim of this study was to investigate the dissipation of spirotetramat and its four metabolites (B-enol, B-keto, B-mono and B-glu) in different parts of vegetables belong to the minor crops (Appiacea and Brassicaceae) and soil from cultivation. The challenge of this study was to apply an optimized clean up step in QuEChERS to obtain one universal sorbent for different complex matrices like leaves with high levels of pigments, roots containing acids, sugars, polyphenolls and pigments and soil with organic ingredients. Eight commercial (Florisil, neutral alumina, GCB, PSA, C18, diatomaceous earth, VERDE and ChloroFiltr) and one organic (Chitosan) sorbents were tested. A modified clean up step in QuEChERS methodology was used for analysis. The dissipation of spirotetramat and its metabolites was described according to a first-order (FO) kinetics equation with R2 between 0.9055 and 0.9838. The results showed that the time after 50% (DT50) of the substance degraded was different for soil, roots and leaves, and amounted to 0.2day, 2.8-2.9days and 2.1-2.4days, respectively. The terminal residues of spiroteramat (expressed as the sum of spirotetramat, B-enol, B-glu, B-keto and B mono) were much lower than the MRLs. PMID- 28624639 TI - Ozone exposure- and flux-based response relationships with photosynthesis, leaf morphology and biomass in two poplar clones. AB - Poplar clones 546 (P. deltoides cv. '55/56'*P. deltoides cv. 'Imperial') and 107 (P. euramericana cv. '74/76') were exposed to five ozone concentrations in 15 open-top chambers (OTCs). Both ozone exposure (AOT40, Accumulation Over a Threshold hourly ozone concentration of 40ppb) and flux-based (POD7, Phytotoxic Ozone Dose above an hourly flux threshold of 7nmol O3 m-2 PLA (projected leaf area) s-1) response relationships were established with photosynthesis, leaf morphology and biomass variables. Increases in both metrics showed significant negative relationships with light-saturated photosynthesis rate, chlorophyll content, leaf mass per area, actual photochemical efficiency of PSII in the light and root biomass but not with stomatal conductance (gs), leaf and stem biomass. Ozone had a greater impact on belowground than on aboveground biomass. The ranking of these indicators from higher to lower sensitivity to ozone was: photosynthetic parameters, morphological index, and biomass. Clone 546 had a higher sensitivity to ozone than clone 107. The coefficients of determination (R2) were similar between exposure- and flux-based dose-response relationships for each variable. The critical levels (CLs) for a 5% reduction in total biomass for the two poplar clones were 14.8ppmh for AOT40 and 9.8mmol O3 m-2 PLA for POD7. In comparison, equivalent reduction occurred at much lower values in photosynthetic parameters (4ppmh for AOT40 and 3mmol O3 m-2 PLA for POD7) and LMA (5.8ppmh for AOT40 and 4mmol O3 m-2 PLA for POD7). While in recent decades different CLs have been proposed for several plant receptors especially in Europe, studies focusing on both flux-based dose-response relationships and CLs are still scarce in Asia. This study is therefore valuable for regional O3 risk assessment in Asia. PMID- 28624640 TI - Neural correlates of preserved facial affect perception in high functioning schizophrenia. AB - Individuals with 'high functioning' schizophrenia (HF-SCZ) may have preserved facial affect perception (FAP) compared to individuals with 'low functioning' schizophrenia (LF-SCZ). The neural mechanisms supporting preserved FAP in HF-SCZ have yet to be evaluated. This study compared brain activation during FAP performance in HF-SCZ, LF-SCZ, and controls. Results demonstrated greater activation in the precuneus in CON compared to both SCZ groups, while HF-SCZ activated this region intermediate to controls and LF-SCZ. These preliminary findings suggest greater precuneus activation may be related to preserved FAP in HF-SCZ compared to LF-SCZ, though future research is needed to further evaluate differences between groups. PMID- 28624641 TI - Text mining applied to electronic cardiovascular procedure reports to identify patients with trileaflet aortic stenosis and coronary artery disease. AB - BACKGROUND: Interrogation of the electronic health record (EHR) using billing codes as a surrogate for diagnoses of interest has been widely used for clinical research. However, the accuracy of this methodology is variable, as it reflects billing codes rather than severity of disease, and depends on the disease and the accuracy of the coding practitioner. Systematic application of text mining to the EHR has had variable success for the detection of cardiovascular phenotypes. We hypothesize that the application of text mining algorithms to cardiovascular procedure reports may be a superior method to identify patients with cardiovascular conditions of interest. METHODS: We adapted the Oracle product Endeca, which utilizes text mining to identify terms of interest from a NoSQL like database, for purposes of searching cardiovascular procedure reports and termed the tool "PennSeek". We imported 282,569 echocardiography reports representing 81,164 individuals and 27,205 cardiac catheterization reports representing 14,567 individuals from non-searchable databases into PennSeek. We then applied clinical criteria to these reports in PennSeek to identify patients with trileaflet aortic stenosis (TAS) and coronary artery disease (CAD). Accuracy of patient identification by text mining through PennSeek was compared with ICD-9 billing codes. RESULTS: Text mining identified 7115 patients with TAS and 9247 patients with CAD. ICD-9 codes identified 8272 patients with TAS and 6913 patients with CAD. 4346 patients with AS and 6024 patients with CAD were identified by both approaches. A randomly selected sample of 200-250 patients uniquely identified by text mining was compared with 200-250 patients uniquely identified by billing codes for both diseases. We demonstrate that text mining was superior, with a positive predictive value (PPV) of 0.95 compared to 0.53 by ICD-9 for TAS, and a PPV of 0.97 compared to 0.86 for CAD. CONCLUSION: These results highlight the superiority of text mining algorithms applied to electronic cardiovascular procedure reports in the identification of phenotypes of interest for cardiovascular research. PMID- 28624642 TI - DrugSemantics: A corpus for Named Entity Recognition in Spanish Summaries of Product Characteristics. AB - For the healthcare sector, it is critical to exploit the vast amount of textual health-related information. Nevertheless, healthcare providers have difficulties to benefit from such quantity of data during pharmacotherapeutic care. The problem is that such information is stored in different sources and their consultation time is limited. In this context, Natural Language Processing techniques can be applied to efficiently transform textual data into structured information so that it could be used in critical healthcare applications, being of help for physicians in their daily workload, such as: decision support systems, cohort identification, patient management, etc. Any development of these techniques requires annotated corpora. However, there is a lack of such resources in this domain and, in most cases, the few ones available concern English. This paper presents the definition and creation of DrugSemantics corpus, a collection of Summaries of Product Characteristics in Spanish. It was manually annotated with pharmacotherapeutic named entities, detailed in DrugSemantics annotation scheme. Annotators were a Registered Nurse (RN) and two students from the Degree in Nursing. The quality of DrugSemantics corpus has been assessed by measuring its annotation reliability (overall F=79.33% [95%CI: 78.35-80.31]), as well as its annotation precision (overall P=94.65% [95%CI: 94.11-95.19]). Besides, the gold-standard construction process is described in detail. In total, our corpus contains more than 2000 named entities, 780 sentences and 226,729 tokens. Last, a Named Entity Classification module trained on DrugSemantics is presented aiming at showing the quality of our corpus, as well as an example of how to use it. PMID- 28624643 TI - Automated detection of records in biological sequence databases that are inconsistent with the literature. AB - We investigate and analyse the data quality of nucleotide sequence databases with the objective of automatic detection of data anomalies and suspicious records. Specifically, we demonstrate that the published literature associated with each data record can be used to automatically evaluate its quality, by cross-checking the consistency of the key content of the database record with the referenced publications. Focusing on GenBank, we describe a set of quality indicators based on the relevance paradigm of information retrieval (IR). Then, we use these quality indicators to train an anomaly detection algorithm to classify records as "confident" or "suspicious". Our experiments on the PubMed Central collection show assessing the coherence between the literature and database records, through our algorithms, is an effective mechanism for assisting curators to perform data cleansing. Although fewer than 0.25% of the records in our data set are known to be faulty, we would expect that there are many more in GenBank that have not yet been identified. By automated comparison with literature they can be identified with a precision of up to 10% and a recall of up to 30%, while strongly outperforming several baselines. While these results leave substantial room for improvement, they reflect both the very imbalanced nature of the data, and the limited explicitly labelled data that is available. Overall, the obtained results show promise for the development of a new kind of approach to detecting low quality and suspicious sequence records based on literature analysis and consistency. From a practical point of view, this will greatly help curators in identifying inconsistent records in large-scale sequence databases by highlighting records that are likely to be inconsistent with the literature. PMID- 28624644 TI - Psychiatric symptom recognition without labeled data using distributional representations of phrases and on-line knowledge. AB - OBJECTIVE: Mental health is becoming an increasingly important topic in healthcare. Psychiatric symptoms, which consist of subjective descriptions of the patient's experience, as well as the nature and severity of mental disorders, are critical to support the phenotypic classification for personalized prevention, diagnosis, and intervention of mental disorders. However, few automated approaches have been proposed to extract psychiatric symptoms from clinical text, mainly due to (a) the lack of annotated corpora, which are time-consuming and costly to build, and (b) the inherent linguistic difficulties that symptoms present as they are not well-defined clinical concepts like diseases. The goal of this study is to investigate techniques for recognizing psychiatric symptoms in clinical text without labeled data. Instead, external knowledge in the form of publicly available "seed" lists of symptoms is leveraged using unsupervised distributional representations. MATERIALS AND METHODS: First, psychiatric symptoms are collected from three online repositories of healthcare knowledge for consumers-MedlinePlus, Mayo Clinic, and the American Psychiatric Association-for use as seed terms. Candidate symptoms in psychiatric notes are automatically extracted using phrasal syntax patterns. In particular, the 2016 CEGS N-GRID challenge data serves as the psychiatric note corpus. Second, three corpora psychiatric notes, psychiatric forum data, and MIMIC II-are adopted to generate distributional representations with paragraph2vec. Finally, semantic similarity between the distributional representations of the seed symptoms and candidate symptoms is calculated to assess the relevance of a phrase. Experiments were performed on a set of psychiatric notes from the CEGS N-GRID 2016 Challenge. RESULTS & CONCLUSION: Our method demonstrates good performance at extracting symptoms from an unseen corpus, including symptoms with no word overlap with the provided seed terms. Semantic similarity based on the distributional representation outperformed baseline methods. Our experiment yielded two interesting results. First, distributional representations built from social media data outperformed those built from clinical data. And second, the distributional representation model built from sentences resulted in better representations of phrases than the model built from phrase alone. PMID- 28624645 TI - Cingulo-opercular activity affects incidental memory encoding for speech in noise. AB - Correctly understood speech in difficult listening conditions is often difficult to remember. A long-standing hypothesis for this observation is that the engagement of cognitive resources to aid speech understanding can limit resources available for memory encoding. This hypothesis is consistent with evidence that speech presented in difficult conditions typically elicits greater activity throughout cingulo-opercular regions of frontal cortex that are proposed to optimize task performance through adaptive control of behavior and tonic attention. However, successful memory encoding of items for delayed recognition memory tasks is consistently associated with increased cingulo-opercular activity when perceptual difficulty is minimized. The current study used a delayed recognition memory task to test competing predictions that memory encoding for words is enhanced or limited by the engagement of cingulo-opercular activity during challenging listening conditions. An fMRI experiment was conducted with twenty healthy adult participants who performed a word identification in noise task that was immediately followed by a delayed recognition memory task. Consistent with previous findings, word identification trials in the poorer signal-to-noise ratio condition were associated with increased cingulo-opercular activity and poorer recognition memory scores on average. However, cingulo opercular activity decreased for correctly identified words in noise that were not recognized in the delayed memory test. These results suggest that memory encoding in difficult listening conditions is poorer when elevated cingulo opercular activity is not sustained. Although increased attention to speech when presented in difficult conditions may detract from more active forms of memory maintenance (e.g., sub-vocal rehearsal), we conclude that task performance monitoring and/or elevated tonic attention supports incidental memory encoding in challenging listening conditions. PMID- 28624646 TI - Instantaneous voltage as an alternative to power- and phase-based interpretation of oscillatory brain activity. AB - For decades, oscillatory brain activity has been characterized primarily by measurements of power and phase. While many studies have linked those measurements to cortical excitability, their relationship to each other and to the physiological underpinnings of excitability is unclear. The recently proposed Function-through-Biased-Oscillations (FBO) hypothesis (Schalk, 2015) addressed these issues by suggesting that the voltage potential at the cortical surface directly reflects the excitability of cortical populations, that this voltage is rhythmically driven away from a low resting potential (associated with depolarized cortical populations) towards positivity (associated with hyperpolarized cortical populations). This view explains how oscillatory power and phase together influence the instantaneous voltage potential that directly regulates cortical excitability. This implies that the alternative measurement of instantaneous voltage of oscillatory activity should better predict cortical excitability compared to either of the more traditional measurements of power or phase. Using electrocorticographic (ECoG) data from 28 human subjects, the results of our study confirm this prediction: compared to oscillatory power and phase, the instantaneous voltage explained 20% and 31% more of the variance in broadband gamma, respectively, and power and phase together did not produce better predictions than the instantaneous voltage. These results synthesize the previously separate power- and phase-based interpretations and associate oscillatory activity directly with a physiological interpretation of cortical excitability. This alternative view has implications for the interpretation of studies of oscillatory activity and for current theories of cortical information transmission. PMID- 28624647 TI - Comparison of Endoscopic Ultrasound-Fine-Needle Aspiration and Endoscopic Ultrasound-Fine-Needle Biopsy for Solid Lesions in a Multicenter, Randomized Trial. AB - BACKGROUND & AIMS: Endoscopic ultrasound with fine-needle aspiration (FNA) is the standard of care for tissue sampling of solid lesions adjacent to the gastrointestinal tract. Fine-needle biopsy (FNB) may provide higher diagnostic yield with fewer needle passes. The aim of this study was to assess the difference in diagnostic yield between FNA and FNB. METHODS: This is a multicenter, prospective randomized clinical trial from 6 large tertiary care centers. Patients referred for tissue sampling of solid lesions were randomized to either FNA or FNB of the target lesion. Demographics, size, location, number of needle passes, and final diagnosis were recorded. RESULTS: After enrollment, 135 patients were randomized to FNA (49.3%), and 139 patients were randomized to FNB (50.7%).The following lesions were sampled: mass (n = 210, 76.6%), lymph nodes (n = 46, 16.8%), and submucosal tumors (n = 18, 6.6%). Final diagnosis was malignancy (n = 192, 70.1%), reactive lymphadenopathy (n = 30, 11.0%), and spindle cell tumors (n = 24, 8.8%). FNA had a diagnostic yield of 91.1% compared with 88.5% for FNB (P = .48). There was no difference between FNA and FNB when stratified by the presence of on-site cytopathology or by type of lesion sampled. A median of 1 needle pass was needed to obtain a diagnostic sample for both needles. CONCLUSIONS: FNA and FNB obtained a similar diagnostic yield with a comparable number of needle passes. On the basis of these results, there is no significant difference in the performance of FNA compared with FNB in the cytologic diagnosis of solid lesions adjacent to the gastrointestinal tract. ClinicalTrials.gov identifier: NCT01698190. PMID- 28624648 TI - Lifestyle Behavior Change in Patients With Nonalcoholic Fatty Liver Disease: A Qualitative Study of Clinical Practice. PMID- 28624649 TI - Diffuse Enlargement of the Pancreas: An Unusual Radiologic Presentation of a Pancreatic Neuroendocrine Tumor. PMID- 28624650 TI - Colon Pathology Characteristics in Li-Fraumeni Syndrome. PMID- 28624651 TI - Efficacy and Optimal Duration of Metallic Stent in the Management of Refractory Anastomotic Stricture After Liver Transplantation. AB - BACKGROUND & AIMS: Anastomotic bile duct stricture (ABS) remains as one of the most common complications in liver transplant patients. Current practice of endoscopic retrograde cholangiopancreatography (ERCP) with insertion of plastic stent often requires multiple procedures before achieving stricture resolution. To date, studies using covered self-expandable metallic stent (cSEMS) in ABS management reported varying degrees of efficacy. The aim of this study was to analyze long-term efficacy of cSEMS in patients with ABS and identify factor(s) influencing the probability of stricture resolution. METHODS: Liver transplant patients with ABS who received cSEMS were identified by query of our endoscopic database. The rate of stricture resolution, duration of stricture-free interval, factors associated with stricture resolution, and adverse outcomes were analyzed. RESULTS: Among 44 liver transplant patients with refractory ABS who underwent ERCP-cSEMS, stricture resolution was observed in 33 patients (75%). Longer duration of cSEMS insertion was the only variable associated with increasing probability of stricture resolution. There was 20% increase in odds of stricture resolution for every additional week cSEMS was in place. Among 33 patients with initial stricture resolution, 26 patients (78.8%) maintained bile duct patency throughout the follow-up period. The most common adverse outcome was internal migration of cSEMS, which occurred in 11 patients (25%). CONCLUSIONS: The rate of ABS resolution observed with cSEMS placement in a single ERCP session appears to be comparable with that of multiple ERCPs with plastic stent placement reported previously. Longer stent insertion period is associated with higher likelihood of ABS resolution. PMID- 28624652 TI - Association of Transferrin Saturation With the Arthropathy of Hereditary Hemochromatosis. PMID- 28624653 TI - Giant Ring Mitochondria in a Patient With Heart Failure and Cerebral White Matter Disease Resulting From an MT-TL1 Mitochondrial Gene Mutation. AB - BACKGROUND: The presence of giant ring mitochondria on endomyocardial biopsy is rarely reported and does not have a well-defined differential diagnosis. METHODS: We report the case of a 54-year-old man with heart failure and preserved ejection fraction and left ventricular hypertrophy, initially thought to have an infiltrative cardiomyopathy. RESULTS: The patient was found to have extensive vacuolization caused by giant ring mitochondria on endomyocardial biopsy. Mitochondrial genetic testing revealed an A3243G mutation in the MT-TL1 gene, which is a mitochondrial encoded transfer RNA-leucine molecule. CONCLUSIONS: Mitochondrial disease should be considered in patients presenting with unexplained cardiomyopathy and skeletal muscle, cerebral, or metabolic abnormalities. In this case, the presence of unexpected extensive cardiomyocyte vacuolization and giant, ring-shaped mitochondria on endomyocardial biopsy prompted mitochondrial genetic testing, which ultimately resulted in the correct diagnosis and treatment. PMID- 28624654 TI - Insulin signaling: An opportunistic target to minify the risk of Alzheimer's disease. AB - Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by accumulation of senile plaques, neurofibrillary tangles (NFT) and neurodegeneration. The diabetes mellitus (DM) is one of the risk factors for AD pathogenesis by impairment in insulin signaling and glucose metabolism in central as well as peripheral system. Insulin resistance, impaired glucose and lipid metabolism are leading to the Abeta (Abeta) aggregation, Tau phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, memory impairment and also mark over Abeta transport through central to peripheral and vice versa. Several pathways, like enzymatic degradation of Abeta, forkhead box protein O1 (FOXO) signaling, insulin signaling shared common pathological mechanism for both AD and DM. Recent evidence showed that hyperinsulinemia and hyperglycemia affect the onset and progression of AD differently. Some researchers have suggested that hyperglycemia influences vascular tone, while hyperinsulinemia may underlie mitochondrial deficit. The objective of this review is to determine whether existing evidence supports the concept that impairment in insulin signaling and glucose metabolism play an important role in pathogenesis of AD. In the first part of this review, we tried to explain the interconnecting link between AD and DM, whereas the second part includes more information on insulin resistance and its involvement in AD pathogenesis. In the final part of this review, we have focused more toward the AD treatment by targeting insulin signaling like anti-diabetic, antioxidant, nutraceuticals and dietary supplements. To date, more researches should be done in this field in order to explore the pathways in insulin signaling, which might ameliorate the treatment options and reduce the risk of AD due to DM. PMID- 28624655 TI - Biological responses to M13 bacteriophage modified titanium surfaces in vitro. AB - : Phage-based materials have showed great potential in tissue engineering application. However, it is unknown what inflammation response will happen to this kind of materials. This work is to explore the biological responses to M13 bacteriophage (phage) modified titanium surfaces in vitro from the aspects of their interaction with macrophages, osteoblasts and mineralization behavior. Pretreated Ti surface, Ti surfaces with noncrosslinked phage film (APP) and crosslinked phage film (APPG) were compared. Phage films could limit the macrophage adhesion and activity due to inducing adherent-cell apoptosis. The initial inflammatory activity (24h) caused by phage films was relatively high with more production of TNF-alpha, but in the later stage (7-10days) inflammatory response was reduced with lower TNF-alpha, IL-6 and higher IL-10. In addition, phage films improved osteoblast adhesion, differentiation, and hydroapatite (HA) forming via a combination of topographical and biochemcial cues. The noncrosslinked phage film displayed the best immunomodulatory property, osteogenic activity and HA mineralization ability. This work provides better understanding of inflammatory and osteogenetic activity of phage-based materials and contributes to their future application in tissue engineering. STATEMENT OF SIGNIFICANCE: In vivo, the bone and immune cells share a common microenvironment, and are being affected by similar cytokines, signaling molecules, transcription factors and membrane receptors. Ideal implants should cause positive biological response, including adequate and appropriate inflammatory reaction, well-balanced bone formation and absorption. Phage-based materials have showed great potential in tissue engineering application. However, at present it is unknown what inflammation response will happen to this kind of materials. A good understanding of the immune response possibly induced by phage-based materials is needed. This work studied the osteoimmunomodulation property of phage films on titanium surface, involving inflammatory response, osteogenic activity and biomineralization ability. It provides more understanding of the phage-based materials and contributes to their future application in tissue engineering. PMID- 28624656 TI - Strontium- and cobalt-substituted bioactive glasses seeded with human umbilical cord perivascular cells to promote bone regeneration via enhanced osteogenic and angiogenic activities. AB - : Designing and developing new biomaterials to accelerate bone healing are currently under progress. In this study, we attempted to promote osteogenesis using strontium- and cobalt-substituted bioactive glasses (BGs) seeded with human umbilical cord perivascular cells (HUCPVCs) in a critical size defect in the distal femur of rabbit animal model. The BG particles were successfully synthesized in the form of granules using the melt-derived route. After being isolated, HUCPVCs were expanded and then characterized to use during in vitro and in vivo procedures. The in vitro effects of the synthesized glasses on the isolated HUCPVCs as well as on cell lines SaOS-2 (selected for screening the osteogenetic potential) and HUVEC (selected for screening the angiogenic potential) were assessed by analyzing cytotoxicity, cell attachment, bone-like nodule formation, and real time PCR. The results of in vitro tests indicated cytocompatibility of the synthesized BG particles. For in vivo study, the HUCPVCs seeded BGs were implanted into the animal's body. Radiographic imaging, histology and immunohistology staining were performed on the harvested specimens at 4 and 12weeks post-surgery. The in vivo evaluation of the samples showed that all the cell/glass constructs accelerated bone healing process in comparison with blank controls. The best in vitro and in vivo results were associated to the BGs containing both strontium and cobalt ions. This group of bioactive glasses is able to promote both osteogenesis and angiogenesis and can therefore be highly suitable for the development of advanced functional bone substitutes. STATEMENT OF SIGNIFICANCE: Bone regeneration is considered as an unmet clinical need. The most recent researches focused on incorporation of strontium (Sr2+) and cobalt (Co2+) ions into bioactive glasses structure. Strontium is an alkaline earth metal which is currently used in the treatment of osteoporosis. Also, cobalt is considered as another promising element in the bone regeneration field that may induce hypoxia-mediated angiogenesis. In this study, the osteogenic potential of the strontium- and cobalt-substituted bioactive glasses in granule form seeded with human umbilical cord perivascular cells (HUCPVCs) was evaluated in vitro and in vivo. Indeed, the main goal of this study was to improve the osteogenenic and angiogenic properties of bioactive glasses through the incorporation of strontium and cobalt ions in the glass composition. Although some researches have been conducted on this subject, the influence of the simultaneous use of strontium and cobalt ions on the improvement of bone healing in vivo has been not yet well understood and, therefore, deserves further investigation. PMID- 28624657 TI - Adiponectin improves the osteointegration of titanium implant under diabetic conditions by reversing mitochondrial dysfunction via the AMPK pathway in vivo and in vitro. AB - : Diabetes-induced reactive oxygen species (ROS) overproduction would result in compromised osteointegration of titanium implant (TI) and high rate of implant failure, yet the underlying mechanisms remain elusive. Adiponectin (APN) is a fat derived adipocytokine with strong antioxidant, mitochondrial-protective and anti diabetic efficacies. We hypothesized that mitochondrial dysfunction under diabetes may account for the oxidative stress in osteoblasts and titanium-bone interface (TBI) instability, which could be ameliorated by APN. To test this hypothesis, we incubated primary rat osteoblasts on TI and tested the cellular behaviors when subjected to normal milieu (NM), diabetic milieu (DM), DM+APN, DM+AICAR (AMPK activator) and DM+APN+Compound C (AMPK inhibitor). In vivo, APN or APN+Compound C were administered to diabetic db/db mice with TI implanted in their femurs. Results showed that diabetes induced structural damage, dysfunction and content decrease of mitochondria in osteoblasts, which led to ROS overproduction, dysfunction and apoptosis of osteoblasts accompanied by the inhibition of AMPK signaling. APN alleviated the mitochondrial damage by activating AMPK, thus reversing osteoblast impairment and improving the osteointegration of TI evidenced by Micro-CT and histological analysis. Furthermore, AICAR showed beneficial effects similar to APN treatment, while the protective effects of APN were abolished when AMPK activation was blocked by Compound C. This study clarifies mitochondrial dysfunction as a crucial mechanism in the impaired bone healing and implant loosening in diabetes, and provides APN as a novel promising active component for biomaterial-engineering to improve clinical performance of TI in diabetic patients. STATEMENT OF SIGNIFICANCE: The loosening rate of titanium implants in diabetic patients is high. The underlying mechanisms remain elusive and, with the rapid increase of diabetic morbility, efficacious strategies to mitigate this problem have become increasingly important. Our study showed that the mitochondrial impairment and the consequent oxidative stress in osteoblasts at the titanium-bone interface (TBI) play a critical role in the diabetes-induced poor bone repair and implant destabilization, which could become therapeutic targets. Furthermore, adiponectin, a cytokine, promotes the bio-functional recovery of osteoblasts and bone regeneration at the TBI in diabetes. This provides APN as a novel bioactive component used in material-engineering to promote the osteointegration of implants, which could reduce implant failure, especially for diabetic patients. PMID- 28624658 TI - Optimisation of HPMC ophthalmic inserts with sustained release properties as a carrier for thermolabile therapeutics. AB - A methodology was developed and optimised for the preparation of a new drug delivery system (DDS) with sustained release properties to allow ocular protein delivery and to limit destructive production steps during manufacturing. Elevated temperatures, shear forces and an oxidative environment should be avoided in order to prevent denaturation or oxidation of proteins. An aqueous HPMC solution was prepared using heat and casted into small semi-rod-shaped PVC blisters. The polymer solution was allowed to cool down and was partially dehydrated at room temperature. A drug solution containing glycerol, drug and water was subsequently added to rehydrate the partially dehydrated polymer matrix at a temperature of 2 degrees C. Several parameters of the production process were varied to determine their influence on the release kinetics from HPMC inserts from three different molecules of different molecular weight. This production method was further optimised in order to shorten the rehydration time from weeks to days, while eliminating heat and shear forces on the selected drug molecules sodium fluorescein, lysozyme and albumin. Slow release kinetics were achieved for sodium fluorescein and lysozyme as model drug molecules. The higher molecular weight of albumin prevented a good penetration into the insert during the rehydration process resulting in predominantly burst release. The biocompatibility of a viscous HPMC solution was evaluated on SV40-human corneal epithelial cells with PrestoBlue(r) and no cytotoxic effects were observed. PMID- 28624659 TI - Surface engineering of Solid Lipid Nanoparticle assemblies by methyl alpha-d mannopyranoside for the active targeting to macrophages in anti-tuberculosis inhalation therapy. AB - This study describes the development of new mannosylated Solid Lipid Nanoparticle assemblies (SLNas) delivering rifampicin for an inhaled treatment of tuberculosis. SLNas were surface engineered with mannose residues to recognize mannose receptors located on infected alveolar macrophages and facilitate cell internalization. Two sets of SLNas were produced by the melt emulsifying technique using biocompatible lipid components, i.e. cholesteryl myristate combined with palmitic acid (PA set) or tripalmitin (TP set), in the presence of the targeting moiety, methyl alpha-d-mannopyranoside. Mannosylated SLNas were examined for their physical properties, drug payloads and release, as well as respirability in terms of emitted dose and respirable fraction determined by Next Generation Impactor. The most appropriate formulations were assessed for mannosylation using FTIR, XPS, SEM coupled with EDX analysis, and wettability assay, in comparison with the respective non-functionalized SLNas. Besides, cytotoxicity and cell internalization ability were established on J774 murine macrophage cell line. Mannosylated SLNas exhibited physical properties suitable for alveolar macrophage passive targeting, adequate rifampicin payloads (10-15%), and feasible drug maintenance within SLNas along the respiratory tract before macrophage internalization. Despite respirability impaired by powder cohesiveness, surface mannosylation provided quicker macrophage phagocytosis, giving evidence of an active targeting promotion. PMID- 28624660 TI - Comparative study on radiolabeling and biodistribution of core-shell silver/polymeric nanoparticles-based theranostics for tumor targeting. AB - A simple and rapid method for radiolabeling of three types of Ag NPs has been performed using 125I isotope, with high labeling yields, >90% without disturbing the optical properties. All the factors affecting labeling yield were studied. In order to monitor the in-vivo tissue uptake of radiolabeled Ag NPs using gamma rays, Ag-based radioiodo-NPs with a maximum labeling yield were intravenously injected in normal and solid tumor bearing mice. The preliminary biodistribution study revealed that this new radioiodo-NPs have a high affinity to be localized in the tumor site for a long period of time. The reported highly efficient method provides new radiolabeled Ag-based NPs as tumor-specific agents for both diagnostic and therapeutic applications. PMID- 28624661 TI - Targeting human liver cancer cells with lactobionic acid-G(4)-PAMAM-FITC sorafenib loaded dendrimers. AB - Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R. PMID- 28624662 TI - A mucosa-mimetic material for the mucoadhesion testing of thermogelling semi solids. AB - Mucosa-mimetic materials are synthetic substrates which aim to replace animal tissue in mucoadhesion experiments. One potential mucosa-mimetic material is a hydrogel comprised of N-acryloyl-d-glucosamine and 2-hydroxyethylmethacrylate, which has been investigated as a surrogate for animal mucosae in the mucoadhesion testing of tablets and solution formulations. This study aims to investigate the efficacy of this mucosa-mimetic material in the testing of thermogelling semi solid formulations, which transition from solution to gel upon warming. Two methods for assessing mucoadhesion have been used; tensile testing and a flow through system, which allow for investigation under dramatically different conditions. It was found that the mucosa-mimetic material was a good surrogate for buccal mucosa using both testing methods. This material may be used to replace animal tissue in these experiments, potentially reducing the number of laboratory animals used in studies of this type. PMID- 28624663 TI - Role of exercise electrocardiogram to screen for T-wave oversensing after implantation of subcutaneous implantable cardioverter-defibrillator. AB - BACKGROUND: During early experience with subcutaneous implantable cardioverter defibrillators (S-ICD), several patients had inappropriate shocks from T-wave oversensing (TWOS) during exercise. This prompted some operators to perform routine treadmill exercise tests after implantation of S-ICD to screen for TWOS. Meanwhile, improvements have been made in the detection algorithms by the manufacturer. OBJECTIVE: To assess whether routine treadmill exercise post S-ICD implantation is warranted. METHODS: Patients undergoing S-ICD implantation from October 2012 to December 2016 who were able to complete a treadmill exercise were included in the study. The amplitude of R and T waves as assessed by the device programmer at rest and peak exercise was calculated and incidence of TWOS recorded. RESULTS: Eighty-seven patients with complete treadmill exercise test data were included in the final analysis. The majority of the patients received S ICD for primary prevention. Nine percent of the included patients had hypertrophic obstructive cardiomyopathy. During treadmill exercise, there was significant increase in the heart rate from rest (77 +/- 14 beats per minute) to peak exercise (133 +/- 14 beats per minute; P < .0001). There was no significant difference between R-wave amplitude at rest (2 +/- 0.77 mV) and peak exercise (1.88 +/- 0.94 mV; P = .36). Similarly, there was no significant difference between T-wave amplitude at rest (0.27 +/- 0.19 mV) and peak exercise (0.33 +/- 0.23 mV; P = .06). The incidence of TWOS during exercise was zero. CONCLUSIONS: With current screening and detection algorithms for S-ICD, routine treadmill exercise does not result in additional discrimination of patients susceptible to TWOS. PMID- 28624665 TI - Protecting the Public: An Investigation of Midwives Perceptions of Regulation and the Regulator. AB - OBJECTIVE: to investigate the perceptions of a group of midwifery registrants about the influence of regulation and the regulatory body, the Nursing and Midwifery Council, on the practice of midwives in the United Kingdom DESIGN: quantitative and qualitative research using an online survey and semi-structured interviews SETTING: The South East of England, which covers both urban and rural practice settings. PARTICIPANTS: (a) 132 (n=70%) midwives responded to the online survey, and (b) 20 midwives participated in the semi-structured interviews FINDINGS: midwives were generally supportive of the need to regulate practice; however, some participants had an uneasy relationship with the Nursing and Midwifery Council and claimed to practice defensively, due to a fear that they could be removed from the register, and believed the regulator to be remote and punitive. For other participants concerns were raised about fitness to practice procedures, particularly in terms of decision-making. KEY CONCLUSIONS: the participants felt that in order for midwifery regulation to be effective the regulator needs to have detailed knowledge and appreciation of the role of the midwife, and the needs of the pregnant woman. PMID- 28624664 TI - Surgical Outcomes of Urinary Tract Deep Infiltrating Endometriosis. AB - OBJECTIVE: To report the outcomes of surgical management of urinary tract endometriosis. DESIGN: Retrospective study based on prospectively recorded data (NCT02294825) (Canadian Task Force classification II-3). SETTING: University tertiary referral center. PATIENTS: Eighty-one women treated for urinary tract endometriosis between July 2009 and December 2015 were included, including 39 with bladder endometriosis, 31 with ureteral endometriosis, and 11 with both ureteral and bladder endometriosis. Owing to bilateral ureteral localization in 8 women, 50 different ureteral procedures were recorded. INTERVENTION: Procedures performed included resection of bladder endometriosis nodules, advanced ureterolysis, ureteral resection followed by end-to-end anastomosis, and ureteroneocystostomy. MEASUREMENTS AND MAIN RESULTS: The main outcome measure was the outcome of the surgical management of urinary tract endometriosis. Fifty women presented with deep infiltrating endometriosis (DIE) of the bladder and underwent either full-thickness excision of the nodule (70%) or excision of the bladder wall without opening of the bladder (30%). Ureteral lesions were treated by ureterolysis in 78% of the patients and by primary segmental resection in 22%. No patient required nephrectomy. Histological analysis revealed intrinsic ureteral endometriosis in 54.5% of cases. Clavien-Dindo grade III complications were present in 16% of the patients who underwent surgery for ureteral nodules and in 8% of those who underwent surgery for bladder endometriosis. Overall delayed postoperative outcomes were favorable regarding urinary symptoms and fertility. Patients were followed up for a minimum of 12 months and a maximum of 7 years postoperatively, with no recorded recurrences. CONCLUSION: Surgical outcomes of urinary tract endometriosis are generally satisfactory; however, the risk of postoperative complications should be taken into consideration. Therefore, all such procedures should be managed by an experienced multidisciplinary team. PMID- 28624667 TI - Schwannoma and neurofibroma of the posterior tibial nerve presenting as tarsal tunnel syndrome: review of the literature with two case reports. AB - We present two case reports of peripheral nerve tumors (schwannoma and neurofibroma) that presented as tarsal tunnel syndrome for many years. There has never been a report of multiple neurofibroma of the posterior tibial nerve presenting as a tarsal tunnel syndrome. Both patients were treated surgically with good outcomes. PMID- 28624666 TI - The nuclear pore complex core scaffold and permeability barrier: variations of a common theme. AB - The study of the nuclear pore complex (NPC) is a fascinating endeavor, as it not only implies uncovering the 'engineering marvel' of its architecture and function, but also provides a key window into a significant evolutionary event: the origin of the eukaryotic cell. The combined efforts of many groups in the field, with the help of novel methodologies and new model organisms, are facilitating a much deeper understanding of this complex assembly. Here we cover recent advances on the characterization of the structure of the NPC scaffold and of the biophysical mechanisms that define the permeability barrier. We identify common architectural and functional principles between those two NPC compartments, expanding the previous protocoatomer hypothesis to suggest possible evolutionary origins for the FG nucleoporins and the NPC permeability barrier. PMID- 28624668 TI - KCNQ1 gene polymorphism is associated with glycaemic response to treatment with DPP-4 inhibitors. AB - AIMS: Only afew gene variants were associated with the response to dipeptidylpeptidase-4 inhibitors (DPP4I). KCNQ1 gene variants were previously related both to type 2 diabetes (T2D) and incretin effect. We hypothesized that T2D related KCNQ1 variants would be associated with smaller glucose-lowering effect of DDP4I. METHODS: We performed a retrospective study in 137 Caucasian subjects with T2D who were followed for 6months after initiation of DPP4I treatment. Genotyping for KCNQ1 rs163184 and rs151290 was performed using PCR HRMA and PCR-RFLP methods, respectively. The main clinical outcome was reduction in HbA1c (DeltaHbA1c) after 6-month DPP4I treatment. RESULTS: KCNQ1 rs163184 T>G variant was associated with the response to DPP4I treatment in genetic additive model (beta=-0.30, p=0.022). For each G allele in the rs163184 genotype, we observed a 0.3% (3.3mmol/mol) less reduction in HbA1c during treatment with a DPP4I. Both the GG homozygotes and G-allele carriers had significantly smaller HbA1c reduction in comparison with the TT homozygotes. CONCLUSIONS: KCNQ1 rs163184 T>G variant was associated with a reduced glycaemic response to DPP4I. The difference of 0.6% (6.5mmol/mol) in HbA1c reduction between the TT and GG homozygotes might be of clinical significance if replicated in further studies. PMID- 28624669 TI - Neutron-activatable radionuclide cancer therapy using graphene oxide nanoplatelets. AB - Neutron-activation is a promising method of generating radiotherapeutics with minimal handling of radioactive materials. Graphene oxide nanoplatelets (GONs) were examined as a carrier for neutron-activatable holmium with the purpose of exploiting inherent characteristics for theranostic application. GONs were hypothesized to be an ideal candidate for this application owing to their desirable characteristics such as a rigid structure, high metal loading capacity, low density, heat resistance, and the ability to withstand harsh environments associated with the neutron-activation process. Non-covalently PEGylated GONs (GONs-PEG) offered enhanced dispersibility and biocompatibility, and also exhibited increased holmium loading capacity nearly two-fold greater than GONs. Holmium leaching was investigated over a wide pH range, including conditions that mimic the tumor microenvironment, following neutron irradiation. The in vitro cell-based cytotoxicity analysis of GONs-based formulations with non-radioactive holmium confirmed their safety profile within cells. The results demonstrate the potential of GONs as a carrier of neutron-activatable radiotherapeutic agents. PMID- 28624671 TI - Radiation exposure of barley seeds can modify the early stages of plants' development. AB - The reactions of barley seeds (Nur and Grace varieties) in terms of the root and sprout lengths, germination and root mass were studied after gamma-irradiation with doses in the range of 2-50 Gy. The dose range in which plants' growth stimulation occurs (16-20 Gy) was identified. It was shown that increased size of seedlings after irradiation with stimulating doses was due to the enhancing pace of development rather than an earlier germination. The activity of the majority of the enzymes studied increased in the range of doses that cause stimulation of seedlings development. The influences of the dose rate, the quality of seeds, their moisture and time interval between irradiation and initiation of germination on the manifestation of the effects of radiation were investigated. The experimental data on the effect of gamma-irradiation on seedlings development were significantly better explained by mathematical models that take into account the hormetic effect. PMID- 28624670 TI - Towards engineering of hormonal crosstalk in plant immunity. AB - Plant hormones regulate physiological responses in plants, including responses to pathogens and beneficial microbes. The last decades have provided a vast amount of evidence about the contribution of different plant hormones to plant immunity, and also of how they cooperate to orchestrate immunity activation, in a process known as hormone crosstalk. In this review we highlight the complexity of hormonal crosstalk in immunity and approaches currently being used to further understand this process, as well as perspectives to engineer hormone crosstalk for enhanced pathogen resistance and overall plant fitness. PMID- 28624672 TI - Analysis of fire deaths in Poland and influence of smoke toxicity. AB - Dwelling fires have changed over the years because building contents and the materials used in then have changed. They all contribute to an ever-growing diversity of chemical species found in fires, many of them highly toxic. These arise largely from the changing nature of materials in interior finishes and furniture, with an increasing content of synthetic materials containing higher levels of nitrogen, halogen and phosphorus additives. While there is still a belief that carbon monoxide is the major lethal toxic agent in fires, the hydrogen cyanide and acid gases released from these additives are now well recognised as major contributory causes of incapacitation, morbidity and mortality in domestic fires. Data for the total number of 263 fire death cases in the Mazowieckie region (mainly Warsaw area) of Poland between 2003-2011 for dwellings fires were obtained from pathologists, forensic toxicologists, fire fighters and analysed. Factors contributing to the death such as the findings of the full post mortem examination (age, sex, health status, burns), the toxicological analysis (carbon monoxide, alcohol etc.), and a thorough investigation of the scene (fire conditions, fuel, etc.) were taken into account and are summarised. PMID- 28624673 TI - A geographical analysis of trafficking on a popular darknet market. AB - Cryptomarkets are online marketplaces, located on the darknet, that facilitate the trading of a variety of illegal goods, mostly drugs. While the literature essentially focus on drugs, various other goods and products related to financial or identity fraud, firearms, counterfeit goods, as well as doping products are also offered on these marketplaces. Through the analysis of relevant data collected on a popular marketplace in 2014-2015, Evolution, this research provides an analysis of the structure of trafficking (types and proportions of products, number of vendors and shipping countries). It also aims at highlighting geographical patterns in the trafficking of these products (e.g. trafficking flows, specialisation of vendors and assessment of their role in the distribution chain). The analysis of the flow of goods between countries emphasises the role of specific countries in the international and domestic trafficking, potentially informing law enforcement agencies to target domestic mails or international posts from specific countries. The research also highlights the large proportion of licit and illicit drug listings and vendors on Evolution, followed by various fraud issues (in particular, financial fraud), the sharing of knowledge (tutorials) and finally goods, currencies and precious metals (principally luxury goods). Looking at the shipping country, there seems to be a clear division between digital and physical products, with more specific information for physical goods. This reveals that the spatial analysis of trafficking is particularly meaningful in the case of physical products (such as illicit drugs) and to a lesser extent for digital products. Finally, the geographical analysis reveals that spatial patterns on Evolution tend to reflect the structure of the traditional illicit market. However, regarding illicit drugs, country-specificity has been observed and are presented in this article. PMID- 28624674 TI - Investigating the association between emotion regulation and distress in adults with psychotic-like experiences. AB - Many individuals in the general population experience psychotic-like experiences in the absence of a psychotic disorder. The degree of psychological distress associated with these experiences is a key predictor of clinical outcomes. One factor that may influence the degree of distress from psychotic-like experiences is emotion regulation. Although it has been demonstrated that emotion regulation deficits are present in psychotic disorders, the association between emotion regulation and subclinical psychotic-like experiences is not well understood. Here, we examined the associations between frequency of and distress from psychotic-like experiences and several key components of emotion regulation: difficulties with emotion regulation; emotion regulation self-efficacy; and emotion regulation strategy use. Difficulties with emotion regulation and maladaptive patterns of emotion regulation strategy use were associated with the frequency of both positive and negative psychotic-like experiences. In addition, results suggest that habitual acceptance use and reappraisal self-efficacy may serve as protective factors against the distress associated with psychotic-like experiences. PMID- 28624675 TI - Relationship between cognitive emotion regulation, social support, resilience and acute stress responses in Chinese soldiers: Exploring multiple mediation model. AB - The current study aimed to explore the association of cognitive emotion regulation, social support, resilience and acute stress responses in Chinese soldiers and to understand the multiple mediation effects of social support and resilience on the relationship between cognitive emotion regulation and acute stress responses. A total of 1477 male soldiers completed mental scales, including the cognitive emotion regulation questionnaire-Chinese version, the perceived social support scale, the Chinese version of the Connor-Davidson resilience scale, and the military acute stress scale. As hypothesized, physiological responses, psychological responses, and acute stress were associated with negative-focused cognitive emotion regulation, and negatively associated with positive-focused cognitive emotion regulation, social supports and resilience. Besides, positive-focused cognitive emotion regulation, social support, and resilience were significantly associated with one another, and negative-focused cognitive emotion regulation was negatively associated with social support. Regression analysis and bootstrap analysis showed that social support and resilience had partly mediating effects on negative strategies and acute stress, and fully mediating effects on positive strategies and acute stress. These results thus indicate that military acute stress is significantly associated with cognitive emotion regulation, social support, and resilience, and that social support and resilience have multiple mediation effects on the relationship between cognitive emotion regulation and acute stress responses. PMID- 28624676 TI - Predictors of daily life suicidal ideation in adults recently discharged after a serious suicide attempt: A pilot study. AB - The aims of the study are to examine the predictive role of fluctuations in daily life mood, social contexts, and behavior on subsequent suicidal ideation (SI); and to identify clinical and psychological factors associated with the general frequency of SI in a high-risk sample. The sample comprised 42 adults (73.8% female) hospitalized for a suicide attempt. Immediately following hospital discharge, they used Ecological Momentary Assessment for seven consecutive days, providing repeated measures of SI, environmental, contextual, and behavioral factors. Controlling for prior SI, a number of contextual variables were associated with subsequent SI. Being at home or at work were both associated with an increased probability of SI, while being in the home of close others, or in a festive or leisure environment decreased SI probability. Working, passive leisure and inactivity all increased the likelihood of SI. Being alone increased SI while being with close others significantly reduced this risk. Finally, no overall effect for stressful events was found but negative family events specifically were associated with increased likelihood of SI (gamma = 0.448, t = 2.255, df = 29, p < 0.05). The findings provide preliminary results regarding proximal environmental and behavioral factors associated with the occurrence of suicidal ideation in a high-risk sample. PMID- 28624677 TI - Cardiorespiratory benefits of group exercise among adults with serious mental illness. AB - This study examined cardiorespiratory fitness (CRF) among adults with serious mental illness (SMI) participating in group exercise classes. Overweight and obese adults with SMI were randomized to either a control condition or a weight management condition with group exercise classes (n = 222). Submaximal bicycle ergometry was used to assess CRF at baseline, 6 and 18 months. Those with >= 66% participation in the exercise classes had a lower heart rate response at 6 and 18 month follow-up. Participation in group exercise classes was associated with improved short and long term cardiovascular fitness among adults with SMI. PMID- 28624678 TI - The relationships between father involvement and parental acceptance on the psychological adjustment of children and adolescents: The moderating effects of clinical status. AB - This study analyzes how a child's clinical condition modifies the relationship of father involvement, parental (fathers and mothers) acceptance and the child's psychological adjustment, including the internalizing and externalizing problems. The cohort studied was composed of 226 subjects (61.94% males) with a mean age of 14.08 years, of which 113 children were from an incidental clinical sample and 113 from the general population. Both groups were matched by sex, age and family status, and the data show that the same structure of parent-child relationships that predict the child's psychological adjustment can be accepted for both the clinical and non-clinical groups of children. However, the intensity of the relationships between the variables father involvement, parental acceptance and the child's outcomes differed in function of the child's clinical status. Specifically, in the clinically-referred sample compared to non-clinical sample father involvement had a stronger effect on the children's internalizing (but not the externalizing) problems and on their global psychological adjustment via their perceived maternal acceptance. The role of father involvement in the family relationships of clinical children is discussed. This study provides important evidence to support the need for enhanced paternal participation in the intervention programs for families. PMID- 28624679 TI - Neuraminidase-based recombinant virus-like particles protect against lethal avian influenza A(H5N1) virus infection in ferrets. AB - Avian influenza A (H5N1) viruses represent a growing threat for an influenza pandemic. The presence of widespread avian influenza virus infections further emphasizes the need for vaccine strategies for control of pre-pandemic H5N1 and other avian influenza subtypes. Influenza neuraminidase (NA) vaccines represent a potential strategy for improving vaccines against avian influenza H5N1 viruses. To evaluate a strategy for NA vaccination, we generated a recombinant influenza virus-like particle (VLP) vaccine comprised of the NA protein of A/Indonesia/05/2005 (H5N1) virus. Ferrets vaccinated with influenza N1 NA VLPs elicited high-titer serum NA-inhibition (NI) antibody titers and were protected from lethal challenge with A/Indonesia/05/2005 virus. Moreover, N1-immune ferrets shed less infectious virus than similarly challenged control animals. In contrast, ferrets administered control N2 NA VLPs were not protected against H5N1 virus challenge. These results provide support for continued development of NA based vaccines against influenza H5N1 viruses. PMID- 28624680 TI - The timing of spontaneous detection and repair of naming errors in aphasia. AB - This study examined the timing of spontaneous self-monitoring in the naming responses of people with aphasia. Twelve people with aphasia completed a 615-item naming test twice, in separate sessions. Naming attempts were scored for accuracy and error type, and verbalizations indicating detection were coded as negation (e.g., "no, not that") or repair attempts (i.e., a changed naming attempt). Focusing on phonological and semantic errors, we measured the timing of the errors and of the utterances that provided evidence of detection. The effects of error type and detection response type on error-to-detection latencies were analyzed using mixed-effects regression modeling. We first asked whether phonological errors and semantic errors differed in the timing of the detection process or repair planning. Results suggested that the two error types primarily differed with respect to repair planning. Specifically, repair attempts for phonological errors were initiated more quickly than repair attempts for semantic errors. We next asked whether this difference between the error types could be attributed to the tendency for phonological errors to have a high degree of phonological similarity with the subsequent repair attempts, thereby speeding the programming of the repairs. Results showed that greater phonological similarity between the error and the repair was associated with faster repair times for both error types, providing evidence of error-to-repair priming in spontaneous self monitoring. When controlling for phonological overlap, significant effects of error type and repair accuracy on repair times were also found. These effects indicated that correct repairs of phonological errors were initiated particularly quickly, whereas repairs of semantic errors were initiated relatively slowly, regardless of their accuracy. We discuss the implications of these findings for theoretical accounts of self-monitoring and the role of speech error repair in learning. PMID- 28624682 TI - Effect of the fungus Piriformospora indica on physiological characteristics and root morphology of wheat under combined drought and mechanical stresses. AB - This study was done to evaluate the effects of the root-colonizing endophytic fungus Piriformospora indica on wheat growth under combined drought and mechanical stresses. Inoculated (colonized) and non-inoculated (uncolonized) wheat (Triticum aestivum L. cv. Chamran) seedlings were planted in growth chambers filled with moist sand (at a matric suction of 20 hPa). Slight, moderate and severe mechanical stresses (i.e., penetration resistance, Qp, of 1.17, 4.17 and 5.96 MPa, respectively) were produced by a dead-load technique (i.e., placing a weight on the sand surface) in the root medium. Slight, moderate and severe drought stresses were induced using PEG 6000 solutions with osmotic potentials of 0, -0.3 and -0.5 MPa, respectively. After 30 days, plant physiological characteristics and root morphology were measured. An increase in Qp from 1.17 to 5.96 MPa led to greater leaf proline concentration and root diameter, and lower relative water content (RWC), leaf water potential (LWP), chlorophyll contents and root volume. Moreover, severe drought stress decreased root and shoot fresh weights, root volume, leaf area, RWC, LWP and chlorophyll content compared to control. Catalase (CAT) and ascorbate peroxidase (APX) activities under severe drought stress were about 1.5 and 2.9 times greater than control. Interaction of the stresses showed that mechanical stress primarily controls plant water status and physiological responses. However, endophyte presence mitigated the adverse effects of individual and combined stresses on plant growth. Colonized plants were better adapted and had greater root length and volume, RWC, LWP and chlorophyll contents under stressful conditions due to higher absorption sites for water and nutrients. Compared with uncolonized plants, colonized plants showed lower CAT activity implying that wheat inoculated with P. indica was more tolerant and experienced less oxidative damage induced by drought and/or mechanical stress. PMID- 28624683 TI - Drought responsive microRNAs in two barley cultivars differing in their level of sensitivity to drought stress. AB - MicroRNAs (miRNAs) are known to be involved in the regulation of gene expression, including that of genes involved in the response to stress. Here, a comparison has been drawn between the miRNA profiles of a drought susceptible, 'Morocco 9 75', and a drought tolerant, 'Yousef', barley cultivars. Leaf water content, shoot dry matter and chlorophyll content decreased in 'Morocco 9-75' more considerably compared with 'Yousef' under drought stress. Furthermore, lower stomatal conductance and higher leaf temperature were observed in 'Morocco 9-75' compared with 'Yousef'. Based on the criteria set for differential abundance, 118 of conserved and novel miRNAs were identified as being responsive to soil water status. Although drought stress resulted in an altered abundance of more miRNAs in 'Morocco 9-75' than in 'Yousef', drought stress was generally associated with an increased miRNA abundance in 'Yousef' and a decreased abundance in 'Morocco 9 75'. An in silico analysis identified 645 genes as putative targets for the drought-responsive miRNAs in 'Yousef' and 3735 in 'Morocco 9-75'. Gene ontology analysis showed that drought stress was associated with the altered abundance of miRNAs targeting growth, development, the juvenile to adult transition and hormone signaling. Some miRNAs which became more abundant in 'Yousef' are thought to target genes intimately involved in development and stress adaptation. In 'Morocco 9-75', drought stress induced changes in the abundance of miRNAs associated with genes affecting growth, development, the juvenile to adult transition and ABA signaling. The data imply that miRNAs may affect the tolerance/sensitivity of barley to drought stress by modulating the expression of a wide set of genes and induction of some physiological changes. PMID- 28624681 TI - Semantic word category processing in semantic dementia and posterior cortical atrophy. AB - There is general agreement that perisylvian language cortex plays a major role in lexical and semantic processing; but the contribution of additional, more widespread, brain areas in the processing of different semantic word categories remains controversial. We investigated word processing in two groups of patients whose neurodegenerative diseases preferentially affect specific parts of the brain, to determine whether their performance would vary as a function of semantic categories proposed to recruit those brain regions. Cohorts with (i) Semantic Dementia (SD), who have anterior temporal-lobe atrophy, and (ii) Posterior Cortical Atrophy (PCA), who have predominantly parieto-occipital atrophy, performed a lexical decision test on words from five different lexico semantic categories: colour (e.g., yellow), form (oval), number (seven), spatial prepositions (under) and function words (also). Sets of pseudo-word foils matched the target words in length and bi-/tri-gram frequency. Word-frequency was matched between the two visual word categories (colour and form) and across the three other categories (number, prepositions, and function words). Age-matched healthy individuals served as controls. Although broad word processing deficits were apparent in both patient groups, the deficit was strongest for colour words in SD and for spatial prepositions in PCA. The patterns of performance on the lexical decision task demonstrate (a) general lexicosemantic processing deficits in both groups, though more prominent in SD than in PCA, and (b) differential involvement of anterior-temporal and posterior-parietal cortex in the processing of specific semantic categories of words. PMID- 28624684 TI - Photoprotection regulated by phosphorus application can improve photosynthetic performance and alleviate oxidative damage in dwarf bamboo subjected to water stress. AB - Water and nutrients, particularly phosphorus (P), are the two most limiting factors for dwarf bamboo growth in tropical and subtropical areas. Dwarf bamboo is highly sensitive to water stress and often causes severe P deficiency in its growing soils due to the characteristics of shallower roots and expeditious growth. However, little is known about its photoprotective response to soil water deficit and the underlying mechanisms regulated by P application. In this study, a completely randomized design with two factors of two water regimes (well watered and water-stressed) and two P levels (with and without P application) was arranged to investigate this issue in dwarf bamboo (Fargesia rufa) plants. Water stress not only decreased water status and photochemical activity but also increased lipid peroxidation due to reactive oxygen species (ROS) accumulation irrespective of P application. In this case, thermal dissipation and antioxidative defense were promoted. Moreover, the role of the water-water cycle under this stress still could not be ignored because it accounted for a large proportion of total energy (JPSII). P application significantly enhanced photochemical activity accompanied by increased chlorophyll content in water stressed plants. Meanwhile, P application remarkably reduced thermal dissipation and hardly affected photorespiration and the water-water cycle under water stress. Although P application only enhanced ascorbate (AsA) level, ROS, particularly hydrogen peroxide (H2O2), and lipid peroxidation were significantly reduced in water-stressed plants. Therefore, P application can improve the photosynthetic capacity by regulating the redistribution of energy absorbed by PSII antennae and independently activating of the H2O2-scavenging function of AsA to alleviate oxidative damage in F. rufa plants, thereby improving their survival under water stress conditions. PMID- 28624685 TI - Bacillus subtilis affects miRNAs and flavanoids production in Agrobacterium Tobacco interaction. AB - Agrobacterium tumefaciens is a very destructive plant pathogen. Selection of effective biological agents against this pathogen depends on more insight into molecular plant defence responses during the biocontrol agent-pathogen interaction. Auxin as a phytohormone is a key contributor in pathogenesis and plant defence and accumulation of auxin transport carriers are accompanied by increasing in flavonoid and miRNAs concentrations during plant interactions with bacteria. The aim of this research was molecular analysis of Bacillus subtilis (ATCC21332) biocontrol effect against A. tumefaciens (IBRC-M10701) pathogen interacting with Nicotiana tabacum plants. Tobacco plants were either treated with both or one of the challenging bacteria and the expression of miRNAs inside the plants were analysed through qRT-PCR. The results indicated that the bacterial treatments affect expression level of nta-miRNAs. In tobacco plants treated only with A. tumefaciens the expression of nta-miR393 was more than that was recorded for nta-miR167 (3.8 folds, P < 0.05 in 3dpi). While the expression level of nta-miR167 was more than the expression of nta-miR393 in other treatments including tobacco plants treated only with B. subtilis (2.1 folds, P < 0.05) and the plants treated with both of the bacteria (3.9 folds, P < 0.05) in 3 dpi. Also, the composition and concentration of rutin, myrecetin, daidzein and vitexin flavanoid derivatives were detected using HPLC and analysed according the standard curves. All of the tested flavanoid compounds were highly detected in Tobacco plants which were only challenged with A. tumefaciens. The amount of these compounds in the plants which were challenged with the B. subtilis alone, was similar to the amount recorded for the plants challenged with the both bacteria. This study suggests a relationship between the upregulation of nta miR167, nta-miR393 and accumulation of flavanoid compounds. Overall, the expression of these miRNAs as well as flavonoid derivatives has the potential of being used as biomarkers for the interaction of B. subtilis and A. tumefaciens model system in N. tabacum. PMID- 28624686 TI - Genetic factors exist behind the high prevalence of reduced high-density lipoprotein cholesterol levels in the Roma population. AB - BACKGROUND AND AIMS: Previous findings showed that reduced plasma high-density lipoprotein cholesterol (HDL-C) levels are more frequent in all age groups of the Hungarian Roma compared to the general population. It suggests that genetic factors may exist behind this phenomenon. Our present study was designed to test this hypothesis, i.e., to define whether genetic factors contribute to the higher prevalence of reduced HDL-C among Roma. Single nucleotide polymorphisms (N = 21) contributing to the variation in plasma HDL-C concentrations were analysed in the Hungarian Roma (N = 646) and general (N = 1542) populations. METHODS: Genetic risk scores, unweighted (GRS) and weighted (wGRS), were computed and compared. Associations between the GRSs and the prevalence of reduced HDL-C levels were analysed. RESULTS: The GRS and wGRS were significantly higher in the Roma compared to the general population (GRS: 22.2 +/- 3.2 vs. 21.5 +/- 3.3; wGRS: 0.57 +/- 0.1 vs. 0.53 +/- 0.1; p<0.001). One half per cent of Roma subjects were in the bottom fifth of the wGRS (wGRS<= 0.3) compared with 1.8% of those in the general population (p=0.025), while 5% of the Roma subjects were in the top fifth of the wGRS (wGRS>= 0.75) compared with 2.6% of those in the general population (p=0.004). The GRS showed similar correlation with reduced plasma HDL-C levels in the two populations, whilst the wGRS showed stronger correlation with the trait among Roma after controlling for confounders. CONCLUSIONS: These results strongly suggest that genetic factors contribute to the higher prevalence of reduced HDL-C levels among Roma, so interventions aiming to improve Roma health status need to consider their increased genetic susceptibility. PMID- 28624687 TI - Estimation of distal arm joint angles from EMG and shoulder orientation for transhumeral prostheses. AB - In this paper, we quantify the extent to which shoulder orientation, upper-arm electromyography (EMG), and forearm EMG are predictors of distal arm joint angles during reaching in eight subjects without disability as well as three subjects with a unilateral transhumeral amputation and targeted reinnervation. Prior studies have shown that shoulder orientation and upper-arm EMG, taken separately, are predictors of both elbow flexion/extension and forearm pronation/supination. We show that, for eight subjects without disability, shoulder orientation and upper-arm EMG together are a significantly better predictor of both elbow flexion/extension during unilateral (R2=0.72) and mirrored bilateral (R2=0.72) reaches and of forearm pronation/supination during unilateral (R2=0.77) and mirrored bilateral (R2=0.70) reaches. We also show that adding forearm EMG further improves the prediction of forearm pronation/supination during unilateral (R2=0.82) and mirrored bilateral (R2=0.75) reaches. In principle, these results provide the basis for choosing inputs for control of transhumeral prostheses, both by subjects with targeted motor reinnervation (when forearm EMG is available) and by subjects without target motor reinnervation (when forearm EMG is not available). In particular, we confirm that shoulder orientation and upper arm EMG together best predict elbow flexion/extension (R2=0.72) for three subjects with unilateral transhumeral amputations and targeted motor reinnervation. However, shoulder orientation alone best predicts forearm pronation/supination (R2=0.88) for these subjects, a contradictory result that merits further study. PMID- 28624688 TI - Relation between Peak Power Output in Sprint Cycling and Maximum Voluntary Isometric Torque Production. AB - From a cycling paradigm, little has been done to understand the relationships between maximal isometric strength of different single joint lower body muscle groups and their relation with, and ability to predict PPO and how they compare to an isometric cycling specific task. The aim of this study was to establish relationships between maximal voluntary torque production from isometric single joint and cycling specific tasks and assess their ability to predict PPO. Twenty male trained cyclists participated in this study. Peak torque was measured by performing maximum voluntary contractions (MVC) of knee extensors, knee flexors, dorsi flexors and hip extensors whilst instrumented cranks measured isometric peak torque from MVC when participants were in their cycling specific position (ISOCYC). A stepwise regression showed that peak torque of the knee extensors was the only significant predictor of PPO when using SJD and accounted for 47% of the variance. However, when compared to ISOCYC, the only significant predictor of PPO was ISOCYC, which accounted for 77% of the variance. This suggests that peak torque of the knee extensors was the best single-joint predictor of PPO in sprint cycling. Furthermore, a stronger prediction can be made from a task specific isometric task. PMID- 28624689 TI - From complex gut communities to minimal microbiomes via cultivation. AB - The mammalian gut microbiota is dominated by populations of bacteria, mostly strict anaerobes. Because these bacteria can influence the health of their host, it is important to investigate their diversity and functions, which can be done via culture-based or molecular approaches. In recent years, microbiologists have very often preferred the use of molecular techniques, as they do not limit the analysis to the fraction of communities that can be grown in the laboratory. In reality, cultivation and molecular methods are complementary, and we are now witnessing a period of unification. Obtaining strains that can be grown in vitro is currently indispensable for the description of novel diversity and eventually the improvement of taxonomic and sequence databases. Moreover, cultivation allows using host-specific minimal consortia of microbes that are helpful for detailed and standardized studies of gut microbial communities and microbe-host interactions. Molecular techniques are helpful because they can provide insights into strain-level diversity and the functional potential of organisms. Furthermore, genomic and metagenomic data allow inferring growth conditions for uncultured bacteria and also enable detailed genetic studies. In the present manuscript, we highlight recent work on culture-based investigation of mammalian gut bacteria and microbe-host interactions and give our opinions on challenges and perspectives in the field. PMID- 28624690 TI - Toward a genetic tool development pipeline for host-associated bacteria. AB - Bacteria reside in externally accessible niches on and in multicellular organisms, often forming mutualistic relationships with their host. Recent studies have linked the composition of these microbial communities with alterations in the host's health, behavior, and development, yet the causative mediators of host-microbiota interactions remain poorly understood. Advances in understanding and engineering these interactions require the development of genetic tools to probe the molecular interactions driving the structure and function of microbial communities as well as their interactions with their host. This review discusses the current challenges to rendering culturable, non-model members of microbial communities genetically tractable - including overcoming barriers to DNA delivery, achieving predictable gene expression, and applying CRISPR-based tools - and details recent efforts to create generalized pipelines that simplify and expedite the tool-development process. We use the bacteria present in the human gastrointestinal tract as representative microbiota to illustrate some of the recent achievements and future opportunities for genetic tool development. PMID- 28624691 TI - Immaturity for gestational age of microvasculature and placental barrier in term placentas with high weight. AB - OBJECTIVE: Villous immaturity for gestational age is a multifactorial developmental deviation associated with unexpected placental insufficiency, fetal hypoxia and term fetal death. In our previous work we have shown that immature CD15+/CD31+/CD34+ endothelial cells were an important indicator of placental villous immaturity and chronic insufficiency. The aim of this study was to perform a comparative analysis of CD15-marked immaturity in the vessel walls between normal and pathological term placentas of clinically and structurally heterogenous groups with normal, low and high weight. STUDY DESIGN: 165 clinically normal and pathological placentas of gestational age 39-42 with normal weight (25-75 percentile), low weight (<10 percentile) and high weight (>90 percentile) were structurally and immunohistochemically analyzed. Excluded were placentas with a severe form of placental insufficiency associated with intrauterine fetal death, low APGAR-score, genetic and chromosomal diseases or placental inflammations. The distribution patterns of CD15, CD31 and CD34 were assessed separately in the macrovasculature, microvasculature and placental barrier (PB) - associated capillaries. RESULTS: All placental groups with normal weight, low weight and high weight include normal, accelerated villous maturation or villous immaturity independent of their weight. However, a significant increase of immature CD15+/CD31+/CD34+ endothelial cells was detected in microvasculature and PB -associated capillaries in high weight-placentas (63.5%/52.2%), compared to those of normal weight (13.8%/8.2%) and low weight (16.1%/17.8%). The distribution of macrovascular immature CD15+/CD31+/CD34+ endothelial cells did not show such marked differences. CONCLUSION: We have identified the immaturity of microvasculature and PB -associated capillaries with a pathological persistency of immature CD15+/CD31+/CD34+ endothelial cells and a reduction of terminally differentiated CD15-/CD31+/CD34+ endothelial cells in a structurally and clinically heterogeneous group of high weight-placentas. We assume that immaturity of placental vessels are part of prenatal adaptational processes that can be recruited in different emergency situations and may provide potential targets of therapeutic correction of placental growth and chronic insufficiency. We therefore recommend the use of CD15-based immunophenotyping as a method to identify latent unfavorable conditions of fetal development in the intrauterine life and individual risk of disease in the postnatal period. PMID- 28624692 TI - Preoperative serum levels of YKL 40 and CA125 as a prognostic indicators in patients with endometrial cancer. AB - OBJECTIVE: To evaluate the utility of YKL-40 and CA125 in endometrial cancer (EC) patients, and to determine their prognostic value in assessing the disease-free survival (DFS) and overall survival (OS). METHODS: We analyzed seventy-four EC patients, treated at a single institution and 25 healthy individuals. CA 125 serum level was evaluated in the Cobas 6000 system and YKL-40, using the ELISA method. RESULTS: Significantly increased serum level of YKL-40 and CA125 was in EC patients in FIGO I-IB when compared to healthy controls. CA125 was significantly higher in patients with more advanced FIGO stage vs. FIGO I, and also in patients with lymph node metastases vs. patients with no metastases. The obtained AUC for YKL-40 was higher than for CA125. There was, however, higher diagnostic sensitivity for YKL-40 in comparison to CA125, both in patients with type I and type II tumours. In patients who had disease progression, both the percentage of elevated concentration of CA 125 and YKL-40 was higher than in patients with remission. The Chi2 test demonstrated the statistically significant differences. The predictive value of CA125 in an aspect of DFS and OS was demonstrated. CONCLUSIONS: A high diagnostic sensitivity of YKL-40 in the early stages of the disease suggests the possibility of using this biomarker at an early diagnostic phase of patients with EC. The patients with increased levels of YKL-40 before treatment are also at the higher risk of relapse. The determination of CA125 before surgery may be helpful in the evaluation of the regional lymph nodes, and is a poor prognostic factor for OS and DFS. PMID- 28624693 TI - Immune-related eosinophilia induced by anti-programmed death 1 or death-ligand 1 antibodies. PMID- 28624694 TI - Immune checkpoints inhibitors for solid tumours after allogeneic haematopoietic stem-cell transplantation: About four clinical cases. PMID- 28624695 TI - First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours. AB - BACKGROUND AND OBJECTIVES: S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS: Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria. RESULTS: A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR. CONCLUSION: S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies. TRIAL REGISTRATION NUMBER: ISRCTN00759419. PMID- 28624696 TI - Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort. AB - AIM: Adjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab. METHODS: A population combining patients from Protocol for Herceptin(r) as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan-Meier method, and comparisons between groups were based on the log rank test. RESULTS: The SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86-1.19) and similar DFS (HR = 1.08; 95% CI: 0.96-1.21). CONCLUSION: These results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting. PMID- 28624697 TI - Waterpipe smoking patterns and symptoms of nicotine dependence: The Waterpipe Dependence in Lebanese Youth Study. AB - INTRODUCTION: Waterpipe typically is smoked intermittently over long smoking sessions. Waterpipe is addictive and its users show symptoms of nicotine dependence (ND). This study examined the risk of developing ND symptoms across waterpipe use patterns among Lebanese youth. METHODS: Waterpipe use patterns (length of smoking session, smoking a whole waterpipe without sharing, past-30day use frequency, number of waterpipes smoked) were assessed. Symptoms of ND were assessed using the 10-item Hooked on Nicotine Checklist (HONC; endorsement of >=1 symptom) and the 6 criteria of the International Classification of Diseases-10th revision (ICD-10 ND; presence of >=3 criteria during 12months). RESULTS: Both the proportion of participants endorsing ND symptoms and the average number of endorsed ND symptoms increased with increasing waterpipe use frequency, number of waterpipes smoked, and length of smoking session. The risk of endorsing>=1 HONC symptom increased with increasing number of waterpipes smoked in the past 30-days (>=10 vs. <4 waterpipes; Hazard ratio (HR)=2.05, 95% CI: 1.52-2.58, p=0.007), and session length (>60min vs. <30min; HR=2.87, 95% CI: 2.83-2.91, p=0.001). The risk of attaining ICD-10 ND increased with increasing number of waterpipes used in the past 30-days (>=10 vs. <4 waterpipes; HR=2.56, 95% CI: 1.89-3.22, p=0.006), and smoking every day/almost every day vs. less than once weekly (HR=2.86, 95% CI: 2.12-3.60, p=0.007). CONCLUSIONS: Increasing use frequency, number of waterpipes smoked, and longer smoking sessions were associated with higher risk of ND. The length of smoking session emerged as a novel indicator of ND among waterpipe smokers. PMID- 28624698 TI - Brief mindfulness training de-couples the anxiogenic effects of distress intolerance on reactivity to and recovery from stress among deprived smokers. AB - OBJECTIVE: We tested whether mindfulness de-couples the expected anxiogenic effects of distress intolerance on psychological and physiological reactivity to and recovery from an anxiogenic stressor among participants experimentally sensitized to experience distress. METHOD: N = 104 daily smokers underwent 18 hours of biochemically-verified smoking deprivation. Participants were then randomized to a 7-min analogue mindfulness intervention (present moment attention and awareness training; PMAA) or a cope-as-usual control condition; and subsequently exposed to a 2.5-min paced over breathing (hyperventilation) stressor designed to elicit acute anxious arousal. Psychological and physiological indices of anxious arousal (Skin Conductance Levels; SCL) as well as emotion (dys)regulation (Respiratory Sinus Arrhythmia; RSA) were measured before, during and following the stressor. RESULTS: We found that PMAA reduced psycho-physiological dysregulation in response to an anxiogenic stressor, as well as moderated the anxiogenic effect of distress intolerance on psychological but not physiological responding to the stressor among smokers pre-disposed to experience distress via deprivation. CONCLUSIONS: The present study findings have a number of theoretical and clinical implications for work on mindfulness mechanisms, distress tolerance, emotion regulation, and smoking cessation interventions. PMID- 28624699 TI - Toll-like receptor 2 rs4696480 polymorphism and risk of oral cancer and oral potentially malignant disorder. AB - OBJECTIVES: The aim of this study was to identify the possible association between TLR polymorphisms and an increased risk of developing head and neck cancer, including oral (OSCC) and laryngeal squamous cell carcinoma (LSCC), and oral potentially malignant disorders, such as oral lichenoid disease (OLD), including oral lichen planus (OLP) and oral lichenoid lesions (OLL). DESIGN: This case-control study included 40 OSCC, 35 LSCC, 175 OLD (129 OLP and 46 OLL) patients and 89 healthy controls, all of them from the Basque Country, Spain. Genetic polymorphisms in TLR1, TLR2, TLR4, TLR6, TLR9, and TLR10 were genotyped by TaqMan(r) assays or pyrosequencing. RESULTS: The chi-square analysis showed that the variant A of the SNP TLR2-rs4696480 polymorphism significantly increased the risk of OSCC (p=0.03) and OLL (p=0.02). CONCLUSIONS: The TLR2-rs4696480 polymorphism may be relevant to OSCC and OLL susceptibility in this population encouraging further studies on the TLR2 pathway and its possible association with this group of oral potentially malignant disorders and oral cancer. This may also prove the use of TLR polymorphisms as risk markers for oral and laryngeal cancer. PMID- 28624700 TI - Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study. AB - The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (Mpro) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV Mpro significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV Mpro. These novel compounds displayed excellent IC50 data in the range of 0.516-5.954 MUM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures. PMID- 28624701 TI - 2-Substituted-thio-N-(4-substituted-thiazol/1H-imidazol-2-yl)acetamides as BACE1 inhibitors: Synthesis, biological evaluation and docking studies. AB - In this work, a series of 2-substituted-thio-N-(4-substituted-thiazol/1H-imidazol 2-yl)acetamide derivatives were developed as beta-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. In addition, the selected compounds were tested with affinity (KD) towards BACE-1, blood brain barrier (BBB) permeability and cytotoxicity. The studies revealed that the most potent analog 41 (IC50 = 4.6 MUM) with high predicted BBB permeability and low cellular cytotoxicity, could serve as a good lead structure for further optimization. PMID- 28624702 TI - Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22. AB - Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1-7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1-7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated 4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro alpha1 adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at alpha1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined. PMID- 28624703 TI - Modification of C-seco taxoids through ring tethering and substituent replacement leading to effective agents against tumor drug resistance mediated by betaIII Tubulin and P-glycoprotein (P-gp) overexpressions. AB - In our efforts to improve the efficacy of taxane-based microtubule (MT) stabilizing agents against tumor drug resistance mediated by multiple mechanisms, two clinically relevant factors were focused: i.e., P-glycoprotein and betaIII tubulin overexpression. Based on the structure of C-seco taxoid 1 m (IDN5390) which was believed to more selectively interact with betaIII-tubulin than paclitaxel, we prepared a series of C-seco taxoids bearing various 7,9-O-linkages and/or different substituents at C2 and C3' positions. Some of them exhibited much more potent binding affinity to MTs and cytotoxicity than their C-seco parent compounds in drug resistant cells with both mechanisms. SAR analysis indicated that C2 modifications significantly enhanced MT binding but brought ambiguous influence to cytotoxicity whereas 7,9-linkage and C3' modifications enhance cytotoxicity more efficiently than improve MT binding. These observations illustrate a better translation of molecular binding effect to cellular activity by C ring closure and C3' modification than C2 modification in C-seco taxoids. PMID- 28624704 TI - Maintenance of redox homeostasis by hypoxia-inducible factors. AB - Oxidative phosphorylation enables cells to generate the large amounts of ATP required for development and maintenance of multicellular organisms. However, under conditions of reduced O2 availability, electron transport becomes less efficient, leading to increased generation of superoxide anions. Hypoxia inducible factors switch cells from oxidative to glycolytic metabolism, to reduce mitochondrial superoxide generation, and increase the synthesis of NADPH and glutathione, in order to maintain redox homeostasis under hypoxic conditions. PMID- 28624705 TI - Controlled release of basic fibroblast growth factor for angiogenesis using acoustically-responsive scaffolds. AB - The clinical translation of pro-angiogenic growth factors for treatment of vascular disease has remained a challenge due to safety and efficacy concerns. Various approaches have been used to design spatiotemporally-controlled delivery systems for growth factors in order to recapitulate aspects of endogenous signaling and thus assist in translation. We have developed acoustically responsive scaffolds (ARSs), which are fibrin scaffolds doped with a payload containing, sonosensitive emulsion. Payload release can be controlled non invasively and in an on-demand manner using focused, megahertz-range ultrasound (US). In this study, we investigate the in vitro and in vivo release from ARSs containing basic fibroblast growth factor (bFGF) encapsulated in monodispersed emulsions. Emulsions were generated in a two-step process utilizing a microfluidic device with a flow focusing geometry. At 2.5 MHz, controlled release of bFGF was observed for US pressures above 2.2 +/- 0.2 MPa peak rarefactional pressure. Superthreshold US yielded a 12.6-fold increase in bFGF release in vitro. The bioactivity of the released bFGF was also characterized. When implanted subcutaneously in mice, ARSs exposed to superthreshold US displayed up to 3.3-fold and 1.7-fold greater perfusion and blood vessel density, respectively, than ARSs without US exposure. Scaffold degradation was not impacted by US. These results highlight the utility of ARSs in both basic and applied studies of therapeutic angiogenesis. PMID- 28624706 TI - Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma. AB - Although asthma, a chronic inflammatory airway disease, is relatively well managed by inhaled corticosteroids, the side effects associated with the long term use of these agents precipitate the need for alternative therapeutic options based on differing modes of action. Bilirubin, a potent endogenous antioxidant, and anti-inflammatory molecule have been shown to ameliorate asthmatic symptoms; however, its clinical translation has been limited owing to its water insolubility and associated potential toxicity. Here we report the first application of bilirubin-based nanoparticles (BRNPs) as a nanomedicine for the treatment of allergic lung inflammatory disease. BRNPs were prepared directly from self-assembly of PEGylated bilirubin in aqueous solution and had a hydrodynamic diameter of ~100 nm. Because allergen-specific type 2 T-helper (Th2) cells play a key role in the pathogenesis and progression of allergic asthma, the effects of BRNPs on Th2 immune responses were investigated both in vivo and in vitro. BRNPs after intravenous injection (i.v.) showed much higher serum concentration and a longer circulation time of bilirubin than the intraperitoneal injection (i.p.) of BRNPs or unconjugated bilirubin (UCB). The anti-asthmatic effects of BRNPs were assessed in a mouse model of allergen-induced asthma. Compared with UCB, treatment with BRNPs suppressed the symptoms of experimental allergic asthma and dramatically ameliorated Th2-related allergic lung inflammation. Consistent with these results, BRNPs caused a reduction of Th2 cell populations and the expression of related cytokines by antibody-stimulated CD4+ T cells in vitro. Therefore, our results establish BRNPs as an important immunomodulatory agent that may be useful as a therapeutic for allergic lung inflammatory disease and other immune-mediated disorders. PMID- 28624707 TI - Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity. AB - The vascular endothelium is subject to diverse mechanical cues that regulate vascular endothelial barrier function. In addition to rigidity sensing through integrin adhesions, mechanical perturbations such as changes in fluid shear stress can also activate force transduction signals at intercellular junctions. This study investigated how extracellular matrix rigidity and intercellular force transduction, activated by vascular endothelial cadherin, coordinate to regulate the integrity of endothelial monolayers. Studies used complementary mechanical measurements of endothelial monolayers grown on patterned substrates of variable stiffness. Specifically perturbing VE-cadherin receptors activated intercellular force transduction signals that increased integrin-dependent cell contractility and disrupted cell-cell and cell-matrix adhesions. Further investigations of the impact of substrate rigidity on force transduction signaling demonstrated how cells integrate extracellular mechanics cues and intercellular force transduction signals, to regulate endothelial integrity and global tissue mechanics. VE cadherin specific signaling increased focal adhesion remodeling and cell contractility, while sustaining the overall mechanical equilibrium at the mesoscale. Conversely, increased substrate rigidity exacerbates the disruptive effects of intercellular force transduction signals, by increasing heterogeneity in monolayer stress distributions. The results provide new insights into how substrate stiffness and intercellular force transduction coordinate to regulate endothelial monolayer integrity. PMID- 28624708 TI - Individual differences in object-processing explain the relationship between early gaze-following and later language development. AB - Gaze-following behaviors play an important role in language development. However, the way in which gaze-following contributes to language development remains unclear. By focusing on two abilities, namely following the gaze direction of others and processing a cued object, the present study investigated how these two influences work together to promote language development in a longitudinal approach on infants from 9 to 18months of age. The results demonstrated that infants who spent more time following the gaze direction toward an object were more efficient in processing the cued object at 9months and had larger vocabularies by 18months. Mediation analyses showed that the relationship between early gaze-following behavior and subsequent vocabulary size was explained by object-processing ability. Importantly, mere extended fixations on a target object without the initiation of another's gaze shift were not related to enhanced object-processing. Our findings suggest that following another's gaze shift toward the object has an impact on object-processing that could contribute to vocabulary development, elucidating a critical step in the path from early gaze-following ability to later language development. PMID- 28624709 TI - Contracted time and expanded space: The impact of circumnavigation on judgements of space and time. AB - The ability to estimate distance and time to spatial goals is fundamental for survival. In cases where a region of space must be navigated around to reach a location (circumnavigation), the distance along the path is greater than the straight-line Euclidean distance. To explore how such circumnavigation impacts on estimates of distance and time, we tested participants on their ability to estimate travel time and Euclidean distance to learned destinations in a virtual town. Estimates for approximately linear routes were compared with estimates for routes requiring circumnavigation. For all routes, travel times were significantly underestimated, and Euclidean distances overestimated. For routes requiring circumnavigation, travel time was further underestimated and the Euclidean distance further overestimated. Thus, circumnavigation appears to enhance existing biases in representations of travel time and distance. PMID- 28624710 TI - Role of impaired vision during dual-task walking in young and older adults. AB - While cognitive-motor interference in dual-task activities is well established, it is still unknown how such interference is influenced by concurrent visual challenges. Nineteen community-dwelling healthy, cognitively intact, older adults (Mean+/-SD=71.45+/-1.25years, 6 males) and nineteen young adults (Mean+/ SD=22.25+/-0.68years, 4 males) performed a cognitive-single-task (serial subtraction by 3), a walking-single-task and a cognitive-walking-dual-task under normal, blurred and peripheral-vision-loss conditions (artificially imposed using goggles). Gait parameters and the number of correct responses were measured. Dual task costs for both walking and cognition were computed. Results showed that higher walking cost was seen with impaired vision (p=0.05) and with older adults (p=0.03); greater cognitive cost was seen with impaired vision (p=0.01), but no difference in cognitive cost was seen between young and older adults. Thus, when faced with impaired vision, both young and older adults appear to allocate less attention to cognition than to walking, and thus prioritize walking. Future work should explore whether dual-task training under visual challenge could reduce cognitive-motor interference and reduce fall risks in older adults. PMID- 28624711 TI - Does the PowersTM strap influence the lower limb biomechanics during running? AB - Previous research has reported a prevalence of running related injuries in 25.9% to 72% of all runners. A greater hip internal rotation and adduction during the stance phase in running has been associated with many running related injuries, such as patellofemoral pain. Researchers in the USA designed a treatment device 'the PowersTM strap' to facilitate an external rotation of the femur and to thereby control abnormal hip and knee motion during leisure and sport activities. However, to date no literature exists to demonstrate whether the PowersTM strap is able to reduce hip internal rotation during running. 22 healthy participants, 11 males and 11 females (age: 27.45+/-4.43 years, height: 1.73+/-0.06m, mass: 66.77+/-9.24kg) were asked to run on a 22m track under two conditions: without and with the PowersTM strap. Three-dimensional motion analysis was conducted using ten Qualisys OQUS 7 cameras (Qualisys AB, Sweden) and force data was captured with three AMTI force plates (BP600900, Advanced Mechanical Technology, Inc.USA). Paired sample t-tests were performed at the 95% confidence interval on all lower limb kinematic and kinetic data. The PowersTM strap significantly reduced hip and knee internal rotation throughout the stance phase of running. These results showed that the PowersTM strap has the potential to influence hip motion during running related activities, in doing so this might be beneficial for patients with lower limb injuries. Future research should investigate the influence of the PowersTM strap in subjects who suffer from running related injuries, such as patellofemoral pain. PMID- 28624712 TI - Classification of ECG heartbeats using nonlinear decomposition methods and support vector machine. AB - Classifying electrocardiogram (ECG) heartbeats for arrhythmic risk prediction is a challenging task due to minute variations in the amplitude, duration and morphology of the ECG signal. In this paper, we propose two feature extraction approaches to classify five types of heartbeats: normal, premature ventricular contraction, atrial premature contraction, left bundle branch block and right bundle branch block. In the first approach, ECG beats are decomposed into intrinsic mode functions (IMFs) using ensemble empirical mode decomposition (EEMD). Later four parameters, namely the sample entropy, coefficient of variation, singular values, and band power of IMFs are extracted as features. In the second approach, the same features are computed from IMFs extracted using an empirical mode decomposition (EMD) algorithm. The features obtained from the two approaches are independently fed to the sequential minimal optimization-support vector machine (SMO-SVM) for classification. We used two arrhythmia databases for our evaluation: MIT-BIH and INCART. We compare the proposed approaches with existing methods using the performance measures given by the average values of (i) specificity, (ii) sensitivity, and (iii) accuracy. The first approach demonstrates significant performance with 98.01% sensitivity, 99.49% specificity, and 99.20% accuracy for the MIT-BIH database and 95.15% sensitivity, 98.37% specificity, and 97.57% accuracy for the INCART database. PMID- 28624713 TI - Aneuploidy identification in pre-B acute lymphoblastic leukemia patients at diagnosis by Multiplex Ligation-dependent Probe Amplification (MLPA). AB - Three-quarters of the patients with acute lymphoblastic leukemia (ALL), show numerical or structural chromosomal alterations, which are important factors in leukemogenesis. The use of Multiplex Ligation-dependent Probes Amplification (MLPA) has been mainly limited for searching copy number alterations of genes, suggesting that MLPA could detect numerical alterations in cancer. However, the use of MLPA in pediatrics to analyze subtelomeric sequences for aneuploidy detection has not been considered in previous studies. The aim of this study was to identify aneuploidy for the first time using MLPA and correlate the results with karyotype and DNA-index (DI), from preB ALL patients. Forty-two bone marrow samples were analyzed by cytogenetics and flow cytometry to determine the DI. The chromosomal gains and/or losses were detected by the SALSA MLPA P036 Subtelomere Mix 1 probemix(r). The chromosomal number matched in 36 out of 42 samples between MLPA and karyotype (R2=0.7829, p=3.7*10-10), 18/42 between MLPA and DI (R2=0.1556, p=0.023), and 20/42 between karyotype and DI (R2=0.1509, p=0.015). MLPA results correlated with karyotype and DI. The use of MLPA led us to identify a gained marker chromosome. Our results indicate that MLPA could be a useful and fast alternative tool for aneuploidy identification in pediatric leukemia. PMID- 28624714 TI - Patient reported outcomes of autologous fat grafting after breast cancer surgery. AB - INTRODUCTION: Autologous fat grafting (AFG) can be used as an adjunct in breast cancer surgery to improve contour defects. Few previous studies have assessed patient reported outcomes (PROs) for AFG. This study analysed AFG use and assessed PROs in terms of physical and psychosocial well-being. MATERIALS AND METHODS: All patients undergoing AFG were identified from a prospective database and asked to complete the validated BREAST-Q questionnaire and a tool to assess patient-perceived change after AFG (5-point Likert-type scale). Descriptive statistics were computed for all BREAST-Q and perceived change subscales. Independent sample t-tests were conducted to compare scores on each of the BREAST Q and perceived change subscales by type of breast cancer surgery and radiotherapy status. RESULTS: 156 AFG sessions were performed over 4 years on 119 breasts in 88 patients. Fifty-seven patients received AFG after reconstruction and 19 after breast conserving surgery. Forty-six patients (52%) completed the questionnaire. BREAST-Q scores (out of 100) and patient-perceived change after AFG (out of 5) were respectively: 54 and 4.0 for Breast satisfaction, 69 and 3.3 for Physical well-being and 60 and 3.6 for Psychosocial well-being. Radiotherapy status and type of surgery made little difference. Number of AFG procedures positively correlated with perceived improvement. DISCUSSION: Autologous fat grafting was associated with improved patient satisfaction despite small volumes transferred. BREAST-Q scores were comparable with previously published series on reconstructive breast surgery. Perceived change after AFG was no different in patients receiving radiotherapy. PMID- 28624715 TI - Impact of physical activity in group versus individual physical activity on fatigue in patients with breast cancer: A pilot study. AB - BACKGROUND: Physical activity improves the quality of life of cancer survivors, but whether there is a difference between individual vs. group physical activity is unknown. OBJECTIVES: To compare fatigue at 12 weeks in breast cancer survivors after participation in a program of group vs. individual video-assisted physical activity. METHODS: This was a randomized phase II pilot study carried out in breast cancer survivors at a tertiary breast cancer center. Eligible patients were randomized to individual or group 12-week physical activity program. The primary outcome was fatigue (FACT-F). Aerobic capacity (6-min walk test), muscular strength, and quality-of-life (FACT-G and FACT-B) were assessed. Because of poor accrual, 200 consecutive breast cancer patients were surveyed about their physical activity habits to assess reasons for low recruitment. RESULTS: For all participants (n = 26; n = 12 for group vs. n = 14 for individual), there were some improvement in FACT-F, FACT-G, FACT-B, physical activity level, aerobic capacity, and shoulder strength. Among the 200 patients surveyed, 58% were interested to increase their physical activity level, 15% declared that they were already exercising enough, 9% declared being unable to, 3% declared having no time, and 2% declared having no interest, and other reasons (13%). Among the 200 patients surveyed, 25% preferred in group, 57% preferred alone, and 18% had no preference. CONCLUSION: Low recruitment precluded conclusions about the efficacy of physical activity practiced in group vs. individually, but both groups derived a benefit. Low willingness to change exercising habits could be the biggest barrier to physical activity in breast cancer survivors. PMID- 28624716 TI - Seizure-related hospital admissions, readmissions and costs: Comparisons with asthma and diabetes in South Australia. AB - PURPOSE: Seizures are listed as an Ambulatory Care Sensitive Condition (ACSC), where, in some cases, hospitalisation may be avoided with appropriate preventative and early management in primary care. We examined the frequencies, trends and financial costs of first and subsequent seizure-related hospital admissions in the adult and paediatric populations, with comparisons to bronchitis/asthma and diabetes admissions in South Australia between 2012 and 2014. METHODS: De-identified hospital separation data from five major public hospitals in metropolitan South Australia were analysed to determine the number of children and adults admitted for the following Australian Refined Diagnosis Related Groups: seizure related conditions; bronchitis/asthma; and diabetes. Additional data included length of hospital stay and type of admission. Demographic data were analysed to identify whether social determinants influence admission, and a macro costing approach was then applied to calculate the financial costs to the Health Care System. RESULTS: The rate of total seizure hospitalizations was 649 per 100,000; lower than bronchitis/asthma (751/100,000), yet higher than diabetes (500/100,000). The highest proportions of subsequent separations were recorded by children with seizures regardless of complexity (47% +CSCC; 17% -CSCC) compared with asthma (11% +CSCC; 14% -CSCC) or diabetes (14% +CSCC; 13% -CSCC), and by adults with seizures with catastrophic or severe complications/comorbidity (25%), compared with diabetes (22%) or asthma (14%). The mean cost per separation in both children and adults was highest for diabetes (AU$4438/$7656), followed by seizures (AU$2408/$5691) and asthma (AU$2084/$3295). CONCLUSIONS: Following the lead of well-developed and resourced health promotion initiatives in asthma and diabetes, appropriate primary care, community education and seizure management services (including seizure clinics) should be targeted in an effort to reduce seizure related hospitalisations which may be avoidable, minimise costs to the health budget, and maximise health care quality. PMID- 28624717 TI - Management of venous thromboembolism in patients with glioma. AB - BACKGROUND: Venous thromboembolism (VTE) is a common complication among patients with glioma. However, data on the safety of therapeutic doses of anticoagulation is scarce in this patient population. OBJECTIVES: The purpose of this study is to evaluate the risk of intracranial hemorrhage (ICH) in glioma patients receiving therapeutic anticoagulation for VTE treatment. PATIENTS AND METHODS: We conducted a case-control study including glioma patients with and without acute VTE from Jan 2010 to March 2015. Controls were matched based on age, gender and tumor grade. RESULT: 569 patients with glioma were identified, 76 (13.3%) developed acute VTE. Of the 70 patients treated with full dose anticoagulant therapy, 14 (20%) patients had a major bleeding including 11 (15.7%) ICH. The odds ratio for ICH in patients with glioma and VTE who were treated with anticoagulation compared to the control group was 7.5 (95% CI, 1.6-34.9) p=0.01. Overall survival was similar for VTE and control group (36 vs. 42months, p=0.93). CONCLUSION: Therapeutic anticoagulation is associated with a 7-fold increase risk of ICH in glioma patients. Data emerging from this study support the need for high quality studies to evaluate the risk of ICH in patients with glioma and VTE. PMID- 28624718 TI - Microparticles in acute coronary syndrome. AB - BACKGROUND: Emerging evidence supports the role of cell-derived microparticles (MPs) in the pathophysiology of acute coronary syndrome (ACS). OBJECTIVES: To explore the relationship between coronary and systemic MP levels, investigate the correlation between MPs, inflammatory markers and Troponin T in patients with ACS. METHODS: Thirty seven patients with ACS scheduled for percutaneous coronary interventions (PCI) were studied. Eleven patients with stable angina (SA) were included as a control group. AnnexinV+MPs (AnV+MPs) and activated platelet monocyte aggregates (PMA) from right atrium (RA) and culprit coronary artery (CO) distal to culprit lesion were measured using flow cytometry. High sensitivity C reactive protein (CRP), Interleukin - 6 (IL-6), tumour necrosis factor - alpha (TNF-alpha), serum amyloid A (SAA) and Troponin T were assayed. RESULTS: Total and cell specific AnV+MP expression were higher in the ACS group in both the CO and RA, with greater levels detected in the CO. Platelet activation showed positive correlation with Troponin-T and platelet MP in both CO and RA of the ACS group (r=0.4 for both; p=0.04 & p=0.03 respectively). Inflammatory markers levels did not differ between the ACS and SA patients. CONCLUSIONS: Elevated coronary and systemic MP levels and positive correlation of platelet activation with Troponin-T and platelet MPs suggest a pathogenic role for MPs in ACS. PMID- 28624719 TI - Reversal of rivaroxaban using Prothromplex Total, a 4-factor prothrombin complex. PMID- 28624720 TI - Retention of perampanel in adults with pharmacoresistant epilepsy at a single tertiary care center. AB - RATIONALE: Observational data on antiepileptic drugs (AEDs) inform about their use in clinical practice. We describe our clinical experience with perampanel (PER) in a large UK tertiary epilepsy center. METHODS: Adults initiated on PER between October 2012 and March 2015 were followed until they discontinued PER or 10 September 2016. Data on epilepsy syndrome, duration, seizure types, concomitant and previous AED use, PER dosing, efficacy and side effects were recorded. Efficacy was categorized as temporary or ongoing (at last follow-up) seizure freedom, >=50% seizure reduction, or other benefit (e.g. No convulsions or daytime seizures). These categories were mutually exclusive except for people with temporary seizure freedom. RESULTS: 391 received a PER prescription, five of whom never took it. No follow-up data were available for ten. 83% had focal epilepsy. People were prescribed PER in addition to 1-7 (Interquartile range [IQR] 2, 2, 3) AEDs and had previously used up to 18 (IQR 5, 7, 10) AEDs. Total exposure was 639patient/years. Retention rates were 60.4% at one year, 48.3% at two years, and 42.7% at three years. 19 (5%) people reported seizure free periods lasting at least six months. A >=50% reduction in seizures lasting at least six months was reported by 76 people (20%), and marked improvement for >=6months was seen in 52 (14%). Five (1%) were taken off other AEDs and continued on PER monotherapy for 4-27months. Seizures were aggravated in 57 (15%). Somatic side effects were reported by 197 (52%), mostly CNS. Mood changes, irritability or challenging behavior were reported by 137 (36%). PER was discontinued by 211 (56%) due to adverse effects (39%), inefficacy (26%), or both (35%). No idiosyncratic adverse events were seen. CONCLUSION: PER resulted in some benefit in 40% of those exposed. Adverse effects on mental health and on balance were common and should be discussed with people before initiating PER. PMID- 28624721 TI - Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy. AB - Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted. PMID- 28624722 TI - Age-related differences in the response of the L5-S1 intervertebral disc to spinal traction. AB - BACKGROUND: Lumbar traction is a common treatment for low back pain; however its mechanisms of action are poorly understood. It has been hypothesized that a key effect of lumbar traction is its capacity to influence fluid movement within the intervertebral disc (IVD). OBJECTIVES: To determine differences in the apparent diffusion coefficient (ADC) obtained with lumbar diffusion-weighted imaging (DWI) of the L5-S1 IVD before, and during, the application of lumbar traction. DESIGN: Case series, repeated measures. METHODS: A static traction load of ~50% of body weight was applied to the low back using a novel "MRI-safe" apparatus. DWI of the lumbar spine was performed prior to, and during the application of the traction load. RESULTS: Participants were currently asymptomatic and included a young adult group (n = 18) and a middle-aged group (n = 15). The young adult group had a non-significant 2.2% increase in ADC (mean change = 0.03 * 10-3 mm2/s, SD = 0.24, 95% CI = -0.09, 0.15). The ADC for the middle-aged group significantly increased by 20% (mean change of 0.18 * 10-3 mm2/s, SD = 0.19; 95% CI = 0.07, 0.28; p = 0.003; effect size = 0.95). There was an inverse relationship between the ADC obtained before traction and the percent increase in ADC that was measured during traction. CONCLUSION: Static traction was associated with an increase in diffusion of water within the L5-S1 IVDs of middle-age individuals, but not in young adults, suggesting age-related differences in the diffusion response. Further study is needed to assess the relationship between these findings and the symptoms of back pain. LEVEL OF EVIDENCE: 4. PMID- 28624723 TI - Repeated end range spinal movement while seated abolishes the proprioceptive deficit induced by prolonged flexed sitting posture. A study assessing the statistical and clinical significance of spinal position sense. AB - BACKGROUND: Sustained spinal flexion has been proposed to affect the properties of spinal tissues, increase postural muscle's activation latency and act detrimentally on proprioception. OBJECTIVES: This study evaluated the effect of flexed posture (FP) on spinal proprioception and assessed the immediate effect of spinal movement on the presumable flexion-induced proprioceptive deficit. DESIGN: Clinical measurement study. METHODS: Marker-based kinematic analyses of the head, spine, and pelvis were conducted on 50 individuals. Subjects were educated in a lordotic sitting posture (IOSP) that they reproduced immediately; after 10 and 30 min in FP; and after sagittal spinal movement. Nine sagittal angles were calculated. Absolute error (AE) and constant error (CE) were used to evaluate repositioning accuracy. Repeated measures ANOVA was used to test for significant differences in angles obtained among postures, as well as for the AE and CE calculated from the trials. RESULTS: No significant differences were found in reposition error (RE) after immediate reproduction of IOSP (all p > 0.0083). Following FP AEs presented significant differences for head (4.1 degrees ), head protraction (1.9 degrees ), head tilt (2.1 degrees ), lumbar (3.2 degrees ) and pelvis angle (2.1 degrees ). CEs revealed significant differences for head protraction (-1.8 degrees ) and lumbar angle (-3.5 degrees ). No significant differences were found for AE and CE after spinal sagittal movement (all p > 0.0083). CONCLUSIONS: Prolonged FP can affect spinal position sense, but sagittal spinal movement can abolish the proprioceptive deficit. The significant differences documented, may be of limited clinical utility given their magnitude, and the reliability data presented may be of use in reinterpreting previously documented proprioceptive analyses. PMID- 28624724 TI - High-throughput screening technologies for enzyme engineering. AB - Emerging technologies are enabling ultra-high-throughput screening of combinatorial enzyme libraries to identify variants with improved properties such as increased activity, altered substrate specificity, and increased stability. Each of these enzyme engineering platforms relies on compartmentalization of reaction components, similar to microtiter plate-based assays which have been commonly used for testing the activity of enzyme variants. The technologies can be broadly divided into three categories according to their spatial segregation strategy: (1) cells as reaction compartments, (2) in vitro compartmentalization via synthetic droplets, and (3) microchambers. Here, we discuss these emerging platforms, which in some cases enable the screening of greater than 10 million enzyme variants, and highlight benefits and limitations of each technology. PMID- 28624725 TI - Multifunctional polymeric micelles loaded with doxorubicin and poly(dithienyl diketopyrrolopyrrole) for near-infrared light-controlled chemo-phototherapy of cancer cells. AB - Polymeric micelles loaded with multiple therapeutic modalities are important to overcome challenges such as drug resistance and improve the therapeutic efficacy. Here we report a new polymer micellar drug carrier that integrates chemotherapy and photothermal therapy in a single platform. Specifically, a narrow bandgap poly(dithienyl-diketopyrrolopyrrole) (PDPP) polymer was encapsulated together with a model anticancer drug doxorubicin (DOX) in the hydrophobic cores of polymeric micelles formed by Pluronic F127, an amphiphilic poly(ethylene oxide) poly(propylene oxide)-poly(ethylene oxide) triblock copolymer. The PDPP polymer served as an organic photothermal agent that absorbs near-infrared light (700 1000nm) and transforms into heat efficiently. The dual functional micelles co loaded with PDPP and DOX in the hydrophobic compartment showed good colloidal stability after being stored at 4 degrees C at least over two months, and remained visibly stable after 808-nm laser irradiation. The loaded DOX had negligible effect on the size and photothermal property of the micelles. The release of DOX from the micelles could be enhanced by the "breathing" effect of shrinking/swelling of the micelles induced by the temperature change, owing to the thermosensitive nature of the F127 polymers. Importantly, the ternary F127/PDPP/DOX micelles under 808-nm laser irradiation showed enhanced cytotoxicity against cancer cells such as HeLa cells, compared to F127 micelles containing single modality of either PDPP or DOX only. PMID- 28624726 TI - Holographic characterization of contaminants in water: Differentiation of suspended particles in heterogeneous dispersions. AB - Determining the size distribution and composition of particles suspended in water can be challenging in heterogeneous multicomponent samples. Light scattering techniques can measure the distribution of particle sizes, but provide no basis for distinguishing different types of particles. Direct imaging techniques can categorize particles by shape, but offer few insights into their composition. Holographic characterization meets this need by directly measuring the size, refractive index, and three-dimensional position of individual particles in a suspension. The ability to measure an individual colloidal particle's refractive index is a unique capability of holographic characterization. Holographic characterization is fast enough, moreover, to build up population distribution data in real time, and to track time variations in the concentrations of different dispersed populations of particles. We demonstrate these capabilities using a model system consisting of polystyrene microbeads co-dispersed with bacteria in an oil-in-water emulsion. We also demonstrate how the holographic fingerprint of different contaminants can contribute to identifying their source. PMID- 28624727 TI - The biogeochemical implications of massive gull flocks at landfills. AB - Gulls have long been observed concentrating in flocks of tens to hundreds of thousands at the anthropogenic food sources provided by landfills. Yet, the biogeochemical implications of the landfill gull phenomenon have been largely ignored. This study has two goals: 1) to understand the magnitude and geographic extent of landfill gulls in North America, and 2) to quantify the amount of carbon (C), nitrogen (N), and phosphorus (P) transported from landfills to gull roosting sites in order to understand their potential impacts on water quality and methane (CH4) emission. We synthesized and mapped data from the eBird Citizen Science database and found that 1.4 million gulls have been documented at landfills throughout North America, though the actual population is probably greater than 5 million. Using a carnivorous bird transport model we estimate that these gulls transport 39,000 to 139,000 kg of P and 240,000 to 858,000 kg of N y 1 to neighboring water bodies and avoid roughly 1.1 to 3.9 Tg y-1 of landfill CH4 emissions. The avoided CH4 emission mitigation is insignificant in the context of gross landfill emissions, but the transported nutrients may be relevant to water quality management at local and continental scales. For example, at the Jordan Lake reservoir in North Carolina, a flock of 49,000 Ring-billed Gulls (Larus delawarensis) annually deposits landfill feces containing 1070 kg P, an amount equivalent to approximately half of total maximum daily load reduction targets and worth roughly $2.2 million USD in nutrient credits. We estimate that continent-wide gull impacts are worth at least $100 million in nutrient offset credits. We conclude that mega-flocks of landfill gulls are common and widespread, and that their capacity to transport nutrients may be contributing to the eutrophication of aquatic ecosystems and water supplies. PMID- 28624728 TI - Nitrite production from urine for sulfide control in sewers. AB - Most commonly used methods for sewer sulfide control involves dosing chemical agents to wastewater, which incurs high operational costs. Here, we propose and demonstrate a cost-effective and environmentally attractive approach to sewer sulfide control through urine separation and its subsequent conversion to nitrite prior to intermittent dosage to sewers. Urine collected from a male toilet urinal was fed to laboratory-scale sequencing batch reactors. The reactors stably converted roughly 50% of the nitrogen in urine to nitrite, with high abundance (at 17.46%) of known ammonia-oxidizing bacteria (AOB) of the genus Nitrosomonas, and absence (below detection level) of typical nitrite-oxidizing bacteria of the genus Nitrospira, according to 454 pyrosequencing analysis. The stable nitrite production was achieved at both relatively high (1.0-2.0 mg/L) and low (0.2-0.3 mg/L) dissolved oxygen concentrations. Dosing tests in laboratory-scale sewer systems confirmed the sulfide control effectiveness of free nitrous acid generated from urine. Life cycle assessment indicated that, compared with commodity chemicals, nitrite/free nitrous acid (FNA) production from urine for sulfide control in sewers would lower the operational costs by approximately 2/3 and greenhouse gas (GHG) emissions by 1/3 in 20 years. PMID- 28624729 TI - MODIS observations of cyanobacterial risks in a eutrophic lake: Implications for long-term safety evaluation in drinking-water source. AB - The occurrence and related risks from cyanobacterial blooms have increased world wide over the past 40 years. Information on the abundance and distribution of cyanobacteria is fundamental to support risk assessment and management activities. In the present study, an approach based on Empirical Orthogonal Function (EOF) analysis was used to estimate the concentrations of chlorophyll a (Chla) and the cyanobacterial biomarker pigment phycocyanin (PC) using data from the MODerate resolution Imaging Spectroradiometer (MODIS) in Lake Chaohu (China's fifth largest freshwater lake). The approach was developed and tested using fourteen years (2000-2014) of MODIS images, which showed significant spatial and temporal variability of the PC:Chla ratio, an indicator of cyanobacterial dominance. The results had unbiased RMS uncertainties of <60% for Chla ranging between 10 and 300 MUg/L, and unbiased RMS uncertainties of <65% for PC between 10 and 500 MUg/L. Further analysis showed the importance of nutrient and climate conditions for this dominance. Low TN:TP ratios (<29:1) and elevated temperatures were found to influence the seasonal shift of phytoplankton community. The resultant MODIS Chla and PC products were then used for cyanobacterial risk mapping with a decision tree classification model. The resulting Water Quality Decision Matrix (WQDM) was designed to assist authorities in the identification of possible intake areas, as well as specific months when higher frequency monitoring and more intense water treatment would be required if the location of the present intake area remained the same. Remote sensing cyanobacterial risk mapping provides a new tool for reservoir and lake management programs. PMID- 28624730 TI - Efficient degradation of tetrabromobisphenol A by synergistic integration of Fe/Ni bimetallic catalysis and microbial acclimation. AB - This study provides a novel technology for the degradation of tetrabromobisphenol A (TBBPA) via an interaction of Fe redox and a shift of functional microbial community. TBBPA was degraded by integration of synthesized Fe-Ni bimetallic particles and enriched microbial consortium within an aqueous system. This cooperative integration yielded the best TBBPA-degrading capacity (100% removal after treatment for 2 h) and highest TOC-removing efficiency (94.5% removal after treatment for 96 h), as well as the lowest toxicity to Vibrio fischeri (almost 0% growth inhibition during reaction). The synergistic mechanism of integrated system was clarified based on systematical analyses of the degradation processes as well as the shifts in microbial community. Owing to the microbial metabolism and the Fenton-like process of leaked Fe2+, Fe3+ and Ni2+ from Fe-Ni bimetallic catalyst, reactive oxidative species (ROS), including superoxide (O2-), hydroxyl radicals (OH) and hydrogen peroxide (H2O2) were produced and evaluated by multiple techniques. Moreover, the quenching experiments indicated that OH was the major ROS leading to TBBPA degradation, rather than H2O2 or O2-. Based on the analysis of the 12 detected intermediates, three parallel pathways were proposed. It was clearly revealed that reductive and oxidative debromination, hydroxylation, and beta-scission simultaneously occurred in the integrated system. Fe non-randomly accelerated the enrichment of TBBPA-degrading microbes (e.g. Pseudomonas sp. and Citrobacter sp., etc.). Above all, this novel technology has great promise for field-applications for remediation of TBBPA contaminated field. PMID- 28624731 TI - Optimizing mixing mode and intensity to prevent sludge flotation in sulfidogenic anaerobic sludge bed reactors. AB - Sludge flotation is a notorious problem in anaerobic wastewater treatment that can occur under various operational conditions and even cause the anaerobic process to completely fail. Despite having been documented for over three decades, its causes and remedies remain elusive, particularly for low-gas production anaerobic processes such as sulfidogenic and anammox processes. This paper systematically studies sludge flotation in an anaerobic sulfidogenic process for saline domestic sewage treatment. Three lab-scale sulfidogenic reactors were operated in parallel with different modes of mixing (hydraulic, mechanical and pneumatic) at various mixing intensity levels at shear rates ranging from 0.7 to 6.6 s-1 to investigate reactor performance and sludge properties and their relationships with sludge flotation potential. The results indicate that a sulfidogenic reactor with low flotation potential have sludge with low hydrophobicity, low viscosity, and low (more negative) surface charge, while the sludge particle surfaces have high compactness and low roughness. These sludge properties enabled a sludge flotation potential of less than 20% to be maintained. Furthermore, our results show that i) mixing and extracellular polymeric substances (EPS), ii) EPS and sludge properties, and iii) sludge properties and sludge flotation potential are all strongly correlated (all the Spearman's rank correlation coefficients (Rs) are either over 0.64 (if positively correlated) or under -0.64 (if negatively correlated), at the 95% confidence level). Accordingly, sludge flotation can be resolved by controlling reactor mixing. Our findings provide a method to optimize the design and operation of anaerobic sulfidogenic reactors that can be extended to similar low-gas production anaerobic bioreactors. PMID- 28624732 TI - Comparison of different treatment methods for protein solubilisation from waste activated sludge. AB - Biomaterials recovery from wasted activated sludge has become an increasing interesting research topic. The purpose of this study was to systemically evaluate different sludge disintegration methods (ultrasonic, alkaline, and thermal treatments) for protein solubilisation from waste activated sludge (WAS). Compared to control without treatment, the soluble protein concentration increased by 11, 23 and 12 times under the optimal treatment conditions (ultrasonic treatment of 1 W mL-1, alkaline treatment of pH 12 and thermal treatment at 80 degrees C). The increased soluble protein were significantly correlated with the release of total organic carbon (TOC), total dissolved nitrogen (TDN) and total organic nitrogen (TON) in soluble EPS, and the degradation of above parameters in tightly bound EPS. For all sludge samples treated by various methods, tyrosine-like protein with molecular weight less than 20 kDa predominated, and alkaline treatment at pH 12 showed the highest protein dominance. Further surface analysis of sludge by X-ray photoelectron spectroscopy indicated this might be related with the significant protein-N conversion occurred at pH 12. The economic analysis indicated alkaline treatment at pH 12 was economically feasible with a net saving of 25.57 USD per ton wet sludge compared to conventional sludge treatment and disposal method. PMID- 28624733 TI - Gastrointestinal illness linked to incidents in drinking water distribution networks in Sweden. AB - During recent years, knowledge gaps on drinking water-related gastrointestinal illness have been identified, especially for non-epidemic cases. Pathogen contamination of drinking water during distribution has been suggested to contribute to these cases, but the risk factors are not yet fully understood. During 2014-2015, we conducted an epidemiological study in five municipalities in Sweden, to assess whether incidents in the drinking water distribution system influence the risk of gastrointestinal illness. Telephone interviews were conducted in the affected areas and in reference areas 7-14 days after a reported incident. Symptoms of gastrointestinal illness occurring during the period were documented for each household member. The results showed a significantly elevated risk of vomiting and acute gastrointestinal illness (AGI) in the affected areas, compared to the reference areas (ORvom. = 2.0, 95% CI: 1.2-3.3; ORAGI = 1.9, 95% CI: 1.2-3.0). Certain conditions, or risk factors, during the incidents, such as sewage and drinking water pipelines at the same level in the trench, were associated with an elevated risk of AGI and vomiting. Safety measures taken during repair work, like flushing, were also associated with an elevated risk of AGI and vomiting. These results show that incidents in the drinking water distribution network contribute to endemic gastrointestinal illness, especially AGI and vomiting, and that external pathogen contamination of the drinking water is a likely cause of these cases of gastrointestinal illness. The results also indicate that safety measures used today may not be sufficient for eliminating the risk of gastrointestinal illness. PMID- 28624734 TI - Indirect influence of eutrophication on air - water exchange fluxes, sinking fluxes, and occurrence of polycyclic aromatic hydrocarbons. AB - How eutrophication affects biogeochemical processes of hydrophobic organic contaminants (HOCs) in aquatic environments is a pending challenge. Although the direct influence of eutrophication on biogeochemical processes of HOCs in waters has been well addressed, the indirect influence of eutrophication on biogeochemical processes of HOCs remains largely unknown. Here we take the large shallow eutrophic Lake Taihu in China and polycyclic aromatic hydrocarbons (PAHs) as examples to provide novel knowledge on the indirect influence of eutrophication on air - water exchange fluxes, sinking fluxes, and occurrence of HOCs. The air - water exchange fluxes of individual PAHs varied dramatically at different sites in all studied seasons. The sinking flux of SigmaPAH16 was 14 855.3 +/- 1579.9, 3548.9 +/- 650.6, and 5588.4 +/- 530.7 ng m-2 d-1 in spring, summer, and winter. The corresponding concentration of SigmaPAH16 in surface sediments was 713.1 +/- 78.6, 339.7 +/- 36.6, and 293.0 +/- 35.2 ng g-1 d.w. Our study for the first time suggested that recruitment of cyanobacteria from surface sediments to water column in spring reduced the concentrations of PAHs in surface sediments, but enhanced their concentrations in the bulk water column, and overwintering of cyanobacteria in winter enhanced the concentrations of PAHs in surface sediments. High pH induced indirectly by eutrophication decreased seasonal air - water exchange fluxes (enhanced net volatilization) of PAHs, reduced the aromaticity of surface sediments and the hydrophobicity of phytoplankton cell surface, and reduced the accumulation of PAHs in surface sediments and phytoplankton consequently. Sinking fluxes and daily loss of PAHs from the water column decreased with phytoplankton biomass because the fraction of organic matter sinking from the water column decreased with phytoplankton biomass. Our study provides novel complementary knowledge for the biological pump for HOCs, and has important implications for understanding the coupling between eutrophication and biogeochemical processes of HOCs in subtropical shallow eutrophic waters. PMID- 28624735 TI - Advances in high-resolution cryo-EM of oligomeric enzymes. AB - Recent advances in cryo-electron microscopy instrumentation and software have made it possible to obtain atomic resolution structures of macromolecular complexes with a small amount of material at low concentration and without the need for crystallisation. Oligomeric enzymes are particularly well suited for this technique because of their symmetry and often large size or rigid structure and can be used to explore the limits of the technique. Conformational changes can reach their full extent in solution, not hampered by crystal contacts, and multiple conformations in a sample can be separated computationally. Cryo-EM structures can be solved de novo for large complexes that resist crystallisation or structure determination by crystallographic techniques. PMID- 28624736 TI - Fluorescence of tautomeric forms of curcumin in different pH and biosurfactant rhamnolipids systems: Application towards on-off ratiometric fluorescence temperature sensing. AB - Medicinal properties of curcumin are widely getting realized. For its applicability as a hydrophobic drug molecule and food spice interaction of curcumin with rhamnolipids, a biosurfactant, bears importance. Here we have explored interaction of curcumin with rhamnolipids biosurfactant and its aggregation behavior. The impact of pH on critical micelle concentration (cmc) of rhamnolipids has been studied using fluorescence of curcumin and found that cmc of rhamnolipids increases with increase in pH of the medium. In acidic, neutral and slightly alkaline medium (pH8), at lambdaex=355nm (for beta-diketone form) curcumin undergoes excited state hydrogen transfer (ESHT) and emits solely from enol form both in the presence and absence of rhamnolipids, but first time we report that in extreme alkaline condition, at pH13, at lambdaex=355nm curcumin emits from both beta-diketone as well as enolic ESHT forms in absence of rhamnolipids but in the presence of rhamnolipids beta-diketone is stabilized and the emission solely comes from beta-diketone by completely revoking ESHT process. Fluorescence quenching by hydrophobic cetylpyridinium bromide confirms curcumin penetrates deep inside the hydrophobic pocket of rhamnolipid aggregates/micelle by reducing the distance between N+-atom of pyridinium ion and curcumin. On the other hand hydrophobic molecule like pyrene stays near to the Stern layer of rhamnolipids facilitating electron transfer from pyrene to N+-atom of pyridinium ion. Even in neutral condition, in the presence of rhamnolipids the beta-diketone form, though in small proportions, can be stabilized in higher temperature in expense of enolic ESHT form, thus, offering an on off ratiometric fluorescence temperature sensing in solution, which bears significance as ratiometric probe molecules. Interaction of curcumin with rhamnolipids stabilizes curcumin in acidic, neutral and moderate alkaline condition but fails at extreme pH13. PMID- 28624737 TI - Optical properties of the human lens constituents. AB - The absorption and fluorescence properties of the metabolomic (MET), water soluble and urea-soluble protein fractions from the middle-age, aged, and cataractous human lenses have been measured. At 280nm and 300nm the major lens absorbers are crystallins, which absorb more than 90% of light in the UV-B region (280-315nm). In middle-aged lenses, the absorption at 360nm is mostly provided by UV filters contained in the MET fraction. With aging, and especially with the cataract development, the absorption of MET fraction in UV-A region (315-400nm) decreases due to the drop of the UV filter concentration, while the absorption of protein fractions increases due to the accumulation of post-translational modifications. Consequently, the contribution of the MET fraction into the total lens absorption at 360nm decays from 63% in middle-aged lenses to 25% in aged lenses to 3% in cataractous lenses. The fluorescence yield of the MET fraction from cataractous lenses also significantly increases. Therefore, the protection of the lens tissue against UV radiation in aged and cataractous lenses weakens: the absorption of UV-A light is mostly provided by modified crystallins and non UV-filter metabolites, which are photochemically more active than the UV filters. The obtained data indicate that the aged and cataractous human lenses are more vulnerable to UV-A light than the middle-aged lenses. PMID- 28624738 TI - Accelerating anodic biofilms formation and electron transfer in microbial fuel cells: Role of anionic biosurfactants and mechanism. AB - Anodic electron transfer is the predominant electricity generation process of MFCs. To accelerate anodic biofilms formation and electron transfer, 40mg/L, 80mg/L, and 120mg/L of rhamnolipid biosurfactants were added to the anolyte, resulting in an increased abiotic capacitance from 15.12F/m2 (control) to 16.54F/m2, 18.00F/m2, and 19.39F/m2, respectively. Anodic biofilm formation was facilitated after dosing 40mg/L of rhamnolipids on the 7th day after inoculation, resulting in an increased anodic biofilm coverage from 0.43% to 42.51%, and an increased maximum power density from 6.92+/-1.18W/m3 to 9.93+/-0.88W/m3. Furthermore, the adsorption of rhamnolipids on the anode caused the Frumkin effect, leading to a decrease of equilibrium potential from -0.43V to -0.56V, and an increase of exchange current density from 5.09*10-3A/m2 to 8.72*10-3A/m2. However, electron transfer was blocked when the rhamnolipid concentration was further increased to 80mg/L, and 120mg/L. Analysis of the anodic bacterial communities revealed that rhamnolipids facilitated the enrichment of exoelectrogen, increasing the total proportion from 65% to 81%. Additionally, biosurfactants were found to have significant impacts on the composition of exoelectrogens. PMID- 28624739 TI - Degradation of 1,4-dioxane by biochar supported nano magnetite particles activating persulfate. AB - Nano magnetite biochar composite (nFe3O4/biochar) was synthesized and used to activate persulfate for the degradation of 1,4-dioxane. Analytical techniques using X-ray diffraction (XRD), fourier transform infrared analysis (FTIR), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) indicated that nFe3O4 was spherical and successfully loaded onto the surface of biochar. The results of batch-scale experiments illustrated that the 1,4-dioxane degradation efficiency in aqueous phase was 98.0% after 120 min reaction with the composite mass ratio of 1:1 between nFe3O4 and the pine needle biochar pyrolyzed at 400 degrees C (P400) under the initial neutral pH. An electron paramagnetic resonance (EPR) study, free radical quenching experiment and XPS analysis were undertaken to illustrate the mechanism of persulfate activation by nFe3O4/biochar. Under acidic and neutral conditions, the predominant free radical was SO4- whereas OH and SO4- predominated when the initial pH was 9.0. The XPS analysis indicated that Fe(II) and oxygenated functional groups activated persulfate. In addition, carbon-carbon double bonds would be transformed into ketone and quinone which could activate persulfate during the reaction. PMID- 28624740 TI - Role of organic acids on the bioavailability of selenium in soil: A review. AB - Organic Acids (OAs) are important components in the rhizosphere soil and influence Se bioavailability in soil. OAs have a bidirectional contrasting effect on Se bioavailability. Understanding the interaction of OAs with Se is essential to assessing Se bioavailability in soil and clarifying the role of OAs in controlling the behavior and fate of Se in soil. This review examines the mechanisms for the (im)mobilization of Se by OAs and discusses the practical implications of these mechanisms in relation to sequestration and bioavailability of Se in soil. PMID- 28624741 TI - Reduced sludge growth at high bulk liquor dissolved oxygen induced by increased secondary cell maintenance. AB - Sludge reduction by physico-chemical methods results in the buildup of chemicals, which may require further treatment. Owing these reasons various biologically sustainable methods of sludge reduction including the application of high oxygenation have been successfully tested. Experiments on actual sewage in two lab-scale sequencing batch reactors (SBRs) were conducted under normal (1.5-2.5 mgDO/L) and high dissolved oxygen (DO) (HDO: 3-6.5 mgDO/L) regimes. It was observed that microorganism allocated substrate between maintenance and growth in the form of maintenance coefficient. Which could be induced by endogenous respiration owing to high solids retention time (SRT), predation on bacteria, chemical toxicity, adverse environment, and viral attack on bacteria. The wastewater treatment process may experience one or more maintenance inducing factors; nevertheless, high SRT and prevailing environmental conditions are imminent and thus considered as primary maintenance (mp), while remaining are classified as secondary maintenance (ms). Average yield coefficient reduction at HDO was 32.7% and 28.2% compared to stoichiometric and at normal DO, respectively. The observed primary and secondary maintenance was 0.11gCOD/gVSS.d (+/-0.01) at an SRT of 25.2 d (+/-2.0) and 0.096 g 0.1 gCOD/gVSS.d (+/-0.045) at an SRT of 24.2 d (+/-3.6d), respectively. The results obtained under the study are not as precise as on pure culture and defined substrate, nevertheless, it gives an idea that how stress factors inducing maintenance need to be addressed more seriously and objectively while managing our efforts on sludge reduction. PMID- 28624742 TI - Ionic liquids toxicity on fresh water microalgae, Scenedesmus quadricauda, Chlorella vulgaris &Botryococcus braunii; selection criterion for use in a two phase partitioning bioreactor (TPPBR). AB - A promising method of Carbon dioxide (CO2) valorization is to use green microalgae photosynthesis to process biofuel. Two Phase Partitioning Bioreactors (TPPBR) offer the possibility to use non-aqueous phase liquids (NAPL) to enhance CO2 solubility; thus making CO2 available to maximize algae growth. This requires relatively less toxic hydrophobic Ionic Liquids (ILs) that comprise a new class of ionic compounds with remarkable physicochemical properties and thus qualifies them as NAPL candidates. This paper concerns the synthesis of ILs with octyl and butyl chains as well as different cations containing aromatic (imidazolium, pyridinium) and non-aromatic (piperidinum, pyrrolidinium) rings for CO2 absorption studies. The authors measured their respective toxicity levels on microalgae species, specifically, Scenedesmus quadricauda, Chlorella vulgaris and Botryococcus braunii. Results revealed that octyl-based ILs were more toxic than butyl-based analogues. Such was the case for bmim-PF6 at double saturation with an absorbance of 0.11, compared to Omim-PF6 at 0.17, bmim-NTf2 at 0.02, and Omim NTf2 at 0.14, respectively. CO2 uptake results for ILs bearing octyl-based chains compared to the butyl analog were 54% (nCO2/nIL) (i.e., moles of CO2 moles of IL) and 38% (nCO2/nIL), respectively. Conclusively, 1-butyl-1-methylpiperidinium absorbed 13% (nCO2/nIL) and appeared the least toxic, having an absorbance of 0.25 at 688 nm (double saturation at 7 d) compared to 1-butyl-3 methylimidazolium, which showed the highest toxicity with zero absorbance. Accordingly, these findings suggest that 1-butyl-1-methylpiperidinium is capable of transporting CO2 to a system containing green microalgae without causing significant harm; thus allowing its use in TPPBR technology. PMID- 28624743 TI - Facile fabrication of carbon microspheres decorated with B(OH)3 and alpha-Fe2O3 nanoparticles: Superior microwave absorption. AB - We demonstrate that novel three-dimensional (3D) B(OH)3 and alpha-Fe2O3 nanoparticles decorated carbon microspheres (B(OH)3/alpha-Fe2O3-CMSs) can be fabricated via a facile thermal treatment process. The carbon microspheres with diameter of 1-3MUm and decorated B(OH)3 and alpha-Fe2O3 nanoparticles with diameters of several to tens of nanometers are successfully fabricated. These novel 3D B(OH)3/alpha-Fe2O3-CMS composites exhibit enhanced microwave absorption with tunable strong absorption wavebands in the frequency range of 2-18GHz. They have a minimum reflection loss (RL) value of -52.69dB at a thickness of 3.0mm, and the effective absorption bandwidth for RL less than -10dB is as large as 5.64GHz. The enhanced microwave absorption performance arises from the synergy of the impedance matching caused by the B(OH)3 nanoparticles, dielectric loss as well as the enhancement of multiple reflection among 3D alpha-Fe2O3 nanocrystals. These results provide a new strategy to tune electromagnetic properties and enhance the capacity of high-efficient microwave absorbers. PMID- 28624744 TI - Optimization of the synthesis of Pd-Au nanoalloys confined in mesoporous carbonaceous materials. AB - Pd-Au nanoalloys confined in mesoporous carbonaceous materials were synthesized by a rapid one-pot microwave assisted approach. Green polymer resins based on phloroglucinol/glyoxylic acid or glyoxal were co-assembled in the presence of a template and metallic salts followed by microwave treatment between 40 and 80 degrees C and subsequent thermal annealing, allowing simultaneous formation of mesoporous carbonaceous materials with in-situ confined Pd-Au nanoparticles. Several Pd-Au compositions were prepared (PdxAu100-x, where x=90; 80; 70 and 50) and their impact on the alloy structure and particle size/distribution evaluated. For Pd90Au10, homogeneously dispersed nanoalloy particles (~8nm) are obtained in the carbonaceous framework. The increase in the Au content in the alloy gradually induces an increase in the particle size and agglomeration of the particles along with the formation of multiphased alloys, i.e., segregated Pd- and Au-rich nanoparticles. The particle agglomeration was avoided by decreasing the thermal annealing time. The homogeneity of the alloy structure was found to strongly depend by two parameters, the chelating/cross-linker agents and the microwave temperature, i.e., the chelating/cross-linker agents containing carboxylic groups and the higher temperatures inducing more heterogeneous structures. The hydrogen absorption in Pd90Au10 particles with different homogeneity degree was studied at room temperature up to 1bar. Generally, hydrogen absorbs in Pd-rich nanoalloys forming a hydride phase whereas Au-rich phases do not absorb hydrogen under the present conditions. PMID- 28624745 TI - Silver chloride enwrapped silver grafted on nitrogen-doped reduced graphene oxide as a highly efficient visible-light-driven photocatalyst. AB - The visible-light-driven plasmonic photocatalyst silver chloride enwrapped silver/nitrogen-doped reduced graphene oxide (AgCl@Ag/N-rGO) was prepared by a facile hydrothermal-in situ oxidation method and characterized by Scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FTIR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and UV-vis diffuse reflectance spectroscopy (UV-vis DRS). The characterization results reveal that Ag nanoparticles (NPs) were first grafted on N-rGO via N groups as anchor sites and then enwrapped by AgCl by in situ oxidation. Close interfacial contact favors efficient electron transfer, leading to high photoactivity and photostability for the degradation of various toxic organic pollutants. The photocatalytic performance of this photocatalyst was significantly higher than that of AgCl@Ag/rGO and other related photocatalysts due to the in situ introduction of N-groups. Additionally, the used catalyst can be recycled without an appreciable loss of catalytic activity. Based on electron spin resonance and cyclic voltammetry analyses, the electron transfer processes were confirmed to occur from plasmon-induced Ag NPs to AgCl and from N-rGO to Ag NPs, and pollutants could be oxidized through the loss of electrons to N-rGO by the interaction between the pollutants and N-rGO. The active species of superoxide anion radicals (O2-), photogenerated holes (h+) and surface-adsorbed OH played roles in pollutant photodegradation. Accordingly, the plasmon-induced electron transfer processes elucidated photostability of AgCl@Ag/N-rGO. AgCl@Ag/N rGO has a potential application in water purification due to its high photoactivity and photostability. PMID- 28624746 TI - Textual properties and catalytic performances of halloysite hybrid CeO2-ZrO2 nanoparticles. AB - Halloysite (Hal) hybridized ceria-zirconia solid solution material (CZ-Hal) for three way catalysis was synthesized through co-precipitation method. X-ray diffraction (XRD), N2 adsorption-desorption isotherms, transmission electronic microscopy (TEM), scanning electronic microscopy (SEM), X-ray energy dispersion spectrum (EDS), and temperature-programmed H2 reduction (H2-TPR) were used to characterize the crystalline, textural, morphological, and reducibility of the products. The three way catalytic performances of the supported products was tested in stoichiometric air/fuel condition. The modified Hal hybridized cerium- zirconium solid solutions showed a rod-like morphology consisted of agglomerated nanoparticles with sizes of about 100nm. The adaption of PEG-4000has guided the formation of the nano-rods in the products. The Hal mineral in the composites retained their tubular morphology. The CZ-Hal composite showed larger BET surface area (130m2/g compared to 71m2/g), concentrated pore size distribution, as well as lower reduction temperature, compared with the pure CZ solid solutions. The supported Pd-Rh/CZ-Hal showed optimized catalytic performances for CO, NOx (conversion up to 98%), and CnHm (70%) at light-off temperatures. PMID- 28624747 TI - Who is most affected by prenatal alcohol exposure: Boys or girls? AB - OBJECTIVE: To examine outcomes among boys and girls that are associated with prenatal alcohol exposure. METHODS: Boys and girls with fetal alcohol spectrum disorders (FASD) and randomly-selected controls were compared on a variety of physical and neurobehavioral traits. RESULTS: Sex ratios indicated that heavy maternal binge drinking may have significantly diminished viability to birth and survival of boys postpartum more than girls by age seven. Case control comparisons of a variety of physical and neurobehavioral traits at age seven indicate that both sexes were affected similarly for a majority of variables. However, alcohol-exposed girls had significantly more dysmorphology overall than boys and performed significantly worse on non-verbal IQ tests than males. A three step sequential regression analysis, controlling for multiple covariates, further indicated that dysmorphology among girls was significantly more associated with five maternal drinking variables and three distal maternal risk factors. However, the overall model, which included five associated neurobehavioral measures at step three, was not significant (p=0.09, two-tailed test). A separate sequential logistic regression analysis of predictors of a FASD diagnosis, however, indicated significantly more negative outcomes overall for girls than boys (Nagelkerke R2=0.42 for boys and 0.54 for girls, z=-2.9, p=0.004). CONCLUSION: Boys and girls had mostly similar outcomes when prenatal alcohol exposure was linked to poor physical and neurocognitive development. Nevertheless, sex ratios implicate lower viability and survival of males by first grade, and girls have more dysmorphology and neurocognitive impairment than boys resulting in a higher probability of a FASD diagnosis. PMID- 28624748 TI - Value of diagnostic imaging for the symptomatic male breast: Can we avoid unnecessary biopsies? AB - PURPOSE: To review the use of diagnostic breast imaging and outcomes for symptomatic male patients. METHODS: We retrospectively evaluated 122 males who underwent diagnostic imaging for breast symptoms at our academic center. RESULTS: The majority (94%) of cases had negative or benign imaging, with gynecomastia being the most common diagnosis (78%). There were two malignancies, both of which had positive imaging. Fifteen patients underwent percutaneous biopsy, and over half (53%) were palpation-guided biopsies initiated by the referring clinician despite negative imaging. Diagnostic imaging demonstrated 100% sensitivity and 96% specificity for identifying cancer. CONCLUSIONS: Malignancy is rarely a cause of male breast symptoms. Diagnostic breast imaging is useful to establish benignity and avert unnecessary biopsies. PMID- 28624749 TI - Prevalence and clinical significance of incidental extra-mammary findings in breast magnetic resonance imaging: A retrospective study of 1070 patients. AB - PURPOSE: The purpose of this study was to analyze the prevalence of extra-mammary findings in magnetic resonance imaging (MRI). MATERIALS AND METHODS: Data from 1070 consecutive breast MRI studies was analyzed. MR-BI-RADS (Breast Imaging Reporting and Data System) was used to classify the risk category. RESULTS: According to MR-BI-RADS, 915 (85.5%) of 1070 women were classified into MR-BI RADS categories 1-3, and 155 (14.5%) into MR-BI-RADS categories 4-5. MR-BI-RADS categories 4-5 had a 10-times higher risk for major extra-mammary findings (odds ratio 10.1, P<0.01). CONCLUSION: Extra-mammary findings are common and may have important clinical consequences. PMID- 28624751 TI - Organophosphate esters flame retardants in the indoor environment. AB - Concentrations of 13 organophosphate ester flame retardants (OPEs) were measured in air, dust and window wipes from 63 homes in Canada, the Czech Republic and the United States in the spring and summer of 2013 to look for abundances, differences among regions, and partitioning behavior. In general, we observed the highest concentrations for halogenated OPEs, particularly TCEP, TCIPP and TDCIPP, and also non-halogenated TPHP. Differences between regions strongly depended on the matrix. The concentrations of OPEs in dust were significantly higher in the US than in Canada (CAN) and Czech Republic (CZ). CZ had the highest concentrations in window film and CAN in air. SigmaOPE concentrations were 2-3 and 1-2 orders of magnitude greater than SigmaBFRs in air, and dust and window films, respectively. We found a significant relationship between the concentrations in dust and air, and between the concentrations in window film and air for OPEs with log KOA values <12, suggesting that equilibrium was reached for these compounds but not for those with log KOA>12. This hypothesis was confirmed by a large discrepancy between values predicted using a partitioning model and the measured values for OPEs with log KOA values >12. PMID- 28624750 TI - Long-term indoor air conditioner filtration and cardiovascular health: A randomized crossover intervention study. AB - The association of short-term air pollution filtration with cardiovascular health has been documented. However, the effect of long-term indoor air conditioner filtration on the association between air pollution and cardiovascular health is still unclear. We recruited 200 homemakers from Taipei and randomly assigned 100 of them to air filtration or control intervention; six home visits were conducted per year from 2013 to 2014. The participants under air filtration intervention during 2013 were reassigned to control intervention in 2014. The air pollution measurements consisted of particulate matter less than or equal to 2.5MUm in diameter (PM2.5) and total volatile organic compounds (VOCs); blood pressure was monitored for each participant during each visit. The following morning, blood samples were collected after air pollution monitoring. The blood samples were used to analyze biological markers, including high sensitivity-C-reactive protein (hs-CRP), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and fibrinogen. Household information, including cleaning, cooking, and air conditioning, was collected by a questionnaire. Mixed-effects models were used to investigate the associations among air pollution measurements, blood pressure and biological markers. The results showed that increased levels of PM2.5 and total VOCs were associated with increased hs-CRP, 8-OHdG and blood pressure. The health variables were higher among participants in the control intervention phase than among those in the air filtration intervention phase. We concluded that air pollution exposure was associated with systemic inflammation, oxidative stress and elevated blood pressure. The long-term filtration of air pollution with an air conditioner filter was associated with cardiovascular health of adults. PMID- 28624752 TI - Skin hydration and lifestyle-related factors in community-dwelling older people. AB - OBJECTIVE: This study aimed to investigate skin hydration status of the lower legs by comparing several methods and examining lifestyle-related factors in community-dwelling older people. METHODS: A cross-sectional study was conducted in three community settings in Japan from autumn to winter. Participants were older people aged >=65 years (n=118). Skin hydration status of the lower legs was evaluated by stratum corneum hydration using an electrical device, clinical symptoms by an expert's observation and the visual analogue scale. Lifestyle factors of skin care were evaluated by a self-administered questionnaire. RESULTS: The mean age of participants was 74.4 years and 83.9% were women. Stratum corneum hydration was significantly correlated with clinical scores by an expert's observation (rho=-0.46, P<0.001), but it was not correlated with the visual analogue scale (rho=-0.08, P=0.435). Among participants who did not perceive dry skin, 57.5% showed low stratum corneum hydration. Hospitalization in the past year (b=-9.4, P=0.008), excessive bathing habits (b=-4.6, P=0.014), and having an outdoor hobby (b=-5.7, P=0.007) were negatively associated, and diuretics (b=11.5, P=0.002) and lotion-type moisturizer use (b=4.6, P=0.022) were positively associated with stratum corneum hydration. CONCLUSION: Stratum corneum hydration measurements show an adequate association with observation-based evaluation by an expert, but poor agreement with subjective evaluation in community-dwelling older people. Hospitalization experience and lifestyle factors are associated with skin hydration. PMID- 28624753 TI - Treatment of asymptomatic UTI in older delirious medical in-patients: A prospective cohort study. AB - BACKGROUND: Despite clinical practice guidelines, asymptomatic bacteriuria (ASB) in older people is frequently treated. A common reason for treating ASB is a change in mental status. OBJECTIVE: To determine how often asymptomatic UTI is treated in older medically ill delirious individuals and its association with functional recovery. METHODS: Consecutive older medical in-patients were screened for delirium, and followed in hospital. Treatment for asymptomatic UTI was defined as documented treatment for a possible urinary tract infection with antibiotics, without concurrent infectious or urinary symptoms. The primary outcome was functional recovery at discharge or 3 months post-discharge. Poor functional recovery was defined by any one of death, new permanent long-term institutionalization or decreased ability to perform activities of daily living. RESULTS: The study sample comprised 343 delirious in-patients, of which 237 (69%) had poor functional recovery. Ninety two (27%) delirious in-patients were treated for asymptomatic UTI. Treatment for asymptomatic UTI was associated with poor functional recovery compared to other delirious in-patients (RR 1.30, 95% CI: 1.14-1.48 overall). Similar results were seen when the analysis was restricted to only bacteriuric delirious individuals. Seven (7.5%) individuals treated for asymptomatic UTI developed Clostridium difficile infection compared to eight (3.2%) in the remainder of the delirious cohort (OR 2.45, 95% CI: 0.86-6.96). CONCLUSIONS: These results suggest that treatment of asymptomatic UTI in older medical in-patients with delirium is common, and of questionable benefit. Further research is needed to establish guidelines to minimize over-treatment of UTI in older delirious in-patients. PMID- 28624754 TI - Automatic segmentation of the lumen region in intravascular images of the coronary artery. AB - Image assessment of the arterial system plays an important role in the diagnosis of cardiovascular diseases. The segmentation of the lumen and media-adventitia in intravascular (IVUS) images of the coronary artery is the first step towards the evaluation of the morphology of the vessel under analysis and the identification of possible atherosclerotic lesions. In this study, a fully automatic method for the segmentation of the lumen in IVUS images of the coronary artery is presented. The proposed method relies on the K-means algorithm and the mean roundness to identify the region corresponding to the potential lumen. An approach to identify and eliminate side branches on bifurcations is also proposed to delimit the area with the potential lumen regions. Additionally, an active contour model is applied to refine the contour of the lumen region. In order to evaluate the segmentation accuracy, the results of the proposed method were compared against manual delineations made by two experts in 326 IVUS images of the coronary artery. The average values of the Jaccard measure, Hausdorff distance, percentage of area difference and Dice coefficient were 0.88 +/- 0.06, 0.29 +/- 0.17 mm, 0.09 +/- 0.07 and 0.94 +/- 0.04, respectively, in 324 IVUS images successfully segmented. Additionally, a comparison with the studies found in the literature showed that the proposed method is slight better than the majority of the related methods that have been proposed. Hence, the new automatic segmentation method is shown to be effective in detecting the lumen in IVUS images without using complex solutions and user interaction. PMID- 28624755 TI - Stereo vision-based tracking of soft tissue motion with application to online ablation control in laser microsurgery. AB - Recent research has revealed that image-based methods can enhance accuracy and safety in laser microsurgery. In this study, non-rigid tracking using surgical stereo imaging and its application to laser ablation is discussed. A recently developed motion estimation framework based on piecewise affine deformation modeling is extended by a mesh refinement step and considering texture information. This compensates for tracking inaccuracies potentially caused by inconsistent feature matches or drift. To facilitate online application of the method, computational load is reduced by concurrent processing and affine invariant fusion of tracking and refinement results. The residual latency dependent tracking error is further minimized by Kalman filter-based upsampling, considering a motion model in disparity space. Accuracy is assessed in laparoscopic, beating heart, and laryngeal sequences with challenging conditions, such as partial occlusions and significant deformation. Performance is compared with that of state-of-the-art methods. In addition, the online capability of the method is evaluated by tracking two motion patterns performed by a high-precision parallel-kinematic platform. Related experiments are discussed for tissue substitute and porcine soft tissue in order to compare performances in an ideal scenario and in a setup mimicking clinical conditions. Regarding the soft tissue trial, the tracking error can be significantly reduced from 0.72 mm to below 0.05 mm with mesh refinement. To demonstrate online laser path adaptation during ablation, the non-rigid tracking framework is integrated into a setup consisting of a surgical Er:YAG laser, a three-axis scanning unit, and a low-noise stereo camera. Regardless of the error source, such as laser-to-camera registration, camera calibration, image-based tracking, and scanning latency, the ablation root mean square error is kept below 0.21 mm when the sample moves according to the aforementioned patterns. Final experiments regarding motion-compensated laser ablation of structurally deforming tissue highlight the potential of the method for vision-guided laser surgery. PMID- 28624756 TI - Fat is fashionable and fit: A comparative content analysis of Fatspiration and Health at Every Size(r) Instagram images. AB - In step with the proliferation of Thinspiration and Fitspiration content disseminated in popular web-based media, the fat acceptance movement has garnered heightened visibility within mainstream culture via the burgeoning Fatosphere weblog community. The present study extended previous Fatosphere research by comparing the shared and distinct strategies used to represent and motivate a fat accepting lifestyle among 400 images sourced from Fatspiration- and Health at Every Size(r)-themed hashtags on Instagram. Images were systematically analyzed for the socio-demographic and body size attributes of the individuals portrayed alongside content reflecting dimensions of general fat acceptance, physical appearance pride, physical activity and health, fat shaming, and eating and weight loss-related themes. #fatspiration/#fatspo-tagged images more frequently promoted fat acceptance through fashion and beauty-related activism; #healthateverysize/#haes posts more often featured physically-active portrayals, holistic well-being, and weight stigma. Findings provide insight into the common and unique motivational factors and contradictory messages encountered in these fat-accepting social media communities. PMID- 28624757 TI - Implementation of a disability management policy in a large healthcare employer: a quasi-experimental, mixed-methods evaluation. AB - OBJECTIVE: This study describes the process and outcomes of the implementation of a strengthened disability management policy in a large Canadian healthcare employer. Key elements of the strengthened policy included an emphasis on early contact, the training of supervisors and the integration of union representatives in return-to-work (RTW) planning. DESIGN: The study applied mixed methods, combining a process evaluation within the employer and a quasi-experimental outcome evaluation between employers for a 3-year period prior to and following policy implementation in January 2012. PARTICIPANTS: Staff in the implementation organisation (n=4000) and staff in a peer group of 29 large hospitals (n=1 19 000). OUTCOMES: Work disability episode incidence and duration. RESULTS: Both qualitative and quantitative measures of the implementation process were predominantly positive. Over the 6-year observation period, there were 624 work disability episodes in the organisation and 8604 in the comparison group of 29 large hospitals. The annual per cent change in episode incidence in the organisation was -5.6 (95% CI -9.9 to -1.1) comparable to the annual per cent change in the comparison group: -6.2 (-7.2 to -5.3). Disability episode durations also declined in the organisation, from a mean of 19.4 days (16.5, 22.3) in the preintervention period to 10.9 days (8.7, 13.2) in the postintervention period. Reductions in disability durations were also observed in the comparison group: from a mean of 13.5 days (12.9, 14.1) in the 2009-2011 period to 10.5 days (9.9, 11.1) in the 2012-2014 period. CONCLUSION: The incidence of work disability episodes and the durations of work disability declined strongly in this hospital sector over the 6-year observation period. The implementation of the organisation's RTW policy was associated with larger reductions in disability durations than observed in the comparison group. PMID- 28624758 TI - Prevalence, incidence and aetiologies of pulmonary hypertension in Africa: a systematic review and meta-analysis protocol. AB - INTRODUCTION: There are no data summarising the epidemiology of pulmonary hypertension (PH) among adults residing in Africa. Establishment of accurate epidemiological data on PH in this region may guide decision-making toward interventions to curb the burden of PH in Africa. The aim of this systematic review is to determine the prevalence, incidence and aetiologies of PH among people residing in Africa. METHODS AND ANALYSIS: This systematic review and meta analysis will follow the MOOSE guidelines for reporting. Relevant abstracts published until 30 September 2016 will be searched in PubMed/Medline, EMBASE (Excerpta Medica Database), African Journals Online and Africa Index Medicus. Full texts of eligible studies will then be accessed through PubMed, Google Scholar, HINARI and the respective journals' websites. Relevant unpublished papers and conference proceedings will also be checked. Data will be analysed using STATA version 13 software. The study-specific estimates will be pooled through a random-effects meta-analysis model to obtain an overall summary estimate of the prevalence/incidence and aetiologies of PH across studies. Heterogeneity of studies will be evaluated by the chi2 test on Cochrane's Q statistic. Funnel plot analysis and Egger's test will be done to detect publication bias. Results will be presented by geographical region (central, eastern, northern, southern and western Africa). ETHICS AND DISSEMINATION: The current study is based on published data; ethical approval is, therefore, not required. This review will guide policy, practice and research by providing information on the magnitude of PH among people residing in Africa. Findings will be presented in evidence tables of individual studies as well as in summary tables. The final report of this systematic review, in the form of a scientific paper, will be published in a peer-reviewed journal. Furthermore, findings will be presented at conferences and submitted to relevant health authorities. REVIEW REGISTRATION NUMBER: PROSPERO CRD42016049351. PMID- 28624759 TI - GPs' attitudes, beliefs and behaviours regarding exercise for chronic knee pain: a questionnaire survey. AB - OBJECTIVES: The aim of this study was to investigate general practitioners' (GPs) attitudes, beliefs and behaviours regarding the use of exercise for patients with chronic knee pain (CKP) attributable to osteoarthritis. SETTING: Primary care GPs in the UK. PARTICIPANTS: 5000 GPs, randomly selected from Binley's database, were mailed a cross-sectional questionnaire survey. OUTCOME MEASURES: GPs' attitudes and beliefs were investigated using attitude statements, and reported behaviours were identified using vignette-based questions. GPs were invited to report barriers experienced when initiating exercise with patients with CKP RESULTS: 835 (17%) GPs responded. Overall, GPs were positive about general exercise for CKP. 729 (87%) reported using exercise, of which, 538 (74%) reported that they would use both general and local (lower limb) exercises. However, only 92 (11% of all responding) GPs reported initiating exercise in ways aligning with best-evidence recommendations. 815 (98%) GPs reported barriers in using exercise for patients with CKP, most commonly, insufficient time in consultations (n=419; 51%) and insufficient expertise (n=337; 41%). CONCLUSIONS: While GPs' attitudes and beliefs regarding exercise for CKP were generally positive, initiation of exercise was often poorly aligned with current recommendations, and barriers and uncertainties were reported. GPs' use of exercise may be improved by addressing the key barriers of time and expertise, by developing a pragmatic approach that supports GPs to initiate individualised exercise, and/or by other professionals taking on this role. PMID- 28624760 TI - How do smoking cessation medicines compare with respect to their neuropsychiatric safety? A protocol for a systematic review, network meta-analysis and cost effectiveness analysis. AB - INTRODUCTION: Cigarette smoking is one of the leading causes of early death in the UK and worldwide. Public health guidance recommends the use of varenicline, bupropion and nicotine replacement therapy (NRT) as smoking cessation aids in the UK. Additionally, the first electronic cigarette has been licensed for use as a smoking cessation medicine. However, there are ongoing concerns about the safety of these medicines. We present a protocol for a systematic review and network meta-analysis (NMA) to determine how these smoking cessation medicines compare to each other with respect to their neuropsychiatric safety in adult smokers. Secondary aims include updating the evidence regarding the effectiveness and cardiovascular safety of these medicines for use in a cost-effectiveness analysis. METHODS AND ANALYSIS: We will include randomised controlled trials and observational studies with control groups comparing monotherapy with varenicline, bupropion, NRT or electronic cigarette and combination therapies to each other, placebo or usual care. The primary composite safety outcome will be serious adverse events, defined as events that resulted in death, were life threatening, required hospitalisation or resulted in significant disability or congenital/birth defect. The preferred effectiveness outcome will be sustained smoking cessation defined as abstinence for a minimum of 6 months as determined by biochemical validation. We will include trials identified by previous reviews and search relevant databases for newly published trials as well as contacting study authors to identify unpublished information. We will conduct fixed-effect and random-effect meta-analyses for each pairwise comparison of treatments and outcome; where these estimates differ, we will consider reasons for heterogeneity, quantified using the between-study variance (tau2). For each outcome, we will construct a NMA in a Bayesian framework which will be compared with the pair-wise results, allowing us to rank treatments. The effectiveness estimates from the NMA will be entered into a probabilistic economic model. ETHICS AND DISSEMINATION: Ethics approval is not required for this evidence synthesis study as it involves analysis of secondary data from randomised controlled trials and observational studies. The review will make an important contribution to the knowledge base around the effectiveness, safety and cost effectiveness of smoking cessation medicines. Results will be disseminated to the general public, healthcare practitioners and clinicians, academics, industry and policy makers. PROSPERO REGISTRATION NUMBER: CRD42016041302. PMID- 28624762 TI - Contraception choices for transgender males. PMID- 28624761 TI - Factors influencing psychological, social and health outcomes after major burn injuries in adults: cohort study protocol. AB - INTRODUCTION: The goal of burn care is that 'the quality of the outcome must be worth the pain of survival'. More research is needed to understand how best to deliver care for patients with burns to achieve this aim. Loss of independence, function as well as loss of income for patients with burns and carers cause a significant burden at both individual and societal levels. Much is being done to advance knowledge in the clinical care field; however, there has been a paucity of research exploring psychosocial outcomes. This paper describes the study background and methods, as implemented in an Australian cohort study of psychosocial outcomes after major burn injuries. METHODS AND ANALYSIS: In this inception cohort study, a target sample of 230 participants, aged 18 years or over, admitted to a single statewide burns centre with a burn injury are identified by hospital staff for inclusion. Baseline survey data are collected either in person or by telephone within 28 days of the injury and participants then followed up with telephone interviews at 3, 6 and 12 months postburn. Injury and burns treatment information is collected from medical records. Social support is measured as a predictor variable using the Multidimensional Scale of Perceived Social Support. Outcome data are collected via standardised measures in the domains of Quality of Life (SF-12, EQ-5D, BSHS-B), depression (PHQ-9), post traumatic stress disorder (PCL-C, PAS), community integration (CIQ-R) and Quality Adjusted Life Years (EQ-5D). Additional survey questions measure life satisfaction, return to work and public services utilisation at 12 months postinjury. Data analysis methods will include analysis of variance, Pearson correlation and hierarchical multiple regression analyses. ETHICS AND DISSEMINATION: Hospital-based and University of Queensland Human Research Ethics Committees have approved the protocol. Results from the study will be disseminated at national and international conferences, in peer-reviewed journals and in a doctoral thesis. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry (ACTRN12616000828426). Retrospectively registered on 23 June 2016; pre-results. PMID- 28624763 TI - Electronic cigarette use among US adults in the Population Assessment of Tobacco and Health (PATH) Study, 2013-2014. AB - BACKGROUND: Electronic cigarette (e-cigarette) use in the USA is increasing. As such, it is critical to understand who uses e-cigarettes, how e-cigarettes are used and what types of products are prevalent. This study assesses patterns of current e-cigarette use among daily and non-daily adult users in the 2013-2014 Population Assessment of Tobacco and Health (PATH) Study. METHODS: We examined the proportion of current adult e-cigarette users (n=3642) reporting infrequent use (use on 'some days' and use on 0-2 of the past 30 days), moderate use (use on 'some days' and use on >2 of the past 30 days) and daily use. We examined demographic characteristics, use of other tobacco products and e-cigarette product characteristics overall and by use category. Adjusted prevalence ratios (aPRs) were calculated using Poisson regression to assess correlates of daily e cigarette use. RESULTS: Among the 5.5% of adult current e-cigarette users in the PATH Study, 42.2% reported infrequent use, 36.5% reported moderate use and 21.3% reported daily use. Cigarette smokers who quit in the past year were more likely to report daily e-cigarette use, compared with current smokers (aPR=3.21, 95% CI=2.75 to 3.76). Those who reported using rechargeable or refillable devices were more likely to report daily use compared with those who did not use these devices (aPR=1.95, 95% CI=1.44 to 2.65 and aPR=2.10, 95% CI=1.75 to 2.52, respectively). CONCLUSIONS: The majority of e-cigarette users in this study reported less than daily use. Compared with non-daily use, daily use was associated with being a former smoker; however, cross-sectional data limits our ability to establish the temporality or directionality of such associations. PMID- 28624764 TI - Recommended core items to assess e-cigarette use in population-based surveys. AB - A consistent approach using standardised items to assess e-cigarette use in both youth and adult populations will aid cross-survey and cross-national comparisons of the effect of e-cigarette (and tobacco) policies and improve our understanding of the population health impact of e-cigarette use. Focusing on adult behaviour, we propose a set of e-cigarette use items, discuss their utility and potential adaptation, and highlight e-cigarette constructs that researchers should avoid without further item development. Reliable and valid items will strengthen the emerging science and inform knowledge synthesis for policy-making. Building on informal discussions at a series of international meetings of 65 experts from 15 countries, the authors provide recommendations for assessing e-cigarette use behaviour, relative perceived harm, device type, presence of nicotine, flavours and reasons for use. We recommend items assessing eight core constructs: e cigarette ever use, frequency of use and former daily use; relative perceived harm; device type; primary flavour preference; presence of nicotine; and primary reason for use. These items should be standardised or minimally adapted for the policy context and target population. Researchers should be prepared to update items as e-cigarette device characteristics change. A minimum set of e-cigarette items is proposed to encourage consensus around items to allow for cross-survey and cross-jurisdictional comparisons of e-cigarette use behaviour. These proposed items are a starting point. We recognise room for continued improvement, and welcome input from e-cigarette users and scientific colleagues. PMID- 28624765 TI - Indications and appropriate selection of novel oral anticoagulants in patients with atrial fibrillation. PMID- 28624766 TI - DHEA protects mitochondria against dual modes of apoptosis and necroptosis in human granulosa HO23 cells. AB - Because ovarian granulosa cells are essential for oocyte maturation and development, we validated human granulosa HO23 cells to evaluate the ability of the DHEA to prevent cell death after starvation. The present study was aimed to investigate whether DHEA could protect against starvation-induced apoptosis and necroptosis in human oocyte granulosa HO23 cells. The starvation was induced by treatment of serum-free (SF) medium for 4 h in vitro Starvation-induced mitochondrial depolarization, cytochrome c release and caspase-3 activation were largely prevented by DHEA in HO23 cells. We found that treatment with DHEA can restore starvation-induced reactive oxygen species (ROS) generation and mitochondrial membrane potential imbalance. In addition, treatment of DHEA prevents cell death via upregulation of cytochrome c and downregulation of BAX in mitochondria. Most importantly, DHEA is ameliorated to mitochondrial function mediated through the decrease in mitochondrial ROS, maintained mitochondrial morphology, and enhancing the ability of cell proliferation and ROS scavenging. Our present data strongly indicate that DHEA reduces programmed cell death (apoptosis and necroptosis) in granulosa HO23 cells through multiple interactions with the mitochondrion-dependent programmed cell death pathway. Taken together, our data suggest that the presence of DHEA could be beneficial to protect human oocyte granulosa HO23 cells under in vitro culture conditions during various assisted reproductive technology (ART) programs.Free Chinese abstract: A Chinese translation of this abstract is freely available at http://www.reproduction online.org/content/154/2/101/suppl/DC1. PMID- 28624767 TI - Effects of NRF1 on steroidogenesis and apoptosis in goat luteinized granulosa cells. AB - During goat follicular development, abnormal expression of nuclear respiratory factor 1 (NRF1) in granulosa cells may drive follicular atresia with unknown regulatory mechanisms. In this study, we investigated the effects of NRF1 on steroidogenesis and cell apoptosis by overexpressing or silencing it in goat luteinized granulosa cells (LGCs). Results showed that knockdown of NRF1 expression significantly inhibited the expression of STAR and CYP19A1, which are involved in sex steroid hormones synthesis, and led to lower estrogen levels. Knockdown of NRF1 resulted in an increased percentage of apoptosis, probably due to the release of cytochrome c from mitochondria, accompanied by upregulating mRNA and protein levels of apoptosis-related markers BAX, caspase 3 and caspase 9. These data indicate that NRF1 might be related with steroidogenesis and cell apoptosis. Furthermore, NRF1 silence reduced mitochondrial transcription factor A (TFAM) transcription activity, mtDNA copy number and ATP level. Simultaneously, knockdown of NRF1 suppressed the transcription and translation levels of SOD, GPx and CAT, decreased glutathione level and increased 8-OHdG level. However, the overexpression of NRF1 in LGCs or gain of TFAM in NRF1 silenced LGCs increased the expression of genes involved in mitochondrial function and biogenesis, and elevated the antioxidant stress system and steroids synthesis. Taken together, aberrant expression of NRF1 could induce mitochondrial dysfunction and disturb the cellular redox balance, which lead to disturbance of steroid hormone synthesis, and trigger LGC apoptosis through the mitochondria-dependent pathway. These findings will be helpful for understanding the role of NRF1 in goat ovarian follicular development and atresia. PMID- 28624768 TI - A revised Asingle model to explain stem cell dynamics in the mouse male germline. AB - Spermatogonial stem cells (SSCs) and progenitor spermatogonia encompass the undifferentiated spermatogonial pool in mammalian testes. In rodents, this population is comprised of Asingle, Apaired and chains of 4-16 Aaligned spermatogonia. Although traditional models propose that the entire Asingle pool represents SSCs, and formation of an Apaired syncytium symbolizes irreversible entry to a progenitor state destined for differentiation; recent models have emerged that suggest that the Asingle pool is heterogeneous, and Apaired/Aaligned can fragment to produce new SSCs. In this review, we explore evidence from the literature for these differing models representing SSC dynamics, including the traditional 'Asingle' and more recently formed 'fragmentation' models. Further, based on findings using a fluorescent reporter transgene (eGfp) that reflects expression of the SSC-specific transcription factor 'inhibitor of DNA binding 4' (Id4), we propose a revised version of the traditional model in which SSCs are a subset of the Asingle population; the ID4-eGFP bright cells (SSCultimate). From the SSCultimate pool, other Asingle and Apaired cohorts arise that are ID4-eGFP dim. Although the SSCultimate possess a transcriptome profile that reflects a self-renewing state, the transcriptome of the ID4-eGFP dim population resembles that of cells in transition (SSCtransitory) to a progenitor state. Accordingly, at the next mitotic division, these SSCtransitory are likely to join the progenitor pool and have lost stem cell capacity. This model supports the concept of a linear relationship between spermatogonial chain length and propensity for differentiation, while leaving open the possibility that the SSCtransitory (some Asingle and potentially some Apaired spermatogonia), may contribute to the self renewing pool rather than transition to a progenitor state in response to perturbations of steady-state conditions. PMID- 28624769 TI - Losing the child's voice and 'the captive mother': an inevitable legacy of family centred care? AB - EBN engages readers through a range of online social media activities to debate issues important to nurses and nursing. EBN Opinion papers highlight and expand on these debates. PMID- 28624770 TI - The dilemma of placebo needles in acupuncture research. PMID- 28624771 TI - Evaluating blinding effectiveness of a novel Ryodoraku sham needle device. PMID- 28624772 TI - Effects of electroacupuncture on the cortical extracellular signal regulated kinase pathway in rats with cerebral ischaemia/reperfusion. AB - OBJECTIVE: To explore the effects of electroacupuncture (EA) on the phosphorylated extracellular signal regulated kinase (p-ERK) pathway of the cerebral cortex in a rat model of focal cerebral ischaemia/reperfusion (I/R). METHODS: 160 adult Sprague-Dawley rats underwent middle carotid artery occlusion (MCAO) to establish I/R injury and were randomly divided into four groups (n=40 each) that remained untreated (I/R group) or received EA at LU5, LI4, ST36 and SP6 (I/R+EA group), the ERK inhibitor PD98059 (I/R+PD group), or both interventions (I/R+PD+EA groups). An additional 40 rats undergoing sham surgery formed a healthy control group. Eight rats from each group were sacrificed at the following time points: 2 hours, 6 hours, 1 day, 3 days and 1 week. Neurological function was assessed using neurological deficit scores, morphological examination was performed following haematoxylin-eosin staining of cortical tissues, and apoptotic indices were calculated after terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labelling. Cortical protein and mRNA expression of p-ERK and ERK were measured by immunohistochemistry and real-time quantitative PCR, respectively. RESULTS: Compared with the I/R group, neurological deficit scores and apoptotic indices were lower in the I/R+EA group at 1 and 3 days, whereas mRNA/protein expression of ERK/p-ERK was higher in the EA group at all time points studied. CONCLUSION: Our results suggest that EA can alleviate neurological deficits and reduce cortical apoptosis in rats with I/R injury. These anti-apoptotic effects may be due to upregulation of p-ERK. Moreover, apoptosis appeared to peak at 1 day after I/R injury, which might therefore represent the optimal time point for targeting of EA. PMID- 28624773 TI - Measuring the effects of acupuncture on muscle stiffness with shear wave elastography. PMID- 28624775 TI - Complexing agents and pH influence on chemical durability of type I moulded glass containers. AB - Among the factors that affect the glass surface chemical durability, pH and complexing agents presence in aqueous solution have the main role (1). Glass surface attack can be also related to the delamination issue with glass particles appearance in the pharmaceutical preparation. A few methods to check for glass containers delamination propensity and some control guidelines have been proposed (2,3). The present study emphasizes the possible synergy between a few complexing agents with pH on the borosilicate glass chemical durability. Hydrolytic attack was performed in small volume 23 ml type I glass containers autoclaved according to EP or USP for 1 hour at 121 degrees C, in order to enhance the chemical attack due to time, temperature and the unfavourable surface/volume ratio. 0,048 M or 0.024 M (moles/liter) solutions of the acids citric, glutaric, acetic, EDTA (ethylenediaminetetraacetic acid) and sodium phosphate with water for comparison, were used for the trials. The pH was adjusted +/- 0,05 units at fixed values 5,5 6,6-7-7,4-8-9 by LiOH diluted solution. Since silicon is the main glass network former, silicon release into the attack solutions was chosen as the main index of the glass surface attack and analysed by ICPAES. The work was completed by the analysis of the silicon release in the worst attack conditions, of moulded glass, soda lime type II and tubing borosilicate glass vials to compare different glass compositions and forming technologies. Surface analysis by SEM was finally performed to check for the surface status after the worst chemical attack condition by citric acid. PMID- 28624774 TI - Sex and Genetic Background Influence Superoxide Dismutase (cSOD)-Related Phenotypic Variation in Drosophila melanogaster. AB - Mutations often have drastically different effects in different genetic backgrounds; understanding a gene's biological function then requires an understanding of its interaction with genetic diversity. The antioxidant enzyme cytosolic copper/zinc superoxide dismutase (cSOD) catalyzes the dismutation of the superoxide radical, a molecule that can induce oxidative stress if its concentration exceeds cellular control. Accordingly, Drosophila melanogaster lacking functional cSOD exhibit a suite of phenotypes including decreased longevity, hypersensitivity to oxidative stress, impaired locomotion, and reduced NADP(H) enzyme activity in males. To date, cSOD-null phenotypes have primarily been characterized using males carrying one allele, cSodn108red, in a single genetic background. We used ANOVA, and the effect size partial eta squared, to partition the amount of variation attributable to cSOD activity, sex, and genetic background across a series of life history, locomotor, and biochemical phenotypes associated with the cSOD-null condition. Overall, the results demonstrate that the cSOD-null syndrome is largely consistent across sex and genetic background, but also significantly influenced by both. The sex-specific effects are particularly striking and our results support the idea that phenotypes cannot be considered to be fully defined if they are examined in limited genetic contexts. PMID- 28624776 TI - Mold Control and Detection in Biological Drug Substance Manufacturing Facilities: An Industry Perspective. PMID- 28624777 TI - A Novel Lack-of-Fit Assessment as a System Suitability Test for Potency Assays. AB - Bioassay data analysis is used to determine the potency of protein therapeutics. To properly determine potency, the experimental data need to be fitted to a model that adequately describes the observed dose-response relationship. Typical models include 4-parameter logistic curve fits, 5-parameter logistic curve fits or parallel line analysis. Lack-of-fit assessment can be used as a measure of potency assay system suitability to ensure appropriate closeness of the chosen model fit to the experimental data. We present a novel lack-of-fit approach that overcomes the shortcomings of previously described lack-of-fit tests, such as the conventional analysis of variance (ANOVA) F-test and the lack-of-fit sum of squares test. Simulation studies and examples are used to assess the performance of the new lack-of-fit test. The results show that the described lack-of-fit approach can effectively reject poorly fitted data while retaining well-fitted data, and has advantages in potency assay applications where instrument-to instrument variability in absolute readout is expected.LAY ABSTRACT: Potency assays are analytical procedures used for characterization as well as release and stability analysis in drug development and for approved products. Dose-response data generated from a drug sample and a well-characterized reference standard are evaluated to determine the potency of the drug sample relative to the reference standard. In order to obtain a potency determination, dose-response data need to be fitted to a proper model that adequately describes the observed dose-response relationship. There are different options described to assess the goodness-of-fit of the data. One approach is the goodness-of-fit assessment based on F-test. This approach compares the lack-of-fit error (representing the discrepancy between observed data and fitted curve) to the pure error (representing the random noise between replicate measurement) to determine if the observed lack-of-fit error can be attributed to random noise. A limitation of goodness of fit assessments via F test lies in its propensity to penalize precise data (small lack-of-fit error can be considered significantly high if the assay has exceptionally low pure error) and accept undesirable noisy data (large undesirable lack-of-fit error can be considered insignificant due to large pure error). An alternative approach based on lack-of-fit sum of squares is only applicable to certain types of assays where the magnitude of measurements is consistent across different instruments given that the lack-of-fit sum of squares will increase when the magnitude of the assay signal measurements increase, even if the relative magnitude of assay data versus fitted curve remains the same. We introduce here a novel approach that overcomes the limitations of F-test and sum of squares-based approaches. This new approach will effectively reject poor data and retain good data, and it is independent of differences in absolute readout across instruments. PMID- 28624778 TI - Students' approaches to medical school choice: relationship with students' characteristics and motivation. AB - Objectives: The aim was to examine main reasons for students' medical school choice and their relationship with students' characteristics and motivation during the students' medical study. Methods: In this multisite cross-sectional study, all Year-1 and Year-4 students who had participated in a selection procedure in one of the three Dutch medical schools included in the study were invited to complete an online survey comprising personal data, their main reason for medical school choice and standard, validated questionnaires to measure their strength of motivation (Strength of Motivation for Medical School-Revised) and autonomous and controlled type of motivation (Academic Self-regulation Questionnaire). Four hundred seventy-eight students participated. We performed frequency analyses on the reasons for medical school choice and regression analyses and ANCOVAs to study their associations with students' characteristics and motivation during their medical study. Results: Students indicated 'city' (Year-1: 24.7%, n=75 and Year-4: 36.0%, n=52) and 'selection procedure' (Year-1: 56.9%, n=173 and Year-4: 46.9%, n=68) as the main reasons for their medical school choice. The main reasons were associated with gender, age, being a first generation university student, ethnic background and medical school, and no significant associations were found between the main reasons and the strength and type of motivation during the students' medical study. Conclusions: Most students had based their medical school choice on the selection procedure. If medical schools desire to achieve a good student-curriculum fit and attract a diverse student population aligning the selection procedure with the curriculum and taking into account various students' different approaches is important. PMID- 28624779 TI - Self-directed learning in veterinary medicine: are the students ready? PMID- 28624780 TI - Physical examination checklist for medical students: can less be more? PMID- 28624781 TI - Predictive value of peripheral regulatory T cells in non-small cell lung cancer patients undergoing radiotherapy. AB - BACKGROUND: Studies increasingly focus on the impact of radiotherapy on immunity; however, the role of peripheral cellular immunity prior to radiotherapy in cancer patients remains largely unknown. In this study, we investigated the predictive roles of lymphocyte subsets on tumor progression in non-small cell lung cancer (NSCLC) patients undergoing radiotherapy, and their expression in NSCLC patients at first relapse. METHODS: We enrolled 70 NSCLC patients and 14 age- and sex matched healthy donors and tested the lymphocyte subsets in their peripheral blood by flow cytometry. Among them, 40 newly diagnosed patients received radiotherapy and were enrolled to investigate the predictive value of lymphocyte subsets on tumor progression after radiotherapy by uni- and multivariate analyses; 30 patients at first relapse were included to evaluate the differences of lymphocyte subsets between them and first diagnosed patients and healthy volunteers. RESULTS: Increased proportions of regulatory T cells, CD8+ T cells, and CD8+CD28- T cells and decreased CD4+ T cells and CD4/CD8 ratios were observed in NSCLC patients at first relapse compared to newly diagnosed patients. In the 40 first diagnosed patients undergoing radiotherapy, uni- and multivariate analyses showed that increased level of regulatory T cells correlated with poor progression-free survival (hazard ratio = 2.55 and 3.76, P = 0.022 and 0.010, respectively). CONCLUSIONS: Peripheral regulatory T cells were increased and independently predict tumor progression in NSCLC patients undergoing radiotherapy, suggesting the promising combination of radiotherapy and immunotherapy. PMID- 28624784 TI - Mitochondrial pyruvate carrier function determines cell stemness and metabolic reprogramming in cancer cells. AB - One of the remarkable features of cancer cells is aerobic glycolysis, a phenomenon known as the "Warburg Effect", in which cells rely preferentially on glycolysis instead of oxidative phosphorylation (OXPHOS) as the main energy source even in the presence of high oxygen tension. Cells with dysfunctional mitochondria are unable to generate sufficient ATP from mitochondrial OXPHOS, and then are forced to rely on glycolysis for ATP generation. Here we report our results in a prostate cancer cell line in which the mitochondrial pyruvate carrier 1 (MPC1) gene was knockout. It was discovered that the MPC1 gene knockout cells revealed a metabolism reprogramming to aerobic glycolysis with reduced ATP production, and the cells became more migratory and resistant to both chemotherapy and radiotherapy. In addition, the MPC1 knockout cells expressed significantly higher levels of the stemness markers Nanog, Hif1alpha, Notch1, CD44 and ALDH. To further verify the correlation of MPC gene function and cell stemness/metabolic reprogramming, MPC inhibitor UK5099 was applied in two ovarian cancer cell lines and similar results were obtained. Taken together, our results reveal that functional MPC may determine the fate of metabolic program and the stemness status of cancer cells in vitro. PMID- 28624785 TI - TRIB1 promotes colorectal cancer cell migration and invasion through activation MMP-2 via FAK/Src and ERK pathways. AB - Colorectal cancer (CRC) is the third most common cancer in the world and distant metastasis is the leading cause of death among CRC patients. However, the underlying mechanisms of distant metastasis remain largely unknown. Amplification of 8q24 is a common chromosomal abnormality in CRC. In the present study, a putative oncogene at 8q24, TRIB1, was characterized for its role in CRC metastasis and underlying molecular mechanisms. Higher expression of TRIB1 protein was detected in 58/83 (69.9%) of CRC tissues, compared with adjacent non tumor tissues. Moreover, the expression of TRIB1 was significantly associated with distant metastasis (P=0.043) and advanced staging (P=0.008) in CRC tissues. TRIB1 overexpression was also correlated with poor prognosis in CRC patients as analyzed in PrognoScan database. In addition, elevated expression of TRIB1 promoted CRC cell motility and adhesive ability, while silencing of TRIB1 reduced those effects. Further study revealed that TRIB1-mediated migration and invasion of CRC cells required up-regulation of MMP-2 through the activation of FAK/Src and ERK pathway. Collectively, the results suggest that TRIB1 promotes CRC cell motility by activation MMP-2 via the FAK/Src and ERK pathways. It may provide a potential diagnostic and therapeutic target for CRC. PMID- 28624786 TI - High expression of GPR116 indicates poor survival outcome and promotes tumor progression in colorectal carcinoma. AB - Previous studies have found that G-protein-coupled receptor 116 (GPR116) is a regulator of breast cancer metastasis. However, the role of GPR116 in colorectal carcinoma (CRC) carcinogenesis and progression is unknown. In this study, We found GPR116 expression was significantly up-regulated in CRC specimens compared with corresponding non-cancerous tissues. Increased GPR116 expression in CRC was correlated with histological differentiation and distant metastasis. In addition, high expression of GPR116 was significantly associated with poor overall survival of CRC patients, which was also confirmed by GSE14333, GSE17536 and GSE33113 datasets from the Gene Expression Omnibus (GEO). Furthermore, we demonstrated that the ability of proliferation and invasion of CRC cell lines HCT116 and LOVO was markedly reduced after transfected with siRNA-GPR116. Meanwhile, GPR116 may drive EMT in CRC cells through AKT/EKR signaling pathway, resulting in metastasis. Thus, GPR116 may be a novel reliable prognostic indicator and a risk factor in CRC progression. PMID- 28624787 TI - Long non-coding RNA UCA1 promotes gallbladder cancer progression by epigenetically repressing p21 and E-cadherin expression. AB - A growing number of studies indicated that long non-coding RNAs (lncRNAs) determine some cellular processes in cancer, such as proliferation, metastasis and differentiation. Urothelial carcinoma associated 1 (UCA1), an lncRNA, had been reported for its overexpression and oncogenic effect on various human cancers. In this study, we found that UCA1 was significantly overexpressed in gallbladder cancer (GBC) and positively correlated with tumor size, lymph node metastasis, TNM stage and short survival time. Moreover, UCA1 promoted GBC cell proliferation and metastasis in vitro and tumor growth in vivo. Mechanically, we identified that UCA1 promoted GBC progression through recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p21 and E-cadherin, and epigenetically suppressing their transcript. PMID- 28624790 TI - Co-targeting of IGF1R/mTOR pathway by miR-497 and miR-99a impairs hepatocellular carcinoma development. AB - Persistent activation of IGF1R/mTOR signaling pathway plays crucial role in the development of hepatocellular carcinoma (HCC). Therefore, our goal was to elucidate microRNAs (miRNAs) targeting IGF1R/mTOR and the therapeutic potential of single or dual miRNA on HCC development. In this study, we found that miR-497 and miR-99a that target the 3'-UTR of both IGF1R and mTOR were down-regulated in HCC human tissues and cell lines. Functional assay revealed that ectopic expression of miR-497 or miR-99a in HCC cells resulted in a significant inhibition on tumor growth and invasiveness in vitro and tumor development in vivo via repressing the expression of IGF1R and mTOR. Such inhibitory effect on tumor growth is reversed by application of IGF1 ((IGF1R ligand) or MHY1485 (mTOR agonist) in vitro. Furthermore, we found that simultaneous over-expression of both miR-497 and miR-99a exhibited much stronger inhibitory effects on tumor growth than their individual effect, which is still correlated with significantly stronger repression of IGF1R and mTOR. Overall, our results suggest that miR-497 and miR-99a both function as tumor-suppressive miRNAs by suppressing IGF1R/mTOR signaling pathway. The synergistic actions of these two miRNAs partly correlated with IGF1R and mTOR levels, which may represent new strategies for the molecular treatment of HCC. PMID- 28624789 TI - Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy. AB - Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21cip1(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine levels after seven days of combination treatment. Although tumor size was not affected due to the short length of the treatment, a significant increase in CASP3 mRNA was observed in the combination group. Taken together, our data suggest that NMR metabolites could be used as biomarkers to detect an early response to combination therapy with PI3K/mTOR inhibitors and radiotherapy in adult and pediatric glioblastoma patients. PMID- 28624791 TI - EphA2 affects the sensitivity of oxaliplatin by inducing EMT in oxaliplatin resistant gastric cancer cells. AB - Erythropoietin-producing hepatocellular receptor A2 (EphA2) is upregulated in gastric cancer tissues and cells, which is accompanied by epithelial-mesenchymal transition (EMT). The current study was designed to establish the oxaliplatin resistant human gastric cancer cell line SGC-7901/L-OHP, to determine if EMT in these cells could be reversed, and to determine if the susceptibility of these cells to oxaliplatin was affected by silencing EphA2 expression. We found that EphA2 expression levels were upregulated in gastric cancer and associated with chemotherapy sensitivity. EphA2 and the EMT molecular markers N-cadherin and Snail were upregulated in SGC-7901/L-OHP cells, while silencing of EphA2 using small interfering RNA had the opposite effect. Moreover, silencing of EphA2 inhibited cell migration and invasion, and significantly enhanced the sensitivity of oxaliplatin-resistant gastric cancer cells to oxaliplatin. These observations demonstrate that EphA2 affects the sensitivity to oxaliplatin by inducing EMT in oxaliplatin-resistant gastric cancer cells. PMID- 28624793 TI - Bufalin reverses ABCB1-mediated drug resistance in colorectal cancer. AB - Multidrug resistance (MDR), mainly mediated by ABCB1 transporter, is a major cause for chemotherapy failure. Bufalin (BU), an active component of the traditional Chinese medicine chan'su, has been reported to have antitumor effects on various types of cancer cells. The purpose of this present study was to investigate the reversal effect of BU on ABCB1-mediated multidrug resistance in colorectal cancer. BU at safe concentration (5, 10, 20 nM) could reverse chemosensitivity of ABCB1-overexpression HCT8/ADR, LoVo/ADR and HCT8/ABCB1 nearly back to their parental cells level. In addition, results from the drug accumulation studies revealed that BU was able to enhance intracellular accumulation of doxorubicin (DOX) and Rhodamine 123 (Rho-123) in a dose-dependent manner. Furthermore, Western blot assays showed that BU significantly inhibited the expression level of ABCB1 protein. Meanwhile, BU stimulated the ATPase activity of ABCB1, which suggested that BU might be a substrate of ABCB1. More interestingly, docking analysis predicted that BU could be docked into the large hydrophobic drug-binding cavity of human ABCB1. Importantly, BU remarkable increased the effect of DOX against the ABCB1 resistant HCT8/ADR colorectal cell xenografts in nude mice, without inducing any obvious toxicity. Overall, we concluded that BU efficiently reversed ABCB1-mediated MDR through not only inhibited the efflux function of ABCB1, but also down-regulate its protein expression, which might represent a potential and superior ABCB1 modulator in colorectal cancer. PMID- 28624794 TI - Knockdown of HDAC1 expression suppresses invasion and induces apoptosis in glioma cells. AB - Glioma is the most common malignant tumor of the central nervous system, with a low survival rate of five years worldwide. Although high expression and prognostic value of histone deacetylase 1 (HDAC1) have been recently reported in various types of human tumors, the molecular mechanism underlying the biological function of HDAC1 in glioma is still unclear. We found that HDAC1 was elevated in glioma tissues and cell lines. HDAC1 expression was closely related with pathological grade and overall survival of patients with gliomas. Downregulation of HDAC1 inhibited cell proliferation, prevented invasion of glioma cell lines, and induced cell apoptosis. The expression of apoptosis and metastasis related molecules were detected by RT-PCR and Western blot, respectively, in U251 and T98G cells with HDAC1 knockdown. We found that HDAC1 knockdown upregulated expression of BIM, BAX, cleaved CASPASE3 and E-CADHERIN, and decreased expression of TWIST1, SNAIL and MMP9 in U251 and T98G cells with HDAC1 knockdown. In vivo data showed that knockdown of HDAC1 inhibited tumor growth in nude mice. In summary, HDAC1 may therefore be considered an unfavorable progression indicator for glioma patients, and may also serve as a potential therapeutic target. PMID- 28624795 TI - Tissue and serum lipidome shows altered lipid composition with diagnostic potential in mycosis fungoides. AB - Mycosis fungoides (MF) is the most common type of cutaneous T cell lymphoma. In this study, we used matrix-assisted laser desorption/ionization-Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR-MS) to perform lipidomic profiling of 5 MF tissue samples and 44 serum samples (22 from MF patients and 22 from control subjects). Multivariate statistical analysis of the mass spectral data showed that MF tissues had altered levels of seven lipids and MF sera had altered levels of twelve. Among these, six phosphotidylcholines, PC (34:2), PC (34:1), PC (36:3), PC (36:2), PC (32:0), and PC (38:4) and one sphingomyelin, SM (16:0) were altered in both MF tissues and sera. PC (34:2), PC (34:1), PC (36:3), and PC (36:2) levels were increased in both tissues and sera from MF patients, whereas SM (16:0), PC (32:0), and PC (38:4) levels were increased in MF sera but were decreased in MF tissues. We have thus identified multiple lipids that are altered in MF tissues and sera. This suggests serological and tissue lipidomic profiling could be an effective approach to screening for diagnostic biomarkers of MF. PMID- 28624796 TI - Comparison of differentiated thyroid carcinoma recurrence and its clinical features in children of different ages. AB - The prevalence of differentiated thyroid carcinoma (DTC) in children is increasing. However, the clinical features and recurrence of DTC in children in different age groups, especially those less than 14 years old, are not well studied. We retrospectively investigated 73 children diagnosed with DTC in our hospital between January 1998 and July 2014. Data were reviewed for different age groups based on the age at initial diagnosis: 5-9, 10-14, or 15-19 years. The mean age of the recurrence group (10.6+/-4.1 years) was lower than that of the non-recurrence group (12.6+/-6.2 years; P=0.004). The main symptom at initial diagnosis was local invasion in the recurrence group, but was thyroid nodules in the non-recurrence group (P<0.001). The recurrence and non-recurrence groups did not differ in TNM stage or risk level. However, according to our age classification, the American Thyroid Association pediatric risk level was significantly different in three age groups (P=0.024). The DTC recurrence rate in each age group decreased as the age of the children increased (P=0.011). Thus, a high risk of recurrence and a high proportion of local invasion cases were observed in the youngest age group, suggesting that younger age is an important risk factor for DTC recurrence in children. PMID- 28624797 TI - Lymph node metastasis and the physicochemical micro-environment of pancreatic ductal adenocarcinoma xenografts. AB - Pancreatic ductal adenocarcinoma (PDAC) patients develop lymph node metastases early and have a particularly poor prognosis. The poor prognosis has been shown to be associated with the physicochemical microenvironment of the tumor tissue, which is characterized by desmoplasia, abnormal microvasculature, extensive hypoxia, and highly elevated interstitial fluid pressure (IFP). In this study, we searched for associations between lymph node metastasis and features of the physicochemical microenvironment in an attempt to identify mechanisms leading to metastatic dissemination and growth. BxPC-3 and Capan-2 PDAC xenografts were used as preclinical models of human PDAC. In both models, lymph node metastasis was associated with high IFP rather than high fraction of hypoxic tissue or high microvascular density. Seven angiogenesis-related genes associated with high IFP associated lymph node metastasis were detected by quantitative PCR in each of the models, and these genes were all up-regulated in high IFP/highly metastatic tumors. Three genes were mutual for the BxPC-3 and Capan-2 models: transforming growth factor beta, angiogenin, and insulin-like growth factor 1. Further comprehensive studies are needed to determine whether there is a causal relationship between the up-regulation of these genes and high IFP and/or high propensity for lymph node metastasis in PDAC. PMID- 28624800 TI - Identifying drug-pathway association pairs based on L1L2,1-integrative penalized matrix decomposition. AB - The traditional methods of drug discovery follow the "one drug-one target" approach, which ignores the cellular and physiological environment of the action mechanism of drugs. However, pathway-based drug discovery methods can overcome this limitation. This kind of method, such as the Integrative Penalized Matrix Decomposition (iPaD) method, identifies the drug-pathway associations by taking the lasso-type penalty on the regularization term. Moreover, instead of imposing the L1-norm regularization, the L2,1-Integrative Penalized Matrix Decomposition (L2,1-iPaD) method imposes the L2,1-norm penalty on the regularization term. In this paper, based on the iPaD and L2,1-iPaD methods, we propose a novel method named L1L2,1-iPaD (L1L2,1-Integrative Penalized Matrix Decomposition), which takes the sum of the L1-norm and L2,1-norm penalties on the regularization term. Besides, we perform permutation test to assess the significance of the identified drug-pathway association pairs and compute the P-values. Compared with the existing methods, our method can identify more drug-pathway association pairs which have been validated in the CancerResource database. In order to identify drug-pathway associations which are not validated in the CancerResource database, we retrieve published papers to prove these associations. The results on two real datasets prove that our method can achieve better enrichment for identified association pairs than the iPaD and L2,1-iPaD methods. PMID- 28624802 TI - Heparin-based coacervate of bFGF facilitates peripheral nerve regeneration by inhibiting endoplasmic reticulum stress following sciatic nerve injury. AB - Creating a microenvironment at the injury site that favors axonal regrowth and remyelinationis pivotal to the success of therapeutic reinnervation. The mature myelin sheath of the peripheral nervous system depends on active participation of Schwann cells to form new cytoskeletal components and tremendous amounts of relevant neurotrophic factors. In this study, we utilized a new biomaterial for growth factor delivery consisting of a biocompatible polycation, poly(ethylene argininylaspartatediglyceride) and heparin. It is capable of binding a variety of growth factors to deliver basic fibroblast growth factor (bFGF) through polyvalent ionic interactions for nerve repair. In vitro assays demonstrated that the bFGF loading efficiency reached 10 MUg and this delivery vehicle could control the release of bFGF. In vivo, the coacervate enhanced bFGF bioavailability, which improved both motor and sensory function. It could also acceleratemyelinated fiber regeneration and remyelination and promote Schwann cells proliferation. Furthermore, the neuroprotective effect of bFGF-coacervate in sciatic nerve injury was associated with the alleviation of endoplasmic reticulum stress signal. This heparin-based delivery platform leads to increased bFGF loading efficiency and better controls its release, which will provide an effective strategy for peripheral nerve injury regeneration therapy. PMID- 28624805 TI - Rcan2 and estradiol independently regulate body weight in female mice. AB - Rcan2 increases food intake and plays an important role in the development of age and diet- induced obesity in male mice. However, in females, wild-type mice grow almost at a similar rate as Rcan2-/- mice on normal chow diet from 6 weeks of age. Here we showed that the ability of Rcan2 to promote weight gain was attenuated by energy expenditure mediated by 17beta-estradiol in female mice. Using ovariectomy-operated models, we found that 17beta-estradiol deprivation did not alter food intake, but induced more weight gain in wild-type mice than Rcan2 /- mice. If wild-type mice ingested equally as Rcan2-/- mice, in the same ovarian state they exhibited similar weight changes, but the mice in ovariectomized groups were significantly heavier than the ovarian-intact mice, suggesting that body weight is not only regulated by Rcan2, but also by 17beta-estradiol. Furthermore, we demonstrated that Rcan2 and 17beta-estradiol independently regulated body weight even on high-fat diets. Therefore, our findings indicate that Rcan2 and 17beta-estradiol regulate body weight through different mechanisms. Rcan2 increases food intake, whereas 17beta-estradiol promotes energy expenditure. These findings provide novel insights into the sexual dimorphism of body weight regulation. PMID- 28624808 TI - YB-1 regulates tumor growth by promoting MACC1/c-Met pathway in human lung adenocarcinoma. AB - Aberrant overexpression of the transcription/translation factor Y-box-binding protein (YB-1) is associated with poor prognosis of lung adenocarcinoma, however the underlying mechanism by which YB-1 acts has not been fully elucidated. Here, we reported that inhibition of YB-1 diminished proliferation, migration and invasion of lung adenocarcinoma cells. Interestingly, we identified metastasis associated in colon cancer-1 (MACC1) as a target of YB-1. Depletion of YB-1 markedly decreased MACC1 promoter activity and suppressed the MACC1/c-Met signaling pathway in lung adenocarcinoma cells. Additionally, chromatin immunoprecipitation (ChIP) assay demonstrated that YB-1 bound to the MACC1 promoter. Moreover, YB-1 was positively correlated with MACC1, and both proteins were over-expressed in lung adenocarcinoma tissues. The Cox-regression analysis indicated that high YB-1 expression was an independent risk factor for prognosis in enrolled patients. Furthermore, depletion of YB-1 attenuated tumorigenesis in a xenograft mouse model and reduced MACC1 expression in tumor tissues. Collectively, our data suggested that targeting YB-1 suppressed lung adenocarcinoma progression through the MACC1/c-Met pathway and that the high expression of YB-1/MACC1 is a potential prognostic marker in lung adenocarcinoma. PMID- 28624809 TI - Genome-wide analysis of aberrantly expressed lncRNAs and miRNAs with associated co-expression and ceRNA networks in beta-thalassemia and hereditary persistence of fetal hemoglobin. AB - The implications of lncRNAs regarding fetal hemoglobin (HbF) induction in hemoglobin disorders remain poorly understood. In this study, microarray analysis was performed to profile lncRNAs, miRNAs and mRNAs in individuals with hereditary persistence of fetal hemoglobin (HPFH), beta-thalassemia carriers with high HbF levels and healthy controls. The results show aberrant expression of 862 lncRNAs, 568 mRNAs and 63 miRNAs in the high-HbF group compared with the control group. Altered NR_001589, NR_120526, T315543, miR-486-3p, miR-19b-1-5p and miR-20a-3p expression was confirmed by quantitative reverse transcription-polymerase chain reaction, and Spearman correlation coefficients revealed significant positive correlations with HbF. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses showed the hematopoietic cell lineage and apoptosis to be most significantly dysregulated in HbF induction. We analyzed coding genes near the lncRNAs and constructed a coding-noncoding co-expression network. Based on the results, lncRNAs likely contribute to increased HbF levels by activating expression of HBE1 and hematopoietic cell lineage-inducible molecules and by inhibiting that of apoptosis-inducible molecules. Finally, through construction of a competing endogenous RNA network, we found that 6 lncRNAs could bind competitively with miR-486-3p, resulting in increased HbF levels. Taken together, our findings provide new insights into the mechanisms of HbF induction and potentially provide new targets for the treatment of beta-thalassemia major. PMID- 28624815 TI - Higher platelet distribution width predicts poor prognosis in laryngeal cancer. AB - BACKGROUND: Activated platelets promote cancer progression and metastasis. However, the prognostic value of platelet indices in laryngeal cancer remains poorly understood. The purpose of this study was to investigate the predictive significance of platelet indices in laryngeal cancer. RESULTS: Of the 241 patients, high platelet distribution width (PDW) levels were observed in 116 (48.1 %) patients. In the Kaplan-Meier analysis, increased PDW was significantly associated with a poorer overall survival (p < 0.001). In the multivariate Cox model, PDW was an independent prognostic index for overall survival (HR=4.381, 95% CI=2.313-8.298, P < 0.001). METHOD: The retrospective study included 241 consecutive patients with laryngeal cancer between January 2009 and December 2009. The relationships between PDW and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of PDW. CONCLUSIONS: Elevated PDW might be a novel prognostic marker in laryngeal cancer. PMID- 28624817 TI - Exploring the Clinical Practice of Speech and Language Therapists with Adults with Dementia: A Cross-Sectional Survey in Portugal. AB - BACKGROUND/AIMS: Adults with acquired communication and swallowing disorders secondary to dementia can benefit from speech and language therapy services. However, there is limited information on the role of speech and language therapists (SLTs) in the treatment of individuals with dementia. The aim of this study was to explore the clinical practice of SLTs with adults with dementia. METHODS: A cross-sectional survey of SLTs was conducted in Portugal using a web based questionnaire designed specifically for the purpose of this study. RESULTS: A total of 230 SLTs responded to the survey. Among the respondents, 52.2% had limited clinical practice with individuals with dementia, with only 14.3% having worked with more than 10 cases. CONCLUSION: In Portugal, the clinical practice of SLTs in dementia is limited and mostly centred on the assessment of language, communication, and swallowing. The current findings highlight the need to address training in dementia within graduate and post-graduate programmes for SLTs. PMID- 28624816 TI - Circulating microRNAs as potential biomarkers for coronary plaque rupture. AB - Coronary plaque rupture is the most common cause of acute coronary syndrome. However, the timely biomarker-based diagnosis of plaque rupture remains a major unmet clinical challenge. Balloon dilatation and stent implantation during percutaneous coronary intervention (PCI) could cause plaque injury and rupture. Here we aimed to assess the possibility of circulating microRNAs (miRNAs) as biomarkers of acute coronary plaque rupture by virtue of the natural model of PCI induced plaque rupture. Stable coronary artery disease patients underwent PCI with single stent implantation were recruited and a three-phase approach was conducted in the present study: (i) profiling of plasma miRNAs in a group of patients before (0 h) and after balloon dilatation for 1 h (1 h vs. 0 h), (ii) replication of significant miRNAs in the second group of patients (1 h vs. 0 h), (iii) validation of a multi-miRNAs panel in the third group of patients (0.5 h, 1 h vs. 0 h). Out of 24 miRNAs selected for replication, 6 miRNAs remained significantly associated with plaque rupture. In the validation phase, combinations of miR-483-5p and miR-451a showed the highest area under the receiver-operating-characteristic curve (AUC) (0.982; CI: 0.907-0.999) in patients with plaque rupture for 0.5 h; combinations of miR-483-5p and miR-155-5p showed the highest AUC (0.898; CI: 0.790-0.962) after plaque rupture for 1 h. In conclusion, using a profiling-replication-validation model, we identified 3 miRNAs including miR-155-5p, miR-483-5p and miR-451a, which may be biomarkers for the early identification of plaque rupture. PMID- 28624818 TI - Maternal Subcutaneous and Visceral Adipose Ultrasound Thickness in Women with Gestational Diabetes Mellitus at 24-28 Weeks' Gestation. AB - OBJECTIVE: To compare the sonographic measurement of maternal subcutaneous and visceral adipose thickness between pregnant women with gestational diabetes mellitus (GDM) and patients with nondiabetic pregnancies. METHODS: Adipose thickness was measured by transabdominal ultrasound in pregnant women attending our antenatal clinics at 24-28 weeks' gestation. All patients underwent a 75-g oral glucose challenge as a diagnostic test for GDM. RESULTS: The study population comprised 56 women with a positive glucose challenge test and 112 nondiabetic pregnancies. Measurements of subcutaneous and visceral adipose tissues were converted into multiples of the median (MoM), adjusted for gestational age. The mean subcutaneous thickness MoM in patients with GDM was significantly higher compared to nondiabetic pregnancies (1.31 vs. 1.07; p = 0.011). Similarly, the mean visceral thickness MoM was higher in women with a positive oral glucose tolerance test compared to controls (1.61 vs. 1.06; p < 0.001). Multivariate logistic regression analysis demonstrated that visceral adipose thickness, but not subcutaneous thickness, was significantly and independently associated with GDM (odds ratio 34.047, 95% confidence interval 9.489-122.166). CONCLUSIONS: Sonographic thickness of maternal visceral adipose tissue at 24-28 weeks' gestation was higher in women with GDM compared to nondiabetic pregnancies, independently from other known risk factors associated with GDM. PMID- 28624819 TI - A Randomized Trial of Antimicrobial Prophylaxis in Patients Undergoing Medical Thoracoscopy (APT). AB - BACKGROUND: There is no data on the role of prophylactic antibiotics in patients undergoing medical thoracoscopy. OBJECTIVE: In this study, we evaluated the efficacy and safety of a single dose of intravenous cefazolin in subjects undergoing medical thoracoscopy. METHODS: Subjects undergoing medical thoracoscopy were randomized 1:1 to receive either intravenous cefazolin 2 g (antibiotic group) or intravenous saline (control group). The primary outcome was the incidence of infections (surgical site infections and empyema) in the study groups, while the secondary outcomes were complications related to intravenous antibiotics. RESULTS: Of the 121 subjects screened, 100 (mean age +/- SD: 52.2 +/ 15.2 years; 38 [38%] women) were randomized to the study groups. The incidence of postprocedural infections was not different between the antibiotic and the control group (4 [8%] vs. 6 [12%], p = 0.28). Surgical site infection occurred in 1 subject (2%) in the antibiotic group and 3 subjects (6%) in the saline group (p = 0.62); empyema occurred in 3 subjects (6%) in each group (p = 1.00). There was no association between age, comorbid illness (diabetes mellitus or chronic kidney disease), study group allocation, type of thoracoscope used, duration of procedure, histological diagnosis (benign or malignant), and the occurrence of infections in the postprocedural period. CONCLUSION: The use of a single dose of cefazolin prior to medical thoracoscopy was not associated with a reduction in the occurrence of postprocedural infection. PMID- 28624820 TI - An Elevated High-Sensitivity C-Reactive Protein Level Is Associated with Unfavorable Functional Outcomes of Small-Artery Occlusion in Patients without Diabetes. AB - BACKGROUND: High-sensitivity C-reactive protein (hs-CRP) is associated with a risk of causing diabetes mellitus and ischemic stroke. However, the association between hs-CRP levels and functional outcome after small-artery occlusion (SAO) is unknown. METHODS: Data for 836 patients diagnosed with SAO were collected from the Department of Neurorehabilitation of Huanhu Hospital. Hs-CRP values were classified according to quartiles (<0.67, 0.67 to <1.46, 1.46 to <3.46, and >=3.46 mg/L). We examined the relationship between hs-CRP levels on admission and modified Rankin Scale (mRS) scores using univariate and multivariate analyses. We further performed subgroup analyses of patients with and without diabetes. RESULTS: Patients in the highest hs-CRP quartile had a significantly higher risk of an unfavorable outcome. In the non-diabetes subgroup, the elevated hs-CRP quartiles were associated with higher mRS scores. In the diabetes subgroup, no statistically significant association was observed between hs-CRP levels and mRS. CONCLUSIONS: Elevated hs-CRP level on admission was associated with a poor functional outcome 3 months after SAO, especially among nondiabetes patients. However, no significant associations were observed in patients with diabetes. PMID- 28624821 TI - On the Social Life and Motivational Changes of Aging Monkeys. AB - Although nonhuman primates have been used in biomedical research to develop a better understanding of physiological aging processes, their value as models for studying age-related differences in motivation, cognition, and decision-making has only recently been appreciated. This paper reviews the state of the art, with a focus on a recent study on Barbary macaques. A number of studies reported that with increasing age, Old World monkeys spend more time resting, have fewer social partners, and/or spend less time in social interactions, though other studies found no such effects. Less was known about changes in cognitive performance and shifts in interest in the physical and social environment across age. A recent comprehensive study of motivational changes in a large age-heterogeneous population of Barbary macaques (Macaca sylvanus) living at "La Foret des Singes" in Rocamadour explicitly tested predictions from social selectivity theory, which posits that in light of a shrinking future time perspective, humans become increasingly selective in terms of their social interactions. Given that nonhuman primates most likely have no conception of their limited lifetime, this allowed disentangling the effects of cognitive insights and basal physiological processes that contribute to changes in the valuation of different activities. The Barbary macaques under study revealed marked and differential motivational shifts with age: while they interacted with fewer social partners, they continued to attend to social information. In contrast, they revealed a marked loss of interest in novel objects in early adulthood, unless these were baited with a food reward. Some of the motivational changes observed during human aging may thus be shared with our closest living relatives. The awareness of a limited future time perspective in humans may enhance the effects of these ancestral processes, but it does not appear to be the only explanation. Future studies should employ a broader array of different cognitive tests to delineate the trajectories of different cognitive processes such as attention, memory, and behavioral flexibility more clearly. Taken together, an evolutionary developmental psychology perspective that combines life span psychology with evolutionary biology appears to be a promising avenue for investigations of age-related changes in motivation and cognition. PMID- 28624822 TI - Debugging: Is Routine Antimicrobial Prophylaxis Indicated in Medical Thoracoscopy? PMID- 28624823 TI - Effect of Interferon-alpha and Combined Interferon-alpha with Lamivudine Treatment on Anthropometric Measurements in Children with Chronic Hepatitis B. PMID- 28624824 TI - Effect of TNF-alpha Inhibition on Bone Marrow-Derived Mesenchymal Stem Cells in Neurological Function Recovery after Spinal Cord Injury via the Wnt Signaling Pathway in a Rat Model. AB - AIM: The present study aimed to examine the effect of tumor necrosis factor-alpha (TNF-alpha) inhibition on bone marrow-derived mesenchymal stem cells (BMSCs) in neurological function recovery after spinal cord injury (SCI) via the Wnt signaling pathway in a rat model. METHODS: The rat model of SCI was established using Allen's method. Seventy-two adult male Sprague Dawley (SD) rats were randomly assigned into 4 groups (18 rats in each group): the sham control group, saline control group, BMSCs group (injection with BMSCs at the injured site) and BMSCs + TNF-alpha group (injection with BMSCs under TNF-alpha treatment at the injured site). Immunochemistry was performed to characterize the culture media after TNF-alpha-induced differentiation. qRT-PCR and Western blotting analyses were performed to detect the mRNA and protein expression of beta-catenin, Wnt3a, GSK-3beta and Axin. The Basso Beattie Bresnahan (BBB) locomotor score, neurological deficit score (NDS), and balance beam test (BBT) score were used to assess neurological functional recovery of SCI rats. RESULTS: In the BMSC group, numerous spherical cell clusters grew in suspension, and the cells were nestin-, NF200- and GFAP-positive. Compared with the sham control and BMSC groups, the beta-catenin and Wnt3a mRNA and protein expression was increased, but the GSK 3beta and Axin mRNA and protein expression was decreased in the BMSCs + TNF-alpha group. The SCI rats in the BMSCs + TNF-alpha group exhibited lower BBB scores, and higher NDSs and BBT scores compared to the BMSCs group. CONCLUSION: Our study provides evidence that TNF-alpha inhibition may weaken the ability of BMSCs in neurological functional recovery after SCI by activating the Wnt signaling pathway. PMID- 28624825 TI - Intraoperative Real-Time Assessment of Liver Function with Near-Infrared Fluorescence Imaging. AB - BACKGROUND: Postoperative liver failure is a serious complication after major hepatectomy, and perioperative prediction of its incidence using current technology is still very difficult. Near-infrared (NIR) fluorescence imaging allows quantitative assessment of the fluorescent signal from indocyanine green (ICG) in regions of interest on the liver surface. This method might offer a new promising modality for evaluating regional liver reserve. However, data are lacking regarding the relationship between liver function and fluorescent signals on the liver surface after intravenous ICG injection. This study was conducted to obtain the data necessary to apply NIR fluorescence imaging as a modality for measuring liver function. MATERIALS AND METHODS: This study included 16 patients who underwent open hepatopancreatobiliary surgery between March 2011 and March 2012. After laparotomy, ICG was injected intravenously at 2.5 mg/L of liver volume, then the fluorescence intensity (FI) and signal-to-background ratio (SBR) in the lateral segment of the liver were assessed for 15 min. Intraoperative blood samples were also obtained to measure the plasma clearance rate of ICG (ICGK). Correlations between ICGK, liver volume, and SBR, as well as between ICGK, liver volume, and rate of change of FI were analyzed. RESULTS: The experimental procedure was performed in all 16 patients. The FI of the liver increased rapidly after ICG injection, then became more gradual, reaching a near plateau after 15 min. A significant correlation was seen between ICGK and the rate of change of FI up to 15 min (|rS| = 0.5725, p < 0.05). CONCLUSION: This is the first report to show a relationship between liver function and fluorescent signals on the liver surface after intravenous ICG injection. Intraoperative NIR fluorescence imaging with ICG may be useful as a new method for assessing liver function. PMID- 28624826 TI - Voice Handicap Index in Persian Speakers with Various Severities of Hearing Loss. AB - OBJECTIVES: The purpose of this study was to assess and compare the total score and subscale scores of the Voice Handicap Index (VHI) in speakers with and without hearing loss. A further aim was to determine if a correlation exists between severities of hearing loss with total scores and VHI subscale scores. PATIENTS AND METHODS: In this cross-sectional, descriptive analytical study, 100 participants, divided in 2 groups of participants with and without hearing loss, were studied. Background information was gathered by interview, and VHI questionnaires were filled in by all participants. RESULTS: For all variables, including mean total score and VHI subscale scores, there was a considerable difference in speakers with and without hearing loss (p < 0.05). The correlation between severity of hearing loss with total score and VHI subscale scores was significant. CONCLUSION: Speakers with hearing loss were found to have higher mean VHI scores than speakers with normal hearing. This indicates a high voice handicap related to voice in speakers with hearing loss. In addition, increased severity of hearing loss leads to more severe voice handicap. This finding emphasizes the need for a multilateral assessment and treatment of voice disorders in speakers with hearing loss. PMID- 28624827 TI - Qualitative Assessment of Verbal Fluency Performance in Frontotemporal Dementia. AB - BACKGROUND/AIMS: Verbal fluency is impaired in patients with frontotemporal dementia (FTD) and primary progressive aphasia (PPA). This study explored qualitative differences in verbal fluency (clustering of words, switching between strategies) between FTD and PPA variants. METHODS: Twenty-nine patients with behavioral variant FTD (bvFTD) and 50 with PPA (13 nonfluent/agrammatic, 14 semantic, and 23 logopenic) performed a semantic and letter fluency task. Clustering (number of multiword strings) and switching (number of transitions between clustered and nonclustered words) were recorded by two independent raters. Between-group differences, associations with memory, language, and executive functioning, and longitudinal change (subsample) in clustering and switching were examined. RESULTS: Interrater reliability was high (median 0.98). PPA patients generated (a) smaller (number of) clusters on semantic and letter fluency than bvFTD patients (p < 0.05). Semantic variant patients used more switches than nonfluent/agrammatic or logopenic variant patients (p < 0.05). Clustering in semantic fluency was significantly associated with memory and language (range standardized regression coefficients 0.24-0.38). Switching in letter fluency was associated with executive functioning (0.32-0.35). CONCLUSION: Clustering and switching in verbal fluency differed between patients with subtypes of FTD and PPA. Qualitative aspects of verbal fluency provide additional information on verbal ability and executive control which can be used for clinically diagnostic purposes. PMID- 28624828 TI - Unique Imaging Features Enabling the Prenatal Diagnosis of Developmental Venous Anomalies: A Persistent Echogenic Brain Lesion Drained by a Collecting Vein in Contrast with Normal Brain Parenchyma on MRI. AB - OBJECTIVE: To describe the prenatal imaging features enabling diagnosis of developmental venous anomalies (DVA). METHODS: Four fetuses with unexplained persistent echogenic parenchymal brain lesions were studied. The evaluation included dedicated neurosonography, fetal MRI, serology for intrauterine infection, screening for coagulation abnormalities, and chromosomal microarray. Postnatal neurodevelopmental follow-up or autopsy results were assessed. RESULTS: DVA presented as very slowly growing echogenic brain lesions without cystic components, calcifications, or structural changes on otherwise normal neurosonographic scans performed at 2- to 3-week intervals. A specific Doppler feature was a collecting vein draining the echogenic parenchyma. Fetal brain MRI depicted normal anatomy on half-Fourier acquisition single-shot turbo spin-echo and diffusion-weighted imaging. The rest of the evaluation was normal. CONCLUSIONS: In cases with a persistent, parenchymal echogenic lesion without clastic or structural changes, DVA should be considered. Demonstration of a collecting vein draining the lesion and normal brain anatomy on MRI confirm the diagnosis. PMID- 28624829 TI - Preoperative C-Reactive Protein Values as a Potential Component in Outcome Prediction Models of Metastasized Renal Cell Carcinoma Patients Receiving Cytoreductive Nephrectomy. AB - PURPOSE: To validate preoperative C-reactive protein (CRP) levels as a prognostic marker for survival in a metastasized renal cell carcinoma (mRCC) patient cohort receiving cytoreductive nephrectomy (CN). PATIENTS AND METHODS: By chart review, 146 mRCC patients receiving CN at our tertiary referral centre from 1997 to 2015 were identified retrospectively. All relevant clinicopathological features including laboratory parameters were collected and correlated to overall survival, progression-free survival and cancer-specific survival (CSS). The mean follow-up was 23 months (range 1-168 months). RESULTS: Besides the already established scoring systems like the MSKCC criteria, an elevated preoperative CRP level (>=0.5 mg/dL) was an independent predictor of CSS in our study group including the chosen postoperative adjuvant therapies (TKI vs. immunotherapy vs. others). With regard to morbidity, patients with a good performance status, small tumour size and adequate renal function/haematopoiesis experienced less complication rates, thereby profiting more from CN. CONCLUSIONS: Our data provide indication that preoperative CRP levels should be implemented in nomograms regarding the outcome prediction in mRCC to identify candidates likely to profit from CN. PMID- 28624830 TI - Activation of Nrf2/HO-1 Pathway by Glycogen Synthase Kinase-3beta Inhibition Attenuates Renal Ischemia/Reperfusion Injury in Diabetic Rats. AB - BACKGROUND/AIMS: Diabetes mellitus can exacerbate renal ischemia-reperfusion (I/R) injury (RI/RI). The aim of the present study was to evaluate the protective effect of GSK-3beta inhibition (TDZD-8) on I/R-induced renal injury through the Nrf2/HO-1 pathway in a streptozocin (STZ)-induced diabetic rat model. METHODS: STZ-induced diabetic rats preconditioned with TDZD-8 and ZnPP were subjected to renal I/R. The extent of renal morphologic lesions. Renal function was assessed from blood urea nitrogen (BUN) and serum creatinine (Scr), as determined utlizing commercial kits. Oxidative stress and inflammatory activity in the kidney tissue was estimated from levels of malondialdehyde (MDA), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO), as well as the activities of superoxide dismutase (SOD) and glutathione (GSH) using qRT-PCR and ELISA. The expressions of Nrf2, HO-1, Bcl-2 and NF-kappaB in the renal tissue were measured by qRT-PCR and western blotting. RESULTS: I/R-induced renal inflammation was reduced significantly by TDZD-8 pretreatment. Preconditioning with TDZD-8 suppressed NF-kappaB expression and enhanced Bcl-2 expression in the renal tissue. The upregulated level of malondialdehyde (MDA), and reduced activities of superoxide dismutase (SOD) and glutathione (GSH) in I/R-shocked rats were markedly restored by TDZD-8 pretreatment. Furthermore, pretreatment with TDZD-8 enhanced activation of the Nrf2/HO-1 pathway in the renal tissue of diabetic RI/RI rats. CONCLUSION: These findings suggest that preconditioning with TDZD-8 may protect the kidney from I/R-induced damage via the activation of the Nrf2/HO-1 pathway in STZ-induced diabetic rats. Further detailed studies are needed to further clarify the underlying mechanisms. PMID- 28624831 TI - Chelerythrine Attenuates Renal Ischemia/Reperfusion-induced Myocardial Injury by Activating CSE/H2S via PKC/NF-kappaB Pathway in Diabetic Rats. AB - BACKGROUND/AIMS: Chelerythrine (CHE), a benzophenanthridine alkaloid, is a potent, selective, and cell-permeable protein kinase C (PKC) inhibitor. The purpose of the present study was to evaluate the effect of CHE on myocardial recovery after renal ischemia/reperfusion (I/R)-induced myocardial injury (RI/RMI) in a streptozocin (STZ)-induced diabetic rat model. METHODS: Diabetes mellitus (DM) rats preconditioned with CHE and D, L-propargylglycine (PAG) were subjected to renal I/R. The extent of cardiac morphologic lesions and the biochemical markers of cardiorenal function and oxidative stress were detected utilizing hematoxylin-eosin staining, commercial kits, and enzyme-linked immunoassay, respectively. The expressions of cystathionine-gamma-lyase (CSE), PKC-alpha, PKC-beta2, and nuclear factor-kappa B (NF-kappaB) in the rat myocardial tissue were measured utilizing western blotting. RESULTS: Renal I/R treatment resulted in myocardial injury. CHE-preconditioning promoted the recovery from myocardial damage by ameliorating the biochemical parameters of myocardial injury, reducing oxidative stress, increasing the H2S level, up regulating the expression of CSE, and down-regulating the expressions of PKC alpha, PKC-beta2, and NF-kappaB. CONCLUSION: These findings suggest that CHE pretreatment may exert a protective effect on the myocardium against RI/RMI by activating endogenous CSE/H2S via PKC/NF-kappaB pathway in STZ-induced diabetic rats. Further studies are needed defining underlying mechanisms. PMID- 28624832 TI - Erratum: Nowak et al. Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease. PMID- 28624833 TI - Erratum: Szeto et al. Plasma mitochondrial DNA Level is a prognostic marker in peritoneal dialysis patients. PMID- 28624834 TI - Quantitative Methods in Psychological Aging Research: A Mini-Review. AB - As research on psychological aging moves forward, it is increasingly important to accurately assess longitudinal changes in psychological processes and to account for their (often complex) associations with sociodemographic, lifestyle, and health-related variables. Traditional statistical methods, though time tested and well documented, are not always satisfactory for meeting these aims. In this mini review, we therefore focus the discussion on recent statistical advances that may be of benefit to researchers in psychological aging but that remain novel in our area of study. We first compare two methods for the treatment of incomplete data, a common problem in longitudinal research. We then discuss robust statistics, which address the question of what to do when critical assumptions of a standard statistical test are not met. Next, we discuss two approaches that are promising for accurately describing phenomena that do not unfold linearly over time: nonlinear mixed-effects models and (generalized) additive models. We conclude by discussing recursive partitioning methods, as these are particularly well suited for exploring complex relations among large sets of variables. PMID- 28624836 TI - Evaluation of scientific output in Dentistry in Spanish Universities. AB - BACKGROUND: The aim of this study was to assess the scientific output of Spanish universities that offer a bachelor's degree in dentistry through the use of various bibliometric indicators. MATERIAL AND METHODS: A total of 21 universities offered a bachelor's degree in dentistry in academic year 2016-2017. The search for papers published by authors associated with these institutions was carried out using the selection of journals listed in the Journal Citation Reports (JCR) and the Web of Knowledge database for the period 1986-2017. On the basis of these data, we determined the output, the h-, g- and hg-indexes, the most productive authors, international collaborations, and the most relevant journals. RESULTS: Public universities obtained better results than private universities. The University of Valencia was ranked first, followed by the Complutense University of Madrid and the University of Granada. The most productive author was Jose Vicente Bagan, but the author with the highest h-index was Mariano Sanz and Manuel Toledado. The universities with the greatest output and highest citation rates had more international collaborations. The most developed fields in Spanish universities were Oral surgery, Oral medicine and Dental materials. The universities had different models of production. At universities such as Barcelona or Valencia, the production was focused on very few departments and authors. At the other extreme, the University of Granada had various sources of research and authors, which meant that its output and citation rate could increase more. CONCLUSIONS: University faculties must provide suitable academic and research training, and therefore must be assessed using objective criteria and bibliometric tools. Although the number of university schools and faculties that teach dentistry has increased, and particularly the number of private universities, there is no correlation between their quality and output and the number of places offered on their courses. PMID- 28624835 TI - CBCT location of the fusion between the buccal and lingual cortical in the mandibular ramus: importance to sagittal split osteotomy. AB - BACKGROUND: Mandibular Sagittal Split Osteotomy (MSSO) is a popular technique in orthognathic surgery used both to advance and to retreat the mandible. However, MSSO may incur in important complications, such as bad splits and sensorineural injuries. Knowing the location of the fusion between the buccal and lingual cortical (FBLC) in the mandibular ramus and the bone thickness in the region where osteotomies will be performed is determinant in MSSO planning to avoid complications. The aim of this study was to document and evaluate possible differences between sexes regarding the location of the FBLC in relation to the superior cortical of mandibular foramen (MF) and bone thickness in the region of interest for MSSO in a Brazilian population. MATERIAL AND METHODS: Eighty five cone-beam Computed Tomography (CBCT) scans were used to perform linear measurements to determine the location of the FBLC. Bone thickness from the mandibular canal (MC) to the cortical external surfaces and the diameter of the MC were measured at three different points: mandibular ramus (A), mandibular angle (B) and mesial of the second molar (C). RESULTS: The FBLC was located at a mean distance of 8.3 mm from the superior cortical of the MF in males and 8.1 mm in females. There was no difference between males and females regarding the mean bone thickness from the MC to the buccal external surface at all the points investigated (p>0.05). Bone thickness from the lingual external surface to the MC was bigger among females than males in regions B and C (p < 0.05). The diameter of the MC was bigger among males in regions B and C. CONCLUSION: Sexual dimorphism regarding mandibular bone thickness but not regarding the location of FBLC was present. This fundamental knowledge may assist to the panning of MSSO. PMID- 28624837 TI - Clinical response to non-surgical periodontal treatment in patients with interleukin-6 and interleukin-10 polymorphisms. AB - BACKGROUND: Genetic polymorphisms are commonly associated with altered transcriptional activity and possibly make individuals more susceptible to periodontal disease development, increased disease severity and poor treatment outcome. The study aimed to determine the effect of Interleukin-6 (IL-6) -572 G/C (rs1800796) and IL-10 -592 C/A (rs1800872) polymorphisms on the outcomes of non surgical periodontal therapy in a Caucasian population. MATERIAL AND METHODS: Sixty-eight patients with chronic periodontal disease were grouped according to their genotype: IL-6, IL-10, IL-6 and IL-10 susceptible (SCP) and non-susceptible (NSCP). All individuals were clinically evaluated at the first visit, and blood sample were collected from patients after checking the inclusion and exclusion criteria of the study. All patients received non-surgical periodontal therapy from a single-blinded periodontist. Clinical periodontal measurements were repeated 45 days after therapy. RESULTS: This population mean aged 47.63 years included 52.2% females and 58.2% non-smokers. Following DNA separation and genotyping, 65.7% of patients were homozygous carriers of the IL-6 - 572G; 49.3% were carriers of the IL-10 -592A- allele (AA and CA genotypes); and 35.8% carried SCP genotypes for both polymorphisms. The clinical parameters after therapy were not associated with the genotype status. The multiple logistic regression analysis did not show any statistically significant association between the genotypes and the variables tested. CONCLUSIONS: Within the limitations of this longitudinal study, it can be suggested that IL-6 -572 G/C and IL-10 -592 C/A polymorphisms as well as their combination do not influence the outcome of nonsurgical periodontal therapy in Caucasian patients diagnosed with chronic periodontal disease. PMID- 28624838 TI - Dental management of pediatric patients affected by pulmonary atresia with ventricular septal defect: A scoping review. AB - BACKGROUND: Congenital Heart Diseases (CHD) involves a wide range of pathological conditions, such as Pulmonary Atresia with Ventricle Septal Defect (PA/VSD). This disorder leads to the systemic circulation of oxygen-poor blood (cyanosis), with associated features and consequences in the oral cavity. MATERIAL AND METHODS: Using scoping review methodology for screening and article selection, the primary objectives of this paper were as follows: first, to pose a research question; second, to identify relevant studies in order to answer the research question; third, to select and retrieve the studies; fourth, to chart the critical data, and finally, to collate, summarize, and report the results from the most important articles on the dental management of children affected with PA/VSD. Relevant articles (Randomized Controlled Trials [RCT], reviews, observational studies, and clinical case reports) published over a 10-year period were identified and retrieved from four Internet databases: PubMed; Embase/Ovid; Cochrane Library, and Google Scholar. RESULTS: By title and abstract screening and after removing duplicates, 24 articles were finally included in the present scoping review. According to the extracted data, the following are the most important clinical issues to be considered when treating children with PA/VSD in the dental setting: prevalence of dental caries; prevention of dental disease (oral hygiene and diet); bacteremia and infective endocarditis risk, and child behavior control and treatment under general anesthesia. CONCLUSIONS: Pediatric Dentists should bear in mind that early diagnosis and treatment, together a long term follow-up of children with PA/VSD, continue to be the best approaches for achieving enhanced patient psychological well-being and, in consequence, their good quality of life. PMID- 28624839 TI - The effects of irrigation volume to the heat generation during implant surgery. AB - BACKGROUND: To evaluate the effects of the amount of irrigation on heat generated during implant site preparation. MATERIAL AND METHODS: Ten freshly dissected sheep mandibles were sectioned into 30 equal bone blocks and transferred into a heat-controlled water tank. Implant socket preparations were performed with four consecutive drills. Temperature measurements were performed with a thermocouple inserted into the bone immediately before the preparation and after the drilling using three different physiologic saline irrigation set-ups: 1- No irrigation, 2- 12 ml/min and 3- 30 ml/min irrigation volume. The temperature differences between three different irrigation set-ups for implant drills 1, 2, 3 and 4, and the temperature differences between the drills for three different irrigation set-ups were separately compared. RESULTS: The temperature difference of no irrigation group was significantly higher than 12 ml/min and 30 ml/min groups for all four drills (p<0.05), whereas no statistically significant difference was found between 12 ml/min and 30 ml/min irrigation groups. (p>0.05) The temperature difference of drill 1 is significantly higher than drills 2, 3 and 4 for no irrigation group. (p<0.05) The temperature differences of drill 1, 2 and 3 were significantly higher than the temperature difference of drill 4 for 12 ml/min irrigation group. (p<0.05) Conclusions: The heat generated during drilling is not directly proportional to the coolant volume. Given that certain amount of irrigation is applied, implant sites can be prepared safely without the need for additional irrigation, which may result in reduced visibility of the surgical site and therefore a suboptimal surgery. PMID- 28624840 TI - Do topical applications of bisphosphonates improve bone formation in oral implantology? A systematic review. AB - BACKGROUND: The aim of this systematic literature review was to evaluate the feasibility of topical bisphosphonate application for preserving/enhancing alveolar bone in oral implantology. MATERIAL AND METHODS: An electronic search was conducted in the PubMed/Medline, EMBASE, Scopus, Web of knowledge, and Google Scholar databases for articles dated from January 2000 to December 2016. Two reviewers assessed the quality of the studies independently. RESULTS: A total of 154 abstracts were identified, of which 18 potentially relevant articles were selected; a final total of nine papers were included for analysis. Comparison of the findings of the selected studies was made difficult by the heterogeneity of the articles, all of them animal research papers that showed heterogeneity in the methodologies used and a high or moderate risk of bias. CONCLUSIONS: The topical application of bisphosphonate solution would appear to favor new bone formation in alveolar defects, and boosts the regenerative capacities of biomaterials resulting in increased bone density. PMID- 28624841 TI - The Neutrophil-to-Lymphocyte ratio as a marker of recovery status in patients with severe dental infection. AB - BACKGROUND: The aim of the study was to assess the value of pretreatment neutrophil/lymphocyte (N/L) ratio and mean platelet volume (MPV) and the correlation between these markers with progression in patients with severe odontogenic infection. MATERIAL AND METHODS: A cohort of 100 patients with severe odontogenic infection were divided into 2 groups according to their length of hospital stay. The N/L ratio and MPV was measured in all patients. The correlation in all patients between preoperative fever, preoperative antibiotic doses, postoperative antibiotic doses, total antibiotic doses and hospital stay with N/L ratio and MPV were analyzed. The Youden index was used to identify the optimal cut-off value. RESULTS: There were positive and statistically significant correlations between N/L ratio and prolonged hospital stay and postoperative antibiotic doses and total antibiotic doses. The optimum cut -off level of N/L ratio was 5.19 according to ROC analysis. However, there was no correlation between MPV and any of these parameters. CONCLUSIONS: N/L ratio may be used as a prognostic marker for patients with odontogenic infections. These patients may need a higher dose of antibiotics and stay more than 1 day in hospital for the treatment of odontogenic infection when the N/L ratio is detected to be more than 5.19. PMID- 28624843 TI - Expressions of Ras Homolog Gene Family, Member A (RhoA) and Cyclooxygenase-2 (COX 2) Proteins in Early Gastric Cancer and Their Role in the Development of Gastric Cancer. AB - BACKGROUND This research focused on detecting the expressions of RhoA and cyclooxygenase-2 (COX-2) proteins in early gastric cancer tissues and to explore their role in the development of gastric cancer. MATERIAL AND METHODS Surgically resected gastric cancer tissues and the paired normal paracancerous tissues were collected from 26 patients with early gastric cancer from January 2015 to November 2015. The expressions of RhoA and COX-2 proteins were detected by using RT-PCR and immunohistochemistry techniques, respectively. Cell proliferation and migration experiments were conducted on the RhoA-silenced A6-B9 cells and COX-2 silenced D7-B8 cells so as to discuss their role in the development of gastric cancer. RESULTS Relative mRNA expressions of RhoA and COX-2 in the cancer tissues were 0.823+/-0.021 and 0.892+/-0.103, respectively, which showed significant differences compared to the normal cancerous tissues (0.295+/-0.014 and 0.129+/ 0.037) (p<0.05). Immunohistochemical staining indicated that the expressions of RhoA and COX-2 proteins in tumor tissues were significantly upregulated as compared to normal cancerous tissues (p<0.05). Cell cloning and streaking assays showed that silencing of RhoA and COX-2 gene caused a considerable decline in the proliferation and migration capacities of the gastric cancer cells, respectively (p<0.05). CONCLUSIONS RhoA and COX-2 were upregulated in early gastric cancer tissues, which facilitated the proliferation and migration of gastric cancer cells. Both proteins may be used as potential markers for the diagnosis of early gastric cancer. PMID- 28624842 TI - Increased Levels of Pro-Inflammatory and Anti-Inflammatory Cellular Responses in Parkinson's Disease Patients: Search for a Disease Indicator. AB - BACKGROUND Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder and it arises when most of the dopaminergic neurons of substantia nigra region die. Several mechanisms have been postulated as the causative event in PD pathology, and neuroinflammation is most crucial among them. MATERIAL AND METHODS We analyzed T-helper 17 (Th17) cells and myeloid derived suppressor cells (MDSCs) from 80 PD patients to assess inflammatory processes and to find a cost-effective means to evaluate PD prognosis. RESULTS We found significantly increased numbers of Th17 cells and MDSCs count in peripheral circulation in PD patients compared with controls (p<0.001). A positive correlation was found between Th17 cells and MDSCs in PD patients (r=0.421, p<0.05). CONCLUSIONS Our results show the effector role of Th17 cells and MDSCs in PD pathology and shows their utility as effective biomarkers for PD diagnosis. PMID- 28624844 TI - The effect of endoscopic sinus surgery on quality of life and absenteeism in patients with chronic rhinosinuitis - a multi-centre study. AB - BACKGROUND: Chronic rhinosinusitis with and without nasal polyps (CRSw/sNP) are common conditions decreasing health-related quality of life (HRQOL). Individual symptoms capable of predicting outcome after endoscopic sinus surgery (ESS) are poorly defined, and the indirect costs of CRS is rarely reported in Europe. METHODOLOGY: Patients with CRSw/sNP admitted for ESS were prospectively enrolled. Patients completed the 22 Sinonasal Outcome Test (SNOT-22), the short-form 36 item questionnaire (SF-36), a Visual Analogue Scale (VAS) and reported CRS related absenteeism pre- and post-operatively. RESULTS: 181 patients were included. The SNOT-22 score diminished from 51.8 (48.7-55.0) pre-operatively to 33.0 (29.2-36.8) at 6 months. 64% achieved a clinically important improvement in the SNOT-22. SF-36 scores improved statistically significantly in all domains except Role Emotional. The VAS score halved from 68 (65-71) to 34 (29-39) at 6 months post-operatively. A pre-operative SNOT-22 score over 20 implied a greater chance of score improvement after 6 months. A multivariate model identified individual items associated with SNOT-22. Further, patients that had lees than 12 months of sinus disease derived greatest benefit. CRS-related absenteeism dropped from 8-14 days to 1-7 days 12 months after ESS. CONCLUSIONS: This prospective study showed that ESS significantly improved the HRQOL and decreased absenteeism of patients with CRSw/sNP. Shorter duration of disease and Need to blow nose and Blockage/congestion of nose of SNOT-22 were identified as predictive factors for good surgical outcome. PMID- 28624845 TI - Web-based teaching video packages on anatomical education. AB - BACKGROUND: The aim of this study was to study the effect of web-based teaching video packages on medical students' satisfaction during gross anatomy education. The objective was to test the hypothesis that individual preference, which can be related to learning style, influences individual utilization of the video packages developed specifically for the undergraduate medical curriculum. METHODS: Web-based teaching video packages consisting of Closed Circuit Audiovisual System and Distance Education of Anatomy were prepared. 54 informative application videos each lasting an average 12 min, competent with learning objectives have been prepared. 300 young adults of the medical school on applied anatomy education were evaluated in terms of their course content, exam performance and perceptions. A survey was conducted to determine the difference between the students who did not use teaching packages with those who used it during or after the lecture. RESULTS: A mean of 150 hits for each student per year was indicated. Academic performance of anatomy has been an increase of 10 points. Positive effects of the video packages on anatomy education have manifested on the survey conducted on students. The survey was compiled under twenty different items including effectiveness, providing education opportunity and affecting learning positively. Additionally, the difference was remarkable that the positive ideas of the second year students on learning were statistically significant from that of the third year students. CONCLUSION: Web based video packages are helpful, definitive, easily accessible and affordable which enable students with different pace of learning to reach information simultaneously in equal conditions and increase the learning activity in crowded group lectures in cadaver labs. We conclude that personality/learning preferences of individual students influence their use of video packages in the medical curriculum. PMID- 28624846 TI - Comment on: The cut surface of the neck as depicted in two paintings of Judith and Holofernes. PMID- 28624847 TI - The microbiome-gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain. AB - With the emergence of knowledge implicating the human gut microbiome in the development and regulation of several physiological systems, evidence has accumulated to suggest a role for the gut microbiome in psychiatric conditions and drug response. A complex relationship between the enteric nervous system, the gut microbiota and the central nervous system has been described which allows for the microbiota to influence and respond to a variety of behaviors and psychiatric conditions. Additionally, the use of pharmaceuticals may interact with and alter the microbiota to potentially contribute to adverse effects of the drug. The gut microbiota has been described in several psychiatric disorders including depression and anxiety, but only a few reports have discussed the role of the microbiome in schizophrenia. The following review examines the evidence surrounding the gut microbiota in behavior and psychiatric illness, the role of the microbiota in schizophrenia and the potential for antipsychotics to alter the gut microbiota and promote adverse metabolic events. PMID- 28624848 TI - 177Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer. AB - PURPOSE: Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with 177Lu-PSMA-617. METHODS: Between December 2014 and January 2017, 59 consecutive patients (median age 72 years; interquartile range, (IQR, 66 76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. RESULTS: The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of 177Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of >=50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). CONCLUSIONS: A PSA decline after the first cycle of 177Lu-PSMA-617 and an initial ALP level <220 U/L were predictors of a longer OS in patients with end-stage mCRPC. An ALP level <220 U/L was additionally associated with a longer PPFS. PMID- 28624849 TI - The accuracy of 68Ga-PSMA PET/CT in primary lymph node staging in high-risk prostate cancer. AB - PURPOSE: To assess the diagnostic accuracy of 68Ga-PSMA PET in predicting lymph node (LN) metastases in primary N staging in high-risk and very high-risk nonmetastatic prostate cancer in comparison with morphological imaging. METHODS: This was a multicentre trial of the Society of Urologic Oncology in Turkey in conjunction with the Nuclear Medicine Department of Cerrahpasa School of Medicine, Istanbul University. Patients were accrued from eight centres. Patients with high-risk and very high-risk disease scheduled to undergo surgical treatment with extended LN dissection between July 2014 and October 2015 were included. Either MRI or CT was used for morphological imaging. PSMA PET/CT was performed and evaluated at a single centre. Sensitivity, specificity and accuracy were calculated for the detection of lymphatic metastases by PSMA PET/CT and morphological imaging. Kappa values were calculated to evaluate the correlation between the numbers of LN metastases detected by PSMA PET/CT and by histopathology. RESULTS: Data on 51 eligible patients are presented. The sensitivity, specificity and accuracy of PSMA PET in detecting LN metastases in the primary setting were 53%, 86% and 76%, and increased to 67%, 88% and 81% in the subgroup with of patients with >=15 LN removed. Kappa values for the correlation between imaging and pathology were 0.41 for PSMA PET and 0.18 for morphological imaging. CONCLUSIONS: PSMA PET/CT is superior to morphological imaging for the detection of metastatic LNs in patients with primary prostate cancer. Surgical dissection remains the gold standard for precise lymphatic staging. PMID- 28624850 TI - The plant LIM proteins: unlocking the hidden attractions. AB - MAIN CONCLUSION: The plant LIMs comprise two sub-families with one (DA1/DAR) and two (2LIM) LIM domains. This review comprehensively discussed the structure and potential role of this protein family in diverse area of plant biology. The description of first eukaryote lineage-specific plant LIM domain (LIN11, ISL1, and MEC3) proteins was observed in Helianthus long back. The successive study of LIM proteins in diverse plants has shown its vital relation to development, metabolism and defence. This nascent gene family has been worked out for their role in actin dynamics, organ size determination and transcription regulation. On grounds of protein architecture, two sub-families have been delineated as DA1/DAR (one LIM domain) and 2LIMs (two LIM domains). The genomic and expression study guides to the identification of diverse sub-categories. The significance of 2LIMs in regulation of actin dynamics leading to pollen growth and development has prospects to understand the plant reproductive behaviour. Interestingly, new facet of these LIMs as a transcriptional regulator in biological pathway/biosynthesis was also reported. Recently, the cumulative contribution of these features was also recognized for obtaining good quality fibre, thus giving translational outlook to this family. The DA1/DAR proteins are orchestrated with additional domains and provide a key role in regulation of organ size and tolerance to biotic and abiotic stress. This review will focus the journey of plant LIMs till date and will cover details of its structure, type, classification and functional relevance. This will provide insight to identify the potential of this gene family in the improvement of desired crop features. PMID- 28624851 TI - Acute effects of constant torque and constant angle stretching on the muscle and tendon tissue properties. AB - PURPOSE: Static stretching induces acute structural changes of the muscle-tendon unit (MTU) that are related to the intensity or duration of stretching. It has been reported that stretching with a constant torque (CT) leads to greater joint range of motion changes than stretching with a constant angle (CA). Whether or not this difference is due to different structural changes of the MTUs of the lower leg and ankle plantar flexors is not known. Therefore, the purpose of this study was to compare the acute effects of single CA and CT stretching on various muscle and tendon mechanical properties. METHOD: Seventeen young, healthy volunteers were tested on two separate days using either CT or CA stretching (4 * 30 s each). Before and after stretching, dorsiflexion range of motion (RoM), passive resistive torque (PRT), and maximum voluntary contraction (MVC) were measured with a dynamometer. Ultrasonography of the medial gastrocnemius (GM) muscle-tendon junction (MTJ) displacement allowed us to determine the length changes in the tendon and muscle, respectively, and hence to calculate their stiffness. RESULTS: Maximum dorsiflexion increased while PRT, muscle-tendon stiffness, and muscle stiffness decreased following both CA and CT stretching. There was a greater increase in RoM following CT stretching compared to CA stretching. Moreover, the decline in PRT was greater during CT stretching compared to CA stretching. As expected, several functional adaptations (RoM, PRT) were different between CT and CA stretching due to the higher intensity of CT stretching. However, no structural differences in the adaptations to the stretching modalities could be detected. CONCLUSION: We suggest that the different functional adaptations between CA and CT stretching are the consequence of different adaptations in the perception of stretch and pain. PMID- 28624852 TI - Vasoconstrictor responsiveness in contracting human muscle: influence of contraction frequency, contractile work, and metabolic rate. AB - PURPOSE: The aim of this study was to examine whether independent effects exist between contractile work and metabolic demand (VO2m) on vasoconstrictor responsiveness (i.e., functional sympatholysis) under different contraction durations matched for total contractile work in exercising human skeletal muscle. METHODS: Ten young men performed rhythmic forearm contractions at 10 and 15% of maximum voluntary contraction (MVC) which consisted of muscle contractions using the same duty cycle but altering the duration of the contraction-relaxation cycles of exercise and included: 1) fast frequency contractions at 10% MVC (FFC10%) using a contraction relaxation cycle at 1:2 s; 2) slow frequency contractions at 10% MVC (SFC10%) at 2:4 s; and 3) SFC at 15% MVC (SFC15%) at 2:4 s. Lower body negative pressure (LBNP) was applied to increase sympathetic vasoconstriction during forearm exercise. Brachial artery diameter and blood velocities (measured via Doppler ultrasound) determined forearm blood flow (FBF), and forearm vascular conductance (FVC) was calculated from FBF (ml min-1) and mean arterial blood pressure. RESULTS: Results revealed that steady-state indices of FBF, FVC, and VO2m were greater (P < 0.05) in FFC10% and SFC15% vs. SFC10%. In addition, the magnitude of vasoconstriction (percent reduction in FVC) in response to reflex increases in sympathetic activity during LBNP was greater with SFC10% vs. FFC10% (-20.6 +/- 3.0 vs. -11.1 +/- 2.0%; P < 0.05), whereas there was no difference with FFC10% vs. SFC15% (-11.1 +/- 2.0 vs. -11.8 +/- 1.8%; P = 0.91). CONCLUSIONS: Our data indicate that faster work-matched muscle contractions increase blood flow and metabolism, leading to improved functional sympatholysis as compared to slower work-matched muscle contractions in humans. PMID- 28624853 TI - Biophysical stimulation improves clinical results of matrix-assisted autologous chondrocyte implantation in the treatment of chondral lesions of the knee. AB - PURPOSE: The purpose of the present study was to evaluate the effects of pulsed electromagnetic fields (PEMFs) on clinical outcome in patients who underwent arthroscopic matrix-assisted autologous chondrocyte implantation (MACI) for chondral lesions of the knee. METHODS: Thirty patients affected by grade III and IV International Cartilage Repair Society chondral lesions of the knee underwent MACI. After surgery, patients were randomly assigned to either experimental group (PEMFs 4 h per day for 60 days) or control group . Clinical outcome was evaluated through International Knee Documentation Committee (IKDC) subjective knee evaluation form, Visual Analog Scale, Short Form-36 (SF-36) and EuroQoL before surgery and 1, 2, 6, and 60 months postoperative. RESULTS: Mean size of chondral lesion was 2.4 +/- 0.6 cm2 in the PEMFs group and 2.5 +/- 0.5 cm2 in the control one. No differences were found between groups at baseline. IKDC score increased in both groups till 6 months, but afterward improvement was observed only in the experimental group with a significant difference between groups at 60 months (p = 0.001). A significant difference between groups was recorded at 60 months for SF 36 (p = 0.006) and EuroQol (p = 0.020). A significant pain reduction was observed in the experimental group at 1-, 2- and 60-month follow-up. CONCLUSION: Biophysical stimulation with PEMFs improves clinical outcome after arthroscopic MACI for chondral lesions of the knee in the short- and long-term follow-up. Biophysical stimulation should be considered as an effective tool in order to ameliorate clinical results of regenerative medicine. The use of PEMFs represents an innovative therapeutic approach for the survival of cartilage-engineered constructs and consequently the success of orthopaedic surgery. LEVEL OF EVIDENCE: II. PMID- 28624854 TI - Superior return to sports rate after patellar tendon autograft over patellar tendon allograft in revision anterior cruciate ligament reconstruction. AB - PURPOSE: After revision anterior cruciate ligament reconstruction (ACLR), the rate of return to the pre-injury type of sport (RTS type) is low and graft choice might be an important factor. The aim of this study was to determine whether there is a difference in outcome after revision ACLR using a patellar tendon allograft compared to an ipsilateral patellar tendon autograft. It was hypothesized that the rate of RTS type using an ipsilateral patellar tendon autograft will be superior to using patellar tendon allograft. METHODS: The design is a retrospective cohort study. Inclusion criteria were patients who underwent revision ACLR with a minimum follow-up of 1 year after revision using a patellar allograft or ipsilateral autograft. Primary study parameter was rate of RTS type. Secondary study parameters were RTS level, subscores of the KOOS, the IKDCsubjective, the Tegner score and reasons for no RTS. RESULTS: Eighty-two patients participated in this study (36 allografts and 46 autografts). In patients with a minimum follow-up of 1 year, rate of RTS type was 51.4% for the patellar tendon allograft and 62.8% for the patellar tendon autograft group (n.s.). In patients with a minimum follow-up rate of 2 years, rate of RTS type was 43.3 versus 75.0%, respectively (p = 0.027). No differences in secondary study parameters were found. In patients with a minimum follow-up of 1 year, rate of RTS type was significantly higher (p = 0.025) for patients without anxiety compared to patients who were anxious to perform certain movements. CONCLUSION: After a minimum follow-up of 2 years, rate of RTS type is in favour of using an ipsilateral patellar tendon autograft when compared to using a patellar tendon allograft in patients undergoing revision ACLR; after a minimum follow-up of 1 year, no significant difference was found. In revision ACLR, the results of this study might influence graft choice in favour of autologous graft when the use of an allograft or autograft patellar tendon is considered. LEVEL OF EVIDENCE: III. PMID- 28624855 TI - CT arthrography visualizes tissue growth of osteochondral defects of the talus after microfracture. AB - PURPOSE: Little is known about the arthroscopic or radiographic outcomes after arthroscopic microfracture of osteochondral lesions of the talus (OLTs). The purpose of this study was to investigate tissue growth after arthroscopic microfracture of OLTs using computed tomography arthrography (CTA) and to identify the relationship between CTA findings and clinical outcomes. We hypothesized that the morphology of the repaired tissue would be similar to that of normal anatomy and correlate with the clinical outcomes. METHODS: Forty-two ankles treated using arthroscopic microfracture of OLTs between 2009 and 2014 were monitored. CTA was performed post-operatively at 6 months and at 1 and 2 years after surgery. The post-operative thickness of the repaired tissue associated with OLT (grade) and the volume of the subchondral cystic lesions were evaluated using CTA. Clinical outcomes, including the pain visual analog scale (VAS) and American Orthopaedic Foot and Ankle Society (AOFAS) ankle functional scores, were evaluated and correlated with CTA. RESULTS: The proportion of fully grown tissue (grade 3) increased over time; specifically, the rates were 12/40 (33.3%) at 6 months, 11/18 (61.1%) at 1 year, and 8/10 (80%) at 2 years after surgery (p = 0.005). The VAS pain (p < 0.001) and AOFAS scores (p < 0.001) were also improved at the final follow-up; however, they were not associated with repaired tissue thickness as shown by CTA (n.s.). CONCLUSIONS: After microfracture of OLTs, tissue growth in the osteochondral defects was well visualized using CT arthrography and was observed in most cases. However, the CTA findings were not related to the clinical outcomes. LEVEL OF EVIDENCE: IV. PMID- 28624856 TI - The glenocapsular ligament and the posterosuperior part of the joint capsule of the shoulder are well vascularized. AB - PURPOSE: A detailed structural anatomy of the posterosuperior shoulder capsule and "glenocapsular ligament" is still rather unknown. The purpose of this study was meticulously to investigate and describe the structure and blood supply of the glenocapsular ligament on the posterosuperior shoulder joint capsule. METHOD: Sixteen fixed and twelve fresh cadaveric shoulder specimens with a mean age of 73.4 (+/-6.4) years were analysed. Dissection without arterial injection was performed on the 16 fixed specimens-using an alcohol-formalin-glycerol solution. Before dissection, the 12 fresh specimens received of arterial injection a 10% aqueous dispersion of latex solution. After the injection, these shoulders were also fixed in an alcohol-formalin-glycerol solution. RESULTS: The glenocapsular ligament was found in all 28 specimens. Single or double parallel-running bundles of connective tissue fibres were found to form a capsular-ligamentous structure on the posterosuperior part of the joint capsule. One part of the ligament was mediosuperior, another posterosuperior. The mediosuperior part varied in shape, and in 12 of 28 cases, it was absent. The glenocapsular ligament arose from the supraglenoid tubercle and posterior part of the collum scapulae and inserted into the semicircular humeral ligament. The posterior ascending branch of the circumflex scapular artery directly fed small branches laterally and medially to the joint capsule, supplying the glenocapsular ligament and the deep layer of the joint capsule. CONCLUSION: The glenocapsular ligament is a constant anatomical structure that consists of one or two different parts. The glenocapsular ligament and the posterosuperior part of the joint capsule appear well vascularized via the posterior ascending branch of the circumflex scapular artery. CLINICAL RELEVANCE: It is the hope of the authors that this anatomical study can help surgeons who perform open or arthroscopic surgery to the posterior part of the shoulder. Knowledge of the vascular anatomy presented in this study may be especially important when incisions are made to the posterior part of the shoulder, and should minimize the risk of complications. PMID- 28624857 TI - Bioaccumulation of heavy metals and ecophysiological responses to heavy metal stress in selected populations of Vaccinium myrtillus L. and Vaccinium vitis idaea L. AB - The aim of this study was to determine the concentrations of heavy metals (Cd, Pb, Zn, Fe, and Mn) in soil, and their bioavailability and bioaccumulation in Vaccinium myrtillus L. and Vaccinium vitis-idaea L. organs. Analysis also concerned the physiological responses of these plants from three polluted sites (immediate vicinity of a zinc smelter in Miasteczko Slaskie, ArcelorMittal Poland S.A. iron smelter in Dabrowa Gornicza-Losien, and Jaworzno III power plant in Jaworzno) and one pseudo-control site (Pazurek nature reserve in Jaroszowiec Olkuski). All of the sites are situated in the southern parts of Poland in the Slaskie or Malopolskie provinces. The contents of proline, non-protein thiols, glutathione, ascorbic acid, and the activity of superoxide dismutase and guaiacol peroxidase in the leaves of Vaccinium myrtillus L. and Vaccinium vitis-idaea L. were measured. In soil, the highest levels of Cd, Pb, and Zn (HNO3 extracted and CaCl2 extracted) were detected at the Miasteczko Slaskie site. At all sites a several times lower concentration of the examined metals was determined in the fraction of soil extracted with CaCl2. Much higher Cd, Pb, Zn and Fe concentrations were found in V. myrtillus and V. vitis-idaea grown at the most polluted site (located near the zinc smelter) in comparison with cleaner areas; definitely higher bioaccumulation of these metals was found in lingonberry organs. Additionally, we observed a large capability of bilberry to accumulate Mn. Antioxidant response to heavy metal stress also differed between V. myrtillus and V. vitis-idaea. In V. myrtillus we found a positive correlation between the level of non-protein thiols and Cd and Zn concentrations, and also between proline and these metals. In V. vitis-idaea leaves an upward trend in ascorbic acid content and superoxide dismutase activity accompanied an increase in Cd, Pb, and Zn concentrations. At the same time, the increased levels of all tested metals in the leaves of V. vitis-idaea were accompanied by a decreased activity of guaiacol peroxidase. In both species increased Mn accumulation caused a decrease in antioxidant response. PMID- 28624858 TI - Sperm parameters that play a major role in the assessment of semen quality after cryopreservation. PMID- 28624859 TI - The -29G/A FSH receptor gene polymorphism is associated with higher FSH and LH levels in normozoospermic men. AB - PURPOSE: The functional role of the FSHR promoter -29G/A polymorphism (rs1394205) in men is not clear. Some studies failed to find a relationship between the FSHR 29G/A and follicle-stimulating hormone (FSH) levels and did not associate the SNP with male infertility. Only one study showed that the FSHR -29 SNP modulates serum FSH levels in Baltic young male cohort. Because the SNP -29G/A has to be shown to have a strong effect on in vitro transcription activity of the FSHR promoter and the activation of FSHR is necessary for a normal FSH function, this study was undertaken to assess whether the FSHR -29G/A SNP modulates the gonadal endocrine function in men. METHODS: A total of 200 men with alteration of conventional sperm parameters or normozoospermia (according to the parameters WHO 2010), were genotyped by TaqMan Assay. Hormone levels were measured by immunoassay, and sperm analysis was performed according to the World Health Organization criteria. RESULTS: A significant gradient of increasing FSH levels across the FSHR -29G/A genotypes was observed (p < 0.01). Among normozoospermic men (n = 110), those with FSHR -29A-allele carriers (GA + AA and AA) had higher serum FSH (p < 0.01) and LH levels (p < 0.05) and higher body mass index (BMI) (p < 0.01) compared to men with the GG genotype. The carrier status of rs1394205 genotypes did not affect the other endocrine parameters neither in men with altered sperm parameters nor in normozoospermic men. CONCLUSIONS: The FSHR -29G/A polymorphism modulates FSH and, for the first time, LH serum levels and BMI in normozoospermic men. These findings underline the importance to pay close attention to the studies of genetic variations associated with clinical-endocrine parameters. PMID- 28624860 TI - Obesity results with smaller oocyte in in vitro fertilization/intracytoplasmic sperm injection cycles-a prospective study. AB - BACKGROUND: Obesity is associated with several fertility disorders. This prospective cohort study was designed to evaluate the effect of body mass index (BMI) (kg/m2) on oocyte diameter and treatment. METHODS: Women undergoing in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) were enrolled in the study. They were divided into two groups according to BMI: obese (BMI > 30) and normal weight (BMI < 25). Mature oocytes were evaluated according to total diameter, zona pellucida, and oolema diameters. RESULTS: A total of 387 oocytes were obtained from the 46 women who participated. Significantly more mature oocytes (M2) were retrieved from normal weight patients compare to obese women (15.1 +/- 6.8 vs. 9.7 +/- 3.9, respectively, P < 0.001). Oocytes from women in the obese group were significantly smaller than those in the normal weight group, including oocyte diameter (157.9 +/- 7.9 vs. 164.3 +/- 5.1 MUm, P < 0.0001), oolema diameter (110.3 +/- 4.5 vs. 113.5 +/- 3.5 MUm, P < 0.0001), and zona pellucida thickness (17.9 +/- 2.6 vs. 19.0 +/- 2.4 MUm, P < 0.000), respectively. Multivariate logistic regression analysis, including oolema diameter, female age, BMI, number of M2 oocytes, and zona pellucida, was conducted to predict pregnancy. Small oolema diameter in obese patient adversely correlated with pregnancy. Larger oolema diameter was positively associated with the probability of pregnancy in the obese group as well as thinner zona pellucida. CONCLUSION: Obesity is associated with smaller oocytes, which adversely affect fertility outcomes. TRIAL REGISTRATION: NIH number NCT01672931. PMID- 28624861 TI - Hemorrhagic ganglioglioma of the third ventricle with atypical pathological findings. PMID- 28624862 TI - Comparison of autologous fibrin glue versus nylon sutures for securing conjunctival autografting in pterygium surgery. AB - PURPOSE: To compare the safety, operating time, postoperative ocular signs, symptoms, overall patient satisfaction, complications rate and recurrence rate of autologous fibrin glue (AFG) and nylon suturing (NS) for attaching conjunctival autografts in pterygium surgery. METHODS: A prospective, randomized, interventional study was performed among 120 patients (120 eyes) with primary pterygium. Superior conjunctival autograft was harvested and transferred on to bare sclera after pterygium excision. For attaching the autograft, AFG (n = 60 eyes) and NS (n = 60 eyes) were used. The patients were followed up for 12 months. The groups were compared for the safety, operative time, postoperative ocular signs, symptoms, overall patient satisfaction, recurrence and complications rate. RESULTS: All conjunctival autografts in both groups were successfully attached. The average operating time for the AFG group was significantly shorter (P < 0.001). Postoperative symptoms were fewer for the AFG group than the suture group. After 12 months of follow-up, no recurrence was reported for the AFG group, but 8.3% of patients experienced recurrence in the NS group. CONCLUSIONS: Our study demonstrated the superiority of AFG to NS in saving operating time and elimination of recurrence without any complications in pterygium surgery. AFG can obviate the need for suturing and increases the viability of tissue flaps. Additional studies are necessary to determine the long term effects considering factors such as primary or recurrent status of pterygium, age and sex of patient, dose and duration of treatment for mitomycin C. PMID- 28624863 TI - Matched-pair analysis of patients with advanced hypopharyngeal cancer: surgery versus concomitant chemoradiotherapy. AB - BACKGROUND: The aim of this study was to compare the therapeutic outcomes of total pharyngolaryngectomy with those of concomitant chemoradiotherapy in advanced hypopharyngeal cancer. METHODS: This is a retrospective multi institutional study. The medical records of 979 patients with hypopharyngeal cancer, who were initially treated between 2006 and 2008, were reviewed. In this study, we matched a group of total pharyngolaryngectomy patients with a second group of chemoradiotherapy patients, according to age, gender, subsite, arytenoid fixation, cartilage invasion, and N classification, and analyzed overall survival, disease-specific survival, and locoregional control rates. RESULTS: The matched-pair analysis included 254 patients. The 5-year overall survival, disease specific survival, and locoregional control rates were 58.5% and 53.5% (P = 0.30), 68.9% and 68.0% (P = 0.80), and 82.2% and 63.6% (P < 0.01), respectively, for patients in the total pharyngolaryngectomy and chemoradiotherapy groups. For T4a patients with cartilage invasion, the matched-pair analysis included 46 patients. The 5-year overall survival, disease-specific, and locoregional control rates were 56.5% and 26.0% (P = 0.092), 56.5% and 41.3% (P = 0.629), and 43.0% and 42.5% (P = 0.779), respectively, for patients in the total pharyngolaryngectomy and chemoradiotherapy groups. CONCLUSIONS: The data from this large-scale multi-institutional joint research program of hypopharyngeal cancer in Japan suggest that chemoradiotherapy may provide adequate survival benefit for hypopharyngeal cancer patients with the distinct advantage of larynx preservation. Our data also suggest that chemoradiotherapy is as beneficial as total pharyngolaryngectomy for the local control of locally advanced hypopharyngeal cancer. PMID- 28624864 TI - The clinical significance of pneumonia in patients with respiratory specimens harbouring multidrug-resistant Pseudomonas aeruginosa: a 5-year retrospective study following 5667 patients in four general ICUs. AB - Pseudomonas aeruginosa is the leading cause of pneumonia in intensive care units (ICUs), with multidrug-resistant (MDR) strains posing a serious threat. The aim of this study was to assess the clinical relevance of MDR Pseudomonas isolates in respiratory clinical specimens. A 5-year retrospective observational study in four medical-surgical ICUs from a referral hospital was carried out. Of 5667 adults admitted to the ICU, 69 had MDR-PA in respiratory samples: 31 were identified as having pneumonia (HAP/VAP): 21 ventilator-associated pneumonia (VAP) and ten hospital-acquired pneumonia (HAP). Twenty-one (67.7%) adults with MDR-PA HAP/VAP died after a median of 4 days (18 of the 21 deaths within 8 days), compared with one (2.6%) without pneumonia at day 8. In a Cox proportional regression model, MDR-PA pneumonia was an independent variable [adjusted hazard ratio (aHR) 5.92] associated with 30-day ICU mortality. Most strains (85.1%) were susceptible to amikacin and colistin. Resistance to beta-lactams (third generation cephalosporins and piperacillin-tazobactam) ranged from 44.1% to 45.3%. Meropenem showed poor overall activity (MIC[50/90] 16/32 mg/dL), with 47.0% having a minimum inhibitory concentration (MIC) breakpoint >8 mg/L. Twenty four (77.4%) HAP/VAP episodes received inappropriate empirical therapy. Although empirical combination therapy was associated with less inappropriate therapy than monotherapy (16.7% vs. 88.3%, p < 0.01), there was no difference in survival (30% vs. 33.3%, p = 0.8). Pneumonia was identified in one-third of adult ICU patients harbouring MDR-PA in respiratory clinical specimens. These patients have a 6-fold risk of (early) death compared to ventilator-associated tracheobronchitis (VAT) and respiratory colonisation. New antibiotics and adjuvant therapies are urgently needed to prevent and treat MDR-PA HAP/VAP. PMID- 28624865 TI - Bone marrow fat contributes to insulin sensitivity and adiponectin secretion in premenopausal women. AB - PURPOSE: Bone marrow fat is a functionally distinct adipose tissue that may contribute to systemic metabolism. This study aimed at evaluating a possible association between bone marrow fat and insulin sensitivity indices. METHODS: Fifty obese (n = 23) and non-obese (n = 27) premenopausal women underwent proton magnetic resonance spectroscopy to measure vertebral bone marrow fat content and unsaturation index at L4 level. Abdominal visceral, subcutaneous fat, and epicardial fat were also measured using magnetic resonance imaging. Bone mineral density was measured by dual-energy X-ray absorptiometry. Body composition was assessed by bioelectrical impedance analysis. Fasting serum glucose, insulin, lipids, adiponectin were measured; the insulin resistance index HOMA (HOMA-IR) was calculated. RESULTS: Bone marrow fat content and unsaturation index were similar in obese and non-obese women (38.5 +/- 0.1 vs. 38.6 +/- 0.1%, p = 0.994; 0.162 +/- 0.065 vs. 0.175 +/- 0.048, p = 0.473, respectively). Bone marrow fat content negatively correlated with insulin and HOMA-IR (r = -0.342, r = -0.352, respectively, p = 0.01) and positively with high density lipoprotein cholesterol (r = 0.270, p = 0.043). From a multivariate regression model including lnHOMA-IR as a dependent variable and visceral, subcutaneous, epicardial fat, and bone marrow fat as independent variables, lnHOMA-IR was significantly associated with bone marrow fat (beta = -0.008 +/- 0.004, p = 0.04) and subcutaneous fat (beta = 0.003 +/- 0.001, p = 0.04). Bone marrow fat, among the other adipose depots, was a significant predictor of circulating adiponectin (beta = 0.147 +/- 0.060, p = 0.021). Bone marrow fat unsaturation index negatively correlated with visceral fat (r = -0.316, p = 0.026). CONCLUSIONS: There is a relationship between bone marrow fat content and insulin sensitivity in obese and non-obese premenopausal women, possibly mediated by adiponectin secretion. Visceral fat does not seem to regulate bone marrow fat content while it may affect bone marrow fat composition. PMID- 28624866 TI - Update on Psychological Trauma, Other Severe Adverse Experiences and Eating Disorders: State of the Research and Future Research Directions. AB - PURPOSE OF REVIEW: This paper provides an updated review of the literature on the relationship between psychological trauma exposure, other severe adverse experiences, and eating disorders. RECENT FINDINGS: Trauma exposure and other severe adverse experiences (e.g., emotional abuse) in both childhood and adulthood are associated with eating disorders. The relationship between traumatic and other adverse experiences and eating disorders appears to be mediated by emotional and behavioral dysregulation, as well as by cognitive factors such as self-criticism. Biological vulnerabilities may also be relevant to this relationship. Overall, the literature is limited by predominantly cross sectional designs. There is clear evidence of a correlational relationship between trauma exposure and other severe adverse events, and eating disorders. Both risk and maintenance factor hypotheses have been put forth; however, prospective research testing these hypotheses remains limited. Future research should use prospective designs and focus on trauma-related symptoms (rather than trauma exposure) in order to advance research on risk and maintaining factors for eating disorders and inform treatment directions. PMID- 28624867 TI - Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th International Workshop on CMV and Immunosenescence. AB - Cytomegalovirus (CMV) is one of the most complex and most ubiquitous latent persistent viruses, with a considerable ability to evade and manipulate the immune system. Following an early-life infection, most immunocompetent humans spend several decades living with CMV, and, because the virus in these hosts does not cause manifest disease, CMV can be considered part of normal aging for more than half of humanity. However, there is accumulating evidence that CMV carriage is not a null event and that both potentially harmful and potentially beneficial outcomes emanate from the interaction of CMV with its mammalian hosts. This article provides an overview of the 6th International Workshop on CMV and Immunosenescence, highlighting the advances in the field made in the past two years, as related to CMV epidemiology/geroscience, CMV virology with an accent on latency, and CMV immune evasion and immune recognition of the virus and its antigens. PMID- 28624869 TI - Incorporation of Cerium Oxide into Hydroxyapatite Coating Protects Bone Marrow Stromal Cells Against H2O2-Induced Inhibition of Osteogenic Differentiation. AB - Oxidative stress exerts a key influence in osteoporosis in part by inhibiting osteogenic differentiation of bone marrow stromal cells (BMSCs). With their unique antioxidant properties and reported biocompatibility, cerium oxide (CeO2) ceramics exhibit promising potential for the treatment of osteoporosis resulting from oxidative stress. In this study, protective effects of CeO2-incorporated hydroxyapatite coatings (HA-10Ce and HA-30Ce) on the viability and osteogenic differentiation of H2O2-treated BMSCs were examined. CeO2-incorporated HA coatings enhanced cell viability and attenuated cell apoptosis caused by H2O2. An increase in CeO2 content in HA coatings better alleviated H2O2-induced inhibition of osteogenic differentiation by increasing alkaline phosphatase (ALP) activity, calcium deposition activity, and mRNA expression levels of osteogenesis markers runt-related transcription factor 2 (Runx2), ALP, and osteocalcin (OCN) in BMSCs. Furthermore, the H2O2-induced decrease of gene and protein expressions of beta catenin and cyclin D1 in the Wnt/beta-catenin signaling pathway was successfully rescued by the CeO2 incorporated HA coatings. Besides, the decreased expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and the increased ratio of osteoprotegerin (OPG)/RANKL in BMSCs on the CeO2-modified coatings was observed, indicating the inhibition of osteoclastogenesis. The above results were mediated by the antioxidant properties of CeO2. The CeO2-incorporated HA coatings reversed the decreased superoxide dismutase (SOD) activity, reduced reactive oxygen species (ROS) generation, and suppressed the malondiadehyde (MDA) formation. The findings suggested that CeO2-modified HA coatings may be promising coating materials for osteoporotic bone regeneration. PMID- 28624868 TI - How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms? AB - Cytomegalovirus (CMV) is an important pathogen for both clinical and population settings. There is a growing body of research implicating CMV in multiple health outcomes across the life course. At the same time, there is mounting evidence that individuals living in poverty are more likely to be exposed to CMV and more likely to experience many of the chronic conditions for which CMV has been implicated. Further research on the causal role of CMV for health and well-being is needed. However, the strong evidence implicating CMV in type 2 diabetes, autoimmunity, cancer, cardiovascular disease, vaccination, and age-related alterations in immune function warrants clinical and public health action. This imperative is even higher among individuals living in socioeconomically disadvantaged settings and those exposed to high levels of chronic psychosocial stress. PMID- 28624870 TI - Translatory hip kinematics measured with optoelectronic surgical navigation. AB - PURPOSE: An optoelectronic surgical navigation system was used to detect small but measurable translational motion of human hip cadavers in high-range passive motions. Kinematic data were also examined to demonstrate the role of soft tissues in constraining hip translation. METHODS: Twelve cadaver hips were scanned using CT, instrumented for navigation, and passively taken through motion assessment. Center of the femoral head was tracked in the acetabular coordinates. Maximum non-impinging translation of the femoral head for each specimen hip was reported. This was repeated for 5 tissue states: whole, exposed to the capsule, partially or fully incised capsule, resection of the ligamentum teres and labrectomy. Femoral motions were compared to the reported value for ideal ball and socket model. RESULTS: Whole and exposed hips underwent maximal translations of [Formula: see text] and [Formula: see text] mm, respectively. These translational motions were statistically significantly different from reported value for a purely spherical joint, [Formula: see text]. Further tissue removal almost always significantly increased maximum non-impingement translational motion with [Formula: see text]. CONCLUSION: We found subtle but definite translations in every cadaver hip. There was no consistent pattern of translation. It is possible to use the surgical navigation systems for the assessment of human hip kinematics intra-operatively and improve the treatment of total hip arthroplasty patients by the knowledge of the fact that their hips translate. Better procedure selection and implantation optimization may arise from improved understanding of the motion of this critically important human joint. PMID- 28624871 TI - Synthesis and application of magnetite dextran-spermine nanoparticles in breast cancer hyperthermia. AB - Cancer treatment has been very challenging in recent decades. One of the most promising cancer treatment methods is hyperthermia, which increases the tumor temperature (41-45 degrees C). Magnetic nanoparticles have been widely used for selective targeting of cancer cells. In the present study, magnetic dextran spermine nanoparticles, conjugated with Anti-HER2 antibody to target breast cancer cells were developed. The magnetic dextran-spermine nanoparticles (DMNPs) were prepared by ionic gelation, followed by conjugation of antibody to them using EDC-NHS method. Then the Prussian blue method was used to estimate the targeting ability and cellular uptake. Cytotoxicity assay by MTT showed that antibody-conjugated MNPs (ADMNPs) have no toxic effect on SKBR3 and human fibroblast cells. Finally, the hyperthermia was applied to show that synthesized ADMNPs, could increase the cancer cells temperature up to 45 degrees C and kill most of them without affecting normal cells. These observations proved that Anti HER2 conjugated magnetic dextran-spermine nanoparticles can target and destroy cancer cells and are potentially suitable for cancer treatment. PMID- 28624872 TI - Abaloparatide: First Global Approval. AB - Abaloparatide (TymlosTM) is a synthetic peptide analogue of human parathyroid hormone-related protein that was developed by Radius Health as an osteoanabolic agent for the treatment of postmenopausal osteoporosis. Abaloparatide acts through selective activation of the parathyroid hormone type 1 receptor signalling pathway. In April 2017, subcutaneous abaloparatide received its first global approval, in the USA, for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. A Marketing Authorization Application for subcutaneous abaloparatide for the treatment of postmenopausal women with osteoporosis was accepted by the European Medicines Agency and is currently under review. Radius is also developing a transdermal formulation of abaloparatide, with administration via a microneedle patch. This article summarizes the milestones in the development of abaloparatide leading to this first approval for the treatment of women with postmenopausal osteoporosis. PMID- 28624873 TI - Short communication: first report of nematodes parasitizing the four-eyed-fish, Anableps anableps (Pisces, Cyprinodontiformes). AB - The genus Anableps is composed of species Anableps anableps, Anableps dowi, and Anableps microlepis. These fishes are tropical and usually live on the surface of brackish water, being popularly known as four-eyed-fishes due to the presence of prominent eyes and a pupil split horizontally. A. anableps and A. microlepis are considered as sister species that live in sympatry in South America. A. dowi, however, is restricted to the Pacific Ocean (Central America) and is considered the most primitive species of this genus. The aims of this study were to investigate the presence of endoparasites in A. anableps from the Parnaiba's Delta and characterize them morphologically. During the necropsy, larvae of Contracaecum sp. in the third larval stage (L3) were collected from the pancreas of A. anableps, but no endoparasites were observed in other organs. The worms had a cuticular tooth and excretory pore located at the anterior end, a thread like body, whitish color, and without distinction of sex. The length of the ventricular appendix of the larvae was much greater than in other studies. This is the first report of endoparasitism in A. anableps and the first report of nematodes in four-eyed-fishes. PMID- 28624874 TI - Reliable molecular differentiation of Trichuris ovis and Trichuris discolor from sheep (Ovis orientalis aries) and roe deer (Capreolus capreolus) and morphological characterisation of their females: morphology does not work sufficiently. AB - The main aim of the study was to evaluate associations between morphological variability of Trichuris females from sheep and roe deer and their rDNA polymorphism in whipworm populations from the Czech Republic. The results introduced the use of new molecular markers based on the internal transcribed spacer (ITS)1-5.8S RNA-ITS2 region polymorphisms, as useful tools for the unambiguous differentiation of congeners Trichuris ovis and Trichuris discolor. These markers revealed both parasites in roe deer and in sheep; however, T. ovis females predominated in sheep while T. discolor females occurred mostly in roe deer. Additional analysis of ITS1-5.8 rRNA-ITS2 discovered the genetic uniformity of the analysed T. discolor but high haplotype variation of T. ovis. Simultaneously, molecularly designated female individuals of both species were categorised into four morphotypes (MT) on the basis of morphology of genital pore area. MT1 and MT4 (vulvar opening on everted vaginal appendage/on visible cuticular bulge) occurred only in T. ovis, MT2 (uneverted vagina-vulvar opening without any elevation) was identified only in T. discolor and MT3 (transient type of vulvar opening on a small swelling) was observed in both species. Statistical analysis of biometric data confirmed that morphology of vulva is not a reliable marker for the species determination. On the basis of the ITS1-5.8S RNA-ITS2 region variability, we carried out a phylogenetic analysis (maximum likelihood method, Hasegawa-Kishino-Yano model) which showed that T. ovis haplotypes from the Czech Republic and Ireland and T. discolor haplotypes from the Czech Republic, Spain, Iran and Japan are sister OTUs. PMID- 28624875 TI - First record of Aedes koreicus (Diptera, Culicidae) in Slovenia. AB - The first record of Aedes koreicus was made in the village of Lovrenc na Dravskem Polju, north-eastern part of the country. The discovery of Ae. koreicus in various continental European countries motivated us to revise samples of the collected Aedes japonicus japonicus. We found Ae. koreicus in samples from 2013, where the larvae were misidentified as Ae. j. japonicus. The species was identified morphologically and molecularly. The first discovery of Ae. koreicus advocates an urgent need for a nationwide mosquito surveillance programme. PMID- 28624876 TI - Morphological and molecular characterization of a new cyprinid gall bladder infecting Chloromyxum species, Chloromyxum peleci sp. n. (Myxozoa: Chloromyxidae), from Pelecus cultratus (L.) in Russia. AB - Extensive sampling to get rich data is very important to resolve the current taxonomic problem of Chloromyxum genus and elucidate the nature phylogenetic relationships among congeneric species. During the parasitological survey of cyprinid fish in Gulf of Finland off the coast of St. Petersburg, a new Chloromyxum species, named as Chloromyxum peleci sp. n., was found to infect the gall bladder of sichel, Pelecus cultratus (L.). Here, we provided the morphological, ultrastructural, and molecular features to describe it. Infection was represented by mono- or disporic plasmodia and mature free-floating spores in the gall bladder. Mature spores are typical of freshwater Chloromyxum species, spherical or subspherical in lateral view, measuring 8.8 +/- 0.5 MUm (7.4-9.5) in length, 7.8 +/- 0.3 MUm (7.0-8.8) in width, and 7.5 +/- 0.4 MUm (6.8-8.2) in thickness. Spores have a cog-like appearance in apical view for sutural ridge, and eight to ten widely spaced extrasutural ridges per valve protrude from the spore valve margin. The surface ridge patterns of the new species are similar with those of Chloromyxum auratum and Chloromyxum cristatum, with some branching. Four polar capsules of slightly unequal in two pairs were oval in apical view and pyriform in side view, locating at the anterior end of the spores. Polar filaments coil with four to five turns. The obtained almost full length of 18S ribosomal DNA (rDNA) of Ch. peleci sp. n. does not match any sequences available in GenBank but was most closely related to that of Chloromyxum fluviatile (97.9%). Phylogenetic analysis indicated that Ch. peleci sp. n. clustered in a Chloromyxum subclade infecting the gall bladder of freshwater teleost, with robust nodal support. However, Chloromyxum sensu lato infecting gall bladder of freshwater teleost was again proved to be polyphyletic. The possible evolutionary history of Chloromyxum morphotype of Chloromyxum sensu lato was discussed based on the rDNA-referred phylogeny. This is the second Chloromyxum species from sichel. PMID- 28624877 TI - Gambling Motives: Do They Explain Cognitive Distortions in Male Poker Gamblers? AB - Gambling behavior is partly the result of varied motivations leading individuals to participate in gambling activities. Specific motivational profiles are found in gamblers, and gambling motives are closely linked to the development of cognitive distortions. This cross-sectional study aimed to predict cognitive distortions from gambling motives in poker players. The population was recruited in online gambling forums. Participants reported gambling at least once a week. Data included sociodemographic characteristics, the South Oaks Gambling Screen, the Gambling Motives Questionnaire-Financial and the Gambling-Related Cognition Scale. This study was conducted on 259 male poker gamblers (aged 18-69 years, 14.3% probable pathological gamblers). Univariate analyses showed that cognitive distortions were independently predicted by overall gambling motives (34.8%) and problem gambling (22.4%) (p < .05). The multivariate model, including these two variables, explained 39.7% of cognitive distortions (p < .05). The results associated with the literature data highlight that cognitive distortions are a good discriminating factor of gambling problems, showing a close inter relationship between gambling motives, cognitive distortions and the severity of gambling. These data are consistent with the following theoretical process model: gambling motives lead individuals to practice and repeat the gambling experience, which may lead them to develop cognitive distortions, which in turn favor problem gambling. This study opens up new research perspectives to understand better the mechanisms underlying gambling practice and has clinical implications in terms of prevention and treatment. For example, a coupled motivational and cognitive intervention focused on gambling motives/cognitive distortions could be beneficial for individuals with gambling problems. PMID- 28624878 TI - A Combination of Three Repurposed Drugs Administered at Reperfusion as a Promising Therapy for Postischemic Brain Injury. AB - Cerebral ischemia leads to multifaceted injury to the brain. A polytherapeutic drug that can be administered immediately after reperfusion may increase protection to the brain by simultaneously targeting multiple deleterious cascades. This study evaluated efficacy of the combination of three clinically approved drugs: lamotrigine, minocycline, and lovastatin, using two mouse models: global and focal cerebral ischemia induced by transient occlusion of the common carotid arteries or the middle cerebral artery, respectively. In vitro, the combination drug, but not single drug, protected neurons against oxygen-glucose deprivation (OGD)-induced cell death. The combination drug simultaneously targeted cell apoptosis and DNA damage induced by ischemia. Besides acting on neurons, the combination drug suppressed inflammatory processes in microglia and brain endothelial cells induced by ischemia. In a transient global ischemia model, the combination drug, but not single drug, suppressed microglial activation and inflammatory cytokine production, and reduced neuronal damage. In a transient focal ischemia model, the combination drug, but not single drug, attenuated brain infarction, suppressed infiltration of peripheral neutrophils, and reduced neurological deficits following ischemic stroke. In summary, the combination drug confers a broad-spectrum protection against ischemia/reperfusion (I/R) injury and could be a promising approach for early neuroprotection after out-of-hospital cardiac arrest or ischemic stroke. PMID- 28624879 TI - LC-MS/MS proteomic analysis of starved Bacillus subtilis cells overexpressing ribonucleotide reductase (nrdEF): implications in stress-associated mutagenesis. AB - The non-appropriate conditions faced by nutritionally stressed bacteria propitiate error-prone repair events underlying stationary-phase- or stress associated mutagenesis (SPM). The genetic and molecular mechanisms involved in SPM have been deeply studied but the biochemical aspects of this process have so far been less explored. Previous evidence showed that under conditions of nutritional stress, non-dividing cells of strain B. subtilis YB955 overexpressing ribonucleotide reductase (RNR) exhibited a strong propensity to generate true reversions in the hisC952 (amber), metB5 (ochre) and leuC425 (missense) mutant alleles. To further advance our knowledge on the metabolic conditions underlying this hypermutagenic phenotype, a high-throughput LC-MS/MS proteomic analysis was performed in non-dividing cells of an amino acid-starved strain, deficient for NrdR, the RNR repressor. Compared with the parental strain, the level of 57 proteins was found to increase and of 80 decreases in the NrdR-deficient strain. The proteomic analysis revealed an altered content in proteins associated with the stringent response, nucleotide metabolism, DNA repair, and cell signaling in amino acid-starved cells of the ?nrdR strain. Overall, our results revealed that amino acid-starved cells of strain B. subtilis ?nrdR that escape from growth limiting conditions exhibit a complex proteomic pattern reminiscent of a disturbed metabolism. Future experiments aimed to understand the consequences of disrupting the cell signaling pathways unveiled in this study, will advance our knowledge on the genetic adaptations deployed by bacteria to escape from growth limiting environments. PMID- 28624880 TI - Wing cross veins: an efficient biomechanical strategy to mitigate fatigue failure of insect cuticle. AB - Locust wings are able to sustain millions of cycles of mechanical loading during the lifetime of the insect. Previous studies have shown that cross veins play an important role in delaying crack propagation in the wings. Do cross veins thus also influence the fatigue behaviour of the wings? Since many important fatigue parameters are not experimentally accessible in a small biological sample, here we use the finite element (FE) method to address this question numerically. Our FE model combines a linear elastic material model, a direct cyclic approach and the Paris law and shows results which are in very good agreement with previously reported experimental data. The obtained results of our study show that cross veins indeed enhance the durability of the wings by temporarily stopping cracks. The cross veins further distribute the stress over a larger area and therefore minimize stress concentrations. In addition, our work indicates that locust hind wings have an endurance limit of about 40% of the ultimate tensile strength of the wing material, which is comparable to many engineering materials. The comparison of the results of the computational study with predictions of two most commonly used fatigue failure criteria further indicates that the Goodman criterion can be used to roughly predict the failure of the insect wing. The methodological framework presented in our study could provide a basis for future research on fatigue of insect cuticle and other biological composite structures. PMID- 28624881 TI - Discriminative self-representation sparse regression for neuroimaging-based alzheimer's disease diagnosis. AB - In this paper, we propose a novel feature selection method by jointly considering (1) 'task-specific' relations between response variables (e.g., clinical labels in this work) and neuroimaging features and (2) 'self-representation' relations among neuroimaging features in a sparse regression framework. Specifically, the task-specific relation is devised to learn the relative importance of features for representation of response variables by a linear combination of the input features in a supervised manner, while the self-representation relation is used to take into account the inherent information among neuroimaging features such that any feature can be represented by a weighted sum of the other features, regardless of the label information, in an unsupervised manner. By integrating these two different relations along with a group sparsity constraint, we formulate a new sparse linear regression model for class-discriminative feature selection. The selected features are used to train a support vector machine for classification. To validate the effectiveness of the proposed method, we conducted experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset; experimental results showed superiority of the proposed method over the state-of-the-art methods considered in this work. PMID- 28624883 TI - Heart Rate Recovery After 6-min Walking Test Predicts Acute Exacerbation in COPD. AB - INTRODUCTION: Abnormalities of autonomic function have been reported in patients with chronic obstructive pulmonary disease (COPD). Our objectives were to identify determinants of abnormal heart rate recovery at 1 min (HRR1) following completion of the 6-min walk test (6MWT) in COPD and to establish whether abnormal HRR1 predicts acute exacerbations (AECOPD). METHODS: Hundred one COPD patients (FEV1 (SD) 53 (19) % predicted) were prospectively recruited in a multi center study. HRR1 after the 6MWT was evaluated as the difference between heart rate at the end of the test and 1 min into the recovery (HRR1). Linear and logistic regression was used to identify predictors of HRR1 and AECOPD, respectively. The best HRR1 cut-off point to predict AECOPD was selected using the receiver operating characteristics (ROC) curves. The follow-up period was 12 months. RESULTS: Distance covered during the 6MWT (m) and DLco (% predicted) were independently associated with HRR1 (r 2 = 0.51, p = 0.001). Among several potential covariates, HRR1 emerged as the most significant predictor of AECOPD (Odds ratio [OR], 0.91 per beat of recovery; 95% confidence interval [CI], 0.85 0.97; p = 0.02). The ROC analysis indicated that subjects with HRR1 less than 14 beats (AUC, 0.71 [CI] 0.60-0.80; p = 0.0001) were more likely to suffer an exacerbation during the follow-up period (for HRR1, p = 0.004 [log-rank test]). CONCLUSIONS: HRR1 after the 6MWT is an independent predictor factor for AECOPD. Further studies are warranted to examine the physiological mechanisms associating a delayed HRR and acute exacerbations in COPD patients. PMID- 28624882 TI - Predicting acute kidney injury: current status and future challenges. AB - Acute kidney injury (AKI) is characterized by an acute decline in renal function and is associated to increased mortality rate, hospitalization time, and total health-related costs. The severity of this 'fearsome' clinical complication might depend on, or even be worsened by, the late detection of AKI, when the diagnosis is based on the elevation of serum creatinine (SCr). For these reasons, in recent years a great number of new tools, biomarkers and predictive models have been proposed to clinicians in order to improve diagnosis and prevent the development of AKI. The purpose of this narrative paper is to review the current state of the art in prediction and early detection of AKI and outline future challenges. PMID- 28624884 TI - Age at menarche and lung function: a Mendelian randomization study. AB - A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta analysis (N = 182,416), with SNP-lung function estimates obtained by meta analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8-47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2-69.9; p = 0.001). In adolescent girls we found an opposite effect (-56.5 mL; -108.3 to -4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than menarche specifically. We found no effect on airway obstruction (FEV1/FVC). PMID- 28624885 TI - Cardiac Rehabilitation Following Acute Coronary Syndrome in Women. AB - OPINION STATEMENT: Acute coronary syndrome (ACS) is among the leading burdens of disease among women. It is a significant driver of morbidity and chronically undermines their quality of life. Cardiac rehabilitation (CR) is indicated for ACS patients in clinical practice guidelines, including those specifically for women. CR is a multi-component model of care, proven to reduce mortality and morbidity, including in women. However, women are significantly less likely to be referred to CR by providers, and if they are referred, to enroll and adhere to programs. Reasons include lack of physician encouragement, preference not to feel fatigue and pain, transportation barriers, comorbidities and caregiving obligations. Strategies to mitigate this under-use include systematic early inpatient referral, tailoring programs to meet women's needs and preferences (e.g., offering dance, opportunities for social interaction), and offering non supervised delivery models. Unfortunately, these strategies are not widely available to women. Given the greater longevity seen in women, the critical role CR plays in augmenting quality of life in this population must be recognized and care providers must do more to facilitate referral to and encourage participating in CR programs. PMID- 28624886 TI - Pharmacokinetic modelling of modified acetylcysteine infusion regimens used in the treatment of paracetamol poisoning. AB - PURPOSE: Paracetamol overdose is common and is treated with acetylcysteine to prevent the development of hepatotoxicity. N-acetyl-p-benzoquinone imine (NAPQI) is the toxic metabolite of paracetamol overdose. We aimed to assess the expected acetylcysteine concentration time profiles following delivery of modified acetylcysteine regimens proposed for those at high and low risk of hepatotoxicity. In addition, we will determine acetylcysteine concentrations post cessation of abbreviated infusions. METHOD: We performed pharmacokinetic simulations using Berkeley Madonna (version 8.3.23.0) comparing the time course of acetylcysteine concentration during and after the cessation of an abbreviated 12-h regimen (250 mg/kg) using a two-bag infusion and compared this to the standard 21-h three-bag (300 mg/kg) regimen. We also simulated extended duration acetylcysteine regimens and other increased dosing strategies that have been recommended in specific paracetamol poisoning scenarios. RESULTS: A more sustained serum concentration is achieved when the acetylcysteine loading dose is delivered over 4 h using the two-bag compared to the 1-h loading dose of the three-bag regimen. When administering an abbreviated 12-h acetylcysteine regimen, circulating acetylcysteine is detectable for 8 h after cessation of the infusion. This may provide a continued hepatoprotective effect if NAPQI is still being generated after the infusion is ceased. CONCLUSION: This pharmacokinetic simulation study is an important step in determining plasma acetylcysteine concentrations that are likely to be achieved using various modified treatment regimens. Importantly, for patients at low risk of liver injury after acute overdose, acetylcysteine is likely to be detectable many hours post-cessation of a 12-h regimen. This should provide a safety factor against development of hepatotoxicity for any ongoing paracetamol metabolism after cessation of the acetylcysteine infusion. PMID- 28624887 TI - Voriconazole-induced QT prolongation among hemato-oncologic patients: clinical characteristics and risk factors. AB - PURPOSE: The purpose of this study is to determine the rate of QTcP and associated risk factors in patients treated with voriconazole. METHODS: We conducted a retrospective chart review of all patients treated with voriconazole in a large tertiary center between 2009 and 2015, using paired comparison of QTc intervals on and off voriconazole treatment, adjusted for comorbidities, electrolyte abnormalities, and concurrent medications. RESULTS: Fifty-four patients were included, of whom 53 were diagnosed with oncologic/hemato-oncologic disease. Mean QTc during voriconazole therapy (448.0 +/- 52.9 msec) was significantly longer compared to QTc off voriconazole (421.8 +/- 42.2 msec; p = 0.002). QTcP >=30 msec and >=60 msec was demonstrated in 43% (23 patients) and 28% (15 patients), respectively. Multivariate analysis showed that QTcP was significantly associated with baseline QTc >= 450 msec (upper QTc quartile) (p < 0.01) and low serum potassium levels (p < 0.01). Contrarily, no significant association was found between mean voriconazole daily and cumulative dose and QTcP. CONCLUSION: Our findings indicate that hemato-oncologic patients treated with voriconazole are at increased risk for QTcP, especially in the presence of baseline QTc >= 450 msec and low serum potassium levels. PMID- 28624888 TI - Steady-state pharmacokinetics of mycophenolic acid in renal transplant patients: exploratory analysis of the effects of cyclosporine, recipients' and donors' ABCC2 gene variants, and their interactions. AB - PURPOSE: The study aims to evaluate the impact of recipients' and donors' polymorphisms in multidrug resistance-associated protein 2 (MRP2) gene ABCC2 24C>T and 1249G>A on disposition of mycophenolic acid (MPA) and their interaction with cyclosporine (CsA) (compared to tacrolimus, TAC) in stable de novo adult renal transplant patients of Croatian origin. METHODS: A total of 68 recipient donor pairs were genotyped. Steady-state pharmacokinetics of MPA was assessed by the model-independent method. RESULTS: Adjusted for MPA formulation, renal function, type of calcineurin inhibitor and recipients' and donors' genotypes at the two loci, donors' A-allele at 1249G>A was associated with a reduced peak (29%) and early (AUC0-2, 33%) exposure and increased MPA clearance (26%). Donors' A-allele combined with CsA was associated with 78% higher MPA clearance, 49% lower early and 48% lower total exposure as compared to wild type homozygosity + TAC. Recipients' SNPs per se did not reflect on MPA disposition. However, A allele at 1249G>A + CsA (compared to wild type + TAC) was associated with a numerically greater increase in MPA clearance (59 vs. 41%), reduction in total exposure (36 vs. 27%) and increase in absorption rate (C max/AUC) (56 vs. 37%) than observed for the main effect of CsA. Less pronounced effects were observed for the combination of variant allele at -24C>T and CsA. CONCLUSION: Considering MPA disposition, data indicate: donors' ABCC2 1249G>A polymorphism increases clearance and reduces exposure; CsA increases clearance and reduces exposure by inhibiting MRP2 in the gut, the liver, and the kidney; donors' ABCC2 1249G>A polymorphism enhances the renal CsA effect, while recipients' polymorphism seems to enhance the liver and the gut CsA effects. PMID- 28624889 TI - Transcriptional control of unequal cleavage in early Tubifex embryos. AB - Early embryos of the clitellate annelid Tubifex (oligochaete) undergo a series of unequal spiral cell divisions before the descendants of the D quadrant micromeres (cells 2d and 4d) divide bilaterally. Here, we show that inhibition of zygotic transcription by microinjection of alpha-amanitin (transcription inhibitor) exclusively converts unequal cleavage in cell 2d11 (granddaughter of 2d) into equal cleavage while other unequal cleavages and ensuing bilateral cleavages in cells 4d and 2d111 (great-granddaughter of 2d) all proceed in a normal fashion in the presence of this inhibitor. These results differ significantly from those reported for embryos of another clitellate annelid Helobdella (leech), in which inhibition of transcription converts bilateral (symmetric) cleavages in cells DNOPQ"' and DM" (equivalent to 2d111 and 4d) into unequal (asymmetric) cleavages while having no apparent effect on unequal cleavage in DNOPQ" (equivalent to 2d11). These differences imply distinct mechanisms for the control of the unequal to-bilateral transition in the two clitellate annelids. PMID- 28624890 TI - In reply: Desflurane anesthesia and cognitive function. PMID- 28624891 TI - Frontal placement of dispersive patch for effective ablation of arrhythmia originating from the anterior right ventricular outflow tract. PMID- 28624892 TI - A meta-analysis of manual versus remote magnetic navigation for ventricular tachycardia ablation. AB - BACKGROUND: There are limited studies on the safety and efficacy of remote magnetic navigation (RMN) versus manual navigation (MAN) in ventricular tachycardia (VT) ablation. METHODS: A comprehensive literature search was performed using the keywords VT ablation, stereotaxis, RMN and MAN in Pubmed, Ebsco, Web of Science, Cochrane, and Google scholar databases. RESULTS: The analysis included seven studies (one randomized, three prospective observational, and three retrospective) including 779 patients [both structural heart disease (SHD) and idiopathic VT] comparing RMN (N = 433) and MAN (N = 339) in VT ablation. The primary end point of long-term VT recurrence was significantly lower with RMN (OR 0.61, 95% CI 0.44-0.85, p = 0.003) compared with MAN. Other end points of acute procedural success (OR 2.13, 95% CI 1.40-3.23, p = 0.0004) was significantly higher with RMN compared with MAN. Fluoroscopy [mean difference -10.42, 95% CI -12.7 to -8.1, p < 0.0001], procedural time [mean difference 9.79, 95% CI -19.27 to -0.3, p = 0.04] and complications (OR 0.35, 95% CI 0.17 0.74, p = 0.0006) were also significantly lower in RMN when compared with MAN. In a subgroup analysis SHD, there was no significant difference in VT recurrence or acute procedural success with RMN vs. MAN. In idiopathic VT, RMN significantly increased acute procedural success with no difference in VT recurrence. CONCLUSION: The results demonstrate that RMN is safe and effective when compared with MAN in patients with both SHD and idiopathic VT undergoing catheter ablation. Further prospective studies are needed to further verify the safety and efficacy of RMN. PMID- 28624893 TI - LY294002, a PI3K inhibitor, attenuates Tourette syndrome in rats. AB - The present study was designed to investigate the effects of LY294002 on Tourette syndrome (TS) in rats. TS model was induced in rats by DOI (the selective 5 HT2A/2C agonist 1- (2, 5- dimethoxy -4 - iodophenyl) -2- aminopropane). Behavior was assessed by stereotypic score and autonomic activity. Inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in serum and striatum were detected. The protein levels of PI3K/Akt/NF-B in striatum were detected by Western Blot. LY294002 treatment significantly reduced IL-6, IL-1beta and TNF-alpha in serum and striatum of TS rats, Also, highly expressed P-PI3K, P-Akt, P-NF-kappaBp65, P-IkappaBalpha in TS rats were restored respectively by LY294002 treatment as indicted in western blot analysis and immunohistochemistry analysis. Thus, it was supposed that the protective effect of LY294002 against TS in rat might be associated with the regulation of PI3K/Akt/NF-B pathway. PMID- 28624894 TI - Suppression of TLR4/NF-kappaB Signaling Pathway Improves Cerebral Ischemia Reperfusion Injury in Rats. AB - The present study aimed to investigate the effects of the toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NF-?B) signaling pathway in cerebral ischemia reperfusion injury. A total of 125 male Sprague Dawley (SD) rats were selected for this study. Fifty SD rats were randomly divided into the control, sham injury, 0.5 h perfusion, 2 h perfusion, and 6 h perfusion groups to establish the model of ischemia-reperfusion. The rat brain injury model was established using the other 75 male SD rats, and different model groups with different treatments were established (15 rats per group): model control group (injected with 10 MUL of saline solution), model + TAK-242 group (injected with resatorvid), model + PDTC group (injected with pyrrolidine dithiocarbamate), model + LPS group (injected with lipopolysaccharide), and sham injury group (incision to the neck skin and injected with 10 MUL of saline solution for normal rats). These five groups were further assigned into three subgroups: day 3 group, day 7 group, and day 21 group. To determine how the TLR4/NF-?B signal pathway affects cerebral ischemia-reperfusion injuries, various methods including the Morris water maze, triphenyl tetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and western blotting were employed in this study. No neurological deficit was observed in rats from the model control and sham injury groups. A slight neurological deficit was found in the 0.5 h reperfusion group, while in the 2 and 6 h perfusion groups, neurological dysfunction was evident. Compared to the sham injury group, the model control group displayed a longer escape latency (EL) and increased cerebral infarction volume and pathological changes with enhanced expression of TLR4 and NF-kappaB (all P < 0.05). The inhibition of the TLR4/NF kappaB signal pathway shortened rat EL and diminished cerebral infarction volume, and the pathological changes became less evident (all P < 0.05), while the activation of the TLR4/NF-kappaB signal pathway elongated rat EL, enlarged infarction volume, and increased cerebral pathological change (all P < 0.05). Pearson correlation analysis demonstrated that TLR4/NF-kappaB expression is correlated with the extent of rat brain damage. Cerebral ischemia-reperfusion injury in rats can be alleviated via the inhibition of the TLR4/NF-kappaB signaling pathway. PMID- 28624896 TI - How can the operation time be shortened by reducing the tract size? PMID- 28624895 TI - Semaphorin4D-PlexinB1 Signaling Attenuates Photoreceptor Outer Segment Phagocytosis by Reducing Rac1 Activity of RPE Cells. AB - Semaphorins form a family of secreted and membrane-bound molecules that were identified originally as axonal guidance factors during neuronal development. Given their wide distribution in many including mature tissues, semaphorin 4D (sema4D) and its main functional receptor plexin B1 (plxnB1) are expected to fulfill additional functions that remain to be uncovered. A main characteristic of the plexin receptor family is its ability to reorganize the cytoskeleton. PlxnB1 specifically may directly interact with Rho family GTPases to regulate F actin driven pathways in cells in culture. Diurnal clearance phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segment fragments (POS) is critical for photoreceptor function and longevity. In this process, rearrangement of RPE cytoskeletal F-actin via activation of the Rho family GTPase Rac1 is essential for POS internalization. Here, we show a novel role in POS phagocytosis by RPE cells in culture and in vivo for plexin B1 and its ligand sema4D. Exogenous sema4D abolishes POS internalization (but not binding) by differentiated RPE cells in culture by decreasing the GTP load of Rac1. In the rat eye, sema4D localizes to retinal photoreceptors, while PlxnB1 is expressed by neighboring RPE cells. At the peak of diurnal retinal phagocytosis after light onset, plxnB1 phosphorylation and sema4D levels are reduced in wild-type rat retina in situ but not in mutant RCS rat retina in which the RPE lacks phagocytic activity. Finally, increased POS phagosome content after light onset is observed in the RPE in situ of mice with either plxnB1 or sema4D gene deletion. Altogether, our results demonstrate a novel physiological function for sema4D/plxnB1 signaling in RPE phagocytosis serving as attenuating brake prior to light onset whose release enables the diurnal phagocytic burst. PMID- 28624897 TI - Corrosion of Harrington rod in idiopathic scoliosis: long-term effects. AB - PURPOSE: Metal implants have been used to treat adolescent idiopathic scoliosis since the 1960s. Only recently, however, it has the issue of metal-bone breakdown secondary to metal corrosion in situ come to light, raising concerns of possible long-term complications from the resulting metallosis and inflammation of spinal tissues. We present a case of a patient with neurological deficit, pain, and disability with Harrington rod in place for over 30 years, to bring attention to the issue of bio-corrosion of metal implants and its effect on human tissue. We call attention to the need for protocols to better diagnose and treat these patients. METHODS: We provide a complete review of the history and clinical manifestations as well as serum metal, X-ray, and CT/myelogram test results. RESULTS: A 52-year-old female with spinal fusion and Harrington rod presents with pain, lymphedema, disability, and neurological deficits including thoracic outlet syndrome, hyperreflexia, peripheral muscle weakness and atrophy, hypertonicity, Raynaud's phenomenon, and balance and gait abnormalities. Serum chromium levels were elevated (26.73 nmol). X-rays showed no evidence of rod breakdown. Serial X rays can demonstrate subtle corrosive changes but were not available. Adhesive arachnoiditis was diagnosed via CT/myelogram. CONCLUSION: We hypothesize that bio corrosion is present in this case and that it is associated with intraspinal metallosis. Trauma secondary to a motor vehicle accident, as well as arachnoiditis, and their possible effects on this case are outlined. Challenges in proper diagnosis and management are discussed. PMID- 28624898 TI - Improving diabetes care at primary care level with a multistrategic approach: results of the DIAPREM programme. AB - AIM: To present results, 1 year postimplementation at primary care level, of an integrated diabetes care programme including systemic changes, education, registry (clinical, metabolic, and therapeutic indicators), and disease management (DIAPREM). METHODS: We randomly selected and trained 15 physicians and 15 nurses from primary care units of La Matanza County (intervention-IG) and another 15 physicians/nurses to participate as controls (control-CG). Each physician-nurse team controlled and followed up 10 patients with type 2 diabetes for 1 year; both groups used structured medical records. Patients in IG had quarterly clinical appointments, whereas those in CG received traditional care. Statistical data analysis included parametric/nonparametric tests according to data distribution profile and Chi-squared test for proportions. RESULTS: After 12 months, the dropout rate was significantly lower in IG than in CG. Whereas in IG HbA1c, blood pressure and lipid profile levels significantly decreased, no changes were recorded in CG. Drug prescriptions showed no significant changes in IG except a decrease in oral monotherapy. CONCLUSIONS: DIAPREM is an expedient and simple multistrategic model to implement at the primary care level in order to decrease patient dropout and improve control and treatment adherence, and quality of care of people with diabetes. PMID- 28624899 TI - Neuropsychological Measures in the Arab World: A Systematic Review. AB - Although Arabic is one of the most widely used languages in the world, little is known on the availability of standardized neuropsychological tests in Arabic. We review the literature published before 2016, using the keywords Arab*, cogniti*, and neuropsycholo*, as well as keywords for each Arab country. PubMed, PsycINFO, Education Source, Academic Search Complete, Education Resources Information Center, Shamaa, and Arabpsynet databases were searched, in addition to a selected number of Arabic medical and educational journals. After excluding case reports, studies conducted on Arab groups residing outside the Arab world or Israel, and studies that employed intelligence scales or cognitive screens without standardization, 384 studies were eventually reviewed. Tests with most extensive use, adaptation, validation and norming were identified. The Raven Matrices, with its variants, was the most normed cognitive test for Arab individuals (normed in 16 countries). The rate of neuropsychology publications from the Arab countries combined, per year, was less than half of that of each American journal (top 10 journals pertaining to cognition). Nonetheless, the rate in Arab countries has increased after 2010. Publications were mostly from Egypt and Saudi Arabia, but the ratio of test adaptation-to-publication was the largest in Jordan and Lebanon. Approximately half of these publications did not employ cognitive tests that were developed, translated, adapted, or standardized according to international guidelines of psychological measurement. We provide recommendations on improving clinical neuropsychology to better serve Arab patients. PMID- 28624900 TI - The cre-inducer doxycycline lowers cytokine and chemokine transcript levels in the gut of mice. AB - The antibiotic doxycycline is used as an inducer of recombinase (cre)-based conditional gene knockout in mice, which is a common tool to show the effect of disrupted gene functions only in one period of a research animal's life. However, other types of such antibiotics have been shown to have a strong impact on the immune system. Here we show that in C57BL/6 mice, the most commonly applied strain for genetic modification, doxycycline treatment lowered transcription of the genes Il1b, Il10, Il18, Tnf, Cxcl1, and Cxcl2 in the ileum, and of the gene Il18 in colon. Cytokines and chemokines encoded by these genes are important in the disease expression in a range of mouse models. Although protein abundances only rarely correlate 100% to transcript levels, and the net result, therefore, may be less dramatic, it seems reasonable to be aware that a broad spectrum antibiotic, such as doxycycline, may impact the transgenic animal in ways unrelated to the activation of the gene deletion. PMID- 28624901 TI - Idio Scale Judgment: evaluation of a new method for estimating responder thresholds. AB - PURPOSE: To pilot the newly developed Idio Scale Judgment method for estimating the amount of score change that matters to patients (i.e., change thresholds). METHODS: An online panel of 500 participants diagnosed with multiple sclerosis (MS) responded to the Neuro-QoL fatigue scale and to demographic and clinical questions. Participants compared their own fatigue to that represented by seven short form summaries (SFSs) that were located relatively close to their own fatigue levels. They judged these as representing the same, greater, or less fatigue than their own. We calculated the distances between patients' own levels of fatigue and the location of SFSs they endorsed as a change that would make a difference in daily life. These distances were used as estimates of change thresholds. Logically inconsistent judgments were tabulated and associations with clinical and demographic variables were estimated. RESULTS: Change thresholds based on mean individual thresholds for consequential change were calculated for improvement (-3.5) and worsening (3.2). The majority of participants had no logically inconsistent judgments (69%). Having one or more reversals in judgment was not significantly associated with education or fatigue score, but was weakly associated with age, gender, and MS type and moderately associated with ratings of confidence in SFS comparisons. CONCLUSIONS: As piloted, Idio Scale Judgment had a number of design strengths. Participants made comparisons to levels of fatigue that were within range of their own, and their judgments were contextualized in personally relevant consequences. The design lends itself to collection of data in large samples allowing evaluation of the range of judgments. Some study limitations could be mitigated with modifications. We concluded that the Idio Scale Judgment has substantial promise as a new tool for estimating change thresholds. PMID- 28624902 TI - Screening for depression in arthritis populations: an assessment of differential item functioning in three self-reported questionnaires. AB - PURPOSE: To determine if persons with arthritis differ systematically from persons without arthritis in how they respond to questions on three depression questionnaires, which include somatic items such as fatigue and sleep disturbance. METHODS: We extracted data on the Centers for Epidemiological Studies Depression (CES-D) scale, the Patient Health Questionnaire-9 (PHQ-9), and the Kessler-6 (K-6) scale from three large population-based national surveys. We assessed items on these questionnaires for differential item functioning (DIF) between persons with and without self-reported physician-diagnosed arthritis using multiple indicator multiple cause models, which controlled for the underlying level of depression and important confounders. We also examined if DIF by arthritis status was similar between women and men. RESULTS: Although five items of the CES-D, one item of the PHQ-9, and five items of the K-6 scale had evidence of DIF based on statistical comparisons, the magnitude of each difference was less than the threshold of a small effect. The statistical differences were a function of the very large sample sizes in the surveys. Effect sizes for DIF were similar between women and men except for two items on the Patient Health Questionnaire-9. For each questionnaire, DIF accounted for 8% or less of the arthritis-depression association, and excluding items with DIF did not reduce the difference in depression scores between those with and without arthritis. CONCLUSIONS: Persons with arthritis respond to items on the CES-D, PHQ 9, and K-6 depression scales similarly to persons without arthritis, despite the inclusion of somatic items in these scales. PMID- 28624904 TI - The Effect of Light on Bacterial Activity in a Seaweed Holobiont. AB - Holobionts are characterized by the relationship between host and their associated organisms such as the biofilm associated with macroalgae. Considering that light is essential to macroalgae survival, the aim of this study was to verify the effect of light on the heterotrophic activity in biofilms of the brown macroalgae Sargassum furcatum during its growth cycle. Measurements of heterotrophic activity were done under natural light levels at different times during a daily cycle and under an artificial extinction of natural light during the afternoon. We also measured Sargassum primary production under these light levels in the afternoon. Both measurements were done with and without photosynthesis inhibitor and antibiotics. Biofilm composition was mainly represented by bacteria but diatoms, cyanobacteria, and other organisms were also common. When a peak of diatom genera was recorded, the heterotrophic activity of the biofilm was higher. Heterotrophic activity was usually highest during the afternoon and the presence of a photosynthesis inhibitor caused an average reduction of 17% but there was no relationship with Sargassum primary production. These results indicate that autotrophic production in the biofilm was reduced by the inhibitor with consequences on bacterial activity. Heterotrophic activity was mainly bacterial and the antibiotics chloramphenicol and penicillin were more effective than streptomycin. We suggest primary producers in the biofilm are more important to increase bacterial activity than the macroalgae itself because of coherence of the peaks of heterotrophic and autotrophic activity in biofilm during the afternoon and the effects of autotrophic inhibitors on heterotrophic activity. PMID- 28624905 TI - Reduced-intensity allogeneic hematopoietic stem cell transplantation combined with imatinib has comparable event-free survival and overall survival to long term imatinib treatment in young patients with chronic myeloid leukemia. AB - The relative merits of reduced intensity hematopoietic stem cell transplantation (RIST) for chronic myeloid leukemia (CML) in the first chronic phase (CP) in imatinib era have not been evaluated. The study was designed to compare the outcomes of combination therapy of RIST plus imatinib (RIST + IM) vs. imatinib (IM) alone for young patients with early CP (ECP) and late CP (LCP). Of the patients, 130 were non-randomly assigned to treatment with IM alone (n = 88) or RIST + IM (n = 42). The 10-year overall survival (OS) and event-free survival (EFS) were comparable between RIST + IM and IM groups. LCP, high Sokal score, and no complete cytogenetic response at 3 months were adverse prognostic factors for survival, but only the time from diagnosis to IM was an independent predictor after multivariate analysis. For ECP, IM was similar to RIST + IM, with 10-year EFS rates of 77.2 vs. 81.6% (p = 0.876) and OS rates of 93.8 vs. 87.9% (p = 0.102), respectively. For LCP, both treatments resulted in similar survival, but more patients in the imatinib group experienced events (10-year EFS 40.8 vs. 66.7%, p = 0.047). The patients with higher EBMT risk scores had an inferior survival than those with lower scores (69.2 vs. 92.9%, p = 0.04). We concluded that RIST + IM was comparable to IM in terms of OS and EFS. However, RIST + IM was more affordable than IM alone in a 10-year scale. Thus, RIST + IM could be considered as an alternative treatment option, especially when the patients have low EBMT risk scores and demand a definite cure for CML. PMID- 28624903 TI - Early Diagnosis of Sepsis: Is an Integrated Omics Approach the Way Forward? AB - Sepsis remains one of the leading causes of death in the USA and it is expected to get worse as the population ages. Moreover, the standard of care, which recommends aggressive treatment with appropriate antibiotics, has led to an increase in multiple drug-resistant organisms. There is a dire need for the development of new antibiotics, improved antibiotic stewardship, and therapies that treat the host response. Development of new sepsis therapeutics has been a disappointment as no drugs are currently approved to treat the various complications from sepsis. Much of the failure has been blamed on animal models that do not accurately reflect the course of the disease. However, recent improvements in metabolomic, transcriptomic, genomic, and proteomic platforms have allowed for a broad-spectrum look at molecular changes in the host response using clinical samples. Integration of these multi-omic datasets allows researchers to perform systems biology approaches to identify novel pathophysiology of the disease. In this review, we highlight what is currently known about sepsis and how integrative omics has identified new diagnostic and predictive models of sepsis as well as novel mechanisms. These changes may improve patient care as well as guide future preclinical analysis of sepsis. PMID- 28624907 TI - Dityrosine administration induces dysfunction of insulin secretion accompanied by diminished thyroid hormones T3 function in pancreas of mice. AB - Oxidized tyrosine products are commonly found in food with high protein content and have been demonstrated to cause damage of liver and kidney in our previous studies. Dityrosine (Dityr) is a typical oxidized tyrosine product. Due to its structural homology with thyroid hormones T3, we assumed that one of the endocrine systems most likely considered in connection with its disruption by Dityr may be the T3 action. T3 plays important roles in insulin synthesis, and thyroid hormone resistance (RTH) is associated with the impairment of glucose metabolism. Therefore, this study determined whether Dityr exposure impaired T3 function in pancreas leading to glucose metabolism disruption. After 10-week gavage with Dityr, mice exhibited impaired glucose tolerance and disturbed energy metabolism. The elevated free THs content in plasma, the up-regulation of THs synthesis-specific genes expressions in thyroid glands, and the increased thyroid follicles histology shapes and areas indicated that Dityr enhanced the THs synthesis in thyroid glands. In addition, Dityr-induced RTH, which reflected as elevated plasma free THs in the presence of unsuppressed thyroid stimulating hormone. The mRNA downregulation of membrane transporter of T3 (MCT8) and co activator factors (RXRalpha, Src-1), together with the decreased protein level of thyroid hormone receptor beta1 (TRbeta1) in pancreas illustrated that the activation ability of T3 to downstream gene involved in insulin synthesis was suppressed by Dityr. In MIN-6 cell experiment, T3 improved glucose-stimulated insulin secretion by upregulating mRNA levels of insulin synthesis-related genes (Ins2, MafA, Pdx1) and T3 action-related genes, as well as increasing protein level of TRbeta1. These data suggest that Dityr suppress T3-regulated insulin synthesis stimulated by glucose via an indirect way of decreasing sensibility to T3 in pancreas. All these findings indicate that Dityr can disrupt THs function in pancreas leading to glucose metabolism disorder. PMID- 28624906 TI - Pathogen reduction/inactivation of products for the treatment of bleeding disorders: what are the processes and what should we say to patients? AB - Patients with blood disorders (including leukaemia, platelet function disorders and coagulation factor deficiencies) or acute bleeding receive blood-derived products, such as red blood cells, platelet concentrates and plasma-derived products. Although the risk of pathogen contamination of blood products has fallen considerably over the past three decades, contamination is still a topic of concern. In order to counsel patients and obtain informed consent before transfusion, physicians are required to keep up to date with current knowledge on residual risk of pathogen transmission and methods of pathogen removal/inactivation. Here, we describe pathogens relevant to transfusion of blood products and discuss contemporary pathogen removal/inactivation procedures, as well as the potential risks associated with these products: the risk of contamination by infectious agents varies according to blood product/region, and there is a fine line between adequate inactivation and functional impairment of the product. The cost implications of implementing pathogen inactivation technology are also considered. PMID- 28624908 TI - Development and validation of KASP markers for the greenbug resistance gene Gb7 and the Hessian fly resistance gene H32 in wheat. AB - KEY MESSAGE: Greenbug and Hessian fly are important pests that decrease wheat production worldwide. We developed and validated breeder-friendly KASP markers for marker-assisted breeding to increase selection efficiency. Greenbug (Schizaphis graminum Rondani) and Hessian fly [Mayetiola destructor (Say)] are two major destructive insect pests of wheat (Triticum aestivum L.) throughout wheat production regions in the USA and worldwide. Greenbug and Hessian fly infestation can significantly reduce grain yield and quality. Breeding for resistance to these two pests using marker-assisted selection (MAS) is the most economical strategy to minimize losses. In this study, doubled haploid lines from the Synthetic W7984 * Opata M85 wheat reference population were used to construct linkage maps for the greenbug resistance gene Gb7 and the Hessian fly resistance gene H32 with genotyping-by-sequencing (GBS) and 90K array-based single nucleotide polymorphism (SNP) marker data. Flanking markers were closely linked to Gb7 and H32 and were located on chromosome 7DL and 3DL, respectively. Gb7 linked markers (synopGBS773 and synopGBS1141) and H32-linked markers (synopGBS901 and IWB65911) were converted into Kompetitive Allele Specific PCR (KASP) assays for MAS in wheat breeding. In addition, comparative mapping identified syntenic regions in Brachypodium distachyon, rice (Oryza sativa), and sorghum (Sorghum bicolor) for Gb7 and H32 that can be used for fine mapping and map-based cloning of the genes. The KASP markers developed in this study are the first set of SNPs tightly linked to Gb7 and H32 and will be very useful for MAS in wheat breeding programs and future genetic studies of greenbug and Hessian fly resistance. PMID- 28624909 TI - Acute ocular traumatic imaging: what the radiologist should know [corrected]. AB - Acute ocular trauma accounts for a substantial number of emergency department visits in the USA, and represents a significant source of disability to patients; however, the orbits remain a potential blind spot for radiologists. The goal of this article is to review the relevant anatomy of the orbit and imaging findings associated with commonly encountered acute ocular traumatic pathology, while highlighting the salient information which should be reported to the ordering clinician. Topics discussed include trauma to the anterior and posterior chamber, lens dislocations, intraocular foreign bodies, and open and contained globe injuries. PMID- 28624912 TI - Sustainable Cattle Ranching in Practice: Moving from Theory to Planning in Colombia's Livestock Sector. AB - A growing population with increasing consumption of milk and dairy require more agricultural output in the coming years, which potentially competes with forests and other natural habitats. This issue is particularly salient in the tropics, where deforestation has traditionally generated cattle pastures and other commodity crops such as corn and soy. The purpose of this article is to review the concepts and discussion associated with reconciling food production and conservation, and in particular with regards to cattle production, including the concepts of land-sparing and land-sharing. We then present these concepts in the specific context of Colombia, where there are efforts to increase both cattle production and protect tropical forests, in order to discuss the potential for landscape planning for sustainable cattle production. We outline a national planning approach, which includes disaggregating the diverse cattle sector and production types, identifying biophysical, and economic opportunities and barriers for sustainable intensification in cattle ranching, and analyzing areas suitable for habitat restoration and conservation, in order to plan for both land sparing and land-sharing strategies. This approach can be used in other contexts across the world where there is a need to incorporate cattle production into national goals for carbon sequestration and habitat restoration and conservation. PMID- 28624913 TI - Persistent Skin Pouches Following Subcutaneous Immunoglobulin Infusions in a Girl with Immunodeficiency, Bullous Skin Lesions and Melanosis Oculi. PMID- 28624914 TI - The effects of a desiccant agent in the treatment of chronic periodontitis: a randomized, controlled clinical trial. AB - OBJECTIVE: Chemotherapeutic agents have been widely used as adjuncts for the treatment of chronic periodontitis (CP). This study investigated and compared a desiccant agent as an adjunct to scaling and root planing (SRP) versus SRP alone for the treatment of CP. MATERIALS AND METHODS: Thirty-six patients with CP were studied. Using a split-mouth design, the maxillary right and left quadrants were randomly assigned to SRP plus desiccant (Hybenx(r) EPIEN Medical, Inc. St. Paul, MN, USA) or SRP alone. Patients were examined on a regular basis for clinical, microbiological, and inflammatory mediator changes over a 1-year period. Clinical attachment level (CAL) was the primary outcome variable. In addition, the red complex bacteria and gingival crevicular fluid (GCF) inflammatory mediators were monitored. RESULTS: Compared to baseline, both treatments demonstrated an improvement in periodontal parameters. Compared to SRP alone, SRP plus desiccant yielded a significant improvement in probing depth (PD) (SRP: 2.23 +/- 0.31 mm vs. desiccant: 3.25 +/- 0.57 mm, p < 0.05), CAL (SRP: 3.16 +/- 0.29 mm vs. desiccant: 4.21 +/- 0.34 mm, p < 0.05 mm) and bleeding on probing (BOP) (SRP: 4.56 +/- 1.5% vs. desiccant: 34.23 +/- 4.2%, p < 0.001) at 12 months. Similarly, in the SRP plus desiccant group, the bacteria of the red complex were significantly reduced (p < 0.05); and the level of inflammatory mediators was significantly reduced (p < 0.003) compared to SRP alone. CONCLUSIONS: SRP plus the desiccant resulted in a greater reduction in clinical, microbial and inflammatory mediators compared to SRP alone. CLINICAL RELEVANCE: Desiccant, when combined to SRP, was demonstrated as a significant approach to control the levels of certain periodontal pathogens, inflammatory mediators in patients with CP. PMID- 28624910 TI - Clinical pharmacology and clinical trials of ribonucleotide reductase inhibitors: is it a viable cancer therapy? AB - PURPOSE: Ribonucleotide reductase (RR) enzymes (RR1 and RR2) play an important role in the reduction of ribonucleotides to deoxyribonucleotides which is involved in DNA replication and repair. Augmented RR activity has been ascribed to uncontrolled cell growth and tumorigenic transformation. METHODS: This review mainly focuses on several biological and chemical RR inhibitors (e.g., siRNA, GTI 2040, GTI-2501, triapine, gemcitabine, and clofarabine) that have been evaluated in clinical trials with promising anticancer activity from 1960's till 2016. A summary on whether their monotherapy or combination is still effective for further use is discussed. RESULTS: Among the RR2 inhibitors evaluated, GTI-2040, siRNA, gallium nitrate and didox were more efficacious as a monotherapy, whereas triapine was found to be more efficacious as combination agent. Hydroxyurea is currently used more in combination therapy, even though it is efficacious as a monotherapy. Gallium nitrate showed mixed results in combination therapy, while the combination activity of didox is yet to be evaluated. RR1 inhibitors that have long been used in chemotherapy such as gemcitabine, cladribine, fludarabine and clofarabine are currently used mostly as a combination therapy, but are equally efficacious as a monotherapy, except tezacitabine which did not progress beyond phase I trials. CONCLUSIONS: Based on the results of clinical trials, we conclude that RR inhibitors are viable treatment options, either as a monotherapy or as a combination in cancer chemotherapy. With the recent advances made in cancer biology, further development of RR inhibitors with improved efficacy and reduced toxicity is possible for treatment of variety of cancers. PMID- 28624915 TI - The contribution of surgical brain mapping to the understanding of the anatomo functional basis of syntax: A critical review. AB - A wide range of studies on language assessment during awake brain surgery is nowadays available. Yet, a consensus on a standardized protocol for intraoperative language mapping is still lacking. More specifically, very limited information is offered about intraoperative assessment of a crucial component of language such as syntax. This review aims at critically analyzing the intraoperative studies investigating the cerebral basis of syntactic processing. A comprehensive query was performed on the literature, returning a total of 18 studies. These papers were analyzed according to two complementary criteria, based on the distinction between morphosyntax and syntax. The first criterion focused on the tasks and stimuli employed intraoperatively. Studies were divided into three different groups: group 1 included those studies that overtly aimed at investigating morphosyntactic processes; group 2 included studies that did not explicitly focus on syntax, yet employed stimuli requiring morphosyntactic processing; and group 3 included studies reporting some generic form of syntactic deficit, although not further investigated. The second criterion focused on the syntactic structures of the sentences assessed intraoperatively, analyzing the canonicity of sentence structure (i.e., canonical versus non-canonical word order). The global picture emerging from our analysis indicates that what was investigated in the intraoperative literature is morphosyntactic processing, rather than pure syntax. The study of the neurobiology of syntax during awake surgery seems thus to be still at an early stage, in need of systematic, linguistically grounded investigations. PMID- 28624916 TI - Interethnic variation in pelvic floor morphology in women with symptomatic pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: There is a lack of epidemiological studies evaluating female pelvic organ prolapse in developing countries. Current studies have largely focused on women of white ethnicity. This study was designed to determine interethnic variation in pelvic floor functional anatomy, namely, levator hiatal distensibility and pelvic organ descent, in women with symptomatic pelvic organ prolapse in a multi-ethnic South African population. METHODS: This prospective observational study included 258 consecutive women referred for pelvic organ prolapse assessment and management at a tertiary urogynaecological clinic. After a detailed history and clinical examination, including POPQ assessment, patients underwent a 4D transperineal ultrasound. Offline analysis was performed using 4D View software. Main outcome measures included levator muscle distensibility, pelvic organ descent, and levator ani defects (avulsion). RESULTS: Mean age was 60.6 (range, 25-91) years, mean BMI 29.83 (range, 18-53). Points Ba and C were lower and the genital hiatus more distensible in black women (all p < 0.05). They were found to have greater hiatal area (p = 0.017 at rest, p = 0.006 on Valsalva) compared with South Asians and whites and showed greater pelvic organ mobility (all p < 0.05) than Caucasians on ultrasound. Levator defects were found in 32.2% (n = 83) of patients and most were bilateral (48.2%, n = 40), with significant interethnic differences (p = 0.014). CONCLUSION: There was significant variation in clinical prolapse stage, levator distensibility, and pelvic organ descent in this racially diverse population presenting with pelvic organ prolapse, with South Asians having a lower avulsion rate than the other two ethnic groups (p = 0.014). PMID- 28624918 TI - Randomized controlled trial of the effect of environment on patient embarrassment and anxiety with urodynamics. AB - INTRODUCTION AND HYPOTHESIS: In previous survey studies, women undergoing urodynamic testing (UDT) have reported bother and embarrassment and have provided suggestions for improving the experience. The suggestions include audio distraction and increased privacy, neither of which have been prospectively examined. We report a prospective randomized controlled trial to evaluate the hypothesis that an improved ambience can decrease UDT-related embarrassment and anxiety. METHODS: A total of 60 participants were recruited to achieve an 80% power to detect a conservative 20-point difference with a significance level of 0.05. Eligible participants were randomized to one of two conditions: dim lighting with light instrumental music (modified group, 30 patients), or no music and standard lighting (standard group, 30 patients). The aim of the dim lighting and music was to provide an increased sense of privacy and audio distraction based on participant feedback in previous studies. RESULTS: The study was complete with 60 participants. Patients in both groups reported less embarrassment after UDT. However, patients in the modified group showed a greater decrease in embarrassment scores (9.72 mm) than patients in the standard group (1.3 mm; p = 0.33). Although the study was under-powered, the difference found approached clinical significance. CONCLUSIONS: Simply dimming the lights and providing music during UDT resulted in a decrease in embarrassment scores of almost ten points. This low-cost and simple measure improved patient experience. PMID- 28624917 TI - Mesh in POP surgery should be based on the risk of the procedure, not the risk of recurrence. AB - The still unfolding story of mesh use in surgery for pelvic organ prolapse (POP) offers insights into the factors that influence how we interpret evidence in assessing new technology. Our adoption of mesh in prolapse surgery was influenced by a paradigm shift from treating to preventing recurrent prolapse. This shift is largely unsupported by data and fails to account for the added risk associated with mesh use. This commentary explores unconscious factors that influence our interpretation of innovation and proposes a new approach to evaluating new surgical technologies that balances benefit and risk. Counseling patients about treatments using the benefit-risk approach offers a more balanced perspective. Using a formal benefit-risk assessment in the scientific evaluation of treatments will also provide a more balanced approach that supports the scientific process and patients who undergo treatment. PMID- 28624919 TI - Physical activity and pelvic floor muscle training in patients with pelvic organ prolapse: a pilot study. AB - INTRODUCTION AND HYPOTHESIS: The details of the physical activity in patients with mild to moderate pelvic organ prolapse (Pmoderate pelvic organ prolapse (POP) remain under-studied. The purpose of the present study was to investigate objective physical activity levels and the changes in pelvic floor muscle(PFM) strength, symptoms and quality of life (QOL) between before and after PFM training (PFMT) in patients with POP. METHODS: In a prospective pilot study, 29 patients with stage II or III POP completed approximately 16 weeks of PFMT. A reliable activity monitor was used to measure physical activity parameters including step counts, activity and total calories expended, and duration at each intensity level. Maximum vaginal squeeze pressure, POP symptoms and QOL were assessed. Changes in these outcome measures were compared before and after PFMT. RESULTS: The step counts per day (mean +/- SD) of women with POP was 7,272.9 +/- 3,091.7 before PFMT and 7,553.4 +/- 2,831.0 after PFMT. There was no significant change between before and PFMT. PFM strength was significantly increased after PFMT. POP-related symptoms including stress urinary incontinence, frequency, postmicturition dribble and interference with emptying the bowels were significantly improved. The QOL scores for general health, physical limitations, emotion, and severity measures were significantly improved after PFMT. CONCLUSIONS: Although PFMT changed PFM strength symptoms, and QOL, there were no changes for any physical activity parameters before and after PFMT. This is probably because the physical activity levels in patients with mild to moderate POP were almost same as in age-matched healthy women. PMID- 28624920 TI - Interobserver agreement in perineal ultrasound measurement of the anovaginal distance: a methodological study. AB - INTRODUCTION AND HYPOTHESIS: Objective outcome measures of the extent of laceration at delivery are needed. In this study we evaluated and describe here a method for learning perineal ultrasound measurement of the anovaginal distance (AVD). The learning period needed for examiners proficient in vaginal ultrasound examination and the interobserver agreement after reaching proficiency in AVD measurement were determined. The hypothesis was that the method is feasible to learn and reproducible for use in further research. METHODS: The method was taught by an examiner experienced in perineal ultrasonography. The distance between the mucosal margin of the internal anal sphincter was measured with a vaginal probe. The studied examiners measured the AVD until similar results (+/-5 mm) were achieved. The AVD in 40 women was then measured and documented by two examiners who were blinded to each other's results. Interobserver agreement was calculated using the kappa score. RESULTS: Examiners with previous experience in vaginal ultrasonography had learned the method after performing five sets of comeasurements. The AVD measurements after the learning period showed almost perfect agreement (kappa = 0.87) between the examiners. CONCLUSIONS: The method for perineal ultrasound measurement of AVD was learned quickly with high interobserver agreement. The method is feasible to learn and reproducible for use in further research. PMID- 28624921 TI - Lung Adenocarcinoma Survival in EGFR-Mutated African-Caribbean Patients: A Multicenter Study in the French West Indies. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Shorter survival has been repeatedly reported for patients of African ancestry. Multivariate analysis demonstrated that this gap could be a consequence of socio economic disparities instead of genetic specificities. However, those results were obtained in a pre-targeted therapies era and the effect of tyrosine kinase inhibitors targeting EGFR are not known in this population. OBJECTIVE: In this French West Indies study, we report overall survival (OS) in a frequently mutated population treated for lung adenocarcinoma within an equal-access healthcare system. PATIENTS AND METHODS: Clinical, demographic, survival, and treatment data have been retrospectively assessed for all patients diagnosed with lung adenocarcinoma in the islands of Martinique and Guadeloupe between 2013 and 2015. RESULTS: Two hundred and forty-one patients (82% African-Caribbean) were included. EGFR mutations were detected in 37% of all tumor specimens and were associated with non-smoker status in multivariate analysis. Median OS was 16.2 months. For patients with advanced disease, median OS was 11.5 months, depending on EGFR mutation (23 vs. 8.3 months for non-mutated patients, p = 0.0012). There was no difference in survival according to ethnicity or island. In multivariate analysis, performance status (PS) and EGFR mutation were the only independent prognostic factors. CONCLUSIONS: Despite a higher frequency of EGFR mutations in African-Caribbean patients, ethnicity was not an independent factor of OS in lung adenocarcinoma. Lower initial PS in this mainly non-smoking African-Caribbean population may explain the absence of a difference in OS. PMID- 28624922 TI - Targeting the PD-1/PD-L1 Immune Checkpoint in EGFR-Mutated or ALK-Translocated Non-Small-Cell Lung Cancer. AB - Immune checkpoint inhibitors, notably antibodies targeting programmed death-1 (PD 1) and programmed death ligand-1 (PD-L1), have modified the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Several PD-1/PD-L1 inhibitors have been approved by health authorities for this indication and others are in clinical development. However, only a subset of patients truly benefits from these agents. For patients with mutated EGFR or translocated ALK NSCLC, for whom an immune checkpoint inhibitor can be prescribed after progression on tyrosine kinase inhibitors and chemotherapy, information is scarce and sometimes contradictory. Phase III randomized clinical trials have evaluated different immune checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab) vs. chemotherapy as second- or subsequent-line therapy in NSCLC, but included very few patients with EGFR/ALK-positive disease. Subgroup analyses found that these patients did not benefit from immune checkpoint inhibitors. Retrospective data show progression-free survival lasting only 1.2-2.1 months. Preclinical data suggested a lower expression of PD-L1 in EGFR/ALK-positive patients compared to EGFR/ALK-negative patients. Our objective herein is to provide an up-to-date review of available data from the various publications on the impact of immune checkpoint inhibitors in patients with EGFR/ALK-positive NSCLC. PMID- 28624923 TI - A comparison of enhancement patterns on dynamic enhanced CT and survival between patients with pancreatic neuroendocrine tumors with and without intratumoral fibrosis. AB - PURPOSE: To compare CT findings and survival between patients with pancreatic neuroendocrine tumors (pNETs) with and without fibrosis. METHODS: Forty-five pNET patients with intratumoral fibrosis (group A) were matched for age, gender, and tumor size and grade with 45 pNET patients without (group B), and CT images were retrospectively reviewed. Hounsfield units (HUs) of tumors in unenhanced, arterial and portal phases, HU ratio (tumor to normal parenchyma) in each phase, enhancement patterns, visible enhancement pattern changes, and survival were compared. RESULTS: Group A showed progressive enhancement patterns, while group B showed early enhancement and wash-out patterns (p < 0.05). HUs of tumors and HU ratio in the unenhanced phase were significantly higher in group A than group B (p <= 0.024), whereas those in the arterial phase were significantly lower in group A than group B (p <= 0.003). Peripheral to full or peripheral to peripheral enhancement change was more frequent in group A, while full to full enhancement change was more frequent in group B (p < 0.05). Group A showed significantly lower overall survival than group B (p = 0.029). CONCLUSIONS: pNETs with fibrosis showed a progressive enhancement pattern and worse overall survival than pNETs without, which showed an early enhancement and wash-out pattern. PMID- 28624925 TI - Liver fibrosis: in vivo evaluation using intravoxel incoherent motion-derived histogram metrics with histopathologic findings at 3.0 T. AB - PURPOSE: To retrospectively determine the feasibility of intravoxel incoherent motion (IVIM) imaging based on histogram analysis for the staging of liver fibrosis (LF) using histopathologic findings as the reference standard. METHODS: 56 consecutive patients (14 men, 42 women; age range, 15-76, years) with chronic liver diseases (CLDs) were studied using IVIM-DWI with 9 b-values (0, 25, 50, 75, 100, 150, 200, 500, 800 s/mm2) at 3.0 T. Fibrosis stage was evaluated using the METAVIR scoring system. Histogram metrics including mean, standard deviation (Std), skewness, kurtosis, minimum (Min), maximum (Max), range, interquartile (Iq) range, and percentiles (10, 25, 50, 75, 90th) were extracted from apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f) maps. All histogram metrics among different fibrosis groups were compared using one-way analysis of variance or nonparametric Kruskal-Wallis test. For significant parameters, receivers operating characteristic curve (ROC) analyses were further performed for the staging of LF. RESULTS: Based on their METAVIR stage, the 56 patients were reclassified into three groups as follows: F0-1 group (n = 25), F2-3 group (n = 21), and F4 group (n = 10). The mean, Iq range, percentiles (50, 75, and 90th) of D* maps between the groups were significant differences (all P < 0.05). Area under the ROC curve (AUC) of the mean, Iq range, 50, 75, and 90th percentile of D* maps for identifying significant LF (>=F2 stage) was 0.901, 0.859, 0.876, 0.943, and 0.886 (all P < 0.0001), respectively; for diagnosing severe fibrosis or cirrhosis (F4), AUC was 0.917, 0.922, 0.943, 0.985, and 0.939 (all P < 0.0001), respectively. The histogram metrics of ADC, D, and f maps demonstrated no significant difference among the groups (all P > 0.05). CONCLUSION: Histogram analysis of D* map derived from IVIM can be used to stage liver fibrosis in patients with CLDs and provide more quantitative information beyond the mean value. PMID- 28624926 TI - Limited awareness of animal influenza prevention and control among Dai Lue smallholder farmers in Southwest China. AB - Awareness of animal influenza and its prevention and control is important for ensuring livestock health, production and welfare. In China, a country stereotyped as a major source of emerging zoonotic infectious diseases, research on the public understanding of animal influenza is limited to the Han, the main ethnic group. The present qualitative study in Southwest China investigated awareness of animal influenza among the Dai, an ethnic minority. The participants (15 men and 10 women, ages 18-83) were smallholder farmers of pigs and poultry in rural areas of Jinghong, Xishuangbanna, Yunnan Province. A mixture of interviews and group discussions took place in homes and villages. The participants were asked about their knowledge of avian influenza (H7N9), swine influenza (H1N1), precautions taken to protect against influenza, procedures when animals were sick and perceived risk of animal influenza. The data were analysed following coding and thematic analysis. The findings demonstrated a limited understanding of animal health and welfare among participants. Specifically, they were largely unaware of animal influenza (H7N9, H1N1) including its causes, symptoms, prevention and treatment. The farmers were also uninformed of the risks they faced and unknowingly engaged in behaviours which increased direct or indirect exposure to infected animals, a risk factor for human infection. They also reported poor usage of veterinary services. In order to guarantee the health, welfare and production of their livestock, immediate action is needed to enable Dai smallholder farmers to prevent and respond to animal influenza effectively and timely. PMID- 28624927 TI - Seroprevalence and risk factors for bovine brucellosis in domestic yaks (Bos grunniens) in Tibet, China. AB - A cross-sectional study was conducted in three counties (Damxung, Maizhokunggar and Yadong) in Tibet in April and May 2015. A total of 1,523 yaks owned by 181 herders were randomly selected and blood sampled. Sera were tested using the rose bengal test (RBT) and a competitive immune-enzymatic assay (C-ELISA) and the test results interpreted in parallel. The individual yak prevalence was 2.8% (95% CI 2.0-3.7) with a herd prevalence of 18.2% (95% CI 12.9-24.6). At the individual level, two predictor variables, age and production system, were significantly associated with seropositivity by a binary logistic regression analysis. The odds of Brucella infection were significantly higher in older Yaks (3-5 years old, OR = 4.51; 95% CI 1.53-19.29; >=6 years old, OR = 3.89; 95% CI 1.23-17.21) compared to those of younger yaks (<=2 years old). The odds of seropositivity for yaks managed under an agro-pastoral production system were 2.9 (95% CI 1.48-5.86) times higher compared to those managed under a pastoral production system. At the herd level, an association between the infection with Brucella and a history of abortions in the herd was observed (OR = 4.98, 95% CI 1.48-16.62). Surprisingly, vaccination was not associated with a lower level of infection (p = 0.49 and p = 0.99 for individual and herd level data, respectively). The results of the survey indicate that bovine brucellosis is endemic among the yak population in the plateau region of China, and the risk factors identified in the study should be considered in the epidemiology of the disease and when developing control programs for the disease. PMID- 28624924 TI - Evaluation of hepatic fibrosis: a review from the society of abdominal radiology disease focus panel. AB - Hepatic fibrosis is potentially reversible; however early diagnosis is necessary for treatment in order to halt progression to cirrhosis and development of complications including portal hypertension and hepatocellular carcinoma. Morphologic signs of cirrhosis on ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) alone are unreliable and are seen with more advanced disease. Newer imaging techniques to diagnose liver fibrosis are reliable and accurate, and include magnetic resonance elastography and US elastography (one-dimensional transient elastography and point shear wave elastography or acoustic radiation force impulse imaging). Research is ongoing with multiple other techniques for the noninvasive diagnosis of hepatic fibrosis, including MRI with diffusion-weighted imaging, hepatobiliary contrast enhancement, and perfusion; CT using perfusion, fractional extracellular space techniques, and dual-energy, contrast-enhanced US, texture analysis in multiple modalities, quantitative mapping, and direct molecular imaging probes. Efforts to advance the noninvasive imaging assessment of hepatic fibrosis will facilitate earlier diagnosis and improve patient monitoring with the goal of preventing the progression to cirrhosis and its complications. PMID- 28624928 TI - A survey analysis of indigenous goat production in communal farming systems of Botswana. AB - A total of 153 communal farmers in four agro-ecological regions of Botswana were interviewed using a structured questionnaire. The aims of the survey were to characterise existing communal goat production systems, evaluate the importance of goats to farmers and identify breeding practices and constraints encountered in goat production in Botswana. Data was collected on socio-economic parameters, general and breeding management practices and major constraints limiting goat production in Botswana. All respondents were small-scale communal farmers with 63% respondents practising mixed crop-livestock farming and 37% keeping livestock as their primary activity. The majority (33%) of respondents were older than 60 years. Over 80% of the farmers kept goats for cash required for tuition, school uniforms and household commodities as well as re-stocking of animals. Most farmers (62%) kept indigenous crossed genotypes. Generally, uncontrolled mating was practised with the majority of farmers (41%) using on-farm reared bucks for more than two years of breeding and communal bucks (36%) as an alternative. The major constraints limiting goat productivity in communal areas included uncontrolled breeding, predators, theft and diseases. Issues raised by farmers should be considered in designing and implementing effective breeding programs for goats to improve their overall productivity and contribution to poverty alleviation in these communities. PMID- 28624929 TI - Latex peptidases of Calotropis procera for dehairing of leather as an alternative to environmentally toxic sodium sulfide treatment. AB - Dehairing of crude leather is a critical stage performed at the beginning of its processing to obtain industrially useful pieces. Tanneries traditionally apply a chemical process based on sodium sulfide. Since this chemical reactive is environmentally toxic and inefficiently recycled, innovative protocols for reducing or eliminating its use in leather depilation are welcomed. Therefore, latex peptidases from Calotropis procera (CpLP) and Cryptostegia grandiflora (CgLP) were assayed for this purpose. Enzyme activity on substrates representative of skin such as hide powder azure (UHPA), elastin (UE), azocollagen (UAZOCOL), keratin (UK), and epidermis (UEP) was determined, while depilation activity was assayed on cow hide. Only CpLP was active against keratin (13.4 UK) and only CgLP was active against elastin (0.12 UE). CpLP (93.0 UHPA, 403.6 UAZOCOL, 36.3 UEP) showed higher activity against the other substrates than CgLP (47.6 UHPA, 261.5 UAZOCOL, 8.5 UEP). In pilot assays, CpLP (0.05% w/v with sodium sulfite 0.6% w/v as activator) released hairs from cow hide pieces. Macroscopic and microscopic analyses of the hide revealed that the dehairing process was complete and the leather structure was preserved. The proteolytic system of C. procera is a suitable bioresources to be exploited by tanneries. PMID- 28624930 TI - Basal and Bolus Insulin Dose Changes after Switching Basal Insulin to Insulin Degludec in Patients with Type 1 Diabetes Mellitus: A Pilot Study. AB - BACKGROUND AND OBJECTIVES: Ultra-long-acting insulin degludec (DEG) has a longer duration of action and less daily variability relative to other basal insulin (BI), and thus may benefit patients with type 1 diabetes mellitus (T1DM). We examined the impact of switching BI to DEG on glycemic control and insulin dose in T1DM. METHODS: T1DM patients (n = 22; six male; mean age: 64.5 +/- 12.6 years) receiving basal-bolus insulin therapy were included. Initially, the BI dose was replaced with DEG in a 1:1 ratio; 80-100% of the total dose was replaced with DEG for multiple basal insulin injections. DEG was titrated according to study protocol. Changes in HbA1c, daily insulin dose, glycemic self-monitored blood glucose variations, and hypoglycemia frequency were evaluated for 24 weeks. RESULTS: Once-daily DEG significantly decreased HbA1c levels when switched from once-daily BI (7.9 +/- 0.8 vs. 7.5 +/- 0.9%, p = 0.020) and maintained HbA1c when switched from twice-daily BI (8.5 +/- 1.6 vs. 8.4 +/- 1.2%, p = 0.457). The BI dose decreased by -7.8 +/- 13.9% (p = 0.017) and -16.6 +/- 16.9% (p = 0.050) when switched from once-daily BI and twice-daily BI, respectively. The total bolus insulin dose significantly decreased when switched from once-daily BI (21.7 +/- 8.3 to 19.3 +/- 8.8 U/day, p = 0.016) especially in the injection before breakfast and evening meal. Body weight and hypoglycemia frequency was not significantly different. CONCLUSION: DEG improved glycemic control when switched from once-daily BI and maintained glycemic control when switched from twice-daily BI without increasing hypoglycemia. PMID- 28624931 TI - Familial Mediterranean fever, review of the literature. AB - Familial Mediterranean fever (FMF) is the most common monogenic periodic fever syndrome and characterized by recurrent episodes of fever, serositis, arthritis, dermal manifestations, and long-term renal complications. The MEFV gene was described in 1997 as the gene responsible for FMF and is inherited in autosomal recessive manner. It encodes mutated protein pyrin, an important player in the innate immune system and the component of inflammasome which leads to exaggerated inflammatory response through uncontrolled production of interleukin-1. The recent progress in molecular genetics and understanding of pathogenesis showed a more complicated picture of FMF inheritance, penetrance, and pathogenesis. The pathogenesis is not completely understood although the gene responsible for FMF has been identified. Whether the pyrin mutation effect in FMF is due to a loss of function or a gain of function is still controversial. The diagnosis is mainly clinical and the genetic testing is indicated to support it. Colchicine remains the mainstay of treatment of FMF since 1972. It decreases the attacks, improves quality of life, and prevents amyloidosis. The recent advances in genetic testing and molecular studies has led to the development of new therapies of interleukin 1 inhibitors; anakinra, canakinumab, and rilonacept. PMID- 28624932 TI - Word-Level and Sentence-Level Automaticity in English as a Foreign Language (EFL) Learners: A Comparative Study. AB - The present study aimed to investigate second language (L2) word-level and sentence-level automatic processing among English as a foreign language students through a comparative analysis of students with different proficiency levels. As a multidimensional and dynamic construct, automaticity is conceptualized as processing speed, stability, and accuracy which are indexed by reaction time, coefficient variation and accuracy rate. Sixty students (39 undergraduate students and 21 graduate students) who majored in English participated in this study. They completed the lexical semantic classification task, the sentence construction task, the sentence verification task under two different modalities (visually- and aurally-presented situations). Multivariate analyses were conducted to examine the differences between the students with different proficiency levels pertaining to their L2 performance. The results indicated that the processing speed was not found to be a good indicator of automatic language processing. Moreover, both levels of students appeared to reach a plateau in word level processing but there were some variations in students' sentential processing. Finally, the findings showed that automatic language processing seemed to be module-specific and non-sharable across different modalities and skills. PMID- 28624933 TI - Influence of food consumption patterns and Galician lifestyle on human gut microbiota. AB - The proportion of different microbial populations in the human gut is an important factor that in recent years has been linked to obesity and numerous metabolic diseases. Because there are many factors that can affect the composition of human gut microbiota, it is of interest to have information about what is the composition of the gut microbiota in different populations in order to better understand the possibilities for improving nutritional management. A group of 31 volunteers were selected according to established inclusion and exclusion criteria and were asked about their diet history, lifestyle patterns, and adherence to the Southern European Atlantic Diet. Fecal samples were taken and subsequently analyzed by real-time PCR. The results indicated different dietary patterns for subjects who consumed a higher amount of fruits, vegetables, legumes, and fish and a lower amount of bakery foods and precooked foods and snacks compared to Spanish consumption data. Most participants showed intermediate or high adherence to Southern European Atlantic Diet, and an analysis of gut microbiota showed high numbers of total bacteria and Actinobacteria, as well as high amounts of bacteria belonging to the genera Lactobacillus spp. and Bifidobacterium spp. A subsequent statistical comparison also revealed differences in gut microbiota depending on the subject's body weight, age, or degree of adherence to the Southern European Atlantic Diet. PMID- 28624934 TI - Low serum diamine oxidase (DAO) activity levels in patients with migraine. AB - Histamine intolerance is a disorder in the homeostasis of histamine due to a reduced intestinal degradation of this amine, mainly caused by a deficiency in the enzyme diamine oxidase (DAO). Among the several multi-faced symptoms associated with histamine intolerance, headache is one of the most recognized and disabling consequences. The aim of this study was to determine the prevalence of DAO deficiency in patients with a confirmed migraine diagnosis according to the current International Headache Society (IHS) and in non-migraine subjects. DAO activity was assessed in a total of 198 volunteers recruited at the Headache Unit of the Hospital General de Catalunya, 137 in the migraine group and 61 as a control group. DAO enzyme activity in blood samples was determined by ELISA test. Values below 80 HDU/ml (Histamine Degrading Unit/ml) were considered as DAO deficient. Mean value of DAO activity from migraine population (64.5 +/- 33.5 HDU/ml) was significantly lower (p < 0.0001) than that obtained from healthy volunteers (91.9 +/- 44.3 HDU/ml). DAO deficiency was more prevalent in migraine patients than in the control group. A high incidence rate of DAO deficiency (87%) was observed in the group of patients with migraine. On the other hand, 44% of non-migranous subjects had levels of DAO activity lower than 80 HDU/ml. Despite the multifactorial aetiology of migraine, these results seem to indicate that this enzymatic deficit could be related to the onset of migraine. PMID- 28624935 TI - Eldecalcitol, an Active Vitamin D3 Derivative, Prevents Trabecular Bone Loss and Bone Fragility in Type I Diabetic Model Rats. AB - Diabetes mellitus is known to adversely affect the bones and be associated with increased fracture risk. We examined whether eldecalcitol (ELD), an active vitamin D3 derivative, could inhibit the diabetic bone loss in streptozotocin induced type I diabetic rats. ELD (10, 20, or 40 ng/kg), alfacalcidol (ALF; 25, 50, or 100 ng/kg), or vehicle was administered 5 times per week for 12 weeks from 1 week after diabetes induction. Normal control rats received the vehicle. Bone turnover markers, bone mineral density (BMD), and biomechanical strength of the lumbar spine and femur were measured, and bone histomorphometry was performed. Content of advanced glycation end products (AGEs) in the femoral shaft was also determined. In diabetic rats, serum osteocalcin (OC) concentration was lower and urinary excretion of deoxypyridinoline (DPD) tended to be higher than in normal rats. Areal BMD and maximum load of the lumbar vertebrae and femoral shaft were lower in diabetic rats than in normal rats. All doses of ELD and the highest dose of ALF reduced urinary DPD excretion, but had no effect on serum OC. The 20 and 40 ng/kg doses of ELD prevented decreases in BMD and the highest dose of ELD prevented the reduction in maximum load of the lumbar vertebrae, while ALF did not change these parameters. ELD and ALF did not affect areal BMD or biomechanical strength of the femoral shaft. In diabetic rats, bone volume and trabecular thickness in the trabecular bone of the lumbar vertebrae decreased and trabecular separation increased compared to normal rats. ELD and ALF prevented diabetes-induced deterioration of trabecular microstructure. AGE content in the femoral cortical bone increased in the diabetic rats, and ELD and ALF did not change AGE content compared to the diabetic rats. These results indicated that ELD suppressed bone resorption and prevented trabecular bone loss and deterioration of trabecular microstructure, resulting in prevention of reduction in biomechanical strength in type I diabetic rats. PMID- 28624936 TI - Breakthrough modeling and experimental design for o-xylene dynamic adsorption onto clay material. AB - The adsorption of o-xylene onto raw clay material in a fixed bed using a thermal conductivity detector gas chromatography was investigated. Experimental and theoretical studies were established to evaluate the removal efficiency of o xylene by adsorption on clay materials and to predict kinetic parameters. Column data were describing at different conditions using Bohart-Adams, Wolborska, Thomas, Yoon and Nelson, dose-response, and bed depth service time models. All used models were satisfactory to predict the breakthrough curves. A suitable advection-dispersion-sorption (ADS) model has been also developed to simulate the measured data, based on the nature of the various equilibrium relationships of solid-gas and diverse descriptions of the mass transfer processes within of the adsorbent particle. The experiments can be fitted with high correlated coefficient R 2 = 0.996. PMID- 28624937 TI - Acute toxicity of chemical pesticides and plant-derived essential oil on the behavior and development of earthworms, Eudrilus eugeniae (Kinberg) and Eisenia fetida (Savigny). AB - Comparative toxicity of two chemical pesticides (temephos and monocrotophos) versus a plant-derived betel leaf oil Piper betle (L.) to earthworm Eudrilus eugeniae (Kinberg) and redworm Eisenia fetida Savigny, historically: Eisenia foetida (Savigny 1826), was evaluated. Mortality rate was more prominent in temephos at 100 MUg concentration to both the earthworms in filter paper test (FPT) as well as 10 mg concentration in artificial soil test (AST). In contrast, P. betle does not display much mortality rate to both the earthworms even at 1000 mg of treatment concentrations. The lethal concentration (LC50) value was observed at 3.89 and 5.26 mg/kg for temephos and monocrotophos against E. eugeniae and 3.81 and 5.25 mg/kg to E. fetida, respectively. Whereas, LC50 value of betel leaf oil was only observed at 3149 and 4081 mg/kg to E. eugeniae and E. fetida, respectively. Correspondingly, the avoidance or attraction assay also displayed that earthworms were more sensitive to the soil containing chemical pesticides. Whereas, the avoidance percentage was decreased in the P. betle oil. Similarly, sublethal concentration of chemical pesticides (5 and 6.5 mg) significantly reduced the earthworm weight and growth rate. However, P. betle oil did not change the developmental rate in the duration of the assay (2, 7 and 14 days) even at 4000 mg treatment concentration. The enzyme ratio of CAT and SOD was also affected significantly after exposure to the chemical pesticides (6.5 mg/kg). Hence, our study implied the risk assessment associated with the chemical pesticides and also recommends plant-derived harmless P. betle oil against beneficial species as an alternative pest control agent. PMID- 28624938 TI - Synergetic integration of laccase and versatile peroxidase with magnetic silica microspheres towards remediation of biorefinery wastewater. AB - In this study, a tailor-made biocatalyst consisting of a co-immobilized lignolytic enzyme cascade on multi-functionalized magnetic silica microspheres (MSMS) was developed. Physical adsorption was the most promising strategy for the synthesis of individual immobilized laccase (IL), immobilized versatile peroxidase (IP), as well as co-immobilized laccase (Lac) and versatile peroxidase (VP) with an enzyme activity recovery of about 79, 93, 27, and 27.5%, respectively. Similarly, the biocatalytic load of 116, 183, 23.6, and 31 U/g was obtained for IL, IP, and co-immobilized Lac and VP, respectively. The co immobilized enzyme system exhibited better pH stability than the free and individual immobilized system by retaining more than 100% residual activity at pH 7.0 after a 150-h incubation; whereas, the thermal stability and kinetics of the co-immobilized biocatalyst were not much improved. IL and IP could be recycled for 10 cycles after which they retained 31 and 44% of their initial activities. Co-immobilized Lac and VP were reused for ten consecutive cycles at the end of which Lac activity was depleted, and 37% of VP activity was left. Free enzymes, IL, IP, co-immobilized Lac, and VP were applied to biorefinery wastewater (BRW) in a batch study to investigate the transformation of phenolic contaminants over a period of 5 days. The major classes of phenolic constituents in terms of their order of removal in a Lac-VP system was phenol >2-chlorophenol > trichlorophenol > dichlorophenol > cresols > dimethylphenol >2 methyl- 4, 6-dinitrophenol > 4 nitrophenol > tetrachlorophenols > pentachlorophenol. The free enzymes and individually immobilized enzymes resulted in 80% dephenolization in 5 days. By contrast, the co-immobilized biocatalyst provided rapid dephenolization yielding the same 80% removal within 24 h and 96% removal of phenols in 60 h after which the system stabilized, which is the major advantage of the co-immobilized biocatalyst. ? Graphical abstract. PMID- 28624939 TI - Additive effect of calcium depletion and low resource quality on Gammarus fossarum (Crustacea, Amphipoda) life history traits. AB - Gammarus fossarum is an often-abundant crustacean detritivore that contributes importantly to leaf litter breakdown in oligotrophic, mainly heterotrophic, headwater streams. This species requires large amounts of Ca to moult, thus allowing growth and reproduction. Because resource quality is tightly coupled to the organism's growth and physiological status, we hypothesised that low Ca concentration [Ca] and low food resource quality (low phosphorus [P] and/or reduced highly unsaturated fatty acid [HUFA] contents) would interactively impair molecular responses (gene expression) and reproduction of G. fossarum. To investigate the effects of food resources quality, we experimentally manipulated the P content of sycamore leaves and also used diatoms because they contain high amounts of HUFAs. Three resource quality treatments were tested: low quality (LQ, unmanipulated leaves: low P content), high quality 1 (HQ1; P-manipulated leaves: high P content), and high quality 2 (unmanipulated leaves supplemented with a pellet containing diatoms: high P and HUFA content). Naturally, demineralised stream water was supplemented with CaSO4 to obtain three Ca concentrations (2, 3.5, and 10.5 mg Ca L-1). For 21 days, pairs of G. fossarum were individually exposed to one of the nine treatments (3 [Ca] * 3 resource qualities). At the individual level, strong and significant delays in moult stage were observed in gammarids exposed to lower [Ca] and to lower resource quality, with additive effects lengthening the duration of the reproductive cycle. Effects at the molecular level were investigated by measuring expression of 12 genes involved in energy production, translation, or Ca or P homeostasis. Expression of ATP synthase beta (higher in HQ2), calcified cuticle protein (higher in HQ1 and HQ2), and tropomyosin (higher in HQ2 compared to HQ1) was significantly affected by resource quality, and significant additive effects on Ca transporting ATPase expression were induced by [Ca] and resource quality (higher for low [Ca] and higher resource quality). These results highlight the potential drastic deleterious effects of water [Ca] depletion on G. fossarum physiology, populations, and ecosystem functioning, especially in oligotrophic environments. PMID- 28624940 TI - Effect of heavy metals on tissue-specific antioxidant response in Indian major carps. AB - Concentrations of heavy metals (Cu, Ni, Zn, Cd and Pb) were measured in sediments, water and liver and kidney tissues of three Indian major carps (Labeo rohita, Catla catla and Cirrhinus cirrhosus), belonging to two different weight groups (250 and 500 g), collected from ponds at two different sites (Nalban bheri and Diamond Harbour). The tissues were analysed for the levels of different antioxidant defence systems such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRd), glutathione S transferase (GST), glutathione (GSH) and malondialdehyde (MDA). Concentrations of all the metals were significantly higher (P < 0.05) in sediment, water and the tissues from Nalban bheri compared to those in Diamond Harbour. Metal concentrations were the lowest in C. cirrhosus, which increased with an increase in fish weight, and the liver accumulated higher amount of metals than the kidney. Activities of all enzymatic and non-enzymatic antioxidant parameters except GPx and GRd were significantly higher (P < 0.05) in the tissues from Nalban bheri than those in Diamond Harbour. Significant multicollinearity was found in the values of SOD, CAT, GST, GRd, GPx and MDA with Pb, Cu and Ni in all three fish species at Nalban and with Cd in L. rohita and C. catla. Principal component analysis results revealed that stress response in a polluted site was directly regulated by an amalgamation of GSH profile and the levels of MDA in a synchronized manner. The study indicated a tissue-specific and species-specific difference for heavy metal-induced oxidative stress response in fish and a correlation between different heavy metals and individual oxidative stress markers. PMID- 28624941 TI - Does static electric field from ultra-high voltage direct-current transmission lines affect male reproductive capacity? Evidence from a laboratory study on male mice. AB - With the development of ultra-high-voltage direct-current (UHVDC) transmission technology and increase in transmission voltage, the issue of environmental static electric field (SEF) pollution is standing out and its possible health effects have caused much public attention. In this study, the effects of chronic exposure to SEF on reproductive capacity of male mice were investigated. Twenty Institute of Cancer Research (ICR) mice were exposed to SEF (56.3 +/- 1.4 kV/m, 49 days) generated by a high-voltage device. Several biological end points related to spermatogenesis and testicular function were evaluated, including reproductive organ coefficients, sperm motility and morphology, serum testosterone level, and testicular histology. No significant differences were found between the SEF-exposed and sham-exposed groups at the end of the exposure period. However, further observation through transmission electron microscopy revealed cristae losses in mitochondria of spermatogenic cells after SEF exposure. Nevertheless, the mitochondria injury did not affect sperm motility, which might be explained from the perspective of energy supply. That is, most of the energy required for sperm movement is generated by glycolysis which occurs in the cytoplasm rather than oxidative phosphorylation which occurs in mitochondria. In conclusion, this study indicates that exposure to SEF (56.3 +/- 1.4 kV/m, 49 days) has limited effects on male reproductive capacity. PMID- 28624942 TI - Toxicity of 56 substances to trees. AB - Toxicity data of substances to higher plants is needed for the purpose of risk assessment, site evaluation, phytoremediation, and plant protection. However, the results from the most common phytotoxicity tests, like the OECD algae and Lemna test, are not necessarily valid for higher terrestrial plants. The willow tree toxicity test uses inhibition of transpiration (aside of growth and water use efficiency) of willow cuttings grown in spiked solutions or soils as end point to quantify toxicity. This overview presents results from 60 studies including 24 new unpublished experiments for 56 different chemicals or substrates. Highest toxicity (EC50 < 1 mg/L) was observed from exposure to heavy metals like copper and cadmium. Also, organotins and free cyanide showed very high toxicity. The toxic effect of chlorophenols on willows was comparable to that on duck weed (Lemna) and green algae, while volatile compounds like chlorinated solvents or benzene, toluene, ethylbenzene, and xylene had less effect on trees than on these aquatic plants, due to volatilization from leaves and test media. In particular low (g/L range) toxicity was observed for tested nanomaterials. Effects of pharmaceuticals (typically weak acids or bases) depended strongly of the solution pH. Like for algae, baseline toxicity was observed for willows, which is related to the water solubility of the compounds, with absolute chemical activity ranging from 0.01 to 0.1, but with several exceptions. We conclude that the willow tree toxicity test is a robust method for relating uptake, accumulation, and metabolism of substances to the toxicity to trees. PMID- 28624943 TI - Hexabromocyclododecane diastereomers in fish and suspended particulate matter from selected European waters-trend monitoring and environmental quality standard compliance. AB - The brominated flame retardant hexabromocyclododecane (HBCD) was monitored in fish and sediment (from one lake) or suspended particulate matter (SPM; from five rivers) at European freshwater sites to study the effects of reduction measures implemented by HBCD producers and users in recent years. Bream (Abramis brama) were sampled annually between 2007 and 2013 in the rivers Gotaalv/SE, Rhone/FR, Western Scheldt/NL, Mersey/UK, and Tees/UK and in Lake Belau/DE. Sediment/SPM was taken every second year between 2008 and 2014. HBCD was analyzed by LC/MS/MS allowing the determination of the alpha-, beta-, and gamma-diastereomers. For most sites, a decrease in ?HBCD was observed in fish (e.g., in the Rhone and Western Scheldt by about 80 and 60%, respectively, with significantly decreasing trends, p < 0.01). In the Rhone, HBCD also decreased in SPM. At the sampling site in the Tees which was impacted by a former HBCD point source, fish HBCD levels decreased only after a major flood event in 2013. While fish data indicate a decline in environmental HBCD concentrations at most sites with diffuse emissions, SPM data were less conclusive. The European environmental quality standard for HBCD in fish of 167 MUg kg-1 wet weight was met by all fish samples in 2013. PMID- 28624944 TI - Effective oil removal from water by magnetically driven superhydrophobic and oleophilic magnetic titania nanotubes. AB - Development of efficient techniques to combat the harmful effects of oil spill is an emerging field, where fabrication of new sorbents for selective removal of oil has become a hot topic for environmental scientists. The present study reports the preparation of superhydrophobic/oleophilic magnetic titania nanotubes via a facile hydrothermal method, followed by the treatment with octadecylamine, as potential magnetically driven sorbent for selective removal of oil from water surface. The magnetic nature (superparamagnetism at 300 K) of the nanotubes enabled magnetic removal of the oil-sorbed material from water surface. Wettability test of the material depicted a static water contact angle of 166 +/- 1 degrees , indicating its superhydrophobic character. Oil uptake experiments and contact angle measurements revealed its superoleophilicity with maximum oil sorption capacity >1.5 g/g for a variety of oils. In addition to the ease of magnetic removal, the nanotubes possess sufficient buoyancy, high selectivity, and quick rate of oil uptake and is more than five times reusable. PMID- 28624945 TI - The potential effect of temperature-humidity index on productive and reproductive performance of buffaloes with different genotypes under hot conditions. AB - The current study was aimed to investigate the impact of THI on productive and reproductive indices of PE and F1 crosses (50% PE and 50% Italian buffaloes) and back crosses (BC) (75% PE and 25% Italian buffaloes) under hot conditions. In this study, 8385 records used PE (1914, 1518, and 1737), F1 (387, 447, and 657), and BC (495, 585, and 645) for low, medium, and high THI, respectively. The high THI reduced the conception rate after first insemination in PE, F1, and BC ((odds ratio, OR) = 1.187, P = 0.007; 2.361, <0.0001 and 1.603, <0.0001, respectively) when compared with low THI. But, stillbirth and calving condition were not significantly influenced by different THI levels in BC and F1. BC was more bearable to the harsh environment; they possessed the highest incidence of conception after first insemination (72.70, 72.60, and 62.40%), producing live calves (98.50, 100, and 99.40%) with easy calving condition (98.50, 100, and 99.40%) when compared to PE and F1 at different levels of THI, respectively. The average daily milk yield and peak of milk production were decreased in PE (4.02 and 5.12%), BC (13.33 and 10.95%), and F1 (25.29 and 12.20%) from low to high THI. However, BC revealed no significant changes in days open, dry period, calving interval, gestation length, service per conception, and the first service post-partum at different levels of THI when compared with PE and F1. Therefore, rearing BC is recommended for improving buffalo productive and reproductive performance under hot conditions. PMID- 28624946 TI - Impact of heavy metal contamination on oxidative stress of Eisenia andrei and bacterial community structure in Tunisian mine soil. AB - The aims of this work were firstly to study the effect of heavy metal-polluted soils from Tunisian mine on earthworm biochemical biomarkers and on bacterial communities and therefore to analyze the interaction between earth worms and bacterial communities in these contaminated soils. For this purpose, we had introduced earthworm Eisenia andrei in six soils: one from mine spoils and five from agricultural soils, establishing a gradient of contamination. The response of worms to the presence of heavy metal was analyzed at the biochemical and transcriptional levels. In a second time, the impact of worm on bacterial community structure was investigated using automated ribosomal intergenic spacer analysis (ARISA) fingerprinting. An impact of heavy metal-contaminated soils on the oxidative status of E. andrei was observed, but this effect was dependent of the level of heavy metal contamination. Moreover, our results demonstrate that the introduction of earthworms E. andrei has an impact on bacterial community; however, the major change was observed in the less contaminated site. Furthermore, a significant correlation between earthworm oxidative status biomarkers and bacterial community structure was observed, mainly in the mine spoils. Therefore, we contribute to a better understanding of the relationships between epigenic earthworms and bacterial communities in heavy metal-contaminated soils. PMID- 28624948 TI - Metal release from contaminated leaf litter and leachate toxicity for the freshwater crustacean Gammarus fossarum. AB - Industrialization has left large surfaces of contaminated soils, which may act as a source of pollution for contiguous ecosystems, either terrestrial or aquatic. When polluted sites are recolonized by plants, dispersion of leaf litter might represent a non-negligible source of contaminants, especially metals. To evaluate the risks associated to contaminated leaf litter dispersion in aquatic ecosystems, we first measured the dynamics of metal loss from leaf litter during a 48-h experimental leaching. We used aspen (Populus tremula L.), a common tree species on these polluted sites, and collected leaf litter on three polluted sites (settling pond of a former steel mill) and three control sites situated in the same geographic area. Then, toxicity tests were carried out on individuals of a key detritivore species widely used in ecotoxicology tests, Gammarus fossarum (Crustacea, Amphipoda), with uncontaminated and contaminated leaf litter leachates, using a battery of biomarkers selected for their sensitivity to metallic stress. Leaf litters collected on polluted sites exhibited not only significantly higher cadmium and zinc concentrations but also lower lignin contents. All leaf litters released high amounts of chemical elements during the leaching process, especially potassium and magnesium, and, in a lesser extent, phosphorus, calcium, and trace metals (copper, cadmium, and zinc but not lead). Toxicity tests revealed that the most important toxic effects measured on G. fossarum were due to leaf litter leachates by themselves, whatever the origin of litter (from polluted or control sites), confirming the toxicity of such substances, probably due to their high content in phenolic compounds. Small additional toxic effects of leachates from contaminated leaf litters were only evidenced on gammarid lipid peroxidation, indicating that contaminated leaf litter leachates might be slightly more toxic than uncontaminated ones, but in a very reduced manner. Further studies will be required to verify if these patterns are generalizable to other species and to investigate the effects of contaminated leaf litter ingestion by consumers on aquatic food webs. Nevertheless, our results do not permit to exclude potential chronic effects of an exposure to contaminated leaf litter leachates in aquatic ecosystems. PMID- 28624947 TI - Physiological and molecular responses of the earthworm Eisenia fetida to polychlorinated biphenyl contamination in soil. AB - Polychlorinated biphenyls (PCBs) are a class of man-made organic compounds ubiquitously present in the biosphere. In this study, we evaluated the toxic effects of different concentrations of PCBs in two natural soils (i.e. red soil and fluvo-aquic soil) on the earthworm Eisenia fetida. The parameters investigated included anti-oxidative response, genotoxic potential, weight variation and biochemical responses of the earthworm exposed to two different types of soils spiked with PCBs after 7 or 14 days of exposure. Earthworms had significantly lower weights in both soils after PCB exposure. PCBs significantly increased catalase (CAT), superoxide dismutase (SOD), and guaiacol peroxidase (POD) activity in earthworms exposed to either soil type for 7 or 14 days and decreased the malondialdehyde (MDA) content in earthworms exposed to red soil for 14 days. Of the enzymes examined, SOD activity was the most sensitive to PCB stress. In addition, PCB exposure triggered dose-dependent coelomocyte DNA damage, even at the lowest concentration tested. This response was relatively stable between different soils. Three-way analysis of variance (ANOVA) showed that the weight variation, anti-oxidant enzyme activities, and MDA contents were significantly correlated with exposure concentration or exposure duration (P < 0.01). Furthermore, weight variation, CAT activity, and SOD activity were significantly affected by soil type (P < 0.01). Therefore, the soil type and exposure time influence the toxic effects of PCBs, and these factors should be considered when selecting responsive biomarkers. PMID- 28624949 TI - Designing more engaging computer-tailored physical activity behaviour change interventions for breast cancer survivors: lessons from the iMove More for Life study. AB - BACKGROUND: Participating in regular physical activity is a recommended cancer recovery strategy for breast cancer survivors. However, tailored support services are not widely available and most survivors are insufficiently active to obtain health benefits. Delivering tailored programs via the Internet offers one promising approach. However, recent evaluations of such programs suggest that major improvements are needed to ensure programs meet the needs of users and are delivered in an engaging way. Understanding participants' experiences with current programs can help to inform the next generation of systems. PURPOSE: The purposes of this study are to explore breast cancer survivor's perspectives of and experiences using a novel computer-tailored intervention and to describe recommendations for future iterations. METHODS: Qualitative data from a sub sample of iMove More for Life study participants were analysed thematically to identify key themes. Participants long-term goals for participating in the program were explored by analysing open-ended data extracted from action plans completed during the intervention (n = 370). Participants negative and positive perceptions of the website and recommendations for improvement were explored using data extracted from open-ended survey items collected at the immediate intervention follow-up (n = 156). RESULTS: The majority of participants reported multi-faceted goals, consisting of two or more outcomes they hoped to achieve within a year. While clear themes were identified (e.g. 'being satisfied with body weight'), there was considerable variability in the scope of the goal (e.g. desired weight loss ranged from 2 to 30 kg). Participants' perceptions of the website were mixed, but clear indications were provided of how intervention content and structure could be improved. CONCLUSIONS: This study provides insight into how to better accommodate breast cancer survivors in the future and ultimately design more engaging computer-tailored interventions. PMID- 28624950 TI - A transient ischemic attack mimic. PMID- 28624951 TI - Prefoveal floaters as a differential diagnosis to optic neuritis: "mouches dormantes". AB - This case series describes a new optical coherence tomography (OCT) specific observation relevant to the differential diagnosis of patients with suspected optic neuritis. A tiny prefoveal floater, only detectable by OCT, was found responsible for the symptoms in three patients, one of whom had been referred with unilateral delayed visual evoked potentials. This case series suggests that with increased use of OCT in routine clinical care, entoptic phenomena can be demonstrated as a relevant differential diagnosis to optic neuritis. Patients should be explained the benign nature of their symptoms. PMID- 28624953 TI - Genome-wide analysis of differential DNA methylation in Silver-Russell syndrome. AB - Silver-Russell Syndrome (SRS) is clinically heterogeneous disorder characterized by low birth weight, postnatal growth restriction, and variable dysmorphic features. Current evidence strongly implicates imprinted genes as an important etiology of SRS. Although almost half of the patients showed DNA hypomethylation at the H19/IGF2 imprinted domain, and approximately 7%-10% of SRS patients have maternal uniparental disomy of chromosome 7 (UPD (7) mat); the rest of the SRS patients shows unknown etiology. In this study, we investigate whether there are further DNA methylation defects in SRS patients. We measured DNA methylation in seven SRS patients and five controls at more than 485,000 CpG sites using DNA methylation microarrays. We analyzed methylation changes genome-wide and identified the differentially methylated regions (DMRs) using bisulfite sequencing and digital PCR. Our analysis identifies epimutations at the previously characterized domains of H19/IGF2, providing proof of principle that our methodology can detect the changes in DNA methylation at imprinted loci. In addition, our results showed a novel SRS associated imprinted gene OSBPL5 located on chromosome 11p14 with the probe cg25963939, which is hypomethylated in 4/7 patients (P=0.023, beta=-0.243). We also report DMRs in other genes including TGFbeta3, HSF1, GAP43, NOTCH4 and MYH14. These DMRs were found to be associated with SRS using GO pathway analysis. In this study, we identified the probe cg25963939, located at the 5'UTR of imprinted gene OSBPL5, as a novel DMR that is associated with SRS. This finding provides new insights into the mechanism of SRS etiology and aid the further stratification of SRS patients by molecular phenotypes. PMID- 28624952 TI - Endocrine functions of the renal interstitium. AB - This review aims to summarize the knowledge about the sensor and endocrine response functions of resident interstitial cells of the kidney. By the production of renin, erythropoietin and arachidonate metabolites (medullipin) subsets of renal interstitial fibroblasts and pericytes in different kidney zones play a central role in salt, blood pressure and oxygen homeostasis of the body. Common to these endocrine functions is that their regulation mainly occurs by (de)recruitment of active cells. PMID- 28624954 TI - AR mutations in 28 patients with androgen insensitivity syndrome (Prader grade 0 3). AB - We investigated the androgen receptor (AR) gene mutation profiles of Chinese patients exhibiting severe androgen insensitivity syndrome (AIS) phenotypes. The present study enrolled 28 patients with genetically diagnosed AIS, who presented with severe phenotypes (Prader grade 0-3). Patients and some family members were screened via amplification and sequencing of their AR exons 1-8, including the corresponding intronic flanking regions. Luteinizing (LH), follicle-stimulating (FSH), and testosterone (T) hormone levels were found to be slightly, but not significantly, higher in patients with complete androgen insensitivity syndrome (CAIS) than in patients with partial androgen insensitivity syndrome (PAIS) (P>0.05). We identified 24 different AR mutations, including 12 that were novel. Ten patients (cases 2, 3, 10, 28, 11, 12, 19, 20, 24, and 25) were found to carry five recurrent mutations (p.Y572S, p.P914S, p.S176R, p.Y782N, and p.R841H); of these, p.Y572S, p.S176R, and p.Y782N were novel. Among the mutations identified in patients with CAIS, six (66.7%) were characterized as single-nucleotide missense mutations, and six (66.7%) were found to be located in the AR ligand binding domain (LBD). Among the mutations identified in patients with PAIS, 15 (93.8%) were found to be missense, and 11 (68.8%) were found to be located in the LBD. Patients 10 and 28 were determined to harbor the same missense mutation (p.P914S), but were diagnosed with CAIS and PAIS, respectively. Sex hormone levels were slightly, but not significantly, elevated in patients with CAIS compared to those with PAIS. Missense mutations spanning AR exons 1-8 were the predominant form of identified mutations, and these were mostly located in the AR LBD. Approximately 50% of the identified mutations were novel, and have enriched the AR gene-mutation database. Patients harboring identical mutations were in some instances found to exhibit divergent phenotypes. PMID- 28624955 TI - Presynaptic inhibition of nociceptive neurotransmission by somatosensory neuron secreted suppressors. AB - Noxious stimuli cause pain by activating cutaneous nociceptors. The Adelta- and C fibers of dorsal root ganglion (DRG) neurons convey the nociceptive signals to the laminae I-II of spinal cord. In the dorsal horn of spinal cord, the excitatory afferent synaptic transmission is regulated by the inhibitory neurotransmitter gamma-aminobutyric acid and modulators such as opioid peptides released from the spinal interneurons, and by serotonin, norepinepherine and dopamine from the descending inhibitory system. In contrast to the accumulated evidence for these central inhibitors and their neural circuits in the dorsal spinal cord, the knowledge about the endogenous suppressive mechanisms in nociceptive DRG neurons remains very limited. In this review, we summarize our recent findings of the presynaptic suppressive mechanisms in nociceptive neurons, the BNP/NPR-A/PKG/BKCa channel pathway, the FSTL1/alpha1Na+-K+ ATPase pathway and the activin C/ERK pathway. These endogenous suppressive systems in the mechanoheat nociceptors may also contribute differentially to the mechanisms of nerve injury-induced neuropathic pain or inflammation-induced pain. PMID- 28624956 TI - DICER1 mutations in twelve Chinese patients with pleuropulmonary blastoma. AB - Our aim is to examine the impact of DICER1 mutations on the pathogenesis of pleuropulmonary blastoma (PPB) by evaluating the mutation frequency and investigating the family history of Chinese patients with PPB. The family histories of 12 children with PPB recruited consecutively were surveyed. Blood samples from patients and their first-degree relatives were tested for DICER1 mutations. Whole-genome sequencing of blood samples and formalin-fixed and paraffin-embedded (FFPE) tumor tissue was performed in one family with twins. Twelve patients with PPB included six type II and six type III cases. Seven of the 12 patients harbored DICER1 mutations, six of which were frameshift or nonsense mutations. Another case carried a germline DICER1 mutation affecting the splice site. FFPE sample had a nonsense mutation in TDG and missense mutations in DICER1. In addition, two cases with DICER1 mutations were found to have lung cysts preceding the diagnosis of PPB. Furthermore, one patient had a family history remarkable for thyroid diseases. Our results indicate that the germline mutation frequency in Chinese patients with PPB is similar to the ones reported for patients from USA, UK, and Japan. Moreover, our study strongly suggests that investigating the family history and detecting germline DICER1 mutations might be of benefit to increasing awareness and improving the accuracy of the differential diagnosis of PPB from non-malignant lung cysts. PMID- 28624957 TI - Detection of mycobacterial and viral DNA in Kikuchi-Fujimoto disease: an analysis of 153 Chinese pediatric cases. PMID- 28624958 TI - Whole-exome sequencing identified compound heterozygous variants in MMKS in a Chinese pedigree with Bardet-Biedl syndrome. AB - Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. At least 21 candidate BBS-associated genes (BBS1-19, NPHP1, and IFT172) have previously been identified, and all of them play important roles in ciliary function. Here, we collected a BBS pedigree with four members and performed whole exome sequencing on the proband. The variants were analyzed and evaluated to confirm their pathogenicity. We found compound heterozygous variants (c.1192C>T, p.Q398* and c.1175C>T, p.T392M) in MKKS in both the siblings, and these were likely to be pathogenic variants. We also found a missense variant (c.2029G>C, p.E677Q) in NPHP1 and a missense variant (c.2470C>T, p.R824C) in BBS9 in the proband only, which are variants of uncertain significance. The compound heterozygous variants were probably responsible for the BBS phenotype in this Chinese pedigree and the missense mutations in NPHP1 and BBS9 might contribute to the mutation load. PMID- 28624959 TI - Systematic Review of Diagnostic Criteria Used in Atopic Dermatitis Randomized Controlled Trials. AB - BACKGROUND: Numerous diagnostic criteria for atopic dermatitis are used in clinical trials, which may limit comparison of results. OBJECTIVE: We sought to determine the most commonly used atopic dermatitis diagnostic criteria in randomized controlled trials internationally. METHODS: We performed a systematic review of randomized controlled trials with a pharmacological intervention from 2007 to 2016. Cochrane Library, EMBASE, GREAT, LILACS, MEDLINE, and Scopus were searched. Two authors independently performed the study selection and data extraction. RESULTS: Two hundred and twelve randomized controlled trials met inclusion/exclusion criteria. Overall, ten different diagnostic criteria were used. The Hanifin and Rajka criteria were most commonly used (41.0%), followed by the UK refinement of the Hanifin and Rajka criteria (9.0%), Japanese Dermatological Association criteria (4.2%), and American Academy of Dermatology criteria (3.8%). No diagnostic criteria were specified in 37.3% of randomized controlled trials. The Hanifin and Rajka criteria were the most commonly used atopic dermatitis diagnostic criteria in clinical trials of topical and systemic interventions, across all years between 2007 and 2016, in pediatric and adult populations, in most countries and regions internationally. CONCLUSIONS: The results highlight the lack of uniformity and documentation of atopic dermatitis diagnostic criteria in randomized controlled trials for atopic dermatitis. We recommend harmonizing the diagnostic criteria for atopic dermatitis in future randomized controlled trials. PMID- 28624960 TI - Drug-Induced Pyoderma Gangrenosum: A Review. AB - Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that may be caused by an adverse drug reaction. We discuss the clinical presentation and outcomes of 52 cases of drug-induced PG reported to date in the literature. We conducted our literature search for case reports of drug-induced PG using keywords on PubMed and Medical Subject Heading (MeSH) terms on MEDLINE and EMBASE. To assess the probability that each case of PG was related to drug therapy, we used the Naranjo criteria. We identified 44 studies in the literature, with a total of 52 cases of drug-induced PG. The mean Naranjo score for cocaine-induced PG (n = 13) was 9.4, indicating a definite adverse drug reaction, while the mean Naranjo scores for isotretinoin (n = 5), propylthiouracil (n = 5), and sunitinib (n = 5) were 6.2, 6.8, and 7.4, respectively, indicating probable adverse drug reactions. Drugs should be considered as a possible triggering event whenever PG is diagnosed, and clinicians should particularly consider this in patients taking isotretinoin, propylthiouracil, or sunitinib, as well as in patients with a history of cocaine use. PMID- 28624961 TI - Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients. AB - T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein-Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVbeta2+CD8+ T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients. PMID- 28624962 TI - The Scope and Nature of Reading Comprehension Impairments in School-Aged Children with Higher-Functioning Autism Spectrum Disorder. AB - This study of 8-16-year-olds was designed to test the hypothesis that reading comprehension impairments are part of the social communication phenotype for many higher-functioning students with autism spectrum disorder (HFASD). Students with HFASD (n = 81) were compared to those with high attention-deficit/hyperactivity disorder symptomatology (ADHD; n = 39), or typical development (TD; n = 44), on a comprehensive battery of oral language, word recognition, and reading comprehension measures. Results indicated that students with HFASD performed significantly lower on the majority of the reading and language tasks as compared to TD and ADHD groups. Structural equation models suggested that greater ASD symptomatology was related to poorer reading comprehension outcomes; further analyses suggested that this relation was mediated by oral language skills. PMID- 28624963 TI - Quality of Life in Parents of Young Adults with ASD: EpiTED Cohort. AB - The impact of ASD on parental QOL was evaluated in the EpiTED cohort study at early adulthood. Two-third of parents of young adults with ASD (66.7%) reported that their QoL was at least moderately altered. The perceived impact of ASD on parental QoL was related to the young adults' level of adaptive skills, as well as to symptom severity and the presence of challenging behaviors, which appeared to be the main risk factor. The study of change between adolescence and early adulthood showed that parents whose children had a decrease in challenging behaviors perceived a decreased impact on their QoL. These results argue for the importance to propose specific interventions to target associated challenging behaviors in ASD. PMID- 28624964 TI - Relations Between Executive Functions, Social Impairment, and Friendship Quality on Adjustment Among High Functioning Youth with Autism Spectrum Disorder. AB - High functioning adolescents with Autism Spectrum Disorder (ASD) often have adjustment difficulties, specifically loneliness and depression. To better understand contributing factors, the current study evaluated associations between several Executive Function (EF) domains, social impairment, and friendship quality on depressive symptoms and loneliness in this population. Participants included 127 high functioning ASD adolescents and a parent/caregiver. Results indicated significant levels of parent-reported EF impairment which were positively correlated with increased levels of loneliness and depressive symptoms. Social impairment was identified as a significant mediator between all studied EF domains and adjustment, while friendship quality only partially mediated the relation between emotional control and loneliness. These results have implications for treatments focusing both on social skills and adjustment in adolescents with ASD. PMID- 28624965 TI - Talking About Death or Suicide: Prevalence and Clinical Correlates in Youth with Autism Spectrum Disorder in the Psychiatric Inpatient Setting. AB - Little is known about suicidal ideation in youth with autism spectrum disorder (ASD), making it difficult to identify those at heightened risk. This study describes the prevalence of thoughts about death and suicide in 107 verbal youth with ASD with non-verbal IQ >55, assessed during inpatient psychiatric admission. Per parent report, 22% of youth with ASD had several day periods when they talked about death or suicide "often," or "very often." Clinical correlates included the presence of a comorbid mood (OR 2.71, 95% CI 1.12-6.55) or anxiety disorder (OR 2.32, 95% CI 1.10-4.93). The results suggest a need for developmentally appropriate suicide risk screening measures in ASD. Reliable detection of suicidal thoughts in this high-risk population will inform suicide prevention strategies. PMID- 28624969 TI - Movement timing and cognitive control: adult-age differences in multi-tasking. AB - Over the course of six sessions, 24 young (M = 19.40 years, SD 1.61) and 24 older participants (M = 71.48 years, SD 3.86) performed simple, repetitive tapping tasks at 300 and 600 ms target durations concurrently with two cognitive tasks under non-switch or switch conditions. Despite substantial improvements, over sessions, reliable switch costs remained, which were pronounced in older adults. Young and older adults alike showed increased drift in the tapping tasks under dual-task conditions. Under dual-task non-switch conditions, older adults maintained the same timing accuracy (variability) as in the single-task condition. However, variability increased when concurrent cognitive task-set switching was required, while young adults even improved timing accuracy relative to the single-task condition. Being at odds with extant models of timing, our findings demonstrate that control of simple repetitive movements is far from automatic even at intervals below 1 s. Interference with timing in older adults is not caused by multi-tasking per se, but depends on the cognitive control demands of the concurrent task. We argue that our findings suggest a critical role of cognitive control processes for the maintenance of representations of target durations during interval production. This hypothesis received further support from patterns of local interference in the timing of individual intervals. PMID- 28624968 TI - Do Cancer Cell Lines Have Fixed or Fluctuating Stem Cell Phenotypes? - Studies with the NTera2 Cell Line. AB - One of the important questions when studying established cancer cell lines is whether such cells contain a subpopulation of primitive cancer stem cells that maintains the expansion of the cell line. To address this issue, we performed studies on the established human embryonal carcinoma cell line NTera2 by evaluating the potential stemness of cells sorted according to their expression of the cell surface stem cell markers CD133 and SSEA4. By performing in vitro and in vivo assays, we observed different properties of cells expressing both, one, or neither of these antigens. While sorted SSEA4+ subpopulations exhibited the greatest propensity for migration toward normal serum and the highest seeding efficiency in the lungs of immunodeficient mice, CD133-SSEA4- cells displayed high seeding efficiency to the bone marrow after injection in vivo. It is worth noting that these properties did not depend on the size of the evaluated cells. To address the question of whether cancer stem cell phenotypes in cell lines are fixed or fluctuating, we sorted single cells according to their expression of CD133 and SSEA4 antigens and observed that cells which did not express these cancer stem cell markers gave rise to cells that express these markers after expansion in vitro. Therefore, our results support the idea that within established cancer cell lines, the phenotype of the cell subpopulation expressing cancer stem cell markers is not fixed but fluctuates during cell line expansion, and cells negative for these markers may acquire their expression. PMID- 28624967 TI - Routes and machinery of primary cilium biogenesis. AB - Primary cilia are solitary, microtubule-based protrusions of the cell surface that play fundamental roles as photosensors, mechanosensors and biochemical sensors. Primary cilia dysfunction results in a long list of developmental and degenerative disorders that combine to give rise to a large spectrum of human diseases affecting almost any major body organ. Depending on the cell type, primary ciliogenesis is initiated intracellularly, as in fibroblasts, or at the cell surface, as in renal polarized epithelial cells. In this review, we have focused on the routes of primary ciliogenesis placing particular emphasis on the recently described pathway in renal polarized epithelial cells by which the midbody remnant resulting from a previous cell division event enables the centrosome for initiation of primary cilium assembly. The protein machinery implicated in primary cilium formation in epithelial cells, including the machinery best known for its involvement in establishing cell polarity and polarized membrane trafficking, is also discussed. PMID- 28624970 TI - Cardiovascular implantable electronic devices: a review of the dangers and difficulties in MR scanning and attempts to improve safety. AB - : An increasing number of patients are being treated with cardiovascular implantable electronic devices (CIEDs), many of which are MR conditional. There is a lack of literature on the safe scanning of MR conditional CIEDs. This review article discusses MR imaging safety in patients with implanted CIEDs. Guidelines on safe use and indications of imaging patients with MR conditional CIEDs are described, followed by a pictorial essay of the radiographic features of these devices. We also discuss the challenges of monitoring the patient in the MR environment, advances in MRI conditional imaging of devices, availability, limitations and workflow including vendor-specific and other collaborative efforts to simplify the scanning process. Radiologists must be able to facilitate the safe utilization of MR imaging in patients who have CIEDs. A thorough knowledge of the hazards of imaging non-MR compatible devices is required as well as knowing how to correctly identify and manage the imaging of patients with MR conditional CIEDs. Finally, we propose steps required to facilitate the safe scanning of patients with MR conditional CIEDs adopted in our institution and a contingency plan in the event that an inadvertent MR scan of a patient with a MRI unsafe CIED should occur. MAIN MESSAGES: * Risks of MR imaging in patients who have CIEDs have been worked around. * There are many technical limitations in enabling safe MR scanning of CIEDs. * Radiological identification of MRI conditional status of CIEDs is useful. * Standardizing conditions for safe MRI scanning is important. * We offer example algorithms for facilitating safe MRI scanning of CIEDs. PMID- 28624966 TI - Molecular mechanisms underlying Th1-like Treg generation and function. AB - Since their 're-discovery' more than two decades ago, FOXP3+ regulatory T cells (Tregs) have been an important subject of investigation in the biomedical field and our understanding of the mechanisms that drive their phenotype and function in health and disease has advanced tremendously. During the past few years it has become clear that Tregs are not a terminally differentiated population but show some degree of plasticity, and can, under specific environmental conditions, acquire the phenotype of effector T cells. In particular, recent works have highlighted the acquisition of a Th1-like phenotype by Tregs in several pathological environments. In this review we give an update on the concept of Treg plasticity and the advances in defining the molecular mechanisms that underlie the generation of Th1-like Tregs during an immune response and in different disease settings. PMID- 28624971 TI - ExcelAutomat: a tool for systematic processing of files as applied to quantum chemical calculations. AB - The processing of the input and output files of quantum chemical calculations often necessitates a spreadsheet as a key component of the workflow. Spreadsheet packages with a built-in programming language editor can automate the steps involved and thus provide a direct link between processing files and the spreadsheet. This helps to reduce user-interventions as well as the need to switch between different programs to carry out each step. The ExcelAutomat tool is the implementation of this method in Microsoft Excel (MS Excel) using the default Visual Basic for Application (VBA) programming language. The code in ExcelAutomat was adapted to work with the platform-independent open-source LibreOffice Calc, which also supports VBA. ExcelAutomat provides an interface through the spreadsheet to automate repetitive tasks such as merging input files, splitting, parsing and compiling data from output files, and generation of unique filenames. Selected extracted parameters can be retrieved as variables which can be included in custom codes for a tailored approach. ExcelAutomat works with Gaussian files and is adapted for use with other computational packages including the non-commercial GAMESS. ExcelAutomat is available as a downloadable MS Excel workbook or as a LibreOffice workbook. PMID- 28624972 TI - SBS symptoms in relation to dampness and ventilation in inspected single-family houses in Sweden. AB - PURPOSE: To investigate the relationships between symptoms compatible with the sick building syndrome (SBS) in adults and building dampness and ventilation in single-family houses. METHODS: Within the Swedish BETSI study, a national sample of single-family houses were inspected by professional building experts, and adults living in the houses answered a questionnaire on SBS. Relationships between building factors and SBS were analysed using logistic regression. RESULTS: Of the respondents, 23% reported having had weekly SBS symptoms during the last three months. A large proportion of houses exhibited building or construction problems. In total, 40% of houses had dampness problems in the foundation, and this was related to a higher prevalence of both mucous and dermal symptoms, and any SBS symptoms. Furthermore, high air humidity was related to more symptoms, with the relationship with absolute humidity being stronger than that with relative humidity or moisture load. Symptoms were also more prevalent in houses with a high U value, reflecting a poor thermal insulation. Compared to natural ventilation, living in a house with mechanical supply and exhaust ventilation was related to a lower prevalence of general symptoms and any SBS symptoms, but there were only weak associations between measured air exchange rate and symptoms. CONCLUSIONS: A large proportion of single-family houses have dampness problems in the foundation, and pollutants may enter the living space of the house and affect the health of the occupants. Furthermore, absolute air humidity should be measured more often in indoor air studies. PMID- 28624973 TI - Gracilibacillus aidingensis sp. nov., a novel moderately halophilic bacterium isolated from Aiding salt lake. AB - A novel Gram-positive, aerobe, moderately halophilic bacterium was isolated from saline soil of Aiding lake in Xinjiang, north-west of China, designated strain YIM 98001T. Cells were rod-shaped, motile and grew at 5-20% (w/v) NaCl (optimum 10%), pH 6-10 (optimum pH 7.0) and 4-45 degrees C (optimum 37 degrees C). The major cellular fatty acids were anteiso C15:0, anteiso C17:0, iso C15:0. The predominant respiratory quinone was MK-7. Diphosphatidylglycerol, phosphatidylglycerol, phosphoglycolipid were the major polar lipids. Meso diaminopimelic acid was the diagnostic diamino acid of the cell-wall peptidoglycan. The G+C content was 36.46 mol%. 16S rRNA gene sequence analysis showed that the strain belongs to the family Bacillaceae, with the highest sequence similarity to the type strain Gracilibacillus thailandensis TP2-8T (96.84%), followed by Gracilibacillus saliphilus YIM 91119T (96.78%) and Gracilibacillus ureilyticus MF38T (96.57%), thus confirming the affiliation of strain YIM 98001T to the genus Gracilibacillus. The polyphasic approach indicates that strain YIM 98001T represents a novel species of the genus Gracilibacillus, for which the name Gracilibacillus aidingensis is proposed. The type strain is YIM 98001T (=KCTC 42683T = DSMZ 104330T). PMID- 28624974 TI - Radiological Response to the Locoregional Treatment in Hepatocellular Carcinoma: RECIST, mRECIST, and Others. PMID- 28624975 TI - Deleterious acute and chronic effects of bradycardic right ventricular apex pacing: consequences for arrhythmic outcome. AB - In the chronic complete atrioventricular (AV) block dog (CAVB) model, both bradycardia and altered ventricular activation due to the uncontrolled idioventricular rhythm contribute to ventricular remodeling and the enhanced susceptibility to Torsade de Pointes (TdP) arrhythmias. We investigated the effect of permanent bradycardic right ventricular apex (RVA) pacing on mechanical and electrical remodeling and TdP. In 23 anesthetized dogs, serial experiments were performed at sinus rhythm (SR), acutely after AV block (AAVB) and 3 weeks of remodeling CAVB at a fixed pacing rate of 60/min. ECG, and left (LV) and right ventricular (RV) monophasic action potentials durations (MAPD) were recorded; activation time (AT) and activation recovery interval (ARI) were determined from ten distinct LV electrograms; interventricular mechanical delay (IVMD) and time to-peak strain (TTP) of the LV septal and lateral wall (DeltaTTP: lateral wall minus septal wall) were obtained echocardiographically. Dofetilide (25 MUg/kg/5 min) was infused to study TdP inducibility. In baseline AAVB, in comparison to SR, RVA bradypacing acutely increased QT interval, LV, and RVMAPD. Echocardiographic IVMD and DeltaTTP were initially increased, which was partially corrected after 3 weeks of RVA pacing (IVMD: 22 +/- 13 vs. 42 +/- 11 vs. 31 +/- 6 ms; DeltaTTP: -2 +/- 47 vs. -114 +/- 38 vs. -36 +/- 22 ms). QT interval (362 +/- 23 vs. 373 +/- 29 ms), LVMAPD (245 +/- 18 vs. 253 +/- 22 ms), RVMAPD (226 +/- 26 vs. 238 +/- 31 ms), and mean LV-ARI (268 +/- 5 vs. 267 +/- 6 ms) were not significantly changed after 3 weeks of RVA pacing. During AAVB, dofetilide increased mean LV-ARI (381 +/- 11 ms) with largest increases in the later activated basal areas (slope AT-ARI: +0.96). In contrast with acute RVA pacing, 3 week pacing increased TdP inducibility (0/13 vs. 11/21) and mean LV-ARI (484 +/- 18 ms), while the slope of AT-ARI responded differently on dofetilide (-2.37), with larger APD increases in the early region. The latter was supported at the molecular level: reduced RNA expressions of three repolarization-related ion channel genes in early (KCNQ1, KCNH2, and KCNJ2) versus two in late regions (KNCQ1 and KCNJ2). In conclusion, bradycardic RVA pacing acutely induced LV intra and interventricular mechanical dyssynchrony, which was partially reversed after 3 weeks of pacing (remodeling). The latter occurred without apparent baseline electrical effects. However, dofetilide clearly unmasked (region-specific) arrhythmic consequences of remodeling. PMID- 28624976 TI - Are Concerns About Irremediableness, Vulnerability, or Competence Sufficient to Justify Excluding All Psychiatric Patients from Medical Aid in Dying? AB - Some jurisdictions that have decriminalized assisted dying (like Canada) exclude psychiatric patients on the grounds that their condition cannot be determined to be irremediable, that they are vulnerable and in need of protection, or that they cannot be determined to be competent. We review each of these claims and find that none have been sufficiently well-supported to justify the differential treatment psychiatric patients experience with respect to assisted dying. We find bans on psychiatric patients' access to this service amount to arbitrary discrimination. Proponents of banning the practice ignore or overlook alternatives to their proposal, like an assisted dying regime with additional safeguards. Some authors have further criticized assisted dying for psychiatric patients by highlighting allegedly problematic practices in those countries which allow it. We address recent evidence from the Netherlands, showing that these problems are either misrepresented or have straightforward solutions. Even if one finds such evidence troubling despite our analysis, other jurisdictions need not adopt every feature of the Dutch system. PMID- 28624977 TI - Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes. AB - PURPOSE: We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy. METHODS: This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size >=2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy. RESULTS: Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non aggressive tumors (>=51 vs. 11-25% OR 2.50, 95% CI 1.94-3.22 vs. OR 2.03, 95% CI 1.70-2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41 0.70 vs. OR 0.71, 95% CI 0.59-0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (>=51 vs. 11-25% OR 3.24, 95% CI 1.75-6.00 vs. OR 1.93, 95% CI 1.25-2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21-0.85 vs. OR 0.56, 95% CI 0.35-0.89, p-heterogeneity = 0.01), even though the interaction was not significant. CONCLUSION: Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users. PMID- 28624978 TI - Preferences for breast cancer risk reduction among BRCA1/BRCA2 mutation carriers: a discrete-choice experiment. AB - PURPOSE: Unaffected women who carry BRCA1 or BRCA2 mutations face difficult choices about reducing their breast cancer risk. Understanding their treatment preferences could help us improve patient counseling and inform drug trials. The objective was to explore preferences for various risk-reducing options among women with germline BRCA1/2 mutations using a discrete-choice experiment survey and to compare expressed preferences with actual behaviors. METHODS: A discrete choice experiment survey was designed wherein women choose between hypothetical treatments to reduce breast cancer risk. The hypothetical treatments were characterized by the extent of breast cancer risk reduction, treatment duration, impact on fertility, hormone levels, risk of uterine cancer, and ease and mode of administration. Data were analyzed using a random-parameters logit model. Women were also asked to express their preference between surgical and chemoprevention options and to report on their actual risk-reduction actions. Women aged 25-55 years with germline BRCA1/2 mutations who were unaffected with breast or ovarian cancer were recruited through research registries at five clinics and a patient advocacy group. RESULTS: Between January 2015 and March 2016, 622 women completed the survey. Breast cancer risk reduction was the most important consideration expressed, followed by maintaining fertility. Among the subset of women who wished to have children in future, the ability to maintain fertility was the most important factor, followed by the extent of risk reduction. Many more women said they would take a chemoprevention drug than had actually taken chemoprevention. CONCLUSIONS: Women with BRCA1/2 mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options. PMID- 28624979 TI - New insights into the pathogenesis of IgA nephropathy. AB - IgA nephropathy is the most common form of glomerulonephritis in many parts of the world and remains an important cause of end-stage renal disease. Current evidence suggests that IgA nephropathy is not due to a single pathogenic insult, but rather the result of multiple sequential pathogenic "hits". An abnormally increased level of circulating poorly O-galactosylated IgA1 and the production of O-glycan-specific antibodies leads to the formation of IgA1-containing immune complexes, and their subsequent mesangial deposition results in inflammation and glomerular injury. While this general framework has formed the foundation of our current understanding of the pathogenesis of IgA nephropathy, much work is ongoing to try to precisely define the genetic, epigenetic, immunological, and molecular basis of IgA nephropathy. In particular, the precise origin of poorly O galactosylated IgA1 and the inciting factors for the production of O-glycan specific antibodies continue to be intensely evaluated. The mechanisms responsible for mesangial IgA1 deposition and subsequent renal injury also remain incompletely understood. In this review, we summarize the current understanding of the key steps involved in the pathogenesis of IgA nephropathy. It is hoped that further advances in our understanding of this common glomerulonephritis will lead to novel diagnostic and prognostic biomarkers, and targeted therapies to ameliorate disease progression. PMID- 28624980 TI - Emerging biomarkers of chronic kidney disease in children. AB - Chronic kidney disease (CKD) has become a significant public health concern, as it is associated with substantial morbidity. Prior research has evaluated multiple novel CKD biomarkers to supplement serum creatinine and proteinuria. The ultimate goal of this research is to find biomarkers that can be used to accurately predict CKD progression and to better time outpatient follow-up, and referral for transplant. Also, an optimal panel of biomarkers can augment the predictive value of proteinuria and serum creatinine by enriching patient enrollment in clinical trials. In this review, we discuss salient findings on 12 candidate plasma and urine biomarkers and their reported association with CKD. We explore the common pathways of CKD progression and the pathophysiologic processes of tubulointerstitial injury, inflammation, repair, and fibrosis that are potentially classified by specific biomarkers. We describe both pediatric and adult findings and highlight the paucity of pediatric research in CKD progression. It will be important for cohorts with longitudinal follow-up to evaluate these CKD biomarkers for potential use in pediatric clinical trials and routine CKD management. PMID- 28624981 TI - How best to quantify and express the levels of substances in the urine? PMID- 28624983 TI - How to Increase Vaccination Acceptance Among Apostolic Communities: Quantitative Results from an Assessment in Three Provinces in Zimbabwe. AB - A worldwide increasing trend toward vaccine hesitancy has been reported. Measles outbreaks in southern Africa in 2009-2010 were linked to objections originating from Apostolic gatherings. Founded in Zimbabwe in the 1950s, the Apostolic church has built up a large number of followers with an estimated 3.5 million in Zimbabwe in 2014. To inform planning of interventions for the 2015 measles rubella vaccination campaign, we assessed vaccination status and knowledge, attitudes and practices among purposive samples of Apostolic caregivers in three districts each in Harare City, Manicaland and Matabeleland South in Zimbabwe. We conducted structured interviews among 97 caregivers of children aged 9-59 months and collected vaccination status for 126 children. Main Apostolic affiliations were Johanne Marange (53%), Madida (13%) and Gospel of God (11%) with considerable variation across assessment areas. The assessment also showed considerable variation among Apostolic communities in children ever vaccinated (14-100%) and retention of immunization cards (0-83%) of ever vaccinated. Overall retention of immunization cards (12%) and documented vaccination status by card (fully vaccinated = 6%) were low compared to previously reported measures in the general population. Mothers living in monogamous relationships reported over 90% of all DTP-HepB-Hib-3, measles and up to date immunizations during the first life year documented by immunization card. Results revealed opportunities to educate about immunization during utilization of health services other than vaccinations, desire to receive information about vaccinations from health personnel, and willingness to accept vaccinations when offered outside of regular services. Based on the results of the assessment, specific targeted interventions were implemented during the vaccination campaign, including an increased number of advocacy activities by district authorities. Also, health workers offered ways and timing to vaccinate children that catered to the specific situation of Apostolic caregivers, including flexible service provision after hours and outside of health facilities, meeting locations chosen by caregivers, using mobile phones to set up meeting locations, and documentation of vaccination in health facilities if home-based records posed a risk for caregivers. Coverage survey results indicate that considerable progress has been made since 2010 to increase vaccination acceptability among Apostolic communities in Zimbabwe. Further efforts will be needed to vaccinate all Apostolic children during routine and campaign activities in the country, and the results from our assessment can contribute toward this goal. PMID- 28624984 TI - The SenhanceTM surgical robotic system ("Senhance") for total hysterectomy in obese patients: a pilot study. AB - This pilot study was aimed to value the feasibility and safety of Senhance Robotic Platform for hysterectomy in obese patients. Ten obese patients (30 < BMI < 40) underwent elective Senhance total extrafascial hysterectomy with bilateral salpingo-oophorectomy at the Division of Gynecologic Oncology of "Policlinico A. Gemelli" Foundation, Rome, Italy. Perioperative and postoperative outcomes data were recorded. The median age was 60 years (range 51-75) and the median BMI was 33.3 kg/m2 (range 30.4-38.3). The median uterine weight was 112.5 g (range 77 225). Indication to total hysterectomy was early-stage (FIGO Stage IA) endometrial cancer in 100% of patients. The median operative time (OT) was 110 min (70-200). The median docking time was 10.5 min (5-25). The median estimated blood loss was 100 mL (50-200). No conversions to laparotomy were recorded. No intra- and 30-day postoperative complications were registered. The median ileus was 17 h (12-36) and the median time to discharge was 2 days (1-4). The median VAS scores registered at 2, 4, 12, and 24 h were, respectively, 2 (1-3), 2 (1-3), 4 (1-8), and 3 (1-5). Our study results suggest that Senhance platform could be safe for hysterectomy even in obese patients. More clinical data are needed to determine whether this approach would offer any additional benefits in a new middle line between standard laparoscopy and robotics. PMID- 28624982 TI - Towards ageing well: Use it or lose it: Exercise, epigenetics and cognition. AB - More and more people are living into the 90s or becoming centenarians. But, the gift of increased 'age span' seldom equates with an improved 'health-span'. Governments across the world are expressing concern about the epidemic of chronic disease, and have responded by initiating policies that make prevention, reduction and treatment of chronic disease, a public health priority. But understanding, how to age long and well, with the avoidance of chronic disease and later life complex disease morbidity is challenging. While inherited genes have an undoubted role to play in the chance of maintaining good health or conversely a predilection to developing disease and chronic ill health, there is increasing evidence that behavioural and environmental life-style choices may contribute up to 50% of the variability of human lifespan. Physical exercise is readily available to everyone, and is a simple cheap and effective form of life style intervention. Exercise appears to help maintain good health and to reduce the risk of developing chronic disease and ill health. Evidence suggests that physical activity improves well-being across many health domains through out life, continues to offer important health benefits in older age groups and tracks with a 'healthy ageing' profile. Although many of the molecular pathways remain to be fully identified, here we discuss how physical activity and exercise is understood to produce changes in the human epigenome, which have the potential to enhance cognitive and psychological health, improve muscular fitness, and lead to better ageing with improved quality of life in older age. PMID- 28624986 TI - Temperature-corrected post-mortem 1.5 T MRI quantification of non-pathologic upper abdominal organs. AB - OBJECTIVES: The present study aimed to evaluate if simultaneous temperature corrected T1, T2, and proton density (PD) 1.5 T post-mortem MR quantification [quantitative post-mortem magnetic resonance imaging (QPMMRI)] is feasible for characterizing and discerning non-pathologic upper abdominal organs (liver, spleen, pancreas, kidney) with regard to varying body temperatures. METHODS: QPMMRI was performed on 80 corpses (25 females, 55 males; mean age 56.2 years, SD 17.2) prior to autopsy. Core body temperature was measured during QPMMRI. Quantitative T1, T2, and PD values were measured in the liver, pancreas, spleen, and left kidney and temperature corrected to 37 degrees C. Histologic examinations were conducted on each measured organ to determine non-pathologic organs. Quantitative T1, T2, and PD values of non-pathologic organs were ANOVA tested against values of other non-pathologic organ types. RESULTS: Based on temperature-corrected quantitative T1, T2, and PD values, ANOVA testing verified significant differences between the non-pathologic liver, spleen, pancreas, and left kidneys. CONCLUSIONS: Temperature-corrected 1.5 T QPMMRI based on T1, T2, and PD values may be feasible for characterization and differentiation of the non pathologic liver, spleen, pancreas, and kidney. The results may provide a base for future specific pathology diagnosis of upper abdominal organs in post-mortem imaging. PMID- 28624985 TI - DUSP1 and KCNJ2 mRNA upregulation can serve as a biomarker of mechanical asphyxia induced death in cardiac tissue. AB - The incidence of death by asphyxia is second to the incidence of death by mechanical injury; however, death by mechanical asphyxia may be difficult to prove in court, particularly in cases in which corpses do not exhibit obvious signs of asphyxia. To identify a credible biomarker of asphyxia, we first examined the expression levels of 47,000 mRNAs in human cardiac tissue specimens from individuals who died of mechanical asphyxia and compared the expression levels with the levels of the corresponding mRNAs in specimens from individuals who died of craniocerebral injury using microarray. We selected 119 differentially expressed mRNAs, examined the expression levels of these mRNAs in 44 human cardiac tissue specimens of individuals who died of mechanical asphyxia, craniocerebral injury, hemorrhagic shock, or other causes. That the expression of dual-specificity phosphatase 1 (DUSP1) and potassium voltage-gated channel subfamily J member 2 (KCNJ2) was upregulated in human cardiac tissues from the mechanical asphyxia group compared with control tissues, regardless of age, environmental temperature, and postmortem interval (PMI), indicating that DUSP1 and KCNJ2 may be associated with mechanical asphyxia-induced death and can thus serve as useful biomarkers of death by mechanical asphyxia. PMID- 28624987 TI - Congenital cytomegalovirus infection in Central Germany: an underestimated risk. AB - PURPOSE: This is the first study to determine the cytomegalovirus (CMV) seronegativity rate for women of childbearing age in Saxony-Anhalt and to determine the prevalence of clinically relevant congenital CMV (cCMV) infection in Central Germany, because there are no valid data available. METHODS: The retrospective study was undertaken between January 2005 and December 2015. For the first time in Germany, the following seven data sources were used to analyze the prevalence of clinically relevant cCMV infection and the rate of CMV seronegative women of childbearing age: CMV Screening in maternity unit, University Women's Hospital, Social Paediatrics Centre (SPC), Malformation Monitoring Centre (MMC), Newborn Hearing Screening (NHS), Neonatal Intensive Care Unit (NICU), and In-house Doctor Department. Key parameters were anti-CMV IgG and IgM, CMV PCR of urine, and clinically relevant symptoms caused by CMV. RESULTS: Between 46 and 52% of women of childbearing age were CMV seronegative. The prevalence of clinically relevant cCMV infection was between 0.008 and 0.04%. CONCLUSIONS: The CMV seronegativity rate of women of childbearing age was confirmed to be in the middle range of estimated data from other sources in Germany. Data from the NICU, SPC, NHS, and MMC show the prevalence of clinically relevant cCMV infection. The risk of all cCMV infections is underestimated. Thus, the true prevalence of clinically relevant and subclinical cCMV infections is >0.04%. PMID- 28624988 TI - Mifepristone vs balloon catheter for labor induction in previous cesarean: a randomized controlled trial. AB - OBJECTIVE: To compare oral mifepristone (400 mg) with trans-cervical balloon catheter for induction of labor (IOL) in post date women with previous one cesarean section (CS). METHODS: In this randomized trial, post date pregnant women (gestation 40 weeks 5 days), with previous one low segment CS (no previous vaginal delivery) were induced either with oral mifepristone (400 mg) or balloon catheter [Foley's catheter (16 Fr); bulb filled with 30 ml normal saline]. They were re-assessed 24 and 48 h later. If at any time Bishop Score was >6; amniotomy was done, followed by oxytocin infusion. Primary outcome of the study was labor onset after first manoeuvre. Secondary outcomes were cervical ripening, need of oxytocin, vaginal delivery and CS, in two groups. RESULTS: From June 2012 to September 2015, we enrolled 107 women. Out of these, 57 received oral tablet mifepristone (400 mg) and 50 were inserted with balloon catheter. Labor onset after first manoeuvre was statistically significantly more in mifepristone group (37/57 vs. 13/50, respectively; p value 0.000). Bishop Score after 24 h was better in balloon catheter (p value 0.000). More women with balloon catheter required oxytocin for IOL (37/50 vs. 20/57, respectively; p value 0.000) along with higher dose [840 (320) mU vs 560 (120) mU, respectively, p value 0.000]. Failure of induction was statistically significantly higher in balloon catheter group (8 out of 50 vs. 2 out of 57, respectively, p value 0.043). There was no statistically significant difference in normal delivery or CS in either group (p value 0.242 and 0.331, respectively). CONCLUSION: Oral mifepristone (400 mg) is associated with statistically significantly higher incidence of labor onset in post date pregnant women with previous one CS, as compared to balloon catheter. Both methods are primarily for cervical ripening and oxytocin should not be delayed in the absence of onset of labor. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry-India, www.ctri.nic.in , CTRI/2012/05/003634. PMID- 28624990 TI - Nutrition Literacy among Cancer Survivors: Feasibility Results from the Healthy Eating and Living Against Breast Cancer (HEAL-BCa) Study: a Pilot Randomized Controlled Trial. AB - Knowledge of nutrition among breast cancer patients is insufficient, despite their motivation to seek valid information about healthy food choices. This study examines the feasibility of nutrition education workshops for cancer survivors, to inform the design of a multi-center intervention. Fifty-nine female English speaking breast cancer patients, who had completed treatment, were enrolled. Participants were randomized to the intervention or control group. The intervention group attended six nutrition education sessions, and the control group received brochures. Measurements were done at baseline and 3-month follow up and included the Assessment Instrument for Breast Cancer (NLit-BCa), fruit/vegetable and general health literacy screeners. Height and weight were measured. Changes in nutrition literacy, health literacy, and food intake from baseline to follow-up (within-group change) were calculated for both groups (effect sizes were reported as Cohen's d). Participants were mostly white, with a mean age of 58 years, BMI of 31.6 kg/m2, and had college degrees. Follow-up rates were high (89% = control and 77% = intervention group). At baseline, participants scored high for most NLit-BCa assessment components except food portions in both groups. At the 3-month follow-up, effect sizes (d) on the NLit-BCa ranged from 0.5 to 0.16. The study met its recruitment goals within 6 months. Focus groups indicated that (a) attending six sessions was acceptable, (b) patients found social/emotional support, (c) improvements should include information for special diets and booster sessions. This pilot study suggests that the intervention was acceptable and that scaling up of this intervention is feasible and could provide benefit to breast cancer survivors. PMID- 28624989 TI - Ponderal index at birth associates with later risk of gestational diabetes mellitus. AB - PURPOSE: Low birth weight (BW) and low ponderal index (PI) are associated with increased risk of type 2 diabetes mellitus. This study has two purposes: first to investigate the influence of PI on the risk of gestational diabetes mellitus (GDM); second, to study the association between glucose metabolism and BW in women with previous GDM. METHODS: GDM cohort: 185 women with GDM in 1978-1996, attending a follow-up study in 2000-2002. Control cohort: 1137 women from a population-based diabetes screening study (Inter99) in a neighbouring county in 1999-2001. BW and birth length were collected from the original midwifery records. BW and PI were stratified into tertiles for analysis. RESULTS: PI in the lower tertiles was associated with an increased risk of GDM [odds ratio 1.59 (95% confidence interval 1.07-2.36, p = 0.021)]. Among women with previous GDM, the area under the curve (AUC) for plasma levels of glucose and insulin during an OGTT was highest for the lower tertiles of BW (for AUCglucose p = 0.048, for AUCinsulin p = 0.047 adjusted for age and BMI). CONCLUSIONS: Lower PI is associated with increased risk of GDM. In women with previous GDM, lower BW is associated with a more severe impairment of glucose metabolism one to two decades after the pregnancy complicated by GDM. PMID- 28624991 TI - A new global and comprehensive model for ICU ventilator performances evaluation. AB - BACKGROUND: This study aimed to provide a new global and comprehensive evaluation of recent ICU ventilators taking into account both technical performances and ergonomics. METHODS: Six recent ICU ventilators were evaluated. Technical performances were assessed under two FIO2 levels (100%, 50%), three respiratory mechanics combinations (Normal: compliance [C] = 70 mL cmH2O-1/resistance [R] = 5 cmH2O L-1 s-1; Restrictive: C = 30/R = 10; Obstructive: C = 120/R = 20), four exponential levels of leaks (from 0 to 12.5 L min-1) and three levels of inspiratory effort (P0.1 = 2, 4 and 8 cmH2O), using an automated test lung. Ergonomics were evaluated by 20 ICU physicians using a global and comprehensive model involving physiological response to stress measurements (heart rate, respiratory rate, tidal volume variability and eye tracking), psycho-cognitive scales (SUS and NASA-TLX) and objective tasks completion. RESULTS: Few differences in terms of technical performance were observed between devices. Non invasive ventilation modes had a huge influence on asynchrony occurrence. Using our global model, either objective tasks completion, psycho-cognitive scales and/or physiological measurements were able to depict significant differences in terms of devices' usability. The level of failure that was observed with some devices depicted the lack of adaptation of device's development to end users' requests. CONCLUSIONS: Despite similar technical performance, some ICU ventilators exhibit low ergonomics performance and a high risk of misusage. PMID- 28624992 TI - Compression therapy after ankle fracture surgery: a systematic review. AB - PURPOSE: The main purpose of this systematic review was to investigate the effect of compression treatment on the perioperative course of ankle fractures and describe its effect on edema, pain, ankle joint mobility, wound healing complication, length of stay (LOS) and time to surgery (TTS). The aim was to suggest a recommendation to clinicians considering implementing compression therapy in the standard care of the ankle fracture patient, based on the existing literature. METHODS: We conducted a systematic search of literature including studies concerning adult patients with unstable ankle fractures undergoing surgery, testing either intermittent pneumatic compression, compression bandage and/or compression stocking and reporting its effect on edema, pain, ankle joint mobility, wound healing complication, LOS and TTS. To conclude on data a narrative synthesis was performed. RESULTS: The review included eight studies (451 patients). Seven studies found a significant effect on edema, two studies described a significant reduction in pain, one a positive effect on ankle movement, two a positive effect on wound healing, one a reduction in LOS and finally two studies reported reduction in TTS. A systematic bias assessment showed that the included studies had methodological limitations influencing the confidence in the effect estimate. CONCLUSIONS: Compression therapy has a beneficial effect on edema reduction and probably a positive effect on pain and ankle joint mobility, but with the methodological limitations in the included studies it is not possible to make a solid conclusion on the effect on wound healing, LOS and TTS. PMID- 28624994 TI - Expression of ezrin and moesin in primary breast carcinoma and matched lymph node metastases. AB - Ezrin, radixin, moesin (ERM) are important membrane-cytoskeletal crosslinkers and are suggested to play important role in cancer progression and metastasis. Even though ERM proteins were generally considered to be functionally redundant and the most studied was ezrin, recent studies highlight their distinct roles in metastatic process. Little information is available regarding the role of individual ERM proteins and their phosphorylated forms in human breast cancer. Our study is the first to examine expression of ezrin, moesin and their phosphorylated forms in primary breast tumors and matched lymph node metastases (LNMs) and their correlation with clinicopathological variables. A total of 88 primary breast cancer, 91 LNMs, 54 intraductal carcinoma and 26 normal adjacent breast tissue samples from tissue microarrays were studied. Expression was determined by immunohistochemistry, the intensity and number of positive cells was scored. Statistical analysis of protein expression and patients' age, tumor grade and hormonal status was performed. No statistical significant difference was found in ezrin, moesin, p-ezrinTyr353 and pan-p ezrinThr567/radixinThr564/moesinThr558 expression between primary tumors and LNMs. Even though it was not significant, moesin expression varied between primary tumors, intraductal carcinoma, normal breast adjacent tissue and LNMs. A significant positive correlation between moesin and tumor grade has been proven. Even though primary tumors and matched LNMs did not show different expression patterns, moesin correlated significantly with higher tumor grade. Its positivity in intraductal carcinoma and normal breast tissue adjacent to cancer might indicate its role in tumor intiation/progression. PMID- 28624995 TI - How does it feel to be a pathology resident? Results of a survey on experiences and job satisfaction during pathology residency. AB - Residents' career choices and professional motivation can be affected from perception of their role and recognition within a medical team as well as their educational and workplace experiences. To evaluate pathology trainees' perceptions of their pathology residency, we conducted a 42-item survey via a web based link questioning respondents' personal and institutional background, workplace, training conditions, and job satisfaction level. For the 208 residents from different European countries who responded, personal expectations in terms of quality of life (53%) and scientific excitement (52%) were the most common reasons why they chose and enjoy pathology. Sixty-six percent were satisfied about their relationship with other people working in their department, although excessive time spent on gross examination appeared less satisfactory. A set residency training program (core curriculum), a set annual scientific curriculum, and a residency program director existed in the program of 58, 60, and 69% respondents, respectively. Most respondents (76%) considered that pathologists have a direct and high impact on patient management, but only 32% agreed that pathologists cooperate with clinicians/surgeons adequately. Most (95%) found that patients barely know what pathologists do. Only 22% considered pathology and pathologists to be adequately positioned in their country's health care system. Almost 84% were happy to have chosen pathology, describing it as "puzzle solving," "a different fascinating world," and "challenging while being crucial for patient management." More than two thirds (72%) considered pathology and pathologists to face a bright future. However, a noticeable number of respondents commented on the need for better physical working conditions, a better organized training program, more interaction with experienced pathologists, and deeper knowledge on molecular pathology. PMID- 28624993 TI - Cancer stem cell marker glycosylation: Nature, function and significance. AB - Glycans are essential for the maintenance of normal biological function, with alterations in glycan expression being a hallmark of cancer. Cancer stem cells (CSCs) are a subset of cells within a tumour capable of self-renewal, cellular differentiation and resistances to conventional therapies. As is the case with stem cells, marker proteins present on the cell surface are frequently used to identify and enrich CSCs, with the expression of these markers statistical correlating with the likelihood of cancer recurrence and overall patient survival. As such CSC markers are of high clinical relevance. The majority of markers currently used to identify CSC populations are glycoproteins, and although the diverse biological roles for many of these markers are known, the nature and function of the glycan moiety on these glycoproteins remains to be fully elucidated. This mini-review summarises our current knowledge regarding the types and extent of CSC marker glycosylation, and the various roles that these glycans play in CSC biology, including in mediating cell adhesion, metastasis, evading apoptosis, tear shear resistance, tumour growth, maintaining pluripotency, self-renewal, trafficking, maintaining stability, maintaining enzymatic activity and aiding epithelial mesenchymal transitioning. Given that CSCs markers have multiple diverse biological functions, and are potentially of significant diagnostic and therapeutic benefit the search for new markers that are uniquely expressed on CSCs is vital to selectively target/identify this subset of cancer cells. As such we have also outlined how high-throughput lectin microarrays can be used to successfully profile the glycosylation status of CSC and to identify glyco-markers unique to CSCs. PMID- 28624996 TI - Exploring the Bioelectrochemical Characteristics of Activated Sludge Using Cyclic Voltammetry. AB - Due to the potential interest, bioelectrochemical responses of activated sludge using the three-electrode system are tested. From the cyclic voltammograms, the oxidation current output is increasing due to incubation time increase, whereas 5, 25 and 39.33 MUA are obtained after 3, 72 and 96 h, respectively. Changing the working electrode from glassy carbon to carbon paste led to the increase in the electrochemical signal from 0.3 to be 3.72 MUA. On the other hand, the use of the lipophilic redox mediator (2,6-dichlorophenolindophenol (DCIP)) amplified the oxidation current to reach 19.9 MUA instead of 2.1 MUA. Based on these findings, the mixed microbial community of the activated sludge is exploited as a catalyst for the bio-oxidation of the degradable organic substrates, while DCIP is used as a mobile electron carrier from the intracellular matrix of the metabolically active cells to the carbon paste electrode which served as the final electron acceptor. Therefore, the extracellular electron transfer from the formed active biofilm at the electrode surface is assisted by the existence of DCIP. PMID- 28624997 TI - Expression and Purification of Cytochrome P450 55B1 from Chlamydomonas reinhardtii and Its Application in Nitric Oxide Biosensing. AB - Cytochrome P450 55B1 from Chlamydomonas reinhardtii is reported to function as a nitric oxide reductase (NOR). Here, we expressed the cytochrome P450 55B1 gene with an HIS-tag in E scherichia coli using a pET28a vector. The native protein was produced at a level of 1.59 MUmol/g of total protein, with approximately 85% of the P450 being soluble. The CYP55B1 protein was characterized spectrally and purified by a HIS-trap column. This procedure allowed recovery of 45% of the expressed protein and CYP55B1 with a specific content of 0.70 MUmol/g of the total protein, which showed a single band on a SDS-PAGE and Western blot. The direct electrochemistry of CYP55B1 in dihexadecylphosphate (DHP) film was realized with an electric potential at -0.47 V at the scan rate of 1 V s-1. We studied the in vitro interaction between P450 55B1 and NO by the fluorescence spectrometric method. The results show that the fluorescence intensity of iron porphyrin in P450 55B1 changes gradually with the addition of NO. The fluorescence intensity change values against NO concentrations were plotted, and it showed a linear range of NO from 0 to 22.5 MUM with a sensitivity of 0.15 MUM/AU and a detection limit of 0.15 MUM. PMID- 28624998 TI - Efficient Conversion of Fructose-Based Biomass into Lipids with Trichosporon fermentans Under Phosphate-Limited Conditions. AB - Limiting nitrogen supply has been routinely used as the master regulator to direct lipid biosynthesis. However, this strategy does not work with nitrogen rich substrates, such as Jerusalem artichoke (JA), a fructose-based biomass, while it is difficult to obtain a high carbon-to-nitrogen (C/N) molar ratio. In this study, an alternative strategy to promote lipid accumulation by the oleaginous yeast Trichosporon fermentans CICC 1368 was developed by limiting phosphorous supply, and this strategy was implemented with JA hydrolysate as substrate. We showed that lipid accumulation was directly correlated with the C/P ratio of the culture media for T. fermentans. The time course of cell growth and lipid production was analyzed in a media with an initial C/P ratio of 6342, and the cellular lipid content could reach up to 48.5% of dry biomass. Moreover, JA hydrolysates were used as substrate for microbial lipid accumulation, under high C/P molar ratio condition, lipid yield, lipid content, and lipid coefficient increased by 10, 30, and 34%, respectively. It showed that by limiting phosphorus, the conversion of sugar into lipids can be improved effectively. Limiting phosphorus provides a promising solution to the problem of microbial lipid production with nitrogen-rich natural materials. PMID- 28625000 TI - Mechanical restraint in an emergency department: a consecutive series of 593 cases. AB - The objective is to describe the characteristics of mechanically restrained patients in the emergency department (ED) of a university hospital and to evaluate the quality of restraint documentation that was filled out according to the dedicated protocol with respect to the law on restraint. All adult patients (>=16 years) who were admitted to the ED from January 2009 to December 2010 and were mechanically restrained were included. We assessed medical and demographic characteristics, the completeness of the dedicated protocol, and the concomitant use of chemical sedation. 72,844 patients were admitted to the ED. Of these, 593 (0.81%) were mechanically restrained. Two types of patients were restrained: young patients under the influence of psychoactive substances who were usually discharged home, and confused older patients who were hospitalized. 186 dedicated protocols were missing (31.4%). From the 407 filled-out protocols, only 119 (29.2%) were complete. Of the mechanically restrained patients, 215 (36.2%) received additional chemical sedation. Even though restraint is strictly regulated by law, many protocols justifying the privation of liberty were not filled out. This emphasizes the need for strict respect of the dedicated protocol and the use of guidelines and training sessions for nursing and medical staff that address specific procedures for the two categories of patients needing to be restrained. PMID- 28624999 TI - In Vitro Biotransformation, Safety, and Chemopreventive Action of Novel 8-Methoxy Purine-2,6-Dione Derivatives. AB - Metabolic stability, mutagenicity, antimutagenicity, and the ability to scavenge free radicals of four novel 8-methoxy-purine-2,6-dione derivatives (compounds 1 4) demonstrating analgesic and anti-inflammatory properties were determined. Metabolic stability was evaluated in Cunninghamella and microsomal models, mutagenic and antimutagenic properties were assessed using the Ames and the Vibrio harveyi tests, and free radical scavenging activity was evaluated with 2,2 diphenyl-1-picrylhydrazyl radical scavenging assay. In the Cunninghamella model, compound 2 did not undergo any biotransformation; whereas 3 and 4 showed less metabolic stability: 1-9 and 53-88% of the parental compound, respectively, underwent biotransformation reactions in different Cunninghamella strains. The metabolites detected after the biotransformation of 3 and 4 were aromatic hydroxylation and N-dealkylation products. On the other hand, the N-dealkylation product was the only metabolite formed in microsome assay. Additionally, these derivatives do not possess mutagenic potential in microbiological models (Vibrio harveyi and Salmonella typhimurium) considered. Moreover, all compounds showed a strong chemopreventive activity in the modified Vibrio harveyi strains BB7X and BB7M. However, radical scavenging activity was not the mechanism which explained the observed chemopreventive activity. PMID- 28625001 TI - Nanostructured SBA-15 host applied in ketorolac tromethamine release system. AB - The ordered mesoporous silica SBA-15 has been applied in studies of ketorolac tromethamine adsorption and release. The SBA-15 materials with hexagonal and regular structure were obtained using a triblock copolymer Pluronic P123 as a template and TEOS as a silica source. Ketorolac tromethamine was adsorbed into SBA-15 silica nanochannels using ethanol as solvent. The physicochemical and textural properties of SBA-15 and ketorolac tromethamine/SBA-15 were characterized by X-ray diffraction, thermogravimetric analysis, transmission electron microscopy, fourier transform infrared spectroscopy and BET surface studies. Drug release was evaluated by soaking the loaded silica mesoporous material into a solution of HCl (0.1 N) at initial time (0-2 h) and buffer pH 7 at high times at 37 degrees C under continuous stirring. Oral commercial Keto tablets (Dolten(r)) and Keto solution (Keto power) were study for the contrast. Release studies were performed in order to evaluate the required therapeutic efficacy. SBA-15 provides significant improvement in the controlled release of ketorolac tromethamine. Release profile of KETO from SBA-15/KETO and control releases. PMID- 28625003 TI - When Science is Not Enough: A Framework Towards More Customer-Focused Drug Development. AB - INTRODUCTION: The purpose of this study was to identify the key barriers to a customer-focused drug development process and develop a comprehensive framework to overcome them. METHODS: The paper draws on existing literature, both academic and practitioner, across a range of disciplines (innovation management, marketing, organizational behavior, behavioral economics, health economics, industry reports). On the basis of this extensive review, a conceptual framework is developed that offers concrete suggestions on how organizations can overcome the barriers and enable a more customer-focused development process. RESULTS: The barriers to collaboration are organized into three distinct categories (economic, behavioral, organizational), and within each category, a one-to-one mapping between barriers and solutions is developed. CONCLUSION: The framework is specifically designed with the objective of offering actionable and practical advice to executives who face these challenges in their organizations. The paper provides a unique theoretical contribution by synthesizing findings from several academic disciplines with concrete examples from the pharmaceutical industry. FUNDING: Mundipharma International Limited. PMID- 28625002 TI - Changes in Dietary Intake and Eating Behavior in Adolescents After Bariatric Surgery: an Ancillary Study to the Teen-LABS Consortium. AB - BACKGROUND: A growing number of studies suggest that bariatric surgery is safe and effective for adolescents with severe obesity. However, surprisingly little is known about changes in dietary intake and eating behavior of adolescents who undergo bariatric surgery. OBJECTIVE: Investigate changes in dietary intake and eating behavior of adolescents with obesity who underwent bariatric surgery (n = 119) or lifestyle modification (LM) (n = 169). SETTING: University-based health systems METHODS: A prospective investigation of 288 participants (219 female and 69 male) prior to bariatric surgery or LM and again 6, 12, and 24 months (surgery patients only) after treatment. Measures included changes in weight, macronutrient intake, eating behavior, and relevant demographic and physiological variables. RESULTS: Adolescents who underwent bariatric surgery experienced significantly greater weight loss than those who received LM. The two groups differed in self-reported intake of a number of macronutrients at 6 and 12 months from baseline, but not total caloric intake. Patients treated with surgery, compared to those treated with LM, also reported significantly greater reductions in a number of disordered eating symptoms. After bariatric surgery, greater weight loss from postoperative month 6 to 12 was associated with self-reported weight consciousness, craving for sweets, and consumption of zinc. CONCLUSIONS: Adolescents who underwent bariatric surgery, compared to those who received LM, reported significantly greater reductions in weight after 1 year. They also reported greater reductions in disordered eating symptoms. These findings provide new information on changes in dietary intake and eating behavior among adolescents who undergo bariatric surgery. PMID- 28625004 TI - Distribution-Weighted Cost-Effectiveness Analysis Using Lifetime Health Loss. AB - BACKGROUND: It is widely acknowledged that concerns for the worse off need to be integrated with the concern for cost effectiveness in priority setting, and several countries are seeking to do so. In Norway, a comprehensive framework for priority setting was recently proposed to specify the worse off in terms of lifetime loss of quality-adjusted life-years (QALYs). However, few studies have shown how to calculate such health losses, how to integrate health loss into cost effectiveness analyses (CEAs) and how such integration impacts the incremental cost-effectiveness ratios (ICERs). The aim of this study was to do so. METHODS: The proposed framework was applied to data from 15 recent economic evaluations of drugs. Available data were used to calculate the lifetime health loss of the target groups, and the proposed marginal weighting function was employed to adjust standard ICERs according to the size of this loss. Standard and weighted ICERs were compared to a threshold of US$35,000 per QALY gained. RESULTS: Lifetime health loss can be calculated with the use of available data and integrated by a marginal weighting function with CEAs. Such integration affected standard ICERs to a varying degree and changed the number of interventions considered cost effective from three to eight. CONCLUSION: Calculation of lifetime health loss and its integration with CEA is feasible and can influence the reimbursement and ranking of interventions. To facilitate regular integration, guidelines for economic evaluations could require (i) adjustment according to distributional concerns and (ii) that data on health loss are extracted directly from the models and reported. Generic databases on health loss could be developed alongside such efforts. PMID- 28625005 TI - Dose dense MVAC prior to radical cystectomy: a real-world experience. AB - PURPOSE: Our primary endpoint was to assess pathological response rate (pT0N0 and <=pT1N0) for patients with BCa treated with the accelerated or dose dense MVAC (ddMVAC) chemotherapy followed by radical cystectomy (RC) in this real-word multi institutional cohort. MATERIALS AND METHODS: We retrospectively reviewed records of patients with urothelial cancer who underwent ddMVAC and RC at seven contributing institutions from 2000 to 2015. Patients with cT2-4a, M0 BCa were included. Presence of cT3-4 disease, hydronephrosis, lymphovascular invasion and/or existence of sarcomatoid, or micropapillary features on the initial transurethral resection of bladder tumor specimen was defined as high-risk disease. Logistic regression models for prediction of pT0N0 and <=pT1N0 were generated for the entire cohort as well as for the cN0 subgroup. The multivariable Cox proportional hazards regression model for survival using post RC data was used to assess hazard ratios (HRs) for the variables of interest. RESULTS: A total of 345 patients received ddMVAC chemotherapy during the study period; 85% had high-risk features. The median number of chemotherapy cycles was 4 (IQR 4-4); >90% of patients completed all scheduled cycles. The observed rates of pT0N0 and <=pT1N0 were 30.4 and 49.3%, respectively, among cN0 patients. On the multivariable regression model, the presence of more than one clinical high risk element was associated with 70% [OR 0.30 95% CI (0.10-0.86); p = 0.02] reduction in the odds of achieving partial pathological response. CONCLUSIONS: A complete response (pT0N0) was observed in one-third of patients after neoadjuvant ddMVAC therapy, and a partial response (<=pT1N0) was observed in nearly half of the cases in this real-world experience with this regimen. To our knowledge, this represents the largest experience outside clinical trial settings. PMID- 28625006 TI - Butterfly cartilage tympanoplasty: an alternative new technique instead of conventional surgery method. AB - Butterfly graft inlay tympanoplasty is a well-established technique for the repair of small- and medium-sized perforations. There are some difficulties with application of conventional butterfly technique and it affects our success rate of graft healing. With some modifications of graft preparation we can make better success rates. The aim of this study was to present the new renovation of conventional method, describe about what kind of changes we made and its technical facilities about the procedure. The study design is a prospective case series. This study was carried out on 18 patients who underwent inlay butterfly cartilage tympanoplasty with the new technique for anterior and inferior perforations at an otolaryngology department of a tertiary medical center between November 2015 and August 2016. Patients were followed with otoscopy and audiometry, and graft healing's success. Anatomic closure at 6th month after tympanoplasty was found in all 18 patients. There was no incidence of cartilage graft rejection or displacement. Preoperative mean PTA was 27.7 dB, which improved 6 months after surgery to 10.5 dB (the average value of hearing thresholds at 0.5, 1, 2 and 4 kHz). Butterfly cartilage tympanoplasty technique is safe and efficient in terms of both anatomical closure of the defect and improvement in hearing. We believe with this new technique, we facilitate this procedure in addition to the improvement of patients' comfort and decrease the morbidity of the procedure. PMID- 28625007 TI - The role of insulin-like growth factor I-II receptor on development of pleomorphic adenoma. AB - Pleomorphic adenoma is a slow-growing salivary gland tumor frequently arising from the parotid gland. In this study, we investigated the role of the insulin like growth factor I-II receptor (IGFI-IIR) levels on the development of parotid gland pleomorphic adenomas. The study included 20 males and 20 females who had superficial parotidectomy with a histopathological diagnosis of pleomorphic adenoma in Firat University Otorhinolaryngology Clinic between 2000 and 2011. The ages of the patients ranged between 20 and 50 years. The control tissues were obtained unilaterally from the parotid glands of five female and five male cadavers during autopsy, and consisted of 0.5 * 0.5 cm sized normal parotid gland tissues. The expression of IGFI-IIR were measured in both tumor and tumor-free normal parotid tissue in the study group while only the normal parotid tissues were studied in the cadavers. Primary polyclonal antibodies against IGFI-IIR were used with "Streptavidin-Biotin Complex" method for immunohistochemical staining of both the study and the control groups' tissue sections. In this study, the IGFI-IIR levels were found significantly higher in the pleomorphic adenoma tissue (p < 0.05). In addition, IGFI-IIR expression was greater in normal parotid tissues of the study group when compared to the normal parotid tissues of the cadavers. However, the difference was not statistically significant (p > 0.017). Greater expression for IGFI-IIR in pleomorphic adenoma when compared to normal parotid tissues of the patients and the cadavers suggests that IGFI-II may be important factors in the development of pleomorphic adenoma. PMID- 28625008 TI - The role of local allergy in the nasal inflammation. AB - Local allergic inflammation (LAI) is recognized recently. 'entopy' was used to define LAI, which was positively correlated with allergen provocation testing, local sIgE up-regulation, inflammatory mediator secretion, and a lack of systemic allergy. The study of LAI is in its infancy and focuses mainly on the respiratory system. It is closely related to nasal inflammation and plays important roles in patients with nonallergic rhinitis (NAR), nonallergic chronic sinusitis with nasal polyps (CRSwNP), and nonallergic fungal rhinosinusitis (NAFRS). Based on studies using nasal allergen provocation testing, 40-57% of patients with NAR exhibited positive results and could be diagnosed as local allergic rhinitis. Total IgE and common airborne allergen-sIgE were up-regulated in eosinophilic CRSwNP patients compared to noneosinophilic CRSwNP patients and healthy controls, possibly due to local allergic inflammation. Some researchers also found that the level of local sIgE was increased in patients with NAFRS; they suggested that local allergic inflammation occurs in NAFRS. Studies of LAI will increase our understanding of nasal inflammation and help to establish novel treatments. However, the diagnosis of local allergic inflammation is complex due to the lack of convenient detection methods. The relationship between local allergic inflammation and systemic allergic inflammation is unclear, and an appropriate treatment for local allergic inflammation is required. PMID- 28625009 TI - Modifications in the treatment of advanced laryngeal cancer throughout the last 30 years. AB - In the last decades, the treatment schemes for patients with locally advanced laryngeal cancer have changed significantly. These changes may have an impact in the survival of these patients. Our objective is to review the treatments administered to patients with locally advanced larynx tumors during a period of 30 years in our institution and to evaluate the prognostic impact of the changes in treatment protocols. Retrospective analysis of a cohort of 830 consecutive patients with T3 or T4 laryngeal carcinomas diagnosed and treated between 1985 and 2014 with a minimum follow-up of 1.5 years. During the study period, we witnessed a reduction in surgery as the initial treatment, as well as a substitution of induction chemotherapy by chemoradiotherapy as an organ preservation strategy. For patients with T3 tumors, there were no differences in cancer-specific survival by type of treatment, while patients with T4 tumors treated surgically showed significantly better survival than those treated with preservation strategies. Patients treated in the last decade (2005-2014) showed worse cancer-specific survival than those treated in the previous decade (1995 2004). The multivariate analysis showed significant differences in cancer specific survival for larger tumors, positive nodal extension, and treatment with radiotherapy alone. The main changes in the management of advanced laryngeal carcinomas are the implementation of organ preservation strategies that reduce the use of surgery and the progressive of chemoradiotherapy as a standard treatment. These changes may have had a negative impact in survival of these patients. PMID- 28625010 TI - Treatment of tongue base masses in children by transoral robotic surgery. AB - The feasibility and effectiveness of transoral robotic surgery (TORS) in children with tongue base masses (TBMs) were evaluated. Eight pediatric patients who were treated with TORS for TBMs between January 2010 and January 2016 at a tertiary hospital included in the study. All pathologies were congenital lesions: four were lingual thyroglossal ductus cysts (LTGDCs), one was a minor salivary gland tumor, one was a vallecular cyst, one was a bronchogenic cyst, and one was an ectopic thyroid tissue. TORS was performed successfully in all cases. The mean robotic set-up and exposure time was 13.0 +/- 2.1 min (range 10-16 min) and the mean robotic surgery time was 8.8 +/- 6.9 min (range 4-25 min). Estimated blood loss was lower than 5 ml for one patient and lower than 50 ml for another one. The remaining patients' estimated blood loss was lower than 10 ml. No patient required tracheostomy intra- or post-operatively. Only one minor complication occurred on day 10 after surgery (minor bleeding), which was resolved without intervention. No major complications or recurrence were observed. Better visualization and small, flexible arms allow surgeons to treat TBM faster and easily using TORS. This leads to decreased morbidity compared to open and transoral endoscopic/microscopic surgical methods. In the future, we believe that TORS may become the gold standard method for the treatment of pediatric TBM with continued development of robotic technology. PMID- 28625011 TI - Liver epithelioid progenitor cells derived from fetal Luxi bovine alleviate liver fibrosis. AB - Liver epithelioid progenitor cells (LEPCs) have important roles in liver therapy because of their hepatic differentiation potency in vitro and in vivo. Despite many researches on humans, mice, and rats, equivalent progenitor cells derived from bovine are relatively rare. The purpose of our current study is to characterize bovine LEPCs, and research on the cure potency of this heteroplastic progenitor cells on mice liver fibrosis. We have used collagenase IV digesting and differential adhesion method to isolate slabstone shape, EpCAM, LGR5, NCAM1 and SOX9 positive progenitor cells from fetal Luxi bovine liver. When cultured in hepatic differentiation media containing 20 ng/ml Oncostatin M, LEPCs can differentiate into hepatocytes in vitro. After 4 weeks of intravenous tail vein injection into CCl4-injured mouse liver, LEPCs engrafted into liver parenchyma, differentiated into ALB positive hepatocytes, and could alleviate liver fibrosis through down regulating fibrosis genes-Tgfb1 and alpha-SMA as well as decreasing expression of collagen gene Col1a1, Col3a1, and Col4a1, and regain liver function by recovering ALT and AST. Our findings provided a useful tool for studying liver development in vitro, new cell resource for heterograft on mouse liver diseases, and a new platform for researches on immune rejection of heterogeneous cell transplantation. PMID- 28625012 TI - The Effects of School-Based Condom Availability Programs (CAPs) on Condom Acquisition, Use and Sexual Behavior: A Systematic Review. AB - We conducted a systematic review to assess the impact of school-based condom availability programs (CAPs) on condom acquisition, use and sexual behavior. We searched PubMed to identify English-language studies evaluating school-based CAPs that reported process (i.e. number of condoms distributed or used) and sexual behavior measures. We identified nine studies that met our inclusion criteria, with the majority conducted in the United States of America. We judged most studies to have medium risk of bias. Most studies showed that school-based CAPs increased the odds of students obtaining condoms (odds ratios (ORs) for individual studies ranged between 1.81 and 20.28), and reporting condom use (OR 1.36-3.2). Three studies showed that school-based CAPs positively influenced sexual behavior, while no studies reported increase in sexual activity. Findings suggest that school-based CAPs may be an effective strategy for improving condom coverage and promoting positive sexual behaviors. PMID- 28625013 TI - Anti-mutagenic Properties of Mono- and Dienoic Acid Biohydrogenation Products from Beef Fat. AB - Unsaturated fatty acid biohydrogenation products from beef fat and pure fatty acids were subjected to the Ames Salmonella mutagenicity testing, including monounsaturated fatty acids [MUFA: oleic acid, vaccenic acid, elaidic acid; beef fatty acid fractions rich in trans (t)11/t13-t14-18:1 (t11,13,14-Frac), t10-18:1 (t10-Frac)] and dienoic fatty acids [linoleic acid, conjugated linoleic isomers cis (c)9,t11-18:2 and t10,c12-18:2, and a mixed beef dienoic fatty acid fraction high in c9,t13-/t8,c12/t11c15-18:2 (MD)]. Significantly higher anti-mutagenic effects of oleic acid, vaccenic acid, t11, 13, 14-Frac, and t10-Frac against daunomycin were observed at 2.5 mg. All dienoic acids except MD significantly reduced daunomycin mutagenicity at >=0.25 mg. Anti-mutagenicity of oleic and vaccenic acids against 2-aminoanthracene was found at 2.5 and 0.25 mg, respectively. All dienoic acids significantly reduced 2-aminoanthracene mutagenicity at >=0.25 mg. Findings of this study show that unsaturated fatty acids, including trans-fatty acids commonly found in beef, can act as strong anti mutagens. PMID- 28625014 TI - Comparison in executive function in Chinese preterm and full-term infants at eight months. AB - Executive function (EF) is increasingly recognized as being responsible for adverse developmental outcomes in preterm-born infants. Several perinatal factors may lead to poor EF development in infancy, and the deficits in EF can be identified in infants as young as eight months. A prospective cohort study was designed to study the EF in Chinese preterm infants and examine the relationship between EF in preterm infants and maternal factors during perinatal period. A total of 88 preterm infants and 88 full-term infants were followed from birth to eight months (corrected age). Cup Task and Planning Test was applied to assess the EF of infants, and the Bayley Scale of Infant Development (BSID-III) was used to evaluate cognitive (MDI) and motor abilities (PDI) of infants. In comparison with full-term infants, the preterm infants performed more poorly on all measures of EF including working memory, inhibition to prepotent responses, inhibition to distraction, and planning, and the differences remained after controlling the MDI and PDI. Anemia and selenium deficiency in mothers during pregnancy contributed to the differences in EF performance. However, maternal depression, hypertension, and diabetes during pregnancy were not related to the EF deficits in preterm infants. Future research should focus on the prevention of anemia and selenium deficiency during pregnancy and whether supplementing selenium in mothers during pregnancy can prevent further deterioration and the development of adverse outcomes of their offspring. PMID- 28625015 TI - CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. AB - T cells engineered with chimeric antigen receptor (CAR) have been successfully applied to treat advanced refractory B cell malignancy. However, many challenges remain in extending its application toward the treatment of solid tumors. The immunosuppressive nature of tumor microenvironment is considered one of the key factors limiting CAR-T efficacy. One negative regulator of Tcell activity is lymphocyte activation gene-3 (LAG-3). We successfully generated LAG-3 knockout Tand CAR-T cells with high efficiency using CRISPR-Cas9 mediated gene editing and found that the viability and immune phenotype were not dramatically changed during in vitro culture. LAG-3 knockout CAR-T cells displayed robust antigen specific antitumor activity in cell culture and in murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates an efficient approach to silence immune checkpoint in CAR-T cells via gene editing. PMID- 28625016 TI - Brugada Syndrome and Exercise Practice: Current Knowledge, Shortcomings and Open Questions. AB - Since its recognition as a clinical entity in 1992, the Brugada Syndrome (BrS), a hereditary disease characterized by a typical electrocardiogram (ECG) pattern potentially predisposing to sudden cardiac death (SCD), has attracted the attention of many physicians for its circadian pattern of ventricular arrhythmias (VA), mostly occurring at rest. Exercise may potentially worsen the ECG abnormalities in BrS patients, resulting in higher peak J-point amplitudes during the vasovagal reaction of the recovery period, possibly leading to an increased risk of cardiac events. Moreover, the enhanced vagal tone in athletes could be both a BrS risk factor and an exercise effect. Therefore, the true risk of a BrS patient during exercise is still unclear. This review summarizes current knowledge, shortcomings and open questions on BrS and exercise. The paper, in particular, underlines specific considerations including BrS diagnostic criteria and differential diagnosis in athletes, the genetic basis, the autonomic imbalance during exercise practice and the recommendations for athletic participation in this patient group. PMID- 28625017 TI - A single-tube flow cytometric procedure for enhancing the diagnosis and prognostic classification of patients with myelodysplastic syndromes. AB - INTRODUCTION: We created a simple and effective flow cytometry scoring system (FCSS) for suspected Myelodysplastic syndromes (MDS) samples and evaluated its diagnostic and prognostic potential. METHODS: Besides evaluating the four parameters suggested by Ogata, we investigated erythroid precursors and mast cells. We evaluated the six-parameter FCSS in a four-color setting (test cohort: 51 patients; 25 controls), then we implemented it into an eight-color setting and tested it on a validation cohort of patients with MDS (n=31). RESULTS: When we compared MDS cases to non-MDS samples in the test cohort, we detected significant differences regarding not only the four major parameters but also two additional ones, namely CD71 rCV% of erythroid precursors (P=.004) and mast cell percentage (MC%) (P=.001). The utilization of the modified six-parameter FCSS provided high sensitivity and specificity both in the four color (84% and 80%, respectively) and in the eight color (81% and 100%, respectively) setting, with an excellent discriminative power between MDS and non-MDS samples. Furthermore, we found significant difference in event-free survival between the risk groups based on the modified six-parameter FCSS (P=.001). CONCLUSION: We evaluated and validated a single-tube flow cytometric procedure for a simple six-parameter FCSS which has not only high diagnostic but also prognostic power. PMID- 28625018 TI - No Pharmacokinetic Interaction Between the Hepatitis C Virus Inhibitors Elbasvir/Grazoprevir and Famotidine or Pantoprazole. AB - Use of agents to suppress gastric acid secretion is common among patients with hepatitis C virus (HCV) infection. The aims of this open-label, three-period, fixed-sequence study were to evaluate the effect of famotidine and pantoprazole on the pharmacokinetics and safety of elbasvir/grazoprevir fixed-dose combination (FDC) in 16 healthy subjects. Elbasvir and grazoprevir each exhibited similar pharmacokinetics following single-dose administration of elbasvir/grazoprevir with or without famotidine or pantoprazole. Geometric mean ratios (GMRs) of grazoprevir AUC(0,infinity), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 0.89 1.17. Similarly, GMRs of elbasvir AUC(0,infinity), Cmax , and C24 (elbasvir/grazoprevir + famotidine or elbasvir/grazoprevir + pantoprazole vs. elbasvir/grazoprevir) ranged from 1.02-1.11. These results indicate that gastric acid-reducing agents do not modify the pharmacokinetics of elbasvir or grazoprevir in a clinically relevant manner and may be coadministered with elbasvir/grazoprevir in HCV-infected patients without restriction. PMID- 28625019 TI - Efficacy of Azithromycin and Compounded Atovaquone for Treatment of Babesia gibsoni in Dogs. AB - BACKGROUND: Approximately one-third of dogs confiscated during dogfighting investigations are infected with Babesia gibsoni. Traditional management of B. gibsoni with polymerase chain reaction (PCR)-screening, treatment with commercially available azithromycin and atovaquone, and PCR testing after 60 and 90 days is costly and impractical for large numbers of dogs at a time. HYPOTHESIS/OBJECTIVES: To assess the efficacy of an alternative protocol in which commercial atovaquone was replaced by compounded medication and PCR monitoring was initiated at 30 days after the end of treatment to decrease the total management time. METHODS: Prospective observational study. Forty-two pit bull type dogs confiscated as part of an investigation of dogfighting, diagnosed with B. gibsoni infection, and judged to be suitable for adoption were treated with azithromycin (10 mg/kg PO q24h) and compounded atovaquone (13.4 mg/kg PO q8h with a fatty meal) for 10 days. PCR testing was repeated at 30 and 60 days after end of treatment if dogs with positive PCR tests at either time were tested at 90 days. Treatment was considered successful; 2 PCR tests 30 days apart were negative. RESULTS: Treatment was successful in 39 dogs (93%) as defined by 2 consecutive PCR-negative test results 30 days apart. In 38 dogs (90%), PCR results were the same at 30 and 60 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Use of compounded atovaquone and a reduced monitoring period can reduce costs and holding times without compromising treatment efficacy. This more economical protocol can remove barriers to mass screening and management of B. gibsoni infections in dogfighting cases. PMID- 28625020 TI - Methylation of the ribosomal RNA gene promoter is associated with aging and age related decline. AB - The transcription of ribosomal RNA genes (rDNA) is subject to epigenetic regulation, as it is abrogated by the methylation of CpG dinucleotides within their promoter region. Here, we investigated, through Sequenom platform, the age related methylation status of the CpG island falling into the rDNA promoter in 472 blood samples from 20- to 105-year-old humans and in different tissues (blood, heart, liver, kidney, and testis) of 15 rats 3-96 weeks old. In humans, we did not find a consistently significant correlation between CpG site methylation and chronological age. Furthermore, the methylation levels of one of the analyzed CpG sites were negatively associated with both cognitive performance and survival chance measured in a 9-year follow-up study. We consistently confirmed such result in a replication sample. In rats, the analysis of the homologous region in the tissues revealed the existence of increased methylation in old rats. rRNA expression data, in both humans and rats, were consistent with observed methylation patterns, with a lower expression of rRNA in highly methylated samples. As chronological and biological ages in rats of a given strain are likely to be much closer to each other than in humans, these results seem to provide the first evidence that epigenetic modifications of rDNA change over time according to the aging decline. Thus, the methylation profile of rDNA may represent a potential biomarker of aging. PMID- 28625021 TI - Antibiotic prophylaxis for elective hysterectomy. AB - BACKGROUND: Elective hysterectomy is commonly performed for benign gynaecological conditions. Hysterectomy can be performed abdominally, laparoscopically, or vaginally, with or without laparoscopic assistance. Antibiotic prophylaxis consists of administration of antibiotics to reduce the rate of postoperative infection, which otherwise affects 40%-50% of women after vaginal hysterectomy, and more than 20% after abdominal hysterectomy. No Cochrane review has systematically assessed evidence on this topic. OBJECTIVES: To determine the effectiveness and safety of antibiotic prophylaxis in women undergoing elective hysterectomy. SEARCH METHODS: We searched electronic databases to November 2016 (including the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), as well as clinical trials registers, conference abstracts, and reference lists of relevant articles. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing use of antibiotics versus placebo or other antibiotics as prophylaxis in women undergoing elective hysterectomy. DATA COLLECTION AND ANALYSIS: We used Cochrane standard methodological procedures. MAIN RESULTS: We included in this review 37 RCTs, which performed 20 comparisons of various antibiotics versus placebo and versus one another (6079 women). The quality of the evidence ranged from very low to moderate. The main limitations of study findings were risk of bias due to poor reporting of methods, imprecision due to small samples and low event rates, and inadequate reporting of adverse effects. Any antibiotic versus placebo Vaginal hysterectomyModerate-quality evidence shows that women who received antibiotic prophylaxis had fewer total postoperative infections (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.19 to 0.40; five RCTs, N = 610; I2 = 85%), less urinary tract infection (UTI) (RR 0.58, 95% CI 0.43 to 0.77; eight RCTs, N = 1790; I2 = 44%), fewer pelvic infections (RR 0.28, 95% CI 0.20 to 0.39; 11 RCTs, N = 2010; I2 = 57%), and fewer postoperative fevers (RR 0.43, 95% CI 0.34 to 0.54; nine RCTs, N = 1879; I2 = 48%) than women who did not receive such prophylaxis. This suggests that antibiotic prophylaxis reduces the average risk of postoperative infection from about 34% to 7% to 14%. Whether this treatment has led to differences in rates of other serious infection remains unclear (RR 0.20, 95% CI 0.01 to 4.10; one RCT, N = 146; very low-quality evidence).Data were insufficient for comparison of adverse effects. Abdominal hysterectomyWomen who received antibiotic prophylaxis of any class had fewer total postoperative infections (RR 0.16, 95% CI 0.06 to 0.38; one RCT, N = 345; low-quality evidence), abdominal wound infections (RR 0.64, 95% CI 0.45 to 0.92; 11 RCTs, N = 2434; I2 = 0%; moderate-quality evidence), UTIs (RR 0.39, 95% CI 0.29 to 0.51; 11 RCTs, N = 2547; I2 = 26%; moderate-quality evidence), pelvic infections (RR 0.50, 95% CI 0.35 to 0.71; 11 RCTs, N = 1883; I2 = 11%; moderate-quality evidence), and postoperative fevers (RR 0.60, 95% CI 0.51 to 0.70; 11 RCTs, N = 2581; I2 = 51%; moderate-quality evidence) than women who did not receive prophylaxis, suggesting that antibiotic prophylaxis reduces the average risk of postoperative infection from about 16% to 1% to 6%. Whether this treatment has led to differences in rates of other serious infection remains unclear (RR 0.44, 95% CI 0.12 to 1.69; two RCTs, N = 476; I2 = 29%; very low-quality evidence).It is unclear whether rates of adverse effects differed between groups (RR 1.80, 95% CI 0.62 to 5.18; two RCTs, N = 430; I2 = 0%; very low-quality evidence). Head-to-head comparisons between antibiotics Vaginal hysterectomyWe identified four comparisons: cephalosporin versus penicillin (two RCTs, N = 470), cephalosporin versus tetracycline (one RCT, N = 51), antiprotozoal versus lincosamide (one RCT, N = 80), and cephalosporin versus antiprotozoal (one RCT, N = 78). Data show no evidence of differences between groups for any of the primary outcomes, except that fewer cases of total postoperative infection and postoperative fever were reported in women who received cephalosporin than in those who received antiprotozoal.Only one comparison (cephalosporin vs penicillin; two RCTs, N = 451) yielded data on adverse effects and showed no differences between groups. Abdominal hysterectomyWe identified only one comparison: cephalosporin versus penicillin (N = 220). Data show no evidence of differences between groups for any of the primary outcomes. Adverse effects were not reported. Combined antibiotics versus single antibiotics Vaginal hysterectomyWe identified three comparisons: cephalosporin plus antiprotozoal versus cephalosporin (one RCT, N = 78), cephalosporin plus antiprotozoal versus antiprotozoal (one RCT, N = 78), and penicillin plus antiprotozoal versus penicillin (one RCT, N = 230). Data were unavailable for most outcomes, including adverse effects. We found no evidence of differences between groups, except that fewer women receiving cephalosporin with antiprotozoal received a diagnosis of total postoperative infection, UTI, or postoperative fever compared with women receiving antiprotozoal. Abdominal hysterectomyWe identified one comparison (penicillin plus antiprotozoal vs penicillin only; one RCT, N = 230). Whether differences between groups occurred was unclear. Adverse effects were not reported. Comparison of cephalosporins in different regimensSingle small trials addressed dose comparisons and provided no data for most outcomes, including adverse effects. Whether differences between groups occurred was unclear. No trials compared route of administration.The quality of evidence for all head-to-head and dose comparisons was very low owing to very serious imprecision and serious risk of bias related to poor reporting of methods. AUTHORS' CONCLUSIONS: Antibiotic prophylaxis appears to be effective in preventing postoperative infection in women undergoing elective vaginal or abdominal hysterectomy, regardless of the dose regimen. However, evidence is insufficient to show whether use of prophylactic antibiotics influences rates of adverse effects. Similarly, evidence is insufficient to show which (if any) individual antibiotic, dose regimen, or route of administration is safest and most effective. The most recent studies included in this review were 14 years old at the time of our search. Thus findings from included studies may not reflect current practice in perioperative and postoperative care and may not show locoregional antimicrobial resistance patterns. PMID- 28625022 TI - Ethical, moral, and theological insights into advances in male pediatric and adolescent fertility preservation. AB - The successful treatment of boys with cancer has led to increasing attention to preserving their quality of life after completing cancer therapy. One of the top priorities for living a full life is keeping open the opportunity to have children. While sperm banking for males facing sterilizing cancer treatment can be effective, this approach requires subsequent use of reproductive procedures such as in vitro fertilization (IVF) or intrauterine insemination (IUI) to achieve a pregnancy. Advances in fertility preservation techniques may allow pre pubertal boys to conceive using advanced stem cell technologies and stem cell transplantation in the future. This review summarizes the ethical positions of leading medical societies and explores the religious and moral stances of major religious institutions regarding these options. PMID- 28625023 TI - [Studyon Renal Cell Carcinoma Detected by Abdominal Ultrasonography during Routine Health Check-Up]. AB - We performed a study on renal cell carcinoma (RCC) detected by abdominal ultrasonography during routine health check-up at Sapporo Teishin Hospital. The study included a total of 13,127 ultrasonographic examinations performed on 4,339 patients who visited our hospital for routine health check-ups during a 21- year period from April 1995 to March 2016. RCC was suspected from ultrasonographic findings and later histopathologically diagnosed in 11 patients in this group (detection rate 0.25%). Patients were male, aged 37 to 64 (median, 52.1 years). None of the patients had subjective symptoms, and all were negative for microscopic hematuria. Greatest dimensions of tumors were 18 to 40 mm (mean, 28 mm) ; anechoic rims, which are a characteristic ultrasonographic finding in RCC, were identified in 8 patients (72. 7%), intratumoral cysts were identified in 8 patients (72.7%), and protrusions from the surface of the kidney were identified in 9 patients (81. 8%). Regarding vascular distribution of renal tumors during Doppler ultrasonography, peripheral patterns or mixed penetrating and peripheral patterns were identified in 100% of cases (8/8). All 11 patients were diagnosed histopathologically with clear cell renal cell carcinoma, and the histological grade was G1 in 6 patients, G1>G2, in 1 patient G2>G1, in 1 patient and G2 in 3 patients. All 11 tumors were classified as pT1a pathological stage according to the TNM classification, and no regional lymph node metastases or distant metastases were identified. We consider that ultrasonography plays an integral role in the early detection of RCC during check-ups and examinations. PMID- 28625024 TI - [Post-Operative Single Immediate Intravesical Instillation Chemotherapy as Prophylaxis for Reccurence after Transurethral Resection of Low Risk Non-Muscle Invasive Bladder Cancer]. AB - We evaluated the efficacy of single-dose instillation of pirarubicine hydrochloride (THP) in the chemoprophylaxis of non-muscle-invasive bladder cancer(NMIBC). In a retrospective study, 135 evaluable patients were assigned to three groups after transurethral resection of bladder tumors (TURBT). In group 1, patients received no adjuvant therapy after TURBT. In group 2, patients received a single-dose of 30 mg THP in 30 ml normal saline immediately after TURBT. In group 3, patients received 30 mg THP in 30 ml normal saline 2 weeks after TURBT , and the instillations were repeated for 4 weeks, then every other week twice and successively monthly for 6 months. Patients were followed with cystoscopy and urine cytology every 3 months for the first 2 years and every 6 months thereafter. The 3- and 5-year non-recurrence rates were 66.9%, and 66.0%, respectively, in group 1, 85.6%, and 85.6%, respectively, in group 2, and 93.6%, and 77.9%, respectively, in group 3. There was a significant difference only between group 1 and group2 (P =0.048). With respect to the recurrence per month, there was a significant difference between the 3 groups (P=0.014) for the first 2 years. However, there was no significant difference thereafter. Limitations of our study are its retrospective and nonrandomized nature with a limited number of patients. PMID- 28625025 TI - [Causative Bacterial Strains and Sensitivityto Antimicrobial Agents in Female Acute Uncomplicated Cystitis]. AB - Recently, wide spreading of fluoloquinolone resistant Escherichia coli is a serious problem inthe treatment of urinary tract infection. To investigate the causative bacterial strains of female acute uncomplicated cystitis (AUC) in the community and their sensitivity to antimicrobial agents, we retrospectively reviewed the medical records of 215 female AUC patients treated at our clinics from April 2014 to June 2015. Two hundred and nineteen strains were isolated as the causative bacteria from the patients'urine samples, including E. coli of 179 strains (82%) followed by Klebsiella pneumoniae (5.5%). One hundred and forty five strains (81%) of the isolated E. coli were sensitive to levofloxacin, whereas 32 strains (17.9%) were levofloxacin-resistant. To fosfomycin, the isolated E. coli showed the highest sensitivity (93.9%) among all antimicrobial agents tested. In univariate analysis, factors associated with levofloxacinresistant E. coli included two or more episodes of cystitis within the past year and levofloxacin use at the latest episode of cystitis. Inmultivariate analysis, two or more episodes of cystitis withinthe past year were found to be associated with levofloxacinresistan ce (p=0.004). To prevent the increasing prevalence of infections caused by antibiotic-resistant bacteria, it is important to confirm the sensitivity of the causative agents for optimal antimicrobial therapy. The community-based surveillance data should be collected and considered when selecting empirical antimicrobial agents. PMID- 28625026 TI - [Risk Factors for Mortalityin Patients with Urosepsis]. AB - Urosepsis is not uncommon and sometimes causes a critical condition including death. We retrospectivelyanaly zed the risk factors for mortalityin urosepsis. We treated 80 patients as urosepsis from 2010 to 2014 in our hospital. Five patients (6%) died within 30 days of hospitalization. The median age of the patients who died of urosepsis was 92 years (range, 83-95 years). The main causes of urosepsis were complicated pyelonephritis in 4 patients and emphysematous pyelonephritis in one. In the subgroup analysis of elderly patients over 75 years old, bad performance status and lower serum albumin were significantlyrelated to mortality(p =0.033, 0.046). The elderlypatients, especiallywith bad performance status and lower serum albumin, are more likelyto die. PMID- 28625027 TI - [A Case of Bilateral Adrenal Incidentaloma in which MTX-Related Lymphoproliferative Disease Could Be Diagnosed by Computed Tomography-Guided Biopsy and MTX Administration History]. AB - The patient was a 76-year-old man. Because bilateral adrenal tumor (right adrenal gland 7 cm, left adrenal gland 1.5 cm) was detected in by computed tomography (CT) in methotrexate (MTX) administration for articular rheumatism from 2011, he was referred to this hospital in February, 2016. An endocrine examination, and imaging study did not lead to a definitive diagnosis and CT-guided lower needle biopsy was performed. The pathological diagnosis was diffuse large B cell lymphoma. Also, in situ hybridization revealed EBER-positive and the diagnosis of MTX-related lymphoproliferative disease (MTXLPD) was made in conjunction with the medical history. After MTX cancellation, the tumor became markedly smaller. The annual incidence of this disorder in the RA patients during MTX internal use is reported as 0.06%. According to the site of origin, lymphatic extranodal disease accounts for approximately half of the cases, but this is the third case of primary adrenal origin reported. PMID- 28625028 TI - [Adult Male Ureterocele Detected by Urinary Frequency]. AB - A 27-year-old Japanese man visited our urological department due to urinary frequency, and we detected a ureterocele by cystoscopy. The treatment consisted of an endoscopic-laser incision of the ureterocele. After the operation, the patient's symptoms subsided, and the vesicoureteral reflux and urinary infection disappeared. With the advances in image diagnostic technology, a ureterocele is easily diagnosed during childhood. In the present case, the ureterocele may have increased in volume over a period of decades, causing the urinary frequency. An endoscopic incision is the standard treatment for ureterocele, but there are concerns about vesicoureteric reflux after the endoscopic-laser incision, the patient is still doing well. The present case indicates that endoscopic-laser incision is an effective treatment for a ureterocele, at least in adult patients. PMID- 28625029 TI - [A Case of Squamous Cell Carcinoma in Bladder Diverticulum Producing Granulocyte Colony Stimulating Factor]. AB - We report a rare case of squamous cell carcinoma (SCC) in bladder diverticulum producing granulocyte colony stimulating factor (G-CSF). A 59-year-old man complaining of hematuria and right hip pain was admitted with a large cancer in the bladder diverticulum. His laboratory data showed leukocytosis of 20,100/ MU l (neutrophils : 92%) with an elevated G-CSF of 76. 6 pg/ml in the peripheral blood. After neoadjuvant chemotherapy (gemcitabine and cisplatin), radical cystectomy was performed to normalize serum leukocytosis and G-CSF. Histopathological diagnosis was G-CSF-producing SCC pT4N0. He appeared with left pelvic lymph node metastasis and right pulmonary metastasis 3 months after surgery. Therefore, he was treated with four courses of combination chemotherapy (paclitaxel, ifosfamide and nedaplatin) and radiation therapy at left pelvic lymph node metastasis. Computed tomography after these treatments showed complete response. The patient is alive with no evidence of tumor 16 months after surgery. PMID- 28625030 TI - The Clinical Nutrition Research Agenda in Indonesia and beyond: ecological strategy for food in health care delivery. AB - Despite progress with the food-associated health agenda in the public health and clinical domains, much remains to be done in Indonesia. There are reasons to be optimistic which include economic development, increasing literacy, progress towards universal health coverage and community organizational arrangements across the archipelago which focus on health through some 10,000 puskesmas. These community health centres are variably staffed with voluntary cadres from the community, bidans (nurses) and general medical practitioners. For more effective prevention and management of nutritionally-related health problems, innovative community and clinical nutrition research and expertise is required. With rapid urbanisation, the growth of the digital economy, increasing socio-economic inequity and climate change, there are imperatives for ecologically sustainable, nonemployment dependent livelihoods which provide energy, food, water, education and health care security. A relevant health care workforce will include those who research and practice clinical nutrition. Here we gather together an account of an extensive body of published and emerging literature which makes a case collectively for a more ecological approach to nutrition and health and how it might revitalise the Indonesian and other health care systems. PMID- 28625031 TI - Inadequate dietary alpha-linolenic acid intake among Indonesian pregnant women is associated with lower newborn weights in urban Jakarta. AB - BACKGROUND: Omega-3 fatty acid intake during pregnancy has been confirmed to affect newborn birth outcomes in the developed world. However, the association between maternal omega-3 fatty acid intake and birth size is unknown in developing countries. OBJECTIVE: To examine the association of maternal omega-3 fatty acid intake with newborn birth size. METHODS AND STUDY DESIGN: A cross sectional study was conducted, involving 282 pregnant women aged 19-40 years who had a gestational age of >32 weeks and received antenatal care at 10 health centres and one referral hospital in East Jakarta, Indonesia. Maternal habitual intake of omega-3 fatty acids, including alpha-linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid, was assessed using a semiquantitative food frequency questionnaire. Birth weight and head circumference were measured using a paediatric weighing scale and tape, respectively, and birth length was obtained from medical records. Multiple linear regression analysis was performed to provide adjusted associations. RESULTS: The median total intake of omega-3 fatty acids, docosahexaenoic acid, eicosapentaenoic acid, and alpha-linolenic acid was lower than the recommended dietary intake. The newborns of mothers with an alpha linolenic acid intake lower than 0.82 g/d had a significantly lower (beta=114, 95% confidence interval=-216, -13.5; p=0.014) weight compared with those of mothers with high alpha-linolenic acid intake, after adjustment for confounding factors. CONCLUSION: Inadequate maternal intake of alpha-linolenic acid, but not omega-3 fatty acids, docosahexaenoic acid, or eicosapentaenoic acid, was associated with lower birth weight. Enhanced promotion of consumption of foods rich in essential fatty acids during pregnancy may facilitate attaining optimal infant weight in urban areas. PMID- 28625032 TI - Intergenerational effects of maternal birth weight, BMI, and body composition during pregnancy on infant birth weight: Tanjungsari Cohort Study, Indonesia. AB - BACKGROUND AND OBJECTIVES: Infant birth weight might be partly contributed to by maternal nutritional status at birth and maternal nutrition during pregnancy. The objective of this study was to analyze intergenerational maternal birth weight, maternal BMI, weight change during pregnancy, and maternal body composition (FM, FFM, and TBW) changes during pregnancy. METHODS AND STUDY DESIGN: We analyzed the associations between the maternal birth weight and body composition of 94 women and infant birth weight by using multiple regression adjusted for socioeconomic and reproductive history. RESULTS: All associations with infant birth weight were positive. The association between infant birth weight and maternal birth weight was 0.28 (95% CI: 0.02-0.54); that for the association between infant birth weight and maternal body weight in the first, second, and third trimesters was 15.1 (95% CI: 4.92-25.3), 13.7 (95% CI: 2.78-24.6), and 16.1 (95% CI: 5.22-27.0), respectively. The association between infant birth weight and fat mass in the second and third trimesters were 18.4 (95% CI: 3.38-33.5) and 16.1 (95% CI: 5.23 27.0), respectively, and those for the association between infant birth weight and fat-free mass in the first and third trimesters were 33.6 (6.38, 60.9) and 34.8 (95% CI: 3.47-66.1), respectively. CONCLUSIONS: This study confirms previous findings that maternal birth weight and body composition during pregnancy are associated with infant birth weight. PMID- 28625033 TI - Hydration status of pregnant women in West Jakarta. AB - BACKGROUND AND OBJECTIVES: During pregnancy, the body exhibits dynamic changes in fluid composition. More than 50%of women experience nausea and vomiting during the first trimester. Studies of hydration status in pregnant women are limited, and not in tropical countries, like in Indonesia. The objective of this study was to investigate the hydration status and appropriate biomarkers for determination of hydration status in pregnant women in West Jakarta. METHODS AND STUDY DESIGN: This study was cross-sectional. A total of 35 pregnant women aged (19-35 years) at the early second trimester of pregnancy was recruited. Urine osmolality, urine specific gravity, and serum osmolality were used to determine hydration status. Subjects then were divided into a hydration group (HG) and a dehydration group (DG). We used independent t tests, chi-square and Spearman rank correlation coefficient to analyse the data. RESULTS: The population was comparably divided between dehydration and hydration groups (57.1% and 42.9%, respectively). The proportions by age, parity, gestational age, height, weight, upper arm circumference, waist circumference, pelvic circumference, body temperature, blood pressure, and fundal height did not differ between groups (p>=0.05). There was a relationship between urine colour and hydration status (p<0.05). Differences in hydration biomarker status (urine osmolality and urine specific gravity) were noted between the groups (p<0.05). CONCLUSIONS: Dehydration may be common during pregnancy in tropical Indonesia and can be confirmed by the hydration biomarkers of urinary specific gravity and osmolality. Fluid balance is necessary to prevent health problems and intrauterine growth restriction in pregnant women. PMID- 28625034 TI - Family support and exclusive breastfeeding among Yogyakarta mothers in employment. AB - BACKGROUND AND OBJECTIVES: Exclusive breastfeeding provides many benefits to both infants and mothers. Despite the introduction of laws aimed at protecting the practice of exclusive breastfeeding, the coverage of exclusive breastfeeding remains low, particularly for working mothers. METHODS AND STUDY DESIGN: This crosssectional study recruited working mothers employed in medium and large companies in Bantul District, Daerah Istimewa Yogyakarta, Indonesia. The study participants were 158 working mothers whose children were aged 6- 12 months, and they were selected using the probability proportional to size technique. The data were analyzed using descriptive statistics, chi-square tests, and multiple logistic regression. RESULTS: Adequate family support for breastfeeding (OR: 2.86; 95% CI: 1.25-6.53) and a high paternal education level (OR: 2.68; 95% CI: 1.11- 6.48) were significantly associated with the practice of exclusive breastfeeding among working mothers. However, the infant's sex and age, parity, and the mother's age and education level were unassociated with exclusive breastfeeding. CONCLUSION: Family support and a high paternal education level are crucial in enabling working mothers to practice exclusive breastfeeding. Interventions that promote exclusive breastfeeding should focus on involving the husband and other family members in health care programs related to breastfeeding. PMID- 28625035 TI - Programming of infant neurodevelopment by maternal obesity: potential role of maternal inflammation and insulin resistance. AB - BACKGROUND AND OBJECTIVES: Recent studies show that maternal obesity is associated with impaired offspring neurodevelopmental outcomes. The mechanism underlying the association is unclear. However, there is evidence to suggest a role for intra-uterine exposure to inflammation and insulin resistance (IR). We aimed to determine if maternal IR and inflammation were associated to fetal neurodevelopment as indicated by fetal heart rate variability (HRV), an index of fetal cardiac autonomic nervous system development. METHODS AND STUDY DESIGN: A total of 44 healthy maternal-fetal pairs (maternal pre-pregnancy BMI distribution: n=20 normal weight, 8 overweight, 16 obese) were analyzed. We assessed maternal inflammation (plasma IL-6 and TNF-alpha) and IR (HOMA index). Fetal HRV, a proxy for fetal neurodevelopment, was assessed using fetal magnetocardiogram at the 36th week of pregnancy. The relationships between maternal inflammation and IR with fetal HRV (SD1 and SD2) were estimated individually by Pearson bivariate correlations. RESULTS: No correlations were observed between the fetal HRV components with maternal HOMA-IR and maternal plasma levels of IL-6 and TNF-alpha (all p<0.05). However, the negative association between maternal TNF-alpha level and fetal SD2 approached significance (correlation coefficient=-0.29, 95% confidence interval=-0.62,-0.03, p=0.07). CONCLUSION: Maternal IR and inflammation during pregnancy were not associated with fetal cardiac autonomic nervous system development. Further studies with a larger sample size and more maternal inflammatory indicators are needed to explore these relationships. PMID- 28625036 TI - Sago worms as a nutritious traditional and alternative food for rural children in Southeast Sulawesi, Indonesia. AB - BACKGROUND AND OBJECTIVES: The sago worm Rhynchophorus ferrugineus is a nutritious food source found in the remaining parts of a sago palm trunk after the removal of sago starch by farmers. The effort to increase sago worm consumption is investigated in an intervention study among children aged <5 years. METHODS AND STUDY DESIGN: Children aged 1-5 years were allocated to a sago worm inclusive diet (n=10) and to a control group eating a usual diet, but without sago worms (n=13). Snacks were served once per day (100 g) for 45 days and designed to contain similar amounts of vegetables (carrots and long beans) and other ingredients including rice, sticky rice, cassava, sweet potato, banana, or tofu with or without sago worms. Food preference was ascertained by interview. Anthropometric measurements were taken at baseline and the endpoint. RESULTS: After mixing all food stuffs into one product for instance nasi gurih, protein and fat content in the intervention group was higher compared to control group (8.8 g and 7.3 g vs 4.7 g and 0.5 g respectively). In the intervention group receiving complementary feeding with sago worms, children's height changed minimally as did the control group (0.3 vs 0.2 cm); no difference was observed between the groups regarding weight or height. CONCLUSIONS: Sago worm consumption can diversify the diet through usage in various dishes, so improving its overall nutritional quality. Worm addition in an intervention program does not compromise, but maintains nutritional value. Local use adds affordability and sustainability to the food and health systems in a sago-consuming culture, so contributing to food security. PMID- 28625037 TI - Tumour necrosis factor-alpha and risk of cardiovascular disease among overfat Indonesian adolescents. AB - BACKGROUND: Overfatness (overweight and obesity) is associated with an increased risk of cardiovascular disease, including elevated blood pressure, dyslipidaemia, and insulin resistance. Chronic inflammation may play a role in mediating these associations. OBJECTIVE: To investigate the association between plasma tumour necrosis factor-alpha and risk factors for cardiovascular disease among overweight and obese adolescents. METHODS AND STUDY DESIGN: This study was an observational analysis with a cross-sectional design for high school students in Yogyakarta, Indonesia. One hundred and fifteen overweight and obese adolescents (mean age 16.8 years; 48.3% female) were involved in the study. Overfatness was specified by body mass index z-scores. Anthropometric measurements, blood pressure, lipid profiles, and fasting glucose were obtained. Fasting plasma insulin and plasma tumour necrosis factor-alpha were quantified using enzyme linked immunosorbent assay. Insulin resistance was represented as the homeostatic model assessment value. Data were analysed using SPSS for Windows, version 23. RESULTS: Plasma tumour necrosis factor-alpha was significantly associated with total cholesterol (p=0.046) and diastolic blood pressure (p=0.018) among the overweight and obese adolescents. Results from path analyses showed that there were indirect effects of z-score BMI on systolic and diastolic blood pressures, HDL and fasting plasma glucose mediated by plasma tumour necrosis factor-alpha concentrations. Meanwhile, there were indirect effects of waist circumference on systolic and diastolic blood pressure by age and height percentile and HDL. There was no significant association between plasma tumour necrosis factor-alpha and insulin resistance. CONCLUSION: The study showed that a proinflammatory marker, plasma tumour necrosis factor-alpha, is associated with blood pressure, HDL and fasting plasma glucose in overweight and obese adolescents. This indicates that inflammation in overweight and obesity may play a role in increasing the risk of cardiovascular disease. PMID- 28625038 TI - Chronic liver disease is a risk factor for malnutrition and growth retardation in children. AB - BACKGROUND: Despite distinct advancements in nutritional therapy, malnutrition and growth retardation remain inevitable consequences of chronic liver disease. The global prevalence of chronic liver disease in children is about 3%, with a quarter undernourished. Malnutrition itself is a negative prognostic indicator of survival. Further research is necessary for delivering adequate nutritional support to reduce morbidity and mortality. OBJECTIVE: To evaluate the nutritional status and growth of children with chronic liver disease and its contributing factors. METHODS AND STUDY DESIGN: Data were gathered about 21 children aged 7 months to 13.3 years diagnosed with chronic liver disease at Harapan Kita Women and Children Hospital between November 2014 and February 2016. Physical growth and nutritional status were evaluated using anthropometric percentiles and z scores. Laboratory measurements were made on their first visit. RESULTS: The mean age of participants was 43.9+/-47.4 months. Mean weight was 13.4+/-9.31 kg, and mean length/height was 88.8+/-27.7 cm. Ten (47.6%) and 3 (14.3%) patients had moderate or severe undernutrition, respectively, and 38% (8 patients) had growth retardation. Of those with good nutritional status, 62.5% were older than 5 years. Malnutrition was correlated with growth failure, a low serum albumin, and elevated aspartate transaminase (p<0.05 in all cases). CONCLUSION: Early diagnosis of malnutrition should encourage nutritional support, delay illness progression and increase survival in children with chronic liver disease. PMID- 28625039 TI - Cooking methods and depressive symptoms are joint risk factors for fatigue among migrant Indonesian women working domestically in Taiwan. AB - BACKGROUND AND OBJECTIVES: Fatigue is a critical occupational health risk among migrant workers. Globally, more than half of migrant workers are women. However, the prevalence rate and risk factors for fatigue in domestically employed migrant women are unknown. METHODS AND STUDY DESIGN: In total, 194 Indonesian women migrants aged 20-50 years who were working in Taipei were studied. Self-perceived acculturation, dietary acculturation, BMI and haemoglobin were evaluated. Fatigue and depressive symptoms were assessed using the Brief Fatigue Inventory and Beck Depression Inventory-II, respectively. RESULTS: The prevalence of fatigue was 27.8%. Depressive symptoms (p<0.0001), cooking methods (p=0.027), and self perceived feelings of sadness and weakness (p=0.003) were associated with fatigue. After adjustment for covariates, the ORs for depressive symptoms (OR: 5.40; 95% CI: 2.32-12.6), deep frying/stir frying (OR: 5.23; 95% CI: 1.27-21.5), and self-perceived feelings of sadness and weakness (OR: 3.41; 95% CI: 1.26-9.25) remained significant. An interactive analysis revealed that women without depressive symptoms who used deep frying/stir frying as a cooking method had a 3.5-fold (1-12.3) higher risk of fatigue than did those who used non-deep frying and stir frying as cooking methods (which served as the reference) for cooking. By contrast, women with depressive symptoms who used non-deep frying and stir frying had a 6.5-fold (2.8-15.3) higher risk of fatigue, and the risk increased sharply to 12.6-fold (1.26-125.8) if they used deep frying and stir frying for cooking. CONCLUSIONS: The risk of fatigue among migrant women working domestically is increased when they exhibit depressive symptoms and their cooking technique is frying. PMID- 28625040 TI - Vitamin D status in under-five children with a history of close tuberculosis contact in Padang, West Sumatra. AB - BACKGROUND AND OBJECTIVE: Serum vitamin D influences cellular immunity against Mycobacterium tuberculosis, particularly in under-five children. Vitamin D insufficiency and deficiency as well as tuberculosis (TB) are highly prevalent in Indonesia. This study described the association of serum vitamin D in the incidence of latent TB in under-five children with a history of close TB contact. METHODS AND STUDY DESIGN: This cross-sectional study examined 178 under-five children with a history of close TB contact, with 98 index cases from primary health care facilities in Padang. Latent TB was defined based on a positive tuberculin skin test. Serum vitamin D was determined using ELISA method. General characteristics for age, sex, socioeconomic status, contact score, BCG scars, and nutritional status were also collected. RESULTS: Of 168 eligible subjects, 40.5% had latent TB, however no differences between 'latent TB' and 'without latent TB' were observed in participant characteristics. Vitamin D deficiency, insufficiency, and sufficiency were observed in 23.3%, 43.5%, and 33.3% of children, respectively. In general, the 'latent TB' group had lower serum vitamin D than those in the 'without latent TB' group, stratified by age, contact score and nutritional status; however, significant differences were observed in children age <1 years (18.0+/-2.6 vs 31.2+/-10.5, respectively, p=0.013). Nevertheless, no associations between the two groups were observed using multivariate analysis. CONCLUSION: Vitamin D status was not associated with the incidence of latent TB among under-five children with a history of close TB contact, although this may not obtain in children aged <1 year old. PMID- 28625041 TI - Energy regulation in newly diagnosed TB with chronic energy deficiency: free fatty acids and RBP4. AB - BACKGROUND AND OBJECTIVES: Energy metabolism may be dysfunctionally integral between host and infective agent in active tuberculosis, mediated by adipocytokines and free fatty acids (FFA) as the products of triglyceride lipolysis in fat, blood or other tissues. Retinol Binding Protein 4 (RBP4) and asymmetric dimethylarginine (ADMA) are candidate adipocytokines. The possibility of a deleterious metabolic nexus in chronic energy deficiency (CED) (BMI <18.5 kg/m2) is explored. METHODS AND DESIGN: Newly diagnosed patients with tuberculosis (n=63) were selected using consecutive random sampling at a Centre for the Care and Treatment of Lung Diseases in Makassar, Indonesia. Diagnosis of pulmonary TB required microscopy with Ziehl-Neelsen stain. Anthropometric measurements were taken. Venesection allowed glomerular filtration rate, FFA, serum glutamic oxaloacetic transaminase and glutamate-pyruvate transaminase to be assessed. RESULTS: CED was evident in 60.3%. For the well and lesser nourished, medians were, respectively, FFA 0.30 and 0.37 mmol/mL (p=0.960); RBP4 199730 ng/mL and 11721 ng/mL (p=0.009); GFR 106 ml/min and 113 ml/min (p=0.673); and ADMA 0.52 ng/mL and 0.51 ng/mL (p=0.172). BMI and serum RBP4 were correlated (rho=0.52, p<0.001), with odds ratios (OR) 5.8 (CI 1.68-20.3). RBP4 in CED was lower than in better nourished patients. Serum FFA is not evidently associated with BMI in patients with active TB. CONCLUSIONS: RBP4 is some 6-fold lower when active TB patients have CED than when BMI >25 kg/m2. However, FFA was not associated with CED in these active TB patients which may be a type 2 error or represent an energy impasse where infection and the host's metabolic needs are in competition. PMID- 28625042 TI - Selenium status and fungi in the protein-losing enteropathy of persistent diarrhea. AB - BACKGROUND AND OBJECTIVES: A vicious cycle of infection, malabsorption, and malnutrition has been implicated in the perpetuation of diarrheal disease. This study examined whether persistent diarrhea is associated with changes in selenium status and stool alpha-1 antitrypsin (AAT) concentration. METHODS AND STUDY DESIGN: This cross-sectional study included 30 children aged 1-12 years with persistent diarrhea who were hospitalized in Cipto Mangunkusumo Hospital and Fatmawati Hospital, Jakarta, and 30 apparently healthy children who were matched by age and sex and lived in a rural area of Jakarta. Clinical examinations, blood routine tests, erythrocyte glutathione peroxidase (GPX) activity and plasma selenium levels as well as AAT in fresh stool samples were performed in all the subjects. RESULTS: Of 30 children with persistent diarrhea, 17 had moderate malnutrition and 13 had severe malnutrition. The mean plasma selenium was significantly lower in children with persistent diarrhea than in children without diarrhea (86.0 MUg/L [95% CI: 76.1-95.9] vs 110 MUg/L [95% CI: 104-116, p<0.0001). The mean stool AAT concentration was significantly higher in children with persistent diarrhea than in those without diarrhea (115 mg/dL [95% CI: 38.5 191] vs 16 mg/dL [95% CI: 4.0-13.5, p<0.0001]). Selenium correlated with AAT (p=0.05). Fecal fungi were persistently present. CONCLUSIONS: Although selenium status in both groups was optimal for the obtained plasma GPX activity, children with persistent diarrhea exhibited lower plasma selenium levels. This study suggests that the decrease in the plasma selenium level may be the consequence of protein loss and that fungi may be involved. PMID- 28625043 TI - Pre- and postprandial acylated ghrelin in obese and normal weight men. AB - BACKGROUND AND OBJECTIVES: The prevalence of obesity in Indonesia has increasing. We have assessed the relationship between plasma acylated ghrelin hormone and self-reported appetite ratings (hunger and desire to eat) in obese and normal weight men. METHODS AND STUDY DESIGN: Thirty-two men participated in an experimental study, where acylated ghrelin and self-reported appetite ratings were compared between a test group of 16 obese men and a control group of 16 men with normal body mass indices. The participants were administered isocaloric mixed meals, and measurements were taken at 0 (before eating), 30, 60, and 120 minutes postprandial. Data were analysed using an independent t test, the Mann Whitney U test, the Pearson correlation, the Spearman rank-order correlation, trapezoidal rule analysis for the area under the curve, and receiver operating curve analysis to determine the optimal cut-off values, sensitivity, and specificity. RESULTS: Acylated ghrelin concentrations were higher in the test group than in the control group at all time points (p<0.01). There were no significant differences in the appetite ratings between the two groups at any time (p>0.05). There was no correlation between the acylated ghrelin concentration and appetite rating. According to the receiver operating curve analysis (sensitivity: 88%; specificity: 100%), the cut-offs for optimal acylated ghrelin immediately before eating and 30 minutes after eating, averaged 2332 pg/mL and 2710 pg/mL, respectively. CONCLUSIONS: The effect on obesity will depend on associated changes in deacylated ghrelin. Acylated ghrelin increases in obese individuals pre- and 30, 60, 90 and 120 minutes post prandial. PMID- 28625044 TI - HER2 Status and Its Heterogeneity in Gastric Carcinoma of Vietnamese Patient. AB - BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is related to the pathogenesis and poor outcome of numerous types of carcinomas, including gastric carcinoma. Gastric cancer patients with HER2 positivity have become potential candidates for targeted therapy with trastuzumab. METHODS: We investigated 208 gastric cancer specimens using immunohistochemistry (IHC), fluorescence in situ hybridization and dual in situ hybridization (ISH). We also investigated the concordance between IHC and ISH. The correlation between HER2 status and various clinicopathological findings was also investigated. RESULTS: In total, 15.9% (33/208) and 24.5% (51/208) of gastric cancers showed HER2 gene amplification and protein overexpression, respectively. A high level of concordance between ISH and IHC analyses (91.3%, kappa = 0.76) was found. A significant correlation between HER2 status and intestinal-type (p < .05) and differentiated carcinomas (p < .05) was also noted. The HER2 heterogeneity was high in gastric cancers; we found 68.8% phenotypic heterogeneity and 57.6% genotypic heterogeneity. Heterogeneity in HER2 protein expression and gene amplification showed a close association with diffuse histologic type and IHC 2+. CONCLUSIONS: HER2 protein overexpression and gene amplification were detected in 24.5% and 15.9% of gastric cancer specimens, respectively. Intestinal-type showed a higher level of HER2 protein overexpression and gene amplification than diffuse type. HER2 status also showed a significant relationship with well- and moderately-differentiated carcinomas. The ratio of phenotypic and genotypic heterogeneity of HER2 was high in gastric carcinomas and was associated with HER2 IHC 2+ and diffuse histologic type. PMID- 28625045 TI - Size-Dependent Heating of Magnetic Iron Oxide Nanoparticles. AB - The ability to generate heat under an alternating magnetic field (AMF) makes magnetic iron oxide nanoparticles (MIONs) an ideal heat source for biomedical applications including cancer thermoablative therapy, tissue preservation, and remote control of cell function. However, there is a lack of quantitative understanding of the mechanisms governing heat generation of MIONs, and the optimal nanoparticle size for magnetic fluid heating (MFH) applications. Here, we show that MIONs with large sizes (>20 nm) have a specific absorption rate (SAR) significantly higher than that predicted by the widely used linear theory of MFH. The heating efficiency of MIONs in both the superparamagnetic and ferromagnetic regimes increased with size, which can be accurately characterized with a modified dynamic hysteresis model. In particular, the 40 nm ferromagnetic nanoparticles have an SAR value approaching the theoretical limit under a clinically relevant AMF. An in vivo study further demonstrated that the 40 nm MIONs could effectively heat tumor tissues at a minimal dose. Our experimental results and theoretical analysis on nanoparticle heating offer important insight into the rationale design of MION-based MFH for therapeutic applications. PMID- 28625046 TI - Conformational Switching of HOCO Radical: Selective Vibrational Excitation and Hydrogen-Atom Tunneling. AB - Conformers of carboxyl radical (HOCO) have been studied by IR spectroscopy in argon and nitrogen matrices. In an argon matrix, only the lower-energy conformer trans-HOCO is observed, whereas both cis and trans conformers are found for deuterated carboxyl radical DOCO. In a nitrogen matrix, both conformers of HOCO and DOCO isotopologues can be prepared, indicating strong stabilization of the higher-energy cis conformer by a nitrogen matrix. Selective vibrational excitation promotes the trans-to-cis and cis-to-trans conversions of DOCO in an argon matrix and HOCO and DOCO in a nitrogen matrix, which is the first conformational photoswitching of an open-shell species. In a nitrogen matrix, the cis-to-trans and trans-to-cis conversions of HOCO is also found upon broadband IR light of the spectrometer, and the ratio of the quantum yields of these processes is about 3.3. The photoswitching peculiarities are in agreement with the available theoretical energy barriers. The higher-energy cis conformer decays to the lower-energy trans conformer via hydrogen-atom tunneling through the torsional barrier, which is also a unique observation for an open-shell species. The tunneling mechanism of the cis-to-trans switching is supported by the low temperature limit of the reaction rate and by the H/D kinetic isotope effect. Our results suggest a large difference in the H/D kinetic isotope effects in nitrogen and argon matrices (~5 and >100, respectively). The stabilizing effect on cis DOCO by a nitrogen matrix (by 2 orders of magnitude versus an argon matrix) is much smaller than that on cis-HOCO (estimated to be >104). PMID- 28625047 TI - Asymmetric Synthesis of the Antiviral Diterpene Wickerol A. AB - Wickerol A (1) is an unusual diterpene with remarkable activity against the H1N1 influenza virus. Its tetracyclic skeleton contains three quaternary carbons and is marked by several syn-pentane interactions which force a six-membered ring into a twist-boat conformation. We present an asymmetric synthesis of wickerol A (1) that is based on a Jung Diels-Alder reaction, an intramolecular alkylation to complete the 6-5-6-6 ring system, and a conjugate addition, all of which overcome considerable steric strain. During the synthesis, we isolated an unexpected cyclopropane that presumably stems from a carbonium ion intermediate. PMID- 28625048 TI - Moisture Influence Reducing Method for Heavy Metals Detection in Plant Materials Using Laser-Induced Breakdown Spectroscopy: A Case Study for Chromium Content Detection in Rice Leaves. AB - Fast detection of heavy metals in plant materials is crucial for environmental remediation and ensuring food safety. However, most plant materials contain high moisture content, the influence of which cannot be simply ignored. Hence, we proposed moisture influence reducing method for fast detection of heavy metals using laser-induced breakdown spectroscopy (LIBS). First, we investigated the effect of moisture content on signal intensity, stability, and plasma parameters (temperature and electron density) and determined the main influential factors (experimental parameters F and the change of analyte concentration) on the variations of signal. For chromium content detection, the rice leaves were performed with a quick drying procedure, and two strategies were further used to reduce the effect of moisture content and shot-to-shot fluctuation. An exponential model based on the intensity of background was used to correct the actual element concentration in analyte. Also, the ratio of signal-to-background for univariable calibration and partial least squared regression (PLSR) for multivariable calibration were used to compensate the prediction deviations. The PLSR calibration model obtained the best result, with the correlation coefficient of 0.9669 and root-mean-square error of 4.75 mg/kg in the prediction set. The preliminary results indicated that the proposed method allowed for the detection of heavy metals in plant materials using LIBS, and it could be possibly used for element mapping in future work. PMID- 28625049 TI - Selective, Metal-Free Approach to 3- or 5-CF3-Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with Hydrazines. AB - A detailed study of the reaction of trifluoroacetylated acetylenes and aryl (alkyl) hydrazines was performed, aimed to the regioselective synthesis of 3- or 5-trifluoromethylated pyrazoles. It was found that the regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents (hexafluoroisopropanol) favor the formation of 3-trifluoromethylpyrazoles. In contrast, when the reaction was performed in polar aprotic solvents (DMSO), the formation of their 5-CF3-substituted isomers was preferentially observed. Alternatively, the regioselective assembly of 3-CF3-substituted pyrazoles can be performed via two-step one-pot procedure. The reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones. The latter can be smoothly transformed into 3-CF3-pyrazoles by treatment with a base. This solvent-switchable procedure was used for the preparation of such important drugs as Celebrex and SC-560 as well as their isomers in gram scale. The possible reaction mechanism is discussed. PMID- 28625050 TI - New Insight into the Chemical Nature of the Plasmonic Nanostructures Synthesized by the Reduction of Au(III) with Sulfide Species. AB - We have studied the products of the controversial synthesis of HAuCl4 with Na2S, which include gold nanostructures (Au NSs) that absorb in the near-infrared (NIR) region and are highly promising for photothermal therapies and other nanomedical applications. From high-resolution transmission electron microscopy, X-ray absorption spectroscopy, and small-angle X-ray scattering, we have found that only metallic Au NSs are formed as a result of this synthesis, with no detectable amount of gold sulfide or other oxidized gold species that could account for the NIR absorption. Different sulfur species are adsorbed on the Au NSs, mainly sulfides (monomeric sulfur) and polysulfides, similar to what is found on the planar gold surfaces, therefore precluding the idea that thiosulfate or other oxidized species are the actual reducing agents for Au(III) ions. The presence of strongly adsorbed S species, which are difficult to remove from the gold surface, is of great importance for their applications as regards toxicity and use of postfunctionalization strategies to anchor biomolecules and/or to increase circulation time after administration. PMID- 28625051 TI - Excited-State Deactivation Pathways and the Photocyclization of BN-Doped Polyaromatics. AB - Boron-nitrogen doping of polyaromatic hydrocarbons (PAH), such as borazine-core hexabenzocoronene, presents possibilities for tuning the properties of organic electronics and nanographene materials while preserving structural characteristics of pure hydrocarbons. Previous photochemical studies have demonstrated extension of a borazine-core PAH network (1,2:3,4:5,6-tris(o,o' biphenylylene)borazine, 1) by photoinduced cyclodehydrogenation. We present steady-state and femtosecond-to-microsecond resolved spectroscopic studies of the photophysics of 1 and a related borazine-core PAH in order to characterize competing excited-state relaxation pathways that determine the efficacy of bond formation by photocyclization. Transient spectra evolve on time scales consistent with S1 fluorescence lifetimes (1-3 ns) to features that persist onto microsecond time scales. Nanosecond-resolved oxygen-quenching measurements reveal that long lived metastable states are triplets rather than cyclized products. Determination of fluorescence and triplet quantum yields reveal that photochemical bond formation is a minor channel in the relaxation of 1 (~5% or less), whereas highly efficient fluorescence and intersystem crossing result in negligible photoinduced bond formation in more extended borazine-core networks. Results of computational investigations at the RICC2 level reveal sizable barriers to cyclization on the S1 potential energy surfaces consistent with quantum yields deduced from experiment. Together these barriers and competing photophysical pathways limit the efficiency of photochemical synthesis of BN-doped polyaromatics. PMID- 28625052 TI - Photochemical Kinetics of a Phosphine Oxide Free Radical Initiator from Femtosecond UV-Pump/Mid-IR-Probe Spectroscopy. AB - Femtosecond UV-pump/mid-infrared-probe spectroscopy was used to explore in detail the primary photochemical events of the free radical initiator, (2,4,6 trimethylbenzoyl)diphenylphosphine oxide, in liquid dichloromethane solution at room temperature. Following electronic excitation of its lowest excited singlet state, S1, the radical initiator undergoes an intersystem crossing to the triplet ground state, T1, with a time constant of 135 ps. A subsequent alpha-cleavage occurs from the triplet state with a time constant of 15 ps and yields a trimethylbenzoyl radical together with a diphenylphosphinoyl radical. Transient absorptions from the S1 and T1 states are observed that can be assigned to the P?O stretching mode and the symmetric in-plane deformation mode of the trimethylphenyl moiety of the radical initiator. PMID- 28625053 TI - Annotation of the Domestic Pig Genome by Quantitative Proteogenomics. AB - The pig is one of the earliest domesticated animals in the history of human civilization and represents one of the most important livestock animals. The recent sequencing of the Sus scrofa genome was a major step toward the comprehensive understanding of porcine biology, evolution, and its utility as a promising large animal model for biomedical and xenotransplantation research. However, the functional and structural annotation of the Sus scrofa genome is far from complete. Here, we present mass spectrometry-based quantitative proteomics data of nine juvenile organs and six embryonic stages between 18 and 39 days after gestation. We found that the data provide evidence for and improve the annotation of 8176 protein-coding genes including 588 novel and 321 refined gene models. The analysis of tissue-specific proteins and the temporal expression profiles of embryonic proteins provides an initial functional characterization of expressed protein interaction networks and modules including as yet uncharacterized proteins. Comparative transcript and protein expression analysis to human organs reveal a moderate conservation of protein translation across species. We anticipate that this resource will facilitate basic and applied research on Sus scrofa as well as its porcine relatives. PMID- 28625054 TI - All-in-One: Achieving Robust, Strongly Luminescent and Highly Dispersible Hybrid Materials by Combining Ionic and Coordinate Bonds in Molecular Crystals. AB - Extensive research has been pursued to develop low-cost and high-performance functional inorganic-organic hybrid materials for clean/renewable energy related applications. While great progress has been made in the recent years, some key challenges remain to be tackled. One major issue is the generally poor stability of these materials, which originates from relatively fragile/weak bonds between inorganic and organic constituents. Herein, we report a unique "all-in-one" (AIO) approach in constructing robust structures with desired properties. Such approach allows formation of both ionic and coordinate bonds within a molecular cluster, which greatly enhances structural stability while maintaining the molecular identity of the cluster and its high luminescence. The novel AIO structures are composed of various anionic (CumIm+n)n- clusters and cationic N-ligands. They exhibit high luminescence efficiency, significantly improved chemical, thermal and moisture stability, and excellent solution processability. Both temperature dependent photoluminescence experiments and DFT calculations are performed to investigate the luminescence origin and emission mechanism of these materials, and their suitability as energy-saving LED lighting phosphors is assessed. This study offers a new material designing strategy that may be generalized to many other material classes. PMID- 28625055 TI - Low Thermal Conductivity and High Thermoelectric Performance in (GeTe)1 2x(GeSe)x(GeS)x: Competition between Solid Solution and Phase Separation. AB - GeTe and its derivatives constituting Pb-free elements have been well known as potential thermoelectric materials for the last five decades, which offer paramount technological importance. The main constraint in the way of optimizing thermoelectric performance of GeTe is the high lattice thermal conductivity (kappalat). Herein, we demonstrate low kappalat (~0.7 W/m.K) and a significantly high thermoelectric figure of merit (ZT = 2.1 at 630 K) in the Sb-doped pseudoternary (GeTe)1-2x(GeSe)x(GeS)x system by two-step strategies. The (GeTe)1 2x(GeSe)x(GeS)x system provides an excellent podium to investigate competition between an entropy-driven solid solution and enthalpy-driven phase separation. In the first step, small concentrations of Se and S were substituted simultaneously in the position of Te in GeTe to reduce the kappalat by phonon scattering due to mass fluctuations and point defects. When the Se/S concentration increases significantly, the system deviates from a solid solution, and phase separation of the GeS1-xSex (5-20 MUm) precipitates in the GeTe1-xSex matrix occurs, which does not participate in phonon scattering. In the second stage, kappalat of the optimized sample is further reduced to 0.7 W/m.K by Sb alloying and spark plasma sintering (SPS), which introduce additional phonon scattering centers such as excess solid solution point defects and grain boundaries. The low kappalat in Sb doped (GeTe)1-2x(GeSe)x(GeS)x is attributed to phonon scattering by entropically driven solid solution point defects rather than conventional endotaxial nanostructuring. As a consequence, the SPS-processed Ge0.9Sb0.1Te0.9Se0.05S0.05 sample exhibits a remarkably high ZT of 2.1 at 630 K, which is reproducible and stable over temperature cycles. Moreover, Sb-doped (GeTe)1-2x(GeSe)x(GeS)x exhibits significantly higher Vickers microhardness (mechanical stability) compared to that of pristine GeTe. PMID- 28625059 TI - Radical 1,2-Alkylarylation/Acylarylation of Allylic Alcohols with Aldehydes via Neophyl Rearrangement. AB - A metal-free 1,2-alkylarylation of allylic alcohols with aliphatic aldehydes through concomitant radical neophyl rearrangement was developed, providing 1,2 diphenyl-3-alkyl propanones in moderate to good yields. Moreover, when cyclopropanecarbaldehyde and aryl carbaldehydes were concerned, acylarylation was involved leading to 1,4-dicarbonyl compounds. PMID- 28625060 TI - Relation between Vibrational Dephasing Time and Energy Gap Fluctuations. AB - Dephasing processes are present in basically all applications in which quantum mechanics plays a role. These applications certainly include excitation energy and charge transfer in biological systems. In a previous study, we have analyzed the vibrational dephasing time as a function of energy gap fluctuation for a large set of molecular simulations. In that investigation, individual molecular subunits were the focus of the calculations. The set of studied molecules included bacteriochlorophylls in Fenna-Matthews-Olson and light-harvesting system 2 complexes as well as bilins in PE545 aggregates. The present work extends this study to entire complexes, including the respective intermolecular couplings. Again, it can be concluded that a universal and inverse proportionality exists between dephasing time and variance of the excitonic energy gap fluctuations, whereas the respective proportionality constants can be rationalized using the energy gap autocorrelation functions. Furthermore, these findings can be extended to the gaps between higher-lying neighboring excitonic states. PMID- 28625058 TI - Structural Basis for Substrate Helix Remodeling and Cleavage Loop Activation in the Varkud Satellite Ribozyme. AB - The Varkud satellite (VS) ribozyme catalyzes site-specific RNA cleavage and ligation reactions. Recognition of the substrate involves a kissing loop interaction between the substrate and the catalytic domain of the ribozyme, resulting in a rearrangement of the substrate helix register into a so-called "shifted" conformation that is critical for substrate binding and activation. We report a 3.3 A crystal structure of the complete ribozyme that reveals the active, shifted conformation of the substrate, docked into the catalytic domain of the ribozyme. Comparison to previous NMR structures of isolated, inactive substrates provides a physical description of substrate remodeling, and implicates roles for tertiary interactions in catalytic activation of the cleavage loop. Similarities to the hairpin ribozyme cleavage loop activation suggest general strategies to enhance fidelity in RNA folding and ribozyme cleavage. PMID- 28625056 TI - Enantioselective Construction of Acyclic Quaternary Carbon Stereocenters: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Amide Enolates. AB - We report a divergent and modular protocol for the preparation of acyclic molecular frameworks containing newly created quaternary carbon stereocenters. Central to this approach is a sequence composed of a (1) regioselective and retentive preparation of allyloxycarbonyl-trapped fully substituted stereodefined amide enolates and of a (2) enantioselective palladium-catalyzed decarboxylative allylic alkylation reaction using a novel bisphosphine ligand. PMID- 28625061 TI - Controlling the Accumulation of Water at Oil-Solid Interfaces with Gradient Coating. AB - In this work, we demonstrate a strategy to control the accumulation of water in the oil-solid interface using a gradient coating. Gradient chemistry on glass surface is created by vapor diffusion of organosilanes, leading to a range of contact angles from 110 to 20 degrees . Hexadecane is placed on the gradient substrate as an oil layer, forming a "water/hexadecane/gradient solid substrate" sandwich structure. During incubation, water molecules spontaneously migrate through the micrometer-thick oil layer and result in the formation of micrometer sized water droplets at the oil-solid interface. It turns out that water droplets at more hydrophobic regions tend to be closer to a regular spherical shape, which is attributed to their higher contact angle with the hydrophobic substrate. However, along the gradient from hydrophobic to hydrophilic, the water droplets gradually form more irregular shapes, as hydrophilic surfaces pin the edges of droplets to form a distorted morphology. It indicates that more hydrophilic surfaces containing more Si-OH groups lead to a higher electrostatic interaction with water and a higher growth rate of interfacial water droplets. This work provides further insights into the mechanism of spontaneous water accumulation at oil-solid interfaces and assists in the rational design for controlling such interfacial phenomenon. PMID- 28625062 TI - Bioinspired Hand-Operated Smart-Wetting Systems Using Smooth Liquid Coatings. AB - Manually controllable "hand-operated" smart systems have been developed in many fields, including smart wetting materials, electronic devices, molecular machines, and drug delivery systems. Because complex morphological or chemical control are generally required, versatile strategies for constructing the system are technologically important. Inspired by the natural phenomenon of raindrops rarely bouncing and usually spreading on a puddle, we introduce a droplet-impact triggering smart-wetting system using "non-smart" smooth liquid coating materials. Changing the droplet impact energy by changing the volume or casting height causes the droplet to completely bounce or spread on the liquid surface, regardless of the miscibility between the two liquids, owing to the stability of air layer. As the bouncing of a droplet on a liquid interface is not usually observed during wetting, we first analyze how the droplet bounces, then prove that the wettability is triggered by the droplet's impact energy, and finally introduce some applications using this system. PMID- 28625063 TI - Mechanism of the Hydrolysis of Endosulfan Isomers. AB - The objective of this study was to elucidate the mechanism of abiotic hydrolysis of ES isomers, i.e., Endosulfan-1 (ES-1) and Endosulfan-2 (ES-2), using a combination of experiments and density functional theory (DFT) calculations. Hydrolysis of both ES-1 and ES-2 resulted in the formation of Endosulfan Alcohol (ES-A). The rate of hydrolysis was first order in all cases and increased with both pH and temperature. Rate expressions describing the hydrolysis rates of ES-1 and ES-2 as a function of pH and temperature were obtained and validated with independent data sets. DFT calculations were performed using three functionals (M06-2X, B3LYP, and MPW1K) and both IEFPCM-UFF and SMD to introduce solvent effects. The geometry optimization of molecules ES-1 and ES-2 showed that the free energy of ES-1 was larger, and therefore, ES-2 was the more thermodynamically stable isomer. DFT calculations also supported a hydrolysis mechanism involving two successive attacks by OH- ions on C-O bonds resulting in the attachment of OH- and the elimination of SO3- from the ES molecule, but only the first attack was rate limiting. Calculations with all functionals and solvent effect combinations supported the experimentally observed result of faster hydrolysis of ES-2 than of ES-1. The MPW1K functional along with IEFPCM-UFF for solvent effect simulated the free energy of activation to be the closest for both ES-1 and ES-2 with less than 3% error with respect to the values computed from the experimental observations. The kinetic rate expression for ES hydrolysis derived on the basis of the proposed mechanism was identical to the rate expression derived from experiments. It was deduced that the hydrolysis rates of both ES isomers may vary over 3 orders of magnitude depending on the prevalent pH and temperature. PMID- 28625064 TI - An OFF-ON Two-Photon Fluorescent Probe for Tracking Cell Senescence in Vivo. AB - A naphthalimide-based two-photon probe (AHGa) for the detection of cell senescence is designed. The probe contains a naphthalimide core, an l-histidine methyl ester linker, and an acetylated galactose bonded to one of the aromatic nitrogen atoms of the l-histidine through a hydrolyzable N-glycosidic bond. Probe AHGa is transformed into AH in senescent cells resulting in an enhanced fluorescent emission intensity. In vivo detection of senescence is validated in mice bearing tumor xenografts treated with senescence-inducing chemotherapy. PMID- 28625065 TI - Physical Texturing for Superhydrophobic Polymeric Surfaces: A Design Perspective. AB - Surface wetting on the textured surface is classically explained by the theories of Cassie-Baxter or Wenzel. However, in recent years, an increasing number of complex surface topographies with superhydrophobic properties have been achieved without prediction or simulation using these theories. One example is biomimetic surfaces. In many instances, theories were used to explain surface properties found in nature but have not led to or predicted the complex topographies. Although new wetting theories continue to emerge, there is not yet a set of design rules to guide the selection of surface topographies to achieve superhydrophobicity. By grouping known surface topographies into common geometrical descriptions and length scale, this paper suggests a set of surface topography classifications to provide selection guidelines for engineering superhydrophobic surfaces. Two key outcomes emerged from the design analysis: first, categorization of frequently reported surface patterns shows that there exists a set of commonly used descriptions among diverse designs; second, the degree of hydrophobicity improvement within a class of topography design can be used to predict the limit of improvement in superhydrophobicity for a given material. The presentation of topography descriptors by categories of design and performance may serve as a prologue to an eventually complete set of design guidelines for superhydrophobic performance. PMID- 28625066 TI - A rectal neuroendocrine neoplasm. AB - The incidence of gastric and rectal carcinoids is increasing. This is probably due to endoscopic screening. The prognosis is primarily dependent upon tumor size, aggressiveness (pathology, Ki-67), metastatic disease and stage. However, neuroendocrine carcinoma usually behaves as an adenocarcinoma. PMID- 28625067 TI - Colonic obstruction secondary to Actinomyces. AB - Actinomycosis is an uncommon granulomatous infection by Gram-positive anaerobic bacteria of the genus Actinomyces. A. israelii is a major human pathogen. The most frequent locations for colonization are cervicofacial (50%), abdominal (20%) and thoracic (15-20%). The abdominal actinomycosis predisposing factors include recent surgery, trauma and neoplasias. Certain cases have been associated with the intrauterine contraception device (IUD). PMID- 28625068 TI - Hepatic glycogenosis: a diagnostic challenge. AB - Recently, several cases of hepatic glycogenosis (HG) have been reported. Garcia Suarez et al. described a young female patient with poorly controlled type 1 diabetes, right upper quadrant pain and elevated serum transaminases and GGT. After other causes of liver disease were excluded and a liver biopsy was performed, the patient was diagnosed with HG. HG is rare and can be misdiagnosed as steatohepatitis. To date, less than 20 cases have been reported in adults. PMID- 28625069 TI - A rare cause of intestinal bleeding: duodenal metastasis from endometrial cancer. AB - With this report we alert to an extremely rare case of duodenal metastases, from an endometrial adenocarcinoma by lymphatic spread and whose primary manifestation was with gastrointestinal bleeding. We think this is the first case reported of duodenal metastases from endometrial carcinoma and with this presentation. PMID- 28625070 TI - McKittrick-Wheelock syndrome: unusual, but potentially lethal. AB - McKittrick-Wheelock syndrome is characterized by extracellular volume depletion and severe fluid and electrolyte imbalance caused by secretory tumors of the rectum, usually villous adenomas. Patients usually present signs of dehydration, hyponatremia, hypokalemia, and prerenal azotemia due to the chronic diarrhea, rich in ions and water. Since this is a potencially lethal entity without treatment, and a very unusual condition, we report a clinical case. Treatment consists in surgical resection of the tumor, although endoscopy polypectomy has also been reported. PMID- 28625071 TI - Adult gastric duplication: an unknown condition within the spectrum of gastric submucosal lesions. AB - BACKGROUND: Gastric duplication is an uncommon condition in adults representing only 4-8% of all gastrointestinal duplications. It develops as a cystic growth within the thick gastric wall that is surrounded by a layer of smooth muscle and lined with gastric mucosa. It is usually asymptomatic but may present with nonspecific abdominal symptoms as well as cyst-related complications such as gastrointestinal (GI) bleeding, ulceration and even pancreatitis. They are difficult to distinguish from other gastric submucosal lesions and may also mimic a gastrointestinal tumor (GIST) or mucinous cyst of the pancreas. Endoscopic ultrasound (EUS) is the most widely used diagnostic procedure and histology provides a definitive diagnosis. CASE REPORT: We report the case of a 36-year-old female patient with a history of a "contained" perforated gastric ulcer that was managed conservatively. The patient was diagnosed with a gastric GIST which prompted a laparoscopic subtotal gastrectomy and Roux-en-Y reconstruction with a good postoperative outcome. DISCUSSION: The definitive histological diagnosis was gastric duplication. Thus, the previous diagnosis of a "contained" perforated gastric ulcer was in fact a complication of the gastric duplication itself. PMID- 28625072 TI - Depression and anxiety among war-widows of Nepal: a post-civil war cross sectional study. AB - Thousands of Nepalese women were widowed as a consequence of a decade (1996-2006) long civil war in Nepal. These women are at grave risk of mental health problems due to both traumatic experiences and violation of natural order of widowhood. The present study explores the depression and anxiety among war-widows. In 2012, a cross-sectional study was designed to interview 358 war-widows using validitated Beck Depression Inventory and Beck Anxiety Inventory in four districts of Nepal - Bardiya, Surkhet, Sindhupalchowk and Kavrepalanchowk with history of high conflict intensity. The prevalence of depression and anxiety was 53% and 63% respectively. Financial stress was significantly associated with depression (2.67, 95% CI: 1.40-5.07) and anxiety (2.37, 95% CI: 1.19-4.72). High autonomy of women as compared to low autonomy, high social support as compared to low social support and literacy as opposed to illiteracy was associated with less likelihood of depression and anxiety. Our results suggest high magnitude of depression and anxiety among war-widows in Nepal. Future policy efforts should be directed at providing mental health services to identify mental health issues among conflict affected individuals with focus on education, employment and activities to promote social support and autonomy at community. PMID- 28625073 TI - The Impact of Structured Self-Monitoring of Blood Glucose Combined With Intensive Education on HbA1c Levels, Hospitalizations, and Quality-of-Life Parameters in Insulin-Treated Patients With Diabetes at Primary Care in Serbia: The Multicenter SPA-EDU Study. AB - BACKGROUND: We assessed the effect of structured self-monitoring of blood glucose (SMBG), in combination with intensive education, on metabolic control, SMBG frequency, hospitalizations, cardiovascular risk factors, and quality-of-life parameters in patients with insulin-treated diabetes in primary health care settings in Serbia. METHODS: This 6-month, observational, noninterventional study, followed 346 insulin-treated diabetes patients (type 1 diabetes [T1D], n = 57; type 2 diabetes [T2D], n = 289) from 28 primary care centers. Patients attended a 10-day course at the specialized educational center and were followed monthly by their primary care physicians. Patients used a simple paper tool to document 3-day, 7-point glucose profiles prior to each monthly clinic visit. Physicians reviewed the completed forms at each visit and used a standardized education program to provide remedial training. Changes in HbA1c levels, SMBG frequency, metabolic risk factors, and Diabetes Distress Scale (DDS) were assessed. RESULTS: Mean (+/- SD) HbA1c within the full cohort was significantly improved from baseline at 6 months (8.85 +/- 1.17% vs 7.91 +/- 1.24%, P < .01). Significant increases in average SMBG frequency per week were seen at 6 months versus baseline (14.6/week vs 4.3/week, P < .001). The mean (+/- SE) number of hospitalizations due to metabolic conditions was significantly lower during the 6 month study compared to the 6-month period prior to the study (0.14 +/- 0.04 vs 0.59 +/- 0.09). DDS scores decreased from 39.6 +/- 13.9 to 33.9 +/- 14.5, P < .01. CONCLUSION: The use of structured SMBG combined with intensive education was associated with clinically significant reductions in HbA1c, increased SMBG frequency, and improved quality of life. PMID- 28625075 TI - 2016 Research Forum Poster Session and Competition: Finalists and Posters. PMID- 28625074 TI - Do checkpoint inhibitors rely on gut microbiota to fight cancer? AB - The field of gut microbiota is of growing interest, especially in the recent discoveries of its interaction with host immune responses, which when disrupted, can further alter immunity. It also plays a role in cancer development, its microenvironment and response to anticancer therapeutics. Several recently published experimental studies had explored the efficacy of modifying microbiota to enhance the response of checkpoint inhibitors, suggesting its beneficial function in cancer management and potential to be targeted as a therapeutic agent to enhance efficacy of checkpoint inhibitors. Here we review available evidence, mechanisms and hypotheses of its use to enhance cancer response. PMID- 28625076 TI - The One Abutment-One Time Protocol: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The use of definitive abutments (DAs) at time of implant placement has been introduced to overcome limitations of dis/reconnection of healing/provisional abutments (PAs). With little and inconsistent information in the literature regarding the effectiveness of using DAs, the aim of this systematic review is to examine marginal bone and soft tissue level changes, technical and biologic complications, and implant failure rate associated with use of DAs and PAs. METHODS: This systematic review was prepared according to guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and online trial registers were searched for studies comparing use of DAs and PAs. The Cochrane Collaboration risk of bias tool was used to assess selected studies, and meta-analyses were performed using statistical software. RESULTS: A total of 1,124 citations were identified. Of these, seven trials with 363 dental implants in 262 participants were included in the analysis. Pooled estimates for marginal bone level changes showed significant differences between the two prosthetic techniques in favor of using DAs. No significant differences were found in soft tissue level changes, technical and biologic complications, or implant failure rate. CONCLUSIONS: Within the limitations of this review, DAs appear to be a viable alternative to PAs at time of implant placement. However, favorable changes in peri-implant marginal bone level associated with use of DAs should be viewed with caution as its clinical significance is still uncertain. PMID- 28625077 TI - Microbiome and Microbial Biofilm Profiles of Peri-Implantitis: A Systematic Review. AB - BACKGROUND: This systematic review assesses microbiologic profiles of peri implantitis, periodontitis, and healthy implants based on studies that evaluated microbial biofilms and entire microbiomes to establish their similarities and differences. METHODS: The Medical Literature Analysis and Retrieval System Online via PubMed, Excerpta Medica Database, and Cochrane Central Register of Controlled Trials, were searched without language restrictions through July 30, 2016. Observational studies that evaluated microbial profiles or entire microbiomes of peri-implantitis compared with healthy implants or periodontitis were considered eligible for inclusion. A descriptive summary was created to determine quantity of data and interstudy variations. RESULTS: Of 126 potentially eligible articles, 26 were included in this study. Twenty-one of these articles evaluated the microbiologic profile of peri-implantitis versus healthy implants or periodontitis using conventional microbiologic techniques. Five articles evaluated the entire microbiome using genomic sequencing. Teeth with periodontitis, healthy implants, or implants with peri-implantitis were colonized by periodontal microorganisms. Porphyromonas gingivalis and especially Prevotella intermedius/nigrescens were often identified at peri-implantitis sites. Peri implantitis sites were also colonized by uncultivable asaccharolytic anaerobic Gram-positive rods and anaerobic Gram-negative rods, which were not frequently identified in teeth with periodontitis or healthy implants. Opportunistic microorganisms were not found very frequently in peri-implantitis sites. CONCLUSIONS: Peri-implantitis represents a heterogeneous mixed infection that includes periodontopathic microorganisms, uncultivable asaccharolytic anaerobic Gram-positive rods and other uncultivable Gram-negative rods, and, rarely, opportunistic microorganisms such as enteric rods and Staphylococcus aureus. Sequencing methods that evaluate the entire microbiome improve identification of microorganisms associated with peri-implantitis. PMID- 28625078 TI - High titers of ADAbs in rheumatic disease patients undergoing anti-TNF therapy is not associated with lupus-like autoimmunity. PMID- 28625079 TI - Retrospective analysis of nephritis response and renal outcome in a cohort of 928 Egyptian lupus nephritis patients: a university hospital experience. AB - Aim We aim to describe the pattern of response to treatment in a cohort of Egyptian lupus nephritis (LN) patients and to define variable prognostic factors. Methods We retrospectively analyzed records of 928 systemic lupus erythematosus (SLE) patients (898 females, 30 males) with biopsy-confirmed LN seen between 2006 and 2012 at Cairo University hospitals. Results Our study involved 928 SLE patients with a mean age of 26.25 +/- 6.487 years, mean LN duration at time of renal biopsy 6.48 +/- 4.27 months, mean SLEDAI 28.22 +/- 11.7, and mean follow-up duration of 44.14 +/- 17.34 months. Induction treatment achieved remission in 683 patients. Remission was achieved in all 32 patients with class II LN, compared to 651/896 (72.7%) patients in classes III, IV, and V. Induction by intravenous (IV) cyclophosphamide achieved response in 435/575 (75.7%) patients, while induction by mycophenolate mofetil (MMF) resulted in response in 216/321 (67.3%) patients ( p = 0.0068). Nephritic flares were least observed when MMF was used for maintenance (30/239 (12.6%) patients), compared to 71/365 patients (19.5%) ( p = 0.0266) when azathioprine (AZA) was used, and 22/79 patients (27.8%) ( p = 0.002) with IV cyclophosphamide. Class IV LN, high chronicity index, presence of crescents, and interstitial fibrosis in biopsies were all associated with chronic kidney disease (CKD) development eventually ( p < 0.001, p = 0.005, p = 0.012, and p = 0.031, respectively). By the end of the study duration, 305 (32.7%) patients had CKD. Logistic regression detected that high baseline serum creatinine, failure to achieve remission, hypertension, and nephritic flare were the main risk factors for poor renal outcome ( p < 0.001, p < 0.001, p = 0.004, and p < 0.001, respectively). The 5 years' mortality was 69 (7.4%) patients with sepsis being the main cause of death. Conclusion IV cyclophosphamide superseded as induction treatment, while MMF was the best maintenance treatment. High serum creatinine, hypertension, and nephritic flare were the main risk factors for poor renal outcome. PMID- 28625080 TI - In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis. AB - BACKGROUND: Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine 18-labeled 9-beta-d-arabinofuranosylguanine ([18F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant induced arthritis (AIA) small animal model. METHODS: Using positron emission tomography-computed tomography imaging, uptake of [18F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry. RESULTS: Differential uptake of [18F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry. CONCLUSION: [18F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials. PMID- 28625081 TI - Integration of Action and Size Perception Through Practice. AB - Size perception is known to influence our usual interactions with environment. Numerous studies highlighted that during the visual presentation of an object, the properties of manual actions vary as a function of this object's size. In order to better understand the dynamic variations of relationships between size perception and action, we used an experimental paradigm consisting in two phases. During a previous implicit learning phase, a manual response (right or left) was specifically associated with the appearance of a large or small stimulus. During further test phase, participants were required to prepare a response while discriminating the color of a stimulus (GO/No GO task). We observed that the response execution was faster when the size of the stimulus was congruent with the size that had been associated to this response (during implicit learning phase). These results suggest that when a response usually co-occurs with visual stimuli characterized by a specific size pattern, the response and the size pattern become integrated. Any subsequent preparation and execution of this action are therefore influenced by the reactivation of this visual pattern. This result brings out new insights on how sensorimotor interactions may modulate the ability to anticipate perceptive size variations in the environment. PMID- 28625082 TI - Incorrect AM/PM Insulin Pump Clock Settings Can Result in an Unstable Insulin Dosing Feedback Loop. PMID- 28625083 TI - Spinal cord ischemia after endoscopic ultrasound guided celiac plexus neurolysis: case report and review of the literature. AB - INTRODUCTION: Endosonography guided celiac plexus neurolysis is efficacious in the management of severe pain due to advanced pancreatic cancer. Although endoscopic ultrasound (EUS) guided celiac neurolysis (CN) is mostly a safer procedure than the percutaneous posterior approach, severe complications such as paraplegia have been reported. CASE REPORT: We describe a patient with advanced adenocarcinoma of the pancreas and severe pain who developed irreversible paraplegia after EUS guided CN. CONCLUSIONS: Endosonography guided celiac plexus neurolysis also might be complicated with paraplegia as already observed with percutaneous approach. The underlying mechanism could not be explained clearly until now. We detected concomitant embolic occlusion of Adamkiewicz and anterior radicularis magna arteries in magnetic resonance angiography. So, this procedure must be considered only for malignancy patients. PMID- 28625084 TI - Objectively assessed physical activity and associated factors of sedentary behavior among survivors of stroke living in Cape Town, South Africa. AB - PURPOSE: To investigate objectively measured physical activity in stroke survivors living in low-income areas of Cape Town, South Africa, specifically to: (a) describe the volume of daily physical activity and time spent in different intensity levels and (b) investigate the association of factors covering the International Classification of Functioning, Disability and Health with sedentary behavior. MATERIALS AND METHODS: A cross-sectional design was used, where forty five ambulatory community-dwelling stroke survivors participated. Volume and intensity of physical activity were assessed with accelerometers for three to five consecutive days. Personal and environmental factors, along with body function and activity, were captured. Multiple linear regression was used to investigate factors associated with the percentage of days spent sedentary. RESULTS: The median number of steps per day was 2393, and of the average 703 minutes of wear time, 80% were spent in sedentary, 15% in light, and 5% in moderate-to-vigorous intensity physical activity. Age, stroke severity, and failing to receive outpatient rehabilitation were independently associated with sedentary, which, taken together, explained 52% of the variance. CONCLUSIONS: Low volumes of physical activity and high amount of sedentary time emphasize the need to develop strategies that will increase physical activity. Providing outpatient rehabilitation in a systematic manner post-stroke is a potential target of health care programs in order to reduce sedentary behavior. Implications for rehabilitation Objectively measured physical activity among community-dwelling survivors of stroke in Cape Town, South Africa was low in volume, and the majority did not meet the recommendations of 150 minutes of at least moderate intensity physical activity. The majority of stroke survivors in South Africa spent most of their time sedentary, which could further increase the risk of cardiovascular impairments. Outpatient rehabilitation should be provided to all patients after stroke since it appears to reduce sedentary time. PMID- 28625085 TI - Enjoyable company in sharing stroke experiences; - lifestyle groups after stroke. AB - BACKGROUND: Even people with mild to moderate stroke will experience changes in their abilities to perform everyday occupations. Group interventions may be appropriate in late-stage rehabilitation. The aim of this study was to explore how the participants involved themselves in person-centered lifestyle groups after stroke in Norway. METHOD: Semi-structured interviews were performed with six older adults with mild-to-moderate stroke who had participated in lifestyle groups over a period of nine months. The interviews were analyzed using qualitative content analysis. RESULTS: The participants involved themselves in the lifestyle groups in a variety of ways by creating enjoyable company in sharing stroke experiences, sharing knowledgeable interest, pushing and forcing each other forward and reflecting on self-worth. Through doing group activities together, they created various ways of being, belonging and becoming, addressing development of strategies for regaining self-belief and a sense of autonomy, and for adapting to everyday life post-stroke. CONCLUSION: The participants were active contributors in the groups and pushed each other and themselves regarding involvement in meaningful occupations. This active participation seemed to bring the participants' resources into focus and contrasted with the frequent negative perceptions of people post-stroke as 'victims'. PMID- 28625087 TI - The ex-pat effect: presence of recent Western immigrants is associated with changes in age at first birth and birth rate in a Maya population from rural Guatemala. AB - BACKGROUND: Economic transitions expose indigenous populations to a variety of ecological and cultural challenges, especially regarding diet and stress. These kinds of challenges are predicted by evolutionary ecological theory to have fitness consequences (differential reproduction) and, indeed, are often associated with changes in fertility dynamics. It is currently unclear whether international immigration might impact the nature of such an economic transition or its consequences for fertility. AIM: To examine measures of fertility, diet and stress in two economically transitioning Maya villages in Guatemala that have been differentially exposed to immigration by Westerners. SUBJECTS AND METHODS: This study compared Maya women's ages at first birth and birth rates between villages and investigated whether these fertility indicators changed through time. It also explored whether the villages differed in relation to diet and/or a proxy of stress. RESULTS: It was found that, in the village directly impacted by immigration, first births occurred earlier, but birth rate was slower. In both villages, over the sampled time window, age at first birth increased, while birth rate decreased. The villages do not differ significantly in dietary indicators, but the immigration-affected village scored higher on the stress proxy. CONCLUSION: Immigration can affect fertility in host communities. This relationship between immigration and fertility dynamics may be partly attributable to stress, but this possibility should be evaluated prospectively in future research. PMID- 28625088 TI - Mitochondrial content and hepcidin are increased in obese pregnant mothers. AB - OBJECTIVE: Maternal obesity is characterized by systemic low-grade inflammation and oxidative stress (OxS) with the contribution of fetal sex dimorphism. We recently described increased mitochondrial content (mtDNA) in placentas of obese pregnancies. Here, we quantify mtDNA and hepcidin as indexes of OxS and systemic inflammation in the obese maternal circulation. METHODS: Forty-one pregnant women were enrolled at elective cesarean section: 16 were normal weight (NW) and 25 were obese (OB). Obese women were further classified according to the presence/absence of maternal gestational diabetes mellitus (GDM); [OB/GDM(-)]: n = 15, [OB/GDM(+)]: n = 10. mtDNA and hepcidin were evaluated in blood (real-time PCR) and plasma (ELISA). RESULTS: mtDNA and hepcidin levels were significantly increased in OB/GDM(-) versus NW, significantly correlating with pregestational BMI. Male/female (M/F) ratio was equal in study groups, and overall F-carrying pregnancies showed significantly higher mtDNA and hepcidin levels than M-carrying pregnancies both in obese and normal weight mothers. CONCLUSIONS: Our results indicate a potential compensatory mechanism to increased obesity-related OxS and inflammation, indicated by the higher hepcidin levels found in obese mothers. Increased placental mitochondrial biogenesis, due to lipotoxic environment, may account for the greater mtDNA amount released in maternal circulation. This increase is namely related to F-carrying pregnancies, suggesting a gender specific placental response. PMID- 28625089 TI - Endoscopic ultrasonography for preoperative staging of esophageal carcinoma. AB - OBJECTIVE: To evaluate the diagnostic value of endoscopic ultrasonography (EUS) in preoperative staging of esophageal carcinoma (EC). MATERIAL AND METHODS: A total of 86 surgical patients with EC who were confirmed by endoscopy and biopsy underwent preoperative TN staging with EUS examination. The EUS findings were compared with surgical pathologic results. RESULTS: The accuracy of EUS in T and N staging of EC was 82.6% and 84.9%, respectively. While determining whether EC invades the muscularis propria or outer membrane, EUS had the favorable sensitivity, specificity, positive predictive value and negative predictive value. The short-axis diameter of lymph nodes of 5mm had high sensitivity and negative predictive value to determine malignance with low specificity and positive predictive value. The short-axis diameter of 10mm presented the satisfactory sensitivity, specificity, positive predictive value and negative predictive value. CONCLUSION: EUS can accurately determine the TN staging of EC and provide a reliable basis for the treatment of EC. PMID- 28625086 TI - Hepatitis C virus-apolipoprotein interactions: molecular mechanisms and clinical impact. AB - INTRODUCTION: Chronic hepatitis C virus (HCV) infection is a leading cause of cirrhosis, hepatocellular carcinoma and liver failure. Moreover, chronic HCV infection is associated with liver steatosis and metabolic disorders. With 130 150 million people chronically infected in the world, HCV infection represents a major public health problem. One hallmark on the virus is its close link with hepatic lipid and lipoprotein metabolism. Areas covered: HCV is associated with lipoprotein components such as apolipoproteins. These interactions play a key role in the viral life cycle, viral persistence and pathogenesis of liver disease. This review introduces first the role of apolipoproteins in lipoprotein metabolism, then highlights the molecular mechanisms of HCV-lipoprotein interactions and finally discusses their clinical impact. Expert commentary: While the study of virus-host interactions has resulted in a improvement of the understanding of the viral life cycle and the development of highly efficient therapies, major challenges remain: access to therapy is limited and an urgently needed HCV vaccine remains still elusive. Furthermore, the pathogenesis of disease biology is still only partially understood. The investigation of HCV lipoproteins interactions offers new perspectives for novel therapeutic approaches, contribute to HCV vaccine design and understand virus-induced liver disease and cancer. PMID- 28625090 TI - Accuracy Assessment of a Blood Glucose Monitoring System for Self-Testing with Three Test Strip Lots Following ISO 15197:2013/EN ISO 15197:2015. PMID- 28625091 TI - Factors related to tinnitus and hyperacusis handicap in older people. AB - OBJECTIVE: The aim was to assess factors related to tinnitus and hyperacusis handicap in older people. DESIGN: Retrospective cross-sectional. STUDY SAMPLE: Data were gathered for 184 patients with an average age of 69 years. RESULTS: Tinnitus handicap as measured via the Tinnitus Handicap Inventory (THI) was significantly predicted by tinnitus annoyance as measured via the visual analogue scale (VAS) (regression coefficient, b = 2.9, p < 0.001) and the effect of tinnitus on the patient's life as measured via the VAS (b = 3.9, p < 0.001). Hyperacusis handicap as measured via the Hyperacusis Questionnaire (HQ) was significantly predicted by the score on the depression subscale of the Hospital Anxiety and Depression Scale (HADS) (b = 0.8, p < 0.001) and to a small extent by the THI score (b = 0.07, p = 0.048). Insomnia scores as measured via the Insomnia Severity Index (ISI) were significantly predicted by scores on the depression subscale of the HADS (b = 0.46, p = 0.007). CONCLUSIONS: Since tinnitus annoyance significantly predicts tinnitus handicap, it is important to explore factors associated with annoyance that may be useful in designing appropriate rehabilitative interventions aimed at reducing tinnitus handicap in older people. Future studies should explore whether hyperacusis and insomnia in older people with tinnitus need to be managed in conjunction with treatment for depression. PMID- 28625092 TI - Factors affecting outcome in ocular myasthenia gravis. AB - AIM OF THE STUDY: 50%-60% of patients with ocular myasthenia gravis (OMG) progress to generalized myasthenia gravis (GMG) within two years. The aim of our study was to explore factors affecting prognosis of OMG and to test the predictive role of several independent clinical variables. MATERIALS AND METHODS: We reviewed a cohort of 168 Caucasian patients followed from September 2000 to January 2016. Several independent variables were considered as prognostic factors: gender, age of onset, results on electrophysiological tests, presence and level of antibodies against acetylcholine receptors (AChR Abs), treatments, thymic abnormalities. The primary outcome was the progression to GMG and/or the presence of bulbar symptoms. Secondary outcomes were either achievement of sustained minimal manifestation status or worsening in ocular quantitative MG subscore (O-QMGS) or worsening in total QMG score (T-QMGS), assessed by Myasthenia Gravis Foundation of America (MGFA) quantitative scores. Changes in mental and physical subscores of health-related quality of life (HRQoL) were assessed with SF-36 questionnaire. Variance analysis was used to interpret the differences between AChR Ab titers at different times of follow up among the generalized and non-generalized patients. RESULTS: Conversion to GMG occurred in 18.4% of patients; it was significantly associated with sex, later onset of disease and anti-AChR Ab positivity. Antibody titer above the mean value of 25.8 pmol/mL showed no significant effect on generalization. Sex and late onset of disease significantly affected T-QMGS worsening. None of the other independent variables significantly affected O-QMGS and HRQoL. CONCLUSIONS: Sex, later onset and anti-AChR Ab positivity were significantly associated with clinical worsening. PMID- 28625093 TI - Response to: The need for narrative reflection and experiential learning in medical education: A lesson learned through an urban indigenous health elective. PMID- 28625094 TI - A new indole alkaloid from the traditional Chinese medicine Chansu. AB - A new indole alkaloid N'-formylserotonin (1), along with five known indole alkaloids N'-methylserotonin (2), 5-hydroxy-1H-indole-3-carbaldehyde (3), N acetylserotonin (4), 6-hydroxy-1-oxo-3,4-dihydro-beta-carboline (5), and bufoserotoin C (6), were isolated from the water extract of traditional Chinese medicine Chansu. Their structures were elucidated on the basis of spectral analyses. The cytotoxicities of 1-6 against human lung adenocarcinoma epithelial cells A549 were tested using the MTT method. Compound 6 exhibited stronger cytotoxic effect than 5-FU, and 1-5 showed no cytotoxic effects. Bufoserotonin C is one of the cytotoxic components in water-soluble extract of Chansu. PMID- 28625095 TI - Fertility preservation in women with gynaecologic cancer: the impact on quality of life and psychological well-being. AB - The aim of this article is to propose a brief commentary about the impact of gynaecologic cancer treatments on the reproductive capacity of affected women and the importance of the fertility preservation treatments to improve quality of life and psychological well-being. The experience of gynaecologic cancer and treatment affects sexual function and psychological well-being of patients. Therefore, the preservation of reproductive potential is central to quality of life. Despite the importance of fertility preservation for cancer survivors' quality of life and psychological well-being, there is still little information about these treatments. We suggest that further studies about the impact on quality of life and psychological outcomes of fertility preservation counselling and fertility preservation treatments should be conducted. PMID- 28625096 TI - Surgical technique and early outcomes of intramedullary nailing of displaced proximal humeral fractures in an Asian population using a contemporary straight nail design. AB - BACKGROUND: Despite being a common orthopedic injury, the optimal management of proximal humeral fractures remains a topic of debate. Although intramedullary nails have been used to treat these fractures, several complications have been reported with older nail devices. We describe our surgical technique and aim to evaluate the early functional and radiological outcomes of displaced Neer's two- to four-part proximal humeral fractures undergoing fixation with a contemporary straight intramedullary nail. METHODS: A prospective cohort study of 22 consecutive patients (mean age 55.7 +/- 18.0) with acute displaced proximal humeral fractures underwent intramedullary nailing (Depuy Synthes MultiLoc Humeral Nail) by a single surgeon in a single institution. According to Neer's classification, 11 had two-part fractures, 9 had three-part fractures, and 2 had four-part fractures. Functional and radiological outcomes, as well as occurrence of complications, were assessed at 12 months postoperatively. RESULTS: The mean Constant-Murley score and American Shoulder and Elbow Surgeons score at 12 months were 75.5 +/- 12.1 and 81.7 +/- 6.2, respectively. Mean range of motion was forward flexion 144.3 +/- 28.4, abduction 141.3 +/- 30.5, external rotation 58.0 +/- 13.9, and internal rotation 62.0 +/- 15.2. Mean visual analog scale score was 1.7 +/- 0.8. Radiographic fracture union was achieved at a mean of 3 months post op. One patient underwent a second surgery for screw removal due to a proximal screw backing out. No other complications were found in our cohort. Notably, no patients had clinical signs and symptoms of subacromial impingement and/or rotator cuff tear. CONCLUSION: Our study demonstrated that intramedullary nailing using the contemporary straight nail design is well suited for Neer's two- and three-part proximal humeral fractures, with good early outcomes and low rates of complications. Results for four-part fractures were, however, inferior in our cohort, suggesting that further studies with larger patient numbers are needed to determine the role of intramedullary nailing for four-part fractures. PMID- 28625098 TI - Endoprosthetic replacement versus cement spacer in reconstruction of proximal humerus after tumor resection: Cost and benefits. AB - BACKGROUND: Proximal end of the humerus is a common site for both primary and metastatic bone tumors. Limb salvage with endoprosthetic replacement is the most common means of reconstruction, but it has been proved that cement spacer are more beneficial for inferior shoulder function. Thus, limb salvage can be replaced by cheaper spacers especially in poor societies. PATIENTS AND METHODS: This study included 20 patients, of whom 14 were female, with a mean age of 40.4 years (range 12-60). Among the study population, six were diagnosed with osteosarcomas, two chondrosarcomas, two myeloma, two lymphoma, four metastatic carcinoma in the breast, two giant cell tumor, and two recurrent chondroplastoma. Limb salvage was successfully done in all patients: Tikhoff-Linberg type I in 12 cases and type V in 8. Endoprosthetic replacement was done in eight cases. An on table fabricated cement spacer was used in 12 cases. RESULTS: Follow-up ranged from 12 to 75 months, with a mean of 25.9 months. Functional outcome was almost comparable in both types of reconstruction, especially patient's satisfaction, with a mean function of 65%. CONCLUSION: A relatively expensive endoprosthesis could be replaced by a much cheaper cement spacer if their function is comparable. PMID- 28625097 TI - Use of the Pirani score in monitoring progression of correction and in guiding indications for tenotomy in the Ponseti method: Are we coming to the same decisions? AB - PURPOSE: The Pirani score is widely used in the treatment of idiopathic clubfoot. Some authors recommended to base decision for Achilles tenotomy in Ponseti method on this score (hindfoot score [HFS] > 1, once reducibility of lateral head of talus (LHT) is zero) instead of originally described indications (dorsiflexion < 10-15 degrees once complete abduction is achieved). Yet correspondence of these indications has not been evaluated. Aim of this study was to verify whether in a cohort, where decision is based on dorsiflexion, the Pirani score corresponds to the limits suggested. Secondarily, to describe temporal variation in Pirani score along treatment, which has not been previously investigated. METHODS: In a prospective study, 79 idiopathic clubfeet in 47 cases consecutively treated with Ponseti method by a single orthopaedic surgeon were evaluated at each casting session with Pirani system; score progression and scores at time of decision to perform tenotomy were determined. RESULTS: HFS and its subcomponents showed minimal improvement during subsequent sessions of casting and then rapid correction with tenotomy. Medial crease resolved rapidly. Midfoot score and its remaining subcomponents corrected gradually. Total Pirani score showed initially a progressive correction and then a more abrupt improvement with tenotomy. At the time of decision to perform tenotomy, in 8 (10.1%) of 79 cases, the decision whether or not to perform tenotomy based on dorsiflexion would have been different based on the cut-offs for Pirani score suggested. CONCLUSION: Using Pirani score in guiding indication for tenotomy may imply different decisions in a portion of cases, which should be considered when comparing series. PMID- 28625099 TI - Toxicology in clinical laboratories: challenging times. AB - In recent years, there have been a number of significant developments in toxicology within clinical laboratories, both with the available instrumentation and in the range of compounds abused by the drug using communities. There have also been developments in the regulation of forensic science in the UK which may in time impact clinical toxicology. This review is designed to provide an update of these changes within toxicology to the more general pathology laboratory audience. For detailed information in specific areas, the reader is referred to the references in the text. In the preparation of this review, the references held by the author as part of his practice of an analytical toxicologist in the NHS were supplemented by a full literature search in Medline and Embase and a review of pertinent UK and European Governments and regulatory agency websites for recent documentation. PMID- 28625100 TI - Applications of meta-analytic structural equation modelling in health psychology: examples, issues, and recommendations. AB - Statistical methods play an important role in behavioural, medical, and social sciences. Two recent statistical advances are structural equation modelling (SEM) and meta-analysis. SEM is used to test hypothesised models based on substantive theories, which can be path, confirmatory factor analytic, or full structural equation models. Meta-analysis is used to synthesise research findings in a particular topic. This article demonstrates another recent statistical advance - meta-analytic structural equation modelling (MASEM) - that combines meta-analysis and SEM to synthesise research findings for the purpose of testing hypothesised models. Using the theory of planned behaviour as an example, we show how MASEM can be used to address important research questions that cannot be answered by univariate meta-analyses on Pearson correlations. Specifically, MASEM allows researchers to: (1) test whether the proposed models are consistent with the data; (2) estimate partial effects after controlling for other variables; (3) estimate functions of parameter estimates such as indirect effects; and (4) include latent variables in the models. We illustrate the procedures with an example on the theory of planned behaviour. Practical issues in MASEM and suggested solutions are discussed. PMID- 28625101 TI - A versatile method for bladder segmentation in computed tomography two dimensional images under adverse conditions. AB - This article presents the design and evaluation of an algorithm for urinary bladder segmentation in medical images, from contrastless computed tomography studies of patients suffering from bladder wall tumours. These situations require versatile methods of segmentation, able to adapt to the structural changes the tumours provoke in the bladder wall, reflected as irregularities on the images obtained, creating adversities to the segmentation process. This semi-automatic method uses fuzzy c-means clustering, a Gaussian-curve-based intensity transformation, and active contour models, requiring only the physician's input of a single seed point for each anatomical view, in order to segment the bladder volume in all frames that include it. The performance of the method was evaluated on eight patients of The Cancer Genome Atlas-Urothelial Bladder Carcinoma collection, achieving approximately 79% of successful segmentations for small tumour patients (below 2.0 cm of diameter) and approximately 72% between 2.0 and 2.9 cm. Successful segmentations for small tumour patients presented an average of 3.7 mm Hausdorff distance and 91.0% degree of overlap. The promising performance attained, especially for small tumour patients, revealed a high potential of this method to serve as basis for an effective early-stage bladder wall tumour computer-aided diagnosis system. PMID- 28625102 TI - Spatiotemporal meta-analysis: reviewing health psychology phenomena over space and time. AB - Individual studies of health psychology are samples taken in particular places at particular times. The results of such studies manifest multiple processes, including those associated with individual, sample, intervention, and study design characteristics. Although extant meta-analyses of health phenomena have routinely considered these factors to explain heterogeneity, they have tended to neglect the environments where studies are conducted, which is ironic, as health phenomena cluster in space and times (e.g., epidemics). The settings in which study participants live, work, and recreate can be characterised by such environmental factors such as disease, weather, local and broad economic trends, the level of stigmatisation of minority groups, and allostatic load due to all causes. We introduce spatiotemporal meta-analysis, designed to address heterogeneity in study environments. We list potential challenges in developing spatiotemporal meta-analyses, and discuss future directions for this form of systematic reviewing methodology. Logically, to the extent that relevant spatiotemporal information on environmental conditions is available and varies widely, it can help to explain variability in study results that is not explained by individual, sample, study, or intervention features. PMID- 28625103 TI - The robustness of false memory for emotional pictures. AB - Emotional material is commonly reported to be more accurately recognised; however, there is substantial evidence of increased false alarm rates (FAR) for emotional material and several reports of stronger influences on response bias than accuracy. This pattern is more frequently reported for words than pictures. Research on the mechanisms underlying bias differences has mostly focused on word lists under short retention intervals. This article presents four series of experiments examining recognition memory for emotional pictures while varying arousal and the control over the content of the pictures at two retention intervals, and one study measuring the relatedness of the series picture sets. Under the shorter retention interval, emotion increased false alarms and reduced accuracy. Under the longer retention interval emotion increased hit rates and FAR, resulting in reduced accuracy and/or bias. At both retention intervals, the pattern of valence effects differed based on the arousal associated with the picture sets. Emotional pictures were found to be more related than neutral pictures in each set; however, the influence of relatedness alone does not provide an adequate explanation for all emotional differences. The results demonstrate substantial emotional differences in picture recognition that vary based on valence, arousal and retention interval. PMID- 28625104 TI - Modelling the effect of immigration on drinking behaviour. AB - A drinking model with immigration is constructed. For the model with problem drinking immigration, the model admits only one problem drinking equilibrium. For the model without problem drinking immigration, the model has two equilibria, one is problem drinking-free equilibrium and the other is problem drinking equilibrium. By employing the method of Lyapunov function, stability of all kinds of equilibria is obtained. Numerical simulations are also provided to illustrate our analytical results. Our results show that alcohol immigrants increase the difficulty of the temperance work of the region. PMID- 28625105 TI - Adsorption of Cr(VI) on nano Uio-66-NH2 MOFs in water. AB - An efficient adsorbent, nano Uio-66-NH2 Metal-organic frameworks (MOFs), for the high efficiency removal of Cr(VI) from aqueous solution was successfully synthesized. The adsorbent was characterized and its performance in Cr(VI) removal was evaluated for the first time. Kinetic data reveal that the Cr(VI) adsorption is rapid in the beginning followed by a slower adsorption process; The Cr(VI) adsorption kinetics were well described by the pseudo-second-order kinetics model. The calculated adsorption capacity of this adsorbent for Cr(VI) by Langmuir model was 32.36 mg/g at pH 6.5. The temperature-dependent isotherms indicated that the adsorption reaction of Cr(VI) on the MOFs was a spontaneous process. Filtration experiments revealed that the membranes fabricated by the MOFs could quickly remove Cr(VI) ions from the aqueous solutions. Electrostatic attraction between Uio-66-NH2 and Cr(VI) should be the mechanism for Cr(VI) adsorption by Uio-66-NH2. PMID- 28625106 TI - Deceptive pollination and insects' learning: a delicate balance. AB - In this paper we propose and discuss a simple two-dimensional model describing the interaction between two species: a plant population that gets pollinated by an insect population. The plants attract the insects deceiving them and not delivering any reward. We are interested in analysing the effect of learning by the insect population due to unsuccessfully visiting the deceiving plants. We are especially interested in three elements: conditions for the simultaneous coexistence of both species, their extinction as a function of the biological cost of the deceptiveness for the pollinator, and the appearance of oscillations in the dynamics. We also look for conditions under which plants would be better off by switching to different strategies, in particular, we look for conditions for the existence and stability of the equilibria of the corresponding differential equations system, and the conditions for the existence of periodic solutions. PMID- 28625108 TI - Memory dynamics under stress. AB - Stressful events have a major impact on memory. They modulate memory formation in a time-dependent manner, closely linked to the temporal profile of action of major stress mediators, in particular catecholamines and glucocorticoids. Shortly after stressor onset, rapidly acting catecholamines and fast, non-genomic glucocorticoid actions direct cognitive resources to the processing and consolidation of the ongoing threat. In parallel, control of memory is biased towards rather rigid systems, promoting habitual forms of memory allowing efficient processing under stress, at the expense of "cognitive" systems supporting memory flexibility and specificity. In this review, we discuss the implications of this shift in the balance of multiple memory systems for the dynamics of the memory trace. Specifically, stress appears to hinder the incorporation of contextual details into the memory trace, to impede the integration of new information into existing knowledge structures, to impair the flexible generalisation across past experiences, and to hamper the modification of memories in light of new information. Delayed, genomic glucocorticoid actions might reverse the control of memory, thus restoring homeostasis and "cognitive" control of memory again. PMID- 28625107 TI - Associations between omega-3 fatty acids and 25(OH)D and psychological distress among Inuit in Canada. AB - BACKGROUND: Inuit in Canada have experienced dietary changes over recent generations, but how this relates to psychological distress has not been investigated. OBJECTIVE: To evaluate how nutritional biomarkers are related to psychological distress. DESIGN: A total of 36 communities in northern Canada participated in the International Polar Year Inuit Health Survey (2007-2008). Of 2796 households, 1901 (68%) participated; 1699 Inuit adults gave blood samples for biomarker analysis and answered the Kessler 6-item psychological distress questionnaire (K6). Biomarkers included n-3 fatty acids and 25-hydroxyvitamin D (25(OH)D). The K6 screens for psychological distress over the last 30 days with six items scored on a 4-point scale. A total score of 13 or more indicates serious psychological distress (SPD). Logistic regression models were used to investigate any associations between SPD and biomarkers while controlling for age, gender, marital status, days spent out on the land, feeling of being alone, income and smoking. RESULTS: The 30-day SPD prevalence was 11.2%, with women below 30 years having the highest and men 50 years and more having the lowest SPD prevalence at 16.1% and 2.6%, respectively. SPD was associated with being female, younger age, not being married or with a common-law partner, spending few days out on the land, feelings of being alone, smoking and low income. Low levels of both 25(OH)D and long-chain n-3 FAs were associated with higher odds for SPD in both unadjusted and adjusted logistic regression models. CONCLUSION: In this cross-sectional analysis, low levels of 25(OH)D and long-chain n-3 FAs were associated with higher odds ratios for SPD, which highlights the potential impact of traditional foods on mental health and wellbeing. Cultural practices are also important for mental health and it may be that the biomarkers serve as proxies for cultural activities related to food collection, sharing and consumption that increase both biomarker levels and psychological well-being. ABBREVIATIONS: n-3 FAs: omega-3 fatty acids; PUFAs: polyunsaturated fatty acids; 25(OH)D: 25 hydroxyvitamin D; IPY: International Polar Year; IHS : Inuit Health Survey; RBC: red blood cell; OR: odds ratio; K6: Kessler 6-item screening scale; SPD: serious psychological distress; EPA: eicosapentaenoic acid (20:5 n-3); DHA: docosahexaenoic acid (22:6 n-3); DPA n-3: docosapentaenoic acid (22:5 n-3); n-3 LC-PUFAs: EPA (20:5 n-3) + DHA (22:6 n-3) + DPA (22:5 n-3); BMI: body mass index (kg m-2). PMID- 28625109 TI - The study of a pilot-scale aerobic/Fenton/anoxic/aerobic process system for the treatment of landfill leachate. AB - In this study, a combined aerobic-Fenton-anoxic/aerobic system was designed for the remediation of raw landfill leachate in a pilot-scale experiment. This system included (i) a granular sludge biological oxidation procedure that achieves the accumulation of nitrite nitrogen ([Formula: see text]) under aerobic conditions; (ii) a Fenton process that improves the biodegradability of the biotreated leachate and (iii) an activated sludge biological oxidation component under anoxic and aerobic conditions. Additionally, a shortcut nitrification and denitrification pathway was achieved. The effects of free ammonia, temperature and pH on nitrite accumulation were discussed. The change in the biochemical oxygen demand/chemical oxygen demand ratio of the effluent after shortcut nitrification was also analysed. The microbial community in the reactor were also investigated. The problem of the lack of carbon source in the denitrification process can be solved by the Fenton reagent method. Moreover, it was beneficial to achieving nitrogen removal as well as the more extensive removal of organic matter. The treatment strategy employed in this study exhibited good results and provided the potential practical application for treating landfill leachate. PMID- 28625110 TI - Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis in elderly patients with pulmonary embolism: A SEATTLE II sub-analysis. AB - Elderly patients with acute pulmonary embolism (PE) have higher mortality than non-elderly patients, but receive systemic fibrinolysis less frequently. In this sub-analysis of the SEATTLE II trial, we evaluated the efficacy and safety of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis in elderly patients with submassive and massive PE. We compared patients ?65 years old with those <65 years old. Eligible patients had proximal PE and a right ventricular-to left ventricular (RV/LV) diameter ratio ?0.9 on chest computed tomography (CT). The primary efficacy outcome was the change in chest CT-measured RV/LV diameter ratio at 48 hours after procedure initiation. The primary safety outcome was major bleeding within 72 hours. Sixty-two patients were ?65 years of age and 88 were <65 years of age. The RV/LV diameter ratio decreased in both groups 48 hours post-procedure, with a mean change of -0.47 in those ?65 and -0.39 in those <65 years old, with no difference between groups ( p = 0.31). Major bleeding occurred in nine (15%) of those ?65 and in six (7%) of those <65 years old ( p = 0.17). Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis resulted in a similar reduction in RV/LV diameter ratio in elderly patients with massive and submassive PE compared with non-elderly patients. PMID- 28625111 TI - Successful adaptation of a research methods course in South America. AB - BACKGROUND: South America has low research productivity. The lack of a structured research curriculum is one of the barriers to conducting research. OBJECTIVE: To report our experience adapting an active learning-based research methods curriculum to improve research productivity at a university in Ecuador. DESIGN: We used a mixed-method approach to test the adaptation of the research curriculum at Universidad Catolica Santiago de Guayaquil. The curriculum uses a flipped classroom and active learning approach to teach research methods. When adapted, it was longitudinal and had 16-hour programme of in-person teaching and a six month follow-up online component. Learners were organized in theme groups according to interest, and each group had a faculty leader. Our primary outcome was research productivity, which was measured by the succesful presentation of the research project at a national meeting, or publication in a peer-review journal. Our secondary outcomes were knowledge and perceived competence before and after course completion. We conducted qualitative interviews of faculty members and students to evaluate themes related to participation in research. RESULTS: Fifty university students and 10 faculty members attended the course. We had a total of 15 groups. Both knowledge and perceived competence increased by 17 and 18 percentage points, respectively. The presentation or publication rate for the entire group was 50%. The qualitative analysis showed that a lack of research culture and curriculum were common barriers to research. CONCLUSIONS: A US-based curriculum can be successfully adapted in low-middle income countries. A research curriculum aids in achieving pre-determined milestones. ABBREVIATIONS: UCSG: Universidad Catolica Santiago de Guayaquil; UM: University of Miami. PMID- 28625112 TI - Effect of the Parent-Adolescent Relationship on Adolescent Boys' Body Image and Subjective Well-Being. AB - Adolescent boys must cope with physical changes that hamper their ability to form a positive body image. Sociocultural messages influence the concepts of body image, personal appearance, and weight, encouraging men to develop lean and muscular bodies. The current study examined adolescent boys' body image and its relationship to their subjective well-being (SWB) and the effect of the parent adolescent relationship on body image and SWB. Participating in the research were 107 adolescent boys in Israel, aged 13 to 18 years. Four questionnaires were utilized: demographic, body mass index, Body Investment Scale, and Personal Well Being Index. The findings indicate a significant, medium positive correlation between SWB and body image. After controlling for the variable of parent adolescent relationship, the correlation weakened, indicating that the parent adolescent relationship has no effect on adolescent boys' SWB and body image. Body image was reported to be a predictor of SWB. PMID- 28625113 TI - Men With a Terminal Illness Relax Their Criteria for Facial Attractiveness. AB - According to the life history paradigm, in life-threatening conditions, sexual selection criteria are relaxed in order to increase the probability of a last resort reproduction, ultimately contributing to reproductive success. This should be reflected in loosened mating preferences - a process observed in nonhuman animals. Studies investigating this aspect in humans, however, are scarce. This study explored the aesthetic preferences towards facial and nonfacial stimuli in terminally ill patients with heart failure (HF) and their healthy, same-sex peers. The aim was to examine if these two groups of men demonstrate different patterns of aesthetic judgments. Using a 7-point scale, 65 male patients with HF and 143 healthy men evaluated the perceived attractiveness of 15 photographs (five adult male faces, five adult female faces, and five nonfacial pictures). A mixed-design analysis of variance was run to assess group differences in aesthetic preferences. Compared to healthy controls, stimuli. HF patients rated the pictures using significantly higher scores, but this applied only to male and female, but not nonfacial, stimuli. We propose that lower criteria for facial attractiveness in HF patients are linked to relaxation of mate preferences as a result of a life-threatening conditions, and that this process can be an adaptive mating strategy from an ultimate, evolutionary perspective. However, other mechanisms (e.g., seeking social support) may be also responsible for the observed patterns. PMID- 28625114 TI - The Role of Testosterone Supplemental Therapy in Opioid-Induced Hypogonadism: A Retrospective Pilot Analysis. AB - Chronic opioid therapy for pain management is known to induce several endocrine changes. The authors examined the effect of testosterone supplemental therapy (TST) in patients with chronic, noncancer pain undergoing opioid therapy. It was hypothesized that treatment of opioid-induced hypogonadism (OIH) can reduce opioid requirements in patients suffering from chronic pain and approve their quality of life. Over 18 months period, patients with OIH were identified in a tertiary referral pain center, Numerical Rating Scale (NRS) pain scores and daily morphine equivalent dose (MED) were the primary outcomes measured. Data were collected and comparative analysis performed between men undergoing TST versus nontreatment group. Twenty-seven OIH patients (total testosterone <300 ng/dL) were identified during the study period. TST group consists of 11 patients, while non-TST group consists of 16 patients as control cohort. Mean patient age (55 and 54.4, p = .4) and basic metabolic index (28.5 and 31.9, p = .07) in TST and non TST groups, respectively. Mean follow-up total testosterone (ng/dL) was significantly higher after TST compared with the non-TST group (497.5 vs. 242.4 ng/dL, p = .03). Median follow-up NRS was 0 and 2 in the TST and non-TST groups ( p = .02). Mean MED (mg) decreased by 21 mg in TST group and increased by 2.5 mg in non-TST group ( p < .05). This study reports that treatment of OIH with TST can reduce opioid requirements in men with chronic pain as quantified by MED. It also confirms previous reports on the potential effects of OIH and that TST is effective in correcting opioid-induced endocrine abnormalities. PMID- 28625115 TI - Do Nonclinical Community-Based Youth-Serving Professionals Talk With Young Men About Sexual and Reproductive Health and Intend to Refer Them for Care? AB - Young men (ages 15-24) may benefit from community-based connections to care since many have sexual and reproductive health (SRH) needs and low care use. This study describes nonclinical community-based youth-serving professionals' (YSPs) SRH knowledge, confidence, past behaviors, and future intentions to talk with young men about SRH and refer them to care, and examines factors associated with care referral intentions. YSPs ( n = 158) from 22 settings in one mid-Atlantic city answered questions about the study's goal, their demographics and work environment from August 2014 to December 2015. Poisson regression assessed factors associated with YSPs' care referral intentions. On average, YSPs answered 58% of knowledge questions correctly, knew 5 of 8 SRH care dimensions of where to refer young men, and perceived being somewhat/very confident talking with young men about SRH (63%) and referring them to care (77%). During the past month, the majority (63%) talked with young men about SRH but only one-third made care referrals; the majority (66%) were somewhat/very likely to refer them to care in the next 3 months. Adjusted models indicated YSPs were more likely to refer young men if they had a very supportive work environment to talk about SRH (adjusted RR = 1.51, 95% CI [1.15, 1.98]), greater confidence in SRH care referral (1.28 [1.00, 1.62]), and greater SRH care referrals in the past month (1.16 [1.02, 1.33]). Nonclinical community-based YSPs have poor-to-moderate knowledge about young men's SRH care, and less than one-third reported referrals in the past month. Findings have implications for educating YSPs about young men's SRH care. PMID- 28625116 TI - The Effects of Immigration and Media Influence on Body Image Among Pakistani Men. AB - This study examined the role of media influence and immigration on body image among Pakistani men. Attitudes toward the body were compared between those living in Pakistan ( n = 56) and those who had immigrated to the United Arab Emirates ( n = 58). Results of a factorial analysis of variance demonstrated a significant main effect of immigrant status. Pakistani men living in the United Arab Emirates displayed poorer body image than those in the Pakistan sample. Results also indicated a second main effect of media influence.Those highly influenced by the media displayed poorer body image. No interaction effect was observed between immigrant status and media influence on body image. These findings suggest that media influence and immigration are among important risk factors for the development of negative body image among non-Western men. Interventions designed to address the negative effects of the media and immigration may be effective at reducing body image disorders and other related health problems in this population. PMID- 28625117 TI - Factors Associated to Health Care Service Use among Latino Day Laborers. AB - Latino day laborers (LDLs) are at elevated risks for disease and injury because of the environments in which they work. Despite this recognition, a comprehensive examination of factors related to LDLs' health service use remains unexamined. Using the Andersen model, the current exploratory study examined predisposing (age, education level, location of educational training, legal status, and marital status), enabling (income, trust in medical personnel, whether the respondent has someone they consider their personal doctor, and whether their doctor speaks the same language, perceived barriers to care), and need (self rated health, number of chronic conditions) variables to predict use of health services among a purposive sample of LDLs ( N = 150). Cross-sectional data were collected in 2012 from 4 day laborer sites in Dallas and Arlington, Texas. Regression results suggest that the strongest predictor of health care use was trust in medical providers (beta = .41). LDLs who were U.S legal residents (beta = .21), reported multiple chronic conditions (beta = .16), and had a doctor who spoke their language (beta = .15) reported significantly higher levels of health care usage. In terms of barriers, not being able to pay for services (beta = .23), lacking health care insurance coverage (beta = -.22), and being embarrassed or having a family member not approve of utilizing services (beta = -.18) were significantly associated with lower health care usage among LDLs. These findings suggest that LDLs are faced with a number of predisposing, enabling, and need factors that comprise health care use. PMID- 28625118 TI - Sexual Behaviors and Sexually Transmitted Infections Among Male Veterans and Nonveterans. AB - Little is known about the sexual health of male veterans. This study used nationally representative data from the 2011 to 2013 National Survey of Family Growth to compare sexual behaviors and history of sexually transmitted infections (STIs) between male veterans and nonveterans. The sample included 3,860 men aged 18 to 44 years who reported ever having sex with a man or woman. The key independent variable was veteran status. Sexual behavior outcomes included >=6 lifetime female partners, >=10 lifetime partners of either sex, >=2 past-year partners of either sex, having past-year partners of both sexes, and condom nonuse at last vaginal sex. STI outcomes included past-year history of chlamydia, gonorrhea, or receiving any STI treatment; lifetime history of herpes, genital warts, or syphilis; and an aggregate measure capturing any reported STI history. Logistic regression models were used to evaluate associations between veteran status and each outcome. In models adjusting for age, race/ethnicity, education, income, and marital status, veterans had significantly greater odds than nonveterans of having >=6 lifetime female partners ( OR = 1.5, 95% CI [1.02, 2.31]). In models adjusting for age and marital status, veterans had significantly greater odds of having partners of both sexes in the past year ( OR = 4.8, 95% CI [1.2, 19.8]), and gonorrhea in the past year ( OR = 3.2, 95% CI [1.2, 8.5]). Male veterans were thus significantly more likely than nonveterans to have STI risk factors. Health care providers should be aware that male veterans may be at higher risk for STIs and assess veterans' sexual risk behaviors. PMID- 28625119 TI - Sociodemographic and Health Profile of Heterosexual Men Living With HIV in Ontario, Canada. AB - In Ontario, Canada, the number of heterosexual men living with HIV has increased over time, yet they remain an understudied population. The study objective was to describe the sociodemographic and clinical characteristics of this population, using data from a multisite clinical cohort of patients receiving HIV care. Sociodemographic and clinical characteristics of men interviewed between 2010 and 2012 were compared according to their self-identified sexual orientation, followed by multivariable linear and logistic regression to assess the association of sexual orientation with CD4 cell count, viral load, hepatitis C co infection, self-rated health, and mental health concerns after adjustment for covariates. A total of 552 men identified as heterosexual, 2,023 as gay, and 171 as bisexual. Compared to gay and bisexual men, heterosexual men were more likely to have been born outside of Canada (34.8%); more likely to report African, Caribbean, or Black ethnicity (26.4%) or Indigenous ethnicity (13.6%); and more likely to have low socioeconomic status (59.5% earning less than $20,000 per year), and/or a history of injection drug use (31.7%). Relative to gay men, heterosexual men had 5.19 times the odds of co-infection with hepatitis C virus regardless of injection drug use history (95% confidence interval = 3.87-6.96), and 40% lower odds of rating their health as excellent or good (95% confidence interval = 0.50-0.84). HIV-positive heterosexual men in Ontario constituted a socially marginalized group characterized by a high prevalence of injection drug use history and hepatitis C co-infection. PMID- 28625120 TI - The Effects of Ramadan Fasting on the Spirometric Data of Healthy Adult Males. AB - The few studies carried out on the effects of Ramadan fasting (RF) on spirometric values present contradictory conclusions. This study aimed at assessing whether RF affects healthy adults' spirometric values. Twenty-nine nonsmoking healthy males ( M +/- standard error of mean [ SEM] of age: 27 +/- 1 years) who fasted during Ramadan (June 29-July 28, 2014) volunteered to the study. Three periods (before-Ramadan [June 23-25], mid-Ramadan [July 14-16] and after-Ramadan [August 11-14]) were selected for spirometry measurements that were consistently performed 5.5 to 3.5 hours (between 15:00 and 17:00 hours) before fasting break. Assessment sessions comprised following: weight (kg), forced vital capacity (FVC), first second expiratory volume (FEV1), FEV1/FVC, peak expiratory flow (PEF), maximal mid expiratory flow (MMEF), and forced expiratory flow rate at the x% of FVC to be exhaled (FEF x%). Spirometric data were expressed in percentages of reference values. Results were analyzed by applying repeated measures analysis of variance. The M +/- SEM of weight (before-R: 81.6 +/- 2.8 kg, mid-R: 80.8 +/- 2.9 kg, after-R: 81.2 +/- 2.9 kg), FEV1 (before-R: 99 +/- 2%, mid-R: 98 +/- 2%, after-R: 98 +/- 2%), FVC (before-R: 103 +/- 2%, mid-R: 101 +/- 2%, after-R: 101 +/- 2%), PEF (before-R: 112 +/- 3%, mid-R: 113 +/- 2%, after-R: 114 +/- 3%), MMEF (before-R: 83 +/- 3%, mid-R: 83 +/- 3%, after-R: 82 +/- 3%), FEF25% (before-R: 90 +/- 5%, mid-R: 89 +/- 6%, after-R: 87 +/- 6%), FEF50% (before-R: 94 +/- 4%, mid R: 91 +/- 4%, after-R: 93 +/- 3%), and FEF75% (before-R: 108 +/- 3%, mid-R: 111 +/- 2%, after-R:111 +/- 3%) were not significantly influenced by RF. To conclude, RF did not bring about any significant changes in the spirometric values of nonsmoking healthy adult males. PMID- 28625121 TI - Nanofiltration fouling propensity caused by wastewater effluent organic matters and surface-water dissolved organic matters. AB - Rejection of dissolved organic matters (DOMs) from wastewater treatment plant effluent (EfOM) and surface reservoir water (RW-DOM) by nanofiltration (NF) was comparatively studied to evaluate their influence on membrane fouling and to unveil the major causations. EfOM and RW-DOM were fractionated to determine the major components that preferentially form fouling layer and initiate biofouling. The results indicated that EfOM induced a rapid membrane permeability loss and a more complicated biofilm diversity than RW-DOM did. Hydrophilic components with small molecular weight (<3 kDa), and SMP in EfOM made a crucial contribution to membrane flux decline, while the hydrophobic large-molecular-weight components (>50 kDa) resulted in initially quick membrane fouling. The complex biofouling resulted from EfOM closely related with significant retention of SMP on the non porous NF membrane surface, where the Proteobacteria phylum dominated the biofouling formed by microbial community growth and accumulation that gave rise to serious irreversible membrane fouling. PMID- 28625122 TI - A ten-year review of chronic cor pulmonale secondary to respiratory diseases in Ghana. AB - Chronic cor pulmonale is defined as right ventricular failure secondary to pulmonary hypertension. Our study reviewed all cases of chronic cor pulmonale secondary to respiratory diseases in a ten-year period (2004-20014) in the Department of Child Health, Korle-Bu Teaching Hospital, Ghana. Nine cases of chronic cor pulmonale were recorded during the period. The age range was 1-9 years (average age = 3 years). Obstructive sleep apnoea secondary to adenoid hypertrophy was the commonest cause of pulmonary hypertension. PMID- 28625124 TI - Occurrence and Importance of Plant Lipids: A Promising Insight into Algae. AB - BACKGROUND: Lipids are biomolecules with interesting structural variability. They are involved in many processes such as the storage of energy, in nutrition and are also of relevance for signal transduction processes, in apoptosis, cell differentiation and phagocytosis, etc. Macroalgae and microalgae are a promising and very diverse group of organisms. These living arganisms inhabit a vaste range of ecosystems from the Antarctic to the Deserts. They account for above half the primary productivity at the base of the food chain because of their multiple nutritional products including, for instance, lipids. RESULTS: Recently, studies on the oleaginous algae encompass their uses for commercial exploitations with applications ranging from human health food, animal feed, aquaculture, nutraceutical, biofuels and others. In this article, updated knowledge of lipids and recent research studies for algae's valorization performed by several authors were reviewed. Special attention was paid to lipids accumulation and their characterization. CONCLUSION: The selection of the prominent species of algae will be of great importance to satisfy the corresponding valorization process. Patents identified with algal lipids composition, production and application are presented. PMID- 28625123 TI - Role of the N-acetylation polymorphism in solithromycin metabolism. AB - AIM: Solithromycin is a new macrolide antibiotic for the potential treatment of bacterial pneumonia. MATERIALS & METHODS: Solithromycin N-acetylation by human NAT1 and NAT2 was investigated following recombinant expression in yeast and in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators. RESULTS: Solithromycin exhibited over twofold higher affinity for recombinant human NAT2 than NAT1. Apparent maximum velocities for the N-acetylation of solithromycin catalyzed by the NAT2 allozyme associated with rapid acetylators were significantly (p < 0.01) higher than by the NAT2 allozymes associated with slow acetylators. Robust gene dose responses (rapid>intermediate>slow acetylators) were exhibited in cryopreserved human hepatocytes in situ following incubation with 100 MUM solithromycin. CONCLUSION: Solithromycin is N-acetylated by human NAT1 and NAT2 and the role of the NAT2 acetylation polymorphism on solithromycin metabolism may be concentration dependent. PMID- 28625126 TI - Enhanced Risk for Specific Somatic Myeloproliferative Neoplastic Mutations in Patients with Stroke. AB - BACKGROUND: Somatic mutations of Janus kinase 2 (JAK2V617F), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) are the major clonal molecules that drive the pathogenesis of myeloproliferative neoplasms (MPN). It is well recognized that MPN patients carry an excessive risk of thrombohemorrhagic complications. However, little is known about the prevalence of these clonal markers in patients with cerebral vascular disease. METHODS: To address this issue, 153 consecutive stroke patients in Taiwan were enrolled in the study. Allele-specific PCR (AS-PCR), real-time AS-PCR, and Illumina paired end sequencing were employed to detect the presence of MPL, JAK2V617F, and CALR exon 9 mutations, respectively. RESULTS: JAK2V617F mutation was detectable in 13 samples (8.5%), but the allele burdens (AB) were greater than 1% in only six (3.9%) of them. Compared to JAK2-unmutated patients, those with JAK2V617F AB > 1% had significantly higher white blood count (p = 0.01), although four of the six did not exhibit MPN phenotypes. Two patients had a heterozygous CALR exon9 mutation locating outside the coding region and did not alter the amino acid sequence of this protein. On the other hand, there were no patients carrying the MPL mutations. Using patient age, baseline hemogram, and stroke-relevant risk factors, we developed a predictive model that could successfully identify stroke patients at risk of carrying clonal JAK2V617F mutation. CONCLUSION: The prevalence of JAK2V617F mutation in stroke patients was higher than that seen in general population. Based on our newly developed probability stratification model, genotyping of JAK2V617F mutation in selected patients with stroke might be warranted. PMID- 28625127 TI - The Hippocampal Autophagic Machinery is Depressed in the Absence of the Circadian Clock Protein PER1 that may Lead to Vulnerability During Cerebral Ischemia. AB - BACKGROUND: Autophagy is an intracellular bulk self-degrading process in which cytoplasmic contents of abnormal proteins and excess or damaged organelles are sequestered into autophagosomes, and degraded upon fusion with lysosomes. Although autophagy is generally considered to be pro-survival, it also functions in cell death processes. We recently reported on the hippocampal, higher vulnerability to cerebral ischemia in mice lacking the circadian clock protein PERIOD1 (PER1), a phenomenon we found to be linked to a PER1-dependent modulation of the expression patterns of apoptotic/autophagic markers. METHODS: To exclude the contribution of vascular or glial factors to the innate vulnerability of Per1 knockout-mice (Per1-/--mice) to cerebral ischemia in vivo, we compared the autophagic machinery between primary hippocampal cultures from wild-type (WT)- and Per1-/--mice, using the lipophilic macrolide antibiotic, Rapamycin to induce autophagy. RESULTS: Development of autophagy in WT cells involved an increased LC3-II-to-LC3-I ratio (microtubule-associated protein 1 light chain 3) and an overall increase in the level of LC3-II. In addition, immunostaining of LC3 in WT cells revealed the typical transformation of LC3 localization from a diffused staining to a dot- and ring-like pattern. In contrast, Per1-/--hippocampal cells were resistant to Rapamycin induced alterations of autophagy hallmarks. CONCLUSION: Our in vitro data suggests that basal activity of autophagy seems to be modulated by PER1, and confirms the in vivo data by showing that the autophagic machinery is depressed in Per1-/--hippocampal neurons.The implication of both autophagy and circadian dysfunction in the pathogenesis of cerebral ischemia suggests that a functional connection between the two processes may exist. PMID- 28625125 TI - Dreams and Psychedelics: Neurophenomenological Comparison and Therapeutic Implications. AB - BACKGROUND: A resurgence of neurobiological and clinical research is currently underway into the therapeutic potential of serotonergic or 'classical' psychedelics, such as the prototypical psychedelic drug lysergic acid diethylamide (LSD), psilocybin (4-phosphoryloxy-N,Ndimethyltryptamine), and ayahuasca - a betacarboline- and dimethyltryptamine (DMT)-containing Amazonian beverage. The aim of this review is to introduce readers to the similarities and dissimilarities between psychedelic states and night dreams, and to draw conclusions related to therapeutic applications of psychedelics in psychiatry. METHODS: Research literature related to psychedelics and dreaming is reviewed, and these two states of consciousness are systematically compared. Relevant conclusions with regard to psychedelicassisted therapy will be provided. RESULTS: Common features between psychedelic states and night dreams include perception, mental imagery, emotion activation, fear memory extinction, and sense of self and body. Differences between these two states are related to differential perceptual input from the environment, clarity of consciousness and meta-cognitive abilities. Therefore, psychedelic states are closest to lucid dreaming which is characterized by a mixed state of dreaming and waking consciousness. CONCLUSION: The broad overlap between dreaming and psychedelic states supports the notion that psychedelics acutely induce dreamlike subjective experiences which may have long-term beneficial effects on psychosocial functioning and well-being. Future clinical studies should examine how therapeutic outcome is related to the acute dreamlike effects of psychedelics. PMID- 28625128 TI - The Wnt/beta-catenin Signalling Pathway Inhibitor Sclerostin is a Biomarker for Early Atherosclerosis in Obesity. AB - BACKGROUND: Sclerostin is an inhibitor of the wingless-type mouse mammary tumor virus integration site family/beta-catenin signalling pathway (WbetacSP), which plays an important role in bone metabolism and in vascular biology. It could act protective regarding atherosclerosis development through its effect on WbetacSP in vascular cells. Nevertheless, results of studies analyzing association between circulating sclerostin level (CSL) and atherosclerotic diseases (AD) are showing conflicting results. The aim of this study is to test the value of CSL as a biomarker of subclinical carotid atherosclerosis (SCA) in obese persons. METHODS: The cross-sectional study included 50 obese persons without previous history of diabetes and AD. Participants underwent adequate anthropometrical, ultrasound and laboratory examinations, including 2h 75 g oral glucose tolerance test (OGTT). RESULTS: Only the presence of SCA significantly indirectly correlated with CSL (p<0.05). Based on the median value of CSL, we formed two groups: low CSL (CSL<7.9 pmol/l) and high CSL (CSL>7.9 pmol/l). There were no statistically significant differences in general (gender, age and current smoking) and anthropometrical characteristics (body mass index, waist circumference, systolic and diastolic blood pressure), inflammatory (total white blood cell count, erythrocyte sedimentation rate, fibrinogen, C-reactive protein and uric acid), glucose metabolism (fasting and 2h OGTT blood glucose, glycated hemoglobin and presence of dysglycemia) and lipid metabolism (low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, apolipoprotein A-I, apolipoprotein B and lipoprotein (a)) parameters between low and high CSL groups. Low CSL group had significantly higher incidence of SCA (p<0.05). CONCLUSION: CSL could serve as a useful biomarker of early atherosclerosis in obese persons without previous history of cardiometabolic disorders but the final conclusion requires further testing. PMID- 28625129 TI - Triamcinolone Acetonide Suppresses Inflammation and Facilitates Vascular Barrier Function in Human Retinal Microvascular Endothelial Cells. AB - BACKGROUND: Diabetic macular edema (DME) is resulted from the retinal microvascular leakage that accompanies the breakdown of blood-retinal barrier. Triamcinolone acetonide (TA) is a therapeutic agent for DME, but since the detailed mechanism of action of TA is not known, part of its action was examined. METHODS: In vitro model to enhance the permeability of human retinal microvascular endothelial cells (HRMECs) was constructed by using DME-related cytokines such as vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). The efficacy of TA and anti-VEGF antibody against retinal permeability was evaluated. Furthermore, the localization of ZO-1 in HRMECs was examined using immunofluorescence staining and the expression level of tight junction proteins (ZO-1, Occludin, and Claudin 5) was examined using immunoblot. RESULTS: TA and anti-VEGF antibody showed inhibitory effects against VEGF-induced permeability enhancement, and TA also inhibited the increase in permeability induced by TNF-alpha and IL-1beta. In addition to the inhibitory effects against cytokine-induced hyperpermeability, TA enhanced the barrier function of HRMECs and reduced the vascular leakage. TA altered the localization of tight junction proteins, but did not increase the upregulation of tight junction proteins. Moreover, the enhancement of barrier function by TA was inhibited by 17-AAG (glucocorticoid receptor inhibitor). CONCLUSION: It was suggested that TA reinforced the barrier function through the glucocorticoid receptor. In this study, we found that TA suppressed the inflammation caused by VEGF, TNF-alpha and IL-1beta, and decreased the retinal vascular hyperpermeability. PMID- 28625131 TI - Long-term Lifestyle-modification Programs for Overweight and Obesity Management in the Arab States: Systematic Review and Meta-analysis. AB - BACKGROUND: Obesity is a growing health problem worldwide. It is associated with serious medical and psychosocial comorbidities that increase the risk of mortality. However, strong evidence confirms lifestyle-modification programs as the cornerstone treatment for excess weight and obesity. The aim of this systematic review was to assess the effectiveness of the lifestyle-modification programs for weight management delivered in Arabic-speaking countries. METHODS: The PubMed database was searched, and studies conducted in humans were identified and screened as per the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) guidelines. Data were collated using meta-analysis and a narrative approach. RESULTS: Of the 1057 articles retrieved, six studies, conducted in four Arab countries, comprising a total of 444 adolescent and adult participants of both genders with overweight and obesity, met the inclusion criteria and were reviewed. Most studies that assessed weight loss at 6-month follow-up showed no significant reduction in body weight. Meta-analysis confirmed that the lifestyle-modification programs delivered were no more effective than other treatments. Only one article reported significant weight-loss maintenance after 12 months of follow-up. However this was a prospective non-controlled study in which the weight loss maintained (=4%) did not conform to the standard for clinical significance (>10%). CONCLUSION: Lifestyle-modification programs for weight management delivered in Arabic-speaking countries seem lacking in effectiveness due to methodological weaknesses in program adaptation, a lack of expert clinical supervision before and during implementation, and the presence of barriers to lifestyle modification, especially for women. Future studies should bear these features in mind. PMID- 28625130 TI - Remote Ischemic Conditioning Improves Cognitive Function During Cerebral Vascular Injury Through the Induction of Autophagy. AB - BACKGROUND: The most valid model for vascular cognitive impairment (VCI) is the mouse bilateral common carotid artery stenosis (BCAS), whose behavioral outcomes are supposedly affected by the remote ischemic conditioning (RIC) through the induction of autophgy. We hope to determine whether RIC contributes to the neuroprotection through the induction of autophagy. METHODS: Wastar male mice were randomized into three groups including the Sham, the BCAS and the RIC+BCAS groups. All the animals were submitted to 4 cycles of 5 min occlusion and 5 min reperfusion of both the femoral vessels performing RIC. Then the animal behaviors were recorded as well as the expression of proteins and the mRNA levels. Notably, the expression of proteins relates to autophagy. By this means, it is possible to estimate the cell death, the severity of pathology and the expression of proteins under different groups. RESULTS: Compared with the sham group, the expression of proteins increased for ATG7, Beclin-1, LC3, ATG5-ATG12 while decreased for P62 in the BCAS group. These changes were further promoted in the RIC+BCAS group, which indicates that the RIC can improve the cognitive function in the BCAS group. Moreover, RT-PCR demonstrated that the mRNA level of BECN1, Atg5, Atg7 in white matter (WM) and Hippocampus in BCAS group was higher than the sham group, while it was much greater in the RIC+BCAS group. This confirmed that the autophagy was activated in the BCAS and the RIC+BCAS groups, especially the RIC+BCAS group. CONCLUSION: Improved cognition during vascular injury and RIC was associated with increased activity of autophagy. PMID- 28625132 TI - Protein Tyrosine Signaling and its Potential Therapeutic Implications in Carcinogenesis. AB - Protein tyrosine phosphorylation is a crucial signaling mechanism that plays a role in epithelial carcinogenesis. Protein tyrosine kinases (PTKs) control various cellular processes including growth, differentiation, metabolism, and motility by activating major signaling pathways including STAT3, AKT, and MAPK. Genetic mutation of PTKs and/or prolonged activation of PTKs and their downstream pathways can lead to the development of epithelial cancer. Therefore, PTKs became an attractive target for cancer prevention. PTK inhibitors are continuously being developed, and they are currently used for the treatment of cancers that show a high expression of PTKs. Protein tyrosine phosphatases (PTPs), the homeostatic counterpart of PTKs, negatively regulate the rate and duration of phosphotyrosine signaling. PTPs initially were considered to be only housekeeping enzymes with low specificity. However, recent studies have demonstrated that PTPs can function as either tumor suppressors or tumor promoters, depending on their target substrates. Together, both PTK and PTP signal transduction pathways are potential therapeutic targets for cancer prevention and treatment. PMID- 28625133 TI - Recent Advances in Targeting the HIV-1 Tat/TAR Complex. AB - Following seminal discoveries by Rosen and co-workers in 1985, the HIV-1 TAR has emerged as one of the most extensively studied regulatory elements of the HIV-1 genome. Located adjacent to the long terminal repeat promoter, this cis-acting motif, in conjunction with the viral Tat protein, plays a critical role in viral genomic RNA synthesis via modification of the transcription complex. As such, the Tat/TAR axis has been the subject of intense efforts aimed at developing therapeutic interventions, directed against both the protein and nucleic acid components. While these efforts have to date been largely unsuccessful, current strategies to develop a functional cure for HIV have spawned renewed interest in targeting the Tat/TAR complex as a means of impairing virus reactivation and ultimately reducing the size of the latent reservoir pool. At the same time, advances in high throughput technologies, coupled with an increased understanding of RNA biology and function, have led to the identification of novel agents with enhanced potency and selectivity against a variety of cis-acting regulatory RNAs. In this review, recent approaches utilized to identify small molecules, peptides and evolved proteins with respect to targeting HIV-1 TAR are discussed. PMID- 28625134 TI - Current Methods of the Circulating Tumor Cells (CTC) Analysis: A Brief Overview. AB - This mini review provides a short overview of the main methods of the selection and analysis of the circulating tumor cells. We briefly focus on the evolution of the technical approaches used in the CTCs analysis from early description of the most discussed contemporary workflows such as Cellsearch and CTC-iChip. In addition, we discuss more "unconventional" approaches such as mass spectrometry and NMR based methods of CTC analysis. PMID- 28625135 TI - Studying Interactions of Drugs with Cell Membrane Nutrient Transporters: New Frontiers of Proteoliposome Nanotechnology. AB - Transport systems are hydrophobic proteins localized in cell membranes where they mediate transmembrane flow of nutrients, ions and any other compounds essential for cell metabolism. More than 400 transporters of the SoLuteCarrier (SLC) group are present in human cells. Transporters take contacts also with xenobiotics, thus mediating absorption and/or interaction with these exogenous compounds. Since drugs belong to xenobiotics, transporters gained interest also in drug discovery. Transporters differentially expressed in pathological conditions are exploited as drug targets. Among the methodologies for defining drug interactions, in silico ligand screening and intact cell transport assay were the most diffused, so far. The first is a predictive methodology based on docking chemicals to transporters. It presents limitations due to the small number of human transporter 3D structures that have to be constructed by homology modeling. Intact cells are used for testing effects of drugs and for validating predictions. The challenges of handling this very complex experimental system, are the interferences caused by other transporters and/or intracellular enzymes. Thus, methodologies with lower complexity are welcome. One of the most updated is the proteoliposome nanotechnology consisting in a cell mimicking phospholipid membrane in which a purified transporter is inserted. In this system, drug transporter interaction can be studied defining kinetics and mechanisms. Several data have been obtained by proteoliposome nanotechnology. An overview of data obtained on the organic cation transporters OCTN1, OCTN2 and on the amino acid transporters ASCT2 and B0AT1 will be presented. Standardized procedures, expected to be pointed out, will enlarge the assay to High Throughput Screenings. PMID- 28625136 TI - Using β-Amino Acids and β-Peptide Templates to Create Bioactive Ligands and Biomaterials. AB - β-Amino acids are being increasingly used in the design of bioactive ligands and more recently in the generation of novel biomaterials. Peptides containing either individual β-amino acid substitutions or peptides comprised entirely of beta-amino acids, display unique properties in terms of their structural and/or chemical characteristics. β-Peptides form well-defined secondary structures that exhibit different geometries compared to the corresponding α-peptides. β-Peptides, including alpha-peptides containing only one or two β-amino acids, can be easily modified with different functional groups and are metabolically stable and, together with the predictable side chain topography, have led to the design of a growing number of bioactive β peptides with a range of biological targets and therapeutic applications. More recently, our understanding of the folding and self-assembly of β-peptides has resulted in the generation of novel biomaterials. The focus of this review is to examine how the structural and chemical properties of β-peptides have been exploited in the design of bioactive peptides and selfassembled nanomaterials. PMID- 28625137 TI - Chemokine Like Receptor-1 (CMKLR-1) Receptor: A Potential Therapeutic Target in Management of Chemerin Induced Type 2 Diabetes Mellitus and Cancer. AB - BACKGROUND: Chemerin is an adipokine that induces insulin resistance by the mechanism of inflammation in adipose tissue but these are still unclear. A high level of chemerin in humans is considered as a marker of inflammation in insulin resistance and obesity as well as in type 2 diabetes mellitus. Despite the role of chemerin in insulin resistance progression, chemerin as one of the novel adipokines is proposed to be involved in high cancer risk and mortality. AIM: The aim of this paper was to review the role of CMKLR-1 receptor and the potential therapeutic target in the management of chemerin induced type 2 diabetes mellitus and cancer. PATHOPHYSIOLOGY: Increased chemerin secretion activates an inflammatory response. The inflammatory response will increase the oxidative stress in adipose tissue and consequently results in an insulin-resistant state. The occurrence of inflammation, oxidative stress and insulin resistance leads to the progression of cancers. CONCLUSION: Chemerin is one of the markers that may involve in development of both cancer and insulin resistance. Chemokine like receptor- 1 (CMKLR-1) receptor that regulates chemerin levels exhibits a potential therapeutic target for insulin resistance, type 2 diabetes and cancer treatment. PMID- 28625138 TI - Membrane-bound ATP-dependent Energy Systems, as Extra- and Intracellular Key Signals for Gastrointestinal Functions and their Regulations in the Gastrointestinal Mucosa. AB - AIMS: Our research group has carried out various biochemical examinations in rat gastric ulcer models and in human gastrointestinal resecates obtained from patient who underwent gastric intervention due to peptic ulcer disease. Biochemical methods gave excellent possibility to approach the biochemical events taking place in tissues, cellular and subcellular regulatory levels during of ulcer development and of its prevetions. This paper gives a brief summary of these biochemical examinations conducted during this study period started from the 1960's up till now. RESULTS AND CONCLUSIONS: 1. The decreased action of gastric acid secretory responses is not needed for duodenal and gastric ulcer healing in patients with peptic ulcer; 2. The surgical and chemical vagotomy resulted in various biochemical changes in the rat stomach; 3. The presence of Na+-K+-dependent ATPase and adenylate cyclase can be demostrated both in the rat and human gastric fundic mucosa; 4. The mitocondrial ATP is a common substrate for these membrane-bound ATP-dependent enzymes, and a multiple feedback mechanism existing between these two membrane-bound enzymes altered by mediators, hormones and drugs; 5. This feedback mechanism exists in the GI mucosa under different pathological conditions and during certain drug actions; 6. The development of mucosal damage and prevention depends on the actual regulatory state of above mentioned feedback mechanism between the membrane-bound ATP-dependent energy systems; 7.The drug actions depend on the actual functional state of target organ; 8. Biochemical gradients exist between the biochemical structure of the fundic, antral, duodenal and jejunal mucosa in patients with gastric hyperacidity, which is gradually downregulated by the decrease of gastric acid secretory responses, and totally disappears in patients with hypacidity; 9. No biochemically proven tissue hypoxia - around the chronic ulcer, duodenal and jejunal ulcers - exists in patients with chronic peptic ulcer; 10. The cellular and tissue protection differ from each other in the gastrointestinal tract; 11. Helicobacter pylori does not produce damage at the level of cell membrane, mitochondrion and DNA - given alone or in combination with indomethacin - on freshly isolated rat gastric mucosal cells. 12. A biochemical explanation is given to ulcer development in humans and in different animal models. PMID- 28625139 TI - Targeting Cholinergic System to Modulate Liver Injury. AB - Over the past few decades, evidence accumulated to indicate that parasympathetic innervation regulates liver injury and regeneration. Liver derives its parasympathetic input via vagus nerve. In animal models, vagus nerve stimulation and transection are frequently used to determine the impact of parasympathetic input on liver injury responses. Such strategies provide limited understanding of postneuronal mechanisms involved in the regulation of liver injury. The hepatic branch of vagus nerve releases acetylcholine (ACh), which activates muscarinic and nicotinic receptors in hepatocytes as well as non-parenchymal cells to modulate cellular functions. Moreover, vagus nerve releases other neurotransmitters such as vasoactive intestinal peptide (VIP), which also modulates liver injury responses and hemodynamics. Therefore, our understanding of the post-neuronal modulation of liver injury in models utilizing vagus nerve activity remains limited. Gene-silencing technologies and pharmacological manipulation of receptor activity have not only improved our understanding of the role of specific cholinergic receptors but also elucidated the role of various liver cell sub-populations in modulating liver injury response. With advent of organ- and cell-specific transgenic mice, our understanding of neural regulation of liver injury is likely to improve further. This review comprehensively provides current understanding of cholinergic regulation of liver injury, and points to potential therapeutic targets to treat liver injury. PMID- 28625140 TI - Recently Patented Viral Nucleotide Sequences and Generation of Virus-Derived Vaccines. AB - BACKGROUND: With an increase in comprehension of the molecular biology of viruses, there has been a recent surge in the application of virus sequences and viral gene expression strategies towards the diagnosis and treatment of diseases. RESULTS: The scope of the patenting landscape has widened as a result and the current review discusses patents pertaining to live / attenuated viral vaccines. The vaccines addressed here have been developed by both conventional means as well as by the state-of-the-art genetic engineering techniques. CONCLUSION: This review also addresses the applications of these patents for clinical and biotechnological purposes. PMID- 28625141 TI - Bedaquiline: A New Hope for Shorter and Better Anti-Tuberculosis Regimens. AB - BACKGROUND: In 2014, an estimated 1.8 million people died from Mycobacterium tuberculosis (MTB); moreover, 680,000 people developed multidrug-resistant TB (MDRTB). METHODS: Currently available anti-MDR and XDR regimens are long-lasting and expensive, need high adherence and are undermined by a high frequency of adverse drug events, thus leading to a low success rate; furthermore, in the last 50 years only two new molecules, bedaquiline (BDQ) and delamanid, have been approved and released for the treatment of MDR-TB. RESULTS: BDQ, patent number US 7,498,343B2, is a diarylquinoline anti-mycobacterial drug, active regardless of the state of MTB; in fact, its efficacy is conserved against replicating and non replicating bacilli, despite extracellular or intracellular location. BDQ has been approved by the Food and Drug Administration (FDA) only for combination treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB), in adult patients, when an effective treatment cannot be provided otherwise due to resistance or poor tolerability; however, due to high bactericidal activity, BDQ may be used in future to treat extrapulmonary tuberculosis and Mycobacterium other than tuberculosis (MOTT) infection. CONCLUSION: BDQ may play a major role to get closer to TB eradication and to ensure higher retention in care, even in fully susceptible MTB strains and against non-replicating mycobacteria in latent TB, providing an alternative to standard regimen. PMID- 28625143 TI - Infection and Malignancy Risk in Patients Treated with TNF Inhibitors for Immune Mediated Inflammatory Diseases. AB - BACKGROUND: Infectious and malignant events are responsible for morbidity and mortality in patients with Immune-Mediated Inflammatory Diseases (IMIDs). Anti tumor necrosis factor (Anti-TNF) agents appear to have an impact, however the individual effect of these agents in the different conditions is still unclear. OBJECTIVE: The aim of this study is to estimate the Incidence Rates (IR) of infections and malignancies in patients treated with anti-TNFs across different IMIDs, as well as potential risk factors. METHODS: IR/100 patient-years were evaluated in adult patients treated for any IMID with an anti-TNF between January 2000 and December 2014. Predictors were tested with bivariate and multivariate statistical analysis. RESULTS: The IR/100 patient-years of serious infections was 4.02 (95% CI 3.20-5.04) with significant differences across IMIDs and anti-TNF agents. The most frequent site of serious infection was the gastrointestinal system. Five cases [IR of 0.28 (95% CI 0.12-0.66) /100 patient-years] of tuberculosis were diagnosed, exclusively in patients treated with monoclonal antibodies. Three (60%) of those were extrapulmonary. The IR/100 patient-years of malignancy was 1.75 (95% CI 1.24-2-47). CONCLUSION: There is significant variability in the IR of infections across indications and agents. Thus, physicians should be thoughtful when generalizing data from literature regarding the use of an anti-TNF agent in a specific IMID. Further studies are necessary to clear aspects regarding the safety of individual anti-TNF biologics and to clarify their impact in the different IMIDs. PMID- 28625142 TI - Proteotoxic Stress Desensitizes TGF-beta Signaling Through Receptor Downregulation in Retinal Pigment Epithelial Cells. AB - BACKGROUND: Proteotoxic stress and transforming growth factor (TGFbeta)- induced epithelial-mesenchymal transition (EMT) are two main contributors of intraocular fibrotic disorders, including proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR). However, how these two factors communicate with each other is not well-characterized. OBJECTIVE: The aim was to investigate the regulatory role of proteotoxic stress on TGFbeta signaling in retinal pigment epithelium. METHODS: ARPE-19 cells and primary human retinal pigment epithelial (RPE) cells were treated with proteasome inhibitor MG132 and TGFbeta. Cell proliferation was analyzed by CCK-8 assay. The levels of mesenchymal markers alpha-SMA, fibronectin, and vimentin were analyzed by real time polymerase chain reaction (PCR), western blot, and immunofluorescence. Cell migration was analyzed by scratch wound assay. The levels of p-Smad2, total Smad2, p-extracellular signal-regulated kinase 1/2 (ERK1/2), total ERK1/2, p focal adhesion kinase (FAK), and total FAK were analyzed by western blot. The mRNA and protein levels of TGFbeta receptor-II (TGFbetaR-II) were measured by realtime PCR and western blot, respectively. RESULTS: MG132-induced proteotoxic stress resulted in reduced cell proliferation. MG132 significantly suppressed TGFbeta-induced upregulation of alpha-SMA, fibronectin, and vimentin, as well as TGFbeta-induced cell migration. The phosphorylation levels of Smad2, ERK1/2, and FAK were also suppressed by MG132. Additionally, the mRNA level and protein level of TGFbetaR-II decreased upon MG132 treatment. CONCLUSION: Proteotoxic stress suppressed TGFbeta-induced EMT through downregulation of TGFbetaR-II and subsequent blockade of Smad2, ERK1/2, and FAK activation. PMID- 28625144 TI - Detection of Poor Quality Artemisinin-based Combination Therapy (ACT) Medicines Marketed in Benin Using Simple and Advanced Analytical Techniques. AB - BACKGROUND: Poor quality antimalarial medicines still represent a threat to the public health, especially in Sub-Saharan Africa which bears a disproportionate share of the global burden of malaria. It is essential and urgent to strengthen mechanisms against counterfeit medicines. One of the approaches is regular market surveillance through quality controls. METHODS: 12 samples of artemether/lumefantrine were collected from formal and informal drug sellers in Cotonou (Benin) as well as additional other similar samples from Rwanda (13 samples) and from D.R. Congo (9 samples). Thin Layer Chromatography (TLC) as classical and simple identification test was applied in Benin while an analytical chemistry laboratory in Belgium (ULg, Pharmacy Department) was asked for further analyses with HPLC and Raman spectroscopy using a developed and validated HPLC method for rapid analysis of artemether/lumefantrine. RESULTS: The results obtained in Belgium confirmed the lack of the two active ingredients in the suspected sample of ACT medicine from Benin whereas some samples from Rwanda and D.R. Congo were found to present risk of substandard drugs either for under dosing or over-dosing. CONCLUSIONS: Counterfeit/falsified of artemisinin-based combination therapy (ACT) medicines are really scourge that needs to be fought through strong collaboration between public health authorities and appropriate quality control laboratories. PMID- 28625145 TI - Clomiphene for the Treatment of Male Infertility: A Case Report of Mood Change and a Literature Overview. AB - BACKGROUND: Clomiphene is normally used in women with ovulatory dysfunction. In men, it is used off label in some cases of infertility. Psychological adverse effects are reported in women but very few in men. CASE: A 34-year-old man treated with clomiphene for oligoteratospermia presented anxiety, decreased appetite, and mood change making him unable to function properly at work, five days after initiation of therapy. Symptoms required reduction followed by discontinuation of treatment four days later because of absence of improvement. Following cessation, the patient noted a gradual then a complete resolution approximately one week later. The patient did not have any psychiatric or other medical condition neither drug nor substance abuse that could explain this clinical presentation. The Naranjo's score was used to prove the clomiphene's imputability. CONCLUSION: Health care providers should advise patients of the risk of psychological adverse effects when initiating treatment with clomiphene and should provide a close monitoring of mood change, especially during the initial weeks. PMID- 28625146 TI - Cephalosporins Associated Pseudomembraneous Colitis in an Elderly Male Patient - A Case Report. AB - INTRODUCTION: Incidence of antibiotic- associated diarrhoea is a common (10-30%) but pseudomembranous colitis (PMC) is less frequent (1-5%). Fluoroquinolones, clindamycin, penicillins, cephalosporins (mostly third generation) are commonly associated with PMC. The association between cephalosporins and PMC is now well established. CASE PRESENTATION: A 78 year old male patient developed pseudomembraneous colitis after administration of Ceftriaxone and Cefazoline for the treatment of pleural effusion. The reaction was confirmed by ultrasonography and CT scan. Causative agents were stopped and patient was managed by systemic therapy. Patient was expired due to respiratory complications as there was complexity in management of disease due to development of pseudomembraneous colitis. CONCLUSION: Increase awareness of prescribers for high-risk drugs, close monitoring, with immediate withdrawal of the culprit drug can reduce the complexity of management that occur due to development of such adverse drug reaction. PMID- 28625147 TI - Adverse Drug Reactions Related to Drug Administration in Hospitalized Patients. AB - INTRODUCTION: Drug treatment may be related to the development of adverse drug reactions (ADRs). AIM: In this paper, we evaluated the ADRs in patients admitted to Catanzaro Hospital. METHODS: After we obtained the approval by local Ethical Committee, we performed a retrospective study on clinical records from March 01, 2013 to April 30, 2015. The association between drug and ADR or between drug and drug-drug-interactions (DDIs) was evaluated using the Naranjo's probability scale and Drug Interaction Probability Scale (DIPS), respectively. RESULTS: During the study period, we analyzed 2870 clinical records containing a total of 11,138 prescriptions, and we documented the development of 770 ADRs. The time of hospitalization was significantly higher (P<0.05) in women with ADRs (12.6 +/- 1.2 days) with respect to men (11.8+/- 0.83 days). Using the Naranjo score, we documented a probable association in 78% of these reactions, while DIPS revealed that about 22% of ADRs were related to DDIs. Patients with ADRs received 3052 prescriptions on 11,138 (27.4%) having a mean of 6.1+/-0.29 drugs that was significantly higher (P<0.01) with respect to patients not experiencing ADRs (mean of 3.4+/-0.13 drugs). About 19% of ADRs were not diagnosed and were treated as new diseases. CONCLUSION: Our results indicate that drug administration induces the development of ADRs also during the hospitalization, particularly in elderly women. Moreover, we also documented that ADRs in some patients are under diagnosed, therefore, it is important to motivate healthcare to report the ADRs in order to optimize the patients' safety. PMID- 28625148 TI - Affinity Crystallography Reveals the Bioactive Compounds of Industrial Juicing Byproducts of Punica granatum for Glycogen Phosphorylase. AB - BACKGROUND: Glycogen phosphorylase (GP) is a pharmaceutical target for the discovery of new antihyperglycaemic agents. Punica granatum is a well-known plant for its potent antioxidant and antimicrobial activities but so far has not been examined for antihyperglycaemic activity. OBJECTIVE: The aim was to examine the inhibitory potency of eighteen polyphenolic extracts obtained from Punica granatum fruits and industrial juicing byproducts against GP and discover their most bioactive ingredients. METHOD: Kinetic experiments were conducted to measure the IC50 values of the extracts while affinity crystallography was used to identify the most bioactive ingredient. The inhibitory effect of one of the polyphenolic extracts was also verified ex vivo, in HepG2 cells. RESULTS: All extracts exhibited significant in vitro inhibitory potency (IC50 values in the range of low MUg/mL). Affinity crystallography revealed that the most bioactive ingredients of the extracts were chlorogenic and ellagic acids, found bound in the active and the inhibitor site of GP, respectively.While ellagic acid is an established GP inhibitor, the inhibition of chlorogenic acid is reported for the first time. Kinetic analysis indicated that chlorogenic acid is an inhibitor with Ki=2.5 x 10-3Mthat acts synergistically with ellagic acid. CONCLUSION: Our study provides the first evidence for a potential antidiabetic usage of Punica granatum extracts as antidiabetic food supplements. Although, more in vivo studies have to be performed before these extracts reach the stage of antidiabetic food supplements, our study provides a first positive step towards this process. PMID- 28625149 TI - Stability Indicating Reverse Phase HPLC Method for Estimation of Rifampicin and Piperine in Pharmaceutical Dosage Form. AB - BACKGROUND: High performance liquid chromatography is an integral analytical tool in assessing drug product stability. HPLC methods should be able to separate, detect, and quantify the various drug-related degradants that can form on storage or manufacturing, plus detect any drug-related impurities that may be introduced during synthesis. OBJECTIVE: A simple, economic, selective, precise, and stability-indicating HPLC method has been developed and validated for analysis of Rifampicin (RIFA) and Piperine (PIPE) in bulk drug and in the formulation. METHOD: Reversed-phase chromatography was performed on a C18 column with Buffer (Potassium Dihydrogen Orthophosphate) pH 6.5 and Acetonitrile, 30:70), (%, v/v), as mobile phase at a flow rate of 1 mL min-1. RESULT: The detection was performed at 341 nm and sharp peaks were obtained for RIFA and PIPE at retention time of 3.3 +/- 0.01 min and 5.9 +/- 0.01 min, respectively. The detection limits were found to be 2.385 ng/ml and 0.107 ng/ml and quantification limits were found to be 7.228ng/ml and 0.325ng/ml for RIFA and PIPE, respectively. The method was validated for accuracy, precision, reproducibility, specificity, robustness, and detection and quantification limits, in accordance with ICH guidelines. CONCLUSION: Stress study was performed on RIFA and PIPE and it was found that these degraded sufficiently in all applied chemical and physical conditions. Thus, the developed RP-HPLC method was found to be suitable for the determination of both the drugs in bulk as well as stability samples of capsule containing various excipients. PMID- 28625150 TI - Update on the Molecular Mechanisms Underlying the Effect of Cholecystokinin and Cholecystokinin-1 Receptor on the Formation of Cholesterol Gallstones. AB - Cholecystokinin (CCK) is an important neuro-intestinal peptide hormone produced by the enteroendocrine I-cells in the upper part of small intestine. Protein- and fat-enriched food plays an important role in triggering CCK secretion from the intestine. Carbohydrates stimulate only small amounts of CCK release. The CCK-1 receptor (CCK-1R) is largely localized in the gallbladder, sphincter of Oddi, pancreas, small intestine, gastric mucosa, and pyloric sphincter, where it is responsible for CCK to regulate multiple digestive processes including gallbladder contraction, pancreatic secretion, small intestinal transit, and gastric emptying. Accumulated evidence clearly demonstrates that CCK regulates gallbladder and small intestinal motility through CCK-1R signaling cascade and the effect of CCK-1R on small intestinal transit is a physiological response for regulating intestinal cholesterol absorption. Disruption of the Cck or the Cck-1r gene in mice significantly increases the formation of cholesterol gallstones by disrupting gallbladder emptying and biliary cholesterol metabolism, as well as promoting intestinal absorption of cholesterol. Abnormalities in gallbladder motility function in response to exogenously administered CCK are found primarily in patients with cholesterol gallstones. Patients with pigment gallstones display an intermediate degree of gallbladder motility defect without gallbladder inflammation and enlarged fasting gallbladder. Dysfunctional gallbladder contractility has been found under several conditions such as pregnancy, obesity, diabetes, celiac disease, and total parenteral nutrition although gallstones are not observed. The gallbladder-specific CCK-1R-selective agonist may lead to an efficacious novel way for preventing gallstone formation by promoting gallbladder emptying, particularly for pregnant women and subjects with dysfunctional gallbladder motility function such as celiac patients, as well as patients with total parenteral nutrition. PMID- 28625151 TI - Na+,K+-ATPase as a target for treatment of tissue fibrosis. AB - Myofibroblast activation is a critical process in the pathogenesis of tissue fibrosis accounting for 45% of all deaths. No effective therapies are available for the treatment of fibrotic diseases. We focus our mini-review on recent data showing that cardiotonic steroids (CTS) that are known as potent inhibitors of Na+,K+-ATPase affect myofibroblast differentiation in a cell type-specific manner. In cultured human lung fibroblasts (HLF), epithelial cells, and cancer associated fibroblasts, CTS blocked myofibroblast differentiation triggered by profibrotic cytokine TGF-beta. In contrast, in the absence of TGF-beta, CTS augmented myofibroblast differentiation of cultured cardiac fibroblasts. The cell type-specific action of CTS in myofibroblast differentiation is consistent with data obtained in in vivo studies. Thus, infusion of ouabain via osmotic mini pumps attenuated the development of lung fibrosis in bleomycin-treated mice, whereas marinobufagenin stimulated renal and cardiac fibrosis in rats with experimental renal injury. In TGF-beta-treated HLF, suppression of myofibroblast differentiation by ouabain is mediated by elevation of the [Na+]i/[K+]i ratio and is accompanied by upregulation of cyclooxygenase COX-2 and downregulation of TGF beta receptor TGFBR2. Augmented expression of COX-2 is abolished by inhibition of Na+/Ca2+ exchanger, suggesting a key role of [Ca2+]i-mediated signaling. What is the relative impact in tissue fibrosis of [Na+]i,[K+]i-independent signaling documented in several types of CTS-treated cells? Do the different conformational transitions of Na+,K+-ATPase alpha1 subunit in the presence of ouabain and marinobufagenin contribute to their distinct involvement in myofibroblast differentiation? Additional experiments should be done to answer these questions and to develop novel pharmacological approaches for the treatment of fibrosis related disorders. PMID- 28625152 TI - Lipid Oxidation Products in the Pathogenesis of Inflammation-related Gut Diseases. AB - BACKGROUND: A defective mucosal barrier function is the principal cause of the uncontrolled onset and progression of a number of human inflammatory gut diseases, most of which are characterized by chronic intermittent immune and inflammatory responses leading to structural intestinal damage, which can represent a potential risk for colorectal cancer development. During the active disease phase the production of pro-inflammatory cytokines and chemokines, and the induction of oxidative reactions by activated leukocytes and epithelial cells represent the main event in the intestinal inflammation. OBJECTIVE: Oxidative stress plays a key role in the development of intestinal damage. Indeed reactive oxygen species and their oxidized by-products regulate redox-sensitive signaling pathways and transcription factors, which sustain inflammation within the intestinal layer. METHODS: Polyunsaturated fatty acids and cholesterol are the principal targets of oxidative modifications. These lipids, which are cell membrane constituents or are present in food, readily undergo non-enzymatic oxidation to form chemically-reactive species that can induce a wide range of biological effects including inflammation, programmed cell death, and proliferation. RESULTS AND CONCLUSIONS: In this review we summarize the current knowledge on the role of lipid oxidation products in regulating redox pathways involved in the pathogenesis of inflammation- related gut diseases. In particular, lipid peroxidation end products, such as isoprostanes and aldehydes, and cholesterol oxidation-derived oxysterols are taken into consideration. The control of oxidative damage and consequently tissue local over-production of lipid oxidation products by using specific antioxidant and anti-inflammatory molecules in the diet may have clinical and therapeutic benefits. PMID- 28625153 TI - STORIES IN ANCIENT DNA. AB - Technology developments are leading to rapid advances in ancient DNA analysis. Nathan Blow talks to researchers peering into the past through ancient DNA. PMID- 28625154 TI - EXPANDING THE GENETIC ALPHABET. AB - Synthetic biologists have engineered a semisynthetic organism that can store increased genetic information using an alphabet consisting of six letters that form three base pairs. Janelle Weaver learns how they did it. PMID- 28625155 TI - Applications of optical DNA mapping in microbiology. AB - Optical mapping (OM) has been used in microbiology for the past 20 years, initially as a technique to facilitate DNA sequence-based studies; however, with decreases in DNA sequencing costs and increases in sequence output from automated sequencing platforms, OM has grown into an important auxiliary tool for genome assembly and comparison. Currently, there are a number of new and exciting applications for OM in the field of microbiology, including investigation of disease outbreaks, identification of specific genes of clinical and/or epidemiological relevance, and the possibility of single-cell analysis when combined with cell-sorting approaches. In addition, designing lab-on-a-chip systems based on OM is now feasible and will allow the integrated and automated microbiological analysis of biological fluids. Here, we review the basic technology of OM, detail the current state of the art of the field, and look ahead to possible future developments in OM technology for microbiological applications. PMID- 28625156 TI - Heteroduplex cleavage assay for screening of probable zygosities resulting from CRISPR mutations in diploid single cell lines. AB - The most common gene editing methods, such as CRISPR, involve random repair of an induced double-stranded DNA break through the non-homologous end joining (NHEJ) repair pathway, resulting in small insertions/deletions. In diploid cells, these mutations can take on one of three zygosities: monoallelic, diallelic heterozygous, or diallelic homozygous. While many advances have been made in CRISPR delivery systems and gene editing efficiency, little work has been done to streamline detection of gene editing events. The only current method to determine the zygosity of an edited gene in a diploid organism is DNA sequencing, which is costly and time-consuming. Here, we describe the development of a T7 endonuclease I (T7EI)-based heteroduplex cleavage assay, along with statistical models relating the percentage of cleaved DNA to the zygosity of a mutation, that provides a rapid screening step prior to DNA sequencing. By isolating candidates likely to contain the desired zygosity for the edited gene, our screening method can decrease the number of clones requiring DNA sequencing. PMID- 28625157 TI - Purification of single-stranded DNA by co-polymerization with acrylamide and electrophoresis. AB - Single-stranded DNA (ssDNA) oligonucleotides are useful as aptamers, hybridization probes and for emerging applications in DNA nanotechnology. Current methods to purify ssDNA require both a strand-separation step and a separate size separation step but may still leave double-stranded DNA (dsDNA) impurities in the sample. Here, we use commercially available acrydite DNA primers to immobilize one strand of a PCR product within a polyacrylamide matrix. Electrophoresis moves the non-crosslinked DNA into the gel where the single-stranded product of desired size can be recovered. Our results show this method produces high yields of pure ssDNA. PMID- 28625158 TI - A minimally-invasive method for sampling human petrous bones from the cranial base for ancient DNA analysis. AB - Ancient DNA (aDNA) research involves invasive and destructive sampling procedures that are often incompatible with anthropological, anatomical, and bioarcheological analyses requiring intact skeletal remains. The osseous labyrinth inside the petrous bone has been shown to yield higher amounts of endogenous DNA than any other skeletal element; however, accessing this labyrinth in cases of a complete or reconstructed skull involves causing major structural damage to the cranial vault or base. Here, we describe a novel cranial base drilling method (CBDM) for accessing the osseous labyrinth from the cranial base that prevents damaging the surrounding cranial features, making it highly complementary to morphological analyses. We assessed this method by comparing the aDNA results from one petrous bone processed using our novel method to its pair, which was processed using established protocols for sampling disarticulated petrous bones. We show a decrease in endogenous DNA and molecular copy numbers when the drilling method is used; however, we also show that this method produces more endogenous DNA and higher copy numbers than any postcranial bone. Our results demonstrate that this minimally-invasive method reduces the loss of genetic data associated with the use of other skeletal elements and enables the combined craniometric and genetic study of individuals with archeological, cultural, and evolutionary value. PMID- 28625159 TI - DNA extraction for streamlined metagenomics of diverse environmental samples. AB - A major bottleneck for metagenomic sequencing is rapid and efficient DNA extraction. Here, we compare the extraction efficiencies of three magnetic bead based platforms (KingFisher, epMotion, and Tecan) to a standardized column-based extraction platform across a variety of sample types, including feces, oral, skin, soil, and water. Replicate sample plates were extracted and prepared for 16S rRNA gene amplicon sequencing in parallel to assess extraction bias and DNA quality. The data demonstrate that any effect of extraction method on sequencing results was small compared with the variability across samples; however, the KingFisher platform produced the largest number of high-quality reads in the shortest amount of time. Based on these results, we have identified an extraction pipeline that dramatically reduces sample processing time without sacrificing bacterial taxonomic or abundance information. PMID- 28625162 TI - A reference genome for Nicotiana tabacum enables map-based cloning of homeologous loci implicated in nitrogen utilization efficiency. AB - BACKGROUND: Tobacco (Nicotiana tabacum) is an important plant model system that has played a key role in the early development of molecular plant biology. The tobacco genome is large and its characterisation challenging because it is an allotetraploid, likely arising from hybridisation between diploid N. sylvestris and N. tomentosiformis ancestors. A draft assembly was recently published for N. tabacum, but because of the aforementioned genome complexities it was of limited utility due to a high level of fragmentation. RESULTS: Here we report an improved tobacco genome assembly, which, aided by the application of optical mapping, achieves an N50 size of 2.17 Mb and enables anchoring of 64% of the genome to pseudomolecules; a significant increase from the previous value of 19%. We use this assembly to identify two homeologous genes that explain the differentiation of the burley tobacco market class, with potential for greater understanding of Nitrogen Utilization Efficiency and Nitrogen Use Efficiency in plants; an important trait for future sustainability of agricultural production. CONCLUSIONS: Development of an improved genome assembly for N. tabacum enables what we believe to be the first successful map-based gene discovery for the species, and demonstrates the value of an improved assembly for future research in this model and commercially-important species. PMID- 28625163 TI - Gamma-delta (gammadelta) T-cell lymphoma - another case unclassifiable by World Health Organization classification: a case report. AB - BACKGROUND: We present a case of gamma-delta T-cell lymphoma that does not fit the current World Health Organization classifications. CASE PRESENTATION: A 74 year-old Caribbean-American woman presented with lymphocytosis, pruritus, and non drenching night sweats. Bone marrow and peripheral blood analyses both confirmed the diagnosis of gamma-delta T-cell lymphoma. An axillary lymph node biopsy was negative for lymphoma. Clinically absent hepatosplenomegaly and skin lesions with biopsy-proven gamma-delta T-cell lymphoma suggest that she is unclassifiable within the current classification system. CONCLUSIONS: We believe this is a case of not otherwise specified gamma-delta T-cell lymphoma. Accumulation of these rare not otherwise specified cases will be important for future classification which further defines the biology of this disease. PMID- 28625164 TI - The effect of weekly specialist palliative care teleconsultations in patients with advanced cancer -a randomized clinical trial. AB - BACKGROUND: Teleconsultation seems to be a promising intervention for providing palliative care to home-dwelling patients; however, its effect on clinically relevant outcome measures remains largely unexplored. Therefore, the purpose of this study was to determine whether weekly teleconsultations from a hospital based specialist palliative care consultation team (SPCT) improved patient experienced symptom burden compared to "care as usual". Secondary objectives were to determine the effects of these teleconsultations on unmet palliative care needs, continuity of care, hospital admissions, satisfaction with teleconsultations, and the burden experienced by informal caregivers. METHODS: Seventy-four home-dwelling patients diagnosed with advanced cancer were recruited from outpatient clinics of a tertiary university hospital and from regional home care organizations between May 2011 and January 2015. Participants were randomized to receive weekly, prescheduled teleconsultations with an SPCT-member (intervention group), or to receive "care as usual" (control group), for a period of 12 weeks. The primary outcome of this study was: patient-experienced symptom burden indicated by the following: (1) Total Distress Score (defined as the sum of all nine subscales of the Edmonton Symptom Assessment System) and (2) the Hospital Anxiety and Depression Scale. Mixed models were used to test for differences between the two groups. RESULTS: The Total Distress Score became significantly higher in the intervention group than in the control group, reaching significance at week 12 (adjusted difference at week 12: 6.90 points, 95% CI, 0.17 to 13.63; P = 0.04). The adjusted anxiety scores were higher in the intervention group than in the control group (estimate effect: 1.40; 95% CI, 0.14 to 2.55; P = 0.03). No difference was found between the groups in adjusted depression scores (estimate effect: 0.30; 95% CI, -1.39 to 1.99; P = 0.73) or in secondary outcome measures. CONCLUSIONS: Adding weekly teleconsultations to usual palliative care leads to worse reported symptom scores among home-dwelling patients with advanced cancer. Possible explanations for these findings include excess attention on symptoms and (potential) suffering, the supply-driven care model for teleconsultations used in this trial, and the already high level of specialist palliative care provided to the control group in this study. TRIAL REGISTRATION: "The Netherlands National Trial Register", NTR2817 , prospectively registered: March 21, 2011. PMID- 28625165 TI - Transpulmonary thermodilution: advantages and limits. AB - BACKGROUND: For complex patients in the intensive care unit or in the operating room, many questions regarding their haemodynamic management cannot be answered with simple clinical examination. In particular, arterial pressure allows only a rough estimation of cardiac output. Transpulmonary thermodilution is a technique that provides a full haemodynamic assessment through cardiac output and other indices. MAIN BODY: Through the analysis of the thermodilution curve recorded at the tip of an arterial catheter after the injection of a cold bolus in the venous circulation, transpulmonary thermodilution intermittently measures cardiac output. This measure allows the calibration of pulse contour analysis. This provides continuous and real time monitoring of cardiac output, which is not possible with the pulmonary artery catheter. Transpulmonary thermodilution provides several variables beyond cardiac output. It estimates the end-diastolic volume of the four cardiac cavities, which is a marker of cardiac preload. It provides an estimation of the systolic function of the combined ventricles. It is more direct than the pulmonary artery catheter, but does not allow the distinct estimation of right and left cardiac function. It is easier and faster to perform than echocardiography, but does not provide a full evaluation of the cardiac structure and function. Transpulmonary thermodilution has the unique advantage of being able to estimate at the bedside extravascular lung water, which quantifies the volume of pulmonary oedema, and pulmonary vascular permeability, which quantifies the degree of a pulmonary capillary leak. Both indices are helpful for guiding fluid strategy, especially in case of acute respiratory distress syndrome. CONCLUSIONS: Transpulmonary thermodilution provides a full cardiovascular evaluation that allows one to answer many questions regarding haemodynamic management. It belongs to the category of "advanced" devices that are indicated for the most critically ill and/or complex patients. PMID- 28625167 TI - Assessment of pulmonary mechanics in mechanical ventilation. PMID- 28625168 TI - Human leukocyte antigen-DR expression might predict outcomes in severe sepsis, but diabetes mellitus cannot be ignored. PMID- 28625166 TI - Impact of Gram stain results on initial treatment selection in patients with ventilator-associated pneumonia: a retrospective analysis of two treatment algorithms. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a common and serious problem in intensive care units (ICUs). Several studies have suggested that the Gram stain of endotracheal aspirates is a useful method for accurately diagnosing VAP. However, the usefulness of the Gram stain in predicting which microorganisms cause VAP has not been established. The purpose of this study was to evaluate whether a Gram stain of endotracheal aspirates could be used to determine appropriate initial antimicrobial therapy for VAP. METHODS: Data on consecutive episodes of microbiologically confirmed VAP were collected from February 2013 to February 2016 in the ICU of a tertiary care hospital in Japan. We constructed two hypothetical empirical antimicrobial treatment algorithms for VAP: a guidelines based algorithm (GLBA) based on the recommendations of the American Thoracic Society-Infectious Diseases Society of America (ATS-IDSA) guidelines and a Gram stain-based algorithm (GSBA) which limited the choice of initial antimicrobials according to the results of bedside Gram stains. The GLBA and the GSBA were retrospectively reviewed for each VAP episode. The initial coverage rates and the selection of broad-spectrum antimicrobial agents were compared between the two algorithms. RESULTS: During the study period, 219 suspected VAP episodes were observed and 131 episodes were assessed for analysis. Appropriate antimicrobial coverage rates were not significantly different between the two algorithms (GLBA 95.4% versus GSBA 92.4%; p = 0.134). The number of episodes for which antimethicillin-resistant Staphylococcus aureus agents were selected as an initial treatment was larger in the GLBA than in the GSBA (71.0% versus 31.3%; p < 0.001), as were the number of episodes for which antipseudomonal agents were recommended as an initial treatment (70.2% versus 51.9%; p < 0.001). CONCLUSIONS: Antimicrobial treatment based on Gram stain results may restrict the administration of broad-spectrum antimicrobial agents without increasing the risk of treatment failure. TRIAL REGISTRATION: UMIN-CTR, UMIN000026457 . Registered 8 March 2017 (retrospectively registered). PMID- 28625169 TI - Is there a decline in bovine spongiform encephalopathy cases born after reinforced feed bans? A modelling study in EU member states. AB - Occasional cases of classical bovine spongiform encephalopathy (BSE) still continue to occur within the European Union (EU) for animals born after reinforced feed bans (BARBs), which should in theory have eliminated all risk of infection. The study aimed to determine (i) whether a common rate of decline of BSE infection was evident across EU member states, i.e. to determine whether control measures have been equally effective in all member states, (ii) whether there was any evidence of spontaneous occurrence of BSE in the data and (iii) the expected date for the last BSE case in UK. It was found that there was no significant difference in the rate of decline of BSE prevalence between member states, with a common rate of decline of 33.9% per annum (95% CI 30.9-37%) in successive annual birth cohorts. Trend analysis indicated an ultimate decline to 0 prevalence, suggesting that spontaneous occurrence does not explain the majority of cases. Projecting forward the trends from the back-calculation model indicated that there was approximately a 50% probability of further cases in the UK, and should the current rate of decline continue, there remains the possibility of further occasional cases up until 2026. PMID- 28625171 TI - The association between adolescent psychopathology and subsequent physical activity in young adulthood: a 21-year birth cohort study. AB - BACKGROUND: The beneficial effects of physical activity (PA) for both physical and mental wellbeing are well established. Given that adolescence presents a critical developmental period during which life-long patterns of PA become established, the exploration of the longitudinal impact of adolescent psychopathology on adult PA status is of interest. METHODS: We analysed prospective data from 3663 young adults who participated in the Mater-University of Queensland Study of Pregnancy. Psychopathology was measured using the Youth Self-Report (YSR) at age 14. Participants' engagement in three types of PA (vigorous exercise, moderate exercise and walking) at age 21 were dichotomised into either 'none' or 'any'. For our main analysis, we examined the association between the YSR score and subsequent PA engagement using logistic regression. We also conducted sensitivity analyses of longitudinal associations between the YSR internalising and externalising symptoms score at age 14 and PA engagement at age 21. RESULTS: We found no longitudinal association between the total YSR score at age 14 and PA engagement at age 21. In addition, there was no longitudinal association between the YSR internalising or externalising symptoms and PA engagement. CONCLUSION: Our findings suggest that there is no longitudinal association between adolescent psychopathology and PA in young adulthood. PMID- 28625170 TI - Indirect Versus Direct Standardization Methods for Reporting Healthcare Associated Infections: An Analysis of Central Line-Associated Bloodstream Infections in Maryland. AB - Whether healthcare-associated infection data should be presented using indirect (current CMS/CDC methodology) or direct standardization remains controversial. We applied both methods to central-line-associated bloodstream infection data from 45 acute-care hospitals in Maryland from 2012 to 2014. We found that the 2 methods generate different hospital rankings with payment implications. Infect Control Hosp Epidemiol 2017;38:989-992. PMID- 28625172 TI - Acute scrotal idiopathic edema: A misleading erythema. PMID- 28625173 TI - Return visits to the pediatric emergency department: A multicentre retrospective cohort study. AB - OBJECTIVE: Return visits to the emergency department (RTED) for the same clinical complaint occur in 2.7% to 8.1% of children presenting to pediatric emergency departments (PEDs). Most studies examining RTEDs have focused solely on PEDs and do not capture children returning to other local emergency departments (EDs). Our objective was to measure the frequency and characterize the directional pattern of RTED to any of 18 EDs serving a large geographic area for children initially evaluated at a PED. METHODS: We conducted a retrospective cohort study of all visits to a referral centre PED between August 2012 and August 2013. We compared demographic variables between children with and without an RTED, measures of flow and disposition outcomes between the initial (index) visit and RTED, and between RTED to the original PED versus to other EDs in the community. RESULTS: Among all PED visits, 7.6% had an RTED within 7 days, of which 13% were to a facility other than the original PED. Children with an RTED had higher acuity and longer length of stay on their index visit. They were also more likely to be admitted on a subsequent visit than the overall PED population. RTED to the original PED had a longer waiting time (WT), length of stay, and more frequently resulted in hospitalization than RTED to a general ED. CONCLUSIONS: A significant proportion of RTED occur at a site other than where the original ED visit occurred. Examining RTED to and from only PEDs underestimates its burden on emergency health services. PMID- 28625174 TI - Quantification of Cardiomyocyte Alignment from Three-Dimensional (3D) Confocal Microscopy of Engineered Tissue. AB - Biological tissues have complex, three-dimensional (3D) organizations of cells and matrix factors that provide the architecture necessary to meet morphogenic and functional demands. Disordered cell alignment is associated with congenital heart disease, cardiomyopathy, and neurodegenerative diseases and repairing or replacing these tissues using engineered constructs may improve regenerative capacity. However, optimizing cell alignment within engineered tissues requires quantitative 3D data on cell orientations and both efficient and validated processing algorithms. We developed an automated method to measure local 3D orientations based on structure tensor analysis and incorporated an adaptive subregion size to account for multiple scales. Our method calculates the statistical concentration parameter, kappa, to quantify alignment, as well as the traditional orientational order parameter. We validated our method using synthetic images and accurately measured principal axis and concentration. We then applied our method to confocal stacks of cleared, whole-mount engineered cardiac tissues generated from human-induced pluripotent stem cells or embryonic chick cardiac cells and quantified cardiomyocyte alignment. We found significant differences in alignment based on cellular composition and tissue geometry. These results from our synthetic images and confocal data demonstrate the efficiency and accuracy of our method to measure alignment in 3D tissues. PMID- 28625175 TI - May the Mediterranean diet attenuate the risk of type 2 diabetes associated with obesity: the Seguimiento Universidad de Navarra (SUN) cohort. AB - It is likely that the Mediterranean diet (MedDiet) may mitigate the adverse effects of obesity on the incidence of type 2 diabetes mellitus (T2DM). We assessed this hypothesis in a cohort of 18 225 participants initially free of diabetes (mean age: 38 years, 61 % women). A validated semi-quantitative 136-item FFQ was used to assess dietary intake and to build a 0-9 score of adherence to MedDiet. After a median of 9.5-year follow-up, 136 incident cases of T2DM were confirmed during 173 591 person-years follow-up. When MedDiet adherence was low (<=4 points), the multivariable-adjusted hazard ratios (HR) were 4.07 (95 % CI 1.58, 10.50) for participants with BMI 25-29.99 kg/m2 and 17.70 (95 % CI 6.29, 49.78) kg/m2 for participants with BMI>=30 kg/m2, (v.4 points), these multivariable-adjusted HR were 3.13 (95 % CI 1.63, 6.01) and 10.70 (95 % CI 4.98, 22.99) for BMI 25-30 and >=30 kg/m2, respectively. The P value for the interaction was statistically significant (P=0.002). When we assessed both variables (BMI and MedDiet) as continuous, the P value for their interaction product-term was marginally significant (P=0.051) in fully adjusted models. This effect modification was not explained by weight changes during follow-up. Our results suggest that the MedDiet may attenuate the adverse effects of obesity on the risk of T2DM. PMID- 28625176 TI - Letter to the Editor: Job strain and clinical depression. PMID- 28625177 TI - Iron deficiency without anaemia is a potential cause of fatigue: meta-analyses of randomised controlled trials and cross-sectional studies. AB - Fe deficiency is a prevalent nutritional disease, and fatigue is a common complaint in the general and patient population. The association between Fe deficiency without anaemia (IDNA) and fatigue is unclear. Here, we performed a meta-analysis to evaluate the therapeutic effect of Fe on fatigue in patients with IDNA and the association between IDNA and fatigue in the population. Articles from the PubMed database up to 19 January 2016 were systematically searched. A total of six relevant randomised controlled trials (RCT) and six relevant cross-sectional studies were identified. All outcomes were converted into effect sizes. In the meta-analysis of the six RCT, we identified a significant therapeutic effect of Fe in fatigue patients with IDNA (pooled effect size 0.33; 95 % CI 0.17, 0.48; I 2=0.0 %; P<0.0001). A sensitivity analysis found that the overall results (i.e. significant association) were robust. In the meta analysis of the six cross-sectional studies, the association between IDNA and fatigue was not significant (pooled effect size 0.10; 95 % CI -0.11, 0.31; I 2=57.4 %; P=0.362). A sensitivity analysis found that the overall results (i.e. no significant association) were not robust; removal of one study made the outcomes significant. These meta-analyses suggest that improving Fe status may decrease fatigue. Further research is necessary to identify diagnostic criteria for selecting fatigue patients who might benefit from Fe therapy and to assess the prevalence of IDNA with fatigue in the general population. PMID- 28625178 TI - Endoscopic electrocautery and fibrin obliteration of an acutely complicated pyriform fossa sinus tract in a septuagenarian. AB - BACKGROUND: Pyriform fossa sinus tracts classically present with neck abscess, recurrent infections and suppurative thyroiditis in children; acute presentation in a geriatric patient is rare. METHODS: Case report and Medline literature review. CASE REPORT: A 79-year-old female presented with a left-sided neck mass and severe odynophagia of 3 days' duration. Magnetic resonance imaging revealed a large-volume, loculated fluid collection extending throughout the deep spaces of the neck on the left, within and around the thyroid gland capsule. There was radiological evidence of internal jugular vein thrombophlebitis. Abscess incision and drainage, and endoscopic evaluation, were performed. A deeply penetrating sinus was seen in the left pyriform apex, the entrance of which was circumferentially cauterised and the lumen obliterated with fibrin glue. Following post-operative intravenous antibiotics, the patient made a complete recovery. CONCLUSION: This paper describes the first use of fibrin glue to obliterate a pyriform fossa sinus tract in an adult. PMID- 28625179 TI - Dietary l-tryptophan leaves a lasting impression on the brain and the stress response. AB - Comparative models suggest that effects of dietary tryptophan (Trp) on brain serotonin (5-hydroxytryptamine; 5-HT) neurochemistry and stress responsiveness are present throughout the vertebrate lineage. Moreover, hypothalamic 5-HT seems to play a central role in control of the neuroendocrine stress axis in all vertebrates. Still, recent fish studies suggest long-term effects of dietary Trp on stress responsiveness, which are independent of hypothalamic 5-HT. Here, we investigated if dietary Trp treatment may result in long-lasting effects on stress responsiveness, including changes in plasma cortisol levels and 5-HT neurochemistry in the telencephalon and hypothalamus of Atlantic salmon. Fish were fed diets containing one, two or three times the Trp content in normal feed for 1 week. Subsequently, fish were reintroduced to control feed and were exposed to acute crowding stress for 1 h, 8 and 21 d post Trp treatment. Generally, acute crowding resulted in lower plasma cortisol levels in fish treated with 3*Trp compared with 1*Trp- and 2*Trp-treated fish. The same general pattern was reflected in telencephalic 5-HTergic turnover, for which 3*Trp-treated fish showed decreased values compared with 2*Trp-treated fish. These long-term effects on post-stress plasma cortisol levels and concomitant 5-HT turnover in the telencephalon lends further support to the fact that the extrahypothalamic control of the neuroendocrine stress response is conserved within the vertebrate lineage. Moreover, they indicate that trophic/structural effects in the brain underlie the effects of dietary Trp treatment on stress reactivity. PMID- 28625180 TI - Abortion and subsequent depressive symptoms: an analysis of the National Longitudinal Study of Adolescent Health. AB - BACKGROUND: Twenty states currently require that women seeking abortion be counseled on possible psychological responses, with six states stressing negative responses. The majority of research finds that women whose unwanted pregnancies end in abortion do not subsequently have adverse mental health outcomes; scant research examines this relationship for young women. METHODS: Four waves of data from the National Longitudinal Study of Adolescent Health were analyzed. Population-averaged lagged logistic and linear regression models were employed to test the relationship between pregnancy resolution outcome and subsequent depressive symptoms, adjusting for prior depressive symptoms, history of traumatic experiences, and sociodemographic covariates. Depressive symptoms were measured using a nine-item version of the Center for Epidemiologic Studies Depression scale. Analyses were conducted among two subsamples of women whose unwanted first pregnancies were resolved in either abortion or live birth: (1) 856 women with an unwanted first pregnancy between Waves 2 and 3; and (2) 438 women with an unwanted first pregnancy between Waves 3 and 4 (unweighted n's). RESULTS: In unadjusted and adjusted linear and logistic regression analyses for both subsamples, there was no association between having an abortion after an unwanted first pregnancy and subsequent depressive symptoms. In fully adjusted models, the most recent measure of prior depressive symptoms was consistently associated with subsequent depressive symptoms. CONCLUSIONS: In a nationally representative, longitudinal dataset, there was no evidence that young women who had abortions were at increased risk of subsequent depressive symptoms compared with those who give birth after an unwanted first pregnancy. PMID- 28625181 TI - When Sterile Processing Goes Down: An Economic Analysis of Alternative Strategies for Supporting the Service. AB - Given steam-quality challenges at our facility, the financial impact of options for reopening the sterile processing service unit were explored; duration of closure was the major driver of costs. Other potential negative effects of operating-room shutdowns include injury to facility reputation, loss of staff, loss of reimbursements, and harm to residency programs. Infect Control Hosp Epidemiol 2017;38:1002-1004. PMID- 28625182 TI - Bovine intra-mammary challenge with Streptococcus dysgalactiae spp. Dysgalactiae to explore the effect on the response of Complement activity. AB - Recently published work as described by the authors highlighted the extent of Complement activity in bovine milk. Localised mastitis infection occurring in the mammary glands of dairy cows is readily detectable by the levels of somatic cells in milk. Thus, it is opportune to monitor Complement activity in milks in association with the animal's innate immune response to mammary infection. Preliminary screening of milk samples taken randomly showed that milk with a high somatic cell count (SCC) reduced growth of the Complement-sensitive strain E. coli O111 to a greater extent (P < 0.05) than when the marker microorganism was grown in milk heated for the purpose of inactivating Complement. A follow-up study set out to determine the effect on Complement activity when a sub-clinical mastitis infection was induced in the mammary gland of four lactating dairy cows. The effect of Str. dysgalactiae spp. dysgalactiae inoculation into selected individual udder quarters of the mammary glands of each animal was followed by monitoring of SCC levels in the milks from the segregated udder samples during subsequent milking. At 72 and 96 h post inoculation (PI), the SCCs for the challenged quarter were increased compared to normal values. At the same time, the bactericidal sequestration assay identified increased E. coli O111 inhibition that can be directly linked to greater Complement activity in those quarter milks affected by induced inflammation. Thus, it can be identified that the high SCC milks were more effective in limiting E. coli O111 growth. Milks from the unchallenged quarters in all four cows were significantly less effective at reducing growth of the assay strain (P < 0.05). An ELISA assay targeting specific activation components of the Complement pathways confirmed that greater bacterial inhibition observed during the bactericidal sequestration assay was attributable to higher Complement activity in the milk samples from the affected quarters, i.e., with higher SCC. The induced infection was confirmed as self-limiting in three of the affected animals and their SCC returned to normal levels within 14 d PI, while the fourth cow required brief antibiotic intervention. PMID- 28625183 TI - Simultaneously occurring Zenker's diverticulum and Killian-Jamieson diverticulum: case report and literature review. AB - BACKGROUND: Pharyngoesophageal diverticula have many subtypes, with Zenker's diverticulum being the most common. First described in 1983, a Killian-Jamieson diverticulum is an outpouching in the anterolateral wall at the pharyngoesophageal junction. This is located inferiorly to the cricopharyngeus muscle, unlike Zenker's diverticula which occur superiorly. Killian-Jamieson diverticula are rare and are commonly misdiagnosed as Zenker's diverticula. Less than 30 reports of Killian-Jamieson diverticula have been described in the literature. CASE REPORT: A 69-year-old man presented with a 2-year symptomatic history, and was found to have simultaneous Zenker's diverticulum and Killian Jamieson diverticulum. He was treated successfully with open surgical excision of both pouches. CONCLUSION: Zenker's diverticulum and Killian-Jamieson diverticulum are diagnosed using radiological studies and endoscopy. Their differentiation is important, as surgical management differs. This paper reviews the literature on Killian-Jamieson diverticula and the management options available. PMID- 28625184 TI - Detection of 70 kDa heat shock protein in the saliva of dairy cows. AB - This Research Communication describes, for the first time, the detection of HSP70 in saliva of dairy cows. Thermal stress is a major environmental stress that limits animal growth, metabolism, and productivity. The cellular response to heat stress involves the synthesis of heat shock proteins (HSPs), presumably to protect the functional stability of cells at increasing temperatures. HSP70 has been found to be present in cattle blood serum and may also be present in other secretory fluids, such as saliva, as already observed in humans. The aim of this study was to detect heat shock protein HSP70 in bovine saliva. Saliva samples were taken from higher- (n = 5) and lower milk producing (n = 5) Holstein Friesian cows in summer and in winter for the detection of HSP70. HSP70 concentrations were assayed using the ELISA technique. Salivary HSP70 concentrations ranged from 0.524 to 12.174 ng/ml in cows. Higher salivary HSP70 concentrations were significantly associated with higher milk production and higher environmental temperature, but not with rectal temperature. PMID- 28625185 TI - Deterioration of visuospatial associative memory following a first psychotic episode: a long-term follow-up study. AB - BACKGROUND: Cognitive deficits are a core feature of schizophrenia, and impairments in most domains are thought to be stable over the course of the illness. However, cross-sectional evidence indicates that some areas of cognition, such as visuospatial associative memory, may be preserved in the early stages of psychosis, but become impaired in later established illness stages. This longitudinal study investigated change in visuospatial and verbal associative memory following psychosis onset. METHODS: In total 95 first-episode psychosis (FEP) patients and 63 healthy controls (HC) were assessed on neuropsychological tests at baseline, with 38 FEP and 22 HCs returning for follow up assessment at 5-11 years. Visuospatial associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery Visuospatial Paired Associate Learning task, and verbal associative memory was assessed using Verbal Paired Associates subtest of the Wechsler Memory Scale - Revised. RESULTS: Visuospatial and verbal associative memory at baseline did not differ significantly between FEP patients and HCs. However, over follow-up, visuospatial associative memory deteriorated significantly for the FEP group, relative to healthy individuals. Conversely, verbal associative memory improved to a similar degree observed in HCs. In the FEP cohort, visuospatial (but not verbal) associative memory ability at baseline was associated with functional outcome at follow-up. CONCLUSIONS: Areas of cognition that develop prior to psychosis onset, such as visuospatial and verbal associative memory, may be preserved early in the illness. Later deterioration in visuospatial memory ability may relate to progressive structural and functional brain abnormalities that occurs following psychosis onset. PMID- 28625186 TI - How predictable are symptoms in psychopathological networks? A reanalysis of 18 published datasets. AB - BACKGROUND: Network analyses on psychopathological data focus on the network structure and its derivatives such as node centrality. One conclusion one can draw from centrality measures is that the node with the highest centrality is likely to be the node that is determined most by its neighboring nodes. However, centrality is a relative measure: knowing that a node is highly central gives no information about the extent to which it is determined by its neighbors. Here we provide an absolute measure of determination (or controllability) of a node - its predictability. We introduce predictability, estimate the predictability of all nodes in 18 prior empirical network papers on psychopathology, and statistically relate it to centrality. METHODS: We carried out a literature review and collected 25 datasets from 18 published papers in the field (several mood and anxiety disorders, substance abuse, psychosis, autism, and transdiagnostic data). We fit state-of-the-art network models to all datasets, and computed the predictability of all nodes. RESULTS: Predictability was unrelated to sample size, moderately high in most symptom networks, and differed considerable both within and between datasets. Predictability was higher in community than clinical samples, highest for mood and anxiety disorders, and lowest for psychosis. CONCLUSIONS: Predictability is an important additional characterization of symptom networks because it gives an absolute measure of the controllability of each node. It allows conclusions about how self-determined a symptom network is, and may help to inform intervention strategies. Limitations of predictability along with future directions are discussed. PMID- 28625187 TI - A comparison study of complications and initial follow-up costs of transcutaneous and percutaneous bone conduction devices. AB - BACKGROUND: The percutaneous osseointegrated bone conduction device can be associated with more soft tissue complications when compared to the magnetic transcutaneous osseointegrated bone conduction device. This study aimed to determine whether fewer soft tissue complications may result in the transcutaneous osseointegrated bone conduction device being a lower cost option in hearing rehabilitation. METHODS: This retrospective case note review included adult patients who underwent implantation with the transcutaneous Cochlear Attract (n = 22) or percutaneous Cochlear DermaLock (n = 25) bone-anchored hearing aids between September 2013 and December 2014. The number of post operative clinic appointments, complications and treatments undertaken, and calculated cost average, were compared between the two groups. RESULTS: Although the transcutaneous device was slightly more expensive than the percutaneous device, the percutaneous device was associated with a greater number of soft tissue complications and, as a result, the percutaneous device had significantly higher follow-up costs in the first six months following surgery. CONCLUSION: The transcutaneous osseointegrated bone conduction device may represent a more cost effective method of hearing rehabilitation compared to the percutaneous osseointegrated bone conduction device. PMID- 28625189 TI - Influence of early maladaptive schemas, depression, and anxiety on the intensity of self-reported cognitive complaint in older adults with subjective cognitive decline. AB - BACKGROUND: Subjective cognitive decline (SCD) designates a self-reported cognitive decline despite preserved cognitive abilities. This study aims to explore, in older adults with SCD, the association between intensity of self reported cognitive complaint and psychological factors including Young's early maladaptive schemas (EMSs) (i.e. enduring cognitive structures giving rise to beliefs about oneself and the world), as well as depression and anxiety. METHODS: Seventy-six subjects (69.22 years +/- 6.1) with intact cognitive functioning were recruited through an advertisement offering free participation in an intervention on SCD. After undergoing a neuropsychological examination (including global cognition (MMSE) and episodic memory (FCSRT)) and a semi-structured interview to assess depressive symptoms (MADRS), they completed a set of online self-reported questionnaires on SCD (McNair questionnaire), Young's EMSs (YSQ-short form), depression (HADS-D), and anxiety (HADS-A and trait-STAI-Y). RESULTS: The McNair score did not correlate with the neuropsychological scores. Instead, it was highly (r > 0.400; p < 0.005) correlated with trait anxiety and three EMSs belonging to the "Impaired autonomy and performance" domain: Dependence/incompetence, Failure to achieve and Vulnerability to harm or illness. Our final regression model comprising depression, anxiety, and these three EMSs as predictors (while controlling for age, gender, and objective cognition) accounted for 38.5% of the observed variance in SCD intensity. CONCLUSIONS: The level of cognitive complaint is significantly associated with Young's EMSs in the category of "Impaired autonomy and performance". We assume that SCD may primarily be driven by profound long-term inner beliefs about oneself that do not specifically refer to self-perceived memory abilities. PMID- 28625188 TI - Symptoms of depression in a large healthy population cohort are related to subjective memory complaints and memory performance in negative contexts. AB - BACKGROUND: Decades of research have investigated the impact of clinical depression on memory, which has revealed biases and in some cases impairments. However, little is understood about the effects of subclinical symptoms of depression on memory performance in the general population. METHODS: Here we report the effects of symptoms of depression on memory problems in a large population-derived cohort (N = 2544), 87% of whom reported at least one symptom of depression. Specifically, we investigate the impact of depressive symptoms on subjective memory complaints, objective memory performance on a standard neuropsychological task and, in a subsample (n = 288), objective memory in affective contexts. RESULTS: There was a dissociation between subjective and objective memory performance, with depressive symptoms showing a robust relationship with self-reports of memory complaints, even after adjusting for age, sex, general cognitive ability and symptoms of anxiety, but not with performance on the standardised measure of verbal memory. Contrary to our expectations, hippocampal volume (assessed in a subsample, n = 592) did not account for significant variance in subjective memory, objective memory or depressive symptoms. Nonetheless, depressive symptoms were related to poorer memory for pictures presented in negative contexts, even after adjusting for memory for pictures in neutral contexts. CONCLUSIONS: Thus the symptoms of depression, associated with subjective memory complaints, appear better assessed by memory performance in affective contexts, rather than standardised memory measures. We discuss the implications of these findings for understanding the impact of depressive symptoms on memory functioning in the general population. PMID- 28625190 TI - Association between early echocardiography, therapy for patent ductus arteriosus, and outcomes in very low birth weight infants. AB - BACKGROUND: In very low birth weight infants, persistence of a patent ductus arteriosus results in morbidity and mortality. Therapies to close the ductus are effective, but clinical outcomes may depend on the accuracy of diagnosis and the timing of administration. The objective of the present study was to characterise the association between early echocardiography, therapy for patent ductus arteriosus, and outcomes in very low birth weight infants. METHODS: This retrospective cohort study used electronic health record data on inborn infants of gestational age ?28 weeks and birth weight <1500 g who were discharged after day of life 7 from 362 neonatal ICU from 1997 to 2013. The primary outcome was death between day of life 7 and discharge. Secondary outcomes included bronchopulmonary dysplasia, necrotising enterocolitis, and grade 3 or 4 intraventricular haemorrhage. RESULTS: This study included a total of 48,551 infants with a median gestational age of 27 weeks (interquartile range 25, 28) and birth weight 870 g (706, 1050). Early echocardiography - that is, performed during days of life 2 to 6 - was performed in 15,971/48,551 (33%) infants, and patent ductus arteriosus was diagnosed in 31,712/48,551 (65%). The diagnosis was more common in infants who had undergone early echocardiography (14,549/15,971 [91%] versus 17,163/32,580 [53%], p<0.001). In multivariable analysis, early echocardiography was not associated with reduced mortality (odds ratio 0.97, 95% CI 0.89-1.05). Results were similar in the subset of infants who received therapy for patent ductus arteriosus (odds ratio 1.01, 95% CI 0.90-1.15). CONCLUSIONS: Early echocardiography was associated with an increased diagnosis of patent ductus arteriosus, but not with decreased mortality. PMID- 28625191 TI - Attraction and consumption of methyl eugenol by male Bactrocera umbrosa Fabricius (Diptera: Tephritidae) promotes conspecific sexual communication and mating performance. AB - The Artocarpus fruit fly, Bactrocera umbrosa (Fabricius) (Diptera: Tephritidae), is an oligophagous fruit pest infesting Moraceae fruits, including jackfruit (Artocarpus heterophyllus Lamarck), a fruit commodity of high value in Malaysia. The scarcity of fundamental biological, physiological and ecological information on this pest, particularly in relation to behavioural response to phytochemical lures, which are instrumental to the success of many area-wide fruit fly control and management programmes, underpins the need for studies on this much-underrated pest. The positive response of B. umbrosa males to methyl eugenol (ME), a highly potent phytochemical lure, which attracts mainly males of many Bactrocera species, was shown to increase with increasing age. As early as 7 days after emergence (DAE), ca. 22% of males had responded to ME and over 50% by 10 DAE, despite no occurrence of matings (i.e. the males were still sexually immature). Male attraction to ME peaked from 10 to 27 DAE, which corresponded with the flies' attainment of sexual maturity. In wind-tunnel assays during the dusk courtship period, ME-fed males exhibited earlier calling activity and attracted a significantly higher percentage of virgin females compared with ME-deprived males. ME-fed males enjoyed a higher mating success than ME-deprived males at 1 day post ME feeding in semi-field assays. ME consumption also promotes aggregation behaviour in B. umbrosa males, as demonstrated in wind-tunnel and semi-field assays. We suggest that ME plays a prominent role in promoting sexual communication and enhancing mating performance of the Artocarpus fruit fly, a finding that is congruent with previous reports on the consequences of ME acquisition by other economically important Bactrocera species. PMID- 28625192 TI - PROLONGED BIRTH INTERVALS IN HAMEDAN, IRAN: VARIATIONS AND DETERMINANTS. AB - SummaryThe enduring sub-replacement level of fertility in Iran is the result of changing timing of births. Using data from the 2015 Hamedan Survey of Fertility, conducted in a representative sample of 3000 married women aged 15-49, this study examined variations in median lengths of birth intervals employing cumulative survival functions, and investigated the determinants of birth interval lengths using regression hazard models. The results showed that the median first, second and third birth intervals, estimated at 28, 74 and 136 months respectively, doubled between 1995 and 2015. The multivariate analysis results indicated the strong impact of contraceptive use and higher education on lengthening birth intervals, with greater effects on the timing of second and third births. The relative risks of second and third births were higher among rural migrants, unemployed women and those with shorter periods of breast-feeding and the death of a preceding birth. Only timing of the third birth was influenced by son preference. The implications of the results for low fertility and maternal and child health in Iran are discussed. PMID- 28625193 TI - Place-based social contact and mixing: a typology of generic meeting places of relevance for infectious disease transmission. AB - This study aims to develop a typology of generic meeting places based on social contact and mixing of relevance for infectious disease transmission. Data were collected by means of a contact diary survey conducted on a representative sample of the Swedish population. The typology is derived from a cluster analysis accounting for four dimensions associated with transmission risk: visit propensity and its characteristics in terms of duration, number of other persons present and likelihood of physical contact. In the analysis, we also study demographic, socio-economic and geographical differences in the propensity of visiting meeting places. The typology identifies the family venue, the fixed activity site, the family vehicle, the trading plaza and the social network hub as generic meeting places. The meeting place typology represents a spatially explicit account of social contact and mixing relevant to infectious disease modelling, where the social context of the outbreak can be highlighted in light of the actual infectious disease. PMID- 28625194 TI - Preoperative malnutrition is associated with increased mortality and adverse outcomes after paediatric cardiac surgery. AB - BACKGROUND: Malnutrition is common in children with CHD and is likely to place them at an increased risk for adverse surgical outcomes. We sought to evaluate the impact of preoperative malnutrition on outcomes after paediatric cardiac surgery. METHODS: We conducted a retrospective analysis of patients from age 0 to 5 years undergoing cardiac surgery at Seattle Children's Hospital from 2006 to 2015. We used regression modelling to examine the impact of malnutrition on surgical outcomes. RESULTS: We found a non-linear relationship between low height for-age and weight-for-age z-scores and mortality after surgery. In the range of z-score ?-2, each additional unit decrease in height-for-age or weight-for-age z score was associated with a 2.9 or 2.1% increased risk for mortality, respectively. Each unit decrease in height-for-age z-score was associated with a 1.2% increased risk for cardiac arrest, 1.1% increased risk for infection, and an average of 1.7 additional hours of mechanical ventilation, 6 hours longer ICU stay, and 13 hours longer hospital stay. Each unit decrease in weight-for-age z score was associated with a 0.7% increased risk for cardiac arrest, 0.8% increased risk for infection, and an average of 1.9 additional hours of mechanical ventilation and 5.3 additional hours of ICU stay. CONCLUSIONS: This study is unique in demonstrating a significant association between malnutrition and 30-day mortality and other adverse outcomes after paediatric cardiac surgery in a mixed population of CHD patients. By evaluating nutritional status as a continuous variable, we were able to clearly distinguish the point at which malnutrition begins to affect mortality. PMID- 28625195 TI - Consistency matters: Consistency in the timing and quality of daily interactions between parents and adolescents predicts production of proinflammatory cytokines in youths. AB - The current study examined whether consistency in day-to-day interactions between children and parents related to inflammatory cytokine production in youths. One hundred twenty-three parents recorded the daily quality of interactions and timing of leisure activities with their adolescent children for 2 weeks, and the degree of variability in those ratings was calculated. One year later, the production of proinflammatory cytokines in youths' blood was measured in response to in vitro exposure to lipopolysaccharide (a bacterial product). The results indicate that greater variability in parent-child relationship quality related to greater stimulated proinflammatory cytokine production in youths, above and beyond overall relationship quality. Greater variability in the timing of parent child leisure activities also predicted greater stimulated proinflammatory cytokine production in youths, regardless of the frequency of interactions. In sum, consistency in both the affective and temporal aspects of parent-child relationships may contribute to inflammatory processes in youth. PMID- 28625196 TI - The Effectiveness of Enhanced Cognitive Behavioural Therapy (CBT-E): A Naturalistic Study within an Out-Patient Eating Disorder Service. AB - BACKGROUND: The effectiveness of enhanced cognitive behavioural Therapy (CBT-E) for adults with a range of eating disorder presentations within routine clinical settings has been examined in only two known published studies, neither of which included a follow-up assessment period. AIM: The current study aimed to evaluate the effectiveness of CBT-E within an out-patient eating disorder service in Brisbane, Queensland, Australia, and incorporated a follow-up assessment period of approximately 20 weeks post-treatment. METHOD: The study involved 114 adult females with a diagnosed eating disorder, who attended an average of 20-40 individual CBT-E sessions with a psychologist or a psychiatry registrar between 2009 and 2013. RESULTS: Of those who began treatment, 50% did not complete treatment, and the presence of psychosocial and environmental problems predicted drop-out. Amongst treatment completers, statistically and clinically significant improvements in eating disorder and general psychopathology were observed at post treatment, which were generally maintained at the 20-week follow-up. Statistically significant improvements in eating disorder and general psychopathology were observed amongst the total sample. CONCLUSIONS: The findings, which were comparable to the previous Australian effectiveness study of CBT-E, indicate that CBT-E is an effective treatment for adults with all eating disorders within out-patient settings. Given the high attrition rate, however, minimizing drop-out appears to be an important consideration when implementing CBT-E within clinical settings. PMID- 28625198 TI - Determining the clinical significance of errors in pediatric radiograph interpretation between emergency physicians and radiologists. AB - OBJECTIVES: Emergency physicians (EPs) interpret plain radiographs for management and disposition of patients. Radiologists subsequently conduct their own interpretations, which may differ. The purposes of this study were to review the rate and nature of discrepancies between radiographs interpreted by EPs and those of radiologists in the pediatric emergency department, and to determine their clinical significance. METHODS: We conducted a retrospective review of discrepant radiology reports from a single-site pediatric emergency department from October 2012 to December 2014. All radiographs were interpreted first by the staff EP, then by a radiologist. The report was identified as a "discrepancy" if these reports differed. Radiographs were categorized by body part and discrepancies classified as false positive, false negative, or not a discrepancy. Clinically significant errors that required a change in management were tracked. RESULTS: There were 25,304 plain radiographs completed during the study period, of which 252 (1.00%) were identified as discrepant. The most common were chest radiographs (41.7%) due to missed pneumonia, followed by upper and lower extremities (26.2% and 17.5%, respectively) due to missed fractures. Of the 252 discrepancies, 207 (82.1%) were false negatives and 45 (17.9%) were false positives. In total, 105 (0.41% of all radiographs) were clinically significant. CONCLUSION: There is a low rate of discrepancy in the interpretation of pediatric emergency radiographs between emergency department physicians and radiologists. The majority of errors occur with radiographs of the chest and upper extremities. The low rate of clinically significant discrepancy allows safe management based on EP interpretation. PMID- 28625197 TI - Do not confuse multidisciplinary task management in nursing homes with interprofessional care! AB - : Problem statement Little is known about how interprofessional healthcare providers in nursing homes work together. We know that interprofessional teamwork evolves from trial and error learning and so interprofessional collaboration has to be actively taught. This study aims to gain insights in the perception of professionals towards interprofessional collaboration in nursing homes and the factors that have an impact on interprofessional collaboration. Approach A qualitative descriptive methodology using focus group interviews and additional semi-structured interviews was performed. In total three focus group sessions with healthcare providers from different disciplines were held and additionally nine semi-structured interviews were executed. A thematic analysis was performed. The transcripts were read to immerse in the data and initial ideas were noted. Both open coding (identification of primary themes) and axial coding (analysis of relationships among themes) were conducted and re-focussed into potential themes. Findings Four main themes emerge from the analysis: context, collaboration, care and experience. From the findings it seems that healthcare teams in nursing homes work as 'separated groups'. A lot of collaboration is perceived, but no common vision or responsibility sharing is found. The role description of the different disciplines does not always seem clear or is not always explicit. CONCLUSION: In usual care the perceived interactions between professionals are called collaboration. Obviously physicians and all healthcare professionals do not work interprofessionally according to definitions from the literature. This study provided evidence of the awareness that interprofessional collaboration in usual care is situational and fragmentary organised. PMID- 28625199 TI - Color vision test to differentiate Alzheimer's disease from vascular dementia. AB - Arnaoutoglou et al. (2017) reported that "Ishihara Color Vision Test - 38 Plate" was useful for the differential diagnosis of dementia between Alzheimer's Disease (AD) and Vascular Dementia (VaD). The authors used sensitivity/specificity analysis, presenting 80.6% and 87.5% to discriminate AD and VaD patients when an optimal (32.5) cut-off value of performance was used. The authors cited a reference of the fact that AD patients suffered from a non-specific type of color blindness (Pache et al., 2003), and I have a query on their study with special reference to statistical method. PMID- 28625200 TI - The value of performing invasive risk stratification in young patients with the Brugada syndrome. PMID- 28625201 TI - A perspective on the editorial by Ken Gillman: '"Much ado about nothing': monoamine oxidase inhibitors, drug interactions, and dietary tyramine''. PMID- 28625202 TI - Development and evaluation of the Dutch Healthy Diet index 2015. AB - OBJECTIVE: To update the Dutch Healthy Diet index, a measure of diet quality, to reflect adherence to the Dutch dietary guidelines 2015 and to evaluate against participants' characteristics and nutrient intakes with the score based on 24 h recall (24 hR) data and FFQ data. DESIGN: The Dutch Healthy Diet index 2015 (DHD15-index) consists of fifteen components representing the fifteen food-based Dutch dietary guidelines of 2015. Per component the score ranges between 0 and 10, resulting in a total score between 0 (no adherence) and 150 (complete adherence). SETTING: Wageningen area, the Netherlands, 2011-2013. SUBJECTS: Data of 885 men and women, aged 20-70 years, participating in the longitudinal NQplus study, who filled out two 24 hR and one FFQ, were used. RESULTS: Mean (sd) score of the DHD15-index was 68.7 (16.1) for men and 79.4 (16.0) for women. Significant inverse trends were found between the DHD15-index and BMI, smoking, and intakes of energy, total fat and saturated fat. Positive trends were seen across sex specific quintiles of the DHD15-index score with energy-adjusted micronutrient intakes. Mean DHD15-index score of the FFQ data was 15.5 points higher compared with 24 hR data, with a correlation coefficient of 0.56 between the scores. Observed trends of the DHD15-index based on FFQ with participant characteristics, macronutrient and energy-adjusted micronutrient intakes were similar to those with the DHD15-index based on 24 hR. CONCLUSIONS: The DHD15-index score assesses adherence to the Dutch dietary guidelines 2015 and indicates diet quality. The DHD15-index score can be based on 24 hR data and on FFQ data. PMID- 28625203 TI - Understanding temporal relationships between depression, falls, and physical activity in a cohort of post-hospitalized older adults - a breakthrough or a conundrum? AB - BACKGROUND: Clinical depression affects approximately 15% of community-dwelling older adults, of which half of these cases present in later life. Falls and depressive symptoms are thought to co-exist, while physical activity may protect an older adult from developing depressive symptoms. This study investigates the temporal relationships between depressive symptoms, falls, and participation in physical activities amongst older adults recently discharged following extended hospitalization. METHODS: A prospective cohort study in which 311 older adults surveyed prior to hospital discharge were assessed monthly post-discharge for six months. N = 218 completed the six-month follow-up. Participants were recruited from hospitals in Melbourne, Australia. The survey instrument used was designed based on Fiske's behavioral model depicting onset and maintenance of depression. The baseline survey collected data on self-reported falls, physical activity levels, and depressive symptoms. The monthly follow-up surveys repeated measurement of these outcomes. RESULTS: At any assessment point, falls were positively associated with depressive symptoms; depressive symptoms were negatively associated with physical activity levels; and, physical activity levels were negatively associated with falls. When compared with data in the subsequent assessment point, depressive symptoms were positively associated with falls reported over the next month (unadjusted OR: 1.20 (1.12, 1.28)), and physical activity levels were negatively associated with falls reported over the next month (unadjusted OR: 0.97 (0.96, 0.99) household and recreational), both indicating a temporal relationship. CONCLUSION: Falls, physical activity, and depressive symptoms were inter-associated, and depressive symptoms and low physical activity levels preceded falls. Clear strategies for management of these interconnected problems remain elusive. PMID- 28625204 TI - Effect of aripiprazole lauroxil in patients with acute schizophrenia as assessed by the Positive and Negative Syndrome Scale-supportive analyses from a Phase 3 study. AB - OBJECTIVE: Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints. METHODS: Patients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression-Improvement (CGI-I) scale score, was also analyzed. RESULTS: Of 622 patients who were randomized, 596 had >=1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92-94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo. CONCLUSION: AL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety. PMID- 28625205 TI - Why Suicide? The Analysis of Motives for Self-Harm. AB - BACKGROUND: There is a gap in understanding the meaning and motives behind suicidal behaviour. Using the Ideal Type methodology, Jean Baechler systematically examined the internal logic of suicidal and self-harming behaviours. He developed a typology of eleven typical meanings/motives: Flight, Grief, Self-punishment, Vengeance, Crime, Blackmail, Appeal, Sacrifice, Transfiguration, Ordeal and Game. AIMS: To develop and validate a standardized instrument to measure the motives/meanings of suicidal and self-harming behaviours, using Baechler's typology. METHOD: We developed a self-fill Likert questionnaire (Ideal Typical Meaning Questionnaire, ITMQ) covering ten of Baechler's eleven types. The questionnaire was completed by 147 patients within four weeks of attempting suicide or self-harm. The Death Attitude Profile-Revised (DAP-R) questionnaire was used to examine the concurrent validity of the Flight and the Transfiguration types and to explore the association between suicidal/self-harming motives and views about death. RESULTS: The final 25-item ITMQ has an eight-factor structure (Appeal/Blackmail, Ordeal/Game, Vengeance, Self-punishment, Sacrifice, Flight, Grief and Transfiguration) supporting Baechler's theory. The types have adequate reliability. Correlations with the DAP R gave some support for the concurrent validity of the Flight and Transfiguration types. CONCLUSIONS: The ITMQ is a measure of suicidal and self-harming motives/meanings based on a sound conceptual framework and could significantly contribute to the understanding of suicidal and self-harming behaviour in research and clinical settings. PMID- 28625206 TI - Organic food consumption during pregnancy and its association with health-related characteristics: the KOALA Birth Cohort Study. AB - OBJECTIVE: To investigate the associations of organic food consumption with maternal pre-pregnancy BMI, hypertension and diabetes in pregnancy, and several blood biomarkers of pregnant women. DESIGN: Prospective cohort study. SETTING: Pregnant women were recruited at midwives' practices and through channels related to consumption of food from organic origin. SUBJECTS: Pregnant women who filled in FFQ and donated a blood sample (n 1339). Participant groups were defined based on the share of consumed organic products; to discriminate between effects of food origin and food patterns, healthy diet indicators were considered in some statistical models. RESULTS: Consumption of organic food was associated with a more favourable pre-pregnancy BMI and lower prevalence of gestational diabetes. Compared with participants consuming no organic food (reference group), a marker of dairy products intake (pentadecanoic acid) and trans-fatty acids from natural origin (vaccenic and rumenic acids) were higher among participants consuming organic food (organic groups), whereas elaidic acid, a marker of the intake of trans-fatty acids found in industrially hydrogenated fats, was lower. Plasma levels of homocysteine and 25-hydroxyvitamin D were lower in the organic groups than in the reference group. Differences in pentadecanoic acid, vaccenic acid and vitamin D retained statistical significance when correcting for indicators of the healthy diet pattern associated with the consumption of organic food. CONCLUSIONS: Consumption of organic food during pregnancy is associated with several health-related characteristics and blood biomarkers. Part of the observed associations is explained by food patterns accompanying the consumption of organic food. PMID- 28625207 TI - Use of psychotropic medications in relation to neuropsychiatric symptoms, cognition and functional performance in Alzheimer's disease over a three-year period: Kuopio ALSOVA study. AB - BACKGROUND: Psychotropic medications are widely prescribed to manage neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD). Our objective was to investigate the longitudinal associations between psychotropic medication use and NPS, cognition, and functional performance in persons with very mild or mild AD at baseline. METHODS: Data were collected as part of the prospective three-year study of home-dwelling persons with AD and their caregivers (n = 236 dyads). The associations between psychotropic medication use and clinical measures were analyzed using repeated measures Generalized Estimating Equation (GEE) models. NPS, cognition, daily functioning, and disease severity were assessed with NPI, CERAD-NB, or MMSE, ADCS-ADL, and CDR-SOB, respectively. All analyses were adjusted for age, gender, education, and co-morbidities. RESULTS: The prevalence of benzodiazepines and related medications increased from 16% to 24% (p = 0.031), antidepressants from 11% to 18% (p = 0.057), and antipsychotics from 4% to 16% (p = 0.011) in the three years following AD diagnosis. In adjusted multivariable analyses, a one-point increase in NPI increased the odds of using any psychotropic medication class by 4% (odds ratio (OR) 1.04, 95% confidence interval (CI) 1.01-1.07). ADCS-ADL (1/OR 1.04, 95% CI 1.02-1.06) and CDR-SOB (OR 1.27, 95% CI 1.13-1.42) were associated with use of antipsychotics. CERAD-NB and MMSE were not associated with any psychotropic medication class use in the models. CONCLUSIONS: Psychotropic medication use increased significantly in relation to increasing dependency in AD, especially with NPS. Furthermore, the use of antipsychotics increased with disease severity, and with decline in daily functioning. Cognitive performance was not associated with psychotropic medication use. PMID- 28625208 TI - Parenting cognitions -> parenting practices -> child adjustment? The standard model. AB - In a large-scale (N = 317) prospective 8-year longitudinal multiage, multidomain, multivariate, multisource study, we tested a conservative three-term model linking parenting cognitions in toddlerhood to parenting practices in preschool to classroom externalizing behavior in middle childhood, controlling for earlier parenting practices and child externalizing behavior. Mothers who were more knowledgeable, satisfied, and attributed successes in their parenting to themselves when their toddlers were 20 months of age engaged in increased supportive parenting during joint activity tasks 2 years later when their children were 4 years of age, and 6 years after that their 10-year-olds were rated by teachers as having fewer classroom externalizing behavior problems. This developmental cascade of a "standard model" of parenting applied equally to families with girls and boys, and the cascade from parenting attributions to supportive parenting to child externalizing behavior obtained independent of 12 child, parent, and family covariates. Conceptualizing socialization in terms of cascades helps to identify points of effective intervention. PMID- 28625209 TI - Involvement of the Left Supramarginal Gyrus in Manipulation Judgment Tasks: Contributions to Theories of Tool Use. AB - OBJECTIVES: Two theories of tool use, namely the gesture engram and the technical reasoning theories, make distinct predictions about the involvement of the left inferior parietal lobe (IPL) in manipulation judgement tasks. The objective here is to test these alternative predictions based on previous studies on manipulation judgment tasks using transcranial magnetic stimulations (TMS) targeting the left supramarginal gyrus (SMG). METHODS: We review recent TMS studies on manipulation judgement tasks and confront these data with predictions made by both tool use theories. RESULTS: The left SMG is a highly intertwined region, organized following several functionally distinct areas and TMS may have disrupted a cortical network involved in the ability to use tools rather than only one functional area supporting manipulation knowledge. Moreover, manipulation judgement tasks may be impaired following virtual lesions outside the IPL. CONCLUSIONS: These data are more in line with the technical reasoning hypothesis, which assumes that the left IPL does not store manipulation knowledge per se. (JINS, 2017, 23, 685-691). PMID- 28625210 TI - Household Everyday Functioning in the Internet Age: Online Shopping and Banking Skills Are Affected in HIV-Associated Neurocognitive Disorders. AB - OBJECTIVES: The Internet is a fundamental tool for completing many different instrumental activities of daily living (IADL), including shopping and banking. Persons with HIV-associated Neurocognitive Disorders (HAND) are at heightened risk for IADL problems, but the extent to which HAND interferes with the performance of Internet-based household IADLs is not known. METHODS: Ninety-three individuals with HIV disease, 43 of whom were diagnosed with HAND, and 42 HIV- comparison participants completed Internet-based tests of shopping and banking. Participants used mock credentials to log in to an experimenter-controlled Web site and independently performed a series of typical online shopping (e.g., purchasing household goods) and banking (e.g., transferring funds between accounts) tasks. RESULTS: Individuals with HAND were significantly more likely to fail the online shopping task than neurocognitively normal HIV+ and HIV- participants. HAND was also associated with poorer overall performance versus HIV+ normals on the online banking task. In the HAND group, Internet-based task scores were correlated with episodic memory, executive functions, motor skills, and numeracy. In the HIV+ sample as a whole, lower Internet-based task scores were uniquely associated with poorer performance-based functional capacity and self-reported declines in shopping and financial management in daily life, but not with global manifest functional status. CONCLUSIONS: Findings indicate that HAND is associated with difficulties in using the Internet to complete important household everyday functioning tasks. The development and validation of effective Internet training and compensatory strategies may help to improve the household management of persons with HAND. (JINS, 2017, 23, 605-615). PMID- 28625211 TI - Paying for convenience: comparing the cost of takeaway meals with their healthier home-cooked counterparts in New Zealand. AB - OBJECTIVE: Convenience and cost impact on people's meal decisions. Takeaway and pre-prepared foods save preparation time but may contribute to poorer-quality diets. Analysing the impact of time on relative cost differences between meals of varying convenience contributes to understanding the barrier of time to selecting healthy meals. DESIGN: Six popular New Zealand takeaway meals were identified from two large national surveys and compared with similar, but healthier, home made and home-assembled meals that met nutrition targets consistent with New Zealand Eating and Activity Guidelines. The cost of each complete meal, cost per kilogram, and confidence intervals of the cost of each meal type were calculated. The time-inclusive cost was calculated by adding waiting or preparation time cost at the minimum wage. SETTING: A large urban area in New Zealand. RESULTS: For five of six popular meals, the mean cost of the home-made and home-assembled meals was cheaper than the takeaway meals. When the cost of time was added, all home-assembled meal options were the cheapest and half of the home-made meals were at least as expensive as the takeaway meals. The home-prepared meals were designed to provide less saturated fat and Na and more vegetables than their takeaway counterparts; however, the home-assembled meals provided more Na than the home-made meals. CONCLUSIONS: Healthier home-made and home-assembled meals were, except one, cheaper options than takeaways. When the cost of time was added, either the home-made or the takeaway meal was the most expensive. This research questions whether takeaways are better value than home-prepared meals. PMID- 28625213 TI - Effect of Residence in Temporary Housing After the Great East Japan Earthquake on the Physical Activity and Quality of Life of Older Survivors. AB - OBJECTIVE: This study aimed to compare the physical activity level and health related quality of life (HRQOL) between older survivors residing in temporary housing after the Great East Japan Earthquake (GEJE; temporary housing group) and older individuals residing in their own homes (control group) and to clarify whether mobility function and muscle strength were correlated with physical activity among older temporary housing residents. METHODS: Subjects were recruited to the temporary housing group (n=64, 19 men and 45 women) or control group (n=64, 33 men and 31 women) according to their residence. Physical activity was assessed by the number of walking steps determined by using a triaxial accelerometer, mobility function by the Timed Up and Go test, muscle strength by the grasping power test, and HRQOL by the Medical Outcome Study 36-Item Short Form Survey v2. RESULTS: In the temporary housing group, reduced physical activity and correlation between physical activity and mobility function in men, and muscle strength in both men and women, were observed. There was no significant difference in HRQOL between groups except for bodily pain in women. CONCLUSION: Support for older evacuees should focus on maintaining their physical activity level as well as on HRQOL to avoid deterioration of health in these survivors. (Disaster Med Public Health Preparedness. 2017;11:701-710). PMID- 28625212 TI - Mental health service use and need for care of Australians without diagnoses of mental disorders: findings from a large epidemiological survey. AB - AIMS: While epidemiological surveys worldwide have found a considerable proportion of people using mental health services not to have a diagnosis of a mental disorder, with possible implications of service overuse, other work has suggested that most people without a current diagnosis who used services exhibited other indicators of need. The aims of the present study were, using somewhat different categorisations than previous work, to investigate whether: (1) Australians without a diagnosis of a mental disorder who used mental health services had other indicators of need; and (2) how rate and frequency of service use in Australia related to level of need, then to discuss the findings in light of recent developments in Australian Mental Health Policy and other epidemiological and services research findings. METHODS: Data from the Australian National Survey of Mental Health and Wellbeing (NSMHWB) 2007 was analysed. RESULTS: Most people using mental health services had evident indicators of need for mental health care (MHC), and most of those with lower evident levels of need did not make heavy use of services. Only a small proportion of individuals without any disorders or need indicators received MHC (4%). Although this latter group comprises a fair proportion of service users when extrapolating to the Australian population (16%), the vast majority of these individuals only sought brief primary-care or counselling treatment rather than consultations with psychiatrists. Access and frequency of MHC consultations were highest for people with diagnosed lifetime disorders, followed by people with no diagnosed disorders but other need indicators, and least for people with no identified need indicators. Limitations include some disorders not assessed in interview and constraints based on survey size to investigate subgroups defined, for instance, by socioeconomic advantage and disadvantage individually or by characteristics of area. CONCLUSIONS: MHC for individuals with no recognised disorders or other reasonable need for such care may be occurring but if so is likely to be an area specific phenomenon. Rather than revealing a large national pool of treatment resources being expended on the so-called 'worried well', the findings suggested a generally appropriate dose-response relationship between need indicators and service use. Definitive ascertainment of area-specific disparities in this national pattern would require a different survey approach. Government proposals for widespread introduction of stepped-care models that may seek to divert patients from existing treatment pathways need to be implemented with care and well informed by local data. PMID- 28625214 TI - Post-traumatic stress disorder associated with sexual assault among women in the WHO World Mental Health Surveys. AB - BACKGROUND: Sexual assault is a global concern with post-traumatic stress disorder (PTSD), one of the common sequelae. Early intervention can help prevent PTSD, making identification of those at high risk for the disorder a priority. Lack of representative sampling of both sexual assault survivors and sexual assaults in prior studies might have reduced the ability to develop accurate prediction models for early identification of high-risk sexual assault survivors. METHODS: Data come from 12 face-to-face, cross-sectional surveys of community dwelling adults conducted in 11 countries. Analysis was based on the data from the 411 women from these surveys for whom sexual assault was the randomly selected lifetime traumatic event (TE). Seven classes of predictors were assessed: socio-demographics, characteristics of the assault, the respondent's retrospective perception that she could have prevented the assault, other prior lifetime TEs, exposure to childhood family adversities and prior mental disorders. RESULTS: Prevalence of Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) PTSD associated with randomly selected sexual assaults was 20.2%. PTSD was more common for repeated than single-occurrence victimization and positively associated with prior TEs and childhood adversities. Respondent's perception that she could have prevented the assault interacted with history of mental disorder such that it reduced odds of PTSD, but only among women without prior disorders (odds ratio 0.2, 95% confidence interval 0.1-0.9). The final model estimated that 40.3% of women with PTSD would be found among the 10% with the highest predicted risk. CONCLUSIONS: Whether counterfactual preventability cognitions are adaptive may depend on mental health history. Predictive modelling may be useful in targeting high-risk women for preventive interventions. PMID- 28625215 TI - Assessing Coagulation by Rotational Thromboelastometry (ROTEM) in Rivaroxaban Anticoagulated Blood Using Hemostatic Agents. AB - : Introduction The use of direct oral anticoagulants (DOACs) such as rivaroxaban (Xarelto) is increasingly common. However, therapies for reversing anticoagulation in the event of hemorrhage are limited. This study investigates the ability of hemostatic agents to improve the coagulation of rivaroxaban anticoagulated blood, as measured by rotational thromboelastometry (ROTEM). Hypothesis/Problem If a chitosan-based hemostatic agent (Celox), which works independently of the clotting cascade, is applied to rivaroxaban-anticoagulated blood, it should improve coagulation by decreasing clotting time (CT), decreasing clot formation time (CFT), and increasing maximum clot firmness (MCF). If a kaolin-based hemostatic agent (QuikClot Combat Gauze), which works primarily by augmenting the clotting cascade upstream of factor Xa (FXa), is applied to rivaroxaban-anticoagulated blood, it will not be effective at improving coagulation. METHODS: Patients (age >18 years; non-pregnant) on rivaroxaban, presenting to the emergency department (ED) at two large, university-based medical centers, were recruited. Subjects (n=8) had blood drawn and analyzed using ROTEM with and without the presence of a kaolin-based and a chitosan-based hemostatic agent. The percentage of patients whose ROTEM parameters responded to the hemostatic agent and percent changes in coagulation parameters were calculated. RESULTS: Data points analyzed included: CT, CFT, and MCF. Of the samples treated with a kaolin-based hemostatic agent, seven (87.5%) showed reductions in CT, eight (100.0%) showed reductions in CFT, and six (75.0%) showed increases in MCF. The average percent change in CT, CFT, and MCF for all patients was 32.5% (Standard Deviation [SD]: 286; Range:-75.3 to 740.7%); -66.0% (SD:14.4; Range: -91.4 to -44.1%); and 4.70% (SD: 6.10; Range: -4.8 to 15.1%), respectively. The corresponding median percent changes were -68.1%, -64.0%, and 5.2%. Of samples treated with a chitosan-based agent, six (75.0%) showed reductions in CT, three (37.5%) showed reductions in CFT, and five (62.5%) showed increases in MCF. The average percent changes for CT, CFT, and MCF for all patients were 165.0% (SD: 629; Range:-96.9 to 1718.5%); 139.0% (SD: 174; Range: 83.3 to 348.0%); and -8.38% (SD: 32.7; Range:-88.7 to 10.4%), respectively. The corresponding median percent changes were -53.7%, 141.8%, and 3.0%. CONCLUSIONS: Rotational thromboelastometry detects changes in coagulation parameters caused by hemostatics applied to rivaroxaban-anticoagulated blood. These changes trended in the direction towards improved coagulability, suggesting that kaolin-based and chitosan-based hemostatics may be effective at improving coagulation in these patients. Bar J , David A , Khader T , Mulcare M , Tedeschi C . Assessing coagulation by rotational thromboelastometry (ROTEM) in rivaroxaban anticoagulated blood using hemostatic agents. Prehosp Disaster Med. 2017;32(5):580-587. PMID- 28625216 TI - Symptom rating scales for schizophrenia and other primary psychotic disorders in ICD-11. AB - The subtype system for categorising presentations of schizophrenia will be removed from International Classification of Diseases 11th Revision. In its place will be a system for rating six domains of psychotic disorder pathology: positive symptoms, negative symptoms, depressive symptoms, manic symptoms, psychomotor symptoms and cognitive symptoms. This paper outlines the rationale and description of the proposed symptom rating scale, including current controversies. In particular, the scale could adopt either a 4-point severity rating or a 2-point presence/absence rating. The 4-point scale has the advantage of gathering more information, but potentially at the cost of reliability. The paper concludes by describing the field testing process for evaluating the proposed scale. PMID- 28625217 TI - The core emergency ultrasound curriculum project: A report from the Curriculum Working Group of the CAEP Emergency Ultrasound Committee. AB - Emergency ultrasound (EUS) is now widely considered to be a "skill integral to the practice of emergency medicine." 1 The Canadian Association of Emergency Physicians (CAEP) initially issued a position statement in 1999 supporting the availability of focused ultrasound 24 hours per day in the emergency department (ED). 2. PMID- 28625218 TI - The response of male and female rats to a high-fructose diet during adolescence following early administration of Hibiscus sabdariffa aqueous calyx extracts. AB - Metabolic syndrome is linked to the consumption of fructose-rich diets. Nutritional and pharmacological interventions perinatally can cause epigenetic changes that programme an individual to predispose or protect them from the development of metabolic diseases later. Hibiscus sabdariffa (HS) reportedly has anti-obesity and hypocholesterolaemic properties in adults. We investigated the impact of neonatal intake of HS on the programming of metabolism by fructose. A total of 85 4-day-old Sprague Dawley rats were divided randomly into three groups. The control group (n=27, 12 males, 15 females) received distilled water at 10 ml/kg body weight. The other groups received either 50 mg/kg (n=30, 13 males, 17 females) or 500 mg/kg (n=28, 11 males, 17 females) of an HS aqueous calyx extract orally till postnatal day (PND) 14. There was no intervention from PND 14 to PND 21 when the pups were weaned. The rats in each group were then divided into two groups; one continued on a normal diet and the other received fructose (20% w/v) in their drinking water for 30 days. The female rats that were administered with HS aqueous calyx extract as neonates were protected against fructose-induced hypertriglyceridaemia and increased liver lipid deposition. The early administration of HS resulted in a significant (P?0.05) increase in plasma cholesterol concentrations with or without a secondary fructose insult. In males, HS prevented the development of fructose-induced hypercholesterolaemia. The potential beneficial and detrimental effects of neonatal HS administration on the programming of metabolism in rats need to be considered in the long-term well being of children. PMID- 28625219 TI - Artist Lee Godie. 'I'm much better than Cezanne'. PMID- 28625220 TI - Economic Spillovers From Public Investments in Medical Countermeasures: A Case Study of a Burn Debridement Product. AB - OBJECTIVE: The US federal government invests in the development of medical countermeasures for addressing adverse health effects to the civilian population from chemical, biological, and radiological or nuclear threats. We model the potential economic spillover effects in day-to-day burn care for a federal investment in a burn debridement product for responding to an improvised nuclear device. METHODS: We identify and assess 4 primary components for projecting the potential economic spillover benefits of a burn debridement product: (1) market size, (2) clinical effectiveness and cost-effectiveness, (3) product cost, and (4) market adoption rates. Primary data sources were the American Burn Association's 2015 National Burn Repository Annual Report of Data and published clinical studies used to gain European approval for the burn debridement product. RESULTS: The study results showed that if approved for use in the United States, the burn debridement product has potential economic spillover benefits exceeding the federal government's initial investment of $24 million a few years after introduction into the burn care market. CONCLUSIONS: Economic spillover analyses can help to inform the prioritizing of scarce resources for research and development of medical countermeasures by the federal government. Future federal medical countermeasure research and development investments could incorporate economic spillover analysis to assess investment options. (Disaster Med Public Health Preparedness. 2017;11:711-719). PMID- 28625221 TI - PTSD or not PTSD? Comparing the proposed ICD-11 and the DSM-5 PTSD criteria among young survivors of the 2011 Norway attacks and their parents. PMID- 28625222 TI - A Small Spot, Inert Gas, Ion Milling Process as a Complementary Technique to Focused Ion Beam Specimen Preparation. AB - This paper reports on the substantial improvement of specimen quality by use of a low voltage (0.05 to ~1 keV), small diameter (~1 MUm), argon ion beam following initial preparation using conventional broad-beam ion milling or focused ion beam. The specimens show significant reductions in the amorphous layer thickness and implanted artifacts. The targeted ion milling controls the specimen thickness according to the needs of advanced aberration-corrected and/or analytical transmission electron microscopy applications. PMID- 28625223 TI - Ultra-processed foods and added sugars in the Chilean diet (2010). AB - OBJECTIVE: To assess the consumption of ultra-processed foods and analyse its association with the content of added sugars in the Chilean diet. DESIGN: Cross sectional study of national dietary data obtained through 24 h recalls and classified into food groups according to the extent and purpose of food processing (NOVA classification). SETTING: Chile. SUBJECTS: A probabilistic sample of 4920 individuals (aged 2 years or above) studied in 2010 by a national dietary survey (Encuesta Nacional de Consumo Alimentario). RESULTS: Ultra processed foods represented 28.6 (se 0.5) % of total energy intake and 58.6 (se 0.9) % of added sugars intake. The mean percentage of energy from added sugars increased from 7.7 (se 0.3) to 19.7 (se 0.5) % across quintiles of the dietary share of ultra-processed foods. After adjusting for several potential sociodemographic confounders, a 5 percentage point increase in the dietary share of ultra-processed foods determined a 1 percentage point increase in the dietary content of added sugars. Individuals in the highest quintile were three times more likely (OR=2.9; 95 % CI 2.4, 3.4) to exceed the 10 % upper limit for added sugars recommended by the WHO compared with those in the lowest quintile, after adjusting for sociodemographic variables. This association was strongest among individuals aged 2-19 years (OR=3.9; 95 % CI 2.7, 5.9). CONCLUSIONS: In Chile, ultra-processed foods are important contributors to total energy intake and to the consumption of added sugars. Actions aimed at limiting consumption of ultra processed foods are being implemented as effective ways to achieve WHO dietary recommendations to limit added sugars and processed foods, especially for children and adolescents. PMID- 28625224 TI - Auditory verbal hallucinations are related to cortical thinning in the left middle temporal gyrus of patients with schizophrenia. AB - BACKGROUND: Auditory verbal hallucinations (AVHs) are one of the most common and severe symptoms of schizophrenia, but the neuroanatomical abnormalities underlying AVHs are not well understood. The present study aims to investigate whether AVHs are associated with cortical thinning. METHODS: Participants were schizophrenia patients from four centers across China, 115 with AVHs and 93 without AVHs, as well as 261 healthy controls. All received 3 T T1-weighted brain scans, and whole brain vertex-wise cortical thickness was compared across groups. Correlations between AVH severity and cortical thickness were also determined. RESULTS: The left middle part of the middle temporal gyrus (MTG) was significantly thinner in schizophrenia patients with AVHs than in patients without AVHs and healthy controls. Inferences were made using a false discovery rate approach with a threshold at p < 0.05. Left MTG thickness did not differ between patients without AVHs and controls. These results were replicated by a meta-analysis showing them to be consistent across the four centers. Cortical thickness of the left MTG was also found to be inversely correlated with hallucination severity across all schizophrenia patients. CONCLUSION: The results of this multi-center study suggest that an abnormally thin left MTG could be involved in the pathogenesis of AVHs in schizophrenia. PMID- 28625225 TI - Legionella longbeachae detected in an industrial cooling tower linked to a legionellosis outbreak, New Zealand, 2015; possible waterborne transmission? AB - A legionellosis outbreak at an industrial site was investigated to identify and control the source. Cases were identified from disease notifications, workplace illness records, and from clinicians. Cases were interviewed for symptoms and risk factors and tested for legionellosis. Implicated environmental sources were sampled and tested for legionella. We identified six cases with Legionnaires' disease and seven with Pontiac fever; all had been exposed to aerosols from the cooling towers on the site. Nine cases had evidence of infection with either Legionella pneumophila serogroup (sg) 1 or Legionella longbeachae sg1; these organisms were also isolated from the cooling towers. There was 100% DNA sequence homology between cooling tower and clinical isolates of L. pneumophila sg1 using sequence-based typing analysis; no clinical L. longbeachae isolates were available to compare with environmental isolates. Routine monitoring of the towers prior to the outbreak failed to detect any legionella. Data from this outbreak indicate that L. pneumophila sg1 transmission occurred from the cooling towers; in addition, L. longbeachae transmission was suggested but remains unproven. L. longbeachae detection in cooling towers has not been previously reported in association with legionellosis outbreaks. Waterborne transmission should not be discounted in investigations for the source of L. longbeachae infection. PMID- 28625226 TI - Tracking Motion Devices as Assessment Tools in Anesthesia Procedures: Have We Been Using Them Well? PMID- 28625227 TI - A brief review of salient factors influencing adult eating behaviour. AB - A better understanding of the factors that influence eating behaviour is of importance as our food choices are associated with the risk of developing chronic diseases such as obesity, CVD, type 2 diabetes or some forms of cancer. In addition, accumulating evidence suggests that the industrial food production system is a major contributor to greenhouse gas emission and may be unsustainable. Therefore, our food choices may also contribute to climate change. By identifying the factors that influence eating behaviour new interventions may be developed, at the individual or population level, to modify eating behaviour and contribute to society's health and environmental goals. Research indicates that eating behaviour is dictated by a complex interaction between physiology, environment, psychology, culture, socio-economics and genetics that is not fully understood. While a growing body of research has identified how several single factors influence eating behaviour, a better understanding of how these factors interact is required to facilitate the developing new models of eating behaviour. Due to the diversity of influences on eating behaviour this would probably necessitate a greater focus on multi-disciplinary research. In the present review, the influence of several salient physiological and environmental factors (largely related to food characteristics) on meal initiation, satiation (meal size) and satiety (inter-meal interval) are briefly discussed. Due to the large literature this review is not exhaustive but illustrates the complexity of eating behaviour. The present review will also highlight several limitations that apply to eating behaviour research. PMID- 28625229 TI - Mass-Gathering Medical Care in Electronic Dance Music Festivals. AB - : Introduction Electronic dance music (EDM) festivals represent a unique subset of mass-gathering events with limited guidance through literature or legislation to guide mass-gathering medical care at these events. Hypothesis/Problem Electronic dance music festivals pose unique challenges with increased patient encounters and heightened patient acuity under-estimated by current validated casualty predication models. METHODS: This was a retrospective review of three separate EDM festivals with analysis of patient encounters and patient transport rates. Data obtained were inserted into the predictive Arbon and Hartman models to determine estimated patient presentation rate and patient transport rates. RESULTS: The Arbon model under-predicted the number of patient encounters and the number of patient transports for all three festivals, while the Hartman model under-predicted the number of patient encounters at one festival and over predicted the number of encounters at the other two festivals. The Hartman model over-predicted patient transport rates for two of the three festivals. CONCLUSION: Electronic dance music festivals often involve distinct challenges and current predictive models are inaccurate for planning these events. The formation of a cohesive incident action plan will assist in addressing these challenges and lead to the collection of more uniform data metrics. FitzGibbon KM , Nable JV , Ayd B , Lawner BJ , Comer AC , Lichenstein R , Levy MJ , Seaman KG , Bussey I . Mass-gathering medical care in electronic dance music festivals. Prehosp Disaster Med. 2017;32(5):563-567. PMID- 28625228 TI - Warnings as a directive front-of-pack nutrition labelling scheme: comparison with the Guideline Daily Amount and traffic-light systems. AB - OBJECTIVE: Warnings have recently been proposed as a new type of directive front of-pack (FOP) nutrition labelling scheme to flag products with high content of key nutrients. In the present work, this system was compared with the two most common FOP nutrition labelling schemes (Guideline Daily Amounts (GDA) and traffic light system) in terms of goal-directed attention, influence on perceived healthfulness and ability to differentiate between products. Design/Setting/Subjects Goal-directed attention to FOP labels was evaluated using a visual search task in which participants were presented with labels on a computer screen and were asked to indicate whether labels with high sodium content were present or absent. A survey with 387 participants was also carried out, in which the influence of FOP labels on perceived healthfulness and ability to identify the healthful alternative were evaluated. RESULTS: Warnings improved consumers' ability to correctly identify a product with high content of a key nutrient within a set of labels compared with GDA and received the highest goal directed attention. In addition, products with high energy, saturated fat, sugar and/or sodium content that featured warnings on the label were perceived as less healthful than those featuring the GDA or traffic-light system. Warnings and the traffic-light system performed equally well in the identification of the most healthful product. CONCLUSIONS: Results from the present work suggest that warnings have potential as directive FOP nutrition labels to improve consumer ability to identify unhealthful products and highlight advantages compared with the traffic-light system. PMID- 28625230 TI - Health Care Student Knowledge and Willingness to Work in Infectious Disease Outbreaks. AB - OBJECTIVE: Health care workers are critical first responders. Understanding which factors motivate their willingness to work (WTW) during infectious disease outbreaks may guide improvements in preparedness. The perspective of health care students, the future workforce, remains largely unexplored. This study compared factors influencing WTW among medical, nursing, and pharmacy students. METHODS: A printed survey was administered to 631 medical, nursing, and pharmacy students. The questionnaire elicited information regarding prior disaster training, disease related knowledge, and WTW in the setting of infectious diseases with contact or respiratory transmission. RESULTS: Analyses of the 579 respondents (92% response rate) demonstrated that students were less fearful for their health and more willing to work during outbreaks with contact transmission than during those with respiratory transmission. Medical students were the most fearful for their health, but they demonstrated the greatest WTW, followed by nursing students, and then pharmacy students. Medical students were also the most knowledgeable about infectious diseases. Prior disaster training was associated with greater WTW. CONCLUSIONS: Extent of disease-related knowledge and prior disaster training appear to influence WTW. Our findings, taken in the context of a remarkable underemphasis on disaster preparedness in health care curricula, call for a broader incorporation of disaster training to improve the WTW of health care students, and, ultimately, health care workers. (Disaster Med Public Health Preparedness. 2017;11:694-700). PMID- 28625232 TI - Breast-feeding duration for the prevention of excess body weight of mother-child pairs concurrently: a 2-year cohort study. AB - OBJECTIVE: To examine the association between breast-feeding duration and the risk of excess body weight (children >85th percentile, mothers BMI>=25.0 kg/m2) concurrently in mother-child pairs two years after delivery. DESIGN: Prospective cohort study in Joinville, Brazil. Multivariable logistic regression was used to examine the independent relationship between breast-feeding duration and risk of excess body weight. SETTING: Brazilian public maternity hospital. SUBJECTS: Three hundred and five mother-child pairs. RESULTS: At 2-year follow-up, 23.6 % of mother-child pairs had excess body weight. Children breast-fed for <2 months were more likely to have excess body weight than children breast-fed for >=6 months (OR=2.4; 95 % CI 1.1, 5.1). Breast-feeding for <2 months was also associated with a greater likelihood of maternal excess body weight compared with those who breast-fed for >=6 months (OR=2.9; 95 % CI 1.1, 8.1). There was a progressive increase in the likelihood of mother-child pairs having excess body weight as breast-feeding duration decreased. In addition to breast-feeding duration, other independent determinants of excess body weight were pre-pregnancy weight, gestational weight gain and number of pregnancies in mothers, and birth weight in children. CONCLUSIONS: Breast-feeding for a longer duration has a parallel protective effect on the risk of excess body weight in mother-child pairs two years after birth. Since members of the same family could be influenced by the same risk factors, continued promotion and support of breast-feeding may help to attenuate the rising prevalence of overweight in mother-child pairs. PMID- 28625231 TI - You'll feel better in the morning: slow wave activity and overnight mood regulation in interepisode bipolar disorder. AB - BACKGROUND: Sleep disturbances are prominent correlates of acute mood episodes and inadequate recovery in bipolar disorder (BD), yet the mechanistic relationship between sleep physiology and mood remains poorly understood. Using a series of pre-sleep mood inductions and overnight sleep recording, this study examined the relationship between overnight mood regulation and a marker of sleep intensity (non-rapid eye movement sleep slow wave activity; NREM SWA) during the interepisode phase of BD. METHODS: Adults with interepisode BD type 1 (BD; n = 20) and healthy adult controls (CTL; n = 23) slept in the laboratory for a screening night, a neutral mood induction night (baseline), a happy mood induction night, and a sad mood induction night. NREM SWA (0.75-4.75 Hz) was derived from overnight sleep EEG recordings. Overnight mood regulation was evaluated using an affect grid pleasantness rating post-mood induction (pre sleep) and the next morning. RESULTS: Overnight mood regulation did not differ between groups following the sad or happy inductions. SWA did not significantly change for either group on the sad induction night compared with baseline. In BD only, SWA on the sad night was related to impaired overnight negative mood regulation. On the happy induction night, SWA increased relative to baseline in both groups, though SWA was not related to overnight mood regulation for either group. CONCLUSIONS: These findings indicate that SWA disruption may play a role in sustaining negative mood state from the previous night in interepisode BD. However, positive mood state could enhance SWA in bipolar patients and healthy adults. PMID- 28625233 TI - [Elevation of red cell distribution width during hospitalization predicts mortality in patients with sepsis]. AB - OBJECTIVE: To investigate the association of red cell distribution width (RDW) with prognosis in patients with sepsis. METHODS: Patients with sepsis admitted to intensive care unit (ICU) of the First Hospital of Soochow University from January 2011 to December 2016 were enrolled. All clinical data were collected for participants, which mainly included basic data, main underlying disease, site of infection, acute physiology and chronic health evaluation II(APACHE II) score, blood routine test, biochemical test, blood gas analysis, coagulation index, procalcitonin (PCT), hospitalization days, and 28-day and 90-day mortality. Patients were divided into two groups according to whether the RDW levels were higher than the time of admission or not. Kaplan-Meier survival curve was performed to analyze 28-day and 90-day cumulative survival rates in two groups. Multivariate Cox regression analysis was done to find the independent risk factors of death in patients with sepsis. RESULTS: 196 septic patients were eligible to participate into this study. 150 patients (53.57%) had higher RDW levels than those at the time of admission. Compared to negative or static change of RDW group, positive change of RDW group had higher APACHE II score (20.42+/ 6.29 vs. 16.17+/-6.37), more percentage of chronic kidney insufficiency (35.24% vs. 19.78%), bloodstream infection (32.38% vs. 15.38%), continuous renal replacement therapy (CRRT: 32.38% vs. 16.48%), higher level of C-reactive protein [CRP (mg/L): 14.71+/-3.52 vs. 11.15+/-7.94], and higher serum creatinine [SCr (MUmol/L): 128.0 (74.0, 263.5) vs. 90.0 (57.0, 145.5)], PCT [MUg/L: 3.45 (2.39, 6.64) vs. 2.35 (0.56, 3.54)], and lactic acid [Lac (mmol/L): 3.40+/-1.72 vs. 2.70+/-1.61]; and had lower levels of hematocrit (Hct: 0.357+/-0.128 vs. 0.437+/ 0.143), hemoglobin [Hb (g/L): 103.60+/-22.63 vs. 115.67+/-28.49], platelets [PLT (*109/L): 133.37+/-87.29 vs. 191.43+/-87.65], albumin [Alb (g/L): 28.15+/-5.72 vs. 35.51+/-5.91], total cholesterol [TC (mmol/L): 2.43+/-1.12 vs. 3.05+/-1.55], estimated glomerular filtration rate [eGFR (mL*min-1*1.73 m-2): 82.02+/-63.90 vs. 125.46+/-83.47], and oxygenation index [PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 229.69+/-60.61 vs. 264.21+/-74.78]; and longer time of hospitalization [days: 17.0 (12.0, 21.7) vs. 11.0 (7.0, 18.0)], higher 28-day and 90-day mortality (57.14% vs. 36.26%, 62.86% vs. 47.25%) with statistically significant differences (all P < 0.05). It was shown by Kaplan-Meier survival curve that the 28-day and 90-day cumulative survival rate in positive change of RDW group was significantly lower than that of negative or static change of RDW group (chi 12 = 8.462, chi 22 = 6.411, both P < 0.05). It was shown by multivariate Cox regression that high APACHE II score [odds ratio (OR) = 1.049, 95% confidence interval (95%CI) = 1.010 1.090, P = 0.013] and positive change of RDW (OR = 0.517, 95%CI = 0.280-0.953, P = 0.034) were the risk factors of death in patients with sepsis. CONCLUSIONS: The change of RDW values during hospitalization was related to the poor outcomes in patients with sepsis. The increase of RDW predicts the progress of sepsis and bad prognosis. Serial surveillance of RDW values could provide useful information for long-term prognosis in sepsis. PMID- 28625234 TI - [Effect of global end diastolic volume index guidance fluid resuscitation in elderly patients with septic shock]. AB - OBJECTIVE: To evaluate the effect of global end diastolic volume index (GEDVI) on fluid resuscitation in elderly patients with septic shock. METHODS: A prospective randomized controlled trial (RCT) was conducted. Septic shock patients over 65 years admitted to intensive care unit (ICU) of Shandong Province, Zibo Central Hospital from January 2013 to December 2015 were enrolled. The patients were randomly divided into control group and observation group, 20 cases in each group. In accordance with the guidelines for the treatment of septic shock, early goal-directed therapy (EGDT), rehydration in the control group was treated with the guide of central venous pressure (CVP); observation group was received pulse indicator continuous cardiac output (PiCCO) monitoring, and rehydration was treated according to the GEDVI and extravascular lung water index (EVLWI), i.e. GEDVI was maintained in 650-800 mL/m2, EVLWI was not obviously increased compared with the basic value and without the emphasis of CVP. Initial acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure score (SOFA), procalcitonin (PCT), mean arterial pressure (MAP), lactic acid (Lac) and oxygenation index (PaO2/FiO2); serial Lac, central venous to arterial carbon dioxide pressure (Pcv-aCO2), fluid balance, the amount of noradrenaline accumulation, PaO2/FiO2 after 6, 24 and 48 hours resuscitation; mechanical ventilation time, incidence of acute heart failure, ICU hospitalization time and 28-day mortality were recorded. RESULTS: There was no significant difference in gender, age, APACHE II score, SOFA score, primary disease, infection site and basal PCT, MAP, Lac, PaO2/FiO2 between the two groups. Compared with the control group, 6 hours Lac, Pcv-aCO2 recovery, positive fluid balance, noradrenaline accumulation and PaO2/FiO2 of the observation group showed no significant difference; positive fluid balance 24 hours in the recovery was significantly reduced (mL: 2 919.80+/-986.44 vs. 3 991.40+/-933.53), Pcv-aCO2 significantly decreased [mmHg (1 mmHg = 0.133 kPa): 5.55+/-1.43 vs. 7.10+/-2.38], PaO2/FiO2 significantly improved (mmHg: 194.80+/-28.57 vs. 177.65+/-23.46), and noradrenaline accumulation was increased significantly (mg: 40.99+/-20.69 vs. 27.31+/-19.34) with statistically significant difference (all P < 0.05); the blood level of Lac 48 hours in the recovery was significantly decreased (mmol/L: 1.16+/-0.89 vs. 1.85+/-1.01), Pcv-aCO2 (mmHg: 5.35+/-1.18 vs. 6.70+/-2.34), and PaO2/FiO2 (mmHg: 215.75+/-33.84 vs. 190.60+/-32.89) were further improved, the positive fluid balance was significantly reduced (mL: 3 141.55+/-1 245.69 vs. 4 533.85+/-1 416.67, all P < 0.05). Compared with the control group, mechanical ventilation time (days: 3.65+/-1.31 vs. 4.50+/-1.19), ICU hospitalization time (days: 5.80+/-1.67 vs. 7.15+/-2.30) was significantly shorter in the observation group (both P < 0.05), acute heart failure rate was decreased significantly (5.0% vs. 30.0%, P < 0.05), but the 28-day mortality showed no statistical significance (25.0% vs. 40.0%, P = 0.311). CONCLUSIONS: Compared to the conventional EGDT methods, fluid resuscitation under the guidance of GEDVI in elderly patients with septic shock with less liquid loading, can achieve better oxygenation and reduce heart failure, shorten the duration of mechanical ventilation and ICU stay, and play an important significant guidance for elderly patients' fluid resuscitation with septic shock. PMID- 28625235 TI - [Pharmacokinetics of vancomycin in patients with severe acute pancreatitis and its influencing factors: analysis of 7 years data]. AB - OBJECTIVE: To observe the change of the serum trough concentration and its pharmacokinetics of vancomycin in patients with severe acute pancreatitis (SAP), and to analyze the factors influencing vancomycin concentration. METHODS: A retrospective analysis was conducted. Steady-state trough concentrations of vancomycin from patients (18-80 years old) with SAP concomitantly with G+ infection admitted to Intensive Care Unit (ICU) of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2010 to December 2016 were enrolled. According to the usage time of vancomycin, the patients with SAP were divided into early group (onset within 21 days), middle group (onset between 21-28 days) and late group (onset over 28 days). The gender, age, body weight, clinical diagnosis, acute physiology and chronic health evaluation II (APACHE II) score, renal function, and the pharmacokinetic parameters were recorded. Influencing factors of vancomycin was analyzed by multiple linear regression and stepwise regression. RESULTS: Fifty-eight patients were enrolled who contained 134 times trough concentrations of vancomycin. There were 41 patients enrolled and 61 times of trough concentrations in the early group, 24 patients enrolled and 33 times of trough concentrations in the middle group, and 28 patients enrolled and 40 times of trough concentrations in the late group. There was no significant difference in gender, age, body weight, serum creatinine, creatinine clearance (CCr), albumin, APACHE II score among the three groups. There was significantly difference in the duration from the onset time to vancomycin administration between early, middle groups and late group (days: 15.9+/-3.2, 23.3+/-2.2 vs. 35.0+/-6.7, both P < 0.05). The positive liquid balance in early group was lower than that of late group (mL: 1 565.2+/-3 132.1 vs. 3 675.1+/-3 411.5, P < 0.01), while it was increased in the middle group as compared with that of late group (mL: 5 078.7+/-3 892.4 vs. 3 675.1+/-3 411.5, P < 0.05). The average daily dose of vancomycin in the early, middle and late groups were (14.7+/-5.0), (15.0+/-2.8), (17.0+/-4.2) mg/kg, respectively, and there was no significant difference (P > 0.05). Compared with the standard concentration (15 mg/L) of vancomycin, the serum trough concentration of vancomycin was significantly reduced in SAP patients [(7.5+/-4.3) mg/L, P < 0.01]. Apparent volume of distribution (Vd) was (72.4+/-15.4) L, and clearance rate (CL) was (9.0+/-2.8) L/h. According to the Bayesian, the serum trough concentration of vancomycin was significantly reduced in early group and middle group compared with late group (mg/L: 5.0+/-2.1, 7.3+/-2.5 vs. 11.5+/-5.1, both P < 0.01), CL was significantly increased (L/h: 10.5+/-3.0, 8.1+/-1.9 vs. 7.4+/ 1.9, both P < 0.05), and Vd was significantly increased in early group compared with late group (L: 73.7+/-15.5 vs. 71.0+/-12.6, P < 0.05). It was shown by multiple linear regression analysis that there was strong relationship between serum trough concentration and the serum creatinine, CCr, average daily dose and the starting time of vancomycin treatment (r value were 0.449, -0.318, 0.373, 0.763, respectively, all P < 0.05). CONCLUSIONS: The serum trough concentration of vancomycin was significantly reduced in SAP patients. And the earlier usage of vancomycin, the lower of the trough concentration is. Therefore, higher dosage regimen was needed to ensure the clinical effect, and reduce the bacterial resistance. PMID- 28625236 TI - [Eosinophil could predict the prognosis of patients with bloodstream infection: a retrospective analysis of 305 cases]. AB - OBJECTIVE: To investigate the value of peripheral blood for the prognosis of patients with bloodstream infection. METHODS: A retrospective analysis of patients with bloodstream infection was conducted in the intensive care unit (ICU) of Mianyang Central Hospital of Sichuan from January 2012 to October 2016. According to the 28-day survival, the patients were divided into survival group and death group. The white blood cell (WBC), neutrophils count (NEU), lymphocyte count (LYM), neutrophil/lymphocyte ratio (NLR), monocyte count (MO), eosinophil count (EO), basophil count (BA), hemoglobin (Hb), platelet count (PLT) and procalcitonin (PCT) in peripheral blood were recorded when patients were diagnosed with blood infection. Receiver operating characteristic curve (ROC), Kaplan-Meier survival analysis and Cox regression were used to evaluate the value of these risk factors for predicting the outcome. RESULTS: 305 patients were enrolled. 182 patients survived while 123 patients died during the 28-day period. (1) There was no significant difference in gender, age and comorbidities between the two groups. There was no significant difference in infection rate between the two groups except for fungal infection rate. The fungal infection rate in the death group was significantly higher than that in the survival group (9.8% vs. 3.3%, P = 0.019). (2) The LYM, MO, EO and PLT in the death group were significantly lower than those in the survival group [LYM (*109/L): 0.58 (0.29, 0.93) vs. 0.76 (0.44, 1.23), MO (*109/L): 0.47 (0.19, 0.80) vs. 0.58 (0.30, 0.94), EO (*109/L): 0.00 (0.00, 0.01) vs. 0.03 (0.01, 0.09), PLT (*1012/L): 89 (47, 148) vs. 126 (82, 186), all P < 0.05]. The NLR in the death group was significantly higher than that in the survival group [17.09 (7.60, 33.51) vs. 12.86 (6.51, 24.85), P < 0.05]. There was no significant difference in the WBC, NEU, BA, Hb and PCT between the two groups. (3) It was shown by ROC curve analysis that the maximum area under the ROC curve (AUC) of EO was 0.755. When the best cut-off value was 0.015*109/L as a predictor of death in 28 days, the sensitivity was 80.3%, and specificity was 64.7%. (4) It was shown by survival analysis that the 28-day survival rate in the patients with EO < 0.015*109/L was significantly lower than that of patients with EO > 0.015*109/L [38.3% (62/162) vs. 83.9% (120/143), chi 2 = 56.999, P = 0.000]. (5) It was shown by Cox regression that EO was the independent factor for 28-day survival (beta = 1.466, chi 2 = 39.535, P = 0.000). Risk of death was 4.331 times greater in patients with EO < 0.015*109/L than in those with EO > 0.015*109/L [hazard ratio (HR) = 4.331, 95% confidence interval (95%CI) = 2.743-6.840]. CONCLUSIONS: Compared to other parameters in peripheral blood, EO has the best correlation with the prognosis of bloodstream infection. EO is the independent prognostic predictor for 28-day survival. PMID- 28625237 TI - [Study on mechanisms and myocardial protective effect of Qishen Yiqi dropping pills on rats with myocardial infarction]. AB - OBJECTIVE: To approach the mechanisms and myocardial protective effect of Qishen Yiqi dropping pills on rats with myocardial infarction. METHODS: Sixty clean healthy male Sprague-Dawley (SD) rats were randomly divided into sham operation group, model group and observation group (each n = 20). The rat model of acute myocardial infarction (AMI) was established by ligation of left anterior descent (LAD) branch of coronary artery. After modeling, the rats in observation group were given 0.135 g/kg of Qishen Yiqi dropping pills, and sham operation group and model group were administered the same amount of normal saline, once a day for consecutive 28 days. At the end of treatment, the levels of serum inflammatory factors of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) were measured by enzyme linked immunosorbent assay (ELISA); the changes of the indexes of hemodynamic [left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), the maximal rate of increase/decrease in left ventricular pressure (+/ dp/dt max)], the ratio of the heart weight/body weight, and the ratio of the left ventricular weight/heart weight (LVW/HW), the myocardial infarction area, myocardial histopathological changes were observed in the three groups; myocardial tissues inflammatory related factors [the mRNA and protein expressions of cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX)], and the expression levels of transforming growth factor-beta (TGF beta)/Smads signal transduction pathway related protein (TGF-beta1, Smad2/3, Collagen I, Collagen III) and cell apoptosis related factors (Bcl-2, Bax) protein were measured. RESULTS: Compared with the sham operation group, levels of serum inflammatory factors, the index of LVEDP, the ratio of the heart weight/body weight, LVW/HW, myocardial infarction area, the mRNA and protein expression levels of inflammatory factors in myocardium, the expression levels of TGF beta/Smads signal transduction pathway related protein and the cell apoptosis related factors protein in model group were all significantly elevated, while LVSP and +/-dp/dt max were obviously decreased in model group. Compared with the model group, the levels of inflammatory factor in serum [LTB4 (ng/L): 370.11+/ 46.98 vs. 633.23+/-83.37, PGE2 (ng/L): 48.75+/-26.35 vs. 131.25+/-29.75, TNF alpha (MUg/L): 177.28+/-22.65 vs. 248.47+/-16.21, IL-6 (MUg/L): 493.22+/-165.99 vs. 638.41+/-191.66], LVEDP [mmHg (1 mmHg = 0.133 kPa): -2.03+/-2.98 vs. 7.03+/ 1.39], the ratio of the heart weight/body weight [(6.53+/-0.11)% vs. (7.14+/ 0.24)%], LVW/HW (0.26+/-0.01 vs. 0.32+/-0.02), myocardial infarction area [(27.21+/-2.87)% vs. (44.98+/-1.52)%], mRNA and protein expression of myocardial inflammatory factors, the expression of TGF-beta/Smads signal transduction pathway related protein, and the protein expression of Bax were all significantly decreased in observation group (all P < 0.05), LVSP (mmHg: 129.01+/-11.93 vs. 108.11+/-12.69), the +dp/dt max (mmHg/s: 3 101.3+/-378.6 vs. 2 105.3+/-245.9), the -dp/dt max (mmHg/s: 2 612.4+/-249.7 vs. 1 654.4+/-188.1), while the protein expression of Bcl-2 in observation group were obviously increased (all P < 0.05). It was demonstrated by hematoxylin-eosin (HE) staining that there were no obvious pathological changes in the sham operation group; obvious infiltration of inflammatory factors in myocardium was shown in model group; pathological changes in the observation group were significantly improved as compared with those in the model group. It was shown by Masson staining that there were slight hyperplasia of myocardial fibers and no obvious pathological changes in the sham operation group. Severe collagen hyperplasia was found in model group, and the degree of fibrosis in the observation group was significantly improved. CONCLUSIONS: Qishen Yiqi dropping pills can reduce the degree of myocardial fibrosis and inhibit the ventricular remodeling via TGF-beta/Smads signal transduction pathway. The dropping pills can also suppress the release of inflammatory factors by reducing cPLA2 to decrease the inflammatory response and inhibit apoptosis and alleviate myocardial injury by up-regulating the expression of Bcl-2 and down-regulating the expression of Bax. PMID- 28625238 TI - [Risk factors of perioperative intra-aortic balloon pump complications in cardiac surgery: a 12-year single-institution analysis]. AB - OBJECTIVE: To investigate the incidence and risk factors of the complications in perioperative intra-aortic balloon pump (IABP) supported cardiac surgical patients. METHODS: The clinical data of adult cardiac surgery patients undergoing IABP in Fuwai Hospital from January 2005 to January 2017 were enrolled. The patients were divided into complications group and no complications group. Demographic characteristics, diagnosis, perioperative clinical parameters, IABP related data, and IABP complications (including ischemia, bleeding, vascular injury and mechanical problems) were collected. The incremental risk factors of complications related IABP were analyzed by logistic regression. RESULTS: During the 12-year period, 522 patients received IABP support, with 388 male and 134 female; the mean age was (61.79+/-9.35) years; the complications related to IABP occurred in 25 patients, and overall complication rate was 4.79%; 87 IABP patients were dead in-hospital, the overall mortality was 16.67%, no patient died due to complications. The complications rate was higher in the female patients (40.00% vs. 24.95%), and was more in patients with age>=65 years old (80.00% vs. 38.03%), more with higher body mass index [BMI (kg/m2): 25.45+/-13.71 vs. 22.95+/ 3.45], diabetes mellitus (44.00% vs. 26.76%), combination treatment with extra corporeal membranous oxygenation (ECMO: 20.00% vs. 5.03%) and prolonged IABP support time (hours: 134.4+/-90.3 vs. 109.8+/-89.1, all P < 0.05). There was no significant difference in the incidence of complications among preoperative IABP support, intra-operative IABP support and post-operative IABP support [3.30% (3/91), 5.46% (10/183), 4.84% (12/248), chi 2 = 0.629, P = 0.730]. Bleeding from puncture site occurred in 14 cases (2.68%) without severe bleeding. Limb ischemia occurred in 9 cases (1.72%). One patient (0.19%) was under another surgery because of retroperitoneal hemorrhage caused by vascular injury. One patient (0.19%) was unsuccessful due to a balloon leak. It was shown by logistic regression analysis that presence of age >= 65 years [odds ratio (OR) = 2.320, 95% confidence interval (95%CI) = 1.011-1.806, P = 0.047], diabetes mellitus (OR = 2.281, 95%CI = 1.016-5.120, P = 0.026) and combination treatment with ECMO (OR = 4.341, 95%CI = 1.240-15.196, P = 0.040) were found to be the risk factors of complications related to IABP. CONCLUSIONS: IABP complication rates are generally low. The frequent complications during IABP support is bleeding from site of catheterization and limb ischemia. When patients were treated with IABP, those with older age, diabetes mellitus and combination with ECMO should be monitored closely in order to reduce complications. PMID- 28625239 TI - [Effects of human umbilical cord mesenchymal stem cells on vascular endothelial growth factor and IL-6 expression in tissue of AMI rats]. AB - OBJECTIVE: To investigate the effects of human umbilical cord mesenchymal stem cells (UC-MSCs) on vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) expression in acute myocardium infarction (AMI) rats. METHODS: The human UC-MSCs were cultured to the 4th generation for experiment. Sixty male Sprague Dawley (SD) rats were randomly divided into sham group, AMI model group and UC MSCs group, with 20 in each group. AMI animal model was produced by ligation of anterior descending coronary artery; in the sham group, the threading vein was gone below without ligation. In UC-MSCs group 2*106 UC-MSCs were infused through the caudal vein at 24 hours after successful model production. The animals were sacrificed after 7 days; the myocardial tissue and coronary artery below the ligation line were harvested. The mRNA and protein expressions of IL-6 in myocardium were detected by reverse transcription-polymerase chain reaction (RT PCR) and Western Blot. The positive expression of VEGF in coronary artery was observed by immunohistochemisty. RESULTS: Compared with the sham group, the mRNA and protein expressions of IL-6 in myocardium in AMI model group were increased significantly (gray value: 0.732+/-0.131 vs. 0.321+/-0.080, 0.678+/-0.191 vs. 0.286+/-0.061, both P < 0.05). Compared with the AMI model group, the mRNA and protein expressions of IL-6 in myocardium in UC-MSCs group were decreased significantly (gray value: 0.300+/-0.104 vs. 0.732+/-0.131, 0.312+/-0.101 vs. 0.678+/-0.191, both P < 0.05). Observation under light microscope, the VEGF positive cells in AMI model group was increased significantly compared with the sham group (cells/HP: 21.1+/-2.2 vs. 7.6+/-1.3, P < 0.05), the VEGF positive cells in UC-MSCs group were increased significantly compared with the AMI model group (cells/HP: 41.5+/-3.1 vs. 21.1+/-2.2, P < 0.05). CONCLUSIONS: Human UC-MSCs could promote angiogenesis by the improvement of VEGF in coronary artery and inhibit the inflammation by the reduction of IL-6 in rats with AMI. PMID- 28625240 TI - [Dynamic changes of complement level in patients with acute coronary syndrome and its relationships with myocardial injury]. AB - OBJECTIVE: To study relationships between myocardial injury and the levels of serum complement C3, C4 and C5b-9 in patients with acute coronary syndrome (ACS). METHODS: A retrospectively analysis was conducted. 170 ACS patients [including 110 cases of ST-segment elevation myocardial infarction (STEMI) and 60 cases of non-ST-segment elevation acute coronary syndrome (NSTE-ACS)] with ischemic chest pain or chest discomfort onset within the prior 12 hours admitted to the cardiology department of Tianjin Union Medicine Center from January 2014 to July 2016 were enrolled. Thirty-six healthy cases were enrolled as control during the same time. The levels of serum complement C3, C4 and C5b-9 on 1, 3 and 7 days after admission and myocardial function indicators were analyzed. Major adverse cardiovascular events (MACE) and readmission rate were analyzed after 1 year follow-up. The correlation between serum complement levels and myocardial function indicators was analyzed by Pearson correlation analysis. RESULTS: (1) The levels of serum C3, C4 and C5b-9 on the first day in NSTE-ACS group and STEMI group were significantly higher than control group [C3 (g/L): 1.04+/-0.33, 1.26+/ 0.35 vs. 0.39+/-0.21, C4 (g/L): 0.31+/-0.14, 0.33+/-0.10 vs. 0.19+/-0.07, C5b-9 (g/L): 575.46+/-197.26, 659.26+/-160.77 vs. 501.40+/-141.51, all P < 0.05]. There were no changes of serum C3, C4 in NSTE-ACS group, but C5b-9 decreased after a peak (g/L: 700.63+/-218.42) at 3 days. Serum complements in STEMI group reached peak on the third day [C3 (g/L): 1.37+/-0.33, C4 (g/L): 0.42+/-0.12, C5b-9 (g/L): 754.72+/-136.22]. The levels of serum C4 and C5b-9 in STEMI group were higher than NSTE-ACS group on the third and seventh day. (2) The levels of troponin T (TnT), creatine kinase-MB (CK-MB), solution intercellular adhesion molecule-1 (sICAM-1), global registry of acute coronary events (GRACE) scores and percutaneous coronary intervention (PCI) numbers in STEMI group were significantly higher than those in the NSTE-ACS group, which were as opposite as left ventricular ejection fraction (LVEF). However, there were no significant differences in levels of serum N-terminal pro-brain nitric peptide (NT-proBNP), Fibrinogen (Fib), readmission rate and incidence of MACE between STEMI and NSTE ACS groups. (3) According to GRACE, patients with ACS were divided into low risk group (<= 108 scores, 26 cases), intermediate risk group (109-140 scores, 61 cases) and highest group (> 140 scores, 83 cases). TnT and sICAM-1 in intermediate risk group were significantly increased as compared with low risk group. Levels of TnT, sICAM-1, C3, C4 and C5b-9 in the highest group were significantly higher than the low and intermediate risk groups, however the lowest LVEF was found in the highest group. (4) It was shown by Pearson correlation analyses that levels of serum C3, C4, C5b-9 were positively correlated with TnT (r value was 0.481, 0.367, 0.292, respectively, all P < 0.01), sICAM-1 (r value was 0.298, 0.249, 0.365, respectively, all P < 0.01), but negatively correlated with LVEF (r value was -0.384, -0.260, -0.200, respectively, all P < 0.01). In addition sICAM-1 positively correlated with TnT (r = 0.536, P = 0.000), but negatively correlated with LVEF (r = -0.341, P = 0.001). CONCLUSIONS: Serum complements activation was found in the acute phase of ACS patients. Serum complement C3, C4 and C5b-9 are involved in the process of myocardial injury, and may reflect severity of myocardial injury and cardiac dysfunction. PMID- 28625241 TI - [Efficacy and safety of intravenous recombinant human brain natriuretic peptide in patients with severe heart failure: a prospective multicenter clinical study]. AB - OBJECTIVE: To explore the efficacy and safety of recombinant human brain natriuretic peptide (rhBNP) in the patients with severe heart failure (HF). METHODS: A prospective multicenter study was conducted. Patients whose age > 18 years old, and with the New York Heart Association (NYHA) cardiac function grade over III-IV, acute cardiac insufficiency and the acute exacerbation of chronic cardiac insufficiency admitted to intensive care unit/cardiovascular care unit (ICU/CCU) of 58 Hospitals in China were enrolled. On the basis of the conventional treatment, all patients would be given rhBNP (neo adjuvant) with a loading dose of 1.5 MUg/kg for 3-5 minutes, and followed by a maintenance dose of 0.010-0.015 MUg*kg-1*min-1 for 3-7 days. Before the treatment and 1, 3, 7 days after treatment, researchers detected indexes of cardiac and renal function, the levels of N-terminal B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), cardiac output (CO), pulmonary capillary wedge pressure (PCWP), central venous pressure (CVP), urea nitrogen (BUN), serum creatinine (SCr), and urine output; the renal function index was re-evaluated at 30 days after administration, and the time entering ICU again, re-admission, cardiovascular events were recorded. RESULTS: 408 patients were enrolled, with 241 males and 167 females. Age range was 28-95 years, the average age was (63.0+/ 15.8) years, and 50-70 years old accounted for 46.8%. Compared with the data before treatment, NT-proBNP, PCWP and CVP significantly decreased at 6 hours after treatment [NT-proBNP (MUg*kg-1*min-1): 4 378.58+/-4 082.29 vs. 6 403.41+/-5 759.48, PCWP (mmHg, 1 mmHg = 0.133 kPa): 12.41+/-2.21 vs. 14.26+/-2.85 , CVP (mmHg): 10.63+/-2.62 vs. 11.45+/-3.45, all P < 0.05], and with the prolongation of injection, NT-proBNP, PCWP and CVP were gradually declined; CO 1 day after treatment (mL: 4.89+/-0.81 vs. 4.40+/-0.92) and LVEF 3 days after treatment (0.465+/-0.100 vs. 0.431+/-0.107) were significantly increased (both P < 0.05), and with the prolongation of injection, CO and LVEF were gradually increased. There were no obvious changes in BUN and SCr during the treatment, but 30 days after treatment, SCr was significantly lower than that pre-treatment (MUmol/L: 110.98+/-47.40 vs. 132.62+/-75.60, P < 0.01). Compared with the data pre treatment, urine output per hour was significantly increased at 3 hours after treatment (mL: 129.59+/-82.16 vs. 89.60+/-53.49, P = 0.000); urine output every 24 hours was significantly increased at day 1 and day 2 after administration (mL: 2 676.54+/-1 006.83, 2 678.74+/-975.97 vs. 2 150.36+/-283.76, both P < 0.01). In 7 days, the re-entry ICU rate was 2.7%, and the re-hospitalization rate was 2.88% within 30 days, re-cardiac failure rate was 1.43% in 30 days, and the overall fatality rate was 9.55% in 30 days. CONCLUSIONS: The rhBNP can significantly improve heart function in patients with HF. And, it has a certain effect on renal function. The rhBNP is effective and safe for the treatment of cardiac insufficiency. PMID- 28625242 TI - [Clinical significance of combined detection of peripheral miR-182 and IL-17 in the early diagnosis of patients with eclampsia complicated with cerebral infarction in ICU]. AB - OBJECTIVE: To observe the effect of peripheral blood microRNA-182 (miR-182) combined with interleukin-17 (IL-17) in the early diagnosis of cerebral infarction (CI) in patients with eclampsia. METHODS: A prospective non-randomized controlled study was conducted. The patients with eclampsia admitted to intensive care unit (ICU) of Liaocheng People's Hospital from January 1st, 2013 to September 30th 2016 were enrolled. Cerebral imaging was conducted in 7 days after admission to make a definite diagnosis of the occurrence of CI, excluding patients with cerebral hemorrhage. Patients were divided into CI group and non-CI group. Twenty healthy women of childbearing age were selected as control group. Peripheral venous blood of all patients with eclampsia at 1 day after admission, the expression of miR-182 was detected by real-time fluorescence quantitative polymerase chain reaction (PCR), regulatory T cells (Treg) and T helper 17 cells (Th17) ratio was detected by flow cytometry, and the level of plasma IL-17 was detected by enzyme linked immunosorbent assay (ELISA). Pearson method was used to analyze the correlation between the indexes. The receiver operating characteristic curve (ROC) was used to analyze the diagnostic value of each index for CI in patients with eclampsia. RESULTS: In the 30 patients with eclampsia, there were 13 cases of CI, including 10 case of cerebral venous thrombosis (CVT) and 3 cases of arterial thrombus; 17 cases of non-CI, including 15 cases of reversible posterior leukoencephalopathy syndrome (RPLS) and 2 cases without obvious abnormalities. Compared with control group, the levels of miR-182, Th17% and IL-17 in non-CI group and CI group were significantly higher, and the Treg% was significantly lower. The levels of parameters mentioned above were further increased in CI group than those in non-CI group [miR-182 (2-Delta DeltaCt): 2.35+/-0.79 vs. 1.75+/-0.56, Th17%: (5.16+/-1.89)% vs. (3.93+/-1.92)%, IL-17 (ng/L): 37.45+/-6.20 vs. 26.65+/-5.13, all P < 0.05]. Pearson correlation analysis showed that miR-182 was positively correlated with Th17% and IL-17 (r1 = 0.761, r2 = 0.842, both P < 0.01). ROC curves showed that when the cut-off value of miR-182 was 2.88, the diagnosis sensitivity of preeclampsia CI was 84.6%, the specificity was 82.4%, and area under the ROC curve (AUC) was 0.816 [95% confidence interval (95%CI) = 0.641-0.992]; when cut-off value of IL-17 was 34.44 ng/L, diagnosis of preeclampsia CI the sensitivity was 71.5%, the specificity was 85.3%, and AUC was 0.773 (95%CI = 0.602-0.945); when miR-182 was combined with IL 17, the diagnosis sensitivity was 92.3%, specificity was 83.6%, and AUC was 0.896 (95%CI = 0.759-1.032). CONCLUSIONS: To some extent the expression of miR-182 and IL-17 in peripheral blood can predict the occurrence of CI in early stage. When the two are used together, the predictive value is better. PMID- 28625243 TI - [Experimental study on effect of airway pressure on cardiopulmonary resuscitation]. AB - OBJECTIVE: To observe the effect of different airway pressure on ventilation, organ perfusion and return of spontaneous circulation (ROSC) of cardiac arrest (CA) pigs during cardiopulmonary resuscitation (CPR), and to explore the possible beneficial mechanism of positive airway pressure during CPR. METHODS: Twenty healthy landrace pigs of clean grade were divided into low airway pressure group (LP group, n = 10) and high airway pressure group (HP group, n = 10) with random number table. The model of ventricular fibrillation (VF) was reproduced by electrical stimulation, and mechanical chest compressions and mechanical ventilation (volume-controlled mode, tidal volume 7 mL/kg, frequency 10 times/min) were performed after 8 minutes of untreated VF. Positive end expiratory pressure (PEEP) in LP group and HP group was set to 0 cmH2O and 6 cmH2O (1 cmH2O = 0.098 kPa) respectively. Up to three times of 100 J biphasic defibrillation was delivered after 10 minutes of CPR. The ROSC of animals were observed, and the respiratory parameters, arterial and venous blood gas and hemodynamic parameters were recorded at baseline, 5 minutes and 10 minutes of CPR. RESULTS: The number of animals with ROSC in the HP group was significantly more than that in the LP group (8 vs. 3, P < 0.05). Intrathoracic pressure during chest compression relaxation was negative in the HP group, and its absolute value was significantly lower than that in LP group at the same time [intrathoracic negative pressure peak (cmH2O): -4.7+/-2.2 vs. -10.8+/-3.5 at 5 minutes, -3.9+/ 2.8 vs. -6.5+/-3.4 at 10 minutes], however, there was significantly difference only at 5 minutes of CPR (P < 0.01). Intrathoracic pressure variation during CPR period in the HP group were significantly higher than those in the LP group (cmH2O: 22.5+/-7.9 vs. 14.2+/-4.4 at 5 minutes, 23.1+/-6.4 vs. 12.9+/-5.1 at 10 minutes, both P < 0.01). Compared to the LP group, arterial partial pressure of oxygen [PaO2 (mmHg, 1 mmHg = 0.133 kPa): 81.5+/-10.7 vs. 68.0+/-12.1], venous oxygen saturation (SvO2: 0.493+/-0.109 vs. 0.394+/-0.061) at 5 minutes of CPR, and PaO2 (mmHg: 77.5+/-13.4 vs. 63.3+/-10.5), arterial pH (7.28+/-0.09 vs 7.23+/ 0.11), SvO2 (0.458+/-0.096 vs. 0.352+/-0.078), aortic blood pressure [AoP (mmHg): 39.7+/-9.5 vs. 34.0+/-6.9], coronary perfusion pressure [CPP (mmHg): 25.2+/-9.6 vs. 19.0+/-7.6], and carotid artery flow (mL/min: 44+/-16 vs. 37+/-14) at 10 minutes of CPR in the HP group were significantly higher (all P < 0.05). Arterial partial pressure of carbon dioxide (PaCO2) in the HP group was significantly lower than that in the LP group at 10 minutes of CPR (mmHg: 60.1+/-9.7 vs. 67.8+/ 8.6, P < 0.05). CONCLUSIONS: Compared to low airway pressure, a certain degree of positive airway pressure can still maintain the negative intrathoracic pressure during relaxation of chest compressions of CPR, while increase the degree of intrathoracic pressure variation. Positive airway pressure can improve oxygenation and hemodynamics during CPR, and is helpful to ROSC. PMID- 28625244 TI - [Establishment of porcine model of prolonged cardiac arrest and cardiopulmonary resuscitation electrically induced by ventricular fibrillation]. AB - OBJECTIVE: To investigate the optimal injury time point of cardiac arrest (CA) induced electrically, and establish a reproducible prolonged CA and cardiopulmonary resuscitation (CPR) model in pigs. METHODS: Forty healthy domestic male pigs were randomly divided into four groups, which were ventricular fibrillation (VF) 8, 10, 11, and 12 minutes groups, each group for 10 animals. In these groups, VF was induced by alternating current delivered to right ventricular endocardium and untreated for 8, 10, 11, and 12 minutes, respectively, followed by 6 minutes of CPR procedure. The resuscitation and survival outcomes were recorded. Hemodynamic parameters and arterial blood gases of animals after successful resuscitation were measured and recorded for 6 hours. Those successful resuscitation animals were regularly evaluated for the neurological deficit score (NDS) and survival outcomes every 24 hours till 96 hours after resuscitation. RESULTS: The shortest duration of CPR (minute: 6.9+/ 1.3) and the highest successful ratio of the first defibrillation (7/10) were observed in group VF 8 minutes, and the ratio of successful resuscitation was 100%. The best coronary perfusion pressure (CPP) during the CPR, less neurological impairment, longer survival time, more stable hemodynamics, and shorter time for arterial pH and lactate level restoring to the original state after CPR were also observed in group VF 8 minutes, and no severe damage was found in those animals. The longest duration of CPR (minute: 10.3+/-2.9) and the lowest successful ratio of the first defibrillation (1/10) were observed in group VF 12 minutes, and only 4 animals achieved restoration of spontaneous circulation (ROSC), and no animal survived to CPR 96 hours. The worst CPP during CPR and the highest NDS after resuscitation were also found in VF 12 minutes animals compared to those animals in the other groups. The injuries caused by ischemia and hypoxia in groups VF 10 minutes and VF 11 minutes were in between those of the groups VF 8 minutes and VF 12 minutes, and the duration of CPR were (7.0+/-2.1) minutes and (8.2+/-2.6) minutes. There were 9 and 7 animals achieved ROSC in groups VF 10 minutes and VF 11 minutes correspondingly, and 6 and 4 animals survived to 96 hours respectively. Obviously unstable hemodynamics was observed during the period of CPR 2 hours in the two groups. At CPR 1 hour, the heart rates (HR, beats/min) in groups VF 10 minutes and VF 11 minutes increased to 172 (155, 201) and 168 (136, 196) respectively, and the mean arterial pressures (MAP, mmHg, 1 mmHg = 0.133 kPa) declined to 97 (92, 100) and 81 (77, 100), the cardiac output (CO, L/min) decreased to 5.0 (4.0, 5.8), 3.7 (3.0, 5.4) correspondingly. Distinct injuries were found in the two groups [CPR 24-96 hours NDS in groups VF 10 minutes and VF 11 minutes: 180 (110, 255)-20 (0, 400) and 275 (223, 350)-240 (110, 400)], and the arterial pH of the two group decreased to 7.26+/-0.09 and 7.23+/-0.09 respectively, and the level of lactate (mmol/L) increased to 9.17+/ 1.48 and 12.80+/-2.71 correspondingly at CPR 0.5 hour. Significantly lower pH was observed in group VF 11 minutes compared to group VF 8 minutes at CPR 0.5 hour (7.23+/-0.09 vs. 7.33+/-0.04, P < 0.05). The highest level of lactate (mmol/L) was also found at the same time point in group VF 11 minutes, which recovered to normal slowly, and was still significantly higher than groups VF 8, 10, 12 minutes (7.58+/-3.99 vs. 2.55+/-1.53, 2.13+/-2.00, 3.40+/-2.30, all P < 0.05) at CPR 4 hours. CONCLUSIONS: The longer duration of CA was, the more severe damage would be, the longer CPR time would be required, and the harder of the animals to achieve ROSC. In this prolonged CA and CPR porcine model, 10-11 minutes for untreated VF, was an optimal time point with appropriate successful rate of resuscitation, survival outcomes, and post-resuscitation injuries. Therefore, we recommended 10-11 minutes might be the rational length of no-flow time in this model. PMID- 28625245 TI - [Effects of different sedation regimens on sedation and inflammatory response in critically ill children with multiple trauma]. AB - OBJECTIVE: To compare the sedation and anti-inflammatory effects of dexmedetomidine and midazolam on critical ill children with multiple trauma. METHODS: A prospective randomized controlled trial was conducted. Sixty-five critical ill children with multiple trauma admitted to pediatric intensive care unit (PICU) of Anhui Province Children's Hospital from January 2014 to September 2016 were enrolled, who were randomly divided into dexmedetomidine group (33 cases) and midazolam group (32 cases). Children of both groups received sufentanil for analgesia. Children in dexmedetomidine group firstly received 1.0 MUg/kg intravenous bolus of dexmedetomidine for 10 minutes, then continuous infusion of 0.2-0.7 MUg*kg-1*h-1, while in midazolam group children received 1-5 MUg*kg-1*min-1 of midazolam in continuous infusion. The goal of sedation was to maintain a Richmond agitation-sedation scale (RASS) score of -1 to 0. The level of serum interleukin (IL-6, IL-8, IL-10, IL-1beta), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) were detected by enzyme linked immunosorbent assay (ELISA) at 24, 48, 72 hours after treatment, and the duration of mechanical ventilation, ratio of continuous renal replacement therapy (CRRT), length of stay in the PICU, ratio of sepsis and multiple organ failure (MOF) and mortality were also recorded. RESULTS: Compared with midazolam, dexmedetomidine decreased the level of pro-inflammatory cytokines and increased the level of anti inflammatory cytokines. At 24 hours after treatment, the levels of serum IL 1beta, TNF-alpha significantly decreased and IL-10 significantly increased [IL 1beta (ng/L): 6.48+/-2.89 vs. 8.07+/-3.14, TNF-alpha (MUg/L): 11.25+/-5.21 vs. 15.44+/-5.97, IL-10 (ng/L): 12.10+/-5.35 vs. 9.58+/-4.71, all P < 0.05]. At 48 hours after treatment, the levels of serum IL-6, IL-8, IL-1beta, TNF-alpha and CRP significantly decreased and IL-10 significantly increased [IL-6 (ng/L): 209.67+/-80.49 vs. 336.31+/-123.94, IL-8 (ng/L): 229.09+/-80.81 vs. 298.28+/ 90.25, IL-1beta (ng/L): 7.31+/-3.02 vs. 8.74+/-3.17, TNF-alpha (MUg/L): 12.52+/ 4.79 vs. 16.58+/-5.98, CRP (g/L): 47.82+/-24.92 vs. 72.35+/-31.71, IL-10 (ng/L): 12.90+/-5.42 vs. 10.01+/-4.79, all P < 0.05]. At 72 hours after treatment, the levels of serum IL-8 and CRP significantly decreased [IL-8 (ng/L): 234.64+/-96.24 vs. 290.28+/-103.97, CRP (g/L): 53.24+/-29.12 vs. 86.58+/-38.30, both P < 0.05]. Compared with midazolam, dexmedetomidine could significantly reduce the duration of mechanical ventilation (days: 4.7+/-1.3 vs. 6.6+/-2.1), length of PICU stay (days: 9.5+/-2.7 vs. 12.3+/-3.9, both P < 0.05), and the ratio of sepsis (33.3% vs. 53.1%, P < 0.05). But there were no significant differences in ratio of CRRT (18.2% vs. 18.8%), MOF (9.1% vs. 18.8%) and mortality (6.1% vs. 12.5%) between two groups (all P > 0.05). CONCLUSIONS: Compared with midazolam, dexmedetomidine had better efficacy in the treatment of severe multiple trauma in children and reduce the level of inflammation. PMID- 28625246 TI - [Effects of high flow hemodialysis on the biomarker of myocardium injury and the cardiac function related records in uremia patients]. AB - OBJECTIVE: To investigate the effects of high flow hemodialysis (HFHD) on cardiac function in uremia patients. METHODS: A prospective randomized controlled study was conducted. Sixty patients who were diagnosed with uremia, taken maintenance hemodialysis (MHD) and 30 healthy controls admitted to the Second People's Hospital of Guiyang from December 2014 to June 2015 were enrolled. They were randomly divided into two groups: HFHD group (HFHD three times a week) and the routine hemodialysis group (HD group, HD three times a week), with 30 in each group. Patients in each group were received hemoperfusion and hemofiltration once a month. Before the treatment and 6 months after the treatment, venous blood from all the patients were collected for testing the brain natriuretic peptide (BNP), cardiac troponin T (cTnT) and the ultrasound cardiograph were done at the same period by a special person, the left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), the left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular posterior wall thickness (LVPWT), interventricular septum thickness (IVST), early and late diastolic blood flow to the largest ratio (E/A), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) were recorded. RESULTS: Compared with the health control group, BNP, cTnT, LVEDD, LVESD, LVESV, LVPWT, IVST were significantly increased, LVEDV were significantly lowered before treatment in the HD group and HFHD group. But no significant differences in the above indexes and E/A, LVEF, LVMI between two groups were found. Compared with the data before treatment, the BNP, LVPWT were significantly lowered after treatment in HD group [BNP (ng/L): 641.50+/-60.09 vs. 2676.20+/ 454.30, LVPWT (mm): 10.57+/-1.16 vs. 12.57+/-1.41, both P < 0.05]. The BNP, LVPWT were significantly lowered in HFHD group as compared with HD group [BNP (ng/L): 253.10+/-48.77 vs. 641.50+/-60.09, LVPWT (mm): 9.29+/-1.08 vs. 10.57+/-1.16, both P < 0.05]; in addition, the cTnT, IVST, LVMI were significantly lowered after the treatment in HFHD group compared with those before treatment [cTnT (MUg/L): 0.014+/-0.005 vs. 0.028+/-0.011, IVST (mm): 7.81+/-1.69 vs. 11.04+/-2.23, LVMI (g/m2): 149.10+/-15.77 vs. 158.70+/-17.25, all P < 0.05], and the LVEF were significantly increased in HFHD group as compared with those before treatment (0.574+/-0.068 vs. 0.528+/-0.082, P < 0.05). CONCLUSIONS: HFHD has obvious advantages than the routine HD in improving cardiac function of uremia patients. PMID- 28625247 TI - [A design and study of a novel electronic device for cuff-pressure monitoring]. AB - OBJECTIVE: To design a novel electronic device for measuring the pressure in the cuff of the artificial airway; and to study the advantage of this device on continuous and intermittent cuff pressure monitoring. METHODS: (1) a portable electronic device for cuff pressure measurement was invented, which could turn pressure signal into electrical signal through a pressure transducer. Meantime, it was possible to avoid pressure leak from the joint and the inside of the apparatus by modified Luer taper and sophisticated design. If the cuff pressure was out of the normal range, the apparatus could release a sound and light alarm. (2) Six traditional mechanical manometers were used to determine the cuff pressure in 6 tracheal tubes. The cuff pressure was maintain at 30 cmH2O (1 cmH2O = 0.098 kPa) by the manometer first, and repeated every 30 seconds for 4 times. (3) Study of continuous cuff pressure monitoring: We used a random number generator to randomize 6 tracheal tubes, 6 mechanical manometers and 6 our products by number 1-6, which has the same number of a group. Every group was further randomized into two balanced groups, one group used the mechanical manometer first, and the other used our product first. The baseline pressure was 30 cmH2O, measurement was performed every 4 hours for 6 times. RESULTS: When traditional mechanical manometer was used for cuff pressure monitoring, cuff pressure was decreased by an average of 2.9 cmH2O for each measurement (F = 728.2, P = 0.000). In study of continually monitoring, at each monitoring point, the pressure measured by electronic manometer was higher than the mechanical manometer. All the pressures measured by mechanical manometer were dropped below 20 cmH2O at 8th hour, and there was no pressure decrease below 20 cmH2O measured by electronic manometer in 24 hours by contrast. In study of intermittent monitoring, the same result was found. The pressure was dropped significantly with time when measured by mechanical manometer (F = 61.795, P = 0.000), the drops below 20 cmH2O began at 8th hour; but when measured by electronic manometer, all the value stayed unchanged around the baseline in 24 hours (F = 0.511, P = 0.796). CONCLUSIONS: Compared with traditional mechanical manometer, cuff pressures monitored by our novel electronic manometer were steadier in both continuous and intermittent monitoring. The device is compact and convenient, and can provide a good solution for continuously monitor of the tracheal cuff pressure. PMID- 28625248 TI - [Core knowledge and skill-based approach to subspecialty construction in critical/intensive care medicine with distinct Chinese peculiarity]. AB - OBJECTIVE: With the rapid development of critical care medicine (CCM) in China, there are increases in the number of intensive care units (ICUs), the scale of one center ICU and the team. Subspecialty construction of CCM is of great concerns for personnel training as well as discipline development, and is currently one of the urgent problems that need to be resolved. Experience of CCM subspecialty construction from Europe and the United States is lacking and it is necessary to propose some opinions on innovation to construct CCM subspecialties with Chinese characteristics. We believe that CCM sub-specialties construction should be based on the core knowledge (pathophysiology) and skill (organ monitoring and support). The following 7 sub-specialties can be set up: (1) acute lung injury and mechanical ventilation; (2) shock, hemodynamic monitoring and treatment; (3) acute kidney injury and blood purification; (4) sepsis and anti infective therapy; (5) stress, sedation and analgesia; (6) nutrition and metabolic support; (7) coagulation, immune and inflammation. The core knowledge and skills of critical care medicine will constantly be updated and enriched. Therefore, sub-specialty settings should be constantly updated as well. PMID- 28625249 TI - [Multicenter investigation on cognition about preoperative nursing of emergency PCI]. AB - OBJECTIVE: To know the mastery degree of percutaneous coronary intervention (PCI) preoperative nursing knowledge in nurses who are working in emergency department and cardiac ward. METHODS: 158 cases of nurses who came from three different class III grade hospitals with qualification for emergency PCI surgery of the Guizhou province were surveyed with self-made questionnaire. The survey was conducted in nurses who were working in different departments, and the educational background, age, title, category, the cognitive situation of the PCI preoperative nursing knowledge and necessity of preoperative preparations were investigated in nurses. RESULTS: The whole pass rate was 48.10%; high qualification, high education, higher title of nurses for the nursing knowledge of the emergency PCI were better; the emergency PCI preoperative preparations for the necessity of cognitive about nurses were on the low side. CONCLUSIONS: The cognition of the nursing knowledge and the necessity of emergency PCI in preoperative preparations as whole are on the low level, so specialized training should be strengthened to enhance the ability of specialized nursing. PMID- 28625250 TI - [Fulminant Clostridium difficile colitis: new challenges in critical care medicine]. AB - OBJECTIVE: Fulminant Clostridium difficile colitis (FCDC) means severe Clostridium difficile colitis (CDC), which often manifested with severe diarrhea, fever, abdominal distention, electrolyte disorder, hypoalbuminemia, and it can lead to pseudo membrane colonitis, toxic megacolon, bowel perforation, septic shock, and multiple organ dysfunction. Now Clostridium difficile (CD) becomes one of the most important medical institutions related infectious pathogens. In particular, the recently discovered mutant CD strain NAP1/BI/ribotype 027 has high pathogenicity in the global epidemic and its outbreak. The morbidity and mortality of FCDC has a significant upward trend in the global in recent years. All broad spectrum antimicrobials usage is considered to be the primary risk factor for the onset of FCDC. Therefore, FCDC has become a new challenge for clinical work. The epidemiology, related risk factors, pathogenesis, diagnosis, severity classification, recent progress in clinical treatment of FCDC were reviewed in order to provide help for clinical treatment of FCDC and related research. PMID- 28625251 TI - [A novel protein peptide associated with ischemic heart disease: dermcidin]. AB - OBJECTIVE: Dermcidin (DCD) was found in isolated human skin sweat glands with antimicrobial effect, and was defined as a kind of new small molecule antimicrobial peptide. It was a part of human sweat glands in the skin as the immune system's innate defense. With the studies of DCD, its extensive biological functions are gradually discovered. Since 2010, a number of studies have shown that DCD may be a new risk factor for atherosclerosis. And the role of DCD in ischemic heart disease has drawn increasing attention in particular its relationship with insulin secretion and glycemic control, nitric oxide (NO) synthesis and hypertension, platelet aggregation and acute myocardial infarction (AMI). In those experiments, it was also confirmed that aspirin had antagonistic and reverse effects on various biological functions of DCD. Further research on the role of DCD in cardiovascular and cerebrovascular diseases may lead to the prevention, early warning, prognosis evaluation and treatment breakthrough of cardiovascular and cerebrovascular events. PMID- 28625253 TI - [What does Sepsis-3 mean beyond definition?] PMID- 28625252 TI - [Cerebral injury induced by heat stroke and the therapeutic effect of hyperbaric oxygen therapy]. AB - OBJECTIVE: With the global warming, the incidence of heat stroke was significantly higher than before. Severe heat stroke has a high mortality, high morbidity and consolidated central nervous system injury characteristics. The main features of severe heat stroke cerebral injury include cognitive impairment, delirium, convulsions and coma. Its mechanism is related with heat shock induced cerebral tissue ischemia and hypoxia, vascular dysfunction, secondary cascade inflammation and so on. Currently, the main treatment of heat stroke cerebral injury is the hypothermia therapy, dehydration for the reduction of intracranial pressure, naloxone and other cerebral protection and nutrition treatments. Hyperbaric oxygen therapy (HBOT) is effective in treating brain injury. HBOT can alleviate tissue ischemia and hypoxia, improve circulation, reduce cerebral edema, and anti-inflammatory, anti-oxidative damage, anti-apoptosis and other molecular biological effects. HBOT also play a wake up-promoting effect of nerve repair in the cerebral injury. The treatment of cerebral injury has been the difficulty and weakness of heat stroke research. Therefore, this article reviewed the epidemiology, pathogenesis, the therapeutic effect and mechanism of hyperbaric oxygen on cerebral injury in severe heat stroke to clarify the advantages of HBOT and to provide experimental basis for further research. PMID- 28625254 TI - [A multicenter confirmatory study about precision and practicability of Sepsis 3]. AB - OBJECTIVE: To clinically validate the precision of diagnostic Sepsis-3 criteria, and to guide and generalize its clinical application. METHODS: A multicenter retrospective observational study was conducted. The patients admitted to intensive care unit (ICU) of 6 tertiary hospitals in Zhejiang Province from January to June 2015 were enrolled, and the patients satisfying the diagnostic criteria of Sepsis-2 and Sepsis-3 were screened. Population characteristics between the patients satisfying two editions were compared, and the diagnosis accuracy rate in different degree hospitals were investigated. According to the doctor's diagnosis, the patients who met the criteria of Sepsis-2 were divided into diagnosis group and non-diagnosis group, and the factors influencing the diagnosis of sepsis were analyzed by logistic regression. The patients meeting Sepsis-2 but no meeting Sepsis-3 were served as exclusion group, and those meeting Sepsis-2 and Sepsis-3 were served as enroll group, and the characteristics of patients between the two groups were compared. Receiver operating characteristic (ROC) curve was plotted to evaluate the predictive value of systemic inflammatory response syndrome (SIRS) score, sepsis-related quick sequential organ failure assessment (qSOFA) and sequential organ failure assessment (SOFA) on death, and whether the consistency of qSOFA and SOFA would affect the sensitivity of definition. The patients meeting Sepsis-2 were divided into non-survived group and survived group, and the factors associated with death were analyzed by logistic regression. RESULTS: Finally, 1 423 patients were enrolled, 3 patients with age < 18 years and 19 patients with missing data were excluded. There were 363 patients and 329 patients met Sepsis-2 and Sepsis-3, respectively. No significant differences were found in population characteristics between the groups of Sepsis-2 and Sepsis-3 (all P > 0.05) except for acute physiology and chronic health evaluation II (APACHE II) score [19.10 (8.00) vs. 20.28 (8.00), P < 0.05]. It was shown on the clinical data analysis of the hospitals that the patients meeting Sepsis-2 and Sepsis-3 in hospital 3 had the highest 28-day mortality (60.4% and 60.0%) with the lowest rate of diagnosis (0). While in the hospital 1, the patients had the lowest 28-day mortality (22.9% and 27.2%), and the rate of diagnosis was 19.5%. Interestingly, the patients in hospital 4 had the highest diagnosis rate of sepsis (44.8%), but 28-day mortality was both 58.6%. It was shown by logistic regression analysis that the patients with old age [odds ratio (OR) = 0.970, P = 0.021], high blood lactate (OR = 0.443, P = 0.004), high blood pressure (OR = 0.957, P = 0.009) and low oxygenation index (OR = 1.004, P = 0.024) were easy to neglect diagnosis. Compared with Sepsis-3 exclude group, the patients in Sepsis-3 enroll group were older [years: 68.52 (26.00) vs. 53.75 (18.00), P < 0.01] with higher APACHEII score [20.38 (8.00) vs. 7.72 (6.00), P < 0.01], higher blood lactate [mmol/L: 3.45 (3.00) vs. 1.95 (1.20), P > 0.05], longer length of ICU stay [days: 22.42 (22.00) vs. 15.13 (16.00), P < 0.01], and higher 28-day mortality [45.29% (149/329) vs. 14.71% (5/34), P < 0.01], indicating that the diagnostic efficiency of Sepsis-2 was low, the diagnostic specificity of Sepsis-3 was high, and the prognosis of Sepsis-3 patients was worse. It was shown by ROC curve analysis that the prognostic value of SIRS, qSOFA and SOFA to mortality was gradually increased [area under ROC curve (AUC) was 0.567, 0.597, 0.683, respectively], but the prognostic value were all low. Comparing patients meeting qSOFA and (or) SOFA in Sepsis-2, significant differences were found in APACHE II score [17.55 (7.00) vs. 23.24 (8.00)] and 28-day mortality [38.75% (31/80) vs. 58.59% (75/128), both P < 0.01]. The patients who just met the qSOFA or SOFA, their 28-day mortality was up to 38.75%, suggesting that qSOFA should not be ignored. Compared with survived group, the patients in survived group were older with higher APACHE II score and shorter length of ICU stay (all P < 0.05). It was shown by logistic regression analysis that APACHE II score (OR = 1.199, P = 0.000) and length of ICU stay (OR = 0.949, P = 0.000) were related with death. CONCLUSIONS: Patients satisfied Sepsis-3 were easier to develop more organ failure, Sepsis-3 and higher death prediction than Sepsis-2 and higher diagnosis specificity, but data shows that there is extra room for improvement. PMID- 28625255 TI - [Effect of vitamin D3 on the severity and prognosis of patients with sepsis: a prospective randomized double-blind placebo study]. AB - OBJECTIVE: To observe the relationship between vitamin D3 and the severity as well as prognosis in patients with sepsis, and to explore whether exogenous vitamin D3 can improve the prognosis in patients with sepsis. METHODS: A prospective randomized double-blind placebo study was conducted. Fifty-seven patients with sepsis admitted to intensive care unit (ICU) of Shengjing Hospital Affiliated to China Medical University from March to November in 2015 were enrolled. Twenty patients with systemic inflammatory response syndrome (SIRS) and 20 healthy volunteers with normal physical examination as control were enrolled during the same time. Patients with sepsis were divided into general sepsis group and severe sepsis group (including septic shock) according to the criteria for the diagnosis of severe sepsis and septic shock in 2012. According to the diagnostic criteria established by the American Endocrine Society, and on the basis of 25-hydroxy vitamin D3 [25(OH)D3], the sepsis patients with deficiency [25(OH)D3 20-30 MUg/L] or insufficiency [25(OH)D3 < 20 MUg/L] of vitamin D were divided into D3 treatment group (supplemented 300 kU vitamin D3) and placebo group (injected 1 mL physiological saline). 28th day was set as the end point, and the patients with sepsis were divided into survival group and death group. The levels of serum 25(OH)D3 in each group were measured by electrochemical luminescence method, and the difference in 25(OH)D3 levels among patients with different severity, gender, and age were recorded. Procalcitonin (PCT), C reactive protein (CRP), blood routine, liver and kidney function, electrolytes and arterial blood gas analysis, acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure score (SOFA), duration of mechanical ventilation, and length of ICU stay of patients with sepsis were observed. Multivariate Cox proportional hazard regression analysis was used to analyze the risk factors of prognosis in patients with sepsis. RESULTS: (1) In 57 patients with sepsis, there were 15 patients in general sepsis group, and 42 in severe sepsis group; 29 in D3 treatment group, and 28 in the placebo group; 8 patients died within 28 days with mortality rate of 14.04%. (2) The levels of serum 25(OH)D3 in sepsis group and SIRS group were significantly lower than those in healthy control group [MUg/L: 3.92 (< 3.00, 11.22), 6.99 (3.51, 9.77) vs. 17.25 (13.48, 22.50), both P < 0.01], but there was no significant difference in the serum 25(OH)D3 level between sepsis group and SIRS group as well as patients with different degrees of sepsis. The serum 25(OH)D3 level in female patients with sepsis (n = 24) was significantly lower than that in male (n = 33), and the difference was statistically significant [MUg/L: <3.00 (<3.00, 3.87) vs. 11.96 (5.14, 17.29), Z = -4.020, P = 0.000]. There was no significant difference in serum 25(OH)D3 level between the young (age <60 years old, n = 30) and the old (age >= 60 years old, n = 27) patients with sepsis [MUg/L: 4.54 (<3.00, 9.88) vs. 3.00 (<3.00, 15.08), Z = -0.601, P = 0.548]. (3) In patients with sepsis, there was no significant difference in the duration of mechanical ventilation [hours: 41.00 (7.50, 82.50) vs. 67.00 (4.75, 127.75)], length of ICU stay (days: 5.48+/ 4.08 vs. 6.68+/-4.87) and 28-day mortality (10.34% vs. 17.86%) between D3 treatment group and placebo group (all P > 0.05). It was shown by Kaplan-Meier survival curve analysis that there was no significance in 28-day accumulated survived rate between the two groups [log-rank test: chi 2 = 0.222, P = 0.638]. It was shown by multivariate Cox regression analysis that APACHE II score [relative risk (RR) = 8.487, 95% confidence interval (95%CI) = 1.506-47.835, P = 0.015] and 25(OH)D3 < 20 MUg/L (RR = 0.088, 95%CI = 0.013-0.592, P = 0.012) were the risk factors of prognosis in patients with sepsis. CONCLUSIONS: The serum 25(OH)D3 level in ICU patients with sepsis was lower than that in healthy people, but there was no significant difference between patients with sepsis and SIRS. The serum 25(OH)D3 level in sepsis patients was related with gender, and the level of the female was lower than that of the male, but was not related with age. Exogenous vitamin D3 supplementation cannot improve the prognosis of ICU patients with sepsis. APACHE II score and 25(OH)D3 < 20 MUg/L were risk factors for the prognosis in ICU patients with sepsis. PMID- 28625256 TI - [Comparison of effect of norepinephrine and terlipressin on patients with ARDS combined with septic shock: a prospective single-blind randomized controlled trial]. AB - OBJECTIVE: To approach the effect of different vasopressor on hemodynamics, volume responsiveness, fluid volume balance, renal function and prognosis in patients with acute respiratory distress syndrome (ARDS) complicated with septic shock. METHODS: A prospective single-blind randomized controlled trial was conducted. ARDS patients with septic shock admitted to the Department of Critical Care Medicine of Jiangxi Provincial People's Hospital from January 1st, 2015 to May 1st, 2016 were enrolled. The patients satisfied ARDS Berlin diagnostic criteria, over 15 years old, needing vasopressor after fluid resuscitation were enrolled. The patients were divided into norepinephrine group (NE group) and terlipressin group (TP group) by randomise number table derived by computer. Patients in TP group were given terlipressin (0.01-0.04 U/min) with an intravenous pump, while those of NE group were given norepinephrine (> 1 MUg/min) with an intravenous pump, and the target mean arterial pressure (MAP) was maintained at 65-75 mmHg (1 mmHg = 0.133 kPa). Hemodynamics and extravascular lung water index (EVLWI) were monitored by pulse indicator continuous cardiac output (PiCCO). The volume responsiveness of patient was evaluated by passive leg raising (PLR) test, and cardiac index (CI) change (DeltaCI >= 10%) served as positive volume responsiveness. The differences in hemodynamics, EVLWI, oxygenation index (OI), lactate clearance rate (LCR), rate of positive volume responsiveness, urinary output, fluid volume balance, renal function, and prognostic indicators were compared between the two groups. RESULTS: Fifty-seven patients with ARDS complicated with septic shock were enrolled, with 26 patients in NE group, and 31 patients in TP group, the baseline data in both groups was balanced with comparability. Compare with NE group, 48-hour and 72-hour heart rate (HR) in TP group was significantly slowed (bpm: 82.1+/-6.8 vs. 87.6+/-7.4, 81.3+/-6.1 vs. 85.6+/-8.3, both P < 0.05), 72-hour central venous pressure (CVP) was significantly decreased (mmHg: 9.4+/-2.6 vs. 10.9+/-3.0, P < 0.05), but no significant difference was found in HR, MAP, CVP, CI, EVLWI, OI and LCR at other time points between the two groups. 48-hour and 72-hour positive volume responsiveness rate in TP group were significantly increased as compared with those of NE group (74.2% vs. 46.2%, 64.5% vs. 38.5%, both P < 0.05), urinary output on the 2nd day (mL/24 h: 2 342.8+/-704.1 vs. 1 944.6+/-684.3) and fluid volume balance (mL: -319.7+/-54.8 vs. -169.6+/-27.2) were significantly decreased (both P < 0.05). There was no significant difference in positive volume responsiveness rate, urine output, fluid volume balance, and the level of serum creatinine at other time points between the two groups. There was no statistically significant difference in the following features between TP group and NE group: duration of mechanical ventilation (days: 8.41+/-2.97 vs. 9.67+/ 3.56), length of intensive care unit (ICU) stay (days: 12.84+/-4.47 vs. 14.77+/ 5.01), total length of hospital stay (days: 19.34+/-7.37 vs. 21.07+/-8.41), and 28-day mortality (29.0% vs. 30.8%, all P > 0.05). CONCLUSIONS: Compared with norepinephrine, terlipressin for ARDS patients with septic shock is more conducive to restrict fluid load, improve the renal perfusion and increase urine output. However, in both groups there was no significant difference in the efficiency of stabilizing hemodynamics, shortening the duration of mechanical ventilation, reducing ICU or hospital days and decreasing 28-day mortality. PMID- 28625257 TI - [Albumin corrected anion gap is an independent risk factor for long-term mortality of patients with sepsis]. AB - OBJECTIVE: To explore whether albumin corrected anion gap (ACAG) is associated with long-term mortality of sepsis patients. METHODS: Adult patients with a diagnosis of sepsis within the first 24 hours (from December 2013 to December 2014) admitted to the intensive care unit (ICU) were included via the Sepsis database of West China Hospital Sichuan University. To record their long-term survival, patients were followed up by telephone interview one year after enrollment. ACAG was calculated according to the anion gap (AG) level within the first 24 hours admitted to ICU, and patients were divided into normal ACAG group (ACAG 12-20 mmol/L) and high ACAG group (ACAG > 20 mmol/L), and clinical characteristics and 1-year mortality were compared between groups. Patients were also divided into survivors and non-survivors according to the 1-year survival outcome, and multivariate logistic regression analysis was conducted to find independent risk factors for long-term mortality of sepsis patients. RESULTS: A total of 296 sepsis patients were enrolled in the study, with 191 (64.5%) in the high ACAG group and 105 (35.5%) in the normal ACAG group. There were no significant differences in age, gender, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), Charlson cormobidity index (CCI) and other background variables between groups. Compared with the normal ACAG group, patients who suffered from multiple organ dysfunction syndrome (MODS) in the high ACAG group were more prone to develop renal and gastrointestinal injury (43.5% vs. 25.7%, 52.9% vs. 33.3%, respectively), had significantly higher serum creatinine [SCr (MUmol/L): 89.0 (61.0, 148.0) vs. 67.1 (48.0, 86.0)], greater need for continuous renal replacement therapy (CRRT, 16.8% vs. 6.7%), and significantly shorter length of ICU stay and hospital stay [days: 11 (5, 22) vs. 16 (18, 31), 21 (14, 39) vs. 28 (20, 47)], with statistically significant differences (all P < 0.05). It was shown by Kaplan-Meier survival analysis that 1-year cumulative survival for the high ACAG group was significantly lower than that of the normal ACAG group (55.0% vs. 67.7%, P = 0.046). It was shown by multivariate logistic regression that ACAG [odds ratio (OR) = 1.201, 95% confidence interval (95%CI) = 1.115-1.293, P = 0.000], APACHE II (OR = 1.053, 95%CI = 1.011-1.098, P = 0.014), the incidence of septic shock (OR = 2.203, 95%CI = 1.245-3.898, P = 0.007), fungus infection (OR = 3.107, 95%CI = 1.702-5.674, P = 0.000), acute renal failure (OR = 2.729, 95%CI = 1.134-6.567, P = 0.025) and complicated with malignancy (OR = 2.929, 95%CI = 1.395-6.148, P = 0.005) were independent risk factors contributing to increased 1-year mortality among sepsis patients. CONCLUSIONS: ACAG was an independent risk factor for 1 year mortality of sepsis patients. PMID- 28625258 TI - [Plasma level of neutrophil extracellular traps in septic patients and its clinical significance: a prospective observational study]. AB - OBJECTIVE: To investigate the changes of neutrophil extracellular traps (NETs) level in plasma of sepsis patients and judge its clinical value for early diagnosing of sepsis. METHODS: A prospective observational study was conducted. The patients after surgery aged > 18 years and expected to stay in the ICU > 24 hours admitted to intensive care unit (ICU) of the First Affiliated Hospital of China Medical University from November 2014 to February 2015 were enrolled. According to the criteria of sepsis diagnosis in 1991, patients were divided into non-sepsis group and sepsis group. The healthy people who taken a physical examination were enrolled in the healthy control group. 3 mL peripheral venous blood was collected at 1 hour after admission to ICU. A fasting blood was collected in the healthy control group in the morning. The plasma free DNA (cf DNA/NETs) was determined by using the fluorescence microplate reader, white blood cell (WBC), neutrophil ratio (NEU), procalcitonin (PCT), C-reactive protein (CRP) in peripheral blood of the patients were detected, and acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) scores were calculated. The correlation between plasma NETs and the risk factors in sepsis patients was analyzed by Spearman correlation analysis. The value of cf-DNA/NETs and WBC level in the diagnosis of sepsis was analyzed by using the receiver operating characteristic curve (ROC). RESULTS: Twenty-three sepsis patients, 20 non-sepsis patients, and 22 healthy persons were enrolled. There were no differences in baseline variables including gender and age among three groups, which indicated baseline data equalization. The plasma concentration of cf-DNA/NETs in sepsis group was significantly higher than that in non-sepsis group and healthy control group (MUg/L: 453.44+/-185.37 vs. 188.35+/-29.66, 203.83+/-43.25, both P < 0.05), and there was no significant difference between last two groups (P > 0.05). WBC, NEU, PCT, CRP, APACHE II and SOFA score in sepsis group were significantly higher than those of non-sepsis group [WBC (*109/L): 9.52+/-5.51 vs. 5.97+/-2.28, NEU: 0.787+/-0.110 vs. 0.655+/ 0.067, PCT (mg/L): 7.14 (3.60, 13.29) vs. 6.07 (3.57, 7.91), CRP (mg/L): 64.44+/ 13.14 vs. 27.00+/-19.47, APACHE II: 10.25+/-4.92 vs. 6.00+/-1.22, SOFA: 6.0+/-5.1 vs. 5.0+/-1.2, all P < 0.05]. Correlation analysis showed that the level of NETs had no obvious correlation with gender, age, WBC, NEU, PCT, CRP, APACHE II and SOFA scores (r value was 0.322, 0.262, 0.194, 0.312, 0.227, 0.454, 0.433, 0.333, respectively, all P > 0.05). The area under the ROC curve (AUC) of plasma cf DNA/NETs for the diagnosis of sepsis was 0.981. When the cut-off value of plasma cf-DNA/NETs was > 257.96 MUg/L, the sensitivity was 91.3%, specialty was 95.2%, and Youden index was 0.865. AUC of WBC in the diagnosis of sepsis was 0.663. When the cut-off value of WBC was > 6.0*109/L, the sensitivity was 78.3% and specificity was 25.0%. CONCLUSIONS: The plasma cf-DNA/NETs levels increased significantly in sepsis patients. In the diagnosis of sepsis, plasma NETs levels had better advantages over WBC. NETs can be used as a biomarker for early diagnosis of sepsis. PMID- 28625259 TI - [Antithrombin III for early diagnosis of DIC in sepsis patients: a retrospective analysis with 445 patients]. AB - OBJECTIVE: To investigated the role of antithrombin III (AT-III) levels in the early diagnosis of disseminated intravascular coagulation (DIC) in patients with sepsis and the predictive effect of AT-III on the development of DIC. METHODS: A retrospective study was conducted. Patients admitted to intensive care unit (ICU) of the First Affiliated Hospital of China Medical University from January to December in 2015 were enrolled. The patients were divided into sepsis group and non-sepsis group according to the diagnostic criteria of sepsis. In addition, sepsis patients were divided into 3 subgroups according to the international society on thrombosis and haemostasis (ISTH) scores on the first day: overt DIC (ISTH >= 5), non-overt DIC (ISTH 1-4) and none DIC group (ISTH = 0). Blood routine test, prothrombin time (PT), fibrinogen (Fib), D-dimer, fibrin degradation products (FDP), acute physiology and chronic health evaluation II (APACHE II) scores, sequential organ failure assessment (SOFA) scores and ISTH scores were recorded on the first ICU day. AT-III was recorded during 7 days. The differences were compared among these 3 groups. Correlations of AT-III with various parameters were calculated by using Pearson correlation analysis in sepsis group and overt DIC group. Receiver operating characteristic (ROC) curves for diagnosis of DIC with AT-III, AT-III+PT were drawn to evaluate the diagnostic efficiency. The AT-III levels of DIC patients were compared between early-onset DIC and late-onset DIC during their ICU stay. The change of AT-III levels with time and prognosis in patients with early-onset DIC was compared between groups. RESULTS: Totally 445 patients were recruited, with 138 patients in sepsis group, and 307 in non-sepsis group. There were 20 patents diagnosed with overt DIC on the first ICU day, 115 patients non-overt DIC and 3 patients of none DIC. Twenty five sepsis patients were diagnosed overt DIC during the ICU days. AT-III level in sepsis patients on the first ICU day were lower than that in non-sepsis patients [(55.29+/-13.92)% vs. (76.54+/-12.31)%, P < 0.01]. Patients with overt DIC had a lower AT-III level than non-overt DIC or none DIC patients [(43.85+/ 13.00)% vs. (56.95+/-13.03)%, (68.00+/-16.52)%, both P < 0.05]. It was shown by Pearson correlation analysis that AT-III level of sepsis patients on the first ICU day was negatively correlated to ISTH score and PT (r value were -0.467, 0.654, both P < 0.01). AT-III level of overt DIC patient on the first ICU day was negatively correlated with PT (r = -0.675, P = 0.001). It was shown by ROC curve that area under ROC curve (AUC) of AT-III combined with PT for diagnosis overt DIC in sepsis patients was higher than that of AT-III or PT alone (0.843 vs. 0.763, 0.834), the sensitivity 90.0%, specificity 73.7%. The cut-off value for overt DIC diagnosis in sepsis patients of AT-III level alone was 48.5%, sensitivity was 78.0%, specificity was 70.0%. On the first ICU day, AT-III level was risen when ISTH score improved in patients with sepsis. There was similar change of AT-III level between patients with early-onset DIC and late-onset DIC. AT-III level increased with DIC improvement. CONCLUSIONS: AT-III level can be used for diagnosing sepsis-associated overt DIC independently or with a combination of PT. When ISTH score improved, AT-III level was risen in patients with sepsis associated DIC. PMID- 28625260 TI - [Predictive value of four different scoring systems for septic patient's outcome: a retrospective analysis with 311 patients]. AB - OBJECTIVE: To study the predicting value of four different scoring systems such as the acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, quick SOFA (qSOFA) score and systemic inflammatory response syndrome (SIRS) score for the prognosis of septic patients. METHODS: A retrospective analysis were conducted. Septic patients in intensive care unit (ICU) of the First People's Hospital of Chenzhou form July 1st, 2012 to June 30th, 2016 were enrolled. Patients were divided into survival group and death group according to 28-day outcome. The difference of clinic data, the worst clinical index value within 24 hours, whether mechanical ventilation performed on first day, length of stay in ICU, APACHE II score, SOFA score, qSOFA score and SIRS score were compared between the two groups. The significant different factors of sepsis outcome in univariate analysis were analyzed by multiple logistic regression, and the ability of four scoring systems was tested by receiver operating characteristic (ROC) curve. RESULTS: 311 patients were enrolled in this study (221 survivals, 90 deaths, 28-day mortality rate 28.9%). Univariate analysis showed age, mechanical ventilation ratio, urine output, length of stay in ICU and the fastest heart beat rate (HR), the lowest systolic blood pressure (SBP), the lowest mean arterial pressure (MAP), HCO3-, minimum arterial blood oxygen partial pressure (PaO2), minimum oxygenation index (PaO2/FiO2), the maximum fraction of inspired oxygen (FiO2), Na+, the highest concentration of blood urea nitrogen (BUN), the highest concentration of serum creatinine (SCr), minimum concentration of plasma albumin (Alb), Glasgow coma score (GCS) score, APACHE II score, SOFA score, qSOFA score, within 24 hours after diagnosis were significantly different between two groups (all P < 0.05). Multiple logistic regression showed age [odds ratio (OR) = 1.388, 95% confidence interval (95%CI) = 1.074-1.794, P = 0.012], PaO2/FiO2 (OR = 0.459, 95%CI = 0.259 0.812, P = 0.007), concentration of plasma Alb (OR = 0.523, 95%CI = 0.303-0.903, P = 0.020), GCS score (OR = 0.541, 95%CI = 0.303-0.967, P = 0.038) and SOFA scores (OR = 3.189, 95%CI = 1.813-5.610, P = 0.000) were independent risk factors for sepsis outcome. ROC curve test showed the APACHE II score, SOFA score and qSOFA score had the ability to predict the outcome in critical ill patients with sepsis, the SOFA score of the most powerful, the area under the ROC curve (AUC) was 0.700, when the cut-off value was 7.5 points, the sensitivity was 73.3% and specificity was 58.8%. CONCLUSIONS: APACHE II score, SOFA score and qSOFA score have the predictive properties for septic patients. SOFA score is an independent prognostic risk factor of sepsis, while qSOFA score can be widely used in clinical practice as the advantage of quick evaluating. PMID- 28625261 TI - [Formulation of combined predictive indicators using logistic regression model in predicting sepsis and prognosis]. AB - OBJECTIVE: To explore the method and performance of using multiple indices to diagnose sepsis and to predict the prognosis of severe ill patients. METHODS: Critically ill patients at first admission to intensive care unit (ICU) of Changzheng Hospital, Second Military Medical University, from January 2014 to September 2015 were enrolled if the following conditions were satisfied: (1) patients were 18-75 years old; (2) the length of ICU stay was more than 24 hours; (3) All records of the patients were available. Data of the patients was collected by searching the electronic medical record system. Logistic regression model was formulated to create the new combined predictive indicator and the receiver operating characteristic (ROC) curve for the new predictive indicator was built. The area under the ROC curve (AUC) for both the new indicator and original ones were compared. The optimal cut-off point was obtained where the Youden index reached the maximum value. Diagnostic parameters such as sensitivity, specificity and predictive accuracy were also calculated for comparison. Finally, individual values were substituted into the equation to test the performance in predicting clinical outcomes. RESULTS: A total of 362 patients (218 males and 144 females) were enrolled in our study and 66 patients died. The average age was (48.3+/-19.3) years old. (1) For the predictive model only containing categorical covariants [including procalcitonin (PCT), lipopolysaccharide (LPS), infection, white blood cells count (WBC) and fever], increased PCT, increased WBC and fever were demonstrated to be independent risk factors for sepsis in the logistic equation. The AUC for the new combined predictive indicator was higher than that of any other indictor, including PCT, LPS, infection, WBC and fever (0.930 vs. 0.661, 0.503, 0.570, 0.837, 0.800). The optimal cut-off value for the new combined predictive indicator was 0.518. Using the new indicator to diagnose sepsis, the sensitivity, specificity and diagnostic accuracy rate were 78.00%, 93.36% and 87.47%, respectively. One patient was randomly selected, and the clinical data was substituted into the probability equation for prediction. The calculated value was 0.015, which was less than the cut-off value (0.518), indicating that the prognosis was non-sepsis at an accuracy of 87.47%. (2) For the predictive model only containing continuous covariants, the logistic model which combined acute physiology and chronic health evaluation II (APACHE II) score and sequential organ failure assessment (SOFA) score to predict in-hospital death events, both APACHE II score and SOFA score were independent risk factors for death. The AUC for the new predictive indicator was higher than that of APACHE II score and SOFA score (0.834 vs. 0.812, 0.813). The optimal cut-off value for the new combined predictive indicator in predicting in-hospital death events was 0.236, and the corresponding sensitivity, specificity and diagnostic accuracy for the combined predictive indicator were 73.12%, 76.51% and 75.70%, respectively. One patient was randomly selected, and the APACHE II score and SOFA score was substituted into the probability equation for prediction. The calculated value was 0.570, which was higher than the cut-off value (0.236), indicating that the death prognosis at an accuracy of 75.70%. CONCLUSIONS: The combined predictive indicator, which is formulated by logistic regression models, is superior to any single indicator in predicting sepsis or in hospital death events. PMID- 28625262 TI - [Predictive value of SOFA score combined AGI grading system in elderly patients with sepsis: a retrospective analysis with 91 patients]. AB - OBJECTIVE: To explore the predictive value of sequential organ failure assessment (SOFA) score combined the acute gastrointestinal injury (AGI) grading system in critical elderly patients with sepsis. METHODS: A retrospective analysis was conducted. Elderly patients with sepsis aged > 60 years admitted to medical intensive care unit (MICU) of General Hospital of Guangzhou Military Command from March 2014 to December 2015 and experiencing critical care over 48 hours were enrolled. Age, gender, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score and AGI score at admission (SOFAinitial, AGIinitial), the highest SOFA score and AGI score within the first week (SOFAmax, AGImax), serum procalcitonin (PCT), C-reactive protein (CRP), albumin (ALB), platelet (PLT), hemoglobin (Hb) and lactate (Lac) levels, length of ICU stay, usage of mechanical ventilation and renal replacement therapy were recorded. The primary end point was 28-day mortality. To extract factors affecting 28-day mortality, the risk factor of death of the senile sepsis patients were analyzed by binary logistic regression analysis (stepwise method). Fitness of the model was assessed by the Hosmer-Lemeshow test and calibration plot (P > 0.05). Receiver operating characteristic (ROC) analysis was performed for APACHE II score, SOFAinitial score, SOFAmax score, AGIinitial score, AGImax score and SOFAmax and combined AGImax score. RESULTS: Ninety-one patients were enrolled, the incidence of AGI in elderly patients with sepsis was 100%; 34 patients died 28 days after the admission, and the 28-day mortality rate was 37.4%. Non-survivors presented a higher APACHE II score, SOFAinitial score, SOFAmax score, AGIinitial score, AGImax score and longer usage of mechanical ventilation and renal replacement therapy. SOFAmax score [odds ratio (OR) = 1.576] and AGImax score (OR = 5.695) were associated with 28-day mortality in binary logistic regression analysis (both P < 0.01). The area under the curve (AUC) and 95% confidence interval (95%CI) of SOFAmax score combined AGImax score was significantly higher than that of SOFAinitial score, SOFAmax score, AGIinitial score, AGImax score and APACHE II score [0.806 (0.710-0.881) vs. 0.723 (0.619-0.812), 0.786 (0.688-0.865), 0.641 (0.533-0.739), 0.633 (0.526-0.881), 0.638 (0.531-0.736), all P < 0.05]. The Youden index (55.37) and positive predict value (5.51) of SOFAmax score combined AGImax score were the largest. When its cut-off value reached 14, the sensitivity and specificity was 67.65% and 87.72%, respectively. According to score of APACHE II, SOFAinitial, SOFAmax or AGImax, the higher of each score, the higher mortality rate could be. CONCLUSIONS: The combination of SOFAmax score and AGImaxscore enable accurate prediction in elderly patients with sepsis. PMID- 28625263 TI - [Bacterial endotoxin-induced endothelial cell injury and calcium overload associated with Toll-like receptor and calcium signal]. AB - OBJECTIVE: To explore the effect of toll-like receptor 4 (TLR4), myeloid differentiation protein-2 (MD2), and stromal interaction molecular 1 (STIM1) for regulating human vascular endothelial calcium overload injury and inflammatory reaction induced by bacterial endotoxin (LPS). METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured in Dulbecco's modification of Eagle's medium (DMEM). (1) The levels of TLR4, MD2 and nuclear factor-kappaB (NF-kappaB) were detected by reverse transcriotion-polymerase chain reaction (RT-PCR) before and 0.5, 1, 6, 12, 24 hours after LPS stimulation. (2) Intracellular calcium peak level was detected by confocal following probe fluo-3 AM loading in HUVEC cells induced with LPS and transfected by psiSTIM or psiTLR. (3) MD2, STIM1 or NF kappaB protein level was detected by immunoprecipitation (IP) and immuno-blotting in HUVEC cells which were transfected by TLR4 inhibited expression (psiTLR) for 12 hours and followed by LPS stimulation for 6 hours. (4) HUVEC cells were randomly divided into 6 groups: control group, LPS group, PDTC 0.1 mg/L group, PDTC 1 mg/L group, psiTLR 1 h group and psiTLR 12 h group. Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA) in supernatant. The mRNA levels of STIM1 and NF kappaB were detected by RT-PCR. RESULTS: (1) The mRNA levels of TLR4, MD2, and NF kappaB gradually increased after LPS induction and peaked at 6 hours (2 DeltaDeltaCt: 23.52+/-2.88, 17.43+/-3.43, 18.13+/-2.99, respectively), which were statistically significant before the stimulation with LPS (2-DeltaDeltaCt: 7.02+/ 2.81, 5.19+/-3.22, 8.11+/-1.42, all P < 0.05). (2) Extracellular calcium influx in LPS group was increased significantly higher than control group (nmol/L: 108.13+/-22.33 vs. 41.57+/-13.19, P < 0.01). Extracellular calcium influx in psiSTIM+LPS group (nmol/L: 62.61+/-14.12 vs. 108.13+/-22.33, P < 0.05) and psiTLR+LPS group (nmol/L: 50.78+/-8.05 vs. 109.43+/-20.21, P < 0.01) were both suppressed as compared with LPS group. While extracellular calcium peak level in psiTLR+psiSTIM+LPS group further decreased (nmol/L: 39.31+/-6.42 vs. 109.43+/ 20.21, P < 0.01). (3) MD2 protein but not STIM1 or NF-kappaB can be detected in anti-TLR4 precipitates in control (ctrl-) by immunoprecipitation. MD2 protein level increased in anti-TLR4 precipitates in LPS group (ctrl+) and was suppressed in TLR4 inhibiting group (psiTLR). (4) The levels of TNF-alpha in PDTC 1 mg/L group were significantly lower than those of LPS group (ng/L: 0.60+/-0.24 vs. 1.77+/-0.66, P < 0.01). The levels of IL-6 in PDTC 0.1 mg/L, 1 mg/L group and psiTLR 12 h group decreased significantly lower than that of LPS group (ng/L: 232.10+/-63.54, 134.32+/-37.23, 284.23+/-56.14 vs. 510.22+/-89.23, all P < 0.05). Compared to LPS group, the mRNA levels of NF-kappaB and STIM1 were obviously inhibited in PDTC 1 mg/L group and psiTLR 12 h group [NF-kappaB mRNA (2 DeltaDeltaCt): 17.22+/-2.35, 13.24+/-3.54 vs. 30.16+/-2.06; STIM1 mRNA (2 DeltaDeltaCt): 12.57+/-2.43, 12.21+/-2.46 vs. 25.12+/-2.02, all P < 0.05]. CONCLUSIONS: TLR4, MD2, NF-kappaB signal and SOC calcium channel STIM1 mediate LPS induced-calcium influx and inflammatory mediators level in HUVEC cells. Extracellular calcium overload and inflammatory response by endotoxin induction can be effectively inhibited by down-regulation of TLR4, NF-kappaB and/or STIM1. PMID- 28625264 TI - [Suppressive effect of CORM-2 on platelet alpha-granule exocytosis in sepsis via SNARE/Munc18b complex formation]. AB - OBJECTIVE: To investigate the suppressive effect of carbon monoxide-releasing molecule II (CORM-2) on LPS induced platelet alpha-granule exocytosis in sepsis via soluble N-ethylmaleimide-sensitive factor attached protein receptor/mammalian uncoordinated 18b (SNARE/Munc18b) complex formation. METHODS: Blood was collected from healthy volunteers' cubital vein, then platelets were isolated by differential centrifugation. Platelets were randomly divided into 5 groups. The control group did not undergo any treatment, the LPS group received 10 mg/L LPS simulation, the CORM-2 group and iCORM-2 group underwent LPS simulation and immediate administration of CORM-2 (10 MUmol/L and 50 MUmol/L) or iCORM-2 (50 MUmol/L), respectively. Samples were incubated in a CO2-incubator at 37 degrees C, 95% humidity, and 5% CO2. Platelet alpha-granule contents were detected by using standard enzyme linked immunosorbent assay (ELISA), including platelet factor 4 (PF4), platelet derived growth factor-BB (PDGF-BB), and matrix metalloproteinase-2 (MMP-2). The expression of P-selectin was detected by flow cytometer. Transmission electron microscope and immunofluorescence microscope was used to assess platelet alpha-granules distribution. Expressions of Munc18b and SNARE proteins including vesicle-associated membrane protein-8 (VAMP-8), synaptosomal-associated protein-23 (SNAP-23) and syntaxin-11 (STX-11) were detected by Western Bolt. The SNARE/Munc18b complex formation was detected by immunoprecipitation. RESULTS: Compared with the control group, levels of PF4, PDGF-BB, MMP-2 and P-selectin in LPS induced platelets were found to markedly elevated, while CORM-2 (10 MUmol/L and 50 MUmol/L) could decrease platelet alpha granule contents exocytosis: [PF4 (MUg/L): 7.69+/-0.58, 6.03+/-0.71 vs. 10.13+/ 0.82; PDGF-BB (MUg/L): 112.71+/-1.79, 102.91+/-5.86 vs. 128.78+/-1.39; MMP-2 (ng/L): 32.94+/-2.73, 27.58+/-3.36 vs. 53.26+/-1.21; P-selectin: (17.14+/-0.57)%, (15.35+/-0.68)% vs. (23.78+/-0.62)%; all P < 0.01]. Transmission electron microscope and immunofluorescence microscope showed that the extent of platelet alpha-granules assembled to platelet plasma membrane was significantly decreased following CORM-2 treatment. Compared with the control group, the expressions of Munc18b and SNARE proteins and SNARE/Munc18b complex formation in LPS-stimulated platelets were significantly increased, while CORM-2 (10 MUmol/L and 50 MUmol/L) inhibited these elevations (Munc18b/GAPDH: 0.80+/-0.08, 0.69+/-0.01 vs. 0.99+/ 0.09; VAMP-8/GAPDH: 0.72+/-0.09, 0.50+/-0.12 vs. 1.18+/-0.14; SNAP-23/GAPDH: 1.18+/-0.22, 0.63+/-0.10 vs. 1.90+/-0.08; STX-11/GAPDH: 0.76+/-0.02, 0.57+/-0.08 vs. 1.16+/-0.23; VAMP-8/Munc18b: 0.65+/-0.09, 0.53+/-0.07 vs. 1.21+/-0.20; SNAP 23/Munc18b: 0.85+/-0.07, 0.55+/-0.09 vs. 1.26+/-0.08; STX-11/Munc18b: 0.78+/ 0.05, 0.61+/-0.10 vs. 1.39+/-0.16; all P < 0.01). Above all, the data showed a dose dependent change. CONCLUSIONS: We could suggest that CORM-2 suppressed alpha granule exocytosis in LPS-stimulated platelets and the potential mechanisms might involve SNARE/Munc18b complex formation. PMID- 28625265 TI - [Protective effect of curcumin on hepatocytes in rats with sepsis]. AB - OBJECTIVE: To investigate the protective effect of curcumin on hepatocytes in rats with sepsis. METHODS: Eighty healthy male Sprague-Dawley (SD) rats were randomly divided into sham operation group, sepsis group, Xuebijing group and curcumin group (20 rats in each group) according to the random number table method. The animal model of sepsis was established by cecal ligation and puncture (CLP). In the sham operation group, the cecum was removed only after the operation. The rats in Xuebijing group and curcumin group were injected with 4 mL/kg Xuebijing, 100 mg/kg curcumin intraperitoneally at 0, 8 and 16 hours after operation (diluted with normal saline to 4 mL/kg) respectively; Sham operation group and sepsis group were injected with the same volume of normal saline. Five rats in each group were sacrificed at 2, 6, 12 and 24 hours after operation, the blood sample was collected, and liver tissues were harvested. The levels of serum procalcitonin (PCT), tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL 6, IL-1beta) were measured by enzyme linked immunosorbent assay (ELISA), the pathological changes of liver tissues were observed by hematoxylin-eosin (HE) staining, and apoptosis index (AI) was measured by TdT-mediated dUTP nick end labeling (TUNEL) method. RESULTS: The degree of hepatocyte injury in sepsis group increased gradually with time, the apoptotic cells gradually increased, and the AI of liver cells increased to 24 hours; serum levels of PCT, TNF-alpha, IL-6 and IL-1beta were significantly higher than those in the sham operated group at 2 hours after operation and gradually increased to peak at 12 hours. The injury degree of liver tissue in Xuebijing group and curcumin group was significantly lighter than that in sepsis group, and the number of apoptotic cells were significantly decreased; the AI of hepatocytes and serum levels of PCT, TNF alpha, IL-6 and IL-1beta were significantly lower than those of sepsis group from 2 hours [AI: (11.89+/-1.34)%, (11.56+/-0.96)% vs. (23.59+/-2.00)% at 2 hours, (28.95+/-1.40)%, (30.35+/-1.20)% vs. (52.05+/-1.31)% at 24 hours; PCT (MUg/L): 1.27+/-0.18, 1.13+/-0.19 vs. 2.41+/-0.21 at 2 hours, 5.07+/-0.45, 5.09+/-0.42 vs. 8.68+/-0.58 at 12 hours; TNF-alpha (ng/L): 127.93+/-9.53, 124.73+/-7.47 vs. 217.28+/-14.24 at 2 hours, 171.03+/-8.58, 168.68+/-6.95 vs. 314.13+/-14.39 at 12 hours; IL-6 (ng/L): 132.15+/-9.27, 136.14+/-8.42 vs. 153.35+/-12.64 at 2 hours, 211.65+/-8.52, 213.37+/-8.96 vs. 298.11+/-12.35 at 12 hours; IL-1beta (ng/L): 33.59+/-1.49, 35.05+/-1.00 vs. 61.84+/-3.21 at 2 hours; 81.76+/-2.80, 84.06+/ 3.42 vs. 132.24+/-2.58 at 12 hours, all P < 0.05]. There was no significant difference in the above indexes between Xuebijing group and curcumin group. CONCLUSIONS: Curcumin can inhibit the inflammatory response of hepatocytes in sepsis rats and reduce the apoptosis of hepatocytes, which can protect hepatocytes from sepsis. PMID- 28625266 TI - [Risk factors of deep venous thrombosis associated with peripherally inserted central venous catheter in upper extremity in ICU]. AB - OBJECTIVE: To analyze the incidence and its risk factors of peripherally inserted central venous catheter related upper extremity deep venous thrombosis (PICC UEDVT) in intensive care unit (ICU). METHODS: Clinical data of the patients received PICCs in ICU of the First Affiliated Hospital of Nanchang University from August 2013 to August 2016 were retrospectively analysed. The inclusion criteria in the study included: the age > 18 years old, catheter indwelling time > 1 week and the complete relevant information. The gender, age, history of deep venous thrombosis (DVT) and PICC; number of illness involved organs; complicated with hypertension, diabetes, infection or not; and acute physiology and chronic health evaluation II (APACHE II), duration of mechanical ventilation; D-dimer, platelet count (PLT), and activated partial thromboplastin time (APTT) were recorded. According to the occurrence of PICC-UEDVT, univariate analysis was performed to identify the risk factors of PICC-UEDVT and variables with statistical difference were selected to do multivariate binary logistic regression analysis for the confirmable independence risk factors. RESULTS: Six patients of the 61 cases occurred PICC-UEDVT with the occurrence rate of 9.8%. Time of occurrence was 9 days, 14 days (2 cases), 22 days, 28 days, 62 days after inserted catheter respectively. Univariate analysis demonstrated that previous DVT, D-dimer and big diameter PICC were risk factors associated with PICC-UEDVT [the previous DVT: 50.00% vs. 7.27%, P = 0.017; D-dimer > 5 mg/L: 66.67% vs. 18.18%, P = 0.021; 5F catheter: 83.33% vs. 29.09%, P = 0.016]. It was shown by multivariate logistic regression analysis that the previous DVT [odds ratio (OR) = 20.539, 95% confidence interval (95%CI) = 1.733-243.875, P = 0.017] and increasing size of catheter (OR = 18.070, 95%CI = 1.317-247.875, P = 0.030) were independent risk factors associated with the development of PICC-UEDVT. CONCLUSIONS: For critical patients with a history of DVT and D-dimer > 5 mg/L, especially for those with the catheter placement over 14 days in ICU, clinical staffs should remain on high alert for the development of PICC-UEDVT and take early effective measures to prevent it. Meanwhile the patient's vascular conditions should be precisely assessed using ultrasound before insertion, and the appropriate catheter size be selected to reduce the incidence of PICC-UEDVT. Color Doppler ultrasonography should be used for dynamic monitoring during the indwelling of PICC, so that PICC-UEDVT can be found as early as possible. PMID- 28625267 TI - [Application of quality control chart in quality control for nosocomial infection in intensive care unit]. AB - OBJECTIVE: To explore the application value of control chart in the management of nosocomial infection in intensive care unit (ICU) by using quality control chart to monitor the infections in ICU. METHODS: From October 2011 to June 2016, ventilator-associated pneumonia (VAP), central line-associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI), namely the three catheters, occurred in ICU of the Affiliated Hospital of Guizhou Medical University were monitored and recorded monthly, then the data was imput into the Excel, and the data was analyzed using SPSS. According to the properties of the data, control chart was derived for monitoring nosocomial infections, finding out problems and for taking actions on time. RESULTS: From October 2011 to June 2016, the numbers of new patients in ICU were 23-103 cases per month and the median was 45.00 (39.00, 55.50) cases per month. The numbers of new VAP patients were 0-7 cases per month which median was 3.00 (1.00, 4.00) cases per month and the VAP rates were 0-22.58 cases per 1 000 ventilation-days which median was 8.62 (3.28, 12.10) cases per 1 000 ventilation-days. The numbers of new CLABSI patients were 0-3 cases per month which median was 0.00 (0.00, 1.00) cases per month and the CLABSI rates were 0-14.82 cases per 1 000 catheter-days which median was 0.00 (0.00, 5.38) cases per 1 000 catheter-days. The numbers of new CAUTI patients were 0-8 cases per month which median was 1.00 (0.00, 2.00) cases per month and the CAUTI rates were 0-14.06 cases per 1 000 catheter-days which median was 3.02 (0.00, 5.86) cases per 1 000 catheter-days. 57 points of the three catheter-associated infections incidences were continuously monitored monthly, in which some data points overstepped the warning limit, only 1 CAUTI infection incidence overstepped the control limit, the other monthly three catheter-associated infections incidences were in the control range and had no abnormal arrangement occurred, so all of them were in a controlled state. By using the control chart, the situation of nosocomial infections were analyzed scientifically and intuitively, the existing problems were discussed in time, the improvement programs were made, and the three catheter-associated infections were in a controlled state. CONCLUSIONS: Control chart has the characteristics of simple operation, intuitive results, and finding problems on time, so it can be used in daily monitoring of nosocomial infection and is worthy of generalization. PMID- 28625268 TI - [Experience of pressure controlled lung recruitment combined with prone position ventilation for the treatment of severe acute respiratory distress syndrome]. PMID- 28625269 TI - [Abdominal lifting and compression cardiopulmonary resuscitation for treatment of a 84-year old cardiac arrest patient]. PMID- 28625270 TI - [Progress in relationship of the long non-coding RNA and sepsis]. AB - OBJECTIVE: The mechanism of long chain non-coding RNA (lncRNA) is diverse. LncRNA can regulate the expression of genes at multiple levels and is closely related to some pathological process, such as tumor formation, viral replication, inflammatory damage, etc. The abnormal expression of lncRNA is involved in the patho-physiological changes of the disease, and plays a key role in many links, such as the stability of mRNA, the regulation of translation level, protein transport, RNA processing and modification, and so on. The development of sepsis inflammatory injury is a complex process involving multiple genes and pathways, in which the abnormal structure and expression of many encoding genes or non coding genes exist. This paper review the research progress on lncRNA in the regulation of chondriokinesis, pro-inflammatory cytokines, calcium ion transport, nuclear factor-kappaB (NF-kappaB) in signal pathway and other inflammatory lesions, which may provide a new method for the diagnosis and treatment of sepsis. PMID- 28625271 TI - [Advances in immunotherapeutic research of sepsis]. AB - OBJECTIVE: Sepsis is a life-threatening organ dysfunction caused by dysregulated host responses to infection. Despite decades of research, it remains the leading cause of death in intensive care units (ICUs). None of the current treatment, including antibiotics, organ protection and liquid resuscitation, is specifically effective for sepsis. Immunosuppression is one of the currently accepted pathogenesis and immunotherapy is one of the hot spot of current sepsis research. Immune related treatments include restricting the release of pathogen toxin and its removal, controlling the excessive inflammatory reaction and apoptosis inhibition, etc. Numerous pre-clinical studies using immunomodulatory agents such as interleukin-7 (IL-7), anti-programmed cell death-1 (PD-1) antibody and others, have demonstrated reversal of T cell dysfunction and improved survival resulting from reviewing recent advances in immunotherapy of sepsis. Therefore, immunotherapy may be a new way of sepsis treatment. PMID- 28625272 TI - [Research progress in the multiple organ dysfunction syndrome caused by heat stroke]. AB - OBJECTIVE: Heat stroke (HS) is a life-threatening illness characterized by core body temperatures above 40 degrees C coupled with central nervous system (CNS) dysfunction, including delirium, convulsions, and/or coma. Its morbidity has increased dramatically in the past few decades. Multiple organ dysfunction syndrome (MODS) is not only the most serious complication of HS, but also the leading cause of deaths. Understanding the pathogenesis, characteristic and advancement pattern of MODS caused by HS will have a profound effect on the clinical treatment, research and mortality decrease. The pathogenesis, injury characteristic of each system and organ, and treatment methods were summarized in this review so as to deepen the clinical recognition of this disease. PMID- 28625274 TI - Beneficial effects of melatonin on in vitro embryo production from juvenile goat oocytes. AB - Melatonin is a universal antioxidant that improves in vitro embryo production in several species. The aims of this study were to determine the melatonin concentration in the ovarian follicular fluid (FF) of juvenile goats and the effect of melatonin during in vitro maturation (IVM) on embryo development. The FF melatonin concentration was 0.57--1.07*10-9 M, increasing with follicular diameter. Oocytes were matured, fertilised and cultured under conventional conditions. Blastocyst development, embryo quality and levels of reactive oxygen species (ROS) and reduced glutathione were assessed. In Experiment 1 different melatonin concentrations (10-3, 10-7, 10-9, 10-11 M) were added to the IVM medium, which contained cysteamine as antioxidant, and no differences were observed. In Experiment 2, melatonin (10-7 M) was tested in the presence or absence of cysteamine (experimental groups: melatonin, cysteamine, melatonin+cysteamine, non-antioxidant). The melatonin group presented a higher blastocyst rate than the non-antioxidant group (28.9 vs 11.7%; P<0.01) and a higher total cell number than the cysteamine group (225.1 vs 129.0; P<0.05). Oocytes from the melatonin and cysteamine groups had lower ROS levels than those from the non-antioxidant group. This study shows that melatonin is an interesting tool for improving oocyte competence in juvenile goats as it increases embryo production and quality. PMID- 28625273 TI - Development of a core outcome set for disease modification trials in mild to moderate dementia: a systematic review, patient and public consultation and consensus recommendations. AB - BACKGROUND: There is currently no disease-modifying treatment available to halt or delay the progression of the disease pathology in dementia. An agreed core set of the best-available and most appropriate outcomes for disease modification would facilitate the design of trials and ensure consistency across disease modification trials, as well as making results comparable and meta-analysable in future trials. OBJECTIVES: To agree a set of core outcomes for disease modification trials for mild to moderate dementia with the UK dementia research community and patient and public involvement (PPI). DATA SOURCES: We included disease modification trials with quantitative outcomes of efficacy from (1) references from related systematic reviews in workstream 1; (2) searches of the Cochrane Dementia and Cognitive Improvement Group study register, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Latin American and Caribbean Health Sciences Literature and PsycINFO on 11 December 2015, and clinical trial registries [International Standard Randomised Controlled Trial Number (ISRCTN) and clinicaltrials.gov] on 22 and 29 January 2016; and (3) hand-searches of reference lists of relevant systematic reviews from database searches. REVIEW METHODS: The project consisted of four workstreams. (1) We obtained related core outcome sets and work from co-applicants. (2) We systematically reviewed published and ongoing disease modification trials to identify the outcomes used in different domains. We extracted outcomes used in each trial, recording how many used each outcome and with how many participants. We divided outcomes into the domains measured and searched for validation data. (3) We consulted with PPI participants about recommended outcomes. (4) We presented all the synthesised information at a conference attended by the wider body of National Institute for Health Research (NIHR) dementia researchers to reach consensus on a core set of outcomes. RESULTS: We included 149 papers from the 22,918 papers screened, referring to 125 individual trials. Eighty-one outcomes were used across trials, including 72 scales [31 cognitive, 12 activities of daily living (ADLs), 10 global, 16 neuropsychiatric and three quality of life] and nine biological techniques. We consulted with 18 people for PPI. The conference decided that only cognition and biological markers are core measures of disease modification. Cognition should be measured by the Mini Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog), and brain changes through structural magnetic resonance imaging (MRI) in a subset of participants. All other domains are important but not core. We recommend using the Neuropsychiatric Inventory for neuropsychiatric symptoms: the Disability Assessment for Dementia for ADLs, the Dementia Quality of Life Measure for quality of life and the Clinical Dementia Rating scale to measure dementia globally. LIMITATIONS: Most of the trials included participants with Alzheimer's disease, so recommendations may not apply to other types of dementia. We did not conduct economic analyses. The PPI consultation was limited to members of the Alzheimer's Society Research Network. CONCLUSIONS: Cognitive outcomes and biological markers form the core outcome set for future disease modification trials, measured by the MMSE or ADAS Cog, and structural MRI in a subset of participants. FUTURE WORK: We envisage that the core set may be superseded in the future, particularly for other types of dementia. There is a need to develop an algorithm to compare scores on the MMSE and ADAS-Cog. STUDY REGISTRATION: The project was registered with Core Outcome Measures in Effectiveness Trials [ www.comet initiative.org/studies/details/819?result=true (accessed 7 April 2016)]. The systematic review protocol is registered as PROSPERO CRD42015027346. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28625276 TI - White Spots on the Conjunctiva. PMID- 28625275 TI - Advance Directives and Powers of Attorney in Intensive Care Patients. AB - BACKGROUND: Advance directives and powers of attorney are increasingly common, yet data on their use in clinical situations remain sparse. METHODS: In this single center cross-sectional study, we collected data by questionnaire from 1004 intensive care patients in a university hospital. The frequencies of advance directives and powers of attorney were determined, and the factors affecting them were studied with multivariate logistic regression analysis. RESULTS: Usable data were obtained from 998 patients. 51.3% stated that they had prepared a document of at least one of these two kinds. Among them, 39.6% stated that they had given the relevant document(s) to the hospital, yet such documents were present in the patient's hospital record for only 23%. 508 patients stated their reasons for preparing an advance directive or a power of attorney: the most common reason (48%) was the fear of being at other people's mercy, of the lack of self determination, or of medical overtreatment. The most important factors associated with a patient's statement that he/she had prepared such a document were advanced age (advance directive: 1.022 [1.009; 1.036], p = 0.001; power of attorney: 1.027 [1.014; 1.040], p<0.001) and elective admission to the hospital (advance directive: 1.622 [1.138; 2.311], p<0.007; power of attorney: 1.459 [1.049; 2.030], p = 0.025). 39.8% of the advance directives and 44.1% of the powers of attorney that were present in the hospital records were poorly interpretable because of the incomplete filling-out of preprinted forms. Half of the patients who did not have such a document had already thought of preparing one, but had not yet done so. CONCLUSION: For patients hospitalized in intensive care units, there should be early discussion about the presence or absence of documents of these kinds and early evaluation of the patient's concrete wishes in critical situations. Future studies are needed to determine how best to assure that these documents will be correctly prepared and then given over to hospital staff so that they can take their place in the patient's record. PMID- 28625279 TI - Excerpts from the World Medical Literature. PMID- 28625278 TI - Acute Infarction of the Spleen. PMID- 28625277 TI - The Diagnosis and Treatment of Hemoptysis. AB - BACKGROUND: Hemoptysis, i.e., the expectoration of blood from the lower airways, has an annual incidence of approximately 0.1% in ambulatory patients and 0.2% in inpatients. It is a potentially life-threatening medical emergency and carries a high mortality. METHODS: This review article is based on pertinent publications retrieved by a selective search in PubMed. RESULTS: Hemoptysis can be a sign of many different diseases. Its cause remains unknown in about half of all cases. Its more common recognized causes include infectious and inflammatory airway diseases (25.8%) and cancer (17.4%). Mild hemoptysis is self-limited in 90% of cases; massive hemoptysis carries a worse prognosis. In patients whose life is threatened by massive hemoptysis, adequate oxygenation must be achieved through the administration of oxygen, positioning of the patient with the bleeding side down (if known), and temporary intubation if necessary. A thorough diagnostic evaluation is needed to identify the underlying pathology, site of bleeding, and vascular anatomy, so that the appropriate treatment can be planned. The evaluation should include conventional chest x-rays in two planes, contrastenhanced multislice computerized tomography, and bronchoscopy. Hemostasis can be achieved at bronchoscopically accessible bleeding sites with interventionalbronchoscopic local treatment. Bronchial artery embolization is the first line of treatment for hemorrhage from the pulmonary periphery; it is performed to treat massive or recurrent hemoptysis or as a presurgical measure and provides successful hemostasis in 75-98% of cases. Surgery is indicated if bronchial artery embolization alone is not successful, or for special indications (traumatic or iatrogenic pulmonary/vascular injury, refractory asper gilloma). CONCLUSION: The successful treatment of hemoptysis requires thorough diagnostic evaluation and close interdisciplinary collaboration among pulmonologists, radiologists, and thoracic surgeons. PMID- 28625280 TI - ? PMID- 28625281 TI - The PETRA (Perinatal Emergency Team Response Assessment) Scale: A High-Fidelity Simulation Validation Study. AB - OBJECTIVE: The objective of this study was to establish the validity and reliability of a new interdisciplinary teamwork assessment scale, the Perinatal Emergency Team Response Assessment (PETRA), to assess team dynamics during a simulated obstetric crisis. METHODS: This observational cohort study was conducted using high-fidelity simulation and multidisciplinary obstetric teams in order to evaluate the validity and reliability of the previously developed PETRA scale for the assessment of teamwork in the management of obstetric crises. Two high-fidelity simulations of preeclampsia and postpartum hemorrhage (PPH) were conducted 50 times; 42 were performed by multidisciplinary teams and eight (four "good," four "poor") were performed by actors. Five raters used the PETRA tool to assess the simulation video recordings. Three additional raters assessed each performance without the use of PETRA as "good" or "poor" in order to provide an overall rating (referred to as the standardized score). The primary outcome measure was the PETRA score. Cronbach's alpha and intra-class correlation coefficients (2,1) with 95% CIs were calculated to examine internal consistency of the scale and level of agreement among raters, respectively. Construct validity was established by comparing the assessments of the raters with the standardized scores. Generalizability theory analysis was performed to demonstrate PETRA's reliability and to investigate the sources of variation in scores. RESULTS: The simulated emergencies were performed by 119 participants. There was overall high consistency (Cronbach's alpha [95% CI] 0.984 [0.981 to 0.987]) and moderate agreement (intra-class correlation coefficients [95% CI] 0.49 [0.35 to 0.63]) among raters. Significantly higher PETRA scores (mean [standard deviation]) were recorded with "good" versus "poor" performing teams (real scenarios 3.8 [0.7] vs. 2.9 [0.7]; P < 0.001; acted scenarios 4.7 [0.5] vs. 2.2 [0.7]; P < 0.001), suggesting strong construct validity. The overall PETRA scores were not different between the PPH (3.7 [0.7]) and preeclampsia (3.7 [0.8]) scenarios (P = 0.49). Generalizability coefficients were 0.83 for PPH and 0.76 for preeclampsia. CONCLUSION: PETRA is a valid and reliable scale that may be a valuable tool in the assessment and training of multidisciplinary teams in their management of obstetric crises. PMID- 28625282 TI - High-Intensity Exercise Training for Improving Reproductive Function in Infertile Patients: A Randomized Controlled Trial. AB - OBJECTIVE: The purpose of this RCT was to investigate whether a 24-week program of high-intensity exercise was beneficial for improving reproductive function in infertile male patients. METHODS: Infertile men (n = 433) were randomly assigned to exercise (n = 218) and non-exercise (n = 215) groups. The seminal markers of inflammation and oxidative stress, semen quality parameters, sperm DNA fragmentation, and pregnancy rate were measured at baseline, at the end of week 12, at the end of week 24, and at 7 and 30 days during recovery. Exercise programs included a treadmill running protocol, three times a week, at an intensity >70% to 85% of maximal oxygen consumption. RESULTS: The exercise group reported significantly attenuated inflammatory biomarkers (interleukin-6 and tumour necrosis factor-alpha), oxidative stress (reactive oxygen species and malondialdehyde), and antioxidants (superoxide dismutase, catalase, and total antioxidant capacity) (P < 0.05), and these changes coincided with favorable improvements in semen parameters, sperm DNA integrity, and pregnancy rate (P < 0.05). These findings indicate that our exercise training program was adequate to elicit improvements in markers of male reproductive function in infertile patients. CONCLUSIONS: We concluded that a high-intensity exercise program could be recommended as an adjunct lifestyle approach to male factor infertility treatment or used in combination with other therapies. PMID- 28625283 TI - Uterine and Ovarian Carcinosarcomas: Do They Behave Similarly? AB - OBJECTIVE: We aimed to compare the clinicopathologic characteristics, recurrence patterns, and survival of patients with ovarian carcinosarcomas (OCs) and uterine carcinosarcomas (UCs). METHODS: Patients who were diagnosed with UCs or OCs on the basis of final pathology reports and who underwent surgery between January 1993 and January 2015 were included in the study. Data of patients were obtained from Gynecological Oncology Clinic electronic database and patient files. RESULTS: The study included 101 and 21 patients who underwent surgery for UCs and OCs, respectively. Forty percent and 67% of patients who had UCs and OCs, respectively, experienced lymph node metastasis (P = 0.051). Median follow-up time was 12 months (range, 1-158 months) for patients with UCs and 24 months (range 1-154 months) for patients with OCs. Recurrence developed outside the abdomen in 58% of patients with UCs and in 10% of patients with OCs (P = 0.005). Median time to recurrence was 9 months (range 3-58 months) in patients with UCs, whereas it was 18 months (range 11-72 months) in patients with OCs (P = 0.002). Five-year disease-free survival was 34% and 19% for patients with UCs and OCs, respectively (P = 0.90). Five-year overall survival was 56% for patients with UCs and 54% for patients with OCs (P = 0.51). CONCLUSION: We found that UCs recurred earlier and extra-abdominally. Recurrence pattern should be kept in mind during the planning of adjuvant therapies for these patients. PMID- 28625284 TI - Gender of Provider-Barrier to Immigrant Women's Obstetrical Care: A Narrative Review. AB - OBJECTIVE: To explore the preference for female obstetrician/gynaecologists among immigrant women, and providers' understandings of these preferences, to identify challenges and potential solutions. METHODS: Five databases (Medline, Embase, CINAHL, Global Health, and Scopus) were searched using combinations of search terms related to immigrant, refugee, or Muslim women and obstetrics or gynaecological provider gender preference. STUDY SELECTION: Peer reviewed, English-language articles were included if they discussed either patient or provider perspectives of women's preference for female obstetrics or gynaecological care provider among immigrant women in Western and non-western settings. After screening, 54 met inclusion criteria and were reviewed. DATA EXTRACTION: Studies were divided first into those specifically focusing on gender of provider, and those in which it was one variable addressed. Each category was then divided into those describing immigrant women, and those conducted in a non Western settings. The research question, study population, methods, results, and reasons given for preferences in each article were then examined and recorded. CONCLUSION: Preference for female obstetricians/gynaecologists was demonstrated. Although many will accept a male provider, psychological stress, delays, or avoidance in seeking care may result. Providers' views were captured in only eight articles, with conflicting perspectives on responding to preferences and the health system impact. PMID- 28625285 TI - Primary Dysmenorrhea. PMID- 28625286 TI - No. 345-Primary Dysmenorrhea Consensus Guideline. AB - OBJECTIVE: This guideline reviews the investigation and treatment of primary dysmenorrhea. INTENDED USERS: Health care providers. TARGET POPULATION: Women and adolescents experiencing menstrual pain for which no underlying cause has been identified. EVIDENCE: Published clinical trials, population studies, and review articles cited in PubMed or the Cochrane database from January 2005 to March 2016. VALIDATION METHODS: Seven clinical questions were generated by the authors and reviewed by the SOGC Clinical Practice-Gynaecology Committee. The available literature was searched. Guideline No. 169 was reviewed and rewritten in order to incorporate current evidence. Recommendations addressing the identified clinical questions were formulated and evaluated using the ranking of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: Primary dysmenorrhea is common and frequently undertreated. Effective therapy is widely available at minimal cost. Treatment has the potential to improve quality of life and to decrease time lost from school or work. GUIDELINE UPDATE: This guideline is a revision and update of No. 169, December 2005. SPONSORS: SOGC. SUMMARY STATEMENTS: RECOMMENDATIONS. PMID- 28625287 TI - ? PMID- 28625288 TI - No. 96-The Reproductive Care of Women Living With Hepatitis C Infection. AB - OBJECTIVE: hepatitis C virus (HCV) is an increasingly important public health problem worldwide. Health care workers providing care to women of childbearing age are uniquely placed in their practices to identify a significant proportion of at-risk patients and to provide appropriate screening and counselling. The primary objective of this guideline is to provide accurate, current information to those offering reproductive care to women living with HCV. This document is also intended to raise awareness of HCV in both the medical and general populations. OPTIONS: the areas of clinical practice considered in formulating this guideline are disease prevention, targeted screening of individuals at risk of contracting HCV, management of identified patients in the context of reproductive care, and the appropriate referral of patients to those with particular expertise. OUTCOMES: implementation of these guidelines should facilitate identification of infected individuals. It should also result in improved physical and mental well-being for patients and their families and reduction in transmission rates. EVIDENCE: the literature between 1966 and 2000, including non- English language publications, was extensively searched utilizing Medline. A multidisciplinary group consisting of experts within the fields of obstetrics and gynaecology, infectious diseases, hepatology, and public health convened in Montreal in February 2000. The working group also included a patient and a representative from the Hepatitis C Society of Canada. The level of evidence for the recommendations has been determined using the criteria described by the Canadian Task Force on Periodic Health Examination. BENEFITS, HARMS AND COSTS: the public health benefits of increased identification of at-risk individuals, diagnosis, treatment, implementation of risk reduction behaviours, and reduced transmission rates, both on an individual and at the community level, are significant. However, it must be remembered that the diagnosis of a chronic disease may have far reaching effects for the individual patient and her family. RECOMMENDATIONS: VALIDATION: references were collected through Medline searches and comparison made to existing current guidelines for assessment of consistency. External reviewers expert in their field were also consulted. PMID- 28625289 TI - No. 207-Genital Herpes: Gynaecological Aspects. AB - OBJECTIVE: The purpose of this guideline is to provide recommendations to gynaecology health care providers on optimal management of genital herpes. OUTCOMES: More effective prevention of complications and transmission of genital herpes. EVIDENCE: Medline was searched for articles published in French and English related to genital herpes and gynaecology. Additional articles were identified through the references of these articles. All study types and recommendation reports were reviewed. RECOMMENDATIONS: PMID- 28625290 TI - ? PMID- 28625291 TI - ? PMID- 28625292 TI - No. 185-HIV Screening in Pregnancy. AB - OBJECTIVE: The purpose of this guideline is to provide recommendations to obstetric health care providers and to minimize practice variations for HIV screening, while taking provincial and territorial recommendations into account. OUTCOMES: The risk of transmission of HIV from mother to fetus is significant if the mother is not treated. The primary outcome of screening for and treating HIV in pregnancy is a marked decrease in the rate of vertical transmission of HIV from mother to fetus. Secondary outcomes include confirmation of HIV infection in the woman, which allows optimization of her health and long-term management. EVIDENCE: The Cochrane Library and Medline were searched for English-language articles published related to HIV screening and pregnancy. Additional articles were identified through the references of these articles. All study types were reviewed. RECOMMENDATIONS: PMID- 28625293 TI - ? PMID- 28625294 TI - No. 192-Fetal Sex Determination and Disclosure Policy Statement. PMID- 28625295 TI - ? PMID- 28625296 TI - No. 193-Laparoscopic Entry: A Review of Techniques, Technologies, and Complications. AB - OBJECTIVE: To provide clinical direction, based on the best evidence available, on laparoscopic entry techniques and technologies and their associated complications. OPTIONS: The laparoscopic entry techniques and technologies reviewed in formulating this guideline include the classic pneumoperitoneum (Veress/trocar), the open (Hasson), the direct trocar insertion, the use of disposable shielded trocars, radially expanding trocars, and visual entry systems. OUTCOMES: Implementation of this guideline should optimize the decision making process in choosing a particular technique to enter the abdomen during laparoscopy. EVIDENCE: English-language articles from Medline, PubMed, and the Cochrane Database published before the end of September 2005 were searched, using the key words laparoscopic entry, laparoscopy access, pneumoperitoneum, Veress needle, open (Hasson), direct trocar, visual entry, shielded trocars, radially expanded trocars, and laparoscopic complications. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on the Periodic Health Examination. RECOMMENDATIONS AND SUMMARY STATEMENT. PMID- 28625297 TI - ? PMID- 28625299 TI - Managing major obstetric haemorrhage: Pharmacotherapy and transfusion. AB - Major obstetric haemorrhage is a leading cause of maternal mortality. A prescriptive approach to early recognition and management is critical to improving outcomes. Uterine atony is the primary cause of post-partum haemorrhage. First-line prevention and treatment include the administration of uterine tonic agents; other conservative measures include uterine cavity tamponade and uterine compression sutures. Interventional radiology procedures have been used for both prophylaxis and treatment, but a hysterectomy may be necessary if conservative measures fail. Assessment of anaemia and coagulation status is an important aspect of the management of haemorrhage. Hypofibrinogenaemia is a predictor of severe haemorrhage. Early and empiric use of fixed transfusion red blood cell:plasma:platelet ratios is controversial and may not be justified for all causes of haemorrhage. Cell salvage may be used safely in obstetric haemorrhage. Goal-directed therapy using point-of-care testing (e.g. thromboelastography) has not been well studied but holds promise for individualising resuscitation measures. PMID- 28625300 TI - Preeclampsia in 2017: Obstetric and Anaesthesia Management. AB - In many centres, anaesthesia now incorporates perioperative medicine. Preeclampsia is a perioperative medical challenge requiring a multi-disciplinary team. New definitions stress the rapid progression of the disease and highlight the importance of early detection. Anaesthesiologists should understand the pathophysiology of the disease and develop the ultrasound skills required to assist in the assessment of disease severity. This facilitates the choice of anaesthesia method and perioperative management in complicated cases. Regional anaesthesia remains central, but there are important developments in the practice of general anaesthesia, if indicated. Appropriate haemodynamic monitoring should be established. Anaesthesiologists should also lead the resuscitation team in the management of cardiorespiratory failure and coagulopathy. PMID- 28625301 TI - Maintenance of epidural labour analgesia: The old, the new and the future. AB - Neuraxial analgesia is considered the gold standard in labour analgesia, providing the most effective pain relief during childbirth. Improvements have enhanced the efficacy and safety of epidural analgesia through better drugs, techniques and delivery systems. This review describes the history of epidural labour analgesia and recent improvements in labour epidural analgesia. We discuss the role of the combined spinal epidural technique, low-concentration local anaesthetic-opioid epidural solutions, patient-controlled epidural analgesia, and programmed intermittent or automated mandatory boluses in the maintenance of epidural labour analgesia. We also review the newer interactive techniques for drug delivery, such as computer-integrated patient-controlled epidural analgesia and variable frequency automated mandatory bolus. Finally, we discuss future clinical research developments, including the use of data analytics and long-term outcomes associated with childbirth pain management. PMID- 28625302 TI - Pharmacogenetics in obstetric anesthesia. AB - The 21st century has been billed as the era of "precision/personalized medicine." Genetic investigation of clinical syndromes may guide therapy as well as reveal previously unknown biological or pharmacological pathways that may result in novel drug therapies. Several clinical issues in obstetrics and obstetric anesthesiology have been targets for genetic investigations. These include evaluation of the genetic effects on preterm labor and the progression of labor, spinal anesthesia-induced hypotension and the response to medications used to treat hypotension, and the effect of gene variants on pain and analgesic responses. Most studies have examined specific single nucleotide polymorphisms. Findings have revealed modest effects of genetic variation without tangible impact on current clinical practice. Over the next decade, increased availability of whole exome and genome sequencing, epigenetics, large genetic databases, computational biology and other information technology, and more rapid methods of real-time genotyping may increase the impact of genetics in the clinical arena of obstetrics and obstetric anesthesia. PMID- 28625303 TI - Parenteral opioid analgesia: Does it still have a role? AB - Parenteral opioids have been used in labour analgesia for many years, but the ideal opioid in this setting is yet to be found. We review the properties of currently used opioids, their analgesic properties and side effects to mother and foetus. Parenteral opioids can be administered as intermittent boluses or through a patient-controlled intravenous administration system. A wide range of opioid drugs are currently used and provide a variable degree of analgesia. All opioids can cause unwanted maternal side effects such as nausea, vomiting, sedation and respiratory depression. They cross the placenta and have the potential to cause neonatal respiratory depression. Remifentanil patient-controlled intravenous analgesia is becoming increasingly available and popular on some delivery suites. It can provide adequate analgesia and is useful when epidural analgesia is contraindicated. Remifentanil patient-controlled analgesia requires close monitoring in an environment familiar with the technique to avoid maternal hypoxia due to respiratory depression. PMID- 28625304 TI - Any news on the postdural puncture headache front? AB - Unintentional dural puncture followed by postdural puncture headache is a well known complication following neuraxial labor analgesia. Risk factors for the development of postdural puncture headache may be related to the patient's history and characteristics, the neuraxial technique, and obstetrical events. The diagnosis of postdural puncture headache is usually made depending on the clinical presentation (orthostatic headache after a neuraxial procedure). Occasionally, neuroimaging and neurological consultation are warranted. Complications following postdural puncture headache may include transient or permanent hypoacusis, cranial nerve palsies, subdural hematoma, and chronic headache. Evidence is limited regarding the safety and effectiveness of different interventions aimed to prevent or treat postdural puncture headache. PMID- 28625305 TI - Decision-to-delivery interval: Is 30 min the magic time? What is the evidence? Does it work? AB - Emergency caesarean section is required when delivery can reduce the risk to the life of the mother or foetus. When a caesarean section is indicated for foetal compromise, a decision-to-delivery interval of 30 min (or less) has been suggested as the ideal time frame within which an obstetric team should achieve delivery. In theory, a short decision-to-delivery interval may minimise intra uterine hypoxia and improve neonatal outcome. Current medical evidence does not support this time frame. There are certain indications for caesarean section that necessitate a much shorter decision-to-delivery interval, but evidence suggests that the majority of neonates may be safely delivered within a longer interval of time. Current tools available for the diagnosis of foetal distress are imperfect, and the concept of foetal distress is poorly defined. Future research should focus on finding accurate means of diagnosing foetal distress in labouring women and establishing universally agreed evidence-based decision-to-delivery targets without compromising maternal or foetal safety. PMID- 28625306 TI - Spinal-induced hypotension: Incidence, mechanisms, prophylaxis, and management: Summarizing 20 years of research. AB - Hypotension commonly occurs in parturients undergoing cesarean delivery under spinal anesthesia. This leads to maternal and neonatal adverse outcomes, including maternal nausea and vomiting and fetal acidosis, and might even lead to cardiovascular collapse if not treated. Arterial dilatation and reduction in systemic vascular resistance are the major contributors to spinal-induced hypotension. Therefore, strategies aimed at expanding the intravascular volume with fluid loading or increasing venous return with lower extremities mechanical compression and lateral tilt have had limited effectiveness in the management of spinal-induced hypotension. Vasopressors are therefore the mainstay for the prophylaxis and treatment of spinal-induced hypotension. Phenylephrine is associated with improved neonatal acid-base status and a lower risk of maternal nausea and vomiting compared with ephedrine and is now considered the vasopressor of choice in obstetric patients. This review discusses the various strategies for managing spinal-induced hypotension with a particular emphasis on the optimal use of vasopressors. PMID- 28625307 TI - Postcesarean delivery analgesia. AB - Effective pain management should be a key priority in women undergoing cesarean delivery. Suboptimal perioperative pain management is associated with chronic pain, greater opioid use, delayed functional recovery, impaired maternal-fetal bonding, and increased postpartum depression. Severe acute postoperative pain is also strongly associated with persistent pain after cesarean delivery. Multimodal analgesia is the core principle for cesarean delivery pain management. The use of neuraxial morphine and opioid-sparing adjuncts such as scheduled nonsteroidal anti-inflammatory medications and acetaminophen is recommended for all women undergoing cesarean delivery with neuraxial anesthesia unless contraindicated. Additional analgesic and opioid-sparing options such as wound instillation of local anesthetics, transversus abdominis plane blocks, dexamethasone, gabapentin, and ketamine may be used as appropriate in women at risk of severe postoperative pain or in women whose postoperative pain is not well controlled despite standard analgesic regimes. PMID- 28625308 TI - The role of ultrasonography in obstetric anesthesia. AB - Ultrasonography is increasingly being viewed as an everyday tool in obstetric anesthesia. For the administration of spinal or epidural anesthesia, it reduces needle redirection attempts in patients with difficult anatomy. In the less frequent scenario of a collapsed patient, it helps with assessment in the form of transthoracic echocardiography. Abdominal blocks require ultrasound guidance for safe and anatomically correct placement. Accurate assessment of gastric volume status with ultrasound would be a useful everyday skill if it is adopted into mainstream practice. We provide a summary of current opinions on the role of ultrasound in practice and highlight the potential for its future use in obstetric anesthesia. PMID- 28625309 TI - Maternal mortality and the role of the obstetric anesthesiologist. AB - Maternal mortality is increasing in the United States and remains unacceptably high in many parts of the world. Pre-existing conditions and social determinants of health frequently contribute to maternal death. General solutions to enhance maternal safety focus on systems to identify women at high risk and to tailor the management before, during, and after pregnancy. This review highlights condition specific solutions for the leading etiologies of maternal death, including cardiac disease, sepsis, hemorrhage, venous thromboembolism, hypertensive disorders of pregnancy, and amniotic fluid embolism. Although anesthesia is an exceedingly rare cause of maternal death, specific hazards remain, including airway management, high neuraxial block, and unintentional dural puncture. The review concludes with an overview of strategies to create an institutional culture of both safety and equity, including multidisciplinary team training, simulation, shared decision-making, family-centered care, and serious morbidity review. PMID- 28625310 TI - ? AB - UPDATED 2016 RECOMMENDATIONS FOR THE CLINICAL PRACTICE OF NICE/SAINT-PAUL-DE VENCE IN OVARIAN CANCER AND ADVANCED CERVICAL CANCER: Since the first edition of the 2012-2013 Clinical Practice Recommendations Nice-Saint-Paul for gynecological cancers, the management of ovarian cancer has become more complex with a better definition of histological subtypes of ovarian cancers, the update of the anatomo clinical classifications, the evolution of the recommended quality criteria for surgery. In addition, the integration of new medical options, such as PARP inhibitors, requires us to review our management of ovarian cnacer patients (including early systematic oncogenetic research of homologous recombination pathway deficiency). Similarly, medical treatment has evolved in advanced cervical cancer with the new option of bevacizumab therapy. On behalf of the GINECO group, we have updated the guidelines for ovarian epithelial cancer (excepted rare tumors) and advanced cervical cancer in order to allow rapid dissemination of the latest advances to the medical community in order to adjust the daily practice. PMID- 28625311 TI - ? AB - BRCA MUTATED OVARIAN CARCINOMAS: GENETIC COUNSELING AND PARP INHIBITORS PRESCRIPTION: Upon the availability of the PARP inhibitors in relapsed ovarian carcinoma, the pathways of the oncogenetic counseling were modified. Any research for a constitutional alteration of the BRCA1 and BRCA2 genes must be accompanied by an oncogenetic counseling. BRCA testing is recommended from the diagnosis to every woman with an ovarian or fallopian tube or peritoneum of high grade adenocarcinoma, whatever the age at the diagnosis and her family history. In case of sensitive relapse or potential inclusion in a clinical trial and in the absence of preliminary constitutional research, the oncogenetic counseling is organized according to a fast track pathway and a somatic analysis can be realized in parallel. Today, olaparib is indicated for patients with a high grade serous ovarian or fallopian tube or peritoneum adenocarcinoma, with deleterious mutation of BRCA genes (constitutional or somatic), and in sensitive platinum relapse, and in maintenance therapy after a response to chemotherapy including platinum. The indication of a treatment with olaparib can be discussed in multidisciplinary staff for the other non-serous high grade ovarian carcinoma if all other criteria are gathered. Olaparib is prescribed in monotherapy, to start at the latest 8 weeks after the last chemotherapy cycle, under narrow surveillance, because of its gastrointestinal and hematologic toxicities. PMID- 28625312 TI - ? AB - TREATMENT FOR PLATINUM SENSITIVE RELAPSES OF OVARIAN CANCER: Despite large improvements in treatment efficacy, the cure rate of ovarian cancer has not radically changed. Relapses both remain frequent and are still synonymous with chronic disease. Most of them are platinum-sensitive, and can be successfully treated with successive lines of chemotherapy. Surgery may have a role to play but its real impact, population selection criteria, and adequate timing still have to be established. Regarding medical treatments, the availability of new targeted therapeutics, such as bevacizumab and olaparib, complicates decision making. Moreover, allergic drug reactions to platins worsen treatment management. In practice, treatment decision making integrates patient profiles and wishes, types and numbers of previous medical treatments along with BRCA status. PMID- 28625313 TI - ? AB - OVARIAN CANCER: EARLY RELAPSE: Early relapse (primary or secondary) is defined by relapse of disease less than 6 months before the last infusion of chemotherapy (with a platinum compound). There is no carcinological surgical indication. Disease should be treated with a non-platinum single agent (pegylated liposomal doxorubicin, weekly paclitaxel, gemcitabine or topotecan). Bevacizumab can be added if patients have not already received it (level of proof 1, grade A). PMID- 28625314 TI - ? AB - METASTATIC OR RECURRENT CERVICAL CANCER/TREATMENT: The prognosis of metastatic or recurrent cervical cancer remains dismal. The poor chemosensitivity of this tumor is an issue, especially in case of recurrence in irradiated fields. Still, chemotherapy has shown some efficacy, and mostly consists in platinum-based doublets. The addition of bevacizumab to chemotherapy has been recently validated. However, most of these patients present with complex clinical situations and the treatment strategy has to be discussed in multidisciplinary tumor boards. PMID- 28625315 TI - ? AB - OVARIAN CANCER, FIRST LINE, MULTIDISCIPLINARITY: Recommendations for the clinical practice of Nice-Saint-Paul de Vence The treatment of advanced epithelial ovarian cancer is multidisciplinary involving surgical teams and surgery and medical oncology, experienced in the management of this disease, following published quality criteria. The strategy must be validated in multidisciplinary consultation meeting (RCP) before any treatment. The pre-therapeutic assessment includes the histological diagnosis, evaluation of the tumor extension (biological assessment, markers, imaging, laparoscopy), assessment of the general state (operability), in order to answer the question of feasibility of an initial optimal surgery. The standard treatment involves complete surgical resections of the lesions by median laparotomy, followed by adjuvant chemotherapy based on carboplatin and paclitaxel, six cycles with the possibility of treatment with bevacizumab during adjuvant treatment and in maintenance. If complete surgery is not feasible as a result of the initial assessment, interval debulking surgery is considered after 3 to 4 courses of induction chemotherapy. PMID- 28625316 TI - Mesenchymal Stem Cell-based Therapy as a New Horizon for Kidney Injuries. AB - Today, the prevalence of kidney diseases is increasing around the world, but there has still been no effective medical treatment. The therapeutic choices are confined to supportive cares and preventive strategies. Currently, mesenchymal stem cells (MSCs)-based cell therapy was proposed for the treatment of kidney injuries. However, after the transplantation of MSCs, they are exposed to masses of cytotoxic factors involving an inflammatory cytokine storm, a nutritionally poor hypoxic environment and oxidative stresses that finally lead to minimize the efficacy of MSCs based cell therapy. Therefore, several innovative strategies were developed in order to potentiate MSCs to withstand the unfavorable microenvironments of the injured kidney tissues and improve their therapeutic potentials. This review aims to introduce MSCs as a new modality in the treatment of renal failure. Here, we discuss the clinical trials of MSCs-based therapy in kidney diseases as well as the in vivo studies dealing with MSCs application in kidney injuries mainly from the proliferation, differentiation, migration and survival points of view. The obstacles and challenges of this new modality in kidney injuries are also discussed. PMID- 28625317 TI - Sphingosine 1-Phosphate Postconditioning Protects Against Myocardial Ischemia/reperfusion Injury in Rats via Mitochondrial Signaling and Akt-Gsk3beta Phosphorylation. AB - BACKGROUND AND AIMS: Although preconditioning of sphingosine 1-phosphate (S1P) has been shown to protect myocytes from hypoxia reoxgenation injury in vitro, the role of S1P postconditioning on myocardial ischemia reperfusion injury (MIRI) in vivo and its related mechanism are unknown. The aim of this study was to investigate the protective role of sphingosine 1-phosphate (S1P) postconditioning in MIRI via its effects on mitochondrial signaling and Akt/Gsk3beta phosphorylation. METHODS: Rats were subjected to MIRI, consisting of 30 min of ischemia followed by 120 min of reperfusion, with S1P administered at the beginning of the reperfusion. Myocardial infarct size and apoptotic index were measured by triphenyltetrazolium (TTC) and terminal deoxynucleotide transferase dUTP nick-end labeling (TUNEL) assays, respectively. Akt and Gsk3beta phosphorylation, caspase-3 cleavage, and cytochrome c translocation were assessed by western blot. Mitochondrial permeability transition pore (MPTP) opening and mitochondrial membrane potential (MMP, DeltaPsi) were also examined to determine overall mitochondrial function. RESULTS: S1P postconditioning significantly decreased myocardial infarct size and apoptosis, as well as enhanced Akt and Gsk3beta phosphorylation, attenuated caspase-3 cleavage and cytosolic cytochrome c translocation, and inhibited MPTP opening, which subsequently preserved Deltapsi. Electron microscopy also confirmed that S1P helped maintain myocardial mitochondria integrity. Moreover, the protective effects of S1P treatment were blocked by cotreatment with a PI3K inhibitor, LY294002. CONCLUSIONS: These results suggest that S1P postconditioning protects against MIRI by regulating mitochondrial signaling and Akt/Gsk3beta phosphorylation. PMID- 28625318 TI - Prognostic Value of Different Allelic Polymorphism of Aldosterone Synthase Receptor in a Congestive Heart Failure European Continental Ancestry Population. AB - : Aldosterone synthase (CYP11B2) is as an 9-exon gene on chromosome 8q22 and exists as a common single nucleotide polymorphism C-T transition for position 344. The aim of this study was to assess the -344T/C polymorphism of the aldosterone synthase promoter in a European continental ancestry congestive heart failure (CHF) population. METHODS: Patients discharged after an acute decompensation were enrolled and underwent echocardiography, determination of BNP, evaluation of non-invasive cardiac outputs and determination of -344 T/C SNP in the aldosterone synthase gene. RESULTS: 175 patients (137 male; age 69.9 +/- 10.2 years) were enrolled. The genotype distribution of -344 T/C SNP demonstrated a TT genotype in 61 patients (34.9%), CT in 80 (45.7%) and finally CC in 34 (19.4%) CHF patients. According to presence of C allele, CHF patients were divided into C group (-CT/CC genotype, 114 subjects) and T Group (-TT genotype, 61 subjects). The two groups did not differ in term of age, non-invasive cardiac output at rest, creatinine level or end-systolic or diastolic left ventricle diameter, LVEF and BNP. In group C patients in comparison than in group T a higher degree of disability (Barthel Index p = 0.004), NYHA class (p = 0.02) and a lower cardiac index (p = 0.01) emerged. Moreover, the two groups showed a similar clinical outcome (death for any cause/hospital readmission for CHF) at 48 month follow-up (p = 0.16; log-rank 1.99). CONCLUSIONS: In European continental ancestry patients the C allele (CC or CT) at -344T/C SNP in the aldosterone synthase gene does not significantly influence clinical prognosis of CHF. PMID- 28625319 TI - Polymorphic Variants rs3088442 and rs2292334 in the Organic Cation Transporter 3 (OCT3) Gene and Susceptibility Against Type 2 Diabetes: Role of their Interaction. AB - AIMS: In this study, we investigated whether two common variants (rs3088442G>A and rs2292334G>A) in the organic cation transporter 3 (OCT3) gene, a high capacity transporter widely expressed in various tissues, affect susceptibility to type 2 diabetes (T2D) in patients newly diagnosed with T2D. METHODS: We performed a study with 150 newly diagnosed patients with T2D and 152 controls. The genetic analyses were performed using the restricted fragment length polymorphism (RFLP) after PCR amplification. RESULTS: For the rs3088442G>A variant, A allele carriers had a significantly lower odds ratio (OR) vs. GG homozygotes in the BMI <30 kg/m2 group (OR = 0.23, p <0.001) compared with the BMI >=30 kg/m2 group (OR = 0.67, p = 0.34). When ORs were adjusted for BMI, age, sex, and blood pressure, our findings showed that the overexpression of the A allele of the rs3088442G>A variant was associated with a decreased risk of T2D (OR = 0.016, p <0.001). A Bayesian logistic model revealed that the interaction of two variants studied were significantly associated with a decreased risk of T2D (OR = 0.61, p = 0.03). CONCLUSIONS: The present study has identified the protective effect of the variant rs3088442G>A in the 3'-untranslated region of the OCT3 gene in susceptibility to T2D, and that the protective role is maintained in the presence of risky alleles of the variant rs2292334G>A. The association of the A allele of rs3088442G>A with T2D become weaker in obese people than that of non-obese. If confirmed in other populations, the rs3088442G>A variant as a genetic marker may potentially assist in the identification of individuals at an increased risk of T2D. PMID- 28625320 TI - Expression of Jagged1/Notch3 Signaling Pathway and their Relationship with the Tumor Angiogenesis in TNBC. AB - BACKGROUND AND AIMS: Jagged1/Notch3 signaling pathway plays a key role in angiogenesis of breast cancer, but little is known in TNBC. This study was designed to investigate the expression of Jagged1/Notch3 mRNA and protein in TNBC, analyze their correlations with clinicopathological characteristics and prognosis. Moreover, the interrelationship among Jagged1/Notch3 and VEGF was initially evaluated. METHODS: Jagged1/Notch3 mRNA and protein expression levels were determined by Q-RT-PCR and Western blotting. Additionally, Immunohistochemistry for Jagged1/Notch3 was detected by Ventana platform, VEGF and CD34 was performed using the EnVision/HRP technique. RESULTS: mRNA transcriptionof Jagged1/Notch3 was in accord with protein expression. TNBC patients with positive Jagged1 expression had poorer DFS (p = 0.008) and OS (p = 0.004). Jagged1 expression was independent predictors of OS (p = 0.038). The expression of VEGF was positively correlative to MVD (p = 0.018), MVD was significantly associated with Jagged1 (p <0.0001) and Notch3 (p <0.0001). The expression of Jagged1/Notch3 has no correlation with VEGF, only in positive VEGF expression of TNBC patients Jagged1/Notch3 had influence on DFS and OS (p <0.05). CONCLUSION: Jagged1/Notch3 was -expressed at both the mRNA and protein levels, Jagged1 served as an independent predictor of poor prognosis. We speculate that there is a cross-talk between Jagged1/Notch3 and VEGF in TNBC angiogenesis. Jagged1/Notch3 is expected to be an important signaling pathway for TNBC progression and a potential target for TNBC neovascularization therapy. PMID- 28625321 TI - Catechol-O-methyltransferase Gene Polymorphism (Val158Met) and Development of Pre eclampsia. AB - OBJECTIVES: Catechol-O-methyltransferase (COMT) is a key enzyme in degradation pathways of estrogens and catecholamines. The present meta-analysis was done to elucidate the association of COMT Val158Met polymorphism with pre-eclampsia among pregnant women. METHODS: A literature search was conducted in electronic databases including PubMed, Scopus, Elsevier, Springer and Google Scholar to find eligible studies. The pooled odds ratios (ORs) with 95% confidence intervals were calculated under dominant, recessive, co-dominant, and allelic models. RESULTS: This meta-analysis included 6 eligible studies consisting 2596 cases and 4223 controls. The ORs for the COMT G472A polymorphism and pre-eclampsia were indicative of positive association under several genetic models. The results indicated that COMT Val158Met polymorphism was significantly associated with the increased risk of pre-eclampsia in recessive model (AA vs. AG + GG: OR = 1.522 [95% CI: 1.089-2.127]; p = 0.014), co-dominant model (AA vs. GG: OR = 1.605 [95% CI: 1.102-2.336]; p = 0.014), and allelic model (A vs. T: OR = 1.200 [95% CI: 1.021-1.402]; p = 0.021). CONCLUSIONS: In summary, COMT Val158Met polymorphism is positively associated with the increased risk of pre-eclampsia among pregnant women, especially the homozygous carriers. It could be of value to investigate its association with pre-eclampsia in combination with additional risk factors. However, very large studies with different ethnic population are required to accurately demonstrate the role of this candidate gene in development of pre eclampsia. PMID- 28625322 TI - Effect of B Vitamins from Diet on Hypertension. AB - BACKGROUND: In western populations, a higher level of dietary B vitamins intake has been associated with a lower risk of hypertension. However, data in Chinese is limited, whose B vitamins consumption is low and rates of hypertension are high. AIM OF THE STUDY: To investigate whether the three B vitamins are associated with hypertension in rural Chinese. METHODS: Cross-sectional survey among 2241 rural Chinese aged 18-80 years was conducted in northwestern China in 2010. Blood pressure was measured by trained medical staff and dietary nutrients were assessed with a semiquantitative food frequency questionnaire. RESULTS: 592 cases of hypertension were newly diagnosed. The deficiency proportions were 20.5% for vitamin B-6, 43.9% for folate and 98.5% for B-12. For females, participants in the highest quartile of B-6 intake had a significantly lower risk of hypertension (OR = 0.69; 95% CI: 0.50-0.93; p for trend <0.05). For males, the multivariable OR for the same comparison was 0.75 (95% CI: 0.56-0.99, p for trend >0.05). No significant associations were observed between B-12, folate intake and hypertension. For females, the highest quartile of both folate and B-6 intake was associated with a reduced risk of hypertension (OR = 0.53; 95% CI: 0.29-0.89), compared with in the middle quartile of both vitamins. CONCLUSIONS: Higher intake of vitamin B-6 is independently associated with lower risk of hypertension in Chinese rural adults. Among females with high folate intake, the association between B-6 and hypertension was strongest. Additional studies are warrant to establish the causal inference. PMID- 28625323 TI - Assessment of Sodium and Potassium Intake by 24 h Urinary Excretion in a Healthy Mexican Cohort. AB - BACKGROUND AND AIMS: A high dietary sodium intake and a low potassium intake are associated with adverse cardiovascular health. Data on these nutrients consumption in Mexico is limited. The aim of this study was to assess sodium and potassium intake by 24 h urinary excretion in a clinically healthy Mexican population. We additionally explored their association with blood pressure. METHODS: 711 clinically healthy participants aged 20-50 years old recruited in the Tlalpan 2020 cohort from September 2014-December 2015, were included in this cross-sectional analysis. All participants provided a 24 h urine sample and underwent anthropometric, biochemical, and blood pressure evaluations. Univariate and multivariate linear regression analyses were used to assess the association of urinary sodium, potassium, and Na/K ratio with blood pressure. RESULTS: Mean (95% confidence interval [CI]) urinary sodium and potassium in the overall population was 3150.1 (3054.2-3246.0) mg/d and 1909.5 (1859.3-1959.6) mg/d, respectively. Overall, only 121 (17%) met the WHO recommendation for sodium intake (<2000 mg/d) and 16 (2.3%) met the goal for potassium intake (>=3510 mg/d). Urinary sodium (beta coefficient 1.3, 95% CI: 0.7, 1.8, p <0.001) and potassium (beta coefficient 2.1, 95% CI: 1.0, 3.2, p <0.001) were found to be associated with systolic blood pressure in the univariate analysis but not in the multivariate analysis. CONCLUSIONS: Sodium intake was higher and potassium intake was lower than the WHO recommendations in this healthy Mexican population. Sodium and potassium intakes were not associated with blood pressure at the mean levels of intake observed in this population, after adjusting for key variables. PMID- 28625324 TI - ESR2 Genetic Variants and Combined Oral Contraceptive Use Associated with the Risk of Stroke. AB - BACKGROUND AND AIM: There is accumulating evidence suggesting an important role of estrogen receptor-beta in the development of cardiovascular disease. The present study aims to investigate the relationship of estrogen receptor beta gene (ESR2) polymorphisms with stroke risk in Chinese women, and further evaluate the gene-environment interaction of ESR2 and combined oral contraceptive (COC) use on stroke risk. METHODS: A case-control study was conducted with 446 first-ever stroke patients and 864 control subjects recruited from our prospective female cohort. Four polymorphisms of ESR2 gene were genotyped, and the information of contraceptive use was obtained by a face-to-face interview. RESULTS: Women with rs1256065 CC genotype were at a 1.59 fold increased risk of stroke. Subtype analyses showed that the risk genotype of rs1256065 was associated with ischemic stroke, but not with hemorrhagic stroke. AA genotype of rs4986938 showed a significant correlation with an elevated risk of hemorrhagic stroke. COC users with rs1256065 CC genotype had a 2.36 fold increased risk of stroke, compared with the non-users with the wild-type genotype. Moreover, a significant multiplicative interaction on hemorrhagic stroke was detected between COC use and rs4986938 (pinteraction = 0.023). The risk of hemorrhagic stroke was significantly elevated among carriers of rs4986938 GA or AA genotype combined with COC use. No associations were observed for rs1256049 and rs1271572. CONCLUSIONS: ESR2 genetic polymorphisms were associated with the risk of first ever stroke in Chinese women, and the AA genotype of rs4986938 combined with COC use could significantly increase the risk of hemorrhagic stroke. PMID- 28625325 TI - Importance of CD117 in the Assignation of a Myeloid Lineage in Acute Leukemias. AB - The correct classification of acute leukemias (AL) is an essential part in the evaluation of any patient with this disease. Historically, CD117 has been an important asset in the diagnosis of patients with mixed-phenotype acute leukemia (MPAL). In an attempt to simplify the diagnosis of MPAL with fewer and more lineage specific markers, the World Health Organization (WHO) proposed in 2008 a new criteria for the diagnosis of this type of AL, which excluded CD117 from the myeloid markers that are utilized to diagnose MPAL. In order to assess whether CD117 is necessary in the diagnosis of MPAL, we evaluated the sensitivity and specificity of CD117 for acute myeloid leukemia (AML) in 331 patients with AL. The calculated sensitivity of CD117 for AML was 85.88% (103/120), while the specificity was 83.9% (177/211). Besides myeloperoxidase (MPO), which was used as the gold standard in differentiating AML from other type of ALs, the most specific markers for AML in our study were CD14 and CD64 (99.5 and 95.6%). Although the specificity of CD117 in this study is not as high as CD14 and CD64, markers concomitantly used in this this study and in the WHO classification, based on the results of other researches (i.e. the specificity of CD117 for AML was 100% in one study) and due to the fact that its specificity for AML in this study is relatively high, we recommend the use CD117 in assigning a myeloid lineage in MPAL. PMID- 28625326 TI - High Thyroid-stimulating Hormone Levels Increase Proinflammatory and Cardiovascular Markers in Patients with Extreme Obesity: Methodological Issues. PMID- 28625327 TI - Response: High Thyroid-stimulating Hormone Levels Increase Proinflammatory and Cardiovascular Markers in Patients with Extreme Obesity. PMID- 28625328 TI - Platelet-Rich Plasma for the Treatment of Photodamage of the Skin of the Hands. AB - BACKGROUND: Platelet-rich plasma (PRP) provides growth factors that stimulate fibroblast activation and induce the synthesis of collagen and other components of the extracellular matrix. The objective of this study was to evaluate the effect of PRP in the treatment of photodamage of the skin of the hands. MATERIAL AND METHODS: Experimental study enrolling persons with photoaged skin on the dorsum of the hands (Glogau photoaging scale, type III, or Fitzpatrick wrinkle classification, type II) were included between August 2012 and January 2013. A histological comparison was made of skin biopsies taken before and after the application of PRP to the skin of the dorsum of the hands. RESULTS: The mean (SD) age of the 18 women enrolled was 47.9 (4.3) years. Histological analysis showed an increase in the number of fibroblasts (P<.001), number of vessels (P<.001), and collagen density (P=.27). These changes produced significant improvements in the Fitzpatrick wrinkle and elastosis scale (P<.001) and in the Glogau photoaging scale (P=.01). CONCLUSIONS: PRP induced a reduction in the manifestations of skin aging, including an improvement in wrinkles and elastosis. PMID- 28625329 TI - Solitary Filiform Papule in the Left Nasal Vestibule. PMID- 28625330 TI - Dermoscopy of Erythromelanosis Follicularis Faciei et Colli. PMID- 28625331 TI - Management Of Early Stage Cervical Cancer: When Is Non-Randomized Data Good Enough? PMID- 28625332 TI - Considerations of developing an NGS assay for clinical applications in precision oncology: The NCI-MATCH NGS assay experience. AB - Next generation sequencing (NGS) technologies have been widely adapted in clinical oncology by utilizing the profiled genetic mutation information to select patients and to guide the choice of target therapy. To fulfill the regulatory compliance, development of an NGS assay that will be used in clinical trials requires an analytical validation to meet its intend clinical use. NCI MATCH trial is the largest precision oncology basket trial which uses a single NGS assay (NCI-MATHC NGS assay) to screen the actionable mutations in 6000 patients, who have relapsed/refractory solid tumors and lymphomas after standard systemic treatment, and assigns matched treatment. This article reviews on the critical considerations during development and validation of NGS assays as an investigational device for genomic based clinical trials and provides the experiences from the development of NCI-MATCH NGS assay. PMID- 28625333 TI - Liver metastases from gastric carcinoma: A Case report and review of the literature. AB - Gastric carcinoma (GC) is the fifth most common malignancy worldwide but the third leading cause of cancer death, and surgery remains the only curative treatment option. Prognosis of patients with liver metastases from gastric carcinoma (LMGC) is poor, and the optimal treatment of metastatic gastric cancer remains a matter of debate. In 2002, a 53-year-old male patient with GC and synchronous oligometastatic lesion in liver VIII segment underwent a total gastrectomy combined with metastasectomy. The pathologic diagnosis was stage IV gastric adenocarcinoma (pT3N2M1), which was treated with adjuvant chemotherapy (cisplatin, epirubicin, leucovorin, and 5-fluorouracil). In 2012, abdominal ultrasound and percutaneous liver biopsy revealed recurrence of the metastasis in the right liver lobe. Progression of the disease was observed after palliative chemotherapy (epirubicin, oxaliplatin, and capecitabine). Nevertheless, an extended right hemihepatectomy, with excision of segments 1, 4A, 5, 6, 7, and 8, was still performed. Pathologic examination confirmed large KRAS- and HER2 negative LMGC. The patient is alive and free of disease 47 months after the repeated hepatectomy and 13 years after removal of the primary GC and synchronous liver metastasis. Based on review of 27 articles, 5-year overall survival rate following gastrectomy and liver metastasectomy may reach 60%, with median survival time up to 74 months. Although the combination of aggressive surgical approach with systemic therapy for LMGC is controversial, it may allow favorable outcome. Careful selection of patients based on evaluable predictive factors for R0 surgical resection of both primary tumor and liver metastases can lead to cure, as shown in our case presentation, where a 10-year relapse-free survival was observed, followed by successful repeated hepatectomy due to liver metastases. PMID- 28625334 TI - Remembering our geriatric leaders of the past and looking to the future. PMID- 28625335 TI - Provision of information to consumers about the calorie content of alcoholic drinks: did the Responsibility Deal pledge by alcohol retailers and producers increase the availability of calorie information? AB - OBJECTIVES: Alcohol is a significant source of dietary calories and is a contributor to obesity. Industry pledges to provide calorie information to consumers have been cited as reasons for not introducing mandatory ingredient labelling. As part of the Public Health Responsibility Deal (RD) in England, alcohol retailers and producers committed to providing consumers with information on the calorie content of alcoholic drinks. This study examines what was achieved following this commitment and considers the implications for current industry commitments to provide information on alcohol calories. STUDY DESIGN: Analysis of RD pledge delivery plans and progress reports. Assessment of calorie information in supermarkets and in online stores. METHODS: (i) Analysis of the content of pledge delivery plans and annual progress reports of RD signatories to determine what action they had committed to, and had taken, to provide calorie information. (ii) Analysis of the availability of calorie information on product labels; in UK supermarkets; and on online shopping sites and websites. RESULTS: No information was provided in any of 55 stores chosen to represent all the main UK supermarkets. Calorie information was not routinely provided on supermarkets' websites, or on product labels. CONCLUSIONS: One of the stated purposes of the RD was to provide consumers with the information to make informed health-related choices, including providing information on the calorie content of alcoholic drinks. This study indicates that this did not take place to any significant extent. The voluntary implementation of alcohol calorie labelling by industry needs to continue to be carefully monitored to determine whether and how it is done. PMID- 28625336 TI - [The prevention and control of iatrogenesis require various fronts and alliances. The Spanish Society for Public Health and Health Administration (SESPAS) calls for collaboration]. PMID- 28625337 TI - Osteogenesis imperfecta - A clinical update. AB - Osteogenesis imperfecta (OI) is the most common inherited form of bone fragility and includes a heterogenous group of genetic disorders which most commonly result from defects associated with type 1 collagen. 85%-90% of cases are inherited in an autosomal dominant manner and are caused by mutations in the COL1A1 and COL1A2 genes, leading to quantitative or qualitative defects in type 1 collagen. In the last decade, defects in several other proteins involved in the normal processing of type 1 collagen have been described. Recent advances in genetics have called for reconsideration of the classification of OI, however, most recent classifications align with the classic clinical classification by Sillence. The hallmark of the disease is bone fragility but other tissues are also affected. Intravenous bisphosphonates (BPs) are the most widely used intervention, having significant favorable effects regarding areal bone mineral density (BMD) and vertebral reshaping following fractures in growing children. BPs have a modest effect in long bone fracture incidence, their effects in adults with OI concerns only BMD, while there are reports of subtrochanteric fractures resembling atypical femoral fractures. Other therapies showing promising results include denosumab, teriparatide, sclerostin inhibition, combination therapy with antiresorptive and anabolic drugs and TGF-beta inhibition. Gene targeting approaches are under evaluation. More research is needed to delineate the best therapeutic approach in this heterogeneous disease. PMID- 28625338 TI - Acute diplopia in the pediatric Emergency Department. A cohort multicenter Italian study. AB - BACKGROUND: Acute diplopia (AD) is an uncommon and distressing symptom of numerous ocular and neurological conditions, with potentially serious sequelaes. No data are present in pediatrics on the presentation and management of AD. AIM: This study investigated characteristics, etiology and health care utilization of the pediatric population with AD accessed to pediatric Emergency Departments (ED), trying to identify "red flags" associated with potentially life-threatening (LT) conditions. METHODS: We conducted a cohort multicenter study on children with AD in ten Italian hospitals. Patients were classified into diagnostic categories, comparing children with and without LT disease. RESULTS: 621 children presented AD at a rate of 3.6 per 10.000. The most frequent diagnosis among no-LT conditions (81.2%) were headache, ocular disorders and minor post-traumatic disease, while LT conditions (18.8%) were represented by brain tumors, demyelinating conditions, idiopathic intracranial hypertension and major post traumatic diseases. The LT group showed a significantly higher age, with the odds increased by 1% for each month of age. Monocular diplopia occurred in 16.1%, but unlike adult one-fifth presented LT conditions. Binocular diplopia, associated ocular manifestations or extraocular neurological signs were significantly more common in the LT group. At regression logistic analysis strabismus and ptosis were associated with LT conditions. CONCLUSION: The majority of children presented no-LT conditions and more than one-fourth of patients had headache. Monocular diplopia in the LT group was never isolated but associated with other signs or symptoms. Our study was able to identify some specific ocular disturbances or neurologic signs potentially useful for ED physician to recognize patients with serious pathologies. PMID- 28625339 TI - Non-invasive ventilation in emergency departments in public hospitals in Catalonia. The VENUR-CAT study. AB - OBJECTIVES: To know the implementation and characteristics of non-invasive ventilation (NIV) in the Emergency Departments (EDs) of public hospitals in Catalonia (Spain) and analyze possible differences based on the typology, degree of activity and the availability of an Intensive Care Unit (ICU) in the hospital. DESIGN: A non-interventional, descriptive study was carried out, using a structured questionnaire divided into 3sections: 1) professional experience and training; 2) devices used; and 3) clinical scenarios and the use of NIV. SETTING: Persons responsible for public EDs in Catalonia. RESULTS: Fifty-two of the 54 public EDs in Catalonia responded (96.3%). Fifty-one perform NIV, which is mainly initiated by emergency care physicians (78.5%); 66.7% maintain the patient in the ED until discharge; and in 43.1% of the cases the length of stay is>24h. Of the EDs, 39.2% have their own protocol, 35.3% of which are established by consensus with other departments (more frequently in non-county hospitals [P=.012], and centers with an ICU [P=.014]), while 25.5% have no protocol, and 43.1% register the activity. Training represents the greatest difficulty for the implementation of NIV, but 19.6% do not provide specific training. When support is needed, the main physician of reference is the intensivist (35.3%) (more frequently in non county hospitals [P=.012], and centers with an ICU [P=.002]). CONCLUSIONS: In most EDs in Catalonia, NIV is performed by emergency care physicians. Areas needing improvement include drainage of patients once NIV has been started, the promotion of protocols, registry of activity, and training of the healthcare professionals. PMID- 28625340 TI - Yes to mechanical ventilation, but not just any. PMID- 28625341 TI - Efficacy and Toxicity of Metronomic Chemotherapy in Metastatic Breast Cancer: Egyptian Experience. AB - BACKGROUND: Metronomic chemotherapy (MC) has shown efficacy in patients with metastatic breast cancer (MBC). We therefore tested the efficacy and toxicity of MC in pretreated MBC. PATIENTS AND METHODS: This prospective phase II study included 50 patients with heavily pretreated MBC who received MC in the form of continuous oral cyclophosphamide 50 mg/day and oral methotrexate 2.5 mg twice per day on days 1 and 2 every week. The primary end point was progression-free survival (PFS), whereas the secondary end points were response rate, overall survival (OS), and safety. RESULTS: Forty-eight patients were assessed. One patient achieved complete response and 10 patients had partial response, whereas 19 patients had stable disease. The median PFS was 5 months, whereas the median OS was 7 months. Patients with negative progesterone receptors, Eastern Cooperative Oncology Group performance status (PS) 1, achieving response, and those who developed leucopenia, neutropenia, and anemia had significant prolonged PFS, whereas patients with early stage at presentation, receiving < 5 previous treatment lines, achieving response, and experiencing anemia with MC had significant superior OS. In multivariate analysis, achieving response, PS 1, a longer time interval from initial diagnosis until starting MC, and anemia were independent prognostic factors for longer PFS. Initial stage at presentation, number of previous treatment lines, and response were independent prognostic factors for OS. CONCLUSIONS: MC is an attractive treatment approach that is effective and less toxic. There are certain groups of patients who seem to benefit more, especially those who experienced toxicity with treatment. Larger trials are warranted to assess this approach early in the course of the disease and with other more active agents. PMID- 28625342 TI - Dental investigation of mummies from the Capuchin Catacombs of Palermo (circa 18th-19th century CE). AB - Within the framework of the Sicily Mummy Project, the orofacial complex of a significant sample of individuals (n=111) from the Capuchin Catacombs of Palermo, Italy, was inspected. The heads and dentitions of the mummies were documented and the recorded findings described: the state of preservation of skeletal and soft tissues; dental pathologies such as carious lesions and alveolar bone loss; enamel hypoplasia; and ante- and post-mortem tooth loss. Despite limitations in data collection, the oral health of these mummies was assessed and the frequencies of pathologies were compared to those of similar populations. From their position within the corridors of the Catacombs, sex and social status of the mummies were also inferred, allowing the dental pathologies to be specified in the social and historical context. Most interestingly, the rate of oral health problems did not differ between the groups of the members of the Capuchin Order and the laymen of the city of Palermo, despite their different lifestyles. PMID- 28625344 TI - Confined photonic mode propagation observed in photoemission electron microscopy. AB - Using photoemission electron microscopy (PEEM) we present a comparative analysis of the wavelength dependence of propagating fields in a simple optical slab waveguide and a thin film photonic crystal W1-type waveguide. We utilize an interferometric imaging approach for light in the near-ultraviolet regime where a 2-photon process is required to produce photoelectron emission. The typical spatial resolution in these experiments is < 30nm. Electromagnetic theory and finite element simulations are shown to be in good agreement with the experimental observations. Our results indicate that multiphoton PEEM is a useful sub-wavelength characterization technique in thin film optics. PMID- 28625343 TI - Short-term cooling increases serum triglycerides and small high-density lipoprotein levels in humans. AB - BACKGROUND: Cold exposure and beta3-adrenergic receptor agonism, which both activate brown adipose tissue, markedly influence lipoprotein metabolism by enhancing lipoprotein lipase-mediated catabolism of triglyceride-rich lipoproteins and increasing plasma high-density lipoprotein (HDL) levels and functionality in mice. However, the effect of short-term cooling on human lipid and lipoprotein metabolism remained largely elusive. OBJECTIVE: The objective was to assess the effect of short-term cooling on the serum lipoprotein profile and HDL functionality in men. METHODS: Body mass index-matched young, lean men were exposed to a personalized cooling protocol for 2 hours. Before and after cooling, serum samples were collected for analysis of lipids and lipoprotein composition by 1H-nuclear magnetic resonance. Adenosine triphosphate-binding cassette A1 (ABCA1)-mediated cholesterol efflux capacity of HDL was measured using [3H]cholesterol-loaded ABCA1-transfected Chinese hamster ovary cells. RESULTS: Short-term cooling increased serum levels of free fatty acids, triglycerides, and cholesterol. Cooling increased the concentration of large very low-density lipoprotein (VLDL) particles accompanied by increased mean size of VLDL particles. In addition, cooling enhanced the concentration of small LDL and small HDL particles as well as the cholesterol levels within these particles. The increase in small HDL was accompanied by increased ABCA1-dependent cholesterol efflux in vitro. CONCLUSIONS: Our data show that short-term cooling increases the concentration of large VLDL particles and increases the generation of small LDL and HDL particles. We interpret that cooling increases VLDL production and turnover, which results in formation of surface remnants that form small HDL particles that attract cellular cholesterol. PMID- 28625345 TI - Editorial: Frontiers in development of intelligent applications for medical imaging processing and computer vision. PMID- 28625346 TI - The role of the motor system in action naming in patients with neurodegenerative extrapyramidal syndromes. AB - Previous studies of patients with brain damage have suggested a close relationship between aphasia and movement disorders. Neurodegenerative extrapyramidal syndromes associated with cognitive impairment provide an interesting model for studying the neural substrates of cognitive and motor symptoms. In this review, we focused on studies investigating language production abilities in patients with Parkinson's disease (PD), Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP). According to some reports, these patients exhibit a reduction in performance in both action and object naming or verb production compared to healthy individuals. Furthermore, a disproportional impairment of action naming compared to object naming was systematically observed in patients with these disorders. The study of these clinical conditions offers the unique opportunity to examine the close link between linguistic features and motor characteristics of action. This particular pattern of language impairment may contribute to the debate on embodiment theory and on the involvement of the basal ganglia in language and in integrating language and movement. From a translational perspective, we suggest that language ability assessments are useful in the clinical work-up, along with neuropsychological and motor evaluations. Specific protocols should be developed in the near future to better characterize language deficits and to permit an early cognitive diagnosis. Moreover, the link between language deficits and motor impairment opens a new issue for treatment approaches. Treatment of one of these two symptoms may ameliorate the other, and treating both may produce a greater improvement in patients' global clinical conditions. PMID- 28625347 TI - Reachability judgement in optic ataxia: Effect of peripheral vision on hand and target perception in depth. AB - The concept of peripersonal space was first proposed by Rizzolatti, Scandolara, Matelli, and Gentilucci (1981), who introduced the term to highlight the close links between somatosensory and visual processing for stimuli close to the body and suggested that this near-body space could in fact be characterized as an action space (Rizzolatti, Fadiga, Fogassi, & Gallese, 1997). Supporting this idea, patients with right hemisphere lesions have been described as impaired in performing actions towards objects and in perceiving their location - but only when the objects were presented within arm's reach (Bartolo, Carlier, Hassaini, Martin, & Coello, 2014; Brain, 1941). Whether the deficit of optic ataxia patients in processing target locations for action has an effect on the representation of peripersonal space has never been explored. The present study highlights optic ataxia patients' specific difficulties in processing hand-to target distances in a motor task and in a perceptual task requiring identification of what is reachable in the visual environment. The difficulties are especially evident when both the target and the hand are perceived in the visual periphery. Indeed, when patient I.G. was able to fixate the target, her reaching accuracy and her perception of reachable space both largely improved. Furthermore, the difficulties were enhanced when the hand and the target were both in the lower visual field (in a fixed-far condition vs a fixed-near condition). This novel up-down dimension of optic ataxia fits with the larger representation of the lower visual field in the posterior parietal cortex (Pitzalis et al., 2013; Previc, 1990). PMID- 28625349 TI - Ulva biomass as a co-substrate for stable anaerobic digestion of spent coffee grounds in continuous mode. AB - Ulva biomass was evaluated as a co-substrate for anaerobic digestion of spent coffee grounds at varying organic loads (0.7-1.6g chemical oxygen demand (COD)/Ld) and substrate compositions. Co-digestion with Ulva (25%, COD basis) proved beneficial for SCG biomethanation in both terms of process performance and stability. The beneficial effect is much more pronounced at higher organic and hydraulic loads, with the highest COD removal and methane yield being 51.8% and 0.19L/g COD fed, respectively. The reactor microbial community structure changed dynamically during the experiment, and a dominance shift from hydrogenotrophic to aceticlastic methanogens occurred with increase in organic loading rate. Network analysis provides a comprehensive view of the microbial interactions involved in the system and confirms a direct positive correlation between Ulva input and methane productivity. A group of populations, including Methanobacterium- and Methanoculleus-related methanogens, was identified as a possible indicator for monitoring the biomethanation performance. PMID- 28625350 TI - Multi-electrode bioelectrochemical system for the treatment of high total dissolved solids bearing chemical based wastewater. AB - Multi-electrode bioelectrochemical treatment system (ME-BET; membrane less) consisting of six electrode assemblies (E1-E6) was designed and fabricated for the treatment of complex chemical based wastewater with high salt concentration. The performance was compared with single electrode assembly BET reactor (SE-BET). Enhanced TDS and COD removal was observed in ME-BET (32%; 56%) compared to SE-BET (15%; 23%) as a result of in situ bio-potential from multi-electrodes through the oxidation of organic substrate in the wastewater. Inorganic pollutants viz., nitrates (28%; 8%), sulphates (25%; 9%) and phosphates (20%; 7%) removal was higher in ME-BET in comparison with SE-BET and this was also supported with bioelectrogenic activity (584; 160mW/m3). The study infers that designing of compact reactors with multiple electrodes in a single system enhances the anodic reactions and enable effective treatment of complex wastewaters with simultaneous power production. PMID- 28625348 TI - Metabolic regulation of the PMCA: Role in cell death and survival. AB - The plasma membrane Ca2+-ATPase (PMCA) is a ubiquitously expressed, ATP-driven Ca2+ pump that is critical for maintaining low resting cytosolic Ca2+ ([Ca2+]i) in all eukaryotic cells. Since cytotoxic Ca2+ overload has such a central role in cell death, the PMCA represents an essential "linchpin" for the delicate balance between cell survival and cell death. In general, impaired PMCA activity and reduced PMCA expression leads to cytotoxic Ca2+ overload and Ca2+ dependent cell death, both apoptosis and necrosis, whereas maintenance of PMCA activity or PMCA overexpression is generally accepted as being cytoprotective. However, the PMCA has a paradoxical role in cell death depending on the cell type and cellular context. The PMCA can be differentially regulated by Ca2+-dependent proteolysis, can be maintained by a localised glycolytic ATP supply, even in the face of global ATP depletion, and can be profoundly affected by the specific phospholipid environment that it sits within the membrane. The major focus of this review is to highlight some of the controversies surrounding the paradoxical role of the PMCA in cell death and survival, challenging the conventional view of ATP dependent regulation of the PMCA and how this might influence cell fate. PMID- 28625351 TI - Challenges of non-flocculating Saccharomyces cerevisiae haploid strain against inhibitory chemical complex for ethanol production. AB - This study provides insight observation based on the gene expression and the metabolomic analysis of the natural robust yeast Saccharomyces cerevisiae NBRC849 during the fermentation in the medium containing inhibitory chemical complexes (ICC) at different concentrations. The tolerance mechanisms involved in the strain might have existed through the upregulation of genes involved in NAD(H)/NADP(H) cofactors generations (ALD6, ZWF1, GND1), membrane robustness for efflux pump (YOR1, PDR5, TPO3) and cation/polyamine transport (TPO3). The alteration of metabolic flux to the shikimic pathway was also found in this strain, resulted in the enhanced formation of aromatic amino acid required for cell survival. Enhanced expression of these genes as well as the increase of metabolic flux to shikimic pathway were suggested to result in the robustness of non-flocculating S. cerevisiae haploid strain. PMID- 28625352 TI - RNA-Seq and metabolic flux analysis of Tetraselmis sp. M8 during nitrogen starvation reveals a two-stage lipid accumulation mechanism. AB - To map out key lipid-related pathways that lead to rapid triacylglyceride accumulation in oleaginous microalgae, RNA-Seq was performed with Tetraselmis sp. M8 at 24h after exhaustion of exogenous nitrogen to reveal molecular changes during early stationary phase. Further gene expression profiling by quantitative real-time PCR at 16-72h revealed a distinct shift in expression of the fatty acid/triacylglyceride biosynthesis and beta-oxidation pathways, when cells transitioned from log-phase into early-stationary and stationary phase. Metabolic reconstruction modeling combined with real-time PCR and RNA-Seq gene expression data indicates that the increased lipid accumulation is a result of a decrease in lipid catabolism during the early-stationary phase combined with increased metabolic fluxes in lipid biosynthesis during the stationary phase. During these two stages, Tetraselmis shifts from reduced lipid consumption to active lipid production. This process appears to be independent from DGAT expression, a key gene for lipid accumulation in microalgae. PMID- 28625354 TI - Foraging Cognition: Reviving the Ecological Intelligence Hypothesis. AB - What are the origins of intelligent behavior? The demands associated with living in complex social groups have been the favored explanation for the evolution of primate cognition in general and human cognition in particular. However, recent comparative research indicates that ecological variation can also shape cognitive abilities. I synthesize the emerging evidence that 'foraging cognition' - skills used to exploit food resources, including spatial memory, decision-making, and inhibitory control - varies adaptively across primates. These findings provide a new framework for the evolution of human cognition, given our species' dependence on costly, high-value food resources. Understanding the origins of the human mind will require an integrative theory accounting for how humans are unique in both our sociality and our ecology. PMID- 28625353 TI - A Closer Look at the Hippocampus and Memory. AB - Current interpretations of hippocampal memory function are blind to the fact that viewing behaviors are pervasive and complicate the relationships among perception, behavior, memory, and brain activity. For example, hippocampal activity and associative memory demands increase with stimulus complexity. Stimulus complexity also strongly modulates viewing. Associative processing and viewing thus are often confounded, rendering interpretation of hippocampal activity ambiguous. Similar considerations challenge many accounts of hippocampal function. To explain relationships between memory and viewing, we propose that the hippocampus supports the online memory demands necessary to guide visual exploration. The hippocampus thus orchestrates memory-guided exploration that unfolds over time to build coherent memories. This new perspective on hippocampal function harmonizes with the fact that memory formation and exploratory viewing are tightly intertwined. PMID- 28625355 TI - Meta-Reasoning: Monitoring and Control of Thinking and Reasoning. AB - Meta-Reasoning refers to the processes that monitor the progress of our reasoning and problem-solving activities and regulate the time and effort devoted to them. Monitoring processes are usually experienced as feelings of certainty or uncertainty about how well a process has, or will, unfold. These feelings are based on heuristic cues, which are not necessarily reliable. Nevertheless, we rely on these feelings of (un)certainty to regulate our mental effort. Most metacognitive research has focused on memorization and knowledge retrieval, with little attention paid to more complex processes, such as reasoning and problem solving. In that context, we recently developed a Meta-Reasoning framework, used here to review existing findings, consider their consequences, and frame questions for future research. PMID- 28625356 TI - Prognostic Markers of Outcome in Patients Undergoing Infra-inguinal Revascularisation: A Prospective Observational Pilot Study. AB - OBJECTIVES: The aim was to investigate whether cardiopulmonary exercise testing (CPET) variables derived from cycle and arm ergonometry correlate, and whether CPET variables and pre-operative N-terminal pro-brain natriuretic peptide (NT proBNP) have prognostic significance and if the combination of the two has incremental value. METHODS: A prospective observational pilot study was conducted; 70 patients who underwent infra-inguinal bypass surgery were recruited. Pre-operatively subjects underwent CPET with both arm and leg ergonometry, to measure peak oxygen consumption, anaerobic threshold (AT), and ventilatory equivalents. In addition pre-operative serum samples of NT-proBNP were obtained. The primary endpoint was 1 year all-cause mortality; in addition, data were collected on complications, morbidity, length of stay, and major adverse cardiac events (MACE). RESULTS: The 1 year mortality rate was 6%, the overall complications rate was 23%, and the combined incidence of MACE and 1 year mortality was 10%. Cycle ergonometry peak VO2 14 mL/kg/min (RR 5.5, 95% CI 1.4 22.4, p = .007) and AT < 10mL/kg/min (RR 3.0, 95% CI 1.1-7.0, p = .03) were predictors of post-operative complications. Pre-operative NT-proBNP > 320 ng/L (RR 18, 95% CI 2.5-140 p = .0003) was the sole predictor of 1 year mortality or MACE. CONCLUSION: The measurement of pre-operative NT-proBNP in peripheral vascular disease patients undergoing infra-inguinal bypass can predict 1 year mortality and MACE. CPET variables from cycle ergonometry are predictors of post operative complications in this patient group. PMID- 28625357 TI - Commentary on "Outcomes of Self Expanding Polytetrafluoroethylene Covered Stent versus Bare Metal Stent for Chronic Iliac Artery Occlusion in Matched Cohorts Using Propensity Score Modeling". PMID- 28625358 TI - Disruption of xanthine oxidoreductase gene attenuates renal ischemia reperfusion injury in mice. AB - AIMS: We examined the roles of xanthine oxidoreductase (XOR) in renal ischemia reperfusion (IR) injury. MAIN METHODS: XOR+/+ and XOR+/- mice were subjected to 24-h reperfusion after a 45-min bilateral renal artery occlusion or sham operation. We evaluated the renal damage based on the concentrations of blood urea nitrogen (BUN) and serum creatinine (Cr), and histological changes were detected by PAS staining. Xanthine dehydrogenase, oxidase (XO) and XOR activities, amounts of blood and urine 8-OHdG, and expressions of TNF-alpha and MCP-1 mRNA were examined. F4/80 and nitrotyrosine-positive cells were assessed by immunohistochemical staining. KEY FINDINGS: The BUN and Cr concentrations in the XOR+/+IR mice were increased significantly compared to those in XOR+/-IR and allopurinol-treated XOR+/+IR mice. XO and XOR activity, which were increased in IR mice, were reduced in the allopurinol-treated XOR+/+IR and XOR+/-IR mice compared to the XOR+/+IR mice. The concentrations of blood and urine 8-OHdG, and the expressions of MCP-1 and TNF-alpha mRNA were increased significantly in the XOR+/+IR mice compared to those in the XOR+/-IR mice. The histological analysis revealed that the XOR+/-IR and allopurinol-treated XOR+/+IR mice showed less tubular injury than the XOR+/+IR mice in the cortex regions, with the reduction of inflammation and oxidative stress assessed by the immunohistological staining for F4/80 and nitrotyrosine. SIGNIFICANCE: Both the disruption of XOR gene in XOR+/- mice and the reduction of XOR activity in allopurinol-treated XOR+/+IR mice attenuated renal tissue injury in this IR model. Reduced XOR activity during renal IR could be a beneficial treatment target. PMID- 28625359 TI - Roles of Arf6 in cancer cell invasion, metastasis and proliferation. AB - ADP-ribosylation factor 6 (Arf6), a member of small GTPases ADP-ribosylation factor (Arf) family, expresses widely in mammalian cells and mainly regulates the functions of membrane traffic and actin remodeling. Current studies indicated that the activation and high expression of Arf6 protein may be significantly correlated with the invasion and metastasis of several tumors, such as breast cancer, pancreatic cancer, lung cancer, etc. Meanwhile, the ability of tumor invasion and metastasis can be suppressed when Arf6 activity is blocked by the inhibitors or small-interfering RNAs of Arf6. To explore the precisely potential mechanisms between Arf6 and the process of tumor invasion, metastasis and proliferation, we concludes the functions and potential signaling pathways of Arf6 in tumor cells and provides an overview about clinical prospects of Arf6 in the screening, diagnosis, treatment and evaluation of prognosis of neoplasms. PMID- 28625360 TI - Hypoxia primed placental mesenchymal stem cells for wound healing. AB - AIMS: To investigate how Placental Mesenchymal Stem Cells (P-MSCs) would adapt themselves and survive under hypoxic conditions which are prevalent in most injury sites. MAIN METHODS: P-MSCs were isolated from term placenta and characterised under normoxia and hypoxia (2-2.5% O2). Cells were examined for morphology and surface marker variations by flow cytometry analysis. Glucose stimulated insulin secretion was assayed by Insulin ELISA Kit. Gene expression levels were estimated using Real Time PCR for hypoxia inducible factor1 alpha, Insulin (INS), Glucose transporters (GLUT-1, GLUT-2 and GLUT-3), Adhesion Proteins- Integrins, Fibronectin1 (FN1), E-Cadherin (CDH1), and N-Cadherin (CDH2) and angiogenesis marker VEGFA. Immunofluorescence assay was done to confirm the presence of C-Peptide, GLUT 2, E-Cadherin and ITGB3. Adhesion was confirmed assessed on fibronectin binding. KEY FINDINGS: We show that insulin secretion is not hampered under hypoxia. We found an upregulation of glucose transporters under hypoxia indicating enhanced glucose uptake needed to cater to metabolic demands of proliferating cells. Up regulation of adhesion molecules was seen under hypoxia indicative of a favoured environment for retention of cells at the injury site. We also found increased level of angiogenesis of P-MSCs under hypoxia. SIGNIFICANCE: Our present study thus demonstrates for the first time that P-MSCs modulate themselves under hypoxic conditions by secreting insulin, up regulating glucose transporters and adhesion molecules and eventually exhibiting an increased angiogenic potential. We thus infer that priming P-MSCs under hypoxia, could make them more suitable for wound healing applications. PMID- 28625361 TI - Dependency distance in language evolution: Comment on "Dependency distance: A new perspective on syntactic patterns in natural languages" by Haitao Liu et al. PMID- 28625362 TI - Urotensin core mimics that modulate the biological activity of urotensin-II related peptide but not urotensin-II. AB - A novel approach for the synthesis of head-to-tail cyclic peptides has been developed and used to prepare two mimics of the urotensin II-related peptide (URP) cyclic core. Mimics 1 and 2 (c[Trp-Lys-Tyr-Gly-psi(triazole)-Gly] and c[Phe Trp-Lys-Tyr-Gly-psi(triazole)-Gly]) were respectively prepared using a combination of solid- and solution-phase synthesis. The silyl-based alkyne modifying (SAM) linker enabled installation of C-terminal alkyne and N-terminal azide moieties onto linear peptide precursors, which underwent head-to-tail copper-catalyzed azide-alkyne cycloaddition (CuAAC) in solution. In an aortic ring contraction assay, neither 1 nor 2 exhibited agonist activity; however, both inhibited selectively URP- but not UII-mediated vasoconstriction. The core phenylalanine residue was shown to be important for enhancing modulatory activity of the urotensinergic system. PMID- 28625363 TI - Design, synthesis and biological evaluation of novel indolin-2-ones as potent anticancer compounds. AB - The indolin-2-one core is a privileged structure for antitumor agents, especially kinase inhibitors. Twenty-three novel indolin-2-ones were designed by molecular dissection of the anticancer drug indirubin. Seventeen of them exhibited significant inhibition against the tested cell lines, and two of them (1c and 1h) showed IC50 values at the submicromolar level against HCT-116 cells. Compounds 1c and 2c were also potent inhibitors of the triple-negative breast cancer (TNBC) cell line MDA-MB-231. Flow cytometry was utilized to explore the antitumor mechanism of 1c and 2c with MDA-MB-231 cells, and distinct effects were observed on 2c. Furthermore, immunocytochemical examination of 1c suggested a destabilization of microtubules, which was significantly different from the effect of IM, an indirubin derivative. PMID- 28625365 TI - When academic research organizations and clinical research organizations disagree: Processes to minimize discrepancies prior to unblinding of randomized trials. PMID- 28625364 TI - Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors. AB - Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state-thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration. PMID- 28625366 TI - Feasibility of transcatheter aortic valve replacement in low-risk patients with symptomatic severe aortic stenosis: Rationale and design of the Low Risk TAVR (LRT) study. AB - BACKGROUND: Safety and effectiveness of transcatheter aortic valve replacement (TAVR) in low-risk patients with symptomatic severe aortic stenosis have not yet been established. HYPOTHESIS: Transcatheter aortic valve replacement is feasible in patients with symptomatic severe aortic stenosis and low risk for surgical aortic valve replacement. DESIGN: The LRT study is the first US Food and Drug Administration-approved Investigational Device Exemption prospective multicenter feasibility trial of TAVR in low-risk patients. Patients determined to be low risk by the Heart Team will be enrolled to undergo TAVR with a commercially available balloon-expandable or self-expandable device. A propensity score matched, site-specific cohort of historical surgical aortic valve replacement patients will serve as a control group treated during the site's enrollment period or within the prior 3 years. Low-risk patients with symptomatic bicuspid aortic stenosis undergoing TAVR will be enrolled into a separate registry arm. All TAVR patients will undergo 4-dimensional contrast-enhanced cardiac computed tomography 4-6 weeks after implantation to assess for subclinical leaflet thrombosis and will be followed up clinically for 5 years with yearly echocardiography to monitor prosthesis function. SUMMARY: The LRT study will test feasibility of TAVR in low-risk patients with symptomatic severe aortic stenosis in the United States with either tricuspid or bicuspid native aortic valves. Enrollment commenced in 2016 and results are expected in 2018. PMID- 28625367 TI - Impact of AHA's 2007 guideline change on incidence of infective endocarditis in infants and children. AB - : Use a nationally representative sample to assess impacts of new clinical guidelines issued by the American Heart Association (AHA) in 2007 for many types of invasive procedures, with recommendations for significant decreases in antimicrobial prophylaxis use. STUDY DESIGN: Interrupted time series analyses of pediatric hospitalizations for Infective Endocarditis (IE), using the Nationwide Inpatient Sample (NIS) ICD-9-CM diagnostic codes, identified IE hospitalizations for patients <18 years old from 2001 to 2012. Changes in IE incidence before and after 2007 AHA guidelines were evaluated, with differences in IE clinical severity assessed using in-hospital mortality and length of stay. Analyses were stratified by pathogen type and age group (0-9 y/o and 10-17 y/o). RESULTS: With 3,748 patients in the study, we observed rising trends in IE incidence, but no significant difference between pre- and post-guideline. There was a significant trend increase for IE due to viridans group streptococci (VGS) for ages >10 years old, comparing pre-guideline to post-guideline periods, but not in children 0-9 years of age. Neither in-hospital mortality nor length of stay changed significantly during study. CONCLUSIONS: The data did not demonstrate an impact of the 2007 guideline changes on overall incidence of pediatric IE. However, a significant increase in disease incidence trend due to VGS was observed for the 10-17 year-old group, compared pre- and post-guideline. PMID- 28625368 TI - Effect of aspirin on renal disease progression in patients with type 2 diabetes: A multicenter, double-blind, placebo-controlled, randomized trial. The renaL disEase progression by aspirin in diabetic pAtients (LEDA) trial. Rationale and study design. AB - : Type 2 diabetes mellitus (T2DM) is one of the most common causes of chronic kidney disease and kidney failure. It has been estimated that the annual decline of estimated glomerular filtration rate (eGFR) among patients with T2DM is approximately 2.0-2.5mL min-1 y-1. Cyclooxygenase-dependent eicosanoids, such as 11-dehydro-thromboxane (Tx)B2, are increased in T2DM patients and are potentially involved in the regulation of renal blood flow. Animal models showed that cyclooxygenase inhibitors, such as aspirin, are associated with improvements in renal plasma flow and eGFR values. HYPOTHESIS: The primary end point of the LEDA trial is to evaluate the 1-year decline of eGFR in T2DM patients treated or not with low-dose aspirin (100mg/d). Secondary end points will be the rapid decline in renal function, defined as a reduction of eGFR >=5mL/min, and change of renal function class after 1-year follow-up. Furthermore, urinary excretion 11-dehydro TxB2 will be related to renal function modifications. STUDY DESIGN: A phase 3 no profit, multicenter, double-blind, randomized intervention trial of aspirin 100mg/dvs placebo (ClinicalTrials.gov Identifier: NCT02895113). All patients will be monitored at 6 and 12months after randomization to assess drug adherence and eGFR changes. SUMMARY: The LEDA trial is the first double-blind, placebo controlled, randomized clinical trial aimed at examining whether aspirin treatment may beneficially affect kidney function in patients with T2DM by reducing the annual eGFR decline. The trial will also examine whether the potential renoprotective effects of aspirin might be partly due to its inhibition of TxB2 production. PMID- 28625369 TI - Rationale and design of the Hunting for the off-target propertIes of Ticagrelor on Endothelial function and other Circulating biomarkers in Humans (HI-TECH) trial. AB - BACKGROUND: Among the 3 approved oral P2Y12 inhibitors for the treatment for patients with acute coronary syndrome (ACS), ticagrelor, but not prasugrel or clopidogrel, has been associated with off-target properties, such as improved endothelial-dependent vasomotion and increased adenosine plasma levels. METHODS: The HI-TECH study (NCT02587260) is a multinational, randomized, open-label, crossover study with a Latin squares design, conducted at 5 European sites, in which patients free from recurrent ischemic or bleeding events >=30 days after a qualifying ACS were allocated to sequentially receive a 30 +/- 5-day treatment with prasugrel, clopidogrel, and ticagrelor in random order. The primary objective was to evaluate whether ticagrelor, at treatment steady state (ie, after 30 +/- 5 days of drug administration), as compared with both clopidogrel and prasugrel, is associated with an improved endothelial function, assessed with peripheral arterial tonometry. Thirty-six patients undergoing evaluable endothelial function assessment for each of the assigned P2Y12 inhibitor were needed to provide 90% power to detect a 10% relative change of the reactive hyperemia index in the ticagrelor group. CONCLUSION: The HI-TECH study is the first randomized, crossover study aiming to ascertain whether ticagrelor, when administered at approved regimen in post-ACS patients, improves endothelial function as compared with both clopidogrel and prasugrel. PMID- 28625370 TI - Rationale and design of the Apixaban for the Reduction of Thrombo-Embolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) trial. AB - BACKGROUND: Device-detected subclinical atrial fibrillation (AF) refers to infrequent, short-lasting, asymptomatic AF that is detected only with long-term continuous monitoring. Subclinical AF is common and associated with an increased risk of stroke; however, the risk of stroke with subclinical AF is lower than for clinical AF, and very few patients with subclinical AF alone have been included in large AF anticoagulation trials. The net benefit of anticoagulation in patients with subclinical AF is unknown. DESIGN: ARTESiA is a prospective, multicenter, double-blind, randomized controlled trial, recruiting patients with subclinical AF detected by an implanted pacemaker, defibrillator, or cardiac monitor, and who have additional risk factors for stroke. Patients with clinical AF documented by surface electrocardiogram will be excluded from the study. Participants will be randomized to receive either apixaban (according to standard AF dosing) or aspirin 81mg daily. The primary outcome is the composite of stroke, transient ischemic attack with diffusion-weighted magnetic resonance imaging evidence of cerebral infarction, and systemic embolism. Approximately 4,000 patients will be enrolled from around 230 clinical sites, with an anticipated mean follow-up of 36months until 248 adjudicated primary outcome events have occurred. SUMMARY: ARTESiA will determine whether oral anticoagulation therapy with apixaban compared with aspirin reduces the risk of stroke or systemic embolism in patients with subclinical AF and additional risk factors. PMID- 28625371 TI - Cardiovascular events and hospital resource utilization pre- and post transcatheter mitral valve repair in high-surgical risk patients. AB - : MitraClip is an approved therapy for mitral regurgitation (MR); however, health care resource utilization pre- and post-MitraClip remains understudied. METHODS: Patients with functional and degenerative MR at high surgical risk in the EVEREST II High-Risk Registry and REALISM Continued-Access Study were linked to Medicare data. Pre- and post-MitraClip all-cause death, stroke, myocardial infarction, heart failure (HF), and bleeding hospitalizations were identified. Inpatient costs, adjusted to 2010 US dollars, were calculated, and event rate ratios and cost ratios were estimated with multivariable modeling. RESULTS: Among 403 linked patients, the mean age was 80 years, 60% were male, mean baseline left ventricular ejection fraction was 49.6%, 83.3% were New York Heart Association class III/IV, 78.2% were MR grade 3+/4+, and 63.3% had functional MR. All-cause hospitalization decreased from 1,854 to 1,435/1,000 person-years (P<.001). HF hospitalization decreased following MitraClip (749 vs 332/1000 person-years, P<.001), but bleeding increased (199 vs 298/1000 person-years, P<.001). Changes in stroke and myocardial infarction were not statistically significant. Overall mean Medicare costs per patient were similar pre- and post-MitraClip, although there was a significant decrease in mean costs among those that survived a full year after MitraClip ($18,131 [SD $25,130] vs $11,679 [SD $22,486], P=.02). CONCLUSIONS: MitraClip was associated with a reduced rate of all-cause and HF hospitalizations and an increased rate of bleeding hospitalizations. One-year Medicare costs were reduced in those who survived a full year after the MitraClip procedure. Payors and providers seeking to reduce HF hospitalizations and associated Medicare costs may consider MitraClip among appropriate patients likely to survive 1 year. PMID- 28625372 TI - Multicenter Automatic Defibrillator Implantation Trial-Subcutaneous Implantable Cardioverter Defibrillator (MADIT S-ICD): Design and clinical protocol. AB - Patients with diabetes mellitus, prior myocardial infarction, older age, and a relatively preserved left ventricular ejection fraction remain at risk for sudden cardiac death that is potentially amenable by the subcutaneous implantable cardioverter defibrillator with a good risk-benefit profile. The launched MADIT S ICD study is designed to test the hypothesis that post-myocardial infarction diabetes patients with relatively preserved ejection fraction of 36%-50% will have a survival benefit from a subcutaneous implantable cardioverter defibrillator. PMID- 28625373 TI - High-risk echocardiographic features predict mortality in pulmonary arterial hypertension. AB - AIMS: Echocardiography is the most common imaging modality for assessment of the right ventricle in patients with pulmonary arterial hypertension (PAH). Echocardiographic parameters were identified as independent risk factors for mortality in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) and other PAH cohorts. We sought to identify readily obtained echocardiographic features associated with PAH survival. METHODS AND RESULTS: Retrospective analysis of 175 patients with Group 1 was performed. Baseline clinical and laboratory assessment including REVEAL risk criteria were obtained and standard 2-Dimensional and Doppler echocardiography performed at baseline was reviewed. Univariate and multivariate analyses of echocardiographic parameters were performed. Estimated right atrial pressure> 15 mmHg (HR 2.39, P = .02), tricuspid regurgitation >= moderate (HR 2.16, P = .04), and presence of pericardial effusion (HR 1.8, P = .05) were identified as independent, high-risk echocardiographic features in PAH. A validation cohort of 677 patients was identified and Kaplan-Meier survival analysis was performed in both cohorts. High risk echocardiographic features stratified survival curves of both cohorts (P < .01 for all). The presence of 3 high-risk echocardiographic features greatly increased risk of 1-year (RR 4.86) and 3-year (RR 3.35) mortality (P < .05 for both). CONCLUSION: Estimated right atrial pressure> 15, tricuspid regurgitation >= moderate, and presence of pericardial effusion are high-risk echocardiographic features in PAH. When seen in combination, these features greatly increase risk of mortality in PAH and may lead to more timely enhanced therapy for patients identified as having an increased risk for death. PMID- 28625374 TI - Change the management of patients with heart failure: Rationale and design of the CHAMP-HF registry. AB - Heart failure (HF) with reduced ejection fraction (HFrEF) is a common and costly condition that diminishes patients' health status and confers a poor prognosis. Despite the availability of multiple guideline-recommended pharmacologic and cardiac device therapies for patients with chronic HFrEF, outcomes remain suboptimal. Currently, there is limited insight into the rationale underlying clinical decisions by health care providers and patient factors that guide the use and intensity of outpatient HF treatments. A better understanding of current practice patterns has the potential to improve patients' outcomes. The CHAnge the Management of Patients with Heart Failure (CHAMP-HF) registry will evaluate the care and outcomes of patients with chronic HFrEF by assessing real-world treatment patterns, as well as the reasons for and barriers to medication treatment changes. CHAMP-HF will enroll approximately 5,000 patients with chronic HFrEF (left ventricular ejection fraction <=40%) at approximately 150 US sites, and patients will be followed for a maximum duration of 24 months. Participating sites will collect data from both providers (HF history, examination findings, results of diagnostic studies, pharmacotherapy treatment patterns, decision making factors, and clinical outcomes) and patients (medication adherence and patient-reported outcomes). The CHAMP-HF registry will provide a unique opportunity to study practice patterns and the adoption of new HF therapies across a diverse mix of health care providers and outpatient practices in the United States that care for HFrEF patients. PMID- 28625375 TI - Decline in peak oxygen consumption over time predicts death or transplantation in adults with a Fontan circulation. AB - : Peak oxygen consumption (pVO2) measured by cardiopulmonary exercise test (CPET) predicts mortality in adults with a Fontan circulation. The purpose of this study was to assess the additive prognostic value of change in pVO2 over time. METHODS: We analyzed a cohort of adults (>=18 years old) with a Fontan circulation who underwent at least 2 maximal CPETs separated by 6-30 months at Boston Children's Hospital between 2000 and 2015. Survival analysis was performed to determine whether changes in CPET variables, including pVO2 between consecutive tests, were associated with subsequent clinical events. The primary outcome was transplant free survival. RESULTS: The study included 130 patients with 287 CPET test pairs. Average age was 26.6+/-9.5 years. Baseline pVO2 averaged 22.0+/-5.7 mL/kg/min or 60.9%+/-13.7% predicted. In the cohort overall, there was no change in mean pVO2 between sequential CPETs. Eleven patients died and 2 underwent transplant. On average, pVO2 declined for patients who subsequently died or underwent transplant but remained stable among those who did not (-9.8%+/-14.6% vs 0.0+/-13.0%, P<.01). Those with a decline in pVO2 between CPETs were at greater risk of death or transplantation (per 10% decrease in pVO2: HR=2.0, 95% CI 1.2-3.1, P=.004). Change in pVO2 remained a significant predictor of death or transplant after adjusting for pVO2 at first CPET (per 10% decline in pVO2: HR=2.5, 95% CI 1.5 4.2, P<.001). CONCLUSIONS: A decline in pVO2 between consecutive CPETs predicts increased risk for death or transplant in adults with a Fontan circulation independent of baseline pVO2. These results support the additive clinical value of serial CPET in this population. PMID- 28625376 TI - Electrocardiographic abnormalities and mortality in aging survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study. AB - BACKGROUND: Electrocardiography (ECG), predictive of adverse outcomes in the general population, has not been studied in cancer survivors. We evaluated the prevalence of ECG abnormalities and associations with mortality among childhood cancer survivors. METHODS: Major and minor abnormalities were coded per the Minnesota Classification system for participants in the St Jude Lifetime Cohort Study (n = 2,715) and community controls (n = 268). Odds ratios (ORs) and 95% CIs were calculated using multivariable logistic regression; and hazard ratios, using Cox proportional hazards regression. RESULTS: Survivors were a median age of 31.3 (range 18.4-63.8) years at evaluation and 7.4 (range 0-24.8) years at diagnosis. Prior therapies included cardiac-directed radiation (29.5%), anthracycline (57.9%), and alkylating (60%) chemotherapies. The prevalence of minor ECG abnormalities was similar among survivors and controls (65.2% vs 67.5%, P = .6). Major ECG abnormalities were identified in 10.7% of survivors and 4.9% of controls (P < .001). Among survivors, the most common major abnormalities were isolated ST/T wave abnormalities (7.2%), evidence of myocardial infarction (3.7%), and left ventricular hypertrophy with strain pattern (2.8%). Anthracyclines >=300 mg/m2 (OR 1.7 95% CI 1.1-2.5) and cardiac radiation (OR 2.1 95% CI 1.5-2.9 [1-1,999 cGy], 2.6 95% CI 1.6-3.9 [2,000-2,999 cGy], 10.5 95% CI 6.5-16.9 [>=3,000 cGy]) were associated with major abnormalities. Thirteen participants had a cardiac-related death. Major abnormalities were predictive of all-cause mortality (hazard ratio 4.0 95% CI 2.1-7.8). CONCLUSIONS: Major ECG abnormalities are common among childhood cancer survivors, associated with increasing doses of anthracyclines and cardiac radiation, and predictive of both cardiac and all-cause mortality. PMID- 28625377 TI - One-year mortality outcomes and hospital readmissions of patients admitted with acute heart failure: Data from the Trivandrum Heart Failure Registry in Kerala, India. AB - BACKGROUND: There are sparse data on outcomes of patients with heart failure (HF) from India. The objective was to evaluate hospital readmissions and 1-year mortality outcomes of patients with HF in Kerala, India. METHODS: We followed 1,205 patients enrolled in the Trivandrum Heart Failure Registry for 1 year. A trained research nurse contacted each participant every 3 months using a structured questionnaire which included hospital readmission and mortality information. RESULTS: The mean (SD) age was 61.2 (13.7) years, and 31% were women. One out of 4 (26%) participants had HF with preserved ejection fraction. Only 25% of patients with HF with reduced ejection fraction received guideline directed medical therapy at discharge. Cumulative all-cause mortality at 1 year was 30.8% (n = 371), but the greatest risk of mortality was in the first 3 months (18.1%). Most deaths (61%) occurred in patients younger than 70 years. One out of every 3 (30.2%) patients was readmitted at least once over 1 year. The hospital readmission rates were similar between HF with preserved ejection fraction and HF with reduced ejection fraction patients. New York Heart Association functional class IV status and lack of guideline-directed medical treatment after index hospitalization were associated with increased likelihood of readmission. Similarly, older age, lower education status, nonischemic etiology, history of stroke, higher serum creatinine, lack of adherence to guideline-directed medical therapy, and hospital readmissions were associated with increased 1-year mortality. CONCLUSIONS: In the Trivandrum Heart Failure Registry, 1 of 3 HF patients died within 1 year of follow-up during their productive life years. Suboptimal adherence to guideline-directed treatment is associated with increased propensity of readmission and death. Quality improvement programs aiming to improve adherence to guideline-based therapy and reducing readmission may result in significant survival benefits in the relatively younger cohort of HF patients in India. PMID- 28625378 TI - The economics of PCSK-9 inhibitors. PMID- 28625379 TI - Reliability of updated left ventricular diastolic function recommendations in predicting elevated left ventricular filling pressure and prognosis. AB - : An updated 2016 echocardiographic algorithm for diagnosing left ventricular (LV) diastolic dysfunction (DD) was recently proposed. We aimed to assess the reliability of the 2016 echocardiographic LVDD grading algorithm in predicting elevated LV filling pressure and clinical outcomes compared to the 2009 version. METHODS: We retrospectively identified 460 consecutive patients without atrial fibrillation or significant mitral valve disease who underwent transthoracic echocardiography within 24 hours of elective heart catheterization. LV end diastolic pressure (LVEDP) and the time constant of isovolumic pressure decay (Tau) were determined. The association between DD grading by 2009 LVDD Recommendations and 2016 Recommendations with hemodynamic parameters and all cause mortality were compared. RESULTS: The 2009 LVDD Recommendations classified 55 patients (12%) as having normal, 132 (29%) as grade 1, 156 (34%) as grade 2, and 117 (25%) as grade 3 DD. Based on 2016 Recommendations, 177 patients (38%) were normal, 50 (11%) were indeterminate, 124 (27%) patients were grade 1, 75 (16%) were grade 2, 26 (6%) were grade 3 DD, and 8 (2%) were cannot determine. The 2016 Recommendations had superior discriminatory accuracy in predicting LVEDP (P<.001) but were not superior in predicting Tau. During median follow-up of 416 days (interquartile range: 5 to 2004 days), 54 patients (12%) died. Significant DD by 2016 Recommendations was associated with higher risk of mortality (P=.039, subdistribution HR1.85 [95% CI, 1.03-3.33]) in multivariable competing risk regression. CONCLUSIONS: The grading algorithm proposed by the 2016 LV diastolic dysfunction Recommendations detects elevated LVEDP and poor prognosis better than the 2009 Recommendations. PMID- 28625380 TI - Factors associated with non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with new-onset atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT AF II). AB - BACKGROUND: Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF. METHODS: The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF. RESULTS: At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age >=75years, Diabetes mellitus, Prior stroke, transient ischemic attack {TIA}, or thromboembolism,Vascular disease, Age 65-74years, Sex category {female}] >=2 in 86% vs 93%; P<.0001). In multivariable analysis, factors associated with NOAC selection versus warfarin included renal function, prior stroke or valve replacement, rhythm control AF management strategy, treatment by a cardiologist, and higher patient education level. CONCLUSIONS: In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01701817. PMID- 28625381 TI - Utilization of cardiac resynchronization therapy in eligible patients hospitalized for heart failure and its association with patient outcomes. AB - OBJECTIVES: We examined trends in CRT utilization overall and by sex and race and to assess whether CRT use is associated with a reduction in HF hospitalization and mortality. BACKGROUND: It is unknown whether underutilization and race/sex based differences in cardiac resynchronization therapy (CRT) use have persisted. The association between CRT and heart failure (HF) hospitalization and mortality in real-world practice remains unclear. METHODS: We linked 72,008 HF patients from 388 hospitals participating in Get With The Guidelines HF eligible for CRT with Centers for Medicare & Medicaid Services data to assess CRT utilization trends, HF hospitalization rates, and all-cause mortality. RESULTS: From 2005 2014, 18,935 (26.3%) eligible patients had CRT in place, implanted, or prescribed. The majority were male (60.0%) and white (61.9%). CRT utilization increased during the study period (P = .0002) especially in the early period. Women were less likely to receive CRT, and this difference increased over time (interaction P = .0037) despite greater mortality risk reduction (interaction P = .0043). Black patients were less likely than white patients to have CRT throughout the study period (adjusted hazard ratio (HR) 0.79; 95% CI 0.74-0.85). Patients with CRT implanted during the index hospitalization had lower mortality (adjusted HR 0.65; 95% CI 0.59-0.71) and were less likely to be readmitted for HF than patients without CRT (adjusted HR 0.64; 95% CI 0.58-0.71). CONCLUSIONS/RELEVANCE: CRT use has increased in all populations, but it remains underutilized. CRT remains more common among white than black HF patients, and women were less likely than men to receive CRT despite deriving greater benefit. PMID- 28625383 TI - The Assessment of the Watchman Device in Patients Unsuitable for Oral Anticoagulation (ASAP-TOO) trial. AB - BACKGROUND: Oral anticoagulants (OACs) reduce stroke risks with nonvalvular atrial fibrillation (AF); however, they are underused because of absolute or relative contraindications due to real or perceived risk of bleeding. Although left atrial appendage closure is increasingly performed in OAC-ineligible patients, this has not been studied in a randomized controlled trial. STUDY OBJECTIVES: The ASAP-TOO study is designed to establish the safety and effectiveness of the Watchman left atrial appendage closure device in patients with nonvalvular AF who are deemed ineligible for OAC. The primary effectiveness end point is the time to first occurrence of ischemic stroke or systemic embolism. The primary safety end point includes all-cause death, ischemic stroke, systemic embolism, or device- or procedural-related event requiring open cardiac surgery or major endovascular intervention. STUDY DESIGN: This is a multinational, multicenter prospective randomized trial. Patients meeting the inclusion criteria with CHA2DS2-VASc score>=2 and who are deemed by 2 study physicians to be unsuitable for OAC will be randomized in a 2:1 allocation ratio to Watchman versus control. Control patients will be prescribed single antiplatelet therapy or no therapy at the discretion of the study physician. Up to 888 randomized subjects will be enrolled from up to 100 global investigational sites. Both device group and control patients will have follow-up visits at 3, 6, and 12months and then every 6months through 60months. SUMMARY: This trial will assess the safety and efficacy of Watchman in this challenging population of high stroke risk AF patients. PMID- 28625382 TI - Impact of continuous positive airway pressure and oxygen on health status in patients with coronary heart disease, cardiovascular risk factors, and obstructive sleep apnea: A Heart Biomarker Evaluation in Apnea Treatment (HEARTBEAT) analysis. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is associated with impaired health related quality of life (HRQL). Treatment with continuous positive airway pressure (CPAP) has variable impacts on HRQL, and this may be influenced by patient's tolerance of therapy. The objective is to determine the impact of nocturnal supplemental oxygen (NSO) and CPAP on HRQL compared with healthy lifestyle education (HLSE) in individuals with OSA. METHODS: Patients with coronary heart disease (CHD) or at least 3 major CHD risk factors with apnea hypopnea index of 15 to 50 events/h were randomized to CPAP, NSO, or HLSE. Health related quality of life was assessed using the Short-Form 36, and depression was assessed with Patient Health Questionnaire-9 at baseline and 12 weeks. The treatment effect on HRQL change scores through 12 weeks was assessed using multivariable models adjusting for study site, presence of CHD at baseline, race, and baseline HRQL. RESULTS: A total of 318 patients were randomized to 1 of 3 treatment arms with 1:1:1 ratio and 94% completed baseline and follow-up HRQL instruments. Mean Short-Form 36 scores were similar at baseline in all 3 groups ranging from 41.8+/-12 to 51.6+/-12 in various domains. In multivariable models, the CPAP group noted a significantly greater improvement than NSO in mental health (+2.33, 95% CI 0.34-4.31, P=.02) and mental composite score (+2.40, 95% CI 0.40-4.41, P=.02). Conversely, the CPAP group noted less improvement than NSO in physical function (-2.68, 95% CI -4.66 to -0.70, P=.008) and physical composite score (-2.17, 95% CI -3.82 to -0.51, P=.01). Compared with HLSE, vitality and Patient Health Questionnaire-9 improved with CPAP but not with NSO. Significant interactions were noted between treatment effects with larger differences in black and sleepy patients. CONCLUSION: These data support the use of CPAP for improving vitality, sleepiness, mental health, social functioning, and depressive symptoms in patients with OSA and established CHD or risk factors. Nocturnal supplemental oxygen may have beneficial effects on perceived physical functioning. PMID- 28625384 TI - Effects of implantable cardioverter/defibrillator shock and antitachycardia pacing on anxiety and quality of life: A MADIT-RIT substudy. AB - : Effects of implantable cardioverter/defibrillator (ICD) shocks and antitachycardia pacing (ATP) on anxiety and quality of life (QoL) in ICD patients are poorly understood. METHODS: We evaluated changes in QoL from baseline to 9 month follow-up using the EQ-5D questionnaire in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) (n=1,268). We assessed anxiety levels using the Florida Shock Anxiety Scale (1-10 score) in patients with appropriate or inappropriate shocks or ATP compared to those with no ICD therapy during the first 9 months postimplant. The analysis was stratified by number of ATP or shocks (0-1 vs >=2) and adjusted for covariates. RESULTS: In MADIT-RIT, 15 patients (1%) had >=2 appropriate shocks, 38 (3%) had >=2 appropriate ATPs. Two or more inappropriate shocks were delivered in 16 patients (1%); >=2 inappropriate ATPs, in 70. In multivariable analysis, patients with >=2 appropriate shocks had higher levels of shock-related anxiety than those with <=1 appropriate shock (P<.01). Furthermore, >=2 inappropriate shocks produced more anxiety than <=1 inappropriate shock (P=.005). Consistently, >=2 appropriate ATPs resulted in more anxiety than <=1 (P=.028), whereas the number of inappropriate ATPs showed no association with anxiety levels (P=.997). However, there was no association between QoL and appropriate or inappropriate ATP/shock (all P values > .05). CONCLUSIONS: In MADIT-RIT, >=2 appropriate or inappropriate ICD shocks and >=2 appropriate ATPs are associated with more anxiety at 9-month follow-up despite no significant changes in the assessment of global QoL by the EQ-5D questionnaire. Innovative ICD programming reducing inappropriate therapies may help deal with patient concerns about the device. PMID- 28625385 TI - Seasonal and circadian variations of acute myocardial infarction: Findings from the Get With The Guidelines-Coronary Artery Disease (GWTG-CAD) program. AB - BACKGROUND: Seasonal variation with winter preponderance of myocardial infarction incidence has been described decades ago, but only a few small studies have classified myocardial infarction based on ST-segment elevation. It is unclear whether seasonal and circadian variations are equally present in warmer and colder regions. We investigated whether seasonal and circadian variations in acute myocardial infarction (AMI) are more prominent in colder northern states compared with warmer southern states. We also investigated the peak time of admission to better understand the circadian rhythm. METHODS: Data from the GWTG CAD database were used. We analyzed 82,971 consecutive acute myocardial infarction (AMI) patients treated at 276 US centers from 2003 to 2008. The country was geographically divided into warmer southern and colder northern states using latitude 35 degrees for this purpose. RESULTS: Overall, acute myocardial infarction (AMI) admissions varied across seasons (P < .01), and were higher in winter (winter vs. spring n = 21,483 vs. 20,291, respectively). When stratified based on type of AMI, non-ST-segment elevation myocardial infarction (NSTEMI) admissions varied across seasons (P < .01) and were highest in winter and lowest in spring. Seasonal variation was not significant in STEMI admissions (P = .30). Seasonal variation with winter predominance was noted in AMI patients in warmer southern states (P < .01), but not in colder states. The distributions of length of stay for AMI patients and door to balloon times for STEMI patients were minimally different across all four seasons (P < .01) with longest occurring in winter. Most patients with AMI presented during daytime with a peak close to 11 am and a nadir at approximately 4 am. CONCLUSIONS: Seasonal variation with winter predominance exists in AMI admissions and was significant in NSTEMI admissions but not in STEMI admissions. Seasonal variation was only significant in warmer southern states. PMID- 28625386 TI - Hemodynamic determinants of mortality after Fontan operation. AB - BACKGROUND: Elevated central venous pressure (CVP), low cardiac output, and mild hypoxia are common early and late after Fontan operations. However, the association of these characteristics with late mortality is unclear. We aimed to elucidate the hemodynamic determinants of mortality after Fontan operation. METHOD: We evaluated early (group early; 0.5-5years postoperatively, n=387) and late (group late; >=15years postoperatively, n=161) Fontan hemodynamics that included CVP (mm Hg), cardiac index (CI; L/min per m2), systemic ventricular end diastolic volume index (mL/m2), ejection fraction (EF; %), and arterial blood oxygen saturation (%). We examined the effect of these variables on 5-year all cause mortality. RESULTS: Mortality was higher in group late than in group early (17 vs 11, P<.0001). In both groups, higher CVP (hazard ratio [HR]1.46 and 1.38, respectively; P<.001-.0001) and lower arterial blood oxygen saturation (HR 1.12, P<.001 for both) were associated with increased mortality. Greater end-diastolic volume index (HR per 20: 1.73) and lower EF (HR per 10%: 3.38) were associated with increased mortality only in group early (P<.0001 for both). In contrast, only in group late was higher CI associated with increased mortality (HR 2.50, 95% CI 1.30-4.55, P<.01). Seven patients in group late with both high CVP (>=14) and CI (>=3.0) had the highest mortality (HR 18.1, 5.55-52.4, P<.0001). CONCLUSIONS: Elevated CVP and low arterial blood oxygen saturation correlate with mortality in both early and late Fontan survivors. End-diastolic volume index and EF are associated with mortality only in the earlier cohort, whereas interestingly, elevated cardiac output is associated with increased mortality in the later cohort. PMID- 28625388 TI - Management of Comorbidities in Older Persons With Type 2 Diabetes. PMID- 28625387 TI - Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial. A registry-based randomized clinical trial. AB - BACKGROUND: Registry studies and case-control studies have demonstrated that the risk of acute myocardial infarction (AMI) is increased following influenza infection. Small randomized trials, underpowered for clinical end points, indicate that future cardiovascular events can be reduced following influenza vaccination in patients with established cardiovascular disease. Influenza vaccination is recommended by international guidelines for patients with cardiovascular disease, but uptake is varying and vaccination is rarely prioritized during hospitalization for AMI. METHODS/DESIGN: The Influenza vaccination After Myocardial Infarction (IAMI) trial is a double-blind, multicenter, prospective, registry-based, randomized, placebo-controlled, clinical trial. A total of 4,400 patients with ST-segment elevation myocardial infarction (STEMI) or non-STEMI undergoing coronary angiography will randomly be assigned either to in-hospital influenza vaccination or to placebo. Baseline information is collected from national heart disease registries, and follow-up will be performed using both registries and a structured telephone interview. The primary end point is a composite of time to all-cause death, a new AMI, or stent thrombosis at 1 year. IMPLICATIONS: The IAMI trial is the largest randomized trial to date to evaluate the effect of in-hospital influenza vaccination on death and cardiovascular outcomes in patients with STEMI or non-STEMI. The trial is expected to provide highly relevant clinical data on the efficacy of influenza vaccine as secondary prevention after AMI. PMID- 28625389 TI - Higher Polyunsaturated Fatty Acid to Saturated Fatty Acid Ratio Is Associated With Cognition, Mobility, Nutrient Intakes, and Higher Diet Quality in Heterogeneous Older Populations. PMID- 28625390 TI - Dopamine protects cerebral autoregulation and prevents hippocampal necrosis after traumatic brain injury via block of ERK MAPK in juvenile pigs. AB - Traumatic brain injury (TBI) contributes to morbidity in children, and more boys experience TBI. Cerebral autoregulation is impaired after TBI, contributing to poor outcome. Cerebral Perfusion Pressure (CPP) is often normalized by use of vasoactive agents to increase mean arterial pressure (MAP). In prior studies of newborn and juvenile pigs, vasoactive agent choice influenced outcome after TBI as a function of age and sex, with none protecting cerebral autoregulation in both ages and sexes. Dopamine (DA) prevents impairment of cerebral autoregulation in male and female newborn pigs via inhibition of upregulation of ERK mitogen activated protein kinase (MAPK) after fluid percussion injury (FPI). We investigated whether DA protects autoregulation and limits histopathology after FPI in juvenile pigs and the role of ERK in that outcome. Results show that DA protects autoregulation in both male and female juvenile pigs after FPI. Papaverine induced dilation was unchanged by FPI and DA. DA blunted ERK MAPK and prevented loss of neurons in CA1 and CA3 hippocampus of males and females after FPI. These data indicate that DA protects autoregulation and limits hippocampal neuronal cell necrosis via block of ERK after FPI in male and female juvenile pigs. Of the vasoactive agents prior investigated, including norepinephrine, epinephrine, and phenylephrine, DA is the only one demonstrated to improve outcome after TBI in both sexes and ages. These data suggest that DA should be considered as a first line treatment to protect cerebral autoregulation and promote cerebral outcomes in pediatric TBI irrespective of age and sex. PMID- 28625391 TI - Twelve-year experience of "radical but conservative" liver surgery for colorectal metastases: impact on surgical practice and oncologic efficacy. AB - BACKGROUND: Liver surgery for colorectal metastases (CLM) is moving toward parenchyma-sparing approaches. The authors reported the technical feasibility of parenchyma-sparing hepatectomy for deeply located tumors, but its impact on daily practice and long-term outcomes remain unclear. METHODS: The patients undergoing liver resection (LR) for CLM with vascular contact (first-/second-order pedicle or hepatic vein (HV) trunk) were considered. Those undergoing major hepatectomy were excluded. The authors' technique included tumor-vessel detachment, partial resection of marginally infiltrated HVs, and detection of communicating vessels (CVs) among HVs to preserve outflow after HV resection. RESULTS: Among 169 patients with major vascular contact, parenchyma-sparing LR was feasible in 146 (86%). Twenty-eight SERPS, 13 transversal hepatectomies, 6 mini mesohepatectomies, and 4 liver tunnels were performed. Sixty-six (45%) patients underwent CLM-vessel detachment, 25 (17%) underwent partial HV resection, and 30 (21%) achieved outflow preservation by CV identification. The mortality and severe morbidity rates were 1.4% and 8.2%, respectively. The 5-year survival rate was 30.7%. The parenchyma-sparing strategy failed in 14 (7%) patients because of recurrence in the spared parenchyma or cut edge; 13 were radically retreated. CONCLUSION: Ultrasound-guided parenchyma-sparing surgery is feasible in most patients with ill-located CLMs. This procedure is safe and achieves adequate oncologic outcomes. PMID- 28625392 TI - A Novel Risk Score to Predict the Need for Nutrition Support After Cardiac Surgery. AB - BACKGROUND: In specific patients, early postoperative nutrition mitigates malnutrition-related morbidity and mortality. The goal of this study was to develop and validate a prediction score designed to stratify patients immediately after cardiac surgery according to risk for nutrition support (NS). METHODS: We identified adult cardiac surgery patients at our institution in 2012 requiring postoperative NS, enteral or parenteral. Using multivariable logistic regression modeling, we developed a Johns Hopkins Hospital Nutrition Support (JHH NS) score from relative odds ratios generated by variables that independently predicted the need for NS. The JHH NS score was then prospectively validated using all patients undergoing cardiac surgery in 2015. RESULTS: Among 1,056 patients in the derivation cohort, 87 (8%) required postoperative NS. Seven variables were identified on multivariable analysis as independent predictors of NS need and were used to create the JHH NS score. Scores ranged from 0 to 36. Each 1-point increase in the JHH NS score was associated with a 20% increase in the risk of requiring NS (odds ratio 1.20, p < 0.001). The c-statistic of the regression model for NS was 0.85. In all, 115 of 1,336 patients (8.6%) in the validation cohort required NS. Observed rates of NS in the validation group correlated positively with predicted rates (r = 0.89). CONCLUSIONS: The JHH NS score reliably stratified patients at risk for the need for postoperative NS. This easily calculable and highly predictive screening tool may expedite timing of initiation of NS in patients at high risk for not being able to physically take in adequate nutrition. PMID- 28625393 TI - Establishment and characterization of uterine sarcoma and carcinosarcoma patient derived xenograft models. AB - OBJECTIVE: Uterine sarcomas (US) and carcinosarcomas (CS) are rare, aggressive cancers. The lack of reliable preclinical models hampers the search for new treatment strategies and predictive biomarkers. To this end, we established and characterized US and CS patient-derived xenograft (PDX) models. METHODS: Tumor fragments of US and CS were subcutaneously implanted into immunocompromised mice. Engrafted xenograft and original tumors were compared by means of histology, immunohistochemistry, whole-genome low-coverage sequencing for copy number variations, and RNA sequencing. RESULTS: Of 13 implanted leiomyosarcomas (LMS), 10 engrafted (engraftment rate of 77%). Also 2 out of 7 CS (29%) and one high grade US (not otherwise specified) models were successfully established. LMS xenografts showed high histological similarity to their corresponding human tumors. Expression of desmin and/or H-caldesmon was detected in 8/10 LMS PDX models. We noticed that in CS models, characterized by the concomitant presence of a mesenchymal and an epithelial component, the relative distribution of the components is varying over the generations, as confirmed by changes in vimentin and cytokeratin expression. The similarity in copy number profiles between original and xenograft tumors ranged from 57.7% to 98.2% for LMS models and from 47.4 to 65.8% for CS models. Expression pattern stability was assessed by clustering RNA expression levels of original and xenograft tumors. Six xenografts clustered together with their original tumor, while 3 (all LMS) clustered apart. CONCLUSIONS: We present here a panel of clinically annotated uterine sarcoma and carcinosarcoma PDX models, which will be a useful tool for preclinical testing of new therapies. PMID- 28625394 TI - Sentinel node mapping in endometrial cancer following Hysteroscopic injection of tracers: A single center evaluation over 200 cases. AB - OBJECTIVES: To analyze detection-rate(DR) and diagnostic-accuracy (A) of sentinel nodes(SLNs) mapping following hysteroscopic-injection of tracer. To compare DR and A between tracers: ICG and Tc99m. METHODS: Evaluation of endometrial-cancer patients who underwent SLNs mapping after hysteroscopic-peritumoral-injection of tracer+/-lymphadenectomy. Analysis of DR (overall-bilateral-aortic) and A in the entire cohort and comparison between tracers. RESULTS: 202 procedures were performed from January/2005 to February/2017. Mean age:60years (28-82); mean BMI: 26.8 kg/m2 (15-47). In 133 cases (65.8%) hysterectomy and mapping procedure were performed laparoscopically. The overall-DR of the technique was 93.2% (179/192) (10 cases were excluded: 9 for technical-equipment failure; 1 for vagal reaction). Bilateral pelvic mapping was found in 59.7% of cases (107/179) and was more frequent in the ICG group (72.8% vs 53.3%; p: 0.012). In 50.8% of cases (91/179) SLNs were mapped both in pelvic and aortic nodes, and in 5 cases (2.8%) only in the aortic area. The mean number of detected SLNs was 3.7 (1-8). 22 patients (12.3%) had nodal involvement: 10-(45.5%)-macrometastases; 5-(22.7%) micrometastases; 7-(31.8%)-ITCs. In 6 cases (27.3%) only aortic nodes were positive; in 5 cases (22.7%) both pelvic and aortic nodes and in 11 cases (50%) only pelvic nodes were involved. Three false-negative results were found, all in the Tc99m group. All had isolated aortic metastases with negative pelvic nodes. Overall-sensitivity was 86.4% (95%CI: 68.4-100) and overall-negative-predictive value (NPV) was 96.4% (95%CI 86.7-100). No differences in terms of overall-DR, overall-sensitivity and overall-NPV were found between the two tracers. CONCLUSIONS: Hysteroscopic-injection of tracer for SLNs mapping in endometrial cancer is as accurate as cervical injection with a higher DR in the aortic area. ICG improves bilateral-DR. Further investigation is warranted on this topic. PMID- 28625395 TI - L1CAM expression associates with poor outcome in endometrioid, but not in clear cell ovarian carcinoma. AB - OBJECTIVE: Our aim was to study the expression of L1CAM in endometrioid and clear cell ovarian carcinomas and to evaluate its correlation with clinical parameters and patient prognosis. METHODS: Tissue microarray -based immunohistochemical analysis of L1CAM expression was performed in 249 endometrioid and 140 clear cell ovarian carcinomas. Concurrent endometrial carcinoma was found in 57 of these patients. RESULTS: L1CAM expression was found in 15% of endometrioid and 23% of clear cell ovarian carcinomas. L1CAM expression was strongly associated with poor disease-specific overall survival and poor disease-free survival in endometrioid (p<0.0001, p=0.0005), but not in clear cell ovarian carcinomas. Significant association of L1CAM expression with poor overall survival was observed in grade 1-2 carcinomas (p<0.0001), but not in grade 3 tumors. In endometrioid ovarian carcinomas, L1CAM expression was associated with aggressive tumor characteristics, such as higher grade and stage, and incomplete response to primary therapy. However, L1CAM expression was not an independent prognostic factor for overall or disease-free survival. Of the 57 patients with concurrent endometrial carcinoma L1CAM positivity was found in 4 cases both in the ovarian and endometrial tumors, and in 3 cases only in the endometrial tumor. All these seven patients with L1CAM positive tumors had poor outcome. CONCLUSIONS: L1CAM expression could serve as a biomarker for predicting clinical outcome and response to therapy in patients with endometrioid ovarian carcinoma, but not in clear cell carcinomas. L1CAM positivity also predicts poor outcome in patients with concurrent endometrioid ovarian and endometrial carcinomas. PMID- 28625396 TI - Management of menopausal symptoms in women with gynecologic cancers. AB - OBJECTIVE: Women with gynecologic malignancies will be cured or may become long term survivors. Management of menopausal symptoms is important in addressing their quality of life. We review the benefit and safety of hormone therapy use in these patients. METHODS: MEDLINE was searched for studies on menopause management published in English through December of 2016. RESULTS: Available data suggest that short-term use of hormone therapy in gynecologic cancer patients who do not have an estrogen-dependent malignancy do not adversely impact oncologic outcome and results in improvement of menopausal vasomotor and genitourinary symptoms. Evidence regarding safety of hormone therapy use in women with estrogen-dependent gynecologic malignances is currently lacking. CONCLUSIONS: Candidates for hormone therapy in gynecologic oncology include women with menopausal symptoms diagnosed with low-grade, early-stage endometrial cancer, cervical, vulvar and vaginal cancer, and ovarian cancer. PMID- 28625397 TI - Quantitative evaluation of heartbeat interval time series using Poincare analysis reveals distinct patterns of heart rate dynamics during cycles of vagus nerve stimulation in patients with heart failure. AB - BACKGROUND: Optimization of stimulation parameters is essential to maximizing therapeutic efficacy and minimizing side effects. METHODS: The ANTHEM-HF study enrolled patients with heart failure who received chronic autonomic regulation therapy (ART) with an implantable vagus nerve stimulation (VNS) system on either the right (n=30) or left side (n=29). Acute effects of continuously cycling VNS on R-R interval dynamics were evaluated using post hoc Poincare analysis of ECG recordings collected during multiple titration sessions over an 8-12week period. During each titration session, VNS intensity associated with maximum tolerable dose was determined. Poincare plots of R-R interval time series were created for epochs when VNS cycled from OFF to ON at varying intensity levels. RESULTS: VNS produced an immediate, relatively small change in beat-to-beat distribution of R R intervals during the 14-sec ON time, which was correlated with stimulation current amplitude (r=0.85, p=0.05). During titration of right-sided stimulation, there was a strong correlation (r=0.91, p=0.01) between stimulus intensity and the Poincare parameter of standard deviation, SD1, which is associated with high frequency heart rate variability. The effect of VNS on instantaneous heart rate was indicated by a shift in the centroid of the beat-to-beat cloud distribution demarcated by the encircling ellipse. As anticipated, left-sided stimulation did not alter any Poincare parameter except at high stimulation intensities (>=2mA). CONCLUSION: Quantitative Poincare analysis reveals a tight coupling in beat-to beat dynamics during VNS ON cycles that is directly related to stimulation intensity, providing a useful measurement for confirming autonomic engagement. PMID- 28625398 TI - Pseudoventricular tachycardia during drilling and screw placement in a cervical vertebra. PMID- 28625399 TI - RV6>RV5 vs. SD+SV4 >=2.8mV in men and >=2.3mV in women in the diagnosis of electrocardiographically-determined left ventricular hypertrophy. PMID- 28625400 TI - Successful treatment of ventricular fibrillation storm triggered by short-long short sequence; time to avoid managed ventricular pacing. AB - Sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) is caused by ventricular tachyarrhythmia that can be effectively treated by implantable cardioverter defibrillator (ICD) therapy. We report of a 28-year-old man with HCM and a dual chamber ICD, originally implanted for primary prevention of SCD, (programmed to AAI(R)-DDD(R); managed ventricular pacing (MVP) mode, Medtronic Inc. St Paul, MN USA). He presented with recurrent ICD shocks due to ventricular fibrillation (VF) despite antiarrhythmic therapy. Careful assessment of the stored electrograms demonstrated a repetitive pattern of VF initiation following short-long-short sequences. Initially, activation of ventricular rate stabilization (VRS) algorithm failed to prevent recurrent VF. Ultimately, deactivation of MVP and reprogramming the device to DDD mode with VRS on, resulted in arrhythmia suppression and avoidance of ICD shocks. Physicians should be aware that although VRS function is available in MVP mode, it does not function in the AAI mode during MVP; in order to effectively treat short-long short sequence induced ventricular arrhythmia by device programming. PMID- 28625401 TI - Stabilization in the Prevalence of Overweight and Obesity in Spanish Children and Young Adolescents. PMID- 28625402 TI - Comparison between catheter-based delivery of paclitaxel after bare-metal stenting and drug-eluting stents in coronary artery disease patients at high risk for in-stent restenosis. AB - BACKGROUND: Drug eluting stents reduce the risk of in-stent restenosis but delay healing of the vascular wall. Recent data on late and very late stent thrombosis after drug-eluting stent (DES) implantation have raised concerns about the long term safety. High lipophilicity of paclitaxel promotes rapid cellular uptake and prolongs its action. This makes paclitaxel a very promising candidate for local drug therapy intended to inhibit the proliferative and migratory processes involved in restenosis following PCI. OBJECTIVES: In a prospective randomized trial, we compared the efficacy of the new catheter based delivery of fluid paclitaxel after bare metal stenting with that of drug eluting stents in patients at high risk for in-stent restenosis. METHODS AND RESULTS: We conducted a prospective, randomized trial comparing the local delivery of fluid paclitaxel after bare metal stent implantation (DDB+BMS group) with the implantation of drug eluting stent (DES group) (1:1) in 68 patients at high risk for in-stent restenosis. The primary end points were in-stent late lumen loss and binary restenosis rate >50%. Secondary end points were procedure success and composite clinical end points (major adverse cardiac events and revascularization of the target lesion) 6months after intervention. At 6months, follow-up angiography showed an in-stent late lumen loss of 1.0+/-1.3mm in (DDB+BMS group) versus 0.94+/-1.3mm in DES group (P=.743) without statistically significant difference in the cumulative overall rate of major cardiac events between both groups. DES subgroup analysis showed in-stent late lumen loss of 0.09+/-0.3mm in everolimus eluting stent (EES) subgroup patients that was statistically significant in comparison with (DDB+BMS group, n=30) (P=.033) and paclitaxel eluting stent (PES, n=19) subgroup patients (P=.006).Target lesion revascularization was 0% in EES subgoup patients, 36.7% in DDB+BMS group patients and 47.7% in PES subgroup patients (P=.026). CONCLUSION: Paclitaxel either in fluid form used in drug delivery balloons or in polymerized form used in drug eluting stents was ineffective in reducing neointimal proliferation, in-stent restenosis, and clinical events. EES was superior compared with PES and catheter based delivery of fluid paclitaxel after bare metal stent implantation regarding primary and secondary end points. PMID- 28625403 TI - Therapeutic effect of sertindole on neurocognitive deficit independently of positive and negative symptoms response: A case report. PMID- 28625404 TI - Editorial. PMID- 28625405 TI - Metabolomic analysis with 1H-NMR for non-invasive diagnosis of hepatic fibrosis degree in patients with chronic hepatitis C. AB - BACKGROUND: The assessment of fibrosis degree in liver diseases is based on several non-invasive techniques, but none has been accurate. AIM: This study employed proton nuclear magnetic resonance spectroscopy to identify metabolic profiles in serum and urine, specific for different fibrosis degree in chronic hepatitis C patients. METHOD: 71 plasma, 73 serum, and 578 urine samples were collected. All samples were analyzed using 1H-NMR spectroscopy technique and three different NMR spectra were acquired for each serum/plasma sample. The data analyses were performed by partial least square regression, principal component analysis, and Monte Carlo cross-validation in a supervised methodology. RESULTS: The cross-validation test correctly assigned each sample to its specific donor with 98.44% accuracy for urine samples and 65% for serum/plasma samples. Advanced fibrosis and cirrhosis were recognized with 71% sensitivity for CPMG plasma spectra and 69% specificity for NOESY serum spectra. Accuracy for NOESY serum spectra was 68%. Noesy spectra recognized advanced fibrosis and cirrhosis with 71% sensitivity, 30% specificity, and 50% accuracy in urine samples. CONCLUSION: Metabolomic analysis of urine spectra using 1H-NMR spectroscopy can recognize a specific individual profile in all patients with chronic hepatitis C. However, this method cannot yet differentiate with sufficient accuracy, patients with advanced fibrosis from patients with milder disease. PMID- 28625406 TI - Ductal stones recurrence after extracorporeal shock wave lithotripsy for difficult common bile duct stones: Predictive factors. AB - BACKGROUND & PURPOSE: Extra-corporeal shock wave lithotripsy (ESWL) can be considered in difficult common bile duct stones (DCBDS), with a success rate greater than 90% but data on stone recurrence after ESWL are limited. We performed a retrospective analysis to evaluate long-term outcomes in patients who underwent ESWL for DCBDS. METHODS: From May 1992 to October 2012, patients who underwent ESWL treatment for DCBDS, not amenable to endoscopic extraction, were included. Data on long-term outcome were collected through phone interviews and medical records. RESULTS: A total of 201 patients with a successful clearance of DCBDS after ESWL were included. During a median follow-up period of 4.64 years, 40 patients (20%) developed a recurrence of bile duct stones. Logistic regression analysis showed that the common bile duct diameter, gallstones presence and the maximum stone size were significantly associated with recurrence. CONCLUSIONS: We observed a recurrence rate of 20% over a median follow-up of 4 years. Gallbladder stones, stone size and a dilated common bile duct diameter are risk factors for recurrent stone formation, while ursodeoxycholic acid treatment did not influence recurrence in our population. PMID- 28625408 TI - A contextual review of the Carnivora of Kanapoi. AB - The Early Pliocene is a crucial time period in carnivoran evolution. Holarctic carnivoran faunas suffered a turnover event at the Miocene-Pliocene boundary. This event is also observed in Africa but its onset is later and the process more drawn-out. Kanapoi is one of the earliest faunas in Africa to show evidence of a fauna that is more typical Pliocene than Miocene in character. The taxa recovered from Kanapoi are: Torolutra sp., Enhydriodon (2 species), Genetta sp., Helogale sp., Homotherium sp., Dinofelis petteri, Felis sp., and Parahyaena howelli. Analysis of the broader carnivoran context of which Kanapoi is an example shows that all these taxa are characteristic of Plio-Pleistocene African faunas, rather than Miocene ones. While some are still extant and some went extinct in the Early Pleistocene, P. howelli is unique in both originating and going extinct in the Early Pliocene. PMID- 28625407 TI - Xenopus-FV3 host-pathogen interactions and immune evasion. AB - We first review fundamental insights into anti-ranavirus immunity learned with the Xenopus laevis/ranavirus FV3 model that are generally applicable to ectothermic vertebrates. We then further investigate FV3 genes involved in immune evasion. Focusing on FV3 knockout (KO) mutants defective for a putative viral caspase activation and recruitment domain-containing (CARD)-like protein (Delta64R-FV3), a beta-hydroxysteroid dehydrogenase homolog (Delta52L-FV3), and an immediate-early18kDa protein (FV3-Delta18K), we assessed the involvement of these viral genes in replication, dissemination and interaction with peritoneal macrophages in tadpole and adult frogs. Our results substantiate the role of 64R and 52L as critical immune evasion genes, promoting persistence and dissemination in the host by counteracting type III IFN in tadpoles and type I IFN in adult frogs. Comparably, the substantial accumulation of genome copy numbers and exacerbation of type I and III IFN gene expression responses but deficient release of infectious virus suggests that 18K is a viral regulatory gene. PMID- 28625409 TI - Ideal Worker and Academic Professional Identity: Perspectives from a Career Flexibility Educational Intervention. PMID- 28625410 TI - Sialadenoma papilliferum in the buccal mucosa detected on 18F-fluorodeoxyglucose positron emission tomography. AB - An incidental discovery of an accumulation of 18F-fluorodeoxyglucose (FDG) in the oral cavity of patients with malignant tumours on FDG positron emission tomography (PET) can pose a problem regarding the differential diagnosis of metastatic lesions. Large accumulations can often be found even when tumours in the salivary or thyroid gland are benign, so FDG-PET is limited in its ability to differentiate between benign and malignant disease. This report describes a rare case of sialadenoma papilliferum in the buccal mucosa that was discovered incidentally on FDG-PET in a patient with multiple metastases to bone after an operation for rectal cancer. PMID- 28625411 TI - Re: Segmental mandibulectomies made easier: a simple drill guide. PMID- 28625412 TI - Diathermy of split-thickness skin graft donor site: a new technique. PMID- 28625413 TI - Invisible people with invisible pain: A commentary on "Even my sister says I'm acting like a crazy to get a check": Race, gender, and moral boundary-work in women's claims of disabling chronic pain. AB - This commentary to Pryma's (2017) article on women with fibromyalgia argues that intersectional approaches to health research can reveal not only how racialized institutions shape illness experience and medical care, but also how these institutions make some individuals visible, while rendering others invisible. Perhaps by adopting an intersectional approach to understanding health, we can start to unpack the multiple jeopardies faced by people of color in pain. PMID- 28625414 TI - Effects of health empowerment intervention on resilience of adolescents in a tribal area: A study using the Solomon four-groups design. AB - RATIONALE: Resilience prevents the emergence of stress-related mental health problems among adolescents. Adolescents in tribal areas of India are more prone to develop such problems. OBJECTIVES: The primary objective was to determine the effect of combined life skills-based health empowerment intervention on the resilience of school-going adolescents in a tribal area. The secondary objectives were to determine the effect of the intervention on internal health locus of control and self-determination and to compare the effect of intervention on resilience between non-tribal and tribal adolescents. METHODS: We conducted this quasi-experimental study using a Solomon four-group design among 742 adolescents in two schools of Purulia, West Bengal, India. Students of the pretested group were examined for resilience using the Child Youth Resilience Measurement scale. A life skills education-based health empowerment intervention was administered among students of the experimental group. Post-test data on resilience, self determination, internal health locus of control and pathological behaviour was obtained 3 months after the completion of intervention. A multi-level general linear mixed model was constructed to determine the effect of intervention on resilience. RESULTS: Resilience was less among tribal adolescents at baseline. The intervention significantly improved resilience [betaAdjusted = 11.19 (95% CI = 10.55, 11.83], with a greater increase for tribal adolescents [betatribal nontribal = 1.53 (95% CI = 0.03, 3.03)]. The intervention also significantly improved internal health locus of control (marginal mean increment 1.38 +/- 0.05), self-determination (marginal mean increment 3.71 +/- 0.09) and reduced pathological behaviour of the adolescents. CONCLUSION: Our study informed the current health policy that the existing life skills education-based programme should be reviewed and modified to include generic life skills, and the life skills education-based programme should be coupled with developmental interventions aimed at improving adult education and family climate for optimum effect on mental health and health behaviour of adolescents. PMID- 28625415 TI - Gastric metastatic extension of invasive ductal carcinoma of the breast with atypical endoscopic presentation. PMID- 28625416 TI - Omeprazole-induced hallucinations. Not as rare as you might think. PMID- 28625418 TI - Undermining government tax policies: Common legal strategies employed by the tobacco industry in response to tobacco tax increases. AB - Effective tobacco tax increases reduce tobacco consumption, threatening the profitability of the tobacco industry. In response, the tobacco industry employs strategies to negate or minimize the full effects of tobacco tax increases. By interacting with various government agencies and non-governmental organizations we identified seven such strategies: stockpiling, changing product attributes or production processes, lowering prices, over-shifting prices, under-shifting prices, timing of price increases, and engaging in price discrimination and/or offering promotions. Each strategy is described in terms of the motivation for their employment, the consequences for tobacco use and tax revenue, and measures to counter them. Country case studies illustrate the successful execution of the strategies and possible government responses. Many of the tobacco industry's responses to tobacco tax increases are predictable, since they are being employed systematically across countries. Governments can and should adopt appropriate measures to eliminate or reduce tobacco industry manipulation. This requires systematic data collection in order to monitor tobacco industry behavior. PMID- 28625417 TI - Modeled auditory nerve responses to amplitude modulated cochlear implant stimulation. AB - Cochlear implants encode speech information by stimulating the auditory nerve with amplitude-modulated pulse trains. A computer model of the auditory nerve's response to electrical stimulation can be used to evaluate different approaches to improving CI patients' perception. In this paper a computationally efficient stochastic and adaptive auditory nerve model was used to investigate full nerve responses to amplitude-modulated electrical pulse trains. The model was validated for nerve responses to AM pulse trains via comparison with animal data. The influence of different parameters, such as adaptation and stochasticity, on long term adaptation and modulation-following behavior was investigated. Responses to pulse trains with different pulse amplitudes, amplitude modulation frequencies, and modulation depths were modeled. Rate responses as well as period histograms, Vector Strength and the fundamental frequency were characterized in different time bins. The response alterations, including frequency following behavior, observed over the stimulus duration were similar to those seen in animal experiments. The tested model can be used to predict complete nerve responses to arbitrary input, and thus to different sound coding strategies. PMID- 28625419 TI - Recommendation of colorectal cancer testing among primary care patients younger than 50 with elevated risk. AB - In the era of precision medicine, efforts are needed to identify and tailor screening recommendations among elevated-risk patients. Individuals younger than 50years are an important target population, as they comprise 15% of colorectal (CRC) cases and often present with more advanced disease than their 50+ counterparts. In this large study, 2470 patients ages 25-49 used a tablet-based program that assessed risks, matched risks with screening guidelines, and generated tailored printed guideline-concordant recommendations for patients and their providers. The tablet-based program identified 121 (4.9%) patients with risk factors warranting screening before age 50. Likelihood of risk warranting screening was greater for ages 40-49 than <40years (OR: 2.38), females than males (OR: 1.82), and African Americans (OR: 1.69) and non-Hispanic Whites (OR: 2.89) compared to Hispanics. Most common risk factors were family history of polyps (23.1%), personal history of inflammatory bowel disease (19.8%), and combined family history of CRC+polyps (18.2%). Receipt of guideline-concordant screening within 6months of identification was low, including only 5.3% of those who needed colonoscopy and 13.3% for whom colonoscopy or FIT was recommended. Although elevated-risk patients younger than 50years can be readily identified, more than notification is necessary to facilitate screening participation. PMID- 28625420 TI - Formation and remodeling of the brain extracellular matrix in neural plasticity: Roles of chondroitin sulfate and hyaluronan. AB - BACKGROUND: The extracellular matrix (ECM) of the brain is rich in glycosaminoglycans such as chondroitin sulfate (CS) and hyaluronan. These glycosaminoglycans are organized into either diffuse or condensed ECM. Diffuse ECM is distributed throughout the brain and fills perisynaptic spaces, whereas condensed ECM selectively surrounds parvalbumin-expressing inhibitory neurons (PV cells) in mesh-like structures called perineuronal nets (PNNs). The brain ECM acts as a non-specific physical barrier that modulates neural plasticity and axon regeneration. SCOPE OF REVIEW: Here, we review recent progress in understanding of the molecular basis of organization and remodeling of the brain ECM, and the involvement of several types of experience-dependent neural plasticity, with a particular focus on the mechanism that regulates PV cell function through specific interactions between CS chains and their binding partners. We also discuss how the barrier function of the brain ECM restricts dendritic spine dynamics and limits axon regeneration after injury. MAJOR CONCLUSIONS: The brain ECM not only forms physical barriers that modulate neural plasticity and axon regeneration, but also forms molecular brakes that actively controls maturation of PV cells and synapse plasticity in which sulfation patterns of CS chains play a key role. Structural remodeling of the brain ECM modulates neural function during development and pathogenesis. GENERAL SIGNIFICANCE: Genetic or enzymatic manipulation of the brain ECM may restore neural plasticity and enhance recovery from nerve injury. This article is part of a Special Issue entitled Neuro glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. PMID- 28625421 TI - Insights into the anticancer properties of the first antimicrobial peptide from Archaea. AB - BACKGROUND: The peptide VLL-28, identified in the sequence of an archaeal protein, the transcription factor Stf76 from Sulfolobus islandicus, was previously identified and characterized as an antimicrobial peptide, possessing a broad-spectrum antibacterial activity. METHODS: Through a combined approach of NMR and Circular Dichroism spectroscopy, Dynamic Light Scattering, confocal microscopy and cell viability assays, the interaction of VLL-28 with the membranes of both parental and malignant cell lines has been characterized and peptide mechanism of action has been studied. RESULTS: It is here demonstrated that VLL-28 selectively exerts cytotoxic activity against murine and human tumor cells. By means of structural methodologies, VLL-28 interaction with the membranes has been proven and the binding residues have been identified. Confocal microscopy data show that VLL-28 is internalized only into tumor cells. Finally, it is shown that cell death is mainly caused by a time-dependent activation of apoptotic pathways. CONCLUSIONS: VLL-28, deriving from the archaeal kingdom, is here found to be endowed with selective cytotoxic activity towards both murine and human cancer cells and consequently can be classified as an ACP. GENERAL SIGNIFICANCE: VLL-28 represents the first ACP identified in an archaeal microorganism, exerting a trans-kingdom activity. PMID- 28625422 TI - Online version of the self-administered food frequency questionnaire for the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC NEXT) protocol: Relative validity, usability, and comparison with a printed questionnaire. AB - BACKGROUND: Online dietary assessment tools offer advantages over printed questionnaires, such as the automatic and direct data storage of answers, and have the potential to become valuable research methods. We developed an online survey system (web-FFQ) for the existing printed FFQ used in the JPHC-NEXT protocol, the platform of a large-scale genetic cohort study. Here, we examined the validity of ranking individuals according to dietary intake using this web FFQ and its usability compared with the printed questionnaire (print-FFQ) for combined usage. METHODS: We included 237 men and women aged 40-74 years from five areas specified in the JPHC-NEXT protocol. From 2012 to 2013, participants were asked to provide 12-day weighed food records (12d-WFR) as the reference intake and to respond to the print- and web-FFQs. Spearman's correlation coefficients (CCs) between estimates using the web-FFQ and 12d-WFR were calculated. Cross classification of intakes was compared with those using the print-FFQ. RESULTS: Most participants (83%) answered that completing the web-FFQ was comparable to or easier than completing the printed questionnaire. The median value of CCs across energy and 53 nutrients for men and women was 0.47 (range, 0.10-0.86) and 0.46 (range, 0.16-0.69), respectively. CCs for individual nutrient intakes were closely similar to those based on the print-FFQ, irrespective of response location. Cross-classification by quintile of intake based on two FFQs was reasonably accurate for many nutrients and food groups. CONCLUSION: This online survey system is a reasonably valid measure for ranking individuals by intake for many nutrients, like the printed FFQ. Mixing of two FFQs for exposure assessments in epidemiological studies appears acceptable. PMID- 28625423 TI - [Cryptogenic organising pneumonia as a cause of chronic cough]. PMID- 28625424 TI - Scheduling non-operating room anesthesia cases in endoscopy: Using the sandbox analogy. AB - STUDY OBJECTIVE: For many hospitals, the non-operating room anesthesia (NORA) workload continues to expand. We developed a new NORA scheduling process with shared block time - a sandbox - amongst all of the gastroenterology groups and measured the efficacy of the intervention using basic operating room management metrics. DESIGN: Prospective analysis, statistical process control. SETTING: Academic, rural hospital; endoscopy suite; postoperative recovery area. PATIENTS: Adults and pediatric patients undergoing elective and/or urgent endoscopic procedures. INTERVENTIONS: In 2014, we divided the NORA block allocations on Thursdays into one afternoon block for pediatric GI, and 1.5 blocks to be shared between the two adult GI groups. We made a provision for an additional afternoon block available if necessary. No changes were made in the release policy. For scheduling, shared block time was released between the three endoscopy groups at 7days and then opened to the general pool at 48h. MEASUREMENTS: Case volumes, under-utilized time (opportunity-unused), elective time-in-block, over-utilized time. MAIN RESULTS: With the addition of a pediatric gastroenterologist, the number of cases per month increased after the change in scheduling procedure from a mean of 107 cases per month to 131, an increase of 23% (p=<0.01) (see Chart 1). Elective time-in-block increased after the intervention by 13% (p=0.09), while under-utilized time (opportunity-unused time) decreased in a reciprocal fashion (15%, p=0.03). Pre-intervention mean over-utilized time was 101min/month, while post-intervention over-utilized time decreased by 84.5% (99% CI +/-3.29) to a mean of 16min/month. CONCLUSIONS: By using a multi-disciplinary, team-based approach, we were able to increase throughput without increasing under-utilized or over-utilized time, thereby increasing efficiency. Despite the additional cases brought in by the pediatric gastroenterologist, opportunity-unused time decreased only moderately-lending support to our prediction that opening an additional NORA block was not only unnecessary to accommodate expansion of the gastroenterology service, but was also financially unviable. One of the challenges in reducing under-utilized time lies in the relatively new role played by anesthesia in the NORA environment. In our study, we showed that the open access policy applies when the block allocations have under-utilized time. As anesthesiologists continue to expand their practice into the NORA environment, good communication, interdepartmental collaboration, and flexible scheduling processes are essential to improving efficiency. PMID- 28625425 TI - Acetaminophen and ondansetron: The central serotonergic connection. PMID- 28625426 TI - Acute pain management in the pediatric ambulatory setting: How do we optimize the child's postoperative experience? PMID- 28625427 TI - Revolutionizing medication administration safety: Automated carts are here - Are anesthesiologists ready? PMID- 28625428 TI - Bioimpedence: A noninvasive measure of stroke volume and cardiac output. PMID- 28625429 TI - Automated anesthesia carts reduce drug recording errors in medication administrations - A single center study in the largest tertiary referral hospital in China. AB - AIM: To clinically evaluate a type of patented automated anesthesia cart in medication administrations in anesthesia. MATERIALS AND METHODS: This was a prospectively randomized open label clinical trial. In 10 designated operating suits in the First Affiliated Hospital of Zhengzhou University, in China. 1066 cases originated from 10,812 medication administrations in anesthesia were randomized. 78 registered anesthesiologists managed the medication. The patients received medication administrations in anesthesia with either an automated or a conventional manual cart. American Society of Anesthesiologists (ASA) score, sex, duration of anesthesia and surgical specialty, errors in administration of medications (incorrect medication given (substitution), medication not given (omission) and drug recordings errors"), compliance and satisfaction were recorded. RESULTS: The total error rate was 7.3% with the automated anesthesia carts (1 in 14 administrations) and 11.9% with conventional manual carts (1 in 8 administrations). Automated anesthesia carts significantly reduced the drug recording error rate compared to conventional manual carts (P<0.01). However, no significant difference of substitution or errors omission errors was found between groups of automated anesthesia carts and conventional manual carts. The anesthesiologists' compliance with the automated anesthesia carts was unsatisfactory, and all the errors in medication recordings with the automated anesthesia carts were due to the incorrect use of the carts. Most of the participating anesthesiologists preferred the automated anesthesia carts (P<0.05). CONCLUSIONS: The utilization of automated anesthesia carts reduced the drug recording errors in medication administrations of anesthesia. PMID- 28625430 TI - Sensorimotor and executive function slowing in anesthesiology residents after overnight shifts. AB - STUDY OBJECTIVE: Medical residents working overnight call shifts experience sleep deprivation and circadian clock disruption. This leads to deficits in sensorimotor function and increases in workplace accidents. Using quick tablet based tasks, we investigate whether measureable executive function differences exist following a single overnight call versus routine shift, and whether factors like stress, rest and caffeine affect these measures. DESIGN: A prospective, observational, longitudinal, comparison study was conducted. SETTING: An academic tertiary hospital's main operating room suite staffed by attending anesthesiologists, anesthesiology residents, anesthesiologist assistants and nurse anesthetists. PATIENTS: Subjects were 30 anesthesiology residents working daytime shifts and 30 peers working overnight call shifts from the University of Texas Health Science Center at Houston. INTERVENTIONS: Before and after their respective work shifts, residents completed the Stanford Sleepiness Scale (SSS) and the ProPoint and AntiPoint tablet-based tasks. These latter tasks are designed to measure sensorimotor and executive functions, respectively. MEASUREMENTS: The SSS is a self-reported measure of sleepiness. Response times (RTs) are measured in the pointing tasks. MAIN RESULTS: Call residents exhibited increased RTs across their shifts (post-pre) on both ProPoint (p=0.002) and AntiPoint (p<0.002) tasks, when compared to Routine residents. Increased stress was associated with decreases in AntiPoint RT for Routine (p=0.007), but with greater increases in sleepiness for Call residents (p<0.001). Further, whether or not a Call resident consumed caffeine habitually was associated with ProPoint RT changes; with Call residents who habitually drink caffeine having a greater Pre Post difference (i.e., more slowing, p<0.001) in ProPoint RT. CONCLUSIONS: These results indicate that (1) overnight Call residents demonstrate both sensorimotor and cognitive slowing compared to routine daytime shift residents, (2) sensorimotor slowing is greater in overnight Call residents who drink caffeine habitually, and (3) increased stress during a shift reduces (improves) cognitive RTs during routine daytime but not overnight call shifts. PMID- 28625431 TI - Fishing for answers in an ocean of data: The potential for big data analytics to enhance our knowledge of the complex regional pain syndromes. PMID- 28625432 TI - The LMA Supreme: Is it a suitable alternative to the i-gel and LMA ProSeal for airway maintenance in children? PMID- 28625433 TI - Dexmedetomidine and Renal Protection after Cardiac Surgery. PMID- 28625434 TI - Overnight call and cognitive functioning: Will tablet-based assessment be the solution for safety check in residents? PMID- 28625435 TI - Neuraxial hypothermia incidence misinterpreted. PMID- 28625436 TI - Can sagittal approach for cadaveric study of TTP block spread more than transverse approach? PMID- 28625437 TI - Inhalation versus intravenous anaesthesia for adults undergoing on-pump or off pump coronary artery bypass grafting: A systematic review and meta-analysis of randomized controlled trials. AB - STUDY OBJECTIVE: To compare the use of inhalation versus intravenous anaesthesia for adults undergoing on-pump or off-pump coronary artery bypass grafting. DESIGN: A systematic review. SETTING: A hospital-affiliated university. MEASUREMENTS: The following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 10), MEDLINE, EMBASE, and LILACS (from inception to October 2016). We used the GRADE approach to rate overall certainty of the evidence. RESULTS: In total we included 58 studies with a total of 6105 participants. The methodological quality was difficult to assess as it was poorly reported in 35 included studies (three or more domains were rated as unclear risk of bias). Two trials of sevoflurane showed a statistically significant reduction in death within 180 to 365days of surgery (on-pump) (RR 4.10, 95% CI 1.42 to 11.79; p=0.009; I2=not applicable; high quality of evidence). There was also a statistically significant difference favouring sevoflurane compared to propofol on both inotropic (RR 2.11, 95% CI 1.53 to 2.90; p<0.00001; I2=0%) and vasoconstrictor support needed (RR 1.51, 95% CI 1.04 to 2.22; p=0.03; I2=0%) after coronary artery bypass grafting on-pump. Two trials of sevoflurane (MD -0.22, 95% CI -0.41 to -0.03; p=0.02; I2=0%) and two further trials of desflurane (MD -0.33, 95% CI -0.45 to -0.20; p<0.00001; I2=82%) showed a statistically significant difference on cardiac index during and after coronary artery bypass grafting on-pump, respectively. CONCLUSIONS: There is high quality evidence that sevoflurane reduces death within 180 to 365days of surgery and, inotropic and vasoconstrictor support compared to propofol for patients undergoing coronary artery bypass grafting. There is also some evidence showing that the cardiac index is minimally influenced by administration of sevoflurane and desflurane compared to propofol. PMID- 28625438 TI - Efficacy of prophylactic doses of intravenous nitroglycerin in preventing myocardial ischemia under general anesthesia: A systematic review and meta analysis with trial sequential analysis. AB - STUDY OBJECTIVE: To evaluate the efficacy of intravenous nitroglycerin (TNG) in preventing intraoperative myocardial ischemia (MI) under general anesthesia. Moreover, we analyzed the hemodynamic changes in heart rate (HR), mean blood pressure (MBP), and pulmonary capillary wedge pressure (PCWP) associated with TNG administration both before and after the induction of anesthesia. DESIGN: Meta analysis. SETTING: Operating room, cardiac surgery or non-cardiac surgery, all surgeries were elective measurements. We performed a computerized search of articles on PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. Meta-analysis was performed using Review Manager. The data from the individual trials were combined using a random-effects model to calculate either the pooled relative risk (RR) or the weighted mean difference (WMD) with 95% confidence interval (CI). We conducted trial sequential analysis (TSA). The primary outcome was the incidence of MI and the secondary outcomes were hemodynamic changes (HR, MBP, and PCWP). MAIN RESULTS: Using electronic databases, we selected 10 trials with a total of 353 patients for our review. Prophylactic intravenous TNG did not significantly decrease the incidence of MI (RR=0.61; CI, 0.33 to 1.13; P=0.12; I2=55). TSA corrected the CI to 0.05 to 7.39 and showed that 9.5% of the required information size was achieved. In terms of hemodynamic changes, intravenous TNG significantly reduced MBP in comparison with the placebo (MBP pre-induction: WMD=-7.27; 95% CI -14.2 to -0.33; P=0.04; I2=97%; MBP post-induction: WMD=-5.13; 95% CI -9.17 to -1.09; P=0.01; I2=73%). CONCLUSIONS: Our analyses showed that prophylactic intravenous TNG does not reduce the incidence of intraoperative MI. Moreover, TSA suggests that further studies are necessary to confirm the results (GRADE: very low). Prophylactic doses of intravenous TNG significantly reduced the MBP both pre and post anesthesia induction (GRADE: very low). PMID- 28625439 TI - Clinical experiences of Ultrasound-guided transversus thoracic muscle plane block for children. PMID- 28625440 TI - Apple body type information improves validity of the STOP-BANG questionnaire for detecting obstructive sleep apnea. PMID- 28625441 TI - The protective effects of dexmedetomidine on ischemic brain injury: A meta analysis. AB - BACKGROUND: Intracranial lesions, trauma or surgery-related damage activate immune inflammation and neuroendocrine responses, causing ischemic brain injury. Studies have shown that inflammatory cascade mediated by neuroendocrine hormones and proinflammatory mediators is implicated in the pathophysiology of ischemic brain injury. Alpha2-adrenoceptor agonists, dexmedetomidine, is widely used as neuroprotectants in anesthesia practice. However, it is still lack of a comprehensive meta-analysis to evaluate the neuroprotection of dexmedetomidine against ischemic brain injury via suppressing these two physiological responses. METHOD: Searched the Cochrane Library, Pub-Med, EMBASE, EBSCO, Ovid, Chinese biological and medical database (CBM). Related literatures published in English or Chinese before January 2017 were enrolled. We assessed the quality of eligible studies and synthesized predefined outcomes with a random-effects model or fixed effects model. RESULT: Nineteen Randomized Controlled Trials including 879 patients were included. Findings for meta-analysis of various outcomes were summarised. Primary results shown that compared with placebo, dexmedetomidine reduced a surge of TNF-alpha [SMD=-2.34, 95%CI (-3.25, -1.44)], IL-6 [SMD=-2.44, 95%CI (-3.40, -1.47)], S100-beta [SMD=-2.73, 95%CI (-3.65, -1.82)], NSE [SMD= 1.69, 95%CI (-2.77, -0.61)], cortisol [SMD=-2.48, 95%CI (-3.38, -1.58)] and glucose [SMD=-1.44, 95%CI (-1.85, -1.04)]; maintained the level of SOD [SMD=1.36, 95%CI (0.62, 2.10)]; decreased the rise in CRP level at postoperative one day. In response to stress reaction, dexmedetomidine attenuated the stress-related increasing of MAP, HR and intracranial pressure without significant effects on cerebral oxygen metabolism. CONCLUSION: Alpha2-adrenoceptor agonists, dexmedetomidine, could reduce the release of inflammatory mediators and neuroendocrine hormones as well as maintain intracranial homoeostasis, alleviating ischemic brain injury and exerting an effect on brain protection. PMID- 28625443 TI - Inattentional blindness - Do we really see what we see? PMID- 28625442 TI - The effect of dexmedetomidine on renal function in patients undergoing cardiac valve replacement under cardiopulmonary bypass: A double-blind randomized controlled trial. AB - STUDY OBJECTIVE: We attempted to explore the effect of Dex on renal function in patients with cardiac valve replacement under cardiopulmonary bypass (CPB). DESIGN: We designed a prospective, randomized, placebo-controlled, single-center, parallel-arm double-blind trial. SETTING: Operating room. PATIENTS: Seven-two eligible patients were randomly divided into Dex group and placebo group. INTERVENTIONS: Dexmedetomidine (Dex) (0.6MUg.kg-1) was administered in patients of Dex group at 15min before anesthesia induction, followed by a treatment of 0.2MUg.kg-1.h-1 Dex until the end of operation. Patients in placebo group were treated with normal saline equally. MEASUREMENTS: The levels of serum urea nitrogen (BUN), creatinine (Cr), neutrophil gelatinase-associated lipocalin (NGAL), urine interleukin-8 (IL-18) and superoxide dismutase (SOD) activity were tested before anesthesia induction (T1) and after operation at 0, 12h, 24h and 72h (T2-5). The urine output during operation and the post-operative complication of acute kidney injury (AKI) were recorded. MAIN RESULTS: The levels of BUN and Cr were significantly increased at T5, and similar findings were found in the levels of NGAL and urine IL-18 at T3 and T4. The SOD activity was significantly declined at T2 and T3 in the two groups. The levels of BUN and Cr at T5 and the NGAL level at T3 and T4 were significantly lower in Dex group, comparable to placebo group. The intraoperative urine output was significantly increased and the postoperative incidence of AKI was significantly lower in Dex group. CONCLUSIONS: Dex may attenuate the renal injury and decrease the incidence of AKI in patients undergoing cardiac valve replacement under CPB. PMID- 28625444 TI - Nitrous oxide for labor analgesia: Utilization and predictors of conversion to neuraxial analgesia. AB - STUDY OBJECTIVE: We examined the characteristics of women who choose nitrous oxide for labor analgesia and identified factors that predict conversion from nitrous oxide to labor neuraxial analgesia. DESIGN: Retrospective descriptive study. SETTING: Labor and Delivery Ward. PATIENTS: 146 pregnant women who used nitrous oxide for analgesia during labor and delivery between September 2014 and September 2015. INTERVENTIONS: Chart review only. MEASUREMENTS: Demographic, obstetric, and intrapartum characteristics of women using nitrous oxide were examined. Multivariable logistic regression was performed to identify factors associated with conversion from nitrous oxide to neuraxial analgesia. Data are presented as n (%), median [IQR], adjusted relative risk (aRR), and 95% confidence intervals (CI) as appropriate. RESULTS: During the study period, 146 women used nitrous oxide for labor analgesia (accounting for 3% of the total deliveries). The majority (71.9%) of women who used nitrous oxide were nulliparous, and over half (51.9%) had expressed an initial preference for "nonmedical birth." The conversion rate to neuraxial blockade was 63.2%, compared to a concurrent institutional rate of 85.1% in women who did not use nitrous oxide. Factors associated with conversion from nitrous oxide to neuraxial blockade were labor induction (aRR=2.0, CI 1.2-3.3) and labor augmentation (aRR=1.7, CI 1.0-2.9). CONCLUSION: Only a small number of women opted to use nitrous oxide during labor, analgesia was minimal, and most converted to neuraxial analgesia. Women with induced and augmented labors should be counseled about the increased likelihood that they will convert to neuraxial analgesia. PMID- 28625445 TI - Prospective double blind randomized placebo-controlled clinical trial of the pectoral nerves (Pecs) block type II. AB - STUDY OBJECTIVE: The aim of this clinical trial was to test the hypothesis whether adding the pectoral nerves (Pecs) block type II to the anesthetic procedure reduces opioid consumption during and after breast surgery. DESIGN: A prospective randomized double blind placebo-controlled study. SETTING: A secondary hospital. PATIENTS: 140 breast cancer stage 1-3 patients undergoing mastectomy or tumorectomy with sentinel node or axillary node dissection. INTERVENTIONS: Patients were randomized to receive either a Pecs block with levobupivacaine 0.25% (n=70) or placebo block with saline (n=70). MEASUREMENTS: The pain levels were evaluated by Numeric Rating Scale (NRS) pain scores at 15 minute intervals during the post anesthesia care unit stay time (PACU), at 2-hour intervals for the first 24h on the ward and at 4-hour intervals for the next 24h. Intraoperative and postoperative opioid consumption were recorded during the full stay. Patient satisfaction was evaluated upon discharge using a 10-point scale. MAIN RESULTS: Intraoperative sufentanil requirements were comparable for the Pecs and placebo group (8.0+/-3.5MUg and 7.8+/-3.0MUg, P=0.730). Patients in the Pecs group experienced significantly less pain than patients in the control group (P=0.048) during their PACU stay. Furthermore, patients in the Pecs group required significant less postoperative opioids (9.16+/-10.15mg and 14.97+/ 14.38mg morphine equivalent, P=0.037) and required significant fewer postsurgical opioid administration interventions than patients in the control group (P=0.045). Both patient-groups were very satisfied about their management (9.6+/-0.6 and 9.1+/-1.8 on a 10-point scale, P=0.211). CONCLUSIONS: The Pecs block reduces postsurgical opioid consumption during the PACU stay time for patients undergoing breast surgery. PMID- 28625446 TI - A novel treatment for chronic opioid use after surgery. AB - In a recent article from the Center for Disease Control, the authors addressed the current opioid epidemic in America and emphasized the importance of utilizing non-opioid analgesic alternatives to opioid medication for treating chronic pain. In cases where non-opioid analgesic drugs alone have failed to produce adequate pain relief, these authors suggested that non-pharmacologic therapies should also be considered. This Case Series describes a pilot study designed to evaluate a novel non-pharmacologic approach to treating long-standing (>1year) opioid dependency. The therapy involved the use of a high intensity cold laser device to treat three patients who had become addicted to prescription opioid-containing analgesic medication for treating chronic (residual) pain after a major operation. After receiving a series of 8-12 treatment sessions lasting 20-40min to the painful surgical area over a 3-4week period of time with the high intensity (42W) Phoenix Thera-lase laser device, an FDA-approved Class IV cold laser, these patients were able to discontinue their use of all oral opioid containing analgesic medications and resume their normal activities of daily living. At a follow-up evaluation 1-2months after their last laser treatment, these patients reported that they have been able to control their pain with over the-counter non-opioid analgesics and they have remained largely opioid-free. Further larger-scale studies are needed to verify these preliminary findings with this powerful cold laser in treating opioid-dependent patients. PMID- 28625447 TI - Ultrasound-guided "lateral" thoracolumbar interfascial plane (TLIP) block: A cadaveric study of the spread of injectate. PMID- 28625448 TI - The effect of race on postsurgical ambulatory medical follow-up among United States Veterans. AB - STUDY OBJECTIVE: To investigate the association between self-identified black or African American race and the presence of ambulatory internal medicine follow-up in the year after surgery. Our hypothesis was that among US Veterans who presented for surgery, black or African American race would be associated with a decreased likelihood to receive ambulatory internal medicine follow-up in the year after surgery. DESIGN: Retrospective observational. SETTING: All US Veterans Affairs hospitals. PATIENTS: A total of 236,200 Veterans undergoing surgery between 2006 and 2011 who were discharged within 10 days of surgery and survived the full 1-year exposure period. INTERVENTIONS: None. MEASUREMENTS: Attendance at an internal medicine follow-up appointment within 1 year after surgery. MAIN RESULTS: After controlling for year of surgery, age, age >=65 years, sex, Hispanic ethnicity, and number of inpatient days, black or African American patients were 11% more likely to lack internal medicine follow-up after surgery (adjusted odds ratio, 1.11; 95% confidence interval, 1.06-1.16). When accounting for geographic region, this difference remained significant at the Bonferoni corrected P < .007 level only in the Midwest United States where black or African American patients were 28% more likely to lack medical follow-up in the year after surgery (odds ratio, 1.28; 95% confidence interval, 1.16-1.42; P < .0001). CONCLUSIONS: The disparity in ambulatory medical follow-up following surgery among black or African American vs nonblack or non-African American Veterans in the Midwest region deserves further study and may lead to important quality improvement initiatives aimed specifically at this population. PMID- 28625449 TI - Ultrasound-guided lateral thoracolumbar interfascial plane (TLIP) block: Description of new modified technique. PMID- 28625450 TI - Vasoplegic syndrome: An update on perioperative considerations. AB - Vasoplegic syndrome (VS) is increasingly recognized as an important clinical entity in perioperative medicine. VS is characterized by significant arterial hypotension, normal or high cardiac output, low systemic vascular resistance, and increased requirements for intravenous volume and vasopressors. Tremendous variations exist regarding incidence reported in the literature and management at different institutions; and the incidence of VS is likely significantly higher than many anesthesiologists believe. Thus the aims of this article are to review the pertinent aspects related to VS and alert clinical anesthesiologists to this under-recognized yet very challenging clinical condition. The potential risk factors include blood transfusion, cardiopulmonary bypass, organ transplantation, trauma and sepsis, and use of specific medications such as angiotensin-converting enzyme inhibitors, Angiotensin-II antagonist, heparin, amiodarone, aprotinin, and protamine. The pathogenesis of VS may have several mechanistic pathways, overproduction of inducible nitric oxide, activation of ATP-dependent K channels, vasopressin V1A-receptor down-regulation, and nuclear factor-kappaB activation. Current management strategies include intravenous administration of volume and catecholamines, vasopressin, methylene blue and high dose hydroxocobalamin. Other treatment could include ATP-sensitive K channel blocker, nuclear factor-kappaB inhibitor, indigo carmine, and hyperbaric oxygen therapy. VS is still associated with significantly increased perioperative morbidity and mortality. PMID- 28625451 TI - Is perioperative administration of 5% dextrose effective in reducing the incidence of PONV in laparoscopic cholecystectomy?: A randomized control trial. AB - STUDY OBJECTIVE: To compare the incidence of postoperative nausea and vomiting (PONV) during perioperative administration of 5% dextrose and normal saline in laparoscopic cholecystectomy. DESIGN: Prospective, randomized, double-blind trial. SETTING: Operating rooms in a tertiary care hospital of Northern India. PATIENTS: One hundred patients with American Society of Anesthesiologists status I to II undergoing laparoscopic cholecystectomy were enrolled in this study. INTERVENTIONS: Patients were randomized into two groups [normal saline (NS) group and 5% dextrose (D) group]. Both the groups received Ringer acetate (Sterofundin ISO) intravenously as a maintenance fluid during intraoperative period. Besides this, patients of group NS received 250ml of 0.9% normal saline and patients of group D received 5% dextrose @ 100ml/h started at the time when gall bladder was taken out. It was continued in the postoperative period with the same rate till it gets finished. MEASUREMENTS: Incidence of PONV, Apfel score, intraoperative opioids used and consumption of rescue antiemetics. MAIN RESULTS: Demographic data was statistically similar. Out of total 100 patients, 47 patients (47%) had PONV. In group D, 14 patients (28%) had PONV while in group NS, 33 patients (66%) had PONV within 24h of surgery (p value 0.001). The incidence of PONV was reduced by 38% in group D which is significantly lower when compared with that of group NS (p value 0.001). The consumption of single dose of rescue antiemetics in group D was also reduced by 26% when compared to that of group NS (p value 0.002). CONCLUSIONS: Perioperative administration of 5% dextrose in patients undergoing laparoscopic surgery can reduce PONV significantly and even if PONV occurs, the quantity of rescue antiemetics to combat PONV is also reduced significantly. PMID- 28625452 TI - Tranversus abdoimis plane (TAP) block with morphine: Local, systemic or no effect? PMID- 28625453 TI - Erector spinae plane block provides effective pain management during pneumothorax surgery. PMID- 28625454 TI - A brand new day for the journal of clinical anesthesia. PMID- 28625455 TI - Post-operative cognitive dysfunction after total knee arthroplasty: It ain't what you do, it's the way that you do it. PMID- 28625456 TI - The effect of ondansetron on analgesic efficacy of acetaminophen after hysterectomy: A randomized double blinded placebo controlled trial. AB - OBJECTIVES: To determine that perioperative ondansetron reduces the analgesic efficacy of acetaminophen. DESIGN: Randomized, double-blinded study. PATIENTS: 120 patients ASA I-II who underwent abdominal hysterectomy. INTERVENTIONS: All the patients were given 1g acetaminophen at skin closure. Patients were divided into two groups; ondansetron HCl (8mg, 2ml IV) (Group I, N=60) and saline (2ml IV) (Group II, N=60) at the skin closure. MEASUREMENT: Postoperative pain scores (VAS) while resting in bed and sitting, total opioid consumption were noted. MAIN RESULTS: Patients randomized to ondansetron had significantly worse pain scores upon arrival to the recovery unit [by 1.7 (99.7% CI: 0.75, 2.59) cm] and at 1h [by 1.3 (0.5, 2.1) cm] while resting in bed. Pain scores while sitting were also significantly greater in ondansetron group at arrival in PACU by 0.6 (99.7% CI: 0.1, 1.0) cm. Thereafter, pain scores did not differ significantly. Median total opioid (tramadol) consumption was 441 [Q1, Q3: 280, 578] mg in the ondansetron group and 412 [309, 574] mg in the placebo group, P=0.95. CONCLUSIONS: Ondansetron significantly decreased the analgesic effect of acetaminophen during the initial postoperative period. Our results thus confirm that acetaminophen analgesia is partially mediated by serotonin receptors. However, the reduction was of marginal clinical importance and short-lived. PMID- 28625457 TI - Erratum to "Anesthesiologists' perceptions of minimum acceptable work habits of nurse anesthetists" [J Clin Anesth 38 (2017) 107-110]. PMID- 28625458 TI - Assessing effects of intubating stylet use on early postoperative pharyngeal pain. PMID- 28625459 TI - Workload, efficiency, and productivity following open access scheduling in a gastrointestinal endoscopy suite. PMID- 28625460 TI - Perioperative use of angiotensin-converting-enzyme inhibitors and angiotensin receptor antagonists. AB - STUDY OBJECTIVE: Clinical repercussions of perioperative treatment with ACEIs/ARBs. DESIGN: Systematic review according to PRISMA statement. SETTING: Perioperative period. PATIENTS: 29 studies 11 cases/cases series, 12 observational studies and 6 randomized studies. MEASUREMENTS: Arterial blood pressure differences, refractory hypotension, other comorbidities. MAIN RESULTS: The studies show different results regarding the topics measured. They are divided in the results regarding blood pressure, long term morbidities and effects in neuraxial anesthesia. CONCLUSIONS: Withholding AECI/ARBs on the morning prior to surgery could be recommended as a potentially effective measure, with a low level of evidence, in order to reduce the appearance of hypotension in the perioperative period of non-cardiac surgery. PMID- 28625461 TI - Did we open a treasure chest of chest blocks? The jury is out. PMID- 28625462 TI - The King-Devick Test and concussion diagnosis. PMID- 28625463 TI - TREX1 Cuts Down on Cancer Immunogenicity. AB - Demaria and colleagues have recently identified three prime repair exonuclease 1 (TREX1) as a key determinant for the limited immunogenicity of cancer cells responding to single high-dose radiation. TREX1 stands out as a promising target for the development of novel strategies to boost anticancer immune responses driven by radiation therapy (RT). PMID- 28625464 TI - Becker's Nevus and Lethal Beta-Actin Mutations. AB - The etiology of Becker's nevus and Becker's nevus syndrome has been until now unknown. Cai et al. provide evidence that these disorders are caused by lethal mutations in ACTB, a gene coding for beta-actin. They hypothesize that these mutations may interfere with Hedgehog pathway signaling. Their findings have important implications for clinical genetics, and they open new aspects in hair research. PMID- 28625465 TI - CON4EI: SkinEthicTM Human Corneal Epithelium Eye Irritation Test (SkinEthicTM HCE EIT) for hazard identification and labelling of eye irritating chemicals. AB - Assessment of ocular irritancy is an international regulatory requirement and a necessary step in the safety evaluation of industrial and consumer products. Although a number of in vitro ocular irritation assays exist, none are capable of fully categorizing chemicals as a stand-alone assay. Therefore, the CEFIC-LRI AIMT6-VITO CON4EI (CONsortium for in vitro Eye Irritation testing strategy) project was developed with the goal of assessing the reliability of eight in vitro/alternative test methods as well as establishing an optimal tiered-testing strategy. One of the in vitro assays selected was the validated SkinEthicTM Human Corneal Epithelium Eye Irritation Test method (SkinEthicTM HCE EIT). The SkinEthicTM HCE EIT has already demonstrated its capacity to correctly identify chemicals (both substances and mixtures) not requiring classification and labelling for eye irritation or serious eye damage (No Category). The goal of this study was to evaluate the performance of the SkinEthicTM HCE EIT test method in terms of the important in vivo drivers of classification. For the performance with respect to the drivers all in vivo Cat 1 and No Cat chemicals were 100% correctly identified. For Cat 2 chemicals the liquids and the solids had a sensitivity of 100% and 85.7%, respectively. For the SkinEthicTM HCE EIT test method, 100% concordance in predictions (No Cat versus No prediction can be made) between the two participating laboratories was obtained. The accuracy of the SkinEthicTM HCE EIT was 97.5% with 100% sensitivity and 96.9% specificity. The SkinEthicTM HCE EIT confirms its excellent results of the validation studies. PMID- 28625466 TI - First Pediatric Patient With Neuromyelitis Optica and Sjogren Syndrome Successfully Treated With Tocilizumab. PMID- 28625467 TI - Portomesenteric vein thrombosis after sleeve gastrectomy is a known entity: what can we do about it? PMID- 28625468 TI - Necrotizing Tenon's capsule infection in a lymphopenic Down syndrome patient following strabismus surgery. AB - Periocular infection is a rare complication of strabismus surgery. We describe a case of necrotizing Tenon's capsule infection after uncomplicated strabismus surgery in a boy with Down syndrome and blepharitis. Pathologic diagnosis was severe acute necrotizing inflammation with Gram positive coccal forms. Resolution of infection occurred after surgical debridement and intravenous and topical antibiotics. Work-up revealed lymphopenia related to Down syndrome. Patients with Down syndrome may have risk factors for postoperative infection including blepharitis and immunologic abnormalities. PMID- 28625469 TI - Herpes zoster ophthalmicus and strabismus: a unique cause of secondary Brown syndrome. AB - Herpes zoster ophthalmicus can be associated with a variety of ocular and visual sequelae, including isolated or even multiple cranial neuropathies, potentially affecting the oculomotor, trochlear, or abducens nerves. We report a case of a secondary Brown syndrome following resolution of a unilateral isolated trochlear nerve palsy associated with herpes zoster ophthalmicus in an immunocompetent 57 year-old man. PMID- 28625470 TI - Magnetic resonance imaging findings in children with spasmus nutans. PMID- 28625471 TI - Central serous chorioretinopathy following medial transposition of split lateral rectus muscle for complete oculomotor nerve palsy. PMID- 28625472 TI - 3D catheter reconstruction in HDR prostate brachytherapy for pre-treatment verification using a flat panel detector. AB - PURPOSE: High dose rate prostate brachytherapy is a widely-practiced treatment, delivering large conformal doses in relatively few treatment fractions. Inter- and intra-fraction catheter displacements have been reported. Unrecognized displacement can have a significant impact on dosimetry. Knowledge of the implant geometry at the time of treatment is important for ensuring safe and effective treatment. In this work we demonstrate a method to reconstruct the catheter positions pre-treatment, using a 'shift' imaging technique, and perform registration with the treatment plan for verification relative to the prostate. METHODS: Two oblique 'shift' images were acquired of a phantom containing brachytherapy catheters, representing the patient immediately pre-treatment. Using a back projection approach, the catheter paths were reconstructed in 3D and registered with the planned catheter paths. The robustness of the reconstruction and registration process was investigated as a function of phantom rotation. Catheter displacement detection was performed and compared to known applied displacements. RESULTS: Reconstruction of the implant geometry in 3D immediately prior to treatment was achieved. A mean reconstruction uncertainty of 0.8mm was determined for all catheters with a mean registration uncertainty of 0.5mm. A catheter displacement detection threshold of 2.2mm was demonstrated. Catheter displacements were all detected to within 0.5mm of the applied displacements. CONCLUSION: This technique is robust and sensitive to assess catheter displacements throughout the implant volume. This approach provides a method to detect, in 3D, changes in catheter positions relative to the prostate. The method has sufficient sensitivity to enable clinically significant decisions immediately prior to treatment delivery. PMID- 28625473 TI - Effect of DIR uncertainty on prostate passive-scattering proton therapy dose accumulation. AB - Deformable image registration (DIR) is important in dose accumulation. Currently, the impact of DIR-algorithm-associated uncertainties in proton therapy is unclear. Here, we quantify the effect of DIR uncertainties on prostate passive scattering proton therapy (PSPT) dose accumulation. Ten patients with an intermediate risk for prostate cancer formerly treated by PSPT (PTV D95=78GyE) were studied. Dose distributions from all verification CT images (five images per patient) were warped and accumulated in the planning CT geometries with DIR. The dose-volume histogram parameters (Dmean, V40, and V70) for rectum and bladder were calculated. Two commercially available DIR software packages were employed: Velocity AI (Varian Medical Systems) and RayStation (RaySearch Laboratories). The dice similarity coefficient (DSC) and surface distance, which were calculated between planning CT contours and deformed contours, were used for DIR validation, with the relationship between the dose parameter and DIR uncertainty ultimately investigated. On average, when using RayStation, the DSC increased by 0.14 and surface distance decreased by 6.4mm, as compared to Velocity. For Dmean, V40, and V70 to the rectum, the average differences between the RayStation and Velocity were 3.9GyE, 5.5%, and 3.2%, respectively. For the bladder, the differences were 5.2GyE, 5.8%, and 5.4%, respectively. The maximum differences in V40 between RayStation and Velocity were 14.4% and 22.8% for the rectum and bladder, respectively, when the average DSC and surface distance differences were more than 0.14 and 6.4mm, respectively. Such results suggest that DIR uncertainties might significantly affect prostate PSPT dose accumulations. PMID- 28625474 TI - Identifying circumstances under which high insecticide dose increases or decreases resistance selection. AB - Insect management strategies for agricultural crop pests must reduce selection for insecticide resistant mutants while providing effective control of the insect pest. One management strategy that has long been advocated is the application of insecticides at the maximum permitted dose. This has been found, under some circumstances, to be able to prevent the resistance allele frequency from increasing. However this approach may, under different circumstances, lead to rapid selection for resistance to the insecticide. To test when a high dose would be an effective resistance management strategy, we present a flexible deterministic model of a population of an insect pest of agricultural crops. The model includes several possible life-history traits including sexual or asexual reproduction, diploid or haplodiploid genetics, univoltine or multivoltine life cycle, so that the high dose strategy can be tested for many different insect pests. Using this model we aim to identify the key characteristics of pests that make either a high dose or a low dose of insecticide optimal for resistance management. Two outputs are explored: firstly whether the frequency of the resistance allele increases over time or remains low indefinitely; and secondly whether lowering the dose of insecticide applied reduces or increases the rate of selection for the resistance allele. It is demonstrated that with high immigration resistance can be suppressed. This suppression however, is rarely lost if the insecticide dose is reduced, and is absent altogether when individuals move from the treated population back into an untreated population. Reducing the dose of insecticide often resulted in slower development of resistance, except where the population combined a high influx of less resistant individuals into the treated population, a recessive resistance gene and a high efficacy, in which case reducing the dose of insecticide could result in faster selection for resistance. PMID- 28625475 TI - Prediction of protein-protein interactions by label propagation with protein evolutionary and chemical information derived from heterogeneous network. AB - Prediction of protein-protein interactions (PPIs) is of great significance. To achieve this, we propose a novel computational method for PPIs prediction based on a similarity network fusion (SNF) model for integrating the physical and chemical properties of proteins. Specifically, the physical and chemical properties of protein are the protein amino acid mutation rate and its hydrophobicity, respectively. The amino acid mutation rate is extracted using a BLOSUM62 matrix, which puts the protein sequence into block substitution matrix. The SNF model is exploited to fuse protein physical and chemical features of multiple data by iteratively updating each original network. Finally, the complementary features from the fused network are fed into a label propagation algorithm (LPA) for PPIs prediction. The experimental results show that the proposed method achieves promising performance and outperforms the traditional methods for the public dataset of H. pylori, Human, and Yeast. In addition, our proposed method achieves average accuracy of 76.65%, 81.98%, 84.56%, 84.01% and 84.38% on E. coli, C. elegans, H. sapien, H. pylori and M. musculus datasets, respectively. Comparison results demonstrate that the proposed method is very promising and provides a cost-effective alternative for predicting PPIs. The source code and all datasets are available at http://pan.baidu.com/s/1dF7rp7N. PMID- 28625476 TI - Feedback loops interlocked at competitive binding sites amplify and facilitate genetic oscillations. AB - Positive and negative feedback loops are often present in regulatory networks for genetic oscillations. Relative time scales and integration of these feedback loops are key to robust oscillations in expression levels. Using examples from the circadian clock and synthetic genetic oscillators, we study positive and negative feedback loops interlocked at competitive binding sites. In the mammalian circadian clock, a key clock gene Bmal1 is regulated by the activator ROR and the repressor REV-ERB. Conversely, Bmal1 activates both of them, forming interlocked feedback loops. Previous experiments indicate that the activator and repressor compete for the same binding sites in the Bmal1 promoter. Transcription patterns predict that ROR peaks later than REV-ERB and, moreover, the peak phase difference between them is small. Using mathematical modeling we reveal an optimal ratio of dissociation constants of an activator and a repressor for the competitive binding sites to enhance the amplitude of Bmal1 oscillations. This optimal ratio arises only when the amplitude of the repressor is larger than that of the activator. Secondly, we reveal that the preference of binding sites for an activator and a repressor depends on their relative time scales. A previous study demonstrated that noncompetitive binding sites are preferable for synthetic genetic oscillators that comprise a fast activator and a slow repressor with a large time scale separation. Here we show that when their time scales are similar, competitive binding sites are more likely to generate oscillation than noncompetitive sites. In contrast, for a slow activator and a fast repressor with a small phase difference as in Bmal1 regulation, noncompetitive binding sites are advantageous for amplifying oscillations. Our results, therefore, predict that additional mechanisms are necessary to compensate the disadvantage of the Bmal1 promoter and further facilitate amplification under the regulation by ROR and REV ERB. PMID- 28625477 TI - Challenges and advances in the diagnosis, biology, and treatment of urothelial upper tract and bladder carcinomas. AB - Urothelial carcinomas span the bladder, ureter, and renal pelvis, and while there had been stagnation in the field of drug approval for the past two decades, there is now accelerated and regular US FDA approval of 5 immunotherapy agents. However, patients who inherently do not respond or progress on such therapies still represent an area of increased unmet need. In this special Seminars issue, we explore varying aspects of bladder urothelial carcinoma treatment with targeted therapies, the unique presentation and challenges in the treatment of upper tract and renal pelvis tumors, as well as new and emerging diagnostic imaging tools for varying genitourinary cancers. PMID- 28625478 TI - A neonatal mouse model of coxsackievirus A10 infection for anti-viral evaluation. AB - Epidemiological data indicate that coxsackievirus A10 (CVA10) has become one of the main causative agents of hand, foot and mouth disease (HFMD) and in recent years has often been found to co-circulate with other enteroviruses, which poses a challenge for the prevention and control of HFMD. Although most CVA10 associated HFMD cases present mild symptoms, severe manifestations and even death can also occur. However, the study of the pathogenesis and the development of drugs and vaccines for CVA10 infection are still far from complete. In this study, we established a neonatal mouse model for anti-viral evaluation and characterized the pathology of CVA10 infection. To develop the mouse model, both inbred and outbred mouse strains were used to compare their sensitivity to CVA10 infection; then, one-day-old BALB/c mice were selected and inoculated intraperitoneally with a CVA10 clinical strain, CVA10-FJ-01. Clinical symptoms, such as wasting, hind-limb paralysis and even death were observed in the CVA10 infected mice. Moreover, pathological examination and immunohistochemistry staining showed that severe myonecrosis with inflammatory infiltration was observed in CVA10-infected mice, indicating that CVA10 exhibited strong tropism to muscle tissue. Using real-time PCR, we also found that the viral load in the blood and muscle was higher than that in other organs/tissues at different time points post-infection, suggesting that CVA10 had a strong tropism to mice muscle and that viremic spread may also contribute to the death of the CVA10-infected mice. Additionally, to evaluate the neonatal mouse model of CVA10 infection, female mice were immunized with formalin-inactivated CVA10 and then allowed to mate after the third immunization. The results showed that maternal antibodies could protect mice against CVA10 infection. In summary, the results demonstrated that the neonatal mice model was a useful tool for evaluating the protective effects of CVA10 vaccines and anti-viral reagents. PMID- 28625480 TI - Adherence to positive airway pressure treatment among minority populations in the US: A scoping review. AB - Minority individuals in the United States (US) have an increased prevalence of obstructive sleep apnea (OSA) compared to their white/Caucasian counterparts. In general, adherence to positive airway pressure (PAP) therapy is poor and some studies suggest that PAP use among minority individuals is inferior to that of whites. However, there has not been a review of the evidence that addresses racial-ethnic disparities for PAP adherence in the treatment of OSA, and no review has systematically examined the contributing factors to poor adherence among minority individuals compared to whites. We searched the literature for studies published between January 1990 to July 2016 that included objective PAP use comparisons between adult US minority individuals and whites. Twenty-two studies met the inclusion criteria. All studies compared the PAP adherence of blacks to whites. Seven studies compared the PAP adherence of additional minority groups to that of whites. Sixteen of the 22 studies (73%) showed worse PAP adherence in blacks compared to whites. Four studies found equivalent PAP use in US Hispanics compared to whites. Little is known about the PAP adherence of other US minority groups. We present a framework and research agenda for understanding PAP use barriers among US minority individuals. PMID- 28625479 TI - The change of adjacent segment after cervical disc arthroplasty compared with anterior cervical discectomy and fusion: a meta-analysis of randomized controlled trials. AB - BACKGROUND CONTEXT: Many meta-analyses have been performed to study the efficacy of cervical disc arthroplasty (CDA) compared with anterior cervical discectomy and fusion (ACDF); however, there are few data referring to adjacent segment within these meta-analyses, or investigators are unable to arrive at the same conclusion in the few meta-analyses about adjacent segment. With the increased concerns surrounding adjacent segment degeneration (ASDeg) and adjacent segment disease (ASDis) after anterior cervical surgery, it is necessary to perform a comprehensive meta-analysis to analyze adjacent segment parameters. PURPOSE: To perform a comprehensive meta-analysis to elaborate adjacent segment motion, degeneration, disease, and reoperation of CDA compared with ACDF. STUDY DESIGN: Meta-analysis of randomized controlled trials (RCTs). METHODS: PubMed, Embase, and Cochrane Library were searched for RCTs comparing CDA and ACDF before May 2016. The analysis parameters included follow-up time, operative segments, adjacent segment motion, ASDeg, ASDis, and adjacent segment reoperation. The risk of bias scale was used to assess the papers. Subgroup analysis and sensitivity analysis were used to analyze the reason for high heterogeneity. RESULTS: Twenty nine RCTs fulfilled the inclusion criteria. Compared with ACDF, the rate of adjacent segment reoperation in the CDA group was significantly lower (p<.01), and the advantage of that group in reducing adjacent segment reoperation increases with increasing follow-up time by subgroup analysis. There was no statistically significant difference in ASDeg between CDA and ACDF within the 24 month follow-up period; however, the rate of ASDeg in CDA was significantly lower than that of ACDF with the increase in follow-up time (p<.01). There was no statistically significant difference in ASDis between CDA and ACDF (p>.05). Cervical disc arthroplasty provided a lower adjacent segment range of motion (ROM) than did ACDF, but the difference was not statistically significant. CONCLUSIONS: Compared with ACDF, the advantages of CDA were lower ASDeg and adjacent segment reoperation. However, there was no statistically significant difference in ASDis and adjacent segment ROM. PMID- 28625482 TI - Equalizing the information amounts of protein and mRNA by information theory. AB - Based on the Shannon's information communication theory, information amount of the entire length of a polymeric macromolecule can be calculated in bits through adding the entropies of each building block. Proteins, DNA and RNA are such macromolecules. When only the building blocks' variation is considered as the source of entropy, there is seemingly lower information in case of the protein if this approach is applied directly on a protein of specific size and the coding sequence size of the mRNA corresponding to the particular length of the protein. This decrease in the information amount seems contradictory but this apparent conflict is resolved by considering the conformational variations in proteins as a new variable in the calculation and balancing the approximated entropy of the coding part of the mRNA and the protein. Probabilities can change therefore we also assigned hypothetical probabilities to the conformational states, which represent the uneven distribution as the time spent in one conformation, providing the probability of the presence in either or one of the possible conformations. Results that are obtained by using hypothetical probabilities are in line with the experimental values of variations in the conformational-state of protein populations. This equalization approach has further biological relevance that it compensates for the degeneracy in the codon usage during protein translation and it leads to the conclusion that the alphabet size for the protein is rather optimal for the proper protein functioning within the thermodynamic milieu of the cell. The findings were also discussed in relation to the codon bias and have implications in relation to the codon evolution concept. Eventually, this work brings the fields of protein structural studies and molecular protein translation processes together with a novel approach. PMID- 28625481 TI - Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors. AB - Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4+ T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4+ T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy. PMID- 28625483 TI - Silymarin protects against renal injury through normalization of lipid metabolism and mitochondrial biogenesis in high fat-fed mice. AB - Obesity is associated with an increased risk of chronic kidney diseases and the conventional treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors is not enough to prevent renal injury and prolong the progression of disease. Recently, silymarin has shown protective effects on renal tissue injury, but the underlying mechanisms remain elusive. The goal of this study was to investigate the potential capacity of silymarin to prevent renal injury during obesity induced by high fat diet (HFD) in mice. In vivo, male C57BL/6 mice received HFD (60% of total calories) for 12 weeks, randomized and treated orally with vehicle saline or silymarin (30mg/kg body weight/d) for 4 weeks. In vitro, human proximal tubular epithelial cells (HK2) were exposed to 300MUM palmitic acid (PA) for 36h followed by silymarin administration at different concentrations. The administration of silymarin significantly ameliorated HFD induced glucose metabolic disorders, oxidative stress and pathological alterations in the kidney. Silymarin significantly mitigated renal lipid accumulation, fatty acid beta-oxidation and mitochondrial biogenesis in HFD mice and PA treated HK2 cells. Furthermore, silymarin partly restored mitochondrial membrane potential of HK2 cells after PA exposure. In conclusion, silymarin can improve oxidative stress and preserve mitochondrial dysfunction in the kidney, potentially via preventing accumulation of renal lipids and fatty acid beta oxidation. PMID- 28625484 TI - Nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) is regulated by O-GlcNAc transferase. AB - The Nrf1 (Nuclear factor E2-related factor 1) transcription factor performs a critical role in regulating cellular homeostasis. Using a proteomic approach, we identified Host Cell Factor-1 (HCF1), a co-regulator of transcription, and O GlcNAc transferase (OGT), the enzyme that mediates protein O-GlcNAcylation, as cellular partners of Nrf1a, an isoform of Nrf1. Nrf1a directly interacts with HCF1 through the HCF1 binding motif (HBM), while interaction with OGT is mediated through HCF1. Overexpression of HCF1 and OGT leads to increased Nrf1a protein stability. Addition of O-GlcNAc decreases ubiquitination and degradation of Nrf1a. Transcriptional activation by Nrf1a is increased by OGT overexpression and treatment with PUGNAc. Together, these data suggest that OGT can act as a regulator of Nrf1a. PMID- 28625485 TI - Motor Cortical Visuomotor Feedback Activity Is Initially Isolated from Downstream Targets in Output-Null Neural State Space Dimensions. AB - Neural circuits must transform new inputs into outputs without prematurely affecting downstream circuits while still maintaining other ongoing communication with these targets. We investigated how this isolation is achieved in the motor cortex when macaques received visual feedback signaling a movement perturbation. To overcome limitations in estimating the mapping from cortex to arm movements, we also conducted brain-machine interface (BMI) experiments where we could definitively identify neural firing patterns as output-null or output-potent. This revealed that perturbation-evoked responses were initially restricted to output-null patterns that cancelled out at the neural population code readout and only later entered output-potent neural dimensions. This mechanism was facilitated by the circuit's large null space and its ability to strongly modulate output-potent dimensions when generating corrective movements. These results show that the nervous system can temporarily isolate portions of a circuit's activity from its downstream targets by restricting this activity to the circuit's output-null neural dimensions. PMID- 28625487 TI - Distinct Feedforward and Feedback Effects of Microstimulation in Visual Cortex Reveal Neural Mechanisms of Texture Segregation. AB - The visual cortex is hierarchically organized, with low-level areas coding for simple features and higher areas for complex ones. Feedforward and feedback connections propagate information between areas in opposite directions, but their functional roles are only partially understood. We used electrical microstimulation to perturb the propagation of neuronal activity between areas V1 and V4 in monkeys performing a texture-segregation task. In both areas, microstimulation locally caused a brief phase of excitation, followed by inhibition. Both these effects propagated faithfully in the feedforward direction from V1 to V4. Stimulation of V4, however, caused little V1 excitation, but it did yield a delayed suppression during the late phase of visually driven activity. This suppression was pronounced for the V1 figure representation and weaker for background representations. Our results reveal functional differences between feedforward and feedback processing in texture segregation and suggest a specific modulating role for feedback connections in perceptual organization. PMID- 28625486 TI - A Corticothalamic Circuit for Dynamic Switching between Feature Detection and Discrimination. AB - Sensory processing must be sensitive enough to encode faint signals near the noise floor but selective enough to differentiate between similar stimuli. Here we describe a layer 6 corticothalamic (L6 CT) circuit in the mouse auditory forebrain that alternately biases sound processing toward hypersensitivity and improved behavioral sound detection or dampened excitability and enhanced sound discrimination. Optogenetic activation of L6 CT neurons could increase or decrease the gain and tuning precision in the thalamus and all layers of the cortical column, depending on the timing between L6 CT activation and sensory stimulation. The direction of neural and perceptual modulation - enhanced detection at the expense of discrimination or vice versa - arose from the interaction of L6 CT neurons and subnetworks of fast-spiking inhibitory neurons that reset the phase of low-frequency cortical rhythms. These findings suggest that L6 CT neurons contribute to the resolution of the competing demands of detection and discrimination. PMID- 28625488 TI - A Central Catecholaminergic Circuit Controls Blood Glucose Levels during Stress. AB - Stress-induced hyperglycemia is a fundamental adaptive response that mobilizes energy stores in response to threats. Here, our examination of the contributions of the central catecholaminergic (CA) neuronal system to this adaptive response revealed that CA neurons in the ventrolateral medulla (VLM) control stress induced hyperglycemia. Ablation of VLM CA neurons abolished the hyperglycemic response to both physical and psychological stress, whereas chemogenetic activation of these neurons was sufficient to induce hyperglycemia. We further found that CA neurons in the rostral VLM, but not those in the caudal VLM, cause hyperglycemia via descending projections to the spinal cord. Monosynaptic tracing experiments showed that VLM CA neurons receive direct inputs from multiple stress responsive brain areas. Optogenetic studies identified an excitatory PVN-VLM circuit that induces hyperglycemia. This study establishes the central role of VLM CA neurons in stress-induced hyperglycemia and substantially expands our understanding of the central mechanism that controls glucose metabolism. PMID- 28625489 TI - Diosmin reduces chronic constriction injury-induced neuropathic pain in mice. AB - Injury or dysfunction of somatosensory system induces a complex syndrome called neuropathic pain, which still needs adequate pharmacological control. The current pharmacological treatments were in part developed from natural compounds. Flavonoids are natural polyphenolic molecules presenting varied biological activities and low toxicity. The flavonoid diosmin is a safe compound with good tolerability and low toxicity. This study evaluated the antinociceptive effect of diosmin in the sciatic nerve chronic constriction injury (CCI)-induced neuropathic pain model. Male Swiss mice were submitted to CCI and 7 days after, diosmin at 1 or 10 mg/kg was administrated intraperitoneally. Mechanical (electronic analgesimeter) and thermal (hot plate) hyperalgesia were evaluated 1 24 h after treatment. The role of the NO/cGMP/PKG/KATP channel signaling pathway in the analgesic effect of diosmin was evaluated using the pretreatment with L NAME (an inhibitor of NOS), ODQ (an inhibitor of soluble guanylate cyclase), KT5823 (an inhibitor of PKG), or glibenclamide (an ATP-sensitive K+ channels blocker). Single treatment with diosmin inhibited in a dose-dependent manner CCI induced mechanical and thermal hyperalgesia by activating the NO/cGMP/PKG/KATP channel signaling pathway and inhibiting spinal cord cytokine (Il-1beta and Il 33/St2) and glial cells activation (microglia - Iba-1, oligodendrocytes - Olig2) mRNA expression markers. Daily treatment during 7 days with diosmin inhibited CCI induced mechanical and thermal hyperalgesia by inhibiting spinal cord cytokine (Il-1beta, Tnfalpha, and Il-33/St2) and glial cells activation (astrocytes - Gfap, Iba-1, and Olig2) markers mRNA expression. In conclusion, diosmin inhibits neuropathic spinal cord nociceptive mechanisms suggesting this flavonoid as a potential therapeutic molecule to reduce nerve lesion-induced neuropathic pain. PMID- 28625490 TI - Hydroxyflavone metal complexes - molecular structure, antioxidant activity and biological effects. AB - High content of hydroxyflavones in fruits, vegetables, cereals and herbs makes them a common component of the human diet. Because of their antioxidant, antiviral, antibacterial, anti-inflammatory, anticancer properties they still pay an attention of many scientific centers. Hydroxyflavones may form complexes with metal cations, and their chelating properties differ significantly depending on the number and position of hydroxyl substituents in the ring. Synthesis of new complexes of hydroxyflavones allows for improvement biological properties, stability, water-solubility, hydrophilicity, bioavailability comparing with the parent hydroxyflavones. It expands the applicability of hydroxyflavones as food additives, diet supplements, preservatives or drug. This paper reviews on the procedures of synthesis of metal complexes with hydroxyflavones, their molecular structure, mode of coordinations, spectroscopic properties and their biological activity. The dependency between the biological activity of these compounds and their molecular structure is discussed. PMID- 28625491 TI - Insulinotropic action of 2, 4-dinitroanilino-benzoic acid through the attenuation of pancreatic beta-cell lesions in diabetic rats. AB - Beta cell destruction plays a key role in the pathogenesis of type 1 diabetes mellitus. It has also been argued that beta-cell mass is compromised in some cases of type 2 diabetes, although this is still debated. Currently, the failure of oral antidiabetic insulin secretagogue drugs to properly manage type 2 diabetes demands novel approaches for the treatment of this condition. The aim of the present study was to investigate the in vitro and in vivo antidiabetic effect in STZ-induced diabetic rats, and maximum tolerated dose (MTD) safety of novel anthranilic acid derivative, 2, 4-dinitroanilino-benzoic acid (1). Anthranilic acid derivative 1 was also evaluated for insulinotropic action on STZ-mediated pancreatic beta-cell lesions in diabetic rats. During an eight week study, oral glucose tolerance test, fasting blood glucose, and serum insulin levels, and pancreatic insulin contents were measured in four different groups of Wistar rats; control, STZ-induced diabetic, gliclazide-treated, and anthranilic acid derivative-treated diabetic rats. Beta-cell number and islet area were also quantified, and immunohistochemical study was performed. In vitro studies in cells showed that 2, 4-dinitroanilino-benzoic acid (1) did not adversely effect the cells viability. We found that the derivative 1 significantly improved the glucose tolerance, fasting blood glucose, and HbA1c levels, serum insulin levels, and pancreatic insulin contents (P < 0.05), comparable to gliclazide-treated group. The derivative 1 exhibited a significant insulinotropic action on diabetic pancreas, and caused an increased immunoreactivity for insulin, as compared to gliclazide-treated group. Together these results suggest that treatment of diabetic rats with 2, 4-dinitroanilino-benzoic acid (1) improved the glucose tolerance, fasting blood glucose, and HbA1c levels most probably by restoring the functional activities of the pancreas via its insulinotropic action. This indicates that the derivative 1 can serve as lead for the treatment of diabetes caused by low insulin levels. PMID- 28625492 TI - CBMG, a novel derivative of mansonone G suppresses adipocyte differentiation via suppression of PPARgamma activity. AB - Mansorins and mansonones have been isolated from Mansonia gagei heartwoods, a traditional herbal medicine used to treat heart failure, and characterized to have anti-oxidant, anti-bacterial, anti-tumor, and anti-estrogenic activities. However, there is as yet no information on their effects on adipogenesis and lipid storage associated with heart disease. In this study, we investigated the effects of naturally occurring compounds on adipogenic differentiation and sought to develop more potent anti-adipogenic compound. We found that mansonone G (MG) suppressed adipocyte differentiation of 3T3-L1 cells, with a 40% decrease in lipid accumulation at 10 MUM. MG derivatives including ether and ester analogues were then synthesized and assayed for their ability to suppress adipogenesis. A novel MG derivative, chlorobenzoyl MG (CBMG) most potently suppressed adipocyte differentiation with the decreased level of aP2 and adiponectin. Interestingly, CBMG treatment decreased the expression of CCAAT enhancer binding protein-alpha (C/EBPalpha) and peroxisome proliferator-activated receptor-gamma (PPARgamma). Further analysis confirmed that CBMG suppressed both the expression and activity of PPARgamma, a master regulator of adipogenesis, and subsequently led to decreases in transcription of C/EBPalpha, aP2, and adiponectin in adipogenesis, thereby attenuating adipocyte differentiation. Our results suggest that a novel MG derivative, CBMG may have beneficial applications in the control of obesity through the suppression of PPARgamma-induced adipocyte differentiation and lipid accumulation. PMID- 28625493 TI - Question 12: What do you consider when discussing treatment adherence in patients with Cystic Fibrosis? PMID- 28625494 TI - Acute stress shifts the balance between controlled and automatic processes in prospective memory. AB - In everyday life we frequently rely on our abilities to postpone intentions until later occasions (prospective memory; PM) and to deactivate completed intentions even in stressful situations. Yet, little is known about the effects of acute stress on these abilities. In the present work we investigated the impact of acute stress on PM functioning under high task demands. (1) Different from previous studies, in which intention deactivation required mostly low processing demands, we used salient focal PM cues to induce high processing demands during intention-deactivation phases. (2) We systematically manipulated PM-monitoring demands in a nonfocal PM task that required participants to monitor for either one or six specific syllables that could occur in ongoing-task words. Eighty participants underwent the Trier Social Stress Test, a standardized stress induction protocol, or a standardized control situation, before performing a computerized PM task. Our primary interests were whether PM performance, PM monitoring costs, aftereffects of completed intentions and/or commission-error risk would differ between stressed and non-stressed individuals and whether these effects would differ under varying task demands. Results revealed that PM performance and aftereffects of completed intentions during subsequent performance were not affected by acute stress induction, replicating previous findings. Under high demands on intention deactivation (focal condition), however, acute stress produced a nominal increase in erroneous PM responses after intention completion (commission errors). Most importantly, under high demands on PM monitoring (nonfocal condition), acute stress led to a substantial reduction in PM-monitoring costs. These findings support ideas of selective and demand dependent effects of acute stress on cognitive functioning. Under high task demands, acute stress might induce a shift in processing strategy towards resource-saving behavior, which seems to increase the efficiency of PM performance (reduced monitoring costs), but might increase initial susceptibility to automatic response activation after intention completion. PMID- 28625495 TI - Assessing the Effect of an Intensive 2-Week Surgical Training and Innovation Program for High-School Students. AB - OBJECTIVE: The summer surgery program (SSP) was founded in 2012 as an educational program for students at the critical juncture between high school and college to engender interest in medicine, science, and innovation. This program has a distinct emphasis on innovation and problem solving based on real-life operative challenges identified by students during surgical observation in the operating room. The effect of the SSP regarding postsecondary education and career goals was evaluated by participants using a follow-up questionnaire. DESIGN: Retrospective cohort study using web-based survey administered to students at least 1 year after participation in the SSP. Associations between demographics and survey responses were made using Fisher's exact test and a Bonferonni correction was used to account for multiple comparisons. PARTICIPANTS: Between July 2012 and August 2015, 119 students enrolled in the SSP. We sent a web-based questionnaire link to all participants who completed the program. The questionnaire contained 80 questions assessing the participant's interest in studying medicine or science in college, knowledge of health care, and their appreciation and understanding of innovation. SETTING: UC Irvine Medical Center, Orange, CA; Institutional tertiary care center. RESULTS: In total, 77 (64.7%) of 119 students who matriculated in the SSP completed the follow-up survey; the mean number of years after the program was 2.09 years. Nearly all students reported the program increased their interest in studying medicine or science in college (97.4%), led them to a better understanding of their own career goals (93.5%) and made them more confident in their ability to succeed in a career in health care (88.3%). The majority indicated the program led them to better understand the training and schooling required of doctors and surgeons (94.8%), and led them to better appreciate the roles of different medical specialties (96.1%). Overall 96% of students reported that the program led them to better understand the importance of innovation and 86% of the respondents noted they better understood the process of innovation. Participants in the SSP were confident they would be able to become a health professional (p < 0.0001). Of note, there was no drop off in the ratings for the program when comparing classes that were 1, 2, 3, or 4 years after their SSP experience. CONCLUSIONS: The follow-up survey revealed that the 2 week SSP had a markedly, long lasting positive effect on participants in areas of academic, career, and innovation-related variables. PMID- 28625496 TI - Can We Get Faculty Interviewers on the Same Page? An Examination of a Structured Interview Course for Surgeons. AB - INTRODUCTION: Guidance on how to train faculty to conduct structured interviews and implement them into current screening processes is lacking. The goal of this study is to describe a structured interview training program designed specifically for surgeons and examine its effectiveness. METHODS: Faculty involved in advanced surgical fellowship interviews completed a 20-item knowledge assessment and video-based applicant interview ratings before taking a half-day course on conducting structured interviews. The course consisted of evidence based strategies and methods for conducting structured interviews, asking questions, and rating applicants in a highly interactive format. After the course, faculty again completed the knowledge assessment and provided ratings for 3 video-based applicant interviews. RESULTS: All faculty members (N = 5) responsible for selecting fellows in minimally invasive and bariatric surgery completed the training. Faculty had an average of 15.8 +/- 9.12 years in practice. Average performance on the precourse knowledge assessment was 35% +/- 6.12% and the group was unable to achieve acceptable agreement for applicant interview scores for any of the competencies assessed. After the course, faculty demonstrated significant improvements (p < 0.01) on the knowledge assessment, more than doubling their scores on the pretest with average scores of 80% +/- 9.35%. Faculty also improved their interrater agreement of applicant competency, with 80% of the applicant interview ratings within 2 points of each other. CONCLUSIONS: Implementation of a half-day course designed to teach principles and skills around structured interviewing and assessment demonstrated significant improvements in both interviewing knowledge and interrater agreement. These findings support the time and resources required to develop and implement a structured interview training program for surgeons for the postgraduate admissions process. PMID- 28625497 TI - Pitfalls and Opportunities for Epigenomic Analyses Focused on Disease Diagnosis, Prognosis, and Therapy. PMID- 28625498 TI - The Impact of Routine Evaluation of Gastric Residual Volumes on the Time to Achieve Full Enteral Feeding in Preterm Infants. AB - OBJECTIVE: To evaluate the time to full enteral feedings in preterm infants after a practice change from routine evaluation of gastric residual volume before each feeding to selective evaluation of gastric residual volume , and to evaluate the impact of this change on the incidence of necrotizing enterocolitis (NEC). STUDY DESIGN: Data were collected on all gavage-fed infants born at <=34 weeks gestational age (GA) for 2 years before (n = 239) and 2 years after the change (n = 233). RESULTS: The median GA was 32.0 (IQR: 29.7-33.0) weeks before and 32.4 (30.4-33.4) weeks after the change (P = .02). Compared with historic controls, infants with selective evaluations of gastric residual volumes weaned from parenteral nutrition 1 day earlier (P < .001) and achieved full enteral feedings (150 cc/kg/day) 1 day earlier (P = .002). The time to full oral feedings and lengths of stay were similar. The rate of NEC (stage >= 2) was 1.7% in the selective gastric residual volume evaluation group compared with 3.3% in the historic control group (P = .4). Multiple regression analyses showed that the strongest predictor of time to full enteral feedings was GA. Routine evaluation of gastric residual volume and increasing time on noninvasive ventilation both prolonged the attainment of full enteral feedings. Findings were consistent in the subgroup with birth weights of <1500 g. Increased weight at discharge was most strongly associated with advancing postmenstrual, age but avoidance of routine evaluations of gastric residual volume also was a significant factor. CONCLUSIONS: Avoiding routine evaluation of gastric residual volume before every feeding was associated with earlier attainment of full enteral feedings without increasing risk for NEC. PMID- 28625499 TI - Reply. PMID- 28625500 TI - Short-, medium-, and long-term assessment of pulmonary dysfunction in extremely low birth weight neonates. PMID- 28625501 TI - Hyperkeratosis and Discoloration of the Toenails in an 8-Year-Old. PMID- 28625509 TI - From the Editor's desk...: May 2017. PMID- 28625508 TI - Surgical Treatment of Female Stress Urinary Incontinence: AUA/SUFU Guideline. AB - PURPOSE: Stress urinary incontinence is a common problem experienced by many women that can have a significant negative impact on the quality of life of those who suffer from the condition and potentially those friends and family members whose lives and activities may also be limited. MATERIALS AND METHODS: A comprehensive search of the literature was performed by ECRI Institute. This search included articles published between January 2005 and December 2015 with an updated abstract search conducted through September 2016. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. RESULTS: The AUA (American Urological Association) and SUFU (Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction) have formulated an evidence-based guideline focused on the surgical treatment of female stress urinary incontinence in both index and non-index patients. CONCLUSIONS: The surgical options for the treatment of stress urinary incontinence continue to evolve; as such, this guideline and the associated algorithm aim to outline the currently available treatment techniques as well as the data associated with each treatment. Indeed, the Panel recognizes that this guideline will require continued literature review and updating as further knowledge regarding current and future options continues to grow. PMID- 28625507 TI - Contemporary Patterns of Care and Outcomes of Men Found to Have Lymph Node Metastases at the Time of Radical Prostatectomy. AB - PURPOSE: A thorough understanding of the natural history and consensus regarding the optimal management of pathological lymph node positive (pN1) prostate cancer are lacking. Our objective was to describe patterns of care and outcomes of a contemporary cohort of men with pN1 prostate cancer. MATERIALS AND METHODS: We used the National Cancer Database to identify 7,791 men who were found to have lymph node metastases at radical prostatectomy. Multinomial logistic regression and Cox proportional hazards regression were used to identify patient, tumor and facility characteristics associated with the choice of management strategy after radical prostatectomy and overall survival, respectively. RESULTS: Initial post prostatectomy management was observation in 63% of the men, androgen deprivation therapy alone in 20%, radiation therapy alone in 5%, and androgen deprivation therapy and radiation therapy in 13%. Younger age, lower comorbidity burden, higher grade and stage, and positive surgical margins were associated with a higher likelihood of receiving combination therapy. Grade group 4-5 disease, pT3b T4 disease, positive surgical margins and a higher number of positive lymph nodes were independent predictors of worse overall survival. The adjusted 10-year overall survival probability decreased from 84% to 32% with the presence of an increasing number of adverse prognostic factors. Treatment with combined androgen deprivation therapy and radiation therapy was associated with better overall survival (multivariable HR 0.69, 95% CI 0.52-0.92, p = 0.010 for combination therapy vs observation). CONCLUSIONS: Patient and tumor characteristics are associated with the choice of management strategy after radical prostatectomy and survival in men with pN1 prostate cancer. Multimodal therapy may be of benefit in this patient population. PMID- 28625515 TI - Ethical, medico-legal and juridical issues regarding the end of life. PMID- 28625514 TI - Aggressive adrenal carcinoma in a young patient with Multiple Endocrine Neoplasia 1 syndrome. PMID- 28625510 TI - Sexual dimorphism of the calcaneus in contemporary Cretans. AB - During the past decade, several studies have been carried out using the calcaneus bone for sex estimation. This paper collected data using ten variables for metric characteristics of the calcaneus of 144 modern Cretans and examined their correlation with known sex. Secondly, the formulae developed by Peckmann et al. (2015) for modern Athenians was put to the test in order to investigate if it could be applied to this modern Cretan sample as well. Results showed a high correlation between the calcaneus metrics and the known sex of the individuals, however the formulae for Athenians do not seem to be suitable for the Cretans due to the high sex bias reported in this study. Thus, new standards were created for sex estimation from the calacanei in our sample. Bilateral asymmetry was noted in the majority of cases, thus formulae were developed for left, right and mean values. Maximum width (MAXW) was the variable that performed the best in the Cretan sample. Overall, the cross-validated accuracies for univariate and multivariate equations reached 84.2% with males most often correctly identified. The calcaneus was proved to be useful for sex estimation in this modern Cretan population. Further work will explore the suitability of the produced standards for other regions of mainland Greece and islands. PMID- 28625503 TI - Thyroid Hormone Status in Sitosterolemia Is Modified by Ezetimibe. AB - OBJECTIVES: To assess the association between biomarkers of thyroid status and 5alpha-stanols in patients with sitosterolemia treated with ezetimibe (EZE). STUDY DESIGN: Eight patients with sitosterolemia (16-56 years of age) were studied during 14 weeks off EZE therapy and 14 weeks on EZE (10 mg/day). Serum thyroid biomarkers (free triiodothyronine [FT3], free thyroxine [FT4], FT3/FT4 ratio, thyroid-stimulating hormone), 5alpha-stanols (sitostanol and cholestanol), and cholestanol precursors (total cholesterol and its synthesis marker lathosterol, and 7alpha-hydroxy-4-cholesten-3-one cholestenol) were measured at baseline and during the 14 weeks off EZE and on EZE. RESULTS: EZE increased FT3/FT4 (10% +/- 4%; P = .02). EZE reduced plasma and red blood cells sitostanol (-38% +/- 6% and -20% +/- 4%; all P < .05) and cholestanol (-18% +/- 6% and -13% +/- 3%; all P < .05). The change in plasma cholestanol level on EZE inversely correlated with the change in FT3/FT4 (r = -0.86; P = .01). EZE lowered total cholesterol (P < .0001) and did not affect 7alpha-hydroxy-4-cholesten-3-one cholestanol. EZE increased (P < .0001) lathosterol initially, but the level was not sustained, resulting in similar levels at week 14 off EZE and on EZE. CONCLUSION: In patients with STSL, 5alpha-stanols levels might be associated with thyroid function. EZE reduces circulating 5alpha-stanols while increasing FT3/FT4, implying increased conversion of T4 to T3, thus possibly improving thyroid hormone status. TRIAL REGISTRATION: ClinicalTrials.govNCT01584206. PMID- 28625516 TI - Eggerthella lenta bacteremia associated to colonic polyps and colon adenocarcinoma. PMID- 28625511 TI - Lung fluid clearance in chronic heart failure patients. AB - Chronic elevation of pulmonary microvascular pressure (Pmv) consistently leads to alveolocapillary barrier thickening and reduction in the filtration coefficient. In animal models of chronic heart failure (CHF) the lung remains dry despite hydrostatic forces. As fluid flux is bi-directional, it has been postulated that an increase in alveolar fluid clearance may facilitate the dry lung when Pmv is chronically elevated. In this study we aimed to examine alveolar fluid clearance in ambulatory patients with CHF secondary to left ventricular (LV) systolic dysfunction compared against non-CHF controls. Lung clearance following aerosol delivery of 99mtechnetium (Tc)-diethyl triaminepentaacetic acid (DTPA) was measured non-invasively by scintigraphy and half time of 99mTc-DTPA clearance (T (1/2)) was calculated by mono-exponential curve fit. Alveolar fluid clearance measured as half time DTPA clearance was significantly faster in CHF patients than controls (P=0.001). This was further defined by NYHA classification. No correlation was found between DTPA clearance and plasma epinephrine, norepinephrine or aldosterone hormone (P>0.05). Our results support an association between increasing alveolar fluid clearance and disease severity in CHF, and the concept of controlled bi-directional fluid flux in CHF associated with increasing Pmv, and represents another defence mechanism of the lung against pulmonary oedema. PMID- 28625513 TI - Relationship between vitamin D, osteoporotic fracture and falls. AB - OBJECTIVE: Link low levels of vitamin D, osteoporotic fracture and falls. PATIENTS AND METHOD: Transversal observational study with the study variables of age, levels of vitamin D, osteoporotic fracture and falls. The study population was patients evaluated by the Rehabilitation Department, Hospital of Sagunto, from January 2013 to December 2014. RESULTS: Of the 242 patients who underwent vitamin D analysis, 70.6% showed levels under 30ng/ml. Forty-eight percent of the patients with below normal levels of vitamin D suffered a fracture, opposed to 32.4% patients with normal levels. Thus, controlling by age, patients with low levels of vitamin D are 4.8 times more likely to suffer a fracture than those with normal levels. Regarding falls, controlling by age, there is a higher risk of falling (adjusted OR 2.68) in those patients with low levels of vitamin D. CONCLUSIONS: Patients with low vitamin D levels are more likely to suffer falls and fractures. PMID- 28625506 TI - Long-term Cost-effectiveness of Two GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus in the Italian Setting: Liraglutide Versus Lixisenatide. AB - PURPOSE: Maintaining glycemic control is the key treatment target for patients with type 2 diabetes mellitus. In addition, the glucagon-like peptide-1 (GLP-1) receptor agonists may be associated with other favorable treatment characteristics, such as reduction in body weight and reduced risk of hypoglycemia compared with traditional diabetes interventions. The aim of the present analysis was to compare the long-term cost-effectiveness of 2 GLP-1 receptor agonists, liraglutide 1.8 mg and lixisenatide 20 MUg (both administered once daily), in the treatment of patients with type 2 diabetes failing to achieve glycemic control with metformin monotherapy in the Italian setting. METHODS: The IMS CORE Diabetes Model was used to project long-term clinical outcomes and subsequent costs (in 2015 Euros [?]) associated with liraglutide 1.8 mg versus lixisenatide 20 MUg treatment in a cohort with baseline characteristics derived from the open-label LIRA-LIXI trial (Efficacy and Safety of Liraglutide Versus Lixisenatide as Add-on to Metformin in Subjects With Type 2 Diabetes; NCT01973231) over patient lifetimes from the perspective of a health care payer. Efficacy data were taken from the 26-week end points of the same trial, including changes in glycated hemoglobin, body mass index, serum lipid levels, and hypoglycemic event rates. Outcomes projected included life expectancy, quality adjusted life expectancy, cumulative incidence and time to onset of diabetes related complications, and direct medical costs. Outcomes were discounted at 3% annually, and sensitivity analyses were performed. FINDINGS: Liraglutide 1.8 mg was associated with improved discounted life expectancy (14.07 vs 13.96 years) and quality-adjusted life expectancy (9.18 vs 9.06 quality-adjusted life years [QALYs]) compared with lixisenatide 20 MUg. These improvements were mostly attributable to a greater reduction in glycated hemoglobin level with liraglutide 1.8 mg versus lixisenatide 20 MUg, leading to reduced incidence and increased time to onset of diabetes-related complications. Compared with lixisenatide 20 MUg, liraglutide 1.8 mg was associated with increased total costs over patient lifetimes (?41,623 vs ?41,380), but this was offset by lower costs of treating diabetes-related complications (?26,682 vs ?27,476). Liraglutide 1.8 mg was associated with an incremental cost-effectiveness ratio of ?2001 per QALY gained versus lixisenatide 20 MUg. At a willingness-to-pay threshold of ?30,000 per QALY gained, liraglutide 1.8 mg had a probability of 77.2% of being cost-effective. IMPLICATIONS: Based on long-term projections, liraglutide 1.8 mg is likely to be considered cost-effective compared with lixisenatide 20 MUg for the treatment of patients with type 2 diabetes in Italy. PMID- 28625502 TI - A Computable Phenotype Improves Cohort Ascertainment in a Pediatric Pulmonary Hypertension Registry. AB - OBJECTIVES: To compare registry and electronic health record (EHR) data mining approaches for cohort ascertainment in patients with pediatric pulmonary hypertension (PH) in an effort to overcome some of the limitations of registry enrollment alone in identifying patients with particular disease phenotypes. STUDY DESIGN: This study was a single-center retrospective analysis of EHR and registry data at Boston Children's Hospital. The local Informatics for Integrating Biology and the Bedside (i2b2) data warehouse was queried for billing codes, prescriptions, and narrative data related to pediatric PH. Computable phenotype algorithms were developed by fitting penalized logistic regression models to a physician-annotated training set. Algorithms were applied to a candidate patient cohort, and performance was evaluated using a separate set of 136 records and 179 registry patients. We compared clinical and demographic characteristics of patients identified by computable phenotype and the registry. RESULTS: The computable phenotype had an area under the receiver operating characteristics curve of 90% (95% CI, 85%-95%), a positive predictive value of 85% (95% CI, 77%-93%), and identified 413 patients (an additional 231%) with pediatric PH who were not enrolled in the registry. Patients identified by the computable phenotype were clinically distinct from registry patients, with a greater prevalence of diagnoses related to perinatal distress and left heart disease. CONCLUSIONS: Mining of EHRs using computable phenotypes identified a large cohort of patients not recruited using a classic registry. Fusion of EHR and registry data can improve cohort ascertainment for the study of rare diseases. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02249923. PMID- 28625505 TI - Bioequivalence Study of a New Fixed-dose Combination Tablet Containing S Amlodipine Nicotinate and Olmesartan Medoxomil in Healthy Korean Male Subjects. AB - PURPOSE: A fixed-dose combination (FDC) pill of amlodipine (relatively old calcium channel blocker as dihydropyridine) and olmesartan (relatively new angiotensin II receptor blocker) is used for hypertension that is not adequately controlled with a single-formulation drug. Because the FDC is a one-pill formulation, and amlodipine and olmesartan have different mechanisms of action, it is expected to improve patients' medication compliance and have an increased blood pressure-lowering efficacy. The purpose of this study was to assess the safety profile and the bioequivalence of two different FDC formulations [amlodipine besylate/olmesartan medoxomil 10/40 mg (reference product) and S amlodipine nicotinate/olmesartan medoxomil 5/40 mg (test product)]. METHODS: A randomized, open-label, single-dose, 2-treatment, 2-way, and 2-period crossover study, including a 3-week washout period, was performed in 32 healthy Korean male volunteers. To analyze the concentration of S-amlodipine or olmesartan, plasma samples were collected up to 144 hours after the dose for S-amlodipine and 48 hours after the dose for olmesartan. Pharmacokinetic parameters, including the Cmax and the area under the curve from time 0 to the last measurable concentration (AUC0-last) for the time versus concentration plot, were calculated. Analysis of variance for bioequivalence was conducted using Cmax and AUC0-last converted to log scale, and the mean ratios and 90% CIs were determined. Safety data included analysis of adverse events (AEs), vital signs, physical examinations, clinical laboratory test, and 12-lead ECGs. FINDINGS: Of the 32 enrolled participants, 29 healthy volunteers completed the study. For both S-amlodipine and olmesartan, the main pharmacokinetic parameters were all within the acceptable range for regulatory bioequivalence. The 90% CIs for the geometric mean ratios of Cmax and AUC0-last were 0.8766 to 0.9760 and 0.8288 to 0.9224, respectively, for S-amlodipine and 0.9097 to 1.1229 and 0.8904 to 1.0407, respectively, for olmesartan. Hypotension was the most frequent AE, and it was observed in 4 volunteers with the test product and 7 volunteers with the reference product. Both the test and reference formulations were well tolerated. IMPLICATIONS: The present study demonstrates that the newly developed FDC product (test drug) and the conventional FDC product (reference drug) have comparable pharmacokinetic characteristics in healthy adult male volunteers. Both the test and reference products indicated good tolerance in this population, and no serious AEs were observed. PMID- 28625512 TI - First experience with edoxaban and atrial fibrillation ablation - Insights from the ENGAGE AF-TIMI 48 trial. AB - BACKGROUND: Atrial fibrillation (AF) ablation procedures are increasingly being performed in patients receiving direct oral anticoagulants (DOACs). Experience regarding the safety of edoxaban in this context is limited. In an exploratory analysis we therefore investigated the outcome of patients undergoing transcatheter AF ablation in the ENGAGE AF-TIMI 48 trial. METHODS & RESULTS: During the trial, 193 transcatheter AF ablation procedures were performed in 169 patients. For the majority of ablations (n=157, 81%), study drug was interrupted >3days (median time of interruption: 18days, interquartile range 3-30days); 86 ablations were performed with <=10days, and 36 ablations with <=3days study drug interruption. During the first 30days after the ablation, one ischemic stroke was observed in the warfarin group and none in the higher-dose edoxaban regimen (HDER) or lower-dose edoxaban regimen (LDER) group. Three clinically relevant non major (CRNM) bleeding events were observed in the warfarin group; one major bleed was seen in the HDER group; one minor bleed occurred in the LDER group. All bleeding events occurred among the patients with <=10days study drug interruption; in contrast, no ischemic events or deaths were observed in these patients. CONCLUSIONS: In this pilot evaluation of the ENGAGE AF-TIMI 48 trial, treatment with edoxaban was associated with a low risk of ischemic and bleeding events during the first 30days post ablation. PMID- 28625504 TI - Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish. AB - Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, abnormal eye movements, and variable cognitive impairment. It is defined by a distinctive brain malformation known as the "molar tooth sign" on axial MRI. Subsets of affected individuals have malformations such as coloboma, polydactyly, and encephalocele, as well as progressive retinal dystrophy, fibrocystic kidney disease, and liver fibrosis. More than 35 genes have been associated with JS, but in a subset of families the genetic cause remains unknown. All of the gene products localize in and around the primary cilium, making JS a canonical ciliopathy. Ciliopathies are unified by their overlapping clinical features and underlying mechanisms involving ciliary dysfunction. In this work, we identify biallelic rare, predicted-deleterious ARMC9 variants (stop gain, missense, splice-site, and single-exon deletion) in 11 individuals with JS from 8 families, accounting for approximately 1% of the disorder. The associated phenotypes range from isolated neurological involvement to JS with retinal dystrophy, additional brain abnormalities (e.g., heterotopia, Dandy-Walker malformation), pituitary insufficiency, and/or synpolydactyly. We show that ARMC9 localizes to the basal body of the cilium and is upregulated during ciliogenesis. Typical ciliopathy phenotypes (curved body shape, retinal dystrophy, coloboma, and decreased cilia) in a CRISPR/Cas9-engineered zebrafish mutant model provide additional support for ARMC9 as a ciliopathy-associated gene. Identifying ARMC9 mutations as a cause of JS takes us one step closer to a full genetic understanding of this important disorder and enables future functional work to define the central biological mechanisms underlying JS and other ciliopathies. PMID- 28625517 TI - Reduced TDP-43 Expression Improves Neuronal Activities in a Drosophila Model of Perry Syndrome. AB - Parkinsonian Perry syndrome, involving mutations in the dynein motor component dynactin or p150Glued, is characterized by TDP-43 pathology in affected brain regions, including the substantia nigra. However, the molecular relationship between p150Glued and TDP-43 is largely unknown. Here, we report that a reduction in TDP-43 protein levels alleviates the synaptic defects of neurons expressing the Perry mutant p150G50R in Drosophila. Dopaminergic expression of p150G50R, which decreases dopamine release, disrupts motor ability and reduces the lifespan of Drosophila. p150G50R expression also causes aggregation of dense core vesicles (DCVs), which contain monoamines and neuropeptides, and disrupts the axonal flow of DCVs, thus decreasing synaptic strength. The above phenotypes associated with Perry syndrome are improved by the removal of a copy of Drosophila TDP-43 TBPH, thus suggesting that the stagnation of axonal transport by dynactin mutations promotes TDP-43 aggregation and interferes with the dynamics of DCVs and synaptic activities. PMID- 28625518 TI - Histone Chaperone ASF1A Predicts Poor Outcomes for Patients With Gastrointestinal Cancer and Drives Cancer Progression by Stimulating Transcription of beta-Catenin Target Genes. AB - Epigenetic mechanisms play a key role in gastrointestinal cancer (GIC) development and progression, and most studies have been focused on aberrant DNA methylation and histone modifying enzymes. However, the histone H3-H4 chaperone ASF1A is an important factor regulating chromatin assembling and gene transcription, while it is currently unclear whether ASF1A is involved in cancer pathogenesis. The present study is thus designed to address this issue. Here we showed that ASF1A expression was widespread in GIC-derived cell lines and up regulated in primary GIC. Higher levels of ASF1A expression predicted significantly shorter patient overall survival in colorectal cancer (P=0.0012). The further analyses of the GEO dataset validate higher ASF1A expression as a prognostic factor for CRC patients. Mechanistically, ASF1A interacted with beta catenin and promoted the transcription of beta-catenin target genes including c MYC, cyclin D1, ZEB1 and LGR5, thereby stimulating proliferation, stemness and migration/invasion of GIC cells. beta-Catenin inhibition abolished these effects of ASF1A. Moreover, the ASF1A-beta-catenin-ZEB1 axis down-regulated E-Cadherin expression, thereby contributing to enhanced migration/invasion of GIC cells. ASF1A over-expression and depletion facilitated and inhibited in vivo tumor growth and/or metastasis in mouse xenograft models, respectively. Taken together, ASF1A is aberrantly over-expressed in GIC tumors and plays key roles in GIC development and progression by stimulating the transcription of beta-catenin target genes. ASF1A may thus be a novel target for GIC therapy and a potential prognostic marker. PMID- 28625519 TI - Multiplex Ultrasensitive Genotyping of Patients with Non-Small Cell Lung Cancer for Epidermal Growth Factor Receptor (EGFR) Mutations by Means of Picodroplet Digital PCR. AB - Epidermal growth factor receptor (EGFR) mutations have been used as the strongest predictor of effectiveness of treatment with EGFR tyrosine kinase inhibitors (TKIs). Three most common EGFR mutations (L858R, exon 19 deletion, and T790M) are known to be major selection markers for EGFR-TKIs therapy. Here, we developed a multiplex picodroplet digital PCR (ddPCR) assay to detect 3 common EGFR mutations in 1 reaction. Serial-dilution experiments with genomic DNA harboring EGFR mutations revealed linear performance, with analytical sensitivity ~0.01% for each mutation. All 33 EGFR-activating mutations detected in formalin-fixed paraffin-embedded (FFPE) tissue samples by the conventional method were also detected by this multiplex assay. Owing to the higher sensitivity, an additional mutation (T790M; including an ultra-low-level mutation, <0.1%) was detected in the same reaction. Regression analysis of the duplex assay and multiplex assay showed a correlation coefficient (R2) of 0.9986 for L858R, 0.9844 for an exon 19 deletion, and 0.9959 for T790M. Using ddPCR, we designed a multiplex ultrasensitive genotyping platform for 3 common EGFR mutations. Results of this proof-of-principle study on clinical samples indicate clinical utility of multiplex ddPCR for screening for multiple EGFR mutations concurrently with an ultra-rare pretreatment mutation (T790M). PMID- 28625520 TI - Immunogenicity of pulsatile-release PLGA microspheres for single-injection vaccination. AB - The World Health Organization's Expanded Programme on Immunization has led to a dramatic rise in worldwide vaccination rates over the past 40years, yet 19.4 million infants remain underimmunized each year. Many of these infants have received at least one vaccine dose but may remain unprotected because they did not receive subsequent booster doses due to logistical challenges. This study aimed to develop injectable controlled release microparticles with kinetics that mimic common vaccine dosing regimens consisting of large antigen doses administered periodically over the course of months in order to eliminate the need for boosters. Sixteen poly(lactic-co-glycolic acid) (PLGA) microsphere formulations containing bovine serum albumin (BSA) as a model vaccine antigen were screened in vitro to determine their respective release kinetics. Three formulations that exhibited desirable pulsatile release profiles were then selected for studying immunogenicity in mice. Two low-dose microsphere formulations induced peak anti-BSA IgG antibody titers of 13.9+/-1.3 and 13.7+/ 2.2 log2 compared to 15.5+/-1.5 log2 for a series of three bolus injections delivered at 0, 4, and 8weeks with an equivalent cumulative dose. Similarly, high dose formulations induced peak antibody titers that were 16.1+/-2.1 log2 compared to 17.7+/-2.2 log2 for controls. All three microparticle formulations studied in vivo induced peak antibody titers that were statistically similar to bolus controls. These results suggest that pulsatile antigen release from polymeric microparticles is a promising approach for single-injection vaccination, which could potentially reduce the logistical burden associated with immunization in the developing world. PMID- 28625521 TI - Protective efficacy of multivalent replication-abortive vaccine strains in horses against African horse sickness virus challenge. AB - African horse sickness virus (AHSV) is an orbivirus, a member of the Reoviridae family. Nine different serotypes have been described so far. AHSV is vectored by Culicoides spp. to equids, causing high mortality, particularly in horses, with considerable economic impacts. For development of a safe attenuated vaccine, we previously established an efficient reverse genetics (RG) system to generate Entry Competent Replication-Abortive (ECRA) virus strains, for all nine serotypes and demonstrated the vaccine potential of these strains in type I interferon receptor (IFNAR)-knockout mice. Here, we evaluated the protective efficacies of these ECRA viruses in AHSV natural hosts. One monoserotype (ECRA.A4) vaccine and one multivalent cocktail (ECRA.A1/4/6/8) vaccine were tested in ponies and subsequently challenged with a virulent AHSV4. In contrast to control animals, all vaccinated ponies were protected and did not develop severe clinical symptoms of AHS. Furthermore, the multivalent cocktail vaccinated ponies produced neutralizing antibodies against all serotypes present in the cocktail, and a foal born during the trial was healthy and had no viremia. These results validate the suitability of these ECRA strains as a new generation of vaccines for AHSV. PMID- 28625523 TI - Induction, treatment and prevention of eczema vaccinatum in atopic dermatitis mouse models. AB - Eczema vaccinatum is a severe and occasionally lethal complication of smallpox vaccine, characterized by systemic viral dissemination, distant from the initial inoculation site of the vaccine. A major risk factor for eczema vaccinatum is a background of atopic dermatitis, a chronic, common allergic, relapsing disorder, manifested by dry and inflamed skin, itchy rash, Th2 biased immune response and hypersensitivity to various antigens. Unlike the severe manifestations of eczema vaccinatum in humans, current models present only mild symptoms that limits examination of potential therapeutics for eczema vaccinatum. The atopic dermatitis and eczema vaccinatum models we present here, are the first to simulate the severity of the diseases in humans. Indeed, dermatitic mice display persistent severe dermatitis, characterized by dry and inflamed skin with barrier dysfunction, epidermal hyperplasia and significant elevation of serum IgE. By exposing atopic dermatitis mice to ectromelia virus, we generated eczema vaccinatum that mimic the human disease better than known eczema vaccinatum models. Similarly to humans, eczematous mice displayed enlarged and disseminated skin lesions, which correlated with elevated viral load. Cidofovir and antiviral antibodies conferred protection even when treatment started at a late eczematous stage. Moreover, we are the first to demonstrate that despite a severe background of atopic dermatitis, modified vaccinia Ankara virus (MVA) vaccination protects against lethal ectromelia virus exposure. We finally show that protection by MVA vaccination is dependent on CD4+ T cells and is associated with significant activation of CD8+ cytotoxic T cells and induction of humoral immunity. PMID- 28625522 TI - Immunogenicity and therapeutic effects of recombinant Ag85AB fusion protein vaccines in mice infected with Mycobacterium tuberculosis. AB - The immune function of tuberculosis (TB) patients is disordered. By using immune regulators to assist chemotherapy for TB the curative effect might be improved. In this study, a vaccine containing Mycobacterium tuberculosis (M. tuberculosis) recombinant Ag85AB fusion protein (rAg85AB) was constructed and evaluated. The mice were immunized intramuscularly three times at two-week intervals with Ag85AB fusion protein combined with Corynebacterium parvum adjuvant (rAg85AB+CP). In comparison to control mice that received either CP alone or saline, the mice that received rAg85AB+CP had significantly higher number of T cells secreting IFN gamma and higher levels of specific antibodies of IgG, IgG1 and IgG2a isotypes in sera. The specific antibodies also had higher ratios of IgG2a to IgG1, indicating a predominant Th1 immune response. To test for immunotherapy of TB, M. tuberculosis infected mice were given three intramuscular doses of 20MUg, 40MUg or 60MUg of rAg85AB in rAg85AB+CP, or phosphate-buffered saline (PBS), or CP or Mycobacterium phlei (M. Phlei) F.U.36. Compared with the PBS group, 20ug, 40ug and 60ug rAg85AB+CP and M. phlei F.U.36 groups reduced the pulmonary bacterial loads by 0.13, 0.15, 0.42 and 0.40 log10, and the liver bacterial loads by 0.64, 0.64, 0.53 and 0.61 log10, respectively. Pathological changes of lungs were less, and the lesions were limited to a certain extent in 40ug and 60ug rAg85AB+CP and M. phlei F.U.36 groups. These results showed that rAg85AB+CP had immunotherapeutic effect on TB, significantly increasing the cellular immune response, and inhibiting the growth of M. tuberculosis. PMID- 28625524 TI - Cross-reactivity and avidity of antibody responses induced in humans by the oral inactivated multivalent enterotoxigenicEscherichia coli (ETEC) vaccine ETVAX. AB - We investigated whether the oral inactivated, multivalent enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX, consisting of four E. coli strains over expressing the colonisation factors (CFs) CFA/I, CS3, CS5 and CS6, combined with the toxoid LCTBA, could induce cross-reactive antibodies to CFs related to the CFA/I and CS5 families. We also evaluated the avidity of vaccine induced antibodies against the toxoid and CFs. Cross-reactivity was analysed in mucosal (faecal and antibodies in lymphocyte supernatants, ALS) samples, and antibody avidity in serum and ALS samples, from two phase I trials: a primary vaccination study, where two oral doses of ETVAX were given+/-the double mutant heat labile toxin (dmLT) adjuvant at a 2-week interval, and a booster vaccination study, where a single booster dose of ETVAX was given 13-23months after primary vaccinations. We found that 65-90% of subjects who had responded to CFA/I in ALS or faecal specimens also developed cross-reactive antibodies to the related CFs tested, i.e. CS1, CS14 and CS17, and that approximately 80% of those responding to CS5 also responded to the closely related CS7. For subjects who had developed cross-reactive antibodies, the magnitudes of responses against vaccine CFs and related non-vaccine CFs were comparable. Using both a simple method of antibody avidity determination based on limiting antigen dilution, as well as a chaotropic ELISA method, we found that the avidity of serum and ALS antibodies to key vaccine antigens increased after a late booster dose compared to after primary vaccination. Our results suggest that the cross-reactive antibody responses against multiple CFs may result in expanded ETEC strain coverage of ETVAX and that repeated vaccinations induce vaccine-specific antibodies with increased binding capacity. PMID- 28625525 TI - Recombinant Lactobacillus casei expressing Clostridium perfringens toxoids alpha, beta2, epsilon and beta1 gives protection against Clostridium perfringens in rabbits. AB - The present study used Lactobacillus casei ATCC 393 as antigen delivery system to express C. perfringens toxoids alpha-beta2-epsilon-beta1 to construct the recombination Lactobacillus casei pPG-2-alpha-beta2-epsilon-beta1/L. casei 393. After being induced by 1% xylose, the specificity and integrity of recombinant strain were determined by Western-blotting. Rabbits as native animal model were immunized orally with pPG-2-alpha-beta2-epsilon-beta1/L. casei 393 and the titers of specific IgG and sIgA were determined by ELISA. The result showed that oral administration with the recombinants could elicit both local mucosal and systemic immune responses. The proliferation of spleen lymphocytes in rabbits immunized with pPG-2-alpha-beta2-epsilon-beta1/L. casei 393 was observed. Levels of IL-4 and IFN-gamma produced were significantly higher in lymphocytes isolated from the vaccine group than those from the control groups. Flow cytometry assay showed that both the percentages of CD4+T cells and CD8+T cells from the vaccine group were significantly increased than the control groups. All these results showed that immunizing with recombinants can elicit both humoral immunity and cellular immunity. Besides, in order to determine the effectiveness of oral immunization with pPG-2-alpha-beta2-epsilon-beta1/L. casei 393, rabbits of vaccine group and control groups were challenged with 1*LD100 unit of culture filtrate of C. perfringens type C and type D toxins respectively. After challenge, 100% of the immunized rabbits survived, while the rabbits of the control group were killed within 48h. Observation on histopathology showed that histopathological changes were obviously found in heart, liver, spleen, lung, kidney, intestine and brain of rabbits from the control groups, while no apparent histopathological change was observed in the vaccine group. All the results show that pPG-2-alpha-beta2 epsilon-beta1/L. casei 393 can eliciteffective immunoprotection against C. perfringens. All of these suggest that the use of pPG-2-alpha-beta2-epsilon beta1/L. casei 393 can be regarded as candidate for the development of a vaccine against C. perfringens. PMID- 28625526 TI - Body Mass Index and All-cause Mortality in Chronic Kidney Disease: A Dose response Meta-analysis of Observational Studies. AB - This article provides a dose-response meta-analysis to evaluate the relationship between body mass index (BMI) and all-cause and disease-specific mortality in chronic kidney disease (CKD) by pooling together early stage, hemodialysis, and peritoneal dialysis patients. We evaluated eligible studies that published between 1966 and December 2014 by searching in PubMed, Object View and Interaction Design (OVID), and the Scopus databases. We used random-effects generalized least squares spline models for trend estimation to derive pooled dose-response estimates. Nonlinear associations of BMI with all-cause mortality were observed (P-nonlinearity < .0001), with an increased rate of mortality with BMIs > 30 kg/m2 in all stages of CKD together. However, reanalysis of data separately by stage of CKD (hemodialysis and peritoneal dialysis) showed that the risk of all-cause mortality decreased with a steep slope in individuals with BMIs > 30 kg/m2. This meta-analysis indicates that higher BMI has protective effects with respect to all-cause mortality in patients with both type of dialysis. PMID- 28625527 TI - Summertime Thoughts. PMID- 28625528 TI - Dietary Reduction of Advanced Glycation End Products: An Opportunity for Improved Nutrition Care. PMID- 28625529 TI - Comparative study on the effect of low intensity laser and growth factors on stem cells used in experimentally-induced liver fibrosis in mice. AB - BACKGROUND AND STUDY AIMS: The therapeutic effects of human umbilical cord derived mesenchymal stem cells (UC-MSCs) exposed to diode laser and/or hepatocyte growth factor (HGF) were compared in mice with experimental liver fibrosis induced by carbon tetra chloride (CCl4). MATERIAL AND METHODS: Animal model of liver cirrhosis was induced by intraperitoneal injection of CCl4 in a dose of 0.4ml/kg, twice a week for 6weeks. UC-MSCs were obtained from normal full term placentas and were exposed to diode laser and/or HGF. Before treatment, UC-MSCs were labelled with red fluorescent PKH26. Fifty four male mice weighing 25-35g were randomly divided into four groups control, stem cells, CCl4, and treated groups. After the experimental period, body and liver weights were recorded, and the liver specimens were processed for histological examination using haematoxylin and eosin, Periodic Acid-Schiff (PAS), and Masson's Trichrome staining (MT). RESULTS: Results showed that administration of UC-MSCs stimulated by diode laser and/or HGF improved body and liver weights, reduced vascular dilatation and congestion, reduced mononuclear cellular infiltration, reduced hepatocyte vacuolation, eosinophilia, and pyknosis. Furthermore, periportal fibrosis was minimized and PAS reaction was increased. These effects were maximum when UC-MSCs were exposed to both diode laser and HGF. CONCLUSION: UC-MSCs stimulated by both diode laser and HGF proved to be an effective therapeutic option in experimental liver fibrosis induced by CCl4 in mice. PMID- 28625530 TI - The Emerging Roles of STING in Bacterial Infections. AB - The STING (Stimulator of Interferon Genes) protein connects microorganism cytosolic sensing with effector functions of the host cell by sensing directly cyclic dinucleotides (CDNs), originating from pathogens or from the host upon DNA recognition. Although STING activation favors effective immune responses against viral infections, its role during bacterial diseases is controversial, ranging from protective to detrimental effects for the host. In this review, we summarize important features of the STING activation pathway and recent highlights about the role of STING in bacterial infections by Chlamydia, Listeria, Francisella, Brucella, Shigella, Salmonella, Streptococcus, and Neisseria genera, with a special focus on mycobacteria. PMID- 28625531 TI - The extended bundle of the tensor veli palatini: Anatomic consideration of the dilating mechanism of the Eustachian tube. AB - OBJECTIVE: The aim of this study was to analyze the topographical structures of the muscles surrounding the Eustachian tube. MATERIALS AND METHODS: We conducted macroscopic and histological studies of 24 halves of 12 heads from Japanese cadavers. RESULTS: The main findings were as follows: 1) the infero-lateral muscle bundles of the tensor veli palatini didn't turn medially at the pterygoid hamulus but were distributed laterally and continuous with the buccinator; 2) the tensor veli palatini attached laterally to the membranous part of the Eustachian tube; 3) the superior pharyngeal constrictor was not only adjacent to the buccinator at the pterygomandibular raphe but also had muscular continuation with it laterally and 4) some bundles of the superior pharyngeal constrictor adhered with the palatine aponeurosis. CONCLUSION: We believe that the cooperation of the muscles contributes to the dilating mechanism of the Eustachian tube, due to the complex topographical structures of the surrounding muscles: the tensor veli palatini, the levator veli palatini, the superior pharyngeal constrictor and the buccinator. PMID- 28625532 TI - Emergency department DNR order in patients with spontaneous intracerebral hemorrhage. AB - OBJECTIVES: To explore the determinant factors and prognostic significance of emergency department do-not-resuscitate (ED-DNR) orders for patients with spontaneous intracerebral hemorrhage (SICH). METHODS: Consecutive adult SICH patients treated in our ED from January 1, 2012 to December 31, 2016 were selected as the eligible cases from our hospital's stroke database. Patients' information was comprehensively reviewed from the database and medical and nursing charts. ED-DNR orders were defined as DNR orders written during ED stay. Multiple logistic regression analysis was used to identify significant determinants of ED-DNR orders. Thirty- and 90-day neurological outcomes were analyzed to test the prognosis impact of ED-DNR orders. RESULTS: Among 835 enrolled patients, 112 (12.1%) had ED-DNR orders. Significant determinant factors of ED-DNR orders were age, ambulatory status before the event, brain computed tomography findings of midline shift, intraventricular extension, larger hematoma size, and ED arrival GCS <=8. Patients with and without ED-DNR orders had a similar 30-day death rate if they had the same initial ICH score point. During 30 to 90days, patients with ED-DNR orders had a significantly increased mortality rate. However, the rate of improvement in neurological status between the two groups was not significantly different. CONCLUSIONS: Older and sicker SICH patients had higher rate of ED-DNR orders. The mortality rates between patients with and without ED-DNR orders for each ICH score point were not significantly different. During the 30-to-90-day follow-up, the rates of neurological improvement in both groups were similar. PMID- 28625533 TI - Medication errors with push dose pressors in the emergency department and intensive care units. PMID- 28625534 TI - Predictors of urinary and rectal toxicity after external conformed radiation therapy in prostate cancer: Correlation between clinical, tumour and dosimetric parameters and radical and postoperative radiation therapy. AB - OBJECTIVE: To determine rectal and urinary toxicity after external beam radiation therapy (EBRT), assessing the results of patients who undergo radical or postoperative therapy for prostate cancer (pancreatic cancer) and their correlation with potential risk factors. METHOD: A total of 333 patients were treated with EBRT. Of these, 285 underwent radical therapy and 48 underwent postoperative therapy (39 cases of rescue and 9 of adjuvant therapy). We collected clinical, tumour and dosimetric variable to correlate with toxicity parameters. We developed decision trees based on the degree of statistical significance. RESULTS: The rate of severe acute toxicity, both urinary and rectal, was 5.4% and 1.5%, respectively. The rate of chronic toxicity was 4.5% and 2.7%, respectively. Twenty-seven patients presented haematuria, and 9 presented haemorrhagic rectitis. Twenty-five patients (7.5%) presented permanent limiting sequela. The patients with lower urinary tract symptoms prior to the radiation therapy presented poorer tolerance, with greater acute bladder toxicity (P=0.041). In terms of acute rectal toxicity, 63% of the patients with mean rectal doses >45Gy and anticoagulant/antiplatelet therapy developed mild toxicity compared with 37% of the patients with mean rectal doses <45 Gy and without anticoagulant therapy. We were unable to establish predictors of chronic toxicity in the multivariate analysis. The long-term sequelae were greater in the patients who underwent urological operations prior to the radiation therapy and who were undergoing anticoagulant therapy. CONCLUSIONS: The tolerance to EBRT was good, and severe toxicity was uncommon. Baseline urinary symptoms constitute the predictor that most influenced the acute urinary toxicity. Rectal toxicity is related to the mean rectal dose and with anticoagulant/antiplatelet therapy. There were no significant differences in severe toxicity between radical versus postoperative radiation therapy. PMID- 28625535 TI - Glial-Specific Functions of Microcephaly Protein WDR62 and Interaction with the Mitotic Kinase AURKA Are Essential for Drosophila Brain Growth. AB - The second most commonly mutated gene in primary microcephaly (MCPH) patients is wd40-repeat protein 62 (wdr62), but the relative contribution of WDR62 function to the growth of major brain lineages is unknown. Here, we use Drosophila models to dissect lineage-specific WDR62 function(s). Interestingly, although neural stem cell (neuroblast)-specific depletion of WDR62 significantly decreased neuroblast number, brain size was unchanged. In contrast, glial lineage-specific WDR62 depletion significantly decreased brain volume. Moreover, loss of function in glia not only decreased the glial population but also non-autonomously caused neuroblast loss. We further demonstrated that WDR62 controls brain growth through lineage-specific interactions with master mitotic signaling kinase, AURKA. Depletion of AURKA in neuroblasts drives brain overgrowth, which was suppressed by WDR62 co-depletion. In contrast, glial-specific depletion of AURKA significantly decreased brain volume, which was further decreased by WDR62 co depletion. Thus, dissecting relative contributions of MCPH factors to individual neural lineages will be critical for understanding complex diseases such as microcephaly. PMID- 28625536 TI - Reconstructing Lineage Hierarchies of Mouse Uterus Epithelial Development Using Single-Cell Analysis. AB - The endometrial layer comprises luminal and glandular epithelia that both develop from the same simple layer of fetal uterine epithelium. Mechanisms of uterine epithelial progenitor self-renewal and differentiation are unclear. This study aims to systematically analyze the molecular and cellular mechanisms of uterine epithelial development by single-cell analysis. An integrated set of single-cell transcriptomic data of uterine epithelial progenitors and their differentiated progenies is provided. Additionally the unique molecular signatures of these cells, characterized by sequential upregulation of specific epigenetic and metabolic activities, and activation of unique signaling pathways and transcription factors, were also investigated. Finally a unique subpopulation of early progenitor, as well as differentiated luminal and glandular lineages, were identified. A complex cellular hierarchy of uterine epithelial development was thus delineated. Our study therefore systematically decoded molecular markers and a cellular program of uterine epithelial development that sheds light on uterine developmental biology. PMID- 28625537 TI - The Developmental Stage of Adult Human Stem Cell-Derived Retinal Pigment Epithelium Cells Influences Transplant Efficacy for Vision Rescue. AB - Age-related macular degeneration (AMD) is a common cause of central visual loss in the elderly. Retinal pigment epithelial (RPE) cell loss occurs early in the course of AMD and RPE cell transplantation holds promise to slow disease progression. We report that subretinal transplantation of RPE stem cell (RPESC) derived RPE cells (RPESC-RPE) preserved vision in a rat model of RPE cell dysfunction. Importantly, the stage of differentiation that RPESC-RPE acquired prior to transplantation influenced the efficacy of vision rescue. Whereas cells at all stages of differentiation tested rescued photoreceptor layer morphology, an intermediate stage of RPESC-RPE differentiation obtained after 4 weeks of culture was more consistent at vision rescue than progeny that were differentiated for 2 weeks or 8 weeks of culture. Our results indicate that the developmental stage of RPESC-RPE significantly influences the efficacy of RPE cell replacement, which affects the therapeutic application of these cells for AMD. PMID- 28625538 TI - A Strong Contractile Actin Fence and Large Adhesions Direct Human Pluripotent Colony Morphology and Adhesion. AB - Cell-type-specific functions and identity are tightly regulated by interactions between the cell cytoskeleton and the extracellular matrix (ECM). Human pluripotent stem cells (hPSCs) have ultimate differentiation capacity and exceptionally low-strength ECM contact, yet the organization and function of adhesion sites and associated actin cytoskeleton remain poorly defined. We imaged hPSCs at the cell-ECM interface with total internal reflection fluorescence microscopy and discovered that adhesions at the colony edge were exceptionally large and connected by thick ventral stress fibers. The actin fence encircling the colony was found to exert extensive Rho-ROCK-myosin-dependent mechanical stress to enforce colony morphology, compaction, and pluripotency and to define mitotic spindle orientation. Remarkably, differentiation altered adhesion organization and signaling characterized by a switch from ventral to dorsal stress fibers, reduced mechanical stress, and increased integrin activity and cell-ECM adhesion strength. Thus, pluripotency appears to be linked to unique colony organization and adhesion structure. PMID- 28625539 TI - Investigating the effects of maximal anaerobic fatigue on dynamic postural control using the Y-Balance Test. AB - OBJECTIVES: The Y Balance Test is one of the most commonly used dynamic balance assessments, providing an insight into the integration of the sensorimotor subsystems. In recent times, there has been an increase in interest surrounding it's use in various clinical populations demonstrating alterations in motor function. Therefore, it is important to examine the effect physiological influences such as fatigue play in dynamic postural control, and establish a timeframe for its recovery. DESIGN: Descriptive laboratory study. METHODS: Twenty male and female (age 23.75+/-4.79years, height 174.12+/-8.45cm, mass 69.32+/ 8.76kg) partaking in competitive sport, completed the Y Balance Test protocol at 0, 10 and 20min, prior to a modified 60s Wingate fatiguing protocol. Post-fatigue assessments were then completed at 0, 10 and 20 min post-fatiguing intervention. RESULTS: Intraclass correlation coefficients demonstrated excellent intra-session reliability (0.976-0.982) across the three pre-fatigue YBT tests. Post-hoc paired sample t-tests demonstrated that all three reach directions demonstrated statistically significant differences between pre-fatigue and the first post fatigue measurement (anterior; p=0.019, posteromedial; p=0.019 & posterolateral; p=0.003). The anterior reach direction returned to pre-fatigue levels within 10min (p=0.632). The posteromedial reach direction returned to pre-fatigue levels within 20min (p=0.236), while the posterolateral direction maintained a statistically significant difference at 20min (p=0.023). CONCLUSIONS: Maximal anaerobic fatigue has a negative effect on normalised Y balance test scores in all three directions. Following the fatiguing protocol, dynamic postural control returns to pre-fatigue levels for the anterior (<10min), posteromedial (<20min) and posterolateral (>20min). PMID- 28625540 TI - Effects of breaking up sitting on adolescents' postprandial glucose after consuming meals varying in energy: a cross-over randomised trial. AB - OBJECTIVES: To explore the impact of uninterrupted sitting versus sitting with resistance-type activity breaks on adolescents' postprandial glucose responses while consuming a diet varying in energy. DESIGN: Cross-over randomised trial. METHODS: Thirteen healthy participants (16.4+/-1.3years) completed a four treatment cross-over trial: (1) uninterrupted sitting+high-energy diet; (2) sitting with breaks+high-energy diet; (3) uninterrupted sitting+standard-energy diet; and (4) sitting with breaks+standard-energy diet. For all four conditions, two identical meals were consumed; at 0h and 3h. A continuous glucose monitoring system (CGM) recorded interstitial glucose concentrations every five minutes. Linear mixed models examined differences in glucose positive incremental area under the curve (iAUC) and total AUC between the sitting and diet conditions for the first meal, second meal and entire trial period. RESULTS: Compared to the uninterrupted sitting conditions, the breaks condition elicited a 36.0mmol/L/h (95%CI 6.6-65.5) and 35.9mmol/L/h (95%CI 6.6-65.5) lower iAUC response after the first and second meal, respectively, but not for the entire trial period or for total AUC. Compared to the standard-energy diet, the high-energy diet elicited a 55.0mmol/L/h (95%CI 25.8-84.2) and 75.7mmol/L/h (95%CI 8.6-142.7) higher iAUC response after the first meal and entire trial, respectively. Similar response to the high-energy diet were observed for total AUC. CONCLUSIONS: According to iAUC, interrupting sitting had a significant effect on lowering postprandial glucose for both dietary conditions, however, it was not significant when examining total AUC. Larger studies are needed to confirm these findings. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12615001145594. PMID- 28625541 TI - Plant-derived antifungal compounds trigger a common transcriptional response. AB - Understanding the mechanism of action of antifungal drugs is vital for better control of mycosis, which kills >1.3 million lives every year thus remains a major health problem worldwide. In this study, we investigate the activities of three different categories of plant-derived antifungal compounds (resveratrol, honokiol and osthole) via transcriptomics and bioinformatics analysis, with the goal of discovering the common Mode-of-Action (MoA) at molecular level. The result shows that a common transcriptional response (72 gene are up-regulated while 10 genes are down-regulated, commonly) are triggered by above representative antifungal compounds in Schizosaccharomyces pombe (S. pombe) yeast. By virtue of gene set enrichment analysis (GSEA) and gene functional annotation study, we identify that the genes involved in oxidative stress response, sugar metabolism, fatty acid metabolism, amino acid metabolism and glycolysis are significantly up-regulated, while the genes involved in nucleosome assembly, transcription and RNA processing are down-regulated, by any of these antifungal compounds. These observations demonstrate that the common MoA includes a strengthened anti-oxidative cell adaptation, a faster metabolic rate and a generally suppressed gene transcriptional activity. It implies a genetically encoded common redistribution of intracellular energy flux and molecules synthesis, after the challenging of antifungal compounds. PMID- 28625542 TI - Analysis of the codon usage of the ORF2 gene of feline calicivirus. AB - Feline calicivirus (FCV) is a highly prevalent pathogen of the domestic cat that causes acute infections of the oral and upper respiratory tract. The E region of the ORF2 protein is responsible for the induction of virus-neutralizing antibodies, thus it is important to understand the codon usage of this gene. Here, analysed 90 coding sequences of ORF2 and show that it undergoes a low codon usage bias. In addition, although mutational bias is one of the factors shaping the codon usage bias of this gene, natural selection plays a more significant role. Our results reveal part of the mechanisms driving FCV evolution, which will lay foundation for the further research of FCV. PMID- 28625543 TI - Characterization of Vibrio cholerae O1 strains that trace the origin of Haitian like genetic traits. AB - Vibrio cholerae O1 is the etiological agent of the severe diarrheal disease cholera. The bacterium has recently been causing outbreaks in Haiti with catastrophic effects. Numerous mutations have been reported in V. cholerae O1 strains associated with the Haitian outbreak. These mutations encompass among other the genes encoding virulence factors such as the pilin subunit of the toxin co-regulated pilus (tcpA), cholera toxin B subunit (ctxB), repeat in toxins (rtxA), and other genes such as the quinolone resistance-determining region (QRDR) of gyrase A (gyrA), rstB of RS element along with the alteration in the number of repeat sequences at the promoter region of ctxAB. Given the numerous genetic changes in those Haitian isolates, we decided to investigate the possible origins of those variations in the Indian subcontinent. Thus, we determined the genetic traits among V. cholerae O1 strains in Delhi, India. A total of 175 strains isolated from cholera patients during 2004 to 2012 were analysed in the present study. Our results showed that all the tested strains carried Haitian type tcpA (tcpACIRS) and variant gyrA indicating their first appearance before 2004 in Delhi. The Haitian variant rtxA and ctxB7 were first detected in Delhi during 2004 and 2006, respectively. Interestingly, not a single strain with the combination of El Tor rtxA and ctxB7 was detected in this study. The Delhi strains carried four heptad repeats (TTTTGAT) in the CT promoter region whereas Haitian strains carried 5 such repeats. Delhi strains did not have any deletion mutations in the rstB like Haitian strains. Overall, our study demonstrates the sequential accumulation of Haitian-like genetic traits among V. cholerae O1 strains in Delhi at different time points prior to the Haitian cholera outbreak. PMID- 28625544 TI - SepsEast: Bridging between East and West. PMID- 28625545 TI - Screening for psychological distress: A new approach to identify the patient's psychological needs in a pilot study on oral cancer patients. AB - OBJECTIVE: A new screening tool has been developed to predict the psychological needs of patients with oral cancer. METHOD: The new screening method was developed inductively. Screening was pretested using interviews and implemented with 71 patients with oral cancer. Factor analysis was carried out to shorten the questionnaire. RESULTS: Negative and positive aspects explain forty per cent of the variance in distress, which should be adequate for a first screening. Seventy nine per cent of the items deal with stable traits such as personality. The patients' objective need for support has to be another important part of this new screening. CONCLUSIONS: Personality and other traits are good predictors for psychological distress. Longitudinal studies need to assess these new aspects of screening cancer patients to find out if they need psycho-oncological support. PMID- 28625546 TI - The lateral parabrachial nucleus and central angiotensinergic mechanisms in the control of sodium intake induced by different stimuli. AB - Angiotensin II (ANG II) is a typical facilitatory stimulus for sodium appetite. Surprisingly, hyperosmolarity and central cholinergic stimulation, two classical antinatriorexigenic stimuli, also facilitate NaCl intake when they are combined with injections of the alpha2-adrenoceptor/imidazoline agonist moxonidine into the lateral parabrachial nucleus (LPBN). In the present study, we tested the relative importance of central angiotensinergic and cholinergic mechanisms for the control of water and NaCl intake by combining different dipsogenic or natriorexigenic stimuli with moxonidine injection into the LPBN. Adult male Holtzman rats (n=9-10/group) with stainless steel cannulas implanted in the lateral ventricle and LPBN were used. Bilateral injections of moxonidine (0.5 nmol) into the LPBN increased water and 0.3M NaCl intake in rats that received furosemide+captopril injected subcutaneously, ANG II (50ng) or carbachol (cholinergic agonist, 4 nmol) injected intracerebroventricularly (icv) or 2M NaCl infused intragastrically (2ml/rat). Losartan (AT1 antagonist, 100MUg) or atropine (muscarinic antagonist, 20 nmol) injected icv abolished the effects on water and 0.3M NaCl of moxonidine combined to either 2M NaCl intragastrically or carbachol icv. However, atropine icv did not change 0.3M NaCl intake produced by direct central action of ANG II like that induced by ANG II icv or furosemide+captopril combined with moxonidine into the LPBN. The results suggest that different stimuli, including hyperosmolarity and central cholinergic stimulation, share central angiotensinergic activation as a common mechanism to facilitate sodium intake, particularly when they are combined with deactivation of the LPBN inhibitory mechanisms. PMID- 28625547 TI - Contextual fear conditioning is enhanced in mice lacking functional sphingosine kinase 2. AB - The lipid sphingosine 1-phosphate (S1P) is a potent neuroprotective signalling molecule that signals through its own family of five G-protein coupled receptors. S1P signalling enhances presynaptic glutamate release and is essential for neural development. S1P is synthesized by the enzymes sphingosine kinases 1 and 2 (SPHK1 and SPHK2), of which SPHK2 mRNA and activity is more abundant in the brain. In this study we investigated the consequences of global SphK2 knockout (SphK2-/-) on basic motor capabilities, anxiety, learning, and memory in mice, using a range of tests including the elevated plus maze, the cheeseboard, contextual and cued fear conditioning, and fear extinction. Loss of SphK2 resulted in an 85-90% reduction in brain S1P levels, and was associated with a notably higher freezing response in a novel context. SphK2 knockout mice also exhibited increased contextual fear conditioning but the extinction of contextual fear memory was similar to control mice. SphK2-/- mice, contrary to their control littermates, did not respond to cue presentation with increased freezing. Anxiety measures in the elevated plus maze were not different between SphK2-/- mice and control littermates. Also, knockout mice showed no deficits in neurological reflexes or motor functions, and performed as well as their control littermates in the spatial memory test. Our findings demonstrate that SphK2 is responsible for the vast majority of S1P synthesis in the mouse brain, and plays a role in freezing responses as evaluated in the fear conditioning paradigm. PMID- 28625548 TI - Effect of a change in housing conditions on body weight, behavior and brain neurotransmitters in male C57BL/6J mice. AB - The development of modern housing regimes such as individually ventilated cage (IVC) systems has become very popular and attractive in order to reduce spreading of pathogenic organisms and to lower the risk to develop a laboratory animal allergy for staff members. Additionally, optimal housing of laboratory animals contributes to improve animal health status and ensures high and comparable experimental and animal welfare standards. However, it has not been clearly elucidated whether 1) a change to IVC systems have an impact on various physiological phenotypic parameters of mice when compared to conventional, standard cages and 2) if this is further affected by changing from social to single housing. Therefore, we investigated the influence of a change in housing conditions (standard cages with social housing changed to standard or IVC cages combined with social or single housing) on body weight, behavior and a neurochemical fingerprint of male C57BL/6J mice. Body weight progression was significantly reduced when changing mice to single or social IVC cages as well as in single standard cages when compared to social standard housing. Automated motor activity measurement in the open field showed that mice maintained in social husbandry with standard cages displayed the lowest exploratory behavior but the highest activity difference upon amphetamine treatment. Elevated plus maze test revealed that a change to IVC single and social housing as well as single standard housing produced anxiety-related behavior when compared to maintenance in social standard housing. Additionally, postmortem neurochemical analysis of the striatum using high-performance liquid chromatography coupled to electrochemical detection showed significant differences in striatal dopamine and serotonin turnover levels. In summary, our data indicate a crucial influence of a change in housing conditions on several mouse phenotype parameters. We propose that the maintenance of well-defined housing conditions is mandatory to ensure reproducible and comparable results and contributes to the application of the 3R refinement principle in animal studies by contributing to welfare and hygienical standards. PMID- 28625549 TI - The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice. AB - Psychosocial stress leads to the activation of kappa opioid receptors (KORs), which induce dysphoria and facilitate depression-like behaviors. However, less is known about the long-term effects of stress and KORs in females. We examined the long-term effects of social defeat stress on the aversive properties of KOR activation in male and female California mice (Peromyscus californicus) using a conditioned place aversion paradigm. Female California mice naive to social defeat, formed a place aversion following treatment with 2.5mg/kg of the KOR agonist U50,488, but females exposed to defeat did not form a place aversion to this dose. This supports the finding by others that social defeat weakens the aversive properties of KOR agonists. In contrast, both control and stressed males formed an aversion to 10mg/kg of U50,488. We also examined EGR1 immunoreactivity, an indirect marker of neuronal activity, in the nucleus accumbens (NAc) and found that stress and treatment with 10mg/kg of U50,488 increased EGR1 immunoreactivity in the NAc core in females but reduced activation in males. The effects of stress and U50,488 on EGR1 were specific to the NAc, as we found no differences in the bed nucleus of the stria terminalis. In summary, our data indicate important sex differences in the long-term effects of stress and indicate the need for further study of the molecular mechanisms mediating the behavioral effects of KOR in both males and females. PMID- 28625550 TI - Maternal exposure to Western diet affects adult body composition and voluntary wheel running in a genotype-specific manner in mice. AB - Some human diseases, including obesity, Type II diabetes, and numerous cancers, are thought to be influenced by environments experienced in early life, including in utero. Maternal diet during the perinatal period may be especially important for adult offspring energy balance, potentially affecting both body composition and physical activity. This effect may be mediated by the genetic background of individuals, including, for example, potential "protective" mechanisms for individuals with inherently high levels of physical activity or high basal metabolic rates. To examine some of the genetic and environmental factors that influence adult activity levels, we used an ongoing selection experiment with 4 replicate lines of mice bred for high voluntary wheel running (HR) and 4 replicate, non-selected control lines (C). Dams (half HR and half C) were fed a "Western" diet (WD, high in fat and sucrose) or a standard diet (SD) from 2weeks prior to mating until their pups could feed on solid food (14days of age). We analyzed dam and litter characteristics from birth to weaning, and offspring mass and physical activity into adulthood. One male offspring from each litter received additional metabolic and behavioral tests. Maternal WD caused pups to eat solid food significantly earlier for C litters, but not for HR litters (interaction of maternal environment and genotype). With dam mass as a covariate, mean pup mass was increased by maternal WD but litter size was unaffected. HR dams had larger litters and tended to have smaller pups than C dams. Home-cage activity of juvenile focal males was increased by maternal WD. Juvenile lean mass, fat mass, and fat percent were also increased by maternal WD, but food consumption (with body mass as a covariate) was unaffected (measured only for focal males). Behavior in an elevated plus maze, often used to indicate anxiety, was unaffected by maternal WD. Maximal aerobic capacity (VO2max) was also unaffected by maternal WD, but HR had higher VO2max than C mice. Adult lean, fat, and total body masses were significantly increased by maternal WD, with greater increase for fat than for lean mass. Overall, no aspect of adult wheel running (total distance, duration, average running speed, maximum speed) or home-cage activity was statistically affected by maternal WD. However, analysis of the 8 individual lines revealed that maternal WD significantly increased wheel running in one of the 4 HR lines. On average, all groups lost fat mass after 6days of voluntary wheel running, but the absolute amount lost was greater for mice with maternal WD resulting in no effect of maternal WD on absolute or % body fat after wheel access. All groups gained lean and total body mass during wheel access, regardless of maternal WD or linetype. Measured after wheel access, circulating leptin, adiponectin, and corticosterone concentrations were unaffected by maternal WD and did not differ between HR and C mice. With body mass as a covariate, heart ventricle mass was increased by maternal WD in both HR and C mice, but fat pads, liver, spleen, and brain masses were unaffected. As found previously, HR mice had larger brains than C mice. Body mass of grand-offspring was unaffected by grand-maternal WD, but grand-offspring wheel running was significantly increased for one HR line and decreased for another HR line by grand-maternal WD. In summary, maternal Western diet had long-lasting and general effects on offspring adult morphology, but effects on adult behavior were limited and contingent on sex and genetic background. PMID- 28625552 TI - Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection. AB - Circular RNAs (circRNAs) generated via back-splicing are enhanced by flanking complementary sequences. Expression levels of circRNAs vary under different conditions, suggesting participation of protein factors in their biogenesis. Using genome-wide siRNA screening that targets all human unique genes and an efficient circRNA expression reporter, we identify double-stranded RNA-binding domain containing immune factors NF90/NF110 as key regulators in circRNA biogenesis. NF90/NF110 promote circRNA production in the nucleus by associating with intronic RNA pairs juxtaposing the circRNA-forming exon(s); they also interact with mature circRNAs in the cytoplasm. Upon viral infection, circRNA expression is decreased, in part owing to the nuclear export of NF90/NF110 to the cytoplasm. Meanwhile, NF90/NF110 released from circRNP complexes bind to viral mRNAs as part of their functions in antiviral immune response. Our results therefore implicate a coordinated regulation of circRNA biogenesis and function by NF90/NF110 in viral infection. PMID- 28625551 TI - Sensing Self and Foreign Circular RNAs by Intron Identity. AB - Circular RNAs (circRNAs) are single-stranded RNAs that are joined head to tail with largely unknown functions. Here we show that transfection of purified in vitro generated circRNA into mammalian cells led to potent induction of innate immunity genes and confers protection against viral infection. The nucleic acid sensor RIG-I is necessary to sense foreign circRNA, and RIG-I and foreign circRNA co-aggregate in cytoplasmic foci. CircRNA activation of innate immunity is independent of a 5' triphosphate, double-stranded RNA structure, or the primary sequence of the foreign circRNA. Instead, self-nonself discrimination depends on the intron that programs the circRNA. Use of a human intron to express a foreign circRNA sequence abrogates immune activation, and mature human circRNA is associated with diverse RNA binding proteins reflecting its endogenous splicing and biogenesis. These results reveal innate immune sensing of circRNA and highlight introns-the predominant output of mammalian transcription-as arbiters of self-nonself identity. PMID- 28625554 TI - Exploring the social determinants of racial/ethnic disparities in prenatal care utilization and maternal outcome. AB - Rates of maternal morbidity and mortality are rising in the United States. Non Hispanic Black women are at highest risk for these outcomes compared to those of other race/ethnicities. Black women are also more likely to be late to prenatal care or be inadequate users of prenatal care. Prenatal care can engage those at risk and potentially influence perinatal outcomes but further research on the link between prenatal care and maternal outcomes is needed. The objective of this article is to review literature illuminating the relationship between prenatal care utilization, social determinants of health, and racial disparities in maternal outcome. We present a theoretical framework connecting the complex factors that may link race, social context, prenatal care utilization, and maternal morbidity/mortality. Prenatal care innovations showing potential to engage with the social determinants of maternal health and address disparities and priorities for future research are reviewed. PMID- 28625555 TI - Adjuvant pertuzumab improves early breast cancer outcomes. PMID- 28625553 TI - Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide. AB - Emerging studies have linked the ribosome to more selective control of gene regulation. However, an outstanding question is whether ribosome heterogeneity at the level of core ribosomal proteins (RPs) exists and enables ribosomes to preferentially translate specific mRNAs genome-wide. Here, we measured the absolute abundance of RPs in translating ribosomes and profiled transcripts that are enriched or depleted from select subsets of ribosomes within embryonic stem cells. We find that heterogeneity in RP composition endows ribosomes with differential selectivity for translating subpools of transcripts, including those controlling metabolism, cell cycle, and development. As an example, mRNAs enriched in binding to RPL10A/uL1-containing ribosomes are shown to require RPL10A/uL1 for their efficient translation. Within several of these transcripts, this level of regulation is mediated, at least in part, by internal ribosome entry sites. Together, these results reveal a critical functional link between ribosome heterogeneity and the post-transcriptional circuitry of gene expression. PMID- 28625556 TI - Alectinib surpasses crizotinib for untreated ALK-positive NSCLC. PMID- 28625557 TI - [More than 3 hours and less than 3 years: Safety of anaesthetic procedures in infants less than 3 years old subected to surgery for more the 3 hours]. AB - An FDA alert in December 2016 on the safety of general anesthesia and sedations in patients less than 3 years of age and pregnant women has raised doubts in relation to the attitude that professionals implicated in these procedures should adopt in relation to these specific group of patients. Confronted with this situation, the following medical scientific societies: Sociedad Espanola de Anestesia y Reanimacion (SEDAR), Sociedad Espanola de Cirugia Pediatrica (SECP), Sociedad Espanola de Cuidados Intensivos Pediatricos (SECIP) y Sociedad Espanola de Neonatologia (SENeo), have established a working group to analyze and clarify the safety of these techniques. In the present article we conclude that at present both general anesthesia and profound sedation are considered safe procedures because there is no evidence of the opposite in studies with human beings. However, this ascertained safety should not obviate the problem which still needs to be followed with attention, especially in patients less than 3 years of age undergoing anesthetic procedures for more than 3 hours or prolonged sedation in the Neonatal or Pediatric Intensive Care Units. PMID- 28625558 TI - Irregular Defects in Hepatocellular Carcinomas During the Kupffer Phase of Contrast-Enhanced Ultrasonography with Perfluorobutane Microbubbles: Pathological Features and Metastatic Recurrence After Surgical Resection. AB - The present study aimed to elucidate the association between post-vascular-phase (Kupffer-phase) images from contrast-enhanced ultrasonography (CEUS) with perfluorobutane microbubbles and metastatic recurrences after the resection of hepatocellular carcinoma (HCC). The study examined 73 patients with solitary HCC <=5 cm in diameter who underwent CEUS before resection. HCC was defined as irregular type (including an irregular defect on Kupffer-phase images) or non irregular type. Intrahepatic metastatic recurrence was defined as >3 intrahepatic recurrences. Metastatic recurrence included both extrahepatic and intrahepatic recurrences. Frequencies of microscopic portal invasion and intrahepatic metastasis were significantly higher in the irregular group than in the non irregular group. Cumulative 5-y metastatic recurrence rates in the irregular and non-irregular groups were 43% and 7% (p = 0.028), respectively. Multivariate analyses identified Kupffer-phase findings as a factor significantly related to metastatic recurrence. In conclusion, HCCs with an irregular defect during Kupffer-phase CEUS are characterized by more frequent microscopic vascular invasion and intrahepatic metastasis and are significantly associated with metastatic recurrence after resection. PMID- 28625559 TI - Feasibility of Combined Doppler-ECG Assessment of Internal Jugular Veins. AB - A standardized combined Doppler-electrocardiography technique was developed for measurement of the triphasic waveform characteristics in the internal jugular vein. Flow velocities at the A, X, V and Y peaks, the RR interval and the PA and RX times were measured. From these the venous impedance index ([X-A]/X) and the ratios PA/RR and RX/RR were calculated. Six measurements were performed at three different locations by two ultrasonographers in 21 randomly selected pregnant and non-pregnant women. Statistical models proved the feasibility and reproducibility of this technique, with the highest concordance correlation coefficients in the right distal internal vein. Bootstrapping revealed that repeating the measurements more than four times would not significantly enhance the precision of the estimated mean. Concordance correlation coefficients for the venous impedance index, PA time and PA/RR ratio were >0.63 for all three locations, proving their possible use in ongoing and future studies, analogous to previous studies in kidney and liver. PMID- 28625560 TI - Small Bowel Ultrasound beyond Inflammatory Bowel Disease: An Updated Review of the Recent Literature. AB - The use of bowel ultrasonography (US) for the evaluation of gut diseases has increased in recent years and has been proven to provide a widely available, non invasive and inexpensive method for the initial work-up and follow-up of different intestinal diseases, limited mostly by technical challenges posed by the patient's anatomy. The present review aims to provide an extensive overview of the main pathologic features at US examination of intestinal diseases other than inflammatory bowel disease, both acute (e.g., acute appendicitis, colonic diverticulitis, infectious diseases and ischemic conditions) and chronic (e.g., celiac disease, cystic fibrosis and other enterocolites). The identification of typical US features may help in the diagnostic process and guide the treatment approach. Therefore, the application of knowledge of the US appearance of gastrointestinal diseases is of relevance in enabling greater diagnostic performance and better patient management. PMID- 28625561 TI - Monitoring the different micelle species and the slow kinetics of tetraethylammonium perfluorooctane-sulfonate by 19F NMR spectroscopy. AB - Since we lack effective tools that can monitor the structures of surfactant micelles in situ, the different equilibrium species and the slow kinetics of micelles are still not well understood. Herein, by using 19F NMR, we simultaneously monitored that micelles of tetraethylammonium perfluorooctanesulfonate (TPFOS, C8F17SO3N(C2H5)4) in water grow more complex in virtue of hydrophobic counterions and the slow kinetic exchange process exists in the system. Apart from the monomeric signals, three sets of micelle signals which correspond to spherical micelles, wormlike/wormlike micelles with rings in end caps and toroidal micelles were successfully detected on the NMR time scale because of the slow exchange rate for surfactant molecules between the monomer and the micelle states. By comparison, other fluoro- and hydrocarbon surfactants with different tail lengths and counterions (+N(CH3)4, +N(C3H7)4, Li+ and Na+) have been studied, and the coexistence of different micelles could also been observed for the aqueous solution of C9F19COON(CH3)4. However, only one set of averaged NMR signals could be observed for these surfactants. The micellization of TPFOS in water is demonstrated to be a predominantly entropy-driven process. Molecular dynamics (MD) simulation revealed an unusual distribution of counterions, providing further understanding of the mechanism of the micelle formation process. PMID- 28625562 TI - Do trauma courses change practice? A qualitative review of 20 courses in East, Central and Southern Africa. AB - BACKGROUND: Trauma courses have been shown to improve clinical knowledge and patient outcomes. However, little is known about the individual drivers of change in practice amongst course participants in their home clinic environment. METHODS: Front-line healthcare workers participated in a two-day Primary Trauma Care (PTC) course. Immediately after the course participants completed an evaluation survey on intended change in the management of trauma patients. Six months after the course, participants completed a survey on actual changes that had occurred. RESULTS: A total of 451 participants were sampled, with 321 responding at 6 months, from 40 courses across East, Central and Southern Africa. The most commonly reported intended change was the adoption of an ABCDE/systematic approach (53%). Six months after the course, 92.7% of respondents reported that they had made changes in their management, with adoption of an ABCDE/systematic approach (50.0%) remaining most common. 77% of participants reported an improvement in departmental trauma management, 26% reported an increase in staffing, 29% an increase in equipment and 68% of participants had gone on to train other healthcare workers in PTC. CONCLUSION: The findings suggest that PTC courses not only improve individual management of trauma patients but also but is also associated with beneficial effects for participants' host institutions with regards to staffing, equipment and training. PMID- 28625563 TI - Testing the effectiveness of simplified search strategies for updating systematic reviews. AB - OBJECTIVE: The objective of the study was to test the overall effectiveness of a simplified search strategy (SSS) for updating systematic reviews. STUDY DESIGN AND METHODS: We identified nine systematic reviews undertaken by our research group for which both comprehensive and SSS updates were performed. Three relevant performance measures were estimated, that is, sensitivity, precision, and number needed to read (NNR). RESULTS: The update reference searches for all nine included systematic reviews identified a total of 55,099 citations that were screened resulting in final inclusion of 163 randomized controlled trials. As compared with reference search, the SSS resulted in 8,239 hits and had a median sensitivity of 83.3%, while precision and NNR were 4.5 times better. During analysis, we found that the SSS performed better for clinically focused topics, with a median sensitivity of 100% and precision and NNR 6 times better than for the reference searches. For broader topics, the sensitivity of the SSS was 80% while precision and NNR were 5.4 times better compared with reference search. CONCLUSION: SSS performed well for clinically focused topics and, with a median sensitivity of 100%, could be a viable alternative to a conventional comprehensive search strategy for updating this type of systematic reviews particularly considering the budget constraints and the volume of new literature being published. For broader topics, 80% sensitivity is likely to be considered too low for a systematic review update in most cases, although it might be acceptable if updating a scoping or rapid review. PMID- 28625564 TI - CRISPR system in filamentous fungi: Current achievements and future directions. AB - As eukaryotes, filamentous fungi share many features with humans, and they produce numerous active metabolites, some of which are toxic. Traditional genetic approaches are generally inefficient, but the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system that has been widely used for basic research on bacteria, mammals and plants offers a simple, fast, versatile technology for systemic research on filamentous fungi. In this review, we summarized the current knowledge on Cas9 and its variants, various selective markers used to screen positive clones, different ways used to detect off-target mutations, and different approaches used to express and transform the CRISPR complex. We also highlight several methods that improve the nuclease specificity and efficiency, and discuss current and potential applications of CRISPR/Cas9 system in filamentous fungi for pathogenesis decoding, confirmation of the gene and pathway, bioenergy process, drug discovery, and chromatin dynamics. We also describe how the synthetic gene circuit of CRISPR/Cas9 systems has been used in the response to various complex environmental signals to redirect metabolite flux and ensure continuous metabolite biosynthesis. PMID- 28625566 TI - Advances in bioremediation of 1,4-dioxane-contaminated waters. AB - 1,4-Dioxane is a contaminant of emerging concern that has been found widespread in groundwater, surface water, and drinking water environments. Many states are implementing lower regulatory advisory levels based on the toxicological profile of 1,4-dioxane and the potential public health risks. However, the unique chemical properties of 1,4-dioxane, such as high water solubility, low Henry's law constant, and importantly, the co-occurrence with chlorinated solvents and other contaminants, increase the challenges to efficiently cleanup 1,4-dioxane. This review summarizes currently available chemical and physical 1,4-dioxane treatment technologies and focuses on recent advances in bioremediation and monitoring tools. We also include laboratory studies and field applications to propose the next steps in 1,4-dioxane bioremediation research. It is important to provide useful references to change the industrial and regulatory perception of 1,4-dioxane biodegradability, to understand treatment mechanisms especially in contaminant mixtures, and to direct research for meeting practical needs. PMID- 28625565 TI - The CEP19-RABL2 GTPase Complex Binds IFT-B to Initiate Intraflagellar Transport at the Ciliary Base. AB - Highly conserved intraflagellar transport (IFT) protein complexes direct both the assembly of primary cilia and the trafficking of signaling molecules. IFT complexes initially accumulate at the base of the cilium and periodically enter the cilium, suggesting an as-yet-unidentified mechanism that triggers ciliary entry of IFT complexes. Using affinity-purification and mass spectrometry of interactors of the centrosomal and ciliopathy protein, CEP19, we identify CEP350, FOP, and the RABL2B GTPase as proteins organizing the first known mechanism directing ciliary entry of IFT complexes. We discover that CEP19 is recruited to the ciliary base by the centriolar CEP350/FOP complex and then specifically captures GTP-bound RABL2B, which is activated via its intrinsic nucleotide exchange. Activated RABL2B then captures and releases its single effector, the intraflagellar transport B holocomplex, from the large pool of pre-docked IFT-B complexes, and thus initiates ciliary entry of IFT. PMID- 28625567 TI - Dose postural control improve following application of transcutaneous electrical nerve stimulation in diabetic peripheral neuropathic patients? A randomized placebo control trial. AB - BACKGROUND: peripheral neuropathy is the most common problem of diabetes. Neuropathy leads to lower extremity somatosensory deficits and postural instability in these patients. However, there are not sufficient evidences for improving postural control in these patients. AIM: To investigate the effects of transcutaneous electrical nerve stimulation (TENS) on postural control in patients with diabetic neuropathy. METHODS: Twenty eighth patients with diabetic neuropathy (40-55 Y/O) participated in this RCT study. Fourteen patients in case group received TENS and sham TENS was used for control group. Force plate platform was used to extract sway velocity and COP displacement parameters for postural control evaluation. RESULTS: The mean sway velocity and center of pressure displacement along the mediolateral and anteroposterior axes were not significantly different between two groups after TENS application (p>0.05). CONCLUSION: Application of 5min high frequency TENS on the knee joint could not improve postural control in patients with diabetic neuropathy. PMID- 28625568 TI - The olive oil phenolic (-)-oleocanthal modulates estrogen receptor expression in luminal breast cancer in vitro and in vivo and synergizes with tamoxifen treatment. AB - Luminal breast cancer represents a therapeutic challenge in terms of aggressive disease and emerging resistance to targeted therapy. (-)-Oleocanthal has demonstrated anticancer activity in multiple human cancers. The goal of this study was to explore the effect of (-)-oleocanthal treatment on growth of luminal breast cancer cells and to examine the effect of combination of (-)-oleocanthal with tamoxifen. Results showed that (-)-oleocanthal inhibited growth of BT-474, MCF-7, and T-47D human breast cancer cells in mitogen-free media with IC50 values of 32.7, 24.07, and 80.93uM, respectively. Similarly, (-)-oleocanthal suppressed growth of BT-474, MCF-7, and T-47D cells in 17beta-estradiol-supplemented media with IC50 values of 22.28, 20.77, and 83.91uM, respectively. Combined (-) oleocanthal and tamoxifen treatments resulted in a synergistic growth inhibition of BT-474, MCF-7, and T-47D cells with combination index values of 0.65, 0.61, and 0.53 for each cell line, respectively. In-silico docking studies indicated high degree of overlapping for the binding of (-)-oleocanthal and 17beta estradiol to estrogen receptors, while (-)-oleocanthal and tamoxifen have distinguished binding modes. Treatment with 5mg/kg or 10mg/kg (-)-oleocanthal resulted in 97% inhibition of tumor growth in orthotopic athymic mice bearing BT 474 tumor xenografts compared to vehicle-treated animals. (-)-Oleocanthal treatment reduced total levels of estrogen receptors in BT-474 cells both in vitro and in vivo. Collectively, (-)-oleocanthal showed a potential beneficial effect in suppressing growth of hormone-dependent breast cancer and improving sensitivity to tamoxifen treatment. These findings provide rational for evaluating the effect of (-)-oleocanthal in combination with endocrine treatments in luminal breast cancer. PMID- 28625569 TI - Synaptic dysfunction in Alzheimer's disease: From the role of amyloid beta peptide to the alpha-secretase ADAM10. AB - Alzheimer's disease (AD) is emerging as the most prevalent and socially disruptive illness of aging populations as more people live long enough to become affected. Although AD is placing a considerable and increasing burden on patients, caregivers and society, it represents the largest unmet medical need in neurology, because it is currently incurable. In the last few years, the amyloid hypothesis, which points to amyloid beta-peptide (Abeta) as the initiating factor in AD, had a central role in the development of therapeutic strategies for AD. However, the recent clinical trials targeting Abeta have been disappointing. The need to obtain a comprehensive picture of AD pathogenesis is strong as ever. In this framework, this review focuses on Abeta effects on the synapses and on ADAM10, the enzyme able to prevent Abeta formation, analysing its function in the synapse, its contribution to AD pathology and discussing its potential as pharmacological target. PMID- 28625570 TI - Progress toward Fulfilling the Potential of Immunomodulation in Childhood Neurodegeneration? PMID- 28625571 TI - Micromanaging Tolerance in Hemophilia A Gene Therapy. PMID- 28625572 TI - Nanoparticle Technology: Having Impact, but Needing Further Optimization. PMID- 28625573 TI - Management: from antibiotic stewardship to clinical microbiology. PMID- 28625574 TI - Rapamycin decreased blood-brain barrier permeability in control but not in diabetic rats in early cerebral ischemia. AB - Diabetes causes functional and structural changes in blood-brain barrier (BBB). The mammalian target of rapamycin (mTOR) has been associated with glucose metabolism, diabetes, and altering BBB permeability. Since there is only a narrow therapeutic window (3h) for stroke victims, it is important to investigate BBB disruption in the early stage of cerebral ischemia. We compared the degree of BBB disruption in diabetic and in control rats at two hours of reperfusion after one hour of middle cerebral artery (MCA) occlusion with or without inhibition of mTOR. Two weeks after streptozotocin ip to induce diabetes, MCA occlusion was performed. In half of the rats, an mTOR inhibitor, rapamycin was given for 2days before MCA occlusion. After one hour of MCA occlusion and two hours of the reperfusion, the transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid was determined to quantify degree of BBB disruption. Ischemia-reperfusion increased the Ki in the control animals. Streptozotocin increased the Ki in the ischemic reperfused (IR-C, +22%) as well as in the contralateral cortex (CC, +40%). Rapamycin decreased the Ki in the IR-C (-32%) as well as in the CC (-26%) in the control rats. However, rapamycin did not affect Ki in the IR-C or in the CC in the diabetic rats. Our data demonstrated a greater BBB disruption in diabetes in the ischemic as well as non-ischemic cortex even in the early stage of cerebral ischemia-reperfusion and that acute administration of rapamycin did not significantly affect BBB permeability in diabetes. From our quantitative analysis of BBB disruption, the vulnerability of BBB in diabetes has been emphasized in the early stage of cerebral ischemia-reperfusion and a less important role of the mTOR pathway is suggested in altering BBB permeability in diabetes. PMID- 28625575 TI - Overexpression of STMN1 is associated with the prognosis of meningioma patients. AB - There is a small part of the pathological type of the meningioma has a malignant tendency and patients have the poor prognosis. Looking for effective biomarkers to predict the degree of malignancy of the tumors, will help us to better manage the patient and guide the treatment. The present study aims at investigating the prognostic value of the expression of Stathmin in a series of meningiomas of different grade. We integrated eight published microarray datasets of meningiomas to screen grade biomarkers in meningiomas patients using the WebArrayDB platform. We focused on Stathmin, Using formalin-fixed paraffin-embedded (FFPE) tumor samples, we corroborated the relationship between Stathmin and patient outcomes using qRT-PCR for gene expression. We also found expression of Stathmin that atypical/anaplastic meningiomas have higher expression than benign meningiomas (p<0.01). No correlation between Stathmin expression and age, gender and tumor extent of resection was found (p>0.05). Moreover, increased Stathmin expression was correlated to higher meningioma grade and shorter disease-free survival (DFS) of meningioma patients with Simpson I resection. Stathmin might be promising targets to improve the cure rates in meningiomas. PMID- 28625576 TI - Mexiletine co-injected with clonidine increases the quality and duration of cutaneous analgesia in response to skin pinpricks in the rat. AB - The goal of the experimental design was to assess the cutaneous analgesic effect of mexiletine by co-injection with clonidine. The effect of nociceptive block was evaluated according to the inhibition of the cutaneous trunci muscle reflex (CTMR) in response to skin pinpricks in rats. The dose-related analgesic effect of mexiletine alone or mexiletine co-administrated with clonidine was constructed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose related cutaneous analgesia. Compared with mexiletine (1.8MUmol), adding clonidine to mexiletine (1.8MUmol) solutions for skin nociceptive block potentiated and prolonged the action (p<0.01). Mexiletine (6MUmol) combined with clonidine extended the duration of cutaneous analgesia when compared with mexiletine (6MUmol) alone (p<0.01). Co-administration of clonidine increases the potency and extends the duration of cutaneous analgesia by mexiletine, and the minimal dose of clonidine to intensify the analgesic effect is 0.06MUmol. PMID- 28625578 TI - Rebuttal From Drs Truog and Tasker. PMID- 28625577 TI - Risk Factors for Chronic Cough Among 14,669 Individuals From the General Population. AB - BACKGROUND: Risk factors for chronic cough in the general population have not been described systematically. We identified and ranked chronic cough risk factors at the individual and community level using data from 14,669 individuals from the Copenhagen General Population Study. METHODS: Severity of chronic cough was assessed using the Leicester Cough Questionnaire (LCQ). We ranked chronic cough risk factors based on magnitude of age-adjusted ORs at the individual level and of the population attributable risks (PARs) at the community level. RESULTS: Prevalence of chronic cough in the general population was 4% overall and 3% in never smokers, 4% in former smokers, and 8% in current smokers. Median score of the LCQ was 5.8 (25th-75th percentile, 5.0-6.3) for physical domain, 5.6 (25th 75th percentile, 4.6-6.3) for psychologic domain, 6.3 (25th-75th percentile, 5.5 6.8) for social domain, and 17.3 (25th- 75th percentile, 15.4-18.9) in total. At the level of the individual, age-adjusted ORs for the three top-ranked risk factors were 5.0 (95% CI, 1.4-18) for bronchiectasis, 2.6 (95% CI, 1.7-3.9) for asthma and 2.3 (95% CI, 1.5-3.4) for gastroesophageal reflux disease in never smokers, 7.1 (95% CI, 2.6-20) for bronchiectasis, 3.1 (95% CI, 2.2-4.4) for asthma and 2.2 (95% CI, 1.5-3.2) for occupational exposure to dust/fumes in former smokers, and 1.9 (95% CI, 1.3-2.9) for airflow limitation in current smokers. At the level of the community, the three top-ranked risk factors were female sex (PAR, 19%), asthma (PAR, 10%), and gastroesophageal reflux disease (PAR, 8%) in never smokers; abdominal obesity (PAR, 20%), low income (PAR, 20%), and asthma (PAR, 13%) in former smokers; and airflow limitation (PAR, 23%) in current smokers. CONCLUSIONS: Risk factors for chronic cough differ at the level of the individual and community, and by smoking status. Strategies to prevent and treat modifiable chronic cough risk factors should be tailored accordingly. PMID- 28625580 TI - COUNTERPOINT: Should Informed Consent Be Required for Apnea Testing in Patients With Suspected Brain Death? Yes. PMID- 28625579 TI - Improved Early Detection of Sepsis in the ED With a Novel Monocyte Distribution Width Biomarker. AB - BACKGROUND: Sepsis most often presents to the ED, and delayed detection is harmful. WBC count is often used to detect sepsis, but changes in WBC count size also correspond to sepsis. We sought to determine if volume increases of circulating immune cells add value to the WBC count for early sepsis detection in the ED. METHODS: A blinded, prospective cohort study was conducted in two different ED populations within a large academic hospital. RESULTS: Neutrophil and monocyte volume parameters were measured in conjunction with routine CBC testing on a UniCel DxH 800 analyzer at the time of ED admission and were evaluated for the detection of sepsis. There were 1,320 subjects in the ED consecutively enrolled and categorized as control subjects (n = 879) and those with systemic inflammatory response syndrome (SIRS) (n = 203), infection (n = 140), or sepsis (n = 98). Compared with other parameters, monocyte distribution width (MDW) best discriminated sepsis from all other conditions (area under the curve [AUC], 0.79; 95% CI, 0.73-0.84; sensitivity, 0.77; specificity, 0.73; MDW threshold, 20.50), sepsis from SIRS (AUC, 0.74; 95% CI, 0.67-0.84), and severe sepsis from noninfected patients in the ED (AUC, 0.88; 95% CI, 0.75-0.99; negative predictive value, 99%). The added value of MDW to WBC count was statistically significant (AUC, 0.89 for MDW + WBC vs 0.81 for WBC alone; P < .01); a decision curve analysis also showed improved performance compared with WBC count alone. CONCLUSIONS: The incorporation of MDW with WBC count is shown in this prospective cohort study to improve detection of sepsis compared with WBC count alone at the time of admission in the ED. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02232750; URL: www.clinicaltrials.gov. PMID- 28625581 TI - POINT: Should Informed Consent Be Required for Apnea Testing in Patients With Suspected Brain Death? No. PMID- 28625582 TI - Rebuttal From Drs Lewis and Greer. PMID- 28625583 TI - Bridging suture makes consistent and secure fixation in double-row rotator cuff repair. AB - BACKGROUND: Inconsistent tension distribution may decrease the biomechanical properties of the rotator cuff tendon after double-row repair, resulting in repair failure. The purpose of this study was to compare the tension distribution along the repaired rotator cuff tendon among three double-row repair techniques. METHODS: In each of 42 fresh-frozen porcine shoulders, a simulated infraspinatus tendon tear was repaired by using 1 of 3 double-row techniques: (1) conventional double-row repair (no bridging suture); (2) transosseous-equivalent repair (bridging suture alone); and (3) compression double-row repair (which combined conventional double-row and bridging sutures). Each specimen underwent cyclic testing at a simulated shoulder abduction angle of 0 degrees or 40 degrees on a material-testing machine. Gap formation and tendon strain were measured during the 1st and 30th cycles. To evaluate tension distribution after cuff repair, difference in gap and tendon strain between the superior and inferior fixations was compared among three double-row techniques. RESULTS: At an abduction angle of 0 degrees , gap formation after either transosseous-equivalent or compression double-row repair was significantly less than that after conventional double-row repair (p < 0.01). During the 30th cycle, both transosseous-equivalent repair (p = 0.02) and compression double-row repair (p = 0.01) at 0 degrees abduction had significantly less difference in gap formation between the superior and inferior fixations than did conventional double-row repair. After the 30th cycle, the difference in longitudinal strain between the superior and inferior fixations at 0 degrees abduction was significantly less with compression double-row repair (2.7% +/- 2.4%) than with conventional double-row repair (8.6% +/- 5.5%, p = 0.03). CONCLUSIONS: Bridging sutures facilitate consistent and secure fixation in double-row rotator cuff repairs, suggesting that bridging sutures may be beneficial for distributing tension equally among all sutures during double-row repair of rotator cuff tears. PMID- 28625584 TI - The role of prophylactic antiepileptic drugs for seizure prophylaxis in meningioma surgery: A systematic review. AB - Meningiomas are the commonest type of primary brain tumours. Whilst most patients are seizure-free prior to surgery, antiepileptic drugs are frequently administered to reduce the risk of developing post-operative seizures. However, evidence to support their efficacy in providing this outcome is sparse. To this end, we performed a systematic review to assess the impact of prophylactic antiepileptic drugs on post-operative epilepsy rates in seizure-naive patients undergoing craniotomy for resection of meningiomas. The literature search was performed using PubMed for studies published between January 1990 and November 2016. The total number of patients in each study was extracted and divided into cohorts according to administration of prophylactic antiepileptic drugs. Clinical characteristics, study type and post-operative epilepsy rates were recorded. A total of 11 studies involving 1143 patients met the selection criteria. There was no statistically significant difference in the number of patients who developed post-operative epilepsy in the cohort that received prophylactic antiepileptic drugs (20 of 766; 2.6%) and the cohort that did not (10 of 377; 2.7%) (Chi-square test; P=0.96). A detailed meta-analysis could not be performed due to the insufficiency in data reported. Based on the results of this systematic review, the routine use of antiepileptic drugs for seizure prophylaxis in seizure-naive patients undergoing meningioma resection could not be substantiated. However, limitations of a systematic review should be considered on interpretation. High quality prospective randomised controlled trials are required to definitively answer this important clinical question. PMID- 28625585 TI - Access disparities to Magnet hospitals for ischemic stroke patients. AB - Access disparities to centers of excellence can have detrimental consequences for population health. We investigated the presence of racial disparities in the access of stroke patients to hospitals recognized by the Magnet Recognition Program of the American Nurses Credentialing Center (ANCC). We performed a cohort study of all ischemic stroke patients who were registered in the New York Statewide Planning and Research Cooperative System (SPARCS) database from 2009 to 2013. We examined the association of African-American race with Magnet status hospitalization after ischemic stroke. A mixed effects propensity adjusted multivariable regression analysis was used to control for confounding. During the study period, 176,557 patients presented with ischemic stroke, and met the inclusion criteria. Overall, 4,624 (13.7%) African-Americans, and 27,468 (19.2%) non African-Americans with ischemic stroke were admitted to Magnet hospitals. Using a multivariable logistic regression, we demonstrate that African-Americans were associated with lower admission rates to Magnet institutions (OR 0.70; 95% CI, 0.68-0.73) (Table 2). This persisted in a mixed effects logistic regression model (OR 0.75; 95% CI, 0.71-0.78) to adjust for clustering at the county level, and a propensity score adjusted logistic regression model (OR 0.87; 95% CI, 0.83 0.90). Using a comprehensive all-payer cohort of ischemic stroke patients in New York State we identified an association of African-American race with lower rates of admission to Magnet hospitals. PMID- 28625586 TI - Corticosteroids in neurological disorders: The dark side. AB - Corticosteroids are among the most commonly prescribed drugs by physicians of nearly all medical specialties. Their widespread use in clinical neurology is based either on randomized studies or, most often, on clinical experience and experts' opinion. Besides the well-known adverse effects of corticosteroids, they may also induce or worsen certain neurological disorders. The purpose of this review is to highlight the negative impact of these drugs on these disorders with emphasis on putative pathophysiological mechanisms of this association. PMID- 28625587 TI - A rabbit model of aneurysmal subarachnoid hemorrhage by ear central artery suprasellar cistern shunt. AB - Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening hemorrhagic cerebrovascular disease. The concept of early brain injury (EBI), induced by sharply increased intracranial pressure (ICP) and low cerebral perfusion pressure (CPP) with cerebral global ischemia following aneurysm rupture, has been increasingly accepted. However, EBI has not been well studied partly due to lack of an ideal animal model. The purpose of this study was to establish a new aSAH model which can mimic the pathophysiological damage of EBI. Right frontal craniotomy was performed on New Zealand rabbits for placing a PE-50 tube at the suprasella cistern and an ICP probe at the anterior cranial fossa. The central ear artery was punctured and blood was shunted into the suprasellar cistern through the PE-50 tube. ICP, blood pressure, CPP and heart rate peri-aSAH were monitored throughout the experiments. The rabbits were examined for neurological deficits at 24h post-SAH. Brain coronal sections near the optic chiasma were assessed by HE and Cresyl violet staining. Three minutes after SAH induction, the ICP peaked to 61.7+/-9.8mmHg while CPP decreased to nadir 23.5+/-8.9mmHg, and both were gradually restored in 15min. At 24h post-SAH, significant neurological deficits were found in SAH rabbits as compared to the sham-operated animals. In addition, neuronal degeneration and loss were also detected. Our results indicate that a new rabbit model of aSAH with EBI is successfully established. Moreover, this model is controllable, economical, and no side-injury to the main artery. PMID- 28625588 TI - Intraventricular mass lesions: Still a question of surgical approach? AB - BACKGROUND: Intraventricular mass lesions represent a small subgroup of intracranial neoplasms with various entities. The anatomy of the ventricular system is complex. Hence multiple surgical approaches are used. We sought to present a single center algorithm regarding surgical approach for intraventricular mass lesion. METHODS: We retrospectively reviewed the data of all patients operated in our institution due to a primary intraventricular tumor between 2011 and 2014. Descriptive statistics were used to evaluate clinical presentation, imaging, histology, surgical approach, complications, and clinical outcome. RESULTS: A total of 52 patients were included in this study comprising 28 (53.8%) female and 24 (46.2%) male patients. The median age was 43.5years. Lesions location in descending order were fourth ventricle (46.2%), lateral ventricles (28.8%) and third ventricle (25.0%). A telovelar approach was used for all lesions in the fourth ventricle. Cystic lesions of the third ventricle were predominantly operated endoscopically. The surgical approach to the lateral ventricle was transcallosal or transcortical depending on the exact location of the lesion inside the lateral ventricle. We achieved a gross total resection in 82.7% and observed perioperative complications in 19.2% of the patients. Permanent morbidity and mortality were low at 7.7% and 1.9%, respectively. CONCLUSION: This single center series reveals a predominately used approach for each part of the ventricular system depending on exact location and texture of the mass lesion. PMID- 28625589 TI - Acute disseminated encephalomyelitis in dengue viral infection. AB - Dengue is the most common arboviral disease affecting many countries worldwide. An RNA virus from the flaviviridae family, dengue has four antigenically distinct serotypes (DEN-1-DEN-4). Neurological involvement in dengue can be classified into dengue encephalopathy immune-mediated syndromes, encephalitis, neuromuscular or dengue muscle dysfunction and neuro-ophthalmic involvement. Acute disseminated encephalomyelitis (ADEM) is an immune mediated acute demyelinating disorder of the central nervous system following recent infection or vaccination. This monophasic illness is characterised by multifocal white matter involvement. Many dengue studies and case reports have linked ADEM with dengue virus infection but the association is still not clear. Therefore, this article is to review and discuss concerning ADEM in dengue as an immune-medicated neurological complication; and the management strategy required based on recent literature. PMID- 28625590 TI - Intranasal cotinine improves memory, and reduces depressive-like behavior, and GFAP+ cells loss induced by restraint stress in mice. AB - Posttraumatic stress disorder (PTSD), chronic psychological stress, and major depressive disorder have been found to be associated with a significant decrease in glial fibrillary acidic protein (GFAP) immunoreactivity in the hippocampus of rodents. Cotinine is an alkaloid that prevents memory impairment, depressive-like behavior and synaptic loss when co-administered during restraint stress, a model of PTSD and stress-induced depression, in mice. Here, we investigated the effects of post-treatment with intranasal cotinine on depressive- and anxiety-like behaviors, visual recognition memory as well as the number and morphology of GFAP+ immunoreactive cells, in the hippocampus and frontal cortex of mice subjected to prolonged restraint stress. The results revealed that in addition to the mood and cognitive impairments, restraint stress induced a significant decrease in the number and arborization of GFAP+ cells in the brain of mice. Intranasal cotinine prevented these stress-derived symptoms and the morphological abnormalities GFAP+ cells in both of these brain regions which are critical to resilience to stress. The significance of these findings for the therapy of PTSD and depression is discussed. PMID- 28625591 TI - Prognostic Significance of a Negative Confirmatory Biopsy on Reclassification Among Men on Active Surveillance. AB - OBJECTIVE: To examine the association between absence of disease on confirmatory biopsy and risk of pathologic reclassification in men on active surveillance (AS). MATERIALS AND METHODS: Men with grade groups 1 and 2 disease on AS between 2002 and 2015 were identified who received a confirmatory biopsy within 1 year of diagnosis and >=3 biopsies overall. The primary outcomes were pathologic reclassification by grade (any increase in primary Gleason pattern or Gleason score) or volume (>33% of sampled cores involved or increase in the number of cores with >50% involvement). The effect of a negative confirmatory biopsy survival was evaluated using Kaplan-Meier analysis and a Cox proportional hazards modeling. RESULTS: Out of 635 men, 224 met inclusion criteria (median follow-up: 55.8 months). A total of 111 men (49.6%) had a negative confirmatory biopsy. Decreased grade reclassification (69.7% vs 83.9%; P = .01) and volume reclassification (66.3% vs 87.4%; P = .004) was seen at 5 years for men with a negative confirmatory biopsy compared with those with a positive biopsy. On adjusted analysis, a negative confirmatory biopsy was associated with a decreased risk of grade reclassification (hazard ratio, 0.51; 95% confidence interval, 0.28 0.94; P = .03) and volume reclassification (hazard ratio, 0.32; 95% confidence interval, 0.17-0.61; P = .0006) at a median of 4.7 years. CONCLUSION: Absence of cancer on the confirmatory biopsy is associated with a significant decrease in rate of grade and volume reclassification among men on AS. This information may be used to better counsel men on AS. PMID- 28625592 TI - A Critical Analysis of Stented and Unstented Tubularized Incised Plate Urethroplasty Through a Prospective Randomized Study and Assessment of Factors Influencing the Functional and Cosmetic Outcomes. AB - OBJECTIVE: To compare, functionally and aesthetically, stented and unstented tubularized incised plate urethroplasty (TIPU). In addition, predictors of repair success were investigated. MATERIALS AND METHODS: One hundred ten children with distal hypospadias were included in this study. The length and width of the urethral plate (UP) and transverse glans diameter (TGD) were measured. Patients were randomized into two groups: stented and unstented TIPU. Postoperative assessment of pain was done using Face, Legs, Activity, Cry, Consolability (FLACC) scale, and cosmetic outcome was evaluated using hypospadias objective scoring evaluation. Uroflow was assessed at 6 months in toilet-trained boys. Complications were graded by the Clavien classification system. RESULTS: In 93 cases, Face, Legs, Activity, Cry, Consolability score, hospital stay, and dressing time were in favor of the unstented group, whereas hypospadias objective scoring evaluation score and uroflow parameters were comparable. TGD and UP width varied significantly between successful and failed cases. Cutoff values of 13.5 mm and 8.5 mm for TGD and UP width, respectively, are required for successful outcome. Acute urinary retention was 12.8% after unstented repair. Detrusor spasm was 47.8% after stented and 8.5% after unstented repair. In both groups, urethrocutaneous fistula of 5.4%, glanular dehiscence of 1.1%, and meatal stenosis of 5.4% were found in cases with small TGD and narrow UP. CONCLUSION: Unstented TIPU evades the associated drawbacks of the stent along with lower postoperative pain, hospital stay, and dressing time. Even without a postoperative stent, the complication rate in infants with distal hypospadias is low, and short-term functional and aesthetic outcomes were not compromised. PMID- 28625593 TI - You Pays Your Money, You Takes Your Choice: Functional Outcomes Following Curative Treatment for Clinically Localized Prostate Cancer: Commentary on: Association Between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-reported Outcomes After 3 Years. PMID- 28625594 TI - Perianal basal cell carcinoma: An infrequent location. PMID- 28625596 TI - Recurrent episodes of nocturnal hemiballism: A post-stroke movement disorder. PMID- 28625597 TI - Structural Heart Disease Australia (SHDA). AB - Structural Heart Disease Australia (SHDA) is a rapidly evolving multidisciplinary group of health care professionals which provides a forum focussed on understanding the rapidly advancing management of structural cardiac disease via Free Open Access Medical Education (FOAM). PMID- 28625595 TI - DCTN1-related neurodegeneration: Perry syndrome and beyond. AB - Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150Glued. Dynactin is a motor protein involved in axonal transport; the p150Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970's but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history. PMID- 28625599 TI - Disparities in Anxiety and its Disorders. AB - Much of the scientific work addressing the enigmas of anxiety and its disorders has been conducted among European Americans. This work has led to great progress into the nature of anxiety psychopathology, including etiologic, maintenance, and relapse processes. Moreover, evidenced-based treatments for anxiety and its disorders have arguably been among the best in the field of psychopathology for well over two decades. Yet, the progress thus far attained on the nature and treatment of anxiety disorders has not benefited all members of society equally. In fact, there are striking gaps of inequalities in anxiety disorder research and practice. The population in the United States (U.S.) and many parts of the industrialized world is rapidly changing in terms of diversity, and gaps between segments of society are growing in many instances (e.g., financial inequity). Health disparities in anxiety disorders are not a generic issue, but rather, reflect a systematic difference disproportionately affecting groups often not afforded a high social status ranking. We developed this Special Issue in the Journal of Anxiety Disorders to call attention to matters of inequality in anxiety disorders. The present special issue is designed to contextualize contemporary health disparity work on anxiety and its disorders. The special issue highlights three domains of study that are starting to guide research and practice in this arena, including sociocultural and contextual influences on anxiety and its disorders; intra-individual transdiagnostic mechanisms underpinning the expression and etiology/maintenance of anxiety psychopathology; and the close interconnection between anxiety processes and health status and health compromising behaviors. By covering a range of issues interconnected by their focus on understanding health disparity issues, it is hoped that this issue will: alert readers to the significance of this work at different levels of analysis; illustrate the many domains currently being explored via innovative approaches; and identify fecund areas for future systematic study. PMID- 28625598 TI - Predictors of Long-Term Outcomes After Drug-Eluting Balloon Angioplasty for Bare Metal Stent Restenosis. AB - BACKGROUND: Clinical trials have investigated efficacy of drug-eluting balloon (DEB) angioplasty for bare-metal stent (BMS) in-stent restenosis (ISR). Few studies have investigated predictors of long-term outcomes following BMS-ISR treatment with DEB. METHODS: From June 2011 to April 2015, 105 patients with 125 BMS-ISR lesions were enrolled from the Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN) registry. All these lesions were treated with DEB angioplasty as final therapy. The major adverse cardiac events (MACEs) were recurrent clinically driven target lesion revascularisation (TLR), myocardial infarction, and cardiac death after DEB angioplasty. RESULTS: After DEB angioplasty, the angiographic stenosis decreased from 84.8%+/-12.4% to 22.6%+/-10.4%. Over a mean follow-up duration of 21.7+/-13.4months, the rates of TLR at 1-12 months and 12-48 months were 4.8% and 4.2%, respectively. The rates of MACEs at 1-12 months and 12-48 months were 6.7% and 6.1%, respectively. Chronic haemodialysis, calcified lesion, chronic total occlusion lesion before stenting, stent with metal-to-artery ratio >16.5%, and residual stenosis >25% after DEB angioplasty were potential risk factors for MACEs in univariate analysis. After adjustment in multivariate analysis, independent predictors of long-term MACEs were identified as chronic haemodialysis, chronic total occlusion lesion before stenting, and residual stenosis >25% after DEB angioplasty. CONCLUSIONS: The long-term results of DEB angioplasty for BMS-ISR are acceptable in this real-world registry. Patient (chronic haemodialysis), lesion (chronic total occlusion) and angioplasty (residual stenosis percentage) related factors predicted long-term outcomes following BMS-ISR treatment with DEB angioplasty. PMID- 28625600 TI - Where to do water testing for Pseudomonas aeruginosa in a healthcare setting. AB - Pseudomonas aeruginosa is an important nosocomial pathogen widely colonizing hospital water supplies. The Department of Health (England) Health Technical Memorandum (HTM) 04-01 addresses the risk posed by recommending water-testing in augmented care areas including outpatient haemodialysis. We discuss how two teaching hospitals independently reviewed the risk to outpatient haemodialysis patients, drawing the same conclusion. The highest number of infection episodes with P. aeruginosa was observed in critical care followed by burns and haematology, with the lowest in haemodialysis. Based on these results, we suggest that water sampling should be undertaken in areas such as critical care, burns, and haematology, but not in outpatient haemodialysis. PMID- 28625602 TI - FRAX Score Can Be Used to Avoid Superfluous DXA Scans in Detecting Osteoporosis in Celiac Disease: Accuracy of the FRAX Score in Celiac Patients. AB - The Fracture Risk Assessment (FRAX) tool has been developed to estimate patients' 10-yr probability of fracture, thus establishing which patients should undergo dual-energy X-ray Absorptiometry (DXA) scan. This study aimed to evaluate if the FRAX tool can replace or optimize the use of DXA scan in celiac disease (CD). We prospectively enrolled all CD patients aged over 40 yr diagnosed at our third level unit. At time of CD diagnosis, all patients underwent FRAX score calculation for risk of major osteoporotic and hip fractures and DXA scan (used as gold standard) to assess the accuracy of the FRAX score. The FRAX score calculation was based on the following 10 variables: age (>40 yr), sex (M/F), body mass index, history of previous fracture (yes/no), parent fractured hip (yes/no), current smoking (yes/no), use of steroids (yes/no), rheumatoid arthritis (yes/no), secondary osteoporosis (yes/no), and alcohol >=3 units/d (yes/no). DXA assessment was performed within 1 week from FRAX calculation. The FRAX score was dichotomized as normal or pathologic in accordance with the National Osteoporosis Guideline Group. A total of 160 CD patients were enrolled (M/F = 20/140; mean age 48.7 yr). A pathologic FRAX score was evident in 14 out of 160 patients (8.7%), whereas osteoporosis based on DXA scan was found in 10 patients (6%) (kappa = 0.6); 3 patients with osteoporosis (1.9%) showed a 10-yr risk of major fracture >10% according to the National Osteoporosis Guideline Group criteria. With regard to diagnostic accuracy, the FRAX score showed sensitivity of 0%, specificity of 91%, positive predictive value of 0%, and negative predictive value of 94%. The prevalence of osteoporosis in adult CD appears to be quite low and only a small proportion of patients would require a DXA investigation. The FRAX score could be an effective tool to avoid useless DXA scans in CD patients in view of its high negative predictive value. PMID- 28625603 TI - Challenges in Environmental Science and Engineering, CESE-2016: 6-10 Nov. 2016, Kaohsiung, Taiwan. PMID- 28625601 TI - Role of social interaction, exercise, diet, and age on developing and untreated diabetes in cynomolgus monkeys. AB - Type 2 diabetes mellitus is the most common form of diabetes that occurs in both human and nonhuman primates. Although spontaneously diabetic nonhuman primates are used extensively in diabetic related research and are a proven valuable tool for the study of the natural history of diabetes, little is known about the key factors that can cause this metabolic disorder and the preventative measures that could be employed to minimize the consequences of diabetes. Using a model of developing and untreated diabetes, this study describes the effects of housing arrangement (socially group- versus individually single-housed), exercise, diet, age, and sex on fasting plasma glucose, key lipids associated with diabetes, and bodyweight in two large cohorts of nonhuman primates. Key findings include exercise/housing arrangement's contribution to significant differences in bodyweight, levels of fasting plasma glucose, total cholesterol, and high- and low-density lipoproteins. Age also had profound effects on glucose, triglyceride and high-density lipoproteins, particularly in single-caged animals. Moreover, females had higher fasting glucose, total cholesterol and triglyceride levels than male counterparts within the same housing situations. These factors may be critical to identifying preventive measures that could eventually be used to minimize obesity and diabetes in humans. PMID- 28625604 TI - 225th ENMC international workshop:: A global FSHD registry framework, 18-20 November 2016, Heemskerk, The Netherlands. PMID- 28625606 TI - Vitamin D supplementation; effects on depressive symptoms in multiple sclerosis. PMID- 28625605 TI - Population-based assessment of relationship between volume of practice and outcomes in head and neck cancer patients treated in a provincially coordinated radiotherapy program. AB - BACKGROUND AND PURPOSE: Literature suggests that higher volumes of practice are associated with better survival outcomes for head and neck cancer (HNC) patients. The objective of this study was to evaluate the effect of treatment center on the overall survival (OS) and cancer-specific survival (CSS) in a provincially coordinated program. MATERIALS AND METHODS: A population-based provincial database was used to identify all patients in BC diagnosed for the first time with a primary non-thyroid HNC and treated with radiotherapy between 2006 and 2011. RESULTS: 2330 HNC patients were included. On multivariable analysis, after controlling for age, gender, cancer stage, anatomical site, treatment and physician case frequency, OS (HR range=0.91-1.05; p=0.60-0.88) did not significantly differ by center. OS was also not significantly different for patients treated by physicians with low case frequency (HR=0.96; 0.81-1.13; p=0.60) and medium case frequency (HR=1.12; 0.84-1.49; p=0.43) in reference to high case frequency. There was no effect on OS or head and neck CSS when physician case frequency was treated as a continuous variable. CONCLUSIONS: In our provincially coordinated radiotherapy program, there was no significant difference in survival between cancer centers after controlling for differences in rurality, physician case volume and other potential confounding variables. PMID- 28625607 TI - Postoperative myocardial infarction in an orthognatic jaw surgery. AB - Cardiovascular complications, in particular perioperative myocardial infarctions, are central contributors to morbidity and mortality after non-cardiac surgery. We present a case of a 41-year-old male, smoker and dyslipidemic, who underwent bimaxillary orthognathic jaw surgery with the development of an acute coronary syndrome in the immediate postoperative period. We managed to early diagnose the myocardial infarction and promptly performed a percutaneous transluminal coronary angioplasty, resulting in a positive outcome. PMID- 28625608 TI - Use of the Totaltrack VLM in unexpected difficult airway in urgent caesarean section. PMID- 28625609 TI - Oxidative stress induced by cumene hydroperoxide produces synaptic depression and transient hyperexcitability in rat primary motor cortex neurons. AB - Pyramidal neurons of the motor cortex are selectively degenerated in Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying neuronal death in ALS are not well established. In the absence of useful biomarkers, the early increased neuronal excitability seems to be the unique characteristic of ALS. Lipid peroxidation caused by oxidative stress has been postulated as one of the possible mechanisms involved in degeneration motor cortex pyramidal neurons. This paper examines the effect of lipid peroxidation on layer V pyramidal neurons induced by cumene hydroperoxide (CH) in brain slices from wild type rats. CH induces a synaptic depression of pyramidal neurons in a time dependent manner, already observable on GABAergic synaptic transmission after 5min application of the drug. Altogether, our whole-cell patch-clamp recording data suggest that the functional changes induced by CH upon pyramidal neurons are due to pre- and postsynaptic mechanisms. CH did not alter mEPSCs or mIPSCs, but decreased the frequency, amplitude, and decay rate of spontaneous EPSCs and IPSCs. These effects may be explained by a presynaptic mechanism causing a decrease in action potential-dependent neurotransmitter release. Additionally, CH induced a postsynaptic inward current that underlies a membrane depolarization. Depressing the input flow from the inhibitory premotor interneurons causes a transient hyperexcitability (higher resistance and lower rheobase) in pyramidal neurons of the motor cortex by presumably altering a tonic inhibitory current. These findings, which resemble relevant cortical pathophysiology of ALS, point to oxidative stress, presumably by lipid peroxidation, as an important contributor to the causes underlying this disease. PMID- 28625610 TI - Current progress in antivascular tumor therapy. AB - The tumor vasculature transports oxygen, nutrients and drugs for crucial roles in tumor therapy. Antivascular therapy directly targets existing tumor vessels to reduce blood perfusion and then inhibit tumor growth. Vascular disrupting agents and ultrasound-stimulated microbubble destruction use chemical toxicity and physical effect, respectively, to damage vascular endothelial cells for antivascular therapy. Moreover, antivascular therapy can break vessel wall barriers and change the tumor microenvironment to compensate for the limitations of conventional chemotherapy or radiotherapy. This review presents current progress and an overview of antivascular therapy, which can inform the development and application in cancer research. PMID- 28625611 TI - Comparing SF-36(r) scores versus biomarkers to predict mortality in primary cardiac prevention patients. AB - BACKGROUND: Risk stratification plays an important role in evaluating patients with no known cardiovascular disease (CVD). Few studies have investigated health related quality of life questionnaires such as the Medical Outcomes Study Short Form-36 (SF-36(r)) as predictive tools for mortality, particularly in direct comparison with biomarkers. Our objective is to measure the relative effectiveness of SF-36(r) scores in predicting mortality when compared to traditional and novel biomarkers in a primary prevention population. METHODS: 7056 patients evaluated for primary cardiac prevention between January 1996 and April 2011 were included in this study. Patient characteristics included medical history, SF-36(r) questionnaire and a laboratory panel (total cholesterol, triglycerides, HDL, LDL, ApoA, ApoB, ApoA1/ApoB ratio, homocysteine, lipoprotein (a), fibrinogen, hsCRP, uric acid and urine ACR). The primary outcome was all cause mortality. RESULTS: A low SF-36(r) physical score independently predicted a 6-fold increase in death at 8years (above vs. below median Hazard Ratio [95% confidence interval] 5.99 [3.86-9.35], p<0.001). In a univariate analysis, SF 36(r) physical score had a c-index of 0.75, which was superior to that of all the biomarkers. It also carried incremental predictive ability when added to non laboratory risk factors (Net Reclassification Index=59.9%), as well as Framingham risk score components (Net Reclassification Index=61.1%). Biomarkers added no incremental predictive value to a non-laboratory risk factor model when combined to SF-36 physical score. CONCLUSION: The SF-36(r) physical score is a reliable predictor of mortality in patients without CVD, and outperformed most studied traditional and novel biomarkers. In an era of rising healthcare costs, the SF 36(r) questionnaire could be used as an adjunct simple and cost-effective predictor of mortality to current predictors. PMID- 28625612 TI - Enhanced production of natural yellow pigments from Monascus purpureus by liquid culture: The relationship between fermentation conditions and mycelial morphology. AB - Natural yellow pigments produced by submerged fermentation of Monascus purpureus have potential economic value and application in the food industry. In the present study, the relationships among fermentation conditions (in terms of pH and shaking/agitation speed), mycelial morphology and the production of Monascus yellow pigments were investigated in both shake-flask and scale-up bioreactor experiments. In the shake-flask fermentation, the highest yield of the Monascus yellow pigments was obtained at pH 5.0 and a shaking speed of 180 rpm. Microscopic images revealed that these results were associated with the formation of freely dispersed small mycelial pellets with shorter, thicker and multi branched hyphae. Further investigation indicated that the hyphal diameter was highly correlated with the biosynthesis of the Monascus yellow pigments. In a scaled-up fermentation experiment, the yield of yellow pigments (401 U) was obtained in a 200-L bioreactor, which is the highest yield to the best of our knowledge. The present findings can advance our knowledge on the conditions used for enhancing the production of Monascus yellow pigments in submerged fermentation and facilitate large-scale production of these natural pigments. PMID- 28625613 TI - Comparison of electrochemical performances and microbial community structures of two photosynthetic microbial fuel cells. AB - Microbial fuel cells (MFCs) have attracted intensive interest for their power generation and pollutants removal characteristics. Electrochemical performances and community structures of two algae cathode photosynthetic MFCs were investigated and compared. Microbial consortia of these two MFCs were taken from wetland sediment (named SMFC) and an up-flow anaerobic wastewater treatment reactor (named UMFC). Maximum power density of the SMFC and UMFC achieved 202.9 +/- 18.1 mW/m2 and 158.2+/-15.1 mW/m2, respectively. The SMFC displayed higher columbic efficiency but lower chemical oxygen demand (COD) removal efficiency than that of UMFC. The results also revealed the addition of riboflavin (RF) and neutral red (NR) decreased the redox current of the SMFC but promoted that of UMFC. Community structure analysis showed the SMFC was dominated by photosynthetic genus Rhodopseudomonas (61.25%), while bacterial genera in the UMFC were more evenly distributed. The difference of electrochemical activities of the two MFCs was caused by the different roles of exoelectrogens such as Rhodopseudomonas spp. and Citrobacter spp. in the electron transfer process. Newly developed photosynthetic microbial fuel cells (PMFCs) provide a suitable process to generate power and remove pollutants. The consortia have a significant role in the performance and microbial community of the system. PMID- 28625614 TI - Characterization of an acquired jumping translocation involving 3q13.31-qter in a patient with de novo acute monocytic leukemia. AB - We studied an adult with de novo acute monocytic leukemia and a dismal outcome where her leukemic cells harbored an acquired rare jumping translocation (JT). We used oligo-based array CGH (oaCGH) analysis, fluorescence in situ hybridization (FISH), and 24-color karyotyping to enhance the characterization of the JT. G banding detected a JT involving the 3q13.3-qter chromosomal segment and the recipient chromosomal regions 17p, 8q, and 15q. Each clone with JT was associated with trisomy 8. oaCGH analysis revealed an additional submicroscopic deletion in 3q13.31 as well as small subtelomeric duplications on several chromosomes. Locus specific FISH with BAC-based probes from the 3q13.31-q13.32 region showed great heterogeneity. Telomere FISH revealed significantly reduced telomeric content in the aberrant cells with JT compared with cytogenetically normal cells at diagnosis and in normal cells at complete remission. A literature search revealed two previous de novo AML-M5 cases of JT involving the 3q13.3-qter chromosomal segment and concomitant trisomy 8. In addition, a case with an unbalanced der(Y)t(Y;3)(q12;q13.31) and additional trisomy 8 was previously reported in a patient with de novo AML-M5. All of these cases had a dismal outcome. In the present case, and in the der(Y)t(Y;3) case, a concurrent submicroscopic deletion at 3q13.31 was observed affecting the TUSC7 gene. Duplication of 3q13.31-qter might be a non-random chromosomal abnormality with concomitant submicroscopic deletion at 3q13.31 occurring in rare cases of acute monocytic leukemia, being associated with adverse prognosis. The impact of shortened telomeres in forming the JT is reviewed. PMID- 28625615 TI - Efficacy and Safety of AbobotulinumtoxinA (Dysport) for the Treatment of Hemiparesis in Adults With Upper Limb Spasticity Previously Treated With Botulinum Toxin: Subanalysis From a Phase 3 Randomized Controlled Trial. AB - OBJECTIVE: To assess the efficacy and safety of abobotulinumtoxinA in adults with upper limb spasticity previously treated with botulinum toxin A (BoNT-A). DESIGN: A post hoc analysis from a Phase 3, prospective, double-blind, randomized, placebo-controlled study (NCT01313299). SETTING: A total of 34 neurology or rehabilitation clinics in 9 countries. PARTICIPANTS: Adults aged 18-80 years with hemiparesis, >=6 months after stroke or traumatic brain injury. This analysis focused on a subgroup of subjects with previous onabotulinumtoxinA or incobotulinumtoxinA treatment (n = 105 of 243 in the total trial population) in the affected limb. The mean age was 52 years, and 62% were male. INTERVENTION: Study subjects were randomized 1:1:1 to receive a single injection session with abobotulinumtoxinA 500 or 1000 U or with placebo in the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]), and >=2 additional muscle groups from the upper limb. MAIN OUTCOME MEASUREMENTS: Efficacy and safety measures were assessed, including muscle tone (Modified Ashworth Scale [MAS] in the PTMG), Physician Global Assessment (PGA), perceived function, spasticity, active movement, and treatment-emergent adverse events. RESULTS: At week 4, more subjects had >=1 grade improvement in MAS for the PTMG with abobotulinumtoxinA versus placebo (abobotulinumtoxinA 500 U, 81.1%; abobotulinumtoxinA 1000 U, 75.0%; placebo, 25.0%). PGA scores >=1 were achieved by 75.7% and 87.5% of abobotulinumtoxinA 500 and 1000 U subjects versus 41.7% with placebo. Perceived function (Disability Assessment Scale), spasticity angle (Tardieu Scale), and active movement were also improved with abobotulinumtoxinA. There were no treatment-related deaths or serious adverse events. CONCLUSIONS: The efficacy and safety of abobotulinumtoxinA in subjects previously treated with BoNT-A were consistent with those in the total trial population. Hence, abobotulinumtoxinA is a treatment option in these patients, and no difference in initial dosing appears to be required compared to that in individuals not treated previously. LEVEL OF EVIDENCE: III. PMID- 28625616 TI - Modelling explicit tides in the Indonesian seas: An important process for surface sea water properties. AB - Very intense internal tides take place in Indonesian seas. They dissipate and affect the vertical distribution of temperature and currents, which in turn influence the survival rates and transports of most planktonic organisms at the base of the whole marine ecosystem. This study uses the INDESO physical model to characterize the internal tides spatio-temporal patterns in the Indonesian Seas. The model reproduced internal tide dissipation in agreement with previous fine structure and microstructure observed in-situ in the sites of generation. The model also produced similar water mass transformation as the previous parameterization of Koch-Larrouy et al. (2007), and show good agreement with observations. The resulting cooling at the surface is 0.3 degrees C, with maxima of 0.8 degrees C at the location of internal tides energy, with stronger cooling in austral winter. The cycle of spring tides and neap tides modulates this impact by 0.1 degrees C to 0.3 degrees C. These results suggest that mixing due to internal tides might also upwell nutrients at the surface at a frequency similar to the tidal frequencies. Implications for biogeochemical modelling are important. PMID- 28625617 TI - Response of the seagrass Halophila ovalis to altered light quality in a simulated dredge plume. AB - Seagrass meadows are globally threatened, largely through activities that reduce light quantity (photosynthetic photon flux density) such as dredging. However, these activities can simultaneously alter the spectral quality of light. Previous studies showed that Halophila ovalis seagrass productivity is reduced under monochromatic yellow/green light, wavelengths associated with dredge plumes, but it is unclear how they respond to spectra produced by real dredging projects. We simultaneously subjected adult H. ovalis plants to altered light quality and quantity simulating a real commercial dredging operation (15mgL-1 TSS, 50 and 200MUmol photonsm-2s-1). There was a significant effect of reduced light quantity on physiological and morphological variables and a significant effect of light quality on the pigment antheraxanthin. The lack of effect of light quality on growth indicates that while seagrass are sensitive to changes in light quality, natural- and anthropogenic-driven changes may not always be sufficient to produce strong effects on H. ovalis. PMID- 28625618 TI - Low incidence of plastics in food loads delivered to nestlings by a zooplanktivorous seabird over a 21-year period. AB - We quantified the amount of plastic found in food loads delivered to nestlings in Cassin's Auklet (Ptychoramphus aleuticus), a small, zooplanktivorous seabird, on Triangle Island, British Columbia, in 1996-2016. The density of plastic in surrounding waters is moderately high, yet few food loads contained any plastic (3 of 850), and none more than two pieces. That result accords well with previous observations on the other four North Pacific auklets (Aethia spp.), leading us to conclude that true auklets rarely transfer plastic to nestlings. However, many hatch-year Cassin's Auklets found dead in coastal British Columbia, Washington and Oregon during the mass mortality event of fall and winter 2014-15 had plastic in their ventriculi. We suggest that these plastic particles would have been obtained at sea after fledging, perhaps while the birds transited south through a region of high plastic density off the west coast of Vancouver Island, Washington and Oregon. PMID- 28625619 TI - Intra-Thoracic Chemo-Hyperthermia for pleural recurrence of thymoma. AB - BACKGROUND: Pleural recurrences are a hallmark of thymomas, and represent a challenge for multidisciplinary management. The purpose of this study was to assess the feasibility and the results in terms of morbidity, mortality and survival rates, of Intra-Thoracic Chemo-Hyperthermia (ITCH) for the treatment of pleural recurrences of thymomas. METHODS: Retrospective analysis of 19 consecutives patients between 1997 and 2015 treated by surgical cytoreduction (pleurectomy) followed by ITCH with 25mg/m2 of mitomycin, and 50mg/m2 of Cisplatin. RESULTS: There were 8 men and 11 women with a median age of 44 years. ITCH was combined with pleurectomy alone in 4 (22%) patients, pleurectomy and wedge resections in 14 (74%) patients; 1 (5%) patient had a pleuropneumonectomy. There were no perioperative deaths, and 5 patients (26%) presented with postoperative complication, including 3 (16%) cases related to chemotherapy (one case of reversible grade 2 bone marrow aplasia, and 2 cases of reversible, acute kidney failure). The median length of stay in intensive care unit and hospital were 1day and 10days, respectively. After a median follow-up period of 39 months (range 10-127 months), median disease-free survival was 42 months. Five patients (26%) died during follow-up. CONCLUSIONS: Our data indicate that ITCH is a feasible option for selected patients with pleural recurrence of thymomas. ITCH clearly provides long local control, without major safety issues, and prolonged survival may be achieved in selected patients. This therapeutic option should be discussed at a multidisciplinary tumor board. PMID- 28625620 TI - Prognostic impact of uncertain parietal pleural invasion at adhesion sites in non small cell lung cancer patients. AB - OBJECTIVES: Pleural invasion has been recognized as an important negative prognostic factor in non-small cell lung cancer (NSCLC), and therefore, accurate evaluation is required. However, when the visceral pleura adheres to the parietal pleura around a tumor and parietal pleural structures are destroyed and unrecognizable as a result of inflammation, it is often difficult to accurately evaluate pleural invasion, and classification of the T stage is unclear. To aid in categorization, we defined this status as pl1-3 and investigated the prognostic impact of the pl1-3 status on NSCLC. MATERIALS AND METHODS: We retrospectively examined the clinicopathological characteristics and prognoses of 929 NSCLC patients who underwent curative surgical resection. The pl1-3 status was defined as invasion beyond the elastic layer of the visceral pleura (pl1 or higher) but showing unclear parietal pleural invasion. We compared the prognoses of pl1-3 status NSCLC patients with that of patients with other pleural invasion statuses. RESULTS: Thirty-one patients (3%) had a pl1-3 status. The 5-year overall survival rate for pl1-3 patients was 58.9%, and the prognosis was significantly worse than pl1 (p=0.04). In pN0 cohort, pl1-3 disease had a significantly worse prognosis than pl1 and pl2 diseases (p=0.01 and 0.04, respectively) and a similar prognosis to pl3 disease. Furthermore, similar relationships were also observed after adjusting for other prognostic factors in multivariate analysis. Among the pl1-3 and pN0 patients, 11 (46%) developed recurrences (9 patients had distant metastasis, one had local recurrence, and one had both). Although the proportion of pl1-3 patients who underwent adjuvant therapy was similar to that of T3 patients, more individuals received oral tegafur-uracil treatment than intravenous chemotherapy. CONCLUSION: These results indicate that pl1-3 patients can be managed in the same manner as patients with T3 and pl3 disease. These results may be informative for treatment decisions during postoperative chemotherapy. PMID- 28625621 TI - Patterns of initial and intracranial failure in metastatic EGFR-mutant non-small cell lung cancer treated with erlotinib. AB - OBJECTIVES: Patients with metastatic EGFR-mutant (mEGFRmt) NSCLC have favorable survival when treated with erlotinib. We hypothesized that treatment failure in most patients is limited to initial sites of disease, in which case incorporating local therapy such as radiation might further delay progression. We therefore analyzed patterns and predictors of failure in a large cohort of such patients. MATERIALS AND METHODS: We reviewed 189 patients treated with erlotinib for mEGFRmt NSCLC. We classified first pattern of failure as involving initial sites only (ISF), new sites only (NSF), or the combination (CSF), and used competing risks regression to identify factors associated with ISF, progression and overall survival (OS). We also separately analyzed intracranial and intrathoracic failure. RESULTS: Of 171 patients who progressed, 103 (60.2%) had ISF, 30 (17.5%) had NSF, and 38 (22.2%) had CSF. Younger age and lack of initial CNS involvement independently correlated with ISF, with a trend for higher T and N stage. Higher T and N stage was also a significant predictor of progression. Factors predicting shorter OS were female gender, weight loss, initial intracranial involvement, and >=4 extracranial metastases. Intrathoracic progression was a component of first failure in 61%, and three-year cumulative incidence of brain metastasis was 30%. CONCLUSION: The main pattern of progression in mEGFRmt NSCLC on erlotinib is in the initial sites of disease. Younger patients and those without brain involvement are particularly likely to develop ISF. This suggests a role for incorporating local therapy into treatment of selected patients with mEGFRmt NSCLC. PMID- 28625622 TI - PD-L1 expression in neuroendocrine tumors of the lung. AB - BACKGROUND: Various tumors express programmed cell death ligand 1 (PD-L1), an immune checkpoint ligand, the expression of which correlates with certain effects of anti-programmed cell death 1 (PD-1)/PD-L1 drugs. The aim of this study was to assess the frequency of PD-L1 expression in each of the types of neuroendocrine tumors of the lung. METHODS: The subjects enrolled in this study were patients who had been diagnosed with neuroendocrine tumors of the lung and had been treated at the National Cancer Center Hospital (Tokyo, Japan) between 1982 and 2010. We performed immunohistochemical analysis on a tissue microarray (TMA) of the surgical specimens using the validated PD-L1 antibody clone, E1L3N. Tumor PD L1 expression scores were calculated semiquantitatively (staining intensity [0 3]*stained area [0-100%]). A score of 1 was used as a cut-off to determine the presence or absence of PD-L1 expression. RESULTS: Among the 227 patients included in this study, the patient demographics were as follows: median age (range), 65 years (19-84); sex (male/female), 168/59; pStage (IA, IB, IIA, IIB, IIIA, IIIB, IV): 79, 36, 25, 29, 47, 6, 5, respectively; and histology was typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), small cell lung cancer (SCLC): 46, 6, 106, 69, respectively. The numbers (proportions) of PD-L1-expression tumors were as follows: TC/AC/LCNEC/SCLC, 0/0/11 (10.4%)/4 (5.8%). CONCLUSIONS: PD-L1 expression was apparent in 10.4% of LCNEC and 5.8% of SCLC tumors, and was not observed in carcinoid tumors. PMID- 28625623 TI - Mesothelioma continues to increase even 40 years after exposure - Evidence from long-term epidemiological observation. AB - BACKGROUND: Because asbestos dust is considered one of the most dangerous types of dust for people's health, issues related to the effects of asbestos exposure still remain questions about the role of cessation of exposure. OBJECTIVES: The aim of the present study was to determine the importance of temporal patterns, especially the time since the end of exposure in the risk of pleural mesothelioma. METHODS: A total of 131 patients with pleural mesothelioma and 655 frequency matched by gender and year of birth controls enrolled in the health surveillance programme for asbestos-related diseases over the years 2000-2014, were included in the analysis. Conditional logistic regression models were applied to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: The results show that the risk of pleural mesothelioma continued to increase even after 40 years since the last exposure. The estimated odds ratio for the subjects who had their last exposure 40 years ago, compared with the odds ratio of those who had their last exposure 5 years ago, was 2.68 (95%CI: 1.16 .621). We also observed that crocidolite exposure was associated with a very high significant mesothelioma risk, 5-fold higher for those working with mixed exposure compared to the subjects who worked only with chrysotile. CONCLUSIONS: Dose-response relationships in populations occupationally exposed are critical to the study related to environment asbestos contamination. Our findings confirm the strong evidence that mesothelioma risk increases along with the increasing time since exposure termination. PMID- 28625624 TI - Peripheral-type small cell lung cancer is associated with better survival and higher frequency of interstitial lung disease. AB - OBJECTIVES: Small cell lung cancer (SCLC) can be subgrouped into central and peripheral types according to the location of the primary lesion. However, the clinical differences between these two types remain unclear. This study compared their clinical features. MATERIALS AND METHODS: Data on 231 patients with pathologically diagnosed SCLC were retrospectively subgrouped into central or peripheral types. Progression-free survival (PFS), overall survival (OS), treatments, responses to first-line therapy, and frequency of interstitial lung disease (ILD) were compared between the two groups. RESULTS: Of the 231 patients, 101 (44%) had central-type and 130 (56%) had peripheral-type SCLC. Peripheral type SCLC was associated with a better performance status, higher frequency of ILD, and higher rate of limited disease stage. Patients with peripheral-type SCLC had a significantly longer OS than did those with central-type SCLC (median, 502 vs 370days, respectively; p=0.0186). Tumor location was not associated with PFS. PFS was poorer in patients with than without ILD (median, 143 vs 213days, respectively; p=0.0038), as was OS (median, 245 vs 545days, respectively; p=0.0014). Among patients without ILD, OS was longer in those with peripheral- than central-type tumors (median, 662 vs 421days, respectively; p=0.0074). Surgical resection was more often chosen for peripheral-type tumors, and this was one reason for the prolonged survival. There was no difference in the response to chemotherapy and/or radiotherapy between central- and peripheral-type SCLC. Multivariate analysis by a Cox proportional hazards model showed that male sex, a poor performance status, extensive disease, the presence of ILD, an elevated serum neuron-specific enolase concentration, and central-type SCLC were poor prognostic factors for OS. CONCLUSION: Peripheral-type SCLC is associated with better OS and a higher frequency of ILD than is central-type SCLC. The presence of ILD is a poor prognostic factor for both PFS and OS. PMID- 28625625 TI - Economic burden of clinical trials in lung cancer in a German Comprehensive Cancer Center. AB - OBJECTIVES: The recent success of individualized lung cancer therapy has triggered fundamental changes in clinical research strategies. To date there is a strong focus on early proof of concept trials in genetically preselected small patient subgroups. This analysis focuses on the economic burden caused by such trials for advanced lung cancer patients in a German Comprehensive Cancer Center (CCC). METHODS: The profit margins between recruiting groups with <=3 and >3 patients were compared. Clinical and economic data from clinical trials for advanced lung cancer (LC), pharma-sponsored trials (PhST) as well as investigator initiated trials (IIT), conducted between 2011 and 2015 at the Center for Integrated Oncology (CIO) Cologne, were analyzed using a profit-center calculation model. RESULTS: 161 patients were enrolled in 27 clinical trials. The key economic parameter determining costs and payments was the 'trial visits'. In comparison of the two groups (A<=3; B>3 patients enrolled) we found negative profit margins for the low recruiting group (? -1444). Concerning the number of visits significant differences were found between PhST and IIT (p=0.009). Additionally, sub-analysis show structural differences in cost composition by conducting PhST and IIT. CONCLUSION: Trials with low patient numbers and IIT, do not cover the cost. To ensure adequate, cost-covering compensation by pharmaceutical companies CCCs have to thoroughly calculate the cost of early proof of concept trials. The findings of this study also underline the need for novel structures in public funding for investigator-initiated clinical trials in precision medicine. PMID- 28625626 TI - Lung cancer incidence trends in California by race/ethnicity, histology, sex, and neighborhood socioeconomic status: An analysis spanning 28 years. AB - OBJECTIVES: Lung cancer incidence trends by histology, sex, race/ethnicity, and neighborhood socioeconomic status (nSES) have not been previously reported. We conducted a population-based study of lung cancer incidence over three peri censal periods: 1988-1992, 1998-2002, and 2008-2012. MATERIALS AND METHODS: We abstracted lung cancer cases from the California Cancer Registry and used US Census and American Community Survey data to develop multidimensional nSES indices for each census period. We calculated nSES tertile-specific incidence rates and rate ratios for each peri-censal period and used incidence rate ratios (IRR) to assess changes in rates from 1988 to 1992 to 1998-2002 and 2008-2012. RESULTS: There were a total of 231,205 lung cancer cases. Males: Among males, incidence rates of lung cancer decreased over time, all race/ethnicities, and all nSES tertiles, with larger declines among males in higher nSES areas. Rates either declined or were stable for adenocarcinoma, with larger declines for other histologic subtypes. Females: Among females, declines in incidence rates of lung cancer were more pronounced for females in higher nSES areas, but diverged more so than for males, with variations by histology and race/ethnicity. Incidence rates of adenocarcinoma increased over time among all females, with greater increase among females in low nSES areas. CONCLUSIONS: Our findings demonstrate differences in incidence trends over three decades by histology, gender, race/ethnicity, and nSES. While incidence rates consistently declined over time for males, there were greater declines in incidence for high nSES populations. In contrast, among females, there was evidence of increases in lung cancer incidence among low SES API females, and for adenocarcinoma. PMID- 28625627 TI - A multicenter, randomized, phase 3 trial comparing fixed dose versus toxicity adjusted dose of cisplatin + etoposide in extensive small-cell lung cancer (SCLC) patients: The Small-cell-lung cancer Toxicity Adjusted Dosing (STAD-1) trial. AB - OBJECTIVES: Data supporting the prognostic role of chemotherapy induced haematological toxicity suggest that toxicity-adjusted-dosing (TAD) of chemotherapy might improve treatment efficacy. We tested whether TAD of the cisplatin-etoposide combination might improve the response rate, in previously untreated extensive stage disease (ED)-SCLC patients, as compared with standard fixed-dosing (FD). METHODS: Patients with ED-SCLC were randomized to receive either TAD or FD of cisplatin-etoposide as first-line treatment. Primary endpoint was the objective response rate (ORR) according to the RECIST 1.0 criteria, secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity. RESULTS: Hundred-fifty-eight patients were randomized. Most patients were male, with ECOG-PS 1, without brain metastases and had not received radiotherapy before study entry. Response rate was 54.4 (95%CI: 43.5-64.9%) and 58.2 (95%CI: 47.2-68.5%) in the control and experimental arms, respectively (P=0.75). No significant differences were found in terms of PFS (HR 1.04; 95%CI: 0.74-1.44, P=0.84) and OS (HR1.01; 95%CI 0.71-1.42, p=0.97). Seven patients died on treatment, one in the standard arm and 6 in the experimental arm. The most frequent cause of death was neutropenia with infection and, apart in one, death was not related to dose modification. Severe toxicity was more frequent in the experimental arm (91% vs 60%). CONCLUSIONS: In our population of chemonaive ED SCLC patients, TAD failed to improve the ORR, PFS and OS over the FD of cisplatin etoposide as first line chemotherapy and was associated with increased toxicity. PMID- 28625628 TI - Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial. AB - INTRODUCTION: In ES-SCLC patients with residual intrathoracic disease after first line chemotherapy, the addition of thoracic radiotherapy reduces the risk of intrathoracic recurrence, and improves 2-year survival. To identify patient subgroups for future trials investigating higher dose (extra)thoracic radiotherapy, we investigated the prognostic importance of number and sites of metastases in patients included in the CREST trial. MATERIALS/ METHODS: Additional data on sites and numbers of metastases were collected from individual records of 260 patients from the top 9 recruiting centers in the randomized CREST trial (53% of 495 study patients), which compared thoracic radiotherapy (TRT) to no TRT in ES-SCLC patients after any response to chemotherapy. All patients received prophylactic cranial irradiation. RESULTS: The clinical characteristics and outcomes of the 260 patients analyzed here did not differ significantly from that of the other 235 patients included in the CREST trial, except that fewer patients had a WHO=0 performance status (24% vs 45%), and a higher proportion had WHO=2 (15% vs 5%; p<0.0001). No distant metastases were recorded in 5%, 39% had metastases confined to one organ, 34% to two, and 22% to three or more organ sites. Metastases were present in the liver (47%), bone (40%), lung (28%), extrathoracic (non-supraclavicular) lymph nodes (19%), supraclavicular nodes (18%), adrenals (17%) and other sites (12%). The OS (p=0.02) and PFS (p=0.04) were significantly better in patients with 2 or fewer metastases, with OS significantly worse if liver (p=0.03) and/or bone metastases (p=0.04) were present. DISCUSSION: This analysis of patients recruited from the top 9 accruing centers in the CREST trial suggests that future studies evaluating more intensive thoracic and extra-thoracic radiotherapy in ES-SCLC should focus on patients with fewer than 3 distant metastases. PMID- 28625629 TI - A phase Ib trial of continuous once-daily oral afatinib plus sirolimus in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer and/or disease progression following prior erlotinib or gefitinib. AB - OBJECTIVES: Dysregulation of the downstream PI3K/AKT/mTOR signaling pathway is a proposed mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We investigated safety and antitumor activity of afatinib plus sirolimus as a potential combination to reverse acquired resistance to EGFR-TKIs in a phase IB trial in patients with EGFR mutation-positive non small-cell lung cancer (EGFR mut NSCLC) and/or disease progression following prior erlotinib/gefitinib. MATERIALS AND METHODS: Patients with EGFR mut NSCLC and/or disease progression following at least prior erlotinib/gefitinib were included in the trial. The primary endpoint was incidence of dose-limiting toxicities (DLT) to determine the maximum tolerated dose (MTD). Four initial dose cohorts were proposed to evaluate DLTs. Other endpoints included tumor response, safety, progression-free survival (PFS) and pharmacokinetics. RESULTS: Thirty nine patients received afatinib and sirolimus. Additional dose cohorts were added since the second cohort (afatinib 40mg/day and sirolimus 5mg/day) was considered to have excessive toxicity. All patients experienced adverse events (AE) [grade 3: 66.7%; serious AE: 56.4%]. The most frequent AEs were diarrhea (94.9%), mucosal inflammation (64.1%), asthenia (53.8%) and rash (53.8%). Discontinuations and dose reduction due to AEs occurred in 23.1% and 25.6% of patients. MTD was determined as afatinib 30mg and sirolimus 1mg. Responses were observed in 5 patients (12.8%) [2 (5.1%) with confirmed partial response (PR); 3 (7.7%) with unconfirmed PR], and stable disease in 18 patients (46.2%). Four of the 5 responses were at doses above MTD. PFS at 6 months was estimated in 33.3% (median PFS 3.4 months). Pharmacokinetic parameters of afatinib and sirolimus were similar after single administration or in combination. CONCLUSION: The combination of afatinib and sirolimus showed lower responses than expected. Together with increased AEs and poor tolerability, this precludes clinical use and further clinical development of this combination. No pharmacokinetic interactions were observed. CLINICALTRIALS. GOV IDENTIFIER: NCT00993499. PMID- 28625630 TI - Improved survival with postoperative radiotherapy in thymic carcinoma: A propensity-matched analysis of Surveillance, Epidemiology, and End Results (SEER) database. AB - OBJECTIVES: Thymic carcinoma is a rare and aggressive malignancy with poor prognosis. Although postoperative radiotherapy (PORT) is used for obtaining better locoregional tumor control, its association with survival has not been established. This study evaluated the prognostic impact of PORT in thymic carcinoma. MATERIALS AND METHODS: We identified patients diagnosed with thymic carcinoma between 2004 and 2013 using the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching with Kaplan-Meier and Cox regression analyses were used to assess prognosis. RESULTS: In the unmatched population (n=312), 184 (59%) patients underwent PORT. The 5-year overall survival rates were better with receipt of PORT, both before and after matching (P=0.012 and 0.007, respectively). After adjusting for related covariates (n=256), age >=63 years (P=0.023), Masaoka stage III (P=0.028) and IV (P<0.001), debulking surgery (P=0.021), and no receipt of PORT (P=0.013) were independently poor prognostic factors. In subgroup analyses, favorable survival impacts of PORT were observed for Masaoka stage III tumors (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.15-0.66), tumors sized >6.0cm (HR 0.48, 95% CI 0.26 0.89), node-negative status (HR 0.58, 95% CI 0.33-1.00), and surgical extent of local excision or partial removal (HR 0.44, 95% CI 0.22-0.86). CONCLUSION: On SEER analysis, survival benefits of PORT in thymic carcinoma were demonstrated. With strong prognostic associations of Masaoka stage and types of surgery, PORT should be considered for non-metastatic locally advanced tumors with limited surgical resection. PMID- 28625631 TI - CD52, CD22, CD26, EG5 and IGF-1R expression in thymic malignancies. AB - BACKGROUND: Thymic epithelial tumours are rare cancers for which new treatment options are required. Identification of putative predictive markers is important for developing clinical trials. We studied the expression of five putative predictive biomarkers, potentially actionable by approved experimental drugs. METHODS: CD52, CD22, CD26, EG5, and IGF-1R expression were investigated by immunohistochemistry in formalin-fixed surgical samples of thymic epithelial tumour patients. All samples containing 10% positive epithelial tumour cells, independent of tumour cell intensity, were considered as positive. Correlation with histological subtype was performed. RESULTS: 106 surgical samples (89 thymomas, 12 thymic carcinoma, and 5 thymic neuroendocrine tumours) were evaluated. Overall, CD52, CD22, CD26, EG5 and IGF-1R expression was observed in 7%, 42%, 25%, 42% and 77% of samples, respectively. CD52 expression was more frequent in B2 and B3 thymoma. All TET subtypes stained for CD22, mainly AB thymoma (68%). CD26 expression also correlated with AB thymoma (68%), and A thymoma (50%) subtype, while IGFR1 was the most common marker expressed by thymic carcinoma samples (92%), followed by EG5 (60%). Only EG5 expression was significantly higher in thymic carcinomas than in thymomas (75% vs. 38%, p=0.026). CONCLUSIONS: Our data were consistent with a previous study of IGF-1R expression. Based on their expression, activity of agents targeting CD52, CD 22, CD26 and EG5 could be further explored in TET patients. PMID- 28625632 TI - A population-based comparative effectiveness study of chemoradiation regimens and sequences in stage III non-small cell lung cancer. AB - OBJECTIVES: In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population based comparative effectiveness approach. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged >=65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach. RESULTS: 1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide. CONCLUSION: Survival outcomes were similar among the five most commonly employed platinum based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival. PMID- 28625633 TI - Cost-effectiveness of implementing computed tomography screening for lung cancer in Taiwan. AB - BACKGROUND: A screening program for lung cancer requires more empirical evidence. Based on the experience of the National Lung Screening Trial (NLST), we developed a method to adjust lead-time bias and quality-of-life changes for estimating the cost-effectiveness of implementing computed tomography (CT) screening in Taiwan. METHODS: The target population was high-risk (>=30 pack-years) smokers between 55 and 75 years of age. From a nation-wide, 13-year follow-up cohort, we estimated quality-adjusted life expectancy (QALE), loss-of-QALE, and lifetime healthcare expenditures per case of lung cancer stratified by pathology and stage. Cumulative stage distributions for CT-screening and no-screening were assumed equal to those for CT-screening and radiography-screening in the NLST to estimate the savings of loss-of-QALE and additional costs of lifetime healthcare expenditures after CT screening. Costs attributable to screen-negative subjects, false-positive cases and radiation-induced lung cancer were included to obtain the incremental cost-effectiveness ratio from the public payer's perspective. RESULTS: The incremental costs were US$22,755 per person. After dividing this by savings of loss-of-QALE (1.16 quality-adjusted life year (QALY)), the incremental cost-effectiveness ratio was US$19,683 per QALY. This ratio would fall to US$10,947 per QALY if the stage distribution for CT-screening was the same as that of screen-detected cancers in the NELSON trial. CONCLUSIONS: Low-dose CT screening for lung cancer among high-risk smokers would be cost-effective in Taiwan. As only about 5% of our women are smokers, future research is necessary to identify the high-risk groups among non-smokers and increase the coverage. PMID- 28625634 TI - Imaging features of TSCT predict the classification of pulmonary preinvasive lesion, minimally and invasive adenocarcinoma presented as ground glass nodules. AB - OBJECTIVES: To comprehensively investigate the role of thin section computed tomography(TSCT) features to distinguish invasive adenocarcinoma(IA) from preinvasive or minimally invasive adenocarcinoma(MIA) appearing as pure or mixed ground glass nodules (pGGNs, mGGNs), and to distinguish adenocarcinoma in situ (AIS) from atypical adenomatous hyperplasia (AAH) in pGGNs. MATERIALS AND METHODS: Three hundred thirteen patients with 334 pathologically diagnosed GGNs according to the 2011 IASLC/ATS/ERS classification were included into this study. The TSCT features of the AAH-MIAs and IAs were compared and analyzed respectively in pGGNs (158 cases) and mGGNs (176 cases). Additionally, AIS (30 cases) and AAH (33 cases) were further analyzed in pGGNs. Receiver operating characteristic(ROC) analysis were performed to determine the cutoff values for the qualitative variables and their diagnostic performances. RESULTS: In pGGNs, significant differences were found in the tumor volume(p=0.017, OR=4.98, 95%CI 1.33-18.62) and tumor mass(p=0.03, OR=5.04, 95%CI 1.17-21.59) between AAH-MIAs (AAH, AIS, MIA) group and IAs group, and tumor mass(p=0.037, OR=4.32, 95%CI 1.09-17.10) and standard deviation(SD) (p=0.019, OR=13.92, 95%CI 1.53-126.57) could distinguish AIS from AAH. In mGGNs, significant differences were found in consolidation size (p=0.006, OR=21.98, 95%CI 2.46-196.67) and consolidation mean CT value (p=0.011, OR=18.20, 95%CI1.96-168.88) between AAH-MIAs group and IAs group. Multivariate and ROC analyses revealed that in pGGNs, tumor size (>=1125mm) and mass (>386) were significantly associated with IAs. SD (>=68) and mass (>=70) were significant in distinguishing AIS from AAH. Larger consolidation of nodules (>=8.1mm) and higher CT values of the solid components (>=-222 HU) in mGGNs were significantly associated with IAs. CONCLUSION: TSCT features can help distinguish IAs from AAH-MIAs both in pGGNs and mGGNs, and identify AIS from AAH in pGGNs, which indicated that imaging features may be helpful to guide the therapeutic choice for patients with GGNs which were considered as high risk of malignant diseases. PMID- 28625635 TI - Trends in treatment and relative survival among Non-Small Cell Lung Cancer patients in the Netherlands (1990-2014): Disparities between younger and older patients. AB - BACKGROUND: This study aimed to describe trends over time regarding disparities in treatment and relative survival (RS) between younger and older patients with non-small cell lung cancer (NSCLC). METHODS: All patients diagnosed with pathologically verified NSCLC in 1990-2014 were included from the Netherlands Cancer Registry (n=187,315). Treatment and RS (adjusted for sex, histology and treatment) were analyzed according to age group (<70 years versus >=70 years), stage and five-year period of diagnosis. RESULTS: Between 1990 and 2014, five year RS increased from 17 to 22% among younger patients and from 12 to 16% among elderly. The application of surgery increased over time for elderly with stage I NSCLC, decreased for elderly with stage II, and was stable but higher for younger patients. Disparities in RS between age groups with stage I became smaller since 2000-2004, but did not change over time for stage II. For stage III and IV, both age groups showed strong increases over time in chemoradiotherapy and chemotherapy from 2000 onwards, although considerably less among elderly. One-, three- and five-year RS increased more strongly over time for the younger group leading to larger disparities between age groups with stage III or IV NSCLC. CONCLUSION: More curative-intent treatment and improved RS for NSCLC were seen over time, but were less profound among elderly. Disparities herein between age groups seemed to become smaller over time for stage I NSCLC, did not change for stage II, and were widening for stage III and IV at the expense of elderly. Future prospective studies should focus on optimizing treatment selection and outcomes for elderly. PMID- 28625636 TI - Prognostic impact of TTF-1 expression in patients with stage IV lung adenocarcinomas. AB - OBJECTIVES: Thyroid transcription factor 1 (TTF-1) is routinely tested in the diagnostic evaluation of suspected lung cancers, is commonly expressed by lung adenocarcinomas, and may modulate lung cancer biology. We examined the role of TTF-1 as a predictive and prognostic marker in patients with advanced lung adenocarcinomas. MATERIALS AND METHODS: We analyzed clinical, pathologic, and molecular features, treatments received, and overall survival obtained from the medical records of 479 consecutive patients at a single site with stage IV lung adenocarcinomas and evaluable TTF-1 expression. TTF-1 expression was determined by immunohistochemistry using antibody 8G7G3/1. RESULTS AND CONCLUSION: TTF-1 expression was evaluable in 479 (75%) of all patients reviewed, and was positive in 383 (80%, 95% CI 76-83%). Clinicopathologic features were similar between TTF 1 positive and TTF-1 negative tumors, except EGFR mutations were more common in TTF-1 positive cases (24% vs 6%, p<0.001). In univariate analysis, overall survival was significantly longer in patients with TTF-1 positive versus TTF-1 negative tumors (18 months vs 9 months, p<0.0001). In multivariate analysis, TTF 1 positivity remained associated with better overall survival (HR=0.38, p<0.0001), exceeding the prognostic impact of Karnofsky performance status >/=80% (HR 0.62, p=0.0003) and receipt of first-line combination chemotherapy or targeted therapy (HR relative to first-line single agent chemotherapy 0.59, p=0.05 and 0.51, p=0.05 respectively). Both patients with TTF-1 positive and TTF 1 negative cancers had longer durations of initial therapy when treated with pemetrexed-based chemotherapy. In patients with advanced lung adenocarcinomas, TTF-1 expression is associated with better survival but is not predictive of distinct benefit from pemetrexed-based chemotherapy. PMID- 28625637 TI - A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non-small cell lung cancer. AB - This phase 2 portion of a phase 1/2 study examined the efficacy and safety of LY2603618, a selective checkpoint kinase 1 inhibitor, combined with pemetrexed and cisplatin (LY+Pem+Cis) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This multicenter, randomized, controlled, open-label study (NCT01139775) enrolled patients with stage IV nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status <=1. Patients were randomized (2:1) to LY+Pem+Cis or pemetrexed and cisplatin (Pem+Cis). Induction therapy comprised four 21-day cycles of 500 mg/m2 pemetrexed and 75mg/m2 cisplatin on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm). Maintenance therapy comprised 500mg/m2 pemetrexed on Day 1 (both arms) and 275mg LY2603618 on Day 2 (LY+Pem+Cis arm) until disease progression. The primary endpoint was progression free survival (PFS). Enrollment was permanently halted before target enrollment was met due to a greater number of thromboembolic events in the LY+Pem+Cis arm. Sixty-two patients were enrolled (LY+Pem+Cis, n=39; Pem+Cis, n=23). Bayesian and frequentist analysis demonstrated superior PFS in the LY+Pem+Cis arm vs the Pem+Cis arm (median [90% confidence interval]: LY+Pem+Cis, 4.7 months [4.-7.1]; Pem+Cis, 1.5 months [1.3-2.9]; P=0.022). Seven patients in the LY+Pem+Cis arm (vs 0 in the Pem+Cis arm) experienced serious thromboembolic events: pulmonary embolism (n=5), ischemic stroke (n=1), and cerebrovascular accident (n=1). Although the primary endpoint was met, the combination of LY2603618+Pem+Cis will not be further developed for treating advanced nonsquamous NSCLC due to the potential increased risk of thromboembolic events with this combination. ClinicalTrials.gov Identifier: NCT01139775. PMID- 28625638 TI - Development of psoriatic arthritis during nivolumab therapy for metastatic non small cell lung cancer, clinical outcome analysis and review of the literature. AB - Lung cancer is the leading cause of cancer-related death worldwide. The most common type, non-small cell lung cancer (NSCLC), is further divided into two main types, squamous cell and non-squamous cell (which includes adenocarcinoma). Nivolumab, a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, has shown not only an overall survival advantage when compared to docetaxel, but also a relatively good side-effect profile among patients with previously treated advanced squamous and non-squamous NSCLC. Psoriatic arthritis (PsA), a heterogeneous chronic inflammatory disease, has a wide clinical spectrum and a variable clinical course that affects mainly musculoskeletal structures, skin and nails. Here we report the second case to the best of our knowledge of PsA development during nivolumab therapy. It is important to note that arthritis activity decreased without nivolumab discontinuation with the use of naproxen and a low dose of corticosteroid. Furthermore, a minimal disease activity was achieved adding methotrexate to the treatment and antitumor therapy efficacy was not influenced (a partial response was documented after eight and 39 cycles of nivolumab). Rheumatic immune-related adverse events management is a challenge and a coordinated multidisciplinary management by medical oncologists, rheumatologists and immunologists will be mandatory in the near future. PMID- 28625639 TI - Longitudinal monitoring of ctDNA EGFR mutation burden from urine correlates with patient response to EGFR TKIs: A case series. AB - Targetable, somatic EGFR mutations are highly prevalent in patients with non small cell lung cancer (NSCLC), making them eligible for tyrosine kinase inhibitor (TKI) therapy. Circulating tumor DNA (ctDNA), isolated from blood or urine, has been demonstrated to reliably identify somatic tumor associated EGFR mutations, specifically in patients with inconclusive biopsy. When conventional imaging modalities are inconclusive, quantitative assessment of systemic ctDNA burden has the potential to assess therapeutic response. We report on the clinical use of non-invasive, urinary ctDNA liquid biopsies for the ultrasensitive detection and longitudinal monitoring of ctDNA EGFR systemic mutation burden in five patients with NSCLC treated with EGFR TKIs. Urinary ctDNA based quantitative assessment of systemic EGFR mutant allele burden is a non invasive molecular diagnostic testing modality that has the potential to be utilized as an ancillary tool to assess disease burden and response to therapy. PMID- 28625640 TI - Association between intensity modulated radiotherapy and survival in patients with stage III non-small cell lung cancer treated with chemoradiotherapy. AB - PURPOSE: To determine the effect of radiotherapy (RT) technique on treatment compliance and overall survival (OS) in patients with stage III non-small lung cancer (NSCLC) treated with definitive chemoradiotherapy (CRT). METHODS AND MATERIALS: This study included patients with stage III NSCLC in the National Cancer Database treated between 2003 and 2011 with definitive CRT to 60-63 Gray (Gy). Radiation treatment interruption (RTI) was defined as a break of >=4 days. Treatment technique was dichotomized as intensity modulated (IMRT) or non-IMRT techniques. RESULTS: Out of the cohort of 7492, 35% had a RTI and 10% received IMRT. With a median follow-up of surviving patients of 32 months, the median survival for those with non-IMRT vs. IMRT was 18.2 months vs. 20 months (p<0.0001). Median survival for those with and without an RTI>=4 days was 16.1 months vs. 19.8 months (p<0.0001). Use of IMRT predicted for a decreased likelihood of RTI (odds ratio, 0.84, p=0.04). On multivariable analysis for OS, IMRT had a HR of 0.89 (95% CI: 0.80-0.98, p=0.01) and RTI had a HR of 1.2 (95% confidence interval (CI): 1.14-1.27, p=0.001). CONCLUSIONS: IMRT was associated with small but significant survival advantage for patients with stage III NSCLC treated with CRT. A RTI led to inferior survival, and both IMRT and RTI were independently associated with OS. Additional research should investigate whether improved tolerability, reduced normal tissue exposure, or superior coverage drives the association between IMRT and improved survival. PMID- 28625641 TI - Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. AB - Acquired epidermal growth factor receptor (EGFR) resistance mutations to osimertinib are common, including the EGFR C797S that abolishes the covalent binding of osimertinib to EGFR. Here we report the emergence of novel EGFR solvent front mutations at Gly796 (G796S/R) in addition to a hinge pocket L792F/H mutations, and C797S/G all in cis with T790M in a single patient on progression on osimertinib as detected by plasma circulating tumor DNA (ctDNA) assay in the course of clinical care. A 69-year-old Caucasian female former light-smoker presented with stage IV EGFR L858R positive adenocarcinoma who developed EGFR T790M mutation after 8 month treatment of erlotinib. The patient was initiated on osimertinib with disease shrinkage after 2 months, but tumor regrowth was observed after 5 months of osimertinib treatment. Assay of plasma ctDNA at this time revealed these different secondary resistance mutations all in trans with each other including distinct mutations at the same codon producing different amino acid changes: G796S/R (mutant allele frequency [MAF]; 14.4%), C797S/G (MAF: 2.26%), L792F/H (MAF: 0.36%), and V802F (MAF: 0.40%), in addition to the pre existing L858R (MAF:17.9%) and T790M (MAF:18.2%) but all in cis with T790M. The G796S/R mutations are homologous with known reported solvent front mutations in ALK G1202R, ROS1 G2032R, TrkA G595R and TrkC G623R, all of which are associated with acquired resistance to type I TKIs. In silico modeling revealed mutation at G796 interferes with osimertinib binding to the EGFR kinase domain at the phenyl aromatic ring position as this residue forms a narrow "hydrophobic sandwich" with L718, while L792F/H mutation interferes with osimertinib binding at the methoxyl group on the phenyl ring. Multiple resistance mutations at differing allele frequencies including novel EGFR solvent front mutations can emerge in a single patient with progression on osimertinib potentially due to tumor hetereogeneity and definitely present a significant therapeutic and drug development challenge. PMID- 28625642 TI - Randomized phase II trial of weekly dose-intensive chemotherapy or amrubicin plus cisplatin chemotherapy following induction chemoradiotherapy for limited-disease small cell lung cancer (JCOG1011). AB - OBJECTIVES: The objective of this study was to select, for a phase III trial, the more promising of weekly-dose intensive chemotherapy or amrubicin+cisplatin chemotherapy as subsequent therapy after induction chemoradiotherapy for previously untreated limited-disease small cell lung cancer (LD-SCLC). MATERIALS AND METHODS: Patients aged 20-70 years with untreated clinical stage II/III LD SCLC were eligible. After one cycle of accelerated hyperfractionation thoracic radiotherapy with etoposide plus cisplatin, patients without progression were randomized to either 3 cycles of cisplatin 25mg/m2 (days 1, 8), doxorubicin 40mg/m2 (day 1), etoposide 80mg/m2 (days 1-3), and vincristine 1mg/m2 (day 8) every 2 weeks (CODE) or amrubicin 40mg/m2 (days 1-3) and cisplatin 60mg/m2 (day 1) every 3 weeks (AP). The primary endpoint was the one-year progression-free survival (PFS). The sample size was 72 to select the arm yielding a better one year PFS (55% vs. 65%) with a probability of 80%. RESULTS: From March 2011 to February 2014, 85 patients were registered. After the induction chemoradiotherapy, 75 patients were randomized to CODE (n=39) or AP (n=36). The one-year PFS (95% confidence interval) was 41.0% (25.7-55.8) in the CODE group and 54.3% (36.6-69.0) in the AP group. Grade 4 neutropenia/grade 3 febrile neutropenia occurred in 47%/16% in the CODE group and 78%/42% in the AP group. CONCLUSION: The one-year PFS was better in the AP group, but it did not reach the expected 55%. Therefore, neither regimen is suitable for a phase III trial. PMID- 28625643 TI - Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC. AB - Osimertinib is an EGFR-T790M-specific TKI, which has demonstrated impressive response rates in NSCLC, after failure to first-line anti-EGFR TKIs. However, acquired resistance to osimertinib is also observed and the molecular mechanisms of resistance are not yet fully understood. Monitoring and managing NSCLC patients who progressed on osimertinib is, therefore, emerging as an important clinical challenge. Sequential liquid biopsies were used to monitor a patient with EGFR-exon19del positive NSCLC, who received erlotinib and progressed through the acquisition of the EGFR-T790M mutation. Erlotinib was discontinued and osimertinib was initiated. Blood samples were collected at erlotinib progression and during osimertinib treatment for the detection of the activating (EGFR exon19del) and resistance mutations (EGFR-T790M, EGFR-C797S, BRAF-V600E, METamp and ERBB2amp) in the plasma DNA using digital droplet PCR. Plasma levels of the activating EGFR-exon19del accurately paralleled the clinical and radiological progression of disease and allowed early detection of AR to osimertinib. Resistance to osimertinib coincided with the emergence of a small tumor cell subpopulation carrying the known EGFR-C797S resistance mutation and an additional subpopulation carrying amplified copies of EGFR-exon19del. Given the existence of multiple AR mechanisms, quantification of the original EGFR activation mutation, instead of the resistance mutations, can be efficiently used to monitor response to osimertinib, allowing early detection of AR. Absolute quantification of both activation and resistance mutations can provide important information on tumor clonal evolution upon progression to osimertinib. Selective amplification of the EGFR-exon19del allele may represent a novel resistance mechanism to osimertinib. PMID- 28625644 TI - Treatment options for EGFR mutant NSCLC with CNS involvement-Can patients BLOOM with the use of next generation EGFR TKIs? AB - With the use of EGFR TKIs, patient survival is now prolonged and as a consequence, a higher chance of development of CNS metastases has been observed during the course of the disease. CNS metastases remains a therapeutically challenging subset of patient to treat owing to the blood-brain barrier (BBB). Prior to routine EGFR mutation testing, surgical resection, stereotactic radiosurgery and/or whole brain radiation therapy (WBRT) were the main treatment options whereas treatment options for patients with leptomeningeal metastases (LM) included intra-thecal chemotherapy, WBRT, and ventriculo-peritoneal shunting. Unfortunately outcome for both BM and LM remains poor with median survival between 3 and 6 months. Systemic treatment with EGFR TKIs had been effective in the treatment of intracranial metastases but efficacy of early generation TKIs were hampered by its limited BBB penetration. The next generation EGFR TKIs osimertinib and AZD3759 have improved BBB penetration and the BLOOM study of osimertinib and AZD3759 has reported highly promising intracranial efficacy and may herald a new frontier to treat this therapeutically challenging subset of advanced EGFR mutant patients. PMID- 28625645 TI - EUS-B-FNA vs conventional EUS-FNA for left adrenal gland analysis in lung cancer patients. AB - INTRODUCTION: In patients with lung cancer, left adrenal glands (LAG) suspected for distant metastases (M1b) based on imaging require further evaluation for a definitive diagnosis. Tissue acquisition is regularly performed using conventional EUS-FNA. The aim of this study was to investigate the success rate of endoscopic ultrasound guided fine-needle aspiration using the EBUS scope (EUS B-FNA) for LAG analysis. METHODS: This is a prospective multicenter study in consecutive patients with (suspected) lung cancer and suspected mediastinal and LAG metastases. Following complete mediastinal staging using the EBUS scope (EBUS+EUS-B), the LAG was evaluated and sampled by both EUS-B (experimental procedure) and conventional EUS (current standard of care). RESULTS: The success rate for LAG analysis (visualized, sampled and adequate tissue obtained) was 89% (39/44; 95% CI 76-95%) for EUS-B-FNA, and 93% (41/44; 95%CI 82-98%) for EUS-FNA. In the absence of metastases at EUS-B and/or EUS, surgical verification of the LAG or 6 months clinical and radiological follow-up was obtained, but missing for 5 patients. The prevalence of LAG metastases was 54% (21/39). In patients in whom LAG was seen and sampled, sensitivity for LAG metastases was at least 87% (95%CI 65-97%) for EUS-B, and at least 83% (95%CI 62-95%) for conventional EUS. CONCLUSION: LAG analysis by EUS-B shows a similar high success rate in comparison to conventional EUS. IMPLICATION: Both a mediastinal nodal and LAG evaluation can be adequately performed with just an EBUS scope and single endoscopist. This staging strategy is likely to reduce patient-burden and costs. PMID- 28625646 TI - EGFR exon 18 delE709_T710insD mutated stage IV lung adenocarcinoma with response to afatinib. AB - Epidermal Growth Factor Receptor (EGFR) targetable mutations have changed the landscape for treatment of advanced stage non-small cell lung cancer in recent years. Three generations of tyrosine kinase inhibitors are now available to target cancers harboring these mutations. The most common EGFR mutations occur in Exons 19 and 21. Exon 18 mutations are extremely rare comprising of 4.1% of all EGFR mutations and the delE709_T710insD mutation accounts for only 0.16% of mutations when occurring as a sole mutation, however, the frequency can vary with the kit utilized for testing. The rarity makes the clinical relevance of these mutations largely unknown. We report a case of a 52year old female with bilateral advanced adenocarcinoma of the lung harboring the delE709_T710insD mutation with significant clinical and radiographic response to treatment with afatinib. We discuss the reported cases of delE709_T710insD mutated non-small cell lung cancer variably treated with geftinib, erlotinib or afatinib. This particular exon 18 mutation seems to preferentially respond to afatinib as reported in two cases including the current case, and in an in vitro experimental model. These reports have implications in guiding decisions for treatment of patients harboring rare EGFR mutations. PMID- 28625647 TI - Quantification of growth patterns of screen-detected lung cancers: The NELSON study. AB - OBJECTIVES: Although exponential growth is assumed for lung cancer, this has never been quantified in vivo. Aim of this study was to evaluate and quantify growth patterns of lung cancers detected in the Dutch-Belgian low-dose computed tomography (CT) lung cancer screening trial (NELSON), in order to elucidate the development and progression of early lung cancer. MATERIALS AND METHODS: Solid lung nodules found at >=3 CT examinations before lung cancer diagnosis were included. Lung cancer volume (V) growth curves were fitted with a single exponential, expressed as V=V1 exp(t/tau), with t time from baseline (days), V1 estimated baseline volume (mm3), and tau estimated time constant. The R2 coefficient of determination was used to evaluate goodness of fit. Overall volume doubling time for the individual lung cancer is given by tau*log(2). RESULTS: Forty-seven lung cancers in 46 participants were included. Forty participants were male (87.0%); mean age was 61.7 years (standard deviation, 6.2 years). Median nodule size at baseline was 99.5mm3 (IQR: 46.8-261.8mm3). Nodules were followed for a median of 770 days (inter-quartile range: 383-1102 days) before lung cancer diagnosis. One cancer (2.1%) was diagnosed after six CT examinations, six cancers (12.8%) were diagnosed after five CTs, 14 (29.8%) after four CTs, and 26 cancers (55.3%) after three CTs. Lung cancer growth could be described by an exponential function with excellent goodness of fit (R2 0.98). Median overall volume-doubling time was 348 days (inter-quartile range: 222-492 days). CONCLUSION: This study based on CT lung cancer screening provides in vivo evidence that growth of cancerous small-to-intermediate sized lung nodules detected at low-dose CT lung cancer screening can be described by an exponential function such as volume-doubling time. PMID- 28625648 TI - Contrasting temporal trends in lung cancer incidence by socioeconomic status among women in New South Wales, Australia, 1985-2009. AB - OBJECTIVE: We examined long-term trends in lung cancer incidence for women by socioeconomic groups in New South Wales (NSW), Australia. METHODS: Data on lung cancer incidence for women were extracted from the NSW Cancer Registry database. We divided the study cohort into five quintiles according to an area-based index of education and occupation (IEO) and calculated annual age-standardised incidence rates by IEO quintile for the period 1985-2009. The age-standardised incidence ratio (SIR) was estimated for IEO quintiles and 5-year period of diagnosis using the highest IEO quintile as the reference. RESULTS: Overall, lung cancer incidence for women aged 25-69 years increased gradually from 19.8 per 100,000 in 1985 to 25.7 per 100,000 in 2009. The trends by IEO quintile were somewhat comparable from 1985 through to 1995, but from then on rates remained relatively stable for women residing in the highest quintile while increasing for women residing in the remaining four quintiles. Consequently, the SIR for all four of the lower IEO quintiles increased significantly over the 25-year period. For example, the SIR in the lowest IEO quintile increased from 1.16 (95% CI, 0.99 1.37) during 1985-1989 to 1.70 (95% CI, 1.50-1.93) during 2005-2009. The corresponding estimates for women aged 70 years or older showed no clear pattern of socioeconomic gradient. CONCLUSION: The increasing gap in lung cancer incidence between women in the highest socioeconomic group and all others suggests that there is a continued need for the broad implementation of tobacco control interventions, so that smoking prevalence is reduced across all segments of the population and the subsequent benefits are shared more equitably across all demographic groups. PMID- 28625649 TI - Investigation of patterns of nodal metastases in BRAF mutant lung cancer. AB - Axillary lymph nodes (axLN) are a rare site of nodal metastases in patients with lung cancer. BRAF mutated lung cancer is a genetically distinct subtype that occurs in 2-5% of non-small cell lung carcinomas (NSCLC). A recent study identified a highly unusual pattern of metastatic spread to axLN in patients with BRAF mutated colorectal cancer (CRC). The purpose of the study is to assess the incidence of axLN metastases in BRAF mutated NSCLC. Baseline computed tomography (CT) imaging at diagnosis and all follow up CTs of patients with BRAF mutated NSCLC treated at our institution were retrospectively reviewed by two radiologists for evidence of axLN metastases. Positron emission tomography (PET)/CT was reviewed when available. A control group of patients with non-BRAF mutated NSCLC was assessed. Three criteria were used for the diagnosis of a metastatic node; pathologic confirmation, radiologic size greater >=1.5cm in short axis diameter or fluorodeoxyglucose avidity on PET/CT and radiologic size >=1.0cm in short axis diameter. Forty-six patients with BRAF mutated NSCLC and CT images on the institutional PACS were identified. 7 (15%) patients with BRAF mutated NSCLC had axLN metastases using the proposed diagnostic criteria. One patient had a pathologic proven axLN metastasis, 3 had axLNs measuring >=1.5cm in short axis, and 3 had nodes which were FDG avid on PET/CT and measured >=1.0cm in short axis. By comparison, 1 of 46 (2%) control patients with non-BRAF mutated NSCLC had axLN metastases. Previous series have reported the prevalence of axLN metastases in patients with NSCLC as 0.61-0.75%. We have found a higher incidence of axLN metastases in BRAF mutated NSCLC patients than described in non-BRAF mutated NSCLC patients. Examination of the axilla should be a routine part of physical examination in this genetically distinct subgroup of lung cancer patients. PMID- 28625651 TI - Long-lasting shrinkage in tumor mass after discontinuation of nivolumab treatment. AB - We report the case of a 62-year-old man treated with nivolumab as fourth-line therapy for stage IV squamous cell carcinoma of the lung. Because of the onset of nivolumab-induced pneumonitis after 2 doses, nivolumab was discontinued. After discontinuation, the tumor gradually continued to decrease in size without any additional treatment for lung cancer. The patient obtained a long-lasting shrinking of the tumor over 6 subsequent treatment-free months after only 2 administrations of nivolumab. This type of response has not been seen for conventional anticancer drug treatments for NSCLC, and we speculate that a small group of patients with NSCLC will obtain sufficient efficacy from a few doses of nivolumab. PMID- 28625650 TI - Switch maintenance chemotherapy using S-1 with or without bevacizumab in patients with advanced non-small cell lung cancer: a phase II study. AB - OBJECTIVES: We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients not showing disease progression after induction platinum based chemotherapy received S-1 at the dose of 40mg/m2 twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. RESULTS: Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1-17.1%) in the S-1 group and 64.1% (90% CI, 50.0-76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S 1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. CONCLUSIONS: Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities. PMID- 28625652 TI - Symptomatic leptomeningeal metastasis improvement with nivolumab in advanced non small cell lung cancer patient. AB - Leptomeningeal metastasis (LM) is reported in 3.8% of non-small-cell lung cancer (NSCLC) patients, more frequently in adenocarcinoma, and it correlates with poor prognosis. Data regarding the activity of immune checkpoint inhibitors in LM is lacking. We present a case report about the efficacy of nivolumab in a patient with advanced NSCLC and symptomatic LM. PMID- 28625653 TI - Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non-small cell lung cancer. AB - OBJECTIVES: The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)-based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). MATERIALS AND METHODS: Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. RESULTS: The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M positive alleles was 97.1% (range, 90.0-100%). Confirmatory analysis by next generation sequencing yielded a corresponding value of 96.7% (range, 89.1-99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. CONCLUSIONS: Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR TKI treatment. PMID- 28625654 TI - LINE-1 hypomethylation is associated to specific clinico-pathological features in Stage I non-small cell lung cancer. AB - OBJECTIVES: We hypothesize that selected genetic and/or epigenetic changes associated with advanced tumours may help identifying early non-small cell lung cancers (NSCLCs) that recur after resection. Among epigenetic changes, long interspersed nuclear element-1 (LINE-1) hypomethylation is seen early during carcinogenesis and may act in concert with genetic alterations to cancer progression. LINE-1 hypomethylation and gene mutations frequently involved in lung cancer, were analysed to evaluate their prognostic role in resected stage I NSCLC. METHODS: Gene mutations and LINE-1 methylation were analysed in 167 Caucasian patients with stage I NSCLC, namely 100 adenocarcinomas (ADC) and 67 squamous-cell carcinomas (SqCC), using mass-spectrometry and pyrosequencing. We evaluated the correlation between molecular results and clinico-pathological data: age, gender, smoking status, period of surgery, histology, grading, pathological stage, p53 expression, LINE-1 hypomethylation. These variables have been assessed as possible predictors of cancer related survival by regression analysis. RESULTS: Frequency and spectrum of gene mutations were significantly different in ADCs compared with SqCCs. p53 positivity was more common in SqCC, while EGFR or KRAS mutations were mainly detected in ADC. LINE1 hypomethylation was associated with SqCC histology, p53 immunoreactivity and smoking habit. Stage IB, LINE-1 hypomethylation and PIK3CA mutation independently predicted a worse cancer-related survival. When combined into a scoring system, their prognostic power was strengthened. CONCLUSIONS: In many stage I NSCLC a mutation pattern of advanced disease was observed. Stage IB, LINE-1 hypomethylation and PIK3CA mutation were associated to poor prognosis. Genetic and epigenetic events occurring in early carcinogenesis may help identifying stage I NSCLC patients who deserve adjuvant therapy. PMID- 28625655 TI - A randomized controlled trial comparing indwelling pleural catheters with talc pleurodesis (NVALT-14). AB - BACKGROUND: Symptomatic malignant pleural effusion (MPE) occurs frequently in patients with metastatic cancer. The associated prognosis is poor and the success rate of talc pleurodesis (TP) is low. Indwelling pleural catheters (IPCs) are commonly inserted when TP has been unsuccessful. METHODS: We compared talc pleurodesis with the use of an indwelling pleural catheter in patients with recurrent MPE in a multicenter randomized controlled trial (superiority design). The primary endpoint was improvement from baseline in Modified Borg Score (MBS) 6weeks after randomized treatment. Secondary endpoints were hospitalization days, re-interventions, and adverse events. RESULTS: Dyspnea improved significantly (p<0.01) after either treatment, but the magnitude of this improvement did not differ significantly between arms (median 3 and 1 for TP:IPC respectively in rest, p=0.16, (TP 13:IPC 16) and 3 and 1 during exercise, p=0.72 (TP 13:IPC 17)). There was no difference in dyspnea during exercise between TP and IPC at week 6 following treatment, while at rest TP patients (n=13) reported less dyspnea than IPC patients (n=18) (median 0 vs 1, p=0.002). Compared to TP, patients with an IPC had significantly less hospital days during randomized treatment (median: 0 vs 5, p<0.0001), and total hospitalizations for all causes (median: 1.6 vs 1.0, p=0.0035). Fewer IPC patients underwent more than one re-intervention (7/45 vs 15/43, p=0.09). The mean number of re-interventions was lower following IPC (0.21 vs 0.53, p=0.05). Equal number of adverse events occurred. CONCLUSIONS: IPC was not superior in the primary endpoint, improvement of the modified Borg scale (MBS). However, IPC patients had lower hospital stay, fewer admissions and fewer re-interventions. The IPC is an effective treatment modality in patients with symptomatic malignant pleural effusion. PMID- 28625656 TI - Semi-automatic volumetric measurement of response to chemotherapy in lung cancer patients: How wrong are we using RECIST? AB - OBJECTIVES: Lung cancer typically starts as a near-spherical lesion, but as it grows it may acquire an irregular radiologic formation. RECIST is based on the assumption that tumors are spherical, and consequently, proportional changes of tumor volume and parallel changes in tumor diameter, and vice versa. Hence, a 30% decrease in diameter (2r) implies a 65% decrease of volume, and a 20% increase in diameter implies a 73% increase of volume. MATERIALS AND METHODS: We compared volumetric measurement based on multi-detector CT technology with calculated volume (CV) according to RECIST in a cohort of 43 patients with advanced, non squamous cell type, lung cancer treated with a combination of platinum and pemetrexed. RESULTS: CV was larger than SMV in most patients both at baseline and at best overall response (BOR). The difference between the sum of volumes based on volumetric measurement (SMV) and CV was larger for higher sum of diameters. The Lin's concordance correlation coefficient between the percent changes in SMV and CV at BOR was 0.757. Of note, four patients (4/43, 9.5%) were categorized as PD according to the method of CV, but SD according to the method of SMV. CONCLUSION: Our study highlights the importance of volumetric measurement for assessing response to treatment in lung cancer patients particularly showing large, irregular lesions. PMID- 28625657 TI - Synergy between next generation EGFR tyrosine kinase inhibitors and miR-34a in the inhibition of non-small cell lung cancer. AB - OBJECTIVES: EGFR tyrosine kinase inhibitors (TKIs) are widely used to treat NSCLC, primarily patients with activating mutations, with more limited response in wild-type disease. However, even with EGFR-mutated disease, many patients fail to respond, most who initially respond fail to respond completely, and almost all develop resistance and inevitably progress. New therapeutic options that improve these outcomes could provide substantial clinical benefit. We previously demonstrated strong synergistic effects between erlotinib and the tumor suppressor microRNA miR-34a, sensitizing NSCLC cells with primary resistance (EGFR wild-type) and restoring sensitivity in cells with acquired resistance. Here, we report results of further research combining miR-34a with newer generation EGFR-TKIs in similar experiments. MATERIALS AND METHODS: Human NSCLC cell lines with varying degrees of primary and acquired resistance to erlotinib were assessed for sensitivity to a broad set of combined doses of miR-34a mimic and afatinib, rociletinib or osimertinib. Multiple analytical approaches were used to characterize effects on cancer cell proliferation as additive, antagonistic or synergistic. RESULTS: Mimics of miR-34a synergized with afatinib, rociletinib or osimertinib in all EFGR-mutant cells tested. Best and consistently strong synergy was observed in cell models with acquired resistance. Synergy was also evident in most EGFR wild-type cells with miR-34a combined with rociletinib and osimertinib, but not with afatinib. The effects were observed across a broad range of dose levels and drug ratios, with maximal synergy at doses yielding high levels of inhibition beyond those possible to be induced by the single agents alone. CONCLUSION: Combined miR-34a and EGFR-TKIs synergistically sensitize both EGFR wild-type and mutant NSCLC cells, supporting clinical investigation of these combinations as a strategy to overcome both primary and acquired resistance to EGFR-TKIs in NSCLC, possibly with an improved therapeutic index. PMID- 28625658 TI - Enhancing anger perception in older adults by stimulating inferior frontal cortex with high frequency transcranial random noise stimulation. AB - Extensive behavioural evidence has shown that older people have declined ability in facial emotion perception. Recent work has begun to examine the neural mechanism that contribute to this, and potential tools to support emotion perception during aging. The aim of this study was to investigate whether high frequency tRNS applied to the inferior frontal cortex would enhance facial expression perception in older adults. Healthy aged adults (60+ years) were randomly assigned to receive active high-frequency or sham tRNS targeted at bilateral inferior frontal cortices. Each group completed tests of facial identity perception, facial happiness perception and facial anger perception. These tasks were completed before and after stimulation. The results showed that, compared to the sham group, the active tRNS group showed greater gains in performance after stimulation in anger perception (relative to performance before stimulation). The same tRNS stimulation did not significantly change performance on the two other face perception tasks assessing facial identity and facial happiness perception. Examination of how inter-individual variability related to changes in anger perception following tRNS indicated that the degree of performance change in anger perception following active tRNS to inferior frontal cortex was predicted by baseline ability and gender of older adult participants. The findings suggest that high frequency tRNS may be a potential tool to aid anger perception in typical aging, but flag that performance variability and gender may interact with stimulation leading to different outcomes. PMID- 28625660 TI - Task-related and resting-state fMRI identify distinct networks that preferentially support remembering the past and imagining the future. AB - The relation between episodic memory and episodic future thought (EFT) remains an active target of research. A growing literature suggests that similar cognitive processes and neural substrates tend to support these acts. However, direct comparisons of whole-brain activity reveal clear differences, with numerous regions more active when engaging in EFT than when remembering, and a smaller collection of regions displaying the opposite pattern of activity. Although various network labels have been applied to prior neuroimaging results, to date no formal resting-state functional connectivity analysis has been conducted. In the current experiment, 48 subjects remembered events from their past and engaged in EFT. Resting-state data were collected from all subjects. Task results replicated recent findings, with more activity during EFT in regions across frontal and parietal cortex, and with more activity during remembering in a smaller number of predominantly parahippocampal and retrosplenial regions. Resting-state connectivity analysis, based on seed locations defined using the fMRI task data, indicated that regions preferentially activated during EFT fell primarily within the default mode network, while those more active during remembering fell primarily within the contextual association network. These results suggest that despite their general similarity, the functional network membership of regions showing task differences is dissociable. We discuss our results in light of several hypotheses that attempt to relate remembering and EFT, and suggest that the data speak to differences in the relative contributions of episodic and semantic memory, as well as controlled and automatic processing, during the acts of remembering or engaging in EFT. PMID- 28625659 TI - Abnormal semantic knowledge in a case of developmental amnesia. AB - An important theory holds that semantic knowledge can develop independently of episodic memory. One strong source of evidence supporting this independence comes from the observation that individuals with early hippocampal damage leading to developmental amnesia generally perform normally on standard tests of semantic memory, despite their profound impairment in episodic memory. However, one aspect of semantic memory that has not been explored is conceptual structure. We built on the theoretically important distinction between intrinsic features of object concepts (e.g., shape, colour, parts) and extrinsic features (e.g., how something is used, where it is typically located). The accrual of extrinsic feature knowledge that is important for concepts such as chair or spoon may depend on binding mechanisms in the hippocampus. We tested HC, an individual with developmental amnesia due to a well-characterized lesion of the hippocampus, on her ability to generate semantic features for object concepts. HC generated fewer extrinsic features than controls, but a similar number of intrinsic features than controls. We also tested her on typicality ratings. Her typicality ratings were abnormal for nonliving things (which more strongly depend on extrinsic features), but normal for living things (which more strongly depend on intrinsic features). In contrast, NB, who has MTL but not hippocampal damage due to surgery, showed no impairments in either task. These results suggest that episodic and semantic memory are not entirely independent, and that the hippocampus is important for learning some aspects of conceptual knowledge. PMID- 28625661 TI - Resting limb muscle perfusion during inspiratory muscle loading in hypoxia and normoxia. AB - INTRODUCTION: Fatiguing of respiratory muscles reduces peripheral muscle perfusion. Further, acute hypoxia enhances respiratory muscle fatigue. This study investigated the effects of inspiratory muscle loading (IML) on resting locomotor muscle perfusion in hypoxia compared to normoxia. METHODS: Ten subjects completed two study days of fatiguing IML (blinded, randomized) in normobaric hypoxia (targeted oxygen saturation 80%) and normoxia, respectively. Contrast-enhanced ultrasound (CEUS) of the gastrocnemius muscle and popliteal doppler ultrasonography were used to monitor muscle perfusion. Based on CEUS and monitored cardiac output, perfusion surrogate parameters (CLPaer and CLPap) were established. RESULTS: Muscle perfusion declines early during IML in normoxia (CLPaer: -54+/-25%, p<0.01; CLPap: -58+/-32%, p<0.01) and hypoxia (CLPaer: -43+/ 23%, p<0.01; CLPap: -41+/-20%, p<0.01). Hypoxia compared to normoxia increased cardiac output before (+23+/-19%, p<0.01 ANOVA) and during (+22+/-20%, p<0.01 ANOVA) IML, while local muscle perfusion during IML remained unchanged (CLPaer: p=0.41 ANOVA; CLPap: p=0.29 ANOVA). CONCLUSION: Acute hypoxia compared to normoxia does not affect locomotor muscle perfusion during fatiguing IML. PMID- 28625662 TI - Experiences and Perceptions of Adults Accessing Publicly Available Nutrition Behavior-Change Mobile Apps for Weight Management. AB - BACKGROUND: Nutrition mobile apps have become accessible and popular weight management tools available to the general public. To date, much of the research has focused on quantitative outcomes with these tools (eg, weight loss); little is known about user experiences and perceptions of these tools when used outside of a research trial environment. OBJECTIVE: Our aim was to understand the experiences and perceptions of adult volunteers who have used publicly available mobile apps to support nutrition behavior change for weight management. DESIGN: We conducted one-on-one semi-structured interviews with individuals who reported using nutrition mobile apps for weight management outside of a research setting. PARTICIPANTS/SETTING: Twenty-four healthy adults (n=19 females, n=5 males) who had used publicly available nutrition mobile apps for weight management for >=1 week within the past 3 to 4 months were recruited from the community in southern Ontario and Edmonton, Canada, using different methods (eg, social media, posters, and word of mouth). QUALITATIVE DATA ANALYSIS: Interviews were audiorecorded, transcribed verbatim, and transcripts were verified against recordings. Data were coded inductively and organized into categories using NVivo, version 10 (QSR International). RESULTS: Participants used nutrition apps for various amounts of time (mean=approximately 14 months). Varied nutrition apps were used; however, MyFitnessPal was the most common. In the interviews, the following four categories of experiences with nutrition apps became apparent: food data entry (database, data entry methods, portion size, and complex foods); accountability, feedback, and progress (goal setting, accountability, monitoring, and feedback); technical and app-related factors; and personal factors (self-motivation, privacy, knowledge, and obsession). Most participants used apps without professional or dietitian support. CONCLUSIONS: This work reveals that numerous factors affect use and ongoing adherence to use of nutrition mobile apps. These data are relevant to professionals looking to better assist individuals using these tools, as well as developers looking to develop new and improved apps. PMID- 28625663 TI - Development of complete dentures based on digital intraoral impressions-Case report. AB - PATIENT: A 60-year-old man presented for refabrication of his maxillary complete denture. In this case, a digital process was chosen to replace the ill-fitted complete maxillary denture. A specialized scan retractor was used to retract the mobile tissues of the lips, cheeks and vestibule while taking a digital impression. The interocclusal record obtained in the patient's mouth was scanned in order to digitally register the occlusal vertical dimension. The denture base and teeth were designed on virtual models that were mounted at the occlusal vertical dimension, and were made using CAD/CAM technology. DISCUSSION: Unlike conventional impression techniques, intraoral scanning is not able to be performed while the tissue is moving. This case report used a scan retractor that facilitated stretching and fixation of the vestibular area. It also helped to retract the lips and cheeks. This report also demonstrates that virtual models at OVD can be obtained without the use of conventional stone models, flasking or processing techniques. One of the main shortcomings in the existing CAD/CAM denture fabrication technology is that it is not able to produce customized denture teeth. The present article demonstrates that the digital denture fabrication workflow can provide customized denture teeth to optimize occlusion. CONCLUSION: This case demonstrated how digital complete dentures can be made without requiring conventional stone models or mounting the models in an articulator. PMID- 28625664 TI - Effects of different numbers of mini-dental implants on alveolar ridge strain distribution under mandibular implant-retained overdentures. AB - PURPOSE: To investigate the strains around mini-dental implants (MDIs) and retromolar edentulous areas when using different numbers of MDIs in order to retain mandibular overdentures. MATERIALS AND METHODS: Four different prosthetic situations were fabricated on an edentulous mandibular model including a complete denture (CD), and three overdentures, retained by four, three or two MDIs in the interforaminal region with retentive attachments. A static load of 200N was applied on the posterior teeth of the dentures under bilateral or unilateral loading conditions. The strains at the mesial and distal of the MDIs and the retromolar edentulous ridges were measured using twelve strain gauges. Comparisons of the mean microstrains among all strain gauges in all situations were analyzed. RESULTS: The strain distribution determined during bilateral loading experienced a symmetrical distribution; while during unilateral loading, the recorded strains tended to change from compressive strains on the loaded side to tensile strains. Overall, the number of MDIs was found to be passively correlated to the generated compressive strain. The highest strains were recorded in the four MDIs followed by three, two MDIs retained overdenture and CD situations, respectively. The highest strain was found around the terminal MDI. CONCLUSIONS: The use of a low number of MDIs tends to produce low strain values in the retromolar denture-bearing area and around the terminal MDIs during posterior loadings. However, when using a high number of MDIs, the overdenture tends to have more stability during function. PMID- 28625665 TI - Color stability of glass-fiber-reinforced polypropylene for non-metal clasp dentures. AB - PURPOSE: The purpose of this study was to investigate the color stability of a glass-fiber-reinforced thermoplastic (GFRTP), for use in non-metal clasp dentures (NMCDs). METHODS: GFRTPs composed of E-glass fibers and polypropylene with 2 mass% of pigments were fabricated using injection molding. According to our previous study on the optimum fiber content for GFRTPs, we prepared GFRTPs with fiber contents of 0, 10, and 20 mass% (GF0, GF10, and GF20). Commercially available NMCD and PMMA materials were used as controls. The color changes of GFRTPs at 24h, and at 1, 2, and 4 weeks of coffee immersion at 37 degrees C were measured by colorimetry, using the Commission Internationale de l'Eclairage (CIE) Lab system. The color stabilities of the GFRTPs were evaluated in two units: the color difference (DeltaE*) and National Bureau of Standards (NBS) units. RESULTS: After immersion, none of the GFRTPs showed visible color change. From the colorimetry measurement using the CIE Lab system, the DeltaE* values of the GFRTPs were 0.65-2.45. The NBS values of the GFRTPs were 0.60-2.25, all lower than the threshold level of 3.0, demonstrating clinically acceptable color changes. On the other hand, an available polyamide-based NMCD material exhibited "appreciable" color change, as measured in NBS units. CONCLUSIONS: The results indicate that the GFRTPs showed clinically acceptable color stability and might be satisfactory for clinical use. Therefore, GFRTPs are expected to become attractive materials for esthetic dentures. PMID- 28625666 TI - A comparative analysis on the physicochemical properties of tick-borne encephalitis virus envelope protein residues that affect its antigenic properties. AB - This work is dedicated to the study of the variability of the main antigenic envelope protein E among different strains of tick-borne encephalitis virus at the level of physical and chemical properties of the amino acid residues. E protein variants were extracted from then NCBI database. Four amino acid residues properties in the polypeptide sequences were investigated: the average volume of the amino acid residue in the protein tertiary structure, the number of amino acid residue hydrogen bond donors, the charge of amino acid residue lateral radical and the dipole moment of the amino acid residue. These physico-chemical properties are involved in antigen-antibody interactions. As a result, 103 different variants of the antigenic determinants of the tick-borne encephalitis virus E protein were found, significantly different by physical and chemical properties of the amino acid residues in their structure. This means that some strains among the natural variants of tick-borne encephalitis virus can potentially escape the immune response induced by the standard vaccine. PMID- 28625667 TI - Dynamics of PVY strains in field grown potato: Impact of strain competition and ability to overcome host resistance mechanisms. AB - Potato virus Y (PVY) is the most important viral pathogen affecting potato crops worldwide. PVY can be transmitted non-persistently by aphids that do not colonize the host plant, resulting in a rapid acquisition and transmission of the virus between plants. PVY exists as a complex of strains that can be distinguished according to their pathogenicity, serology and genomic analysis. While virus incidence remains low in Scottish seed potato crops, PVY has become the increasingly prevalent virus. The monitoring of PVYN and PVYO serotypes has revealed a recent shift towards PVYN which now accounts for more than 90% of all PVY cases. A survey of the molecular diversity of PVYN isolates indicated that 80%-90% belong to the recombinant European (EU)-NTN group, with North-American (NA)-NTN and non-recombinant EU-N variants accounting for the remainder. The shift from non-recombinant to recombinant PVY isolates is a common trend observed worldwide. Surveys of a range of PVY isolates representing the main strain and phylogenetic groups suggest that PVY has the ability to overcome hypersensitive response-mediated resistance with significant differences between isolates of the same strain group. Contrastingly, genes mediating extreme resistance (Ryadg, Rysto) provide efficient resistance to PVY transmission to progeny tubers. Transmission experiments in field conditions of PVY isolates representing the three main molecular groups (PVYO, PVYEU-NTN, PVYNA-NTN) indicate that PVYEU-NTN has the highest transmission rate. Our results suggest that PVYEU-NTN isolate has a competitive advantage over PVYO and PVYNA-NTN isolates which is likely to be an important factor in shaping the evolution of viruses and the population dynamics of PVY. PMID- 28625668 TI - Towards area wide management of insect vectored viruses of tomatoes in the Bowen district. AB - The Bowen region of Northern Queensland is an important winter production area for tomatoes in Australia. There are three economically important viruses in the region that affect tomato, Tomato yellow leaf curl virus (TYLCV), Tomato spotted wilt virus (TSWV) and Potato leafroll virus (PLRV), which are vectored by whiteflies, thrips and aphids, respectively. An area wide management approach is required to lower the primary inoculum throughout the district. To this end, we undertook investigations into the virus incidence and alternative hosts for the virus and vectors in different cropping regions throughout the district, as well as local management options such as insecticide application and possible non-host cover crops for the wet-season break in production. The initial incidence of Potato leafroll virus was very high, most probably due to abnormal weather patterns for the district, and has ceased to be a problem. Tomato yellow leaf curl virus is a continual problem even at the beginning of the season, indicating large reservoir host(s) in the environment. Only four alternative hosts have been identified: Stachytarpheta jamaicensis (TSWV), Solanum americanum (PLRV and TYLCV) Trianthema portulacastrum (TYLCV), and Amaranthus viridis(TLYCV). Different insecticide and application options were trialled for protection against Tomato yellow leaf curl virus, with the best possible option yielding marketable fruit more than ninety percent of a resistant hybrid. A trial of yield vs time of infection of TYLCV found that whitefly exclusion for 6 weeks post transplant yielded an average increase of nearly three kilograms of marketable fruit per plant. A number of pulse crops have been confirmed as non-hosts of tomato yellow leaf curl for use as cover crops in the wet-season break. Most of the production has moved to dual resistant TYLCV/TSWV hybrids, though an area wide management program still needs to be established to reduce the primary inoculum throughout the district, giving growers more varietal options, especially early in the season. PMID- 28625669 TI - Role of language discordance in complication and readmission rate after infrainguinal bypass. AB - OBJECTIVE: Studies have shown that language discordance between treatment teams and patients leads to worse patient outcomes, including longer hospital stays, higher rates of readmission, impaired comprehension of discharge instructions, and lower treatment adherence. Yet, there is a paucity of data evaluating the effects of language discordance on postoperative outcomes among vascular surgery patients. This study compared 30-day postoperative complications and readmissions after nonemergent infrainguinal bypass between non-English-speaking (NES) and English-speaking (ES) patients. METHODS: Consecutive patients who underwent nonemergent infrainguinal bypass for claudication, ischemic rest pain, and tissue loss at an urban, academic medical center between 2007 and 2014 were identified. Patients were stratified into NES or ES groups by their self-identified primary language. Crude comparisons and multivariable analyses were performed to assess the association of primary language status with 30-day wound infections, adverse graft events (wound infections, graft thromboses, or hematomas), readmissions, and Emergency Department return visits. RESULTS: The study included 261 patients who underwent an infrainguinal bypass: 51 NES and 210 ES patients. The NES patients were older (67.4 +/- 9.8 vs 63.1 +/- 9.9 years; P = .005) and had a higher rate of diabetes (78.4% vs 58.6%; P = .009) and a lower rate of chronic obstructive pulmonary disease (5.9% vs 28.6%; P = .001). Other comorbidities were comparable between the two groups. The NES patients were more likely to be Medicaid beneficiaries (51.0% vs 21.4%; P < .001). Across all outcomes compared, crude analyses showed no significant difference between NES and ES patients. Adjusted analysis revealed that language discordance did not affect the odds of adverse outcomes of wound infections (odds ratio [OR], 1.87; 95% confidence interval [CI], 0.90-3.88; P = .095), adverse graft events (OR, 1.23; 95% CI, 0.62 2.45; P = .556), readmissions (OR, 1.51; 95% CI, 0.77-2.95; P = .478), or Emergency Department return visits (OR, 1.28; 95% CI, 0.58-2.83; P = .546). CONCLUSIONS: Our study suggests that language discordance does not affect 30-day complication and readmission rates after infrainguinal bypass. PMID- 28625670 TI - Carotid occlusion is associated with more frequent neurovascular events than moderately severe carotid stenosis. AB - OBJECTIVE: Asymptomatic internal carotid artery occlusion (CO) presents a clinical dilemma, and presently, the natural history, stroke risk, and optimal management remain ill defined. This study compared outcomes, including neurovascular events (NVEs) and health care costs, between patients with CO and patients with asymptomatic carotid artery stenosis (CS). METHODS: A prospectively maintained database was queried to identify patients with CO and CS with at least >50% carotid stenosis by duplex. We identified and reviewed 622 consecutive patients with asymptomatic carotid artery disease at one academic medical center between 2011 and 2013. Patients with CO (n = 97) were identified and propensity matched by age and gender in a 1:2 ratio with CS patients (n = 194) for further analyses. Univariate and multivariate models were used to analyze baseline characteristics, clinical variables, and 1-year follow-up data from the date of diagnosis. Multivariate analysis was performed by multiple linear regression modeling. Institutional Review Board approval was obtained. RESULTS: Follow-up data were available for 99% of matched patients. CO patients were younger (72 vs 75 years; P < .01) and more likely male (67% vs 53%; P = .01) compared with CS patients. After propensity matching, baseline characteristics were similar between groups, with a trend toward higher use of statin therapy among patients with CO. Antiplatelet therapy was used in 79% of patients with CS and in 74% of patients with CO (P = .45). The rate of NVE among CO patients was higher than among CS patients at 1 year of follow-up (14% vs 7%; P = .03). Among those with NVE, neither antiplatelet therapy (64% vs 77%; P = .49) nor statin therapy (86% vs 77%; P = .58) appeared to have a significant effect. Health care costs ($14,361 vs $12,142; P = .44) and hospital admission rate (63% vs 71%; P = .18) were similar between groups. Not surprisingly, the rate of vascular procedures was higher in the CS group (55% vs 27%; P = .04). CONCLUSIONS: Patients with asymptomatic CO experience more NVEs compared with similar patients with moderately severe CS. Further study of preventative strategies, including intensity of medical therapy, is warranted. PMID- 28625671 TI - Intrinsic parameters for the synthesis and tuned properties of amphiphilic chitosan drug delivery nanocarriers. AB - Chitosan (CS) is a material derived from chitin, the most abundant biopolymer on the planet. It has shown potential among a wide variety of biomedical applications especially within the context of self-assembling nanocarriers usable in biomedical applications such as drug delivery, macroscopic injectables, tissue engineering scaffolds, and nano-imaging agents. To date, many reviews have been focused on the biomedical properties and applications of CS-based nanocarriers, but a review is lacking on the role and prospects of different factors such as formulation parameters and preparation conditions on the properties of amphiphilic chitosan nanocarriers (ACNs) that have shown critical value in advancing drug delivery. PMID- 28625672 TI - Evolution of the scientific literature on drug delivery: A 1974-2015 bibliometric study. AB - This study charts the growth of the drug delivery literature published during 1974-2015 from journals indexed in the Science Citation Index Expanded database. The growth of publications on drug delivery paralleled the total scientific publications for three decades (1974-2003); however, from 2004 to 2015 it exploded fourfold, while the total increased only 1.75 fold. Industrialized countries (USA, UK, Germany, Japan, Italy, France and Canada) were the most prolific during the first decades, but in 2014-2015 China, India and South Korea ranked 1st, 3rd and 4th respectively among the productive countries. The number of participating countries increased fivefold (from 19 to 96). During the last 15years, the journals targeted by drug delivery research increased nearly 2.4 fold (416 to 1001) and three journals (Journal of Controlled Release, Advanced Drug Delivery Reviews, and International Journal of Pharmaceutics) published nearly one-fifth of the drug delivery research in 2014-2015. PMID- 28625673 TI - Exploiting passive nanomedicine accumulation at sites of enhanced vascular permeability for non-cancerous applications. AB - Over the past few decades, enhanced permeability of tumor vasculature was actively exploited for targeted delivery of anticancer nanomedicines resulting in numerous pharmaceutical products. Formation of new immature and leaky vessels along with inflammatory remodeling of existing vessels accompany development of numerous diseases beyond cancer and present an opportunity for passive accumulation of intravenously administered nanomedicines in many pathological tissues. To date, applications of non-cancerous enhanced permeation have been relatively unexploited as target tissues and may create new therapy and prevention technologies for many disorders. Herein, we summarize the current knowledge on the nature of enhanced vascular permeability in multiple non cancerous pathological tissues. We also discuss the clinical status of nanotherapeutics with selectivity based on passive accumulation in non-cancerous target tissues, their challenges, and prospects. PMID- 28625674 TI - Regional cerebral cortical thickness correlates with autonomic outflow. AB - Dysregulation of autonomic control often develops with advancing age, favoring a chronic state of heightened sympathetic outflow with parasympathetic withdrawal. However, the mechanisms of this age-related autonomic impairment are not known. This study tested the hypothesis that inter-individual differences in autonomic outflow across the adult age-span are related to cerebral cortex thickness. A total of 55 healthy, active individuals participated in this study (21-73years; 18 female). Physical fitness was treated as a possible covariate (VO2peak: 26 81mL/kg/min). Cardiovagal baroreflex sensitivity, heart rate variability, and muscle sympathetic nerve activity (MSNA) were assessed during a laboratory session. T1-weighted images acquired at 3T facilitated measures of cortical thickness (Brain Voyager 2.8.4). A priori cortical regions of interest included the medial prefrontal cortex (MPFC) and insula cortex. Cortical thickness at the MPFC correlated strongly with markers of autonomic outflow including heart rate variability (ln-high frequency power (slope: -16, r2=0.65), SDNN (slope: 22, r2=0.22), total power (slope: 2872, r2=0.24)), and MSNA variables (burst frequency (slope: 1, r2=0.16), burst incidence (slope: -26, r2=0.62) and total MSNA (slope: -847, r2=0.56)). Further associations with burst incidence were observed within the left insula (p<0.05). Importantly, the strength of the relationship between autonomic variables and cortical thickness was determined by age, and was not altered following adjustments for cardiorespiratory fitness. The current results implicate cortical atrophy in the frontal lobe as a contributor to both the sympathetic and parasympathetic changes that occur with age. PMID- 28625675 TI - Distal migration of contraceptive device in a sub-segmental branch of the pulmonary artery. PMID- 28625676 TI - Comprehensive determination of macrolide antibiotics, their synthesis intermediates and transformation products in wastewater effluents and ambient waters by liquid chromatography-tandem mass spectrometry. AB - Macrolide antibiotics are a prominent group of emerging contaminants frequently found in wastewater effluents and wastewater-impacted aquatic environments. In this work, a novel analytical method for simultaneous determination of parent macrolide antibiotics (azithromycin, erythromycin, clarithromycin and roxithromycin), along with their synthesis intermediates, byproducts, metabolites and transformation products in wastewater and surface water was developed and validated. Samples were enriched using solid-phase extraction on Oasis HLB cartridges and analyzed by reversed-phase liquid chromatography coupled to electrospray ionization tandem mass spectrometry. The target macrolide compounds were separated on an ACE C18 PFP column and detected using multiple reaction monitoring in positive ionization polarity. The optimized method, which included an additional extract clean-up on strong anion-exchange cartridges (SAX), resulted in high recoveries and accuracies, low matrix effects and improved chromatographic separation of the target compounds, even in highly complex matrices, such as raw wastewater. The developed method was applied to the analysis of macrolide compounds in wastewater and river water samples from Croatia. In addition to parent antibiotics, several previously unreported macrolide transformation products and/or synthesis intermediates were detected in municipal wastewater, some of them reaching MUg/L levels. Moreover, extremely high concentrations of macrolides up to mg/L level were found in pharmaceutical industry effluents, indicating possible importance of this source to the total loads into ambient waters. The results revealed a significant contribution of synthesis intermediates and transformation products to the overall mass balance of macrolides in the aquatic environment. PMID- 28625677 TI - Profiling of Vitis vinifera L. canes (poly)phenolic compounds using comprehensive two-dimensional liquid chromatography. AB - Grapevine canes, a pruning-derived by-product, possess a great amount of bioactive (poly)phenolic compounds belonging to different chemical classes, thus, having a good potential for further valorization. However, in order to properly design valorization strategies, the precise chemical composition of this material has to be known. Up to now, this chemical characterization has been based on analysis of different groups of components individually, due to difficulties related to their huge chemical variability. In this work, a comprehensive two dimensional liquid chromatography-based method (LC*LC) is developed to obtain the profiles of (poly)phenolic compounds present in grapevine canes from several varieties. Three different set-ups have been tested and compared; the combination of diol and C18 columns produced the best results, allowing the characterization of the (poly)phenolic profile in around 80min. This way, 81 different components were detected in the samples; most of them could be tentatively assigned using the information provided by the DAD and MS detectors employed. Indeed, it has been possible to detect in a single run components belonging to stilbenoids, procyanidins and prodelphinidins of varying degrees of polymerization, some of them not formerly described in this natural source. The method has shown extremely good separation capabilities, and is characterized by high effective peak capacity (842) and orthogonality (A0=78%). The obtained results demonstrate that Vitis vinifera L. canes may retain a great potential to be used as an underexploited natural source of bioactive compounds, with potential applications in different fields. PMID- 28625678 TI - Rapid protein production from stable CHO cell pools using plasmid vector and the cumate gene-switch. AB - To rapidly produce large amounts of recombinant proteins, the generation of stable Chinese Hamster Ovary (CHO) cell pools represents a useful alternative to large-scale transient gene expression (TGE). We have developed a cell line (CHOBRI/rcTA) allowing the inducible expression of recombinant proteins, based on the cumate gene switch. After the identification of optimal plasmid DNA topology (supercoiled vs linearized plasmid) for PEIproTM mediated transfection and of optimal conditions for methionine sulfoximine (MSX) selection, we were able to generate CHOBRI/rcTA pools producing high levels of recombinant proteins. Volumetric productivities of up to 900mg/L were reproducibly achieved for a Fc fusion protein and up to 350mg/L for an antibody after 14days post-induction in non-optimized fed-batch cultures. In addition, we show that CHO pool volumetric productivities are not affected by a freeze-thaw cycle or following maintenance in culture for over one month in the presence of MSX. Finally, we demonstrate that volumetric protein production with the CR5 cumate-inducible promoter is three- to four-fold higher than with the human CMV or hybrid EF1alpha-HTLV constitutive promoters. These results suggest that the cumate-inducible CHOBRI/rcTA stable pool platform is a powerful and robust system for the rapid production of gram amounts of recombinant proteins. PMID- 28625679 TI - Phenotype databases for genetic screens in human cells. AB - Genetic screens are powerful tools to identify components that make up biological systems. Perturbations introduced by methods such as RNA interference (RNAi) or CRISPR/Cas9-mediated genome editing lead to biological phenotypes that can be examined to understand the molecular function of genes in the cell. Over the years, many of such experiments have been conducted providing a wealth of knowledge about genotype-to-phenotype relationships. These data are a rich source of information and it is in a common interest to make them available in a simplified and integrated format. Thus, an important challenge is that genetic screening data can be stored in databases in standardized ways, allowing users to gain new biological insights through data mining and integrated analyses. Here, we provide an overview of available phenotype databases for human cells. We review in detail two databases for high-throughput screens, GenomeRNAi and GenomeCRISPR, and describe how these resources are integrated into the German Network for Bioinformatics Infrastructure de.NBI as part of the European infrastructure for life-science information ELIXIR. PMID- 28625680 TI - Plant-made potyvirus-like particles used for log-increasing antibody sensing capacity. AB - Deployment of the elongated flexuous virions of Turnip mosaic virus (TuMV), a potyvirus, for peptide display on their external surface has been previously reported by us. Nonetheless, both in TuMV and other potyviruses some peptides hinder the ability of the virus to infect host plants. We found that a peptide derived from the human thrombin receptor (TR) inhibited TuMV infectivity. In an effort to get around this problem, TuMV virus-like particles (VLPs) were produced in plants by transient high-level expression of wild-type or recombinant coat protein (CP). Significant production of both recombinant and non-recombinant CP proteins was obtained from plant leaves. Assembled particles of each of these two proteins into VLPs were observed under the electron microscope. The capacity of TR-CP VLPs to log-increase the ability of TR antibody-sensing was confirmed. These results confirm that the use of VLPs is an effective way to overcome the problem of displaying infectivity-interfering peptides. This is yet another way of exploiting the use of plant-made flexuous elongated VLPs for nanobiotechnological purposes. PMID- 28625681 TI - Variation of calcium, copper and iron levels in serum, bile and stone samples of patients having different types of gallstone: A comparative study. AB - BACKGROUND: Epidemiological data among the human population has shown a significantly increased incidence of gallstone (GS) disease worldwide. It was studied that some essential (calcium) and transition elements (iron and copper) in bile play an important role in the development of GS. METHOD: The estimation of calcium, copper and iron were carried out in the serum, gall bladder bile and different types of GS (cholesterol, mixed and pigmented) of 172 patients, age ranged 20-55years. For comparative purpose age matched referents not suffering from GS diseases were also selected. Biliary concentrations of calcium (Ca), iron (Fe) and copper (Cu) were correlated with their concentrations in serum and different types of GS samples. The ratio of Ca, Fe and Cu in bile with serum was also calculated. Understudy metals were determined by flame atomic absorption spectroscopy after acid decomposition of matrices of selected samples. RESULTS: The Ca concentrations in serum samples were significantly higher in patients with pigmented GS as compared to controls (p<0.005), whereas for patients having cholesterol and mixed GS the concentrations were on the lower side. Biliary Ca concentrations of patients were found to be higher than controls, but difference was significant for pigmented GS patients (p>0.001). The contents of Cu and Fe in serum and bile of all patients (except female cholesterol GS patient have low serum iron concentration) were found to be higher than control, but difference was significant in those patients who have pigmented GS. The concentration of Ca, Fe and Cu in different types GS were found in the order, Pigmented>mixed>cholesterol. The bile/serum ratio for Ca, Cu and Fe was found to be significantly higher in pigmented GS patients. Gall bladder bile was slightly alkaline in patients as compared to referents. The density of bile was found to be higher in patients as compared to the referents. Various functional groups present in different types of GS samples were confirmed by Fourier transform infra-red spectroscopy. CONCLUSION: The higher density and pH of bile, elevated concentrations of transition elements in all types of biological samples (serum, bile and GS), could be an important factor for the formation of different types of GS. PMID- 28625682 TI - Are circadian rhythms new pathways to understand Autism Spectrum Disorder? AB - Autism Spectrum Disorder (ASD) is a frequent neurodevelopmental disorder. ASD is probably the result of intricate interactions between genes and environment altering progressively the development of brain structures and functions. Circadian rhythms are a complex intrinsic timing system composed of almost as many clocks as there are body cells. They regulate a variety of physiological and behavioral processes such as the sleep-wake rhythm. ASD is often associated with sleep disorders and low levels of melatonin. This first point raises the hypothesis that circadian rhythms could have an implication in ASD etiology. Moreover, circadian rhythms are generated by auto-regulatory genetic feedback loops, driven by transcription factors CLOCK and BMAL1, who drive transcription daily patterns of a wide number of clock-controlled genes (CCGs) in different cellular contexts across tissues. Among these, are some CCGs coding for synapses molecules associated to ASD susceptibility. Furthermore, evidence emerges about circadian rhythms control of time brain development processes. PMID- 28625683 TI - A developmental and clinical perspective of rhythmic interpersonal coordination: From mimicry toward the interconnection of minds. AB - Imitation plays a critical role in the development of intersubjectivity and serves as a prerequisite for understanding the emotions and intentions of others. In our review, we consider spontaneous motor imitation between children and their peers as a developmental process involving repetition and perspective-taking as well as flexibility and reciprocity. During childhood, this playful dynamic challenges developing visuospatial abilities and requires temporal coordination between partners. As such, we address synchrony as form of communication and social signal per se, that leads, from an experience of similarity, to the interconnection of minds. In this way, we argue that, from a developmental perspective, rhythmic interpersonal coordination through childhood imitative interactions serves as a precursor to higher- level social and cognitive abilities, such as theory of mind (TOM) and empathy. Finally, to clinically illustrate our idea, we focus on developmental coordination disorder (DCD), a condition characterized not only by learning difficulties, but also childhood deficits in motor imitation. We address the challenges faced by these children on an emotional and socio-interactional level through the perspective of their impairments in intra- and interpersonal synchrony. PMID- 28625684 TI - Brand Medications and Medicare Part D: How Eye Care Providers' Prescribing Patterns Influence Costs. AB - PURPOSE: To quantify costs of eye care providers' Medicare Part D prescribing patterns for ophthalmic medications and to estimate the potential savings of generic or therapeutic drug substitutions and price negotiation. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: Eye care providers prescribing medications through Medicare Part D in 2013. METHODS: Medicare Part D 2013 prescriber public use file and summary file were used to calculate medication costs by physician specialty and drug. Savings from generic or therapeutic drug substitutions were estimated for brand drugs. The potential savings from price negotiation was estimated using drug prices negotiated by the United States Veterans Administration (USVA). MAIN OUTCOME MEASURES: Total cost of brand and generic medications prescribed by eye care providers. RESULTS: Eye care providers accounted for $2.4 billion in total Medicare part D prescription drug costs and generated the highest percentage of brand name medication claims compared with all other providers. Brand medications accounted for a significantly higher proportion of monthly supplies by volume, and therefore, also by total cost for eye care providers compared with all other providers (38% vs. 23% by volume, P < 0.001; 79% vs. 56% by total cost, P < 0.001). The total cost attributable to eye care providers is driven by glaucoma medications, accounting for $1.2 billion (54% of total cost; 72% of total volume). The second costliest category, dry eye medications, was attributable mostly to a single medication, cyclosporine ophthalmic emulsion (Restasis, Allergan, Irvine, CA), which has no generic alternative, accounting for $371 million (17% of total cost; 4% of total volume). If generic medications were substituted for brand medications when available, $148 million would be saved (7% savings); if generic and therapeutic substitutions were made, $882 million would be saved (42% savings). If Medicare negotiated the prices for ophthalmic medications at USVA rates, $1.09 billion would be saved (53% savings). CONCLUSIONS: Eye care providers prescribe more brand medications by volume than any other provider group. Efforts to reduce prescription expenditures by eye care providers should focus on increasing the use of generic medications, primarily through therapeutic substitutions. Policy changes enabling Medicare to negotiate prescription drug prices could decrease costs to Medicare. PMID- 28625685 TI - Objective Quantification of Anterior Chamber Inflammation: Measuring Cells and Flare by Anterior Segment Optical Coherence Tomography. AB - PURPOSE: To assess the ability of swept-source (SS) optical coherence tomography (OCT) of the anterior segment (AS) to measure anterior chamber (AC) inflammation (both flare and cells) objectively. To compare OCT-derived inflammatory indices with standard techniques. DESIGN: Prospective evaluation of a diagnostic test. PARTICIPANTS: Patients diagnosed with anterior uveitis (active or inactive) and controls. METHODS: Participants underwent an AC inflammation evaluation including: clinical cell and flare grading and laser flare photometry (LFP). Uveitis patients were divided into active or inactive uveitis status according to clinical grading. Anterior segment SS-OCT scans were obtained for each participant. Tomographic images were analyzed to count the AC cells, and to calculate to absolute measurements of aqueous signal intensity. The absolute values were compared with the signal measured by the scan outside the eye, generating an optical density ratio (aqueous-to-air relative intensity [ARI] index). Correlations between OCT-derived AC inflammatory indexes and LFP, clinical grading, participant category (active or inactive uveitis, control), age, gender, and central corneal thickness (CCT) were assessed. MAIN OUTCOME MEASURES: Correlation between OCT-derived AC inflammatory indexes (ARI index and AC cells on OCT) and standard clinical techniques (LFP, clinical cell grading). RESULTS: Two hundred thirty-seven eyes (70 active uveitis, 97 inactive uveitis, and 70 controls) were included. Anterior chamber cells count on OCT did not differ between inactive uveitis and controls, but was significantly higher in active uveitis compared to the other categories (both P < 0.0001). All groups had different LFP (all P < 0.0001). Active uveitis had significantly higher ARI index compared with inactive uveitis and controls (both P < 0.0001). Interobserver agreement (intraclass correlation coefficient) for ARI index was 0.78. The ARI index correlated positively with age (P = 0.043) and negatively with CCT (P = 0.006). The ARI index correlated with LFP in the active uveitis group (P < 0.0001), but not in the others. Anterior chamber cells on OCT increased among all cell clinical grades (P < 0.0001). The ARI index increased among all flare clinical grades (P < 0.005). CONCLUSIONS: Anterior segment SS-OCT could be used for a comprehensive assessment of AC inflammation, providing objective measurements of inflammatory cells and aqueous flare. PMID- 28625686 TI - The Influence of Contamination and Cleaning on the Strength of Modular Head Taper Fixation in Total Hip Arthroplasty. AB - BACKGROUND: Intraoperative interface contamination of modular head-stem taper junctions of hip implants can lead to poor fixation strength, causing fretting and crevice corrosion or even stem taper fracture. Careful cleaning before assembly should help to reduce these problems. The purpose of this study was to determine the effect of cleaning (with and without drying) contaminated taper interfaces on the taper fixation strength. METHODS: Metal or ceramic heads were impacted onto titanium alloy stem tapers with cleaned or contaminated (fat or saline solution) interfaces. The same procedure was performed after cleaning and drying the contaminated interfaces. Pull-off force was used to determine the influence of contamination and cleaning on the taper strength. RESULTS: Pull-off forces after contamination with fat were significantly lower than those for uncontaminated interfaces for both head materials. Pull-off forces after application of saline solution were not significantly different from those for uncontaminated tapers. However, a large variation in taper strength was observed, pull-off forces for cleaned and dried tapers were similar to those for uncontaminated tapers for both head materials. CONCLUSION: Intraoperative contamination of taper interfaces may be difficult to detect but has a major influence on taper fixation strength. Cleaning of the stem taper with saline solution and drying with gauze directly before assembly allows the taper strength of the pristine components to be achieved. Not drying the taper results in a large variation in pull-off forces, emphasizing that drying is essential for sufficient and reproducible fixation strength. PMID- 28625687 TI - Can Surgeons Reduce the Risk for Dislocation After Primary Total Hip Arthroplasty Performed Using the Posterolateral Approach? AB - BACKGROUND: Hip dislocation is one of the most common postoperative complications after total hip arthroplasty (THA). Potential contributors include patient- and surgical-related factors. We performed a retrospective cohort study to identify risk factors for postoperative dislocation in patients receiving THA via the posterolateral approach. METHODS: We assessed 1326 consecutive primary THAs performed between 2010 and 2015. Patient information was documented, and plain radiographic films were used to evaluate cup positioning, hip offset, and hip length change. A multiple logistic regression was used to identify risk factors for dislocation. Follow-up was coordinated by the Danish National Patient Registry. RESULTS: Age and American Society of Anesthesiologists scores were higher in dislocating THA compared with those in the nondislocating THA. Cup anteversion was less in dislocating THA compared with that in nondislocating THA. Independent risk factors for cup dislocation were increased age, body mass index <25 and >30 kg/m2, and leg shortening of >5 mm. CONCLUSION: Surgeons should aim for a shortening of leg length <5 mm to reduce the risk of postoperative dislocation in primary THA. Although anteversion was reduced for dislocating THA, there is likely no universal safe zone for cup positioning. Hip stability is multifactorial, and optimal cup positioning may vary from patient to patient. PMID- 28625688 TI - Electrically atomised formulations of timolol maleate for direct and on-demand ocular lens coatings. AB - Advances in nanotechnology have enabled solutions for challenging drug delivery targets. While the eye presents numerous emerging opportunities for delivery, analysis and sensing; issues persist for conventional applications. This includes liquid phase formulation localisation on the ocular surface once administered as formulated eye-drops; with the vast majority of dosage (>90%) escaping from the administered site due to tear production and various drainage mechanisms. The work presented here demonstrates a single needle electrohydrodynamic (EHD) engineering process to nano-coat (as an on demand and controllable fiber depositing method) the surface of multiple contact lenses rendering formulations to be stationary on the lens and at the bio-interface. The coating process was operational based on ejected droplet charge and glaucoma drug timolol maleate (TM) was used to demonstrate surface coating optimisation, bio-surface permeation properties (flux, using a bovine model) and various kinetic models thereafter. Polymers PVP, PNIPAM and PVP:PNIPAM (50:50%w/w) were used to encapsulate the active. Nano-fibrous and particulate samples were characterised using SEM, FTIR, DSC and TGA to confirm structural and thermal stability of surface coated formulations. More than 52% of nano-structured coatings (for all formulations) were <200nm in diameter. In vitro studies show coatings to exhibit biphasic release profiles; an initial burst release followed by sustained release; with TM loaded PNIPAM coating releasing most drug after 24h (89.8%). Kinetic modelling (Higuchi, Korsmeyer-Peppas) was indicative of quasi-Fickian diffusion whilst biological evaluation demonstrates adequate ocular tolerability. Results from permeation studies indicate coated lenses are ideal to reduce dosing regimen, which in turn will reduce systemic drug absorption. Florescent microscopy demonstrated probe and probe embedded coating behaviour from lens surface in vitro. The multiple lens surface coating method demonstrates sustained drug release yielding promising results; suggesting both novel device and method to enhance drug activity at the eyes surface which will reduce formulation drainage. PMID- 28625689 TI - Multiple and complex influences of connexins and pannexins on cell death. AB - Cell death is a fundamental process for organogenesis, immunity and cell renewal. During the last decades a broad range of molecular tools were identified as important players for several different cell death pathways (apoptosis, pyroptosis, necrosis, autosis...). Aside from these direct regulators of cell death programs, several lines of evidence proposed connexins and pannexins as potent effectors of cell death. In the present review we discussed the potential roles played by connexins, pannexins and innexins in the different cell death programs at different scales from gap junction intercellular communication to protein-protein interactions. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28625690 TI - What Have Patients Been Hearing From Providers Since the 2012 USPSTF Recommendation Against Routine Prostate Cancer Screening? AB - BACKGROUND: In this study we aimed to determine the relationship between prostate specific antigen (PSA)-related information obtained from the provider and PSA test uptake. With recent focus on patient-provider communication (PC) and the guidelines recommending against PSA tests for prostate cancer (PCa), PC regarding the PSA test might affect PSA screening rates. MATERIALS AND METHODS: We used the fourth edition of the Health Information National Trends Survey, a nationally representative US survey on the use of cancer-related information. The survey was conducted in 3 cycles: October 2011 to January 2012 (cycle 1); October 2012 to January 2013 (cycle 2); September 2013 to October 2013 (cycle 3). Logistic regression was used to study the effect of PC on respondents' uptake of the PSA test. RESULTS: Most of the respondents were 51 to 65 years old, white, with college or higher education, were married, and had health insurance. PC regarding the PSA test greatly increased the chances of screening for PCa using the PSA test in all 3 cycles (odds ratio [OR], 2.51 [95% confidence interval (CI), 2.03 3.10] in cycle 1; OR, 3.50 [95% CI, 2.51-4.88] in cycle 2; OR, 2.69 [95% CI, 2.02 3.58] in cycle 3). CONCLUSION: Our study showed that PC increased the likelihood of patients undergoing PSA screening. In light of the 2012 US Preventive Services Task Force guidelines recommending against screening for PCa, PC seemed to have an opposite effect. Although updated PC that educates patients on the risks and benefits of PSA screening is needed, patients classically overemphasize benefits and underemphasize risks-which might increase rather than decrease PSA screening rates. PMID- 28625691 TI - A Case of Locally Advanced Castration-resistant Prostate Cancer With Remarkable Response to Nivolumab. PMID- 28625692 TI - Implementation of clinical effectiveness guidelines for solid organ injury after trauma: 10-year experience at a level 1 pediatric trauma center. AB - BACKGROUND: Diagnostic imaging of pediatric blunt abdominal trauma is evolving in light of increased attention to radiation exposure. We hypothesize that the implementation of imaging guidelines has reduced total CT scans without missing clinically significant injury. METHODS: We retrospectively reviewed blunt trauma patients age 0-17 with solid organ injury who underwent CT scan at our academic level 1 pediatric trauma center between 2005 and 2014. Variables including total annual trauma admissions and CT scans, demographics, injury characteristics, and procedures were recorded. Descriptive statistics, Fisher exact and rank sum testing were performed. p<0.05 defined significance. RESULTS: Overall percentage of abdominal CT scans decreased significantly after protocol implementation. There were 498 solid organ injuries in 403 subjects. There was a significant decrease in the median percentage of low grade injuries (1.3% versus 0.6%; p=0.019) but no difference in high grade injuries (1.3% versus 1.1%; p=0.394). No patient had death, readmission or delayed diagnosis of injury requiring intervention. CONCLUSION: Implementation of imaging guidelines for blunt abdominal trauma decreased the incidence of low grade solid organ injuries at our institution, but did not inhibit diagnosis and safe management of high grade injuries. Selective imaging of trauma patients decreases childhood radiation exposure and does not result in delayed bleeding or death. LEVEL OF EVIDENCE: Level III, retrospective study. PMID- 28625693 TI - Long-term functional outcomes after replacement of the esophagus in pediatric patients: A systematic literature review. AB - BACKGROUND: The indications of esophageal replacement (ER) in pediatric patients include long gap esophageal atresia (LGEA), intractable post-corrosive esophageal strictures (PCES), and some rare esophageal diseases. Various conduits and procedures are currently used worldwide with a lack of consensus regarding the ideal substitute to replace the esophagus replacement. The short-term outcomes of these advanced procedures are well known; there are few data available describing long-term functional outcomes of these patients with long life expectancy. OBJECTIVES: The objective of this study is to investigate the long-term functional outcomes of the most widely used techniques for ER in pediatric patients based on a comprehensive literature search covering the last 10years. METHODS: Eligible were all clinical studies reporting outcomes after esophagectomy in pediatric patients, which contained information on at least 3years of follow-up after the operation. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic web-based search using MEDLINE, the Cochrane Library and EMBASE databases was performed, reviewing all medical literature published between January 2006 and December 2015. RESULTS: The scientific quality of the data was generally poor, converging toward only 14 full-text articles for the final analysis. The stomach was the preferred organ for esophageal replacement, where the tubulization of the stomach resulted in significant gastroesophageal reflux. Dysphagia symptoms were more seldom reported, but several authors presented growing figures with the length of follow-up. Dumping syndrome and delayed gastric emptying were only scarcely reported upon. Following colonic graft, chronic gastrocolic reflux affects these patients, in the range of 35-70.8%, while 4 studies reported any dysphagia from 2.7% to 50% of the children. Only one study reported the outcome of the use of a long jejunal segment, where presence of symptoms of functional obstruction was mentioned in 46% of cases. Very few if any data were available on a structured assessment of postprandial dumping and disturbed bowel functions. CONCLUSIONS: Available data in pediatric patients, on the long-term functional outcomes after esophageal replacement with a gastric tube, colonic graft or a long jejunal segment, are of poor scientific quality. Although symptoms are frequently reported currently no conclusions can be drawn regarding potential advantages of one graft over another. TYPE OF STUDY: Treatment study, systematic review. LEVEL OF EVIDENCE: IV. PMID- 28625694 TI - The incidence of chylous ascites after liver transplantation and the proposal of a diagnostic and management protocol. AB - BACKGROUND: No protocol has been established for the diagnosis and management of chylous ascites after liver transplantation (LT). In this study, we retrospectively reviewed our cases of posttransplant chylous ascites (PTCA) and aimed to propose a diagnostic and management protocol. PATIENTS AND METHODS: We retrospectively reviewed the clinical records of 96 LT recipients who underwent LT at our department. The incidence of PTCA and the associated risk factors were analyzed and our protocol for chylous ascites was evaluated. RESULTS: PTCA occurred in 6 (6.3%) patients (mean age: 10.7+/-11.0years) at a mean of 10.8+/ 3.6days after LT. The primary disease in all of PTCA cases was biliary atresia (BA). The periportal lymphadnopathy was an independent risk factor for PTCA. In all cases PTCA successfully resolved according to our protocol. Octreotide was administered in 4 of our 6 PTCA cases. The mean postoperative hospital stay was 40.2+/-8.4days, which was similar to that of cases without PTCA. CONCLUSIONS: The incidence of PTCA in LT patients, especially in those with BA, is relatively high. Our diagnostic criteria and our management protocol were helpful for patients with refractory ascites after LT. TYPE OF STUDY: Diagnostic test: Level II. Treatment study: Level III. PMID- 28625695 TI - Arbitrary and semantic associations in subjective memory impairment and amnestic mild cognitive impairment among Taiwanese individuals: A cross-sectional study. AB - BACKGROUND/PURPOSE: Researchers have recently proposed a preclinical stage of dementia of Alzheimer's type (DAT), referred to as subjective memory impairment (SMI), with the aim of developing methods for the early detection of DAT and subsequent intervention. It has been proposed that the objective memory functions of individuals with SMI are normal; however, arbitrary and semantic associations are both used to describe the processes of memory. No previous studies have investigated these processes among individuals with SMI. METHODS: Cross-sectional analysis was used to compare the memory function of individuals with SMI, amnestic mild cognitive impairment (aMCI), or DAT. One hundred and eighty-three participants were recruited from the Memory Clinic of National Taiwan University Hospital and communities in northern Taiwan, including individuals with no memory complaints (HC, n = 30) and individuals with SMI (n = 61), aMCI-single domain (n = 24), aMCI-multiple domain (n = 33), or DAT (n = 35). The Word Sequence Learning Test (WSLT) was used to assess the formation of arbitrary associations and the Logical Memory subtest of the Wechsler Memory Scale-Third Edition was used to assess the formation of semantic associations. RESULTS: Compared to the HC group, the SMI group performed poorly only on the WSLT, whereas the other groups performed poorly on both of the memory tasks. This study demonstrated that SMI individuals tend to perform poorly in the formation of arbitrary associations. CONCLUSION: Our findings suggest that tasks requiring arbitrary associations may provide greater sensitivity in the detection cognitive changes associated with preclinical DAT. PMID- 28625697 TI - Surgical site infections in very small hospitals in inner Brazil: Unveiling a relevant issue for developing countries. PMID- 28625698 TI - A cold hard menace: A contaminated ice machine as a potential source for transmission of carbapenem-resistant Acinetobacter baumannii. AB - During an investigation of potential sources of transmission of multidrug resistant gram-negative bacilli on a spinal cord injury unit, we recovered genetically related carbapenem-resistant Acinetobacter baumannii isolates from the stool of 3 patients, the hands of a nurse, and an ice machine water outlet spout and drain. Our findings suggest that contaminated ice machines could serve as a potential reservoir for dissemination of multidrug-resistant gram-negative bacilli. PMID- 28625696 TI - Comparative Visualization of the RNA Suboptimal Conformational Ensemble In Vivo. AB - When a ribonucleic acid (RNA) molecule folds, it often does not adopt a single, well-defined conformation. The folding energy landscape of an RNA is highly dependent on its nucleotide sequence and molecular environment. Cellular molecules sometimes alter the energy landscape, thereby changing the ensemble of likely low-energy conformations. The effects of these energy landscape changes on the conformational ensemble are particularly challenging to visualize for large RNAs. We have created a robust approach for visualizing the conformational ensemble of RNAs that is well suited for in vitro versus in vivo comparisons. Our method creates a stable map of conformational space for a given RNA sequence. We first identify single point mutations in the RNA that maximally sample suboptimal conformational space based on the ensemble's partition function. Then, we cluster these diverse ensembles to identify the most diverse partition functions for Boltzmann stochastic sampling. By using, to our knowledge, a novel nestedness distance metric, we iteratively add mutant suboptimal ensembles to converge on a stable 2D map of conformational space. We then compute the selective 2' hydroxyl acylation by primer extension (SHAPE)-directed ensemble for the RNA folding under different conditions, and we project these ensembles on the map to visualize. To validate our approach, we established a conformational map of the Vibrio vulnificus add adenine riboswitch that reveals five classes of structures. In the presence of adenine, projection of the SHAPE-directed sampling correctly identified the on-conformation; without the ligand, only off-conformations were visualized. We also collected the whole-transcript in vitro and in vivo SHAPE-MaP for human beta-actin messenger RNA that revealed similar global folds in both conditions. Nonetheless, a comparison of in vitro and in vivo data revealed that specific regions exhibited significantly different SHAPE-MaP profiles indicative of structural rearrangements, including rearrangement consistent with binding of the zipcode protein in a region distal to the stop codon. PMID- 28625699 TI - Influence of staff infection control training on infection-related quality measures in US nursing homes. AB - Health care-associated infections are a leading cause of morbidity and mortality in US nursing home residents. Ongoing training of nursing home staff is vital to the implementation of infection prevention and control processes. Our aim was to describe associations between methods, frequency, and timing of staff infection prevention and control training and infection-related quality measures. In this national survey of nursing homes, timing of staff infection prevention and control training was associated with reduced indwelling urinary catheter use. PMID- 28625700 TI - The effectiveness of sterilization for flexible ureteroscopes: A real-world study. AB - BACKGROUND: There are no guidelines or quality benchmarks specific to ureteroscope reprocessing, and patient injuries and infections have been linked to ureteroscopes. This prospective study evaluated ureteroscope reprocessing effectiveness. METHODS: Reprocessing practices at 2 institutions were assessed. Microbial cultures, biochemical tests, and visual inspections were conducted on sterilized ureteroscopes. RESULTS: Researchers examined 16 ureteroscopes after manual cleaning and sterilization using hydrogen peroxide gas. Every ureteroscope had visible irregularities, such as discoloration, residual fluid, foamy white residue, scratches, or debris in channels. Tests detected contamination on 100% of ureteroscopes (microbial growth 13%, adenosine triphosphate 44%, hemoglobin 63%, and protein 100%). Contamination levels exceeded benchmarks for clean gastrointestinal endoscopes for hemoglobin (6%), adenosine triphosphate (6%), and protein (100%). A new, unused ureteroscope had hemoglobin and high protein levels after initial reprocessing, although no contamination was found before reprocessing. CONCLUSIONS: Flexible ureteroscope reprocessing methods were insufficient and may have introduced contamination. The clinical implications of residual contamination and viable microbes found on sterilized ureteroscopes are unknown. Additional research is needed to evaluate the prevalence of suboptimal ureteroscope reprocessing, identify sources of contamination, and determine clinical implications of urinary tract exposure to reprocessing chemicals, organic residue, and bioburden. These findings reinforce the need for frequent audits of reprocessing practices and the routine use of cleaning verification tests and visual inspection as recommended in reprocessing guidelines. PMID- 28625701 TI - One needle, one syringe, only one time? A survey of physician and nurse knowledge, attitudes, and practices around injection safety. AB - BACKGROUND: To inform development, targeting, and penetration of materials from a national injection safety campaign, an evaluation was conducted to assess provider knowledge, attitudes, and practices related to unsafe injection practices. METHODS: A panel of physicians (n = 370) and nurses (n = 320) were recruited from 8 states to complete an online survey. Questions, using 5-point Likert and Spector scales, addressed acceptability and frequency of unsafe practices (eg, reuse of a syringe on >1 patient). Results were stratified to identify differences among physician specialties and nurse practice locations. RESULTS: Unsafe injection practices were reported by both physicians and nurses across all surveyed physician specialties and nurse practice locations. Twelve percent (12.4%) of physicians and 3% of nurses indicated reuse of syringes for >1 patient occurs in their workplace; nearly 5% of physicians indicated this practice usually or always occurs. A higher proportion of oncologists reported unsafe practices occurring in their workplace. CONCLUSIONS: There is a dangerous minority of providers violating basic standards of care; practice patterns may vary by provider group and specialty. More research is needed to understand how best to identify providers placing patients at risk of infection and modify their behaviors. PMID- 28625702 TI - National trends in the frequency of bladder catheterization and physician diagnosed catheter-associated urinary tract infections: Results from the Medicare Patient Safety Monitoring System. AB - BACKGROUND: It is unclear if bladder catheterization and catheter-associated urinary tract infection (CAUTI) rates have changed since the implementation of public reporting in 2011. METHODS: We analyzed data from the Medicare Patient Safety Monitoring System, a national, chart abstraction-based surveillance system, for hospitalized adults with a principal discharge diagnosis of heart failure (HF), acute myocardial infarction (AMI), or pneumonia and patients who had undergone certain major surgeries. We assessed bladder catheterization frequency (percentage of patients catheterized) and risk-adjusted CAUTI frequency (percentage of catheterized patients developing CAUTI) from 2009-2014. RESULTS: Bladder catheterization frequency declined significantly (6.6% for AMI patients, 8.0% for HF patients, and 5.7% for surgical patients). For pneumonia patients, there was a nonsignificant increase of 1.1%. The risk-adjusted CAUTI rate among AMI patients decreased by 9.7% each year relative to the year before. For surgical patients, the decrease was 9.1% per year. There was no significant decline among HF or pneumonia patients. The overall burden of CAUTI among surgical patients was higher than for the other conditions because surgical patients were more likely to be catheterized. CONCLUSIONS: There were statistically significant declines in observed bladder catheterization frequency and adjusted CAUTI frequency in some patient populations between 2009 and 2014. PMID- 28625703 TI - Sterilization of dental handpieces. PMID- 28625704 TI - Mental health consequences of exercise withdrawal: A systematic review. AB - OBJECTIVE: A sedentary lifestyle has been associated with mental health disorders. Many medical conditions result in the cessation of exercise, which may increase the risk of developing mental health problems. The purpose of this article is to systematically review the literature examining the effects of exercise withdrawal on mental health. METHOD: Literature was searched using PubMed, PsycINFO, and SPORTdiscus for studies that experimentally manipulated the withdrawal of exercise and included mental health as outcome measure. RESULTS: A total of 19 studies met inclusion criteria (total N=689 with 385 individuals participating in an exercise withdrawal condition). Exercise withdrawal consistently resulted in increases in depressive symptoms and anxiety. Other mental health outcomes were investigated infrequently. Severe mental health issues requiring clinical intervention after experimentally controlled exercise withdrawal was rare. Heterogeneity in methods and outcomes was observed, especially in terms of the duration of exercise withdrawal (range 1 to 42days, median=7days), with stronger effects if exercise withdrawal exceeded 2weeks. CONCLUSION: Experimentally controlled exercise withdrawal has adverse consequences for mental health. These observations in healthy individuals may help to understand the onset of mental health problems in response to acute and chronic medical conditions associated with reduced physical activity. Future research is needed to investigate potential mechanisms explaining the adverse mental health consequences of cessation of exercise that will provide new targets for clinical interventions. PMID- 28625705 TI - The feasibility of improved live-dead distinction in qPCR-based microbial source tracking. AB - PCR-based microbial source tracking (MST) has become a useful tool to identify dominant sources of fecal pollution in water. The method has previously been successfully combined with viability PCR (using propidium monoazide) allowing the preferential detection of membrane-intact bacteria. This study aimed at further improving the selectivity for intact cells when targeting host-specific markers in Bacteroidales bacteria. One approach was to increase amplicon sizes that had been shown to be useful for other applications of viability PCR. For this purpose, two different amplicon sizes were compared when targeting either the genus of Bacteroidales or subgroups thereof specifically associated with human and ruminant fecal material. When applied to different environmental samples, the proposed proportion of intact cells could drop by up to 38% (for sewage treatment effluent from 64 to 26%) when targeting longer sequences. Furthermore co incubation of the viability dye with dimethylsulfoxide (DMSO) was found to be beneficial, although this observation is currently still empirical. When examining signal decay of artificially contaminated unfiltered river water over six weeks, the PMA treatment effect was observed from the beginning, but the ratio of intact and damaged cells remained constant over time with signals disappearing at the same rate independent of PMA treatment. In this instance the contribution of other factors to overall signal decay seemed more important than loss of membrane integrity. PMID- 28625706 TI - Utility of Acridine Orange staining for detection of bacteria from positive blood cultures. AB - The diagnostic performance of AO stain was evaluated for the detection of bacteria and or fungi from positive blood cultures. The sensitivity of Gram stain (GS) was 98.26% while Acridine Orange (AO) stain proved to be more sensitive (100%) with a Positive and Negative Predictive Value of 100% each. The specificity of both the stains was 100%. Overall agreement between the two stains was 98.23% (688/700). The organisms that were missed by GS and positive by AO were Candida species (Sutton, 2006) and Gram negative bacilli (GNB) (Sutton, 2006). Sensitivity of GS was 82.35% and AO was 100% among mixed cultures. Immediate reporting of the results of AO stain would have a significant impact on clinical management of patients with serious blood stream infections. PMID- 28625707 TI - [Algorithms based on medico-administrative data in the field of endocrine, nutritional and metabolic diseases, especially diabetes]. AB - BACKGROUND: Medico-administrative databases represent a very interesting source of information in the field of endocrine, nutritional and metabolic diseases. The objective of this article is to describe the early works of the Redsiam working group in this field. METHODS: Algorithms developed in France in the field of diabetes, the treatment of dyslipidemia, precocious puberty, and bariatric surgery based on the National Inter-schema Information System on Health Insurance (SNIIRAM) data were identified and described. RESULTS: Three algorithms for identifying people with diabetes are available in France. These algorithms are based either on full insurance coverage for diabetes or on claims of diabetes treatments, or on the combination of these two methods associated with hospitalizations related to diabetes. Each of these algorithms has a different purpose, and the choice should depend on the goal of the study. Algorithms for identifying people treated for dyslipidemia or precocious puberty or who underwent bariatric surgery are also available. CONCLUSION: Early work from the Redsiam working group in the field of endocrine, nutritional and metabolic diseases produced an inventory of existing algorithms in France, linked with their goals, together with a presentation of their limitations and advantages, providing useful information for the scientific community. This work will continue with discussions about algorithms on the incidence of diabetes in children, thyroidectomy for thyroid nodules, hypothyroidism, hypoparathyroidism, and amyloidosis. PMID- 28625708 TI - [Algorithms for the identification of hospital stays due to osteoporotic femoral neck fractures in European medical administrative databases using ICD-10 codes: A non-systematic review of the literature]. AB - BACKGROUND: Osteoporotic hip fractures (OHF) are associated with significant morbidity and mortality. The French medico-administrative database (SNIIRAM) offers an interesting opportunity to improve the management of OHF. However, the validity of studies conducted with this database relies heavily on the quality of the algorithm used to detect OHF. The aim of the REDSIAM network is to facilitate the use of the SNIIRAM database. The main objective of this study was to present and discuss several OHF-detection algorithms that could be used with this database. METHODS: A non-systematic literature search was performed. The Medline database was explored during the period January 2005-August 2016. Furthermore, a snowball search was then carried out from the articles included and field experts were contacted. The extraction was conducted using the chart developed by the REDSIAM network's "Methodology" task force. RESULTS: The ICD-10 codes used to detect OHF are mainly S72.0, S72.1, and S72.2. The performance of these algorithms is at best partially validated. Complementary use of medical and surgical procedure codes would affect their performance. Finally, few studies described how they dealt with fractures of non-osteoporotic origin, re hospitalization, and potential contralateral fracture cases. CONCLUSIONS: Authors in the literature encourage the use of ICD-10 codes S72.0 to S72.2 to develop algorithms for OHF detection. These are the codes most frequently used for OHF in France. Depending on the study objectives, other ICD10 codes and medical and surgical procedures could be usefully discussed for inclusion in the algorithm. Detection and management of duplicates and non-osteoporotic fractures should be considered in the process. Finally, when a study is based on such an algorithm, all these points should be precisely described in the publication. PMID- 28625709 TI - Review and analysis of physical exercise at hormonal and brain level, and its influence on appetite. AB - Due to the currently growing rate of obesity, it is important to maintain good control of food intake. The main purpose of the present study is to determine the influence of physical exercise on appetite, changes in hormone concentrations, and changes in certain neuronal regions. To achieve this, a literature search was conducted using different data bases. The results show how exercise produces changes in the appetite perception, in the amount of energy intake, and in different weight-control related hormones, as well as in specific neuronal responses. In conclusion, it can be shown that exercise leads to changes in appetite, hunger, and energy intake. In addition, exercise decreases the ghrelin levels and increases concentrations of leptin. Likewise, it is shown how physical exercise alters the responses of certain neuronal regions after visualizing specific food elements decreasing so the appetite or the intake of them. PMID- 28625710 TI - Effect of an individualised physical exercise program on lipid profile in sedentary patients with cardiovascular risk factors. AB - : Physical exercise has become in an important tool in the reduction of cardiovascular risk. OBJECTIVES: To evaluate the effectiveness of an unsupervised physical exercise program that on the physical condition and the lipid profile. METHOD: The final sample included 49 sedentary men and women, who were non smokers, with dyslipidaemia, overweight, and type1 obesity. The 4-month program included walking for 30-60minutes every day, and for three days a week, 30minutes of cycling at an intensity of 40-60% of maximum functional capacity, as well as isometric abdominals and static stretching. Anthropometrics, physical condition (6minute test), and the lipid profile were evaluated before and after the physical exercise program. The objective was to achieve a caloric expenditure between 1200-2000kcal/week. RESULTS: At the end of the program it was observed, in both sexes, that there was a decrease in total cholesterol (P<0.02), LDL cholesterol (P<0.01), VLDL cholesterol (P<0.01), and triglycerides (P<0.05), and an increase HDL cholesterol (P<0.05). There was also an increase in the distance travelled in the 6minute test of 52m in men and 39.5m in women (P<0.002), plus a decrease in the perception of fatigue on the Borg scale of 1.19 in men, and 0.96 in women (P<0.01). There were no anthropometric changes. CONCLUSIONS: The physical exercise improved physical condition and the lipid profile in the sample that has been studied, with 64% of participants continuing to do it. PMID- 28625711 TI - Why Parents Seek Care for Acute Illness in the Clinic or the ED: The Role of Health Literacy. AB - OBJECTIVE: To explore the decision to seek care and decision-making regarding location of care among parents with low and adequate health literacy. METHODS: Parents of children 8 years old or younger who presented for 'sick child' visits at a clinic or a nonurgent emergency department (ED) visit (triage level 5) were interviewed. The Newest Vital Sign was used to categorize parental health literacy. Interviewers followed a semistructured interview guide to understand: 1) care-seeking for current illness, and 2) choice of clinic or ED. Themes emerged using a grounded theory process, facilitated by NVivo version 10.0 software (QSR International, Melbourne, Australia). Themes included the experiences of low and adequate health literacy in the clinic as well as in the ED. RESULTS: Fifty semistructured interviews were completed with parents who brought their child to the ED for a nonurgent visit (n = 30) and clinic parents (n = 20) with 56% possessing low health literacy. Parents with low health literacy were more inclined to overestimate severity of illness and seek care sooner to gain answers about the illness and treatment options, and visit the clinic only when an appointment was available within hours. Parents with adequate health literacy sought reassurance for their ongoing illness management and valued close relationships with their physician, and were willing to wait longer for an appointment. Fever, vomiting, and young child age prompted some parents to seek expedient care regardless of health literacy. CONCLUSIONS: Caregiving skills (eg, assessing and treating illness, understanding illness severity, and navigating the health care system) in addition to physician-parent relationships and perception of care seem to influence the behavior of parents managing their child's mild acute illness. These factors might be amenable to a future health literacy intervention. PMID- 28625712 TI - How common is remission in juvenile idiopathic arthritis: A systematic review. AB - OBJECTIVES: The ideal goal of treatment for juvenile idiopathic arthritis (JIA) is disease remission. However, many sets of remission criteria have been developed and no systematic review of remission in JIA exists. The current systematic review investigated (1) how remission has been defined across JIA clinical cohorts and (2) the frequency of remission overall and within disease categories. METHODS: Studies using prospective inception cohorts published after 1972 were selected if they estimated remission in cohorts of >=50 patients. Articles focusing on specific medical interventions, not defining remission clearly or not reporting disease duration at remission assessment were excluded. Studies were selected from Medline, Embase, PubMed and bibliographies of selected articles. Risks of selection, missing outcome data and outcome reporting biases were assessed. RESULTS: Within 17 studies reviewed, 88% had majority female participants and patient disease duration ranged from 0.5 to 17 years. Thirteen sets of criteria for clinically inactive disease and remission were identified. Uptake of Wallace's preliminary criteria was good in studies recruiting or following patients after their publication (78%). Remission frequencies increased with longer disease duration from 7% within 1.5 years to 47% by 10 years following diagnosis. Patients with persistent oligoarticular and rheumatoid factor positive polyarticular JIA were most and least likely to achieve remission, respectively. CONCLUSIONS: Achievement of remission increased with longer disease duration, but many patients remain in active disease, even in contemporary cohorts. Multiple sets of outcome criteria limited comparability between studies. PMID- 28625714 TI - Proteomic analysis of seminal plasma from locally-adapted "Curraleiro Pe-Duro bulls" (Bos taurus): identifying biomarkers involved in sperm physiology in endangered animals for conservation of biodiversity. AB - The present study was aimed at evaluating the seminal plasma proteins and sperm parameters of Curraleiro Pe-Duro bulls. Semen was collected from 10 bulls by electroejaculation, and sperm parameters were evaluated in fresh and frozen thawed semen. Seminal plasma proteins were analyzed by 2-D SDS-PAGE and mass spectrophotometry. Tools in computational biology were used to generate bioinformatic knowledge and evaluate gene ontology, protein-protein interactions, phylogenetic trees and multiple sequence alignments. Sperm motility in fresh and frozen-thawed semen was 78.8+/-1.8% and 21.2+/-1.6%, respectively. Pearson's correlations were evaluated (p<0.05). Sperm motility and vigor in fresh semen were correlated with clusterin, TIMP2 and cathepsin S (r=0.64-0.71) and sperm defects were related to inhibitor of carbonic anhydrase and BSP 5 (r=0.78-0.80). Clusterin, BSP 5, alpha-enolase, creatine kinase M-type, glyceraldehyde-3 phosphate dehydrogenase, BSP 3, albumin, and 5'-nucleotidase and legumain were correlated with acrosome intact live sperm (r=0.80-0.64). Associations were detected between sperm vigor and spermadhesin 1 (r=-0.89), and between sperm defects in fresh semen and spermadhesin 1 and clusterin (r=-0.81). Sperm motility in frozen-thawed semen was associated with BSP 1, spermadhesin 1, clusterin and spermadhesin Z13 (r=0.64-0.85). The percent of motile sperm after freeze-thawing was negatively correlated (r=-0.64) with the amount of spermadhesin 1 in the seminal plasma. Based on in silico analysis, TIMP2 interacted with BSP1, BSP3, BSP5 and metalloproteinases. Molecular functions of proteins associated with sperm parameters were binding, catalytic activity and enzymatic regulation. Amino acid sequences of spermadhesin 1 and BSP 1 from Bos taurus, and other domestic species were similar. Phylogenetic tree analysis demonstrated that clusterin from Bos taurus was related to Ovis aries and domains of clusterin, spermadhesin 1, BSP 1 and inhibitor of carbonic anhydrase were conserved as well. In summary, specific seminal proteins are associated with sperm parameters of locally-adapted bulls. Use of the endangered mammalian as a model may assist in understanding aspects of evolutionary adaptations and could improve assisted reproductive biotechnologies. PMID- 28625713 TI - Individual- and Area-Level SES in Diabetes Risk Prediction: The Multi-Ethnic Study of Atherosclerosis. AB - INTRODUCTION: The purpose of this study was to evaluate if adding SES to risk prediction models based upon traditional risk factors improves the prediction of diabetes. METHODS: Risk prediction models without and with individual- and area level SES predictors were compared using the prospective Multi-Ethnic Study of Atherosclerosis. Cox proportional hazards models were utilized to estimate hazard ratios for SES predictors and to generate 10-year predicted risks for 5,021 individuals without diabetes at baseline followed from 2000 to 2012. C-statistics were used to compare model discrimination, and the proportion of individuals reclassified into higher or lower risk categories with the addition of SES predictors was calculated. The accuracy of risk prediction by SES was assessed by comparing observed and predicted risks across tertiles of the SES variables. Statistical analyses were performed in 2015-2016. RESULTS: Over a median of 9.2 years of follow-up, 615 individuals developed diabetes. Individual- and area level SES variables did not significantly improve model discrimination or reclassify substantial numbers of individuals across risk categories. Models without SES predictors generally underestimated risk for low-SES individuals or individuals residing in low-SES areas (underestimates ranging from 0.31% to 1.07%) and overestimated risk for high-SES individuals or individuals residing in high-SES areas (overestimates ranging from 0.70% to 1.30%), and the addition of SES variables largely mitigated these differences. CONCLUSIONS: Standard diabetes risk models may underestimate risk for low-SES individuals and overestimate risk for those of high SES. Adding SES predictors helps correct this systematic misestimation, but may not improve model discrimination. PMID- 28625715 TI - Discovery of simplified leucyladenylate sulfamates as novel leucyl-tRNA synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1) inhibitors. AB - Leucyl-tRNA synthetase (LRS) has been reported to be a possible mediator of intracellular amino acids signaling to mTORC1. Given that mTORC1 is associated with cell proliferation and tumorigenesis, the LRS-mediated mTORC1 pathway may offer an alternative strategy in anticancer therapy. In this study, we developed a series of simplified analogues of leucyladenylate sulfamate (1) as LRS-targeted mTORC1 inhibitors. We replaced the adenylate group with a N-(3,4 dimethoxybenzyl)benzenesulfonamide (2a) or a N-(2-phenoxyethyl)benzenesulfonamide groups (2b) that can maintain specific binding, but has more favorable physicochemical properties such as reduced polarity and asymmetric centers. Among these simplified analogues, compound 16 and its constrained analogue 22 effectively inhibited S6K phosphorylation in a dose-dependent manner and exhibited cancer cell specific cytotoxicity against six different types of cancer cells. This result supports that LRS is a viable target for novel anticancer therapy. PMID- 28625716 TI - Application of in-vitro screening methods on hypoxia inducible factor prolyl hydroxylase inhibitors. AB - Anemia resulting from the reduced expression of erythropoietin (EPO) is a common complication of patients with chronic kidney diseases (CKD). Hypoxia inducible transcription factor-alpha (HIF-alpha), which adapts cellular hypoxia condition, regulates the expression of many downstream genes including the EPO gene. Hypoxia inducible transcription factor prolyl hydroxylase 2 (HIF-PHD2), as the key regulator of hypoxia response, is function of hydroxylating specify proline residues of HIF-alpha, which may lead to the degradation of HIF-alpha and eventually cause disenabling the expression of erythropoietin. Therefore, it is valid to improve anemia by inhibiting HIF-PHD2. In-vitro screening plays a vital role in searching for novel small molecule HIF-PHD2 inhibitors, thus, this review classified in-vitro screening methods which are used to hit novel HIF-PHD2 inhibitors. PMID- 28625717 TI - Clinical impact of non-antibiotic recommendations by a multi-disciplinary antimicrobial stewardship team. AB - INTRODUCTION: The multi-disciplinary antimicrobial stewardship team at the study hospital conducts prospective review and feedback on all inpatient orders of piperacillin-tazobactam and carbapenems. In addition, the team provides non antibiotic recommendations (i.e. additional investigations and infectious disease reviews). This study aimed to describe the impact of these recommendations on patient outcomes. METHODS: Patients on carbapenem and piperacillin-tazobactam who received at least one non-antibiotic recommendation between January 2012 and August 2014 were included in this study. Acceptance and rejection of non antibiotic recommendations by the managing physician were compared. The primary outcome was 30-d mortality. RESULTS: Non-antibiotic recommendations were made in 166 patients. There were no differences in baseline characteristics between patients for whom recommendations were accepted and patients for whom recommendations were rejected. Thirty-day mortality (18.0% vs. 34.5%, P = 0.02) was significantly lower in patients who had at least one non-antibiotic recommendation accepted. Multi-variate analysis found that Charlson's comorbidity score [odds ratio (OR) 1.20, 95% confidence interval (CI) 1.03-1.42, P = 0.03], APACHE II score (OR 1.10, 95% CI 1.01-1.19, P < 0.01), hepatobiliary source of infection (OR 10.19, 95% CI 1.44-72.13, P = 0.02) and acceptance of at least one non-antibiotic recommendation (OR 0.39, 95% CI 0.17-0.88, P = 0.02) were independently associated with 30-d mortality. CONCLUSIONS: During prospective review and feedback of piperacillin-tazobactam and carbapenems, acceptance of non antibiotic recommendations was found to be associated with a reduction in 30-d mortality. PMID- 28625718 TI - Synaptic functions of endocannabinoid signaling in health and disease. AB - Endocannabinoids (eCBs) are a family of lipid molecules that act as key regulators of synaptic transmission and plasticity. They are synthetized "on demand" following physiological and/or pathological stimuli. Once released from postsynaptic neurons, eCBs typically act as retrograde messengers to activate presynaptic type 1 cannabinoid receptors (CB1) and induce short- or long-term depression of neurotransmitter release. Besides this canonical mechanism of action, recent findings have revealed a number of less conventional mechanisms by which eCBs regulate neural activity and synaptic function, suggesting that eCB mediated plasticity is mechanistically more diverse than anticipated. These mechanisms include non-retrograde signaling, signaling via astrocytes, participation in long-term potentiation, and the involvement of mitochondrial CB1. Focusing on paradigmatic brain areas, such as hippocampus, striatum, and neocortex, we review typical and novel signaling mechanisms, and discuss the functional implications in normal brain function and brain diseases. In summary, eCB signaling may lead to different forms of synaptic plasticity through activation of a plethora of mechanisms, which provide further complexity to the functional consequences of eCB signaling. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". PMID- 28625719 TI - Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons. AB - Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed "atypical DAT inhibitors" has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders. PMID- 28625721 TI - Kiloniella majae sp. nov., isolated from spider crab (Maja brachydactyla) and pullet carpet shell clam (Venerupis pullastra). AB - Ten Gram-negative, rod-shaped and motile bacterial strains were isolated from spider crab (M27.10, M27.11a, F36.1, F36.4, M56.1, F76.17b, M146.1, M166.3 and M166.6) and pullet carpet shell clam (SBRF 1.10) collected in the coast of Galicia. Analyses of the 16S rRNA genes showed that the strains belong to the genus Kiloniella and have high similarity with the species Kiloniella spongiae (99.44-99.86%) and Kiloniella litopenaei (99.0-99.5%). Strains M56.1T (=CECT 9195, =LMG 29925), M146.1 (=CECT 9193, =LMG 29926) and SBRF 1.10 (=CECT 9194, =LMG 29927) were selected on the basis of genotyping by enterobacterial repetitive intergenic consensus PCR (ERIC-PCR). Phylogenetic analysis based on concatenated sequences of the genes gyrB, ftsZ, rpoD and mreB showed that the isolates form a differentiated branch within the genus Kiloniella. Moreover, the average nucleotide identity (ANIm, ANIb and OrthoANI) and in silico estimated DNA DNA reassociation values between selected Galician isolates and Kiloniella species were below the established cut-off for species deliniation. The results obtained in the genetic and phenotypical analyses indicate that the isolates represent a new species of the genus Kiloniella, for which the name Kiloniella majae sp. nov. is proposed with strain M56.1T (=CECT 9195T, =LMG 29925T) as the type strain. PMID- 28625722 TI - The Number of Ports in Lung Resection Surgery: A Pointless Debate. PMID- 28625723 TI - GOLD 2017: The Spanish Perspective. PMID- 28625720 TI - The cannabinoid system and pain. AB - Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1receptors); 2. The EC System and stress induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". PMID- 28625724 TI - The Binary System of Ibuprofen-Nicotinamide Under Nanoscale Confinement: From Cocrystal to Coamorphous State. AB - Coamorphous systems have gained success in stabilizing amorphous drugs and improving their solubility and dissolution. Here we proposed to confine a binary mixture of drug and coformer (CF) within nanopores to obtain a nanoconfined coamorphous (NCA) system. For proving feasibility of this proposal, a poorly water-soluble drug (ibuprofen) and a frequently used pharmaceutical CF (nicotinamide) were loaded into nanopores of mesoporous silica microspheres. The solid state of NCA system was characterized by differential scanning calorimetry, X-ray powder diffraction, infrared spectrum, and solid-state nuclear magnetic resonance. With large numbers of nanopores, mesoporous silica microspheres appear to be a feasible carrier to transform a cocrystal system into coamorphism by nanoscale confinement. Benefiting from both nanoscale confinement and CF, the NCA system of ibuprofen achieved synchronic increase in dissolution properties and physical stability. Consequently, the NCA strategy is effective in achieving coamorphous state and offers a promising alternative for formulating poorly water soluble drugs. PMID- 28625725 TI - Closing the Gap: Counting and Sizing of Particles Across Submicron Range by Flow Cytometry in Therapeutic Protein Products. AB - Quantification and size distribution characterization of subvisible particles in parenteral biopharmaceutics, present as both proteinaceous and nonproteinaceous particles in the size range from 0.1 to 100 MUm, are important for biopharmaceutical industry due to their potential safety and efficacy implications. Although a number of analytical techniques are available to count and size subvisible particles, characterization of particles <=2 MUm remains a significant challenge due to technical limitations of existing particle counting instruments. In this article, we demonstrate the ability of an optimized flow cytometry system to detect and quantify size distribution of subvisible particles without additional labeling that includes the critical submicron range in biopharmaceutical formulations. In addition, these qualitative and quantitative determinations are performed in a high-throughput manner using sample volumes that allow statistically significant evaluations. This approach can be used not only to ascertain the quality of therapeutic protein products but also to evaluate numerous conditions during the screening of drug candidates and their prospective formulations. PMID- 28625726 TI - Pulmonary Administration of Soluble Antigen Arrays Is Superior to Antigen in Treatment of Experimental Autoimmune Encephalomyelitis. AB - Antigen-specific immunotherapy has been used to hyposensitize patients to allergens and offers an enticing approach for attenuating autoimmune diseases. Applying antigen-specific immunotherapy to mucosal surfaces such as the lungs may engage unique immune response pathways to improve efficacy. Pulmonary delivery of soluble antigen arrays (SAgAs) was explored in mice with experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. SAgAs were designed to impede immune response to autoantigen epitopes and are composed of a hyaluronan backbone with peptides PLP139-151 (proteolipid protein) and LABL, a disease causing proteolipid peptide epitope and an intracellular cell-adhesion molecule-1 ligand, respectively. Pulmonary instillation of SAgAs decreased disease score, improved weight gain, and decreased incidence of disease in EAE mice compared to pulmonary delivery of hyaluronic acid polymer, LABL, or PLP. Interestingly, treating with PLP alone also showed some improvement. Splenocytes from SAgA treated animals showed increased interferon-gamma levels, and interleukin-6 (IL 6) and IL-17 were elevated in SAgA-treated animals compared to PLP treatments. IL 10, IL-2, and tumor necrosis factor-alpha levels showed no significant difference, yet trends across all cytokines suggested SAgAs induced a very different immune response compared to treatment with PLP alone. This work suggests that codelivery of peptide components is essential when treating EAE via pulmonary instillation, and the immune response may have shifted toward immune tolerance. PMID- 28625727 TI - Incomplete Loading of Sodium Lauryl Sulfate and Fasted State Simulated Intestinal Fluid Micelles Within the Diffusion Layers of Dispersed Drug Particles During Dissolution. AB - Poorly water soluble drug candidates have been common in developmental pipelines over the last several decades. This has fueled considerable research around understanding how bile salt and model micelles can improve drug particle dissolution rates and human drug exposure levels. However, in the pharmaceutical context only a single mechanism of how micelles load solute has been assumed, that being the direct loading mechanism put forth by Cussler and coworkers (Am Inst Chem Eng J. 1976;22(6):1006-1012) 40 years ago. In this model, micelles load at the particle surface and will be loaded to their equilibrium loading values. More recently, Kumar and Gandhi and coworkers (Langmuir. 2003;19:4014-4026) developed a comprehensive theory of micelle solubilization which also features an indirect loading mechanism which they argue should operate in ionic surfactant systems. In this mechanism, micelles cannot directly load at the solute particle surface and thus may not reach equilibrium loading values within the particle diffusion layer. In this work, we endeavor to understand if the indirect micelle loading mechanism represents a plausible description in the pharmaceutical context. The overall data in SLS and FaSSIF systems obtained here, as well as several other previously published datasets, can be described by the indirect micelle loading mechanism. Implications for pharmaceutical development of poorly soluble compounds are discussed. PMID- 28625728 TI - Treatment of persistent ventricular tachycardia: Drugs or ablation? AB - Implantable cardioverter defibrillators (ICDs) reduce the mortality risk associated with recurrent ventricular tachycardia (VT) and can frequently terminate VT episodes painlessly, but do not prevent recurrent episodes. For patients with symptomatic recurrences, frequent asymptomatic recurrences, ICD shocks, or VT storm, most clinicians recommend strategies to suppress VT. The proarrhythmic mortality risk of antiarrhythmic drugs (AADs) may be mitigated by the presence of an ICD, but these medications are limited by high recurrence rates, and unfavorable side effect profiles. Catheter ablation is an alternative or adjunctive option, but is also limited by incomplete efficacy and procedural risk. PMID- 28625729 TI - Vaccinols J-S, ten new salicyloid derivatives from the marine mangrove-derived endophytic fungus Pestalotiopsis vaccinii. AB - Ten new salicyloid derivatives, namely vaccinols J-S (1-10), along with five known compounds (11-15) were isolated from Pestalotiopsis vaccinii (cgmcc3.9199) endogenous with the mangrove plant Kandelia candel (L.) Druce (Rhizophoraceae). Their structures including absolute configurations were established on the basis of spectroscopic analysis, optical rotation, CD spectra, quantum ECD calculations. To the best of our knowledge, vaccinol J (1) is the first example of salicyloid derivatives containing 2-methylfuran moiety. All of the new compounds were tested for their anti-enterovirus 7l (EV71) and cytotoxic activities. Among them, vaccinol J (1) exhibited in vitro anti-EV71 with IC50 value of 30.7MUM (IC50 177.0MUM for the positive control ribavirin). PMID- 28625730 TI - Terpenoids from Curcuma wenyujin increased glucose consumption on HepG2 cells. AB - Thirty four terpenoids, including two new cadinane-type sesquiterpenoids containing conjugated aromatic-ketone moieties, curcujinone A (1) and curcujinone B (2), were isolated from 95% ethanol extract of the root tubers of Curcuma wenyujin. Their structures were determined by spectroscopic methods, especially 2D NMR and HRMS techniques. The relative and absolute configurations of 1 and 2 were identified by quantum chemical DFT and TDDFT calculations of the 13C NMR chemical shifts, ECD spectra, and specific optical rotations. All compounds and extracts were evaluated for their anti-diabetic activities with a glucose consumption model on HepG2 Cells. The petroleum fraction CWP (10MUg/mL) and compounds curcumenol (4), 7alpha,11alpha-epoxy-5beta-hydroxy-9-guaiaen-8-one (5), curdione (17), (1S, 4S, 5S 10S)-germacrone (18), zederone (20), a mixture of curcumanolide A (25) and curcumanolide B (26), gajutsulactone B (27), and wenyujinin C (30) showed promising activities with over 45% increasing of glucose consumption at 10MUM. PMID- 28625731 TI - Antibacterial neolignans from the leaves of Melaleuca bracteata. AB - Phytochemical study on the leaves of Melaleuca bracteata resulted in the isolation of ten compounds including three new neolignans, named melaleucins A-C (1-3). Among them, melaleucin B shares a rarely occurring nor-neolignan skeleton, and both melaleucins B and C bear a novel aldehyde moiety, which might also be response for the delicate fragrance of M. bracteata. Their structures were extensively assigned by spectral data interpretation and biomimetic total synthesis. Moreover, their biosynthetic pathway with oxidative radical coupling and Michael addition as critical reactions was also confirmed. The antimicrobial activity evaluation revealed that melaleucin A exhibited considerable antimicrobial activity towards methicillin-resistant Staphylococcus aureus. PMID- 28625732 TI - New cucurbitane triterpenoids with cytotoxic activities from Hemsleya penxianensis. AB - Seven new cucurbitane triterpenoids, Pengxianencins A-G (1-7) including one alkaloid, were isolated from the ethanol extract of the tubers of Hemsleya penxianensis. Their structures were elucidated on the basis of extensive spectroscopic data, including 1D and 2D NMR spectra as well as HR-ESI-MS. The evaluation of inhibition activity against human Hela, MCF-7, and A-549 cell lines showed that compounds 1, 4, 6, 7 have different levels of cytotoxic activities, with IC50 values ranging from 1.67 to 45.28MUM. PMID- 28625733 TI - New grape stems' isolated phenolic compounds modulate reactive oxygen species, glutathione, and lipid peroxidation in vitro: Combined formulations with vitamins C and E. AB - The antioxidant potential of grape (Vitis vinifera L.) stems has been reported in the last decade although no identification of the individual compounds responsible for such action has been done. In this work, polyphenolic extract of grape stems was processed resorting to semi-preparative HPLC, allowing to obtain 5 purified polyphenols (caftaric acid, malvidin-3-O-glucoside, quercetin-3-O glucuronide, mailvidin-3-O-(6-O-caffeoyl)-glucoside, and Sigma-viniferin), which were fully characterized by HPLC-PDA-ESI-MSn. Isolated compounds were featured on their radical scavenging capacity (DPPH and ABTS), cell viability, anti inflammatory activity, and capacity to modulate the level of reactive oxygen species, glutathione, lipid peroxidation, and overall oxidative stress in a biological model (human keratinocytes) in vitro, under basal and oxidative conditions. The results obtained noticed the combinations malvidin-3-O glucoside+Vitamin E and quercetin-3-O-glucuronide+vitamin C as the most effective, allowing to improve the capacity of complete extracts or individual compounds, and being candidates to be used in the development of new functional products. PMID- 28625734 TI - Synthesis and cardiomyocyte protection activity of crocetin diamide derivatives. AB - A series of novel diamide derivatives (2-8) of crocetin (1) were synthesized and evaluated for their cardioprotective activity in vitro. Using well-established model of hypoxia-induced injury in H9c2 cells, we investigated the effects of 9 compounds and positive drug nicorandil on cellular cytotoxicity by MTT assay, mitochondrial viable staining, LDH activity and mitochondrial membrane potential (MMP). Among the new derivatives, compounds 3 and 4 with good liposolubility showed significantly potent activity than crocetin (1) against hypoxia-induced cytotoxicity. Further mechanisms studies indicated that the cardioprotective effect of compounds 3 and 4 was due to these abilities by decreasing LDH release, preserving mitochondrial viabilities and reducing oxidative stress-induced depolarization of MMP. Our results demonstrated that compounds 3 and 4 as a new class of crocetin diamide derivatives could be developed as potential agents in our further drug development studies for ischemic heart disease. PMID- 28625735 TI - Analgesic and physiological effect of electroacupuncture combined with epidural lidocaine in goats. AB - OBJECTIVE: To investigate physiological and antinociceptive effects of electroacupuncture (EA) with lidocaine epidural nerve block in goats. STUDY DESIGN: Prospective experimental trial. ANIMALS: Forty-eight hybrid male goats weighing 27 +/- 2 kg. METHODS: The goats were randomly assigned to six groups: L2.2, epidural lidocaine (2.2 mg kg-1); L4.4, epidural lidocaine (4.4 mg kg-1); EA; EA-L1.1, EA with epidural lidocaine (1.1 mg kg-1); EA-L2.2, EA with epidural lidocaine (2.2 mg kg-1); and EA-L4.4, EA with epidural lidocaine (4.4 mg kg-1). EA was administered for 120 minutes. Epidural lidocaine was administered 25 minutes after EA started. Nociceptive thresholds of flank and thigh regions, abdominal muscle tone, mean arterial pressure (MAP), heart rate (HR), respiratory frequency (fR) and rectal temperature were recorded at 30, 60, 90, 120, 150 and 180 minutes. RESULTS: Lidocaine dose-dependently increased nociceptive thresholds. There were no differences in nociceptive thresholds between L4.4 and EA from 30 to 120 minutes. The threshold in EA-L2.2 was lower than in EA-L4.4 from 30 to 120 minutes, but higher than in EA-L1.1 from 30 to 150 minutes or in L4.4 from 30 to 180 minutes. The abdominal muscle tone in EA-L2.2 was higher at 30 minutes, but lower at 90 and 120 minutes than at 0 minutes. There were no differences in muscle tone between L4.4 and L2.2 or EA-L4.4, and between any two of the three EA-lidocaine groups from 0 to 180 minutes. The fR and HR decreased in L4.4 at 60 and 90 minutes compared with 0 minutes. No differences in fR, HR, MAP and temperature among the groups occurred from 30 to 180 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: EA combined with 2.2 mg kg-1 epidural lidocaine provides better antinociceptive effect than 4.4 mg kg-1 epidural lidocaine alone in goats. EA provided antinociception and allowed a decrease in epidural lidocaine dose. PMID- 28625736 TI - Use of bioconjugation with cytochrome P450 enzymes. AB - Bioconjugation, defined as chemical modification of biomolecules, is widely employed in biological and biophysical studies. It can expand functional diversity and enable applications ranging from biocatalysis, biosensing and even therapy. This review summarizes how chemical modifications of cytochrome P450 enzymes (P450s or CYPs) have contributed to improving our understanding of these enzymes. Genetic modifications of P450s have also proven very useful but are not covered in this review. Bioconjugation has served to gain structural information and investigate the mechanism of P450s via photoaffinity labeling, mechanism based inhibition (MBI) and fluorescence studies. P450 surface acetylation and protein cross-linking have contributed to the investigation of protein complexes formation involving P450 and its redox partner or other P450 enzymes. Finally, covalent immobilization on polymer surfaces or electrodes has benefited the areas of biocatalysis and biosensor design. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. PMID- 28625737 TI - Insights into the conformations and dynamics of intrinsically disordered proteins using single-molecule fluorescence. AB - Most proteins are not static structures, but many of them are found in a dynamic state, exchanging conformations on various time scales as a key aspect of their biological function. An entire spectrum of structural disorder exists in proteins and obtaining a satisfactory quantitative description of these states remains a challenge. Single-molecule fluorescence spectroscopy techniques are uniquely suited for this task, by measuring conformations without ensemble averaging and kinetics without interference from asynchronous processes. In this paper we review some of the recent successes in applying single-molecule fluorescence to different disordered protein systems, including interactions with their cellular targets and self-aggregation processes. We also discuss the implementation of computational methods and polymer physics models that are essential for inferring global dimension parameters for these proteins from smFRET data. Regarding future directions; 3- or 4-color FRET methods can provide multiple distances within a disordered ensemble simultaneously. In addition, integrating complementary experimental data from smFRET, NMR and SAXS will provide meaningful constraints for molecular simulations and will lead to more accurate structural representations of disordered proteins. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28625739 TI - Changes in the fine root proteome of Fagus sylvatica L. trees associated with P deficiency and amelioration of P-deficiency. AB - : Phosphorus is often the least available macronutrient in soil. Lack in phosphorus has detrimental effect on growth and biomass production of European Fagus sylvatica L., a major trees species in temperate forests. In contrast to leaf tissues, few studies have examined changes in the root system and no study has ever investigated the proteomic changes affected in beech roots by a lack in available phosphate (P). Here, we studied roots of young Fagus sylvatica L. trees in their native soils from two forests sites with contrasting availability of P: one P rich and P poor soil. To understand also the response to P fertilization, the trees were fertilized with triple superphosphate and the proteome of fine roots of all conditions was compared. Gel-free mass-spectrometry-based shotgun proteomics revealed that the proteome was differentially affected by diverging P availabilities. The proteomic changes that took place as the result of P fertilization were dependent on the supply level of P before the fertilization. When P was supplied to the P-rich soil proteins related to cell biogenesis exhibited increased abundances. Addition of P to soil that was strongly limited in P resulted in increased abundance of proteins associated with amino acid metabolism and transport. BIOLOGICAL SIGNIFICANCE: Beech (Fagus sylvatica L.) forests have a huge ecological and economic value across Europe. In recent years, however, these forest sites increasingly suffer under phosphorus (P) deficiency. As the consequence, growth and vitality of beech forests is impaired. For this reason, this study was conducted with the aim to identify and understand proteomic impairments and adjustments that evolve in the fine roots under both, a P deficiency and an amelioration thereof. For this, we analyzed (1) the fine root proteome of young beech trees grown (2) at two soil sites that contrast in their degree of availability P (low vs. high) in dependency (3) to a fertilization with P. This experiment revealed fundamental differences with respect to proteomic changes in dependency on the severity of P limitation and helped to identify processes that take place after amelioration of the deficiency. This information is useful to understand which physiological processes are impaired under P deficiency and, thus, impair growth. The fertilization experiment enabled to identify developmental processes that take place in fine roots when concentration of available P was increased. They are "cellular component organization and biogenesis" in the P rich soil and "synthesis of organonitrogen-containing compounds" in the P poor soil. PMID- 28625738 TI - Mechanisms of Paradoxical Activation of AMPK by the Kinase Inhibitors SU6656 and Sorafenib. AB - SU6656, a Src kinase inhibitor, was reported to increase fat oxidation and reduce body weight in mice, with proposed mechanisms involving AMP-activated protein kinase (AMPK) activation via inhibition of phosphorylation of either LKB1 or AMPK by the Src kinase, Fyn. However, we report that AMPK activation by SU6656 is independent of Src kinases or tyrosine phosphorylation of LKB1 or AMPK and is not due to decreased cellular energy status or binding at the ADaM site on AMPK. SU6656 is a potent AMPK inhibitor, yet binding at the catalytic site paradoxically promotes phosphorylation of Thr172 by LKB1. This would enhance phosphorylation of downstream targets provided the lifetime of Thr172 phosphorylation was sufficient to allow dissociation of the inhibitor and subsequent catalysis prior to its dephosphorylation. By contrast, sorafenib, a kinase inhibitor in clinical use, activates AMPK indirectly by inhibiting mitochondrial metabolism and increasing cellular AMP:ADP and/or ADP:ATP ratios. PMID- 28625740 TI - Comparative proteomic analysis of two transgenic low-gliadin wheat lines and non transgenic wheat control. AB - : Gluten proteins are major determinants of the bread making quality of wheat, but also of important wheat-related disorders, including coeliac disease (CD), and allergies. We carried out a proteomic study using the total grain proteins from two low-gliadin wheat lines, obtained by RNAi, and the untransformed wild type as reference. The impact of silencing on both target and on non-target proteins was evaluated. Because of the great protein complexity, we performed separate analyses of four kernel protein fractions: gliadins and glutenin subunits, and metabolic and CM-like proteins, by using a classical 2D electrophoresis gel based approach followed by RP-HPLC/nESI-MS/MS. As a result of the strong down-regulation of gliadins, the HMW-GS, metabolic and chloroform/methanol soluble proteins were over-accumulated in the transgenic lines, especially in the line D793, which showed the highest silencing of gliadins. Basing on these data, and considering that metabolic proteins and chloroform/methanol soluble proteins (CM-like), such as the alpha-amylase/trypsin inhibitor family, beta-amylase and serpins, were related to wheat allergens, further in vivo analysis will be needed, especially those related to clinical trials in controlled patients, to determine if these lines could be used for food preparation for celiac or other gluten intolerant groups. BIOLOGICAL SIGNIFICANCE: Several enteropathies and allergies are related to wheat proteins. Biotechnological techniques such as genetic transformation and RNA interference have allowed the silencing of gliadin genes, providing lines with very low gliadin content in the grains. We report a proteomic-based approach to characterize two low-gliadin transgenic wheat lines obtained by RNAi technology. These lines harbor the same silencing fragment, but driven by two different endosperm specific promoters (gamma-gliadin and D-hordein). The comprehensive proteome analysis of these transgenic lines, by combining two-dimensional electrophoresis and RP-HPLC/nESI-MS/MS, provided a large number of spots differentially expressed between the control and the transgenic lines. Hence, the results of this study will facilitate further safety evaluation of these transgenic lines. PMID- 28625741 TI - The effect of transcranial direct current stimulation on auditory hallucination in patients with schizophrenia. PMID- 28625742 TI - The gender gap in schizophrenia research. PMID- 28625743 TI - Time consumption in mind-reading: A potentially important factor for social cognition assessment in early psychosis. PMID- 28625744 TI - The anterior sagittal transrectal approach (ASTRA) for cases associated with rectal implantation of the urethra: A retrospective review of six cases. AB - INTRODUCTION: Severe genital abnormalities such as urogenital sinus and urethral duplication with ectopic urethra in the rectum represent a major challenge in reconstructive urology. OBJECTIVE: We aimed to review our cases presenting with functional ectopic urethra implanted in the rectum that were treated through an ASTRA approach. METHODS: We reviewed the medical records of all patients who had undergone an ASTRA approach from 2005-2016. We collected data with interest to primary diagnosis, clinical presentation, additional procedure, immediate clinical outcome, complications, bowel habits after surgery, voiding and bladder emptying pattern and long term follow-up. RESULTS: Since 2005, we treated 6 cases using this method, consisting of 3 patients with congenital aphallia and 3 with Y type urethral duplication. Two aphallia patients underwent De Castro's neophalloplasty with simultaneous anastomosis of proximal urethra to a tubed buccal mucosa neourethra and one had a neophalloplasty with transverse skin flaps and primary perineal urethrostomy. Two patients with Y-type urethral duplication had a complete urethroplasty performed (one end-to-end anastomosis and a two stage repair). Last patient had a definitive perineal urethrostomy. At mean follow-up of 83.5 meses, only one patient voids through the urethra, four have a Mitrofanoff channel and two have a perineal urethrostomy. Immediate follow-up was uneventful and none of our patients had any bowel complications nor fecal incontinence. DISCUSSION: Domini et al. were the first proponents of the anterior sagittal transanorectal approach (ASTRA) as an alternative to classic Pena approach. Later, De Castro popularized specifically this technique as a relevant part of his neophalloplasty procedure to treat congenital aphallia. We did not find in this series any complications related to ASTRA technique in regards to bowel habits, fecal incontinence or infection but most of cases we tried to create a new anterior urethra and connect to the proximal stump failed. Moreover, we are skeptic to support simultaneous urethral repair when there is a dysplastic bulbar segment between the proximal stump and the end of the penile urethra normally at penoscrotal junction area by urethral duplication. Treatment at two stages is also prone to fail in the midterm. At end, most of them will have either a Mitrofanoff or perineal urethral stoma as shown in our data. CONCLUSION: The ASTRA approach proved to be useful for cases of rectal implantation of the urethra. No complications related to anterior sphincter incision were documented. We believe it should be regarded as the treatment of choice for cases alike ours. PMID- 28625745 TI - Lifelong dietary intervention does not affect hematopoietic stem cell function. AB - Hematopoietic stem cells (HSCs) undergo a profound functional decline during normal aging. Because caloric or dietary restriction has been shown to delay multiple aspects of the aging process in many species, we explored the consequences of lifelong caloric restriction, or conversely, lifelong excess caloric intake, on HSC numbers and function. Although caloric restriction prevented age-dependent increases in bone marrow cellularity, caloric restriction was not able to prevent functional decline of aged, long-term HSC functioning. A lifelong high-fat diet also did not affect HSC function. We conclude that lifelong caloric interventions fail to prevent or induce loss of age-associated HSC functioning. PMID- 28625746 TI - The fragmentation mechanism and immune-protective effect of CfTEP in the scallop Chlamys farreri. AB - Thioester-containing proteins (TEPs), characterized by a unique intrachain beta cysteinyl-gamma-glutamyl thioester bond, form an ancient and diverse family of secreted proteins that play central roles in the innate immune response. But the existence form and immune protection mechanism of TEP in invertebrates still remain unclear, especially in the mollusks. The fragmentation and the immune protective effect of thioester bond in CfTEP, a previously identified thioester containing protein in scallop Chlamys farreri, were characterized in the present study. During the early embryonic development of scallop, the mRNA transcript of CfTEP could be detected in all the stages, and its expression levels in D-larvae, veliger larvae and eye-spot larvae were significantly higher than that in eggs. The CfTEP protein was also detected in peripheral of D-larvae, veliger larvae and eye-spot larva by immunofluorescence. In the adult scallop, the CfTEP protein was mainly distributed in the hepatopancreas, gill, kidney, gonad, and mantle. The expression of CfTEP mRNA in the hemocytes of adult scallop was significantly up regulated when the scallops were stimulated by LPS, PGN or beta-glucan. Two bands (100 and 55 kDa) were detected using anti-CfTEP-R1 (spanned the C-terminal portion of the thioester, A2M-comp and A2M-recep domain, 942-1472), and a single band (46 kDa) was detected by using anti-CfTEP-R2 (the N-terminal portion of the following A2M-N-2 domain, 452-496) in the serum of scallop at 12 h after LPS stimulation. When the thioester bond of CfTEP protein was inactivated by injecting methylamine, the survival rate of scallop was significantly decreased after challenged by Vibrio angulillarum. All these results suggested that CfTEP protein existed as fragments similar to vertebrate C3, and played central roles in the immune response against pathogen in the innate immunity of scallops. PMID- 28625747 TI - Molecular identification and characterization of haptoglobin in teleosts revealed an important role on fish viral infections. AB - Haptoglobin (Hp) molecule has been cloned and characterized in two marine teleosts (gilthead seabream and European sea bass), obtaining putative proteins of 319 residues encoded by an ORF of 960 bp in both species. However, the matrix of similarity revealed low identities among bony fish species 78.9% (seabream-sea bass), 43% (seabream/seabass-zebrafish) and lower than 20% with sharks and human. The protein sequences showed a signal peptide from the position 1 to 23, a trypsin domain from 47 to 297, and several predicted disulfide bridges and glycosylation sites. The expression of hp transcript levels during ontogeny showed a progressive increase of expression in seabream whilst remained almost unaltered in sea bass. By tissues, this gene was found constitutively expressed with the highest levels on liver in both species. The main results on hp transcript levels showed the up-regulation in gilthead seabream suffering from naturally occurring lymphocystis disease; and the down-regulation and up regulation after nodavirus infection in the resistant gilthead seabream and the susceptible European sea bass, respectively. These findings demonstrate for the first time an important role of haptoglobin against viral infections, operating differently in two of the most important marine farmed fish species. PMID- 28625748 TI - Comparison of liposomal drug formulations for transdermal iontophoretic drug delivery. AB - This study was aimed to evaluate the in vitro transdermal direct/pulsed current iontophoretic delivery of an amphiphilic model compound from various lipid vesicle-encapsulated formulations compared to free-drug formulation. Conventional, pegylated, ultradeformable liposomes (transfersomes) and ethosomes loaded with a negatively charged drug diclofenac sodium (DS) were prepared and characterized. All the liposomes possessed an average size of ~100-150nm and negative zeta potential. No changes in colloidal stability were detected after 8h incubation of any vesicle formulation under constant or pulsed iontophoretic current. DS was released from all the liposome formulations with a similar, limited rate (~50% in 24h), leading therefore to significantly lower transdermal fluxes across full-thickness porcine skin compared to the respective free drug formulation. From the tested lipid vesicle formulations, the transfersomes resulted in the highest passive flux and the ethosomes in the highest iontophoretic flux under direct constant current treatment. Higher negative surface charge of the vesicle led to better transport efficiency due to the higher mobility of the drug carrier under electric field. Pulsed current iontophoresis had no advantage over constant current treatment in combination with any type of lipid vesicular nanocarriers, in contrast to what has been described earlier with drug-loaded polymeric nanocarriers. PMID- 28625749 TI - Preclinical evaluation of melanocortin-1 receptor (MC1-R) specific 68Ga- and 44Sc labeled DOTA-NAPamide in melanoma imaging. AB - PURPOSE: Alpha melanocyte stimulating hormone (alpha-MSH) enhances melanogenesis in melanoma malignum by binding to melanocortin-1 receptors (MC1-R). Earlier studies demonstrated that alpha-MSH analog NAPamide molecule specifically binds to MC1-R receptor. Radiolabeled NAPamide is a promising radiotracer for the non invasive detection of melanin producing melanoma tumors by Positron Emission Tomography (PET). In this present study the MC1-R selectivity of the newly developed Sc-44-labeled DOTA-NAPamide was investigated in vitro and in vivo using melanoma tumors. METHODS: DOTA-NAPamide was labeled with Ga-68 and Sc-44 radionuclides. The MC1-R specificity of Ga-68- and Sc-44-labeled DOTA-NAPamide was investigated in vitro and in vivo using MC1-R positive (B16-F10) and negative (A375) melanoma cell lines. For in vivo imaging studies B16-F10 and A375 tumor bearing mice were injected with 44Sc/68Ga-DOTA-NAPamide (in blocking studies with alpha-MSH) and whole body PET/MRI scans were acquired. Radiotracer uptake was expressed in terms of standardized uptake values (SUVs). RESULTS: 44Sc/68Ga labeled DOTA-NAPamide were produced with high specific activity (approx. 19 GBq/MUmol) and with excellent radiochemical purity (99%<). MC1-R positive B16-F10 cells showed significantly (p<=0.01) higher in vitro radiotracer accumulation than that of receptor negative A375 melanoma cells. In animal experiments, also significantly (p<=0.01) higher Ga-68-DOTA-NAPamide (SUVmean: 0.38+/-0.02), and Sc 44-DOTA-NAPamide (SUVmean: 0.52+/-0.13) uptake was observed in subcutaneously growing B16-F10 tumors, than in receptor negative A375 tumors, where the SUVmean values of Ga-68-DOTA-NAPamide and Sc-44-DOTA-NAPamide were 0.04+/-0.01 and 0.07+/ 0.01, respectively. Tumor-to-muscle (T/M SUVmean) ratios were approximately 15 fold higher in B16-F10 tumor-bearing mice, than that of A375 tumors, and this difference was also significant (p<=0.01) using both radiotracers after 60 min incubation time. CONCLUSION: Our newly synthesized 44Sc-labeled DOTA-NAPamide probe showed excellent binding properties to melanocortin-1 receptor (MC1-R) positive melanoma cell and tumors. Due to its high specificity and sensitivity 44Sc-DOTA-NAPamide is a promising radiotracer in molecular imaging of malignant melanoma. PMID- 28625750 TI - Postoperative Delirium in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting According to the Anesthetic Agent: A Retrospective Study. AB - OBJECTIVE: To evaluate the effect of two anesthetic agents (sevoflurane or propofol) on postoperative delirium (POD) in patients undergoing off-pump coronary artery bypass grafting (CABG). DESIGN: Retrospective observational design. SETTING: University hospital. PARTICIPANTS: Two hundred ninety-two patients undergoing off-pump CABG who were anesthetized with sevoflurane or propofol. METHODS: Incidence of POD, laboratory data, and pre-, intra-, and 24 hour postoperative clinical variables were reviewed retrospectively. The independent predictors of POD were evaluated. MEASUREMENTS AND MAIN RESULTS: The cumulative incidence of POD after off-pump CABG was 10.6% (31 of 292 patients) and the incidence rates of POD were not statistically significant in the sevoflurane and propofol groups (13% [20 of 156 patients] and 8% [11 of 136 patients], respectively; p = 0.137). Other variables, including the laboratory and clinical data also did not differ significantly between the anesthetic groups. Age >=75 years (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.44 16.27; p = 0.011), postoperative pneumonia (OR, 10.84; 95% CI, 3.32-35.34; p < 0.001), 6 or more packed red blood cell units transfusion in the first 24 hours postoperatively (OR, 5.30; 95% CI, 1.32-21.27; p = 0.019), and 24-hour postoperative albumin <3.0 g/dL (OR, 3.38; 95% CI, 1.20-9.31; p = 0.021) were independent predictors of POD after off-pump CABG. CONCLUSIONS: The incidence of POD in patients undergoing off pump-CABG did not differ between those receiving sevoflurane versus propofol-based anesthesia. PMID- 28625751 TI - Stellate Ganglion Block: Important Weapon in the Anesthesiologists' Armamentarium. PMID- 28625752 TI - Neurologic Complications of Extracorporeal Membrane Oxygenation: A Review. AB - OBJECTIVE: To review the evidence on neurologic complications in adult extracorporeal membrane oxygenation (ECMO) patients with regard to incidence, pathophysiology, risk factors, diagnosis, monitoring techniques, prevention, and management. DESIGN: Literature review. SETTING: Observational studies and case reports from a variety of institutions. PARTICIPANTS: Adult ECMO patients. INTERVENTIONS: Six electronic databases were searched from their dates of inception to October 2016. MEASUREMENTS AND MAIN RESULTS: The range of neurologic complications reported in adult ECMO patients included stroke, intracranial hemorrhage, and brain death. Due to a lack of standardized reporting, their true incidence may have been underestimated significantly. A variety of pathophysiologic mechanisms and risk factors have been proposed. Some of these are specific to venoarterial ECMO, whereas others may be more relevant to venovenous ECMO (eg, rapid correction of hypercarbia). With regard to diagnosis and monitoring, clinical examination alone can be challenging and insufficiently sensitive, particularly for the confirmation of brain death. Computed tomography is the main imaging modality for acute neurologic assessment because magnetic resonance imaging is not feasible in these patients. Options for neuromonitoring are limited, although cerebral near-infrared spectroscopy may be useful. There are very limited data to guide the management of specific complications such as intracranial hemorrhage, which remains a leading cause of mortality in ECMO patients. CONCLUSIONS: ECMO can be lifesaving and is being used increasingly for severe respiratory and/or cardiac failure. However, it remains associated with significant neurologic morbidity and mortality. Greater research clearly is needed to determine the best approach to the assessment and management of neurologic complications in this rapidly growing patient population. PMID- 28625753 TI - Detection of Acute Arterial Occlusion During Artery Bypass Surgery for a Lower Extremity by Monitoring Regional Saturation of Oxygen of the Sole of the Foot. PMID- 28625754 TI - Inefficacy of Platelet Transfusion in a Heart Transplant Patient Under Continuous Ticagrelor. PMID- 28625755 TI - Multilevel engineering of the upstream module of aromatic amino acid biosynthesis in Saccharomyces cerevisiae for high production of polymer and drug precursors. AB - A multilevel approach was implemented in Saccharomyces cerevisiae to optimize the precursor module of the aromatic amino acid biosynthesis pathway, which is a rich resource for synthesizing a great variety of chemicals ranging from polymer precursor, to nutraceuticals and pain-relief drugs. To facilitate the discovery of novel targets to enhance the pathway flux, we incorporated the computational tool YEASTRACT for predicting novel transcriptional repressors and OptForce strain-design for identifying non-intuitive pathway interventions. The multilevel approach consisted of (i) relieving the pathway from strong transcriptional repression, (ii) removing competing pathways to ensure high carbon capture, and (iii) rewiring precursor pathways to increase the carbon funneling to the desired target. The combination of these interventions led to the establishment of a S. cerevisiae strain with shikimic acid (SA) titer reaching as high as 2.5gL-1, 7 fold higher than the base strain. Further expansion of the platform led to the titer of 2.7gL-1 of muconic acid (MA) and its intermediate protocatechuic acid (PCA) together. Both the SA and MA production platforms demonstrated increases in titer and yield nearly 300% from the previously reported, highest-producing S. cerevisiae strains. Further examination elucidated the diverged impacts of disrupting the oxidative branch (ZWF1) of the pentose phosphate pathway on the titers of desired products belonging to different portions of the pathway. The investigation of other non-intuitive interventions like the deletion of the Pho13 enzyme also revealed the important role of the transaldolase in determining the fate of the carbon flux in the pathways of study. This integrative approach identified novel determinants at both transcriptional and metabolic levels that constrain the flux entering the aromatic amino acid pathway. In the future, this platform can be readily used for engineering the downstream modules toward the production of important plant-sourced aromatic secondary metabolites. PMID- 28625756 TI - Limitation of ischaemic tissue response in a reconstruction with short ischaemia time during free flap surgery. PMID- 28625757 TI - Sentinel node biopsy status is strongly predictive of survival in cutaneous melanoma: Extended follow-up of Oxford patients from 1998 to 2014. AB - INTRODUCTION: Sentinel lymph node biopsy (SLNB) is widely used as a key investigatory tool for cutaneous melanoma, with results incorporated into the latest AJCC staging guidelines. We present the results of our extended follow-up of sentinel lymph node biopsy for melanoma over a sixteen-year period. METHODS: Data were collected prospectively from June 1998 to December 2014 from a single tertiary skin cancer referral centre. Chi-squared analysis was used to analyse patient demographics and primary tumour pathology. Survival analysis was conducted using Cox regression models and Kaplan-Meier survival curves. RESULTS: Over a sixteen-year period 1527 patients underwent SLNB in 1609 basins, with 2876 nodes harvested. 347 patients (23%) had a positive biopsy. The most common primary tumour sites for males was the back (32%); women had a significantly higher number of melanomas occurring on the lower and upper limbs (45% and 26% respectively) [all p < 0.0001, Chi-squared]. Mean follow-up time was 4.9 years. Patients with a positive SLNB at diagnosis were significantly more likely to die from melanoma (subhazard ratio 5.59, p = 0.000, 95% CI 3.59-8.69). Breslow thickness and ulceration were also significant predictors of melanoma-specific mortality. For patients with a primary Breslow >4.0 mm ten-year disease free survival was 52% for SLNB negative and 26% for SLNB positive patients. For Breslow thicknesses of 2.01-4 mm these values were 66% and 32% respectively. CONCLUSIONS: Sentinel lymph node biopsy status is strongly predictive of survival across all thicknesses of primary cutaneous melanoma. PMID- 28625758 TI - Body contouring after obesity surgery is associated with a weight loss benefit among patients. AB - BACKGROUND: Patients who undergo obesity surgery often require body contouring procedures to eliminate excess skin. Recent studies suggest that body contouring surgery may provide psychological benefits to patients after obesity surgery. However, it remains unclear how body contouring may affect weight loss maintenance after obesity surgery. METHODS: This is a retrospective review of patients who underwent obesity surgery with or without body contouring at a single institution from 2000 to 2005. Charts were reviewed for demographic, medical, and surgical information. The primary outcome of interest was the difference in weight loss maintenance among patients who underwent body contouring versus those who did not. RESULTS: A total of 318 patients were included for analysis in this study, of which 70 underwent obesity surgery with body contouring and 248 underwent obesity surgery without body contouring. The mean change in BMI among patients who did not undergo body contouring was 19.7 kg/m2. The mean change in BMI among patients who underwent body contouring was 22.1 kg/m2. Among patients who underwent body contouring surgery, 2.9% (2/70) of patients did not maintain at least a 20% decrease in body weight during the entire follow-up period (mean follow-up time 92.2 months). Among patients who did not undergo body contouring surgery, 10% (25/248) of patients did not maintain at least a 20% decrease in body weight during the entire follow-up period (mean follow-up time 39.0 months) (chi2 = 3.67, p = 0.055). CONCLUSIONS: Body contouring surgery may have a positive effect on weight loss maintenance after body contouring determined from the mean weight change and on percentage of patients who maintain at least a 20% decrease in body weight. PMID- 28625759 TI - Predictive value of serum HCG concentrations in pregnancies achieved after single fresh or vitrified-warmed blastocyst transfer. AB - Possible differences between serum HCG levels in pregnancies achieved after transfer of a single fresh or a vitrified-warmed blastocyst were evaluated. Out of 1130 single blastocyst transfers resulting in positive HCG results, 789 were single fresh blastocyst transfers and 341 single vitrified-warmed blastocyst transfers. The initial serum HCG levels of 869 clinical intrauterine pregnancies were evaluated, 638 after the transfer of a single fresh blastocysts and 231 after the transfer of a single vitrified-warmed blastocysts. The HCG levels from cycles resulting in a clinical intrauterine pregnancy were significantly higher after the transfer of a single vitrified-warmed blastocyst (383 +/- 230 IU/l) versus a fresh transfer (334 +/- 192 IU/l; P = 0.01). Threshold values for predicting a clinical pregnancy for a fresh blastocyst were 111 IU/l and for a vitrified-warmed blastocyst 137 IU/l. Our study shows that the overall beta-HCG levels are comparable after the transfer of a fresh or vitrified-warmed blastocyst, suggesting that vitrification most probably does not affect the ability of the embryos to produce beta-HCG. This study further shows that when clinicians counsel patients, they should take into account that higher HCG levels are needed after a vitrified-warmed blastocyst transfer to predict a clinical intrauterine pregnancy. PMID- 28625760 TI - Multifetal pregnancy reduction of triplets to twins compared with non-reduced triplets: a meta-analysis. AB - The current systematic review and meta-analysis evaluate the perinatal outcomes in twin pregnancies following multifetal pregnancy reduction (MPR) compared with non-reduced triplet pregnancies. All studies comparing perinatal outcome of twin pregnancies following MPR to non-reduced triplet pregnancies were considered. MEDLINE, non-indexed MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science were searched for relevant published articles up to August 2016. The search yielded 653 publications of which 92 were assessed for eligibility. A total of 24 studies met the inclusion criteria. Overall, the outcomes of pregnancies following MPR were better compared with expectantly managed triplets. The MPR group delivered at a later gestational age and was less likely to be delivered before 32 or 28 weeks' gestation. Newborns in the MPR group had significantly higher birthweight at delivery (mean difference 500 g [95% CI 439.95, 560.04]). Rates of pregnancy loss before 24 weeks' gestation and overall infant survival were comparable between the groups. This meta-analysis suggests that MPR of triplet pregnancies to twins is associated with improved perinatal outcome compared with non-reduced triplets. Should primary prevention of high order multiple pregnancy fail, MPR is an appropriate alternative to minimize the perinatal morbidity and mortality of triplet pregnancies. PMID- 28625761 TI - Impact of vitamin D levels on ovarian reserve and ovarian response to ovarian stimulation in oocyte donors. AB - Recently, growing interest in vitamin D has emerged from findings that demonstrate a low vitamin D status in populations. Similarly, much interest has been shown in the role that anti-Mullerian hormone (AMH) plays in reproductive physiology. Considerable confusion as to whether vitamin D status is related to ovarian function can be found in the literature. Our retrospective study was performed from June 2014 to April 2015. Oocyte donors were recruited and stimulated under the antagonist protocol with gonadotrophin-releasing hormone (GnRH) agonist to trigger ovulation. In 851 stimulation cycles, we determined the association among serum total and bioavailable vitamin D levels, ovarian reserve and response to ovarian stimulation and the reproductive outcome in their recipients. We showed that vitamin D levels were unrelated to ovarian reserve or ovarian response after ovarian stimulation; in oocyte recipients, gestational outcome did not differ according to a donor's vitamin D serum status. No correlation was observed between serum AMH and vitamin D. Bioavailable vitamin D was not related to recipients' ongoing pregnancy rate. Highly prevalent vitamin D insufficiency neither impaired ovarian reserve nor response or oocyte quality in egg donors. No evidence was found for recommending the analysis of vitamin D status in oocyte donors. PMID- 28625762 TI - Fungal peritonitis by Thermoascus crustaceus in a peritoneal dialysis patient from Chile. AB - BACKGROUND: Fungal peritonitis is a relatively uncommon infection in peritoneal dialysis patients. However, it can be associated with significant morbimortality. In recent reports, Candida species and other filamentous fungi have been reported as being aetiological agents. Thermoascus species are ubiquitous, thermophilic fungi, with an anamorph in the Paecilomyces genus. Here we present the first report of fungal peritonitis by Thermoascus crustaceus from Chile. CASE REPORT: We present the case of an 83-year-old female patient, with a history of cholecystectomy, hernia repair, severe arterial hypertension, hip and knee osteoarthritis and several episodes of peritoneal dialysis with a cloudy exudate. Bacterial cultures were negative. In addition, a history of two months with intermittent fever peaks mainly in the evening was reported. Blood culture bottles inoculated with peritoneal fluid revealed the presence of fungal growth. Morphological and molecular studies allowed us to identify the aetiological agent as Thermoascus crustaceus. An antifungal susceptibility test was performed using the M38-A2 method, developed by the Clinical and Laboratory Standards Institute (CLSI). The MIC values to amphotericin B, itraconazole, voriconazole and echinochandins were 0.5, 0.25, 0.25 and 0.125MUg/ml, respectively. Antifungal treatment with amphotericin B was prescribed, with good patient progress. CONCLUSIONS: Fungal peritonitis is a very rare entity. Moreover, the spectrum of fungal pathogens continues to expand, a reason for which morphological and molecular studies are necessary for a rapid diagnosis. PMID- 28625763 TI - Effects of tectonics and large scale climatic changes on the evolutionary history of Hyalomma ticks. AB - Hyalomma Koch, 1844 are ixodid ticks that infest mammals, birds and reptiles, to which 27 recognized species occur across the Afrotropical, Palearctic and Oriental regions. Despite their medical and veterinary importance, the evolutionary history of the group is enigmatic. To investigate various taxonomic hypotheses based on morphology, and also some of the mechanisms involved in the diversification of the genus, we sequenced and analysed data derived from two mtDNA fragments, three nuclear DNA genes and 47 morphological characters. Bayesian and Parsimony analyses based on the combined data (2242 characters for 84 taxa) provided maximum resolution and strongly supported the monophyly of Hyalomma and the subgenus Euhyalomma Filippova, 1984 (including H. punt Hoogstraal, Kaiser and Pedersen, 1969). A predicted close evolutionary association was found between morphologically similar H. dromedarii Koch, 1844, H. somalicum Tonelli Rondelli, 1935, H. impeltatum Schulze and Schlottke, 1929 and H. punt, and together they form a sister lineage to H. asiaticum Schulze and Schlottke, 1929, H. schulzei Olenev, 1931 and H. scupense Schulze, 1919. Congruent with morphological suggestions, H. anatolicum Koch, 1844, H. excavatum Koch, 1844 and H. lusitanicum Koch, 1844 form a clade and so also H. glabrum Delpy, 1949, H. marginatum Koch, 1844, H. turanicum Pomerantzev, 1946 and H. rufipes Koch, 1844. Wide scale continental sampling revealed cryptic divergences within African H. truncatum Koch, 1844 and H. rufipes and suggested that the taxonomy of these lineages is in need of a revision. The most basal lineages in Hyalomma represent taxa currently confined to Eurasia and molecular clock estimates suggest that members of the genus started to diverge approximately 36.25 million years ago (Mya). The early diversification event coincides well with the collision of the Indian and Eurasian Plates, an event that was also characterized by large scale faunal turnover in the region. Using S-Diva, we also propose that the closure of the Tethyan seaway allowed for the genus to first enter Africa approximately 17.73Mya. In concert, our data supports the notion that tectonic events and large scale global changes in the environment contributed significantly to produce the rich species diversity currently found in the genus Hyalomma. PMID- 28625764 TI - Genome-wide identification and expression profiling of EIL gene family in woody plant representative poplar (Populus trichocarpa). AB - This study aimed to improve current understanding on ethylene-insensitive 3-like (EIL) members, least explored in woody plants such as poplar (Populus trichocarpa Torr. & Grey). Herein, seven putative EIL members were identified in P. trichocarpa genome and were roughly annotated either as EIN3-like sequence associated with ethylene pathway or EIL3-like sequences related with sulfur (S) pathway. Motif-distribution pattern of proteins also corroborated this annotation. They were distributed on six chromosomes (chr1, 3, 4 and 8-10), and were revealed to encode a protein of 509-662 residues with nuclear localization. The presence of ethylene insensitive 3 (EIN3; PF04873) domain (covering first 80 280 residues from N-terminus) was confirmed by Hidden Markov Model-based search. The first half of EIL proteins (~80-280 residues including EIN3 domain) was substantially conserved. The second half (~300-600 residues) was considerably diverged. Additionally, first half of proteins harbored acidic, proline-rich and glutamine-rich sites, and supported the essentiality of these regions in the transcriptional-activation and protein-function. Moreover, identified six segmental and one-tandem duplications demonstrated the negative or purifying selective nature of mutations. Furthermore, expression profile analysis indicated the possibility of a crosstalk between EIN3- and EIL3-like genes, and co expression networks implicated their interactions with very diverse panels of biological molecules. PMID- 28625765 TI - Flavin-dependent epitranscriptomic world. AB - RNAs molecules fulfill key roles in the expression and regulation of the genetic information stored within the DNA chromosomes. In addition to the four canonical bases, U, C, A and G, RNAs harbor various chemically modified derivatives which are generated post-transcriptionally by specific enzymes acting directly at the polymer level. More than one hundred naturally occurring modified nucleosides have been identified to date, the largest number of which is found in tRNAs and rRNA. This remarkable biochemical process produces widely diversified RNAs further expanding the functional repertoires of these nucleic acids. Interestingly, several RNA-modifying enzymes use a flavin bioorganic molecule as a coenzyme in RNA modification pathways. Some of these reactions are simple while others are extremely complex using challenging chemistry orchestrated by large flavoenzymatic systems. In this review, we summarize recent knowledges on the flavin-dependent RNA-modifying enzymes and discuss the relevance of their activity within a cellular context. PMID- 28625766 TI - Amine oxidation by d-arginine dehydrogenase in Pseudomonas aeruginosa. AB - d-Arginine dehydrogenase from Pseudomonas aeruginosa (PaDADH) is a flavin dependent oxidoreductase, which is part of a novel two-enzyme racemization system that functions to convert d-arginine to l-arginine. PaDADH contains a noncovalently linked FAD that shows the highest activity with d-arginine. The enzyme exhibits broad substrate specificity towards d-amino acids, particularly with cationic and hydrophobic d-amino acids. Biochemical studies have established the structure and the mechanistic properties of the enzyme. The enzyme is a true dehydrogenase because it displays no reactivity towards molecular oxygen. As established through solvent and multiple kinetic isotope studies, PaDADH catalyzes an asynchronous CH and NH bond cleavage via a hydride transfer mechanism. Steady-state kinetic studies with d-arginine and d-histidine are consistent with the enzyme following a ping-pong bi-bi mechanism. As shown by a combination of crystallography, kinetic and computational data, the shape and flexibility of loop L1 in the active site of PaDADH are important for substrate capture and broad substrate specificity. PMID- 28625767 TI - Early life stress perturbs the function of microglia in the developing rodent brain: New insights and future challenges. AB - The role of the innate immune system in mediating some of the consequences of childhood abuse and neglect has received increasing attention in recent years. Most of the work to date has focused on the role that neuroinflammation plays in the long-term adult psychiatric and medical complications associated with childhood maltreatment. The effects of stress-induced neuroinflammation on neurodevelopment have received little attention because until recently this issue has not been studied systematically in animal models of early life stress. The primary goal of this review is to explore the hypothesis that elevated corticosterone during the first weeks of life in mice exposed to brief daily separation (BDS), which is a mouse model of early life stress, disrupts microglial function during a critical period of brain development. We propose that perturbations of microglial function lead to abnormal maturation of several neuronal and non-neuronal cellular processes resulting in behavioral abnormalities that emerge during the juvenile period and persist in adulthood. Here, we highlight recent work demonstrating that exposure to BDS alters microglial cell number, morphology, phagocytic activity, and gene expression in the developing hippocampus in a manner that extends into the juvenile period. These changes in microglial function are associated with abnormalities in developmental processes mediated by microglia including synaptogenesis, synaptic pruning, axonal growth, and myelination. We examine the changes in microglial gene expression in the context of previous work demonstrating developmental and behavioral abnormalities in BDS mice and in other animal models of early life stress. The possible utility of these findings for developing novel PET imaging to assess microglial function in individuals exposed to childhood maltreatment is also discussed. PMID- 28625769 TI - Mechanisms of aortic dissection smooth muscle cell phenotype switch. AB - OBJECTIVE: To investigate the expression of Nanog homeobox (NANOG) in thoracic aortic dissection (TAD) and the role of NANOG in regulating human aortic vascular smooth muscle cells (VSMCs) phenotype switch. METHODS: Aortic specimens were collected from 20 patients undergoing TAD and 10 controls. VSMCs were isolated by adherent cultivation approach. The expression of NANOG, osteopontin (OPN), and VSMCs phenotype markers were determined by quantitative real-time polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. Cell counting, scratch wound-healing assay, Transwell migration, and apoptosis assays were used for cell function assessment. Deoxyribonucleic acid-protein binding detection was performed by chromatin immunoprecipitation. RESULTS: Our experiment results showed that NANOG and OPN were highly expressed in TAD aortic wall and VSMCs, both accompanying VSMCs phenotype switch. Overexpression of NANOG induced the up-regulation of VSMCs synthetic marker matrix metalloproteinase 2 and the down-regulation of VSMCs contractile markers alpha-smooth muscle actin and smooth muscle 22alpha. Overexpression of NANOG also enhanced the proliferation, migration, and antiapoptosis capabilities of VSMCs. The results also showed that these functions of NANOG was via OPN and NANOG directly up-regulated OPN by binding to its promoter region. CONCLUSIONS: Our study suggests that NANOG is highly expressed in TAD aortic wall and VSMCs. Increased NANOG promotes VSMCs phenotype switch by directly up-regulating OPN through binding to its promoter region. PMID- 28625770 TI - Secondary sclerosing cholangitis following cardiac surgery: An uncommon but deadly gastrointestinal complication. PMID- 28625768 TI - Screening and characterization of lactic acid bacterial strains that produce fermented milk and reduce cholesterol levels. AB - OBJECTIVE: To screen for and characterize lactic acid bacteria strains with the ability to produce fermented milk and reduce cholesterol levels. METHODS: The strains were isolated from traditional fermented milk in China. In vitro and in vivo evaluation of cholesterol-reduction were used to identify and verify strains of interest. Characteristics were analyzed using spectrophotometry and plate counting assays. RESULTS: The isolate HLX37 consistently produced fermented milk with strong cholesterol-reducing properties was identified as Lactobacillus plantarum (accession number: KR105940) and was thus selected for further study. The cholesterol reduction by strain HLX37 was 45.84%. The isolates were acid tolerant at pH 2.5 and bile-tolerant at 0.5% (w/v) in simulated gastric juice (pH 2.5) for 2h and in simulated intestinal fluid (pH 8.0) for 3h. The auto aggregation rate increased to 87.74% after 24h, while the co-aggregation with Escherichia coli DH5 was 27.76%. Strain HLX37 was intrinsically resistant to antibiotics such as penicillin, tobramycin, kanamycin, streptomycin, vancomycin and amikacin. Compared with rats in the model hyperlipidemia group, the total cholesterol content in the serum and the liver as well as the atherogenic index of rats in the viable fermented milk group significantly decreased by 23.33%, 32.37% and 40.23%, respectively. Fewer fat vacuoles and other lesions in liver tissue were present in both the inactivated and viable fermented milk groups compared to the model group. CONCLUSION: These studies indicate that strain HLX37 of L. plantarum demonstrates probiotic potential, potential for use as a candidate for commercial use for promoting health. PMID- 28625772 TI - Discussion. PMID- 28625771 TI - Comparison of plasma to tissue DNA mutations in surgical patients with non-small cell lung cancer. AB - OBJECTIVE: Noninvasive liquid biopsies of circulating tumor DNA (ctDNA) can be used to assess non-small cell lung cancer (NSCLC), but previous work focused on patients with advanced-stage cancer. Thus, we evaluated the feasibility and their potential clinical application of circulating tumor DNA approached for surgical patients with NSCLC. METHOD: Consecutive patients with suspected lung cancer who underwent curative-intent lung resection were enrolled prospectively in this study. Targeted DNA sequencing with a next-generation sequencing platform was used to identify a series of somatic mutations in matched tumor tissue DNA (tDNA) and plasma ctDNA samples. Plasma was collected before, during, and after surgery. Concordance was defined as matched tDNA and ctDNA with the same identified mutations or with no mutations. RESULTS: In the enrolled 76 patients with lung cancer who were included, 31 had concordant mutations and 21 had no mutation in both ctDNA and tDNA, yielding an overall concordance of 68.4%. ctDNA samples obtained before and during surgery had the same mutations with a low variance in mutation frequency (1.2%) that was reduced to an average of 0.28% after surgery (P < .001). More patients were positive as assayed by ctDNA (48; 63.2%) than with serum tumor protein markers (36; 49.3%). The area under the curve was greater in ctDNA (0.887, 95% confidence interval [CI], 0.788-0.986) than for the 2 prediction models (0.803, 95% CI, 0.647-0.959; 0.69, 95% CI, 0.512-0.869) for estimating malignancy of solitary pulmonary nodules. CONCLUSION: ctDNA mutation analysis for stage I-III surgical patients with NSCLC is feasible. More studies are needed to investigate its clinical application. PMID- 28625773 TI - Reoperative root replacement: To do or not to do. PMID- 28625774 TI - Revisiting Ginsberg and Rubinstein's study. PMID- 28625775 TI - The Ross procedure is the best operation to treat aortic stenosis in young and middle-aged adults. PMID- 28625776 TI - Beta-carotene preferentially regulates chicken myoblast proliferation withdrawal and differentiation commitment via BCO1 activity and retinoic acid production. AB - The enzyme beta-carotene oxygenase 1 (BCO1) catalyzes the breakdown of provitamin A, including beta-carotene (BC), into retinal, prior to its oxidation into retinoic acid (RA). Allelic variation at the BCO1 locus results in differential expression of its mRNA and affects carotenoid metabolism specifically in chicken Pectoralis major muscle. In this context, the aim of this study was to evaluate the potential myogenic effect of BC and the underlying mechanisms in chicken myoblasts. BCO1 mRNA was detected in myoblasts derived from chicken satellite cells. Treating these myoblasts with BC led to a significant decrease in BrdU incorporation. This anti-proliferative effect was confirmed by a cell cycle study using flow cytometry. BC also significantly increased the differentiation index, suggesting a positive effect on the commitment of avian myoblasts to myogenic differentiation. Addition of DEAB, a specific inhibitor of RALDH activity, significantly reduced BC anti-proliferative and pro-differentiating effects, suggesting that BC exerted its biological effect on chicken myoblasts through activation of the RA pathway. We also observed that in myoblast showing decreased BCO1 expression consecutive to a natural mutation or to a siRNA treatment, the response to BC was inhibited. Nevertheless, BCO1 siRNA transfection increased expression of BCO2 which inhibited cell proliferation in control and BC treated cells. PMID- 28625778 TI - Analysis of phytoplankton assemblage structure in the Mediterranean Sea based on high-throughput sequencing of partial 18S rRNA sequences. AB - Studying taxonomic and ecological diversity of phytoplankton assemblages is often difficult because morphological analysis cannot provide a complete description of their composition. Therefore, more robust and feasible approaches have to be chosen to elucidate the interactions between environmental and human pressures and phytoplankton assemblages. The Ocean Sampling Day (OSD) allowed collecting seawater samples from a wide range of oceanic regions including the Mediterranean Sea. In this study, a total of 754,167 V4-18S ribosomal DNA (rDNA) metabarcodes derived from 20 plankton samples collected at 19 sampling sites across the coastal areas of the Mediterranean Sea were analyzed to explore the relationships between phytoplankton assemblages' composition, sub-regional environmental features and human pressures. We reduced the whole set of autotroph plankton (1398 OTUs) to a smaller number of ecologically relevant entities (205 taxa) and used the latter for analysing the structure of phytoplankton assemblages. Chaetoceros was the only genus occurring in all the samples, while the number of taxa was maximum in the W Mediterranean. Based on the assigned OTUs, the structure of E Mediterranean phytoplankton was the most homogeneous. Further, phytoplankton assemblages from the three Mediterranean sub-regions (Western, Adriatic and Eastern) were significantly different (R=0.25, p=0.0136) based on Jaccard similarity. We also observed that phytoplankton diversity and human impact on marine ecosystems were not significantly related to each other based on Mantel's test. PMID- 28625779 TI - Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets. AB - SYNE1 (synaptic nuclear envelope 1) encodes multiple isoforms of Nesprin1 (nuclear envelope spectrin 1) that associate with the nuclear envelope (NE) through a C-terminal KASH (Klarsicht/Anc1/Syne homology) domain (Figure 1A) [1 4]. This domain interacts directly with the SUN (Sad1/Unc84) domain of Sun proteins [5-7], a family of transmembrane proteins of the inner nuclear membrane (INM) [8, 9], to form the so-called LINC complexes (linkers of the nucleoskeleton and cytoskeleton) that span the entire NE and mediate nuclear positioning [10 12]. In a stark departure from this classical depiction of Nesprin1 in the context of the NE, we report here that rootletin recruits Nesprin1alpha at the ciliary rootlets of photoreceptors and identify asymmetric NE aggregates of Nesprin1alpha and Sun2 that dock filaments of rootletin at the nuclear surface. In NIH 3T3 cells, we show that recombinant rootletin filaments also dock to the NE through the specific recruitment of an ~600-kDa endogenous isoform of Nesprin1 (Nes1600kDa) and of Sun2. In agreement with the association of Nesprin1alpha with photoreceptor ciliary rootlets and the functional interaction between rootletin and Nesprin1 in fibroblasts, we demonstrate that multiple isoforms of Nesprin1 are integral components of ciliary rootlets of multiciliated ependymal and tracheal cells. Together, these data provide a novel functional paradigm for Nesprin1 at ciliary rootlets and suggest that the wide spectrum of human pathologies linked to truncating mutations of SYNE1 [13-15] may originate in part from ciliary defects. PMID- 28625780 TI - Enhanced Depolymerization of Actin Filaments by ADF/Cofilin and Monomer Funneling by Capping Protein Cooperate to Accelerate Barbed-End Growth. AB - A living cell's ability to assemble actin filaments in intracellular motile processes is directly dependent on the availability of polymerizable actin monomers, which feed polarized filament growth [1, 2]. Continued generation of the monomer pool by filament disassembly is therefore crucial. Disassemblers like actin depolymerizing factor (ADF)/cofilin and filament cappers like capping protein (CP) are essential agonists of motility [3-8], but the exact molecular mechanisms by which they accelerate actin polymerization at the leading edge and filament turnover has been debated for over two decades [9-12]. Whereas filament fragmentation by ADF/cofilin has long been demonstrated by total internal reflection fluorescence (TIRF) [13, 14], filament depolymerization was only inferred from bulk solution assays [15]. Using microfluidics-assisted TIRF microscopy, we provide the first direct visual evidence of ADF's simultaneous severing and rapid depolymerization of individual filaments. Using a conceptually novel assay to directly visualize ADF's effect on a population of pre-assembled filaments, we demonstrate how ADF's enhanced pointed-end depolymerization causes an increase in polymerizable actin monomers, thus promoting faster barbed-end growth. We further reveal that ADF-enhanced depolymerization synergizes with CP's long-predicted "monomer funneling" [16] and leads to skyrocketing of filament growth rates, close to estimated lamellipodial rates. The "funneling model" hypothesized, on thermodynamic grounds, that at high enough extent of capping, the few non-capped filaments transiently grow much faster [15], an effect proposed to be very important for motility. We provide the first direct microscopic evidence of monomer funneling at the scale of individual filaments. These results significantly enhance our understanding of the turnover of cellular actin networks. PMID- 28625781 TI - ADF/Cofilin Accelerates Actin Dynamics by Severing Filaments and Promoting Their Depolymerization at Both Ends. AB - Actin-depolymerizing factor (ADF)/cofilins contribute to cytoskeletal dynamics by promoting rapid actin filament disassembly. In the classical view, ADF/cofilin sever filaments, and capping proteins block filament barbed ends whereas pointed ends depolymerize, at a rate that is still debated. Here, by monitoring the activity of the three mammalian ADF/cofilin isoforms on individual skeletal muscle and cytoplasmic actin filaments, we directly quantify the reactions underpinning filament severing and depolymerization from both ends. We find that, in the absence of monomeric actin, soluble ADF/cofilin can associate with bare filament barbed ends to accelerate their depolymerization. Compared to bare filaments, ADF/cofilin-saturated filaments depolymerize faster from their pointed ends and slower from their barbed ends, resulting in similar depolymerization rates at both ends. This effect is isoform specific because depolymerization is faster for ADF- than for cofilin-saturated filaments. We also show that, unexpectedly, ADF/cofilin-saturated filaments qualitatively differ from bare filaments: their barbed ends are very difficult to cap or elongate, and consequently undergo depolymerization even in the presence of capping protein and actin monomers. Such depolymerizing ADF/cofilin-decorated barbed ends are produced during 17% of severing events. They are also the dominant fate of filament barbed ends in the presence of capping protein, because capping allows growing ADF/cofilin domains to reach the barbed ends, thereby promoting their uncapping and subsequent depolymerization. Our experiments thus reveal how ADF/cofilin, together with capping protein, control the dynamics of actin filament barbed and pointed ends. Strikingly, our results propose that significant barbed-end depolymerization may take place in cells. PMID- 28625782 TI - Complex Sexual Deception in an Orchid Is Achieved by Co-opting Two Independent Biosynthetic Pathways for Pollinator Attraction. AB - Sexually deceptive orchids lure their specific male pollinators using volatile semiochemicals that mimic female sex pheromones. To date, the semiochemicals known to be involved consist of blends of chemically and biosynthetically related compounds. In contrast, we report that (S)-beta-citronellol and 2-hydroxy-6 methylacetophenone, two biosynthetically distinct compounds, are the active semiochemicals in Caladenia plicata, which is pollinated by male Zeleboria sp. thynnine wasps. They are also sex pheromone components of the female Zeleboria. A 1:4 blend elicits a high rate of attempted copulation (~70%) in bioassays, equivalent to rates observed at orchid flowers. Whereas beta-citronellol is well known, 2-hydroxy-6-methylacetophenone appears to be previously unknown as a floral volatile. Production of the two compounds is restricted to glandular sepal tips; thus, differential expression analysis of contrasting floral tissue transcriptomes was employed to illuminate the biosynthesis. As expected, production of (S)-beta-citronellol commences with the terpene synthase GES1 catalyzing the irreversible conversion of geranyl diphosphate (GPP) to geraniol. Contrary to prediction, biosynthesis subsequently proceeds in three steps, commencing with the oxidation of geraniol to geranial by alcohol dehydrogenase ADH3, followed by the enantioselective reduction of a double bond in geranial by geranial reductase GER1 to give (S)-beta-citronellal. Finally, ADH3-catalyzed reduction of (S)-beta-citronellal results in (S)-beta-citronellol. In line with previous work on insects showing that 2-hydroxy-6-methylacetophenone is derived from a polyketide pathway, we report a differentially expressed polyketide synthase (PKS) gene candidate. Thus, in this unique example of sexual deception, pollination is achieved by co-opting and regulating two independent biosynthetic pathways of floral volatile compounds. VIDEO ABSTRACT. PMID- 28625784 TI - Heightened sympathetic arousal is demonstrated by skin conductance responsivity to auditory stimuli in a small cohort of neonates with opiate withdrawal. AB - To determine the effects of auditory stimulus on skin conductance (SC) in infants with severe neonatal abstinence syndrome (NAS) that required morphine treatment (MT) compared with NAS infants that did not require morphine treatment (non-MT). We prospectively enrolled opiate-exposed term infants without polysubstance exposure. Skin conductance responses to an auditory stimulus (ringing a bell for 3s) near the time of discharge were obtained. Skin conductance was measured before, during, and after the stimulus. Non-parametric tests were used to determine between group and within phase differences. Infants were off MT at the time of SC measurement in response to an auditory stimulus. In a 2-group comparison of MT vs. non-MT infants, there was significantly higher SC responsivity to an auditory stimulus (p <0.05) in the MT group as compared with the non-MT group near discharge. The mean +SE peak morphine dose was 0.85+0.20mg/kg/day in the MT group. The mean Length of Stay (LOS) was 32 vs. 7 (p <0.05) days respectively, for the MT vs. the non-MT group. Our preliminary data suggest that in infants with severe NAS symptoms, higher sympathetic arousal in response to an auditory stimulus persists at discharge, underscoring the need for ongoing evaluation and specialized care at home. PMID- 28625783 TI - Probabilistic Invasion Underlies Natural Gut Microbiome Stability. AB - Species compositions of gut microbiomes impact host health [1-3], but the processes determining these compositions are largely unknown. An unexplained observation is that gut species composition varies widely between individuals but is largely stable over time within individuals [4, 5]. Stochastic factors during establishment may drive these alternative stable states (colonized versus non colonized) [6, 7], which can influence susceptibility to pathogens, such as Clostridium difficile. Here we sought to quantify and model the dose response, dynamics, and stability of bacterial colonization in the fruit fly (Drosophila melanogaster) gut. Our precise, high-throughput technique revealed stable between host variation in colonization when individual germ-free flies were fed their own natural commensals (including the probiotic Lactobacillus plantarum). Some flies were colonized while others remained germ-free even at extremely high bacterial doses. Thus, alternative stable states of colonization exist even in this low complexity model of host-microbe interactions. These alternative states are driven by a fundamental asymmetry between the inoculum population and the stably colonized population that is mediated by spatial localization and a population bottleneck, which makes stochastic effects important by lowering the effective population size. Prior colonization with other bacteria reduced the chances of subsequent colonization, thus increasing the stability of higher-diversity guts. Therefore, stable gut diversity may be driven by inherently stochastic processes, which has important implications for combatting infectious diseases and for stably establishing probiotics in the gut. PMID- 28625785 TI - Cerebral ischemia/repefusion injury: From bench space to bedside. AB - While stroke research represents the primary interface between circulation and brain research, the hemostasis system also carries a pivotal role in the mechanism of vascular brain injury. The complex interrelated events triggered by the energy crisis have a specific spatial and temporal pattern arching from the initial damage to the final events of brain repair. The complexity of the pathophysiology make it difficult to model this disease, therefore it is challenging to find appropriate therapeutic targets. The ever-persistent antagonism between the positive results of drug candidates in the experimental stroke models and the failures of the clinical trials prompts changes in the research strategy, especially in the field of potential neuroprotective therapies. System biology approach could initiate new directions in the future for both preclinical and clinical research. Incentive methods aimed at anti apoptosis mechanisms and the augmentation of post-ischemic brain repair could benefit the facts, that these processes can be targeted much longer following the cell-necrosis in the hyper-acute phase. Sequential monitoring of candidate genes and proteins responsible for stroke progression and post-stroke repair seems to be useful both in therapeutic target-identification, and in clinical testing. Understanding the mechanism behind the effect of selegiline and other drugs capable of activating the anti-apoptotic gene expression could help to find new approaches to enhance the regenerative potential in the remodeling of neuronal and microvascular networks. PMID- 28625786 TI - Drug induces depression-like phenotypes and alters gene expression profiles in Drosophila. AB - BACKGROUND: Major depressive disorder (MDD) is a severe mental illness that affects more than 350 million people worldwide. However, the molecular mechanisms of depression are currently unclear. Studies suggest that Drosophila and humans have similar depression-like symptoms under pressure. In this research, we choose Drosophila melanogaster as the animal model to explore the molecular mechanisms that trigger depression. RESULTS: We found that feeding D. melanogaster with the medium containing Levodopa or Chlorpromazine could induce depression-like phenotypes in both behavioral and biochemical biomarkers, including significantly decreased food intake, mating frequency, serotonin (5-HT) concentration, and increased malondialdehyde (MDA) concentration as well as reduced activity of superoxide dismutase (SOD). Moreover, the progeny of Chlorpromazine-treated flies also showed these depression-like features. By RNA-seq technology, we identified 467 genes that were differentially expressed between Chlorpromazine treated (CPZ) and control male flies [fold-change of >=2 (q-value<5%)]. When comparing CPZ with control flies, 312 genes were upregulated and 155 genes downregulated. Differential expression of genes related to metabolic pathway, Parkinson's disease, Huntington's disease, Alzheimer's disease and lysozyme pathways were observed. Quantitative reverse transcriptase PCR (qRT-PCR) confirmed that 19 genes are differentially expressed in CPZ and control male flies. CONCLUSIONS: Levodopa, or Chlorpromazine can induce depression-like phenotypes in D. melanogaster regarding changes of appetite and sexual activity, and some key biochemical markers. A total of 467 genes were identified by RNA-seq analysis to have at least a 2-fold-change in expression between CPZ and control flies, including genes involved in metabolism, neurological diseases and lysozyme pathways. Our data provide additional insight into molecular mechanisms underlying depressive disorders in humans and may also contribute to clinical treatment. PMID- 28625787 TI - Structural Snapshots and Loop Dynamics along the Catalytic Cycle of Glycosyltransferase GpgS. AB - Glycosyltransferases (GTs) play a central role in nature. They catalyze the transfer of a sugar moiety to a broad range of acceptor substrates. GTs are highly selective enzymes, allowing the recognition of subtle structural differences in the sequences and stereochemistry of their sugar and acceptor substrates. We report here a series of structural snapshots of the reaction center of the retaining glucosyl-3-phosphoglycerate synthase (GpgS). During this sequence of events, we visualize how the enzyme guides the substrates into the reaction center where the glycosyl transfer reaction takes place, and unveil the mechanism of product release, involving multiple conformational changes not only in the substrates/products but also in the enzyme. The structural data are further complemented by metadynamics free-energy calculations, revealing how the equilibrium of loop conformations is modulated along these itineraries. The information reported here represent an important contribution for the understanding of GT enzymes at the molecular level. PMID- 28625789 TI - Maltoporin LamB Unfolds beta Hairpins along Mechanical Stress-Dependent Unfolding Pathways. AB - Upon mechanical pulling at either terminal end, beta barrel outer membrane proteins stepwise unfold beta strands or beta hairpins until entirely extracted from the membrane. This unique unfolding pathway has been described for beta barrels comprising 8, 14, or 22 beta strands. Here we mechanically unfold the 18 stranded beta barrel outer membrane protein LamB from Escherichia coli. We find that its mechanical unfolding pathway is shaped by the stepwise unfolding of beta hairpins. However, we also observe that beta hairpins can unfold groupwise. Thereby, beta hairpins unfolding at higher pulling forces show a higher probability to unfold collectively, whereas beta hairpins unfolding at lower forces tend to unfold individually. This result suggests that the collective unfolding of beta hairpins resembles a far-from-equilibrium process, whereas the unfolding of individual beta hairpins describes a closer-to-equilibrium process. Our findings support a direct link between outer membrane protein structure and the unfolding pathway and contribute to a better understanding of their unfolding in response to mechanical stress. PMID- 28625788 TI - Structural and Functional Trends in Dehydrating Bimodules from trans Acyltransferase Polyketide Synthases. AB - In an effort to uncover the structural motifs and biosynthetic logic of the relatively uncharacterized trans-acyltransferase polyketide synthases, we have begun the dissection of the enigmatic dehydrating bimodules common in these enzymatic assembly lines. We report the 1.98 A resolution structure of a ketoreductase (KR) from the first half of a type A dehydrating bimodule and the 2.22 A resolution structure of a dehydratase (DH) from the second half of a type B dehydrating bimodule. The KR, from the third module of the bacillaene synthase, and the DH, from the tenth module of the difficidin synthase, possess features not observed in structurally characterized homologs. The DH architecture provides clues for how it catalyzes a unique double dehydration. Correlations between the chemistries proposed for dehydrating bimodules and bioinformatic analysis indicate that type A dehydrating bimodules generally produce an alpha/beta-cis alkene moiety, while type B dehydrating bimodules generally produce an alpha/beta trans, gamma/delta-cis diene moiety. PMID- 28625790 TI - Preprotein Conformational Dynamics Drive Bivalent Translocase Docking and Secretion. AB - Most bacterial secretory proteins destined beyond the plasma membrane are secreted post-translationally by the Sec translocase. In the first step of translocation, preproteins are targeted for binding to their 2-site receptor SecA, the peripheral ATPase subunit of the translocase. We now reveal that secretory preproteins use a dual-key mechanism to bridge the signal peptide and mature domain receptor sites and cooperatively enhance their affinities. Docking of targeting-competent mature domains requires that their extensive disorder is finely tuned. This is achieved through amino-terminal mature domain regions acting as conformational rheostats. By being linked to the rheostats, signal peptides regulate long-range preprotein disorder. Concomitant conformational changes in SecA sterically adapt its two receptor sites to optimally recognize hundreds of dissimilar preproteins. This novel intramolecular conformational crosstalk in the preprotein chains and the dynamic interaction with their receptor are mechanistically coupled to preprotein engagement in the translocase and essential for secretion. PMID- 28625791 TI - On Plant Modularity Traits: Functions and Challenges. AB - On-spot persistence, space occupancy, and recovery after damage are key plant functions largely understudied. Traits relevant to these functions are difficult to assess because of their relationships to plant modularity. We suggest that developing collection protocols for these traits is feasible and could facilitate their inclusion in global syntheses. PMID- 28625792 TI - Remembering the basics: interventions to improve sputum collection for tuberculosis diagnosis. PMID- 28625777 TI - Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study's primary analysis of 2573 patients. AB - AIM: To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin(r) SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). METHODS: Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to <=10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. RESULTS: In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade >= 3 AEs and 326 (12.7%) experienced serious AEs. Grade >= 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. CONCLUSION: SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC. PMID- 28625794 TI - [Rupture of ventricular false tendon without cardiopathy]. PMID- 28625793 TI - Comparison of sputum collection methods for tuberculosis diagnosis: a systematic review and pairwise and network meta-analysis. AB - BACKGROUND: The performance of laboratory tests to diagnose pulmonary tuberculosis is dependent on the quality of the sputum sample tested. The relative merits of sputum collection methods to improve tuberculosis diagnosis are poorly characterised. We therefore aimed to investigate the effects of sputum collection methods on tuberculosis diagnosis. METHODS: We did a systematic review and meta-analysis to investigate whether non-invasive sputum collection methods in people aged at least 12 years improve the diagnostic performance of laboratory testing for pulmonary tuberculosis. We searched PubMed, Google Scholar, ProQuest, Web of Science, CINAHL, and Embase up to April 14, 2017, to identify relevant experimental, case-control, or cohort studies. We analysed data by pairwise meta analyses with a random-effects model and by network meta-analysis. All diagnostic performance data were calculated at the sputum-sample level, except where authors only reported data at the individual patient-level. Heterogeneity was assessed, with potential causes identified by logistic meta-regression. FINDINGS: We identified 23 eligible studies published between 1959 and 2017, involving 8967 participants who provided 19 252 sputum samples. Brief, on-demand spot sputum collection was the main reference standard. Pooled sputum collection increased tuberculosis diagnosis by microscopy (odds ratio [OR] 1.6, 95% CI 1.3-1.9, p<0.0001) or culture (1.7, 1.2-2.4, p=0.01). Providing instructions to the patient before sputum collection, during observed collection, or together with physiotherapy assistance increased diagnostic performance by microscopy (OR 1.6, 95% CI 1.3-2.0, p<0.0001). Collecting early morning sputum did not significantly increase diagnostic performance of microscopy (OR 1.5, 95% CI 0.9-2.6, p=0.2) or culture (1.4, 0.9-2.4, p=0.2). Network meta-analysis confirmed these findings, and revealed that both pooled and instructed spot sputum collections were similarly effective techniques for increasing the diagnostic performance of microscopy. INTERPRETATION: Tuberculosis diagnoses were substantially increased by either pooled collection or by providing instruction on how to produce a sputum sample taken at any time of the day. Both interventions had a similar effect to that reported for the introduction of new, expensive laboratory tests, and therefore warrant further exploration in the drive to end the global tuberculosis epidemic. FUNDING: Wellcome Trust, Joint Global Health Trials consortium, Innovation For Health and Development, and Bill & Melinda Gates Foundation. PMID- 28625795 TI - [Right-side aortic arch with aberrant left subclavian artery and Kommerell's diverticulum. A cause of vascular ring]. AB - The right-side aortic arch may be associated with aberrant left subclavian artery, in some cases this artery originates from an aneurismal dilation of the aorta called Kommerell's diverticulum. A report is presented on 2 cases of vascular ring formed by a right-side aortic arch, anomalous left subclavian artery, Kommerell's diverticulum and left patent ductus arteriosus. A review the literature was also performed as regards the embryological development and the imaging methods used to help in the diagnosis of this rare vascular anomaly. PMID- 28625796 TI - The characterization of RHEB gene and its responses to hypoxia and thermal stresses in the small abalone Haliotis diversicolor. AB - RHEB (Ras Homolog Enriched in Brain) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mechanistic target of rapamycin (mTOR) pathway, and regulates the cell cycle progression and growth. The goal of this study was to characterize the RHEB gene in the small abalone Haliotis diversicolor, and identify the responses of RHEB gene to stresses of hypoxia or/and thermal. The objectives were to: 1) clone the full-length cDNA RHEB gene in the H. diversicolor (HdRHEB); 2) quantify the expression of HdRHEB gene in tissues of haemocytes, mantle, kidney, gill, digestive tract, colleterial gland, and hepatopancreas by using RT-PCR, and 3) evaluate the responses of HdRHEB in gill and haemocyte to stresses of hypoxia (0.2mg/l00ml), thermal (31 degrees C), and combination of hypoxia (0.4mg/l00ml) and thermal (30 degrees C) at exposure time of 0, 4, 24, 96, and 192h. The full length cDNA of HdRHEB was 1044bp encoding a peptide of 182 amino acid residues. Expression of HdRHEB gene was detected in all of the 7 tissues and showed the highest in mantle (P<0.05). Under hypoxia, expression of HdRHEB in gill increased significantly at 4h, 24h and 96h (P<0.05), and that in haemocyte increased significantly at 24h, 96h and 192h (P<0.05). Under thermal stress, expression of HdRHEB gene in gill decreased significantly at 4h and 24h, while expression in haemocyte decreased significantly all the time. Under thermal and hypoxia stresses, expression of HdRHEB gene in gill and haemocyte was up-regulated significantly at 24h and 96h (P<0.05). The results in this study demonstrated for the first time that RHEB gene in abalones is able to response to stress stimuli of hypoxia or/and thermal. PMID- 28625797 TI - Breast implant-associated anaplastic large cell lymphoma - From diagnosis to treatment. AB - Breast lymphomas comprise a rare group of malignant breast tumors. Among these, a new entity has emerged as a potentially under-diagnosed disease. Breast implant associated anaplastic large cell lymphoma (BI-ALCL) most often manifests as a late periprosthetic effusion between 1 and 10 years after the implantation of silicone or saline-filled breast prostheses. BI-ALCL is an anaplastic lymphoma kinase-negative T-cell lymphoma that has a distinctively different clinical course than other breast lymphomas or ALCLs. Diagnosis is based on aspiration of the effusion around the implant and CD30 positivity of the sample. Every periprosthetic effusion after breast augmentation or reconstruction using implants should be considered as potential BI-ALCL until proven otherwise. The majority of cases at diagnosis are in the in situ stage, i.e., confined to the lumen around the prosthesis. Most patients have an excellent prognosis when complete removal of the capsule and prosthesis with negative margins is achieved surgically. Some patients, however, develop infiltrative disease with a potentially life-threatening clinical course. Treatment planning regarding the extent of surgery and role of adjuvant therapy, especially in advanced cases, requires further investigation. PMID- 28625798 TI - Melanoma patient imaging in the era of effective systemic therapies. AB - Imaging plays a critical role in the current multi-disciplinary management of patients with melanoma. It is used for primary disease staging, surgical planning, and surveillance in high-risk patients, and for monitoring the effects of systemic or loco-regional therapies. Several different imaging modalities have been utilised in the past. Contemporary imaging practises vary geographically depending on clinical guidelines, physician preferences, availability and cost. Targeted therapies and immunotherapies have revolutionised the treatment of patients with metastatic melanoma over the last few years. With this have come new patterns of disease that were not observed after conventional therapies, and new criteria to assess therapeutic responses. In this article we review the role of imaging for patients with melanoma in the era of effective systemic therapies and discuss likely future developments. PMID- 28625799 TI - Continuous glucose monitoring in a cystic fibrosis patient to predict pulmonary exacerbation? AB - Patients with cystic fibrosis (CF) experience a significant decline in pulmonary status before the diagnosis of cystic fibrosis related diabetes (CFRD). We hypothesized that hyperglycemia may be a factor in the decline of pulmonary function and increased frequency of pulmonary exacerbations. Long term continuous glucose monitoring (CGM) has not been reported in patients with CF and impaired glucose tolerance. We performed CGM for three months in a 17year old male with F508del and F553X CF mutations, baseline forced expiratory volume in 1s (FEV1) of 92% predicted, and impaired glucose tolerance to evaluate changes in glucose levels prior to the diagnosis of a pulmonary exacerbation. Results revealed elevated overnight, fasting and post-prandial glucose levels up to one week prior to diagnosis of a pulmonary exacerbation compared to baseline. In addition, mean glucose was elevated and the patient spent a greater percentage of time with interstitial glucose>140mg/dL up to one week prior to diagnosis of a pulmonary exacerbation. This emphasizes the hypothesis that hyperglycaemia may be a factor in pulmonary exacerbations in this population. This case study strengthens the evidence base to support larger longitudinal studies to understand the impact of glycaemic control and pulmonary function in patients with CF and glucose intolerance. PMID- 28625800 TI - Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. AB - Arsenic contamination of drinking water and food threatens the health of hundreds of millions of people worldwide by increasing the risk of numerous diseases. Arsenic exposure has been associated with infectious lung disease in epidemiological studies, but it is not yet understood how ingestion of low levels of arsenic increases susceptibility to bacterial infection. Accordingly, the goal of this study was to examine the effect of arsenic on gene expression in primary human bronchial epithelial (HBE) cells and to determine if arsenic altered epithelial cell responses to Pseudomonas aeruginosa, an opportunistic pathogen. Bronchial epithelial cells line the airway surface, providing a physical barrier and serving critical roles in antimicrobial defense and signaling to professional immune cells. We used RNA-seq to define the transcriptional response of HBE cells to Pseudomonas aeruginosa, and investigated how arsenic affected HBE gene networks in the presence and absence of the bacterial challenge. Environmentally relevant levels of arsenic significantly changed the expression of genes involved in cellular redox homeostasis and host defense to bacterial infection, and decreased genes that code for secreted antimicrobial factors such as lysozyme. Using pathway analysis, we identified Sox4 and Nrf2-regulated gene networks that are predicted to mediate the arsenic-induced decrease in lysozyme secretion. In addition, we demonstrated that arsenic decreased lysozyme in the airway surface liquid, resulting in reduced lysis of Microccocus luteus. Thus, arsenic alters the expression of genes and proteins in innate host defense pathways, thereby decreasing the ability of the lung epithelium to fight bacterial infection. PMID- 28625801 TI - Clinical features, antifungal susceptibility, and outcome of Candida guilliermondii fungemia: An experience in a tertiary hospital in mid-Taiwan. AB - BACKGROUNDS: Candida guilliermondii is rarely isolated from clinical specimen. C. guilliermondii fungemia is seldom reported in the literature. The aims of this study were to report the clinical features, antifungal susceptibility, and outcomes of patients with C. guilliermondii fungemia. METHODS: From 2003 to 2015, we retrospectively analyzed the clinical and laboratory data of patients with C. guilliermondii fungemia in a tertiary hospital in mid-Taiwan. We performed a multivariable logistic regression analysis to identify the risk factors of mortality. The Sensititre YeastOne microtiter panel assessed the susceptibility of antifungal agents. RESULTS: In this study, we identified 36 patients with C. guilliermondii fungemia. The median age of patients was 50.5 years (range, 17 days to 96 year) and 20 cases (56%) were male. The incidence of C. guilliermondii fungemia was 0.05 per 1000 admissions. Malignancy was the most common co morbidity, and 25 (69%) patients had central venous catheter in place. Thirty-day overall mortality was 16.7%. In multivariate logistical regression analysis, catheter retention was an independent risk factor of mortality. According to epidemiological cutoff values, most clinical isolates (21/22, 95.5%) belonged to the wild-type MIC distributions for amphotericin B and flucytosine; however, the isolates were less susceptible to fluconazole (68%) and echinocandins (77-91%). CONCLUSION: Despite the lower mortality rate associated with C. guilliermondii fungemia, the removal of a central venous catheter remained an independent factor influencing the outcome of patients. The clinical significance of less susceptibility of C. guilliermondii to triazoles and echinocandins remains to be elucidated. PMID- 28625802 TI - A questionable conclusion by Ido Stahl et al. PMID- 28625803 TI - Reply to letter to the editor titled "a questionable conclusion by Ido Stahl et al." PMID- 28625804 TI - Visibility of healthcare research institutes through the Web of Science database. AB - OBJECTIVES: The strategic importance of healthcare research institutes (HRIs) in health sciences research in Spain has motivated this analysis of the feasibility of studing their contribution to the Spanish scientific output through their presence as a signatory institution in the publications. MATERIAL AND METHODS: We identified the output of the HRIs in the Web of Science database, comparing their observed output (the institutes are explicitly listed in the authors' workplace) and potential output (estimated based on the linked hospitals). RESULTS AND CONCLUSIONS: The studies based on scientific publications do not help us reliably identify the contribution of the HRIs because their observed production is much lower than the potential output, although their visibility tends to increase over time. This article highlights the importance of HRI members including the institute among their work addresses to increase the visibility of these organisations and to facilitate studies aimed at assessing their activity in the national and international context. PMID- 28625805 TI - Responsiveness and minimal important difference of the urticaria control test. PMID- 28625806 TI - A randomized, placebo-controlled, double-blinded, crossover trial of pioglitazone for severe asthma. PMID- 28625808 TI - Relationship between EASI and SCORAD severity assessments for atopic dermatitis. PMID- 28625809 TI - Influence of chronic lymphocytic thyroiditis on the risk of persistent and recurrent disease in patients with papillary thyroid carcinoma and elevated antithyroglobulin antibodies after initial therapy. AB - INTRODUCTION: In patients with papillary thyroid carcinoma who have negative serum thyroglobulin after initial therapy, the risk of structural disease is higher among those with elevated antithyroglobulin antibodies compared to patients without antithyroglobulin antibodies. Other studies suggest that the presence of chronic lymphocytic thyroiditis is associated with a lower risk of persistence/recurrence of papillary thyroid carcinoma. OBJECTIVE: This prospective study evaluated the influence of chronic lymphocytic thyroiditis on the risk of persistence and recurrence of papillary thyroid carcinoma in patients with negative thyroglobulin but elevated antithyroglobulin antibodies after initial therapy. METHODS: This was a prospective study. Patients with clinical examination showing no anomalies, basal Tg<1ng/mL, and elevated antithyroglobulin antibodies 8-12 months after ablation were selected. The patients were divided into two groups: Group A, with chronic lymphocytic thyroiditis on histology; Group B, without histological chronic lymphocytic thyroiditis. RESULTS: The time of follow-up ranged from 60 to 140 months. Persistent disease was detected in 3 patients of Group A (6.6%) and in 6 of Group B (8.8%) (p=1.0). During follow-up, recurrences were diagnosed in 2 patients of Group A (4.7%) and in 5 of Group B (8%) (p=0.7). Considering both persistent and recurrent disease, structural disease was detected in 5 patients of Group A (11.1%) and in 11 of Group B (16.1%) (p=0.58). There was no case of death related to the disease. CONCLUSION: Our results do not support the hypothesis that chronic lymphocytic thyroiditis is associated with a lower risk of persistent or recurrent disease, at least in patients with persistently elevated antithyroglobulin antibodies after initial therapy for papillary thyroid carcinoma. PMID- 28625811 TI - Intra-operative radiological diagnosis of a tip roll-over electrode array displacement using fluoroscopy, when electrophysiological testing is normal: the importance of both techniques in cochlear implant surgery. PMID- 28625810 TI - Evaluating the ototoxicity of an anti-MRSA peptide KR-12-a2. AB - INTRODUCTION: Methicillin-resistant staphylococcus aureus is an emerging problem for the treatment of chronic suppurative otitis media, and also for pediatric tympanostomy tube otorrhea. To date, there are no effective topical antibiotic drugs to treat methicillin-resistant staphylococcus aureus otorrhea. OBJECTIVE: In this study, we evaluated the ototoxicity of topical KR-12-a2 solution on the cochlea when it is applied topically in the middle ear of guinea pigs. METHODS: The antimicrobial activity of KR-12-a2 against methicillin-resistant staphylococcus aureus strains was examined by using the inhibition zone test. Topical application of KR-12-a2 solution, gentamicin and phosphate buffered saline were applied in the middle ear of the guinea pigs after inserting ventilation tubes. Ototoxicity was assessed by auditory brainstem evoked response and scanning electron microscope examination. RESULTS: KR-12-a2 produced an inhibition zone against methicillin-resistant staphylococcus aureus from 6.25 MUg. Hearing threshold in the KR-12-a2 and PBS groups were similar to that before ventilation tube insertion. However, the gentamicin group showed elevation of the hearing threshold and there were statistically significant differences compared to the phosphate buffered saline or the KR-12-a2 group. In the scanning electron microscope findings, the KR-12-a2 group showed intact outer hair cells. However, the gentamicin group showed total loss of outer hair cells. In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. CONCLUSION: In our experiment, topically applied KR-12-a2 solution did not cause hearing loss or cochlear damage in guinea pigs. The KR-12 a2 solution can be used as ototopical drops for treating methicillin-resistant staphylococcus aureus otorrhea; however, further evaluations, such as the definition of optimal concentration and combination, are necessary. PMID- 28625807 TI - Evidence for altered levels of IgD in the nasal airway mucosa of patients with chronic rhinosinusitis. AB - BACKGROUND: IgD is an enigmatic antibody isotype best known when coexpressed with IgM on naive B cells. However, increased soluble IgD (sIgD) levels and increased IgD+IgM- B-cell populations have been described in the human upper respiratory mucosa. OBJECTIVE: We assessed whether levels of sIgD and IgD+ B cell counts are altered in nasal tissue from patients with chronic rhinosinusitis (CRS). We further characterized IgD+ B-cell populations and explored clinical and local inflammatory factors associated with tissue sIgD levels. METHODS: sIgD levels were measured by means of ELISA in nasal tissues, nasal lavage fluid, sera, and supernatants of dissociated nasal tissues. IgD+ cells were identified by using immunofluorescence and flow cytometry. Inflammatory mediator levels in tissues were assessed by using real-time PCR and multiplex immunoassays. Bacterial cultures from the middle meatus were performed. Underlying medical history and medicine use were obtained from medical records. RESULTS: sIgD levels and numbers of IgD+ cells were significantly increased in uncinate tissue (UT) of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) compared with that of control subjects (4-fold, P < .05). IgD+ cells were densely scattered in the periglandular regions of UT from patients with CRSsNP. We also found that IgD+CD19+CD38bright plasmablast numbers were significantly increased in tissues from patients with CRSsNP compared with control tissues (P < .05). Among numerous factors tested, IL-2 levels were increased in UT from patients with CRSsNP and were positively correlated with tissue IgD levels. Additionally, supernatants of IL-2-stimulated dissociated tissue from patients with CRSsNP had significantly increased sIgD levels compared with those in IL-2-stimulated dissociated control tissue ex vivo (P < .05). Tissue from patients with CRS with preoperative antibiotic use or those with pathogenic bacteria showed higher IgD levels compared with tissue from patients without these variables (P < .05). CONCLUSION: sIgD levels and IgD+CD19+CD38bright plasmablast counts were increased in nasal tissue of patients with CRSsNP. IgD levels were associated with increased IL-2 levels and the presence of pathogenic bacteria. These findings suggest that IgD might contribute to enhancement mucosal immunity or inflammation or respond to bacterial infections in patients with CRS, especially CRSsNP. PMID- 28625812 TI - Did the Great Recession increase suicides in the USA? Evidence from an interrupted time-series analysis. AB - PURPOSE: Research suggests that the Great Recession of 2007-2009 led to nearly 5000 excess suicides in the United States. However, prior work has not accounted for seasonal patterning and unique suicide trends by age and gender. METHODS: We calculated monthly suicide rates from 1999 to 2013 for men and women aged 15 and above. Suicide rates before the Great Recession were used to predict the rate during and after the Great Recession. Death rates for each age-gender group were modeled using Poisson regression with robust variance, accounting for seasonal and nonlinear suicide trajectories. RESULTS: There were 56,658 suicide deaths during the Great Recession. Age- and gender-specific suicide trends before the recession demonstrated clear seasonal and nonlinear trajectories. Our models predicted 57,140 expected suicide deaths, leading to 482 fewer observed than expected suicides (95% confidence interval -2079, 943). CONCLUSIONS: We found little evidence to suggest that the Great Recession interrupted existing trajectories of suicide rates. Suicide rates were already increasing before the Great Recession for middle-aged men and women. Future studies estimating the impact of recessions on suicide should account for the diverse and unique suicide trajectories of different social groups. PMID- 28625813 TI - Neurogenesis in the aging brain. AB - Adult neurogenesis is the process of producing new neurons from neural stem cells (NSCs) for integration into the brain circuitry. Neurogenesis occurs throughout life in the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus. However, during aging, NSCs and their progenitors exhibit reduced proliferation and neuron production, which is thought to contribute to age-related cognitive impairment and reduced plasticity that is necessary for some types of brain repair. In this review, we describe NSCs and their niches during tissue homeostasis and how they undergo age-associated remodeling and dysfunction. We also discuss some of the functional ramifications in the brain from NSC aging. Finally, we discuss some recent insights from interventions in NSC aging that could eventually translate into therapies for healthy brain aging. PMID- 28625814 TI - A multi-technique characterization of the stability of surfactant containing solid dispersion based buccal patches prepared by hot melt injection moulding. AB - This study investigates the stability of typically complex multi-component hydrophilic solid dispersions that could be used in a clinical application. Felodipine solid dispersions in two types of blends consisting of PEG, PEO and Tween 80 or Vit E TPGS were prepared by hot melt-injection moulding (HMIM) across a range of drug loadings and subjected to a range of storage conditions. Microscopy, thermal analysis, spectroscopy and powder X-ray diffraction were used to characterize the systems. The semi-solid surfactant TPGS showed a better solubilizing effect on the drug than the liquid surfactant Tween 80 in the fresh state and offered some degree of protection over the chemical degradation of PEG/PEO. Better storage stability was observed for the systems with low drug loading. Crystallization of a new metastable polymorphic form of felodipine in the patches with drug loadings at and above the saturation point was observed. Quantitative comparison of the data sets was achieved by a normalisation process and calculation of statistical variance. TPGS containing patches were more sensitive to the aging process than Tween containing patches. For both surfactants, such instability is more responsive to the storage temperature than humidity. This study established a methodology for probing the complex stabilities of multi-component dispersions. PMID- 28625815 TI - Risk of Pneumonia Caused by Pneumocystis jiroveci in Inflammatory Bowel Disease: The Role of Concomitant Pulmonary Comorbidities. PMID- 28625816 TI - A Prospective Multicenter Study Evaluating Learning Curves and Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography Among Advanced Endoscopy Trainees: The Rapid Assessment of Trainee Endoscopy Skills Study. AB - BACKGROUND & AIMS: On the basis of the Next Accreditation System, trainee assessment should occur on a continuous basis with individualized feedback. We aimed to validate endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) learning curves among advanced endoscopy trainees (AETs) by using a large national sample of training programs and to develop a centralized database that allows assessment of performance in relation to peers. METHODS: ASGE recognized training programs were invited to participate, and AETs were graded on ERCP and EUS exams by using a validated competency assessment tool that assesses technical and cognitive competence in a continuous fashion. Grading for each skill was done by using a 4-point scoring system, and a comprehensive data collection and reporting system was built to create learning curves by using cumulative sum analysis. Individual results and benchmarking to peers were shared with AETs and trainers quarterly. RESULTS: Of the 62 programs invited, 20 programs and 22 AETs participated in this study. At the end of training, median number of EUS and ERCP performed/AET was 300 (range, 155-650) and 350 (125-500), respectively. Overall, 3786 exams were graded (EUS, 1137; ERCP-biliary, 2280; ERCP-pancreatic, 369). Learning curves for individual end points and overall technical/cognitive aspects in EUS and ERCP demonstrated substantial variability and were successfully shared with all programs. The majority of trainees achieved overall technical (EUS, 82%; ERCP, 60%) and cognitive (EUS, 76%; ERCP, 100%) competence at conclusion of training. CONCLUSIONS: These results demonstrate the feasibility of establishing a centralized database to report individualized learning curves and confirm the substantial variability in time to achieve competence among AETs in EUS and ERCP. ClinicalTrials.gov: NCT02509416. PMID- 28625817 TI - Natural History of Adult Ulcerative Colitis in Population-based Cohorts: A Systematic Review. AB - BACKGROUND & AIMS: A comprehensive knowledge of the natural history of ulcerative colitis (UC) helps understand disease evolution, identify poor prognostic markers and impact of treatment strategies, and facilitates shared decision-making. We systematically reviewed the natural history of UC in adult population-based cohort studies with long-term follow-up. METHODS: Through a systematic literature review of MEDLINE through March 31, 2016, we identified 60 studies performed in 17 population-based inception cohorts reporting the long-term course and outcomes of adult-onset UC (n = 15,316 UC patients). RESULTS: Left-sided colitis is the most frequent location, and disease extension is observed in 10%-30% of patients. Majority of patients have a mild-moderate course, which is most active at diagnosis and then in varying periods of remission or mild activity; about 10% 15% of patients experience an aggressive course, and the cumulative risk of relapse is 70%-80% at 10 years. Almost 50% of patients require UC-related hospitalization, and 5-year risk of re-hospitalization is ~50%. The 5-year and 10 year cumulative risk of colectomy is 10%-15%; achieving mucosal healing is associated with lower risk of colectomy. About 50% of patients receive corticosteroids, although this proportion has decreased over time, with a corresponding increase in the use of immunomodulators (20%) and anti-tumor necrosis factor (5%-10%). Although UC is not associated with an increased risk of mortality, it is associated with high morbidity and work disability, comparable to Crohn's disease. CONCLUSIONS: UC is a disabling condition over time. Prospective cohorts are needed to evaluate the impact of recent strategies of early use of disease-modifying therapies and treat-to-target approach with immunomodulators and biologics. Long-term studies from low-incidence areas are also needed. PMID- 28625818 TI - Quantitative assessment of lung and bladder cancer risk and oral exposure to inorganic arsenic: Meta-regression analyses of epidemiological data. AB - Inorganic arsenic (iAs) in drinking water varies geographically and is prevalent worldwide. While exposures in the US are generally low, there are some areas with higher levels of naturally occurring iAs (potentially >100MUg/L) where residents rely on unregulated drinking water wells. Much of the evidence on the association between iAs and cancer comes from epidemiological studies conducted in South American and Asian populations. These populations have generally been exposed to much higher levels of iAs and have differing underlying characteristics, both of which make comparing them to Western populations difficult. A key question is whether and how one should extrapolate from these high exposure studies to estimate cancer risk at lower exposures. We conducted an independent analysis to determine the most appropriate cancer endpoints, studies, and models to support an oral carcinogenicity assessment of iAs, taking into consideration factors that affect the apparent potency of iAs across geographically and culturally distinct populations. We identified bladder and lung cancer as high-priority endpoints and used meta-regression to pool data across studies from different regions of the world to derive oral cancer slope factors (CSFs) and unit risks (excess risk per MUg/L) for iAs based on the background risks of bladder and lung cancer in the US. We also calculated concentrations of iAs in water that are not likely to result in cancer risk above what is considered acceptable by the United States Environmental Protection Agency (US EPA). While we derived these factors assuming a linear, no-threshold relationship between iAs and cancer risk, we also evaluated the shape of the dose-response curves and assessed the evidence for overall nonlinearity. Overall, we found that the incremental risks of bladder and lung cancer associated with iAs were relatively low. The sensitivity analyses we conducted suggested that populations with relatively high iAs exposures appeared to drive the pooled cancer risk estimates, but many of our other tested assumptions did not substantially alter these estimates. Finally, we found that the mode of action evidence supports there being a threshold, but making a robust quantitative demonstration of a threshold using epidemiological data is difficult. When considered in the context of typical exposure levels in the US, our potency estimates indicate that iAs-induced cancer risk is much lower than observed bladder and lung cancer incidences. This suggests that the low iAs levels to which much of the general US population is exposed likely do not result in substantial additional cancer risk. PMID- 28625819 TI - Outcomes of relocation of basilic vein in brachiobasilic fistulas in chronic renal failure. AB - BACKGROUND: In patients without or with injured cephalic vein, using the basilic vein for creating arteriovenous fistula (AVF) is the best way for hemodialysis. In order to create AVF, the basilic vein should be superficialized and lateralized. This study sought to examine outcome of relocation of basilic vein in brachiobasilic fistulas in patients with chronic renal failure (CRF). METHODS: We evaluated the outcome of creation of brachiobasilic fistula with transposition of basilic vein in 27 patients (14 males and 13 females with mean age of 60.03 +/ 8.04 years) with CRF. The success rate and complications were recorded during the follow-up period. The fistula was regarded efficient if cannulation was feasible conveniently and a minimum flow rate of 250 ml/min for 4 h at least for 3 consecutive hemodialysis sessions through both lines was documented 30 days postoperatively. RESULTS: The mean time gap between previous AVF creation or try and the relocation of basilic vein was 3.55 months. Thirty days postoperatively, 85.2% of the created AVFs were efficiently working. There were postoperative complications in 40.7% of patients including venous hypertension (14.8%), bleeding (7.4%), hematoma (7.4%) and distal paresthesia (11.1%). CONCLUSIONS: Brachiobasilic AVF fistula provides a suitable option for vascular access in cases with failed previous AVF. Relocation of basilic vein for brachiobasilic AVF is technically feasible, safe and with excellent patency in short-term and complication rates are acceptable. PMID- 28625820 TI - The effect of economic downturn on the volume of surgical procedures: A systematic review. AB - BACKGROUND: Economic downturn can have a wide range of effects on medicine at both individual and national levels. We aim to describe these effects in relation to surgical volume to guide future planning for physician specialization, patient expectations in the face of economic crises, or estimating healthcare expenditure. We hypothesized that because of high out-of-pocket costs, cosmetic procedure volumes would be most affected by economic decline. METHODS: A systematic review was conducted using MEDLINE, Embase, and ABI/INFORMS. The main search terms were "economic recession" and "surgical procedures, operative". Studies were included if surgical volumes were measured and economic indicators were used as predictors of economic conditions. RESULTS: Twelve studies were included, and the most common subject was cosmetic (n = 5), followed by orthopedic (n = 2) and cardiac surgeries (n = 2). The majority of studies found that in periods of economic downturn, surgical volume decreased. Among the eight studies using Pearson's correlation analysis, there were no significant differences between cosmetic procedures and other elective procedures, indicating that cosmetic procedures may display trends similar to those of non-cosmetic elective procedures in periods of economic downturn. CONCLUSIONS: Surgical volume generally decreased when economic indicators declined, observed for both elective and non-elective surgery fields. However, a few specific procedure volumes such as vasectomy and caesarean section for male babies increased during the economic downturn. Knowledge of these trends can be useful for future surgical planning and distribution of healthcare resources. PMID- 28625821 TI - The use of study registration and protocols in plastic surgery research: A systematic review. AB - BACKGROUND: In 2013, the Declaration of Helsinki changed to mandate that all research studies involving human subjects, rather than just clinical trials alone, must have a protocol registered in a publicly accessible database prior to the enrolment of the first patient. The objective of this work was to assess the number of research studies involving human participants published in leading journals of plastic surgery that had either published a protocol or registered a protocol with a publicly accessible database. MATERIALS AND METHODS: This systematic review examined all research articles involving human participants published in Plastic and Reconstructive Surgery, The Journal of Plastic Reconstructive and Aesthetic Surgery and The Annals of Plastic Surgery from 1st April 2014-31st March 2015. The primary outcome measure was whether each study had either published or registered a protocol with any mainstream registry database. ClinicalTrials.gov, the International Standard Randomized Control Trial Number (ISRCTN) registry, the WHO (World Health Organisation) International Clinical Trials Registry Platform, The Cochrane Collaboration, the Research Registry, PROSPERO and PubMed were all reviewed. RESULTS: Of 595 included articles, the most common study designs were case series (n = 185, 31.1%). There were 24 randomized controlled trials (RCTs, 4.0%). A total of 24 studies had a protocol registered (4.0%). The most common database to register a protocol was with ClinicalTrials.gov (n = 17). The study design that most commonly had a registered protocol was the RCT (n = 8 of 24, 33.3% of RCTs). Three studies published a protocol in a journal (0.6%). CONCLUSION: Publication or registration of protocols for recent studies involving human participants in major plastic surgery journals is low. There is considerable scope to improve this and guidance is provided. PMID- 28625822 TI - Comparison of the expression and spatial localization of glucose transporters in the rat, bovine and human lens. AB - The energy required to drive lens transparency is derived from the metabolism of glucose. In the lens, the uptake of glucose is likely to involve either facilitative glucose uptake mediated by members of the GLUT family or Na+ dependent glucose uptake via members of the SGLT family, or both. While GLUT1 and GLUT3 have previously been identified in the rat lens, the expression of SGLTs is unknown. Since antibodies directed against the N and C-terminal epitopes of the GLUT and SGLT family are now commercially available, the purpose of this study is to extend our screening of glucose transporters in the rat lens to include the SGLTs and compare the expression profiles of GLUTs and SGLTs in the different regions of the rat, bovine and human lens. Using a combination of reverse transcriptase PCR, western blotting and immunohistochemistry, we have shown that GLUT1 appears to be the predominant glucose transporter in the rat lens since it was expressed in all regions of the lens. In contrast GLUT3, SGLT1 and SGLT2 had more restricted expression patterns and were only found localised to the inner cortex and core regions of the rat lens. GLUT1 was the only transporter found in the epithelium and appears to exist as a full length form in this region, while in differentiating fiber cells; GLUT1 appears to undergo a modification to its N terminus. Translating our work to bovine and human lenses revealed that GLUT1 is the only glucose transporter expressed in bovine and human lenses. While GLUT1 in the bovine lens appears to be unmodified throughout the entire lens, GLUT1 in human lenses appears to be N-terminally modified in all regions, including the epithelium. Finally, it appears that GLUT1 expression is maintained in all regions of the human lens with increasing age indicating that there is no further regional or age-dependent processing of GLUT1 in the human lens. Taken together, these studies have identified GLUT1 to be the primary transporter that mediates glucose uptake in the rat, bovine and human lens. PMID- 28625823 TI - The leukocyte-associated immunoglobulin (Ig)-like receptor-1 modulating cell apoptosis and inflammatory cytokines secretion in THP-1 cells after Helicobacter pylori infection. AB - OBJECTIVE: Helicobacter pylori is a Gram-negative, microaerophilic bacteria usually found in the stomach, which may evade its host's immune system and present long-term symptoms in affected individuals. This study aimed to evaluate the functional role of leukocyte-associated immunoglobulin (Ig)-like receptor-1 (LAIR-1) in the strategies and underlying molecular mechanisms by which H. pylori escapes the host's immune responses. METHODS: LAIR-1 knockdown THP-1 cells were used to detect cell apoptosis, cell proliferation, interleukin-8 (IL-8), IL-10, and activation of intracellular signaling induced by H. pylori. RESULTS: Cell apoptosis, cell proliferation, IL-8, and IL-10 were increased in THP-1 cells after 24 h of H. pylori infection. Functional analysis indicated LAIR-1 silencing obviously inhibited the phosphorylation of IkappaBalpha, eIF2alpha, JNK, and Smad2 in the THP-1 after H. pylori infection. In addition, there were no significant differences in proliferation rates between control siRNA group and LAIR-1 siRNA group regardless of whether THP-1 cells were infected by H. pylori. CONCLUSION: These results together indicated that LAIR-1 modulated cell apoptosis and inflammatory cytokines secretion in THP-1 cells, which might help sustain inflammation and prevent removal of the bacteria by the immune responses. PMID- 28625824 TI - Polymorphism study of Cryptosporidium hominis gp60 subtypes circulating in Tunisia. AB - Cryptosporidium spp. are a major cause of gastrointestinal diseases in humans worldwide. While a single subtype of Cryptosporidium hominis has been shown to be responsible for several large outbreaks related to water contamination in developed countries, little is known about the epidemiology of C. hominis in developing countries. This study reports the first genetic characterization of C. hominis at the subtype level in several human populations in Tunisia using the gp60 gene. Eighteen isolates were identified as C. hominis by a restriction fragment length polymorphism (RFLP) analysis. The prevalence of this species in different human populations ranges from 1.53% to 13.04% with a high prevalence being reported in immunocompromised children (13.04%) followed by patients with malignent myeloma (5.5%) and HIV-infected patients (4.59%). The gp60 analysis on C. hominis isolates, performed in 14 cases, showed the presence of a single subtype family: "Ia". Different subtypes were identified within this family (A11G1R1, A12R3, A23G1R1, A26G1R1, A27G1R1, A28G1R1). The IaA26G1R1 subtype was the most dominant subtype described in this area (50%). Despite the high genetic diversity of Cryptosporidium spp, a low heterogeneity at the subtype level was observed within C. hominis circulating in Tunisia. This distribution is an indicator for intensive and stable anthroponotic cryptosporidiosis in this region. Besides, the presence of a unique genotype in 5 HIV-infected patients attending the same hospital ward suggests the possible occurrence of hospital acquired infection and underlines the need to implement preventive measures to avoid nosocomial transmission. PMID- 28625825 TI - Red blood cell transfusion in surgical cancer patients: Targets, risks, mechanistic understanding and further therapeutic opportunities. AB - Anemia is present in more than half of cancer patients and appears to be an independent prognostic factor of short- and long-term adverse outcomes. It increases in the advanced period of cancer and perioperatively, in patients with solid tumors who undergo surgery. As a result, allogeneic red blood cell (RBC) transfusion is an indispensable treatment in cancer. However, its safety remains controversial, based on several laboratory and clinical data reporting a linkage with increased risk for cancer recurrence, infection and cancer-related mortality. Immunological, inflammatory and thrombotic reactions mediated by the residual leukocytes and platelets, the stored RBCs per se, the biological response modifiers and the plasticizer of the unit may underlie infection and tumor-promoting effects. Although the causality between transfusion and infection has been established, the effects of transfusion on cancer recurrence remain confusing; this is mainly due to the extreme biological heterogeneity that characterizes RBC donations and cancer context. In fact, the functional interplay between donation-associated factors and recipient characteristics, including tumor biology per se, inflammation, infection, coagulation and immune activation state and competence may synergistically and individually define the clinical impact of each transfusion in any given cancer patient. Our understanding of how the potential risk is mediated is important to make RBC transfusion safer and to pave the way for novel, promising and highly personalized strategies for the treatment of anemia in surgical cancer patients. PMID- 28625827 TI - Cells as advanced therapeutics: State-of-the-art, challenges, and opportunities in large scale biomanufacturing of high-quality cells for adoptive immunotherapies. AB - Therapeutic cells hold tremendous promise in treating currently incurable, chronic diseases since they perform multiple, integrated, complex functions in vivo compared to traditional small-molecule drugs or biologics. However, they also pose significant challenges as therapeutic products because (a) their complex mechanisms of actions are difficult to understand and (b) low-cost bioprocesses for large-scale, reproducible manufacturing of cells have yet to be developed. Immunotherapies using T cells and dendritic cells (DCs) have already shown great promise in treating several types of cancers, and human mesenchymal stromal cells (hMSCs) are now extensively being evaluated in clinical trials as immune-modulatory cells. Despite these exciting developments, the full potential of cell-based therapeutics cannot be realized unless new engineering technologies enable cost-effective, consistent manufacturing of high-quality therapeutic cells at large-scale. Here we review cell-based immunotherapy concepts focused on the state-of-the-art in manufacturing processes including cell sourcing, isolation, expansion, modification, quality control (QC), and culture media requirements. We also offer insights into how current technologies could be significantly improved and augmented by new technologies, and how disciplines must converge to meet the long-term needs for large-scale production of cell-based immunotherapies. PMID- 28625828 TI - Precision monitoring of immunotherapies in solid organ and hematopoietic stem cell transplantation. AB - Pharmacological immunotherapies are a key component of post-transplant therapy in solid-organ and hematopoietic stem cell transplantation. In current clinical practice, immunotherapies largely follow a one-size fits all approach, leaving a large portion of transplant recipients either over- or under-immunosuppressed, and consequently at risk of infections or immune-mediated complications. Our goal here is to review recent and rapid advances in precision and genomic medicine approaches to monitoring of post-transplant immunotherapies. We will discuss recent advances in precision measurements of pharmacological immunosuppression, measurements of the plasma and gut microbiome, strategies to monitor for allograft injury and post-transplant malignancies via circulating cell-free DNA, and comprehensive measurements of the B and T cell immune cell repertoire. PMID- 28625829 TI - Combinatorial immunotherapy and nanoparticle mediated hyperthermia. AB - Immune checkpoint therapy has become the first widely adopted immunotherapy for patients with late stage malignant melanoma, with potential for a wide range of cancers. While some patients can experience long term disease remission, this is limited only to a subset of patients and tumor types. The path forward to expand this therapy to more patients and tumor types is currently thought to be combinatorial treatments, the combination of immunotherapy with other treatments. In this review, the combinatorial approach of immune checkpoint therapy combined with nanoparticle-assisted localized hyperthermia is discussed, starting with an overview of the different nanoparticle hyperthermia approaches in development, an overview of the state of immune checkpoint therapy, recent reports of immune checkpoint therapy and nanoparticle-assisted hyperthermia in a combinatorial approach, and finally a discussion of future research topics and areas to be explored in this new combinatorial approach to cancer treatment. PMID- 28625826 TI - Drug discovery and therapeutic delivery for the treatment of B and T cell tumors. AB - Hematological malignancies manifest as lymphoma, leukemia, and myeloma, and remain a burden on society. From initial therapy to endless relapse-related treatment, societal burden is felt not only in the context of healthcare cost, but also in the compromised quality of life of patients. Long-term therapeutic strategies have become the standard in keeping hematological malignancies at bay as these cancers develop resistance to each round of therapy with time. As a result, there is a continual need for the development of new drugs to combat resistant disease in order to prolong patient life, if not to produce a cure. This review aims to summarize advances in targeting lymphoma, leukemia, and myeloma through both cutting-edge and well established platforms. Current standard of treatment will be reviewed for these malignancies and emphasis will be made on new therapy development in the areas of antibody engineering, epigenetic small molecule inhibiting drugs, vaccine development, and chimeric antigen receptor cell engineering. In addition, platforms for the delivery of these and other drugs will be reviewed including antibody-drug conjugates, micro- and nanoparticles, and multimodal hydrogels. Lastly, we propose that tissue engineered constructs for hematological malignancies are the missing link in targeted drug discovery alongside mouse and patient-derived xenograft models. PMID- 28625830 TI - Bioengineering strategies for inducing tolerance in autoimmune diabetes. AB - Type 1 diabetes is an autoimmune disease marked by the destruction of insulin producing beta cells in the pancreatic islets. Strategies to delay onset or prevent the autoimmune recognition of beta cell antigens or T cell-mediated killing of beta cells have mainly focused on systemic immunomodulation and antigen-specific immunotherapy. To bridge the fields of type 1 diabetes immunology and biomaterials engineering, this article will review recent trends in the etiology of type 1 diabetes immunopathology and will focus on the contributions of emerging bioengineered strategies in the fight against beta cell autoimmunity in type 1 diabetes. PMID- 28625832 TI - A Diet Low in FODMAPs Reduces Symptoms in Patients With Irritable Bowel Syndrome and A Probiotic Restores Bifidobacterium Species: A Randomized Controlled Trial. AB - BACKGROUND & AIMS: Dietary restriction of fermentable carbohydrates (a low FODMAP diet) has been reported to reduce symptoms in some patients with irritable bowel syndrome (IBS). We performed a randomized, placebo-controlled study to determine its effects on symptoms and the fecal microbiota in patients with IBS. METHODS: We performed a 2*2 factorial trial of 104 patients with IBS (18-65 years old), based on the Rome III criteria, at 2 hospitals in the United Kingdom. Patients were randomly assigned (blinded) to groups given counselling to follow a sham diet or diet low in FODMAPs for 4 weeks, along with a placebo or multistrain probiotic formulation, resulting in 4 groups (27 receiving sham diet/placebo, 26 receiving sham diet/probiotic, 24 receiving low FODMAP diet /placebo, and 27 receiving low FODMAP diet/probiotic). The sham diet restricted a similar number of staple and non-staple foods as the low FODMAP diet; the diets had similar degrees of difficulty to follow. Dietary counselling was given to patients in all groups and data on foods eaten and compliance were collected. The incidence and severity of 15 gastrointestinal symptoms and overall symptoms were measured daily for 7 days before the study period; along with stool frequency and consistency. At baseline, global and individual symptoms were measured, along with generic and disease-specific health-related quality of life, using standard scoring systems. All data were collected again at 4 weeks, and patients answered questions about adequate symptom relief. Fecal samples were collected at baseline and after 4 weeks and analyzed by quantitative PCR and 16S rRNA sequencing. The co-primary endpoints were adequate relief of symptoms and stool Bifidobacterium species abundance at 4 weeks. RESULTS: There was no significant interaction between the interventions in adequate relief of symptoms (P = .52) or Bifidobacterium species (P = .68). In the intention-to-treat analysis, a higher proportion of patients in the low FODMAP diet had adequate symptom relief (57%) than in the sham diet group (38%), although the difference was not statistically significant (P = .051). In the per-protocol analysis, a significantly higher proportion of patients on the low FODMAP diet had adequate symptom relief (61%) than in the sham diet group (39%) (P = .042). Total mean IBS-Severity Scoring System score was significantly lower for patients on the low FODMAP diet (173 +/- 95) than the sham diet (224 +/ 89) (P = .001), but not different between those given probiotic (207 +/- 98) or placebo (192 +/- 93) (P = .721) Abundance of Bifidobacterium species was lower in fecal samples from patients on the low FODMAP diet (8.8 rRNA genes/g) than patients on the sham diet (9.2 rRNA genes/g) (P = .008), but higher in patients given probiotic (9.1 rRNA genes/g) than patients given placebo (8.8 rRNA genes/g) (P = .019). There was no effect of the low FODMAP diet on microbiota diversity in fecal samples. CONCLUSIONS: In a placebo-controlled study of patients with IBS, a low FODMAP diet associates with adequate symptom relief and significantly reduced symptom scores compared with placebo. It is not clear whether changes resulted from collective FODMAP restriction or removal of a single component, such as lactose. Co-administration of the multistrain probiotic increased numbers of Bifidobacterium species, compared with placebo, and might be given to restore these bacteria to patients on a low FODMAP diet. Trial registration no: ISRCTN02275221. PMID- 28625831 TI - Engineering challenges for brain tumor immunotherapy. AB - Malignant brain tumors represent one of the most devastating forms of cancer with abject survival rates that have not changed in the past 60years. This is partly because the brain is a critical organ, and poses unique anatomical, physiological, and immunological barriers. The unique interplay of these barriers also provides an opportunity for creative engineering solutions. Cancer immunotherapy, a means of harnessing the host immune system for anti-tumor efficacy, is becoming a standard approach for treating many cancers. However, its use in brain tumors is not widespread. This review discusses the current approaches, and hurdles to these approaches in treating brain tumors, with a focus on immunotherapies. We identify critical barriers to immunoengineering brain tumor therapies and discuss possible solutions to these challenges. PMID- 28625833 TI - Colorectal Cancer Cell Line Proteomes Are Representative of Primary Tumors and Predict Drug Sensitivity. AB - BACKGROUND AND AIMS: Proteomics holds promise for individualizing cancer treatment. We analyzed to what extent the proteomic landscape of human colorectal cancer (CRC) is maintained in established CRC cell lines and the utility of proteomics for predicting therapeutic responses. METHODS: Proteomic and transcriptomic analyses were performed on 44 CRC cell lines, compared against primary CRCs (n=95) and normal tissues (n=60), and integrated with genomic and drug sensitivity data. RESULTS: Cell lines mirrored the proteomic aberrations of primary tumors, in particular for intrinsic programs. Tumor relationships of protein expression with DNA copy number aberrations and signatures of post transcriptional regulation were recapitulated in cell lines. The 5 proteomic subtypes previously identified in tumors were represented among cell lines. Nonetheless, systematic differences between cell line and tumor proteomes were apparent, attributable to stroma, extrinsic signaling, and growth conditions. Contribution of tumor stroma obscured signatures of DNA mismatch repair identified in cell lines with a hypermutation phenotype. Global proteomic data showed improved utility for predicting both known drug-target relationships and overall drug sensitivity as compared with genomic or transcriptomic measurements. Inhibition of targetable proteins associated with drug responses further identified corresponding synergistic or antagonistic drug combinations. Our data provide evidence for CRC proteomic subtype-specific drug responses. CONCLUSIONS: Proteomes of established CRC cell line are representative of primary tumors. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared with genomic and transcriptomic profiles. Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine. PMID- 28625834 TI - Association Between Natural Killer Cell Activity and Colorectal Cancer in High Risk Subjects Undergoing Colonoscopy. AB - BACKGROUND & AIMS: Low activity of natural killer (NK) cells has been associated with increased risk of cancer and has been reported in patients with colorectal cancer (CRC). Activity of NK cells can be measured in a small volume of whole blood by a commercially available test. We investigated whether this test could be used to identify patients with CRC, using findings from colonoscopy as a reference standard. METHODS: We performed an open-label, prospective, cross sectional study of 872 high-risk subjects (more than 40 years old) screened for CRC by colonoscopy at a university hospital in Montreal, Canada from October 2014 through January 2016. Blood samples were collected on the day of colonoscopy, prior to the procedure. The test involves stimulation of whole blood with cytokine that induces NK cells to secrete interferon gamma (IFNG), which is quantified by an ELISA. Tissue samples were taken from lesions during the colonoscopy and analyzed histologically; subjects were classified as having no evidence of disease, adenomatous polyps of less than 10 mm, of 10 mm or more, or CRC. We used the non-parametric Mann-Whitney test to compare NK cell activity between subjects with no evidence of CRC and subjects found to have CRC. Receiver operating characteristic curve analysis was used to assess the ability of the test to identify individuals with CRC. The primary objective was to determine the difference in NK cell activity between subjects with vs without CRC. The secondary objective was the test performance, based on receiver operating characteristic analysis, and cut-off value that most accurately identified individuals with CRC. RESULTS: We found a significant difference in NK cell activity between the 23 subjects with CRC (based on pathology analysis) and the 849 subjects without CRC: subjects found to have CRC by colonoscopy had a median level of 86.0 pg IFNG/mL (inter-quartile range, 43.3-151.0 pg IFNG/mL), whereas subjects without CRC had a median level of 298.1 pg IFNG/mL (inter-quartile range, 100.4-920.2 pg IFNG/mL) (P = .0002). The cut-off value that most accurately identified subjects with CRC was 181 pg/mL. The NK cell activity test identified subjects with CRC with 87.0% sensitivity, 60.8% specificity, a positive predictive value of 5.7%, and a negative predictive value of 99.4%. The odds ratio for detection of CRC in subjects with low NK cell activity vs subjects with higher NK cell activity was 10.3 (95% CI, 3.03-34.9). CONCLUSIONS: Using colonoscopy as the reference standard, a test for NK cell activity in whole blood samples identified patients with CRC with 87.0% sensitivity and a negative predictive value of 99.4%. Subjects with low NK cell activity had a 10-fold higher risk of CRC compared with subjects with high NK cell activity. This test might be used in clinical practice to assess patients for risk of CRC. Clinicaltrials.gov number: NCT02291198. PMID- 28625836 TI - Molecular interaction studies of acetylcholinesterase with potential acetylcholinesterase inhibitors from the root of Rhodiola crenulata using molecular docking and isothermal titration calorimetry methods. AB - (-)-Epicatechin gallate ((-)-ECG), 1,2,3,4,6-O-pentagalloylglucose (PGG), rhodionin, herbacetin and rhodiosin isolated from the root of Rhodiola crenulata exhibited potent, dose-dependent inhibitory effects on acetylcholinesterase (AChE) with IC50 ranged from 57.50+/-5.83 to 2.43+/-0.34MUg/mL. With the aim of explaining the differences in activity of these active ingredients and clarifying how they inhibit AChE, the AChE-inhibitor interactions were further explored using molecular docking and isothermal titration calorimetry (ITC) methods in the present study. Molecular docking studies revealed that all compounds except PGG showed binding energy values ranging from -10.30 to -8.00kcal/mol while the binding energy of galantamine, a known AChE inhibitor, was -9.53kcal/mol; they inhibited the AChE by binding into the ligand pocket with the similar binding pattern to that of galantamine by interacting with Glu199 of AChE. Inhibition constant of these active ingredients had a positive correlation with binding energy. The interaction between AChE and PGG was further evaluated with the ITC method and the results indicated that the PGG-AChE interaction was relevant to AChE concentration. The results revealed a possible mechanism for the AChE inhibition activity of these bioactive ingredients, which may provide some help in lead compounds optimization in the future. PMID- 28625835 TI - Robust composite silk fibers pulled out of silkworms directly fed with nanoparticles. AB - This paper reports the impacts of direct feeding silkworms with different nanoparticles (Cu, Fe, and TiO2) on the morphology, structures, and mechanical properties of the resulting silk fiber (SF). The contents of the Cu nanoparticles were 38 times higher in the posterior silk glands and only 2-3 times higher in the SF and in the middle silk glands compared with the controlled groups. Significant changes of the surface morphology, structures, and diameter of the Cu nanoparticle fed SF have been observed, which are attributed to a slight SF protein reconstruction or conformational change in the mixture of silk fibroin and sericin in the silk glands. The resulting Cu-containing SF exhibits good tensile strength of 360MPa and reaches a strain of 38%, which are 89% and 36% higher than those of the natural SF. This study offers a new green strategy for the easy modification to achieve robust composite SF. PMID- 28625837 TI - Enhanced corrosion inhibition effect of chitosan for St37 in 15% H2SO4 environment by silver nanoparticles. AB - The inhibitive performance of chitosan and silver nanoparticles - chitosan (AgNPs Chi) composite towards St37 steel corrosion in 15% H2SO4 solution was studied using weight loss and electrochemical techniques in addition to surface morphological examination. Results obtained show that chitosan could fairly protect St37 steel surface by 45%. Inhibition efficiency above 94% has been achieved with AgNPs-Chi composite. AgNPs-Chi composite performs better at longer immersion time and elevated temperature. AgNPs-Chi retards both anodic and cathodic redox reactions. The mode of adsorption of AgNPs-Chi onto St37 surface has been described using Langmuir adsorption isotherm. Surface screening results ascertain the adsorption of AgNPs-Chi molecules on St37 surface. PMID- 28625838 TI - Comparison of 'time to detection' values between BacT/ALERT VIRTUO and BacT/ALERT 3D instruments for clinical blood culture samples. AB - OBJECTIVES: The early detection of bacteraemia and fungemia is of paramount importance to guide antimicrobial therapy in septic patients. In this study the 'time to detection' (TTD) value for the new blood culture system BacT/ALERT VIRTUO (VIRTUO) was evaluated in 1462 positive clinical bottles and compared with the TTD for 1601 positive clinical bottles incubated in the BacT/ALERT 3D system (BTA-3D). METHODS: The most representative microorganisms isolated from bottles incubated in both blood culture systems were divided into eight categories (in order of frequency): coagulase-negative staphylococci (CoNS), Escherichia coli, Enterobacteriaceae (other than E. coli), Staphylococcus aureus, Enterococcus spp, viridans group streptococci, Pseudomonas aeruginosa, and Candida spp. RESULTS: The comparison of TTD values for the two blood culture systems strongly indicated that growth of the first five groups listed above was detected earlier with VIRTUO than with BTA-3D (p < 0.05). CONCLUSIONS: The new VIRTUO blood culture system can reduce the TTD for more than 75% of isolated microorganisms. PMID- 28625840 TI - Survival of Litopenaeus vannamei shrimp fed on diets supplemented with Dunaliella sp. is improved after challenges by Vibrio parahaemolyticus. AB - Survival of Litopenaeus vannamei was evaluated during a Vibrio parahaemolyticus infection. This bacteria has been causing significant economic losses in the shrimp industry due to the appearance of early mortality syndrome (EMS), also known as acute hepatopancreatic necrosis disease (AHPND). Control of bacteria in ponds is difficult to achieve with antibiotics due to environmental infections and antibiotic resistance. New methods have been proposed to control and prevent the impact of bacterial infections. The physiological response indicated by plasma biochemical parameters in shrimp can determine their health and stress status. Meanwhile, shrimp immunology is the key factor in establishing strategies to control diseases. Immunostimulants are the best alternative to antibiotics to prevent or minimize disease damage, and at the same time, these stimulants improve the immune system in shrimp. Four diets containing 1.5, 2, 2.5 and 3% of Dunaliella sp. with high beta-carotene content were tested in the present study. After 20days of feeding, organisms were infected with V. parahaemolyticus. Protein, glucose, lactate, triglyceride and cholesterol levels, as well as activity of prophenoloxidase and phenoloxidase, were determined 48 h post infection (hpi). Shrimp fed a diet with 3% Dunaliella sp. showed the highest survival. Glucose, cholesterol, and triglyceride levels, as well as prophenoloxidase and phenoloxidase activity, were not observed to be suitable indicators during this bacterial infection. The results indicated that the inclusion of Dunaliella sp. in diet increases survival in L. vannamei infected with V. parahaemolyticus. PMID- 28625839 TI - Surveillance of upper respiratory infections using a new multiplex PCR assay compared to conventional methods during the influenza season in Taiwan. AB - OBJECTIVES: To improve diagnosis as part of laboratory surveillance in Taiwan, influenza-like illness (ILI) surveillance was conducted using a new multiplex PCR assay (FilmArray) and the results compared to those of conventional methods The study was performed during the winter months. METHODS: Throat swabs from patients with an ILI presenting to physicians in sentinel practices were collected during the 2016-2017 influenza season. RESULTS: A total of 52 samples tested positive by FilmArray Respiratory Panel. Forty percent were influenza A virus, and subtype H3N2 virus was the major epidemic strain. However, nearly 60% of ILI cases seen at sentinel sites were caused by non-influenza pathogens. The results of the FilmArray assay and cell culture were identical, and this assay was more sensitive than a rapid influenza diagnostic test. Genetic analyses revealed new influenza A H3N2 variants belonging to a novel subclade 3C.2a2. CONCLUSIONS: The FilmArray assay facilitates urgent testing and laboratory surveillance for common viral and bacterial respiratory pathogens. This study demonstrated the use of a highly sensitive assay using clinical samples that is feasible for application worldwide. This may lead to an increased rate of diagnosis of viral infections and to improved patient outcomes, and in particular to a reduction in the overuse of antibiotics and antivirals. PMID- 28625841 TI - Identification of a new subtilisin-like protease NbSLP2 interacting with cytoskeletal protein septin in Microsporidia Nosema bombycis. AB - Nosema bombycis is the pathogen of pebrine which brings heavy losses to sericulture every year. As a member of serine proteases, subtilisin-like protease (SLP) is related to the pathogenicity in fungi. In this study, we characterized a novel 63.8kDa subtilisin-like protease NbSLP2 with a predicted transmembrane domain from Microsporidia, N. bombycis. RT-PCR showed that the transcript of NbSLP2 was detected from third day post infection. Immunofluorescence assay (IFA) indicated that NbSLP2 mainly scattered around the spore wall of N. bombycis. Co immunoprecipitation data and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis revealed that NbSLP2 directly interacts with septin2 of N. bombycis, which is a cytoskeletal protein. IFA showed that NbSLP2 and Nbseptin2 co-localized beneath the spore wall. NbSLP2 can be pulled down by Nbseptin2, further confirming the interaction between NbSLP2 and Nbseptin2. As an important serine protease with a transmembrane domain, NbSLP2 interacting with Nbseptin2, a scaffold protein adjacent to the membrane may provide advantages to stabilize the NbSLP2 for its hydrolysis function. PMID- 28625842 TI - Dynamics of scientific publications on the MERS-CoV outbreaks in Saudi Arabia. AB - Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an emerging disease with a relatively high case fatality rate. Most cases have been reported from Saudi Arabia, and the disease epidemic potential is considered to be limited. However, human-human transmission has occurred, usually in the context of healthcare facility-associated outbreaks. The scientific and medical community depends on timely publication of epidemiological information on emerging diseases during outbreaks to appropriately target public health responses. In this review, we considered the academic response to four MERS CoV outbreaks that occurred in Al-Hasa in 2013, Jeddah in 2014 and Riyadh in 2014 and 2015. We analysed 68 relevant epidemiology articles. For articles for which submission dates were available, six articles were submitted during the course of an outbreak. One article was published within a month of the Al-Hasa outbreak, and one each was accepted during the Jeddah and Riyadh outbreaks. MERS-CoV epidemiology articles were cited more frequently than articles on other subjects in the same journal issues. Thus, most epidemiology articles on MERS-CoV were published with no preferential advantage over other articles. Collaboration of the research community and the scientific publishing industry is needed to facilitate timely publication of emerging infectious diseases. PMID- 28625843 TI - Re: The Economic Implications of a Reusable Flexible Digital Ureteroscope: A Cost Benefit Analysis. PMID- 28625844 TI - Post-prostatectomy Radiotherapy: Does "Salvage" Really Equal "Adjuvant"? PMID- 28625845 TI - Injury and defective regeneration of the epithelial basement membrane in corneal fibrosis: A paradigm for fibrosis in other organs? AB - Myofibroblast-mediated fibrosis is important in the pathophysiology of diseases in most organs. The cornea, the transparent anterior wall of the eye that functions to focus light on the retina, is commonly affected by fibrosis and provides an optimal model due to its simplicity and accessibility. Severe injuries to the cornea, including infection, surgery, and trauma, may trigger the development of myofibroblasts and fibrosis in the normally transparent connective tissue stroma. Ultrastructural studies have demonstrated that defective epithelial basement membrane (EBM) regeneration after injury underlies the development of myofibroblasts from both bone marrow- and keratocyte-derived precursor cells in the cornea. Defective EBM permits epithelium-derived transforming growth factor beta, platelet-derived growth factor, and likely other modulators, to penetrate the stroma at sustained levels necessary to drive the development of vimentin+ alpha-smooth muscle actin+ desmin+ (V+A+D+) mature myofibroblasts and promote their persistence. Defective versus normal EBM regeneration likely relates to the severity of the stromal injury and a resulting decrease in fibroblasts (keratocytes) and their contribution of EBM components, including laminin alpha-3 and nidogen-2. Corneal fibrosis may resolve over a period of months to years if the inciting injury is eliminated through keratocyte facilitated regeneration of normal EBM, ensuing apoptosis of myofibroblasts, and reorganization of disordered extracellular matrix by repopulating keratocytes. We hypothesize the corneal model of fibrosis associated with defective BM regeneration and myofibroblast development after epithelial or parenchymal injury may be a paradigm for the development of fibrosis in other organs where chronic injury or defective BM underlies the pathophysiology of disease. PMID- 28625846 TI - Biogenesis of the Flagellar Switch Complex in Escherichia coli: Formation of Sub Complexes Independently of the Basal-Body MS-Ring. AB - Direction switching in the flagellar motor of Escherichia coli is under the control of a complex on the rotor formed from the proteins FliG, FliM, and FliN. FliG lies at the top of the switch complex (i.e., nearest the membrane) and is arranged with its C-terminal domain (FliGC) resting on the middle domain (FliGM) of the neighboring subunit. This organization requires the protein to adopt an open conformation that exposes the surfaces engaging in intersubunit FliGC/FliGM contacts. In a recent study, Baker and coworkers [13] obtained evidence that FliG in the cytosol is monomeric and takes on a more compact conformation, with FliGC making intramolecular contact with FliGM of the same subunit. In the present work, we examine the conformational preferences and interactions of FliG through in vivo crosslinking experiments in cells that lack either all other flagellar proteins or just the MS-ring protein FliF. The results indicate that FliG has a significant tendency to form multimers independently of other flagellar components. The multimerization of FliG is promoted by FliF and also by FliM. FliM does not multimerize efficiently by itself but does so in the presence of FliG. Thus, pre-assemblies of the switch-complex proteins can form in the cytosol and might function as intermediates in assembly. PMID- 28625848 TI - Regulation of E2s: A Role for Additional Ubiquitin Binding Sites? AB - Attachment of ubiquitin to proteins relies on a sophisticated enzyme cascade that is tightly regulated. The machinery of ubiquitylation responds to a range of signals, which remarkably includes ubiquitin itself. Thus, ubiquitin is not only the central player in the ubiquitylation cascade but also a key regulator. The ubiquitin E3 ligases provide specificity to the cascade and often bind the substrate, while the ubiquitin-conjugating enzymes (E2s) have a pivotal role in determining chain linkage and length. Interaction of ubiquitin with the E2 is important for activity, but the weak nature of these contacts has made them hard to identify and study. By reviewing available crystal structures, we identify putative ubiquitin binding sites on E2s, which may enhance E2 processivity and the assembly of chains of a defined linkage. The implications of these new sites are discussed in the context of known E2-ubiquitin interactions. PMID- 28625847 TI - HnRNP A1 Alters the Structure of a Conserved Enterovirus IRES Domain to Stimulate Viral Translation. AB - Enteroviruses use a type I Internal Ribosome Entry Site (IRES) structure to facilitate protein synthesis and promote genome replication. Type I IRES elements require auxiliary host proteins to organize RNA structure for 40S ribosomal subunit assembly. Heterogeneous nuclear ribonucleoprotein A1 stimulates enterovirus 71 (EV71) translation in part through specific interactions with its stem loop II (SLII) IRES domain. Here, we determined a conjoined NMR-small angle x-ray scattering structure of the EV71 SLII domain and a mutant that significantly attenuates viral replication by abrogating hnRNP A1 interactions. Native SLII adopts a locally compact structure wherein stacking interactions in a conserved 5'-AUAGC-3' bulge preorganize the adjacent helices at nearly orthogonal orientations. Mutating the bulge sequence to 5'-ACCCC-3' ablates base stacking in the loop and globally reorients the SLII structure. Biophysical titrations reveal that the 5'-AUAGC-3' bulge undergoes a conformational change to assemble a functional hnRNP A1-RNA complex. Importantly, IRES mutations that delete the bulge impair viral translation and completely inhibit replication. Thus, this work provides key details into how an EV71 IRES structure adapts to hijack a cellular protein, and it suggests that the SLII domain is a potential target for antiviral therapy. PMID- 28625850 TI - Structure and Function of Viral Deubiquitinating Enzymes. AB - Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication. PMID- 28625849 TI - Leveraging Reciprocity to Identify and Characterize Unknown Allosteric Sites in Protein Tyrosine Phosphatases. AB - Drug-like molecules targeting allosteric sites in proteins are of great therapeutic interest; however, identification of potential sites is not trivial. A straightforward approach to identify hidden allosteric sites is demonstrated in protein tyrosine phosphatases (PTP) by creation of single alanine mutations in the catalytic acid loop of PTP1B and VHR. This approach relies on the reciprocal interactions between an allosteric site and its coupled orthosteric site. The resulting NMR chemical shift perturbations (CSPs) of each mutant reveal clusters of distal residues affected by acid loop mutation. In PTP1B and VHR, two new allosteric clusters were identified in each enzyme. Mutations in these allosteric clusters altered phosphatase activity with changes in kcat/KM ranging from 30% to nearly 100-fold. This work outlines a simple method for identification of new allosteric sites in PTP, and given the basis of this method in thermodynamics, it is expected to be generally useful in other systems. PMID- 28625851 TI - Care in post-traumatic syndrome due to gender violence: a case report. AB - This article describes a clinical case of a patient attended at a continuous care point for a generalized anxiety disorder, principally due to abuse suffered from her ex partner. The patient was followed up at family nursing clinic, and the appropriate nursing interventions were developed to cover a series of needs prioritized by nurses using the AREA method and taking into account the prioritization of the user herself. PMID- 28625852 TI - Evolution of care indicators after an early discharge intervention in preterm infants. AB - OBJECTIVE: To evaluate the evolution of health outcomes in preterm infants included in an early discharge programme. METHOD: Controlled, non-randomised trial with an intervention group and a control group children admitted to the Neonatal Intensive Care Unit of the University Hospital Virgen de las Nieves of Granada were included in the study. The intervention group comprised preterm infants admitted to the neonatal unit clinically stable, whose family home was located within 20km. from the hospital. They were discharged two weeks before the established time and a skilled nurse in neonatal care monitored them at home. The control group comprised infants who could not be included in home monitoring due to the distance to the hospital criterion or because their families did not give their consent and who received the usual care until their discharge. The study variables were the outcome indicators of the Nursing Outcomes Classification. RESULTS: Differences were found in the Nursing Outcomes Classification scores in the intervention group compared to the control group. CONCLUSIONS: The early discharge of preterm infants followed up at home by an expert nurse in neonatal care is a health service that achieves results in preparating parents for the care of their child, enabling them to learn about the health services, adapt to their new life, and establishbreastfeeding times. It constitutes safe intervention for children and is beneficial to parents. PMID- 28625853 TI - Photoelicitation: a useful tool to investigate management of the vulnerability of homeless women. AB - AIMS: The proposal of the manuscript is to provide a methodological reflection on the use of photo-elicitation as a data gathering strategy to explore vulnerability management among homeless women. METHODS: A grounded theory study was carried out. Photo elicitation was one of the data gathering techniques used between February 2015 and February 2017. Five women were selected through intentional sampling. All of them were over 18 years old and residents in 4 shelters within the Madrid Care for the Homeless network. Participants used disposable cameras or mobile phones to record their experiences living in the shelters or on the street through photographs. An interview was conducted with each participant in order to explore the meaning of the photos after they were developed. Data analysis comprised, firstly, describing the obvious content of the photos and, secondly, comparing it with the latent content provided by participants during the interviews. RESULTS: Only 3 women finished the task. Through data analysis some theoretical proposals were discovered, which contributed to a deeper knowledge of some previously established categories and subcategories such as: "The good professionals", "The safe places in the street" and "The threats in the street". CONCLUSIONS: Photo-elicitation enabled an approach to participants' experiences with minimal imposition, allowing them much of the control over the data production. However, it is a demanding technique that requires deep reflection before its implementation, on the part of both participants and researchers. PMID- 28625854 TI - Promoting healthier children's meals at quick-service and full-service restaurants: Results from a pilot and feasibility study. AB - High-calorie restaurant foods contribute to childhood overweight. Increased consumer demand for healthier kids' meals may motivate the restaurant industry to provide additional healthy options. This study pilot-tested a combination of four strategies (toy incentive, placemats, server prompts, signage) designed to increase demand for healthier kids' meals, which were defined as those eligible for the National Restaurant Association's Kids LiveWell program. Relative sales of healthier kids' meals were examined before (n = 3473 total kids' meal orders) and during Month 1 (n = 3546 total kids' meal orders) and Month 2 of implementation (n = 3645 total kids' meal orders) of an 8-week intervention in two locations each of a quick-service (QSR) and full-service (FSR) restaurant chain. Convenience samples of children (n = 27) and their parents (n = 28) were surveyed regarding parent and child perceptions of intervention components. Findings regarding the effectiveness and feasibility of the intervention were mixed. At the FSRs, the relative percentage of monthly sales from healthier kids' meals increased from 5.0% of kids' meal orders at baseline to 8.3% during Month 1, ending at 6.4% during Month 2. At the QSRs, the relative percentage of monthly sales from healthier kids' entrees decreased from 27.5% at baseline to 25.2% during Month 1, ending at 25.9% during Month 2. Implementation quality tracking showed that consistent implementation of intervention components was a challenge; parent- and child-reported awareness of intervention components supported this finding. Future directions are discussed, aiming to build upon these findings and maximize the feasibility, effectiveness, and sustainability of efforts to promote healthier eating in restaurants. PMID- 28625855 TI - Children's purchase behavior in the snack market: Can branding or lower prices motivate healthier choices? AB - BACKGROUND: Children's dietary-related diseases and their associated costs have expanded dramatically in many countries, making children's food choice a policy issue of increasing relevance. As children spend a considerable amount of money on energy-dense, nutrient-poor (EDNP) products, a better understanding of the main drivers of children's independent food purchase decisions is crucial to move this behavior toward healthier options. OBJECTIVE: The objective of the study is to investigate the role of branding and price in motivating children to choose healthier snack options. METHODS: The study investigates snack choices of children ages 8 to 11, using a survey and a purchase experiment. The research took place in after-school programs of selected schools in the Boston area. Participants included 116 children. Products in the choice experiment differed on three factors: product type, brand, and price. Data were analyzed using aggregated and mixed logit models. RESULTS: Children's purchase decisions are primarily determined by product type (Importance Value (IV) 56.6%), while brand (IV 22.8%) and price (IV 20.6%) prove to be of less relevance. Only those children who state that they like the familiar brand reveal a preference for the branded product in their purchase decision. Price is a significant predictor of choice when controlling for whether or not children obtain an allowance. CONCLUSION: It is not simple brand awareness but a child's liking of the brand that determines whether a brand is successful in motivating a child to choose a product. The extent of children's experience with money influences their price responsiveness. To the extent that children who receive an allowance are primarily the ones buying food snacks, higher prices for EDNP snacks could be successful in motivating children to choose a healthier option. PMID- 28625856 TI - Nitroglycerin increases serotonin transporter expression in rat spinal cord but anandamide modulated this effect. AB - Migraine is one of the most prevalent neurological diseases, which affects 16% of the total population. The exact pathomechanism of this disorder is still not well understood, but it seems that serotonin and its transporter have a crucial role in the pathogenesis. One of the animal models of migraine is the systemic administration of nitroglycerin (NTG), a nitric oxide (NO) donor. NO can initiate a central sensitization process in the trigeminal system, which is also present in migraineurs. Recent studies showed that the endocannabinoid system has a modulatory role on the trigeminal activation and sensitization. Our aim was to investigate the effect of an endogenous cannabinoid, anandamide (AEA) on the NTG induced changes on serotonin transporter (5-HTT) expression in the upper cervical spinal cord (C1-C2) of the rat, where most of the trigeminal nociceptive afferents convey. The animals were divided into four groups. Rats in the first group, called placebo, received only the vehicle solution as treatment. In the second group, they were treated with an intraperitoneal (i.p.) injection of NTG (10mg/kg). Rats in the third and fourth groups received i.p. AEA (2*5mg/kg) half hour before and one hour after the placebo or NTG treatment. Four hours after placebo/NTG injection, the animals were perfused and the cervical spinal cords were removed for immunohistochemistry and Western blotting. Our results show that both NTG and AEA alone are able to increase 5-HTT expression in the C1-C2 segments. Combination of NTG and AEA has an opposing effect on this marker, nullifying the effects of non-combined administration, probably by negative feedback mechanisms. PMID- 28625857 TI - Validation of the Visible Occlusal Plaque Index (VOPI) in estimating caries lesion activity. AB - OBJECTIVE: The present study appraises the construct validity of the Visible Occlusal Plaque Index (VOPI) along with its sub-types, convergent and discriminant validity. METHODS: 618 10-15year old Brazilian adolescents were included. The VOPI has a four-point ordinal scale ranging from no plaque to heavy plaque. VOPI scores and caries status on permanent molars were mapped and recorded at individual anatomical sites of the groove-fossa-system and at surface level. Outcomes were presence of sound site/surface and site/surface with active or inactive caries lesions (non-cavitated or cavitated). RESULTS: Construct validity was assumed based on qualitative assessment as no plaque (score 0) and thin plaque (score 1) reflected the theoretical knowledge that a regular disorganization of the dental biofilm either maintains the caries process at sub clinical levels or inactivate it clinically. The VOPI also showed convergent validity since the likelihood that anatomical sites with no or thin plaque had inactive lesions simultaneously with sites with thick plaque (score 2) or heavy plaque (score 3) having active lesions were overall significant (RR=1.0-7.8). At surface level, discriminant validity of the VOPI was evidenced with multivariable analysis (GEE), by its ability to discriminate between the groups of adolescents with different oral hygiene status; negative association between adolescents with thick and heavy plaque and those with sound occlusal surfaces was found (OR=0.3, p<0.001). CONCLUSION: The VOPI has construct as well as convergent and discriminant validity and is therefore recommended as an additional clinical tool to estimate caries lesions activity and support treatment decisions. CLINICAL SIGNIFICANCE: The Visible Occlusal Plaque Index is an additional clinical tool to the assessment of oral hygiene and caries lesion activity. The VOPI is recommended to standardize and categorize information on the occlusal biofilm, thus being suitable for direct application in research and clinical settings. PMID- 28625858 TI - Stem cells, pluripotency and glial cell markers in peripheral blood of bipolar patients on long-term lithium treatment. AB - BACKGROUND: We investigated the effect of long-term lithium treatment on very small embryonic-like stem cells (VSELs) and the mRNA expression of pluripotency and glial markers, in peripheral blood, in patients with bipolar disorder (BD). METHODS: Fifteen BD patients (aged 53+/-7years) not treated with lithium, with duration of illness >10years, 15 BD patients (aged 55+/-6years) treated with lithium for 8-40years (mean 16years) and 15 control subjects (aged 50+/-5years) were included. The number of VSELs was measured by flow cytometric analysis. Assessment of the mRNA levels of pluripotency markers (Oct-4, Sox 2 and Nanog) and glial markers (glial fibrillary acidic protein - GFAP, Olig1 and Olig2) was performed, using the Real-time quantitative reverse transcription PCR. RESULTS: In BD patients not taking lithium, the number of VSELs was significantly higher than in control subjects and correlated with the duration of illness. The expression of pluripotency markers was significantly higher than in the controls and correlated with the number of VSELs. The mRNA levels of the Olig1 and Olig 2 were higher than in the controls and those of the GFAP were higher than in patients receiving lithium. In lithium-treated BD patients the number of VSELs was similar to controls and correlated negatively with the duration of lithium treatment and serum lithium concentration. The mRNA levels of Oct-4, Sox-2, GFAP and Olig1 were not different from controls. The mRNA expression of Nanog was significantly higher and correlated with the number of VSELs. The mRNA expression of Olig 2 was higher than in the BD patients not taking lithium. CONCLUSION: Long term treatment with lithium may suppress the activation of regenerative processes by reducing the number of VSELs circulating in PB. These cells, in BD patients not treated with lithium, may provide a new potential biological marker of the illness and its clinical progress. The higher expression of peripheral mRNA markers in BD patients may involve ongoing inflammatory process, compensatory mechanisms and regenerative responses. Long-term lithium treatment may attenuate these mechanisms, especially in relation to the transcription factors Oct-4, Sox 2, GFAP and Olig1. PMID- 28625860 TI - Impact of telephone counseling on the quality of life of patients discharged after coronary artery bypass grafts. AB - BACKGROUND: This study aimed to assess the impact of telephone counseling on quality of life in patients with coronary artery bypass graft. METHODS: A quasi experimental study was conducted with 71 discharged patients after coronary artery bypass graft surgery at Ekbatan Edcuational hospital in Hamadan, Iran, in 2014. The patients were randomly allocated into intervention (n=36) and control group (n=35). The intervention group received education and counseling about therapeutic plan via telephone after discharge. Patients in the control group received only routines. All patients completed the quality of life questionnaire before and after the intervention period of five weeks. RESULTS: There was no significant difference between intervention and control group about quality of life before intervention (p=0.696). However, there was significant and positive deference between the two groups in favor of the telephone counseling after the intervention (P=0.01) and control group (P=0.04). Quality of life in the intervention group was significantly better compared to control group (P=0.01). CONCLUSIONS: Telephone counseling could be a cost-effective patient counseling plan for therapeutic adherence after coronary artery bypass surgery in order to improve the patients' quality of life. PRACTICE IMPLICATIONS: Telephone counseling is feasible to implement and well accepted for patient counseling for many diseases. PMID- 28625859 TI - Harmine produces antidepressant-like effects via restoration of astrocytic functions. AB - Depression is a world-wide disease with no effective therapeutic methods. Increasing evidence indicates that astrocytic pathology contributes to the formation of depression. In this study, we investigated the effects of harmine, a natural beta-carboline alkaloid and potent hallucinogen, known to modulate astrocytic glutamate transporters, on chronic unpredictable stress (CUS)-induced depressive-like behaviors and astrocytic dysfunctions. Results showed that harmine treatment (10, 20mg/kg) protected the mice against the CUS-induced increases in the immobile time in the tail suspension test (TST) and forced swimming test (FST), and also reversed the reduction in sucrose intake in the sucrose preference experiment. Harmine treatment (20mg/kg) prevented the reductions in brain-derived neurotrophic factor (BDNF) protein levels and hippocampal neurogenesis induced by CUS. In addition, harmine treatment (20mg/kg) increased the protein expression levels of glutamate transporter 1 (GLT-1) and prevented the CUS-induced decreases in glial fibrillary acidic protein (GFAP) protein expressions in the prefrontal cortex and hippocampus, suggesting that restoration of astrocytic functions may be a potential mechanism underlying the antidepressant-like effects of harmine. This opinion was proved by the results that administration of mice with l-Alpha-Aminoadipic Acid (L-AAA), a gliotoxin specific for astrocytes, attenuated the antidepressant-like effects of harmine, and prevented the improvement effects of harmine on BDNF protein levels and hippocampal neurogenesis. These results provide further evidence to confirm that astrocytic dysfunction contributes critically to the development of depression and that harmine exerts antidepressant-like effects likely through restoration of astrocytic functions. PMID- 28625861 TI - The policy effects of feed-in tariff and renewable portfolio standard: A case study of China's waste incineration power industry. AB - Among the regulatory policies, feed-in tariffs (FIT) and renewable portfolio standards (RPS) are the most popular to promote the development of renewable energy power industry. They can significantly contribute to the expansion of domestic industrial activities in terms of sustainable energy. This paper uses system dynamics (SD) to establish models of long-term development of China's waste incineration power industry under FIT and RPS schemes, and provides a case study by using scenario analysis method. The model, on the one hand, not only clearly shows the complex logical relationship between the factors but also assesses policy effects of the two policy tools in the development of the industry. On the other hand, it provides a reference for scholars to study similar problems in different countries, thereby facilitating an understanding of waste incineration power's long-term sustainable development pattern under FIT and RPS schemes, and helping to provide references for policy-making institutions. The results show that in the perfect competitive market, the implementation of RPS can promote long-term and rapid development of China's waste incineration power industry given the constraints and actions of the mechanisms of RPS quota proportion, the TGC valid period, and fines, compared with FIT. At the end of the paper, policy implications are offered as references for the government. PMID- 28625862 TI - Recent progress in the diagnosis and treatment of pelvic ring and acetabular fracture. PMID- 28625863 TI - Reply to the Letter by M. Nikolic and A. Stankovic. PMID- 28625864 TI - A systematic study of the effect of low pH acid treatment on anti-drug antibodies specific for a domain antibody therapeutic: Impact on drug tolerance, assay sensitivity and post-validation method assessment of ADA in clinical serum samples. AB - We developed a homogeneous bridging anti-drug antibody (ADA) assay on an electro chemiluminescent immunoassay (ECLIA) platform to support the immunogenicity evaluation of a dimeric domain antibody (dAb) therapeutic in clinical studies. During method development we evaluated the impact of different types of acid at various pH levels on polyclonal and monoclonal ADA controls of differing affinities and on/off rates. The data shows for the first time that acids of different pH can have a differential effect on ADA of various affinities and this in turn impacts assay sensitivity and drug tolerance as defined by these surrogate controls. Acid treatment led to a reduction in signal of intermediate and low affinity ADA, but not high affinity or polyclonal ADA. We also found that acid pretreatment is a requisite for dissociation of drug bound high affinity ADA, but not for low affinity ADA-drug complexes. Although we were unable to identify an acid that would allow a 100% retrieval of ADA signal post-treatment, use of glycine pH3.0 enabled the detection of low, intermediate and high affinity antibodies (Abs) to various extents. Following optimization, the ADA assay method was validated for clinical sample analysis. Consistencies within various parameters of the clinical data such as dose dependent increases in ADA rates and titers were observed, indicating a reliable ADA method. Pre- and post-treatment ADA negative or positive clinical samples without detectable drug were reanalyzed in the absence of acid treatment or presence of added exogenous drug respectively to further assess the effectiveness of the final acid treatment procedure. The overall ADA results indicate that assay conditions developed and validated based on surrogate controls sufficed to provide a reliable clinical data set. The effect of low pH acid treatment on possible pre-existing ADA or soluble multimeric target in normal human serum was also evaluated, and preliminary data indicate that acid type and pH also affect drug-specific signal differentially in individual samples. The results presented here represent the most extensive analyses to date on acid treatment of a wide range of ADA affinities to explore sensitivity and drug tolerance issues. They have led to a refinement of our current best practices for ADA method development and provide a depth of data to interrogate low pH mediated immune complex dissociation. PMID- 28625865 TI - Reply to Theilen et al 2017: Economic evaluations of clinician training - Make your research meaningful to decision makers. PMID- 28625866 TI - Genome analysis of crude oil degrading Franconibacter pulveris strain DJ34 revealed its genetic basis for hydrocarbon degradation and survival in oil contaminated environment. AB - Franconibacter pulveris strain DJ34, isolated from Duliajan oil fields, Assam, was characterized in terms of its taxonomic, metabolic and genomic properties. The bacterium showed utilization of diverse petroleum hydrocarbons and electron acceptors, metal resistance, and biosurfactant production. The genome (4,856,096bp) of this strain contained different genes related to the degradation of various petroleum hydrocarbons, metal transport and resistance, dissimilatory nitrate, nitrite and sulfite reduction, chemotaxy, biosurfactant synthesis, etc. Genomic comparison with other Franconibacter spp. revealed higher abundance of genes for cell motility, lipid transport and metabolism, transcription and translation in DJ34 genome. Detailed COG analysis provides deeper insights into the genomic potential of this organism for degradation and survival in oil contaminated complex habitat. This is the first report on ecophysiology and genomic inventory of Franconibacter sp. inhabiting crude oil rich environment, which might be useful for designing the strategy for bioremediation of oil contaminated environment. PMID- 28625868 TI - Distinct characteristics of neonatal platelet reactivity. AB - Platelets undergo a process of developmental maturation, and hence its regulation of vascular integrity and control of hemostasis at various stages of neonatal ages deserves better characterization. Functional assays for platelets require a larger volume of blood than what is feasible to collect in neonates, creating a technical hurdle that has been a challenge to investigate neonatal platelets. For this reason, the current knowledge of neonatal platelet function has been based on studies from cord blood-derived platelets as a surrogate for neonatal peripheral blood. Studies indicate that neonatal platelets are hypofunctional to various agonists, although neonates tend to maintain normal hemostasis. This apparently paradoxical finding may be due to several factors, such as elevated functionally potent von Willebrand factor multimers or hematocrit levels, in the neonatal blood that enhance the platelet and vessel wall interaction, and counteract platelet hyporeactivity. This review describes the functional characteristics of neonatal platelets, differences in platelet reactivity between neonates and adults, and potential biomarkers of platelet activation. PMID- 28625869 TI - An historical perspective on the pioneering experiments of John Saunders. AB - John Saunders was a highly skilled embryologist who pioneered the study of limb development. His studies on chick embryos provided the fundamental framework for understanding how vertebrate limbs develop. This framework inspired generations of scientists and formed the bridge from experimental embryology to molecular mechanisms. Saunders investigated how feathers become organized into tracts in the skin of the chick wing and also identified regions of programmed cell death. He discovered that a region of thickened ectoderm that rims the chick wing bud - the apical ectodermal ridge - is required for outgrowth and the laying down of structures along the proximo-distal axis (long axis) of the wing, identified the zone of polarizing activity (ZPA; polarizing region) that controls development across the anteroposterior axis ("thumb to little finger "axis) and contributed to uncovering the importance of the ectoderm in development of structures along the dorso-ventral axis ( "back of hand to palm" axis). This review looks in depth at some of his original papers and traces how he made the crucial findings about how limbs develop, considering these findings both in the context of contemporary knowledge at the time and also in terms of their immediate impact on the field. PMID- 28625870 TI - Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons. AB - Transcription factors are key orchestrators of the emergence of neuronal diversity within the developing spinal cord. As such, the two paralogous proteins Pax3 and Pax7 regulate the specification of progenitor cells within the intermediate neural tube, by defining a neat segregation between those fated to form motor circuits and those involved in the integration of sensory inputs. To attain insights into the molecular means by which they control this process, we have performed detailed phenotypic analyses of the intermediate spinal interneurons (IN), namely the dI6, V0D, V0VCG and V1 populations in compound null mutants for Pax3 and Pax7. This has revealed that the levels of Pax3/7 proteins determine both the dorso-ventral extent and the number of cells produced in each subpopulation; with increasing levels leading to the dorsalisation of their fate. Furthermore, thanks to the examination of mutants in which Pax3 transcriptional activity is skewed either towards repression or activation, we demonstrate that this cell diversification process is mainly dictated by Pax3/7 ability to repress gene expression. Consistently, we show that Pax3 and Pax7 inhibit the expression of Dbx1 and of its repressor Prdm12, fate determinants of the V0 and V1 interneurons, respectively. Notably, we provide evidence for the activity of several cis-regulatory modules of Dbx1 to be sensitive to Pax3 and Pax7 transcriptional activity levels. Altogether, our study provides insights into how the redundancy within a TF family, together with discrete dynamics of expression profiles of each member, are exploited to generate cellular diversity. Furthermore, our data supports the model whereby cell fate choices in the neural tube do not rely on binary decisions but rather on inhibition of multiple alternative fates. PMID- 28625867 TI - Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System. AB - The human gastrointestinal tract is populated by a diverse, highly mutualistic microbial flora, which is known as the microbiome. Disruptions to the microbiome have been shown to be associated with severe pathologies of the host, including metabolic disease, cancer, and inflammatory bowel disease. Mood and behavior are also susceptible to alterations in the gut microbiota. A particularly striking example of the symbiotic effects of the microbiome is the immune system, whose cells depend critically on a diverse array of microbial metabolites for normal development and behavior. This includes metabolites that are produced by bacteria from dietary components, metabolites that are produced by the host and biochemically modified by gut bacteria, and metabolites that are synthesized de novo by gut microbes. In this review, we highlight the role of the intestinal microbiome in human metabolic and inflammatory diseases and focus in particular on the molecular mechanisms that govern the gut-immune axis. PMID- 28625872 TI - Decreased enteritis resistance ability by dietary low or excess levels of lipids through impairing the intestinal physical and immune barriers function of young grass carp (Ctenopharyngodon idella). AB - The current study explores the hypothesis that low or excess levels of lipids decrease the enteritis resistance ability through impairing the intestinal physical and immune barrier function of young grass carp (Ctenopharyngodon idella). A total of 540 young grass carp with an average initial weight of 261.41 +/- 0.53 g were fed diets containing six graded levels of lipids at 5.9, 21.4, 36.0, 50.2, 66.6 and 80.1 g/kg for 8 weeks. After that, a challenge trial was conducted by injection of Aeromonas hydrophila over 2 weeks. The results show that compared with optimal lipids level, low or excess levels of lipids impair fish immune barrier function through declining humoral compounds and down regulating the mRNA levels of interleukin 4/13A (IL-4(13)A) [not in the proximal intestine (PI)], IL-4(13)B, IL-6, IL-10, transforming growth factor beta1 (TGF beta1), inhibitor of kappaBalpha (IkappaBalpha), TOR and ribosomal p70S6 kinase (S6K1) (P < 0.05), and up-regulating tumor necrosis factor alpha (TNF-alpha), interferon gamma2 (IFN-gamma2), IL-1beta, IL-8, IL-12 p40 (not p35), nuclear factor kappaB p65 (NF-kappaB p65), IkappaB kinase alpha (IKKalpha), IKKbeta, IKKgamma, and eIF4E-binding protein (4EBP) in the intestine of young grass carp (P < 0.05). In addition, low or excess levels of lipids also decrease young grass carp physical barrier function through down-regulating the mRNA levels of zonula occludens (ZO-1), ZO-2b [only in the distal intestine (DI)], Claudin b, c, 3, 12, 15a, 15b (only in the DI), 7b (not 7a) and Occludin by MAPKK 6/p38 MAPK (not JNK)/MLCK signaling molecules, down-regulating B-cell lymphoma-2 (Bcl-2) and inhibitor of apoptosis protein (IAP) and up-regulating the mRNA levels of apoptotic protease activating factor-1 (Apaf-1), Caspase-3, -8 and -9 and Fas ligand (FasL) (not in the DI), and decreasing antioxidant ability via Kelch-like ECH-associating protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) signaling molecules in the intestine. Based on the quadratic regression analysis for the enteritis resistance ability, LA activities and GSH content in the MI were established to be 54.5, 49.91 and 47.83 g lipid/kg diets, respectively. PMID- 28625871 TI - miR-27 regulates chondrogenesis by suppressing focal adhesion kinase during pharyngeal arch development. AB - Cranial neural crest cells are a multipotent cell population that generate all the elements of the pharyngeal cartilage with differentiation into chondrocytes tightly regulated by temporal intracellular and extracellular cues. Here, we demonstrate a novel role for miR-27, a highly enriched microRNA in the pharyngeal arches, as a positive regulator of chondrogenesis. Knock down of miR-27 led to nearly complete loss of pharyngeal cartilage by attenuating proliferation and blocking differentiation of pre-chondrogenic cells. Focal adhesion kinase (FAK) is a key regulator in integrin-mediated extracellular matrix (ECM) adhesion and has been proposed to function as a negative regulator of chondrogenesis. We show that FAK is downregulated in the pharyngeal arches during chondrogenesis and is a direct target of miR-27. Suppressing the accumulation of FAK in miR-27 morphants partially rescued the severe pharyngeal cartilage defects observed upon knock down of miR-27. These data support a crucial role for miR-27 in promoting chondrogenic differentiation in the pharyngeal arches through regulation of FAK. PMID- 28625873 TI - An approach to the study of the immunity functions of bivalve haemocytes: Physiology and molecular aspects. AB - The Mediterranean mussel Mytilus galloprovincialis is an ecologically and economically important species. It has been used in programs of monitoring of pollution, since it is sessile organism that is capable of accumulating pollutants in tissues through filter feeding. Due to an increase of pollutants in the environment, marine mussels present physiological alterations that compromise their innate immune system, which can latter lead to opportunistic diseases. The haemocytes are the cells in charge of the immune response in the Mediterranean mussel and in other mollusks. In this review, we summarize the physiological and genetic response capacity of these immune cells to the presence of xenobiotics, pathogens and the interplay. The identification of the basic mechanisms of immunity and their modulation in mussels can give important information for the possible utilization of this species as an invertebrate model for studies on innate immunity, future immunotoxicological studies, and predict changes in the community for the future. PMID- 28625874 TI - Negative regulation of the RLH signaling by the E3 ubiquitin ligase RNF114. AB - The retinoic acid-inducible gene-I (RIG-I)-like helicases (RLH)s are cytoplasmic pattern recognition receptors expressed in both immune and non-immune cells that are essential for detection of intracellular RNA products, primarily of viral origin. Upon binding to viral RNA, RLHs interact with mitochondrial antiviral signaling protein (MAVS) to activate interferon (IFN)-mediated antiviral responses. The RLH/MAVS signaling pathway is regulated by ubiquitination/deubiquitination, in which several ubiquitin-editing proteins play critical roles. The really interesting new gene (RING) finger protein 114 (RNF114) was originally identified as a psoriasis susceptibility gene broadly expressed in human tissues. Earlier studies implicated RNF114 in regulating cellular dsRNA responses, cell cycle progression, NF-kappaB activity and T-cell activation. We found that RNF114 inhibited cellular dsRNA responses and RLH mediated IFN production. RNF114 functioned as an E3 ubiquitin ligase, and MAVS was identified as a potential target for RNF114-mediated polyubiquitination and degradation. Splenocytes and blood harvested from RNF114 KO showed increased basal IFN level and sensitized responses to dsRNA. However, RNF114 knockout mice failed to exhibit enhance resistance to infection by two acute RNA viruses. These data suggested the potential physiological function of RNF114 in inflammation and host antiviral responses, but demonstrate complexity in the regulation of innate immunity by ubiquitin ligases. PMID- 28625876 TI - Mental health in Zimbabwe: a health systems analysis. AB - There has been little external analysis of Zimbabwe's mental health system. We did a systems analysis to identify bottlenecks and opportunities for mental health service improvement in Zimbabwe and to generate cost-effective, policy relevant solutions. We combined in-depth interviews with a range of key stakeholders in health and mental health, analysis of mental health laws and policies, and publicly available data about mental health. Five themes are key to mental health service delivery in Zimbabwe: policy and law; financing and resources; criminal justice; workforce, training, and research; and beliefs about mental illness. We identified human resources, rehabilitation facilities, psychotropic medication, and community mental health as funding priorities. Moreover, we found that researchers should prioritise measuring the economic impact of mental health and exploring substance use, forensic care, and mental health integration. Our study highlights forensic services as a central component of the mental health system, which has been a neglected concept. We also describe a tailored process for mental health systems that is transferable to other low income settings and that garners political will, builds capacity, and raises the profile of mental health. PMID- 28625875 TI - Individual differences in functional connectivity during naturalistic viewing conditions. AB - Naturalistic viewing paradigms such as movies have been shown to reduce participant head motion and improve arousal during fMRI scanning relative to task free rest, and have been used to study both functional connectivity and stimulus evoked BOLD-signal changes. These task-based hemodynamic changes are synchronized across subjects and involve large areas of the cortex, and it is unclear whether individual differences in functional connectivity are enhanced or diminished under such naturalistic conditions. This work first aims to characterize variability in BOLD-signal based functional connectivity (FC) across 2 distinct movie conditions and eyes-open rest (n=31 healthy adults, 2 scan sessions each). We found that movies have higher within- and between-subject correlations in cluster-wise FC relative to rest. The anatomical distribution of inter-individual variability was similar across conditions, with higher variability occurring at the lateral prefrontal lobes and temporoparietal junctions. Second, we used an unsupervised test-retest matching algorithm that identifies individual subjects from within a group based on FC patterns, quantifying the accuracy of the algorithm across the three conditions. The movies and resting state all enabled identification of individual subjects based on FC matrices, with accuracies between 61% and 100%. Overall, pairings involving movies outperformed rest, and the social, faster-paced movie attained 100% accuracy. When the parcellation resolution, scan duration, and number of edges used were increased, accuracies improved across conditions, and the pattern of movies>rest was preserved. These results suggest that using dynamic stimuli such as movies enhances the detection of FC patterns that are unique at the individual level. PMID- 28625877 TI - RIFM fragrance ingredient safety assessment, isodecyl alcohol, CAS registry number 25339-17-7. PMID- 28625878 TI - RIFM fragrance ingredient safety assessment, Methyl hexyl oxo cyclopentanone carboxylate, CAS Registry Number 37172-53-5. PMID- 28625879 TI - RIFM fragrance ingredient safety assessment, benzenepropanenitrile, 4-ethyl .alpha.,.alpha.-dimethyl, CAS Registry Number 134123-93-6. PMID- 28625880 TI - Predicting biomedical metadata in CEDAR: A study of Gene Expression Omnibus (GEO). AB - A crucial and limiting factor in data reuse is the lack of accurate, structured, and complete descriptions of data, known as metadata. Towards improving the quantity and quality of metadata, we propose a novel metadata prediction framework to learn associations from existing metadata that can be used to predict metadata values. We evaluate our framework in the context of experimental metadata from the Gene Expression Omnibus (GEO). We applied four rule mining algorithms to the most common structured metadata elements (sample type, molecular type, platform, label type and organism) from over 1.3million GEO records. We examined the quality of well supported rules from each algorithm and visualized the dependencies among metadata elements. Finally, we evaluated the performance of the algorithms in terms of accuracy, precision, recall, and F measure. We found that PART is the best algorithm outperforming Apriori, Predictive Apriori, and Decision Table. All algorithms perform significantly better in predicting class values than the majority vote classifier. We found that the performance of the algorithms is related to the dimensionality of the GEO elements. The average performance of all algorithm increases due of the decreasing of dimensionality of the unique values of these elements (2697 platforms, 537 organisms, 454 labels, 9 molecules, and 5 types). Our work suggests that experimental metadata such as present in GEO can be accurately predicted using rule mining algorithms. Our work has implications for both prospective and retrospective augmentation of metadata quality, which are geared towards making data easier to find and reuse. PMID- 28625881 TI - Effects of exposure to biomass burning on pulmonary inflammatory markers and pulmonary function in individuals with COPD. AB - INTRODUCTION: Pulmonary rehabilitation (PR) has many benefits for individuals with COPD. However, it is not clear whether PR could prevent the hazards of air pollution exposure. This study aimed to analyze the effects of biomass burning exposure on pulmonary inflammatory markers and pulmonary function in individuals with COPD, participants and non-participants of PR. METHODS: 35 subjects were divided into three groups: individuals with COPD who received PR (G1, n=15), those who did not (G2, n=10), and a control group composed of healthy individuals without COPD (CG, n=10). Measurements of lung function and concentrations of IL 6, IL-10, and TNF-alpha in exhaled breath condensate samples were collected. The assessment and concentrations of particulate matter (PM10), nitrogen dioxide (NO2), ozone (O3), temperature (T), and relative air humidity (RAH) were recorded in biomass burning and non-burning periods. RESULTS: There was a significant increase in the concentrations of air pollutants in the biomass burning period. In this period, an increase in IL-6 (G1p=0.041, G2 p=.012), and a reduction in the FEV1/FVC ratio (G1p=0.021, G2 p=.007) were observed in individuals with COPD. In G1, the increase in IL-6 concentrations correlated positively with O3 (r=0.693; p=.006), and negatively with RAH (r=-0.773; p=.003) in the burning period. CONCLUSIONS: Individuals with COPD exposed to biomass burning demonstrated increased pulmonary inflammation and a reduction in the FEV1/FVC ratio, regardless of their engagement in PR. PMID- 28625882 TI - Analysis of sarcoidosis in the Oporto region (Portugal). AB - BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Epidemiological studies of different populations are essential because clinical presentation, organ involvement, disease severity, and prognosis vary significantly according to region and population. The aim of this study was to assess epidemiological and clinical characteristics, staging factors, and clinical course in patients with sarcoidosis from a tertiary hospital in Oporto, Portugal. METHODS: A retrospective analysis of patients with sarcoidosis and at least 2 years of follow-up evaluated at the Centro Hospitalar de Sao Joao between 2000 and 2014. RESULTS: We identified 409 patients with sarcoidosis (females, 58.9%; mean age at diagnosis, 38.9+/-13.4 years; smokers, 14.4%]. All the patients were diagnosed according to the ERS/ATS/WASOG consensus statement and 64.1% had evidence of noncaseating epithelioid cell granulomas in biopsy specimens. Bronchoalveolar lavage was performed as part of the diagnostic work-up in 289 patients and 90.2% had lymphocytosis (CD4/CD8 ratio >=3.5 in 60.9% of cases). Exertion dyspnea, cough, and constitutional symptoms were the most common presenting symptoms; 10.1% of patients were asymptomatic, 22.8% had Lofgren syndrome, and 50.5% had extrathoracic involvement. Radiographic stages of disease according to the Scadding criteria were as follows: stage 0 (5.2%), stage I (33.7%), stage II (47.0%), stage III (8.4%), and stage IV (5.7%). Impaired respiratory function was observed in 45.6% patients and was mostly mild. Systemic treatment was administered in 58.6% of cases. Overall, 45.3% of patients experienced disease resolution. CONCLUSION: The epidemiological and clinical characteristics of this cohort of patients with sarcoidosis from the Oporto region in northern Portugal revealed epidemiological and clinical characteristics that were generally similar to those described in other Western Europe populations and in the US ACCESS study. However, we found a higher proportion of patients who progressed to chronic forms. PMID- 28625883 TI - TCR+CD3+CD4-CD8- effector T cells in psoriasis. AB - The autoimmune/inflammatory disorder psoriasis is characterized by keratinocyte proliferation and immune cell infiltration of the skin. TCR+CD3+CD4-CD8- "double negative" (DN) T cells can derive from CD8+ T cells through the down-regulation of CD8. The inhibitory molecule programmed death (PD-)1 is expressed on activated T cells and plays a role in the maintenance of peripheral tolerance. A subset of DN T cells, characterized by the expression of PD-1, has recently been demonstrated to be self-reactive. We demonstrate that a majority of DN T cells exhibits effector memory phenotypes, express IFN-gamma, and fail to proliferate. DN T cells from psoriasis patients are characterized by reduced DNA methylation of the IFNG gene and increased PD-1 expression. Furthermore, PD-1 positive DN T cells infiltrate the epidermis in psoriatic skin lesions. Our observations offer additional insight into the molecular pathophysiology of plaque psoriasis and show promise as potential disease biomarkers and/or therapeutic targets for future interventions. PMID- 28625884 TI - Lack of evidence for post-vaccine onset of autoimmune/lymphoproliferative disorders, during a nine-month follow-up in multiply vaccinated Italian military personnel. AB - Anecdotal case reports, amplified by mass media and internet-based opinion groups, have recently indicated vaccinations as possibly responsible for autoimmunity/lymphoproliferation development. Multiply vaccinated Italian military personnel (group 1, operating in Italy, group 2, operating in Lebanon) were followed-up for nine months to monitor possible post-vaccine autoimmunity/lymphoproliferation onset. No serious adverse event was noticed in both groups. Multivariate analysis of intergroup differences only showed a significant association between lymphocyte increase and tetanus/diphtheria vaccine administration. A significant post-vaccine decrease in autoantibody positivity was observed. Autoantibodies were also studied by microarray analysis of self-proteins in subjects exposed to >=4 concurrent vaccinations, without observing significant difference among baseline and one and nine months post vaccine. Moreover, HLA-A2 subjects have been analyzed for the possible CD8T-cell response to apoptotic self-epitopes, without observing significant difference between baseline and one month post-vaccine. Multiple vaccinations in young adults are safe and not associated to autoimmunity/lymphoproliferation onset during a nine-month-long follow-up. PMID- 28625886 TI - Zoonotic and Vector-Borne Diseases in Urban Slums: Opportunities for Intervention. AB - Urban slums provide conditions that increase the risk of exposure to vector-borne and zoonotic pathogens. Large interventions, such as social and sanitary changes, are a priority but their implementation is challenging. Integration between the multidisciplinary understanding of pathogens' dynamics and community participatory approaches is a key prevention strategy. PMID- 28625885 TI - DOCK8 deficiency: Insights into pathophysiology, clinical features and management. AB - Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent infections to include atopy, autoimmunity and cancer. It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton. Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3. DOCK8 deficiency impairs immune cell migration, function and survival, and it impacts both innate and adaptive immune responses. Clinically, DOCK8 deficiency is characterized by allergic inflammation as well as susceptibility towards infections, autoimmunity and malignancy. This review details the pathophysiology, clinical features and management of DOCK8 deficiency. It also surveys the recently discovered combined immunodeficiency due to DOCK2 deficiency, highlighting in the process the emerging spectrum of PIDs resulting from DOCK protein family abnormalities. PMID- 28625887 TI - Time-resolved cryo-electron microscopy: Recent progress. AB - Time-resolved cryo-electron microscopy (cryo-EM) combines the known advantages of single-particle cryo-EM in visualizing molecular structure with the ability to dissect the time progress of a reaction between molecules in vitro. Here some of the recent progress of this methodology and its first biological applications are outlined. PMID- 28625888 TI - Combined venom profiling and cytotoxicity screening of the Radde's mountain viper (Montivipera raddei) and Mount Bulgar Viper (Montivipera bulgardaghica) with potent cytotoxicity against human A549 lung carcinoma cells. AB - Here we report the first characterization of the endemic Mount Bulgar Viper (Montivipera bulgardaghica) and Radde's mountain viper (Montivipera raddei) venom by a combined approach using intact mass profiling and bottom-up proteomics. The cytotoxicity screening of crude venom as well as isolated serine proteases revealed a high activity against A549 human lung carcinoma cells. By means of intact mass profiling of native and reduced venom we observed basic and acidic phospholipases type A2. Moreover, the analysis revealed snake venom metalloproteases, cysteine-rich secretory proteins, disintegrins, snake venom serine proteases, C-type lectins, a vascular endothelial growth factor and an L amino acid oxidase. PMID- 28625889 TI - Massive attack of honeybee on macaws (Ara ararauna and Ara chloropterus) in Brazil - A case report. AB - Three adult birds of the species Ara chloropterus and five of the species Ara ararauna from a conservation breeding facility suffered a massive attack by honeybees. The A. chloropterus birds presented swollen puncture lesions with stingers (mainly in the facial regions without feathers), swelling of the eyelids and subcutaneous tissue, and respiratory distress, and they were treated with intramuscular injections of 1.67 mg/kg of promethazine and 10 mg/kg of hydrocortisone followed by removal of the stingers. Complete remission of the clinical signs occurred 48 hours after start of treatment. The five A. ararauna birds died before they arrived at the veterinary hospital, and the necropsies found stingers in the areas of the face without feathers and the subcutaneous tissue, which were associated with erythema, bruising, and swelling. Food content from the crop was found in the oral cavity and the tracheal lumen, and marked congestion was observed in the heart, liver, spleen, lungs, kidneys, brain, and cerebellum. Among the histopathological findings, significant swelling of the myocytes in the endocardium and vascular dilation with erythroid repletion were observed, and there were multifocal areas of centrilobular necrosis associated with severe congestion and hemorrhaging in the hepatic tissue. Severe acute tubular necrosis and hydropic-vacuolar degeneration were observed in the kidneys. The clinical signs and pathological findings suggest envenomation due to a massive bee attack, the first such report for Psittacidae. PMID- 28625891 TI - Who can be a legitimate author on an article? PMID- 28625890 TI - Acute effects of coffee on skin blood flow and microvascular function. AB - OBJECTIVE: Studies on the acute effects of coffee on the microcirculation have shown contradicting results. This study aimed to investigate if intake of caffeine-containing coffee changes blood flow and microvascular reactivity in the skin. METHODS: We measured acute changes in cutaneous vascular conductance (CVC) in the forearm and the tip of the finger, the microvascular response to transdermal iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP) and post-occlusive reactive hyperemia (PORH) in the skin, after intake of caffeinated or decaffeinated coffee. RESULTS: Vasodilatation during iontophoresis of ACh was significantly stronger after intake of caffeinated coffee compared to after intake of decaffeinated coffee (1.26+/-0.20PU/mmHg vs. 1.13+/-0.38PU/mmHg, P<0.001). Forearm CVC before and after PORH were not affected by caffeinated and decaffeinated coffee. After intake of caffeinated coffee, a more pronounced decrease in CVC in the fingertip was observed compared to after intake of decaffeinated coffee (-1.36PU/mmHg vs. -0.52PU/mmHg, P=0.002). CONCLUSIONS: Caffeine, as ingested by drinking caffeinated coffee acutely improves endothelium dependent microvascular responses in the forearm skin, while endothelium independent responses to PORH and SNP iontophoresis are not affected. Blood flow in the fingertip decreases markedly during the first hour after drinking caffeinated coffee compared to decaffeinated coffee. PMID- 28625892 TI - Consumers' acceptance of medicinal herbs: An application of the technology acceptance model (TAM). AB - ETHNOPHARMACOLOGICAL RELEVANCE: The shift in consumers' preferences from synthetic to 'natural' products has led to a resurgence of interest in medicinal plants, particularly in developing countries. However, research data about consumers' preferences for particular products is hard to find. AIMS AND OBJECTIVES: The main objective of this study was to contribute to the general understanding of consumers' intention for selecting medicinal herbs for consumption. MATERIALS AND METHODS: Factors underpinning consumers' acceptance of medicinal herbs were studied with the technology acceptance model (TAM) in Rasht City of Iran using a structured questionnaire. RESULTS: Most respondents had low to moderate familiarity with consumption of medicinal herbs. However, about half of the respondents (47.5%) showed a high level of acceptance of medicinal herbs. Herbs like spearmint (Mentha spicata L.), spinach (Spinacia oleracea L.), basil (Ocimum basilicum L.), Damask rose (Rosa * damascena Herrm.), saffron (Crocus sativus L.), cinnamon (Cinnamomum verum J.Presl), flixweed [Descurainia sophia (L.) Webb ex Prantl], red feathers (Echium amoenum Fisch. & C.A.Mey.), and green tea [Camellia sinensis (L.) Kuntze] had the highest consumption rate among the majority (over 75%) of citizens of Rasht. The highest rate of perceived usefulness of medicinal herbs was related to their perceived role in healing diseases. The variable of importance of use of medicinal herbs had the strongest direct effect and the variables of perceived usefulness and attitude towards use had the second and third strongest direct effect on the acceptance of medicinal herbs' use at p < 0.01. CONCLUSIONS: Findings provide a useful evaluation of the acceptance of medicinal herbs and may serve as a benchmark for future research and evaluation concerning the use of medicinal herbs over time. For plant producers, more effective and targeted crop development should be encouraged, whereas for retailers better marketing and delivery strategies should be sought. PMID- 28625893 TI - Investigation of the influence of emotions on working memory capacity using ERP and ERSP. AB - Recent studies have reported that there are individual differences in working memory (WM), and that WM may be affected by emotions. To date, it remains controversial whether emotions impair or facilitate WM and whether there are individual differences in their effect on WM. In this study, three emotions (negative, neutral, and positive) were induced by a video database that was established according to the emotional stimuli habit of Chinese people. A change detection paradigm was used to examine the effect of emotions on the visual WM. Participants were divided into high- and low-capacity groups according to their WM capacity. The behavioral results revealed that both negative and positive emotions may enhance WM capacity in the high-capacity group compared with the neutral emotion. In contrast, an opposite effect was observed in the low-capacity group. Analysis of the contralateral delay activity and P300 components demonstrated significantly higher amplitudes in the high-capacity group following positive and negative emotions; the effects were opposite in the low-capacity group. The event-related spectral perturbation results demonstrated a more powerful event-related synchronization in the alpha-band (300-400ms) in the low capacity group in positive and negative emotions; opposite results were observed in the high-capacity group. The consistence of the behavioral and electrophysiological results suggests interindividual differences in the impact of emotions on the WM capacity. Moreover, both positive and negative emotions can facilitate WM capacity in the high-capacity group, while they impair WM capacity in the low-capacity group. PMID- 28625894 TI - Evaluation of protective immunity induced by DNA vaccination with genes encoding Toxoplasma gondii GRA17 and GRA23 against acute toxoplasmosis in mice. AB - Toxoplasma gondii, an obligatory intracellular protozoan, can cause serious public health problems and economic losses worldwide. Two novel dense granule proteins (GRA17 and GRA23) were recently identified as T. gondii-secreted proteins which are localized to the parasitophorous vacuole membrane (PVM) and can mediate the movement of small molecules between the host cell and parasitophorous vacuole (PV). In the present study, we evaluated the protective immunity induced by DNA vaccination with genes encoding GRA17 and GRA23 against acute toxoplasmosis in mice. Eukaryotic expressing plasmids pVAX-TgGRA17 and pVAX TgGRA23 were constructed. Then, BALB/c mice were intramuscularly immunized with pVAX-TgGRA17, pVAX-TgGRA23, or pVAX-TgGRA17 + pVAX-TgGRA23 followed by challenge infection with the highly virulent RH strain of T. gondii. The specific immune responses and protective efficacy against T. gondii were examined by cytokine and serum antibody measurements, lymphocyte proliferation assays, flow cytometry of lymphocytes and the survival time after challenge. Our results showed that mice immunized with pVAX-TgGRA17, pVAX-TgGRA23, or pVAX-TgGRA17 + pVAX-TgGRA23 induced specific humoral and cellular responses, with higher level of IgG antibody, increased levels of Th1-type cytokines IFN-gamma and IL-12 (p70), and CD3+CD4+CD8 and CD3+CD8+CD4- T cells, as well as prolonged survival time (9.1 +/- 0.32 days for pVAX-TgGRA17, 10.8 +/- 0.79 days for pVAX-TgGRA23, and 12.6 +/- 2.55 days for pVAX-TgGRA17 + pVAX-TgGRA23) compared to the blank control (7.11 +/- 0.33 days), PBS control (7.22 +/- 0.44 days), and pVAX I control (7.11 +/- 0.33 days). These results demonstrated that both TgGRA17 and TgGRA23 are potential vaccine candidates, TgGRA23 has a better immunogenicity, and co-immunization of pVAX TgGRA17 and pVAX-TgGRA23 induces better protective efficacy. PMID- 28625895 TI - Expression analyses of salinity stress- associated ESTs in Aeluropus littoralis. AB - Salinity is among the most important abiotic stresses affecting crop production throughout the earth. Halophyte plants can sustain high salinity levels, therefore elucidating molecular mechanisms underlying their salinity resistance is beneficial for crop improvement. Aeluropus littoralis, a halophyte weed, is a great genetic resource for this purpose. Isolated expressed sequence taq (EST) sequences from A. littoralis under salinity stress, have given us the chance to find and analyze transcripts of genes involved in response to salinity. Transcriptome analyses indicated the expression levels of mRNAs corresponding to 10 of sequences were increased under treatments. All mRNAs were significantly induced under salt treatment with the highest peaks observed at different hours of treatments. Moreover, the full-length cDNA of vacuolar H+-pyrophosphatase (VP) was isolated utilizing 3' and 5' rapid amplification of cDNA ends polymerase chain reaction (RACE-PCR) and characterized (GenBank accession number of KT253223.1). The extracted full-length of VP was 2732 bp, which contained ORF of 2292 bp encoding 763 amino acids. PMID- 28625896 TI - Lateralization of housekeeping genes in the brain of one-day old chicks. AB - Real-time quantitative PCR is an exceptionally sensitive method that can detect even very small differences in gene expression and, as such, it is essential to use suitable reference genes. Domestic chickens are used in a wide range of studies including neurobiology, behavior, ecology and disease transmission. In recent avian gene expression experiments, 18S (18S ribosomal RNA), beta actin (ACTB) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) have frequently been used; however, there is not enough evidence that these reference genes are suitable for all types of experiments. There is considerable evidence for lateralization in numerous learning tasks and for differences in the functional contribution of the two brain hemispheres. Therefore, the purpose of this study was to identify a set of reference genes for chick brain region called an intermediate medial mesopallium (IMM), which is connected with memory formation in the chick brain, whilst also taking into consideration the differences between the left and right hemispheres. This study evaluated the expression stability of eleven candidate housekeeping genes in the IMM region of the 1-day old chick brain. In our experimental system, the most reliable results were given by the NormFinder algorithm. The results show for the first time that ACTB, commonly used as an avian reference gene, is not suitable for investigation of gene expression in the chick brain and that brain lateralization exact selection of different reference gens for each hemisphere. For memory process investigations using tasks in one-day old chicks the most effective reference genes for the left hemisphere were HMBS and SDHA, and for the right hemisphere the most effective was RPL19. PMID- 28625897 TI - Differential expression of long noncoding RNAs in congenital microtia. AB - OBJECTIVE: To analyse lncRNA expression profiles in microtia using bioinformatics analysis. METHODS: We examined lncRNA expression profiles in residual ear cartilage and normal ear cartilage from individual congenital microtia patients. RESULTS: The gene chips used in this study included 30586 lncRNAs and 26109 mRNA probes. Intotal, 180 lncRNAs with differential expression weredetected in the residual ear cartilage compared with the normal cartilage, including 74 up regulated and 106down-regulated lncRNAs. Signalling pathway analysis highlighted glyceride metabolism, osteoclast differentiation, andtumour growth. The results of qRT-PCR analysis were consistent with those of themicroarray. CONCLUSION: Differential expression of lncRNAs occurs in microtia. These lncRNAs and related signalling pathways may play an important role in the occurrence and development ofmicrotia. PMID- 28625898 TI - Doctor says you are cured, but you still feel the pain. Borrelia DNA persistence in Lyme disease. AB - Lyme disease is a zoonosis caused by infection with Borrelia burgdorferi (Bb). A great amount of research has attempted to elucidate the mechanisms by which Bb causes inflammation and chronic symptomatology in some patients. Patients often seek unconventional treatments that lack scientific evidence, as medical care is unable to effectively explain and treat their illness. Bb-DNA can persist for long periods of time in some individuals, even after antibiotic therapy. Herein, scientific rationale is presented for a new therapeutic approach against remaining bacterial DNA, and/or increasing the ability of human macrophages to remove extracellular Bb DNA. PMID- 28625899 TI - Medulloblastoma with Atypical Dynamic Imaging Changes: Case Report with Literature Review. AB - OBJECTIVE: We analyzed a case of medulloblastoma with atypical dynamic imaging changes retrospectively to summarize the atypical magnetic resonance imaging (MRI) features of medulloblastoma by reviewing the literature. METHODS: An atypical case of medulloblastoma in the cerebellar hemisphere confirmed by pathology was analyzed retrospectively, and the literature about it was reviewed. RESULTS: The radiologic findings of the patient were based on 3 examinations. The first examination showed that the cortex of the bilateral cerebellar hemisphere had diffuse nodular thickening, with a high signal on diffusion-weighted imaging and significant enhancement. Contrast enhancement MRI 1 year later showed the signal of cerebellar hemisphere returned to normal but revealed an enhanced nodule. A reexamination 6 months later showed an irregular mass with a high density shadow in the cerebellar vermis on CT scan. The T2-weighted image revealed multiple degenerative cysts, and the mass had significant enhancement. CONCLUSION: The radiologic characteristics of atypical medulloblastomas vary in adults and children. Understanding the radiologic characteristics of medulloblastomas, such as MRI features, age of onset, and location of atypical medulloblastomas, can help improve the diagnosis of medulloblastomas. PMID- 28625900 TI - Delayed Brainstem Hemorrhage Secondary to Mild Traumatic Head Injury: Report of Case with Good Recovery. AB - BACKGROUND: In clinical practice, secondary traumatic brainstem hemorrhage often develops during descending transtentorial herniation due to raised intracranial pressure, which is known as Duret hemorrhage. Although usually considered a fatal and irreversible event, in rare circumstances, victims of Duret hemorrhage could gain favorable outcomes. To our knowledge, secondary brainstem hemorrhage due to mild traumatic head injury without descending transtentorial herniation has never been reported. In this report, we present a case of delayed brainstem hemorrhage secondary to a relatively mild traumatic brain injury that experienced a rapid and favorable recovery. CASE DESCRIPTION: A 48-year-old man was admitted for a motorcycle accident. Head computed tomography 2 hours after the accident revealed mild subarachnoid hemorrhage at the interpeduncular cistern. In the following in hospital days, he experienced 2 episodes of mental state deterioration and increase of the SAH and hematoma extension to the brainstem. A digital subtraction angiography was performed with no positive finding of vascular anomaly and evident cerebral vasospasm. He experienced a rapid and favorable recovery. His Glasgow Outcome Scale score was 5 at 3 months' follow-up. CONCLUSIONS: We present a rare case of secondary traumatic brainstem hemorrhage that experienced a rapid and good recovery process. The mechanism is still obscure to us and needs to be further studied. Although traumatic brainstem hemorrhage usually means a fatal event to most of the patients, some patients may experience a favorable recovery. This rare circumstance should be stressed in prognosis consultation and clinical management of these kinds of patients. PMID- 28625901 TI - Effect of Aspirin in Postoperative Management of Adult Ischemic Moyamoya Disease. AB - BACKGROUND: Aspirin has been implicated in the postoperative management of moyamoya disease (MMD) in order to avoid bypass failure and decrease the incidence of subsequent stroke. However, its effect has not been completely determined yet. METHODS: In this study, we retrospectively reviewed data of 184 adult patients (197 hemispheres) presented with ischemic-onset MMD who had undergone direct or combined revascularization in our hospital, to clarify the effect of postoperative aspirin therapy in the management of moyamoya disease. Fifty-nine hemispheres that had been administered with aspirin (100 mg/day) after bypass surgery were defined as the "aspirin group," whereas 138 that hadn't been given aspirin postoperatively were defined as the "control group". RESULTS: Among 197 hemispheres, the mortality rate was 0. The incidence of postoperative newly developed infarction, transient ischemic attack, and hemorrhage were not significantly different between the aspirin and control groups. The patency rate of bypass graft was not significantly different between the groups, either. Notably, more patients experienced major stroke in the control group (9/138) than the aspirin group (1/59), but no statistical difference was found (P > 0.05). In the aspirin group, more patients had improved outcome than the control group (P = 0.04). CONCLUSIONS: Our findings showed that aspirin might not decrease the incidence of postoperative ischemic stroke or increase patency rate of bypass graft, but it does not increase the risk of hemorrhages, either. Also, postoperative aspirin therapy might improve outcome. More studies are needed to provide evidence for postoperative antiplatelet therapy in MMD management. PMID- 28625902 TI - Obesity in Neurosurgery: A Narrative Review of the Literature. AB - Obesity is an important consideration in neurosurgical practice. Of Australian adults, 28.3% are obese and it is estimated that more than two thirds of Australia's population will be overweight or obese by 2025. This review of the effects of obesity on neurosurgical procedures shows that, in patients undergoing spinal surgery, an increased body mass index is a significant risk factor for surgical site infection, venous thromboembolism, major medical complications, prolonged length of surgery, and increased financial cost. Although outcome scores and levels of patient satisfaction are generally lower after spinal surgery in obese patients, obesity is not a barrier to deriving benefit from surgery and, when the natural history of conservative management is taken into account, the long-term benefits of surgery may be equivalent or even greater in obese patients than in nonobese patients. In cranial surgery, the impact of obesity on outcome and complication rates is generally lower. Specific exceptions are higher rates of distal catheter migration after shunt surgery and cerebrospinal fluid leak after posterior fossa surgery. Minimally invasive approaches show promise in mitigating some of the adverse effects of obesity in patients undergoing spine surgery but further studies are needed to develop strategies to reduce obesity-related surgical complications. PMID- 28625903 TI - The Need for Clinical Practice Guidelines in Assessing and Managing Perioperative Neurologic Deficit: Results from a Survey of the AOSpine International Community. AB - OBJECTIVES: There is no standardized approach to assess and manage perioperative neurologic deficit (PND) in patients undergoing spinal surgery. This survey aimed to evaluate the awareness and usage of clinical practice guidelines (CPGs) as well as investigate how surgeons performing spine surgeries feel about and manage PND and how they perceive the value of developing CPGs for the management of PND. METHODS: An invitation to participate was sent to the AOSpine International community. Questions were related to the awareness, usage of CPGs, and demographics. Results from the entire sample and subgroups were analyzed. RESULTS: Of 770 respondents, 659 (85.6%) reported being aware of the existence of guideline(s), and among those, 578 (87.7%) acknowledged using guideline(s). Overall, 58.8% of surgeons reported not feeling comfortable managing a patient who wakes up quadriplegic after an uneventful multilevel posterior cervical decompression with instrumented fusion. Although 22.9% would consider an immediate return to the operating room, the other 77.1% favored conducting some kind of investigation/medical intervention first, such as performing magnetic resonance imaging (85.9%), administrating high-dose corticosteroids (50.2%), or increasing the mean arterial pressure (44.7%). Overall, 90.6% of surgeons believed that CPGs for the management of PND would be useful and 94.4% would be either likely or extremely likely to use these CPGs in their clinical practice. CONCLUSIONS: Most respondents are aware and routinely use CPGs in their practice. Most surgeons performing spine surgeries reported not feeling comfortable managing PND. However, they highly value the creation and are likely to use CPGs in its management. PMID- 28625904 TI - Subarachnoid Hemorrhage Because of Distal Superior Cerebellar Artery Dissection in Neurofibromatosis Type 1. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a rare disease with an incidence of 1 in every 3000 births. Numerous studies have focused on the main function of NF1 as a tumor suppressor, whereas few have examined the cerebrovascular abnormalities observed in patients with NF1. It is worth noting that intracranial aneurysms are uncommon in this condition. CASE DESCRIPTION: We report a case of NF1 with a dissection of the distal segment of the superior cerebellar artery. A 36-year-old woman presented with a distal superior cerebellar artery (SCA) dissection causing subarachnoid hemorrhage. Subsequently, because of the rich collateral blood flow distal to the dissection, N-butyl cyanoacrylate (NBCA) glue embolization was unsuccessful. Therefore, direct trapping of the artery was necessary. The patient was discharged after an uneventful postoperative period, and has remained without complications. CONCLUSIONS: In the treatment of subarachnoid hemorrhage because of a distal SCA dissection in patients with NF1, NBCA glue embolization may be a safer option than microsurgery or coil embolization, in the acute phase, considering the possible vulnerability of the vessel wall, accessibility, morphology of the lesions, and the risk of developing unpredictable infarcts in the case of parent artery occlusion. However, regular reevaluation of the blood flow is necessary to monitor recurrence, given the rich collateral circulation. PMID- 28625905 TI - Influence of Magnetic Resonance Imaging Features on Surgical Decision-Making in Degenerative Cervical Myelopathy: Results from a Global Survey of AOSpine International Members. AB - OBJECTIVE: We conducted a survey to understand how specific pathologic features on magnetic resonance imaging (MRI) influence surgeons toward an anterior or posterior surgical approach in degenerative cervical myelopathy (DCM). METHODS: A questionnaire was sent out to 6179 AOSpine International members via e-mail. This included 18 questions on a 7-point Likert scale regarding how MRI features influence the respondent's decision to perform an anterior or posterior surgical approach. Influence was classified based on the mean and mode. Variations in responses were assessed by region and training. RESULTS: Of 513 respondents, 51.7% were orthopedic surgeons, 36.8% were neurosurgeons, and the remainder were fellows, residents, or other. In ascending order, multilevel bulging disks, cervical kyphosis, and a high degree of anterior cord compression had a moderate to strong influence toward an anterior approach. A high degree of posterior cord compression had a moderate to strong influence, whereas multilevel compression, ossification of the posterior longitudinal ligament, ligamentum flavum enlargement, and congenital stenosis had a moderate influence toward a posterior approach. Neurosurgeons chose anterior approaches more and posterior approaches less in comparison with orthopedic surgeons (P < 0.01). Of note, 59.8% of respondents were equally comfortable performing multilevel (3 or more levels) anterior and posterior procedures, whereas 61.5% did not feel comfortable in determining the surgical approach based on MRI alone. CONCLUSIONS: Specific DCM pathology influences the choice for anterior or posterior surgical approach. These data highlight factors based on surgeon experience, training, and region of practice. They will be helpful in defining future areas of investigation in an effort to provide individualized surgical strategies and optimize patient outcomes. PMID- 28625906 TI - Impact of Associated Nidal Lesions in Outcome of Brain Arteriovenous Malformations After Radiosurgery with or without Embolization. AB - BACKGROUND: Radiosurgery is a valuable option to treat arteriovenous malformations. There are correlations between some morphologic nidal features and final results, and the benefits of preradiosurgical embolization have not been well established thus far. METHODS: Analysis of a longitudinal cohort of 47 consecutive patients who underwent radiosurgery with or without previous embolization. Embolizations were performed exclusively with n-butyl cyanoacrylate. Radiosurgery was delivered either as a single fraction or divided in up to 5 equal fractions. Clinical and radiologic follow-up of at least 36 months was obtained. Presence of nidal lesions, such as aneurysms, venous outflow stenosis, venous outflow ectasias, and/or intranidal arteriovenous fistulas, were evaluated, and their relation with outcome and complications were studied. RESULTS: Of the patients, 68.1% presented with hemorrhagic event; of these, 62.5% harbored intranidal arteriovenous fistulas, 83.3% had venous ectasias, and 90% had venous outflow stenosis. Occlusion rate of embolization plus radiosurgery was 46.1%, and stereotactic radiosurgery alone was 52.4% (P = 0.671). Variables significantly associated with obliteration were lower nidus volume, lack of intranidal arteriovenous fistula, higher stereotactic radiosurgery dose, and lower radiosurgical-based arteriovenous malformation scale score. CONCLUSIONS: An untreated arteriovenous fistula inside the arteriovenous malformation at the moment of stereotactic radiosurgery was associated with lower cure rates (P = 0.001). Embolization followed by radiosurgery was not superior to radiosurgery alone; however, targeted embolization of intranidal arteriovenous fistulas to increase obliteration rates and to protect the patient from bleeding during the radiosurgery latency period should be considered. PMID- 28625908 TI - "On the Spot": The Use of Four-Dimensional Computed Tomography Angiography to Differentiate a True Spot Sign From a Distal Intracranial Aneurysm. AB - BACKGROUND: Spontaneous intracerebral hemorrhage may arise from underlying abnormalities, including aneurysms. Computed tomography angiography (CTA) is widely used for the detection of possible underlying causes, which is important because it may have immediate therapeutic consequences. In addition, CTA is used to detect the so-called spot sign, indicating active hemorrhage, which carries a worse prognosis. However, CTA is a snapshot in time. Four-dimensional (4D) CTA is a dynamic type of imaging and has emerged as a valuable imaging technique for different neurovascular disorders. CASE DESCRIPTION: Two patients with intracerebral hemorrhage both showed an assumed spot sign on CTA, suggesting active hemorrhage. Additional 4D-CTA showed true active hemorrhage in one patient and a distal intracranial aneurysm in the other. This aneurysm was initially falsely interpreted as a spot sign on conventional CTA. CONCLUSIONS: Our case findings show how 4D-CTA can discern active bleeding from aneurysmal hemorrhage in cases with hemorrhagic stroke. This finding proves the additional value of this relatively new technique, because the detected underlying disorders have different therapeutic consequences in the acute setting. PMID- 28625907 TI - Long-Standing Isolated Autoimmune Hypothalamitis Diagnosed with Endoscopic Transventricular Biopsy. AB - BACKGROUND: Autoimmune hypothalamitis, which is among the causes of acquired central diabetes insipidus, has seldom been described in the literature. This condition is probably provoked by the production of anti-vasopressin-secreting cell antibodies and antihypothalamus antibodies and is often associated with pituitary or polyendocrine autoimmunity. Correct diagnosis and immediate treatment are essential to avoid the progression of the pathologic process. CASE DESCRIPTION: A woman diagnosed with central diabetes insipidus 12 years ago, who had panhypopituitarism and mild memory deficit, came to our attention. She refused radiologic studies. Magnetic resonance imaging performed in our unit showed a contrast-enhancing hypothalamic lesion. Lumbar puncture was negative for neoplastic markers. We decided to perform a biopsy of the lesion to obtain a histopathologic examination of the tissue and chose an endoscopic transventricular approach to reach the floor of the third ventricle. Autoimmune hypothalamitis was diagnosed and treatment with steroids and azathioprine was started. The lesion size decreased and was stable after 17 months of follow-up. CONCLUSIONS: The endoscopic transventricular approach has proved to be an effective and safe way to obtain tissue samples for histopathologic examination from a region that is usually difficult to reach; it also gives direct visualization of the lesion, which makes sampling easier. The lesion size decreased after treatment but no clinical improvement was detected, either on the cognitive or on the endocrinologic side. PMID- 28625909 TI - Multilevel Anterior Cervical Diskectomy and Fusion with Zero-Profile Devices: Analysis of Safety and Feasibility, with Focus on Sagittal Alignment and Impact on Clinical Outcome: Single-Institution Experience and Review of Literature. AB - BACKGROUND: In multilevel degenerative conditions posterior approaches are often preferred, but anterior approaches provide comparable clinical results and better alignment. Anterior plating entails higher rates of soft tissue injuries and dysphagia, particularly in multilevel cases. This study evaluates efficacy and safety of zero-profile devices in 3- and 4-level anterior cervical diskectomy and fusion, analyzing patients' clinical and radiologic long-term outcomes. METHODS: We prospectively enrolled 24 patients with cervical spondylotic myeloradiculopathy who underwent 3- and 4-level anterior cervical diskectomy and fusion with the zero-profile device. Mean follow-up was 39 months (range 24-72). Nurick grading was used for myelopathy, Neck Disability Index and Visual Analog Scale scores for arm and neck pain, and Short Form 36 survey for physical and mental health status. Postoperative radiograph and computed tomography were obtained after surgery, at 6 and 12 months, and at last follow-up to assess fusion rate and complications. Cervical alignment was measured by Cobb angle. Incidence of postoperative dysphagia was monitored according to Bazaz dysphagia index. RESULTS: On last computed tomography scan, fusion was present in 49% of spaces (40 of 82). Mean neck and arm pain visual analog scale decreased from 6.7 1.6 (P < 0.01) and 5.9-0.9 (P < 0.01), respectively. Improvements in the Short Form 36 survey and Neck Disability Index were documented (P < 0.01). Lordosis was restored in all patients. Five of 24 patients complained of mild dysphagia (20.8%): in three (12.5%) short-term dysphagia and in two (8.3%) medium-term dysphagia. No long-term dysphagia (>=6 months) was observed. CONCLUSION: Anterior cervical diskectomy and fusion with a zero-profile device is effective and safe for 3- and 4-level cervical spondylotic myeloradiculopathy. It allows to restore cervical lordosis and achieve long-term satisfactory clinical outcome. PMID- 28625910 TI - A high fat diet enhances the sensitivity of chick adipose tissue to the effects of centrally injected neuropeptide Y on gene expression of adipogenesis associated factors. AB - The purpose of this study was to determine how dietary macronutrient composition and exogenous neuropeptide Y (NPY) affect mRNA abundance of factors associated with lipid metabolism in chick adipose tissue. Chicks were fed one of three isocaloric (3000kcal metabolizable energy (ME)/kg) diets after hatch: high carbohydrate (HC; control), high fat (HF; 30% of ME from soybean oil) or high protein (HP; 25% crude protein). On day 4 post-hatch, vehicle or 0.2nmol of NPY was injected intracerebroventricularly and abdominal and subcutaneous fat depots collected 1h later. In abdominal fat, mRNA abundance of peroxisome proliferator activated receptor gamma (PPARgamma) and fatty acid binding protein 4 (FABP4) increased after NPY injection in HF diet-fed chicks. NPY injection decreased expression of PPARgamma and sterol regulatory element-binding transcription factor 1 (SREBP1) in the subcutaneous fat of HC diet-fed chicks, whereas SREBP1 expression was increased in the subcutaneous fat of HF diet-fed chicks after NPY injection. An acutely increased central concentration of NPY in chicks affects adipose tissue physiology in a depot- and diet-dependent manner. The chick may serve as a model to understand the relationship between diet and the brain-fat axis' role in maintaining whole body energy homeostasis, as well as to understand metabolic distinctions among fat depots. PMID- 28625911 TI - White shrimp Litopenaeus vannamei recombinant lactate dehydrogenase: Biochemical and kinetic characterization. AB - Shrimp lactate dehydrogenase (LDH) is induced in response to environmental hypoxia. Two protein subunits deduced from different transcripts of the LDH gene from the shrimp Litopenaeus vannamei (LDHvan-1 and LDHvan-2) were identified. These subunits are expressed by alternative splicing. Since both subunits are expressed in most tissues, the purification of the enzyme from the shrimp will likely produce hetero LDH containing both subunits. Therefore, the aim of this study was to overexpress, purify and characterize only one subunit as a recombinant protein, the LDHvan-2. For this, the cDNA from muscle was cloned and overexpressed in E. coli as a fusion protein containing an intein and a chitin binding protein domain (CBD). The recombinant protein was purified by chitin affinity chromatography column that retained the CBD and released solely the full and active LDH. The active protein appears to be a tetramer with molecular mass of approximately 140 kDa and can use pyruvate or lactate as substrates, but has higher specific activity with pyruvate. The enzyme is stable between pH 7.0 to 8.5, and between 20 and 50 degrees C with an optimal temperature of 50 degrees C. Two pKa of 9.3 and 6.6, and activation energy of 44.8 kJ/mol degrees K were found. The kinetic constants Km for NADH was 23.4 +/- 1.8 MUM, and for pyruvate was 203 +/- 25 MUM, while Vmax was 7.45 MUmol/min/mg protein. The shrimp LDH that is mainly expressed in shrimp muscle preferentially converts pyruvate to lactate and is an important enzyme for the response to hypoxia. PMID- 28625912 TI - Isolation of recombinant human untagged glyceraldehyde-3-phosphate dehydrogenase from E. coli producer strain. AB - The goal of the present work was expression of human glyceraldehyde-3-phosphate dehydrogenase (hGAPDH) without additional tag constructions in E. coli cells and elaboration of the procedure for purification of untagged hGAPDH from the extract of the producer cells. We present a simple method for purification of untagged hGAPDH including ammonium sulfate fractionation and gel filtration on a G-100 Sephadex column. The method allows isolation of 2 mg of pure hGAPDH from 600 ml of cell culture (7 g of the cell biomass). The specific activity of the freshly purified hGAPDH constitutes 117 +/- 5 MUmol NADH/min per mg protein (pH 9.0, 22 degrees C), which is close to the specific activity of rabbit muscle glyceraldehyde-3-phosphate dehydrogenase determined under the same conditions and several times exceeds the specific activity of his-tagged GAPDH preparations. The high enzymatic activity suggests that the recombinant enzyme retains its native structure. The described procedure may be useful for researchers who need a preparation of native hGAPDH without admixture of misfolded forms for their investigations. PMID- 28625913 TI - Use of rodent data for cancer risk assessment of smokeless tobacco in the regulatory context. AB - To support risk management decisions, information from different fields has been integrated in this presentation to provide a realistic quantitative cancer risk assessment of smokeless tobacco. Smoking among Swedish men is currently below 10%, while about 20% use a special smokeless tobacco (snus) as a substitute for cigarettes. Epidemiological data and molecular biomarkers demonstrate that rodent bioassays with tobacco specific nitrosamines (TSNA) overestimate cancer risk from snus by more than one order of magnitude. The underlying reasons are discussed. DNA damage constitutes a necessary, although not sufficient prerequisite for cancer initiation. Individuals who have not used tobacco exhibit DNA lesions identical with those induced by TSNA. No increase above this adduct background can be shown from snus, and extensive epidemiological studies in Sweden have failed to demonstrate elevated cancer risks even in long term users. A "bench mark" for acceptable risk of 1/10(6) derived from rodent data has been suggested when regulating snus. By relating similarly derived estimates for some food contaminants, the implementation even of a limit of 1/10(4) may be unrealistic. The management of smokeless tobacco products has rarely been based on a scientifically sound risk assessment, where attention is given to the outstandingly higher hazards associated with smoking. PMID- 28625914 TI - Prioritizing disease-causing microbes based on random walking on the heterogeneous network. AB - As we all know, the microbiota show remarkable variability within individuals. At the same time, those microorganisms living in the human body play a very important role in our health and disease, so the identification of the relationships between microbes and diseases will contribute to better understanding of microbes interactions, mechanism of functions. However, the microbial data which are obtained through the related technical sequencing is too much, but the known associations between the diseases and microbes are very less. In bioinformatics, many researchers choose the network topology analysis to solve these problems. Inspired by this idea, we proposed a new method for prioritization of candidate microbes to predict potential disease-microbe association. First of all, we connected the disease network and microbe network based on the known disease-microbe relationships information to construct a heterogeneous network, then we extended the random walk to the heterogeneous network, and used leave-one-out cross-validation and ROC curve to evaluate the method. In conclusion, the algorithm could be effective to disclose some potential associations between diseases and microbes that cannot be found by microbe network or disease network only. Furthermore, we studied three representative diseases, Type 2 diabetes, Asthma and Psoriasis, and finally presented the potential microbes associated with these diseases by ranking candidate disease-causing microbes, respectively. We confirmed that the discovery of the new associations will be a good clinical solution for disease mechanism understanding, diagnosis and therapy. PMID- 28625916 TI - ER stress disturbs SR/ER-mitochondria Ca2+ transfer: Implications in Duchenne muscular dystrophy. AB - Besides its role in calcium (Ca2+) homeostasis, the sarco-endoplamic reticulum (SR/ER) controls protein folding and is tethered to mitochondria. Under pathophysiological conditions the unfolded protein response (UPR) is associated with disturbance in SR/ER-mitochondria crosstalk. Here, we investigated whether ER stress altered SR/ER-mitochondria links, Ca2+ handling and muscle damage in WT (Wild Type) and mdx mice, the murine model of Duchenne Muscular Dystrophy (DMD). In WT mice, the SR/ER-mitochondria links were decreased in isolated FDB muscle fibers after injection of ER stress activator tunicamycin (TM). Ca2+ imaging revealed an increase of cytosolic Ca2+ transient and a decrease of mitochondrial Ca2+ uptake. The force generating capacity of muscle dropped after TM. This impaired contractile function was accompanied by an increase in autophagy markers and calpain-1 activation. Conversely, ER stress inhibitors restored SR/ER mitochondria links, mitochondrial Ca2+ uptake and improved diaphragm contractility in mdx mice. Our findings demonstrated that ER stress-altered SR/ER mitochondria links, disturbed Ca2+ handling and muscle function in WT and mdx mice. Thus, ER stress may open up a prospect of new therapeutic targets in DMD. PMID- 28625915 TI - High fat diet-induced obesity increases myocardial injury and alters cardiac STAT3 signaling in mice after polymicrobial sepsis. AB - Little is known about how obesity affects the heart during sepsis and we sought to investigate the obesity-induced cardiac effects that occur during polymicrobial sepsis. Six-week old C57BL/6 mice were randomized to a high fat (HFD) (60% kcal fat) or normal diet (ND) (16% kcal fat). After 6weeks of feeding, mice were anesthetized with isoflurane and polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Plasma and cardiac tissue were obtained for analysis. Echocardiography was performed on a separate cohort of mice at 0 and 18h after CLP. Following 6-weeks of dietary intervention, plasma cardiac troponin I was elevated in obese mice at baseline compared to non-obese mice but troponin increased only in non-obese septic mice. IL-17a expression was 27-fold higher in obese septic mice versus non-obese septic mice. Cardiac phosphorylation of STAT3 at Ser727 was increased at baseline in obese mice and increased further only in obese septic mice. Phosphorylation of STAT3 at Tyr705 was similar in both groups at baseline and increased after sepsis. SOCS3, a downstream protein and negative regulator of STAT3, was elevated in obese mice at baseline compared to non-obese mice. After sepsis non-obese mice had an increase in SOCS3 expression that was not observed in obese mice. Taken together, we show that obesity affects cardiac function and leads to cardiac injury. Furthermore, myocardial injury in obese mice during sepsis may occur through alteration of the STAT3 pathway. PMID- 28625917 TI - The cholangiocyte primary cilium in health and disease. AB - Cholangiocytes, like most cells, express primary cilia extending from their membranes. These organelles function as antennae which detect stimuli from bile and transmit the information into cells regulating several signaling pathways involved in secretion, proliferation and apoptosis. The ability of primary cilia to detect different signals is provided by ciliary associated proteins which are expressed in its membrane. Defects in the structure and/or function of these organelles lead to cholangiociliopathies that result in cholangiocyte hyperproliferation, altered fluid secretion and absorption. Since primary cilia dysfunction has been observed in several epithelial tumors, including cholangiocarcinoma (CCA), primary cilia have been proposed as tumor suppressor organelles. In addition, the loss of cilia is associated with dysregulation of several molecular pathways resulting in CCA development and progression. Thus, restoration of the primary cilia may be a potential therapeutic approach for several ciliopathies and CCA. PMID- 28625918 TI - Body composition by DXA. AB - Body composition measurements from DXA have been available since DXA technology was developed 30years ago, but are historically underutilized. Recently, there have been rapid developments in body composition assessment including the analysis and publication of representative data for the US, official usage guidance from the International Society for Clinical Densitometry, and development of regional body composition measures with clinical utility. DXA body composition is much more than whole body percent fat. In this paper celebrating 30years of DXA for body composition, we will review the principles of DXA soft tissue analysis, practical clinical and research applications, and what to look for in the future. PMID- 28625919 TI - C1q/TNF-related protein 1 promotes endothelial barrier dysfunction under disturbed flow. AB - Endothelial hyper-permeability is a major determinant factor that contributes to the accelerated development of atherosclerotic lesions at hemodynamically disturbed sites. Previously, we showed that C1q/TNF related protein (CTRP) 1 promotes endothelium-leukocyte interactions and inflammatory responses in vascular cells. Here, we sought to investigate the role of CTRP1 in modulation of endothelial permeability under disturbed flow condition. By using en face staining of mouse aorta, we found CTRP1 expression was significantly increased in vascular endothelial cells under disturbed flow as compared to steady laminar flow. Vascular permeability to Evans blue dye was notably enhanced in CTRP1 knockin mice as compared to wild type animals, whereas aortic hyper-permeability at disturbed sites was remarkably restored after deletion of CTRP1. In cultured endothelial cells, treatment of CTRP1 led to increased permeability to fluorescent-labelled dextran and apparent formation of paracellular holes as observed after disturbed flow exposure, which was evidently reduced in the presence of a CTRP1-specific neutralizing antibody. Mechanistically, we found activation of VEGFR2 by CTRP1 might be involved in vascular hyper-permeability under disturbed flow condition. Taken together, this study suggests that CTRP1 is a mechano-sensitive proinflammatory factor that mediates disturbed flow-induced vascular barrier dysfunction. Inhibition of CTRP1 may inhibit the pathogenesis of atherosclerosis at early stage. PMID- 28625920 TI - C-terminal tail of NADPH oxidase organizer 1 (Noxo1) mediates interaction with NADPH oxidase activator (Noxa1) in the NOX1 complex. AB - NOX1 (NADPH oxidase) similar to phagocyte NADPH oxidase, is expressed mainly in the colon epithelium and it is responsible for host defense against microbial infections by generating ROS (reactive oxygen species). NOX1 is activated by two regulatory cytosolic proteins that form a hetero-dimer, Noxo1 (NOX organizer 1) and Noxa1 (NOX activator 1). The interaction between Noxa1 and Noxo1 is critical for activating NOX1. However no structural studies for interaction between Noxa1 and Noxo1 has not been reported till date. Here, we studied the inter-molecular interaction between the SH3 domain of Noxa1 and Noxo1 using pull-down assay and NMR spectroscopy. 15N/13C-labeled SH3 domain of Noxa1 has been purified for hetero-nuclear NMR experiments (HNCACB, CBCACONH, HNCA, HNCO, and HSQC). TALOS analysis using backbone assignment data of the Noxa1 SH3 domain showed that the structure primarily consists of beta-sheets. Data from pull-down assay between the Noxo1 and Noxa1 showed that the SH3 domains (Noxa1) is responsible for interaction with Noxo1 C-terminal tail harboring proline rich region (PRR). The concentration-dependent titration of the Noxo1 C-terminal tail to Noxa1 shows that Noxo1 particularly in the RT loop: Q407*, H408, S409, A412*, G414*, E416, D417, L418, and F420; n-Src loop: C430, E431*, V432*, A435, W436, and L437; and terminal region: I447; F448*, F452* and V454 interact with Noxa1. Our results will provide a detailed understanding for interaction between Noxa1 and Noxo1 at the molecular level, providing insights into their cytoplasmic activity-mediated functioning as well as regulatory role of C-terminal tail of Noxo1 in the NOX1 complex. PMID- 28625921 TI - Binding of coronin 1B to TbetaRI negatively regulates the TGFbeta1 signaling pathway. AB - Coronin 1B is an actin-binding protein that regulates several actin-dependent cellular processes including migration and endocytosis. However, the role of coronin 1B in the tumor growth factor (TGF)beta signaling pathway is largely unknown. Here, we investigated whether coronin 1B affects the TGFbeta signaling cascade and found that coronin 1B negatively regulates the TGFbeta signaling pathway. Immunoprecipitation and glutathione-S-transferase-pulldown assays revealed that coronin 1B directly associated with TGFbeta receptor I (TbetaRI). Overexpression of coronin 1B inhibited the TGFbeta1-induced interaction between TbetaRI and Smad2/3 in plasmid-transfected HEK293T cells. Coronin 1B was basally bound to TbetaRI in vascular smooth muscle cells (VSMCs), but TGFbeta1 stimulation did not affect their association, suggesting constitutive binding between coronin 1B and TbetaRI. Overexpression of coronin 1B suppressed TGFbeta1 induced activation of a Smad-binding element-luciferase reporter construct and a plasminogen activator inhibitor (PAI)-1 promoter-luciferase reporter construct in HEK293T cells. By contrast, depletion of coronin 1B by siRNA transfection increased TGFbeta1-induced Smad2/3 phosphorylation and PAI-1 expression in VSMCs. These results suggest that coronin 1B regulates the TGFbeta1 signaling cascade by constitutively interacting with TbetaRI and inhibiting the binding of Smad2/3 to TbetaRI in response to TGFbeta1 stimulation. PMID- 28625922 TI - Macrophage infiltration regulates the adipose ECM reconstruction and the fibrosis process after fat grafting. AB - BACKGROUND: Fat grafting experiences a regeneration process from free lipoaspirate to intact adipose tissue. The adipose extracellular matrixes (ECM) provide the structure and biochemical support for surrounding cells; inflammatory cells, like macrophages, regulate the process. Our hypothesis states that transferred fat undergoes ECM remodeling after fat grafting and this process is regulated by macrophage infiltration. METHODS: Lipoaspirate was injected subcutaneously into the back of nude mice. The micro-structure of the fat grafts was observed and evaluated using scanning electron microscope (SEM) and collagen I immunohistostaining. The gene transcription level of collagen proteins and the matrix metalloproteinases (MMPs) were assessed by qRT-PCR. Local injection of clodronate-encapsulated liposome was used to evaluate the role of macrophages of fat grafts at different stages in ECM remodeling, depletion of macrophages, at different time points (Week 1 and Week 4). RESULTS: Results from the SEM analysis showed that liposuction caused severe damage to the ECM structure in freshly aspirated adipose tissue. On Day 1 post-transplantation, the surface of adipocytes was covered with platelets and this secreted fibrin network on the fat grafts. An integral adipose structure was already established with an intact ECM at the end of Week 1. The early depletion of macrophages remarkably hindered ECM reconstruction process by down-regulating the expression of collagen proteins and MMPs. Expression of Collagen I was significantly decreased after depletion of macrophages in both gene and protein levels. Results also showed that the depletion of macrophages at the later stage of fat grafting resulted in less fibrosis and capsule formation. CONCLUSION: Free fat aspirates undergo a prompt ECM reconstruction process and completed in the first week; this process can be initiated with platelets and mainly modulated by inflammatory cells such as macrophages. It was also observed that prolonged macrophage infiltration contributes to fibrosis and capsule formation in fat grafts. PMID- 28625923 TI - Preliminary identification of endometrial cancer stem cells in vitro and in vivo. AB - Stem cells play a critical role in endometrial cancer progression. However, the current methodologies used to isolate endometrial cancer stem cells (ECSCs) remain unsatisfactory. The ECSCs were isolated by serumfree suspension cultivation. The stem cells-related genes CD44, CD133, Oct4, Sox2 and Nanog were analyzed, and the biological behaviour of ECSCs was evaluated in vitro and vivo. The results suggest that (i) serumfree suspension cultivation is non-toxic and a convenient way for isolating the ECSCs, and is not limited to specific surface markers; (ii) Ishikawa cells can be used as an effective source of ECSCs, and the obtained ECSCs expressing the pluripotent stem cells markers CD44, CD133, Oct4, Sox2, and Nanog; (iii) ECSCs originated from Ishikawa cells showed an increased ability to invasion and metastasis in vitro, and exhibited a high proliferative capacity and pluripotency in vivo and vitro. These findings indicate that serumfree suspension cultivation is an effective method for isolating ECSCs from Ishikawa cells, and the obtained ECSCs are tumorigenic and display stem cell-like properties. PMID- 28625924 TI - Protoporphyrin IX fluorescence as potential indicator of psoriasis severity and progression. AB - BACKGROUND AND OBJECTIVES: In psoriatic lesions, fluorescence diagnosis with blue light can detect protoporphyrin IX accumulation, especially after topical 5 aminolaevulinic acid (ALA) application. However, variable fluorescence distributions, interpersonal variations and long incubation time limit its wide application in clinic. This study is aimed to identify a consistent and convenient method to facilitate diagnosis and evaluation of psoriatic lesions. METHODS: 104 psoriatic lesions from 30 patients were evaluated. Single lesion PSI scoring and fluorescence by macrospectrofluorometry were recorded on each lesion before and after treatment with narrow-band UVB. RESULTS: Punctate red fluorescence, emitted mainly by protoporphyrin IX, is observed in some psoriatic lesions. According to psoriasis severity index, fluorescence-positive lesions are more severe than lesions without fluorescence. We found a significant positive correlation between psoriasis severity and fluorescence intensity from protoporphyrin IX. CONCLUSIONS: Protoporphyrin IX-induced red fluorescence can be used as a novel and convenient approach for psoriasis diagnosis and progression evaluation. PMID- 28625925 TI - Vanadium exposure-induced striatal learning and memory alterations in rats. AB - Occupational and environmental exposure to vanadium has been associated with toxicities in reproductive, respiratory, and cardiovascular systems. The knowledge on whether and how vanadium exposure caused neurobehavioral changes remains incomplete. This study was designed to investigate the changes in learning and memory following drinking water exposure to vanadium, and to conduct the preliminary study on underlying mechanisms. Male Sprague-Dawley rats were exposed to vanadium dissolved in drinking water at the concentration of 0.0, 0.5, 1.0 and 2.0g/L, as the control, low-, medium-, and high- dose groups, respectively, for 12 weeks. The results by the Morris water maze test showed that the time for the testing animal to find the platform in the high exposed group was increased by 82.9% and 49.7%, as compared to animals in control and low-dose groups (p<0.05). There were significantly fewer rats in the medium- and high- dose groups than in the control group who were capable of crossing the platform (p<0.05). Quantitation of vanadium by atomic absorption spectrophotometry revealed a significant dose-dependent accumulation of vanadium in striatum (r=0.931, p<0.01). Histopathological examination further demonstrated a degenerative damage in vanadium-exposed striatum. Interestingly, with the increase of the dose of vanadium, the contents of neurotransmitter ACh, 5-HT and GABA in the striatum increased; however, the levels of Syn1 was significantly reduced in the exposed groups compared with controls (p<0.05). These data suggest that vanadium exposure apparently reduces the animals' learning ability. This could be due partly to vanadium's accumulation in striatum and the ensuing toxicity to striatal structure and synaptic plasticity. Further research is warranted for mechanistic understanding of vanadium-induced neurotoxicity. PMID- 28625926 TI - Prenatal caffeine exposure induced high susceptibility to metabolic syndrome in adult female offspring rats and its underlying mechanisms. AB - Our previous studies have demonstrated that prenatal caffeine exposure (PCE) induced an intrauterine programming of hypothalamic-pituitary-adrenal axis (HPAA) associated neuroendocrine metabolism in 3-month-old offspring rats. In this study, we aimed to confirm this programming disorder and high susceptibility to metabolic syndrome (MS) in 10-month-old female PCE offspring with postnatal catch up growth. We found that PCE female offspring rats showed decreased bodyweight but a higher rate of weight gain after birth. Moreover, in the offspring, basal hyperinsulinemia and insulin resistance were observed before unpredictable chronic stress (UCS), but serum total cholesterol (TCH) levels and triglyceride/high-density lipoprotein-cholesterol (TG/HDL-C), TCH/HDL-C and low density lipoprotein-cholesterol/HDL-C (LDL-C/HDL-C) ratio changes were increased after UCS, accompanied by morphological damage of the related tissues. These results suggested that PCE adult female offspring rats were highly susceptible to MS, which is related to HPAA-associated neuroendocrine-metabolic programming disorder. PMID- 28625927 TI - Entrainment and high-density three-dimensional mapping in right atrial macroreentry provide critical complementary information: Entrainment may unmask "visual reentry" as passive. AB - BACKGROUND: With the recent advent of high-density (HD) 3-dimensional (3D) mapping, the utility of entrainment is uncertain. However, the limitations of visual representation and interpretation of these high-resolution 3D maps are unclear. OBJECTIVE: The purpose of this study was to determine the strengths and limitations of both HD 3D mapping and entrainment mapping during mapping of right atrial macroreentry. METHODS: Fifteen patients were studied. The number and type of circuits accounting for >=90% of the tachycardia cycle length using HD 3D mapping were verified using systematic entrainment mapping. Entrainment sites with an unexpectedly long postpacing interval despite proximity to the active circuit were evaluated. RESULTS: Based on HD 3D mapping, 27 circuits were observed: 12 peritricuspid, 2 upper loop reentry, 10 lower loop reentry, and 3 lateral wall circuits. With entrainment, 17 of the 27 circuits were active: all 12 peritricuspid and 2 upper loop reentry. However, lower loop reentry was confirmed in only 3 of 10, and none of the 3 lateral wall circuits were present. Mean percentage of tachycardia cycle length covered by active circuits was 98% +/ 1% vs 97% +/- 2% for passive circuits (P = .09). None of the 345 entrainment runs terminated tachycardia or changed tachycardia mechanism. In 8 of 15 patients, 13 examples of unexpectedly long postpacing interval were observed at entrainment sites located distal to localized zones of slow conduction seen on HD 3D mapping. CONCLUSION: Using HD 3D mapping, "visual reentry" may be due to passive circuitous propagation rather than a critical reentrant circuit. HD 3D mapping provides new insights into regional conduction and helps explain unusual entrainment phenomena. PMID- 28625928 TI - Second-generation cryoballoon ablation in the setting of left common pulmonary veins: Procedural findings and clinical outcome. AB - BACKGROUND: A left common pulmonary vein (LCPV) accounts for the most frequent PV variation. Use of the cryoballoon (CB) for isolating these veins is still debatable. To date, no data are available regarding the feasibility, acute PV isolation, and clinical outcome of the second-generation CB (CB-A) in this setting. OBJECTIVE: The purpose of this study was to investigate the performance of the CB-A in patients with LCPVs. METHODS: In a total cohort of 433 patients having undergone CB-A ablation for drug-refractory atrial fibrillation together with preprocedural computed tomographic scanning, 146 patients presented an LCPV. Measurement of ostial area and trunk distance was performed, together with analysis of procedural and fluoroscopic data in order to determine the ablation strategy. The latter 146 LCPV+ patients were compared for outcome with a cohort of 146 propensity-score matched LCPV- patients. RESULTS: Electrical isolation could be achieved in all left-sided veins. A long left common trunk (>15 mm) was found in 25% (37/146) of the LCPV+ patients. LCPVs treated with a single-shot freeze strategy presented a longer trunk (22 +/- 5 mm vs 9 +/- 4 mm, P <.001) and smaller ostial area (305 +/- 109 mm2 vs 400 +/- 108 mm2, P <.001) compared to LCPV patients in whom a segmental (superior and inferior) freeze was delivered. Survival free from atrial fibrillation was similar between LCPV+ and LCPV- patients during mean follow-up of 19 +/- 10 months (log rank P = .33). CONCLUSION: CB-A ablation in LCPV+ patients is effective and showed no difference in clinical outcome compared to LCPV- patients. PMID- 28625930 TI - The geriatric medicine rolled around to the four winds. PMID- 28625929 TI - Verification of a novel atrial fibrillation cryoablation dosing algorithm guided by time-to-pulmonary vein isolation: Results from the Cryo-DOSING Study (Cryoballoon-ablation DOSING Based on the Assessment of Time-to-Effect and Pulmonary Vein Isolation Guidance). AB - BACKGROUND: There are no recommendations on the optimal dosing for cryoablation of atrial fibrillation (Cryo-AF). OBJECTIVE: The purpose of this study was to develop and prospectively test a Cryo-AF dosing protocol guided exclusively by time-to-pulmonary vein (PV) isolation (TT-PVI) in patients undergoing a first time Cryo-AF. METHODS: In this multicenter study, we examined the acute/long-term safety/efficacy of Cryo-AF using the proposed dosing algorithm (Cryo-AFDosing; n = 355) against a conventional, nonstandardized approach (Cryo-AFConventional; n = 400) in a nonrandomized fashion. RESULTS: Acute PV isolation was achieved in 98.9% of patients in Cryo-AFDosing (TT-PVI = 48 +/- 16 seconds) vs 97.2% in Cryo AFConventional (P = .18). Cryo-AFDosing was associated with shorter (149 +/- 34 seconds vs 226 +/- 46 seconds; P <.001) and fewer (1.7 +/- 0.8 vs 2.9 +/- 0.8; P <.001) cryoapplications, reduced overall ablation (16 +/- 5 minutes vs 40 +/- 14 minutes; P <.001), fluoroscopy time (13 +/- 6 minutes vs 29 +/- 13 minutes; P <.001), left atrial dwell time (51 +/- 14 minutes vs 118 +/- 25 minutes; P <.001), and total procedure time (84 +/- 23 minutes vs 145 +/- 49 minutes; P <.001) but similar nadir balloon temperature (-47 degrees C +/- 8 degrees C vs 48 degrees C +/- 6 degrees C; P = .41) and total thaw time (43 +/- 27 seconds vs 45 +/- 19 seconds; P = .09) as compared to Cryo-AFConventional. Adverse events (2.0% vs 2.7%; P = .48), including persistent phrenic nerve palsy (0.6% vs 1.2%; P = .33) and 12-month freedom from all atrial arrhythmias (82.5% vs 78.3%; P = .14), were similar between Cryo-AFDosing and Cryo-AFConventional. However, Cryo AFDosing was specifically associated with fewer atypical atrial flutters/tachycardias during long-term follow-up (8.5% vs 13.5%; P = .02) as well as fewer late PV reconnections at redo procedures (5.0% vs 18.5%; P <.001). CONCLUSION: A novel Cryo-AF dosing algorithm guided by TT-PVI can help individualize the ablation strategy and yield improved procedural endpoints and efficiency as compared to a conventional, nonstandardized approach. PMID- 28625931 TI - Overview of the risk areas associated with care in nursing homes. AB - As the number of dependant elderly people rises, the place occupied by nursing homes in the French health care system becomes more and more important, and the question of resident safety is more significant than ever. A transfer of the notions developed for hospitals is useful but insufficient, as they mainly focus on the technical facet of care. In order to propose a wider view of risk management in nursing homes, we reviewed the French medical literature published between 2005 and 2016 in search of articles about adverse events related to health care in French nursing homes. Forty-nine articles were included and allowed the identification of 11, unequally documented: technical care and support, falls, infections and outbreaks, drugs and medical devices, resident identification, food, home accident, information, suicide, health care management and civil rights. We propose a patient-centered conceptual mapping of these risks that could be updated depending on the results of our future studies. PMID- 28625932 TI - Frailty in elderly: a brief review. AB - The identification of frail older persons is a public health priority. Frailty is defined as an extreme vulnerability of the organism to endogenous and exogenous stressors, a syndrome that exposes the individual at higher risk of negative health-related outcomes as well as a transition phase between successful aging and disability. The theoretical concept of frailty is largely agreed, its practical translation still presents some limitations due to the existence of multiple tools and operational definition. In this brief review, we would like to clarify the frailty concept regarding scientific literature. PMID- 28625933 TI - Experience for caregivers of dependent elderly persons with dementia. AB - Dependent elderly people with dementia require constant attention and significant care most of which are provided by family caregivers. The aim of our study is to highlight the feelings of caregivers of elderly with dementia and dependent. This qualitative study based on grounded theory method with semi-structured interviews with caregivers of dependent elderly. A comparative analysis of interviews to interview was conducted to identify themes, from the codes compared on a semantic level. 39 caregivers were interviewed until data saturation. The average age of caregivers was 61 years and 7 months IC (55 years 8 months 63 years and 4 months), consisting of 28 women and 11 men. Data analysis revealed six main themes: family duty, social isolation, an acceptance of the illness, stress and depression, physical morbidity and financial costs. The acceptance of the illness of his loved one is an indispensable element in the construction process of the caregiver close relationship dependent. But the balance between personal life and caregiving is not easy, caregivers have reported effects on their health since they occupy that role. Caregivers seem less watching their health and ignore some signs of disease. Caring for a family member with an illness such as dementia is extremely difficult, and many caregivers experience negative experiences such as stress or depression worse. PMID- 28625934 TI - Evaluation of the quality of medical certificates in the context of the opening of a measure of legal protection for adults over 60 years of age. AB - In France between 700,000 and 800,000 people will be covered by legal protection. The opening of any measure is conditioned by a detailed medical certificate. It is drawn up by a doctor registered on the list drawn up by the public prosecutor. No specific training is required. A single piece of legislation frames the content of the certificates. We therefore investigated whether the medical certificates currently produced were in compliance with the code of civil procedure. 111 medical certificates collected and anonymized by the tribunal d'instance of Saint-Etienne, from 4 January to 3 April 2016. The certificates concerned applications for the opening of legal protection for adults over 60 years of age. 57% of detailed medical certificates satisfied the requirements of article 1219 of the code of civil procedure, with no difference between requests for curatorship and guardianship. 76% of adults had cognitive impairment, 14% had a psychiatric disability, and 10% had a functional disability. 72% medical certificates proposed a guardianship measure, 21% a reinforced curatorship and 7% a simple curatorship. The circumstances justifying the opening of a measure of protection and the way of life of the adult were respectively found in 32% and 83% of the certificates. In 49% of the cases, the doctors dispensed the majority of hearing with the judge and the right to vote was retained in 10% of the adults subject to a guardianship application. The study showed a deficiency in the application of article 1219 of the code of civil procedure but also in the information that was requested. The drafting of the detailed medical certificate requires specific medical and legal knowledge. This raises the question of the training of doctors on the list of public prosecutors. Like the medical assessment carried out in the context of the assessment of bodily injury, the detailed medical certificate must become a real expertise carried out by doctors trained in this exercise. PMID- 28625935 TI - Evaluation of prescription along three health-care periods in the elderly. AB - Polypharmacy, potentially inappropriate prescriptions and inadequate coordination between prescribers are among main factors explaining the occurrence of adverse drug events in elderly patients. Prospective and descriptive study of medication prescriptions for elderly patients during a continuous period of health-care: entry in an acute geriatric unit (T1), at discharge (T2) and two months after hospitalization (T3). A global iatrogenic risk was defined: presence of poly pharmacy and/or PPI (Laroche criteria) and/or absence of quality indicators for prescription according to the French health authority. For the 79 patients (mean age 87), mean number of medication decreased from 7.33 (T1) to 6 (T2) (p=0.0018) and 6 (T3). Number of quality indicators for prescription improved from 6.67 (T1) to 6.92 (T2) (p=0.001) then decreased to 6.84 (T3). Number of PPI decreased from 1.16 to 0.42 between T1 and T2 (p=0.001) then increased to 0.59 at T3. The global iatrogenic risk indicator fluctuated from 80% (T1) to 64% (T2) and 75% (T3). Selected interventions were developed to prevent adverse drug events during hospitalization and ambulatory follow-up. If geriatric intervention can enhance quality of prescription, iatrogenic risk remains frequent all along health-care follow-up. A local study of prescriptions can be a first step to develop an adequate program for adverse drug events prevention. PMID- 28625936 TI - Do medical French students know how to properly score a mini mental state examination? AB - The mini mental state examination (MMSE) is a validated tool to assess global cognitive function. Training is required before scoring. Inaccurate scoring can lead to inappropriate medical decisions. In France, MMSE is usually scored by medical students. To assess if medical French students know how to properly score a mini mental state examination. Two " physician-patient " role playings performed by 2 specialized physicians, were performed in front of University Paris V medical students. Role playing A: Scoring of a MMSE according to a script containing five tricks; Role playing B: Find the 5 errors committed in a pre filled MMSE form, according to the second script. One hundred and five students (64.4% of women, 49.5% in fifth medical school year) anonymously participated. Eighty percent of students had already scored a MMSE and 40% had been previously trained to MMSE scoring. Forty five percent of students previously scored an MMSE, without previously being trained. In test A, 16% of students did not commit any errors, 45.7% one error and 38.1% two errors. In test B, the proportion of students who provided 0, 1, 2, 3, 4 and 5 good answers was 3.3%, 29.7%, 29.7%, 25.3%, 7.7% and 4.4% respectively. No association between medical school year, previous training to MMSE scoring and performances at both tests were found. French students do not properly score MMSE. MMSE scoring is not enough or accurately taught (by specialists). The university will provide on line the tests and a short filmed teaching course performed by neuropsychological specialists. PMID- 28625937 TI - Editorial. PMID- 28625938 TI - Language disturbances after non-thalamic subcortical stroke: a review of the literature. AB - Language disorders following subcortical non-thalamic stroke show great variability across literature and a well-defined profile in these aphasic disturbances is yet to be established. The lack of recent and consistent literature on the subject complicates the management of subcortical aphasia. The aim of this study is to review the literature describing oral language disturbances following subcortical non-thalamic stoke affecting the basal ganglia and the surrounding white matter. A review of the literature of three databases (PubMed, PsycNet and LLBA), identifying research articles from 1997 to 2015, was completed. The quality of the selected studies was assessed using the Checklist for the assessment of methodological quality. Twenty-two articles met criteria for review and oral language assessment data were extracted for 114 subjects. The results suggest a predominance of deficits in more complex and demanding language levels (ex. discourse, syntax) and in language production (vs comprehension). Rapid recovery is expected, especially for lexical-semantic and receptive deficits. These findings show the importance of a complete oral language evaluation after subcortical stoke and provide recent data relative to expected deficits and recovery to guide clinicians in the management of these patients. They also suggest that a descriptive approach of the deficits may be more efficient and accurate than the use of a traditional classification of aphasia. PMID- 28625939 TI - Promoting the maintenance of satisfactory communication: strategies used by caregivers and medical staff with people suffering from Alzheimer's disease. AB - The goal of this literature review was to determine communication strategies that foster interactions between individuals with Alzheimer's disease (AD) and caregivers or medical staff. A search of PubMed and PsycINFO databases was conducted using combinations of the following terms: Alzheimer, family, caregiver, communication, language, treatment, intervention, therapy, communication strategies, functional communication and daily living activities. Studies were chosen based on the original language of the text, year of publication, peer-review status and specificity of the results regarding communication strategies in AD. This review covers 14 articles published between 1994 and 2014. The in-depth analysis of these studies shows that various communication strategies used by caregivers and medical staff are effective to promote interactions with people with AD at different stages of the disease. For caregivers, these strategies include producing short and syntactically simple sentences, relying on semantic memory rather than on episodic memory, providing more information and reformulate, removing potential distractions from the environment, specifying the topic of the conversation, using precise terms to identify communication breakdowns. Other strategies also appeared to be effective for medical staff, such as asking close-ended questions, providing response choices, verbalizing the actions performed during medical care and activities, paying attention to the needs expressed through verbal and non-verbal messages, adopting a supportive way of speaking. Furthermore, other communication strategies rather appear to be harmful to functional communication. These harmful strategies involve insisting that the person produce a specific word, asking him/her to repeat or tune out in case of communication breakdown. Finally, contradictory outcomes are reported for some strategies such as speaking slowly, repeating or rephrase questions and information. This article provides some useful avenues to better interact with people with AD. Further studies are needed to confirm and refine some results, in particular as regards the effectiveness of communication strategies at the different stages of the disease through longitudinal research design. PMID- 28625940 TI - Prodromal stage of disease (dementia) with Lewy bodies, how to diagnose in practice? AB - Disease with Lewy bodies or dementia with Lewy bodies (DLB), particularly at the prodromal stage, is a complex disease to diagnose because of different clinical beginnings and variable paths in terms of clinical expression. Thus DLB can be entcountered in different input modes: mild cognitive impairment, depression, acute behavioral disorders, confusion and delirium, or sleep disorders. In the aim to better diagnose the disease, should be sought obviously to search for the key symptoms: fluctuations, hallucinations, extra-pyramidal syndrome, and REM sleep behavior disorder. These symptoms are more subtle at the prodromal stage (mild neurocognitive disorder) than at the major stage. Thus fluctuations can be cognitive, simply as attentionnal fluctuations, or of alertness, such as sleepiness or more frequent nap; the visual phenomena can begin by sensation of passage, sensation of presence, or illusions; the extra-pyramidal syndrome can be really subtle such as isolated amimia or rigidity detected only with Froment's manoeuvre. The frequent accompagnying symptoms are autonomic symptoms such as rhinorrhea or constipation, or sensorial symptoms such as olfactory impairment. The clinician has to be aware of the frequent presence of geriatric syndroms, also at the prodromal stage and including: falls, orthostatic hypotension, syncopa, urinary troubles, depression, delirium (after surgery, during infection...). On neuropsychological tests, sub-cortical frontal syndrome is frequent, visual memory impairment, visuospatial impairment and visuo constructive difficulties are also characteristics. On brain MRI, isolated diminished insula is to look for. CSF analysis is usually normal but sometimes with low Abeta-42. Dat-Scan and MIBG scintigraphy were not enough explored in this context. Thus, with every patient presenting a compatible input mode, the search for symptoms of DLB has to be systematic, in the aim to have an etiological diagnosis of prodromal DLB, to avoid adverse drug events (neuroleptics) and to optimize care for patients. PMID- 28625941 TI - Meditation and successful aging: can meditative practices counteract age-related cognitive decline? AB - Life expectancy is constantly increasing in the developed countries due to medical, hygiene and socio-economic advances. Unfortunately, a longer life not always corresponds to a healthier life. Indeed, aging is associated with growing risk factors for illness associated with societal conditions (isolation, maltreatment), and neurodegenerative diseases. Even normal aging is associated with a cognitive decline that can hinder independence and quality of life of elderly. Thus, one major societal challenge is to build policies that support people of all ages to maintain a maximum health and functional capacity throughout their lives. Meditation could be a promising intervention in contrasting the negative effects of aging. Indeed, it has been shown to enhance cognitive efficiency in several domains, such as attention and executive functions in young adults. Nevertheless, whether these effects extend to old participants is still a matter of debate. Few studies have directly investigated this issue, reporting encouraging results in a large panel of cognitive functions, such as: attention, executive functions and memory. However, a final conclusion about the causal role of meditation and the generalization of these results is made difficult due to several methodological limitations. We propose a roadmap for future studies to pass these limitations with the hope that the present work would contribute to the development of the young research field of meditation in gerontology. PMID- 28625942 TI - Cognitive stimulation in healthy older adults: a cognitive stimulation program using leisure activities compared to a conventional cognitive stimulation program. AB - The aim of this study was to compare two methods of cognitive stimulation for the cognitive functions. The first method used an usual approach, the second used leisure activities in order to assess their benefits on cognitive functions (speed of processing; working memory capacity and executive functions) and psychoaffective measures (memory span and self esteem). 67 participants over 60 years old took part in the experiment. They were divided into three groups: 1 group followed a program of conventional cognitive stimulation, 1 group a program of cognitive stimulation using leisure activities and 1 control group. The different measures have been evaluated before and after the training program. Results show that the cognitive stimulation program using leisure activities is as effective on memory span, updating and memory self-perception as the program using conventional cognitive stimulation, and more effective on self-esteem than the conventional program. There is no difference between the two stimulated groups and the control group on speed of processing. Neither of the two cognitive stimulation programs provides a benefit over shifting and inhibition. These results indicate that it seems to be possible to enhance working memory and to observe far transfer benefits over self-perception (self-esteem and memory self perception) when using leisure activities as a tool for cognitive stimulation. PMID- 28625944 TI - Intractable ictal vomiting: a new form of reflex epilepsy? AB - In this description of the clinical course of a young female with persistent and protracted vomiting along with occasional loss of consciousness and subtle motor manifestations, the differential diagnosis is debated. The epileptic origin of her symptoms was substantiated by the presence of interictal epileptiform discharges and dramatic response to valproate monotherapy. Possible lobar localizations are discussed with the support of existing literature on this rare ictal manifestation [Published with video sequence on www.epilepticdisorders.com]. PMID- 28625945 TI - HIV: treatment catching-up is a priority in West and Central Africa. PMID- 28625946 TI - Educational needs of epileptologists regarding psychiatric comorbidities of the epilepsies: a descriptive quantitative survey. AB - Psychiatric disorders are relatively frequent comorbidities in epilepsy and they have an impact on morbidity, mortality, and quality of life. This is a report from the Task Force on Education of the ILAE Commission on Neuropsychiatry based on a survey about educational needs of epileptologists regarding management of the psychiatric comorbidities of epilepsy. The Task Force designed a quantitative questionnaire to survey the self-perceived confidence of child and adult epileptologists and psychiatrists in managing major psychiatric comorbidities of epilepsy to identify: (1) critical areas of improvement from a list of skills that are usually considered necessary for effective management of these conditions, and (2) the preferred educational format for improving these skills. A total of 211 respondents from 36 different countries participated in the survey. Confidence and usefulness scores suggest that responders would most value education and training in the management of specific clinical scenarios. Child neurologists identified major Axis I disorders, such as mood and anxiety disorders, while adult neurologists identified attention deficit hyperactivity disorder, intellectual disabilities, and autistic spectrum disorder as key areas. Both adult and child neurologists identified screening skills as the priority. Psychiatrists mainly valued specific training in the management of psychiatric complications of epilepsy surgery or psychiatric adverse events of antiepileptic drugs. Sessions during congresses and face-to-face meetings represent the preferred educational format, while e-learning modules and review papers were chosen by a minority of respondents. Results of this survey identify key areas for improvement in managing the psychiatric comorbidities of epilepsy and suggest specific strategies to develop better training for clinicians involved in epilepsy care. PMID- 28625947 TI - Intracranial investigation of a patient with nodular heterotopia and hippocampal sclerosis: dealing with a dual pathology. AB - The pre-operative assessment and surgical management of patients with dual pathology is challenging. We describe a patient with drug-resistant focal epilepsy with hippocampal sclerosis and extensive periventricular nodular heterotopia in the same hemisphere. The semiology, scalp EEG, and imaging were divergent, but the presence of focal interictal and ictal epileptic discharges of the putative ictal onset zone resulted in successful localization of the epileptogenic zone. A less aggressive resection was performed based on intracranial EEG recording. The patient has been seizure-free for three years since resection. Electroclinical hypotheses and challenges in defining the epileptogenic network are discussed. PMID- 28625948 TI - Anticholinesterase activity and identification of huperzine A in three Mexican lycopods: Huperzia cuernavacensis, Huperzia dichotoma and Huperzia linifolia (Lycopodiaceae). AB - Huperzine A (Hup A), the alkaloid produced by the Chinese medicinal plant Huperzia serrata, has been documented to be a promising agent for the treatment of Alzheimer's disease due to its potent acetylcholinesterase inhibitory (AChEI) activity. The search for anticholinesterase natural products, as well as for alternative sources of Hup A in Mexican lycopods, prompted us to investigate these plants. The action of methanolic and alkaloidal extracts of three Huperzia species (H. cuernavacensis, H. dichotoma, and H. linifolia) was evaluated using an in vitro anticholinesterase activity assay. Also, chromatographic and spectroscopic analyses were employed to detect the presence of Hup A. Methanolic and alkaloidal extracts of H. cuernavacensis showed IC50 =5.32+/-0.8MUg/mL and 0.74+/-0.05MUg/mL; H. dichotoma displayed AChEI with IC50 values =14.11+/ 2.1MUg/mL and 0.64+/-0.09MUg/mL; and H. linifolia presented IC50 =158.37+/ 8.7MUg/mL and 4.2+/-1.24MUg/mL, respectively, compared to the control Hup A (IC50= 0.16+/-0.03MUg/mL). Hup A was identified in the extracts of H. dichotoma, but it was not detected in the extracts of H. cuernavacensis and H. linifolia by 1H NMR techniques. This study reveals H. dichotoma as a new source of Hup A, and presents H. linifolia and H. cuernavacensis as potential candidates to obtain other anticholinesterase compounds useful in the Alzheimer's disease treatment. PMID- 28625949 TI - Discussion on the risk factors of developing cardiovascular diseases (CVD) after the kidney transplantation. AB - To discuss the risk factors of developing cardiovascular disease (CVD) after the kidney transplantation. Retrospective analysis on the data of 1106 patients who had been underwent kidney allotransplantation in People's Hospital of Zhengzhou from July, 2010 to Dec, 2014 and conformed to the inclusion criteria was taken. Cox proportional hazard model was used to analyze the risk factors of developing CVD after the kidney transplantation. 7 days, 1 month, 3 months, 6 months and 12 months before and after the operation, the data collection and following-up visits were respectively arranged. 12 months after the operation, the following up visits were arranged once a half year until the end of March, 2014. 216 (19.5%) patients developed CVD after the kidney transplantation. Among them, 47 (4.2%) patients developed CVD within the first three months after the operation, which accounted for 26.8% in the CVD patients; 125 (11.3%) patients developed CVD within the first one year after the operation, which accounted for 47.9% in the CVD patients. 51 (4.6%) patients died after the operation. Among them, 19 (2.7%) patients died of CVD, which accounted for 37.3% in the whole died patients. Multiple factors analysis revealed that the following were the risk factors to develop CVD after the kidney transplantation: The age of receptors was greater than 50 (OR=2.39, 95%CI 1.15-3.60); The receptors had diabetes before the surgery (OR=3.18, 95%CI 1.56-6.42); The receptors had CVD medical history before the surgery (OR=3.85, 95%CI 2.15-7.54); The primary diseases of receptors were diabetic nephropathy (DN) (OR=2.12, 95%CI 1.14-3.98); The preoperative dialysis time was greater than 12 months(OR=1.27, 95%CI 0.98-1.38); The postoperative serum creatinine of the receptors was greater than 200 MUmol/L (OR=2.78, 95%CI 1.35~4.53); The delayed graft failure (DGF) occurred (OR=1.24, 95%CI 1.02~1.42); Acute rejection appeared(AR)(OR=2.98, 95%CI 1.56~5.72); Renal allograft dysfunction appeared (OR=4.86, 95%CI 3.15~7.78). The morbidity of CVD is high after the kidney transplantation and the risk factors are diversified. That revising or excluding relevant risk factors may lower the morbidity of developing CVD and is in favor of the long-term survival for the transplanted kidney. PMID- 28625950 TI - Effect of solvent polarity on the extraction of components of pharmaceutical plastic containers. AB - A study of the extraction of polymeric material and dyes from the pharmaceutical plastic containers using various organic solvents was conducted to evaluate the effect of polarity on the extraction process. The plastic containers used included semi-opaque, opaque, transparent and amber colored and the solvent used were acetonitrile, methanol, ethanol, acetone, dichloroethane, chloroform and water. The determination of extractable material was carried out by gravimetric and spectrometric methods. The yield of extractable materials from containers in 60 h was 0.10-1.29% (w/w) and the first-order rate constant (kobs) for the extraction of polymeric material ranged from 0.52-1.50 * 10-3 min-1 and for the dyes 6.43- 6.74 x10-3min-1. The values of (kobs) were found to be an inverse function of solvent dielectric constant and decreased linearly with the solvent acceptor number. The extractable polymeric materials exhibited absorption in the 200-400 nm region and the dyes in the 300-500nm region. The rates of extraction of polymeric material and dyes from plastic containers were dependent on the solvent dielectric constant. The solvents of low polarity were more effective in the extraction of material indicating that the extracted material were of low polarity or have non-polar character. The dyes were soluble in acetone and chloroform. No plastic material was found to be extracted from the containers in aqueous solution. PMID- 28625951 TI - Evaluation of supplementing active peptide's effect on recovering skeletal muscle micro-injury after track and field exercises. AB - : To explore the effect of supplementing active peptide on recovering skeletal muscle injury after track and field exercises. METHOD: choose 80 patients (contain teenagers) with skeletal muscle micro-injury after the track and field exercises from March 2015 to July 2016, divide them into two groups. Normal treatment of micro-injury of skeletal muscle is given to the control group while active peptide is supplemented to the experimental group based on normal treatment. Compare the two groups to find the differences in relevant indexes of skeletal muscle after track and field exercises. RESULT: Patients with micro injury of skeletal muscle after track and field exercises may have inflammation at the early stage, so they need a long time for recovery. Relevant indexes of the experimental group after the treatment of supplementing active peptide are better than those of the control group (P<0.05). CONCLUSION: To supplement active peptide can promote the synthesis of protein, which is conducive to the recovery of micro-injury on skeletal muscle and reduce the extravasations of creatine kinase in the cell, so as to improve the patients' anti-fatigue ability and endurance level. PMID- 28625952 TI - Daily consumption of commercial chicken feed and meat lead to alterations in serum cholesterol and steroidal sex hormones in female rats. AB - Poultry consumption is increased worldwide owing to better taste, easy availability and low cost. The present study was designed to investigate the effects of the chicken feed, conventional chicken meat and organic chicken meat on the % growth rate, serum cholesterol, progesterone, testosterone and estrogen levels in female rats. Hundred female Albino Wistar rats were randomly assigned to four groups (n=25). Group I was control rats fed on standard chow, group II treated with commercial chicken feed, group III rats fed with conventional chicken meat and group IV with organic chicken meat for a period of 6 weeks. % Growth rate, serum cholesterol, progesterone, testosterone and estrogen levels were estimated after the treatment. The present study showed significant increase in growth rate, serum cholesterol levels and imbalance in serum steroidal hormone levels. It is therefore, suggested from the present study that the intake of commercial chicken feed and commercial chicken meat may be the potential cause of development of polycystic ovary syndrome in females due to steroid hormonal imbalance. PMID- 28625953 TI - The relationship between the expressions of tumor associated fibroblasts Cav-1 and MCT4 and the prognosis of papillary carcinoma of breast. AB - The aim of this study was to evaluate the expression levels of Cav-1 and MCT4 in the tumor stroma CAFs. Immunohistochemical method was used to detect the expression of Cav-1 and MCT4 in 86 cases of IMPC, with 105 cases of non-specific invasive ductal carcinoma (IDC-NOS) as control. Their differential expression in different histological types were compared and relationship between the expression of Cav-1 and IMPC in the MCT4 and the main pathological features such as age, tumor size and histological grades were analyzed. The study confirmed that the loss expression of Cav-1 on CAFs and the up-regulation of MCT4 may be the possible mechanisms of CAFs in tumorigenesis, which may be one of the molecular mechanisms leading to the poor prognosis of IMPC. The expression of CAFs related proteins in tumor microenvironment suggested that CAFs could be used as the target of tumor therapy and provide new evidence for the treatment of breast cancer. PMID- 28625954 TI - Attenuation of cadmium-induced decline in spatial, habituation and recognition memory by long-term administration of almond and walnut supplementation: Role of cholinergic function. AB - Excessive exposure of cadmium which is regarded as a neurotoxin can stimulate aging process by inducing abnormality in neuronal function. It has been reported that supplementation of almond and walnut attenuate age-related memory loss. Present study was designed to investigate the weekly administration of cadmium for one month on learning and memory function with relation to cholinergic activity. Cadmium was administered at the dose of 50 mg/kg/week. Whereas, almond and walnut was supplemented at the dose of 400 mg/kg/day along with cadmium administration to separate set of rats. At the end of experiment, memory function was assessed by Morris water maze, open field test and novel object recognition test. Results of the present study showed that cadmium administration significantly reduced memory retention. Reduced acetylcholine levels and elevated acetyl cholinesterase activity were also observed in frontal cortex and hippocampus of cadmium treated rats. Malondialdehyde levels were also significantly increased following the administration of cadmium. Daily supplementation of almond and walnut for 28 days significantly attenuated cadmium induced memory impairment in rats. Results of the present study are discussed in term of cholinergic activity in cadmium-induced memory loss and its attenuation by nuts supplementation in rats. PMID- 28625955 TI - Experiment of vitreous liquefaction induced by C3F8. AB - To investigate the effect and safety of vitreous liquefaction induced by C3F8 (an inert gas) injected into vitreous cavit of rabbit eyes. 24 rabbits (48 eyes) were randomly divided into four groups, named group A, group B, group C and group D, with 6 rabbits in each group. The right eye in each rabbit was taken as the experimental eye while the left as the control eye. The experimental eyes in group A were injected with 0.1mL disinfectant air; the experimental eyes in group B, group C and group D were all injected with C3F8 0.1mL, 0.2mL and 0.3mL respectively after receiving anterior chamber penetration; and the controlled eyes in all group were injected with 0.1mL balanced salt solution (BSS). During the first 7 d after injection, all the rabitts' eyes were examined by slit lamp, ophthalmoscope, intraocular pressure (IOP) and dark-adapted retina Electroretinography (ERG) each day. After that, the examination of IOG and ERP were reviewed weekly. Besides, B ultrasound should be examined to observe the situation of posterior vitreous detachment (PVD) in the 4th and 8th weeks. The rabbits were killed in the end of the 8th week, with their specimens examined by the light microscope, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Except group A, all the experimental eyes were produced with vitreous liquefaction. In group C and group D, in addition to the produced vitreous liquefaction, posterior vitreous detachment (PVD), even complete PVD, were induced in different extent. But in group B, the vitreous body was returned to the gel state at 2 weeks after gas absorption. In group C and group D, the vitreous body was not found to recover its original state at 8 weeks. In group D, there was a little increase of intraocular pressure, a mild delay of wave a and wave b after ERG in the 4th day after the gas injection. While there was no such situation in other groups. After the examination of B ultrasound in the 8th week, the complete PVD occurred in group C (with 2 experimental eyes occurred) and group D (with 4 experimental eyes occurred). Light microscope and transmission electron microscope examination showed no obvious abnormality. Smooth inner limiting membrane could be seen in the eye with PVD occurred when scanning electron microscope used. The injection of C3F8 into rabbit eyes can improve the vitreous liquefaction of the vitreous body and a certain volume of C3F8 can successfully and safely induce the PVD, and a larger volume of C3F8 was also effective but with a transient high IOP in rabbit eyes. PMID- 28625956 TI - Comparison of Anti BPH capsule (herbal) and Terazosin HCl in the treatment of benign prostate hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a disease of senile age, usually occurring> 60 years of age. BPH is a disease that involves cell proliferation of the prostate. Pathological hyperplasia affects the elements of the glandular and connective tissue of the prostate. This study is designed to scrutinize the efficacy and tolerability of herbal drug Anti BPH capsule for the management of benign prostate hyperplasia (BPH), in this study we select the 100 patients in which 50 received the Anti BPH capsule and 50 received the Terazosin HCl. We use the American Urological Association BPH Symptom Score Index Questionnaire to measure the quality of life of the patients. We compare the before treatment and after treatment results for each symptom. We record the following symptoms, incomplete emptying of bladder, Frequency, Intermittency, Urgency, Weak stream, Straining, Nocturia and weight of prostate gland by USG. We compare the both drug by using paired sample t-test. The level of significance of incomplete emptying of bladder before treatment and after treatment is 0.013 in test group and 0.032 in control group. Similarly the level of significance of Frequency before treatment and after treatment in test groups in, intermittency, Urgency, Weak stream, staining, Nocturia and mean weight of prostate gland are 0.007, 0.015, 0.044, 0.012, 0.017, 0.004 and 0.020; where as in control group afford as 0.031, 0.044, 0.044, 0.032, 0.024, 0.009 and 0.035 respectively. The herbal drug Anti BPH capsule is more effective in the treatment of BPH than Allopathic medicine Terazosin HCl. PMID- 28625957 TI - Studies on antihyperlipidemic and endothelium modulatory activities of polyherbal formulation (POL4) and its ingredients in high fat diet-fed rats. AB - A compound herbal formulation (POL4) is used traditionally in interior parts (Distt. Badin) of Sindh, Pakistan, for the treatment of metabolic disorders like diabetes and hyperlipidemia. This study is aimed to determine the effectiveness of POL4 and its ingredients in hyperlipidemia and associated endothelial dysfunction and hypertension. POL4 is composed of equal proportion of Nigella sativa, Cichorium intybus, Trigonella foenum graecum and Gymnema sylvestre mixed in powdered form. Chronic (6 to 7 weeks) administration of POL4 and its ingredients mixed in diet caused a notable attenuation in total cholesterol, low density lipoprotein cholesterol, triglycerides, atherogenic index, C-reactive protein and glucose, while it has increased high density lipoprotein levels. POL4 intervention markedly (p<0.01) reduced systolic blood pressure in rats to 127+/ 1.92 vs. 145.4+/-1.07 mm of Hg using tail-cuff method and significantly (p<0.05) improved endothelium-dependent relaxation (75+/-2.88 vs. 82.75+/-1.22%) to acetylcholine in isolated aortae of rats in treatment groups using force transducer and PowerLab system. Similar activities were assessed on the part of ingredients of POL4. These findings indicate that POL4 and its ingredients possess antihyperlipidemic, endothelium-dependent modulatory and antihypertensive activities, thus providing an evidence to the vernacular use of POL4 in hyperlipidemia and hypertension. PMID- 28625958 TI - Pain management of pancreatic cancer patients with high-intensity focused ultrasound therapy. AB - This study was performed to evaluate cancer pain control of high-Intensity focused ultrasound ablation (HIFU) and to manage the HIFU treatment pain in advanced pancreatic cancer patients with analgesics. We collected 71 locally advanced pancreatic cancer patients treated with HIFU from 2013 March to 2014 January in our hospital. The cancer pain (pre-HIFU and two weeks after HIFU) and HIFU treatment pain were evaluated respectively. The numeric rating scale (NRS) was used as the tool of pain evaluation. The related factors with pains were analyzed. The 70.42% cancer painless rate before HIFU was improved to 92.96% (P<0.05) 2 weeks after HIFU in 71 advanced pancreatic cancer patents without analgesics adjustment. The HIFU treatment pain occurred in 42 of 71 treated patients (59.15 %). The average duration was 3.93 days and pain score was 3.22. HIFU can improve cancer pain relief further in the advanced pancreatic cancer patients with third ladder analgesics, meanwhile HIFU treatment pain can be managed easy because of its short duration and low pain score. PMID- 28625959 TI - Curative effect of Maimendong decoction in treating advanced lung cancer with Qi Yin deficiency cough. AB - The objective of this paper is to analyze the curative effect of Maimendong Decoction in treating advanced lung cancer with Qi-Yin deficiency cough. 60 patients with advanced lung cancer with Qi-Yin deficiency cough admitted to our hospital were selected and randomly divided into two groups, among which 30 cases treated with Maimendong Decoction were experimental group, and another 30 cases treated with ambroxol hydrochloride oral solution were control group. After treatment, the clinical therapeutic effects of the two groups were compared and analyzed. After 40 d treatment, the total effective rate of the treatment group was significantly higher than that of control group, with statistical significance (P<0.05). There is a definitive therapeutic effect of Maimendong Decoction in the treatment of advanced lung cancer with Qi-Yin deficiency cough, which is worthy of application and promotion in clinic. PMID- 28625960 TI - Production of an antibiotic enterocin from a marine actinobacteria strain H1003 by metal-stress technique with enhanced enrichment using response surface methodology. AB - Elicitation by chemical means including heavy metals is one of a new technique for drug discoveries. In this research, the effect of heavy metals on marine actinobacteria Streptomyces sp. H-1003 for the production of enterocin, with a strong broad spectrum activity, along optimized fermented medium was firstly investigated. The optimum metal stress conditions consisted of culturing marine actinobacteria strain H-1003 with addition of cobalt ions at 2mM in optimized Gause's medium having starch at 20mg/L for 10 days at 180 revolution/min. Under these conditions, enterocin production was enhanced with a value of 5.33mg/L, which was totally absent at the normal culture of strain H-1003 and much higher than other tested metal-stress conditions. This work triumphantly announced a prodigious effect of heavy metals on marine actinobacteria with fringe benefits as a key tool of enterocin production. PMID- 28625961 TI - Effect of Atorvastatin on lower extremity function of patients with hypertension and peripheral arterial disease. AB - This paper aims to discuss the short-term effect of Atorvastatin on lower extremity function of patients with hypertension and peripheral arterial disease (PAD). 40 patients with hypertension and ankle-brachial index (ABI) less than 0.9 were divided into the control group (20 cases) and Atorvastatin group (20 cases) and treated for 6 months. The variation between the 6-min walk and the gait speed of 4-m-walk before and after the treatment were respectively observed. With regard to the two groups, differences of the drop-out values before and after the treatment were adjusted in accordance with gender, ages, body mass index (BMI), difference values of systolic pressure, ABI, difference values of total cholesterol (TC), difference values of low density lipoprotein, triacylglycerol, smoking and drug-taking situation. After the treatment, the 6-min walk had no obvious change between the two groups (P>0.05), but the 4-m normal and rapid walking speed changed obviously (P<0.01). Short-term therapy with atorvastatin can significantly delay the decline of the walking speed in short distance and improve the lower-extremity function of patients with hypertension and PAD. PMID- 28625962 TI - Application research on nerve sparing radical hysterectomy for rectal function. AB - This paper aims to discuss the clinical significance of laparotomy nerve sparing radical hysterectomy (NSRH) on rectal function of early cervical cancer patients, compared with conventional radical hysterectomy. 30 cases of early cervical carcinoma patients who had received surgery in the First Affiliated Hospital of Zhengzhou University from June 2010 to June 2014 were selected as subjects. Patients were divided into two groups, with 15 in each gorup, in which Group A had received NSRH, B received CRH, and all them were in stage IB-IIA1. In the surgery, 2 cases of patients in NSRH group failed in nerve sparing operation, and were grouped into CRH group. The postoperative condition of two groups were observed, recorded and compared as well, especially the comparison between the postoperative recovery condition of rectal function of two groups. The comparison were conducted between two groups on the operation time, bleeding volume, quantity of cleaned pelvic lymph node, resection length of parametrium, resection length of vagina, etc. There was no statistical significance (P>0.05). The postoperative urinary catheter indwelling time in NSRH group was shorter than CRH group, with statistical significance (P<0.05). The postoperative maximum urine flow, maximum cystometric capacity, maximum detrusor pressure and urinary complications in NSRH group were significantly better than the postoperative condition in CRH group, with statistical significance (P<0.05). NSRH surgery was safe and reliable, which not only had obvious advantage in improving postoperative rectal function and bladder function, but also had a significantly effect on improving postoperative life quality as well. The results proved that patients had low disease morbidity and with great clinical significance. PMID- 28625963 TI - Identification and lead-in characterization of novel B3 metallo-beta-lactamases. AB - Metallo-beta-lactamases (MBLs) are zinc ion dependent enzymes that are responsible for the emergence and spread of beta-lactam resistance among bacterial pathogens. There are uncharacterized putative MBLs in the environment and their emergence is major interference in the generation of universal MBL inhibitors so it is important to identify and characterize novel MBLs. In this study two novel MBLs from Luteimonas sp. J29 and Pseudoxanthomonas mexicana were identified using B3 MBLs as query in BLAST database search. 3D models of putative MBLs generated by SWISS-MODEL server taking AIM-1 as a structural template were verified using web based structure assessment and validation programs. Multiple sequence alignment revealed that residues important for substrate binding were conserved and loop region residues (156-162 and 223-230) important for catalysis are variable in these novel MBLs. Homology models showed typical MBL alpha/beta/beta/alpha sandwich fold containing six alpha helices, twelve beta strands and metal interacting residues are conserved in similar way as with other B3 MBLs. We report promising putative B3 MBLs with some variations and substrate docking studies revealed that novel MBLs have attributes close to acquired B3 MBLs. PMID- 28625964 TI - Antegrade Dissection and Reentry as Part of the Hybrid Chronic Total Occlusion Revascularization Strategy: A Subanalysis of the RECHARGE Registry (Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom). AB - BACKGROUND: Development of the CrossBoss and Stingray devices for antegrade dissection and reentry (ADR) of chronic total occlusions has improved historically suboptimal outcomes. However, the outcomes, safety, and failure modes of the technique have to be studied in a larger patient cohort. This preplanned substudy of the RECHARGE registry (Registry of CrossBoss and Hybrid Procedures in France, the Netherlands, Belgium and United Kingdom) aims to evaluate the value and use of ADR and determine its future position in contemporary chronic total occlusion intervention. METHODS AND RESULTS: Patients were selected if an ADR strategy was applied. Outcomes, safety, and failure modes of the technique were assessed. The ADR technique was used in 23% (n=292/1253) of the RECHARGE registry and was mainly applied for complex lesions (Japanese chronic total occlusion score=2.7+/-1.1). ADR was the primary strategy in 30% (n=88/292), of which 67% were successful. Bail-out ADR strategies were successful in 63% (n=133/210). The Controlled ADR (ie, combined CrossBoss-Stingray) subtype was applied most frequently (32%; n=93/292) and successfully (81%; n=75/93). Overall per-lesion success rate was 78% (n=229/292), after use of additional bail out strategies. The inability to reach the distal target zone (n=48/100) or to reenter (n=43/100) most commonly led to failure. ADR-associated major events occurred in 3.4% (n=10/292). CONCLUSIONS: Although mostly applied as a bail-out strategy for complex lesions, the frequency, outcomes, and low complication rate of the ADR technique and its subtypes confirm the benefit and value of the technique in hybrid chronic total occlusion percutaneous coronary intervention, especially when antegrade wiring or retrograde approaches are not feasible. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02075372. PMID- 28625965 TI - Letter by Muntane-Carol et al Regarding Article, "Bioresorbable Vascular Scaffolds for the Treatment of Chronic Total Occlusions: An International Multicenter Registry". PMID- 28625966 TI - Response by Mitomo et al to Letter Regarding Article, "Bioresorbable Vascular Scaffolds for the Treatment of Chronic Total Occlusions: An International Multicenter Registry". PMID- 28625967 TI - RNase II regulates RNase PH and is essential for cell survival during starvation and stationary phase. AB - RNase II is the most active exoribonuclease in Escherichia coli cell extracts. Yet, its removal appears to have no deleterious effect on growing cells. Here, we show that RNase II is required for cell survival during prolonged stationary phase and upon starvation. The absence of RNase II leads to greatly increased rRNA degradation and to the accumulation of rRNA fragments, both of which lead to a decline in cell survival. The deleterious effects of RNase II removal can be completely reversed by the simultaneous absence of a second exoribonuclease, RNase PH, an enzyme known to be required to initiate ribosome degradation in starving cells. We have now found that the role of RNase II in this process is to regulate the amount of RNase PH present in starving cells, and it does so at the level of RNase PH stability. RNase PH normally decreases as much as 90% during starvation because the protein is unstable under these conditions; however, in the absence of RNase II the amount of RNase PH remains relatively unchanged. Based on these observations, we propose that in the presence of RNase II, nutrient deprivation leads to a dramatic reduction in the amount of RNase PH, thereby limiting the extent of rRNA degradation and ensuring cell survival during this stress. In the absence of RNase II, RNase PH levels remain high, leading to excessive ribosome loss and ultimately to cell death. These findings provide another example of RNase regulation in response to environmental stress. PMID- 28625969 TI - Correction for Wertz et al., "Genomic and Physiological Characterization of the Verrucomicrobia Isolate Didymococcus colitermitum gen. nov., sp. nov., Reveals Microaerophily and Nitrogen Fixation Genes". PMID- 28625968 TI - Long-Term Dose-Dependent Agalsidase Effects on Kidney Histology in Fabry Disease. AB - BACKGROUND AND OBJECTIVES: Dose-dependent clearing of podocyte globotriaosylceramide has previously been shown in patients with classic Fabry disease treated with enzyme replacement. Our study evaluates the dose-dependent effects of agalsidase therapy in serial kidney biopsies of patients treated for up to 14 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty patients with classic Fabry disease (12 men) started enzyme replacement therapy at a median age of 21 (range =7-62) years old. Agalsidase-alpha or -beta was prescribed for a median of 9.4 (range =5-14) years. The lower fixed dose group received agalsidase 0.2 mg/kg every other week throughout the follow-up period. The higher dose group received a range of agalsidase doses (0.2-1.0 mg/kg every other week). Dose changes were made due to disease progression, suboptimal effect, or agalsidase-beta shortage. Serial kidney biopsies were performed along with clinical assessment and biomarkers and scored according to recommendations from the International Study Group of Fabry Nephropathy. RESULTS: No statistical differences were found in baseline or final GFR or albuminuria. Kidney biopsies showed significant reduction of podocyte globotriaosylceramide in both the lower fixed dose group (-1.39 [SD=1.04]; P=0.004) and the higher dose group (-3.16 [SD=2.39]; P=0.002). Podocyte globotriaosylceramide (Gb3) reduction correlated with cumulative agalsidase dose (r=0.69; P=0.001). Arterial/arteriolar intima Gb3 cleared significantly in the higher dose group, all seven patients with baseline intimal Gb3 cleared the intima, one patient gained intimal Gb3 inclusions (P=0.03), and medial Gb3 did not change statistically in either group. Residual plasma globotriaosylsphingosine levels remained higher in the lower fixed dose group (20.1 nmol/L [SD=11.9]) compared with the higher dose group (10.4 nmol/L [SD=8.4]) and correlated with cumulative agalsidase dose in men (r=0.71; P=0.01). CONCLUSIONS: Reduction of podocyte globotriaosylceramide was found in patients with classic Fabry disease treated with long-term agalsidase on different dosing regimens, correlating with cumulative dose. Limited clearing of arterial/arteriolar globotriaosylceramide raises concerns regarding long-term vascular effects of current therapy. Residual plasma globotriaosylsphingosine correlated with cumulative dose in men. PMID- 28625971 TI - Peripheral leptochoroid: clinical and anatomical findings. AB - BACKGROUND/AIMS: To investigate the clinical findings and anatomical characteristics of patients with a thinned peripheral choroid (leptochoroid) presenting with bilateral macular geographical hyperpigmented fundus and compare with matched controls. METHODS: A retrospective, observational case series of 44 eyes (24 patients): 22 study eyes (12 study patients) with clinical findings of leptochoroid (geographical hyperpigmented fundus centred in the macula) matched with 22 control eyes (12 control patients). All eyes received enhanced depth imaging optical coherence tomography at Memorial Sloan Kettering Cancer Center. Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings, and compare patient and eye characteristics. RESULTS: Study patients had a female predominance and median age of 70 years. Iris colour and refractive error of these eyes were varied: 8 eyes were myopic (one of which was highly myopic with a refractive error of -9.00) and 14 eyes were emmetropic or hyperopic (up to+3.00). The best-corrected visual acuity was 20/40 or better in all study eyes. The geographical macular areas of relative hyperpigmentation correspond to normal choroidal thickness compared with controls (p=0.74). The relative hypopigmented surrounding fundus had significantly thinner choroid compared with controls (p value=0.0001). Choroidal thickness had a strong interobserver correlation (r=0.99, p<0.0001). CONCLUSION: Described here is a clinical entity referred to as peripheral leptochoroid. It appears as geographical hyperpigmented fundus centred in the macula, with adjacent relative hypopigmented fundus. Compared with matched normal subjects, the hyperpigmented and hypopigmented fundus correspond with equivocal and decreased choroidal thickness, respectively. PMID- 28625972 TI - Prevalence, subtypes, severity and determinants of ocular trauma: The Singapore Chinese Eye Study. AB - PURPOSE: To describe the prevalence, subtypes, severity and determinants of ocular trauma (OT) in a population-based study in Singapore. METHODS: We included 3353 Chinese adults aged >=40 years from the Singapore Chinese Eye Study, a population-based study, conducted between 2009 and 2011. OT was defined as self reported history of any eye injury requiring medical attention with or without hospitalisation, and further classified as blunt object, sharp object or chemical burns related. Age and gender-standardised prevalence was estimated using the 2010 Singapore Chinese population census. Multivariable models were used to assess the independent associations of OT with age, gender, income, education, literacy, alcohol consumption, smoking and history of falls. RESULTS: The mean (SD) age was 59.7 (9.9) years and 49.4% were male. There were 138 OT cases, giving a crude and age and gender-standardised prevalence of 4.1% (95% CI 3.5% to 4.8%) and 4.4% (95% CI 3.7% to 5.2%), respectively. Of these, 45 (32.6%), 56 (40.6%) and 10 (7.3%) were blunt object, sharp object and chemical burns-related trauma, respectively. Twenty eight (20.3%) required hospitalisation, with no difference between subtypes. In multivariable models, men (OR (95% CI): 2.80 (1.79-4.39)), younger persons (per year decrease in age (1.03 (1.00-1.05)) and lower education levels (1.8 (1.25-2.60); comparing <=6 years vs >6 years of education) were independent determinants of OT. CONCLUSIONS: OT affected one in 25 adults, with 20% of these requiring hospitalisation. Because OT is preventable, raising awareness and education strategies in the population would allow prevention of vision loss particularly in men, and younger and lesser educated individuals. PMID- 28625973 TI - Prevalence and correlates of electronic cigarette use among Canadian students: cross-sectional findings from the 2014/15 Canadian Student Tobacco, Alcohol and Drugs Survey. AB - BACKGROUND: Over the past decade, youth tobacco use has declined, and electronic cigarettes (e-cigarettes) have entered the market. The aims of this study were to describe the prevalence of e-cigarette use among youth in Canada, by province, across sociodemographic variables and smoking-related correlates; and to examine associations among e-cigarette use, sociodemographic variables and smoking related correlates, with adjustment for other factors. METHODS: The 2014/15 Canadian Student Tobacco, Alcohol and Drugs Survey, a biennial, school-based survey, was administered to students in grades 6-12 in all Canadian provinces. Logistic regression models were fitted to estimate odds of ever and past 30-day e cigarette use by sociodemographic variables and smoking-related correlates. RESULTS: A total of 336 schools from 128 school boards (47% of eligible schools approached) and 42 094 students (66% of eligible students approached) participated in the survey. In Canada, 17.7% (95% confidence interval [CI] 16.4% 18.9%) of students in grades 6-12 reported ever using e-cigarettes, and 5.7% (95% CI 5.2%-6.3%) reported past 30-day use. Substantial variation was observed across provinces. Female students had decreased odds of past 30-day use relative to male students (odds ratio [OR] 0.71, 95% CI 0.59-0.86), whereas current smokers (OR 10.0, 95% CI 6.66-15.02) and experimental smokers (OR 3.61, 95% CI 2.40-5.42) had increased odds relative to never smokers. Students who perceived that access was easy also had increased odds of using e-cigarettes relative to students who perceived that access was difficult (OR 3.86, 95% CI 2.96-5.03). Students who believed that regular use entailed slight risk (OR 0.68, 95% CI 0.52-0.88) and those who did not know risk levels (OR 0.31, 95% CI 0.21-0.46) had decreased odds compared with those perceiving no risk. INTERPRETATION: Our data confirm that many youth used e-cigarettes in the 30 days preceding the survey, although rates were substantially higher among current and experimental smokers than among students who had never tried smoking. PMID- 28625974 TI - Pseudobulbar affective disorder, emotion and the brain. PMID- 28625975 TI - A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors. AB - Primary tumors are often heterogeneous, composed of therapy-sensitive and emerging therapy-resistant cancer cells. Interestingly, treatment of therapy sensitive tumors in heterogeneous tumor microenvironments results in apoptosis of therapy-resistant tumors. In this study, we identify a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein. PAF caused apoptosis in cancer cells resistant to therapy and inhibited tumor growth. A VASA segment of Par-4 mediated its binding and degradation by the ubiquitin ligase Fbxo45, resulting in loss of Par-4 proapoptotic function. Conversely, PAF, which contains this VASA segment, competitively bound to Fbxo45 and rescued Par-4-mediated induction of cancer cell specific apoptosis. Collectively, our findings identify a molecular decoy naturally generated during apoptosis that inhibits a ubiquitin ligase to overcome therapy resistance in tumors. Cancer Res; 77(15); 4039-50. (c)2017 AACR. PMID- 28625976 TI - A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220. AB - Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. The mechanisms underlying drug resistance in AML are poorly understood. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are the most common molecular abnormality in AML. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3 ITD-positive and -negative AML patients and as maintenance therapy. To understand the mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR-pooled library to screen new genes whose loss of function confers resistance to AC220. We identified SPRY3, an intracellular inhibitor of FGF signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated reactivation of downstream FGF/Ras/ERK and Wnt signaling as major mechanisms of resistance to AC220. We confirmed these findings in primary AML patient samples. Expression of SPRY3 and GSK3A was dramatically reduced in AC220-resistant AML samples, and SPRY3-deleted primary AML cells were resistant to AC220. Intriguingly, expression of SPRY3 was greatly reduced in GSK3 knockout AML cells, which positioned SPRY3 downstream of GSK3 in the resistance pathway. Taken together, our study identified novel genes whose loss of function conferred resistance to a selective FLT3 inhibitor, providing new insight into signaling pathways that contribute to acquired resistance in AML. Cancer Res; 77(16); 4402 13. (c)2017 AACR. PMID- 28625977 TI - Acetylation of Mastermind-like 1 by p300 Drives the Recruitment of NACK to Initiate Notch-Dependent Transcription. AB - Although it has long been appreciated that p300 acts as a critical Notch coactivator, the mechanistic details of p300 in Notch-mediated transcription remain unclear. We previously demonstrated that PEAK1-related kinase activating pseudokinase 1 (NACK), also known as SGK223, is a critical coactivator of Notch signaling and binds to the Notch1 ternary complex. Herein we report that p300 and CBP acetylate Mastermind-like 1 (Maml1) on amino acid residues K188 and K189 to recruit NACK to the Notch1 ternary complex, which results in the recruitment of RNA polymerase II to initiate transcription. NACK is recruited to the ternary complexes containing Maml1 and Maml3, but not Maml2. Simultaneous inhibition of p300/CBP and Notch has a synergistic effect in esophageal adenocarcinoma. In summary, this study provides a deeper mechanistic understanding of the assembly of the Notch transcriptional complex and provides rationale and proof of concept for a combinatorial therapeutic attack on Notch-dependent cancers. Cancer Res; 77(16); 4228-37. (c)2017 AACR. PMID- 28625978 TI - The Alkylating Chemotherapeutic Temozolomide Induces Metabolic Stress in IDH1 Mutant Cancers and Potentiates NAD+ Depletion-Mediated Cytotoxicity. AB - IDH1-mutant gliomas are dependent upon the canonical coenzyme NAD+ for survival. It is known that PARP activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of temozolomide on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to temozolomide, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis. The acute time period (<3 hours) after temozolomide treatment displayed a burst of NAD+ consumption driven by PARP activation. In IDH1-mutant expressing cells, this consumption reduced further the abnormally lowered basal steady-state levels of NAD+, introducing a window of hypervulnerability to NAD+ biosynthesis inhibitors. This effect was selective for IDH1-mutant cells and independent of methylguanine methyltransferase or mismatch repair status, which are known rate-limiting mediators of adjuvant temozolomide genotoxic sensitivity. Combined temozolomide and NAMPT inhibition in an in vivo IDH1-mutant cancer model exhibited enhanced efficacy compared with each agent alone. Thus, we find IDH1 mutant cancers have distinct metabolic stress responses to chemotherapy-induced DNA damage and that combination regimens targeting nonredundant NAD+ pathways yield potent anticancer efficacy in vivo Such targeting of convergent metabolic pathways in genetically selected cancers could minimize treatment toxicity and improve durability of response to therapy. Cancer Res; 77(15); 4102-15. (c)2017 AACR. PMID- 28625979 TI - Intestine-Specific Homeobox Gene ISX Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression. AB - The intestine-specific homeobox transcription factor intestine-specific homeobox (ISX) is an IL6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma, but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan catabolism, and immune suppression. We found that ISX-mediated IL6-induced expression of the tryptophan catabolic enzymes Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3 dioxygenase in hepatocellular carcinoma cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. RNAi-mediated attenuation of ISX or AHR reversed these effects. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and programmed death ligand-1 (PD-L1), through which ISX conferred a significant suppressive effect on the CD8+ T-cell response. In hepatocellular carcinoma specimens, expression of IDO1, kynurenine, AHR, and PD-L1 correlated negatively with survival. Overall, our results identified a feed forward mechanism of immune suppression in hepatocellular carcinoma organized by ISX, which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by hepatocellular carcinoma, which may improve its therapeutic management. Cancer Res; 77(15); 4065-77. (c)2017 AACR. PMID- 28625980 TI - Functional Analysis of a Novel beta-(1,3)-Glucanase from Corallococcus sp. Strain EGB Containing a Fascin-Like Module. AB - A novel beta-(1,3)-glucanase gene designated lamC, cloned from Corallococcus sp. strain EGB, contains a fascin-like module and a glycoside hydrolase family 16 (GH16) catalytic module. LamC displays broad hydrolytic activity toward various polysaccharides. Analysis of the hydrolytic products revealed that LamC is an exo acting enzyme on beta-(1,3)(1,3)- and beta-(1,6)-linked glucan substrates and an endo-acting enzyme on beta-(1,4)-linked glucan and xylan substrates. Site directed mutagenesis of conserved catalytic Glu residues (E304A and E309A) demonstrated that these activities were derived from the same active site. Excision of the fascin-like module resulted in decreased activity toward beta (1,3)(1,3)-linked glucans. The carbohydrate-binding assay showed that the fascin like module was a novel beta-(1,3)-linked glucan-binding module. The functional characterization of the fascin-like module and catalytic module will help us better understand these enzymes and modules.IMPORTANCE In this report of a bacterial beta-(1,3)(1,3)-glucanase containing a fascin-like module, we reveal the beta-(1,3)(1,3)-glucan-binding function of the fascin-like module present in the N terminus of LamC. LamC displays exo-beta-(1,3)/(1,6)-glucanase and endo beta-(1,4)-glucanase/xylanase activities with a single catalytic domain. Thus, LamC was identified as a novel member of the GH16 family. PMID- 28625982 TI - Stress Survival Islet 2, Predominantly Present in Listeria monocytogenes Strains of Sequence Type 121, Is Involved in the Alkaline and Oxidative Stress Responses. AB - The foodborne pathogen Listeria monocytogenes is able to survive a variety of stress conditions leading to the colonization of different niches like the food processing environment. This study focuses on the hypervariable genetic hot spot lmo0443 to lmo0449 haboring three inserts: the stress survival islet 1 (SSI-1), the single-gene insert LMOf2365_0481, and two homologous genes of the nonpathogenic species Listeria innocua: lin0464, coding for a putative transcriptional regulator, and lin0465, encoding an intracellular PfpI protease. Our prevalence study revealed a different distribution of the inserts between human and food-associated isolates. The lin0464-lin0465 insert was predominantly found in food-associated strains of sequence type 121 (ST121). Functional characterization of this insert showed that the putative PfpI protease Lin0465 is involved in alkaline and oxidative stress responses but not in acidic, gastric, heat, cold, osmotic, and antibiotic stresses. In parallel, deletion of lin0464 decreased survival under alkaline and oxidative stresses. The expression of both genes increased significantly under oxidative stress conditions independently of the alternative sigma factor sigmaB Furthermore, we showed that the expression of the protease gene lin0465 is regulated by the transcription factor lin0464 under stress conditions, suggesting that lin0464 and lin0465 form a functional unit. In conclusion, we identified a novel stress survival islet 2 (SSI-2), predominantly present in L. monocytogenes ST121 strains, beneficial for survival under alkaline and oxidative stresses, potentially supporting adaptation and persistence of L. monocytogenes in food processing environments.IMPORTANCEListeria monocytogenes strains of ST121 are known to persist for months and even years in food processing environments, thereby increasing the risk of food contamination and listeriosis. However, the molecular mechanism underlying this remarkable niche specific adaptation is still unknown. Here, we demonstrate that the genomic islet SSI-2, predominantly present in L. monocytogenes ST121 strains, is beneficial for survival under alkaline and oxidative stress conditions, which are routinely encountered in food processing environments. Our findings suggest that SSI-2 is part of a diverse set of molecular determinants contributing to niche-specific adaptation and persistence of L. monocytogenes ST121 strains in food processing environments. PMID- 28625981 TI - Heterologous Expression of the Clostridium carboxidivorans CO Dehydrogenase Alone or Together with the Acetyl Coenzyme A Synthase Enables both Reduction of CO2 and Oxidation of CO by Clostridium acetobutylicum. AB - With recent advances in synthetic biology, CO2 could be utilized as a carbon feedstock by native or engineered organisms, assuming the availability of electrons. Two key enzymes used in autotrophic CO2 fixation are the CO dehydrogenase (CODH) and acetyl coenzyme A (acetyl-CoA) synthase (ACS), which form a bifunctional heterotetrameric complex. The CODH/ACS complex can reversibly catalyze CO2 to CO, effectively enabling a biological water-gas shift reaction at ambient temperatures and pressures. The CODH/ACS complex is part of the Wood Ljungdahl pathway (WLP) used by acetogens to fix CO2, and it has been well characterized in native hosts. So far, only a few recombinant CODH/ACS complexes have been expressed in heterologous hosts, none of which demonstrated in vivo CO2 reduction. Here, functional expression of the Clostridium carboxidivorans CODH/ACS complex is demonstrated in the solventogen Clostridium acetobutylicum, which was engineered to express CODH alone or together with the ACS. Both strains exhibited CO2 reduction and CO oxidation activities. The CODH reactions were interrogated using isotopic labeling, thus verifying that CO was a direct product of CO2 reduction, and vice versa. CODH apparently uses a native C. acetobutylicum ferredoxin as an electron carrier for CO2 reduction. Heterologous CODH activity depended on actively growing cells and required the addition of nickel, which is inserted into CODH without the need to express the native Ni insertase protein. Increasing CO concentrations in the gas phase inhibited CODH activity and altered the metabolite profile of the CODH-expressing cells. This work provides the foundation for engineering a complete and functional WLP in nonnative host organisms.IMPORTANCE Functional expression of CO dehydrogenase (CODH) from Clostridium carboxidivorans was demonstrated in C. acetobutylicum, which is natively incapable of CO2 fixation. The expression of CODH, alone or together with the C. carboxidivorans acetyl-CoA synthase (ACS), enabled C. acetobutylicum to catalyze both CO2 reduction and CO oxidation. Importantly, CODH exhibited activity in both the presence and absence of ACS. 13C-tracer studies confirmed that the engineered C. acetobutylicum strains can reduce CO2 to CO and oxidize CO during growth on glucose. PMID- 28625983 TI - Strain-Level Metagenomic Analysis of the Fermented Dairy Beverage Nunu Highlights Potential Food Safety Risks. AB - The rapid detection of pathogenic strains in food products is essential for the prevention of disease outbreaks. It has already been demonstrated that whole metagenome shotgun sequencing can be used to detect pathogens in food but, until recently, strain-level detection of pathogens has relied on whole-metagenome assembly, which is a computationally demanding process. Here we demonstrated that three short-read-alignment-based methods, i.e., MetaMLST, PanPhlAn, and StrainPhlAn, could accurately and rapidly identify pathogenic strains in spinach metagenomes that had been intentionally spiked with Shiga toxin-producing Escherichia coli in a previous study. Subsequently, we employed the methods, in combination with other metagenomics approaches, to assess the safety of nunu, a traditional Ghanaian fermented milk product that is produced by the spontaneous fermentation of raw cow milk. We showed that nunu samples were frequently contaminated with bacteria associated with the bovine gut and, worryingly, we detected putatively pathogenic E. coli and Klebsiella pneumoniae strains in a subset of nunu samples. Ultimately, our work establishes that short-read alignment-based bioinformatics approaches are suitable food safety tools, and we describe a real-life example of their utilization.IMPORTANCE Foodborne pathogens are responsible for millions of illnesses each year. Here we demonstrate that short-read-alignment-based bioinformatics tools can accurately and rapidly detect pathogenic strains in food products by using shotgun metagenomics data. The methods used here are considerably faster than both traditional culturing methods and alternative bioinformatics approaches that rely on metagenome assembly; therefore, they can potentially be used for more high-throughput food safety testing. Overall, our results suggest that whole-metagenome sequencing can be used as a practical food safety tool to prevent diseases or to link outbreaks to specific food products. PMID- 28625984 TI - Indole-Induced Reversion of Intrinsic Multiantibiotic Resistance in Lysobacter enzymogenes. AB - Lysobacter species are a group of environmental bacteria that are emerging as a new source of antibiotics. One characteristic of Lysobacter is intrinsic resistance to multiple antibiotics, which had not been studied. To understand the resistance mechanism, we tested the effect of blocking two-component regulatory systems (TCSs) on the antibiotic resistance of Lysobacter enzymogenes, a prolific producer of antibiotics. Upon treatment with LED209, an inhibitor of the widespread TCS QseC/QseB, L. enzymogenes produced a large amount of an unknown metabolite that was barely detectable in the untreated culture. Subsequent structural elucidation by nuclear magnetic resonance (NMR) unexpectedly revealed that the metabolite was indole. Indole production was also markedly induced by adrenaline, a known modulator of QseC/QseB. Next, we identified two TCS genes, L. enzymogenesqseC (Le-qseC) and Le-qseB, in L. enzymogenes and found that mutations of Le-qseC and Le-qseB also led to a dramatic increase in indole production. We then chemically synthesized a fluorescent indole probe that could label the cells. While the Le-qseB (cytoplasmic response regulator) mutant was clearly labeled by the probe, the Le-qseC (membrane sensor) mutant was not labeled. It was reported previously that indole can enhance antibiotic resistance in bacteria. Therefore, we tested if the dramatic increase in the level of indole production in L. enzymogenes upon blocking of Le-qseC and Le-qseB would lead to enhanced antibiotic resistance. Surprisingly, we found that indole caused the intrinsically multiantibiotic-resistant bacterium L. enzymogenes to become susceptible. Point mutations at conserved amino acids in Le-QseC also led to antibiotic susceptibility. Because indole is known as an interspecies signal, these findings may have implications.IMPORTANCE The environmental bacterium Lysobacter is a new source of antibiotic compounds and exhibits intrinsic antibiotic resistance. Here, we found that the inactivation of a two-component regulatory system (TCS) by an inhibitor or by gene deletion led to a remarkable increase in the level of production of a metabolite in L. enzymogenes, and this metabolite was identified to be indole. We chemically synthesized a fluorescent indole probe and found that it could label the wild type and a mutant of the TCS cytoplasmic response regulator but not a mutant of the TCS membrane sensor. Indole treatment caused the intrinsically multidrug-resistant bacterium L. enzymogenes to be susceptible to antibiotics. Mutations of the TCS sensor also led to antibiotic susceptibility. Because indole is known as an interspecies signal between gut microbiota and mammalian hosts, the observation that indole could render intrinsically resistant L. enzymogenes susceptible to common antibiotics may have implications. PMID- 28625985 TI - Periplasmic Nicotine Dehydrogenase NdhAB Utilizes Pseudoazurin as Its Physiological Electron Acceptor in Agrobacterium tumefaciens S33. AB - Agrobacterium tumefaciens S33 can grow with nicotine as the sole source of carbon, nitrogen, and energy via a novel hybrid of the pyridine pathway and the pyrollidine pathway. Characterization of the enzymes involved in the hybrid pathway is important for understanding its biochemical mechanism. Here we report that the molybdenum-containing nicotine dehydrogenase (NdhAB), which catalyzes the initial step of nicotine degradation, is located in the periplasm of strain S33, while the 6-hydroxynicotine oxidase and 6-hydroxypseudooxynicoine oxidase are in the cytoplasm. This is consistent with the fact that NdhA has a Tat signal peptide. Interestingly, an ORF adjacent to the ndhAB gene was verified to encode a copper-containing electron carrier, pseudoazurin (Paz), that has a typical signal peptide of bacterial Paz. Both were transported into the periplasm after being produced in the cytoplasm. We purified NdhAB from the periplasmic fraction of strain S33 and found that, with Paz as the physiological electron acceptor, NdhAB catalyzed the hydroxylation of nicotine at a specific rate of 110.52 +/- 8.09 MUmol min-1 mg protein-1, where the oxygen atom in the hydroxyl group of the product 6-hydroxynicotine was derived from H2O. The apparent Km values for nicotine and Paz were 1.64 +/- 0.07 MUM and 3.61 +/- 0.23 MUM, respectively. NAD(P)+, O2, and ferredoxin could not serve as electron acceptors. Disruption of the paz gene disabled the strain for nicotine degradation, indicating that Paz is required for nicotine catabolism in the strain. These findings help our understanding of electron transfer during nicotine degradation in bacteria.IMPORTANCE Nicotine is a toxic and addictive N-heterocyclic aromatic alkaloid produced in tobacco. Its catabolism in organisms and degradation in tobacco wastes have become the major concerns of health and the environment. Bacteria usually decompose nicotine using the classical strategy of hydroxylating the pyridine ring with the help of activated oxygen by nicotine dehydrogenase, which binds one molybdopterin, two [lsqb]2Fe2S[rsqb] clusters, and usually one FAD as well. However, the physiological electron acceptor for the reaction is still unknown. In this study, we found the two-component nicotine dehydrogenase from Agrobacterium tumefaciens S33, naturally lacking FAD-binding domain, is located in the periplasmic space and uses a copper-containing electron carrier, pseudoazurin, as its physiological electron acceptor. We report here the role of pseudoazurin in a reaction catalyzed by a molybdopterin-containing hydroxylase occurring in the periplasmic space. These results provide new biochemical knowledge in microbial degradation of N-heterocyclic aromatic compound. PMID- 28625986 TI - The Irr and RirA Proteins Participate in a Complex Regulatory Circuit and Act in Concert To Modulate Bacterioferritin Expression in Ensifer meliloti 1021. AB - In this work we found that the bfr gene of the rhizobial species Ensifer meliloti, encoding a bacterioferritin iron storage protein, is involved in iron homeostasis and the oxidative stress response. This gene is located downstream of and overlapping the smc03787 open reading frame (ORF). No well-predicted RirA or Irr boxes were found in the region immediately upstream of the bfr gene although two presumptive RirA boxes and one presumptive Irr box were present in the putative promoter of smc03787 We demonstrate that bfr gene expression is enhanced under iron-sufficient conditions and that Irr and RirA modulate this expression. The pattern of bfr gene expression as well as the response to Irr and RirA is inversely correlated to that of smc03787 Moreover, our results suggest that the small RNA SmelC759 participates in RirA- and Irr-mediated regulation of bfr expression and that additional unknown factors are involved in iron-dependent regulation.IMPORTANCEE. meliloti belongs to the Alphaproteobacteria, a group of bacteria that includes several species able to associate with eukaryotic hosts, from mammals to plants, in a symbiotic or pathogenic manner. Regulation of iron homeostasis in this group of bacteria differs from that found in the well-studied Gammaproteobacteria In this work we analyzed the effect of rirA and irr mutations on bfr gene expression. We demonstrate the effect of an irr mutation on iron homeostasis in this bacterial genus. Moreover, results obtained indicate a complex regulatory circuit where multiple regulators, including RirA, Irr, the small RNA SmelC759, and still unknown factors, act in concert to balance bfr gene expression. PMID- 28625987 TI - Metabolic Engineering of Actinobacillus succinogenes Provides Insights into Succinic Acid Biosynthesis. AB - Actinobacillus succinogenes, a Gram-negative facultative anaerobe, exhibits the native capacity to convert pentose and hexose sugars to succinic acid (SA) with high yield as a tricarboxylic acid (TCA) cycle intermediate. In addition, A. succinogenes is capnophilic, incorporating CO2 into SA, making this organism an ideal candidate host for conversion of lignocellulosic sugars and CO2 to an emerging commodity bioproduct sourced from renewable feedstocks. In this work, we report the development of facile metabolic engineering capabilities in A. succinogenes, enabling examination of SA flux determinants via knockout of the primary competing pathways-namely, acetate and formate production-and overexpression of the key enzymes in the reductive branch of the TCA cycle leading to SA. Batch fermentation experiments with the wild-type and engineered strains using pentose-rich sugar streams demonstrate that the overexpression of the SA biosynthetic machinery (in particular, the enzyme malate dehydrogenase) enhances flux to SA. Additionally, removal of competitive carbon pathways leads to higher-purity SA but also triggers the generation of by-products not previously described from this organism (e.g., lactic acid). The resultant engineered strains also lend insight into energetic and redox balance and elucidate mechanisms governing organic acid biosynthesis in this important natural SA-producing microbe.IMPORTANCE Succinic acid production from lignocellulosic residues is a potential route for enhancing the economic feasibility of modern biorefineries. Here, we employ facile genetic tools to systematically manipulate competing acid production pathways and overexpress the succinic acid-producing machinery in Actinobacillus succinogenes Furthermore, the resulting strains are evaluated via fermentation on relevant pentose-rich sugar streams representative of those from corn stover. Overall, this work demonstrates genetic modifications that can lead to succinic acid production improvements and identifies key flux determinants and new bottlenecks and energetic needs when removing by-product pathways in A. succinogenes metabolism. PMID- 28625988 TI - Modification of a Pollen Trap Design To Capture Airborne Conidia of Entomophaga maimaiga and Detection of Conidia by Quantitative PCR. AB - The goal of this study was to develop effective and practical field sampling methods for quantification of aerial deposition of airborne conidia of Entomophaga maimaiga over space and time. This important fungal pathogen is a major cause of larval death in invasive gypsy moth (Lymantria dispar) populations in the United States. Airborne conidia of this pathogen are relatively large (similar in size to pollen), with unusual characteristics, and require specialized methods for collection and quantification. Initially, dry sampling (settling of spores from the air onto a dry surface) was used to confirm the detectability of E. maimaiga at field sites with L. dispar deaths caused by E. maimaiga, using quantitative PCR (qPCR) methods. We then measured the signal degradation of conidial DNA on dry surfaces under field conditions, ultimately rejecting dry sampling as a reliable method due to rapid DNA degradation. We modified a chamber-style trap commonly used in palynology to capture settling spores in buffer. We tested this wet-trapping method in a large-scale (137-km) spore-trapping survey across gypsy moth outbreak regions in Pennsylvania undergoing epizootics, in the summer of 2016. Using 4-day collection periods during the period of late instar and pupal development, we detected variable amounts of target DNA settling from the air. The amounts declined over the season and with distance from the nearest defoliated area, indicating airborne spore dispersal from outbreak areas.IMPORTANCE We report on a method for trapping and quantifying airborne spores of Entomophaga maimaiga, an important fungal pathogen affecting gypsy moth (Lymantria dispar) populations. This method can be used to track dispersal of E. maimaiga from epizootic areas and ultimately to provide critical understanding of the spatial dynamics of gypsy moth-pathogen interactions. PMID- 28625989 TI - Rapid, high-throughput identification of anthrax-causing and emetic Bacillus cereus group genome assemblies using BTyper, a computational tool for virulence based classification of Bacillus cereus group isolates using nucleotide sequencing data. AB - The Bacillus cereus group comprises nine species, several of which are pathogenic. Differentiating between isolates that may cause disease and those that do not is a matter of public health and economic importance, but can be particularly challenging due to the high genomic similarity of the group. To this end, we have developed BTyper, a computational tool that employs a combination of (i) virulence gene-based typing, (ii) multi-locus sequence typing (MLST), (iii) panC clade typing, and (iv) rpoB allelic typing to rapidly classify B. cereus group isolates using nucleotide sequencing data. BTyper was applied to a set of 662 B. cereus group genome assemblies to (i) identify anthrax-associated genes in non-B. anthracis members of the B. cereus group, and (iI) identify assemblies from B. cereus group strains with emetic potential. With BTyper, anthrax toxin genes cya, lef and pagA were detected in 8 genomes classified in NCBI as B. cereus that clustered into two distinct groups using k-medoids clustering, while B. anthracis poly-gamma-D-glutamate capsule biosynthesis genes capABCDE or hyaluronic acid capsule gene hasA were detected in an additional 16 assemblies classified as either B. cereus or B. thuringiensis isolated from clinical, environmental, and food sources. Emetic toxin genes cesABCD were detected in 24 assemblies belonging to panC clades III and VI that had been isolated from food, clinical, and environmental settings. The command line version of BTyper is available at https://github.com/lmc297/BTyper In addition, BMiner, a companion application for analyzing multiple BTyper output files in aggregate, can be found at https://github.com/lmc297/BMinerImportanceBacillus cereus is a foodborne pathogen that is estimated to cause tens of thousands of illnesses each year in the United States alone. Even with molecular methods, it can be difficult to distinguish non-pathogenic B. cereus group isolates from their pathogenic counterparts, including the human pathogen B. anthracis, which is responsible for anthrax, as well as insect pathogen B. thuringiensis By using the variety of typing schemes employed by BTyper, users can rapidly classify, characterize, and assess the virulence potential of any isolate using its nucleotide sequencing data. PMID- 28625990 TI - Bioavailability of Carbohydrate Content in Natural and Transgenic Switchgrasses for the Extreme Thermophile Caldicellulosiruptor bescii. AB - Improving access to the carbohydrate content of lignocellulose is key to reducing recalcitrance for microbial deconstruction and conversion to fuels and chemicals. Caldicellulosiruptor bescii completely solubilizes naked microcrystalline cellulose, yet this transformation is impeded within the context of the plant cell wall by a network of lignin and hemicellulose. Here, the bioavailability of carbohydrates to C. bescii at 70 degrees C was examined for reduced lignin transgenic switchgrass lines COMT3(+) and MYB Trans, their corresponding parental lines (cultivar Alamo) COMT3(-) and MYB wild type (WT), and the natural variant cultivar Cave-in-Rock (CR). Transgenic modification improved carbohydrate solubilization by C. bescii to 15% (2.3-fold) for MYB and to 36% (1.5-fold) for COMT, comparable to the levels achieved for the natural variant, CR (36%). Carbohydrate solubilization was nearly doubled after two consecutive microbial fermentations compared to one microbial step, but it never exceeded 50% overall. Hydrothermal treatment (180 degrees C) prior to microbial steps improved solubilization 3.7-fold for the most recalcitrant line (MYB WT) and increased carbohydrate recovery to nearly 50% for the least recalcitrant lines [COMT3(+) and CR]. Alternating microbial and hydrothermal steps (T->M->T->M) further increased bioavailability, achieving carbohydrate solubilization ranging from 50% for MYB WT to above 70% for COMT3(+) and CR. Incomplete carbohydrate solubilization suggests that cellulose in the highly lignified residue was inaccessible; indeed, residue from the T->M->T->M treatment was primarily glucan and inert materials (lignin and ash). While C. bescii could significantly solubilize the transgenic switchgrass lines and natural variant tested here, additional or alternative strategies (physical, chemical, enzymatic, and/or genetic) are needed to eliminate recalcitrance.IMPORTANCE Key to a microbial process for solubilization of plant biomass is the organism's access to the carbohydrate content of lignocellulose. Economically viable routes will characteristically minimize physical, chemical, and biological pretreatment such that microbial steps contribute to the greatest extent possible. Recently, transgenic versions of plants and trees have been developed with the intention of lowering the barrier to lignocellulose conversion, with particular focus on lignin content and composition. Here, the extremely thermophilic bacterium Caldicellulosiruptor bescii was used to solubilize natural and genetically modified switchgrass lines, with and without the aid of hydrothermal treatment. For lignocellulose conversion, it is clear that the microorganism, plant biomass substrate, and processing steps must all be considered simultaneously to achieve optimal results. Whether switchgrass lines engineered for low lignin or natural variants with desirable properties are used, conversion will depend on microbial access to crystalline cellulose in the plant cell wall. PMID- 28625991 TI - Different Amplicon Targets for Sequencing-Based Studies of Fungal Diversity. AB - Target-gene amplicon sequencing is the most exploited high-throughput sequencing application in microbial ecology. The targets are taxonomically relevant genes, with 16S rRNA being the gold standard for bacteria. As for fungi, the most commonly used target is the internal transcribed spacer (ITS). However, the uneven ITS length among species may promote preferential amplification and sequencing and incorrect estimation of their abundance. Therefore, the use of different targets is desirable. We evaluated the use of three different target amplicons for the characterization of fungal diversity. After an in silico primer evaluation, we compared three amplicons (the ITS1-ITS2 region [ITS1-2], 18S ribosomal small subunit RNA, and the D1/D2 domain of the 26S ribosomal large subunit RNA), using biological samples and a mock community of common fungal species. All three targets allowed for accurate identification of the species present. Nevertheless, high heterogeneity in ITS1-2 length was found, and this caused an overestimation of the abundance of species with a shorter ITS, while both 18S and 26S amplicons allowed for more reliable quantification. We demonstrated that ITS1-2 amplicon sequencing, although widely used, may lead to an incorrect evaluation of fungal communities, and efforts should be made to promote the use of different targets in sequencing-based microbial ecology studies.IMPORTANCE Amplicon-sequencing approaches for fungi may rely on different targets affecting the diversity and abundance of the fungal species. An increasing number of studies will address fungal diversity by high-throughput amplicon sequencing. The description of the communities must be accurate and reliable in order to draw useful insights and to address both ecological and biological questions. By analyzing a mock community and several biological samples, we demonstrate that using different amplicon targets may change the results of fungal microbiota analysis, and we highlight how a careful choice of the target is fundamental for a thorough description of the fungal communities. PMID- 28625992 TI - Flow Cytometry Is a Powerful Tool for Assessment of the Viability of Fungal Conidia in Metalworking Fluids. AB - Fungal contamination of metalworking fluids (MWF) is a dual problem in automated processing plants because resulting fungal biofilms obstruct cutting, drilling, and polishing machines. Moreover, some fungal species of MWF comprise pathogens such as Fusarium solani Therefore, the development of an accurate analytical tool to evaluate conidial viability in MWF is important. We developed a flow cytometric method to measure fungal viability in MWF using F. solani as the model organism. To validate this method, viable and dead conidia were mixed in several proportions and flow was cytometrically analyzed. Subsequently, we assessed the fungicidal activity of two commercial MWF using flow cytometry (FCM) and compared it with microscopic analyses and plating experiments. We evaluated the fungal growth in both MWF after 7 days using quantitative PCR (qPCR) to assess the predictive value of FCM. Our results showed that FCM distinguishes live from dead conidia as early as 5 h after exposure to MWF, whereas the microscopic germination approach detected conidial viability much later and less accurately. At 24 h, microscopic analyses of germinating conidia and live/dead analyses by FCM correlated well, although the former consistently underestimated the proportion of viable conidia. In addition, the reproducibility and sensitivity of the flow cytometric method were high and allowed assessment of the fungicidal properties of two commercial MWF. Importantly, the obtained flow cytometric results on viability of F. solani conidia at both early time points (5 h and 24 h) correlated well with fungal biomass measurements assessed via a qPCR methodology 7 days after the start of the experiment.IMPORTANCE This result shows the predictive power of flow cytometry (FCM) in assessing the fungicidal capacity of MWF formulations. It also implies that FCM can be implemented as a rapid detection tool to estimate the viable fungal load in an industrial processing matrix (MWF). PMID- 28625993 TI - Survival of Highly Pathogenic Avian Influenza H5N1 Virus in Tissues Derived from Experimentally Infected Chickens. AB - Eurasian lineage highly pathogenic avian influenza (HPAI) H5N1 virus has been a severe threat to the poultry industry since its emergence in 1996. The carcass or tissues derived from infected birds may present the risk of the virus spreading to humans, animals, and the surrounding environment. In this study, we investigated the survival of the virus in feather, muscle, and liver tissues collected from six chickens (Gallus gallus) experimentally infected with HPAI H5N1 virus. The tissues were stored at +4 degrees C or +20 degrees C, and viral isolation was performed at different times for 360 days. The maximum periods for viral survival were observed in samples stored at +4 degrees C in all tissue types and were 240 days in feather tissues, 160 days in muscle, and 20 days in liver. The viral infectivity at +20 degrees C was maintained for a maximum of 30 days in the feather tissues, 20 days in muscle, and 3 days in liver. The viral inactivation rates partly overlapped in the feather and muscle tissues at the two temperatures. The virus was inactivated rapidly in the liver. Our experimental results indicate that the tissue type and temperature can greatly influence the survival of HPAI H5N1 virus in the tissues of infected chickens.IMPORTANCE Highly pathogenic avian influenza virus of the H5N1 subtype can cause massive losses of poultry, and people need to handle a large number of chicken carcasses contaminated with the virus at outbreak sites. This study evaluated how long the virus can keep its infectivity in the three types of tissues derived from chickens infected with the virus. Our experimental results indicate that the virus can survive in tissues for a specific period of time depending on the tissue type and temperature. Our results are valuable for better understanding of viral ecology in the environment and for reducing the risk of the virus spreading via bird tissues contaminated with the virus. PMID- 28625994 TI - The Small Protein HemP Is a Transcriptional Activator for the Hemin Uptake Operon in Burkholderia multivorans ATCC 17616. AB - Iron and heme play very important roles in various metabolic functions in bacteria, and their intracellular homeostasis is maintained because high concentrations of free forms of these molecules greatly facilitate the Fenton reaction-mediated production of large amounts of reactive oxygen species that severely damage various biomolecules. The ferric uptake regulator (Fur) from Burkholderiamultivorans ATCC 17616 is an iron-responsive global transcriptional regulator, and its fur deletant exhibits pleiotropic phenotypes. In this study, we found that the phenotypes of the fur deletant were suppressed by an additional mutation in hemP The transcription of hemP was negatively regulated by Fur under iron-replete conditions and was constitutive in the fur deletant. Growth of a hemP deletant was severely impaired in a medium containing hemin as the sole iron source, demonstrating the important role of HemP in hemin utilization. HemP was required as a transcriptional activator that specifically binds the promoter containing region upstream of a Fur-repressive hmuRSTUV operon, which encodes the proteins for hemin uptake. A hmuR deletant was still able to grow using hemin as the sole iron source, albeit at a rate clearly lower than that of the wild-type strain. These results strongly suggested (i) the involvement of HmuR in hemin uptake and (ii) the presence in ATCC 17616 of at least part of other unknown hemin uptake systems whose expression depends on the HemP function. Our in vitro analysis also indicated high-affinity binding of HemP to hemin, and such a property might modulate transcriptional activation of the hmu operon.IMPORTANCE Although the hmuRSTUV genes for the utilization of hemin as a sole iron source have been identified in a few Burkholderia strains, the regulatory expression of these genes has remained unknown. Our analysis in this study using B. multivorans ATCC 17616 showed that its HemP protein is required for expression of the hmuRSTUV operon, and the role of HemP in betaproteobacterial species was elucidated for the first time, to our knowledge, in this study. The HemP protein was also found to have two additional properties that have not been reported for functional homologues in other species; one is that HemP is able to bind to the promoter-containing region of the hmu operon to directly activate its transcription, and the other is that HemP is also required for the expression of an unknown hemin uptake system. PMID- 28625995 TI - NOVEL ANTIBIOTIC RESISTANCE DETERMINANTS FROM AGRICULTURAL SOIL EXPOSED TO ANTIBIOTICS WIDELY USED IN HUMAN MEDICINE AND ANIMAL FARMING. AB - Antibiotic resistance has emerged globally as one of the biggest threats to human and animal health. Although the excessive use of antibiotics is recognized for accelerating the selection for resistance, there is a growing body of evidence suggesting that natural environments are "hotspots" for the development of both ancient and contemporary resistance mechanisms. Given that pharmaceuticals can be entrained onto agricultural land through anthropogenic activities, this could be a potential driver for the emergence and dissemination of resistance in soil bacteria. Using functional metagenomics, we interrogated the "resistome" of bacterial communities found in a collection of Canadian agricultural soil, some of which had been receiving antibiotics widely used in human medicine (macrolides) or food animal production (sulfamethazine, chlortetracycline and tylosin) for up to 16 years. Of the 34 new antibiotic resistance genes (ARGs) recovered, the majority were predicted to encode for (multi)drug efflux systems, while a few share little to no homology with established resistance determinants. We characterized several novel gene products, including putative enzymes that can confer high-level resistance against aminoglycosides, sulfonamides, and broad range of beta-lactams, with respect to their resistance mechanisms and clinical significance. By coupling high-resolution proteomics analysis with functional metagenomics, we discovered an unusual peptide, PPPAZI 4, encoded within an alternative open-reading frame not predicted by bioinformatics tools. Expression of the proline-rich PPPAZI 4 can promote resistance against different macrolides but not other ribosomal-targeting antibiotics, implicating a new macrolide specific resistance mechanism that could be fundamentally linked to the evolutionary design of this peptide.IMPORTANCE Antibiotic resistance is a clinical phenomenon with an evolutionary link to the microbial pangenome. Genes and protogenes encoding for specialized and potential resistance mechanisms are abundant in natural environments, but understanding of their identity and genomic context remain limited. Our discovery of several previously-unknown antibiotic resistance genes from uncultured soil microorganisms indicates that soil is a significant reservoir of resistance determinants, which, once acquired and "re purposed" by pathogenic bacteria, can have serious impacts on therapeutic outcomes. This study provides valuable insights into the diversity and identity of resistance within the soil microbiome. The finding of a novel peptide-mediated resistance mechanism involving an unpredicted gene product also highlights the usefulness of integrating proteomics analysis into metagenomics-driven gene discovery. PMID- 28625996 TI - Natural DNA transformation is functional in Lactococcus lactis ssp. cremoris KW2. AB - Lactococcus lactis is one of the most commonly used lactic acid bacteria in the dairy industry. Activation of competence for natural DNA transformation in this species would greatly improve the selection of novel strains with desired genetic traits. Here, we investigated the activation of natural transformation in L. lactis ssp. cremoris KW2, a strain of plant origin whose genome encodes the master competence regulator ComX and the complete set of proteins usually required for natural transformation. In the absence of knowledge about competence regulation in this species, we constitutively overproduced ComX in a reporter strain of late competence phase activation and showed, by transcriptomic analyses, a ComX-dependent induction of all key competence genes. We further demonstrated that natural DNA transformation is functional in this strain and requires the competence DNA uptake machinery. Since constitutive ComX overproduction is unstable, we alternatively expressed comX under the control of an endogenous xylose-inducible promoter. This regulated system was used to successfully inactivate the adaptor protein MecA and subunits of the Clp proteolytic complex, which were previously shown to be involved in ComX degradation in streptococci. In the presence of a low amount of ComX, the deletion of mecA, clpC, or clpP genes markedly increased the activation of the late competence phase and transformability. Altogether, our results report the functionality of natural DNA transformation in L. lactis and pave the way for the identification of signaling mechanisms that trigger the competence state in this species.IMPORTANCELactococcus lactis is a lactic acid bacterium of major importance, which is used as a starter species for milk fermentation, a host for heterologous protein production, and a delivery platform for therapeutic molecules. Here, we report the functionality of natural transformation in L. lactis ssp. cremoris KW2 by the overproduction of the master competence regulator ComX. The developed procedure enables a flexible approach to modify the chromosome with single point mutation, sequence insertion, or sequence replacement. These results represent an important step for the genetic engineering of L. lactis that will facilitate the design of strains optimized for industrial applications. This will also help to discover natural regulatory mechanisms controlling competence in the genus Lactococcus. PMID- 28625997 TI - Quantifying Vibrio cholerae enterotoxicity in a zebrafish infection model. AB - Vibrio cholerae is the etiological agent of cholera, an acute intestinal infection in humans characterized by voluminous watery diarrhea. Cholera is spread through ingestion of contaminated food or water, primarily in developing countries that lack the proper infrastructure for proper water and sewage treatment. Vibrio cholerae is an aquatic bacterium that inhabits coastal and estuarine areas, and is known to have several environmental reservoirs, including fish. Our laboratory has recently described the use of the zebrafish as a new animal model for the study of V. cholerae intestinal colonization, pathogenesis, and transmission.As early as six hours after exposure to V. cholerae, zebrafish develop diarrhea. Prior work in our laboratory has shown that this is not due to the action of cholera toxin. We hypothesize that accessory toxins produced by V. cholerae are the cause of diarrhea in infected zebrafish. In order to assess the effects of accessory toxins in the zebrafish, it was necessary to develop a method of quantifying diarrheal volume as a measure of pathogenesis. Here, we have adapted cell density, protein, and mucin assays, along with enumeration of V. cholerae in the zebrafish intestinal tract and in the infection water, to achieve this goal. Combined, these assays should help us determine which toxins have the greatest diarrheagenic effect in fish, and consequently, which toxins may play a role in environmental transmission.Importance Identification of the accessory toxins that cause diarrhea in zebrafish can help us understand more about the role of fish in the wild as aquatic reservoirs for V. cholerae It is plausible that accessory toxins can act to prolong colonization and subsequent shedding of V. cholerae back into the environment, thus perpetuating and facilitating transmission during an outbreak. It is also possible that accessory toxins help to maintain low levels of intestinal colonization in fish, giving V. cholerae an advantage when environmental conditions are not optimal for survival in the water. Studies such as this one are critical because fish could be an overlooked source of cholera transmission in the environment. PMID- 28625998 TI - Structures, Compositions, and Activities of Live Shewanella Biofilms Formed on Graphite Electrodes in Electrochemical Flow Cells. AB - An electrochemical flow cell equipped with a graphite working electrode (WE) at the bottom was inoculated with Shewanella oneidensis MR-1 expressing an anaerobic fluorescent protein, and biofilm formation on the WE was observed over time during current generation at WE potentials of +0.4 and 0 V (versus standard hydrogen electrodes), under electrolyte-flow conditions. Electrochemical analyses suggested the presence of unique electron-transfer mechanisms in the +0.4-V biofilm. Microscopic analyses revealed that, in contrast to aerobic biofilms, current-generating biofilm (at +0.4 V) was thin and flat (~10 MUm in thickness), and cells were evenly and densely distributed in the biofilm. In contrast, cells were unevenly distributed in biofilm formed at 0 V. In situ fluorescence staining and biofilm recovery experiments showed that the amounts of extracellular polysaccharides (EPSs) in the +0.4-V biofilm were much smaller than those in the aerobic and 0-V biofilms, suggesting that Shewanella cells suppress the production of EPSs at +0.4 V under flow conditions. We suggest that Shewanella cells perceive electrode potentials and modulate the structure and composition of biofilms to efficiently transfer electrons to electrodes.IMPORTANCE A promising application of microbial fuel cells (MFCs) is to save energy in wastewater treatment. Since current is generated in these MFCs by biofilm microbes under horizontal flows of wastewater, it is important to understand the mechanisms for biofilm formation and current generation under water-flow conditions. Although massive work has been done to analyze the molecular mechanisms for current generation by model exoelectrogenic bacteria, such as Shewanella oneidensis, limited information is available regarding the formation of current-generating biofilms over time under water-flow conditions. The present study developed electrochemical flow cells and used them to examine the electrochemical and structural features of current-generating biofilms under water-flow conditions. We show unique features of mature biofilms actively generating current, creating opportunities to search for as-yet-undiscovered current-generating mechanisms in Shewanella biofilms. Furthermore, information provided in the present study is useful for researchers attempting to develop anode architectures suitable for wastewater treatment MFCs. PMID- 28625999 TI - Andrea Ventura: Decrypting noncoding RNAs. AB - Ventura explores the biological functions of noncoding RNAs in cancer and development. PMID- 28626001 TI - KRS: A cut away from release in exosomes. AB - Cancer cells often trigger an inflammatory process, which in some cases may be driven by the presence of lysyl-tRNA synthetase (KRS) in the medium. Kim et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201605118) now demonstrate that cleavage of the KRS by caspase-8 inside cells triggers its interaction with syntenin and its release in inflammatory exosomes. PMID- 28626000 TI - BAIAP3, a C2 domain-containing Munc13 protein, controls the fate of dense-core vesicles in neuroendocrine cells. AB - Dense-core vesicle (DCV) exocytosis is a SNARE (soluble N-ethylmaleimide sensitive fusion attachment protein receptor)-dependent anterograde trafficking pathway that requires multiple proteins for regulation. Several C2 domain containing proteins are known to regulate Ca2+-dependent DCV exocytosis in neuroendocrine cells. In this study, we identified others by screening all (~139) human C2 domain-containing proteins by RNA interference in neuroendocrine cells. 40 genes were identified, including several encoding proteins with known roles (CAPS [calcium-dependent activator protein for secretion 1], Munc13-2, RIM1, and SYT10) and many with unknown roles. One of the latter, BAIAP3, is a secretory cell-specific Munc13-4 paralog of unknown function. BAIAP3 knockdown caused accumulation of fusion-incompetent DCVs in BON neuroendocrine cells and lysosomal degradation (crinophagy) of insulin-containing DCVs in INS-1 beta cells. BAIAP3 localized to endosomes was required for Golgi trans-Golgi network 46 (TGN46) recycling, exhibited Ca2+-stimulated interactions with TGN SNAREs, and underwent Ca2+-stimulated TGN recruitment. Thus, unlike other Munc13 proteins, BAIAP3 functions indirectly in DCV exocytosis by affecting DCV maturation through its role in DCV protein recycling. Ca2+ rises that stimulate DCV exocytosis may stimulate BAIAP3-dependent retrograde trafficking to maintain DCV protein homeostasis and DCV function. PMID- 28626002 TI - Ride the wave: Retrograde trafficking becomes Ca2+ dependent with BAIAP3. AB - The functions of four of the five proteins in the mammalian uncoordinated-13 (Munc13) family have been identified as priming factors in SNARE-dependent exocytosis. In this issue, Zhang et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201702099) show that the fifth member, BAIAP3 (brain specific angiogenesis inhibitor I-associated protein 3), acts in retrograde trafficking by returning secretory vesicle material to the trans-Golgi network. In its absence, secretory vesicle formation is impaired, leading to accumulation of immature vesicles, or lysosomal vesicle degradation. PMID- 28626003 TI - Transcriptional Complexity and Distinct Expression Patterns of auts2 Paralogs in Danio rerio. AB - Several genes that have been implicated in autism spectrum disorders (ASDs) have multiple transcripts. Therefore, comprehensive transcript annotation is critical for determining the respective gene function. The autism susceptibility candidate 2 (AUTS2) gene is associated with various neurological disorders, including autism and brain malformation. AUTS2 is important for activation of transcription of neural specific genes, neuronal migration, and neurite outgrowth. Here, we present evidence for significant transcriptional complexity in the auts2 gene locus in the zebrafish genome, as well as in genomic loci of auts2 paralogous genes fbrsl1 and fbrs Several genes that have been implicated in ASDs are large and have multiple transcripts. Neurons are especially enriched with longer transcripts compared to nonneural cell types. The human autism susceptibility candidate 2 (AUTS2) gene is ~1.2 Mb long and is implicated in a number of neurological disorders including autism, intellectual disability, addiction, and developmental delay. Recent studies show AUTS2 to be important for activation of transcription of neural specific genes, neuronal migration, and neurite outgrowth. However, much remains to be understood regarding the transcriptional complexity and the functional roles of AUTS2 in neurodevelopment. Zebrafish provide an excellent model system for studying both these questions. We undertook genomic identification and characterization of auts2 and its paralogous genes in zebrafish. There are four auts2 family genes in zebrafish: auts2a, auts2b, fbrsl1, and fbrs The absence of complete annotation of their structures hampers functional studies. We present evidence for transcriptional complexity of these four genes mediated by alternative splicing and alternative promoter usage. Furthermore, the expression of the various paralogs is tightly regulated both spatially and developmentally. Our findings suggest that auts2 paralogs serve distinct functions in the development and functioning of target tissues. PMID- 28626004 TI - Sex Chromosome Evolution, Heterochiasmy, and Physiological QTL in the Salmonid Brook Charr Salvelinus fontinalis. AB - Whole-genome duplication (WGD) can have large impacts on genome evolution, and much remains unknown about these impacts. This includes the mechanisms of coping with a duplicated sex determination system and whether this has an impact on increasing the diversity of sex determination mechanisms. Other impacts include sexual conflict, where alleles having different optimums in each sex can result in sequestration of genes into nonrecombining sex chromosomes. Sex chromosome development itself may involve sex-specific recombination rate (i.e., heterochiasmy), which is also poorly understood. The family Salmonidae is a model system for these phenomena, having undergone autotetraploidization and subsequent rediploidization in most of the genome at the base of the lineage. The salmonid master sex determining gene is known, and many species have nonhomologous sex chromosomes, putatively due to transposition of this gene. In this study, we identify the sex chromosome of Brook Charr Salvelinus fontinalis and compare sex chromosome identities across the lineage (eight species and four genera). Although nonhomology is frequent, homologous sex chromosomes and other consistencies are present in distantly related species, indicating probable convergence on specific sex and neo-sex chromosomes. We also characterize strong heterochiasmy with 2.7-fold more crossovers in maternal than paternal haplotypes with paternal crossovers biased to chromosome ends. When considering only rediploidized chromosomes, the overall heterochiasmy trend remains, although with only 1.9-fold more recombination in the female than the male. Y chromosome crossovers are restricted to a single end of the chromosome, and this chromosome contains a large interspecific inversion, although its status between males and females remains unknown. Finally, we identify quantitative trait loci (QTL) for 21 unique growth, reproductive, and stress-related phenotypes to improve knowledge of the genetic architecture of these traits important to aquaculture and evolution. PMID- 28626005 TI - The Auxin Biosynthetic TRYPTOPHAN AMINOTRANSFERASE RELATED TaTAR2.1-3A Increases Grain Yield of Wheat. AB - Controlling the major auxin biosynthetic pathway to manipulate auxin content could be a target for genetic engineering of crops with desired traits, but little progress had been made because low or high auxin contents often cause developmental inhibition. Here, we performed a genome-wide analysis of bread wheat (Triticum aestivum) to identify the Tryptophan Aminotransferase of Arabidopsis1/Tryptophan Aminotransferase-Related (TAA1/TAR) genes that function in the tryptophan-dependent pathway of auxin biosynthesis. Sequence mining together with gene cloning identified 15 TaTAR genes, among which 12 and three genes were phylogenetically close to Arabidopsis (Arabidopsis thaliana) AtTAR2 and AtTAR3, respectively. TaTAR2.1 had the most abundant transcripts in the TaTAR2 genes and was expressed mainly in roots and up-regulated by low nitrogen (N) availability. Knockdown of TaTAR2.1 caused vegetative and reproductive deficiencies and impaired lateral root (LR) growth under both high- and low-N conditions. Overexpressing TaTAR2.1-3A in wheat enhanced LR branching, plant height, spike number, grain yield, and aerial N accumulation under different N supply levels. In addition, overexpressing TaTAR2.1-3A in Arabidopsis elevated auxin accumulation in the primary root tip, LR tip, LR primordia, and cotyledon and hypocotyl and increased primary root length, visible LR number, and shoot fresh weight under high- and low-N conditions. Our results indicate that TaTAR2.1 is critical for wheat growth and also shows potential for genetic engineering to reach the aim of improving the grain yield of wheat. PMID- 28626006 TI - AtAIRP2 E3 Ligase Affects ABA and High-Salinity Responses by Stimulating Its ATP1/SDIRIP1 Substrate Turnover. AB - AtAIRP2 is a cytosolic RING-type E3 ubiquitin ligase that positively regulates an abscisic acid (ABA) response in Arabidopsis (Arabidopsis thaliana). Yeast two hybrid screening using AtAIRP2 as bait identified ATP1 (AtAIRP2 Target Protein1) as a substrate of AtAIRP2. ATP1 was found to be identical to SDIRIP1, which was reported recently to be a negative factor in ABA signaling and a target protein of the RING E3 ligase SDIR1. Accordingly, ATP1 was renamed ATP1/SDIRIP1. A specific interaction between AtAIRP2 and ATP1/SDIRIP1 and ubiquitination of ATP1/SDIRIP1 by AtAIRP2 were demonstrated in vitro and in planta. The turnover of ATP1/SDIRIP1 was regulated by AtAIRP2 in cell-free degradation and protoplast cotransfection assays. The ABA-mediated germination assay of 35S:ATP1/SDIRIP1 RNAi/atairp2 double mutant progeny revealed that ATP1/SDIRIP1 acts downstream of AtAIRP2. AtAIRP2 and SDIR1 reciprocally complemented the ABA- and salt insensitive germination phenotypes of sdir1 and atairp2 mutants, respectively, indicating their combinatory roles in seed germination. Subcellular localization and bimolecular fluorescence complementation experiments in the presence of MG132, a 26S proteasome inhibitor, showed that AtAIRP2 and ATP1/SDIRIP1 were colocalized to the cytosolic spherical body, which lies in close proximity to the nucleus, in tobacco (Nicotiana benthamiana) leaf cells. The 26S proteasome subunits RPN12a and RPT1 and the molecular chaperones HSP70 and HSP101 were colocalized to these discrete punctae-like structures. These results raised the possibility that AtAIRP2 and ATP1/SDIRIP1 interact in the cytosolic spherical compartment. Collectively, our data suggest that the down-regulation of ATP1/SDIRIP1 by AtAIRP2 and SDIR1 RING E3 ubiquitin ligases is critical for ABA and high-salinity responses during germination in Arabidopsis. PMID- 28626007 TI - Establishment of Photosynthesis through Chloroplast Development Is Controlled by Two Distinct Regulatory Phases. AB - Chloroplasts develop from undifferentiated proplastids present in meristematic tissue. Thus, chloroplast biogenesis is closely connected to leaf development, which restricts our ability to study the process of chloroplast biogenesis per se. As a consequence, we know relatively little about the regulatory mechanisms behind the establishment of the photosynthetic reactions and how the activities of the two genomes involved are coordinated during chloroplast development. We developed a single cell-based experimental system from Arabidopsis (Arabidopsis thaliana) with high temporal resolution allowing for investigations of the transition from proplastids to functional chloroplasts. Using this unique cell line, we could show that the establishment of photosynthesis is dependent on a regulatory mechanism involving two distinct phases. The first phase is triggered by rapid light-induced changes in gene expression and the metabolome. The second phase is dependent on the activation of the chloroplast and generates massive changes in the nuclear gene expression required for the transition to photosynthetically functional chloroplasts. The second phase also is associated with a spatial transition of the chloroplasts from clusters around the nucleus to the final position at the cell cortex. Thus, the establishment of photosynthesis is a two-phase process with a clear checkpoint associated with the second regulatory phase allowing coordination of the activities of the nuclear and plastid genomes. PMID- 28626009 TI - Abdominal Aortic Calcification Among Individuals With and Without Diabetes: The Jackson Heart Study. PMID- 28626008 TI - A Dual Role for the OsK5.2 Ion Channel in Stomatal Movements and K+ Loading into Xylem Sap. AB - The roles of potassium channels from the Shaker family in stomatal movements have been investigated by reverse genetics analyses in Arabidopsis (Arabidopsis thaliana), but corresponding information is lacking outside this model species. Rice (Oryza sativa) and other cereals possess stomata that are more complex than those of Arabidopsis. We examined the role of the outward Shaker K+ channel gene OsK5.2. Expression of the OsK5.2 gene (GUS reporter strategy) was observed in the whole stomatal complex (guard cells and subsidiary cells), root vasculature, and root cortex. In stomata, loss of OsK5.2 functional expression resulted in lack of time-dependent outward potassium currents in guard cells, higher rates of water loss through transpiration, and severe slowdown of stomatal closure. In line with the expression of OsK5.2 in the plant vasculature, mutant plants displayed a reduced K+ translocation from the root system toward the leaves via the xylem. The comparison between rice and Arabidopsis show that despite the strong conservation of Shaker family in plants, substantial differences can exist between the physiological roles of seemingly orthologous genes, as xylem loading depends on SKOR and stomatal closure on GORK in Arabidopsis, whereas both functions are executed by the single OsK5.2 Shaker in rice. PMID- 28626010 TI - Hyperglycemia Is the Main Mediator of Prediabetes- and Type 2 Diabetes-Associated Impairment of Microvascular Function: The Maastricht Study. PMID- 28626011 TI - Effects of Ventral Striatum Lesions on Stimulus-Based versus Action-Based Reinforcement Learning. AB - Learning the values of actions versus stimuli may depend on separable neural circuits. In the current study, we evaluated the performance of rhesus macaques with ventral striatum (VS) lesions on a two-arm bandit task that had randomly interleaved blocks of stimulus-based and action-based reinforcement learning (RL). Compared with controls, monkeys with VS lesions had deficits in learning to select rewarding images but not rewarding actions. We used a RL model to quantify learning and choice consistency and found that, in stimulus-based RL, the VS lesion monkeys were more influenced by negative feedback and had lower choice consistency than controls. Using a Bayesian model to parse the groups' learning strategies, we also found that VS lesion monkeys defaulted to an action-based choice strategy. Therefore, the VS is involved specifically in learning the value of stimuli, not actions.SIGNIFICANCE STATEMENT Reinforcement learning models of the ventral striatum (VS) often assume that it maintains an estimate of state value. This suggests that it plays a general role in learning whether rewards are assigned based on a chosen action or stimulus. In the present experiment, we examined the effects of VS lesions on monkeys' ability to learn that choosing a particular action or stimulus was more likely to lead to reward. We found that VS lesions caused a specific deficit in the monkeys' ability to discriminate between images with different values, whereas their ability to discriminate between actions with different values remained intact. Our results therefore suggest that the VS plays a specific role in learning to select rewarded stimuli. PMID- 28626012 TI - Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of the Locus Ceruleus in Humans. AB - State-dependent activity of locus ceruleus (LC) neurons has long suggested a role for noradrenergic modulation of arousal. However, in vivo insights into noradrenergic arousal circuitry have been constrained by the fundamental inaccessibility of the human brain for invasive studies. Functional magnetic resonance imaging (fMRI) studies performed during site-specific pharmacological manipulations of arousal levels may be used to study brain arousal circuitry. Dexmedetomidine is an anesthetic that alters the level of arousal by selectively targeting alpha2 adrenergic receptors on LC neurons, resulting in reduced firing rate and norepinephrine release. Thus, we hypothesized that dexmedetomidine induced altered arousal would manifest with reduced functional connectivity between the LC and key brain regions involved in the regulation of arousal. To test this hypothesis, we acquired resting-state fMRI data in right-handed healthy volunteers 18-36 years of age (n = 15, 6 males) at baseline, during dexmedetomidine-induced altered arousal, and recovery states. As previously reported, seed-based resting-state fMRI analyses revealed that the LC was functionally connected to a broad network of regions including the reticular formation, basal ganglia, thalamus, posterior cingulate cortex (PCC), precuneus, and cerebellum. Functional connectivity of the LC to only a subset of these regions (PCC, thalamus, and caudate nucleus) covaried with the level of arousal. Functional connectivity of the PCC to the ventral tegmental area/pontine reticular formation and thalamus, in addition to the LC, also covaried with the level of arousal. We propose a framework in which the LC, PCC, thalamus, and basal ganglia comprise a functional arousal circuitry.SIGNIFICANCE STATEMENT Electrophysiological studies of locus ceruleus (LC) neurons have long suggested a role for noradrenergic mechanisms in mediating arousal. However, the fundamental inaccessibility of the human brain for invasive studies has limited a precise understanding of putative brain regions that integrate with the LC to regulate arousal. Our results suggest that the PCC, thalamus, and basal ganglia are key components of a LC-noradrenergic arousal circuit. PMID- 28626013 TI - Sleep Disrupts High-Level Speech Parsing Despite Significant Basic Auditory Processing. AB - The extent to which the sleeping brain processes sensory information remains unclear. This is particularly true for continuous and complex stimuli such as speech, in which information is organized into hierarchically embedded structures. Recently, novel metrics for assessing the neural representation of continuous speech have been developed using noninvasive brain recordings that have thus far only been tested during wakefulness. Here we investigated, for the first time, the sleeping brain's capacity to process continuous speech at different hierarchical levels using a newly developed Concurrent Hierarchical Tracking (CHT) approach that allows monitoring the neural representation and processing-depth of continuous speech online. Speech sequences were compiled with syllables, words, phrases, and sentences occurring at fixed time intervals such that different linguistic levels correspond to distinct frequencies. This enabled us to distinguish their neural signatures in brain activity. We compared the neural tracking of intelligible versus unintelligible (scrambled and foreign) speech across states of wakefulness and sleep using high-density EEG in humans. We found that neural tracking of stimulus acoustics was comparable across wakefulness and sleep and similar across all conditions regardless of speech intelligibility. In contrast, neural tracking of higher-order linguistic constructs (words, phrases, and sentences) was only observed for intelligible speech during wakefulness and could not be detected at all during nonrapid eye movement or rapid eye movement sleep. These results suggest that, whereas low level auditory processing is relatively preserved during sleep, higher-level hierarchical linguistic parsing is severely disrupted, thereby revealing the capacity and limits of language processing during sleep.SIGNIFICANCE STATEMENT Despite the persistence of some sensory processing during sleep, it is unclear whether high-level cognitive processes such as speech parsing are also preserved. We used a novel approach for studying the depth of speech processing across wakefulness and sleep while tracking neuronal activity with EEG. We found that responses to the auditory sound stream remained intact; however, the sleeping brain did not show signs of hierarchical parsing of the continuous stream of syllables into words, phrases, and sentences. The results suggest that sleep imposes a functional barrier between basic sensory processing and high-level cognitive processing. This paradigm also holds promise for studying residual cognitive abilities in a wide array of unresponsive states. PMID- 28626014 TI - BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis. AB - Mutations in amyloid beta precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, beta-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp1 site to generate C99 for amyloid beta protein (Abeta) production, and predominantly at major Glu11 site to generate C89, resulting in truncated Abeta production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential beta-cleavage site of BACE1 in APP from the Glu11 site to the Asp1 site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited gamma-secretase cleavage of the mutant C99 to generate Abeta, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.SIGNIFICANCE STATEMENT beta-site APP cleaving enzyme 1 (BACE1) is essential for amyloid beta protein production. We discovered that A673V mutation shifted the BACE1 cleavage site from the Glu11 to the Asp1 site, resulting in much higher C99 level and C99/C89 ratio. All other mutations at this site of amyloid beta precursor protein (APP) reduced C99 generation and decreased the C99/C89 ratio. Furthermore, A673V mutation resulted in stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited gamma-secretase cleavage of the mutant C99 to generate amyloid beta protein, leading to recessively inherited Alzheimer's disease (AD). The results demonstrate that APP673 regulates APP processing, and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development. PMID- 28626015 TI - Reciprocal Interaction of Dendrite Geometry and Nuclear Calcium-VEGFD Signaling Gates Memory Consolidation and Extinction. AB - Nuclear calcium is an important signaling end point in synaptic excitation transcription coupling that is critical for long-term neuroadaptations. Here, we show that nuclear calcium acting via a target gene, VEGFD, is required for hippocampus-dependent fear memory consolidation and extinction in mice. Nuclear calcium-VEGFD signaling upholds the structural integrity and complexity of the dendritic arbor of CA1 neurons that renders those cells permissive for the efficient generation of synaptic input-evoked nuclear calcium transients driving the expression of plasticity-related genes. Therefore, the gating of memory functions rests on the reciprocally reinforcing maintenance of an intact dendrite geometry and a functional synapse-to-nucleus communication axis. In psychiatric and neurodegenerative disorders, therapeutic application of VEGFD may help to stabilize dendritic structures and network connectivity, which may prevent cognitive decline and could boost the efficacy of extinction-based exposure therapies.SIGNIFICANCE STATEMENT This study uncovers a reciprocal relationship between dendrite geometry, the ability to generate nuclear calcium transients in response to synaptic inputs, and the subsequent induction of expression of plasticity-related and dendritic structure-preserving genes. Insufficient nuclear calcium signaling in CA1 hippocampal neurons and, consequently, reduced expression of the nuclear calcium target gene VEGFD, a dendrite maintenance factor, leads to reduced-complexity basal dendrites of CA1 neurons, which severely compromises the animals' consolidation of both memory and extinction memory. The structure-protective function of VEGFD may prove beneficial in psychiatric disorders as well as neurodegenerative and aging-related conditions that are associated with loss of neuronal structures, dysfunctional excitation transcription coupling, and cognitive decline. PMID- 28626016 TI - The mTOR Substrate S6 Kinase 1 (S6K1) Is a Negative Regulator of Axon Regeneration and a Potential Drug Target for Central Nervous System Injury. AB - The mammalian target of rapamycin (mTOR) positively regulates axon growth in the mammalian central nervous system (CNS). Although axon regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion of PTEN, a negative regulator of mTOR, increases mTOR activity and induces robust axon growth and regeneration. It has been suggested that inhibition of S6 kinase 1 (S6K1, gene symbol: RPS6KB1), a prominent mTOR target, would blunt mTOR's positive effect on axon growth. In contrast to this expectation, we demonstrate that inhibition of S6K1 in CNS neurons promotes neurite outgrowth in vitro by twofold to threefold. Biochemical analysis revealed that an mTOR-dependent induction of PI3K signaling is involved in mediating this effect of S6K1 inhibition. Importantly, treating female mice in vivo with PF-4708671, a selective S6K1 inhibitor, stimulated corticospinal tract regeneration across a dorsal spinal hemisection between the cervical 5 and 6 cord segments (C5/C6), increasing axon counts for at least 3 mm beyond the injury site at 8 weeks after injury. Concomitantly, treatment with PF-4708671 produced significant locomotor recovery. Pharmacological targeting of S6K1 may therefore constitute an attractive strategy for promoting axon regeneration following CNS injury, especially given that S6K1 inhibitors are being assessed in clinical trials for nononcological indications.SIGNIFICANCE STATEMENT Despite mTOR's well-established function in promoting axon regeneration, the role of its downstream target, S6 kinase 1 (S6K1), has been unclear. We used cellular assays with primary neurons to demonstrate that S6K1 is a negative regulator of neurite outgrowth, and a spinal cord injury model to show that it is a viable pharmacological target for inducing axon regeneration. We provide mechanistic evidence that S6K1's negative feedback to PI3K signaling is involved in axon growth inhibition, and show that phosphorylation of S6K1 is a more appropriate regeneration indicator than is S6 phosphorylation. PMID- 28626017 TI - Amyloid-beta Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory. AB - High levels of amyloid-beta peptide (Abeta) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Abeta are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Abeta levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Abeta due to a change in the approximation of amyloid precursor protein (APP) and the beta-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Abeta function, by using anti-murine Abeta antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Abeta levels in the healthy brain which, in turn, boosts synaptic plasticity and memory.SIGNIFICANCE STATEMENT Amyloid-beta (Abeta) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Abeta, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Abeta levels and function during LTP. We show that cGMP enhances Abeta production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Abeta, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Abeta. PMID- 28626018 TI - Dissecting the Function of Hippocampal Oscillations in a Human Anxiety Model. AB - Neural oscillations in hippocampus and medial prefrontal cortex (mPFC) are a hallmark of rodent anxiety models that build on conflict between approach and avoidance. Yet, the function of these oscillations, and their expression in humans, remain elusive. Here, we used magnetoencephalography (MEG) to investigate neural oscillations in a task that simulated approach-avoidance conflict, wherein 23 male and female human participants collected monetary tokens under a threat of virtual predation. Probability of threat was signaled by color and learned beforehand by direct experience. Magnitude of threat corresponded to a possible monetary loss, signaled as a quantity. We focused our analyses on an a priori defined region-of-interest, the bilateral hippocampus. Oscillatory power under conflict was linearly predicted by threat probability in a location consistent with right mid-hippocampus. This pattern was specific to the hippocampus, most pronounced in the gamma band, and not explained by spatial movement or anxiety like behavior. Gamma power was modulated by slower theta rhythms, and this theta modulation increased with threat probability. Furthermore, theta oscillations in the same location showed greater synchrony with mPFC theta with increased threat probability. Strikingly, these findings were not seen in relation to an increase in threat magnitude, which was explicitly signaled as a quantity and induced similar behavioral responses as learned threat probability. Thus, our findings suggest that the expression of hippocampal and mPFC oscillatory activity in the context of anxiety is specifically linked to threat memory. These findings resonate with neurocomputational accounts of the role played by hippocampal oscillations in memory.SIGNIFICANCE STATEMENT We use a biologically relevant approach-avoidance conflict test in humans while recording neural oscillations with magnetoencephalography to investigate the expression and function of hippocampal oscillations in human anxiety. Extending nonhuman studies, we can assign a possible function to hippocampal oscillations in this task, namely threat memory communication. This blends into recent attempts to elucidate the role of brain synchronization in defensive responses to threat. PMID- 28626019 TI - Neural Mechanisms of Updating under Reducible and Irreducible Uncertainty. AB - Adaptive decision making depends on an agent's ability to use environmental signals to reduce uncertainty. However, because of multiple types of uncertainty, agents must take into account not only the extent to which signals violate prior expectations but also whether uncertainty can be reduced in the first place. Here we studied how human brains of both sexes respond to signals under conditions of reducible and irreducible uncertainty. We show behaviorally that subjects' value updating was sensitive to the reducibility of uncertainty, and could be quantitatively characterized by a Bayesian model where agents ignore expectancy violations that do not update beliefs or values. Using fMRI, we found that neural processes underlying belief and value updating were separable from responses to expectancy violation, and that reducibility of uncertainty in value modulated connections from belief-updating regions to value-updating regions. Together, these results provide insights into how agents use knowledge about uncertainty to make better decisions while ignoring mere expectancy violation.SIGNIFICANCE STATEMENT To make good decisions, a person must observe the environment carefully, and use these observations to reduce uncertainty about consequences of actions. Importantly, uncertainty should not be reduced purely based on how surprising the observations are, particularly because in some cases uncertainty is not reducible. Here we show that the human brain indeed reduces uncertainty adaptively by taking into account the nature of uncertainty and ignoring mere surprise. Behaviorally, we show that human subjects reduce uncertainty in a quasioptimal Bayesian manner. Using fMRI, we characterize brain regions that may be involved in uncertainty reduction, as well as the network they constitute, and dissociate them from brain regions that respond to mere surprise. PMID- 28626020 TI - Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo controlled RCT. AB - OBJECTIVES: Data suggest a potential role for vitamin D in autism spectrum disorder (ASD). We wanted to assess the effect of vitamin D3 supplementation compared with placebo in children with ASD. DESIGN: This was a double-blind, randomised, placebo-controlled trial. SETTING: A paediatric outpatient centre at high latitude over the winter season in Dublin, Ireland (53 degrees N). PATIENTS: 42 children with ASD. INTERVENTIONS: 2000 IU vitamin D3 supplementation or placebo daily for 20 weeks. MAIN OUTCOME MEASURES: Assessments were completed at baseline and after 20 weeks of supplementation. The primary outcome was the stereotypic behaviour subscale from the Aberrant Behaviour Checklist (ABC). Secondary exploratory outcomes included additional subscales from the ABC, the Social Responsiveness Scale and rating on the Developmental Disabilities Children's Global Assessment Scale (DD-CGAS) as well as biochemical parameters of total vitamin D status (25-hydroxyvitamin D (25(OH)D)), immunity and systemic inflammation. RESULTS: 38 children completed the trial. Baseline 25(OH)D was 54.2+/-19.7 nmol/L. Following vitamin D3 supplementation, there was a significant increase in 25(OH)D to 83.8 nmol/L (p=0.0016) but no effect on the primary endpoint. However, there was an improvement in self-care on DD-CGAS (p=0.02). In contrast, there was also a trend toward decreased inappropriate speech in the placebo group (p=0.08). CONCLUSION: Vitamin D supplementation had no effect on the primary outcome with limited and inconsistent effects in children with ASD. Considering the other promising data as well as the relative safety and cheapness of vitamin D supplementation, further trials are warranted. TRIAL REGISTRATION: NCT02508922. PMID- 28626021 TI - Acute segmental poliomyelitis-like flaccid paralysis in an adult in the UK, associated with enterovirus D68. AB - Enterovirus D68 has been associated with a poliomyelitis-like illness, notably during an outbreak in 2014, and particularly affecting children in the USA. We report a case of acute segmental flaccid paralysis with respiratory involvement in an adult in the UK, with enterovirus D68 detected in a sputum sample. MR imaging of cervical spinal cord showed a longitudinally extensive T2 hyperintensity in the anterior cord. Cerebrospinal fluid showed an elevated white cell count, predominantly lymphocytic, with otherwise normal constituents and negative viral PCRs. His respiratory function improved after intravenous immunoglobulin, suggesting that this may be useful in such cases. Clinicians should consider enterovirus D68 infection in the differential diagnosis of Guillain-Barre syndrome, particularly the pharyngeal-cervical-brachial variant. PMID- 28626022 TI - Apraxia: another view. PMID- 28626024 TI - Intersectin 2 controls actin cap formation and meiotic division in mouse oocytes through the Cdc42 pathway. AB - Intersectins (ITSNs), an evolutionarily conserved adaptor protein family, have been implicated in multiple biologic processes; however, their functions in mammalian oocytes have not been addressed. Here, we report delayed meiotic resumption and defective cytokinesis upon specific depletion of ITSN2 in mouse oocytes. In particular, abnormal spindle, misaligned chromosomes, and loss of cortical actin cap are readily observed in ITSN2-depleted oocytes. Similarly, a small molecule that targets the Cdc42-ITSN interaction also disrupts oocyte maturation and actin polymerization. Moreover, we find that ITSN2 depletion reduces the activity of Cdc42 in oocytes and, of note, that forced expression of the dominant-positive mutant of Cdc42, in part, prevents the effects of ITSN2 knockdown on actin cap formation. In addition, the localization of WASP and Arp2, the downstream effector proteins of Cdc42, is altered in ITSN2-depleted oocytes accordingly. In summary, our data support a model in which ITSN2 depletion induces the inactivation of Cdc42, which, in turn, influences the distribution and function of Arp2/3 and WASP, consequently disrupting oocyte polarity establishment and meiotic division.-Zhang, J., Ma, R., Li, L., Wang, L., Hou, X., Han, L., Ge, J., Li, M., Wang, Q. Intersectin 2 controls actin cap formation and meiotic division in mouse oocytes through the Cdc42 pathway. PMID- 28626023 TI - Microarray analysis of aging-associated immune system alterations in the rostral ventrolateral medulla of F344 rats. AB - The rostral ventrolateral medulla (RVLM) is an area of the brain stem that contains diverse neural substrates that are involved in systems critical for physiological function. There is evidence that aging affects some neural substrates within the RVLM, although age-related changes in RVLM molecular mechanisms are not well established. The goal of the present study was to characterize the transcriptomic profile of the aging RVLM and to test the hypothesis that aging is associated with altered gene expression in the RVLM, with an emphasis on immune system associated gene transcripts. RVLM tissue punches from young, middle-aged, and aged F344 rats were analyzed with Agilent's whole rat genome microarray. The RVLM gene expression profile varied with age, and an association between chronological age and specific RVLM gene expression patterns was observed [P < 0.05, false discovery rate (FDR) < 0.3]. Functional analysis of RVLM microarray data via gene ontology profiling and pathway analysis identified upregulation of genes associated with immune- and stress-related responses and downregulation of genes associated with lipid biosynthesis and neurotransmission in aged compared with middle-aged and young rats. Differentially expressed genes associated with the complement system and microglial cells were further validated by quantitative PCR with separate RVLM samples (P < 0.05, FDR < 0.1). The present results have identified age-related changes in the transcriptomic profile of the RVLM, modifications that may provide the molecular backdrop for understanding age-dependent changes in physiological regulation. PMID- 28626025 TI - Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease. AB - Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed the in vivo efficacy of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) on AWR in a murine model of chronic allergic airways disease (AAD)/asthma. Female Balb/c mice were subjected to a 9-wk model of ovalbumin (Ova)-induced chronic AAD and treated intravenously or intranasally with MCA-MSCs from weeks 9 to 11. Changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were assessed. Ova-injured mice presented with AI, goblet cell metaplasia, epithelial thickening, increased airway TGF-beta1 levels, subepithelial myofibroblast and collagen accumulation, total lung collagen concentration, and AHR (all P < 0.001 vs. uninjured control group). Apart from epithelial thickness, all other parameters measured were significantly, although not totally, decreased by intravenous delivery of MCA MSCs to Ova-injured mice. In comparison, intranasal delivery of MCA-MSCs to Ova injured mice significantly decreased all parameters measured (all P < 0.05 vs. Ova group) and, most notably, normalized aberrant airway TGF-beta1 levels, airway/lung fibrosis, and AHR to values measured in uninjured animals. MCA-MSCs also increased collagen-degrading gelatinase levels. Hence, direct delivery of MCA-MSCs offers great therapeutic benefit for the AWR and AHR associated with chronic AAD.-Royce, S. G., Rele, S., Broughton, B. R. S., Kelly, K., Samuel, C. S. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease. PMID- 28626026 TI - Protein kinase Cbeta activates fat mass and obesity-associated protein by influencing its ubiquitin/proteasome degradation. AB - Protein kinase Cbeta (PKCbeta) is a serine-threonine kinase associated with obesity and diabetic complications; its activation contributes to weight gain, and deletion of its gene results in resistance to genetic- and diet-induced obesity. Fat mass and obesity-associated (FTO) protein is a recently identified RNA demethylase, and its overexpression in mice leads to increased body weight as well as fat mass. Although sharing some features in anabolism regulation, PKCbeta and FTO have not been investigated together; therefore, their relationship has not been established. We report that PKCbeta positively regulates FTO on the posttranslation level, evidenced by the facts that PKCbeta activation contributes to high-glucose-induced FTO up-regulation, and overexpression of PKCbeta suppresses ubiquitin-proteasome degradation of FTO, whereas PKCbeta inactivation acts in the opposite manner. It was also found that PKCbeta can phosphorylate FTO on threonine, and this phosphorylation requires both catalytic and regulatory domains of PKCbeta. Moreover, PKCbeta inhibition can suppress 3T3-L1 cell differentiation in normal and FTO-overexpressing cells but not in FTO-silenced or -inhibited cells. We propose that PKCbeta acts to suppress the degradation of FTO protein and reveals the associated role of PKCbeta and FTO in adipogenesis, suggesting a new pathway that affects the development of obesity and metabolic diseases.-Tai, H., Wang, X., Zhou, J., Han, X., Fang, T., Gong, H., Huang, N., Chen, H., Qin, J., Yang, M., Wei, X., Yang, L., Xiao, H. Protein kinase Cbeta activates fat mass and obesity-associated protein by influencing its ubiquitin/proteasome degradation. PMID- 28626027 TI - Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis. AB - Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of diabetic nephropathy and renal fibrosis; however, the causative role of sustained EGFR activation is unclear. Here, we generated a novel kidney fibrotic mouse model of persistent EGFR activation by selectively expressing the EGFR ligand, human heparin-binding EGF-like growth factor (hHB-EGF), in renal proximal tubule epithelium. hHB-EGF expression increased tyrosine kinase phosphorylation of EGFR and the subsequent activation of downstream signaling pathways, including ERK and AKT, as well as the profibrotic TGF-beta1/SMAD pathway. Epithelial specific activation of EGFR was sufficient to promote spontaneous and progressive renal tubulointerstitial fibrosis, as characterized by increased collagen deposition, immune cell infiltration, and alpha-smooth muscle actin (alpha-SMA) positive myofibroblasts. Tubule-specific EGFR activation promoted epithelial dedifferentiation and cell-cycle arrest. Furthermore, EGFR activation in epithelial cells promoted the proliferation of alpha-SMA+ myofibroblasts in a paracrine manner. Genetic or pharmacologic inhibition of EGFR tyrosine kinase activity or downstream MEK activity attenuated the fibrotic phenotype. This study provides definitive evidence that sustained activation of EGFR in proximal epithelia is sufficient to cause spontaneous, progressive renal tubulointerstitial fibrosis, evident by epithelial dedifferentiation, increased myofibroblasts, immune cell infiltration, and increased matrix deposition. Overstreet, J. M., Wang, Y., Wang, X., Niu, A., Gewin, L. S., Yao, B., Harris, R. C., Zhang, M.-Z. Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis. PMID- 28626028 TI - Excess centrosomes induce p53-dependent senescence without DNA damage in endothelial cells. AB - Tumor blood vessels support tumor growth and progression. Centrosomes are microtubule organization centers in cells, and often up to 30% of tumor endothelial cells (ECs) acquire excess (>2) centrosomes. Although excess centrosomes can lead to aneuploidy and chromosome instability in tumor cells, how untransformed ECs respond to excess centrosomes is poorly understood. We found that the frequency of primary human ECs with excess centrosomes was quickly reduced in a p53-dependent manner. Excess centrosomes in ECs were associated with p53 phosphorylation at Ser33, increased p21 levels, and decreased cell proliferation and expression of senescence markers, but independent of DNA damage and apoptosis. Aspects of the senescence-associated phenotype were also observed in mouse ECs that were isolated from tumors with excess centrosomes. Primary ECs with excess centrosomes in vascular sprouts also had elevated Ser33 p53 phosphorylation and expressed senescence markers. Our work demonstrates that nontransformed ECs respond differently to excess centrosomes than do most tumor cells-they undergo senescence in vascular sprouts and vessels, which suggests that pathologic outcomes of centrosome overduplication depend on the transformation status of cells.-Yu, Z., Ruter, D. L., Kushner, E. J., Bautch, V. L. Excess centrosomes induce p53-dependent senescence without DNA damage in endothelial cells. PMID- 28626029 TI - A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features. AB - BACKGROUND: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain. OBJECTIVE: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families. METHODS: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease. RESULTS: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold. CONCLUSION: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function. PMID- 28626030 TI - Gender, race and the presentation of acute coronary syndrome and serious cardiopulmonary diagnoses in ED patients with chest pain. AB - OBJECTIVE: To assess the relationship between reported chest pain symptoms and a diagnosis of acute coronary syndrome (ACS) and serious cardiopulmonary diagnoses (SCPD) in black males, white males, black females and white females. METHODS: This was a secondary analysis of a prospective cohort study of 4162 ED patients with chest pain enrolled between 1999 and 2008. We used logistic regression, adjusting for age and cardiovascular comorbidities to test the association between 24 chest pain symptoms and 30-day ACS for the primary outcome and SCPD as the secondary outcome. RESULT: In black males, diaphoresis was associated with ACS (OR 1.47; 95% CI 1.02 to 2.13), while in white males, left arm radiation, pressure/tightness and substernal pain were associated with ACS (OR 1.73, 95% CI 1.16 to 2.59; OR 1.65, 95% CI 1.16 to 2.59; OR 1.51, 95% CI 1.07 to 2.11, respectively). In black females, diaphoresis, palpitations and left arm radiation were associated with ACS (OR 1.66, 95% CI 1.17 to 2.35; 1.66, 95% CI 1.13 to 2.45; 1.44, 95% CI 1.02 to 2.03, respectively) while pleuritic pain, and left anterior chest pain lowered ACS risk (OR 0.69, 95% CI 0.5 to 0.96; 0.54, 95% CI 0.35 to 0.84). No symptoms predicted ACS or SCPD in white females. Fewer but similar symptoms predicted SCPD in white males and black females. No symptoms predicted SCPD in black males. CONCLUSION: Chest pain symptoms are important predictors of ACS and SCPD in certain combinations of race and gender but less so in others. These differences might explain difficulties using symptoms to identify patients at higher or lower risk of ACS and SCPD in practice. PMID- 28626036 TI - Treating ER+ Breast Cancer with CDK4/6 Inhibitors. AB - Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment. PMID- 28626038 TI - Phenology of perennial, native grass, belowground axillary buds in the northern mixed-grass prairie. AB - PREMISE OF THE STUDY: Vegetative reproduction from belowground bud banks is the primary driver of grassland systems. Despite the importance of bud banks, the timing of recruitment and the crucial link between formation and maintenance is unknown. METHODS: We assessed patterns of belowground bud development, dormancy, and mortality associated with three perennial native grasses in the northern Great Plains. Temperature and soil moisture were measured below the soil surface to determine relationships with belowground bud development. KEY RESULTS: Blue grama (Bouteloua gracilis) generated more buds over winter that remained dormant; whereas, C3 species needle-and-thread (Hesperostipa comata) and western wheatgrass (Pascopyrum smithii), maintained limited dormant buds throughout winter. Soil temperature was a good predictor for C4 species bud production; whereas, soil moisture was a reliable predictor for C3 buds. Distinct differences existed between C4 species blue grama and C3 species needle-and-thread, whereas C3 species western wheatgrass (Pascopyrum smithii) was intermediate, indicating there is likely a species-specific continuum between the C3 and C4 extremes rather than a stark difference. CONCLUSIONS: The ability to predict belowground bud development is a novel insight to native perennial grasses. Native grass species' strategies and adaptability regarding belowground bud bank size and bud phenology are important factors optimizing tiller recruitment given the variable growing conditions. Patterns of bud dormancy and development will provide insight to the underlying mechanisms by which management practices and fluctuations in precipitation amount and growing season length can alter mixed-grass prairie plant community dynamics. PMID- 28626037 TI - Autopolyploidization, geographic origin, and metabolome evolution in Arabidopsis thaliana. AB - PREMISE OF THE STUDY: Autopolyploidy, or whole-genome duplication, is a recurrent phenomenon in plant evolution. Its existence can be inferred from the presence of massive levels of genetic redundancy revealed by comparative plant phylogenomics. Whole-genome duplication is theoretically associated with evolutionary novelties such as the development of new metabolic reactions and therefore contributes to the evolution of new plant metabolic profiles. However, very little is yet known about the impact of autopolyploidy on the metabolism of recently formed autopolyploids. This study provides a better understanding of the relevance of this evolutionary process. METHODS: In this study, we compared the metabolic profiles of wild diploids, wild autotetraploids, and artificial autotetraploids of Arabidopsis thaliana using targeted ultra-high performance liquid chromatography-triple quadrupole- mass spectrometry (UPLC-QqQ-MS) metabolomics. KEY RESULTS: We found that wild and artificial A. thaliana autotetraploids display different metabolic profiles. Furthermore, wild autotetraploids display unique metabolic profiles associated with their geographic origin. CONCLUSIONS: Autopolyploidy might help plants adapt to challenging environmental conditions by allowing the evolution of novel metabolic profiles not present in the parental diploids. We elaborate on the causes and consequences leading to these distinct profiles. PMID- 28626039 TI - The role of idioblasts in leaf water relations of tropical Rhododendron. AB - PREMISE OF THE STUDY: Although much is known about the anatomy of idioblasts, the relationship of leaf idioblasts to leaf physiology is poorly known. Our goal was to understand the relationship between idioblast abundance and leaf water relations. Tropical epiphytic and shrub Rhododendron species were the model system. METHODS: Leaf succulence and idioblast metrics of 61 plants representing 17 species were compared with stomatal and water relation metrics. Correlation, ANOVA, and regression were used to understand which water relation traits were best aligned with the proportion of the leaf occupied by idioblasts for epiphytic and shrub species. KEY RESULTS: Idioblast volume per leaf area varied from 1.4 9.5 mm3.cm-2 among accessions, and an index of stomatal area per leaf area varied from 0.08-3.3. Succulence, stomatal, and water relation metrics varied significantly among species. Total idioblast volume was negatively correlated with leaf succulence metrics, and positively correlated with relative water content at the turgor loss point. Idioblasts were better related to capacitance in thin leaves. All idioblast metrics were significantly greater in epiphytic species. CONCLUSIONS: Leaf idioblasts can have a significant effect on leaf lamina water relations. Idioblasts likely function as a water buffering system for thin leaves in tropical Rhododendron species. The association of idioblast prominence with leaf water buffering is greatest for epiphytic species with thin leaves. Thus, the proliferation of leaf idioblasts may have been an important innovation for Rhododendron species diversification into tropical epiphytic habitats. PMID- 28626040 TI - Pollinia transfer on moth legs in Hoya carnosa (Apocynaceae). AB - PREMISE OF THE STUDY: The genus Hoya (Apocynaceae; Asclepiadoideae) is characterized by a set of complex floral characters unique among the asclepiads, but their role in pollination is poorly understood. Here, we report a new mechanism of asclepiad pollination in the wax plant Hoya carnosa: the pollinaria are transferred on the legs of medium or large settling moths. METHODS: Floral visitors and their behavior were observed on Amami-Oshima Island during 2013 2015, and the efficacy of different pollinators was determined by counting the pollinarium loads on different flower visitors. The floral characters were studied to establish the process of pollination in relation to pollinator behavior on the flower. KEY RESULTS: Hoya carnosa was visited by various settling moths at night, but pollinia attachment was confirmed predominantly on the legs of the large moth Erebus ephesperis (Noctuidae) and less frequently on the legs of the medium-sized moths Bastilla arcuata (Crambidae) and Cleora injectaria (Geometridae). The moths walked around and searched for nectar on the inflorescence, and the corpusculum became clipped to the arolia (adhesive pads on moth tarsi) as they stepped on the pollinaria between the staminal corona. The downward spherical inflorescence of aggregated flowers with flat, velvety petals and a slippery corona provides restricted footholds for the visitors, which efficiently leads pollinator legs to the pollinaria. CONCLUSIONS: Although the pollination system of Hoya is largely unknown, pollination by insect legs may be a major pollination system in this genus because these basic floral characters are shared among many species. PMID- 28626041 TI - Reply to Yang et al.: Coastal wetlands are not well represented by protected areas for endangered birds. PMID- 28626042 TI - Protect coastal wetlands in China to save endangered migratory birds. PMID- 28626044 TI - Revascularisation compared with initial medical therapy for non-ST-elevation acute coronary syndromes in the elderly: a meta-analysis. AB - OBJECTIVE: Whether revascularisation is superior to medical therapy in older populations presenting with non-ST-elevation acute coronary syndromes (NSTEACS) remains contentious, with inconclusive evidence from randomised trials. We aimed to compare routine invasive therapy with initial medical management in the elderly presenting with NSTEACS. METHODS: MEDLINE, EMBASE and Cochrane Controlled Trial Register were searched for studies comparing routine invasive therapy with initial medical management in patients >=75 years old presenting with NSTEACS. Endpoints included long-term mortality, myocardial infarction (MI), revascularisation, rehospitalisation, stroke and major bleeding reported as ORs. RESULTS: Four randomised trials and three observational studies met inclusion criteria, enrolling a total of 20 540 patients followed up from 6 months to 5 years. Routine invasive therapy reduced mortality (OR 0.67, CI 0.61 to 0.74), MI (OR 0.56, CI 0.45 to 0.70) and stroke (OR 0.53, CI 0.30 to 0.95). Analyses restricted to randomised controlled trials (RCTs) confirmed a reduction in MI (OR 0.51, CI 0.40 to 0.66), revascularisation (OR 0.27, CI 0.13 to 0.56) and a trend to reduced mortality (OR 0.84, CI 0.66 to 1.06) at the expense of major bleeding (OR 2.19, CI 1.12 to 4.28). Differences in major bleeding were unapparent in more recent studies. CONCLUSION: Routine invasive therapy reduces MI and repeat revascularisation and may reduce mortality at the expense of major bleeding in elderly patients with NSTEACS. Our findings highlight the need for further RCTs to better determine the effect on mortality and contemporary bleeding risk. PMID- 28626045 TI - Care Innovations: Sharing Practical Care Delivery Tools and Discoveries. PMID- 28626046 TI - Perpetual change: autophagy, the endothelium, and response to vascular injury. AB - Current studies of vascular health, aging, and autophagy emphasize how the endothelium adapts to stress and contributes to disease. The endothelium is far from an inert barrier to blood-borne cells, pathogens, and chemical signals; rather, it actively translates circulating mediators into tissue responses, changing rapidly in response to physiologic stressors. Macroautophagy-the cellular ingestion of effete organelles and protein aggregates to provide anabolic substrates to fuel bioenergetics in times of stress-plays an important role in endothelial cell homeostasis, vascular remodeling, and disease. These roles include regulating vascular tone, sustaining or limiting cell survival, and contributing to the development of atherosclerosis secondary to infection, inflammation, and angiogenesis. Autophagy modulates these critical functions of the endothelium in a dynamic and perpetual response to tissue and intravascular cues. PMID- 28626047 TI - With a Little Help From My Friends: Seeking Consistent and Persuasive Evidence. PMID- 28626048 TI - Contributors to the Excess Stroke Mortality in Rural Areas in the United States. AB - BACKGROUND AND PURPOSE: Stroke mortality is 30% higher in the rural United States. This could be because of either higher incidence or higher case fatality from stroke in rural areas. METHODS: The urban-rural status of 23 280 stroke-free participants recruited between 2003 and 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) was classified using the Rural-Urban Commuting Area scheme as residing in urban, large rural town/city, or small rural town or isolated areas. The risk of incident stroke was assessed using proportional hazards analysis, and case fatality (death within 30 days of stroke) was assessed using logistic regression. Models were adjusted for demographics, traditional stroke risk factors, and measures of socioeconomic status. RESULTS: After adjustment for demographic factors and relative to urban areas, stroke incidence was 1.23-times higher (95% confidence intervals, 1.01-1.51) in large rural town/cities and 1.30-times higher (95% confidence intervals, 1.03-1.62) in small rural towns or isolated areas. Adjustment for risk factors and socioeconomic status only modestly attenuated this association, and the association became marginally nonsignificant (P=0.071). There was no association of rural-urban status with case fatality (P>0.47). CONCLUSIONS: The higher stroke mortality in rural regions seemed to be attributable to higher stroke incidence rather than case fatality. A higher prevalence of risk factors and lower socioeconomic status only modestly contributed to the increased risk of incident stroke risk in rural areas. There was no evidence of higher case fatality in rural areas. PMID- 28626049 TI - Dose-Dependent Effect of Statin Pretreatment on Preventing the Periprocedural Complications of Carotid Artery Stenting. AB - BACKGROUND AND PURPOSE: We investigated whether statin pretreatment can dose dependently reduce periprocedural complications in patients undergoing carotid artery stenting because of symptomatic carotid artery stenosis. METHODS: We enrolled a consecutive series of 397 symptomatic carotid artery stenosis (>=50% stenosis on conventional angiography) treated with carotid artery stenting at 2 tertiary university hospitals over a decade. Definition of periprocedural complications included any stroke, myocardial infarction, and death within 1 month after or during the procedure. Statin pretreatment was divided into 3 categories according to the atorvastatin equivalent dose: none (n=158; 39.8%), standard dose (<40 mg of atorvastatin, n=155; 39.0%), and high dose (>=40 mg; n=84; 21.2%). A multivariable logistic regression analysis with the generalized estimating equation method was used to investigate independent factors in periprocedural complications. RESULTS: The patients' mean age was 68.7 years (81.6% men). The periprocedural complication rates across the 3 categories of statin use were 12.0%, 4.5%, and 1.2%. After adjustment, a change in the atorvastatin dose category was associated with reduction in the odds of periprocedural complications for each change in dose category (standard-dose statin: odds ratio, 0.24; 95% confidence interval, 0.07-0.81; high-dose statin: odds ratio, 0.11; 95% confidence interval, 0.01-0.96; P for trend=0.01). Administration of antiplatelet drugs was also an independent factor in periprocedural complications (OR, 0.18; 95% CI, 0.05-0.69). CONCLUSIONS: This study shows that statin pretreatment may reduce the incidence of periprocedural complications dose dependently in patients with symptomatic carotid artery stenting. PMID- 28626050 TI - Admission Brain Cortical Volume: An Independent Determinant of Poststroke Cognitive Vulnerability. AB - BACKGROUND AND PURPOSE: Several markers of poststroke cognitive impairment have been reported. The role of brain cortical volume remains uncertain. The aim of this study was to evaluate the influence of brain cortical volume on cognitive outcomes using a voxel-based morphometry approach in subjects without prestroke dementia. METHODS: Ischemic stroke patients were prospectively recruited 24 to 72 hours post stroke (M0). Cognition was evaluated at M0, 3 months, and 1 year (M12) using the Montreal Cognitive Assessment, the Isaacs set test, and the Zazzo's cancellation task. A 3-T brain magnetic resonance imaging was performed at M0. Grey matter (GM) was segmented using Statistical Parametric Mapping 12 software. Association between global GM volume and cognitive score slopes between M0 and M12 was evaluated using a linear mixed model. Correlations between focal GM volumes and changes in cognitive performance were evaluated using Statistical Parametric Mapping 12. RESULTS: Two-hundred forty-eight patients were included (mean age 65+/-SD 14 years old, 66% men). Global GM volume was significantly associated with changes in Montreal Cognitive Assessment scores (beta=0.01; P=0.04) and in the number of errors on the Zazzo's cancellation task (beta=-0.02; P=0.04) independently of other clinical/radiological confounders. Subjects with lower GM volumes in the left fronto-temporo-insular cortex were more vulnerable to transient Montreal Cognitive Assessment and Isaacs set test impairment. Subjects with lower GM volumes in right temporo-insular cortex, together with basal ganglia, were more vulnerable to transient cognitive impairment on the Zazzo's cancellation task. CONCLUSIONS: Smaller cortical volumes in fronto temporo-insular areas measured 24 to 72 hours post stroke are associated with cognitive vulnerability in the subacute stroke phase. PMID- 28626051 TI - Letter by Kawada Regarding Article, "Silent Brain Infarctions and Leukoaraiosis in Patients With Retinal Ischemia: A Prospective Single-Center Observational Study". PMID- 28626043 TI - The Diverse Roles of Arrestin Scaffolds in G Protein-Coupled Receptor Signaling. AB - The visual/beta-arrestins, a small family of proteins originally described for their role in the desensitization and intracellular trafficking of G protein coupled receptors (GPCRs), have emerged as key regulators of multiple signaling pathways. Evolutionarily related to a larger group of regulatory scaffolds that share a common arrestin fold, the visual/beta-arrestins acquired the capacity to detect and bind activated GPCRs on the plasma membrane, which enables them to control GPCR desensitization, internalization, and intracellular trafficking. By acting as scaffolds that bind key pathway intermediates, visual/beta-arrestins both influence the tonic level of pathway activity in cells and, in some cases, serve as ligand-regulated scaffolds for GPCR-mediated signaling. Growing evidence supports the physiologic and pathophysiologic roles of arrestins and underscores their potential as therapeutic targets. Circumventing arrestin-dependent GPCR desensitization may alleviate the problem of tachyphylaxis to drugs that target GPCRs, and find application in the management of chronic pain, asthma, and psychiatric illness. As signaling scaffolds, arrestins are also central regulators of pathways controlling cell growth, migration, and survival, suggesting that manipulating their scaffolding functions may be beneficial in inflammatory diseases, fibrosis, and cancer. In this review we examine the structure-function relationships that enable arrestins to perform their diverse roles, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners. We conclude with a discussion of arrestins as therapeutic targets and the settings in which manipulating arrestin function might be of clinical benefit. PMID- 28626052 TI - Evolution of the Modified Rankin Scale and Its Use in Future Stroke Trials. PMID- 28626053 TI - Histological Composition and the Origin of the Thrombus: A New Diagnostic Assay for Secondary Stroke Prevention? PMID- 28626054 TI - Prediction of Recurrent Stroke or Transient Ischemic Attack After Noncardiogenic Posterior Circulation Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Posterior circulation ischemic stroke (IS) is generally considered an illness with a poor prognosis. However, there are no effective rating scales to predict recurrent stroke following it. Therefore, our aim was to identify clinical or radiological measures that could assist in predicting recurrent cerebral ischemic episodes. METHODS: We prospectively enrolled 723 noncardiogenic posterior circulation IS patients with onset of symptoms <7 days. Stroke risk factors, admission symptoms and signs, topographical distribution and responsible cerebral artery of acute infarcts, and any recurrent IS or transient ischemic attack (TIA) within 1 year were assessed. Cox regression was used to identify risk factors associated with recurrent IS or TIA within the year after posterior circulation IS. RESULTS: A total of 40 patients (5.5%) had recurrent IS or TIA within 1 year of posterior circulation IS. Multivariate Cox regression identified chief complaint with dysphagia (hazard ratio [HR], 4.16; 95% confidence interval [CI], 1.69-10.2; P=0.002), repeated TIAs within 3 months before the stroke (HR, 15.4; 95% CI, 5.55-42.5; P<0.0001), responsible artery stenosis >=70% (HR, 7.91; 95% CI, 1.00-62.6; P=0.05), multisector infarcts (HR, 5.38; 95% CI, 1.25-23.3; P=0.02), and not on antithrombotics treatment at discharge (HR, 3.06; 95% CI, 1.09-8.58; P=0.03) as independent predictors of recurrent IS or TIA. CONCLUSIONS: Some posterior circulation IS patients are at higher risk for recurrent IS or TIA. Urgent assessment and preventive treatment should be offered to these patients as soon as possible. PMID- 28626055 TI - Ischemic Stroke: What Does the Histological Composition Tell Us About the Origin of the Thrombus? AB - BACKGROUND AND PURPOSE: The introduction of stent retrievers allows for a complete extraction and histological analysis of human thrombi. Ischemic stroke is a major health issue, and differentiation of underlying causes is highly relevant to prevent recurrent stroke. Therefore, histopathologic analysis of the embolic clots after removal may provide valuable information about underlying pathologies. This study analyzes histological clot composition and aims to identify specific patterns that might help to distinguish causes of ischemic stroke. METHODS: Patients with occlusion of the carotid-T or middle cerebral artery who underwent thrombectomy at our university medical center between December 2013 and February 2016 were included. Samples were histologically analyzed (hematoxylin and eosin, Elastica van Gieson, and Prussian blue), additionally immunohistochemistry for CD3, CD20, and CD68/KiM1P was performed. These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. RESULTS: One hundred eighty seven patients were included, of these, in 77 patients, cardioembolic; in 46 patients, noncardioembolic; and in 64 patients, cryptogenic pathogenesis was determined. Cardioembolic thrombi had higher proportions of fibrin/platelets (P=0.027), less erythrocytes (P=0.005), and more leucocytes (P=0.026) than noncardioembolic thrombi. We observed a strong overlap of cryptogenic strokes and cardioembolic strokes concerning thrombus histology. The immunohistochemical parameters CD3, CD20, and CD68/KiM1P showed no statistically noticeable differences between stroke subtypes. CONCLUSIONS: Histological thrombus features vary significantly according to the underlying cause and may help to differentiate between cardioembolic and noncardioembolic stroke. In addition, our study supports the hypothesis that most cryptogenic strokes have a cardioembolic cause. PMID- 28626056 TI - Early Reperfusion After Brain Ischemia Has Beneficial Effects Beyond Rescuing Neurons. AB - BACKGROUND AND PURPOSE: Recent studies show that successful endovascular thrombectomy 6 to 12 hours after stroke onset enhances functional outcomes 3 months later. In this study, we investigated the effects of reperfusion after ischemia on repair processes in the ischemic areas, as well as on functional recovery, using mouse stroke models. METHODS: We examined time-dependent histological changes and functional recovery after transient middle cerebral artery occlusion of different durations, including permanent middle cerebral artery occlusion, using the CB-17 (CB-17/lcr-+/+Jcl) mouse strain, which has poor pial collateral blood flow. RESULTS: Large microtubule-associated protein 2 negative areas of neuronal death were produced in mice subjected to >=60 minutes of ischemia followed by reperfusion on day 1, while restricted microtubule associated protein 2-negative regions were observed in mice subjected to a 45 minute period of ischemia. A substantial reduction in microtubule-associated protein 2-negative areas was observed on day 7 in mice given early reperfusion and was associated with better functional recovery. Kluver-Barrera staining demonstrated that white matter injury on day 1 was significantly lesser in mice with reperfusion. Immunohistochemistry and electron microscopy revealed that a greater number of endothelial cells were present in the infarct areas in mice with earlier reperfusion and were associated with a more rapid recruitment of platelet-derived growth factor receptor beta-positive pericytes and subsequent intrainfarct fibrosis. Early reperfusion also resulted in a greater accumulation of glial fibrillary acidic protein-positive astrocytes in peri-infarct areas. Peri-infarct astrogliosis was attenuated in platelet-derived growth factor receptor beta heterozygous knockout mice. CONCLUSIONS: Early reperfusion after ischemia enhances the survival of endothelial cells and pericytes within ischemic areas even after the infarct is established, resulting in efficient intrainfarct fibrosis and peri-infarct astrogliosis. These effects might be associated with efficient peri-infarct reorganization and functional recovery. PMID- 28626058 TI - Risk of Stroke With Various Types of Menopausal Hormone Therapies: A National Cohort Study. AB - BACKGROUND AND PURPOSE: Double-blind randomized studies on the effects of oral postmenopausal hormone therapies were stopped mainly because of increased risk of stroke. We aimed to assess the risk of all strokes and various subtypes associated with hormone therapy and explore the influence of regimens and routes of administration. METHODS: A national historical cohort of women aged 51 to 70 years from 1995 to 2010 was established by linking 5 Danish registries. The National Registry of Medicinal Product Statistics provided information on hormone therapy exposure and the National Patient or Cause of Death Registries supplied data regarding stroke diagnoses (ischemic/hemorrhagic/subarachnoid hemorrhage). Multiply adjusted rate ratios with time-varying covariates were fitted in Poisson regression models. RESULTS: Of the 980 003 included women, 20 199 suffered a stroke (78% ischemic, 12% hemorrhagic, and 10% subarachnoid hemorrhage). In total, 36% of women used hormone therapy. Current use conferred a relative rate of 1.16 (95% confidence interval, 1.12-1.22). Compared with never users, the increased rate ratio of all stroke with continuous, cyclic combined estrogen/progestin, and estrogen only oral therapies were 1.29 (95% confidence interval, 1.21-1.37), 1.11 (95% confidence interval, 1.04-1.20), and 1.18 (95% confidence interval, 1.10-1.26), respectively. The increased risk was because of ischemic stroke, but not hemorrhagic stroke. Transdermal application of hormone therapy was not associated with risk of stroke. Vaginal estrogen was associated with a decreased risk of stroke. CONCLUSIONS: In a national setting, we found an increased risk of stroke, based on ischemic stroke, with oral hormone therapies that was comparable to findings from randomized studies. We found no risk of stroke with transdermal application and a reduced risk with vaginal estrogen. PMID- 28626057 TI - Abnormal P-Wave Axis and Ischemic Stroke: The ARIC Study (Atherosclerosis Risk In Communities). AB - BACKGROUND AND PURPOSE: Abnormal P-wave axis (aPWA) has been linked to incident atrial fibrillation and mortality; however, the relationship between aPWA and stroke has not been reported. We hypothesized that aPWA is associated with ischemic stroke independent of atrial fibrillation and other stroke risk factors and tested our hypothesis in the ARIC study (Atherosclerosis Risk In Communities), a community-based prospective cohort study. METHODS: We included 15 102 participants (aged 54.2+/-5.7 years; 55.2% women; 26.5% blacks) who attended the baseline examination (1987-1989) and without prevalent stroke. We defined aPWA as any value outside 0 to 75 degrees using 12-lead ECGs obtained during study visits. Each case of incident ischemic stroke was classified in accordance with criteria from the National Survey of Stroke by a computer algorithm and adjudicated by physician review. Multivariable Cox regression was used to estimate hazard ratios and 95% confidence intervals for the association of aPWA with stroke. RESULTS: During a mean follow-up of 20.2 years, there were 657 incident ischemic stroke cases. aPWA was independently associated with a 1.50 fold (95% confidence interval, 1.22-1.85) increased risk of ischemic stroke in the multivariable model that included atrial fibrillation. When subtyped, aPWA was associated with a 2.04-fold (95% confidence interval, 1.42-2.95) increased risk of cardioembolic stroke and a 1.32-fold (95% confidence interval, 1.03-1.71) increased risk of thrombotic stroke. CONCLUSIONS: aPWA is independently associated with ischemic stroke. This association seems to be stronger for cardioembolic strokes. Collectively, our findings suggest that alterations in atrial electric activation may predispose to cardiac thromboembolism independent of atrial fibrillation. PMID- 28626059 TI - Electromechanical-Assisted Training for Walking After Stroke: A Major Update of the Evidence. PMID- 28626060 TI - Response by Golsari and Thomalla to Letter Regarding Article, "Silent Brain Infarctions and Leukoaraiosis in Patients With Retinal Ischemia: A Prospective Single-Center Observational Study". PMID- 28626061 TI - Intensive Blood Pressure Lowering in Intracerebral Hemorrhage. PMID- 28626062 TI - Insights into the function of n-3 PUFAs in fat-1 transgenic cattle. AB - The n-3 PUFAs have many beneficial effects on human health, including roles in immunity, neurodevelopment, and preventing cardiovascular disease. In this study, we established reliable model fat-1 transgenic cattle using transgenic technology and performed a systematic investigation to examine the function of n-3 PUFAs. Our results showed that expression of the fat-1 gene improved several biochemical parameters related to liver function and to plasma glucose and plasma lipid metabolism. Results of global gene and plasma protein expression analysis showed that 310 genes and 13 plasma proteins differed significantly in the blood of fat 1 transgenic cattle compared with WT cattle, reflecting their regulatory roles in the immune and cardiovascular systems. Finally, changes in the gut microflora were also noted in the fat-1 transgenic cattle, suggesting novel roles for n-3 PUFAs in the metabolism of glucose and lipids, as well as anti-stress properties. To the best of our knowledge, this is the first report using multiple parallel analyses to investigate the role of n-3 PUFAs using models such as fat-1 transgenic cattle. This study provides novel insights into the regulatory mechanism of fat-1 in the immune and cardiovascular systems, as well as its anti stress role. PMID- 28626063 TI - No fuzzy space for intracellular Na+ in healthy ventricular myocytes. PMID- 28626064 TI - Monitoring C3aR Expression Using a Floxed tdTomato-C3aR Reporter Knock-in Mouse. AB - C3a exerts multiple biologic functions through activation of its cognate C3a receptor. C3-/- and C3aR-/- mice have been instrumental in defining important roles of the C3a/C3aR axis in the regulation of acute and chronic inflammatory diseases, including ischemia/reperfusion injury, allergic asthma, autoimmune nephritis, and rheumatoid arthritis. Surprisingly little is known about C3aR expression and function in immune and stromal cells. To close this gap, we generated a floxed tandem-dye Tomato (tdTomato)-C3aR reporter knock-in mouse, which we used to monitor C3aR expression in cells residing in the lung, airways, lamina propria (LP) of the small intestine, brain, visceral adipose tissue, bone marrow (BM), spleen, and the circulation. We found a strong expression of tdTomato-C3aR in the brain, lung, LP, and visceral adipose tissue, whereas it was minor in the spleen, blood, BM, and the airways. Most macrophage and eosinophil populations were tdTomato-C3aR+ Interestingly, most tissue eosinophils and some macrophage populations expressed C3aR intracellularly. BM-derived dendritic cells (DCs), lung-resident cluster of differentiation (CD) 11b+ conventional DCs (cDCs) and monocyte-derived DCs, LP CD103+, and CD11b+ cDCs but not pulmonary CD103+ cDCs and splenic DCs were tdTomato-C3aR+ Surprisingly, neither BM, blood, lung neutrophils, nor mast cells expressed C3aR. Similarly, all lymphoid-derived cells were tdTomato-C3aR-, except some LP-derived type 3 innate lymphoid cells. Pulmonary and LP-derived epithelial cells expressed at best minor levels of C3aR. In summary, we provide novel insights into the expression pattern of C3aR in mice. The floxed C3aR knock-in mouse will help to reliably track and conditionally delete C3aR expression in experimental models of inflammation. PMID- 28626065 TI - Metabolic Reprogramming Commits Differentiation of Human CD27+IgD+ B Cells to Plasmablasts or CD27-IgD- Cells. AB - B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-alpha markedly induced the differentiation of CD27+IgD+ unswitched memory B cells into CD27hiCD38hi plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27-IgD- memory B cells with high cytokine production, but such differentiation was suppressed by IFN-alpha. AMP-activated protein kinase activation enhanced the differentiation to CD27-IgD- B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19+ B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-alpha amplifies mTORC1-glycolysis pathways) or CD27-IgD- memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE. PMID- 28626066 TI - Cytoplasmic Form of Carlr lncRNA Facilitates Inflammatory Gene Expression upon NF kappaB Activation. AB - Long noncoding RNAs (lncRNAs) have emerged as critical regulators of inflammation. To further understand the interaction between inflammatory signaling pathways and lncRNAs, we characterized the function of cardiac and apoptosis-related lncRNA (Carlr), an lncRNA expressed in both mouse and human cells of diverse tissues. Carlr expression is increased following NF-kappaB signaling in macrophages, with concomitant translocation to, and enrichment of, the transcript in the cytoplasm. Knockdown of Carlr results in impaired expression of NF-kappaB pathway genes and influences the interaction between macrophages and intestinal cells in an inflammatory environment. In human celiac disease patient samples, increased levels of the Carlr transcript were detected in the cytoplasm, alongside elevated expression of NF-kappaB pathway genes. These findings suggest that increased Carlr expression and/or cytoplasmic localization is required for efficient NF-kappaB signaling and is associated with the inflamed tissue state observed in human celiac disease. PMID- 28626067 TI - The Impact of a Population-Based Screening Program on Income- and Immigration Related Disparities in Colorectal Cancer Screening. AB - Background: A population-based program promoting the Fecal Occult Blood Test (FOBT) for colorectal cancer screening was introduced in 2008 in Ontario, Canada, where opportunistic screening with colonoscopy had been increasing in frequency. We evaluated the impact of the program on income and immigration-related disparities in screening.Methods: We used linked administrative data to calculate colorectal cancer screening rates for eligible Ontarians in each year between 2001/02 (n = 2,852,619) and 2013/14 (n = 4,139,304). We quantified disparities using an "inequality ratio" of screening rates in the most disadvantaged group relative to the most advantaged group. We performed segmented logistic regression analyses stratified by screening modality and adjusted for age, sex, rurality, comorbidity, and morbidity.Results: Between 2001/02 and 2013/14, the income and immigration inequality ratios narrowed from 0.74 to 0.80 and 0.55 to 0.69, respectively. Before the screening program, the income inequality ratio was widening by 1% per year (95% CI 1% to 1%); in the year it was introduced, it narrowed by 4% (95% CI 2% to 7%) and in the years following, it remained stable [0% decrease (95% CI 1% decrease to 0% decrease) per year]. Results were similar for immigration-related disparities. After program introduction, disparities in receiving FOBT were narrowing at a faster rate while disparities in receiving colonoscopy were widening at a slower rate.Conclusions: Introduction of a population-based screening program promoting FOBT for colorectal cancer was associated with only modest improvements in immigration and income-related disparities.Impact: Reducing immigration and income-related disparities should be a focus for future research and policy work. Disparities in Ontario seem to be driven by a higher uptake of colonoscopy among more advantaged groups. Cancer Epidemiol Biomarkers Prev; 26(9); 1401-10. (c)2017 AACR. PMID- 28626068 TI - Colorectal Cancer Screening: How Health Gains and Cost-Effectiveness Vary by Ethnic Group, the Impact on Health Inequalities, and the Optimal Age Range to Screen. AB - Background: Screening programs consistently underserve indigenous populations despite a higher overall burden of cancer. In this study, we explore the likely health gains and cost-effectiveness of a national colorectal cancer screening program for the indigenous Maori population of New Zealand (NZ).Methods: A Markov model estimated: health benefits (quality-adjusted life-year; QALY), costs, and cost-effectiveness of biennial immunochemical fecal occult blood testing (FOBTi) of 50- to 74-year-olds from 2011. Input parameters came from literature reviews, the NZ Bowel Screening Programme Pilot, and NZ linked health datasets. Equity analyses substituted non-Maori values for Maori values of background (noncolorectal cancer) morbidity and mortality, colorectal cancer survival and incidence, screening coverage, and stage-specific survival. We measured the change in "quality-adjusted life expectancy" (QALE) as a result of the intervention.Results: Based upon a threshold of GDP per capita (NZ$45,000), colorectal cancer screening in NZ using FOBTi is cost-effective: NZ$2,930 (US$1,970) per QALY gained [95% uncertainty interval: cost saving to $6,850 (US$4,610)]. Modeled health gains per capita for Maori were less than for non Maori: half for 50- to 54-year-olds (0.031 QALYs per person for Maori vs. 0.058 for non-Maori), and a fifth (0.003 c.f. 0.016) for 70- to 74-year-olds and ethnic inequalities in QALE increased with colorectal cancer screening.Conclusions: Colorectal cancer screening in NZ using FOBTi is likely to be cost-effective but risks increasing inequalities in health for Maori.Impact: To avoid or mitigate the generation of further health inequalities, attention should be given to underserved population groups when planning and implementing screening programs. Cancer Epidemiol Biomarkers Prev; 26(9); 1391-400. (c)2017 AACR. PMID- 28626069 TI - How Many Deaths from Colorectal Cancer Can Be Prevented by 2030? A Scenario-Based Quantification of Risk Factor Modification, Screening, and Treatment in Norway. AB - Background: Colorectal cancer mortality can be reduced through risk factor modification (adherence to lifestyle recommendations), screening, and improved treatment. This study estimated the potential of these three strategies to modify colorectal cancer mortality rates in Norway.Methods: The potential reduction in colorectal cancer mortality due to risk factor modification was estimated using the software Prevent, assuming that 50% of the population in Norway-who do not adhere to the various recommendations concerning prevention of smoking, physical activity, body weight, and intake of alcohol, red/processed meat, and fiber started to follow the recommendations. The impact of screening was quantified assuming implementation of national flexible sigmoidoscopy screening with 50% attendance. The reduction in colorectal cancer mortality due to improved treatment was calculated assuming that 50% of the linear (positive) trend in colorectal cancer survival would continue to persist in future years.Results: Risk factor modification would decrease colorectal cancer mortality by 11% (corresponding to 227 prevented deaths: 142 men, 85 women) by 2030. Screening and improved treatment in Norway would reduce colorectal cancer mortality by 7% (149 prevented deaths) and 12% (268 prevented deaths), respectively, by 2030. Overall, the combined effect of all three strategies would reduce colorectal cancer mortality by 27% (604 prevented deaths) by 2030.Conclusions: Risk factor modification, screening, and treatment all have considerable potential to reduce colorectal cancer mortality by 2030, with the largest potential reduction observed for improved treatment and risk factor modification.Impact: The estimation of these health impact measures provides useful information that can be applied in public health decision-making. Cancer Epidemiol Biomarkers Prev; 26(9); 1420-6. (c)2017 AACR. PMID- 28626070 TI - Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes. AB - Background: Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection.Methods: We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk.Results: In the discovery phase, 32,946 SNPs located at +/-10 kb of 2,001 obesity-related genes were extracted from MDA RCC GWAS and analyzed using multivariable logistic regression. Proxies (R2 > 0.8) were searched or imputation was performed if SNPs were not directly genotyped in the validation sets. Twenty-one SNPs with P < 0.05 in both MDA RCC GWAS and NCI RCC GWAS were subsequently evaluated in MDA RCC OncoArray. In the overall meta analysis, significant (P < 0.05) associations with RCC risk were observed for SNP mapping to IL1RAPL2 [rs10521506-G: ORmeta = 0.87 (0.81-0.93), Pmeta = 2.33 * 10 5], PLIN2 [rs2229536-A: ORmeta = 0.87 (0.81-0.93), Pmeta = 2.33 * 10-5], SMAD3 [rs4601989-A: ORmeta = 0.86 (0.80-0.93), Pmeta = 2.71 * 10-4], MED13L [rs10850596 A: ORmeta = 1.14 (1.07-1.23), Pmeta = 1.50 * 10-4], and TSC1 [rs3761840-G: ORmeta = 0.90 (0.85-0.97), Pmeta = 2.47 * 10-3]. We did not observe any significant cis expression quantitative trait loci effect for these SNPs in the TCGA KIRC data.Conclusions: Taken together, we found that genetic variation of obesity related genes could influence RCC susceptibility.Impact: The five identified loci may provide new insights into disease etiology that reveal importance of obesity related genes in RCC development. Cancer Epidemiol Biomarkers Prev; 26(9); 1436 42. (c)2017 AACR. PMID- 28626071 TI - NLRX1 dampens oxidative stress and apoptosis in tissue injury via control of mitochondrial activity. AB - Mitochondrial dysfunction is the most prominent source of oxidative stress in acute and chronic kidney disease. NLRX1 is a receptor of the innate immune system that is ubiquitously expressed and localized in mitochondria. We investigated whether NLRX1 may act at the interface of metabolism and innate immunity in a model of oxidative stress. Using a chimeric mouse model for renal ischemia reperfusion injury, we found that NLRX1 protects against mortality, mitochondrial damage, and epithelial cell apoptosis in an oxidative stress-dependent fashion. We found that NLRX1 regulates oxidative phosphorylation and cell integrity, whereas loss of NLRX1 results in increased oxygen consumption, oxidative stress, and subsequently apoptosis in epithelial cells during ischemia-reperfusion injury. In line, we found that NLRX1 expression in human kidneys decreased during acute renal ischemic injury and acute cellular rejection. Although first implicated in immune regulation, we propose that NLRX1 function extends to the control of mitochondrial activity and prevention of oxidative stress and apoptosis in tissue injury. PMID- 28626072 TI - 5-HT causes splanchnic venodilation. AB - Serotonin [5-hydroxytryptamine (5-HT)] causes relaxation of the isolated superior mesenteric vein, a splanchnic blood vessel, through activation of the 5-HT7 receptor. As part of studies designed to identify the mechanism(s) through which chronic (>=24 h) infusion of 5-HT lowers blood pressure, we tested the hypothesis that 5-HT causes in vitro and in vivo splanchnic venodilation that is 5-HT7 receptor dependent. In tissue baths for measurement of isometric contraction, the portal vein and abdominal inferior vena cava relaxed to 5-HT and the 5-HT1/7 receptor agonist 5-carboxamidotryptamine; relaxation was abolished by the 5-HT7 receptor antagonist SB-269970. Western blot analyses showed that the abdominal inferior vena cava and portal vein express 5-HT7 receptor protein. In contrast, the thoracic vena cava, outside the splanchnic circulation, did not relax to serotonergic agonists and exhibited minimal expression of the 5-HT7 receptor. Male Sprague-Dawley rats with chronically implanted radiotelemetry transmitters underwent repeated ultrasound imaging of abdominal vessels. After baseline imaging, minipumps containing vehicle (saline) or 5-HT (25 MUg.kg-1.min-1) were implanted. Twenty-four hours later, venous diameters were increased in rats with 5-HT-infusion (percent increase from baseline: superior mesenteric vein, 17.5 +/- 1.9; portal vein, 17.7 +/- 1.8; and abdominal inferior vena cava, 46.9 +/- 8.0) while arterial pressure was decreased (~13 mmHg). Measures returned to baseline after infusion termination. In a separate group of animals, treatment with SB 269970 (3 mg/kg iv) prevented the splanchnic venodilation and fall in blood pressure during 24 h of 5-HT infusion. Thus, 5-HT causes 5-HT7 receptor-dependent splanchnic venous dilation associated with a fall in blood pressure.NEW & NOTEWORTHY This research is noteworthy because it combines and links, through the 5-HT7 receptor, an in vitro observation (venorelaxation) with in vivo events (venodilation and fall in blood pressure). This supports the idea that splanchnic venodilation plays a role in blood pressure regulation. PMID- 28626074 TI - A-type K+ channels contribute to the prorenin increase of firing activity in hypothalamic vasopressin neurosecretory neurons. AB - Recent studies have supported an important contribution of prorenin (PR) and its receptor (PRR) to the regulation of hypothalamic, sympathetic, and neurosecretory outflows to the cardiovascular system, including systemic release of vasopressin (VP), both under physiological and cardiovascular disease conditions. Still, the identification of precise cellular mechanisms and neuronal/molecular targets remain unknown. We have recently shown that PRR is expressed in VP neurons and that their activation increases neuronal activity. However, the underlying ionic channel mechanisms are undefined. Here, we performed patch-clamp electrophysiology from identified VP neurons in acute hypothalamic slices obtained from enhanced green fluorescent protein-VP transgenic rats. Voltage clamp recordings showed that PR inhibited the magnitude of A-type K+ current (IA; ~50% at -25 mV), a subthreshold voltage-dependent current that restrains VP firing activity. PR also increased the inactivation rate of IA and shifted the steady-state voltage-dependent inactivation function toward more hyperpolarized membrane potential (~7 mV shift), thus resulting in less channel availability to be activated at any given membrane potential. PR also inhibited a sustained component of IA ("window" current). PR-mediated changes in action potential waveform and increased firing activity were occluded when IA was blocked by 4 aminopyridine. Finally, PR failed to increase superoxide production within the supraoptic nucleus/paraventricular nucleus, and PR excitatory effects persisted in slices treated with the SOD mimetic tempol. Taken together, these experiments indicated that PR excitatory effects on vasopressin neurons involve inhibition of IA, due, in part, to increases in its voltage-dependent inactivation properties. Moreover, our results indicate that PR effects did not involve an increase in oxidative stress.NEW & NOTEWORTHY Here, we demonstrate that prorenin/the prorenin receptor is an important signaling unit for the regulation of vasopressin firing activity and, thus, systemic hormonal release. We identified A-type K+ channels as key molecular targets mediating prorenin stimulation of vasopressin neuronal activity, thus standing as a potential therapeutic target for neurohumoral activation in cardiovascular disease. PMID- 28626073 TI - Increased vascular and uteroplacental matrix metalloproteinase-1 and -7 levels and collagen type I deposition in hypertension in pregnancy: role of TNF-alpha. AB - Preeclampsia is a pregnancy-related disorder manifested as maternal hypertension in pregnancy (HTN-Preg) and fetal growth restriction. Placental ischemia could be an initiating event that leads to abnormal vascular and uteroplacental remodeling in HTN-Preg; however, the molecular targets and intermediary mechanisms involved are unclear. We tested the hypothesis that placental ischemia could target vascular and uteroplacental matrix metalloproteinases (MMPs) through an inflammatory cytokine-mediated mechanism. MMP levels and distribution were measured in the aorta, uterus, and placenta of normal pregnant (Preg) rats and pregnant rats with reduced uterine perfusion pressure (RUPP). Maternal blood pressure was higher and the litter size and pup weight were lower in RUPP compared with Preg rats. Gelatin zymography showed prominent uterine MMP-2 and MMP-9 activity that was dependent on the amount of loaded protein. At saturating protein loading, both gelatin and casein zymography revealed two additional bands corresponding to MMP-1 and MMP-7 that were greater in the aorta, uterus, and placenta of RUPP compared with Preg rats. Western blots and immunohistochemistry confirmed increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of RUPP versus Preg rats. The levels of MMP-1 and MMP-7 substrate collagen type I were greater in tissues of RUPP compared with Preg rats. In organ culture, TNF-alpha increased MMP-1 and MMP-7 in the aorta, uterus, and placenta of Preg rats, and a TNF-alpha antagonist prevented the increases in MMPs in tissues of RUPP rats. Thus, placental ischemia, possibly through TNF-alpha, increases vascular and uteroplacental MMP-1 and MMP-7, which, in turn, alter collagen deposition and cause inadequate tissue remodeling in HTN-Preg. Cytokine antagonists may reverse the increase in MMP-1 and MMP-7 expression/activity and, in turn, restore proper vascular and uteroplacental remodeling in HTN-Preg and preeclampsia.NEW & NOTEWORTHY The molecular mechanisms of preeclampsia are unclear, making it difficult to predict, prevent, or manage the pregnancy-associated disorder. This study showed that placental ischemia, possibly through the release of TNF-alpha, causes increases in the levels of matrix metalloproteinase (MMP)-1 and MMP-7, which could alter collagen deposition and cause inadequate uteroplacental and vascular remodeling in hypertension in pregnancy. The data suggest that targeting MMP-1 and MMP-7 and their upstream modulators, such as TNF-alpha, could provide a new approach in the management of hypertension in pregnancy and preeclampsia. PMID- 28626077 TI - Radiation-induced HFpEF model as a potential tool for the exploration of novel therapeutic targets. PMID- 28626076 TI - Cardiac fibroblast transcriptome analyses support a role for interferogenic, profibrotic, and inflammatory genes in anti-SSA/Ro-associated congenital heart block. AB - The signature lesion of SSA/Ro autoantibody-associated congenital heart block (CHB) is fibrosis and a macrophage infiltrate, supporting an experimental focus on cues influencing the fibroblast component. The transcriptomes of human fetal cardiac fibroblasts were analyzed using two complementary approaches. Cardiac injury conditions were simulated in vitro by incubating human fetal cardiac fibroblasts with supernatants from macrophages transfected with the SSA/Ro associated noncoding Y ssRNA. The top 10 upregulated transcripts in the stimulated fibroblasts reflected a type I interferon (IFN) response [e.g., IFN induced protein 44-like (IFI44L), of MX dynamin-like GTPase (MX)1, MX2, and radical S-adenosyl methionine domain containing 2 (Rsad2)]. Within the fibrotic pathway, transcript levels of endothelin-1 (EDN1), phosphodiesterase (PDE)4D, chemokine (C-X-C motif) ligand (CXCL)2, and CXCL3 were upregulated, while others, including adenomedullin, RAP guanine nucleotide exchange factor 3 (RAPGEF3), tissue inhibitor of metalloproteinase (TIMP)1, TIMP3, and dual specificity phosphatase 1, were downregulated. Agnostic Database for Annotation, Visualization and Integrated Discovery analysis revealed a significant increase in inflammatory genes, including complement C3A receptor 1 (C3AR1), F2R-like thrombin/trypsin receptor 3, and neutrophil cytosolic factor 2. In addition, stimulated fibroblasts expressed high levels of phospho-MADS box transcription enhancer factor 2 [a substrate of MAPK5 (ERK5)], which was inhibited by BIX 02189, a specific inhibitor of ERK5. Translation to human disease leveraged an unprecedented opportunity to interrogate the transcriptome of fibroblasts freshly isolated and cell sorted without stimulation from a fetal heart with CHB and a matched healthy heart. Consistent with the in vitro data, five IFN response genes were among the top 10 most highly expressed transcripts in CHB fibroblasts. In addition, the expression of matrix-related genes reflected fibrosis. These data support the novel finding that cardiac injury in CHB may occur secondary to abnormal remodeling due in part to upregulation of type 1 IFN response genes.NEW & NOTEWORTHY Congenital heart block is a rare disease of the fetal heart associated with maternal anti-Ro autoantibodies which can result in death and for survivors, lifelong pacing. This study provides in vivo and in vitro transcriptome-support that injury may be mediated by an effect of Type I Interferon on fetal fibroblasts. PMID- 28626078 TI - State-space representation of the extended Guyton's model. PMID- 28626079 TI - The PRKAG2 gene and hypertrophic cardiomyopathy: an energetically imbalanced relationship. PMID- 28626080 TI - Cyp2c44-mediated decrease of 15-HETE exacerbates pulmonary hypertension. PMID- 28626075 TI - Sex differences in vascular physiology and pathophysiology: estrogen and androgen signaling in health and disease. AB - Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institutes of Health have enacted guidelines expressly to gain knowledge about ways the sexes differ in both normal function and diseases at the various research levels (molecular, cellular, tissue, and organ system). Greater understanding of these sex differences will be used to steer future directions in the biomedical sciences and translational and clinical research. This review describes sex-based differences in the physiology and pathophysiology of the vasculature, with a special emphasis on sex steroid receptor (estrogen and androgen receptor) signaling and their potential impact on vascular function in health and diseases (e.g., atherosclerosis, hypertension, peripheral artery disease, abdominal aortic aneurysms, cerebral aneurysms, and stroke). PMID- 28626081 TI - Why publish in the American Journal of Physiology-Heart and Circulatory Physiology? PMID- 28626082 TI - Significant role of the cardiopostural interaction in blood pressure regulation during standing. AB - Cardiovascular and postural control systems have been studied independently despite the increasing evidence showing the importance of cardiopostural interaction in blood pressure regulation. In this study, we aimed to assess the role of the cardiopostural interaction in relation to cardiac baroreflex in blood pressure regulation under orthostatic stress before and after mild exercise. Physiological variables representing cardiovascular control (heart rate and systolic blood pressure), lower limb muscle activation (electromyography), and postural sway (center of pressure derived from force and moment data during sway) were measured from 17 healthy participants (25 +/- 2 yr, 9 men and 8 women) during a sit-to-stand test before and after submaximal exercise. The cardiopostural control (characterized by baroreflex-mediated muscle-pump effect in response to blood pressure changes, i.e., muscle-pump baroreflex) was assessed using wavelet transform coherence and causality analyses in relation to the baroreflex control of heart rate. Significant cardiopostural blood pressure control was evident counting for almost half of the interaction time with blood pressure changes that observed in the cardiac baroreflex (36.6-72.5% preexercise and 34.7-53.9% postexercise). Thus, cardiopostural input to blood pressure regulation should be considered when investigating orthostatic intolerance. A reduction of both cardiac and muscle-pump baroreflexes in blood pressure regulation was observed postexercise and was likely due to the absence of excessive venous pooling and a less stressed system after mild exercise. With further studies using more effective protocols evoking venous pooling and muscle pump activity, the cardiopostural interaction could improve our understanding of the autonomic control system and ultimately lead to a more accurate diagnosis of cardiopostural dysfunctions.NEW & NOTEWORTHY We examined the interaction between cardiovascular and postural control systems during standing before and after mild exercise. Significant cardiopostural input to blood pressure regulation was shown, suggesting the importance of cardiopostural integration when investigating orthostatic hypotension. In addition, we observed a reduction of baroreflex mediated blood pressure regulation after exercise. PMID- 28626083 TI - Cellular and disease functions of the Prader-Willi Syndrome gene MAGEL2. AB - Melanoma antigen L2 (MAGEL2 or MAGE-L2) is a member of the MAGE family of ubiquitin ligase regulators. It is maternally imprinted and often paternally deleted or mutated in the related neurodevelopmental syndromes, Prader-Willi Syndrome (PWS) and Schaaf-Yang Syndrome (SHFYNG). MAGEL2 is highly expressed in the hypothalamus and plays an important role in a fundamental cellular process that recycles membrane proteins from endosomes through the retromer sorting pathway. MAGEL2 is part of a multi-subunit protein complex consisting of MAGEL2, the TRIM27 E3 ubiquitin ligase, and the USP7 deubiquitinating enzyme. The MAGEL2 USP7-TRIM27 (or MUST) complex facilitates the retromer recycling pathway through ubiquitination and activation of the WASH actin nucleation promoting factor. This review provides an overview of the MAGE protein family of ubiquitin ligases regulators and details the molecular and cellular role of MAGEL2 in ubiquitination, actin regulation and endosomal sorting processes, as well as MAGEL2 implications in PWS and SHFYNG disorders. The physiological functions of MAGEL2, elucidated through the study of Magel2 knockout mouse models, are also discussed. PMID- 28626084 TI - Optimization of RAS/BRAF Mutational Analysis Confirms Improvement in Patient Selection for Clinical Benefit to Anti-EGFR Treatment in Metastatic Colorectal Cancer. AB - In metastatic colorectal cancer (mCRC), recent studies have shown the importance to accurately quantify low-abundance mutations of the RAS pathway because anti EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of an extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR- (n = 255) or bevacizumab- (n = 328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas, therascreen, and dPCR. We evaluated concordance between techniques using the Cohen kappa index. Response rate, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen kappa index around 0.75). We observed an inverse correlation between MAF and response in the anti EGFR cohort (P < 0.001). Likelihood ratio analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value. PFS and OS were significantly longer in RAS/BRAF wild-type patients, independently of the technique. However, the predictability of both PFS and OS were higher when we considered a threshold of 1% in the RAS scenario (HR = 1.53; CI 95%, 1.12-2.09 for PFS, and HR = 1.9; CI 95%, 1.33-2.72 for OS). Although the rate of mutations observed among techniques is different, RAS and BRAF mutational analysis improved prediction of response to anti-EGFR therapy. Additionally, dPCR with a threshold of 1% outperformed the other platforms. Mol Cancer Ther; 16(9); 1999-2007. (c)2017 AACR. PMID- 28626085 TI - Diabetes insipidus is an unfavorable prognostic factor for response to glucocorticoids in patients with autoimmune hypophysitis. AB - INTRODUCTION: Autoimmune hypophysitis (AH) has a variable clinical presentation and natural history; likewise, its response to glucocorticoid therapy is often unpredictable. OBJECTIVE: To identify clinical and radiological findings associated with response to glucocorticoids. DESIGN AND METHODS: 12 consecutive patients with AH, evaluated from 2008 to 2016. AH was the exclusion diagnosis after ruling out other pituitary masses and secondary causes of hypophysitis. Mean follow-up time was 30 +/- 27 months (range 12-96 months). RESULTS: MRI identified two main patterns of presentation: global enlargement of the pituitary gland or panhypophysitis (n = 4, PH), and pituitary stalk abnormality only, or infundibulo-neuro-hypophysitis (n = 8, INH). Multiple tropin defects were more common in PH (100%) than those in INH (28% P = 0.014), whereas diabetes insipidus was more common in INH (100%) than that in PH (50%; P = 0.028). All 4 PH and 4 out of 8 INH were treated with glucocorticoids. Pituitary volume significantly reduced in all PH patients (P = 0.012), defective anterior pituitary function recovered only in the two patients without diabetes insipidus (50%) and panhypopituitarism persisted, along with diabetes insipidus, in the remaining 2 (50%). In all INH patients, either treated or untreated, pituitary stalk diameter reduced (P = 0.008) but diabetes insipidus persisted in all. CONCLUSIONS: Glucocorticoid therapy may improve anterior pituitary function in a subset of patients but has no effect on restoring posterior pituitary function. Diabetes insipidus appears as a negative prognostic factor for response to glucocorticoids. PMID- 28626086 TI - Nursing skill mix in European hospitals: cross-sectional study of the association with mortality, patient ratings, and quality of care. AB - OBJECTIVES: To determine the association of hospital nursing skill mix with patient mortality, patient ratings of their care and indicators of quality of care. DESIGN: Cross-sectional patient discharge data, hospital characteristics and nurse and patient survey data were merged and analysed using generalised estimating equations (GEE) and logistic regression models. SETTING: Adult acute care hospitals in Belgium, England, Finland, Ireland, Spain and Switzerland. PARTICIPANTS: Survey data were collected from 13 077 nurses in 243 hospitals, and 18 828 patients in 182 of the same hospitals in the six countries. Discharge data were obtained for 275 519 surgical patients in 188 of these hospitals. MAIN OUTCOME MEASURES: Patient mortality, patient ratings of care, care quality, patient safety, adverse events and nurse burnout and job dissatisfaction. RESULTS: Richer nurse skill mix (eg, every 10-point increase in the percentage of professional nurses among all nursing personnel) was associated with lower odds of mortality (OR=0.89), lower odds of low hospital ratings from patients (OR=0.90) and lower odds of reports of poor quality (OR=0.89), poor safety grades (OR=0.85) and other poor outcomes (0.80A, 215C>G, 537T>G, 743G>A) were identified in p53 gene encoding region in 9 patients of breast cancer. Moreover, one same sense mutation 141G>A in exon 4, one 16 bases deletion in intron 3, and 9 single nucleotide polymorphisms in p53 gene introns were also identified. The total mutation frequency of p53 gene in 150 patients with familial breast cancer and early-onset breast cancer from part population of southern China was 6.00%, and the mutation frequency of familial breast cancer and early-onset breast cancer was 6.81% and 6.25%, respectively.? Conclusion: The total mutation frequency of p53 gene in 150 patients with familial breast cancer and early-onset breast cancer from partpopulation of southern China is higher than the frequency previously reported. The pathogenicity of the novel mutations (insert mutation) 869_888ins20 will be confirmed by function analysis in the future study. The deletion mutation 643_660del18 enriches the p53 gene mutation database among Chinese population, which is probably the specific mutation of breast cancer in Chinese population. PMID- 28626093 TI - [Expression of regulatory factor R-spondin family in ?Wnt signaling pathway in colorectal cancer and ?its clinical significance]. AB - OBJECTIVE: To explore the expression of R-spondin family in colorectal cancer tissues and adjacent tissues, and to evaluate its relationship with clinic pathological stage.? Methods: A total of 64 samples of colorectal cancer tissues and adjacent tissues were collected from the patients, who received radical surgery in Xiangya Hospital, Central South University between January 2014 and August 2014. The mRNA and protein expression levels of R-spondin 1-4 and beta catenin in the colorectal cancer tissues and adjacent tissues were detected by qRT-PCR and immunohistochemistry. The relationship between the expression level of R-spondin 1-4 and the clinic-pathological factors were analyzed to explore the correlation between the expression level of R-spondin 1-4 and beta-catenin in colorectal cancer.? Results: Compared with the adjacent tissues, the mRNA and protein expression levels of R-spondin 1 were elevated in the colorectal cancer tissues (P<0.05). The mRNA and protein expression levels of R-spondin 2-4 were increased in the colorectal cancer tissues than those in the normal tissues (P<0.05), but there was no significant difference between the colorectal cancer tissues and adjacent tissues (P>0.05). The expression level of R-spondin 1 was positively correlated with the nuclear expression of beta-catenin in the colorectal cancer tissues (r=0.6307, P<0.05).? Conclusion: Compared with the adjacent tissues, the mRNA and protein expression levels of R-spondin 1 are significantly elevated in the colorectal cancer tissues. R-spondin 1 may play a role in promoting carcinogenesis by regulating the activity of beta-catenin in the downstream of Wnt signaling pathway. PMID- 28626094 TI - [Effect of trehalose on survival rate for ?fat cells after cryopreservation]. AB - OBJECTIVE: To explore effects of trehalose as a cryopreserve agent on survival rate of fatty tissue after cryopreservation.? Methods: The liposuction was used on the abdomen of adult female. After centrifugation and purification, adipose was randomized into the following three groups, the trehalose group, the fetal bovine serum (FBS)+10%DMSO group and the physiological saline group. The specimens were cryopreserved at -196 C for 3 months and then the HE staining, glucose transfer method and CK method were used to detect the cell survival rate in each group.? Results: The activity of adipose in the trehalose group and FBS+10%DMSO group adipose was higher than that in the physiological saline group (P<0.05); while there was no significant difference between the trehalose group and FBS+10%DMSO group (P>0.05).? Conclusion: As cryoprotectant, trehalose could keep fat cell viability, and adipose tissue can be used for clinical transplantation after 3 months' freezing. PMID- 28626095 TI - [Role of the autophagy in the treatment of neuropathic pain with pulsed radiofrequency]. AB - OBJECTIVE: To detect the effect of pulse radiofrequency (PRF) treatment on the neuropathic pain established by L5-spinal nerve ligation (SNL) on rats, and to investigate if PRF treatment would affect the expression of autophagy related protein LC3 and autophagy related receptor P62 at the dorsal horn.? Methods: A total of 36 male Sprague-Dawley rats were randomly divided into 3 groups: a Sham group, a SNL group, and a SNL+PRF group. The 50% paw withdrawal mechanical threshold (PWMT) was detected at 1 day before and 1, 3, 7, 14 and 28 days post operation by using Von-Frey filaments. The autophagy related protein LC3 and autophagy related receptor P62 were investigated by Western blot.? Results: Compared with the Sham group, the PWMT significantly decreased in the SNL group at each time points (P<0.05); in SNL+PRF group, PRF treatment could elevate the PWMT at the 1st day post-operation and lasted for 28 days (P<0.05). What's more, SNL could elevate the LC3-II and P62 levels at the 7th day post-operation (P<0.05), which were decreased by the PRF treatment (P<0.05).? Conclusion: PRF treatment could improve SNL-induced the neuropathic pain, which might be partly due to the regulatory effects on the autophagy levels at the spinal dorsal horn. PMID- 28626096 TI - [Analgesic effect of buccal acupuncture on acute arthritis in rabbits and underlying mechanisms]. AB - OBJECTIVE: To observe the analgesic effect of acupuncture and to explore its central analgesic mechanism in rheumatoid arthritis rabbits.? Methods: A total of 60 flap-eared white rabbits were randomly assigned into a normal control group (n=6), a model group (n=6), a body-acupuncture group (n=24), and a buccal acupuncture group (n=24). The later 2 groups were further randomly assigned into 0, 0.5, 1, and 2 h subgroups, with 6 cases in each group. The rheumatoid arthritis model was established by induction of egg-albumin. In the body acupuncture group, bilateral "Xiyan" and "Zusanli" were punctured for 15 s while in the buccal acupuncture group, acupuncture was applied to "Xi" for 15 s, with the needle retaining for 30 min. The pain threshold was detected with PL-200, taking struggle movements of rabbits as a measurement index, response latency from irradiation to struggling movements as the rabbit's pain threshold. The contents of beta-endorplhin (beta-EP) and cholecystokinin-8 (CCK-8) in cerebrospinal fluid were examined by radioimmunoassay.? Results: Compared with the control group, pain threshold and CCK-8 levels decreased significantly (P<0.01) and the concentration of beta-EP significantly increased (P<0.05) in the model group. The pain threshold in the body-acupuncture group and the buccal acupuncture group at 0 and ?1 h (P<0.05 or P<0.01) increased significantly, while the beta-EP and CCK-8 contents in the body-acupuncture group and the buccal acupuncture group were significantly higher than those in the model group (P<0.01 or P<0.05). Both beta-EP and CCK-8 contents in the buccal acupuncture group at 0 h were significantly higher than those in the body-acupuncture group (P<0.05).? Conclusion: The analgesic effect of buccal acupuncture is superior to that of body-acupuncture. Both buccal acupuncture and body-acupuncture can effectively raise the pain threshold in acute arthritis rabbits, which is closely associated with their effects in the up-regulation of beta-EP and CCK-8 contents in cerebrospinal fluid. PMID- 28626097 TI - [Visceral sensitivity, gut barrier function and autonomic nerve function in patients with diarrhea-predominant irritable bowel syndrome]. AB - OBJECTIVE: To evaluate visceral sensitivity, gut barrier function and autonomic nerve function (ANF) in patients with diarrhea-predominant irritable bowel syndrome (IBS-D), and to explore their roles in IBS-D pathophysiology.? Methods: A total of 46 IBS-D patients (IBS-D group) were selected from the Department of Gastroenterology of China-Japan Friendship Hospital from October 2015 to March 2016, and 20 healthy volunteer were served as a control group (HC group). Clinical and psychological symptoms were evaluated by questionnaire, and visceral sensitivity to rectal balloon distention, gut barrier function and autonomic nerve function (ANF) were examined. The difference in the above-mentioned indexes were compared between the 2 groups, and the correlations in the parameters were analyzed in the IBS-D group.? Results: The scores of IBS symptom severity scale (IBS-SSS), Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD) and visceral sensitivity index (VSI) were significantly higher in the IBS-D group than those in the HC group (P<0.01). In the visceral sensitivity test, maximum tolerable threshold in the IBS-D group was significantly decreased compared to that in the HC group (P<0.01); there was no significant difference in first sensation threshold and defecating sensation threshold between the two groups (P>0.05). As gut barrier function markers, the serum diamine oxidase (DAO) and d lactate were significantly increased in the IBS-D group (P<0.05). In ANF test, the total score and parasympathetic score as well as the proportion of abnormal scores in the IBS-D group were significantly higher than those in the HC group (P<0.05). In IBS-D group, the HAMA, VSI and serum DAO were positively correlated with IBS-SSS (r=0.528, 0.575, 0.507; P<0.01), while the 3 visceral sensitivity thresholds were negatively correlated with IBS-SSS (r=?-0.636, -0.476, -0.697; P<0.01); in addition to the IBS-SSS, the HAMA, HAMD, VSI and serum DAO were also significant negatively correlated with the visceral sensitivity thresholds (all P<0.05); no significant correlations were found between the ANF and the other parameters.? Conclusion: IBS-D patients show psychological symptoms, visceral hypersensitivity, impaired gut barrier function and abnormal ANF characterized by parasympathetic dysfunction; the former 3 factors are all associated with disease severity, and thus may play vital roles in IBS-D pathophysiology. PMID- 28626098 TI - [Association between glycosylated hemoglobin and ?non-alcoholic fatty liver disease in ?health examination population]. AB - OBJECTIVE: To investigate associations between glycosylated hemoglobin (HbA1c) levels and non-alcoholic fatty liver disease (NAFLD) in population who underwent periodic heath examination.? Methods: A total of 912 subjects were selected from the health examination adults in University of Hong Kong Shenzhen Hospital from June to November 2013, and they were assigned into a NAFLD group, an else hepatic disease group, and a control group. The physical examination results of these subjects were analyzed retrospectively. ? Results: The prevalence of NAFLD was 29.7%. The related factors such as age, body mass index, and the levels of systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, fasting glucose, HbA1c and alanine aminotransferase in the NAFLD group were higher than those in the else hepatic disease group and the control group (P<0.05). Aspartate aminotransferase levels in the NAFLD group were higher than those in the control group (P<0.05). High density lipoprotein cholesterol levels in the NAFLD group were lower than those in the else hepatic disease group and the control group (P<0.05). According to the quartile of HbA1c level, these subjects were divided into 4 groups, Q1, Q2, Q3, and Q4, and the prevalence of NAFLD in the Q1,Q2, Q3, and Q4 were 17.5%, 21.5%, 31%, and 59.4%, respectively. The prevalence of NAFLD increased along with the increase in the level of HbA1c (chi2=100.092, P<0.05). Logistic regression analysis showed that the risk factor for NAFLD was increased in the subjects of Q4 as compared with the subjects of Q1 after adjusting for the related factors including age, gender, body mass index, etc.? Conclusion: There is a positive correlation between the prevalence of NAFLD and HbA1c level, and the risk of NAFLD increases with the elevating level of HbA1c. High HbA1c level is an independent risk factor for NAFLD. Thus it should be listed as a routine medical test in the health examination. PMID- 28626099 TI - [A cross-sectional study on the correlation between MRI signal for IPFP and knee osteoarthritis]. AB - OBJECTIVE: To investigate the correlation between MRI signal for infrapatellar fat pad (IPFP) and pathological changes in knee osteoarthritis (KOA), and to analyze the role of IPFP in the development of knee osteoarthritis.? Methods: A total of 114 subjects (without special knee disease) were enrolled for this study. The intensity of MRI signal for IPFP was determined by fat-suppressed proton-density-weighted turbospin-echo magnetic resonance imaging. Based on the cartilage defects and osteophytes of knee joint, the subjects were divided into a KOA group and a control group. The difference of MRI signal for IPFP between two groups was analyzed.? Results: After excluding the potential confounders of age, gender and BMI, the intensity of MRI signal for IPFP was positively correlated with defections in patellar, medial femur, lateral tibial or knee joint (OR 1.333 to 2.168, P 0.006 to 0.023); the intensity of MRI signal for IPFP was also positively correlated with osteophytes in patellar, medial femur, lateral tibial or knee joint (OR 1.309 to1.781, P 0.004 to 0.046); the intensity of MRI signal for IPFP in the KOA group was significantly higher than that in the control group (P=0.028).? Conclusion: The increase in the density of MRI signal for IPFP is an imaging manifestation for knee degeneration. IPFP inflammation and endocrine abnormalities may play an important role in KOA. PMID- 28626100 TI - [Neuronavigator-assisted microsurgical resection of glioma located in cerebral functional areas]. AB - OBJECTIVE: To evaluate value of neuronavigator-assisted microsurgery of glioma located in cerebral functional areas.? Methods: Patients with glioma located in cerebral functional areas were underwent operation in Xiangya Hospital. Of 64 patients, 34 patients were performed neuronavigator-assisted microsurgery, and 30 were underwent routine surgical operation.? Results: The neuronavigator-assisted microsurgery group showed high complete resection rate with low neurological deficit and cerebral edema compared with the routine surgical group (P<0.05).? Conclusion: Neuronavigator-assisted microsurgery is effective and characterized by accurate location, personalized operative incision design, and higher rate of tumor resection. PMID- 28626101 TI - [Comparison of short-term outcomes between minimally invasive McKeown esophagectomy and Ivor-Lewis esophagectomy for esophageal cancer]. AB - OBJECTIVE: To summarize the outcomes of 74 patients with minimally invasive McKeown esophagectomy (MIE-McKeown), and to discuss the short-term outcomes by comparing with Ivor-Lewis esophagectomy (ILE) procedure.? Methods: A total of 74 patients with esophageal carcinoma underwent MIE-McKeown in Xiangya Hospital from November 2014 to July 2016 were retrospectively reviewed, and 85 patients underwent ILE procedure were selected as a control group. Perioperative and short term outcomes were analyzed.? Results: Compared with the ILE group, patients underwent MIE-McKeown had less blood loss, less pulmonary infection, longer resection length and more harvested lymph nodes (P<0.05), but they had more anastomotic leakage and stricture rate, longer operation time and hospital stay as well (P<0.05). The total rate of lymph node metastatic in all patients was 52.8%, and the rate of cervical lymph node metastases was 9.5% in the MIE-McKeown group. Multiple carcinomas were found in 16 cases, and 7 were proximally located. The distance from the distal margin of the second lesion to the center of the main lesion was 20-85 (50.7+/-23.0) mm, while the distance in 9 second carcinomas distally located was 30-90 (57.8+/-20.5) mm.? Conclusion: Compared with Ivor Lewis esophagectomy procedure, MIE-McKeown procedure has a more complete lesion dissection and more harvested lymph nodes with smaller incisions, better short term outcomes and more safety. It is an appropriate procedure for esophagectomy. However, it should be optimized for its high rate of anastomotic leakage and stricture. PMID- 28626102 TI - [Effects of dexmedetomidine on perioperative cardiac adverse events in elderly patients with ?coronary heart disease]. AB - OBJECTIVE: To investigate the effects of dexmedetomidine on perioperative cardiac adverse events in elderly patients with coronary heart disease.? Methods: Sixty elderly patients, who were diagnosed as coronary heart disease and underwent gastric cancer operation, were randomly divided into 2 groups (n=30): the dexmedetomidine group (Dex group) and the control group. In the Dex group, dexmedetomidine was administered intravenously at 0.5 MUg/(kg.h) after a bolus infusion at 0.5 MUg/kg for 10 min before anesthesia induction. In the control group, equal volume of normal saline was infused instead of dexmedetomidine. The 2 groups received the same anesthesia treatment. The venous bloods were collected at the preoperative 0 h and postoperative 24 h. The concentrations of cardiac troponin (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP) and hypersensitive C-reactive protein (hs-CRP) were determined. The ECG was monitored at the above time and the postoperative incidence of cardiac adverse events was recorded.? Results: The levels of cTnI, NT-proBNP and hs-CRP in serum were elevated in the 2 groups after the operation. Compared with the control group, the levels of cTnI, NT-proBNP and hs-CRP were significantly decreased in the Dex group (P<0.05). Compared with the control group, the incidence of bradycardia were significantly increased, while the myocardial ischemia and tachycardia were significantly decreased in the Dex group during the operation (P<0.05); the incidence of silent myocardial ischemia and arrhythmia was significantly reduced at 3 days after operation in the Dex group (P<0.05).? Conclusion: Dexmedetomidine could decrease the incidence of cardiac adverse events in elderly patients with coronary heart disease. PMID- 28626103 TI - [Study on lifestyle in patients with gastroesophageal ?reflux disease]. AB - OBJECTIVE: To investigate the correlation between certain unhealthy lifestyles and the incidence of gastroesophageal reflux disease (GERD), thus to provide the lifestyle guidelines for GERD patients.? Methods: Retrospective study were conducted for 402 GERD and 276 non-GERD out-patients in Department of Gastroenterology, Third Xiangya Hospital, Central South University from August, 2014 to August, 2015 based on questionnaire survey, then the correlation of unhealthy lifestyles with GERD were analyzed.? Results: The top 10 common symptoms for GERD were as follows: reflux, acid regurgitation, postprandial fullness, heartburn, swallow obstruction or pain, epigastric burning sensation, paraesthesia pharynges, poststernal pain, chronic laryngopharyngitis, and chronic cough. The top 8 unhealthy habits closely related to GERD were as follows: fast eating, over-eating, spicy preferred diet, sweets preferred diet, anxious, soup preferred diet, high-fat diet, and hot eating. Single-factor analysis showed that GERD was markedly correlated to gender (male), age (>=60 years), BMI, smoking, alcohol, fast-eating, over-eating, hot-eating, spicy preferred diet, high-fat diet, acid preferred diet, sweets preferred diet, hard food preference, strong tea preference, coffee preference, immediately on bed after meal, difficult defecation, dyscoimesis, anxious, and too tight belt, respectively (P<0.05). Logistic multiple regression analysis indicated that the largest risk factor for GERD was the fast-eating (OR=3.214, 95% CI 2.171 to 4.759, P<0.001) followed by the over-eating (OR=2.936, 95% CI 1.981 to 4.350, P<0.001), elderly population (OR=2.047, 95% CI 1.291 to 3.244, P=0.002), too tight belt (OR=2.003, 95% CI 1.013 to 3.961, P=0.046), and hot-eating (OR=1.570, 95% CI 1.044 to 2.362, P=0.030).? Conclusion: The elderly people are at high risk for GERD, and unhealthy habits like fast-eating, over-eating, too tight belt, and hot-eating is closely related to GERD. The lifestyles such as chewing food thoroughly, splitting the meals up, warm and cool diet, keeping patients out of the too tight belt are necessary for GERD patients. PMID- 28626104 TI - [Prevalence of vitamin D insufficiency/deficiency among overweight and obese preschool children in ?Yuelu District of Changsha]. AB - OBJECTIVE: To investigate the prevalence of vitamin D insufficiency/deficiency among 3-5 years old overweight and obese children in Yuelu district of Changsha and to give scientific suggestion for children health promotion.? Methods: Based on the stratified cluster sampling method, 2 872 children aged 3-5 years old from Yuelu district were enrolled from Oct to Dec 2015. All participants have received biochemical and physical examination. According to the body mass index, the prevalence rates of vitamin D insufficiency [serum 25(OH)D level 20-<30 ng/mL] and deficiency [serum 25(OH)D level<20 ng/mL] among normal weight, overweight/obese children were calculated, respectively. Multivariate logistic regression was used to evaluate the association between overweight/obese and vitamin D insufficiency/deficiency.? Results: The prevalence rates of vitamin D insufficiency/deficiency among children aged 3-5 years old were 39.6% (95% CI 37.8% to 41.4%) and 19.5% (95% CI 18.1% to 21.0%), respectively. Compared to children with normal weight, overweight/obese children had higher prevalence rate of vitamin D insufficiency [48.6% (95% CI 44.4% to 52.9%)] and deficiency [24.6% (95% CI 21.1% to 28.4%)] (P<0.017). After adjustment with confounding variables, the associations between overweight/obese and vitamin D insufficiency/deficiency were still statistically significant [for insufficiency ORadj=1.17 (95% CI 1.06 to 1.43); for deficiency ORadj=1.22 (95% CI 1.12 to 1.51)].? Conclusion: Compared with normal weight children, overweight/obese children have higher prevalence rate of vitamin D insufficiency/deficiency. More attention should be paid to those populations for prevention of vitamin D insufficiency/deficiency. PMID- 28626105 TI - [Association rule regarding chronic disease-relevant risk factors for the adults in Haidian District]. AB - OBJECTIVE: To investigate the association patterns of chronic disease-relevant risk factors for the adults in Haidian District.? Methods: Data for chronic disease-relevant risk factors for 3 219 adults in Haidian District in 2014 were collected and analyzed. SPSS 18.0 was used for statistical description and logistic regression. SPSS Modeler 14.1 was used to explore the association among the chronic disease-relevant risk factors.? Results: Among men, 5 patterns of chronic disease-relevant risk factors were identified, which suggested that heavy drinking, inadequate intake of fruit and vegetables, and physical inactivity were associated with smoking while inadequate intake of fruit and vegetables and smoking were associated with physical inactivity. Among women, one pattern of chronic disease-relevant risk factor was identified, which suggested that inadequate intake of fruit and vegetables was associated with physical inactivity.? Conclusion: Chronic disease-relevant risk factors are intercorrelated among the adults in Haidian District. Information on patterns of chronic disease-relevant risk factors could assist interventions targeting multiple behaviors simultaneously. PMID- 28626106 TI - [SEEDi: Basic strategies for the primary and secondary prevention of atherosclerotic cardiovascular disease]. AB - ABCDE strategy, mainly based on drugs or medications and the lifestyle modification (named as "main medical strategy"), is popular in the guideline for primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in China and foreign countries. Here, the author recommends a non invasive and non-pharmacologic "Zhongzi" rule, which includes 4 healthy elements: Sleep, emotion, exercise, and diet (SEED), and also called SEED intervention (SEEDi) strategy. It is the basic strategy for primary and secondary prevention of non-infectious diseases, especially for ASCVD. The strategy of SEEDi could decrease ASCVD morbidity and mortality. If the strategy of SEEDi is conducted positively and widely in the clinical work, it will achieve "three major changes" for ASCVD: From passive to active, from how to treat to how to prevent, and from hospital treatment to home care. It will create a new situation with less costs and better effects in ASCVD prevention and treatment in China. The morbidity and mortality for ASCVD will decrease significantly, and the prognosis and quality of life (QOL) will be improved significantly. PMID- 28626107 TI - [Molecular basis for prostate carcinogenesis]. AB - Prostate cancer is the most prevalent male urogenital malignancy. Androgen deprivation therapy is the principal method for initial treatment for the patients, but the majority of them will eventually develop progressive disease, a status called castration-resistant prostate carcinoma. Lots of susceptibility genes, tumor suppressor genes and oncogenes, and their variations relevant to the occurrence and development of prostate cancer have been revealed by the studies of molecular oncology. These findings on the molecular basis of prostate carcinogenesis will further improve the strategies on prevention, diagnosis and clinical management for prostate carcinoma. PMID- 28626108 TI - [A case of partial deletion of the long arm of chromosome 7]. AB - Partial deletion of the long arm of chromosome 7 is a rare disease and is prone to missing the diagnosis or being misdiagnosed. Here we present a case of a 13 year-old boy that showed symptoms such as growth-retardation, moderate intellectual disability, hypotelorism, microcephaly, epicanthal folds, genu varum and lumbar vertebral cleft, but it did not show serious symptoms like cleft lip, urogenital malformation and hypotonia. He was eventually diagnosed as partial deletion of the long arm of chromosome 7 syndrome through gene analysis. Considering the rare incidence of this disease and more rarely for being hospitalized to endocrine ward due to growth retardation, this case report can provide more information for clinic diagnosis and differential diagnosis for growth retardation. PMID- 28626109 TI - [Secondary infection of traumatic pulmonary cyst misdiagnosed as cholesterol encapsulated pleural effusion: a rare case and review of literature]. AB - Pulmonary cyst is a relatively common benign lesion. It is easy to be misdiagnosed when the cyst complicated with infection. This paper reported a case of a giant traumatic pulmonary cyst (diameter 10 cm) combined with chronic infection. Firstly, the patient was diagnosed as cholesterol pleurisy after undergoing thoracoscopic biopsy. With repeated pleural effusion, the patient was scheduled for right anterolateral thoracotomy, which showed a thin-walled cyst (10 cm in diameter) attached to parietal and diaphragm, with the stem of cavity originated from the right lower lobe after the cyst cavity was dissociated. Pathological examination revealed that it was apseudocyst, which could be diagnosed as traumatic pulmonary cyst combined with chronic infection according to history of trauma. After undergoing right lower lobectomy and stripping of fiberboard, the prognosis was good. Traumatic pulmonary cyst, which was discovered interval 10 years after chest trauma, was rare. Traumatic pulmonary cyst combined with cholesterol cystic fluid was very rare. Huge pulmonary cyst complicated with infection was easily misdiagnosed as loculated pleural effusion. Therefore, to be correct diagnosis and treatment, clinician must carefully ask medical history. In addition, early image examination should be considered in those patients with chest trauma whether there are clinical symptoms or not. PMID- 28626110 TI - [One case of gastric duplication cyst with?ectopic pancreas in adults]. AB - Gastric duplication cyst is a very rare gastrointestinal tract malformation that accounts for 2%-4% of alimentary tract duplications. It is a diagnostic dilemma for doctors because its clinical and radiological manifest is usually nonspecific. At the present stage, it can only rely on surgery. We should pay attention to ectopic pancreas resection and ligation of pancreatic duct during operation. There was one case of gastric duplication cyst with ectopic pancreas in adults from the Second Affiliated Hospital of Nanchang University. PMID- 28626111 TI - [Initial experience with robot-assisted laparoscopic prostatectomy for complicated cases]. AB - OBJECTIVE: To present our initial experience with robot-assisted laparoscopic prostatectomy (RALP) for complicated cases.? Methods: Clinical and pathological data from 4 complicated prostate cancer cases, who underwent RALP from October to November in 2015, were analyzed retrospectively. All the cases were conducted transurethral plasmakinetic enucleation of prostate and hormonal therapy before RALP.? Results: All surgeries were done successfully. The age, baseline prostatic special antigen, clinical tumor stage, operation time and estimated blood loss were 58-70 years, 6.04-70.15 ng/mL, T2b-T3b, 210-360 min and 50-250 mL, respectively. No blood transfusion was needed. All surgical margin were negative.? Conclusion: Although previous transurethral surgeries and hormonal therapies may increase the difficulty for operations, RALP is still appropriate for the complicated cases of prostate cancer. PMID- 28626112 TI - Experience with long-term administration of tolvaptan to patients with acute decompensated heart failure. AB - Tolvaptan (TLV) is an oral selective vasopressin type 2 receptor antagonist. Long term use of TLV is not recommended in patients with heart failure (HF) if fluid retention disappears and/or body weight is within the target range. However, some patients require long-term use of TLV. The current study investigated the efficacy and safety of long-term use of TLV. Subjects were 258 consecutive patients with HF who received TLV during hospitalization from January 2011 to March 2015. The rate of continuing administration of TLV was evaluated. Moreover, the one-year mortality rate and rate of re-hospitalization either with or without TLV were investigated. Results at discharge and one year later were compared for patients who continued to receive TLV one year after discharge. Oral concomitant medications, blood pressures, heart rate, blood tests, chest X-ray and transthoracic echocardiography were investigated. In-hospital and one-year mortality rates were 15.9% and 27.8%, respectively. Moreover, the mortality rate and/or rate of re-hospitalization within one year was 54.4%. The rate of re hospitalization for HF was significantly higher in patients who continued to receive TLV after discharge compared to patients who ceased receiving TLV after discharge (p < 0.001). However, the subjects who continued to receive TLV for up to one year after discharge tended to have a longer duration until re hospitalization for HF and significantly decreased brain natriuretic peptide levels (577.6 +/- 528.5 pg/mL to 397.3 +/- 365.8 pg/mL, p = 0.015). Long-term use of TLV might delay re-hospitalization for HF in patients with severe HF. Large scale clinical studies are necessary to verify these results. PMID- 28626113 TI - Effects of beta-estradiol on cold-sensitive receptor channel TRPM8 in ovariectomized rats. AB - Transient receptor potential cation channel subfamily M member 8 (TRPM8) is associated with sensitivity to cold sensation in mammals. A previous study demonstrated that TRPM8 was overexpressed in the skin of ovariectomized (OVX) rats due to the loss of estrogen. In the present study, we investigated whether estrogen replacement restricts overexpression of the TRPM8 channel in the skin of OVX rats. We divided 15 Sprague Dawley rats into three groups: a non-operated group (NON-OPE), an ovariectomy group (OVX), and a group subjected to estrogen replacement during 4 weeks beginning 7 days after ovariectomy (OVX + E2). Five weeks later, TRPM8 channel mRNA and protein in lumbar skin were quantified by real-time RT-PCR, protein ELISA, and immunohistochemistry. The OVX + E2 group exhibited a trend for decreased expression of the TRPM8 channel in the lumbar skin in comparison with the OVX group, whereas ELISA data and immunohistochemistry data and immunohistochemistry graphs relating to TRPM8 protein did not show any obvious differences between the OVX group and the OVX + E2 group. Estrogen replacement may restrict the overexpression of TRPM8 in the dermis of OVX rats. PMID- 28626114 TI - Thyroid-stimulating hormone stimulation downregulates autophagy and promotes apoptosis in chondrocytes. AB - Subclinical hypothyroidism (SCH) patients have normal thyroid hormone levels but increased thyroid stimulating hormone (TSH) level in serum. It has been reported that high TSH is related to abnormal skeletal development in mice with hypothyroidism. However, the cellular mechanism is not fully understood. In the present study, we aim to investigate the direct effects of TSH stimulation on chondrocytes, and the putative role of autophagy in this process. By using EdU incorporation assay and flow cytometry for mitochondrial membrane potential assay, we demonstrated deceased proliferation and promoted apoptosis in TSH stimulated primary mouse chondrocytes. And the balance of Bcl-2 and BAX expression on protein level was broken. More interestingly, the expression of autophagic markers Beclin-1 and LC3II was reduced in TSH stimulated chondrocytes, accompanied by less autophagosomes and accumulated p62 protein, indicating an impaired autophagic flux. More interestingly, mTOR was upregulated and AMPK activity was decreased in TSH stimulated PMCs, suggesting that mTOR/AMPK pathway is get involved in the regulation of TSH on autophagy in PMCs. Collectively, we found an increased apoptosis and suppressed autophagy in TSH stimulated primary chondrocytes, which is meaningful in understanding the effects of increased TSH level on articular cartilage and the role of autophagy in this process, and thus provide a potential novel therapeutic target in related cartilage damages. PMID- 28626115 TI - Reappraisal of "cyst fluid only" on thyroid fine-needle aspiration cytology. AB - According to the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), cyst fluid only (CFO) cases are classified in the non-diagnostic category. To date, no large study focusing on CFO has been conducted. To reassess the diagnostic significance of CFO, we compared CFO nodules with non-diagnostic nodules excluding CFO (ND-other). We reviewed the conventional thyroid smears of 715 CFO and 766 ND-other nodules. We compared the timing of and findings at re aspiration, the histology of resected specimens, and the proportion of malignant nodules between the two groups. Re-aspiration was performed in 9.0% of CFO and 23.8% of ND-other cases. In 12.5% of CFO and 49.4% of ND-other cases, the interval between the first and second aspirations was <3 months. Despite this, there were no cases in which cytological interpretation was complicated by the first aspiration. Overall, 77 CFO nodules (10.8%) were surgically resected; 14 were malignant. In all cases in which re-aspiration cytology revealed malignancy, the initial ultrasound interpretation was a high or intermediate suspicion pattern. The proportion of malignancies subsequently diagnosed in nodules initially classified as CFO and ND-other was 2.0% and 5.6%, respectively (p<0.01). As CFO and ND-other thyroid nodules have different clinical management and malignancy rates, we would like to assert that CFO and ND-other nodules should be separated, and that the former should be considered diagnostic. In terms of clinical management, we recommend that only CFO cases with concerning features on ultrasound undergo re-aspiration. PMID- 28626116 TI - Mitochondrial quality control by mitochondrial ubiquitin ligase MITOL/MARCH5. PMID- 28626117 TI - Physiological roles of mitochondria and mitofusins on Ca2+ signaling in smooth muscles. PMID- 28626118 TI - Mitochondrial proteolysis and its roles in stress responses. PMID- 28626119 TI - Eco-pharma of approved drug focused on mitochondria fission. PMID- 28626120 TI - Toward understanding structure and function of neural circuits in the visual system. PMID- 28626121 TI - In silico drug discovery by supercomputer "K". PMID- 28626122 TI - Pharmacological properties and clinical findings of rifaximin (RIFXIMA(r) TABLETS 200 mg). PMID- 28626123 TI - Significance of Intratracheal Instillation Tests for the Screening of Pulmonary Toxicity of Nanomaterials. AB - Inhalation tests are the gold standard test for the estimation of the pulmonary toxicity of respirable materials. Intratracheal instillation tests have been used widely, but they yield limited evidence of the harmful effects of respirable materials. We reviewed the effectiveness of intratracheal instillation tests for estimating the hazards of nanomaterials, mainly using research papers featuring intratracheal instillation and inhalation tests centered on a Japanese national project. Compared to inhalation tests, intratracheal instillation tests induced more acute inflammatory responses in the animal lung due to a bolus effect regardless of the toxicity of the nanomaterials. However, nanomaterials with high toxicity induced persistent inflammation in the chronic phase, and nanomaterials with low toxicity induced only transient inflammation. Therefore, in order to estimate the harmful effects of a nanomaterial, an observation period of 3 months or 6 months following intratracheal instillation is necessary. Among the endpoints of pulmonary toxicity, cell count and percentage of neutrophil, chemokines for neutrophils and macrophages, and oxidative stress markers are considered most important. These markers show persistent and transient responses in the lung from nanomaterials with high and low toxicity, respectively. If the evaluation of the pulmonary toxicity of nanomaterials is performed in not only the acute but also the chronic phase in order to avoid the bolus effect of intratracheal instillation and inflammatory-related factors that are used as endpoints of pulmonary toxicity, we speculate that intratracheal instillation tests can be useful for screening for the identification of the hazard of nanomaterials through pulmonary inflammation. PMID- 28626124 TI - Two Cases of Tuberous Sclerosis Complex Suggestive of Complicating Multifocal Micronodular Pneumocyte Hyperplasia: A Case Report. AB - Multifocal micronodular pneumocyte hyperplasia (MMPH) is pathologically characterized by multifocal nodular hyperplasia of type II pneumocyte-like cells. MMPH is usually complicated with tuberous sclerosis complex (TSC). MMPH patients tend to be asymptomatic or only slightly symptomatic. MMPH tends to progress slowly and needs no treatment. We herein describe two cases of MMPH with its characteristic radiological features and clinical manifestations of TSC. Case 1: a 20-year-old female with definitive TSC in infancy. Chest CT at the age of 18 revealed multiple nodular opacities and ground-glass attenuations in a scattered and random distribution in the bilateral lungs. Case 2: a 44-year-old female with probable TSC at 36 years of age. Chest CT at the age of 43 showed random areas of small ground-glass attenuations, predominantly in the upper lung fields. Case 1 and Case 2 have had no respiratory symptoms or radiographic changes in the recent two years and four years, respectively. Although pathological examinations of the lung were not performed because consent for surgical lung biospies was unobtainable, we considered that these pulmonary manifestations were most likely MMPH with TSC because of these characteristic radiographical findings of multiple nodular opacities and ground-glass attenuations of 10 mm or less in size and their scattered distribution, and because there have been no abnormal laboratory data or changes in their chest radiological findings for years. Neither patient is under treatment for pulmonary lesions. Although MMPH is a rare disease, multiple nodules and ground-glass attenuations on lung imaging findings should be considered as pulmonary manifestations in patients with TSC. PMID- 28626126 TI - Conduct of Occupational Health During Major Disasters: A Comparison of Literature on Occupational Health Issues in the World Trade Center Terrorist Attack and the Fukushima Nuclear Power Plant Accident. AB - Workers who respond to large-scale disasters can be exposed to health hazards that do not exist in routine work. It is assumed that learning from past cases is effective for preparing for and responding to such problems, but published information is still insufficient. Accordingly, we conducted a literature review about the health issues and occupational health activities at the World Trade Center (WTC) terrorist attack and at the Fukushima Nuclear Power Plant accident to investigate how occupational health activities during disasters should be conducted. Seven studies about the WTC attack were extracted and categorized into the following topics: "in relation to emergency systems including occupational health management"; "in relation to improvement and prevention of health effects and occupational hygiene"; and "in relation to care systems aimed at mitigating health effects." Studies about the Fukushima Nuclear Power Plant accident have been used in a previous review. We conclude that, to prevent health effects in workers who respond to large-scale disasters, it is necessary to incorporate occupational health regulations into the national response plan, and to develop practical support functions that enable support to continue for an extended period, training systems for workers with opportunities to report accidents, and care systems to mitigate the health effects. PMID- 28626125 TI - The Importance of the Maternal/Self-Role Satisfaction for Reducing Anxiety: A Cross-Sectional Survey of Japanese Mothers. AB - Women who rear children have two types of roles: the maternal role and the self role. Previous studies have suggested that maternal role satisfaction is related to anxiety, but the importance of self-role satisfaction in promoting the health of mothers has received less attention. The changing roles of women in society, especially in urban areas, have altered mothers' views of child-rearing. Our primary focus was on the relationship between maternal/self-role satisfaction and anxiety in mothers. To examine this, we conducted a cross-sectional survey using self-administered questionnaires that were distributed in 2011 to 2,342 mothers attending the 18-month health checkup of their children, in 7 cities of the Tokyo metropolitan area. A total of 881 responded (effective response rate = 38.0%). Multiple regression analysis revealed that maternal role satisfaction and self role satisfaction were both significantly and negatively associated with anxiety. Thus, self-role satisfaction should be considered alongside maternal role satisfaction in evaluating and reducing anxiety. Health care professionals in community settings should conduct comprehensive assessments of maternal role satisfaction and self-role satisfaction. PMID- 28626127 TI - A Case of Retroperitoneal Paraganglioma. AB - We report a surgical case of retroperitoneal paraganglioma. A paraganglioma is a catecholamine-producing tumor originating in the chromaffin cells of the sympathetic ganglion. It is a kind of pheochromocytoma which occurs on the outside of the adrenal gland. The patient was a 72 year old male with a history of hypertension and a pacemaker implantation. A mass in the ventral side of the right iliopsoas muscle was detected during a routine contrasting computed tomography (CT) examination for checking his pacemaker. The mass was considered to be malignant, and a laparotomy and mass enucleation was performed. It was diagnosed as phaeochromocytoma, based on the pathology and immunestology of the excised specimen. The hypertension was cured soon after the surgery. Nine months after surgery, there is no evidence of any abnormality or recurrence. There is a previous report of a recurrence 25 years after surgery, so a careful follow-up of this patient will be necessary in the future. PMID- 28626128 TI - A Case of Matrix-Producing Carcinoma of the Breast. AB - A 61-year-old woman was referred to our hospital because of a right breast mass. A 19 mm hard mass was palpable in the A area of the right breast. A contrast enhanced MRI showed rim enhancement at the peripheral region of the tumor, which was thought to represent the carcinoma component mainly at the periphery and the matrix component inside the tumor. A low density mass with rim enhancement at the peripheral region was observed in a contrast-enhanced CT, the same as in the MRI. Neither axillary lymph node metastasis nor distant metastasis was observed. A core needle biopsy of the tumor lead to a diagnosis of matrix-producing carcinoma (MPC). A breast-conserving mastectomy with sentinel lymph nodes biopsy was performed on the right breast MPC (T1c, N0, M0 Stage I). Histopathologically, the tumor demonstrated overt carcinoma with direct transition to a cartilaginous or osseous matrix and lacked an intervening spindle cell component. Immunohistochemistry showed estrogen receptor (ER) (-), progesterone receptor (PgR) (-), human epidermal growth factor receptor 2 (HER2) (-), and Ki67 index of 50%, so-called triple negative breast cancer. The tumor was also positive for SRY related HMG box-9 (SOX9), which is a useful marker of chondroid differentiation in normal and neoplastic tissues. The patient lived free from recurrence for 5 years, even though her adjuvant therapy was only radiation therapy without adjuvant chemotherapy. MPC is an uncommon and relatively rare variant of metaplastic carcinoma, and the prognosis for patients with MPC is poorer than that for patients with ordinary breast cancer. Here we report a case of MPC of the breast with characteristic rim enhancement in contrast-enhanced MRI and CT. The intrinsic subtype and prognosis of MPC is controversial, and then we may need more experience with MPC cases. PMID- 28626129 TI - Nursing Education Trial Using a Virtual Nightingale Ward. AB - Nursing department students are expected to correctly grasp the entire concept of nursing through their education. The authors created a movie of a Nightingale ward (virtual ward, hereafter) with an architectural computer design software for education. The students' reaction to the virtual ward was categorized into three viewpoints: that of nurses, of patients, and of nurses and patients in common. Most of the reactions in each viewpoint were: "easy to observe patients" in the nurses' viewpoint; "no privacy" in the patients' viewpoint; and "wide room" in the common viewpoint, respectively. These reactions show the effectiveness of using a virtual ward in nursing education. Because these reactions are characteristics of a Nightingale ward, and even students, who have generally less experiences, recognized these characteristics from the both viewpoints of nurses and patients. PMID- 28626130 TI - Examination of a New Desorption Method for Solid Adsorption Method of Working Environment Measurement -Attempt to Improve Desorption Efficiency of Organic Solvents from a Coconut-Shell-Activated Carbon Using Surfactant Solutions-. AB - For a new desorption method development for working environment measurement, desorption efficiency of organic solvent vapors from an activated carbon was examined using desorption solutions that consisted of anionic and nonionic surfactants. Ten MUl of an aqueous solution of isopropyl alcohol or methyl ethyl ketone diluted with distilled water was spiked into a 10 ml vial with a coconut shell-activated carbon (100 mg). The vial was left for 24 h, and 5 ml a desorption solution was added. Afterwards, the vial was put into an incubator at 60 degrees C and left for 24 h, then the desorption efficiency was determined by analyzing the headspace gas in the vial with a gas chromatograph equipped with flame ionization detector. By adding one or four kinds of nonionic surfactants to the aqueous solution containing two kinds of anionic surfactants, the effect adding nonionic surfactant to the desorption efficiency was investigated, but improvement of desorption efficiency was not observed. On the other hand, desorption efficiency varied depending on the production lot of the coconut-shell activated carbon tube used as the adsorbent. PMID- 28626131 TI - Homozygous DUOXA2 mutation (p.Tyr138*) in a girl with congenital hypothyroidism and her apparently unaffected brother: Case report and review of the literature. AB - Mutations in DUOXA2, encoding dual oxidase maturation factor 2, is a rare genetic cause of congenital hypothyroidism. Only four biallelic DUOXA2 mutation carriers have been described to date. This study was conducted to report the clinical and genetic findings of a DUOXA2 mutation-carrying family, and to review the previously reported cases. The proband was a 4-year-old girl, who was diagnosed as having congenital hypothyroidism in the frame of newborn screening. She had a high serum TSH level (138 mU/L) and a low free T4 level (0.4 ng/dL). Ultrasonography revealed goiter. She was immediately treated with levothyroxine. At age 3 years, reevaluation of her thyroid function showed a slightly elevated serum TSH level (11.0 mU/L) with normal free T4 level. Screening of the eleven congenital hypothyroidism-related genes demonstrated a previously reported nonsense DUOXA2 mutation (p.Tyr138*) in the homozygous state. Unexpectedly, we also found that the elder brother of the proband, who had no significant past medical history, had the identical homozygous mutation. Using expression experiments with HEK293 cells, we confirmed that p.Tyr138* was a loss-of-function mutation. In the literature, clinical courses of three patients were described, showing characteristic age-dependent improvement of the thyroid function. In conclusion, The proband showed comparable clinical phenotype to previously reported cases, while her brother was unaffected. The phenotypic spectrum of DUOXA2 mutations could be broader than currently accepted. PMID- 28626132 TI - Performance of Palm-Based C16/18 Methyl Ester Sulphonate (MES) in Liquid Detergent Formulation. AB - Liquid detergents are more convenient than powdered detergents as they dissolve readily in water, generate less dust and dosing is easy. However, the stability of liquid detergents is an issue of concern. Therefore, the objective of this research is to study the formulation requirement to produce heavy-duty liquid detergents based on palm-based methyl esters sulphonate (MES) with desirable properties and performance. MES is produced from renewable and sustainable feedstock suitable to replace the conventional fossil-based surfactant, linear alkyl benzene sulphonates (LAS). Five palm-based liquid detergents (PBLDs) were formulated using C16/18 MES as the primary surfactant. The physical properties, washing performance, stability and biodegradability of PBLDs were evaluated. Performance of the PBLDs was evaluated against two commercial liquid detergents which use LAS and alcohol glucoside as surfactant (benchmark product) and it was found that the PBLDs exhibited excellent performance. PBLDs can be formulated with or without phosphates and still demonstrate good detergency. The stability study of PBLDs indicated that no appreciable hydrolysis occurred. PBLDs exhibited better biodegradability profiles compared to commercial detergent containing LAS. PBLDs passed the 60% biodegradability level within 3 to 8 d, while commercial detergent took 24 d. It was shown that palm-based C16/18 MES could be potentially formulated into liquid detergents and gave better performance than LAS based liquid detergent. Attributes of C16/18 MES should not be overlooked, which include an abundant and naturally derived palm stearin as raw material and environmental safety profiles that are superior to most synthetic surfactants. PMID- 28626133 TI - Simple Synthesis Hydrogenated Castor Oil Fatty Amide Wax and Its Coating Characterization. AB - A simple method for incorporating amine groups in hydrogenated castor oil (HCO) to produce wax for beeswax or carnauba wax substitution in packaging and coating was developed. From the conversion rate of the products, HCO was reacted with ethanolamine at 150 degrees C for 5 h, and the molar ratio of HCO and ethanolamine was 1:4. The hardness of the final product was seven times higher than that of beeswax, the cohesiveness of the final product was 1.3 times higher than that of beeswax and approximately one half of that of carnauba wax, and the melting point of the final product is 98 degrees C. The Fourier transform Infrared spectroscopy showed that the amide groups were incorporated to form the amide products. In coating application, the results showed that the force of the final product coating cardboard was higher than that of beeswax and paraffin wax and less than that of carnauba wax. After 24 h soaking, the compression forces were decreased. HCO fatty acid wax can be an alternative wax for carnauba wax and beeswax in coating applications. PMID- 28626134 TI - Synthesis and Detection by HPLC of 3-Oxohexadecanoyl-CoA for the Study of Peroxisomal Bifunctional Proteins. AB - 3-oxohexadecanoyl-CoA was synthesized for the study of D-bifunctional protein (EC 4. 2. 1. 107, EC 4. 2. 1. 119, EC 1. 1. 1. n12) and L-bifunctional protein (EC 4. 2. 1. 17, EC 5. 3. 3. 8, EC 1. 1. 1. 35). First, tetradecanal was subjected to the Reformatsky reaction with ethyl bromoacetate, and the product was then converted into ethyl 3-oxohexadecanoate. After acetalization of the 3-oxo ester with ethylene glycol, 3,3-ethlenedioxyhexadecanoic acid was obtained by alkaline hydrolysis. The acid was condensed with coenzyme A (CoA) by the mixed anhydride method, and the resulting CoA ester was deprotected with 4 M HCl to obtain 3 oxohexadecanoyl-CoA. In addition, the behavior of the CoA ester under several conditions of high-performance liquid chromatography (HPLC) was also investigated. We established separation detection of (R)-3-hydroxyhexadecanoyl CoA, (S)-3-hydroxyhexadecaboyl-CoA, 3-oxohexadecanoyl-CoA, and trans-2 hexadecenoyl-CoA. PMID- 28626135 TI - Adsorption of the Three-phase Emulsion on Various Solid Surfaces. AB - The present study investigates the adsorption of the three-phase emulsion on various solid/water interfaces. Vesicles can be used as emulsifiers in the three phase emulsions and act as an independent phase unlike the surfactant used in conventional emulsions; therefore, it is expected that the three-phase emulsion formed by the adhesion of vesicles to the oil/water interface will adsorb on various solid/water interfaces. The cationic three-phase emulsion was prepared to encourage emulsion adsorption on negatively charged solid substrates in water. The emulsifier polyoxyethylene-(10) hydrogenated castor oil was rendered cationic by mixing with the surfactant cetyltrimethylammonium bromide and then used to prepare the cationic three-phase emulsion of hexadecane-in-water. Three solid substrates (silicon, glass, and copper) were dipped in the cationic emulsion and the emulsion was found to adsorb on the solid substrates while maintaining its structure. The amount of hexadecane adsorbed on the various surfaces was investigated by gas chromatography and found to increase with increasing hexadecane concentration in the emulsion and eventually plateaued just like molecular adsorption. The maximum surface coverage of the emulsion on the substrates was approximately 80%. However, even the equivalent nonionic three phase emulsion was found to adsorb on the three solid surfaces. This was attributed to a novel mechanism of irreversible adhesion via the van der Waals attractive force. PMID- 28626136 TI - Effect of Hydroxyl Groups on Solubilization States of Alkandiols in DTAB Micelles: Application of a Differential Conductivity Technique. AB - The partition coefficients, Kx, of 1,2-alkanediols and alpha,omega-alkanediols between dodecyltrimethylammonium bromide (DTAB) micelles and water, and the change of the degree of counterion dissociation, dalpha/dXam, on DTAB micelles associated with solubilization of the alkanediols are determined by a differential conductivity technique. The standard Gibbs energy change of transfer per methylene group, DeltaG0(CH2), is estimated from a dependence of logarithmic value of the Kx on the carbon number of alkyl chain in the alkanediols. The dalpha/dXam is independent of the carbon number of alkyl chain in the alkanediols. Comparing the present results with those of DTAB/1-alkanols system, it is suggested that solubilization states of the alkanediols in DTAB micelles are as follows: 1,2-alkanediols are solubilized as its alkyl chain is oriented to micellar interior just like 1-alkanols, while alpha,omega-alkanediols are solubilized as its alkyl chain is partly located in micellar surface region. PMID- 28626137 TI - Novel Palm Fatty Acid Functionalized Magnetite Nanoparticles for Magnetic Solid Phase Extraction of Trace Polycyclic Aromatic Hydrocarbons from Environmental Samples. AB - A novel adsorbent, palm fatty acid coated magnetic Fe3O4 nanoparticles (MNP-FA) was successfully synthesized with immobilization of the palm fatty acid onto the surface of MNPs. The successful synthesis of MNP-FA was further confirmed by X Ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR) and Energy dispersive X-Ray spectroscopy (EDX) analyses and water contact angle (WCA) measurement. This newly synthesized MNP-FA was applied as magnetic solid phase extraction (MSPE) adsorbent for the enrichment of polycyclic aromatic hydrocarbons (PAHs), namely fluoranthene (FLT), pyrene (Pyr), chrysene (Cry) and benzo(a)pyrene (BaP) from environmental samples prior to High Performance Liquid Chromatography- Diode Array Detector (HPLC-DAD) analysis. The MSPE method was optimized by several parameters such as amount of sorbent, desorption solvent, volume of desorption solvent, extraction time, desorption time, pH and sample volume. Under the optimized conditions, MSPE method provided a low detection limit (LOD) for FLT, Pyr, Cry and BaP in the range of 0.01-0.05 ng mL-1. The PAHs recoveries of the spiked leachate samples ranged from 98.5% to 113.8% with the RSDs (n = 5) ranging from 3.5% to 12.2%, while for the spiked sludge samples, the recoveries ranged from 81.1% to 119.3% with the RSDs (n = 5) ranging from 3.1% to 13.6%. The recyclability study revealed that MNP-FA has excellent reusability up to five times. Chromatrographic analysis demonstrated the suitability of MNP-FA as MSPE adsorbent for the efficient extraction of PAHs from environmental samples. PMID- 28626138 TI - Evaluation of Sorption Mechanism of Pb (II) and Ni (II) onto Pea (Pisum sativum) Peels. AB - The present study was carried out to know the sorption mechanism of Pb (II) and Ni (II) in aqueous solution using pea peels under the influence of sorbent dose, pH, temperature, initial metal ion concentration and contact time. SEM and FTIR were used for characterization of pea peels. The study showed that solution pH affects sorption process and the optimum pH for Pb (II) was 6.0 while for that of Ni (II) was 7.0. Pseudo-second order kinetic model was found to be the most suitable one to explain the kinetic data not only due to high value of R2 (>0.99) but also due to the closeness of the experimental sorption capacity values to that of calculated sorption capacity values of pseudo second order kinetic model. It can be seen from the results that Freundlich isotherm explains well the equilibrium data (R2>0.99). Sorption capacity of pea peels was 140.84 and 32.36 for Pb (II) and Ni (II) mg g-1 respectively. The positive value of DeltaH degrees and negative values of DeltaG degrees suggest that sorption of Pb (II) and Ni (II) onto pea peels is an endothermic and spontaneous process respectively. PMID- 28626139 TI - Synthesis of Ricinoleic Acid Estolides by the Esterification of Ricinoleic Acids Using Functional Acid Ionic Liquids as Catalysts. AB - Estolides of ricinoleic acid (RA) have been used as lubricants and pigment dispersant in many industries. In this paper, functional acid ionic liquids (ILs) were firstly used as catalysts to prepare RA estolides by the esterification of RAs in solvent-free system. Different ILs were used as catalysts for the esterification. Effect of reaction variables (IL amount, reaction temperature and reaction time) on the esterification were also investigated and optimized using response surface methodology (RSM). Among all tested ILs, [BSO3HMIM]TS showed the best performance for the esterification. Arrhenius equation for the esterification was lnV0 =14.897-7558.7/T, and the activation energy (Ea) was 62.84 kJ/mol. A high degree of polymerization with an acid value of 48.0+/-2.5 mg KOH/g was achieved at the optimized conditions (IL load 12%, reaction temperature 140 degrees C, and reaction time 12 h). The effect of reaction variables on the esterification decreased in the order of catalyst loading of IL > reaction temperature > reaction time. PMID- 28626140 TI - Long-chain Polyunsaturated Fatty Acid Supplementation Improves Mood in Elderly Japanese Men. AB - Although several studies have reported the effects of long-chain polyunsaturated fatty acid (LCPUFA) supplementation on the mood in healthy adults, the effects of LCPUFA on elderly individuals remain unclear. Thus, we hypothesized that LCPUFA supplementation improves mood in the elderly. To address this hypothesis, 115 elderly Japanese men aged 55-64 years were assigned and randomly allocated to the LCPUFA or placebo group. Participants received 4 weeks of supplementation with LCPUFA-containing oil (docosahexaenoic acid (DHA) 300 mg/day, eicosapentaenoic acid (EPA) 100 mg/day, arachidonic acid (ARA) 120 mg/day) or a placebo oil. Mood was assessed using the Profile of Mood States (POMS) before and after supplementation as the secondary outcome in a previously performed randomized controlled trial on cognitive function. A total of 113 participants completed the supplementation period. One hundred participants (LCPUFA, n = 51; placebo, n = 49) who were eligible for evaluation of mood were analyzed. Increases in vigor scores on POMS, reflecting a positive mood, were significantly larger in the LCPUFA group than in the placebo group (LCPUFA, +1.8; placebo, -0.5). No significant differences were observed in changes in other negative mood scores between groups. DHA and ARA content in plasma phospholipids were increased by 0.8% and 0.7%, respectively, in the LCPUFA group, and were significantly larger than those in the placebo group. Dietary DHA, EPA, and ARA intake was unchanged during the study. These results suggest that LCPUFA supplementation may improve vigor (positive mood) in elderly Japanese men. PMID- 28626141 TI - Dietary Starfish Oil Prevents Hepatic Steatosis and Hyperlipidemia in C57BL/6N Mice Fed High-fat Diet. AB - Starfish oil (SO) is characterized by functional lipids, including n-3 polyunsaturated fatty acid (both in the form of triacylglycerol and in the form of phospholipid), and carotenoids, which may exert beneficial effects on metabolic disorders in obesity-associated diseases. In the present study, the effect of SO on dysregulation of lipid metabolism was examined using C57BL/6N mice treated with high-fat (HF) diet. Mice were fed HF, HF with 2% SO, or HF with 5% SO diet for 8 weeks. Weight gain, blood glucose, serum and hepatic lipid contents, and hepatic fatty acid composition were measured. Fatty acid beta oxidation activity was monitored by measuring the catabolic rate of 13C-labeled fatty acid, assessed as 13CO2/12CO2 ratio using isotope ratio mass spectrometry (IR-MS). Although there were no differences in body weight or white adipose tissue weight among the test groups, dietary SO reduced blood glucose, and dose dependently improved hyperlipidemia and decreased hepatic lipid accumulation. Analysis of hepatic fatty acid composition revealed a significant decrease in the ratio of monounsaturated fatty acid to saturated fatty acid, which is attributed to stearoyl-CoA desaturase activity. IR-MS analysis suggested that beta-oxidation activity was enhanced in the mice treated with 5% SO. These results demonstrate that dietary SO improves lipid metabolism measures in HF diet-induced obese mice, suggesting that SO holds promise as an agent for the prevention and treatment of lipid metabolism disorders in the liver. PMID- 28626142 TI - Surface Modification of PDMS and Plastics with Zwitterionic Polymers. AB - Surface modification of PDMS, polycarbonate, and acrylic resin was examined using various methacryl polymers bearing sulfobetaine, phosphoryl choline, and oligoethylene glycol units. We have found that zwitterionic polymers are adsorbed on the PDMS surface treated with plasma. The surface of PDMS is stable to keep high hydrophilicity after a month of the modification. On the other hand, one of sulfobetaine polymers showed distinguished adsorption behavior in the case of polycarbonate surface treated with plasma. Suppression effect for nonspecific adsorption of BSA was evaluated using polycarbonate and acrylic resin modified with the polymers. The modified surfaces showed suppression effect for nonspecific adsorption of BSA compared with the surface only treated with plasma. PMID- 28626143 TI - Effect of Conjugated Linoleic Acid Intake on Endurance Exercise Performance and Anti-fatigue in Student Athletes. AB - Conjugated linoleic acids (CLA) intake has been reported to reduce body fat mass or increase lean body mass and to improve exercise outcome by modulating testosterone in humans. These reports have studied mostly overweight subjects; few were athletes. Therefore, in this study, the effect of CLA intake on endurance performance and anti-fatigue in student athletes was investigated. A double-blind, crossover study was conducted with 10 male student athletes. Each subject was administered with either CLA (net 0.9 g/day) or a placebo for 14 days. They were subjected to an exercise tolerance test (steady loading) using a cycle ergometer on days 0 and 14. Peak VO2 was determined for each subject using a graded loading test. The steady loading test was performed with a pedaling exercise load of 50% peak VO2 for 40 min and then with a load of 70% peak VO2 until exhaustion. Blood sampling and measurement of critical flicker frequency (CFF) were performed before and after exercise. The rate of perceived exertion (RPE) was measured serially during exercise. In the results, amount of body weight variation significantly increased and amount of body fat percentage variation tended to decrease by CLA intake, it might have an effect by increase in muscle mass. In addition, amount of exercise time variation significantly increased, amount of variation of CFF before and after exercise tended to increase, that of RPE during exercise tended to decrease, and that of creatine phosphokinase before and after exercise tended to decrease in the CLA group. These results suggested that CLA intake for 14 days might have an effect on endurance performance and anti-fatigue in student athletes. PMID- 28626144 TI - Glass Bead-based Genetic Transformation:An Efficient Method for Transformation of Thraustochytrid Microorganisms. AB - Here, we describe a new method for genetic transformation of thraustochytrids, well-known producers of polyunsaturated fatty acids (PUFAs) like docosahexaenoic acid, by combining mild glass (zirconia) bead treatment and electroporation. Because the cell wall is a barrier against transfer of exogenous DNA into cells, gentle vortexing of cells with glass beads was performed prior to electroporation for partial cell wall disruption. G418-resistant transformants of thraustochytrid cells (Aurantiochytrium limacinum strain SR21 and thraustochytrid strain 12B) were successfully obtained with good reproducibility. The method reported here is simpler than methods using enzymes to generate spheroplasts and may provide advantages for PUFA production by using genetically modified thraustochytrids. PMID- 28626145 TI - Hydrophilic Polymer Embolism in the Lung as an Adverse Event - Autopsy Case of Thromboembolisms in Multiple Organs Associated With Heparin-Induced Thrombocytopenia. PMID- 28626146 TI - Mitral Valve Structure in Addition to Myocardial Viability Determines the Outcome of Functional Mitral Regurgitation After Coronary Artery Bypass Grafting. AB - BACKGROUND: Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated with ischemic heart disease, although the predictive factors or mechanisms of reversibility of functional MR after CABG are not fully understood.We investigated whether mitral valve structure is associated with the outcome of functional MR after CABG.Methods and Results:From a consecutive series of 98 patients with mild-moderate functional MR preoperatively who underwent isolated CABG, we enrolled 66 patients who were followed up for >1 year postoperatively using echocardiography. The degree of MR was reduced in 34 patients (52%) postoperatively, in association with a lower rate of in-hospital treatment for cardiac failure in the long term, compared with the 32 patients (48%) with residual MR postoperatively. The patients with reduced MR postoperatively had longer estimated coaptation length and more anteriorly or centrally directed MR jets than those without reduced MR. On statistical analysis, the addition of estimated coaptation length and jet direction to the reported predictors (ejection fraction, left ventricular end-diastolic dimension, and tenting height) more accurately predicted changes in post-CABG MR than the reported 3 factors alone. CONCLUSIONS: Residual MR was associated with the emergence of congestive heart failure in the long term after CABG. A specific mitral valve structure, such as large mitral leaflet size or predominant tethering of the posterior leaflet, was a predictive factor for the reversibility of post-CABG functional MR. PMID- 28626147 TI - Depleted Leukocyte Mitochondrial DNA Copy Number Correlates With Unfavorable Left Ventricular Volumetric and Spherical Shape Remodeling in Acute Myocardial Infarction After Primary Angioplasty. AB - BACKGROUND: Left ventricular (LV) shape influences LV systolic function. It is possible to assess LV shape using 3-D echocardiography sphericity index (SI). Maintaining mitochondrial DNA copy number (MCN) is important for preserving mitochondrial function and LV systolic function after acute myocardial infarction (AMI). Information is limited, however, regarding the relationship between leukocyte MCN and the subsequent change in LV shape after AMI.Methods and Results:Fifty-five AMI patients undergoing primary angioplasty were recruited. Plasma MCN was measured before primary angioplasty using quantitative polymerase chain reaction. 3-D echocardiography measurement of SI was performed at baseline, and at 1-, 3-, and 6-month follow-up. AMI subjects with MCN lower than the median had a higher 6-month SI and LV volume compared with those with higher MCN. Baseline echocardiographic parameters were similar between the 2 groups. MCN was negatively correlated with 3- and 6-month SI, and 3- and 6-month LV volume. On multiple linear regression analysis, baseline plasma MCN could predict LV SI and LV volume at 6 months after primary angioplasty for AMI, even after adjusting for traditional prognostic factors. CONCLUSIONS: In AMI patients, higher plasma leukocyte MCN at baseline was associated with favorable LV shape and remodeling at 6-month follow-up. Plasma leukocyte MCN may provide a novel prognostic biomarker for LV remodeling after AMI. PMID- 28626148 TI - Prevalence of Thin-Cap Fibroatheroma in Relation to the Severity of Anatomical and Physiological Stenosis. AB - BACKGROUND: The relationship between the features of morphologically unstable plaque and physiological lesion severity remains elusive. We aimed to investigate this relationship using optical coherence tomography (OCT)-derived high-risk plaque characteristics and fractional flow reserve (FFR) as the degree of anatomical and physiological stenosis severity.Methods and Results:We investigated 286 de novo intermediate and severe coronary lesions in 248 patients who underwent OCT and FFR examinations. Lesions were divided into tertiles based on either FFR or quantitative coronary angiographic diameter stenosis (QCA-%DS). The OCT findings were compared among the tertiles of FFR and QCA-%DS. FFR and QCA tertiles were defined as follows: FFR-T1 (FFR <0.74), FFR-T2 (0.74<=FFR<=0.81), and FFR-T3 (FFR >0.81); and QCA-T1 (%DS >=61%), QCA-T2 (51%<=%DS<61%), and QCA-T3 (%DS <51%). The prevalence of thin-cap fibroatheroma (TCFA) was significantly greater in FFR-T1 (20.0%) than in FFR-T2 and FFR-T3 (7.0%, P=0.03 and 7.7%, P=0.04, respectively), although no significant differences were observed among the QCA tertiles. CONCLUSIONS: Physiological severity of coronary stenosis evaluated by FFR correlated with plaque instability in terms of TCFA. Preferable clinical outcomes for lesions with negative FFR based on the existing clinical evidence might be attributable to less likelihood of TCFA. PMID- 28626149 TI - Use of CHA2DS2-VASc Score to Predict New-Onset Atrial Fibrillation in Chronic Obstructive Pulmonary Disease Patients - Large-Scale Longitudinal Study. AB - BACKGROUND: The aim of this study was to assess the accuracy of CHA2DS2-VASc score in predicting new-onset atrial fibrillation (AF) in patients with chronic obstructive pulmonary disease (COPD).Methods and Results:A total of 50,430 COPD patients were enrolled in this study. The area under the receiver operating characteristic curve (AUC) and the Cox model c-statistic were used to assess the association between new-onset AF risk and CHA2DS2-VASc score in COPD patients. After adjustment for comorbidities other than the components of CHA2DS2-VASc score, risk of new-onset AF in COPD patients increased from 1.24 (95% confidence interval (CI): 1.01-1.52) for a score of 1, to 2.15 (95% CI: 1.62-2.86) for score >=6 (trend test, P<0.001), compared with CHA2DS2-VASc score 0. The AUC for CHA2DS2-VASc score in predicting new-onset AF in COPD patients was 0.69 (95% CI: 0.68-0.70). The c-statistic of Cox model in predicting incident AF was 0.73. CONCLUSIONS: Risk of new-onset AF in COPD patients increased with increasing CHA2DS2-VASc score. The predictive ability of the score was moderate. CHA2DS2 VASc score might be used as a screening tool for AF in COPD patients. PMID- 28626151 TI - Changes in social interaction over 20 years and the effects of community resources use among community-dwelling elderly persons. AB - Objectives Recently, social isolation has been reported to be a critical problem among Japanese elderly persons. However, few studies have compared social interaction in the past and the present or investigated its predictive factors. This study aimed to clarify the transitional changes in social interaction over 20 years and explore the factors related to social interaction focusing on the use of community resources.Methods The participants were community-dwelling elderly persons aged 65 years and over. A survey was conducted 8 times from 1994 to 2014 in the suburban area of Tobishima, Japan. The Index of Social Interaction Scale was used and each subscale and the total score were calculated. Subsequently, the 2014 scores were compared with the 1994 scores using the Wilcoxon rank sum test. Logistic regression analysis was conducted to clarify the factors related to social interaction, focusing on the association between the use of community resources (local elderly management center, health care center, health promotion facility, library) in 2011 and social interaction 3 years later. Age, gender, disease, and mobility were also entered into the model as control variables.Results Comparing social interaction in 1994 and 2014, total scores were found to have significantly increased in all age groups. Independence scores significantly increased in the overall group and in females aged 75-84. Curiosity scores also increased in both males and females. These results show that social interaction has increased over 2 decades. In addition, the use of local elderly management and health care centers, and health promotion facilities was associated with total social interaction scores 3 years later.Conclusion The current study clarified changes in social interaction, both comprehensively and for each of its aspects, among community-dwelling elderly adults. Increasing social isolation has been reported in recent years; however, the current study showed that social interaction, including social curiosity and independence, has increased over 20 years. The effect of preventive intervention in local elderly management centers, health care centers, and health promotion facilities may be one of the causes for this increase. PMID- 28626150 TI - Comparison of sperm subpopulation structures in first and second ejaculated semen from Japanese black bulls by a cluster analysis of sperm motility evaluated by a CASA system. AB - In the present study, bull sperm in the first and second ejaculates were divided into subpopulations based on their motility characteristics using a cluster analysis of data from computer-assisted sperm motility analysis (CASA). Semen samples were collected from 4 Japanese black bulls. Data from 9,228 motile sperm were classified into 4 clusters; 1) very rapid and progressively motile sperm, 2) rapid and circularly motile sperm with widely moving heads, 3) moderately motile sperm with heads moving frequently in a short length, and 4) poorly motile sperm. The percentage of cluster 1 varied between bulls. The first ejaculates had a higher proportion of cluster 2 and lower proportion of cluster 3 than the second ejaculates. PMID- 28626152 TI - Development of risk assessment scales for Needed Support/Long-Term Care certification: A longitudinal study using the Kihon Checklist and medical assessment data. AB - Objectives This study aimed to develop risk assessment scales for predicting the incidence of Needed Support/Long-Term Care certification, by aggregating data from the Kihon Checklist, medical assessments, and long-term care insurance certification during a follow-up period (a maximum of 4 years and 2 months) conducted in a municipality.Methods This retrospective cohort study included 72,127 older adults aged 65 years or older living in K City (an ordinance designated city) who responded to the Kihon Checklist in 2011. We linked their medical assessment data (examined/unexamined, blood pressure, and five blood biochemical items) from 2011 and information on the incidence of long-term care insurance certification from 2011 to 2015 to the Kihon Checklist data (the 12 essential items and seven optional items from the Needs Survey). We constructed four Cox proportional hazards models as follows: 1) age, sex, and the Needs Survey's 12 essential items; 2) model 1 plus seven optional items; 3) model 2 plus examined/unexamined at medical assessment; and 4) model 3 plus blood pressure and five blood biochemical items, as independent variables. Recent requirement for Support/Long-Term Care certification was included as an outcome with stepwise forward selection. We assigned scores for each item based on the non-standardized regression coefficients obtained (B) and the sum of those scores was used to establish the risk assessment scales for predicting Needed Support/Long-Term Care certification from each model. A receiver operating characteristic (ROC) analysis was conducted to estimate the sensitivity and specificity in order to compare predictive validity of the scales.Results During the follow-up period, 11,039 (15.3%) individuals required a new incidence of a Needed Support/Needed Long-Term Care certification. A risk assessment scale of 0 55 was established based on age, sex, and the 10 essential items from the Needs Survey's. The incidence of certification were 3.2%, 14.7%, 31.6%, 56.7%, and 75.0% at scores of 10, 20, 30, 40, and 50, respectively. The area under the ROC curve (AUC) was 0.783, and the sensitivity and the specificity were 0.705 and 0.731, respectively (cut-off: 21/22). These values remained almost unchanged despite the addition of optional and medical assessment items (AUC: 0.786-0.787, sensitivity: 0.721-0.730, and specificity: 0.710-0.717).Conclusion Although the medical assessment data was not aggregated, the scale developed from the Kihon Checklist's 10 items (included in the Needs Survey's essential items) is useful for predicting the incidence of Needed Support/Long-Term Care certification. The scale, which evaluates the risk of needed support/long-term care at individual and community levels, was developed using the existing Kihon Checklist data or the Needs Survey's data collected subsequently by municipalities. PMID- 28626153 TI - Association between lifestyle factors assessed by standard question items of specific health checkup and the incidence of metabolic syndrome and hypertension in community dwellers: A five-year cohort study of National Health Insurance beneficiaries in Habikino City. AB - Objective From April 2008, specific health checkups have been implemented to prevent metabolic syndrome (MetS) and related cardiovascular diseases based on assurance of medical care for the elderly in Japan. In its "Standard Health Checkup and Counseling Guidance Program," 22 standard question items are recommended to assess health conditions of Japanese citizens. However, there are few community-based studies to clarify the relationship between question items and new onset of high risk conditions for cardiovascular diseases such as MetS. Accordingly, we performed a 5-year follow-up study of community dwellers who participated in health checkups of National Health Insurance beneficiaries in Habikino City, Osaka.Method Lifestyle factors assessed by standard question items in 2008 were defined as exposures at baseline survey. In the analysis of MetS, we followed-up 4,720 participants without MetS; and in the analysis of hypertension, we followed-up 3,326 participants without hypertension until the end of March in 2013. New-onset MetS or hypertension during follow-up were defined as outcomes. Cox proportional hazard model was used to evaluate the relationship between lifestyle factors and the incidence of MetS or hypertension after adjustment for age and waist circumference.Results The median follow-up period for incidence of MetS was 3.1 years for men and 3.6 years for women. We observed 570 new cases of MetS during follow-up. For men, "taking dinner within 2 hours before going to sleep" and "body weight increase by 10 kg or greater from 20 years old" were significantly associated with MetS (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.09-1.88 and HR, 1.33; 95% CI, 1.19-1.75, respectively). Occasional consumption of alcohol in men was negatively associated with MetS. For women, "increase or decrease of body weight by 3 kg or greater within 1 year" and "body weight increase by 10 kg or greater from age of 20" were significantly associated with MetS (HR, 1.83; 95% CI, 1.40-2.40 and HR, 2.02; 95% CI, 1.52 2.68, respectively). Daily alcohol consumption from 1 to less than 2 gou (about 23 to 45 g of ethanol) in women was positively associated with MetS (HR, 2.64; 95% CI, 1.51-4.64). We observed 1,045 new cases of hypertension; however, except for daily alcohol consumption for men, no lifestyle factors were associated with incidence of hypertension.Conclusion Most standard question items of specific health checkups did not predict new-onset MetS or hypertension, at least within 5 years. Thus, development of more predictive question items is warranted. PMID- 28626154 TI - Medical examination, cancer screening, and health information channels of people with sight impairment: A survey of the resisters of a braille library or a sight impairment support group. PMID- 28626155 TI - Errata: Public health activities in Osaka: A way of implementing collective medicine. AB - Nihon Koshu Eisei Zasshi(JAPANESE JOURNAL OF PUBLIC HEALTH), Vol. 64 (2017) No. 4 p. 179-189: p189(Ref. 16). PMID- 28626156 TI - A method to establish a mouse model of bone marrow microenvironment injury. AB - A normal bone marrow microenvironment plays a very important role in the normal functioning of hematopoietic stem cells. Once disturbed, this microenvironment can become favorable for the occurrence of blood disorders, cancers, and other diseases. Therefore, further studies on the bone marrow microenvironment should be performed to reveal regulatory and stem cell fate determination mechanisms and promote the development of bone marrow transplantation, tissue repair and regenerative medicine, and other fields. A small animal model for further research is also urgently needed. In this study, an electric shock device was designed to elicit a femur bone marrow microenvironment injury in mice. A wire was inserted into the distal femur but not into the proximal femur, and the bone marrow microenvironment was evidently damaged by application of 100 +/- 10 V for 1.5 +/- 0.5 min ; mortality, however, was low in the mice. Gross observation, hematoxylin and eosin staining, immunohistochemistry, bright-field microscopy, and micro-CT scanning were also conducted. A large number of new blood capillaries and sinusoids appeared in the injured distal femur after 2 weeks. The capillaries in the injured femur disappeared after 4 weeks, and mature blood vessels were scattered throughout the injured area. Red blood cells disappeared, and the cellular structure and trabecular bone were better than those observed 2 weeks previously. Thus, we developed a simply operated, accurate, reliable, and easily controlled small animal model as a good technical platform to examine angiogenesis and segmentation damage in the bone marrow microenvironment. PMID- 28626157 TI - Protein restriction does not affect body temperature pattern in female mice. AB - Daily torpor is a physiological adaptation in mammals and birds characterized by a controlled reduction of metabolic rate and body temperature during the resting phase of circadian rhythms. In laboratory mice, daily torpor is induced by dietary caloric restriction. However, it is not known which nutrients are related to daily torpor expression. To determine whether dietary protein is a key factor in inducing daily torpor in mice, we fed mice a protein-restricted (PR) diet that included only one-quarter of the amount of protein but the same caloric level as a control (C) diet. We assigned six non-pregnant female ICR mice to each group and recorded their body weights and core body temperatures for 4 weeks. Body weights in the C group increased, but those in the PR group remained steady or decreased. Mice in both groups did not show daily torpor, but most mice in a food restricted group (n=6) supplied with 80% of the calories given to the C group exhibited decreased body weights and frequently displayed daily torpor. This suggests that protein restriction is not a trigger of daily torpor; torpid animals can conserve their internal energy, but torpor may not play a significant role in conserving internal protein. Thus, opportunistic daily torpor in mice may function in energy conservation rather than protein saving. PMID- 28626158 TI - Ducks as a potential reservoir for Pasteurella multocida infection detected using a new rOmpH-based ELISA. AB - Pasteurella multocida is an important pathogen of numerous domestic poultry and wild animals and is associated with a variety of diseases including fowl cholera. The aim of this study was to develop an indirect enzyme-linked immunosorbent assay (ELISA) based on recombinant outer-membrane protein H (rOmpH) for detection of anti-P. multocida antibodies in serum to determine their prevalence in Chinese ducks. The P. multocida ompH gene was cloned into pET32a, and rOmpH was expressed in Escherichia coli BL21 (DE3). Western blotting revealed that purified rOmpH was recognized by duck antisera against P. multocida, and an indirect ELISA was established. During analysis of serum samples (n=115) from ducks, the rOmpH ELISA showed 95.0% specificity, 100% sensitivity and a 92.0% kappa coefficient (95% confidence interval 0.844-0.997) as compared with a microtiter agglutination test. Among 165 randomly selected serum samples, which were collected in 2015 and originated from six duck farms across Fujian Province, China, anti-P. multocida antibodies were detected in 22.42% of apparently healthy ducks, including 25 of 90 sheldrakes (27.8%), eight of 50 Peking ducks (16.0%) and four of 25 Muscovy ducks (16%). Overall, the data suggest that rOmpH is a suitable candidate antigen for the development of an indirect ELISA for detection of P. multocida in ducks; moreover, our results showed that ducks could serve as a potential reservoir for P. multocida infection. PMID- 28626159 TI - Limbal xanthogranuloma in a dog. AB - A 10-year-old female spayed American Pitt Bull Terrier was presented with a slow growing mass on the temporal limbus area of the right eye. Canine nodular granulomatous episclerokeratitis was suspected, and the affected eye was treated with 1% prednisolone acetate ophthalmic suspension and 0.03% Tacrolimus ophthalmic solution. As the lesion did not respond to the medical treatments and continued to grow, the mass was excised by lamellar sclerokeratectomy. Microscopically, the mass was composed of granulomatous inflammation with intrahistiocytic lipids and lakes of acicular cholesterol clefts, histopathology findings consistent with xanthogranuloma. To the authors' knowledge, this is the first canine report of limbal xanthogranuloma. PMID- 28626160 TI - Effect of Anemia on Cardiovascular Hemodynamics, Therapeutic Strategy and Clinical Outcomes in Patients With Heart Failure and Hemodynamic Congestion. AB - BACKGROUND: We investigated the effect of anemia on cardiovascular hemodynamics, therapeutic strategies and clinical outcomes in heart failure (HF) patients.Methods and Results:We divided 198 consecutive HF patients who underwent right heart catheterization before in-hospital HF treatment into 2 groups according to the presence or absence of hemodynamic congestion (HC: mean pulmonary capillary wedge pressure >=15 mmHg and/or mean right atrial pressure >=10 mmHg). The hemoglobin level correlated with the cardiac index (CI) and systemic vascular resistance index (SVRI) (r=-0.34 and 0.42, P<0.05, respectively), and was the strongest contributor of SVRI only in the HC group. Anemic patients more frequently required intravenous inotropic support despite having higher CI and lower SVRI than non-anemic patients in the HC group. The novel hemodynamic subsets based on mean right atrial pressure and estimated left ventricular stroke work index but not Forrester subsets appropriately predicted the need for intravenous inotropic support. The probability of hospitalization for worsening HF during 2-year follow-up period was significantly higher in anemic patients than in non-anemic patients in the HC group. CONCLUSIONS: Anemia had a direct effect on cardiovascular hemodynamics and thus can confound therapeutic planning in HF patients with HC. The novel hemodynamic subsets can be applied in daily clinical practice regardless of the presence or absence of anemia. PMID- 28626161 TI - Morning and Evening Blood Pressures Are Associated With Intima-Media Thickness in a General Population - The Hisayama Study. AB - BACKGROUND: The association of morning and evening home blood pressures (HBPs) with carotid atherosclerosis has been uncertain in general populations, so we aimed to investigate it in a general Japanese population.Methods and Results:We performed a cross-sectional survey of 2,856 community-dwelling individuals aged >=40 years to examine the association of morning and evening HBPs with carotid mean intima-media thickness (IMT). The age- and sex-adjusted geometric averages of carotid mean IMT increased significantly with increasing morning HBP (optimal: 0.67 mm; normal: 0.69 mm; high normal: 0.72 mm; grade 1 hypertension: 0.74 mm; and grade 2+3 hypertension: 0.76 mm) and with increasing evening HBP (0.68 mm, 0.71 mm, 0.73 mm, 0.76 mm, and 0.78 mm, respectively) (both P for trend <0.001). These associations remained significant even after adjusting for potential confounding factors. Likewise, both isolated morning hypertension (morning HBP >=135/85 mmHg and evening HBP <135/85 mmHg) and isolated evening hypertension (evening HBP >=135/85 mmHg and morning HBP <135/85 mmHg) as well as sustained hypertension (both morning and evening HBP >=135/85 mmHg) were significantly associated with thicker mean IMT. CONCLUSIONS: Our findings suggested that both morning and evening HBPs were significantly associated with carotid atherosclerosis in this general Japanese population. PMID- 28626162 TI - Intervention of the Nuss Procedure on the Mental Health of Pectus Excavatum Patients. AB - Pectus excavatum (PE) is the most common congenital chest wall deformity, but little is known about the influence of the Nuss surgical procedure on mental health of patients with PE. In this study, we aimed to evaluate the influence of the PE Nuss surgical procedure on mental health in Chinese patients and identify the predictors of psychological status for PE. Patients with PE (n = 266) underwent a standard surgical procedure by the same surgeon and did the Symptom Checklist 90 (SCL-90) and the Self-rating Depression Scale (SDS) questionnaires before and 1 year after surgery. Additionally, platelet reactivity of postoperative PE patients was assessed. We found that PE patients after surgery performed better in the questionnaires and the frequency of mental health problems in the patients was lower than before. Most significantly, four mental disorders were alleviated after surgery, namely somatization, interpersonal sensitivity, depression, and anxiety. What is more, age, suffering year, and platelet aggregation responses to serotonin and epinephrine of PE patients partially were involved with the postoperative alleviation of mental disorders. In conclusion, the mental health level of PE patients could be effectively improved via the Nuss surgical procedure, and the earlier surgery might turn out better. PMID- 28626163 TI - Lower Serum Levels of miR-29c-3p and miR-19b-3p as Biomarkers for Alzheimer's Disease. AB - MicroRNAs (miRNAs) are short noncoding RNA that participate in posttranscriptional gene regulation. However, little is understood about the roles of miRNAs in Alzheimer's disease (AD). In this study, we used next generation sequencing on RNA extracted from the serum samples of 20 AD patients and 20 controls, yielding a total of 72 miRNAs with significantly changed expression levels. Among these candidates, we selected 9 miRNAs with most significant alteration in disease, and validated their expression levels using RT qPCR analysis on serum samples from 45 AD patients and 40 control subjects. Thus, the serum levels of miR-146a-5p, 106b-3p, 195-5p, 20b-5p, and 497-5p were significantly higher, while those of miR-125b-3p, 29c-3p, 93-5p and 19b-3p were significantly lower in AD patients, compared with control subjects. Two miRNAs, miR-29c-3p and miR-19b-3p, were selected because both RNA deep-sequencing and q PCR methods indicated lower serum levels of these miRNAs in AD patients. Computational analysis predicted that 3'-untranslated region of signal transduction and activator of transcription 3 (STAT3) mRNA is targeted both by miR-29c-3p and miR-19b-3p. Using SH-SY5Y human neuroblastoma cells, we showed that transfection with miR-29c-3p or miR-19b-3p inhibitor significantly increased STAT3 phosphorylation. Furthermore, Water maze test, which assesses the learning and memory deficits in rodents, showed that escape latency was significantly shorter in AD rats with overexpression of miR-29c-3p or miR-19b-3p than in control AD rats. These results suggest that miR-29c-3p or miR-19b-3p may contribute to the cognitive function. In conclusion, the serum levels of miR-29c 3p and miR-19b-3p are helpful biomarkers for AD. PMID- 28626164 TI - Diagnostic Significance of Measuring Vascular Endothelial Growth Factor for the Differentiation between Malignant and Tuberculous Pleural Effusion. AB - Malignancy and tuberculosis are common causes of lymphocytic exudative pleural effusion. However, it is occasionally difficult to differentiate malignant pleural effusion from tuberculous pleural effusion. Vascular endothelial growth factor (VEGF) is a critical cytokine in the pathogenesis of malignant pleural effusion. Endocan is a dermatan sulfate proteoglycan that is secreted by endothelial cells. Importantly, endocan mediates the vascular growth-promoting action of VEGF. The aim of this study was to evaluate the diagnostic significance of VEGF and endocan in pleural effusion. We thus measured the levels of VEGF and endocan in the pleural effusion and serum samples of patients with lung cancer (n = 59) and those with tuberculosis (n = 32) by enzyme-linked immunosorbent assay. Lung cancer included 40 cases of adenocarcinoma, 13 of squamous cell carcinoma, and 6 of small cell carcinoma. Pleural effusion VEGF levels were significantly higher in the malignant group than in the tuberculosis group (2,091.47 +/- 1,624.80 pg/mL vs. 1,291.05 +/- 1,100.53 pg/mL, P < 0.05), whereas pleural effusion endocan levels were similar between the two groups (1.22 +/- 0.74 ng/mL vs. 0.87 +/- 0.53 ng/mL). The areas under the curve of VEGF and endocan were 0.73 and 0.52, respectively. Notably, the VEGF levels were similar in malignant pleural effusion, irrespective of the histological type of lung cancer. Moreover, no significant difference was found in the serum VEGF and endocan levels between patients with lung cancer and those with tuberculosis. In conclusion, high VEGF levels in pleural effusion are suggestive of malignant pleural effusion. PMID- 28626165 TI - Identification and Functional Profiling of Differentially Expressed Long Non Coding RNAs in Nasal Mucosa with Allergic Rhinitis. AB - Long non-coding RNAs (lncRNAs) have been proved to play important roles in a variety of human immune diseases. However, their pathological effects on the development of allergic rhinitis (AR) have not been clearly understood. The aim of this study was to determine the expression profile of lncRNAs in nasal mucosa of AR patients by lncRNA microarray and to predict potential roles of specific lncRNAs in the pathogenic mechanisms of AR by analysis of lncRNA-mRNA co expression network, Gene Ontology (GO) and pathway. The lncRNA microarray analysis showed that a total of 2,259 lncRNAs (1,033 up-regulated and 1,226 down regulated) and 704 mRNAs (157 up-regulated and 547 down-regulated) were significantly differentially expressed in the nasal mucosa samples from 4 AR patients as compared to those from 4 non-allergic subjects (fold change > 2; P < 0.05). In addition, the lncRNA-mRNA co-expression network contained 143 network nodes including 76 lncRNAs and 67 mRNAs, in which 117 significant correlation pairs presented as positive, and 108 pairs presented as negative. The results from GO and pathway analysis indicated that the lncRNAs-coexpressed mRNAs were enriched in several biological processes and cellular signaling pathways related to AR development, such as positive regulation of interleukin-13 secretion, Fc epsilon RI signaling pathway and NF-kappa B signaling pathway. To summary, our study provides important information on the molecular mechanisms and biological functions of these AR-related lncRNAs, which could be utilized for developing novel therapeutic strategies for AR. PMID- 28626166 TI - Efficacy of Denosumab for Osteoporosis in Three Female Patients with Osteogenesis Imperfecta. AB - Osteogenesis imperfecta (OI) is an inherited bone disorder that causes fractures due to impaired production of collagen type I. In recent years, denosumab, a human monoclonal antibody against receptor activator of nuclear factor kappaB ligand (RANKL), has become widely used as an anti-osteoclastic agent for osteoporosis. This study investigated osteoporotic cases of OI to examine effects of denosumab on bone fragility. This was a retrospective, consecutive case series that included 3 female patients aged 42, 40, and 14 years, respectively. One patient carries a point mutation (c.G769A) in the COL1A1 gene, encoding collagen type I alpha 1 chain, which causes an amino-acid substitution (p.G257R). By contrast, no mutation was found in the analyzed regions of the OI responsive genes in another two patients (mother and daughter). These three patients underwent subcutaneous injection of denosumab every 6 months. All patients underwent dual-energy X-ray absorptiometry for bone mineral density (BMD) measurement of the lumbar 1-4 spine (L-BMD) and bilateral hips (H-BMD) before and during treatment. BMD and laboratory data were evaluated before, between 2 and 4 months, and at 6, 12, 18, and 24 months of therapy. No fractures or severe side effects, such as hypocalcemia, were observed during denosumab treatment. Both L BMD and H-BMD were increased by denosumab. At 24 months, the mean percentage changes in L-BMD and H-BMD were 14.7% and 15.1%, respectively. In conclusion, no bone fragility fractures occurred during 2 years of denosumab administration in OI patients. Denosumab therefore is a good therapeutic option in the OI patients. PMID- 28626167 TI - A Human Glucagon-Like Peptide-1-albumin Recombinant Protein with Prolonged Hypoglycemic Effect Provides Efficient and Beneficial Control of Glucose Metabolism in Diabetic Mice. AB - GW002 is a recombinant protein engineered by fusing the C-terminal region of human glucagon-like peptide-1 (GLP-1) to the N-terminal region of human serum albumin (HSA) with a peptide linker. This study aims to evaluate its anti diabetic effects both in vitro and in vivo. The GLP-1 receptor-dependent luciferase reporter plasmid was transiently transfected in NIT-1 cells to calculate the half-maximal concentration (EC50) for GLP-1 receptor activation, and normal ICR mice and diabetic KKAy mice were acutely injected with GW002 (1, 3, 9 mg/kg) subcutaneously to evaluate the hypoglycemic action, while the diabetic KKAy and db/db mice were treated with GW002 once daily for 7 weeks to evaluate the effects on glucose metabolism. The results showed that GW002 activated GLP-1 receptor in NIT-1 cells with higher EC50 versus exendin-4 (46.7 vs. 7.89 nM), and single subcutaneous injection of GW002 at doses of 1, 3 and 9 mg/kg efficiently restrained the glycemia variation after oral glucose loading in ICR mice for at least 4 d, as well as reducing the non-fasting blood glucose in KKAy mice for about 2 d, while repeated injections of GW002 significantly improved abnormal glycaemia, hemoglobin (Hb)A1c levels, oral glucose intolerance and beta-cell function in diabetic db/db mice. These results suggested that GW002 showed prolonged hypoglycemic action by activating its cognate receptor and provided efficient control of glucose metabolism. Thus GW002 may be a potential treatment for the management of type 2 diabetes. PMID- 28626168 TI - Indications for Small-bowel Capsule Endoscopy in Patients with Chronic Abdominal Pain. AB - Objective The aim of the present study is to assess the difference in the detection rates of small-bowel lesions in chronic abdominal pain (CAP) patients with irritable bowel syndrome (IBS) and non-IBS. Patients Ninety-nine CAP patients who were scheduled to undergo capsule endoscopy (CE) to investigate their abdominal symptoms were included in this study. Among the subjects, 34 patients fulfilled the Rome III criteria for IBS (IBS group); the remaining 65 patients were categorized as the non-IBS group. CE was performed in both groups and the total enteroscopy achievement rate, small-bowel lesion detection rate, and the presence of small-bowel lesions were evaluated. We also evaluated the patients' blood test results and the rate at which abdominal symptoms improved following internal medication. Results Total enteroscopy was achieved in 62% (21/34) and 86% (56/65) of the IBS and non-IBS patients, respectively. The total enteroscopy achievement rate was significantly higher in non-IBS patients. The small-bowel lesion detection rates were 3% (1/34) and 19% (12/65), respectively, and the detection rate was significantly higher in the non-IBS patients. In the non-IBS patients, mean C-reactive protein (CRP) was significantly higher in the patients with small-bowel lesions. The abdominal symptoms of 12 (92%) of the CAP patients with small-bowel lesions were improved by internal medication. Conclusion CE may be considered for non-IBS CAP patients with high levels of CRP. PMID- 28626169 TI - New Discriminant Method for Identifying the Aggressive Disease Phenotype of Non alcoholic Fatty Liver Disease. AB - Objective To detect the aggressive phenotype (AP) of non-alcoholic fatty liver disease (NAFLD) based on the initial laboratory data and clinical characteristics. Methods We enrolled 144 patients with histologically proven NAFLD. For the first analysis, 24 NAFLD patients underwent repeat biopsy to establish a discriminant formula for predicting the AP of NAFLD (D-APN). The AP was defined by NAFLD that had been maintained or progressed to a fibrotic stage beyond stage 2. In the second analysis, we analyzed the distribution of the AP in each stage of disease and the incidence of the PNPLA3 rs738409 GG genotype in AP in 120 other patients. Results After the analysis, the following function was found to discriminate the disease phenotype: z=0.150*body mass index (kg/m2)+0.085*age (years)+1.112*ln (AST) (IU/L)+0.127*ln (m-AST)-12.96. A positive result indicates the AP of NAFLD. The discriminant functions had a positive predictive value of 94% and a negative predictive value of 71%. The distribution of the AP and the incidence of the PNPLA3 GG genotype in the AP in each stage of the disease among the 120 patients were as follows: non-alcoholic fatty liver, 30%/33%; non-alcoholic steatohepatitis (NASH) stage 1, 53%/26%; stage 2, 71%/70%; stage 3, 92%/57%; and stage 4, 93%/64%; there was a significant increase in the incidence of the AP as the disease progressed (p<0.001). Conclusion The new discriminant formula was useful for predicting disease progression potential in NAFLD patients and the incidence of the PNPLA3 GG genotype was elevated according to the distribution of AP. PMID- 28626170 TI - Investigating the Relationship between Morning Glycemic Variability and Patient Characteristics Using Continuous Glucose Monitoring Data in Patients with Type 2 Diabetes. AB - Objective To investigate the relationship between patient characteristics and morning glycemic variability. Methods We retrospectively evaluated 106 patients with type 2 diabetes who underwent continuous glucose monitoring during admission. The highest postprandial glucose level (within 3 hours after breakfast; 'highest level'), the time from the start of breakfast to the highest postprandial glucose level ('highest time'), the difference between the pre breakfast and highest postprandial breakfast glucose level ('increase'), the area under the curve (AUC; >=180 mg/dL) for the glycemic variability within 3 hours after breakfast ('morning AUC'), and the post-breakfast glucose gradient ('gradient') were calculated. We analyzed the associations between these factors and nocturnal hypoglycemia and the patients' characteristics by using a regression analysis. Results After stepwise multivariate adjustment, significant independent associations were found between 'highest level' and high age, low BMI, and high HbA1c; 'highest time' and high HbA1c, low C-peptide immunoreactivity (CPR), and low fasting plasma glucose (FPG); the 'increase' and high age, low BMI, high HbA1c, low FPG and hypoglycemia; 'morning AUC' and high age, high HbA1c and hypoglycemia; and 'gradient' and long duration of diabetes and low BMI. Conclusion Higher age and lower BMI are associated with higher 'highest' and 'increase' levels. Higher HbA1c levels were linked to a longer 'highest time', and longer durations of the diabetes, while lower BMI values were related to a higher 'gradient'. PMID- 28626171 TI - Association between Overall Lifestyle Changes and the Incidence of Proteinuria: A Population-based, Cohort Study. AB - Objective This study aimed to examine the association between the changes in an overall healthy lifestyle, as quantified by the number of unhealthy lifestyle factors and obesity status, and the incidence of proteinuria in the general Japanese population. Methods A retrospective cohort study was conducted among 99,404 (men, 36.9%) participants aged from 40-74 years of age who underwent two health check-ups with a 1-year interval in Japan between 2008 and 2009. Any participants with chronic kidney disease at baseline were excluded. The smoking status, body mass index, physical activity, alcohol consumption, and healthy eating habits were combined into a simple overall healthy lifestyle score ranging from 0 to 5. The changes in overall healthy lifestyle scores from baseline (range, -5 to +5) and the incidence of proteinuria, defined by a dipstick urinalysis (score >=1+), were assessed at the second check-up. A logistic regression analysis was used to examine the association between the changes in overall healthy lifestyle scores and the incidence of proteinuria. Results After one year of follow-up, 3.9% of men and 2.4% of women developed proteinuria. Each increase (or decrease) in the changes in overall healthy lifestyle scores was associated with a reduced (or increased) risk of proteinuria in both men (odds ratio (OR) 0.87; 95% confidence interval (CI), 0.81-0.94) and women (OR 0.87; 95%CI, 0.80-0.94) after adjusting for age, baseline lifestyle scores, hypertension, diabetes mellitus, and hypercholesterolemia. Stratified analyses based on age, the presence or absence of hypertension, or diabetes mellitus revealed similar results. Conclusion Overall lifestyle changes, even within a year, were found to influence the incidence of proteinuria. PMID- 28626172 TI - Pulmonary Nocardiosis: A Clinical Analysis of 30 Cases. AB - Objective Pulmonary nocardiosis frequently develops as an opportunistic infection in patients with malignant tumor and is treated with steroids. This study was performed to clarify the clinical features of pulmonary nocardiosis in Japan. Methods The patients definitively diagnosed with pulmonary nocardiosis at our hospital between January 1995 and December 2015 were retrospectively investigated. Results Nineteen men and 11 women (30 in total) were diagnosed with pulmonary nocardiosis. Almost all patients were complicated by a non-pulmonary underlying disease, such as malignant tumor or collagen vascular disease, or pulmonary disease, such as chronic obstructive pulmonary disease or interstitial pneumonia, and 13 patients (43.3%) were treated with steroids or immunosuppressors. Gram staining was performed in 29 patients, and a characteristic Gram-positive rod was detected in 28 patients (96.6%). Thirty-one strains of Nocardia were isolated and identified. Seven strains of Nocardia farcinica were isolated as the most frequent species, followed by Nocardia nova isolated from 6 patients. Seventeen patients died, giving a crude morality rate of 56.7% and a 1-year survival rate of 55.4%. The 1-year survival rates in the groups with and without immunosuppressant agents were 41.7% and 59.7%, respectively, showing that the outcome of those receiving immunosuppressants tended to be poorer than those not receiving them. Conclusion Pulmonary nocardiosis developed as an opportunistic infection in most cases. The outcome was relatively poor, with a 1-year survival rate of 55.4%, and it was particularly poor in patients treated with immunosuppressant agents. Pulmonary nocardiosis should always be considered in patients presenting with an opportunistic respiratory infection, and an early diagnosis requires sample collection and Gram staining. PMID- 28626173 TI - Prevalence of Right to Left Shunts in Japanese Patients with Migraine: A Single center Study. AB - Objective Several studies have shown an increased prevalence of right-to-left shunt (RLs) in migraine patients, particularly those with aura. However, the prevalence of RLs and its relation to Japanese patients with migraine are unknown. We investigated the prevalence of RLs in Japanese patients with migraine. Methods In total, 112 consecutive patients with migraine were recruited from our headache outpatient clinic. Migraine with aura (MA) and migraine without aura (MWOA) were diagnosed according to the International Classification of Headache Disorders, 3rd edition (beta-version). Contrast transcranial Doppler ultrasound was used to detect RLs, including patent foramen ovale (PFO). Then, the associations between RLs and patients' backgrounds and presence of aura were assessed. Results The overall prevalence of RLs and PFO in migraine patients was 54.5% and 43.8%, respectively. The prevalence of RLs and PFO in the MA group were significantly higher than in the MWOA group (RLs, 62.9% vs. 44.0%, p=0.046; PFO, 54.8% vs. 30.0%, p=0.008). There were no marked differences in the prevalence of large, middle and small shunts between MA and MWOA patients. Compared with the MWOA patients, the MA patients were younger (p=0.013) and had early onset age (p=0.013) and increased prevalence of photophobia (p=0.008). Conclusion RLs were found in over half of the Japanese patients with migraine. Our study suggests a possible link between RLs and MA. PMID- 28626174 TI - Lifestyle Changes and Oxidative Stress in a High-incidence Area of Amyotrophic Lateral Sclerosis in the Southwestern Kii Peninsula, Japan. AB - Objective Lifestyle changes may play an important role in the incidence reduction and delay of onset age of amyotrophic lateral sclerosis (ALS) in the Koza/Kozagawa/Kushimoto (K) area. The aim of this study was to evaluate recent lifestyle changes in the K area and to investigate the relationships between lifestyle and oxidative stress among the residents. Methods We conducted a medical checkup for elderly residents in the K area and the control area and evaluated the urinary 8-OHdG levels, cognitive function test scores and metal contents in serum and scalp hair, coupled with a lifestyle questionnaire survey between 2010 and 2015. Results Recent lifestyle changes among the K residents, including a decrease in the Japanese pickle consumption, increase in fresh vegetable consumption and decrease in farm work, were evaluated in this study. Low consumption of Japanese pickles, high consumption of fresh vegetables, rare farm work and low levels of 8-OHdG/creatinine were all associated with high scores in the cognitive function tests. Frequent farm work and consumption of Japanese pickles was associated with high contents of transition metals, such as Mn, Al and V, in the scalp hair. Conclusion These lifestyle changes among residents in the K area may be associated with their oxidative stress. PMID- 28626175 TI - Characteristics and Gender Differences in the Medical Interview Skills of Japanese Medical Students. AB - Objective To examine the characteristics of the communication skills of medical students, we observed their performance during introductory medical interview training with simulated patients (SPs). Methods The subjects of the present study included fifth-year medical students (male, n=180, female, n=99) who were undergoing clinical training in Japan from 2012 to 2014. Each student was assigned to one of four 10-minute clinical scenarios, which was conducted with an SP. Three or four teachers observed and assessed the performance of each of the students. The overall performance was rated on a 10-point scale, and nine basic communication skills that were common to each of the scenarios were rated using a four-point scale. The students also assessed their own performance on these items. The SPs assessed the students' performance from a patient's perspective on four items. Results There were significant correlations between the teacher and student scores. However, the students tended to score themselves significantly lower than the teachers. The female students were rated significantly higher by the teachers on the following four items; 'eye contact and appropriate attitude,' 'nodding and back-channeling,' 'giving empathic verbal responses,' and 'acquisition of patient's psychosocial information.' However, the self assessments of the female students were only significantly higher than the male students in one item, 'acquisition of patient's psychosocial information.' In contrast, self-assessments of the male students were significantly higher in two items; none of their items was scored higher by the teachers. There was no significant gender difference in the assessments made by the SPs. Conclusion There were significant gender differences in the communication skills of the medical students during introductory training, suggesting the possibility that there were gender-specific traits and gender-based differences in the students' degrees of readiness. PMID- 28626176 TI - Gastroduodenal Intussusception with a Gastric Gastrointestinal Stromal Tumor Treated by Endoscopic Submucosal Dissection. AB - A 95-year-old Japanese woman presented to our hospital with intermittent vomiting and several episodes of melena. Abdominal computed tomography revealed intussusception of the gastric tumor into the duodenum. After endoscopic reduction, endoscopic ultrasonography identified a hypoechogenic lesion limited to the submucosal layer. Endoscopic resection was performed as a localized treatment for the prevention of recurrent gastroduodenal intussusception. To our knowledge, there have been no other reports describing a gastric gastrointestinal stromal tumor presenting with gastroduodenal intussusception and treated using an endoscopic submucosal dissection technique. PMID- 28626177 TI - Recurrence 30 Years after Surgical Resection of a Localized Rectal Neuroendocrine Tumor. AB - Localized small rectal neuroendocrine tumors (NETs) without any vascular involvement rarely metastasize, and their resection alone is considered curative. We herein report a case of localized rectal NET (10*8 mm) without vascular involvement. Although resected initially, it recurred as liver metastasis 30 years later. For rectal NETs smaller than 10 to 20 mm, surveillance for 12 months is considered sufficient. However, this case suggests that such tumors can recur even 30 years after curative resection. The interval of recurrence is the longest among reported cases. PMID- 28626178 TI - Hypoglycemic Coma Induced by the Use of Succinic Acid Cibenzoline in Frail Late stage Elderly Subjects. AB - Succinic acid cibenzoline (CZ) is an antiarrhythmic agent often used for the treatment of tachyarrhythmia. However, hypoglycemia should be avoided in the treatment of diabetes. We herein report two late-stage elderly subjects who experienced a severe and prolonged hypoglycemic coma after the usage of CZ. These cases suggest that, when CZ is administered to elderly subjects with renal dysfunction and/or frailty, we should be aware of the possibility that this medicine may induce hypoglycemia and should adjust the dose as appropriate and monitor the concentration of CZ to avoid severe hypoglycemia. PMID- 28626179 TI - Two Patients with Familial Hypercholesterolemia Who Were Successfully Weaned from Low-density Lipoprotein Apheresis after Treatment with Evolocumab. AB - Two elderly patients (a 76-year-old man and a 75-year-old woman), who had been previously diagnosed with familial hypercholesterolemia (at 58 and 48 years of age, respectively) underwent long-term treatment with oral therapy and low density lipoprotein (LDL) apheresis. As their LDL cholesterol levels remained high (>150 mg/dL and >120 mg/dL, respectively) and their familial hypercholesterolemia was complicated with angina pectoris, we added evolocumab to their prescription. Thereafter, their LDL cholesterol levels decreased rapidly, and the patients were successfully weaned from LDL apheresis. Evolocumab therapy should thus be considered when LDL apheresis cannot achieve the target LDL cholesterol levels, though the prognosis of such treatment remains unclear. PMID- 28626180 TI - Pregnancy Is a Risk Factor for Secondary Focal Segmental Glomerulosclerosis in Women with a History of Very Low Birth Weight. AB - Low birth weight (LBW) has been known to increase the susceptibility to renal injury in adulthood. A 26-year-old woman developed proteinuria in early pregnancy; she had been born with very LBW. The clinical course was progressive, and an emergency Caesarean section was performed at 36 weeks due to acute kidney injury. A renal biopsy provided a diagnosis of post-adaptive focal segmental glomerulosclerosis. Increased demand for glomerular filtration during early pregnancy appeared to have initiated the renal injury. This report highlights the fact that pregnancy might be a risk factor for renal injury in women born with LBW. PMID- 28626181 TI - Long-term Low-density Lipoprotein Apheresis in a Patient with Refractory Idiopathic Membranous Glomerulonephritis. AB - A 61-year-old Japanese man developed nephrotic syndrome (NS) due to idiopathic membranous glomerulonephritis (MGN). He received immunosuppressive therapy for two years, including prednisolone, cyclophosphamide, and cyclosporine A, but the NS persisted. Low-density lipoprotein apheresis (LDL-A) was initiated at a frequency of twice a month and continued for 9 years (203 sessions in total). His proteinuria reduced to less than 1 g daily after 9 years. LDL-A was stopped, and the NS has not relapsed for five years. This case suggests that long-term LDL-A therapy may be a treatment option for idiopathic MGN refractory to immunosuppressive therapy or short-term LDL-A. PMID- 28626182 TI - Small Cell Lung Cancer in a 20-year-old Non-Smoking Man with Systemic Sclerosis. AB - Small cell lung cancer (SCLC) is a neuroendocrine tumor, and the median age of onset is about 70 years old. A 20-year-old non-smoking man with known systemic sclerosis presented with discomfort in his left chest. Chest X-ray showed a mass shadow in the left upper zone. A transbronchial lung biopsy revealed small cell carcinoma, and imaging studies reached the diagnosis of extensive disease small cell lung cancer. He had concurrent interstitial lung disease with a non-specific interstitial pneumonia pattern and anti-Scl-70 antibodies. He died eight months after the diagnosis during fifth-line chemotherapy. We herein report the youngest case to date of SCLC with systemic sclerosis. PMID- 28626183 TI - Desquamative Interstitial Pneumonia Complicated with IgG4-related Lung Disease. AB - As an idiopathic interstitial pneumonia, desquamative interstitial pneumonia (DIP) is an uncommon form of interstitial lung disease and is considered to be a smoking- or dust inhalation-related interstitial pneumonia in the majority of cases. However, the details regarding immunoglobulin G4 (IgG4)-related lung disease remain unclear and controversial. We herein report the first case of DIP complicated with IgG4-related lung disease. Even if a patient has a smoking history, we emphasize the importance of exploring the association between DIP and IgG4-related lung disease to clarify the pathogenesis of these two disorders. PMID- 28626184 TI - A 16-year Follow-up Case of Interstitial Pneumonia with Systemic Sclerosis rheumatoid Arthritis Overlap Syndrome. AB - Interstitial pneumonia is a common and major comorbidity affecting the prognosis of patients with systemic sclerosis (SSc). However, there are few reported cases of SSc-rheumatoid arthritis (RA) overlap-associated interstitial pneumonia. We herein report a case in which the clinical behavior and histopathology of interstitial pneumonia with SSc-RA overlap syndrome was followed over a long clinical course. When clinicians are deciding on the treatment strategy for patients with SSc-RA overlap syndrome-associated interstitial pneumonia, a pathological examination of a surgical lung biopsy may be useful. PMID- 28626185 TI - Miliary Tuberculosis that Developed after Intravesical Bacillus Calmette-Guerin Therapy. AB - As a treatment for superficial transitional cell carcinoma, Bacillus Calmette Guerin (BCG) intravesical instillation can rarely cause unpredictable systemic side effects. We describe a patient admitted due to continuous pyrexia and general fatigue. He was previously treated with intravesical BCG. Laboratory data indicated a hepatic disorder, and chest computed tomography revealed extensive bilateral miliary nodules. Transbronchial lung biopsy specimens showed several small noncaseating granulomas. The diagnosis was unsolved on the basis of acid fast staining, polymerase chain reaction and microbiological cultures, so we considered the possibility of BCG side effect-induced granuloma. Two months after treatment with antituberculous agents and corticosteroids, his clinical symptoms were improved. PMID- 28626186 TI - Reversible Cerebral Vasoconstriction Syndrome Presenting with Transient Global Amnesia. AB - A 65-year-old man who had been diagnosed with transient global amnesia (TGA) 15 years previously was admitted to hospital with complaints of amnesia and headache. His symptoms improved on day-2. The initial brain MRI and electroencephalography findings were normal. He was diagnosed with a recurrence of TGA and discharged. However, he returned with right leg weakness and complained of a thunderclap headache. MRI demonstrated subarachnoid hemorrhage and multifocal segmental narrowing of the left posterior cerebral artery (PCA) and large intracranial arteries, and he was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS). He was discharged on day-30 without any neurological deficits. This case suggested that TGA should be interpreted as one of the symptoms of RCVS or a prodromal symptom of RCVS. PMID- 28626187 TI - Efficacy of Intravenous Cyclophosphamide Pulse Therapy for P-Glycoprotein expressing B Cell-associated Active True Renal Lupus Vasculitis in Lupus Nephritis. AB - True renal lupus vasculitis (TRLV), a vascular lesion usually associated with proliferative lupus nephritis (LN), is resistant to conventional treatments. The expression of P-glycoprotein (P-gp) on activated lymphocytes causes drug resistance. We herein report a patient with TRLV, minimal change LN, overexpression of P-gp on peripheral B cells, and accumulation of P-gp+ B cells at the site of TRLV. High-dose corticosteroids combined with intravenous cyclophosphamide pulse therapy resulted in clinical remission and the long-term normal renal function. PMID- 28626188 TI - Discoid Lupus Erythematosus Complicated with Pregnancy-induced Hemophagocytic Syndrome. AB - A 35-year-old woman with discoid lupus erythematosus (DLE) was admitted at 11 weeks' gestation with a persistent fever. Laboratory studies revealed pancytopenia, elevated liver enzymes, and hyperferritinemia. Bone marrow aspiration confirmed the diagnosis of hemophagocytic syndrome (HPS). She had no findings of infection or active systemic lupus erythematosus. The administration of high-dose corticosteroids resolved the clinical and laboratory findings. She delivered a healthy baby at 35 weeks' gestation. This case suggests that DLE can be a predisposing factor for pregnancy-induced HPS. PMID- 28626189 TI - Successful Switch to Golimumab for Eosinophilia and Skin Symptoms Related to Multiple Biologics in a Patient with Rheumatoid Arthritis. AB - Biologics used in the treatment of rheumatoid arthritis (RA) rarely cause eosinophilia. We herein report a patient with RA being treated with infliximab, adalimumab, and tocilizumab who developed eosinophilia with skin symptoms. Interestingly, the marked eosinophilia and skin symptoms did not reappear after the patient's medication was switched to golimumab. In this case, the presence of biologics-specific antibodies suggested that immunogenicity caused the eosinophilia. Therefore, switching to a biologic with a lower immunogenicity was effective. These findings may be helpful for clinicians treating patients with biologics-induced eosinophilia. PMID- 28626190 TI - Miliary Tuberculosis in a Young Woman with Hemophagocytic Syndrome: A Case Report and Literature Review. AB - We herein report a rare case of miliary tuberculosis-associated hemophagocytic syndrome (HPS) complicated with respiratory failure. A 19-year-old Japanese woman with a fever, general malaise, and chest radiograph abnormalities was referred to our hospital. After admission, she developed respiratory failure with pancytopenia. A histological examination of lung and bone marrow biopsy samples revealed noncaseating granulomas without evidence of acid-fast bacilli or lymphoma. In addition, a bone marrow biopsy showed marked histiocyte hyperplasia with hemophagocytosis, and a bronchoalveolar lavage fluid culture grew Mycobacterium tuberculosis. Therefore, a diagnosis of miliary tuberculosis associated HPS was made. The patient was successfully treated with antituberculous therapy. PMID- 28626192 TI - Increased 18F-FDG Uptake in IgG4-related Coronary Periarterial Pseudotumor. PMID- 28626191 TI - Hemophagocytic Lymphohistiocytosis in a Fatal Case of Severe Fever with Thrombocytopenia Syndrome. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease caused by a novel Bunyavirus with a high mortality rate. We herein report a fatal case of an 86-year-old woman with SFTS complaining of a fever, fatigue, and bicytopenia. Her condition deteriorated with rapid progression of bleeding tendency, disturbance of consciousness, and multiple organ failure leading to death on Day 6 of her illness. The histopathological findings in the autopsy revealed marked infiltration of macrophages with hemophagocytosis in the bone marrow, liver, and spleen leading to a diagnosis of hemophagocytic lymphohistiocytosis (HLH). HLH might be a critical pathogenesis in fatal cases of SFTS. PMID- 28626193 TI - Uremic Tumoral Calcinosis Resolved by Improvements in Hyperphosphatemia. PMID- 28626194 TI - Spontaneous Improvement of Interstitial Pneumonia with Autoimmune Features. PMID- 28626195 TI - Pyomyositis in a Patient with AIDS. PMID- 28626196 TI - Acute Calcific Prevertebral Tendinitis. PMID- 28626197 TI - Evaluation of CYP2D6 Protein Expression and Activity in the Small Intestine to Determine Its Metabolic Capability in the Japanese Population. AB - CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the first-pass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals. Normal jejunal tissues were obtained from 31 patients who had undergone pancreaticoduodenectomy, and the CYP2D6*10 variant was identified in these tissues. CYP2D6 mRNA and CYP2D6 protein levels were analyzed using real-time RT-PCR and Western blotting, respectively. Bufuralol 1'-hydroxylation, a marker of CYP2D6 activity, was analyzed using HPLC. Frequencies of the CYP2D6*1/*1, *1/*10, and *10/*10 genotypes in the jejunal tissue were 29.0% (n=9), 35.5% (n=11), and 35.5% (n=11), respectively. CYP2D6 protein and activity levels did not differ significantly between the genotypes. A positive correlation was found between CYP2D6 protein and activity levels. Furthermore, CYP2D6 protein levels and activity in the small intestine were significantly lower than those in the liver. These findings suggest that the metabolic capacity of CYP2D6 in the small intestine of the Japanese population has a relatively small effect on drug metabolism. PMID- 28626198 TI - The Therapeutic Effect of Dexmedetomidine on Rat Diabetic Neuropathy Pain and the Mechanism. AB - : Diabetic neuropathy pain (DNP) is a common chronic complication of diabetes characterized by spontaneous pain, hyperalgesia and allodynia. Dexmedetomidine is a selective alpha2 adrenergic agonist that relieves sympathetic nervous tension and reduces the release of glutamate. Thus, it is possible that dexmedetomidine may relieve DNP as well. In this study, we examined the effect of dexmedetomidine on DNP in the presence or absence of the alpha2 adrenergic antagonist yohimbine in rats utilizing a streptozotocin (STZ)-induced diabetes as a model of DNP. To examine DNP, we examined behavior using the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests, and microglia and astrocyte activation was examined by immunofluorescence staining. The levels of pro inflammatory cytokine tumor necrosis factor (TNF)-alpha and interleukin (IL) 1beta in the spinal cord were measured by enzyme-linked immunosorbent assay (ELISA). Cell apoptosis in spinal cord was examined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Glutamate production in caudal lumbar was measured by HPLC. We found that STZ treated rats had decreased pain threshold, elevated activation of microglia but not astrocytes, increased level of pro-inflammatory cytokines, increased apoptosis and glutamate production compared to control animals, and these effects were ameliorated by dexmedetomidine treatment. Pretreatment of yohimbine abolished almost all of the protective effects of dexmedetomidine except for glutamate production. IN CONCLUSION: our data confirmed that dexmedetomidine can relieve hyperalgesia in diabetic neuropathy pain, and protect spinal cord cells from apoptotic death. The mechanism may be related to dexmedetomidine-mediated inhibition of microglia activation, reduction of inflammatory reaction in the spinal cord, and suppression of glutamate production. PMID- 28626199 TI - Oxygen and Glucose as Stimulation Agents for BOLD Functional MR Imaging of Rabbit Liver: A Feasibility Study. AB - PURPOSE: To assess the feasibility of using oxygen and glucose as stimulating agents in blood-oxygen-level-dependent (BOLD) Functional Magnetic Resonance Imaging (fMRI) of rabbit liver and analyze the impacts by blood flow. METHODS: Pure oxygen inhalation, intravenous injection and oral administration of glucose were given to 11 New Zealand white rabbits to compare the differences of liver T2*, aortic flow (AF), portal vein flow (PVF), aortic area (AA) and portal vein area (PVA) before and at 5 min, 10 min, 20 min, 30 min after administrations. AF and PVF were acquired by two dimensional (2D) Phase Contrast MR (2D-PCMR). The impacts of AF and PVF upon BOLD fMRI were analyzed. RESULTS: AF and PVF declined at 5 min after oxygen inhalation and were significantly different from baseline, then reverted to baseline. No significant difference was observed in liver T2*, AA and PVA before and after oxygen inhalation. AF, PVF, AA and PVA showed no significant difference before and after glucose intravenous injection, while liver T2* increased gradually with significant difference. AF and liver T2* were significantly different before and after glucose oral administration and increased gradually, AA was significantly different before and after glucose administration at 10 min and 20 min. PVF and PVA started to be different from baseline at 10 min. Greatest variation of T2* (19.6%) was induced by glucose oral administration after 30 min. CONCLUSION: Rabbit liver T2* increasing by glucose intravenous injection is possibly associated with glycogen synthesis, provides the possibility to evaluate liver function. Glucose oral administration demonstrated an optimal comparative effect of raising T2*, however, resulted from the superposition of increased glycogen synthesis and blood flow. Inhalation of pure oxygen didn't alter the rabbit liver T2*, which may possibly result from an offset between the increased concentration of oxyhemoglobin and decreased blood flow. PMID- 28626200 TI - Inferior Vena Cava Thrombi Caused by Enlarged, Solitary Hepatic Cyst. PMID- 28626201 TI - Survival and Heart Failure Hospitalization in Patients With Cardiac Resynchronization Therapy With or Without a Defibrillator for Primary Prevention in Japan - Analysis of the Japan Cardiac Device Treatment Registry Database. AB - BACKGROUND: Randomized control trials comparing the effectiveness of cardiac resynchronization therapy devices, with (CRT-D) or without (CRT-P) a defibrillator, are scarce in heart failure patients with no prior sustained ventricular tachyarrhythmias.Methods and Results:The Japan Cardiac Device Treatment Registry (JCDTR) has data for 2714 CRT-D and 555 CRT-P recipients for primary prevention with an implantation date between January 2011 and August 2015. Of these patients, follow-up data were available for 717. Over the mean follow-up period of 21 months, Kaplan-Meier curves of survival free of combined events for all-cause death or heart failure hospitalization (whichever came first) diverged between the CRT-D (n=620) and CRT-P (n=97) groups with a rate of 22% vs. 42%, respectively, at 24 months (P=0.0011). However, this apparent benefit of CRT-D over CRT-P was no longer significant after adjustment for covariates. With regard to mortality, including heart failure death or sudden cardiac death, there was no significant difference between the 2 groups. CONCLUSIONS: In patients without sustained ventricular tachyarrhythmias enrolled in the JCDTR, there was no significant difference in mortality between the CRT-D and CRT-P groups, despite a lower trend in CRT-D recipients. This study was limited by large clinical and demographic differences between the 2 groups. PMID- 28626202 TI - Stent Fracture and Peri-Stent Contrast Staining After Everolimus-Eluting Stent Implantation - 5-Year Outcomes. AB - BACKGROUND: Stent fracture (SF) and peri-stent contrast staining (PSS) after sirolimus-eluting stent implantation are reported to be risk factors of adverse events. However, the effect of these after everolimus-eluting stent (EES) implantation on long-term outcomes remains unclear.Methods and Results:The study sample comprised 636 patients (1,081 lesions) undergoing EES implantation in 2010 and follow-up angiography within 1 year. The 5-year cumulative rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE: a combination of all-cause death, myocardial infarction, and TLR) were compared between patients with and without SF or PSS. SF was observed in 2.7%, and PSS in 3.0%. The cumulative rates of MACE and TLR were significantly higher in the SF group than in the non-SF group (51.7% vs. 27.5% and 48.3% vs. 13.4%, respectively), but showed no significant differences between the PSS and non-PSS groups. In a landmark analysis, the rate of TLR within 1 year was significantly higher in the SF group than in the non-SF group (44.8% vs. 7.2%), but beyond 1 year showed no significant difference (6.3% vs 6.7%). CONCLUSIONS: The 5-year clinical outcomes suggested that SF after EES implantation is related to increased risk of MACE and TLR, especially within 1 year after the procedure, but PSS after EES implantation is unrelated. PMID- 28626203 TI - Rheological approach for determining yield stresses in flowable resin composites prior to setting. AB - The purpose of this study is to develop a method for quantifying the fluidity of flowable resin composites using determinations of yield stress. Five commercially available composites (AliteFlo LV, Flow-it ALC, Venus flow, Tetric N-flow, Revolution Formula2) were investigated. Yield stress values were obtained by plotting shear stresses for a range of shear rates, followed by fitting of Casson fluid models to flow curve data and extrapolation to the stress axis. To confirm that yield stress reflected fluidity, apparent viscosity at the lower shear rate (0.2 s-1) was calculated from flow curves. Yield stresses ranged from 5.4 to 43.1 Pa, and were found to capture differences in the fluidity of composites that were not captured by viscosity measurement at the low shear rate. Yield stress is directly proportional to fluidity, and could serve as a simple and precise indicator for selecting flowable resin composites for use in various clinical applications. PMID- 28626204 TI - Intrapulpal temperature changes during curing of different bulk-fill restorative materials. AB - The aim of this study was to evaluate the intrapulpal temperature changes during the curing of different bulk-fill restorative materials. Ten mandibular molar teeth were selected and occlusal surfaces were removed to obtain a standard 0.5 mm occlusal dentin thickness. Five bulk-fill restorative materials and a conventional resin composite (control) were applied. The intrapulpal temperature changes during the curing of these materials were determined by a device simulating pulpal blood microcirculation. The difference between the initial and maximum temperature values (Deltat), was recorded. The data were statistically analyzed with one-way ANOVA and Tukey's HSD test (p<0.05). There were statistically significant differences between materials (p<0.001). The light curing bulkfill restoratives exhibited the highest Deltat values. Equia Forte showed the lowest Deltat values among all the groups (p<0.05). Bulk-fill restorative materials causes significantly different temperature changes in the pulp chamber according to curing type. Therefore, clinicians should be considered when using these materials. PMID- 28626205 TI - Designing an antibacterial acrylic resin using the cosolvent method -Effect of ethanol on the optical and mechanical properties of a cold-cure acrylic resin. AB - Antimicrobial cetylpyridinium chloride (CPC) has low miscibility with acrylic resin monomer but can be homogeneously mixed using ethanol as a cosolvent. This study investigated the effects of ethanol addition on the properties of a cold cure acrylic resin. Ethanol was an excellent cosolvent for CPC and methyl methacrylate monomer (MMA), but the cured resin exhibited a strong change in coloration to yellow (DeltaE*ab>8) and a drastically reduced bending strength (from 97 to 25 MPa) and elastic modulus (from 2.7 to 0.6 GPa) when equal volumes of ethanol and monomer were used together, possibly due to the solvation and deactivation of radicals by ethanol. However, these unfavorable effects diminished when the ethanol/MMA ratio was reduced to 0.25, and became smaller when each specimen was depressurized and excess ethanol was removed. Thus, it may be possible to develop a molecularly uniform antibacterial acrylic resin with acceptable color and strength using this simple technique. PMID- 28626206 TI - In vitro/in vivo evaluation of the efficacy of gatifloxacine-loaded PLGA and hydroxyapatite composite for treating osteomyelitis. AB - Molten 10 wt% gatifloxacine (GLFX-loaded poly(lactide-co-glycolide) (PLGA) was introduced into three-dimensionally interconnected pores and onto the surfaces of hydroxyapatite (HA) granules. The composite granules exhibited clinically sufficient bactericidal activities against Streptococcus milleri and Bacteroides fragilis from 3 h to 10 days. The composite granules were implanted in bone defects created by debridement of osteomyelitis lesions in rabbit mandibles. After 4-week implantation, inflammation in the composite granule-implanted group was significantly smaller than that in the debridement group (p<0.05). Moreover, newly formed bone was observed in the pores and on the surface of HA granules of the composite. These findings show that GFLX/HA composite controls bacterial infection and supports bone regeneration for osteomyelitis treatment. PMID- 28626207 TI - Influence of polymerization properties of 4-META/MMA-based resin on the activity of fibroblast growth factor-2. AB - Dental adhesive resins based on 4-methacryloxyethyl trimellitate anhydride (4 META)/methyl methacrylate (MMA) have been utilized for root-end filling and the bonding of fractured roots. To increase the success rate of these treatments, it would be beneficial to promote the healing of surrounding tissue by applying growth factors. In this study, the influences of the polymerization properties of 4-META/MMA-based resins on the activity of fibroblast growth factor-2 (FGF-2) were evaluated in vitro. The temperature increase caused by the heat generation during polymerization of the 4-META/MMA-based resin was insufficient to change the structure and function of FGF-2. Unpolymerized monomers released from the cured 4-META/MMA-based resin had no negative influences on the ability of FGF-2 to promote the proliferation of osteoblast-like cells. These findings suggest that it is possible to use FGF-2 in combination with 4-META/MMA-based resins. PMID- 28626208 TI - Posttraumatic stress disorder eliminates association of TrkB rs1187327 with HDL-C in Chinese Han adolescents. AB - Tropomyosin-related kinase receptor B (TrkB) has been observed to be a common player in posttraumatic stress disorder (PTSD) and the regulation of serum lipids levels. However, interplays of PTSD with TrkB on serum lipids levels have not been explored yet. This study was to investigate the interplays of PTSD and TrkB rs1187327 on serum lipid profiles. Variants of TrkB rs1187327 of 709 high school students were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analyses and verified by DNA sequencing. The PTSD Checklist Civilian Version (PCL-C) was used to assess PTSD. Colorimetric methods were used to determine the serum levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and glucose. The results show that the GG homozygotes had a significantly higher level of HDL-C than the A allele carriers of TrkB rs1187327 after the adjustment for gender, age and body mass index (BMI) (1.44 +/- 0.299 mmol/L vs. 1.39 +/- 0.266 mmol/L, p = 0.036). When PTSD was taken into account, the higher than the A allele carriers level of HDL-C of the GG homozygotes was observed significant after the adjustment for gender, age and BMI only in the subjects without PTSD (1.44 +/- 0.293 mmol/ L vs. 1.39 +/- 0.267 mmol/L, p = 0.030), but not in the subjects with PTSD. These results suggest that the A allele of TrkB rs1187327 may be associated with decreased levels of serum HDL-C in general healthy adolescents, but not in adolescents with PTSD. PMID- 28626209 TI - Paeoniflorin prevents TLR2/4-mediated inflammation in type 2 diabetic nephropathy. AB - Paeoniflorin is an effective Chinese traditional medicine with anti-inflammatory and immune-regulatory effects. The aim of this study was to investigate the underlying renoprotective mechanism of Paeoniflorin. In vivo, db/db mice were intraperitoneally injected with Paeoniflorin at a dose of 15, 30, or 60 mg/kg respectively. The immunostaining of TLR2, TLR4, CD68, NF-kB p65 and the mRNA level of inflammatory factors, together with the protein expression of TLR2/4 signaling were evaluated. Our data demonstrated that Paeoniflorin could decrease the urinary albumin excretion rate and inhibit macrophage infiltration and activation through blockage of the TLR2/4 signaling pathway compared with the db/db group in vivo. In vitro, RAW264.7 cells were categorized into control, bovin serum albumin (BSA)-stimulated, advanced glycation end products (AGEs) stimulated, Paeoniflorin intervention and oxidized phospholipid (OxPAPC) inhibited groups. The cell viability, the optimal stimulated time and concentration were measured as well as the TLR2/4 signaling activation determined by RT-PCR, Western blot and ELISA. Our data demonstrated that Paeoniflorin reduced the AGEs-induced TLR2/4 activation and inflammatory responses, which was consistent with the TLR2/4 inhibitor group. These findings indicate that Paeoniflorin prevents macrophage activation via inhibition of TLR2/4 signaling expression in type 2 diabetic nephropathy. PMID- 28626210 TI - Clinical correspondence to hepatocellular carcinoma-related lesions with atypical radiological pattern. AB - In patients at risk of hepatocarcinogenesis, tumors are frequently detected with atypical radiological patterns related to hepatocellular carcinoma (HCC) on imaging studies. Despite their high potential for malignancy, whether to resect such lesions immediately is controversial. Based on histological findings, patients with non-enhanced tumors or enhanced tumors without washout were divided into two groups: those with tumors that should be treated containing well, moderately, and poorly differentiated HCC (Group 1), and those that can be observed containing early HCC, hepatocellular adenoma, focal nodular hyperplasia, dysplastic nodules, and regenerative nodules (Group 2), and we elucidated the clinical correspondence to these tumors. Seventy-two patients had a single tumor with atypical radiological pattern: 39 patients had HCC (Group 1), while 33 patients had benign tumors or early HCC (Group 2). Among nine baseline variables, serum alpha-fetoprotein (AFP) level in Group 1 (median, 13.2 ng/mL; range, 0.6 5881.6) was significantly higher than that in Group 2 (5.6 ng/mL; 0.8-86.3, P = 0.003). The cut-off value of AFP was 36.4 ng/mL for prediction of Group 1, and the median overall and recurrence-free survival periods of 23 patients in the high-AFP (>= 36.4 ng/mL) group (5.3 years; 95%CI, 2.1 - N.A. and 1.6 years; 0.5 2.2) were significantly shorter than those of the 49 patients in the low-AFP (< 36.4) group (7.5 years; 7.5 - N.A., P = 0.047, and 2.8 years; 1.9-3.3, P = 0.001). Taken together, HCC-related tumors with an atypical radiological pattern could be observed unless serum AFP level is elevated. PMID- 28626211 TI - Once malaria is eliminated, more attention should be paid to imported malaria: Data from five years of surveillance in the City of Yiwu in eastern China. AB - This study reviewed and analyzed data on malaria cases in Yiwu from 2012 to 2016 via a webbased system for managing and reporting information on infectious diseases. A total of 161 cases were diagnosed (77.02% due to Plasmodium falciparum, 18.01% due to P. vivax, 4.35% due to P. ovale, and 0.62% due to P. malariae). One case was imported from Yunnan Province in China and the others were imported from overseas. The ratio of male to female patients was 7.47:1. The average age was 36.34 years (SD: 9.63). Most cases (87.58%) were imported from 1 of 30 countries in Africa. As malaria is gradually being eliminated in China, the main task at this stage has transitioned to the prevention and control of cases of imported malaria. Particular attention should be paid to malaria cases from Africa. PMID- 28626212 TI - A Huge Subcutaneous Hematoma in an Adult with Kasabach-Merritt Syndrome. AB - BACKGROUND Kasabach-Merritt syndrome is a potentially fatal disease that consists of hemangioma(s) with thrombocytopenia, microangiopathic hemolytic anemia, and coagulopathy. Extensive hemangiomatosis is rare. We present the radiological features and treatment strategy of a young adult suffering from Kasabach-Merritt syndrome with widespread hemangiomas and an infected huge hematoma in the right thigh. CASE REPORT A 33-year-old Taiwanese male presented with a painful 20-cm mass over his right thigh and gross hematuria for 2 days. Hemangiomatosis was bioptically proven in infancy and the patient was under regular follow-up. Physical examination revealed normal heart rate, respiratory rate, and body temperature. Multiple palpable lumps with brown and purple areas of skin over the neck, trunk, and right thigh were noted. Laboratory examinations revealed thrombocytopenia anemia and elevated fibrin degradation products. There were no signs of sepsis. Blood transfusion and steroid therapy were executed. Computed tomography showed a huge complicated subcutaneous hematoma in the right thigh. Drainage of the huge hematoma was performed and antibiotics were prescribed. After the local infection in the right thigh and the bleeding tendency were controlled, the patient was discharged in a stable condition two weeks later. CONCLUSIONS A huge infected hematoma and widespread hemangiomas are extremely rare complications of Kasabach-Merritt syndrome. There are no known treatment guidelines currently available. Our patient was successfully treated with steroids, drainage, and antibiotics. PMID- 28626213 TI - The Efficacy of Imrecoxib and Celecoxib in Axial Spondyloarthritis and Their Influence on Serum Dickopff-Related Protein 1 (DKK-1) Levels. AB - BACKGROUND To observe and demonstrate therapeutic effects and side effects of two selective COX-2 inhibitors, imrecoxib and celecoxib, on patients with axial spondyloarthritis (axSpA) and observe the correlation between imaging scores and serum DKK-1 levels. MATERIAL AND METHODS Sixty patients with axSpA were randomly assigned to receive 200 mg imrecoxib or 200 mg celecoxib twice daily. Fifty-one patients who completed follow-up were included in the study. At baseline, week 4, and week 12, the clinical parameters, inflammatory markers (ESR, CRP), and adverse reactions were recorded. Serum DKK-1 levels were investigated by enzyme linked immunosorbent assay. Radiographic scores were calculated by sacroiliac joint SPARCC (Spondyloarthritis Research Consortium of Canada) score method at baseline serum DKK-1 levels and week 12. RESULTS Patients in the imrecoxib group (n=25) and patients in the celecoxib group (n=26) were improved at week 4. At week 12, all clinical parameters and inflammatory markers were improved in the two groups and the differences was not statistically significant. Serum DKK-1 levels were decreased and the differences were not statistically significant. Serum DKK-1 levels in patients in the imrecoxib group at baseline were negatively correlated with all study parameters, while those in the celecoxib group had correlations with BASFI (r=-0.048, p=0.027) and Schober test (r=0.437, p=0.048), without any correlation with other clinical parameters or inflammatory markers. CONCLUSIONS Patients experienced significant improvement in disease activity, functional parameters, and inflammatory markers when treated with selective COX-2 inhibitors for 12 weeks, and the efficacy of imrecoxib was not inferior to celecoxib. Selective COX-2 inhibitors imrecoxib and celecoxib had no obvious effects on serum DKK-1 levels. PMID- 28626214 TI - Growth hormone-releasing hormone is produced by adipocytes and regulates lipolysis through growth hormone receptor. AB - BACKGROUND: Growth hormone-releasing hormone (GHRH) has a crucial role in growth hormone (GH) secretion, but little is known about its production by adipocytes and its involvement in adipocyte metabolism. OBJECTIVES: To determine whether GHRH and its receptor (GHRH-R) are present in human adipocytes and to study their levels in obesity. Also, to analyze the effects of GHRH on human adipocyte differentiation and lipolysis. METHODS: GHRH/GHRH-R and GH/GH-R mRNA expression levels were analyzed in human mature adipocytes from non-obese and morbidly obese subjects. Human mesenchymal stem cells (HMSC) were differentiated to adipocytes with GHRH (10-14-10-8 M). Adipocyte differentiation, lipolysis and gene expression were measured and the effect of GH-R silencing was determined. RESULTS: Mature adipocytes from morbidly obese subjects showed a higher expression of GHRH and GH-R, and a lower expression of GHRH-R and GH than non obese subjects (P<0.05). A total of 10-14-10-10 M GHRH induced an inhibition of lipid accumulation and PPAR-gamma expression (P<0.05), and an increase in glycerol release and HSL expression (P<0.05) in human differentiated adipocytes. A total of 10-12-10-8 M GHRH decreased GHRH-R expression in human differentiated adipocytes (P<0.05). A total of 10-10-10-8 M GHRH increased GH and GH-R expression in human differentiated adipocytes (P<0.05). The effects of GHRH at 10 10 M on adipocyte differentiation and lipolysis were blocked when GH-R expression was silenced. CONCLUSIONS: GHRH and GHRH-R are expressed in human adipocytes and are negatively associated. GHRH at low doses may exert an anti-obesity effect by inhibiting HMSC differentiation in adipocytes and by increasing adipocyte lipolysis in an autocrine or paracrine pathway. These effects are mediated by GH and GH-R. PMID- 28626215 TI - Genetic variation in the obesity gene FTO is not associated with decreased fat oxidation: the NEO study. AB - BACKGROUND: The fat mass and obesity-associated (FTO) gene harbors the strongest common genetic variant associated with obesity. Recently, rs1421085-T to -C substitution mapped in FTO was shown to induce a developmental shift of human adipocytes from an energy-combusting beige to an energy-storing white phenotype in vitro. As browning of adipocytes selectively enhances fat oxidation (FatOx), we hypothesized that rs1421085-C in FTO is associated with deceased FatOx compared with carbohydrate oxidation (CarbOx) and an increased respiratory quotient (RQ). METHODS: In the Netherlands Epidemiology of Obesity study, a population-based cohort study of middle-aged individuals (45-65 years), anthropometry and genotyping was performed (n=5744), in addition to indirect calorimetry (n=1246). With linear regression analyses, we examined associations of rs1421085 genotype with FatOx, CarbOx and RQ. RESULTS: In the total study population, 36.7% carried the rs1421085-TT genotype, 47.6% rs1421085-CT and 15.7% rs1421085-CC. Mean (s.d.) age was 56 (6) years, mean (s.d.), body mass index (BMI) was 26.3 (4.4) kg m-2 and 56% of the total population were women. Measures of adiposity (difference, 95% confidence interval) were higher in CC carriers compared with that in rs1421085-TT carriers: BMI +0.56 (0.15, 0.98) kg m-2, waist circumference +1.25 (0.02, 2.49) cm and total body fat mass +1.21 (0.28, 2.14) kg. However, no differences in mean FatOx (+2.5 (-2.4, 7.4) mg min-1), CarbOx ( 6.1 (-17.4, 5.2) mg min-1) or RQ (-0.01 (-0.02, 0.01)) were observed between the two genotypes. CONCLUSIONS: We observed no evidence for associations of rs1421085 in FTO with FatOx and RQ. This indicates that the rs1421085-C allele in FTO induces obesity likely via other pathways than via reduced FatOx. PMID- 28626216 TI - Therapeutic effects of CSF1R-blocking antibodies in multiple myeloma. AB - Our previous studies showed that macrophages (MFs), especially myeloma-associated MFs (MAMs), induce chemoresistance in human myeloma. Here we explored the potential of targeting MFs, by using colony-stimulating factor 1 receptor (CSF1R) blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MFs and MAMs, and repolarized MAMs towards M1-like MFs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4+ T-cell response. Similarly, genetically depleting MFs in myeloma-bearing MMDTR mice retarded myeloma growth in vivo. Furthermore, the combination of CSF1R blockade and chemotherapy such as bortezomib or melphalan displayed an additive therapeutic efficacy against established myeloma. Finally, a fully human CSF1R blocking mAb, similar to its murine counterpart, was able to inhibit the differentiation, proliferation and survival of human MFs. Thus, this study provides the first direct in vivo evidence that MPhis and MAMs are indeed important for myeloma development and progression. Our results also suggest that targeting MAMs by CSF1R blocking mAbs may be promising methods to (re)sensitize myeloma cells to chemotherapy and promote anti-myeloma immune responses in patients. PMID- 28626217 TI - Irf8 regulates the progression of myeloproliferative neoplasm-like syndrome via Mertk signaling in zebrafish. AB - Interferon regulatory factor (IRF)-8 is a critical transcription factor involved in the pathogenesis of myeloid neoplasia. However, the underlying mechanisms in vivo are not well known. Investigation of irf8-mutant zebrafish in this study indicated that Irf8 is evolutionarily conserved as an essential neoplastic suppressor through tight control of the proliferation and longevity of myeloid cells. Surviving irf8 mutants quickly developed a myeloproliferative neoplasm (MPN)-like disease with enhanced output of the myeloid precursors, which recurred after transplantation. Multiple molecules presented notable alteration and Mertk signaling was aberrantly activated in the hematopoietic cells in irf8 mutants. Transgenic mertk overexpression in Tg(coro1a:mertk) zebrafish recapitulated the myeloid neoplasia-like syndrome in irf8 mutants. Moreover, functional interference with Mertk, via morpholino knockdown or genetic disruption, attenuated the myeloid expansion phenotype caused by Irf8 deficiency. Therefore, Mertk signaling is a critical downstream player in the Irf8-mediated regulation of the progression of myeloid neoplasia. Our study extends the understanding of the mechanisms underlying leukemogenesis. PMID- 28626218 TI - Molecular characterization of EZH2 mutant patients with myelodysplastic/myeloproliferative neoplasms. AB - Mutations in the epigenetic regulator gene EZH2 are frequently observed in patients with myelodysplastic/myeloproliferative neoplasms (MDS/MPN; 10-13%) and are associated with a poor outcome. To gain more insight into EZH2 pathology, we sought to genetically characterize a cohort of 41 EZH2-mutated MDS/MPN patients using targeted deep next-generation sequencing (NGS), colony-forming progenitor assays and transcriptome analysis. Stable short hairpin RNA (shRNA)-mediated downregulation of EZH2 was performed in MDS-derived F-36P, MOLM-13 and OCI-M2 cells to study EZH2-specific changes. Targeted NGS revealed a complex pattern of mutations with a total of 190 individual mutations. EZH2 mutations frequently co occur with TET2 (58%), RUNX1 (40%) and ASXL1 (34%) mutations. Colony assays indicated EZH2 mutations to be mostly early events in leukemogenesis and showed a complex mutational hierarchy. Gene expression data revealed a number of differently expressed genes between EZH2 wild-type and mutant patients including known EZH2 targets. Comparison of patient transcriptome to EZH2-downregulated cell line data revealed several genes as novel EZH2 targets, showing opposite as well as unidirectional regulation between cell lines and patients. Some genes, such as CXXC5, ETS1 and VAV3 have previously been implied to have a role in leukemogenesis. Their precise role in MDS/MPN needs to be further investigated. PMID- 28626219 TI - Base excision repair proteins couple activation-induced cytidine deaminase and endonuclease G during replication stress-induced MLL destabilization. AB - The breakpoint cluster region of the MLL gene (MLLbcr) is frequently rearranged in therapy-related and infant acute leukaemia, but the destabilizing mechanism is poorly understood. We recently proposed that DNA replication stress results in MLLbcr cleavage via endonuclease G (EndoG) and represents the common denominator of genotoxic therapy-induced MLL destabilization. Here we performed a siRNA screen for new factors involved in replication stress-induced MLL rearrangements employing an enhanced green fluorescent protein-based reporter system. We identified 10 factors acting in line with EndoG in MLLbcr breakage or further downstream in the repair of the MLLbcr breaks, including activation-induced cytidine deaminase (AID), previously proposed to initiate MLLbcr rearrangements in an RNA transcription-dependent mechanism. Further analysis connected AID and EndoG in MLLbcr destabilization via base excision repair (BER) components. We show that replication stress-induced recruitment of EndoG to the MLLbcr and cleavage are AID/BER dependent. Notably, inhibition of the core BER factor Apurinic-apyrimidinic endonuclease 1 protects against MLLbcr cleavage in tumour and human cord blood-derived haematopoietic stem/progenitor cells, harbouring the cells of origin of leukaemia. We propose that off-target binding of AID to the MLLbcr initiates BER-mediated single-stranded DNA cleavage, which causes derailed EndoG activity ultimately resulting in leukaemogenic MLLbcr rearrangements. PMID- 28626220 TI - A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. AB - The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ?10 g/dl, low transfusion burden and serum erythropoietin (EPO) ?500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 MUg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140). PMID- 28626221 TI - Epidemiology: The global burden of reduced GFR: ESRD, CVD and mortality. PMID- 28626223 TI - Development: Tfcp2l1 drives Notch signalling and epithelial diversity in the collecting duct. PMID- 28626222 TI - The role of epigenetics in renal ageing. AB - An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction. Mechanistic insight into how epigenetic factors regulate ageing throughout the life course, linked to a decline in renal function with ageing, is already proving to be of value in the analyses of clinical and epidemiological cohorts. Noncoding RNAs provide epigenetic regulatory circuits within the kidney, which reciprocally interact with DNA methylation processes, histone modification and chromatin. These interactions have been demonstrated to reflect the biological age and function of renal allografts. Epigenetic factors control gene expression and activity in response to environmental perturbations. They also have roles in highly conserved signalling pathways that modulate ageing, including the mTOR and insulin/insulin-like growth factor signalling pathways, and regulation of sirtuin activity. Nutrition, the gut microbiota, inflammation and environmental factors, including psychosocial and lifestyle stresses, provide potential mechanistic links between the epigenetic landscape of ageing and renal dysfunction. Approaches to modify the renal epigenome via nutritional intervention, targeting the methylome or targeting chromatin seem eminently feasible, although caution is merited owing to the potential for intergenerational and transgenerational effects. PMID- 28626225 TI - Neurodevelopment: Organizing the second brain. PMID- 28626226 TI - Sleep: Labelling sleep generators. PMID- 28626227 TI - Neural circuits: An angle on navigation. PMID- 28626224 TI - Reference standards for next-generation sequencing. AB - Next-generation sequencing (NGS) provides a broad investigation of the genome, and it is being readily applied for the diagnosis of disease-associated genetic features. However, the interpretation of NGS data remains challenging owing to the size and complexity of the genome and the technical errors that are introduced during sample preparation, sequencing and analysis. These errors can be understood and mitigated through the use of reference standards - well characterized genetic materials or synthetic spike-in controls that help to calibrate NGS measurements and to evaluate diagnostic performance. The informed use of reference standards, and associated statistical principles, ensures rigorous analysis of NGS data and is essential for its future clinical use. PMID- 28626228 TI - Neurodevelopmental disorders: Taking on FXS with a diabetes drug. PMID- 28626229 TI - Linking social context and addiction neuroscience: a computational psychiatry approach. PMID- 28626232 TI - The RIP3-RIP1-NF-kappaB signaling axis is dispensable for necroptotic cells to elicit cross-priming of CD8+ T cells. PMID- 28626230 TI - Engineering of obligate intracellular bacteria: progress, challenges and paradigms. AB - It is estimated that approximately one billion people are at risk of infection with obligate intracellular bacteria, but little is known about the underlying mechanisms that govern their life cycles. The difficulty in studying Chlamydia spp., Coxiella spp., Rickettsia spp., Anaplasma spp., Ehrlichia spp. and Orientia spp. is, in part, due to their genetic intractability. Recently, genetic tools have been developed; however, optimizing the genomic manipulation of obligate intracellular bacteria remains challenging. In this Review, we describe the progress in, as well as the constraints that hinder, the systematic development of a genetic toolbox for obligate intracellular bacteria. We highlight how the use of genetically manipulated pathogens has facilitated a better understanding of microbial pathogenesis and immunity, and how the engineering of obligate intracellular bacteria could enable the discovery of novel signalling circuits in host-pathogen interactions. PMID- 28626231 TI - The resilience of the intestinal microbiota influences health and disease. AB - The composition of the intestinal microbiota varies among individuals and throughout development, and is dependent on host and environmental factors. However, although the microbiota is constantly exposed to environmental challenges, its composition and function in an individual are stable against perturbations, as microbial communities are resilient and resistant to change. The maintenance of a beneficial microbiota requires a homeostatic equilibrium within microbial communities, and also between the microorganisms and the intestinal interface of the host. The resilience of the healthy microbiota protects us from dysbiosis-related diseases, such as inflammatory bowel disease (IBD) or metabolic disorder. By contrast, a resilient dysbiotic microbiota may cause disease. In this Opinion article, we propose that microbial resilience has a key role in health and disease. We will discuss the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications for human health. PMID- 28626233 TI - Themis releases the brakes on TCR signaling during thymocyte selection by disabling SHP-1. PMID- 28626235 TI - Human gammadelta T cells: rapid, stable and clonally reactive. PMID- 28626236 TI - Themis2: setting the threshold for B-cell selection. PMID- 28626234 TI - B cell regulation in cancer and anti-tumor immunity. AB - The balance between immune effector cells and immunosuppressive cells and how this regulates the tumor microenvironment has been well described. A significant contribution of immune regulatory cells, including regulatory T cells, to tumor progression has been widely reported. An emerging body of evidence has recently recognized a role for B cells in modulating the immune response to tumors and lymphoid malignancies. Regulatory B cells (Bregs) are a newly designated subset of B cells that have been shown to play a pivotal role in regulating immune responses involved in inflammation, autoimmunity and, more recently, cancer. Bregs can suppress diverse cell subtypes, including T cells, through the secretion of anti-inflammatory mediators, such as IL-10, and can facilitate the conversion of T cells to regulatory T cells, thus attenuating anti-tumor immune responses. Similar B-cell subpopulations have been reported to be recruited to the tumor but to acquire their immunosuppressive properties within the tumor bed and thereby attenuate anti-tumor immune responses. However, despite a pivotal role for Bregs in promoting inflammation and carcinogenesis, the phenotypic diversity of the cell surface markers that are unique to Bregs remains unclear in mice and humans. In this review, we summarize the characteristics of Bregs and review our current knowledge of Bregs and their inhibition of anti-tumor immune responses in murine tumor models and cancer patients. PMID- 28626237 TI - CD4+ T cells memorize obesity and promote weight regain. AB - Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown. In this study, we report that immune cells, especially CD4+ T cells, mediate the 'memory' of previous obese status. In a weight gain-loss-regain model, we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain. This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice. Surprisingly, such obesity memory was abrogated by dexamethasone treatment, whereas immunodeficient Rag1-/- and H2A-/- mice failed to establish such memory. Rag1-/- mice repossessed the obesity memory when immune cells or CD4+ T cells isolated from previously obese mice were transferred. Furthermore, depletion of CD4+ T cells led to obesity memory ablation. Taken together, we conclude that CD4+ T cells mediate obesity memory and promote weight regain. PMID- 28626238 TI - IRF1 and BATF: key drivers of type 1 regulatory T-cell differentiation. PMID- 28626239 TI - IRFs as competing pioneers in T-cell differentiation. PMID- 28626240 TI - Efficacy of Blended Preservice Training for Resource Parents. AB - To evaluate a new way of meeting the growing demand for training prospective resource parents, our study compared the efficacy of a blended online and in person approach with a traditional classroom-only approach. Findings based on a sample of 111 resource parent prospects showed significantly greater gains in knowledge from pre- to posttest for the blended approach over the classroom-only approach. The blended approach also produced dramatically lower dropout rates during preservice training. Both groups made significant gains in parenting awareness from pre to post, but those gains were greater for the classroom-only approach. Post hoc analyses examined this finding more closely. Satisfaction with training was comparably high for both groups. Gains in knowledge and awareness were sustained at a 3-month follow-up assessment. PMID- 28626241 TI - Flow-induced corrosion of absorbable magnesium alloy: In-situ and real-time electrochemical study. AB - An in-situ and real-time electrochemical study in a vascular bioreactor was designed to analyze corrosion mechanism of magnesium alloy (MgZnCa) under mimetic hydrodynamic conditions. Effect of hydrodynamics on corrosion kinetics, types, rates and products was analyzed. Flow-induced shear stress (FISS) accelerated mass and electron transfer, leading to an increase in uniform and localized corrosions. FISS increased the thickness of uniform corrosion layer, but filiform corrosion decreased this layer resistance at high FISS conditions. FISS also increased the removal rate of localized corrosion products. Impedance-estimated and linear polarization-measured polarization resistances provided a consistent correlation to corrosion rate calculated by computed tomography. PMID- 28626242 TI - Work-related change in residential elderly care: Trust, space and connectedness. AB - Increasing care needs and a declining workforce put pressure on the quality and continuity of long-term elderly care. The need to attract and retain a solid workforce is increasingly acknowledged. This study reports about a change initiative that aimed to improve the quality of care and working life in residential elderly care. The research focus is on understanding the process of workforce change and development, by retrospectively exploring the experiences of care professionals. A responsive evaluation was conducted at a nursing home department in the Netherlands one year after participating in the change program. Data were gathered by participant observations, interviews and a focus and dialogue group. A thematic analysis was conducted. Care professionals reported changes in workplace climate and interpersonal interactions. We identified trust, space and connectedness as important concepts to understand perceived change. Findings suggest that the interplay between trust and space fostered interpersonal connectedness. Connectedness improved the quality of relationships, contributing to the well-being of the workforce. We consider the nature and contradictions within the process of change, and discuss how gained insights help to improve quality of working life in residential elderly care and how this may reflect in the quality of care provision. PMID- 28626243 TI - Characterization of an Aerosol Microconcentrator for Analysis Using Microscale Optical Spectroscopies. AB - Efficient microconcentration of aerosols to a substrate is essential for effectively coupling the collected particles to microscale optical spectroscopies such as laser-induced or spark microplasma, or micro-Raman or infrared spectroscopies. In this study, we present detailed characterization of a corona based aerosol microconcentration technique developed previously (Diwakar and Kulkarni, 2012). The method involves two coaxial electrodes separated by a few millimeters, one held at a high electrical potential and the other grounded. The particles are collected on the collection (i.e., ground) electrode from a coaxial aerosol flow in a one-step charge-and-collect scheme using corona discharge and electrical precipitation between the two electrodes. Performance of the corona microconcentration method was determined experimentally by measuring collection efficiency, wall losses, and particle deposition density. An intrinsic spectroscopic sensitivity was experimentally determined for the aerosol microconcentrator. Using this sensitivity, we show that corona-based microconcentration is much superior to alternative methods, including filtration, focused impaction using aerodynamic lens, and spot collection using condensational growth. The method offers unique advantages for compact, hand-held aerosol analytical instrumentation. PMID- 28626244 TI - Grandparents' Education and Infant Health: Pathways across Generations. AB - Using data from the Fragile Families and Child Wellbeing survey linked to respondents' medical records (N=2,870), this study examines the association between grandparents' education and birth outcomes and explores potential pathways underlying this relationship. Results show that having a grandfather with less than a high school education was associated with a 93 gram reduction in birthweight, a 59% increase in the odds of low birthweight, and a 136% increase in the odds of a neonatal health condition, compared to having a grandfather with a high school education or more. These associations were partially accounted for by mother's educational attainment and marital status, as well as by prenatal history of depression, hypertension, and prenatal health behaviors, depending on the specific outcome. The findings from this study call for heightened attention to the multigenerational influences of educational attainment for infant health. PMID- 28626245 TI - Psychological Well-Being among Older Adults: The Role of Partnership Status. AB - Today's older adults are increasingly unmarried. Some are in cohabiting unions, others are dating, and many remain unpartnered. Unmarried older adults are at risk of poorer well-being than the married, but it is unclear whether older cohabitors fare worse than or similar to their married counterparts. Nor have well-being differences among cohabitors, daters, and unpartnered persons been considered. Conceptualizing marital status as a continuum of social attachment, data from Waves I and II of the National Social Life, Health, and Aging Project are used to examine how older married, cohabiting, dating, and unpartnered individuals differ across multiple indicators of psychological well-being. Among men, cohabitors appear to fare similarly to the married, and better than daters and the unpartnered. In contrast, there are few differences in psychological well being by partnership status for women. PMID- 28626246 TI - The complexity of divisibility. AB - We address two sets of long-standing open questions in linear algebra and probability theory, from a computational complexity perspective: stochastic matrix divisibility, and divisibility and decomposability of probability distributions. We prove that finite divisibility of stochastic matrices is an NP complete problem, and extend this result to nonnegative matrices, and completely positive trace-preserving maps, i.e. the quantum analogue of stochastic matrices. We further prove a complexity hierarchy for the divisibility and decomposability of probability distributions, showing that finite distribution divisibility is in P, but decomposability is NP-hard. For the former, we give an explicit polynomial time algorithm. All results on distributions extend to weak-membership formulations, proving that the complexity of these problems is robust to perturbations. PMID- 28626248 TI - Dental health status and oral health behavior among university students from five ASEAN countries. AB - The aim of this study was to investigate dental health status and oral health behavior and associated factors among university students in five ASEAN countries (Indonesia, Malaysia, Myanmar, Thailand and Vietnam). Using anonymous questionnaires, data were collected from 3,344 undergraduate university students (mean age 20.5, SD=1.6; 58.3% female) from five ASEAN countries. Results indicate that 27.7% of students reported to have sometimes, most of the time or always having tooth ache in the past 12 months, 39.4% reported to have one or more cavities, 20.3% did not brush their teeth twice or more times a day, and 30.9% had never been to a dentist (or did not know it). In multivariate logistic regression analysis, older age, living in a lower middle income country, consumption of chocolate or candy, having made a dental care visit, and poor mental health was associated with tooth ache in the past 12 months. Being male, being 20 to 21 years old, coming from a wealthier family background, living in a lower middle income country, frequent consumption of soft drinks, not having consulted with a dentist in the past 12 months and weak beliefs in the benefits of tooth brushing were associated with inadequate tooth brushing frequency (=0.9 had significantly worse survival outcomes (28.9% vs 92.6%; p < 0.01). Univariate analysis showed that prognosis was significantly correlated with clinical T stage, local recurrence, perineural invasion, vascular invasion, and PET parameters (p < 0.05 for all). Multivariate analysis showed that local recurrence (hazard ratio = 3.60; p = 0.02) and DeltaSUVmax (hazard ratio = 8.43; p < 0.01) were independent prognostic factors. DeltaSUVmax determined using DTP 18F-FDG PET may be an additional prognostic factor in OTSCC patients. PMID- 28626255 TI - Underlying Cause of Death Recorded during 2013 to 2015 at a Tertiary General Hospital in Vientiane Capital, Lao PDR. AB - In Lao People's Democratic Republic (Lao PDR), the cause of death is not registered in death reports. As a result, the government cannot produce official reports that show mortality according to cause of death. This study aimed to report the underlying cause of death in a tertiary general hospital (Mittaphab Hospital) in Vientiane capital. Mittaphab hospital is a governmental teaching hospital with 300 beds for inpatient services specialized in orthopedics, neurology, and hemodialysis. Since a children hospital exists beside Mittaphab Hospital, severe pediatric cases are referred to the child hospital. HIV-positive cases and sputum positive tuberculosis are also transferred to the other specialized hospitals. All of the subjects in this study were patients who died in 2013-2015 at Mittaphab Hospital. Paper-based medical charts were examined by a medical doctor and staff from the medical records division. This chart review revealed that 1,509 patients (1,006 males and 503 females) died in this hospital during the study period. Of those, the number of patients aged <20 years and >80 years was small (6.2% and 7.7%, respectively). The most common underlying causes were injury (29.7%), cerebrovascular diseases (26.8%), renal disease (13.3%), infectious diseases (12.4%), and malignant neoplasm including brain tumor (4.8%). Among those aged 20-59 years, these percentages were 37.9%, 23.7%, 12.3%, 10.2%, and 5.0%, respectively. Although the patients visiting the hospital did not represent the whole population, the distribution of cause of death in the hospital was the only available information reported in Lao PDR. PMID- 28626256 TI - Postoperative chemoradiation therapy using high dose cisplatin and fluorouracil for high- and intermediate-risk uterine cervical cancer. AB - The purpose of this retrospective study was to analyze data in patients with stage IB-IIB uterine cervical cancer who were treated with concurrent chemoradiotherapy (CCRT) with high dose cisplatin and fluorouracil as postoperative adjuvant therapy. Between February 2003 and November 2011, 76 patients with FIGO stage IB-IIB cervical cancer were analyzed. Seventy patients were treated with postoperative CCRT and 6 patients were treated with radiation therapy alone. Data related to overall survival (OS), disease-free survival (DFS), toxicity, and failure pattern were analyzed. The median patient age was 45 years (range, 20-80 years). The median follow-up duration was 63 months (range, 10-125 months). Fifty-eight patients (76.3%) had a squamous cell histologic type, 55 patients (72.4%) had lymphovascular invasion, 31 patients (40.8%) had parametrial invasion, and 28 patients (36.8%) had lymph node metastases. Five year OS and DFS were 96% and 92%, respectively. Five-year DFS in stage IB1 patients was significantly higher than in stage IB2-IIB patients (p = 0.022). Nineteen patients (25%) had grade 3 or 4 neutropenia, 13 patients (17.1%) had grade 3 anemia, and 2 patients (2.6%) had grade 3 thrombocytopenia, but none of these patients died from the disease. Three patients experienced chronic toxicity: one had bladder perforation, one had hydronephrosis, and one experienced ileus. CCRT as postoperative adjuvant therapy resulted in good survival and outcome without severe toxicity. PMID- 28626257 TI - Multi-center rater-blinded study of early intervention with the Hand Incubator for breast cancer-related lymphedema (the BEAT-EDEMA trial): Proposal of a research protocol. AB - Postoperative lymphedema is considered irreversible once it has developed, and significantly lowers the patient's quality of life. However, lymphatic function has recently been clarified, and it is possible that lymphedema can be cured if early treatment is started. This two-arm randomized clinical trial (UMIN000026124) will prospectively evaluate 24 patients with early-stage breast cancer-related lymphedema at the Nagoya University Hospital and Aichi Cancer Center Hospital. The eligibility criteria will be patients who are diagnosed with stage 0-1 breast cancer-related lymphedema, as defined by the International Society of Lymphology, within 12 weeks after breast cancer surgery. The diagnosis of lymphedema will be confirmed using a bioimpedance spectroscopy device (L Dex(r)). Participants will be randomized 1:1 into the intervention and control groups. The physicians and patients will be aware of their group assignment, although treatment efficacy will be evaluated by raters who are blinded to the group assignments. The intervention group will complete grasping exercises in the Hand Incubator device for 4 weeks. The primary outcome will be the change in the affected upper limb's volume after the intervention, as measured using the water displacement method. This study may help establish a standard treatment for postoperative lymphedema. PMID- 28626258 TI - Formative research for the nationwide promotion of a multidisciplinary community based educational program on end-of-life care. AB - Although one of the most important missions of end-of-life education is to ensure proper inter-professional education (IPE), in Japan, end-of-life care IPE has not been given enough attention especially in community settings. This study aims at developing an effective workshop facilitator training program on end-of-life care IPE and acquiring the know-how to set up and efficiently run administrative offices. We first developed a tentative facilitation training program and conducted it in five cities nationwide. The training strategy was as follows: (1) participating in the workshop, (2) attending a lecture on facilitation, (3) conducting a preparatory study, (4) attending one workshop session as a facilitator, and (5) reflecting on one's attitude as a facilitator based on workshop participants' questionnaire, peer-feedback, and video recording. A total of 10 trainees completed the training program. We assessed the level of improvement in the trainees' facilitation skills and the efficacy of the training course using a qualitative approach. This formative study helped us identify several aspects needing improvement, especially in the areas of information technology and social media. Progress in these areas may have a positive impact on the education of community health care professionals whose study hours are limited, helping provide continued facilitation training. PMID- 28626259 TI - Lao language version of the Revised Hasegawa's Dementia Scale. AB - With the aging of society, the number of elderly with reduced cognitive function has been increasing worldwide. As a test to measure the cognitive function, the Revised Hasegawa's Dementia Scale (HDS-R) has been used in Japan, Korea, and China. Since there was no HDS-R version for Laotians, the questionnaire and manual were developed through the cooperation of Lao and Japanese researchers. Back-translation was conducted to confirm the accuracy of the translation. The score on the 9-item HDS-R ranges 0 to 30 points, and reduced cognitive function is usually defined as a score of 20 points or lower. After receiving explanation regarding the use of the tool and practicing its implementation, 3 female doctors interviewed 30 superficially healthy volunteers aged 31 to 84 years (12 males and 18 females) who lived with his/her family in Vientiane Capital, Lao PDR. Their score distributed from 4 to 30 points, with an average of 24.7 (standard deviation 5.4) points. Six (20.0%) participants scored 20 points or lower. The discussion before and after the pilot interviews revealed that the following changes needed to be made in accordance to the culture of Lao people; 1) order of date in Question 2, 2) words to be memorized in Questions 4 and 7, 3) objects to be memorized using pictures, not actual objects, in Question 8. Additionally, we introduced new two rules; a clear time definition for no reply (10 seconds), and repetition of questions twice for those with ear problems. The revised version of the HDS-R was thought to be an appropriate standard questionnaire for use in studies on cognitive function among Laotians. PMID- 28626260 TI - A case of API2-MALT1-positive gastric MALT lymphoma with concomitant diffuse large B-cell lymphoma. AB - API2-MALT1 translocation-positive gastric marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) lymphoma is thought to transform to diffuse large B-cell lymphoma (DLBCL) rarely. A 69-year-old man presented with epigastralgia. Esophagogastroduodenoscopy showed multiple ulcerations in the stomach. Endoscopic biopsies revealed MALT lymphoma, with Helicobacter pylori infection. The patient underwent eradication therapy with no improvement, and was thereafter followed without additional therapy at his request. Twelve years after initial diagnosis, follow-up computed tomography (CT) showed multiple nodules in bilateral lungs, and a needle biopsy revealed MALT lymphoma, the same as in the stomach and API2-MALT1 translocation was found. Because he again refused additional therapy, follow-up was continued. 15 years after initial diagnosis, CT showed lymphadenopathy at the splenic hilum. At first we suspected disease progression of gastric MALT lymphoma, however a needle biopsy revealed DLBCL without API2-MALT1. Thus, the tumor at the splenic hilum was finally diagnosed as a de novo DLBCL as a second malignancy. Although treatment with rituximab given his age and his wishes was attempted, he died of DLBCL 15 years after the initial diagnosis. We experienced an API2-MALT1-positive gastric MALT lymphoma with concomitant DLBCL, not transformed to DLBCL over a 15-year clinical course. PMID- 28626261 TI - A case of metachronous left ovarian metastasis 8 years after surgery for cecal cancer and right ovarian metastasis: Report of a case. AB - Metachronous ovarian metastasis of colorectal adenocarcinoma is mostly identified within 3 years. Here we present a case of a 64-year-old woman with cecal cancer who underwent right oophorectomy for ovarian metastasis. Imaging was performed because of abdominal bloating; it detected a swollen right ovary with ascites. On laparotomy, a right ovarian tumor and cecal cancer were identified. After right oophorectomy, a diagnosis of unilateral ovarian metastasis from colon cancer was made. One month later, right hemicolectomy was performed. Eight years after initial surgery, the patient presented with vaginal bleeding. A computed tomography (CT) scan revealed a pelvic mass approximately 10 cm in diameter, but no mass was evident on a CT image taken 6 months before. The patient was diagnosed with left ovarian metastasis from colon cancer. A third laparotomy revealed a left ovarian tumor, but there was no evidence of other metastases or peritoneal dissemination. Left oophorectomy was performed. Oophorectomy is considered to be associated with a survival benefit in ovarian metastasis without other extensive metastasis. However, ovarian metastasis is often bilateral. Although complete resection was achieved in the present case, the findings support performing prophylactic bilateral oophorectomy if metastasis is identified in a unilateral ovary. PMID- 28626262 TI - A case of anterior communicating artery aneurysm successfully treated after a stent migration during stent assisted endovascular coil embolization. AB - Stent migration is a complication associated with endovascular coil embolization of intracranial aneurysms. We report a case of anterior communicating artery (ACoA) aneurysm that was successfully treated after stent migration during endovascular coil embolization without retrieval of the stent. A 47-year-old man presented with sudden onset severe headache. Patient was noted to have subarachnoid hemorrhage from a ruptured ACoA aneurysm. Emergency endovascular coil embolization was performed. The second coil embolization was scheduled for the neck-remnant portion with a stent after 16 days from the initial operation. At first, a stent was deployed from the right perpendicular division of anterior cerebral artery (A2) to the left horizontal division of anterior cerebral artery (A1) entirely across the aneurysmal neck. Although the stent position looked fine, the stent migrated inferiorly to the proximal A1 portion when its delivery wire was withdrawn. Fortunately, the stent could be pushed into the distal A1 portion, when we trying to re-access the aneurysm thorough the stent with a pig tail shaped microguidewire. Additional coil embolization was achieved using the assistance of distal tip of the stent as a scaffold of the coil. The patient was discharged without any complication on the postoperative day 6. Although there are various choices of rescue treatment after stent migration, this is the first reported case of stent repositioning with a microguidewire. Our technique may represent an effective option in case of stent migration. PMID- 28626263 TI - 11C-Choline positive but 18F-FDG negative pancreatic metastasis from renal cell carcinoma on PET. AB - Choline is a new PET tracer, which uptake may occur via a choline-specific transporter protein and be accelerated during the proliferation of tumor cells. We report a 61-year-old woman with a metastatic pancreatic tumor from renal cell carcinoma, measuring 35*40 mm. PET scans demonstrated accumulation of 11C-choline in the metastatic pancreatic tumor, but no accumulation of 18F-FDG. Choline PET/CT may play a useful and complementary imaging modality, especially when FDG PET/CT does not show expected findings or when the evaluation of tumor viability is needed, in patients with renal cell carcinoma. PMID- 28626264 TI - Terrestrial and lacustrine gastropods from the Priabonian (upper Eocene) of the Sultanate of Oman. AB - Terrestrial and aquatic gastropods from the upper Eocene (Priabonian) Zalumah Formation in the Salalah region of the Sultanate of Oman are described. The assemblages reflect the composition of the continental mollusc fauna of the Palaeogene of Arabia, which, at that time, formed parts of the southeastern Tethys coast. Several similarities with European faunas are observed at the family level, but are rarer at the genus level. These similarities point to an Eocene (Priabonian) rather than to a Rupelian age, although the latter correlation cannot be entirely excluded. At the species level, the Omani assemblages lack any relations to coeval faunas. This suggests the possible presence of a distinct biogeographic province during the Palaeogene or may simply reflect the extremely sparse non-marine fossil record of the Eocene in the Tethys region. The occurrence of the genera Lanistes, Pila, and Gulella along with some pomatiids, probably related to extant genera, suggests that the modern African Arabian continental faunas can be partly traced back to Eocene times and reflect very old autochthonous developments. In contrast, the diverse Vidaliellidae went extinct, and the morphologically comparable Neogene Achatinidae may have occupied the equivalent niches in extant environments. Carnevalea Harzhauser and Neubauer nov. gen., Arabiella Kadolsky, Harzhauser and Neubauer nov. gen., Pyrgulella Harzhauser, Kadolsky and Neubauer nov. gen., Salalahia Kadolsky, Harzhauser and Neubauer nov. gen., Omanitopsis Harzhauser and Neubauer nov. gen., Arabicolaria Harzhauser and Neubauer nov. gen., Pacaudiella Harzhauser and Neubauer nov. gen., Goniodomulus Harzhauser and Neubauer nov. gen., Eoquickia Harzhauser and Neubauer nov. gen., Omanillya H. Nordsieck nov. gen. and Omanifera H. Nordsieck nov. gen. are introduced as new genera. Pila neuberti Harzhauser and Neubauer nov. sp., Arabiella arabica Kadolsky, Harzhauser and Neubauer nov. sp., Pyrgulella parva Harzhauser, Kadolsky and Neubauer nov. sp., Salalahia thaytinitiensis Kadolsky, Harzhauser and Neubauer nov. sp., Omanitopsis vandammei Harzhauser and Neubauer nov. sp., Procyclotopsis eocenica Harzhauser and Neubauer nov. sp., Palaeocyclotus kuehschelmi Harzhauser and Neubauer nov. sp., Arabicolaria arabica Harzhauser and Neubauer nov. sp., Pacaudiella omanica Harzhauser and Neubauer nov. sp., Pacaudiella flammulata Harzhauser and Neubauer nov. sp., Goniodomulus solaniformis Harzhauser and Neubauer nov. sp., Cerastus hyznyi Harzhauser and Neubauer nov. sp., Omanillya lunellifera H. Nordsieck nov. sp., Omanillya costellata H. Nordsieck nov. sp., and Omanifera euclista H. Nordsieck nov. sp. are described as new species. PMID- 28626265 TI - Computer-aided evaluation of neuroblastoma on whole-slide histology images: Classifying grade of neuroblastic differentiation. AB - Neuroblastoma (NB) is one of the most frequently occurring cancerous tumors in children. The current grading evaluations for patients with this disease require pathologists to identify certain morphological characteristics with microscopic examinations of tumor tissues. Thanks to the advent of modern digital scanners, it is now feasible to scan cross-section tissue specimens and acquire whole-slide digital images. As a result, computerized analysis of these images can generate key quantifiable parameters and assist pathologists with grading evaluations. In this study, image analysis techniques are applied to histological images of haematoxylin and eosin (H&E) stained slides for identifying image regions associated with different pathological components. Texture features derived from segmented components of tissues are extracted and processed by an automated classifier group trained with sample images with different grades of neuroblastic differentiation in a multi-resolution framework. The trained classification system is tested on 33 whole-slide tumor images. The resulting whole-slide classification accuracy produced by the computerized system is 87.88%. Therefore, the developed system is a promising tool to facilitate grading whole-slide images of NB biopsies with high throughput. PMID- 28626266 TI - Deterring Rearrests for Drinking and Driving. AB - This study assesses why some individuals are re-arrested for driving while intoxicated (DWI). Using longitudinal data from North Carolina containing information on arrests and arrest outcomes, we test hypotheses that individuals prosecuted and convicted of DWI are less likely to be re-arrested for DWI. We allow for possible endogeneity of prosecution and conviction outcomes by using instrumental variables for the prosecutor's prosecution rate and the judge's conviction rate. With a three-year follow-up, the probability of DWI re-arrest was reduced by 6.6 percent if the person was prosecuted for DWI and, for those prosecuted, by 24.5 percent if convicted on this charge. Prosecution and conviction for DWI deters re-arrest for DWI. PMID- 28626267 TI - A Facile Semi-Synthetic Approach towards Halogen-Substituted Aminobenzoic Acid Analogues of Platensimycin. AB - Platensimycin (PTM), produced by several strains of Streptomyces platensis, is a promising drug lead for infectious diseases and diabetes. The recent pilot-scale production of PTM from S. platensis SB12026 has set the stage for the facile semi synthesis of a focused library of PTM analogues. In this study, gram-quantity of platensic acid (PTMA) was prepared by the sulfuric acid-catalyzed ethanolysis of PTM, followed by a mild hydrolysis in aqueous lithium hydroxide. Three PTMA esters were also obtained in near quantitative yields in a single step, suggesting a facile route to make PTMA aliphatic esters. 1 [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU)-catalyzed coupling of PTMA and 33 aminobenzoates resulted in the synthesis of 28 substituted aminobenzoate analogues of PTM, among which 26 of them were reported for the first time. Several of the PTM analogues showed weak antibacterial activity against methicillin-resistant Staphylococcus aureus. Our study supported the potential utility to integrate natural product biosynthetic and semi-synthetic approaches for structure diversification. PMID- 28626268 TI - Sex Differences in Antipsychotic Related Metabolic Functioning in Schizophrenia Spectrum Disorders. AB - The adverse metabolic risks associated with second generation antipsychotics (SGAs) are well known, and likely contribute to the high rate of premature mortality due to cardiovascular disease in schizophrenia. Female schizophrenia patients appear to be diagnosed with metabolic diseases at higher rates than males, which may reflect disparate adverse responses to SGAs. However, the relationship between sex, metabolic risk, and drug use is less developed. We aimed to explore this relationship further by identifying rates of metabolic disease in community dwelling schizophrenia patients by sex and SGA risk. Schizophrenia participants (N = 287, 40.4% female) were included in this analysis. Oneway-ANOVA and Fisher's Exact Test were used to compare groups, as appropriate, and Cohen's d was employed to estimate the effect size of sex. In the group as a whole, the rate of metabolic syndrome was higher than previously reported, but did not differ by sex. For females, greater metabolic disturbances across all medication risk groups were seen in BMI and waist circumference (p < 0.005) but most commonly in those receiving high risk medication (clozapine or olanzapine). Additionally, the number of participants receiving medications for these metabolic disturbances was extremely low (<30%). These results suggest that female schizophrenia patients taking clozapine or olanzapine represent a group at uniquely high risk for metabolic dysfunction and future adverse cardiovascular outcomes, and warrant close monitoring by clinicians to prevent worsening of metabolic risk through proper monitoring and interventions. PMID- 28626270 TI - Impact of a Student Pharmacist Driven Medication Reconciliation and Antidepressant Treatment History Project at a Depression Clinic: A Pilot Study. AB - OBJECTIVES: To improve treatment of patients with depression, a new pilot service project involving student pharmacists who would conduct medication reconciliation and review of antidepressant treatment history was created and evaluated. EXPERIMENTAL DESIGN: A prospective study conducted at the University of Michigan Depression Center. PRINCIPAL OBSERVATIONS: From an initial sample of 78 referrals, 41 subjects were reached by phone, with 34 completing medication reconciliation and antidepressant treatment history. Of the 34 patients, 25 (73.5%) had at least one discrepancy identified in their medication list, resulting in 164 medication changes in the electronic medical record (EMR). A total of 105 past antidepressant trials were documented in the 34 individuals, with 34 (32.4%) trials found to be inadequate. Thirteen (38.2%) patients reported failure to respond to two different antidepressants from different classes. All 34 patients participated well in the phone calls and were willing to consult a pharmacist at their upcoming clinic visit. CONCLUSIONS: A student pharmacist pilot was feasible, identified many discrepancies in the medication record, and identified important medication treatment history in patients with depression in advance of the clinic visit. The project provides support for a specialized role for student pharmacists and demonstrates that interprofessional care can contribute to improved treatment of depression. PMID- 28626269 TI - The Addition of Amphetamine to Potentially Sedating Medication Regimens: An Exploratory Investigation of the Impact upon Reaction Time and Sustained Attention. AB - OBJECTIVES: The addition of amphetamine to a sedating medication may reduce sedation but does it augment reaction time and sustained attention for workers? The purpose of this exploratory study was gain insight into between group differences that would assist hypothesis formation for a subsequent hypothesis testing study. METHODS: This study examined psychomotor vigilance task (PVT) performance for a group taking potentially sedating medications (opiates, benzodiazepines, anticholinergics, barbiturates or polypharmacy) while taking amphetamine to a group not taking amphetamine. Data was assessed using two-way between groups multivariate analysis of variance. RESULTS: Multivariate testing found a (p = .05; eta2 = .044) difference in combined PVT measures between the amphetamine use groups. Tests of between-subjects effects established (p = .006; eta2 = .042) a difference in the number of minor lapses between the groups. Estimated marginal means of minor lapses revealed that the group taking amphetamine had 2.8 times the mean number of minor lapses than the group not taking amphetamine. A non-statistically significant trend was noted for the estimated marginal means of each sedating medication class and the use or nonuse of amphetamines that appears to correspond with the sedating medication's effect upon the cholinergic component of the attention system. CONCLUSION: Using PVT data, this exploratory study has provided information useful for generating the hypothesis that co-administration of an amphetamine with a sedating medication will result in arousal with a deficit of sustained attention related to the sedating medication's level of effect upon cholinergic activity. PMID- 28626271 TI - Long-Acting Injectable Paliperidone Palmitate: A Review of Efficacy and Safety. AB - OBJECTIVE: Summarize and synthesize the current literature regarding long-acting injectable paliperidone palmitate for the treatment of schizophrenia. METHODS: A literature search of PubMed, Embase, and Web of Science was conducted in February 2016, using the following search terms in varying permutations: schizophrenia; antipsychotic medication; long-acting injectable; paliperidone palmitate; 3 monthly injectable. RESULTS: Once-monthly injectable paliperidone palmitate (PDP) has demonstrated comparable efficacy as 1st-generation long-acting injectable antipsychotics (LAIAs) in reducing disease severity and re-hospitalizations in schizophrenic patients. However, PDP leads to significantly less extrapyramidal symptoms than these older medications indicating a superior safety profile. Compared to oral 2nd-generation antipsychotics, PDP has shown less incidence of disease relapse related to medication non-compliance, particularly in real world populations. It also showed a similar safety profile as oral 2nd-generation antipsychotics, but with greater incidence of mild injection-site pain. A novel 3 monthly formulation of PDP has shown similar safety and efficacy as once-monthly PDP compared to placebo. CONCLUSIONS: Overall, both 1-month and 3-month formulations of PDP are safe and effective in the treatment of schizophrenia and schizoaffective disorder. They may be most effective in patients with prior failed treatment of oral antipsychotics or other LAIAs, in patients with a history of medication noncompliance, or in patients with an individual preference for less frequent dosing. PMID- 28626272 TI - Aripiprazole-induced Asymptomatic Hypertension: A Case Report. AB - Aripiprazole is a second generation antipsychotic widely prescribed for the treatment of psychiatric diseases. It is generally known that antipsychotics have hypotensive effects. In this case report, however, we present the case of a medically healthy patient with schizophrenia who developed hypertension (HT) after the initiation of aripiprazole. The patient's blood pressure returned to normal after discontinuation of aripiprazole, suggesting that aripiprazole may have led to asymptomatic acute HT. PMID- 28626273 TI - Combined Antipsychotics and Electroconvulsive Therapy in an Acutely Psychotic Patient with Treatment-resistant Schizophrenia. AB - Treatment of patients with Treatment-resistant Schizophrenia (TRS), who fail to respond to multiple antipsychotic trials, including clozapine (CLZ), is challenging. Several alternative strategies are reported in studies, one of which includes augmenting antipsychotics (AP) with Electroconvulsive therapy (ECT). We discuss a case of an acutely psychotic patient with TRS who responded effectively and sustained remission to this strategy which was ECT combined with two AP, CLZ and aripiprazole. Notable improvement in clinical and cognitive outcomes was seen with just five right unilateral ECT sessions, CLZ titrated up to 62.5 mg/d and aripiprazole 20 mg/d with no adverse effects. Nine days into the psychiatric hospitalization, patient had decreased total scores on the Positive and Negative Syndrome Scale by 44% and an improved score on the St. Louis University Mental Status Exam by increasing from 3 to 22. This case report suggests that a subgroup of patients with TRS could benefit from a trial of adjunct ECT combined with AP to achieve a rapid alleviation of positive and negative symptoms which allows patients to have greater functional stability. PMID- 28626274 TI - Associations of intelligence across the life course with optimism and pessimism in older age. AB - Maintaining good cognitive function is important for successful aging, and it has been suggested recently that having and optimistic outlook may also be valuable. However few have studied the relationship between cognitive ability and dispositional optimism and pessimism in older age. It is unclear whether associations found previously between cognitive ability and pessimism in older age, are evident across the life course, and are consistent at different points in older age. In the present study we examined associations between dispositional optimism and pessimism measured in the eighth and ninth decade of life and childhood and older age cognitive ability, and lifetime change in cognitive ability. Participants were two independent narrow-age samples of older individuals with mean ages about 73 (n = 847) and 87 (n = 220) years from the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921), respectively. Higher cognitive ability in childhood and older-age, and healthier cognitive change across the lifetime were associated with lower pessimism in older age: age-11 IQ (LBC1936: beta = - 0.17, p < 0.001; LBC1921: beta = - 0.29, p = 0.001), older-age IQ (LBC1936: beta = - 0.18, p < 0.001; LBC1921: beta = - 0.27, p < 0.001), cognitive change (LBC1936: beta = - 0.06, p < 0.04; LBC1921: beta = - 0.15, p = 0.05). Cognitive ability was not significantly associated with optimism in bivariate analyses, and after adjustment for covariates had only small associations with optimism and only in the LBC1936. The results are consistent with differential associations between cognitive functions and optimism and pessimism, and indicate that their associations with cognitive ability are similar in the eighth and ninth decades of life. PMID- 28626276 TI - Standing and travelling waves in a spherical brain model: The Nunez model revisited. AB - The Nunez model for the generation of electroencephalogram (EEG) signals is naturally described as a neural field model on a sphere with space-dependent delays. For simplicity, dynamical realisations of this model either as a damped wave equation or an integro-differential equation, have typically been studied in idealised one dimensional or planar settings. Here we revisit the original Nunez model to specifically address the role of spherical topology on spatio-temporal pattern generation. We do this using a mixture of Turing instability analysis, symmetric bifurcation theory, centre manifold reduction and direct simulations with a bespoke numerical scheme. In particular we examine standing and travelling wave solutions using normal form computation of primary and secondary bifurcations from a steady state. Interestingly, we observe spatio-temporal patterns which have counterparts seen in the EEG patterns of both epileptic and schizophrenic brain conditions. PMID- 28626277 TI - Linking crop yield anomalies to large-scale atmospheric circulation in Europe. AB - Understanding the effects of climate variability and extremes on crop growth and development represents a necessary step to assess the resilience of agricultural systems to changing climate conditions. This study investigates the links between the large-scale atmospheric circulation and crop yields in Europe, providing the basis to develop seasonal crop yield forecasting and thus enabling a more effective and dynamic adaptation to climate variability and change. Four dominant modes of large-scale atmospheric variability have been used: North Atlantic Oscillation, Eastern Atlantic, Scandinavian and Eastern Atlantic-Western Russia patterns. Large-scale atmospheric circulation explains on average 43% of inter annual winter wheat yield variability, ranging between 20% and 70% across countries. As for grain maize, the average explained variability is 38%, ranging between 20% and 58%. Spatially, the skill of the developed statistical models strongly depends on the large-scale atmospheric variability impact on weather at the regional level, especially during the most sensitive growth stages of flowering and grain filling. Our results also suggest that preceding atmospheric conditions might provide an important source of predictability especially for maize yields in south-eastern Europe. Since the seasonal predictability of large scale atmospheric patterns is generally higher than the one of surface weather variables (e.g. precipitation) in Europe, seasonal crop yield prediction could benefit from the integration of derived statistical models exploiting the dynamical seasonal forecast of large-scale atmospheric circulation. PMID- 28626278 TI - Natural stranding of Atlantic sturgeon (Acipenser oxyrinchus Mitchill, 1815) in Scot's Bay, Bay of Fundy, Nova Scotia, from populations of concern in the United States and Canada. AB - Natural mortality of Atlantic sturgeon (Acipenser oxyrinchus) has been determined to be low (M = 0.07). Reported herein is the mortality by beach stranding of 11 Atlantic sturgeon in Scot's Bay, part of the inner Bay of Fundy in Nova Scotia, Canada on 22 June 2014. Genetic analyses, histological analysis and age determination were performed to determine origin, maturity stage and age of the stranded Atlantic sturgeon. Microsatellite and mitochondrial DNA analyses indicated that four of the Atlantic sturgeon (2 males and 2 females) were from the Saint John River, NB population, which was designated as threatened by the Committee on the Status of Endangered Wildlife in Canada. Seven Atlantic sturgeon (1 male, 5 females, 1 unknown) were from the Kennebec River, Maine population, that was listed as threatened under the Endangered Species Act in the U. S. Ageing of A. oxyrinchus by pectoral fin spine analysis determined that the mean age of the individuals from the Saint John River ( [Formula: see text] years, sd = 5.0) and the Kennebec River ( [Formula: see text] years, sd = 3.5) were not significantly different. This is the first report of a stranding event of Atlantic sturgeon, and describes a source of natural mortality affecting populations of concern in both Canada and the U. S. PMID- 28626275 TI - Phylogeny of saprobic microfungi from Southern Europe. AB - During a survey of saprophytic microfungi on decomposing woody, herbaceous debris and soil from different regions in Southern Europe, a wide range of interesting species of asexual ascomycetes were found. Phylogenetic analyses based on partial gene sequences of SSU, LSU and ITS proved that most of these fungi were related to Sordariomycetes and Dothideomycetes and to lesser extent to Leotiomycetes and Eurotiomycetes. Four new monotypic orders with their respective families are proposed here, i.e. Lauriomycetales, Lauriomycetaceae; Parasympodiellales, Parasympodiellaceae; Vermiculariopsiellales, Vermiculariopsiellaceae and Xenospadicoidales, Xenospadicoidaceae. One new order and three families are introduced here to accommodate orphan taxa, viz. Kirschsteiniotheliales, Castanediellaceae, Leptodontidiaceae and Pleomonodictydaceae. Furthermore, Bloxamiaceae is validated. Based on morphology and phylogenetic affinities Diplococcium singulare, Trichocladium opacum and Spadicoides atra are moved to the new genera Paradiplococcium, Pleotrichocladium and Xenospadicoides, respectively. Helicoon fuscosporum is accommodated in the genus Magnohelicospora. Other novel genera include Neoascotaiwania with the type species N. terrestris sp. nov., and N. limnetica comb. nov. previously accommodated in Ascotaiwania; Pleomonodictys with P. descalsii sp. nov. as type species, and P. capensis comb. nov. previously accommodated in Monodictys; Anapleurothecium typified by A. botulisporum sp. nov., a fungus morphologically similar to Pleurothecium but phylogenetically distant; Fuscosclera typified by F. lignicola sp. nov., a meristematic fungus related to Leotiomycetes; Pseudodiplococcium typified by P. ibericum sp. nov. to accommodate an isolate previously identified as Diplococcium pulneyense; Xyladictyochaeta typified with X. lusitanica sp. nov., a foliicolous fungus related to Xylariales and similar to Dictyochaeta, but distinguished by polyphialidic conidiogenous cells produced on setiform conidiophores. Other novel species proposed are Brachysporiella navarrica, Catenulostroma lignicola, Cirrenalia iberica, Conioscypha pleiomorpha, Leptodontidium aureum, Pirozynskiella laurisilvatica, Parasympodiella lauri and Zanclospora iberica. To fix the application of some fungal names, lectotypes and/or epitypes are designated for Magnohelicospora iberica, Sporidesmium trigonellum, Sporidesmium opacum, Sporidesmium asperum, Camposporium aquaticum and Psilonia atra. PMID- 28626279 TI - Nutritional status of foster children in the U.S.: Implications for cognitive and behavioral development. AB - OBJECTIVE: Children in foster care are at greater risk for poor health, physical, cognitive, behavioral, and developmental outcomes than are children in the general population. Considerable research links early nutrition to later cognitive and behavioral outcomes. The aim of this narrative review is to examine the prevalence of poor nutrition and its relation to subsequent health and development in foster children. METHOD: Relevant studies for inclusion were identified from numerous sources (e.g., PubMed, Google Scholar, and reference sections). Inclusion criteria were studies published between 1990 and 2016 of (i) the nutritional status of children in foster care or (ii) the nutritional status of children exposed to early adversity (e.g., low-income and internationally adopted children) or (iii) the developmental effects of poor nutrition and micronutrient deficiencies. RESULTS: Two key findings that have adverse implications for cognitive development emerged: (i) the prevalence of anemia and iron-deficiency anemia is higher among foster children than among the general population of children in the U.S., and (ii) the developmental demands of catch up growth post-placement may lead to micronutrient deficiencies even after children have begun sufficient dietary intake of these nutrients. Moreover, there is a paucity of recent studies on the nutritional status of children in foster care, despite the multiple factors that may place them at risk for malnutrition. CONCLUSION: Attention to nutritional status among care providers and medical professionals may remove one of the possible negative influences on foster children's development and in turn significantly alter their trajectories and place them on a more positive path early in life. Recommendations for further research, policy, and practice are discussed. PMID- 28626281 TI - Measurement of uranium-236 in particles by secondary ion mass spectrometry. AB - The determination of the relative isotopic abundance by secondary ion mass spectrometry of 236U in uranium-containing material is complicated by the presence of 235U1H+ ions at the same nominal mass as the uranium isotopic peak. The net intensity of the 236U signal is usually determined by a peak-stripping procedure, whereby the 235U1H+ contribution is obtained by applying the 238U1H+/238U+ ratio to the 235U+ signal. The subtraction of one signal from another has consequences for the uncertainty of the final 236U abundance determination that may be especially significant when the amount of sample is limited, as is the case with small uranium particles that are of great interest for nuclear safeguards. We have developed a model based on Poisson counting statistics to determine the effects of various parameters on the uncertainty of the 236U abundance, including uranium enrichment level, hydride-to-parent ratio, uranium mass consumed during analysis, single versus multichannel counting, and sample substrate composition. The model predictions have been successfully tested against experimental measurements of uranium oxide particles of both 3% and 90% enrichment in 235U. PMID- 28626280 TI - Children's Executive Function in a CPS-Involved Sample: Effects of Cumulative Adversity and Specific Types of Adversity. AB - Prior research has identified the presence of executive function (EF) deficits in child protective service (CPS) involved (versus non-involved) children but minimal work has examined predictors that might explain individual differences within these CPS-involved children. Here, we sought to characterize EF in a large sample (N=694) of CPS-involved children and examine how specific adversities (physical abuse, neglect, caregiver domestic violence, and caregiver substance dependence) and cumulative adversity (at ages 0-3 and 3-6 years) predict EF (at approximately 5-6 years). It was expected that the sample would exhibit low EF overall based on previous research in maltreated children. Specific adversity and cumulative adversity analyses were largely exploratory given the limited previous work in this area. Results indicated poor EF overall, with 43.5% of children performing worse than chance. Amongst children who performed greater than chance, higher cumulative adversity, physical abuse, and caregiver substance use (at ages 3-6 years) predicted better EF. These findings join literature documenting that, within CPS-involved children, the presence of certain adversities predicts variable cognitive function. Findings highlight the potential relevance of evolutionary psychology to understanding how alterations in behavior linked to harsh and unpredictable early environments may cue accelerated brain development underlying relative cognitive advantages, within at-risk, low performing samples. Longitudinal studies are critical to determine if the relative EF advantages linked to higher adversity persist over time or result in lower EF later on, reflecting a more rapid, but overall limited, trajectory of cognitive development. PMID- 28626282 TI - Learning About Long-Term Complications of Pediatric Type 1 Diabetes: Parents' Preferences. PMID- 28626283 TI - Assessment of cavitation in artificial approximal dental lesions with near-IR imaging. AB - Bitewing radiography is still considered state-of-the-art diagnostic technology for assessing cavitation within approximal carious dental lesions, even though radiographs cannot resolve cavitated surfaces but instead are used to measure lesion depth in order to predict cavitation. Clinicians need new technologies capable of determining whether approximal carious lesions have become cavitated because not all lesions progress to cavitation. Assessing lesion cavitation from near-infrared (NIR) imaging methods holds great potential due to the high transparency of enamel in the NIR region from lambda=1300-1700-nm, which allows direct visualization and quantified measurements of enamel demineralization. The objective of this study was to measure the change in lesion appearance between non-cavitated and cavitated lesions in artificially generated lesions using NIR imaging modalities (two-dimensional) at lambda =1300-nm and lambda=1450-nm and cross-polarization optical coherence tomography (CP-OCT) (thee-dimensional) lambda =1300-nm. Extracted human posterior teeth with sound proximal surfaces were chosen for this study and imaged before and after artificial lesions were made. A high speed dental hand piece was used to create artificial cavitated proximal lesions in sound samples and imaged. The cavitated artificial lesions were then filled with hydroxyapatite powder to simulate non-cavitated proximal lesions. PMID- 28626284 TI - Near-infrared imaging of enamel hypomineralization due to developmental defects. AB - The increasing prevalence of mild hypomineralization due to developmental defects on tooth surfaces poses a challenge for caries detection and caries risk assessment and reliable methods need to be developed to discriminate such lesions from active caries lesions that need intervention. Previous studies have demonstrated that areas of hypomineralization are typically covered with a relatively thick surface layer of highly mineralized and transparent enamel similar to arrested lesions. Seventy-six extracted human teeth with mild to moderate degrees of suspicious fluorosis were imaged using near-infrared reflectance and transillumination. Enamel hypomineralization was clearly visible in both modalities. However, it was difficult to distinguish hypomineralization due to developmental defects from caries lesions with contrast measurements alone. The location of the lesion on tooth coronal surface (i.e. generalized vs. localized) seems to be the most important indicator for the presence of enamel hypomineralization due to developmental defects. PMID- 28626285 TI - Selective Laser Ablation of Carious Lesions using Simultaneous Scanned Near-IR Diode and CO2 Lasers. AB - Previous studies have established that carious lesions can be imaged with high contrast using near-IR wavelengths coincident with high water absorption, namely 1450-nm, without the interference of stains. It has been demonstrated that computer-controlled laser scanning systems utilizing IR lasers operating at high pulse repetition rates can be used for serial imaging and selective removal of caries lesions. In this study, a point-to-point scanning system was developed integrating a 1450-nm diode laser with the CO2 ablation laser. This approach is advantageous since it does not require an expensive near-IR camera. In this pilot study, we demonstrate the feasibility of a combined NIR and IR laser system for the selective removal of carious lesions. PMID- 28626286 TI - Synergistic effect of fluoride and laser irradiation for the inhibition of the demineralization of dental enamel. AB - Both laser irradiation and fluoride treatment alone are known to provide increased resistance to acid dissolution. CO2 lasers tuned to a wavelength of 9.3 MUm can be used to efficiently convert the carbonated hydroxyapatite of enamel to a much more acid resistant purer phase hydroxyapatite (HAP). Further studies have shown that fluoride application to HAP yields fluoroapatite (FAP) which is even more resistant against acid dissolution. Previous studies show that CO2 lasers and fluoride treatments interact synergistically to provide significantly higher protection than either method alone, but the mechanism of interaction has not been elucidated. We recently observed the formation of microcracks or a "crazed" zone in the irradiated region that is resistant to demineralization using high resolution microscopy. The microcracks are formed due to the slight contraction of enamel due to transformation of carbonated hydroxyapatite to the more acid resistant pure phase hydroxyapatite (HAP) that has a smaller lattice. In this study, we test the hypothesis that these small cracks will provide greater adhesion for topical fluoride for greater protection against acid demineralization. PMID- 28626287 TI - High-Contrast Reflectance Imaging of Composite Restorations Color-Matched to Tooth Structure at 1000-2300-nm. AB - A major advantage of composite restoration materials is that they can be color matched to the tooth. However, this presents a challenge when composites fail and they need to be replaced. Dentists typically spend more time repairing and replacing composites than placing new restorations. We have shown in previous studies that high-contrast images of composite can be acquired in occlusal transmission mode at near-IR wavelengths coincident with higher water absorption. The purpose of this study was to determine if similar high-contrast images can be acquired in reflectance mode at longer wavelengths where water absorption is even higher. Extracted human teeth with existing composite restoration (n=14) were imaged at wavelengths from 900-2300 using an extended range InGaAs camera. Our results indicate that NIR wavelengths longer than 1400-nm coincident with higher water absorption yield the highest contrast between dental composites and tooth structure in reflectance. PMID- 28626288 TI - Assessment of radicular dentin permeability after irradiation with CO2 laser and endodontic irrigation treatments with thermal imaging. AB - Previous studies have demonstrated that the permeability changes due to the surface modification of dentin can be quantified via thermal imaging during dehydration. The CO2 laser has been shown to remove the smear layer and disinfect root canals. Moreover, thermal modification via CO2 laser irradiation can be used to convert dentin into a highly mineralized enamel-like mineral. The purpose of this study is to evaluate the radicular dentin surface modification after CO2 laser irradiation by measuring the permeability with thermal imaging. Human molar specimens (n=12) were sectioned into 4 axial walls of the pulp chamber and treated with either 10% NaClO for 1 minute, 5% EDTA for 1 minute, CO2 laser or none. The CO2 laser was operated at 9.4 MUm with a pulse duration of 26 MUs, pulse repetition rate of 300 Hz and a fluence of 13 J/cm2. The samples were dehydrated using an air spray for 60 seconds and imaged using a thermal camera. The resulting surface morphological changes were assessed using 3D digital microscopy. The images from digital microscopy confirmed melting of the mineral phase of dentin. The area enclosed by the time-temperature curve during dehydration, DeltaQ, measured with thermal imaging increased significantly with treatments with EDTA and the CO2 laser (P<0.05). These results indicate that the surface modification due to CO2 laser treatment increases permeability of radicular dentin. PMID- 28626289 TI - Comparison of High Resolution X-Ray detectors with Conventional FPDs using Experimental MTFs and Apodized Aperture Pixel Design for Reduced Aliasing. AB - Apodized Aperture Pixel (AAP) design, proposed by Ismailova et. al, is an alternative to the conventional pixel design1. The advantages of AAP processing with a sinc filter in comparison with using other filters include non-degradation of MTF values and elimination of signal and noise aliasing, resulting in an increased performance at higher frequencies, approaching the Nyquist frequency3. If high resolution small field-of-view (FOV) detectors with small pixels used during critical stages of Endovascular Image Guided Interventions (EIGIs) could also be extended to cover a full field-of-view typical of flat panel detectors (FPDs) and made to have larger effective pixels, then methods must be used to preserve the MTF over the frequency range up to the Nyquist frequency of the FPD while minimizing aliasing. In this work, we convolve the experimentally measured MTFs of an Microangiographic Fluoroscope (MAF) detector, (the MAF-CCD with 35MUm pixels) and a High Resolution Fluoroscope (HRF) detector (HRF-CMOS50 with 49.5MUm pixels) with the AAP filter and show the superiority of the results compared to MTFs resulting from moving average pixel binning and to the MTF of a standard FPD. The effect of using AAP is also shown in the spatial domain, when used to image an infinitely small point object. For detectors in neurovascular interventions, where high resolution is the priority during critical parts of the intervention, but full FOV with larger pixels are needed during less critical parts, AAP design provides an alternative to simple pixel binning while effectively eliminating signal and noise aliasing yet allowing the small FOV high resolution imaging to be maintained during critical parts of the EIGI. PMID- 28626290 TI - Joint Optimization of Fluence Field Modulation and Regularization in Task-Driven Computed Tomography. AB - PURPOSE: This work presents a task-driven joint optimization of fluence field modulation (FFM) and regularization in quadratic penalized-likelihood (PL) reconstruction. Conventional FFM strategies proposed for filtered-backprojection (FBP) are evaluated in the context of PL reconstruction for comparison. METHODS: We present a task-driven framework that leverages prior knowledge of the patient anatomy and imaging task to identify FFM and regularization. We adopted a maxi min objective that ensures a minimum level of detectability index (d') across sample locations in the image volume. The FFM designs were parameterized by 2D Gaussian basis functions to reduce dimensionality of the optimization and basis function coefficients were estimated using the covariance matrix adaptation evolutionary strategy (CMA-ES) algorithm. The FFM was jointly optimized with both space-invariant and spatially-varying regularization strength (beta) - the former via an exhaustive search through discrete values and the latter using an alternating optimization where beta was exhaustively optimized locally and interpolated to form a spatially-varying map. RESULTS: The optimal FFM inverts as beta increases, demonstrating the importance of a joint optimization. For the task and object investigated, the optimal FFM assigns more fluence through less attenuating views, counter to conventional FFM schemes proposed for FBP. The maxi min objective homogenizes detectability throughout the image and achieves a higher minimum detectability than conventional FFM strategies. CONCLUSIONS: The task-driven FFM designs found in this work are counter to conventional patterns for FBP and yield better performance in terms of the maxi-min objective, suggesting opportunities for improved image quality and/or dose reduction when model-based reconstructions are applied in conjunction with FFM. PMID- 28626292 TI - A 65k pixel, 150k frames-per-second camera with global gating and micro-lenses suitable for fluorescence lifetime imaging. AB - This paper presents our work on a 65k pixel single-photon avalanche diode (SPAD) based imaging sensor realized in a 0.35MUm standard CMOS process. At a resolution of 512 by 128 pixels the sensor is read out in 6.4MUs to deliver over 150k monochrome frames per second. The individual pixel has a size of 24MUm2 and contains the SPAD with a 12T quenching and gating circuitry along with a memory element. The gating signals are distributed across the chip through a balanced tree to minimize the signal skew between the pixels. The array of pixels is row addressable and data is sent out of the chip on 128 lines in parallel at a frequency of 80MHz. The system is controlled by an FPGA which generates the gating and readout signals and can be used for arbitrary real-time computation on the frames from the sensor. The communication protocol between the camera and a conventional PC is USB2. The active area of the chip is 5% and can be significantly improved with the application of a micro-lens array. A micro-lens array, for use with collimated light, has been designed and its performance is reviewed in the paper. Among other high-speed phenomena the gating circuitry capable of generating illumination periods shorter than 5ns can be used for Fluorescence Lifetime Imaging (FLIM). In order to measure the lifetime of fluorophores excited by a picosecond laser, the sensor's illumination period is synchronized with the excitation laser pulses. A histogram of the photon arrival times relative to the excitation is then constructed by counting the photons arriving during the sensitive time for several positions of the illumination window. The histogram for each pixel is transferred afterwards to a computer where software routines extract the lifetime at each location with an accuracy better than 100ps. We show results for fluorescence lifetime measurements using different fluorophores with lifetimes ranging from 150ps to 5ns. PMID- 28626291 TI - Machine learning in a graph framework for subcortical segmentation. AB - Automated and reliable segmentation of subcortical structures from human brain magnetic resonance images is of great importance for volumetric and shape analyses in quantitative neuroimaging studies. However, poor boundary contrast and variable shape of these structures make the automated segmentation a tough task. We propose a 3D graph-based machine learning method, called LOGISMOS-RF, to segment the caudate and the putamen from brain MRI scans in a robust and accurate way. An atlas-based tissue classification and bias-field correction method is applied to the images to generate an initial segmentation for each structure. Then a 3D graph framework is utilized to construct a geometric graph for each initial segmentation. A locally trained random forest classifier is used to assign a cost to each graph node. The max-flow algorithm is applied to solve the segmentation problem. Evaluation was performed on a dataset of T1-weighted MRI's of 62 subjects, with 42 images used for training and 20 images for testing. For comparison, FreeSurfer and FSL approaches were also evaluated using the same dataset. Dice overlap coefficients and surface-to-surfaces distances between the automated segmentation and expert manual segmentations indicate the results of our method are statistically significantly more accurate than the other two methods, for both the caudate (Dice: 0.89 +/- 0.03) and the putamen (0.89 +/- 0.03). PMID- 28626293 TI - CD146 Promoter Polymorphism (rs3923594) Is Associated with Recurrence of Clear Cell Renal Cell Carcinoma in Chinese Population. AB - INTRODUCTION: CD146 is a membrane signal receptor in tumor-induced angiogenesis. However, limited studies have focused on the CD146 promoter polymorphisms in clear cell renal cell carcinoma (ccRCC). PURPOSE: The purpose of this study was to investigate the association between polymorphisms located in the promoter region of the CD146 gene and characteristics of ccRCC in Chinese population. The association between the CD146 promoter polymorphisms and CD146 expression was also investigated in ccRCC. MATERIALS AND METHODS: A total of 600 samples including 300 ccRCC patients and 300 healthy controls were collected for analysis of the CD146 promoter polymorphisms by direct sequence. The CD146 expressions were measured by qRT-PCR. RESULTS: We had not found any significant differences in genotypic and allelic frequencies of CD146 promoter polymorphisms between ccRCC patients and controls. The rs3923594 was associated with stage and metastasis (300 cases) and recurrence (263 cases) of ccRCC in Chinese population. A significant association was also observed between the rs3923594 and CD146 expression (227 cases) in ccRCC. CONCLUSIONS: CD146 promoter polymorphisms were not associated with the risk of ccRCC in Chinese population. The rs3923594 was an independent predictor of recurrence in Chinese patients with localized ccRCC. PMID- 28626294 TI - Optical molecular fluorescence determination of ultra-trace beryllium in occupational and environmental samples using highly alkaline conditions. AB - Exposures to beryllium (Be), even at extremely low levels, can cause severe health effects in a percentage of those exposed; consequently, occupational exposure limits (OELs) promulgated for this element are the lowest established for any element. This work describes the advantages of using highly alkaline dye solutions for determination of Be in occupational hygiene and environmental samples by means of an optical molecular fluorescence technique after sample extraction in 1-3% (w?w-1) aqueous ammonium bifluoride (NH4HF2). Improved attributes include the ability to further enhance the detection limits of Be in extraction solutions of high acidity with minimal dilution, which is particularly beneficial when NH4HF2 solutions of higher concentration are used for extraction of Be from soil samples. Significant improvements in Be method detection limits (MDLs) are obtained at levels many-fold below those reported previously for this methodology. Notably, MDLs for Be of <0.01 ng l-1 / 0.1 ng per sample have been attained, which are superior to MDLs routinely reported for this element by means of the most widely used ultra-trace elemental measurement technique, inductively coupled plasma mass spectrometry (ICP-MS). Very low MDLs for Be are essential in consideration of reductions in OELs for this element in workplace air by health organizations and regulatory agencies in the USA and internationally. Applications of enhanced Be measurements to air filter samples, surface wipe samples, soils and newly-designed occupational air sampler inserts are illustrated. PMID- 28626295 TI - Restoring effective sleep tranquility (REST): A feasibility and pilot study. AB - INTRODUCTION: The purpose of this pilot study was to establish the feasibility of completing a future controlled trial of a multi-component cognitive behavioral therapy for insomnia program for military veterans with sleep disturbance. METHOD: This was a single-arm feasibility and pilot study. Participants were United States post-9/11 veterans with service-connected injuries, university students, and had self-reported sleep disturbances. Restoring Effective Sleep Tranquility was a multi-component cognitive behavioral therapy for insomnia intervention consisting of seven sessions of group therapy and eight 1:1 sessions delivered by occupational therapists. Feasibility and pilot indicators were process, resources, management, and scientific, including pre-post-assessments of sleep difficulties, dysfunctional sleep beliefs, participation, and pain interference. FINDINGS: Indicators were supportive of feasibility, including reduced sleep difficulties (for example Medical Outcomes Study Sleep Measure [t = 3.29, p = .02]), reduced nightmares: t = 2.79, p = .03; fewer dysfunctional sleep beliefs: t = 3.63, p = .01, and greater ability to participate in social roles: t = -2.86, p = .03, along with trends towards improved satisfaction with participation and reduced pain interference. CONCLUSION: The Restoring Effective Sleep Tranquility program may reduce sleep difficulties and improve participation in US veterans with service-connected injuries, and evidence indicates a controlled trial would be feasible to deliver. PMID- 28626296 TI - Big Data Analytics with Datalog Queries on Spark. AB - There is great interest in exploiting the opportunity provided by cloud computing platforms for large-scale analytics. Among these platforms, Apache Spark is growing in popularity for machine learning and graph analytics. Developing efficient complex analytics in Spark requires deep understanding of both the algorithm at hand and the Spark API or subsystem APIs (e.g., Spark SQL, GraphX). Our BigDatalog system addresses the problem by providing concise declarative specification of complex queries amenable to efficient evaluation. Towards this goal, we propose compilation and optimization techniques that tackle the important problem of efficiently supporting recursion in Spark. We perform an experimental comparison with other state-of-the-art large-scale Datalog systems and verify the efficacy of our techniques and effectiveness of Spark in supporting Datalog-based analytics. PMID- 28626297 TI - Improved Synthesis of the C-Glucuronide/Glycoside of 4-Hydroxybenzylretinone (4 HBR). AB - Improvements in the synthesis of carbon-linked glucuronide/glucoside conjugates of cancer chemopreventive retinoids have been achieved starting with 2,3,4,6 tetra-O-benzyl-D-glucopyranose. The revised approach demonstrates better yields, eliminates the use of an expensive, carcinogenic protecting group reagent, and avoids much painstaking chromatography. The new approach should allow synthesis of larger quantities of the agents for detailed animal and mechanistic studies. PMID- 28626298 TI - Stress and Coping: Latino Youth Coming of Age in a New Latino Destination. AB - Previous research has linked stress to adverse mental health outcomes among Latino adolescents living in the United States. The mechanism through which this process operates continues to be explored, especially in regions of the country where Latin American immigrants and their children have only recently begun to migrate. Our study aimed to contextualize the processes of stress and coping among Latino adolescents growing up in an emerging Latino destination in the US North Carolina (NC). All adolescents in our study were either the first or second generation children of immigrants from Latin American countries including Colombia, El Salvador, Honduras, and Mexico. We employed a longitudinal qualitative design, conducting in-depth interviews with 12 parent-adolescent dyads during each adolescent's first year of high school (2006-2007) and four years later (2009-2010). We identified four stress-coping trajectories that varied on the following dimensions: primary sources of stress, buffers countering these stressors, coping approaches and the effects of these processes on adolescents' striving for socioeconomic mobility. Our findings underscore the interplay between family, school, and community environments within an emerging Latino destination. PMID- 28626299 TI - NEUTRON RADIOGRAPHY MEASUREMENT OF SALT SOLUTION ABSORPTION IN MORTAR. AB - Some concrete pavements in the US have recently exhibited premature joint deterioration. It is hypothesized that one component of this damage can be attributed to a reaction that occurs when salt-laden water is absorbed in the concrete and reacts with the matrix. This study examines the absorption of CaCl2 solution in mortar via neutron imaging. Mortar specimens were prepared with water to cement ratios, (w/c), of 0.36, 0.42 and 0.50 by mass and exposed to chloride solutions with concentrations ranging from 0 % to 29.8 % by mass. Depth of fluid penetration and moisture content along the specimen length were determined for 96 h after exposure. At high salt concentration (29.8 %), the sorption rate decreased by over 80 % in all samples. Along with changes in surface tension and viscosity, CaCl2 reacts with the cement paste to produce products (Friedel's salt, Kuzel's salt, or calcium oxychloride) that block pores and reduce absorption. PMID- 28626300 TI - Comparison of the trapezius and serratus anterior muscles isolation ratio during different shoulder abduction exercises. AB - [Purpose] To measure the activities of the upper, middle, and lower trapezius and serratus anterior muscles during shoulder abduction at two angles and compare their relative isolation. [Subjects and Methods] Ten men were enrolled. The tester measured the isolation ratios of upper, middle, and lower trapezius and serratus anterior muscles during shoulder abduction exercises at 60 degrees and 120 degrees . [Results] Neither the upper nor the lower trapezius isolation ratios differed statistically between 60 degrees and 120 degrees . The middle trapezius showed higher isolation ratio at 60 degrees than at 120 degrees . The serratus anterior showed higher isolation ratio at 120 degrees than at 60 degrees . [Conclusion] The upper, lower, and middle trapezius can be strengthened sufficiently with exercises at a low range of angles. PMID- 28626301 TI - Effect of neurodevelopmental treatment-based physical therapy on the change of muscle strength, spasticity, and gross motor function in children with spastic cerebral palsy. AB - [Purpose] This study aimed to investigate the effectiveness of neurodevelopmental treatment-based physical therapy on muscle tone, strength, and gross motor function in children with spastic cerebral palsy. [Subjects and Methods] One hundred-seventy-five children with spastic cerebral palsy (88 diplegia; 78 quadriplegia) received neurodevelopmental treatment-based physical therapy for 35 minutes per day, 2-3 times per week for 1 year. Spasticity, muscle strength, and gross motor function were measured before and after treatment with the Modified Ashworth Scale, Manual Muscle Testing, and Gross Motor Function Measure, respectively. [Results] Spasticity was significantly reduced after 1 year of treatment. The Gross Motor Functional Classification System levels I-II group showed a significant increase in muscle strength compared with the Gross Motor Functional Classification System levels III-V, and the latter showed a significant decrease in spasticity compared with the former. [Conclusion] Neurodevelopmental treatment-based physical therapy in children with cerebral palsy seems to be effective in reducing spasticity, but does not improve gross motor function. Therefore, other interventional approaches are needed to improve gross motor function in children with cerebral palsy. PMID- 28626302 TI - The immediate effect of diaphragm taping with breathing exercise on muscle tone and stiffness of respiratory muscles and SpO2 in stroke patient. AB - [Purpose] This study aimed to examine the immediate effects of diaphragm taping with breathing exercise on the tone and stiffness in the respiratory muscles of patient with stroke. [Subjects and Methods] A total of 28 subjects, 14 in the diaphragm taping with breathing exercise group and 14 in the breathing exercise group, were administered respective intervention methods. Subsequently, the muscle tone and stiffness in upper trapezius, scalene, external oblique abdominal and ractus abdominis muscle of both the respiratory muscles were measured. [Results] The comparison of respiratory muscles on the affected and non-affected sides in stroke patients showed statistically significant declines in the muscle tone and stiffness of all measured muscles but not in the stiffness of the external oblique abdominal muscle and rectus abdominis muscles. After intervention, the diaphragm taping with breathing exercise group exhibited statistically significant increases in the muscle tone of all measured muscles and in the stiffness of the upper trapezius and scalene muscles, and statistically significant declines in the saturation of peripheral oxygen. However, the breathing exercise group showed statistically significant increases only in the muscle tone of the upper trapezius and external oblique abdominal muscles. [Conclusion] This study demonstrated that diaphragm taping with breathing exercise had positive effects of immediately increasing the muscles tone and stiffness in the respiratory muscles. PMID- 28626303 TI - The comparison of clinical features and quality of life after total knee replacement. AB - [Purpose] The purpose of this study is to provide fundamental information for efficient management of patients after a total knee replacement (TKR) through the evaluation of changes of range of motion, pain, functional level, and quality of life. [Subjects and Methods] For a total of 63 knee osteoarthritis patients, VAS, KSKS, KSFS, HSS, WOMAC scores and quality of life were evaluated for functional levels at pre-operation, post-operation, six months after operation, and 12 months after operation. [Results] After the TKR operations, participants showed significant improvement in KSKS, KSFS, WOMAC, and SF-36 scores when compared to pre-operation. [Conclusion] After a TKR operation, ROM, and pain management, along with a therapeutic program for improvement of function, should be conducted 6 months after the operation. PMID- 28626305 TI - Inter-rater and intra-rater reliability of the fluid goniometer for measuring active knee flexion in painful knees; correlations do not mean agreement. AB - [Purpose] The fluid goniometer is an instrument for measuring range of motion. Reliability of the fluid goniometer has not been established for subjects with painful knee joints. The purpose of this study was to determine the inter-rater and intra-rater reliability of the fluid goniometer in measuring active knee flexion of painful knees and to test its agreement with the gold standard ruler goniometer. [Subjects and Methods] Twenty-five individuals with either unilateral or bilateral painful knees participated in the study. Two raters each took three measurements with the same Baseline(r) fluid goniometer on 35 knees. [Results] Intraclass correlation coefficients (ICC) were 0.97 for both intra-rater and inter-rater measurements, denoting high relative reliability. The large standard error of measurement (SEM) value of 6.6 degrees, and the 95% limits of agreement, which revealed a potential difference of 18.4 degrees between raters of similar subjects, however, revealed poor absolute reliability. The smallest detectable difference (SDD) of 18 degrees was also large. [Conclusion] The results revealed excellent relative reliability, but a large amount of variability between the raters' measurements. The sensitivity of the fluid level of the goniometer to end range tremors of the lower leg flexed against gravity in the obligatory prone position may contribute significantly to the large variability in knee ROM values. PMID- 28626304 TI - Obesity and low back pain: a retrospective cohort study of Japanese males. AB - [Purpose] This study evaluated whether obesity is a risk factor for low back pain, by using body fat percentage (%FAT) and body mass index (BMI) as indices of obesity among Japanese males. [Subjects and Methods] This study included 1,152 males (average age: 28.0 +/- 4.6 years). BMI was calculated from subject's height and weight, and %FAT was estimated by the thickness of two parts of skin. Low back pain, drinking and smoking were surveyed using a self-administered questionnaire, and maximal oxygen uptake was measured by a submaximal exercise test using a cycle ergometer. [Results] A significant positive dose-response relationship was shown between %FAT and persistent low back pain prevalence. Similarly, a significant positive dose-response relationship was confirmed between BMI and persistent low back pain. [Conclusion] This study suggests that both high %FAT and BMI are risk factors for persistent low back pain. PMID- 28626306 TI - Effects of task-oriented circuit training on balance and gait ability in subacute stroke patients: a randomized controlled trial. AB - [Purpose] The aim of this study was to investigate the effects of the task oriented circuit training on balance and gait ability in subacute patients with stroke. [Subjects and Methods] Participants were randomly allocated to two groups: group 1 (subjects who performed task-oriented circuit training) and group 2 (subjects who underwent conventional physical therapy). Berg balance scale, timed up and go test, functional ambulation category, 6-minute walk test were assessed before and after four weeks of training. [Results] There were significant differences between groups for the 6-minute walk test. [Conclusion] The result of this study showed that task-oriented circuit training could improve the gait ability in patients with subacute stroke. PMID- 28626307 TI - Effect of breathing maneuver combined with upper extremity exercise on respiratory capacity in healthy adult men. AB - [Purpose] This study aimed to determine the effect of the breathing maneuver combined with dynamic motion of the upper limbs on respiratory capacity in healthy adult men. [Subjects and Methods] Twenty-four healthy adult men participated in this study. Subjects were randomly assigned to a control group (n=12) or an experimental group (n=12). The subjects in the control group performed the breathing maneuver without the upper extremity exercise. The subjects in the experimental group performed upper extremity exercise with the breathing maneuver three times a week for 4 weeks. Outcomes were measured using maximum inspiratory and expiratory pressures. [Results] There was a significant difference in maximum inspiratory and expiratory pressures before and after intervention in the experimental group and the control group. In addition, there was a significant difference in maximal expiratory pressure between groups after intervention. [Conclusion] The results of this study suggest the respiration maneuver combined with upper extremity exercise could be used as a program for clinical respiration training. PMID- 28626308 TI - Relationship between trunk function evaluated using the trunk righting test and physical function in patients with knee osteoarthritis. AB - [Purpose] The present study was to validate the importance of the trunk function evaluated by trunk righting test (TRT) with motor function in patients with knee osteoarthritis (OA) and to show the clinical use of TRT. [Subjects and Methods] This study included 50 patients with knee osteoarthritis who underwent total knee arthroplasty in our hospital. Correlations between physical functional test, such as muscle strength, balance function, and performance and TRT were statistically evaluated. [Results] The independent factors for ipsilateral TRT were maximal isometric knee extensor strength test and ipsilateral step test. The operator and non-operator side TRT were significantly associated with TUG. [Conclusion] The results showed that the physical functions are correlated with the trunk function evaluated by TRT of patients with knee OA, suggesting that healthcare workers must take into consideration the trunk function, as well as lower extremity function to improve physical function. PMID- 28626310 TI - Can blood pressure be measured during exercise with an automated sphygmomanometer based on an oscillometric method? AB - [Purpose] This study investigated the reliability of an automated sphygmomanometer based on an oscillometric method, when used during exercise. [Subjects and Methods] Ten healthy subjects were included. Blood pressure (BP) was measured with an automated sphygmomanometer based on a cuff-oscillometric method. The experiment consisted of five tests: sitting posture at rest, walking with swinging the upper limbs, walking without swinging the upper limbs, walking on a treadmill, and riding a bicycle ergometer. Right and left brachial artery BP was measured twice at the same times. If the difference in systolic BP on bilateral testing was less than 15 mmHg, it was judged to be accurate, and accurate measurement rates were calculated. [Results] BP could not be measured in most limbs on walking with swinging the upper limbs, walking without swinging the upper limbs, or walking on a treadmill. The accurate measurement rates in bilateral limbs were 95.0% in sitting posture at rest, 0.0% on walking with swinging upper limbs, 5.0% on walking without swinging upper limbs, 15.0% on walking on a treadmill, and 65.0% on riding a bicycle ergometer. [Conclusion] An automated sphygmomanometer based on an oscillometric method was useful for BP measurement only at rest. PMID- 28626309 TI - Does the weakening of intrinsic foot muscles cause the decrease of medial longitudinal arch height? AB - [Purpose] There are no reliable evidences that the weakening of intrinsic foot muscles causes the decrease of the medial longitudinal arch (MLA) height. The purpose of this study was to confirm whether the fatigue of intrinsic foot muscles decrease the MLA height during standing and gait using 3D motion analysis system. [Subjects and Methods] Twenty healthy male subjects participated in this study. Foot kinematics was measured using an Oxford Foot Model before and after fatigue-inducing exercises of the abductor hallucis and flexor hallucis brevis muscles. [Results] Following fatigue-inducing exercise, in both standing and gait, the MLA height did not decrease but slightly increased. In addition, the reduction of a rear foot eversion angle was noted. [Conclusion] Fatigue of the abductor hallucis and flexor hallucis brevis muscles did not cause a change associated with collapsing of the MLA during both standing and gait. This suggested that the MLA support force from these muscles would be compensated by other MLA support structures, such as extrinsic foot muscles. PMID- 28626311 TI - Influence of structural integration and fascial fitness on body image and the perception of back pain. AB - [Purpose] The aim of this study was to examine the influence of Structural Integration and Fascial Fitness, a new form of physical exercise, on body image and the perception of back pain. [Subjects and Methods] In total, 33 participants with non-specific back pain were split into two groups and performed three sessions of Structural Integration or Fascial Fitness within a 3-week period. Before and after the interventions, perception of back pain and body image were evaluated using standardized questionnaires. [Results] Structural Integration significantly decreased non-specified back pain and improved both "negative body image" and "vital body dynamics". Fascial Fitness led to a significant improvement on the "negative body image" subscale. Benefits of Structural Integration did not significantly vary in magnitude from those for fascial fitness. [Conclusion] Both Structural Integration and Fascial Fitness can lead to a more positive body image after only three sessions. Moreover, the therapeutic technique of Structural Integration can reduce back pain. PMID- 28626312 TI - Bacterial contamination in physical therapy departments in the State of Kuwait. AB - [Purpose] Interferential therapy and electrical stimulation are electrophysical modalities commonly used in physical therapy departments to treat patients with musculoskeletal problems. These machines are applied directly to the patient's skin via a medium or electrodes, which can facilitate the transmission of microorganisms from one patient to another. The purpose of this study was to determine the extent of microorganism contamination in the machines sponges at physical therapy departments in Kuwait hospitals. [Subjects and Methods] Sixty samples comprising sponges from interferential therapy and electrical stimulation machines, and water from hot pack units were collected from 5 physical therapy departments in 5 different hospitals. The samples were analyzed at a Medical Laboratory to explore the extent and type of microorganisms present. [Results] Forty-one of the 60 samples (68.3%) were positive for microorganism contamination. Of the 41 contaminated samples, 28 (68.3%) were sponges and 13 (31.7%) were water samples. The major microorganisms found were Acinetobacter baumannii (21.9%), Serratia marcescens (12.2%), and Staphylococcus lentus (7.3%). [Conclusion] Interferential therapy and electrical stimulation in physical therapy departments have a high probability of causing cross contamination between patients. Physical therapists are encouraged to adhere to safety guidelines, such as disinfection management, disposal of used sponges, and regular sponge replacement. PMID- 28626313 TI - Comparison of the tibialis anterior and soleus muscles isolation ratios during the sit-to-stand movement in elderly people. AB - [Purpose] To compared activation of the tibialis anterior and soleus muscles during the sit-to-stand movement in elderly people. [Subjects and Methods] Ten elderly women were enrolled. The activities of the dominant lower extremity muscles were measured using a wireless electromyography system. Subjects performed natural sit-to-stand tasks. [Results] In the pre-thigh off phase, the tibialis anterior isolation ratio was significantly higher than the soleus isolation ratio. In the post-thigh off phase, the tibialis and soleus isolation ratios did not significantly differ. [Conclusion] This result suggests that selective soleus exercises might help to reduce the risk of falling in the elderly. PMID- 28626314 TI - Effect of sleep posture on neck muscle activity. AB - [Purpose] This study investigated the effect of sleep posture on neck muscle activity. [Subjects and Methods] The study recruited 20 healthy subjects, who were positioned in three supine sleeping positions: both hands at sides, both hands on the chest, and dominant hand on the forehead. The activities of the scalene and upper trapezius muscles bilaterally were measured by surface electromyography. [Results] The upper trapezius and scalene muscle activity on the right side was significantly greater in the supine with dominant hand on the forehead position than in the other positions. [Conclusion] Sleep posture is important and prevent neck and shoulder musculoskeletal pain. PMID- 28626315 TI - Availability of the Two-step Test to evaluate balance in frail people in a day care service. AB - [Purpose] This study evaluated balance tests in users of a day care service who needed nursing care or support, and investigated the usefulness of the Two-step Test for evaluating balance. [Subjects and Methods] The subjects were users of a day care service, and had certified need for long-term care or support. All subjects were able to undergo the balance evaluations. Balance tests included the 3-m Timed Up and Go test (TUG), the one-leg standing time, and the Two-step Test. [Results] The Two-step Test and other balance tests were strongly correlated. [Conclusion] In this study of subjects who needed nursing care or support, the results were the same as in a previous study of subjects who did not need nursing care or support. The Two-step Test should be considered as an indicator of balance ability in elderly individuals requiring nursing care or support. PMID- 28626316 TI - Immediate effects of ankle eversion taping on dynamic and static balance of chronic stroke patients with foot drop. AB - [Purpose] This study evaluates the immediate effect of ankle eversion taping on dynamic and static balance of chronic stroke patients with foot drop. [Subjects and Methods] This study was conducted with nine subjects who were diagnosed with stroke. A cross-over randomized design was used. Each subject performed three interventions in a random order. Subjects were randomly assigned to an ankle everion taping, placebo taping, and no taping. For dynamic and static balance, ability was measured using BIO Rescue. Limit of stability, sway length and sway speed for one minute were measured. [Results] The Limit of Stability, Sway length and Sway speed differed significantly among the three different taping methods. [Conclusion] We conclude that ankle eversion taping that uses kinesiology tape instantly increases the dynamic and static balance ability of chronic stroke patients with foot drop. PMID- 28626317 TI - The effect of the push-up plus on shoulder muscle activation while using a sling with a pulley. AB - [Purpose] This study was conducted to investigate the effects of the push-up plus while using a balance ball, a sling, and a sling with a pulley in a creeping position on an unstable floor. [Subjects and Methods] The subjects were divided into three groups of 15 members each who performed the different three type methods of push-up plus (with scapulae protruding) in a random order while in a creeping posture. The muscle activity of each group in the push-up plus posture was measured using electromyography, and the measurement values were compared among the groups using one-way analysis of variance (ANOVA). [Results] The intergroup comparison revealed that the activation of the pectoralis major muscle of the balance ball exercise group was significantly decreased. In this comparison, the activity ratio for the pectoralis major muscles of the balance ball exercise group significantly decreased, and the activity ratio of their serratus anterior muscles significantly increased. From the post analysis, the differences in the activity ratios of the pectoralis major and serratus anterior muscles for the balance ball exercise group were significant when compared with those of the other groups. [Conclusion] Among the three different exercise methods in unstable situations presented in this study, the push-up plus exercise in a creeping posture using the balance ball can be recommended for the selective strengthening of the serratus anterior muscle. PMID- 28626318 TI - The effects of repetitive transcranial magnetic stimulation (rTMS) on depression, visual perception, and activities of daily living in stroke patients. AB - [Purpose] The present study aimed to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on visual perception, depression, and activities of daily livings (ADLs) in stroke patients. [Subjects and Methods] Forty-four stroke patients were divided equally into an experimental group that underwent rTMS and a control group that underwent mock rTMS. Changes in patient visual perception, depression, and ADLs were evaluated. All subjects underwent treatment for 20 minutes, 5 times per week, for 4 weeks. Beck Depression Inventory (BDI), Motor-free Visual Perception Test (MVPT) and Functional Independent Measurement (FIM) were respectively used to assess depression, visual perception and ADLs. [Results] The experimental group showed significant improvements in depression, visual perception, and ADLs between week 1 and 4, between week 1 and 8, and between week 4 and 8. Meanwhile, the control group showed no differences between week 1 and 4, and although, like in the experimental group, a significant difference was observed in depression and visual perception between Week 1 and 8, there was no significant difference in ADLs. [Conclusion] These demonstrate that rTMS has a positive impact on visual perception, depression, and ADLs. PMID- 28626319 TI - Short-term effect of spiral taping on the pain and walking performance of individuals with chronic ankle instability. AB - [Purpose] This study was designed to investigate the effects of spiral taping (ST) on the pain and walking performance of individual with chronic ankle instability (CAI). [Subjects and Methods] 12 men and 13 women (mean: 21.52 years; range: 20-31 years) with unilateral CAI (Cumberland ankle instability score: <=24) were included. All the participants received 3 mm-wide ST. The latter was applied in a 3 * 4 cross shape onto the medial malleolus, the lateral malleolus, and the anterior talotibial joint of the unstable ankle. The pain and walking performance were measured on the visual analogue scale (VAS) and with a timed up and go test (TUGT) at the baseline and 30 minutes after the intervention. [Results] VAS and TUGT scores were significantly improved after application of the ST. [Conclusion] The results indicated that ST can improve the pain and walking performance of CAI individuals. PMID- 28626320 TI - Effects of pulling direction on upper trapezius and rhomboid muscle activity. AB - [Purpose] This study examined the activation of the rhomboid muscle according to the angle of the arm. [Subjects and Methods] The current study was conducted on 15 healthy males. The participants performed the pulling exercise in 5 conditions. The surface electromyography system was used to measure the muscle activities of the rhomboid and upper trapezius. [Results] The activity of the upper trapezius in condition 5 was significantly increased compared to that in condition 4. The activity of the rhomboid in condition 4 was significantly increased compared to that in conditions 1 and 5. [Conclusion] This study showed that performing a pulling exercise with the arms raised above the head (shoulder flexion at 120 degrees ) is more effective for reducing upper trapezius tension, while also selectively strengthening the rhomboid muscle. PMID- 28626321 TI - The effects of changes in support and inclined boards on lower-extremity muscle activity. AB - [Purpose] The purpose of this study was to identify the effects of changes in support and inclined boards on lower-extremity muscle activity. [Subjects and Methods] The study subjects were 15 healthy adult males. Aero-Step equipment was used as an unstable support, and an inclined board was used to maintain angles of 0 degrees and 20 degrees . Electromyography was employed to analyze lower extremity muscle activity. [Results] The vastus lateralis, vastus medialis, rectus femoris, gastrocnemius, soleus, and tibialis anterior muscles showed significant differences according to changes in the support and inclined board. In post-hoc tests the vastus lateralis, vastus medialis, and rectus femoris muscles showed significantly increased activity when exercises were performed on the unstable inclined board (20 degrees ) than the stable support (0 degrees ), unstable support (0 degrees ), or stable inclined board (20 degrees ). The gastrocnemius, soleus, and tibialis anterior muscles showed significantly increased activity when exercises were performed on the unstable support (0 degrees ), stable inclined board (20 degrees ), or unstable inclined board (20 degrees ) than on the stable support (0 degrees ). [Conclusion] An unstable support and increased slope of the inclined board may increase lower-extremity muscle activity. PMID- 28626322 TI - The effect of age on hamstring passive properties after a 10-week stretch training. AB - [Purpose] Degenerative changes take place in the musculoskeletal system of elderly people, resulting in a reduced range of motion. For this reason, stretch training is recommended for elderly individuals. To date, there have been no studies of the adaptations of the passive properties of muscles following long term stretch training. The aim of this study is to investigate the hamstring elasticity of elderly people following a 10-week stretch training and compare the results to a younger cohort. [Subjects and Methods] The experimental groups consisted of 15 younger (24.0 +/- 4.0 years) and 14 older (65.1 +/- 7.9 years) individuals. Both experimental groups undertook a standardised 10-week static passive hamstring stretch training. Passive properties of the hamstring were measured with an instrumented Straight Leg Raise Test. [Results] After a 10-week stretch training, there were increases in range of motion, passive resistive force and passive elastic energy in both age groups. Passive elastic stiffness decreased. Changes of hamstring passive properties did not differ significantly between age groups after a 10-week stretch training. [Conclusion] Increasing age has a negative effect on muscle passive properties, but older individuals benefit from regular stretch training, just as younger individuals do. PMID- 28626323 TI - Effect of diaphragm breathing exercise applied on the basis of overload principle. AB - [Purpose] The purpose of this study was to examine effects of diaphragm breathing exercise applied on the basis overload principle on respiratory function. [Subjects and Methods] The subjects of this study were 35 normal adults. They were randomly assigned to two group; the maneuver-diaphragm exercise group and self-diaphragm exercise group. The respiratory function was evaluated using the CardioTouch 3000S (BIONET, Korea) as a pulmometry device. [Results] The maneuver diaphragm exercise was more effective on functional vital capacity and forced expiratory volume at one second when compared to the self-diaphragm exercise. [Conclusion] According to the results of this study, although the self-diaphragm exercise did not show effects as much as the maneuver one, but the self-diaphragm exercise had a similar effects as the maneuver-diaphragm exercise. The self diaphragmatic respiration applied on the basis of overload principle may be used as an effective respiratory exercise as a part of home respiration program. PMID- 28626324 TI - Lower trunk muscle activity-induced alignment and cop position during single-leg standing. AB - [Purpose] The purpose of this study was to clarify fundamental changes induced by lower trunk muscle contraction during single-leg standing. [Subjects and Methods] Ten healthy normal males participated in this study. All subjects could accurately perform lower trunk muscle contraction-type Abdominal Expansion (AE), Abdominal Bracing (AB), and Abdominal Cave-in (AC). The alignment and position of the center of foot pressure (COP) during single-leg standing with SLR and step position after rotating the body from single-leg standing with maximum SLR were measured in each lower trunk muscle contraction type. [Results] When AC was performed during single-leg standing with SLR, the SLR angle increased, COP shifted backward, and the posterior tilt angle of the trunk and cross step distance decreased. [Conclusion] It was assumed that AC during wind-up increases the angle of lower limb elevation and decreases the posterior tilt angle of the trunk and cross step distance. PMID- 28626325 TI - The reliability and validity of the Korean version of the Upper Limb Functional Index. AB - [Purpose] The purpose of this study was to establish the reliability and validity of Upper Limb Functional Index (ULFI), which has been translated into Korean, in treating patients with upper limb complaints. [Subjects and Methods] Fourty-nine subjects with upper limb disorder, 20 males and 29 females, participated in this study. Reliability was determined by using the intra class correlation coefficient and Cronbach's alpha for internal consistency. Validity was examined by correlating ULFI scores with Disability of Arm, Shoulder and Hand (DASH). [Results] Test-retest reliability was 0.90. The criterion-related validity was established by a comparison with the Korean version of DASH. [Conclusion] The Korean version of ULFI was shown to be a reliable and valid instrument for assessing upper limb complaints. PMID- 28626326 TI - Effects of measurement posture and stimulation intensity on the nociceptive flexion reflex (RIII reflex). AB - [Purpose] The purpose of this study was to examine the effects of the measurement posture and stimulation intensity on the nociceptive flexion reflex (RIII reflex). [Subjects and Methods] Thirty normal female adult subjects were selected for this study. Their RIII reflexes were measured in three positions and with three degrees of stimulation intensity. The measurement posture was randomly selected. The analysis items were the stimulation intensity of the induced RIII reflex, the amplitude of the RIII reflex, and the numeric rating scale (NRS). [Results] The study results showed statistically significant differences in the interaction effects between the measurement posture and the stimulation intensity. The NRS showed no statistically significant differences in the interaction effects but showed statistically significant differences in the main effect. The amplitude of the RIII reflex showed no statistically significant differences in the interaction effects and showed statistically significant differences only in the stimulation intensity. [Conclusion] The study results suggest that the RIII reflex may be influenced by the measurement posture and stimulation intensity. PMID- 28626327 TI - The effects of dynamic exercise using the proprioceptive neuromuscular facilitation pattern on posture in healthy adults. AB - [Purpose] The purpose of this study is to examine the effects of dynamic exercise utilizing the proprioceptor neuromuscular facilitation pattern accompanied by abdominal drawing-in exercises on posture in healthy adults. [Subjects and Methods] The total number of subjects were 32; 16 were randomly placed in the training group, and the remaining 16 made up the control group. The subjects in the training group conducted 5 sets of dynamic exercises utilizing the proprioceptor neuromuscular facilitation patterns each day, 3 times a week for 6 weeks. Using BackMapper, their trunk inclination, trunk imbalance, pelvic position, pelvic torsion, pelvic rotation and the position of their scapula were evaluated. [Results] When the training group's posture pre-test and post-test were compared in this study, there was a statistical significance in trunk inclination, pelvic position, pelvic torsion, pelvic rotation and the position of their scapula. [Conclusion] Dynamic exercise utilizing the proprioceptor neuromuscular facilitation patterns increased the posture that are the basis of trunk stabilization. PMID- 28626328 TI - Differences in attention, hand dexterity, and lower extremity activities in the presence or absence of a time limit. AB - [Purpose] The purpose of this study was to investigate how a time limit affects day-to-day tasks such as attention, hand dexterity, and sit to standing and sitting activity. The grounds for using a time limit as a method of learning tasks related to daily living are examined based on the results of this investigation. [Subjects and Methods] The subjects consisted of 51 healthy college students (20 males and 31 females). The task performance time for SESSION 1, in which there was no time limit, was measured and the task duration privately recorded. The task performance for SESSION 2 was then measured with a time limit of the same duration as the time recorded for SESSION 1. Attention was measured using the trail-making test, hand dexterity using the Purdue pegboard test, and lower extremity activity using the sit to standing and sitting test. [Results] The levels for the attention, hand dexterity, and lower extremity activities were high in the environment in which a time limit was set. The differences between the genders depending on the presence or absence of a time limit was insignificant. [Conclusion] A time limit environment can be used as a task training method for attention, hand dexterity, and lower extremity activities. PMID- 28626329 TI - Effects of high intensity laser therapy on pain and function of patients with chronic back pain. AB - [Purpose] This study examined the effects of High Intensity Laser Therapy on pain and function of patients with chronic back pain. [Subjects and Methods] This study evenly divided a total of 20 patients with chronic back pain into a conservative physical therapy group that received conservative physical therapy, and a high intensity laser therapy group that received High Intensity Laser Therapy after conservative physical therapy. All patients received the therapy three times a week for four weeks. For the high intensity laser therapy group, treatment was applied to the L1-L5 and S1 regions for 10 minutes by using a high intensity laser device while vertically maintaining the separation distance from handpiece to skin at approximately 1 cm. A visual analog scale was used to measure the pain and Oswestry Disability Index was used for functional evaluation. [Results] In a within-group comparison of the conservative physical therapy and high intensity laser therapy groups, both the visual analog scale and Oswestry Disability Index significantly decreased. In a between-group comparison after treatment, the high intensity laser therapy group showed a significantly lower visual analog scale and Oswestry Disability Index than the conservative physical therapy group. [Conclusion] High Intensity Laser Therapy can be an effective nonsurgical intervention method for reducing pain and helping the performance of daily routines of patients who have chronic back pain. PMID- 28626330 TI - The reliability and validity of the Korean version of the spine functional index. AB - [Purpose] The purpose of this study was to establish the reliability and validity of the Korean version of the Spine Functional Index (K-SFI), a translated version of the original SFI used with patients with spinal disorders. [Subjects and Methods] Sixty participants with spine disorder, 22 males and 38 females, participated in the study. Reliability was determined by using the intra class correlation coefficient and Cronbach's alpha for internal consistency. Validity was examined by correlating K-SFI scores with the Roland Morris Disability Questionnaire (RMDQ), Neck Disability index (NDI), and the Functional Rating Index (FRI). [Results] Test-retest reliability was 0.94. The criterion-related validity was established by comparison with the Korean version of the RMDQ, NDI and FRI. [Conclusion] The Korean version of the SFI was shown to be a reliable and valid instrument for assessing spine complaints. PMID- 28626331 TI - The effects of training using EMG biofeedback on stroke patients upper extremity functions. AB - [Purpose] While electromyography (EMG) biofeedback has been recently used in diverse therapeutic interventions for stroke patients, research on its effects has been lacking. Most existing studies are confined to functions of the lower extremities, and research on upper extremity functional recovery using EMG biofeedback training is limited. Therefore, this study examined the effects of training using EMG biofeedback on stroke patients' upper extremity functions. [Subjects and Methods] The subjects of this study included 30 hemiplegia patients whose disease duration was longer than six months. They were randomly divided into a control group (n=15) receiving traditional rehabilitation therapy and an experimental group (n=15) receiving both traditional rehabilitation therapy and training using EMG biofeedback. The program lasted for a total of four weeks. In order to examine the subjects' functional recovery, the author measured their upper limb function using the Fugl-Meyer Assessment and Manual Function Test, and activities of daily living using the Functional Independence Measure before and after training. [Results] A comparison of the study groups revealed that those in the experimental group experienced greater improvement in upper extremity function after training in all tests compared to the control group; however, there was no significant difference in terms of the activities of daily living between the two groups. The results of this study were as follows. [Conclusion] Thus, stroke patients receiving intensive EMG biofeedback showed more significant upper extremity functional recovery than those who only received traditional rehabilitation therapy. PMID- 28626332 TI - 3D motion analysis of the wrist splint effect to wrist joint movement. AB - [Purpose] This study aimed to investigate the degree of straightness of the wrist joint, depending on the use of a wrist splint while opening a bottle cap. Its results may provide data for later studies on preventing accidents at workplaces and improving efficiency. [Subjects and Methods] Thirty Male and Female in their twenties who did not have hand-related diseases, fractures, or history that included neurological impairments associated with the hand were selected as subjects of the study. Wrist splints were made to fit the hand and lower arm of each subject. Evaluation assignments were carried out without and with the splints after 10 minutes of rest. To analyze the wrist movement in opening the bottle cap, a three-dimensional movement analyzing system by Zebris was used. [Results] Wrist angle decreased while opening caps of four different diameters while wearing splints, but not when splints were not worn. This means that wearing a splint may aid weakened wrist muscles. [Conclusion] Future studies should be conducted among subjects with damaged wrist muscles and evaluate the subjects in actual workplaces to obtain more objective and more valid data. PMID- 28626333 TI - Peripheral circulation indicators in veteran trail runners. AB - [Purpose] Competitive sport places strict demands on the cardiovascular systems of veteran trail runners. Our research objective was to evaluate the dynamics of microcirculation parameters of veteran runners in hypoxic and mid-altitude conditions. [Subjects and Methods] Seven male runners from Russia and Italy between the ages of 50 and 60 years were examined whilst competing at mid altitude (1,500-2,000 m above sea level). The same runners were examined in a simulated mid-altitude hypoxic environment, which was a hypoxic chamber with 16% oxygen concentration, for 720 minutes. Under both conditions, peripheral circulation was studied using a laser Doppler flowmeter attached to the distal phalange of the second finger of the subject's right hand. All subjects had a microcirculation parameter assessed, which was the standard deviation of the erythrocytes flow vibration in peripheral circulation, under both conditions. In order to assess the intensity of vasomotor reactions of the microcirculatory vessels, the coefficient of variation was used. [Results] In the hypoxic environment, a decrease in the microcirculation parameter was noted in the short term (360 minutes), with a subsequent compensatory increase in the long-term (720 minutes). However, the coefficient of variation showed a reverse trend with an increase in the vasomotor activity of microvessels from 12.4% to 18.2% at the stage of maximum training load within one month in the mid-altitude in the hypoxic environment, with a consequent reduction in preparation for the start. [Conclusion] In the hypoxic environment, the subjects demonstrated a two-stage change in the dynamics of the microcirculation parameter: an initial fall and a subsequent increase reaching the initial values. Similar changes were found when subjects were competing at mid-altitude. Our results show that the assessment of the peripheral circulation in a simulated mid-altitude hypoxic environment can be used to determine the readiness of veteran sportsmen for long-term trail running in mid-altitude conditions. PMID- 28626334 TI - Effect of Neuro-Development Treatment on motor development in preterm infants. AB - [Purpose] To investigate the effects of Neuro-Development Treatment on development in the preterm infants. [Subjects and Methods] A total of 96 premature infants were recruited for this study; 62 low birth weight preterm infants (<2.5 kg, high risk infants for developmental delay) and 34 premature infants (>2.5 kg, low risk infants for developmental delay). High risk infants were divided into intervention group (32 infants) and control group (30 infants) at time of admission. Low risk infants were into comparative group (34 infants). All infants received general nursing care in Neonatal Intensive Care Unit. Additionally, Intervention group received Neuro-Development Treatment for 15 minutes 4 times per week up to 40 week postconceptional age. We evaluated Test of Infant Movement Performance at baseline, 2 weeks after and 40 week postconceptional age. [Results] In score on Test of Infant Movement Performance there was more increase in intervention group than in control group and comparative group. [Conclusion] According to findings in this study, we find that Neuro-Development Treatment in Neonatal Intensive Care Unit has an effect on development in the preterm infants. PMID- 28626335 TI - 2-dimensional analysis of low limb taping methods on ambulation for stroke patients. AB - [Purpose] The purpose of this study was to investigate the effect of treatment on the type of taping applied before proprioceptive neuromuscular facilitation treatment. [Subjects and Methods] This study was conducted on thirty patients diagnosed with stroke. The study subjects were divided into three groups: experimental group 1, experimental group 2, and control group 3. Experimental group 1 applied Kinesio taping to the lower limb before applying proprioceptive neuromuscular facilitation technique. Experimental group 2 applied McConnell taping to the lower limb before applying proprioceptive neuromuscular facilitation technique and control group applied only proprioceptive neuromuscular facilitation technique. In this study was used Dartfish to analyze the gait of the lower limbs. [Results] Experiment group 1 showed a significant difference of ankle angle compared to the control group, but a statistically significant difference of ankle angle was observed in week 8. Experiment group 1 and experiment group 2 showed a significantly longer stride length on the affected side than the control group. [Conclusion] Application of Kinesio taping has a more positive effect on the ambulation than McConnell taping. PMID- 28626336 TI - Rehabilitation in a convalescent rehabilitation ward following an acute ward improves functional recovery and mortality for hip fracture patients: a sequence in a single hospital. AB - [Purpose] The convalescent rehabilitation ward (CRW) plays an important role for hip fracture patients in Japanese super-aged society. The purpose of this study is to clarify the usefulness of the CRW concomitant with acute wards in a single hospital. [Subjects and Methods] 110 hip fracture patients were evaluated; 63 patients were moved from acute wards to the CRW in the same hospital (Group C) and 47 patients were treated in acute wards only (Group A). Patient selection was determined by each attending doctor. The outcomes were examined from medical records. [Results] 90.5% of patients in the group C were discharged to home and 57.4% in the group A. 92.9% of patients in the group C had regained their ambulatory ability at discharge and 88.9% in the group A. The average total functional independence measure scores at discharge were 96.4 in the group C and 85.0 in the group A. The one-year mortality was 2.4% in the group C and 8.3% in the group A. [Conclusion] Using a CRW concomitant with acute wards in a single hospital could achieve a high home-discharge rate, good functional recovery, and low mortality in hip fracture patients. PMID- 28626337 TI - Is robot-assisted therapy effective in upper extremity recovery in early stage stroke? -a systematic literature review. AB - [Purpose] The aim of this study was to systematically investigate the effects of robot-assisted therapy on the upper extremity in acute and subacute stroke patients. [Subjects and Methods] The papers retrieved were evaluated based on the following inclusion criteria: 1) design: randomized controlled trials; 2) population: stroke patients 3) intervention: robot-assisted therapy; and 4) year of publication: May 2012 to April 2016. Databased searched were: EMBASE, PubMed and COCHRAN databases. The Physiotherapy Evidence Database (PEDro) scale was used to assess the methodological quality of the included studies. [Results] Of the 637 articles searched, six studies were included in this systematic review. The PEDro scores range from 7 to 9 points. [Conclusion] This review confirmed that the robot-assisted therapy with three-dimensional movement and a high degree of freedom had positive effects on the recovery of upper extremity motor function in patients with early-stage stroke. We think that the robot-assisted therapy could be used to improve upper extremity function for early stage stroke patients in clinical setting. PMID- 28626338 TI - Effect of pain scrambler therapy on antineuralgic pain and quality of life after shingles. AB - [Purpose] The aim of this study was to analyze the effect of pain scrambler therapy on antineuralgic pain and quality of life after shingles. [Subjects and Methods] Daily pain scrambler therapy was administered to antineuralgic patients for 10 days, with each session lasting approximately 40 minutes. Pain was measured using the visual analog scale, and quality of life was assessed with the short form 36-item (SF-36). [Results] After10 sessions of pain scrambler therapy, pain had significantly reduced compared to that experienced prior to treatment. The quality of life had also improved following completion of 10 treatment sessions. [Conclusion] Pain scrambler therapy decreased patients' post-shingles antineuralgic pain and improved quality of life. PMID- 28626339 TI - Effects of 2-week intermittent training in hypobaric hypoxia on the aerobic energy metabolism and performance of cycling athletes with disabilities. AB - [Purpose] The present study aimed at examining changes in aerobic energy metabolism and performance in cycling athletes after 2 weeks of intermittent training in a multistep hypobaric hypoxia environment. [Subjects and Methods] We also aimed at using the findings to propose an efficient training program in hypobaric hypoxia for endurance athletes with disabilities. The study participants were three cycling athletes with physical disabilities from the Korean national team (A, B, and C athletes). They underwent complex (repetition, interval, and continued) training with a roller-type cycle in a multistep hypobaric hypoxia environment (simulated altitude, 4,000 m above sea level). The training was conducted in twelve 60-min sessions for 2 weeks and it was based on the ventilatory threshold intensity, measured in an exercise stress test, conducted prior to training, at constant temperature (23 degrees C +/- 2 degrees C) and humidity conditions (50% +/- 5%). [Results] B and C athletes showed no noticeable changes in relative VO2max and HRmax values after training. A, B, and C athletes all showed increases in all-out time, 2'09" (13.1%), 2'43" (18.7%), and 1'22" (7.4%), respectively after training. Although the relative VO2max and HRmax values were not improved, submaximal exercise performance ability was improved. [Conclusion] Therefore, 2 weeks of intermittent training in a hypobaric hypoxia environment positively affected aerobic energy metabolism and performance. PMID- 28626340 TI - Conductors for commercial MRI magnets beyond NbTi: requirements and challenges. AB - Magnetic Resonance Imaging (MRI), a powerful medical diagnostic tool, is the largest commercial application of superconductivity. The superconducting magnet is the largest and most expensive component of an MRI system. The magnet configuration is determined by competing requirements including optimized functional performance, patient comfort, ease of siting in a hospital environment, minimum acquisition and lifecycle cost including service. In this paper, we analyze conductor requirements for commercial MRI magnets beyond traditional NbTi conductors, while avoiding links to a particular magnet configuration or design decisions. Potential conductor candidates include MgB2, ReBCO and BSCCO options. The analysis shows that no MRI-ready non-NbTi conductor is commercially available at the moment. For some conductors, MRI specifications will be difficult to achieve in principle. For others, cost is a key barrier. In some cases, the prospects for developing an MRI-ready conductor are more favorable, but significant developments are still needed. The key needs include the development of, or significant improvements in: (a) conductors specifically designed for MRI applications, with form-fit-and-function readily integratable into the present MRI magnet technology with minimum modifications. Preferably, similar conductors should be available from multiple vendors; (b) conductors with improved quench characteristics, i.e. the ability to carry significant current without damage while in the resistive state; (c) insulation which is compatible with manufacturing and refrigeration technologies; (d) dramatic increases in production and long-length quality control, including large-volume conductor manufacturing technology. In-situ MgB2 is, perhaps, the closest to meeting commercial and technical requirements to become suitable for commercial MRI. Conductor technology is an important, but not the only, issue in introduction of HTS / MgB2 conductor into commercial MRI magnets. These new conductors, even when they meet the above requirements, will likely require numerous modifications and developments in the associated magnet technology. PMID- 28626341 TI - Intercorporeality and aida: Developing an interaction theory of social cognition. AB - The aim of this article is to develop an interaction theory (IT) of social cognition. The central issue in the field of social cognition has been theory of mind (ToM), and there has been debate regarding its nature as either theory theory or as simulation theory. Insights from phenomenology have brought a second person perspective based on embodied interactions into the debate, thereby forming a third position known as IT. In this article, I examine how IT can be further elaborated by drawing on two phenomenological notions-Merleau-Ponty's intercorporeality and Kimura's aida. Both of these notions emphasize the sensory motor, perceptual, and non-conceptual aspects of social understanding and describe a process of interpersonal coordination in which embodied interaction gains autonomy as an emergent system. From this perspective, detailed and nuanced social understanding is made possible through the embodied skill of synchronizing with others. PMID- 28626342 TI - Effects of Src Kinase Inhibition on Expression of Protein Tyrosine Phosphatase 1B after Brain Hypoxia in a Piglet Animal Model. AB - BACKGROUND: Protein tyrosine phosphatases (PTPs) in conjunction with protein tyrosine kinases (PTKs) regulate cellular processes by posttranslational modifications of signal transduction proteins. PTP nonreceptor type 1B (PTP-1B) is an enzyme of the PTP family. We have previously shown that hypoxia induces an increase in activation of a class of nonreceptor PTK, the Src kinases. In the present study, we investigated the changes that occur in the expression of PTP-1B in the cytosolic component of the brain of newborn piglets acutely after hypoxia as well as long term for up to 2 weeks. METHODS: Newborn piglets were divided into groups: normoxia, hypoxia, hypoxia followed by 1 day and 15 days in FiO2 0.21, and hypoxia pretreated with Src kinase inhibitor PP2, prior to hypoxia followed by 1 day and 15 days. Hypoxia was achieved by providing 7% FiO2 for 1 hour and PTP-1B expression was measured via immunoblotting. RESULTS: PTP-1B increased posthypoxia by about 30% and persisted for 2 weeks while Src kinase inhibition attenuated the expected PTP-1B-increased expression. CONCLUSIONS: Our study suggests that Src kinase mediates a hypoxia-induced increased PTP-1B expression. PMID- 28626343 TI - Anti-OSM Antibody Inhibits Tubulointerstitial Lesion in a Murine Model of Lupus Nephritis. AB - The purpose of this study was to investigate the role of oncostatin M (OSM) in tubulointerstitial lesion (TIL) in lupus nephritis (LN). We found that OSM was highly expressed in the renal tissue of LN mice. OSM is one of the interleukin-6 cytokine family members. In order to clarify the role and mechanism of OSM in LN, mice with LN were treated with anti-OSM antibody or isotype antibody. We evaluated the tubular epithelial-mesenchymal transdifferentiation (EMT) by detecting the E-cadherin, alpha-smooth muscle actin (alpha-SMA), and fibronectin (FN) expression. We analyzed the inflammation by observing the monocyte chemotactic factor-1 (MCP-1) and intercellular adhesion molecule (ICAM-1) expression and calculated the tubulointerstitial fibrosis area by Masson staining. The results showed that anti-OSM antibody, rather than isotype antibody, improved EMT, inflammation, and tubulointerstitial fibrosis. In addition, the signal transducer and activator of transcription (STAT) 1 and STAT3 signaling was activated by tyrosine phosphorylation in LN mouse renal tissue, indicating that the phosphorylated STAT1 (p-STAT1) and p-STAT3 were involved in kidney injury. Moreover, decreased p-STAT3 instead of p-STAT1 has been observed after anti-OSM antibody injection. Thus, we concluded that OSM is associated with TIL in lupus nephritis, which may be connected with the activation of STAT3 rather than that of STAT1. PMID- 28626344 TI - Increased Transendothelial Transport of CCL3 Is Insufficient to Drive Immune Cell Transmigration through the Blood-Brain Barrier under Inflammatory Conditions In Vitro. AB - Many neuroinflammatory diseases are characterized by massive immune cell infiltration into the central nervous system. Identifying the underlying mechanisms could aid in the development of therapeutic strategies specifically interfering with inflammatory cell trafficking. To achieve this, we implemented and validated a blood-brain barrier (BBB) model to study chemokine secretion, chemokine transport, and leukocyte trafficking in vitro. In a coculture model consisting of a human cerebral microvascular endothelial cell line and human astrocytes, proinflammatory stimulation downregulated the expression of tight junction proteins, while the expression of adhesion molecules and chemokines was upregulated. Moreover, chemokine transport across BBB cocultures was upregulated, as evidenced by a significantly increased concentration of the inflammatory chemokine CCL3 at the luminal side following proinflammatory stimulation. CCL3 transport occurred independently of the chemokine receptors CCR1 and CCR5, albeit that migrated cells displayed increased expression of CCR1 and CCR5. However, overall leukocyte transmigration was reduced in inflammatory conditions, although higher numbers of leukocytes adhered to activated endothelial cells. Altogether, our findings demonstrate that prominent barrier activation following proinflammatory stimulation is insufficient to drive immune cell recruitment, suggesting that additional traffic cues are crucial to mediate the increased immune cell infiltration seen in vivo during neuroinflammation. PMID- 28626345 TI - Fungal Dimorphism and Virulence: Molecular Mechanisms for Temperature Adaptation, Immune Evasion, and In Vivo Survival. AB - The thermally dimorphic fungi are a unique group of fungi within the Ascomycota phylum that respond to shifts in temperature by converting between hyphae (22-25 degrees C) and yeast (37 degrees C). This morphologic switch, known as the phase transition, defines the biology and lifestyle of these fungi. The conversion to yeast within healthy and immunocompromised mammalian hosts is essential for virulence. In the yeast phase, the thermally dimorphic fungi upregulate genes involved with subverting host immune defenses. This review highlights the molecular mechanisms governing the phase transition and recent advances in how the phase transition promotes infection. PMID- 28626347 TI - Syntactic Complexity Effects of Russian Relative Clause Sentences in Children with and without Developmental Language Disorder. AB - We investigated relative clause (RC) comprehension in 44 Russian-speaking children with typical language (TD) and developmental language disorder (DLD); M age = 10.67, SD = 2.84, and 22 adults. Flexible word order and morphological case in Russian allowed us to isolate factors that are obscured in English, helping us to identify sources of syntactic complexity and evaluate their roles in RC comprehension by children with typical language and their peers with DLD. We administered a working memory and an RC comprehension (picture-choice) task, which contained subject- and object-gap center-embedded and right branching RCs. The TD group, but not adults, demonstrated the effects of gap, embedding, and case. Their lower accuracy relative to adults was not fully attributable to differences in working memory. The DLD group displayed lower than TD children overall accuracy, accounted for by their lower working memory scores. While the effect of gap and embedding on their performance was not different from what was found for the TD group, children with DLD exhibited a diminished effect of case, suggesting reduced sensitivity to morphological case markers as processing cues. The implications of these results to theories of syntactic complexity and core deficits in DLD are discussed. PMID- 28626346 TI - Neutrophils in Tuberculosis: Heterogeneity Shapes the Way? AB - Infection with M. tuberculosis remains one of the most common infections in the world. The outcome of the infection depends on host ability to mount effective protection and balance inflammatory responses. Neutrophils are innate immune cells implicated in both processes. Accordingly, during M. tuberculosis infection, they play a dual role. Particularly, they contribute to the generation of effector T cells, participate in the formation of granuloma, and are directly involved in tissue necrosis, destruction, and infection dissemination. Neutrophils have a high bactericidal potential. However, data on their ability to eliminate M. tuberculosis are controversial, and the results of neutrophil depletion experiments are not uniform. Thus, the overall roles of neutrophils during M. tuberculosis infection and factors that determine these roles are not fully understood. This review analyzes data on neutrophil defensive and pathological functions during tuberculosis and considers hypotheses explaining the dualism of neutrophils during M. tuberculosis infection and tuberculosis disease. PMID- 28626348 TI - GPU-powered Shotgun Stochastic Search for Dirichlet process mixtures of Gaussian Graphical Models. AB - Gaussian graphical models are popular for modeling high-dimensional multivariate data with sparse conditional dependencies. A mixture of Gaussian graphical models extends this model to the more realistic scenario where observations come from a heterogenous population composed of a small number of homogeneous sub-groups. In this paper we present a novel stochastic search algorithm for finding the posterior mode of high-dimensional Dirichlet process mixtures of decomposable Gaussian graphical models. Further, we investigate how to harness the massive thread-parallelization capabilities of graphical processing units to accelerate computation. The computational advantages of our algorithms are demonstrated with various simulated data examples in which we compare our stochastic search with a Markov chain Monte Carlo algorithm in moderate dimensional data examples. These experiments show that our stochastic search largely outperforms the Markov chain Monte Carlo algorithm in terms of computing-times and in terms of the quality of the posterior mode discovered. Finally, we analyze a gene expression dataset in which Markov chain Monte Carlo algorithms are too slow to be practically useful. PMID- 28626349 TI - Identifying Mixtures of Mixtures Using Bayesian Estimation. AB - The use of a finite mixture of normal distributions in model-based clustering allows us to capture non-Gaussian data clusters. However, identifying the clusters from the normal components is challenging and in general either achieved by imposing constraints on the model or by using post-processing procedures. Within the Bayesian framework, we propose a different approach based on sparse finite mixtures to achieve identifiability. We specify a hierarchical prior, where the hyperparameters are carefully selected such that they are reflective of the cluster structure aimed at. In addition, this prior allows us to estimate the model using standard MCMC sampling methods. In combination with a post-processing approach which resolves the label switching issue and results in an identified model, our approach allows us to simultaneously (1) determine the number of clusters, (2) flexibly approximate the cluster distributions in a semiparametric way using finite mixtures of normals and (3) identify cluster-specific parameters and classify observations. The proposed approach is illustrated in two simulation studies and on benchmark datasets. Supplementary materials for this article are available online. PMID- 28626350 TI - Shape-based Similarity Retrieval of Doppler Images for Clinical Decision Support. AB - Flow Doppler imaging has become an integral part of an echocardiographic exam. Automated interpretation of flow doppler imaging has so far been restricted to obtaining hemodynamic information from velocity-time profiles depicted in these images. In this paper we exploit the shape patterns in Doppler images to infer the similarity in valvular disease labels for purposes of automated clinical decision support. Specifically, we model the similarity in appearance of Doppler images from the same disease class as a constrained non-rigid translation transform of the velocity envelopes embedded in these images. The shape similarity between two Doppler images is then judged by recovering the alignment transform using a variant of dynamic shape warping. Results of similarity retrieval of doppler images for cardiac decision support on a large database of images are presented. PMID- 28626351 TI - Measurement of RF propagation around corners in underground mines and tunnels. AB - This paper reports measurement results for radio frequency (RF) propagation around 90 degrees corners in tunnels and underground mines, for vertically, horizontally and longitudinally polarized signals. Measurements of signal power attenuation from a main entry into a crosscut were performed at four frequencies 455, 915, 2450 and 5800 MHz - that are common to underground radio communication systems. From the measurement data, signal power loss was determined as a function of signal coupling from the main entry into the crosscut. The resultant power loss data show there are many factors that contribute to power attenuation from a main entry into a crosscut, including frequency, antenna polarization and cross-sectional entry dimensions. PMID- 28626352 TI - Design of intelligent proximity detection zones to prevent striking and pinning fatalities around continuous mining machines. AB - The continuous mining machine is a key piece of equipment used in underground coal mining operations. Over the past several decades these machines have been involved in a number of mine worker fatalities. Proximity detection systems have been developed to avert hazards associated with operating continuous mining machines. Incorporating intelligent design into proximity detection systems allows workers greater freedom to position themselves to see visual cues or avoid other hazards such as haulage equipment or unsupported roof or ribs. However, intelligent systems must be as safe as conventional proximity detection systems. An evaluation of the 39 fatal accidents for which the Mine Safety and Health Administration has published fatality investigation reports was conducted to determine whether the accident may have been prevented by conventional or intelligent proximity. Multiple zone configurations for the intelligent systems were studied to determine how system performance might be affected by the zone configuration. Researchers found that 32 of the 39 fatalities, or 82 percent, may have been prevented by both conventional and intelligent proximity systems. These results indicate that, by properly configuring the zones of an intelligent proximity detection system, equivalent protection to a conventional system is possible. PMID- 28626353 TI - Processing of Spanish-English Code-Switches by Late Bilinguals. PMID- 28626354 TI - Exact-Permutation Based Sign Tests for Clustered Binary Data via Weighted and Unweighted Test Statistics. AB - Clustered binary data occur frequently in many application areas. When analyzing data of this form, ignoring key features, such as the intracluster correlation, may lead to inaccurate inference; e.g., inflated Type I error rates. For clustered binary data, Gerard and Schucany (2007) proposed an exact test for examining whether the marginal probability of a response differs from 0.5, which is the null hypothesis considered in the classic sign test. This new test maintains the specified Type I error rate and has more power, when compared to both the classic sign and permutation tests. The test statistic proposed by these authors equally weights the observed data from each cluster, regardless of whether the clusters are of equal size. To further improve the performance of the Gerard and Schucany test, a weighted test statistic is proposed and two weighting schemes are investigated. Seeking to further improve the performance of the proposed test, empirical Bayes estimates of the cluster level success probabilities are utilized. These adaptations lead to 5 new tests, each of which are shown through simulation studies to be superior to the Gerard and Schucany (2007) test. The proposed tests are further illustrated using data from a chemical repellency trial. PMID- 28626355 TI - Classifier Performance in Primary Somatosensory Cortex Towards Implementation of a Reinforcement Learning Based Brain Machine Interface. AB - Increasingly accurate control of prosthetic limbs has been made possible by a series of advancements in brain machine interface (BMI) control theory. One promising control technique for future BMI applications is reinforcement learning (RL). RL based BMIs require a reinforcing signal to inform the controller whether or not a given movement was intended by the user. This signal has been shown to exist in cortical structures simultaneously used for BMI control. This work evaluates the ability of several common classifiers to detect impending reward delivery within primary somatosensory (S1) cortex during a grip force match to sample task performed by a nonhuman primate. The accuracy of these classifiers was further evaluated over a range of conditions to identify parameters that provide maximum classification accuracy. S1 cortex was found to provide highly accurate classification of the reinforcement signal across many classifiers and a wide variety of data input parameters. The classification accuracy in S1 cortex between rewarding and non-rewarding trials was apparent when the animal was expecting an impending delivery or an impending withholding of reward following trial completion. The high accuracy of classification in S1 cortex can be used to adapt an RL based BMI towards a user's intent. Real-time implementation of these classifiers in an RL based BMI could be used to adapt control of a prosthesis dynamically to match the intent of its user. PMID- 28626356 TI - Pilot Study for Grip Force Prediction Using Neural Signals from Different Brain Regions. AB - The design of brain machine interfaces (BMI) has been improving over the past decade. Such improvements have led to advanced capability in terms of restoring the functionality of a paralyzed/amputated limb and producing fine controlled movements of a robotic arm and hand. However, there is still more to be invested towards producing advanced BMI features such as producing appropriate forces when gripping and carrying an object using an artificial limb. This feature requires direct supervision and control from the brain to produce accurate results. Toward this goal, this work investigates the processing of neural signals from four brain regions in a nonhuman primate to predict maximum grip force. The signals received from each of the primary motor (M1) cortex, primary somatosensory (S1) cortex, dorsal premotor (PmD) cortex, and ventral premotor (PmV) cortex are used to build regression models to predict the applied maximum grip force. Comparisons of model prediction results are presented. The relative prediction accuracy from all brain regions would assist in further investigation to build robust approaches for controlling the force values. The brain regions and their interactions could eventually be summed in a weighted manner to complete the targeted approach. PMID- 28626357 TI - Test of a 32-channel Prototype ASIC for Photon Counting Application. AB - A new low-power application-specific integrated circuit (ASIC) for Cadmium Zinc Telluride (CZT) detectors for single-photon emission computed tomography (SPECT) application is being developed at BNL. As the first step, a 32-channel prototype ASIC was designed and tested recently. Each channel has a preamplifier followed by CR-RC3 shaping circuits and three independent energy bins with comparators and 16-bit counters. The ASIC was fabricated with TSMC 0.35-MUm complementary metal oxide-semiconductor (CMOS) process and tested in laboratories. The power consumption is around 1 mW/ch with a 2.5-V supply. With a gain of 400 mV/fC and the peaking time of 500 ns, the equivalent noise charge (ENC) of 360 e- has been measured in room temperature while the crosstalk rate is less than 0.3%. The 10 bit DACs for global thresholds have an integral nonlinearity (INL) less than 0.56% and differential nonlinearity (DNL) less than 0.33%. In the presentation, we will report the detailed test results with this ASIC. PMID- 28626358 TI - Psychosocial correlates of patient-provider family planning discussions among HIV infected pregnant women in South Africa. AB - Patient-provider family planning discussions and preconception counseling can reduce maternal and neonatal risks by increasing adherence to provider recommendations and antiretroviral medication. However, HIV-infected women may not discuss reproductive intentions with providers due to anticipation of negative reactions and stigma. This study aimed to identify correlates of patient provider family planning discussions among HIV-infected women in rural South Africa, an area with high rates of antenatal HIV and suboptimal rates of prevention of mother-to-child transmission (PMTCT) of HIV. Participants were N=673 pregnant HIV-infected women who completed measures of family planning discussions and knowledge, depression, stigma, intimate partner violence, and male involvement. Participants were, on average, 28 +/- 6 years old, and half of them had completed at least 10-11 years of education. Most women were unemployed and had a monthly income of less than ~US$76. Fewer than half of the women reported having family planning discussions with providers. Correlates of patient provider family planning discussions included younger age, discussions about PMTCT of HIV, male involvement, and decreased stigma (p < 0.05). Depression was indirectly associated with patient-provider family planning discussions through male involvement (b = -0.010, bias-corrected 95% confidence interval [bCI] [ 0.019, -0.005]). That is, depression decreased male involvement, and in turn, male involvement increased patient-provider family planning discussions. Therefore, by decreasing male involvement, depression indirectly decreased family planning discussions. Study findings point to the importance of family planning strategies that address depression and facilitate male involvement to enhance communication between patients and providers and optimize maternal and neonatal health outcomes. This study underscores the need for longitudinal assessment of men's impact on family planning discussions both pre- and postpartum. Increasing support for provision of mental health services during pregnancy is merited to ensure the health of pregnant women living with HIV and their infants. PMID- 28626359 TI - Noble metal-modified octahedral anatase titania particles with enhanced activity for decomposition of chemical and microbiological pollutants. AB - Octahedral anatase particles (OAPs) were prepared by hydrothermal (HT) reaction of titanate nanowires (TNWs). OAPs were modified with noble metals (Au, Ag, Cu and Pt) by two photodeposition methods: in the absence and in the initial presence of oxygen in the system. Photocatalytic activities for oxidative decomposition of acetic acid and anaerobic dehydrogenation of methanol under UV/vis irradiation and for oxidation of 2-propanol under visible light irradiation were investigated. Antibacterial activities for bacteria (Escherichia coli) and fungi (Candida albicans) were investigated in the dark and under UV irradiation and/or visible light irradiation. It was found that the kind of metal deposition significantly influenced the properties of photocatalysts obtained and thus their photocatalytic and antimicrobial activities. Modification of OAPs with metallic deposits resulted in enhanced photocatalytic activities for all tested systems. Pt-modified OAPs showed the highest activity for dehydrogenation of methanol due to their highest work function and lowest activation overpotential of hydrogen evolution. Cu-modified OAPs exhibited the highest activity for oxidative decomposition of acetic acid under UV/vis irradiation, probably due to the heterojunction between Cu oxides and TiO2. On the other hand, Au-modified OAPs showed the highest photocatalytic activity under visible light irradiation due to their plasmonic properties. Bare OAPs, prepared with various durations of the HT reaction, did not have any antibacterial properties in the dark, while their activity under UV/vis irradiation was correlated with their photocatalytic activities for dehydrogenation of methanol and decomposition of acetic acid. Antimicrobial activity of modified OAPs in the dark and under visible light irradiation was the highest for Ag-modified OAPs. Under UV irradiation, Cu modified OAPs showed the highest activity for inactivation of both bacteria and fungi. PMID- 28626360 TI - Delays and Disabilities: NP Screening and Care Management. AB - Neurodevelopmental Disorders (ND) impair functioning and are associated with increased physical and psychological health risks. ND care is increasingly being provided by NPs in primary care settings. To assess NP's knowledge and care management practices for pediatric patients with potential or existing ND, practicing NPs in North Carolina were invited to complete an online survey. NC NP's provide care to ND patients in a variety of settings and have varied levels of experience with ND. Differences in knowledge, screening, and management practices are identified. Methods for improving outcomes and supporting NPs providing care for this at-risk population are discussed. PMID- 28626362 TI - Nanoporous Gold Biointerfaces: Modifying Nanostructure to Control Neural Cell Coverage and Enhance Electrophysiological Recording Performance. AB - Nanostructured neural interface coatings have significantly enhanced recording fidelity in both implantable and in vitro devices. As such, nano-porous gold (np Au) has shown promise as a multifunctional neural interface coating due, in part, to its ability to promote nanostructure-mediated reduction in astrocytic surface coverage while not affecting neuronal coverage. The goal of this study is to provide insight into the mechanisms by which the np-Au nanostructure drives the differential response of neurons versus astrocytes in an in vitro model. Utilizing microfabricated libraries that display varying feature sizes of np-Au, it is demonstrated that np-Au influ-ences neural cell coverage through modulating focal adhesion formation in a feature size-dependent manner. The results here show that surfaces with small (~30 nm) features control astrocyte spreading through inhibition of focal adhesion formation, while surfaces with large (~170 nm and greater) features control astrocyte spreading through other mechanotransduction mechanisms. This cellular response combined with lower electrical impedance of np-Au electrodes significantly enhances the fidelity and stability of electrophysiological recordings from cortical neuronglia co-cultures relative to smooth gold electrodes. Finally, by leveraging the effect of nanostructure on neuronal versus glial cell attachment, the use of laser-based nanostructure modulation is demonstrated for selectively patterning neurons with micrometer spatial resolution. PMID- 28626363 TI - HOXB4 Increases Runx1 Expression to Promote the de novo Formation of Multipotent Hematopoietic Cells. AB - BACKGROUND: The de novo generation of patient-specific hematopoietic stem and progenitor cells from induced pluripotent stem cells (iPSCs) has become a promising approach for cell replacement therapies in the future. However, efficient differentiation protocols for producing fully functional human hematopoietic stem cells are still missing. In the mouse model, ectopic expression of the human homeotic selector protein HOXB4 has been shown to enforce the development of hematopoietic stem cells (HSCs) in differentiating pluripotent stem cell cultures. However, the mechanism how HOXB4 mediates the formation of HSCs capable of long-term, multilineage repopulation after transplantation is not well understood yet. METHODS: Using a mouse embryonic stem (ES) cell-based differentiation model, we asked whether retrovirally expressed HOXB4 induces the expression of Runx1/AML1, a gene whose expression is absolutely necessary for the formation of definitive, adult HSCs during embryonic development. RESULTS: During ES cell differentiation, basal expression of Runx1 was observed in all cultures, irrespective of ectopic HOXB4 expression. However, only in those cultures ectopically expressing HOXB4, substantial amounts of hematopoietic progenitors were generated which exclusively displayed increased Runx1 expression. CONCLUSIONS: Our results strongly suggest that HOXB4 does not induce basal Runx1 expression but, instead, mediates an increase of Runx1 expression which appears to be a prerequisite for the formation of hematopoietic stem and progenitor cells. PMID- 28626361 TI - Molecular Biomarkers of Colorectal Cancer and Cancer Disparities: Current Status and Perspective. AB - This review provides updates on the efforts for the development of prognostic and predictive markers in colorectal cancer based on the race/ethnicity of patients. Since the clinical consequences of genetic and molecular alterations differ with patient race and ethnicity, the usefulness of these molecular alterations as biomarkers needs to be evaluated in different racial/ethnic groups. To accomplish personalized patient care, a combined analysis of multiple molecular alterations in DNA, RNA, microRNAs (miRNAs), metabolites, and proteins in a single test is required to assess disease status in a precise way. Therefore, a special emphasis is placed on issues related to utility of recently identified genetic and molecular alterations in genes, miRNAs, and various "-omes" (e.g., proteomes, kinomes, metabolomes, exomes, methylomes) as candidate molecular markers to determine cancer progression (disease recurrence/relapse and metastasis) and to assess the efficacy of therapy in colorectal cancer in relation to patient race and ethnicity. This review will be useful for oncologists, pathologists, and basic and translational researchers. PMID- 28626364 TI - Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells. AB - BACKGROUND: Pluripotent stem cells, including induced pluripotent stem cells (iPSCs), have the capacity to differentiate towards all three germ layers and have been highlighted as an attractive cell source for the field of regenerative medicine. Thus, stable expression of therapeutic transgenes in iPSCs, as well as thereof derived progeny of hematopoietic lineage, may lay the foundation for innovative cell replacement therapies. METHODS: We have utilized human iPSC lines genetically modified by lentiviral vector technology or targeted integration of reporter genes to evaluate transgene expression during hematopoietic specification and differentiation towards macrophages. RESULTS: Use of lentiviral vectors equipped with an ubiquitous chromatin opening element (CBX3-UCOE) as well as zinc finger nuclease-mediated targeting of an expression cassette into the human adeno-associated virus integration site 1 (AAVS1) safe harbor resulted in stable transgene expression in iPSCs. When iPSCs were differentiated along the myeloid pathway into macrophages, both strategies yielded sustained transgene expression during the hematopoietic specification process including mature CD14+ and CD11b+ macrophages. CONCLUSION: Combination of human iPSC technology with either lentiviral vector technology or designer nuclease-based genome editing allows for the generation of transgenic iPSC-derived macrophages with stable transgene expression which may be useful for novel cell and gene replacement therapies. PMID- 28626365 TI - Emergence of CD43-Expressing Hematopoietic Progenitors from Human Induced Pluripotent Stem Cells. AB - BACKGROUND: The ex vivo generation of human hematopoietic stem cells (HSCs) with long-term repopulating capacity and multi-lineage differentiation potential represents the holy grail of hematopoiesis research. In principle, human induced pluripotent stem cells (hiPSCs) provide the tool for both studying molecular mechanisms of hematopoietic development and the ex vivo production of 'true' HSCs for transplantation purposes and lineage-specific cells, e.g. red blood cells, for transfusion purposes. CD43-expressing cells have been reported as the first hematopoietic cells during development, but whether or not these possess multilineage differentiation and long-term engraftment potential is incompletely understood. METHODS: We performed ex vivo generation of hematopoietic cells from hiPSCs using an embryoid body(EB)-based, xeno-product-free differentiation protocol. We investigated the multilineage differentiation potential of different FACS-sorted CD43-expressing cell subsets by colony-forming assays in semisolid media. Further, erythroid differentiation was investigated in more detail using established protocols. RESULTS: By using CD43, we were able to measure hematopoietic induction efficiency during hiPSC-derived EB differentiation. Further, we determined CD43+ cells as the cell population of origin for in vitro erythropoiesis. Furthermore, colony formation demonstrates that the multipotent hematopoietic stem and progenitor cell fraction is particulary enriched in the CD43hi CD45+ population. PMID- 28626367 TI - Towards the Manufacture of Megakaryocytes and Platelets for Clinical Application. AB - Platelet transfusions are used in standard clinical practice to prevent hemorrhage in patients suffering from thrombocytopenia or platelet dysfunctions. Recently, a constant rise on the demand of platelets for transfusion has been registered. This may be associated with several factors including demographic changes, population aging as well as incidence and prevalence of hematological diseases. In addition, platelet-regenerative properties have been started to be exploited in different areas such as tissue remodeling and anti-cancer therapies. These new applications are also expected to increase the future demand on platelets. Thus, in vitro generated platelets may constitute a highly desirable alternative to meet the rising demand on platelets. Several factors have been considered in the road trip of producing in vitro megakaryocytes and platelets for clinical application. From selection of the cell source, differentiation protocols and culture conditions to the design of optimal bioreactors, several strategies have been proposed to maximize production yields while preserving functionality. This review summarizes new advances in megakaryocyte and platelet differentiation and their production upscaling. PMID- 28626366 TI - Current Developments in Mobilization of Hematopoietic Stem and Progenitor Cells and Their Interaction with Niches in Bone Marrow. AB - The clinical application of hematopoietic stem and progenitor cells (HSPCs) has evolved from a highly experimental stage in the 1980s to a currently clinically established treatment for more than 20,000 patients annually who suffer from hematological malignancies and other severe diseases. Studies in numerous murine models have demonstrated that HSPCs reside in distinct niches within the bone marrow environment. Whereas transplanted HSPCs travel through the bloodstream and home to sites of hematopoiesis, HSPCs can be mobilized from these niches into the blood either physiologically or induced by pharmaceutical drugs. Firstly, this review aims to give a synopsis of milestones defining niches and mobilization pathways for HSPCs, including the identification of several cell types involved such as osteoblasts, adventitial reticular cells, endothelial cells, monocytic cells, and granulocytic cells. The main factors that anchor HSPCs in the niche, and/or induce their quiescence are vascular cell adhesion molecule(VCAM)-1, CD44, hematopoietic growth factors, e.g. stem cell factor (SCF) and FLT3 Ligand, chemokines including CXCL12, growth-regulated protein beta and IL-8, proteases, peptides, and other chemical transmitters such as nucleotides. In the second part of the review, we revise the current understanding of HSPC mobilization. Here, we discuss which mechanisms found to be active in HSPC mobilization correspond to the mechanisms relevant for HSPC interaction with niche cells, but also deal with other mediators and signals that target individual cell types and receptors to mobilize HSPCs. A multitude of questions remain to be addressed for a better understanding of HSPC biology and its implications for therapy, including more comprehensive concepts for regulatory circuits such as calcium homeostasis and parathormone, metabolic regulation such as by leptin, the significance of autonomic nervous system, the consequences of alteration of niches in aged patients, or the identification of more easily accessible markers to better predict the efficiency of HSPC mobilization. PMID- 28626369 TI - Biophysical and Biochemical Markers of Red Blood Cell Fragility. AB - BACKGROUND: Red blood cells (RBCs) undergo a natural aging process occurring in the blood circulation throughout the RBC lifespan or during routine cold storage in the blood bank. The aging of RBCs is associated with the elevation of mechanical fragility (MF) or osmotic fragility (OF) of RBCs, which can lead to cell lysis. The present study was undertaken to identify RBC properties that characterize their susceptibility to destruction under osmotic/mechanical stress. METHODS: RBCs were isolated from freshly donated blood or units of packed RBCs (PRBCs) and suspended in albumin-supplemented phosphate-buffered saline (PBS). In addition, PRBCs were separated by filtration through a microsphere column into two fractions: enriched with rigid (R-fraction) and deformable (D-fraction) cells. The RBCs were subjected to determination of deformability, MF and OF, moreover, the level of cell surface phosphatidylserine (PS) and the stomatin level in isolated RBC membranes were measured. RESULTS: In the RBC population, the cells that were susceptible to mechanical and osmotic stress were characterized by low deformability and increased level of surface PS. The OF/MF was higher in the R-fraction than in the D-fraction. Stomatin was depleted in destroyed cells and in the R-fraction. CONCLUSION: RBC deformability, the levels of surface PS, and membrane stomatin can be used as markers of RBC fragility. PMID- 28626368 TI - Crosstalk between Stem and Progenitor Cellular Mediators with Special Emphasis on Vasculogenesis. AB - The cellular components and molecular processes of signaling during vasculogenesis have been investigated for decades. Considerable efforts have been made to unravel regulatory mechanisms of vasculogenesis through crosstalk between vasculogenic playmakers located in the vascular niche, namely hematopoietic stem cells, endothelial progenitor cells, and mesenchymal stem and progenitor cells. Recent studies have increased the knowledge about signaling events within vascular microenvironment that leads to vasculogenesis. Findings from these recent studies indicate the impact of cellular crosstalk through signaling pathways such as vascular endothelial growth factor signaling, wingless and Notch signaling in vasculogenesis and vascular development. In this review, we highlight the signaling signature between stem and progenitor cellular mediators during vasculogenesis. We further focus on hematopoietic stem cell-endothelial progenitor cell crosstalk during vasculogenesis and discuss their potential implications and benefits for therapeutic interventions and regenerative therapy. PMID- 28626370 TI - Donor Safety in Haemapheresis: Development of an Internet-Based Registry for Comprehensive Assessment of Adverse Events from Healthy Donors. AB - BACKGROUND: Currently, there is an extensive but highly inconsistent body of literature regarding donor adverse events (AEs) in haemapheresis. As the reports diverge with respect to types and grading of AEs, apheresis procedures and machines, the range of haemapheresis-related AEs varies widely from about 0.03% to 6.6%. METHODS: The German Society for Transfusion Medicine and Immunohaematology (DGTI) formed a 'Haemapheresis Vigilance Working Party' (Arbeitsgemeinschaft Hamapheresevigilanz; AGHV) to create an on-line registry for comprehensive and comparable AE assessment with all available apheresis devices in all types of preparative haemapheresis: plasmapheresis (PLS), plateletpheresis (PLT), red blood cell apheresis, all kind of leukaphereses (autologous/allogeneic blood stem cell apheresis, granulocyte apheresis, lymphocyte/monocyte apheresis) and all possible types of multi-component apheresis. To ensure the comparability of the data, the AGHV adopted the 'Standard for Surveillance of Complications Related to Blood Donation' from the International Society for Blood Transfusion in cooperation with the International Haemovigilance Network (IHN) and the American Association of Blood Banks for AE acquisition and automated evaluation. The registry is embedded in a prospective observational multi-centre study with a study period of 7 years. RESULTS: A preliminary evaluation encompassed the time period from January, 2012 to December, 2015. During this time, the system proved to be safe and stable. Out of approximately 345,000 haemaphereses 16,477 AEs were reported (4.9%) from 20 participating centres. The majority of AEs occurred in PLSs (63%), followed by PLT (34.5%) and SC (2.2%). Blood access injuries (BAI) accounted for about 55% of the supplied AEs, whereas citrate toxicity symptoms, vasovagal reactions and technical events (e.g. disposable leakages, software failures) rather equally affected haemaphereses at 8-15%. Out of 12,348 finalized AEs, 8,759 (70.1%) were associated with a procedure-related break-off, with BAI being the prevailing cause (5,463/8,759; 62.4%). An automated centre- and procedure-specific AE evaluation according to the latest IHN standard and AGHV pre-settings is available within a few minutes. CONCLUSIONS: An on-line electronic platform for comprehensive assessment and centre-specific automated evaluation of AEs in haemaphereses has been developed and proved to be stable and safe over a period of 4 years. PMID- 28626371 TI - Carcinoma of the Papilla of Vater after Diversion Operation for Pancreaticobiliary Maljunction. AB - Pancreaticobiliary maljunction (PBM) is a congenital malformation that is associated with biliary cancer development. When patients are diagnosed with PBM, a diversion operation is recommended. Although a risk remains for developing residual bile duct carcinoma following diversion, the development of a carcinoma of the ampulla of Vater after a diversion operation for PBM is rare. We present a treated case of carcinoma of the ampulla of Vater after a diversion operation for PBM. A 65-year-old woman presented with abdominal pain. She had undergone extrahepatic bile duct resection and cholecystectomy 2 years 9 months previously for the treatment of type Ic PBM according to the Todani classification. At the current admission for evaluation of the abdominal pain, computed tomography and magnetic resonance imaging showed only dilation of the main pancreatic duct. However, gastrointestinal endoscopy showed a tumor at the papilla of Vater, and biopsy revealed adenocarcinoma of the papilla of Vater. We performed pylorus preserving pancreaticoduodenectomy, and the pathological diagnosis was moderately differentiated tubular adenocarcinoma of the papilla of Vater with no metastasis to the lymph nodes. The patient remained in good health for 3 years postoperatively. Carcinoma of the papilla of Vater after a diversion operation for PBM is rare. In this case, a diagnosis could not be made by computed tomography or magnetic resonance imaging; the definitive diagnosis was obtained with gastrointestinal endoscopy. Careful postoperative follow-up with gastrointestinal endoscopy in addition to imaging examination may be needed after a diversion operation for PBM. PMID- 28626372 TI - Acute Appendicitis Caused by Previous Endoscopic Submucosal Dissection for an Adenoma Adjacent to the Appendiceal Orifice. AB - Endoscopic submucosal dissection (ESD) is a groundbreaking treatment for tumors adjacent to the appendiceal orifice that are difficult to remove by conventional endoscopic mucosal resection, and successful cases are increasingly reported. However, little is known about the subsequent complications, especially long-term complications. A female in her early 70s with a 15-mm cecal tumor adjacent to the appendiceal orifice - discovered incidentally during a screening colonoscopy - underwent hybrid ESD of the lesion. We completely resected the tumor, and she was discharged 5 days later with a pathological diagnosis of high-grade tubular adenoma. Ten months postoperatively, she experienced sudden-onset right lower quadrant pain and was diagnosed with acute appendicitis at another hospital. Due to suspicion that her condition was the result of residual tumor, her surgeon performed an emergency laparoscopic cecectomy. The pathological examination of the resected specimen showed thick scarring adjacent to the appendiceal orifice and no residual tumor. The previous ESD was identified as the cause of the scar, and the scar was the only finding to account for the patient's appendicitis. This case is significant because the patient required additional surgery due to a complication of ESD. Further, it indicates that acute appendicitis may be a late complication of submucosal dissection near the appendiceal orifice. As ESD becomes more widely used, it is likely that more cecal tumors will be treated endoscopically. It is important to be aware of the late complications of ESD for these tumors. PMID- 28626373 TI - Biliary-Pleural Fistula following Portal Vein Embolization for Perihilar Cholangiocarcinoma. AB - Biliary-pleural fistula (BPF), an abnormal communication between the biliary tract and pleural space, is a rare but potentially life-threatening complication following percutaneous biliary intervention. We report a case of BPF following portal vein embolization (PVE) in a 79-year-old woman with obstructive jaundice secondary to perihilar cholangiocarcinoma. The patient successfully underwent right-sided PVE; however, the patient developed a symptomatic right-sided bilious pleural effusion the following day. Despite aggressive drainage of the pleural effusion with a large-bore chest tube and maximal medical management, the patient died from respiratory failure and pneumonia. Although rare, knowledge of this complication is important when performing PVE in patients with biliary obstruction because it can be life-threatening. Early recognition and management of this complication are crucial to avoid a poor outcome. PMID- 28626374 TI - Bochdalek Hernia in an Adult with Upper Gastrointestinal Bleeding. AB - Bochdalek hernia (BH) can be a life-threatening condition in infants. Approximately 85.3% of newborns with a BH are immediately at high risk and have a high mortality rate due to respiratory insufficiency [Kocakusak et al.: Hernia 2005;9: 284-287]. However, BH is almost asymptomatic in adults and discovered only incidentally [Wilkins et al.: Clin Imaging 1994;18: 224-229]. Complicated BH in adults might present with visceral incarceration and lethal complications. Upper gastrointestinal bleeding and acute pancreatitis are rarely reported in the literature as complications of BH in adults. Here we report the case of a 42-year old male who presented with upper gastrointestinal bleeding and acute pancreatitis. He was found to have abdominal visceral organ herniation to the posterior right thoracic cavity. His diagnosis was achieved early and with a close follow-up, we succeeded in stabilizing the patient's condition. Then he was subjected to reconstructive thoracotomy for hernial repair and restoring abdominal viscera. PMID- 28626375 TI - Intravenous Bevacizumab Therapy in a Patient with Hereditary Hemorrhagic Telangiectasia, ENG E137K, Alcoholic Cirrhosis, and Portal Hypertension. AB - Intravenous bevacizumab decreased mucosal bleeding in some patients with hereditary hemorrhagic telangiectasia (HHT). We treated a 47-year-old male who had HHT, severe epistaxis, and gastrointestinal bleeding, alcoholic cirrhosis, and portal hypertension with intravenous bevacizumab 2.5 mg/kg every 2 weeks. We tabulated these measures weekly during weeks 1-33 (no bevacizumab); 34-57 (bevacizumab); and 58-97 (no bevacizumab): hemoglobin (Hb) levels; platelet counts; units of transfused packed erythrocytes (PRBC units); and quantities of iron infused as iron dextran to support erythropoiesis. We performed univariate and multivariable analyses. We sequenced his ENG and ACVRL1 genes. Epistaxis and melena decreased markedly during bevacizumab treatment. He reported no adverse effects due to bevacizumab. Mean weekly Hb levels were significantly higher and mean weekly PRBC units and quantities of intravenous iron were significantly lower during bevacizumab treatment. We performed a multiple regression on weekly Hb levels using these independent variables: bevacizumab treatment (dichotomous); weekly platelet counts; weekly PRBC units; and weekly quantities of intravenous iron. There was 1 positive association: (bevacizumab treatment; p = 0.0046) and 1 negative association (PRBC units; p = 0.0004). This patient had the novel ENG mutation E137K (exon 4; c.409G->A). Intravenous bevacizumab treatment 2.5 mg/kg every 2 weeks for 24 weeks was well-tolerated by a patient with HHT due to ENG E137K and was associated with higher weekly Hb levels and fewer weekly PRBC units. PMID- 28626376 TI - Successful Treatment for Chronic Hepatitis C-Autoimmune Hepatitis Overlap Syndrome due to Daclatasvir and Asunaprevir. AB - Persistent hepatitis C virus (HCV) infection may induce autoimmune diseases and chronic hepatitis C is sometimes accompanied by autoimmune hepatitis (AIH). However, we are worried about the treatment for chronic hepatitis C-AIH overlap syndrome because interferon-based antiviral therapies may enhance autoimmunity and immunosuppressive corticosteroid administration may promote viral replication. Here, we report a patient having chronic hepatitis C-AIH overlap syndrome treated with the direct-acting antivirals (DAA), daclatasvir and asunaprevir. A 50-year-old man was referred to our hospital because of positive anti-HCV antibody and liver dysfunction at a health checkup. Blood tests showed increased immunoglobulin G (IgG) and a high titer of antinuclear antibody (ANA) in addition to elevated serum alanine aminotransferase (ALT) and HCV-RNA. Infiltration of lymphocytes and plasma cells in Glisson's capsule and severe interface hepatitis were observed in biopsied specimen, which fulfilled the criteria of AIH. We first started oral corticosteroid administration, and serum ALT levels decreased once but elevated again. We commenced daclatasvir and asunaprevir (60 and 200 mg/day, respectively) and serum HCV-RNA became negative after 6 weeks. Adverse effects were not found during the DAA treatment, and serum ALT, IgG, and ANA were significantly decreased. Corticosteroid could be tapered and stopped, but no recurrence occurred. DAA treatment appears to be effective and safe for the patients with chronic hepatitis C-AIH overlap syndrome. PMID- 28626377 TI - Kidney Injury due to Ureteral Obstruction Caused by Compression from Infected Simple Hepatic Cyst. AB - Simple hepatic cysts are common and most often asymptomatic. In symptomatic cases, hemorrhage, rupture, and infection are major complications. However, urinary tract obstruction caused by a simple hepatic cyst is rare. We treated an 82-year-old Japanese man with an infected giant hepatic cyst causing right hydronephrosis who had a past history of left nephrectomy for renal cell carcinoma. The patient underwent ultrasound-guided percutaneous drainage and sclerotherapy with minocycline hydrochloride for the infected hepatic cyst. Right hydronephrosis was relieved, and renal dysfunction improved with regression of the hepatic cyst after treatment. This is the first report of hydronephrosis due to ureteral obstruction caused by compression from a hepatic cyst. PMID- 28626378 TI - Partial Hepatectomy with Middle Hepatic Vein Reconstruction Using a Left Inferior Vena Cava Graft. AB - Duplicated inferior vena cava (IVC) is a rare congenital anomaly. We describe the utility of a new graft from the left IVC in a patient with duplicated IVC for reconstructing the middle hepatic vein (MHV) after partial hepatectomy with MHV resection. A 67-year-old woman with hepatitis C was found to have a liver tumor. Magnetic resonance imaging confirmed that the tumor, which was attached to the MHV, was hepatocellular carcinoma. Central bisectionectomy (S4, S5, and S8 resection) could not be tolerated because of poor liver function and a low future liver remnant volume. Therefore, partial hepatectomy with MHV resection was performed. The left IVC was harvested as a venous graft and was substituted for the resected MHV. She recovered uneventfully and was discharged on postoperative day 12. To the best of our knowledge, this is the first report of using the left IVC as a venous graft. The left IVC is a good candidate graft for the MHV or for portal vein reconstruction because of its length, diameter, and easy harvesting (it did not require an extra incision) in a patient with duplicated IVC. PMID- 28626379 TI - Fifteen-Year-Old Male with Type 2 Autoimmune Pancreatitis: An Argument for Endoscopy. AB - Type 2 autoimmune pancreatitis, an increasingly recognized etiology of pancreatitis in patients less than 20 years old, has characteristically been diagnosed with the histological finding of duct-centric pancreatitis in a patient who lacks elevated serum immunoglobulin G4. We present the case of a nonobese 15 year-old male, without any chronic medical conditions, who presented with the chief complaint of abdominal pain. The laboratory study results were remarkable for a lipase level of 5,419 U/L and a gamma-glutamyl transferase level of 373 U/L. Magnetic resonance cholangiopancreatography revealed delayed contrast enhancement of the pancreas, diffuse parenchymal enlargement, and lack of normal lobulation. The patient's serum immunoglobulin G4 level was found to be 66 mg/dL, which was within normal limits and supportive of a diagnosis of type 2 autoimmune pancreatitis. Despite the absence of intestinal complaints, the patient underwent subsequent endoscopy due to the correlation of type 2 autoimmune pancreatitis with inflammatory bowel disease that has been described in recent literature. Pan colonic mild colitis was visualized, and the patient began treatment with steroids, to which he quickly responded. Performing endoscopy on this patient allowed for confident initiation of early therapy for both autoimmune pancreatitis and inflammatory bowel disease, and may have limited further surgical intervention and disease progression. For these reasons, this case highlights the utility of endoscopy in pediatric patients with suspected type 2 autoimmune pancreatitis, even in the absence of intestinal symptoms. PMID- 28626380 TI - Clinical and Pathologic Remission of Pediatric Ulcerative Colitis with Serum Derived Bovine Immunoglobulin Added to the Standard Treatment Regimen. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is particularly troublesome for pediatric patients, as current therapeutic options consist of biologic agents and steroids which alter the immune response and have the harmful side effect of leaving the patient more susceptible to opportunistic infections and eventual surgery. Another option for therapy exists in the form of serum-derived bovine immunoglobulin/protein isolate (SBI), the key ingredient in a medical food, EnteraGam(r). The FDA has reviewed the safety of SBI and issued a no challenge letter to the generally recognized as safe (GRAS) findings for this medical food. The product also has no known food or drug interactions, no significant adverse effects, and no contraindications, save for beef allergy. SBI has been shown to induce clinical remission in adult populations and to decrease markers of inflammation in pediatric patients. Here, we present a detailed case of pediatric UC, including documentation of mucosal healing and decrease in pediatric UC activity index in a difficult to treat pediatric patient, after the addition of SBI to this patient's treatment regimen. PMID- 28626381 TI - Nilotinib-Induced Acute Pancreatitis in a Patient with Chronic Myeloid Leukemia. AB - Nilotinib, a second-generation tyrosine kinase inhibitor, is used for treatment of chronic myeloid leukemia (CML); it has been widely used especially for imatinib-resistant CML. Despite being a novel drug in this therapeutic class, it has the potential to be harmful. We present the case of an elderly woman who developed life-threatening acute pancreatitis as an adverse event after having started the drug. There is only one reported case in the literature of nilotinib induced acute pancreatitis. The purpose of this case report is to educate physicians who prescribe this medication to be aware of potential life threatening adverse events. As more and more therapies are available, physicians should be aware of potential effects of cancer treatment that could be life threatening to patients. PMID- 28626382 TI - A Symptomatic Coffee Bean: Acute Sigmoid Volvulus. AB - An acute sigmoid volvulus is due to the torsion of the sigmoid colon around its mesenteric axis. It mainly occurs in elderly patients and represents an abdominal emergency requiring urgent treatment. A 53-year-old male patient with severe craniocerebral injury and traumatic subarachnoidal bleeding 3 weeks prior presented on the ward with distended abdomen without abdominal pain, muscular defense, or resistances. He featured large volume diarrhea within the last few hours without signs of bleeding. A plain abdominal X-ray demonstrated a coffee bean sign indicating a sigmoid volvulus. A consequent CT scan of the abdomen revealed a deep outlet obstruction with massively dilated, elongated and twisted loop of the sigmoid colon and no signs of perforation. We performed emergency colonoscopy under the assumption of an acute sigmoid volvulus. After careful insertion of the endoscope completely refraining from insufflation of air or CO2, endoscopic reposition of the sigma could be achieved and a colonic drainage was placed over an inserted guide wire up to the proximal transverse colon. No relapse occurred and a diagnostic colonoscopy after 4 weeks revealed no tumor or polyps. Our report describes a classic case of acute sigmoid volvulus and undermines the potential of colonoscopy as conservative primary treatment of choice. PMID- 28626383 TI - An Alternative Approach to the Terminal Management of Ogilvie Syndrome. AB - Ogilvie syndrome is defined as colonic pseudo-obstruction due to nonmechanical causes. Mortality of nearly 50% is associated with perforation of the distended, pseudo-obstructed colon. While conservative medical therapy has proven to be beneficial in a majority of cases, >3% of patients have significant distention or perforation of the colon that warrants surgical resection. The case of a 48-year old male with progressive abdominal discomfort and distention 12 days following knee replacement surgery is presented. He was subsequently diagnosed with colonic pseudo-obstruction and definitively treated with subtotal colectomy and colostomy. We propose that a more conservative approach to treatment of colonic pseudo-obstruction may prevent the need for colostomy, significantly improving quality of life. PMID- 28626384 TI - Acute Pancreatitis: An Atypical Presentation. AB - Acute pancreatitis is an important cause of acute upper abdominal pain. Because its clinical features are similar to a number of other acute illnesses, it is difficult to make a diagnosis only on the basis of symptoms and signs. The diagnosis of acute pancreatitis is based on 2 of the following 3 criteria: (1) abdominal pain consistent with pancreatitis, (2) serum lipase and/or amylase >=3 times the upper limit of normal, and (3) characteristic findings from abdominal imaging. The sensitivity and specificity of lipase in diagnosing acute pancreatitis are undisputed. However, normal lipase level should not exclude a pancreatitis diagnosis. In patients with atypical pancreatitis presentation, imaging is needed. We experienced two cases of acute pancreatitis associated with normal serum enzyme levels. Both patients were diagnosed based on clinical and radiological evidence. They were successfully treated with intravenous fluids and analgesics with clinical and laboratory improvement. The importance of this case series is the unlikely presentation of acute pancreatitis. We believe that more research is needed to determine the exact proportion of acute pancreatitis patients who first present with normal serum lipase, since similar cases have been seen in case reports. PMID- 28626385 TI - Urinary Tract Infection Associated with a Celiac Crisis: A Preceding or Precipitating Event? AB - Celiac crisis is a rare life-threatening presentation of celiac disease that manifests as profuse diarrhea, hypoproteinemia, and severe metabolic disturbances. It may be precipitated by a general immune stimulus such as surgery, infection, or pregnancy. We report the case of a 26-year-old woman who presented with a celiac crisis, potentially triggered by a preceding urinary tract infection. Metabolic derangement is caused by malabsorption and profuse diarrhea, which can be unremitting unless the celiac crisis is recognized, and treatment with gluten restriction is initiated. PMID- 28626386 TI - Minimal Effects of Age and Exposure to a Noisy Environment on Hearing in Alpha9 Nicotinic Receptor Knockout Mice. AB - Studies have suggested a role of weakened medial olivocochlear (OC) efferent feedback in accelerated hearing loss and increased susceptibility to noise. The present study investigated the progression of hearing loss with age and exposure to a noisy environment in medial OC-deficient mice. Alpha9 nicotinic acetylcholine receptor knockout (alpha9KO) and wild types were screened for hearing loss using auditory brainstem responses. alpha9KO mice housed in a quiet environment did not show increased hearing loss compared to wild types in young adulthood and middle age. Challenging the medial OC system by housing in a noisy environment did not increase hearing loss in alpha9KO mice compared to wild types. ABR wave 1 amplitudes also did not show differences between alpha9KO mice and wild types. These data suggest that deficient medial OC feedback does not result in early onset of hearing loss. PMID- 28626387 TI - The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease. AB - The "therapeutic chelation" approach to treating Alzheimer's disease (AD) evolved from the metals hypothesis, with the premise that small molecules can be designed to prevent transition metal-induced amyloid deposition and oxidative stress within the AD brain. Over more than 20 years, countless in vitro studies have been devoted to characterizing metal binding, its effect on Abeta aggregation, ROS production, and in vitro toxicity. Despite a lack of evidence for any clinical benefit, the conjecture that therapeutic chelation is an effective approach for treating AD remains widespread. Here, the author plays the devil's advocate, questioning the experimental evidence, the dogma, and the value of therapeutic chelation, with a major focus on copper ions. PMID- 28626388 TI - Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease. AB - Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA), a deacetylase that catabolizes N-acetylaspartate (NAA). The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA) twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation), expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF-2) in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms. PMID- 28626389 TI - Rac1 Guides Porf-2 to Wnt Pathway to Mediate Neural Stem Cell Proliferation. AB - The molecular and cellular mechanisms underlying the anti-proliferative effects of preoptic regulator factor 2 (Porf-2) on neural stem cells (NSCs) remain largely unknown. Here, we found that Porf-2 inhibits the activity of ras-related C3 botulinum toxin substrate 1 (Rac1) protein in hippocampus-derived rat NSCs. Reduced Rac1 activity impaired the nuclear translocation of beta-catenin, ultimately causing a repression of NSCs proliferation. Porf-2 knockdown enhanced NSCs proliferation but not in the presence of small molecule inhibitors of Rac1 or Wnt. At the same time, the repression of NSCs proliferation caused by Porf-2 overexpression was counteracted by small molecule activators of Rac1 or Wnt. By using a rat optic nerve crush model, we observed that Porf-2 knockdown enhanced the recovery of visual function. In particular, optic nerve injury in rats led to increased Wnt family member 3a (Wnt3a) protein expression, which we found responsible for enhancing Porf-2 knockdown-induced NSCs proliferation. These findings suggest that Porf-2 exerts its inhibitory effect on NSCs proliferation via Rac1-Wnt/beta-catenin pathway. Porf-2 may therefore represent and interesting target for optic nerve injury recovery and therapy. PMID- 28626391 TI - Commentary: The Brain Basis for Misophonia. PMID- 28626390 TI - Profiles of VGF Peptides in the Rat Brain and Their Modulations after Phencyclidine Treatment. AB - From the VGF precursor protein originate several low molecular weight peptides, whose distribution in the brain and blood circulation is not entirely known. Among the VGF peptides, those containing the N-terminus portion were altered in the cerebro-spinal fluid (CSF) and hypothalamus of schizophrenia patients. "Hence, we aimed to better investigate the involvement of the VGF peptides in schizophrenia by studying their localization in the brain regions relevant for the disease, and revealing their possible modulations in response to certain neuronal alterations occurring in schizophrenia". We produced antibodies against different VGF peptides encompassing the N-terminus, but also C-terminus-, TLQP-, GGGE- peptide sequences, and the so named NERP-3 and -4. These antibodies were used to carry out specific ELISA and immunolocalization studies while mass spectrometry (MS) analysis was also performed to recognize the intact brain VGF fragments. We used a schizophrenia rat model, in which alterations in the prepulse inhibition (PPI) of the acoustic startle response occurred after PCP treatment. In normal rats, all the VGF peptides studied were distributed in the brain areas examined including hypothalamus, prefrontal cortex, hippocampus, accumbens and amygdaloid nuclei and also in the plasma. By liquid chromatography high resolution mass, we identified different intact VGF peptide fragments, including those encompassing the N-terminus and the NERPs. PCP treatment caused behavioral changes that closely mimic schizophrenia, estimated by us as a disruption of PPI of the acoustic startle response. The PCP treatment also induced selective changes in the VGF peptide levels within certain brain areas. Indeed, an increase in VGF C-terminus and TLQP peptides was revealed in the prefrontal cortex (p < 0.01) where they were localized within parvoalbumin and tyrosine hydroxylase (TH) containing neurons, respectively. Conversely, in the nucleus accumbens, PCP treatment produced a down-regulation in the levels of VGF C-terminus-, N-terminus- and GGGE- peptides (p < 0.01), expressed in GABAergic- (C-terminus/GGGE) and somatostatin- (N-terminus) neurons. These results confirm that VGF peptides are widely distributed in the brain and modulated in specific areas involved in schizophrenia. PMID- 28626392 TI - Sensing the Worst: Neurophenomenological Perspectives on Neutral Stimuli Misperception in Schizophrenia Spectrum. AB - While investigating social cognitive impairments in schizophrenia, prominent evidence has been found that patients with schizophrenia show a tendency to misclassify neutral stimuli as negatively valenced. Within this population, patients presenting delusions are more prone to this phenomenon. In a previous study, Schizophrenia spectrum (SzSp) patients rated positive, negative and neutral stimuli that were multimodally presented, while assessed with a checklist exploring anomalous subjective experiences and evaluated for positive and negative symptomatology. In the present work, we aimed to further explore the relationship between neutral stimuli misperception, anomalous experiences and positive/negative symptoms in SzSp patients. To this end, we adopted a dimensional approach by reconstructing from available data: (1) four a priori scales representing essential dimensions of SzSp experiential pathology following Parnas et al. (2005); and (2) five clinically meaningful factors to describe illness severity derived by Toomey et al. (1997). Results showed that although overall patients correctly recognized the target emotions, those who misinterpreted neutral auditory cues as negatively valenced also presented higher scores in Perplexity (PY), Bizarre Delusions (BD) and Disorganization (Di) dimensions. Moreover, a positive association between BD and both PY and Self Disorder (SD) dimensions emerged, suggesting that psychotic symptoms may be directly linked to patients' subjectivity. In an attempt to comprehensively capture the multilayered neutral stimuli misperception phenomenon in SzSp, we aimed at bridging phenomenology and neurobiology by connecting the levels of molecular neurochemistry (i.e., altered dopaminergic neurotransmission), system neuroscience (aberrant salience of perceptual details) and psychopathology (the chain involving hyper-reflexivity, self-disorders and the emergence of delusions). PMID- 28626393 TI - A SSVEP Stimuli Encoding Method Using Trinary Frequency-Shift Keying Encoded SSVEP (TFSK-SSVEP). AB - SSVEP is a kind of BCI technology with advantage of high information transfer rate. However, due to its nature, frequencies could be used as stimuli are scarce. To solve such problem, a stimuli encoding method which encodes SSVEP signal using Frequency Shift-Keying (FSK) method is developed. In this method, each stimulus is controlled by a FSK signal which contains three different frequencies that represent "Bit 0," "Bit 1" and "Bit 2" respectively. Different to common BFSK in digital communication, "Bit 0" and "Bit 1" composited the unique identifier of stimuli in binary bit stream form, while "Bit 2" indicates the ending of a stimuli encoding. EEG signal is acquired on channel Oz, O1, O2, Pz, P3, and P4, using ADS1299 at the sample rate of 250 SPS. Before original EEG signal is quadrature demodulated, it is detrended and then band-pass filtered using FFT-based FIR filtering to remove interference. Valid peak of the processed signal is acquired by calculating its derivative and converted into bit stream using window method. Theoretically, this coding method could implement at least 2 n-1 (n is the length of bit command) stimulus while keeping the ITR the same. This method is suitable to implement stimuli on a monitor and where the frequency and phase could be used to code stimuli is limited as well as implementing portable BCI devices which is not capable of performing complex calculations. PMID- 28626394 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000447353.]. PMID- 28626395 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000453608.]. PMID- 28626396 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000450598.]. PMID- 28626397 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000447352.]. PMID- 28626398 TI - Esophageal Metastasis from Rectal Cancer Successfully Treated with Fluorouracil Based Chemotherapy with Bevacizumab: A Case Report and Review of the Literature. AB - Esophageal metastasis from colorectal carcinoma is uncommon, and diagnosis of esophageal metastasis is difficult. We report a case of a 54-year-old woman with postoperative recurrence of rectal cancer metastasizing to the esophagus. She underwent rectectomy and adjuvant chemotherapy with fluorouracil, leucovorin plus oxaliplatin for stage IIIB rectal cancer. Three years later, she presented with dysphagia and cough. Computed tomography showed thickening of the esophagus wall, enlargement of the lymph nodes in the mediastinum and abdomen, and ground-glass opacities in the right lung. Endoscopy revealed a submucosal tumor of the midthoracic esophagus. Histopathological analysis of the tumor biopsy showed infiltration of adenocarcinoma cells into the stroma of the esophagus; tumor cells were positive for caudal type homeobox 2 and negative for thyroid transcription factor 1. A transbronchial biopsy indicated pulmonary lymphangitic carcinomatosis of rectal adenocarcinoma. Based on those findings, she was diagnosed with recurrent rectal cancer. She received fluorouracil-based chemotherapy plus bevacizumab, which ameliorated her symptoms and induced a durable response without severe adverse events. Diagnosis of esophageal metastasis from rectal cancer can thus be made by repeated biopsy. Furthermore, aggressive systemic treatment with fluorouracil-containing chemotherapy and bevacizumab is a treatment option for colorectal cancer patients with esophageal metastasis. PMID- 28626399 TI - Sigmoid Adenocarcinoma with Regional Scrotal Metastasis. AB - Colorectal cancer is a common disease, representing the third and second most common cause of cancer death in the United States in women and men, respectively. [Ahnen et al.: Mayo Clin Proc 2014;89: 216-224; Siegel et al.: CA Cancer J Clin 2016;66: 7]. It is estimated that 20% of patients have distant metastatic disease at time of diagnosis [Ahnen et al.: Mayo Clin Proc 2014;89: 216-224; Siegel et al.: CA Cancer J Clin 2016;66: 7]. The most common metastatic sites include regional lymph nodes, liver, lungs, and peritoneum via lymphatic/hematogenous dissemination as well as contiguous and transperitoneal routes [Ahnen et al.: Mayo Clin Proc 2014;89: 216-224; Siegel et al.: CA Cancer J Clin 2016;66: 7]. Upon review of the literature, we found that metastatic colon cancer to the scrotum is rare. The following case report proved to be a unique example of this type of metastasis. This rare regional metastasis is theorized to have resulted from a colo-urethro-scrotal fistula that precipitated from the patient's prior traumatic event. PMID- 28626400 TI - Long-Term Efficacy of S-1 Chemotherapy plus Administration of Octreotide for a Patient with Metastatic Neuroendocrine Tumor (Gastrinoma). AB - Metastatic neuroendocrine tumors (gastrinomas) have a poor prognosis. Octreotide can reduce gastrin levels and alleviate hormonal symptoms, and possibly slow tumor growth as well. No drugs were available except streptozocin for the treatment of metastatic pancreatic neuroendocrine tumor (PNET) in 2008. We report a case of PNET in a 53-year-old woman with multiple liver tumors treated with S-1 plus octreotide. After 6 months from the initiation of the treatment, the pancreatic tumor and liver metastases regressed, and the patient achieved partial response without the development of any serious adverse event. For more than 8 years, the patient has remained asymptomatic without disease progression and is continuing treatment with octreotide and S-1. A marked suppression of gastrin levels has also been achieved. Combination therapy with octreotide and S-1 has been effective and well tolerated in patients with metastatic gastrinoma. PMID- 28626401 TI - Pneumothorax during Pemetrexed Treatment in a Patient with Non-Small Cell Lung Cancer: A Case Report and Literature Review. AB - Pemetrexed is a multitargeted antifolate that has demonstrated antitumor activity in non-small cell lung cancer. A 70-year-old male presented with a stage IV non small cell lung cancer. The patient was treated with pemetrexed as third-line chemotherapy. However, a pneumothorax occurred 16 days after the administration of the second cycle of pemetrexed. The pneumothorax was slight and the patient was observed without undergoing any additional treatment. Twenty-four days after its initial occurrence, the pneumothorax had improved. This is the first case of pneumothorax that has been observed during pemetrexed treatment. Pneumothorax during chemotherapy is rare; however, it is a life-threatening complication and should not be overlooked. PMID- 28626402 TI - Effect of the Combination of Trabectedin and Pegylated Liposomal Doxorubicin in a BRCA2 Mutation Carrier with Recurrent Platinum-Sensitive Ovarian Cancer. AB - INTRODUCTION: The current standard of care for ovarian cancer is optimal cytoreduction with adjuvant chemotherapy based on a platinum/taxane combination. Although the response rate to this therapy is high, most patients ultimately relapse. Response to second-line therapy and prognosis are linked to the platinum free interval (PFI); when both improve, the PFI increases. As a result, there is an increasing interest in the PFI extension strategies including platinum-free combinations. CASE PRESENTATION: A 50-year-old postmenopausal woman presented with ovarian serous carcinoma with peritoneal carcinomatosis. First-line neoadjuvant chemotherapy with carboplatin plus paclitaxel was initiated, followed by surgery and carboplatin plus paclitaxel chemotherapy. Eight months after the last cycle, CT revealed extensive supra- and infradiaphragmatic node involvement, and second-line chemotherapy was initiated with trabectedin and pegylated liposomal doxorubicin (PLD). Partial response was achieved and successfully maintained for 18 cycles. After the 18th cycle and a 25-month PFI, CT imaging evidenced disease progression. As the patient was a BRCA2 mutation carrier, third line chemotherapy was initiated with carboplatin and gemcitabine every 3 weeks. After the third cycle, imaging confirmed complete response, which was maintained after the sixth and final cycle. Maintenance treatment with olaparib was initiated. At present - 6 months after the start of maintenance chemotherapy with olaparib - the patient is disease free. CONCLUSIONS: Second-line chemotherapy with a nonplatinum combination - trabectedin plus PLD - was effective in a BRCA2 mutation carrier with recurrent partially platinum-sensitive ovarian cancer. PMID- 28626403 TI - A Twenty-Four-Year-Old Woman with Left Flank Lipoma-Like Hibernoma. AB - A 24-year-old woman presented with a 5-month history of a left flank mass that was painful on palpation. Magnetic resonance imaging revealed a 10.0 * 6.0 * 2.5 cm mass consistent with lipoma. A fatty lobulated mass was excised and subjected to H&E staining and immunohistochemical analyses. The specimen consisted of mature univacuolated adipocytic cells, with intermixed multivacuolated eosinophilic granular cells. No atypia or hyperchromasia was identified. Most of the cells were S100 positive and Ki-67 immunonegative. A diagnosis of a lipoma like hibernoma was rendered. Hibernomas are rare benign lipomatous tumors that show differentiation toward brown fat. The lipoma-like hibernoma subtype is rare and can be misdiagnosed as atypical lipoma or well-differentiated liposarcoma. Here we describe an example of this rare tumor. PMID- 28626405 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000464440.]. PMID- 28626404 TI - Case of Ovarian Cancer in a Woman with Undiagnosed Graves' Disease: A Case Report and Review of the Literature. AB - Epithelial ovarian cancer (OC) is a leading cause of death among females in the United States, due in part to challenges of diagnosis in the early stages of the disease. While efforts are underway to develop a high-quality screening test, it is equally important to consider whether high-risk populations are appropriate to screen. One such population may be females with hyperthyroidism, as epidemiologic studies have shown an association between this condition and OC. In this report, we present a case of a female with OC and Graves' disease to highlight the potential significance of this association. PMID- 28626406 TI - Late-Onset Inflammatory Bowel Disease-Like Syndrome after Ipilimumab Therapy: A Case Report. AB - BACKGROUND: Antitumor immunotherapy has become a major player in cancer therapy. Ipilimumab is a humanized monoclonal antibody against the cytotoxic T lymphocyte associated antigen 4 (CTLA-4), an important downregulator of T-cell activation. Ipilimumab has demonstrated tumor regression and improvement in overall survival in patients with metastatic melanoma. Unfortunately, immune activation induced by this drug has been associated with several immune-mediated adverse effects, namely diarrhea and colitis. CASE PRESENTATION: We report the case of a 71-year old male patient diagnosed with BRAF wild-type metastatic melanoma treated with three cycles of ipilimumab, after which he developed grade 3 enteritis. The patient improved on treatment with steroids, and ipilimumab was permanently discontinued at this point. Three years later, the patient's diarrhea returned and colonoscopy revealed active chronic colitis with ulceration resembling inflammatory bowel disease. He was started on Asacol (mesalamine). The patient did not report extraintestinal symptoms typically associated with inflammatory bowel disease, nor did he have a personal or family history of bowel disorders. Moreover, his presentation was not typical of inflammatory bowel disease in the elderly. CONCLUSION: Our findings suggest a link between ipilimumab-induced grade 3 enteritis and late-onset inflammatory bowel disease-like syndrome. To our knowledge, the case is the first in the literature to report late-onset inflammatory bowel disease-like syndrome years after discontinuation of ipilimumab treatment. PMID- 28626407 TI - Systemic Therapy Outcomes in Adult Patients with Ewing Sarcoma Family of Tumors. AB - BACKGROUND: The Ewing sarcoma family of tumors (ESFT) is a rare but curable bone neoplastic entity. The current standard of care involves chemotherapy and local disease control with surgery or radiation regardless of the extent of disease at presentation. Data that document the effectiveness of the current approach in the adult patient population are limited. METHODS: We performed a retrospective review including all ESFT patients older than 19 years of age who received systemic therapy between January 2002 and December 2013 at our institution. The main study outcome was overall survival; secondary outcomes were objective response rate, disease-free survival, and progression-free survival. RESULTS: Eighteen patients with ESFT were identified. The median overall survival for the entire group was 20.65 months (range 0.43-114.54). In patients with localized disease, the 1-, 2-, and 3-year survival rates were 90, 80, and 70%, respectively. Age was not correlated with overall survival (r = 0.58, p = 0.76). The 3-year disease-free survival rate was 70%. In patients with metastatic disease, the 1-year survival rate was 40%. In patients treated in the neoadjuvant and palliative setting with chemotherapy, we observed an objective response rate of 61.54%. The time to progression in patients with metastatic disease treated with chemotherapy ranged from 0.69 to 4.93 months. CONCLUSION: In this group of adult patients with ESFT treated with multimodality therapy, the outcomes were similar to those reported in well-known larger clinical trials that typically included younger patients. Age was not associated with worse survival. PMID- 28626408 TI - PD-1 Checkpoint Inhibitor Associated Autoimmune Encephalitis. AB - OBJECTIVE: To report first-hand narrative experience of autoimmune encephalitis and to briefly review currently available evidence of autoimmune encephalitis in cancer patients treated with immune checkpoint inhibitors. SETTING: A case study is presented on the management of a patient who developed autoimmune encephalitis during nivolumab monotherapy occurring after 28 weeks on anti-PD-1 monotherapy (nivolumab 3 mg/kg every 2 weeks) for non-small cell lung cancer. RESULTS: No substantial improvement was observed by antiepileptic treatment. After administration of 80 mg methylprednisolone, neurologic symptoms disappeared within 24 h and the patient fully recovered. CONCLUSIONS: Immune checkpoint inhibitor treatment can lead to autoimmune encephalitis. Clinical trial data indicate a frequency of autoimmune encephalitis of >=0.1 to <1% with a higher probability during combined or sequential anti-CTLA-4/anti-PD-1 therapy than during anti-PD-1 or anti-PD-L1 monotherapy. Further collection of evidence and translational research is warranted. PMID- 28626409 TI - HIV-Associated Cerebellar Dysfunction and Improvement with Aminopyridine Therapy: A Case Report. AB - Apart from infectious causes and cerebellar dysfunction associated with acquired immune deficiency syndrome dementia or HIV-associated neurocognitive disorder, cerebellar dysfunction in HIV-positive individuals has been ascribed to granule cell neuronopathy as well as primary cerebellar atrophy without identifiable etiology. We report the case of a patient with progressive cerebellar dysfunction as the primary manifestation of HIV infection. No symptom improvement was seen under combination antiretroviral therapy, which had been established upon diagnosis, but the patient improved rapidly under 4-aminopyridine treatment, which was recommended 1 year later. Our report, adding to the rather small number of reports of HIV-associated cerebellar atrophy and dysfunction as a primary manifestation of HIV infection, draws attention to HIV as a possible differential etiology of a cerebellar syndrome. Further, rapid improvement of symptom severity under 4-aminopyridine treatment warrants further investigation with longer-term follow-up into the effectiveness of this compound in gait disorder associated with HIV infection. PMID- 28626410 TI - Neuromyelitis Optica Spectrum Disorder Coinciding with Spinocerebellar Ataxia Type 31. AB - We report the unusual case of a 63-year-old man with spinocerebellar ataxia (SCA) type 31 who developed neuromyelitis optica spectrum disorder (NMOSD) 14 years after the onset of cerebellar symptoms. In addition to cerebellar atrophy, magnetic resonance imaging showed multiple high-intensity areas in the brain and a long thoracic cord lesion from Th1/2 to Th11. The combination of NMOSD and SCA31 is accidental. However, our case suggests that inflammatory processes could be involved in the pathogenesis of NMOSD and SCA31. PMID- 28626411 TI - Dissociated Crossed Speech Areas in a Tumour Patient. AB - In the past, the eloquent areas could be deliberately localised by the invasive Wada test. The very rare cases of dissociated crossed speech areas were accidentally found based on the clinical symptomatology. Today functional magnetic resonance imaging (fMRI)-based imaging can be employed to non-invasively localise the eloquent areas in brain tumour patients for therapy planning. A 41 year-old, left-handed man with a low-grade glioma in the left frontal operculum extending to the insular cortex, tension headaches, and anomic aphasia over 5 months underwent a pre-operative speech area localisation fMRI measurement, which revealed the evidence of the transhemispheric disposition, where the dominant Wernicke speech area is located on the left and the Broca's area is strongly lateralised to the right hemisphere. The outcome of the Wada test and the intraoperative cortico-subcortical stimulation mapping were congruent with this finding. After tumour removal, language area function was fully preserved. Upon the occurrence of brain tumours with a risk of impaired speech function, the rare dissociate crossed speech areas disposition may gain a clinically relevant meaning by allowing for more extended tumour removal. Hence, for its identification, diagnostics which take into account both brain hemispheres, such as fMRI, are recommended. PMID- 28626412 TI - Congenital Bilateral C2 Transverse Foramina Stenosis Causing Adult-Onset Vertebrobasilar Insufficiency and Posterior Circulation Stroke. AB - Vertebrobasilar insufficiency leading to posterior circulation infarcts caused by congenital hypoplasia of the bilateral transverse foramina at the C2 level, affecting the caliber and flow of the bilateral distal cervical vertebral arteries in an adult, has not been previously reported. A 41-year-old male presented with episodic dizziness for a period of 1 year prior to consultation. Computed tomography angiography of the head and neck demonstrated congenital hypoplasia of the bilateral C2 transverse foramina, with absence of the vertebral arteries in each of the foramina and collateral reconstitution of diminutive intracranial vertebral artery segments. Brain MRI showed postinfarction encephalomalacia in the bilateral cerebellar hemispheres. The patient was considered not a surgical or endovascular candidate and was managed conservatively with antiplatelet therapy. Congenital anomalies of the bilateral cervical transverse foramina may present with vertebrobasilar insufficiency and infarction in adulthood. PMID- 28626413 TI - The Crossed Flexor Plantar Response in Patients with Klippel-Feil Syndrome. AB - The plantar reflex is one of most important and widely tested components of the neurological examination. We describe 3 subjects with Klippel-Feil syndrome and mirror movements where unilateral cutaneous stimulation of the foot leads to flexor plantar responses in both feet. We discuss the evidence which suggests that this "crossed flexor" plantar response reveals a transcortical pathway for the flexor plantar response. PMID- 28626414 TI - An Unusual Differential Diagnosis of Orbital Cavernous Hemangioma: Ancient Schwannoma. AB - Schwannomas are rare lesions of the orbit that can be confused with cavernous hemangioma on imaging studies. We report the case of an 84-year-old woman with a 9-year history of a tumoral lesion in the inferolateral left orbit. The imaging studies did not reveal specific characteristics, only bone remodeling due to the long evolution of the tumor. The patient underwent complete excision of the tumor by anterior orbitotomy via the inferior conjunctival fornix. The histopathological examination revealed an ancient schwannoma, a variant of schwannoma with uncommon histological features. The follow-up was uneventful. The present case emphasizes the importance of considering neural tumors in the differential diagnosis of orbital masses with bone changes and degenerative alterations such as hemorrhagic areas, cysts, and/or calcifications. PMID- 28626415 TI - A Case of Childhood-Onset Giant Cell Tumor that Caused Optic Nerve Atrophy in Both Eyes. AB - PURPOSE: The purpose of this study was to report the case of a female patient who had a giant cell tumor in the paranasal sinus during childhood, and while undergoing multiple resection surgeries experienced optic atrophy in both eyes. CASE PRESENTATION: This study involved a 35-year-old woman who was previously diagnosed with a giant cell tumor of the paranasal sinus bone at age 13. A CT scan revealed a large tumor extending from the sphenoid sinus to the ethmoid sinus. At age 14, a tumor resection was performed in conjunction with radiation therapy. However, after resection and radiation therapy there were repeated recurrences, and additional resections were performed. Ophthalmically, there was marked optical atrophy in both eyes, and Goldmann visual field perimetry revealed that only the arcuate peripheral area remained on the nasal side of the right eye, and that there were dark spots in the paracentral area of the left eye. CONCLUSIONS: In this case, a large giant cell tumor occurred in the sphenoid sinus and ethmoid sinus during childhood, and it is thought that optic atrophy was caused by compressive optic neuropathy. The sphenoid sinus and ethmoid sinuses are anatomically close to the optic nerve, and when a tumor grows larger at this site it can easily put pressure on the optic nerve. Therefore, early detection and treatment are important. PMID- 28626416 TI - Multiquadrant Subtenon Triamcinolone Injection for Acute Corneal Graft Rejection: A Case Report. AB - BACKGROUND: We report a case of reversal of an acute corneal graft rejection following multiquadrant subtenon triamcinolone injection. CASE PRESENTATION: A 19 year-old woman who had acute corneal graft rejection failed to show resolution of the graft rejection after standard treatment with systemic, intravenous, and topical steroids. The graft rejection, however, responded to injection of triamcinolone in multiple subtenon quadrants. CONCLUSIONS: For corneal graft rejection, multiquadrant subtenon triamcinolone injections may be a safe adjunct to systemic treatment. PMID- 28626417 TI - Spironolactone as an Adjunctive Treatment in Neovascular Age-Related Macular Degeneration. AB - Neovascular age-related macular degeneration (AMD) is a potentially sight threatening condition. The current standard-of-care treatment regimen is serial intravitreal antivascular endothelial growth factor injections. While these typically have great success, they do carry exceptional treatment burden on the patient, cost burden due to their required frequency of use, and the risk of endophthalmitis, which can be devastating. This case report explores an alternative potential option as a treatment adjunct for neovascular AMD (nAMD), and identifies some of the overlap between nAMD and central serous chorioretionpathy. Future research is needed to better understand the role of mineralocorticoid receptor antagonist treatment in this disease spectrum. PMID- 28626418 TI - Rapid Cataract Progression after Nd:YAG Vitreolysis for Vitreous Floaters: A Case Report and Literature Review. AB - PURPOSE: We report a case of rapid cataract progression after Nd:YAG vitreolysis for vitreous floaters. CASE REPORT: A 55-year-old man presented with acute onset of blurred vision following Nd:YAG vitreolysis for symptomatic floaters in the left eye. His initial best corrected visual acuity (BCVA) was 20/1,000 in the left eye. Ocular examinations showed frost-like opacities of the lens and a suspected break of the posterior capsule in the left eye. There were no detectable retinal lesions. Cataract surgery was then arranged. Posterior capsular rupture and vitreous loss occurred during surgery, which required a subsequent pars plana vitrectomy. After the surgery, BCVA in the left eye gradually improved to 20/20 and was maintained during a 1-year follow-up period. CONCLUSION: Crystalline lens injuries and rapid cataract progression may occur following Nd:YAG vitreolysis. While dealing with this type of complicated cataract, clinicians should be aware of the possibility of posterior lens capsule rupture during surgery and the need for combined vitrectomy. PMID- 28626419 TI - Shallow Anterior Chamber in a Severe Case of Unilateral Acute Central Serous Retinal Detachment. AB - BACKGROUND: Atypical serous chorioretinopathy can present with symptoms similar to those of other pachychoroid diseases; however, a proper differential diagnosis will prevent unnecessary intensive treatments. To this end, we report on the shallowness of anterior chamber and transitory anterior vitreous cells in a patient with atypical severe serous retinal detachment. CASE PRESENTATION: A 42 year-old woman presented with unilateral visual loss accompanied by mild, vague eye pain for 4 days. Spectral-domain OCT scans of the left eye showed macular and peripapillary serous detachment. Optical biometry showed the clinically significant shallow anterior chamber. CONCLUSIONS: Severe central serous chorioretinopathy can show up in an atypical fashion with macular, extramacular, juxtapapillary serous detachments, temporary existence of anterior vitreous cells, clinically detectable decreased anterior chamber depth, and mild eye pain of short duration. PMID- 28626421 TI - Divergent Metabolic Regulation of Autophagy and mTORC1-Early Events in Alzheimer's Disease? AB - Alzheimer's disease (AD) is a progressive disease associated with the production and deposition of amyloid beta-peptide (Abeta) aggregates and neurofibrillary tangles, which lead to synaptic and neuronal damage. Reduced autophagic flux has been widely associated with the accumulation of autophagic vacuoles (AV), which has been proposed to contribute to aggregate build-up observed in AD. As such, targeting autophagy regulation has received wide review, where an understanding as to how this mechanism can be controlled will be important to neuronal health. The mammalian target of rapamycin complex 1 (mTORC1), which was found to be hyperactive in AD brain, regulates autophagy and is considered to be mechanistically important to aberrant autophagy in AD. Hormones and nutrients such as insulin and leucine, respectively, positively regulate mTORC1 activation and are largely considered to inhibit autophagy. However, in AD brain there is a dysregulation of nutrient metabolism, linked to insulin resistance, where a role for insulin treatment to improve cognition has been proposed. Recent studies have highlighted that mitochondrial proteins such as glutamate dehydrogenase and the human branched chain aminotransferase protein, through metabolism of leucine and glutamate, differentially regulate mTORC1 and autophagy. As the levels of the hBCAT proteins are significantly increased in AD brain relative to aged-matched controls, we discuss how these metabolic pathways offer new potential therapeutic targets. In this review article, we highlight the core regulation of autophagy through mTORC1, focusing on how insulin and leucine will be important to consider in particular with respect to our understanding of nutrient load and AD pathogenesis. PMID- 28626420 TI - Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management. AB - Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and alpha2delta agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered. PMID- 28626423 TI - Ubiquitin-Proteasome-Collagen (CUP) Pathway in Preterm Premature Rupture of Fetal Membranes. AB - Spontaneous preterm birth (sPTB) occurs before 37 gestational weeks, with preterm premature rupture of the membranes (PPROM) and spontaneous preterm labor (sPTL) as the predominant adverse outcomes. Previously, we identified altered expression of long non-coding RNAs (lncRNAs) and message RNAs (mRNAs) related to the ubiquitin proteasome system (UPS) in human placentas following pregnancy loss and PTB. We therefore hypothesized that similar mechanisms might underlie PPROM. In the current study, nine pairs of ubiquitin-proteasome-collagen (CUP) pathway related mRNAs and associated lncRNAs were found to be differentially expressed in PPROM and sPTL. Pathway analysis showed that the functions of their protein products were inter-connected by ring finger protein. Twenty variants including five mutations were identified in CUP-related genes in sPTL samples. Copy number variations were found in COL19A1, COL28A1, COL5A1, and UBAP2 of sPTL samples. The results reinforced our previous findings and indicated the association of the CUP pathway with the development of sPTL and PPROM. This association was due not only to the genetic variation, but also to the epigenetic regulatory function of lncRNAs. Furthermore, the findings suggested that the loss of collagen content in PPROM could result from degradation and/or suppressed expression of collagens. PMID- 28626424 TI - Relationship of Mycotoxins Accumulation and Bioactive Components Variation in Ginger after Fungal Inoculation. AB - Ginger has got increasing worldwide interests due to its extensive biological activities, along with high medical and edible values. But fungal contamination and mycotoxin residues have brought challenges to its quality and safety. In the present study, the relationship of content of mycotoxins accumulation and bioactive components variation in ginger after infection by toxigenic fungi were investigated for the first time to elucidate the influence of fungal contamination on the inherent quality of ginger. After being infected by Aspergillus flavus and Aspergillus carbonarius for different periods, the produced mycotoxins was determined by an immunoaffinity column clean-up based ultra-fast liquid chromatography coupled with tandem mass spectrometry, and the main bioactive components in ginger were analyzed by ultra performance liquid chromatography-photodiode array detection. The results showed that consecutive incubation of ginger with A. flavus and A. carbonarius within 20 days resulted in the production and accumulation of aflatoxins (especially AFB1) and ochratoxin A, as well as the constant content reduction of four bioactive components, which were confirmed through the scanning electron microscope images. Significantly negative correlation was expressed between the mycotoxins accumulation and bioactive components variation in ginger, which might influence the quality and safety of it. Furthermore, a new compound was detected after inoculation for 6 days, which was found in our study for the first time. PMID- 28626422 TI - Sphingosine 1-Phosphate Receptors: Do They Have a Therapeutic Potential in Cardiac Fibrosis? AB - Sphingosine 1-phosphate (S1P) is a bioactive lipid that is characterized by a peculiar mechanism of action. In fact, S1P, which is produced inside the cell, can act as an intracellular mediator, whereas after its export outside the cell, it can act as ligand of specific G-protein coupled receptors, which were initially named endothelial differentiation gene (Edg) and eventually renamed sphingosine 1-phosphate receptors (S1PRs). Among the five S1PR subtypes, S1PR1, S1PR2 and S1PR3 isoforms show broad tissue gene expression, while S1PR4 is primarily expressed in immune system cells, and S1PR5 is expressed in the central nervous system. There is accumulating evidence for the important role of S1P as a mediator of many processes, such as angiogenesis, carcinogenesis and immunity, and, ultimately, fibrosis. After a tissue injury, the imbalance between the production of extracellular matrix (ECM) and its degradation, which occurs due to chronic inflammatory conditions, leads to an accumulation of ECM and, consequential, organ dysfunction. In these pathological conditions, many factors have been described to act as pro- and anti-fibrotic agents, including S1P. This bioactive lipid exhibits both pro- and anti-fibrotic effects, depending on its site of action. In this review, after a brief description of sphingolipid metabolism and signaling, we emphasize the involvement of the S1P/S1PR axis and the downstream signaling pathways in the development of fibrosis. The current knowledge of the therapeutic potential of S1PR subtype modulators in the treatment of the cardiac functions and fibrinogenesis are also examined. PMID- 28626425 TI - Lemons, or Squeezed for Resources? Information Symmetry and Asymmetric Resources in Biotechnology. AB - Thousands of biotech companies are developing promising products, but have insufficient resources to complete the clinical testing process, while large, well-funded companies have increasingly focused on the need to access external innovation. As a result, licensing deals are an essential and growing part of this industry. Yet, casting a shadow over the licensing market is the classic Lemons Problem: Does asymmetrical information put licensees at a severe disadvantage, leading to a market dominated by inferior opportunities, with the best products retained for internal development? Our analysis of clinical stage products developed over three decades shows that there is no Lemons Problem. We discuss the results of this first apples-to-apples analysis of the biomedical licensing market, and suggest reasons why the Lemons Problem does not exist where it might be most expected-in a high technology, knowledge-based industry. PMID- 28626427 TI - Distinctive Steady-State Heart Rate and Blood Pressure Responses to Passive Robotic Leg Exercise during Head-Up Tilt: A Pilot Study in Neurological Patients. AB - Introduction: Robot-assisted tilt table therapy was proposed for early rehabilitation and mobilization of patients after diseases such as stroke. A robot-assisted tilt table with integrated passive robotic leg exercise (PE) mechanism has the potential to prevent orthostatic hypotension usually provoked by verticalization. In a previous study with rather young healthy subjects [average age: 25.1 +/- 2.6 years (standard deviation)], we found that PE effect on the cardiovascular system depends on the verticalization angle of the robot assisted tilt table. In the current study, we investigated in an older population of neurological patients (a) whether they show the same PE effects as younger healthy population on the cardiovascular system at different tilt angles, (b) whether changing the PE frequency (i.e., stepping speed) influences the PE effect on the cardiovascular system, (c) whether PE could prevent orthostatic hypotension, and finally, (d) whether PE effect is consistent from day to day. Methods: Heart rate (HR), and systolic and diastolic blood pressures (sBP, dBP) in response to PE at two different tilt angles (alpha = 20 degrees , 60 degrees ) with three different PE frequencies (i.e., 0, 24, and 48 steps per minute) of 10 neurological patients [average age: 68.4 +/- 13.5 years (standard deviation)] were measured on 2 consecutive days. Linear mixed models were used to develop statistical models and analyze the repeated measurements. Results: The models show that: PE significantly increased sBP and dBP but had no significant effect on HR. (a) Similar to healthy subjects the effect of PE on sBP was dependent on the tilt angle with higher tilt angles resulting in a higher increase. Head-up tilting alone significantly increased HR and dBP but resulted in a non significant drop in sBP. PE, in general, had a more additive effect on increasing BP. (b) The effect of PE was not influenced by its speed. (c) Neither during head up tilt alone nor in combination with PE did participants experience orthostatic hypotension. (d) The measurement day was not a statistically significant factor regarding the effects of verticalization and PE on the cardiovascular response. Conclusion: We provide evidence that PE can increase steady-state values of sBP and dBP in neurological patients during head-up tilt. Similar to healthy subjects the effect on sBP depends on the verticalization angle of the robot-assisted tilt table. PE might have the potential to prevent orthostatic hypotension, but as the amount of drop in BP in response to head-up tilting was not leading to orthostatic hypotension in our patients, we could neither conclude nor reject such a preventive compensatory effect. Furthermore, we found that changing the PE speed does not influence the steady-state cardiovascular response. PMID- 28626426 TI - Potential of Central, Eastern and Western Africa Medicinal Plants for Cancer Therapy: Spotlight on Resistant Cells and Molecular Targets. AB - Cancer remains a major health hurdle worldwide and has moved from the third leading cause of death in the year 1990 to second place after cardiovascular disease since 2013. Chemotherapy is one of the most widely used treatment modes; however, its efficiency is limited due to the resistance of cancer cells to cytotoxic agents. The present overview deals with the potential of the flora of Central, Eastern and Western African (CEWA) regions as resource for anticancer drug discovery. It also reviews the molecular targets of phytochemicals of these plants such as ABC transporters, namely P-glycoprotein (P-gp), multi drug resistance-related proteins (MRPs), breast cancer resistance protein (BCRP, ABCG2) as well as the epidermal growth factor receptor (EGFR/ErbB-1/HER1), human tumor suppressor protein p53, caspases, mitochondria, angiogenesis, and components of MAP kinase signaling pathways. Plants with the ability to preferentially kills resistant cancer cells were also reported. Data compiled in the present document were retrieved from scientific websites such as PubMed, Scopus, Sciencedirect, Web-of-Science, and Scholar Google. In summary, plant extracts from CEWA and isolated compounds thereof exert cytotoxic effects by several modes of action including caspases activation, alteration of mitochondrial membrane potential (MMP), induction of reactive oxygen species (ROS) in cancer cells and inhibition of angiogenesis. Ten strongest cytotoxic plants from CEWA recorded following in vitro screening assays are: Beilschmiedia acuta Kosterm, Echinops giganteus var. lelyi (C. D. Adams) A. Rich., Erythrina sigmoidea Hua (Fabaceae), Imperata cylindrical Beauv. var. koenigii Durand et Schinz, Nauclea pobeguinii (Pobeg. ex Pellegr.) Merr. ex E.M.A., Piper capense L.f., Polyscias fulva (Hiern) Harms., Uapaca togoensis Pax., Vepris soyauxii Engl. and Xylopia aethiopica (Dunal) A. Rich. Prominent antiproliferative compounds include: isoquinoline alkaloid isotetrandrine (51), two benzophenones: guttiferone E (26) and isoxanthochymol (30), the isoflavonoid 6alpha hydroxyphaseollidin (9), the naphthyl butenone guieranone A (25), two naphthoquinones: 2-acetylfuro-1,4-naphthoquinone (4) and plumbagin (37) and xanthone V1 (46). However, only few research activities in the African continent focus on cytotoxic drug discovery from botanicals. The present review is expected to stimulate further scientific efforts to better valorize the African flora. PMID- 28626428 TI - Molecular Surgery Concept from Bench to Bedside: A Focus on TRPV1+ Pain-Sensing Neurons. AB - "Molecular neurosurgery" is emerging as a new medical concept, and is the combination of two partners: (i) a molecular neurosurgery agent, and (ii) the cognate receptor whose activation results in the selective elimination of a specific subset of neurons in which this receptor is endogenously expressed. In general, a molecular surgery agent is a selective and potent ligand, and the target is a specific cell type whose elimination is desired through the molecular surgery procedure. These target cells have the highest innate sensitivity to the molecular surgery agent usually due to the highest receptor density being in their plasma membrane. The interaction between the ligand and its receptor evokes an overactivity of the receptor. If the receptor is a ligand-activated non selective cation channel, the overactivity of receptor leads to excess Ca2+ and Na+ influx into the cell and finally cell death. One of the best known examples of such an interaction is the effect of ultrapotent vanilloids on TRPV1 expressing pain-sensing neurons. One intrathecal resiniferatoxin (RTX) dose allows for the receptor-mediated removal of TRPV1+ neurons from the peripheral nervous system. The TRPV1 receptor-mediated ion influx induces necrotic processes, but only in pain-sensing neurons, and usually within an hour. Besides that, target-specific apoptotic processes are also induced. Thus, as a nano surgery scalpel, RTX removes the neurons responsible for generating pain and inflammation from the peripheral nervous system providing an option in clinical management for the treatment of morphine-insensitive pain conditions. In the future, the molecular surgery concept can also be exploited in cancer research for selectively targeting the specific tumor cell. PMID- 28626430 TI - Behavior Patterns of Antisocial Teenagers Interacting with Parents and Peers: A Longitudinal Study. AB - Antisocial behavior may begin during childhood and if maintained during adolescence, is likely to continue and escalate during adulthood. During adolescence, in particular, it has been established that antisocial behavior may be reinforced and shaped by exchanges between the teenager and his parents and peers, although the molecular process of these relations is as yet unknown. This paper explores the patterns of social interaction established by adolescents with and without the risk of engaging in antisocial behavior in order to understand the exchanges of them with their most important social groups, during 2 years. The study involved a sample of 70 adolescents classified into these two groups (with risk of antisocial behavior and control group). They were video-recorded interacting with one of their parents and one of their peers, independently. The interaction was done about the negotiation of conflictive conversational topics. Those video-records were registered by pairs of trained observers, using an observational catalog with nineteen behavioral categories, to know about the molecular interactional patterns characteristics. Thirty participants were evaluated only once, 30 were evaluated two times, and the other 10 were evaluated three times, the evaluations were performed annually. It was found that a higher occurrence of eye contact and use of open questions and elaborate answers appears to act as a protective factor for engaging in antisocial behavior. PMID- 28626429 TI - The Potential for Circulating Tumor Cells in Pancreatic Cancer Management. AB - Pancreatic cancer is one the most lethal malignancies. Only a small proportion of patients with this disease benefit from surgery. Chemotherapy provides only a transient benefit. Though much effort has gone into finding new ways for early diagnosis and treatment, average patient survival has only been improved in the order of months. Circulating tumor cells (CTCs) are shed from primary tumors, including pre-malignant phases. These cells possess information about the genomic characteristics of their tumor source in situ, and their detection and characterization holds potential in early cancer diagnosis, prognosis, and treatment. Liquid Biopsies present an alternative to tumor biopsy that are hard to sample. Below we summarize current methods of CTC detection, the current literature on CTCs in pancreatic cancer, and future perspectives. PMID- 28626431 TI - Artificial Intelligence-Assisted Online Social Therapy for Youth Mental Health. AB - Introduction: Benefits from mental health early interventions may not be sustained over time, and longer-term intervention programs may be required to maintain early clinical gains. However, due to the high intensity of face-to-face early intervention treatments, this may not be feasible. Adjunctive internet based interventions specifically designed for youth may provide a cost-effective and engaging alternative to prevent loss of intervention benefits. However, until now online interventions have relied on human moderators to deliver therapeutic content. More sophisticated models responsive to user data are critical to inform tailored online therapy. Thus, integration of user experience with a sophisticated and cutting-edge technology to deliver content is necessary to redefine online interventions in youth mental health. This paper discusses the development of the moderated online social therapy (MOST) web application, which provides an interactive social media-based platform for recovery in mental health. We provide an overview of the system's main features and discus our current work regarding the incorporation of advanced computational and artificial intelligence methods to enhance user engagement and improve the discovery and delivery of therapy content. Methods: Our case study is the ongoing Horyzons site (5-year randomized controlled trial for youth recovering from early psychosis), which is powered by MOST. We outline the motivation underlying the project and the web application's foundational features and interface. We discuss system innovations, including the incorporation of pertinent usage patterns as well as identifying certain limitations of the system. This leads to our current motivations and focus on using computational and artificial intelligence methods to enhance user engagement, and to further improve the system with novel mechanisms for the delivery of therapy content to users. In particular, we cover our usage of natural language analysis and chatbot technologies as strategies to tailor interventions and scale up the system. Conclusions: To date, the innovative MOST system has demonstrated viability in a series of clinical research trials. Given the data-driven opportunities afforded by the software system, observed usage patterns, and the aim to deploy it on a greater scale, an important next step in its evolution is the incorporation of advanced and automated content delivery mechanisms. PMID- 28626432 TI - Visible Social Interactions Do Not Support the Development of False Belief Understanding in the Absence of Linguistic Input: Evidence from Deaf Adult Homesigners. AB - Congenitally deaf individuals exhibit enhanced visuospatial abilities relative to normally hearing individuals. An early example is the increased sensitivity of deaf signers to stimuli in the visual periphery (Neville and Lawson, 1987a). While these enhancements are robust and extend across a number of visual and spatial skills, they seem not to extend to other domains which could potentially build on these enhancements. For example, congenitally deaf children, in the absence of adequate language exposure and acquisition, do not develop typical social cognition skills as measured by traditional Theory of Mind tasks. These delays/deficits occur despite their presumed lifetime use of visuo-perceptual abilities to infer the intentions and behaviors of others (e.g., Pyers and Senghas, 2009; O'Reilly et al., 2014). In a series of studies, we explore the limits on the plasticity of visually based socio-cognitive abilities, from perspective taking to Theory of Mind/False Belief, in rarely studied individuals: deaf adults who have not acquired a conventional language (Homesigners). We compared Homesigners' performance to that of two other understudied groups in the same culture: Deaf signers of an emerging language (Cohort 1 of Nicaraguan Sign Language), and hearing speakers of Spanish with minimal schooling. We found that homesigners performed equivalently to both comparison groups with respect to several visual socio-cognitive abilities: Perspective Taking (Levels 1 and 2), adapted from Masangkay et al. (1974), and the False Photograph task, adapted from Leslie and Thaiss (1992). However, a lifetime of visuo-perceptual experiences (observing the behavior and interactions of others) did not support success on False Belief tasks, even when linguistic demands were minimized. Participants in the comparison groups outperformed the Homesigners, but did not universally pass the False Belief tasks. Our results suggest that while some of the social development achievements of young typically developing children may be dissociable from their linguistic experiences, language and/or educational experiences clearly scaffolds the transition into False Belief understanding. The lack of experience using a shared language cannot be overcome, even with the benefit of many years of observing others' behaviors and the potential neural reorganization and visuospatial enhancements resulting from deafness. PMID- 28626433 TI - War or Peace? How the Subjective Perception of Great Power Interdependence Shapes Preemptive Defensive Aggression. AB - Why do great powers with benign intentions end up fighting each other in wars they do not seek? We utilize an incentivized, two-person "Preemptive Strike Game" (PSG) to explore how the subjective perception of great power interdependence shapes defensive aggression against persons from rival great powers. In Study 1, college students from the United States (N = 115), China (N = 106), and Japan (N = 99) made PSG decisions facing each other. This natural experiment revealed that Chinese and Japanese participants (a) made more preemptive attacks against each other and Americans than against their compatriots, and that (b) greater preexisting perceptions of bilateral competition increased intergroup attack rates. In Study 2, adult Americans (N = 127) watched real CNN expert interviews portraying United States-China economic interdependence as more positive or negative. This randomized experiment revealed that the more positive portrayal reduced preemptive American strikes against Chinese (but not Japanese), while the more negative portrayal amplified American anger about China's rise, increasing preemptive attacks against Chinese. We also found, however, that preemptive strikes were primarily defensive and not offensive. Interventions to reduce defensive aggression and promote great power peace are discussed. PMID- 28626434 TI - The Effect of Diaphragmatic Breathing on Attention, Negative Affect and Stress in Healthy Adults. AB - A growing number of empirical studies have revealed that diaphragmatic breathing may trigger body relaxation responses and benefit both physical and mental health. However, the specific benefits of diaphragmatic breathing on mental health remain largely unknown. The present study aimed to investigate the effect of diaphragmatic breathing on cognition, affect, and cortisol responses to stress. Forty participants were randomly assigned to either a breathing intervention group (BIG) or a control group (CG). The BIG received intensive training for 20 sessions, implemented over 8 weeks, employing a real-time feedback device, and an average respiratory rate of 4 breaths/min, while the CG did not receive this treatment. All participants completed pre- and post-tests of sustained attention and affect. Additionally, pre-test and post-test salivary cortisol concentrations were determined in both groups. The findings suggested that the BIG showed a significant decrease in negative affect after intervention, compared to baseline. In the diaphragmatic breathing condition, there was a significant interaction effect of group by time on sustained attention, whereby the BIG showed significantly increased sustained attention after training, compared to baseline. There was a significant interaction effect of group and time in the diaphragmatic breathing condition on cortisol levels, whereby the BIG had a significantly lower cortisol level after training, while the CG showed no significant change in cortisol levels. In conclusion, diaphragmatic breathing could improve sustained attention, affect, and cortisol levels. This study provided evidence demonstrating the effect of diaphragmatic breathing, a mind body practice, on mental function, from a health psychology approach, which has important implications for health promotion in healthy individuals. PMID- 28626435 TI - Reproducibility in Psychological Science: When Do Psychological Phenomena Exist? AB - Scientific evidence has recently been used to assert that certain psychological phenomena do not exist. Such claims, however, cannot be made because (1) scientific method itself is seriously limited (i.e., it can never prove a negative); (2) non-existence of phenomena would require a complete absence of both logical (theoretical) and empirical support; even if empirical support is weak, logical and theoretical support can be strong; (3) statistical data are only one piece of evidence and cannot be used to reduce psychological phenomena to statistical phenomena; and (4) psychological phenomena vary across time, situations and persons. The human mind is unreproducible from one situation to another. Psychological phenomena are not particles that can decisively be tested and discovered. Therefore, a declaration that a phenomenon is not real is not only theoretically and empirically unjustified but runs counter to the propositional and provisional nature of scientific knowledge. There are only "temporary winners" and no "final truths" in scientific knowledge. Psychology is a science of subtleties in human affect, cognition and behavior. Its phenomena fluctuate with conditions and may sometimes be difficult to detect and reproduce empirically. When strictly applied, reproducibility is an overstated and even questionable concept in psychological science. Furthermore, statistical measures (e.g., effect size) are poor indicators of the theoretical importance and relevance of phenomena (cf. "deliberate practice" vs. "talent" in expert performance), not to mention whether phenomena are real or unreal. To better understand psychological phenomena, their theoretical and empirical properties should be examined via multiple parameters and criteria. Ten such parameters are suggested. PMID- 28626436 TI - Judgments at Gaze Value: Gaze Cuing in Banner Advertisements, Its Effect on Attention Allocation and Product Judgments. AB - Banner advertising is a popular means of promoting products and brands online. Although banner advertisements are often designed to be particularly attention grabbing, they frequently go unnoticed. Applying an eye-tracking procedure, the present research aimed to (a) determine whether presenting human faces (static or animated) in banner advertisements is an adequate tool for capturing consumers' attention and thus overcoming the frequently observed phenomenon of banner blindness, (b) to examine whether the gaze of a featured face possesses the ability to direct consumers' attention toward specific elements (i.e., the product) in an advertisement, and (c) to establish whether the gaze direction of an advertised face influences consumers subsequent evaluation of the advertised product. We recorded participants' eye gaze while they viewed a fictional online shopping page displaying banner advertisements that featured either no human face or a human face that was either static or animated and involved different gaze directions (toward or away from the advertised product). Moreover, we asked participants to subsequently evaluate a set of products, one of which was the product previously featured in the banner advertisement. Results showed that, when advertisements included a human face, participants' attention was more attracted by and they looked longer at animated compared with static banner advertisements. Moreover, when a face gazed toward the product region, participants' likelihood of looking at the advertised product increased regardless of whether the face was animated or not. Most important, gaze direction influenced subsequent product evaluations; that is, consumers indicated a higher intention to buy a product when it was previously presented in a banner advertisement that featured a face that gazed toward the product. The results suggest that while animation in banner advertising constitutes a salient feature that captures consumers' visual attention, gaze cuing can be an effective tool for driving viewers' attention toward specific elements in the advertisement and even shaping consumers' intentions to purchase the advertised product. PMID- 28626437 TI - Counter-Stereotypes and Feminism Promote Leadership Aspirations in Highly Identified Women. AB - Although women who highly identify with other women are more susceptible to stereotype threat effects, women's identification might associate with greater leadership aspirations contingent on (1) counter-stereotype salience and (2) feminist identification. When gender counter-stereotypes are salient, women's identification should associate with greater leadership aspiration regardless of feminism, while when gender stereotypes are salient, women's identification would predict greater leadership aspirations contingent on a high level of feminist identification. In our study US-based women (N = 208) attended to gender stereotypic (vs. counter-stereotypic) content. We measured identification with women and identification with feminism, and, following the manipulation, leadership aspirations in an imagined work scenario. The interaction between identification with women, identification with feminism, and attention to stereotypes (vs. counter-stereotypes) significantly predicted leadership aspirations. In the counter-stereotypic condition women's identification associated with greater leadership aspirations regardless of feminist identification. In the stereotypic condition women's identification predicted leadership aspirations only at high levels of feminist identification. We conclude that salient counter-stereotypes and a strong identification with feminism may help high women identifiers increase their leadership aspirations. PMID- 28626438 TI - Sensitivity to Stroke Emerges in Kindergartners Reading Chinese Script. AB - To what extent are young children sensitive to individual stroke, the smallest unit of writing in Chinese that carries no phonological or semantic information? The present study examined Chinese kindergartners' sensitivity to stroke and the contribution of reading ability and age to stroke sensitivity. Fifty five children from Beijing, including 28 4-year-olds (Mage = 4.55 years, SD = 0.28, 16 males) and 29 5-year-olds (Mage = 5.58 years, SD = 0.30, 14 males), were administered an orthographic matching task and assessed on non-verbal IQ and Chinese word reading. In the orthographic matching task, children were asked to decide whether two items were exactly the same or different in three conditions, with stimuli being correctly written characters (e.g., ""), stroke-missing or redundant characters (e.g., ""), and Tibetan alphabets (e.g., ""), respectively. The stimuli were presented with E-prime 2.0 software and were displayed on a Surface Pro. Children responded by touching the screen and reaction time was used as a measure of processing efficiency. The 5-year-olds but not the 4-year-olds processed correctly written characters more efficiently than stroke missing/redundant characters, suggesting emergence of stroke sensitivity from age 5. The 4- and 5-year-olds both processed correctly written characters more efficiently than Tibetan alphabets, ruling out the possibility that the 5 year olds' sensitivity to stroke was due to the unusual look of the stimuli. Hierarchical regression analyses showed that Chinese word reading explained 10% additional variance in stroke sensitivity after having statistically controlled for age. Age did not account for additional variance in stroke sensitivity after having considered Chinese word reading. Taken together, findings of this study revealed that despite the visually highly complex nature of Chinese and the fact that individual stroke carries no phonological or semantic information, children develop sensitivity to stroke from age 5 and such sensitivity is significantly associated with reading experience. PMID- 28626439 TI - Attentive Observation Is Essential for the Misattribution of Agency to Self Performance. AB - Recent studies have repeatedly demonstrated a false memory phenomenon in which people falsely remember having performed an action by oneself when in fact they have only observed the action by another person. We investigated the attentional effect to the action itself on the observation inflation. Fifty-four participants first performed and read actions (Phase 1); then, they observed the action video that showed another's actions (Phase 2), some of which they had not performed in Phase 1. In the Phase 2, they were required to focus on either the actor's performance (i.e., attentive observation condition) or irrelevant objects, which were presented in the background (i.e., inattentive observation condition) to modulate their attention. Around 2 weeks later, participants took a surprise source-memory test (Phase 3). In this phase, we asked them to judge whether they "performed," "read," or "not presented" the action in Phase 1. Three participants were removed from analysis, because they could not attend Phase 3 within 10-16 days after completion of the second phase. We found observation inflation only in the attentive condition, which contradicted the notions from other false memory studies that showed that attention to the target stimuli reduced false memory in general. We discussed the observation inflation mechanism from the perspective of the "like me" system, including the mirror neuron system, self-ownership, and self-agency. PMID- 28626440 TI - Executive Function in Adolescence: Associations with Child and Family Risk Factors and Self-Regulation in Early Childhood. AB - Executive functions are important higher-order cognitive skills for goal-directed thought and action. These capacities contribute to successful school achievement and lifelong wellbeing. The importance of executive functions to children's education begins in early childhood and continues throughout development. This study explores contributions of child and family factors in early childhood to the development of executive function in adolescence. Analyses draw on data from the nationally representative study, Growing up in Australia: The Longitudinal Study of Australian Children. Participants are 4819 children in the Kindergarten Cohort who were recruited at age 4-5 years. Path analyses were employed to examine contributions of early childhood factors, including family socio-economic position (SEP), parenting behaviors, maternal mental health, and a child behavioral risk index, to the development of executive function in adolescence. The influence of children's early self-regulatory behaviors (attentional regulation at 4-5 years and approaches to learning at 6-7 years) were also taken into account. A composite score for the outcome measure of executive function was constructed from scores on three Cogstate computerized tasks for assessing cognition and measured visual attention, visual working memory, and spatial problem-solving. Covariates included child gender, age at assessment of executive function, Aboriginal and Torres Strait Islander status, speaking a language other than English at home, and child's receptive vocabulary skills. There were significant indirect effects involving child and family risk factors measured at 4-5 years on executive function at age 14-15 years, mediated by measures of self regulatory behavior. Child behavioral risk, family SEP and parenting behaviors (anger, warmth, and consistency) were associated with attentional regulation at 4 5 years which, in turn, was significantly associated with approaches to learning at 6-7 years. Both attentional regulation and approaches to learning were directly associated with executive functioning at 14-15 years. These findings suggest that children's early self-regulatory capacities are the basis for later development of executive function in adolescence when capabilities for planning and problem-solving are important to achieving educational goals. PMID- 28626441 TI - Teaching Improvisation through Processes. Applications in Music Education and Implications for General Education. AB - Improvisation is an articulated multidimensional activity based on an extemporaneous creative performance. Practicing improvisation, participants expand sophisticated skills such as sensory and perceptual encoding, memory storage and recall, motor control, and performance monitoring. Improvisation abilities have been developed following several methodologies mainly with a product-oriented perspective. A model framed under the socio-cultural theory of learning for designing didactic activities on processes instead of outcomes is presented in the current paper. The challenge is to overcome the mere instructional dimension of some practices of teaching improvisation by designing activities that stimulate self-regulated learning strategies in the students. In the article the present thesis is declined in three ways, concerning the following three possible areas of application: (1) high-level musical learning, (2) musical pedagogy with children, (3) general pedagogy. The applications in the music field focusing mainly on an expert's use of improvisation are discussed. The last section considers how these ideas should transcend music studies, presenting the benefits and the implications of improvisation activities for general learning. Moreover, the application of music education to the following cognitive processes are discussed: anticipation, use of repertoire, emotive communication, feedback and flow. These characteristics could be used to outline a pedagogical method for teaching music improvisation based on the development of reflection, reasoning, and meta-cognition. PMID- 28626442 TI - Influence of Cognitive Functioning on Age-Related Performance Declines in Visuospatial Sequence Learning. AB - Objectives: The aim of this study was to investigate how age-related performance differences in a visuospatial sequence learning task relate to age-related declines in cognitive functioning. Method: Cognitive functioning of 18 younger and 18 older participants was assessed using a standardized test battery. Participants then undertook a perceptual visuospatial sequence learning task. Various relationships between sequence learning and participants' cognitive functioning were examined through correlation and factor analysis. Results: Older participants exhibited significantly lower performance than their younger counterparts in the sequence learning task as well as in multiple cognitive functions. Factor analysis revealed two independent subsets of cognitive functions associated with performance in the sequence learning task, related to either the processing and storage of sequence information (first subset) or problem solving (second subset). Age-related declines were only found for the first subset of cognitive functions, which also explained a significant degree of the performance differences in the sequence learning task between age-groups. Discussion: The results suggest that age-related performance differences in perceptual visuospatial sequence learning can be explained by declines in the ability to process and store sequence information in older adults, while a set of cognitive functions related to problem solving mediates performance differences independent of age. PMID- 28626443 TI - Eye Movements Reveal Optimal Strategies for Analogical Reasoning. AB - Analogical reasoning refers to the process of drawing inferences on the basis of the relational similarity between two domains. Although this complex cognitive ability has been the focus of inquiry for many years, most models rely on measures that cannot capture individuals' thought processes moment by moment. In the present study, we used participants' eye movements to investigate reasoning strategies in real time while solving visual propositional analogy problems (A:B::C:D). We included both a semantic and a perceptual lure on every trial to determine how these types of distracting information influence reasoning strategies. Participants spent more time fixating the analogy terms and the target relative to the other response choices, and made more saccades between the A and B items than between any other items. Participants' eyes were initially drawn to perceptual lures when looking at response choices, but they nonetheless performed the task accurately. We used participants' gaze sequences to classify each trial as representing one of three classic analogy problem solving strategies and related strategy usage to analogical reasoning performance. A project-first strategy, in which participants first extrapolate the relation between the AB pair and then generalize that relation for the C item, was both the most commonly used strategy as well as the optimal strategy for solving visual analogy problems. These findings provide new insight into the role of strategic processing in analogical problem solving. PMID- 28626444 TI - Aging with Cerebral Small Vessel Disease and Dizziness: The Importance of Undiagnosed Peripheral Vestibular Disorders. AB - Recent studies showed a link between cerebral small vessel white matter disease (SVD) and dizziness: patients whose dizziness cannot be explained by vestibular disease show severe SVD and gait abnormalities; however, little is still known about how SVD can cause this symptom. The primary aim of this study is to examine the possible underlying causes of dizziness in neurovascular patients; this is in order to assess whether treatable causes could be routinely disregarded. A secondary aim is to possibly define a central oculomotor pattern induced per se by SVD. This could help the diagnosis of SVD-related dizziness. In this single blind prospective study, 60 patients referred to a neurovascular clinic because of dizziness and SVD on imaging were divided into an L-SVD and a H-SVD group (low and high SVD burden, respectively), and then blindly examined with vestibulometric tests. In H-SVD group, the percentage of unexplained dizziness reached 82.8%. There was a higher prevalence of peripheral vestibular abnormalities in the L-SVD patient group (51.6%) than in the H-SVD (17.2%; p = 0.012). We found no differences in central oculomotor findings between the two groups. Although oculomotricity does not show any consistent pattern, a severe SVD can directly represent a cause of dizziness. However, a patient with mild SVD is more likely to suffer by a peripheral vestibular disorder. Therefore, given the high incidence of vestibular disease in neurovascular or geriatric clinics, clinicians should be cautious when ascribing dizziness solely to the presence of SVD as easily treatable peripheral vestibular causes may be missed. PMID- 28626445 TI - Adverse Childhood Experiences Are Linked to Age of Onset and Reading Recognition in Multiple Sclerosis. AB - BACKGROUND: Adverse childhood experiences (ACEs) exert a psychological and physiological toll that increases risk of chronic conditions, poorer social functioning, and cognitive impairment in adulthood. OBJECTIVE: To investigate the relationship between childhood adversity and clinical disease features in multiple sclerosis (MS). METHODS: Sixty-seven participants with MS completed the ACE assessment and neuropsychological assessments as part of a larger clinical trial of cognitive remediation. RESULTS: Adverse childhood experience scores, a measure of exposure to adverse events in childhood, significantly predicted age of MS onset (r = -0.30, p = 0.04). ACEs were also linked to reading recognition (a proxy for premorbid IQ) (r = -0.25, p = 0.04). ACE scores were not related to age, current disability, or current level of cognitive impairment measured by the Symbol Digit Modalities Test (SDMT). CONCLUSION: Childhood adversity may increase the likelihood of earlier age of onset and poorer estimated premorbid IQ in MS. PMID- 28626446 TI - GnRH Induces ERK-Dependent Bleb Formation in Gonadotrope Cells, Involving Recruitment of Members of a GnRH Receptor-Associated Signalosome to the Blebs. AB - We have previously described a signaling complex (signalosome) associated with the GnRH receptor (GnRHR). We now report that GnRH induces bleb formation in the gonadotrope-derived LbetaT2 cells. The blebs appear within ~2 min at a turnover rate of ~2-3 blebs/min and last for at least 90 min. Formation of the blebs requires active ERK1/2 and RhoA-ROCK but not active c-Src. Although the following ligands stimulate ERK1/2 in LbetaT2 cells: EGF > GnRH > PMA > cyclic adenosine monophosphate (cAMP), they produced little or no effect on bleb formation as compared to the robust effect of GnRH (GnRH > PMA > cAMP > EGF), indicating that ERK1/2 is required but not sufficient for bleb formation possibly due to compartmentalization. Members of the above mentioned signalosome are recruited to the blebs, some during bleb formation (GnRHR, c-Src, ERK1/2, focal adhesion kinase, paxillin, and tubulin), and some during bleb retraction (vinculin), while F-actin decorates the blebs during retraction. Fluorescence intensity measurements for the above proteins across the cells showed higher intensity in the blebs vs. intracellular area. Moreover, GnRH induces blebs in primary cultures of rat pituitary cells and isolated mouse gonadotropes in an ERK1/2 dependent manner. The novel signalosome-bleb pathway suggests that as with the signalosome, the blebs are apparently involved in cell migration. Hence, we have extended the potential candidates which are involved in the blebs life cycle in general and for the GnRHR in particular. PMID- 28626447 TI - Autoimmune Thyroiditis and Glomerulopathies. AB - Autoimmune thyroiditis (AIT) is generally associated with hypothyroidism. It affects ~2% of the female population and 0.2% of the male population. The evidence of thyroid function- and thyroid autoantibody-unrelated microproteinuria in almost half of patients with AIT and sometimes heavy proteinuria as in the nephrotic syndrome point to a link of AIT with renal disease. The most common renal diseases observed in AIT are membranous nephropathy, membranoproliferative glomerulonephritis, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, and amyloidosis. Different hypotheses have been put forward regarding the relationship between AIT and glomerulopathies, and several potential mechanisms for this association have been considered. Glomerular deposition of immunocomplexes of thyroglobulin and autoantibodies as well as the impaired immune tolerance for megalin (a thyrotropin-regulated glycoprotein expressed on thyroid cells) are the most probable mechanisms. Cross-reactivity between antigens in the setting of genetic predisposition has been considered as a potential mechanism that links the described association between ANCA vasculitis and AIT. PMID- 28626448 TI - The Common Follicle-Stimulating Hormone Receptor (FSHR) Promoter Polymorphism FSHR -29G > A Affects Androgen Production in Normal Human Small Antral Follicles. AB - Follicle-stimulating hormone receptors (FSHRs) are almost exclusively expressed on granulosa cells, and FSH action is probably most clearly reflected in intrafollicular hormone milieu of antral follicles. Little is known about the possible effects of the common single nucleotide polymorphism (SNP) FSHR -29G > A (rs1394205) on hormonal conditions in humsan small antral follicles (hSAFs) obtained from women in the natural menstrual cycle. This study investigated the follicle fluid (FF) concentrations of anti-Mullerian hormone, estradiol, progesterone, androstenedione, and testosterone in hSAF in relation to the different genotypes of FSHR -29G > A. FF from 362 follicles was collected in 95 women undergoing fertility preservation, who did not suffer from a disease that directly affected ovarian function. The testosterone levels of the minor A/A genotype were significantly increased compared to the A/G and the G/G genotype. Furthermore, significantly reduced androstenedione levels were observed for the G/G genotype, as compared to the A/G genotype, while the other hormones did not show statistical significant differences. In conclusion, the androgen levels of hSAF were significantly elevated in the minor SNP genotype in the FSHR promoter polymorphism FSHR -29G > A. PMID- 28626449 TI - Characterization of Feruloyl Esterases Produced by the Four Lactobacillus Species: L. amylovorus, L. acidophilus, L. farciminis and L. fermentum, Isolated from Ensiled Corn Stover. AB - Lactic acid bacteria (LAB) play important roles in silage fermentation, which depends on the production of sufficient organic acids to inhibit the growth of undesirable microorganisms. However, LAB are not able to degrade cellulose and hemicellulose. Bacteria and fibrolytic enzymes are usually used as inoculants to improve the silage quality and digestibility. In the present study, we isolated four Lactobacillus strains (L. amylovorus CGMCC 11056, L. acidophilus CCTCC AB2010208, L. farciminis CCTCC AB2016237 and L. fermentum CCTCC AB2010204) with feruloyl esterase (FAE) activities from ensiled corn stover (CS) by a plate screening assay. The genes encoding FAEs were cloned and hetero-expressed in Escherichia coli. The optimal temperature and pH of these purified enzymes ranged from 45 to 50 degrees C and from 7.0 to 8.0, respectively. They could hydrolyze hydroxycinnamoyl esters in a substrate-specific manner when methyl ferulate, methyl caffeate, methyl rho-coumarate and methyl sinapinate were used as substrates. Moreover, these four FAEs were able to hydrolyze CS to release hydroxycinnamic acids. Furthermore, these strains could degrade hydroxycinnamic esters, and L. amylovorus CGMCC 11056 was the most efficient strain among these four isolates. These results provided a new target for the development of inoculants to improve silage quality and digestibility. PMID- 28626450 TI - Microbial Phosphorus Solubilization and Its Potential for Use in Sustainable Agriculture. AB - The use of excess conventional Phosphorus (P) fertilizers to improve agricultural productivity, in order to meet constantly increasing global food demand, potentially causes surface and ground water pollution, waterway eutrophication, soil fertility depletion, and accumulation of toxic elements such as high concentration of selenium (Se), arsenic (As) in the soil. Quite a number of soil microorganisms are capable of solubilizing/mineralizing insoluble soil phosphate to release soluble P and making it available to plants. These microorganisms improve the growth and yield of a wide variety of crops. Thus, inoculating seeds/crops/soil with Phosphate Solubilizing Microorganisms (PSM) is a promising strategy to improve world food production without causing any environmental hazard. Despite their great significance in soil fertility improvement, phosphorus-solubilizing microorganisms have yet to replace conventional chemical fertilizers in commercial agriculture. A better understanding of recent developments in PSM functional diversity, colonizing ability, mode of actions and judicious application should facilitate their use as reliable components of sustainable agricultural systems. In this review, we discussed various soil microorganisms that have the ability to solubilize phosphorus and hence have the potential to be used as bio fertilizers. The mechanisms of inorganic phosphate solubilization by PSM and the mechanisms of organic phosphorus mineralization are highlighted together with some factors that determine the success of this technology. Finally we provide some indications that the use of PSM will promote sustainable agriculture and conclude that this technology is ready for commercial exploitation in various regions worldwide. PMID- 28626451 TI - Dependency of B-1 Cells in the Maintenance of Splenic Interleukin-10 Producing Cells and Impairment of Macrophage Resistance in Visceral Leishmaniasis. AB - Visceral leishmaniasis is a neglected disease caused by Leishmania protozoa parasites transmitted by infected sand fly vectors. This disease represents the second in mortality among tropical infections and is associated to a profound immunosuppression state of the host. The hallmark of this infection-induced host immunodeviation is the characteristic high levels of the regulatory interleukin 10 (IL-10) cytokine. In the present study, we investigated the role of B-1 cells in the maintenance of splenic IL-10 levels that could interfere with resistance to parasite infection. Using an experimental murine infection model with Leishmania (L.) infantum chagasi we demonstrated an improved resistance of B-1 deficient BALB/XID mice to infection. BALB/XID mice developed a reduced splenomegaly with diminished splenic parasite burden and lower levels of IL-10 secretion of purified splenocytes at 30 days post-infection, as compared to BALB/c wild-type control mice. Interestingly, we found that resident peritoneal macrophages isolated from BALB/XID mice were more effective to control the parasite load in comparison to cells isolated from BALB/c wild-type mice. Our findings point to a role of B-1 cells in the host susceptibility to visceral leishmaniasis. PMID- 28626452 TI - Proteomic Differences between Developmental Stages of Toxoplasma gondii Revealed by iTRAQ-Based Quantitative Proteomics. AB - Toxoplasma gondii has a complex two-host life-cycle between intermediate host and definitive host. Understanding proteomic variations across the life-cycle stages of T. gondii may improve the understanding of molecular adaption mechanism of T. gondii across life-cycle stages, and should have implications for the development of new treatment and prevention interventions against T. gondii infection. Here, we utilized LC-MS/MS coupled with iTRAQ labeling technology to identify differentially expressed proteins (DEPs) specific to tachyzoite (T), bradyzoites containing cyst (C) and sporulated oocyst (O) stages of the cyst-forming T. gondii Prugniuad (Pru) strain. A total of 6285 proteins were identified in the three developmental stages of T. gondii. Our analysis also revealed 875, 656, and 538 DEPs in O vs. T, T vs. C, and C vs. O, respectively. The up- and down regulated proteins were analyzed by Gene Ontology enrichment, KEGG pathway and STRING analyses. Some virulence-related factors and ribosomal proteins exhibited distinct expression patterns across the life-cycle stages. The virulence factors expressed in sporulated oocysts and the number of up-regulated virulence factors in the cyst stage were about twice as many as in tachyzoites. Of the 79 ribosomal proteins identified in T. gondii, the number of up-regulated ribosomal proteins was 33 and 46 in sporulated oocysts and cysts, respectively, compared with tachyzoites. These results support the hypothesis that oocyst and cystic stages are able to adapt to adverse environmental conditions and selection pressures induced by the host's immune response, respectively. These findings have important implications for understanding of the developmental biology of T. gondii, which may facilitate the discovery of novel therapeutic targets to better control toxoplasmosis. PMID- 28626453 TI - Zinc Oxide Nanoparticles Influence Microflora in Ileal Digesta and Correlate Well with Blood Metabolites. AB - Zinc oxide nanoparticles (ZnO NPs) are used widely in consumer and industrial products, however, their influence on gut microbiota and metabolism and their mutual interactions are not fully understood. In this study, the effects of ZnO NPs on ileal bacterial communities, plasma metabolites, and correlations between them were investigated. Hens were fed with different concentrations of ZnO NPs [based on Zn; 0 mg/kg (control), 25 mg/kg, 50 mg/kg, and 100 mg/kg] for 9 weeks. Subsequently, ileal digesta and blood plasma were collected for analysis of microflora and metabolites, respectively. The V3-V4 region of the 16S rRNA gene of ileal digesta microbiota was sequenced using the Illumina HiSeq 2500 platform. The predominant bacterial community in the ileum belongs to the phylum Firmicutes. The richness of the bacterial community was negatively correlated with increasing amounts of ZnO NPs (r = -0.636, P < 0.01); when ZnO NP levels were at 100 mg/kg, microbiota diversity was significantly decreased (P < 0.05). The community structure determined by LEfSe analysis indicated that Bacilli, Fusobacteria, and Proteobacteria were changed, and Lactobacillus was reduced by ZnO NPs. Moreover, metabolism as analyzed by nuclear magnetic resonance (NMR) indicated that glucose, some amino acids, and other metabolites were changed by ZnO NPs. Choline, lactate, and methionine were positively correlated with bacterial richness. In summary, ZnO NPs could influence the levels of microflora in ileal digesta, particularly Lactobacillus. Furthermore, the richness of the microbiota was related to changes in choline, lactate, and methionine metabolism. PMID- 28626455 TI - Editorial: Resource Recovery from Wastewater by Biological Technologies. PMID- 28626454 TI - A Syst-OMICS Approach to Ensuring Food Safety and Reducing the Economic Burden of Salmonellosis. AB - The Salmonella Syst-OMICS consortium is sequencing 4,500 Salmonella genomes and building an analysis pipeline for the study of Salmonella genome evolution, antibiotic resistance and virulence genes. Metadata, including phenotypic as well as genomic data, for isolates of the collection are provided through the Salmonella Foodborne Syst-OMICS database (SalFoS), at https://salfos.ibis.ulaval.ca/. Here, we present our strategy and the analysis of the first 3,377 genomes. Our data will be used to draw potential links between strains found in fresh produce, humans, animals and the environment. The ultimate goals are to understand how Salmonella evolves over time, improve the accuracy of diagnostic methods, develop control methods in the field, and identify prognostic markers for evidence-based decisions in epidemiology and surveillance. PMID- 28626456 TI - Bactericidal Effect of Photodynamic Therapy, Alone or in Combination with Mupirocin or Linezolid, on Staphylococcus aureus. AB - Antibiotic treatments frequently fail due to the development of antibiotic resistance, underscoring the need for new treatment strategies. Antimicrobial photodynamic therapy (aPDT) could constitute an alternative therapy. In bacterial suspensions of Staphylococcus aureus, which is commonly implicated in cutaneous and mucosal infections, we evaluated the in vitro efficacy of aPDT, using the photosensitizing agents rose bengal (RB) or methylene blue (MB), alone or combined with the antibiotics mupirocin (MU) or linezolid (LN). RB or MB, at concentrations ranging from 0.03 to 10 MUg/ml, were added to S. aureus ATCC 29213 suspensions containing >108 cells/ml, in the absence or presence of MU or LN (1 or 10 MUg/ml). Suspensions were irradiated with a white metal halide (lambda 420 700 nm) or light-emitting diode lamp (lambda 515 and lambda 625 nm), and the number of viable bacteria quantified by counting colony-forming units (CFU) on blood agar. Addition of either antibiotic had no significant effect on the number of CFU/ml. By contrast, RB-aPDT and MB-aPDT effectively inactivated S. aureus, as evidenced by a 6 log10 reduction in bacterial growth. In the presence of MU or LN, the same 6 log10 reduction was observed in response to aPDT, but was achieved using significantly lower concentrations of the photosensitizers RB or MB. In conclusion, the combination of MU or LN and RB/MB-aPDT appears to exert a synergistic bactericidal effect against S. aureus in vitro. PMID- 28626458 TI - Corrigendum: Identification of Rare PB2-D701N Mutation from a Patient with Severe Influenza: Contribution of the PB2-D701N Mutation to the Pathogenicity of Human Influenza. AB - [This corrects the article on p. 575 in vol. 8, PMID: 28421062.]. PMID- 28626457 TI - Characterization of Novel Integrons, In1085 and In1086, and the Surrounding Genes in Plasmids from Enterobacteriaceae, and the Role for attCaadA16 Structural Features during attI1 * attC Integration. AB - Novel class 1 integrons In1085 and In1086, containing the class D beta-lactamase encoding gene blaOXA, were identified in clinical enterobacterial strains. In this study, we aimed to characterize the genetic contexts of In1085 and In1086, with the goal of identifying putative mechanisms of integron mobilization. Four plasmids, approximately 5.3, 5.3, 5.7, and 6.6 kb, from 71 clinical Enterobacteriaceae strains were found to contain class 1 integrons (In37, In62, In1085, and In1086, respectively). Two of these plasmids, pEco336 and pNsa292, containing In1085 and In1086, respectively, were further characterized by antibiotic susceptibility testing, conjugation experiments, PCR, sequencing, and gene mapping. The OXA-type carbapenemase activities of the parental strains were also assessed. The results revealed that the novel integrons had different genetic environments, and therefore demonstrated diverse biochemical characteristics. Using evolutionary inferences based on the recombination of gene cassettes, we also identified a role for attCaadA16 structural features during attI1 * attC insertion reactions. Our analysis showed that gene cassette insertions in the bottom strand of attCaadA16 in the correct orientation lead to the expression the encoded genes from the Pc promoter. Our study suggests that the genetic features harbored within the integrons are inserted in a discernable pattern, involving the stepwise and parallel evolution of class 1 integron variations under antibiotic selection pressures in a clinical setting. PMID- 28626459 TI - The Immunogenicity and Immune Tolerance of Pluripotent Stem Cell Derivatives. AB - Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into all cell types in human body, and therefore hold great potential for cell therapy of currently incurable diseases including neural degenerative diseases, heart failure, and macular degeneration. This potential is further underscored by the promising safety and efficacy data from the ongoing clinical trials of hESC-based therapy of macular degeneration. However, one main challenge for the clinical application of hESC-based therapy is the allogeneic immune rejection of hESC-derived cells by the recipient. The breakthrough of the technology to generate autologous-induced pluripotent stem cells (iPSCs) by nuclear reprogramming of patient's somatic cells raised the possibility that autologous iPSC-derived cells can be transplanted into the patients without the concern of immune rejection. However, accumulating data indicate that certain iPSC-derived cells can be immunogenic. In addition, the genomic instability associated with iPSCs raises additional safety concern to use iPSC-derived cells in human cell therapy. In this review, we will discuss the mechanism underlying the immunogenicity of the pluripotent stem cells and recent progress in developing immune tolerance strategies of human pluripotent stem cell (hPSC) derived allografts. The successful development of safe and effective immune tolerance strategy will greatly facilitate the clinical development of hPSC-based cell therapy. PMID- 28626460 TI - Differential Effect of Cytomegalovirus Infection with Age on the Expression of CD57, CD300a, and CD161 on T-Cell Subpopulations. AB - Immunosenescence is a progressive deterioration of the immune system with aging. It affects both innate and adaptive immunity limiting the response to pathogens and to vaccines. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, and its persistent infection results in functional and phenotypic changes to the T-cell repertoire, the aim of this study was to analyze the effect of CMV-seropositivity and aging on the expression of CD300a and CD161 inhibitory receptors, along with the expression of CD57 marker on CD4+, CD8+, CD8+CD56+ (NKT-Like) and CD4-CD8- (DN) T-cell subsets. Our results showed that, regardless of the T-cell subset, CD57-CD161-CD300a+ T cells expand with age in CMV-seropositive individuals, whereas CD57-CD161+CD300a+ T-cells decrease. Similarly, CD57+CD161-CD300a+ T-cells expand with age in CMV seropositive individuals in all subsets except in DN cells and CD57-CD161+CD300a- T-cells decrease in all T-cell subsets except in CD4+ T-cells. Besides, in young individuals, CMV latent infection associates with the expansion of CD57+CD161 CD300a+CD4+, CD57-CD161-CD300a+CD4+, CD57+CD161-CD300a+CD8+, CD57-CD161 CD300a+CD8+, CD57+CD161-CD300a+NKT-like, and CD57+CD161-CD300a+DN T-cells. Moreover, in young individuals, CD161 expression on T-cells is not affected by CMV infection. Changes of CD161 expression were only associated with age in the context of CMV latent infection. Besides, CD300a+CD57+CD161+ and CD300a CD57+CD161+ phenotypes were not found in any of the T-cell subsets studied except in the DN subpopulation, indicating that in the majority of T-cells, CD161 and CD57 do not co-express. Thus, our results show that CMV latent infection impact on the immune system depends on the age of the individual, highlighting the importance of including CMV serology in any study regarding immunosenescence. PMID- 28626461 TI - Neoglycoconjugate of Tetrasaccharide Representing One Repeating Unit of the Streptococcus pneumoniae Type 14 Capsular Polysaccharide Induces the Production of Opsonizing IgG1 Antibodies and Possesses the Highest Protective Activity As Compared to Hexa- and Octasaccharide Conjugates. AB - Identifying protective synthetic oligosaccharide (OS) epitopes of Streptococcus pneumoniae capsular polysaccharides (CPs) is an indispensable step in the development of third-generation carbohydrate pneumococcal vaccines. Synthetic tetra-, hexa-, and octasaccharide structurally related to CP of S. pneumoniae type 14 were coupled to bovine serum albumin (BSA), adjuvanted with aluminum hydroxide, and tested for their immunogenicity in mice upon intraperitoneal prime boost immunizations. Injections of the conjugates induced production of opsonizing anti-OS IgG1 antibodies (Abs). Immunization with the tetra- and octasaccharide conjugates stimulated the highest titers of the specific Abs. Further, the tetrasaccharide ligand demonstrated the highest ability to bind OS and CP Abs. Murine immune sera developed against tetra- and octasaccharide conjugates promoted pathogen opsonization to a higher degree than antisera against conjugated hexasaccharide. For the first time, the protective activities of these glycoconjugates were demonstrated in mouse model of generalized pneumococcal infections. The tetrasaccharide conjugate possessed the highest protective activities. Conversely, the octasaccharide conjugate had lower protective activities and the lowest one showed the hexasaccharide conjugate. Sera against all of the glycoconjugates passively protected naive mice from pneumococcal infections. Given that the BSA-tetrasaccharide induced the most abundant yield of specific Abs and the best protective activity, this OS may be regarded as the most promising candidate for the development of conjugated vaccines against S. pneumoniae type 14 infections. PMID- 28626462 TI - Editorial: Inflammatory Signaling in Bone Marrow Failure and Hematopoietic Malignancy. PMID- 28626464 TI - Toward Unveiling the Mechanisms for Transcriptional Regulation of Proline Biosynthesis in the Plant Cell Response to Biotic and Abiotic Stress Conditions. AB - Proline accumulation occurs in plants following the exposure to a wide array of stress conditions, as well as during numerous physiological and adaptive processes. Increasing evidence also supports the involvement of proline metabolism in the plant response to pathogen attack. This requires that the biosynthetic pathway is triggered by components of numerous and different signal transduction chains. Indeed, several reports recently described activation of genes coding for enzymes of the glutamate pathway by transcription factors (TFs) belonging to various families. Here, we summarize some of these findings with special emphasis on rice, and show the occurrence of a plethora of putative TF binding sites in the promoter of such genes. PMID- 28626465 TI - Altered Expression of OsNLA1 Modulates Pi Accumulation in Rice (Oryza sativa L.) Plants. AB - Current agricultural practices rely on heavy use of fertilizers for increased crop productivity. However, the problems associated with heavy fertilizer use, such as high cost and environmental pollution, require the development of crop species with increased nutrient use efficiency. In this study, by using transgenic approaches, we have revealed the critical role of OsNLA1 in phosphate (Pi) accumulation of rice plants. When grown under sufficient Pi and nitrate levels, OsNLA1 knockdown (Osnla1-1, Osnla1-2, and Osnla1-3) lines accumulated higher Pi content in their shoot tissues compared to wild-type, whereas, over expression lines (OsNLA1-OE1, OsNLA1-OE2, and OsNLA1-OE3) accumulated the least levels of Pi. However, under high Pi levels, knockdown lines accumulated much higher Pi content compared to wild-type and exhibited Pi toxicity symptoms in the leaves. In contrast, the over-expression lines had 50-60% of the Pi content of wild-type and did not show such symptoms. When grown under limiting nitrate levels, OsNLA1 transgenic lines also displayed a similar pattern in Pi accumulation and Pi toxicity symptoms compared to wild-type suggesting an existence of cross-talk between nitrogen (N) and phosphorous (P), which is regulated by OsNLA1. The greater Pi accumulation in knockdown lines was a result of enhanced Pi uptake/permeability of roots compared to the wild-type. The cross talk between N and P was found to be nitrate specific since the knockdown lines failed to over-accumulate Pi under low (sub-optimal) ammonium level. Moreover, OsNLA1 was also found to interact with OsPHO2, a known regulator of Pi homeostasis, in a Yeast Two-Hybrid (Y2H) assay. Taken together, these results show that OsNLA1 is involved in Pi homeostasis regulating Pi uptake and accumulation in rice plants and may provide an opportunity to enhance P use efficiency by manipulating nitrate supply in the soil. PMID- 28626463 TI - Cereal Crop Proteomics: Systemic Analysis of Crop Drought Stress Responses Towards Marker-Assisted Selection Breeding. AB - Sustainable crop production is the major challenge in the current global climate change scenario. Drought stress is one of the most critical abiotic factors which negatively impact crop productivity. In recent years, knowledge about molecular regulation has been generated to understand drought stress responses. For example, information obtained by transcriptome analysis has enhanced our knowledge and facilitated the identification of candidate genes which can be utilized for plant breeding. On the other hand, it becomes more and more evident that the translational and post-translational machinery plays a major role in stress adaptation, especially for immediate molecular processes during stress adaptation. Therefore, it is essential to measure protein levels and post translational protein modifications to reveal information about stress inducible signal perception and transduction, translational activity and induced protein levels. This information cannot be revealed by genomic or transcriptomic analysis. Eventually, these processes will provide more direct insight into stress perception then genetic markers and might build a complementary basis for future marker-assisted selection of drought resistance. In this review, we survey the role of proteomic studies to illustrate their applications in crop stress adaptation analysis with respect to productivity. Cereal crops such as wheat, rice, maize, barley, sorghum and pearl millet are discussed in detail. We provide a comprehensive and comparative overview of all detected protein changes involved in drought stress in these crops and have summarized existing knowledge into a proposed scheme of drought response. Based on a recent proteome study of pearl millet under drought stress we compare our findings with wheat proteomes and another recent study which defined genetic marker in pearl millet. PMID- 28626466 TI - Identification, Characterization, and Functional Validation of Drought-responsive MicroRNAs in Subtropical Maize Inbreds. AB - MicroRNA-mediated gene regulation plays a crucial role in controlling drought tolerance. In the present investigation, 13 drought-associated miRNA families consisting of 65 members and regulating 42 unique target mRNAs were identified from drought-associated microarray expression data in maize and were subjected to structural and functional characterization. The largest number of members (14) was found in the zma-miR166 and zma-miR395 families, with several targets. However, zma-miR160, zma-miR390, zma-miR393, and zma-miR2275 each showed a single target. Twenty-three major drought-responsive cis-regulatory elements were found in the upstream regions of miRNAs. Many drought-related transcription factors, such as GAMYB, HD-Zip III, and NAC, were associated with the target mRNAs. Furthermore, two contrasting subtropical maize genotypes (tolerant: HKI-1532 and sensitive: V-372) were used to understand the miRNA-assisted regulation of target mRNA under drought stress. Approximately 35 and 31% of miRNAs were up-regulated in HKI-1532 and V-372, respectively. The up-regulation of target mRNAs was as high as 14.2% in HKI-1532 but was only 2.38% in V-372. The expression patterns of miRNA-target mRNA pairs were classified into four different types: Type I- up regulation, Type II- down-regulation, Type III- neutral regulation, and Type IV- opposite regulation. HKI-1532 displayed 46 Type I, 13 Type II, and 23 Type III patterns, whereas V-372 had mostly Type IV interactions (151). A low level of negative regulations of miRNA associated with a higher level of mRNA activity in the tolerant genotype helped to maintain crucial biological functions such as ABA signaling, the auxin response pathway, the light-responsive pathway and endosperm expression under stress conditions, thereby leading to drought tolerance. Our study identified candidate miRNAs and mRNAs operating in important pathways under drought stress conditions, and these candidates will be useful in the development of drought-tolerant maize hybrids. PMID- 28626467 TI - Mutation in HvCBP20 (Cap Binding Protein 20) Adapts Barley to Drought Stress at Phenotypic and Transcriptomic Levels. AB - CBP20 (Cap-Binding Protein 20) encodes a small subunit of the cap-binding complex (CBC), which is involved in the conserved cell processes related to RNA metabolism in plants and, simultaneously, engaged in the signaling network of drought response, which is dependent on ABA. Here, we report the enhanced tolerance to drought stress of barley mutant in the HvCBP20 gene manifested at the morphological, physiological, and transcriptomic levels. Physiological analyses revealed differences between the hvcbp20.ab mutant and its WT in response to a water deficiency. The mutant exhibited a higher relative water content (RWC), a lower stomatal conductance and changed epidermal pattern compared to the WT after drought stress. Transcriptome analysis using the Agilent Barley Microarray integrated with observed phenotypic traits allowed to conclude that the hvcbp20.ab mutant exhibited better fitness to stress conditions by its much more efficient and earlier activation of stress-preventing mechanisms. The network hubs involved in the adjustment of hvcbp20.ab mutant to the drought conditions were proposed. These results enabled to make a significant progress in understanding the role of CBP20 in the drought stress response. PMID- 28626468 TI - Efficacy and Safety of MLC601 in the Treatment of Mild Cognitive Impairment: A Pilot, Randomized, Double-Blind, Placebo-Controlled Study. AB - BACKGROUND AND AIM: Mild cognitive impairment (MCI) is characterized by declined cognitive function greater than that expected for a person's age. The clinical significance of this condition is its possible progression to dementia. MLC601 is a natural neuroprotective medication that has shown promising effects in Alzheimer disease. Accordingly, we conducted this randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of MLC601 in MCI patients. METHODS: Seventy-two patients with a diagnosis of MCI were recruited. The included participants were randomly assigned to groups to receive either MLC601 or placebo. An evaluation of global cognitive function was performed at baseline as well as at 3-month and 6-month follow-up visits. Global cognitive function was assessed by Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores. Efficacy was evaluated by comparing global function scores between the 2 groups during the study period. Safety assessment included adverse events (AEs) and abnormal laboratory results. RESULTS: Seventy patients completed the study, 34 in the MLC601 group and 36 in the placebo group. The mean changes (+/-SD) in cognition scores over 6 months in the MLC601 group were -2.26 (+/-3.42) for the MMSE and 3.82 (+/-6.16) for the ADAS-cog; in the placebo group, they were -2.66 (+/-3.43) for the MMSE and 4.41 (+/-6.66) for the ADAS-cog. The cognition changes based on both MMSE and ADAS-cog scores were statistically significant between the placebo and the MLC601 group (p < 0.001). Only 5 patients (14.7%) reported minor AEs in the MLC601 group, the most commonly reported of which were gastrointestinal, none of them leading to patient withdrawal. CONCLUSION: MLC601 has shown promising efficacy and acceptable AEs in MCI patients. PMID- 28626469 TI - Serum Amino Acid Profiles in Normal Subjects and in Patients with or at Risk of Alzheimer Dementia. AB - BACKGROUND/AIMS: Abnormalities in the plasma amino acid profile have been reported in Alzheimer disease (AD), but no data exist for the prodromal phase characterized by subjective memory complaint (SMC). It was our aim to understand if serum amino acid levels change along the continuum from normal to AD, and to identify possible diagnostic biomarkers. METHODS: Serum levels of 15 amino acids and 2 organic acids were determined in 4 groups of participants - 29 with probable AD, 18 with mild cognitive impairment (MCI), 24 with SMC, and 46 cognitively healthy subjects (HS) - by electrospray tandem mass spectrometry. RESULTS: Glutamate, aspartate, and phenylalanine progressively decreased, while citrulline, argi-ninosuccinate, and homocitrulline progressively increased, from HS over SMC and MCI to AD. The panel including these 6 amino acids and 4 ratios (glutamate/citrulline, citrulline/phenylalanine, leucine plus isoleucine/phenylalanine, and arginine/phenylalanine) discriminated AD from HS with about 96% accuracy. Other panels including 20 biomarkers discriminated SMC or MCI from AD or HS with an accuracy ranging from 88 to 75%. CONCLUSION: Amino acids contribute to a characteristic metabotype during the progression of AD along the continuum from health to frank dementia, and their monitoring in elderly individuals might help to detect at-risk subjects. PMID- 28626471 TI - Early-versus Late-Onset Alzheimer Disease: Long-Term Functional Outcomes, Nursing Home Placement, and Risk Factors for Rate of Progression. AB - BACKGROUND/AIMS: Whether age at onset influences functional deterioration in Alzheimer disease (AD) is unclear. We, therefore, investigated risk factors for progression in activities of daily living (ADL) and nursing home placement (NHP) in cholinesterase inhibitor (ChEI)-treated patients with early-onset AD (EOAD) versus late-onset AD (LOAD). METHODS: This 3-year, prospective, observational, multicenter study included 1,017 participants with mild-to-moderate AD; 143 had EOAD (onset <65 years) and 874 LOAD (onset >=65 years). Possible sociodemographic and clinical factors that could affect functional outcome and NHP were analyzed using mixed-effects models and logistic regression, respectively. RESULTS: Younger individuals exhibited longer illness duration before AD diagnosis, whereas 6-month functional response to ChEI therapy, 3-year changes in ADL capacities, time from diagnosis to NHP, and survival time in nursing homes were similar between the groups. In LOAD, a higher ChEI dose, no antidepressant use, and lower education level were protective factors for slower instrumental ADL (IADL) decline. In EOAD, antihypertensives/cardiac therapy implied faster IADL progression but lower risk of NHP. CONCLUSION: This study highlights the clinical importance of an earlier diagnosis and treatment initiation and the need for functional evaluations in EOAD. Despite the age differences between EOAD and LOAD, a similar need for nursing homes was observed. PMID- 28626470 TI - Multi-Infarct Dementia: A Historical Perspective. AB - BACKGROUND: Multi-infarct dementia (MID), a prominent subtype of vascular dementia (VaD), has only achieved recognition in the last 4 decades. Since its original description, the characterization, etiological understanding, and therapeutic direction of MID and other VaD subtypes has progressed at an astounding rate. SUMMARY: This paper divides the landmark discoveries and emergence of new research strategies for MID into decade-defining patterns so that a condensed picture of the total history of MID and its eventual inclusion as a VaD subtype emerges. This paper follows the first descriptive decade, a shift to a preventative focus, a renewed interest coinciding with timely advances in research technology, and a hopeful return to treatment possibilities for VaD. KEY MESSAGE: Concisely tracing the historical lineage of the modern understanding of MID, both as a singular entity and as part of the VaD con-stellation of disorders, provides a novel perspective on the foundation upon which future advances in combating vascular contributions to dementia will be based. PMID- 28626472 TI - In IgA Nephropathy, Glomerulosclerosis Is Associated with Increased Urinary CD80 Excretion and Urokinase-Type Plasminogen Activator Receptor-Positive Podocyturia. AB - BACKGROUND: Podocyturia may determine the evolution to podocytopenia, glomerulosclerosis, and renal failure. According to the Oxford classification of IgA nephropathy (IgAN), the S1 lesion describes glomerulosclerosis. Urokinase type plasminogen activator receptor (uPAR) participates in podocyte attachment, while CD80 increases in glomerulosclerosis. We measured uPAR-positive urinary podocytes and urinary CD80 (uCD80) in controls and in IgAN subjects with M1E0S0T0 and M1E0S1T0 Oxford scores to assess a potential association between podocyturia, inflammation, and glomerulosclerosis. METHODS: The groups were as follows: controls (G1), n = 20 and IgAN group (G2), n = 39, subdivided into M1E0S0T0 (G2A), n = 21 and M1E0S1T0 (G2B), n = 18. Among the included variables, we determined uPAR-positive podocytes/gram of urinary creatinine (gUrCr) and uCD80 ng/gUrCr. Biopsies with interstitial fibrosis and tubular atrophy <10% were included. RESULTS: Groups were not different in age and gender; urinary protein creatinine (uP/C) ratio, Chronic Kidney Disease-Epidemiology Collaboration (CKD EPI) equation, uPAR-positive podocytes/gUrCr, and uCD80 were significantly increased in G2 versus G1. G2A and G2B were not different in age, gender, hypertension, and follow-up. G2B displayed significantly higher uP/C, uPAR positive podocytes, uCD80, and lower CKD-EPI versus G2A. Strong significant correlations were encountered between uCD80 and podocyturia in G2A and G2B. However, when G1 was compared to G2A and G2B separately, the differences with respect to uP/C, uPAR-positive podocytes, and podocyturia were significantly stronger versus G2B than versus G2A. CONCLUSIONS: IgAN presents elevated uCD80 excretion and uPAR-positive podocyturia, while CD80 correlates with podocyturia. Glomerulosclerosis (S1) at the time of biopsy is associated with higher uP/C, lower renal function, increased uPAR-positive podocyturia, and CD80 excretion, and is independent of M1. In IgAN, uPAR may participate in podocyte detachment. PMID- 28626473 TI - Clinical Applicability of Whole-Exome Sequencing Exemplified by a Study in Young Adults with the Advanced Cryptogenic Cholestatic Liver Diseases. AB - BACKGROUND: The proper use of new medical tests in clinical practice requires the establishment of their value and range of diagnostic usefulness. While whole exome sequencing (WES) has already entered the medical practice, recognizing its diagnostic usefulness in multifactorial diseases has not yet been achieved. AIMS: The objective of this study was to establish usability of WES in determining genetic background of chronic cholestatic liver disease (CLD) in young patients. METHODS: WES was performed on six young patients (between 17 and 22 years old) with advanced fibrosis or cirrhosis due to CLD and their immediate families. Sequencing was performed on an Ion Proton sequencer. RESULTS: On average, 19,673 variants were identified, of which from 7 to 14 variants of an individual were nonsynonymous, homozygous, recessively inherited, and considered in silico as pathogenic. Although monogenic cause of CLD has not been determined, several heterozygous rare variants and polymorphisms were uncovered in genes previously known to be associated with CLD, including ATP8B1, ABCB11, RXRA, and ABCC4, indicative of multifactorial genetic background. CONCLUSIONS: WES is a potentially useful diagnostic tool in determining genetic background of multifactorial diseases, but its main limitation results from the lack of opportunities for direct linkage between the uncovered genetic variants and molecular mechanisms of disease. PMID- 28626475 TI - Stereospecific pharmacokinetic characterization of liquiritigenin in the rat. AB - Liquiritigenin is a chiral flavonoid present in licorice and other medicinal plants. The nature of its biological fate with respect to the individual enantiomers has not been examined. In this study, we characterize, for the first time, the stereoselective pharmacokinetics of liquiritigenin. Liquiritigenin was intravenously (20 mg/kg) and orally (50 mg/kg) administered to male Sprague Dawley rats (n = 4 per route of administration). Concentrations in serum and urine were characterized via stereospecific reversed-phase, isocratic HPLC method with UV detection. Serum concentrations were quantified but rapidly fell to undetectable levels. S-liquiritigenin showed a short half-life (0.25-0.54 h), while a better estimation of half-life (26-77 h) and other pharmacokinetic parameters was observed using urinary data. The flavonoid is predominantly excreted via non-renal routes (fe values of 0.16-3.46 %), and undergoes rapid and extensive phase II metabolism. Chiral differences in the chemical structure of the compound result in some pharmacokinetic differences. Serum concentrations rapidly declined, making modeling difficult. S-liquiritigenin showed an increased urinary half-life. PMID- 28626474 TI - Status and Prospects of Robotic Gastrectomy for Gastric Cancer: Our Experience and a Review of the Literature. AB - Since the first report of robotic gastrectomy, experienced laparoscopic surgeons have used surgical robots to treat gastric cancer and resolve problems associated with laparoscopic gastrectomy. However, compared with laparoscopic gastrectomy, the superiority of robotic procedures has not been clearly proven. There are several advantages to using robotic surgery for gastric cancer, such as reduced estimated blood loss during the operation, a shorter learning curve, and a larger number of examined lymph nodes than conventional laparoscopic gastrectomy. The increased operation time observed with a robotic system is decreasing because surgeons have accumulated experience using this procedure. While there is limited evidence, long-term oncologic outcomes appear to be similar between robotic and laparoscopic gastrectomy. Robotic procedures have a significantly greater financial cost than laparoscopic gastrectomy, which is a major drawback. Recent clinical studies tried to demonstrate that the benefits of robotic surgery outweighed the cost, but the overall results were disappointing. Ongoing studies are investigating the benefits of robotic gastrectomy in more complicated and challenging cases. Well-designed randomized control trials with large sample sizes are needed to investigate the benefits of robotic gastrectomy compared with laparoscopic surgery. PMID- 28626476 TI - Chemical compositions and biological activities of Scutellaria pinnatifida A. Hamilt aerial parts. AB - Phytochemical analysis of the methanolic and dichloromethane extracts of the aerial parts of Scutellaria pinnatifida led to the isolation of a phenylpropanoid, 1-o-feruloyl-beta-D-glucose (1), two known flavonoids including luteolin-7-o-glucoside (2) and apigenin-7-o-glucoside (3), three known phenylethanoid glycosides composed of phlomisethanoside (4), syringalide A (5), and verbascoside (6), and oleic acid (7). Isolation and structural elucidation of compounds were accomplished by HPLC and spectroscopic methods (UV, 1H-NMR, 13C NMR). The extracts were also evaluated for their radical scavenging activity and insecticidal property by 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay and contact toxicity method, respectively. Among the extracts, the methanol extract showed the most potent free radical scavenging activity with a RC50 value of 0.044 +/- 0.350 mg/mL which could be attributed to the presence of the isolated phenolic compounds. In the case of insecticidal activity, the n-hexane extract displayed the most potent activity and caused 10%, 15%, and 40% mortality to Oryzaephilus mercator at the concentration of 5, 10, and 15 mg/mL after 4 h of exposure. PMID- 28626477 TI - In vitro evaluation of dihydropyridine-3-carbonitriles as potential cytotoxic agents through PIM-1 protein kinase inhibition. AB - PIM-1 protein kinase inhibitor belongs to a novel class of serine/threonine kinases. As PIM-1 is overexpressed in cancer cells and possesses oncogenic functions, its inhibition provides a new option in cancer therapy. In this study, in vitro inhibitory effects of seven analogues of 1, 2-dihydropyridine-3 carbonitrile derivatives Ia-c, IIa-d on the activity of recombinant PIM-1 were evaluated using dimethylthiazol diphenyltetrazolium bromide (MTT) assay. The PIM 1 protein kinase inhibitory potencies and the cytotoxicity effects of tested compounds were respectively as follows: Ic > IIa > Ia > IIb > Ib > IId > IIc and IIb > IIa > Ia > IIc > Ic > Ib > IId, respectively. The compound Ic with methylthio imidazole substituent at C-3 position and benzodioxole substituent at C-6 position of 2-imino-1, 2-dihydropyridine-3- carbonitrile structure showed the strongest PIM-1 inhibitory effect (IC50 = 111.01 nM), while the compound IIc with methythio imidazole substituent at C-3 position and benzodioxole substituent at C 6 position of 2-oxo-1, 2-dihydropyridine-3- carbonitrile structure exhibited the least inhibition activity (IC50 = 433.71 nM). The docking results showed that all tested compounds localized appropriately in the middle of binding cavity after docking procedure, demonstrating suitable interactions between ligands and protein. This study demonstrated that the PIM-1 inhibitory potencies of newly synthesized compounds were in submicromolar concentrations (IC50 < 150 nM) while they exhibited low cytotoxicity on HT-29 cell line (IC50> 130 MUM). Altogether, our data indicated that compounds Ic, IIa, Ia could be considered as new potent non-toxic PIM-1 inhibitors which could be used in combination with routine anti proliferative drugs. PMID- 28626478 TI - Comparative effects of chronic administrations of gabapentin, pregabalin and baclofen on rat memory using object recognition test. AB - Memory impairment is one of the greatest concerns when it comes to long-term CNS affecting drug administration. Drugs like gabapentin, pregabalin and baclofen are administered in a long-term period in conditions such as epilepsy, neuropathic pain, spasticity associated with spinal cord injury or multiple sclerosis. Despite their wide spread use, few data are available on the effects of these drugs on cognitive functions, such as learning memory. In the present study, the effects of long-term administration of gabapentin, pregabalin and baclofen on memory were investigated in a comparative manner. Male Wistar rats received intraperitoneal (i.p.) injection of gabapentin (30 mg/kg), pregabalin (30 mg/kg), baclofen (3 mg/kg), combination of gabapentin/baclofen (30/3 mg/kg) and combination of pregabalin/baclofen (30/3 mg/kg) once a day for 3 weeks respective to their groups. After the end of treatments, rat memories were assessed using the object-recognition task. The discrimination and recognition indices (RI and DI) in the T2 trials were used as the memory indicating factors. The results showed that daily i.p. administrations of pregabalin but not gabapentin or baclofen significantly decreased DI and RI compared to saline group. In combination groups, either gabapentin or pregabalin impaired discrimination between new and familiar objects. Our findings suggested that pregabalin alone or in combination with baclofen significantly caused cognitive deficits. PMID- 28626479 TI - The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population. AB - The genetic factors are determinants in required dosage changes of warfarin among which are polymorphisms of CYP2C9 and VKORC1 genes. The present study aimed to determine the allele and genotype frequency of CYP2C9 and VKORC1 genes in Birjand population. This study was conducted on 120 individuals who referred to Imam Reza and Vali-Asr hospitals for PT/INR test. After extracting the genomic DNA, the considered sequences were amplified by PCR, and restriction fragment length polymorphism analysis was done by AvaII and KpnI enzymes to determine allele polymorphisms. Moreover, related sequences of VKORC1, after amplification, were sequenced for determining the genotype. Allelic and genotypic frequencies as well as Hardy-Weinberg equilibrium, observed heterozygosity, expected heterozygosity, and polymorphism information content were calculated by PowerMarker V 3.25 software. Amongst 120 individuals in this study with the mean age of 58.12 +/- 12.7 years, 80.8%, 9.1%, and 10% exhibited the alleles of 1, 2, and 3 CYP2C9 gene, respectively. The genotype frequencies of 1/1, 1/2, 2/2, 3/1, 3/2, and 3/3 of this gene were found to be 64.1, 15.8, 0, 17.5, 2.5, and 0 %, respectively. In -1639 G>A region, VKORC1 had normal homozygote genotype (GG) and in 1173 C>T region, heterozygote (CT) with the frequency of 48.7% and 45.9% had the most prevalence. Compared with other populations, there is a considerable difference between the allele frequency of CYP2C9 and VKORC1 genetic variance. Since 35.8% of the selected populations carry an abnormal allele causing sensitivity to warfarin, the specialists at medical centers must be informed about the genotypes of patients before prescribing warfarin. PMID- 28626480 TI - Development of dry powder inhaler containing tadalafil-loaded PLGA nanoparticles. AB - Inhalable dry powders containing poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) were developed for the delivery of tadalafil (TAD) for treatment of life-treating pulmonary arterial hypertension. Taguchi design was employed to evaluate the effects of different formulation variables on the physicochemical characteristics of PLGA-NPs prepared using emulsion solvent evaporation method. Inhalable PLGA-NPs of TAD were successfully prepared by co spray drying the PLGA-NPs with inert carriers. Physicochemical characteristics and in vitro deposition of the aerosolized drug were also evaluated. The optimized formulation was prepared using 7.5 mg of PLGA, 2.5 mg of TAD, sonication time of 6 min and 2% polyvinyl alcohol (PVA) as the stabilizer. The optimized aqueous/oil phase ratio for PLGA-NPs preparation was 10:1. Polymer/drug ratio was the most effective parameter on the release efficiency. Encapsulation efficiency, zeta potential and particle size of PLGA-NPs were more affected by aqueous/organic phase ratio. The spray dried powders containing PLGA-NPs had a mass median aerodynamic diameter (MMAD) in the range of 1.4-2.8 MUm that was suitable for TAD delivery to the deep region of lung. The presence of L- leucine in mannitol containing formulations decreased the interparticulate forces between particles and increased significantly the process yield and fine particle fraction (FPF). The results indicated that prepared dry powders containing TAD loaded PLGA-NPs were suitable for inhalation and has the potential for the treatment of pulmonary arterial hypertension. PMID- 28626481 TI - Quantum mechanical/molecular mechanical and docking study of the novel analogues based on hybridization of common pharmacophores as potential anti-breast cancer agents. AB - In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran-imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method. In this study, due to the positive charge on the imidazole ring of the designed ligands and also, the presence of heme iron in the active site of the enzyme, it was decided to optimize the ligand inside the protein to obtain more realistic atomic charges for it. Quantum mechanical/molecular mechanical (QM/MM) method was used to obtain more accurate atomic charges of ligand for docking calculations by considering the polarization effects of CYP19 on ligands. It was observed that the refitted charge improved the binding energy of the docked compounds. Also, the results showed that these novel hybrid compounds were adopted properly within the aromatase binding site, thereby suggesting that they could be potential inhibitors of aromatase. The main binding modes in these complexes were through hydrophobic and H bond interactions showing agreement with the basic physicochemical features of known anti aromatase compounds. Finally, the complex structures obtained from the docking study were used for single point QM/MM calculations to obtain more accurate electronic interaction energy, considering the electronic polarization of the ligand by its protein environment. PMID- 28626482 TI - The possible mechanisms of analgesia produced by microinjection of morphine into the lateral habenula in the acute model of trigeminal pain in rats. AB - This study aimed to assess the effect of intra-habenular injection of morphine on acute trigeminal pain in rats. Also here, we examined the involvement of raphe nucleus opioid and 5HT3 receptors on the antinociceptive activity of intra habenular morphine to explore the possibility of existence of descending antinociceptive relay between the habenula and raphe nucleus. The numbers of eye wiping response elicited by applying a drop (40 MUL) of NaCl (5 M) solution on the corneal surface were taken as an index of acute trigeminal nociception. Intra habenular microinjection of morphine at a dose of 2 MUg was without effect, whereas at doses of 5 and 8 MUg significantly produced antinociception. Microinjection of naltrexone (4 MUg) and ondansetron (1 MUg) into the dorsal raphe nucleus prior to intra-habenular saline did not produce any significant effect on corneal pain perception. Pretreatment of the raphe nucleus with ondansetron but not naltrexone prevented intra habenular morphine (8 MUg) induced antinociception. Also, intra habenular injection of lidocaine (2%, 0.5 MUL reduced corneal pain response. Moreover, intra-habenular microinjection of L glutamic acid (1 and 2 MUg/site) did not produce any analgesic activity in this model of pain. In conclusion, the present results suggest that the activation of the habenular MU opioid receptor by microinjection of morphine or inhibition of habenular neurons by microinjection of lidocaine produced an analgesic effect in the acute trigeminal model of pain in rats. The analgesic effect of intra habenular morphine was blocked by intra-dorsal raphe injection of serotonin 5-HT3 antagonist. PMID- 28626483 TI - Bioassay-directed isolation of falcarindiol and isoacetovanillon from Pycnocycla caespitosa based on KCl-induced contraction in rat uterus smooth muscles. AB - Hydroalcoholic extract and essential oil of aerial parts of Pycnocycla caespitosa have spasmolytic activity on rat ileum contractions. The objective of this research was to separate fractions of total hydroalcoholic extract of P. caespitosa guided by their spasmolytic activity on rat uterus. Aerial parts of P. caespitosa were extracted with ethanol. The concentrated extract was subjected to column chromatography and thin layer chromatography (TLC) for isolation fractions, then one of the bioactive fractions was subjected to further isolation to find its active components. Five fractions were obtained (Fr.1-Fr.5) and their anti-spasmodic activities were examined on uterus contraction induced by KCl (80 mM) and compared with ritodrine. In addition, spasmolytic effect of Fr.4 (one of the bioactive fractions) was determined on rat uterus induced by oxytocin (0.0005 IU/mL) and compared with ritodrine. Hydroalcoholic extract of P. caespitosa (0.032-2 mg/mL) reduced the responses to KCl but the inhibitory effect was not complete with 2 mg/mL extract in the bath. Four fractions (Fr.1, Fr.2, Fr.3 and Fr.4) (32-500 MUg/mL) inhibited rat uterus contractions on the uterus while Fr.4 was slightly more active than others (IC50 = 146 +/- 23 MUg/mL). Falcarindiol and isoacetovanillone were identified from Fr.4 using phytochemical methods including high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and TLC. In conclusion, in this research bioactivity guided technique was successfully used for separation of active fraction of P. caespitosa. Falcarindiol and isoacetovanillone were identified from the active fraction which inhibited both tonic and rhythmic contractile responses in rat isolated uterus. PMID- 28626484 TI - Cognitive enhancing of pineapple extract and juice in scopolamine-induced amnesia in mice. AB - The objective of the present study was to evaluate the cognitive enhancing of pineapple juice and ethanolic extract in scopolamine-induced cognitive deficit mice. The ethanolic extract of pineapple (Ananas comosus (L.) Merr.) was prepared by maceration method and its juice was obtained by a homogenizer. Object recognition task was used to evaluate the mice memory. Exploration time in the first and second trial was recorded. The differences in exploration time between a familiar and a novel object in the second trial were taken as a memory index. Animals were randomly assigned into 15 groups of 6 each including: control group (normal saline + vehicle), positive control group (scopolamine + rivastigmine), seven experimental groups (received scopolamine alone or scopolamine + ethanolic extract of pineapple in different doses), six other experimental groups were treated by ethanolic extract or juice of pineapple in different doses. Scopolamine (100 MUL, 1 mg/kg, i.p.) and pineapple juice or extract (50, 75 and 100 mg/kg, i.p.) were administered 40 and 30 min before starting the second trial in the experimental groups. Object discrimination was impaired after scopolamine administration. Results showed that juice and ethanolic extract of pineapple significantly restored object recognition ability in mice treated with scopolamine. These finding suggested that pineapple had a protective role against scopolamine-induced amnesia, indicating its ability in management of cognitive disorders. PMID- 28626485 TI - Isolation and Characterization of Isofraxidin 7-O-(6'-O-p-Coumaroyl)-beta glucopyranoside from Artemisia capillaris Thunberg: A Novel, Nontoxic Hyperpigmentation Agent That Is Effective In Vivo. AB - Abnormalities in skin pigmentation can produce disorders such as albinism or melasma. There is a research need to discover novel compounds that safely and effectively regulate pigmentation. To identify novel modulators of pigmentation, we attempted to purify compounds from a bioactive fraction of the Korean medicinal plant Artemisia capillaris Thunberg. The novel compound isofraxidin 7-O (6'-O-p-coumaroyl)-beta-glucopyranoside (compound 1) was isolated and its pigmentation activity was characterized in mammalian melanocytes. Compound 1 stimulated melanin accumulation and increased tyrosinase activity, which regulates melanin synthesis. Moreover, compound 1 increased the expression of tyrosinase and the key melanogenesis regulator microphthalmia-associated transcription factor (MITF) in melanocytes. Compared to the parent compound, isofraxidin, compound 1 produced greater effects on these pigmentation parameters. To validate compound 1 as a novel hyperpigmentation agent in vivo, we utilized the zebrafish vertebrate model. Zebrafish treated with compound 1 showed higher melanogenesis and increased tyrosinase activity. Compound 1 treated embryos had no developmental defects and displayed normal cardiac function, indicating that this compound enhanced pigmentation without producing toxicity. In summary, our results describe the characterization of novel natural product compound 1 and its bioactivity as a pigmentation enhancer, demonstrating its potential as a therapeutic to treat hypopigmentation disorders. PMID- 28626486 TI - Solanum paranense Extracts and Solanine Present Anti-Inflammatory Activity in an Acute Skin Inflammation Model in Mice. AB - The aim of the study was to evaluate the anti-inflammatory activity of the S. paranense crude extract, S. paranense alkaloid fraction, and solanine alkaloid. These samples reduce the croton oil-induced ear edema in a dose-dependent manner and a maximum inhibition of 81%, 98%, and 80% in the doses of 1.0, 0.73, and 0.37 mg/ear, respectively. Moreover, the samples inhibit the MPO activity with an inhibition maximum of 51%, 40%, and 46% in the doses of 1.0, 0.73, and 0.37 mg/ear, respectively. Similar results were found for dexamethasone 0.10 mg/ear (positive control), which showed inhibitions of ear edema and MPO activity of 100% and 65%, respectively. These results found probably are related to the presence of solanine which is present in significant quantity in the alkaloid fraction and others as rutin and rosmarinic, chlorogenic, and gallic acids. These results support the use of S. paranense for the treatment of inflammatory skin disorders. PMID- 28626487 TI - Identification of the Chemical Constituents in Simiao Wan and Rat Plasma after Oral Administration by GC-MS and LC-MS. AB - Simiao Wan (SMW), an important multiherbal formula used in traditional Chinese medicine, is extensively used to treat rheumatoid arthritis. However, the knowledge of the bioactive components of SMW remains unclear. Thus, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) were used to analyze the chemical constituents of volatile and nonvolatile extracts of SMW, as well as its absorbed components in rat plasma after oral SMW administration. Identification of several compounds was enabled by comparison of retention times, MS spectra, and MS/MS spectral data with the standard substance and reference materials reported in the literature. In the volatile extracts, GC-MS identified 26 compounds in vitro, three of which observed in blood by GC-MS. In the nonvolatile extracts, LC-MS identified 49 compounds in SMW; 18 compounds containing 7 prototype compounds, 5 metabolites, and 6 unknown compounds were absorbed by blood. The proposed GC-MS and LC-MS method was appropriate not only for the rapid screening and identification of multiple components of an SMW extract but also for screening its bioactive constituents in vivo. The proposed method could be a promising tool for the quality control of other Chinese herbal medicines. PMID- 28626488 TI - Hepatotoxicity in Rats Induced by Aqueous Extract of Polygoni Multiflori Radix, Root of Polygonum multiflorum Related to the Activity Inhibition of CYP1A2 or CYP2E1. AB - The objective of this study is to investigate the relationship between the hepatotoxicity induced by Polygoni Multiflori Radix (PMR, root of Polygonum multiflorum Thunb., He Shou Wu) and the activity of CYP1A2 or CYP2E1 in the rat liver. Levels of rat serum transaminases ALT and AST were not altered but the activity of CYP1A2 or CYP2E1 in the rat liver was significantly inhibited after oral administration of aqueous extract of PMR under the experimental dosage. However, levels of ALT and AST were significantly increased and the activity of CYP1A2 or CYP2E1 was significantly decreased after injection of specific inhibitor for CYP1A2 or CYP2E1 combined with oral administration of aqueous extract of PMR, especially under the repeated treatment over interval times. Liver histopathological observation showed that a moderate liver injury occurred in rats receiving PMR treatment with the activity of CYP1A2 or CYP2E1 inhibited, but there was no significant liver damage in rats receiving PMR treatment or CYP inhibitor alone. These suggested that low level activity of CYP1A2 or CYP2E1 from genetic polymorphism among people might be one of the important reasons for the hepatotoxicity induced by PMR in clinical practice. PMID- 28626489 TI - Conference report on the Indo Global Summit on Head and Neck Oncology (IGSHNO 2017-BMCON-IV), 24-26 February 2017, Jaipur, India. AB - 'The multidisciplinary approach: expanding treatment horizons for head and neck cancer' was the major theme of the Indo Global Summit on Head and Neck Oncology (IGSHNO 2017-BMCON-IV). The meeting, held in Jaipur (Rajasthan, India) from 24 to 26 February 2017, assembled 600 participants from India and worldwide. It was organised by the Bhagwan Mahaveer Cancer Hospital and Research Centre (BMCHRC), Jaipur. BMCHRC Jaipur is one of the largest superspeciality oncology research and treatment centres in north India. The vision of BMCHRC has been to foster collaboration between oncologists, encouraging dialogue in an open forum that improves the care and outcomes of patients with cancer using the latest advances in cancer treatment. IGSHNO 2017 was part of this aim and vision. The organising team, including Dr Anil Gupta (Organising Secretary), Dr Lalit Mohan Sharma (Organising Secretary), Dr Pawan Singhal (Chairperson, scientific programme), Dr Tej Prakash Soni (Treasurer, Organising Secretary, Radiotherapy workshop), Dr Umesh Bansal and Dr Dinesh Yadav (Joint Organising Secretary), Dr Anjum Khan (Organising Secretary, Palliative care workshop), Dr Gaurav Pal Singh (Organising Secretary, Dental and prosthodontics workshop) and Dr (Maj Gen) SC Pareek (Medical Director, BMCHRC, Jaipur, India) worked hard for the previous 6 months to make this conference a successful academic event. IGSHNO 2017, held over three days, is a chance for oncologists from different parts of India to come together and discuss ongoing research, recent announcements and introduce new developments in head and neck cancer. It consisted of 51 lectures, seven debates, 10 panel discussions, oral paper presentations, e-poster sessions, a quiz for postgraduate students, a live surgery workshop, a prosthodentics workshop for dentists, a radiotherapy contouring workshop for radiation oncologists, a pain and palliative care workshop and a meet the expert session-all focusing on the multidisciplinary treatment of head and neck cancer. Special highlights from IGSHNO 2017 included the radiotherapy contouring workshop, the live surgery workshop by internationally renowned head and neck oncosurgeons, the dental and prosthodontics workshop and the pain and palliative care workshop. PMID- 28626490 TI - Soft-tissue sarcomas in the head and neck: 25 years of experience. AB - : Sarcomas are infrequent and heterogeneous tumours. They represent 1-2% of all malignant neoplasms in adults and between 4% and 10% of head and neck cancers. METHODS: The research was retrospective, descriptive, and cross-sectional. RESULTS: A study population of 62 patients with a mean age of 44 years was obtained; the most frequent location was the soft tissues of the neck (25.3%) and the mean tumour size was 7.1 cm; the most frequent diagnosis was undifferentiated pleomorphic sarcoma (25.5%) and the majority were stage III (41.4%). The lowest survival rates were associated with T2a and T2b tumours (p = 0.014), the presence of lymph node metastasis (p = 0.001), advanced stages (p = 0.003), and invasion of bone, blood vessels and/or nerves (p = 0.008). CONCLUSIONS: Late diagnosis is the main factor associated with decreased survival in patients with head and neck sarcomas. PMID- 28626491 TI - The impact of a coordinated joint multidisciplinary breast cancer clinic. AB - INTRODUCTION: Timely access to cancer treatment is expected to improve patients' satisfaction and treatment outcome. A joint multidisciplinary breast cancer clinic (JMDBCC) was developed in January 2011 which aimed to accelerate access to breast cancer care. Here, we assess the efficacy of this approach. METHODS: Metric data of access to care in 2010 represent the pre-JMDBCC era while those during the subsequent 5 years (2011-2015 inclusive) represent the post-JMDBCC era. The JMDBCC is comprised of three separate but closely adjacent subclinics conducted at the same time representing the three main relevant clinic-based disciplines supported by a breast cancer coordinator. The primary aim of the clinic is to provide service to new patients within 7 days at each of the following stages: acceptance to first clinic visit (S1), first clinic visit to completion of appropriate investigations (S2), and completion of investigations to start of active treatment (S3). Thus, the total duration from acceptance to treatment (S1-3) is aimed to be within 21 days. RESULTS: Five hundred and fifty visits to the relevant clinics were recorded at the pre-JMDBCC era. Mean time metrics for new patients were as follows: 13, 18, 21, and 46 days for S1, S2, S3, and S1-3, respectively. The JMDBCC achieved reduction in all time metrics from the first year of implementation, reaching 3.6, 4.9, 7.3, and 15.9 days for S1, S2, S3, and S1-3, respectively, in year 2015. The number of new patients and total recorded clinic visits increased from 49/550, respectively, in the pre JMDBCC era to 92/654, 183/1816, 158/2797, 174/4426, and 180/5883 in subsequent years. CONCLUSIONS: A JMDBCC dramatically accelerates access to specialist multidisciplinary care. All institutions managing patients with breast cancer are encouraged to adopt such a coordinated service. The impact of an effective JMDBCC on disease-specific outcome should be addressed in future studies. PMID- 28626492 TI - Cross-formational flow of water into coalbed methane reservoirs: controls on relative permeability curve shape and production profile. AB - Coalbed methane (CBM) wells tend to produce large volumes of water, especially when there is hydraulic connectivity between coalbed and nearby formations. Cross formational flow between producing coal and adjacent formations can have significant production and environmental implications, affecting economic viability of production from these shallow reservoirs. Such flows can also affect how much gas can be removed from a coalbed prior to mining and thus can have implications for methane control in mining as well. The aim of this paper is to investigate the impact of water flow from an external source into coalbed on production performance and also on reservoir variables including cleat porosity and relative permeability curves derived from production data analysis. A reservoir model is constructed to investigate the production performance of a CBM well when cross-formational flow is present between the coalbed and the overlying formation. Results show that cleat porosity calculated by analysis of production data can be more than one order of magnitude higher than actual cleat porosity. Due to hydraulic connectivity, water saturation within coalbed does not considerably change for a period of time, and hence, the peak of gas production is delayed. Upon depletion of the overlying formation, water saturation in coalbed quickly decreases. Rapid decline of water saturation in the coalbed corresponds to a sharp increase in gas production. As an important consequence, when cross-flow is present, gas and water relative permeability curves, derived from simulated production data, have distinctive features compared to the initial relative permeability curves. In the case of cross-flow, signatures of relative permeability curves are concave downward and low gas permeability for a range of water saturation, followed by rapid increase afterward for water and gas, respectively. The results and analyses presented in this work can help to assess the impact of cross-formational flow on reservoir variables derived from production data analysis and can also contribute to identifying hydraulic connectivity between coalbed and adjacent formations. PMID- 28626493 TI - A Kinematic Study of Prosodic Structure in Articulatory and Manual Gestures: Results from a Novel Method of Data Collection. AB - The primary goal of this work is to examine prosodic structure as expressed concurrently through articulatory and manual gestures. Specifically, we investigated the effects of phrase-level prominence (Experiment 1) and of prosodic boundaries (Experiments 2 and 3) on the kinematic properties of oral constriction and manual gestures. The hypothesis guiding this work is that prosodic structure will be similarly expressed in both modalities. To test this, we have developed a novel method of data collection that simultaneously records speech audio, vocal tract gestures (using electromagnetic articulometry) and manual gestures (using motion capture). This method allows us, for the first time, to investigate kinematic properties of body movement and vocal tract gestures simultaneously, which in turn allows us to examine the relationship between speech and body gestures with great precision. A second goal of the paper is thus to establish the validity of this method. Results from two speakers show that manual and oral gestures lengthen under prominence and at prosodic boundaries, indicating that the effects of prosodic structure extend beyond the vocal tract to include body movement. PMID- 28626494 TI - Towards a consensus on the understanding and analysis of the pulse waveform: Results from the 2016 Workshop on Arterial Hemodynamics: Past, present and future. AB - This paper aims to summarize and map contemporary views on some contentious aspects of arterial hemodynamics that have remained unresolved despite years of research. These were discussed during a workshop entitled Arterial hemodynamics: past, present and future held in London on June 14 and 15, 2016. To do this we formulated a list of potential consensus statements informed by discussion at the meeting in London and quantified the degree of agreement and invited comments from the participants of the workshop. Overall the responses and comments show a high measure of quantitative agreement with the various proposed 'consensus' statements. Taken together, these statements seem a useful basis for proceeding with a more detailed and comprehensive consensus document on the current understanding and approaches to analysis of the pulse waveform. Future efforts should be directed at identifying remaining areas of dispute and future topics for research. PMID- 28626496 TI - Suppurative Flexor Tenosynovitis Secondary to Hematogenous Seeding. PMID- 28626495 TI - Control of protein orientation on gold nanoparticles. AB - Gold nanoparticles (Au NPs) have attracted much attention due to their potential applications in nano-medicine. While numerous studies have quantified biomolecular adsorption to Au NPs in terms of equilibrium binding constants, far less is known about biomolecular orientation on nanoparticle surfaces. In this study, the binding of the protein alpha-synuclein to citrate and (16 mercaptohexadecyl) trimethylammonium bromide (MTAB) coated 12 nm Au NPs is examined by heteronuclear single quantum coherence NMR spectroscopy to provide site-specific measurements of protein-nanoparticle binding. Molecular dynamics simulations support the orientation assignments, which show N-terminus binding to the Au NP for citrate-capped NPs, and C-terminus binding for the MTAB-capped NPs. PMID- 28626497 TI - Hepatoprotective Effect of Polyphenol-Enriched Fraction from Folium Microcos on Oxidative Stress and Apoptosis in Acetaminophen-Induced Liver Injury in Mice. AB - Folium Microcos (FM), the leaves of Microcos paniculata L., shows various biological functions including antioxidant activity and alpha-glucosidase inhibitory effect. However, its therapeutic potential in acute liver injury is still unknown. This study investigated the hepatoprotective effect and underlying mechanisms of the polyphenol-enriched fraction (FMF) from Folium Microcos. FMF exhibited strong free radical scavenging activities and prevented HepG2/Hepa1-6 cells from hydrogen peroxide- (H2O2-) induced ROS production and apoptosis in vitro. Antioxidant activity and cytoprotective effects were further verified by alleviating APAP-induced hepatotoxicity in mice. Western blot analysis revealed that FMF pretreatment significantly abrogated APAP-mediated phosphorylation of MAPKs, activation of proapoptotic protein caspase-3/9 and Bax, and restored expression of antiapoptotic protein Bcl2. APAP-intoxicated mice pretreated with FMF showed increased nuclear accumulation of nuclear factor erythroid 2-related factor (Nrf2) and elevated hepatic expression of its target genes, NAD(P)H:quinine oxidoreductase 1 (NQO1) and hemeoxygenase-1(HO-1). HPLC analysis revealed the four predominantly phenolic compounds present in FMF: narcissin, isorhamnetin-3-O-beta-D-glucoside, isovitexin, and vitexin. Consequently, these findings indicate that FMF possesses a hepatoprotective effect against APAP induced hepatotoxicity mainly through dual modification of ROS/MAPKs/apoptosis axis and Nrf2-mediated antioxidant response, which may be attributed to the strong antioxidant activity of phenolic components. PMID- 28626498 TI - Tubulin Beta-3 Chain as a New Candidate Protein Biomarker of Human Skin Aging: A Preliminary Study. AB - Skin aging is a complex process, and a lot of efforts have been made to identify new and specific targets that could help to diagnose, prevent, and treat skin aging. Several studies concerning skin aging have analyzed the changes in gene expression, and very few investigations have been performed at the protein level. Moreover, none of these proteomic studies has used a global quantitative labeled proteomic offgel approach that allows a more accurate description of aging phenotype. We applied such an approach on human primary keratinocytes obtained from sun-nonexposed skin biopsies of young and elderly women. A total of 517 unique proteins were identified, and 58 proteins were significantly differentially expressed with 40 that were downregulated and 18 upregulated with aging. Gene ontology and pathway analysis performed on these 58 putative biomarkers of skin aging evidenced that these dysregulated proteins were mostly involved in metabolism and cellular processes such as cell cycle and signaling pathways. Change of expression of tubulin beta-3 chain was confirmed by western blot on samples originated from several donors. Thus, this study suggested the tubulin beta-3 chain has a promising biomarker in skin aging. PMID- 28626499 TI - The Effects of Blast Exposure on Protein Deimination in the Brain. AB - Oxidative stress and calcium excitotoxicity are hallmarks of traumatic brain injury (TBI). While these early disruptions may be corrected over a relatively short period of time, long-lasting consequences of TBI including impaired cognition and mood imbalances can persist for years, even in the absence of any evidence of overt injury based on neuroimaging. This investigation examined the possibility that disordered protein deimination occurs as a result of TBI and may thus contribute to the long-term pathologies of TBI. Protein deimination is a calcium-activated, posttranslational modification implicated in the autoimmune diseases rheumatoid arthritis and multiple sclerosis, where aberrant deimination creates antigenic epitopes that elicit an autoimmune attack. The present study utilized proteomic analyses to show that blast TBI alters the deimination status of proteins in the porcine cerebral cortex. The affected proteins represent a small subset of the entire brain proteome and include glial fibrillary acidic protein and vimentin, proteins reported to be involved in autoimmune-based pathologies. The data also indicate that blast injury is associated with an increase in immunoglobulins in the brain, possibly representing autoantibodies directed against novel protein epitopes. These findings indicate that aberrant protein deimination is a biomarker for blast TBI and may therefore underlie chronic neuropathologies of head injury. PMID- 28626502 TI - Reflections, Predictions, and Admonitions. PMID- 28626500 TI - Mitophagy Transcriptome: Mechanistic Insights into Polyphenol-Mediated Mitophagy. AB - Mitochondria are important bioenergetic and signalling hubs critical for myriad cellular functions and homeostasis. Dysfunction in mitochondria is a central theme in aging and diseases. Mitophagy, a process whereby damaged mitochondria are selectively removed by autophagy, plays a key homeostatic role in mitochondrial quality control. Upregulation of mitophagy has shown to mitigate superfluous mitochondrial accumulation and toxicity to safeguard mitochondrial fitness. Hence, mitophagy is a viable target to promote longevity and prevent age related pathologies. Current challenge in modulating mitophagy for cellular protection involves identification of physiological ways to activate the pathway. Till date, mitochondrial stress and toxins remain the most potent inducers of mitophagy. Polyphenols have recently been demonstrated to protect mitochondrial health by facilitating mitophagy, thus suggesting the exciting prospect of augmenting mitophagy through dietary intake. In this review, we will first discuss the different surveillance mechanisms responsible for the removal of damaged mitochondrial components, followed by highlighting the transcriptional regulatory mechanisms of mitophagy. Finally, we will review the functional connection between polyphenols and mitophagy and provide insight into the underlying mechanisms that potentially govern polyphenol-induced mitophagy. PMID- 28626503 TI - Does a Free Office Visit Affect Primary Care-Seeking Behavior? A Study of New Exchange Health Plan Enrollees in Mississippi. AB - BACKGROUND: Given the positive association between primary care and overall health, several health plans are offering doctors' visits without patient copay, with the intent to increase primary care use. However, the effectiveness of these offers has not been established in the literature. OBJECTIVE: To evaluate the impact of a free primary care provider (PCP) office visit offered by a health plan on primary care-seeking behaviors. METHODS: This nonrandomized concurrent control study used event/trials logistic regression to compare the differences in primary care utilization between new exchange enrollees in Mississippi who were offered a free nonpreventive PCP visit and concurrent controls from Georgia and Tennessee who were not offered a free visit, between January 1, 2014, and December 31, 2014, which was the first year of the exchange plans. Regression models adjusted for age, sex, plan type, rural-urban designation, and enrollment month. Visits to alternative sites of care were also assessed. RESULTS: The adjusted number of nonpreventive PCP visits did not differ between the states (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.97-1.00). Mississippi residents were significantly more likely to go to the emergency department than the Georgia-Tennessee cohort (OR, 1.33; 95% CI, 1.28-1.39), but they were less likely to visit an urgent care center (OR, 0.10; 95% CI, 0.09-0.11) or a retail clinic (OR, 0.13; 95% CI, 0.11-0.17) than their counterparts. CONCLUSIONS: Despite being eligible for a free nonpreventive visit, enrollees in Mississippi were no more likely than their counterparts in Georgia and Tennessee to visit a PCP. These findings suggest that removing the cost barrier alone may be insufficient to change primary care-seeking behaviors, and other barriers to care should be addressed. PMID- 28626501 TI - NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells. AB - NADPH oxidases (NOX) are reactive oxygen species- (ROS-) generating enzymes regulating numerous redox-dependent signaling pathways. NOX are important regulators of cell differentiation, growth, and proliferation and of mechanisms, important for a wide range of processes from embryonic development, through tissue regeneration to the development and spread of cancer. In this review, we discuss the roles of NOX and NOX-derived ROS in the functioning of stem cells and cancer stem cells and in selected aspects of cancer cell physiology. Understanding the functions and complex activities of NOX is important for the application of stem cells in tissue engineering, regenerative medicine, and development of new therapies toward invasive forms of cancers. PMID- 28626504 TI - Comparing Healthcare Utilization and Costs Among Medicaid-Insured Patients with Chronic Noncancer Pain with and without Opioid-Induced Constipation: A Retrospective Analysis. AB - BACKGROUND: Constipation is a common adverse effect of opioid use and has been associated with increased healthcare utilization and costs among patients receiving opioids for pain management. OBJECTIVE: To compare the healthcare utilization and costs of Medicaid patients with chronic noncancer pain with and without constipation who were receiving opioids. METHODS: This retrospective, claims-based study was conducted using data from the Truven Health MarketScan Medicaid Multi-State database. Patients with no evidence of cancer who initiated opioid therapy between January 1, 2009, and June 30, 2013, were eligible for the study. Patients had to have continuous enrollment in the database in the 6 months before and 12 months after opioid initiation, with no evidence of substance abuse or functional or inflammatory bowel disease. Medical and pharmacy claims during the 12 months after opioid initiation were evaluated for a diagnosis of constipation or for prescription or over-the-counter medications indicative of constipation. All-cause healthcare utilization and costs were measured over the same period and were compared between propensity score-matched cohorts of patients with evidence of constipation and patients without constipation. RESULTS: Of the 25,744 patients meeting the study inclusion criteria, 2716 (10.5%) had evidence of constipation. After 1:1 propensity score matching, the 2 cohorts had similar demographic and clinical characteristics (ie, mean age, 47 years; 26%-27% male). During the 12-month follow-up period, healthcare utilization was more frequent among patients with constipation, including inpatient admissions and emergency department visits, than in the matched patients without constipation. The total all-cause mean healthcare costs were substantially higher among the patients with constipation ($28,234; 95% confidence interval [CI], $24,307-$32,160) than in the patients without constipation ($13,709; 95% CI, $12,618-$14,801), with a median cost difference of $4166 per patient (P <.001). CONCLUSION: Among Medicaid enrollees who receive opioids for chronic noncancer pain, constipation is associated with increased all cause healthcare utilization and costs. PMID- 28626505 TI - Payers' Perspective: Incorporating Real-World Evidence in Patient Care. AB - The following summaries represent a sample of the many real-world, evidence-based studies presented at the 29th Annual Meeting of the Academy of Managed Care Pharmacy (AMCP), March 27-30, 2017, in Denver, CO. PMID- 28626507 TI - Guru Insights. PMID- 28626506 TI - Impact of Nonadherence to Inhaled Corticosteroid/LABA Therapy on COPD Exacerbation Rates and Healthcare Costs in a Commercially Insured US Population. AB - BACKGROUND: Evidence of poor patient adherence to medications for chronic obstructive pulmonary disease (COPD) is well-documented, but its impact on disease exacerbation rates and associated healthcare costs remains unclear. OBJECTIVE: To assess the association between adherence levels to different inhaled corticosteroid/long-acting beta2-adrenergic agonist (LABA) and COPD exacerbation rates and costs in a commercially insured population. METHODS: In this observational cohort study, patients with COPD (aged >=40 years) who were treatment-naive to inhaled corticosteroid/LABA and were initiating budesonide plus formoterol or fluticasone plus salmeterol between March 1, 2009, and January 31, 2014, were identified in a national representative claims database and were followed for up to 12 months. The date of the first prescription fill for either drug was defined as the index date. Patients were divided into 4 cohorts based on adherence to the index therapy, which was measured by proportion of days covered (PDC); the cohorts were classified as adherent (PDC >=0.8), mildly nonadherent (0.5 <= PDC <0.8), moderately nonadherent (0.3 <= PDC <0.5), and highly nonadherent (PDC <0.3). Each nonadherent group was matched in a 1:1 ratio to the adherent group independently, based on prognostically important variables, using propensity score analyses. Exacerbation rates and healthcare costs were analyzed for 1 year after treatment initiation. RESULTS: During the study period, 13,657 eligible patients with COPD initiated inhaled corticosteroid/LABA; of these, only 1898 (13.9%) patients were adherent during follow-up. Group matching resulted in 1572 patients per group for comparison 1 (adherent vs mildly nonadherent), 1604 patients for comparison 2 (adherent vs moderately nonadherent), and 1755 patients for comparison 3 (adherent vs highly nonadherent). The moderately and highly nonadherent cohorts had higher exacerbation rates than the adherent patients (comparison 2: rate ratio [RR], 1.11; 95% confidence interval [CI], 1.01-1.21; P = .03; comparison 3: RR, 1.11; 95% CI, 1.01-1.21; P = .02). Adherent patients incurred significantly lower healthcare costs than all the nonadherent groups (comparison 1, $22,671 vs $25,545; P <.01; comparison 2, $22,508 vs $24,303; P <.01; comparison 3, $22,460 vs $25,148; P <.01). CONCLUSIONS: Patients adhered to their inhaled corticosteroid/LABA treatments had lower COPD exacerbation rates and lower healthcare costs compared with the moderately and highly nonadherent patients. Better adherence to maintenance therapies may help to reduce the clinical and economic burdens of COPD. PMID- 28626509 TI - Academic Detailing Has a Positive Effect on Prescribing and Decreasing Prescription Drug Costs: A Health Plan's Perspective. AB - BACKGROUND: When initiated by a health plan, academic detailing can be used to change prescribing practices, which can lead to increased safety and savings. OBJECTIVE: To evaluate the impact of academic detailing on prescribing and prescription drug costs of cefixime to a health plan. METHODS: A prospective intervention study was carried out that evaluated the prescribing practices and prescription drug costs of cefixime. A total of 11 prescribers were detailed by 1 pharmacist between August 2014 and March 2015. Two of the 11 prescribers did not respond to the academic detailing and were not followed up. The physicians' prescribing habits and prescription costs were compared before and after detailing to evaluate the effectiveness of the intervention. Data were collected for approximately 5 months before and after the intervention. Each prescriber served as his or her own control. RESULTS: Overall, an approximate 36% reduction in the number of cefixime prescriptions written and an approximate 20% decrease in prescription costs was seen with academic detailing compared with the year before the intervention. In 9 of 11 (82%) prescribers, intervention with academic detailing was successful and resulted in fewer prescriptions for cefixime during the study period. CONCLUSION: Academic detailing had a positive impact on prescribing, by decreasing the number of cefixime prescriptions and lowering the drug costs to the health plan. PMID- 28626508 TI - Rate of Adverse Events and Healthcare Costs Associated with the Topical Treatment of Rosacea. AB - BACKGROUND: Rosacea is a condition more common in women than in men, and in people aged >=30 years than in younger patients. Adverse events associated with the use of topical medications for rosacea may lead to a lack of treatment adherence. Previous studies have reported low treatment adherence rates among patients with rosacea. OBJECTIVE: To describe the rate of treatment discontinuation resulting from adverse events and the associated healthcare costs among patients with rosacea who are receiving a topical medication. METHODS: We conducted a retrospective cohort study of patients diagnosed with rosacea based on International Classification of Diseases, Ninth Revision, Clinical Modification code 695.3 who were newly initiating topical treatment with metronidazole, azelaic acid, sodium sulfacetamide/sulfur, or benzoyl peroxide between January 1, 2009, and September 30, 2013. Patients were identified from the MarketScan Commercial Claims and Encounters database and the Medicare Supplemental database and had to be aged >=30 years, have continuous coverage with medical and pharmacy benefits >=12 months before treatment and >=3 months after treatment inititation, and have no evidence of oral antibiotic use or ocular rosacea during the study period. The 3-month period immediately after the index date (ie, first topical rosacea treatment) was defined as the postindex period and was used to evaluate the outcome measures, which included the rate of adverse events, treatment patterns, and healthcare costs. RESULTS: The final cohort included 49,351 patients, with a mean age of 54 years, and 74.5% of the patients were female. Metronidazole was the most common (72.7%) treatment, followed by azelaic acid (21.7%), sodium sulfacetamide/sulfur (3.4%), and benzoyl peroxide (2.2%). A total of 6270 (12.7%) patients had a coded adverse event, of whom 199 (3.2%) continued treatment despite the adverse event, 466 (7.4%) switched to another treatment within 8.8 days, and 5605 (89.4%) discontinued therapy within 31.1 days. Patients with adverse events incurred, on average, a cost of $325 (medical, $143; pharmacy, $182) in rosacea-related costs; patients without adverse events incurred, on average, a cost of $172 (medical, $14; pharmacy, $157) in rosacea-related costs. CONCLUSIONS: The majority of adverse events associated with current topical drugs for rosacea resulted in treatment switch or discontinuation. Drugs with a different mechanism of action or new formulations of existing drugs may provide additional treatment options for patients and may lead to improved adherence and better symptom control. PMID- 28626510 TI - Multispecialty Rating of Evidence-Based Conditions for Intravenous Immunoglobulin Therapy Using a 3-Axis Prioritization Algorithm. AB - BACKGROUND: A 3-axis prioritization algorithm was proposed and was evaluated in a US multispecialist pilot study to obtain uniform consensus regarding effective practices for the use of intravenous immunoglobulin (IVIG) therapy. OBJECTIVE: The primary objective was to use consensus-building methodologies to rate disease states for IVIG utilization while considering disease severity and the efficacy of alternative therapeutic options to IVIG from the perspective of US multispecialists. METHODS: A 7-member multispecialty physician expert panel was surveyed to rate 50 disease states and to determine their level of agreement with the American Academy of Allergy, Asthma & Immunology (AAAAI) evidence-based medicine (EBM) ratings. The disease states were then rated across the 2 domains of disease severity and the perceived efficacy of therapeutic alternatives. An interquartile deviation (IQD) of <=0.5 was used to determine consensus for disease states within each domain. Disease states reaching consensus across both domains were ranked according to a 2 * 4 algorithmic scale to establish priority for IVIG utilization. RESULTS: Overall, a high level of agreement was found with the AAAAI ratings for EBM. Based on an IQD of <=0.5, the panel reached consensus on the severity of all 50 disease states. Of the 50 disease states, consensus was reached on the efficacy of therapeutic alternatives for 39 disease states. Using the same panel of experts, the 11 disease states without consensus in the first survey were resurveyed, and consensus was subsequently reached on 4 of them. Discussion among the experts, and the resurvey, resulted in expert consensus increasing from 78% to 86% postdiscussion and a change in the overall rating of IVIG on 4 conditions. CONCLUSIONS: Multispecialty input of 7 experts on evidence based IVIG use, augmented with disease severity and efficacy of therapeutic alternatives, enables a balanced perspective on IVIG therapy prioritization. Moreover, multispecialty dialogue improved consensus building among panel members on the effective use of IVIG therapy in several clinical conditions. PMID- 28626511 TI - Assessment of Real-World Central Nervous System Events in Patients with Advanced Prostate Cancer Using Abiraterone Acetate, Bicalutamide, Enzalutamide, or Chemotherapy. AB - BACKGROUND: Central nervous system (CNS) events are frequently reported among patients with advanced prostate cancer as a consequence of the treatments used in this patient population. OBJECTIVE: To assess the incidence of CNS events in patients with advanced prostate cancer who initiated treatment with abiraterone acetate, bicalutamide, enzalutamide, or chemotherapy. METHODS: The Truven Health MarketScan Research databases were used to retrospectively identify patients with prostate cancer who initiated treatment with abiraterone acetate, enzalutamide, bicalutamide, or chemotherapy after September 1, 2012 (ie, the index date). The chemotherapy agents included cabazitaxel, docetaxel, mitoxantrone hydrochloride, and estramustine, and were used as monotherapy or as combination therapy. Patients were followed until December 31, 2014, the end of exposure to treatment, or until loss to follow-up. Kaplan-Meier rates and adjusted Cox proportional hazard models were used to compare the incidence of CNS events between the abiraterone acetate cohort and the other cohorts. A sensitivity analysis of patients with a diagnosis of metastasis was also conducted. RESULTS: A total of 1067 patients receiving abiraterone acetate, 5524 receiving bicalutamide, 592 receiving enzalutamide, and 256 receiving chemotherapy were identified. After 12 months, patients who received abiraterone acetate were less likely to have a CNS event than patients who received enzalutamide (39.5% vs 46.0%, respectively; P = .0036) or chemotherapy (39.5% vs 51.1%, respectively; P = .0277), and were more likely to have a CNS event than patients who received bicalutamide (39.5% vs 34.2%, respectively; P = .0397). After multivariate adjustment, at 12 months, patients who initiated abiraterone acetate treatment had 20% (P = .0388) reduction in the risk for a CNS event compared with patients who initiated enzalutamide; 8% (P = .3622) versus bicalutamide; and 27% (P = .0456) versus chemotherapy. The sensitivity analysis yielded similar results. CONCLUSION: The results of this large observational study suggest that among patients with metastatic prostate cancer, treatment with abiraterone acetate is associated with a significantly lower likelihood of having a CNS event compared with treatment with enzalutamide or chemotherapy, but not with bicalutamide, even when controlling for metastatic disease. PMID- 28626512 TI - NON-RIGID REGISTRATION GUIDED BY LANDMARKS AND LEARNING. AB - Registration methods frequently rely on prior information in order to generate anatomical meaningful transformations between medical scans. In this paper, we propose a novel intensity based non-rigid registration framework, which is guided by landmarks and a regularizer based on Principle Component Analysis (PCA). Unlike existing methods in this domain, the computational complexity of our approach reduces with the number of landmarks. Furthermore, our PCA is invariant to translations. The additional regularizer is based on the outcome of this PCA. We register a skull CT scan to MR scans aquired by a MR/PET hybrid scanner. This aligned CT scan can then be used to gain an attenuation map for PET reconstruction. As a result we have a Dice coefficient for bone areas at 0.71 and a Dice coefficient for bone and soft issue areas at 0.97. PMID- 28626513 TI - NONRIGID VOLUME REGISTRATION USING SECOND-ORDER MRF MODEL. AB - In this paper, we introduce a nonrigid registration method using a Markov Random Field (MRF) energy model with second-order smoothness priors. The registration determines an optimal labeling of the MRF energy model where the label corresponds to a 3D displacement vector. In the MRF energy model, spatial relationships are constructed between nodes using second-order smoothness priors. This model improves limitations of first-order spatial priors which cannot fully incorporate the natural smoothness of deformations. Specifically, the second order smoothness priors can generate desired smoother displacement vector fields and do not suffer from fronto-parallel effects commonly occurred in first-order priors. The usage of second-order priors in the energy model enables this method to produce more accurate registration results. In the experiments, we will show comparative results using uni- and multi-modal Brain MRI volumes. PMID- 28626514 TI - Where Are Drugs Invented, and Why Does It Matter? AB - Globalization has disrupted many industries, initially shifting unskilled labor employment from high wage-cost industrialized nations to lower wage-cost emerging economies. There has been a trend toward moving increasingly skilled work away from industrialized nations, which raises the question-has innovative research and development been affected by globalization, and why is relocation of innovation much more than a simple economic concern? PMID- 28626515 TI - Inhibitors of DNA Gyrase-GyrB Subunit and/or Topoisomerase IV-ParE Subunit May Treat Infectious Diseases Caused by Antibiotic-Resistant Bacteria. PMID- 28626516 TI - Inhibitors of Adaptor-Associated Kinase 1 (AAK1) May Treat Neuropathic Pain, Schizophrenia, Parkinson's Disease, and Other Disorders. PMID- 28626517 TI - Janus-Associated Kinase 1 (JAK1) Inhibitors as Potential Treatment for Immune Disorders. PMID- 28626518 TI - Practical High-Throughput Experimentation for Chemists. AB - Large arrays of hypothesis-driven, rationally designed experiments are powerful tools for solving complex chemical problems. Conceptual and practical aspects of chemical high-throughput experimentation are discussed. A case study in the application of high-throughput experimentation to a key synthetic step in a drug discovery program and subsequent optimization for the first large scale synthesis of a drug candidate is exemplified. PMID- 28626519 TI - Discovery of Potent and Selective Tricyclic Inhibitors of Bruton's Tyrosine Kinase with Improved Druglike Properties. AB - In our continued effort to discover and develop best-in-class Bruton's tyrosine kinase (Btk) inhibitors for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic lupus erythematosus, we devised a series of novel tricyclic compounds that improved upon the druglike properties of our previous chemical matter. Compounds exemplified by G-744 are highly potent, selective for Btk, metabolically stable, well tolerated, and efficacious in an animal model of arthritis. PMID- 28626520 TI - JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules. AB - A competitive fluorescence polarization (FP) assay is reported for determining binding affinities of probe molecules with the pseudokinase JAK2 JH2 allosteric site. The syntheses of the fluorescent 5 and 6 used in the assay are reported as well as Kd results for 10 compounds, including JNJ7706621, NVP-BSK805, and filgotinib (GLPG0634). X-ray crystal structures of JAK2 JH2 in complex with NVP BSK805, filgotinib, and diaminopyrimidine 8 elucidate the binding poses. PMID- 28626521 TI - Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders. AB - Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT signaling pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity. Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein. In this study, small molecule binders of JAK2 JH2 were identified via an in vitro screen. Top hits were characterized using biophysical and structural approaches. Development of pseudokinase-selective compounds may offer novel pharmacological opportunities for treating cancers driven by JAK2 V617F and other oncogenic JAK mutants. PMID- 28626522 TI - Study of para-Quinone Methide Precursors toward the Realkylation of Aged Acetylcholinesterase. AB - Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed. PMID- 28626523 TI - Antiobesity Effect of a Short-Length Peptide YY Analogue after Continuous Administration in Mice. AB - Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY3-36 and a 12-amino acid PYY analogue, benzoyl-[Cha27,28,36,Aib31]PYY25-36 (1), showed similar anorectic activity by activating the Y2 receptor (Y2R). However, food intake inhibition and body weight loss were not observed upon continuous subcutaneous administration of 1 with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of 1, together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d Hyp24,Cha27,28,36,Aib31]PYY23-36 (18), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY3-36. In addition, the continuous subcutaneous administration of 18 at 0.3 mg/(kg.day) induced significant body weight loss in DIO mice. These results suggest that a short-length PYY analogue can be a lead compound for antiobesity therapy in a sustained-release formulation. PMID- 28626524 TI - 19F-NMR-Based Dual-Site Reporter Assay for the Discovery and Distinction of Catalytic and Allosteric Kinase Inhibitors. AB - In modern kinase drug discovery, allosteric inhibitors have become a focus of attention due to their potential selectivity, but such compounds are difficult to identify. Here we describe an NMR-based competition assay using 19F-containing reporter molecules, which allows for rapid identification and discrimination between ATP-competitive and allosteric kinase inhibitors. We illustrate the principle of such a dual-site competition assay with the example of catalytic and allosteric ABL1 kinase inhibitors. The assay can also be used to identify and characterize mixed binding modes of well-known drugs, as shown for crizotinib and fingolimod. PMID- 28626525 TI - Identification of Better Pharmacokinetic Benzothiazinone Derivatives as New Antitubercular Agents. AB - A series of new 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one(BTZ) derivatives containing a C-2 nitrogen spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent in vitro activity (MIC < 0.15 MUM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains. Compounds 11l and 11m display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery. PMID- 28626526 TI - Efficient Divergent Synthesis of New Immunostimulant 4"-Modified alpha Galactosylceramide Analogues. AB - A synthesis strategy for the swift generation of 4"-modified alpha galactosylceramide (alpha-GalCer) analogues is described, establishing a chemical platform to comprehensively investigate the structure-activity relationships (SAR) of this understudied glycolipid part. The strategy relies on a late-stage reductive ring-opening of a p-methoxybenzylidene (PMP) acetal to regioselectively liberate the 4"-OH position. The expediency of this methodology is demonstrated by the synthesis of a small yet diverse set of analogues, which were tested for their ability to stimulate invariant natural killer T-cells (iNKT) in vitro and in vivo. The introduction of a p-chlorobenzyl ether yielded an analogue with promising immunostimulating properties, paving the way for further SAR studies. PMID- 28626527 TI - Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands. AB - In this study, we report a ligand-centric data mining approach that guided the identification of suitable target profiles for treating obesity. The newly developed method is based on identifying target pairs for synergistic positive effects and also encompasses the exclusion of compounds showing a detrimental effect on obesity treatment (off-targets). Ligands with known activity against obesity-relevant targets were compared using fingerprint representations. Similar compounds with activities to different targets were evaluated for the mechanism of action since activation or deactivation of drug targets determines the pharmacological effect. In vitro validation of the modeling results revealed that three known modulators of melanin-concentrating hormone receptor 1 (MCHR1) show a previously unknown submicromolar affinity to the histamine H3 receptor (H3R). This synergistic activity may present a novel therapeutic option against obesity. PMID- 28626529 TI - Photoaffinity Labeling of the Human A2A Adenosine Receptor and Cross-link Position Analysis by Mass Spectrometry. AB - Photoaffinity labeling (PAL) is widely used for the identification of ligand binding proteins and elucidation of ligand-binding sites. PAL has also been employed for the characterization of G protein-coupled receptors (GPCRs); however, a limited number of reports has successfully identified their cross linked amino acids. This report is the first of its kind to determine the cross link position of the human A2A adenosine receptor by PAL with the novel diazirine based photoaffinity probe 9. PMID- 28626528 TI - Exploitation of Conformational Dynamics in Imparting Selective Inhibition for Related Matrix Metalloproteinases. AB - Matrix metalloproteinases (MMPs) have numerous physiological functions and share a highly similar catalytic domain. Differential dynamical information on the closely related human MMP-8, -13, and -14 was integrated onto the benzoxazinone molecular template. An in silico library of 28,099 benzoxazinones was generated and evaluated in the context of the molecular-dynamics information. This led to experimental evaluation of 19 synthesized compounds and identification of selective inhibitors, which have potential utility in delineating the physiological functions of MMPs. Moreover, the approach serves as an example of how dynamics of closely related active sites may be exploited to achieve selective inhibition by small molecules and should find applications in other enzyme families with similar active sites. PMID- 28626530 TI - Discovery of a Series of Indazole TRPA1 Antagonists. AB - A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed significant activity in these models when administered either systemically or topically. Protein chimeras were constructed to indicate compounds from the series bound in the S5 region of the channel, and a computational docking model was used to propose a binding mode for example compounds. PMID- 28626531 TI - Saccharin Aza Bioisosteres-Synthesis and Preclinical Property Comparisons. AB - Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster B), and two new types of aza-saccharins (clusters C and D). We demonstrate a convenient protocol to selectively synthesize products in cluster C or D when primary amines are used. Preclinical characterization of selected matched-pair products is reported. Through comparison of two diastereomers, we highlight how stereochemistry affects the preclinical properties. Given that saccharin-based derivatives are widely used in many chemistry fields, we foresee that structures exemplified by clusters C and D offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two different nitrogens. PMID- 28626532 TI - Development of Quinazoline/Pyrimidine-2,4(1H,3H)-diones as Agonists of Cannabinoid Receptor Type 2. AB - Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists. PMID- 28626533 TI - Synthesis and Anti-HCV Activity of a Novel 2',3'-Dideoxy-2'-alpha-fluoro-2'-beta C-methyl Guanosine Phosphoramidate Prodrug. AB - A novel 2',3'-dideoxy-2'-alpha-fluoro-2'-beta-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 MUM) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC50 = 0.39-1.1 MUM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons. PMID- 28626534 TI - A Bright Light to Reveal Mobility: Single Quantum Dot Tracking Reveals Membrane Dynamics and Cellular Mechanisms. AB - This perspective describes recent progress in single quantum dot techniques, with an emphasis on their applications in exploring membrane dynamics and cellular mechanisms. In these cases, conventional population measurements, such as fluorescence recovery after photobleaching, yield only a mean value on an ensemble or bulk collection of molecules, where the behavior of individual proteins and vehicles is missing. In recent years, the single quantum dot imaging approach has been introduced as a sub-category of single molecule fluorescent techniques to reveal single protein/vehicle dynamics in real-time. One of the major advantages of using single quantum dots is the high signal-to-noise ratio originating from their unique photophysical properties such as extraordinarily high molar extinction coefficients and large effective Stokes shifts. In addition to a brief overview on the principle of single quantum dot imaging techniques, we highlight recent discoveries and discuss future directions in the field. PMID- 28626535 TI - Assessment Effect of Breast Milk on Diaper Dermatitis. AB - Diaper dermatitis is the most common dermatological disease of infancy, which occurs and caused by the combined effect of irritants such as diaper, urine and faces. In this study, we intend to evaluate the effect of breast milk on the healing of diaper dermatitis. This study was a clinical trial of 30 infants between 0-12 months of age that were suffering from diaper dermatitis and referred to the Health Centers in Tehran, Iran. The subjects were selected by open study. Infants were divided into two matched groups: case and control. Data gathering tools were the questionnaire that contained two parts: the demographic characteristics of infants and the status of care and condition of the lesion. Data analysis was performed using SPSS/18 software and Mann-Whitney and Chi Square tests were used. The findings revealed a significant difference between the case and control groups in the number and lesion score of the rashes at the first and third day (P=0.013, P=0.005), these differences were more significant at the fifth day (P=0.004, P=0.001). Because of positive effects of breast milk on healing of diaper dermatitis, it is proposed that educational programs in health centers should be considered by health officials, and the managers would play a key role in increasing knowledge behavior changes in mothers. PMID- 28626536 TI - School-Based Health Education in Yucatan, Mexico about the Chikungunya Virus and Mosquito Illness Prevention. AB - The Chikungunya virus (CHIKV) has been rapidly spreading throughout Latin America, utilizing pre-existing vectors to infiltrate the immunologically naive populations. With the current rise of the Zika Virus, there is an urgent need for more rigorous vector control efforts to prevent further Zika breakout. We designed a school-based education module on CHIKV and mosquito prevention and presented it to the local students of ages of 6-18 in a rural town called Sudzal in Yucatan, Mexico. We distributed questionnaires before and after education to test the students' knowledge of CHIKV and mosquito prevention. Chi-squared test was performed to determine the efficacy of the presentation in increasing their knowledge. The education presentation has proven to effectively educate the local residents in several critical methods of mosquito prevention, increasing the average test scores by 67% post-education. These include applying repellent, staying hydrated during recuperation, and cleaning indoor water containers to eliminate breeding sites (P<0.001). Furthermore, the questionnaire captured the residents' behavioral patterns regarding CHIKV and mosquito prevention and identified cultural, ecological, and socioeconomic factors hindering effective implementation of vector control. PMID- 28626537 TI - Epidemiological Distribution of Rodents as Potent Reservoirs for Infectious Diseases in the Provinces of Mazandaran, Gilan and Golestan, Northern Iran. AB - Rodents are mammals that comprise more than 2000 species and approximately 30 families. There are many morphological and ecological differences among them as variations in their shape, size, weight and habitat. In addition to significant economic losses, rodents have a major role in the dissemination of infectious diseases caused by viruses, bacteria, parasites or other micro-organisms. Rodents are important reservoirs of diseases which have been observed in many cities of Iran provinces especially along Caspian Sea border to Alborz Mountain. The aim of this study is to assess the geographical distribution of rodents in three provinces of northern part of Iran as reservoir of potential endemic infectious diseases. Rodents in 10 major parts of each of the three provinces of Mazandaran, Gilan and Golestan, northern Iran were collected and a total of 404 rodents were trapped alive. They were determined by the key characteristics such as gender, genus, species, different locations and topological situation. Statistical analysis was performed to characterize the study sample and to correlate all variables and parameters. The distribution frequencies of three, five and six genera of rodents were identified in Mazandaran, Gilan and Golestan provinces respectively. The overall distribution frequency of eight genera of rodents in the three provinces were identified as Rattus (R.) norvegicus (67.3%), R. rattus (13.6%), Apodemus sylvaticus (13.9%), Arvicola (1%), Mus musculus (0.3%), Nesokia indica (2.5%), Cricetulus migrates (0.7%) and Rhombomys opimus (0.7%). The results of this study determined the geographic distribution of the rodents in the three northern provinces of Iran. It is indicated the association of various distribution and diversity of rodents with provincial location. The overall distribution frequency of eight genera of rodents was recognized in the above three provinces geographical locations. This study confirms epidemiological distribution of various rodents as potent reservoirs for infectious diseases, such as leptospirosis, salmonellosis, tularemia, leishmaniasis, etc. in the three provinces. PMID- 28626538 TI - Septic Thrombophlebitis with Persistent Methicillin-Resistant Staphylococcus Aureus Bacteremia and de Novo Resistance to Vancomycin and Daptomycin. AB - Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with significant risk of mortality, especially when it occurs while on appropriate antimicrobial therapy. We herein describe an unusual case of a patient with prosthetic aortic tissue valve, who suffered from central venous catheter related MRSA bacteremia with septic thrombus formation in the superior vena cava. MRSA bacteremia persisted despite removal of the catheter and appropriate antimicrobial therapy including vancomycin, rifampin, and daptomycin. Subsequently, the MRSA strain exhibited de novo resistance to vancomycin, rifampin and daptomycin. Eventually, salvage combination therapy with high dose daptomycin and trimethoprim-sulfamethoxazole was successful and achieved clearance of MRSA bacteremia. The case illustrates the growing complexity of treating MRSA infections. PMID- 28626539 TI - Resistance to Colistin in Klebsiella Pneumoniae: A 4.0 Strain? AB - The global rise of multidrug-resistant gram-negative bacteria represents an increasing threat to patient safety. From the first observation of a carbapenem resistant gram-negative bacteria a global spread of extended-spectrum beta lactamases and carbapenemases producing Klebsiella pneumoniae has been observed. Treatment options for multidrug-resistant K. pneumoniae are actually limited to combination therapy with some aminoglycosides, tigecycline and to older antimicrobial agents. Unfortunately, the prevalence of colistin-resistant and tigecycline-resistant K. pneumoniae is increasing globally. Infection due to colistin-resistant K. pneumoniae represents an independent risk factor for mortality. Resistance to colistin in K. pneumoniae may be multifactorial, as it is mediated by chromosomal genes or plasmids. The emergence of transmissible, plasmid-mediated colistin resistance is an alarming finding. The absence of new agents effective against resistant Gram-negative pathogens means that enhanced surveillance, compliance with infection prevention procedures, and antimicrobial stewardship programs will be required to limit the spread of colistin-resistant K. pneumoniae. PMID- 28626540 TI - Acute Crises and Complications of Sickle Cell Anemia Among Patients Attending a Pediatric Tertiary Unit in Kinshasa, Democratic Republic Of Congo. AB - In the Democratic Republic of Congo, the incidence of sickle cell anemia (SCA) is estimated to affect 30,000 to 40,000 neonates per year. However, there is paucity of data on acute clinical manifestations in sickle cell children. In these circumstances, it is difficult to develop a health care policy for an adequate management of sickle cell patients. This was a seven years' retrospective study of children admitted with acute sickle cell crisis in the Department of Pediatrics in University Hospital of Kinshasa, Kinshasa, the Democratic Republic of Congo. A total of 108 patients were identified as having SCA. There were 56 (51%) girls and 52 (49%) boys. Median age was 10.5 years (range 1-24 years). No child was diagnosed by neonatal screening. The median age of diagnosis of sickle cell anemia was 90 months (range: 8-250 months). The median age at the first transfusion was 36 months (range 4-168). In this series, 61 (56.5%) patients were eligible for hydroxyurea. However, this treatment was only performed in 4 (6.6%) of them. Pain episodes, acute anemic crisis and severe infection represent respectively 38.2%, 34.3% and 21.9% of events. Altered sensorium and focal deficit were encountered occasionally and represented 3.4% of acute events. Acute renal manifestations, cholelithiasis and priapism were rarely reported, in this cohort. In Kinshasa, the care of patients suffering from sickle cell anemia is characterized by the delayed diagnosis and low detection of organ complications compared to reports of Western countries. This situation is due to resources deficiencies. PMID- 28626541 TI - A Rare Case of Three Distinct Epstein-Barr Virus Associated Lymphoproliferative Disorders Over Sixteen Years of Human Immunodeficiency Virus Infection. AB - Epstein Barr virus (EBV) is well known to cause different types of malignancies. In immunocompromised patients, such as those infected with human immunodeficiency virus (HIV), there is a higher likelihood of EBV related malignant transformation. Diagnosis of EBV related malignancies may be difficult and sometimes requires clinical and pathological correlation. It is very rare to have more than one type of EBV related malignancy in a single patient. Until now, there are no specific guidelines for treatment of EBV related malignancies and lymphoproliferative disorders (LPD). We present a patient who developed three different types of EBV related LPD during a sixteen-year course of HIV infection. PMID- 28626542 TI - Invasive Aspergillosis with Disseminated Skin Involvement in a Patient with Acute Myeloid Leukemia: A Rare Case. AB - Invasive pulmonary aspergillosis is most commonly seen in immunocompromised patients. Besides, skin lesions may also develop due to invasive aspergillosis in those patients. A 49-year-old male patient was diagnosed with acute myeloid leukemia. The patient developed bullous and zosteriform lesions on the skin after the 21st day of hospitalization. The skin biopsy showed hyphae. Disseminated skin aspergillosis was diagnosed to the patient. Voricanazole treatment was initiated. The patient was discharged once the lesions started to disappear. PMID- 28626543 TI - Cerebral Stroke in a Teenage Girl with Paroxysmal Nocturnal Hemoglobinuria. AB - We report a case of paroxysmal nocturnal hemoglobinuria (PNH) in a 14 year-old girl presenting a cerebral arterial thrombosis. The initial diagnosis was carential anemia due to menarche following identification of slight macrocytic anemia, leucopenia and mild thrombocytopenia at routine blood analysis. The child was eventually referred to a children's hospital after the onset of progressive fatigue, anorexia and paleness. Severe anemia (hemoglobin 6 g/dL) with negative Coombs test, mild leucopenia (white blood cells 4.9*109/L) and thrombocytopenia (platelets 97*109/L) and high values of lactate dehydrogenase (2855 U/L) were identified; a packed red cells transfusion was administered. Her condition worsened and she subsequently presented complete right hemiplegia, aphasia and coma; magnetic resonance imaging revealed a massive ischemic lesion. A diagnosis of PNH was eventually made following high sensitivity flow cytometry, which identified a PNH clone (CD66b negative equal to 93.7% of granulocytes). Fast recovery from neurologic and hematological problems occurred in response to anticoagulant therapy and intravenous therapy with eculizumab. We are convinced that PNH should be included in the differential diagnosis of children presenting with cytopenia. PMID- 28626544 TI - Atypical Hemolytic Uremic Syndrome: A Brief Review. AB - Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The histopathologic lesions of aHUS include thrombotic microangiopathy involving the glomerular capillaries and thrombosis involving arterioles or interlobar arteries. Extra-renal manifestations occur in up to 20% of patients. The majority of aHUS is caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury. Pathologic mutations include those resulting in loss-of-function in a complement regulatory gene (CFH, CFI, CD46 or THBD) or gain-of-function in an effector gene (CFB or C3). Treatment with the late complement inhibitor, eculizumab - a monoclonal antibody directed against C5 - is effective. PMID- 28626545 TI - Case of Acute ST Segment Elevation Myocardial Infarction in Infective Endocarditis-Management with Intra Coronary Stenting. AB - Embolic events from infective endocarditis can cause acute coronary syndrome. Mortality rate is high and optimal management might be different from those chosen in setting of classic atherosclerotic coronary artery disease. We present a case of 56-year-old male who had received 5 weeks of antibiotics for aortic valve endocarditis and developed acute ST segment elevation myocardial infarction in hospital settings. Interestingly, patient had recent left heart catheterization that was normal. This was recognized as embolic event from sterile vegetation. Patient was managed with balloon angioplasty and placement of intracoronary stent. Following re-vascularization, patient chest pain and electrocardiogram normalized and he improved in short term. However due to multiple comorbidities he had to be intubated and placed on dialysis. PMID- 28626546 TI - O Blood Group as a Risk Factor for Helicobacter Pylori IgG Seropositivity Among Pregnant Sudanese Women. AB - The objective was to investigate the prevalence and the association between blood groups and Helicobacter pylori IgG seropositivity among pregnant Sudanese women. A cross-sectional survey was carried-out at Saad Abul Ela Maternity Hospital, Khartoum, Sudan during the period of July 2014 through December 2015. Questionnaires covering socio-demographic and obstetrics information were administered. Specific H. pylori IgG antibody was analysed using ELISA. One hundred eighty six pregnant women were enrolled. The mean (SD) of the age, parity was 28.3 (2.6) years and 2.6 (3.5), respectively. Of the 186 women, 42 (22.6%), 24 (12.9%), 11(5.9%) and 109 (58.6%) had blood group A, B, AB and O, respectively. H. pylori IgG seropositivity rate was 132/186 (71.0%). There was no significant difference in age and parity between women with H. pylori IgG seropositive and seronegative. Compared with the women with H. pylori IgG seronegative, significantly higher numbers of women with H. pylori IgG seropositive had O blood group, [84/132(63.6) versus 25/54(46.3), P<0.001]. In binary logistic regression, women with O blood group (OR= 2.084, 95% CI=1.060 4.097, P=0.033) were at a higher H. pylori IgG seropositivity. The current study showed that women with blood group O were at higher risk for H. pylori IgG seropositivity. PMID- 28626547 TI - Structure-guided optimization of quinoline inhibitors of Plasmodium N myristoyltransferase. AB - The parasite Plasmodium vivax is the most widely distributed cause of recurring malaria. N-Myristoyltransferase (NMT), an enzyme that catalyses the covalent attachment of myristate to the N-terminal glycine of substrate proteins, has been described as a potential target for the treatment of this disease. Herein, we report the synthesis and the structure-guided optimization of a series of quinolines with balanced activity against both Plasmodium vivax and Plasmodium falciparum N-myristoyltransferase (NMT). PMID- 28626548 TI - Nonomuraea sp. ATCC 55076 harbours the largest actinomycete chromosome to date and the kistamicin biosynthetic gene cluster. AB - Glycopeptide antibiotics (GPAs) have served as potent clinical drugs and as an inspiration to chemists in various disciplines. Among known GPAs, complestatin, chloropeptin, and kistamicin are unique in that they contain an unusual indole phenol crosslink. The mechanism of formation of this linkage is unknown, and to date, the biosynthetic gene cluster of only one GPA with an indole-phenol crosslink, that of complestatin, has been identified. Here, we report the genome sequence of the kistamicin producer Nonomuraea sp. ATCC 55076. We find that this strain harbours the largest actinobacterial chromosome to date, consisting of a single linear chromosome of ~13.1 Mbp. AntiSMASH analysis shows that ~32 biosynthetic gene clusters and ~10% of the genome are devoted to production of secondary metabolites, which include 1,6-dihydroxyphenazine and nomuricin, a new anthraquinone-type pentacyclic compound that we report herein. The kistamicin gene cluster (kis) was identified bioinformatically. A unique feature of kis is that it contains two cytochrome P450 enzymes, which likely catalyze three crosslinking reactions. These findings set the stage for examining the biosynthesis of kistamicin and its unusual indole-phenol crosslink in the future. PMID- 28626549 TI - Stoichiometric to catalytic reactivity of the aryl cycloaurated species with arylboronic acids: insight into the mechanism of gold-catalyzed oxidative C(sp2) H arylation. AB - Based on the well-defined five-membered aryl gold(iii) complexes, [Au(tpy)X2] (3a and 3b) and [AuBr(Ph)(tpy)] (7), as well as the aryl gold(iii) complex [AuCl2(Ph)(tpy)] (8) (tpy = 2-(o-tolyl)pyridine) as reliable models, we present a detailed study of the mechanism for gold(iii)-catalyzed oxidative cross-coupling reactions between cycloaurable arenes and arylboronic acids. Here we report the direct evidence for a mechanistic proposal including arene C-H activation, transmetallation and biaryl reductive elimination. The chelation-assisted C-H activation strategy has been used for the development of the gold(iii)-catalyzed C-H bond arylation of arenes with aryl reagents to forge extended pi-conjugated systems. PMID- 28626550 TI - Enantioselective dearomatization of isoquinolines by anion-binding catalysis en route to cyclic alpha-aminophosphonates. AB - An enantioselective dearomatization of isoquinolines has been developed using chiral anion-binding catalysis. This transformation, catalyzed by a simple and easy to prepare tert-leucine-based thiourea derivative, makes use of silyl phosphite as a nucleophile and generates cyclic alpha-aminophosphonates. This is the first time asymmetric anion-binding catalysis has been applied to the synthesis of alpha-aminophosphonates. PMID- 28626551 TI - Pickering emulsions stabilized by coloured organic pigment particles. AB - The possibility of stabilizing emulsions of water and non-polar alkane with pure, coloured organic pigment particles is explored. Seven pigment types each possessing a primary colour of the rainbow were selected. Their solubility in water or heptane was determined using a spectrophotometric method and their surface energies were derived from the contact angles of probe liquids on compressed disks of the particles. As expected, most of the pigments are relatively hydrophobic but pigment orange is quite hydrophilic. At equal volumes of oil and water, preferred emulsions were water-in-oil (w/o) for six pigment types and oil-in-water (o/w) for pigment orange. The emulsion type is in line with calculated contact angles of the particles at the oil-water interface being either side of 90 degrees . Their stability to coalescence increases with particle concentration. Emulsions are shown to undergo limited coalescence from which the coverage of drop interfaces by particles has been determined. In a few cases, close-packed primary particles are visible around emulsion droplets. At constant particle concentration, the influence of the volume fraction of water (phiw) on emulsions was also studied. For the most hydrophilic pigment orange, emulsions are o/w at all phiw, whereas they are w/o for the most hydrophobic pigments (red, yellow, green and blue). For pigments of intermediate hydrophobicity however (indigo and violet), catastrophic phase inversion becomes possible with emulsions inverting from w/o to o/w upon increasing phiw. For the first time, we link the pigment surface energy to the propensity of emulsions to phase invert transitionally or catastrophically. PMID- 28626552 TI - A new microfluidic approach for the one-step capture, amplification and label free quantification of bacteria from raw samples. AB - A microfluidic method to specifically capture and detect infectious bacteria based on immunorecognition and proliferative power is presented. It involves a microscale fluidized bed in which magnetic and drag forces are balanced to retain antibody-functionalized superparamagnetic beads in a chamber during sample perfusion. Captured cells are then cultivated in situ by infusing nutritionally rich medium. The system was validated by the direct one-step detection of Salmonella Typhimurium in undiluted unskimmed milk, without pre-treatment. The growth of bacteria induces an expansion of the fluidized bed, mainly due to the volume occupied by the newly formed bacteria. This expansion can be observed with the naked eye, providing simple low-cost detection of only a few bacteria and in a few hours. The time to expansion can also be measured with a low-cost camera, allowing quantitative detection down to 4 cfu (colony forming unit), with a dynamic range of 100 to 107 cfu ml-1 in 2 to 8 hours, depending on the initial concentration. This mode of operation is an equivalent of quantitative PCR, with which it shares a high dynamic range and outstanding sensitivity and specificity, operating at the live cell rather than DNA level. Specificity was demonstrated by controls performed in the presence of a 500* excess of non-pathogenic Lactococcus lactis. The system's versatility was demonstrated by its successful application to the detection and quantitation of Escherichia coli O157:H15 and Enterobacter cloacae. This new technology allows fast, low-cost, portable and automated bacteria detection for various applications in food, environment, security and clinics. PMID- 28626553 TI - Stepwise crystallographic visualization of dynamic guest binding in a nanoporous framework. AB - Binding sites are at the heart of all host-guest systems, whether biological or chemical. When considering binding sites that form covalent bonds with the guest, we generally envision a single, highly specific binding motif. Through single crystal X-ray crystallography, the dynamic binding of a guest that displays a variety of covalent binding motifs in a single site of adsorption is directly observed for the first time. The stepwise crystallographic visualization of the incorporation of I2 within a porous MOF is presented, wherein the preferred binding motifs throughout the uptake process are identified. The guest I2 molecules initially bind with terminal iodide atoms of the framework to form [I4]2- units. However, as the adsorption progresses, the I2 molecules are observed to form less energetically favorable I3- groups with the same framework iodide atoms, thereby allowing for more guest molecules to be chemisorbed. At near saturation, even more binding motifs are observed in the same pores, including both physisorbed and chemisorbed guest molecules. Herein, we present the successful identification of a unique set of host-guest interactions which will drive the improvement of high capacity iodine capture materials. PMID- 28626554 TI - Tuning the polarity of charge carriers using electron deficient thiophenes. AB - Thiophene-1,1-dioxide (TDO) oligomers have fascinating electronic properties. We previously used thermopower measurements to show that a change in charge carrier from hole to electron occurs with increasing length of TDO oligomers when single molecule junctions are formed between gold electrodes. In this article, we show for the first time that the dominant conducting orbitals for thiophene/TDO oligomers of fixed length can be tuned by altering the strength of the electron acceptors incorporated into the backbone. We use the scanning tunneling microscope break-junction (STM-BJ) technique and apply a recently developed method to determine the dominant transport channel in single-molecule junctions formed with these systems. Through these measurements, we find that increasing the electron affinity of thiophene derivatives, within a family of pentamers, changes the polarity of the charge carriers systematically from holes to electrons, with some systems even showing mid-gap transport characteristics. PMID- 28626555 TI - Live imaging of follicle stimulating hormone receptors in gonads and bones using near infrared II fluorophore. AB - In vivo imaging of hormone receptors provides the opportunity to visualize target tissues under hormonal control in live animals. Detecting longer-wavelength photons in the second near-infrared window (NIR-II, 1000-1700 nm) region affords reduced photon scattering in tissues accompanied by lower autofluorescence, leading to higher spatial resolution at up to centimeter tissue penetration depths. Here, we report the conjugation of a small molecular NIR-II fluorophore CH1055 to a follicle stimulating hormone (FSH-CH) for imaging ovaries and testes in live mice. After exposure to FSH-CH, specific NIR-II signals were found in cultured ovarian granulosa cells containing FSH receptors. Injection of FSH-CH allowed live imaging of ovarian follicles and testicular seminiferous tubules in female and male adult mice, respectively. Using prepubertal mice, NIR-II signals were detected in ovaries containing only preantral follicles. Resolving earlier controversies regarding the expression of FSH receptors in cultured osteoclasts, we detected for the first time specific FSH receptor signals in bones in vivo. The present imaging of FSH receptors in live animals using a ligand-conjugated NIR-II fluorophore with low cell toxicity and rapid clearance allows the development of non-invasive molecular imaging of diverse hormonal target cells in vivo. PMID- 28626556 TI - Regulating the topology of 2D covalent organic frameworks by the rational introduction of substituents. AB - The topology of a covalent organic framework (COF) is generally believed to be dictated by the symmetries of the monomers used for the condensation reaction. In this context, the use of monomers with different symmetries is usually required to afford COFs with different topologies. Herein, we report a conceptual strategy to regulate the topology of 2D COFs by introducing alkyl substituents into the skeleton of a parent monomer. The resulting monomers, sharing the same C2 symmetry, were assembled with a D2h symmetric tetraamine to generate a dual-pore COF or single-pore COFs, depending on the sizes of the substituents, which were evidenced using PXRD studies and pore size distribution analyses. These results demonstrate that the substituent is able to exert a significant influence on the topology of COFs, which is crucial for their application. PMID- 28626557 TI - Electrostatically driven resonance energy transfer in "cationic" biocompatible indium phosphide quantum dots. AB - Indium Phosphide Quantum Dots (InP QDs) have emerged as an alternative to toxic metal ion based QDs in nanobiotechnology. The ability to generate cationic surface charge, without compromising stability and biocompatibility, is essential in realizing the full potential of InP QDs in biological applications. We have addressed this challenge by developing a place exchange protocol for the preparation of cationic InP/ZnS QDs. The quaternary ammonium group provides the much required permanent positive charge and stability to InP/ZnS QDs in biofluids. The two important properties of QDs, namely bioimaging and light induced resonance energy transfer, are successfully demonstrated in cationic InP/ZnS QDs. The low cytotoxicity and stable photoluminescence of cationic InP/ZnS QDs inside cells make them ideal candidates as optical probes for cellular imaging. An efficient resonance energy transfer (E ~ 60%) is observed, under physiological conditions, between the cationic InP/ZnS QD donor and anionic dye acceptor. A large bimolecular quenching constant along with a linear Stern Volmer plot confirms the formation of a strong ground state complex between the cationic InP/ZnS QDs and the anionic dye. Control experiments prove the role of electrostatic attraction in driving the light induced interactions, which can rightfully form the basis for future nano-bio studies between cationic InP/ZnS QDs and anionic biomolecules. PMID- 28626558 TI - Multifunctional mixed-metal nanoscale coordination polymers for triple-modality imaging-guided photodynamic therapy. AB - The one-step self-assembly preparation of multifunctional gadolinium (Gd) ytterbium (Yb) mixed-metal nanoscale coordination polymers (NCPs) with Ru[4,4' (COOH)2bpy]32+ (LRu , bpy = bipyridyl) as a ligand is reported. The Gd/Yb ratio in the NCPs is easily tuned by their ratio in the precursors while the self limiting growth is realized with the high coordination valence and rigid steric structure of the precursors. The inherent properties of the precursors, including the magnetic resonance (MR) response of Gd3+, the X-ray attenuation properties of Yb3+, and the red fluorescence and the singlet-oxygen generation of LRu , are well retained in the mixed-metal NCPs. In vivo fluorescence-MR-X-ray computed tomography (CT), triple-modality imaging and photodynamic therapy (PDT) are achieved using the mixed-metal NCPs as a probe. The triple-modality imaging integrates the high sensitivity of red fluorescence imaging, the deep penetration of MR imaging, and the 3D spatial resolution of CT imaging, thus providing comprehensive and complementary imaging information and facilitating the efficient imaging-guided PDT. For the first time, triple-modality imaging and a PDT agent were prepared with an easy and robust procedure, a tunable mixed-metal ratio, a high yield, and endogenous signal units. PMID- 28626559 TI - Reversible mechanical protection: building a 3D "suit" around a T-shaped benzimidazole axle. AB - The T-shaped benzimidazolium/crown ether recognition motif was used to prepare suit[1]anes. These novel mechanically interlocked molecules (MIMs) were fully characterized by 1H and 13C NMR spectroscopy, single-crystal X-ray diffraction, UV-vis absorption and fluorescence spectroscopy. By conversion to a suit[1]ane, a simple benzimidazole was shown to be protected from deprotonation by strong base. Moreover, it was demonstrated that this unique three-dimensional encapsulation can be made reversible, thus introducing the concept of "reversible mechanical protection"; a protecting methodology that may have potential applications in synthetic organic chemistry and the design of molecular machinery. PMID- 28626560 TI - Selective single molecule nanopore sensing of proteins using DNA aptamer functionalised gold nanoparticles. AB - Single molecule detection methods, such as nanopore sensors have found increasing importance in applications ranging from gaining a better understanding of biophysical processes to technology driven solutions such as DNA sequencing. However, challenges remain especially in relation to improving selectivity to probe specific targets or to alternatively enable detection of smaller molecules such as small-sized proteins with a sufficiently high signal-to-noise ratio. In this article, we propose a solution to these technological challenges by using DNA aptamer-modified gold nanoparticles (AuNPs) that act as a molecular carrier through the nanopore sensor. We show that this approach offers numerous advantages including: high levels of selectivity, efficient capture from a complex mixture, enhanced signal, minimized analyte-sensor surface interactions, and finally can be used to enhance the event detection rate. This is demonstrated by incorporating a lysozyme binding aptamer to a 5 nm AuNP carrier to selectively probe lysozyme within a cocktail of proteins. We show that nanopores can reveal sub-complex molecular information, by discriminating the AuNP from the protein analyte, indicating the potential use of this technology for single molecule analysis of different molecular analytes specifically bound to AuNP. PMID- 28626561 TI - Enantioselective carbohydrate recognition by synthetic lectins in water. AB - Carbohydrate receptors with a chiral framework have been generated by combining a tetra-aminopyrene and a C3-symmetrical triamine via isophthalamide spacers bearing water-solubilising groups. These "synthetic lectins" are the first to show enantiodiscrimination in aqueous solution, binding N-acetylglucosamine (GlcNAc) with 16 : 1 enantioselectivity. They also show exceptional affinities. GlcNAc is bound with Ka up to 1280 M-1, more than twice that measured for previous synthetic lectins, and three times the value for wheat germ agglutinin, the lectin traditionally employed to bind GlcNAc in glycobiological research. Glucose is bound with Ka = 250 M-1, again higher than previous synthetic lectins. The results suggest that chirality can improve complementarity to carbohydrate substrates and may thus be advantageous in synthetic lectin design. PMID- 28626562 TI - Shining a light on transition metal chalcogenides for sustainable photovoltaics. AB - Transition metal chalcogenides are an important family of materials that have received significant interest in recent years as they have the potential for diverse applications ranging from use in electronics to industrial lubricants. One of their most exciting properties is the ability to generate electricity from incident light. In this perspective we will summarise and highlight the key results and challenges in this area and explain how transition metal chalcogenides are a good choice for future sustainable photovoltaics. PMID- 28626563 TI - Chemistry with semi-classical electrons: reaction trajectories auto-generated by sub-atomistic force fields. AB - For a century now, "Lewis dots" have been a mainstay of chemical thinking, teaching and communication. However, chemists have assumed that this semi classical picture of electrons needs to be abandoned for quantitative work, and the recourse in computational simulations has been to the extremes of first principles treatments of electrons on the one hand and force fields that avoid explicit electrons on the other hand. Given both the successes and limitations of these highly divergent approaches, it seems worth considering whether the Lewis dot picture might be made quantitative after all. Here we review progress to that end, including variations that have been implemented and examples of applications, specifically the acid-base behavior of water, several organic reactions, and electron dynamics in silicon fracture. In each case, the semi classical approach is highly efficient and generates reasonable and readily interpreted reaction trajectories in turnkey fashion (i.e., without any input about products). Avenues for further progress are also discussed. PMID- 28626564 TI - Integration of G-quadruplex and DNA-templated Ag NCs for nonarithmetic information processing. AB - To create sophisticated molecular logic circuits from scratch, you may not believe how common the building blocks can be and how diverse and powerful such circuits can be when scaled up. Using the two simple building blocks of G quadruplex and silver nanoclusters (Ag NCs), we experimentally construct a series of multifunctional, label-free, and multi-output logic circuits to perform nonarithmetic functions: a 1-to-2 decoder, a 4-to-2 encoder, an 8-to-3 encoder, dual transfer gates, a 2 : 1 multiplexer, and a 1 : 2 demultiplexer. Moreover, a parity checker which is capable of identifying odd and even numbers from natural numbers is constructed conceptually. Finally, a multi-valued logic gate (ternary inhibit gate) is readily achieved by taking this DNA/Ag NC system as a universal platform. All of the above logic circuits share the same building blocks, indicating the great prospects of the assembly of nanomaterials and DNA for biochemical logic devices. Considering its biocompatibility, the novel prototypes developed here may have potential applications in the fields of biological computers and medical diagnosis and serve as a promising proof of principle in the not-too-distant future. PMID- 28626565 TI - Site-specific azide-acetyllysine photochemistry on epigenetic readers for interactome profiling. AB - Chemical modifications on DNA, RNA and histones are recognized by an array of 'reader' modules to regulate transcriptional programming and cell fate. However, identification of reader-specific interacting partners in a dynamic cellular environment remains a significant challenge. Herein, we report a chemoproteomic approach termed 'interaction-based protein profiling' (IBPP) to characterize novel interacting partners of potentially any reader protein. IBPP harnesses a photosensitive amino acid introduced into the hydrophobic pocket of a reader module to crosslink and enrich transient interacting partners that are inaccessible to traditional methods. Using bromodomain-containing protein 4 (BRD4) as a paradigm, we engineer an 'aromatic cage' of the bromodomain to introduce 4-azido-l-phenylalanine (pAzF) without compromising its ability to recognize acetylated lysine residues in histone proteins. We establish the binding efficiency, substrate specificity and crosslinking ability of the engineered 'reader' module in biochemical assays. Applying IBPP, we uncovered novel acetylated interacting partners of BRD4, such as transcription factors, expanding on its previously unappreciated role in diverse biological processes. By setting up an azide-acetyllysine photoreaction deep inside the bromodomain aromatic cage as a means to detect protein acetylation, our approach provides a potentially general platform for rapid and unbiased profiling of interacting partners of diverse epigenetic readers whose functions in eukaryotic gene regulation remain convoluted. PMID- 28626566 TI - Functional metal-organic framework boosting lithium metal anode performance via chemical interactions. AB - Dendrite growth and low coulombic efficiency are two major factors that limit the utilization of Li metal electrodes in future generations of high-energy-density rechargeable batteries. This article reports the first study on metal-organic framework (MOF) materials for boosting the electrochemical performance of Li metal electrodes and demonstrates the power of molecular-structure functionalization for realizing desirable ion transport and Li metal nucleation and growth. We show that dendrite-free dense Li deposition and stable Li plating/stripping cycling with high coulombic efficiency are enabled by modifying a commercial polypropylene separator with a titanium-based MOF (NH2-MIL-125(Ti)) material. The NH2-MIL-125(Ti)-coated-separator renders Li|Cu cells that can run for over 200 cycles at 1 mA cm-2-1 mA h cm-2 with average coulombic efficiency of 98.5% and Li|Li symmetric cells that can be cycled at 1 mA cm-2-1 mA h cm-2 for more than 1200 h without short circuiting. The superior cycling stability is attributed to the amine substituents in the NH2-MIL-125(Ti) structure which induce increased Li+ transference numbers and uniform and dense early-stage Li deposition. PMID- 28626567 TI - Shape controlled synthesis of porous tetrametallic PtAgBiCo nanoplates as highly active and methanol-tolerant electrocatalyst for oxygen reduction reaction. AB - Mechanistic control is a powerful means for manufacturing specific shapes of metal nanostructures and optimizing their performance in a variety of applications. Thus, we successfully synthesized multimetallic nanoplates (PtAgBiCo and PtAgBi) by combining the concepts of crystal symmetry, oxidative etching and seed ratio, and tuned their activity, stability and methanol tolerance, as well as Pt utilization, for the oxygen reduction reaction in direct methanol fuel cells. Systematic studies reveal that the formation of PtAgBiCo triangular nanoplates with a high morphological yield (>90%) can be achieved by crystallinity alteration, while electrochemical measurements indicate that the PtAgBiCo nanoplates have superior electrocatalytic activity towards the oxygen reduction reaction. The specific and mass activity of the PtAgBiCo nanoplates are 8 and 5 times greater than that of the commercial Pt/C catalyst, respectively. In addition, the tetrametallic PtAgBiCo nanoplates exhibit a more positive half-wave potential for the oxygen reduction reaction and possess an excellent methanol tolerance limit compared with the commercial Pt/C catalyst. PMID- 28626568 TI - Dual-targeted peptide-conjugated multifunctional fluorescent probe with AIEgen for efficient nucleus-specific imaging and long-term tracing of cancer cells. AB - Precisely targeted transportation of a long-term tracing regent to a nucleus with low toxicity is one of the most challenging concerns in revealing cancer cell behaviors. Here, we report a dual-targeted peptide-conjugated multifunctional fluorescent probe (cNGR-CPP-NLS-RGD-PyTPE, TCNTP) with aggregation-induced emission (AIE) characteristic, for efficient nucleus-specific imaging and long term and low-toxicity tracing of cancer cells. TCNTP mainly consists of two components: one is a functionalized combinatorial peptide (TCNT) containing two targeted peptides (cNGR and RGD), a cell-penetrating peptide (CPP) and a nuclear localization signal (NLS), which can specifically bind to a cell surface and effectively enter into the nucleus; the other one is an AIE-active tetraphenylethene derivative (PyTPE, a typical AIEgen) as fluorescence imaging reagent. In the presence of aminopeptidase N (CD13) and integrin alphavbeta3, TCNTP can specifically bind to both of them using cNGR and RGD, respectively, lighting up its yellow fluorescence. Because it contains CPP, TCNTP can be effectively integrated into the cytoplasm, and then be delivered into the nucleus with the help of NLS. TCNTP exhibited strong fluorescence in the nucleus of CD13 and integrin alphavbeta3 overexpression cells due to the specific targeting ability, efficient transport capacity and AIE characteristic in a more crowded space. Furthermore, TCNTP can be applied for long-term tracing in living cells, scarcely affecting normal cells with negligible toxicity in more than ten passages. PMID- 28626569 TI - Importance of double-resonance effects in two-photon absorption properties of Au25(SR)18. AB - The two-photon absorption (TPA) cross-sections of small thiolate-protected gold clusters have been shown to be much larger than typical small organic molecules. In comparison with larger nanoparticles, their TPA cross-sections per gold atom are also found to be larger. Theoretical simulations have suggested that the large enhancement of these TPA cross-sections comes from a one-photon double resonance mechanism. However, it remains difficult to simulate TPA cross-sections of thiolate-protected gold clusters due to their large system size and a high density of states. In this work, we report a time-dependent density functional theory (TDDFT) study of the TPA spectra of the Au25(SR)18- cluster based on a damped response theory formalism. Damped response theory enables a consistent treatment of on- and off-resonance molecular properties even for molecules with a high density of states, and thus is well-suited for studying the TPA properties of gold clusters. Our results indicate that the one- and two-photon double resonance effect is much smaller than previously found, and thus is unlikely to be the main cause of the large TPA cross-sections found experimentally. The effect of symmetry breaking of the Au25(SR)18- cluster due to the ligands on the TPA cross-sections has been studied and was found to only slightly increase the cross-section. Furthermore, by comparing with larger nanoparticles we find that the TPA cross-section per gold atom scales linearly with the diameter of the particles, and that the Kerr non-linear response of the Au25(SR)18- cluster is on the same order as that of bulk gold films. PMID- 28626570 TI - Riboflavin as a bioorthogonal photocatalyst for the activation of a PtIV prodrug. AB - Encouraging developments demonstrate that few transition metal and organometallic catalysts can operate in a bioorthogonal fashion and promote non-natural chemistry in living systems by minimizing undesired side reactions with cellular components. These catalytic processes have potential for applications in medicinal chemistry and chemical biology. However, the stringent conditions of the cell environment severely limit the number of accessible metal catalysts and exogenous reactions. Herein, we report an unorthodox approach and a new type of bioorthogonal catalytic reaction, in which a metal complex is an unconventional substrate and an exogenous biological molecule acts as a catalyst. In this reaction, riboflavin photocatalytically converts a PtIV prodrug into cisplatin within the biological environment. Due to the catalytic activity of riboflavin, cisplatin-like apoptosis is induced in cancer cells under extremely low doses of light, potentially preventing systemic off-target reactions. Photocatalytic and bioorthogonal turnover of PtIV into PtII species is an attractive strategy to amplify the antineoplastic action of metal-based chemotherapeutics with spatio temporal control. PMID- 28626571 TI - Integrative approach for the analysis of the proteome-wide response to bismuth drugs in Helicobacter pylori. AB - Bismuth drugs, despite being clinically used for decades, surprisingly remain in use and effective for the treatment of Helicobacter pylori infection, even for resistant strains when co-administrated with antibiotics. However, the molecular mechanisms underlying the clinically sustained susceptibility of H. pylori to bismuth drugs remain elusive. Herein, we report that integration of in-house metalloproteomics and quantitative proteomics allows comprehensive uncovering of the bismuth-associated proteomes, including 63 bismuth-binding and 119 bismuth regulated proteins from Helicobacter pylori, with over 60% being annotated with catalytic functions. Through bioinformatics analysis in combination with bioassays, we demonstrated that bismuth drugs disrupted multiple essential pathways in the pathogen, including ROS defence and pH buffering, by binding and functional perturbation of a number of key enzymes. Moreover, we discovered that HpDnaK may serve as a new target of bismuth drugs to inhibit bacterium-host cell adhesion. The integrative approach we report, herein, provides a novel strategy to unveil the molecular mechanisms of antimicrobial metals against pathogens in general. This study sheds light on the design of new types of antimicrobial agents with multiple targets to tackle the current crisis of antimicrobial resistance. PMID- 28620450 TI - Predicting Outcomes of Hormone and Chemotherapy in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) Study by Biochemically-inspired Machine Learning. AB - Genomic aberrations and gene expression-defined subtypes in the large METABRIC patient cohort have been used to stratify and predict survival. The present study used normalized gene expression signatures of paclitaxel drug response to predict outcome for different survival times in METABRIC patients receiving hormone (HT) and, in some cases, chemotherapy (CT) agents. This machine learning method, which distinguishes sensitivity vs. resistance in breast cancer cell lines and validates predictions in patients; was also used to derive gene signatures of other HT (tamoxifen) and CT agents (methotrexate, epirubicin, doxorubicin, and 5 fluorouracil) used in METABRIC. Paclitaxel gene signatures exhibited the best performance, however the other agents also predicted survival with acceptable accuracies. A support vector machine (SVM) model of paclitaxel response containing genes ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2, SLCO1B3, TUBB1, TUBB4A, and TUBB4B was 78.6% accurate in predicting survival of 84 patients treated with both HT and CT (median survival >= 4.4 yr). Accuracy was lower (73.4%) in 304 untreated patients. The performance of other machine learning approaches was also evaluated at different survival thresholds. Minimum redundancy maximum relevance feature selection of a paclitaxel-based SVM classifier based on expression of genes BCL2L1, BBC3, FGF2, FN1, and TWIST1 was 81.1% accurate in 53 CT patients. In addition, a random forest (RF) classifier using a gene signature ( ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2,SLCO1B3, TUBB1, TUBB4A, and TUBB4B) predicted >3-year survival with 85.5% accuracy in 420 HT patients. A similar RF gene signature showed 82.7% accuracy in 504 patients treated with CT and/or HT. These results suggest that tumor gene expression signatures refined by machine learning techniques can be useful for predicting survival after drug therapies. PMID- 28626572 TI - Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone. AB - The optical control over biological function with small photoswitchable molecules has gathered significant attention in the last decade. Herein, we describe the design and synthesis of a small library of photoswitchable peptidomimetics based upon human atrial natriuretic peptide (ANP), in which the photochromic amino acid [3-(3-aminomethyl)phenylazo]phenylacetic acid (AMPP) is incorporated into the peptide backbone. The endogeneous hormone ANP signals via the natriuretic peptide receptor A (NPR-A) through raising intracellular cGMP concentrations, and is involved in blood pressure regulation and sodium homeostasis, as well as lipid metabolism and pancreatic function. The cis- and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro. Despite this seemingly small difference, TOP271 enables large, optically-induced conformational changes ex vivo and transforms the NPR-A into an endogenous photoswitch. Thus, application of TOP271 allows the reversible generation of cGMP using light and remote control can be afforded over vasoactivity in explanted murine aortic rings, as well as pancreatic beta cell function in islets of Langerhans. This study demonstrates the broad applicability of TOP271 to enzyme-dependent signalling processes, extends the toolbox of photoswitchable molecules to all classes of transmembrane receptors and utilizes photopharmacology to deduce receptor activation on a molecular level. PMID- 28620450 TI - Predicting Outcomes of Hormone and Chemotherapy in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) Study by Biochemically-inspired Machine Learning. AB - Genomic aberrations and gene expression-defined subtypes in the large METABRIC patient cohort have been used to stratify and predict survival. The present study used normalized gene expression signatures of paclitaxel drug response to predict outcome for different survival times in METABRIC patients receiving hormone (HT) and, in some cases, chemotherapy (CT) agents. This machine learning method, which distinguishes sensitivity vs. resistance in breast cancer cell lines and validates predictions in patients; was also used to derive gene signatures of other HT (tamoxifen) and CT agents (methotrexate, epirubicin, doxorubicin, and 5 fluorouracil) used in METABRIC. Paclitaxel gene signatures exhibited the best performance, however the other agents also predicted survival with acceptable accuracies. A support vector machine (SVM) model of paclitaxel response containing genes ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2, SLCO1B3, TUBB1, TUBB4A, and TUBB4B was 78.6% accurate in predicting survival of 84 patients treated with both HT and CT (median survival >= 4.4 yr). Accuracy was lower (73.4%) in 304 untreated patients. The performance of other machine learning approaches was also evaluated at different survival thresholds. Minimum redundancy maximum relevance feature selection of a paclitaxel-based SVM classifier based on expression of genes BCL2L1, BBC3, FGF2, FN1, and TWIST1 was 81.1% accurate in 53 CT patients. In addition, a random forest (RF) classifier using a gene signature ( ABCB1, ABCB11, ABCC1, ABCC10, BAD, BBC3, BCL2, BCL2L1, BMF, CYP2C8, CYP3A4, MAP2, MAP4, MAPT, NR1I2,SLCO1B3, TUBB1, TUBB4A, and TUBB4B) predicted >3-year survival with 85.5% accuracy in 420 HT patients. A similar RF gene signature showed 82.7% accuracy in 504 patients treated with CT and/or HT. These results suggest that tumor gene expression signatures refined by machine learning techniques can be useful for predicting survival after drug therapies. PMID- 28620451 TI - The refined biomimetic NeuroDigm GELTM model of neuropathic pain in a mature rat. AB - Background: Many humans suffering with chronic neuropathic pain have no objective evidence of an etiological lesion or disease. Frequently their persistent pain occurs after the healing of a soft tissue injury. Based on clinical observations over time, our hypothesis was that after an injury in mammals the process of tissue repair could cause chronic neural pain. Our objectives were to create the delayed onset of neuropathic pain in rats with minimal nerve trauma using a physiologic hydrogel, and characterize the rats' responses to known analgesics and a targeted biologic. Methods: In mature male Sprague Dawley rats (age 9.5 months) a percutaneous implant of tissue-derived hydrogel was placed in the musculofascial tunnel of the distal tibial nerve. Subcutaneous morphine (3 mg/kg), celecoxib (10 mg/kg), gabapentin (25 mg/kg) and duloxetine (10 mg/kg) were each screened in the model three times each over 5 months after pain behaviors developed. Sham and control groups were used in all screenings. A pilot study followed in which recombinant human erythropoietin (200 units) was injected by the GELTM neural procedure site. Results: The GEL group gradually developed mechanical hypersensitivity lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses demonstrated profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months, p <= 0.001. Histology of the GEL group tibial nerve revealed a site of focal neural remodeling, with neural regeneration, as found in nerve biopsies of patients with neuropathic pain. Conclusion: The refined NeuroDigm GELTM model induces a neural response resulting in robust neuropathic pain behavior. The analgesic responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin at the ectopic neural lesion appears to alleviate the persistent pain behavior in the GELTM model rodents. PMID- 28620455 TI - haploR: an R package for querying web-based annotation tools. AB - We developed haploR, an R package for querying web based genome annotation tools HaploReg and RegulomeDB. haploR gathers information in a data frame which is suitable for downstream bioinformatic analyses. This will facilitate post-genome wide association studies streamline analysis for rapid discovery and interpretation of genetic associations. PMID- 28620452 TI - Metabolic reprogramming during the Trypanosoma brucei life cycle. AB - Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism. PMID- 28626579 TI - Treatment of Escape-Maintained Challenging Behavior Using Chained Schedules: An Evaluation of the Effects of Thinning Positive plus Negative Reinforcement During Functional Communication Training. AB - OBJECTIVE: Previous research has supported functional communication training (FCT) as an effective intervention for reducing challenging behavior. Clinicians often program schedule-thinning procedures to increase the portability of the treatment (i.e., reinforcement is provided less frequently). For individuals with escape-maintained problem behavior, chained schedules have proven effective in increasing task completion and supplemental procedures may ameliorate reemergence of challenging behavior as access to reinforcement is decreased. The present study compared the use of a chained schedule-thinning procedure with and without alternative reinforcement (e.g., toys and activities) embedded in an intervention in which escape from the task is provided contingent on a request for a break. METHOD: Two individuals with escape-maintained challenging behavior participated. We compared two treatment conditions, escape-only and escape-to-tangibles, using a single-subject, alternating treatments design with each treatment implemented in a distinct academic context. RESULTS: With the escape-to-tangibles treatment, we reached the final schedule in both contexts with both participants (4 successes out of 4 applications). We did not reach the final schedule with either participant with the escape-only intervention (0 successes out of 2 applications). CONCLUSION: The current results provided preliminary confirmation that providing positive plus negative reinforcement would decrease destructive behavior, increase compliance, and facilitate reinforcer-schedule thinning. PMID- 28620456 TI - Effects of physical activity on the link between PGC-1a and FNDC5 in muscle, circulating Iotarisin and UCP1 of white adipocytes in humans: A systematic review. AB - Background: Exercise may activate a brown adipose-like phenotype in white adipose tissue. The aim of this systematic review was to identify the effects of physical activity on the link between peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and fibronectin type III domain-containing protein 5 (FNDC5) in muscle, circulating Irisin and uncoupling protein one (UCP1) of white adipocytes in humans. Methods: Two databases (PubMed 1966 to 08/2016 and EMBASE 1974 to 08/2016) were searched using an appropriate algorithm. We included articles that examined physical activity and/or exercise in humans that met the following criteria: a) PGC-1a in conjunction with FNDC5 measurements, and b) FNDC5 and/or circulating Irisin and/or UCP1 levels in white adipocytes. Results: We included 51 studies (12 randomised controlled trials) with 2474 participants. Out of the 51 studies, 16 examined PGC-1a and FNDC5 in response to exercise, and only four found increases in both PGC-1a and FNDC5 mRNA and one showed increased FNDC5 mRNA. In total, 22 out of 45 studies that examined circulating Irisin in response to exercise showed increased concentrations when ELISA techniques were used; two studies also revealed increased Irisin levels measured via mass spectrometry. Three studies showed a positive association of circulating Irisin with physical activity levels. One study found no exercise effects on UCP1 mRNA in white adipocytes. Conclusions: The effects of physical activity on the link between PGC-1a, FNDC5 mRNA in muscle and UCP1 in white human adipocytes has attracted little scientific attention. Current methods for Irisin identification lack precision and, therefore, the existing evidence does not allow for conclusions to be made regarding Irisin responses to physical activity. We found a contrast between standardised review methods and accuracy of the measurements used. This should be considered in future systematic reviews. PMID- 28626580 TI - Hernias- Is it a primary defect or a systemic disorder? Role of collagen III in all hernias- A case control study. AB - INTRODUCTION: The need of this study is to assess the role of collagen III in all hernias which include primary inguinal hernias ventral and recurrent abdominal hernias. Collagen type III represents the mechanically instable, less cross linked collagen synthesized during the early days of wound healing. Quantitative assessment of collagen III in scar tissue on transversalis fascia as tissue obtained from cases operated for various hernias and compared to that of patients operated for abdominal surgeries for indications other than hernia was compared. MATERIALS AND METHODS: In this study we had a total of 90 patients, of which 45 patients underwent mesh repair for the various hernias and 45 patients who underwent laparotomies for various reasons were included as controls. Size of 1 * 1cm transversalis fascia was taken in both subjects and was sent for quantitative assessment using Immunohistochemistry test. All the above cases were randomized as per age,sex,BMI, co morbidities and materials used for repair. RESULTS: Results were analysed quantitatively and classified into following groups:Based on intensity of staining into Mild, Intermediate and Well stained and based on Quantity of Collagen III into Grade 0---NIL, Grade 1--1-25%, Grade 2-26-50%, Grade 3--51-75%, Grade 4--76-100% (Table 1). In the case group we had 52.4%,35.7% and 11.9% of the cases in Grade 4, Grade 3 and Grade 2 which proved that there was increased presence of Collagen 3, where as 84.4%,4.4% and 11.1% of patients in the control group were classified as Grade 1, Grade 2, Grade 0. For the quantitative study -Chi square test value -81.279 and the p value < 0.001. For the intensity of staining -Chi square test value -57.64 and p value is < 0.001. CONCLUSION: This study signifies that ventral, recurrent and primary inguinal hernias are not just caused because of a primary defect but an acquired disorder with respect to collagen distribution. PMID- 28626582 TI - Fluorescent flavonoids for endoplasmic reticulum cell imaging. AB - Visualization of subcellular organelles in vivo is critical for basic biomedical research and clinical applications. Two new flavonoids with an amide substituent were synthesized and characterized. The flavonoids were nearly non-fluorescent in aqueous environment, but exhibited two emission peaks (one lambdaem at 495-536 nm and the other at 570-587 nm) in organic solvents, which were assigned to the excited normal (N*) and tautomer (T*) emission. When the dyes were examined on oligodendrocyte cells, they were found to selectively accumulate in the endoplasmic reticulum (ER), a eukaryotic organelle involved in lipid and protein synthesis, giving fluorescence turn-on. The ER-selective flavonoids could be a valuable tool due to its low molecular mass (<500), large Stokes' shift, low toxicity, and biocompatibility. PMID- 28626581 TI - Carcinosarcoma of the maxillary sinus: A rare case report. AB - INTRODUCTION: Carcinosarcoma is a highly malignant tumor characterized by dual malignant histologic differentiation of epithelial and mesenchymal components. The tumor is extremely rare in the sinonasal tract, with only 13 cases reported since 1957 in the literature. PRESENTATION OF CASE: We report a case of a 55-year old man with right-sided face pain revealed a mass in the right maxillary sinus and nasal cavity. A large incisional biopsy from the nasal cavity concluded the diagnosis of carcinosarcoma. The patient was treated with chemoradiation, but no significant effect was obtained. The patient died 4 months after initial examination. DISCUSSION: In our case, the patient consulted late with a large tumor which darkens his prognosis. According to some authors, this histological type of tumors is known by local recurrences and its lethal metastases. Prognosis is related to location, tumor size, the invasion and stage of disease. Wide surgical excision is the treatment of choice. Radiotherapy can be discussed in inoperable cases. CONCLUSION: This is an aggressive tumor, rapidly progressive with a poor prognosis. The management of this rare condition remains undetermined. PMID- 28626583 TI - Complete genome sequence and description of Lactococcus garvieae M14 isolated from Algerian fermented milk. AB - We describe using a polyphasic approach that combines proteomic by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) analysis, genomic data and phenotypic characterization the features of Lactococcus garvieae strain M14 newly isolated from the fermented milk (known as raib) of an Algerian cow. The 2 188 835 bp containing genome sequence displays a metabolic capacity to form acid fermentation that is very useful for industrial applications and encodes for two bacteriocins responsible for its eventual bioprotective properties. PMID- 28626584 TI - Enteric multiplex PCR panels: A new diagnostic tool for amoebic liver abscess? AB - Invasive amoebiasis is a life-threatening infection requiring immediate detection and treatment. However, diagnosis is challenging because conventional methods such as light microscopy and serology are unreliable. Molecular techniques are therefore considered the new diagnostic reference standard, but most of the developed assays are research tools and not widely available. Recently commercial multiplex PCR panels have been introduced which permit the simultaneous detection of multiple enteric pathogens including Entamoeba histolytica in stool samples. Our report demonstrates for the first time that these new assays might also serve as a rapid tool to diagnose amoebic liver abscess in patients with cystic focal liver lesions. PMID- 28626585 TI - First detection of DS-1-like G1P[8] human rotavirus strains from children with diarrhoea in the Philippines. PMID- 28626586 TI - Prevalence of multidrug-resistant tuberculosis cases among HIV-positive and HIV negative patients eligible for retreatment regimen in Togo using GeneXpert MTB/RIF. AB - Drug-resistant tuberculosis (TB) is emerging as an important health problem in Togo. From sputum of previously treated TB patients, multidrug-resistant (MDR) TB was diagnosed in 24% (10/42) patients via GeneXpert MTB/RIF compared to 25% (6/24) patients via conventional drug susceptibility testing (BACTEC MGIT 960 system). The agreement between these two methods to detect MDR-TB is excellent. However, GeneXpert MTB/RIF offers the advantage of rapidly detecting Mycobacterium tuberculosis complex in sputum samples in instances where the cultures are negative (33%, 14/42) or contaminated (9.5%, 4/42). GeneXpert MTB/RIF permitted us to estimate the prevalence of MDR-TB in previously treated TB patients and to improve TB diagnostics among HIV-positive and -negative patients in Togo, where culturing M. tuberculosis complex from sputum samples is challenging. PMID- 28626587 TI - KRAS testing and first-line treatment among patients diagnosed with metastatic colorectal cancer using population data from ten National Program of Cancer Registries in the United States. AB - BACKGROUND: In 2011, the National Comprehensive Cancer Network (NCCN) recommended KRAS testing for metastatic colorectal cancer (mCRC) patients. Our study assessed KRAS testing prevalence and its association with socio-demographic and clinical factors and examined first-line treatment. METHODS: Ten state population-based registries supported by Centers for Disease Control and Prevention's (CDC) National Program of Cancer Registries (NPCR) collected detailed cancer information on mCRC cases diagnosed in 2011, including KRAS biomarker testing and first-line treatment from ten central cancer registries. Data were analyzed with Chi-square tests and multivariate logistic regression. RESULTS: Of the 3,608 mCRC cases, 27% (n = 992) had a documented KRAS test. Increased age at diagnosis (p < 0.0001), racial/ethnic minorities (p = 0.0155), public insurance (p = 0.0018), and lower census tract education (p = 0.0023) were associated with less KRAS testing. Significant geographic variation in KRAS testing (p < 0.0001) ranged from 46% in New Hampshire to 18% in California. After adjusting for all covariates, age and residence at diagnosis (both p < 0.0001) remained predictors of KRAS testing. Non-Hispanic Blacks had less KRAS testing than non-Hispanic Whites (OR = 0.77, 95% CI = 0.61-0.97). Among those tested and found to have normal (wild-type) KRAS, 7% received anti-EGFR treatment; none received such treatment among those with KRAS mutated gene. CONCLUSIONS: Despite NCCN guideline recommendations, 73% of mCRC cases diagnosed in 2011 had no documented KRAS test. Disparities in KRAS testing existed based on age, race, and residence at diagnosis. IMPACT: These findings show the capacity of monitoring KRAS testing in the US using cancer registry data and suggest the need to understand the low uptake of KRAS testing, and associated treatment choices during the first year since diagnosis. PMID- 28626588 TI - UHRF1 is required for basal stem cell proliferation in response to airway injury. AB - Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration. PMID- 28626589 TI - The Effects of Food Labelling on Postexercise Energy Intake in Sedentary Women. AB - Food labelling has been previously reported to influence energy intake (EI). Whether food labels influence postexercise EI remains to be determined. We assessed how food labelling and exercise (Ex) interact to influence food perception and postexercise EI. In this randomized crossover design, 14 inactive women participated in 4 experimental conditions: Ex (300 kcal at 70% of VO2peak) and lunch labelled as low in fat (LF), Ex and lunch labelled as high in fat (HF), Rest and LF, and Rest and HF. The lunch was composed of a plate of pasta, yogurt, and oatmeal cookies, which had the same nutritional composition across the 4 experimental conditions. EI at lunch and for the 48-hour period covering the testing day and the following day was assessed. Furthermore, perceived healthiness of the meal and appetite ratings were evaluated. There were no effects of exercise and food labelling on EI. However, meals labelled as LF were perceived as heathier, and this label was associated with higher prospective food consumption. Initial beliefs about food items had a stronger effect on healthiness perception than the different food labels and explain the positive correlation with the amount of food consumed (rho = 0.34, P < 0.001). PMID- 28626590 TI - Antiglycemic Effect of Water Extractable Arabinoxylan from Wheat Aleurone and Bran. AB - The studies on the effects of arabinoxylan (AX) polysaccharides on postprandial glucose response have resulted in contrasting results owing to the diversity in AX structures. Four water extractable AX (WEAX) extracts obtained from wheat aleurone and bran were used to investigate (a) the effect of AX on activities of alpha-amylase and alpha-glucosidase, (b) influence of AX chemical composition on their inhibition potency, and (c) kinetics of enzyme inhibition. alpha-Amylase activity was not significantly affected by the presence WEAX fractions regardless of type or concentration. WEAX inhibited alpha-glucosidase activity only when maltose was used as a substrate but not sucrose. The IC50 values of WEAX (4.88 +/ 0.3-10.14 +/- 0.5 mg/mL) were highly correlated to ferulic acid content (R = 0.89), arabinose to xylose ratio (R = -0.67), and relative proportions of xylose being unsubstituted (R = 0.69), disubstituted (R = -0.63), and monosubstituted (R = -0.76). The Lineweaver-Burk plot suggested an uncompetitive enzyme inhibition mode. Thus, our results suggest that antiglycemic properties of WEAX may be derived from direct inhibition of alpha-glucosidase activity. PMID- 28626591 TI - A Case of Trapezium Avascular Necrosis Treated Conservatively. AB - INTRODUCTION: Avascular necrosis (AVN) of the bones of the wrist most commonly involves the lunate followed by the proximal pole of the scaphoid and the capitate. Trapezium avascular necrosis is extremely rare with only two cases reported in the literature, both of which were treated surgically. In this article, we report a unique case of trapezium avascular necrosis treated conservatively. CASE PRESENTATION: A 38-year-old man complaining of a 4-month history of mild pain on the base of his right thumb. MRI scan was performed. The clinical presentation and the imaging findings indicated avascular osteonecrosis of the trapezium. The patient was treated with immobilization of the wrist joint for a period of six weeks. Three months later, the patient was free of symptoms and the MRI scan revealed a normal trapezium. CONCLUSION: AVN of trapezium is extremely rare. Our case shows that immobilization of an early stage avascular necrosis of the trapezium might be a treatment option. PMID- 28626592 TI - Diffuse B Cell Non-Hodgkin's Lymphoma Presenting Atypically as Periprosthetic Joint Infection in a Total Hip Replacement. AB - The occurrence of extranodal primary B cell non-Hodgkin's lymphoma is rare. Total hip replacement is one of the most common orthopaedic procedures performed. There has been an increased incidence of primary lymphomas involving periprosthetic sites. Chronic inflammation due to metal debris arising from the prosthetic implants has been evidenced as one of the causes for the development of soft tissue lymphomas albeit rarely. We describe a case report of a 77-year-old patient who had underwent a cemented total hip replacement in the past who further developed large B cell primary non-Hodgkin's lymphoma. She presented initially with signs and symptoms highly suggestive of underlying periprosthetic infection. The radiological imaging was also indicative of periprosthetic infection. The diagnosis was eventually confirmed after an open biopsy. This case underlines the importance of considering and including soft tissue malignancy in the differential diagnosis of suspected chronic periprosthetic infection. PMID- 28626593 TI - Langerhans Cell Sarcoma: A Case Report Demonstrating Morphological and Immunophenotypical Variability within a Single Lesion. AB - Langerhans cells are antigen presenting dendritic cells and tumours arising from these are rare. The tumours arising from these dendritic cells are divided into two categories according to a WHO classification: Langerhans cell histiocytosis and Langerhans cell sarcoma. It is the degree of atypia and clinical aggressiveness that distinguishes the two subtypes. Langerhans cell sarcoma (LCS) is a neoplastic proliferation of Langerhans cells which can occur in skin, bone marrow, lymph nodes, spleen, liver, and lung. LCS can present with multiple cutaneous and systemic lesions. We present a case of Langerhans cell sarcoma with a unique morphological appearance and variable immunohistochemical profile within a single cutaneous lesion. LCS is a rare malignancy and its diagnosis is based on morphology, immunophenotypical examination, and ultrastructural analysis by electron microscopy. Our case highlights a unique morphological description of LCS wherein the pleomorphic neoplastic cells show epidermotropism and are surrounded by a variable amount of inflammatory infiltrate within a single cutaneous lesion. A single cutaneous lesion of Langerhans cell sarcoma with variable immunohistochemical profile has not been described so far. PMID- 28626594 TI - A Case Report: Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm with Aggressive Neuroendocrine Component. AB - Mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) is defined as mixed epithelial neoplasms composed of both neuroendocrine and nonneuroendocrine components with variable proportions for each component. Neuroendocrine component can show morphological features including well- or poorly differentiated neuroendocrine neoplasms and nonneuroendocrine component can present different tumor types depending on the site of origin. Recently, studies of tumors have shown that MiNENs are not as rare as our traditional belief, due to the wide application for immunohistochemistry. However, our knowledge of MiNENs is still limited. There is no universal consensus about nomenclature, classification, and guideline of treatment. Hereby, we would like to present a case report of gastric MiNEN with aggressive neuroendocrine component to contribute a small part towards common understanding of gastric MiNENs. PMID- 28626595 TI - Williams-Beuren Syndrome and Congenital Lobar Emphysema: Uncommon Association with Common Pathology? AB - INTRODUCTION: Congenital lobar emphysema (CLE) and Williams-Beuren Syndrome are two rare conditions that have only been reported together in a single case study. CASE PRESENTATION: We report another case of a male Caucasian newborn with nonspecific initial respiratory distress, with detection of CLE on repeat chest X ray on Day 25 of life and concurrent ventricular septal defect, supravalvular aortic stenosis, and branch pulmonary stenosis, in whom a 7q11.23 deletion consistent with Williams-Beuren Syndrome was made. CONCLUSION: A diagnosis of congenital lobar emphysema should prompt further screening for congenital heart disease and genetic deletion, and further research is needed to investigate the role of elastin gene mutation in the development of the neonatal lung. PMID- 28626596 TI - Management of Severe Developmental Regression in an Autistic Child with a 1q21.3 Microdeletion and Self-Injurious Blindness. AB - We report the case of a young boy with nonverbal autism and intellectual disability, with a rare de novo 1q21.3 microdeletion. The patient had early and extreme self-injurious behaviours that led to blindness, complicated by severe developmental regression. A significant reduction in the self-injurious behaviours and the recovery of developmental dynamics were attained in a multidisciplinary neurodevelopmental inpatient unit. Improvement was obtained after managing all causes of somatic pains, using opiate blockers and stabilizing the patient's mood. We offered both sensorimotor developmental approach with therapeutic body wrap and specific psychoeducation adapted to his blindness condition for improving his communication abilities. PMID- 28626597 TI - Substance Abuse Counselors' Recovery Status and Self-Schemas: Preliminary Implications for Empirically Supported Treatment Implementation. AB - PURPOSE: The purpose of this paper is to better understand the relationship between substance abuse counselors' personal recovery status, self-schemas, and willingness to use empirically supported treatments for substance use disorders. METHODS: A phenomenological qualitative study enrolled 12 practicing substance abuse counselors. RESULTS: Within this sample, recovering counselors tended to see those who suffer from addiction as qualitatively different from those who do not and hence themselves as similar to their patients, while nonrecovering counselors tended to see patients as experiencing a specific variety of the same basic human struggles everyone experiences, and hence also felt able to relate to their patients' struggles. DISCUSSION: Since empirically supported treatments may fit more or less neatly within one or the other of these viewpoints, this finding suggests that counselors' recovery status and corresponding self-schemas may be related to counselor willingness to learn and practice specific treatments. PMID- 28626598 TI - Design concerns of room and pillar retreat panels. AB - Why do some room and pillar retreat panels encounter abnormal conditions? What factors deserve the most consideration during the planning and execution phases of mining and what can be done to mitigate those abnormal conditions when they are encountered? To help answer these questions, and to determine some of the relevant factors influencing the conditions of room and pillar (R & P) retreat mining entries, four consecutive R & P retreat panels were evaluated. This evaluation was intended to reinforce the influence of topographic changes, depth of cover, multiple-seam interactions, geological conditions, and mining geometry. This paper details observations were made in four consecutive R & P retreat panels and the data were collected from an instrumentation site during retreat mining. The primary focus was on the differences observed among the four panels and within the panels themselves. The instrumentation study was initially planned to evaluate the interactions between primary and secondary support, but produced rather interesting results relating to the loading encountered under the current mining conditions. In addition to the observation and instrumentation, numerical modeling was performed to evaluate the stress conditions. Both the LaModel 3.0 and Rocscience Phase 2 programs were used to evaluate these four panels. The results of both models indicated a drastic reduction in the vertical stresses experienced in these panels due to the full extraction mining in overlying seams when compared to the full overburden load. Both models showed a higher level of stress associated with the outside entries of the panels. These results agree quite well with the observations and instrumentation studies performed at the mine. These efforts provided two overarching conclusions concerning R & P retreat mine planning and execution. The first was that there are four areas that should not be overlooked during R & P retreat mining: topographic relief, multiple-seam stress relief, stress concentrations near the gob edge, and geologic changes in the immediate roof. The second is that in order to successfully retreat an R & P panel, a three-phased approach to the design and analysis of the panel should be conducted: the planning phase, evaluation phase, and monitoring phase. PMID- 28626600 TI - Distant brain recurrence in patients with five or more newly diagnosed brain metastases treated with focal stereotactic radiotherapy alone. AB - BACKGROUND: To assess the clinical outcomes in patients with greater than 4 newly diagnosed brain metastases treated with focal stereotactic radiotherapy alone. METHODS: All patients with five or more brain metastases who received focal radiotherapy without whole brain radiation or resection were included in this retrospective analysis. Distant brain failure (DBF), overall survival (OS) and toxicity were reported. RESULTS: Thirty-six patients met inclusion with median clinical follow-up of 6.3 months (range: 1.1, 51.4). Twenty-nine patients received stereotactic radiosurgery (SRS) to a median dose of 20 Gy (16-20), and 7 received fractionated stereotactic radiotherapy (FSRT) to a median dose of 30 Gy (25, 30) in five fractions. The median lesion number and total brain metastases volume was 6 (5, 14) and 1.55 cc (0.12, 32.96), respectively. The Kaplan-Meier estimate of DBF at six-month was 58%, and survival probability at 1 year was 49%. Twenty percent of patients experienced systemic death without CNS relapse. Eight percent experienced grade 3 toxicity with no grade 4 or 5 toxicity. Neither tumor volume nor number predicted DBF. CONCLUSIONS: DBF, OS and treatment toxicity were similar to historical controls with fewer than five metastases treated with focal radiation. Focal stereotactic radiotherapy alone without whole brain RT is a reasonable treatment strategy for five or more brain metastases. PMID- 28626599 TI - Breaking Amides using Nickel Catalysis. AB - Amides have been widely studied for decades, but their synthetic utility has remained limited in reactions that proceed with rupture of the amide C-N bond. Using Ni catalysis, we have found that amides can now be strategically employed in several important transformations: esterification, transamidation, Suzuki Miyaura couplings, and Negishi couplings. These methodologies provide exciting new tools to build C-heteroatom and C-C bonds using an unconventional reactant (i.e., the amide), which is ideally suited for use in multi-step synthesis. It is expected that the area of amide C-N bond activation using nonprecious metals will continue to flourish and, in turn, will promote the growing use of amides as synthons in organic synthesis. PMID- 28626601 TI - Long-Term Efficacy of GMP Grade Xeno-Free hESC-Derived RPE Cells Following Transplantation. AB - PURPOSE: Retinal pigment epithelium (RPE) dysfunction underlies the retinal degenerative process in age-related macular degeneration (AMD), and thus RPE cell replacement provides an optimal treatment target. We characterized longitudinally the efficacy of RPE cells derived under xeno-free conditions from clinical and xeno-free grade human embryonic stem cells (OpRegen) following transplantation into the subretinal space of Royal College of Surgeons (RCS) rats. METHODS: Postnatal (P) day 20 to 25 RCS rats (n = 242) received a single subretinal injection of 25,000 (low)-, 100,000 (mid)-, or 200,000 (high)-dose xeno-free RPE cells. BSS+ (balanced salt solution) (vehicle) and unoperated eyes served as controls. Optomotor tracking (OKT) behavior was used to quantify functional efficacy. Histology and immunohistochemistry were used to evaluate photoreceptor rescue and transplanted cell survival at 60, 100, 150, and 200 days of age. RESULTS: OKT was rescued in a dose-dependent manner. Outer nuclear layer (ONL) was significantly thicker in cell-treated eyes than controls up to P150. Transplanted RPE cells were identified in both the subretinal space and integrated into the host RPE monolayer in animals of all age groups, and often contained internalized photoreceptor outer segments. No pathology was observed. CONCLUSIONS: OpRegen RPE cells survived, rescued visual function, preserved rod and cone photoreceptors long-term in the RCS rat. Thus, these data support the use of OpRegen RPE cells for the treatment of human RPE cell disorders including AMD. TRANSLATIONAL RELEVANCE: Our novel xeno-free RPE cells minimize concerns of animal derived contaminants while providing a promising prospective therapy to the diseased retina. PMID- 28626603 TI - Impact of isolation method on doubling time and the quality of chondrocyte and osteoblast differentiated from murine dental pulp stem cells. AB - BACKGROUND: Stem cells are normally isolated from dental pulps using the enzymatic digestion or the outgrowth method. However, the effects of the isolation method on the quality of the isolated stem cells are not studied in detail in murine models. The aim of this study was to compare the matrices secreted by osteoblast and chondrocytes differentiated from dental pulp stem cells isolated through different means. METHOD: DPSC from murine incisors were isolated through either the outgrowth (DPSC-OG) or the enzymatic digestion (DPSC ED) method. Cells at passage 4 were used in this study. The cells were characterized through morphology and expression of cell surface markers. The cells' doubling time when cultured using different seeding densities was calculated and analyzed using one-way ANOVA and Tukey's multiple comparison post test. The ability of cells to differentiate to chondrocyte and osteoblast was evaluated through staining and analysis on the matrices secreted. RESULTS: Gene expression analysis showed that DPSC-OG and DPSC-ED expressed dental pulp mesenchymal stem cell markers, but not hematopoietic stem cell markers. The least number of cells that could have been used to culture DPSC-OG and DPSC-ED with the shortest doubling time was 5 * 102 cells/cm2 (11.49 +/- 2.16 h) and 1 * 102 cells/cm2 (10.55 h +/- 0.50), respectively. Chondrocytes differentiated from DPSC ED produced 2 times more proteoglycan and at a faster rate than DPSC-OG. FTIR revealed that DPSC-ED differentiated into osteoblast also secreted matrix, which more resembled a calvaria. DISCUSSION: Isolation approaches might have influenced the cell populations obtained. This, in turn, resulted in cells with different proliferation and differentiation capability. While both DPSC-OG and DPSC-ED expressed mesenchymal stem cell markers, the percentage of cells carrying each marker might have differed between the two methods. Regardless, enzymatic digestion clearly yielded cells with better characteristics than outgrowth. PMID- 28626602 TI - Association between Corneal Biomechanical Properties with Ocular Response Analyzer and Also CorvisST Tonometry, and Glaucomatous Visual Field Severity. AB - PURPOSE: To investigate the association between corneal biomechanical properties measured with the Ocular Response Analyzer (ORA) and also CorvisST (CST) tonometry, and glaucomatous visual field (VF) severity. METHODS: One hundred forty-six eyes of 91 patients with primary open-angle glaucoma who performed Humphrey Field Analyzer 30-2 or 24-2 SITA-Standard, ORA, and CST within 180 days were included in this multicentral, observational cross-sectional study. The association between ORA parameters (corneal hysteresis [CH] and corneal resistant factor [CRF]), CST parameters (A1 and A2 time, A1 and A2 length, A1 and A2 velocity, A1 and A2 deformation amplitude, highest deformation amplitude, highest concavity time, peak distance, and radius), and other basic parameters (age, intraocular pressure with Goldmann applanation tonometry, central corneal thickness, and axial length) against mean total deviation (mTD) were analyzed using a linear mixed-model and model selection with corrected Akaike Information Criterion (AICc). RESULTS: The optimal model of VF severity included ORA's CH as well as a number of CST parameters, including A1 length, A2 time, radius, and highest concavity deformation amplitude (AICc: 971.7). The possibility this model describes visual field severity more accurately than the optimal model without CST parameters was 99.98%. CONCLUSION: Glaucomatous VF severity was best described by both ORA and CST parameters. Eyes with corneas that experience sharp and deep indentation at the maximum deformation, wide indentation at the first applanation, and early second applanation in the CST measurement are more likely to show advanced VF severity. TRANSLATIONAL RELEVANCE: CorvisST tonometry parameters are related to VF severity in glaucoma patients. PMID- 28626604 TI - Seasonal shifts in accumulation of glycerol biosynthetic gene transcripts in mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae), larvae. AB - Winter mortality is a major factor regulating population size of the mountain pine beetle, Dendroctonus ponderosae Hopkins (Coleoptera: Curculionidae). Glycerol is the major cryoprotectant in this freeze intolerant insect. We report findings from a gene expression study on an overwintering mountain pine beetle population over the course of 35 weeks. mRNA transcript levels suggest glycerol production in the mountain pine beetle occurs through glycogenolytic, gluconeogenic and potentially glyceroneogenic pathways, but not from metabolism of lipids. A two-week lag period between fall glycogen phosphorylase transcript and phosphoenolpyruvate carboxykinase transcript up-regulation suggests that gluconeogenesis serves as a secondary glycerol-production process, subsequent to exhaustion of the primary glycogenolytic source. These results provide a first look at the details of seasonal gene expression related to the production of glycerol in the mountain pine beetle. PMID- 28626605 TI - No relationship between vertebral column shifts and limb fluctuating asymmetry in human foetuses. AB - Disturbance from the normal developmental trajectory of a trait during growth-the so-called developmental instability-can be observed morphologically through phenodeviants and subtle deviations from perfect symmetry (fluctuating asymmetry). This study investigates the relationship between phenodeviance in the human vertebral column (as a result of axial patterning defects) and limb fluctuating asymmetry. Since both types of markers of developmental instability have been found associated with congenital abnormalities in humans, we anticipate a relationship between them if the concept of developmental instability, measured through either phenodeviants or asymmetry, would reflect an organism-wide process. Yet we did not find any support for this hypothesis. We argue that the vast differences in the developmental processes involved in both systems renders these two markers of developmental instability unrelated, in spite of their associations with other congenital abnormalities. Our results thus contribute to the growing awareness that developmental instability is not an organism-wide property. PMID- 28626606 TI - The ways parents cope with stress in difficult parenting situations: the structural equation modeling approach. AB - The purpose of this study was to verify a theoretical model of parents' responses to difficulties they experienced with their child. The model presents relationships between seven variables: (a) discrepancy between parental goal and the child's current level of development, (b) parental experience of a difficulty, (c) representation of the child in the parent's mind, (d) parent's withdrawal from the parenting situation, (e) seeking help, (f) distancing oneself from the situation, and (g) applying pressure on the child. The study involved 319 parents of preschool children: 66 parents of three-year-olds, 85 parents of four-year-olds, 99 parents of five-year-olds and 69 parents of six-year-old children. Structural equations modeling (SEM) was used to verify the compounds described in the theoretical model. The studies revealed that when a parent is experiencing difficulties, the probability increases that the parent will have one of two reactions towards that type of stress: withdrawal from the situation or applying pressure on the child. Experiencing difficulties has no connection with searching for help and is negatively related to distancing oneself from the situation. PMID- 28626607 TI - Phenotypic variation in dorsal fin morphology of coastal bottlenose dolphins (Tursiops truncatus) off Mexico. AB - Geographic variation in external morphology is thought to reflect an interplay between genotype and the environment. Morphological variation has been well described for a number of cetacean species, including the bottlenose dolphin (Tursiops truncatus). In this study we analyzed dorsal fin morphometric variation in coastal bottlenose dolphins to search for geographic patterns at different spatial scales. A total of 533 dorsal fin images from 19 available photo identification catalogs across the three Mexican oceanic regions (Pacific Ocean n = 6, Gulf of California n = 6 and, Gulf of Mexico n = 7) were used in the analysis. Eleven fin shape measurements were analyzed to evaluate fin polymorphism through multivariate tests. Principal Component Analysis on log transformed standardized ratios explained 94% of the variance. Canonical Discriminant Function Analysis on factor scores showed separation among most study areas (p < 0.05) with exception of the Gulf of Mexico where a strong morphometric cline was found. Possible explanations for the observed differences are related to environmental, biological and evolutionary processes. Shape distinction between dorsal fins from the Pacific and those from the Gulf of California were consistent with previously reported differences in skull morphometrics and genetics. Although the functional advantages of dorsal fin shape remains to be assessed, it is not unlikely that over a wide range of environments, fin shape may represent a trade-off among thermoregulatory capacity, hydrodynamic performance and the swimming/hunting behavior of the species. PMID- 28626608 TI - c-Kit modifies the inflammatory status of smooth muscle cells. AB - BACKGROUND: c-Kit is a receptor tyrosine kinase present in multiple cell types, including vascular smooth muscle cells (SMC). However, little is known about how c-Kit influences SMC biology and vascular pathogenesis. METHODS: High-throughput microarray assays and in silico pathway analysis were used to identify differentially expressed genes between primary c-Kit deficient (KitW/W-v) and control (Kit+/+) SMC. Quantitative real-time RT-PCR and functional assays further confirmed the differences in gene expression and pro-inflammatory pathway regulation between both SMC populations. RESULTS: The microarray analysis revealed elevated NF-kappaB gene expression secondary to the loss of c-Kit that affects both the canonical and alternative NF-kappaB pathways. Upon stimulation with an oxidized phospholipid as pro-inflammatory agent, c-Kit deficient SMC displayed enhanced NF-kappaB transcriptional activity, higher phosphorylated/total p65 ratio, and increased protein expression of NF-kappaB regulated pro-inflammatory mediators with respect to cells from control mice. The pro-inflammatory phenotype of mutant cells was ameliorated after restoring c-Kit activity using lentiviral transduction. Functional assays further demonstrated that c-Kit suppresses NF-kappaB activity in SMC in a TGFbeta-activated kinase 1 (TAK1) and Nemo-like kinase (NLK) dependent manner. DISCUSSION: Our study suggests a novel mechanism by which c-Kit suppresses NF-kappaB regulated pathways in SMC to prevent their pro-inflammatory transformation. PMID- 28626610 TI - Tiny pollen grains: first evidence of Saururaceae from the Late Cretaceous of western North America. AB - BACKGROUND: The Saururaceae, a very small family of Piperales comprising only six species in four genera, have a relatively scanty fossil record outside of Europe. The phylogenetic relationships of the four genera to each other are resolved, with the type genus Saururus occurring in both eastern North America and East Asia. No extant species occurs in western Eurasia. The most exceptional find so far has been an inflorescence with in-situ pollen, Saururus tuckerae S.Y.Sm. & Stockey from Eocene of North America with strong affinities to extant species of Saururus. Recent dated trees suggest, however, an Eocene or younger crown age for the family. METHODS: Dispersed fossil pollen grains from the Campanian (82-81 Ma) of North America are compared to dispersed pollen grains from the Eocene strata containing S. tuckerae, the Miocene of Europe, and extant members of the family using combined LM and SEM imaging. RESULTS: The unambiguous fossil record of the Saururaceae is pushed back into the Campanian (82-81 Ma). Comparison with re investigated pollen from the Eocene of North America, the Miocene of Europe, and modern species of the family shows that pollen morphology in Saururaceae is highly conservative, and remained largely unchanged for the last 80 million years. DISCUSSION: Campanian pollen of Saururaceae precludes young (Eocene or younger) estimates for the Saururaceae root and crown age, but is in-line with maximum age scenarios. Saururus-type pollen appear to represent the primitive pollen morphology of the family. Often overlooked because of its small size, dispersed Saururaceae pollen may provide a unique opportunity to map the geographic history of a small but old group of Piperales, and should be searched for in Paleogene and Cretaceous sediment samples. PMID- 28626609 TI - Detection and drug resistance profile of Escherichia coli from subclinical mastitis cows and water supply in dairy farms in Saraburi Province, Thailand. AB - Subclinical mastitis is a persistent problem in dairy farms worldwide. Environmental Escherichia coli is the bacterium predominantly responsible for this condition. In Thailand, subclinical mastitis in dairy cows is usually treated with various antibiotics, which could lead to antibiotic resistance in bacteria. E. coli is also a reservoir of many antibiotic resistance genes, which can be conveyed to other bacteria. In this study, the presence of E. coli in milk and water samples was reported, among which enteropathogenic E. coli was predominant, followed by enteroaggregative E. coli and enterohemorrhagic E. coli, which was found only in milk samples. Twenty-one patterns of antibiotic resistance were identified in this study. Ampicillin- and carbenicillin-resistant E. coli was the most common among the bacterial isolates from water samples. Meanwhile, resistance to ampicillin, carbenicillin, and sulfamethoxazole trimethoprim was the pattern found most commonly in the E. coli from milk samples. Notably, only the E. coli from water samples possessed ESBL phenotype and carried antibiotic resistance genes, blaTEM and blaCMY-2. This indicates that pathogenic E. coli in dairy farms is also exposed to antibiotics and could potentially transfer these genes to other pathogenic bacteria under certain conditions. PMID- 28626611 TI - Discrimination factors of carbon and nitrogen stable isotopes in meerkat feces. AB - Stable isotope analysis of feces can provide a non-invasive method for tracking the dietary habits of nearly any mammalian species. While fecal samples are often collected for macroscopic and genetic study, stable isotope analysis can also be applied to expand the knowledge of species-specific dietary ecology. It is somewhat unclear how digestion changes the isotope ratios of animals' diets, so more controlled diet studies are needed. To date, most diet-to-feces controlled stable isotope experiments have been performed on herbivores, so in this study I analyzed the carbon and nitrogen stable isotope ratios in the diet and feces of the meerkat (Suricata suricatta), a small omnivorous mammal. The carbon trophic discrimination factor between diet and feces (Delta13Cfeces) is calculated to be 0.1 +/- 1.50/00, which is not significantly different from zero, and in turn, not different than the dietary input. On the other hand, the nitrogen trophic discrimination factor (Delta15Nfeces) is 1.5 +/- 1.10/00, which is significantly different from zero, meaning it is different than the average dietary input. Based on data generated in this experiment and a review of the published literature, carbon isotopes of feces characterize diet, while nitrogen isotope ratios of feces are consistently higher than dietary inputs, meaning a discrimination factor needs to be taken into account. The carbon and nitrogen stable isotope values of feces are an excellent snapshot of diet that can be used in concert with other analytical methods to better understand ecology, diets, and habitat use of mammals. PMID- 28626612 TI - Postmortem succession of gut microbial communities in deceased human subjects. AB - The human microbiome has demonstrated an importance for the health and functioning in living individuals. However, the fate of the microbiome after death is less understood. In addition to a better understanding of microbe mediated decomposition processes, postmortem succession of human-associated microbial communities has been suggested as a possible forensic tool for estimating time since death, or postmortem interval (PMI). The objective of our study was to document postmortem changes in human gut bacterial communities. Gut microflora were repeatedly sampled from the caeca of cadavers as they decayed under natural environmental conditions. 16S rRNA gene amplicon sequencing revealed that over time, bacterial richness significantly increased (rs = 0.449) while diversity decreased (rs = - 0.701). The composition of gut bacterial communities changed in a similar manner over time towards a common decay community. OTUs belonging to Bacteroidales (Bacteroides, Parabacteroides) significantly declined while Clostridiales (Clostridium, Anaerosphaera) and the fly-associated Gammaproteobacteria Ignatzschineria and Wohlfahrtiimonas increased. Our examination of human caeca microflora in decomposing cadavers adds to the growing literature on postmortem microbial communities, which will ultimately contribute to a better understanding of decomposition processes. PMID- 28626613 TI - Modelling environmental drivers of black band disease outbreaks in populations of foliose corals in the genus Montipora. AB - Seawater temperature anomalies associated with warming climate have been linked to increases in coral disease outbreaks that have contributed to coral reef declines globally. However, little is known about how seasonal scale variations in environmental factors influence disease dynamics at the level of individual coral colonies. In this study, we applied a multi-state Markov model (MSM) to investigate the dynamics of black band disease (BBD) developing from apparently healthy corals and/or a precursor-stage, termed 'cyanobacterial patches' (CP), in relation to seasonal variation in light and seawater temperature at two reef sites around Pelorus Island in the central sector of the Great Barrier Reef. The model predicted that the proportion of colonies transitioning from BBD to Healthy states within three months was approximately 57%, but 5.6% of BBD cases resulted in whole colony mortality. According to our modelling, healthy coral colonies were more susceptible to BBD during summer months when light levels were at their maxima and seawater temperatures were either rising or at their maxima. In contrast, CP mostly occurred during spring, when both light and seawater temperatures were rising. This suggests that environmental drivers for healthy coral colonies transitioning into a CP state are different from those driving transitions into BBD. Our model predicts that (1) the transition from healthy to CP state is best explained by increasing light, (2) the transition between Healthy to BBD occurs more frequently from early to late summer, (3) 20% of CP infected corals developed BBD, although light and temperature appeared to have limited impact on this state transition, and (4) the number of transitions from Healthy to BBD differed significantly between the two study sites, potentially reflecting differences in localised wave action regimes. PMID- 28626614 TI - Identification of two CiGADs from Caragana intermedia and their transcriptional responses to abiotic stresses and exogenous abscisic acid. AB - BACKGROUND: Glutamate decarboxylase (GAD), as a key enzyme in the gamma aminobutyric acid (GABA) shunt, catalyzes the decarboxylation of L-glutamate to form GABA. This pathway has attracted much interest because of its roles in carbon and nitrogen metabolism, stress responses, and signaling in higher plants. The aim of this study was to isolate and characterize genes encoding GADs from Caragana intermedia, an important nitrogen-fixing leguminous shrub. METHODS: Two full-length cDNAs encoding GADs (designated as CiGAD1 and CiGAD2) were isolated and characterized. Multiple alignment and phylogenetic analyses were conducted to evaluate their structures and identities to each other and to homologs in other plants. Tissue expression analyses were conducted to evaluate their transcriptional responses to stress (NaCl, ZnSO4, CdCl2, high/low temperature, and dehydration) and exogenous abscisic acid. RESULTS: The CiGADs contained the conserved PLP domain and calmodulin (CaM)-binding domain in the C-terminal region. The phylogenetic analysis showed that they were more closely related to the GADs of soybean, another legume, than to GADs of other model plants. According to Southern blotting analysis, CiGAD1 had one copy and CiGAD2-related genes were present as two copies in C. intermedia. In the tissue expression analyses, there were much higher transcript levels of CiGAD2 than CiGAD1 in bark, suggesting that CiGAD2 might play a role in secondary growth of woody plants. Several stress treatments (NaCl, ZnSO4, CdCl2, high/low temperature, and dehydration) significantly increased the transcript levels of both CiGADs, except for CiGAD2 under Cd stress. The CiGAD1 transcript levels strongly increased in response to Zn stress (74.3-fold increase in roots) and heat stress (218.1-fold increase in leaves). The transcript levels of both CiGADs significantly increased as GABA accumulated during a 24-h salt treatment. Abscisic acid was involved in regulating the expression of these two CiGADs under salt stress. DISCUSSION: This study showed that two CiGADs cloned from C. intermedia are closely related to homologs in another legume, soybean. CiGAD2 expression was much higher than that of CiGAD1 in bark, indicating that CiGAD2 might participate in the process of secondary growth in woody plants. Multiple stresses, interestingly, showed that Zn and heat stresses had the strongest effects on CiGAD1 expression, suggesting that CiGAD1 plays important roles in the responses to Zn and heat stresses. Additionally, these two genes might be involved in ABA dependent pathway during stress. This result provides important information about the role of GADs in woody plants' responses to environmental stresses. PMID- 28626615 TI - Getting off to a good start? Genetic evaluation of the ex situ conservation project of the Critically Endangered Montseny brook newt (Calotriton arnoldi). AB - Ex situ management strategies play an important role in the conservation of threatened species when the wild survival of the species cannot be ensured. Molecular markers have become an outstanding tool for the evaluation and management of captive breeding programs. Two main genetic objectives should be prioritized when planning breeding programs: the maintenance of maximum neutral genetic diversity, and to obtain "self-sustaining" captive populations. In this study, we use 24 microsatellite loci to analyze and evaluate the genetic representativity of the initial phases of the captive breeding program of the Montseny brook newt, Calotriton arnoldi, an Iberian endemic listed as Critically Endangered. The results show that the initial captive stock has 74-78% of the alleles present in the wild populations, and captures roughly 93-95% of their total genetic diversity as observed in a previous study on wild newts, although it does not reach the desired 97.5%. Moreover, the percentage of unrelatedness among individuals does not exceed 95%. Therefore, we conclude that the genetic diversity of the captive stock should be improved by incorporating genetic material from unrelated wild newts. In recognition of the previously described significant genetic and morphological differentiation between eastern and western wild populations of C. arnoldi, we suggest maintaining two distinct breeding lines, and we do not recommend outbreeding between these lines. Our comparisons of genetic diversity estimates between real and distinct sample-sized simulated populations corroborated that a minimum of 20 individuals are needed for each captive population, in order to match the level of genetic diversity present in the wild populations. Thus, the current initial stock should be reinforced by adding wild specimens. The captive stock and subsequent cohorts should be monitored in order to preserve genetic variation. In order to avoid genetic adaptation to captivity, occasionally incorporating previously genotyped individuals from the wild into the captive populations is recommended. PMID- 28626616 TI - Discrimination of Picea chihuahuana Martinez populations on the basis of climatic, edaphic, dendrometric, genetic and population traits. AB - BACKGROUND: Picea chihuahuana, which is endemic to Mexico, is currently listed as "Endangered" on the Red List. Chihuahua spruce is only found in the Sierra Madre Occidental (SMO), Mexico. About 42,600 individuals are distributed in forty populations. These populations are fragmented and can be classified into three geographically distinct clusters in the SMO. The total area covered by P. chihuahuana populations is less than 300 ha. A recent study suggested assisted migration as an alternative to the ex situ conservation of P. chihuahuana, taking into consideration the genetic structure and diversity of the populations and the predictions regarding the future climate of the habitat. However, detailed background information is required to enable development of plans for protecting and conserving species and for successful assisted migration. Thus, it is important to identify differences between populations in relation to environmental conditions. The genetic diversity of populations, which affect vigor, evolution and adaptability of the species, must also be considered. In this study, we examined 14 populations of P. chihuahuana, with the overall aim of discriminating the populations and form clusters of this species. METHODS: Each population was represented by one 50 * 50 m plot established in the center of its respective location. Climate, soil, dasometric, density variables and genetic and species diversities were assessed in these plots for further analyses. The putatively neutral and adaptive AFLP markers were used to calculate genetic diversity. Affinity Propagation (AP) clustering technique and k-means clustering algorithm were used to classify the populations in the optimal number of clusters. Later stepwise binomial logistic regression was applied to test for significant differences in variables of the southern and northern P. chihuahuana populations. Spearman's correlation test was used to analyze the relationships among all variables studied. RESULTS: The binomial logistic regression analysis revealed that seven climate variables, the geographical longitude and sand proportion in the soil separated the southern from northern populations. The northern populations grow in more arid and continental conditions and on soils with lower sand proportion. The mean genetic diversity using all AFLP studied of P. chihuahuana was significantly correlated with the mean temperature in the warmest month, where warmer temperatures are associated to larger genetic diversity. Genetic diversity of P. chihuahuana calculated with putatively adaptive AFLP was not statistically significantly correlated with any environmental factor. DISCUSSION: Future reforestation programs should take into account that at least two different groups (the northern and southern cluster) of P. chihuahuana exist, as local adaptation takes place because of different environmental conditions. PMID- 28626617 TI - DOC concentrations across a depth-dependent light gradient on a Caribbean coral reef. AB - Photosynthates released by benthic primary producers (BPP), such as reef algae and scleractinian corals, fuel the dissolved organic carbon (DOC) production on tropical coral reefs. DOC concentrations near BPP have repeatedly been observed to be elevated compared to those in the surrounding water column. As the DOC release of BPP increases with increasing light availability, elevated DOC concentrations near them will, in part, also depend on light availability. Consequently, DOC concentrations are likely to be higher on the shallow, well-lit reef terrace than in deeper sections on the fore reef slope. We measured in situ DOC concentrations and light intensity in close proximity to the reef alga Dictyota sp. and the scleractinian coral Orbicella faveolata along a depth dependent light gradient from 5 to 20 m depth and compared these to background concentrations in the water column. At 10 m (intermediate light), DOC concentrations near Dictyota sp. were elevated by 15 umol C L-1 compared to background concentrations in the water column, but not at 5 and 20 m (high and low light, respectively), or near O. faveolata at any of the tested depths. DOC concentrations did not differ between depths and thereby light environments for any of the tested water types. However, water type and depth appear to jointly affect in situ DOC concentrations across the tested depth-dependent light gradient. Corroborative ex situ measurements of excitation pressure on photosystem II suggest that photoinhibition in Dictyota sp. is likely to occur at light intensities that are commonly present on Curacaoan coral reefs under high light levels at 5 m depth during midday. Photoinhibition may have thereby reduced the DOC release of Dictyota sp. and DOC concentrations in its close proximity. Our results indicate that the occurrence of elevated DOC concentrations did not follow a natural light gradient across depth. Instead, a combination of multiple factors, such as water type, light availability (including the restriction by photoinhibition), and water movement are proposed to interactively determine the DOC concentrations in the close vicinity of BPP. PMID- 28626618 TI - Cytoplasmic expression of C-MYC protein is associated with risk stratification of mantle cell lymphoma. AB - AIM: To investigate the association of C-MYC protein expression and risk stratification in mantle cell lymphoma (MCL), and to evaluate the utility of C MYC protein as a prognostic biomarker in clinical practice. METHODS: We conducted immunohistochemical staining of C-MYC, Programmed cell death ligand 1 (PD-L1), CD8, Ki-67, p53 and SRY (sex determining region Y) -11 (SOX11) to investigate their expression in 64 patients with MCL. The staining results and other clinical data were evaluated for their roles in risk stratification of MCL cases using ANOVA, Chi-square, and Spearman's Rank correlation coefficient analysis. RESULTS: Immunohistochemical staining in our study indicated that SOX11, Ki-67 and p53 presented nuclear positivity of tumor cells, CD8 showed membrane positivity in infiltrating T lymphocytes while PD-L1 showed membrane and cytoplasmic positivity mainly in macrophage cells and little in tumor cells. We observed positive staining of C-MYC either in the nucleus or cytoplasm or in both subcellular locations. There were significant differences in cytoplasmic C-MYC expression, Ki 67 proliferative index of tumor cells, and CD8 positive tumor infiltrating lymphocytes (CD8+TIL) among three risk groups (P = 0.000, P = 0.037 and P=0.020, respectively). However, no significant differences existed in the expression of nuclear C-MYC, SOX11, p53, and PD-L1 in MCL patients with low-, intermediate-, and high risks. In addition, patient age and serum LDH level were also significantly different among 3 groups of patients (P = 0.006 and P = 0.000, respectively). Spearman's rank correlation coefficient analysis indicated that cytoplasmic C-MYC expression, Ki-67 index, age, WBC, as well as LDH level had significantly positive correlations with risk stratification (P = 0.000, 0.015, 0.000, 0.029 and 0.000, respectively), while CD8+TIL in tumor microenvironment negatively correlated with risk stratification of patients (P = 0.006). Patients with increased positive cytoplasmic expression of C-MYC protein and decreased CD8+TIL appeared to be associated with a poor response to chemotherapy, but the correlation was not statistically significant. CONCLUSION: Our study suggested that assessment of cytoplasmic C-MYC overexpression and cytotoxic T lymphocytes (CTLs) by immunohistochemical staining might be helpful for MCL risk stratification and outcome prediction. However, large cohort studies of MCL patients with complete follow up are needed to validate our speculation. PMID- 28626619 TI - African penguins follow the gaze direction of conspecifics. AB - Gaze following is widespread among animals. However, the corresponding ultimate functions may vary substantially. Thus, it is important to study previously understudied (or less studied) species to develop a better understanding of the ecological contexts that foster certain cognitive traits. Penguins (Family Spheniscidae), despite their wide interspecies ecological variation, have previously not been considered for cross-species comparisons. Penguin behaviour and communication have been investigated over the last decades, but less is known on how groups are structured, social hierarchies are established, and coordination for hunting and predator avoidance may occur. In this article, we investigated how African penguins (Spheniscus demersus) respond to gaze cues of conspecifics using a naturalistic setup in a zoo environment. Our results provide evidence that members of the family Spheniscidae follow gaze of conspecifics into distant space. However, further tests are necessary to examine if the observed behaviour serves solely one specific function (e.g. predator detection) or is displayed in a broader context (e.g. eavesdropping on relevant stimuli in the environment). In addition, our findings can serve as a starting point for future cross-species comparisons with other members of the penguin family, to further explore the role of aerial predation and social structure on gaze following in social species. Overall, we also suggest that zoo-housed animals represent an ideal opportunity to extend species range and to test phylogenetic families that have not been in the focus of animal cognitive research. PMID- 28626621 TI - Simultaneous Bilateral Intertrochanteric Fractures of the Femur: A Case Report and Review of the Literature. AB - Simultaneous bilateral intertrochanteric fractures are very rare, and only a few cases have been reported in the literature. They usually result from severe trauma. They are serious injuries with high morbidity and mortality rates. Successful management of these patients involves adequate resuscitation, treatment of associated injuries, early single-stage stable fixation, and good rehabilitation. We report the case of a 47-year-old male who presented with a simultaneous bilateral intertrochanteric fracture along with associated injuries following a car crash. PMID- 28626620 TI - Tissue Chips to aid drug development and modeling for rare diseases. AB - INTRODUCTION: The technologies used to design, create and use microphysiological systems (MPS, "tissue chips" or "organs-on-chips") have progressed rapidly in the last 5 years, and validation studies of the functional relevance of these platforms to human physiology, and response to drugs for individual model organ systems, are well underway. These studies are paving the way for integrated multi organ systems that can model diseases and predict drug efficacy and toxicology of multiple organs in real-time, improving the potential for diagnostics and development of novel treatments of rare diseases in the future. AREAS COVERED: This review will briefly summarize the current state of tissue chip research and highlight model systems where these microfabricated (or bioengineered) devices are already being used to screen therapeutics, model disease states, and provide potential treatments in addition to helping elucidate the basic molecular and cellular phenotypes of rare diseases. EXPERT OPINION: Microphysiological systems hold great promise and potential for modeling rare disorders, as well as for their potential use to enhance the predictive power of new drug therapeutics, plus potentially increase the statistical power of clinical trials while removing the inherent risks of these trials in rare disease populations. PMID- 28626622 TI - An Enhanced Understanding of Therapeutic Communities Worldwide. AB - Therapeutic communities posit favorable treatment outcomes by relying on the community as the healing agent (Deleon 2000). Active treatment participation and treatment tenure are two domains that are positive predictors of positive treatment outcomes over time. Some of the more important domains that remain to be thoroughly investigated in international research on therapeutic community (TC) treatment outcome studies are the underlying effects of culture on the treatment process. Cultural components play a significant role, as also reported by various TC participants over the years (such as the effects of health literacy on sustaining abstinence from drug use over the long term, Tiburcio 2008). In recent years, health literacy has taken on a significant role in order for individuals to readily understand their needs (Schillinger et al 2002; Jorm et al 1997); or as pertains to feeling shamed in the process (Parikh et al 1996). As these and other studies suggest, the cultural competence of the providers is equally important. To our knowledge the "International TC Study" and findings presented herein constitute one of only a few studies that have conducted investigations comparing therapeutic community treatment modifications internationally, from the perspective of the participants themselves and which consider cultural components of this process. One key advantage of the resulting Qualitative datasets and analyses is that it not only includes residents' perspectives, and staff experiential elements, but importantly, incorporates staff debriefings about their respective interactions at each of the international treatment modalities, presenting well rounded depictions of each of these milieus. To that end, the data examined here presents an enhanced portrait of the provider-patient treatment dynamic, and lends voice to the various aspects of treatment participation in light of these cultural issues, and from the perspective of providers, as well as the participants. PMID- 28626623 TI - Interdisciplinary Management of a Perforated Aneurysmal Arteria Lusoria: A Case Report. AB - Background An aberrant right subclavian artery (RSA) or arteria lusoria is the most common congenital abnormality of the aortic arch with an incidence of 0.3 to 3.0%. Case Description We report a case of a perforated aneurysmal aberrant RSA, managed using a hybrid approach. Conclusion In emergency cases with acute bleeding, we recommend an endovascular approach to avoid the lethal sequel of arterial leakage. Whenever possible, the pulsatile blood flow to the right arm should be restored. Management should be tailored to the nature of the aneurysmal aberrant RSA, patient's comorbidities, and concomitant lesions. PMID- 28626624 TI - Biocompatibility and in vivo operation of implantable mesoporous PVDF-based nanogenerators. AB - The rapid developments of implantable biomedical electronics give rise to the motivation of exploring efficient and durable self-powered charging system. In this paper, we report a mesoporous polyvinylidene fluoride (PVDF)-based implantable piezoelectric nanogenerator (NG) for in vivo biomechanical energy harvesting. The NG was built with a sponge-like mesoporous PVDF film and encapsulated by polydimethylsiloxane (PDMS). After embedding this NG into rodents, a Voc of ~200 mV was produced from the gentle movement of rodent muscle. Meanwhile, no toxicity or incompatibility sign was found in the host after carrying the packaged NG for 6 weeks. Moreover, the electric output of this NG was extremely stable and exhibited no deterioration after 5 days of in vivo operation or 1.512 * 108 times mechanical deformation. This NG device could practically output a constant voltage of 52 mV via a 1 uF capacitor under living circumstance. The outstanding efficiency, magnificent durability and exceptional biocompatibility promise this mesoporous PVDF-based NG in accomplishing self powered bioelectronics with potentially lifespan operation period. PMID- 28626625 TI - Engagement in health and wellness: An online incentive-based program. AB - Increasingly, corporate health promotion programs are implementing wellness programs integrating principles of behavioral economics. Employees of a large firm were provided a customized online incentive program to design their own commitments to meet health goals. This study examines patterns of program participation and engagement in health promotion activities. Subjects were US based employees of a large, nondurable goods manufacturing firm who were enrolled in corporate health benefits in 2010 and 2011. We assessed measures of engagement with the workplace health promotion program (e.g., incentive points earned, weight loss). To further examine behaviors indicating engagement in health promotion activities, we constructed an aggregate, employee-level engagement index. Regression models were employed to assess the association between employee characteristics and the engagement index, and the engagement index and spending. 4220 employees utilized the online program and made 25,716 commitments. Male employees age 18-34 had the highest level of engagement, and male employees age 55-64 had the lowest level of engagement overall. Prior year health status and prior year spending did not show a significant association with the level of engagement with the program (p > 0.05). Flexible, incentive-based behavioral health and lifestyle programs may reach the broader workforce including those with chronic conditions and higher levels of health spending. PMID- 28626626 TI - Television viewing time among statin users and non-users. The Polish Norwegian Study (PONS). AB - Sedentary behavior has emerged as an independent cardiovascular disease risk factor. Uncertainty exists about the behaviors of statin users, who may exhibit either a healthy adherer or a false reassurance effect. We conducted this study in order to assess and compare TV viewing among statin users and nonusers. We used data from a cross-sectional study of 12,754 participants, from south-east Poland, age 45 to 64 years in 2010-11. Statin use during last 30 days was recorded by trained nurses. Participants reported time spent viewing TV/week. There were 1728 (13.5%) statin users of which 628 (36.34%) had cardiovascular diseases. The prevalence of viewing TV >= 21 h/week was higher among statin users (29.72%) compared to non-users (23.10%) and remained 15% higher after adjusting for age, sex, education, smoking, chronic obstructive pulmonary disease and other chronic diseases (prevalence ratio, PR 1.15, 95% CI 1.06 to 1.25). We found a similar pattern in both those with and without prevalent cardiovascular disease. In conclusion, we found a higher prevalence of prolonged TV-viewing among statin users than non-users. Future studies are needed to explore innovative behavioral interventions and patient counseling strategies to reduce TV viewing among statin users. PMID- 28626627 TI - Tonsillar ulceration as manifestation of disseminated African histoplasmosis in an immunocompetent Portuguese host. AB - Histoplasmosis is a systemic mycosis caused by Histoplasma capsulatum. Rare in Europe but endemic in some regions of Brazil, United States, Africa and Asia. Most of the cases are asymptomatic. Disseminated form is defined by the presence of an extra-pulmonary focus, particularly associated with immunosuppression. We report a case of an unilateral persisted tonsillar ulceration, in an immunocompetent Portuguese host, as manifestation of disseminated African histoplasmosis 45 years later after living 3 years in Africa. PMID- 28626628 TI - Assessing fracture risk in early stage breast cancer patients treated with aromatase-inhibitors: An enhanced screening approach incorporating trabecular bone score. AB - INTRODUCTION: Aromatase-inhibitors (AIs) are commonly used for treatment of patients with hormone-receptor positive breast carcinoma, and are known to induce bone density loss and increase the risk of fractures. The current standard-of care screening tool for fracture risk is bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA). The fracture risk assessment tool (FRAX(r)) may be used in conjunction with BMD to identify additional osteopenic patients at risk of fracture who may benefit from a bone-modifying agent (BMA). The trabecular bone score (TBS), a novel method of measuring bone microarchitecture by DXA, has been shown to be an independent indicator of increased fracture risk. We report how the addition of TBS and FRAX(r), respectively, to BMD contribute to identification of elevated fracture risk (EFR) in postmenopausal breast cancer patients treated with AIs. METHODS: 100 patients with early stage hormone positive breast cancer treated with AIs, no prior BMAs, and with serial DXAs were identified. BMD and TBS were measured from DXA images before and following initiation of AIs, and FRAX(r) scores were calculated from review of clinical records. EFR was defined as either: BMD <=-2.5 or BMD between -2.5 and -1 plus either increased risk by FRAX(r) or degraded microstructure by TBS. RESULTS: At baseline, BMD alone identified 4% of patients with EFR. The addition of FRAX(r) increased detection to 13%, whereas the combination of BMD, FRAX(r) and TBS identified 20% of patients with EFR. Following AIs, changes in TBS were independent of changes in BMD. On follow-up DXA, BMD alone detected an additional 1 patient at EFR (1%), whereas BMD+ FRAX(r) identified 3 additional patients (3%), and BMD+FRAX(r)+TBS identified 7 additional patients (7%). CONCLUSIONS: The combination of FRAX(r), TBS, and BMD maximized the identification of patients with EFR. TBS is a novel assessment that enhances the detection of patients who may benefit from BMAs. PMID- 28626629 TI - Arthroscopic Rotator Cuff Tear Transosseous Repair System: The Sharc-FT Using the Taylor Stitcher. AB - Transosseous rotator cuff tear repair was first described in 1944. Over the years, it has represented the gold standard for such lesions. Through open and mini-open approaches, as well as the arthroscopic approach, the transosseous repair system represents one of the most reliable surgical techniques from a biological and mechanical perspective. Nevertheless, further improvements are required. This article describes an arthroscopic rotator cuff tear transosseous repair system, developed in collaboration with NCS Lab (Carpi, Italy): the Sharc FT using the Taylor Stitcher. Our first experience in the clinical application of the arthroscopic technique using the transosseous suture system has shown encouraging clinical outcomes, confirming its efficacy. The patient satisfaction rate was high, and no patient expressed concern about the implant. The complication rate was very low. By improving the suture technique in the treatment of rotator cuff tears, a remarkable increase in the success rate in the treatment of this pathology could be reached; nevertheless, complications such as retears of the rotator cuff still occur. PMID- 28626630 TI - Arthroscopic Removal of Proximal Humerus Plates in Chronic Post-traumatic Shoulder Stiffness. AB - Proximal humerus fracture fixation may be complicated by persistent postsurgical stiffness or implant-related problems. Arthroscopic plate removal is a cosmetic and functionally beneficial procedure; however, the procedure is technically difficult in the presence of severe subdeltoid scarring. The technique described here shows an arthroscopic subdeltoid adhesiolysis and proximal humerus plate removal using systematic access to 5 regions of screw positions on the plate. After initial glenohumeral adhesiolysis, a thorough subacromial and subdeltoid bursectomy is performed. The axillary nerve and deltoid are retracted via an anterosuperolateral portal, and a posterolateral portal is used for panoramic viewing along the plate length. Lateral portals are placed above and below the axillary nerve, and these are used for screw removal. Finally, the plate is removed via a 1-inch incision along the previous surgical scar. The technique is cosmetic and minimally invasive, and early rehabilitation restores range of motion and strength. Technical tips for safe dissection in the scarred subdeltoid space and guidelines for protection of neurovascular structures are presented. PMID- 28626631 TI - Chronic eosinophilic pneumonia: Adjunctive therapy with inhaled steroids. AB - Idiopathic chronic eosinophilic pneumonia (ICEP) is a rare form of diffuse parenchymal lung disease first identified by Carrington et al. in 1969. It is characterized by the presence of constitutional and respiratory symptoms with associated peripheral opacities on imaging and elevated serum and/or bronchoalveolar eosinophilia. Although data is limited regarding etiology or prevalence, it is known that ICEP has a 2:1 female: male predominance and typically affects non-smokers. Diagnosis rests on the clinical constellation of respiratory symptoms of at least 2-4 weeks duration, the presence of diffuse pulmonary alveolar consolidation, classically described as the "photographic negative of pulmonary edema", the presence of eosinophils >=40% on bronchoalveolar lavage or >=1000/mm3 eosinophils on peripheral blood and the exclusion of other known causes of eosinophilic lung diseases such as drugs, toxins, fungi, parasites, and collagen-vascular disorders. A dramatic response is achieved with systemic corticosteroids, which is typically dosed over 6 months to 1 year. Despite this response, approximately 30-50% of patients will relapse upon cessation of steroids or during the taper. Although these patients respond well to another trial of steroids, the side effects of long term steroids are well known, including osteoporosis, diabetes, hypertension and cataracts. Inhaled corticosteroids as monotherapy has been trialed in the past without success. However, we report a case of a patient who underwent treatment with systemic corticosteroids followed by inhaled steroids who has remained in remission for 2 years. PMID- 28626632 TI - Synchronous mucinous and non-mucinous lung adenocarcinomas with different epidermal growth mutational status. AB - In recent years, the spread of more-sensitive diagnostic methods has resulted in an increase of synchronous multiple primary lung cancer diagnosis. Nevertheless, its occurrence is still rare. Distinction between synchronous lesions from second independent primary tumors is a problem when dealing with multiple lung tumors, particularly if the histological type is the same. We present a case report of a 78-year-old female patient referred to our institution due to pneumonia. A subsequent thoracic computed tomography (CT) was performed showing two suspicious lesions, one in the right upper lobe and the other in the right inferior lobe. The CT-guided transthoracic needle biopsy of both pulmonary lesions revealed two adenocarcinomas, but with a rare combination of distinct morphologic variants, as well as different immunophenotypes and epidermal growth factor receptor (EGFR) gene status. The patient refused surgery and was submitted to stereotactic body radiation therapy (SBRT). She maintained tight follow-up and until now, she has not shown any signs of relapse or metastasis. A multidisciplinary approach with clinical, morphologic and molecular evaluation in multiple lung cancer is important to diagnosis and treatment guidance. PMID- 28626633 TI - Mediastinal hemangioendothelioma: Case report and review of the literature. AB - BACKGROUND: Epithelioid haemangioendothelioma (EHE) is a rare low-grade vascular neoplasm that can arise in the lung, liver, soft tissues or, less commonly, bone. Due to its low prevalence of less than one in a million and its non-specific clinical features, EHE is often misdiagnosed and managed inappropriately. Here we discuss the case of a 58 year-old gentleman with mediastinal EHE and review existing literature on pulmonary EHE (PEH). CASE HISTORY: A 58 year-old gentleman presented to our outpatient Clinic with chest discomfort and palpitations. A whole-body FDG-CT-PET showed an FDG-avid single 6.3cm nodule in the superior anterior mediastinum which was fully excised by robotic approach. Histology showed a nodular structure with clusters of epithelioid and spindled cells with a low proliferative index and mitotic count, suspended in a sclerotic stroma. Immunohistochemistry staining was positive for CD3 and CD34, confirming endothelial lineage, and SMA, identifying smooth muscle clusters. DISCUSSION: PEH typically presents in young Caucasian women, either incidentally as multiple small pulmonary nodules on CT or with respiratory symptoms that include cough, dyspnoea, chest pain and occasionally pleural effusions. Aetiology and prognosis remain unclear, although indicators of poor prognosis include the presence of respiratory symptoms, male gender, older age and multi-organ disease. Diagnosis is difficult and PEH is often misidentified as chronic granulomatous disease, amyloidosis or other malignancy of the lung. Histological features suggestive of PEH include nodules of hypocellular sclerotic stroma containing spindle-shaped tumour cells with abundant eosinophilic cytoplasm, vacuoles containing erythrocytes and low mitotic counts. CD31, CD34 and Fli-1 positive immunohistochemistry is strongly indicative of epithelioid lineage. There is no standard treatment for PEH but curative resection is the preferred treatment option where possible, with chemotherapy being used as adjuvant treatment or in widespread inoperable disease. CONCLUSION: This case report outlines the clinicopathological features that are characteristic of EHE with the hope of facilitating correct and early diagnosis in the future. PMID- 28626634 TI - An unusual late onset of pulmonary alveolar microlithiasis: A case report and literature review. AB - Pulmonary alveolar microlithiasis (PAM) is an uncommon genetic disorder associated with alveolar cell injury. This injury is caused in most cases by inactivating mutations in SLC34A2 gene, which is responsible for the production of a sodium-dependent phosphate co-transporter. The dysfunction or deficiency of this transporter leads to the aggregation of local phosphate intra-alveolarly and formation of microliths. Most of the patients are asymptomatic at the time of the diagnosis but as the disease progress it leads to fatal respiratory or cardiac failure. We describe a case of a 63-year-old man referred to our department for a surgical lung biopsy. He has been symptomatic for one year with progressive shortness of breath and deteriorating exercise tolerance. The imaging was suggestive of extensive interstitial bilateral lung disease. Histological findings after the lung biopsy by video-assisted thoracic surgery (VATS) established the diagnosis of pulmonary alveolar microlithiasis. His sister suffered from the same disease and passed away at the age of 54. It is remarkably rare for PAM to have such a late onset with a previous normal X-ray and only a few cases have been reported worldwide. PMID- 28626635 TI - Eosinophilic meningoencephalitis associated with rat lungworm (Angiostrongylus cantonensis) migration in two nine-banded armadillos (Dasypus novemcinctus) and an opossum (Didelphis virginiana) in the southeastern United States. AB - Angiostrongylus cantonensis, the rat lungworm, was the cause of neural larval migrans in two nine-banded armadillos (Dasypus novemcinctus) and one Virginia opossum (Didelphis virginiana) from the southeastern United States. Histologic findings in all three cases included eosinophilic meningoencephalitis with variable numbers of nematode larvae in the meninges or the neuroparenchyma. In two of the three cases, nematodes were extracted from brain tissue via a "squash prep" method. Identification of the nematodes was confirmed by amplification and sequence analysis of the partial cytochrome c oxidase subunit I gene from all three cases. Sequences (704bp) from the two cases from Louisiana were identical and 99.7% similar to nematodes detected in the armadillo from Florida. As A. cantonensis is now considered endemic in the southern United States, it should be considered as an important differential for any wild or domestic animal or human patient with neurological signs and eosinophilic meningitis. Many wildlife species frequently consume snails and slugs and could serve as sentinels for the detection of this parasite in regions where the presence of this parasite has not been confirmed. To the authors' knowledge, this is the first report of neural larval migrans due to A. cantonensis in an armadillo and provides additional documentation that this nematode can cause disease in wildlife species in the southeastern United States. PMID- 28626636 TI - An examination of endoparasites and fecal testosterone levels in flying squirrels (Glaucomys spp.) using high performance liquid chromatography-ultra-violet (HPLC UV). AB - The immuno-competence hypothesis proposes that higher levels of testosterone increases the susceptibility to parasitism. Here we examined the testosterone levels in two species of flying squirrels (Glaucomys): one known to regularly host a nematode species (Strongyloides robustus) without ill effects (G. volans) and a closely related species that is considered negatively affected by the parasite. We quantified fecal testosterone levels in northern and southern flying squirrels (G. sabrinus, G. volans) with high-performance liquid chromatography ultraviolet spectroscopy (HPLC-UV), and compared levels to endoparasites detected in individual squirrels. Qualitatively, we found highest levels of testosterone in male northern flying squirrels infected with Strongyloides robustus. This analytical approach represents an alternative and equally reliable method to using enzyme-linked immunosorbent assay (ELISA), for detecting and quantifying fecal testosterone levels. PMID- 28626637 TI - Transcriptome analysis of reproductive tissue differentiation in Jatropha curcas Linn. AB - Shoot and inflorescence are central physiological and developmental tissues of plants. Flowering is one of the most important agronomic traits for improvement of crop yield. To analyze the vegetative to reproductive tissue transition in Jatropha curcas, gene expression profiles were generated from shoot and inflorescence tissues. RNA isolated from both tissues was sequenced using the Ilumina HiSeq 2500 platform. Differential gene expression analysis identified key biological processes associated with vegetative to reproductive tissue transition. The present data for J. curcas may inform the design of breeding strategies particularly with respect to reproductive tissue transition. The raw data of this study has been deposited in the NCBI's Sequence Read Archive (SRA) database with the accession number SRP090662. PMID- 28626638 TI - Transcriptome of barley under three different heavy metal stress reaction. AB - In the present study, we used Illumina sequencing technology (HiSeq 2000) to sequence the transcriptome of barley (Hordeum vulgare L., cv. Morex) under three different heavy metal stress conditions: copper, zinc and cadmium. For each of those metals, the concentration causing a 50% inhibitory effect for root growth (EC50) was determined. We sequenced the total RNA of both roots and shoots from barley with and without heavy metal treatments in three replicates. Raw reads of the transcriptome project have been deposited in NCBI's BioProject accession number PRJNA382490. The obtained transcriptomic data will be useful for further studies focusing on heavy metal tolerance and comparative transcriptome analysis in barley. PMID- 28626639 TI - A non-mosaic PORCN mutation in a male with severe congenital anomalies overlapping focal dermal hypoplasia. AB - Mutations in the PORCN gene cause the X-linked dominant condition focal dermal hypoplasia (FDH). Features of FDH include striated pigmentation of the skin, ocular and skeletal malformations. FDH is generally associated with in utero lethality in non-mosaic males and most of the currently reported male patients show mosaicism due to de novo post-zygotic mutations in the PORCN gene. There is only one previous report of a surviving male with an inherited mutation in the PORCN gene. Here, we report two male siblings with multiple malformations including skeletal, ocular and renal defects overlapping with FDH. A novel PORCN mutation (p.Ser250Phe) was identified in a non-mosaic, hemizygous state in one of the siblings who survived to 8 years of age. The mother is a heterozygous carrier, has a random X-inactivation pattern and is asymptomatic. Findings unusual for FDH include dysplastic clavicles and bilateral Tessier IV facial clefts. This is the second case report of a non-mosaic PORCN mutation in a male individual with multiple congenital anomalies. While the pathogenicity of this mutation remains to be further investigated, the survival of a male with a non mosaic mutation in PORCN is suggestive of a functionally mild mutation leading to an X-linked recessive mode of inheritance. PMID- 28626640 TI - Accumulated substancies and calorific capacity in adipose tissue: Physical and chemical clinical trial. AB - AIM: To study physical and chemical structures and properties including calorific value of human adipose tissue in different anatomical location in autopsy assigned clinical trial. METHODS: A pilot physical and chemical descriptive randomized autopsy-assigned trial. Adipose tissue 252 sampled from 36 individuals at autopsy who between 36 and 63 years old died from road accidents. Interventions: Chemical functional groups and calorific value were studied using infrared and atomic adsorptive spectrometries, elemental chemical analysis and differential scanning calorimetry. Adipose tissue was sampled from the 7 various anatomical locations. RESULTS: The highest levels of the analysed chemical substancies were found in dense atherosclerotic plaque. Dense atherosclerotic plaque contains the most of metabolic products, organic and inorganic elements. Dense atherosclerotic plaque has the most of calorific value. The lowest calorific capacity has a pararenal fat. CONCLUSIONS: Human body lipids serve as a harbor for various organic substances, they may absorb different metabolic products, and they have different calorific capacity depending on their location and forms. Atherosclerotic plaque contains the most of organic and inorganic elements, and brings the highest energy potential. PMID- 28626642 TI - Bioleaching of incineration fly ash by Aspergillus niger - precipitation of metallic salt crystals and morphological alteration of the fungus. AB - This study examines the bioleaching of municipal solid waste incineration fly ash by Aspergillus niger, and its effect on the fungal morphology, the fate of the ash particles, and the precipitation of metallic salt crystals during bioleaching. The fungal morphology was significantly affected during one-step and two-step bioleaching; scanning electron microscopy revealed that bioleaching caused distortion of the fungal hyphae (with up to 10 MUm hyphae diameter) and a swollen pellet structure. In the absence of the fly ash, the fungi showed a linear structure (with 2-4 MUm hyphae diameter). Energy-dispersive X-ray spectroscopy and X-ray diffraction confirmed the precipitation of calcium oxalate hydrate crystals at the surface of hyphae in both one-step and two-step bioleaching. Calcium oxalate precipitation affects bioleaching via the weakening of the fly ash, thus facilitating the release of other tightly bound metals in the matrix. PMID- 28626641 TI - Evaluation of in vitro cytotoxic activity of mono-PEGylated StAP3 (Solanum tuberosum aspartic protease 3) forms. AB - StAP3 is a plant aspartic protease with cytotoxic activity toward a broad spectrum of pathogens, including potato and human pathogen microorganisms, and cancer cells, but not against human T cells, human red blood cells or plant cells. For this reason, StAP3 could be a promising and potential drug candidate for future therapies. In this work, the improvement of the performance of StAP3 was achieved by means of a modification with PEG. The separation of a mono PEGylated StAP3 fraction was easily performed by gel filtration chromatography. The mono-PEGylated StAP3 fraction was studied in terms of in vitro antimicrobial activity, exhibiting higher antimicrobial activity against Fusarium solani spores and Bacillus cereus, but slightly lower activity against Escherichia coli than native protein. Such increase in antifungal activity has not been reported previously for a PEGylated plant protein. In addition, PEGylation did not affect the selective cytotoxicity of StAP3, since no hemolytic activity was observed. PMID- 28626643 TI - Process development of short-chain polyols synthesis from corn stover by combination of enzymatic hydrolysis and catalytic hydrogenolysis. AB - Currently short-chain polyols such as ethanediol, propanediol, and butanediol are produced either from the petroleum feedstock or from the starch-based food crop feedstock. In this study, a combinational process of enzymatic hydrolysis with catalytic hydrogenolysis for short-chain polyols production using corn stover as feedstock was developed. The enzymatic hydrolysis of the pretreated corn stover was optimized to produce stover sugars at the minimum cost. Then the stover sugars were purified and hydrogenolyzed into polyols products catalyzed by Raney nickel catalyst. The results show that the yield of short-chain polyols from the stover sugars was comparable to that of the corn-based glucose. The present study provided an important prototype for polyols production from lignocellulose to replace the petroleum- or corn-based polyols for future industrial applications. PMID- 28626644 TI - Mechanism-based site-directed mutagenesis to shift the optimum pH of the phenylalanine ammonia-lyase from Rhodotorula glutinis JN-1. AB - Phenylalanine ammonia-lyase (RgPAL) from Rhodotorula glutinis JN-1 stereoselectively catalyzes the conversion of the l-phenylalanine into trans cinnamic acid and ammonia, and was used in chiral resolution of dl-phenylalanine to produce the d-phenylalanine under acidic condition. However, the optimum pH of RgPAL is 9 and the RgPAL exhibits low catalytic efficiency at acidic side. Therefore, a mutant RgPAL with a lower optimum pH is expected. Based on catalytic mechanism and structure analysis, we constructed a mutant RgPAL-Q137E by site directed mutagenesis, and found that this mutant had an extended optimum pH 7-9 with activity of 1.8-fold higher than that of the wild type at pH 7. As revealed by Friedel-Crafts-type mechanism of RgPAL, the improvement of the RgPAL-Q137E might be due to the negative charge of Glu137 which could stabilize the intermediate transition states through electrostatic interaction. The RgPAL-Q137E mutant was used to resolve the racemic dl-phenylalanine, and the conversion rate and the eeD value of d-phenylalanine using RgPAL-Q137E at pH 7 were increased by 29% and 48%, and achieved 93% and 86%, respectively. This work provides an effective strategy to shift the optimum pH which is favorable to further applications of RgPAL. PMID- 28626645 TI - An intrabody specific for the nucleophosmin carboxy-terminal mutant and fused to a nuclear localization sequence binds its antigen but fails to relocate it in the nucleus. AB - The cytoplasmic accumulation of NPM1 (NPMc+) is found in acute myeloid leukemia (AML) with NPM1 mutation. NPM1 must shuttle between nucleus and cytoplasm to assure physiological protein synthesis and, therefore, the elimination of NPMc+ is not a suitable therapeutic option. We isolated, characterized, and produced a functional scFv intrabody fused to nuclear localization signal(s) (NLS) that does not recognize NPM1 but binds to the mutant-specific C-terminal NES (nuclear export signal) of NPMc+, responsible for its cytoplasmic accumulation. The scFv NLS fusion accumulated in the nuclei of wild type cells and strongly bound to its antigen in the cytoplasm of NPMc+ expressing cells. However, it failed to relocate the majority of NPMc+ in the nucleus, even when fused to four NLS. Our results show the technical feasibility of producing recombinant intrabodies with defined sub-cellular targeting and nuclear accumulation but the lack of information concerning the features that confer variable strength to the signal peptides impairs the development of biomolecules able to counteract pathological sub-cellular distribution of shuttling proteins. PMID- 28626646 TI - Development of fed-batch profiles for efficient biosynthesis of catechol-O methyltransferase. AB - Catechol-O-methyltransferase (COMT, EC 2.1.1.6) plays a crucial role in dopamine metabolism which has intimately linked this enzyme to some neurodegenerative diseases, such as Parkinson's disease. In recent years, in the attempt of developing new therapeutic strategies for Parkinson's disease, there has been a growing interest in the search for effective COMT inhibitors. In order to do so, large amounts of COMT in an active form are needed, and the best way to achieve this is by up-scaling its production through biotechnological processes. In this work, a fed-batch process for the biosynthesis of the soluble isoform of COMT in Escherichia coli is proposed. This final process was selected through the evaluation of the effect of different dissolved oxygen concentrations, carbon and nitrogen source concentrations and feeding profiles on enzymatic production and cell viability, while controlling various parameters (pH, temperature, starting time of the feeding and induction phases and carbon source concentration) during the process. After several batch and fed-batch experiments, a final specific COMT activity of 442.34 nmol/h/mg with approximately 80% of viable cells at the end of the fermentation were achieved. Overall, the results described herein provide a great improvement on hSCOMT production in recombinant bacteria and provide a new and viable option for the use of a fed-batch fermentation with a constant feeding profile to the large scale production of this enzyme. PMID- 28626647 TI - Use of a capacitive affinity biosensor for sensitive and selective detection and quantification of DNA-A model study. AB - A capacitive DNA-sensor model system was used to monitor the capture of complementary single-stranded DNAs. The sensor chip consisted of a gold electrode, which was carefully insulated with a polytyramine layer and covalently tagged with 25-mer oligo-C. As low as 10-11 moles per liter of target oligo-G could be detected by injecting 250 MUL of sample. Elevated temperature was used to reduce non-specific hybridization. Less than 10% of non-target 25-mer oligo-T interacted nonspecifically with the oligo-C probes when hybridization process was performed at 50 degrees C. Studying the relationship of length of the analyte to the signal strength, the output from the capacitive DNA-sensor increased to almost the double; from 50 to 88-nF cm-2, when a 25-mer oligo-G was used instead of a 15-mer. By sandwich hybridization at room temperature, it was possible to further increase the signal, from 78-nF cm-2 for the target 50-mer oligo-G alone, to 114-nF cm-2. PMID- 28626648 TI - Reusable urine glucose sensor based on functionalized graphene oxide conjugated Au electrode with protective layers. AB - An electrochemical based system with multiple layers coated on a functionalized graphene oxide Au electrode was developed to measure glucose concentration in urine in a more stable way. Two types of gold printed circuit boards were fabricated and graphene oxide was immobilized on their surface by chemical adsorption. Multiple layers, composed of a couple of polymers, were uniformly coated on the surface electrode. This device exhibited higher electrochemical responses against glucose, a greater resistivity in the presence of interferential substances in urine, and durable stabilities for longer periods of time than conventional units. The efficiency in current level according to the order and ratio of solution was evaluated during the immobilization of the layer. The fabricated electrodes were then also evaluated using hyperglycemic clinical samples and compared with the patterns of blood glucose measured with commercially available glucose meters. Our findings show that not only was their pattern similar but this similarity is well correlated. PMID- 28626649 TI - Effect of ball-milling on the physicochemical properties of maize starch. AB - The effect of ball-milling on physicochemical properties of maize starch was evaluated. Results found that the cold water solubility (CWS) of maize starch was positively correlated with the time of milling up to 3 h. There was no significant influence of using a ceramic pot versus a stainless steel pot on CWS. However, following 5 h of ball-milling CWS increased quite dramatically in the ceramic pot (72.6%) and in the stainless steel pot (70.7%), as compared to the untreated maize starches (2.9%). In addition, as CWS increased, the regions of amorphism enlarged at the expense of the crystalline regions, resulting in a change from the native starch state (oval with a smooth surface) to having more of a rough, abrasive surface. Finally, the transparency of the starch increased as CWS increased and that the syneresis of freeze-thawed ball-milled maize starch also increased with an increase in the number of freeze-thaw cycles. PMID- 28626650 TI - Recrystallization inhibition in ice due to ice binding protein activity detected by nuclear magnetic resonance. AB - Liquid water present in polycrystalline ice at the interstices between ice crystals results in a network of liquid-filled veins and nodes within a solid ice matrix, making ice a low porosity porous media. Here we used nuclear magnetic resonance (NMR) relaxation and time dependent self-diffusion measurements developed for porous media applications to monitor three dimensional changes to the vein network in ices with and without a bacterial ice binding protein (IBP). Shorter effective diffusion distances were detected as a function of increased irreversible ice binding activity, indicating inhibition of ice recrystallization and persistent small crystal structure. The modification of ice structure by the IBP demonstrates a potential mechanism for the microorganism to enhance survivability in ice. These results highlight the potential of NMR techniques in evaluation of the impact of IBPs on vein network structure and recrystallization processes; information useful for continued development of ice-interacting proteins for biotechnology applications. PMID- 28626651 TI - Microcontact-BSA imprinted capacitive biosensor for real-time, sensitive and selective detection of BSA. AB - An analytical method is presented, combining novel microcontact imprinting technique and capacitive biosensor technology for the detection of BSA. Glass cover slips were used for preparation of protein stamps. The microcontact-BSA imprinted gold electrodes were prepared in the presence of methacrylic acid (MAA) and poly-ethylene glycol dimethacrylate (PEGDMA) as the cross-linker by bringing the protein stamp and the gold electrode into contact under UV-polymerization. Real-time BSA detection studies were performed in the concentration range of 1.0 * 10-20-1.0 * 10-8 M with a limit of detection (LOD) of 1.0 * 10-19 M. Cross reactivity towards HSA and IgG were 5 and 3%, respectively. The electrodes were used for >70 assays during 2 months and retained their binding properties during all that time. The NIP (non-imprinted) electrode was used as a reference. The microcontact imprinting technology combined with the biosensor applications is a promising technology for future applications. PMID- 28626652 TI - Multi-response optimization of rhamnolipid production using grey rational analysis in Taguchi method. AB - The present paper envisages the multi-response optimization of certain process parameters like total sugars concentration, C/N ratio and incubation time on rhamnolipid yield, surface tension reduction, biomass formation and substrate utilization, in rhamnolipid production by a Pseudomonas aeruginosa mutant strain grown on clarified blackstrap molasses, under L9 orthogonal array in Taguchi design. The results have been analyzed by using grey relational analysis for the identification of an optimum level of process parameters. The validity of the results was checked though confirmation experiment, under grey relational analysis. Subsequently, the rhamnolipid yield improved from 1.45 to 1.50 g/L, substrate utilization reduced from 26 to 14% (w/v) and lesser biomass was formed. Moreover, the volumetric productivity of the process improved from 0.0086 to 0.0208 g/L/h by 142%. Furthermore, using analysis of variance method, significant contributions of process parameters were determined. PMID- 28626653 TI - Enzymatic hydrolysis of steam exploded corncob residues after pretreatment in a twin-screw extruder. AB - A modified twin-screw extruder incorporated with a filtration device was used as a liquid/solid separator for xylose removal from steam exploded corncobs. A face centered central composite design was used to study the combined effects of various enzymatic hydrolysis process variables (enzyme loading, surfactant addition, and hydrolysis time) with two differently extruded corncobs (7% xylose removal, 80% xylose removal) on glucose conversion. The results showed that the extrusion process led to an increase in cellulose crystallinity, while structural changes could also be observed via SEM. A quadratic polynomial model was developed for predicting the glucose conversion and the fitted model provided an adequate approximation of the true response as verified by the analysis of variance (ANOVA). PMID- 28626654 TI - Stable lentiviral transformation of CHO cells for the expression of the hemagglutinin H5 of avian influenza virus in suspension culture. AB - Avian influenza virus H5N1 has caused extensive damage worldwide among poultry and humans. Effective expression systems are needed for the production of viral proteins required for monitoring this devastating disease. The present study deals with the establishment of a stable expression system for the hemagglutinin H5 (HAH5) of avian influenza virus using CHO cells in suspension culture transduced with a recombinant lentiviral vector. The synthetic gene coding the HAH5 protein was inserted in a lentiviral vector with the aim of performing a stable transduction of CHO cells. After the selection of recombinant clones, the one with the highest expression level was adapted to suspension culture and the HAH5 protein was purified by immunoaffinity chromatography from the culture supernatant. There were no significant differences when this protein, purified or direct from the culture supernatant of CHO or SiHa cells, was utilized in an immunologic assay using positive and negative sera as reference. It was also demonstrated that the HAH5 protein in its purified form is able to bind anti-HAH5 antibodies generated with proper and non-proper folded proteins. The results demonstrate that the CHO cell line stably transduced with a lentiviral vector coding the sequence of the HAH5 protein and cultured in suspension can be a suitable expression system to obtain this protein for diagnostic purpose in a consistent and reliable manner. PMID- 28626655 TI - Comparison of droplet digital PCR and quantitative real-time PCR in mcrA-based methanogen community analysis. AB - Two different quantitative PCR platforms, droplet digital PCR (dd-PCR) and quantitative real-time PCR (qPCR), were compared in a mcrA-based methanogen community assay that quantifies ten methanogen sub-groups. Both technologies exhibited similar PCR efficiencies over at least four orders of magnitude and the same lower limits of detection (8 copies MUL-DNA extract-1). The mcrA-based methanogen communities in three full-scale anaerobic digesters were examined using the two technologies. dd-PCR detected seven groups from the digesters, while qPCR did five groups, indicating that dd-PCR is more sensitive for DNA quantification. Linear regression showed quantitative agreements between both of the technologies (R2 = 0.59-0.98) in the five groups that were concurrently detected. Principal component analysis from the two datasets consistently indicated a substantial difference in the community composition among the digesters and revealed similar levels of differentiation among the communities. The combined results suggest that dd-PCR is more promising for examining methanogenic archaeal communities in biotechnological processes. PMID- 28626656 TI - Effect of small interfering RNAs on matrix metalloproteinase 1 expression. AB - Three small double strand siRNAs (506-MMP1, 859-MMP1 and 891-MMP1), each contains 25-26 nucleotides, with high specific to human MMP1 were designed according to mRNA sequence of human MMP1 (NCBI, NM_002421). To monitor the MMP1 gene expression, the total RNAs of human skin fibroblast (Detroit 551, BCRC 60118) were extracted. One human matrix metalloproteinase 1 (MMP1) partial sequence cDNA, included all the three siRNA target sequences, amplified specifically via RT-PCR and PCR reactions, and three synthesized siRNA target DNAs were cloned individually into pAcGFP1-N3 with green fluorescent protein (GFP). These reporter plasmids were then transfected individually into malignant melanoma (MeWo, BCRC 60540) and the GFP was detected after 48 h. Fluorescence results indicated that the 859 siRNA revealed highest inhibitory ability (almost 90%), and was, accordingly, transfected into MeWo cells. According to the real-time quantitative PCR and western blot, the exhibition ability to silence MMP1 gene expression was 85-89%. PMID- 28626657 TI - Chondroitin sulphate extracted from antler cartilage using high hydrostatic pressure and enzymatic hydrolysis. AB - Chondroitin sulphate (CS), a major glycosaminoglycan, is an essential component of the extracellular matrix in cartilaginous tissues. Wapiti velvet antlers are a rich source of these molecules. The purpose of the present study was to develop an effective isolation procedure of CS from fresh velvet antlers using a combination of high hydrostatic pressure (100 MPa) and enzymatic hydrolysis (papain). High CS extractability (95.1 +/- 2.5%) of total uronic acid was obtained following incubation (4 h at 50 degrees C) with papain at pH 6.0 in 100 MPa compared to low extractability (19 +/- 1.1%) in ambient pressure (0.1 MPa). Antler CS fractions were isolated by Sephacryl S-300 chromatography and identified by western blot using an anti-CS monoclonal antibody. The antler CS fraction did not aggregate with hyaluronic acid in CL-2B chromatography and possessed DPPH radical scavenging activity at 78.3 +/- 1.5%. The results indicated that high hydrostatic pressure and enzymatic hydrolysis procedure may be a useful tool for the isolation of CS from antler cartilaginous tissues. PMID- 28626658 TI - Preparation of functionalized porous nano-gamma-Al2O3 powders employing colophony extract. AB - This study reports the synthesis of porous nano alumina employing carboxylato alumoxanes [Al(O) x (OH) y (O2CR) z ] n as precursors for controlling the pore size, pore size distribution and porosity of the alumina, using a new process ecofriendly. The carboxylato-alumoxanes was prepared by the reaction of boehmite with carboxylic acids. The boehmite was obtained by the hydrolysis of aluminum alkoxide in an aqueous solution. The colophony extract is employed as a source of carboxylic acids. The materials were characterized, using XRD, TGA, N2 physical adsorption, SEM, TEM, NMR and FTIR. A mechanism was proposed for the formation of the synthesized structures. TEM measurements confirmed particle size ranged from 5 to 8 nm. PMID- 28626659 TI - Electron beam irradiation enhances the digestibility and fermentation yield of water-soaked lignocellulosic biomass. AB - In order to overcome the limitation of commercial electron beam irradiation (EBI), lignocellulosic rice straw (RS) was pretreated using water soaking-based electron beam irradiation (WEBI). This environment-friendly pretreatment, without the formation (or release) of inhibitory compounds (especially hydroxymethylfurfural and furfural), significantly increased the enzymatic hydrolysis and fermentation yields of RS. Specifically, when water-soaked RS (solid:liquid ratio of 100%) was treated with WEBI doses of 1 MeV at 80 kGy, 0.12 mA, the glucose yield after 120 h of hydrolysis was 70.4% of the theoretical maximum. This value was predominantly higher than the 29.5% and 52.1% measured from untreated and EBI-treated RS, respectively. Furthermore, after simultaneous saccharification and fermentation for 48 h, the ethanol concentration, production yield, and productivity were 9.3 g/L, 57.0% of the theoretical maximum, and 0.19 g/L h, respectively. Finally, scanning electron microscopy images revealed that WEBI induced significant ultrastructural changes to the surface of lignocellulosic fibers. PMID- 28626660 TI - Simply red: A novel spectrophotometric erythroid proliferation assay as a tool for erythropoiesis and erythrotoxicity studies. AB - Most mammalian cell proliferation assays rely on manual or automated cell counting or the assessment of metabolic activity in colorimetric assays, with the former being either labor and time intensive or expensive and the latter being multistep procedures requiring the addition of several reagents. The proliferation of erythroid cells from hematopoietic stem cells and their differentiation into mature red blood cells is characterized by the accumulation of large amounts of hemoglobin. Hemoglobin concentrations are easily quantifiable using spectrophotometric methods due to the specific absorbance peak of the molecule's heme moiety between 400 and 420 nm. Erythroid proliferation can therefore be readily assessed using spectrophotometric measurement in this range. We have used this feature of erythroid cells to develop a simple erythroid proliferation assay that is minimally labor/time- and reagent-intensive and could easily be automated for use in high-throughput screening. Such an assay can be a valuable tool for investigations into hematological disorders where erythropoiesis is dysregulated, i.e., either inhibited or enhanced, into the development of anemia as a side-effect of primary diseases such as parasitic infections and into cyto-(particularly erythro-) toxicity of chemical agents or drugs. PMID- 28626661 TI - Acalypha indica Linn: Biogenic synthesis of silver and gold nanoparticles and their cytotoxic effects against MDA-MB-231, human breast cancer cells. AB - This study reports the in vitro cytotoxic effect of biologically synthesized silver and gold nanoparticles against MDA-MB-231, human breast cancer cells. Formation of silver and gold nanoparticles was observed within 30 min and the various characterization techniques such as UV-vis spectrophotometer, FE-SEM, TEM and XRD studies were confirmed the synthesis of nanoparticles. Further, MTT, acridine orange and ethidium bromide (AO/EB) dual staining, caspase-3 and DNA fragmentation assays were carried out using various concentrations of silver and gold nanoparticles ranging from 1 to 100 MUg/ml. At 100 MUg/ml concentration, the plant extract derived nanoparticles exhibited significant cytotoxic effects and the apoptotic features were confirmed through caspase-3 activation and DNA fragmentation assays. Thus, the results of the present study indicate that biologically synthesized silver and gold nanoparticles might be used to treat breast cancer; however, it necessitates clinical studies to ascertain their potential as anticancer agents. PMID- 28626662 TI - Proliferation extent of CD34+ cells as a key parameter to maximize megakaryocytic differentiation of umbilical cord blood-derived hematopoietic stem/progenitor cells in a two-stage culture protocol. AB - Co-infusion of ex-vivo generated megakaryocytic progenitors with hematopoietic stem/progenitor cells (HSC/HPC) may contribute to a faster platelet recovery upon umbilical cord blood (UCB) transplantation. A two stage protocol containing cell expansion and megakaryocyte (Mk) differentiation was established using human UCB CD34+-enriched cells. The expansion stage used a pre-established protocol supported by a human bone marrow mesenchymal stem cells (MSC) feeder layer and the differentiation stage used TPO (100 ng/mL) and IL-3 (10 ng/mL). 18% of culture-derived Mks had higher DNA content (>4 N) and were able to produce platelet-like particles. The proliferation extent of CD34+ cells obtained in the expansion stage (FI-CD34+), rather than expansion duration, determined as a key parameter for efficient megakaryocytic differentiation. A maximum efficiency yield (EY) of 48 +/- 7.7 Mks/input CD34+ cells was obtained for a FI-CD34+ of 17 +/- 2.5, where a higher FI-CD34+ of 42 +/- 13 resulted in a less efficient megakaryocytic differentiation (EY of 22 +/- 6.7 and 19 +/- 4.6 %CD41). PMID- 28626663 TI - Screening of Bacillus coagulans strains in lignin supplemented minimal medium with high throughput turbidity measurements. AB - The aim of this study was to extend the options for screening and characterization of microorganism through kinetic growth parameters. In order to obtain data, automated turbidimetric measurements were accomplished to observe the response of strains of Bacillus coagulans. For the characterization, it was decided to examine the influence of varying concentrations of lignin with respect to bacterial growth. Different mathematical models are used for comparison: logistic, Gompertz, Baranyi and Richards and Stannard. The growth response was characterized by parameters like maximum growth rate, maximum population, and the lag time. In this short analysis we present a mathematical approach towards a comparison of different microorganisms. Furthermore, it can be demonstrated that lignin in low concentrations can have a positive influence on the growth of B. coagulans. PMID- 28626664 TI - Relative examination of antioxidative enzymatic activities in plantlets of Cardiospermum halicacabum L. differentiated from hypocotyls in in vivo and ex vitro environment. AB - A plant regeneration protocol was devised for Cardiospermum halicacabum by means of aseptically extracted 7 days old hypocotyls forming adventitious shoots on Murashige and Skoog (MS) medium harmonized with 0.7 MUM thidiazuron (TDZ) producing a maximum of 18.20 +/- 0.98 number of shoots in 94% cultures following 4 weeks. Subsequent subculturing for five passages, on a medium without plant growth regulators, tempted the highest shoot number (40.00 +/- 1.15) with an average shoot length of 6.53 +/- 0.49 cm after the fourth subculture. Histological sections confirmed the formation of multiple buds from hypocotyl explants. The expression of antioxidant enzymes like superoxide dismutase, catalase, ascorbate peroxidase and glutathione reductase was found to be higher in acclimatized plants than in the in vitro cultured ones suggesting the involvement of these enzymes in shoot differentiation and in growth under external environment partly due to their ability to cope up with oxidative stress. PMID- 28626665 TI - Biosynthesis and metabolism of beta-d-salicin: A novel molecule that exerts biological function in humans and plants. AB - beta-d-Salicin 1 (Mahdi et al. [8]) is an interesting medicinal phytochemical that exhibits cross functions in plants and humans immunologically. This molecule 1 (Mahdi et al. [8]) has attracted the attention of scientists in various interdisciplinary fields, including chemistry, pharmacology and medicine. The biological cross functions of beta-d-salicin 1 (Mahdi et al. [8]) serve in plant survival and healing processes via salicylic acid 2 (Pierpont [23]). Thus, this raise a question whether plant biosynthesis and human metabolism crosstalk to induce therapy via molecular recognition. If so, biotechnology and bioinformatics are significant techniques for new strategies in drug development. Thus, understanding the biosynthesis, metabolism and the cross-molecular setting of recognition may encourage further discussion and research on its medicinal and biological activity virtues. PMID- 28626666 TI - Evaluation of limiting factors for current density in microbial electrochemical cells (MXCs) treating domestic wastewater. AB - This study quantitatively assessed three limiting factors for current density in a microbial electrochemical cell (MXC) treating domestic wastewater: (1) buffer concentration, (2) biodegradability, and (3) particulates. Buffer concentration was not significant for current density in the MXC fed with filtered domestic wastewater (180 mg COD/L). Current density reduced by 67% in the MXC fed with filtered sewage having similar COD concentration to acetate medium, which indicates poor biodegradability of soluble organics in the wastewater. Particulate matters seriously decreased current density down to 76%, probably due to the accumulation of particulates on biofilm anode. Our study quantitatively showed that buffer concentration does not limit current density much, but biodegradability of soluble organics and fermentation rate of particulate matters in domestic wastewater mainly control current density in MXCs. PMID- 28626668 TI - Microbial interactions for enhancement of alpha-amylase production by Bacillus amyloliquefaciens 04BBA15 and Lactobacillus fermentum 04BBA19. AB - Interactions occurring between Saccharomyces cerevisiae and two thermostable alpha-amylase producing strains (Bacillus amyloliquefaciens 04BBA15 and Lactobacillus fermentum 04BBA19) were analyzed by comparing their growth patterns obtained in isolation with those obtained in mixture. The difference between the patterns was assessed using analysis of variance (ANOVA) in order to measure how much the growth of an organism was affected by other. The results showed two types of interactions in mixed culture; commensalism between S. cerevisiae and B. amyloliquefaciens 04BBA15 and mutualism between S. cerevisiae and L. fermentum 04BBA19. In mixed culture, the alpha-amylase production increased significantly compared to that observed in monoculture (P < 0.05). Response surface optimization of fermentation parameters in mixed cultures (initial yeast to bacteria ratio 1.125, temperature 33.5 degrees C, pH 5.5) resulted in about 1.8 fold higher enzyme production than that observed in the unoptimized fermentation. PMID- 28626667 TI - Potential applications of ferulic acid from natural sources. AB - Ferulic acid (FA), a ubiquitous natural phenolic phytochemical present in seeds, leaves, bothin its free form and covalently conjugated to the plant cell wall polysaccharides, glycoproteins,polyamines, lignin and hydroxy fatty acids. FA plays a vital role in providing the rigidity to the cell wall and formation of other important organic compounds like coniferyl alcohol, vanillin, sinapic, diferulic acid and curcumin. FA exhibits wide variety of biological activities such as antioxidant, antiinflammatory, antimicrobial, antiallergic, hepatoprotective, anticarcinogenic, antithrombotic, increase sperm viability, antiviral and vasodilatory actions, metal chelation, modulation of enzyme activity, activation of transcriptional factors, gene expression and signal transduction. PMID- 28626669 TI - Presentation on mechanisms and applications of chalcopyrite and pyrite bioleaching in biohydrometallurgy - a presentation. AB - This review outlines classic and current research, scientific documents and research achievements in bioleaching, particularly in respect of the bioleaching of chalcopyrite and pyrite. The diversity and commonality of the microbial leaching process can be easily studied through comparing the bioleaching mechanism and the application of these two metal sulfides. The crystal, electronic and surface structures of chalcopyrite and pyrite are summarized in detail in this paper. It determines the specific and complicated interaction pathways, kinetics of the atmospheric/aqueous oxidation, and the control process of bioleaching of the minerals as the precondition. Bioleaching of metal sulfides is performed by a diverse group of microorganisms and microbial communities. The species of the bacteria which have a significant effect on leaching ores are miraculously diverse. The newly identified acidophilic microorganisms with unique characteristics for efficient bioleaching of sulfidic minerals are increasing sharply. The cell-to-cell communication mechanisms, which are still implicit, elusive and intangible at present day, have gradually become a research hotspot. The different mineralogy characteristics and the acid solubility of the metal sulfides (e.g., chalcopyrite and pyrite) cause two different dissolution pathways, the thiosulfate and the polysulfide pathways. The bioleaching mechanisms are categorized by contact (an electrostatic attachment) and noncontact (planktonic) process, with emphasis on the produce of extracellular polymeric substances and formation of biofilm on the surface of the metal sulfides in this paper. The division of the direct and indirect effect are not adopted due to the redox chain, the reduction of the ferric iron and oxidation of the ferrous iron. The molecular oxygen is reduced by the electrons extracted from the specific metal sulfide, via a redox chain forming a supercomplex spanning the periplasmic space and connecting both outer and inner membrane. The passivation of the mineral surface can obviously hinder the dissolution of metal sulfides during the bioleaching process, which is significantly affected by the kinetic model, microenvironment on the surface of ore and the leach conditions, such as temperature, pH and Eh. The new development of mechanism research, enhanced and intensified technologies on the bioleaching of chalcopyrite and pyrite, are conducted and summarized from the different branches of natural science. Some are depicted and explained based on molecular level in this paper. Catalyst and catalytic mechanisms in bioleaching and biooxidation for this two sulfide minerals have been concluded and applied for several decades, the continuous emergence of the new material and technology are also gradually applied into the biohydrometallurgy. The industrial applications of the bioleaching on chalcopyrite and pyrite are totally based on the understanding of the interaction mechanism between microbes and minerals, the optimization of ore leaching conditions and the development of new material and the leaching equipment. It is not incredible and unimaginable to take a different bioleaching process and diagram to deal with the two sulfuric metals, which is vital to succeed in elevating the leaching rate of copper. PMID- 28626670 TI - Enhanced production and extraction of phenolic compounds from wheat by solid state fermentation with Rhizopus oryzae RCK2012. AB - Antioxidant phenolic compounds (PCs) are gaining popularity day by day for their health promoting properties. Wheat is a very good source of natural antioxidant PCs. In the present study, extraction of PCs was improved by solid-state fermentation (SSF) of wheat by Rhizopus oryzae RCK2012 which helped to release the bound compounds from matrix. Different extraction conditions such as solvent composition (water, methanol, 70% methanol, ethanol, 70% ethanol, acetone and 70% acetone), extraction temperature (30-60 degrees C), extraction time (15-90 min) and solid-to-solvent ratio (1:2.5 to 1:20, w/v) have been optimized for the extraction of PCs from R. oryzae fermented wheat. Maximum PCs were extracted by water at 40 degrees C within 45 min with solid-to-solvent ratio of 1:15 (w/v). Compositional analysis of PCs was carried out by UPLC and TLC. Improved ABTS*+ [2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)] and DPPH (2,2-diphenyl-1 picrylhydrazyl), hydroxyl radical and hydrogen peroxide scavenging capacities, ferric reducing property and in vivo antioxidant capacity using Saccharomyces cerevisiae were observed in case of freeze-dried water extract of fermented wheat as compared to unfermented sample. Hence, SSF could be a promising technology to enhance the production and extraction of phenolic compounds for the design of different functional foods and for the specific use as nutraceuticals. PMID- 28626671 TI - Density-dependent enhancement of methane oxidation activity and growth of Methylocystis sp. by a non-methanotrophic bacterium Sphingopyxis sp. AB - Methanotrophs are a biological resource as they degrade the greenhouse gas methane and various organic contaminants. Several non-methanotrophic bacteria have shown potential to stimulate growth of methanotrophs when co-cultured, and however, the ecology is largely unknown. Effects of Sphingopyxis sp. NM1 on methanotrophic activity and growth of Methylocystis sp. M6 were investigated in this study. M6 and NM1 were mixed at mixing ratios of 9:1, 1:1, and 1:9 (v/v), using cell suspensions of 7.5 * 1011 cells L-1. Methane oxidation of M6 was monitored, and M6 population was estimated using fluorescence in situ hybridization (FISH). Real-time PCR was applied to quantify rRNA and expression of transcripts for three enzymes involved in the methane oxidation pathway. NM1 had a positive effect on M6 growth at a 1:9 ratio (p < 0.05), while no significant effects were observed at 9:1 and 1:1 ratios. NM1 enhanced the methane oxidation 1.34-fold at the 1:9 ratio. NM1 increased the population density and relative rRNA level of M6 by 2.4-fold and 5.4-fold at the 1:9 ratio, indicating that NM1 stimulated the population growth of M6. NM1 increased the relative transcriptional expression of all mRNA targets only at the 1:9 ratio. These results demonstrated that NM1 enhanced the methanotrophic activity and growth of M6, which was dependent on the proportion of NM1 present in the culture. This stimulation can be used as management and enhancement strategies for methanotrophic biotechnological processes. PMID- 28626672 TI - Evaluation of five in situ lysis protocols for PCR amenable metagenomic DNA from mangrove soils. AB - Microbes in nature are rarely amenable to growth by standard microbiological methods, with the majority being unculturable. Metagenomic methods help to bypass and overcome the limitations of traditional culturing method; wherein total community DNA is isolated, cloned into suitable vector and host systems. However, isolation of total community DNA itself remains a challenge. In this study five methods of total community DNA isolation from three different mangrove soils were evaluated to test its PCR amenability. The yield and purity of the isolated DNA was also analysed. The quantity of DNA by all 5 methods although reasonably high, contained residual humic contaminants. Of the five, the method employing liquid nitrogen yielded readily amplifiable DNA, while that by all others required further downstream processing to achieve purity and PCR amenability. PMID- 28626673 TI - Production of melanin by soil microbial isolate on fruit waste extract: two step optimization of key parameters. AB - In this study, optimization of production parameters influencing melanin production in an economical fruit waste extract was attempted using a garden soil isolate (Bacillus safensis). Taguchi approach was adopted for screening of critical parameters and further optimization was done using a central composite design of response surface methodology (RSM). At optimum conditions (pH 6.84 and Temp 30.7 degrees C), a significant yield of ~6.96 mg/mL was observed. Statistical analysis revealed that the experimental results fitted well to the statistical model with model R2 value 0.982. The optimization of process parameters using RSM reported a 15% increase in the pigment yield than average yield obtained from the studied model. The melanin produced was confirmed by UV visible spectroscopy, FTIR and XRD analysis. Moreover melanin obtained has significant photoprotective, radical scavenging and metal chelating activity. Thus, B. safensis has the potential to be a new source for the production of melanin, which is of industrial interest. PMID- 28626674 TI - Co-encapsulation of Daphnia magna and microalgae in silica matrices, a stepping stone toward a portable microcosm. AB - We report on the first silica encapsulation of a metazoan (Daphnia magna), with a high initial viability (96% of the population remained active 48 h after encapsulation). Moreover, the co-encapsulation of this crustacean and microalgae (Pseudokirchneriella subcapitata) was achieved, creating inside a silica monolith, the smallest microcosm developed to present. This artificial ecosystem in a greatly diminished scale isolated inside a silica nanoporous matrix could have applications in environmental monitoring, allowing ecotoxicity studies to be carried out in portable devices for on-line and in situ pollution level assessment. PMID- 28626675 TI - Decolouration of industrial metal-complex dyes in successive batches by active cultures of Trametes pubescens. AB - The decolouration of the metal-complex dyes Bemaplex Navy M-T (150 mg/L) and Bezaktiv Blue BA (150 mg/L) in nine successive batches by immobilised cultures of the white-rot fungus Trametes pubescens was studied. Two different types of immobilisation supports were used: the commercial carriers KaldnesTM K1 (synthetic supports) and sunflower-seed shells (SS) (natural supports). Bemaplex showed more resistance to degradation by T. pubescens cultures than Bezaktiv, especially in the K1 cultures. Thus, SS cultures led to decolouration percentages higher than 59% for Bemaplex in all the batches save for the last two and higher than 50% for Bezaktiv in all the batches except for the 2nd and 9th ones. K1 cultures showed decolouration percentages for Bemaplex higher than 42% in batches 1, 3, 4, 5 and 7 and for Bezaktiv higher than 70% in all the batches save for the last one. Dye decolouration was mainly due to enzyme action (biodegradation). PMID- 28626676 TI - Microbial surfactant mediated degradation of anthracene in aqueous phase by marine Bacillus licheniformis MTCC 5514. AB - The present study emphasizes the biosurfactant mediated anthracene degradation by a marine alkaliphile Bacillus licheniformis (MTCC 5514). The isolate, MTCC 5514 degraded >95% of 300 ppm anthracene in an aqueous medium within 22 days and the degradation percentage reduced significantly when the concentration of anthracene increased to above 500 ppm. Naphthalene, naphthalene 2-methyl, phthalic acid and benzene acetic acid are the products of degradation identified based on thin layer chromatography, high performance liquid chromatography, gas chromatography and mass analyses. It has been observed that the degradation is initiated by the biosurfactant of the isolate for solubilization through micellation and then the alkali pH and intra/extra cellular degradative enzymes accomplish the degradation process. Encoding of genes responsible for biosurfactant production (licA3) as well as catabolic reactions (C23O) made with suitable primers designed. The study concludes in situ production of biosurfactant mediates the degradation of anthracene by B. licheniformis. PMID- 28626677 TI - Acetylcholinesterase enzyme inhibitor activity of some novel pyrazinamide condensed 1,2,3,4-tetrahydropyrimidines. AB - A new series of some novel pyrazinamide condensed 1,2,3,4-tetrahydropyrimidines was prepared by reacting of N-(3-oxobutanoyl)pyrazine-2-carboxamide with urea/thiourea and appropriate aldehyde in the presence of catalytic amount of laboratory made p-toluenesulfonic acid as an efficient catalyst. Confirmation of the chemical structure of the synthesized compounds (4a-l) was substantiated by TLC, different spectral data IR, 1H NMR, mass spectra and elemental analysis. The synthesized compounds were evaluated for acetyl and butyl cholinesterase (AChE and BuChE) inhibitor activity. The titled compounds exhibited weak, moderate or high AChE and BuChE inhibitor activity. Especially, compound (4l) showed the best AChE and BuChE inhibitory activity of all the 1,2,3,4-tetrahydropyrimidine derivatives, with an IC50 value of 0.11 MUM and 3.4 MUM. PMID- 28626678 TI - TiO2 nanoparticle biosynthesis and its physiological effect on mung bean (Vigna radiata L.). AB - TiO2 nanoparticle (NPs) biosynthesis is a low cost, ecofriendly approach developed using the fungi Aspergillus flavus TFR 7. To determine whether TiO2 NPs is suitable for nutrient, we conducted a two part study; biosynthesis of TiO2 NP and evaluates their influence on mung bean. The characterized TiO2 NPs were foliar sprayed at 10 mgL-1 concentration on the leaves of 14 days old mung bean plants. A significant improvement was observed in shoot length (17.02%), root length (49.6%), root area (43%), root nodule (67.5%), chlorophyll content (46.4%) and total soluble leaf protein (94%) as a result of TiO2 NPs application. In the rhizosphere microbial population increased by 21.4-48.1% and activity of acid phosphatase (67.3%), alkaline phosphatase (72%), phytase (64%) and dehydrogenase (108.7%) enzyme was observed over control in six weeks old plants owing to application of TiO2 NPs. A possible mechanism has also been hypothesized for TiO2 NPs biosynthesis. PMID- 28626679 TI - Bacterial diversity losses: A potential extracellular driving mechanism involving the molecular ecological function of hydrophobic polycyclic aromatic hydrocarbons. AB - The DNA transformation is vital to the horizontal gene transfer (HGT). The low efficiency transformation of bare plasmid exposed to hydrophobic polycyclic aromatic hydrocarbons (PAHs) decreases the gene transfer level, and is possibly related to the loss of bacterial diversity at present. PAHs have great affinity for bare DNA through dispersion force and pi-pi overlap between PAHs and bases. These noncovalent interactions between PAHs and bases reduced the transformational efficiency of plasmid into bacterial recipients. Meanwhile these low-efficiency transformations for plasmid are controlled by the ions like Ca2+ in environment, in turn, presence of 0.5 mmol L-1 Ca2+ recovered the efficiency from 3.2 (phenanthrene), 3.5 (pyrene) to about 4.45 and 4.75, respectively. The combination of Ca2+ with the -POO-- groups in DNA forms strong electrovalent bonds, weakening the molecular effect of DNA on PAHs and in turn promoting the gene transfer exposed to PAHs. PMID- 28626680 TI - Laccase production by Pleurotus ostreatus and its application in synthesis of gold nanoparticles. AB - In this work, the production of fungal laccase was optimized from local isolate of Pleurotus ostreatus using solid state fermentation. Factorial design was used to study the effect of several nutrients on enzyme production. Purification and characterization of the enzyme and the effect of temperature, pH and gamma radiation on fungal growth and enzyme production was investigated. Optimization of production conditions yielded an enzyme with activity over 32,450 IU/g of fermented substrate. Factorial design was capable of establishing the conditions that multiplied the activity of the enzyme several folds, consequently, reducing the cost of production. The enzyme was capable of decolorizing several dyes with over 80% reduction in color confirming the aromatic degrading capability of laccase. The enzyme was also used in the synthesis of gold nanoparticles, proving that laccase from Pleurotus ostreatus has a strong potential in several industrial applications. PMID- 28626681 TI - A new nuclear DNA marker from ubiquitin ligase gene region for genetic diversity detection of walnut germplasm resources. AB - Development of more sensitive nuclear DNA markers for identification of species, particularly closely allied taxa has been a challenging task that has attracted interest from scientists in fields of biotechnological development and genetic diversity detection. In this study, the sequence of the ubiquitin ligase gene (UBE3) region of nuclear DNA was tested for applicability and efficacy in revealing genetic diversity of walnut resources, with an emphasis on inter- and intra-specific levels. Analysis on genetic relationship among the taxa was conducted with the neighbor-joining (NJ) method. The number of variable bases in the UBE3 region was 20 sites. All nine taxa (species/variety/cultivars) were distinguished using the UBE3 sequence. In addition, each taxon was characterized molecularly with a unique nucleotide molecular formula using ten variable base sites derived from the nuclear DNA UBE3 gene sequence. This study presents a good complementary methodology for developing new DNA markers for identification of genus Juglans. PMID- 28626682 TI - The use of the carbon/nitrogen ratio and specific organic loading rate as tools for improving biohydrogen production in fixed-bed reactors. AB - This study assessed the effect of the carbon/nitrogen (C/N) ratio on the hydrogen production from sucrose-based synthetic wastewater in upflow fixed-bed anaerobic reactors. C/N ratios of 40, 90, 140, and 190 (g C/g N) were studied using sucrose and urea as the carbon and nitrogen sources, respectively. An optimum hydrogen yield of 3.5 mol H2 mol-1 sucrose was obtained for a C/N ratio of 137 by means of mathematical adjustment. For all C/N ratios, the sucrose removal efficiency reached values greater than 80% and was stable after the transient stage. However, biogas production was not stable at all C/N ratios as a consequence of the continuous decreasing of the specific organic loading rate (SOLR) when the biomass accumulated in the fixed-bed, causing the proliferation of H2-consuming microorganisms. It was found that the application of a constant SOLR of 6.0 g sucrose g-1 VSS d-1 stabilized the system. PMID- 28626684 TI - Mechanisms of plastein formation, and prospective food and nutraceutical applications of the peptide aggregates. AB - Plastein is a protease-induced peptide aggregate with prospective application in enhancing the nutritional quality of proteins and debittering protein hydrolysates. These properties are yet to be applied in product development possibly due to economic considerations (production cost vs. product yields). This paper reviews currently proposed mechanisms of plastein formation including condensation, transpeptidation and physical interaction of aggregating peptides. Emerging findings indicate that plastein possesses bioactivities, thereby expanding its prospective application. The role of proteases in inducing peptide interaction in plastein remains unclear. Understanding the protease function will facilitate the development of efficient proteases and scalable industrial processes for plastein production. PMID- 28626683 TI - Modelling and simulation of the chondrocyte cell growth, glucose consumption and lactate production within a porous tissue scaffold inside a perfusion bioreactor. AB - Mathematical and numerical modelling of the tissue culture process in a perfusion bioreactor is able to provide insight into the fluid flow, nutrients and wastes transport, dynamics of the pH value, and the cell growth rate. Knowing the complicated interdependence of these processes is essential for optimizing the culture process for cell growth. This paper presents a resolved scale numerical simulation, which allows one not only to characterize the supply of glucose inside a porous tissue scaffold in a perfusion bioreactor, but also to assess the overall culture condition and predict the cell growth rate. The simulation uses a simplified scaffold that consists of a repeatable unit composed of multiple strands. The simulation results explore some problematic regions inside the simplified scaffold where the concentration of glucose becomes lower than the critical value for the chondrocyte cell viability and the cell growth rate becomes significantly reduced. PMID- 28626685 TI - Protein production by Arthrospira (Spirulina) platensis in solid state cultivation using sugarcane bagasse as support. AB - The genus Arthrospira comprises a group of filamentous multicellular cyanobacteria and can be used for animal feed and human food. Solid state fermentation or cultivation (SSF) involves the use of a culture medium composed of solid material with given moisture content. No studies have been published about the cultivation of microalgae or cyanobacteria on solid medium. Furthermore, although sugar-cane bagasse is used as source of energy in alcohol distilleries in Brazil, the excess could be a support to photosynthetic microorganism growth. The experimental design methodology was used to evaluate the protein production by Arthrospira platensis under SSF using sugarcane bagasse as support, taking into account the moisture content of the medium, light intensity and inoculum concentration. Moisture was found to have a strong influence on the performance of the process. The best conditions were: moisture of 98.8%; inoculum concentration of 0.15 g biomass.kg wet culture medium-1 and light intensity of 6.0 klx. PMID- 28626686 TI - The prospects of Jerusalem artichoke in functional food ingredients and bioenergy production. AB - Jerusalem artichoke, a native plant to North America has recently been recognized as a promising biomass for bioeconomy development, with a number of advantages over conventional crops such as low input cultivation, high crop yield, wide adaptation to climatic and soil conditions and strong resistance to pests and plant diseases. A variety of bioproducts can be derived from Jerusalem artichoke, including inulin, fructose, natural fungicides, antioxidant and bioethanol. This paper provides an overview of the cultivation of Jerusalem artichoke, derivation of bioproducts and applicable production technologies, with an expectation to draw more attention on this valuable crop for its applications as biofuel, functional food and bioactive ingredient sources. PMID- 28626687 TI - Investigations on ideal mode of cell disruption in extremely halophilic Actinopolyspora halophila (MTCC 263) for efficient release of glycine betaine and trehalose. AB - Actinopolyspora halophila produces glycine betaine and trehalose intracellularly in considerable quantities. These biomolecules are commercially important as they have applications in food, pharmaceuticals, and agricultural sector. Development of an efficient cell disruption technique is an important step for the release of these biomolecules. In this study, various cell disruption methods such as chemical, enzymatic, physico-mechanical and physical methods were evaluated. Cell disruption by osmotic shock was found to be the best suited method for A. halophila which also has a potential to be industrially scaled up. Cell bursting pressure that is generated during osmotic shock in A. halophila was computed using Morse equation and was found to be pi = 238.37 +/- 29.54 atm or 2.35 +/- 0.29 kPa. In addition, it was found that osmotic shock followed a first order release rate kinetics in A. halophila. The findings can be used for commercially important biomolecules from other halophilic and/or halotolerant microbes. PMID- 28626688 TI - Characterization of the bacterial communities of aerobic granules in a 2 fluorophenol degrading process. AB - Aerobic granular sludge constitutes a novel technology for wastewater treatment. This study focused on the effect of 2-fluorophenol (2-FP) shock loadings on the microbial community diversity present in aerobic granules before and after inoculation with a bacterial strain able to degrade 2-FP, Rhodococcus sp. strain FP1. After bioaugmentation, apart from strain FP1, five culturable bacteria were isolated from the 2-FP degrading granules, belonging to the following genera: Serratia, Chryseobacterium, Xanthomonas, Pimelobacter and Rhodococcus. The latter two isolates are able to degrade 2-FP. Changes in the aerobic granules' bacterial communities related to 2-FP shock loadings were examined using denaturing gradient gel electrophoresis (DGGE) of 16S rRNA gene pool. Numerical analysis of the DGGE profiles showed high diversity with an even distribution of species. Based on cluster analysis of the DGGE profiles, the bacterial communities present in the aerobic granules changes were related to the sampling time and the 2-FP concentration fed. PMID- 28626689 TI - Screening of cyanobacteria and microalgae for their ability to synthesize silver nanoparticles with antibacterial activity. AB - The aim of this study was to assess the ability of selected strains of cyanobacteria and microalgae to biosynthesize silver nanoparticles (Ag-NPs) by using two procedures; (i) suspending the live and washed biomass of microalgae and cyanobacteria into the AgNO3 solution and (ii) by adding AgNO3 into a cell free culture liquid. Ag-NPs were biosynthesized by 14 out of 16 tested strains. In most of the cases Ag-NPs were formed both in the presence of biomass as well as in the cell-free culture liquid. This indicates that the process of Ag-NPs formation involves an extracellular compound such as polysaccharide. TEM analysis showed that the nanoparticles were embedded within an organic matrix. Ag-NPs varied in shape and sizes that ranged between 13 and 31 nm, depending on the organism used. The antibacterial activity of Ag-NPs was confirmed in all but one strain of cyanobacterium (Limnothrix sp. 37-2-1) which formed the largest particles. PMID- 28626690 TI - Comparison on structural modification of industrial lignin by wet ball milling and ionic liquid pretreatment. AB - As the most abundant aromatic compounds, lignin is still underutilized due to its relatively low quality. In order to improve its quality, two pretreatment technologies, wet ball milling (WBM) and ionic liquid pretreatment (ILP) were tested on the industrial lignin and evaluated on the average molecular weight and polydispersity, surface morphology, and functional groups changes. The results showed that the lignin pretreated by the WBM with phosphoric acid presented dramatic decrease of polydipersity (23%) and increase of phenolic hydroxyl content (9%). While, the ILP treated samples exhibited the significant reduction of the average molecular weight and polydispersity. The decrease on the particle size and the emergence of the porous structure were found when treated with [Emim][OAc]. In addition, the remarkable reduction of the methoxy groups were observed to be 50% and 45% after treated with [Bmim]Cl and [Emim][OAc], respectively. PMID- 28626691 TI - A novel method to augment extraction of mangiferin by application of microwave on three phase partitioning. AB - This work reports a novel approach where three phase partitioning (TPP) was combined with microwave for extraction of mangiferin from leaves of Mangifera indica. Soxhlet extraction was used as reference method, which yielded 57 mg/g in 5 h. Under optimal conditions such as microwave irradiation time 5 min, ammonium sulphate concentration 40% w/v, power 272 W, solute to solvent ratio 1:20, slurry to t-butanol ratio 1:1, soaking time 5 min and duty cycle 50%, the mangiferin yield obtained was 54 mg/g by microwave assisted three phase partitioning extraction (MTPP). Thus extraction method developed resulted into higher extraction yield in a shorter span, thereby making it an interesting alternative prior to down-stream processing. PMID- 28626692 TI - Efficient utilisation of hydrogel preparations with encapsulated enzymes - a case study on catalase and hydrogen peroxide degradation. AB - The size of the gel preparation, the concentration of the encapsulated enzyme and the ratio of the preparation volume to the volume of the reaction mixture influence the reaction efficiency with encapsulated biocatalysts. A model of first order enzymatic reaction with substrate diffusion is presented and validated by the decomposition reaction of hydrogen peroxide by catalase. The Thiele modulus (F) contains the modified (including the enzyme concentration) enzymatic reaction constant (k'). Based on the model analysis, the Thiele modulus should not exceed a value of 2 (optimally less than 0.5). This value can be controlled by appropriate selection of the enzyme concentration inside and the size of the capsule. A lower F value gives a flat substrate concentration profile inside the gel capsule and all the enzyme molecules are involved in the reaction. The optimal diameter of the gel capsule with respect to their separation from the reaction mixture is 1-2 mm. PMID- 28626693 TI - Co-metabolic formation of substituted phenylacetic acids by styrene-degrading bacteria. AB - Some soil bacteria are able to metabolize styrene via initial side-chain oxygenation. This catabolic route is of potential biotechnological relevance due to the occurrence of phenylacetic acid as a central metabolite. The styrene degrading strains Rhodococcus opacus 1CP, Pseudomonas fluorescens ST, and the novel isolates Sphingopyxis sp. Kp5.2 and Gordonia sp. CWB2 were investigated with respect to their applicability to co-metabolically produce substituted phenylacetic acids. Isolates were found to differ significantly in substrate tolerance and biotransformation yields. Especially, P. fluorescens ST was identified as a promising candidate for the production of several phenylacetic acids. The biotransformation of 4-chlorostyrene with cells of strain ST was shown to be stable over a period of more than 200 days and yielded about 38 mmolproduct gcelldryweight-1 after nearly 350 days. Moreover, 4-chloro-alpha-methylstyrene was predominantly converted to the (S)-enantiomer of the acid with 40% enantiomeric excess. PMID- 28626694 TI - Improving the biophysical properties of anti-ricin single-domain antibodies. AB - Single-domain antibodies (sdAbs) derived from heavy-chain only antibodies produced in camelids are attractive immunoreagents due to their small size, high affinity, and ability to refold and retain binding activity after denaturation. It has been observed that some sdAbs, however, exhibit undesirable properties including reduced solubility when subjected to heating or upon long-term storage at production-relevant concentrations, which can limit their usefulness. Using a multi-step, rational design approach that included consensus-sequence driven sequence repairs, the alteration of net protein charge, and the introduction of non-native disulfide bonds, augmented solubility and increased melting temperatures were achieved. The improved sdAbs tolerated storage in solution at high concentration (10 mg/mL) and were able to withstand multiple cycles of heating to high temperature (70 degrees C). This work demonstrates a pathway for improving the biophysical characteristics of sdAbs which is essential for expanding their utility for both diagnostic as well as therapeutic applications. PMID- 28626695 TI - A new transient expression system for large-scale production of recombinant proteins in plants based on air-brushing an Agrobacterium suspension. AB - Plant transient expression using virus-based vectors is advantageous when high level of gene expression is desired within a short time. In this study, a new system, named "air-brush," has been developed to facilitate a scale-up production of recombinant proteins in plants. GFP was expressed successfully in Nicotiana benthamiana (Nb) plants by air-brushing an Agrobacterium suspension that contained the TMV-based vector p35S-30B-GFP. Key factors influencing the gene expression were optimized, including the Agrobacterium cell density, seedling age, and the growth temperature of plant materials. In addition, the pharmaceutical protein human acidic fibroblast growth factor (ha FGF) was also expressed in Nb plants by the air-brush system. The results demonstrated that using this system is highly advantageous; it is convenient, quick, easily scaled up, and has a higher expression efficiency than leaf infiltration. PMID- 28626696 TI - An improved superoxide-generating nanodevice for oxidative stress studies in cultured cells. AB - The effects of reactive oxygen species on cells have attracted great attention from both physiological and pathological aspects. Superoxide (O2-) is the primary reactive oxygen species formed in animals. We previously developed an O2- generating nanodevice consisting of NADPH oxidase 2 (Nox2) and modulated activating factors. However, the device was subsequently found to be unstable in a standard culture medium. Here we improved the device in stability by cross linking. This new nanodevice, Device II, had a half-life of 3 h at 37 degrees C in the medium. Device II induced cell death in 80% of HEK293 cells after 24 h of incubation. Superoxide dismutase alone did not diminish the effect of the device, but eliminated the effect when used together with catalase, confirming that the cell death was caused by H2O2 derived from O2-. Flow cytometric analyses revealed that Device II induced caspase-3 activation in HEK293 cells, suggesting that the cell death proceeded largely through apoptosis. PMID- 28626697 TI - Evaluation of antimicrobial activity of Curcuma longa rhizome extract against Staphylococcus aureus. AB - The in vitro antimicrobial activity of different fractions obtained from rhizome of Curcuma longa was investigated against standard strain and clinical isolates of Staphylococcus aureus. The clinical isolates were found more sensitive for different fractions, than the standard strain of S. aureus. Scanning electron microscopic observations revealed that test pathogen treated with C. longa extract showed morphological deformity, with partial lack of the cytoplasmic membrane, which leads to cell disruption The ability of rhizome of C. longa extracts to inhibit the growth of test pathogen is an indication of its broad spectrum antimicrobial potential which may be employed in the management of microbial infections. PMID- 28626698 TI - Nature curing cancer - review on structural modification studies with natural active compounds having anti-tumor efficiency. AB - Cancer treatment has raised many drugs and radiation therapies whose side-effects are visible. Ongoing research throughout the world for effective treatment mainly concentrates on methods either in the form of drugs or therapies against this lethal disease. However returning to ayurvedic roots enlightens the fact that nature has many efficient components with anti-cancerous, anti-proliferating and anti-angiogenesis effects. Evidences confirm the participation of plants extracts in synthesizing many medicines against already existing and even emerging diseases. Structure activity relationship (SAR) studies and structural modifications are helping in observing the basis of compounds characteristics to exhibit inhibitor's nature against carcinogenic agents by modifying parent compounds for creating an improved and potent compound. Many components are under clinical trials but most of them still need attention. In this review an attempt has been made to focus on the natural components gifted by nature and even included in our diet with their structures and sources that could be supportive in designing drug either by computational methods or by experimental methods. PMID- 28626699 TI - Highly efficient in vitro regeneration, establishment of callus and cell suspension cultures and RAPD analysis of regenerants of Swertia lawii Burkill. AB - Highly efficient in vitro regeneration system has been developed for Swertia lawii Burkill, an important herb used as substitute for Swertia chirayita. Shoot tips explants were cultured on MS medium with various phytohormones for multiple shoot production. The best shoot production frequency (100%) and maximum shoots (10.4 +/- 0.8) were obtained on MS media containing TDZ (3.0 mg l-1) in combination with IBA (0.3 mg l-1). Maximum callus induction (95 +/- 4.8%) and callus growth (1.7 +/- 0.4 gm) was achieved on MS medium with 2, 4-D (3.0 mg l 1). Cell suspension cultures were established and studied for their growth kinetics. Shoots were rooted best (22.1 +/- 2.5) in 1/2 MS medium with IAA (3.0 mg l-1). The genetic uniformity of the micropropagated clones was assessed using RAPD markers. Out of 405 bands, 400 (98.76%) were monomorphic and rest 5 (1.24%) were polymorphic. High multiplication frequency and low risk of genetic instability ensures the efficacy of this protocol. PMID- 28626700 TI - Purification and properties of an endoglucanase from Thermoascus aurantiacus. AB - An Endo-cellulase was purified to homogeneity using ammonium sulfate precipitation, ion exchange and size exclusion chromatography from newly isolated strain of Thermoascus aurantiacus RBB-1. The recovery and purification fold were 13.3% and 6.6, respectively, after size exclusion chromatography. The purified cellulase has a molecular mass (M) of 35 kDa. Optimum temperature for the enzyme was found to be 70 degrees C and stability was upto 80 degrees C for 1 h. Along with higher stability at 80 degrees C, enzyme showed half lives of 192 h and 144 h at 50 and 70 degrees C respectively. The purified cellulase was optimally active at pH 4.0 and was stable over a broad pH range of 3.0-7.0. The enzyme purified showed apparent Km and Vmax values of 37 mg/ml and 82.6 U/min/mg protein respectively with higher salt tolerance of 10% for 1 h. PMID- 28626701 TI - Operator training simulation for integrating cultivation and homogenisation in protein production. AB - Operating training simulators (OTS) are virtual simulation tools used for training of process operators in industry in performing procedures and running processes. Based on structured mathematical models of the unit operations of a bioprocess an OTS can train a process operator by visualising changing conditions during the process, allow testing operator actions, testing controller settings, experience unexpected technical problems and getting practice in using prescribed standard procedures for a plant. This work shows the design of an OTS where two sequential steps of a recombinant protein production process, a fed-batch cultivation and a high-pressure homogenisation, are integrated. The OTS was evaluated on a user test group and showed that the OTS promoted and developed their understanding of the process, their capability to identify parameters influencing process efficiency and the skills of operating it. PMID- 28626702 TI - 1,3-Propanediol production by Klebsiella oxytoca NRRL-B199 from glycerol. Medium composition and operational conditions. AB - Production of 1,3-propanediol from glycerol using Klebsiella oxytoca NRRL-B199 has been studied. Medium composition has been optimized by means of a statistical design based on the Taguchi method. Strong influences of glycerol and phosphate concentrations have been detected on biomass and product yields. Other factors, such as magnesium concentration and K:Na ratio, have shown a small influence on both responses, biomass and product concentrations. An optimized medium composition has been proposed, leading to a final 1,3-propanediol concentration of 12.4 g/L with a selectivity of 72% with respect to glycerol consumed at shaken bottle-scale. Once the medium composition had been optimized, the scale-up from shaken bottles to STBR was conducted. Several experiments in a 2 L STBR have been conducted in order to determine the best operating conditions concerning temperature and agitation. Under the best operating conditions, i.e., a programmed variable stirring rate ranging from 50 to 100 rpm and a temperature of 37 degrees C, a final concentration of 13.5 g/L of 1,3-propanediol with a selectivity of 86% with respect to the glycerol consumed was obtained. PMID- 28626703 TI - Protein freeze concentration and micro-segregation analysed in a temperature controlled freeze container. AB - To examine effects of varied freezing conditions on the development of spatial heterogeneity in the frozen protein solution, macroscopic freeze concentration and micro-segregation of bovine serum albumin (BSA) were investigated in a temperature-controlled 200-ml freeze container. Freezing to -40 degrees C promoted formation of protein concentration gradients (69-114 MUg ml-1) in frozen samples taken from 12 different freezer positions, whereby slow freezing in 4 h or longer facilitated the evolution of strong spatial heterogeneities and caused local concentration increases by 1.15-fold relative to the initial protein concentration (100 MUg ml-1). To visualize protein micro-segregation during phase separation, BSA was conjugated with fluorescein isothiocyanate and confocal laser scanning fluorescence microscopy was used to localize and size the freeze concentrated protein regions. Slow freezing resulted in distinctly fewer and larger protein domains in the frozen bulk than fast freezing. Surface stress on the protein during freezing would therefore be minimized at low cooling rates; microscopic freeze concentration would however be highest under these conditions, potentially favoring protein aggregation. PMID- 28626704 TI - Extracellular expression of alkaline phytase in Pichia pastoris: Influence of signal peptides, promoters and growth medium. AB - Alkaline phytase isolated from pollen grains of Lilium longiflorum (LlALP) possesses unique catalytic and thermal stability properties that suggest it has the potential to be used as a feed supplement. However, substantial amounts of active enzymes are needed for animal feed studies and endogenous levels of LlALP in lily pollen are too low to provide the required amounts. Active rLlALP2 (coded by LlAlp2, one of two isoforms of alkaline phytase cDNA identified in lily pollen) has been successfully expressed in intracellular compartments of Pichia pastoris, however enzyme yields have been modest (25-30 mg/L) and purification of the enzyme has been challenging. Expression of foreign proteins to the extracellular medium of P. pastoris greatly simplifies protein purification because low levels of endogenous proteins are secreted by the yeast. In this paper, we first describe the generation of P. pastoris strains that will secrete rLlALP2 to the extracellular medium. Data presented here indicates that deletion of native signal peptides at the N- and C-termini of rLlALP2 enhanced alpha mating factor (alpha-MF)-driven secretion by four-fold; chicken egg white lysozyme signal peptide was ineffective in the extracellular secretion of rLlALP2. Second, we describe our efforts to increase expression levels by employing a constitutive promoter from the glyceraldehyde-3-phosphate dehydrogenase gene (PGAP) in place of the strong, tightly controlled promoter of alcohol oxidase 1 gene (PAOX1). PGAP enhanced the extracellular expression levels of rLlALP2 compared to PAOX1. Finally, we report on the optimization of the culture medium to enhance yields of rLlALP2. The strength of PGAP varies depending on the carbon source available for cell growth; secreted expression of rLlALP2 was highest when glycerol was the carbon source. The addition of histidine and Triton X-100 also enhanced extracellular expression. Taken together, the employment of PGAP under optimized culture conditions resulted in approximately eight-fold (75-80 mg/L) increase in extracellular activity compared to PAOXI (8-10 mg/L). The P. pastoris expression system can be employed as a source of active alkaline phytase for animal feed studies. PMID- 28626705 TI - Increasing importance of protein flexibility in designing biocatalytic processes. AB - Enzymes require some flexibility for catalysis. Biotechnologists prefer stable enzymes but often this stabilization comes at the cost of reduced efficiency. Enzymes from thermophiles have low flexibility but poor catalytic rates. Enzymes from psychrophiles are less stable but show good catalytic rates at low temperature. In organic solvents enzymes perform poorly as the prior drying makes the enzyme molecules very rigid. Adding water or increasing reaction temperature improves flexibility and catalytic rates. In case of hydrolases, flexibility and enantioselectivity have interdependence. Understanding the complex role of protein flexibility in biocatalysis can help in designing biotechnological processes. PMID- 28626706 TI - Relative efficiency of zinc sulfide (ZnS) quantum dots (QDs) based electrochemical and fluorescence immunoassay for the detection of Staphylococcal enterotoxin B (SEB). AB - In this paper an attempt was made to detect Staphylococcal enterotoxin B (SEB) both by electrochemical and fluorescence immunoassay methods using zinc sulphide (ZnS) QDs. Wet-chemical method was adopted for the preparation of fluorescent ZnS QDs (diameter ~ 5-10 nm). These QDs were bioconjugated with monoclonal antibodies and then characterized by various method. A detection limit of 0.02 ng mL-1 by fluorescence assay and 1.0 ng mL-1 by electrochemical assay for SEB was achieved. While by sandwich ELISA it is possible to detect 0.24 ng mL-1 only. The sensitivity of all techniques is very good, since the LD50 of SEB is 20 ng kg-1. Electrochemical assay is faster, need low-cost instrument, independent to the size of QDs and found to be one of the best alternative methods as compared to the other existing methods studied herein. The presented method could be expanded to the development of electrochemical and fluorescence biosensors for various agents for field and laboratory use. PMID- 28626707 TI - Properties of microalgal enzymatic protein hydrolysates: Biochemical composition, protein distribution and FTIR characteristics. AB - Chlorella vulgaris SAG 211-12, a green microalga, as model organism was cultivated photomixotrophically using various organic carbon and nitrogen sources at Erlenmeyer scale. The modified medium selected for the experiments was standard BG11 supplemented with 5 g l-1 glucose and 1 g l-1 proteose peptone (PP). To evaluate the effects of light/dark cycles, 12:12; 18:6 and 24:0 light/dark cycle conditions were examined on hourly basis. 24:0 continuous illumination condition was chosen to continue 2 l continuous stirred tank photobioreactor (CSTR) experiments under 1 vvm aeration, 120 rpm mixing time, 23 +/- 2 degrees C, and 70 MUE m-2 s-1 illumination conditions. The results showed significant effect of the culture conditions on the cellular composition. To enhance digestibility of the intact cell; dry biomass was digested with pancreatin enzyme solution and in vitro protein digestibility (IVPD) of crude biomass (UTS), cell debris (CVA) and protein hydrolysates (CVH) was measured. IVPD values of UTS, CVA and CVH were found to be 33-41%, 46-58%, 67-89%; respectively with no significant changes regarding culture conditions (p > 0,05). Results also showed the positive effect of the enzyme treatment for digestion which is a key advantage for nutritional characteristic of the algal biomass. PMID- 28626708 TI - Improved activity of lipase immobilized in microemulsion-based organogels for (R, S)-ketoprofen ester resolution: Long-term stability and reusability. AB - Microemulsion-based organogels (MBGs) were effectively employed for the immobilization of four commonly used lipases. During the asymmetric hydrolysis of ketoprofen vinyl ester at 30 degrees C for 24 h, lipase from Rhizomucor miehei and Mucor javanicus immobilized in microemulsion-based organogels (RML MBGs and MJL MBGs) maintained good enantioselectivities (eep were 86.2% and 99.2%, respectively), and their activities increased 12.8-fold and 7.8-fold, respectively, compared with their free forms. They gave higher yields compared with other lipase MBGs and exhibited better enantioselectivity than commercial immobilized lipases. Immobilization considerably increased the tolerance to organic solvents and high temperature. Both MJL MBGs and RML MBGs showed excellent reusability during 30 cycles of repeated 24 h reactions at 30 degrees C (over 40 days). The system maintained yields of greater than 50%, while the ees values of RML MBGs and MJL MBGs remained nearly constant at 95% and 88%, respectively. PMID- 28626709 TI - Validation of three viable-cell counting methods: Manual, semi-automated, and automated. AB - A viable cell count is essential to evaluate the kinetics of cell growth. Since the hemocytometer was first used for counting blood cells, several variants of the methodology have been developed towards reducing the time of analysis and improving accuracy through automation of both sample preparation and counting. The successful implementation of automated techniques relies in the adjustment of cell staining, image display parameters and cell morphology to obtain equivalent precision, accuracy and linearity with respect to the hemocytometer. In this study we conducted the validation of three trypan blue exclusion-based methods: manual, semi-automated, and fully automated; which were used for the estimation of density and viability of cells employed for the biosynthesis and bioassays of recombinant proteins. Our results showed that the evaluated attributes remained within the same range for the automated methods with respect to the manual, providing an efficient alternative for analyzing a huge number of samples. PMID- 28626710 TI - The application of the Escherichia coli giant spheroplast for drug screening with automated planar patch clamp system. AB - Kv2.1, the voltage-gated ion channel, is ubiquitously expressed in variety of tissues and dysfunction of this ion channel is responsible for multiple diseases. Electrophysiological properties of ion channels are so far characterized with eukaryotic cells using the manual patch clamp which requires skilful operators and expensive equipments. In this research, we created a simple and sensitive drug screen method using bacterial giant spheroplasts and the automated patch clamp which does not require special skills. We expressed a eukaryotic voltage gated ion channel Kv2.1 in Escherichia coli using prokaryotic codon, and prepared giant spheroplasts large enough for the patch clamp. Human Kv2.1 currents were successfully recorded from giant spheroplasts with the automated system, and Kv2.1-expressed E. coli spheroplasts could steadily reacted to the dose-response assay with TEA and 4-AP. Collectively, our results indicate for the first time that the bacterial giant spheroplast can be applied for practical pharmaceutical assay using the automated patch clamp. PMID- 28626711 TI - Effects of light intensity and temperature on photoautotrophic growth of a green microalga, Chlorococcum littorale. AB - A highly CO2-tolerant green alga, Chlorococcum littorale, was investigated at temperatures ranging from 8 to 28 degrees C, light intensities from 30 to 170 MUmol m-2 s-1, a constant CO2 concentration of 5% (v/v) and atmospheric pressure. The experimental results showed that a specific growth rate MU, defined in terms of cell growth rate under a logarithmic growth phase, increased with temperature up to the maximum value (ca. 22 degrees C), while the MU decreased at higher temperatures. These promotion and inhibition of the cell growth rate were expressed by both a multiple linear regression and a mathematical model taking account of the Arrhenius activation/deactivation energies. Light intensity affected on the cell growth was independently treated in the mathematical model. The proposed growth model agreed well with the experimental data to within 6.6 %, which provides good correlation for both temperature and light intensity effects on the microalgal cell growth. PMID- 28626712 TI - Modification of a bi-functional diguanylate cyclase-phosphodiesterase to efficiently produce cyclic diguanylate monophosphate. AB - Cyclic-diGMP is a bacterial messenger that regulates many physiological processes, including many attributed to pathogenicity. Bacteria synthesize cyclic diGMP from GTP using diguanylate cyclases; its hydrolysis is catalyzed by phosphodiesterases. Here we report the over-expression and purification of a bi functional diguanylate cyclase-phosphodiesterase from Agrobacterium vitis S4. Using homology modeling and primary structure alignment, we identify several amino acids predicted to participate in the phosphodiesterase reaction. Upon altering selected residues, we obtain variants of the enzyme that efficiently and quantitatively catalyze the synthesis of cyclic-diGMP from GTP without hydrolysis to pGpG. Additionally, we identify a variant that produces cyclic-diGMP while immobilized to NiNTA beads and can catalyze the conversion of [alpha-32P]-GTP to [32P]-cyclic-diGMP. In short, we characterize a novel cyclic-diGMP processing enzyme and demonstrate its utility for efficient and cost-effective production of cyclic-diGMP, as well as modified cyclic-diGMP molecules, for use as probes in studying the many important biological processes mediated by cyclic-diGMP. PMID- 28626713 TI - Production of a recombinant membrane protein in an Escherichia coli strain for the whole cell biosynthesis of phenylacetic acids. AB - The styrene oxide isomerase (SOI) represents a membrane-bound enzyme of the microbial styrene degradation pathway and has been discussed as promising biocatalyst. It catalyzes the isomerization of styrene oxide to phenylacetaldehyde. In this study a styC gene, which encodes the SOI of Rhodococcus opacus 1CP, was optimized for optimal expression in Escherichia coli BL21(DE3) pLysS. The expression of this synthetic styC was investigated and subsequently optimized. Highly active biomass was obtained yielding an SOI activity of 44.5 +/- 8.7 U mg-1 after 10 h. This represents the highest SOI activity reported for crude cell extracts of SOI-containing bacterial strains. Remarkably, this biomass can be applied as whole cell biocatalyst for the production of phenylacetic acids from styrene oxides. In the case of non substituted styrene oxide, nearly 730 mg l-1 phenylacetic acid (~85% yield) was formed over a period of 20 days. PMID- 28626714 TI - Bioadsorption of a reactive dye from aqueous solution by municipal solid waste. AB - The biosorbent was obtained from municipal solid waste (MSW) of the Mostaganem city. Before use the MSW was dried in air for three days and washed several times. The sorption of yellow procion reactive dye MX-3R onto biomass from aqueous solution was investigated as function of pH, contact time and temperature. The adsorption capacity of MX-3R was 45.84 mg/g at pH 2-3 and room temperature. MX-3R adsorption decreases with increasing temperature. The Langmuir, Freundlich and Langmuir-Freundlich adsorption models were applied to describe the related isotherms. Langmuir-Freundlich equation has shown the best fitting with the experimental data. The pseudo first-order, pseudo second-order and intra-particle diffusion kinetic models were used to describe the kinetic sorption. The results clearly showed that the adsorption of MX-3R onto biosorbent followed the pseudo second-order model. The enthalpy (DeltaH degrees ), entropy (DeltaS degrees ) and Gibbs free energy (DeltaG degrees ) changes of adsorption were calculated. The results indicated that the adsorption of MX-3R occurs spontaneously as an exothermic process. PMID- 28626715 TI - Stimulation of rhamnolipid biosurfactants production in Pseudomonas aeruginosa AK6U by organosulfur compounds provided as sulfur sources. AB - A Pseudomonas aeruginosa AK6U strain produced rhamnolipid biosurfactants to variable extents when grown on MgSO4 or organosulfur compounds as sulfur sources and glucose as a carbon source. Organosulfur cultures produced much higher biosurfactants amounts compared to the MgSO4 cultures. The surface tension of the growth medium was reduced from 72 mN/m to 54 and 30 mN/m in cultures containing MgSO4 and 4,6-dimethyldibenzothiophene (4,6-DM-DBT), respectively. AK6U cultures produced different rhamnolipid congener profiles depending on the provided sulfur source. The dibenzothiophene (DBT) culture produced more diverse and a higher number of rhamnolipid congeners as compared to the DBT-sulfone and MgSO4 cultures. The number of mono-rhamnolipid congeners in the DBT culture was also higher than that detected in the DBT-sulfone and MgSO4 cultures. Di-rhamnolipids dominated the congener profiles in all the analyzed cultures. The sulfur source can have a profound impact on the quality and quantity of the produced biosurfactants. PMID- 28626716 TI - Highly sensitive detection of influenza virus in saliva by real-time PCR method using sugar chain-immobilized gold nanoparticles; application to clinical studies. AB - A highly sensitive and convenient method for detecting influenza virus was developed using modified end-point melt curve analysis of a RT-qPCR SYBR Green method and influenza virus-binding sugar chain-immobilized gold-nanoparticles (SGNP). Because SGNPs capture influenza viruses, the virus-SGNP complex was separated easily by centrifugation. Viral RNA was detected at very low concentrations, suggesting that SGNP increased sensitivity compared with standard methods. This method was applied to clinical studies. Influenza viruses were detected in saliva of patients or inpatients who had been considered influenza free by a rapid diagnostic assay of nasal swabs. Furthermore, the method was applied to a human trial of prophylactic anti-influenza properties of yogurt containing Lactobacillus acidophilus L-92. The incidence of influenza viruses in saliva of the L-92 group was found to be significantly lower compared to the control group. Thus, this method was useful for monitoring the course of anti influenza treatment or preventive measures against nosocomial infection. PMID- 28626717 TI - Evaluation of different carbon sources for high frequency callus culture with reduced phenolic secretion in cotton (Gossypium hirsutum L.) cv. SVPR-2. AB - An efficient protocol was developed to control excessive phenolic compound secretion during callus culture of cotton. As cotton is naturally rich in phenolic compounds factors influencing the phenolic compound secretion, callus induction and proliferation were optimized for getting high frequency callus culture. Different carbon sources such as fructose, glucose, sucrose and maltose were tested at various concentrations to control phenolic secretion in callus culture. Among them, 3% maltose was found to be the best carbon source for effectively controlling phenolic secretion in callus induction medium. High frequency of callus induction was obtained on MSB5 medium supplemented with 3% Maltose, 2,4-D (0.90 MUM) and Kinetin (4.60 MUM) from both cotyledon and hypocotyl explants. The best result of callus induction was obtained with hypocotyl explant (94.90%) followed by cotyledon explant (85.20%). MSB5 medium supplemented with 2,4-D (0.45 MUM) along with 2iP (2.95 MUM) gave tremendous proliferation of callus with high percentage of response. Varying degrees of colors and textures of callus were observed under different hormone treatments. The present study offers a solution for controlling phenolic secretion in cotton callus culture by adjusting carbon sources without adding any additives and evaluates the manipulation of plant growth regulators for efficient callus culture of SVPR-2 cotton cultivar. PMID- 28626718 TI - Rapid transient expression of human granulocyte-macrophage colony-stimulating factor in two industrial cultivars of tobacco (Nicotiana tabacum L.) by agroinfiltration. AB - We report the production of hGM-CSF cytokine in leaves of industrial tobacco cultivars DH-17 and DH-27 by using Agrobacterium-mediated transient expression. We prove the concept that very high biomass industrial tobacco plants are suitable platforms for rapid, low cost production of foreign proteins. Successful transient expression of the GM-CSF was achieved in less than three months, opening the possibility for future applications of this approach in rapid response production of various proteins of non-plant origin in industrial tobacco. PMID- 28626719 TI - Rice husk extracted lignin-TEOS biocomposites: Effects of acetylation and silane surface treatments for application in nickel removal. AB - A novel lignosilicate (LS) composite was synthesized from pre-extracted (hot water, 80% ethanol, 0.3 N NaOH) lignin of rice husk (RH) using TEOS as matrix. The extracted lignins were subjected to surface modification by acetylation followed by in situ synthesis of lignosilicate (LS) composites by sol-gel method for application in nickel removal. LS were characterized by FT-IR, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), particle size distribution (PSD) and atomic absorption spectroscopy (AAS). FT-IR studies showed acetyl group in the range of 1680-1690 cm-1 whereas for adsorbed Si-O-Ni2+ the band appeared at 870 cm-1. Findings suggest that alkali extracted LS with mean PSD of 14.89 nm are thermally more stable (Tm = 337 degrees C) than ethanol (ELS) and hot water (HLS) extracted LS, and exhibit potential for Ni2+ removal (38.74%). SEM and PSD (D50) analyses confirmed their rough surfaces and dispersive nature, respectively, suitable for metal biosorption. PMID- 28626720 TI - Exploring the potential of the glycerol-3-phosphate dehydrogenase 2 (GPD2) promoter for recombinant gene expression in Saccharomyces cerevisiae. AB - A control point for keeping redox homeostasis in Saccharomyces cerevisiae during fermentative growth is the dynamic regulation of transcription for the glycerol-3 phosphate dehydrogenase 2 (GPD2) gene. In this study, the possibility to steer the activity of the GPD2 promoter was investigated by placing it in strains with different ability to reoxidise NADH, and applying different environmental conditions. Flow cytometric analysis of reporter strains expressing green fluorescent protein (GFP) under the control of the GPD2 promoter was used to determine the promoter activity at the single-cell level. When placed in a gpd1Deltagpd2Delta strain background, the GPD2 promoter displayed a 2-fold higher activity as compared to the strong constitutive glyceraldehyde-3-phosphate dehydrogenase (TDH3). In contrast, the GPD2 promoter was found to be inactive when cells were cultivated in continuous mode at a growth rate of 0.3 h-1 and in conditions with excess oxygen (i.e. with an aeration of 2.5 vvm, and a stirring of 800 rpm). In addition, a clear window of operation where the gpd1Deltagpd2Delta strain can be grown with the same efficiency as wild type yeast was identified. In conclusion, the flow cytometry mapping revealed conditions where the GPD2 promoter was either completely inactive or hyperactive, which has implications for its implementation in future biotechnological applications such as for process control of heterologous gene expression. PMID- 28626721 TI - Multicomponent mixtures for cryoprotection and ligand solubilization. AB - Mixed cryoprotectants have been developed for the solubilization of ligands for crystallization of protein-ligand complexes and for crystal soaking. Low affinity lead compounds with poor solubility are problematic for structural studies. Complete ligand solubilization is required for co-crystallization and crystal soaking experiments to obtain interpretable electron density maps for the ligand. Mixed cryo-preserving compounds are needed prior to X-ray data collection to reduce radiation damage at synchrotron sources. Here we present dual-use mixes that act as cryoprotectants and also promote the aqueous solubility of hydrophobic ligands. Unlike glycerol that increases protein solubility and can cause crystal melting the mixed solutions of cryo-preserving compounds that include precipitants and solubilizers, allow for worry-free crystal preservation while simultaneously solubilizing relatively hydrophobic ligands, typical of ligands obtained in high-throughput screening. The effectiveness of these mixture has been confirmed on a human transthyretin crystals both during crystallization and in flash freezing of crystals. PMID- 28626722 TI - Optimization of tannase production by a novel Klebsiella pneumoniae KP715242 using central composite design. AB - A novel tannase producing bacterial strain was isolated from rhizospheric soil of Acacia species and identified as Klebsiella pneumoniae KP715242. A 3.25-fold increase in tannase production was achieved upon optimization with central composite design using response surface methodology. Four variables namely pH, temperature, incubation period, and agitation speed were used to optimize significant correlation between the effects of these variables on tannase production. A second-order polynomial was fitted to data and validated by ANOVA. The results showed a complex relationship between variables and response given that all factors were significant and could explain 99.6% of the total variation. The maximum production was obtained at 5.2 pH, 34.97 degrees C temperature, 103.34 rpm agitation speed and 91.34 h of incubation time. The experimental values were in good agreement with the predicted ones and the models were highly significant with a correlation coefficient (R2) of 0.99 and a highly significant F-value of 319.37. PMID- 28626723 TI - A low cost fermentation medium for potential fibrinolytic enzyme production by a newly isolated marine bacterium, Shewanella sp. IND20. AB - Agro-residues were used as the substrate for the production of fibrinolytic enzyme in solid state fermentation. In this study, two-level full factorial design (25) and response surface methodology were applied to optimize a fermentation medium for the production of fibrinolytic enzyme from the marine isolate Shewanella sp. IND20. The 25 factorial design demonstrated that the physical factors (pH and moisture) and nutrient factors (trehalose, casein, and sodium dihydrogen phosphate) had significant effect on fibrinolytic enzyme production. Central composite design was employed to search for the optimal concentration of the three factors, namely moisture, pH, and trehalose, and the experimental results were fitted with a second-order polynomial model at 99% level (p < 0.0001). The optimized medium showed 2751 U/mL of fibrinolytic activity, which was 2.5-fold higher than unoptimized medium. The molecular weight of fibrinolytic enzyme was found to be 55.5 kDa. The optimum pH and temperature were 8.0 and 50 degrees C, respectively. PMID- 28626724 TI - Effect of antibiotics on callus regeneration during transformation of IR 64 rice. AB - We report here the effect of antibiotics on the regeneration potential of recalcitrant indica rice cultivar, IR64. Different protocols reporting high efficiency agro-bacterium-mediated transformation of mature seed-derived regenerative calli were used and compared. The putative transgenic (T0) plants were analyzed for integration of the transgene through polymerase chain reaction and Southern blotting analyses. It was observed that the high-efficiency transformation of scutellar-derived regenerative calli could be obtained by using maltose as a carbon source and increased quantity of 2,4-D on a medium containing a higher concentration of gelling agent. The percentage of regeneration is greatly affected by the presence of antibiotics. PMID- 28626725 TI - Statistical optimization of harvesting Chlorella vulgaris using a novel bio source, Strychnos potatorum. AB - The present study was aimed at harvesting microalga, Chlorella vulgaris, by bioflocculation using seed powder of clearing nut, Strychnos potatorum. The research was essentially the prime step to yield a large biomass for utilising the cells in biodiesel production. Optimization of the parameters influencing bioflocculation was carried out statistically using RSM. The optimized conditions were 100 mg L-1 bioflocculant concentration, 35 degrees C temperature, 150 rpm agitation speed and 30 min incubation time and resulted in a maximum efficiency of 99.68%. Through cell viability test, using Trypan blue stain, it was found that cells were completely intact when treated with bioflocculant, but destroyed when exposed to chemical flocculant, alum. The overall study represented that S. potatorum could potentially be a bioflocculant of microalgal cells and a promising substitute for expensive and hazardous chemical flocculants. Moreover, this bioflocculant demonstrated their utility to harvest microalgal cells by economically, effectively and in an ecofriendly way. PMID- 28626726 TI - Cancer Stem Cells in Oral Cavity Squamous Cell Carcinoma: A Review. AB - Cancer stem cells (CSCs) have been identified in oral cavity squamous cell carcinoma (OCSCC). CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells and cancer cells that drive tumor growth. Studies of many cancer types including OCSCC have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple CSC subtypes within OCSCC, making investigation reliant on the use of multiple markers. This review examines the current knowledge in CSC markers OCT4, SOX2, NANOG, ALDH1, phosphorylated STAT3, CD44, CD24, CD133, and Musashi-1, specifically focusing on their use and validity in OCSCC CSC research and how they may be organized into the CSC hierarchy. OCSCC CSCs also express components of the renin-angiotensin system (RAS), which suggests CSCs may be novel therapeutic targets by modulation of the RAS using existing medications. PMID- 28626728 TI - Commentary: Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. PMID- 28626727 TI - Mast Cell Infiltration in Human Brain Metastases Modulates the Microenvironment and Contributes to the Metastatic Potential. AB - Metastatic brain tumors continue to be a clinical problem, despite new therapeutic advances in cancer treatment. Brain metastases (BMs) are among the most common mass lesions in the brain that are resistant to chemotherapies, have a very poor prognosis, and currently lack any efficient diagnostic tests. Predictions estimate that about 40% of lung and breast cancer patients will develop BM. Despite this, very little is known about the immunological and genetic aberrations that drive tumorigenesis in BM. In this study, we demonstrate the infiltration of mast cells (MCs) in a large cohort of human BM samples with different tissues of origin for primary cancer. We applied patient-derived BM cell models to the study of BM cell-MC interactions. BM cells when cocultured with MCs demonstrate enhanced growth and self-renewal capacity. Gene set enrichment analyses indicate increased expression of signal transduction and transmembrane proteins related genes in the cocultured BM cells. MCs exert their effect by release of mediators such as IL-8, IL-10, matrix metalloprotease 2, and vascular endothelial growth factor, thereby permitting metastasis. In conclusion, we provide evidence for a role of MCs in BM. Our findings indicate MCs' capability of modulating gene expression in BM cells and suggest that MCs can serve as a new target for drug development against metastases in the brain. PMID- 28626729 TI - A New Era of Systemic Therapy for Hepatocellular Carcinoma with Regorafenib and Lenvatinib. PMID- 28626730 TI - Albumin-Bilirubin Grade and Hepatocellular Carcinoma Treatment Algorithm. PMID- 28626731 TI - How to Differentiate Borderline Hepatic Nodules in Hepatocarcinogenesis: Emphasis on Imaging Diagnosis. AB - BACKGROUND: Rapid advances in liver imaging have improved the evaluation of hepatocarcinogenesis and early diagnosis and treatment of hepatocellular carcinoma (HCC). In this situation, detection of early-stage HCC in its development is important for the improvement of patient survival and optimal treatment strategies. Because early HCCs are considered precursors of progressed HCC, precise differentiation between a dysplastic nodule (DN), especially a high grade DN, and early HCC is important. In clinical practice, these nodules are frequently called "borderline hepatic nodules." SUMMARY: This article discusses radiological and pathological characteristics of these borderline hepatic nodules and offers an understanding of multistep hepatocarcinogenesis by focusing on the descriptions of the imaging changes in the progression of DN and early HCC. Detection and accurate diagnosis of borderline hepatic nodules are still a challenge with contrast enhanced ultrasonography, CT, and MRI with extracellular contrast agents. However, gadoxetic acid-enhanced MRI may be useful for improving the diagnosis of these borderline nodules. KEY MESSAGES: Since there is a net effect of incomplete neoangiogenesis and decreased portal venous flow in the early stage of hepatocarcinogenesis, borderline hepatic nodules commonly show iso or hypovascularity. Therefore, precise differentiation of these nodules remains a challenging issue. In MRI using hepatobiliary contrast agents, signal intensity of HCCs on hepatobiliary phase (HBP) is regarded as a potential imaging biomarker. Borderline hepatic nodules are seen as nonhypervascular and hypointense nodules on the HBP, which is important for predicting tumor behavior and determining appropriate therapeutic strategies. PMID- 28626732 TI - Albumin-Bilirubin (ALBI) Grade as Part of the Evidence-Based Clinical Practice Guideline for HCC of the Japan Society of Hepatology: A Comparison with the Liver Damage and Child-Pugh Classifications. AB - AIM/BACKGROUND: The purpose of this study was to evaluate the validity of 3 classifications for assessing liver function, the liver damage and Child-Pugh classifications and the newly proposed albumin-bilirubin (ALBI) grade, in order to examine the feasibility of evaluating hepatic function using ALBI grade with the hepatocellular carcinoma (HCC) treatment algorithm used in Japan. METHODS: We analyzed the medical records of 3,495 Japanese HCC patients admitted from 2000 to 2015, which were comprised of 1,580 patients hospitalized in the Ehime Prefecture area and used as a training cohort (Ehime group), and 1,915 others who were used for validation (validation group). ALBI score used for grading (<=-2.60 = grade 1, greater than -2.60 to <=-1.39 = grade 2, greater than -1.39 = grade 3) as well as clinical features and prognosis (Japan Integrated Staging [JIS], modified JIS, ALBI-TNM [ALBI-T] score) were retrospectively investigated. RESULTS: For prediction of liver damage A, the values for sensitivity and specificity, positive predictive and negative predictive values, and positive and negative likelihood ratios of ALBI-1 and Child-Pugh A were similar among the 2 groups. Akaike information criterion results showed that prognosis based on ALBI grade/ALBI-T score was better than that based on liver damage/modified JIS score and Child-Pugh/JIS score (22,291.8/21,989.4, 22,379.6/22,076.0, 22,392.1/22,075.1, respectively). The cutoff values for ALBI score for indocyanine green retention rate at 15 min (ICG-R15) <10, <20, and <30% were 2.623 (area under the curve [AUC]: 0.798), -2.470 (AUC: 0.791), and -2.222 (AUC: 0.843), respectively. The distribution of ICG-R15 (<10%, 10 to <20%, 20 to <30%, and >=30%) for ALBI grade 1 was similar to that for liver damage A. There were only small differences with regard to therapeutic selection with the Japanese HCC treatment algorithm between liver damage and ALBI grade. CONCLUSION: ALBI grade is a useful and easy classification system for assessment of hepatic function for therapeutic decision making. PMID- 28626733 TI - The Overall Survival of Patients with Hepatocellular Carcinoma Correlates with the Newly Defined Time to Progression after Transarterial Chemoembolization. AB - AIM/BACKGROUND: The ultimate aim of any treatment for hepatocellular carcinoma (HCC) is to improve overall survival (OS); however, the clinical significance of time to progression (TTP) after transarterial chemoembolization (TACE) is unclear. This retrospective study examined the association between OS and the newly defined time to TACE progression (TTTP) to assess whether TTTP can be an alternative to OS in HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B. METHODS: Between January 2006 and December 2013, 592 patients with HCC (BCLC B1, n = 118; BCLC B2, n = 170) underwent TACE. TTTP was then redefined as time to progression from the first image taken after TACE. The relationship between TTTP and OS was then examined based on survival time. RESULTS: Survival analysis revealed significant differences in the OS of patients with BCLC B1 and those with BCLC B2 (median OS: 42.3 months, 95% confidence interval [CI] 34.4-50.7; and 29.3 months, 95% CI 26.1-37.6, respectively, p = 0.0348). The median TTTP values were 9.5 months (95% CI 7.0-10.9) and 5.3 months (95% CI 4.6-6.7), respectively (p = 0.0078). There was a moderate positive correlation between OS and TTTP for both B1 (R2 = 0.6563, p = 0.0045) and B2 (R2 = 0.6433, p = 0.0052) substages. There was also a positive correlation between OS and TTTP for the combined B1 and B2 substages (R2 = 0.6590, p = 0.0024). CONCLUSIONS: There was a moderate correlation between the TTTP and OS of patients with HCC after TACE therapy, where the patients with short TTTP represented short OS, indicating that TTTP is an alternative parameter for survival analysis of HCC patients with BCLC stage B tumors who undergo TACE. PMID- 28626734 TI - Beneficial Effect of Maintaining Hepatic Reserve during Chemotherapy on the Outcomes of Patients with Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) usually develops in chronically damaged liver. We investigated hepatic reserves during chemotherapy of patients with advanced HCC and compensated liver function to evaluate the effect on patients' outcomes of maintaining hepatic reserve after chemotherapy. We retrospectively reviewed the medical records of 190 patients with Child-Pugh A with advanced HCC who were treated with sorafenib or hepatic arterial infusion chemotherapy (HAIC). We investigated the Child-Pugh score and albumin-bilirubin grade for hepatic reserve, and evaluated the effect of the change in Child-Pugh scores on patients' outcomes. Subjects were treated with sorafenib (n = 59) or HAIC (n = 131). Of patients with Child-Pugh data, 66.7% maintained or improved their Child-Pugh score after 4 weeks. Treatment with HAIC was the only factor that significantly contributed to maintaining Child-Pugh scores after 4 weeks. The overall survival of patients with a higher Child-Pugh score after 4 weeks was shorter than that of patients whose Child-Pugh classification was unchanged. Multivariate analysis demonstrated that an increased Child-Pugh score after 4 weeks was one of the independent unfavorable prognostic factors. The change of hepatic reserve as a function of albumin-bilirubin grade did not significantly correlate with patients' outcomes. Maintaining the Child-Pugh score during chemotherapy benefits the outcomes of patients with advanced HCC, even those with sufficient hepatic reserve. PMID- 28626735 TI - Third edition of the Central and Eastern European Meeting on Viral Hepatitis and Co-infection with HIV. PMID- 28626736 TI - Enterococcus spp. and S. aureus colonization in neutropenic febrile children with cancer. AB - INTRODUCTION: Febrile neutropenia is one of the most serious treatment-related complications in cancer patients. Susceptible to rapidly progressing infections, which result in prolonged hospitalization and use of broad-spectrum antibiotics, neutropenic patients are subject to colonization by multiresistant agents, which enhances the risk of infections. METHODS: In this study we included samples collected with nasal, oropharyngeal and anal swabs from hospitalized children with febrile neutropenia following chemotherapy, between March 2014 and 2015, aiming to elucidate colonization by S. aureus and Enterococcus spp., as well as their resistance profile. RESULTS: S. aureus was found in 22% of the patients and 14% of the events. Methicillin-resistant S. aureus colonized 13.6% of patients. Including anal swabs in the screening increased the identification of colonized patients by 20%. Enterococcus spp. was found in 27% of patients and 17% of episodes. Enterococcal isolates resistant to vancomycin, accounting for 25% of the total, were not isolated in anal swabs at any time, with the oropharyngeal site being much more important. The rate of infection by Enterococcus spp. was 4.5% of all patients and 16% among the colonized patients. CONCLUSION: Especially in this population, colonization studies including more sites can yield a higher chance of positive results. Establishing the colonization profile in febrile neutropenic children following chemotherapy may help to institute an empirical antibiotic treatment aimed at antibiotic adequacy and lower induction of resistance, thereby decreasing the risk of an unfavorable clinical outcome. PMID- 28626737 TI - High level bacterial contamination of secondary school students' mobile phones. AB - INTRODUCTION: While contamination of mobile phones in the hospital has been found to be common in several studies, little information about bacterial abundance on phones used in the community is available. Our aim was to quantitatively determine the bacterial contamination of secondary school students' mobile phones. METHODS: Altogether 27 mobile phones were studied. The contact plate method and microbial identification using MALDI-TOF mass spectrometer were used for culture studies. Quantitative PCR reaction for detection of universal 16S rRNA, Enterococcus faecalis 16S rRNA and Escherichia coli allantoin permease were performed, and the presence of tetracycline (tetA, tetB, tetM), erythromycin (ermB) and sulphonamide (sul1) resistance genes was assessed. RESULTS: We found a high median bacterial count on secondary school students' mobile phones (10.5 CFU/cm2) and a median of 17,032 bacterial 16S rRNA gene copies per phone. Potentially pathogenic microbes (Staphylococcus aureus, Acinetobacter spp., Pseudomonas spp., Bacillus cereus and Neisseria flavescens) were found among dominant microbes more often on phones with higher percentage of E. faecalis in total bacterial 16S rRNA. No differences in contamination level or dominating bacterial species between phone owner's gender and between phone types (touch screen/keypad) were found. No antibiotic resistance genes were detected on mobile phone surfaces. CONCLUSION: Quantitative study methods revealed high level bacterial contamination of secondary school students' mobile phones. PMID- 28626738 TI - Streptococcus pneumoniae serotype prevalence and antibiotic resistance among young children with invasive pneumococcal disease: experience from a tertiary care center in South India. AB - INTRODUCTION: We performed a study to describe the clinical profile, antimicrobial susceptibility and prevalent serotypes of pneumococcal isolates from children with suspected invasive pneumococcal disease (IPD) admitted to a tertiary care hospital in South India. METHODS: Hospitalized children, <= 5 years with fever (>38 degrees C); increased respiratory rate or neurological symptoms were recruited, (as part of the Alliance for Surveillance of Invasive Pneumococci - ASIP - project) from January 2011 to March 2013. Identification of pneumococcal isolates from blood or cerebrospinal fluid samples was done by routine culture methods. Isolates were analyzed for antimicrobial susceptibility, and confirmed by serotyping (using Quellung's test) and multiplex PCR. RESULTS: Out of the 171 samples received in the lab, 17 grew pneumococci identified by standard methods. Fourteen of them were confirmed by multiplex PCR. Maximum recruitment was observed during the months of January and February (36.4%, 28.6%). The average age of affected subjects was 21 months. The common clinical presentation was pneumonia (42.8%). Two isolates belonging to the 19F and 19B serotypes were resistant to penicillin (on Etest). The observed serotype distribution was 6B and 19F (2 each), and 1, 2, 6A, 9V, 10A, 14, 15A, 19B, 21, 35F (1 each). The overall fatality rate was 14.3% (n=2); the S. pneumoniae isolates from these two patients belonged to the non-vaccine serotype 19B and vaccine serotype 19F and demonstrated in vitro resistance to penicillin and erythromycin. CONCLUSION: Our study demonstrates the presence of invasive pneumococcal disease among under-5 year-old children in India caused by serotypes that are in large part covered by available pneumococcal vaccines. PMID- 28626739 TI - Systematic review and meta-analysis of imipenem-resistant Pseudomonas aeruginosa prevalence in Iran. AB - INTRODUCTION: Imipenem-resistant Pseudomonas aeruginosa (IRPA), due to resistance to different classes of antibiotics and its remarkable capacity to survive in harsh and adverse conditions such as those in the hospital environment, is considered a serious threat to the healthcare system. Given the great impact of IRPA on patients' outcome and in order to possibly improve antibiotic prescription, this study was conducted to determine the prevalence of clinical isolates of IRPA in different parts of Iran. METHODS: A systematic literature search was performed in PubMed, Web of Science, Google Scholar and Scopus, as well as in two Iranian domestic search engines, i.e., Iranian Scientific Information Database and Magiran. Finally, after applying exclusion and inclusion criteria 37 articles with full-texts describing the prevalence of imipenem resistant P. aeruginosa were selected for meta-analysis and systematic review. RESULTS: The pooled estimation of 5227 P. aeruginosa isolates in this analysis showed that the percentage of imipenem-resistant P. aeruginosa is about 54% in the Iranian population (95%CI: 0.47-0.62, logit event rate=0.19, 95%CI: 0.12,0.49). CONCLUSION: The findings of this analysis show that in the majority of Iranian hospitals the relative frequency of IRPA is high, therefore, in order to prevent further dissemination of IRPA, more appropriate antibiotic prescription and infection control policies must be implemented by decision makers. PMID- 28626740 TI - Simplified protocol of gel-based multiple locus variable number of tandem repeats analysis (MLVA) for Staphylococcus aureus typing. PMID- 28626741 TI - Isolation and Identification of Two Phenolic Compounds from a Moderately Cytotoxic Fraction of Cousinia verbascifolia Bunge. AB - BACKGROUND: Little information is available about chemical components of the Cousinia genus. A primary cytotoxicity screening on Cousinia verbascifolia showed moderate cytotoxic activity against OVCAR-3 ovarian and HT-29 colon cancer cells. Therefore, the aim of this study is a phytochemical investigation to identify the compounds responsible for this bioactivity. MATERIALS AND METHODS: Extraction was done through percolation and fractionations by reverse phase column chromatography and normal column chromatography. Using standard 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay Fr.b8 with moderate cytotoxicity was selected for identification of major components. Fr.b8 was subjected to polyamide column chromatography. More purification was done using a new modified recycle high-performance liquid chromatography (HPLC) with flow splitter. RESULTS: Two known compounds: Apigenin (flavone) and caffeic acid (phenolic acid) were obtained from phenolic bioactive fraction for the first time from this plant. CONCLUSIONS: Apigenin and caffeic acid with known antitumor and matrix metalloproteinase inhibitory effects seem to be the bioactive components responsible for moderate cytotoxicity of phenolic fraction. Recycle HPLC following with flow splitting is a new method useful for isolation of closely eluted compounds in HPLC chromatogram. PMID- 28626742 TI - Association Study of Glutathione S-transferases Gene Polymorphisms (GSTM1 and GSTT1) with Ulcerative Colitis and Crohn's Disease in the South of Iran. AB - BACKGROUND: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders of the gastrointestinal tract. A combination of environmental factors and interactions with a genetic predisposition are suggested to play an important role in the etiology and pathogenesis of the IBD. Glutathione S-transferases (GSTs) are multifunctional enzymes involved in the cellular oxidative stress handling. Possible associations between GSTs gene polymorphisms and susceptibility to UC and CD have been reported in different population. The relationship between GSTM1 and GSTT1 deletion polymorphisms and susceptibility to UC and CD were investigated in the Iranian population. MATERIALS AND METHODS: The study was performed in 106 IBD patients and 243 age- and sex-matched healthy Iranian controls consulting the IBD registry center of the Motahari Clinic, Shiraz University of Medical Sciences, Shiraz, Iran, between 2011 and 2013. GSTM1 and GSTT1 genotyping were performed using multiplex polymerase chain reaction and differences in the distribution of gene polymorphisms were analyzed statistically between the studied groups. RESULTS: Statistically significant higher frequency of GSTM1 null genotype was observed in IBD patients (P = 0.01) and in the subgroup of patients with UC (P = 0.04) compared to healthy controls, whereas this was not true for CD patients. No significant association was found between GSTT1 gene polymorphism and UC or CD. CONCLUSIONS: Absence of GSTT1 functional gene does not play an important role in the pathophysiology and development of IBD, UC, and CD in Iranian population whereas GSTM1 null genotype could be considered as a possible genetic predisposing factor for more susceptibility to IBD and UC. PMID- 28626743 TI - Phytochemical Screening and Cytotoxic Evaluation of Euphorbia turcomanica on Hela and HT-29 Tumor Cell Lines. AB - BACKGROUND: Cancer is a term for a large group of different diseases, all involving uncontrolled cell growth. Many of Euphorbiaceae plants have been traditionally used for the treatment of ulcers, tumors, warts, and other diseases. In addition, in the last decade, there are studies showing cytotoxic effects of different species of Euphorbia on tumor cell lines. In this study, we attempted to determine if Euphorbia turcomanica possess any cytotoxic activity. MATERIALS AND METHODS: Solvents extracted the plant powder with various polarities by a maceration method, and qualitative phytochemical analyzes were carried out on them to identify the constituents. On the other hand, the possible cytotoxicity of different extracts on Hela and HT-29 tumor cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 50% reduction in cell survival was considered as a cytotoxic effect. Analyze of variance followed by Student-Newman-Keuls test was used to see the differences among the groups. RESULTS: Phytochemical analysis of E. turcomanica showed the presence of flavonoid, alkaloid, anthraquinone and tannin in plant aerial parts. Methanol-water, acetone, dichloromethane, methanol, and heptane extracts of E. turcomanica significantly reduced viability of Hela cells (P < 0.05) with inhibitory concentration 50% (IC50) of 50, 90, 230, 420, and 450 MUg/ml, respectively. While methanol-water, dichloromethane, methanol, ethyl acetate, and heptane extracts were cytotoxic with IC50 of 43, 115, 125, 250, and 390 MUg/ml, respectively (P < 0.05), on HT-29 cells. CONCLUSION: It can be concluded that E. turcomanica is a good candidate for further study toward cytotoxic agents. PMID- 28626744 TI - Central Beneficial Effects of Trimetazidine on Psychomotor Performance in Normal Healthy Volunteers. AB - BACKGROUND: Trimetazidine is a fatty oxidation inhibitor, leading to shifting of energy substrate from fatty acid oxidation toward glucose oxidation that leads to the reduction of oxygen requirement. The aims of the present study were to elucidate the effects of trimetazidine on psychomotor performance and vigilance on normal healthy volunteers. MATERIALS AND METHODS: A total of 234 subjects (age 22-25 years) were recruited in this study. The volunteers were randomizing into two groups with 117 volunteers in each group. Group I received an inert starch capsule served as a control, and Group II received trimetazidine tablet 15 mg/day. The duration of therapy was 5 days. Test procedure was done at 9.00 a.m. on the psychomotor tester. Before the drug administration, prescore values were recorded and then after 5 days of therapy, the postscore values were recorded. RESULTS: The placebo did not demonstrate a significant effect on all psychomotor performances and flicker-fusion elements (P > 0.05). Trimetazidine therapy produced a highly significant effect on all components of psychomotor performances and flicker-fusion parameters (P < 0.001) compared with pretreatment era. CONCLUSION: We conclude that trimetazidine improves psychomotor performance and vigilance in normal healthy volunteers through advancing total reaction time and critical flicker-fusion frequency. PMID- 28626745 TI - Investigating the Effect of Extracorporeal Shock Wave Therapy on Reducing Chronic Pain in Patients with Pes Anserine Bursitis: A Randomized, Clinical- Controlled Trial. AB - BACKGROUND: Knee pain, is one of the most common causes of patients' referring to physiatric clinics, and several factors, are involved in its creation. One of these factors is pes anserine bursitis (PAB) for which various treatment methods are used. This study aims to investigate the effect of this method on reducing chronic pain in these patients. MATERIALS AND METHODS: This clinical trial was conducted in 2013- 2014 on patients with PAB referring to academic, physical medicine clinics. The patients with chronic PAB (pain duration more than 3 months), who were refractory to conservative treatments, were randomly divided into two 20-member experimental groups (extracorporeal shock wave therapy [ESWT] and sham ESWT). Pain scores of all patients were measured using the Visual Analog Scale (VAS) and McGill Pain Questionnaire (MPQ) (total and present pain indexes [TPIs and PPIs]) before intervention, immediately after intervention (3rd week), and after 8 weeks. The pain scores were then compared and statistically analyzed. RESULTS: In the ESWT group, the mean patient pain score of the VAS and TPI in MPQ were significantly lower than in the sham ESWT group immediately after intervention (3rd week): P =0.02, P = 0.04 respectively; and 8 weeks after the end of treatment: P =0.01, P = 0.000. Moreover, the PPI in both groups had significantly decreased over time, although in ESWT group this decrement was significantly more than sham ESWT group (P < 0.001). CONCLUSION: The results showed that ESWT could be effective in reducing the pain and treating PAB. PMID- 28626746 TI - Frequency of Cutaneous Fungal Infections and Azole Resistance of the Isolates in Patients with Diabetes Mellitus. AB - BACKGROUND: Diabetic patients are more susceptible to cutaneous fungal infections. The higher blood sugar levels cause increasing the cutaneous fungal infections in these patients. The main objective of this study was to find the frequency of fungal infections among cutaneous lesions of diabetic patients and to investigate azole antifungal agent susceptibility of the isolates. MATERIALS AND METHODS: In this study, type 1diabetes (n = 78) and type 2 diabetes (n = 44) comprised 47 cases (38.5%) with diabetic foot ulcers and 75 cases (61.5%) with skin and nail lesions were studied. Fungal infection was confirmed by direct examination and culture methods. Antifungal susceptibility testing by broth microdilution method was performed according to the CLSI M27-A and M38-A references. RESULTS: Out of 122 diabetic patients, thirty (24.5%) were affected with fungal infections. Frequency of fungal infection was 19.1% in patients with diabetic foot ulcer and 28% of patients with skin and nail lesions. Candida albicans and Aspergillus flavus were the most common species isolated from thirty patients with fungal infection, respectively. Susceptibility testing carried out on 18 representative isolates (13 C. albicans, five C. glabrata) revealed that 12 isolates (10 C. albicans and two C. glabrata isolates) (66.6%) were resistant (minimum inhibitory concentration [MIC] >=64 mg/ml) to fluconazole (FCZ). Likewise, eight isolates (80%) of Aspergillus spp. were resistant (MIC >=4 mg/ml), to itraconazole. CONCLUSION: Our finding expands current knowledge about the frequency of fungal infections in diabetic patients. We noted the high prevalence of FCZ-resistant Candida spp., particularly in diabetic foot ulcers. More attention is important in diabetic centers about this neglected issue. PMID- 28626747 TI - Risk Assessment to Evaluate if Crayons Complying with the Consumer Product Safety Improvement Act of 2008 for Lead, Also Comply with California Proposition 65. PMID- 28626749 TI - A Century Spent Combating Rabies in Morocco (1911-2015): How Much Longer? AB - Rabies has no known beginning in Morocco and to date, government control efforts and plans fail to eradicate the disease. A review and analysis of available epidemiological data are crucial to learn lessons from the past and to propose effective actions. Legally, animal rabies is a notifiable disease since 1913 and legislation has been updated periodically since. Dogs have always been considered as both the disease's vector and reservoir, while cattle, other herbivores, and humans are victims. Animal rabies cases evolution from 1942 to 2015 is characterized by ascending phase then decreasing one following structured rabies control plan implementation in 1980s. Indeed, from 1986 to 2010, three rabies control plans have been conducted based on free of charge rabies vaccination of owned dogs through mass campaigns. The geographical distribution of rabies is stable over the years with highest cases number in rich rural areas and around cities. Human rabies cases are decreasing over the time (1976-2015) thanks to the opening of new antirabic treatment centers in the last decade which permit the administration of more PEPs. After a century of rabies control, Morocco registered an average of 301 animal cases and 21 human cases annually for the last decade (2005-2015). Few reasons led to those limited results. The lack in law enforcement and, moreover, the fact that the law do not take into account responsible dog ownership aspect are of importance. Lack of dog population knowledge and management and intersectoral coordination deficiency are additional failure reasons. The gathered data will help to build a new strategy with a focus on a "One Health" approach. Dog population ecology parameters' study is of primary importance. We estimated dog population to be 2.8 million dogs based on human:dog ratio. Enhancing vaccination coverage of dog population is feasible by combining parenteral vaccination and complementary oral vaccination. Updating legislation by inclusion of responsible dog ownership and law enforcement are crucial. Over the last century, Morocco registered a slow decreasing tendency in the number of animal and human rabies cases. Urgent strategy need to be implemented because rabies elimination is an achievable goal in Morocco. PMID- 28626750 TI - Quantifying Preferences of Farmers and Veterinarians for National Animal Health Programs: The Example of Bovine Mastitis and Antimicrobial Usage in Switzerland. AB - Bovine udder health in Switzerland is of a relatively high level. However, antimicrobial usage (AMU) seems high in comparison to other European countries also. A new udder health and AMU improvement program could improve this situation but it is uncertain whether there is support from the field. This study aimed to quantify preferences of dairy farmers and veterinarians for the start and design characteristics of a new national udder health and AMU improvement program in Switzerland. A total of 478 dairy farmers and 98 veterinarians completed an online questionnaire. Questions on their demographics and their mindset toward AMU were complemented with an adaptive choice-based conjoint interview, a novel conjoint analysis technique to quantify preferences of respondents for characteristics of a product for which multiple trade-off decisions must be made (here a bovine udder health and AMU improvement program). The conjoint analysis was followed by a multivariate multiple regression analysis to identify groups of respondents with different program design preferences. Logistic regression models were used to associate covariates with respondents' preference to start a new udder health and AMU improvement program. Most farmers (55%) and veterinarians (62%) were in favor of starting a new voluntary udder health and AMU improvement program, but the program design preferences agreed moderately between the two stakeholder groups. Farmers preferred an udder health and AMU improvement program that did not contain a penalty system for high AMU, was voluntary for all dairy herds, and aimed to simultaneously improve udder health and reduce AMU. Veterinarians preferred a program that had the veterinary organization and the government taking the lead in program design decision making, did not contain a penalty system for high AMU, and aimed to simultaneously improve udder health and reduce AMU. Differences between groups of farmers and veterinarians concerning their start preference were identified. Also, the magnitude of various program design preferences changed for farmers with different opinions toward AMU. The information obtained from this study may support the decision-making process and the communication to the field afterward, when discussing national strategies to improve udder health and AMU in Switzerland. PMID- 28626748 TI - The Multiple Roles of FGF Signaling in the Developing Spinal Cord. AB - During vertebrate embryonic development, the spinal cord is formed by the neural derivatives of a neuromesodermal population that is specified at early stages of development and which develops in concert with the caudal regression of the primitive streak. Several processes related to spinal cord specification and maturation are coupled to this caudal extension including neurogenesis, ventral patterning and neural crest specification and all of them seem to be crucially regulated by Fibroblast Growth Factor (FGF) signaling, which is prominently active in the neuromesodermal region and transiently in its derivatives. Here we review the role of FGF signaling in those processes, trying to separate its different functions and highlighting the interactions with other signaling pathways. Finally, these early functions of FGF signaling in spinal cord development may underlay partly its ability to promote regeneration in the lesioned spinal cord as well as its action promoting specific fates in neural stem cell cultures that may be used for therapeutical purposes. PMID- 28626751 TI - Feeder Cell Type Affects the Growth of In Vitro Cultured Bovine Trophoblast Cells. AB - Trophectoderm cells are the foremost embryonic cells to differentiate with prospective stem-cell properties. In the current study, we aimed at improving the current approach for trophoblast culture by using granulosa cells as feeders. Porcine granulosa cells (PGCs) compared to the conventional mouse embryonic fibroblasts (MEFs) were used to grow trophectoderm cells from hatched bovine blastocysts. Isolated trophectoderm cells were monitored and displayed characteristic epithelial/cuboidal morphology. The isolated trophectoderm cells expressed mRNA of homeobox protein (CDX2), cytokeratin-8 (KRT8), and interferon tau (IFNT). The expression level was higher on PGCs compared to MEFs throughout the study. In addition, primary trophectoderm cell colonies grew faster on PGCs, with a doubling time of approximately 48 hrs, compared to MEFs. PGCs feeders produced a fair amount of 17beta-estradiol and progesterone. We speculated that the supplementation of sex steroids and still-unknown factors during the trophoblasts coculture on PGCs have helped to have better trophectoderm cell's growth than on MEFs. This is the first time to use PGCs as feeders to culture trophectoderm cells and it proved superior to MEFs. We propose PGCs as alternative feeders for long-term culture of bovine trophectoderm cells. This model will potentially benefit studies on the early trophoblast and embryonic development in bovines. PMID- 28626752 TI - Protective Effect of a Polyherbal Aqueous Extract Comprised of Nigella sativa (Seeds), Hemidesmus indicus (Roots), and Smilax glabra (Rhizome) on Bleomycin Induced Cytogenetic Damage in Human Lymphocytes. AB - This study was carried out to determine the chemoprotective potential of a polyherbal aqueous decoction comprised of Nigella sativa (seeds), Hemidesmus indicus (roots), and Smilax glabra (rhizome) against bleomycin induced cytogenetic damage in human lymphocytes. Isolated peripheral blood lymphocytes (PBLs) were exposed to bleomycin at a dose of 40 ug/mL for 2 hrs in the presence or absence of different doses of the decoction (100, 300, and 600 ug/mL). Modulatory effect of the decoction on bleomycin induced cytogenetic damage was evaluated by (a) degree of chromosomal aberrations (CA), (b) formation of micronuclei (MN), and (c) induction of gammaH2AX foci in lymphocytes exposed to bleomycin. Lymphocytes pretreated with the decoction showed that a significant reduction (p < 0.05) in bleomycin induced (a) stable and unstable chromosome aberrations (CA), (b) MN formation, and (c) formation of gammaH2AX foci, when compared to lymphocytes treated only with bleomycin. The decoction by itself did not induce any significant cytogenetic damage in PBLs. Overall results of the present study confirm that the decoction can attenuate the cytogenetic damage mediated by bleomycin in human PBLs. PMID- 28626753 TI - Health Brokers: How Can They Help Deal with the Wickedness of Public Health Problems? AB - BACKGROUND: The role of health broker is a relatively new one in public health. Health brokers aim to create support for efforts to optimise health promotion in complex or even "wicked" public health contexts by facilitating intersectoral collaborations and by exchanging knowledge with different stakeholders. The current study aimed to explore the role of health brokers, by examining the motivational, contextual, and behaviour-related factors they have to deal with. METHODS: Fifteen professionals from various backgrounds and from various policy and practice organisations were recruited for a semistructured interview. To structure the interviews, we developed the "Health Broker Wheel" (HBW), a framework we then specified with more details derived from the interviews. RESULTS: We identified seven primary types of behaviour that health brokers need to engage in: recognizing opportunities, agenda setting, implementing, network formation, intersectoral collaboration, adaptive managing, and leadership. Determinants of health brokers' behaviours were identified and categorised as capability, opportunities, motivation, and local or national contextual factors. CONCLUSION: The health brokers' role can be seen as an operational approach and is visualised in the HBW. This framework can assist further research to monitor and evaluate this role, and health promotion practitioners can use it as a tool to implement the health brokers' role and to facilitate intersectoral collaboration. PMID- 28626754 TI - Infections Caused by HRSV A ON1 Are Predominant among Hospitalized Infants with Bronchiolitis in Sao Paulo City. AB - Human respiratory syncytial virus is the main cause of respiratory infections in infants. Several HRSV genotypes have been described. Goals. To describe the main genotypes that caused infections in Sao Paulo (2013-2015) and to analyze their clinical/epidemiological features. Methods. 94 infants (0-6 months) with bronchiolitis were studied. Clinical/epidemiological information was collected; a search for 16 viruses in nasopharyngeal secretion (PCR-real-time and conventional, sequencing, and phylogenetic analyses) was performed. Results. The mean age was 2.4 m; 48% were male. The mean length of hospital stay was 4.4 d (14% in the Intensive Care Unit). The positive rate of respiratory virus was 98.9%; 73 cases (77.6%) were HRSV (76,7% HRSVA). HRSVA formed three clusters: ON1 (n = 34), NA1 (n = 1), and NA2 (n = 4). All HRSVB were found to cluster in the BA genotype (BA9-n = 10; BA10-n = 3). Clinical analyses showed no significant differences between the genotype AON1 and other genotypes. Conclusion. This study showed a high rate of HRSV detection in bronchiolitis. HRSVA ON1, which has recently been described in other countries and has not been identified in previous studies in the southeast region of Brazil, was predominant. The clinical characteristics of the infants that were infected with AON1 were similar to infants with infections by other genotypes. PMID- 28626755 TI - Can Rehabilitation Influence the Efficiency of Control Signals in Complex Motion Strategies? AB - The factor determining quality of life in Parkinson's disease (PD) is the worsening of a patient's walking ability. The use of external stimuli can improve gait when performing complex motor patterns. The aim of this study was to evaluate the effect of rehabilitation on the effectiveness of control signals in people with PD. The study was performed on 42 people with idiopathic PD in the third stage of disease. The control group consisted of 19 patients who did not participate in rehabilitation activities. The experimental group was systematically participating in rehabilitation activities twice a week (60 minutes) for 9 months. Gait speed, mean step length, and step frequency were calculated on the basis of the obtained results. These parameters were compared in both groups by single factor variance analyses. The best results were obtained using rhythmic external auditory signals. The group with patients actively participating in rehabilitation showed statistically significant improvement in gait speed (12.35%), mean step length (18.00%), and frequency step (2.40%) compared to the control group. The presented research showed the positive effect of rehabilitation and was based on the performance of complex motion patterns, using external control signals for their effectiveness in new motion tasks. PMID- 28626756 TI - A Pilot Study on Bioactive Constituents and Analgesic Effects of MyrLiq(r), a Commiphora myrrha Extract with a High Furanodiene Content. AB - The analgesic properties of myrrh (Commiphora myrrha) have been known since ancient times and depend on the presence of bioactive sesquiterpenes with furanodiene skeletons. MyrLiq is a C. myrrha extract with a standardized content of curzerene, furanoeudesma-1,3-diene, and lindestrene (12.31 +/- 0.05 g kg-1, 18.84 +/- 0.02 g kg-1, and 6.23 +/- 0.01 g kg-1, resp.) and a high total furanodiene content (40.86 +/- 0.78 g kg-1). A balanced sample of 95 female and 89 male volunteers (with ages ranging from 18 to older than 60 years) exhibiting different pain pathologies, including headache, fever-dependent pain, joint pain, muscle aches, lower back pain, and menstrual cramps, was divided into two groups. The experimental group received 1 capsule/day containing either 200 mg or 400 mg of MyrLiq (corresponding to 8 mg and 16 mg of bioactive furanodienes, resp.) for 20 days, and the placebo group was given the same number of capsules with no MyrLiq. A score was recorded for all volunteers based on their previous experience with prescribed analgesics. For the male volunteers, pain alleviation was obtained with 400 mg of MyrLiq/day for almost all pathologies, whereas, for female volunteers, alleviation of lower back pain and fever-dependent pain was observed with only 200 mg of MyrLiq/day. These results indicate that MyrLiq has significant analgesic properties. PMID- 28626757 TI - ACTN3 Gene and Susceptibility to Sarcopenia and Osteoporotic Status in Older Korean Adults. AB - BACKGROUND: Little information is available about molecular markers for sarcopenia and osteoporosis in Asian populations. OBJECTIVE: This study investigated the association of the ACTN3 polymorphism with sarcopenia and osteoporotic status in older Korean adults. METHODS: Older Korean 62 men and 270 women (mean age 73.7 +/- 6.6 years) participated in this study. Body mass index, percent body fatness, appendicular skeletal muscle mass, and bone mineral density of the lumbar spine, femur, and total body were analyzed with dual-energy X-ray absorptiometry. ACTN3 R/X genotyping was determined using TaqMan probes. RESULTS: Determination of odds ratios (ORs) and 95% confidence intervals (CIs) using binary logistic regression analyses showed that XX homozygotes were at a significantly higher risk of sarcopenia (OR = 2.056, 95% CI = 1.024-4.127, p = 0.043) and osteoporosis (OR = 2.794, 95% CI = 1.208-5.461, p = 0.016) than RR homozygotes (reference group, OR = 1). The OR of XX homozygotes for having sarcopenia remained significant (OR = 2.237, 95% CI = 1.044-4.836, p = 0.038) after adjustments for age, gender, body fatness, and serum vitamin D. The OR of XX homozygotes for having osteoporosis was no longer significant (OR = 2.682, 95% CI = 0.960-7.942, p = 0.075) after adjustments for the covariates. CONCLUSION: Our findings suggest that the ACTN3 R577X genotype may influence decline in muscle and bone health phenotypes in older Korean adults. PMID- 28626758 TI - A Novel Pan-Flavivirus Detection and Identification Assay Based on RT-qPCR and Microarray. AB - The genus Flavivirus includes arthropod-borne viruses responsible for a large number of infections in humans and economically important animals. While RT-PCR protocols for specific detection of most Flavivirus species are available, there has been also a demand for a broad-range Flavivirus assay covering all members of the genus. It is particularly challenging to balance specificity at genus level with equal sensitivity towards each target species. In the present study, a novel assay combining a SYBR Green-based RT-qPCR with a low-density DNA microarray has been developed. Validation experiments confirmed that the RT-qPCR exhibited roughly equal sensitivity of detection and quantification for all flaviviruses tested. These PCR products are subjected to hybridization on a microarray carrying 84 different oligonucleotide probes that represent all known Flavivirus species. This assay has been used as a screening and confirmation tool for Flavivirus presence in laboratory and field samples, and it performed successfully in international External Quality Assessment of NAT studies. Twenty six Flavivirus strains were tested with the assay, showing equivalent or superior characteristics compared with the original or even with species-specific RT-PCRs. As an example, test results on West Nile virus detection in a panel of 340 mosquito pool samples from Greece are presented. PMID- 28626759 TI - Sertraline Induces Toxicity and Behavioral Alterations in Planarians. AB - Toxicity attributed to sertraline has been demonstrated recently in different cell types and also in some organisms. We investigated the effect of sertraline on planarians, which are considered suitable for investigations in neurotoxicology and currently are widely used as an animal model in neuropharmacological studies. Planarians treated with 10 uM sertraline showed a rapid reduction in their spontaneous movement until they became completely motionless and then showed a series of asynchronous paroxysms (seizures) followed by progressive tissue damage, beginning 48 h after the sertraline treatment, and died approximately 72 h later. Our data showed that sertraline does not cause planarian death within the range of therapeutic concentrations; however, behavioral alterations were observed with concentrations that can be considered compatible with therapeutic ones, such as a significant reduction in planarian locomotory activity at 0.4 uM. Treatment with 4 uM sertraline had a significant effect, reducing planarian locomotory activity and increasing the number of asynchronous paroxysms; both effects were significantly maintained even 24 h after the sertraline was withdrawn. These behavioral changes observed at low micromolar concentrations suggest that sertraline might have residual biological consequences for planarians, even after it is withdrawn. PMID- 28626760 TI - Txndc9 Is Required for Meiotic Maturation of Mouse Oocytes. AB - Txndc9 (thioredoxin domain containing protein 9) has been shown to be involved in mammalian mitosis; however, its function in mammalian oocyte meiosis remains unclear. In this study, we initially found that Txndc9 is expressed during meiotic maturation of mouse oocytes and higher expression of Txndc9 mRNA and protein occurred in germinal vesicle (GV) stage. By using confocal scanning, we observed that Txndc9 localized at both nucleus and cytoplasm, especially at spindle microtubules. Specific depletion of Txndc9 by siRNA in mouse oocyte resulted in decreasing the rate of first polar body extrusion and increasing abnormal spindle assemble. Moreover, knockdown of Txndc9 in germinal vesicle (GV) stage oocytes led to higher level of reactive oxygen species (ROS) and lower level of antioxidant glutathione (GSH) as compared with control oocytes, which indicated that Txndc9 may be involved in mediating the redox balance. In summary, our results demonstrated that Txndc9 is crucial for mouse oocyte maturation by regulating spindle assembly, polar body extrusion, and redox status. PMID- 28626761 TI - Bioremediation of Mercury by Vibrio fluvialis Screened from Industrial Effluents. AB - Thirty-one mercury-resistant bacterial strains were isolated from the effluent discharge sites of the SIPCOT industrial area. Among them, only one strain (CASKS5) was selected for further investigation due to its high minimum inhibitory concentration of mercury and low antibiotic susceptibility. In accordance with 16S ribosomal RNA gene sequences, the strain CASKS5 was identified as Vibrio fluvialis. The mercury-removal capacity of V. fluvialis was analyzed at four different concentrations (100, 150, 200, and 250 MUg/ml). Efficient bioremediation was observed at a level of 250 MUg/ml with the removal of 60% of mercury ions. The interesting outcome of this study was that the strain V. fluvialis had a high bioremediation efficiency but had a low antibiotic resistance. Hence, V. fluvialis could be successfully used as a strain for the ecofriendly removal of mercury. PMID- 28626762 TI - Comparison of Antibacterial Activity of Lactobacillus plantarum Strains Isolated from Two Different Kinds of Regional Cheeses from Poland: Oscypek and Korycinski Cheese. AB - Oscypek and korycinski are traditional Polish cheeses, exclusively produced in Tatra and in Podlasie region, respectively, produced from raw, unpasteurized milk. The 29 Lactobacillus plantarum strains were isolated on MRS agar from 12 cheese samples and used as a material for study. The main purpose of the work was to assess the antimicrobial properties and recognition of selected strains for the unique antagonistic activity and preservation role in food. It has been found that the highest antimicrobial activity was observed in the case of L. monocytogenes strains; however, the level of that activity was different depending on the Lb. plantarum strain. Strains from oscypek produced broad spectrum, and a few strains isolated from korycinski cheese produced a narrow spectrum of antimicrobial compounds, other than organic acids and hydrogen peroxide. Moreover, the antagonistic activity shown by Lb. plantarum strains is connected with the source from which a given strain was isolated. Strains isolated from oscypek cheese represented stronger activity against L. monocytogenes, whereas strains isolated from korycinski cheese were more active against E. coli. Strains Lb. plantarum Os13 and Kor14 could be considered as good candidates for protective cultures to extend durability of food products. PMID- 28626763 TI - Implant Stability in the Posterior Maxilla: A Controlled Clinical Trial. AB - AIM: To evaluate the primary and secondary stability of implants in the posterior maxilla. METHODS: Patients were allocated into three groups: (A) native bone, (B) partially regenerated bone, and (C) nearly totally regenerated bone. Insertion torque (IT) and implant stability quotient (ISQ) were measured at placement, to evaluate whether satisfactory high primary stability (IT >= 45 N/cm; ISQ >= 60) was achieved; ISQ was measured 15, 30, 45, and 60 days after placement, to investigate the evolution to secondary stability. RESULTS: 133 implants (Anyridge(r), Megagen) were installed in 59 patients: 55 fixtures were placed in Group A, 57 in Group B, and 21 in Group C. Fifty-two implants had satisfactory high primary stability (IT >= 45 N/cm; ISQ >= 60). A positive correlation was found between all variables (IT, ISQ at t = 0, t = 60), and statistically higher IT and ISQ values were found for implants with satisfactory high primary stability. Significant differences were found for IT and ISQ between the groups (A, B, and C); however, no drops were reported in the median ISQ values during the healing period. CONCLUSIONS: The evaluation of the primary and secondary implant stability may contribute to higher implant survival/success rates in critical areas, such as the regenerated posterior maxilla. The present study is registered in the ISRCTN registry with ID ISRCTN33469250. PMID- 28626764 TI - Does Chemotherapy for Gynecological Malignancies during Pregnancy Cause Fetal Growth Restriction? AB - Cancer and pregnancy rarely coincide. Gynecological cancers are among the most common malignancies to occur during pregnancy, and chemotherapy with or without surgery is the primary treatment option. The main concern of administering chemotherapy during pregnancy is congenital malformation, although it can be avoided by delaying treatment until after organogenesis. The dose, frequency, choice of chemotherapeutic agents, time of treatment commencement, and method of administration can be adjusted to obtain the best maternal treatment outcomes while simultaneously minimizing fetal toxicity. Use of chemotherapy after the first trimester, while seemingly safe, can cause fetal growth restriction. However, the exact effect of chemotherapy on such fetal growth restriction has not been fully established; information is scarce owing to the rarity of malignancy occurring during pregnancy, the lack of uniform treatment protocols, different terminologies for defining certain fetal growth abnormalities, the influence of mothers' preferred options, and ethical issues. Herein, we present up-to-date findings from the literature regarding the impact of chemotherapy on fetal growth. PMID- 28626765 TI - Serum Metabolomics Profiling to Identify Biomarkers for Unstable Angina. AB - Although statistical evidence is clear regarding the dangerousness of unstable angina (UA), a form of coronary heart disease (CHD) characterised by high mortality and morbidity globally, it is important to recognise that diagnostic precision for the condition is unfavourable. In the present research, to gain insight into candidate biomarkers, the author draws on 1H NMR-based serum metabolic profiling to analyze the unstable angina pectoris (UAP) metabolic signatures; this constitutes an effective way to produce medical diagnosis. 101 unstable angina pectoris patients and 132 healthy controls were enrolled and 22 serum samples from each group were analyzed. Effective separation was noted regarding the UAP and control groups, and, for the former group considered in relation to their counterpart, the serum concentrations of Lac, m-I, lipid, VLDL, 3-HB, and LDL were higher whereas the concentrations of Thr, Cr, Cho, PC/GPC, Glu, Gln, Lys, HDL, Ile, Leu, and Val were lower. The conclusion drawn in view of the results is that the plasma metabolomics examined by 1H NMR displayed promise for biomarker identification for UA. In addition to this, the analysis illuminated the metabolic processes of UA. PMID- 28626767 TI - Closer to a Uniform Language in Colposcopy: Study on the Potential Application of 2011 International Federation for Cervical Pathology and Colposcopy Terminology in Clinical Practice. AB - As the newest colposcopic terminology, the 2011 International Federation for Cervical Pathology and Colposcopy (IFCPC) classification provides standardized interpretation of colposcopic findings. In this study, we analyzed the colposcopic accuracy and the significance of individual findings according to the 2011 IFCPC classification in 525 patients, reviewed by 13 trained colposcopists. Results show that colposcopic diagnoses are in 64.95% perfect agreement with cervical pathology, with 63.64% sensitivity and 96.01% specificity for high-grade squamous intraepithelial lesion (HSIL+). And the accuracy is reproducible across different experienced examiners. Many individual findings, especially the two new signs, inner border sign and ridge sign, are proved to have good predictive accuracy, while iodine negativity demonstrates an inferior performance. However, the distribution of three cervical transformation zone (TZ) types is heterogeneous in examiners. A comparison was also made of the findings of another two colposcopists without nomenclature training according to the Reid Colposcopic Index (RCI), modified RCI, and Swede Score. Results show that colposcopic accuracies in them are lower than in those nomenclature trained colposcopists. The 2011 IFCPC nomenclature improves colposcopic accuracy in trained colposcopists, like speaking the same language. However, the reproducibility of TZ and the predictive value of a few signs remain to be discussed. PMID- 28626766 TI - Involvement of the Toll-Like Receptor/Nitric Oxide Signaling Pathway in the Pathogenesis of Cervical Cancer Caused by High-Risk Human Papillomavirus Infection. AB - Human papillomavirus (HPV) can activate Toll-like receptor (TLR)/nitric oxide (NO) signaling pathways; however, whether the TLR/NO pathway is involved in cervical cancer caused by high-risk HPV (HR-HPV) remains unclear. In this study, 43 HR-HPV-positive patients with cervical cancer (CC group), 39 HR-HPV-positive patients with a healthy cervix (HR-HPV group), and 33 HR-HPV-negative controls were recruited. NO concentration in cervical canal and expression of inducible NO synthase (iNOS) in cervical tissues were detected. Expressions of key TLR/NO pathway genes (TLR3/4/7/8, NF-kappaB p65, and iNOS) in cervical epithelial cells were detected by quantitative reverse transcription PCR. Expressions of TLR4, NF kappaB p65, and iNOS in CaSki, HeLa, and C33a cells were determined by Western blot. NO concentration in cervical canal of CC group was significantly higher than in other groups (P < 0.05). Positive rates of iNOS in cervical tissues were 72.1%, 28.2%, and 3.1% in the CC group, HR-HPV group, and controls, respectively (P < 0.05). Levels of TLR3, TLR4, TLR7, TLR8, NF-kappaB p65, and iNOS in cervical epithelial cells were higher in CC group than in other groups (P < 0.05). Both mRNA and protein levels of TLR4, NF-kappaB p65, and iNOS were higher in HPV positive HeLa and CaSki cells than in HPV-negative C33a cells (P < 0.05). Together, these results suggest that TLR/NO signaling pathway may be involved in pathogenesis of cervical cancer caused by HR-HPV. PMID- 28626768 TI - Effect of Amplatz Sheath on Cystolithotripsy for Women with Large Bladder Stone. AB - OBJECTIVE: This study compared the effect of endourological procedures with or without the Amplatz sheath (AS) on cystolithotripsy. METHODS: We retrospectively analysed 18 patients who underwent treatment for bladder stone over 30 mm. This study consisted of two groups, namely, patients who underwent cystolithotripsy with an AS (AS group) and those who underwent standard procedure without an AS (SP group). The stone-free rate, total energy used for operation, operation time, days of admission after operation, and complication of both groups were compared. RESULTS: The number of patients in the AS and SP groups was 10 and 8, respectively. Significant differences were not found between these two groups with regard to age, stone burden, stone volume, number of stones, and history of neurogenic bladder. All patients in both groups achieved a stone-free state. Total energy was significantly increased and operation time was shorter in the AS group. No significant difference was observed in terms of days of admission after operation. Any complications were not increased by the use of AS. Struvite was the most common stone component in both groups. CONCLUSION: Use of an AS can shorten the operation time of cystolithotripsy without increasing perioperative complication. PMID- 28626769 TI - The Effect of Social Support on Glycemic Control in Patients with Type 2 Diabetes Mellitus: The Mediating Roles of Self-Efficacy and Adherence. AB - Ample evidence suggests that social support, self-efficacy, and adherence significantly, independently, and together affect glycemic control in patients with type 2 diabetes mellitus (T2DM), but the pathway from social support to glycemic control remains unclear. This study hypothesized that the effect of social support on glycemic control was mediated sequentially by self-efficacy and adherence. Patients with T2DM were recruited from two hospitals in Guangzhou, China, from January 1 to July 31, 2014, and their sociodemographic clinical data and their assessments on social support, self-efficacy, and adherence were obtained from medical records and self-completed questionnaires. Of the 532 patients who participated, 35% achieved glycemic control (i.e., HbA1c < 7%). Social support, self-efficacy, and adherence had significant correlations with each other and with glycemic control (P < 0.05). Regression analyses and structural equation modeling showed that better social support was associated to better patient self-efficacy, which, in turn, was associated with better medical adherence, which was associated with improved glycemic control, and the relationship between social support and glycemic control was sequentially and completely mediated by self-efficacy and adherence. The five goodness-of-fit indices confirmed that our data fitted the hypothesized pathway model strongly. PMID- 28626770 TI - Upregulation of Tumor Necrosis Factor-alpha-Induced Protein 8-Like 2 mRNA Is Negatively Correlated with Serum Concentrations of Tumor Necrosis Factor-alpha and Interleukin 6 in Type 2 Diabetes Mellitus. AB - BACKGROUND: Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2 or TNFAIP8L2) is a negative regulator of natural and adaptive immunity. The role of TIPE2 in type 2 diabetes mellitus (T2DM) remains unknown, although TIPE2 plays key roles in preserving inflammatory homeostasis. METHODS: TIPE2 expression was measured by Western blotting and real-time polymerase chain reaction (RT-PCR) in peripheral blood mononuclear cells (PBMCs) isolated from T2DM patients and healthy controls, and tumor necrosis factor-alpha (TNF-alpha), high-sensitivity C reactive protein (hsCRP), interleukin 6 (IL-6), and other related biometabolic parameters were detected using a nephelometer or by ELISA. Differentiated THP-1 cells were exposed to siTIPE2 and TIPE2 adenovirus. RESULTS: TIPE2 was significantly increased in PBMCs from T2DM patients compared with those from healthy controls and was negatively correlated with serum TNF-alpha, IL-6, and hsCRP concentrations but positively correlated with HbA1c and LDL-C in T2DM patients. High glucose treatment (50 mmol/L) can upregulate the expression of TIPE2 and cytokine secretion in differentiated THP-1 cells. siTIPE2 infection exacerbated the increased TNF-alpha and IL-6 concentrations in differentiated THP 1 cells under high glucose conditions (50 mmol/L), while infection with TIPE2 adenovirus reversed the increased TNF-alpha concentration. CONCLUSIONS: The present study indicates that TIPE2 may participate in T2DM by regulating TNF alpha production. PMID- 28626771 TI - Inadequate Triglyceride Management Worsens the Durability of Dipeptidyl Peptidase 4 Inhibitor in Subjects with Type 2 Diabetes Mellitus. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are often used all over the world and exert various beneficial effects including glucose-lowering effect in many subjects with type 2 diabetes. It is poorly understood, however, which factors are closely related with the durability of glucose-lowering effect by DPP-4 inhibitor. In this study, we examined retrospectively which factors could mainly influence the durability of DPP-4 inhibitor. We enrolled 212 participants with type 2 diabetes to whom DPP-4 inhibitor was administered for over 1 year without an addition or increase of other hypoglycemic agents. Age and baseline HbA1c level were significantly higher in the effective group than those in the ineffective group. The effective group had a tendency of smaller amounts of weight change, average total cholesterol, and average triglyceride compared with the ineffective group. Multiple logistic regression analysis showed that average triglyceride and baseline HbA1c were independent predictors associated with the durability of DPP-4 inhibitor. Moreover, an average triglyceride level contributed to the durability of DPP-4 inhibitor in the obese group (BMI >= 25 kg/m2) but not in the nonobese group (BMI < 25 kg/m2). These results suggest the importance of strict triglyceride management to maintain the durability of glucose-lowering effect by DPP-4 inhibitor, especially in obese subjects with type 2 diabetes. PMID- 28626772 TI - Leptin/Adiponectin Ratios Using Either Total Or High-Molecular-Weight Adiponectin as Biomarkers of Systemic Insulin Sensitivity in Normoglycemic Women. AB - Plasma leptin/adiponectin ratio (LAR) is negatively associated with insulin sensitivity indexes. High-molecular-weight adiponectin (HMWA) was proposed as the most biologically active form of this insulin-sensitizing adipokine. There are no studies assessing the relative merits of leptin/HMWA ratio over LAR as a biomarker of systemic insulin sensitivity. A standard 2-hour oral glucose tolerance test (OGTT; 75 g of glucose) and a short minimal-model intravenous glucose tolerance test (IVGTT; 0.3 g/kg body weight) were performed in 58 Chilean normoglycemic women (age: 27 +/- 6.3 years, BMI 23.6 +/- 3.2 kg/m2). LAR was negatively associated with HOMA-S (r = -0.49; p < 0.0001), Matsuda-ISICOMP (r = 0.54; p < 0.0001), and the calculated sensitivity index (CSi) derived from IVGTT (r = -0.38; p = 0.007). In comparison to LAR, leptin/HMWA ratio did not increase neither the linear fit (r2) nor the magnitude of association with insulin sensitivity indexes (slope of multiple linear regression). The discriminatory capacity of both ratios to classify insulin-resistant versus insulin-sensitive subjects was similar for HOMA-S (p = 0.84), Matsuda-ISICOMP (p = 0.43), or CSi (p = 0.50). In conclusion, LAR showed consistent negative associations with different systemic insulin sensitivity indexes. The use of HMWA to generate leptin/HMWA ratio did not show any advantage over LAR as a biomarker of systemic insulin sensitivity in normoglycemic women. PMID- 28626773 TI - HLA Epitopes: The Targets of Monoclonal and Alloantibodies Defined. AB - Sensitization to human leukocyte antigens (HLA) in organ transplant patients causes graft rejection, according to the humoral theory of transplantation. Sensitization is almost ubiquitous as anti-HLA antibodies are found in almost all sera of transplant recipients. Advances in testing assays and amino acid sequencing of HLA along with computer software contributed further to the understanding of antibody-antigen reactivity. It is commonly understood that antibodies bind to HLA antigens. With current knowledge of epitopes, it is more accurate to describe that antibodies bind to their target epitopes on the surface of HLA molecular chains. Epitopes are present on a single HLA (private epitope) or shared by multiple antigens (public epitope). The phenomenon of cross reactivity in HLA testing, often explained as cross-reactive groups (CREGs) of antigens with antibody, can be clearly explained now by public epitopes. Since 2006, we defined and reported 194 HLA class I unique epitopes, including 56 cryptic epitopes on dissociated HLA class I heavy chains, 83 HLA class II epitopes, 60 epitopes on HLA-DRB1, 15 epitopes on HLA-DQB1, 3 epitopes on HLA DQA1, 5 epitopes on HLA-DPB1, and 7 MICA epitopes. In this paper, we provide a summary of our findings. PMID- 28626774 TI - Adenosine Triphosphate Promotes Allergen-Induced Airway Inflammation and Th17 Cell Polarization in Neutrophilic Asthma. AB - Adenosine triphosphate (ATP) is a key mediator to alert the immune dysfunction by acting on P2 receptors. Here, we found that allergen challenge caused an increase of ATP secretion in a murine model of neutrophilic asthma, which correlated well with neutrophil counts and interleukin-17 production. When ATP signaling was blocked by intratracheal administration of the ATP receptor antagonist suramin before challenge, neutrophilic airway inflammation, airway hyperresponsiveness, and Th17-type responses were reduced significantly. Also, neutrophilic inflammation was abrogated when airway ATP levels were locally neutralized using apyrase. Furthermore, ATP promoted the Th17 polarization of splenic CD4+ T cells from DO11.10 mice in vitro. In addition, ovalbumin (OVA) challenge induced neutrophilic inflammation and Th17 polarization in DO11.10 mice, whereas administration of suramin before challenge alleviated these parameters. Thus, ATP may serve as a marker of neutrophilic asthma, and local blockade of ATP signaling might provide an alternative method to prevent Th17-mediated airway inflammation in neutrophilic asthma. PMID- 28626775 TI - Referential choice in a second language: evidence for a listener-oriented approach. AB - One central question in research on spoken language communication concerns how speakers decide how explicit to make a referential expression. In the present paper, we address the debate between a discourse-based approach and a listener based approach to the choice of referring expressions by testing second language (L2) learners of English on the production of English referential expressions, and comparing their performance to a group of monolingual speakers of English. In two experiments, we found that when native speakers of English use full noun phrases, the L2 speakers tend to choose a pronoun, even when the use of a pronoun leads to ambiguity. Our results show that the pattern observed is not the result of cross-linguistic interference from the L1. Furthermore, a clear dissociation is found between calculating the discourse information and taking the listener's perspective into account, supporting a listener's based approach to the choice of referring expressions. PMID- 28626776 TI - Aging and the Resting State: Is Cognition Obsolete? AB - Recent years have seen the rise in popularity of the resting state approach to neurocognitive aging, with many studies examining age differences in functional connectivity at rest and relating these differences to cognitive performance outside the scanner. There are many advantages to the resting state that likely contribute to its popularity and indeed, many insights have been gained from this work. However, there are also several limitations of the resting state approach that restrict its ability to contribute to the study of neurocognitive aging. In this opinion piece, we consider some of those limitations and argue that task based studies are still essential to developing a mechanistic understanding of how age affects the brain in a cognitively relevant manner - a fundamental goal of neuroscientific research into aging. PMID- 28626777 TI - Long-Term Efficacy and Safety of Insulin and Glucokinase Gene Therapy for Diabetes: 8-Year Follow-Up in Dogs. AB - Diabetes is a complex metabolic disease that exposes patients to the deleterious effects of hyperglycemia on various organs. Achievement of normoglycemia with exogenous insulin treatment requires the use of high doses of hormone, which increases the risk of life-threatening hypoglycemic episodes. We developed a gene therapy approach to control diabetic hyperglycemia based on co-expression of the insulin and glucokinase genes in skeletal muscle. Previous studies proved the feasibility of gene delivery to large diabetic animals with adeno-associated viral (AAV) vectors. Here, we report the long-term (~8 years) follow-up after a single administration of therapeutic vectors to diabetic dogs. Successful, multi year control of glycemia was achieved without the need of supplementation with exogenous insulin. Metabolic correction was demonstrated through normalization of serum levels of fructosamine, triglycerides, and cholesterol and remarkable improvement in the response to an oral glucose challenge. The persistence of vector genomes and therapeutic transgene expression years after vector delivery was documented in multiple samples from treated muscles, which showed normal morphology. Thus, this study demonstrates the long-term efficacy and safety of insulin and glucokinase gene transfer in large animals and especially the ability of the system to respond to the changes in metabolic needs as animals grow older. PMID- 28626778 TI - Single Cell-Based Vector Tracing in Patients with ADA-SCID Treated with Stem Cell Gene Therapy. AB - Clinical improvement in stem cell gene therapy (SCGT) for primary immunodeficiencies depends on the engraftment levels of genetically corrected cells, and tracing the transgene in each hematopoietic lineage is therefore extremely important in evaluating the efficacy of SCGT. We established a single cell-based droplet digital PCR (sc-ddPCR) method consisting of the encapsulation of a single cell into each droplet, followed by emulsion PCR with primers and probes specific for the transgene. A fluorescent signal in a droplet indicates the presence of a single cell carrying the target gene in its genome, and this system can clearly determine the ratio of transgene-positive cells in the entire population at the genomic level. Using sc-ddPCR, we analyzed the engraftment of vector-transduced cells in two patients with severe combined immunodeficiency (SCID) who were treated with SCGT. Sufficient engraftment of the transduced cells was limited to the T cell lineage in peripheral blood (PB), and a small percentage of CD34+ cells exhibited vector integration in bone marrow, indicating that the transgene-positive cells in PB might have differentiated from a small population of stem cells or lineage-restricted precursor cells. sc-ddPCR is a simplified and powerful tool for the detailed assessment of transgene-positive cell distribution in patients treated with SCGT. PMID- 28626779 TI - Optical coherence tomography and visual evoked potentials in pediatric MS. AB - OBJECTIVE: To determine the relative ability of optical coherence tomography (OCT) and pattern-reversal visual evoked potentials (pVEPs) to detect visual pathway involvement in pediatric-onset MS. METHODS: Pediatric-onset MS participants (onset <18 years) and healthy controls (HCs) underwent OCT (Cirrus HD-OCT) and pVEPs. Retinal nerve fiber layer (RNFL), ganglion cell layer to inner plexiform layer (GCL-IPL), and P100 pVEP latency were measured. Generalized estimating equation models were used to compare the groups, adjusting for age and intereye correlations. RESULTS: Twenty-four pediatric MS participants, 14 with a history of remote (>6 months) optic neuritis (ON) in one eye (8 participants) or both the eyes (6 participants), and 24 HCs were enrolled. RNFL thinning (<83 MUm, 2 SDs below HC eyes) occurred in 50% of ON eyes vs 5% of non-ON eyes. Prolonged VEP latency (>109 msec) occurred in 58% of ON eyes and 55% of non-ON eyes. A clinical history of ON predicted RNFL (p < 0.001) and GCL-IPL thinning (p = 0.011), whereas prolonged pVEP latency in children with MS occurred independent of ON history. CONCLUSIONS: OCT and pVEPs provide complementary but distinct insights. OCT is sensitive to retinal changes in the context of clinical ON, whereas pVEPs are useful to detect disseminated lesions of the visual pathway in children with MS. PMID- 28626780 TI - IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG. AB - OBJECTIVE: To increase the detection of MuSK-Abs using a CBA and test their pathogenicity. METHODS: Sera from 69 MuSK-RIA-positive patients with myasthenia gravis (MG) (Definite MuSK-MG), 169 patients negative for MuSK-RIA and AChR-RIA (seronegative MG, SNMG), 35 healthy individuals (healthy controls, HCs), and 16 NMDA receptor-Ab-positive (NMDAR-Ab) disease controls were tested for binding to MuSK on a CBA using different secondary antibodies. RESULTS: Initially, in addition to 18% of SNMG sera, 11% of HC and 19% of NMDAR-Ab sera showed positive binding to MuSK-transfected cells; this low specificity was due to anti-IgG(H+L) detection of IgM bound nonspecifically to MuSK. Using an IgG Fc gamma-specific secondary antibody, MuSK-Abs were detected by CBA in 68/69 (99%) of Definite MuSK MG, 0/35 HCs, 0/16 NMDAR-Ab, and 14/169 (8%) of SNMG sera, providing increased sensitivity with high specificity. The RIA-negative, CBA-positive MuSK-IgG sera, but not IgM-MuSK-binding sera, reduced agrin-induced AChR clustering in C2C12 myotubes, qualitatively similar to RIA-positive MuSK-Abs. CONCLUSIONS: An IgG specific MuSK-CBA can reliably detect IgG MuSK-Abs and increase sensitivity. In the MuSK-CBA, IgG specificity is essential. The positive sera demonstrated pathogenic potential in the in vitro AChR-clustering assay, although less effective than Definite MuSK-MG sera, and the patients had less severe clinical disease. Use of IgG-specific secondary antibodies may improve the results of other antibody tests. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that an IgG-specific MuSK-CBA identifies patients with MG. PMID- 28626781 TI - Both cladribine and alemtuzumab may effect MS via B-cell depletion. AB - OBJECTIVE: To understand the efficacy of cladribine (CLAD) treatment in MS through analysis of lymphocyte subsets collected, but not reported, in the pivotal phase III trials of cladribine and alemtuzumab induction therapies. METHODS: The regulatory submissions of the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) (NCT00213135) cladribine and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data were extracted and statistically analyzed. RESULTS: Either dose of cladribine (3.5 mg/kg; 5.25 mg/kg) tested in CLARITY reduced the annualized relapse rate to 0.16-0.18 over 96 weeks, and both doses were similarly effective in reducing the risk of MRI lesions and disability. Surprisingly, however, T-cell depletion was rather modest. Cladribine 3.5 mg/kg depleted CD4+ cells by 40%-45% and CD8+ cells by 15%-30%, whereas alemtuzumab suppressed CD4+ cells by 70%-95% and CD8+ cells by 47%-55%. However, either dose of cladribine induced 70%-90% CD19+ B-cell depletion, similar to alemtuzumab (90%). CD19+ cells slowly repopulated to 15%-25% of baseline before cladribine redosing. However, alemtuzumab induced hyperrepopulation of CD19+ B cells 6-12 months after infusion, which probably forms the substrate for B-cell autoimmunities associated with alemtuzumab. CONCLUSIONS: Cladribine induced only modest depletion of T cells, which may not be consistent with a marked influence on MS, based on previous CD4+ T-cell depletion studies. The therapeutic drug response relationship with cladribine is more consistent with lasting B-cell depletion and, coupled with the success seen with monoclonal CD20+ depletion, suggests that B-cell suppression could be the major direct mechanism of action. PMID- 28626782 TI - Anti-DPPX encephalitis: prominent nystagmus reflected by extraocular muscle FDG PET avidity. PMID- 28626783 TI - Vanishing spinal cord after varicella-zoster virus myelitis. PMID- 28626784 TI - Acute liver injury in a Glatopa-treated patient with MS. PMID- 28626785 TI - Blunted amygdala functional connectivity during a stress task in alcohol dependent individuals: A pilot study. AB - BACKGROUND: Scant research has been conducted on neural mechanisms underlying stress processing in individuals with alcohol dependence (AD). We examined neural substrates of stress in AD individuals compared with controls using an fMRI task previously shown to induce stress, assessing amygdala functional connectivity to medial prefrontal cortex (mPFC). MATERIALS AND METHODS: For this novel pilot study, 10 abstinent AD individuals and 11 controls completed a modified Trier stress task while undergoing fMRI acquisition. The amygdala was used as a seed region for whole-brain seed-based functional connectivity analysis. RESULTS: After controlling for family-wise error (p = 0.05), there was significantly decreased left and right amygdala connectivity with frontal (specifically mPFC), temporal, parietal, and cerebellar regions. Subjective stress, but not craving, increased from pre-to post-task. CONCLUSIONS: This study demonstrated decreased connectivity between the amygdala and regions important for stress and emotional processing in long-term abstinent individuals with AD. These results suggest aberrant stress processing in individuals with AD even after lengthy periods of abstinence. PMID- 28626786 TI - Interaction between estradiol and 5-HT1A receptors in the median raphe nucleus on acquisition of aversive information and association to the context in ovariectomized rats. AB - The median raphe nucleus (MRN) is related to stress resistance and defensive responses, a crucial source of serotonergic neurons that project to prosencephalic structures related to stress and anxiety. Estrogen receptors were identified in this mesencephalic structure. It is possible that the estrogen action is related to serotonin effect on somatodendritic 5-HT1A receptors, inhibiting the function of serotonergic neurons and thus preventing of the stress effect and inducing anxiolysis. So, in order to evaluate these aspects, female Wistar rats were ovariectomized and 21 days later were given a direct microinjection of estradiol benzoate (EB) (1200 ng) into the MRN, preceded by microinjections of saline or WAY100.635 (100 ng), a 5-HT1A receptor antagonist. Immediately after the two microinjections, the ovariectomized rats were conditioned with an aversive event (foot shock) session in a Skinner box. Twenty four hours later, they were exposed to the same context in a test session for 5 min for behavioral assessment: freezing, rearing, locomotion, grooming, and autonomic responses (fecal boluses and micturition). EB microinjection in the MRN prior to the exposure of animals to the foot shocks in the conditioning session did not alter their behavior in this session, but neutralized the association of the aversive experience to the context: there was a decrease in the expression of freezing and an increased rearing activity in the test session. This effect was reversed by prior microinjection of WAY100.635. In conclusion, EB acted on serotonergic neurons in the MRN of the ovariectomized rats, impairing the association of the aversive experience to the context, by co-modulating the functionality of somatodendritic 5-HT1A. PMID- 28626788 TI - A high resolution shapefile of the Andean biogeographical region. AB - Biogeographical analyses have proven to be an efficient complement to classic ecology. An ecoregional layer based on Morrone understanding of the Andean region and its sub-regions was constructed. This high-resolution layer was generated with GIS software, and it enables to include ecoregions as categorical variables into species distribution modeling software. PMID- 28626787 TI - 5-HT2A receptor deficiency alters the metabolic and transcriptional, but not the behavioral, consequences of chronic unpredictable stress. AB - Chronic stress enhances risk for psychiatric disorders, and in animal models is known to evoke depression-like behavior accompanied by perturbed neurohormonal, metabolic, neuroarchitectural and transcriptional changes. Serotonergic neurotransmission, including serotonin2A (5-HT2A) receptors, have been implicated in mediating specific aspects of stress-induced responses. Here we investigated the influence of chronic unpredictable stress (CUS) on depression-like behavior, serum metabolic measures, and gene expression in stress-associated neurocircuitry of the prefrontal cortex (PFC) and hippocampus in 5-HT2A receptor knockout (5 [Formula: see text]) and wild-type mice of both sexes. While 5-[Formula: see text] male and female mice exhibited a baseline reduced anxiety-like state, this did not alter the onset or severity of behavioral despair during and at the cessation of CUS, indicating that these mice can develop stress-evoked depressive behavior. Analysis of metabolic parameters in serum revealed a CUS-evoked dyslipidemia, which was abrogated in 5-[Formula: see text] female mice with a hyperlipidemic baseline phenotype. 5-[Formula: see text] male mice in contrast did not exhibit such a baseline shift in their serum lipid profile. Specific stress-responsive genes (Crh, Crhr1, Nr3c1, and Nr3c2), trophic factors (Bdnf, Igf1) and immediate early genes (IEGs) (Arc, Fos, Fosb, Egr1-4) in the PFC and hippocampus were altered in 5-[Formula: see text] mice both under baseline and CUS conditions. Our results support a role for the 5-HT2A receptor in specific metabolic and transcriptional, but not behavioral, consequences of CUS, and highlight that the contribution of the 5-HT2A receptor to stress-evoked changes is sexually dimorphic. PMID- 28626789 TI - Dataset on the electronic and thermal transport properties of quaternary compounds of (PbTe)0.95-x(PbSe)x(PbS)0.05. AB - The data presented in this article are related to the research article entitled "High thermoelectric performance in pseudo quaternary compounds of (PbTe)0.95-x (PbSe)x(PbS)0.05 by simultaneous band convergence and nano precipitation" (Ginting et al., 2017) [1]. We measured electrical and thermal transport properties such as temperature-dependent Hall carrier density nH , Hall mobility MUH , thermal diffusivity D, heat capacity Cp , and power factor S2sigma in (PbTe)0.95-x (PbSe)x(PbS)0.05 (x=0.0, 0.05, 0.10, 0.15, 0.20, 0.35, and 0.95) compounds with other related compounds from references. From the theoretical fitting of thermal conductivity kappa, we found that the temperature-dependent thermal conductivity follows nano-structure model as well as alloy scattering. Transmission electron microscopy images shows that there are numerous nano-scale precipitates in a matrix. Owing to the low thermal conductivity and high power factor, we report high thermoelectric performances such as the high ZT, engineering ZTeng , efficiency eta. PMID- 28626790 TI - Data on records of indoor temperature and relative humidity in a University building. AB - Good indoor comfort and air quality are essential for correct educational development. Most reports in this field focus on primary and secondary school buildings, with numerous projects conducted in the Mediterranean Zone. However, little has been done in the context of university buildings. Data on indoor temperature and relative humidity data acquired trough field surveys of a seminar room located in the Architecture Faculty in San Sebastian (Spain) is provided in this paper. The seminar room was monitored during a typical spring week. The data presented in the article are related to the research article entitled Retrofit strategies towards Net Zero Energy Educational Buildings: a case study at the University of the Basque Country (Ref. 0378-7788). PMID- 28626791 TI - HIV Risk-Reduction Prevention Interventions Targeting African American Adolescent Women. AB - African American young women are overwhelmingly disproportionately burdened by HIV/AIDS in the United States today. The purpose of the current systematic review was to identify the characteristics of efficacious HIV risk-reduction prevention interventions targeting African American adolescent women in order to inform future intervention development and expansion. We searched PubMed, PsychInfo, and ProQuest databases for journal articles and dissertations published between 2000 and 2015 reporting the impacts of HIV risk-reduction prevention interventions in the U.S. targeting African American adolescent women under age 25. Twenty articles assessing the efficacy of 12 interventions were eligible for inclusion. Selected interventions represented a total of 5,556 African American adolescent women and primarily drew from self-efficacy and self-empowerment-based theoretical frameworks. One intervention targeted girls under age 13; eight included participants ages 13-17; ten targeted adolescents aged 18-24 years; and five interventions included women over age 24 among their participants. Most interventions consisted of in-person knowledge and skills-based group or individual sessions led by trained African American female health professionals. Three were delivered via personal electronic devices. All programs intervened directly at the individual-level; some additionally targeted mothers, friends, or sexual partners. Overall, efficacious interventions among this population promote gender and ethnic pride, HIV risk-reduction self-efficacy, and skills building. They target multiple socio-ecological levels and tailor content to the specific age range, developmental period, and baseline behavioral characteristics of participants. However, demonstrated sustainability of program impacts to date are limited and should be addressed for program enhancements and expansions. PMID- 28626792 TI - Is Methicillin-Resistant Staphylococcus Aureus Colonization Associated with Worse Outcomes in COPD Hospitalizations? AB - BACKGROUND: Although methicillin-resistant Staphylococcus aureus (MRSA) colonization is common in chronic obstructive pulmonary disease (COPD) patients, its effect on the course of COPD hospitalization remains unknown. METHODS: Records of 160 patients hospitalized at our institution January 1, 2008 to May 1, 2010 with acute exacerbations of COPD who were screened for MRSA were examined and outcomes from their hospitalizations were quantified. RESULTS: Of the 160 patients, 33 (20.6%) were MRSA colonized on screening. These patients had similar demographics, spirometry, Charlson Indexes, and APACHE-II scores when compared to patients who were not MRSA colonized (n=127), but MRSA colonized patients had more hospitalizations within the 2 years prior to admission (2 [1-4.8] versus 1 [0-3], p = 0.03). While hospitalized, MRSA colonized patients had a longer length of stay (9 [5.3-15.5] versus 5 [3-7.8] days, p = 0.01) and more antibiotic days (7 [5-10.8] versus 5 [0-7] days, p = 0.01). They were also more likely to receive intensive care (51.5% versus 23.6%, p = 0.01) and to develop respiratory failure that required noninvasive ventilation (56.3% versus 38.2%, p = 0.05). Trends towards increased use of invasive mechanical ventilation and readmission within 30 days were also present. CONCLUSIONS: COPD patients colonized with MRSA have longer hospitalizations, require longer courses of antibiotics, and are more likely to require intensive care. PMID- 28626794 TI - Febrile ataxia and myokymia broaden the SPG26 hereditary spastic paraplegia phenotype. PMID- 28626795 TI - Developmental Environmental Exposure Alters the Epigenetic Features of Myometrial Stem Cells. PMID- 28626793 TI - Acidic pH-targeted chitosan capped mesoporous silica coated gold nanorods facilitate detection of pancreatic tumors via multispectral optoacoustic tomography. AB - We present a cancer nanomedicine based on acidic pH targeted gold nanorods designed for multispectral optoacoustic tomography (MSOT). We have designed gold nanorods coated with mesoporous silica and subsequently capped with chitosan (CMGs). We have conjugated pH-sensitive variant 7 pHLIP peptide to the CMGs (V7 CMG) to provide targeting specificity to the acidic tumor microenvironment. In vitro, treatment of S2VP10 and MiaPaca2 cells with V7-CMG containing gemcitabine resulted in significantly greater cytotoxicity with 97% and 96.5% cell death, respectively than gemcitabine alone 60% and 76% death at pH 6.5 (S2VP10 pH 6.5 p=0.009; MiaPaca2 pH 6.5 p=0.0197). In vivo, the V7-CMGs provided the contrast and targeting specificity necessary for MSOT of retroperitoneal orthotopic pancreatic tumors. In the in vivo S2VP10 model, the V7-CMG particle preferentially accumulated within the tumor at 17.1 MSOT a.u. signal compared with 0.7 MSOT a.u. in untargeted CMG control in tumor (P = 0.0002). Similarly, V7 CMG signal was 9.34 MSOT a.u. in the S2013 model compared with untargeted CMG signal at 0.15 MSOT a.u. (P = 0.0004). The pH-sensitivity of the targeting pHLIP peptide and chitosan coating makes the particles suitable for simultaneous in vivo tumor imaging and drug delivery. PMID- 28626796 TI - Determining Underground Mining Work Postures Using Motion Capture and Digital Human Modeling. AB - According to Mine Safety and Health Administration (MSHA) data, during 2008-2012 in the U.S., there were, on average, 65 lost-time accidents per year during routine mining and maintenance activities involving remote-controlled continuous mining machines (CMMs). To address this problem, the National Institute for Occupational Safety and Health (NIOSH) is currently investigating the implementation and integration of existing and emerging technologies in underground mines to provide automated, intelligent proximity detection (iPD) devices on CMMs. One research goal of NIOSH is to enhance the proximity detection system by improving its capability to track and determine identity, position, and posture of multiple workers, and to selectively disable machine functions to keep workers and machine operators safe. Posture of the miner can determine the safe working distance from a CMM by way of the variation in the proximity detection magnetic field. NIOSH collected and analyzed motion capture data and calculated joint angles of the back, hips, and knees from various postures on 12 human subjects. The results of the analysis suggests that lower body postures can be identified by observing the changes in joint angles of the right hip, left hip, right knee, and left knee. PMID- 28626797 TI - Intrathoracic Fat Measurements Using Multidetector Computed Tomography (MDCT): Feasibility and Reproducibility. AB - Intrathoracic fat volume, more specifically, epicardial fat volume, is an emerging imaging biomarker of adverse cardiovascular events. The purpose of this work is to show the feasibility and reproducibility of intrathoracic fat volume measurement applied to contrast-enhanced multidetector computed tomography images. A retrospective cohort study of 62 subjects free of cardiovascular disease (55% females, age = 49 +/- 11 years) conducted from 2008 to 2011 formed the study group. Intrathoracic fat volume was defined as all fat voxels measuring -50 to -250 Hounsfield Unit within the intrathoracic cavity from the level of the pulmonary artery bifurcation to the heart apex. The intrathoracic fat was separated into epicardial and extrapericardial fat by tracing the pericardium. The measurements were obtained by 2 readers and compared for interrater reproducibility. The fat volume measurements for the study group were 141 +/- 72 cm3 for intrathoracic fat, 58 +/- 27 cm3 for epicardial fat, and 84 +/- 50 cm3 for extrapericardial fat. There was no statistically significant difference in intrathoracic fat volume measurements between the 2 readers, with correlation coefficients of 0.88 (P = .55) for intrathoracic fat volume and -0.12 (P = .33) for epicardial fat volume. Voxel-based measurement of intrathoracic fat, including the separation into epicardial and extrapericardial fat, is feasible and highly reproducible from multidetector computed tomography scans. PMID- 28626798 TI - Demographic, Health and Diabetes Self-management Correlates of Medical Skepticism Among Rural Older Adults. AB - This study examines the demographic, health, and diabetes self-management correlates of medical skepticism among an ethnically diverse sample of older (>60 years) rural adults. Participants (n=564) received a hemoglobin A1c (A1c) test and completed a survey including measures of diabetes management behaviors and the four-item medical skepticism scale. Significant associations were observed between medical skepticism and demographic and health characteristics; overall greater medical skepticism was associated with lower A1c values. In multivariate analysis, overall medical skepticism scores were inversely associated with participating in diabetes education classes and positively associated with participating in exercise sessions. Two of the four individual medical skepticism items were associated with diabetes management: diabetes class participation and exercising and eating > 5 daily servings of fruits and vegetables. This study shows that a brief medical skepticism tool may be useful in clinical and research settings in assessing the degree to which older adults with diabetes adhere to diabetes management. PMID- 28626799 TI - Acute Ischemic Lesions Associated with Impairments in Expression and Recognition of Affective Prosody. AB - PURPOSE: We aimed to: (a) review existing data on the neural basis of affective prosody;(b) test the hypothesis that there are double dissociations in impairments of expression and recognition of affective prosody; and (c) identify areas of infarct associated with impaired expression and/or recognition of affective prosody after acute right hemisphere (RH) ischemic stroke. METHODS: Participants were tested on recognition of emotional prosody in content-neutral sentences. Expression was evaluated by measuring variability in fundamental frequency. Voxel-based symptom mapping was used to identify areas associated with severity of expressive deficits. RESULTS: We found that 9/23 patients had expressive prosody impairments; 5/9 of these patients also had impaired recognition of affective prosody; 2/9 had selective deficits in expressive prosody; recognition was not tested in 2/9. Another 6/23 patients had selective impairment in recognition of affective prosody. Severity of expressive deficits was associated with lesions in right temporal pole; patients with temporal pole lesions had deficits in expression and recognition. CONCLUSIONS: Expression and recognition of prosody can be selectively impaired. Damage to right anterior temporal pole is associated with impairment of both, indicating a role of this structure in a mechanism shared by expression and production of affective prosody. PMID- 28626800 TI - DNA damage-induced nuclear factor-kappa B activation and its roles in cancer progression. AB - DNA damage is a vital challenge to cell homeostasis. Cellular responses to DNA damage (DDR) play essential roles in maintaining genomic stability and survival, whose failure could lead to detrimental consequences such as cancer development and aging. Nuclear factor-kappa B (NF-kappaB) is a family of transcription factors that plays critical roles in cellular stress response. Along with p53, NF kappaB modulates transactivation of a large number of genes which participate in various cellular processes involved in DDR. Here the authors summarize the recent progress in understanding DNA damage response and NF-kappaB signaling pathways. This study particularly focuses on DNA damage-induced NF-kappaB signaling cascade and its physiological and pathological significance in B cell development and cancer therapeutic resistance. The authors also discuss promising strategies for selectively targeting this genotoxic NF-kappaB signaling aiming to antagonize acquired resistance and resensitize refractory cancer cells to cytotoxic treatments. PMID- 28626801 TI - B lymphocytes and cancer: a love-hate relationship. PMID- 28626803 TI - Estimation of insulin secretion, glucose uptake by tissues, and liver handling of glucose using a mathematical model of glucose-insulin homeostasis in lean and obese mice. AB - Destruction of the insulin-producing beta-cells is the key determinant of diabetes mellitus regardless of their types. Due to their anatomical location within the islets of Langerhans scattered throughout the pancreas, it is difficult to monitor beta-cell function and mass clinically. To this end, we propose to use a mathematical model of glucose-insulin homeostasis to estimate insulin secretion, glucose uptake by tissues, and hepatic handling of glucose. We applied the mathematical model by Lombarte et al. (2013) to compare various rate constants representing glucose-insulin homeostasis between lean (11% fat)- and high fat diet (HFD; 45% fat)-fed mice. Mice fed HFD (n = 12) for 3 months showed significantly higher body weights (49.97 +/- 0.52 g vs. 29.86 +/- 0.46 g), fasting blood glucose levels (213.08 +/- 10.35 mg/dl vs. 121.91 +/- 2.26 mg/dl), and glucose intolerance compared to mice fed lean diet (n = 12). Mice were injected with 1 g/kg glucose intraperitoneally and blood glucose levels were measured at various intervals for 120 min. We performed simulation using ArenaTM software based on the mathematical model and estimated the rate constants (9 parameters) for various terms in the differential equations using OptQuestTM. The simulated data fit accurately to the observed data for both lean and obese mice, validating the use of the mathematical model in mice at different stages of diabetes progression. Among 9 parameters, 5 parameters including basal insulin, k2 (rate constant for insulin-dependent glucose uptake to tissues), k3 (rate constant for insulin-independent glucose uptake to tissues), k4 (rate constant for liver glucose transfer), and Ipi (rate constant for insulin concentration where liver switches from glucose release to uptake) were significantly different between lean- and HFD-fed mice. Basal blood insulin levels, k3, and Ipi were significantly elevated but k2 and k4 were reduced in mice fed a HFD compared to those fed a lean diet. Non-invasive assessment of the key components of glucose insulin homeostasis including insulin secretion, glucose uptake by tissues, and hepatic handling of glucose may be helpful for individualized drug therapy and designing a customized control algorithm for the artificial pancreas. PMID- 28626802 TI - Cohesin Mutations in Myeloid Malignancies. AB - Acute Myeloid Leukemia (AML) is a hematologic malignancy with a poor prognosis. Recent genome-wide sequencing studies have identified frequent mutations in genes encoding members of the cohesin complex. Mutations in cohesin contribute to myeloid malignancies by conferring enhanced self-renewal of hematopoietic stem and progenitor cells but the mechanisms behind this phenotype have not been fully elucidated. Of note, cohesin mutations are highly prevalent in acute megakaryocytic leukemia associated with Down syndrome (DS-AMKL), where they occur in over half of patients. Evidence suggests that cohesin mutations alter gene expression through changes in chromatin accessibility and/or aberrant targeting of epigenetic complexes. In this review we discuss the pathogenic mechanisms by which cohesin mutations contribute to myeloid malignancies. PMID- 28626804 TI - Reflectance-based detection for long term environmental monitoring. AB - Here, the potential of colorimetric sensors utilizing porphyrin indicators for long term environmental monitoring is demonstrated. Prototype devices based on commercial color sensing chips (six per device) were combined with in-house developed algorithms for data analysis. The devices are intended to provide real time sensing of threats. An initial outdoor data set was collected using prototype devices with occasional spiked exposure to targets. This data was supported by similar data collected in a controlled indoor environment. Weaknesses in the noted performance of the devices during these experiments were addressed through altering device parameters, algorithm parameters, and array element composition. Additional outdoor data sets totaling 1,616 h and indoor data sets totaling 728 h were collected in support of assessing these changes to the system configuration. The optimized system provided receiver operating characteristics (ROC) of specificity 0.97 and sensitivity 1.0. PMID- 28626805 TI - In situ polarization and dielectric property measurements of Pb(Zr0.52Ti0.48)O3 ferroelectric nanocrystals. AB - Pb(Zr0.52Ti0.48)O3/polycarbonate (PZT/PC) composite films with different concentration of PZT ferroelectric nanocrystals are prepared. The polarization and dielectric relaxation behavior of PZT ferroelectric nanocrystals are characterized using in situ transmittance and X-ray diffraction (XRD) measurements for the first time. It's found that 10% PZT/PC composite film has the largest orientation change and negligible dielectric relaxation after poling (the phi value of 13.8% is almost constant with time even for 168 h). Based on the XRD results, we consider that the preferential orientation of PZT nanocrystals to align in PC matrix after poling is [001] direction. PMID- 28626806 TI - A brief measure to predict exercise behavior: the Archer-Garcia Ratio. AB - BACKGROUND: Different forms of conscious and planned physical exercise and activity that individuals perform improve not only physical but also psychological health, well-being, and both physical and intellectual performance. Here we put forward and test the predictive validity of the Archer-Garcia Ratio, a brief measure for exercise frequency computed using participants' responses to two questions. METHOD: The participants (N = 158) were recruited from a training facility in the south of Sweden. The Archer-Garcia Ratio was constructed by standardizing (i.e., z-scores) and then summarizing individuals' responses to two questions: "How often do you exercise?" (1 = never, 5 = 5 times/week or more) and "Estimate the level of effort when you exercise" (1 = none or very low, 10 = very high). Participants responded also to the Godin Leisure-Time Exercise Questionnaire and allowed the collection of electronic data to track the number of times they had trained six months before and both six and twelve months after the survey. RESULTS: The Archer-Garcia Ratio predicted, moderately, how often individuals had trained during the six months before and both six months and twelve months after the survey. CONCLUSION: The Archer-Garcia Ratio is a brief and valid self-report measure that can be used to predict actual retrospective and prospective exercise behavior. It offers a simple and straightforward form to estimate adherence, compliance and propensities of peoples' exercise habits. PMID- 28626807 TI - The association between Western and Prudent dietary patterns and fasting blood glucose levels in type 2 diabetes and normal glucose metabolism in older Australian adults. AB - High blood glucose and type 2 diabetes are associated with a range of adverse health and cognitive outcomes. One factor that contributes to high blood glucose and type 2 diabetes is dietary intake. This study investigated the relationship between dietary patterns, fasting blood glucose and diabetes status in a sample of 209 participants aged 60-65. Blood plasma glucose was measured from venous blood samples. Individual Prudent and Western dietary patterns were estimated from a self-completed food frequency questionnaire. The relationship between dietary patterns, diabetes, and blood glucose was assessed via general linear model analyses controlling for age, sex, height, and total caloric intake. Results indicated that there was no association between Prudent diet and fasting blood glucose levels, or type 2 diabetes. In contrast, an individual in the upper tertile for Western dietary score had a significantly higher risk of having diabetes than an individual in the lower tertile for Western dietary score. However, there was no significant association between Western diet and fasting blood glucose. Western diet may be associated with type 2 diabetes through mechanisms beyond impacting blood plasma glucose directly. The fact that the association between Western diet and type 2 diabetes remained even when total caloric intake was controlled for highlights the need for policy and population health interventions targeting the reduction of unhealthy food consumption. PMID- 28626808 TI - Attenuation of opioid tolerance by ETB receptor agonist, IRL-1620, is independent of an accompanied decrease in nerve growth factor in mice. AB - AIM: ETA receptor antagonists reverse opioid tolerance but the involvement of ETB receptors is unknown. In morphine or oxycodone tolerant mice we investigated (1) the effect of ETB receptor agonist, IRL-1620, on analgesic tolerance; (2) changes in expression of the brain ETA and ETB receptors; and (3) alterations in the brain VEGF, NGF, PI3K and notch-1 expression. MAIN METHODS: Body weight, body temperature, and tail-flick latency were assessed before and after a challenge dose of morphine or oxycodone in vehicle or IRL-1620 treated mice. Expression studies were carried out using Western blots. KEY FINDINGS: Tail flick latency to a challenge dose of opioid was significantly increased by IRL-1620 from 39% to 100% in morphine tolerant and from 8% to 83% in oxycodone tolerant mice. Morphine or oxycodone did not alter ETA or ETB receptor expression. IRL-1620 had no effect on ETA however it increased (61%) expression of ETB receptors. IRL-1620-induced increase in ETB receptor expression was attenuated by morphine (39.8%) and oxycodone (51.8%). VEGF expression was not affected by morphine or oxycodone and was unaltered by IRL-1620. However, NGF and PI3K expression was decreased (P < 0.001) by morphine and oxycodone and was unaffected by IRL-1620. Notch-1 expression was not altered by morphine, oxycodone or IRL-1620. SIGNIFICANCE: ETB receptor agonist, IRL-1620, restored analgesic tolerance to morphine and oxycodone, but it did not affect morphine and oxycodone induced decrease in NGF/PI3K expression. It is concluded that IRL-1620 attenuates opioid tolerance without the involvement of NGF/PI3K pathway. PMID- 28626809 TI - Epidermal growth factor prevents APOE4-induced cognitive and cerebrovascular deficits in female mice. AB - Cerebrovascular dysfunction is re-emerging as a major component of aging, and may contribute to the risk of developing Alzheimer's disease (AD). Two important risk factors for cerebrovascular dysfunction are APOE and female sex, which are primarily researched in the context of high amyloid-beta (Abeta) levels as found in AD. However, APOE4 and sex modulate Abeta-independent pathways that may induce cerebrovascular dysfunction as a downstream consequence. Therefore, testing the activity of factors that target cerebrovascular dysfunction in Abeta-independent models that incorporate APOE4 and female sex is crucial. We have previously demonstrated that peripheral administration of the epidermal growth factor (EGF) prevents cognitive dysfunction, cerebrovascular leakiness, and cerebrovascular coverage deficits in female mice that express APOE4 and overproduce Abeta, without affecting Abeta levels. These data raise the question of whether EGF protects the cerebrovasculature from general stress-induced damage. Therefore, the goal of this study was to determine whether EGF prevents Abeta-independent cerebrovascular dysfunction. In eight-month old mice that express human APOE, the interaction of APOE4 and female sex induced cognitive dysfunction, increased cerebrovascular leakiness and lowered vessel coverage. Importantly, in a prevention paradigm (from six to eight and a half months of age), EGF ameliorated cognitive decline and cerebrovascular deficits in female mice that express APOE4. Thus, developing treatment strategies based on EGF signaling could provide alternative therapeutic options for age-related cerebrovascular dysfunction and reduce AD risk. PMID- 28626810 TI - Human papillomavirus (HPV) in young women in Britain: Population-based evidence of the effectiveness of the bivalent immunisation programme and burden of quadrivalent and 9-valent vaccine types. AB - BACKGROUND: In 2008, the UK introduced an HPV immunisation programme in girls. Population-based prevalence estimates of bivalent (HPV-16/18), quadrivalent (HPV 6/11/16/18) and 9-valent (HPV-6/11/16/18/31/33/45/52/58) vaccine types, and comparison over time, are needed to monitor impact, evaluate effectiveness and guide decision-making on vaccination strategies. METHODS: The third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) in 2010-12, tested urine for HPV from 2569 sexually-experienced women aged 16-44. We report type-specific HPV prevalence and compare results with 1798 women in Natsal-2 (1999-2001) using age adjusted prevalence ratios (APR). FINDINGS: In Natsal-3, 4.2% of women aged 16 44y were positive for HPV-16/18 and 2.9% for HPV-6/11. In 16-20 year olds, 4.5%, 10.8% and 20.7% had at least one bivalent, quadrivalent or 9-valent vaccine type, respectively. Three-dose vaccine coverage was 52.0% in women aged 18-20y. In this age group, HPV-16/18 prevalence was lower in Natsal-3 than Natsal-2 (5.8% vs 11.2%; APR=0.48[95%CI: 0.24-0.93]), however, prevalences of HPV-6/11, HPV 31/33/45 and HPV-52/58 were unchanged. HPV-16/18 prevalence was also unchanged in women aged 21-44y (APR=0.85[0.61-1.19]). INTERPRETATION: These probability surveys provide evidence of the impact of the bivalent immunisation programme. Reductions were specific to HPV-16/18 and to the age group eligible for vaccination. However, substantial vaccine-preventable HPV remains. PMID- 28626811 TI - The ENRICH Study to evaluate the effectiveness of a combination intervention package to improve isoniazid preventive therapy initiation, adherence and completion among people living with HIV in Ethiopia: rationale and design of a mixed methods cluster randomized trial. AB - BACKGROUND: Isoniazid preventive therapy (IPT) prevents tuberculosis among HIV positive individuals, however implementation is suboptimal. Implementation science studies are needed to identify interventions to address this evidence-to program gap. OBJECTIVE: The ENRICH Study is a mixed methods cluster randomized trial aimed at evaluating the effectiveness and acceptability of a combination intervention package (CIP) to improve IPT implementation in Ethiopia. DESIGN: Ten health centers were randomized to receive the CIP or standard of care. The CIP includes: nurse training and mentorship using a clinical algorithm, tool to identify IPT-eligible family members, and data review at multidisciplinary team meetings; patient transport reimbursement; and adherence support using peer educators and interactive voice response messages. Routine data were abstracted for all newly-enrolled IPT-eligible HIV-positive patients; anticipated sample size was 1400 individuals. A measurement cohort of patients initiating IPT was recruited; target enrollment was 500 individuals, to be followed for the duration of IPT (6-9 months). Inclusion criteria were: HIV-positive; initiated IPT; age >=18; Amharic-, Oromiffa-, Harari-, or Somali-speaking; and capable of informed consent. Three groups were recruited from CIP health centers for in-depth interviews: IPT initiators; IPT non-initiators; and health care providers. Primary outcomes are: IPT initiation; and IPT completion. Secondary outcomes include: retention; adherence; change in CD4+ count; adverse events; and acceptability. Follow-up is complete. DISCUSSION: The ENRICH Study evaluates a CIP targeting barriers to IPT implementation. If the CIP is found effective and acceptable, this study has the potential to inform TB prevention strategies for HIV patients in resource-limited countries in sub-Saharan Africa. PMID- 28626812 TI - Electrocortical Reactivity During Self-referential Processing in Female Youth With Borderline Personality Disorder. AB - BACKGROUND: Borderline personality disorder (BPD) is debilitating, and theoretical models have postulated that cognitive-affective biases contribute to the onset and maintenance of BPD symptoms. Despite advances, our understanding of BPD pathophysiology in youth is limited. The present study used event-related potentials (ERPs) to identify cognitive-affective processes that underlie negative self-referential processing in BPD youth. METHODS: Healthy females (n = 33) and females with BPD (n = 26) 13 to 22 years of age completed a self referential encoding task while 128-channel electroencephalography data were recorded to examine early (i.e., P1 and P2) and late (late positive potential [LPP]) ERP components. Whole-brain standardized low-resolution electromagnetic tomography explored intracortical sources underlying significant scalp ERP effects. RESULTS: Compared to healthy females, participants with BPD endorsed, recalled, and recognized fewer positive and more negative words. Moreover, unlike the healthy group, females with BPD had faster reaction times to endorse negative versus positive words. In the scalp ERP analyses, the BPD group had greater P2 and late LPP positivity to negative as opposed to positive words. For P2 and late LPP, whole-brain standardized low-resolution electromagnetic tomography analyses suggested that females with BPD overrecruit frontolimbic circuitry in response to negative stimuli. CONCLUSIONS: Collectively, these findings show that females with BPD process negative self-relevant information differently than healthy females. Clinical implications and future directions are discussed. PMID- 28626814 TI - Latest developments and advances in the prevention of blindness, a global perspective. PMID- 28626813 TI - Hallucinations as top-down effects on perception. AB - The problem of whether and how information is integrated across hierarchical brain networks embodies a fundamental tension in contemporary cognitive neuroscience, and by extension, cognitive neuropsychiatry. Indeed, the penetrability of perceptual processes in a 'top-down' manner by higher-level cognition-a natural extension of hierarchical models of perception-may contradict a strictly modular view of mental organization. Furthermore, some in the cognitive science community have challenged cognitive penetration as an unlikely, if not impossible, process. We review the evidence for and against top-down influences in perception, informed by a predictive coding model of perception and drawing heavily upon the literature of computational neuroimaging. We extend these findings to propose a way in which these processes may be altered in mental illness. We propose that hallucinations - perceptions without stimulus - can be understood as top-down effects on perception, mediated by inappropriate perceptual priors. PMID- 28626815 TI - Part-time versus full-time occlusion therapy for treatment of amblyopia: A meta analysis. AB - PURPOSE: To compare full-time occlusion (FTO) and part-time occlusion (PTO) therapy in the treatment of amblyopia, with the secondary aim of evaluating the minimum number of hours of part-time patching required for maximal effect from occlusion. METHODS: A literature search was performed in PubMed, Scopus, Science Direct, Ovid, Web of Science and Cochrane library. Methodological quality of the literature was evaluated according to the Oxford Center for Evidence Based Medicine and modified Newcastle-Ottawa scale. Statistical analyses were performed using Comprehensive Meta-Analysis (version 2, Biostat Inc., USA). RESULTS: The present meta-analysis included six studies [three randomized controlled trials (RCTs) and three non-RCTs]. Pooled standardized difference in the mean changes in the visual acuity was 0.337 [lower and upper limits: -0.009, 0.683] higher in the FTO as compared to the PTO group; however, this difference was not statistically significant (P = 0.056, Cochrane Q value = 20.4 (P = 0.001), I2 = 75.49%). Egger's regression intercept was 5.46 (P = 0.04). The pooled standardized difference in means of visual acuity changes was 1.097 [lower and upper limits: 0.68, 1.513] higher in the FTO arm (P < 0.001), and 0.7 [lower and upper limits: 0.315, 1.085] higher in the PTO arm (P < 0.001) compared to PTO less than two hours. CONCLUSIONS: This meta-analysis shows no statistically significant difference between PTO and FTO in treatment of amblyopia. However, our results suggest that the minimum effective PTO duration, to observe maximal improvement in visual acuity is six hours per day. PMID- 28626816 TI - Evaluation of topical bevacizumab as an adjunct to mitomycin C augmented trabeculectomy. AB - PURPOSE: To investigate the safety and synergistic effect of topical bevacizumab after trabeculectomy surgery with mitomycin C (MMC). METHODS: In this prospective, non-randomized, comparative interventional study, 40 eyes from 40 patients with uncontrolled open-angle glaucoma were studied after they underwent primary trabeculectomy with mitomycin C (0.02% for 2 min). Following the procedure topical bevacizumab (4 mg/mL) was used for 2 weeks 4 times daily in group A. Patients in group B received routine postoperative care. The outcome measures were the intraocular pressure (IOP), number of anti-glaucoma medications, complications, and bleb evaluation. RESULTS: Of the 32 eyes that had at least 6 months follow-up, 16 were treated with adjuvant topical bevacizumab. The mean preoperative IOP in group A improved from 26.7 +/- 9.3 mmHg with 2.8 +/- 1.3 anti-glaucoma medications to 10.5 +/- 2.8 mmHg with 0.7 +/- 1 anti-glaucoma medications at last follow-up (P < 0.001). The mean preoperative IOP in group B improved from 21.8 +/- 6.6 mmHg with 3 +/- 0.8 anti-glaucoma medications to 11.4 +/- 3.6 mmHg with 0.8 +/- 1.2 anti-glaucoma medications at last follow-up (P < 0.001). There was an overall reduction of 54.4% and 43.7% in the IOP in groups A and B, respectively (P = 0.18). The cystic type of bleb was less common in group A (P = 0.043). One patient in group A developed a streptococcal corneal ulcer 1.5 months after surgery. CONCLUSION: Administration of topical bevacizumab 4 mg/ml for two weeks following trabeculectomy with mitomycin-C did not significantly affect the IOP trend, but significantly decreased the cystic bleb formation in short-term follow-up. PMID- 28626817 TI - Comparison of current tonometry techniques in measurement of intraocular pressure. AB - PURPOSE: To compare four tonometry techniques: Goldmann applanation tonometer (GAT), Dynamic contour tonometer (DCT), Non-contact tonometer (NCT), and Ocular Response Analyzer (ORA) in the measurement of intraocular pressure (IOP) and the impact of some corneal biomechanical factors on their performance. METHODS: In this cross-sectional study, volunteers with normal ophthalmic examination and no history of eye surgery (except for uncomplicated cataract surgery) or trauma were selected. Twenty-five subjects were male, and 21 were female. The mean age was 48 +/- 19.2 years. Anterior segment parameters were measured with Scheimpflug imaging. IOP was measured with GAT, DCT, NCT, and ORA in random order. A 95% limit of agreement of IOPs was analyzed. The impact of different parameters on the measured IOP with each device was evaluated by regression analysis. RESULTS: The average IOP measured with GAT, DCT, NCT, and ORA was 16.4 +/- 3.5, 18.1 +/- 3.4, 16.2 +/- 3.9, and 17.3 +/- 3.4 mmHg, respectively. The difference of IOP measured with NCT and GAT was not significant (P = 0.382). Intraocular pressure was significantly different between GAT with DCT and IOPCC (P < 0.001 and P = 0.022, respectively). The 95% limit of agreement of DCT, NCT, and IOPCC with GAT was -5.7 to 2.5, -4.1 to 4.7, and -5.3-3.7 mmHg, respectively. Simple regression model corneal resistance factor (CRF) and central corneal thickness (CCT) and multivariate model CRF had a significant relationship with IOP measured with the four devices. CONCLUSION: Although the mean difference of measured IOP by NCT, DCT, and ORA with GAT was less than 2 mmHg, the limit of agreement was relatively large. CCT and CRF were important influencing factors in the four types of tonometers. PMID- 28626818 TI - Astigmatic treatment with photorefractive keratectomy: Investigations of non keratometric ocular astigmatism. AB - PURPOSE: To evaluate the effect of non-keratometric ocular astigmatisms on visual and refractive outcomes after photorefractive keratectomy (PRK) for correction of myopic astigmatisms. METHODS: Seventy one eyes of 36 subjects were enrolled in this study. Patients underwent PRK for treatment of myopia. Subjects were evaluated for refractive error, keratometry, and visual acuity before and six months after surgery. Pre- and post-op non-keratometric astigmatisms were calculated by vectorial analysis of the difference between the corneal plane refractive astigmatism and keratometric astigmatism. Astigmatic analysis explored the contribution of non-keratometric astigmatisms. RESULTS: The pre-op spherical equivalent (SE) was -6.27 +/- 1.48 with 1.16 +/- 1.02 diopters of corneal plane refractive astigmatism and 1.44 +/- 0.47 diopters keratometric astigmatism. Post op values were -0.60 +/- 0.85, 0.56 +/- 0.47, and 1.06 +/- 0.57, respectively, 6 months after surgery. Pre- and post-op non-keratometric astigmatisms were 0.76 +/ 0.41 and 0.76 +/- 0.46, respectively, (P = 0.976) with significant correlation (r = 0.37, P = 0.002). Pre-op non-keratometric astigmatisms correlated to the pre op SE (r = -0.25, P = 0.04). Pre-op non-keratometric astigmatisms had significant correlation with keratometric difference vector of astigmatic correction (r = 0.369, P = 0.002). Post-op non-keratometric astigmatisms correlated to keratometric induced astigmatism (r = 0.334, P = 0.006), keratometric index of success (r = 0.571, P < 0.001), and post-op keratometric astigmatism (r = 0.736, P < 0.001). CONCLUSIONS: Higher or lower non-keratometric ocular astigmatisms did not have any effect on refractive and visual outcome after PRK. PRK effectively corrected total refractive astigmatism through correction of keratometric astigmatism and additional adjustment to compensate for non-keratometric ocular astigmatisms. PMID- 28626819 TI - Comparison of bandage contact lens removal on the fourth versus seventh postoperative day after photorefractive keratectomy: A randomized clinical trial. AB - PURPOSE: To compare the outcomes of bandage contact lens (BCL) removal on the fourth versus seventh post-operative day following photorefractive keratectomy (PRK). METHODS: This study recruited eyes of patients who underwent PRK surgery. The patients were randomly assigned to 2 groups. In Group 1 BCL was removed on the 4th postoperative day, while in Group 2, BCL was removed on the 7th postoperative day. After BCL removal, patients were asked to express their pain score and eye discomfort. At one and three months follow-up examinations, visual acuity scale was assessed. Slit-lamp examination was performed in all visits to evaluate complications. RESULTS: 260 eyes of 130 patients underwent PRK. The age and sex ratio were not significantly different between the two groups. One month after the surgery, the logMAR uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were significantly lower in Group 2 (P value = 0.016, 0.001 respectively), however, the UDVA and CDVA were not significantly different after 3 months (P > 0.05). In Group 1, filamentary keratitis (FK) was observed in 10 (7.6%) eyes, 6 (4.61%) eyes were diagnosed with recurrent corneal erosion (RCE) and corneal haze was detected in 3 (2.3%) eyes. However, in Group 2, RCE was observed in 4 (2.3%) and FK was noted in 4 (3.07%) eyes. No haze was seen in Group 2. The difference in rate of complications was statistically significant (14.6% and 6.1% in Groups 1 and 2, respectively, P = 0.02). Pain and eye discomfort scores were not significantly different (P > 0.05). There was no major complications including infectious keratitis in either groups. CONCLUSION: Following PRK surgery, BCL removal on the seventh postoperative day yields faster visual rehabilitation and lower rate of postoperative complications with no increase in eye pain, discomfort or infection. PMID- 28626820 TI - Factors associated with surface epithelial keratopathy after optical penetrating keratoplasty. AB - PURPOSE: The aim of the study was to evaluate the various donor and recipient factors associated with short-term prevalence of surface epithelial keratopathy after optical penetrating keratoplasty (OPK). METHODS: Preoperative and postoperative data of 91 eyes of 91 patients were reviewed retrospectively who had undergone OPK from March 2013 to February 2016. Donor and recipient data were analyzed for age and sex of the donor, cause of death, death to enucleation time (DET), death to preservation time (DPT), enucleation to utilisation time (EUT) and total time (TT), age and sex of recipient, indications of penetrating keratoplasty (PK), associated glaucoma and recipient size (RS). The presence of various epitheliopathies were recorded at various postoperative visits. RESULTS: The range of age of recipient in this study was 10-83 yrs (mean 49.19 +/- 19.35 yrs). The donor age ranged in between 17 and 95 years (70.27 +/- 15.11 years). Age and preoperative diagnosis of host showed significant influence on epitheliopathy till two weeks and one month post-PK (P = 0.032 and 0.05), respectively. Donor's age and gender showed significant impact on surface keratopathy (SK) till two weeks follow-up with P value of 0.04 and 0.004, respectively. DET, DPT, EUT, and TT affected the surface epithelium significantly with P value of 0.007, 0.001, 0.05, and 0.03, respectively. On first postoperative day 33 (36.26%) eyes developed epithelial defect involving >1/2 of cornea. CONCLUSION: Various donor and recipient factors showed influence on various epithelial abnormalities of surface epithelium in early postoperative period. PMID- 28626821 TI - Mesopic visual quality after accelerated corneal cross linking: A 12-month follow up study. AB - PURPOSE: To determine the 1-year changes of mesopic higher order aberrations (HOAs) and contrast sensitivity (CS) after accelerated corneal cross linking (CXL) in progressive keratoconus. METHODS: In this prospective case series, 70 eyes of 62 keratoconic patients underwent accelerated CXL (18 mW/cm2, 5 min). HOAs and CS were measured using the OPD Scan III and CSV-1000 CS test charts under mesopic conditions before and 6 and 12 months after CXL. RESULTS: At 1 year, logarithmic mesopic CS in spatial frequencies of 3, 6, 12, and 18 cycles per degree (CPD) had increased by 0.05 +/- 0.29 (P = 0.029), 0.04 +/- 0.88 (P = 0.012), 0.27 +/- 0.46 (P = 0.172), and 0.06 +/- 0.22 (P = 0.020), respectively. The decrease in ocular HOAs (0.10 +/- 0.69 MUm, P = 0.992) [coma (0.08 +/- 1.01 MUm, P = 0.613), trefoil (0.03 +/- 0.37 MUm, P = 0.659), and spherical aberration (SA) (0.10 +/- 0.59 MUm, P = 0.743)] and corneal HOAs (0.40 +/- 1.69 MUm, P = 0.874) [coma (0.39 +/- 1.59 MUm, P = 0.401), trefoil (0.33 +/- 2.16 MUm, P = 0.368), and SA (1.27 +/- 1.14 MUm, P = 0.354)] were not statistically significant. The correlations between mesopic CS and HOAs were weak before and after CXL. CONCLUSION: One year after accelerated CXL, CS significantly improved, but changes in HOAs were statistically insignificant. CS changes were independent of HOAs. PMID- 28626822 TI - A prospective randomized trial of azithromycin versus trimethoprim/sulfamethoxazole in treatment of toxoplasmic retinochoroiditis. AB - PURPOSE: To assess the efficacy of oral azithromycin in the treatment of toxoplasmic retinochoroiditis. METHODS: A randomized interventional comparative study was conducted on 14 patients with ocular toxoplasmosis who were treated with oral azithromycin and 13 patients who were treated with oral trimethoprim/sulfamethoxazole for 6-12 weeks. The achievement of treatment criteria in the two groups and lesion size reduction were considered as primary outcome measures. RESULTS: The resolution of inflammatory activity, decrease in the size of retinochoroidal lesions, and final best corrected visual acuity (BCVA) did not differ between the two treatment groups. The lesion size declined significantly in all patients (P = 0.001). There was no significant difference in the reduction of the size of retinal lesions between the two treatment groups (P = 0.17). Within each group, there was a significant improvement in BCVA after treatment; BCVA increased by 0.24 logMAR in the azithromycin group (P = 0.001) and by 0.3 logMAR in the trimethoprim/sulfamethoxazole group (P = 0.001). CONCLUSIONS: Drug efficacy in terms of reducing the size of retinal lesions and visual improvement was similar in a regimen of trimethoprim/sulfamethoxazole or azithromycin treatment. Therefore, if confirmed with further studies, therapy with azithromycin seems to be an acceptable alternative for the treatment of ocular toxoplasmosis. PMID- 28626823 TI - A survey of ophthalmologists and gynecologists regarding termination of pregnancy and choice of delivery mode in the presence of eye diseases. AB - PURPOSE: To evaluate and compare the attitudes of ophthalmologists and gynecologists in suggesting appropriate approach to pregnancy in different ocular conditions. METHODS: Specialty-specific questionnaires on delivery mode and abortion indications for ophthalmic patients (refractive, vascular, oncologic, retinal, glaucoma, postoperation, posttrauma, and infectious) were designed and distributed among physician staff of Farabi Eye Hospital and Yas Women Hospital in Tehran. Attitudes and preferences of the ophthalmologists and gynecologists were quantified and compared. RESULTS: Participants were 29 ophthalmologists and 19 gynecologists. Their mean age was 49.73 +/- 7.57 and 46.79 +/- 1.36 years, respectively. More than 50-70% ophthalmologists were in favor of normal vaginal delivery (NVD) in all ocular diseases. All gynecologists (100%) expressed their need for an ophthalmologist's opinion for decision-making. Ophthalmologists' top choices for conditions potentially requiring a caesarean section were corneal transplants (34.5%), high myopia (23%), retinal detachment (29%), and orbital tumors (34.5%), while two gynecologists recommended abortion in the presence of intraocular and orbital tumors and retinal detachment. In the case of a history of refractive surgery, orbital tumor and intraocular tumor, ophthalmologists recommend NVD over caesarean section twice as much as their gynecologist peers. For history of retinal detachment, glaucoma, retinal vascular accident and intraocular hemorrhage, no single gynecologist recommend NVD. The corresponding figure for ophthalmologist-recommended NVD were 67, 84, 72, and 81%. CONCLUSIONS: There is extreme inconsistency among ophthalmologists and gynecologists in managing ophthalmic-obstetric scenarios, especially for caesarean section indications. Clinical guideline development and consultation for decision-making in challenging cases are recommended. PMID- 28626824 TI - Atypical chronic central serous chorioretinopathy with cystoid macular edema: Therapeutic response to medical and laser therapy. AB - PURPOSE: To describe an atypical case of chronic central serous chorioretinopathy (CSCR). METHODS: A 58-year-old man with longstanding, bilateral visual impairment was self-referred for a second opinion. RESULTS: Findings by direct ophthalmoscopy, optical coherence tomography, fluorescein angiography, and fundus autofluorescence (FAF) were suggestive of atypical, chronic CSCR. Treatment with oral anti-mineralocorticoids resulted in moderate improvement, and photodynamic therapy (PDT) had minimal effect. CONCLUSION: Chronic CSCR may lack cardinal features of CSCR. Once retinal degenerative changes ensue, current treatments may not be effective in improving anatomical and visual outcomes in patients with chronic CSCR. PMID- 28626825 TI - PHACE(S) syndrome: Report of a case with new ocular and systemic manifestations. AB - PURPOSE: To describe an infant with PHACE(S) syndrome [posterior fossa anomalies (P), hemangiomas (H), arterial anomalies (A), cardiac abnormalities and coarctation of aorta (C), eye abnormalities (E), and the sternal defects (S)] with unusual strabismus, congenital glaucoma, and new systemic manifestations. METHODS: A 6-month-old girl was referred with large hemangiomas on the left side of the face. RESULTS: In the ocular examination, right esotropia and hypotropia, and limitation of elevation in adduction in the right eye were seen. Morning glory disk anomaly was seen in the left fundus. Intraocular pressure (IOP) was 28 mmHg in the right eye and 15 mmHg in the left eye. Brain computed tomography (CT) scan demonstrated Dandy-Walker malformation. In the CT angiography of the thoracic arteries, coarctation of aorta in descending part, the aberrant origin of the left subclavian artery from the end of the aortic arch, and anomalous origin of the left vertebral artery from the posterior aspect of the aortic arch were found. Therefore, the presence of large facial hemangioma, posterior fossa anomaly, aortic arch anomalies, and morning glory disk confirmed the diagnosis of PHACE(S) syndrome. Propranolol (0.5 mg/kg/day) was initiated to treat hemangioma and coarctation of aorta. Due to uncontrolled glaucoma, goniotomy was performed in the right eye 3 months after the first visit. One year after the initial visit, the hypotropia and esotropia of the right eye considerably decreased. CONCLUSIONS: To our knowledge, this report was the first report of a pattern like Brown's syndrome (may be called apparent Brown's syndrome) and the second report of the congenital glaucoma in a case of PHACE(S) syndrome. In addition, the anomalous origin of the vertebral artery from the aortic arch has not been reported in the PHACE(S) syndrome. Thus, the clinicians should perform the glaucoma work-up for each patient with this syndrome. PMID- 28626826 TI - Adverse drug events leading to emergency department visits at an eye hospital: A brief report. AB - PURPOSE: To evaluate adverse drug events (ADEs) resulting in emergency department visits in an eye hospital. METHOD: Emergency department visits at Farabi Eye Hospital were assessed for a 7-day period. The patients' eye disorders and drug history were evaluated to detect ADEs. RESULTS: Of 1631 emergency visits, 5 (0.3%, 95% CI: 0.13-0.71%) were drug related. Tetracaine eye drops accounted for 4 (80%, 95% CI: 38-96%) cases with corneal involvement. The other case was an intense conjunctival injection due to naphazoline eye drops. CONCLUSION: ADEs should be considered in differential diagnosis of ocular emergency problems and preventive measure should be considered. PMID- 28626827 TI - The effect of rapid privatisation on mortality in mono-industrial towns in post Soviet Russia: a retrospective cohort study. AB - BACKGROUND: Population-level data suggest that economic disruptions in the early 1990s increased working-age male mortality in post-Soviet countries. This study uses individual-level data, using an indirect estimation method, to test the hypothesis that fast privatisation increased mortality in Russia. METHODS: In this retrospective cohort study, we surveyed surviving relatives of individuals who lived through the post-communist transition to retrieve demographic and socioeconomic characteristics of their parents, siblings, and male partners. The survey was done within the framework of the European Research Council (ERC) project PrivMort (The Impact of Privatization on the Mortality Crisis in Eastern Europe). We surveyed relatives in 20 mono-industrial towns in the European part of Russia (ie, the landmass to the west of the Urals). We compared ten fast privatised and ten slow-privatised towns selected using propensity score matching. In the selected towns, population surveys were done in which respondents provided information about vital status, sociodemographic and socioeconomic characteristics and health-related behaviours of their parents, two eldest siblings (if eligible), and first husbands or long-term partners. We calculated indirect age-standardised mortality rates in fast and slow privatised towns and then, in multivariate analyses, calculated Poisson proportional incidence rate ratios to estimate the effect of rapid privatisation on all-cause mortality risk. FINDINGS: Between November, 2014, and March, 2015, 21 494 households were identified in 20 towns. Overall, 13 932 valid interviews were done (with information collected for 38 339 relatives [21 634 men and 16 705 women]). Fast privatisation was strongly associated with higher working-age male mortality rates both between 1992 and 1998 (age-standardised mortality ratio in men aged 20-69 years in fast vs slow privatised towns: 1.13, SMR 0.83, 95% CI 0.77-0.88 vs 0.73, 0.69-0.77, respectively) and from 1999 to 2006 (1.15, 0.91, 0.86-0.97 vs 0.79, 0.75-0.84). After adjusting for age, marital status, material deprivation history, smoking, drinking and socioeconomic status, working-age men in fast-privatised towns experienced 13% higher mortality than in slow-privatised towns (95% CI 1-26). INTERPRETATION: The rapid pace of privatisation was a significant factor in the marked increase in working-age male mortality in post Soviet Russia. By providing compelling evidence in support of the health benefits of a slower pace of privatisation, this study can assist policy makers in making informed decisions about the speed and scope of government interventions. FUNDING: The European Research Council. PMID- 28626828 TI - Contribution of risk factors to excess mortality in isolated and lonely individuals: an analysis of data from the UK Biobank cohort study. AB - BACKGROUND: The associations of social isolation and loneliness with premature mortality are well known, but the risk factors linking them remain unclear. We sought to identify risk factors that might explain the increased mortality in socially isolated and lonely individuals. METHODS: We used prospective follow-up data from the UK Biobank cohort study to assess self-reported isolation (a three item scale) and loneliness (two questions). The main outcomes were all-cause and cause-specific mortality. We calculated the percentage of excess risk mediated by risk factors to assess the extent to which the associations of social isolation and loneliness with mortality were attributable to differences between isolated and lonely individuals and others in biological (body-mass index, systolic and diastolic blood pressure, and handgrip strength), behavioural (smoking, alcohol consumption, and physical activity), socioeconomic (education, neighbourhood deprivation, and household income), and psychological (depressive symptoms and cognitive capacity) risk factors. FINDINGS: 466 901 men and women (mean age at baseline 56.5 years [SD 8.1]) were included in the analyses, with a mean follow up of 6.5 years (SD 0.8). The hazard ratio for all-cause mortality for social isolation compared with no social isolation was 1.73 (95% CI 1.65-1.82) after adjustment for age, sex, ethnic origin, and chronic disease (ie, minimally adjusted), and was 1.26 (95% CI 1.20-1.33) after further adjustment for socioeconomic factors, health-related behaviours, depressive symptoms, biological factors, cognitive performance, and self-rated health (ie, fully adjusted). The minimally adjusted hazard ratio for mortality risk related to loneliness was 1.38 (95% CI 1.30-1.47), which reduced to 0.99 (95% CI 0.93-1.06) after full adjustment for baseline risks. INTERPRETATION: Isolated and lonely people are at increased risk of death. Health policies addressing risk factors such as adverse socioeconomic conditions, unhealthy lifestyle, and lower mental wellbeing might reduce excess mortality among the isolated and the lonely. FUNDING: Academy of Finland, NordForsk, and the UK Medical Research Council. PMID- 28626829 TI - Socioeconomic status as an effect modifier of alcohol consumption and harm: analysis of linked cohort data. AB - BACKGROUND: Alcohol-related mortality and morbidity are high in socioeconomically disadvantaged populations compared with individuals from advantaged areas. It is unclear if this increased harm reflects differences in alcohol consumption between these socioeconomic groups, reverse causation (ie, downward social selection for high-risk drinkers), or a greater risk of harm in individuals of low socioeconomic status compared with those of higher status after similar consumption. We aimed to investigate whether the harmful effects of alcohol differ by socioeconomic status, accounting for alcohol consumption and other health-related factors. METHODS: The Scottish Health Surveys are record-linked cross-sectional surveys representative of the adult population of Scotland. We obtained baseline demographics and data for alcohol consumption (units per week and binge drinking) from Scottish Health Surveys done in 1995, 1998, 2003, 2008, 2009, 2010, 2011, and 2012. We matched these data to records for deaths, admissions, and prescriptions. The primary outcome was alcohol-attributable admission or death. The relation between alcohol-attributable harm and socioeconomic status was investigated for four measures (education level, social class, household income, and area-based deprivation) using Cox proportional hazards models. The potential for alcohol consumption and other risk factors (including smoking and body-mass index [BMI]) mediating social patterning was explored in separate regression models. Reverse causation was tested by comparing change in area deprivation over time. FINDINGS: 50 236 participants (21 777 men and 28 459 women) were included in the analytical sample, with 429 986 person years of follow-up. Low socioeconomic status was associated consistently with strikingly raised alcohol-attributable harms, including after adjustment for weekly consumption, binge drinking, BMI, and smoking. Evidence was noted of effect modification; for example, relative to light drinkers living in advantaged areas, the risk of alcohol-attributable admission or death for excessive drinkers was increased (hazard ratio 6.12, 95% CI 4.45-8.41 in advantaged areas; and 10.22, 7.73-13.53 in deprived areas). We found little support for reverse causation. INTERPRETATION: Disadvantaged social groups have greater alcohol attributable harms compared with individuals from advantaged areas for given levels of alcohol consumption, even after accounting for different drinking patterns, obesity, and smoking status at the individual level. FUNDING: Medical Research Council, NHS Research Scotland, Scottish Government Chief Scientist Office. PMID- 28626831 TI - Validating Population Estimates for Harmonized Census Tract Data, 2000-2010. AB - Social scientists regularly rely on population estimates when studying change in small areas over time. Census tract data in the United States are a prime example, since there are substantial shifts in tract boundaries from decade to decade. This study compares alternative estimates of the 2000 population living within 2010 tract boundaries to the Census Bureau's own re-tabulation. All methods of estimation are subject to error; this is the first study to directly quantify the error in alternative interpolation methods for U.S. census tracts. A simple areal weighting method closely approximates the estimates provided by one standard source (the Neighborhood Change Data Base or NCDB), with some improvement provided by considering only area not covered by water. More information is used by the Longitudinal Tract Data Base (LTDB), which relies on a combination of areal and population interpolation as well as ancillary data about water-covered areas. Another set of estimates provided by NHGIS uses data about land cover in 2001 and the current road network and distribution of population and housing units at the block level. Areal weighting alone results in a large error in a substantial share of tracts that were divided in complex ways. The LTDB and NHGIS perform much better in all situations, but are subject to some error when boundaries of both tracts and their component blocks are redrawn. Users of harmonized tract data should be watchful for potential problems in either of these data sources. PMID- 28626830 TI - Overweight, obesity, and risk of cardiometabolic multimorbidity: pooled analysis of individual-level data for 120 813 adults from 16 cohort studies from the USA and Europe. AB - BACKGROUND: Although overweight and obesity have been studied in relation to individual cardiometabolic diseases, their association with risk of cardiometabolic multimorbidity is poorly understood. Here we aimed to establish the risk of incident cardiometabolic multimorbidity (ie, at least two from: type 2 diabetes, coronary heart disease, and stroke) in adults who are overweight and obese compared with those who are a healthy weight. METHODS: We pooled individual participant data for BMI and incident cardiometabolic multimorbidity from 16 prospective cohort studies from the USA and Europe. Participants included in the analyses were 35 years or older and had data available for BMI at baseline and for type 2 diabetes, coronary heart disease, and stroke at baseline and follow up. We excluded participants with a diagnosis of diabetes, coronary heart disease, or stroke at or before study baseline. According to WHO recommendations, we classified BMI into categories of healthy (20.0-24.9 kg/m2), overweight (25.0 29.9 kg/m2), class I (mild) obesity (30.0-34.9 kg/m2), and class II and III (severe) obesity (>=35.0 kg/m2). We used an inclusive definition of underweight (<20 kg/m2) to achieve sufficient case numbers for analysis. The main outcome was cardiometabolic multimorbidity (ie, developing at least two from: type 2 diabetes, coronary heart disease, and stroke). Incident cardiometabolic multimorbidity was ascertained via resurvey or linkage to electronic medical records (including hospital admissions and death). We analysed data from each cohort separately using logistic regression and then pooled cohort-specific estimates using random-effects meta-analysis. FINDINGS: Participants were 120 813 adults (mean age 51.4 years, range 35-103; 71 445 women) who did not have diabetes, coronary heart disease, or stroke at study baseline (1973-2012). During a mean follow-up of 10.7 years (1995-2014), we identified 1627 cases of multimorbidity. After adjustment for sociodemographic and lifestyle factors, compared with individuals with a healthy weight, the risk of developing cardiometabolic multimorbidity in overweight individuals was twice as high (odds ratio [OR] 2.0, 95% CI 1.7-2.4; p<0.0001), almost five times higher for individuals with class I obesity (4.5, 3.5-5.8; p<0.0001), and almost 15 times higher for individuals with classes II and III obesity combined (14.5, 10.1-21.0; p<0.0001). This association was noted in men and women, young and old, and white and non-white participants, and was not dependent on the method of exposure assessment or outcome ascertainment. In analyses of different combinations of cardiometabolic conditions, odds ratios associated with classes II and III obesity were 2.2 (95% CI 1.9-2.6) for vascular disease only (coronary heart disease or stroke), 12.0 (8.1-17.9) for vascular disease followed by diabetes, 18.6 (16.6-20.9) for diabetes only, and 29.8 (21.7-40.8) for diabetes followed by vascular disease. INTERPRETATION: The risk of cardiometabolic multimorbidity increases as BMI increases; from double in overweight people to more than ten times in severely obese people compared with individuals with a healthy BMI. Our findings highlight the need for clinicians to actively screen for diabetes in overweight and obese patients with vascular disease, and pay increased attention to prevention of vascular disease in obese individuals with diabetes. FUNDING: NordForsk, Medical Research Council, Cancer Research UK, Finnish Work Environment Fund, and Academy of Finland. PMID- 28626832 TI - Fragment Binding to beta-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches. AB - An approach to identify beta-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2. Protein-observed NMR (two dimensional 15N heteronuclear single-quantum coherence spectroscopy) and crystallographic studies with the soluble domain of BACE1 identified a unique and novel binding mode for compound 12, a fragment that still occupies the active site while not making any interactions with catalytic Asps. This novel approach of combining orthogonal fragment screening techniques, for both wild-type and mutant enzymes, as well as binding competition studies could be generalized to other targets to overcome undesired interaction motifs and as a hit-generation approach in highly constrained intellectual property space. PMID- 28626834 TI - Effects of local and spinal administrations of mu-opioids on postoperative pain in aged versus adult mice. PMID- 28626833 TI - The Lung is a Host Defense Niche for Immediate Neutrophil-Mediated Vascular Protection. AB - Bloodstream infection is a hallmark of sepsis, a medically emergent condition requiring rapid treatment. However, upregulation of host defense proteins through toll-like receptors and NFkappaB requires hours after endotoxin detection. Using confocal pulmonary intravital microscopy, we identified that the lung provides a TLR4-Myd88-and abl tyrosine kinase-dependent niche for immediate CD11b-dependent neutrophil responses to endotoxin and Gram-negative bloodstream pathogens. In an in vivo model of bacteremia, neutrophils crawled to and rapidly phagocytosed Escherichia coli sequestered to the lung endothelium. Therefore, the lung capillaries provide a vascular defensive niche whereby endothelium and neutrophils cooperate for immediate detection and capture of disseminating pathogens. PMID- 28626835 TI - Disrupted ER-to-Golgi Trafficking Underlies Anti-HIV Drugs and Alcohol-Induced Cellular Stress and Hepatic Injury. AB - : Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in anti-human immunodeficiency virus (HIV) drugs and alcohol-induced liver disease in a significant number of patients infected with HIV. However, the precise mechanism by which the drugs and alcohol cause ER stress remains elusive. We found that ritonavir-boosted lopinavir (RL) activated two canonical UPR branches without activation of the third canonical activating transcription factor 6 (ATF6) branch in either HepG2 cells or primary mouse hepatocytes. In the RL-treated cells, ATF6 localization in the Golgi apparatus required for its activation was reduced; this was followed by Golgi fragmentation and dislocation/redistribution of Golgi-resident enzymes. Severities of Golgi fragmentation induced by other anti-HIV drugs varied and were correlated with the ER stress response. In the liver of mice fed RL, alcohol feeding deteriorated the Golgi fragmentation, which was correlated with ER stress, elevated alanine aminotransferase, and liver steatosis. The Golgi stress response (GSR) markers GCP60 and HSP47 were increased in RL-treated liver cells, and knockdown of transcription factor for immunoglobulin heavy-chain enhancer 3 of the GSR by small interfering RNA worsened RL-induced cell death. Cotreatment of pharmacological agent H89 with RL inhibited the RL-induced Golgi enzyme dislocation and ER stress. Moreover, the coat protein complex II (COPII) complexes that mediate ER-to-Golgi trafficking accumulated in the RL-treated liver cells; this was not due to interference of RL with the initial assembly of the COPII complexes. RL also inhibited Golgi fragmentation and reassembly induced by short treatment and removal of brefeldin A. CONCLUSION: Our study indicates that ER-to-Golgi trafficking is disrupted by anti-HIV drugs and/or alcohol, and this contributes to subsequent ER stress and hepatic injury. PMID- 28626836 TI - Pediatric Intussusception: Decreased Surgical Risk with Timely Transfer to a Children's Hospital. AB - INTRODUCTION: Intussusception is a potentially life-threatening condition, and a frequent cause of bowel obstruction during the first two years of life. We hypothesized that patients who were transferred from outside community hospitals, or OSH, without tertiary care capabilities for pediatric services to a large academic children's hospital with intussusception were more likely to require operative management for their intussusception than those who were directly admitted. METHODS: The electronic medical record was queried for patients presenting to Ann and Robert H. Lurie Children's Hospital of Chicago with a diagnosis of intussusception (July 1st, 2009-July 1st, 2014). Age, sex, symptom duration, radiologic management, and surgical care were recorded. OSH and transfer reports were analyzed for those patients that presented as a transfer. Statistical analysis was performed. RESULTS: We identified 270 patients with intussusception. 232 (80%) were successfully treated non-surgically. 58 (20%) required surgical management. Of the patients requiring surgery, there were 38 reductions (24 laparoscopic, 14 open) and 20 bowel resections (1 laparoscopic, 19 open). Of those patients requiring surgery, 37 (63.8%) had presented as a transfer from an OSH. We found that transferred patients, requiring surgery, spent a mean 7.77 hours at the OSH compared to 4.03 hours for the transferred patients that did not require surgery (p=0.0188). There was no significant difference in transport time (p=0.44). CONCLUSION: In conclusion, we identified the amount of time patients spend at hospitals without pediatric surgical capabilities as an independent risk factor necessitating surgical management of intussusception. These data suggest that patients with intussusception who present to hospitals without pediatric radiology or pediatric surgery, should be transferred in an expedited fashion. In the event of a failed enema reduction at an OSH, the transport of the patient should not be delayed as this may result in a higher likelihood of surgical management. PMID- 28626837 TI - The Histogenesis of Ewing Sarcoma. PMID- 28626838 TI - Morphological Classification: Application to Cardiac MRI of Tetralogy of Fallot. AB - This paper presents an image-based classification method, and applies it to classification of cardiac MRI scans of individuals with Tetralogy of Fallot (TOF). Clinicians frequently diagnose cardiac disease by measuring the ventricular volumes from cardiac MRI scans. Interrater variability is a common issue with these measurements. We address this issue by proposing a fully automatic approach for detecting structural changes in the heart. We first extract morphological features of each subject by registering cardiac MRI scans to a template. We then reduce the size of the features via a nonlinear manifold learning technique. These low dimensional features are then fed into nonlinear support vector machine classifier identifying if the subject of the scan is effected by the disease. We apply our approach to MRI scans of 12 normal controls and 22 TOF patients. Experimental result demonstrates that the method can correctly determine whether subject is normal control or TOF with 91% accuracy. PMID- 28626839 TI - Auditory-Tactile integration: Effects of Phase of Sinusoidal Stimulation at 50 and 250 Hz. AB - The perceptual integration of 50- and 250-Hz, 500-ms vibrotactile and auditory tones was studied in detection experiments as a function of the relative phase (0 degrees , 72 degrees , 144 degrees , 216 degrees , and 288 degrees ) of the tone pulses. Vibrotactile stimuli were delivered through a single-channel vibrator to the left middle fingertip and auditory stimuli were presented diotically through headphones in a background of 50 dB SPL broadband noise. The observers were four adults with normal hearing. The vibrotactile and auditory stimulus levels used each yielded 63-77%-Correct unimodal detection performance in a two-interval two alternative forced-choice task. Scores for the auditory-alone and tactile-alone conditions averaged roughly 70%-Correct. Mean scores for the auditory plus tactile conditions averaged across different phases were 77.1%-Correct at 50 Hz and 79.6%-Correct at 250 Hz. At 50 Hz, no differences in performance were observed as a function of the relative phase at which the combined auditory and tactile signals were presented. At 250 Hz, significantly higher scores were observed for one phase combination (72 degrees ) compared to two of the other four relative phases. Performance on the auditory plus tactile conditions resulted in significant integrative effects and was generally more consistent with a "Pythagorean Sum" model than with either an "Algebraic Sum" or an "Optimum Single Cannel" model of perceptual integration. PMID- 28626840 TI - Role of Lactoferrin in the Carcinogenesis of Triple-Negative Breast Cancer. PMID- 28626841 TI - Incorporating Non-rigid Registration into Expectation Maximization Algorithm to Segment MR Images. AB - The paper introduces an algorithm which allows the automatic segmentation of multi channel magnetic resonance images. We extended the Expectation Maximization Mean Field Approximation Segmenter, to include Local Prior Probability Maps. Thereby our algorithm estimates the bias field in the image while simultaneously assigning voxels to different tissue classes under prior probability maps. The probability maps were aligned to the subject using nonrigid registration. This allowed the parcellation of cortical sub-structures including the superior temporal gyrus. To our knowledge this is the first description of an algorithm capable of automatic cortical parcellation incorporating strong noise reduction and image intensity correction. PMID- 28626842 TI - Automated Segmentation of Knee MRI Using Hierarchical Classifiers and Just Enough Interaction Based Learning: Data from Osteoarthritis Initiative. AB - We present a fully automated learning-based approach for segmenting knee cartilage in presence of osteoarthritis (OA). The algorithm employs a hierarchical set of two random forest classifiers. The first is a neighborhood approximation forest, the output probability map of which is utilized as a feature set for the second random forest (RF) classifier. The output probabilities of the hierarchical approach are used as cost functions in a Layered Optimal Graph Segmentation of Multiple Objects and Surfaces (LOGISMOS). In this work, we highlight a novel post-processing interaction called just-enough interaction (JEI) which enables quick and accurate generation of a large set of training examples. Disjoint sets of 15 and 13 subjects were used for training and tested on another disjoint set of 53 knee datasets. All images were acquired using double echo steady state (DESS) MRI sequence and are from the osteoarthritis initiative (OAI) database. Segmentation performance using the learning-based cost function showed significant reduction in segmentation errors (p < 0.05) in comparison with conventional gradient-based cost functions. PMID- 28626843 TI - Globally Optimal Label Fusion with Shape Priors. AB - Multi-atlas label fusion methods have gained popularity in a variety of segmentation tasks given their attractive performance. Graph-based segmentation methods are widely used given their global optimality guarantee. We propose a novel approach, GOLF, that combines the strengths of these two approaches. GOLF incorporates shape priors to the label-fusion problem and provides a globally optimal solution even for the multi-label scenario, while also leveraging the highly accurate posterior maps from a multi-atlas label fusion approach. We demonstrate GOLF for the joint segmentation of the left and right pairs of caudate, putamen, globus pallidus and nucleus accumbens. Compared to the FreeSurfer and FIRST approaches, GOLF is significantly more accurate on all reported indices for all 8 structures. We also present comparisons to a multi atlas approach, which reveals further insights on the contributions of the different components of the proposed framework. PMID- 28626844 TI - Multimodal Registration of White Matter Brain Data via Optimal Mass Transport. AB - The elastic registration of medical scans from different acquisition sequences is becoming an important topic for many research labs that would like to continue the post-processing of medical scans acquired via the new generation of high field-strength scanners. In this note, we present a parameter-free registration algorithm that is well suited for this scenario as it requires no tuning to specific acquisition sequences. The algorithm encompasses a new numerical scheme for computing elastic registration maps based on the minimizing flow approach to optimal mass transport. The approach utilizes all of the gray-scale data in both images, and the optimal mapping from image A to image B is the inverse of the optimal mapping from B to A. Further, no landmarks need to be specified, and the minimizer of the distance functional involved is unique. We apply the algorithm to register the white matter folds of two different scans and use the results to parcellate the cortex of the target image. To the best of our knowledge, this is the first time that the optimal mass transport function has been applied to register large 3D multimodal data sets. PMID- 28626845 TI - Temporally Factorized Network Modeling for Evolutionary Network Analysis. AB - The problem of evolutionary network analysis has gained increasing attention in recent years, because of an increasing number of networks, which are encountered in temporal settings. For example, social networks, communication networks, and information networks continuously evolve over time, and it is desirable to learn interesting trends about how the network structure evolves over time, and in terms of other interesting trends. One challenging aspect of networks is that they are inherently resistant to parametric modeling, which allows us to truly express the edges in the network as functions of time. This is because, unlike multidimensional data, the edges in the network reflect interactions among nodes, and it is difficult to independently model the edge as a function of time, without taking into account its correlations and interactions with neighboring edges. Fortunately, we show that it is indeed possible to achieve this goal with the use of a matrix factorization, in which the entries are parameterized by time. This approach allows us to represent the edge structure of the network purely as a function of time, and predict the evolution of the network over time. This opens the possibility of using the approach for a wide variety of temporal network analysis problems, such as predicting future trends in structures, predicting links, and node-centric anomaly/event detection. This flexibility is because of the general way in which the approach allows us to express the structure of the network as a function of time. We present a number of experimental results on a number of temporal data sets showing the effectiveness of the approach. PMID- 28626846 TI - Salt-bridge networks within globular and disordered proteins: characterizing trends for designable interactions. AB - There has been considerable debate about the contribution of salt bridges to the stabilization of protein folds, in spite of their participation in crucial protein functions. Salt bridges appear to contribute to the activity-stability trade-off within proteins by bringing high-entropy charged amino acids into close contacts during the course of their functions. The current study analyzes the modes of association of salt bridges (in terms of networks) within globular proteins and at protein-protein interfaces. While the most common and trivial type of salt bridge is the isolated salt bridge, bifurcated salt bridge appears to be a distinct salt-bridge motif having a special topology and geometry. Bifurcated salt bridges are found ubiquitously in proteins and interprotein complexes. Interesting and attractive examples presenting different modes of interaction are highlighted. Bifurcated salt bridges appear to function as molecular clips that are used to stitch together large surface contours at interacting protein interfaces. The present work also emphasizes the key role of salt-bridge-mediated interactions in the partial folding of proteins containing long stretches of disordered regions. Salt-bridge-mediated interactions seem to be pivotal to the promotion of "disorder-to-order" transitions in small disordered protein fragments and their stabilization upon binding. The results obtained in this work should help to guide efforts to elucidate the modus operandi of these partially disordered proteins, and to conceptualize how these proteins manage to maintain the required amount of disorder even in their bound forms. This work could also potentially facilitate explorations of geometrically specific designable salt bridges through the characterization of composite salt bridge networks. Graphical abstract ?. PMID- 28626847 TI - Injury, intense dust exposure, and chronic disease among survivors of the World Trade Center terrorist attacks of September 11, 2001. AB - BACKGROUND: The World Trade Center attack of September 11, 2001 in New York City (9/11) exposed thousands of people to intense concentrations of hazardous materials that have resulted in reports of increased levels of asthma, heart disease, diabetes, and other chronic diseases along with psychological illnesses such as post-traumatic stress disorder (PTSD). Few studies have discriminated between health consequences of immediate (short-term or acute) intense exposures versus chronic residential or workplace exposures. METHODS: We used proportional hazards methods to determine adjusted hazard ratios (AHRs) for associations between several components of acute exposures (e.g., injury, immersion in the dust cloud) and four chronic disease outcomes: asthma, other non-neoplastic lung diseases, cardiovascular disease, and diabetes, in 8701 persons free of those conditions prior to exposure and who were physically present during or immediately after the World Trade Center attacks. Participants were followed prospectively up to 11 years post-9/11. RESULTS: Heart disease exhibited a dose response association with sustaining injury (1 injury type: AHR =2.0, 95% CI (Confidence Interval) 1.1-3.6; 2 injury types: AHR = 3.1, 95% CI 1.2-7.9; 3 or more injury types: AHR = 6.8, 95% CI 2.0-22.6), while asthma and other lung diseases were both significantly associated with dust cloud exposure (AHR = 1.3, 95% CI 1.0-1.6). Diabetes was not associated with any of the predictors assessed in this study. CONCLUSION: In this study we demonstrated that the acute exposures of injury and dust cloud that were sustained on 9/11/2001 had significant associations with later heart and respiratory diseases. Continued monitoring of 9/11 exposed persons' health by medical providers is warranted for the foreseeable future. PMID- 28626848 TI - Older adult falls prevention behaviors 60 days post-discharge from an urban emergency department after treatment for a fall. AB - BACKGROUND: Falls are a common and debilitating health problem for older adults. Older adults are often treated and discharged home by emergency department (ED) based providers with the hope they will receive falls prevention resources and referrals from their primary care provider. This descriptive study investigated falls prevention activities, including interactions with primary care providers, among community-dwelling older adults who were discharged home after presenting to an ED with a fall-related injury. METHODS: We enrolled English speaking patients, aged >= 65 years, who presented to the ED of an urban level one trauma center with a fall or fall related injury and discharged home. During subjects' initial visits to the ED, we screened and enrolled patients, gathered patient demographics and provided them with a flyer for a Matter of Balance course. Sixty days post enrollment, we conducted a phone follow-up interview to collect information on post-fall behaviors including information regarding the efforts to engage family and the primary care provider, enroll in a falls prevention program, assess patients' attitudes towards falling and experiences with any subsequent falls. RESULTS: Eighty-seven community-dwelling people between the ages of 65 and 90 were recruited, the majority (76%) being women. Seventy-one percent of subjects reported talking to their provider regarding the fall; 37% reported engaging in falls prevention activities. No subjects reported enrolling in a fall prevention program although two reported contacting falls program staff. Fourteen percent of subjects (n=12) reported a recurrent fall and 8% (7) reported returning to the ED after a recurrent fall. CONCLUSIONS: Findings indicate a low rate of initiating fall prevention behaviors following an ED visit for a fall-related injury among community-dwelling older adults, and highlight the ED visit as an important, but underutilized, opportunity to mobilize health care resources for people at high risk for subsequent falls. PMID- 28626850 TI - Prescribing indicators in primary health care in Belo Horizonte, Brazil: associated factors. AB - Background The prescription is one of the factors that influences rational use of medicines. The evaluation of prescribing indicators should contribute to organization of primary health care services. Objective The aim of this study was to evaluate prescribing indicators and associated factors in primary health care in the northeast health district, Belo Horizonte, Brazil. Setting Twenty primary health care units in the Northeast Health District, Belo Horizonte, Brazil. Method The study was cross sectional. Indicators proposed by World Health Organization were used to evaluate rational use of medicines. Main outcome measure Indicators evaluated were average number of medicines per prescription, proportion of medicines with antibiotic, injectable, medicines prescribed by generic name and medicines present in the essential medicines list. Results Three hundred and ninety-nine patients were interviewed. The average number of medicines per prescription was 3.5 (SD 2.2). The proportion of medicines with antibiotic, injectable, medicines prescribed by generic name and medicines present in the essential medicines list was 17.8, 9.8, 94.9, 91.4%, respectively. Patient age >=60 years was positively associated with number of medicines per prescription (P = 0.00). Conclusion In the northeast health district of Belo Horizonte, the proportion of prescriptions of antibiotics and injections, the adoption of prescribing by generic name and the prescribing of essential medicines were satisfactory in this study considering reference values for these indicators and international scientific literature. However, the mean number of prescribed medicines requires a more in-depth evaluation. PMID- 28626849 TI - Equal Treatment and Outcomes for Everyone with Multiple Myeloma: Are We There Yet? AB - Multiple myeloma treatment has changed tremendously over recent years leading to overall improvement in patient outcomes. With therapeutic advancements, patient care has become increasingly complex and variability is seen in healthcare delivery as well as outcomes when various patient subgroups are analyzed based on sociodemographic factors. It is imperative to understand this variability so that while overall the outcomes get better, specific focus is placed on subgroups that may remain disadvantaged and may not be able to fully access the advancements in therapeutics. Research in multiple myeloma has specifically looked at several such patient subgroups based on socioeconomic status, age, race/ethnicity, insurance carrier, and geographic location that may affect healthcare utilization and patient outcomes. Exploring and understanding these would certainly help address disparities and lead to further equity in healthcare access and, hopefully, patient outcomes. PMID- 28626851 TI - Counselling pregnant women at the crossroads of Europe and Asia: effect of Teratology Information Service in Turkey. AB - Background Previous studies from western countries demonstrated the effectiveness of Teratology Information Service (TIS) counselling in reducing the teratogenic risk perception of pregnant women. Objective To assess whether TIS counselling would be effective in reducing the teratogenic risk perception of the Turkish pregnant women. Setting A TIS (Terafar) operating in a university hospital in Turkey. Methods A cross-sectional survey study. Pregnant women with non teratogenic medication exposures were asked to assign scores on visual analogue scales (VAS) in response to the questions aiming to measure their teratogenic risk perception. The mean score before and after counselling were compared and the associations with maternal socio-demographic characteristics were analysed using SPSS (Version 20.0). Main outcome measures The differences in the mean scores of the perception regarding the baseline risk of pregnancy, own teratogenic risk and the likelihood of termination of pregnancy before and after counselling and their possible associations with maternal socio-demographic characteristics. Results 102 pregnant women participated in the study. The counselling significantly reduced the mean own teratogenic risk perception score and the mean score for the likelihood of termination of pregnancy whereas the mean baseline risk perception score was not significantly changed. Pregnancy week <8 and the exposed number of active ingredients <3 were significantly associated with the difference in the mean score for the likelihood of termination of pregnancy. Conclusions TIS counselling lowers the teratogenic risk perception of Turkish pregnant women and increases their likelihood to continue the pregnancy as it does in the western countries. PMID- 28626852 TI - Global Epidemiology of Hepatocellular Carcinoma (HCC Epidemiology). PMID- 28626853 TI - Conjunctival melanoma in Southwestern Nigeria: a case series and review of literature. AB - PURPOSE: Conjunctival melanoma is a rare tumor worldwide and is extremely rare among black population. This study aims to report the demographics, clinical presentation, treatment, and outcome of patients seen in an indigenous black population in Southwestern Nigeria. METHODS: All patients histologically diagnosed with conjunctival melanoma and managed in the facility were reviewed. Their demographics, clinical presentation, treatment received, outcome of treatment, and histopathological features were analyzed. RESULTS: Six patients (males = 2) with a mean age of 49.8 years were managed over 11 years (range 25-75 years). The right eye was involved in three patients, while one patient had bilateral non-simultaneous tumor. All six patients presented with pigmented growth over the ocular surface of varying duration, confirmed as malignant melanoma at histopathology after an excision biopsy (two patients), incision biopsy (one patient), or orbital exenteration (three patients). One patient who had complete adjuvant treatment postoperatively remained alive and tumor-free at 7-year follow-up, one patient is presently on chemotherapy, one patient died while on admission, and the remaining three patients abandoned further postoperative treatment and defaulted from follow-up. CONCLUSION: Conjunctival melanoma is a rare ocular malignancy in Southwestern Nigeria, and patients present with advanced disease with potential poor outcome. PMID- 28626854 TI - Spatial indices of repolarization correlate with non-ST elevation myocardial ischemia in patients with chest pain. AB - Mild-to-moderate ischemia does not result in ST segment elevation on the electrocardiogram (ECG), but rather non-specific changes in the T wave, which are frequently labeled as non-diagnostic for ischemia. Robust methods to quantify such T wave heterogeneity can have immediate clinical applications. We sought to evaluate the effects of spontaneous ischemia on the evolution of spatial T wave changes, based on the eigenvalues of the spatial correlation matrix of the ECG, in patients undergoing nuclear cardiac imaging for evaluating intermittent chest pain. We computed T wave complexity (TWC), the ratio of the second to the first eigenvalue of repolarization, from 5-min baseline and 5-min peak-stress Holter ECG recordings. Our sample included 30 males and 20 females aged 63 +/- 11 years. Compared to baseline, significant changes in TWC were only seen in patients with ischemia (n = 10) during stress testing, but not among others. The absolute changes in TWC were significantly larger in the ischemia group compared to others, with a pattern that seemed to depend on the severity or anatomic distribution of ischemia. Our results demonstrate that ischemia-induced changes in T wave morphology can be meaningfully quantified from the surface 12-lead ECG, suggesting an important opportunity for improving diagnostics in patients with chest pain. PMID- 28626855 TI - A scaling method to individualise muscle force capacities in musculoskeletal models of the hand and wrist using isometric strength measurements. AB - Because the force-generating capacities of muscles are currently estimated using anatomical data obtained from cadaver specimens, hand musculoskeletal models provide only a limited representation of the specific features of individual subjects. A scaling method is proposed to individualise muscle capacities using dynamometric measurements and electromyography. For each subject, a strength profile was first defined by measuring net moments during eight maximum isometric contractions about the wrist and metacarpophalangeal joints. The capacities of the five muscle groups were then determined by adjusting several parameters of an initial musculoskeletal model using an optimisation procedure which minimised the differences between measured moments and model estimates. Sixteen volunteers, including three particular participants (one climber, one boxer and one arthritic patient), were recruited. Compared with the initial literature-based model, the estimated subject-specific capacities were on average five times higher for the wrist muscles and twice as high for the finger muscles. The adjustments for particular subjects were consistent with their expected specific characteristics, e.g. high finger flexor capacities for the climber. Using the subject-specific capacities, the model estimates were markedly modified. The proposed protocol and scaling procedure can capture the specific characteristics of the participants and improved the representation of their capacities in the musculoskeletal model. PMID- 28626856 TI - Delivery parameters, neonatal parameters and incidence of urinary incontinence six months postpartum: a cohort study. AB - INTRODUCTION: Contradictory results have been reported regarding most delivery parameters as risk factors for urinary incontinence. We investigated the association between the incidence of urinary incontinence six months postpartum and single obstetric risk factors as well as combinations of risk factors. MATERIAL AND METHODS: This study was based on the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health during 1998 2008. This substudy was based on 7561 primiparous women who were continent before and during pregnancy. Data were obtained from questionnaires answered at weeks 15 and 30 of pregnancy and six months postpartum. Data were linked to the Medical Birth Registry of Norway. Single and combined delivery- and neonatal parameters were analyzed by logistic regression analyses. RESULTS: Birthweight was associated with significantly higher risk of urinary incontinence six months postpartum [3541-4180 g: odds ratio (OR) 1.4, 95% confidence interval (CI) 1.2 1.6; >4180 g: OR 1.6, 95% CI 1.2-2.0]. Fetal presentation, obstetric anal sphincter injuries, episiotomy and epidural analgesia were not significantly associated with increased risk of urinary incontinence. The following combinations of risk factors among women delivering by spontaneous vaginal delivery increased the risk of urinary incontinence six months postpartum; birthweight >=3540 g and >=36 cm head circumference; birthweight >=3540 g and forceps, birthweight >=3540 g and episiotomy; and >=36 cm head circumference and episiotomy. CONCLUSION: Some combinations of delivery parameters and neonatal parameters seem to act together and may increase the risk of incidence of urinary incontinence six months postpartum in a synergetic way. PMID- 28626857 TI - Fetal intracranial hemorrhage: role of fetal MRI. AB - OBJECTIVE: To date, prenatal diagnosis of intracranial hemorrhage (ICH) is mainly based on ultrasound (US) findings rather than magnetic resonance imaging (MRI). We aimed to investigate the role of MRI in the diagnosis of fetal ICH among pregnancies referred to fetal MRI and to characterize the topography of fetal ICH using MRI. METHODS: We retrospectively identified fetal ICH cases diagnosed by MRI from 2008 to 2015 and reviewed their prenatal and postnatal medical records. RESULTS: Of the 2638 MRIs performed during the study period, 36 had ICH (median age 27 weeks). The most common US indication for MRI was a suspected cerebral anomaly (86%): 20 (55%) fetuses were referred for ventriculomegaly, 8 (22%) for ICH, and the other 8 had a variety of different indications. We distinguished two broad topographic patterns: (1) those related to hemorrhage of the periventricular germinal matrix (GMH, n = 24; 67%) and (2) those not related to GMH (non-GMH, n = 12; 33%). GMH fetuses were referred to MRI later (median 28 vs 22 weeks, p = 0.005). Intrauterine demise was more frequent in non-GMH (58% vs 4%, p < 0.001). CONCLUSION: Magnetic resonance imaging is an important tool in prenatal diagnosis of ICH, especially when US describes nonspecific intracranial abnormalities. GMH occurs more frequently and later in pregnancy than non-GMH. (c) 2017 John Wiley & Sons, Ltd. PMID- 28626858 TI - Antibiotics for acute bronchitis. AB - BACKGROUND: The benefits and risks of antibiotics for acute bronchitis remain unclear despite it being one of the most common illnesses seen in primary care. OBJECTIVES: To assess the effects of antibiotics in improving outcomes and to assess adverse effects of antibiotic therapy for people with a clinical diagnosis of acute bronchitis. SEARCH METHODS: We searched CENTRAL 2016, Issue 11 (accessed 13 January 2017), MEDLINE (1966 to January week 1, 2017), Embase (1974 to 13 January 2017), and LILACS (1982 to 13 January 2017). We searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 5 April 2017. SELECTION CRITERIA: Randomised controlled trials comparing any antibiotic therapy with placebo or no treatment in acute bronchitis or acute productive cough, in people without underlying pulmonary disease. DATA COLLECTION AND ANALYSIS: At least two review authors extracted data and assessed trial quality. MAIN RESULTS: We did not identify any new trials for inclusion in this 2017 update. We included 17 trials with 5099 participants in the primary analysis. The quality of trials was generally good. At follow-up there was no difference in participants described as being clinically improved between the antibiotic and placebo groups (11 studies with 3841 participants, risk ratio (RR) 1.07, 95% confidence interval (CI) 0.99 to 1.15). Participants given antibiotics were less likely to have a cough (4 studies with 275 participants, RR 0.64, 95% CI 0.49 to 0.85; number needed to treat for an additional beneficial outcome (NNTB) 6) and a night cough (4 studies with 538 participants, RR 0.67, 95% CI 0.54 to 0.83; NNTB 7). Participants given antibiotics had a shorter mean cough duration (7 studies with 2776 participants, mean difference (MD) -0.46 days, 95% CI -0.87 to -0.04). The differences in presence of a productive cough at follow-up and MD of productive cough did not reach statistical significance.Antibiotic-treated participants were more likely to be improved according to clinician's global assessment (6 studies with 891 participants, RR 0.61, 95% CI 0.48 to 0.79; NNTB 11) and were less likely to have an abnormal lung exam (5 studies with 613 participants, RR 0.54, 95% CI 0.41 to 0.70; NNTB 6). Antibiotic-treated participants also had a reduction in days feeling ill (5 studies with 809 participants, MD -0.64 days, 95% CI -1.16 to 0.13) and days with impaired activity (6 studies with 767 participants, MD -0.49 days, 95% CI -0.94 to -0.04). The differences in proportions with activity limitations at follow-up did not reach statistical significance. There was a significant trend towards an increase in adverse effects in the antibiotic group (12 studies with 3496 participants, RR 1.20, 95% CI 1.05 to 1.36; NNT for an additional harmful outcome 24). AUTHORS' CONCLUSIONS: There is limited evidence of clinical benefit to support the use of antibiotics in acute bronchitis. Antibiotics may have a modest beneficial effect in some patients such as frail, elderly people with multimorbidity who may not have been included in trials to date. However, the magnitude of this benefit needs to be considered in the broader context of potential side effects, medicalisation for a self limiting condition, increased resistance to respiratory pathogens, and cost of antibiotic treatment. PMID- 28626859 TI - Very preterm children with fetal growth restriction demonstrated altered white matter maturation at nine years of age. AB - AIM: This study evaluated the role of preterm birth and fetal growth restriction on white matter maturation in schoolchildren without any severe neurodevelopmental impairment. METHODS: The study group comprised 56 very preterm children and 21 term children born between November 1998 and November 2002 at Oulu University Hospital, Finland. The mean gestational age of the preterm children was 28.7 (24.1-31.9) weeks. All children underwent diffusion tensor imaging at a mean age of 9.0 (8.6-9.6) years. Voxel-wise statistical analyses of the imaging data were carried out using tract-based spatial statistics. RESULTS: Preterm children with fetal growth restriction had lower fractional anisotropy and higher radial diffusivity than term controls (p < 0.05), bilaterally in several white matter areas. Preterm children without fetal growth restriction had higher mean diffusivity and axial diffusivity than term controls (p < 0.05) in analogous areas, but more asymmetrically. CONCLUSION: Preterm children had microstructural differences in white matter, compared to term-born children at a mean age of nine, and those with poor fetal growth showed widespread changes in white matter maturation compared to term-born children. Fetal growth and prematurity seemed to affect white matter maturation in a way that was still visible at that age. PMID- 28626860 TI - The Longitudinal Associations Among Temperament, Parenting, and Turkish Children's Prosocial Behaviors. AB - In Turkey, responsive behaviors toward kin are expected from children. Despite this, we know little about the factors that influence young Turkish children's prosocial behaviors. The goal was to explore how temperament and parenting are related to children's prosocial development in Turkey. A total of 293 Turkish children (Mage = 49 months; 48.12% females) were followed up for 3 years. Mothers completed measures of their child's prosocial behaviors, as well as measures of their warmth, inductive reasoning, and the child's approach and reactivity. Maternal warmth predicted children's reactivity, and maternal induction predicted children's sociability. Children's reactivity was inversely related to children's helping behavior and sociability was related to more prosocial behavior. Maternal warmth had indirect links with helping through lessening children's reactivity. PMID- 28626861 TI - Diphenylcyclopropenone for the treatment of cutaneous in-transit melanoma metastases - results of a prospective, non-randomized, single-centre study. AB - BACKGROUND: Current treatments for in-transit melanoma (ITM) metastases are frequently invasive and do not improve overall survival. Recently, there has been increasing investigation into the use of topical agents. Diphenylcyclopropenone or diphencyprone (DPCP) is a novel, topical therapy that has been reported to have immune-sensitizing properties useful in the treatment of ITM. OBJECTIVE: To assess the clinical outcomes of patients treated within a prospective, non randomized, non-comparative study using DPCP for cutaneous ITM metastases. METHODS: A review was conducted assessing the outcomes of 58 patients prospectively treated using DPCP. Patients had satellite or in-transit disease (stage IIIB+), with all lesion morphology types included. The patients were treated through a single, specialized clinic with regular outpatient follow-up. DPCP was topically applied as an aqueous cream in 0.005-1% concentrations once to twice per week for up to 24-48 h of duration. To assess variables associated with response, a per-protocol statistical analysis was performed. RESULTS: Fifty-four patients were treated who satisfied eligibility criteria for analysis. The overall response rates were as follows: complete response 22%, partial response 39%, stable disease 24% and progressive disease 15%. The mean time to complete response was 10.5 months, mean duration (disease-free interval) 12.3 months and recurrence rate in complete responders 41%. Lesion morphology was predictive of clinical benefit with a higher response in epidermotropic disease (P < 0.05). CONCLUSIONS: DPCP provided a well-tolerated, convenient and efficacious treatment for cutaneous ITM metastases. Identifying patterns of response may assist treatment selection and improve patient-rated outcomes. PMID- 28626862 TI - Acoustic field characterization of a clinical magnetic resonance-guided high intensity focused ultrasound system inside the magnet bore. AB - PURPOSE: With the expanding clinical application of magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU), acoustic field characterization of MR-HIFU systems is needed for facilitating regulatory approval and ensuring consistent and safe power output of HIFU transducers. However, the established acoustic field measurement techniques typically use equipment that cannot be used in a magnetic resonance imaging (MRI) suite, thus posing a challenge to the development and execution of HIFU acoustic field characterization techniques. In this study, we developed and characterized a technique for HIFU acoustic field calibration within the MRI magnet bore, and validated the technique with standard hydrophone measurements outside of the MRI suite. METHODS: A clinical Philips MR HIFU system (Sonalleve V2, Philips, Vantaa, Finland) was used to assess the proposed technique. A fiber-optic hydrophone with a long fiber was inserted through a 24-gauge angiocatheter and fixed inside a water tank that was placed on the HIFU patient table above the acoustic window. The long fiber allowed the hydrophone control unit to be placed outside of the magnet room. The location of the fiber tip was traced on MR images, and the HIFU focal point was positioned at the fiber tip using the MR-HIFU therapy planning software. To perform acoustic field mapping inside the magnet, the HIFU focus was positioned relative to the fiber tip using an MRI-compatible 5-axis robotic transducer positioning system embedded in the HIFU patient table. To perform validation measurements of the acoustic fields, the HIFU table was moved out of the MRI suite, and a standard laboratory hydrophone measurement setup was used to perform acoustic field measurements outside the magnetic field. RESULTS: The pressure field scans along and across the acoustic beam path obtained inside the MRI bore were in good agreement with those obtained outside of the MRI suite. At the HIFU focus with varying nominal acoustic powers of 10-500 W, the peak positive pressure and peak negative pressure measured inside the magnet bore were 3.87-68.67 MPa and 3.56 12.06 MPa, respectively, while outside the MRI suite the corresponding pressures were 3.27-67.32 MPa and 3.06-12.39 MPa, respectively. There was no statistically significant difference (P > 0.05) between measurements inside the magnet bore and outside the MRI suite for the p+ and p- at any acoustic power level. The spatial peak pulse-average intensities (ISPPA ) for these powers were 312-17816 W/cm2 and 220-15698 W/cm2 for measurements inside and outside the magnet room, respectively. In addition, when the scanning step size of the HIFU focus was increased from 100 MUm to 500 MUm, the execution time for scanning a 4 * 4 mm2 area decreased from 210 min to 10 min, the peak positive pressure decreased by 14%, the peak negative pressure decreased by 5%, and the lateral full width at half maximum dimension of pressure profiles increased from 1.15 mm to 1.55 mm. CONCLUSIONS: The proposed hydrophone measurement technique offers a convenient and reliable method for characterizing the acoustic fields of clinical MR-HIFU systems inside the magnet bore. The technique was validated for use by measurements outside the MRI suite using a standard hydrophone calibration technique. This technique can be a useful tool in MR-HIFU quality assurance and acoustic field assessment. PMID- 28626863 TI - Prolactin correction for adequacy of petrosal sinus cannulation may diminish diagnostic accuracy in Cushing's disease. AB - OBJECTIVE: Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS), beyond that achieved with ACTH measurement alone, in diagnosing a pituitary ACTH source and determining corticotrophinoma side (L/R). Our objective was to assess the effect of using prolactin to confirm adequacy of petrosal cannulation in a cohort of patients with ACTH-dependent Cushing's syndrome. DESIGN: Retrospective cohort study. PATIENTS: Thirteen patients with clinical and biochemical Cushing's syndrome who underwent IPSS. MEASUREMENTS: Serum prolactin and ACTH in peripheral and inferior petrosal sinus blood before and after corticotrophin-releasing hormone (CRH) injection. RESULTS: Thirteen consecutive patients were diagnosed with Cushing's disease using uncorrected ACTH ratios. The side of PRL excess was the same as the side of ACTH excess in all cases. Use of various published prolactin-related equations suggested that the ACTH non-dominant side was not cannulated in four, six or seven patients depending on the equation used. The equations generally decreased the central-to-peripheral gradient on the uncorrected ACTH dominant side, increased the central-to-peripheral gradient on the contralateral side and diminished or even reversed the ACTH intersinus gradient. CONCLUSIONS: Consistent co-lateralisation of prolactin and ACTH in IPSS strongly suggests that prolactin cannot act as an independent guide to the diagnosis and lateralisation of Cushing's disease. All patients with Cushing's disease had a prolactin intersinus gradient towards the tumourous side of the pituitary, for likely biological reasons. PRL-corrected ACTH concentrations may threaten the sensitivity and specificity of IPSS in diagnosing Cushing's disease and conceal lateralisation. PMID- 28626864 TI - Detecting genetic association through shortest paths in a bidirected graph. AB - Genome-wide association studies (GWASs) commonly use marginal association tests for each single-nucleotide polymorphism (SNP). Because these tests treat SNPs as independent, their power will be suboptimal for detecting SNPs hidden by linkage disequilibrium (LD). One way to improve power is to use a multiple regression model. However, the large number of SNPs preclude simultaneous fitting with multiple regression, and subset regression is infeasible because of an exorbitant number of candidate subsets. We therefore propose a new method for detecting hidden SNPs having significant yet weak marginal association in a multiple regression model. Our method begins by constructing a bidirected graph locally around each SNP that demonstrates a moderately sized marginal association signal, the focal SNPs. Vertexes correspond to SNPs, and adjacency between vertexes is defined by an LD measure. Subsequently, the method collects from each graph all shortest paths to the focal SNP. Finally, for each shortest path the method fits a multiple regression model to all the SNPs lying in the path and tests the significance of the regression coefficient corresponding to the terminal SNP in the path. Simulation studies show that the proposed method can detect susceptibility SNPs hidden by LD that go undetected with marginal association testing or with existing multivariate methods. When applied to real GWAS data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), our method detected two groups of SNPs: one in a region containing the apolipoprotein E (APOE) gene, and another in a region close to the semaphorin 5A (SEMA5A) gene. PMID- 28626865 TI - Positional changes of maxillary central incisors following orthodontic treatment using single-crown implants as fixed reference markers. AB - OBJECTIVES: This follow-up study (1) compares tooth displacement of central incisors in patients with and without pre-implant orthodontic treatment and (2) investigates whether sex, age, or orthodontic retention have an effect on tooth displacement after the insertion of single-crown implants. MATERIALS AND METHODS: Fifty-seven patients - thirty-seven with (test group) and twenty without pre implant orthodontic treatment (control group) - were rehabilitated with 89 single crown implants in the upper maxilla. Clinical and radiographic data, clinical photographs, and dental casts were collected during baseline examinations after prosthetic rehabilitation and at the final follow-up examination at least 5 years later. A total of 114 dental casts were digitalized and aligned using a software program to measure changes in the positions of the central incisors. RESULTS: After a follow-up period of at least five years, 87% of the central incisors measured in the test group were displaced >0.25 mm vertically compared with 70% in the control group. Seventy-eight percent of the test group teeth had moved >0.25 mm horizontally compared with 55% in the control group. These differences were not significant, and there were no significant correlations with patient age or sex. CONCLUSION: The majority of patients had minor vertical (60%) or horizontal (67%) tooth displacement of the central incisors (0.25-0.75 mm) after a minimum follow-up period of 5 years. This study found no significant differences in tooth displacement comparing patients with and without pre-implant orthodontic treatment. No significant effect of sex, age, orthodontic retention, or implant location was observed on tooth displacement. PMID- 28626866 TI - Activation of catalase by pioglitazone: Multiple spectroscopic methods combined with molecular docking studies. AB - Pioglitazone is an important prescription antidiabetic drug with positive roles in controlling high blood sugar in patients with type 2 diabetes. In the present study, we investigated the effects of pioglitazone on the structure and function of bovine liver catalase (BLC) using different spectroscopic and theoretical methods. UV-Vis absorption, fluorescence spectroscopy, synchronous fluorescence, and circular dichroism studies revealed conformational changes in the BLC structure and heme group in the presence of different concentrations of pioglitazone. Kinetic studies indicated that pioglitazone can increase BLC activity by approximately threefold compared with free enzyme. The fluorescence quenching data showed one binding site for pioglitazone, and the binding constants at 298, 304, and 310 K were calculated as 5.01 * 107 M-1 , 5.8 * 107 M-1 , and 6.6 * 107 M-1 , respectively. The static type of quenching mechanism was mainly involved in the quenching of intrinsic emission of the enzyme. Thermodynamic data suggested that hydrophobic interactions played a major role in the binding reaction of pioglitazone with BLC. The molecular docking studies indicated that pioglitazone interacts with the cavity in the middle of the beta barrel and wrapping domain of BLC. Thus, pioglitazone can increase catalase activity by changing the BLC structure. PMID- 28626867 TI - Kind of blue: A systematic review and meta-analysis of music interventions in cancer treatment. AB - OBJECTIVES: Music may be a valuable and low-cost coping strategy for cancer patients. We conducted a systematic review and meta-analysis to identify the psychological and physical effects of music interventions in cancer treatment. METHODS: We included randomized, controlled trials with adult patients in active cancer treatment exposed to different music interventions versus control conditions. Qualitative studies and systematic reviews were excluded. We identified a total of 2624 records through 2 systematic searches (June 2015 and September 2016) in PubMed, Scopus, EMBASE, Cinahl, Web of Science, Cochrane, and PsycINFO and used Risk of Bias Assessment, GRADE and Checklist for Reporting Music-Based Interventions to evaluate the music applied and quality of the studies. We conducted meta-analyses using Review Manager (version 5.3). PROSPERO reg. no. CRD42015026024. RESULTS: We included 25 RCT's (N = 1784) of which 20 were eligible for the meta-analysis (N = 1565). Music reduced anxiety (SMD -0.80 [95% CI, -1.35 to -0.25]), pain (SMD -0.88 [95% CI -1.45 to -0.32]), and improved mood (SMD -0.55 [95% CI, -0.98 to -0.13]). However, studies were hampered by heterogeneity with I2 varying between 54% and 96%. Quality of the studies ranged from very low to low. The most effective mode of music intervention appeared to be passive listening to self-selected, recorded music in a single session design. CONCLUSIONS: Music may be a tool in reducing anxiety, pain, and improving mood among patients with cancer in active treatment. However, methodological limitations in the studies conducted so far prevent firm conclusions. PMID- 28626868 TI - Intrathecal dexamethasone vs. meperidine for prevention of shivering during transurethral prostatectomy: a randomized controlled trial. AB - BACKGROUND: Shivering is a common complication after spinal anesthesia. Also, during transurethral prostatectomy a large amount of irrigating fluids is used which may cause hypothermia and shivering. We hypothesized that intrathecal dexamethasone could effectively attenuate post-spinal shivering following transurethral prostatectomy as intrathecal meperidine. METHODS: Ninety male patients, ASA II-III, 50-75 years old were included in this prospective and randomized double-blind study. Patients were divided into three equal groups; Group D received 8 mg dexamethasone, Group M received 0.2 mg/kg meperidine, and Group C received 2 ml of normal saline, each in addition to intrathecal hyperbaric bupivacaine 0.5%. Shivering incidence, intensity and recurrence, dose of IV meperidine required to treat shivering, and adverse events were recorded for 150 min after the start of spinal anesthesia. RESULTS: The number of patients with shivering was higher in Group C (13) than in Group D (2) and Group M (3) with no differences between Group D and M; P = 0.001. Intensity and recurrence of shivering and dose of IV meperidine used to treat shivering were higher in Group C compared to Group D and Group M; P = 0.01, P = 0.064, and P = 0.004, respectively. Adverse events were not different between groups except sedation and pruritus which occurred only in Group M compared to Group D and Group C; P = 0.005 and P = 0.001, respectively. CONCLUSION: Intrathecal dexamethasone was as effective as intrathecal meperidine in attenuation of shivering compared to placebo in patients scheduled for prostate surgery under spinal anesthesia with less adverse events. PMID- 28626870 TI - The chicken or the egg? Sildenafil therapy for fetal cardiovascular dysfunction during hypoxic development: studies in the chick embryo. PMID- 28626871 TI - Successful living donor liver retransplantation for graft failure within 7 days due to acute de novo donor-specific anti-human leukocyte antigen antibody mediated rejection. AB - Growing evidence suggests a relationship between antibody-mediated rejection (AMR) and early graft failure due to a previously unknown etiology in liver transplantation (LTx). We herein report a 3-year-old boy who developed rapid graft failure due to de novo donor-specific antibody (DSA)-driven AMR a week after living donor LTx, requiring a second transplant on the 10th day after the first LTx. The pathology of the first graft showed massive necrosis in zone 3 along with positive C4d and inflammatory cell infiltrates in portal areas. The mean fluorescence intensity against human leukocyte antigen (HLA)-DR15, which was possessed by both the first and the second donor, peaked at 12 945 on the day before the second LTx. Antithymocyte globulin, plasma exchange along with i.v. immunoglobulin, rituximab, and the local infusion of prostaglandin E1, steroids, and Mesilate gabexate through a portal catheter were provided to save the second graft. To our knowledge, this is the first report to show a clear association between de novo DSA and acute AMR within 7 days of a LTx. Furthermore, we successfully rescued the recipient with a second graft despite possessing the same targeted HLA. The rapid decision to carry out retransplantation and specific strategies overcoming AMR were crucial to achieving success in this case of immunologically high-risk LTx. PMID- 28626869 TI - Identification of miRNAs involved in DRG neurite outgrowth and their putative targets. AB - Peripheral neurons regenerate their axons after injury. Transcriptional regulation by microRNAs (miRNAs) is one possible mechanism controlling regeneration. We profiled miRNA expression in mouse dorsal root ganglion neurons after a sciatic nerve crush, and identified 49 differentially expressed miRNAs. We evaluated the functional role of each miRNA using a phenotypic analysis approach. To predict the targets of the miRNAs we employed RNA-Sequencing and examined transcription at the isoform level. We identify thousands of differentially expressed isoforms and bioinformatically associate the miRNAs that modulate neurite growth with their putative target isoforms to outline a network of regulatory events underlying peripheral nerve regeneration. MiR-298, let-7a, and let-7f enhance neurite growth and target the majority of isoforms in the differentially expressed network. PMID- 28626872 TI - A Longitudinal Analysis of Well-Being of Ghanaian Children in Transnational Families. AB - This study is the first to employ panel data to examine well-being outcomes-self rated health, happiness, life satisfaction, and school enjoyment-of children in transnational families in an African context. It analyzes data collected in 2013, 2014, and 2015 from secondary schoolchildren and youth (ages 12-21) in Ghana (N = 741). Results indicate that children with fathers, mothers, or both parents away and those cared for by a parent, a family, or a nonfamily member are equally or more likely to have higher levels of well-being as children in nonmigrant families. Yet, there are certain risk factors-being a female, living in a family affected by divorce or by a change in caregiver while parents migrate-that may decrease child well-being. PMID- 28626873 TI - Assessing prefrontal cortex oxygenation after sport concussion with near-infrared spectroscopy. AB - BACKGROUND: Clinicians typically rely on neuropsychological and balance tests to track concussion recovery. The aforementioned tests imply impairments that are based on performance, but these tests do not directly measure brain physiology throughout concussion recovery. Because of these issues, an objective biomarker that can index severity and the recovery timeline is needed. Moreover, the number of concussions occurring at a recreational level requires the biomarker to be easily administered in a cost effective manner, and the results easily interpreted. METHODS: To address these issues, near-infrared spectroscopy was used to assess the relative changes in oxy (HbO2 )- and deoxyhaemoglobin and the associated standard deviations (SD) in the prefrontal cortex. Resting haemoglobin, and haemoglobin changes in response to hypercapnia (five repeated 20s breath holds), was measured in all participants. Data were aggregated into healthy baselines (n = 115), and concussed participants on days 1-3 (n = 14), 4-6 (n = 8), and 7-14 (n = 11). The data were statistically compared using a 1 * 4 ANOVA. RESULTS: Resting HbO2 values progressively lowered from days 1-3 to 7-14 (with no differences compared to controls). The second major finding showed that hypercapnic HbO2 SD was significantly lower than resting values on days 1-3 and 4 6, but reversed back towards the healthy control group on day 7-14. CONCLUSION: Monitoring cerebral oxygenation changes is a viable biomarker to assess the physiological state of the brain following concussion. PMID- 28626874 TI - 'Is nitrogen mustard contamination responsible for the reported MT-45 toxicity?' Reply from the authors. PMID- 28626875 TI - Effect of ketogenic diet and other dietary therapies on anti-epileptic drug concentrations in patients with epilepsy. AB - WHAT IS KNOWN AND OBJECTIVE: The ketogenic diet (KD) is an effective high-fat, adequate-protein, low-carbohydrate diet for patients with refractory epilepsy. The aim of this study was to investigate the potential effects of the KD and other dietary therapies on the concentrations of anticonvulsants in patients with epilepsy. METHODS: Patients with epilepsy who were treated with the KD and other dietary therapies for more than 30 days with at least one measurement performed both before and during the diet were evaluated. The mean serum concentrations and the mean serum concentrations per weight per daily dose per bioavailability (F) of anti-epileptic drugs (AEDs) before and during the treatment were assessed. We also compared the rates of events out of reference ranges of the AEDs between before and during the KD and other dietary therapies. We compared the serum albumin, alanine transaminase and aspartate transaminase data of patients with valproic acid before and during the KD. RESULTS AND DISCUSSION: One-hundred thirty-nine patients including 81 male patients were enrolled. The median age of the patients was 2.91 (0.15-15.46) years. The median duration of the dietary therapies was 153 (35-2307) days. After the dietary therapies, the serum concentrations of carbamazepine, lamotrigine, levetiracetam, topiramate and valproic acid decreased, whereas that of phenobarbital slightly increased. However, statistical significance was found only with valproic acid (67.07+/ 25.89 MUg/mL vs 51.00+/-20.19 MUg/mL, P<.05). The serum concentrations per weight per daily dose per drug F significantly decreased for valproic acid (1.38+/ 1.39*10-2 vs 0.82+/-0.82*10-2 MUg d mL-1 F-1 ) and phenobarbital (6.66+/ 7.20*10-2 vs 4.75+/-4.07*10-2 MUg d mL-1 F-1 , P<.05). The rate of occurrence of events out of reference ranges significantly increased with valproic acid (36.08% vs 57.23%, P<.05). WHAT IS NEW AND CONCLUSIONS: Most anti-epileptic drug serum concentrations remained stable during the KD and other related dietary therapies except those of valproic acid. Therefore, serum concentrations of valproic acid should be monitored when the KD and other dietary therapies are concomitantly administered. PMID- 28626876 TI - Optical molecular imaging-guided radiation therapy part 2: Integrated x-ray and fluorescence molecular tomography. AB - PURPOSE: Differentiating tumor from its surrounding soft tissues is challenging for x-ray computed tomography (CT). Fluorescence molecular tomography (FMT) can directly localize the internal tumors targeted with specific fluorescent probes. A FMT system was developed and integrated onto a CT-guided irradiator to improve tumor localization for image-guided radiation. METHODS: The FMT system was aligned orthogonal to the cone-beam CT onboard our previously developed image guided small animal arc radiation treatment system (iSMAART). Through rigorous physical registration, the onboard CT provides accurate surface contour which is used to generate three-dimensional mesh for FMT reconstruction. During FMT experiments, a point laser source perpendicular to the rotating axis was used to excite the internal fluorophores. The normalized optical images from multiple projection angles were adopted for tomographic reconstruction. To investigate the accuracy of the FMT in locating the tumor and recovering its volume, in vivo experiments were conducted on two breast cancer models: MDA-MB-231 cancer xenograft on nude mice and 4T1 cancer xenograft on white mice. Both cancer cell lines overexpress the epidermal growth factor receptor (EGFR). A novel fluorescent poly(lactic-co-glycolic) acid (PLGA) nanoparticle conjugated with anti-EGFR was intravenously injected to specifically target the breast cancer cells. Another ex vivo experiment on a mouse bearing a surgically implanted Indocyanine Green-containing glass tube was conducted, to additionally validate the precision of FMT-guided radiation therapy. RESULTS: The FMT can accurately localize the single-nodule breast tumors actively targeted with fluorescent nanoparticles with localization error < 0.5 mm calculated between the centers of mass of tumors in FMT and CT. The reconstructed tumor volume in FMT was significantly correlated with that in the iodinated contrast-enhanced CT (R2 = 0.94, P < 0.001). The FMT was able to guide focal radiation delivery with submillimeter accuracy. CONCLUSION: Using the tumor-targeting fluorescent probes, the iSMAART with onboard FMT system can accurately differentiate tumors from their surrounding soft tissue, guide precise focal radiation delivery, and potentially assess tumor response in cancer research. PMID- 28626877 TI - Factors associated with the difficulty in hospital acceptance among elderly emergency patients: A population-based study in Osaka City, Japan. AB - AIM: We aimed to investigate prehospital factors associated with difficulty in hospital acceptance among elderly emergency patients. METHODS: We reviewed ambulance records in Osaka City from January 2013 through December 2014, and enrolled all elderly emergency patients aged >=65 years who were transported by on-scene emergency medical service personnel to a hospital that the personnel had selected. The definition of difficulty in hospital acceptance was to the requirement for >=4 phone calls to hospitals by emergency medical service personnel before receiving a decision from the destination hospitals. Prehospital factors associated with difficulty in hospital acceptance were examined through logistic regression analysis. RESULTS: During the study period, 72 105 elderly patients were included, and 13 332 patients (18.5%) experienced difficulty in hospital acceptance. In the simple linear regression model, hospital selection time increased significantly with an increasing number of phone calls (R2 = 0.774). In the multivariable analysis, older age (P for trend <0.001), calls from a healthcare facility (adjusted odds ratio [AOR] 1.23, 95% confidence interval [CI] 1.15-1.32), night-time (AOR 2.17, 95% CI 2.08-2.26) and weekend/holidays (AOR 1.43, 95% CI 1.38-1.49) were significantly associated with difficulty in hospital acceptance. A positive association was observed between gastrointestinal emergency-related symptoms and difficulty in hospital acceptance among elderly patients with symptoms of internal disease (AOR 1.71, 95% CI 1.53-1.91). CONCLUSIONS: In Japan, which has a rapidly aging population, a comprehensive strategy for elderly emergency patients, especially for advanced age groups or nursing home residents, is required. Geriatr Gerontol Int 2017; 17: 2441-2448. PMID- 28626878 TI - Should women be advised to use calcium supplements during pregnancy? A decision analysis. AB - Adequate calcium intake during pregnancy is important in the prevention of pre eclampsia. A substantial proportion of pregnant women do not meet the recommended daily calcium intake, even in developed countries. Nonetheless, calcium supplementation is not routinely advised to pregnant women in most countries. We aimed to predict the impact of advising pregnant women to use calcium supplements (1,000 mg/day) on the number of cases of pre-eclampsia prevented and related health care costs. By use of a decision-analytic model, we assessed the expected impact of advising calcium supplementation to either (1) all pregnant women, (2) women at high risk of developing pre-eclampsia, or (3) women with a low dietary calcium intake compared with current care. Calculations were performed for a hypothetical cohort of 100,000 pregnant women living in a high-income country, although input parameters of the model can be adjusted so as to fit other settings. The incidence of pre-eclampsia could be reduced by 25%, 8%, or 13% when advising calcium supplementation to all pregnant women, women at high risk of pre eclampsia, or women with a low dietary calcium intake, respectively. Expected net financial benefits of the three scenarios were of ?4,621,465, ?2,059,165, or ?2,822,115 per 100,000 pregnant women, respectively. Advising pregnant women to use calcium supplements can be expected to cause substantial reductions in the incidence of pre-eclampsia as well as related health care costs. It appears most efficient to advise calcium supplementation to all pregnant women, not subgroups only. PMID- 28626879 TI - Snipper, an Eri1 homologue, affects histone mRNA abundance and is crucial for normal Drosophila melanogaster development. AB - The conserved 3'-5' RNA exonuclease ERI1 is implicated in RNA interference inhibition, 5.8S rRNA maturation and histone mRNA maturation and turnover. The single ERI1 homologue in Drosophila melanogaster Snipper (Snp) is a 3'-5' exonuclease, but its in vivo function remains elusive. Here, we report Snp requirement for normal Drosophila development, since its perturbation leads to larval arrest and tissue-specific downregulation results in abnormal tissue development. Additionally, Snp directly interacts with histone mRNA, and its depletion results in drastic reduction in histone transcript levels. We propose that Snp protects the 3'-ends of histone mRNAs and upon its absence, histone transcripts are readily degraded. This in turn may lead to cell cycle delay or arrest, causing growth arrest and developmental perturbations. PMID- 28626880 TI - The use of blood coagulation products requires a thorough re-evaluation. PMID- 28626881 TI - Direct Growth of High Mobility and Low-Noise Lateral MoS2 -Graphene Heterostructure Electronics. AB - Reliable fabrication of lateral interfaces between conducting and semiconducting 2D materials is considered a major technological advancement for the next generation of highly packed all-2D electronic circuitry. This study employs seed free consecutive chemical vapor deposition processes to synthesize high-quality lateral MoS2 -graphene heterostructures and comprehensively investigated their electronic properties through a combination of various experimental techniques and theoretical modeling. These results show that the MoS2 -graphene devices exhibit an order of magnitude higher mobility and lower noise metrics compared to conventional MoS2 -metal devices as a result of energy band rearrangement and smaller Schottky barrier height at the contacts. These findings suggest that MoS2 -graphene in-plane heterostructures are promising materials for the scale-up of all-2D circuitry with superlative electrical performance. PMID- 28626883 TI - Weighting (also) the risk of post-operative nausea and vomiting in bariatric surgery: time for opioid free anesthesia. PMID- 28626882 TI - Quantitative proteome analysis of plasma microparticles for the characterization of HCV-induced hepatic cirrhosis and hepatocellular carcinoma. AB - PURPOSE: Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor and a leading cause of cancer-related deaths worldwide. Cirrhosis induced by hepatitis-C virus (HCV) infection is the most critical risk factor for HCC. However, the mechanism of HCV-induced carcinogenesis is not fully understood. Plasma microparticles (PMP) contribute to numerous physiological and pathological processes and contain proteins whose composition correlates to the respective pathophysiological conditions. EXPERIMENTAL DESIGN: We analyzed PMP from 22 HCV-induced cirrhosis patients, 16 HCV-positive HCC patients with underlying cirrhosis and 18 healthy controls. PMP were isolated using ultracentrifugation and analyzed via label-free LC-MS/MS. RESULTS: We identified 840 protein groups and quantified 507 proteins. 159 proteins were found differentially abundant between the three experimental groups. PMP in both disease entities displayed remarkable differences in the proteome composition compared to healthy controls. Conversely, the proteome difference between both diseases was minimal. GO analysis revealed that PMP isolated from both diseases were significantly enriched in proteins involved in complement activation, while endopeptidase activity was downregulated exclusively in HCC patients. CONCLUSION: This study reports for the first time a quantitative proteome analysis for PMP from patients with HCV-induced cirrhosis and HCC. Data are available via ProteomeXchange with identifier PXD005777. PMID- 28626885 TI - Intraocular surgery - assessment and transfer of skills using a virtual-reality simulator. PMID- 28626884 TI - Empirical Tests of a Brain-Based Model of Executive Function Development. AB - Executive function (EF) plays a foundational role in development. A brain-based model of EF development is probed for the experiences that strengthen EF in the dimensional change card sort task in which children sort cards by one rule and then are asked to switch to another. Three-year-olds perseverate on the first rule, failing the task, whereas 4-year-olds pass. Three predictions of the model are tested to help 3-year-olds (N = 54) pass. Experiment 1 shows that experience with shapes and the label "shape" helps children. Experiment 2 shows that experience with colors-without a label-helps children. Experiment 3 shows that experience with colors induces dimensional attention. The implications of this work for early intervention are discussed. PMID- 28626886 TI - Investigation of the Integration of Supports for Youth Thriving Into a Community Based Mentoring Program. AB - A randomized control trial involving 806 youth (ages 10-16; 85.4% low-income households) served in U.S. Big Brothers Big Sisters affiliates investigated effects of incorporating activities to promote youth thriving into mentoring relationships over a 15-month period. Outcomes included support for thriving in youths' relationships with adults, youths' personal resources for thriving, and levels of problem behavior. Intent-to-treat analyses revealed no differences in outcomes based on assignment to thriving promotion or standard services. There was substantial variability in youth exposure to thriving promotion activities, primarily in association with premature endings of mentoring relationships. In path analyses, positive engagement with the activities predicted enhanced support for thriving from adults and, via this support, increased personal resources for thriving and reduced problem behavior. PMID- 28626887 TI - Using numerical plant models and phenotypic correlation space to design achievable ideotypes. AB - Numerical plant models can predict the outcome of plant traits modifications resulting from genetic variations, on plant performance, by simulating physiological processes and their interaction with the environment. Optimization methods complement those models to design ideotypes, that is, ideal values of a set of plant traits, resulting in optimal adaptation for given combinations of environment and management, mainly through the maximization of performance criteria (e.g. yield and light interception). As use of simulation models gains momentum in plant breeding, numerical experiments must be carefully engineered to provide accurate and attainable results, rooting them in biological reality. Here, we propose a multi-objective optimization formulation that includes a metric of performance, returned by the numerical model, and a metric of feasibility, accounting for correlations between traits based on field observations. We applied this approach to two contrasting models: a process-based crop model of sunflower and a functional-structural plant model of apple trees. In both cases, the method successfully characterized key plant traits and identified a continuum of optimal solutions, ranging from the most feasible to the most efficient. The present study thus provides successful proof of concept for this enhanced modelling approach, which identified paths for desirable trait modification, including direction and intensity. PMID- 28626888 TI - Clinical and radiographic evaluation of early loaded narrow-diameter implants: 5 year follow-up of a multicenter prospective clinical study. AB - OBJECTIVE: This study was initiated to evaluate the 5-year implant survival rate and marginal bone levels around a 3.0-mm implant when replacing a single tooth in the anterior region. MATERIALS AND METHODS: The study was designed as a prospective, single-arm, multicenter clinical study. Patients missing 12, 22, 32, 31, 41 or 42 teeth were included, and implants of 3.0 mm diameter and different lengths were placed by a one-stage surgery protocol. Definitive cemented crowns were placed 6-10 weeks later. Clinical and radiographic measurements were taken at implant installation, at loading and at the 6-, 12-, 24-, 36-, 48- and 60 month follow-up visits. RESULTS: Sixty-nine patients with 97 implants were included in this study. Four implants were lost before loading (4.12% failure rate). Implant marginal bone levels did not differ statistically after the 1-year follow-up visit. After 5 years, no bone loss was observed for 50.60% of the implants and only 8.43% of them lost more than 1 mm. Similarly, probing pocket depths and gingival zenith scores did not change significantly. CONCLUSIONS: The use of the two-piece narrow 3.0-mm titanium dental implant for the restoration of upper lateral or lower incisors is safe and results in stable marginal bone levels and probing pocket depths after 5 years of function. PMID- 28626889 TI - From basal cell carcinoma morphogenesis to the alopecia induced by hedgehog inhibitors: connecting the dots. AB - The deciphering of the hedgehog (Hh) signalling pathway implicated in the tumorigenesis of basal cell carcinoma (BCC) led to the development of targeted drug therapies, the Hh pathway inhibitors (HPIs) vismodegib and sonidegib. In the skin, physiological Hh signalling is activated in growing hair follicles (HFs), where it is required for proliferation of the epithelium of HFs during morphogenesis and for their postnatal growth. The effects of HPI treatment leading to the regression of BCC and the development of alopecia underpin the central role of the Hh pathway in BCC formation, as well as hair cycling. Given the fact that BCC is a follicular-driven tumour, it is a fine tuning of events that regulate hair cycling that may drive towards the formation of benign follicular hamartomas or malignant BCC neoplasms. Wnt/beta-catenin signalling interacts with the Hh signalling during HF morphogenesis, normal hair cycling and BCC development. The aim of this review is to present how key molecular events implicated in Hh pathway crosstalk in the HF are also involved in BCC pathogenesis and result in the alopecia developed by HPI treatment. PMID- 28626890 TI - Transcriptomic analysis of rice aleurone cells identified a novel abscisic acid response element. AB - Seeds serve as a great model to study plant responses to drought stress, which is largely mediated by abscisic acid (ABA). The ABA responsive element (ABRE) is a key cis-regulatory element in ABA signalling. However, its consensus sequence (ACGTG(G/T)C) is present in the promoters of only about 40% of ABA-induced genes in rice aleurone cells, suggesting other ABREs may exist. To identify novel ABREs, RNA sequencing was performed on aleurone cells of rice seeds treated with 20 MUM ABA. Gibbs sampling was used to identify enriched elements, and particle bombardment-mediated transient expression studies were performed to verify the function. Gene ontology analysis was performed to predict the roles of genes containing the novel ABREs. This study revealed 2443 ABA-inducible genes and a novel ABRE, designated as ABREN, which was experimentally verified to mediate ABA signalling in rice aleurone cells. Many of the ABREN-containing genes are predicted to be involved in stress responses and transcription. Analysis of other species suggests that the ABREN may be monocot specific. This study also revealed interesting expression patterns of genes involved in ABA metabolism and signalling. Collectively, this study advanced our understanding of diverse cis regulatory sequences and the transcriptomes underlying ABA responses in rice aleurone cells. PMID- 28626892 TI - Letter to the Editor re: 'Long-term complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow-up'. PMID- 28626891 TI - Evaluation of Serum 3-Bromotyrosine Concentrations in Dogs with Steroid Responsive Diarrhea and Food-Responsive Diarrhea. AB - BACKGROUND: The clinical usefulness of serum 3-BrY concentrations for subclassifying dogs with food-responsive diarrhea (FRD) and steroid-responsive diarrhea (SRD) has not been studied. HYPOTHESIS/OBJECTIVES: To compare serum 3 BrY concentrations in dogs with FRD, dogs with SRD, and healthy control dogs. ANIMALS: 38 dogs with FRD, 14 dogs with SRD, and 46 healthy dogs. METHODS: Prospective study. Measurement of 3-BrY concentration in serum samples was performed by gas chromatography/mass spectrometry. RESULTS: There was no association of peripheral eosinophilia in dogs with FRD, SRD, and healthy control dogs (P = 0.069). There was no significant correlation between peripheral eosinophil counts and serum 3-BrY concentrations (rho = -0.15, P = 0.13). Serum 3 BrY concentrations in dogs with SRD (median [range] = 3.27, 0.9-26.23 MUmol/L) were significantly higher than in dogs with FRD (median [range] = 0.99, 0.62-8.82 MUmol/L; P = 0.007) or in healthy dogs (median [range] = 0.62, 0.62-1.79 MUmol/L; P < 0.001). Also, serum 3-BrY concentrations in dogs with FRD were significantly higher than in healthy dogs (P = 0.025). There was no significant correlation between the canine chronic enteropathy clinical activity index and serum 3-BrY concentrations (rho = 0.17, P = 0.23). CONCLUSIONS AND CLINICAL IMPORTANCE: Measurement of serum 3-BrY concentrations, but not the peripheral eosinophil count, is helpful for detecting dogs with SRD and FRD. PMID- 28626893 TI - Random skin biopsy in the diagnosis of intravascular lymphoma. AB - BACKGROUND: Random skin biopsy (RSB) is a method for diagnosis of intravascular lymphoma (IVL). However, the indications for RSB to diagnose IVL have not yet been established. The aim of this study was to determine the appropriate indications for RSB to diagnose IVL. METHODS: Thirty-two patients with fever of unknown origin (FUO) and without skin lesion underwent RSB for diagnosis of IVL. Clinical data, including fever, neurological symptoms, hematologic disorders, organomegaly, bone marrow (BM) study, hypoxemia and serum level of lactate dehydrogenase (LDH), were evaluated. RESULTS: Seven of 32 patients were definitively diagnosed with IVL. In addition to FUO, 2 IVL patients also suffered from dyspnea and neurological disorders. Patients who had FUO with accompanying hematologic disorders, high LDH, negative BM study and no lymphadenopathy or hepatosplenomegaly had a significant tendency to have IVL by RSB (P = .03). FUO with hypoxemia was also identified as a significant indication for RSB (P = .02). CONCLUSIONS: RSB is a reliable method for diagnosis of IVL, especially in patients with FUO and any 1 or more of the 4 following abnormalities: (1) hematologic abnormalities; (2) high serum LDH; (3) hypoxemia; and/or, (4) unusual neurological symptoms with co-existing hematologic abnormalities and without lymphadenopathy, hepatosplenomegaly or BM abnormality. PMID- 28626894 TI - Timing surgery for previa-accreta: patient selection based on a priori risk factors. PMID- 28626895 TI - Khat chewing habit produces a significant adverse effect on periodontal, oral health: A systematic review and meta-analysis. AB - Although there is a general agreement that a khat chewing habit produces clinicopathological changes in the oral mucosa. However there is no reliable evidence of the effects of a khat chewing habit on the periodontal tissues. Thus, authors aimed to investigate the influence of khat chewing habits on periodontal, oral health, by comparing khat chewers to non-chewers in respect of gingival recession, periodontal pocketing depth and loss of attachment. A systematic review and meta-analysis were conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, the Cochrane Library, Web of Science, Scopus and grey literature. The inclusion criteria were all studies with aims of comparing khat chewers and/or sides to non chewers and/or sides in respect of gingival recession, periodontal pocketing depth and loss of attachment. For continuous data, we computed weighted mean difference or standard mean difference analyses. An odds ratio using a random effect model was used if heterogeneity was detected; otherwise, a fixed effects model with a 95% confidence interval was used for continuous data. Two subgroups were analysed: khat chewers vs non-chewers and khat chewer sides vs non-chewer sides of the chewer's individuals. A total of 6373 participants were enrolled in 12 studies (khat chewers=3812, non-chewers=2561). There were statistically significant differences between khat and non-chewers in both subgroup analyses regarding gingival recession, periodontal pocketing depth and loss of attachment (P<.05). The odds ratios for khat chewers compared to non-chewers, in respect of depth of periodontal pocket and gingival recession were 4.797 and 6.853 respectively. The results of this meta-analysis have shown that the khat chewing habit produces a destructive and adverse effect on periodontal, oral health. PMID- 28626896 TI - Gestation length and racing performance in 115 Thoroughbred foals with incomplete tarsal ossification. AB - BACKGROUND: Incomplete ossification of the cuboidal bones of the carpus and tarsus in foals has the potential for significant consequences including chronic lameness and decreased athletic ability. OBJECTIVES: To determine if the degree of ossification of the cuboidal bones is associated with gestational length and if the diagnosis of incomplete ossification is a predictor of performance in Thoroughbred racehorses. STUDY DESIGN: Retrospective cohort study. METHODS: The medical records of Thoroughbred foals less than 90 days of age from 1994 to 2011 were examined and records containing tarsal radiographs identified. Radiographs of the tarsus were examined for signs of incomplete ossification and those that were incompletely ossified graded on a scale of 1-4 using a modification of a previously reported index, with Grade 1 being the least ossified and Grade 4 being the most. Gestational length was determined by examining breeding records and foaling dates reported to the Jockey Club. Race records for 2- and 3-year-old affected foals and their maternal siblings were obtained and compared. RESULTS: Foals with Grades 1 and 2 ossification were usually premature (gestation length <325 days), but Grades 3 and 4 were not. Foals with Grades 2 and 3 ossification were significantly less likely to race than their maternal siblings and Grades 1, 2, 3 and 4 foals earned less money. MAIN LIMITATIONS: A larger sample size of foals with Grade 1 ossification would increase the power of the study. Foals radiographed at an older age may have had lower ossification scores if radiographed earlier. CONCLUSIONS: Incomplete ossification, especially Grades 1 and 2, is associated with a short gestation length. Foals with Grades 2 and 3 incomplete ossification were less likely to race and Grades 1, 2 and 3 earned around $30,000 less than their maternal siblings. PMID- 28626897 TI - Ultrastable Near-Infrared Conjugated-Polymer Nanoparticles for Dually Photoactive Tumor Inhibition. AB - It is highly desired that satisfactory photoactive agents with ideal photophysical characteristics are explored for potent cancer phototherapeutics. Herein, bifunctional nanoparticles of low-bandgap donor-acceptor (D-A)-type conjugated-polymer nanoparticles (CP-NPs) are developed to afford a highly efficient singlet-to-triplet transition and photothermal conversion for near infrared (NIR) light-induced photodynamic (PDT)/photothermal (PTT) treatment. CP NPs display remarkable NIR absorption with the peak at 782 nm, and perfect resistance to photobleaching. Photoexcited CP-NPs undergo singlet-to-triplet intersystem crossing through charge transfer in the excited D-A system and simultaneous nonradiative decay from the electron-deficient electron acceptor isoindigo derivative under single-wavelength NIR light irradiation, leading to distinct singlet oxygen quantum yield and high photothermal conversion efficiency. Moreover, the CP-NPs display effective cellular uptake and cytoplasmic translocation from lysosomes, as well as effective tumor accumulation, thus promoting severe light-triggered damage caused by favorable reactive oxygen species (ROS) generation and potent hyperthermia. Thus, CP-NPs achieve photoactive cell damage through their photoconversion ability for synergistic PDT/PTT treatment with tumor ablation. The proof-of-concept design of D-A-type conjugated-polymer nanoparticles with ideal photophysical characteristics provides a general approach to afford potent photoactive cancer therapy. PMID- 28626898 TI - Polo-like kinase-1 immunoreactivity is associated with metastases in cutaneous melanoma. AB - BACKGROUND: Polo-like kinase-1 (PLK-1) is one of the key regulators of cell cycle progression. Increased expression of PLK-1 was observed in several tumor types. METHODS: We immunohistochemically assessed PLK-1 expression in neoplastic and stromal compartments of 96 cutaneous melanomas, and analyzed associations between PLK-1 expression and clinicopathological characteristics. RESULTS: PLK-1 expression in cancer cells was not associated with basic clinical (eg, age, gender and tumor location) or histopathological (eg, Breslow thickness, mitotic rate and ulceration) parameters. However, increased PLK-1 was more frequent in tumors with concurrent regional nodal metastases and positive sentinel lymph node biopsy status. All primary tumors associated with co-existing distant metastases exhibited high PLK-1 expression in melanoma cells. Conversely, PLK-1 expression in stromal cells was more frequent in tumors without nodal metastases. PLK-1 expression in both compartments was not associated with survival. CONCLUSION: PLK 1 expression is associated with metastatic potential in cutaneous melanoma. PMID- 28626899 TI - Consideration of the presence of inflammation is essential for interpretation of serum micronutrient results. PMID- 28626900 TI - Oral ofloxacin and clindamycin as an alternative to the classic rifampicin clindamycin in hidradenitis suppurativa: retrospective analysis of 65 patients. PMID- 28626901 TI - Elevated levels of serum IgM anti-phosphatidylserine-prothrombin complex antibodies in patients with cancer-associated vasculitis. PMID- 28626902 TI - Haemophilus influenzae oral vaccination for preventing acute exacerbations of chronic bronchitis and chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic bronchitis and chronic obstructive pulmonary disease (COPD) are serious conditions in which patients are predisposed to viral and bacterial infections resulting in potentially fatal acute exacerbations. Chronic obstructive pulmonary disease is defined as a lung disease characterised by obstruction to lung airflow that interferes with normal breathing. Antibiotic therapy has not been particularly useful in eradicating bacteria such as non typeable Haemophilus influenzae (NTHi) because they are naturally occurring flora of the upper respiratory tract in many people. However, they can cause opportunistic infection. An oral NTHi vaccine has been developed to protect against recurrent infective acute exacerbations in chronic bronchitis. OBJECTIVES: To assess the effectiveness of an oral, whole-cell NTHi vaccine in protecting against recurrent episodes of acute exacerbations of chronic bronchitis and COPD in adults. To assess the effectiveness of NTHi vaccine in reducing NTHi colonising the respiratory tract during recurrent episodes of acute exacerbations of COPD. SEARCH METHODS: We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), CINAHL (1981 to January 2017), LILACS (1985 to January 2017), and Web of Science (1955 to January 2017). We also searched trials registries and contacted authors of trials requesting unpublished data. SELECTION CRITERIA: We included randomised controlled trials comparing the effects of an oral monobacterial NTHi vaccine in adults with recurrent acute exacerbations of chronic bronchitis or COPD when there was overt matching of the vaccine and placebo groups on clinical grounds. The selection criteria considered populations aged less than 65 years and those older than 65 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data from original records and publications for incidence and severity of bronchitis episodes and carriage rate of NTHi measured in the upper respiratory tract, as well as data relevant to other primary and secondary outcomes. MAIN RESULTS: We identified six placebo-controlled randomised controlled trials with a total of 557 participants. These trials investigated the efficacy of enteric-coated, killed preparations of H influenzae in populations prone to recurrent acute exacerbations of chronic bronchitis or COPD. The vaccine preparation and immunisation regimen in all trials consisted of at least three courses of formalin-killed H influenzae in enteric-coated tablets taken at intervals (e.g. days 0, 28, and 56). Each course generally consisted of two tablets taken after breakfast over three consecutive days. In all cases the placebo groups took enteric-coated tablets containing glucose. Risk of bias was moderate across the studies, namely due to the lack of information provided about methods and inadequate presentation of results.Meta-analysis of the oral NTHi vaccine showed a small, non-statistically significant reduction in the incidence of acute exacerbations of chronic bronchitis or COPD (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.57 to 1.10; P = 0.16). There was no significant difference in mortality rate between the vaccine and placebo groups (odds ratio (OR) 1.62, 95% CI 0.63 to 4.12; P = 0.31).We were unable to meta-analyse the carriage levels of NTHi in participants as each trial reported this result using different units and tools of measurement. Four trials showed no significant difference in carriage levels, while two trials showed a significant decrease in carriage levels in the vaccinated group compared with the placebo group.Four trials assessed severity of exacerbations measured by requirement for antibiotics. Three of these trials were comparable and when meta-analysed showed a statistically significant 80% increase in antibiotic courses per person in the placebo group (RR 1.81, 95% CI 1.35 to 2.44; P < 0.001). There was no significant difference between the groups with regard to hospital admission rates (OR 0.96, 95% CI 0.13 to 7.04; P = 0.97). Adverse events were reported in five trials but were not necessarily related to the vaccine; a point estimate is suggestive that they occurred more frequently in the vaccine group, however this result was not statistically significant (RR 1.43, 95% CI 0.70 to 2.92; P = 0.87). Quality of life was not meta-analysed but was reported in two trials, with results at six months showing an improvement in quality of life in the vaccinated group (scoring at least two points better than placebo). AUTHORS' CONCLUSIONS: Analyses demonstrate that NTHi oral vaccination of people with recurrent exacerbations of chronic bronchitis or COPD does not yield a significant reduction in the number and severity of exacerbations. Evidence was mixed, and the individual trials that showed a significant benefit of the vaccine are too small to advocate widespread oral vaccination of people with COPD. PMID- 28626903 TI - Economical Sponge Phantom for Teaching, Understanding, and Researching A- and B Line Reverberation Artifacts in Lung Ultrasound. AB - This project evaluated a low-cost sponge phantom setup for its capability to teach and study A- and B-line reverberation artifacts known from lung ultrasound and to numerically simulate sound wave interaction with the phantom using a finite-difference time-domain (FDTD) model. Both A- and B-line artifacts were reproducible on B-mode ultrasound imaging as well as in the FDTD-based simulation. The phantom was found to be an easy-to-set up and economical tool for understanding, teaching, and researching A- and B-line artifacts occurring in lung ultrasound. The FDTD method-based simulation was able to reproduce the artifacts and provides intuitive insight into the underlying physics. PMID- 28626904 TI - Do real world data support and extend our ability to predict reverse remodelling following cardiac resynchronization therapy based on QRS morphology and width? PMID- 28626905 TI - Genome architecture enables local adaptation of Atlantic cod despite high connectivity. AB - Adaptation to local conditions is a fundamental process in evolution; however, mechanisms maintaining local adaptation despite high gene flow are still poorly understood. Marine ecosystems provide a wide array of diverse habitats that frequently promote ecological adaptation even in species characterized by strong levels of gene flow. As one example, populations of the marine fish Atlantic cod (Gadus morhua) are highly connected due to immense dispersal capabilities but nevertheless show local adaptation in several key traits. By combining population genomic analyses based on 12K single nucleotide polymorphisms with larval dispersal patterns inferred using a biophysical ocean model, we show that Atlantic cod individuals residing in sheltered estuarine habitats of Scandinavian fjords mainly belong to offshore oceanic populations with considerable connectivity between these diverse ecosystems. Nevertheless, we also find evidence for discrete fjord populations that are genetically differentiated from offshore populations, indicative of local adaptation, the degree of which appears to be influenced by connectivity. Analyses of the genomic architecture reveal a significant overrepresentation of a large ~5 Mb chromosomal rearrangement in fjord cod, previously proposed to comprise genes critical for the survival at low salinities. This suggests that despite considerable connectivity with offshore populations, local adaptation to fjord environments may be enabled by suppression of recombination in the rearranged region. Our study provides new insights into the potential of local adaptation in high gene flow species within fine geographical scales and highlights the importance of genome architecture in analyses of ecological adaptation. PMID- 28626906 TI - Behavioural implications of traditional treatment and closed-loop automated insulin delivery systems in Type 1 diabetes: applying a cognitive restraint theory framework. AB - As the prevalence of obesity in Type 1 diabetes rises, the effects of emerging therapy options should be considered in the context of both weight and glycaemic control outcomes. Artificial pancreas device systems will 'close the loop' between blood glucose monitoring and automated insulin delivery and may transform day-to-day dietary management for people with Type 1 diabetes in multiple ways. In the present review, we draw directly from cognitive restraint theory to consider unintended impacts that closed-loop systems may have on ingestive behaviour and food intake. We provide a brief overview of dietary restraint theory and its relation to weight status in the general population, discuss the role of restraint in traditional Type 1 diabetes treatment, and lastly, use this restraint framework to discuss the possible behavioural implications and opportunities of closed-loop systems in the treatment of Type 1 diabetes. We hypothesize that adopting closed-loop systems will lift the diligence and restriction that characterizes Type 1 diabetes today, thus requiring a transition from a restrained eating behaviour to a non-restrained eating behaviour. Furthermore, we suggest this transition be leveraged as an opportunity to teach people lifelong eating behaviour to promote healthy weight status by incorporating education and cognitive reappraisal. Our aim was to use a transdisciplinary approach to highlight critical aspects of the emerging closed loop technologies relating to eating behaviour and weight effects and to promote discussion of strategies to optimize long-term health in Type 1 diabetes via two key outcomes: glycaemic control and weight management. PMID- 28626907 TI - Controlled population-based comparative study of USA and international adult [55 74] neurological deaths 1989-2014. AB - OBJECTIVES: A population-based controlled study to determine whether adult (55-74 years) neurological disease deaths are continuing to rise and are there significant differences between America and the twenty developed countries 1989 91 and 2012-14. METHOD: Total Neurological Deaths (TND) rates contrasted against control Cancer and Circulatory Disease Deaths (CDD) extrapolated from WHO data. Confidence intervals compare USA and the other countries over the period. The Over-75's TND and population increases are examined as a context for the 55-74 outcomes. RESULTS: Male neurological deaths rose >10% in eleven countries, the other countries average rose 20% the USA 43% over the period. Female neurological deaths rose >10% in ten counties, averaging 14%, the USA up 68%. USA male and female neurological deaths increased significantly more than twelve and seventeen countries, respectively. USA over-75s population increased by 49%, other countries 56%. Other countries TND up 187% the USA rose fourfold. Male and female cancer and CDD fell in every country averaging 26% and 21%, respectively, and 64% and 67% for CDD. Male neurological rates rose significantly more than Cancer and CCD in every country; Female neurological deaths rose significantly more than cancer in 17 countries and every country for CDD. There was no significant correlation between increases in neurological deaths and decreases in control mortalities. CONCLUSIONS: There are substantial increases in neurological deaths in most countries, significantly so in America. Rises in the 55-74 and over-75's rates are not primarily due to demographic changes and are a matter of concern warranting further investigation. PMID- 28626908 TI - Challenges and Perspectives for NASICON-Type Electrode Materials for Advanced Sodium-Ion Batteries. AB - Sodium-ion batteries (SIBs) have attracted increasing attention in the past decades, because of high overall abundance of precursors, their even geographical distribution, and low cost. Apart from inherent thermodynamic disadvantages, SIBs have to overcome multiple kinetic problems, such as fast capacity decay, low rate capacities and low Coulombic efficiencies. A special case is sodium super ion conductor (NASICON)-based electrode materials as they exhibit - besides pronounced structural stability - exceptionally high ion conductivity, rendering them most promising for sodium storage. Owing to the limiting, comparatively low electronic conductivity, nano-structuring is a prerequisite for achieving satisfactory rate-capability. In this review, we analyze advantages and disadvantages of NASICON-type electrode materials and highlight electrode structure design principles for obtaining the desired electrochemical performance. Moreover, we give an overview of recent approaches to enhance electrical conductivity and structural stability of cathode and anode materials based on NASICON structure. We believe that this review provides a pertinent insight into relevant design principles and inspires further research in this respect. PMID- 28626909 TI - Adaptation During a Great Economic Recession: A Cohort Study of Greek and Immigrant Youth. AB - This study examined how Greek and immigrant youth adapted to school life during the economic recession in Greece. Two cohorts of adolescents (Mage = 12.6 years) were compared, one assessed before the crisis and the other during the crisis (N = 1,057 and 1,052, respectively). Cohort findings were disaggregated by immigrant status, generation, and ethnic group. Crisis-cohort youth experienced more economic problems, displayed worse conduct, higher levels of absenteeism, and lower self-efficacy than precrisis youth. The cohorts did not differ in well being, school engagement, and academic achievement. Most crisis-cohort groups showed a pervasive increase in conduct problems compared to the precrisis cohort. However, some of these groups also showed an increase in academic achievement. PMID- 28626910 TI - Intravenous and Intracavitary Use of Contrast-Enhanced Ultrasound in the Evaluation and Management of Complicated Pediatric Pneumonia. AB - Pediatric pneumonia can be complicated by necrotizing pneumonia or a parapneumonic effusion either in the form of an empyema or a clear effusion. Ultrasonography (US) and computed tomography represent well-established modalities for evaluation of complicated pediatric pneumonia. Contrast-enhanced ultrasound (CEUS) was recently introduced and is gaining increasing acceptance in pediatric imaging. In this case series, we present our initial experience with both intravenous and intracavitary use of CEUS in children with complicated pneumonia. Intravenous CEUS accurately and confidently showed necrotizing pneumonia and delineated pleural effusions, whereas intracavitary CEUS accurately identified the chest catheter location and patency and showed the presence of loculations, suggesting the use of fibrinolytics. PMID- 28626911 TI - Clinical findings and management of 153 horses with large colon sand accumulations. AB - OBJECTIVE: To determine the influence of radiographic quantification of sand accumulation on the medical versus surgical management of large colon sand accumulations. To compare short- and long-term outcomes and complications associated with medical and surgical management of these horses. STUDY DESIGN: Retrospective. SAMPLE POPULATION: A total of 153 horses. METHODS: Medical records and abdominal radiographs of horses presented for colic between 2004 and 2014 were reviewed. Severity of sand accumulation was quantified by tracing and measuring a region of interest with a commercial software program. Breed, weight, amount of sand, presence of diarrhea at presentation, treatment, and the development of complications were recorded. RESULTS: Records from 153 horses were reviewed. The mean cross-sectional area of sand accumulation was 692.9 cm2 (median = 658.7 cm2 , 84.6-1780.7 cm2 ). Increased accumulation of gas on radiographs and abnormal transrectal examination findings were associated with an increased likelihood of surgery. The most common complication was the development of diarrhea (20.3%) with only 4 (2.6%) horses positive for Salmonella spp. Horses had a favorable prognosis, with 94.8% of horses treated medically and 94.7% of those treated surgically surviving to discharge. CONCLUSION: Increased accumulation of gas on radiographs and transrectal palpation of impaction or intestinal gas distension increase the likelihood of surgery. Both medical and surgical treatments carry a good prognosis. CLINICAL RELEVANCE: The sheer quantity of sand is not a factor when determining surgical intervention. Attention should be paid to the presence of increased gas accumulation on rectal or radiographic examination. PMID- 28626912 TI - Structural Characterisation of Acetogenins from Annona muricata by Supercritical Fluid Chromatography Coupled to High-Resolution Tandem Mass Spectrometry. AB - INTRODUCTION: Acetogenins are plant polyketides known to be cytotoxic and proposed as antitumor candidates. They are also suspected to be alimentary neurotoxins. Their occurrence as complex mixtures renders their dereplication and structural identification difficult using liquid chromatography coupled to tandem mass spectrometry and efforts are required to improve the methodology. OBJECTIVE: To develop a supercritical fluid chromatography (SFC) high-resolution tandem mass spectrometry method, involving lithium post-column cationisation, for the structural characterisation of Annonaceous acetogenins in crude extracts. METHODOLOGY: The seeds of Annona muricata L. were extracted with methanol. Supercritical fluid chromatography of the extract, using a 2-ethylpyridine stationary phase column, was monitored using a high-resolution quadrupole time-of flight mass spectrometer. Lithium iodide was added post-column in the make-up solvent. For comparison, the same extract was analysed using high-pressure liquid chromatography coupled to the same mass spectrometer, with a column based on solid core particles. RESULTS: Sensitivity was similar for both HPLC and SFC approaches. Retention behaviour and fragmentation pathways of three different isomer groups are described. A previously unknown group of acetogenins was also evidenced for the first time. CONCLUSION: The use of SFC-MS/MS allows the reduction of the time of analysis, of environmental impact and an increase in the chromatographic resolution, compared to liquid chromatography. This new methodology enlightened a new group of acetogenins, isomers of montanacin-D. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28626913 TI - Reply to: Sorbello et al., PONV in bariatric surgery: time for opioid-free anaesthesia. PMID- 28626914 TI - Synthesis, preclinical, and pharmacokinetic evaluation of a new zoledronate derivative as a promising antiosteoporotic candidate using radiolabeling technique. AB - A novel zoledronic acid (ZL) derivative, 3-(2-ethyl-4-methyi-1H-imidazole-1-yl)-1 hydroxy-1-phosphonopropyl phosphonic acid (EMIHPBP), was synthesized, characterized, and successfully radiolabeled with 99m Tc. The in vivo biodistribution of 99m Tc-EMIHPBP was investigated and compared with the previously reported zoledronate derivatives aiming to formulate a novel zoledronate derivative with a high-potential uptake to bone as a promising antiosteoporotic candidate. To further evaluate the bone uptake efficiency, the pharmacokinetics of 99m Tc-EMIHPBP was investigated and showed that maximum concentration in bone (Cmax ) was 31.60 +/- 0.15%ID/gram after 60 minutes (tmax ). Cumulative residence of 99m Tc-EMIHPBP in the bone [AUC (0-infinity) (%ID?min/gram bone)] was 3685.23, mean residence time was 384.354 minutes, and the calculated bone bioavailability was 15.831%. Finally, the time needed for half of the 99m Tc-EMIHPBP formulation to be eliminated from bone (t1/2 ) was 263.914 minutes. Excellent bone uptake can be obtained 1-hour postinjection with high bone/blood ratio of 23.76 detected with gamma counter. The biodistribution and kinetic studies could recommend EMIHPBP as a promising antiosteoporotic candidate with high selectivity to the skeletal system and rapid clearance from soft tissues. PMID- 28626915 TI - Editorial covering DDW 2017 (6-9 May 2017). PMID- 28626916 TI - Joseph Rudinger memorial lecture: Unexpected functions of angiotensin converting enzyme, beyond its enzymatic activity. AB - Angiotensin converting enzyme (ACE) is a well-known enzyme, largely studied for its action on hypertension, as it produces angiotensin II from angiotensin I. This paper describes two original behaviours of ACE. We showed that ACE could hydrolyse gastrin, a neuropeptide from the gastrointestinal tract, releasing the C-terminal amidated dipeptide H-Asp-Phe-NH2 . This dipeptide is believed to be involved in the gastrin-induced acid secretion in the stomach. This hypothetic mechanism of action of gastrin resulted in a strategy to rationally design gastrin receptor antagonists. Beyond, we showed that the brain renin angiotensin system (RAS) could be activated by a new characterized peptide named acein, resulting in stimulation of dopamine release within the striatum. This new and original 'receptor-like' activity for brain membrane-bound ACE is quite significant taking into account the role of dopamine in the brain, particularly in neurodegenerative diseases. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28626917 TI - Comments regarding "four cases of mucous membrane pemphigoid with clinical features of oral lichen planus". PMID- 28626918 TI - Marinesco bodies and substantia nigra neuron density in Parkinson's disease. AB - AIM: Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. METHODS: Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. RESULTS: Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein epsilon4 alleles. CONCLUSIONS: While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes. PMID- 28626919 TI - Letter to the Editor. PMID- 28626920 TI - Experimental verification of EGSnrc Monte Carlo calculated depth doses within a realistic parallel magnetic field in a polystyrene phantom. AB - PURPOSE: Integrating a linac with a magnetic resonance imager (MRI) will revolutionize the accuracy of external beam radiation treatments. Irradiating in the presence of a strong magnetic field, however, will modify the dose distribution. These dose modifications have been investigated previously, mainly using Monte Carlo simulations. The purpose of this work is to experimentally verify the use of the EGSnrc Monte Carlo (MC) package for calculating percent depth doses (PDDs) in a homogeneous phantom, in the presence of a realistic parallel magnetic field. METHODS: Two cylindrical electromagnets were used to produce a 0.207 T magnetic field parallel to the central axis of a 6 MV photon beam from a clinical linac. The magnetic field was measured at discrete points along orthogonal axes, and these measurements were used to validate a full 3D magnetic field map generated using COMSOL Multiphysics. Using a small parallel plate ion chamber, the depth dose was measured in a polystyrene phantom placed inside the electromagnet bore at two separate locations: phantom top surface coinciding with top of bore, and phantom top surface coinciding with center of bore. BEAMnrc MC was used to model the linac head which was benchmarked against the linac's commissioning measurements. The depth dose in polystyrene was simulated using DOSXYZnrc MC. For the magnetic field case, the DOSXYZnrc code was slightly modified to implement the previously calculated 3D magnetic field map to be used in the standard electromagnetic macros. RESULTS: The calculated magnetic field matched the measurements within 2% of the maximum central field (0.207 T) with most points within the experimental uncertainty (1.5%). For the MC linac head model, over 93% of all simulated points passed the 2%, 2 mm gamma acceptance criterion, when comparing measured and simulated lateral beam and depth dose profiles. The parallel magnetic field caused a surface dose increase, compared to the no magnetic field case, due to the Lorentz force confining contaminant electrons within the beam. The surface dose increase was measured to be approximately 10% (relative to no field Dmax ) when the phantom surface coincided with the top of the electromagnet's bore. This effect was enhanced by moving the phantom surface to the center of the magnet's bore in relatively high magnetic field (> 0.13 T). The surface dose for this setup increased by 30% and the entire buildup region was affected. When the dimensions and composition of the ion chamber air cavity and entrance window were included, EGSnrc was able to accurately simulate these dose increases, both at the surface and in the buildup region. All the simulated points were within 1% of the measurements for both setups. The ferromagnetic linac head was determined to have a negligible effect on the final PDD comparison. CONCLUSIONS: Irradiating in the presence of a parallel magnetic field causes measurable surface and buildup depth dose increases. We have experimentally verified that the EGSnrc Monte Carlo package is able to accurately calculate the PDDs with these surface and buildup dose modifications in a homogeneous phantom. PMID- 28626921 TI - The Arts as a Venue for Developmental Science: Realizing a Latent Opportunity. AB - Children in all cultures readily engage in artistic activities, yet the arts (dance, drama, drawing, and music) have traditionally been marginal topics in the discipline of developmental science. We argue that developmental psychologists cannot afford to ignore such naturalistic activities that involve so many basic phenomena-attention, engagement, motivation, emotion regulation, understanding of others, and so on. Despite historical issues with research methodologies and overdrawn conclusions, a current wave of methodologically rigorous studies shows the depth of arts learning, as well as how arts engagement can be harnessed for transfer to other skills. Here, we present 21 exemplary research case studies, covering an age range of 18 months to 17 years old and discuss how the arts are no more difficult to study than other real-world developmental phenomena and deserve a thorough examination. PMID- 28626922 TI - The importance of risk communication and documentation for patients with cutaneous adverse drug reactions. PMID- 28626923 TI - Comparative performance of deciduous and permanent dental morphology in detecting biological relatives. AB - OBJECTIVES: Dental morphology plays a key role in reconstructing population history and evolutionary relationships at global, regional, and intracemetery scales. At the inter-individual level, it is assumed that close biological kin exhibit greater phenotypic similarity than non-relatives. Heritability estimates provide one measure of phenotypic resemblance but are not easily incorporated into analyses of archaeological samples. In this study we evaluate the assumption that relatives are more similar phenotypically than non-relatives. We compare results for permanent dental morphology to those obtained using deciduous dental morphology in a matched dataset (Paul & Stojanowski, ). MATERIALS AND METHODS: Permanent trait expression was scored from dental casts representing 69 sibling pairs, curated as part of the longitudinal Burlington Growth Study. Simulating a biodistance approach, 22 morphological traits of permanent tooth crowns were used to generate 69 inter-relative and 2,076 non-relative Euclidean distances. Following distance ordination, family-specific dispersion values were calculated from multidimensional scaling coordinates. Output was compared to that of a previous study that focused on deciduous crown variation in the same set of individuals (Paul & Stojanowski, ). Mantel tests were used to evaluate the correlation of a proxy genetic distance matrix to both the permanent and deciduous dental distance matrices. RESULTS: On average, inter-relative distances generated from morphological traits of permanent tooth crowns were smaller than expected by chance based on resampling (p < 0.001). While family-specific dispersion varied greatly for both permanent and deciduous datasets, over 75% of the families exhibited greater dispersion with permanent traits. This suggests that morphological traits of the permanent dentition provide a less faithful reflection of biological relatedness than morphological traits of the deciduous dentition. Mantel tests indicate that both the deciduous and permanent distance matrices are significantly correlated with a matrix of genetic relatedness coefficients; however, the magnitude of the correlations was low. DISCUSSION: Overall, morphological traits of permanent tooth crowns perform moderately well in distinguishing relatives from non-relatives, but deciduous crown variations may provide a more direct reflection of the underlying genetic structure of intra site or intra-cemetery samples. These findings have implications for bioarchaeological research and biodistance practices. In particular, morphological traits of the deciduous dentition should be incorporated into standard data collection protocols because of their stronger signal of relatedness. PMID- 28626925 TI - Stoichiometric analysis of oligomeric states of three class-A GPCRs, chemokine CXCR4, dopamine-D2, and prostaglandin-EP1 receptors, on living cells. AB - G-protein-coupled receptors (GPCRs) form the largest family of transmembrane receptors, and their oligomerization has been suggested to be related to their functions. Despite extensive studies, their oligomeric states are highly controversial. One of the reasons is the overestimation of oligomerization by conventional methods. We recently established a stoichiometric analysis method for precisely determining the oligomeric state of membrane proteins on living cells with the combined use of the coiled-coil labeling method and a spectral imaging technique and showed that the prototypical class-A GPCR beta2 -adrenergic receptor (beta2 AR) did not form functional oligomers. In this study, we expanded our study to three well-studied class-A GPCRs: C-X-C chemokine receptor of stromal cell-derived factor-1alpha (CXCR4), dopamine receptor D2 short isotype (D2R), and prostaglandin E receptor subtype 1 (EP1R). We found that these receptors did not form constitutive homooligomers. The receptors exhibited calcium signaling upon agonist stimulation as monomers, although CXCR4 and EP1R gradually clustered after fast signaling. We conclude that homooligomerization is not necessary for the signal transductions of these four class-A GPCRs. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28626926 TI - Angiotensin-converting enzyme gene rs4343 polymorphism increases susceptibility to migraine. PMID- 28626924 TI - Group 2 ILCs: A way of enhancing immune protection against human helminths? AB - Group 2 innate lymphoid cells (ILC2s) play crucial roles in type 2 immune responses associated with allergic and autoimmune diseases, viral and helminth infections and tissue homoeostasis. Experimental models show that in helminth infections ILC2s provide an early source of type 2 cytokines and therefore are essential for the induction of potentially protective type 2 responses. Much of our knowledge of ILC2s in helminth infections has come from experimental mouse models with very few studies analysing ILC2s in natural human infections. In attempts to harness knowledge from paradigms of the development of protective immunity in human helminth infections for vaccine development, the role of ILC2 cells could be pivotal. So far, potential vaccines against human helminth infections have failed to provide effective protection when evaluated in human studies. In addition to appropriate antigen selection, it is apparent that more detailed knowledge on mechanisms of induction and maintenance of protective immune responses is required. Therefore, there is need to understand how ILC2 cells induce type 2 responses and subsequently support the development of a protective immune response in the context of immunizations. Within this review, we summarize the current knowledge of the biology of ILC2s, discuss the importance of ILC2s in human helminth infections and explore how ILC2 responses could be boosted to efficiently induce protective immunity. PMID- 28626927 TI - Carbon Nanotube-Multilayered Graphene Edge Plane Core-Shell Hybrid Foams for Ultrahigh-Performance Electromagnetic-Interference Shielding. AB - Materials with an ultralow density and ultrahigh electromagnetic-interference (EMI)-shielding performance are highly desirable in fields of aerospace, portable electronics, and so on. Theoretical work predicts that 3D carbon nanotube (CNT)/graphene hybrids are one of the most promising lightweight EMI shielding materials, owing to their unique nanostructures and extraordinary electronic properties. Herein, for the first time, a lightweight, flexible, and conductive CNT-multilayered graphene edge plane (MLGEP) core-shell hybrid foam is fabricated using chemical vapor deposition. MLGEPs are seamlessly grown on the CNTs, and the hybrid foam exhibits excellent EMI shielding effectiveness which exceeds 38.4 or 47.5 dB in X-band at 1.6 mm, while the density is merely 0.0058 or 0.0089 g cm-3 , respectively, which far surpasses the best values of reported carbon-based composite materials. The grafted MLGEPs on CNTs can obviously enhance the penetration losses of microwaves in foams, leading to a greatly improved EMI shielding performance. In addition, the CNT-MLGEP hybrids also exhibit a great potential as nano-reinforcements for fabricating high-strength polymer-based composites. The results provide an alternative approach to fully explore the potentials of CNT and graphene, for developing advanced multifunctional materials. PMID- 28626928 TI - Predictors for secondary therapy after surgical resection of nonfunctioning pituitary adenomas. AB - OBJECTIVE: Factors determining recurrence of nonfunctioning pituitary adenomas (NFAs) that require further therapy are unclear as are postoperative follow-up imaging guidelines. We aimed to identify predictors for secondary therapy after surgical resection of NFAs and use this knowledge to inform postoperative management. DESIGN AND PATIENTS: A single-centre retrospective study of surgically resected NFAs in 108 patients followed for up to 15 years. Serial tumour images were analysed for size, location and growth rate (GR) and tissue analysed for hormone cell type and proliferation indices with secondary treatment as outcome measure. RESULTS: Twenty-four of 66 (36%) patients harbouring a postoperative remnant required secondary treatment, all occurring within 10 years. No secondary treatment was required in any of 42 patients with complete tumour resection. Age, gender, remnant volume and tumour histology were not different between patients requiring and not requiring secondary therapy. Remnant GRs in those requiring secondary therapy were more than 10-fold higher (P<.01). Tumours with a GR >=80 mm3 /y (Hazard Ratio[HR]: 8.1, Confidence Interval [CI]: 2.4-27.3,P<.01) and those located in the suprasellar region (HR: 6.1, CI: 1.1-32, P=.03) had a higher risk for secondary therapy. Tumour GR in the first three postoperative years correlated significantly (r2 =.6, P<.01) with GR during the period of follow-up. CONCLUSION: In surgically resected NFAs further treatment is dependent on the presence of residual tumour, growth rate and location but not tumour histology. Postoperative growth rate of NFAs in the first 3 years of imaging can be used to tailor long-term follow-up to optimize use of health resources. PMID- 28626929 TI - Successful liver transplantation for non-resectable desmoplastic nested spindle cell tumor complicated by Cushing's syndrome. AB - Desmoplastic spindle cell tumors of liver are rare tumors of low malignant potential characterized by well-demarcated nests of spindle and epithelioid cells in a dense desmoplastic stroma. While surgery remains the definitive treatment, there have been reports of tumor recurrence locally and metastasis which respond poorly to chemotherapy. Hepatic transplant has been attempted in cases of recurrence or large size of primary tumor. Long-term follow-up and imaging surveillance are required as these tumors have shown a tendency for recurrence many years after initial therapy. PMID- 28626930 TI - Commentary: Positive Youth Development Goes Mainstream. AB - Evidence has accumulated that confirms the success of a positive youth development (PYD) approach. Importantly, a positive development approach is just that-an approach. It is not a particular program or curriculum but a set of practices designed to achieve one or more positive outcomes. As such, PYD practices can be added onto other programs to make positive outcomes more likely. For example, a tutoring program can work hard to hire and train staff to work with students in a trusting, respectful relationship. Camp counselors can be encouraged to build rapport and positive bonds among the campers. PMID- 28626931 TI - Insecticide resistance and intracellular proteases. AB - Pesticide resistance is an example of evolution in action with mechanisms of resistance arising from mutations or increased expression of intrinsic genes. Intracellular proteases have a key role in maintaining healthy cells and in responding to stressors such as pesticides. Insecticide-resistant insects have constitutively elevated intracellular protease activity compared to corresponding susceptible strains. This increase was shown for some cases originally through biochemical enzyme studies and subsequently putatively by transcriptomics and proteomics methods. Upregulation and expression of proteases have been characterised in resistant strains of some insect species, including mosquitoes. This increase in proteolysis results in more degradation products (amino acids) of intracellular proteins. These may be utilised in the resistant strain to better protect the cell from stress. There are changes in insect intracellular proteases shortly after insecticide exposure, suggesting a role in stress response. The use of protease and proteasome inhibitors or peptide mimetics as synergists with improved application techniques and through protease gene knockdown using RNA interference (possibly expressed in crop plants) may be potential pest management strategies, in situations where elevated intracellular proteases are relevant. (c) 2017 Society of Chemical Industry. PMID- 28626932 TI - Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization. AB - Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. PMID- 28626933 TI - Conductive Carbon Nitride for Excellent Energy Storage. AB - Conductive carbon nitride, as a hypothetical carbon material demonstrating high nitrogen doping, high electrical conductivity, and high surface area, has not been fabricated. A major challenge towards its fabrication is that high conductivity requires high temperature synthesis, but the high temperature eliminates nitrogen from carbon. Different from conventional methods, a facile preparation of conductive carbon nitride from novel thermal decomposition of nickel hydrogencyanamide in a confined space is reported. New developed nickel hydrogencyanamide is a unique precursor which provides self-grown fragments of ?N?C?N? or N?C?C?N and conductive carbon (C-sp2 ) catalyst of Ni metal during the decomposition. The final product is a tubular structure of rich mesoporous and microporous few-layer carbon with extraordinarily high N doping level (~15 at%) and high extent of sp2 carbon (~65%) favoring a high conductivity (>2 S cm-1 ); the ultrahigh contents of nongraphitic nitrogen, redox active pyridinic N (9 at%), and pyrrolic N (5 at%), are stabilized by forming Ni?N bonds. The conductive carbon nitride harvests a large capacitance of 372 F g-1 with >90% initial capacitance after 10 000 cycles as a supercapacitor electrode, far exceeding the activated carbon electrodes that have <250 F g-1 . PMID- 28626934 TI - Thermal physiology: A new dimension of the pace-of-life syndrome. AB - Current syndrome research focuses primarily on behaviour with few incorporating components of physiology. One such syndrome is the pace-of-life syndrome (POLS) which describes covariation between behaviour, metabolism, immunity, hormonal response, and life-history traits. Despite the strong effect temperature has on behaviour, thermal physiology has yet to be considered within this syndrome framework. We proposed the POLS to be extended to include a new dimension, the cold-hot axis. Under this premise, it is predicted that thermal physiology and behaviour would covary, whereby individual positioning along the thermal continuum would coincide with that of the behavioural continuum. This hypothesis was tested by measuring thermal traits of delicate skinks (Lampropholis delicata) and linking it to their behaviour. Principal components analysis and structural equation modelling were used to determine if traits were structured within the POLS and to characterize the direction of their interactions. Model results supported the inclusion of the cold-hot axis into the POLS and indicated that thermal physiology was the driver of this relationship, in that thermal traits either constrained or promoted activity, exploration, boldness and social behaviour. This study highlights the need to integrate thermal physiology within a syndrome framework. PMID- 28626935 TI - Editorial Comment to Substitution urethroplasty using oral mucosa graft for male anterior urethral stricture disease: Current topics and reviews. PMID- 28626936 TI - A pilot study comparing histological and immunophenotypic patterns in stage 4 skin graft vs host disease from toxic epidermal necrolysis. AB - BACKGROUND: Stage 4 skin graft-versus-host disease (GVHD) is associated with poor prognosis and high mortality rates. Clinical and histologic similarities with toxic epidermal necrolysis (TEN) make it difficult to distinguish between these 2 life-threatening conditions. METHODS: A retrospective cohort study was conducted from a tertiary referral center. Skin biopsies were obtained from 11 patients who developed stage 4 skin GVHD and 11 patients who developed TEN between 2005 and 2012. The CD8+/CD4+ T lymphocyte ratios were assessed in lesional skin specimens. RESULTS: Average CD8+and CD4+ cell counts co-expressing CD3 were 126.29 (range 86.42-173.06) and 84.60 (29.87-197.20) for stage 4 skin GVHD patients, and 61.97 (45.79-146.67) and 7.65 (0.00-39.50) for TEN patients, respectively. Immunohistochemical studies of stage 4 skin GVHD and TEN skin demonstrated average CD8+/CD4+ ratios of 1.78 (range 0.69-3.09) and 7.33 (1.16-12.3), respectively (P = .013). CONCLUSIONS: Stage 4 skin GVHD and TEN are processes with cytotoxic profiles. TEN is notable for a greater relative depletion of CD4+ T lymphocytes compared with stage 4 skin GVHD, while stage 4 skin GVHD tends to be more inflammatory than TEN. These data suggest an immunohistologic method by which these 2 entities may be distinguished. PMID- 28626938 TI - Role of parasite transmission in promoting inbreeding: I. Infection intensities drive individual parasite selfing rates. AB - Among parasitic organisms, inbreeding has been implicated as a potential driver of host-parasite co-evolution, drug-resistance evolution and parasite diversification. Yet, fundamental topics about how parasite life histories impact inbreeding remain to be addressed. In particular, there are no direct selfing rate estimates for hermaphroditic parasites in nature. Our objectives were to elucidate the mating system of a parasitic flatworm in nature and to understand how aspects of parasite transmission could influence the selfing rates of individual parasites. If there is random mating within hosts, the selfing rates of individual parasites would be an inverse power function of their infection intensities. We tested whether selfing rates deviated from within-host random mating expectations with the tapeworm Oochoristica javaensis. In doing so, we generated, for the first time in nature, individual selfing-rate estimates of a hermaphroditic flatworm parasite. There was a mixed-mating system where tapeworms self-mated more than expected with random mating. Nevertheless, individual selfing rates still had a significant inverse power relationship to infection intensities. The significance of this finding is that the distribution of parasite infection intensities among hosts, an emergent property of the transmission process, can be a key driver in shaping the primary mating system, and hence the level of inbreeding in the parasite population. Moreover, we demonstrated how potential population selfing rates can be estimated using the predicted relationship of individual selfing rates to intensities and showed how the distribution of parasites among hosts can indirectly influence the primary mating system when there is density-dependent fecundity. PMID- 28626939 TI - Technical Note: A 3-D rendering algorithm for electromechanical wave imaging of a beating heart. AB - PURPOSE: Arrhythmias can be treated by ablating the heart tissue in the regions of abnormal contraction. The current clinical standard provides electroanatomic 3 D maps to visualize the electrical activation and locate the arrhythmogenic sources. However, the procedure is time-consuming and invasive. Electromechanical wave imaging is an ultrasound-based noninvasive technique that can provide 2-D maps of the electromechanical activation of the heart. In order to fully visualize the complex 3-D pattern of activation, several 2-D views are acquired and processed separately. They are then manually registered with a 3-D rendering software to generate a pseudo-3-D map. However, this last step is operator dependent and time-consuming. METHODS: This paper presents a method to generate a full 3-D map of the electromechanical activation using multiple 2-D images. Two canine models were considered to illustrate the method: one in normal sinus rhythm and one paced from the lateral region of the heart. Four standard echographic views of each canine heart were acquired. Electromechanical wave imaging was applied to generate four 2-D activation maps of the left ventricle. The radial positions and activation timings of the walls were automatically extracted from those maps. In each slice, from apex to base, these values were interpolated around the circumference to generate a full 3-D map. RESULTS: In both cases, a 3-D activation map and a cine-loop of the propagation of the electromechanical wave were automatically generated. The 3-D map showing the electromechanical activation timings overlaid on realistic anatomy assists with the visualization of the sources of earlier activation (which are potential arrhythmogenic sources). The earliest sources of activation corresponded to the expected ones: septum for the normal rhythm and lateral for the pacing case. CONCLUSIONS: The proposed technique provides, automatically, a 3-D electromechanical activation map with a realistic anatomy. This represents a step towards a noninvasive tool to efficiently localize arrhythmias in 3-D. PMID- 28626940 TI - Overexpression of Hevea brasiliensis ethylene response factor HbERF-IXc5 enhances growth and tolerance to abiotic stress and affects laticifer differentiation. AB - Ethylene response factor 1 (ERF1) is an essential integrator of the jasmonate and ethylene signalling pathways coordinating a large number of genes involved in plant defences. Its orthologue in Hevea brasiliensis, HbERF-IXc5, has been assumed to play a major role in laticifer metabolism and tolerance to harvesting stress for better latex production. This study sets out to establish and characterize rubber transgenic lines overexpressing HbERF-IXc5. Overexpression of HbERF-IXc5 dramatically enhanced plant growth and enabled plants to maintain some ecophysiological parameters in response to abiotic stress such as water deficit, cold and salt treatments. This study revealed that HbERF-IXc5 has rubber-specific functions compared to Arabidopsis ERF1 as transgenic plants overexpressing HbERF IXc5 accumulated more starch and differentiated more latex cells at the histological level. The role of HbERF-IXc5 in driving the expression of some target genes involved in laticifer differentiation is discussed. PMID- 28626937 TI - Glutamatergic regulation of cognition and functional brain connectivity: insights from pharmacological, genetic and translational schizophrenia research. AB - The pharmacological modulation of glutamatergic neurotransmission to improve cognitive function has been a focus of intensive research, particularly in relation to the cognitive deficits seen in schizophrenia. Despite this effort, there has been little success in the clinical use of glutamatergic compounds as procognitive drugs. Here, we review a selection of the drugs used to modulate glutamatergic signalling and how they impact on cognitive function in rodents and humans. We highlight how glutamatergic dysfunction, and NMDA receptor hypofunction in particular, is a key mechanism contributing to the cognitive deficits observed in schizophrenia and outline some of the glutamatergic targets that have been tested as putative procognitive targets for this disorder. Using translational research in this area as a leading exemplar, namely, models of NMDA receptor hypofunction, we discuss how the study of functional brain network connectivity can provide new insight into how the glutamatergic system impacts on cognitive function. Future studies characterizing functional brain network connectivity will increase our understanding of how glutamatergic compounds regulate cognition and could contribute to the future success of glutamatergic drug validation. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc. PMID- 28626942 TI - Effect of obesity and type 2 diabetes, and glucose ingestion on circulating spexin concentration in adolescents. AB - Spexin is a novel peptide that has been reported to be down regulated in obese adults and children and in normoglycemic adults following glucose ingestion. Spexin may therefore have a role in metabolic regulation. The purpose of the current study was to determine the effect of obesity and type 2 diabetes (T2DM), and the effect of glucose ingestion on circulating spexin concentration in adolescents. Boys and girls (mean age 16 years old) classified as healthy normal weight (NW, n = 22), obese (Ob, n = 10), or obese with T2DM (n = 12) completed measurements of body composition, blood pressure, cardiorespiratory fitness, and blood concentrations of glucose, insulin, and lipids. The median fasting serum spexin concentration did not differ between groups (NW: 0.35; Ob: 0.38, T2DM: 0.34 ng/mL, respectively). In 10 NW participants who completed a standard oral glucose tolerance test, spexin concentration was unchanged at 30 and 120 minutes relative to the fasting baseline. Finally, spexin was not significantly correlated with any of the body composition, fitness, or blood biochemical measurements. These data do not support the proposed role of spexin as a metabolic regulator or biomarker of glucose control in adolescents. PMID- 28626943 TI - Bending, Curling, Rolling, and Salient Behavior of Molecular Crystals Driven by [2+2] Cycloaddition of a Styrylbenzoxazole Derivative. AB - We report interesting photomechanical behaviors of the dynamic molecular crystals of (E)-2-(2,4-dichlorostyryl)benzo[d]oxazole (BOACl24). The photosalient effect of the rod-like crystal based on a metal-free olefin driven by photodimerization is observed. Moreover, the needle-like crystals of BOACl24 exhibit a reversible bending away from a UV light source. The nanofibers curl easily under UV irradiation in an organogel, in which the photo-induced rolling of a small slice occurs. This suggests that the rapid release of the accumulated strain during photodimerization may lead to a photosalient effect, and the bending or curling happens when the strain is released slowly. Notably, [2+2] cycloaddition takes place between two different conformational isomers of BOACl24 on account of the rotation of the benzoxazole ring around the C-C bond in an excited state before photodimerization. Such topo-photochemical reaction has not been reported elsewhere. PMID- 28626941 TI - Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments. AB - While the cytosolic events of Wnt/beta-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Moreover, Wnt/beta-catenin signaling is significantly reduced when the membrane order is disturbed by specific inhibitors of certain lipids that prefer to localize at the ordered environments. Similarly, a reduction in Wnt signaling activity is observed in Niemann-Pick Type C disease cells where trafficking of ordered membrane lipid components to the plasma membrane is genetically impaired. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity. PMID- 28626944 TI - Food insecurity and eating disorder pathology. AB - OBJECTIVE: The primary aim of this study was to investigate eating disorder (ED) pathology in those living with food insecurity. A secondary aim was to investigate whether any-reason dietary restraint, weight self-stigma, and worry increased as level of food insecurity increased. METHOD: Participants (N = 503) seeking food from food pantries completed questionnaires assessing level of food insecurity, demographics, ED pathology, dietary restraint, weight self-stigma, and worry. RESULTS: Consistent with hypotheses, participants with the highest level of food insecurity (i.e., adults who reported having hungry children in their household) also endorsed significantly higher levels of binge eating, overall ED pathology, any-reason dietary restraint, weight self-stigma, and worry compared to participants with lower levels of food insecurity. Contrary to hypotheses, compensatory behaviors also increased as level of food insecurity worsened. Overall, 17% of those in the child hunger food insecurity group reported clinically significant ED pathology. DISCUSSION: This is the first study to assess the full spectrum of ED pathology in a low-income, marginalized population with food insecurity. Given that food insecurity is a global concern, results from this study suggest that greater attention to the association between ED pathology and food insecurity is warranted by researchers around the world. PMID- 28626945 TI - European corn borer (Ostrinia nubilalis Hbn., Lepidoptera: Crambidae): comparing the performance of a new bisexual lure with that of synthetic sex pheromone in five countries. AB - BACKGROUND: Phenylacetaldehyde is a flower volatile and attractant for among others the European corn borer Ostrinia nubilalis. The addition of 4 methoxyphenethyl alcohol has recently been reported to increase O. nubilalis catches four to five times, yielding a bisexual lure for the species. RESULTS: The bisexual lure significantly outperformed synthetic pheromone lures of O. nubilalis at 11 out of 13 experiments conducted in Bulgaria, Hungary, Italy, Slovenia and Turkey. CONCLUSION: The bisexual lure will provide growers with a new and efficient method for detection and monitoring of O. nubilalis. (c) 2017 Society of Chemical Industry. PMID- 28626946 TI - Do changes in gene expression contribute to sexual isolation and reinforcement in the house mouse? AB - Expression divergence, rather than sequence divergence, has been shown to be important in speciation, particularly in the early stages of divergence of traits involved in reproductive isolation. In the two European subspecies of house mice, Mus musculus musculus and Mus musculus domesticus, earlier studies have demonstrated olfactory-based assortative mate preference in populations close to their hybrid zone. It has been suggested that this behaviour evolved following the recent secondary contact between the two taxa (~3,000 years ago) in response to selection against hybridization. To test for a role of changes in gene expression in the observed behavioural shift, we conducted a RNA sequencing experiment on mouse vomeronasal organs. Key candidate genes for pheromone-based subspecies recognition, the vomeronasal receptors, are expressed in these organs. Overall patterns of gene expression varied significantly between samples from the two subspecies, with a large number of differentially expressed genes between the two taxa. In contrast, only ~200 genes were found repeatedly differentially expressed between populations within M. m. musculus that did or did not display assortative mate preferences (close to or more distant from the hybrid zone, respectively), with an overrepresentation of genes belonging to vomeronasal receptor family 2. These receptors are known to play a key role in recognition of chemical cues that handle information about genetic identity. Interestingly, four of five of these differentially expressed receptors belong to the same phylogenetic cluster, suggesting specialization of a group of closely related receptors in the recognition of odorant signals that may allow subspecies recognition and assortative mating. PMID- 28626948 TI - Racial and ethnic differences among children with new-onset autoimmune Type 1 diabetes. AB - AIM: To compare demographic and clinical characteristics among children from ethnic minorities and non-Hispanic white children with new-onset autoimmune Type 1 diabetes. METHODS: We analysed a single-centre series of 712 children with new onset autoimmune Type 1 diabetes between January 2008 and March 2011. The median (range) age was 9.7 (0.3-18.1) years, the mean (sd) BMI percentile was 69.7 (25.4) and 48.3% of the cohort were girls. The cohort comprised 57.3% non Hispanic white, 20.5% Hispanic and 14.8% African-American children, and 7.4% were of other, mixed or unknown race. RESULTS: The Hispanic subgroup, compared with non-Hispanic white subgroup, had a higher mean (sd) C-peptide level [0.82 (1.62) vs 0.55 (0.47) ng/ml; P=0.004), and a greater proportion of children with elevated BMI (overweight or obesity; 49.6% vs 32.5%; P<0.001) and diabetic ketoacidosis (51.8% vs 38.2%; P=0.006). The African-American group had a higher mean (sd) glucose level [24.4 (12.8) vs 21.4 (10.7) mmol/l; P=0.017], a greater proportion of children with ketoacidosis (56.7% vs 38.2%; P=0.001), a greater proportion with elevated BMI (52.9% vs 32.5%; P<0.001), and a lower proportion of children at pre-pubertal stage (49.0% vs 61.6%; P=0.01), and tended to have higher C-peptide levels [0.65 (0.59) vs 0.55 [0.47] ng/ml; P=0.079) compared with the non-Hispanic white children. The differences in C-peptide levels compared with non-Hispanic white children persisted for Hispanic (P=0.01) but not African American children (P=0.29) after adjustment for age, sex, BMI, ketoacidosis, glucose, Tanner stage and autoantibody number. CONCLUSION: At the onset of paediatric autoimmune Type 1 diabetes, Hispanic, but not African-American children had higher C-peptide levels, after adjustment for potential confounders, compared with non-Hispanic white children. These findings suggest that ethnicity may contribute to the heterogeneity of Type 1 diabetes pathogenesis, with possible implications for intervention. PMID- 28626947 TI - Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma. AB - This phase 4, single-arm, non-randomized, open-label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (>=20 years) with measurable secretory multiple myeloma (serum monoclonal IgG >=10, IgA/IgE >=5, IgD >=0.5 g/L, IgM present [regardless of level], and urine M protein of >=200 mg/24 h) received intravenous bortezomib 1.3 mg/m2 , twice weekly for 2 weeks, followed by a 10-day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) Cmax (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non-Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half-life (t1/2 ), area under the plasma concentration-time curve from time 0 to infinity (AUCinfinity ), volume of distribution (Vz ), and systemic clearance were not assessable. All patients experienced treatment-emergent adverse events (TEAEs); 78% were drug-related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUClast [SD]: 230 [147] ng.h/mL) with twice weekly intravenous administration was comparable with non-Asian population (AUClast [SD]: 241 [82] ng.h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy. PMID- 28626949 TI - Diagnosis and treatment of concurrent dermal malignant melanoma and melanocytomas in a pygmy hippopotamus (Choeropsis liberiensis). AB - BACKGROUND: Dermal melanocytic neoplasms are common in some even-toed ungulates (Artiodactyla), yet this entity has not been reported in the pygmy hippopotamus to date. Concurrent occurrence of multiple benign and malignant melanocytic neoplasms is unusual. Malignant transformation occurs in a small percentage of benign melanocytic tumours in people but this phenomenon has not been well documented in animals. OBJECTIVES: To report the diagnosis and treatment of concurrent dermal melanocytomas and malignant melanomas in a pygmy hippopotamus. ANIMALS: A 36-year-old intact male pygmy hippopotamus, part of a zoological collection, housed with a 10-year-old female of the same species, presented with multiple raised and pigmented skin masses. METHODS: Initial impression smears of one ulcerated lesion were consistent with inflammation; subsequent histopathological findings from a skin biopsy revealed an underlying malignant melanoma. The animal was anaesthetised, ultrasonographic imaging of the local lymph nodes indicated no local involvement and all skin lesions were removed. Recovery from anaesthesia was unremarkable, skin healing was within normal limits for the species. There was no sign of recurrence 34 months post-surgery. RESULTS: A diagnosis of malignant melanomas and concurrent melanocytomas was made on histopathological evaluation. CONCLUSION AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, this is the first reported case of melanocytic neoplasia in the pygmy hippopotamus. The occurrence of both benign and malignant melanocytic skin tumours should be considered in this species. PMID- 28626950 TI - Myxoid variant of primary cutaneous anaplastic large cell lymphoma: First 2 cases. AB - Anaplastic large cell lymphoma (ALCL) is a CD30+ T-cell non-Hodgkin lymphoma with 2 main clinical presentations: primary cutaneous ALCL (pcALCL) and systemic ALCL (sALCL). While rare cases of myxoid sALCL have been reported, there are no previous cases of myxoid pcALCL reported. We present 2 unusual cases of pcALCL showing prominent collections of dermal mucin closely intermingling with the anaplastic lymphocytes. Patient 1 was a 30-year-old woman who presented with ulcerated nodules on her neck, abdomen, chest and shoulders. A systemic lymphoma was excluded by physical examination, positron emission tomography and computed tomography (PET-CT) scan, as well as by bone marrow biopsy and flow cytometry studies. The patient was closely followed-up for 10 months without evidence of systemic involvement. The biopsy showed diffuse infiltration of the dermis by a CD2+, CD30+, anaplastic lymphoma kinase (ALK)-negative ALCL. Patient 2 was a 55 year-old woman who presented with a single nodule on her right arm. A systemic lymphoma was excluded by physical examination as well as by a PET-CT scan. The biopsy showed diffuse and dense lymphoid infiltration of the whole biopsy by a CD3+, CD4+, CD30+, ALK-negative ALCL. The atypical lymphocytes were intermingled with large amounts of dermal stromal mucin. PMID- 28626951 TI - Considering the unintentional consequences of pollinator gardens for urban native plants: is the road to extinction paved with good intentions? AB - Urban centers are important foci for plant biodiversity and yet widespread planting of wildflower gardens in cities to sustain pollinator biodiversity is on the rise, without full consideration of potential ecological consequences. The impact of intentional wildflower plantings on remnant native plant diversity in urban and peri-urban settings has not received attention, although shared pollinators are likely to mediate several types of biotic interactions between human-introduced plants and remnant native ones. Additionally, if wildflower species escape gardens these indirect effects may be compounded with direct ones. We review the potential positive and negative impacts of wildflower gardens on urban native flowering plants, and we reveal substantial gaps in our knowledge. We present a roadmap for research to address whether wildflower gardens, while benefiting pollinators, could also hasten the extinction of native remnant plants in urban settings, or whether they could have other effects that enrich urban biodiversity. Goals of future wildflower mixes should consider the totality of potential interactions. PMID- 28626952 TI - Multivariate binary classification of imbalanced datasets-A case study based on high-dimensional multiplex autoimmune assay data. AB - The classification of a population by a specific trait is a major task in medicine, for example when in a diagnostic setting groups of patients with specific diseases are identified, but also when in predictive medicine a group of patients is classified into specific disease severity classes that might profit from different treatments. When the sizes of those subgroups become small, for example in rare diseases, imbalances between the classes are more the rule than the exception and make statistical classification problematic when the error rate of the minority class is high. Many observations are classified as belonging to the majority class, while the error rate of the majority class is low. This case study aims to investigate class imbalance for Random Forests and Powered Partial Least Squares Discriminant Analysis (PPLS-DA) and to evaluate the performance of these classifiers when they are combined with methods to compensate imbalance (sampling methods, cost-sensitive learning approaches). We evaluate all approaches with a scoring system taking the classification results into consideration. This case study is based on one high-dimensional multiplex autoimmune assay dataset describing immune response to antigens and consisting of two classes of patients: Rheumatoid Arthritis (RA) and Systemic Lupus Erythemathodes (SLE). Datasets with varying degrees of imbalance are created by successively reducing the class of RA patients. Our results indicate possible benefit of cost-sensitive learning approaches for Random Forests. Although further research is needed to verify our findings by investigating other datasets or large-scale simulation studies, we claim that this work has the potential to increase awareness of practitioners to this problem of class imbalance and stresses the importance of considering methods to compensate class imbalance. PMID- 28626953 TI - Translation and validation of the Insulin Treatment Appraisal Scale in Hong Kong primary care patients. AB - AIMS/INTRODUCTION: Patients with type 2 diabetes mellitus often delay the initiation or titration of insulin treatment due to psychological factors. This phenomenon is referred to as psychological insulin resistance (PIR). The Insulin Treatment Appraisal Scale (ITAS) is a 20-item instrument for assessing PIR. A previous Chinese version of the ITAS (C-ITAS) was found to be subject to problems arising from its translation. The present study aimed to translate and validate this instrument, which will facilitate research and aid in counseling in a clinical setting. MATERIALS AND METHODS: The C-ITAS was modified to develop the Hong Kong version of the C-ITAS (C-ITAS-HK) according to published guidelines for the translation of transcultural research. A total of 328 diabetes mellitus patients who were followed-up in 10 different publically funded primary care outpatient clinics were recruited for self-administration of the C-ITAS-HK. Demographic data were recorded, and clinical data (e.g., presence of diabetes mellitus complications) were obtained from case records. The C-ITAS-HK results were subjected to psychometric analysis, including the assessment of Cronbach's alpha, factor analysis and test-retest reliability. RESULTS: Factor analysis supported a two-factor structure with good internal consistency (whole scale 0.846, negative subscale 0.882, positive subscale 0.619). The test-retest reliability correlation coefficients for all items were positive, at 0.871, 0.782, and 0.692 for the whole scale, negative subscale and positive subscale, respectively. The ITAS scores differed significantly between participants with PIR and those without in the expected direction, suggesting good discriminant validity. CONCLUSIONS: The C-ITAS-HK is a valid tool for measuring and assessing PIR in the Hong Kong primary care diabetes mellitus population. PMID- 28626955 TI - Expression profile of urothelial transcription factors in bladder biopsies with interstitial cystitis. AB - OBJECTIVES: To characterize interstitial cystitis pathology based on the expression profile of urothelial tissue-specific master transcription factors. METHODS: Bladder carcinoma cell lines derived from the urothelial stem cells (epithelial or mesenchymal) were used to identify candidate urothelial master transcription factors. Gene expression was measured with quantitative reverse transcription polymerase chain reaction. From the initial screening of 170 transcription factors (human homologs of Drosophila segmentation genes and known master transcription factors from a database), 28 transcription factors were selected. Subsequently, messenger ribonucleic acid from bladder biopsies of interstitial cystitis patients was purified, and gene expression levels of known urothelial marker genes and candidate master transcription factors were measured. Multivariate expression data were analyzed with spss software. RESULTS: Factor analysis decomposed the expression profile into four axes: principal axis 1 included retinoic acid receptors and 17 candidate master transcription factors. Principal axis 2 included KRT5 and five candidates. Principal axis 3 included transcription factor TP63 and two candidates. Principal axis 4 included SHH and two candidates. Principal component analysis segregated biopsies from Hunner's lesion in the principal component 1 (retinoic acid)/principal component 2 (SOX13)/principal component 3 (TP63) space. CONCLUSIONS: Urothelial master transcription factors could serve as novel diagnostic markers and potentially explain the molecular pathology of interstitial cystitis. PMID- 28626954 TI - Isolated growth hormone deficiency due to the R183H mutation in GH1: Clinical analysis of a four-generation family. PMID- 28626957 TI - Graves' disease with severe neutropenia: Any clues? PMID- 28626956 TI - Markedly increased incidence of critical illness in adults with Type 1 diabetes. AB - AIMS: To compare the incidence of and mortality after intensive care unit admission in adults with paediatric-onset Type 1 diabetes vs the general population. METHODS: Using population-based administrative data from Manitoba, Canada, we identified 814 cases of paediatric-onset Type 1 diabetes, and 3579 general population controls matched on age, sex and region of residence. We estimated the incidence of intensive care unit admission in adulthood, and compared the findings between populations using incidence rate ratios and multivariable Cox proportional hazards regression, adjusting for age, sex, comorbidity and socio-economic status. We estimated age- and sex-standardized mortality rates after intensive care unit admission. RESULTS: Between January 2000 and October 2009, the average annual incidence of intensive care unit admission among prevalent cohorts was 910 per 100 000 in the Type 1 diabetes population, and 106 per 100 000 in matched controls, an eightfold increased risk (incidence rate ratio 8.6; 95% CI 5.5, 14.0). The adjusted risk of intensive care unit admission was elevated to a greater extent among women with Type 1 diabetes compared with matched women (hazard ratio 14.7; 95% CI 7.2, 29.4) than among men with Type 1 diabetes compared with matched men (hazard ratio 4.92; 95% CI 10.3, 2.36) The most common reasons for admission in the diabetes cohort were diabetic ketoacidosis, infection and ischaemic heart disease. At 30%, 5-year mortality was higher in the diabetes cohort than in the matched cohort (relative risk 5.7; 95% CI 1.2, 8.9). CONCLUSIONS: Compared with the general population, the risk of intensive care unit admission was higher in adults with paediatric-onset Type 1 diabetes, and mortality after admission was also higher. PMID- 28626958 TI - Letter to the Editor. PMID- 28626959 TI - Intramolecular Singlet Fission in an Antiaromatic Polycyclic Hydrocarbon. AB - Singlet fission (SF), in which one singlet exciton (S1 ) splits into two triplets (T1 ) on adjacent molecules through a correlated triplet-pair 1 (TT) state, requires precise but difficult tuning of exciton energetics and intermolecular electronic couplings in the solid state. Antiaromatic 4npi dibenzopentalenes (DPs) are demonstrated as a new class of single-chromophore-based intramolecular SF materials that exhibit an optically allowed S2 state with E(S2 )>2*E(T1 ) and an optically forbidden S1 state. Ultrafast population transfer from a high-lying S2 state to a 1 (TT) state was observed in monomeric solution of styryl substituted DP (SDP) on a sub-picosecond timescale. There is evidence of exciton diffusion (ED) of the 1 (TT) state to yield two individual long-lived triplets in SDP thin film. The overall triplet yield via intramolecular SF and subsequent triplet-pair diffusion can be as high as 142+/-10 % in thin film. PMID- 28626960 TI - Whole-Blood Taurine Concentrations in Cats With Intestinal Disease. AB - BACKGROUND: Increased delivery of taurine-conjugated bile acids to the distal bowel can lead to dysbiosis resulting in colitis in mouse models of inflammatory bowel disease. A similar situation also could occur in cats with intestinal disease and might therefore result in decreased whole-body taurine concentration. HYPOTHESIS/OBJECTIVES: To determine whether whole-blood taurine concentrations are decreased at the time of diagnosis in cats with intestinal disease and to correlate concentrations with clinical and laboratory variables. ANIMALS: Twenty one cats with chronic inflammatory enteropathy and 7 cats with intestinal neoplasia from the University of Bristol. METHODS: Cats that had undergone a thorough investigation consisting of a CBC, serum biochemistry, serum cobalamin and folate concentrations, transabdominal ultrasound examination and histopathology of intestinal biopsy specimens, as well as additional testing if indicated, were included. Whole-blood from these cats collected at the time of histologic diagnosis and stored in ethylenediaminetetraacetic acid was retrospectively analyzed for taurine with an automated high-performance liquid chromatography amino acid analyzer. RESULTS: Although whole-blood taurine concentrations remained within the reference range, those cats with predominantly large intestinal clinical signs had significantly lower concentrations than did cats with small intestinal and mixed bowel clinical signs (P = 0.033) and this difference also was significant when assessed only in cats with chronic inflammatory enteropathy (P = 0.019). CONCLUSIONS AND CLINICAL IMPORTANCE: Additional studies are needed to determine whether large intestinal signs in cats with chronic inflammatory enteropathy are caused by alterations in the microbiota arising as a consequence of increased delivery of taurine-conjugated bile acids. PMID- 28626961 TI - Comparing polyarteritis nodosa in children and adults: a single center study. AB - OBJECTIVE: Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium/small arteries. We aimed to examine the characteristics of adult- and childhood-onset PAN. METHODS: Fifteen pediatric (? 18 years) and 22 adult PAN patients who fulfilled the Ankara 2008 and American College of Rheumatology 1990 criteria, respectively, were included in the study. RESULTS: Five children had cutaneous and all the rest of the patients had systemic PAN. Weight loss was more common (59.1% vs. 20%, P = 0.041) and presence of an angiography at diagnosis was more frequent (81.8% vs. 33.3%, P = 0.003) in adults than children. Arthralgia/arthritis and skin involvement were more common in children (86.7% vs. 59.1%; 93.3% vs. 72.7%, respectively) while renal and neurologic involvement were more frequently observed in adult patients (50% vs. 20%; 59.1% vs. 40%, respectively) (P > 0.05 for all). Cutaneous PAN patients were treated with corticosteroids only. All but one adult patient received cyclophosphamide while mycophenolate mofetil was used in five and cyclophosphamide was used in four children as induction treatment. The median duration of induction treatment was longer in adults than children (12 vs. 3 months, respectively; P = 0.004). The most common maintenance drug was mycophenolate mofetil in children and azathioprine in adults. The mortality rate was 13.6% (n = 3) and 0% in adults and children, respectively. CONCLUSION: To our knowledge, this is the first study comparing characteristics of adult and childhood onset PAN. Our results have suggested that juvenile PAN had a more benign course (with less renal and neurologic involvement, shorter duration of induction treatment) than adult onset PAN. PMID- 28626962 TI - Three-dimensional motion corrected sensitivity encoding reconstruction for multi shot multi-slice MRI: Application to neonatal brain imaging. AB - PURPOSE: To introduce a methodology for the reconstruction of multi-shot, multi slice magnetic resonance imaging able to cope with both within-plane and through plane rigid motion and to describe its application in structural brain imaging. THEORY AND METHODS: The method alternates between motion estimation and reconstruction using a common objective function for both. Estimates of three dimensional motion states for each shot and slice are gradually refined by improving on the fit of current reconstructions to the partial k-space information from multiple coils. Overlapped slices and super-resolution allow recovery of through-plane motion and outlier rejection discards artifacted shots. The method is applied to T2 and T1 brain scans acquired in different views. RESULTS: The procedure has greatly diminished artifacts in a database of 1883 neonatal image volumes, as assessed by image quality metrics and visual inspection. Examples showing the ability to correct for motion and robustness against damaged shots are provided. Combination of motion corrected reconstructions for different views has shown further artifact suppression and resolution recovery. CONCLUSION: The proposed method addresses the problem of rigid motion in multi-shot multi-slice anatomical brain scans. Tests on a large collection of potentially corrupted datasets have shown a remarkable image quality improvement. Magn Reson Med 79:1365-1376, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28626964 TI - Impact of prior distributions and central tendency measures on Bayesian intravoxel incoherent motion model fitting. AB - PURPOSE: Bayesian model fitting has been proposed as a robust alternative for intravoxel incoherent motion (IVIM) model-fitting parameter estimation. However, consensus regarding choice of prior distribution and posterior distribution central tendency measure is needed. The aim of this study was to compare the quality of IVIM parameter estimates produced by different prior distributions and central tendency measures, and to gain knowledge about the effect of these choices. METHODS: Three prior distributions (uniform, reciprocal, and lognormal) and two measures of central tendency (mean and mode) found in the literature were studied using simulations and in vivo data from a tumor mouse model. RESULTS: Simulations showed that the uniform and lognormal priors were superior to the reciprocal prior, especially for the parameters D and f and clinically relevant SNR levels. The choice of central tendency measure had less effect on the results, but had some effects on estimation bias. Results based on simulations and in vivo data agreed well, indicating high validity of the simulations. CONCLUSIONS: Choice of prior distribution and central tendency measure affects the results of Bayesian IVIM parameter estimates. This must be considered when comparing results from different studies. The best overall quality of IVIM parameter estimates was obtained using the lognormal prior. Magn Reson Med 79:1674-1683, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28626963 TI - Exercise training modulates the hepatic renin-angiotensin system in fructose-fed rats. AB - NEW FINDINGS: What is the central question of this study? What are the effects of exercise training on the hepatic renin-angiotensin system and their contribution to damage resulting from fructose overload in rats? What is the main finding and its importance? Exercise training attenuated the deleterious actions of the angiotensin-converting enzyme/angiotensin II/angiotensin II type 1 receptor axis and increased expression of the counter-regulatory (angiotensin-converting enzyme 2/angiotensin (1-7)/Mas receptor) axis in the liver. Therefore, our study provides evidence that exercise training modulates the hepatic renin-angiotensin system, which contributes to reducing the progression of metabolic dysfunction and non-alcoholic fatty liver disease in fructose-fed rats. The renin-angiotensin system (RAS) has been implicated in the development of metabolic syndrome. We investigated whether the hepatic RAS is modulated by exercise training and whether this modulation improves the deleterious effects of fructose overload in rats. Male Wistar rats were divided into (n = 8 each) control (CT), exercise control (CT-Ex), high-fructose (HFr) and exercise high-fructose (HFr-Ex) groups. Fructose-drinking rats received d-fructose (100 g l-1 ). After 2 weeks, CT-Ex and HFr-Ex rats were assigned to a treadmill training protocol at moderate intensity for 8 weeks (60 min day-1 , 4 days per week). We assessed body mass, glucose and lipid metabolism, hepatic histopathology, angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activity, the angiotensin concentration and the expression profile of proteins affecting the hepatic RAS, gluconeogenesis and inflammation. Neither fructose overload nor exercise training influenced body mass gain and serum ACE and ACE2 activity. The HFr group showed hyperinsulinaemia, but exercise training normalized this parameter. Exercise training was effective in preventing hepatic steatosis and in preventing triacylglycerol and glycogen accumulation. Furthermore, exercise improved the response to the deleterious effects of HFr overload by normalizing the gluconeogenesis pathway and the protein levels of interleukin-6 and tumour necrosis factor-alpha. The HFr rats displayed increased hepatic ACE activity and protein expression and angiotensin II concentration, which were attenuated by exercise training. Exercise training restored the ACE2/angiotensin-(1-7)/Mas receptor axis. Exercise training may favour the counter-regulatory ACE2/angiotensin-(1-7)/Mas receptor axis over the classical RAS (ACE/angiotensin II/angiotensin II type 1 receptor axis), which could be responsible for the reduction of metabolic dysfunction and the prevention of non-alcoholic fatty liver disease. PMID- 28626965 TI - The growth of epidemiology in diabetes research. PMID- 28626966 TI - Anode Improvement in Rechargeable Lithium-Sulfur Batteries. AB - Owing to their theoretical energy density of 2600 Wh kg-1 , lithium-sulfur batteries represent a promising future energy storage device to power electric vehicles. However, the practical applications of lithium-sulfur batteries suffer from poor cycle life and low Coulombic efficiency, which is attributed, in part, to the polysulfide shuttle and Li dendrite formation. Suppressing Li dendrite growth, blocking the unfavorable reaction between soluble polysulfides and Li, and improving the safety of Li-S batteries have become very important for the development of high-performance lithium sulfur batteries. A comprehensive review of various strategies is presented for enhancing the stability of the anode of lithium sulfur batteries, including inserting an interlayer, modifying the separator and electrolytes, employing artificial protection layers, and alternative anodes to replace the Li metal anode. PMID- 28626967 TI - Strategy over operation: neural activation in subtraction and multiplication during fact retrieval and procedural strategy use in children. AB - Arithmetic development is characterized by strategy shifts between procedural strategy use and fact retrieval. This study is the first to explicitly investigate children's neural activation associated with the use of these different strategies. Participants were 26 typically developing 4th graders (9- to 10-year-olds), who, in a behavioral session, were asked to verbally report on a trial-by-trial basis how they had solved 100 subtraction and multiplication items. These items were subsequently presented during functional magnetic resonance imaging. An event-related design allowed us to analyze the brain responses during retrieval and procedural trials, based on the children's verbal reports. During procedural strategy use, and more specifically for the decomposition of operands strategy, activation increases were observed in the inferior and superior parietal lobes (intraparietal sulci), inferior to superior frontal gyri, bilateral areas in the occipital lobe, and insular cortex. For retrieval, in comparison to procedural strategy use, we observed increased activity in the bilateral angular and supramarginal gyri, left middle to inferior temporal gyrus, right superior temporal gyrus, and superior medial frontal gyrus. No neural differences were found between the two operations under study. These results are the first in children to provide direct evidence for alternate neural activation when different arithmetic strategies are used and further unravel that previously found effects of operation on brain activity reflect differences in arithmetic strategy use. Hum Brain Mapp 38:4657-4670, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28626968 TI - 3D Printing All-Aromatic Polyimides using Mask-Projection Stereolithography: Processing the Nonprocessable. AB - High-performance, all-aromatic, insoluble, engineering thermoplastic polyimides, such as pyromellitic dianhydride and 4,4'-oxydianiline (PMDA-ODA) (Kapton), exhibit exceptional thermal stability (up to ~600 degrees C) and mechanical properties (Young's modulus exceeding 2 GPa). However, their thermal resistance, which is a consequence of the all-aromatic molecular structure, prohibits processing using conventional techniques. Previous reports describe an energy intensive sintering technique as an alternative technique for processing polyimides with limited resolution and part fidelity. This study demonstrates the unprecedented 3D printing of PMDA-ODA using mask-projection stereolithography, and the preparation of high-resolution 3D structures without sacrificing bulk material properties. Synthesis of a soluble precursor polymer containing photo crosslinkable acrylate groups enables light-induced, chemical crosslinking for spatial control in the gel state. Postprinting thermal treatment transforms the crosslinked precursor polymer to PMDA-ODA. The dimensional shrinkage is isotropic, and postprocessing preserves geometric integrity. Furthermore, large area mask-projection scanning stereolithography demonstrates the scalability of 3D structures. These unique high-performance 3D structures offer potential in fields ranging from water filtration and gas separation to automotive and aerospace technologies. PMID- 28626969 TI - Different patterns of expression of cell cycle control and local invasion-related proteins in oral squamous cell carcinoma affecting young patients. AB - OBJECTIVES: Oral squamous cell carcinoma (OSCC) predominantly affects males in the fifth decade of life; nevertheless, an increased incidence in young patients has been reported worldwide, and the clinical and behavioral characteristics of tumors in this group are controversial, and the literature shows divergent results. PURPOSE: To investigate the clinicopathological features and prognostic significance of the immunoexpression of cell cycle and local invasion proteins in OSCC affecting young patients (<=40 years old). METHODS: A tissue microarray was performed with 132 OSCC samples (61 cases of young patients vs 71 cases of elderly patients) and submitted to immunohistochemical reactions with Ki67, p53, p16, Bcl-2, Cyclin D1, C-ErbB2, p21, Myc, EGFR, MMP-9, SMA, Cathepsin K and FGF-2 antibodies. RESULTS: Clinicopathological features and survival rates were similar in both groups. Although overexpression of EGFR (P=.042) and MMP-9 (P=.001) was more frequent in young patients, only C-ErbB-2 (P=.048) and SMA (P=.048) expression correlated with lower disease-free survival (DFS) in this group of patients. CONCLUSION: Clinicopathological features and survival rates are similar between younger and older patients with OSCC. The different patterns of C-ErbB2, EGFR, MMP-9, and SMA expression between the groups merits further investigation to understand their role in the early tumor onset in young patients. PMID- 28626970 TI - Surgical treatment of peri-implantitis intrabony lesions by means of deproteinized bovine bone mineral with 10% collagen: 7-year-results. AB - OBJECTIVES: The aim of this study was to evaluate the long-term results of the surgical treatment of single peri-implantitis intrabony defects, by means of deproteinized bovine bone mineral with 10% collagen (DBBMC). MATERIAL AND METHODS: The original population consisted of 26 patients with one crater-like defect, around either sandblasted and acid-etched (SLA) or titanium plasma sprayed (TPS) dental implants, with a probing depth (PD) >=6 mm and no implant mobility (Roccuzzo et al. J Clin Periodontol. 2011; 38: 738). Implants were mechanically debrided and treated using EDTA gel and chlorhexidine gel. The bone defects were filled with DBBMC, and the flap was sutured around the non-submerged implant. Patients were placed on an individually tailored supportive periodontal therapy (SPT). RESULTS: Two patients were lost to follow-up. During SPT, additional antibiotic and/or surgical therapy was necessary in eight implants, and four of these were removed for biologic complications. At 7-year, the survival rate was 83.3% for SLA implants and 71.4% for TPS. PD was significantly reduced from 6.6 +/- 1.3 to 3.2 +/- 0.7 mm in SLA and 7.2 +/- 1.5 to 3.4 +/- 0.6 mm in TPS. Bleeding on probing decreased from 75.0 +/- 31.2% to 7.5 +/- 12.1% (SLA) and from 90.0 +/- 12.9% to 30.0 +/- 19.7% (TPS). When successful therapy was defined as PD <=5 mm, absence of bleeding/suppuration on probing, and no further bone loss, treatment success was obtained in 2 of 14 (14.3%) of the TPS and in 7 of 12 (58.3%) of the SLA implants. CONCLUSIONS: Seven years after surgical treatment with DBBMC, patients, in an adequate SPT, maintained sufficient peri-implant conditions in many cases, particularly around SLA implants. Nevertheless, some patients required further treatment and some lost implants. The clinical decision on whether implants should be treated or removed should be based on several factors, including implant surface characteristics. PMID- 28626971 TI - Genetics and developmental biology of cooperation. AB - Despite essential progress towards understanding the evolution of cooperative behaviour, we still lack detailed knowledge about its underlying molecular mechanisms, genetic basis, evolutionary dynamics and ontogeny. An international workshop "Genetics and Development of Cooperation," organized by the University of Bern (Switzerland), aimed at discussing the current progress in this research field and suggesting avenues for future research. This review uses the major themes of the meeting as a springboard to synthesize the concepts of genetic and nongenetic inheritance of cooperation, and to review a quantitative genetic framework that allows for the inclusion of indirect genetic effects. Furthermore, we argue that including nongenetic inheritance, such as transgenerational epigenetic effects, parental effects, ecological and cultural inheritance, provides a more nuanced view of the evolution of cooperation. We summarize those genes and molecular pathways in a range of species that seem promising candidates for mechanisms underlying cooperative behaviours. Concerning the neurobiological substrate of cooperation, we suggest three cognitive skills necessary for the ability to cooperate: (i) event memory, (ii) synchrony with others and (iii) responsiveness to others. Taking a closer look at the developmental trajectories that lead to the expression of cooperative behaviours, we discuss the dichotomy between early morphological specialization in social insects and more flexible behavioural specialization in cooperatively breeding vertebrates. Finally, we provide recommendations for which biological systems and species may be particularly suitable, which specific traits and parameters should be measured, what type of approaches should be followed, and which methods should be employed in studies of cooperation to better understand how cooperation evolves and manifests in nature. PMID- 28626972 TI - NIRCa: An artificial neural network-based insulin resistance calculator. AB - BACKGROUND: Direct measurement of insulin sensitivity in children with type 1 diabetes is cumbersome and time consuming. OBJECTIVE: The aim of our study was to develop novel, accurate machine learning-based methods of insulin resistance estimation in children with type 1 diabetes. METHODS: A hyperinsulinemic hyperglycemic clamp study was performed to evaluate the glucose disposal rate (GDR) in a study group consisting of 315 patients aged 7.6 to 19.7 years. The group was randomly divided into a training and independent testing set for model performance assessment. GDR was estimated on the basis of simple clinical variables using 2 non-linear methods: artificial neural networks (ANN) and multivariate adaptive regression splines (MARSplines). The results were compared against the most frequently used predictive model, based on waist circumference, triglyceride (TG), and HbA1c levels. RESULTS: The reference model showed moderate performance ( R 2 = 0.26) with a median absolute percentage error of 49.1%, and with the worst fit observed in young (7-12 years) children ( R 2 = 0.17). Predictions of the MARSplines model were significantly more accurate than those of the reference model (median error 3.6%, R 2 = 0.44 P < .0001). The predictions of the ANN, however, showed significantly lower error than those of the reference model (P < .0001) and MARSplines (P < .0001) and better fit regardless of patient age. ANN-estimated GDRs were within a +/-20% error range in 75% of cases with a median error of 0.6% and an R 2 = 0.66. The predictive tool is available at http://link.konsta.com.pl/gdr. CONCLUSIONS: The developed GDR estimation model reliant on ANN allows for an optimized prediction of GDR for research and clinical purposes. PMID- 28626973 TI - Role of parasite transmission in promoting inbreeding: II. Pedigree reconstruction reveals sib-transmission and consequent kin-mating. AB - Even though parasitic flatworms are one of the most species-rich groups of hermaphroditic organisms, we know virtually nothing of their mating systems (selfing or kin-mating rates) in nature. Hence, we lack an understanding of the role of inbreeding in parasite evolution. The natural mating systems of parasitic flatworms have remained elusive due to the inherent difficulty in generating progeny-array data in many parasite systems. New developments in pedigree reconstruction allow direct inference of realized selfing rates in nature by simply using a sample of genotyped individuals. We built upon this advancement by utilizing the closed mating systems, that is, individual hosts, of endoparasites. In particular, we created a novel means to use pedigree reconstruction data to estimate potential kin-mating rates. With data from natural populations of a tapeworm, we demonstrated how our newly developed methods can be used to test for cosibling transmission and inbreeding depression. We then showed how independent estimates of the two mating system components, selfing and kin-mating rates, account for the observed levels of inbreeding in the populations. Thus, our results suggest that these natural parasite populations are in inbreeding equilibrium. Pedigree reconstruction analyses along with the new companion methods we developed will be broadly applicable across a myriad of parasite species. As such, we foresee that a new frontier will emerge wherein the diverse life histories of flatworm parasites could be utilized in comparative evolutionary studies to broadly address ecological factors or life history traits that drive mating systems and hence inbreeding in natural populations. PMID- 28626974 TI - Refractory cutaneous polyarteritis nodosa: Successful treatment with etanercept. PMID- 28626975 TI - Congenital syphilis. PMID- 28626976 TI - Prevalence of sleep problems in Japanese preschoolers in a medium-sized city: Community-based survey using the Children's Sleep Habits Questionnaire. AB - Although the mean score of the Children's Sleep Habits Questionnaire (CSHQ) differs between countries, there are no normative data for the CSHQ of Japanese preschoolers based on a community sample. The aims of this study were therefore to present normative data for the CSHQ and determine the prevalence and characteristics of sleep problems in Japanese preschoolers. Parents or the primary caregiver of 482 preschoolers aged 4-5 years completed the CSHQ and the Strength and Difficulties Questionnaire. Approximately 80% of preschoolers scored above the cut-off for sleep disturbance on the CSHQ. In addition, co-sleeping was prevalent in Japanese preschoolers but the habit of co-sleeping contributed little to behavioral and emotional problems. Sleep problems appear to be prevalent in Japanese preschoolers based on the CSHQ, and could be associated with the Japanese sleep habit of co-sleeping. PMID- 28626978 TI - A fast multitarget inverse treatment planning strategy optimizing dosimetric measures for high-dose-rate (HDR) brachytherapy. AB - PURPOSE: In this study, we introduce a novel, fast, inverse treatment planning strategy for interstitial high-dose-rate (HDR) brachytherapy with multiple regions of interest solely based on dose-volume-histogram-related dosimetric measures (DMs). METHODS: We present a new problem formulation of the objective function that approximates the indicator variables of the standard DM optimization problem with a smooth logistic function. This problem is optimized by standard gradient-based methods. The proposed approach is then compared against state-of-the-art optimization strategies. RESULTS: All generated plans fulfilled prescribed DMs for all organs at risk. Compared to clinical practice, a statistically significant improvement (p=0.01) in coverage of target structures was achieved. Simultaneously, DMs representing high-dose regions were significantly reduced (p=0.01). The novel optimization strategies run-time was (0.8 +/- 0.3) s and thus outperformed the best competing strategies of the state of the art. In addition, the novel DM-based approach was associated with a statistically significant (p=0.01) increase in the number of active dwell positions and a decrease in the maximum dwell time. CONCLUSIONS: The generated plans showed a clinically significant increase in target coverage with fewer hot spots, with an optimization time approximately three orders of magnitude shorter than manual optimization currently used in clinical practice. As optimization is solely based on DMs, intuitive, interactive, real-time treatment planning, which motivated the adoption of manual optimization in our clinic, is possible. PMID- 28626977 TI - Magnetic compression anastomosis for postoperative biliary atresia. AB - We report a case of successful magnetic compression anastomosis (MCA) for obstructed cyst-jejunostomy in a young woman who had undergone surgery for type 1 biliary atresia (BA) on day 78 of life. A 16-year-old girl was admitted with obstructive jaundice. Jaundice resolved with percutaneous trans-hepatic cholangiodrainage (PTCD) but contrast medium injected from the PTCD tube did not flow through the anastomosis. Magnets were placed on each side of the anastomosis, in the cyst and the jejunum, to compress the partition. On postoperative day (POD) 6, the anastomosis was recanalized and the PTCD tube placed trans-anastomotically until POD 245. The patient remained free from jaundice after removal of the PTCD tube. MCA can be a useful and less invasive procedure for treating biliary tract anastomotic obstruction in patients with BA. PMID- 28626979 TI - Electro-clinical criteria and surgical outcome: Is there a difference between mesial and lesional temporal lobe epilepsy? AB - OBJECTIVES: Mesial temporal lobe epilepsy syndrome (MTLE) with specific electrophysiological and clinical characteristics and hippocampal sclerosis (HS) on MRI is considered the prototype of a syndrome with good surgical prognosis. Ictal onset zones in MTLE have been found to extend outside the hippocampus and neocortical seizures often involve mesial structures. It can, thus, be questioned whether MTLE with HS is different from lesional temporal epilepsies with respect to electro-clinical characteristics and surgical prognosis. We assessed whether MTLE with HS is distinguishable from lesional TLE and which criteria determine surgical outcome. METHODS: People in a retrospective cohort of 389 individuals with MRI abnormalities who underwent temporal lobectomy, were divided into "HS only" or "lesional" TLEs. Twenty-six presented with dual pathology and were excluded from further analysis. We compared surgical outcome and electro-clinical characteristics. RESULTS: Over half (61%) had "HS only." Four electro-clinical characteristics (age at epilepsy onset, febrile seizures, memory dysfunction and contralateral dystonic posturing) distinguished "HS only" from "lesional" TLE, but there was considerable overlap. Seizure freedom 2 years after surgery (Engel class 1) was similar: 67% ("HS only") vs 69% ("lesional" TLE). Neither presence of HS nor electro-clinical criteria was associated with surgical outcome. CONCLUSIONS: Despite small differences in electrophysiological and clinical characteristics between MTLE with HS and lesional TLE, surgical outcomes are similar, indicating that aetiology seems irrelevant in the referral for temporal surgery. PMID- 28626980 TI - Comparison of management regimens following ultrasound diagnosis of nontubal ectopic pregnancies: a retrospective cohort study. AB - OBJECTIVE: To review management options for nontubal ectopic pregnancies. DESIGN: Retrospective cohort study. SETTING: Tertiary hospital in Melbourne, Australia. POPULATION: A total of 100 nontubal pregnancies: 1 abdominal, 32 caesarean scar, 14 cervical, 41 cornual-interstitial, 12 ovarian. METHODS: Cases were classified according to ectopic site. Management categories were medical, surgical, combination or expectant. Use of minimally invasive approaches (ultrasound-guided intra-sac injections or selective surgical techniques) was identified. Primary management was considered to be successful if no further unplanned interventions were required. MAIN OUTCOME MEASURES: Success of primary management and frequency of unplanned interventions. RESULTS: A high rate of success (82%) was demonstrated for all management regimens, with minimal morbidity and no deaths occurring. A high success rate was shown when the primary management regimen was systemic methotrexate or ultrasound-guided intra-sac injection (88%). The success rate for primary surgical management was 57%. High success rates were reported for both primary management with ultrasound-guided injections or in combination with systemic methotrexate (94%) and for primary management with systemic methotrexate alone (81%). Seventy-five per cent of women managed with minimally invasive surgical approaches avoided the need for more extensive surgery, but required longer follow up and additional interventions. CONCLUSION: Minimally invasive approaches were found to be safe and effective treatment for women desiring to conserve fertility. Ultrasound-guided intra-sac injection and laparoscopic ectopic removal procedures aimed at preserving reproductive organs should be included as minimally invasive primary management tools in addition to the well-recognised option of systemic methotrexate. TWEETABLE ABSTRACT: Nontubal ectopics: minimally invasive procedures a safe alternative to surgery in selected cases. PMID- 28626982 TI - Vaginal seeding or vaginal microbial transfer from the mother to the caesarean born neonate: a commentary regarding clinical management. PMID- 28626981 TI - Post-discharge nausea and vomiting after total intravenous anaesthesia and standardised PONV prophylaxis for ambulatory surgery. AB - BACKGROUND: The incidence of post-discharge nausea and vomiting (PDNV) after ambulatory anaesthesia using total intravenous anaesthesia with a risk-stratified anti-emetic approach is not well documented in the literature. In this study, we outline such an approach. The goal was to achieve an acceptably low rate of PDNV both immediately and the day after surgery. METHODS: With ethics committee approval, adult patients undergoing outpatient surgery received a Propofol-based general anaesthetic plus standardised PONV-prophylaxis corresponding to their Apfel risk-score (0-4); ondansetron (risk-score 2), additional dexamethasone (risk-score 3), and additional droperidol (risk-score 4). On post-operative days one and two, patients scored PDNV and pain (numeric rating scale (NRS); 0 = none at all; 10 = worst imaginable). On post-operative day two, patients indicated the level of interference of PDNV and/or pain with their quality of life. Data are descriptive (%) or mean. RESULTS: There were 222 patients included (age 43 years, 44% female, anaesthesia time 95 min). On the day of surgery, 69.4% of patients did not experience any nausea, 10.4% complained about severe (NRS > 6) nausea, 6.3% experienced vomiting or retching. On the first and second postoperative day, nausea was absent in 88.7% of patients and 97.3%, respectively. Quality of life was impacted (NRS >= 4) more by pain (32.8% of cases), than by PDNV (13.6%). CONCLUSION: Acceptably low rates of PDNV were achieved with the proposed standardised approach to PDNV prophylaxis. For almost 90% of patients, PDNV was not an issue the first day after surgery. Pain after discharge was a more common problem. PMID- 28626983 TI - Comparison of systemic pharmacodynamic effects of two combination pressurized metered dose inhalers that deliver salmeterol and fluticasone propionate. AB - AIM: The aim of this study was to test the systemic pharmacodynamic effects of the salmeterol component of two pressurized metered dose inhalers that delivered a combination of salmeterol and fluticasone propionate (SM/FP). METHODS: This was a six-way crossover study in 43 adult subjects, using a single blind design (subject blinded to product and clinical assessor blinded for all measurements). Each subject received single doses of two, six, and twelve inhalations from test and reference products that delivered SM/FP as 25/125 mcg per inhalation. Heart rate, QTcB, and plasma potassium and glucose were monitored over 6 h. RESULTS: Safety equivalence was shown by relative potency analysis for primary endpoints of maximum heart rate and maximum QTcB, since the 90% confidence intervals for both endpoints were within the acceptance limit of (0.67, 1.50). There were six secondary analyses for relative potency and equivalence was met for five of these endpoints. There were also 18 pairwise comparisons performed at each dose level. No statistical differences (95% confidence intervals included zero) among these pairwise comparisons were seen at the two-inhalation dose (therapeutic dose) or the six-inhalation dose. At the supratherapeutic dose of twelve inhalations, the test product was either comparable to or statistically less than that of the reference product for all comparisons. Overall, the results demonstrated comparable systemic safety. No differences were seen between the products in reported adverse events. CONCLUSION: The safety equivalence of the systemic pharmacodynamic effects of the SM component of the test and reference SM/FP products was demonstrated. PMID- 28626984 TI - Biologically Controlled Morphology and Twinning in Guanine Crystals. AB - Guanine crystals are widely used in nature as components of multilayer reflectors. Guanine-based reflective systems found in the copepod cuticle and in the mirror of the scallop eye are unique in that the multilayered reflectors are tiled to form a contiguous packed array. In the copepod cuticle, hexagonal crystals are closely packed to produce brilliant colors. In the scallop eye, square crystals are tiled to obtain an image-forming reflecting mirror. The tiles are about 1 MUm in size and 70 nm thick. According to analysis of their electron diffraction patterns, the hexagon and square tiles are not single crystals. Rather, each tile type is a composite of what appears to be three crystalline domains differently oriented and stacked onto one another, achieved through a twice-repeated twinning about their ?011? and ?021? crystal axes, respectively. By these means, the monoclinic guanine crystal mimics higher symmetry hexagonal and tetragonal structures to achieve unique morphologies. PMID- 28626985 TI - PASH syndrome (pyoderma gangrenosum, acne and hidradenitis suppurativa): a disease with genetic heterogeneity. PMID- 28626986 TI - Trends in sleep studies performed for Medicare beneficiaries. AB - OBJECTIVES/HYPOTHESIS: To quantify trends and characteristics of sleep studies performed for Medicare beneficiaries in the United States. STUDY DESIGN: Retrospective longitudinal study of the Centers for Medicare and Medicaid Services' Part B National Summary Data and Medicare Provider Utilization and Payment Data from 2000 to 2014. METHODS: Sleep study data were analyzed according to type of study performed, total expenditure amount, provider specialty, and geographic location. RESULTS: In 2014, 845,569 sleep studies were completed by 1.4% of Medicare beneficiaries for a total of $189 million. Since 2010, annual expenditures for sleep studies have declined, whereas the number of studies performed has increased by 9.1%. In 2014, polysomnography, split-night polysomnography, and unattended home sleep studies accounted for 40%, 48%, and 12%, respectively, of total sleep studies. This represents a dramatic growth in the number of unattended sleep studies performed since 2000, when they represented only 0.9%. Pulmonologists, independent diagnostic testing facilities, and neurologists are the top specialties that bill for sleep studies. Sleep medicine is a growing specialty and ranked fifth among providers, whereas otolaryngologists ranked eighth. CONCLUSIONS: The healthcare burden of administering sleep studies is substantial, although the annual cost is declining. Unattended sleep studies contribute to decreasing costs and should be considered for patients who meet the correct indications. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2891-2896, 2017. PMID- 28626988 TI - Photodermatitis in a woman on antiretroviral therapy: report of a rare cutaneous adverse drug reaction of efavirenz and review of literature. PMID- 28626987 TI - Prolactinomas diagnosed in the postmenopausal period: Clinical phenotype and outcomes. AB - OBJECTIVE: Most prolactinomas in females are diagnosed during the reproductive age, and the majority are microadenomas. Prolactinomas detected in the postmenopausal period are less common with limited published data on their presentation and prognosis. Our objective was to assess the presenting clinical, biochemical and imaging findings, as well as the outcomes of women diagnosed with a prolactinoma in the postmenopausal period. DESIGN AND METHODS: We undertook a retrospective cohort study of women diagnosed with prolactinoma after menopause and followed up in a large UK pituitary centre. Information on presentation, management and outcomes was collected. RESULTS: Seventeen women with a median age at diagnosis of 63 years (range 52-78) were identified. Headaches and/or visual deterioration were the most commonly reported complaints at detection of the adenoma (47%). Acute pituitary apoplexy was diagnosed at presentation or during follow-up in 18% of the cases. The median serum prolactin was 12 364 mU/L (range 2533-238 479). Macroprolactinomas comprised 94% of the tumours, and 88% of them had supra/parasellar extension. All patients with macroprolactinoma were offered dopamine agonist, and normal prolactin was achieved in 94% of them (median follow up 91.5 months). Adenoma shrinkage was observed in all women. Improvement or resolution of visual disturbances documented at presentation was observed in 86% of cases. CONCLUSIONS: The clinical phenotype of prolactinomas diagnosed in the postmenopausal period is characterized by dominance of macroadenomas, with frequent supra/parasellar extension and a relative high rate of acute pituitary apoplexy. In this group of patients, the response of the macroadenomas to dopamine agonists is good. PMID- 28626989 TI - Electrical isolation of the left atrial appendage by Maze-like catheter substrate modification: A reproducible strategy for pulmonary vein isolation nonresponders? AB - INTRODUCTION: The ablation strategy for atrial fibrillation (AF) despite pulmonary vein isolation (PVI) is controversial. Left atrial appendage isolation (LAAI) may contribute to improve outcome. We describe an ablation approach ("Maze like"-LAAI) that (1) modifies the underlying LA substrate by linear ablation (2) eliminates the LAA as a putative AF trigger site and (3) incorporates an unambiguous procedural endpoint. The role of LAA closure (LAAC) after LAAI was investigated. METHODS: Patients with atrial tachyarrhythmias nonresponsive to PVI underwent a LAAI ablation procedure. LAAI was achieved by combining (a) an anterior line, (b) a LA roof line and (c) a mitral isthmus line. Patients continued oral anticoagulation (OAC) therapy or underwent LAAC >=6 weeks after LAAI. RESULTS: Maze-like LAAI was attempted in our center in 107 of 3,611 AF ablation procedures (2.9%) and achieved in 88 of 107 patients (82%). In 8 of 107 (7%) patients cardiac tamponade occurred, all managed conservatively. During follow-up sinus rhythm was established in 65% at 1 year. After LAAI, 45 patients remained on OAC and 40 underwent LAAC. In both groups 1 patient experienced a bleeding complication. Thromboembolism exclusively occurred in the OAC group in 3 (7%) patients. CONCLUSION: LAA isolation by Maze-like substrate modification may be considered a viable option for PVI non-responders. It offers a reproducible approach with an unambiguous procedural endpoint and leads to a favorable clinical outcome. However, extensive LA ablation increased the risk of tamponade. Consecutive LAA occlusion may offer a nonpharmacologic strategy to overcome the high thromboembolic risk associated with absent mechanical LAA contraction. PMID- 28626991 TI - Discharge Against Medical Advice of Elderly Inpatients in the United States. AB - Discharge against medical advice (DAMA) is associated with greater risk of hospital readmission and higher morbidity, mortality, and costs, but with a rapidly increasing elderly inpatient population, there is a lack of national data on DAMA in this subgroup. The National Inpatient Sample (2003-2013 for trends, 2013 for multivariable analysis, n = 29,290,852) was used to describe trends in DAMA in elderly inpatients, to study diagnosis codes associated with admission, and to assess factors associated with DAMA using multivariable logistic regression. Odds ratios (ORs) and 95% confidence intervals (CIs) are reported for risk factors of interest. Although DAMA rates in individuals aged 65 and older were one fourth of those found in individuals aged 18 to 64, an increasing trend was found in both groups. From 2003 to 2013, rates increased in individuals aged 18 to 64 (from 1.44% to 1.78%) and in those aged 65 and older (from 0.37% to 0.42% (both P < .001). In both age groups, individuals admitted for mental illness had the highest risk of DAMA. Factors associated with higher adjusted odds of DAMA were generally similar between age groups, although risk of DAMA was higher in elderly adults than in those aged 18 to 64 for blacks (OR 1.65, 95% CI 1.49-1.82 vs OR 1.16, 95% CI 1.12-1.20), Hispanics (OR 1.58, 95% CI 1.41-1.77 vs OR 0.83, 95% CI 0.79-0.87), and those in the lowest income quartile (OR 1.57, 95% CI 1.43-1.72 vs OR 1.12, 95% CI 1.08-1.17), suggesting that race/ethnicity and poverty are more pronounced as risk factors for DAMA in elderly inpatients. PMID- 28626992 TI - Recurrent conjunctivitis secondary to Gram-positive bacillus, Bacillus thuringiensis. PMID- 28626990 TI - Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma. AB - BACKGROUND: Asthma is a chronic inflammatory airway disease, associated with episodes of exacerbations. Therapy with inhaled corticosteroids (ICS) targets airway inflammation, which aims to maintain and restore asthma control. Clinical features are only modestly associated with airways inflammation. Therefore, we hypothesized that exhaled volatile metabolites identify longitudinal changes between clinically stable episodes and loss of asthma control. OBJECTIVES: To determine whether exhaled volatile organic compounds (VOCs) as measured by gas chromatography/mass-spectrometry (GC/MS) and electronic nose (eNose) technology discriminate between clinically stable and unstable episodes of asthma. METHODS: Twenty-three patients with (partly) controlled mild to moderate persistent asthma using ICS were included in this prospective steroid withdrawal study. Exhaled metabolites were measured at baseline, during loss of control and after recovery. Standardized sampling of exhaled air was performed, after which samples were analysed by GC/MS and eNose. Univariate analysis of covariance (ANCOVA), followed by multivariate principal component analysis (PCA) was used to reduce data dimensionality. Next paired t tests were utilized to analyse within-subject breath profile differences at the different time-points. Finally, associations between exhaled metabolites and sputum inflammation markers were examined. RESULTS: Breath profiles by eNose showed 95% (21/22) correct classification for baseline vs loss of control and 86% (19/22) for loss of control vs recovery. Breath profiles using GC/MS showed accuracies of 68% (14/22) and 77% (17/22) for baseline vs loss of control and loss of control vs recovery, respectively. Significant associations between exhaled metabolites captured by GC/MS and sputum eosinophils were found (Pearson r>=.46, P<.01). CONCLUSIONS & CLINICAL RELEVANCE: Loss of asthma control can be discriminated from clinically stable episodes by longitudinal monitoring of exhaled metabolites measured by GC/MS and particularly eNose. Part of the uncovered biomarkers was associated with sputum eosinophils. These findings provide proof of principle for monitoring and identification of loss of asthma control by breathomics. PMID- 28626993 TI - Izatt-Christensen Award: H. L. Anderson / Cram Lehn Pedersen Prize: T. F. A. de Greef / Bob Hay Lectureship: S. M. Goldup and S. L. Cockroft. PMID- 28626994 TI - Promoting Inclusion Via Cross-Group Friendship: The Mediating Role of Change in Trust and Sympathy. AB - To understand the conditions fostering positive outcomes of inclusive schooling, this two-wave study examined the role of individual change in trust and sympathy for adolescents' cross-group friendships and inclusive attitudes toward students with low academic achievement. Cross-group friendships, intergroup trust, intergroup sympathy, and inclusive attitudes were obtained from surveys completed by 1,122 Swiss adolescents (Mage T1 = 11.54 years, Mage T2 = 12.58 years) from 61 school classes. Results from a parallel latent change score model revealed that the number of cross-group friendships positively related to individual change in trust and sympathy; this growing trust and sympathy in turn predicted adolescents' inclusive attitudes. These findings are discussed regarding theories of intergroup contact and inclusive schooling. PMID- 28626995 TI - 'Synaptic autocontrol'. PMID- 28626996 TI - Vortex-ultrasound-assisted dispersive liquid-liquid microextraction coupled with gas chromatography-mass spectrometry for the analysis of volatile bioactive components and comparative pharmacokinetic study of the herb-herb interactions in Guanxin Shutong Capsule. AB - Guanxin Shutong Capsule, an effective traditional Chinese medicine, is widely used for coronary heart disease clinically. Volatile components are one of its important bioactive constituents. To better understand the material basis for the therapeutic effects, the components of Guanxin Shutong Capsule absorbed into the blood and their metabolites were identified based on gas chromatography with mass spectrometry coupled with vortex-ultrasound-assisted dispersive liquid-liquid microextraction. As a result, three prototypes and 15 metabolites were identified or tentatively characterized in rat plasma. Subsequently, a pharmacokinetic study was carried out to monitor the concentrations of the main bioactive constituents and metabolites (isoborneol, borneol, eugenol, and camphor) by gas chromatography with mass spectrometry in rat plasma following oral administration of single herb extract and different combinations of herbs in this prescription. Compared to other groups, a statistically significant difference of the pharmacokinetic properties was obtained when the total complex prescription was administered, indicating possible drug-drug interactions among the complex ingredients of Guanxin Shutong Capsule. These findings provided an experimental basis concerning the clinical application and medicinal efficacy of Guanxin Shutong Capsule in the treatment of coronary heart disease. PMID- 28626997 TI - Discovery of a Calcium-Dependent Enzymatic Cascade for the Selective Assembly of Hapalindole-Type Alkaloids: On the Biosynthetic Origin of Hapalindole U. AB - Hapalindole U (4) is a validated biosynthetic precursor to ambiguine alkaloids (Angew. Chem. Int. Ed. 2016, 55, 5780), of which biogenetic origin remains unknown. The recent discovery of AmbU4 (or FamC1) protein encoded in the ambiguine biosynthetic pathway (J. Am. Chem. Soc. 2015, 137, 15366), an isomerocyclase that can rearrange and cyclize geranylated indolenine (2) to a previously unknown 12-epi-hapalindole U (3), raised the question whether 3 is a direct precursor to 4 or an artifact arising from the limited in vitro experiments. Here we report a systematic approach that led to the discovery of an unprecedented calcium-dependent AmbU1-AmbU4 enzymatic complex for the selective formation of 4. This discovery refuted the intermediacy of 3 and bridged the missing links in the early-stage biosynthesis of ambiguines. This work further established the isomerocyclases involved in the biogenesis of hapalindole-type alkaloids as a new family of calcium-dependent enzymes, where the metal ions are shown critical for their enzymatic activities and selectivities. PMID- 28626998 TI - Large coverage black-bright blood interleaved imaging sequence (LaBBI) for 3D dynamic contrast-enhanced MRI of vessel wall. AB - PURPOSE: To propose a large coverage black-bright blood interleaved imaging sequence (LaBBI) for 3D dynamic contrast-enhanced MRI (DCE-MRI) of the vessel wall. METHODS: LaBBI consists of a 3D black-blood stack-of-stars golden angle radial acquisition with high spatial resolution for vessel wall imaging and a 2D bright-blood Cartesian acquisition with high temporal resolution for arterial input function estimation. The two acquisitions were performed in an interleaved fashion within a single scan. Simulations, phantom experiments, and in vivo tests in three patients were performed to investigate the feasibility and performance of the proposed LaBBI. RESULTS: In simulation tests, the estimated Ktrans and vp by LaBBI were more accurate than conventional bright-blood DCE-MRI with lower root mean square error in all the tested conditions. In phantom test, no signal interference was found on the 2D scan in LaBBI. Pharmacokinetic analysis of the patients' data acquired by LaBBI showed that Ktrans was higher in fibrous tissue (0.0717 +/- 0.0279 min-1 ), while lower in necrotic core (0.0206 +/- 0.0040 min-1 ) and intraplaque hemorrhage (0.0078 +/- 0.0007 min-1 ), compared with normal vessel wall (0.0273 +/- 0.0052 min-1 ). CONCLUSION: The proposed LaBBI sequence, with high spatial and temporal resolution, and large coverage blood suppression, was promising to probe the perfusion properties of vessel wall lesions. Magn Reson Med 79:1334-1344, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28626999 TI - Presence of time-dependent diffusion in the brachial plexus. AB - PURPOSE: This work describes the development of a method to measure the variation of apparent diffusion coefficient (ADC) with diffusion time (Delta) in the brachial plexus, as a potential method of probing microstructure. METHODS: Diffusion-weighted MRI with body signal suppression was used to highlight the nerves from surrounding tissues, and sequence parameters were optimized for sensitivity to change with diffusion time. A porous media-restricted diffusion model based on the Latour-Mitra equation was fitted to the diffusion time dependent ADC data from the brachial plexus nerves and cord. RESULTS: The ADC was observed to reduce at long diffusion times, confirming that diffusion was restricted in the nerves and cord in healthy subjects. T2 of the nerves was measured to be 80 +/- 5 ms, the diffusion coefficient was found to vary from (1.5 +/- 0.1) * 10-3 mm2 /s at a diffusion time of 18.3 ms to (1.0 +/- 0.2) * 10-3 mm2 /s at a diffusion time of 81.3 ms. CONCLUSION: A novel method of probing restricted diffusion in the brachial plexus was developed. Resulting parameters were comparable with values obtained previously on biological systems. Magn Reson Med 79:789-795, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28627000 TI - Pencil beam scanned protons for the treatment of patients with Ewing sarcoma. AB - BACKGROUND: Few data exist regarding the clinical outcome of patients with Ewing sarcoma (EWS) treated with pencil beam scanning proton therapy (PT). We report the outcome of children, adolescents and young adults (AYA) treated with PT at the Paul Scherrer Institute. MATERIALS: Thirty-eight patients (median age, 9.9 years) received a median dose of 54.9 Gy(RBE) (where RBE is relative biologic effectiveness). Size of the tumor ranged from 1.7 to 24 cm. Most common primary site was axial/pelvic (n = 27; 71%). Four patients (11%) presented with metastases at diagnosis. Twenty (53%) patients had chemo-PT only. Median follow up was 49.6 months (range, 9.2-131.7). RESULTS: The 5-year actuarial rate of local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were 81.5%, 76.4%, and 83.0%, respectively. All local recurrences occurred in field and in patients with nonextremity primaries. Six patients died, all of tumor progression. Age < 10 years was a favorable factor of borderline significance for LC (P = 0.05) and OS (P = 0.05), but was significant for DMFS (P = 0.003). Tumor volume <200 ml was a significant prognostic factors for DMFS (P = 0.03), but not for OS (P = 0.07). Metastasis at diagnosis was a strong predictor of local failure (P = 0.003). Only two grade 3 late toxicities were observed. The 5-year actuarial rate of grade 3 toxicity-free survival was 90.9%. CONCLUSIONS: These preliminary data suggest that the outcomes of children and AYA with EWS are good and PT was well tolerated with few late adverse events. The local and distant tumor control for older patients with large pre-PT tumor volumes remains problematic. PMID- 28627001 TI - Tissue blood flow to a pedicled jejunal autograft in the dog: A pilot study. AB - OBJECTIVE: To determine the viability of a pedicled jejunal autograft after ligation of up to 3 jejunal arteries. STUDY DESIGN: Prospective crossover study. ANIMALS: Three adult dogs. METHODS: Dogs were instrumented for measurement of hemodynamic parameters. Two segments of jejunum with 4 arcadial vessels were isolated from the abdomen in each dog. An individual ligature was secured around the 4th, 3rd, and 2nd jejunal artery. The 1st jejunal artery was maintained to serve as the sole blood supply to the pedicled segment of jejunum. Colored microspheres were used to evaluate the effect of each ligation on tissue blood flow. RESULTS: Mean arterial blood pressure (P = .709) and heart rate (P = .905) did not differ between ligation groups. Tissue blood flow to a pedicled segment of jejunum was unchanged after ligation of 3 jejunal arteries. CONCLUSION: Tissue blood flow of an isolated jejunal segment maintained in normal position remains unaffected, when supplied by a single jejunal artery, after ligation of up to 3 concurrent jejunal arteries. PMID- 28627002 TI - Does personalized melanoma genomic risk information trigger conversations about skin cancer prevention and skin examination with family, friends and health professionals? AB - BACKGROUND: Receiving information about genomic risk of melanoma might trigger conversations about skin cancer prevention and skin examinations. OBJECTIVES: To explore conversations prompted by receiving personalized genomic risk of melanoma with family, friends and health professionals. METHODS: We used a mixed-methods approach. Participants without a personal history and unselected for a family history of melanoma (n = 103, aged 21-69 years, 53% women) completed questionnaires 3 months after receiving a personalized melanoma genomic risk assessment. Semistructured interviews were undertaken with 30 participants in high, average and low genomic risk categories, and data were analysed thematically. RESULTS: From the questionnaires, 74% of participants communicated their genomic risk information with family, and 49% with friends. Communication with a health professional differed by risk level: 41%, 16% and 12% for high, average and low risk, respectively (P = 0.01). Qualitative analysis showed that perceived 'shared risk' and perceived interest of family and friends were motivations for discussing risk or prevention behaviours. The information prompted conversations with family and health professionals about sun protection and skin checks, and general conversations about melanoma risk with friends. Reasons for not discussing with family included existing personal or family health concerns, or existing high levels of sun protection behaviour among family members. CONCLUSIONS: Personalized melanoma genomic risk information can prompt risk-appropriate discussions about skin cancer prevention and skin examinations with family and health professionals. Sharing this information with others might increase its impact on melanoma prevention and skin examination behaviours, and this process could be used to encourage healthy behaviour change within families. PMID- 28627003 TI - Sonographic screening for Wilms tumor in children with CLOVES syndrome. AB - BACKGROUND: CLOVES syndrome is associated with somatic mosaic PIK3CA mutations and characterized by congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies. Wilms tumor (WT) is a malignant embryonal renal neoplasm associated with hemihypertrophy and certain overgrowth disorders. After identifying WT in a child with CLOVES, we questioned whether ultrasonographic screening was necessary in these patients. METHODS: We retrospectively reviewed patients with CLOVES syndrome in our Vascular Anomalies Center at Boston Children's Hospital between 1998 and 2016 to identify those who developed WT. A PubMed literature search was also conducted to find other patients with both conditions. RESULTS: A total of 122 patients with CLOVES syndrome were found in our database (mean age 7.7 years, range 0-53 years). Four patients developed WT; all were diagnosed by 2 years of age. The incidence of WT in our CLOVES patient population (3.3%) was significantly greater than the incidence of WT in the general population (1/10,000) (P < 0.001). Four additional patients with WT and CLOVES syndrome were identified in our literature review. CONCLUSION: Patients with CLOVES syndrome have an increased risk of WT. Given the benefits of early detection and treatment, children with CLOVES syndrome should be considered for quarterly abdominal ultrasonography until age 7 years. Screening may be most beneficial for patients under 3 years of age. PMID- 28627004 TI - Utility of the urine reagent strip leucocyte esterase assay for the diagnosis of meningitis in resource-limited settings: meta-analysis. AB - OBJECTIVE: Diagnosis of bacterial meningitis often requires cytometry, chemistry and/or microbiologic culture capabilities. Unfortunately, laboratory resources in low-resource settings (LRS) often lack the capacity to perform these studies. We sought to determine whether the presence of white blood cells in CSF detected by commercially available urine reagent strips could aid in the diagnosis of bacterial meningitis. METHODS: We searched PubMed for studies published between 1980 and 2016 that investigated the use of urine reagent strips to identify cerebrospinal fluid (CSF) pleocytosis. We assessed studies in any language that enrolled subjects who underwent lumbar puncture and had cerebrospinal fluid testing by both standard laboratory assays and urine reagent strips. We abstracted true-positive, false-negative, false-positive and true-negative counts for each study using a diagnostic threshold of >=10 white blood cells per microlitre for suspected bacterial meningitis and performed mixed regression modelling with random effects to estimate pooled diagnostic accuracy across studies. RESULTS: Our search returned 13 studies including 2235 participants. Urine reagent strips detected CSF pleocytosis with a pooled sensitivity of 92% (95% CI: 84-96), a pooled specificity of 98% (95% CI: 94-99) and a negative predictive value of 99% when the bacterial meningitis prevalence is 10%. CONCLUSIONS: Urine reagent strips could provide a rapid and accurate tool to detect CSF pleocytosis, which, if negative, can be used to exclude diagnosis of bacterial meningitis in settings without laboratory infrastructure. Further investigation of the diagnostic value of using protein, glucose and bacteria components of these strips is warranted. PMID- 28627005 TI - Serum Interleukin-37: a new player in Lupus Nephritis? AB - INTRODUCTION: Interleukin-37 (IL-37) has been proved to be a fundamental natural suppressor of innate immunity and inflammatory responses in autoimmune diseases such as systemic lupus erythematous (SLE). The purpose of this study was to assess serum IL-37 level in SLE patients and its correlation with disease activity and clinical and laboratory manifestations of SLE patients. PATIENTS/METHODS: The serum level of IL-37 was assessed and analyzed in 100 SLE patients and 50 healthy controls by using enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory manifestations and disease activity using SLE Disease Activity Index (SLEDAI) were also assessed. RESULTS: IL-37 serum level was significantly higher among SLE patients than controls. It has statistically significant correlation with disease activity, renal and mucocutaneous involvement in SLE patients. CONCLUSION: IL-37 level is elevated in SLE patients in comparison to healthy controls and is correlated to high disease activity, mucocutaneous and renal involvement. PMID- 28627006 TI - Parents' perceptions during the transition to home for their child with a congenital heart defect: How can we support families of children with hypoplastic left heart syndrome? AB - PURPOSE: The aim of the study was to explore the literature related to transitions in healthcare between the hospital and home that caregivers experience with a child who has a congenital heart defect (CHD), specifically related to hypoplastic left heart syndrome (HLHS). DESIGN AND METHODS: A systematic literature review was conducted searching OVID Medline, CINAHL, and PubMed to discover the caregivers' perceptions on their transitions between hospital care and home care of their child with a CHD. Articles included those with focus on the transitions of caregivers between hospital and home care for children with CHD. Excluded articles were studies focused on adolescents, transition to adult healthcare, mortality results, other diseases associated with CHDs, comparison of CHD treatments, feasibility studies, differences in care between hospitals, home monitoring, and comparison of videoconference and telephone home communication. RESULTS: Ten articles were selected. Many parents voiced their concerns with feeding their child, learning medical skills and knowledge, reported a disrupted relationship between parents and their child, and identified stress and anxiety associated with taking care of a child with a CHD. PRACTICE IMPLICATIONS: There were limited studies on caregivers' transitions with a child with HLHS, but there also was limited focus on the caregivers' experiences with transitions between hospital and home care for their child with any CHD. Research on the transition experience between hospital care and home care for caregivers of children born with a CHD, and a specific focus on HLHS from the caregivers' viewpoint, would provide insight into the perspective of caregivers during the numerous transitions. PMID- 28627007 TI - Optical molecular imaging-guided radiation therapy part 1: Integrated x-ray and bioluminescence tomography. AB - PURPOSE: X-ray CT faces challenges in differentiating tumors from surrounding healthy tissues. A bioluminescence tomography (BLT) system which can directly reconstruct the internal luminescent tumors, was developed and integrated with CT system to accurately guide radiation dose delivery. METHODS: The BLT system, employing a lens-coupled CCD camera, was physically registered with an onboard cone beam CT system in an image-guided small animal arc radiation treatment system (iSMAART). The onboard CT provides animal anatomy and accurate surface contour used to construct the three-dimensional mesh for the BLT reconstruction. Bioluminescence projections were captured from multiple angles, once every 90 degrees rotation. The BLT reconstruction was performed on an orthotopic prostate tumor model to evaluate its robustness and accuracy in locating and delineating bioluminescent tumors. The location and volume of the tumor identified from iodinated contrast CT was used to validate the BLT performance. Phantom experiment was also conducted to confirm the precision of BLT-guided radiation. RESULTS: The BLT was able to accurately locate the bioluminescent tumors with < 0.5 mm error. The tumor volume in BLT was significantly correlated with that in the iodinated contrast CT (R2 = 0.81, P < 0.001). Phantom experiments further validated that BLT can be used to guide radiation with submillimeter accuracy. CONCLUSION: Together with CT, BLT can provide precision radiation guidance and robust tumor volume assessment in small animal cancer research. PMID- 28627008 TI - Invasive Trichophyton rubrum mimicking blastomycosis in a patient with solid organ transplant. AB - We present a case of tissue invasive Trichophyton rubrum (T. rubrum) histologically mimicking blastomycosis in a patient with kidney transplant on chronic immunosuppression. Invasive dermatophyte infections are rare, and present a diagnostic challenge to the dermatopathologist due to atypical clinical and histopathological presentations. PMID- 28627009 TI - Iron-Catalyzed Radical Decarboxylative Oxyalkylation of Terminal Alkynes with Alkyl Peroxides. AB - An iron-catalyzed oxyalkylation of alkynes with alkyl peroxides as the alkylating reagents has been investigated. Alkyl peroxides are readily available from aliphatic acids and serve simultaneously as the alkylating reagents and internal oxidants. Primary, secondary, and tertiary alkyl groups of aliphatic acids were readily incorporated into C-C triple bonds and diverse alpha-alkylated ketones were synthesized. Mechanism studies revealed that this reaction involves highly reactive alkyl free radicals. A unique equilibrium between lauric acid and water catalyzed by the iron(III) catalyst was observed. PMID- 28627010 TI - A turtle cognition research demonstration enhances visitor engagement and keeper animal relationships. AB - Environmental enrichment techniques present animals with cognitive challenges while providing them opportunities to make choices and exert control over their environment. In this way, cognitive research and training is enriching to animals and can be used as a form of enrichment in zoos and aquariums. Cognitive research demonstrations also provide an opportunity to enhance visitor experience, as well as foster interactions between animals and keepers. We investigated how cognitive research sessions involving eastern box turtles (Terrapene carolina carolina) at Disney's Animal Kingdom(r) impacted both the rate of visitors coming to the exhibit and the amount of time they spent engaged. Further, we used a questionnaire to assess the impact of keeper participation in these sessions on their relationships with and perceptions of the turtles. While visitation rate to the exhibit was not impacted, cognitive research sessions held visitor attention for longer than keeper interpretation or at times during which no keepers or researchers were present. We also found that keepers that had worked with the turtles for longer and keepers that regularly participated in cognitive research sessions reported stronger bonds with the turtles. Our research suggests that use of cognitive research and training demonstrations for guest viewing in zoos and aquariums may enhance visitor learning opportunities by increasing the amount of time they spend at the exhibit. Our study also provides evidence that participation in such demonstrations by zoo and aquarium professionals can be related to improved keeper-animal bonds, potentially resulting in better husbandry and enhanced animal welfare. PMID- 28627011 TI - When Gesture Becomes Analogy. AB - Analogy researchers do not often examine gesture, and gesture researchers do not often borrow ideas from the study of analogy. One borrowable idea from the world of analogy is the importance of distinguishing between attributes and relations. Gentner (, ) observed that some metaphors highlight attributes and others highlight relations, and called the latter analogies. Mirroring this logic, we observe that some metaphoric gestures represent attributes and others represent relations, and propose to call the latter analogical gestures. We provide examples of such analogical gestures and show how they relate to the categories of iconic and metaphoric gestures described previously. Analogical gestures represent different types of relations and different degrees of relational complexity, and sometimes cohere into larger analogical models. Treating analogical gestures as a distinct phenomenon prompts new questions and predictions, and illustrates one way that the study of gesture and the study of analogy can be mutually informative. PMID- 28627012 TI - Effect of Betamethasone on Fetal Pulmonary and Umbilical Artery Doppler Velocimetry and Relationship With Respiratory Distress Syndrome Development. AB - OBJECTIVES: Respiratory distress syndrome (RDS) is a major cause of neonatal morbidity and mortality. It is primarily a disease of premature neonates. The aim of this study was to evaluate the impact of maternal betamethasone administration on the fetal pulmonary arteries (PAs) and umbilical arteries (UAs) and the correlation between RDS development and PA Doppler results. METHODS: Forty singleton pregnancies between 24 and 34 gestational weeks with a diagnosis of preterm birth were included prospectively. They received corticosteroids to enhance fetal lung maturity. Fetal PA and UA Doppler parameters were evaluated before and 48 to 72 hours after steroid administration. Maternal records were matched to neonatal charts, and demographic and outcome data were abstracted. RESULTS: There were no differences between groups for maternal age, body mass index, mode of delivery, and mean GA at steroid administration. Apgar scores at 1 and 5 minutes were significantly lower for neonates who developed RDS (P < .05). There were no statistically significant differences in PA Doppler results between fetuses who developed RDS and those who did not, and there were no significant differences in PA Doppler results before and after steroid administration for both groups. The UA pulsatility and resistive indices were significantly lower after steroid administration for the neonates who developed RDS (P < .05). CONCLUSIONS: There were no significant differences in PA Doppler indices for fetuses with or without RDS after steroid administration. PMID- 28627013 TI - Regular exercise improves the well-being of parents of children with cancer. AB - AIM: Parents of children with cancer describe impaired physical and social functioning, sleep disturbance and poor mental health. Exercise-related interventions impact positively on these quality of life domains, but have not been examined in this population. The aim of this longitudinal pilot study was to explore the feasibility of a 12-week pedometer-monitored walking intervention among parents of children with cancer, assessing adherence to a set activity target of 70,000 steps per week, and to explore the benefits of physical activity on mental and physical health. METHODS: Parents were provided with a pedometer and requested to achieve a daily step count of 10,000 steps per day for 12 weeks. Mood, well-being and psychological distress were examined using validated questionnaires (Profile of Mood States 2nd edition [POMS-2], Distress Thermometer for Parents [DT-P] and Depression Anxiety Stress Scales [DASS-42]) at baseline, midpoint (6 weeks) and endpoint (12 weeks) to identify changes in these domains with increased activity. RESULTS: Fifteen parents were recruited. The majority increased their counts during the first 4 weeks of the study and maintained this to week 8 (n = 12). Time-dependent improvements were identified in the following psychometric test outcomes at week 12: DT-P score (likelihood ratio test [LRT] P = 0.02), POMS-2 total mood disturbance (LRT P = 0.03), fatigue inertia (LRT P = 0.009), tension anxiety (LRT P = 0.007) and vigour activity (LRT P = 0.001). CONCLUSIONS: Mental health benefits of a pedometer-based exercise intervention for parents of children with cancer were identified. Such programs should be included in a holistic approach to improve the psychological outcomes of parents whose children are receiving treatment for cancer. PMID- 28627015 TI - Small Proteins Encoded by Unannotated ORFs are Rising Stars of the Proteome, Confirming Shortcomings in Genome Annotations and Current Vision of an mRNA. AB - Short ORF-encoded peptides and small proteins in eukaryotes have been hiding in the shadow of large proteins for a long time. Recently, improved identifications in MS-based proteomics and ribosome profiling resulted in the detection of large numbers of small proteins. The variety of functions of small proteins is also emerging. It seems to be the right time to reflect on why small proteins remained invisible. In addition to the obvious technical challenge of detecting small proteins, they were mostly forgotten from annotations and they escaped detection because they were not sought. In this review, we identify conventions that need to be revisited, including the assumption that mature mRNAs carry only one coding sequence. The large-scale discovery of small proteins and of their functions will require changing some paradigms and undertaking the annotation of ORFs that are still largely perceived as irrelevant coding information compared to already annotated coding sequences. PMID- 28627014 TI - Review article: Paediatric status epilepticus in the pre-hospital setting: An update. AB - Paediatric status epilepticus (SE) is a medical emergency and a common critical condition confronting pre-hospital providers. Management in the pre-hospital environment is challenging but considered extremely important as a potentially modifiable factor on outcome. Recent data from multicentre clinical trials, quality observational studies and consensus documents have influenced management in this area, and is important to both pre-hospital providers and emergency physicians. The objective of this review was to: (i) present an overview of the available evidence relevant to pre-hospital care of paediatric SE; and (ii) assess the current pre-hospital practice guidelines in Australia and New Zealand. The review outlines current definitions and guidelines of SE management, regional variability in pre-hospital protocols within Australasia and aspects of pre hospital care that could potentially be improved. Contemporary data is required to determine current practice in our setting. It is important that paediatric neurologists, emergency physicians and pre-hospital care providers are all engaged in future endeavours to improve clinical care and knowledge translation efforts for this patient group. PMID- 28627016 TI - Unique clinical conditions associated with different acinar regions of fibrosis in long-term surviving pediatric liver grafts. AB - In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and gammaGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions. PMID- 28627018 TI - The nucleotide-free state of heterotrimeric G proteins alpha-subunit adopts a highly stable conformation. AB - Deciphering the mechanism of activation of heterotrimeric G proteins by their cognate receptors continues to be an intriguing area of research. The recently solved crystal structure of the ternary complex captured the receptor-bound alpha subunit in an open conformation, without bound nucleotide has improved our understanding of the activation process. Despite these advancements, the mechanism by which the receptor causes GDP release from the alpha-subunit remains elusive. To elucidate the mechanism of activation, we studied guanine nucleotide induced structural stability of the alpha-subunit (in response to thermal/chaotrope-mediated stress). Inherent stabilities of the inactive (GDP bound) and active (GTP-bound) forms contribute antagonistically to the difference in conformational stability whereas the GDP-bound protein is able to switch to a stable intermediate state, GTP-bound protein loses this ability. Partial perturbation of the protein fold reveals the underlying influence of the bound nucleotide providing an insight into the mechanism of activation. An extra stable, pretransition intermediate, 'empty pocket' state (conformationally active state like) in the unfolding pathway of GDP-bound protein mimics a gating system the activation process having to overcome this stable intermediate state. We demonstrate that a relatively more complex conformational fold of the GDP-bound protein is at the core of the gating system. We report capturing this threshold, 'metastable empty pocket' conformation (the gate) of alpha-subunit of G protein and hypothesize that the receptor activates the G protein by enabling it to achieve this structure through mild structural perturbation. PMID- 28627017 TI - Functional expression of calcium-permeable canonical transient receptor potential 4-containing channels promotes migration of medulloblastoma cells. AB - KEY POINTS: The proton sensing ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) promotes expression of the canonical transient receptor potential channel subunit TRPC4 in normal and transformed cerebellar granule precursor (DAOY) cells. OGR1 and TRPC4 are prominently expressed in healthy cerebellar tissue throughout postnatal development and in primary cerebellar medulloblastoma tissues. Activation of TRPC4-containing channels in DAOY cells, but not non transformed granule precursor cells, results in prominent increases in [Ca2+ ]i and promotes cell motility in wound healing and transwell migration assays. Medulloblastoma cells not arising from granule precursor cells show neither prominent rises in [Ca2+ ]i nor enhanced motility in response to TRPC4 activation unless they overexpressTRPC4. Our results suggest that OGR1 enhances expression of TRPC4-containing channels that contribute to enhanced invasion and metastasis of granule precursor-derived human medulloblastoma. ABSTRACT: Aberrant intracellular Ca2+ signalling contributes to the formation and progression of a range of distinct pathologies including cancers. Rises in intracellular Ca2+ concentration occur in response to Ca2+ influx through plasma membrane channels and Ca2+ release from intracellular Ca2+ stores, which can be mobilized in response to activation of cell surface receptors. Ovarian cancer G protein coupled receptor 1 (OGR1, aka GPR68) is a proton-sensing Gq -coupled receptor that is most highly expressed in cerebellum. Medulloblastoma (MB) is the most common paediatric brain tumour that arises from cerebellar precursor cells. We found that nine distinct human MB samples all expressed OGR1. In both normal granule cells and the transformed human cerebellar granule cell line DAOY, OGR1 promoted expression of the proton-potentiated member of the canonical transient receptor potential (TRPC) channel family, TRPC4. Consistent with a role for TRPC4 in MB, we found that all MB samples also expressed TRPC4. In DAOY cells, activation of TRPC4-containing channels resulted in large Ca2+ influx and enhanced migration, while in normal cerebellar granule (precursor) cells and MB cells not derived from granule precursors, only small levels of Ca2+ influx and no enhanced migration were observed. Our results suggest that OGR1-dependent increases in TRPC4 expression may favour formation of highly Ca2+ -permeable TRPC4-containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of MB. PMID- 28627019 TI - Identification of differentially regulated maize proteins conditioning Sugarcane mosaic virus systemic infection. AB - Sugarcane mosaic virus (SCMV) is the most important cause of maize dwarf mosaic disease. To identify maize genes responsive to SCMV infection and that may be involved in pathogenesis, a comparative proteomic analysis was performed using the first and second systemically infected leaves (termed 1 SL and 2 SL, respectively). Seventy-one differentially expressed proteins were identified in 1 SL and 2 SL upon SCMV infection. Among them, eight proteins showed the same changing patterns in both 1 SL and 2 SL. Functional annotations of regulated proteins and measurement of photosynthetic activity revealed that photosynthesis was more inhibited and defensive gene expression more pronounced in 1 SL than in 2 SL. Knockdown of regulated proteins in both 1 SL and 2 SL by a brome mosaic virus-based gene silencing vector in maize indicated that protein disulfide isomerase-like and phosphoglycerate kinase were required for optimal SCMV replication. By contrast, knockdown of polyamine oxidase (ZmPAO) significantly increased SCMV accumulation, implying that ZmPAO activity might contribute to resistance or tolerance. The results suggest that combining comparative proteomic analyses of different tissues and virus-induced gene silencing is an efficient way to identify host proteins supporting virus replication or enhancing resistance to virus infection. PMID- 28627020 TI - Structural studies of a hyperthermophilic thymidylate kinase enzyme reveal conformational substates along the reaction coordinate. AB - : Thymidylate kinase (TMK) is a key enzyme which plays an important role in DNA synthesis. It belongs to the family of nucleoside monophosphate kinases, several of which undergo structure-encoded conformational changes to perform their function. However, the absence of three-dimensional structures for all the different reaction intermediates of a single TMK homolog hinders a clear understanding of its functional mechanism. We herein report the different conformational states along the reaction coordinate of a hyperthermophilic TMK from Aquifex aeolicus, determined via X-ray diffraction and further validated through normal-mode studies. The analyses implicate an arginine residue in the Lid region in catalysis, which was confirmed through site-directed mutagenesis and subsequent enzyme assays on the wild-type protein and mutants. Furthermore, the enzyme was found to exhibit broad specificity toward phosphate group acceptor nucleotides. Our comprehensive analyses of the conformational landscape of TMK, together with associated biochemical experiments, provide insights into the mechanistic details of TMK-driven catalysis, for example, the order of substrate binding and the reaction mechanism for phosphate transfer. Such a study has utility in the design of potent inhibitors for these enzymes. DATABASE: Structural data are available in the PDB under the accession numbers 2PBR, 4S2E, 5H5B, 5XAI, 4S35, 5XB2, 5H56, 5XB3, 5H5K, 5XB5, and 5XBH. PMID- 28627021 TI - Superficial papular neuroma: Case series of a new entity. AB - BACKGROUND: Dermal neural lesions arise in various circumstances and may be difficult to classify. METHODS: We describe the clinical, histopathologic and immunophenotypic features of a series of terminally differentiated neural lesions not described previously, to our knowledge. RESULTS: Four cases from men aged 58 to 66 years were included. Some lesions reportedly bled, but no inciting trauma or prior biopsies were reported. None recurred after biopsy, with follow-up ranging from 19 to 113 months. All lesions were papular, with vertically oriented S100-positive spindled cells and nerve fibers in the papillary dermis. Slight epidermal hyperplasia, dilated superficial thin-walled vessels and minimal to mild inflammation were seen in each. Fibers were uniformly fine in 3 cases, with slightly thicker central fibers in the fourth. Three had parakeratotic scale. None were associated with dermal fibrosis or adnexal proliferation. Neurofilament stained axons in each. EMA was negative in all cases. CD34, melan-A and HMB45 were negative when performed. CONCLUSIONS: We report a small series of benign neural lesions and propose the name "superficial papular neuroma" for this distinct entity. Awareness is important to understand the clinical significance of these lesions and avoid misinterpretation that could lead to overtreatment, unnecessary work-up and increased cost. PMID- 28627022 TI - DFT Studies of Dimerization Reactions of Boroles. AB - Boroles undergo dimerization reactions to give Diels-Alder (DA) dimers, bridged bicyclic (BB) dimers or spiro dimers (SD) depending on the substituents on the borole. We performed DFT calculations to investigate how different substituents at the carbon atoms of the butadiene backbone as well as at the boron atom influence the dimerization reaction pathways. The DFT results show that, in general, both the DA and BB dimers are easily accessible kinetically, and the DA dimers are thermodynamically more stable than the BB dimers. When the substituent substituent repulsive steric interactions are alleviated to a certain extent, the BB dimers are more stable than the DA dimer, and become accessible. The SD dimers are generally kinetically difficult to obtain. However, we found that aryl substituents promote the formation of the SD dimers. PMID- 28627023 TI - Cinchona alkaloid derivatives catalyzed asymmetric aza-Friedel-crafts reaction of alpha-naphthols with aryl aldimines. AB - Cinchona alkaloid derivatives as organocatalysts were applied in the asymmetric aza-Friedel-Crafts reaction of alpha-naphthol with aryl aldimines. The desired chiral aminoarylnaphthols were obtained in 85% enantiomeric excess. PMID- 28627024 TI - The applicability of a weight loss grading system in cancer cachexia: a longitudinal analysis. AB - BACKGROUND: A body mass index (BMI) adjusted weight loss grading system (WLGS) is related to survival in patients with cancer. The aim of this study was to examine the applicability of the WLGS by confirming its prognostic validity, evaluating its relationship to cachexia domains, and exploring its ability to predict cachexia progression. METHODS: An international, prospective observational study of patients with incurable cancer was conducted. For each patient, weight loss grade was scored 0-4. Weight loss grade 0 represents a high BMI with limited weight loss, progressing through to weight loss grade 4 representing low BMI and a high degree of weight loss. Survival analyses were used to confirm prognostic validity. Analyses of variance were used to evaluate the relationship between the WLGS and cachexia domains [anorexia, dietary intake, Karnofsky performance status (KPS), and physical and emotional functioning]. Cox regression was used to evaluate if the addition of cachexia domains to the WLGS improved prognostic accuracy. Predictive ability of cachexia progression was assessed by estimating proportion of patients progressing to a more advanced weight loss grade. RESULTS: One thousand four hundred six patients were analysed (median age 66 years; 50% female, 63% KPS <= 70). The overall effect of the WLGS on survival was significant as expressed by change in -2 log likelihood (P < 0.001) and persisted after adjustment for age, sex, and cancer type and stage (P < 0.001). Median survival decreased across the weight loss grades ranging from 407 days (95% CI 312-502)-weight loss grade 0 to 119 days (95% CI 93-145)-weight loss grade 4. All cachexia domains significantly deteriorated with increasing weight loss grade, and deterioration was greatest for dietary intake, with a difference corresponding to 0.87 standard deviations between weight loss grades 0 and 4. The addition of KPS, anorexia, and physical and emotional functioning improved the prognostic accuracy of the WLGS. Likelihood of cachexia progression was greater in patients with weight loss grade 2 (39%) than that with weight loss grade 0 (19%) or 1 (22%). CONCLUSIONS: The WLGS is related to survival, cachexia domains, and the likelihood of progression. Adding certain cachexia domains to the WLGS improves prognostic accuracy. PMID- 28627025 TI - Novel RANKL DE-loop mutants antagonize RANK-mediated osteoclastogenesis. AB - Bone is a dynamic tissue that is maintained by continuous renewal. An imbalance in bone resorption and bone formation can lead to a range of disorders, such as osteoporosis. The receptor activator of NF-kappaB (RANK)-RANK-ligand (RANKL) pathway plays a major role in bone remodeling. Here, we investigated the effect of mutations at position I248 in the DE-loop of murine RANKL on the interaction of RANKL with RANK, and subsequent activation of osteoclastogenesis. Two single mutants, RANKL I248Y and I248K, were found to maintain binding and have the ability to reduce wild-type RANKL-induced osteoclastogenesis. The generation of RANK-antagonists is a promising strategy for the exploration of new therapeutics against osteoporosis. PMID- 28627026 TI - Two NHX-type transporters from Helianthus tuberosus improve the tolerance of rice to salinity and nutrient deficiency stress. AB - The NHX-type cation/H+ transporters in plants have been shown to mediate Na+ (K+ )/H+ exchange for salinity tolerance and K+ homoeostasis. In this study, we identified and characterized two NHX homologues, HtNHX1 and HtNHX2 from an infertile and salinity tolerant species Helianthus tuberosus (cv. Nanyu No. 1). HtNHX1 and HtNHX2 share identical 5'- and 3'-UTR and coding regions, except for a 342-bp segment encoding 114 amino acids (L272 to Q385 ) which is absent in HtNHX2. Both hydroponics and soil culture experiments showed that the expression of HtNHX1 or HtNHX2 improved the rice tolerance to salinity. Expression of HtNHX2, but not HtNHX1, increased rice grain yield, harvest index, total nutrient uptake under K+ -limited salt-stress or general nutrient deficiency conditions. The results provide a novel insight into NHX function in plant mineral nutrition. PMID- 28627027 TI - Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis. AB - BACKGROUND: We aimed to elucidate the relationship between serum myostatin levels and other markers including skeletal muscle mass and to investigate the influence of serum myostatin levels on survival for patients with liver cirrhosis (LC). METHODS: A total of 198 LC subjects were analysed in this study. Myostatin levels were measured using stored sera. We retrospectively investigated the relationship between myostatin level and other markers, and the influence of myostatin level on overall survival (OS). Assessment of skeletal muscle mass was performed using the psoas muscle index (PMI) on computed tomography images at baseline. PMI indicates the sum of bilateral psoas muscle mass calculated by hand tracing at the lumber three level on computed tomography images divided by height squared (cm2 /m2 ). The study cohort was divided into two groups based on the median myostatin value in each gender. RESULTS: Our study cohort included 108 male and 90 female patients with a median age of 67.5 years. The median (range) myostatin level for male patients was 3419.6 pg/mL (578.4-12897.7 pg/mL), whereas that for female patients was 2662.4 pg/mL (710.4-8782.0 pg/mL) (P = 0.0024). Median (range) serum myostatin level for Child-Pugh A patients (n = 123) was 2726.0 pg/mL (578.4-12667.2 pg/mL), whereas that for Child-Pugh B or C patients (n = 75) was 3615.2 pg/mL (663.3-12897.7 pg/mL) (P = 0.0011). For the entire cohort, the 1 , 3-, 5-, and 7-year cumulative OS rates were 93.94%, 72.71%, 50.37%, and 38.47%, respectively, in the high-myostatin group and 96.97%, 83.27%, 73.60%, and 69.95%, respectively, in the low-myostatin group (P = 0.0001). After excluding hepatocellular carcinoma patients (at baseline) from our analysis (n = 158), the 1-, 3-, 5-, and 7-year cumulative OS rates were 96.0%, 77.93%, 52.97%, and 39.08%, respectively, in the high-myostatin group and 96.39%, 87.58%, 77.63%, and 73.24%, respectively, in the low-myostatin group (P = 0.0005). Higher age (P = 0.0111) and lower PMI (P < 0.0001) were identified as significant predictors of poorer OS in our multivariate analysis, while higher serum myostatin (P = 0.0855) tended to be a significant adverse predictor. In both genders, PMI, serum albumin, prothrombin time, and branched-chain amino acid to tyrosine ratio showed a significantly inverse correlation with myostatin levels, and serum ammonia levels showed a significantly positive correlation with myostatin levels. CONCLUSIONS: Higher serum myostatin levels correlated with muscle mass loss, hyperammonemia, and impaired protein synthesis, as reflected by lower serum albumin levels and lower branched-chain amino acid to tyrosine ratio levels. High serum myostatin levels were also associated with a reduced OS rate in LC patients. PMID- 28627028 TI - Common Findings in Late-Gestation Fetal Echocardiography. AB - OBJECTIVES: Fetal echocardiography provides detailed information about cardiac structure and function in utero. Limited information is available regarding normal findings late in pregnancy. We therefore sought to identify and describe common cardiac findings in late gestation. METHODS: Fetuses with structurally normal hearts were identified in mid gestation within a subset of pregnant women in a prospective study. The atrioventricular valves, right and left atria, aortic isthmus and ductus arteriosus dimensions and flow abnormalities, aneurysm of the septum primum, and presence and grade of tricuspid regurgitation were assessed throughout pregnancy. Linear and logistic regression analyses were used to characterize changes in quantitative and qualitative fetal echocardiographic parameters by gestational age (GA). RESULTS: Forty fetuses between 24 and 38 weeks' GA were studied. Each had a fetal echocardiographic study completed before and after 34 weeks' gestation, which were compared. Tricuspid-to-mitral valve and right-to-left atrium ratios increased with GA (P < .001). More frequently noted after 34 weeks were tapering of the ductus arteriosus (2.5% versus 32%), prominent aortic isthmus diastolic flow (5% versus 67%), prominent ductus arteriosus diastolic flow (2.5% versus 25%), trivial or mild tricuspid regurgitation (35% versus 80%), and aneurysms of the septum primum (37.5% versus 80%). These findings all increased linearly with GA (P < .001). CONCLUSIONS: Atrioventricular valve and right/left atrium disproportion, mild ductus arteriosus tapering, prominent aortic isthmus and ductus arteriosus diastolic flow, trivial or mild tricuspid regurgitation, and aneurysms of the septum primum are frequently identified after 34 weeks' GA. Their identification suggests that these fetal echocardiographic findings in isolation are likely normal and are results of the physiologic alterations that occur late in the third trimester. PMID- 28627029 TI - Treatment by a moisturizer of xerosis and cracks of the feet in men and women with diabetes: a randomized, double-blind, placebo-controlled study. AB - AIM: To evaluate a moisturizer containing urea, glycerine and petrolatum for healing deep open fissures on the feet of people with diabetes. If left untreated, open fissures, an entry point for bacteria, can lead to infection, ulceration and further complications. METHODS: This randomized, double-blind, multicentre study at 19 hospitals, general practices and diabetologists in France and Belgium included participants with diabetes and a deep open target fissure on their heel. Participants were randomized to test cream or placebo (1 : 1) for 4 weeks. Complete target fissure healing after 4 weeks (primary criterion) and 2 weeks, target fissure closure, overall fissure healing and xerosis were assessed. RESULTS: Some 167 participants were randomized (80 to test cream; 87 to placebo); all were included in the efficacy analyses. The percentage of participants with complete target fissure healing after 4 weeks was higher with test cream than placebo (46.3% vs. 33.3%): the difference did not reach statistical significance (P = 0.088). Fewer participants still had a deep open target fissure with test cream than placebo, the difference was statistically significant and clinically relevant after 2 (24.7% vs. 42.7%, P = 0.027) and 4 weeks (6.4% vs. 24.1%, P = 0.002). The difference in overall fissure healing between test cream and placebo was significant (P < 0.001) and test cream resulted in greater xerosis improvement (P < 0.001 and P = 0.002 at 2 and 4 weeks, respectively). CONCLUSION: The activity of the test cream for treating feet fissures of people with diabetes was confirmed by an improvement in open fissure healing and xerosis. The cream was well tolerated. PMID- 28627031 TI - The Influence of Oxygen Atoms on Conformation and pi-pi Stacking of Ladder-Type Donor-Based Polymers and Their Photovoltaic Properties. AB - A novel ladder-type donor pyran-bridged indacenodithiophene (IDTP) is developed by introducing two oxygen atoms into indacenodithiophene unit. IDTP possesses a twisted backbone and leads to facially asymmetric arrangement of side chains, resulting in enhanced local pi-pi stacking of according polymer poly[(5,5,11,11 tetrakis(4-octylphenyl)-5,11-dihydrothieno[2',3':5,6]pyrano[3,4-g]thieno[3,2 c]isochromene)-alt-4,7-(5-fluoro-2,1,3-benzothiadiazole)] (PIDTP)-FBT, which shows extended absorption range. Moreover, oxygen atoms render deeper highest occupied molecular orbital (HOMO) levels of poly[indacenodithiophene-alt-4,7-(5 fluoro-2,1,3-benzothiadiazole)] (PIDTP)-FBT compared with PIDT-FBT, therefore bringing a higher open-circuit voltage (Voc ). PMID- 28627030 TI - MiR-375/SLC7A11 axis regulates oral squamous cell carcinoma proliferation and invasion. AB - We aimed to detect the functions of miR-375/SLC7A11 axis on oral squamous cell carcinoma (OSCC) cell proliferation and invasion. Expression levels of miR-375 and SLC7A11 in OSCC tissues and cells were measured with RT-qPCR and western blot. Targeting site was predicted by TargetScan and confirmed by dual luciferase reporting assay. By way of manipulating the expression level of miR-375 and SLC7A11 in CAL-27 and Tca8113 cell lines, the cell biological abilities were evaluated. MTT, colony formation, Transwell, wound healing assays and flow cytometry were used to detect OSCC cell viability, proliferation, invasion, migration and apoptosis, respectively. MiR-375 was significantly downregulated in OSCC tissues and cells compared to adjacent tissue and normal oral cell line respectively while SLC7A11 was upregulated. Targeting relationship was verified by luciferase reporting assay, and miR-375 could effectively suppress SLC7A11 level in OSCC cells. Replenishing of miR-375 significantly repressed OSCC cell viability, proliferation, invasion and migration and induced cell apoptosis and G1/G0 arrest. Overexpression of SLC7A11 recovered those biological abilities in miR-375 upregulated cells. Collective data suggested that miR-375 served as a tumor suppressor via regulating SLC7A11. Replenishing of miR-375 or knockout of SLC7A11 could be therapeutically exploited. PMID- 28627032 TI - Tooth autotransplantation as a pillar for 3D regeneration of the alveolar process after severe traumatic injury: A case report. AB - In dental traumatology, the loss of teeth and the supporting alveolar bone in children compromise the proper development of maxillofacial structures and also limit the solutions that can be offered. In this case report, multidisciplinary management is described of a child with a significant loss of alveolar bone and associated teeth due to a traffic accident at 8 years of age. The management involved staged teeth autotransplantation into surgically prepared sites with bone expanders, orthodontic treatment and dental implants. The 3D regeneration of the alveolar process was successfully stimulated by teeth autotransplantation. At the 4-year follow-up visit, evaluation of the autotransplanted teeth and the implants indicated a successful outcome for the patient. PMID- 28627033 TI - Silodosin versus naftopidil in the treatment of premature ejaculation: A prospective multicenter trial. AB - OBJECTIVES: To determine the efficacy of two alpha1-adrenoceptor antagonists with different affinities for alpha1-adrenoceptor subtypes, silodosin and naftopidil, in the treatment of premature ejaculation. METHODS: This was a prospective, open label, multicenter trial. A total of 26 patients with untreated acquired premature ejaculation were enrolled. Premature ejaculation was defined based on the International Society for Sexual Medicine recommendation. Patients self administered on demand silodosin 4 mg or naftopidil 25 mg 1 h before intercourse, alternating drugs at least three times each. Clinical global impression change for premature ejaculation, premature ejaculation profile, and intravaginal ejaculation latency time were evaluated at baseline and during treatment. RESULTS: Due to clinical global impression change, 24 patients (92%) and 12 patients (46%) reported improvement in their own premature ejaculation problems under silodosin and nafitopidil administration, respectively. Silodosin treatment produced a significantly higher improvement rate compared with naftopidil (P = 0.0002). Objectively, silodosin significantly prolonged intravaginal ejaculation latency time compared with baseline and naftopidil (P < 0.01). Mean intravaginal ejaculation latency times were 1.9, 4.1, and 7.6 min at baseline, control and with silodosin, respectively. The rate of reduced semen volume during silodosin treatment was higher than during naftopidil treatment. There were no adverse systemic effects in either group. CONCLUSIONS: Silodosin, a highly selective alpha1A-adrenoceptor antagonist, produces greater improvements in premature ejaculation profiles and related symptoms along with intravaginal ejaculation latency time in acquired premature ejaculation patients with or without erectile dysfunction. This result supports the clinical use of silodosin as an alternative treatment for premature ejaculation. PMID- 28627034 TI - Brief mindfulness meditation group training in aphasia: exploring attention, language and psychophysiological outcomes. AB - BACKGROUND: Stroke is currently the leading cause of long-term disability in adults in the United States. There is a need for accessible, low-cost treatments of stroke-related disabilities such as aphasia. AIMS: To explore an intervention for aphasia utilizing mindfulness meditation (MM). This preliminary study examines the feasibility of teaching MM to individuals with aphasia. Since physiological measures have not been collected for those with aphasia, the study was also an exploration of the potential attention, language and physiological changes after MM in adults with aphasia during a brief, daily group training. METHODS & PROCEDURES: A 5-day MM group training was provided to adults with aphasia (n = 5) with a waitlist control group (n = (3) who engaged in 'mind wandering'. Participants were assigned to groups in a pseudo-random manner. A double baseline (2 days apart) was administered prior to the training and/or control group beginning. Both the training and the control groups met in a group setting. Salivary cortisol, heart rate and heart rate variability were measured during each day for both groups. Measures of attention, auditory comprehension and fluency were collected immediately after the study period and 1 week post completion. OUTCOME & RESULTS: This study reinforces findings from previous work indicating that adults with aphasia can learn MM. Although not statistically significant, the training group demonstrated improved fluency immediately after MM; however, changes were not maintained at follow-up. Physiological measures showed little effect associated with MM training. No changes in attention were observed for either group. CONCLUSION & IMPLICATIONS: This is an emerging area of interest due to the potential low cost of MM training. Furthermore, MM is easily taught to patients, suggesting the possibility for widespread use in clinical practice as a supplement to existing language-focused interventions. PMID- 28627035 TI - Detection of the HLA-DQB1 allele, DQB1*03:82, in a Kazakh patient with acute myeloid leukemia. AB - HLA-DQB1*03:82 differs from DQB1*03:01 at nucleotide 223 in exon 2 from G to A. PMID- 28627036 TI - Validation of masks for determination of VO2 max in horses exercising at high intensity. AB - BACKGROUND: The need for a horse to be ridden while wearing a measurement device that allows unrestricted ventilation and gas exchange has hampered accurate measurement of its maximal oxygen consumption (VO2 max) under field conditions. OBJECTIVES: Design and validate a facemask with the potential to measure VO2 max accurately in the field. STUDY DESIGN: Experiment with 6 * 6 Latin square design. METHODS: Two variations of a mask and associated electronic control module (ECM) were designed to enable breath-by-breath measurement of airflows through two 7.8 cm diameter pneumotachometers located 7.5 cm in front of each narus. The ECM was comprised of an analogue-to-digital converter and a lithium-ion battery that provided power and signal filtering to the pneumotachometers and an oxygen sensing cell, and powered a pump connected to gas sampling ports between the nares and pneumotachometers. Airflow and oxygen content of inspired and expired gases were recorded through the ECM and electronically transferred to a notebook. VO2 was determined from these recordings using a customised software program. Mask B encased the lower jaw. Mask R left the jaw free so the horse could wear a bit if ridden. VO2 max and arterial blood gases were measured in 6 horses during multiple treadmill tests. Each mask was worn twice and results compared to those from an established open flow-through system (O) by ANOVA-RM (P<0.05). System utility was evaluated using the intraclass correlation coefficient of 4 independent raters. RESULTS: Blood gases and VO2 max (151.9+/-7.0 [mean+/-s.d.; O], 151.5+/-9.6 [B], 149.5+/-7.5 [R] ml/[kg.min]) were not different between masks. VO2 max measures were reproducible for each mask. Intraclass correlation coefficient between raters = 0.99. MAIN LIMITATIONS: Some rebreathing of expired air from mask dead space. CONCLUSION: Masks capable of measuring VO2 max during treadmill exercise were developed, tested and found to be accurate. Mask R has potential application to measurement of VO2 max under field conditions. PMID- 28627037 TI - Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA SPGR at 9.4T. AB - PURPOSE: We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived. METHODS: We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms. Normal Wistar rats underwent Gd-DOTA infusion into CSF via the cisterna magna and continuous MRI for approximately 130 min using T1-weighted imaging. Dynamic Gd-DOTA concentration maps were calculated and parenchymal uptake was estimated. RESULTS: In the phantom study, T1 discrepancies between the VFA-SPGR and IR-RARE sequences were approximately 6% with a transmit coil inhomogeneity correction. In the in vivo study, contrast transport profiles indicated maximal parenchymal retention of approximately 19% relative to the total amount delivered into the cisterna magna. CONCLUSION: Imaging strategies for accurate 3D contrast concentration mapping at 9.4T were developed and whole brain dynamic concentration maps were derived to study solute transport via the glymphatic system. The newly developed approach will enable future quantitative studies of the glymphatic system in health and disease states. Magn Reson Med 79:1568-1578, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28627038 TI - Estimating the number of female sex workers in Cote d'Ivoire: results and lessons learned. AB - OBJECTIVE: To report on the results of three size estimations of the populations of female sex workers (FSW) in five cities in Cote d'Ivoire and on operational lessons learned, which may be relevant for key population programmes in other parts of the world. METHODS: We applied three methods: mapping and census, capture-recapture and service multiplier. All were applied between 2008 and 2009 in Abidjan, San Pedro, Bouake, Yamoussoukro and Abengourou. RESULTS: Abidjan was the city with the highest number of FSW by far, with estimations between 7880 (census) and 13 714 (service multiplier). The estimations in San Pedro, Bouake and Yamoussoukro were very similar, with figures ranging from 1160 (Yamoussoukro, census) to 1916 (San Pedro, capture-recapture). Important operational lessons were learned, including strategies for mapping, the importance of involving peer sex workers for implementing the capture-recapture and the identification of the right question for the multiplier method. CONCLUSIONS: Successful application of three methods to estimate the population size of FSW in five cities in Cote d'Ivoire enabled us to make recommendations for size estimations of key population in low-income countries. PMID- 28627039 TI - Consensus-building on developing dysphagia competence: a North West of England perspective. AB - BACKGROUND: Dysphagia has been an increasing area of practice for speech and language therapists (SLTs) for over 20 years, and throughout that period there has been debate about how practical skills in dysphagia can best be developed. The implementation of the new Royal College of Speech and Language Therapists (RCSLT) framework was considered from a regional perspective seeking to establish consensus across different speech and language therapy settings. AIM: To explore practical solutions to the development of dysphagia competency in new graduates whilst acknowledging the wide variation in staffing and clinical dysphagia experience across the geographical and clinical landscape in the North West of England. METHODS & PROCEDURES: A four-phase study involved a literature search; interviews with experts in the field of dysphagia; a survey to identify current practice; and a two-round Delphi process. OUTCOMES & RESULTS: Five themes emerged for dysphagia competency development: development of practical skills; supervision; clinical excellence networks; workforce planning; and postgraduate formal training. Challenges, and solutions to these, were identified through the phases of the study. A model for dysphagia competency development relevant to the North West context was achieved by consensus. CONCLUSIONS & IMPLICATIONS: There are many practical ways of developing dysphagia competency. The themes and model generated provide constructive support to services in adopting the most appropriate methods for their own settings. PMID- 28627040 TI - A Facile Approach Toward Scalable Fabrication of Reversible Shape-Memory Polymers with Bonded Elastomer Microphases as Internal Stress Provider. AB - The present communication reports a novel strategy to fabricate reversible shape memory polymer that operates without the aid of external force on the basis of a two-phase structure design. The proof-of-concept material, crosslinked styrene butadiene-styrene block copolymer (SBS, dispersed phase)/polycaprolactone-based polyurethane (PU, continuous phase) blend, possesses a closely connected microphase separation structure. That is, SBS phases are chemically bonded to crosslinked PU by means of a single crosslinking agent and two-step crosslinking process for increasing integrity of the system. Miscibility between components in the blend is no longer critical by taking advantage of the reactive blending technique. It is found that a suitable programming leads to compressed SBS, which serves as internal expansion stress provider as a result. The desired two-way shape-memory effect is realized by the joint action of the temperature-induced reversible opposite directional deformabilities of the crystalline phase of PU and compressed SBS, accompanying melting and orientated recrystallization of the former. Owing to the broadness of material selection and manufacturing convenience, the proposed approach opens an avenue toward mass production and application of the smart polymer. PMID- 28627041 TI - Prior exercise speeds pulmonary oxygen uptake kinetics and increases critical power during supine but not upright cycling. AB - NEW FINDINGS: What is the central question of this study? Critical power (CP) represents the highest work rate for which a metabolic steady state is attainable. The physiological determinants of CP are unclear, but research suggests that CP might be related to the time constant of phase II oxygen uptake kinetics (tauVO2). What is the main finding and its importance? We provide the first evidence that tauVO2 is mechanistically related to CP. A reduction of tauVO2 in the supine position was observed alongside a concomitant increase in CP. This effect may be contingent on measures of oxygen availability derived from near-infrared spectroscopy. Critical power (CP) is a fundamental parameter defining high-intensity exercise tolerance and is related to the time constant of phase II pulmonary oxygen uptake kinetics (tauVO2). To test the hypothesis that this relationship is causal, we determined the impact of prior exercise ('priming') on CP and tauVO2 in the upright and supine positions. Seventeen healthy men were assigned to either upright or supine exercise groups, whereby CP, tauVO2 and muscle deoxyhaemoglobin kinetics (tau[HHb] ) were determined via constant-power tests to exhaustion at four work rates with (primed) and without (control) priming exercise at ~31%Delta. During supine exercise, priming reduced tauVO2 (control 54 +/- 18 s versus primed 39 +/- 11 s; P < 0.001), increased tau[HHb] (control 8 +/- 4 s versus primed 12 +/- 4 s; P = 0.003) and increased CP (control 177 +/- 31 W versus primed 185 +/- 30 W, P = 0.006) compared with control conditions. However, priming exercise had no effect on tauVO2 (control 37 +/- 12 s versus primed 35 +/- 8 s; P = 0.82), tau[HHb] (control 10 +/- 5 s versus primed 14 +/- 10 s; P = 0.10) or CP (control 235 +/- 42 W versus primed 232 +/- 35 W; P = 0.57) during upright exercise. The concomitant reduction of tauVO2 and increased CP following priming in the supine group, effects that were absent in the upright group, provide the first experimental evidence that tauVO2 is mechanistically related to critical power. The increased tau[HHb+Mb] suggests that this effect was mediated, at least in part, by improved oxygen availability. PMID- 28627042 TI - Deciding about nursing home care in dementia: A conjoint analysis of how older people balance competing goals. AB - AIM: "Don't put me in a home" is a common preference of older people, but so too is "I don't want to be a burden on my family." These and other goals often conflict with each other when people have worsening dementia and the issue of possible nursing home admission arises. METHODS: Community-dwelling older hospital patients were asked to imagine that they lived alone, had dementia and were experiencing increasing practical difficulties, and were presented with 11 possible "outcome packages." Conjoint analysis was used to investigate how participants ranked possible outcomes and traded-off between these factors: place of residence (home or nursing home), burden on their family, risk of harm and duration of life. RESULTS: Of 122 potential participants, 102 inpatients aged 65 80 years completed the study. Of these participants, 46 (46%) patients give the greatest weight to reducing the burden on their family, 39 (39%) to remaining at home, 11 (11%) to minimizing the risk of harm and five (5%) to maximizing the length of life. There were no significant clinical or demographic differences between these groups. There was a strong negative correlation (Spearman's rho 0.59, P < 0.0001) between importance scores for place of residence and for burden on family. CONCLUSIONS: There are important differences in how individual older people would balance the competing priorities of reducing the burden on their family and remaining at home in the event of developing dementia. Geriatr Gerontol Int 2017; 17: 2435-2440. PMID- 28627044 TI - Adherence to treatment in patients with Behcet's disease. AB - AIM: Behcet's disease (BD) is a chronic, inflammatory disease with multisystem involvement. Adherence to treatment is low in chronic diseases as well as inflammatory and autoimmune diseases. This study assessed factors associated with non-adherence to treatment in patients with BD. METHODS: All the patients with BD who visited in the outpatient clinic of Connective Tissue Diseases Research Center in Tabriz University of Medical Sciences were included in the study. Adherence to treatment was evaluated by the consideration of medication compliance and appointment-keeping behavior. The relationships between adherence rate and six groups of variables were examined. A regression analysis was performed. RESULTS: A total of 137 patients (84 male and 53 female) were included. Totally, 50.7% of the patients were non-adherent to treatment. Side effects of medications and the high cost of treatment were the most frequent causes of non-adherence. Non-adherence was significantly more common in men, patients with low income, patients who were unaware of the disease complications, employed persons, and in patients who were on treatment with non-steroidal anti inflammatory drugs (NSAIDs). CONCLUSIONS: Non-adherence is common in patients with BD. Male sex, low income, low knowledge about the disease, being employed and being on treatment with NSAIDs are the main risk factors for non-adherence. PMID- 28627043 TI - Fabrication of Millimeter-Long Carbon Tubular Nanostructures Using the Self Rolling Process Inherent in Elastic Protein Layers. AB - Millimeter-long conducting fibers can be fabricated from carbon nanomaterials via a simple method involving the release of a prestrained protein layer. This study shows how a self-rolling process initiated by polymerization of a micropatterned layer of fibronectin (FN) results in the production of carbon nanomaterial-based microtubular fibers. The process begins with deposition of carbon nanotube (CNT) or graphene oxide (GO) particles on the FN layer. Before polymerization, particles are discrete and nonconducting, but after polymerization the carbon materials become entangled to form an interconnected conducting network clad by FN. Selective removal of FN using high-temperature combustion yields freestanding CNT or reduced GO microtubular fibers. The properties of these fibers are characterized using atomic force microscopy and Raman spectroscopy. The data suggest that this method may provide a ready route to rapid design and fabrication of aligned biohybrid nanomaterials potentially useful for future electronic applications. PMID- 28627045 TI - Heart rate and its reduction in chronic heart failure and beyond. AB - Heart rate (HR) is associated with cardiovascular outcomes in all the stages of the cardiovascular continuum as well as in patients with pulmonary, cerebrovascular, and renal disease, sepsis, cancer, and erectile dysfunction. In patients with cardiovascular disease, but also in the general population, increased HR represents an important indicator of mortality with each acceleration of HR over 70 b.p.m. increasing the risk. In patients in sinus rhythm with chronic heart failure with reduced ejection fraction (HFrEF), a HR >70 b.p.m. increased the risk of hospitalization, and >75 b.p.m. the risk of cardiovascular death as shown in the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT). Reducing HR with ivabradine by 11 b.p.m. (placebo-controlled) reduced the primary composite endpoint (cardiovascular death and hospitalization for worsening heart failure). Ivabradine was well tolerated showing benefit irrespective of age or diabetes status, and also in the presence of low systolic blood pressure and severe heart failure (SHIFT trial). Therefore, HR qualifies as a modifiable risk factor in heart failure. In patients with stable coronary disease, HR is a risk marker but HR reduction with ivabradine does not improve outcomes. The role of selective HR lowering remains unclear in patients with pulmonary, renal, cerebrovascular, and other diseases, as the potential benefit of interventions on HR has not been explored in these conditions. Future studies should scrutinize if HR reduction improves outcomes, defining HR as a potential risk factor and therapeutic target in other conditions beyond heart failure. PMID- 28627046 TI - Donor-specific antibodies are associated with micro- and macrovascular coronary disease, restrictive myocardial damage, and poor outcome in heart-transplanted patients. AB - AIMS: We examined the relationship between donor-specific HLA antibody (DSA) presence and graft function, hemodynamics, cardiac allograft vasculopathy (CAV), and major adverse cardiac events (MACE) in stable long-term heart-transplanted (HTx) patients. METHODS: Sera from 79 patients (median 7.5 years after HTx) were analyzed for DSA presence. Graft function was evaluated by echocardiography and right heart catheterization. CAV burden was determined by coronary angiography, optical coherence tomography (OCT), and coronary flow velocity reserve (CFVR). Patients were prospectively followed after DSA assessment. MACE included significant CAV progression, heart failure, treated rejection, and cardiovascular death. RESULTS: Sixty patients had no DSA, and 19 patients were sensitized. The vasculopathy burden by angiography, OCT, and CFVR was more pronounced in DSA positive patients than in DSA-negative patients. DSA-positive patients had higher pulmonary capillary wedge pressure (16 [8; 21] vs 9 mm Hg [7; 11], P<.05) and right atrial pressure (8 [6; 9] vs 4 mm Hg [2; 6], P<.01) and lower global longitudinal strain (-13% [-10; -15] vs -16% [-14; -17], P<.01) than DSA-negative patients. DSA presence was a strong MACE predictor (HR 4.7 (95% CI 2.0-11.4), P<.001). CONCLUSIONS: DSA-positive patients had higher vasculopathy burden, higher filling pressures, and lower longitudinal myocardial deformation than DSA negative patients. The DSA presence was a strong MACE predictor. PMID- 28627047 TI - Hysterectomy trends in Australia, 2000-2001 to 2013-2014: joinpoint regression analysis. AB - INTRODUCTION: Hysterectomy is a common gynecological procedure, particularly in middle and high income countries. The aim of this paper was to describe and examine hysterectomy trends in Australia from 2000-2001 to 2013-2014. MATERIAL AND METHODS: For women aged 25 years and over, data on the number of hysterectomies performed in Australia annually were sourced from the National Hospital and Morbidity Database. Age-specific and age-standardized hysterectomy rates per 10 000 women were estimated with adjustment for hysterectomy prevalence in the population. Using joinpoint regression analysis, we estimated the average annual percentage change over the whole study period (2000-2014) and the annual percentage change for each identified trend line segment. RESULTS: A total of 431 162 hysterectomy procedures were performed between 2000-2001 and 2013-2014; an annual average of 30 797 procedures (for women aged 25+ years). The age standardized hysterectomy rate, adjusted for underlying hysterectomy prevalence, decreased significantly over the whole study period [average annual percentage change -2.8%; 95% confidence interval (CI) -3.5%, -2.2%]. The trend was not linear with one joinpoint detected in 2008-2009. Between 2000-2001 and 2008-2009 there was a significant decrease in incidence (annual percentage change -4.4%; 95% CI -5.2%, -3.7%); from 2008-2009 to 2013-2014 the decrease was minimal and not significantly different from zero (annual percentage change -0.1%; 95% CI 1.7%, 1.5%). A similar change in trend was seen in all age groups. CONCLUSIONS: Hysterectomy rates in Australian women aged 25 years and over have declined in the first decade of the 21st century. However, in the last 5 years, rates appear to have stabilized. PMID- 28627048 TI - Derivatives of Holomycin and Cyclopropaneacetic Acid from Streptomyces sp. DT A37. AB - On the basis of the one strain-many compounds strategy, five compounds including two new holomycin derivatives 2 - 3, two new cyclopropaneacetic acid derivatives 4 - 5, together with one known compound holomycin (1) were isolated from a marine derived bacterium Streptomyces sp. DT-A37. Their structures were elucidated using NMR and HR-ESI-MS analyses. All these compounds were evaluated for their antimicrobial activity, cytotoxic activity, and inhibitory activity against BRD4 protein. Compound 1 exhibited potent cytotoxicity against H1975 cells with IC50 value of 1 MUm, and its minimal inhibitory concentration values against Escherichia coli and Staphylococcus aureus were both 64 MUm. PMID- 28627049 TI - Making group inferences using sparse representation of resting-state functional mRI data with application to sleep deprivation. AB - Past studies on drawing group inferences for functional magnetic resonance imaging (fMRI) data usually assume that a brain region is involved in only one functional brain network. However, recent evidence has demonstrated that some brain regions might simultaneously participate in multiple functional networks. Here, we presented a novel approach for making group inferences using sparse representation of resting-state fMRI data and its application to the identification of changes in functional networks in the brains of 37 healthy young adult participants after 36 h of sleep deprivation (SD) in contrast to the rested wakefulness (RW) stage. Our analysis based on group-level sparse representation revealed that multiple functional networks involved in memory, emotion, attention, and vigilance processing were impaired by SD. Of particular interest, the thalamus was observed to contribute to multiple functional networks in which differentiated response patterns were exhibited. These results not only further elucidate the impact of SD on brain function but also demonstrate the ability of the proposed approach to provide new insights into the functional organization of the resting-state brain by permitting spatial overlap between networks and facilitating the description of the varied relationships of the overlapping regions with other regions of the brain in the context of different functional systems. Hum Brain Mapp 38:4671-4689, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28627050 TI - Effects of a community disability prevention program for frail older adults at 48 month follow up. AB - AIM: The present prospective study was carried out to determine whether participation in community-based intervention studies exerted a positive impact on disability prevention in older adults with physical frailty. METHODS: A total of 514 community-dwelling older adults (aged >=65 years) with physical frailty who had undergone baseline assessment and participated in community-based intervention studies (participants) or did not (non-participants) were included in the present study. Non-participants were selected through propensity score matching, to balance potential covariates at baseline. Disability incidence was followed up at 48 months as a main outcome. Demographic data (age, sex and medical history), global cognitive function, grip strength, walking speed, and blood test results including serum albumin and brain-derived neurotrophic factor at baseline were included as covariates. RESULTS: Disability incidence rates differed significantly between participants (11.3%) and non-participants (19.8%) of community-based intervention studies during the 48-month follow-up period (P = 0.007). Participation in community-based intervention studies (hazard ratio 0.55, 95% confidence interval 0.35-0.88) was significantly associated with the incidence of disability in older adults with physical frailty. CONCLUSIONS: Participation in community-based intervention studies could reduce the incidence of disability in older adults with physical frailty. Thus, strategies designed to increase the number of participants in community-based intervention programs should be considered in community-based approaches for the prevention of disability in older adults with physical frailty. Geriatr Gerontol Int 2017; 17: 2347-2353. PMID- 28627051 TI - Investigating the job satisfaction of healthcare providers at primary healthcare centres in Lebanon: A national cross-sectional study. AB - Low job satisfaction is linked to higher staff turnover and intensified shortages in healthcare providers (HCP). This study investigates the level of, and factors associated with, HCP job satisfaction in the national primary healthcare (PHC) network in Lebanon. The study adopts a cross-sectional design to survey HCP at 99 PHC centres distributed across the country between October 2013 and May 2014. The study questionnaire consisted of four sections: socio-demographics/professional background, employment characteristics, level of job satisfaction (Measure of Job Satisfaction scale) and level of professional burnout (Maslach Burnout Inventory HSS scale). A total of 1,000 providers completed the questionnaire (75.8% response rate). Bivariate and multivariate regression analyses were used to identify factors significantly associated with job satisfaction. Findings of the study highlight an overall mean job satisfaction score of 3.59 (SD 0.54) indicating that HCP are partially satisfied. Upon further examination, HCP were least satisfied with pay, training and job prospects. Gender, age, career plans, salary, exposure to violence, and level of burnout were significantly associated with the overall level of job satisfaction which was also associated with increased likelihood to quit. Overall, the study highlights how compensation, development and protection of PHC HCP can influence their job satisfaction. Recommendations include the necessity of developing a nationally representative committee, led by the Ministry of Public Health, to examine the policies and remuneration scales within the PHC sector and suggest mechanisms to bridge the pay differential with other sectors. The effective engagement of key stakeholders with the development, organisation and evaluation of professional development programmes offered to HCP in the PHC sector remains crucial. Concerned stakeholders should assess and formulate initiatives and programmes that enrich the physical, psychological and professional well-being of their HCP. The aforementioned suggestions are necessary to strengthen and sustain PHC HCP and support the provision of universal health coverage to the Lebanese population. PMID- 28627052 TI - Influence of different protein sources in the broiler diet on the presence of Campylobacter spp. in excreta and caecal content. AB - The aim of the present study was to examine possible effects of a different protein supply on the presence of Campylobacter in excreta and caecal content of broiler chickens. Therefore, 220 one-day-old chickens were fed five different diets in the experimental period (day 8 onwards). In the control group (CON; n = 3 boxes), a soya bean-based industrially produced complete diet containing 5-10% whole wheat and coccidiostats was fed, whereas in the remaining groups, four own made complete diets with four protein sources and combinations (4 * 2 boxes; soya bean meal-based diet = SBM; rapeseed meal-containing diet = RSM; haemoglobin meal containing diet = HGP; algae-containing diet = ALG) were offered. During the 6 week trial period, data concerning performance parameters, excreta and litter characteristics and microbiological analysis of excreta and caecal content at dissection were collected. The qualitative bacteriological investigation was based on the EN ISO 10272-1:2006, taken from the official collection of analysis methods in accordance with S 64 LFBG. For quantitative bacteriological tests, a 10-fold dilution series was made followed by culture-based quantification methods on approved selective media in duplicate. Comparing the results of the final dissection (day 44/45), nearly all samples of animals receiving the own-made complete diet were Campylobacter positive in the caecal content, whereas only seven of fifteen samples were positive in the CON group. With regard to the CFU in the caecal content, the counts of Campylobacter were significantly lower for animals fed the commercial diet (2.47 +/- 3.06 vs. 7.36 +/- 0.66 log10 CFU/g). When only the positive animals were evaluated, significant differences were also found between the CON group and the total of the other groups (5.30 +/- 2.08 vs. 7.54 +/- 1.70 log10 CFU/g). Although significant differences were seen in the results, no final recommendation can be given how to create a diet to reduce an infection with Campylobacter. PMID- 28627053 TI - Recovery of insulin sensitivity and optimal body composition after rapid weight loss in obese dogs fed a high-protein medium-carbohydrate diet. AB - This study investigated the effects of an experimental high-protein medium carbohydrate diet (protein level, 46% metabolizable energy, ME). First, postprandial plasma glucose and insulin kinetics were determined in steady-state overweight/obese Beagle dogs (28%-41% excess body weight) for an experimental high-protein medium-carbohydrate diet (protein level, 46% ME) and a commercial high-carbohydrate medium-protein diet (protein level, 24%ME) in obese dogs. Secondly, all the dogs were included in a weight loss programme. They were fed the high-protein medium-carbohydrate diet, and the energy allocation was gradually reduced until they reached their optimal body weight. Insulin sensitivity and body composition were evaluated before and after weight loss using a euglycaemic-hyperinsulinaemic clamp and the deuterium oxide dilution technique respectively. For statistical analysis, linear mixed effect models were used with a significance level of 5%. Postprandial plasma glucose and insulin concentrations were substantially lower with the high-protein medium-carbohydrate diet than the high-carbohydrate medium-protein diet. These differences can be explained mainly by the difference in carbohydrate content between the two diets. Energy restriction (35% lower energy intake than in the obese state) resulted in a 2.23 +/- 0.05% loss in body weight/week, and the dogs reached their optimal body weight in 12-16 weeks. Weight loss was associated with a significant increase in insulin sensitivity. The high-protein medium-carbohydrate diet allowed fat-free mass preservation despite a relatively high rate of weekly weight loss. The increase in insulin sensitivity indicated improved control of carbohydrate metabolism, possible due to weight loss and to the nature of the diet. Thus, a high-protein medium-carbohydrate diet is a good nutritional solution for managing the weight of overweight dogs. This diet may improve glycaemic control, which could be beneficial for preventing or managing impaired glucose tolerance in obese dogs and for safe and successful weight loss while preserving lean body mass. PMID- 28627054 TI - Effect of Moringa oleifera leaf powder supplementation on growth performance and intestinal morphology in broiler chickens. AB - Due to public health hazards of subtherapeutic use of antibiotics in poultry feed, there is a need for alternatives. Moringa oleifera is a phytobiotic, which is reported to possess antimicrobial and immuno-modulatory properties. This study aimed to investigate effects of M. oleifera leaf powder (MOLP) supplementation on growth performance and intestinal microarchitecture of broiler chickens. Day-old broiler chicks (n = 100) were randomly divided into five groups with four replicates each having five birds. Birds were fed a corn-based basal diet or the same diet supplemented with 0.6, 0.9, 1.2 and 1.5% MOLP. Body weight and feed conversion ratio were recorded on weekly basis. On day 35, two birds per replicate were selected to collect samples of duodenum, jejunum, ileum, caecal tonsils and bursa of Fabricius. Tissue samples were stained with haematoxylin and eosin or combined alcian blue and PAS technique. Supplementation of MOLP had no effect on feed intake, feed conversion ratio, bursa weight and intra-epithelial lymphocytes (IEL) count. Birds fed with 1.2% MOLP had higher (p < 0.05) body weight, length and empty weight of small intestine, and weight of empty and filled ceca. Villus height (duodenum, jejunum, ileum), villus surface area (duodenum) and villus height:crypt depth (ileum) were higher (p < 0.05) in 1.2% MOLP group compared with non-supplemented group. In duodenum, total goblet cell count was higher (p < 0.05) in all the supplemented groups when compared with non supplemented birds. Acidic mucin count was higher (p < 0.05) in duodenum, jejunum and ileum of 1.2% MOLP group compared with the control group. Bursal follicle count was higher (p < 0.05) in 1.2% MOLP group compared with non-supplemented group. In conclusion, dietary supplementation of 1.2% MOLP modulated intestinal microarchitecture and acidic mucin production without any apparent effect on growth. PMID- 28627055 TI - Cholelithiasis in adult bearded dragons: retrospective study of nine adult bearded dragons (Pogona vitticeps) with cholelithiasis between 2013 and 2015 in southern Germany. AB - With an increased number of pet reptiles, many diseases occur due to nutritional disorders. Between 2013 and 2015, irregular gallbladder contents (sludge/choleliths) in adult bearded dragons (Pogona vitticeps) were recorded in many of the routinely conducted necropsies at the reptile rescue station in Munich (Auffangstation fur Reptilien, Munchen e.V., Munich, Germany). Nine animals, six from the rescue station and three from an associated veterinary practice (Tierarztliche Praxis fur Exoten, Augsburg, Germany), were studied. Gallbladder contents from all animals were analysed at the Institute for Clinical Chemistry in Zurich, Switzerland. In three of nine animals, one cholelith composed of 100% calcium carbonate (CaCO3 ) was detected and it precipitated either as pure calcite or as a calcite:vaterite combination. In the remaining six animals, analyses suggested a protein-based material. The detection of choleliths/sludge was not anticipated at necropsy or surgery in eight of nine animals. The diet of the six animals from the rescue station was retrospectively described as mainly insects, whereas the diet of the three animals from the veterinary practice also contained little plant matter. Fed insect species were mealworm larva (Tenebrio molitor), house cricket (Acheta domestica), migratory locust (Locusta migratoria) and zophobas larva (Zophobas morio), all high in protein and fat. In other species, a nidus must be present for CaCO3 to precipitate. As a protein-based sludge was detected in six gallbladders, it is possible that a high-protein diet could lead to such a nidus and subsequently to cholelith formation. Cholelithiasis seems to be a rising problem in adult bearded dragons and is likely underdiagnosed, as many choleliths were found at necropsy. This rise in cholelithiasis may correlate with an unnatural high-protein, high fat insect-based diet instead of a balanced plant-based diet. PMID- 28627056 TI - Feed intake patterns of sport ponies and warmblood horses following iso-energetic intake of pelleted fibre-rich mixed feed, muesli feed and semicrushed oat grains. AB - The aim of the study was to compare diverse feed intake patterns in sport ponies and warmblood-type horses after feeding iso-energetic amounts of three different concentrates: a pelleted fibre-rich mixed feed (PF), a muesli feed (MF) and semicrushed oat grains (OG). Four sport ponies and six warmblood-type horses received the concentrates and meadow hay according to maintenance (0.52 MJ metabolizable energy (ME) kg body weight (BW)0.75 /day). Both breeds were allocated at random to three groups and received once daily for 8 days either OG (1 g starch/kg BW/meal) or iso-energetic quantities of PF and MF according to a crossover design. On the 8th day, feed intake patterns (chewing frequency (CF) in number of chewings (NC), NC/s), feed intake time (FITDM , min/kg dry matter (DM); FIT(neutral detergent fibre)NDF , min/kg NDF) and chewing intensity (CI, NC/kg DM) were measured using modified halters. In warmbloods, PF tended to be ingested faster than MF and OG (10.3 +/- 1.9, 13.0 +/- 1.3, 14.4 +/- 2.0 min/kg DM, respectively; p = 0.05). In ponies, a similar trend was observed (13.5 +/- 2.5, 13.6 +/- 2.0 and 15.4 +/- 1.1 min/kg DM, respectively; p > 0.05). Ponies needed more time to ingest PF than warmbloods (p < 0.05). The CF of ponies was affected by the type of concentrate (PF and MF 1.43 +/- 0.11 vs. OG 1.28 +/- 0.093 NC/s; p < 0.05). The results indicate that concentrate intake of breeds follows a similar pattern and that breed differences were limited to PF only. In both breeds, PF induced chewing patterns different from those observed for OG and/or MF. However, an interpretation of these differences needs to take into consideration the diverse chemical compositions of the concentrates. Upcoming studies should address the throwback regarding PF and also examine the metabolic consequences of concentrate intake in ponies. PMID- 28627057 TI - Vitamin D metabolism in growing pigs: influence of UVB irradiation and dietary vitamin D supply on calcium homeostasis, its regulation and bone metabolism. AB - The aim of this study was to prove whether pigs are able to synthesize vitamin D (vitD) in the skin and to investigate the influence of ultraviolet irradiation (UVB) on vitD status and calcium (Ca) homeostasis of growing pigs. Thirty-two 11 week-old pigs were kept without access to sunlight and divided into four groups receiving the following treatment in a 2 * 2 factorial design: (i) UVB irradiation or not and (ii) vitD in feed or not. Blood, urine and faeces were sampled every third week. In serum, vitD metabolites, Ca, phosphorus (P), magnesium (Mg) and bone markers were analysed. Digestibility of Ca, P and Mg as well as urinary excretion of these minerals was analysed. After 14 weeks, the animals were slaughtered, and samples of skin, intestines, kidneys and bones (metatarsus) were taken for further analyses: sterols of vitD synthesis in the skin, Ca flux rates in the intestines, expression of genes involved in Ca transport in the intestines and kidneys, bone mineral density (BMD) with the aid of peripheral quantitative computer tomography and bone mineral content by ashing the metatarsus. Irradiated animals showed higher levels of 7-dehydrocholesterol and tachysterol in the skin, higher levels of 25-hydroxycholecalciferol and 1,25 dihydroxycholecalciferol in the serum and higher Ca net flux rates were determined in Ussing chambers. In contrast, the expression of genes involved in Ca transport in the intestines and kidneys was not altered. Similarly, the digestibility of Ca and P as well as the urinary excretion was not affected. With respect to the metatarsus, no differences in mineral contents and BMD were found between groups. At the end of the study, some subclinical signs of beginning vitD 'insufficiency' were observed in the group without access to vitD (represented by higher expression of 1alpha-hydroxylase in the kidney and increased parathyroid hormone in serum). PMID- 28627058 TI - Survey: nutrition, body condition and activities of dogs in Switzerland. AB - Interest in species-appropriate activities and nutrition of dogs increases. A huge variety of feedstuff available, myths and different feeding theories confuse dog owners and lead to inadequate nutrition of their pets. As one result, obesity in pets can be observed with a high incidence in veterinary practice. Although comorbidities of obesity are well known, only few pet owners realize consequently the necessity of weight reduction to support their pet's health. We hypothesized that pet owners in Switzerland underestimate body condition of their dogs and are unsure about how to manage nutritional challenges. This study assessed the current nutrition, owner's perception of body weight and body condition score (BCS) of their dog. At a dog exhibition, dog owners filled in a questionnaire on age, breed, activity, housing, nutrition and source of information for questions concerning nutrition. Owners evaluated the BCS with the help of a poster and determined the ideal weight of their dog. Body weight was measured and BCS evaluated by two veterinarians. The study included 43 bitches [25 (58%) spayed] and 35 male dogs [21 (60%) neutered] with an age of 4.7 +/- 3.6 years (mean +/- STD). Average current body weight was 18.9 kg +/- 14.1 and corresponded approximately to the ideal body weight estimated by the owners (18.6 kg +/- 14.1). Four (5%) of the dogs were judged by the owners to be underweight, 55 (70%) ideal, 14 (18%) overweight and five (6%) obese. Owner's evaluation of BCS averaged 4.54 +/- 1.13; veterinary's evaluation was significantly higher with 5.20 +/- 1.20 (difference of 0.77 +/- 0.59; P < 0.05). Although the awareness of the importance of adequate nutrition and activity for pets is rising among pet owners, they are overwhelmed by the variety of diets and sources of information available. This might lead to malnutrition and identifies a clear need for competent specialists of pet nutrition. PMID- 28627059 TI - First detailed nutritional survey in a referral companion animal population. AB - Optimal nutrition in every life stage and certainly in diseased animals will contribute greatly to improve overall health and quality of life. The 5th VA guidelines have been designed to help veterinarians to implement a nutritional assessment into every patient, every time it comes into their practice. This nutritional survey in referral patients was conducted by one person skilled in acquiring detailed nutritional information and evaluating nutritional status. Two goals were set as follows: first to gain more insight into the nutritional status and management of referred patients and second to gain more insight in the nutritional recommendations given by the treating veterinarian. Using an online survey program, a detailed nutritional survey was designed using the 5th VA guidelines as a roadmap. Ultimately, 100 surveys were completed using referral patients with following results: only 15% of referred patients were cats; obesity occurrence was high with 53% of cats and 35% of dogs being overweight or obese; eleven per cent of animals had an abnormal MCS; and five of seven dogs with an abnormal MCS dogs died within 6 months. Several nutritional risk factors were undiagnosed and consequently untreated in these patients. Therefore, continued efforts must be made to educate practicing veterinarians into using the nutritional guidelines. The routine use of these guidelines by veterinarians will ultimately improve the nutritional status of all companion animals and might reduce the prevalence of diseases where poor nutrition or management has a contributing role. PMID- 28627060 TI - Clinical nutrition counselling service in the veterinary hospital: retrospective analysis of equine patients and nutritional considerations. AB - Nutrition plays a very important role in the healthy and in the ill horse. Although research in this field clearly shows that incorrect nutritional practices may lead to severe pathologies, inappropriate feeding plans often continue to be used. A clinical nutrition counselling (CNC) service could thus be of great use to both horse owners and veterinarians. The aim of this study was to provide information on equine patients referred to the CNC service of the University of Turin and to provide standard dietary protocols as used in our Veterinary Teaching Hospital for the most common nutrition-related pathologies. The data were obtained by retrospective analysis of the nutritional records of referred equine patients. The data collected included information about anamnesis, nutritional assessment, current diet, referring person and follow-up of each patient. Sixty-one horses were included in the study. The majority were adult males. The most common breeds were the Italian Saddle Horse and the Friesian Horse. Old horses (>19 years) had a statistically lower BCS than brood mares or other adult horses (p < 0.01). The most common nutritional pathologies were chronic weight loss (CWL), chronic diarrhoea (CD) and equine gastric ulcer syndrome. All horses received first-cut meadow hay; 85% also ate concentrates. Young horses (<2 years) received more hay as a percentage of body weight (BW) than old horses or adults. The hay percentage of BW per day given to animals with CWL was statistically higher than those with CD (p < 0.01). The concentrate percentage of BW given to old horses was statistically lower compared to that given to young horses (p < 0.05). The concentrate percentage of BW per day given to horses with colic was statistically higher than that given to horses with CD (p < 0.05). 28% of cases were referred by the owner and 72% by a veterinarian. Follow-up evaluation was deemed to be 'good' in 92% cases and 'poor' in 8%. In summary, the CNC service could provide an epidemiological observatory to study the prevalence of nutritional issues in the equine population. PMID- 28627061 TI - Glycaemic and insulinaemic responses of adult healthy warm-blooded mares following feeding with Jerusalem artichoke meal. AB - This study aimed to investigate the impact of the supplementation of a pre-biotic compound [Jerusalem artichoke meal (JAM)] on the glycaemic and insulinaemic response in healthy, non-obese warm-blooded horses. Six adult mares [mean body weight (bwt) 529 +/- 38.7 kg; body condition score 5.1 +/- 0.49/9] were used. In two equal meals per day, the horses received crushed oat grains (1 g starch/kg bwt per day) and meadow hay (2 kg/100 kg bwt per day) which together were likely to meet the energy recommendation for light work (GfE, ). Additionally, they received either 0.15 g fructo-oligosaccharides and inulin (FOS+INU)/kg bwt per day via commercial JAM or maize cob meal without grains as control (CON) in 2 * 3 week periods according to a crossover design. Blood was collected on d21 of the feeding period at different ante- and postprandial (PP) time points (-60, 0, 30, 60, 90, 120, 180, 240 and 300 min), and the plasma glucose and serum insulin levels were determined. Feeding JAM vs. CON did not change the PP peak of glucose or insulin (glucose: 6.3 +/- 0.40 vs. 7.0 +/- 0.87 mmol/l; insulin: 0.508 +/- 0.087 vs. 0.476 +/- 0.082 nmol/l) nor did it cause different AUCs until 120 and 300 min PP for glucose and insulin, respectively (AUC120 , glucose: 997 +/- 41.6 vs. 1015 +/- 41.63 mmol/l per minute, insulin: 49 +/- 6.3 vs. 42 +/- 6.3 nmol/l per minute; AUC300 , glucose: 1943 +/- 142.3 vs. 2115 +/- 142.3 mmol/l per minute, insulin: 94 +/- 14.8 vs. 106 +/- 14.8 nmol/l per minute; p > 0.05). Following JAM vs. CON feeding, glucose and insulin levels declined more rapidly until 240 min PP and tended to be lower (p = 0.053 and p = 0.056, respectively) at this time point. This result might be promising and should further be studied more detailed. PMID- 28627062 TI - Effects of a carbohydrase complex added in different inclusion rates in feeds for broilers on growth performance, digesta viscosity and foot pad health. AB - Foot pad dermatitis (FPD) is a widespread disease in poultry and important for economic and animal welfare reasons. It is well recognized that using non-starch polysaccharide (NSP)-degrading enzymes can affect excreta/litter quality (not only in terms of moisture content but also regarding water evaporation) at high stocking densities and might help to prevent FPD and further negative effects of NSP. This study aimed to evaluate effects of a carbohydrase complex (CC) in different dietary inclusion rates on performance, digesta viscosity and foot pad health in broilers from 9 to 37 days of life. In total, 240 broilers were divided into 12 floor pens of 20 birds and received one of four different experimental diets. The four wheat- and soyabean meal-based diets only differed in the inclusion rate of CC: 0%, 50%, 100% and 500% of the recommended dose of CC (Endo 1,4-beta-xylanase and Endo-1,3(4)-beta-glucanase; 50 g/t). The addition of CC led to a significant decrease of digesta viscosity in the proximal small intestine, a tendency of improved feed conversion ratio, and significantly favoured FPD-scores (Treatment 2). At the higher tested inclusion rate of CC (500% of recommended dose), the FPD score was worser than in the treatments with 50% and 100% of the recommended enzyme dosage. No improvements among treatments were observed in terms of body weight and dry matter content of excreta and litter at the end of trial. The low positive effects on foot pad health in this study were presumably associated with the low NSP content in the experimental diets (soluble arabinoxylans: 7.38 g/kg as fed). In conclusion, the addition of the evaluated CC reduced digesta viscosity. An improvement of foot pad health could only be seen in the treatment with 50% of the recommended enzyme dosage in the diet. PMID- 28627063 TI - Beet pulp intake and hairball faecal excretion in mixed-breed shorthaired cats. AB - Hairball formation may induce vomiting and intestinal obstruction in predisposed cats. Some insoluble fibres as sugarcane fibre and cellulose can prevent hairball formation. The aim of this study was to evaluate the effect of beet pulp consumption, a moderate soluble and fermentable fibre source, on faecal trichobezoars excretion in adult shorthaired cats fed kibble diets. Eighteen mixed-breed shorthaired cats and three extruded diets were used as follows: a basal diet without added fibre source (PB0-8.8% dietary fibre); BP8-8% inclusion of beet pulp (17.5% of dietary fibre); BP16-16% inclusion of beet pulp (23.8% of dietary fibre). The cats were fed during 31 days and faeces quantitatively collected during three periods of 3 days each (from days 3-5; 15-17; 26-28). Gastrointestinal transit time was determined in the last 3 days of study (from days 29-31). The trichobezoars were separated from faeces, collected, dried and washed in ether for complete removal of all faecal material. The results were submitted to repeated-measure analysis of variance and means evaluated by polynomial contrast (p < 0.05). Beet pulp increased faecal production (p < 0.001) and reduced gastrointestinal transit time (p = 0.003). No alterations were found on trichobezoar faecal excretion, both as considered in number per cat per day of mg per cat per day (p > 0.05). Beet pulp intake did not reduce the number or the size of hairballs eliminated via faeces of shorthaired cats. PMID- 28627064 TI - Effects of isoenergetic quantities of a low-starch muesli feed high in fat and fibre vs. oat grains on the glycemic and insulinemic responses and feed intake patterns in sport ponies. AB - Aim of this study was to compare glycemic and insulinemic responses and feed intake patterns in sport ponies after feeding isoenergetic quantities of low starch muesli feed high in fat and fibre (FF) or oat grains (OG). Six sport ponies were randomly assigned to one of these two treatment groups for 2 * 3 weeks according to a crossover-design. Ponies received two equal meals/day of either semi-crushed OG (1 g starch/kg bwt*meal-1 ) or an isoenergetic quantity of FF. Hay was also given in two equal meals/day and provided the remaining metabolisable energy up to 1.3-fold maintenance level. On day 21, blood was sampled 1 h after each pony received 0.5 kg hay (0 min). Then, the concentrate was provided and blood sampled 30, 60, 90, 120, 180, 240 and 300 min thereafter. Plasma glucose and serum insulin were analysed, and the areas under the curve (AUC) was calculated 120 and 300 min postprandial (PP). Feed intake patterns were measured in 4 ponies/group via a modified halter. OG was ingested faster than FF (feed intake time; FITDM in min/kg DM: 8.8 +/- 1.6 vs. 15.9 +/- 1.62, p < 0.05) combined with a higher chewing frequency (p < 0.05). The AUCsgluc120/300, ins120/300 were statistically higher with OG than FF (mmol/L*min-1 : AUCgluc120 : 776 +/- 128 vs. 676 +/- 80.4; AUCgluc300 : 1811 +/- 295.3 vs. 1569 +/- 126.3; nmol/L*min-1 : AUCins120 : 38 +/- 18 vs. 22 +/- 8.1; AUCins300 : 83 +/- 39 vs. 35 +/- 12; p < 0.05). Plasma glucose tended to decline following the intake of FF, which might be beneficial for equines with reduced glucose tolerance. This, however, requires further investigation. In this study, the ponies consumed OG unexpectedly rapidly. The rate of feed intake was similar to the results previously reported in the literature for warmblood horses. PMID- 28627065 TI - Evaluation of an in vitro system to simulate equine foregut digestion and the influence of acidity on protein and fructan degradation in the horse's stomach. AB - The aim of this study was to improve an in vitro system in order to gather optimized information on the digestion of different forages in the horse's upper gastrointestinal tract. Therefore, foregut digestion of several forages was simulated in vitro (Part 1). The effect of different pH values on in vitro fructan degradation of two selected grasses (Part 2) was tested subsequently. Part 1: We hypothesized that our system produces representative results simulating digestive processes in the upper alimentary tract, but neglects microbial fermentation. In vitro digestion of six forages (grass mixture for horses, grass mixture for cows (GMC), tall fescue, English perennial ryegrass (ER), white clover, lucerne) was performed in two phases with pepsin and pancreatin. The results are consistent with current data from in vivo studies, including a degradation of crude protein and monosaccharides as well as a relative increase in fibres. Interestingly, a loss of fructan was measured in two feedstuffs (ER/GMC: 4.1/4.4% DM fructan before and 0.59/0.00% DM after simulated foregut digestion). Part 2: As fructans are thought not to be fragmented by digestive enzymes, another hypothesis was developed: acidic hydrolysis leads to a degradation of fructans. To evaluate the influence of gastric pH on the digestion of fructan and protein, different pH values (2, 3 and 4) were adjusted in a second series of in vitro foregut digestion trials with ER and GMC. As expected, the highest degradation of protein was seen at the lowest pH (protein in ER/GMC at pH 2: 6.11/8.28% DM and at pH 4: 7.73/10.64% DM), whereas fructan degradation was highest at pH 4 (fructan in ER/GMC at pH 2: 1.63/1.95% DM and at pH 4: 1.31/0.91% DM). We presume that not only acidic hydrolysis but also plant enzymes cause the loss of fructans in an acidic environment. PMID- 28627066 TI - Little differences in digestive efficiency for protein and fat in mammals of different trophic guilds and digestive strategies: data constraints or fundamental functional similarity? AB - Carnivores do not vary markedly in their digestive efficiency for protein and fat, but whether they resemble other trophic guilds (omnivores and herbivores) in this respect has not been evaluated. We collated data on apparent crude protein (CP) and crude fat (ether extracts, EE) digestibility in 157 mammal species, applying the Lucas principle of regressing digestible nutrient content against nutrient content, where the slope of the regression equation represents the true digestibility and the intercept the metabolic losses per unit dry matter intake. The data collection is marked by the evident uneven distribution of dietary nutrient contents across trophic guilds and differences in the nutrient range by which different species have been evaluated, making statistical interpretation difficult. Results indicate a lower true digestibility of CP in herbivores compared to carnivores, most likely due to a lower digestibility of fibre-bound protein in herbivore diets. Metabolic CP losses did not appear to differ between trophic guilds, but herbivores had higher metabolic EE losses, compatible with the hypothesis that a higher proportion of metabolic CP losses were bound in microbes that also contain lipids in herbivores. Among herbivores, no clear pattern was evident that would indicate a difference in metabolic losses associated with microbes between digestive strategies (coprophagy, foregut/hindgut fermentation). Foregut fermenters had a lower true EE digestibility, possibly linked to the hydrogenation of lipids in their forestomach prior to digestion. The results do not demonstrate clear differences in digestive efficiency and metabolic losses for protein and fat between mammalian trophic guilds and digestive strategies, leading to the hypothesis that the process of CP and EE digestion is not physiologically challenging and hence does not lead to a noticeable differentiation between species or species groups. PMID- 28627067 TI - A by-product of swine slaughtering as a protein source in broiler diets: effects on performance, composition of excreta, litter quality and on foot pad health. AB - Foot pad dermatitis (FPD) is of great concern in poultry industry, and dietary strategies are needed to improve foot pad health because of animal welfare and economic reasons. As the main factor for the development of FPD is the DM content of litter (consisting mainly of excreta; Kamphues et al., 2011), there are different dietary approaches to influence this disease pattern. In two consecutive trials, a total of 200 broilers were kept from day 7 until the 35th day of life. They were divided into four groups at each trial and fed with one of four experimental diets, based on wheat and corn mainly, but differing in the protein source: Group 1 was fed a diet with soya bean meal (SBM) as the main protein source, whereas Group 2, Group 3 and Group 4 were assigned to diets with 4, 8 and 12% of a protein-rich (66.7% CP in DM) by-product of swine slaughtering [Swine Protein Meal (SPM); in exchange for SBM]. The inclusion of 12% SPM resulted in a decreased dietary potassium content of about 3 g/kg diet (Group 1 vs. 4). Increasing dietary levels of the by-product (8 and 12%) led to lowered feed intake (Group 1 vs. 4: ~10%) and weight gain (Group 1 vs. Group 4: ~8.5%). Although highest DM contents of excreta and litter were determined in Group 4, foot pad health was not influenced positively as hypothesized. Remarkable was the observed 'stickiness' of excreta when the by-product was included in the diet at increasing levels, presumably due to the high proportion of bones in the by product. In conclusion, substituting SBM by 4% of the by-product of swine slaughtering in broiler diets did not impair performance parameters, but led to the most favourable foot pad scores in this study. PMID- 28627068 TI - Feed restriction regime in a rabbit line selected for growth rate alters oocyte maturation manifested by alteration in MSY2 gene expression. AB - Young rabbit females selected for growth rate may have nutritional needs, which may not be met with the common practice of feed restriction during rearing in commercial rabbit production. The aim of this study was to analyse whether two different feeding programmes: ad libitum or restricted (130 g/day) feeding, applied in young rabbit females for 1 month at the end of rearing, could modulate the origin of ovulation process and the quality of the oocytes. At 16 weeks of age, 34 females were randomly assigned to restricted or ad libitum feeding, maintaining these conditions for a month. Then, in an initial experiment, transcriptional profiling of hypothalamus-hypophysis tissue was performed to assess failure to ovulate. In the second experiment, the gene expression analysis of some candidate genes related to oocytes quality was performed. Our results demonstrated that neither of the two feeding programmes modified the transcription of hypothalamus-hypophysis tissue, while the only differences in MSYR expression were found in in vivo mature oocytes ready for successful fertilization. Specifically, MSYR was over-expressed in oocytes from females fed ad libitum. MSYR is one of the most abundant proteins in the oocyte and has proven to be a key regulator of maternal RNA transcription and translation. This finding suggests that MSYR gene is a promising gene in our understanding of the relationship between high growth rate and reproductive performance decline. PMID- 28627069 TI - Who delivers where? The effect of obstetric risk on facility delivery in East Africa. AB - OBJECTIVES: Skilled attendance at birth is key for the survival of pregnant women. This study investigates whether women at increased risk of maternal and newborn complications in four East African countries are more likely to deliver in a health facility than those at lower risk. METHODS: Demographic and Health Survey data for Kenya 2014, Rwanda 2014-15, Tanzania 2015-16 and Uganda 2011 were used to study women with a live birth in the three years preceding the survey. A three-level obstetric risk index was created using known risk factors. Generalised linear Poisson regression was used to investigate the association between obstetric risk and facility delivery. RESULTS: We analysed data from 13 119 women across the four countries of whom 42-45% were considered at medium risk and 12-17% at high risk, and the remainder were at low risk. In Rwanda, 93% of all women delivered in facilities but this was lower (59-66%) in the other three countries. There was no association between a woman's obstetric risk level and her place of delivery in any country; greater wealth and more education were, however, independently strongly associated with facility delivery. CONCLUSIONS: In four East African countries, women at higher obstetric risk were not more likely to deliver in a facility than those with lower risk. This calls for a renewed focus on antenatal risk screening and improved communication on birth planning to ensure women with an increased chance of maternal and newborn complications are supported to deliver in facilities with skilled care. PMID- 28627070 TI - Lack of immunogenicity of hydrolysed wheat flour in patients with coeliac disease after a short-term oral challenge. AB - BACKGROUND: A gluten-free diet is currently the only reliable therapeutic strategy that is approved for coeliac disease (CD). For many patients, however, compliance remains inadequate. AIM: To investigate the immunogenicity of wheat flour that was pre-treated with selected lactobacilli and fungal proteases (hydrolysed wheat gluten) in coeliac patients. METHODS: The immunogenicity of hydrolysed wheat gluten was evaluated both in vitro in intestinal T cell lines (TCLs) and in vivo in treated CD patients after a short-term gluten challenge. Twenty treated CD patients were enrolled and equally randomised into two groups. The patients ate bread that was prepared with hydrolysed wheat flour or natural wheat flour (10 g of gluten/d for 3 days). The interferon (INF)-gamma responses to natural gliadin and a 33-mer peptide were assessed by the enzyme-linked immunospot (ELISPOT) assay on peripheral blood mononuclear cells (PBMCs) both before and 6 days after the start of the challenge. RESULTS: Hydrolysed wheat was not able to activate the TCLs from the coeliac intestinal mucosa. Consistent with the in vitro results, no significant increase in INF-gamma secretion was observed in patients who consumed hydrolysed wheat flour. Conversely, the consumption of natural wheat gluten mobilised INF-gamma secreting cells in the blood (P<.05). CONCLUSIONS: We confirm that fermentation of wheat flour with sourdough lactobacilli and fungal proteases is capable of abolishing the T cell immunogenicity of gluten in coeliac patients. Our data also validate the short term oral challenge as a useful tool for testing the efficacy of novel therapeutic approaches. PMID- 28627071 TI - Oral health status of children and adolescents with intellectual disabilities: a systematic review and meta-analysis. AB - AIM: To compare the oral health status of children and adolescents affected by intellectual disabilities with their unaffected counterparts. METHOD: Citations published in English were searched from electronic databases (PubMed, Embase, Web of Science, and Scopus) from their start dates to March 2017. The whole process was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. The PICO (population, intervention/interest, comparator, outcome) principle was used to formulate the topic. Studies were synthesized through qualitative summary or, whenever possible, meta-analysis. RESULTS: The initial search yielded 2393 records. Thirty-nine studies from 22 countries were identified for qualitative analysis; 26 studies were eligible for meta-analysis. Participants with intellectual disabilities had higher levels of dental plaque, worse gingival status, fewer decayed and filled permanent teeth, and similar caries experience between males and females. These findings were supported by both qualitative and quantitative analysis. Various patterns of caries experiences were indicated by qualitative analysis, but it was not substantiated by meta-analysis. INTERPRETATION: There is increasing worldwide interest in oral health status of children with intellectual disabilities. Differences in dental plaque deposition, gingival inflammation, and the number of decayed and filled permanent teeth were investigated between children and adolescents with and without intellectual disabilities. Evidence remains elusive about the pattern of caries experience among those children. PMID- 28627072 TI - Reply to "Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma" by Mesbah Ardakani et al. PMID- 28627073 TI - Determination of Radical-Radical Distances in Light-Active Proteins and Their Implication for Biological Magnetoreception. AB - Light-generated short-lived radial pairs have been suggested to play pivotal roles in cryptochromes and photolyases. Cryptochromes are very probably involved in magnetic compass sensing in migratory birds and the magnetic-field-dependent behavior of insects. We examined photo-generated transient states in the cryptochrome of Drosophila melanogaster and in the structurally related DNA repair enzyme Escherichia coli DNA photolyase. Using pulsed EPR spectroscopy, the exchange and dipolar contributions to the electron spin-spin interaction were determined in a straightforward and direct way. With these parameters, radical pair partners may be identified and the magnetoreceptor efficiency of cryptochromes can be evaluated. We present compelling evidence for an extended electron-transfer cascade in the Drosophila cryptochrome, and identified W394 as a key residue for flavin photoreduction and formation of a spin-correlated radical pair with a sufficient lifetime for high-sensitivity magnetic-field sensing. PMID- 28627074 TI - MOF-Based Metal-Doping-Induced Synthesis of Hierarchical Porous Cu?N/C Oxygen Reduction Electrocatalysts for Zn-Air Batteries. AB - A transition-metal-nitrogen/carbon (TM-N/C, TM = Fe, Co, Ni, etc.) system is a popular, nonprecious-metal oxygen reduction reaction (ORR) electrocatalyst for fuel cell and metal-air battery applications. However, there remains a lack of comprehensive understanding about the ORR electrocatalytic mechanism on these catalysts, especially the roles of different forms of metal species on electrocatalytic performance. Here, a novel Cu?N/C ORR electrocatalyst with a hybrid Cu coordination site is successfully fabricated with a simple but efficient metal-organic-framework-based, metal-doping-induced synthesis strategy. By directly pyrolyzing Cu-doped zeolitic-imidazolate-framework-8 polyhedrons, the obtained Cu?N/C catalyst can achieve a high specific surface area of 1182 m2 g-1 with a refined hierarchical porous structure and a high surface N content of 11.05 at%. Moreover, regulating the Cu loading can efficiently tune the states of Cu(II) and Cu0 , resulting in the successful construction of a highly active hybrid coordination site of N?Cu(II)?Cu0 in derived Cu?N/C catalysts. As a result, the optimized 25% Cu?N/C catalyst possesses a high ORR activity and stability in 0.1 m KOH solution, as well as excellent performance and stability in a Zn-air battery. PMID- 28627075 TI - Chemistry of Two Distinct Aeolid Spurilla Species: Ecological Implications. AB - The lipophilic extracts of two marine aeolid nudibranch molluscs of the genus Spurilla collected in distinct geographical areas have been chemically analyzed. The Et2 O extracts of the nudibranchs were dominated by the presence of usual fatty acids and sterols and contained terpenoid compounds 1 - 3 as minor metabolites. Spurillin A (1) and spurillin B (3) were new molecules whereas cis gamma-monocyclofarnesol (2) was already reported in the literature as a synthesis product. Interestingly, bursatellin (4), previously isolated from anaspidean molluscs of the genus Bursatella, was found in the butanol extract of both Spurilla species. Compounds 1 - 4 were not detected in the extracts of the sea anemone preys collected together with the molluscs. PMID- 28627076 TI - Supportive housing for chronically homeless individuals: Challenges and opportunities for providers in Chicago, USA. AB - Chronically homeless individuals often have extensive health, mental health and psychosocial needs that pose barriers to obtaining and maintain supportive housing. This study aims to qualitatively explore supportive housing providers' experiences and challenges with housing chronically homeless individuals and examine opportunities to improve supportive housing systems of care. In 2014, we conducted qualitative in-depth interviews with 65 programme administrators and case managers of supportive housing programmes in Chicago, IL. Data were analysed using an inductive thematic content analysis. Analysis revealed four themes that capture the primary challenges faced by housing providers: housing priorities, funding cuts, co-ordinated entry and permanency of housing. Housing for the chronically homeless has been prioritised, yet service providers are being expected to provide the necessary services to meet the needs of this population without commensurate funding increases or agency capacity. Additionally, case managers and administrators discussed the tension over housing tenure and the permanency of supportive housing. Findings provide qualitative insight into the challenges providers face implementing supportive housing for chronically homeless individuals. PMID- 28627077 TI - Phase-Separable Polyisobutylene Palladium-PEPPSI Precatalysts: Synthesis and Application in Buchwald-Hartwig Amination. AB - This paper reports the efficient synthesis of the first class of polyisobutylene(PIB)-supported palladium-PEPPSI precatalyst (PEPPSI = pyridine enhanced precatalyst preparation, stabilization, and initiation). The new complexes are employed in Buchwald-Hartwig amination of aryl chlorides and are found to be reasonably active in the titled cross-coupling reaction. The supported catalysts are tested in polar (1,4-dioxane and 1,2-dimethoxyethane) as well as in aliphatic reaction media (toluene and n-heptane) and display superior activity in the highly lipophilic solvent (n-heptane). The catalytic efficacy of PIB-Pd-PEPPSI precatalyst is measured to be comparable to its nonsupported analog. Pd-leaching is determined by inductively coupled plasma mass spectrometry (ICP-MS) after a simple liquid/liquid extraction and is found to be 2 ppb in the product phase, translating into a recovery of ~99.8% of the palladium. PMID- 28627078 TI - Gas adsorption in Mg-porphyrin-based porous organic frameworks: A computational simulation by first-principles derived force field. AB - A novel type of porous organic frameworks, based on Mg-porphyrin, with diamond like topology, named POF-Mgs is computationally designed, and the gas uptakes of CO2 , H2 , N2 , and H2 O in POF-Mgs are investigated by Grand canonical Monte Carlo simulations based on first-principles derived force fields (FF). The FF, which describes the interactions between POF-Mgs and gases, are fitted by dispersion corrected double-hybrid density functional theory, B2PLYP-D3. The good agreement between the obtained FF and the first-principle energies data confirms the reliability of the FF. Furthermore our simulation shows the presence of a small amount of H2 O (<= 0.01 kPa) does not much affect the adsorption quantity of CO2 , but the presence of higher partial pressure of H2 O (>= 0.1 kPa) results in the CO2 adsorption decrease significantly. The good performance of POF-Mgs in the simulation inspires us to design novel porous materials experimentally for gas adsorption and purification. (c) 2017 Wiley Periodicals, Inc. PMID- 28627079 TI - Persistently misunderstood and malignant: the case of heart failure vs. cancer. PMID- 28627080 TI - Comparison of subconjunctival scarring after microincision vitrectomy surgery using 20-, 23-, 25- and 27-gauge systems in rabbits. AB - PURPOSE: To compare subconjunctival scarring after vitrectomy in rabbit eyes using different gauge systems by analysing anterior segment optical coherence tomography (AS-OCT) images and histological sections. METHODS: Vitrectomy using 20-, 23-, 25- and 27-gauge systems was performed for rabbits. Anterior segment optical coherence tomography (AS-OCT) images of the incision sites were obtained before and at day 1, 7 and 1 month after surgery. We measured the thickness of conjunctival epithelium, stroma, Tenon's capsule and total conjunctiva of these three layers, then determined the preservation rates of the borderlines between each layer. Surgical invasion was estimated by histological observation. RESULTS: The thickness of total conjunctiva, or the thickness of both conjunctival stroma and Tenon's capsule in the 20-gauge group was significantly thicker than that in the 27-gauge group at day 1 and day 7 after surgery. Preservation rates of the conjunctival stroma/Tenon's capsule borderline were significantly lower in the 20 gauge group than in the 25- and 27-gauge groups at day 1, day 7 and 1 month. Preservation rates of the Tenon's capsule/sclera borderline were significantly lower in the 20-gauge group than in the 25- and 27-gauge groups at 1 month. In the 27-gauge group, the number of alpha-smooth muscle actin-positive fibroblasts was significantly smaller than in the 20-gauge group at day 7. CONCLUSION: Based on the finding of AS-OCT and histology, micro incision vitreous surgery, especially using 27-gauge, contributed to less subconjunctival scarring postoperatively. Therefore, the 27-gauge pars plana vitrectomy (PPV) may be a more effective technique for preserving the structure of conjunctiva. PMID- 28627081 TI - Arginase-2, a miR-1299 target, enhances pigmentation in melasma by reducing melanosome degradation via senescence-induced autophagy inhibition. AB - Expression profiles revealed miR-1299 downregulation concomitant with arginase-2 (ARG2) upregulation in hyperpigmented skin of melasma patients. Opposite regulation of tyrosinase and PMEL17 by miR-1299 and inverse relationship between miR-1299 and ARG2 expression denoted a role of miR-1299 in pigmentation with ARG2 as a miR-1299 target. ARG2 overexpression or knock-down in keratinocytes, the main source of ARG2 in epidermis, positively regulated tyrosinase and PMEL17 protein levels, but not mRNA levels or melanosome transfer. ARG2 overexpression in keratinocytes reduced autophagy equivalent to 3-MA, an autophagy inhibitor which also increased tyrosinase and PMEL17 protein levels, whereas ARG2 knock down induced opposite results. Autophagy inducer rapamycin reduced ARG2-increased tyrosinase and PMEL17 protein levels. Also, autophagy was reduced in late passage induced senescent keratinocytes showing ARG2 upregulation. ARG2, but not 3-MA, stimulated keratinocyte senescence. These results suggest that ARG2 reduces autophagy in keratinocytes by stimulating cellular senescence, resulting in skin pigmentation by reducing degradation of transferred melanosomes. PMID- 28627082 TI - Dependence and resistance in community mental health care-Negotiations of user participation between staff and users. AB - : WHAT IS KNOWN ON THE SUBJECT?: Implementation of user participation is described as a change from a paternalistic healthcare system to ideals of democratization where users' voices are heard in relational interplays with health professionals. The ideological shift involves a transition from welfare dependency and professional control towards more active service-user roles with associated rights and responsibilities. A collaborative relationship between users and professionals in mental health services is seen as important by both parties. Nevertheless, the health professionals find it challenging in practice to reorient their roles and to find productive ways to cooperate. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study illuminates how user participation is negotiated and involves multiple and shifting subject positions in the collaboration between users and professionals in community mental health care. By taking different positions, the relationship between users and professionals develops through dynamic interaction. This study challenges understandings of equality and implicit "truths" in user participation by illuminating subtle forms of power and dilemmas that arise in user-professional negotiations. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Instead of denying the appearance of power, it is important to question the execution of power in the interplay between users and professionals. Focusing on the negotiation processes between users and professionals is important for increasing reflection on and improving understanding of the dynamic in collaboration and speech. By focusing on negotiations, power can be used in productive ways in user-professional relationships. ABSTRACT: Introduction Implementation of user participation is considered important in today's mental health care. Research shows, however, that user participation lacks clarity and provokes uncertainty regarding shifting roles. Aim To investigate negotiation of user participation in a microstudy of interplay between users and health professionals in community mental health care. Method This qualitative study is based on semi-structured in-depth interviews, involving ten service users and ten professionals in community mental health care in Norway. The analysis is inspired by Willig's model for Foucauldian discourse analysis. Results The study illuminates the dynamic nature of user participation that arises through negotiation between users' and professionals' positions as change enablers, dependents, resisters, persuaders and knowledge holders. Discussion Discourses of user participation allow for different subject positions in mental health care. User participation also involves government and questions of power, as well as ambitions of change and control. Professionals act in different ways to make and keep users active, participating, enterprising and self-governing, and users respond and take part within the same discursive framework. Implications for practice Awareness of subjects' positions in discourses is important to increase reflection on the dynamic interplay in user professional collaboration. PMID- 28627083 TI - A review of important electroencephalogram features for the assessment of brain maturation in premature infants. AB - : This review describes the maturational features of the baseline electroencephalogram (EEG) in the neurologically healthy preterm infant. Features such as continuity, sleep state, synchrony and transient waveforms are described, even from extremely preterm infants and includes abundant illustrated examples. The physiological significance of these EEG features and their relationship to neurodevelopment are highlighted where known. This review also demonstrates the importance of multichannel conventional EEG monitoring for preterm infants as many of the features described are not apparent if limited channel EEG monitors are used. CONCLUSION: This review aims to provide healthcare professionals in the neonatal intensive care unit with guidance on the more common normal maturational features seen in the EEG of preterm infants. PMID- 28627084 TI - Water-Catalyzed Oxidation of Few-Layer Black Phosphorous in a Dark Environment. AB - Black phosphorus (BP) shows great potential in electronic and optoelectronic devices owing to its semiconducting properties, such as thickness-dependent direct bandgap and ambipolar transport characteristics. However, the poor stability of BP in air seriously limits its practical applications. To develop effective schemes to protect BP, it is crucial to reveal the degradation mechanism under various environments. To date, it is generally accepted that BP degrades in air via light-induced oxidation. Herein, we report a new degradation channel via water-catalyzed oxidation of BP in the dark. When oxygen co-adsorbs with highly polarized water molecules on BP surface, the polarization effect of water can significantly lower the energy levels of oxygen (i.e. enhanced electron affinity), thereby facilitating the electron transfer from BP to oxygen to trigger the BP oxidation even in the dark environment. This new degradation mechanism lays important foundation for the development of proper protecting schemes in black phosphorus-based devices. PMID- 28627085 TI - Examining levels, distribution and correlates of health insurance coverage in Kenya. AB - OBJECTIVE: To examine the levels, inequalities and factors associated with health insurance coverage in Kenya. METHODS: We analysed secondary data from the Kenya Demographic and Health Survey (KDHS) conducted in 2009 and 2014. We examined the level of health insurance coverage overall, and by type, using an asset index to categorise households into five socio-economic quintiles with quintile 5 (Q5) being the richest and quintile 1 (Q1) being the poorest. The high-low ratio (Q5/Q1 ratio), concentration curve and concentration index (CIX) were employed to assess inequalities in health insurance coverage, and logistic regression to examine correlates of health insurance coverage. RESULTS: Overall health insurance coverage increased from 8.17% to 19.59% between 2009 and 2014. There was high inequality in overall health insurance coverage, even though this inequality decreased between 2009 (Q5/Q1 ratio of 31.21, CIX = 0.61, 95% CI 0.52 0.0.71) and 2014 (Q5/Q1 ratio 12.34, CIX = 0.49, 95% CI 0.45-0.52). Individuals that were older, employed in the formal sector; married, exposed to media; and male, belonged to a small household, had a chronic disease and belonged to rich households, had increased odds of health insurance coverage. CONCLUSION: Health insurance coverage in Kenya remains low and is characterised by significant inequality. In a context where over 80% of the population is in the informal sector, and close to 50% live below the national poverty line, achieving high and equitable coverage levels with contributory and voluntary health insurance mechanism is problematic. Kenya should consider a universal, tax-funded mechanism that ensures revenues are equitably and efficiently collected, and everyone (including the poor and those in the informal sector) is covered. PMID- 28627086 TI - The hypertension of hemophilia is associated with vascular remodeling in the joint. AB - OBJECTIVE: Hemophilic arthropathy is associated with pronounced vascular joint remodeling. Also, compared to the general population, PWH have a higher prevalence of hypertension not explained by usual risk factors. As vascular remodeling in various vascular beds is a hallmark of hypertension, we hypothesized that vascular joint remodeling is associated with elevated blood pressures and hypertension. METHODS: Elbows, knees, and ankles of 28 adult PWH were evaluated for vascular abnormalities with MSKUS/PD, as well as for radiographic and clinical status and pain. Logistic and linear regression models were fitted to examine associations between hypertension, blood pressure, and PD score. RESULTS: The extent of vascular abnormalities was associated with hypertension and blood pressures. Hypertensive patients had a higher PD score compared to nonhypertensive patients, and the risk of hypertension increased steeply with PD score. SBP was also strongly associated with PD score, while DBP was only weakly associated. CONCLUSIONS: Vascular remodeling in hemophilic joints is associated with hypertension and elevated blood pressures. As hypertension is a grave risk factor for intracranial hemorrhage, a prominent cause of mortality in hemophilia patients, future studies are needed to address the causal pathways between vascular joint remodeling and blood pressure. PMID- 28627087 TI - Familial seborrhoeic keratosis associated with multiple 'pure reticulated acanthomas' and infundibulocystic basal cell carcinomas. AB - BACKGROUND: A variety of genodermatoses with multiple cutaneous tumours and germline genetic alterations, such as PTCH1 mutations, have been described. Other cutaneous syndromes have been associated with somatic gene mutations, such as FGFR3 in familial seborrhoeic keratosis. OBJECTIVES: To describe the clinical, dermoscopic and histopathological features of multiple cutaneous lesions, mostly infundibulocystic basal cell carcinomas (ICBCCs) and pure reticulated acanthomas, present in a family affected by familial seborrhoeic keratosis. In addition, we tested for possible germline alterations in FGFR3 and PTCH1. METHODS: Ten members of one family were clinically examined and 92 skin biopsy specimens were evaluated. Blood samples from six individuals were analysed for FGFR3 and PTCH1 germline alterations. We reviewed the literature concerning genetic FGFR3 alterations in seborrhoeic keratosis. RESULTS: Individuals of all generations affected by familial seborrhoeic keratosis also presented other skin tumours that corresponded histologically to reticulated acanthomas without apocrine or sebaceous differentiation, as well as ICBCCs. In addition, two novel germline variants, p.Pro449Ser (c.1345C>T) in FGFR3 and p.Pro725Ser (c.2173C>T) in exon 14 of PTCH1 were identified in five participants. CONCLUSIONS: We characterize for the first time the clinical, dermoscopic and histopathological features of multiple reticulated acanthomas without apocrine or sebaceous differentiation, for which we propose the term 'pure reticulated acanthoma', and ICBCCs associated with familial seborrhoeic keratosis. We identified FGFR3 and PTCH1 germline polymorphisms whose influence in the development of reticulated acanthomas is unknown. PMID- 28627088 TI - Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus. AB - AIMS: Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). METHODS: The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. RESULTS: iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. CONCLUSIONS: Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH. PMID- 28627089 TI - Analysis of PTPN22, ZFAT and MYO9B polymorphisms in Turner Syndrome and risk of autoimmune disease. AB - Turner syndrome (TS) is one of the most common sexual chromosome abnormalities and is clearly associated with an increased risk of autoimmune diseases, particularly thyroid disease and coeliac disease (CD). Single-nucleotide polymorphism analyses have been shown to provide correlative evidence that specific genes are associated with autoimmune disease. Our aim was to study the functional polymorphic variants of PTPN22 and ZFAT in relation to thyroid disease and those of MYO9B in relation to CD. A cross-sectional comparative analysis was performed on Mexican mestizo patients with TS and age-matched healthy females. Our data showed that PTPN22 C1858T (considered a risk variant) is not associated with TS (X2 = 3.50, p = .61, and OR = 0.33 [95% CI = 0.10-1.10]). Also, ZFAT was not associated with TS (X2 = 1.2, p = .28, and OR = 1.22 [95% CI = 0.84-1.79]). However, for the first time, rs2305767 MYO9B was revealed to have a strong association with TS (X2 = 58.6, p = .0001, and OR = 10.44 [95% C = 5.51-19.80]), supporting a high level of predisposition to CD among TS patients. This report addresses additional data regarding the polymorphic variants associated with autoimmune disease, one of the most common complications in TS. PMID- 28627090 TI - Silver-Catalyzed Stereoselective Aminosulfonylation of Alkynes. AB - A silver-catalyzed intermolecular aminosulfonylation of terminal alkynes with sodium sulfinates and TMSN3 is reported. This three-component reaction proceeds through sequential hydroazidation of the terminal alkyne and addition of a sulfonyl radical to the resultant vinyl azide. The method enables the stereoselective synthesis of a wide range of beta-sulfonyl enamines without electron-withdrawing groups on the nitrogen atom. These enamines are found to be suitable for a variety of further transformations. PMID- 28627091 TI - Acute myeloid leukemia in a child with dedicator of cytokinesis 8 (DOCK8) deficiency. PMID- 28627092 TI - The contextual-level effects of social trust on health in transitional countries: Instrumental variable analysis of 26 countries. AB - We analyse the effect of contextual-level social capital on health status in a sample of 26 transitional countries of Central and South Europe, Mongolia, and the former Soviet Union for 2006-2010 (N = 51 911). Contextual-level social capital is conceptualized as country-level social trust, while health status is conceptualized as self-rated health. We use ordinary least squares and instrumental variable regressions to address endogeneity and especially to rule out reverse causality. Both instrumental variable and ordinary least squares regressions suggest a strong positive effect of country-level trust on health. This finding is consistent for the whole sample as well as separate regional estimations. PMID- 28627094 TI - Spectrum of hepatitis B and renal involvement. AB - Renal involvement in hepatitis B occurs in various spectrums and its knowledge is important for clinicians in management of patients. The renal diseases most commonly associated with hepatitis B virus (HBV) infection include membranous nephropathy, membranoproliferative glomerulonephritis and Polyarteritis nodosa. The widespread use of hepatitis B vaccination has decreased the incidence of HBV related renal diseases. The incidence of HBV infection in dialysis patients has significantly decreased over the past few decades because of screening of blood products for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody, implementation of infection control measures and hepatitis B vaccination. The definition of acute kidney injury has been recently modified in cirrhotic population, helping in prognosis and prediction of mortality. The most common etiologies of acute kidney injury in this cirrhotic population, which account for 80% to 90% of all cases, include volume depletion, acute tubular necrosis and hepatorenal syndrome. Treatment with oral nucleoside/tide analogues (NA) brought a new paradigm in the management of HBsAg positive glomerulonephritis, kidney transplant recipients and dialysis patients, resulting in effective viral suppression, reduced hepatic complications and improved patient survival, without compromising renal allograft outcome. NAs are cleared by the kidneys and therefore their dosage has to be adjusted in all patients with impaired renal function. This article reviews the recent knowledge of the pathogenesis and treatment of HBV-related glomerulonephritis and discusses the management of hepatitis B in patients on dialysis, kidney transplant recipients and cirrhotics, which is continuously evolving. PMID- 28627095 TI - Sporotrichosis masquerading as pyoderma gangrenosum. PMID- 28627093 TI - Characterization of thrombosis in patients with Proteus syndrome. AB - Patients with overgrowth and complex vascular malformation syndromes, including Proteus syndrome have an increased risk of thromboembolism. Proteus syndrome is a mosaic, progressive overgrowth disorder involving vasculature, skin, and skeleton, and caused by a somatic activating mutation in AKT1. We conducted a comprehensive review of the medical histories and hematologic evaluations of 57 patients with Proteus syndrome to identify potential risk factors for thrombosis. We found that six of ten patients, who were deceased, died secondary to deep venous thrombosis and/or pulmonary embolism. Of the remaining 47 living patients, six had thromboembolic events that all occurred postoperatively and in an affected limb. Eleven of 21 patients had an abnormal hypercoagulable panel including Factor V Leiden heterozygotes, antithrombin III deficiency, positive lupus anticoagulant, or Protein C or S deficiencies. We observed that eight of 17 patients had an abnormal D-dimer level >0.5 mcg/dl, but deep venous thromboses occurred in only four of those with D-dimer >1.0 mcg/dl. We conclude that the predisposition to thrombosis is likely to be multifaceted with risk factors including vascular malformations, immobility, surgery, additional prothrombotic factors, and possible pathophysiologic effects of the somatic AKT1 mutation on platelet function or the vascular endothelium. The D-dimer test is useful as a screen for thromboembolism, although the screening threshold may need to be adjusted for patients with this disorder. We propose developing a registry to collect D-dimer and outcome data to facilitate adjustment of the D-dimer threshold for Proteus syndrome and related disorders, including PIK3CA-Related Overgrowth Spectrum. PMID- 28627096 TI - High titer of anti-citrullinated peptide antibody is a risk factor for severe carotid atherosclerotic plaque in patients with rheumatoid arthritis: the TOMORROW study. AB - AIM: Cardiovascular disease is one of the complications of rheumatoid arthritis (RA). We researched the morbidity and severity of existing carotid atherosclerosis plaque and associated risk factors in patients with RA. METHOD: This study included 413 participants, including 208 patients with RA and 205 age- and sex-matched healthy volunteers. Carotid ultrasound, clinical data collection and assessment of cardiovascular risk factors were performed. Atherosclerotic plaque was defined as an intima-media thickness >= 1.1 mm. Severity of plaque was assessed by plaque score, defined as the sum of the maximal thickness of all plaques in bilateral carotid arteries. RESULTS: Data were analyzed from 200 patients with RA and 202 controls. Carotid plaque was observed more frequently in patients with RA than controls (47.0 vs. 36.1%, P = 0.027). Moreover, plaque score was significantly higher in RA patients (P = 0.032). In logistic regression analysis, RA represented an independent risk factor for the presence of plaque (adjusted odds ratio, 1.68; 95% confidence interval, 1.03-2.74). Comparing RA patients with and without plaque, anti-cyclic citrullinated peptide (anti-CCP) antibodies titer was significantly higher in patients with plaque (315.8 +/- 454.1 U/mL) than in patients without (165.7 +/- 281.1 U/mL; P = 0.005). Moreover, multiple linear regression analysis clarified that anti-CCP antibody titer was associated with plaque score in patients with RA. CONCLUSION: High prevalence of any carotid plaques and severe carotid plaques were more frequent in patients with RA. High titer of anti-CCP antibodies represented a risk factor for severe carotid atherosclerotic plaque in patients with RA. PMID- 28627097 TI - Stability of outcomes after 5 years of treatment in an early intervention programme. AB - AIM: It has been hypothesized that the first 5 years are critical in determining long-term recovery from psychotic disorders. We examine stability in recovery indices after 5 years for 56 patients treated in an early intervention programme for psychosis. METHODS: Assessments of symptom remission and functional recovery were carried out 5 and 10 years after initiation of treatment. RESULTS: Although overall rates of recovery were comparable at both times, there were significant changes for individuals reflecting both improvement and deterioration. CONCLUSIONS: Evidence concerning the critical period hypothesis should examine stability in individuals rather than relying on cumulative indices. PMID- 28627098 TI - Effect of Concomitant Birth Defects and Genetic Anomalies on Infant Mortality in Tetralogy of Fallot. AB - BACKGROUND: A substantial proportion of infants born with tetralogy of Fallot (TOF) die in infancy. A better understanding of the heterogeneity associated with TOF, including extracardiac malformations and chromosomal anomalies is vital to stratifying risk and optimizing outcomes during infancy. METHODS: Using the North Carolina Birth Defects Monitoring Program, infants diagnosed with TOF and born between 2003 and 2012 were included. Kaplan-Meier survival curves were used to estimate cumulative 1-year mortality, stratified by the presence of concomitant birth defects (BDs) and chromosomal anomalies. Multivariable logistic regression was used to estimate the direct effect of each concomitant BD, after adjusting for all others. RESULTS: A total of 496 infants with TOF were included, and 15% (n = 76) died. The number of concomitant BD systems was significantly associated with the risk of death at 1-year, p < 0.0001. Specifically, the risk of mortality was 8% among infants with TOF with or without additional cardiac defects, 16% among infants with TOF and 1 extracardiac BD system, 19% among infants with 2 extracardiac BD systems, and 39% among infants with >= 3 extracardiac BD systems. After adjustment, concomitant eye and gastrointestinal defects were significantly associated increased with 1-year mortality, odds ratio 2.83 (95% confidence interval, 1.08-7.32) and odds ratio 4.43 (95% confidence interval, 1.57, 12.45), respectively. Infants with trisomy 13 or trisomy 18 were also significantly more likely to die, p < 0.0001. CONCLUSION: Both concomitant BDs and genetic anomalies increase the risk of mortality among infants with TOF. Future studies are needed to identify the underlying genetic and socioeconomic risk factors for high-risk TOF infants. Birth Defects Research 109:1154-1165, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28627099 TI - Fossils, proxies, and models: Geobiology at critical transitions in the Proterozoic-Paleozoic. PMID- 28627100 TI - Subcutaneous extraskeletal osteosarcoma in a metatarsal footpad in a cat. AB - BACKGROUND: Extraskeletal osteosarcomas (ESOSAs) are rare neoplasms in humans and animals. In cats, ESOSA has been reported to arise from orbital, ocular, intestinal, mammary and subcutaneous locations. Subcutaneous ESOSA occurs most commonly at sites used for vaccination including interscapular, dorsal lumbar or thigh areas. Previous reports of feline cases have not documented the use of advanced diagnostic imaging to exclude a primary bone tumour. OBJECTIVE: To describe the clinicopathological and advanced imaging findings of a subcutaneous ESOSA occurring in a metatarsal footpad of a cat and to report the one year follow-up status. ANIMAL: A 9-year-old neutered male domestic short hair cat. METHODS: Physical, abdominal ultrasonographic and computed tomographic examinations, and excisional biopsy for histopathological and immunohistochemical evaluation. RESULTS: The cat presented with mild focal erythematous swelling of the left metatarsal pad. ESOSA was diagnosed through advanced diagnostic imaging and histopathological examinations. Histopathological findings were consistent with osteosarcoma. No primary bone disease was observed on computed tomography. The owners declined limb amputation. One year after diagnosis, the cat was alive without disease progression. CONCLUSIONS AND CLINICAL IMPORTANCE: Extraskeletal osteosarcoma should be considered in the differential diagnosis of soft tissue swelling in footpads in cats. Advanced diagnostic imaging is recommended to exclude primary bone tumours. PMID- 28627101 TI - Depletion of cdc-25.3, a Caenorhabditis elegans orthologue of cdc25, increases physiological germline apoptosis. AB - In Caenorhabditis elegans hermaphrodites, physiological germline apoptosis is higher in cdc-25.3 mutants than in wild-type. The elevated germline apoptosis in cdc-25.3 mutants seems to be induced by accumulation of double-stranded DNA breaks (DSBs). Both DNA damage and synapsis checkpoint genes are required to increase the germline apoptosis. Notably, the number of germ cells that lose P granule components, PGL-1 and PGL-3, increase in cdc-25.3 mutants, and the increase in germline apoptosis requires the activity of SIR-2.1, a Sirtuin orthologue. These results suggest that elevation of germline apoptosis in cdc 25.3 mutants is induced by accumulation of DSBs, leading to a loss of PGL-1 and PGL-3 in germ cells, which promotes cytoplasmic translocation of SIR-2.1, and finally activates the core apoptotic machinery. PMID- 28627103 TI - Intimacy: The drama and beauty of encountering the Other. PMID- 28627102 TI - Quantitation of gamma-aminobutyric acid in equine plasma by hydrophilic interaction liquid chromatography with tandem mass spectrometry. AB - gamma-Aminobutyric acid is the principal inhibitory neurotransmitter in the central nervous system and regulates the neuronal excitability. There has been anecdotal evidence that gamma-aminobutyric acid has been used within a few hours prior to competition in equine sports to calm down nervous horses. However, regulating the use of gamma-aminobutyric acid is challenging because it is an endogenous substance in the horse. gamma-Aminobutyric acid is usually present at low ng/mL levels in equine plasma; therefore, a sensitive method has to be developed to quantify these low background levels. Measuring low concentrations of endogenous gamma-aminobutyric acid is essential to establish a threshold that can be used to differentiate levels attributable to exogenous administrations of gamma-aminobutyric acid. A hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry method was developed and validated for the quantitation of gamma-aminobutyric acid in equine plasma. Calibrators were prepared in artificial surrogate matrix consisting of 35 mg/mL equine serum albumin in phosphate buffered saline. Samples were prepared by protein precipitation with acetonitrile. Utilizing this methodology, a total of 403 equine plasma samples collected post-competition from horses participating in equestrian events in Canada were analyzed. PMID- 28627104 TI - Intimacy: The tank in the bedroom. PMID- 28627105 TI - Reverie-informed research interviewing. AB - Drawing on Thomas Ogden's notion of 'reverie', the role of self-reflection in research interviewing is explored. Ogden views reverie as a co-created intersubjective phenomenon, a 'third', distinct from both analyst and patient. Two face-to-face research interviews with adolescent depression sufferers are described, showing how reverie can be used to help overcome impasse, and develop research hypotheses. Participant-centred research interviews were thus shown to be enhanced by psychoanalytically informed self-reflection as accessed through reverie. The role of reverie in research interviewing, in part spontaneous and ineffable, in part defined and systematic, is discussed. PMID- 28627106 TI - Letter from Argentina. PMID- 28627107 TI - Intimacy thwarted and established: Following a girl from infancy to child psychotherapy. PMID- 28627109 TI - High-power Magnetotherapy: A New Weapon in Urinary Incontinence? AB - OBJECTIVE: Urinary incontinence (UI) is one of the most common urinary system diseases that mostly affects women but also men. We evaluated the therapeutic efficacy of functional magnetic stimulation (FMS) as potential UI treatment with improvements in the pelvic floor musculature, urodynamic tests and quality of life. METHODS: A total of 20 UI patients (10 females and 10 men, mean age 64, 14 years), including 10 with stress UI, four with urgency UI and six with mixed UI, were treated with FMS (20 min/session) twice a week for 3 weeks. The patients' impressions, records in urinary diaries, and scores of three life stress questionnaires (overactive bladder symptom questionnaire [OAB-q], urogenital distress inventory questionnaire-short form [UDI-6], incontinence impact questionnaire-short form [IIQ-7]) were performed pre- and post-treatment. RESULTS: Significant reductions (P < 0.01) of micturition number and nocturia after magnetic treatment were evidenced. The urodynamic tests recorded a significant increase in cystometric capacity (147 +/- 51.3%), in maximum urethral closure pressure (110 +/- 34%), in urethral functional length (99.8 +/- 51.8%), and in pressure transmission ratio (147 +/- 51.3%) values compared with the baseline values. CONCLUSIONS: These preliminary findings suggest that FMS with Magneto STYM (twice weekly for 3 weeks) improves the UI and may be an effective treatment for this urogenital disease. PMID- 28627110 TI - Patient preferences for healthcare delivery through community pharmacy settings in the USA: A discrete choice study. AB - WHAT IS KNOWN AND OBJECTIVE: In order to improve public health, it is necessary to facilitate patients' easy access to affordable high-quality primary health care, and one enhanced approach to do so may be to provide primary healthcare services in the community pharmacy setting. Discrete choice experiments to evaluate patient demand for services in pharmacy are relatively limited and have been hampered by a focus on only a few service alternatives, most focusing on changes in more traditional pharmacy services. The study aim was to gauge patient preferences explicitly for primary healthcare services that could be delivered through community pharmacy settings in the USA, using a very large sample to accommodate multiple service delivery options. METHODS: An online survey was administered to a total of 9202 adult patients from the general population. A subsequent online survey was administered to 50 payer reimbursement decision makers. The patient survey included a discrete choice experiment (DCE) which showed competing scenarios describing primary care service offerings. The respondents chose which scenario would be most likely to induce them to switch from their current pharmacy, and an optimal patient primary care service model was derived. The likelihood this model would be reimbursed was then determined in the payer survey. RESULTS AND DISCUSSION: The final optimal service configuration that would maximize patient preference included the pharmacy: offering appointments to see a healthcare provider in the pharmacy, having access to their full medical record, provide point-of-care diagnostic testing, offer health preventive screening, provide limited physical examinations such as measuring vital signs, and drug prescribing in the pharmacy. The optimal model had the pharmacist as the provider; however, little change in demand was evident if the provider was a nurse-practitioner or physician's assistant. The demand for this optimal model was 2-fold higher (25.5%; 95% Bayesian precision interval (BPI) 23.5%-27.0%) than for a base pharmacy offering minimal primary care services (12.6%; 95% BPI 12.2%-13.2%), and was highest among Hispanic (30.6%; 95% BPI: 25.7%-34.3%) and African American patients (30.7%; 95% BPI: 27.1%-35.2%). In the second reimbursement decision-maker survey, the majority (66%) indicated their organization would be likely to reimburse the services described in the optimal patient model if provided in the pharmacy setting. WHAT IS NEW AND CONCLUSION: This United States national study provides empirical support for a model of providing primary care services through community pharmacy settings that would increase access, with the potential to improve the public health. PMID- 28627111 TI - European Surveillance System on Contact Allergies (ESSCA): results with the European baseline series, 2013/14. AB - BACKGROUND: Contact allergy is a common condition and can severely interfere with daily life or professional activities. Due to changes in exposures, such as introduction of new substances, new products or formulations and regulatory intervention, the spectrum of contact sensitization changes. OBJECTIVE: To evaluate the current spectrum of contact allergy to allergens present in the European baseline series (EBS) across Europe. METHODS: Retrospective analysis of data collected by the European Surveillance System on Contact Allergies (ESSCA, www.essca-dc.org) in consecutively patch-tested patients, 2013/14, in 46 departments in 12 European countries. RESULTS: Altogether, 31 689 patients were included in the analysis. Compared to a similar analysis in 2004, the prevalence of contact allergy to methylisothiazolinone went up to around 20% in several departments. In comparison, contact allergy to the metals nickel, cobalt and chromium remained largely stable, at 18.1%, 5.9% and 3.2%, respectively, similar to mostly unchanged prevalence with fragrance mix I, II and Myroxylon pereirae (balsam of Peru) at 7.3%, 3.8% and 5.3%, respectively. In the subgroup of departments diagnosing (mainly) patients with occupational contact dermatitis, the prevalence of work-related contact allergies such as epoxy resin or rubber additives was found to be increased, compared to general dermatology departments. CONCLUSION: Continuous surveillance of contact allergy based on network data offers the identification of time trends or persisting problems, and thus enables focussing in-depth research (subgroup analyses, exposure analysis) on areas where it is needed. PMID- 28627112 TI - Asymptotic distribution of ?AUC, NRIs, and IDI based on theory of U-statistics. AB - The change in area under the curve (?AUC), the integrated discrimination improvement (IDI), and net reclassification index (NRI) are commonly used measures of risk prediction model performance. Some authors have reported good validity of associated methods of estimating their standard errors (SE) and construction of confidence intervals, whereas others have questioned their performance. To address these issues, we unite the ?AUC, IDI, and three versions of the NRI under the umbrella of the U-statistics family. We rigorously show that the asymptotic behavior of ?AUC, NRIs, and IDI fits the asymptotic distribution theory developed for U-statistics. We prove that the ?AUC, NRIs, and IDI are asymptotically normal, unless they compare nested models under the null hypothesis. In the latter case, asymptotic normality and existing SE estimates cannot be applied to ?AUC, NRIs, or IDI. In the former case, SE formulas proposed in the literature are equivalent to SE formulas obtained from U-statistics theory if we ignore adjustment for estimated parameters. We use Sukhatme-Randles-deWet condition to determine when adjustment for estimated parameters is necessary. We show that adjustment is not necessary for SEs of the ?AUC and two versions of the NRI when added predictor variables are significant and normally distributed. The SEs of the IDI and three-category NRI should always be adjusted for estimated parameters. These results allow us to define when existing formulas for SE estimates can be used and when resampling methods such as the bootstrap should be used instead when comparing nested models. We also use the U-statistic theory to develop a new SE estimate of ?AUC. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28627113 TI - Can tissue dielectric constant measurements assess circulating blood volume changes in patients undergoing haemodialysis? AB - BACKGROUND: The tissue dielectric constant (TDC) method uses an open-ended coaxial probe to achieve non-invasive measurement of water content in skin. The aim of our study was to test the hypothesis that the changes in circulating blood volume would be associated with the changes in TDC values in patients undergoing haemodialysis. METHODS: In this prospective descriptive study, TDC measurements were performed for three parts of the body (the face, shin and hand) before and after patients underwent haemodialysis (N = 83). The primary outcome measure was the correlation between the amount of water removal and DeltaTDC at each body site measured (DeltaTDC = posthaemodialysis TDC-prehaemodialysis TDC). The secondary outcome measure was the mean difference in TDC value before and after haemodialysis. RESULTS: The TDC values measured at each part of the body were significantly reduced after haemodialysis, but the percentage difference between pre- haemodialysis and posthaemodialysis was small for the face, shin and hand, with %mean +/- SE values of -4.4 +/- 0.70, -3.2 +/- 0.98 and -6.0 +/- 1.6; 95 per cent confidence intervals (lower bound to upper bound) of 3.0-5.8, 1.3-5.2 and 2.7-9.2; and P values of P = 0.000, P = 0.000 and P = 0.000, respectively. The inverse correlation between DeltaTDC and the amount of water removal was also weak (correlation at the face, r = -0.25, P = 0.028; at the shin, r = -0.26, P = 0.018; and at the hand, no significant correlation). CONCLUSION: Our results indicate that TDC measurement can be used to assess the changes in local oedema, but may be unlikely to evaluate real-time changes in the circulating blood volume in a clinical setting. PMID- 28627115 TI - Pup recycling regulates the proteasome. AB - The Pup proteasome system (PPS) in bacteria is equivalent to the eukaryotic ubiquitin proteasome system (UPS) that allows controlled protein degradation. Unlike the UPS, however, the PPS machinery and regulation is still poorly understood. In this issue of The FEBS Journal, Gur and colleagues combine experimental and modelling analyses to show how the PPS maintains steady-state levels of protein pupylation and consequently tightly controlled protein degradation. PMID- 28627117 TI - The cognitive features of idiopathic and DYT1 dystonia. AB - Dystonia is a common movement disorder. In this paper, we review the literature on cognitive function in idiopathic and DYT1 dystonia. In idiopathic or DYT1 dystonia, cognition is largely intact with only isolated executive dysfunction. Dystonia patients also have increased temporal and spatial discrimination thresholds, considered endophenotypes of the disorder because deficits are also shown by unaffected relatives and nonmanifesting carriers of the DYT1 mutation. Anticholinergic medication in high doses can be associated with memory impairment in dystonia. The successful treatment of dystonia with botulinum toxin injections or deep brain stimulation does not produce any major adverse effects on cognition. The aspects of cognition that require further investigation in future studies of dystonia include inhibitory control, decision making, and social cognition. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28627118 TI - Optical Microresonators for Sensing and Transduction: A Materials Perspective. AB - Optical microresonators confine light to a particular microscale trajectory, are exquisitely sensitive to their microenvironment, and offer convenient readout of their optical properties. Taken together, this is an immensely attractive combination that makes optical microresonators highly effective as sensors and transducers. Meanwhile, advances in material science, fabrication techniques, and photonic sensing strategies endow optical microresonators with new functionalities, unique transduction mechanisms, and in some cases, unparalleled sensitivities. In this progress report, the operating principles of these sensors are reviewed, and different methods of signal transduction are evaluated. Examples are shown of how choice of materials must be suited to the analyte, and how innovations in fabrication and sensing are coupled together in a mutually reinforcing cycle. A tremendously broad range of capabilities of microresonator sensors is described, from electric and magnetic field sensing to mechanical sensing, from single-molecule detection to imaging and spectroscopy, from operation at high vacuum to in live cells. Emerging sensing capabilities are highlighted and put into context in the field. Future directions are imagined, where the diverse capabilities laid out are combined and advances in scalability and integration are implemented, leading to the creation of a sensor unparalleled in sensitivity and information content. PMID- 28627119 TI - Australian Century. AB - Let the corks pop! This year, the Royal Australian Chemical Institute (RACI), a partner of the Asian Chemical Editorial Society (ACES) and co-owner of Chemistry An Asian Journal, celebrates its 100th anniversary. This special issue honors that occasion. In the Editorial, Chemistry - An Asian Journal Editor Theresa Kueckmann and RACI CEO Roger Stapleford look at the connection between the journal, ACES and RACI and how RACI has become a driving force in connecting chemists among themselves and within Australian society. PMID- 28627120 TI - New insights into human primordial germ cells and early embryonic development from single-cell analysis. AB - Human preimplantation developmental studies are difficult to accomplish due to associated ethical and moral issues. Preimplantation cells are rare and exist only in transient cell states. From a single cell, it is very challenging to analyse the origination of the heterogeneity and complexity inherent to the human body. However, recent advances in single-cell technology and data analysis have provided new insights into the process of early human development and germ cell specification. In this Review, we examine the latest single-cell datasets of human preimplantation embryos and germ cell development, compare them to bulk cell analyses, and interpret their biological implications. PMID- 28627121 TI - Cushing's syndrome caused by use of synthetic ocular steroid. AB - WHAT IS KNOWN AND OBJECTIVE: Cases of Cushing's syndrome (CS) following ocular steroid use have been reported in recent years, albeit rarely. CASE DESCRIPTION: We report a case of iatrogenic CS in a child induced by fluorometholone containing eyedrops. Our patient was referred to our endocrinology clinic due to rapid weight gain. His history revealed that 1.5 months previously he had been started on fluorometholone eyedrops. WHAT IS NEW AND CONCLUSION: To the best of our knowledge, no cases of CS have been reported following ocular fluorometholone use. Although eyedrops containing potent glucocorticoids may lead to CS, fluorometholone, a relatively less potent steroid, may also cause the syndrome, as in our case. PMID- 28627122 TI - A biotinylated peptide, BP21, as a novel potent anti-anaphylactic agent targeting platelet-activating factor. AB - Platelet-activating factor (PAF) is an important mediator of anaphylaxis and is therefore an anti-anaphylactic drug target. We recently reported that synthetic N terminally biotinylated peptides (BP4-BP29) inhibit PAF by directly interacting with PAF and its metabolite/precursor lyso-PAF. In this study, we investigated whether the biotinylated peptides can inhibit anaphylactic reactions in vivo. In mouse models of anaphylaxis, one of the peptides, BP21, markedly and dose dependently inhibited hypothermia with a maximum dose-response within 30 min after administration, even at doses 20 times lesser than doses of the known PAF antagonist CV-3988. In contrast, the anti-hypothermic effect of BGP21, in which the Tyr-Lys-Asp-Gly sequence in BP21 was modified to a Gly-Gly-Gly-Gly sequence, was less than that of BP21. The alanine scanning and shuffling the amino acid residues of BP4 (Tyr-Lys-Asp-Gly) demonstrated that the Tyr-Lys-Asp-Gly consensus sequence is important for the inhibitory effect of the peptide on hypothermia. BP21 also suppressed vascular permeability during anaphylaxis with a maximum dose response within 30 min of administration. In a rat model of hind paw oedema, BP21 significantly inhibited the oedema induced by PAF but not that induced by the other pro-inflammatory mediators, such as histamine, serotonin, and bradykinin. Tryptophan fluorescence measurements showed that BP21 interacted with PAF, but not with histamine, serotonin, or bradykinin. In contrast, BGP21 did not interact with PAF. These results suggest that biotinylated peptides, especially BP21, can specifically and markedly inhibit anaphylactic reactions in vivo and that this involves direct interaction of its Tyr-Lys-Asp-Gly region with PAF. Therefore, a biotinylated peptide, BP21, can be used as novel potential anti-anaphylactic drugs targeting PAF. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28627123 TI - Pharmacokinetics and Relative Bioavailability of Orally Administered Innovator Formulated Itraconazole Capsules and Solution in Healthy Dogs. AB - BACKGROUND: Itraconazole is commonly used for treatment of systemic and cutaneous mycoses in veterinary medicine. Two formulations, capsule and solution, are used interchangeably in dogs. However, marked differences in bioavailability have been reported in other species. Similar investigations have not been performed in dogs. OBJECTIVE: To determine and compare pharmacokinetics of itraconazole in dogs after oral administration of commercially available capsule and solution formulations intended for use in humans. ANIMALS: Eight healthy, adult, purpose bred dogs. METHODS: Dogs received approximately 10 mg/kg of innovator-formulated itraconazole solution and capsule PO in randomized, crossover design with a 10 day washout period. To ensure maximal absorption, solution was administered to fasted dogs, whereas capsules were co-administered with food. Blood samples were collected at predetermined time points, and plasma drug concentrations were measured using high-pressure liquid chromatography. Pharmacokinetic parameters were determined with compartmental analysis. RESULTS: The mean relative bioavailability of the capsule was 85% that of the solution, but drug absorption was variable, and overall drug concentrations were similar between formulations. Mean elimination half-lives of both formulations were nearly identical at approximately 33 hours. Regardless of formulation, simulations suggest that a loading dose of 20 mg/kg, followed by 10 mg/kg once every 24 hours, will result in plasma concentrations considered to be adequate in most dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Contrary to findings reported in other species, overall drug exposures after capsule and solution administration are not substantially different in dogs. Despite some pharmacokinetic differences between itraconazole capsule and solution, formulation-specific dosages do not appear to be necessary. PMID- 28627124 TI - Cross-resistance to purified Bt proteins, Bt corn and Bt cotton in a Cry2Ab2-corn resistant strain of Spodoptera frugiperda. AB - BACKGROUND: Gene-pyramiding by combining two or more dissimilar Bacillus thuringiensis (Bt) proteins into a crop has been used to delay insect resistance. The durability of gene-pyramiding can be reduced by cross-resistance. Fall armyworm, Spodoptera frugiperda, is a major target pest of the Cry2Ab2 protein used in pyramided Bt corn and cotton. Here, we provide the first experimental evaluation of cross-resistance in S. frugiperda selected with Cry2Ab2 corn to multiple Bt sources including purified Bt proteins, Bt corn and Bt cotton. RESULTS: Concentration - response bioassays showed that resistance ratios for Cry2Ab2-resistant (RR) relative to Cry2Ab2-susceptible (SS) S. frugiperda were 1.4 for Cry1F, 1.2 for Cry1A.105, >26.7 for Cry2Ab2, >10.0 for Cry2Ae and -1.1 for Vip3A. Larvae of Cry2Ab2-heterozygous (RS), SS and RR S. frugiperda were all susceptible to Bt corn and Bt cotton containing Cry1 (Cry1F or Cry1A.105) and/or Vip3A proteins. Pyramided Bt cotton containing Cry1Ac + Cry2Ab2 or Cry1Ab + Cry2Ae were also effective against SS and RS, but not RR. CONCLUSION: These findings suggest that Cry2Ab2-corn-selected S. frugiperda is not cross-resistant to Cry1F, Cry1A.105 or Vip3A protein, or corn and cotton plants containing these Bt proteins, but it can cause strong cross-resistance to Cry2Ae and Bt crops expressing similar Bt proteins. (c) 2017 Society of Chemical Industry. PMID- 28627125 TI - The role of long-term physical exercise on performance and brain activation during the Stroop colour word task in fibromyalgia patients. AB - The Stroop colour word test (SCWT) has been widely used to assess changes in cognitive performance such as processing speed, selective attention and the degree of automaticity. Moreover, the SCWT has proven to be a valuable tool to assess neuronal plasticity that is coupled to improvement in performance in clinical populations. In a previous study, we showed impaired cognitive processing during SCWT along with reduced task-related activations in patients with fibromyalgia. In this study, we used SCWT and functional magnetic resonance imagingFMRI to investigate the effects of a 15-week physical exercise intervention on cognitive performance, task-related cortical activation and distraction-induced analgesia (DIA) in patients with fibromyalgia and healthy controls. The exercise intervention yielded reduced fibromyalgia symptoms, improved cognitive processing and increased task-related activation of amygdala, but no effect on DIA. Our results suggest beneficial effects of physical exercise on cognitive functioning in FM. PMID- 28627126 TI - Consumption of obesogenic foods in non-Hispanic black mother-infant dyads. AB - Obesity continues to be a problem in the United States. Of particular concern is the epidemic of early childhood obesity. A significant predictor of child diet is maternal diet, but little is known about this relationship during infancy. This study examined the association between maternal and infant consumption of key food groups from 6 to 18 months using data from the Infant Care, Feeding, and Risk of Obesity Study, a prospective cohort of 217 non-Hispanic black, low income, first-time mothers. Using data from 24-hr dietary recalls collected during in-home visits at 6, 9, 12, and 18 months, we assessed longitudinal associations between mother and child intake of both energy-dense, nutrient-poor (obesogenic) food groups and fibre-, nutrient-rich food groups using random intercept logistic regression. Both mothers and their infants had high intake of sugar-sweetened beverages, desserts, and sweets and low intake of vegetables and whole grains. Infant consumption of key food groups was strongly associated with maternal consumption, suggesting the need for focused interventions to target maternal diet as a pathway to decreasing risk for the establishment of poor dietary patterns early in life. PMID- 28627127 TI - Metal-Organic-Framework-Derived Hybrid Carbon Nanocages as a Bifunctional Electrocatalyst for Oxygen Reduction and Evolution. AB - The oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are cornerstone reactions for many renewable energy technologies. Developing cheap yet durable substitutes of precious-metal catalysts, especially the bifunctional electrocatalysts with high activity for both ORR and OER reactions and their streamlined coupling process, are highly desirable to reduce the processing cost and complexity of renewable energy systems. Here, a facile strategy is reported for synthesizing double-shelled hybrid nanocages with outer shells of Co-N-doped graphitic carbon (Co-NGC) and inner shells of N-doped microporous carbon (NC) by templating against core-shell metal-organic frameworks. The double-shelled NC@Co NGC nanocages well integrate the high activity of Co-NGC shells into the robust NC hollow framework with enhanced diffusion kinetics, exhibiting superior electrocatalytic properties to Pt and RuO2 as a bifunctional electrocatalyst for ORR and OER, and hold a promise as efficient air electrode catalysts in Zn-air batteries. First-principles calculations reveal that the high catalytic activities of Co-NGC shells are due to the synergistic electron transfer and redistribution between the Co nanoparticles, the graphitic carbon, and the doped N species. Strong yet favorable adsorption of an OOH* intermediate on the high density of uncoordinated hollow-site C atoms with respect to the Co lattice in the Co-NGC structure is a vital rate-determining step to achieve excellent bifunctional electrocatalytic activity. PMID- 28627128 TI - Signatures of soft sweeps across the Dt1 locus underlying determinate growth habit in soya bean [Glycine max (L.) Merr.]. AB - Determinate growth habit is an agronomically important trait associated with domestication in soya bean. Previous studies have demonstrated that the emergence of determinacy is correlated with artificial selection on four nonsynonymous mutations in the Dt1 gene. To better understand the signatures of the soft sweeps across the Dt1 locus and track the origins of the determinate alleles, we examined patterns of nucleotide variation in Dt1 and the surrounding genomic region of approximately 800 kb. Four local, asymmetrical hard sweeps on four determinate alleles, sized approximately 660, 120, 220 and 150 kb, were identified, which constitute the soft sweeps for the adaptation. These variable sized sweeps substantially reflected the strength and timing of selection and indicated that the selection on the alleles had been completed rapidly within half a century. Statistics of EHH, iHS, H12 and H2/H1 based on haplotype data had the power to detect the soft sweeps, revealing distinct signatures of extensive long-range LD and haplotype homozygosity, and multiple frequent adaptive haplotypes. A haplotype network constructed for Dt1 and a phylogenetic tree based on its extended haplotype block implied independent sources of the adaptive alleles through de novo mutations or rare standing variation in quick succession during the selective phase, strongly supporting multiple origins of the determinacy. We propose that the adaptation of soya bean determinacy is guided by a model of soft sweeps and that this model might be indispensable during crop domestication or evolution. PMID- 28627129 TI - Cobalt-Based Active Species Molecularly Immobilized on Carbon Nanotubes for the Oxygen Reduction Reaction. AB - Hybrid systems in which molecule-based active species are combined with nanoscale materials may offer valuable routes to enhance catalytic performances for electrocatalytic reactions. The development of rationally designed, cost effective, efficient catalysts for the oxygen reduction reaction (ORR) is a crucial challenge for applications in fuel cells and metal-air batteries. A new hybrid ORR catalyst has been synthesized through a well-defined reaction between Co-based organometallic molecules and N-doped multiwalled carbon nanotubes (MWCNTs) at room temperature. The hybrid ORR catalyst shows excellent catalytic performance with an onset potential of 0.95 V [vs. the reversible hydrogen electrode (RHE)], superior durability, and good methanol tolerance. Chemical and structural characterization after many reaction cycles reveals that the Co-based organometallic species maintained the original structure of cobalt(II) acetylacetonate with coordination to the heteroatoms of the MWCNTs. A thorough electrochemical investigation indicates that the major catalytically active site is Co-O4 -NCNT . PMID- 28627132 TI - A Porphyrin Complex as a Self-Conditioned Electrode Material for High-Performance Energy Storage. AB - The novel functionalized porphyrin [5,15-bis(ethynyl)-10,20 diphenylporphinato]copper(II) (CuDEPP) was used as electrodes for rechargeable energy-storage systems with an extraordinary combination of storage capacity, rate capability, and cycling stability. The ability of CuDEPP to serve as an electron donor or acceptor supports various energy-storage applications. Combined with a lithium negative electrode, the CuDEPP electrode exhibited a long cycle life of several thousand cycles and fast charge-discharge rates up to 53 C and a specific energy density of 345 Wh kg-1 at a specific power density of 29 kW kg-1 . Coupled with a graphite cathode, the CuDEPP anode delivered a specific power density of 14 kW kg-1 . Whereas the capacity is in the range of that of ordinary lithium-ion batteries, the CuDEPP electrode has a power density in the range of that of supercapacitors, thus opening a pathway toward new organic electrodes with excellent rate capability and cyclic stability. PMID- 28627134 TI - U.S. Food and Drug Administration approval summary: Eltrombopag for the treatment of pediatric patients with chronic immune (idiopathic) thrombocytopenia. AB - The U.S. Food and Drug Administration (FDA) approved eltrombopag for pediatric patients with chronic immune (idiopathic) thrombocytopenia (ITP) ages >=6 on June 11, 2015, and ages >=1 on August 24, 2015. Approval was based on the FDA review of two randomized trials that included 159 pediatric patients with chronic ITP who had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. This manuscript describes the basis for approval of these applications. The FDA concluded that eltrombopag has shown efficacy and a favorable benefit to risk profile for pediatric patients with chronic ITP. PMID- 28627135 TI - In Situ Electrochemistry of Rechargeable Battery Materials: Status Report and Perspectives. AB - The development of rechargeable batteries with high performance is considered to be a feasible way to satisfy the increasing needs of electric vehicles and portable devices. It is of vital importance to design electrodes with high electrochemical performance and to understand the nature of the electrode/electrolyte interfaces during battery operation, which allows a direct observation of the complicated chemical and physical processes within the electrodes and electrolyte, and thus provides real-time information for further design and optimization of the battery performance. Here, the recent progress in in situ techniques employed for the investigations of material structural evolutions is described, including characterization using neutrons, X-ray diffraction, and nuclear magnetic resonance. In situ techniques utilized for in depth uncovering the electrode/electrolyte phase/interface change mechanisms are then highlighted, including transmission electron microscopy, atomic force microscopy, X-ray spectroscopy, and Raman spectroscopy. The real-time monitoring of lithium dendrite growth and in situ detection of gas evolution during charge/discharge processes are also discussed. Finally, the major challenges and opportunities of in situ characterization techniques are outlined toward new developments of rechargeable batteries, including innovation in the design of compatible in situ cells, applications of dynamic analysis, and in situ electrochemistry under multi-stimuli. A clear and in-depth understanding of in situ technique applications and the mechanisms of structural evolutions, surface/interface changes, and gas generations within rechargeable batteries is given here. PMID- 28627133 TI - Mesocorticolimbic hemodynamic response in Parkinson's disease patients with compulsive behaviors. AB - BACKGROUND: PD patients treated with dopamine therapy can develop maladaptive impulsive and compulsive behaviors, manifesting as repetitive participation in reward-driven activities. This behavioral phenotype implicates aberrant mesocorticolimbic network function, a concept supported by past literature. However, no study has investigated the acute hemodynamic response to dopamine agonists in this subpopulation. OBJECTIVES: We tested the hypothesis that dopamine agonists differentially alter mesocortical and mesolimbic network activity in patients with impulsive-compulsive behaviors. METHODS: Dopamine agonist effects on neuronal metabolism were quantified using arterial-spin labeling MRI measures of cerebral blood flow in the on-dopamine agonist and off dopamine states. The within-subject design included 34 PD patients, 17 with active impulsive compulsive behavior symptoms, matched for age, sex, disease duration, and PD severity. RESULTS: Patients with impulsive-compulsive behaviors have a significant increase in ventral striatal cerebral blood flow in response to dopamine agonists. Across all patients, ventral striatal cerebral blood flow on-dopamine agonist is significantly correlated with impulsive-compulsive behavior severity (Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease- Rating Scale). Voxel-wise analysis of dopamine agonist induced cerebral blood flow revealed group differences in mesocortical (ventromedial prefrontal cortex; insular cortex), mesolimbic (ventral striatum), and midbrain (SN; periaqueductal gray) regions. CONCLUSIONS: These results indicate that dopamine agonist therapy can augment mesocorticolimbic and striato nigro-striatal network activity in patients susceptible to impulsive-compulsive behaviors. Our findings reinforce a wider literature linking studies of maladaptive behaviors to mesocorticolimbic networks and extend our understanding of biological mechanisms of impulsive compulsive behaviors in PD. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28627136 TI - Enhancer of rudimentary homologue interacts with scaffold attachment factor B at the nuclear matrix to regulate SR protein phosphorylation. AB - Scaffold attachment factor B1 (SAFB1) is an integral component of the nuclear matrix of vertebrate cells. It binds to DNA on scaffold/matrix attachment region elements, as well as to RNA and a multitude of different proteins, affecting basic cellular activities such as transcription, splicing and DNA damage repair. In the present study, we show that enhancer of rudimentary homologue (ERH) is a new molecular partner of SAFB1 and its 70% homologous paralogue, scaffold attachment factor B2 (SAFB2). ERH interacts directly in the nucleus with the C terminal Arg-Gly-rich region of SAFB1/2 and co-localizes with it in the insoluble nuclear fraction. ERH, a small ubiquitous protein with striking homology among species and a unique structure, has also been implicated in fundamental cellular mechanisms. Our functional analyses suggest that the SAFB/ERH interaction does not affect SAFB1/2 function in transcription (e.g. as oestrogen receptor alpha co repressors), although it reverses the inhibition exerted by SAFB1/2 on the splicing kinase SR protein kinase 1 (SRPK1), which also binds on the C-terminus of SAFB1/2. Accordingly, ERH silencing decreases lamin B receptor and SR protein phosphorylation, which are major SRPK1 substrates, further substantiating the role of SAFB1 and SAFB2 in the co-ordination of nuclear function. PMID- 28627137 TI - Effect of sympathetic nerve blockade on low-frequency oscillations of forearm and leg skin blood flow in healthy humans. AB - OBJECTIVE: To Examine the effect of inhibiting sympathetic function on cutaneous vasomotion in the forearm and leg. METHODS: Intradermal microdialysis fibers were placed in the forearm and leg, one as an untreated control (lactated Ringer's) and the other perfused with bretylium tosylate to block sympathetic nerves. Skin blood flow was monitored using laser Doppler flowmetry. Baseline was collected for 10 minutes before local skin temperature was increased to 42 degrees C. Spectral analysis was performed using a Morlet wavelet. RESULTS: Bretylium tosylate increased skin blood flow during baseline in the forearm (d=1.6, P<.05) and leg (d=0.5, P<.05) and decreased skin blood flow at both sites during both the initial peak (d>=1.0, P<.05) and plateau (d>=0.8, P<.05). Treatment with bretylium tosylate reduced wavelet amplitude associated with neural activity during baseline in the forearm (d=1.6, P<.05) and leg (d=0.9, P<.05). This reduction in wavelet amplitude at bretylium tosylate-treated sites was also observed during the initial vasodilation to local heating in both the forearm (d=1.6, P<.05) and leg (d=1.4, P<.05) and during the sustained vasodilation in both the forearm (d=1.6, P<.05) and leg (d=1.2, P<.05). CONCLUSIONS: Our data support that the frequency band (0.021-0.052 Hz) associated with neurogenic activity appears to be correct having a large sympathetic component. PMID- 28627138 TI - Predictors of BRCA1/2 genetic testing among Black women with breast cancer: a population-based study. AB - Evidence shows that Black women diagnosed with breast cancer are substantially less likely to undergo BRCA testing and other multipanel genetic testing compared to White women, despite having a higher incidence of early-age onset breast cancer and triple-negative breast cancer (TNBC). Our study identifies predictors of BRCA testing among Black women treated for breast cancer and examines differences between BRCA testers and nontesters. We conducted an analysis of 945 Black women ages 18-64 diagnosed with localized or regional-stage invasive breast cancer in Pennsylvania and Florida between 2007 and 2009. Logistic regression was used to identify predictors of BRCA 1/2 testing. Few (27%) (n = 252) of the participants reported having BRCA testing. In the multivariate analysis, we found that perceived benefits of BRCA testing (predisposing factor) ([OR], 1.16; 95% CI: 1.11-1.21; P < 0.001), income (enabling factor) ([OR], 2.10; 95% CI: 1.16 3.80; p = 0.014), and BRCA mutation risk category (need factor) ([OR], 3.78; 95% CI: 2.31-6.19; P < 0.001) predicted BRCA testing. These results suggest that interventions to reduce disparities in BRCA testing should focus on identifying patients with high risk of mutation, increasing patient understanding of the benefits of BRCA testing, and removing financial and other administrative barriers to genetic testing. PMID- 28627139 TI - Direct Electro-oxidation of Dimethyl Ether on Pt-Cu Nanochains. AB - A new platinum-copper alloy electrocatalyst for the direct electro-oxidation of dimethyl ether (DME) has been synthesized in an easy and low-cost approach and studied by using an array of techniques, including X-ray diffraction, scanning electron microscopy, high-resolution transmission electron microscopy, and elemental analysis. Structural characterization revealed that the synthesized PtCu nanoparticles (3 nm on average) formed homogeneous nanochains without aggregation of metallic platinum or copper. The catalyst's activity towards electro-oxidation of DME was tested using cyclic voltammetry (CV) and in membrane electrode assembly (MEA) in a full cell and was found to be promising. The direct DME fuel cell (DDMEFC) studied in this work has relatively high energy density, of 13.5 mW cm-1 and thus shows great potential as fuel for low power fuel cells. The newly synthesized PtCu catalyst exhibited almost double the performance of commercial PtRu in electrocatalytic DME oxidation. PMID- 28627141 TI - [Non-tenured researchers: a successful story]. PMID- 28627140 TI - [Non-tenured public health researchers in Italy: bibliometric data from a public institute for treatment and research (IRCCS)]. PMID- 28627142 TI - [Theatre in jail: a starting point for a social epidemiology project?] PMID- 28627144 TI - [Environmental pollution: is epidemiological research always the best response?] PMID- 28627143 TI - [Causal inference in epidemiology: a fruitful debate]. PMID- 28627145 TI - [What can I eat, doc?] PMID- 28627146 TI - [HIA guidelines: the Report of the Italian National Institute for Health forgets epidemiology]. PMID- 28627147 TI - [Medicina Democratica: 40 years of battles for health]. PMID- 28627148 TI - [To get in the game]. PMID- 28627149 TI - [Are there no monitoring stations? We'll build them ourselves]. PMID- 28627150 TI - [Applying a set of indicators to evaluate the primary health care]. AB - OBJECTIVES: to develop a system of indicators to monitor the quality of health care, in terms of safety, effectiveness, and appropriateness to allow the integrated promotion of the welfare of the effectiveness and quality. DESIGN: retrospective study. SETTING AND PARTICIPANTS: all general practitioners (GPs) with at least 100 patients in loading at 1.1.2015 were included. The setting chosen is the Primary Care of the Agency for Health Protection of the Province of Milan (Northern Italy). MAIN OUTCOME MEASURES: for each GPs 39 indicators were calculated, including 7 on the mix of patients, 4 on prevention, 5 on ER, 5 on hospital admissions, 8 on outpatient, and 10 on pharmaceutical prescription. The correlations between individual indicators were considered and patterns to classify the GPs were determined by the factor analysis and the multiple correspondence analysis. RESULTS: among the expected correlations, we observed those between institutional colorectal screening and institutional breast cancer screening. Among not-expected correlations, the one between pump-inhibitor drugs and routines blood chemistry in the population between 20 and 50 years identifies a positive association between two practices of unrecognized clinical validity. Classifying the 2,217 GPs on the basis of the maximum factorial score, six main factors were identified. CONCLUSION: using approaches based on multivariate methods, interventions aimed at changing the profile of MMG exerting the government primary health care can be proposed, not only by means of system rules or approaches based on economic incentives, but on complex governance mechanisms. PMID- 28627151 TI - [Assessment of an algorithm to identify paediatric-onset celiac disease cases through administrative healthcare databases]. AB - OBJECTIVES: to assess the role of four administrative healthcare databases (pathology reports, copayment exemptions, hospital discharge records, gluten-free food prescriptions) for the identification of possible paediatric cases of celiac disease. DESIGN: population-based observational study with record linkage of administrative healthcare databases. SETTING AND PARTICIPANT S: children born alive in the Friuli Venezia Giulia Region (Northern Italy) to resident mothers in the years 1989-2012, identified using the regional Medical Birth Register. MAIN OUTCOME MEASURES: we defined possible celiac disease as having at least one of the following, from 2002 onward: 1. a pathology report of intestinal villous atrophy; 2. a copayment exemption for celiac disease; 3. a hospital discharge record with ICD-9-CM code of celiac disease; 4. a gluten-free food prescription. We evaluated the proportion of subjects identified by each archive and by combinations of archives, and examined the temporal relationship of the different sources in cases identified by more than one source. RESULT S: out of 962 possible cases of celiac disease, 660 (68.6%) had a pathology report, 714 (74.2%) a copayment exemption, 667 (69.3%) a hospital discharge record, and 636 (66.1%) a gluten-free food prescription. The four sources coexisted in 42.2% of subjects, whereas 30.2% were identified by two or three sources and 27.6% by a single source (16.9% by pathology reports, 4.2% by hospital discharge records, 3.9% by copayment exemptions, and 2.6% by gluten-free food prescriptions). Excluding pathology reports, 70.6% of cases were identified by at least two sources. A definition based on copayment exemptions and discharge records traced 80.5% of the 962 possible cases of celiac disease; whereas a definition based on copayment exemptions, discharge records, and gluten-free food prescriptions traced 83.1% of those cases. The temporal relationship of the different sources was compatible with the typical diagnostic pathway of subjects with celiac disease. CONCLUSIONS: the four sources were only partially consistent. A relevant proportion of all possible cases of paediatric celiac disease were identified exclusively by pathology reports. PMID- 28627152 TI - [Effectiveness of inspections in the construction sites on reducing innjuries: a pilot study in a Health Unit of Piedmont Region (Northern Italy)]. AB - OBJECTIVES: to describe a pilot study to evaluate the impact on injury rates of Occupational health and safety (OHS) inspections conducted in the construction sites of the Novara Health Unit territory during 2005-2007. DESIGN: study design is "treated/non treated" where: "treated" are construction companies inspected during 2005-2007 and not inspected in the periods before and after; "non treated" are construction companies never inspected during 2002-2010. SETTING AND PARTICIPANTS: two information sources have been used: Italian Workers' Compensation Authority databases and Novara Health Unit inspection database. The period of analysis is 2002-2010 divided into sub-periods: pre-inspection (2002 2004); inspection (2005-2007); post-inspection (2008-2010). MAIN OUTCOME MEASURES: two injury rates, total and serious, have been calculated and the difference-in-differences (DID) method was used to assess the effectiveness. RESULTS: passing from pre-inspection to post-inspection period, the rate of total injuries in the companies inspected decreased more than the rate of the companies not inspected (DID: -1,95; 95%CI -15,30; 11,39). No effect was shown on severe injuries (DID: -0,27; 95%CI -7,84;7,31). CONCLUSION: the inspections conducted during 2005-2007 on the construction sites operating in the Novara Health Unit territory seem to have had a slight positive impact on reducing the injury rates. The procedures developed in this pilot study can be used in other Italian Health Units. Further research is needed to confirm the results and to clarify the mechanism by which the inspections were effective. PMID- 28627153 TI - [Implementation of DNA-HPV primary screening in Italian cervical cancer screening programmes. Results of the MIDDIR Project]. AB - OBJECTIVES: to obtain data on conversion paths to HPV testing as part of screening programmes and to harmonize the introduction of HPV testing in primary cervical cancer screening protocols of Italian programmes. DESIGN: survey by questionnaire on strategies adopted by screening programmes for transition to primary HPV testing; systematic review of the literature; discussion among experts. SETTING AND PARTICIPANT S: managers of Italian Regions' cervical cancer screening programmes. MAIN OUTCOME MEASURES: transition planning; activity volumes; modalities of centralization; criteria for dismissal; staff training; communication initiatives. RESULTS: nine cervical screening programmes responded to the survey. Most of them chose to schedule a transition of a few years to allow for adjustment of the volume of activity in the passage from the three-year screening interval to the five-year one. To select women to be given precedence, 7 programmes use the age, starting from the oldest. The liquid base is the choice by far preferred both for HPV test and for Pap test. The reading of HPV test "born" already centralized, but a centralization process is in place also for cytology. CONCLUSIONS: the survey on conversion strategies to primary HPV testing showed the opportunity to schedule a transition phase. For HPV test, cost, organization, and quality benefits of centralization are clear, thus the central organization should be preferred and managed immediately. Moreover, the need for a centralization of cytology is evident. The tariff scheme should be based on the whole process rather than on single performances. Dismissal strategies have to be tailored on peculiarities of single services, but some typologies can be outlined. PMID- 28627154 TI - [Mortality study in a cohort of workers employed in the hot working processing of plastics and rubber]. AB - OBJECTIVES: to study mortality rates among workers in companies manufacturing thermoplastic and rubber articles (excluding tyres). DESIGN: cohort study. SETTING AND PARTICIPANTS: the cohort includes 4,543 workers employed up to 2000 in 131 companies in the Province of Bologna (Emilia-Romagna Region, Northern Italy) exposed to emissions from hot processing of plastics (3,937) and rubber (606). MAIN OUTCOME MEASURES: general- and cause-specific Standardized Mortality Rates (SMR), with 95% confidence intervals; entire reference population resides in the Emilia-Romagna Region. RESULTS: excess mortality for all causes (116 Obs; SMR: 1.20; 95%CI 1.00-1.44) and for lung cancer (18 Obs; SMR: 1.67; 95%CI 1.05 2.65) in men of the rubber factories. Increased mortality rates for oesophageal cancers in women (3 Obs; SMR: 5.41; 95%CI 1.74-16.8) and in men (6 Obs; SMR: 2.16; 95%CI 0.97-4.81), for malignant tumours of pancreas (16 Obs; SMR: 1.65; 95%CI 1.01- 2.70), rectum (11 Obs; SMR: 2.17; 95%CI 1.20-3.92) and kidney (11 Obs; SMR: 1.98; 95%CI 1.10-3.58) in men occupied in plastic processing. CONCLUSION: in this study, we observed an excess of mortality rates for lung cancer in men of rubber factories and for malignant tumours of the digestive tract, pancreas, and kidney in workers employed in the production of plastic articles. Nevertheless, these results must be interpreted with caution, because exposures to non-occupational risk factors, like tobacco smoke or other occupational exposures outside the companies concerned, are not known. The results suggest to continue epidemiological surveillance. PMID- 28627155 TI - [Environmental justice in the epidemiological surveillance system of residents in Italian National Priority Contaminated Sites (SENTIERI Project)]. AB - OBJECTIVES: descriptive evaluation of distributional justice in the epidemiological surveillance system of populations residing in Italian National priority Contaminated Sites (NPCSs) of SENTIERI project. Analysis of the feasibility of monitoring different Environmental Justice dimensions in SENTIERI. DESIGN: descriptive study and ecological meta-analysis. SETTING AN PARTICIPANTS: residents in 298 municipalities included in 44 NPCSs in SENTIERI. Description of their level of deprivation and mortality analysis by deprivation level in the first period evaluated in SENTIERI, years 1995-2002. MAIN OUTCOME MEASURES: an index of multiple deprivation at municipality level DI-SENTIERI, built using 4 indicators based on variables from the Italian 2001 Census, was used to describe deprivation in communities living in NPCSs. The risk of mortality for all causes and all tumors in the pool of NPCSs municipalities by deprivation level was assessed using meta-Standardized Mortality Ratios (meta-SMRs). RESULTS: sixty percent of municipalities (No. 179) in NPCSs belong to the two more deprived quintiles. The socioeconomic disadvantage of communities resident in NPCS has a North-South gradient: the proportion of municipalities belonging to the two more deprived quintiles is 29% in the North, 68% in the Centre, 92% in the South. Meta SMRs for all causes in less deprived municipalities were 98 (90%CI 95-100) in men e 101 (90%CI 97-104) in women, the values for all cancers were 99 (90%CI 94-103) in men and 100 (90%CI 95-105) in women. The corresponding estimates in more deprived municipalities were, respectively in men and women, 103 (90%CI 101- 104) and 102 (90%CI 100-104) for all causes, 104 (90%CI 102-106) and 102 (90%CI 100 104) for all cancers. CONCLUSIONS: residents in NPCSs are exposed to environmental stressors and are generally more deprived. The socioeconomic disadvantage is mostly affecting Central and Southern Italy populations. Furthermore, in these deprived communities the risk of mortality for all diseases and all cancers is higher. Populations living in NPCSs are affected by distributional injustice. To monitor the different dimensions of Environmental Justice, the DI-SENTIERI should be developed and other socioeconomic indicators implemented. PMID- 28627156 TI - [TNM Classification of malignant tumours - Eighth edition: which news?] AB - The eighth edition of TNM classification of malignant tumours has been published by the Union for International Cancer Control in January 2017. As for the previous editions - from the third on - it has been translated into Italian and recently published in our Country. This article explains the main changes from the previous edition: new classifications, some major revisions of cancer staging rules, the introduction of a grid of prognostic factors for each neoplasia and the addition of two chapters. These two chapters are about the essential TNM and the paediatric tumours, and have been developed in order to facilitate the use of data by Cancer Registries. PMID- 28627157 TI - [Indicators to measure benefits of COP21 on health will be forthcoming]. PMID- 28627158 TI - Evaluation of Serum Interleukin-21 and HLA-C1 Polymorphism in Pediatrician Hematopoietic Stem Cell Transplantation for Early Diagnosis of Acute Graft-Versus Host Disease AB - Background: Allogenic hematopoietic stem cell transplantation (HSCT) is a strategy used for treatment of different malignant diseases. However, success of allo-HSCT can be hampered by graft-versus-host-disease (GVHD). Natural killer (NK) cells may play an important role in activating antigen presenting cells and subsequent activation of T cells. The main purpose of this study was the evaluation of IL-21, as a blood biomarker, for early detection of acute GVHD (aGVHD) in children after HSCT and also the study of human leukocytes antigen (HLA)-C1 polymorphism, as a targeting ligand for NK cells in these patients. Methods: Fifty one children receiving HSCT were studied. Blood samples were collected at -8, 7, and 14 days of transplantation. The -8-day samples were analyzed for HLA-C1 polymorphism by PCR-sequence-specific primer technique and pre-transplantation IL-21 assay. To study the serum levels of IL-21, two blood samples were collected on days +7 and +14 and analyzed by ELISA technique. Results: The results indicated that the incidence of aGVHD in pediatric is associated with a polymorphism of HLA-C1, as alleles HLA-C01:12 (P<0.001), HLA C01:22 (P<0.004), and HLA-C01:67 (P<0.009). On the other hand, the serum levels of IL-21 in children with aGVHD were decreased after transplantation compared to before transplantation. The serum levels of the IL-21 at 14 days after transplantation had a significant correlation with the occurrence of aGVHD (P=0.05). Conclusion: Based on the findings of this study, there is a significant correlation between HLA-C1 polymorphisms and the serum levels of IL-21 with the incidence of aGVHD. PMID- 28627159 TI - ? PMID- 28627160 TI - [Early detection of autism spectrum disorders: emerging symptoms and biomarkers]. AB - Early recognition of Autism Spectrum Disorders (ASD) in patients before the age of 24 months significantly enhances the prognosis of affected children. That's why researchers try to identify behavioral and/or neurophysiological precursors in the first months of life of children. Prospective studies are specifically performed in infant siblings at risk of ASD. The longitudinal high-risk sibling studies of ASD follow a cohort of children with an older sibling already diagnosed with ASD. Of these, 10-20% will be diagnosed with ASD during their third year. This review aims to summarize the clinical and neurophysiological studies investigating early markers associated with the emergence of autistic symptoms in children. PMID- 28627161 TI - Synthesis and Properties of Covalently Linked AzaBODIPY-BODIPY Dyads and AzaBODIPY-(BODIPY)2 Triads. AB - The azaBODIPYs containing one and two formyl functional groups on the 1,7-aryl groups present at the azaBODIPY core were synthesized over sequence of steps and characterized by mass, NMR, absorption, and electrochemical techniques. The monoformylated and diformylated azaBODIPYs are very useful synthons to prepare a wide variety of new fluorescent compounds. The mono- and diformylated azaBODIPYs were treated with pyrrole under mild acidic conditions followed by column chromatographic purification to afford azaBODIPYs appended with one and two dipyrromethanyl groups. The dipyrramethanyl groups of azaBODIPYs were oxidized with DDQ and complexed with BF3.Et2O to obtain covalently linked azaBODIPY-BODIPY dyads and azaBODIPY-(BODIPY)2 triads. The dyads and triads were characterized in detail by HR-MS, 1D and 2D NMR, absorption, fluorescence, and electrochemical techniques and the structure of one of the triads was deduced by X-ray crystallography. The crystal structure of azaBODIPY-(BODIPY)2 triad revealed that the two BODIPY units were in perpendicular orientation with azaBODIPY unit. The absorption and electrochemical studies indicated a weak interaction among the BODIPY and azaBODIPY moieties and the moieties retain their independent characteristic features in dyads and triads. The preliminary fluorescence studies supported an efficient energy transfer from BODIPY unit(s) to azaBODIPY unit in dyads and triads. PMID- 28627162 TI - Fabrication and Characterization of Surfaces Modified with Carboxymethylthio Ligands for Chelate-Assisted Trapping of Copper. AB - The metal ion chelating property was conferred onto silicon (Si) and gold (Au) surfaces by direct electrografting of the 4-[(carboxymethyl)thio]benzenediazonium cation (4-CMTBD). Infrared spectroscopic ellipsometry showed the presence of characteristic phenyl and carbonyl vibrational bands on the functionalized surfaces as a proof of existence of surface-bound organic units of 4 [(carboxymethyl)thio]benzene, (4-CMTB). The loss of diazonium group (N=N+) upon electrografting of 4-CMTBD was investigated using IR spectroscopy. A Faradaic efficiency of about 18.8-20.0% was realized in mass deposition experiments for grafting 4-CMTB on the Au surface using an electrochemical quartz crystal microbalance technique. Raman spectroscopy performed on the Si-(4-CMTB) surface after treatment with copper (Cu) ion solution provided evidence of metal ion chelation based on an observed v(Cu-O) peak at about 487 cm-1 and a v(Cu-S) signal at about 267 cm-1. The binding of Cu ions by the chelating ligands also caused a red shift of about 10 cm-1 in the Raman spectrum of the Si-(4-CMTB)-Cu surface within the spectral region, characteristic of the v(C-O) signal. X-ray photoelectron spectroscopy investigations showed indications of the Cu(II) ion species chelated by the surface-bound carboxymethylthio ligands. The functionalized surface, Si-(4-CMTB), constitutes an alternative metal ion chelating surface that may potentially be developed for applications in trace level trapping of Cu ions. PMID- 28627163 TI - Molecular Structures and Functions of Chlorophylls-a Esterified with Geranylgeranyl, Dihydrogeranylgeranyl, and Tetrahydrogeranylgeranyl Groups at the 17-Propionate Residue in a Diatom, Chaetoceros calcitrans. AB - The 17-propionate ester group of chlorophyll(Chl)-a in some oxygenic phototrophs was investigated using HPLC. Chls-a esterified with partially dehydrogenated forms of a phytyl group were found in fully grown cells of a diatom, Chaetoceros calcitrans: geranylgeranyl (GG), dihydrogeranylgeranyl (DHGG), and tetrahydrogeranylgeranyl (THGG). Chls-a bearing such esterifying groups were reported to be found only in greening processes of higher plants, and thus these Chls-a have been thought to be biosynthetic precursors for phytylated Chl-a. Their molecular structures were unambiguously determined using 1H and 13C NMR spectroscopy and mass spectrometry. In particular, the positions of C?C double bonds in DHGG were identified at C2?C3, C6?C7, and C14?C15, and those in THGG were determined to be at C2?C3 and C14?C15. Notably, the present DHGG was different from the previously determined DHGG of bacteriochlorophyll-a in purple bacteria (C2?C3, C10?C11, and C14?C15). Moreover, thylakoid membranes as well as fucoxanthin-chlorophyll-a/c proteins called FCPs were isolated from the diatom, and their Chl-a compositions were analyzed. Chls-a esterified with GG, DHGG, and THGG were detected by HPLC, indicating that such Chls-a were not merely biosynthetic precursors, but photosynthetically active pigments. PMID- 28627165 TI - Room-Temperature Processed Nb2O5 as the Electron-Transporting Layer for Efficient Planar Perovskite Solar Cells. AB - In this work, we demonstrate high-efficiency planar perovskite solar cells (PSCs), using room-temperature sputtered niobium oxide (Nb2O5) as the electron transporting layer (ETL). Widely spread ETL-like TiO2 often requires high temperature (>450 degrees C) sintering, which is not desired for the fabrication of flexible devices. The amorphous Nb2O5 (labeled as a-Nb2O5) ETL, without any heat treatment, can give a best power conversion efficiency (PCE) of 17.1% for planar PSCs. Interestingly, the crystalline Nb2O5 (labeled as c-Nb2O5), with high temperature (500 degrees C) annealing, results in a very similar PCE of 17.2%, indicating the great advantage of a-Nb2O5 in energy saving. We thus carried out a systematical investigation on the properties of the a-Nb2O5 film. The Hall effect measurements indicate both high mobility and conductivity of the a-Nb2O5 film. Kelvin probe force microscopy measurements define the Fermi levels of a-Nb2O5 and c-Nb2O5 as -4.31 and -4.02 eV, respectively, which allow efficient electron extraction at the Nb2O5/perovskite interface, regardless of the additional heat treatment on Nb2O5 film. Benefitting from the low-temperature process, we further demonstrated flexible PSCs based on a-Nb2O5, with a considerable PCE of 12.1%. The room-temperature processing and relatively high device performance of a-Nb2O5 suggest a great potential for its application in optoelectrical devices. PMID- 28627164 TI - Thermodynamic and Structural Adaptation Differences between the Mesophilic and Psychrophilic Lactate Dehydrogenases. AB - The thermodynamics of substrate binding and enzymatic activity of a glycolytic enzyme, lactate dehydrogenase (LDH), from both porcine heart, phLDH (Sus scrofa; a mesophile), and mackerel icefish, cgLDH (Chamapsocephalus gunnari; a psychrophile), were investigated. Using a novel and quite sensitive fluorescence assay that can distinguish protein conformational changes close to and distal from the substrate binding pocket, a reversible global protein structural transition preceding the high-temperature transition (denaturation) was surprisingly found to coincide with a marked change in enzymatic activity for both LDHs. A similar reversible structural transition of the active site structure was observed for phLDH but not for cgLDH. An observed lower substrate binding affinity for cgLDH compared to that for phLDH was accompanied by a larger contribution of entropy to DeltaG, which reflects a higher functional plasticity of the psychrophilic cgLDH compared to that of the mesophilic phLDH. The natural osmolyte, trimethylamine N-oxide (TMAO), increases stability and shifts all structural transitions to higher temperatures for both orthologs while simultaneously reducing catalytic activity. The presence of TMAO causes cgLDH to adopt catalytic parameters like those of phLDH in the absence of the osmolyte. Our results are most naturally understood within a model of enzyme dynamics whereby different conformations of the enzyme that have varied catalytic parameters (i.e., binding and catalytic proclivity) and whose population profiles are temperature-dependent and influenced by osmolytes interconvert among themselves. Our results also show that adaptation can be achieved by means other than gene mutations and complements the synchronic evolution of the cellular milieu. PMID- 28627166 TI - Self-Assembled Conjugated Polymer/Chitosan-graft-Oleic Acid Micelles for Fast Visible Detection of Aliphatic Biogenic Amines by "Turn-On" FRET. AB - A fluorescent "turn-on" sensor for fast measurement of aliphatic biogenic amines (BAs) was developed based on fluorescent carboxylated polyfluorene (PFTBTCOOH)/chitosan-graft-oleic acid (CS-graft-OA) micelles. In this system, biobased CS-graft-OA micelles, prepared by graft modification of CS with OA, serve as the vector of the hydrophobic fluorescent probe. Bright turn-on fluorescence was achieved by the intermolecular fluorescence resonance energy transfer of the encapsulated PFTBTCOOH, driven by the formation of an electrostatic complex with aliphatic BAs, which facilitate visual identification. The peak intensity ratio of the PFTBTCOOH/CS-graft-OA micelles toward an increasing amount of aliphatic BAs was calibrated, giving a linear relationship. The fluorescence response of PFTBTCOOH/CS-graft-OA micelles to aliphatic BAs in milk and yogurt matrixes reaches a detection concentration as low as 10 MUM, showing that the PFTBTCOOH/CS-graft-OA micelle solution is a potential chemosensor for fast and selective detection of trace aliphatic BAs, which is of great significance to public health and food safety. PMID- 28627167 TI - Plasma Pharmacokinetics, Bioavailability, and Tissue Distribution of Four C Glycosyl Flavones from Mung Bean (Vigna radiata L.) Seed Extracts in Rat by Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry. AB - The main polyphenols in mung bean (Vigna radiata L.) seed (MBS), an edible legume with various biological activities, are C-glycosyl flavones (vitexin, isovitexin, isovitexin-6"-O-alpha-l-glucoside, and dulcinoside). In our study, a validated ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) method was developed to quantitate the concentrations of four C-glycosyl flavones from MBS extracts in the plasma and various tissues of rats and successfully applied to study their pharmacological profile and tissue distribution in vivo. Four C-glycosyl flavones were rapidly absorbed after oral administration, achieving a Cmax at around 1.5 h, and they could be distributed widely and rapidly in tested tissues. The concentrations of four C-glycosyl flavones in all of the tested tissues decreased obviously in 4 h, which indicated that there was not a trend of long-term accumulation of them. This is the first time to report on pharmacokinetic and tissue distribution studies of four C glycosyl flavones in rat. The results provided a significative basis for the application of MBS. PMID- 28627169 TI - Influence of the Fruit Juice Carriers on the Ability of Lactobacillus plantarum DSM20205 to Improve in Vitro Intestinal Barrier Integrity and Its Probiotic Properties. AB - This study investigates the influence of tomato and feijoa juices as fermentable carriers of Lactobacillus plantarum (LP DSM20205) on the ability of the bacterium to improve intestinal barrier function using the trans-epithelial electrical resistance (TEER) assay in an apical anaerobic model. The survival of LP DSM20205 in different fruit juices during in vitro digestion, its adhesion capacity, and potential cytotoxic effect on Caco-2 cells were also studied. The results showed that carrier fruit juices have a significant influence on LP DSM20205 growth, survival during in vitro digestion, adhesion capacity, and TEER. All fermented samples were not cytotoxic to Caco-2 cells. The fermented tomato juice showed the largest improvement to intestinal barrier integrity. The digested fermented juices did not increase TEER, although the LP DSM20205 in these samples adhered well. Therefore, LP DSM20205 has the potential to be used as a probiotic in the production of fermented tomato and feijoa juices. PMID- 28627168 TI - Mitochondria-Associated Apoptosis in Human Melanoma Cells Induced by Cardanol Monoene from Cashew Nut Shell Liquid. AB - Cardanol monoene (CM) is the major phenolic component extracted from cashew nut shell liquid (CNSL), which has been relevant to wide range of biological effects. In this study, we found that CM could inhibit the M14 human melanoma cells proliferation in a dose dependent and time dependent manner, and the IC50 values were determined to be 23.15 +/- 2.42 MUM and 12.30 +/- 1.67 MUM after 24 and 48 h treatment, respectively. The flow cytometric analysis demonstrated that CM induced M14 cell cycle arrest at the S phase, along with the collapse of mitochondrial membrane potential (DeltaPsim) and the accumulation of reactive oxygen species (ROS) level in cells, but the apoptotic cells reduced when treated with Z-VAD-FMK (pan-caspase inhibitor). Western blotting showed that the expressions of p53, cytosol cytochrome C, cleaved-caspase-3, and cleaved-PARP were up-regulated, and the expression level of Bax/Bcl-2 ratio increased significantly. The 2527 significant differentially expressed genes were obtained by RNA-seq, which were assigned to 270 KEGG pathways. These results indicated that CM induced M14 cells apoptosis via the ROS triggered mitochondrial associated pathways, which supports the potential application of CM for the therapy of melanoma cancer. PMID- 28627170 TI - Role of the Nozaki-Hiyama-Takai-Kishi Reaction in the Synthesis of Natural Products. AB - The Nozaki-Hiyama-Takai-Kishi (NHTK) reaction was discovered in the late 1970s and, since then, its main application has been its use in total synthesis. In this comprehensive review, the efficiency of the NHKT reaction in the synthesis of a great number of different scaffolds present in complex natural products is analyzed. The preparation of enol and allylic and propargylic alcohol motifs is discussed, highlighting factors such as yield, chemoselectivity, stereoselectivity, or the importance of protecting groups. The review is divided into two main sections: intermolecular and intramolecular NHTK reactions. A final discussion about the current "state-of-art" and future perspectives for the use of this transformation in total synthesis is also included. PMID- 28627171 TI - Commercial Applications for Enzyme-Mediated Protein Conjugation: New Developments in Enzymatic Processes to Deliver Functionalized Proteins on the Commercial Scale. AB - The field of protein conjugation most commonly refers to the chemical, enzymatic, or chemoenzymatic formation of new covalent bonds between two polypeptides, or between a single polypeptide and a new molecule (polymer, small molecule, nucleic acid, carbohydrate, etc.). Due to the modest selectivity of chemical methods for protein conjugation, there are increased efforts to develop biocatalysts that confer regioselectivity for site-specific modification, thereby complementing the existing toolbox of chemical conjugation strategies. This review summarizes key advances in the use of enzymes to functionalize proteins with commercial relevance. The examples put forth have demonstrated value at the industrial level or show promising industrial potential in the laboratory. PMID- 28627173 TI - Ternary Gold Hydrides: Routes to Stable and Potentially Superconducting Compounds. AB - In a search for gold hydrides, an initial discouraging result of no theoretical stability in any binary AuHn at P < 300 GPa was overcome by introducing alkali atoms as reductants. A set of AAuH2 compounds, A = Li, Na, K, Rb, and Cs, is examined; of these, certain K, Rb, and Cs compounds are predicted to be thermodynamically stable. All contain AuH2- molecular units and are semiconducting at P = 1 atm, and some form metallic and superconducting symmetrically bonded AuHAu sheets under compression. To induce metallicity by bringing the Au atoms closer together under ambient conditions, we examined alkaline earth ion substitution for two A, i.e., materials of composition AE(AuH2)2. For AE = Ba and Sr, the materials are already marginally metallic at P = 1 atm and the combination of high and low phonon frequencies and good electron phonon coupling leads to reasonably high calculated superconducting transition temperatures for these materials. PMID- 28627172 TI - Regiodivergent Glycosylations of 6-Deoxy-erythronolide B and Oleandomycin-Derived Macrolactones Enabled by Chiral Acid Catalysis. AB - This work describes the first example of using chiral catalysts to control site selectivity for the glycosylations of complex polyols such as 6 deoxyerythronolide B and oleandomycin-derived macrolactones. The regiodivergent introduction of sugars at the C3, C5, and C11 positions of macrolactones was achieved by selecting appropriate chiral acids as catalysts or through introduction of stoichiometric boronic acid-based additives. BINOL-based chiral phosphoric acids (CPAs) were used to catalyze highly selective glycosylations at the C5 positions of macrolactones (up to 99:1 rr), whereas the use of SPINOL based CPAs resulted in selectivity switch and glycosylation of the C3 alcohol (up to 91:9 rr). Additionally, the C11 position of macrolactones was selectively functionalized through traceless protection of the C3/C5 diol with boronic acids prior to glycosylation. Investigation of the reaction mechanism for the CPA controlled glycosylations revealed the involvement of covalently linked anomeric phosphates rather than oxocarbenium ion pairs as the reactive intermediates. PMID- 28627174 TI - Integrative Analysis of Renal Ischemia/Reperfusion Injury and Remote Ischemic Preconditioning in Mice. AB - Remote ischemic preconditioning (RIPC) is a strategy to induce resistance in a target organ against the oxidative stress and injury caused by ischemia and reperfusion (IR). RIPC harnesses the body's endogenous protective capabilities through brief episodes of IR applied in organs remote from the target. Few studies have analyzed this phenomenon in the kidney. Furthermore, the window of protection representing RIPC efficacy has not been fully elucidated. Here, we performed a multiomics study to specify those associated with protective effects of RIPC against the IR injury. A total of 30 mice were divided to four groups: sham, IR only, late RIPC + IR, and early RIPC + IR. We found that IR clearly led to tubular injury, whereas both preconditioning groups exhibited attenuated injury after the insult. In addition, renal IR injury produced changes of the metabolome in kidney, serum, and urine specimens. Furthermore, distinctive mRNA and associated protein expression changes supported potential mechanisms. Our findings revealed that RIPC effectively reduces renal damage after IR and that the potential mechanisms differed between the two time windows of protection. These results may potentially be extended to humans to allow non- or minimally invasive diagnosis of renal IR injury and RIPC efficacy. PMID- 28627175 TI - Pull-and-Paste of Single Transmembrane Proteins. AB - How complex cytoplasmic membrane proteins insert and fold into cellular membranes is not fully understood. One problem is the lack of suitable approaches that allow investigating the process by which polypeptides insert and fold into membranes. Here, we introduce a method to mechanically unfold and extract a single polytopic alpha-helical membrane protein, the lactose permease (LacY), from a phospholipid membrane, transport the fully unfolded polypeptide to another membrane and insert and refold the polypeptide into the native structure. Insertion and refolding of LacY is facilitated by the transmembrane chaperone/insertase YidC in the absence of the SecYEG translocon. Insertion into the membrane occurs in a stepwise, stochastic manner employing multiple coexisting pathways to complete the folding process. We anticipate that our approach will provide new means of studying the insertion and folding of membrane proteins and to mechanically reconstitute membrane proteins at high spatial precision and stoichiometric control, thus allowing the functional programming of synthetic and biological membranes. PMID- 28627176 TI - Correction to "Proteomic Characterization of the Cellular Response to Nitrosative Stress Mediated by S-Nitrosoglutathione Reductase Inhibition". PMID- 28627177 TI - Rhodium(III)-Catalyzed Selective C-H Acetoxylation and Hydroxylation Reactions. AB - An efficient Cp*Rh(III)-catalyzed, chelation-assisted C(sp2)-H acetoxylation and hydroxylation reaction has been developed for the first time. The reaction proceeds under mild conditions and allows for selective preparation of C-H acetoxylation and hydroxylation products, thus providing a good complement to previous C-H oxygenation reactions and expanding the field of Cp*Rh(III) catalyzed C-H functionalizations. PMID- 28627178 TI - Turning the Page: Advancing Paper-Based Microfluidics for Broad Diagnostic Application. AB - Infectious diseases are a major global health issue. Diagnosis is a critical first step in effectively managing their spread. Paper-based microfluidic diagnostics first emerged in 2007 as a low-cost alternative to conventional laboratory testing, with the goal of improving accessibility to medical diagnostics in developing countries. In this review, we examine the advances in paper-based microfluidic diagnostics for medical diagnosis in the context of global health from 2007 to 2016. The theory of fluid transport in paper is first presented. The next section examines the strategies that have been employed to control fluid and analyte transport in paper-based assays. Tasks such as mixing, timing, and sequential fluid delivery have been achieved in paper and have enabled analytical capabilities comparable to those of conventional laboratory methods. The following section examines paper-based sample processing and analysis. The most impactful advancement here has been the translation of nucleic acid analysis to a paper-based format. Smartphone-based analysis is another exciting development with potential for wide dissemination. The last core section of the review highlights emerging health applications, such as male fertility testing and wearable diagnostics. We conclude the review with the future outlook, remaining challenges, and emerging opportunities. PMID- 28627179 TI - Water-Lean Solvents for Post-Combustion CO2 Capture: Fundamentals, Uncertainties, Opportunities, and Outlook. AB - This review is designed to foster the discussion regarding the viability of postcombustion CO2 capture by water-lean solvents, by separating fact from fiction for both skeptics and advocates. We highlight the unique physical and thermodynamic properties of notable water-lean solvents, with a discussion of how such properties could translate to efficiency gains compared to aqueous amines. The scope of this review ranges from the purely fundamental molecular-level processes that govern solvent behavior to bench-scale testing, through process engineering and projections of process performance and cost. Key discussions of higher than expected CO2 mass transfer, water tolerance, and compatibility with current infrastructure are presented along with current limitations and suggested areas where further solvent development is needed. We conclude with an outlook of the status of the field and assess the viability of water-lean solvents for postcombustion CO2 capture. PMID- 28627180 TI - Nano Ce2O2S with Highly Enriched Oxygen-Deficient Ce3+ Sites Supported by N and S Dual-Doped Carbon as an Active Oxygen-Supply Catalyst for the Oxygen Reduction Reaction. AB - The design of rare-earth-metal oxide/oxysulfide catalysts with high activity and durability for the oxygen reduction reaction (ORR) is still a grand challenge at present. In this study, Ce-species (Ce2O2S/CeO2)/N, S dual-doped carbon (Ce species/NSC) catalysts with promising oxygen storage/release capacities are prepared at different temperatures (800-1000 degrees C) to enhance the ORR efficiency. Mechanisms for the effects of temperature on crystalline phase transition between CeO2 and Ce2O2S and structure evolution of Ce-species/NSCs are inferred to better understand their catalytic activity. Porous Ce2O2S/NSC (950 degrees C) catalyst as the air-breathing cathode exhibits a maximum power density of 1087.2 mW m-2, which is higher than those of other Ce-species/NSCs and commercial Pt/C (989.13 mW m-2) in microbial fuel cells. The decline of the power density of Ce2O2S/NSC (950 degrees C) cathode is 8.7% after 80 days of operation, which is far lower than that of Pt/C (36.7%). Ce2O2S/NSC (950 degrees C) has a four-electron selectivity toward the ORR and a low charge-transfer resistance (5.49 Omega), contributing to high ORR activity and durability. The promising ORR catalytic activity of Ce2O2S/NSC (950 degrees C) is attributed to its high specific surface area (338.9 m2 g-1), varied active sites, high electrical conductivity, and sufficient oxygen vacancies in the Ce2O2S skeleton. The high content of Ce3+ in Ce2O2S/NSC (950 degrees C) facilitates the formation of more oxygen-deficient Ce3+ sites that generate more oxygen vacancies to release/store more oxygen to stabilize the available oxygen for the ORR. Thus, this study provides a new perspective for preparation and application of this new type of the ORR catalyst. PMID- 28627181 TI - Running for your sperm; benefits of physical exercise on seminal quality PMID- 28627182 TI - Predictive factors of hypertriglyceridemia in inhospital patients during total parenteral nutrition AB - Introduction: Total parenteral nutrition (TPN) is a kind of nutritional support indicated for patients whose clinical situation makes it impossible to cover their nutritional requirements enterally. Despite the fact that TPN is a safe and effective therapy, some complications have been described. One of the most frequent is hypertriglyceridemia. The etiology of this metabolic complication is complex and multifactorial.Objetive: The aim of this work was to determine risk factors associated with the development of hypertrilgyceridemia in adult inhospital non critical patients who carry TPN for a short term. A secondary aim was to evaluate the effect that a lipid emulsion fortified with omega-3 poliunsaturated fatty acids causes on this metabolic complication.Material and methods: This is an observational retrospective cohort study, in which adult inhospital non critical patients have been included. Only those who needed TPN during more than seven days were included. Hypertriglyceridemia was defined as plasma triglycerides levels higher than 200 mg/dl. The lipid emulsions were composed whether by a combination of 50% long-chain (LCT) and medium-chain (MCT) triglycerides or 40% LCT/50% MCT/10% omega-3. Clinical, nutritonal and biochemical parameters were included. Analitical samples were obtained before starting TPN, and weekly until withdrawal. Multivariate logistic regression analysis was used to identify predictive factors of the appearance of hypertriglyceridemia.Results: One hundred and one patients were included (61.4% male). Thirty-three per cent of them developed hypertriglyceridemia. In the multivariate analysis the independent risk factors associated with the presence of hypertriglyceridemia were the initial plasmatic triglycerides levels, the body mass index (BMI) and an input of glucose in the TPN higher than 3.1 g/kg/day. The infusion of a lipid emulsion fortified with 3-omega fatty acids was associated with a nonsignificant reduction of the risk of appearance of hypertriglyceridemia.Conclusion: The patient's clinical metabolic situation, as well as the load of carbohydrates in the TPN are essential for the development of the TPN-associated hypertriglyceridemia. The administration of a lipid emulsion fortified with omega-3 fatty acids is safe, even though it was not associated with a signifi cant protective effect over the risk of appearance of this metabolic complication. PMID- 28627183 TI - Gastrostomy vs nasogastric tube feeding in patients with head and neck cancer during radiotherapy alone or combined chemoradiotherapy AB - INTRODUCTION: Patients with head and neck cancer (HNC) submitted to radiotherapy alone or combined chemoradiotherapy present a high prevalence of malnutrition at baseline. Prophylactic use of gastrostomy has been suggested for these patients for delivering enteral nutrition. On the other hand, other authors have failed to demonstrate the effectiveness of this measure over nasogastric tube feeding. MATERIAL AND METHODS: We studied 40 patients with HNC with moderate or severe malnutrition who were offered either prophylactic percutaneous gastrostomy before starting oncologic treatment or close follow-up with nutritional counseling with the placement of a nasogastric tube when necessary. RESULTS: There were no significant changes throughout the study period in weight (p = 0.338), body mass index (BMI) (p = 0.314) or serum proteins (p = 0.729), and these changes showed no differences between the gastrostomy vsnasogastric tube feeding groups. The amount of delivered energy was above the estimated energy needs with both gastrostomy and nasogastric tube feeding, but there were no differences in the total energy provided by enteral nutrition between groups. Patients in the gastrostomy group received enteral nutrition support for a longer period of time (p = 0.007). CONCLUSIONS: Both gastrostomy and nasogastric tube feeding are effective methods of delivering enteral nutrition in patients with HNC submitted to radiotherapy alone or combined chemoradiotherapy, with no differences between them in terms of avoiding further nutritional deterioration. PMID- 28627184 TI - Establishment of a clinical pathway for home enteral nutrition prescription in Murcia. Profile and sample characteristics AB - Introduction: Before 2010, prescribed home enteral nutrition (HEN) in Murcia was characterized by the great variability of the receptor patients, in addition to a higher use compared with other geographical areas. Objectives: Developing and describing a clinical pathway for attending candidates for HEN, and analyzing their profi le and prescription characteristics. Methods: Establishment of a clinical pathway for HEN prescription. Bidirectional observational study of the samples of HEN in a specific area (Health Area I of the Region of Murcia) during 2010 (HEN1) and 2013-14 (HEN2).Results: An official management statement was established, generalizing the clinical pathway for the rest of the regional areas (Instruction no. 4/2012 of July 12th). Although most prevalent diseases in both samples were neurological, followed, with a wide spread, by oncological and digestive cases, there was a signifi cant difference regarding distribution. The HEN1 sample showed a great number of no candidate patients according to the management statement. In both samples, the most prevalent route of administration was oral, but with a trend reversal to feeding tube and gastrostomy in HEN2, where the specifi c formulas were also reduced. Conclusions: The profile of HEN, before and after the deployment of the clinical pathway, changes signifi cantly concerning the main disease, the route of administration and the formula. It has been proved that there is a need for controlling HEN for an appropriate prescription. PMID- 28627185 TI - Adherence and tolerance as key in brake on weight loss in cancer patients with nutritional risk after intervention with a high calorie nutritional and specific hyperproteic supplement AB - Background: In patients with nutritional risk, the European Society for Clinical Nutrition and Metabolism (ESPEN) recommends nutritional supplements during cancer treatment to prevent weight loss.Objectives: Our goal is to determine the acceptability, compliance and tolerance of a hyperproteic, high-calorie, omega-3 enriched supplement in cancer patients.Methods: Unicentric, prospective observational study in cancer patients with hyperproteic, high-calorie, rich in omega 3 and low volume nutritional supplement. Thirty patients with malnutrition or risk of malnutrition were included. Supplementation lasted six days. Compliance (packaging used), acceptability (Madrid scale), anthropometric variables and gastrointestinal adverse events (AEs) were evaluated.Results: Seventy per cent were men, with an average age of 60 years (range 32-79), with lung (43.3%), ENT (26.7%) and breast neoplasms (13.3%), stage III-IV (56.7%), and treated with radiotherapy (93.3%), chemotherapy (60%) and surgery (16.7%). The product was accepted by all patients. A compliance rate of 100% was observed. Gastrointestinal AE (grade II) related to the supplement was observed in two patients (6.7%). Both subjects had previous gastrointestinal diseases. The median weight, body mass index (BMI) and protein intake increased during supplementation (0.2 kg, 0.1 kg/m2 and 6.2 g). No differences were observed regarding calorie, fat and carbohydrates intake.Conclusion: The high acceptance and compliance with the specific nutritional supplement was associated with an improved nutritional status for cancer patients, and reversed the weight loss without severe gastrointestinal problems, or producing intake displacement. PMID- 28627186 TI - Glycemic index, glycemic load and insulin response of two formulas of isoglucose with different sweeteners and dietary fiber in healthy adults and type-2 diabetes AB - Objective: The aim of this study is to compare the glycemic index (GI) and glycemic load (GL) of two formulas with the same glucose content with different sweeteners and dietary fiber for diabetics in healthy adults and in patients with type-2 diabetes (DM2).Methodology: In this randomized, double-blind crossover research, eleven healthy people and six with DM2 consumed two enteral formulas, Glucerna SR(r), Laboratorios Abbott C.A. (GF) and Enterex Diabetic(r), Victus C.A. (EF), sweetened with fructose y sucralose, with 1.2 and 1.3 g/100 ml of fiber source respectively (four times). Additionally, they consumed glucose solution once, obtaining blood samples at 0, 15, 30, 45, 60, 90 and 120 min for controls; in the diabetics, minutes 150 and 180 were added for measuring blood glucose, basal and postprandial insulin after two and three hours.Results: The incremental area under the curve (IAUC) was lower for the formulas rather than for SG. In the healthy controls was 12,857 +/- 422 for EF and 11,601 +/- 272 for GF (p < 0.014). In diabetics, this curve reduced for GF (28,656 +/- 123) compared to EF (29,855 +/- 496) (p < 0.01). The IG resulted in 58.07 +/- 8.4 and 60.7 +/- 2 for GF and EF, respectively, in the controls, and 65.16 +/- 0.2 and 68.06 +/- 1 in diabetics, without significant differences, as well as in post-prandial insulin. Conclusions: The GI and the GL of the two formulas resulted in an intermediate value in both groups, with a glycemic profile inferior to SG. No significant differences were observed regarding insulin behavior, showing that the absorption rate of carbohydrates in these formulas is slower, with a lower glycemic impact than the pattern product; thus, making its indication acceptable for the diabetic patient. PMID- 28627187 TI - [Is plasma selenium correlated to transthyretin levels in critically ill patients?] AB - BACKGROUND: Selenium is an essential trace element, but critically ill patients using total parenteral nutrition (PN) do not receive selenium because this mineral is not commonly offered. Threfore, the eval uation of plasma selenium levels is very important for treating or preventing this deficiency. Recent studies have shown that transthyretin may reflect the selenium intake and could be considered a biomarker. However, this issue is still little explored in the literature. OBJECTIVE: This study aims to investigate the correlation of transthyretin with the plasma selenium of critically ill patients receiving PN. METHOD: This was a prospective cohort study with 44 patients using PN without selenium. Blood samples were carried out in 3 stages: initial, 7th and 14th day of PN. In order to evaluate the clinical condition and the inflammatory process, albumin, C-reactive protein (CRP), transthyretin, creatinine and HDL cholesterol levels were observed. To assess the selenium status, plasma selenium and glutathione peroxidase (GPx) in whole blood were measured. Descriptive analyses were performed and the ANOVA, Mann-Whitney and Spearman's coefficient tests were conducted; we assumed a significance level of 5%. RESULTS: A positive correlation of selenium with the GPx levels (r = 0.46; p = 0.03) was identified. During two weeks, there was a positive correlation of transthyretin with plasma selenium (r = 0.71; p = 0.05) regardless of the CRP values. CONCLUSION: Transthyretin may have reflected plasma selenium, mainly because the correlation was verified after the acute phase. PMID- 28627188 TI - Effect of glutamine on liver injuries induced by intestinal ischemia-reperfusion in rats AB - INTRODUCTION: Intestinal ischemia-reperfusion (I/R) injury may cause cell and tissue damage, reaching also other organs such as the liver. Because of the involvement of free radicals in I/R injury, treatment options with antioxidants have been studied and tested. OBJECTIVE: To evaluate the effect of glutamine (Gln) in the liver of animals with intestinal I/R injury. METHODS: We used 20 male Wistar rats divided into four groups: sham-operated (SO); glutamine + sham operated (G+SO); intestinal ischemia-reperfusion (I/R); glutamine + intestinal ischemia-reperfusion (G+I/R). The superior mesenteric artery was clamped for 30 minutes and reperfused for 15 minutes. Gln (25 mg/kg/day) diluted in 1 ml of saline was administered intraperitoneally on the two days before I/R induction. RESULTS: Levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), lipid peroxidation (LPO) and expressions of interleukin-6 (IL-6) and nuclear factor kappa B (NF-kB) showed a significant reduction in the G+I/R group as compared with the I/R group. The activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the levels of glutathione (GSH) showed an increase in the G+I/R group as compared with the I/R group. CONCLUSION: Pretreatment with Gln reduced oxidative, tissue damage and showed a decrease expression of inflammatory mediators. PMID- 28627189 TI - [Nitrogenous content in parenteral nutrition: a four-year experience in a general hospital. Critically-ill patient specificity]. AB - INTRODUCTION: There have been several studies focusing on caloric intake during the last years, while protein content relevance has been underestimated. Some recent evidence has shown that protein deficiency has also an impact on patient outcomes. We have studied the nitrogen (N) content in parenteral nutrition (PN) bags administered to adult patients in a Spanish tertiary level hospital for four years. MATERIAL AND METHODS: Patients who received parenteral nutrition in the general ward and Intensive Care Unit (ICU) were recorded. Caloric and protein content were registered and adjusted to weight and length of stay. Data were compared among three group of patients: those in the general ward, those in the ICU and those requiring renal replacement therapy (RRT). The one-factor analysis of variance (ANOVA) test was used after checking data normality and homoscedasticity. RESULTS: There was an increase in the mean g N/stay year after year (p < 0.01) from 14 to 15.5 g, with a decrease in non-protein caloric content (p < 0.001) from 111.6 to 101.8 kcal/g N. The range was established from 4.1 to 32.6 g. PN diets with >= 18 g N% ranged from 12.8% (2010) to 19.6% (2013). There were significant differences among the groups when comparing the variable g N/stay (p < 0.0001): 13.5 general ward vs15.9 ICU patients vs17.6 ICU with RRT, also when referring to adjusted weight. CONCLUSIONS: According to most recent recommendations nitrogen has been provided in higher amounts than previously, especially in critical care patients with RRT. PMID- 28627190 TI - [Relationships between umbilical vein and mother iron status]. AB - INTRODUCTION: Iron is an essential micronutrient in the growing fetus. OBJECTIVE: The purpose of this study is to find the possible correlations that may exist between maternal and fetal iron status and newborn weight. MATERIAL AND METHODS: The study included 97 mothers scheduled to give birth by elective caesarean section in the central maternity of Tebessa (east of Algeria) between January and August 2014. The blood collection was sampled from the antecubital vein of the mother and the umbilical vein. The mean concentrations of parameters in maternal and fetal sides, respectively, were 10.64 +/- 1.37 g/dl and 14.83 +/- 1.79 g/dl for hemoglobin, 51.57 +/- 20.82 ug/dl and 112.47 +/- 32.34 MUg/dl for serum iron, and 12.37 +/- 9.58 ng/ml and 109.64 +/- 58.76 ng/ml for serum ferritin. Except for ferritin, other fetal parameters were correlated with those of mothers. Birth weight was only significantly correlated with maternal hemoglobin (r = 0.22, p = 0.02) and hematocrit (r = 0.2, p = 0.004). CONCLUSION: The fetal-maternal exchanges of iron were highlighted and iron status of the newborn was linked to that of the mother. The low maternal hemoglobin was associated with low newborn weight. PMID- 28627191 TI - [Associations between insulin resistance and three B-vitamins in European adolescents: the HELENA study]. AB - OBJECTIVE: To assess whether adolescents with high body mass index (BMI), or fat mass index (FMI), in combination with insulin resistance (assessed with the Homeostatic Model Assessment [HOMA] index), had also lower blood vitamin B6, folate and vitamin B12 concentrations. METHODS AND MATERIALS: Six hundred and fifteen adolescents from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study, with data on B-vitamins (both intakes and status), and BMI, FMI, HOMA, were selected. Intakes were assessed by two non-consecutive 24-h recalls. B-vitamins biomarkers were measured by chromatography and immunoassay. Analysis of covariance was applied to elucidate the differences in B vitamins between combinations of groups defined according to the median of the z scores of markers of body composition and insulin sensitivity. RESULTS: When considering energy intakes and education of the mother in the model, in females, vitamin B6 intakes were higher in the high BMI/high HOMA group than in the high BMI-low HOMA group. Similarly, vitamin B6 intakes were higher in the high FMI/high HOMA group than in the low FMI/low HOMA group. Plasma vitamin B12 was significantly lower in males in the high FMI/high HOMA group than in the low FMI/low HOMA group, keeping also significant their trends throughout the groups, a fact that can be observed also for females (p < 0.05). CONCLUSION: Adolescents with combined higher adiposity and higher HOMA insulin sensitivity showed lower vitamin B12 plasma concentrations. These differences do not seem to be explained by dietary vitamin B12 intake. PMID- 28627192 TI - [Excess weight in patients with cystic fibrosis: is it always beneficial?] AB - INTRODUCTION: The primary objective of this study was to find out the prevalence of overweight and obese status, as well as their association to pulmonary function, total cholesterol and vitamin D in patients with cystic fibrosis (CF). MATERIALS AND METHODS: This is a multicenter descriptive and cross-sectional study. Twelve Spanish hospitals participated. 451 patients with CF were included. Adults were classified according to body mass index (BMI) and children were classified according to BMI percentiles (WHO tables). Pearson's correlation, Anova, Student's t-test and multiple linear regression were conducted. RESULTS: Mean age was 12.3 (range 4-57) years old, 51% were male and 18% had pancreatic sufficiency. Participants were classified in five nutritional status categories: 12% were malnourished; 57%, at nutritional risk; 24%, normally nourished; 6%, overweight; and 1%, obese. Pulmonary function in overweight or obese patients (91 +/- 19%) was better than in malnourished patients (77 +/- 24%) (p = 0.017). However, no difference was observed between those at nutritional risk (86 +/- 19%) or normally nourished (90 +/- 22%) groups. Overweight and obese patients had higher levels of total cholesterol (p = 0.0049), a greater proportion of hypercholesterolemia (p = 0.001), as well as lower levels of 25 OH vitamin D (p = 0.058). CONCLUSIONS: Prevalence of overweight and obese was 6 and 1%. Excess weight status does not offer any benefit in pulmonary function in comparison to normally nourished patients. PMID- 28627193 TI - [Menus offered in long-term care homes: quality of meal service and nutritional analysis]. AB - BACKGROUND: Institutionalization is a risk factor for malnutrition. Low energy intake and/or nutrient deficiencies are considered to be the main causes. OBJECTIVE: To evaluate the quality of meals and meal service as well as the nutritional value of the main menus (regular menu, menu for diabetics, and pureed menu) offered in three long-term care (LTC) homes located in the metropolitan area of Granada (Spain). METHODS: Cross-sectional study. A validated "quality of meals and meal service" set of indicators was applied. The menus were assessed by weighed food records on 14 consecutive days. The results were compared with the dietary reference intakes (DRIs) and the recommended number of servings. RESULTS: Important deficiencies in the quality of meals and meal service have been reported. Average energy varies from 1,788 to 2,124 kcal/day in the regular menus, from 1,687 to 1,924 kcal/day in the menus for diabetics, and from 1,518 to 1,639 kcal/day in the pureed menus. Average protein varied from 71.4 to 75.4 g/day, from 72.6 to 76.1 g/day, and from 50.5 to 54.7 g/day, respectively. None of the menus complied with the recommendations for fiber, potassium, magnesium, iodine, vitamin D, vitamin E, folate, nor for vegetables, fruit, milk products, olive oil, legumes, or nuts. CONCLUSIONS: It is necessary to ensure the implementation of regular routines for controlling the quality of meals and meal service as well as the nutritional value of the menus offered in LTC homes. PMID- 28627194 TI - Metabolic syndrome and cardiovascular risk in diabetic population of El Hierro, Canary Islands AB - Introduction: In the Canary Islands there is a high prevalence of vascular risk factors.Objective: To analyze the clinical characteristics of 300 patients with type 2 diabetes in El Hierro, in the Canary Islands.Methods: Patients were assessed at the Internal Medicine Unit of the hospital from 1982 to 2010, and followed up until December 2014 or until death. The sample is composed of 154 women and 156 men (52%).Results: mean age was 66.40 +/- 11.60 years, with an average follow-up time of 11.04 +/- 4.93 years, and 80.3% were diagnosed of metabolic syndrome, signifi cantly more frequent among women (86.43% vs74.67%, chi2 = 5.62, p = 0.018). During the follow-up period, 51 patients died and a signifi cant proportion developed new cardiovascular complications, such as heart failure (6.7%), ischemic heart disease (17.3%), atrial fi brillation (14.3%), stroke 7%), or peripheral arterial disease (6.9%). Cox regression analysis showed that, although advanced age was the major factor involved in the development of all these complications and in mortality, low cholesterol levels were related to the development of ischemic heart disease and mortality, results that were not dependent on the consumption of statins (as in other examples of inverse epidemiology). Ethanol consumption was related to the incidence of peripheral arterial disease.Conclusions: Old age was the main factor involved in the development of complications and mortality. In addition, low cholesterol levels were related to the development of ischemic heart disease and mortality. PMID- 28627195 TI - Exercise improved semen quality and reproductive hormone levels in sedentary obese adults AB - INTRODUCTION: From the previously published literature on the relationship between obesity and infertility, it is clear that male obesity negatively impacts semen quality. Accordingly, this study was conducted to determine whether regular exercise may improve semen quality in sedentary obese adults. MATERIAL AND METHODS: Ninety obese adults were randomly allocated to the intervention (n = 45) or control group (n = 45). Participants in the intervention group performed a 16 week aerobic training program in a treadmill, three sessions per week, consisting of a warm-up (10-15 minutes), 35-50 minutes treadmill exercise (increasing five minutes per four weeks) at a work intensity of 50-65% of peak heart rate (increasing a 5% per four weeks) and cooling-down (5-10 minutes). Semen quality assessment included semen volume, sperm concentration and the percentages of progressive motility and normal morphology. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone and estradiol were determined by ELISA. Body composition and physical fitness were also assessed. RESULTS: After the completion of the training program, sperm count, motility and normal morphology were significantly increased. A second key finding was that exercise improved reproductive hormone levels by increasing serum testosterone. Lastly, significant correlations were found between seminal outcomes and abdominal obesity. CONCLUSION: A short-term intervention program based on aerobic training improved semen quality in sedentary obese adults. This finding may be explained, at least in part, by an improvement of the reproductive hormone profile. PMID- 28627196 TI - Comparison of gene expression profile between blood cells and white adipose tissue of patients with obesity AB - INTRODUCTION: Gene expression analyses from peripheral blood mononuclear cells (PBMC) and white adipose tissue are conflicting. It seems that results from single tissue are not enough to explain how changes affect humans as a complex biological system. OBJECTIVE: The aim of this study was to compare, from obesity subjects, PBMC and white adipose tissue gene expression that regulates adipogenesis (perilipin 1 [PLIN1], adrenoreceptor beta 3 [ADRB3] and peroxisome proliferator-activated receptor [PPARG2]) and the energy metabolism (uncoupling protein UCP1, UCP2 and UCP3) process. METHODS: This study enrolled 35 obese patients, with a body mass index (BMI) > 40 kg/m2 (obesity group [OG]), and ten eutrophic health subjects, 18 > BMI > 24.9 kg/m2 (control group [CG]). Anthropometric and body composition data were assessed at recruitment using standardized protocols. Samples of peripheral blood and subcutaneous adipose tissue (biopsy) were collected to analyze gene expression by RT-qPCR technique. For statistical analysis, we used the Shapiro-Wilk test and Wilcoxon tests by the SPSS software version 20.0; a p < 0.05 significance level was adopted. RESULTS: There were significant differences of PLIN1, ADRB3, PPARG2 and UCP3 expression between blood against adipose tissue samples, showing that these genes are upregulated in adipose tissue. UCP2 expression was upregulated in PBMC. CONCLUSION: The PLIN1, ADRB3, PPARG2 and UCP3 genes were preferentially expressed in adipose tissue. However, UCP2 was upregulated in PBMC, suggesting that this gene may be assessed in a peripheral blood cell, which is easily accessible, safe and practical. PMID- 28627197 TI - Dietary antioxidant quality score (DAQs) is associated with bone mass assessed by calcaneal quantitative ultrasound in young women AB - INTRODUCTION: Evidence suggests that intake of antioxidants could positively influence bone mass by preventing bone metabolism against oxidative stress. OBJECTIVE: We aimed to investigate the possible influence of single antioxidant intakes and dietary antioxidant quality score (DAQs) on calcaneal quantitative ultrasound (QUS) in a population of young adults. METHODS: A total of 605 young Spanish adults participated in this study (median age 20.38 +/- 2.67). Bone mass was measured by calcaneal QUS to determine broadband ultrasound attenuation (BUA, dB/MHz) parameter. Body composition was assessed by bioelectrical impedance analysis and dietary intakes were determined using a 72-hour diet recall interview. DAQs was applied to calculate antioxidant nutrients intake. Linear regression analyses were performed to investigate the possible influence of DAQs on calcaneal QUS. RESULTS: Most of young adults showed a low-quality antioxidant intake (only 17.6% of women and 20.3% of men had a score of 4 or 5 in DAQs). A positive correlation between DAQs and BUA was observed in women (r = 0.117; p = 0.024). Linear regression analysis revealed that DAQs was significantly associated with BUA parameter in women after adjusting by body weight, height, calcium intake and physical activity (PA) (p = 0.035). No significant associations between single antioxidant and calcaneus QUS measurement were found. CONCLUSION: Our findings suggest that high-quality antioxidant intakes could influence bone health in young women. Future studies should further investigate the protective role of antioxidant nutrients against osteoporosis. PMID- 28627198 TI - Triceps skinfold compressibility in hospitalized patients AB - OBJECTIVE: To explore triceps skinfold (TSF) compressibility and its associated factors among hospitalized patients. METHODS: A cross-sectional study was conducted among hospitalized adult patients. Evolution of tissue compressibility during two seconds was registered and 120 TSF values were obtained using a digital calliper. Compressibility was determined according to the difference between the initial value and the final value (TSF difference) and according to time (tau). Multivariable linear regression models were performed in order to identify factors associated with TSF compressibility. RESULTS: One hundred and six patients (30.2% aged >= 65 years) composed the study sample. Compressibility based on TSF difference was independently associated with TSF thickness (regression coefficient, 95% confidence interval [CI] = 0.38, 0.01-0.05, p = 0.002) and nutritional risk (regression coefficient, 95% CI = 0.23, 0.12-1.23, p = 0.018), but time of compressibility (tau) was not significantly associated with any of the studied variables. CONCLUSIONS: Among a sample of hospitalized patients, undernutrition risk and higher TSF thickness were factors independently associated with higher compressibility assessed by the difference between the initial and final TSF value. Time of compressibility (tau) was not affected by any of the studied factors. PMID- 28627199 TI - Hand span influences optimal grip span in adolescents with Down syndrome AB - INTRODUCTION: The hand grip strength test provides useful and reliable information about overall health. Different studies have investigated the optimal grip span for determining maximal hand grip strength in different populations such as adults, adolescents and children without disabilities. OBJECTIVE: To ascertain whether there is an optimal grip span for determining maximal hand grip strength in adolescents with Down syndrome (DS). METHODS: Twenty-seven right handed youths with DS (seven females) aged 15.5 +/- 3.6 years were evaluated in this methodological study. Each hand was randomly tested on ten times using five different grip spans, allowing one-minute rest between attempts. The hand span was measured from the tip of the thumb to the tip of the small finger with the hand widely opened. To confirm the usefulness of the optimal grip span, a new group of 15 adolescents with DS were recruited. RESULTS: An optimal grip span was identified for the dominant hand in adolescents with DS. The equation relating grip span as a function of dominant hand span in this group is formulated as follows: y = 0.342x - 1.161 cm (r = 0.63, p < 0.05). In the case of non-dominant hand, a tendency towards a linear association (p = 0.058) was found; the equation is formulated as follows: y = 0,210x + 1.324 cm. CONCLUSION: It is important to standardize the procedure and increase reliability when measuring hand grip strength in DS population. The values stated in this study are recommended to assess hand grip strength in adolescents with Down syndrome. PMID- 28627200 TI - Body composition changes after sport detraining period AB - Introduction: The infl uence of exercise in trained subjects has beneficial effects in the physical fi tness and body composition; however, detraining has an unfavorable effect in all of them. Objective: The current study was designed to ascertain the infl uence of a six week-detraining period on body composition in both well-trained young soccer players (GE, n = 43) and sedentary male adolescents (GC, n = 10). Methods: Forty-three well-trained soccer players and ten sedentary adolescents accepted to participate in the study. Body composition measurements included fat mass and skeletal muscle mass (SMM), which were estimated by anthropometry. In addition, total body water (TBW), intracellular water (ICW) and extracellular water (ECW) were assessed by bioelectrical impedance analysis (BIA) at the end of training and after detraining periods. Results: After the six-week-detraining period, signifi cant increments were found in TBW (35.5 +/- 5.2 vs.36.7 +/- 4.9 kg; p < 0.001), ICW (14.2 +/- 1.8 vs. 14.8 +/- 1.6 kg; p < 0.001) and ECW (21.5 +/- 3.6 vs. 22.0 +/- 3.4 kg; p < 0.001) in soccer players. Conversely, no changes were observed in ECW/TBW (0.4 +/- 0.02 vs. 0.4 +/- 0.02; p > 0.05) and ICW/TBW (0.6 +/- 0.02 vs. 0.597 +/- 0.02; p > 0.05) ratios. Finally, fat mass was significantly increased (8.6 +/- 3.2 vs. 8.95 +/- 3.1 kg; p < 0.01) in the detrained group. No signifi cant changes were found in SMM (21.2 +/- 2.5 vs. 22.22 +/- 2.8 kg, p > 0.05). Conclusions: After a six-week detraining period, body composition changed signifi cantly in well-trained adolescents. The main fi nding of this study was that increments of TBW and water distribution were observed in the soccer group, which refl ects an increase of fat free mass compartment. The physiological importance of this miss-adaptation needs to be elucidated in future research. Further studies on this topic are still required to assess its impact on physical performance. PMID- 28627201 TI - Degree of malnutrition and its relationship with major structural and eating factors in Honduran preschool population. Prevalence of breastfeeding AB - Introduction: Child malnutrition remains a serious public health problem in Honduras, with a national prevalence according to the World Health Organization (WHO) reference values of 29% in children under fi ve. In addition, the average chronic malnutrition in the region amounts to 80% in poor and indigenous communities, making Honduras the second country in Central America with the highest incidence of chronic malnutrition. Another problem of the region is the early cessation of exclusive breastfeeding: only 29.7% of children were exclusively breastfed until they were six months. Therefore, the study seeks to understand, identify and quantify the situation determinants and provide information for the design of public policies.Material and method:: The study consisted of a cross-sectional descriptive anthropometric assessment in which the nutritional status and the prevalence of undernourishment, malnutrition and malnutrition in 141 children aged between six months and fi ve years, belonging to urban and rural regions of the country, were analyzed, as well as assessing the prevalence of breastfeeding in fi ve Honduran departments (Intibuca, Lempira, Atlantida, Olancho and Francisco Morazan).Results and conclusion: When making the analysis by departments, differences regarding nutritional status and breastfeeding were observed between urban and rural areas, the latter being doubled in the case of chronic malnutrition and underweight, with percentages of 14.6% in urban areas versus28.8% in rural areas, and 4.6% in urban areas compared to 9% in rural areas, respectively. However, with respect to acute malnutrition and overweight in both regions, similar values were observed, above 1.1% for acute and 14% for overweight malnutrition. In relation to exclusive breastfeeding for six months, the departments of Olancho and Lempira maintained it for two years, with a percentage distribution of 80% and 48%, respectively. It must be noted that 36% of mothers did not provide breastfeeding, with the highest rate (15%) in the department of Francisco Morazan. PMID- 28627202 TI - Maternal underweight and perinatal outcomes: a restrospective cohort study AB - Introduction: Some studies have linked maternal underweight with adverse perinatal outcomes such as spontaneous abortion, abruptio placentae,small for gestational age newborn, intrauterine growth retardation and preterm birth.Objective: To determine the influence of maternal underweight in the onset of labor, route of delivery, birth weight, Apgar score and preterm birth.Methods: Retrospective cohort study. We included pregnant women from the Hospital Universitario de Puerto Real. Period of study: 2002-2011. Study group: underweight at the beginning of gestation (BMI < 18.5 kg/m2). Control group: pregnant women with normal body mass index (BMI) at the beginning of gestation (18.5-24.9 kg/m2). The risk (OR) of induction of labor, cesarean section, small for gestational age newborn, macrosomia, 5' Apgar score < 7, and preterm birth was calculated.Results: The prevalence of underweight was 2.5% versus 58.9% of pregnant women who had a normal BMI. We found no significant differences in the rate of induction of labor, fetal macrosomia, Apgar at 5' < 7 or preterm delivery. Maternal underweight was associated with a decreased risk of caesarean section (adjusted OR 0.45, 95% CI 0.22 to 0.89) and an increased risk of small for gestational age newborn (adjusted OR 1.74; 95% CI 1.05 to 2.90).Conclusions: Maternal underweight at the start of pregnancy is associated with a lower risk of caesarean section and a greater risk of small for gestational age newborns (birth weight < P10). PMID- 28627203 TI - Association between meal intake behavior and blood pressure in Spanish adults AB - INTRODUCTION AND OBJECTIVES: Eating frequency has been suggested to modify blood pressure. Yet, the results are inconclusive, possibly because eating frequency, particularly meal intake behavior (MIB), does not differentiate between meals and snacks. Hence, the aim of this study was to examine the association between more specific MIBs, like the consumption of the three main meals, the intake of forenoon and afternoon meals and snacking between the regular meals, and systolic/diastolic blood pressure (SBP/DBP). METHODS: This cross-sectional study includes 1,314 Spanish adults aged 20-79 years. Data collection occurred during cardiovascular health day events organized in four Spanish cities (Madrid, Las Palmas, Seville and Valencia) in 2008. Linear regression analysis was performed to assess the independent association between the mentioned MIBs and SBP/DBP, controlling for several confounders in multiples models. RESULTS: After adjusting for sex, age and individual risk factors, having an afternoon meal was associated with lower SBP (beta -3.91, 95% CI [-6.33, -1.49]) and DBP (beta -2.35, 95% CI [ 3.76, -0.94]). This association was attenuated when introducing dietary intake and waist circumference in the predictive models (SBP: beta -2.83, 95% CI [-5.25, -0.40]; DBP: beta -1.67, 95% CI [-3.04, -0.31]), although it still remained significant. None of the other investigated MIBs showed any associations with SBP/DBP. CONCLUSIONS: This study suggests that SBP/DBP might be reduced by the intake of an afternoon meal. However, population-based prospective studies are needed in order to confirm the consequences of the investigated associations on health. PMID- 28627204 TI - Iodine levels are associated with oxidative stress and antioxidant status in pregnant women with hypertensive disease AB - BACKGROUND: The antioxidant function of iodine and iodine deficiency as a risk factor of preeclampsia have been previously reported. AIM: To analyze the association between iodine deficiency, oxidative stress and antioxidant status with hypertensive disease of pregnancy (HPD). METHOD: Fifty-seven pregnant women were recruited in the last trimester of pregnancy; 20 were diagnosed with hypertensive disease (HPD) of pregnancy and 37 were normotensive pregnant women. Urinary iodine concentration (UIC), TSH, free T4 (fT4), total antioxidant status (FRP), superoxide dismutase (SOD), catalase (CAT), and oxidative stress (TBARS) were evaluated by colorimetric methods. RESULTS: UIC median for all pregnant women was 151.9 ug/l. The UIC for pregnant women with HPD was 50-149 ug/l, compared to 150-249 ug/l in normotensive women. No significant differences in levels of TSH and fT4 in normotensive pregnant compared with HPD women were found. Pregnant women with HPD had significant high levels of TBARS, and significant low levels of FRP, SOD, CAT and UIC compared to normotensive pregnant. In addition, pregnant women with optimal levels of UIC had a higher SOD activity (r = 0.354, p = 0.011), while iodine deficiency was associated with HPD (r = -0,281, p = 0.039). Similarly, pregnant women with HPD had a significant negative association with SOD activity (r = -0.702, p = 0.005), CAT (r = -0.409, p = 0.002), and FRP (r = -0.624, p = 0.003), and a positive association with TBARS (r = 0.744, p = 0.001). CONCLUSION: Iodine contributes to redox balance during pregnancy; its deficiency is associated with HPD. This study shows the importance of iodine during pregnancy. PMID- 28627205 TI - A low fermentable oligo-di-mono-saccharides and polyols (FODMAP) diet is a balanced therapy for fibromyalgia with nutritional and symptomatic benefits AB - INTRODUCTION: Fibromyalgia is a chronic rheumatic disease producing widespread pain, associated to a major comorbidity -irritable bowel syndrome. Low FODMAPS diet (low fermentable oligo-di-mono-saccharides and polyols diet) has been effective in controlling irritable bowel syndrome symptoms. Overweight is an aggravating factor for fibromyalgia. We studied effects of low fermentable oligo di-mono-saccharides and polyols diets on fibromyalgia symptoms and weight status. METHODS: A longitudinal study was performed on 38 fibromyalgia patients using a four-week, repeated assessment as follow: M1 = first assessments/presentation of individual low fermentable oligo-di-mono-saccharides and polyols diet; M2 = second assessments/reintroduction of FODMAPs; M3 = final assessments/nutritional counselling. The assessment instruments applied were: Fibromyalgia Survey Questionnaire (FSQ); Severity Score System (IBS-SSS); visual analogic scale (VAS). Body mass-index/composition and waist circumference (WC) were also measured. Daily macro-micronutrients and FODMAP intake were quantified at each moment of the study. RESULTS: The studied cohort was 37% overweight, 34% obese (average body mass-index 27.4 +/- 4.6; excess fat mass 39.4 +/- 7%). Weight, body mass-index and waist circumference decreased significantly (p < 0.01) with low fermentable oligo-di-mono-saccharides and polyols diet, but no significant effect on body composition was observed. All fibromyalgiasymptoms, including somatic pain, declined significantly post-LFD (p < 0.01); as well for severity of fibromyalgia [Fibromyalgia survey questionnaire: M1 = 21.8; M2 = 16.9; M3 = 17.0 (p < 0.01)]. The intake of essential nutrients (fiber, calcium, magnesium and vitamin D) showed no significant difference. The significant reduction in FODMAP intake (M1 = 24.4 g; M2 = 2.6g; p < 0.01) reflected the "Diet adherence" (85%). "Satisfaction with improvement of symptoms" (76%), showed correlating with "diet adherence" (r = 0.65; p < 0.01). CONCLUSIONS: Results are highly encouraging, showing low fermentable oligo-di-mono-saccharides and polyols diets as a nutritionally balanced approach, contributing to weight loss and reducing the severity of FM fibromyalgiasymptoms. PMID- 28627206 TI - Investigation on the endemic characteristics of Metorchis orientalisin Huainan area, China AB - OBJECTIVE: To investigate the endemic characteristics of Metorchis orientalis (M. orientalis)in the Huainan area, Anhui province, China. METHODS: The first intermediate host, second-intermediate host and reservoir hosts were collected, and the endemic characteristics of M. orientalis were examined through field investigation and artificial infection. RESULTS: Investigation was completed in 89 domestic ducks, 156 domestic chicken, 41 domestic geese, 20 domestic cats and 19 dogs. The infection rate of M. orientaliswas 18.0% (16/89) in ducks, 12.2% (19/156) in chicken, 9. 8% (4/41) in geese, 5.0% (1/20) in cats and 5.3% (1/19) in dogs. Sixty-seven cercariae of M. orientaliswere identified in 1,000 Parafossarulu s striatulus,with a natural infection rate of 6.7%, and 19 cercariae occurred in 300 Pseudorasbora parva, with a natural infection rate of 6.33%. The activity of the cercariae of M. orientaliswas associated with light intensity and temperature. The full life cycle of M. orientalisranged from 120 to 140 days; it occurred approximately in 89 days in snails, 28 days in fish and 20 days in ducks. CONCLUSION: M. orientalisis prevalent in the Huainan area, and it may complete its life cycle in Parafossarulus striatulus, Pseudorasbora parva and natively rais ed ducks. PMID- 28627207 TI - The effect of defatted cocoa powder on cholesterol-induced changes of serum lipids in rats AB - INTRODUCTION: Cocoa has been known for many health benefits, but its lipid lowering activity still remains unresolved. OBJECTIVES: To investigate effects of varying amounts of defatted cocoa on serum lipids in cholesterol-fed rats. METHODS: Forty-eight male Sprague-Dawley rats were randomly assigned into four cholesterol-free (control) and four cholesterol-supplemented (experimental) diets containing 0, 1, 2 or 3% defatted cocoa (DC) and given ad libitumto the rats for ten weeks. Serum total cholesterol (TC), low- and very low-density lipoprotein cholesterol (LDL-C and VLDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were quantified, atherogenic index (AI) was calculated, and other biological parameters were assessed. RESULTS: Food intake and body weight did not respond to DC. Compared to 0% DC, 3% DC had the most prominent effect on serum lipids inducing significant fall in LDL-C and TG, and rise in TC/TG in cholesterol-deprived rats, and increase in VLDL-C and AI, and decrease in HDL-C in cholesterol-fed rats. Compared to cholesterol-deprived rats, 3% DC caused significant rise in VLDL-C, AI and TC/TG, and fall in TG in cholesterol-fed rats. This lipid-modifying effect was markedly substantiated by corresponding linear trend responses to DC. Differences in lipid variables of rats fed on DC diets were less evident. CONCLUSIONS: Results suggest that, in contrast to cholesterol free situations, defatted cocoa is seemingly incapable of counteracting the atherogenic effect of cholesterol in rats, perhaps in an interaction that is likely to have clinical implications in cardiometabolic conditions. PMID- 28627208 TI - Irisin is weakly associated with usual physical activity in young overweight women AB - PURPOSE: To determine if irisin plasma levels are associated with regular physical activity, body composition and metabolic parameters in women subjected to calorie restriction. SUBJECTS AND METHODS: We studied 42 women aged 34 +/- 13 years with a body mass index of 27.7 +/- 1.8 kg/m2, who were subjected to a calorie restriction for three months. At baseline and at the end of the study, weight, waist and hip circumference, laboratory parameters, body composition by DEXA, resting and activity energy expenditure by indirect calorimetry and 72 hours actigraphy were measured. Fasting serum irisin was quantified using an ELISA kit. RESULTS: After the intervention period, participants lost 1.5 (0.4 3.4) kg and irisin levels did not change. Irisin baseline levels were positively but weakly correlated with the level of physical activity. This association was lost at the end of the intervention. No association was found between irisin levels and body composition or insulin sensitivity or their changes after calorie restriction. No association between serum irisin levels and PGC-1alphaexpression in peripheral blood mononuclear cells and serum irisin was observed. CONCLUSIONS: Fasting serum irisin was weakly associated with usual physical activity and did not change after calorie restriction. PMID- 28627209 TI - Anorexia and bulimia nervosa: virtual diffusion of the disease as a lifestyle AB - Introduction: Adolescence is a vulnerable period for the onset of eating disorders (ED) such as anorexia and bulimia nervosas. Body dissatisfaction, a precipitating factor for ED, leads adolescents to seek information on the Internet about diets. In this context, pro-Ana (proanorexia) and pro-Mia (probulimia) are on-line pages that promulgate highly harmful contents for health related to weight loss and ED.Objectives: The aim of this study was to analyze quantity, quality and social diffusion strategies used by pro-Ana and pro-Mia webpages.Methods: A web search was done in the Google Chrome browser, using the keywords "anorexia", "bulimia", "eating disorders", "Ana and Mia", "pro-Ana and pro-Mia", "anorexic nation", "obesity", "healthy lifestyles" and "healthy nutrition". The top 20 results for each search were selected and analyzed according to positioning rates (PageRank, PR). The quality of these resources was analyzed by a previously published questionnaire. Finally, a study of the diffusion in social networks like Facebook and Twitter was performed for pro-Ana and pro-Mia pages using SharedCount.Results: Searches for pro-Ana and pro-Mia reported more than a million entries. The pages were poorly positioned. Blog contents were the most shared between all the analyzed pages.Conclusions: pro-Ana and pro-Mia are resources with a clear intention to establish a contact with people with an eating disorder or who are at risk for developing one, in order to strengthen the communication through the blogosphere. PMID- 28627210 TI - Lactobacillus rhamnosusGG reduces hepatic fibrosis in a model of chronic liver disease in rats AB - BACKGROUND: The intestinal dysbiosis is common in chronic liver disease and can induce to inflammatory responses and mediate the collagen deposition in the liver. AIM: To evaluate the probiotic Lactobacillus rhamnosus GG (LGG) for the treatment of liver fibrosis in a model of chronic cholestatic liver disease in rats. METHODS: Male adult Wistar rats (n = 29) were submitted to common bile duct ligation (BDL groups) or manipulation of common bile duct without ligation (Ctrl groups).Two weeks after surgery, each group was randomly divided to receive 1 ml of PBS (Ctrl and BDL) or PBS containing 2.5 x 107 CFU of LGG (Ctrl-P and BDL-P) through gavages for 14 days. Euthanasia occurred 33 days after surgery when samples of blood and liver tissue were collected. RESULTS: The hepatic gene expression of Tlr4, Tnfalpha, IL-6, Tgfbeta, and metalloproteinase-2 and -9 were higher in the BDL groups in comparison to Ctrl. The ductular reaction evaluated by immunocontent of cytokeratin-7 (CK7) and the content of collagen were increased in BDL groups. Also, there was an imbalance in the antioxidant defenses (superoxide dismutase and catalase) and an increase in the oxidative stress marker sulfhydryl in BDL groups. The treatment with LGG significantly reduced gene expression of IL-6, collagen deposition, and ductular reaction in hepatic tissue of animals from BDL-P groups. CONCLUSION: The treatment with the probiotic LGG was able to reduce liver fibrosis, ductular reaction, and hepatic gene expression of IL-6 in a model of cholestatic liver disease in rats. PMID- 28627211 TI - Egg intake and cardiovascular disease: a scientifi c literature review AB - Eggs are a highly nutritive food. They contain high quality protein and several nutrients with potential health benefi ts. Nevertheless, the appearance of cardiovascular disease as an important public health issue, with high morbidity and mortality rates worldwide, along with the identifi cation of high blood cholesterol levels as a risk factor for this disease, was responsible for the advice to limit dietary cholesterol (and, therefore, eggs) that was promoted by health care professionals and institutions during the 70s. To date, several cohort studies show that the intake of one egg a day does not increase cardiovascular risk in the general population. However, this evidence is not clear among diabetic patients, and raises the questionwhether its consumption in large quantities is entirely safe in this particular population. Additionally, intervention studies have shown that egg consumption does not adversely affect cardiovascular risk factors neither in healthy individuals nor in those with cardiometabolic disease. Moreover, these studies suggest that the incorporation of egg to the diet could bring additional benefits such as promoting a less atherogenic lipid profile. PMID- 28627212 TI - Efficacy of enteral nutritional support after hospital discharge in major gastrointestinal surgery patients: a systematic review AB - INTRODUCTION: Nutritional support for malnourished patients undergoing gastrointestinal surgery reduces the complication rate and shortens the length of stay. The efficacy of nutritional support after hospital discharge was analyzed in this systematic review. METHODS: The search strategy (nutrition OR "enteral nutrition" OR "nutritional supplements" OR "oral nutritional supplements" OR "sip feed" OR "sip feeding" OR "dietary counseling") AND ("patient discharge" OR discharge OR postdischarge) AND (surgery OR operation OR "surgical procedure") was followed in Medline, CENTRAL, and Trip databases. Inclusion criteria comprised: type of study (randomized controlled trial), language (English, Spanish), and subjects (patients undergoing gastrointestinal surgery). The risk of bias was assessed by using the Cochrane methodology. RESULTS: Five studies which were published in six different articles and recruited 446 patients were included. A high risk of bias was detected for most of them. Nutritional support improved energy intake and protein intake when high-protein oral supplements were provided. The intervention was associated with better weight prognosis, but the data about body composition were inconsistent. In most of the trials, nutritional intervention did not enhance functional capacity or quality of life. None of the studies analyzed the effects on complications after discharge. CONCLUSION: Nutritional support provided at discharge may increase dietary intake and improve body weight, but the low quality of studies can weaken the validity of results. PMID- 28627213 TI - Nonalcoholic fatty liver disease (NAFLD) pathophysiology in obese children and adolescents: update AB - OBJECTIVE: Although the nonalcoholic fatty liver disease was first identified in 1980, it presents multifactorial and unclear pathophysiology. In this review, we intend to update the pathophysiological mechanisms of a high morbidity and mortality associated disease that is affecting obese children worldwide. DATA SOURCES: The PubMed and the Cochrane Library databases were used in the search strategy for articles related to nonalcoholic fatty liver disease and published in the last three decades. DATA SUMMARY: This review describes the current knowledge on the different mechanisms related to the pathophysiology of nonalcoholic fatty liver disease focused on histological, anatomical and biochemical aspects involved in triggering steatohepatitis and leading to cirrhosis. CONCLUSIONS: The clinical research and advanced technological resources demonstrated several determinants pathophysiological mechanisms of nonalcoholic fatty liver disease trying to assist in their treatment and change its natural course. PMID- 28627214 TI - Effects of green tea and its epigallocatechin (EGCG) content on body weight and fat massin humans: a systematic review AB - The prevalence and incidence of overweight and obesity worldwide continues to increase, as well as diseases related to these conditions. This is attributed to an increase in energy intake and a decrease in energy expenditure. Consumption of green tea has been linked to a reduction in body fat and body weight. However, research on green tea has been very diverse. This review assesses the investigations that have been made with green tea and its epigallocatechin gallato (EGCG) content, evaluating its effect on body fat and body weight in humans. A search was made in the PubMed and Web of the Science databases that gave a first total result of 424 potential articles; 409 were excluded and 15 articles were used for this systematic review. Research has been very varied, however, daily consumption of green tea with doses of EGCG between 100 and 460 mg/day has shown greater effectiveness on body fat and body weight reduction in intervention periods of 12 weeks or more. In addition, the use of caffeine doses between 80 and 300 mg/day has been shown to be an important factor for this effects, when the participants did not have a high caffeine intake (> 300 mg/day) prior to the intervention. PMID- 28627215 TI - The health educator network as a nutrition education strategy: the example of the EDALNUprogramme (1963-1994) AB - Food and nutrition education is an essential tool to ensure public health. The year 1961 saw the launch of the Food and Nutrition Education Programme(EDALNU), which helped Spanish population to complete their nutrition transition. The aim of this study was to analyze the characteristicsof the health education network which was created as part of the program.A total of 46,752 people, 94% of whom were women, received training on food and nutrition. Of these, 89.54% obtained the basic certificate, and8.80% were awarded the diploma. Some 1,407 courses were given, reaching a peak in 1979 with 131 courses and 4,029 students. The most active provinces were Madrid, with 26.65% of the courses; Valencia, with 7.60%; Murcia, with 7.53%, and Malaga, with 6.75%. The Spanish Ministry of Culture and Education organized the largest number of courses (26.23%), followed by the Women's Section (11.16%) and Catholic Action (5.12%). Diploma courses were taught for 160 hours, while basic courses lasted 40 hours.The training delivered was affected by changes in the EDALNU program and the Spanish administrative and political structure. Our researchrevealed that the development and gender balance of the network of trainers presented regional inequalities, and that a wide range of institutionswere involved in delivering the courses PMID- 28627216 TI - Pediatric parenteral nutrition: clinical practice guidelines from the Spanish Society of Parenteral and Enteral Nutrition (SENPE), the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP) and the Spanish Society of Hospital Pharmacy (SEFH) AB - Introduction:Parenteral nutrition (PN) in childhood is a treatment whose characteristics are highly variable depending on the age and pathology of the patient.Material and methods: The Standardization and Protocols Group of the Spanish Society for Parenteral and Enteral Nutrition (SENPE) is an interdisciplinary group formed by members of the SENPE, the Spanish Society of Gastroenterology, Hepatology and Pediatric Nutrition (SEGHNP) and the Spanish Society of Hospital Pharmacy (SEFH) that intends to update this issue. For this, a detailed review of the literature has been carried out, looking for the evidences that allow us to elaborate a Clinical Practice Guide following the criteria of the Oxford Center for Evidence-Based Medicine.Results: This manuscript summarizes the recommendations regarding indications, access routes, requirements, modifi cations in special situations, components of the mixtures, prescription and standardization, preparation, administration, monitoring, complications and home NP. The complete document is published as a monographic number.Conclusions: This guide is intended to support the prescription of pediatric PN. It provides the basis for rational decisions in the context of the existing evidence. No guidelines can take into account all of the often compelling individual clinical circumstances. PMID- 28627218 TI - Performance evaluation of three platforms with ultrasensitive ligand-binding assay potential. AB - AIM: We evaluated three immunoassay-based technologies and their biomarker kits, by determining precision, parallelism and detectability of analytes of interest. MATERIALS & METHODS: We compared ultrasensitive assays for three biomarkers: interleukins IL-6, IL-13 and IL-17A using kits obtained from Roche (IMPACT platform - proprietary platform), Singulex (Erenna(r)) and Quanterix (SimoaTM). We defined the true LLOD as the LLOQs, and provided disease-specific parallelism results and detectability levels for endogenous analyte, which were good across platforms, though they varied from analyte to analyte. CONCLUSION: We highlight a simplified approach employed for evaluating ultrasensitive kits and provide an overview of the methodologies used to compare available assays. All three platforms are able to detect very low-level analytes. We recommend all three platforms for detection of very low-level analytes. PMID- 28627217 TI - Using Plantar Electrical Stimulation to Improve Postural Balance and Plantar Sensation Among Patients With Diabetic Peripheral Neuropathy: A Randomized Double Blinded Study. AB - OBJECTIVE: People with diabetic peripheral neuropathy (DPN) often exhibit deteriorations in motor-performance mainly due to lack of plantar-sensation. The study explored effectiveness of plantar electrical-stimulation therapy to enhance motor-performance among people with DPN. DESIGN AND METHODS: Using a double blinded model, 28 volunteers with DPN (age: 57.8 +/- 10.2 years) were recruited and randomized to either intervention (IG: n = 17) or control (CG: n = 11) group. Both groups received identical plantar-stimulation devices for six weeks of daily use at home; however, only the IG devices were set to deliver stimulation. Balance (ankle, hip, and center of mass [COM] sway) and gait (stride velocity [SV], stride time [ST], stride length [SL], and cadence) were measured using validated wearable sensors. Outcomes were assessed at baseline and at six-week. Clinical assessment including vascular as measured by ankle-brachial-index (ABI) and plantar-sensation as quantified by vibratory plantar threshold (VPT) were also measured at baseline and six weeks. RESULTS: No difference were observed between groups for baseline characteristics ( P > .050). Posttherapy, ankle and COM sway with eyes open were significantly improved ( P < .05, Cohen's effect size d = 0.67-0.76) in the IG with no noticeable changes in CG. All gait parameters were significantly improved in the IG with highest effect size observed for cadence ( d = 1.35, P = .000). Results revealed improvement in VPT ( P = .004, d = 1.15) with significant correlation with stride velocity improvement ( r = .56, P = .037). ABI was improved in the IG in particulate among those with ABI>1.20 ( P = .041, d = 0.99) Conclusion: This study suggests that daily home use of plantar electrical-stimulation may be a practical means to enhance motor performance and plantar-sensation in people with DPN. PMID- 28627219 TI - Accuracy Assessment of an Improved Version of an Established Blood Glucose Monitoring System for Self-Testing Following ISO 15197:2013. PMID- 28627220 TI - The German Version of the Perceived Stress Scale (PSS-10): Evaluation of Dimensionality, Validity, and Measurement Invariance With Exploratory and Confirmatory Bifactor Modeling. AB - The Perceived Stress Scale (PSS) is a popular instrument for measuring the degree to which individuals appraise situations in their lives as excessively uncontrollable and overloaded. Despite its widespread use (e.g., for evaluating intervention effects in stress management studies), there is still no agreement on its factor structure. Hence, the aim of the present study was to examine the dimensionality, measurement invariance (i.e., across gender, samples, and time), reliability, and validity of the PSS. Data from 11,939 German adults (73% women) were used to establish an exploratory bifactor model for the PSS with one general and two specific factors and to cross-validate this model in a confirmatory bifactor model. The model displayed strong measurement invariance across gender and was replicated in Study 2 in data derived from six randomized controlled trials investigating a web-based stress management training. In Study 2 (overall N = 1,862), we found strong temporal invariance. Also, our analyses of concurrent and predictive validity showed associations with depressive symptoms, anxiety, and insomnia severity for the three latent PSS factors. These results show the implications of the bifactor structure of the PSS that might be of consequence in empirical research. PMID- 28627222 TI - Reply: Extensive Bruising and Elevated Rivaroxaban Plasma Concentration in a Patient Receiving Cobicistat-Boosted Elvitegravir. PMID- 28627221 TI - RETRACTED: Management and Family Burdens Endorsed by Parents of Youth <7 Years Old With Type 1 Diabetes. PMID- 28627223 TI - Advances in derivatization approaches for increasing the sensitivity of small molecules. PMID- 28627224 TI - Real-Time Smart Textile-Based System to Monitor Pressure Offloading of Diabetic Foot Ulcers. AB - BACKGROUND: The lifetime risk of developing a diabetic foot ulcer (DFU) is at least 25%. A DFU carries a 50% risk for infection and at least 20% of those receive some form of amputation. The most significant parameter that prevents or delays ulcer healing is high plantar pressure. To improve the patient's healing process, the DFU's plantar pressure should remain cumulatively low. Therefore, a tool that continuously measures the DFU loading, and provides real-time feedback can improve the healing outcome. METHODS: We report the development of a system capable of continuously measuring the pressure, which could have applications to monitor DFU. The system contains a textile pressure sensor attached to a stretchable band, hardware that collects data and transmits them via Bluetooth to a phone, an app that gathers the data and stores them in the cloud, and a web dashboard that displays the data to the clinician. The sensor was characterized in vitro using the system, and the web-dashboard was developed and tested on simulated patient data. RESULTS: We demonstrate the feasibility of developing the system and characterize the pressure response of the device. As a result, we demonstrate a viable method for monitoring DFU off-loading in real time. CONCLUSIONS: The presented study demonstrates the feasibility to develop a simple, modular wearable system that opens up new possibilities for diabetic foot ulcer care by providing a way of monitoring the pressure under the ulcer in real time. PMID- 28627225 TI - The Relationships Between BNP and Neurocardiac Injury Severity, Noninvasive Cardiac Output, and Outcomes After Aneurysmal Subarachnoid Hemorrhage. AB - INTRODUCTION: Neurocardiac injury, a type of myocardial dysfunction associated with neurological insult to the brain, occurs in 31-48% of aneurysmal subarachnoid hemorrhage (aSAH) patients. Cardiac troponin I (cTnI) is commonly used to diagnose neurocardiac injury. Brain natriuretic peptide (BNP), another cardiac marker, is more often used to evaluate degree of heart failure. The purpose of this study was to examine the relationships between BNP and (a) neurocardiac injury severity according to cTnI, (b) noninvasive continuous cardiac output (NCCO), and (c) outcomes in aSAH patients. METHOD: This descriptive longitudinal study enrolled 30 adult aSAH patients. Data collected included BNP and cTnI levels and NCCO parameters for 14 days and outcomes (modified Rankin Scale [mRS] and mortality) at discharge and 3 months. Generalized estimating equations were used to evaluate associations between BNP and cTnI, NCCO, and outcomes. RESULTS: BNP was significantly associated with cTnI. For every 1 unit increase in log BNP, cTnI increased by 0.05 ng/ml ( p = .001). Among NCCO parameters, BNP was significantly associated with thoracic fluid content ( p = .0003). On multivariable analyses, significant associations were found between BNP and poor mRS. For every 1 unit increase in log BNP, patients were 3.16 times more likely to have a poor mRS at discharge ( p = .021) and 5.40 times more likely at 3 months ( p < .0001). CONCLUSION: There were significant relationships between BNP and cTnI and poor outcomes after aSAH. BNP may have utility as a marker of neurocardiac injury and outcomes after aSAH. PMID- 28627226 TI - Light Absorptive Properties of Articular Cartilage, ECM Molecules, Synovial Fluid, and Photoinitiators as Potential Barriers to Light-Initiated Polymer Scaffolding Procedures. AB - Objective Many in vivo procedures to repair chondral defects use ultraviolet (UV) photoinitiated in situ polymerization within the cartilage matrix. Chemical species that absorb UV light might reduce the effectiveness of these procedures by acting as light absorption barriers. This study evaluated whether any of the individual native biochemical components in cartilage and synovial fluid interfered with the absorption of light by common scaffolding photosensitizers. Materials UV-visible spectroscopy was performed on each major component of cartilage in solution, on bovine synovial fluid, and on four photosensitizers, riboflavin, Irgacure 2959, quinine, and riboflavin-5'-phosphate. Molar extinction and absorption coefficients were calculated at wavelengths of maximum absorbance and 365 nm. Intact articular cartilage was also examined. Results The individual major biochemical components of cartilage, Irgacure 2959, and quinine did not exhibit a significant absorption at 365 nm. Riboflavin and riboflavin-5' phosphate were more effectual light absorbers at 365 nm, compared with the individual native species. Intact cartilage absorbed a significantly greater amount of UV light in comparison with the native species. Conclusion Our results indicate that none of the individual native species in cartilage will interfere with the absorption of UV light at 365 nm by these commonly used photoinitiators. Intact cartilage slices exhibited significant light absorption at 365 nm, while also having distinct absorbance peaks at wavelengths less than 300 nm. Determining the UV absorptive properties of the biomolecules native to articular cartilage and synovial fluid will aid in optimizing scaffolding procedures to ensure sufficient scaffold polymerization at a minimum UV intensity. PMID- 28627228 TI - Affinity extraction LC-MS for small-molecule drug quantification: considerations, challenges and potential applications. PMID- 28627227 TI - Smarter Sole Survival: Will Neuropathic Patients at High Risk for Ulceration Use a Smart Insole-Based Foot Protection System? AB - OBJECTIVE: This study examined adherence to alert-based cues for plantar pressure offloading in patients with diabetic foot disease. METHOD AND DESIGN: Participants (n = 17) with in diabetic foot remission (history of neuropathic ulceration) were instructed to wear a smart insole system (the SurroSense Rx, Orpyx Medical Technologies Inc, Calgary, Canada) over a three-month period. This device is designed to cue offloading to manage unprotected sustained plantar pressures in an effort to prevent foot ulceration. A successful response to an alert was defined as pressure offloading, which occurred within 20 minutes of the alert onset. Patient adherence, defined as daily hours of device wear, was determined using sensor data and patient questionnaires. Changes in these parameters were assessed monthly. RESULTS: Patients demonstrating increased adherence over the course of the study received more alerts (0.82 +/- 0.31 alerts/hour) than patients whose adherence did not improve (0.36 +/- 0.46 alerts/hour, P = .156). By the final stages of the study, participants who had received at least one alert every two hours were more adherent with offloading than participants who received fewer alerts (52.5 +/- 4.1% vs 24.7 +/- 22.4%, P = .043). Furthermore, duration of time from alert generation to successful offloading was significantly greater in the group receiving fewer alerts. This was measured in the third month with an effect size Cohen's d = 1.739, P = .043. CONCLUSION: The results suggest a minimum number of alerts (one every two hours) is required for patients with diabetic neuropathy to optimally respond to offloading cues from a smart insole system. PMID- 28627230 TI - Relationship between community hospital versus pre-hospital location of randomisation and clinical outcomes in ST-elevation myocardial infarction patients: insights from the Stream study. AB - AIMS: The STREAM study randomly assigned ST-elevation myocardial infarction (STEMI) patients to receive a pharmacoinvasive versus primary percutaneous coronary intervention reperfusion strategy. We assessed whether there was an association between outcomes based on randomisation at a community hospital versus a prehospital location. METHODS/RESULTS: Community hospital patients (358/1866 (19.2%)) were compared to prehospital patients and their outcomes categorised into pharmacoinvasive according to their treatment assignment. Compared to prehospital patients, community hospital patients had more diabetes (17.8% vs. 11.5%, P=0.001), higher Killip Class >1 (9.4% vs. 5.0%, P=0.002) and thrombolysis in myocardial infarction risk scores ?5 (18.2% vs. 12.4%, P=0.005). The 30-day primary endpoint (death, shock, congestive heart failure and re infarction) for community hospital patients was 14.9% versus 13.2% for prehospital patients ( P=0.403). Community hospital pharmacoinvasive patients tended to receive less rescue (35.1% vs. 42.8%, P=0.062); when deployed their rescue was delayed 43 minutes. Community hospital patients undergoing primary percutaneous coronary intervention experienced a delay of 31 minutes versus prehospital patients. Pharmacoinvasive patients receiving scheduled angiography from a community hospital and prehospital patients had comparable times to angiography (17.7 vs. 18.7 hours) and low event rates (6.2% vs. 8.0%). Although the interaction between randomisation location and treatment received on the primary endpoint was not significant ( Pinteraction=0.065) those pharmacoinvasive patients requiring rescue from community hospitals had worse outcomes than prehospital rescue patients (odds ratio 2.28, 95% confidence interval 1.16-4.49). CONCLUSION: Within STREAM, STEMI patients randomly assigned at community hospitals had a higher baseline risk but similar outcomes compared to those studied prehospital patients irrespective of successful pharmacoinvasive therapy or primary percutaneous coronary intervention. However, worse outcomes in the pharmacoinvasive patients requiring rescue in community hospitals emphasises their need for immediate transfer to a percutaneous coronary intervention-capable hospital. PMID- 28627229 TI - Cobicistat Versus Ritonavir: Similar Pharmacokinetic Enhancers But Some Important Differences. AB - OBJECTIVE: To describe properties of cobicistat and ritonavir; compare boosting data with atazanavir, darunavir, and elvitegravir; and summarize antiretroviral and comedication interaction studies, with a focus on similarities and differences between ritonavir and cobicistat. Considerations when switching from one booster to another are discussed. DATA SOURCES: A literature search of MEDLINE was performed (1985 to April 2017) using the following search terms: cobicistat, ritonavir, pharmacokinetic, drug interactions, booster, pharmacokinetic enhancer, HIV, antiretrovirals. Abstracts from conferences, article bibliographies, and product monographs were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language studies or those conducted in humans were considered. DATA SYNTHESIS: Similar exposures of elvitegravir, darunavir, and atazanavir are achieved when combined with cobicistat or ritonavir. Cobicistat may not be as potent a CYP3A4 inhibitor as ritonavir in the presence of a concomitant inducer. Ritonavir induces CYP1A2, 2B6, 2C9, 2C19, and uridine 5'-diphospho-glucuronosyltransferase, whereas cobicistat does not. Therefore, recommendations for cobicistat with comedications that are extrapolated from studies using ritonavir may not be valid. Pharmacokinetic properties of the boosted antiretroviral can also affect interaction outcome with comedications. Problems can arise when switching patients from ritonavir to cobicistat regimens, particularly with medications that have a narrow therapeutic index such as warfarin. CONCLUSIONS: When assessing and managing potential interactions with ritonavir- or cobicistat-based regimens, clinicians need to be aware of important differences and distinctions between these agents. This is especially important for patients with multiple comorbidities and concomitant medications. Additional monitoring or medication dose adjustments may be needed when switching from one booster to another. PMID- 28627231 TI - A Novel Risk Scoring System to Predict Cardiovascular Death in Patients With Acute Myocardial Infarction: CHA2DS2-VASc-CF Score. AB - The present study aimed to determine the long-term prognostic validity of the CHA2DS2-VASc score in patients with acute myocardial infarction (AMI). In addition, we formulated a novel scoring system, the CHA2DS2-VASc-CF (which includes cigarette smoking and a family history of coronary artery disease as risk factors). This study included 4373 consecutive patients with AMI who presented to the emergency department of our hospital and underwent cardiac catheterization procedures between December 2009 and September 2016. Among these patients, 1427 were diagnosed with ST elevation myocardial infarction (STEMI) and 2946 were diagnosed with non-STEMI. The study included 4373 patients. The study population was divided into 2 groups according to the occurrence of cardiovascular death during the follow-up period. Multivariate logistic regression analysis showed that the CHA2DS2-VASc-CF score, CHA2DS2-VASc score, major adverse cardiac events, current cigarette smoking, older age, hypertension, and family history of coronary artery disease were significantly higher, and that the left ventricular ejection fraction and glomerular filtration rate were significantly lower in the cardiovascular death (+) group. Using a cutoff score of >3 for the CHA2DS2-VASc-CF score, long-term cardiovascular death was predicted with a sensitivity of 78.4% and specificity of 76.4%. The CHA2DS2-VASc-CF score is suitable for use in all patients with AMI, regardless of the type of treatment, presence of atrial fibrillation, and type of AMI. This risk score, which is easy to calculate, provides important prognostic data. In the future, we think that interventional cardiologists will be able to use this novel scoring system to identify patients with a high risk of long-term cardiovascular death. PMID- 28627232 TI - Development and Validation of the Self-Awareness of Falls in Elderly Scale Among Elderly Inpatients. AB - The objectives of this study were to develop the Self-Awareness of Falls in Elderly (SAFE) scale and test its reliability and validity among elderly inpatients. A cross-sectional study design and convenience sampling were used to test the validity and reliability of the SAFE scale. Explanatory factor analysis and confirmatory factor analysis yielded an acceptable goodness of model fit, confirming the 21 items in the SAFE scale that were distributed among four factors: awareness of activity safety and environment, awareness of physical functions, awareness of medication, and awareness of cognitive behavior. The values of interrater reliability and Cronbach's alpha were at least .70, indicating that reliability of the SAFE scale was acceptable. The SAFE scale is the first instrument to measure self-awareness of fall risk among high-risk groups. Further management and fall prevention can then be designed to reduce the incidence of falls among elderly people in clinical care. PMID- 28627233 TI - Raman Spectroscopic Detection for Simulants of Chemical Warfare Agents Using a Spatial Heterodyne Spectrometer. AB - Raman spectroscopic detection is one of the suitable methods for the detection of chemical warfare agents (CWAs) and simulants. Since the 1980s, many researchers have been dedicated to the research of chemical characteristic of CWAs and simulants and instrumental improvement for their analysis and detection. The spatial heterodyne Raman spectrometer (SHRS) is a new developing instrument for Raman detection that appeared in 2011. It is already well-known that SHRS has the characteristics of high spectral resolution, a large field-of-view, and high throughput. Thus, it is inherently suitable for the analysis and detection of these toxic chemicals and simulants. The in situ and standoff detection of some typical simulants of CWAs, such as dimethyl methylphosphonate (DMMP), diisopropyl methylphosphonate (DIMP), triethylphosphate (TEP), diethyl malonate (DEM), methyl salicylate (MES), 2-chloroethyl ethyl sulfide (CEES), and malathion, were tried. The achieved results show that SHRS does have the ability of in situ analysis or standoff detection for simulants of CWAs. When the laser power was set to as low as 26 mW, the SHRS still has a signal-to-noise ratio higher than 5 in in situ detection. The standoff Raman spectra detection of CWAs simulants was realized at a distance of 11 m. The potential feasibility of standoff detection of SHRS for CWAs simulants has been proved. PMID- 28627234 TI - Detection of the Freshness State of Cooked Beef During Storage Using Hyperspectral Imaging. AB - The freshness of meat products during storage has received unprecedented attention. This study was conducted to investigate the feasibility of a hyperspectral imaging (HSI) technique to determine the freshness state of cooked beef during storage and identify the contaminated areas on the surface of spoiled samples. Hyperspectral images of cooked beef were acquired in the wavelength range of 400-1000 nm and the freshness state of all samples was divided into three classes (freshness, medium freshness, and spoilage) using the measured total viable count (TVC) of bacteria. Fifteen feature spectra variables were extracted by random frog (RF); based on this, six optimal wavelength variables were further selected by correlation analysis (CA). Partial least squares (PLS) and least squares-support vector machine (LS-SVM) classification models were established using different spectral variables. The results indicated that the performance of the RF-CA-LS-SVM classification model with a high overall classification accuracy of 97.14%, the results of sensitivity and specificity in the range of 0.92-1, and the kappa coefficient of 0.9575 in the prediction set were obviously superior to other models. Spoiled samples were further obtained using a RF-CA-LS-SVM model, and then six feature images were extracted and further fused by principal component analysis (PCA). A PC3 image was used to segment successfully the contaminated areas from normal areas of cooked beef images using the Otsu threshold algorithm. The results demonstrated that HSI has great potential in classifying the freshness of cooked beef and identifying the contaminated areas. This current study provides a foundational basis for the classification and grading of meat production in further online detection. PMID- 28627235 TI - Translating Guidelines Into Practice: Interpreting the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk. AB - OBJECTIVE: In 2016, the American College of Cardiology released a decision pathway, based on expert consensus, to guide use of non-statin agents in the management of atherosclerotic cardiovascular disease risk. The purpose of this article is to assist practitioners, health systems and managed care entities with interpreting this consensus statement in order to simplify implementation of the recommendations into patient care. METHODS: Major themes from the consensus statement are briefly summarized and explained. Drug therapy recommendations are condensed into a single algorithm, while tables correlate each recommended regimen with the appropriate patient population from both a patient-level and systems-level perspective. Finally, a patient case with evidence-based decision support is explored. RESULTS: These tools allow practitioners to make appropriate patient-specific decisions about the use of non-statin pharmacotherapy and enable health systems and managed care entities to more readily identify guideline appropriate use of these agents upon review of patient profiles or prescribing patterns. CONCLUSION: This article provides resources for healthcare providers that facilitate uptake of these recommendations into clinical practice. PMID- 28627236 TI - Estrogen Receptor 1 ( ESR1) Gene Polymorphisms and Obesity Phenotypes in a Population of Young Adults. AB - Obesity is considered an increasingly serious health problem determined by multiple genetic and environmental factors. Estrogens have been found to play a major role in body weight and adiposity regulation through estrogen receptor 1 ( ESR1). The aim of this study was to determine whether genotype and haplotype frequencies of ESR1 polymorphisms are associated with body composition measures in a population of 572 young adults. A lack of significant association between genotypes of ESR1 gene polymorphisms and obesity phenotypes was seen after adjustment for confounding factors. Linkage disequilibrium (LD) analysis identified a single LD block for the ESR1 gene including PvuII and XbaI single nucleotide polymorphisms (SNPs) (pairwise r2 = .66). None of the haplotypes identified revealed statistically significant associations with any of the obesity phenotypes. Our results suggest that polymorphisms of the ESR1 gene do not contribute significantly to the genetic risk for obesity phenotypes in a population of young Caucasian adults. PMID- 28627237 TI - Characteristic Analysis of Complementary and Alternative Medicine in Randomized Controlled Trials of Oncology: A Comparison of Published Studies. AB - BACKGROUND: Complementary and alternative medicine (CAM) has been widely used by cancer patients and oncologists in the past decades. The present study aimed to examine and compare the characteristics and registration status of published studies in a sample of recently published CAM randomized controlled trial (RCT) reports of oncology in leading journals of 3 categories: general and internal medicine (GIM), clinical oncology (CO), and CAM. METHODS: Articles published in the top 5 journals of the 3 categories from 2006 to 2015 were searched in PubMed. Basic characteristics, registration information, impact factor, and citations were identified and extracted from the included RCTs. Data were summarized by frequency, mean, and median and compared using chi2 test and Kruskal-Wallis H test. RESULTS: A total of 59 RCTs were included; among them, 34 (58%) could be identified with a registration number. GIM journals (15) enjoyed the highest average number of citations per article, followed by CO (12) and CAM (3) journals ( P < .0001). ClinicalTrials.gov was the most popular registry for these RCTs. Of the RCTs registered in ClinicalTrials.gov , 24% (4/17) of the published studies in CO journals put their results in the registry; however, no study in GIM and CAM journals put the result in the registry ( P = .372). CONCLUSION: The top GIM, CO, and CAM journals rarely published CAM RCTs of oncology from 2006 to 2015, and the CAM articles of oncology were less cited. However, there was a clear improvement in the trial registration rate over the past decades. PMID- 28627238 TI - Immune responses to killed reassorted influenza virus supplemented with natural adjuvants. AB - In this study, we investigated the immunomodulatory effects of a supplemented killed influenza virus (V) by Echinacea purpurea (E) and Nigella sativa (N) extracts and effect of changing the route of immunization from intramuscular (IM) to intraperitoneal (IP). At the 2nd-, 3rd- and 4th-week post-IM immunizations (WPIMI), the supplemented V with N (VN) induced the most significant IgM response unlike N alone. At the 2nd WPIMI, V or VN induced the highest significant IgG levels. At the 2nd-week post-IP immunization (WPIPI), E and VN induced the most significant IgG levels. Both at the 3rd and 4th WPIMI or WPIPI, various treatments induced significant increases in IgG. At the 4th WPIMI, E, V, and V with E (VE) induced significant increases in the CD4+ thymocytes while all IP treatments caused significant increase in their counts. V and VN induced the most significant IM induction of CD8+ thymocytes while their best IP stimulation was induced by N, VE, and VN. At the 4th WPIMI, various treatments caused significant increases in the mesenteric lymph node (MLN) CD4+, CD8+ counts. WPIPI with V or VE caused significant increases in both the CD4+- and CD8+ MLN cells, whereas VN significantly induced CD8+ MLN cells only. WPIPI with various treatments caused significant increases in the B-cell counts and the peak was obtained by VN. PMID- 28627239 TI - Complex multicellular functions at a unicellular eukaryote level: Learning, memory, and immunity. AB - According to experimental data, eukaryote unicellulars are able to learn, have immunity and memory. Learning is carried out in a very primitive form, and the memory is not neural but an epigenetic one. However, this epigenetic memory, which is well justified by the presence and manifestation of hormonal imprinting, is strong and permanent in the life of cell and also in its progenies. This memory is epigenetically executed by the alteration and fixation of methylation pattern of genes without changes in base sequences. The immunity of unicellulars is based on self/non-self discrimination, which leads to the destruction of non self invaders and utilization of them as nourishment (by phagocytosis). The tools of learning, memory, and immunity of unicellulars are uniformly found in plasma membrane receptors, which formed under the effect of dynamic receptor pattern generation, suggested by Koch et al., and this is the basis of hormonal imprinting, by which the encounter between a chemical substance and the cell is specifically memorized. The receptors and imprinting are also used in the later steps of evolution up to mammals (including man) in each mentioned functions. This means that learning, memory, and immunity can be deduced to a unicellular eukaryote level. PMID- 28627240 TI - Quercetin Has Antimetastatic Effects on Gastric Cancer Cells via the Interruption of uPA/uPAR Function by Modulating NF-kappab, PKC-delta, ERK1/2, and AMPKalpha. AB - Gastric cancer (GC) is a malignancy with few effective treatment options after metastasis occurs. Quercetin (Qu) intake has been associated with reduced incidence and slow development of GC, probably due to its anti-proliferative and apoptotic effects, but it is unclear whether Qu can inhibit the metastatic activity. The urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system plays an important role in cancer metastasis. In this study, we measured both uPA activity and uPAR expression in GC and pericarcinous tissues, and we investigated the correlation between uPAR expression and the migratory and invasive activities of various GC cell lines. GC BGC823 and AGS cells were subjected to treatment with 10 MUM Qu for 72 hours and uPAR knockdown, alone or in combination, before evaluating cell metastasis. The results showed that uPA activity and uPAR expression were higher in GC tissues than in pericarcinous tissues. Migratory and invasive activities of GC cell lines positively correlated with uPAR expression. Qu treatment decreased BGC823 and AGS cell migration and invasion, accompanied by reduced uPA and uPAR protein expression. Both Qu treatment and uPAR knockdown decreased matrix metalloproteinase-2 and -9 activity and blocked Pak1-Limk1 cofilin signaling. Qu treatment was associated with inhibition of NF-kappab, PKC delta, and ERK1/2, and with AMPKalpha activation. Specific inhibitors of NF kappab, PKC, and ERK1/2, and an AMPKalpha activator suppressed uPA and uPAR expression in GC cells. Collectively, Qu showed an antimetastatic effect on GC cells via the interruption of uPA/uPAR function and modulation of NF-kappab, PKC delta, ERK1/2, and AMPKalpha. This suggests that Qu is a promising agent against GC metastasis. PMID- 28627241 TI - Neonatal Intensive Care Unit Layout and Nurses' Work. AB - Neonatal intensive care units (NICUs) remain one of the few areas in hospitals that still use an open bay (OPBY) design for patient stays greater than 24 hr, housing multiple infants, staff, and families in one large room. This creates high noise levels, contributes to the spread of infection, and affords families little privacy. These problems have given rise to the single-family room NICU. This represents a significant change in the care environment for nurses. This literature review answers the question: When compared to OPBY layout, how does a single family room layout impact neonatal nurses' work? Thirteen studies published between 2006 and 2015 were located. Many studies reported both positive and negative effects on nurses' work and were therefore sorted by their cited advantages and disadvantages. Advantages included improved quality of the physical environment; improved quality of patient care; improved parent interaction; and improvements in nurse job satisfaction, stress, and burnout. Disadvantages included decreased interaction among the NICU patient care team, increased nurse workload, decreased visibility on the unit, and difficult interactions with family. This review suggests that single-family room NICUs introduce a complex situation in which trade-offs occur for nurses, most prominently the trade-off between visibility and privacy. Additionally, the literature is clear on what elements of nurses' work are impacted, but how the built environment influences these elements, and how these elements interact during nurses' work, is not as well understood. The current level of research and directions for future research are also discussed. PMID- 28627242 TI - The Effects of a Mindfulness Meditation Program on Quality of Life in Cancer Outpatients: An Exploratory Study. AB - OBJECTIVE: Numerous studies have investigated the efficacy of mindfulness meditation (MM) in managing quality of life (QoL) in cancer populations, yet only a few have studied the Asian population. The aim of this exploratory study is to evaluate the effect of a MM program on the QoL outcomes in Taiwanese cancer outpatients. METHODS: Patients with various cancer diagnoses were enrolled and assigned to the MM group and usual care (UC) group. The meditation intervention consisted of 3 sessions held monthly. The outcomes of the whole intervention were measured using the World Health Organization Quality of Life (WHOQOL-BREF) instrument. RESULTS: A total of 35 participants in the MM group and 34 in the UC group completed the study. The results showed that the postintervention scores were significantly higher than the preintervention scores in the MM group. In the UC group, there was no significant difference between preintervention and postintervention scores, except for the lower environment domain scores. There was no significant difference between the follow-up scores and postintervention scores in the MM group, indicating that improvement can be maintained for 3 months after completing the MM course. CONCLUSIONS: The present study provides preliminary outcomes of the effects on the QoL in Taiwanese cancer patients. The results suggest that MM may serve as an effective mind-body intervention for cancer patients to improve their QoL, and the benefits can persist over a 3-month follow-up period. This occurred in a diverse cancer population with various cancer diagnoses, strengthening the possibility of general use. PMID- 28627243 TI - Hypoglycemia and Clinical Outcomes in Hospitalized Patients With Diabetes: Does Association With Adverse Outcomes Remain When Number of Glucose Tests Performed Is Accounted For? AB - BACKGROUND: Hypoglycemia is associated with increased length of stay in hospital patients, but previous studies have not considered the confounding effect of increased hypoglycemia detection associated with increased capillary blood glucose (CBG) measurement in prolonged admissions. We aimed to determine the effect of recorded hypoglycemia on length of stay of hospital inpatients (LOS) when this mathematical association is subtracted. METHODS: CBG data were analyzed for inpatients within our health board area (01/2009-01/2015). A simulated CBG data set was generated for each patient with an identical sampling frequency to the measured CBG data set. The mathematical component of increased LOS was determined using the simulated data set. Subtraction of this confounding mathematical association was used to provide measurement of the true clinical association between recorded hypoglycemia (CBG < 4 mmol [< 72mg/dl]) and LOS. RESULTS: A total of 196 962 admissions of 52 475 individuals with known diabetes were analyzed. 68 809 admissions of 29 551 individuals had >4 CBG measurements made and were included in analysis. After subtraction of the mathematical association of increased sample number, the clinical effect of recorded hypoglycemia is reduced-but persists-compared to previous studies. 1-2 days with recorded hypoglycemia has a relatively minor effect on LOS. LOS increases rapidly if there are >=3 days with recorded hypoglycemia, with an increase of 0.75 days LOS per additional day with hypoglycemia. CONCLUSIONS: This technique increases accuracy of economic modeling of the impact of hypoglycemia on health care systems. This could assist study of the impact of hypoglycemia on other outcomes by factoring for bias of increased sample numbers. PMID- 28627244 TI - A comparative study of Mentha arvensis L. and Mentha haplocalyx Briq. by HPLC. AB - We have developed a new method to simultaneously determine five marker compounds in Menthae Herba via HPLC/PDA - including hesperidin (1), rosmarinic acid (2), diosmin (3), didymin (4) and buddleoside (5). The newly developed method was successfully used to analyse for two species (Mentha arvensis L. and Mentha haplocalyx Briq.) of Menthae Herba, and the satisfactory results were obtained from the validation of developed method. The pattern analysis could greatly discriminate between M. arvensis L. and M. haplocalyx Briq. In conclusion, the proposed HPLC/PDA method is suitable for quality evaluation of Menthae Herba. PMID- 28627245 TI - Phytochemical screening and in-vitro evaluation of pharmacological activities of peels of Musa sapientum and Carica papaya fruit. AB - Aqueous, absolute and 80% ethanolic extract of fruit peels of Musa sapientum and Carica papaya were investigated for their antibacterial activity, measured by disc diffusion method and antioxidant activity, measured by four different methods. Papaya and banana peels were found to contain terpenoids, tannins, alkaloids, saponins steroid, phenols, fixed oils and fats. 80% ethanolic extract of banana peel was found to contain highest total phenolic content (TPC), total flavonoid content (TFC) and antioxidant activity but in papaya peel, highest TPC and reducing activity was shown by water extract while, TFC and radical scavenging activity was given by 80% ethanolic extract. In banana, water extract showed highest antibacterial activity against tested bacteria while in case of papaya, absolute ethanolic extract showed highest antibacterial activity. The present study revealed that peels of banana and papaya fruits are potentially good source of antioxidant and antibacterial agents. PMID- 28627246 TI - How Much Hemolysis Is Acceptable When Undertaking Deep Lancing for Finger Stick Derived Capillary Plasma Glucose Measurement? PMID- 28627247 TI - Exploring Knowledge, Attitudes, and Practice Associated With Meditation Among Patients With Melanoma. AB - AIM: To explore the knowledge, attitudes, and practices associated with meditation among people with melanoma and investigate the relationship between perceived stress, trait mindfulness, and meditation. Factors associated with interest to participate in an online meditation program were also explored. METHODS: A survey-based cross-sectional study of 291 patients attending a melanoma outpatient clinic assessed knowledge of meditation, attitudes toward meditation using Determinants of Meditation Practice Inventory (DMPI), and meditation experience. Perceived stress and trait mindfulness were measured using the Perceived Stressed Scale and Cognitive and Affective Mindfulness Scale, respectively. RESULTS: Participants who had tried meditation (43%) were likely to be younger, female, and have completed higher education or be employed. Perceived stress score was higher among women, younger participants, and those treated in the past year but did not differ by melanoma stage. Participants reported a good understanding of the potential benefits of meditation, but even among people with meditation experience, common misconceptions prevailed. The main barrier to meditation was a perceived lack of knowledge about meditation . Higher DMPI scores were associated with lower education, moderate to low access to service centers, or living in disadvantaged neighborhoods . Participants practicing meditation that involved self-reflection reported less stress and higher trait mindfulness compared with participants practicing another type of meditation. People interested in participating in an online meditation-based program reported higher perceived stress than those not interested. CONCLUSION: A meditation-based intervention teaching self-reflective practices, targeted at people with melanoma, may have the potential to assist them with managing their stress. PMID- 28627248 TI - Methodological challenges involved in compiling the Nahua pharmacopeia. AB - Recent work in the history of science has questioned the Eurocentric nature of the field and sought to include a more global approach that would serve to displace center-periphery models in favor of approaches that take seriously local knowledge production. Historians of Iberian colonial science have taken up this approach, which involves reliance on indigenous knowledge traditions of the Americas. These traditions present a number of challenges to modern researchers, including availability and reliability of source material, issues of translation and identification, and lack of systematization. This essay explores the challenges that emerged in the author's attempt to compile a pre-contact Nahua pharmacopeia, the reasons for these challenges, and the ways they may - or may not - be overcome. PMID- 28627249 TI - Astrology in court: The Spanish Inquisition, authority, and expertise. AB - Astrology, its legitimacy, and the limits of its acceptable practice were debated in sixteenth- and seventeenth-century Europe. Many of the related arguments were mediated by the work of Giovanni Pico della Mirandola and the responses to it. Acknowledging the complexities of the relationship between astrological ideas and Christian teachings, this paper focuses on the Catholic debates by specifically considering the decisions about astrology taken by the Spanish Inquisition. The trials of astrologers are examined with the aim of understanding the role of experts in astrology in early modern Spain. This study brings into view the specific nature of the debate on astrology in Spain, the consequences of the actions of the Inquisition and the social control it exerted. The historical events discussed comprise a particular case and also mirror the general debates about astrology taking place in early modern Europe. The experts' opinions expressed in trials and in reports about the discipline received by the Inquisition reveal two key traits of the debate: the dispute about who had the authority to decide on the legitimacy of astrology and the disagreement about what constituted natural and judicial astrological practices. These led to different opinions about what was to be done with each defendant and about what content in their books ought to be forbidden. PMID- 28627250 TI - Exploring the Frequency Domain of Continuous Glucose Monitoring Signals to Improve Characterization of Glucose Variability and of Diabetic Profiles. AB - BACKGROUND: Continuous glucose monitoring (CGM) devices measure interstitial glucose concentrations (normally every 5 minutes), allowing observation of glucose variability (GV) patterns during the whole day. This information could be used to improve prescription of treatments and of insulin dosages for people suffering diabetes. Previous efforts have been focused on proposing indices of GV either in time or glucose domains, while the frequency domain has been explored only partially. The aim of this work is to explore the CGM signal in the frequency domain to understand if new indexes or features could be identified and contribute to a better characterization of glucose variability. METHODS: The direct fast Fourier transform (FFT) and the Welch method were used to analyze CGM signals from three different profiles: people at risk of developing type 2 diabetes (P@R), T2D patients, and type 1 diabetes (T1D) patients. RESULTS: The results suggests that features extracted from the FFT (ie, the localization and power of the maximum peak of the power spectrum and the bandwidth at 3 dB) are able to provide a characterization for all the three populations under study compared with the Welch approach. CONCLUSIONS: Such preliminary results can represent a good insight for futures investigations with the possibility of building and using new indexes of glucose variability based on the frequency features. PMID- 28627251 TI - Direct Liquid Chromatography/Mass Spectrometry Analysis for Complete Characterization of Recombinant Adeno-Associated Virus Capsid Proteins. AB - The requirement for robust analytical methods to characterize adeno-associated virus (AAV) vectors is immediate, as the field advances more AAV gene therapies into the clinic and onto commercialization. AAV capsid proteins (VPs) are critical for viral infectivity and vector potency. Thus, complete characterization of the constituent viral capsid proteins of AAV vectors, including their sequences and post-translational modifications (PTMs), is highly recommended to ensure AAV product quality and consistency. Typically, SDS-PAGE analysis followed by in-gel enzymatic digestion and liquid chromatography/tandem mass spectrometry (LC/MS/MS) is used for the characterization of viral capsid proteins. However, due to the limited recovery of digested peptides from the gel, determination of N-terminal sequences of VPs has not been reported to date. In this study, a direct liquid chromatography/mass spectrometry (LC/MS) intact protein analysis was developed to characterize viral capsid proteins in a variety of AAV serotypes. Both N- and C-terminal sequences of six AAV serotypes have been identified based on accurate mass measurement. This method can be used to confirm the identity of AAV serotype and monitor potential capsid protein heterogeneity. Complete sequence confirmation of AAV2 VPs was achieved through LC/MS/MS analysis of peptides generated using multiple enzymatic digestions. LC/MS/MS analysis confirmed the sequences for both N- and C-termini of capsid VPs and revealed acetylation on the N-termini of VP1 and VP3, consistent with LC/MS intact protein analysis. PMID- 28627252 TI - Phytochemical and antioxidant properties of some Cassia species. AB - In this study, the antioxidant activity of aqueous and ethanol extracts of four plants from the genus Cassia were evaluated by various antioxidant assays, including ferric reducing antioxidant power (FRAP), DPPH free radical scavenging, metal chelating activity, phosphomolybdenum reducing power, hydrogen peroxide radical scavenging, hydroxyl radical scavenging, deoxyribose degradation and beta carotene bleaching assay. The various antioxidant activities were compared to standard antioxidant such as ascorbic acid. All the extracts showed antioxidant activity in the tested methods. Among the four species, Cassia auriculata has been found to possess highest activity in most of the tested models. In addition to the antioxidant activity, the total phenolics and flavonoids were measured in the extracts. The ethanolic extract exhibited highest phenolics and flavonoid contents and had also shown potent antioxidant activity in comparison to the aqueous extracts. The possible antioxidant mechanism of the ethanol extract can be due to its hydrogen or electron donating and direct free radical scavenging properties. Hence, the ethanol extract represents a source of potential antioxidants that could be used in pharmaceutical industries. PMID- 28627253 TI - Protective effects of quercetin on nicotine induced oxidative stress in 'HepG2 cells'. AB - Nicotine is a natural component of tobacco plants and is responsible for the addictive properties of tobacco. Nicotine has been recognized to result in oxidative stress by inducing the generation of reactive oxygen species (ROS). The purpose of this work was to estimate the hepatotoxicity effect of nicotine on viability and on antioxidant defense system in cultures of HepG2 cell line and the other hand, ameliorative effect of quercetin (Q) as an antioxidant was analyzed. Nicotine induced concentration dependent loss in HepG2 cell line viability. The results indicated that nicotine decreased activity of superoxide dismutase (SOD) and glutathione reductase (GR) and increased activities of catalase (CAT) and glutathione peroxidase (GPx) and glutathione (GSH) content in the HepG2 cells. Q significantly increased activity of SOD, GR and GSH content and decreased activity of GPX in nicotine + Q groups. Our data demonstrate that Q plays a protective role against the imbalance elicited by nicotine between the production of free radicals and antioxidant defense systems, and suggest that administration of this antioxidant may find clinical application where cellular damage is a consequence of ROS. PMID- 28627254 TI - Randomized Trial of a Lifestyle Physical Activity Intervention for Breast Cancer Survivors: Effects on Transtheoretical Model Variables. AB - This study examined whether a physical activity intervention affects transtheoretical model (TTM) variables that facilitate exercise adoption in breast cancer survivors. Sixty sedentary breast cancer survivors were randomized to a 6-month lifestyle physical activity intervention or standard care. TTM variables that have been shown to facilitate exercise adoption and progress through the stages of change, including self-efficacy, decisional balance, and processes of change, were measured at baseline, 3 months, and 6 months. Differences in TTM variables between groups were tested using repeated measures analysis of variance. The intervention group had significantly higher self efficacy ( F = 9.55, p = .003) and perceived significantly fewer cons of exercise ( F = 5.416, p = .025) at 3 and 6 months compared with the standard care group. Self-liberation, counterconditioning, and reinforcement management processes of change increased significantly from baseline to 6 months in the intervention group, and self-efficacy and reinforcement management were significantly associated with improvement in stage of change. The stage-based physical activity intervention increased use of select processes of change, improved self-efficacy, decreased perceptions of the cons of exercise, and helped participants advance in stage of change. These results point to the importance of using a theory-based approach in interventions to increase physical activity in cancer survivors. PMID- 28627255 TI - Retraction Notice. PMID- 28627257 TI - Toward the Development of a Glucose Dehydrogenase-Based Saliva Glucose Sensor Without the Need for Sample Preparation. AB - BACKGROUND: Strict glycemic control is known to be a vital key in the management of diabetes mellitus (DM). However, traditional methods face limitations in their efficacy due to the pain and invasiveness of needle pricking which often discourages DM patients from performing the required number of tests per day. Saliva glucose (SG) sensing has long been considered a noninvasive alternative to blood glucose monitoring for diabetes management, however the sample preparation and sensor detection limit have been deemed as challenges to overcome. Herein, we describe a preliminary clinical validation of a disposable SG sensor without any requirement for sample preparation. METHODS: The sensor utilizes glucose dehydrogenase flavine-adenine dinucleotide (GDH-FAD) in conjunction with disposable screen printed electrodes to measure glucose levels in saliva collected directly from 9 healthy subjects. Cyclic voltammetry and amperometric time (Amp-it) assays were used to develop calibration curves and test subjects. Sensor calibration was performed using simulated saliva at 6.5 pH and 37oC. RESULTS: The lower limit of detection was determined to be 0.11 mg/dL. A lag time of 15 minutes with a positive correlation between SG and BG levels was found, which agrees with literature results. The detected SG ranges from 2.38 to 3.40 mg/dL over a BG range of 90 to 143 mg/dL. CONCLUSION: This is the first reported use of measuring SG with GDH-FAD without prior sample preparation. Upon optimization, the sensor has the potential to serve as a supplement to blood glucose monitoring. PMID- 28627256 TI - Potential Contributions of Antioxidants to Cancer Therapy: Immunomodulation and Radiosensitization. AB - Antioxidants play important roles in the maintenance of cellular integrity and thus are critical in maintaining the homeostasis of the host immune system. A balance between the levels of pro-oxidants and antioxidants defines the cellular fate of genomic integrity via maintaining the redox status of the cells. An aberration in this balance modulates host immunity that affects normal cellular signaling pathways resulting in uncontrolled proliferation of cells leading to neocarcinogenesis. For decades, there have been scientific debates on the use of antioxidants for the treatment of human cancers. This review is focused on current updates on the implications of antioxidant use as adjuncts in cancer therapy with an emphasis on immunomodulation and radiosensitization. PMID- 28627258 TI - New water soluble glycosides of 11-keto-beta-boswellic acid: A paradigm. AB - Though several glycosides of various triterpenes are known, but surprisingly no boswellic acid glycosides are reported so far. With a view to make water soluble boswellic acids, prepared glycosides of 11-keto boswellic acid for the first time. Naturally occurring boswellic acids which are anti-inflammatory agents are lipophylic in nature and thus, become a limiting factor in terms of their bioavailability. Among boswellic acids, 11-keto-beta-boswellic acid is found to exhibit superior biological activity and hence successfully prepared its glucosyl and maltosyl derivatives viz., 11-keto-beta-boswellic acid-24-O-beta-D glucopyranoside (9) and 11-keto-beta-boswellic acid-24-O-alpha-D-glucopyranosyl (1 -> 4)-beta-D-glucopyranoside (15) which are water soluble. Both these compounds are soluble in water to the extent of 10% (w/w) which is very significant. PMID- 28627259 TI - First total synthesis of a novel amide alkaloid derived from Aconitum taipeicum and its anticancer activity. AB - A concise total synthesis of a naturally occurring 3-isopropyl tetrahydropyrrolo[1, 2-a]pyrimidine-2, 4(1H, 3H)-dione (ITPD) isolated from Aconitum taipeicum with a three-step approach was depicted in this study for the first time. Two key intermediates, diethyl isopropylmalonate (2) and pyrrolidin-2 amine (3), being synthsesised separately from initial diethyl malonate (4) and 3, 4-dihydro-2H-pyrrol-5-amine (5), were utilised to obtain the compound entitled ITPD. ITPD showed a promising anticancer activity in vitro on SMMC-7721 cell lines. Flow cytometry and cell cycle analysis revealed that ITPD could induce apoptosis and cell cycle arrest in S phase. The occurrence of apoptosis possibly attributed to the mechanism that ITPD could mediate the mitochondrial pathway through activating caspase-3/9 and increasing the ratio of Bax/Bcl-2 to finally trigger cell apoptosis and DNA damage. Collectively, the possibility to produce sufficient quantity of synthetic ITPD provided the base for further bio evaluation in vivo and in vitro. The bioactive assay suggested that it may be a potential candidate for further chemical optimisation and use in cancer therapy. PMID- 28627260 TI - A novel and efficient synthesis of 3,4-dihydroxyphenylacetic ester and amide derivatives/conjugates and assessment of their antioxidant activity. AB - Phenolic acids, a sub-class of polyphenols, are widely studied. By contrary, 3,4 dihydroxyphenylacetic acid is scarcely studied. For this purpose, a series of 3,4 dihydroxyphenylacetic acid ester and amide derivatives/conjugates were synthesised for the first time. A systematic study has been performed to quantitatively identify the functional groups present in these compounds using different techniques such as 1H NMR, 13C NMR and ESI MS. The synthesised compounds were evaluated for their in vitro antioxidant activity by a DPPH radical-scavenging assay. Their physico-chemical profile is also studied using Molinspiration tool. Among all tested compounds, amidoester 36 showed the best scavenging activity possessing an EC50 17 MUMU and improved physico-chemical properties compared to the parent compound. PMID- 28627261 TI - Maternal Psychological Distress and Perceived Impact on Child Feeding Practices in South Kivu, DR Congo. AB - BACKGROUND: Maternal mental health problems are associated with poor child growth and suboptimal child feeding practices, yet little qualitative research has been conducted to understand mothers' perceptions about how maternal mental ill health and child nutrition are related. OBJECTIVE: The objective of the study was to understand maternal perceptions on sources of psychological distress, and how distress impacts functioning, especially related to childcare and feeding practices among mothers of young children in South Kivu, DR Congo. METHODS: Mothers of young children who were participating in a larger study were eligible. Using purposive sampling, participants were selected if they had high or low levels of psychological distress, based on their mean item score on measures of symptoms of depression, anxiety, and post-traumatic stress. Twenty in-depth interviews and 2 focus group discussions were conducted, with a total of 35 mothers. Key informant interviews were conducted with 5 local health workers. Audio recordings were transcribed and coded, and the analysis was guided by Grounded Theory methodology. RESULTS: Major themes to emerge were that women's husbands were a significant source of distress, with husbands' infidelity, abandonment, and lack of financial support mentioned by participants. Psychological distress resulted in appetite and weight loss, and poor nutritional status made it difficult to breastfeed. Participants perceived psychological distress caused milk insufficiency and difficulty breastfeeding. CONCLUSION: Mothers experiencing psychological distress may need greater support for maternal nutrition and breastfeeding, and engaging fathers through responsible parenting interventions may reduce psychological distress and have a positive impact on child health. PMID- 28627262 TI - A longitudinal study investigating cervical changes during labor using a wireless ultrasound device. AB - PURPOSE: Cervical assessment during digital vaginal examination (DVE) includes assessing cervical dilatation, effacement, position and consistency. Only cervical dilatation during labor has been previously researched. We investigated cervical changes, including cervical dilatation and effacement, using a wireless ultrasound (US) device. MATERIALS AND METHODS: This was a longitudinal study investigating cervical changes during labor using a wireless US device. Twenty five women in labor participated in a serial comparison of cervical dilatation, length and thickness measured during intrapartum transperineal sonography using a wireless mobile US device (SONON) with measurements of cervical dilatation and effacement obtained during serial DVEs. RESULTS: Intrapartum sonography showed strong correlation with DVE in assessing cervical changes during labor including the measurement of cervical dilatation and thickness (p < .001). The failure rate of cervical length image collection was high; therefore, we could not determine the correlation between cervical length and effacement. CONCLUSIONS: We developed a new technique for evaluating effacement with cervical thickness. Cervical dilation and thickness using a transperineal intrapartum US demonstrated significant correlation with DVE findings. The use of a wireless US device is convenient and may be advantageous in the labor ward; however, further research is needed to define the role of this wireless device. PMID- 28627263 TI - Association of interleukin-1A insertion/deletion gene polymorphism and possible high risk factors with non-alcoholic fatty liver disease in Egyptian patients. AB - CONTEXT: Interleukin-1A (IL-1A) is a cytokine involved in inflammatory process. IL-1A (rs3783553) gene polymorphism is comprised in the regulation of IL-1A expression. OBJECTIVE: This study aims to evaluate association of IL-1A (I/D) gene polymorphism with NAFLD and its component traits among Egyptian populations. METHODS: The study included 75 healthy subjects and 75 patients with NAFLD. Different genotypes of IL-1A (I/D) gene polymorphism were determined by PCR-PAGE technique, serum IL-1A level and other biochemical parameters were measured. RESULTS: The major D allele was significantly associated with NAFLD patients (p = .002). DD genotype showed a significant increase in BMI and decrease in HDL-C. Also serum IL-1A was significantly correlated with the DD genotype. Serum IL-1A showed a significant positive correlation with BMI, triglycerides, total cholesterol, LDL-C, VLDL-C and FBG, and a significant negative correlation with HDL-C. CONCLUSIONS: Major D allele of IL-1A (I/D) gene polymorphism is associated with NAFLD in the Egyptian population. PMID- 28627264 TI - Utility of in vitro and in vivo systems for studying the permeability of capsaicin and nonivamide through different intestinal regions. AB - 1. The present study determined and compared the permeability of capsaicin and nonivamide along the length of the intestine in rats. Accordingly, the purpose was to evaluate this synthetic analog as a clinical substitute for capsaicin.. 2. Permeabilities of capsaicin and nonivamide were measured in experiments utilizing Ussing chambers and in vivo methods. Capsaicin concentrations were examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). 3. Both capsaicin (0.80 * 10-6 cm/s) and nonivamide (0.22 * 10-6 cm/s, p > 0.05) had poor permeabilities across the jejunal membrane. The permeability of nonivamide (10.12 * 10-6 cm/s) was significantly greater than that of capsaicin (5.34 * 10-6 cm/s, p < 0.05) across the iliac membrane. In contrast, the permeability of nonivamide (8.42 * 10-6 cm/s) across the colonic membrane was markedly lower than that of capsaicin (14.48 * 10-6 cm/s, p < 0.05). In accordance with the in vitro study, the drug concentration-time curve of nonivamide was significantly higher in the ileum (F = 14.18, p < 0.05) but lower in the colon (F = 11.86, p < 0.05) compared with capsaicin. 4. The results demonstrate that capsaicin and nonivamide exhibit varying permeabilities across several different intestinal tissues. The relevance of such extended investigations to healthcare is underscored by the lower cost of nonivamide versus capsaicin, along with potential application in prevention and management of the disease. PMID- 28627266 TI - Anti-inflammatory effect of a novel formulation of coconut inflorescence sap against ox-LDL induced inflammatory responses in human peripheral blood mononuclear cells by modulating TLR-NF-kappaB signaling pathway. AB - Oxidized low density lipoprotein (ox LDL) induced inflammatory response was reported to play an important role in the pathogenesis of atherosclerosis. The purpose of this study was to explore the anti-inflammatory effect of a novel formulation of coconut inflorescence sap (CSP); COCOZENTM against ox-LDL induced inflammatory responses in human peripheral blood mononuclear cells (hPBMCs). The hPBMCs were isolated from healthy human volunteers and cultured in collagen coated plates at 37 degrees C. The cells were grouped as Group I (Control), Group II (ox-LDL treated) and Group III (ox-LDL + CSP treated). Further analysis of inflammatory markers, reactive oxygen species, mRNA and protein expression levels indicated increased expressions of TLR-4, TNF-alpha, IL-6 and VCAM-1 in ox LDL treated group along with the nuclear translocation of NF-kappaB. Other inflammatory markers such as LOX, PGE2, NO, total COX and lipid peroxidation level were also found to be significantly (p < .05) increased upon Ox-LDL treatment. The treatment with CSP on the other hand was found to down regulate and reverse the ox-LDL-induced alterations indicating its potential anti inflammatory effect on hPBMCs via TLR-NF-kappaB signaling pathway. PMID- 28627265 TI - ATM, radiation, and the risk of second primary breast cancer. AB - PURPOSE: It was first suggested more than 40 years ago that heterozygous carriers for the human autosomal recessive disorder Ataxia-Telangiectasia (A-T) might also be at increased risk for cancer. Subsequent studies have identified the responsible gene, Ataxia-Telangiectasia Mutated (ATM), characterized genetic variation at this locus in A-T and a variety of different cancers, and described the functions of the ATM protein with regard to cellular DNA damage responses. However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. This review considers these questions in the context of contralateral breast cancer (CBC). CONCLUSIONS: Heterozygous carriers of loss of function mutations in ATM that are A-T causing, are at increased risk of breast cancer. However, examination of a range of genetic variants, both rare and common, across multiple cancers, suggests that ATM may have additional effects on cancer risk that are allele dependent. In the case of CBC, selected common alleles at ATM are associated with a reduced incidence of CBC, while other rare and predicted deleterious variants may act jointly with radiation exposure to increase risk. Further studies that characterize germline and somatic ATM mutations in breast cancer and relate the detected genetic changes to functional outcomes, particularly with regard to radiation responses, are needed to gain a complete picture of the complex relationship between ATM, radiation and breast cancer. PMID- 28627267 TI - beta-Cyclodextrin-based ternary complexes of haloperidol and organic acids: the effect of organic acids on the drug solubility enhancement. AB - Haloperidol (HALO) is a weak base with very low aqueous solubility that is used as an antipsychotic drug. This study aimed to improve its solubility by forming HALO/beta-cyclodextrin (beta-CD)-based ternary complexes with organic acids. The solubility of HALO/beta-CD binary and HALO/beta-CD/organic acid ternary complexes in different media (i.e. citrate buffer pH 3 and 6) was explored. The stoichiometric ratio between the drug and beta-CD was 1:1 in all complexes formed. The solubility of HALO/beta-CD binary complexes significantly increased in citrate buffer pH 3 compared with citrate buffer pH 6. For the ternary complexes, HALO/beta-CD/tartaric acid and HALO/beta-CD/lactic acid in citrate buffer pH 3 increased HALO solubility compared with HALO/beta-CD/succinic acid due to their higher unionized species. The highest stability constant and complexation efficiency values in citrate buffer pH 3 were shown by the ternary complexes with lactic acid followed by tartaric acid and succinic acid, respectively. Results indicated that lactic acid provided the greatest binding strength and solubilization efficiency for the complex. PMID- 28627268 TI - The significance of drug-to-lipid ratio to the development of optimized liposomal formulation. AB - Liposomes are considered to be one of the most extensively investigated drug delivery nanosystems. Each drug can be loaded either in the liposomal hydrophilic core or within the lipidic bilayer and delivered eventually to the proper site into the organism. There are already many marketed approved liposomal products. The development of a liposomal product is a quite complicated process, while many critical parameters have to be investigated during the preparation process. The present study deals with the drug-to-lipid ratio (D/L ratio), which is a critical process parameter, expresses the actual capacity of the liposome to accommodate the drug and can play a key role at the optimization of every liposomal formulation. D/L ratio is affected by the composition, the different biomaterials and the loading method being used, so the improvement of D/L ratio can optimize the liposomal formulation. D/L ratio can be used as an index of the effectiveness of the preparation method too. Furthermore, D/L ratio influences the therapeutic efficacy of the liposomal product, expressing the actual dose of the drug being administrated. There is a variety of analytical methods, quantifying the drug and the lipids and estimating eventually the D/L ratio. According to the regulatory framework of nanomedicine, about the development of nanosimilars, D/L ratio is a necessary element for the nanosimilar product description and the statement of product comparability. PMID- 28627269 TI - Profiling and identification of chlorogenic acid metabolites in rats by ultra high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer. AB - 1. Chlorogenic acids (CGAs), one kind of major bioactive constituents isolated from Flos Lonicera Japonica, possess many biological activities, such as antibacterial, antioxidant and antiviral activities. In this study, we established an efficient strategy using ultra-high-performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometry (UHPLC-LTQ Orbitrap MS) to profile the in vivo metabolic fate of CGAs in rat urine and plasma. 2. The extract from Flos Lonicera Japonica was orally administrated to Sprague-Dawley (SD) rats at a dose of 1000 mg/kg body weight. Then, a combination of various post-acquisition data mining methods, including high-resolution extracted ion chromatogram (HREIC) and multiple mass defect filters (MMDFs) and diagnostic product ions (DPIs), were adopted to characterize the known and unknown CGA metabolites in SD rats. 3. As a result, a total of 68 CGA metabolites were unambiguously or tentatively screened and characterized. These metabolites, including 18 prototype compounds and 50 metabolites, were deduced to be yielded via methylation, hydrogenation, demethylation, dehydration, sulfate conjugation, glucuronide conjugation, glycosylation conjugation and their composite reactions, which mainly occurred to caffeoylquinic acids, dicaffeoylquinic acids, p coumaroylquinic acids and feruloylquinic acids. 4. In conclusion, this study profiled CGA metabolites, which are useful in understanding the in vivo metabolic fate, effective forms, and pharmacological and toxic actions of CGAs. PMID- 28627271 TI - Vancomycin Trough Concentration Poorly Characterizes AUC: Is It Time to Transition to AUC-Based Vancomycin Monitoring? PMID- 28627270 TI - Novel benzopyran derivatives and their therapeutic applications: a patent review (2009-2016). AB - INTRODUCTION: The benzopyran derivatives present a wide variety of biological activity and behaviour. At the same time the benzopyran derivatives support their use as therapeutic agents for multiple diseases. Their structural characteristics correlated to physicochemical properties seem to define the extent of the biological activity. Areas covered: This review summarizes new patents published on new benzopyran derivatives from 2009 to 2016. Expert opinion: Many benzopyran derivatives have vivo/vitro biological responses. Their clinical evaluation will be critical to assess therapeutic utility. The compounds containing benzopyran moiety is well defined as lead compounds for design of new more promising molecules. PMID- 28627272 TI - Depression and insomnia are independently associated with satisfaction and enjoyment of life in medication-overuse headache patients. AB - Objective Medication-overuse headache is often comorbid with emotional disturbances and disordered personality traits. The aim of the present study was to determine whether depression and insomnia complaints were associated with satisfaction and enjoyment with one's own life in medication-overuse headache patients, and whether insomnia complaints were able to explain part of the variance of Quality of Life explained by depression. Methods Participants were 187 consecutive adult outpatients admitted to the Regional Referral Headache Centre of the Sant'Andrea Hospital in Rome, Italy. Patients were administered the Quality of Life Enjoyment and Satisfaction Questionnaire, the Beck Depression Inventory - II, and the Athens Insomnia Scale. Results The Beck Depression Inventory was associated with all the dimensions of the Quality of Life Enjoyment and Satisfaction Questionnaire, with more severe depression being associated independently with lower satisfaction and enjoyment with one's own life. The Athens Insomnia Scale was independently and significantly associated only with physical health, such that patients with more insomnia complaints were 3.1 times ( p < 0.001) more likely to report lower physical health satisfaction. Conclusions Our findings confirmed that medication-overuse headache patients has a negative impact on quality of life and suggested that depression and insomnia were independently associated with satisfaction and enjoyment of life in medication-overuse headache patients. The early recognition and appropriate treatment of comorbid psychopathological symptoms are crucial to improve satisfaction and enjoyment of life in medication-overuse headache patients. PMID- 28627274 TI - The Relation Between Aggression and the Living Group Climate in a Forensic Treatment Unit for Adolescents: A Pilot Study. AB - In the current study, the associations between inpatient aggression and the living group climate as perceived by the adolescents admitted to a forensic psychiatric treatment unit, are investigated based on carefully registered longitudinal data. Multilevel regression analyses revealed a significant inverse relation between the number and severity of aggressive incidents and the amount of support, as well as with the possibilities of growth perceived by the adolescents. No significant associations of aggression and the perception of repression or atmosphere are found. Our study reveals preliminary evidence for the relation between the prevalence of aggressive incidents and how the adolescents perceive social contextual factors in daily forensic treatment practices. Moreover, preliminary evidence that evidence-based treatment programs and psychiatric care have an important influence on experienced possibilities for growth and support and as such prevent institutional aggression, is found. PMID- 28627273 TI - Nanoparticle interactions with co-existing contaminants: joint toxicity, bioaccumulation and risk. AB - With their growing production and application, engineered nanoparticles (NPs) are increasingly discharged into the environment. The released NPs can potentially interact with pre-existing contaminants, leading to biological effects (bioaccumulation and/or toxicity) that are poorly understood. Most studies on NPs focus on single analyte exposure; the existing literature on joint toxicity of NPs and co-existing contaminants is rather limited but beginning to develop rapidly. This is the first review paper evaluating the current state of knowledge regarding the joint effects of NPs and co-contaminants. Here, we review: (1) methods for investigating and evaluating joint effects of NPs and co contaminants; (2) simultaneous toxicities from NPs co-exposed with organic contaminants, metal/metalloid ions, dissolved organic matter (DOM), inorganic ligands and additional NPs; and (3) the influence of NPs co-exposure on the bioaccumulation of organic contaminants and heavy metal ions, as well as the influence of contaminants on NPs bioaccumulation. In addition, future research needs are discussed so as to better understand risk associated with NPs contaminant co-exposure. PMID- 28627275 TI - The Effects of Exercise on Patient-Reported Outcomes and Performance-Based Physical Function in Adults With Acute Leukemia Undergoing Induction Therapy: Exercise and Quality of Life in Acute Leukemia (EQUAL). AB - INTRODUCTION: Fatigue is a distressing symptom for adults with acute leukemia, often impeding their ability to exercise. OBJECTIVES: 1) Examine effects of a 4 week mixed-modality supervised exercise program (4 times a week, twice a day) on fatigue in adults with acute leukemia undergoing induction chemotherapy. 2) Evaluate effects of exercise program on cognition, anxiety, depression, and sleep disturbance. 3) Evaluate effect of intervention on adherence to exercise. METHODS: 17 adults (8 intervention, 9 control), aged 28-69 years, newly diagnosed with acute leukemia were recruited within 4 days of admission for induction treatment. Patient-reported outcomes (PROs) (fatigue, cognition, anxiety, depression, sleep disturbance, mental health, and physical health) and fitness performance-based measures (Timed Up and Go [TUG], Karnofsky Performance Status, and composite strength scoring) were assessed at baseline and at discharge. Changes in PRO and performance-based physical function measures from baseline to time of discharge were compared between groups using Wilcoxon Rank Sum tests. RESULTS: With PROMIS (Patient-Reported Outcomes Measurement Information System) Fatigue, we found a median change in fatigue (-5.95) for the intervention group, which achieved a minimally important difference that is considered clinically relevant. Intervention group reduced their TUG performance by 1.73 seconds, whereas the control group remained fairly stable. A concerning finding was that cognition decreased for both groups during their hospitalization. 80% adherence of visits completed with a mean of 6 sessions attended per week. CONCLUSIONS: Our study provides information on the impact of exercise on symptomatology, with focus on fatigue and other psychosocial variables in acute leukemia. PMID- 28627276 TI - Comprehensive graphical presentation of data from incurred sample reanalysis. AB - AIM: Incurred sample reanalysis (ISR) contributes to the reliability of pharmacokinetic studies. Despite regulatory guidelines having adopted ISR methodology, graphical presentation of data has been overlooked. MATERIALS & METHODS: Different graphs were tested for datasets including limited, standard and large numbers of ISR pairs. The datasets covered both passed and failed cases. RESULTS: We have developed a combination of complementary plots enabling the visual inspection of ISR data quality: %difference versus mean concentration and cumulative ISR plot. The former shows individual ISR datapoints and concentration-dependent trends, while the latter presents the contribution of individual pairs to the overall result as well as time-dependent trends. CONCLUSION: The proposed visualization of ISR data shows at a glance whether acceptance criteria for each sample and whole experiment are met or not. Standardized graphical presentation of ISR outcomes may increase quality of bioanalytical data. PMID- 28627277 TI - Anti-acne drugs in phase 1 and 2 clinical trials. AB - INTRODUCTION: Despite the impressive increase of knowledge on acne etiology accumulated during the last 20 years, few efforts have been overtaken to introduce new therapeutic regiments targeting the ideal treatment of acne. The increasing emergence of microbial resistance associated with antibiotics, teratogenicity, particularly associated with systemic isotretinoin, and the need for an adverse drug profile, which can be tolerated by the patient, make the need of new pathogenesis relevant anti-acne agents an emerging issue. Areas covered: A search for phase 1 and 2 acne treatment trials in the US National Institutes of Health database of clinical trials and the European Medicines Agency database with the key words 'acne' and 'treatment' was carried out, on 6 January 2017. Expert opinion: The detected trials mostly investigate topical agents that may act via sebosuppressive effects, antimicrobial properties or anti-inflammatory actions. The compounds under investigation include olumacostat glasaretil, cortexolone 17alpha-propionate, stearoyl-CoA desaturase 1 inhibitors, agents affecting the melanocortin system, omiganan, and minocycline. Systemic studied anti-acne drugs include finasteride, biologics, low dose anti-inflammatory antibiotics, and leukotriene B4 inhibitors. PMID- 28627278 TI - Methotrexate for the treatment of pediatric alopecia areata. AB - PURPOSE: Alopecia areata is a form of nonscarring hair loss that occurs in pediatric and adult patients, with presentation varying from round or ovoid patches of alopecia to alopecia totalis or universalis. While frustrating for patients, it can also be frustrating for clinicians to treat, as there is no definitive treatment. Dermatologists are very familiar with the use of methotrexate for psoriasis and other inflammatory skin diseases, and this medication is generally well tolerated in children. MATERIALS/METHODS: This study presents a case series reviewing the efficacy of methotrexate in our pediatric patients with alopecia areata, making use of a retrospective chart review design from 2011 to 2016. RESULTS: In this data set, 8/14 subjects (57%) experienced good regrowth with methotrexate, while 3/14 (21%) had a response that could not be assessed due to loss to follow-up or premature discontinuation of the medication. No cases discontinued the medication due to recognized methotrexate side effects. CONCLUSIONS: This review suggests methotrexate is a generally safe and often effective medication in pediatric alopecia areata. PMID- 28627279 TI - Maternal autoimmune disorders and fetal defects. AB - Maternal autoantibodies can cross the placenta and cause fetal damage. This article summarizes the development and management of fetal thyroid goiter in response to maternal Graves' disease and/or its treatment with antithyroid medication, fetal heart block due to maternal anti-Ro and anti-La antibodies, fetal athrogryposis multiplex congenita in association with maternal myasthenia gravis and fetal brain hemorrhage due to maternal autoimmune thrombocytopenia. PMID- 28627280 TI - The targeting effect of Hm2E8b-NCTD-liposomes on B-lineage leukaemia stem cells is associated with the HLF-SLUG axis. AB - To identify an agent with specific activity against B-lineage leukaemia stem cells (B-LSCs), we generated norcantharidin (NCTD)-encapsulated liposomes modified with a novel humanised anti-human CD19 monoclonal antibody, Hm2E8b (Hm2E8b-NCTD-liposomes). These liposomes were specially designed to recognise and kill B-LSCs in vitro, and to decrease non-specific cytotoxicity to untargeted cells. Hm2E8b-NCTD-liposomes selectively ablated B-LSCs through targeting hepatic leukaemia factor (HLF), which is implicated in haematopoietic stem cell regulation and is overexpressed in LSCs. Hm2E8b-NCTD-liposomes decreased HLF protein levels and induced apoptosis in the HAL-01 cell line harbouring the oncoprotein E2A-HLF. This resulted in modulation of the expression of several molecules that govern survival pathways, including HLF, SLUG, NFIL3 and C-Myc, thereby causing the induction of p53 and the mitochondrial caspase cascade. Therefore, the potent in vitro effect of Hm2E8b-NCTD-liposomes on B-LSC activity and survival pathways have the potential to be exploited clinically with appropriate drug combinations. PMID- 28627281 TI - Mirroring "meaningful" actions: sensorimotor learning modulates imitation of goal directed actions. AB - Imitation is important in the development of social and technological skills throughout the lifespan. Experiments investigating the acquisition and modulation of imitation (and of its proposed neural substrate, the mirror neuron system) have produced evidence that the capacity for imitation depends on associative learning in which connections are formed between sensory and motor representations of actions. However, evidence that the development of imitation depends on associative learning has been found only for non-goal-directed actions. One reason for the lack of research on goal-directed actions is that imitation of such actions is commonly confounded with the tendency to respond in a spatially compatible manner. However, since the most prominent account of mirror neuron function, and hence of imitation, suggests that these cells encode goal-directed actions, it is important to establish whether sensorimotor learning can also modulate imitation of goal-directed actions. Experiment 1 demonstrated that imitation of goal-directed grasping can be measured while controlling for spatial compatibility, and Experiment 2 showed that this imitation effect can be modulated by sensorimotor training. Together these data support the hypothesis that the capacity for behavioural imitation, and the properties of the mirror neuron system, are constructed in the course of development through associative learning. PMID- 28627282 TI - Gallic acid-PAMAM and gallic acid-phospholipid conjugates, physicochemical characterization and in vivo evaluation. AB - Gallic acid (GA) is a naturally occurring compound with valuable antioxidant activity. Its oral bioavailability is limited by its high metabolism and rapid clearance. In this paper, GA was conjugated with two different materials, phosphatidylcholine (PC) and polyamidoamine (PAMAM) dendrimer. The prepared conjugates were characterized by FTIR, DSC, and SEM. Also, they were tested for drug content and in vitro drug release. It was found that GA conjugation with both materials have significantly prolonged its release up to 12 h. In vivo hepatoprotective activity of free and conjugated GA was studied in rats after carbon tetrachloride (CCl4)-induced oxidative damage in rat liver through measurement of different liver marker enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT)), in addition to the total protein and albumin level in rat serum. Also, histopathological examination of liver cell of all rat groups was done. Results showed that both prepared conjugates have significantly reduced the hepatic marker enzymes accompanied by normalizing total protein and albumin levels in rat serum and with respect to CCl4-induced group (p < .05). Histopathological examination showed that pretreatment of rats with GA-PC or GA PAMAM before CCL4 could reduce the induced cellular histopathological changes. It appears that conjugation of GA could enhance its bioavailability and increase its hepatoprotective effect. PMID- 28627283 TI - Epidemiological investigation of euthanasia in an Ontario animal shelter. AB - Objectives The objective was to evaluate factors associated with euthanasia in an animal shelter in Kitchener-Waterloo, Ontario, Canada. Methods Data from 3737 cats admitted to the shelter between January and December 2011 were evaluated. Results Overall, 1989/3737 (53%) of admitted cats were euthanized. Male cats had greater odds of being euthanized than females (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.29-2.05; P <0.001) and surrendered cats were more likely to be euthanized than strays (OR 38.0, 95% CI 14.8-97.69; P <0.001). Black cats were more likely to be euthanized than cats of another color (OR 1.45, 95% CI 1.16-1.80; P <0.001). Cats that spent >5 days in the shelter were more likely to be euthanized than those that spent <5 days in the shelter (OR 1.57, 95% CI 1.25-1.97; P <0.001). Cats that spent >20 days in the shelter were less likely to be euthanized than those that spent <5 days in the shelter (OR 0.26, 95% CI 0.19 0.34; P <0.001). Age, an age quadratic term, neuter status and interactions among these variables were statistically significant; the odds of unneutered animals being euthanized was high and relatively stable across age groups, but in neutered animals the odds of being euthanized increased with age before plateauing in older cats. Conclusions and relevance With >50% of the cats admitted to the shelter in 2011 euthanized, it is important to understand the contributing risk factors that predispose shelter cats to euthanasia and what changes can be made to the shelter system and in owner education to lower the incidence of euthanasia. PMID- 28627284 TI - Treatment of Neotrombicula species infestation in cats using a 10% (w/v) fipronil topical spot-on formulation: a pilot study. AB - Objectives Few data are available concerning therapeutic aspects of feline trombiculiasis. This study evaluated the efficacy of a 10% w/v fipronil-based spot-on solution in 15 cats with natural Neotrombicula species infestation. Methods Ten cats received 1 drop per affected site on day (D)0 and D14, with the rest of the 0.5 ml pipette applied on the skin between the shoulders. Five cats served as non-treated controls. Parasite score (0 = absent; 3 = severe, >10 parasites/zone) was assessed on D0, D14 and D28 on all animals. Skin lesions (SCORing Feline Allergic Dermatitis lesion severity scale [SCORFAD]) and investigator pruritus scale (IPS; 0 = cat comfortable, grooming like any normal cat; 4 = cat uncomfortable, pruritic all the time) were assessed on treated cats on the same days. Global assessment of efficacy, tolerance and ease of use (GAS; 1 = very poor; 5 = excellent) was assessed on D28. Results All the cats completed the study. Parasite scores of the control cats were maintained throughout the trial (mean +/- SD: D0 4 +/- 0.7, D14 3.2 +/- 1.1 and D28 3.2 +/- 0.4). In treated cats, SCORFAD (D0 3.2 +/- 5.4, D14 1.1 +/- 2.1 [ P <0.002] and D28 0.5 +/ 1.3 [ P <0.002]), parasite (D0 3.9 +/- 1.3, D14 1.2 +/- 0.8 [ P <0.005] and D28 0.4 +/- 0.5 [ P <0.005]) and IPS (D0 1 +/- 1.2, D14 0.5 +/- 1.1 [ P <0.05] and D28 0.3 +/- 0.7 [ P <0.05]) scores significantly decreased throughout the trial. On D28, the GAS was 4.2 +/- 0.9. There were no adverse effects from treatment. Conclusions and relevance The 10% w/v fipronil preparation appeared to be effective, safe and practical in the treatment of localised Neotrombicula species infestation in these cats. PMID- 28627285 TI - Older Military Veteran Care: Many Still Believe They Are Forgotten. AB - BACKGROUND: Almost 44% of our nation's 23 million men and women veterans are 65 years of age or older. Most are proud of their service, yet many believe their services for our country were forgotten, especially those in combat between 1950 and 1975. PURPOSE: Further information to ultimately assist their holistic well being will be important for nursing practice as countless older veterans are beginning to obtain more care within civilian facilities. Using the Korean War (1950-1953) as a backdrop to illustrate the interconnectiveness of older veteran physical, emotional, and spiritual concerns that can occur from a military deployment, the major purposes of this article are to provide a brief historical snapshot of that war and discuss prior-era military environmental situations that now are producing the lingering effects from their combat exposure. DESIGN: Relevant literature about the Korean War and Veterans was compiled. FINDINGS: Some of these health risks for both the Korean men and women veterans are cold exposure, neurologic, and posttraumatic stress disorder concerns, as well as the need for hepatitis C and suicide assessments. CONCLUSIONS: To ultimately improve their bio-psycho-socio-spiritual well-being, prompt identification of the older military veteran, their lingering combat effects, and reminiscing will be important. PMID- 28627286 TI - Constipation-Related Health Care Utilization in Children Before and After Hospitalization for Constipation. AB - We studied constipation-related health care among children before and after constipation admission. Index admissions for constipation in 2010-2011 were identified in the Truven Marketscan Database, which includes children receiving Medicaid in 10 states. We measured number of and spending for outpatient constipation visits 12 months before and after index hospitalizations. We also measured spending for constipation hospitalizations and rehospitalization rate. There were 780 index constipation admissions. The median number of outpatient constipation visits was 1 (interquartile range [IQR] = 0, 3) in the 12 months before and 2 (IQR [0, 4]) after admission ( P = .001). Median outpatient spending for constipation was $110 (IQR [0, 429]) before and $132 (IQR [0, 431]) after admission ( P = .2). Median spending for index constipation admissions was $5295 (IQR [2756, 8267]); 78 children (10%) were rehospitalized for constipation within 12 months. Constipation-related health care utilization increased after constipation admission. Median spending for one constipation admission was 50 times the median spending for 12 months of outpatient constipation visits. PMID- 28627287 TI - Utilizing the Electronic Health Record to Improve Advance Care Planning: A Systematic Review. AB - PURPOSE: Advance care planning may ensure care that is concordant with patient wishes. However, advance care plans are frequently absent when needed due to failure to engage patients in planning, inability to access prior documentation, or poor documentation quality. Interventions utilizing tools within the electronic health record (EHR) may address these barriers at the point of care. We aimed to identify EHR interventions previously utilized to improve advance care plans. METHODS: We systematically searched 7 databases for observational and experimental studies of EHR interventions associated with advance care plans. We abstracted information on the study populations, EHR and non-EHR components of the interventions, and the efficacy for advance care plan-related outcomes. RESULTS: We identified 16 articles that contained an EHR intervention to improve advance care plans. Study populations, study designs, and EHR components of the interventions were heterogeneous. Documentation templates were the most common EHR tool reported (n = 8), followed by automated prompts (n = 7) and electronic order sets (n = 5). The most common reported outcomes were documentation of an advance care planning conversation in the EHR (n = 7) and the placement of code status orders (n = 7). All studies reporting efficacy (n = 9) demonstrated an improvement in 1 or more advance care planning outcomes. CONCLUSIONS: The use of EHR interventions may improve advance care plan completion and availability at the point of care. Further work should seek to develop and evaluate standardized EHR tools for advance care planning. PMID- 28627288 TI - Biocompatibility of filomicelles prepared from poly(ethylene glycol)-polylactide diblock copolymers as potential drug carrier. AB - A series of poly(ethylene glycol)-polylactide (PEG-PLA) diblock copolymers were synthesized by ring-opening polymerization of l-lactide using monomethoxy PEG as macroinitiator and zinc lactate as catalyst. Filomicelles were prepared from the resulting copolymers by co-solvent evaporation method. The biocompatibility of the various filomicelles was evaluated with the aim of assessing their potential as drug carriers. Various aspects of biocompatibility were considered, including agar diffusion test, MTT assay, release of cytokines, hemolytic test, dynamic clotting time, protein adsorption in vitro, and zebrafish embryonic compatibility in vivo. The results revealed that the filomicelles present good cytocompatibility and hemocompatibility in vitro. Moreover, the cumulative effects of filomicelles throughout embryos deveploping stages have no toxicity in vivo. It is thus concluded that filomicelles prepared from PEG-PLA copolymers with outstanding biocompatibility are promising as potential drug carrier. PMID- 28627289 TI - Snap-N-Send: A valid and reliable method for assessing the energy intake of elite adolescent athletes. AB - To ensure that elite adolescent athletes meet their unique training, growth and maturation demands, it is imperative to have access to valid measures of energy intake. Contemporary methods demand close attention-to-detail, meaning that athletes often do not fully adhere to real-time protocols. This study represents the first investigation of a real-time dietary assessment designed using a comprehensive behaviour change framework (COM-B). In a crossover design, 12 elite adolescent male rugby players recorded their energy intake via an estimated food diary (est-FD) and photography-based mobile assessment ('Snap-n-Send'), combined with a 24-h dietary recall interview. Two 4-day assessment periods were divided into three separate recording environments: 96 h free-living and researcher observed; 72 h free-living and 10 h researcher-observed. Assessment periods were one month apart. All foods and beverages were provided and weighed by the research team to quantify actual intakes. 'Snap-n-Send' reported a small mean bias for under-reporting across 96 h (-0.75 MJ day-1; 95% confidence interval [CI] for bias = -5.7% to -2.2%, p < .001), 72 h (-0.76 MJ day-1; 95% CI for bias = -5.6% to -2.1%, p = .004) and 10 h (-0.72 MJ day-1; 95% CI for bias = -8.1% to 0.1%; p = .067) environments. The est-FD reported a moderate mean bias for under reporting across 96 h (-2.89 MJ day-1; 95% CI for bias = -17.9% to -10.2%; p < .001), 72 h (-2.88 MJ day-1; 95% CI for bias = -17.9% to -10.1%; p < .001) and 10 h (-2.52 MJ day-1;-26.1% to -5.3%; p = .023) environments. Results evidence the ability of 'Snap-n-Send' to accurately assess the diet of elite adolescent athletes, signalling the exciting promise of this comprehensive and theoretical behavioural approach within valid dietary assessment. PMID- 28627290 TI - Continuous adductor canal block added to local infiltration analgesia (LIA) after total knee arthroplasty has no additional benefits on pain and ambulation on postoperative day 1 and 2 compared with LIA alone. AB - Background and purpose - The additional effects of a continuous adductor canal block (ACB) compared with a single-dose local infiltration anesthesia (LIA) after total knee arthroplasty (TKA) has not been widely researched. Both methods have good effect individually. We hypothesized that a continuous ACB added to a single dose LIA would lower pain scores while ambulating on postoperative day 1 (POD1) and postoperative day 2 (POD2). Patients and methods - 69 participants were included in this prospective, randomized, double-blind, placebo-controlled trial. The TKA was performed under spinal analgesia and every participant was given single-dose LIA intraoperatively. Patients were then randomized into 2 groups, treatment group receiving 0.2% ropivacaine and control group receiving normal saline. First a 20 mL bolus was given into the adductor canal and 4 hours later a continuous flow at 6 mL/h was initiated for 2 postoperative days through a catheter placed in the adductor canal. Results - Worst pain score during movement of the operated knee on POD1 and POD2 was similar between the groups. No other ambulation tests done on POD1 and POD2 showed any statistically significant difference. Morphine consumption on the day of surgery, POD1 and POD2 was similar between the groups. Interpretation - The results indicate no benefit of continuous infusion ACB added to a single-dose LIA compared with LIA alone on pain while ambulating on POD1 and POD2. Furthermore, the ACB showed no superiority in ambulation ability on the 2 postoperative days. PMID- 28627291 TI - Early Complications, Morbidity, and Mortality in Octogenarians and Nonagenarians Undergoing Posterior Intra-Operative Spinal Navigation-Based C1/2 Fusion for Type II Odontoid Process Fractures. AB - Type II odontoid fractures represent the most common cervical spine injury in the elderly. The decision for surgical treatment is still controversial, particularly with regard to the elevated peri-operative risk attributed to frequent comorbidities and poor bone quality. The purpose of this study was to assess both short-term mortality and mid-term clinical and radiological outcome in the elderly. Between January 2007 and December 2015, 35 patients with type II odontoid process fractures who underwent posterior atlanto-axial instrumentation using a modified Goel-Harms technique were retrospectively analyzed and prospectively examined clinically and radiologically. Comorbidities, mortality, and length of intensive care unit (ICU) and hospital stay were determined, as were medical and surgical complications. Quality of life was measured using the EuroQol five dimensions (EQ-5D) and Short Form-36 (SF-36) questionnaires at final follow-up. Average age was 86.5 years. All patients had severe comorbidities pre operatively. No in-hospital mortality was observed. Average length of hospital stay was 13.8 days and 2.0 days for the ICU. Three patients developed cardiopulmonary complications; one wound infection developed post-operatively. Mean follow-up was 22 months (range, 6-72 months). The quality of life measured by EQ-5D showed a good outcome (0.7 +/- 0.1). All SF-36 domains were reduced in comparison to a representative group. Solid bony fusion could be achieved in all patients. Atlanto-axial fusion by using intra-operative spinal navigation is a safe and effective procedure in the elderly, with few complications and preservation of favorable post-operative quality of life. The overall major complication rate was 11%. Surgery in the very old should be considered as first choice treatment. PMID- 28627292 TI - Mood-dependent retrieval in visual long-term memory: dissociable effects on retrieval probability and mnemonic precision. AB - Although memories are more retrievable if observers' emotional states are consistent between encoding and retrieval, it is unclear whether the consistency of emotional states increases the likelihood of successful memory retrieval, the precision of retrieved memories, or both. The present study tested visual long term memory for everyday objects while consistent or inconsistent emotional contexts between encoding and retrieval were induced using background grey-scale images from the International Affective Picture System (IAPS). In the study phase, participants remembered colours of sequentially presented objects in a negative (Experiment 1a) or positive (Experiment 2a) context. In the test phase, participants estimated the colours of previously studied objects in either negative versus neutral (Experiment 1a) or positive versus neutral (Experiment 2a) contexts. Note, IAPS images in the test phase were always visually different from those initially paired with the studied objects. We found that reinstating negative context and positive context at retrieval resulted in better mnemonic precision and a higher probability of successful retrieval, respectively. Critically, these effects could not be attributed to a negative or positive context at retrieval alone (Experiments 1b and 2b). Together, these findings demonstrated dissociable effects of emotion on the quantitative and qualitative aspects of visual long-term memory retrieval. PMID- 28627293 TI - New evidence of relative age effects in "super-elite" sportsmen: a case for the survival and evolution of the fittest. AB - The relative age effect (RAE) describes an overrepresentation of players born early (Q1) in a selection year and is highly prevalent within youth sport pathways. However, a dearth of research has investigated the RAE at the "super elite" level. The present research assessed the presence of RAE in super-elite performers. Study 1 investigated RAEs in the world's best international Test cricketers (N = 262) over a 20-year period according to a robust and stringent "super-elite" criteria. Results revealed the RAE (Q1) when all disciplines were combined. Upon closer examination, this effect was also observed for the batting and spin bowling disciplines, whereas no RAE was found for the pace bowling discipline. Study 2 investigated RAEs in super-elite rugby union players (N = 691) over a 20 year period. Results revealed the RAE for backs (Q1) and a reversal of the traditional RAE (Q4) for forwards, and when all rugby union positions were combined. These findings provide new evidence of RAEs at the super elite level and present both inter and intra sports differences. Potential explanations for these findings are explored, owing to the survival and evolution of the fittest concepts, and the implications for future research and applied practice are presented. PMID- 28627295 TI - Socialization of prosocial behavior: Gender differences in the mediating role of child brain volume. AB - Evidence has been accumulating for the impact of normal variation in caregiving quality on brain morphology in children, but the question remains whether differences in brain volume related to early caregiving translate to behavioral implications. In this longitudinal population-based study (N = 162), moderated mediation was tested for the relation between parental sensitivity and child prosocial behavior via brain volume, in boys and girls. Both maternal and paternal sensitivity were repeatedly observed between 1 and 4 years of age. Brain volume was assessed using magnetic resonance imaging measurements at age 8, and self-reported prosocial behavior of children was assessed at 9 years of age. Parental sensitivity was positively related to child brain volume, and to child prosocial behavior at trend level. Child brain volume was negatively related to child prosocial behavior. A significant gender-by-brain interaction was found, illustrating that daughters of sensitive parents were more prosocial and that less prosocial behavior was reported for girls with a larger total brain volume. Child gender significantly moderated the indirect effect of parental sensitivity on prosocial behavior via total brain volume. A significant indirect pathway was found only in girls. The results warrant replication but indicate the importance of considering gender when studying the behavioral implications of differences in brain volume related to early caregiving experiences. PMID- 28627294 TI - Polyphenolic characterisation and bioactivity of an Oxalis pes-caprae L. leaf extract. AB - The present work is focused on the characterisation of the polyphenolic content of an Oxalis pes-caprae L. leaf extract and on the evaluation of its bioactivity with particular interest on its vascular activity and antioxidant potential. The polyphenolic content was characterised by HPLC-DAD and LC-MS/MS. The vascular activity was evaluated according to the influence on the serotonergic and adrenergic systems of the human internal mammary artery (HIMA). Antioxidant and neuroprotective studies were also conducted. Several luteolin and apigenin derivatives were identified as main constituents of the extract, which did not present any contractile effect nor had any effect on the serotonergic system of HIMA. However, it showed antagonistic effect on the adrenergic system, inhibiting the contraction to noradrenaline (reduction of 58.44% of maximum contraction). The extract showed antioxidant activity and standardised luteolin and apigenin derivatives showed neuroprotective potential, particularly homoorientin. PMID- 28627296 TI - Sexual Violation of Patients by Physicians: A Mixed-Methods, Exploratory Analysis of 101 Cases. AB - A mixed-method, exploratory design was used to examine 101 cases of sexual violations in medicine. The study involved content analysis of cases to characterize the physicians, patient-victims, the practice setting, kinds of sexual violations, and consequences to the perpetrator. In each case, a criminal law framework was used to examine how motives, means, and opportunity combined to generate sexual misconduct. Finally, cross-case analysis was performed to identify clusters of causal factors that explain specific kinds of sexual misconduct. Most cases involved a combination of five factors: male physicians (100%), older than the age of 39 (92%), who were not board certified (70%), practicing in nonacademic settings (94%) where they always examined patients alone (85%). Only three factors (suspected antisocial personality, physician board certification, and vulnerable patients) differed significantly across the different kinds of sexual abuse: personality disorders were suspected most frequently in cases of rape, physicians were more frequently board certified in cases of consensual sex with patients, and patients were more commonly vulnerable in cases of child molestation. Drawing on study findings and past research, we offer a series of recommendations to medical schools, medical boards, chaperones, patients, and the national practitioners database. PMID- 28627297 TI - A Bayesian Simulation Model for Breast Cancer Screening, Incidence, Treatment, and Mortality. AB - BACKGROUND: The important but complicated research questions regarding the optimization of mammography screening for the detection of breast cancer are unable to be answered through any single trial or a simple meta-analysis of related trials. The Cancer Intervention and Surveillance Network (CISNET) breast groups provide answers using complex statistical models to simulate population dynamics. Among them, the MD Anderson Cancer Center (Model M) takes a unique approach by not making any assumptions on the natural history of breast cancer, such as the distribution of the indolent time before detection, but simulating only the observable part of a woman's disease and life. METHODS: The simulations start with 4 million women in the age distribution found in the year 1975, and follow them over several years. Input parameters are used to describe their breast cancer incidence rates, treatment efficacy, and survival. With these parameters, each woman's history of breast cancer diagnosis, treatment, and survival are generated and recorded each year. Research questions can then be answered by comparing the outcomes of interest, such as mortality rates, quality adjusted life years, number of false positives, differences between hypothetical scenarios, such as different combinations of screening and treatment strategies. We use our model to estimate the relative contributions of screening and treatments on the mortality reduction in the United States, for both overall and different molecular (ER, HER2) subtypes of breast cancer. RESULTS: We estimate and compare the benefits (life-years gained) and harm (false-positives, over diagnoses) of mammography screening strategies with different frequencies (annual, biennial, triennial, mixed) and different starting (40 and 50 years) and end ages (70 and 80 years). CONCLUSIONS: We will extend our model in future studies to account for local, regional, and distant disease recurrences. PMID- 28627298 TI - A Prospective Transcranial Doppler Ultrasound-Based Evaluation of the Acute and Cumulative Effects of Sport-Related Concussion on Neurovascular Coupling Response Dynamics. AB - Sport-related concussion has been shown to alter cerebral blood flow (CBF) both acutely and chronically, and may exert cumulative effects across multiple injuries. Such dysfunction may be mediated by trauma-induced deficits to CBF control mechanisms, though our understanding of these effects is limited, including dynamics of neurovascular coupling (NVC) responses (i.e., CBF responses to neurologic demand). A total of 179 junior-level contact sport athletes completed preseason testing; 42 reported never having experienced a concussion (Hx-) while 31 had endured three or more (Hx3+). A total of 18 athletes suffered concussions during the study period and were re-tested 3 days, 2 weeks, and 1 month post-injury. NVC dynamics were indexed via CBF velocity in the posterior (PCAv) and middle (MCAv) cerebral arteries during cycles of 20 sec eyes closed and 40 sec eyes open to a visual stimulus (reading). Acutely following concussion, peak rate of PCAv increase during the activation phase was delayed by over 50% and PCAv response magnitude was elevated by over 30%, compared with preseason. Response magnitude remained elevated at 2 weeks despite symptom resolution. Independent medical clearance for full return-to-play was inversely related to the magnitude of increase in the NVC response at 3 days post-injury. No post-injury changes were observed in MCAv, blood pressure, or end-tidal carbon dioxide levels during visual stimulation. No NVC metric differences were observed between the Hx- and Hx3+ groups at preseason. Via multiple potential mechanisms, acute sport-related concussion may induce compensatory alterations in NVC response dynamics that may be related to clinical recovery. Such effects do not appear to be persistent across multiple injuries. PMID- 28627299 TI - Improving Student Commitment to Healthcare-Related Design Practice by Improving the Studio Learning Experience. AB - OBJECTIVE: This case study explores the influence of the healthcare design studio experience on students' short-term professional goals as measured through rates of healthcare-related certification and internship/employment. BACKGROUND: The value and relevance of interior design is evident in the healthcare design sector. However, interior design students may not perceive this value if it is not communicated through their design education. Students' experience in the design studio plays a crucial role in determining career choices, and students may be more committed to career goals when there is clear connection between major coursework and professional practice. METHOD: The authors compared healthcare-related certification and internship/employment levels between two student cohorts in a capstone undergraduate interior design healthcare design studio course. The first cohort was led by the existing curriculum. The second cohort was led by the revised curriculum that specifically aimed at encouraging students to commit to healthcare-related design practice. RESULTS: When measured at 3 months from graduation, the second cohort, led by the revised curriculum, saw a 30% increase in Evidence-based Design Accreditation and Certification exam pass rates and a 40% increase in healthcare-related internship/employment. CONCLUSION: The challenge of interior design education is to instill in emerging professionals not only professional competence but also those professional attitudes that will make them better prepared to design spaces that improve quality of life, particularly in healthcare environments. The results exceeded the project goals, and so this could be considered a promising practice for courses focused on healthcare design education. PMID- 28627300 TI - Reduced Effective Emotion Regulation in Night Owls. AB - Previous research has demonstrated a clear link between late chronotype and depression. The vulnerability factors underpinning this link, however, are unclear. Here the relationship between two specific emotion regulation strategies, cognitive reappraisal and expressive suppression, and chronotype was investigated using multiple regression. Two hundred and forty participants (age range 18-80, 189 females) completed validated self-report questionnaires assaying chronotype, neuroticism, depressive symptomatology, sleep quality, and emotion regulation. Eveningness was associated with increased expressive suppression, and morningness was associated with increased cognitive reappraisal after controlling for age, gender, depressive symptomatology, neuroticism, and sleep quality. Trait expressive suppression and reduced cognitive reappraisal are known to increase depression risk. Our results suggest that eveningness is associated with impaired emotion regulation, which may confer risk for future depression. These findings suggest modifiable markers that could be therapeutically targeted to prevent the onset of depression in late chronotype individuals. PMID- 28627301 TI - Learned Changes in Outcome Associability. AB - When a cue reliably predicts an outcome, the associability of that cue will change. Associative theories of learning propose this change will persist even when the same cue is paired with a different outcome. These theories, however, do not extend the same privilege to an outcome; an outcome's learning history is deemed to have no bearing on subsequent new learning involving that outcome. Two experiments were conducted which sought to investigate this assumption inherent in these theories using a serial letter-prediction task. In both experiments participants were exposed, in Stage 1, to a predictable outcome ('X') and an unpredictable outcome ('Z'). In Stage 2 participants were exposed to the same outcomes preceded by novel cues which were equally predictive of both outcomes. Both experiments revealed that participants' learning toward the previously predictable outcome was more rapid in Stage 2 than the previously unpredicted outcome. The implications of these results for theories of associative learning are discussed. PMID- 28627302 TI - Taking Costs and Diagnostic Test Accuracy into Account When Designing Prevalence Studies: An Application to Childhood Tuberculosis Prevalence. AB - BACKGROUND: When planning a study to estimate disease prevalence to a pre specified precision, it is of interest to minimize total testing cost. This is particularly challenging in the absence of a perfect reference test for the disease because different combinations of imperfect tests need to be considered. We illustrate the problem and a solution by designing a study to estimate the prevalence of childhood tuberculosis in a hospital setting. METHODS: All possible combinations of 3 commonly used tuberculosis tests, including chest X-ray, tuberculin skin test, and a sputum-based test, either culture or Xpert, are considered. For each of the 11 possible test combinations, 3 Bayesian sample size criteria, including average coverage criterion, average length criterion and modified worst outcome criterion, are used to determine the required sample size and total testing cost, taking into consideration prior knowledge about the accuracy of the tests. RESULTS: In some cases, the required sample sizes and total testing costs were both reduced when more tests were used, whereas, in other examples, lower costs are achieved with fewer tests. CONCLUSION: Total testing cost should be formally considered when designing a prevalence study. PMID- 28627303 TI - The 'surprise' question in paediatric palliative care: A prospective cohort study. AB - BACKGROUND: The question 'would you be surprised if this patient died in the next 12-months' is widely used for identifying adult patients in the last year of life. However, this has not yet been studied in children. AIM: To assess the prognostic accuracy of the surprise question when used by a multidisciplinary team to predict survival outcomes of children with life-limiting conditions over a 3 and 12 month period. DESIGN: A prospective cohort study. SETTING/PARTICIPANTS: Six multidisciplinary team members working in a children's hospice answered a 3 and 12 month surprise question about 327 children who were either newly referred or receiving care at the hospice between 2011 and 2013. RESULTS: The prognostic accuracy of the multidisciplinary team for the 3 (and 12)month surprise question were: sensitivity 83.3% (83.3%), specificity 93.2% (70.7%), positive predictive value 41.7% (23.6%), negative predictive value 99% (97.5%) and accuracy 92.6% (71.9%). Patients with a 'no' response had an increased risk of death at 3 (hazard ratio, 22.94, p ? 0.001) and 12 months (hazard ratio, 6.53, p ? 0.001). CONCLUSION: The surprise question is a highly sensitive prognostic tool for identifying children receiving palliative care who are in the last 3 and 12 months of life. The tool is accurate at recognising children during stable periods demonstrated through a high negative predictive value. In practice, this tool could help identify children who would benefit from specialist end of life care, act as a marker to facilitate communications on advance care planning and assist in resource allocation. PMID- 28627304 TI - The effects of selected phytochemicals on biofilm formed by five methicillin resistant Staphylococcus aureus. AB - The aim of this study was to evaluate the ability of 0.1% thyme oil (TO), trans cinnamaldehyde (TC), ferulic acid (FA), p-coumaric acid (p-CA), caffeic acid (CA), lavender essential oil (LO), geranium essential oil (GO) and tee tree oil (TTO) to control biofilms formed by methicillin-resistant Staphylococcus aureus (MRSA) strains. Depending on the strains, TO reduced 59.7-85% of biofilm mass, while TC 52.9-82.4% after 48 h of treatment. Reduction of metabolic activity of biofilms in ranges 79.3-86% and 85.9-88.7% was observed after 48 h of TC and TO of treatment, respectively. In the case of some strains, reduction of biofilm mass in the presence of FA, CA, GO, LO and TTO was not observed. This study showed that TO and TC might have therapeutic potential as an inhibitory agents for use in MRSA biofilm-related infections. PMID- 28627305 TI - Variability of Diabetes Alert Dog Accuracy in a Real-World Setting. AB - BACKGROUND: Diabetes alert dogs (DADs) are growing in popularity as an alternative method of glucose monitoring for individuals with type 1 diabetes (T1D). Only a few empirical studies have assessed DAD accuracy, with inconsistent results. The present study examined DAD accuracy and variability in performance in real-world conditions using a convenience sample of owner-report diaries. METHOD: Eighteen DAD owners (44.4% female; 77.8% youth) with T1D completed diaries of DAD alerts during the first year after placement. Diary entries included daily BG readings and DAD alerts. For each DAD, percentage hits (alert with BG <= 5.0 or >= 11.1 mmol/L; <=90 or >=200 mg/dl), percentage misses (no alert with BG out of range), and percentage false alarms (alert with BG in range) were computed. Sensitivity, specificity, positive likelihood ratio (PLR), and true positive rates were also calculated. RESULTS: Overall comparison of DAD Hits to Misses yielded significantly more Hits for both low and high BG. Total sensitivity was 57.0%, with increased sensitivity to low BG (59.2%) compared to high BG (56.1%). Total specificity was 49.3% and PLR = 1.12. However, high variability in accuracy was observed across DADs, with low BG sensitivity ranging from 33% to 100%. Number of DADs achieving >= 60%, 65% and 70% true positive rates was 71%, 50% and 44%, respectively. CONCLUSIONS: DADs may be able to detect out-of-range BG, but variability across DADs is evident. Larger trials are needed to further assess DAD accuracy and to identify factors influencing the complexity of DAD accuracy in BG detection. PMID- 28627307 TI - Sleep Quality Associated With Different Work Schedules: A Longitudinal Study of Nursing Staff. AB - PURPOSE: To explore the differences in sleep parameters between nurses working a slow, forward rotating shift and those working a fixed day shift. METHOD: A longitudinal parallel-group comparison design was used in this prospective study. Participants (female) were randomly assigned to a rotating shift or a fixed day shift group. Participants in the rotating shift group worked day shift for the first 4 weeks, followed by evening shift for the second and night shift the third. Those in the day shift group worked day shift for all 12 weeks. Each kept a sleep diary and wore an actigraph (actigraph data were used to calculate total sleep time [TST], sleep onset latency [SOL], wake after sleep onset [WASO], and sleep efficiency [SE]) for 12 days, from Workday 1-4 in each of Weeks 4, 8, and 12. RESULTS: TST in nurses working evening rotating shift was higher than that for those working the day or night rotating shift and fixed day shift. WASO was significantly longer on Day 2 for rotating shift participants working evening versus day shift. SOL and SE were significantly shorter and lower in rotating shift nurses working night versus both day and evening shifts. CONCLUSIONS: A comprehensive understanding of the sleep patterns and quality of nurses with different work shifts may lead to better management of work shifts that reduces the influence of shift work on sleep quality. PMID- 28627308 TI - Hormonal and Neuromuscular Responses to Breastfeeding: A Pilot Study. AB - OBJECTIVES: Difficult breastfeeding in the first weeks after birth may result in muscle tension in infants and activation of the maternal hypothalamic-pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Our primary objective was to examine the feasibility of collecting neuroendocrine markers of maternal HPA axis and SNS activation (salivary cortisol and alpha-amylase [sAA]) and electromyographic (EMG) markers of infant distress during feeding in the first 2 weeks after birth. We also examined the relationships of these indices to each other and to mother-infant interactive behaviors during feeding. METHODS: We recruited mothers in the postpartum unit of a teaching hospital and observed a feeding in the dyad's home. Cortisol and sAA were sampled before feeding, 10 min into feeding, at feeding end, and 20 min after feeding. Infant muscle activity was recorded continuously with an EMG data logger. We used the Nursing Child Assessment Feeding Scale to measure mother-infant interaction. RESULTS: The 20 mothers reported no disruption to breastfeeding and no change in infant behavior due to collection measures. Mean cortisol levels decreased significantly; there was no significant change in sAA levels. Relationships were found between interactive behavior and trends in neuroendocrine biomarkers. Longer bursts of infant muscle activity were associated with higher levels of maternal cortisol during feeding but not mother-infant interactive behaviors. CONCLUSIONS: Maternal salivary biomarkers and their association with feeding behaviors can be a useful tool for clinical longitudinal research beginning soon after birth. Infant EMG data may be useful for assessing maternal arousal. PMID- 28627309 TI - Measuring Light at Night and Melatonin Levels in Shift Workers: A Review of the Literature. AB - Shift work, especially that involving rotating and night shifts, is associated with an increased risk of diseases, including cancer. Attempts to explain the association between shift work and cancer in particular have focused on the processes of melatonin production and suppression. One hypothesis postulates that exposure to light at night (LAN) suppresses melatonin, whose production is known to slow the development of cancerous cells, while another proposes that circadian disruption associated with shift work, and not just LAN, increases health risks. This review focuses on six studies that employed quantitative measurement of LAN and melatonin levels to assess cancer risks in shift workers. These studies were identified via searching the PubMed database for peer-reviewed, English-language articles examining the links between shift work, LAN, and disease using the terms light at night, circadian disruption, health, risk, cancer, shift work, or rotating shift. While the results indicate a growing consensus on the relationship between disease risks (particularly cancer) and circadian disruption associated with shift work, the establishment of a direct link between LAN and disease has been impeded by contradictory studies and a lack of consistent, quantitative methods for measuring LAN in the research to date. Better protocols for assessing personal LAN exposure are required, particularly those employing calibrated devices that measure and sample exposure to workplace light conditions, to accurately assess LAN's effects on the circadian system and disease. Other methodologies, such as measuring circadian disruption and melatonin levels in the field, may also help to resolve discrepancies in the findings. PMID- 28627311 TI - Landmark cure rate models with time-dependent covariates. AB - We propose a class of landmark cure rate models by incorporating time-dependent covariates. The landmark approach enables us to obtain dynamic predictions of a patient's survival probabilities as new clinical information emerges during the follow-up time. The proposed method extends the landmark model for failure time data with a possible cure fraction. We specify a series of landmark time points, and for each of time point, we construct a landmark data set consisting of only those at-risk individuals at the landmark time. The time-dependent covariates can be fixed at the values evaluated at the landmark time point. Through landmarking, our framework accommodates the Cox proportional hazards model, accelerated failure time model and censored quantile regression model in the presence of a cure proportion. We conduct simulation studies to assess the estimation accuracy of the proposed method, and illustrate it with data from a heart transplant study. PMID- 28627310 TI - Comparing cluster-level dynamic treatment regimens using sequential, multiple assignment, randomized trials: Regression estimation and sample size considerations. AB - Cluster-level dynamic treatment regimens can be used to guide sequential treatment decision-making at the cluster level in order to improve outcomes at the individual or patient-level. In a cluster-level dynamic treatment regimen, the treatment is potentially adapted and re-adapted over time based on changes in the cluster that could be impacted by prior intervention, including aggregate measures of the individuals or patients that compose it. Cluster-randomized sequential multiple assignment randomized trials can be used to answer multiple open questions preventing scientists from developing high-quality cluster-level dynamic treatment regimens. In a cluster-randomized sequential multiple assignment randomized trial, sequential randomizations occur at the cluster level and outcomes are observed at the individual level. This manuscript makes two contributions to the design and analysis of cluster-randomized sequential multiple assignment randomized trials. First, a weighted least squares regression approach is proposed for comparing the mean of a patient-level outcome between the cluster-level dynamic treatment regimens embedded in a sequential multiple assignment randomized trial. The regression approach facilitates the use of baseline covariates which is often critical in the analysis of cluster-level trials. Second, sample size calculators are derived for two common cluster randomized sequential multiple assignment randomized trial designs for use when the primary aim is a between-dynamic treatment regimen comparison of the mean of a continuous patient-level outcome. The methods are motivated by the Adaptive Implementation of Effective Programs Trial which is, to our knowledge, the first ever cluster-randomized sequential multiple assignment randomized trial in psychiatry. PMID- 28627313 TI - An Integrative Theoretical Model of Public Support for Ex-Offender Reentry. AB - Prior research suggests that public and ex-offender characteristics are associated with attitudes toward ex-offenders and support for their reentry; however, research examining reasons for these associations is limited. Research also is limited on the association between attitudes toward ex-offenders generally, and support for their reentry, specifically. Implicit theory offers a new approach to explaining public attitudes through beliefs in the fixed or malleable nature of people (i.e., mindsets). We developed and tested an integrative model applying implicit theory to investigate mechanisms through which beliefs explain support for reentry. Results showed that growth mindsets predicted more positive attitudes toward ex-offenders, which, in turn, predicted greater support for reentry. Belief in a just world, prior contact with an ex offender, and political orientation were among the covariates of reentry support. Beyond supporting the application of implicit theory in this context, findings suggest that anti-stigma interventions should target growth mindsets to promote community reintegration. PMID- 28627314 TI - Thicker endometrial linings are associated with better IVF outcomes: a cohort of 6331 women. AB - Our objective was to determine if a correlation exists between endometrial thickness measured on the day of ovulation trigger during an in vitro fertilization (IVF) cycle and pregnancy outcomes among non-cancelled cycles. We performed a retrospective cohort study looking at 6331 women undergoing their first, fresh autologous IVF cycle from 1 May 2004 to 31 December 2012 at Boston IVF (Waltham, MA). Our primary outcome was the risk ratio (RR) of live birth and positive beta-hCG. We found that thicker endometrial linings were associated with positive beta-hCG and live birth rates. For each additional millimetre of endometrial thickness, we found a statistically significant increased risk of positive beta-hCG (adjusted RR: 1.14; 95% CI: 1.09-1.18) and live birth (RR: 1.08; 95% CI: 1.05-1.11). There was no association between endometrial thickness and miscarriage (RR: 0.99; 95% CI: 0.91-1.07). Similar results were seen when categorizing endometrial thickness. Compared with an endometrial thickness >7 to <11 mm, the likelihood of a live birth was significantly higher for an endometrial thickness >=11 mm (adjusted RR: 1.23; 95% CI: 1.11-1.37) and significantly lower for the <=7 mm group (adjusted RR: 0.64; 95% CI: 0.45-0.90). In conclusion, thicker endometrial linings were associated with increased pregnancy and live birth rates. PMID- 28627315 TI - Bioabsorbable Fixation Screw for Proximal Interphalangeal Arthrodesis of Lesser Toe Deformities. AB - BACKGROUND: Although standard fixation of proximal interphalangeal (PIP) arthrodesis by K-wire is relatively inexpensive and well established, it does have some drawbacks, making newer fixation devices interesting. The aim of this study was to clinically and radiologically assess the operative correction of the lesser toe deformation in the form of a PIP arthrodesis using a bioabsorbable 2.7 mm fixation screw. METHODS: From January 2011 until October 2013, 34 patients underwent a PIP arthrodesis using the TRIM-IT (Arthrex) 2.7-mm fixation screw and were contacted for this retrospective cohort study. At an average of 3.3 years after the operation, 24 patients and 26 toes were evaluated clinically, radiologically, through pedobarography, and a patient-satisfaction survey. RESULTS: Using the PLLA screw for fixation, 84.6% showed bony union of the arthrodesis, and 84.6% were satisfied. Mean AOFAS score was 82.7 points and thus regarded as good. The mean VAS score was 1.3/10. Overall, 73.1% of the toes showed good alignment, and 7.7% had a painless recurrence of deformity and were still satisfied with the intervention. In addition, 34.6% had floating toes, but only 4.2% without Weil osteotomy or encroachment. Further, 3.8% were advised to undergo a revision because of severe misalignment. CONCLUSION: The 2.7-mm bioabsorbable fixation screw yielded results that were comparable to other fixation devices for PIP fusion fixation regarding success rate, revisions, and patient acceptance. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28627316 TI - Associations between management practices and colostrum quality on New Zealand dairy farms. AB - AIMS: To describe colostrum quality in spring-calving dairy herds in New Zealand, in terms of Brix, pH and total and coliform bacterial counts and to investigate associations between farm management practices and these measures of colostrum quality. METHODS: In June 2015, commercial dairy farms (n=105), located in North and South Islands of New Zealand, were visited shortly after the first cows had calved, and when approximately 50% and 80% of the herd had calved (early, middle and late visits). One litre of pooled colostrum that was being fed to newborn calves was collected at each visit and used to determine Brix, pH, total bacterial and coliform counts. A survey of calf management practices was conducted with the herd manager or calf rearer after the final visit. RESULTS: Of 298 pooled colostrum samples tested 29/298 (9.7%) had Brix >22%. Brix was higher on farms where calves were picked up twice daily compared with once daily (18.2 (95% CI=16.5-19.9)% vs. 15.9% (95% CI=15.2-16.6)%; p=0.012), and was lower where first milking colostrum was combined with colostrum obtained at later milkings (15.0 (95% CI=13.9-16.1)%) compared with where it was not (16.9 (95% CI=16.3 17.6)%; p=0.002). Vaccination of all cows against calf diarrhoeal pathogens was associated with increased Brix compared with no vaccination (18.1 (95% CI=16.6 19.6)% vs. 16.3 (95% CI=15.6-17.0)%; p=0.033). Mean pH of samples tested decreased from 5.97 (95% CI=5.84-6.09) to 5.58 (95% CI=5.45-5.71) for early and late-season visits, respectively (p<0.001). Of 268 samples tested, 23 (8.6%) had bacterial counts below the recommended threshold of 1.00*105 cfu/mL. Mean bacterial counts increased from 2.75 (95% CI=1.80-3.70)*108 to 4.99 (95% CI=3.95 6.03)*108 cfu/mL for early and late-season visits, respectively (p<0.001). Of 259 samples tested, 23 (8.9%) had coliform counts below the recommended threshold of 1.00*104 cfu/mL. CONCLUSIONS AND CLINICAL RELEVANCE: On a large majority of dairy farms included in this study the pooled colostrum fed to newborn calves had sub optimal Brix and excessive bacterial counts. Farm-level risk factors such as twice daily pick up of calves from the paddocks, herd vaccination and feeding pooled colostrum that did not combine colostrum obtained at later milkings with first milking colostrum were associated with colostrum quality measures. PMID- 28627317 TI - The European system for the control of the safety of food-contact materials needs restructuring: a review and outlook for discussion. AB - The present European system to assure the safety of migrates from food-contact materials (FCMs) needs improvement. It is proposed to implement better the self control by the producers through improved official control and more attractive listing of approved substances and materials (the latter being subject of another discussion paper). The initial concept of a positive list for the substances used, a limit for the overall migration and regulation of compliance testing was recognised as insufficient long ago, as it does not properly cover reaction products (including oligomers) and impurities. It also turned out to be unrealistic to cover all 17 types of FCMs owing to lack of resources by the authorities. Therefore, European Union legislation shifted the focus to the compliance work carried out by the business operators (in-house documentation and declaration of compliance). However, this approach has not been properly implemented. This is partly due to lack or unsuccessful control by authorities. A suitable structure of this control still needs to be built. It is proposed that specialised document-collection centres working with dedicated tools harmonised throughout Europe be created. Further, since most migrating substances are not listed, the toxicological evaluation reported by industry must be checked by risk assessment authorities. Finally, effective and harmonised measures are needed to react in case of non-compliance. The currently large gap between the legal requirements and reality must be bridged by introducing flexibility: authorised work plans by industry are proposed. It is also proposed to encourage certified private institutes to approve compliance work, driven by the attractive listing of approved materials and exploiting market forces. In the long run, the focus of the authorities might change from evaluating the substances used and regulating migration testing to the evaluation of the compliance work performed by industry, which means moving from legislation supporting industry towards checking self control. PMID- 28627318 TI - Effects of gamma rays on the regeneration of murine hair follicles in the natural hair cycle. AB - PURPOSE: This review evaluates the effects of gamma-rays on the regeneration of murine hair follicles in the natural hair cycle. A series of studies were performed to investigate this issue, in which the whole bodies of C57BL/10JHir mice in the 1st telogen phase of the hair cycle were irradiated with gamma-rays. RESULTS: The dermis of the irradiated skin showed a decrease in hair follicle density and induction of curved hair follicles along with the presence of white hairs and hypopigmented hair bulbs in the 2nd and 3rd anagen phases. An increased frequency of hypopigmented hair bulbs was still observed in the later hair cycle at postnatal day 200. There was no significant difference in the number of stem cells in the hair bulge region between control and irradiated skin. CONCLUSIONS: These results show that the effects of gamma-rays on the pigmentation of murine hair follicles are persistently carried over to later hair cycles, although those on the number and structure of hair follicles appear to be hidden by the effects of aging. Our findings may be important for understanding the mechanisms of the actions of stem cells on hair regeneration in connection with age-related phenotypes. PMID- 28627319 TI - Selection and Evaluation of Media for Behavioral Health Interventions Employing Critical Media Analysis. AB - Although a growing number of psychosocial health promotion interventions use the critical analysis of media to facilitate behavior change, no specific guidelines exist to assist researchers and practitioners in the selection and evaluation of culturally relevant media stimuli for intervention development. Mobilizing Our Voices for Empowerment is a critical consciousness-based health enhancement intervention for HIV-positive Black young gay/bisexual men that employs the critical analysis of popular media. In the process of developing and testing this intervention, feedback on media stimuli was collected from youth advisory board members (n = 8), focus group participants (n = 19), intervention participants (n = 40), and intervention facilitators (n = 6). A thematic analysis of qualitative data resulted in the identification of four key attributes of media stimuli and participants' responses to media stimuli that are important to consider when selecting and evaluating media stimuli for use in behavioral health interventions employing the critical analysis of media: comprehension, relevance, emotionality, and action. These four attributes are defined and presented as a framework for evaluating media, and adaptable tools are provided based on this framework to guide researchers and practitioners in the selection and evaluation of media for similar interventions. PMID- 28627320 TI - An Exploratory Study on the Anti-inflammatory Effects of Fucoidan in Relation to Quality of Life in Advanced Cancer Patients. AB - BACKGROUND: Conventional anticancer therapies still cause difficulties with selective eradication and accompanying side effects that reduce patients' quality of life (QOL). Fucoidan is extracted from seaweeds and has already exhibited broad bioactivities, including anticancer and anti-inflammatory properties, in basic studies. It is expected to enhance therapeutic efficacy and minimize side effects in cancer patients; however, despite its potential benefits, there are very few clinical trials using fucoidans. Therefore, we performed an exploratory clinical study for advanced cancer patients to examine the efficacy of fucoidans, especially focusing on inflammation in relation to QOL scores. METHODS: We conducted a prospective, open-label clinical study for advanced cancer patients using fucoidans via oral administration; 20 advanced cancer patients with metastases were recruited and were given 400 mL/d fucoidan (10 mg/mL) for at least 4 weeks. Inflammatory biomarkers, including high-sensitivity C-reactive protein and various cytokines, and QOL scores were monitored before treatment, after 2 weeks, and after 4 weeks of fucoidan ingestion. RESULTS: The main proinflammatory cytokines, including interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were significantly reduced after 2 weeks of fucoidan ingestion. QOL scores, including fatigue, stayed almost stable without significant changes during the study period. The univariate and multivariate analyses revealed that the responsiveness of IL-1beta was a significant independent prognostic factor. CONCLUSION: This is the first study providing evidence of the anti-inflammatory effects of fucoidans for advanced cancer patients. In future studies, larger blinded, controlled trials are required to establish the efficacy of fucoidan as supportive care for cancer patients, especially those undergoing chemotherapy. PMID- 28627321 TI - Diabetes Knowledge, Management, and Prevention Among Haitian Immigrants in Philadelphia. AB - Purpose Guided by the PEN-3 Cultural Model, the purpose of this study is to generate culturally framed insight into diabetes knowledge, management, and prevention among Haitians. Despite the disproportionate distribution of type II diabetes mellitus among US minorities, limited research explores outcomes within racial ethnic groups. It is particularly important to disaggregate the large racial-ethnic groups of black given the population growth among foreign-born blacks, such as Haitians, whose population has more than quadrupled in recent decades. Methods Focus group interviews were employed to understand diabetes knowledge, management, and prevention in the Haitian immigrant population in Philadelphia. Interviews were conducted in 2 groups: (1) people living with diabetes and (2) an at-risk sample for diabetes (defined as 30 and older with self-reported family history of diabetes). Interviews were recorded and transcribed verbatim in preparation for content analysis. Results Of the 10 participants, who were recruited through a Philadelphia church-based population, ages ranged from 41 to 91, with an average of 65. Content analysis revealed 3 emergent themes across: (1) cultural identity, including person, extended family, and neighborhood; (2) relationships and expectations, including perceptions, enablers, and nurturers; and (3) cultural empowerment, including positive, existential, and negative. Conclusions Results may inform culturally appropriate diabetes interventions for Haitians. Future research should explore compliance with food recommendations as well as the cultural competency of health care professional's information delivery. PMID- 28627322 TI - Orienting to see what's important: Learn to ignore the irrelevant. AB - The current study used a triad judgment task to assess whether blocking by comparison type in a triad judgment task could lead people to pay less attention to surface-level (irrelevant) features and pay more attention to deep (structural) features of information. A sample of 313 participants recruited through Mechanical Turk participated in this study. On each triad, participants were asked to evaluate which of two source scenarios went best with the target scenario. Three types of triads were constructed with materials related to the ability to perceive ethical issues within the practice of psychology. One type of triad contrasted a scenario that was similar to the target in terms of surface level features and a scenario that was similar in terms of deep features (similar surface-similar deep, SS/SD). A second triad type contrasted a scenario that was similar in terms of deep features with an unrelated scenario (similar deep unrelated, SD/U). The third contrasted a scenario that was similar in terms of surface features with an unrelated scenario (similar surface-unrelated, SS/U). There were 10 triads of each type. We found that with all the blocking orders except two, participants reliably chose the SS scenario over the SD scenario for the SS/SD triads. However, participants who started out with the SD/U triads did not. The results provide evidence that people often have the ability to perceive the deep, but they are distracted by the surface-level features. The results also show that people can be oriented away from being distracted by the surface-level features so that they can see the deep. PMID- 28627323 TI - Perspective of alphavbeta6-Integrin Imaging for Clinical Management of Pancreatic Carcinoma and Its Precursor Lesions. AB - beta6-integrin immunohistochemistry analysis of a large number of pancreatic ductal adenocarcinoma (PDAC, 383 primary tumors, 7 lymph node, and 8 distant metastases) and 34 pancreatic intraepithelial neoplasia (PanIN) specimens revealed a high prevalence of alphavbeta6-integrin expression in PDAC primaries (88%) and in almost all metastases, as well as in PanIN (57%). These findings underscore the high potential of a novel alphavbeta6-integrin targeting positron emission tomography (PET) radiopharmaceutical, Ga-68-Avebehexin, for early diagnosis of pancreatic cancer. PMID- 28627324 TI - Preparation, characterization, and in vitro cytotoxicity of chitosan hydrogels containing silver nanoparticles. AB - Hydrogels, chitosan as well as silver nanoparticles become in recent years materials characterized by a great interest. In present paper hydrogel based on chitosan and containing mentioned type of nano-sized particles have been synthesized by means of photopolymerization. Sorption capacity in selected liquids as well as behavior in simulated body fluid (such as Ringer's liquid) have been determined. Particularly attention was paid to the studies on toxicity of the hydrogels in relation to the epidermal cells as well as on their impact on growth of selected strain of bacteria (Escherichia coli). Furthermore, impact of introduction of nanosilver into hydrogel matrix on its properties has also been defined. Surface morphology of attained hydrogels by means of SEM analysis and chemical structure using spectroscopy have been checked. The most interesting conclusion is the fact that proposed chitosan based hydrogels modified with nanosilver do not affect negatively on epidermal cells. However, they inhibit a growth of E. coli. These two observations make them very interesting from the medical point of view. PMID- 28627325 TI - The Association Between Handgrip Strength and Diabetes on Activities of Daily Living Disability in Older Mexican Americans. AB - OBJECTIVE: The aim of this study is to determine the independent and joint effects of muscle weakness and diabetes on incident activities of daily living (ADL) disability in older Mexican Americans. METHOD: A subsample of 2,270 Mexican Americans aged at least 65 years at baseline were followed for 19 years. Handgrip strength was normalized to body weight (normalized grip strength [NGS]). Weakness was defined as NGS <=0.46 in males and <=0.30 in females. Diabetes and ADL disability were self-reported. RESULTS: Compared with participants that were not weak and did not have diabetes, those that had diabetes only, were weak only, and were both weak and had diabetes experienced a 1.94 (95% confidence interval [CI] = [1.89, 1.98]), 1.17 (CI = [1.16, 1.19]), and 2.12 (CI = [2.08, 2.16]) higher rate for ADL disability, respectively. DISCUSSION: Muscle weakness and diabetes were independently and jointly associated with higher rates for ADL disability in older Mexican Americans. PMID- 28627326 TI - Triphenylamines Induce Cell Death Upon 2-Photon Excitation. AB - Photodynamic therapy (PDT) is a promising therapeutic method for several diseases, in particular for cancer. This approach uses a photosensitizer, oxygen, and an external light source to produce reactive oxygen species (ROS) at lethal doses to induce cell death. One drawback of current PDT is the use of visible light which has poor penetration in tissues. Such a limitation could be overcome by the use of novel organic compounds compatible with photoactivation under near infrared light excitation. Triphenylamines (TPAs) are highly fluorescent compounds that are efficient to induce cell death upon visible light excitation (458 nm), but outside the biological spectral window. Interestingly, we recently showed that TPAs target cytoplasmic organelles of living cells, mainly mitochondria, and induce a high ROS production upon 2-photon excitation (in the 760-860 nm range), leading to a fast apoptosis process. However, we observed significant differences among the tested TPA compounds in terms of cell distribution and time courses of cell death-related events (apoptosis vs necrosis). In summary, TPAs represent serious candidates as photosensitizers that are compatible with 2-photon excitation to simultaneously trigger and imaging cell death although the relationship between their subcellular localization and the cell death mechanism involved is still a matter of debate. PMID- 28627327 TI - Paolo Mantegazza and the dream of 'making' science popular circa 1860-1900. PMID- 28627329 TI - Passages on Brazilian scientific cinema. AB - The article examines the conditions of production and recognition of scientific cinema in Brazil by comparing three distinct moments and contexts: the first moment takes place in the nineteenth century, and it is related to the contribution of a Brazilian astronomer otherwise little known to Brazilian film scholars, the second addresses Benedito Junqueira Duarte's voluminous mid twentieth-century filmography, and the third moment documents recent scientific film experiences within ultra high resolution movies transmitted over photonic networks. Future trajectories for aesthetic concerns and practical issues such as the archiving of ultra high definition cinema are usefully informed by these histories of scientific cinema, even as a current generation of multidisciplinary teams including scientists, filmmakers, computer scientists, and network engineers reinvent, rediscover, and necessarily expand the scientific cinema toward concerns of real time collaboration and teaching. PMID- 28627331 TI - Dynamic Transmit-Receive Beamforming by Spatial Matched Filtering for Ultrasound Imaging with Plane Wave Transmission. AB - During conventional ultrasound imaging, the need for multiple transmissions for one image and the time of flight for a desired imaging depth limit the frame rate of the system. Using a single plane wave pulse during each transmission followed by parallel receive processing allows for high frame rate imaging. However, image quality is degraded because of the lack of transmit focusing. Beamforming by spatial matched filtering (SMF) is a promising method which focuses ultrasonic energy using spatial filters constructed from the transmit-receive impulse response of the system. Studies by other researchers have shown that SMF beamforming can provide dynamic transmit-receive focusing throughout the field of view. In this paper, we apply SMF beamforming to plane wave transmissions (PWTs) to achieve both dynamic transmit-receive focusing at all imaging depths and high imaging frame rate (>5000 frames per second). We demonstrated the capability of the combined method (PWT + SMF) of achieving two-way focusing mathematically through analysis based on the narrowband Rayleigh-Sommerfeld diffraction theory. Moreover, the broadband performance of PWT + SMF was quantified in terms of lateral resolution and contrast from both computer simulations and experimental data. Results were compared between SMF beamforming and conventional delay-and sum (DAS) beamforming in both simulations and experiments. At an imaging depth of 40 mm, simulation results showed a 29% lateral resolution improvement and a 160% contrast improvement with PWT + SMF. These improvements were 17% and 48% for experimental data with noise. PMID- 28627330 TI - GPU-accelerated Kernel Regression Reconstruction for Freehand 3D Ultrasound Imaging. AB - Volume reconstruction method plays an important role in improving reconstructed volumetric image quality for freehand three-dimensional (3D) ultrasound imaging. By utilizing the capability of programmable graphics processing unit (GPU), we can achieve a real-time incremental volume reconstruction at a speed of 25-50 frames per second (fps). After incremental reconstruction and visualization, hole filling is performed on GPU to fill remaining empty voxels. However, traditional pixel nearest neighbor-based hole-filling fails to reconstruct volume with high image quality. On the contrary, the kernel regression provides an accurate volume reconstruction method for 3D ultrasound imaging but with the cost of heavy computational complexity. In this paper, a GPU-based fast kernel regression method is proposed for high-quality volume after the incremental reconstruction of freehand ultrasound. The experimental results show that improved image quality for speckle reduction and details preservation can be obtained with the parameter setting of kernel window size of [Formula: see text] and kernel bandwidth of 1.0. The computational performance of the proposed GPU-based method can be over 200 times faster than that on central processing unit (CPU), and the volume with size of 50 million voxels in our experiment can be reconstructed within 10 seconds. PMID- 28627332 TI - Dissociation between wanting and liking for alcohol and caffeine: A test of the Incentive Sensitisation Theory. AB - Limited human studies have directly tested the dissociation between wanting and liking with human substance users, a core tenet of the Incentive Sensitisation Theory (IST). The aim of this study is to test the dissociation between wanting and liking in humans across two commonly used licit substances, alcohol and caffeine. The STRAP-R (Sensitivity To Reinforcement of Addictive and other Primary Rewards) questionnaire was administered to 285 alcohol users (mean age=33.30, SD= 8.83) and 134 coffee users (mean age=33.05, SD=8.10) ranging in their levels of substance use to assess wanting and liking. Findings showed that in high risk alcohol users wanting may drive alcohol consumption more so than liking, compared with low risk alcohol users. However, wanting and liking did not significantly dissociate as alcohol consumption increased. These findings partially support IST. Additionally, IST was not supported in coffee users. It is possible that caffeine functions differently at the neurological level compared with alcohol, perhaps explaining the lack of dissociation emerging in coffee users as caffeine use increased. Nevertheless, the current study makes several contributions to IST research. Future studies should focus on utilising the STRAP R with a clinically dependent sample to test the dissociation between wanting and liking. PMID- 28627333 TI - Influence of preservation methods on the quality of colostrum sourced from New Zealand dairy farms. AB - AIMS: To assess the effect of two temperatures (ambient temperature and 4 degrees C), three preservation methods (no preservative, yoghurt and potassium sorbate), and two periods of storage (3 and 7 days) on Brix and total bacterial and coliform counts of colostrum collected from New Zealand dairy farms. METHODS: One litre of colostrum destined to be fed to newborn calves was collected from 55 New Zealand dairy farms in the spring of 2015. Six aliquots of 150 mL were obtained from each colostrum sample, with two aliquots left untreated, two treated with potassium sorbate and two with yoghurt, and one of each pair of aliquots stored at ambient temperature and the other at 4 degrees C. All samples were tested for Brix, total bacterial counts and coliform counts before treatment (Day 0), and after 3 and 7 days of storage. The effect of preservation method and storage temperature on the change in Brix, bacterial and coliform counts after 3 or 7 days of storage was analysed using multivariable random effects models. RESULTS: For all outcome variables there was a temperature by preservation interaction. For aliquots preserved with potassium sorbate, changes in Brix and bacterial counts did not differ between aliquots stored at ambient temperature or 4 degrees C, but for aliquots preserved with yoghurt or no preservative the decrease in Brix and increase in bacterial counts was greater for aliquots stored at ambient temperature than 4 degrees C (p<0.001). For aliquots preserved with potassium sorbate, coliform counts decreased at both temperatures, but for aliquots preserved with yoghurt or no preservative coliform counts increased for aliquots stored at 4 degrees C, but generally decreased at ambient temperatures (p<0.001). There was also an interaction between duration of storage and temperature for bacterial counts (p<0.001). The difference in the increase in bacterial counts between aliquots stored at 4 degrees C and ambient temperature after 3 days was greater than between aliquots stored at 4 degrees C and ambient temperature after 7 days. CONCLUSIONS AND CLINICAL RELEVANCE: Use of potassium sorbate to preserve colostrum for 3 or 7 days resulted in little or no reduction in Brix and a lower increase in total bacterial counts than colostrum stored without preservative or with yoghurt added. Colostrum quality was not affected by storage temperature for samples preserved with potassium sorbate, but storage at 4 degrees C resulted in better quality colostrum than storage at ambient temperatures for colostrum with no preservative or yoghurt added. PMID- 28627334 TI - Wheelchair pushing and turning: lumbar spine and shoulder loads and recommended limits. AB - The objective of this study was to determine how simulated manual wheelchair pushing influences biomechanical loading to the lumbar spine and shoulders. Sixty two subjects performed simulated wheelchair pushing and turning in a laboratory. An electromyography-assisted biomechanical model was used to estimate spinal loads. Moments at the shoulder joint, external hand forces and net turning torque were also assessed. Multiple linear regression techniques were employed to develop biomechanically based wheelchair pushing guidelines relating resultant hand force or net torque to spinal load. Male subjects experienced significantly greater spinal loading (p < 0.01), and spine loads were also increased for wheelchair turning compared to straight wheelchair pushing (p < 0.001). Biomechanically determined maximum acceptable resultant hand forces were 17-18% lower than psychophysically determined limits. We conclude that manual wheelchair pushing and turning can pose biomechanical risk to the lumbar spine and shoulders. Psychophysically determined maximum acceptable push forces do not appear to be protective enough of this biomechanical risk. Practitioner Summary: This laboratory study investigated biomechanical risk to the low back and shoulders during simulated wheelchair pushing. Manual wheelchair pushing posed biomechanical risk to the lumbar spine (in compression and A/P shear) and to the shoulders. Biomechanically determined wheelchair pushing thresholds are presented and are more protective than the closest psychophysically determined equivalents. PMID- 28627335 TI - Effects of exposure pathways on the accumulation and phytotoxicity of silver nanoparticles in soybean and rice. AB - The widespread use of silver nanoparticles (AgNPs) raises concerns both about their accumulation in crops and human exposure via crop consumption. Plants take up AgNPs through their leaves and roots, but foliar uptake has been largely ignored. To better understand AgNPs-plant interactions, we compared the uptake, phytotoxicity and size distribution of AgNPs in soybean and rice following root versus foliar exposure. At similar AgNP application levels, foliar exposure led to 17-200 times more Ag bioaccumulation than root exposure. Root but not foliar exposure significantly reduced plant biomass, while root exposure increased the malondialdehyde and H2O2 contents of leaves to a larger extent than did foliar exposure. Following either root or foliar exposure, Ag-containing NPs larger (36.0-48.9 nm) than the originally dosed NPs (17-18 nm) were detected within leaves. These particles were detected using a newly developed macerozyme R-10 tissue extraction method followed by single-particle inductively coupled plasma mass spectrometry. In response to foliar exposure, these NPs were stored in the cell wall and plamalemma of leaves. NPs were also detected in planta following Ag ion exposure, indicating their in vivo formation. Leaf-to-leaf and root-to-leaf translocation of NPs in planta was observed but the former did not alter the size distribution of the NPs. Our observations point to the possibility that fruits, seeds and other edible parts may become contaminated by translocation processes in plants exposed to AgNPs. These results are an important contribution to improve the risk assessment of NPs under environmental exposure scenarios. PMID- 28627336 TI - [Chinese expert consensus on the medical measures for inhalation injury due to the poisoning smoke grenade explosion in 2017]. PMID- 28627337 TI - [Consensus on diagnosis and treatment of black spider stung in Xinjiang region]. PMID- 28627338 TI - [Problems of flying medical treatment and transport in critically ill patients are worthy of attention and research]. PMID- 28627339 TI - [Evaluation of adsorption effect of activated charcoal on oral paraquat poisoning: an experimental study on large animal]. AB - OBJECTIVE: To study the adsorption effect of activated charcoal suspension on paraquat (PQ) in gastrointestinal tract of beagles exposed to PQ. METHODS: Twenty healthy male beagles were randomly divided into experimental group and control group, with 6 beagles in each group. 20% PQ solution (a dose of 30 mg/kg) was prescribed through stomach for beagles in both groups. After exposure to PQ for 30 minutes, the beagles in experimental group were given activated charcoal suspension (1.0 g/kg of type I activated charcoal powder mixed with 100 mL of normal saline) by gavage, while the control group was only given equal volume of normal saline. After exposure to PQ for 10 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, and 48 hours, blood was collected from hepatic portal veins and peripheral veins to detect the PQ concentration change in the plasma. The toxicokinetics software DAS 2.1.1 was applied to analyze PQ concentration and compare the change in toxicokinetics parameters between the both groups. The change in vital signs including heart rate (HR), respiratory rate (RR) and pulse oxygen saturation (SpO2) was dynamically monitored 10 minutes before exposure, 4 hours and each day from the 1st to the 7th day after exposure. RESULTS: After exposure to PQ, the poison concentration in the plasma of hepatic portal veins and peripheral veins in the control group rose quickly and reached peak 4 hours later. It fell quickly at first, and fell slowly 8 hours later. But in the experimental group, the increase rate to the peak was significantly slow. Besides, PQ peak fell more obviously than that in the control group and it was about 50% of the control group (MUg/L: 123.50+/-11.67 vs. 255.18+/-12.29 in blood from hepatic portal veins, 122.35+/-11.72 vs. 250.86+/-11.15 in blood from peripheral veins). After 8 hours it fell much more quickly than that of the control group. After exposure to PQ for 48 hours, PQ concentration in the plasma was still lower than that of the control group (MUg/L: 0.53+/-0.18 vs. 15.98+/ 5.58 in blood from hepatic portal veins, 0.31+/-0.01 vs. 15.03+/-4.82 in blood from peripheral veins, both P < 0.01). With the toxicokinetics analysis, compared with the control group, the maximum concentration (Cmax) and area under the curve (AUC) of PQ in the plasma of hepatic portal veins and peripheral veins in the experimental group were significantly decreased [Cmax (MUg/L): 125.07+/-9.49 vs. 255.18+/-12.29 in blood from hepatic portal veins, 123.38+/-9.52 vs. 250.86+/ 11.15 in blood from peripheral veins; AUC (mg*L-1*h-1): 1.6+/-0.2 vs. 3.3+/-0.4 in blood from hepatic portal veins, 1.5+/-0.2 vs. 3.2+/-0.3 in blood from peripheral veins], time to the peak (Tmax) of PQ was slowed (hours: 5.3+/-1.9 vs. 4.0+/-0.0 in blood from hepatic portal veins, 4.7+/-1.5 vs. 4.0+/-0.0 in blood from peripheral veins), and PQ plasma half-life (t1/2) and mean retention time (MRT) were significantly shortened [t1/2 (hours): 3.8+/-1.2 vs. 15.4+/-3.7 in blood from hepatic portal veins, 3.5+/-1.0 vs. 15.5+/-2.7 in blood from peripheral veins; MRT (hours): 8.0+/-1.5 vs. 13.4+/-1.2 in blood from hepatic portal veins, 7.6+/-1.3 vs. 13.3+/-1.2 in blood from peripheral veins; all P < 0.01]. After exposure to PQ, HR and RR in both the experimental group and the control group increased and reached to the peak about the 4th day and then the increase rate began to slow down gradually; SpO2 slowed down gradually and reached to the valley about the 4th day and then it began to recover, but the change range of vital signs in the experimental group was smaller than that of the control group, and the parameters were significantly better than those of control group [4-day HR (bpm): 134.50+/-3.04 vs. 142.00+/-6.43, 4-day RR (times/min): 31.00+/-0.58 vs. 34.33+/-0.94, 4-day SpO2: 0.900+/-0.006 vs. 0.873+/ 0.005, all P < 0.05]. CONCLUSIONS: Activated charcoal administrated at 30 minutes after PQ poisoning can slow down the increase rate of PQ concentration in the plasma, decrease the peak concentration and has less influence on vital signs in beagles. PMID- 28627340 TI - [Experimental study on formation of neutrophil extracellular traps in human peripheral blood induced by paraquat in vitro]. AB - OBJECTIVE: To explore whether paraquat (PQ) can induce the formation of neutrophil extracellular traps (NETs) in human peripheral blood. METHODS: Neutrophils were isolated from healthy human peripheral blood, and the cells were identified by hematoxylin-eosin (HE) strain. The cells were treated with different concentrations of PQ [0 (as control), 200, 400, 600, 800, 1 000 and 1 200 MUmol/L], and the cell viability was measured by cell proliferation and CCK-8 cytotoxicity detection kit, and the median lethal concentration of PQ was selected. The cells were treated with the median lethal concentration of PQ (PQ poisoning group), and the untreated cells were served as the control. Immunofluorescence staining was adopted to evaluate NETs formation. PicoGreen dye was used to determine the quantitative content of circulating free DNA. Western Blot was used to determine the expressions of citrullinated histone 3 (H3Cit) and myeloperoxidase (MPO) in the supernatant. RESULTS: The purity of neutrophils was about 95% by HE staining. The cells were treated with different concentrations of PQ, and the result showed that the viability of cells was (58+/-2)% with 800 MUmol/L PQ for treatment. The immunofluorescence showed that there were few expressions of H3Cit and MPO in neutrophils in the control group, and there was no NETs formation, which was composed of DNA, H3Cit and MPO. Compared with the control group, a large amount of NETs was generated from neutrophils stimulated by 800 MUmol/L of PQ. Meanwhile, quantitative result showed that the content of cell free DNA in the supernatant was significantly increased in PQ poisoning group as compared with that of control group (MUg/L: 2 235+/-462 vs. 561+/-87, P < 0.01). The protein expressions of H3Cit and MPO in the supernatant were also significantly increased as compared with those of control group [H3Cit protein expression (gray value): 0.23+/-0.03 vs. 0.11+/-0.01, MPO protein expression (gray value): 0.47+/-0.05 vs. 0.21+/-0.04, both P < 0.05]. CONCLUSIONS: 800 MUmol/L of PQ can induce the formation of NETs in human peripheral blood. PMID- 28627341 TI - [Protective effects of valproic acid on gut barrier function after major burn injury and its mechanism]. AB - OBJECTIVE: To investigate the potential protective effects of valproic acid (VPA) on gut barrier function after major burn injury in rats and its mechanism. METHODS: Forty male Sprague-Dawley (SD) rats were divided into sham + normal saline (NS), sham + VPA, scald + NS, and scald + VPA groups, with 10 rats in each group. Rat with 55% total body surface area (TBSA) third-degree severe-burns model was reproduced by immersing into 80 degrees C water, and the rats in sham groups were given sham-burns by immersing into 37 degrees C water. The rats after severe-burns were immediately treated with 0.25 mL of 300 mg/kg VPA or NS by subcutaneous injection. Rats were sacrificed at 2 hours and 6 hours after injury, and abdominal aortic blood and ileal tissue were harvested. The levels of vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assay (ELISA). The intestinal permeability was evaluated by fluorescein isothiocyanate-dextran (FITC-dextran) determination. The histomorphological changes in gut barrier were evaluated by Chiu grading system. Levels of acetylated lysine at the ninth position of histone 3 protein (Ac-H3K9), hypoxia-inducible factor 1alpha (HIF-1alpha), zona occludens 1 (ZO-1) and myosin light chain kinase (MLCK) were determined by immunofluorescence staining and Western Blot. RESULTS: Compared with sham + NS group, rats in scald + NS group showed intestinal mucosal damage 2 hours after burn injury, as well as increased mucosal permeability, protein expression levels of HIF-1alpha, VEGF, MLCK, and lowered levels of AC-H3K9 and ZO-1. These changes were much more prominent at 6 hours after injury. VPA treatment significantly attenuated the burn-induced intestinal damage. Compared with scald + NS group, the protective effects in scald + VPA group was not evident at 2 hours after injury; however, intestinal damage was much less severe at 6 hours after injury (Chiu score: 2.03+/-0.27 vs. 3.12+/-0.15), intestinal permeability was significantly decreased [FITC-dextran (MUg/L): 709+/-76 vs. 1 138+/-75], histone acetylation was enhanced [Ac-H3K9 (gray value): 1.55+/-0.12 vs. 0.48+/-0.12], ZO-1 degradation was significantly inhibited (gray value: 0.69+/-0.12 vs. 0.43+/-0.16), the protein expression levels of VEGF and MLCK were significantly down-regulated [VEGF (ng/mg): 51.7+/ 3.7 vs. 71.2+/-4.3, MLCK (gray value): 1.98+/-0.20 vs. 2.80+/-0.24], while the HIF-1alpha protein expression levels were significantly reduced at both 2 hours and 6 hours after injury (gray value: 2.50+/-0.39 vs. 3.88+/-0.42 at 2 hours, 1.83+/-0.42 vs. 4.42+/-0.41 at 6 hours, all P < 0.05). CONCLUSIONS: Severe burn injury can induce histone deacetylation, ZO-1 degradation and intestinal barrier dysfunction. VPA can improve the levels of histone acetylation and ZO-1, and protect intestinal epithelial barrier function. These may probably be mediated through inhibiting HIF-1alpha and its downstream gene VEGF and MLCK. PMID- 28627342 TI - [Baicalein attenuates acute lung injury induced by intestinal ischemia/reperfusion via inhibition of nuclear factor-kappaB pathway in mice]. AB - OBJECTIVE: To investigate the effects of baicalein (Bai) on acute lung injury (ALI) induced by intestinal ischemia/reperfusion (I/R) and its mechanism in mice. METHODS: Twenty-four male C57BL/6J mice were divided into three groups by random number table: namely sham group, I/R group and Bai+I/R group, with 8 mice in each group. Intestinal I/R induced lung injury model was reproduced by clamping superior mesenteric artery for 90 minutes, followed by reperfusion. Bai (100 mg/kg) was intraperitoneally injected 1 hour before ischemic challenge in the Bai+I/R group. The mice in sham group underwent the similar procedure with I/R group but without vascular occlusion. All mice were sacrificed at 4 hours of reperfusion, and blood was collected from inferior vena cava and lung tissues were harvested. Lung tissues were stained with hematoxylin-eosin (HE), and histological changes were examined under light microscope for pathological score. Lung wet/dry (W/D) ratio was calculated. Lung cell apoptosis was determined by TdT-mediated dUTP nick end labeling (TUNEL) technique. Serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA expressions of TNF-alpha and IL-6 in lung tissues were determined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). The protein expression levels of cytoplasmic inhibitory factor-alpha of nuclear factor-kappaB (IkappaB-alpha) and nucleus NF-kappaB were determined by Western Blot. RESULTS: Under light microscope, a normal lung tissue structure was shown in the sham group and no evidence of obvious lung injury was found. In the I/R group, the alveolar structure was seriously damaged. The alveolar wall was widened and there was significant interstitial edema and leukocytes infiltration. In the Bai+I/R group, pathological damage was significantly decreased as indicated by reduced lung tissue edema and leukocytes infiltration. Compared with the sham group, the lung pathological scores, W/D ratio and cellular apoptosis in the I/R group were significantly increased. Both serum TNF-alpha and IL-6 contents and lung TNF alpha and IL-6 mRNA expressions were significantly increased. Furthermore, I/R significantly resulted in a decrease of IkappaB-alpha in the cytoplasm and an increase of NF-kappaB in the nucleus. Notably, Bai treatment significantly attenuated ALI induced by intestinal I/R injury. Compared with the I/R group, the lung pathological scores and W/D ratio in the Bai+I/R group were significantly decreased (lung pathological score: 4.59+/-1.17 vs. 6.27+/-1.34, W/D ratio: 3.79+/-0.28 vs. 4.32+/-0.57), cellular apoptosis was significantly decreased [(4.85+/-2.47)% vs. (8.15+/-2.33)%], both serum TNF-alpha and IL-6 contents and lung TNF-alpha and IL-6 mRNA expressions were significantly decreased [serum TNF alpha (pg/L): 124.18+/-30.49 vs. 167.72+/-38.65, IL-6 (ng/L): 1.65+/-0.69 vs. 2.43+/-0.57; lung TNF-alpha mRNA (2-DeltaDeltaCt): 4.75+/-2.38 vs. 7.69+/-2.32, IL-6 mRNA (2-DeltaDeltaCt): 16.45+/-4.39 vs. 27.69+/-6.82], additionally, Bai pretreatment significantly increased cytoplasmic IkappaB-alpha protein expression (gray value: 0.47+/-0.11 vs. 0.27+/-0.09), while decreased nuclear NF-kappaB protein expression (gray value: 0.57+/-0.13 vs. 1.07+/-0.14, all P < 0.05). CONCLUSIONS: Bai could attenuate intestinal I/R injury induced ALI via the inhibition of inflammation and apoptosis. PMID- 28627343 TI - [Study on the role of autophagy in heme oxygenase 1 preventing hepatic ischemia/reperfusion injury in rats]. AB - OBJECTIVE: To identify the role of autopahgy in the protective mechanism of heme oxygenase 1 (HO-1) against hepatic ischemia/reperfusion (I/R) injury. METHODS: Forty healthy male Sprague-Dawley (SD) rats were randomly (random number table) divided into five groups (n = 8 in each group), namely sham group, model group, cobalt protoporphyrin (CoPP) group, zinc protoporphyrin (ZnPP) group and 6-amino 3-methylpurine (3-MA) group. Partial hepatic I/R model was established by clamping the pedicles of left and median lobes for 1 hour and reopening for 6 hours in rats, and the rats in sham group were only received celiotomp without hepatic I/R. In the CoPP group, CoPP (a HO-1 inducer, 5 mg/kg) was administered i.p 24 hours before I/R. In the ZnPP or 3-MA group, besides pretreatment with CoPP, the rats were given ZnPP (a HO-1 inhibitor, 25 mg/kg) or 3-MA (an autophagy inhibitor, 30 mg/kg) i.p 1 hour before I/R. Serum alanine aminotransferase (ALT) was determined with automatic biochemistry analyzer. The hepatic pathological scores (PS) were determined under light microscope using hematoxylin-eosin (HE) staining. The hepatocyte apoptosis index (AI) was assessed with terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Autophagosomes in liver tissue were counted under electron microscope. The mRNA expressions of HO-1, caspase-3, Beclin-1 and Atg-5 in the liver were determined by reverse transcription-polymerase chain reaction (RT-PCR). The HO-1 activity was also measured by the generation of bilirubin with the method of double-wave spectrophotometry. RESULTS: Compared with the sham group, the level of serum ALT significantly increased in the I/R group (U/L: 560.3+/-73.6 vs. 49.1+/-13.8, P < 0.01), HE staining showed a severe hepatic injury (PS: 12.0+/-2.0 vs. 1.3+/-0.9, P < 0.01), TUNEL staining showed a higher hepatocytes apoptosis and the expression of caspase-3 significantly increased [AI: (19.38+/-3.07)% vs. (3.25+/ 1.28)%, caspase-3 mRNA (2-DeltaDeltaCt): 4.62+/-0.40 vs. 1.05+/-0.15, both P < 0.01]. However, there was no significant difference in the expression of HO-1 and the genes associated with autophagy between the two groups. In the CoPP group, the hepatic injury was blunted compared with that in the I/R group [ALT (U/L): 223.3+/-34.4 vs. 560.3+/-73.6, PS: 5.6+/-2.3 vs. 12.0+/-2.0, AI: (11.38+/-2.39)% vs. (19.38+/-3.07)%, caspase-3 mRNA (2-DeltaDeltaCt): 2.42+/-0.33 vs. 4.62+/ 0.40, all P < 0.01]. HO-1 was induced in the CoPP group and autophagy was also increased significantly after I/R when compared with those in the I/R group [HO-1 mRNA (2-DeltaDeltaCt): 3.01+/-0.71 vs. 1.14+/-0.20, HO-1 activity (pmol*mg-1*h 1): 259+/-37 vs. 113+/-26, the number of autophagosomes: 8.75+/-0.87 vs. 1.25+/ 0.71, Beclin-1 mRNA (2-DeltaDeltaCt): 2.85+/-0.28 vs. 1.15+/-0.11, Atg-5 mRNA (2 DeltaDeltaCt): 2.44+/-0.25 vs. 1.14+/-0.12, all P < 0.01]. In the ZnPP group, the activity of HO-1 was much lower than that in the CoPP group, and as a result autophagy was decreased and liver injury was increased. In the 3-MA group, although there was no difference in the activity of HO-1 compared with that in the CoPP group, autophagy was inhibited, and the protective effect of CoPP was eliminated. CONCLUSIONS: HO-1 could regulate the level of autophagy during liver I/R, and in turn autophagy might mediate the protective effects of HO-1 against liver I/R injury. PMID- 28627344 TI - [Protective effect of BAG-1L mediated by lentivirus in human neuroblastoma cells induced by hypoxia]. AB - OBJECTIVE: To investigate the protective effects of lentivirus mediated Bcl-2 associated athanogene 1L (BAG-1L) over-expression on human neuroblastoma cells (SH-SY5Y) induced by hypoxia/re-oxygenation, and to study its effect on the phosphoinositide 3 kinase serine/threonine protein kinase (PI3K/AKT) pathway. METHODS: SH-SY5Y cells were cultured in vitro, and the cells at logarithmic phase were collected, and they were divided into recombined lentiviral infection group [infected by lentivirus containing BAG-1L and green fluorescent protein (GFP) gene], vector control group (infected by lentivirus containing GFP without BAG-1L gene) and cell control group (non-infection). Western Blot was used to detect the expression of BAG-1L in target cells after infection for 48 hours. SH-SY5Y cells were subjected to hypoxia for 8 hours and re-oxygenation for 24 hours, then the cell counting kit-8 (CCK-8) was used to detect the cell activity, and the apoptosis was detected by flow cytometry after allophycocyanin labeled annexin V/7-amino actinomycin D (Annexin V-APC/7-AAD) staining. Western Blot was used to detect the protein expressions of BAG-1L, heat shock protein 70 (HSP70), AKT and phosphorylated AKT (p-AKT). RESULTS: After infection for 48 hours, exogenous BAG 1L protein bands were observed in recombined lentiviral infection group, but not observed in cell control group and vector control group. After hypoxia/re oxygenation treatment, the cell viability in recombined lentiviral infection group was significantly higher than that in cell control group and vector control group (A value: 0.689+/-0.036 vs. 0.425+/-0.013, 0.400+/-0.012), apoptosis was significantly decreased [apoptosis rate: (26.97+/-1.82)% vs. (36.60+/-1.45)%, (35.77+/-3.74)%], the protein levels of BAG-1L, HSP70 and p-AKT were significantly increased [BAG-1L protein (gray value): 2.405+/-0.167 vs. 0.529+/ 0.141, 0.601+/-0.099; HSP70 protein (gray value): 0.997+/-0.123 vs. 0.634+/ 0.091, 0.584+/-0.106; p-AKT protein (gray value): 1.234+/-0.118 vs. 0.661+/ 0.210, 0.712+/-0.199, all P < 0.01], but the protein level of AKT was slightly increased (gray value: 1.103+/-0.269 vs. 0.646+/-0.188, 0.791+/-0.326) without statistically significant differences (both P > 0.05). There was no significant difference in all parameters between cell control group and vector control group (all P > 0.05). CONCLUSIONS: Lentivirus mediated BAG-1L gene over-expression can protect nerve cells against hypoxic injury and apoptosis, and the protective effect may be related to the activation increase of pathway on PI3K/AKT. PMID- 28627345 TI - [Effects of microRNA-21 inhibitor on apoptosis of type II alveolar epithelial cells in rats with hyperoxia-induced acute lung injury]. AB - OBJECTIVE: To observe the effects of microRNA-21 (miR-21) inhibitor on apoptosis of type II alveolar epithelial cells (AEC II) in rats with hyperoxia-induced acute lung injury (HALI). METHODS: Eighty Sprague-Dawley (SD) rats were divided into air-control group, hyperoxia injury group, empty-virus control group (200 MUL solution with lentivirus was dropped into the nasal) and miR-21 inhibitor pretreatment group (200 MUL solution with lentivirus contained miR-21 inhibitor was dropped through the nasal) by random number table. After treatment, the rats in all groups were fed in the hyperoxia incubator with oxygen concentration exceeding 90% for production of HALI model, and the rats in air-control group were fed normally without any treatment. Ten rats were selected at 0, 24, 48 and 72 hours after exposure in hyperoxia environment respectively, and the general changes of lung tissues were observed in light microscope. The right lung tissues were harvested to observe the pathological changes under light microscopy. The left lung tissues of other 10 rats in each group were harvested at 48 hours after execution, the miR-21 expression was determined by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR), the protein expression of cysteinyl aspartate-specific proteinase-3 (caspase-3) was determined by Western Bolt, and apoptosis of AEC II was detected by TdT-mediated dUTP nick end labeling (TUNEL). RESULTS: (1) No abnormal appearance in lung tissues was observed at all time points in the air-control group. In hyperoxia injury group, the lung injury would be more severe if the exposure time was longer, and lung tissues turned dark red after exposure for 72 hours, with patchy hemorrhage in several places; the structure of lung tissues was disordered, the alveolar wall was broken, the alveolar septum was significantly edematous and broadened, and there was plenty of inflammatory cell infiltration and edema fluid appeared inside the alveolar space. In miR-21 inhibitor pretreatment group, the degree of lung tissue injury was more severe than that of the hyperoxia injury group, and there was no significant change in empty-virus control group. (2) Compared with air-control group, miR-21 expression of the hyperoxia injury group was significantly decreased (2-DeltaDeltaCt: 0.021+/-0.005 vs. 0.037+/-0.006), and the protein expression of caspase-3 was significantly increased (A value: 0.423+/-0.081 vs. 0.123+/-0.023, both P < 0.05). After pretreatment with miR-21 inhibitor, the expression of miR-21 was further decreased (2-DeltaDeltaCt: 0.014+/-0.003 vs. 0.021+/-0.005), while the protein expression of caspase-3 was further increased (A value: 0.691+/-0.085 vs. 0.423+/-0.081, both P < 0.05). There were no statistically significant differences in the expression of miR-21 (2-DeltaDeltaCt: 0.025+/-0.007 vs. 0.021+/-0.005) and caspase-3 (A value: 0.475+/ 0.062 vs. 0.423+/-0.081) between empty-virus control group and hyperoxia injury group (both P > 0.05). (3) Compared with air-control group, the apoptosis cells in hyperoxia injury group were increased, which was further increased after pretreatment of miR-21 inhibitor, but no changes were found in empty-virus control group. CONCLUSIONS: Inhibition of miR-21 expression in vivo could aggravate the injury of lung tissue in HALI rats, and increase the apoptosis of AEC II. PMID- 28627346 TI - [Study on Rac1/MAPK/ERK pathway mediated mechanism and role in rats with ventilator induced lung injury]. AB - OBJECTIVE: To investigate the role of Ras-related C3 botulinum toxin substrate 1/mitogen-activated protein kinase/extracellular signal-regulated kinase (Rac1/MAPK/ERK) signal pathway in rats with ventilator induced lung injury (VILI) and its mechanism. METHODS: Thirty Sprague-Dawley (SD) rats were randomly divided into spontaneous respiration group, normal tidal volume (VT) group and high VT group with 10 rats in each group. The rats in spontaneous respiration group were kept their spontaneous breathing. The rats in normal VT group and high VT group were performed tracheal intubation after tracheostomy, and underwent mechanical ventilation on bilateral lungs with 6 mL/kg and 40 mL/kg VT respectively with maintenance anesthesia. After 4-hour ventilation, heart blood, bronchoalveolar lavage fluid (BALF) and lung tissues were harvested. The levels of interleukins (IL-1beta, IL-6), tumor necrosis factor-alpha (TNF-alpha), myeloperoxidase (MPO) and macrophage inflammatory protein-2 (MIP-2) in serum and BALF were determined by enzyme linked immunosorbent assay (ELISA). Lung wet/dry radio (W/D) was determined. The lung tissues were stained with hematoxylin and eosin (HE), and pathological changes were observed, and pathological scores were evaluated. The ultra structure changes in type II alveolar epithelial cells (AEC II) were observed with transmission electron microscope. The positive expressions of phosphorylation of extracellular signal-regulated kinase (p-ERK) were determined by immunohistochemistry, and those of Rac1 and F-actin were determined by immunofluorescence. The mRNA expressions of ERK and Rac1 were determined by real time fluorescent quantitation reverse transcription-polymerase chain reaction (RT qPCR), and protein expressions of Rac-1, p-ERK and F-actin were determined by Western Blot. RESULTS: (1) Compared with spontaneous breathing group, lung W/D in both mechanical ventilation groups was significantly increased, with more significant increase in the high VT group (6.64+/-0.88 vs. 1.79+/-0.36, P < 0.01). (2) There was no obvious pathological changes in the lung tissue and AEC II of the spontaneously breathing group. In the normal VT group, there was slight edema and infiltration of inflammatory cells; AEC II had less lamellar bodies and uniform distribution of the villi of the alveolar epithelium. In the high VT group, the edema of the lung tissue, the widening of the pulmonary septum, the alveolus congestion, the infiltration of inflammatory cells, and alveolar structure disorder were found; and AEC II was irregular, the number of lamellar bodies in the plastids was decreased and was unevenly distributed. The pulmonary histopathological score in the high VT group was significantly higher than that in the spontaneous breathing group and the normal VT group (12.00+/-2.00 vs. 6.00+/-1.51, 8.50+/-0.53, both P < 0.01). (3) Compared with spontaneous breathing group, IL-1beta, IL-6, TNF-alpha, MPO, and MIP-2 in serum and BALF in both mechanical ventilation groups were significantly increased, with more significant increase in the high VT group [serum IL-1beta (ng/L): 104.2+/-15.1 vs. 20.3+/ 8.3, IL-6 (ng/L): 46.6+/-11.5 vs. 22.7+/-7.5, TNF-alpha (ng/L): 39.4+/-6.5 vs. 5.4+/-1.9, MPO (ng/L): 0.66+/-0.24 vs. 0.06+/-0.03, MIP-2 (ng/L): 109.2+/-25.8 vs. 22.8+/-8.4; BALF IL-1beta (ng/L): 121.5+/-25.6 vs. 24.0+/-7.5, IL-6 (ng/L): 136.7+/-32.7 vs. 31.4+/-10.5, TNF-alpha (ng/L): 98.0+/-14.8 vs. 10.1+/-2.6, MPO (ng/L): 0.80+/-0.31 vs. 0.08+/-0.04, MIP-2 (ng/L): 144.4+/-28.9 vs. 41.2+/-20.7; all P < 0.01]. (4) There were only a few p-ERK, Rac1 and F-actin positive expressions in the spontaneous breathing group. The positive expressions in normal VT group were increased. In high VT group, the positive expression of p ERK was significantly increased; Rac1 and F-actin were mainly distributed in the cell membrane and cytoplasm respectively, the positive expressions were further enhanced. (5) The gene expressions of ERK and Rac1, and protein expressions of p ERK, Rac1 and F-actin in the high VT group were significantly higher than those in the spontaneous breathing group and normal VT group [ERK mRNA (2 DeltaDeltaCt): 8.23+/-2.83 vs. 1, 3.02+/-1.38, p-ERK protein (gray value): 1.15+/ 0.36 vs. 0.61+/-0.23, 0.88+/-0.22; Rac1 mRNA (2-DeltaDeltaCt): 4.45+/-2.26 vs. 1, 1.22+/-0.39, Rac1 protein (gray value): 0.91+/-0.16 vs. 0.48+/-0.11, 0.55+/-0.10; F-actin protein (gray value): 0.70+/-0.09 vs. 0.49+/-0.08, 0.55+/-0.04; all P < 0.01]. CONCLUSIONS: F-actin expression in lung tissue was up-regulated in rats with VILI, which resulted in reconstruction of AEC II cyto-skeleton, and variation of cell membrane permeability through Rac1/MAPK/ERK signaling pathway during VILI. PMID- 28627347 TI - [Clinical effect of pulmonary rehabilitation therapy including respiratory exercise and vibration expectoration on patients with pulmonary infection after abdominal surgery]. AB - OBJECTIVE: To investigate the clinical effect of pulmonary rehabilitation therapy including respiratory exercise and vibration expectoration on patients with pulmonary infection after abdominal surgery. METHODS: A retrospective case control study was conducted. Seventy-six patients with pulmonary infection after abdominal surgery admitted to the First Affiliated Hospital of Hunan Normal University from September 2015 to September 2016 were enrolled. According to whether accept the pulmonary rehabilitation therapy or not, the patients were divided into two groups. In the control group (n = 35), the conventional expectoration method was adopted. The patients in pulmonary rehabilitation group (n = 41) received both methods of the control group and pulmonary rehabilitation treatment, including respiratory exercise (effective cough, lip reduction breathing), respiratory exercise device (respiratory exerciser tri-ball), and vibrated expectoration. The 24-hour sputum volume, degree of comfort, inflammatory and pulmonary function parameters, and recovery situation were recorded in the two groups. RESULTS: (1) There were no significant differences in the parameters of inflammation and pulmonary function before treatment between the two groups. After treatment, the white blood cell (WBC) and C-reactive protein (CRP) in both groups were significantly decreased, and the forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC) were significantly increased. The above changes in pulmonary rehabilitation group were more significant than those of the control group [WBC (*109/L): 11.12+/-2.88 vs. 13.42+/-2.62 at 3 days, 8.22+/-1.48 vs. 9.27+/-1.92 at 5 days; CRP (mg/L): 13.47+/-4.77 vs. 16.03+/-4.94 at 3 days, 9.69+/-1.56 vs. 11.77+/-1.41 at 5 days; FEV1 (L): 2.48+/-0.14 vs. 2.29+/-0.16 at 3 days, FEV1/FVC: 0.78+/-0.04 vs. 0.75+/ 0.04 at 3 days; all P < 0.05]. (2) The 24-hour sputum volume within 3 days of pulmonary rehabilitation group were significantly higher than that of the control group (mL: 30.51+/-4.15 vs. 18.30+/-3.64 at 1 day, 31.08+/-3.22 vs. 20.37+/-3.20 at 2 days, 29.03+/-2.55 vs. 19.03+/-2.51 at 3 days, all P < 0.01]. (3) In the pulmonary rehabilitation group, the recovery time of pulmonary infection symptoms (days: 5.44+/-1.45 vs. 6.20+/-1.55), the days of antibiotic use (days: 12.61+/ 3.15 vs. 15.03+/-3.78), the time of getting out of the bed (days: 4.05+/-0.74 vs. 4.51+/-0.89), and the hospital days (days: 19.95+/-3.90 vs. 22.00+/-4.42) were significantly shorter than those of the control group (all P < 0.05), and the degree of comfort was significantly better than that of the control group (comfort score: 2.71+/-0.90 vs. 2.14+/-0.91, P < 0.01). CONCLUSIONS: The application of pulmonary rehabilitation including respiratory exercise and vibration expectoration in abdominal surgery patients with pulmonary infection can promote recovery, and it has a good clinical and practical application value. PMID- 28627348 TI - [Effect of hydrogen-rich water on the CD34 expression in lesion boundary brain tissue of rats with traumatic brain injury]. AB - OBJECTIVE: To observe the effect of hydrogen-rich water on the CD34 expression and angiogenesis in lesion boundary brain tissue of rats with traumatic brain injury (TBI). METHODS: A total of 54 adult male Sprague-Dawley (SD) rats were divided into three groups by random number table: namely sham-operated group (sham group), trauma group (TBI group), and trauma + hydrogen-rich water group (TBI+HW group), the rats in each group were subdivided into 1, 3 and 7 days subgroups according to the time points after trauma, with 6 rats in each subgroup. The TBI model was reproduced by using a modified Feency method for free fall impact, and the rats in sham group were not given brain impact after craniotomy. The rats in TBI+HW group were given intraperitoneal injection of hydrogen-rich water (5 mL/kg) after TBI model reproduction, and then once a day until being sacrificed, and the rats in sham group and TBI group were given the same amount of normal saline. The neurological severity scores (NSS) for neurologic deficits were calculated at corresponding time points, and then the rats were sacrificed for brain tissue at 3 mm around lesion boundary. After hematoxylin-eosin (HE) staining, the pathological changes in lesion boundary brain tissue were observed under light microscope. The expression of CD34+ cells was observed by immunohistochemical analysis, which markers were used to count the newborn blood capillary sprouts around the traumatic brain tissue. The protein expression of CD34 was determined by Western Blot. RESULTS: NSS scores at all time points in sham group were 0. NSS scores in TBI and TBI+HW groups showed a decreased tendency with time prolongation after TBI, which showed more significant in TBI+HW group, NSS scores at 3 days and 7 days were significantly lower than those of TBI group (3 day: 8.67+/-0.52 vs. 11.56+/-1.94, 7 days: 7.33+/-0.52 vs. 8.17+/-0.98, both P < 0.05). Under light microscope, the brain tissue of rats in sham group was normal. After injury, pathological changes in lesion boundary brain tissue in TBI group were characterized by obvious hemorrhagic necrosis, severe brain edema, a large number of degeneration and necrosis of nerve cells and inflammatory cell infiltration, and the pathological changes were more obvious at 3 days. The edema area in TBI+HW group was slightly smaller than that of TBI group, and the surrounding edema was slightly reduced. It was shown by immunohistochemistry that only a very small number of neoformative capillaries were found in sham group. The number of neoformative capillaries in lesion boundary brain tissue was gradually increased with time prolongation in TBI group. The number of neoformative capillaries in TBI+HW group was more significantly, which was significantly higher than that of TBI group at 3 days and 7 days after injury (cells/HP: 10.59+/-1.88 vs. 8.61+/-1.22 at 3 days, 23.20+/-3.16 vs. 17.01+/-2.64 at 7 days, both P < 0.05). It was shown by Western Blot that the expression of CD34 protein at all time points in TBI group was significantly increased as compared with that of sham group. The expression of CD34 protein at 1 day and 3 days in TBI+HW group was slightly increased as compared with that of TBI group without significant difference, but it was significantly up-regulated at 7 days after injury, which was significantly higher than that of TBI group (gray value: 1.36+/-0.36 vs. 0.74+/-0.08, P < 0.05). CONCLUSIONS: Hydrogen-rich water promote CD34+ cells home to the site of injured tissue in rats with TBI, is involved in angiogenesis, and improve clinical outcomes during brain functional recovery. PMID- 28627349 TI - [Clinical application of cardiopulmonary resuscitation with abdominal lifting and compression in emergency treatment]. AB - OBJECTIVE: To investigate the clinical value of cardiopulmonary resuscitation (CPR) with abdominal lifting and compression on patients with breathing and cardiac arrest induced by severe chest trauma. METHODS: Sixty-six breathing and cardiac arrest patients induced by severe chest trauma admitted to the General Hospital of Jingyuan Coal Industry Group Company from October 2011 to October 2016 were enrolled, and they were divided into abdominal lifting and compression group (n = 32) and unarmed abdominal compression group (n = 34) by random number table. The patients in both two groups were given the airway open, respiration support, defibrillation treatment, venous access establishment, vasoactive drugs application and other conventional treatments. On the basis of the routine treatment, the patients in abdominal lifting and compression group were given application of abdominal lifting and compression device with 100 times/min frequency and continuously alternating press down to lift the abdomen, the amplitude of pressing and pulling were 3-5 cm below or above the original level of the abdomen. Those in unarmed abdominal compression group were given abdominal CPR pressing method by hand, the frequency of pressing and depth of subsidence was the same as abdominal lifting and compression group. Heart rate (HR) and arterial blood gas at 30 minutes after CPR as well as the success rate of resuscitation were compared between the two groups. The changes in HR, mean arterial pressure (MAP) and pulse oxygen saturation (SpO2) before and 30 minutes and 60 minutes after CPR were dynamically observed in patients with restoration of spontaneous circulation (ROSC) after abdominal lifting and compression CPR treatment. RESULTS: Compared with the unarmed abdominal compression group, HR (bmp: 136.13+/-6.14 vs. 148.45+/-5.16) and arterial partial pressure of carbon dioxide [PaCO2 (mmHg, 1 mmHg = 0.133 kPa): 48.51+/-2.60 vs. 62.51+/-2.50] at 30 minutes after CPR in abdominal lifting and compression group were significantly lowered, and arterial partial pressure of oxygen (PaO2) was significantly increased (mmHg: 88.07+/-3.92 vs. 74.12+/-2.12, all P < 0.05). Four patients with ROSC were found in abdominal lifting and compression group, and 2 in unarmed abdominal compression group. The success rate of resuscitation in abdominal lifting and compression group was significantly higher than that of unarmed abdominal compression group (12.50% vs. 5.82%, P < 0.05). In 4 patients with ROSC after abdominal lifting and compression CPR showed a downward trend in HR and an upward trend in MAP and SpO2 with CPR time prolongation. CONCLUSIONS: The effect of abdominal lifting and compression CPR is better than that of unarmed abdominal compression CPR, which is of great value for the life saving of patients with breathing and cardiac arrest induced by severe chest trauma. PMID- 28627350 TI - [Construction and outlook of sharing information in pre-hospital emergency and emergency disposal in hospital]. PMID- 28627351 TI - [Experience of aero-medical evacuation of a patient with severe craniocerebral injury: a case report]. PMID- 28627352 TI - [Acute cor pulmonale in acute respiratory distress syndrome]. AB - OBJECTIVE: Acute respiratory distress syndrome (ARDS) is a severe respiratory condition that is characterized by rapidly progressive hypoxemia with noncardiogenic pulmonary edema. Despite the improvement of therapeutic methods, the mortality of ARDS is in the range of 40%-50% all over the world. Some studies have shown that a significant number of patients with ARDS had acute cor pulmonale (ACP), and ACP is independently associated with the mortality of patients with ARDS, which has attracted wide attention in recent years. This paper reviewed recent related studies, summarized the prevalence, pathogenesis and diagnostic approaches of ACP in ARDS, especially echocardiography which was considered as a cornerstone for ACP diagnosis, and elucidated the beneficial effects of right ventricular protective ventilatory strategy and prone positioning on the pulmonary vasculature and right heart, in order to provide a novel idea for the therapy of ACP in ARDS. PMID- 28627353 TI - [Ultrasonographic evaluation of diaphragm structure and function]. AB - OBJECTIVE: Diaphragm is the principal respiratory muscle. Diaphragm dysfunction resulting from mechanical ventilation, chronic cardiopulmonary disease, medicine, cardio-thoracic surgery, septic shock and chronic malnutrition predisposes to weaning failure from mechanical ventilation and prolongs intensive care unit (ICU) stay. Traditionally, the method of assessment of diaphragm structure and function was invasive, lacking specific, and was difficult to be used bedside. A number of recent studies have been suggested that ultrasonographic evaluation has been proposed as an accurate, safe and noninvasive method of quantification of diaphragm structure and function. This article reviews the related researches of technique and the clinical applications of ultrasonography in the evaluation of diaphragmatic structure and function, which may possibly result in timely identification of patients with diaphragm dysfunction and improve the assessment of recovery from diaphragm weakness. PMID- 28627354 TI - [Principle and influence factors of aerosolized antibiotics in the treatment of ventilator associated pneumonia]. AB - OBJECTIVE: Ventilator associated pneumonia (VAP) is a challenging complication of critical illness. Aerosolized antibiotic is an option for the management of VAP currently, as it is reported that it could increase levels of drug in alveolar without increasing systemic toxicity. The articles that focused on the aerosolized antibiotics in the treatment of VAP and its influence factors were reviewed, and it was found that to achieve maximum drug delivery efficiency and reduce the influence of nebulization method, some factors, such as ventilation modes, tidal volume, nebulizer type, should be adjusted and monitored during the treatment. PMID- 28627355 TI - [Recent advances in the pathogenesis and treatment of hypoproteinemia after surgical stress]. AB - OBJECTIVE: After major operation, a series of complicated pathological and physiological changes will occur during the trauma and stress state. The protein synthesis is affected, which results in negative nitrogen balance. In addition, the release of inflammatory factors can damage the capillary endothelial cells and increase the permeability of micrangium, induce vascular colloidal albumin leakage to the extravascular tissue, decrease plasma albumin, make wound edema, eventually lead to postoperative hypoproteinemia. Except for albumin supplement, it should be aimed at the mechanism to control the stress response and reduce the leakage caused by the release of inflammatory factors to solve this problem radically in clinical work. The reports about the causes and treatment of hypoproteinemia after major surgery were reviewed to provide evidence for clinical treatment. PMID- 28627356 TI - Aquatic therapy for children with Duchenne muscular dystrophy: a pilot feasibility randomised controlled trial and mixed-methods process evaluation. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent. OBJECTIVES: To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work. DESIGN: Parallel-group, single-blind, randomised pilot trial with nested qualitative research. SETTING: Six paediatric neuromuscular units. PARTICIPANTS: Children with DMD aged 7-16 years, established on corticosteroids, with a North Star Ambulatory Assessment (NSAA) score of 8-34 and able to complete a 10-m walk without aids/assistance. Exclusions: > 20% variation between baseline screens 4 weeks apart and contraindications. INTERVENTIONS: Participants were allocated on a 1 : 1 ratio to (1) optimised, manualised LBT (prescribed by specialist neuromuscular physiotherapists) or (2) the same plus manualised AT (30 minutes, twice weekly for 6 months: active assisted and/or passive stretching regime; simulated or real functional activities; submaximal exercise). Semistructured interviews with participants, parents (n = 8) and professionals (n = 8) were analysed using Framework analysis. An independent rater reviewed patient records to determine the extent to which treatment was optimised. A cost-impact analysis was performed. Quantitative and qualitative data were mixed using a triangulation exercise. MAIN OUTCOME MEASURES: Feasibility of recruiting 40 participants in 6 months, participant and therapist views on the acceptability of the intervention and research protocols, clinical outcomes including NSAA, independent assessment of treatment optimisation and intervention costs. RESULTS: Over 6 months, 348 children were screened - most lived too far from centres or were enrolled in other trials. Twelve (30% of target) were randomised to AT (n = 8) or control (n = 4). People in the AT (n = 8) and control (n = 2: attrition because of parental report) arms contributed outcome data. The mean change in NSAA score at 6 months was -5.5 [standard deviation (SD) 7.8] for LBT and -2.8 (SD 4.1) in the AT arm. One boy suffered pain and fatigue after AT, which resolved the same day. Physiotherapists and parents valued AT and believed that it should be delivered in community settings. The independent rater considered AT optimised for three out of eight children, with other children given programmes that were too extensive and insufficiently focused. The estimated NHS costs of 6-month service were between L1970 and L2734 per patient. LIMITATIONS: The focus on delivery in hospitals limits generalisability. CONCLUSIONS: Neither a full-scale frequentist randomised controlled trial (RCT) recruiting in the UK alone nor a twice-weekly open-ended AT course delivered at tertiary centres is feasible. Further intervention development research is needed to identify how community-based pools can be accessed, and how families can link with each other and community physiotherapists to access tailored AT programmes guided by highly specialised physiotherapists. Bayesian RCTs may be feasible; otherwise, time series designs are recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41002956. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 27. See the NIHR Journals Library website for further project information. PMID- 28627358 TI - Long-Term Changes in Bone Height After Mandibular Reconstruction Using a Free Fibula Graft in an Elderly Population. AB - PURPOSE: This study evaluated short-term and long-term changes in bone height after mandibular reconstruction using an osteotomized fibula graft, with the aim of identifying factors associated with atrophy of the graft in an elderly population. PATIENTS AND METHODS: This retrospective study involved patients who underwent mandibular reconstruction using a free vascularized fibula graft from 2005 through 2015 and had at least 12 months of follow-up. Postoperative panoramic radiographs were used to measure bone height at standardized locations on each segment of the graft at 1 year postoperatively and at later follow-up. RESULTS: The sample was composed of 30 patients (15 men, 15 women; mean age, 62.6 years; age range, 50 to 80 years). According to the HCL classification (H, hemimandibular segment including the condyle; C, central segment including both mandibular canine teeth; L, lateral segment without the condyle), mandibular defect types were L (n = 19), LC (n = 7), LCL (n = 3), and H (n = 1). There were 0 to 3 segmental osteotomies with the fibula graft. None of the patients received an osseointegrated dental implant during a mean follow-up of 4.0 years (range, 1.5 to 9.7 yr). All patients underwent reconstruction of the mandibular body, 10 of whom also underwent reconstruction of the mandibular ramus. Atrophy of the fibula graft was observed in 9.9 and 15.0% of the body segment and 5.9 and 6.6% of the ramal segment at 1 year postoperatively and at later follow-up, respectively. Graft hypertrophy occurred in the ramal segment in 2 patients. Multivariate analysis showed a significantly higher rate of graft atrophy in women than in men at later follow-up (P = .033). CONCLUSIONS: Fibula grafts showed long-term stability, and in 2 cases even a gain in bone height, in this elderly population. Female gender was identified as a risk factor for atrophy of the fibula bone graft in the body segment of the reconstructed mandible. PMID- 28627357 TI - The heat shock protein 90 of Toxoplasma gondii is essential for invasion of host cells and tachyzoite growth. AB - Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects almost all warm-blooded vertebrates. Heat shock proteins (HSP) regulate key signal transduction events in many organisms, and heat shock protein 90 (Hsp90) plays an important role in growth, development, and virulence in several parasitic protozoa. Here, we discovered increased transcription of the Hsp90 gene under conditions for bradyzoite differentiation, i.e. alkaline and heat shock conditions in vitro, suggesting that Hsp90 may be connected with bradyzoite development in T. gondii. A knockout of the TgHsp90 strain (DeltaHsp90) and a complementation strain were constructed. The TgHsp90 knockout cells were found to be defective in host-cell invasion, were not able to proliferate in vitro in Vero cells, and did not show long-time survival in mice in vivo. These inabilities of the knockout parasites were restored upon complementation of TgHsp90. These data unequivocally show that TgHsp90 contributes to bradyzoite development, and to invasion and replication of T. gondii in host cells. PMID- 28627359 TI - Evaluation of Early Postoperative Complications Following Tracheotomy. AB - PURPOSE: The purpose of this study was to evaluate the early postoperative complications related to tracheotomy performed by surgeons and residents in the Department of Oral and Maxillofacial Surgery (OMS) at the University of Florida College of Dentistry (UFCD; Gainesville, FL). The authors hypothesized that complications with this surgical technique would be substantially different among the different medical diagnoses of these patients and the number of complications would positively correlate with the American Society of Anesthesiologists (ASA) physical status classification. PATIENTS AND METHODS: The authors implemented a retrospective study of all patients who underwent a tracheotomy procedure by the UFCD OMS department from July 2011 through March 2015. Patients were evaluated for medical comorbidities (predictor variables) and tracheotomy complications (outcome variable) within 1 week of the procedure and were compared across ASA classes. RESULTS: A total of 319 patients were evaluated in this retrospective study. There were 14 patients identified with recorded complications, including 11 patients with a bleeding complication (3.4%), and 3 patients with other complications (0.9%). The other complications included dislodgement of the tube, subcutaneous emphysema, and cellulitis. The distribution of patients across ASA groups was not statistically different for patients with no bleeding versus bleeding complications (P > .05 by chi2 test). However, the distribution of patient gender was found to differ across ASA groups (P < .001 by chi2 test). The proportion of men to women in the bleeding complications group was not statistically different (P > .1 by binomial test). However, mean age was found to be statistically different for bleeding complications between men and women (63.4 yr for men; 42.7 yr for women; P < .05 by t test). CONCLUSIONS: The result of this study supports a low rate of complications after a tracheotomy procedure performed by faculty and residents at the UFCD OMS department and is lower than published tracheotomy complication rates reported by other surgical specialties. PMID- 28627361 TI - Incorporating the airway microbiome into asthma phenotyping: Moving toward personalized medicine for noneosinophilic asthma. PMID- 28627360 TI - The Plasmodium falciparum exported protein PF3D7_0402000 binds to erythrocyte ankyrin and band 4.1. AB - Plasmodium falciparum extensively modifies the infected red blood cell (RBC), resulting in changes in deformability, shape and surface properties. These alterations suggest that the RBC cytoskeleton is a major target for modification during infection. However, the molecular mechanisms leading to these changes are largely unknown. To begin to address this question, we screened for exported P. falciparum proteins that bound to the erythrocyte cytoskeleton proteins ankyrin 1 (ANK1) and band 4.1 (4.1R), which form critical interactions with other cytoskeletal proteins that contribute to the deformability and stability of RBCs. Yeast two-hybrid screens with ANK1 and 4.1R identified eight interactions with P. falciparum exported proteins, including an interaction between 4.1R and PF3D7_0402000 (PFD0090c). This interaction was first identified in a large-scale screen (Vignali et al., Malaria J, 7:211, 2008), which also reported an interaction between PF3D7_0402000 and ANK1. We confirmed the interactions of PF3D7_0402000 with 4.1R and ANK1 in pair-wise yeast two-hybrid and co precipitation assays. In both cases, an intact PHIST domain in PF3D7_0402000 was required for binding. Complex purification followed by mass spectrometry analysis provided additional support for the interaction of PF3D7_0402000 with ANK1 and 4.1R. RBC ghost cells loaded with maltose-binding protein (MBP)-PF3D7_0402000 passed through a metal microsphere column less efficiently than mock- or MBP loaded controls, consistent with an effect of PF3D7_0402000 on RBC rigidity or membrane stability. This study confirmed the interaction of PF3D7_0402000 with 4.1R in multiple independent assays, provided the first evidence that PF3D7_0402000 also binds to ANK1, and suggested that PF3D7_0402000 affects deformability or membrane stability of uninfected RBC ghosts. PMID- 28627362 TI - How to predict global trends in HCC mortality if neglecting more than half the world's cases? PMID- 28627364 TI - Modulating perceptual complexity and load reveals degradation of the visual working memory network in ageing. AB - Previous neuroimaging studies have reported a posterior to anterior shift of activation in ageing (PASA). Here, we explore the nature of this shift by modulating load (1,2 or 3 items) and perceptual complexity in two variants of a visual working memory task (VWM): a 'simple' color and a 'complex' shape change detection task. Functional near-infrared spectroscopy (fNIRS) was used to record changes in activation in younger (N=24) and older adults (N=24). Older adults exhibited PASA by showing lesser activation in the posterior cortex and greater activation in the anterior cortex when compared to younger adults. Further, they showed reduced accuracy at loads 2 and 3 for the simple task and across all loads for the complex task. Activation in the posterior and anterior cortices was modulated differently for younger and older adults. In older adults, increasing load in the simple task was accompanied by decreasing activation in the posterior cortex and lack of modulation in the anterior cortex, suggesting the inability to encode and/or maintain representations without much aid from higher-order centres. In the complex task, older adults recruited verbal working memory areas in the posterior cortex, suggesting that they used adaptive strategies such as labelling the shape stimuli. This was accompanied by reduced activation in the anterior cortex reflecting the inability to exert top-down modulation to typical VWM areas in the posterior cortex to improve behavioral performance. PMID- 28627365 TI - Mitochondria/metabolic reprogramming in the formation of neurons from peripheral cells: Cause or consequence and the implications to their utility. AB - The induction of pluripotent stem cells (iPSC) from differentiated cells such as fibroblasts and their subsequent conversion to neural progenitor cells (NPC) and finally to neurons is intriguing scientifically, and its potential to medicine is nearly infinite, but unrealized. A better understanding of the changes at each step of the transformation will enable investigators to better model neurological disease. Each step of conversion from a differentiated cell to an iPSC to a NPC to neurons requires large changes in glycolysis including aerobic glycolysis, the pentose shunt, the tricarboxylic acid cycle, the electron transport chain and in the production of reactive oxygen species (ROS). These mitochondrial/metabolic changes are required and their manipulation modifies conversions. These same mitochondrial/metabolic processes are altered in common neurological diseases so that factors related to the disease may alter the cellular transformation at each step including the final phenotype. A lack of understanding of these interactions could compromise the validity of the disease comparisons in iPSC derived neurons. Both the complexity and potential of iPSC derived cells for understanding and treating disease remain great. PMID- 28627363 TI - Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. AB - BACKGROUND AND AIMS: Although treatment for hepatitis C virus has been dramatically improved by the development of direct-acting antiviral agents (DAAs), whether interferon (IFN)-free therapy reduces hepatocarcinogenesis in an equivalent manner to IFN-based therapy remains controversial. The aims of this study were to evaluate the occurrence and recurrence of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients treated with DAAs and to identify biomarkers of HCC development after antiviral treatment. METHODS: A restrospective review of a prospective database of 1,897 CHC patients who were treated with IFN-based (1,145) or IFN-free therapies (752) was carried out. Cumulative HCC occurrence and recurrence rates were compared using propensity score-matched analysis. Predictors of HCC development after viral eradication were identified by multivariate analysis. RESULTS: Propensity score-matched analysis showed no significant difference in HCC occurrence (p=0.49) and recurrence rates (p=0.54) between groups treated with IFN-based or IFN-free therapies. In multivariate analysis, higher levels of post-treatment alpha fetoprotein (AFP) or Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+M2BP) were independently associated with HCC occurrence and recurrence after viral eradication. Only post-treatment WFA+M2BP level was significantly associated with HCC occurrence and recurrence among patients without severe fibrosis. The area under the receiver operating characteristic (ROC) curve for WFA+M2BP levels was greater than that for AFP levels in ROC analysis. CONCLUSION: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. Patients with high WFA+M2BP levels after antiviral treatment, even without severe fibrosis, must be followed up carefully for HCC development. Lay summary: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. PMID- 28627366 TI - PQBP1, an intrinsically disordered/denatured protein at the crossroad of intellectual disability and neurodegenerative diseases. AB - PQBP1 (polyglutamine binding protein-1) is the earliest identified molecule among the group of disease-related intrinsically disordered/denatured proteins. PQBP1 interacts with splicing-related factors via the disordered/denatured domain and regulates post-transcriptional gene expression. The mutations cause intellectual disability due to decreased dendritic spines and abnormal expression of synapse molecules in neurons, and microcephaly due to elongated cell cycle time and abnormal expression of cell cycle proteins in neural stem progenitor cells. Meanwhile, PQBP1 interacts with polyglutamine tract sequences translated from CAG triplet disease genes via their disordered/denatured structures. The second hit on PQBP1 by such neurodegenerative disease proteins is supposed to similarly impair synapse functions in neuron and proliferation of stem cells. The alteration of gene expression profile and consequently induced phenotypes of neuron and stem cells via secondary impairment of the intrinsically disordered/denatured protein PQBP1, which are similar to developmental disorders by PQBP1 gene mutations, could be a part of the main pathologies shared by multiple neurodegenerative diseases. PMID- 28627367 TI - Nrf2 pathway activation upon rotenone treatment in human iPSC-derived neural stem cells undergoing differentiation towards neurons and astrocytes. AB - Activation of Nrf2/ARE signaling pathway occurs ubiquitously in most cell types upon induction of oxidative stress. Rotenone, an inhibitor of mitochondrial complex I, can be used to trigger oxidative stress, stimulate the activation of Nrf2 pathway in neuronal and astrocytic cells and assess neurotoxicity. We have previously demonstrated that an acute treatment with rotenone can induce Nrf2 activation, which leads to astrocyte activation and dopaminergic (DA) neuronal cell death in a mixed neuronal/astrocytic cell model derived from human induced pluripotent stem cells (hiPSCs). In this study, we characterized the effects of a repeated dose treatment with rotenone (14 days) on hiPSC-derived neural stem cells (NSCs) undergoing differentiation, assessing the expression and the activation of the Nrf2 pathway. Our results show that Nrf2 signaling increases during NSC differentiation. Moreover, we observed that rotenone treatment induced a progressive activation of Nrf2 signaling together with a induction of astrocyte reactivity, a reduction of neurite length leading to neuronal cell death, in particular of DA neurons. Altogether these data indicate that hiPSC-NSC models are relevant test systems for the evaluation of Nrf2 pathway activation upon induced oxidative stress, allowing further understanding of the molecular mechanisms underlying exposure to (developmental) neurotoxicants. PMID- 28627368 TI - Photoactivation of ERK/CREB/VMAT2 pathway attenuates MPP+-induced neuronal injury in a cellular model of Parkinson's disease. AB - The vesicular monoamine transporter 2 (VMAT2) pumps dopamine from cytoplasm into synaptic vesicles for subsequent release, and the deficits of VMAT2 has been implicated in the dopaminergic neuronal cell loss which is considered as a typical pathological feature of Parkinson's disease (PD). Low-power laser irradiation (LPLI), a potent noninvasive physiotherapy approach, is capable of penetrating into nerve tissue to exert beneficial effects such as promoting nerve regeneration and ATP production. In the present study, we demonstrated that LPLI protects against MPP+-induced neurotoxicity via upregulation of VMAT2 in SH-SY5Y human dopaminergic neuroblastoma cells. The photoactivation of ERK phosphorylated cAMP-response element binding protein (CREB) at Ser133, and thus increased the ability of CREB binding to the promoter region of VMAT2, leading to elevated VMAT2 expression, which contributes to dopamine release and cell survival. Taken together, for the first time to our knowledge, the results showed that LPLI attenuates MPP+-induced neurotoxicity through activation of ERK/CREB/VMAT2 pathway, suggesting that the manipulation of VMAT2 by LPLI may provide a potential therapeutic strategy for PD. PMID- 28627369 TI - PLEKHO2 is essential for M-CSF-dependent macrophage survival. AB - Macrophage-colony stimulating factor (M-CSF) is crucial for macrophage survival; however, the mechanism associated with this signaling has not been fully elucidated. Here, we identified pleckstrin homology domain-containing family O member 2 (PLEKHO2), a protein with unknown function, as a novel regulator of macrophage survival in vitro and in vivo. We found that PLEKHO2-deficient mice exhibited severe reductions in macrophage population in the peritoneal cavity, spleen, and blood, and that PLEKHO2 expression was upregulated during macrophage differentiation and maturation. Additionally, PLEKHO2-deficient bone marrow derived macrophages displayed increased apoptotic cell death in the absence of M CSF, although PLEKHO2 deficiency did not affect macrophage differentiation and proliferation. Furthermore, although signaling pathways downstream of M-CSF appeared unaffected, caspase activation was elevated in PLEKHO2-deficient macrophages. Our results provided genetic evidence of roles for PLEKHO2 in promoting macrophage survival. PMID- 28627371 TI - Structure-activity relationship study of tetrapeptide inhibitors of the Vascular Endothelial Growth Factor A binding to Neuropilin-1. AB - Neuropilin-1 is considered as one of the key receptors responsible for signaling pathways involved in pathological angiogenesis necessary for tumor progression, therefore targeting of VEGF165 binding to NRP-1 could be a relevant strategy for antiangiogenic treatment. It was shown before that the VEGF165/NRP-1 interaction can be inhibited by short tetrapeptides with K/RXXR sequence. Here, we present a structure-activity relationship study of the systematic optimization of amino acid residues in positions 1-3 in the above tetrapeptides. All the 13 synthesized analogs possessed C-terminal arginine that is a necessary element for interaction with NRP-1. The obtained results of the inhibitory activity and modeling by molecular dynamics indicate that simultaneous interactions of the basic amino acid residues in position 1 and 4 (Arg) with Neuropilin-1 are crucial and their cooperation strongly affects the inhibitory activity. In addition, the binding strength is modulated by the flexibility of the peptide backbone (in the central part of the peptide), and the nature of the side chain of the amino acids at the second or third position. A dramatic decrease in the activity to the receptor is observed in flexible derivatives that are missing proline residues. The results described in this paper should prove useful for future studies aimed at establishing the best pharmacophore for inhibitors of VEGF165 binding to NRP-1. PMID- 28627372 TI - Regulatory role of melatonin and BMP-4 in prolactin production by rat pituitary lactotrope GH3 cells. AB - The effects of melatonin on prolactin production and its regulatory mechanism remain uncertain. We investigated the regulatory role of melatonin in prolactin production using rat pituitary lactotrope GH3 cells by focusing on the bone morphogenetic protein (BMP) system. Melatonin receptor activation, induced by melatonin and its receptor agonist ramelteon, significantly suppressed basal and forskolin-induced prolactin secretion and prolactin mRNA expression in GH3 cells. The melatonin MT2 receptor was predominantly expressed in GH3 cells, and the inhibitory effects of melatonin on prolactin production were reversed by treatment with the receptor antagonist luzindole, suggesting functional involvement of MT2 action in the suppression of prolactin release. Melatonin receptor activation also suppressed BMP-4-induced prolactin expression by inhibiting phosphorylation of Smad and transcription of the BMP-target gene Id-1, while BMP-4 treatment upregulated MT2 expression. Melatonin receptor activation suppressed basal, BMP-4-induced and forskolin-induced cAMP synthesis; however, BtcAMP-induced prolactin mRNA expression was not affected by melatonin or ramelteon, suggesting that MT2 activation leads to inhibition of prolactin production through the suppression of Smad signaling and cAMP synthesis. Experiments using intracellular signal inhibitors revealed that the ERK pathway is, at least in part, involved in prolactin induction by GH3 cells. Thus, a new regulatory role of melatonin involving BMP-4 in prolactin secretion was uncovered in lactotrope GH3 cells. PMID- 28627370 TI - Chasing c-Kit through the heart: Taking a broader view. AB - Stem cell mediated cardiac repair is an exciting and controversial area of cardiovascular research that holds the potential to produce novel, revolutionary therapies for the treatment of heart disease. Extensive investigation to define cell types contributing to cardiac formation, homeostasis and regeneration has produced several candidates, including adult cardiac c-Kit+ expressing stem and progenitor cells that have even been employed in a Phase I clinical trial demonstrating safety and feasibility of this therapeutic approach. However, the field of cardiac cell based therapy remains deeply divided due to strong disagreement among researchers and clinicians over which cell types, if any, are the best candidates for these applications. Research models that identify and define specific cardiac cells that effectively contribute to heart repair are urgently needed to resolve this debate. In this review, current c-Kit reporter models are discussed with respect to myocardial c-Kit cell biology and function, and future designs imagined to better represent endogenous myocardial c-Kit expression. PMID- 28627373 TI - Development and application of a population physiologically based pharmacokinetic model for penicillin G in swine and cattle for food safety assessment. AB - Penicillin G is a widely used antimicrobial in food-producing animals, and one of the most predominant drug residues in animal-derived food products. Due to reduced sensitivity of bacteria to penicillin, extralabel use of penicillin G is common, which may lead to violative residues in edible tissues and cause adverse reactions in consumers. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict drug residues in edible tissues and estimate extended withdrawal intervals for penicillin G in swine and cattle. A flow-limited PBPK model was developed with data from Food Animal Residue Avoidance Databank using Berkeley Madonna. The model predicted observed drug concentrations in edible tissues, including liver, muscle, and kidney for penicillin G both in swine and cattle well, including data not used in model calibration. For extralabel use (5* and 10* label dose) of penicillin G, Monte Carlo sampling technique was applied to predict times needed for tissue concentrations to fall below established tolerances for the 99th percentile of the population. This model provides a useful tool to predict tissue residues of penicillin G in swine and cattle to aid food safety assessment, and also provide a framework for extrapolation to other food animal species. PMID- 28627374 TI - Characterization of the concurrent metabolic changes in brain and plasma during insulin-induced moderate hypoglycemia using 1H NMR spectroscopy in juvenile rats. AB - Treatment of hypoglycemia in children is currently based on plasma glucose measurements. This approach may not ensure neuroprotection since plasma glucose does not reflect the dynamic state of cerebral energy metabolism. To determine whether cerebral metabolic changes during hypoglycemia could be better characterized using plasma metabolomic analysis, insulin-induced acute hypoglycemia was induced in 4-week-old rats. Brain tissue and concurrent plasma samples were collected from hypoglycemic (N=7) and control (N=7) rats after focused microwave fixation to prevent post-mortem metabolic changes. The concentration of 29 metabolites in brain and 34 metabolites in plasma were determined using 1H NMR spectroscopy at 700MHz and examined using partial least squares-discriminant analysis. The sensitivity of plasma glucose for detecting cerebral energy failure was assessed by determining its relationship to brain phosphocreatine. The brain and plasma metabolite profiles of the hypoglycemia group were distinct from the control group (brain: R2=0.92, Q2=0.31; plasma: R2=0.95, Q2=0.74). Concentration differences in glucose, ketone bodies and amino acids were responsible for the intergroup separation. There was 45% concordance between the brain and plasma metabolite profiles. Brain phosphocreatine correlated with brain glucose (control group: R2=0.86; hypoglycemia group: R2=0.59; p<0.05), but not with plasma glucose. The results confirm that plasma glucose is an insensitive biomarker of cerebral energy changes during hypoglycemia and suggest that a plasma metabolite profile is superior for monitoring cerebral metabolism. PMID- 28627375 TI - Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat. AB - Essential tremor (ET) is one of the most common movement disorders with unknown etiology. Despite lack of effective clinical treatments, some potential therapeutic factors and modulation of some neurotransmitters have been utilized to ameliorate motor symptoms in the animal models of tremor. In the current study, male Wistar rats (n=10 in each group) weighing 40-60g were divided into vehicle control groups (saline or DMSO), saline/DMSO+harmaline (30mg/kg, i.p.)+fingolimod (FTY720) (1mg/kg, i.p, 1h before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor function. The results demonstrated that administration of FTY720 can improve harmaline-induced tremor in rats. Moreover, FTY720 ameliorated gait disturbance. The results showed that FTY720 can recover step width, left and right step length; however, FTY720 failed to recover mobility duration. FTY720 also improved falling time and time spent in wire grip and rotarod, respectively. The current study provides the first evidence for the effectiveness of FTY720 on motor function in the harmaline model of ET. Furthermore, neuroprotective effects of FTY720 demonstrated in this study offer sphingosine-1-phosphate receptor (S1PR) modulators as a potential neuroprotective candidate against substance-induced tremor and a possible strategy for the treatment of patients with tremor. PMID- 28627376 TI - Inhaled salbutamol dose delivered by jet nebulizer, vibrating mesh nebulizer and metered dose inhaler with spacer during invasive mechanical ventilation. AB - BACKGROUND: Patient receiving invasive mechanical ventilation (IMV) may benefit from medical aerosol, but guidance on dosing with different aerosol devices is limited to in-vitro studies. The study was designed to compare aerosol delivery with five different types of aerosol generators during IMV. METHOD: In randomized design, 60 (30 female) mechanically ventilated chronic obstructive pulmonary disease (COPD) patients were assigned to one of 5 groups. Groups 1-4 received 5000 MUg salbutamol using Aerogen Pro (PRO), Aerogen Solo (SOLO), NIVO vibrating mesh and jet nebulizers (JN), respectively, while group 5 received 800 MUg (8 puffs) of salbutamol via metered dose inhaler with AeroChamber-MV (MDI-AC). All devices were place in the inspiratory limb of ventilator downstream from humidifier which was switched off while delivery. Patients received the inhaled dose on day 1 and provided urine 30 post dosing. They also recived the same inhaled dose with a filter before the endotracheal tube on day 2. Amount of salbutamol excreted in urine 30 min post inhalation and the amount deposited on the filter from all the COPD patients were determined as indeces of pulmonary deposition and systemic absorption, respectively. RESULTS: No significant difference was found between the 3 vibrating mesh nebulizers (VMNs). The in-vivo and ex-vivo testing showed that all the VMNs resulted in better aerosol delivery compared to JN (p < 0.01). However, MDI-AC resulted in better aerosol delivery to VMNs but must be accompanied with careful attention and proper delivery of MDI-AC doses by healthcare provider. CONCLUSIONS: VMNs can be exchanged with each other, with no dose adjustment. However, dose adjustment is a must when replacing VMNs by JN or MDI-AC. This similarity and difference between the 5 aerosol delivery methods suggest that for IMV patients, aerosol delivery methods should be chosen or substituted with care. PMID- 28627377 TI - Mikania glomerata Sprengel extract and its major compound ent-kaurenoic acid display activity against bacteria present in endodontic infections. AB - The search for new, effective and safe antimicrobial compounds from plant sources has continued to play an important role in the maintenance of human health since ancient times. Such compounds can be used to help to eradicate microorganisms from the root canal system, preventing/healing periapical diseases. Mikania glomerata (Spreng.), commonly known as "guaco," is a native climbing plant from Brazil that displays a wide range of pharmacological properties. Many of its activities have been attributed to its phytochemical composition, which is mainly composed of diterpenes, such as ent-kaurenoic acid (KA). The present study evaluated the potential activity of an ent-kaurenoic-rich (KA) extract from Mikania glomerata (i.e. Mikania glomerata extract/MGE) and its major compound KA against bacteria that can cause endodontic infections. Time-kill assays were conducted and the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), anti-biofilm activity, and synergistic antimicrobial activity of MGE and KA were determined. The MGE exhibited MIC and MBC values, which ranged from 6.25 to 100 MUg/mL and 12.5 to 200 MUg/mL respectively. The MIC and MBC results obtained for the KA, ranged from 3.12 to 100 MUg/mL and 3.12 to 200 MUg/mL respectively. Time-kill and anti-biofilm activity assays conducted for KA at concentrations between 3.12 and 12.5 MUg/mL exhibited bactericidal activity between 6 and 72 h of incubation and 50% inhibition of biofilm formation for Porphyromonas gingivalis (clinical isolate), Propionibacterium acnes (ATCC 6919), Prevotella nigrescens (ATCC 33563), P. melaninogenica (ATCC 25845), Aggregatibacter actinomycetemcomitans (ATCC 43717). For synergistic antimicrobial activity, KA combined with chlorhexidine dichlorohydrate (CHD) had an additive effect with increased efficacy against P. gingivalis (clinical isolate) compared to CHD alone. It was concluded that M. glomerata extract and its major compound ent-kaurenoic acid (KA) showed in vitro antibacterial activity, the latter being a potential biofilm inhibitory agent. They may play important roles in the search for novel sources of agents that can act against bacteria present in endodontic infections. PMID- 28627378 TI - Practical risk score for 5-, 10-, and 20-year prediction of dementia in elderly persons: Framingham Heart Study. AB - INTRODUCTION: With a rapidly aging population, general practitioners are confronting the challenge of how to determine those who are at greatest risk for dementia and potentially need more specialized follow-up to mitigate symptoms early in its course. We created a practical dementia risk score and provided individualized estimates of future dementia risk. METHODS: Using the Framingham Heart Study data, we built our prediction model using Cox proportional hazard models and developed a point system for the risk score and risk estimates. RESULTS: The score system used total points ranging from -1 to 31 and stratifies individuals into different levels of risk. We estimated 5-, 10-, and 20-year dementia risk prediction and incorporated these into the points system. DISCUSSION: This risk score system provides a practical tool because all included predictors are easy to assess by practitioners. It can be used to estimate future probabilities of dementia for individuals. PMID- 28627379 TI - Microvascular changes in Down syndrome with Alzheimer's-type pathology: Insights into a potential vascular mechanism for Down syndrome and Alzheimer's disease. AB - INTRODUCTION: The mechanism triggering degeneration in Alzheimer's disease (AD) remains uncertain. Therapeutic failure following amyloid beta (Abeta) removal casts doubt on amyloid neurotoxicity per se as the primary cause of AD. Impaired microvascular function has been suggested as an alternative etiology. People with Down syndrome (DS) develop Alzheimer's pathology, but whether microvascular impairment also occurs in DS (as in AD) is unknown. METHODS: We examined brain microvasculature in five DS subjects with AD-type histopathology, seven AD cases, and seven controls without AD-type pathology. We counted microvessels in five anatomic regions and assessed endothelial integrity by CD31 immunohistochemistry. RESULTS: Microvascular numbers and endothelial integrity were significantly diminished in DS brains compared with controls and were similar to AD brains. DISCUSSION: People with DS and trisomy 21 produce a large amount of Abeta. If Alzheimer's pathology occurred in DS without microvascular loss or endothelial impairment, a direct neurotoxic Abeta mechanism would be supported and microvascular impairment rejected. The observation of microvascular impairment in DS with Alzheimer's disease changes fails to reject the microvascular hypothesis and provides some support for this potential mechanism of injury. PMID- 28627380 TI - Post-traumatic stress disorder and risk of dementia among members of a health care delivery system. AB - INTRODUCTION: Post-traumatic stress disorder (PTSD) is associated with an increased risk of dementia in male veterans, but little is known in females and civilians. METHODS: PTSD and comorbidities were abstracted from medical records from 1/1/1996 to 12/31/2001. Dementia incidence from 1/1/2002 to 12/31/2014 in 499,844 health care members aged 60+ years over an average of 8.2 years. Cox proportional hazard models were adjusted for age, demographics, and comorbidities. RESULTS: PTSD was associated with increased risk of dementia over an average of 8 years of follow-up (females: hazard ratio [HR] = 1.59, 95% confidence interval [CI] = 1.30-1.95; males: HR = 1.96, 95% CI = 1.51-2.55). There was a two-fold risk of dementia in those with both PTSD and depression (females: HR = 2.08; 95% CI = 1.66-2.59; males: HR = 2.06; 95% CI = 1.47-2.91) versus those without. DISCUSSION: PTSD was a risk factor for dementia in both sexes, with a heightened risk in those with comorbid depression. PMID- 28627381 TI - Mechanosensing in hypothalamic osmosensory neurons. AB - Osmosensory neurons are specialized cells activated by increases in blood osmolality to trigger thirst, secretion of the antidiuretic hormone vasopressin, and elevated sympathetic tone during dehydration. In addition to multiple extrinsic factors modulating their activity, osmosensory neurons are intrinsically osmosensitive, as they are activated by increased osmolality in the absence of neighboring cells or synaptic contacts. This intrinsic osmosensitivity is a mechanical process associated with osmolality-induced changes in cell volume. This review summarises recent findings revealing molecular mechanisms underlying the mechanical activation of osmosensory neurons and highlighting important roles of microtubules, actin, and mechanosensitive ion channels in this process. PMID- 28627382 TI - BPAG1, a distinctive role in skin and neurological diseases. AB - Spectraplakins are multifunctional cytoskeletal linker proteins that act as important communicators, connecting cytoskeletal components with each other and to cellular junctions. Bullous pemphigoid antigen 1 (BPAG1)/dystonin is a member of spectraplakin family and expressed in various tissues. Alternative splicing of BPAG1 gene produces various isoforms with unique structure and domains. BPAG1 plays crucial roles in numerous biological processes, such as cytoskeleton organization, cell polarization, cell adhesion, and cell migration as well as signaling transduction. Genetic mutation of BPAG1 isoforms is the miscreant of epidermolysis bullosa and multifarious, destructive neurological diseases. In this review, we summarize the recent advances of BPAG1's role in various biological processes and in skin and neurological diseases. PMID- 28627383 TI - Science communication at scientific societies. AB - Scientific societies can play a key role in bridging the research and practice of scientists' engagement of public audiences. Societies are beginning to support translation of science communication research, connections between scientists and audiences, and the creation of opportunities for scientists to engage publics without extensive customization. This article suggests roles, strategies, and mechanisms for scientific societies to promote and enhance their member's engagement of public audiences. PMID- 28627384 TI - Cadherin genes and evolutionary novelties in the octopus. AB - All animals with large brains must have molecular mechanisms to regulate neuronal process outgrowth and prevent neurite self-entanglement. In vertebrates, two major gene families implicated in these mechanisms are the clustered protocadherins and the atypical cadherins. However, the molecular mechanisms utilized in complex invertebrate brains, such as those of the cephalopods, remain largely unknown. Recently, we identified protocadherins and atypical cadherins in the octopus. The octopus protocadherin expansion shares features with the mammalian clustered protocadherins, including enrichment in neural tissues, clustered head-to-tail orientations in the genome, and a large first exon encoding all cadherin domains. Other octopus cadherins, including a newly identified cadherin with 77 extracellular cadherin domains, are elevated in the suckers, a striking cephalopod novelty. Future study of these octopus genes may yield insights into the general functions of protocadherins in neural wiring and cadherin-related proteins in complex morphogenesis. PMID- 28627385 TI - Advances in antibody-drug conjugates: A new era of targeted cancer therapy. AB - Antibody-drug conjugates (ADCs), a potent class of anticancer therapeutics, comprise a high-affinity antibody (Ab) and cytotoxic payload coupled via a suitable linker for selective tumor cell killing. In the initial phase of their development, two ADCs, Mylotarg(r), and Adcetris(r) were approved by the US Food and Drug Administration (FDA) for treating hematological cancer, but the real breakthrough came with the discovery of the breast cancer-targeting ADC, Kadcyla(r). With advances in bioengineering, linker chemistry, and potent cytotoxic payload, ADC technology has become a more powerful tool for targeted cancer therapy. In addition, ADCs with improved safety using humanized Abs with a unified 'drug:antibody ratio' (DAR) have been achieved. Concomitantly, there has been a significant increase in the number of clinical trials with anticancer ADCs with high translation potential. PMID- 28627386 TI - Big data analysis of global advances in pharmaceutics and drug delivery 1980 2014. AB - This review provides a comprehensive perspective of the global research advances and frontiers in pharmaceutics from 1980 to 2014. Furthermore, a historical view and future prospects of drug delivery are discussed. PMID- 28627387 TI - Observational fear learning in degus is correlated with temporal vocalization patterns. AB - Some animals learn to fear a situation after observing another individual come to harm, and this learning is influenced by the animals' social relationship and history. An important but sometimes overlooked factor in studies of observational fear learning is that social context not only affects observers, but may also influence the behavior and communications expressed by those being observed. Here we sought to investigate whether observational fear learning in the degu (Octodon degus) is affected by social familiarity, and the degree to which vocal expressions of alarm or distress contribute. 'Demonstrator' degus underwent contextual fear conditioning in the presence of a cagemate or stranger observer. Among the 15 male pairs, observers of familiar demonstrators exhibited higher freezing rates than observers of strangers when returned to the conditioning environment one day later. Observer freezing during testing was, however, also related to the proportion of short- versus long- inter-call-intervals (ICIs) in vocalizations recorded during prior conditioning. In a regression model that included both social relationship and ICI patterns, only the latter was significant. Further investigation of vocalizations, including use of a novel, directed k-means clustering approach, suggested that temporal structure rather than tonal variations may have been responsible for communicating danger. These data offer insight into how different expressions of distress or fear may impact an observer, adding to the complexity of social context effects in studies of empathy and social cognition. The experiments also offer new data on degu alarm calls and a potentially novel methodological approach to complex vocalizations. PMID- 28627388 TI - Improved soluble bacterial expression and properties of the recombinant flavonoid glucosyltransferase UGT73G1 from Allium cepa. AB - Glycosylation of quercetin using flavonol-specific glycosyltransferases offers an alternate method for isoquercitrin production. Obtaining sufficient quantities of bioactive enzymes is an important prerequisite for highly effective biocatalysis and biotransformation. In this study, a codon-optimized gene for the flavonoid glucosyltransferase UGT73G1 from Allium cepa was heterologously expressed in the preferred prokaryotic expression host Escherichia coli. By combining expression as a fusion protein with 6-histidine tags with coexpression with molecular chaperones, increased soluble expression of UGT73G1 was achieved in E. coli. Two terminal 6-histidine tags contributed more to the expression than molecular chaperones, as demonstrated by comparison of specific activities in crude extracts obtained from the recombinant E. coli strains. Studies of the catalytic properties of purified UGT73G1 indicated that its activity was significantly promoted by Mn2+ and Mg2+, while it was strongly inhibited by Cu2+. These expression strategies enhanced the solubility and activity of the overexpressed protein and enabled characterization of this plant-derived glucosyltransferase expressed in a prokaryotic host. PMID- 28627389 TI - Association of genetic variation in B-cell activating factor with chronic hepatitis B virus infection. AB - The outcome of hepatitis B virus (HBV) infection is considered to be related to the host immunogenetic susceptibility. B cell activating factor (BAFF) is involved in both B cell and T cell mediated immunity and its circulating levels were shown to be significantly elevated in HBV-related liver diseases. This study examined BAFF rs9514828 and rs12583006 polymorphisms in 386 patients with various liver diseases related to chronic HBV infection, 69 HBV infection resolvers, and 191 healthy controls. Both rs9514828 and rs12583006 polymorphisms and serum BAFF levels were determined in 232 patients with chronic HBV infection, and 61 healthy controls. The results showed that patients with chronic hepatitis had higher frequencies of rs9514828 genotype TT (19.75% vs. 11.86%, OR=2.397, 95% CI=1.121 5.125, P=0.023), genotypes CT+TT (74.69% vs. 63.55%, OR=1.478, 95% CI=1.050 2.080, P=0.045), and allele T (47.22% vs. 37.72%, OR=1.478, 95% CI=1.050-2.080, P=0.025) compared with patients with cirrhosis. Patients with chronic HBV infection and HBV infection resolvers had higher frequency of rs9514828 and rs12583006 haplotype TA compared with healthy controls (21.6% vs. 15.0%, OR=1.672, 95% CI=1.138-2.456, P=0.009 and 27.3% vs. 15.0%, OR=2.258, 95%CI=1.272 4.007, P=0.005, respectively). The rs9514828 and rs12583006 genotypes had no significant association with serum BAFF levels. These results suggest that the rs9514828 allele T may predispose to the liver inflammation in chronic HBV infection, and the rs9514828 and rs12583006 polymorphisms may combinatorially confer susceptibility to chronic HBV infection and resolution of the infection, possibly not through direct effect on serum BAFF levels. PMID- 28627390 TI - Classification of hydrocolloids based on in vitro starch digestibility and rheological properties of Segoami gel. AB - The influence of hydrocolloids on in vitro starch digestibility and rheological properties of Segoami (a new rice variety fortified with amylose and dietary fiber) gel was investigated in terms of type (sodium alginate, arabic gum, guar gum, locust bean gum, and xanthan gum) and addition levels (0.3-0.7% for rice flour weight) of hydrocolloids. In addition, the behavior of hydrocolloids was analyzed by principal component analysis (PCA) based on both properties of various Segoami-hydrocolloids gels. The first and second principle components (PC) explained 80.93% of the total variation; PC1 and PC2 explained 50.40% and 30.53% of the total variance, respectively, implying that the two components provided a strong summary of the data. PC1, represented in vitro starch digestibility and was affected by the addition level of hydrocolloids: PC2, represented rheological parameters and was highly affected by the type of hydrocolloids. Moreover, there was a non-linear relationship between in vitro starch digestibility and rheological properties of Segoami-hydrocolloids gels. The hydrocolloids used in this study showed similar features according to the addition levels of hydrocolloids regardless of type. Segoami-0.5% arabic gum gel was the optimum preparation for retarding in vitro starch digestibility and maintaining rheological properties. PMID- 28627392 TI - The great barrier belief: The blood-brain barrier and considerations for juvenile toxicity studies. AB - Juvenile animal studies can be warranted to support the development of pediatric medicines. Drugs acting on the CNS or those which penetrate into the brain merit particular attention. The blood-brain barrier is functionally mature at birth, but undergoes functional postnatal modulation to provide a suitable microenvironment for the developing brain. In the past, dosing in rat juvenile studies has often commenced at 4 or 7days of age. However, rodents are very neurologically immature at birth compared with humans. We suggest that dosing of rat pups below two weeks of age is generally not warranted for the assessment of pediatric drugs. In the rare circumstances where exposure of younger rats is required to address a particular concern (e.g., an indication in preterm babies), consideration should be given to likely misleading signals of toxicity arising from high brain penetration of the drug, which may not be predictive for the human. PMID- 28627391 TI - Low molecular weight fucoidan and its fractions inhibit renal epithelial mesenchymal transition induced by TGF-beta1 or FGF-2. AB - We investigated the renal protective effects of low molecular weight fucoidan (LMWF) and its two fractions (F0.5 and F1.0), which were extracted from Laminaria japonica, on the epithelial-mesenchymal transition (EMT) induced by transforming growth factor beta 1 (TGF-beta1) and fibroblast growth factor 2 (FGF-2) in HK-2 human renal proximal tubular cells. Cell morphology and EMT markers (fibronectin and alpha-smooth muscle actin) demonstrated that cells treated with TGF-beta1 or FGF-2 developed EMT to a significant extent. Treatment with LMWF or its fractions markedly attenuated the EMT and decreased expression of the EMT markers. The F1.0 fraction, the sulfated fucan fraction, was found to be the main active component of LMWF, and heparanase (HPSE) was a key factor in renal tubular epithelial trans differentiation. The F1.0 fraction inhibited elevated HPSE and matrix metallopeptidase 9 expression, thereby attenuating the progress of EMT. PMID- 28627393 TI - The potential and challenges of CRISPR-Cas in eradication of hepatitis B virus covalently closed circular DNA. AB - Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection, primarily because of the persistence of covalently closed circular DNA (cccDNA). Although nucleos(t)ide analogues (NAs) can inhibit the reverse transcriptase of HBV and suppress its replication to levels below the detection limit, viremia often rebounds after cessation of therapy. Nuclear cccDNA serves as the HBV replicative template and exhibits extraordinary stability, and is not affected by NAs. Therefore, curing chronic hepatitis B (CHB) requires novel therapy for purging cccDNA from patients. The CRISPR/Cas9 system is a newly developed programmable genome-editing tool and allows for sequence-specific cleavage of DNA. Compared to other genome-editing tools, the CRIPSR/Cas9 system is advantageous for its simplicity and flexibility of design. Theoretically, Cas9 can be redirected to specifically cleave any desired genome sequences simply by designing guide RNAs with about 20 nucleotides that match the particular sequences of genomes with downstream protospacer adjacent motifs. Recently, it has been demonstrated that the CRIPSR/Cas9 system can specifically destruct HBV genomes in vitro and in vivo. Although promising, the CRISPR/Cas9 system faces several challenges that need to be overcome for the clinical application, namely, off-target cleavage and the in vivo delivery efficiency. Cutting integrated HBV genomes by CRISPR/Cas9 also raises serious concern because this has the risk of genome instability. In summary, the CRISPR/Cas9 system bears the potential for curing CHB as long as several challenging issues can be successfully solved. PMID- 28627394 TI - Novel non-canonical genetic rearrangements termed "complex structural variations" in HBV genome. AB - BACKGROUNDS AND AIMS: Chronic hepatitis B virus (HBV) infection is an important worldwide public health issue. Further knowledge on the characteristics of HBV will facilitate its eradication. Genome structural variations (SVs) are defined by its canonical form such as duplication, deletion, and insertion. However, recent studies have reported complex SVs that cannot be explained by those canonical SVs. A HBV strain (UK2) with an unusual genome structure rearrangement that was completely different from known mutations or rearrangements was previously reported. Thus, this study was conducted to confirm the rearrangement in UK2 as a novel complex SV, and to find additional HBV strains with complex SVs. Further, the contribution of complex SVs in hepadnavirus variability was investigated. METHODS: The genome rearrangement pattern in UK2 was analyzed. Further, a search of online databases retrieved additional HBV strains which were candidates to harbor complex SVs. The architecture of each rearrangement in the candidate strains was analyzed by bioinformatical tools. In addition, alignment of woolly monkey hepatitis virus (WMHV) and HBV from human and non-human primates was performed to investigate the contribution of complex SVs to variability of hepadnavirus. RESULTS: The rearrangement in UK2 was confirmed as a complex SV. An additional 15 HBV strains were retrieved from databases, and confirmed as harboring complex SVs. Complex combinations of deletion, insertion, and duplication characterized the novel rearrangements. The complex SVs in six strains (37.5%) were composed of deletion, insertion, and duplication. The complex SVs in another six strains (37.5%) consisted of deletion and insertion, followed by insertions and duplication in three strains (18.8%), and deletion and duplication in one strain (6.3%). In addition, unique preS1 promoter insertions, which contained the hepatocyte nuclear factor 1 binding site, were observed in seven (43.8%) of 16 strains. Further, analysis of the genetic sequences of WMHV and HBV from human and non-human primates showed that complex combinations of deletions and insertions accounted for their genetic differences. CONCLUSIONS: Non-canonical genetic rearrangements termed complex SVs were observed in HBV. Further, complex SVs accounted for the genetic differences of WMHV and HBV from human and non-human primates. PMID- 28627395 TI - The opioid epidemic is an historic opportunity to improve both prevention and treatment. AB - The current narrative describing the national opioid epidemic as the result of overprescribing opioid pain medicines fails to capture the full dimensions of the problem and leads to inadequate and even confounding solutions. Overlooked is the fact that polysubstance use is nearly ubiquitous among overdose deaths, demonstrating that the opioid overdose death problem is bigger than opioids. The foundation of the nation's opioid overdose crisis - and the totality of the nation's drug epidemic - is widespread recreational pharmacology, the use of drugs for fun or "self-medication." The national focus on opioid overdose deaths provides important new opportunities in both prevention and treatment to make fundamental changes to the way that substance use disorders and related problems are understood and managed. The first-ever US Surgeon General's report on addiction provides a starting point for systemic changes in the nation's approach to preventing, treating and managing substance use disorders as serious, chronic diseases. New prevention efforts need to encourage youth to grow to adulthood not using alcohol, nicotine, marijuana or other drugs for reasons of health. New addiction treatment efforts need to focus on achieving long-term recovery including no use of alcohol, marijuana and other drugs. PMID- 28627396 TI - Prostate Mass as a First Manifestation of Myeloid Sarcoma in a Patient With an Occult Acute Myeloid Leukemia-A Case Report. AB - Myeloid sarcoma (MS) with either primary or secondary prostate involvement is extremely rare. Its diagnostic is particularly challenging when prostate lesion precedes the systemic manifestation of a myeloproliferative disorder. We report such a case in a 44-year-old man with a prostate mass as a first manifestation of myeloid sarcoma associated with acute myeloid leukemia. The diagnosis of lymphoproliferative disorder was suspected in the prostate magnetic resonance imaging, and myeloid sarcoma was confirmed after transrectal ultrasound-guided prostate core biopsy. PMID- 28627398 TI - Stones First! A Gas Pyelo-nephroscopy Strategy for Laparoscopic Pyeloplasty and Renal Stone Extraction. AB - OBJECTIVE: To report our experience on gas endoscopy as the first step of pelvi ureteric junction (PUJ) obstruction repair when complicated by nephrolithiasis. MATERIALS AND METHODS: Stone formation because of urine stasis is a known complication of PUJ obstruction and an indication for its surgical repair. The undisputed results of the Anderson-Hynes dismembered pyeloplasty make it a quasi gold standard; however, the identification and extraction of calyceal stones through the laparoscopic route can be challenging. Between 2009 and 2016, 39 patients underwent laparoscopic pyeloplasty at Ygia Polyclinic, with a subgroup of 6 patients having concomitant calyceal stones. These 6 patients first underwent gas pyelo-nephroscopy before dismembering the PUJ. Demographic data, intraoperative technical details, outcomes, as well as postoperative outcomes, were collected and analyzed. RESULTS: We report a small series (n = 6) with 3 minor modifications of the laparoscopic repair of PUJ obstruction complicated by stones. One modification is to carry out a pyelo-nephroscopy for stone extraction before dismembering the junction. The second modification is the use of gas medium to distend the renal cavity, and the third is the use of a flexible cystoscope. Postoperative recovery was uncomplicated in all 6 patients, with successful relief of the PUJ obstruction and stable stone free results demonstrated on follow-up for all patients. CONCLUSION: We claim that these modifications overcome the usual challenges related to working in a collapsed cavity and using fluid media, while achieving desirable outcomes. PMID- 28627397 TI - Long-Term Efficacy of Young-Dees Bladder Neck Reconstruction: Role of the Associated Bladder Neck Injection for the Treatment of Children With Urinary Incontinence. AB - OBJECTIVE: To compare the long-term efficacy of Young-Dees bladder neck reconstruction (YDBNR) alone versus YDBNR plus bladder neck injection (BNI) in patients with urinary incontinence caused by urethral sphincter insufficiency. PATIENTS AND METHODS: Between 1987 and 2006, we assessed the continence rates obtained with YDBNR and BNI as a supplementary treatment for persistent outlet insufficiency in patients with neurogenic bladder (group 1, n = 35) and bladder exstrophy (group 2, n = 20). Median postoperative follow-up was 16 years (range: 5-29). RESULTS: A total of 55 children (23 males and 32 females) underwent YDBNR at the median age of 7.6 years (range: 1.9-17.25). Only 10 patients (18%) were considered continent after the isolated YDBNR; 17% (n = 6/35) from group 1 and 20% (n = 4/20) from group 2 (p = 1). Because of unsatisfactory results after YDBNR, 81.8% (n = 45/55) received BNI. Fifteen patients (33%) became continent with an average of 2.29 injections (+/-1.1); 44.8% (n = 13/29) from group 1 and 12.5% (n = 2/16) from group 2. A significant difference was found on comparing the social continence rate attained with YDBNR plus BNI between patients from group 1 and group 2 (54% vs 30%, P = .04). The difference between males and females in terms of continence rates was not statistically significant. CONCLUSION: Long-term results of YDBNR are modest. BNI does increase the results of YDBNR, especially in patients with neurogenic bladder. PMID- 28627399 TI - Elucidation of the impact of cell culture conditions of Caco-2 cell monolayer on barrier integrity and intestinal permeability. PMID- 28627400 TI - Improved tacrolimus skin permeation by co-encapsulation with clobetasol in lipid nanoparticles: Study of drug effects in lipid matrix by electron paramagnetic resonance. AB - Combined therapy with corticosteroids and immunosuppressant-loaded nanostructured lipid carriers (NLC) could be useful in the treatment of skin diseases. To circumvent NLC loading capacity problems, loaded drugs should have different physicochemical characteristics, such as tacrolimus (TAC) and clobetasol (CLO). Therefore, in the present study, TAC and CLO were encapsulated in NLC (TAC-NLC, CLO-NLC and TAC+CLO-NLC), coated or otherwise with chitosan. Electron paramagnetic resonance (EPR) spectroscopy of different spin labels was used to investigate the impact of drug and oil incorporation on the lipid dynamic behavior of the lipid matrices. In addition, the impact of co-encapsulation on drug release and skin permeation was evaluated. Entrapment efficiency was greater than 90% for both drugs, even when the maximum drug loading achieved for TAC-NLC and CLO-NLC was kept at TAC+CLO-NLC, because TAC is more soluble in the solid lipid and CLO in the liquid lipid. EPR data indicated that both drugs reduced the lipid fluidity near the polar surface of the lipid matrix, which suggests their presence in this region. In addition, EPR data showed that liquid lipid is also present in more superficial regions of the nanoparticle matrix. CLO was released faster than TAC from TAC+CLO-NLC, probably because it is more soluble in the liquid lipid. TAC skin penetration was affected by CLO. A 5-fold increase in TAC penetration was observed from TAC+CLO-NLC when compared to TAC-NLC formulations. Coating also increased TAC and CLO permeation to deeper skin layers (1.8-fold and 1.6-fold, respectively). TAC+CLO-NLC seems to be an effective strategy for topical delivery of TAC and CLO, and thus constitutes promising formulations for the treatment of skin diseases. PMID- 28627401 TI - Educational nutrition messaging at breakfast reduces snack intake and influences snack preferences in adult men and women. AB - Breakfast skipping is associated with increased risk of weight gain and obesity in young adults, possibly due to increased snacking later in the day. Recent research suggests that providing and animal versus a plant source of protein at breakfast can reduce snack intake later in the day. In addition, providing nutrition information via a nutrition label, front-of-pack information, or via text messaging has been shown to help individuals make healthier food choices. The objective of this study was to determine if educational nutrition messaging and protein source influenced snack intake 2 h following the breakfast meal. Participants (n = 33) were randomly assigned to one of two groups: educational nutrition messaging (EM; n = 16) or no messaging (NM; n = 17) group. The study was conducted using a randomized, cross-over design in which each participant received each of two breakfast beverages, whey protein- (WP) and pea protein (PP) based. Appetite was assessed at 0, 15, 30, 60, 90, and 120 min after each test breakfast using visual analog scales. Participants were then provided with a selection of healthy and unhealthy snacks for 60 min. There was no effect of protein source on appetite or snack intake. However, participants presented with EM had reduced snack intake over the snacking period compared to NM (P = 0.058) and, of the snacks consumed, the EM group consumed a higher percentage of healthy versus unhealthy snacks compared to NM (P < 0.0001), resulting in lower calorie intake. Taken together these data suggest that protein source, as part of a higher protein breakfast, does not affect appetite response or snack intake, but EM may help play a role in reducing snack intake between meals. PMID- 28627402 TI - Attention! Can choices for low value food over high value food be trained? AB - People choose high value food items over low value food items, because food choices are guided by the comparison of values placed upon choice alternatives. This value comparison process is also influenced by the amount of attention people allocate to different items. Recent research shows that choices for food items can be increased by training attention toward these items, with a paradigm named cued-approach training (CAT). However, previous work till now has only examined the influence of CAT on choices between two equally valued items. It has remained unclear whether CAT can increase choices for low value items when people choose between a low and high value food item. To address this question in the current study participants were cued to make rapid responses in CAT to certain low and high value items. Next, they made binary choices between low and high value items, where we systematically varied whether the low and high value items were cued or uncued. In two experiments, we found that participants overall preferred high over low value food items for real consumption. More important, their choices for low value items increased when only the low value item had been cued in CAT compared to when both low and high value items had not been cued. Exploratory analyses revealed that this effect was more pronounced for participants with a relatively small value difference between low and high value items. The present research thus suggests that CAT may be used to boost the choice and consumption of low value items via enhanced attention toward these items, as long as the value difference is not too large. Implications for facilitating choices for healthy food are discussed. PMID- 28627403 TI - Accepting Hearts From Hepatitis C-Positive Donor: Can We Expand the Donor Pool? AB - BACKGROUND: Until recently, transplantation from hepatitis C-positive donors was relatively contraindicated as eradication of active hepatitis C previously required an interferon-based regimen that has been associated with rejection in solid organ transplantation. New interferon-free treatment regimens for hepatitis C have fewer adverse events and higher cure rates than interferon-based regimens. Interferon-free regimens have been shown to be safe in the liver transplantation literature, but little is known about the safety and efficacy of treatment in heart transplantation. CASE DESCRIPTION AND DISCUSSION: Here we report a case of successful eradication of hepatitis C with a non-interferon-based regimen using ledipasvir-sofosbuvir following combined orthotopic heart and liver transplantation. Based on the prevalence of hepatitis C in the general population, inclusion of hepatitis C-positive donors for heart transplantation can expand this component of the donor pool 3- to 6-fold. CONCLUSIONS: In carefully selected patients and recipients, inclusion of hepatitis C-positive donors may allow for expansion of the donor pool. PMID- 28627404 TI - Pattern and Outcome of Heart Failure-Related Hospitalization Over 5 Years in a Remote Australian Population: A Retrospective Administrative Data Cohort of 617 Indigenous and non-Indigenous Cases. AB - OBJECTIVE: The aim of this work was to understand the pattern and outcomes for heart failure (HF)-related hospitalization among Indigenous and non-Indigenous patients living in Central Australia. METHODS AND RESULTS: A retrospective analysis of administrative data for patients presenting with a primary or secondary diagnosis of HF to Central Australia's Alice Springs Hospital during 2008-2012 was performed. The population rate of admission and subsequent outcomes (including mortality and readmission) during the 5-year study period were examined. A total of 617 patients, aged 55.8 +/- 17.5 years and 302 (49%) female constituted the study cohort. The 446 Indigenous patients (72%) were significantly younger (50.8 +/- 15.9 vs 68.7 +/- 14.9; P < .001) and clinically more complex compared with the non-Indigenous patients. Annual prevalence of any HF hospitalization was markedly higher in the Indigenous population (1.9%, 95% CI 1.7-2.1) compared with the non-Indigenous population (0.5%, 95% CI 0.4-0.6); the greatest difference being for women. Overall, non-Indigenous patients had poorer outcomes and were significantly more likely to die (P < .0001), but this was largely driven by age differences. Alternatively, Indigenous patients were significantly more likely to have a higher number of hospitalizations, although indigeneity was not a predictor for 30- or 365-day rehospitalization from the index admission. CONCLUSION: The pattern of HF among Indigenous Australians in Central Australia is characterized by a younger population with more clinically complex cases and greater health care utilization. PMID- 28627405 TI - The effects of dietary leucine on the growth performances, body composition, metabolic abilities and innate immune responses in black carp Mylopharyngodon piceus. AB - The present study was focused on the growth, body composition, metabolic abilities and innate immune responses in juvenile black carp Mylopharyngodon piceus fed with six levels of dietary leucine (7.3, 12.4, 16.2, 21.9, 28.3 and 34.5 g kg-1) for 9 weeks. Results showed that the highest weight gain (WG) and the lowest feed conversion ratio (FCR) was obtained at 23.5 and 23.9 g kg-1 dietary leucine using second-order polynomial model, respectively. Adequate dietary leucine content (21.9 and 28.3 g kg-1) could significantly up-regulate the expression levels of neuropeptide Y (NPY) and ghrelin (GRL) in the brain of black carp juveniles. The protein efficiency ratio (PER), feed efficiency ratio (FER) and protein deposition ratio (PDR) were also significantly increased by adequate dietary leucine content (21.9 and 28.3 g kg-1) (p < 0.05). Adequate dietary leucine content (21.9 and 28.3 g kg-1) could significantly up-regulate the activities of metabolic enzymes, such as alpha amylase, trypsin, chymotrypsin and elastase in the liver of Black carp (p < 0.05). However, the activities of alanine transaminase (ALT), aspartate aminotransferase (AST) and leucine aminopeptidase (LAP) were significantly reduced in the fish serum by adequate dietary leucine content (21.9 and 28.3 g kg-1) compared with leucine-deficient diet (7.3 and 12.4 g kg-1). In addition, 21.9 and 28.3 g kg-1 dietary leucine could significantly increase complement component 3 (C3) and C4 contents, lysozyme (LYZ) activities in the serum compared with the leucine-deficient diet (7.3 and 12.4 g kg-1) (p < 0.05). Furthermore, optimal dietary leucine could also significantly up-regulate the mRNA expression levels of LYZ, interferon alpha (IFN-alpha), hepcidin (HEPC), natural resistance-associated macrophage protein (NRAMP), C3 and C9 in the blood of juvenile black carp compared with the leucine deficient diets (7.3 and 12.4 g kg-1) (p < 0.05). In conclusion, these results suggest that adequate dietary leucine (21.9 and 28.3 g kg-1) could increase growth performances, improve metabolic abilities and then enhance non-specific immunities in black carp juveniles. PMID- 28627406 TI - Multi-omics facilitated variable selection in Cox-regression model for cancer prognosis prediction. AB - MOTIVATION: New developments in high-throughput genomic technologies have enabled the measurement of diverse types of omics biomarkers in a cost-efficient and clinically-feasible manner. Developing computational methods and tools for analysis and translation of such genomic data into clinically-relevant information is an ongoing and active area of investigation. For example, several studies have utilized an unsupervised learning framework to cluster patients by integrating omics data. Despite such recent advances, predicting cancer prognosis using integrated omics biomarkers remains a challenge. There is also a shortage of computational tools for predicting cancer prognosis by using supervised learning methods. The current standard approach is to fit a Cox regression model by concatenating the different types of omics data in a linear manner, while penalty could be added for feature selection. A more powerful approach, however, would be to incorporate data by considering relationships among omics datatypes. METHODS: Here we developed two methods: a SKI-Cox method and a wLASSO-Cox method to incorporate the association among different types of omics data. Both methods fit the Cox proportional hazards model and predict a risk score based on mRNA expression profiles. SKI-Cox borrows the information generated by these additional types of omics data to guide variable selection, while wLASSO-Cox incorporates this information as a penalty factor during model fitting. RESULTS: We show that SKI-Cox and wLASSO-Cox models select more true variables than a LASSO-Cox model in simulation studies. We assess the performance of SKI-Cox and wLASSO-Cox using TCGA glioblastoma multiforme and lung adenocarcinoma data. In each case, mRNA expression, methylation, and copy number variation data are integrated to predict the overall survival time of cancer patients. Our methods achieve better performance in predicting patients' survival in glioblastoma and lung adenocarcinoma. PMID- 28627407 TI - Sources, mechanisms, and consequences of chemical-induced mitochondrial toxicity. PMID- 28627409 TI - Comments on: "Microbial flora on cell-phones in an orthopedic surgery room before and after decontamination." by J. Murgier, J.F. Coste, E. Cavaignac, X. Bayle Iniguez, P. Chiron, P. Bonnevialle, J.M. Laffosse, published in Orthop Traumatol Surg Res. 2016;102:1093-1096. PMID- 28627408 TI - Developmental exposure to glyphosate-based herbicide and depressive-like behavior in adult offspring: Implication of glutamate excitotoxicity and oxidative stress. AB - We have previously demonstrated that maternal exposure to glyphosate-based herbicide (GBH) leads to glutamate excitotoxicity in 15-day-old rat hippocampus. The present study was conducted in order to investigate the effects of subchronic exposure to GBH on some neurochemical and behavioral parameters in immature and adult offspring. Rats were exposed to 1% GBH in drinking water (corresponding to 0.36% of glyphosate) from gestational day 5 until postnatal day (PND)-15 or PND60. Results showed that GBH exposure during both prenatal and postnatal periods causes oxidative stress, affects cholinergic and glutamatergic neurotransmission in offspring hippocampus from immature and adult rats. The subchronic exposure to the pesticide decreased L-[14C]-glutamate uptake and increased 45Ca2+ influx in 60-day-old rat hippocampus, suggesting a persistent glutamate excitotoxicity from developmental period (PND15) to adulthood (PND60). Moreover, GBH exposure alters the serum levels of the astrocytic protein S100B. The effects of GBH exposure were associated with oxidative stress and depressive like behavior in offspring on PND60, as demonstrated by the prolonged immobility time and decreased time of climbing observed in forced swimming test. The mechanisms underlying the GBH-induced neurotoxicity involve the NMDA receptor activation, impairment of cholinergic transmission, astrocyte dysfunction, ERK1/2 overactivation, decreased p65 NF-kappaB phosphorylation, which are associated with oxidative stress and glutamate excitotoxicity. These neurochemical events may contribute, at least in part, to the depressive-like behavior observed in adult offspring. PMID- 28627410 TI - Current and upcoming mitochondrial targets for cancer therapy. AB - Mitochondria are essential intracellular organelles that regulate energy metabolism, cell death, and signaling pathways that are important for cell proliferation and differentiation. Therefore, mitochondria are fundamentally implicated in cancer biology, including initiation, growth, metastasis, relapse, and acquired drug resistance. Based on these implications, mitochondria have been proposed as a major therapeutic target for cancer treatment. In addition to classical view of mitochondria in cancer biology, recent studies found novel pathophysiological roles of mitochondria in cancer. In this review, we introduce recent concepts of mitochondrial roles in cancer biology including mitochondrial DNA mutation and epigenetic modulation, energy metabolism reprogramming, mitochondrial channels, involvement in metastasis and drug resistance, and cancer stem cells. We also discuss the role of mitochondria in emerging cancer therapeutic strategies, especially cancer immunotherapy and CRISPR-Cas9 system gene therapy. PMID- 28627411 TI - Impact of Procedural Training on Pregnancy Outcomes and Career Satisfaction in Female Postgraduate Medical Trainees in the United States. AB - BACKGROUND: Compared with nonprocedural fields, procedural specialization requires longer training, less flexible schedules, and greater physical demands. The impact of these factors on pregnancy, maternity outcomes, and career satisfaction has not been well described. STUDY DESIGN: Data were gathered from 738 US postgraduate medical trainee mothers via an anonymous, IRB-approved online survey. Univariate analysis was performed using chi-square tests. A logistic regression model was used to investigate the impact of procedural training on odds of assisted reproduction use and pregnancy complications, adjusting for age at first pregnancy. RESULTS: Of the 738 respondents, 221 (30.0%) were in procedural fields. A greater percentage of procedural trainees were more than 30 years old at the time of first pregnancy (52.9% vs 43.1%; p = 0.01). Controlling for maternal age, procedural trainees were significantly more likely to require assisted reproduction (odds ratio [OR] 1.28; 95% CI 1.01 to 1.61; p = 0.04), and trended toward increased odds of prolonged time to conceive (OR 1.62; 95% CI 0.99 to 2.65; p = 0.06). After delivery, procedural trainees also had higher adjusted odds of shorter maternity leave (OR 1.52; 95% CI 1.06 to 2.18; p = 0.03) and were significantly more likely to report a desire to have chosen a less demanding specialty or job (OR 1.95; 95% CI 1.40 to 2.72; p < 0.001). CONCLUSIONS: Procedural trainees have higher rates of assisted reproduction, shorter maternity leave, and are ultimately more likely to express career dissatisfaction. These findings illustrate the need for adequate support for trainee mothers, particularly in procedural specialties. PMID- 28627412 TI - Macrophages Regulate Unilateral Ureteral Obstruction-Induced Renal Lymphangiogenesis through C-C Motif Chemokine Receptor 2-Dependent Phosphatidylinositol 3-Kinase-AKT-Mechanistic Target of Rapamycin Signaling and Hypoxia-Inducible Factor-1alpha/Vascular Endothelial Growth Factor-C Expression. AB - Lymphangiogenesis occurs during renal fibrosis in patients with chronic kidney diseases and vascular endothelial growth factor (VEGF)-C is required for the formation of lymphatic vessels; however, the underlying mechanisms remain unclear. We demonstrate that macrophages can regulate unilateral ureteral obstruction (UUO)-induced renal lymphangiogenesis by expressing high levels of VEGF-C by C-C motif chemokine receptor 2 (CCR2)-mediated signaling. Mice deficient in Ccr2 manifested repressed lymphangiogenesis along with attenuated renal injury and fibrosis after UUO induction. The infiltrated macrophages after UUO induction generated a microenvironment in favor of lymphangiogenesis, which likely depended on Ccr2 expression. Mechanistic studies revealed that CCR2 is required for macrophages to activate phosphatidylinositol 3-kinase (PI3K)-AKT mechanistic target of rapamycin (mTOR) signaling in response to its ligand monocyte chemoattractant protein 1 stimulation, whereas hypoxia-inducible factor (HIF)-1alpha is downstream of PI3K-AKT-mTOR signaling. HIF-1alpha directly bound to the VEGF-C promoter to drive its expression to enhance lymphangiogenesis. Collectively, we characterized a novel regulatory network in macrophages, in which CCR2 activates PI3K-AKT-mTOR signaling to mediate HIF-1alpha expression, which then drives VEGF-C expression to promote lymphangiogenesis. PMID- 28627413 TI - Modeling Esophagitis Using Human Three-Dimensional Organotypic Culture System. AB - Esophagitis, whether caused by acid reflux, allergic responses, graft-versus-host disease, drugs, or infections, is a common condition of the gastrointestinal tract affecting nearly 20% of the US population. The instigating agent typically triggers an inflammatory response. The resulting inflammation is a risk factor for the development of esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Research into the pathophysiology of these conditions has been limited by the availability of animal and human model systems. Three-dimensional organotypic tissue culture (OTC) is an innovative three-dimensional multicellular in vitro platform that recapitulates normal esophageal epithelial stratification and differentiation. We hypothesized that this platform can be used to model esophagitis to better understand the interactions between immune cells and the esophageal epithelium. We found that human immune cells remain viable and respond to cytokines when cultured under OTC conditions. The acute inflammatory environment induced in the OTC significantly affected the overlying epithelium, inducing a regenerative response marked by increased cell proliferation and epithelial hyperplasia. Moreover, oxidative stress from the acute inflammation induced DNA damage and strand breaks in epithelial cells, which could be reversed by antioxidant treatment. These findings support the importance of immune cell mediated esophageal injury in esophagitis and confirms the utility of the OTC platform to characterize the underlying molecular events in esophagitis. PMID- 28627415 TI - Examination to assess the clinical examination and documentation of spine pathology among orthopedic residents. AB - BACKGROUND CONTEXT: The Accreditation Council for Graduate Medical Education (ACGME) guidelines requires residency programs to teach and evaluate residents in six overarching "core competencies" and document progress through educational milestones. To assess the progress of orthopedic interns' skills in performing a history, physical examination, and documentation of the encounter for a standardized patient with spinal stenosis, an objective structured clinical examination (OSCE) was conducted for 13 orthopedic intern residents, following a 1-month boot camp that included communications skills and curriculum in history and physical examination. Interns were objectively scored based on their performance of the physical examination, communication skills, completeness and accuracy of their electronic medical record (EMR), and their diagnostic conclusions gleaned from the patient encounter. PURPOSE: The purpose of this study was to meaningfully assess the clinical skills of orthopedic post-graduate year (PGY)-1 interns. The findings can be used to develop a standardized curriculum for documenting patient encounters and highlight common areas of weakness among orthopedic interns with regard to the spine history and physical examination and conducting complete and accurate clinical documentation. STUDY SETTING: A major orthopedic specialty hospital and academic medical center. METHODS: Thirteen PGY-1 orthopedic residents participated in the OSCE with the same standardized patient presenting with symptoms and radiographs consistent with spinal stenosis. Videos of the encounters were independently viewed and objectively evaluated by one investigator in the study. This evaluation focused on the completeness of the history and the performance and completion of the physical examination. The standardized patient evaluated the communication skills of each intern with a separate objective evaluation. Interns completed these same scoring guides to evaluate their own performance in history, physical examination, and communications skills. The interns' documentation in the EMR was then scored for completeness, internal consistency, and inaccuracies. RESULTS: The independent review revealed objective deficits in both the orthopedic interns' history and the physical examination, as well as highlighted trends of inaccurate and incomplete documentation in the corresponding medical record. Communication skills with the patient did not meet expectations. Further, interns tended to overscore themselves, especially with regard to their performance on the physical examination (p<.0005). Inconsistencies, omissions, and inaccuracies were common in the corresponding medical notes when compared with the events of the patient encounter. Nine of the 13 interns (69.2%) documented at least one finding that was not assessed or tested in the clinical encounter, and four of the 13 interns (30.8%) included inaccuracies in the medical record, which contradicted the information collected at the time of the encounter. CONCLUSIONS: The results of this study highlighted significant shortcomings in the completeness of the interns' spine history and physical examination, and the accuracy and completeness oftheir EMR note. The study provides a valuable exercise for evaluating residents in a multifaceted, multi-milestone manner that more accurately documents residents' clinical strengths and weaknesses. The study demonstrates that orthopedic residents require further instruction on the complexities of the spinal examination. It validates a need for increased systemic support for improving resident documentation through comprehensive education and evaluation modules. PMID- 28627414 TI - AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B Cell Lymphoma. AB - AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy. PMID- 28627416 TI - A combined application of tunable diode laser absorption spectroscopy and isothermal micro-calorimetry for calorespirometric analysis. AB - Calorespirometry is the simultaneous analysis of the rate of heat emission (Rq), O2 consumption (RO2) and CO2 production (RCO2) by living systems such as tissues or organism cultures. The analysis provides useful knowledge about thermodynamic parameters relevant for e.g. biotechnology where parameter based yield maximization (fermentation) is relevant. The determination of metabolism related heat emission is easy and normally done by a calorimeter. However, measuring the amount of consumed O2 and produced CO2 can be more challenging, as additional preparation or instrumentation might be needed. Therefore, tunable diode laser absorption spectroscopy (TDLAS) was investigated as an alternative approach for respirometric analysis in order to facilitate the data collection procedure. The method determines by a spectroscopic laser non-invasively CO2 and O2 gas concentration changes in the respective vial headspaces. The gathered growth data from Pseudomonas aeruginosa cultured in two different scarce media was used to compute respiratory quotient (RQ) and calorespirometric ratios (CRCO2 [Rq/RCO2], CRO2 [Rq/RO2]). A comparison of the computed (experimental) values (for RQ, CRCO2 and CRO2) with values reported in the literature confirmed the appropriateness of TDLAS in calorespirometric studies. Thus, it could be demonstrated that TDLAS is a well-performing and convenient way to evaluate non-invasively respiratory rates during calorespirometric studies. Therefore, the technique is definitively worth to be investigated further for its potential use in research and in diverse productive environments. PMID- 28627417 TI - Regulation of primary motor cortex excitability by repetitive passive finger movement frequency. AB - Somatosensory input induced by passive movement activates primary motor cortex (M1). We applied repetitive passive movement (RPM) of different frequencies to test if modulation of M1 excitability depends on RPM frequency. Twenty-seven healthy subjects participated in this study. Motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) to left M1 were recorded from the right first dorsal interosseous muscle (FDI) to assess corticospinal excitability (experiment 1: n=15), and F-waves were measured from the right FDI as an index of spinal motoneuron excitability (experiment 2: n=15). Passive abduction/adduction of the right index finger was applied for 10min at 0.5, 1.0, 3.0, and 5.0Hz. Both 0.5Hz-RPM and 1.0Hz-RPM decreased MEPs for 2min (p<0.05), and 5.0Hz-RPM decreased MEPs for 15min compared with baseline (p<0.05); however, there was no difference in MEPs after 3.0Hz-RPM. No F-wave changes were observed following any RPM intervention. Based on the results of experiments 1 and 2, we investigated whether RPM modulates cortical inhibitory circuit using the paired pulse TMS technique (experiment 3: n=12). Short-interval intracortical inhibition (SICI) was measured using paired-pulse TMS (inter-stimulus interval of 3ms) before and after 1.0, 3.0, and 5.0Hz-RPM. Both 1.0 and 5.0Hz-RPM increased SICI compared with baseline (p<0.05). These experiments suggest that M1 excitability decreases after RPM depending on movement frequency, possibly through frequency dependent enhancement of cortical inhibitory circuit in M1. PMID- 28627418 TI - Alterations in neuronal control of body weight and anxiety behavior by glutathione peroxidase 4 deficiency. AB - Elevated levels of oxidative stress and neuronal inflammation in the hypothalamus or ventral midbrain, respectively, represent common denominators for obesity and Parkinson's Disease (PD). However, little is known about defense mechanisms that protect neurons in these regions from oxidative damage. Here, we aimed to assess whether murine Gpx4, a crucial antioxidant enzyme that protects neurons from membrane damage and ferroptosis, is critical for the protection from neuronal inflammation in two distinct pathophysiologic diseases, namely metabolic dysfunction in diet-induced obesity or PD. Gpx4 was deleted from either AgRP or POMC neurons in the hypothalamus, essential for metabolic homeostasis, or from dopaminergic neurons in the ventral midbrain, governing behaviors such as anxiety or voluntary movement. To induce a pro-inflammatory environment, AgRP and POMC neuron-specific Gpx4 knockout mice were subjected to high-fat high-sucrose (HFHS) diet. To exacerbate oxidative stress in dopaminergic neurons of the ventral midbrain, we systemically co-deleted the PD-related gene DJ-1. Gpx4 was dispensable for the maintenance of cellular health and function of POMC neurons, even in mice exposed to obesogenic conditions. In contrast, HFHS-fed mice with Gpx4 deletion from AgRP neurons displayed increased body adiposity. Gpx4 expression and activity were diminished in the hypothalamus of HFHS-fed mice compared to standard diet-fed controls. Gpx4 deletion from dopaminergic neurons induced anxiety behavior, and diminished spontaneous locomotor activity when DJ-1 was co-deleted. Overall, these data suggest a physiological role for Gpx4 in balancing metabolic control signals and inflammation in AgRP but not POMC neurons. Moreover, Gpx4 appears to constitute an important rheostat against neuronal dysfunction and PD-like symptoms in dopaminergic circuitry within the ventral midbrain. PMID- 28627420 TI - Distinct neural processes support post-success and post-error slowing in the stop signal task. AB - Executive control requires behavioral adaptation to environmental contingencies. In the stop signal task (SST), participants exhibit slower go trial reaction time (RT) following a stop trial, whether or not they successfully interrupt the motor response. In previous fMRI studies, we demonstrated activation of the right hemispheric ventrolateral prefrontal cortex, in the area of inferior frontal gyrus, pars opercularis (IFGpo) and anterior insula (AI), during post-error slowing (PES). However, in similar analyses we were not able to identify regional activities during post-success slowing (PSS). Here, we revisited this issue in a larger sample of participants (n=100) each performing the SST for 40 min during fMRI. We replicated IFGpo/AI activation to PES (p<=0.05, FWE corrected). Further, PSS engages decreased activation in a number of cortical regions including the left inferior frontal cortex (IFC; p<=0.05, FWE corrected). We employed Granger causality mapping to identify areas that provide inputs each to the right IFGpo/AI and left IFC, and computed single-trial amplitude (STA) of stop trials of these input regions as well as the STA of post-stop trials of the right IFGpo/AI and left IFC. The STAs of the right inferior precentral sulcus and supplementary motor area (SMA) and right IFGpo/AI were positively correlated and the STAs of the left SMA and left IFC were positively correlated (slope>0, p's<=0.01, one-sample t test), linking regional responses during stop success and error trials to those during PSS and PES. These findings suggest distinct neural mechanisms to support PSS and PES. PMID- 28627419 TI - ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons. AB - The Aristaless-related homeobox gene (ARX) is indispensable for interneuron development. Patients with ARX polyalanine expansion mutations of the first two tracts (namely PA1 and PA2) suffer from intellectual disability of varying severity, with seizures a frequent comorbidity. The impact of PA1 and PA2 mutations on the brain development is unknown, hindering the search for therapeutic interventions. Here, we characterized the disturbances to cortical interneuron development in mice modeling the two most common ARX polyalanine expansion mutations in human. We found a consistent ~40-50% reduction of calbindin-positive interneurons, but not Stt+ or Cr+ interneurons, within the cortex of newborn hemizygous mice (p=0.024) for both mutant strains compared to wildtype (p=0.011). We demonstrate that this was a consequence of calbindin precursor cells being arrested or delayed at the ventral subpallium en route of tangential migration. Ex-vivo assay validated this migration deficit in PA1 cells (p=0.0002) suggesting that the defect is contributed by intrinsic loss of Arx function within migrating cells. Both humans and mice with PA1 mutations present with severe clinical features, including intellectual disability and infantile spasms. Our data further demonstrated the pathogenic mechanism was robustly shared between PA1 and PA2 mutations, as previously reported including Arx protein reduction and overlapping transcriptome profiles within the developing mouse brains. Data from our study demonstrated that cortical calbindin interneuron development and migration is negatively affected by ARX polyalanine expansion mutations. Understanding the cellular pathogenesis contributing to disease manifestation is necessary to screen efficacy of potential therapeutic interventions. PMID- 28627421 TI - HLA-G*14bp Insertion and the KIR2DS1-HLAC2 Complex Impact on Behavioral Impairment in Children with Autism Spectrum Disorders. AB - Activating KIR-HLA-C ligand complexes and HLA-G*14bp insertion/deletion (+/-) polymorphism were associated to Autism Spectrum Disorders (ASD) and were suggested to correlate with inflammation during fetal development. We evaluated whether HLA-G*14bp(+/-) and KIR-HLA-C complexes are associated with cognitive and behavioral scores and EEG profile in 119 ASD children (58 from Sardinia, 61 from Peninsular Italy). KIR2DS1-C2; KIR2DS2-C1; KIR2DL1-C2; KIR2DL2-C1; KIR2DL3-C1 and HLA-G*14bp(+/-) were molecularly genotyped by Single Specific Primer PCR and gel electrophoresis. Univariate linear model analysis adjusted for age, gender and provenience showed statistically higher scores of Childhood Autism Rating Scale (CARS) and Autistic Core Behavior in KIR2DS1-C2+/HLA-G*14bp+ASD children (43.7+/ 1.5, p=0.03; 3.3+/-0.1, p=0.03, respectively). These results suggested a synergistic polygenic association of KIR2DS1-HLAC2+/HLA-G*14bp+ pattern with behavioral impairment in ASD children. PMID- 28627422 TI - Down-Regulation of KV4 Channel in Drosophila Mushroom Body Neurons Contributes to Abeta42-Induced Courtship Memory Deficits. AB - Accumulation of amyloid-beta (Abeta) is widely believed to be an early event in the pathogenesis of Alzheimer's disease (AD). Kv4 is an A-type K+ channel, and our previous report shows the degradation of Kv4, induced by the Abeta42 accumulation, may be a critical contributor to the hyperexcitability of neurons in a Drosophila AD model. Here, we used well-established courtship memory assay to investigate the contribution of the Kv4 channel to short-term memory (STM) deficits in the Abeta42-expressing AD model. We found that Abeta42 over expression in Drosophila leads to age-dependent courtship STM loss, which can be also induced by driving acute Abeta42 expression post-developmentally. Interestingly, mutants with eliminated Kv4-mediated A-type K+ currents (IA) by transgenically expressing dominant-negative subunit (DNKv4) phenocopied Abeta42 flies in defective courtship STM. Kv4 channels in mushroom body (MB) and projection neurons (PNs) were found to be required for courtship STM. Furthermore, the STM phenotypes can be rescued, at least partially, by restoration of Kv4 expression in Abeta42 flies, indicating the STM deficits could be partially caused by Kv4 degradation. In addition, IA is significantly decreased in MB neurons (MBNs) but not in PNs, suggesting Kv4 degradation in MBNs, in particular, plays a critical role in courtship STM loss in Abeta42 flies. These data highlight causal relationship between region-specific Kv4 degradation and age-dependent learning decline in the AD model, and provide a mechanism for the disturbed cognitive function in AD. PMID- 28627423 TI - Severe developmental timing defects in the prothoracicotropic hormone (PTTH) deficient silkworm, Bombyx mori. AB - The insect neuropeptide prothoracicotropic hormone (PTTH) triggers the biosynthesis and release of the molting hormone ecdysone in the prothoracic gland (PG), thereby controlling the timing of molting and metamorphosis. Despite the well-documented physiological role of PTTH and its signaling pathway in the PG, it is not clear whether PTTH is an essential hormone for ecdysone biosynthesis and development. To address this question, we established and characterized a PTTH knockout line in the silkworm, Bombyx mori. We found that PTTH knockouts showed a severe developmental delay in both the larval and pupal stages. Larval phenotypes of PTTH knockouts can be classified into three major classes: (i) developmental arrest during the second larval instar, (ii) precocious metamorphosis after the fourth larval instar (one instar earlier in comparison to the control strain), and (iii) metamorphosis to normal-sized pupae after completing the five larval instar stages. In PTTH knockout larvae, peak levels of ecdysone titers in the hemolymph were dramatically reduced and the timing of peaks was delayed, suggesting that protracted larval development is a result of the reduced and delayed synthesis of ecdysone in the PG. Despite these defects, low basal levels of ecdysone were maintained in PTTH knockout larvae, suggesting that the primary role of PTTH is to upregulate ecdysone biosynthesis in the PG during molting stages, and low basal levels of ecdysone can be maintained in the absence of PTTH. We also found that mRNA levels of genes involved in ecdysone biosynthesis and ecdysteroid signaling pathways were significantly reduced in PTTH knockouts. Our results provide genetic evidence that PTTH is not essential for development, but is required to coordinate growth and developmental timing. PMID- 28627424 TI - Channeling in native microbial pathways: Implications and challenges for metabolic engineering. AB - Intracellular enzymes can be organized into a variety of assemblies, shuttling intermediates from one active site to the next. Eukaryotic compartmentalization within mitochondria and peroxisomes and substrate tunneling within multi-enzyme complexes have been well recognized. Intriguingly, the central pathways in prokaryotes may also form extensive channels, including the heavily branched glycolysis pathway. In vivo channeling through cascade enzymes is difficult to directly measure, but can be inferred from in vitro tests, reaction thermodynamics, transport/reaction modeling, analysis of molecular diffusion and protein interactions, or steady state/dynamic isotopic labeling. Channeling presents challenges but also opportunities for metabolic engineering applications. It rigidifies fluxes in native pathways by trapping or excluding metabolites for bioconversions, causing substrate catabolite repressions or inferior efficiencies in engineered pathways. Channeling is an overlooked regulatory mechanism used to control flux responses under environmental/genetic perturbations. The heterogeneous distribution of intracellular enzymes also confounds kinetic modeling and multiple-omics analyses. Understanding the scope and mechanisms of channeling in central pathways may improve our interpretation of robust fluxomic topology throughout metabolic networks and lead to better design and engineering of heterologous pathways. PMID- 28627425 TI - A Multicenter Retrospective Analysis Stressing the Importance of Long-Term Follow Up after Hematopoietic Cell Transplantation for beta-Thalassemia. AB - Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with beta-thalassemia major. However, most reports on HCT outcomes lack long-term follow-up data with the exception of single-center reports. An international multicenter retrospective data collection and analysis was conducted in 176 beta thalassemia patients who were 1 year or beyond after first HCT to evaluate follow up methods and outcomes at 7 centers. Median age at HCT was 5.5 years (range, .6 to 18.5), and median follow-up was 7 years (range, 1 to 20). HCT was predominantly from HLA-matched related donors (91%) with bone marrow as stem cell source (91%) and myeloablative conditioning regimens (88%). Late mortality or persistent chronic graft-versus-host disease (GVHD) was rare (<2%). Graft rejection was reported in 23% (24% of these occurred beyond 1 year) post-HCT. Of 119 patients with donor chimerism results available for >=4 years post-HCT, 50% had >95%, 22% had 50% to 95%, 7% had 20% to 50% and 25 (21%) had <20% donor chimerism. Organ dysfunction was identified in 10% pre-HCT and in 20% post-HCT even without complete clinical details on all patients. Hypogonadism and elevated creatinine for age were most commonly reported and significantly higher in recipients >= 7 years at the time of HCT (P = .007) and in those with pre existing morbidity before HCT (P = .02). Outcomes were unaffected by pre-HCT ferritin or GVHD. Mean z scores for height and weight were low at baseline and remained low post-HCT (79%), confirming that growth impairment from disease lacked recovery post-HCT during this follow-up period. HCT for beta-thalassemia has a high rate of cure and low mortality, especially in the young and from HLA matched related donors. Half of the number of recipients live with mixed chimerism that requires continued follow-up because of a risk of late graft rejection (14%). Organ function after HCT when <7 years of age was generally preserved. Hypogonadism, renal dysfunction, and growth impairment that failed to correct were late complications identified most frequently in older transplant recipients. Systematic follow-up of individual organs such as lung and heart were inadequate but important. These data support the development of simple measures of uniformly tracking long-term HCT outcomes and organ functions in children and adolescents who undergo HCT for thalassemia, allowing for systematic identification and implementation of standardized surveillance strategies and interventions. PMID- 28627426 TI - Neurodegenerative signaling factors and mechanisms in Parkinson's pathology. AB - Parkinson's disease (PD) is a chronic and progressive degenerative disorder of central nervous system which is mainly characterized by selective loss of dopaminergic neurons in the nigrostrial pathway. Clinical symptoms of this devastating disease comprise motor impairments such as resting tremor, bradykinesia, postural instability and rigidity. Current medications only provide symptomatic relief but fail to halt the dopaminergic neuronal death. While the etiology of dopaminergic neuronal death is not fully understood, combination of various molecular mechanisms seems to play a critical role. Studies from experimental animal models have provided crucial insights into the molecular mechanisms in disease pathogenesis and recognized possible targets for therapeutic interventions. Recent findings implicate the involvement of abnormal protein accumulation and phosphorylation, mitochondrial dysfunction, oxidative damage and deregulated kinase signaling as key molecular mechanisms affecting the normal function as well survival of dopaminergic neurons. Here we discuss the relevant findings on the PD pathology related mechanisms and recognition of the cell survival mechanisms which could be used as targets for neuroprotective strategies in preventing this devastating disorder. PMID- 28627427 TI - Efficacy and safety of a once-daily single-tablet regimen of tenofovir, lamivudine, and efavirenz assessed at 144 weeks among antiretroviral-naive and experienced HIV-1-infected Thai adults. AB - OBJECTIVE: To assess the efficacy and safety of a new single-tablet regimen (STR) of tenofovir disoproxil fumarate (TDF) 300mg, lamivudine (3TC) 300mg, and efavirenz (EFV) 600mg in HIV-infected Thai patients. METHODS: This was a prospective study performed for 144 weeks among 51 treatment-naive patients and 49 experienced patients on separate tablets of TDF, 3TC, and EFV with HIV RNA<50 copies/ml. CD4, HIV RNA, liver and renal function, and lipid profiles were assessed at baseline, weeks 12, 24, and 48, and then every 24 weeks. RESULTS: The median baseline CD4 cell count was 512 cells/MUl for treatment-experienced patients and 230 cells/MUl for treatment-naive patients. Median baseline log10 HIV-1 RNA for treatment-naive subjects was 4.9 copies/ml. From the intention-to treat (ITT) analysis, the proportion of subjects with HIV RNA <50 copies/ml at week 48, 96, and 144 was 95%, 94%, and 94%, respectively, for antiretroviral experienced patients and 88%, 90%, and 80%, respectively, for antiretroviral naive patients. One virological failure at week 12 had primary drug resistance of K70R, T69D, V75L. Three serious adverse events occurred (tension headache, infective endocarditis, and cervical dysplasia) and another three discontinued the study drug due to EFV intolerance. CONCLUSIONS: This generic STR TDF/3TC/EFV is effective and well-tolerated. These findings lend support to the use of this generic STR as first-line antiretroviral therapy in resource-limited settings. PMID- 28627428 TI - Occupational exposure of cashew nut workers to Kyasanur Forest disease in Goa, India. AB - A series of suspected cases of Kyasanur Forest disease (KFD) in subjects returning to Belgaum in Karnataka State from Goa, India, is reported herein. KFD was confirmed in 13 out of 76 cases, either by real time RT-PCR or IgM ELISA. No case fatality was recorded. KFD virus positivity was also recorded among humans and monkeys from Sattari taluk in Goa during the same period. The envelope gene sequence of positive human samples from Belgaum showed highest identity of 99.98% to 99.99% with sequences of KFD virus isolated from human cases and monkeys from Goa. KFD activity has been reported from Goa among humans and monkeys since 2015. However, it has not been reported from Belgaum to date. These findings suggest that the cases (migrant laborers) contracted infection during cashew nut harvesting from KFD-affected Keri village, Sattari taluk, Goa and became ill after or during migration from the affected area to their native residence. PMID- 28627429 TI - Impact of rotavirus vaccination on child mortality, morbidity, and rotavirus related hospitalizations in Bolivia. AB - BACKGROUND: The public health impact of rotavirus vaccination in countries with high child mortality rates remains to be established. The RV1 rotavirus vaccine was introduced in Bolivia in August 2008. This study describes the trends in deaths, hospitalizations, and healthcare visits due to acute gastroenteritis (AGE) and in rotavirus-related hospitalizations, among children <5 years of age, during the pre- and post-vaccination periods. METHODS: Data were obtained from the National Health Information System to calculate vaccine coverage and AGE related health indicators. Trend reductions in the main health indicators were examined using the pre-vaccine period as baseline. The effect of vaccination on the epidemiology of rotavirus-related AGE was assessed using data from the active surveillance hospitals. RESULTS: Compared with the 2001-2008 pre-vaccine baseline, the mean number of rotavirus-related hospitalizations was reduced by 40.8% (95% confidence interval (CI) 21.7-66.4%) among children <5years of age in the post-vaccine period (2009-2013). Reductions were most pronounced in children <1year of age, eligible for vaccination. The mean proportions of AGE-related deaths, AGE-related hospitalizations, and AGE-related healthcare visits during 2009-2014 were reduced by 52.5% (95% CI 47.4-56.3), 30.2% (95% CI 23.5-36.1), and 12.9% (95% CI 12.0-13.2), respectively. The greatest effect in reduction of AGE related deaths was found during the months with seasonal peaks of rotavirus disease. Over the post-vaccine period, changes in rotavirus epidemiology were observed, manifested by variations in seasonality and by a shift in the mean age of those with rotavirus infection. CONCLUSIONS: The significant decrease in main AGE-related health indicators in children <5years of age after the introduction of rotavirus vaccine provides evidence of a substantial public health impact of rotavirus vaccination in Bolivia, as a measure for protecting children against AGE. PMID- 28627430 TI - Changes in eosinophil count during bacterial infection: revisiting an old marker to assess the efficacy of antimicrobial therapy. AB - INTRODUCTION: Eosinopenia as a criterion of sepsis has been the subject of debate for decades. Different authors have proposed different cut-off values. METHODS: A prospective study was conducted from February to August 2016. Hospitalized adults suffering from a bacterial infection with eosinopenia, defined as an eosinophil count <100/mm3, were included. Patients were divided into two groups according to the first day of effective antimicrobial therapy. They were observed for 5days in order to evaluate whether recovery from eosinopenia was predictive of an appropriate antibiotic regimen. RESULTS: One hundred and twenty-two patients were screened and 96 were included. Group 1 patients (n=70) received effective antimicrobial therapy from day 0. Their eosinophil count increased significantly between day 0 and day 1 (p<0.0001). Group 2 patients (n=26) received delayed effective antimicrobial therapy, and there was no significant difference in eosinophil count between day 0 and day 1 (p=0.55). Moreover, eosinophil counts normalized on day 5 in both groups. The mean duration of antimicrobial therapy was comparable in the two groups (7.7+/-1.16 days). The antibiotics most often prescribed in both groups were intravenous cephalosporins. During follow-up, all patients were considered to be cured after day 30. CONCLUSIONS: The eosinophil count appears to normalize faster than C-reactive protein (CRP) and polymorphonuclear neutrophils in eosinopenic patients on appropriate antimicrobial therapy. This simple test is easy to perform as part of a regular complete blood count, with no additional costs as required for CRP or procalcitonin. PMID- 28627431 TI - Evaluation of the Quantamatrix Multiplexed Assay Platform system for simultaneous detection of Mycobacterium tuberculosis and the rifampicin resistance gene using cultured mycobacteria. AB - BACKGROUND: The differentiation of Mycobacterium tuberculosis complex (MTBC) from non-tuberculous mycobacteria (NTM) is of primary importance for infection control and the selection of anti-tuberculosis drugs. Up to date data on rifampicin (RIF) resistant tuberculosis (TB) is essential for the early management of multidrug resistant TB. The aim of this study was to evaluate the usefulness of a newly developed multiplexed, bead-based bioassay (Quantamatrix Multiplexed Assay Platform, QMAP) for the rapid differentiation of 23 Mycobacterium species including MTBC and RIF-resistant strains. METHODS: A total of 314 clinical Mycobacterium isolates cultured from respiratory specimens were used in this study. RESULTS: The sensitivity and specificity of the QMAP system for Mycobacterium species were 100% (95% CI 99.15-100%, p<0.0001) and 97.8% (95% CI 91.86-99.87%, p<0.0001), respectively. The results of conventional drug susceptibility testing and the QMAP Dual-ID assay were completely concordant for all clinical isolates (100%, 95% CI 98.56-100%). Out of 223 M. tuberculosis (MTB) isolates, 196 were pan-susceptible and 27 were resistant to RIF according to QMAP results. All of the mutations in the RIF resistance-determining region detected by the QMAP system were confirmed by rpoB sequence analysis and a REBA MTB-Rifa reverse blot hybridization assay. The majority of the mutations (n=26, 96.3%), including those missing wild-type probe signals, were located in three codons (529-534, 524-529, and 514-520), and 17 (65.4%) of these mutations were detected by three mutation probes (531TTG, 526TAC, and 516GTC). CONCLUSIONS: The entire QMAP system assay takes about 3h to complete, while results from the culture based conventional method can take up to 48-72h. Although improvements to the QMAP system are needed for direct respiratory specimens, it may be useful for rapid screening, not only to identify and accurately discriminate MTBC from NTM, but also to identify RIF-resistant MTB strains in positive culture samples. PMID- 28627432 TI - High diversity of multidrug-resistant Mycobacterium tuberculosis Central Asian Strain isolates in Nepal. AB - OBJECTIVES: Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) poses a major public health problem in Nepal. Although it has been reported as one of the dominant genotypes of MTB in Nepal, little information on the Central Asian Strain (CAS) family is available, especially isolates related to multidrug resistance (MDR) cases. This study aimed to elucidate the genetic and epidemiological characteristics of MDR CAS isolates in Nepal. METHODS: A total of 145 MDR CAS isolates collected in Nepal from 2008 to 2013 were characterized by spoligotyping, mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) analysis, and drug resistance-associated gene sequencing. RESULTS: Spoligotyping analysis showed CAS1_Delhi SIT26 as predominant (60/145, 41.4%). However, by combining spoligotyping and MIRU-VNTR typing, it was possible to successfully discriminate all 145 isolates into 116 different types including 18 clusters with 47 isolates (clustering rate 32.4%). About a half of these clustered isolates shared the same genetic and geographical characteristics with other isolates in each cluster, and some of them shared rare point mutations in rpoB that are thought to be associated with rifampicin resistance. CONCLUSIONS: Although the data obtained show little evidence that large outbreaks of MDR-TB caused by the CAS family have occurred in Nepal, they strongly suggest several MDR-MTB transmission cases. PMID- 28627433 TI - Comparison of G protein sequences of South African street rabies viruses showing distinct progression of the disease in a mouse model of experimental rabies. AB - Rabies is a fatal zoonotic disease and infections generally lead to a fatal encephalomyelitis in both humans and animals. In South Africa, domestic (dogs) and the wildlife (yellow mongoose) host species maintain the canid and mongoose rabies variants respectively. In this study, pathogenicity differences of South African canid and mongoose rabies viruses were investigated in a murine model, by assessing the progression of clinical signs and survivorship. Comparison of glycoprotein gene sequences revealed amino acid differences that may underpin the observed pathogenicity differences. Cumulatively, our results suggest that the canid rabies virus may be more neurovirulent in mice than the mongoose rabies variant. PMID- 28627434 TI - A different kind of love - lipid droplet contact sites. AB - Lipid droplets (LDs) store lipids and hence serve as energy reservoir and as a source for building-blocks for the organelle membrane systems. LD biology therefore depends on tight communication with other organelles. The unique architecture of LDs, consisting of a neutral lipid core shielded by a phospholipid-monolayer, is however an obstacle to bulk-exchange of bilayer bounded vesicles with other organelles. In recent years, it is emerging that contact sites, places where two organelles are positioned in close proximity allowing vesicle-independent communication, are an important way to integrate LDs into the organellar landscape. However, few LD contact sites have been studied in depth and our understanding of their structure, extent and function is only starting to emerge. Here, we highlight recent findings on the functions of LD contact sites and on the proteins involved in their formation and hypothesize about the unique characteristics of the contact sites formed by these intriguing organelles. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28627436 TI - Folate-targeted polymersomes loaded with both paclitaxel and doxorubicin for the combination chemotherapy of hepatocellular carcinoma. AB - : Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In this study, folate (FA) receptor-targeted polymersomes with apparent bilayered lamellar structure were successfully developed to co-encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (PTX and DOX) in a single vesicle for enhancing the combination chemotherapeutic effect. Hydrophobic PTX was loaded into the thick hydrophobic lamellar membrane by the self-assembly of triblock copolymer PCL8000 PEG8000-PCL8000, while hydrophilic DOX was encapsulated into the hydrophilic reservoir using a trans-membrane ammonium sulfate gradient method. In vitro release study indicated that the drugs were released from the polymersomes in a controlled and sustained manner. Cellular uptake study indicated that FA-targeted Co-PS had higher internalization efficiency in FA receptor-overexpressing BEL 7404 cells than non-targeted Co-PS. In vitro cytotoxicity assay demonstrated that FA-targeted Co-PS exhibited less cytotoxic effect than free drug cocktail, but suppressed the growth of tumor cells more efficiently than non-targeted Co-PS. Ex vivo imaging biodistribution studies revealed that FA-targeted Co-PS led to highly efficient targeting and accumulation in the BEL-7404 xenograft tumor. Furthermore, the in vivo antitumor study showed that the combination chemotherapy of polymersomes to BEL-7404 tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy. STATEMENT OF SIGNIFICANCE: Combination chemotherapy is a promising method of improving cancer treatment, but the distinct pharmacokinetics of combined drugs and non-specific drug distribution slow down the development in the clinic. In our study, novel folate-targeted co-delivery polymersomes (Co-PS) were successfully developed to encapsulate a hydrophobic-hydrophilic chemotherapeutic drug pair (paclitaxel and doxorubicin) into the different compartments of the vesicle. In vivo studies revealed that the combination chemotherapy of polymersomes to BEL-7404 xenograft tumor via intravenous injection was superior to free drug cocktail treatment, and the FA-targeted Co-PS exhibited significantly higher tumor growth inhibition than non-targeted Co-PS group. Therefore, the newly developed FA-targeted co-delivery polymersomes hold great promise for simultaneous delivery of multiple chemotherapeutics and would have great potential in tumor-targeting and combination chemotherapy. PMID- 28627437 TI - Molecular characterization and functional analysis of PPARalpha promoter in yellow catfish Pelteobagrus fulvidraco. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand activated transcription factor that plays critical roles in the regulation of many important physiological processes. In the present study, the 1686-bp PPARalpha promoter for yellow catfish Pelteobagrus fulvidraco was first cloned and characterized. The transcription start site (TSS) of PPARalpha gene was mapped using RLM-5'RACE method. The luciferase vectors were constructed and transiently transfected into HepG2 cells and HEK293 cells, respectively, for functional analysis of promoters. Bioinformatics analysis revealed the putative core promoter regions including a TATA-box and a CAAT-box located at -35bp and 75bp upstream of the TSS, respectively. A cluster of putative binding sites of several transcription factors, such as AP1, C2H2ZFP, E-box, HNF4alpha, NF-kappaB, PPAR, Sp1 and STAT1, were identified. Deletion analysis indicated that these transcriptional factor binding sites were essential to the basal promoter activity. Subsequent mutation analysis showed that the PPARalpha promoter activity was down-regulated following mutation of the TFBSs including NF-kappaB, PPAR and HNF4alpha, indicating that these TFBSs were responsible for PPARalpha activation. Furthermore, the transcription activity of the PPARalpha promoter was increased and PPARalpha mRNA expression was up-regulated after fenofibrate treatment. Overall, the present study provided new insights into the mechanisms for transcriptional regulation of PPARalpha in fish. PMID- 28627435 TI - Establishing the lipid droplet proteome: Mechanisms of lipid droplet protein targeting and degradation. AB - Lipid droplets (LDs) are ubiquitous, endoplasmic reticulum (ER)-derived organelles that mediate the sequestration of neutral lipids (e.g. triacylglycerol and sterol esters), providing a dynamic cellular storage depot for rapid lipid mobilization in response to increased cellular demands. LDs have a unique ultrastructure, consisting of a core of neutral lipids encircled by a phospholipid monolayer that is decorated with integral and peripheral proteins. The LD proteome contains numerous lipid metabolic enzymes, regulatory scaffold proteins, proteins involved in LD clustering and fusion, and other proteins of unknown functions. The cellular role of LDs is inherently determined by the composition of its proteome and alteration of the LD protein coat provides a powerful mechanism to adapt LDs to fluctuating metabolic states. Here, we review the current understanding of the molecular mechanisms that govern LD protein targeting and degradation. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28627438 TI - Genome wide identification, phylogeny, and expression of bone morphogenetic protein genes in tetraploidized common carp (Cyprinus carpio). AB - Bone morphogenetic proteins (Bmps) are a group of signaling molecules known to play important roles during formation and maintenance of various organs, not only bone, but also muscle, blood and so on. Common carp (Cyprinus carpio) is one of the most intensively studied fish due to its economic and environmental importance. Besides, common carp has encountered an additional round of whole genome duplication (WGD) compared with many closely related diploid teleost, which make it one of the most important models for genome evolutionary studies in teleost. Comprehensive genome resources of common carp have been developed recently, which facilitate the thorough characterization of bmp gene family in the tetraploidized common carp genome. We identified a total of 44 bmps from the common carp genome, which are twice as many as that of zebrafish. Phylogenetic analysis revealed that most of bmps are highly conserved. Comparative analysis was performed across six typical vertebrate genomes. It appeared that all the bmp genes in common carp were duplicated. Obviously, the expansion of the bmp gene family in common carp was due to the latest additional round of whole genome duplication and made it more abundant than other diploid teleosts. Expression signatures were assessed in major tissues, including gill, intestine, liver, spleen, skin, heart, gonad, muscle, kidney, head kidney, brain and blood, which demonstrated the comprehensive expression profiles of bmp genes in the tetraploidized genome. Significant gene expression divergences were observed which revealed substantial functional divergences of those duplicated bmp genes post the latest WGD event. The conserved synteny blocks of bmp5s revealed the genome rearrangement of common carp post the 4R WGD. The whole set of bmp gene family in common carp provides insight into gene fate of tetraploidized common carp genome post recent WGD. PMID- 28627439 TI - Mitochondrial prohibitin and its ubiquitination during spermatogenesis of the swimming crab Charybdis japonica. AB - It has been proposed that prohibitin (PHB) involved in multiple cellular functions, including cell proliferation, differentiation, apoptosis, senescence and carcinogenesis. Various cellular compartment location of PHB demonstrates its diverse roles. Based on the full-length sequence of PHB gene, we analyzed the deduced amino acid sequence and the predicted protein structure of this gene in the swimming crab Charybdis japonica. It shows that the structure and function of PHB are conservative. The expression level of PHB mRNA and protein in different tissues were analyzed by sqRT-PCR and western blot respectively, which showed its high expression in testis. We then traced PHB protein by immunofluorescence, and we found its diverse distribution in cytoplasm and mitochondria at different stages. We propose that PHB may participate actively in spermatogenic cell anti apoptosis, cell nucleus distortion as well as acrosome morphogenesis during the spermatogenesis in Charybdis japonica. Furthermore, PHB was found to be ubiquitinated at different levels. Its signal was weak in spermatocytes and Stage 1 spermatids, stronger in stage 2-4 spermatids, and lowest in mature sperm. Our data shows that PHB may mediate the paternal mitochondrial material degradation by ubiquitination. We conclude that PHB is indispensable in the spermatogenesis of the swimming crab Charybdis japonica through different testis developmental stages. PMID- 28627440 TI - MicroRNA-21 regulates hepatic glucose metabolism by targeting FOXO1. AB - Abnormal activation of hepatic gluconeogenesis is a major contributor to fasting hyperglycemia in type 2 diabetes; however, the potential role of microRNAs in gluconeogenesis remains unclear. Here, we showed that hepatic expression levels of microRNA-21 (miR-21) were decreased in db/db and high-fat diet (HFD)-induced diabetic mice. Adenovirus-mediated overexpression of miR-21 decreased the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and inhibited glucose production in primary mouse hepatocytes. Silencing of miR-21 reversed this effect. Overexpression of miR-21 in the livers of db/db and HFD-induced mice was able to suppress hepatic gluconeogenesis, subsequently decreasing blood glucose levels and improving glucose and insulin intolerance. Furthermore, overexpression of miR-21 in primary mouse hepatocytes and mouse livers decreased the protein levels of FOXO1 and increased hepatic insulin sensitivity. By contrast, silencing of miR-21 increased the protein levels of FOXO1, subsequently leading to a decrease in insulin sensitivity and impaired glucose intolerance in C57BL/6 mice fed with high-fat diet for 4weeks. Finally, we confirmed that FOXO1 was a potential target of miR-21. These results suggest that miR-21 is a critical regulator in hepatic gluconeogenesis and may provide a novel therapeutic target for treating insulin resistance and type 2 diabetes. PMID- 28627441 TI - Clinical and genetic characteristics of 17 Chinese patients with glycogen storage disease type IXa. AB - Glycogen storage disease (GSD) type IXa is caused by PHKA2 mutation, which accounts for about 75% of all the GSD type IX cases. Here we first summarized the clinical data and analyzed the PHKA2 gene of 17 Chinese male patients suspected of having GSD type IXa. Clinical symptoms of our patients included hepatomegaly, growth retardation, and liver dysfunction. The clinical and biochemical manifestations improved and even disappeared with age. We detected 14 mutations in 17 patients, including 8 novel mutations; exons 2 and 4 were hot spots in this research. In conclusion, glycogen storage disease type IXa is a mild disorder with a favorable prognosis, and there was no relationship between genotype and phenotype of this disease. PMID- 28627442 TI - The association of rs710886 in lncRNA PCAT1 with bladder cancer risk in a Chinese population. AB - OBJECTIVE: The long noncoding RNA PCAT1 is an important gene involved in urinary tumors. In this study, we aimed to explore the association between polymorphisms in PCAT1 and bladder cancer susceptibility. METHODS: A two-stage case-control study was conducted to assess the association between four tagging SNPs (i.e., rs4871771, rs1902432, rs16901904 and rs710886) and bladder cancer risk. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated with unconditional univariate and multivariate logistic regression. RESULTS: At the first stage of discovery, we identified that SNP rs710886A>G was significantly associated with bladder cancer risk (OR=0.86, 95% CI=0.74-0.99, P=0.046). At the following stage of validation, individuals with GG genotype were found to have a significant reduction in bladder cancer risk compared with those carrying AA genotype (adjusted OR=0.83, 95% CI=0.74-0.93, P=0.001). Furthermore, stratified analyses showed that protective effect of rs710886 was more pronounced in subgroup of age>60 and never smoking, and had little to do with sex. Besides, rs710886 was identified as an eQTL for PCAT1. G allele was consistent with lower PCAT1 expression. CONCLUSION: This study indicates that genetic variants in lncRNA PCAT1 were associated with bladder cancer susceptibility and the SNP rs710886 may act as a potential biomarker for bladder cancer risk. PMID- 28627443 TI - Impact of the BCR-ABL1 fusion transcripts on different responses to Imatinib and disease recurrence in Iranian patients with Chronic Myeloid Leukemia. AB - BACKGROUND: One genomic breakpoint can result in variable BCR-ABL1 transcript types due to alternative splicing. The influence of different BCR-ABL1 transcript types on clinical outcome is still controversial. AIM OF THE STUDY: The objective of this analysis was to determine the impact of transcript type on response, clinical outcome, recurrence risk after treatment with Imatinib mesylate in Chronic Myeloid Leukemia (CML) patients. METHODS: Sixty CML patients in chronic phase were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and banding standard protocols. RESULTS: There was a significant difference in collective incidence of complete cytogenetic response (CCR) between the e14a2 and e13a2 groups (P=0.04). The median time to achieve CCR was shorter in e14a2 patients than to e13a2 (P=0.01). This finding is paralleled by the molecular response where the median of the BCR-ABL1/ABL1 expression levels were significantly lower in e14a2 transcript compared to e13a2 type at 3, 6, 9 and 12months from the start of therapy (P<0.01). The probability of recurrence after treatment discontinuation was 9.33 fold higher in e13a2 transcript, that is reported here for the first time (chi2=5.49; P=0.01; OR: 9.33; 95% CI: 1.59, 54.67). No significant difference was observed regarding overall survival (OS), although Patients with e14a2 transcript displayed a significant tendency toward a higher event free survival (EFS) ratio (P=0.03). CONCLUSION: We found that patients with the e14a2 transcript achieved better and faster responses to Imatinib mesylate. In this study, parallel data regarding molecular and cytogenetic responses, impact of transcript type on the probability of recurrence might suggest a general outcome that the type of transcript can be used as a prognostic marker at diagnosis. PMID- 28627444 TI - Associative role of TYMS6bpdel polymorphism and resulting hyperhomocysteinemia in the pathogenesis of preterm delivery and associated complications: A study from Northeast India. AB - : Aberrations including genetic alterations in folate pathway are detrimental in multiple disease pathogenesis, including pregnancy. The present study is based on the screening of the associative role of TYMS 14946bp deletion(del) polymorphism and associated hyperhomocysteinemia in susceptibility to preterm delivery (PTD), which is strongly associated with neonatal mortality and morbidity. METHODS: A total of 209 PTD cases {extremely preterm (n=22), very preterm (n=43) and moderately preterm (n=144)} and 194 term delivery cases were evaluated for TYMS 14946bp deletion and its association with preterm delivery, pregnancy outcome, baby birth weight and homocysteine estimation. RESULTS: The results showed that the distribution of TYMS 14946bp del/del genotype significantly increased the risk of PTD [OR=2.801, p=0.002] and is associated with fetal death. The TYMS 6bp ins/del and 6bp del/del genotype was associated with low birth weight (LBW) compared to 6bp ins/ins genotype in both term and PTD groups, and in case of very (p=0.024) and moderately (p=0.045) sub-cohorts of PTD significantly. Elevated serum homocysteine levels were significantly associated with PTD (p<0.001) and fetal death (p=0.013); and was also found to significantly correlate with TYMS 14946bp del/del genotype in all the pregnancy cases (p=0.008). TYMS 6bp del/del genotype was associated with higher homocysteine levels compared to ins/ins (p=0.005) and ins/del (p=0.062) genotypes within the PTD group. CONCLUSION: The study provides crucial information regarding the importance of TYMS6bpdel/del genotype and associated hyperhomocysteinemia in susceptibility to PTD, fetal death and LBW; and thus indicating their prognostic significance of TYMS 6bp del/del genotype in PTD which is of clinical importance. PMID- 28627445 TI - Right-sided acute diverticulitis: A single Western center experience. AB - INTRODUCTION: Right sided diverticular disease is a rare condition in Western countries whereas is common amongst Asian population. The aim of this study is to evaluate options and outcomes for the treatment of right colonic diverticulitis. METHOD: We included only patients undergoing surgery with right colon diverticulitis (RCD) proven at histological specimen examination from September 2011 to December 2016. RESULTS: We performed 18 operations for RCD. Age was lower compared to left sided disease (49 +/- 16 vs 67 +/- 14; P < 0.001). Three patients were Asian (16.7%). RCD was diagnosed preoperatively in 8 cases (44.4%), whereas appendicitis was suspected in 9 cases (50%) and neoplasm in one (5.6%). We performed resection with anastomosis in 13 patients (72.2%) and in 5 cases we performed a diverticulectomy. Laparoscopy was performed in 14 cases (77.8%). Postoperative morbidity occurred in 3 patients (16.7%; grade 2 or 3a according to Clavien-Dindo) with no mortality. No postoperative events occured after diverticulectomy with shorter hospital stay (4 +/- 1.5 vs 11 +/- 13; P = 0.022), as no recurrence or need for elective surgery after a mean follow-up of 20 months. CONCLUSION: RCD is a rare but not irrelevant condition. Minimally invasive surgery is often feasible and complication rate is low. In selected patients, diverticulectomy can be a valid alternative to treat this condition providing improved postoperative results. PMID- 28627446 TI - Lipid profile and suicide attempt in bipolar disorder: A meta-analysis of published and unpublished data. AB - Evidence suggests an association between low lipid levels and suicidality in subjects with severe mental disorders. This is the first systematic review and meta-analysis aimed at exploring differences in lipid profile between suicide attempters and non-attempters with bipolar disorder. We included observational studies providing comparative cross-sectional data on total cholesterol, LDL cholesterol and triglycerides levels. We searched main Electronic Databases, identifying 11 studies that met our inclusion criteria, including also unpublished data. Meta-analyses based on random-effects models were carried out, generating pooled standardized mean differences (SMDs). Heterogeneity among studies was estimated using the I2 index. The meta-analyses included data on lipid profile from 11 studies based on 288 subjects with and 754 without suicide attempt, respectively. No differences in total cholesterol (SMD: -0.10; 95%CI: 0.30 to 0.10; p=0.34), LDL-cholesterol (SMD: -0.26; 95%CI: -0.65 to 0.13; p=0.19), and triglycerides (SMD: -0.06; 95%CI: -0.31 to 0.19; p=0.63) were detected. Heterogeneity across studies was low-moderate and no risk of publication bias was found. Subgroup analyses showed no differences on effect size across different study characteristics, including different time-frames of suicide attempt, except for small sample size. Therefore, the evidence for an association between serum lipid profile and suicidality in bipolar disorder cannot be claimed. More research is needed to better understand the mechanisms underlying suicidal behaviours in bipolar patients, exploring further peripheral biomarkers as this may help clinicians screen and prevent suicidality. PMID- 28627447 TI - Pain with traumatic brain injury and psychological disorders. AB - Traumatic brain injury (TBI) is the cause for long-term disability in more than 3 million patients in the US alone, with chronic pain being the most frequently reported complain. To date, predisposing mechanisms for chronic pain in TBI patients are largely unknown. Psychological disorders, including post-traumatic stress disorder, depression and anxiety following TBI are commonly reported comorbidities to post-traumatic pain. Long term consequences can be debilitating and affect quality of life even when the injury is mild. In this review, we present the most commonly reported chronic pain conditions across the spectrum of severity of TBI, mainly focusing on mild TBI. We discuss chronic post- traumatic headaches, widespread pain as well as post-traumatic central pain. We discuss pain in the context of injury severity and military versus civilian populations. We are only starting to understand the biological mechanisms behind post traumatic pain and associated psychological distress following TBI, with genetic, biochemical and imaging studies pointing to the dopaminergic, neurotrophic factors and the role of Apolipoprotein. Physiological and neurological mechanisms are proposed to partially explain this interaction between post-traumatic pain and psychological distress. Nevertheless, the evidence for the role of structural brain damage remains incomplete and to a large extent debatable, as it is still difficult to establish clear causality between brain trauma and chronic pain. Finally, general aspects of management of chronic pain post-TBI are addressed. PMID- 28627448 TI - Opiate exposure state controls dopamine D3 receptor and cdk5/calcineurin signaling in the basolateral amygdala during reward and withdrawal aversion memory formation. AB - The dopamine (DA) D3 receptor (D3R) is highly expressed in the basolateral nucleus of the amygdala (BLA), a neural region critical for processing opiate related reward and withdrawal aversion-related memories. Functionally, D3R transmission is linked to downstream Cdk5 and calcineurin signaling, both of which regulate D3R activity states and play critical roles in memory-related synaptic plasticity. Previous evidence links D3R transmission to opiate-related memory processing, however little is known regarding how chronic opiate exposure may alter D3R-dependent memory mechanisms. Using conditioned place preference (CPP) and withdrawal aversion (conditioned place aversion; CPA) procedures in rats, combined with molecular analyses of BLA protein expression, we examined the effects of chronic opiate exposure on the functional role of intra-BLA D3R transmission during the acquisition of opiate reward or withdrawal aversion memories. Remarkably, we report that the state of opiate exposure during behavioural conditioning (opiate-naive/non-dependent vs. chronically exposed and in withdrawal) controlled the functional role of intra-BLA D3R transmission during the acquisition of both opiate reward memories and withdrawal-aversion associative memories. Thus, whereas intra-BLA D3R blockade had no effect on opiate reward memory formation in the non-dependent state, blockade of intra-BLA D3R transmission prevented the formation of opiate reward and withdrawal aversion memory in the chronically exposed state. This switch in the functional role of D3R transmission corresponded to significant increases in Cdk5 phosphorylation and total expression levels of calcineurin, and a corresponding decrease in intra BLA D3R expression. Inhibition of either intra-BLA Cdk5 or calcineurin reversed these effects, switching intra-BLA associative memory formation back to a D3R independent mechanism. PMID- 28627449 TI - MicroRNA-214 regulates immunity-related genes in bovine mammary epithelial cells by targeting NFATc3 and TRAF3. AB - In human, microRNA-214 (miR-214) plays crucial roles in mechanisms of immunity. However, the potential importance of miR-214 in immune mechanisms in dairy cows has not been investigated. In this study, we assessed potential immunity-related functions of miR-214 in human 293A cells and in bovine mammary epithelial cells (BMECs). We found that NFATc3 and TRAF3 could be targeted by miR-214 in both 293A cells and BMECs. We also found that miR-214 indirectly inhibited the expression of MAP3K14, TBK1 and inflammatory cytokines IL-6 and IL-1beta. Taken together, our data revealed miR-214 regulated immunity-related genes by targeting NFATc3 and TRAF3, which provides insight into the molecular basis of immunity. PMID- 28627450 TI - Impact of fixation artifacts and threshold selection on high resolution melting analysis for KRAS mutation screening. AB - INTRODUCTION: Treatment in metastatic colorectal cancer (mCRC) has expanded with monoclonal antibodies targeting epidermal growth factor receptor, but is restricted to patients with a wild-type (WT) KRAS mutational status. The most sensitive assays for KRAS mutation detection in formalin-fixed paraffin embedded (FFPE) tissues are based on real-time PCR. Among them, high resolution melting analysis (HRMA), is a simple, fast, highly sensitive, specific and cost-effective method, proposed as adjunct for KRAS mutation detection. However the method to categorize WT vs mutant sequences in HRMA is not clearly specified in available studies, besides the impact of FFPE artifacts on HRMA performance hasn't been addressed either. METHODS: Avowedly adequate samples from 104 consecutive mCRC patients were tested for KRAS mutations by TherascreenTM (FDA Validated test), HRMA, and HRMA with UDG pre-treatment to reverse FFPE fixation artifacts. Comparisons of KRAS status allocation among the three methods were done. Focusing on HRMA as screening test, ROC curve analyses were performed for HRMA and HMRA UDG against TherascreenTM, in order to evaluate their discriminative power and to determine the threshold of profile concordance between WT control and sample for KRAS status determination. RESULTS: Comparing HRMA and HRMA-UDG against TherascreenTM as surrogate gold standard, sensitivity was 1 for both HRMA and HRMA-UDG; and specificity and positive predictive values were respectively 0.838 and 0.939; and 0.777 and 0.913. As evaluated by the McNemar test, HRMA-UDG allocated samples to a WT/mutated genotype in a significatively different way from HRMA (p > 0.001). On the other hand HRMA-UDG did not differ from TherascreenTM (p = 0.125). ROC-curve analysis showed a significant discriminative power for both HRMA and HRMA-UDG against TherascreenTM (respectively, AUC of 0.978, p > 0.0001, CI 95% 0.957-0.999; and AUC of 0.98, p > 0.0001, CI 95% 0.000 1.0). For HRMA as a screening tool, the best threshold (degree of concordance between sample curves and WT control) was attained at 92.14% for HRMA (specificity of 0.887), and at 92.55% for HRMA-UDG (specificity of 0.952). CONCLUSIONS: HRMA is a highly sensitive method for KRAS mutation detection, with apparently adequate and statistically significant discriminative power. FFPE sample fixation artifacts have an impact on HRMA results, so for HRMA on FFPE samples pre-treatment with UDG should be strongly suggested. The choice of the threshold for melting curve concordance has also great impact on HRMA performance. A threshold of 93% or greater might be adequate if using HRMA as a screening tool. Further validation of this threshold is required. PMID- 28627451 TI - Leadless pacemaker surrounded by three valvular prostheses. PMID- 28627452 TI - Engineering of unconventional yeast Yarrowia lipolytica for efficient succinic acid production from glycerol at low pH. AB - Yarrowia lipolytica is considered as a potential candidate for succinic acid production because of its innate ability to accumulate citric acid cycle intermediates and its tolerance to acidic pH. Previously, a succinate-production strain was obtained through the deletion of succinate dehydrogenase subunit encoding gene Ylsdh5. However, the accumulation of by-product acetate limited further improvement of succinate production. Meanwhile, additional pH adjustment procedure increased the downstream cost in industrial application. In this study, we identified for the first time that acetic acid overflow is caused by CoA transfer reaction from acetyl-CoA to succinate in mitochondria rather than pyruvate decarboxylation reaction in SDH negative Y. lipolytica. The deletion of CoA-transferase gene Ylach eliminated acetic acid formation and improved succinic acid production and the cell growth. We then analyzed the effect of overexpressing the key enzymes of oxidative TCA, reductive carboxylation and glyoxylate bypass on succinic acid yield and by-products formation. The best strain with phosphoenolpyruvate carboxykinase (ScPCK) from Saccharomyces cerevisiae and endogenous succinyl-CoA synthase beta subunit (YlSCS2) overexpression improved succinic acid titer by 4.3-fold. In fed-batch fermentation, this strain produced 110.7g/L succinic acid with a yield of 0.53g/g glycerol without pH control. This is the highest succinic acid titer achieved at low pH by yeast reported worldwide, to date, using defined media. This study not only revealed the mechanism of acetic acid overflow in SDH negative Y. lipolytica, but it also reported the development of an efficient succinic acid production strain with great industrial prospects. PMID- 28627453 TI - Design and development of multi-walled carbon nanotube-liposome drug delivery platforms. AB - The aim of this study is to design and develop delivery platforms made of liposomes and multi-walled carbon nanotubes (MWCNTs). We used different lipids with different main transition temperature (Tm) and differently functionalized MWCNTs with organic addends possessing either positive or negative charge. The phospholipids used for the formulations were 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) (Tm=41 degrees C) and L-alpha-phosphatidylcholine, hydrogenated Soy (HSPC) (Tm=53 degrees C). By Differential Scanning Calorimetry (DSC), we studied the interaction between the DPPC and HSPC bilayers and MWCNTs. Liposome-MWCNTs delivery platforms prepared according to the protocol used in the literature. We used dynamic and electrophoretic light scattering in order to investigate the physicochemical characteristics of these mixed nanocarriers. The presence of MWCNTs causes alterations of the size of the conventional HSPC and DPPC liposomes. The zeta-potential values of mixed nanocarriers are near zero. This observation indicates the effective incorporation of MWCNTs into the lipid bilayer of liposomes. Fluorescence spectroscopy has been utilized to exact some qualitative information on the internal nanostructure and nanoenvironment of the lipid/carbon nanotube mixed structures. Finally, we conclude that we successfully prepare and completely characterize mixed nanocarriers composed of lipids and MWCNTs, with low toxicity as indicated by in vitro screening. PMID- 28627454 TI - Synthesis, physiochemical characterization, and in vitro antitumor activity of the amide and pH cleavable hydrazone conjugates of gamma-tocotrienol isomer of vitamin E with methoxy-poly(ethylene) glycol. AB - The anticancer activity of water soluble methoxy polyethylene glycol (mPEG) derivatives of tocotrienol (T3) isomers of vitamin E was previously found to be reduced when compared to the parent free isomers. This could be due to the ester bond formation between the mPEG and the 6-OH group on the chroman moiety of the T3 isomer. To further investigate, the objectives of the current study were to (1) synthesize and characterize stable amide and cleavable hydrazone conjugates between mPEG and carbon-5 on the chroman moiety of T3, and (2) examine the cytotoxicity of the newly synthesized mPEG conjugates against breast (MCF-7 and MDA-MB-231) and pancreatic (BxPC-3 and PANC-1) cancer cells. Conjugates were synthesized by direct conjugation of succinyl chloride derivatives of mPEG to the alpha-tocopherol and gamma-tocotrienol isomers of vitamin E, and were characterized by 1H NMR, FT-IR, and mass spectrometry. The micelles of the amide and hydrazone self-assembled conjugates were characterized for size, zeta, CMC, and stability at different pH media. The hydrolysis of the hydrazone conjugate was pH dependent with highest release at acidic (pH 5.5) conditions, whereas the amide conjugate was stable in all tested media. The amide conjugate nonetheless showed greater cytotoxicity than the hydrazone conjugate, which suggested that maintaining solubility and the presence of free 6-OH group are important for gamma-T3 to exert anticancer activity in vitro. The results from the current study demonstrated the importance of considering the nature of the chemical bond between T3 and mPEG when designing functional ingredients for use in drug delivery. PMID- 28627456 TI - Effect of the surface layer on drug release from delefilcon-A (Dailies Total1(r)) contact lenses. AB - Contact lenses are receiving significant attention for delivering ophthalmic drugs with higher bioavailability compared to eye drops. Here we explore drug transport from delefilcon-A Dailies Total1(r) lenses which are designed to have a thin, high-water content layer on the surface. Our goal is to determine the impact of this high water content layer on drug transport for both hydrophobic (dexamethasone and cyclosporine) and hydrophilic (timolol and levofloxacin) drugs. Drugs were loaded into the lens by soaking in aqueous drug solutions till equilibrium, followed by release in phosphate buffered saline. The concentration data during release was fitted to the diffusion equation without considering the surface layer. If fits were poor, the surface layer was include in the model, as a burst release. Results showed that surface layer resulted in a burst release of about 35% of the loaded drug for the two hydrophilic drugs, and the model did not fit the data unless the surface layer was incorporated as a burst release. For the hydrophobic drugs, there was no burst release and the model fitted the data without including the surface layer likely because of the low partition coefficient of the hydrophobic drugs in the surface layer compared to the lens. The results further confirm the presence of the high water content surface layer on the Dailies Total1(r) lenses. The release profile of the burst release for hydrophilic drugs could be therapeutically useful for antibiotics where a high dose is desirable initially. The effect of vitamin E loading-an established procedure for increasing drug release time in other commercial lenses, was also tested on the release of timolol maleate and levofloxacin. A 20% vitamin E loading was found to increase the release time of timolol and levofloxacin by a factor of 5 and 3-fold respectively, but this increase proved much less effective compared to vitamin E's effect on other commercial silicone hydrogels. PMID- 28627455 TI - Gemcitabine-vitamin E conjugates: Synthesis, characterization, entrapment into nanoemulsions, and in-vitro deamination and antitumor activity. AB - Gemcitabine is the first line therapy for pancreatic cancer. It is, however, extensively metabolized to the inactive form by deamination enzymatic reaction. Conjugation of gemcitabine with fatty acids on its 4-amino group was found to protect it from deamination deactivation reaction. The objective of the present study was to test the in-vitro anticancer activity of gemcitabine conjugated to the gamma-tocotrienol isomer of vitamin E against pancreatic tumor cells. This objective was based on reported studies in which it was demonstrated that free tocotrienol isomers of vitamin E can potentiate the anticancer activity of gemcitabine. To accomplish this objective, a full synthesis scheme for gemcitabine conjugation to fatty acids (stearic and linoleic) and the tocopherol and tocotrienol isomers of vitamin E (alpha-T and gamma-T3) was presented. The conjugates were characterized by 1H NMR and mass spectrometry analysis and tested for their susceptibility to deamination. Also discussed is the impact of entrapping the conjugates into nanoemulsions on the physiochemical properties of the delivery system and the in vitro anticancer activity of gemcitabine against Bx-PC-3 and PNAC-1 pancreatic cancer cells. In-vitro enzymatic deamination study showed that the gamma-T3 conjugate of gemcitabine was least affected by deamination deactivation reaction when compared with the free and conjugated gemcitabine in solution. Furthermore, in-vitro cytotoxicity study demonstrated that entrapment of gemcitabine-lipid conjugates into nanoemulsions significantly enhanced their anticancer activity when compared to the free drug. It was concluded that conjugation to the gamma-T3 isomer is a viable option for gemcitabine delivery and is worthy of further investigation. PMID- 28627457 TI - Analysis of the origins of content non-uniformity in high-shear wet granulation. AB - In this study, the origins of granule content non-uniformity in the high-shear wet granulation of a model two-component pharmaceutical blend were investigated. Using acetaminophen as the active pharmaceutical ingredient (API) and microcrystalline cellulose as the excipient, the distribution of the API across the granule size classes was measured for a range of conditions that differed in the duration of the initial dry mixing stage, the overall composition of the blend and the wet massing time. The coarse granule fractions were found to be systematically sub-potent, while the fines were enriched in the API. The extent of content non-uniformity was found to be dependent on two factors - powder segregation during dry mixing and redistribution of the API between the granule size fractions during the wet massing phase. The latter was demonstrated in an experiment where the excipient was pre-granulated, the API was added later and wet massed. The content non-uniformity in this case was comparable to that obtained when both components were present in the granulator from the beginning. With increasing wet massing time, the extent of content non-uniformity decreased, indicating that longer wet massing times might be a solution for systems with a natural tendency for component segregation. PMID- 28627458 TI - siRNA-loaded biodegradable nanocarriers for therapeutic MAPK1 silencing against cisplatin-induced ototoxicity. AB - Ototoxicity represents a major adverse side-effect of cis diamminedichloroplatinum-II (cisplatin, CDDP). The mitogen-activated protein kinase (MAPK) pathway is thought to play a central role in potentiating the apoptotic effect of CDDP within the cochlea. We hypothesized that prophylactic inhibition of MAPK signaling, using small interfering RNA (siRNA), might confer a protective effect against CDDP-induced apoptosis within the auditory sensory epithelia. To enhance the therapeutic utility of this approach, we synthesized biocompatible siMAPK1-loaded nanoparticles (NPs) and performed physicochemical characterizations for size, morphology, drug loading and release kinetics, using dynamic light scattering, electron microscopy and spectrophotometric analyses, respectively. Our findings show 183.88+/-6.26 nm-sized spherical siMAPK1-loaded NPs with -27.12+/-6.65mV zeta potential and 112.78+/-0.24pmol/mg of siMAPK1 loading that exhibit a sustained release profile for prolonged therapeutic efficacy. Synthesized NPs were validated for biocompatibility and prophylactically protected against CDDP-induced cytotoxicity in HEI-OC1 cells and hair cell loss in murine organotypic cochlear explants. Our study confirms a pivotal role for MAPK1 signaling as a potentiating factor for CDDP-induced apoptosis and cochlear hair cell loss, and highlights siMAPK1 NP treatment as a therapeutic strategy for limiting the ototoxic side-effects associated with systemic CDDP administration. PMID- 28627459 TI - Peripheral blood gene expression of acute phase proteins in people with first episode psychosis. AB - BACKGROUND: There is a growing interest in the association between schizophrenia and the activation of inflammatory system with signs of acute phase (AP) response. Majority of such studies had focused on C-reactive protein (CRP). The aims of the present study were (i) to examine the gene expression profiles of other acute phase proteins (APP), namely haptoglobin (HP), alpha-1 antitrypsin (A1T), and alpha-2 macroglobulin (A2M) in patients with first episode psychosis (FEP) over a period of three months and (ii) to explore the association between APP levels and severity of symptoms. METHODS: In this study, HP, A1T and A2M gene expression levels from whole blood were measured at recruitment, 1- and 3-month follow-up visits using quantitative PCR (qPCR) in 43 patients with FEP and in 57 healthy controls. Diagnoses was ascertained on the Structured Clinical Interview for DSM-IV-TR. Severity of symptoms in patients was assessed on the Positive and Negative Syndrome Scale (PANSS) and a previously validated 5-factor PANSS structure was applied in the subsequent analyses. RESULTS: The FEP sample comprised of 28 (65.1%) individuals with schizophrenia, 12 (27.9%) with schizophreniform disorder and 3 (7%) with schizoaffective disorder. HP gene expression level was noted to be significantly higher in patients than controls at all three time points: recruitment (P=0.049), 1-month follow up (P=0.002) and 3-month follow up (P=0.005). PANSS positive, depression, and excitement symptom factors showed significant associations with HP (P=0.002), A1T (P=0.016) and A2M (P=0.034), respectively. These findings remained significant after controlling for age, gender, smoking status and accumulated chlorpromazine dosage. CONCLUSION: The current study provides information on HP, A1T and A2M gene expression profiles in FEP patients and their associations with psychopathology. This provides support for the hypothesis that inflammation is related to schizophrenia and further encourages studies on immune-inflammatory markers to understand the relationship between inflammation and schizophrenia. PMID- 28627460 TI - Polysaccharides from Epimedium koreanum Nakai with immunomodulatory activity and inhibitory effect on tumor growth in LLC-bearing mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium koreanum Nakai is documented as tonic herbal in China for over a thousand years and has the potential to enhance the body's immunity according to the theory of traditional Chinese medicine. Polysaccharides are one of the most important effective compounds in Epimedium koreanum Nakai. Accumulating evidence indicated polysaccharides derived from traditional Chinese medicine have potent immune-enhancing properties and relatively nontoxic effects in cancer treatment. However, information about immunological regulation in tumor of Epimedium koreanum Nakai polysaccharides is limited and the reports of purification, characterization of polysaccharides have remained less. The purpose of our study was to further investigate the active polysaccharides from Epimedium koreanum Nakai by evaluating the immune-regulation activities in tumor-bearing mice and provide reasonable explanation for traditional application. MATERIALS AND METHODS: We firstly purified Epimedium koreanum polysaccharide (EPS) from crude extracts and evaluated EPS in vitro using immunological experiments including maturation and Ag presentation function of DCs, CD4 T-cell differentiation and secretion of anti-cancer cytokines. In LLC bearing mice model, we investigated its antitumor activities through evaluation of tumor cell proliferative activity, calculation of immune organ indexes and relative host immune system function tests. RESULTS: Results showed that EPS (180 * 104Da) was composed of mannose (Man), rhamnose (Rha), glucuronic acid (GlcUA), galactosamine (GalN), glucose (Glc), galactose (Gal), arabinose (Ara) and fructose (Fuc). Chemical composition assay indicated EPS was a fraction with 28.20% uronic acid content. FT-IR suggested the presence of pyraoid ring in EPS and SEM displayed smooth surface embedded by several pores. Moreover, Our study suggested EPS could remarkably stimulate macrophages to secrete substantial anti cancer cytokines and promote maturation as well as Ag presentation function of DCs. Strikingly, CD4 T-cell differentiation and increased INF-gamma production stimulated by EPS-activated macrophages were observed in the research. Furthermore, EPS exhibited prominent antitumor activities through regulating host immune system function in LLC-bearing mice. Taken together, experimental findings suggested EPS could be regarded as a potential immune-stimulating modifier for cancer therapy. CONCLUSION: Our studies demonstrated the polysaccharide (180 * 104Da) purified from Epimedium koreanum Nakai could promote maturation and Ag presentation function of DCs, increase the level of immunomodulatory cytokines and activate CD4 T-cell differentiation. Furthermore, it may inhibit the tumor growth in LLC-bearing mice through regulating host immune system function. PMID- 28627461 TI - 8-methoxypsoralen reduces AKT phosphorylation, induces intrinsic and extrinsic apoptotic pathways, and suppresses cell growth of SK-N-AS neuroblastoma and SW620 metastatic colon cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: 8-methoxypsoralen (8-MOP) is a furanocoumarin and an active compound of a traditional Egyptian medicinal plant Ammi majus L, whose juice/fruit has been used for many years in folk phototherapy for the treatment of vitiligo or a hyperproliferative skin disorder, psoriasis. 8-MOP together with UVA light is also used as an anticancer drug for the treatment of cutaneous T cell lymphoma. However, furanocoumarins exert anticancer activity even without UV irradiation. AIM OF THE STUDY: Evaluation UV-independent anticancer activity of 8 MOP in human cancer cell lines and identification of the mechanisms involved in this action. Results could provide new data about a potential role of 8-MOP in prevention and growth suppression in a broad spectrum of cancers. MATERIALS AND METHODS: 8-MOP (99%, HPLC/MS assay) was isolated from A. majus fruits by chromatographic methods. The effect of 8-MOP on cell viability was evaluated by the MTT test in several human cancer cell lines. Anti-proliferative activity of 8 MOP was evaluated by the BrdU assay in neuroblastoma (SK-N-AS) and metastatic colon cancer (SW620) cells. The Hoechst/PI staining was used for morphological analysis of cell death. An annexin V-FITC/PI double labelling and Cell Death Detection ELISA kit were used to detect apoptosis. The expression of apoptosis associated proteins and the AKT activation status were determined by Western blot analysis. RESULTS: 8-MOP inhibited cell growth in several cancer cell lines. The SK-N-AS and SW620 cells were the most sensitive to the compound. 8-MOP reduced the phosphorylation of AKT308, decreased the expression of Bcl-2, increased the Bax protein level, and activated caspases -8, -9, and -3 in both cell lines. CONCLUSIONS: 8-MOP impairs the PI3K/AKT signalling pathway and, independently of photoactivation, can inhibit the growth of neuroblastoma and colon cancer cells by induction of apoptosis via intrinsic and extrinsic pathways. PMID- 28627462 TI - Clinical and Pathological Staging Validation in the Eighth Edition of the TNM Classification for Lung Cancer: Correlation between Solid Size on Thin-Section Computed Tomography and Invasive Size in Pathological Findings in the New T Classification. AB - INTRODUCTION: The aim of this study was to validate the new eighth edition of the TNM classification and to elucidate whether radiological solid size corresponds to pathological invasive size incorporated in this T factor. METHODS: We analyzed the data on 1792 patients who underwent complete resection from 2003 to 2011 at the National Cancer Center Hospital East, Japan. We reevaluated preoperative thin section computed tomography (TSCT) to determine solid size and pathological invasive size using the fourth edition of the WHO classification and reclassified them according to the new TNM classification. The discriminative power of survival curves by the seventh edition was compared with that by the eighth edition by using concordance probability estimates and Akaike's information criteria calculated using a univariable Cox regression model. Pearson's correlation coefficient was calculated to elucidate the correlation between radiological solid size using TSCT and pathological invasive size. RESULTS: The overall survival curves in the eighth edition were well distinct at each clinical and pathological stage. The 5-year survival rates of patients with clinical and pathological stage 0 newly defined were both 100%. The concordance probability estimate and Akaike's information criterion values of the eighth edition were higher than those of the seventh edition in discriminatory power for overall survival. Solid size on TSCT scan and pathological invasive size showed a positive linear relationship, and Pearson's correlation coefficient was calculated as 0.83, which indicated strong correlation. CONCLUSIONS: This TNM classification will be feasible regarding patient survival, and radiological solid size correlates significantly with pathological invasive size as a new T factor. PMID- 28627463 TI - Pre-operative assessment of residual disease in locally advanced breast cancer patients: A sequential study by quantitative diffusion weighted MRI as a function of therapy. AB - PURPOSE: The potential of diffusion weighted imaging (DWI) in assessing pathologic response and surgical margins in locally advanced breast cancer patients (n=38) undergoing neoadjuvant chemotherapy was investigated. METHODS: DWI was performed at pre-therapy (Tp0), after I (Tp1) and III (Tp3) NACT at 1.5T. Apparent diffusion coefficient (ADC) of whole tumor (ADCWT), solid tumor (ADCST), intra-tumoral necrosis (ADCNec) was determined. Further, ADC of 6 consecutive shells (5mm thickness each) including tumor margin to outside tumor margins (OM1 to OM5) was calculated and the data analyzed to define surgical margins. RESULTS: Of 38 patients, 6 were pathological complete responders (pCR), 19 partial responders (pPR) and 13 were non-responders (pNR). Significant increase was observed in ADCST and ADCWT in pCR and pPR following therapy. Pre-therapy ADC was significantly lower in pCR compared to pPR and pNR indicating the heterogeneous nature of tumor which may affect drug perfusion and consequently the response. ADC of outside margins (OM1, OM2, and OM3) was significantly different among pCR, pPR and pNR at Tp3 which may serve as response predictive parameter. Further, at Tp3, ADC of outside margins (OM1, OM2, and OM3) was significantly lower compared to that seen at Tp0 in pCR, indicating the presence of residual disease in these shells. CONCLUSION: Pre-surgery information may serve as a guide to define cancer free margins and the extent of residual disease which may be useful in planning breast conservation surgery. PMID- 28627464 TI - Analysis of protein complexes in Arabidopsis leaves using size exclusion chromatography and label-free protein correlation profiling. AB - Protein complexes are fundamentally important for diverse cellular functions, and create functionalities that could never be achieved by a single polypeptide. Knowledge of the protein complex assemblies that exist in plant cells are limited. To close this gap, we applied an integrative proteomic approach that combines cell fractionation, protein chromatography and quantitative mass spectrometry (MS) to analyze the oligomerization state of thousands of proteins in a single experiment. Soluble extracts from intact Arabidopsis leaves were fractionated using size exclusion chromatography (SEC), and abundance profiles across the column fractions were quantified using label-free precursor ion (MS1) intensity. In duplicate experiments, we reproducibly detected 1693 proteins, of which 983 proteins were cytosolic. Based on the SEC profiles, approximately one third of all of the soluble proteins were predicted to be oligomeric. Our dataset includes both subunits of previously known complexes as well as hundreds of new protein complexes. The label-free MS1-based quantification method described here produced a highly useful dataset for the plant biology community, and provided a foundation to incorporate orthogonal protein complex separation methods so the composition and dynamics of protein complexes can be analyzed based on LC/MS profile data alone. PMID- 28627465 TI - Differential proteome analysis of hippocampus and temporal cortex using label free based 2D-LC-MS/MS. AB - : Hippocampus and temporal cortex are important brain regions, which play distinct, but complimentary roles in mediating learning and memory. Herein, we utilized label-free differential proteome strategy to explore function of normal human hippocampus and temporal cortex in learning and memory. As a result, a total of 5529 and 5702 proteins were identified in hippocampus and temporal cortex, respectively, 516 of which were significantly differential expressed, with abundance span 5 orders of magnitudes. Pathways analysis showed that temporal cortex was involved in growth of axons growth and synapse density regulation, through which could regulate long-term potentiation and long-term retention of trace memory. Hippocampus was involved in regulation of cell survival and cell viability, and regulates neurons proliferation by actin dynamics changes, through which involved in both short-term memory and long-term memory. Four selected differential proteins were further validated by Western blot and immunohistochemistry. For the first time, we identified proteins and associated pathways of hippocampus and temporal cortex in human cognition process using proteomic strategy, which would provide references for generating corresponding insights in hippocampus and temporal cortex-related cognitive function. The original data files can be downloaded at http://211.102.209.254/page/PSV023.html;?url=1489542083729AFHp (password: kYxh). SIGNIFICANCE: This study explored the potential molecular mechanism of hippocampus and temporal cortex in human cognition function using proteomics strategy, which will offer a baseline reference for further cognitive disorders study and reveal insights into physiology of temporal cortex and hippocampus. PMID- 28627467 TI - Time to review the gold standard for genotyping vancomycin-resistant enterococci in epidemiology: Comparing whole-genome sequencing with PFGE and MLST in three suspected outbreaks in Sweden during 2013-2015. AB - Vancomycin-resistant enterococci (VRE) are a challenge to the health-care system regarding transmission rate and treatment of infections. VRE outbreaks have to be controlled from the first cases which means that appropriate and sensitive genotyping methods are needed. The aim of this study was to investigate the applicability of whole genome sequencing based analysis compared to Pulsed-Field Gel Electrophoresis (PFGE) and Multi-Locus Sequence Typing (MLST) in epidemiological investigations as well as the development of a user friendly method for daily laboratory use. Out of 14,000 VRE - screening samples, a total of 60 isolates positive for either vanA or vanB gene were isolated of which 38 were from patients with epidemiological links from three suspected outbreaks at Uppsala University Hospital. The isolates were genotypically characterised with PFGE, MLST, and WGS based core genome Average Nucleotide Identity analysis (cgANI). PFGE was compared to WGS and MLST regarding reliability, resolution, and applicability capacity. The PFGE analysis of the 38 isolates confirmed the epidemiological investigation that three outbreaks had occurred but gave an unclear picture for the largest cluster. The WGS analysis could clearly distinguish six ANI clusters for those 38 isolates. As result of the comparison of the investigated methods, we recommend WGS-ANI analysis for epidemiological issues with VRE. The recommended threshold for Enterococcus faecium VRE outbreak strain delineation with core genome based ANI is 98.5%. All referred sequences of this study are available from the NCBI BioProject number PRJNA301929. PMID- 28627466 TI - Patterns of intra-articular injection use after initiation of treatment in patients with knee osteoarthritis: data from the osteoarthritis initiative. AB - OBJECTIVE: We sought to describe and evaluate longitudinal use of intra-articular injections after treatment initiation among adults with radiographically confirmed knee osteoarthritis (OA). METHOD: Using data from the Osteoarthritis Initiative (OAI), we included participants with radiographically confirmed OA (Kellgren-Lawrence grade (K-L) >= 2) in >=1 knee at baseline. With 9 years of data, 412 participants newly initiating hyaluronic acid or corticosteroid injections with their index visit were identified. For each type of injection initiated, socio-demographic and clinical characteristics were described by patterns of treatments (one-time use, switched, or continued injections). Multinomial logistic models estimated the extent to which patient-reported symptoms (post-initial injection and changes over time) were associated with patterns of injection use. RESULTS: Of those initiating injections, ~19% switched, ~21% continued injection type, and ~60% did not report any additional injections. For participants initiating corticosteroid injections, greater symptoms post-initial injection were associated with lower odds of continued use compared to one-time users (adjusted odds ratio (aOR) for Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain: 0.91; 95%, confidence interval (CI): 0.83 to 0.99; aORstiffness: 0.77; CI: 0.63 to 0.94; aORphysical function: 0.97; CI: 0.94 to 1.00). Symptom changes over time (e.g., worsened or improved) were not associated with patterns of injections use. CONCLUSION: After treatment initiation, the proportion of patients switching injection use and one time users was substantial. Symptoms post-initial injection appear to be associated with patterns of injection use. The extent to which these patterns are an indication of lack of impact on patient-reported symptoms should be explored. PMID- 28627468 TI - A novel chalcone derivative, LQFM064, induces breast cancer cells death via p53, p21, KIT and PDGFRA. AB - This study shows the design, synthesis and antitumoral potential evaluation of a novel chalcone-like compound, (E)-3- (3, 5-di-ter-butyl-4-hydroxyphenyl)-1- (4 hydroxy-3-methoxyphenyl) prop-2-en-1-one [LQFM064) (4)], against human breast adenocarcinoma MCF7 cells. Some toxicological parameters were also investigated. LQFM064) (4) exhibited cytotoxic activity against MCF7 cells (IC50=21MUM), in a concentration dependent-manner, and triggered significant changes in cell morphology and biochemical/molecular parameters, which are suggestive of an apoptosis inductor. LQFM064) (4) (21MUM) induced cell cycle arrest at G0/G1 phase with increased p53 and p21 expressions. It was also shown that the compound (4) did not interfere directly in p53/MDM2 complexation of MCF7 cells. In these cells, externalization of phosphatidylserine, cytochrome c release, increased expression of caspases-7, -8 and -9, reduced mitochondrial membrane potential and ROS overgeneration were also detected following LQFM064 (4) treatment. Further analysis revealed the activation of both apoptotic pathways via modulation of the proteins involved in the extrinsic and intrinsic pathways with an increase in TNF R1, Fas-L and Bax levels and a reduction in Bcl-2 expression. Furthermore, KIT proto-oncogene receptor tyrosine kinase, insulin-like growth factor (IGF1) and platelet-derived growth factor receptor A (PDGFRA) were downregulated, while glutathione S-transferase P1 (GSTP1) and interferon regulatory factor 5 (IRF5) expressions were increased by LQFM064 (4)-triggered cytotoxic effects in MCF7 cells. Moreover, it can be inferred that compound (4) has a moderate acute oral systemic toxicity hazard, since its estimated LD50 was 452.50mg/kg, which classifies it as UN GHS Category 4 (300mg/kg>LD50<2000mg/kg). Furthermore, LQFM064 (4) showed a reduced potential myelotoxicity (IC50=150MUM for mouse bone marrow hematopoietic progenitors). In conclusion, LQFM064 (4) was capable of inducing breast cancer cells death via different cytotoxic pathways. Thus, it is a promising alternative for the treatment of neoplasias, especially in terms of the drug resistance development. PMID- 28627469 TI - Modeling and comparison of release profiles: Effect of the dissolution method. AB - During the last decades, the study of the in vitro dissolution of pharmaceuticals has been strongly encouraged by the FDA in order to determine its relationship with the in vivo bioavailability of a drug. In this work immediate and extended release formulations containing diclofenac, a BCS class II drug, were studied using different dissolution methods. The release profiles obtained in USP Apparatus II and USP Apparatus IV were evaluated and compared to determine the effect of the fluid dynamic conditions on the release. The influence of the mixing conditions (i.e. the paddle rotation speed in USP Apparatus II or the inlet flow rate in USP Apparatus IV) on the drug release were evaluated, finding that, for the extended release formulations, they do not affect significantly the release profile. An in vitro device simulating the peristaltic contractions of the stomach during the digestion was used to simulate fluid dynamics closer to the real physiology. The tablets were found to behave in a completely different way if tested in the artificial stomach. Both model-independent and model dependent approaches were used to compare and fit the dissolution profiles, respectively. Fit factors were used as indicators of similarity of two dissolution profiles; model equations (such as zero-order, first-order, or Korsmeyer-Peppas equations) were used to fit the experimental data. With the identification of the best fitting model by the use of correlation factors and Akaike Information Criterion, the transport phenomena that determine the behavior of each formulation were identified. PMID- 28627470 TI - Investigation of itraconazole ternary amorphous solid dispersions based on povidone and Carbopol. AB - We investigate a ternary system that consists of itraconazole (ITZ) and two polymers: povidone K12 and Carbopol 907. The interactions between these two polymers and their effects on the properties of ternary ITZ amorphous solid dispersions (ASDs) are studied. These two polymers can form a water-insoluble complex in acidic aqueous media. The critical pH is determined to be 4.17. The weight percentage of Carbopol 907 in the interpolymer complex range from 59 to 70%, depending on the initial ratios between these two polymers in the starting solutions. This complexation is driven by a negative enthalpy change from the H bonding between the two polymers and a positive entropy change from the freed water molecules. Due to the slow precipitation of the interpolymer complex in aqueous media, the attempt to prepare ternary ASD using solvent-controlled coprecipitation is not successful. Melt extrusion is identified to be the only viable method to prepare this ternary ASD. We find that interpolymer complex based ASDs are physically less stable and demonstrate the poorest drug-release properties when compared to individual polymer-based binary ASDs. This study illustrates that the too strong interaction between polymers in ternary ASDs is detrimental to their performance. PMID- 28627471 TI - Phospholipid-drug conjugates as a novel oral drug targeting approach for the treatment of inflammatory bowel disease. AB - The enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA2 as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH2 units) were studied. The four PL-diclofenac conjugates were synthesized and characterized by LC/MS and NMR. PLA2-mediated activation of the prodrugs was analyzed in-vitro, and the remaining intact complex and free drug liberation were assessed after incubation with PLA2. The rate and degree of PLA2-mediated activation were highly dependent on the linker length; 2- and 4-carbon linker conjugates were activated to lower extent than the 6-carbon conjugate, and longer linker again decreased the affinity towards PLA2. The 6-carbon linker conjugate was found to be the optimal and released ~95% of the free drug after incubation with PLA2, whereas only ~20% were delivered by the 2-carbon linker prodrug. The 6-carbon linker conjugate was shown to be stable in intestinal perfusate, fresh plasma, and pH4.0 and 6.8 buffers, but not at pH1.0. In conclusion, the results of this work confirm the feasibility of our general aim to exploit PLA2 as a prodrug activating enzyme of PL-drug conjugates. This may provide a novel oral drug targeting approach in IBD therapy. PMID- 28627472 TI - Molecular Dynamics as a tool for in silico screening of skin permeability. AB - Prediction of skin permeability can have manifold applications ranging from drug delivery to toxicity prediction. Along with the semi-empirical or mechanistic models proposed in the last decades, Molecular Dynamics simulations have recently become a fruitful tool for investigating membrane permeability, in particular as they allow the involved mechanisms to be modelled at a molecular level. Despite their significant structural complexity, Molecular Dynamics simulations can also be utilized to study permeation through the lipid matrix that characterizes the stratum corneum. In this work, Steered Molecular Dynamics simulations are performed on a suitably developed stratum corneum lipid matrix model. Regardless of their actual tortuous path within the stratum corneum, the permeants, taken from a Fully Validated dataset of 80 compounds of known permeability coefficient, are moved through the bilayer along its normal. This allows the exploration of all the possible conformational and physicochemical constraints the molecule experiences when moving through the bilayer. The so performed Steered Molecular Dynamics simulations are then utilized to extract the corresponding lipophilicity and diffusion parameters as computed by subdividing the entire path in 18 regions of different polarity and composition. Correlative analyses showed that the water lipids interface is the best performing region and that significant enhancements can be gained by including parameters accounting for the temperature effect. Taken together, the developed models possess an enhanced predictive power compared to the existing equations and statistics are approaching the best possible results, given the uncertainty in the utilized permeability data. PMID- 28627473 TI - Glycyrrhetic acid, but not glycyrrhizic acid, strengthened entecavir activity by promoting its subcellular distribution in the liver via efflux inhibition. AB - Entecavir (ETV) is a superior nucleoside analogue used to treat hepatitis B virus (HBV) infection. Although its advantages over other agents include low viral resistance and the elicitation of a sharp decrease in HBV DNA, adverse effects such as hepatic steatosis, hepatic damage and lactic acidosis have also been reported. Glycyrrhizin has long been used as hepato-protective medicine. The clinical combination of ETV plus glycyrrhizin in China displays better therapeutic effects and lower rates of liver damage. However, there is little evidence explaining the probable synergistic mechanism that exists between these two drugs from a pharmacokinetics view. Here, alterations in the plasma pharmacokinetics, tissue distribution, subcellular distribution, and in vitro and in vivo antiviral activity of ETV after combination with glycyrrhizic acid (GL) were analysed to determine the synergistic mechanisms of these two drugs. Specific efflux transporter membrane vesicles were also used to elucidate their interactions. The primary active GL metabolite, glycyrrhetic acid (GA), did not affect the plasma pharmacokinetics of ETV but promoted its accumulation in hepatocytes, increasing its distribution in the cytoplasm and nucleus and augmenting the antiviral efficiency of ETV. These synergistic actions were primarily due to the inhibitory effect of GA on MRP4 and BCRP, which transport ETV out of hepatocytes. In conclusion, GA interacted with ETV at cellular and subcellular levels in the liver through MRP4 and BCRP inhibition, which enhanced the antiviral activity of ETV. Our results partially explain the synergistic mechanism of ETV and GL from a pharmacokinetics view, providing more data to support the use of these compounds together in clinical HBV treatment. PMID- 28627474 TI - Sox9 positive periosteal cells in fracture repair of the adult mammalian long bone. AB - INTRODUCTION: The phases of fracture healing have been well characterized. However, the exact source and genetic profile of the skeletal progenitors that participate in bone repair is somewhat unclear. Sox9 expression in skeletal elements precedes bone and cartilage formation and a Sox9+ cell type is retained in the adult periosteum. We hypothesized that Sox9+ periosteal cells are multipotent skeletal progenitors normally participating in fracture repair. METHODS: To test this hypothesis we used tamoxifen (TM)-mediated lineage tracing of Sox9+ cells in Sox9CreErt2:Td-Tomato mice. Intact femora were analyzed with immunostaining and RNA sequencing to evaluate the skeletal distribution and gene expression profile of Td-Tomato positive, Sox9-descendent cells in the adult femur. To assess the role of Td-tomato+cells in the fracture healing process, mice underwent a closed mid-diaphyseal femoral fracture. Fractured hind limbs were analyzed by X-ray, histology and immuno-staining at 3, 9 or 56days post fracture. RESULTS: In the intact adult mouse femur, Td-Tomato-labeled cells were observed in the primary spongiosa, periosteum and endosteum. RNA sequencing showed that Td-Tomato positive periosteal cells were co-enriched for Sox9 transcripts, and mRNAs for osteoblast and chondrocyte specific genes. In a femoral fracture model, we showed that pre-labeled Td-Tomato positive descendent cells were mobilized during the early stages of bone repair (day 3 post-op) contributing to the fracture repair process by differentiating into chondrocytes, osteoblasts and osteocytes. CONCLUSION: A Sox9+ skeletal progenitor population resides in the adult periosteum. Fate tracing studies show that descendants of the Sox9+ periosteal progenitors give rise to chondrocytes, osteoblasts and mature cortical osteocytes in repair of the fractured femur. To our knowledge this is the first report of a reparative Sox9+ progenitor population in the periosteum of the adult long bone. Taken together with developmental studies, our data suggest a broad role for Sox9+ osteochondroprogenitors in development and repair of the mammalian skeleton. PMID- 28627475 TI - Joint-specific risk of impaired function in fibrodysplasia ossificans progressiva (FOP). AB - BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) causes progressive disability due to heterotopic ossification from episodic flare-ups. Using data from 500 FOP patients (representing 63% of all known patients world-wide), age- and joint-specific risks of new joint involvement were estimated using parametric and nonparametric statistical methods. RESULTS: Compared to data from a 1994 survey of 44 individuals with FOP, our current estimates of age- and joint specific risks of new joint involvement are more accurate (narrower confidence limits), based on a wider range of ages, and have less bias due to its greater comprehensiveness (captures over three-fifths of the known FOP patients worldwide). For the neck, chest, abdomen, and upper back, the estimated hazard decreases over time. For the jaw, lower back, shoulder, elbow, wrist, fingers, hip, knee, ankle, and foot, the estimated hazard increases initially then either plateaus or decreases. At any given time and for any anatomic site, the data indicate which joints are at risk. CONCLUSIONS: This study of approximately 63% of the world's known population of FOP patients provides a refined estimate of risk for new involvement at any joint at any age, as well as the proportion of patients with uninvolved joints at any age. Importantly, these joint-specific survival curves can be used to facilitate clinical trial design and to determine if potential treatments can modify the predicted trajectory of progressive joint dysfunction. PMID- 28627477 TI - Corrigendum to "The interdigitating loop of the enolase superfamily as a specificity binding determinant or 'flying buttress'" [Biochim. Biophys. Acta] 1865 (2017) 619-630. PMID- 28627476 TI - Deciphering the protein-protein interaction network regulating hepatocellular carcinoma metastasis. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of mortality related to cancer all over the world. To better understand the molecular mechanisms of HCC metastasis, we analyzed the proteome of three HCC cell lines with different metastasis potentials by quantitative proteomics and bioinformatics analysis. As a result, we identified 378 cellular proteins potentially associated to HCC metastasis, and constructed a highly connected protein-protein interaction (PPI) network. Functional annotation of the network uncovered prominent pathways and key roles of these proteins, suggesting that the metabolism and cytoskeleton biological processes are greatly involved with HCC metastasis. Furthermore, the integrative network analysis revealed a rich-club organization within the PPI network, indicating a hub center of connections. The rich-club nodes include several well-known cancer-related proteins, such as proto-oncogene non-receptor tyrosine kinase (SRC) and pyruvate kinase M2 (PKM2). Moreover, the differential expressions of two identified proteins, including PKM2 and actin-related protein 2/3 complex subunit 4 (ARPC4), were validated using Western blotting. These two proteins were revealed as potential prognostic markers for HCC as shown by survival rate analysis. PMID- 28627480 TI - Editorial Comment. PMID- 28627478 TI - A glimpse into the specialization history of the lipases/acyltransferases family of CpLIP2. AB - Lipases/acyltransferases homologous to CpLIP2 from Candida parapsilosis belong to the alpha/beta hydrolase superfamily as lipase A from Moesziomyces antarcticus (Candida antarctica), and constitute a consistent phylogenetic subgroup with at least 56% identity. Lipases/acyltransferases share the phenotypic characteristic of a high acyltransfer activity even in aqueous media with very high water thermodynamic activity. Previous mutagenesis and evolution strategies have given insights into the role of key residues and protein subdomains in the reaction and substrate specificities of these enzymes. However, multiple mutations are often deleterious for the activity and the identification of all the residues that historically led to the function is complicated. A new complementary approach to elucidate structural determinant was conducted in this study, based on the resurrection of ancestral proteins to understand how the evolution led to the present properties of the biocatalysts. By doing so, the comparison with the extant proteins can lead to the identification of key residues involved in the enzymes' specialization. Using Ancestral Sequence Reconstruction, we have generated a putative ancestral lipases/acyltransferases, PaleoLAc. This enzyme shares a high level of identity with CpLIP2 but has a different catalytic behavior. PaleoLAc allowed the identification of putative key residues involved in acyltransfer ability and supports the hypothesis that this exceptional property within the lipases/acyltransferases family is linked to a cluster of residues in the vicinity of the active site. As a representative of the ancestral origin of the diversity of the catalytic behaviors observed in modern lipases/acyltransferases, PaleoLAc constitutes a powerful tool for further engineering toward targeted specialization. PMID- 28627481 TI - Editorial Comment. PMID- 28627483 TI - Editorial Comment. PMID- 28627484 TI - Editorial Comment. PMID- 28627485 TI - Limitations of vitamin D supplementation trials: Why observational studies will continue to help determine the role of vitamin D in health. AB - Observational studies have shown that low vitamin D status is associated with an increased risk of a wide range of diseases. The body of observational evidence now is so large, that there have been many calls for randomized controlled trials (RCT) of vitamin D supplementation to confirm once and for all whether increasing body vitamin D levels prevents these diseases. These calls have arisen because of concern that confounding and reverse causation may explain many of the results from observational studies. However, RCTs also are prone to limitations that compromise their validity. These include low response rates that affect their external validity; and biases that affect their internal validity, such as recruitment of vitamin D sufficient people which decreases the power to detect beneficial effects, studies of long-term outcomes requiring participation for many years which decreases compliance and retention, and easy access for participants to vitamin D supplements and blood testing which increase contamination and unblinding. Because of these potential limitations, it is possible that RCTs of vitamin D supplementation may not to give a clear answer by themselves. Future decisions about the role of vitamin D in health are likely to be based on the evidence from a range of study designs including RCTs, mendelian randomization studies and other observational designs. PMID- 28627487 TI - Epicellular coccidiosis in goldfish. AB - In a goldfish stock held in a pet fish pond, heavy coccidian infection, caused by an epicellularly developing Goussia species, appeared in April of 3 consecutive years (2014 to 2016). The shape and size of the oocysts resembled those of an inadequately described species, Goussia carassiusaurati (Romero-Rodriguez, 1978). In histological sections, gamogonic and sporogonic stages infested mostly the second fifth of the intestine, where almost all epithelial cells were infected. Both gamonts and young oocysts occurred intracellularly but in an extracytoplasmal position, seemingly outside the cells. Oocysts were shed non sporulated. Spheroid to ellipsoidal non-sporulated oocysts measured 12.4 * 13.5 um on average, but after 48 h sporulation in tap water they reached a size of 16 * 13 um. The 4 elliptical sporocysts located loosely within the sporulated oocysts measured 13 * 5.4 um. The oocysts and sporocysts were smaller than those of the better-known Goussia species G. aurati (Hoffman, 1965). PMID- 28627486 TI - The association between detected drug resistance mutations and CD4+ T-cell decline in HIV-positive individuals maintained on a failing treatment regimen. AB - BACKGROUND: To analyse the effect of drug resistance mutations (DRM) on CD4+ T cell (CD4) trends in HIV-positive people maintained on virologically failing antiretroviral therapy (ART). METHODS: Individuals from two large cohorts experiencing virological failure (VF) while maintained on ART with >=1 CD4 count and >=1 resistance test were included. CD4 slopes were estimated using linear mixed models. Principal component analysis (PCA) was used to assess the effect of clusters of mutations, defined using extracted component based scores from the PCA, on CD4 decline. RESULTS: 5,357 individuals contributing 7,661 VF episodes were included: any DRM were detected in 88.8% of episodes. After adjustment, CD4 counts declined less steeply during episodes where DRM were detected compared to episodes with no DRM (difference =28 cells/mm3/year, 95% CI =18, 39; P<0.001). Among individuals with at least one DRM, we found evidence that any nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance, the reverse transcriptase (RT) mutations M184V, D67N and T215Y as well as the protease mutations V82A and I54V were associated with reduced CD4 declines. The detection of any non-nucleoside reverse transcriptase inhibitor resistance, the RT mutations V179D and L74V were associated with steeper CD4 declines. The presence of some mutation patterns similar to the clusters identified by the PCA also affected the CD4 decline. CONCLUSIONS: Detection of resistance and of certain DRM during VF of ART has a small but significant favourable effect on CD4 decline. PMID- 28627488 TI - Diversity of Veronaea botryosa from different hosts and evaluation of laboratory challenge models for phaeohyphomycosis in Acipenser transmontanus. AB - Veronaea botryosa has been identified as a pathogen of cultured white sturgeon Acipenser transmontanus. In 2015, samples from 19 white sturgeon were received for diagnosis, of which 14 cultured positive for V. botryosa. Intraspecific variability among V. botryosa isolates from different clinically affected hosts and geographic regions was investigated using repetitive extragenic palindromic PCR fingerprinting (rep-PCR). The rep-PCR profiles of 16 V. botryosa isolates from a human, sea turtles, and cultured fish were distinct from those of other phaeoid fungi belonging to the genera Cladophialophora and Exophiala. To gain a better understanding of the pathogenesis of V. botryosa mycosis, 5 laboratory challenge methods were evaluated in white sturgeon fingerlings. Intramuscular (IM) and intracoelomic (IC) injection challenges produced cumulative mortalities of 13.3% (8/60) and 3.3% (2/60), respectively, and V. botryosa was recovered from 100% (10/10) of dead fingerlings. Affected fish exhibited abnormal orientation and/or failure to maintain neutral buoyancy, emaciation, coelomic distension, exophthalmos, cutaneous erythema, and ulcerated skin. After 6 wk, surviving fish were euthanized, and samples of liver were taken for mycological evaluation. Viable fungus was detected in 90% and 100% of fish surviving IM and IC challenge, respectively. No V. botryosa-associated mortality was detected in other groups challenged by immersion, immersion with abrasion, or orally. Both IM and IC challenge routes appear suitable for the induction of V. botryosa infection in white sturgeon and can serve as models for the study of disease pathogenesis associated with this emergent pathogen. PMID- 28627489 TI - Treatment of Francisella infections via PLGA- and lipid-based nanoparticle delivery of antibiotics in a zebrafish model. AB - We tested the efficiency of 2 different antibiotics, rifampicin and oxolinic acid, against an established infection caused by fish pathogen Francisella noatunensis ssp. orientalis (F.n.o.) in zebrafish. The drugs were tested in the free form as well as encapsulated into biodegradable nanoparticles, either polylactic-co-glycolic acid (PLGA) nanoparticles or nanostructured lipid carriers. The most promising therapies were PLGA-rifampicin nanoparticles and free oxolinic acid; the PLGA nanoparticles significantly delayed embryo mortality while free oxolinic acid prevented it. Encapsulation of rifampicin in both PLGA and nanostructured lipid carriers enhanced its efficiency against F.n.o. infection relative to the free drug. We propose that the zebrafish model is a robust, rapid system for initial testing of different treatments of bacterial diseases important for aquaculture. PMID- 28627490 TI - Genotyping and antimicrobial resistance genes of Yersinia ruckeri isolates from rainbow trout farms. AB - In this study, we compared 142 Yersinia ruckeri isolates collected between 2013 and 2016 from 6 different regions in Turkey. A total of 18 different genogroups were found, though most of the isolates clustered into the same genogroup as serotype O1. As immunization of fish with inactivated Y. ruckeri by injection, immersion, or feeding provide minimal protection against Y. ruckeri infection in Turkey, many fish producers use antimicrobials unrestrictedly, resulting in antimicrobial resistance in aquatic pathogens. Accordingly, we investigated resistance to the antimicrobials most commonly used to treat yersiniosis. More than 80% of the Y. ruckeri isolates were susceptible to sulfamethoxazole trimethoprim (SXT), florfenicol (FFC), and tetracycline, whereas none were susceptible to sulfamethoxazole. The most commonly used antimicrobials (SXT and FFC) can be effectively administered because the resistance levels to these drugs are the lowest among those reported for agents used to control enteric red mouth disease (12.6 and 14.7%, respectively). In conclusion, to the best of our knowledge, this study is the first characterization of the antimicrobial resistance genes floR, sulI, tetC, tetD, and tetE in Y. ruckeri isolates from aquaculture. Additionally, we detected the sulII gene but not the tetA, tetB, tetM, tetS, or sulIII genes. PMID- 28627491 TI - Survival, growth performance and immune capacity of the juvenile lined seahorse Hippocampus erectus fed with rifampicin-treated copepods. AB - Gastrointestinal disease is one of the most serious diseases in cultured seahorse juveniles. Treatment with antimicrobials of live food (i.e. copepods and Artemia) that is used to feed the juveniles may be a promising measure to alleviate the occurrence of gastrointestinal disease. However, relevant investigations are rare. In the present study, we first investigated the antimicrobial efficacies on bacteria within copepods that were treated with 4 antimicrobials, including 3 antibiotics (i.e. enrofloxacin hydrochloride, oxytetracycline and rifampicin [RFP]) that are approved for use in aquaculture and 1 disinfectant (i.e. povidone iodine). We then assessed the effects of copepods treated with the antimicrobial that had the best antimicrobial efficacy on survival, growth performance and immune capacity of juvenile lined seahorses Hippocampus erectus. The results showed that RFP had the best antimicrobial efficacy on both Pseudoalteromonas spp. and Vibrio spp., 2 dominant bacteria with potential pathogenicity within the copepods; the proper concentration of RFP was 6 mg l-1. Moreover, H. erectus juveniles fed with RFP-treated copepods demonstrated an improved survivorship and immune capacity and had a lower abundance of pathogenic bacteria within their gastrointestinal tracts compared to juveniles fed with untreated copepods. These results suggest that treating live food with RFP is a potential measure for reducing the incidence of gastrointestinal disease in seahorse juveniles. PMID- 28627492 TI - Fate of redspotted grouper nervous necrosis virus (RGNNV) in experimentally challenged Manila clam Ruditapes philippinarum. AB - Redspotted grouper nervous necrosis virus (RGNNV), genus Betanodavirus, family Nodaviridae, is the causative agent of viral encephalopathy and retinopathy (otherwise known as viral nervous necrosis) and can infect several fish species worldwide. Betanodaviruses, including RGNNV, are very resilient in the aquatic environment, and their presence has already been reported in several wild marine species including invertebrates. In order to investigate the interaction between a bivalve mollusc (Manila clam Ruditapes philippinarum) and RGNNV, we optimised a culture-based method. The bioaccumulation of the pathogenic RGNNV by R. philippinarum and the potential shedding of viable RGNNV from RGNNV-exposed clams were evaluated through a culture-based method. R. philippinarum clearly accumulated viable RGNNV in their hepatopancreatic tissue and were able to release viable RGNNV via faecal matter and filtered water into the surrounding environment. The role of clams as bioaccumulators and shedders of viable RGGNV could put susceptible cohabiting cultured fish at risk. RGNNV-contaminated molluscs could behave as reservoirs for this virus and may modify the virus epidemiology. PMID- 28627493 TI - Parasitic infections in the East Asian finless porpoise Neophocaena asiaeorientalis sunameri living off the Chinese Yellow/Bohai Sea coast. AB - Parasitic disease is among the major causes of health problems in marine mammals. However, little information on parasitic species composition and infection levels in finless porpoises (Neophocaena spp.) is available. In this study, we report the first systematic survey on parasitic infections in the East Asian finless porpoise N. asiaeorientalis sunameri (EAFP) living off the Chinese Yellow/Bohai Sea coast. Using both morphological and molecular methods, 5 parasitic helminths were identified: Campula oblonga in the liver and pancreas; Synthesium seymouri in the pyloric stomach and duodenum ampulla; Anisakis pegreffii in the forestomach, main stomach, and esophagus; Halocercus sp. in the lungs; and Crassicauda magna in the mammary glands and muscle. Among these helminths, C. oblonga (80.7%), S. seymouri (80.7%), A. pegreffii (80.7%), and Halocercus sp. (77.4%) were the most prevalent, whereas C. magna (6.5%) were only observed in 2 EAFP individuals. All juvenile and adult EAFPs were parasitized by at least 3 parasites species (C. oblonga, S. seymouri, and A. pegreffii), whereas in neonates, only Halocercus sp. were detected. We observed no significant difference in parasite prevalence between males and females. In addition, A. pegreffii and C. magna represented new infection records in Neophocaena. A pathological examination associated with parasitic lesions in EAFPs showed damage or destruction of cells or tissues to some extent. This study represents the first systematic survey on parasitic infections in EAFPs, providing important and valuable parasitological information for the research and conservation of this coastal marine mammal. PMID- 28627494 TI - First record of proliferative kidney disease agent Tetracapsuloides bryosalmonae in wild brown trout and European grayling in Finland. AB - The myxozoan endoparasite Tetracapsuloides bryosalmonae causes temperature-driven proliferative kidney disease (PKD) in salmonid fishes. Despite the economic and ecological importance of PKD, information about the distribution of the parasite is still scarce. Here, we report for the first time the occurrence of T. bryosalmonae in wild brown trout Salmo trutta and European grayling Thymallus thymallus populations in Finland. We detected T. bryosalmonae at high prevalence in both brown trout and European grayling from the transboundary Finnish-Russian River Koutajoki system (Rivers Oulankajoki, Kuusinkijoki, Kitkajoki, Maaninkajoki, and Juumajoki) in north-eastern Finland. In southern Finland, T. bryosalmonae was detected in River Siuntionjoki young-of-the-year brown trout collected both in 2015 and 2016 (100% prevalence), while the parasite was not observed in fish from 3 other rivers (Ingarskila, Mustajoki, and Vantaanjoki) flowing to the Gulf of Finland. Our results, together with those from recent studies of Atlantic salmon, indicate that T. bryosalmonae is distributed over much higher latitudes in northern Europe than previously appreciated. We expect that increasing water temperatures will likely cause new PKD outbreaks in these more northerly regions in the future. PMID- 28627495 TI - Disease and mortality among Yesso scallops Patinopecten yessoensis putatively caused by infection with Francisella halioticida. AB - During the fall of 2015, up to 40% mortality occurred in juvenile Yesso scallops Patinopecten yessoensis at an aquaculture site in Baynes Sound, British Columbia, Canada. Macroscopic lesions were present in 11% of the scallops, and histopathology consisting of multifocal and diffuse haemocyte infiltration was observed in 44% of the specimens examined. Histologically, small Gram-negative intracellular bacteria-like particles were observed within necrotic haemocytes of the lesions, suggesting a bacterial aetiology. DNA was extracted from adductor muscle lesions of diseased scallops, and the 16s rDNA gene as well as the DNA directed RNA polymerase beta subunit (rpoB) were amplified by PCR. Sequence analyses of the resulting 413 and 925 bp fragments were a 100% match to the reference sequence for Francisella halioticida, originally described as the cause of mortality in abalone from Japan. Isolation and culture of the bacteria was not possible at the time, as no further diseased specimens were available. Results from in situ hybridization assays as well as examination by transmission electron microscopy provide further evidence supporting the hypothesis that F. halioticida was the most probable causative agent of the lesions and mortality. PMID- 28627496 TI - Controllable synthesis of nickel bicarbonate nanocrystals with high homogeneity for a high-performance supercapacitor. AB - The electrochemical performance of supercapacitors might be associated with the homogeneous structure of the electrode materials. However, the relationship between the degree of uniformity for the electrode materials and the electrochemical performance of the supercapacitor is not clear. Herein, we synthesize two types of nickel bicarbonate nanocrystals with different degrees of uniformity to investigate this relationship. As the electroactive material, the nickel bicarbonate nanocrystals with a homogeneous structure could provide a larger space and offer more exposed atoms for the electrochemical reaction than the nanocrystals with a heterogeneous structure. The homogeneous nickel bicarbonate nanocrystals exhibit better electrochemical performance and show excellent specific capacitance (1596 F g-1 at 2 A g-1 and 1260 F g-1 at 30 A g 1), which is approximately twice that of the heterogeneous nickel bicarbonate nanocrystals. The cycling stability for the homogeneity (~80%) is higher than the inhomogeneity (~61%) at a high current density of 5 A g-1. PMID- 28627497 TI - Fluorescent carbon nanodots facilely extracted from Coca Cola for temperature sensing. AB - A novel method for the fabrication of carbon nanodots (CDs) is introduced: extracting CDs from the well-known soft drink Coca Cola via dialysis. The obtained CDs are of good monodispersity with a narrow size distribution (average diameter of 3.0 nm), good biocompatibility, high solubility (about 180 mg ml-1) and stable fluorescence even at a high salt concentration. Furthermore, they are sensitive to the temperature change with a linear relationship between the fluorescence intensity and temperature from 5 degrees C-95 degrees C. The CDs have been applied in high stable temperature sensing. This protocol is quite simple, green, cost-effective and technologically simple, which might be used for a range of applications including sensing, catalysts, drug and gene delivery, and so on. PMID- 28627498 TI - Highly stable red-emitting polymer dots for cellular imaging. AB - Polymer dots (Pdots) have emerged as a new type of fluorescent probe material for biomedical applications and have attracted great interest due to their excellent optical properties and biocompatability. In this work, we report on a red emitting P3HT Pdot fluorescent probe for intracellular bioimaging. The as prepared Pdot fluorescent probe exhibits good stability and has a large Stokes shift (121 nm) compared to molecules in tetrahydrofuran (THF). Furthermore, the probe shows low cytotoxicity, broad absorption spectrum, resistance against photodegradation, and good water dispersibility. These advantageous characteristics make P3HT Pdots a promising fluorescent probe material for bioimaging. PMID- 28627499 TI - First-principles studies of chromium line-ordered alloys in a molybdenum disulfide monolayer. AB - Density functional theory calculations have been performed to study the thermodynamic stability, structural and electronic properties of various chromium (Cr) line-ordered alloy configurations in a molybdenum disulfide (MoS2) hexagonal monolayer for band gap engineering. Only the molybdenum (Mo) sites were substituted at each concentration in this study. For comparison purposes, different Cr line-ordered alloy and random alloy configurations were studied and the most thermodynamically stable ones at each concentration were identified. The configurations formed by the nearest neighbor pair of Cr atoms are energetically most favorable. The line-ordered alloys are constantly lower in formation energy than the random alloys at each concentration. An increase in Cr concentration reduces the lattice constant of the MoS2 system following the Vegard's law. From density of states analysis, we found that the MoS2 band gap is tunable by both the Cr line-ordered alloys and random alloys with the same magnitudes. The reduction of the band gap is mainly due to the hybridization of the Cr 3d and Mo 4d orbitals at the vicinity of the band edges. The band gap engineering and magnitudes (1.65 eV to 0.86 eV) suggest that the Cr alloys in a MoS2 monolayer are good candidates for nanotechnology devices. PMID- 28627500 TI - Nanowire-based thermoelectrics. AB - Research on thermoelectrics has seen a huge resurgence since the early 1990s. The ability of tuning a material's electrical and thermal transport behavior upon nanostructuring has led to this revival. Nevertheless, thermoelectric performances of nanowires and related materials lag far behind those achieved with thin-film superlattices and quantum dot-based materials. This is despite the fact that nanowires offer many distinct advantages in enhancing the thermoelectric performances of materials. The simplicity of the strategy is the first and foremost advantage. For example, control of the nanowire diameters and their surface roughnesses will aid in enhancing their thermoelectric performances. Another major advantage is the possibility of obtaining high thermoelectric performances using simpler nanowire chemistries (e.g., elemental and binary compound semiconductors), paving the way for the fabrication of thermoelectric modules inexpensively from non-toxic elements. In this context, the topical review provides an overview of the current state of nanowire-based thermoelectrics. It concludes with a discussion of the future vision of nanowire based thermoelectrics, including the need for developing strategies aimed at the mass production of nanowires and their interface-engineered assembly into devices. This eliminates the need for trial-and-error strategies and complex chemistries for enhancing the thermoelectric performances of materials. PMID- 28627501 TI - Two-dimensional hybrid layered materials: strain engineering on the band structure of MoS2/WSe2 hetero-multilayers. AB - In this paper, we report a comprehensive modeling and simulation study of constructing hybrid layered materials by alternately stacking MoS2 and WSe2 monolayers. Such hybrid MoS2/WSe2 hetero-multilayers exhibited direct bandgap semiconductor characteristics with bandgap energy (E g) in a range of 0.45-0.55 eV at room temperature, very attractive for optoelectronics (wavelength range 2.5 2.75 MUm) based on thicker two-dimensional (2D) materials. It was also found that the interlayer distance has a significant impact on the electronic properties of the hetero-multilayers, for example a five orders of magnitude change in the conductance was observed. Three material phases, direct bandgap semiconductor, indirect bandgap semiconductor, and metal were observed in MoS2/WSe2 hetero multilayers, as the interlayer distance decreased from its relaxed (i.e., equilibrium) value of about 6.73 A down to 5.50 A, representing a vertical pressure of about 0.8 GPa for the bilayer and 1.5 GPa for the trilayer. Such new hybrid layered materials are very interesting for future nanoelectronic pressure sensor and nanophotonic applications. This study describes a new approach to explore and engineer the construction and application of tunable 2D semiconductors. PMID- 28627502 TI - Domain wall magnetoresistance in BiFeO3 thin films measured by scanning probe microscopy. AB - We measure the magnetotransport properties of individual 71 degrees domain walls in multiferroic BiFeO3 by means of conductive-atomic force microscopy (C-AFM) in the presence of magnetic fields up to one Tesla. The results suggest anisotropic magnetoresistance at room temperature, with the sign of the magnetoresistance depending on the relative orientation between the magnetic field and the domain wall plane. A consequence of this finding is that macroscopically averaged magnetoresistance measurements for domain wall bunches are likely to underestimate the magnetoresistance of each individual domain wall. PMID- 28627503 TI - Three-layered polyplex as a microRNA targeted delivery system for breast cancer gene therapy. AB - MicroRNAs (miRNAs), small non-coding RNAs, play an important role in modulating cell proliferation, migration, and differentiation. Since miRNAs can regulate multiple cancer-related genes simultaneously, regulating miRNAs could target a set of related oncogenic genes or pathways. Owing to their reduced immune response and low toxicity, miRNAs with small size and low molecular weight have become increasingly promising therapeutic drugs in cancer therapy. However, one of the major challenges of miRNAs-based cancer therapy is to achieve specific, effective, and safe delivery of therapeutic miRNAs into cancer cells. Here we provide a strategy using three-layered polyplex with folic acid as a targeting group to systemically deliver miR-210 into breast cancer cells, which results in breast cancer growth being inhibited. PMID- 28627504 TI - Nature of the spin-glass phase in dense packings of Ising dipoles with random anisotropy axes. AB - Using tempered Monte Carlo simulations, we study the the spin-glass phase of dense packings of Ising dipoles pointing along random axes. We consider systems of dipoles (i) placed on the sites of a simple cubic lattice with lattice constant d, and (ii) placed at the center of random close packed spheres of diameter d that occupy 64% of the volume. For both cases, we find a spin-glass phase below a certain temperature T sg. By analysing the data obtained for the overlap parameter, the associated correlation length, as well as the statistics of the overlap distributions of individual samples, we find a behavior consistent with quasi-long-range order in the spin-glass phase, similar to the one previously found in strongly diluted dipolar systems. PMID- 28627505 TI - Monitoring alert and drowsy states by modeling EEG source nonstationarity. AB - OBJECTIVE: As a human brain performs various cognitive functions within ever changing environments, states of the brain characterized by recorded brain activities such as electroencephalogram (EEG) are inevitably nonstationary. The challenges of analyzing the nonstationary EEG signals include finding neurocognitive sources that underlie different brain states and using EEG data to quantitatively assess the state changes. APPROACH: This study hypothesizes that brain activities under different states, e.g. levels of alertness, can be modeled as distinct compositions of statistically independent sources using independent component analysis (ICA). This study presents a framework to quantitatively assess the EEG source nonstationarity and estimate levels of alertness. The framework was tested against EEG data collected from 10 subjects performing a sustained-attention task in a driving simulator. MAIN RESULTS: Empirical results illustrate that EEG signals under alert versus drowsy states, indexed by reaction speeds to driving challenges, can be characterized by distinct ICA models. By quantifying the goodness-of-fit of each ICA model to the EEG data using the model deviation index (MDI), we found that MDIs were significantly correlated with the reaction speeds (r = -0.390 with alertness models and r = 0.449 with drowsiness models) and the opposite correlations indicated that the two models accounted for sources in the alert and drowsy states, respectively. Based on the observed source nonstationarity, this study also proposes an online framework using a subject-specific ICA model trained with an initial (alert) state to track the level of alertness. For classification of alert against drowsy states, the proposed online framework achieved an averaged area-under-curve of 0.745 and compared favorably with a classic power-based approach. SIGNIFICANCE: This ICA based framework provides a new way to study changes of brain states and can be applied to monitoring cognitive or mental states of human operators in attention critical settings or in passive brain-computer interfaces. PMID- 28627506 TI - Antiferromagnetism, charge density wave, and d-wave superconductivity in the extended t-J-U model: role of intersite Coulomb interaction and a critical overview of renormalized mean field theory. AB - In the first part of the paper, we study the stability of antiferromagnetic (AF), charge density wave (CDW), and superconducting (SC) states within the t-J-U-V model of strongly correlated electrons by using the statistically consistent Gutzwiller approximation (SGA). We concentrate on the role of the intersite Coulomb interaction term V in stabilizing the CDW phase. In particular, we show that the charge ordering appears only above a critical value of V in a limited hole-doping range delta. The effect of the V term on SC and AF phases is that a strong interaction suppresses SC, whereas the AF order is not significantly influenced by its presence. In the second part, separate calculations for the case of a pure SC phase have been carried out within an extended approach (the diagrammatic expansion for the Gutzwiller wave function, DE-GWF) in order to analyze the influence of the intersite Coulomb repulsion on the SC phase with the higher-order corrections included beyond the SGA method. The upper concentration for the SC disappearance decreases with increasing V, bringing the results closer to experiment. In appendices A and B we discuss the ambiguity connected with the choice of the Gutzwiller renormalization factors within the renormalized mean filed theory when either AF or CDW orders are considered. At the end, we overview briefly the possible extensions of the current models to put descriptions of the SC, AF, and CDW states on equal footing. PMID- 28627508 TI - Corrigendum: An approach to and web-based tool for infectious disease outbreak intervention analysis. AB - This corrects the article DOI: 10.1038/srep46076. PMID- 28627507 TI - Semivertical Incision: An Aesthetically and Electrophysiologically Effective Mini Incision Technique for Carpal Tunnel Decompression. AB - BACKGROUND The purpose of this study was to present the clinical results of our retrospective series of carpal tunnel release (CTR) operations. For these operations we used a unique type of incision, for the first time, for treatment of carpal tunnel syndrome (CTS) consisting of a 1-cm semi-vertical (SV) incision made into the wrist crease for macroscopic open CTR. MATERIAL AND METHODS This retrospective study included 114 patients (101 females and 13 males) with CTR who were operated upon in our neurosurgery clinic between December 2010 and June 2015. Patient ages ranged from 35 to 83 years (mean 55.05+/-12.04 years). In total, 127 hands (73 right and 54 left) were operated upon using the SV skin incision technique. After an average follow-up of 18 months (ranging from 6 to 30 months), clinical and electrophysiological (EP) evaluations were performed. RESULTS A review of the English language literature published since 1957, when Phalen first popularised the diagnosis and treatment of this disease, determined that no previous reports of the mini-open incision technique as described in our study have been published. In our retrospective patient case review, we found that after operations using the SV incision technique, statistically significant differences were detected in electromyography (EMG) improvements (p<0.01). In addition, patients who showed improvement in EMG studies (n=90) were satisfied with the result of their surgery. CONCLUSIONS Our study demonstrated that 1-cm skin SV incision was a cosmetically satisfying, fast, and safe approach to CTR that was not only clinically effective but also electrophysiologically effective. PMID- 28627509 TI - Corrigendum: Developing informative microsatellite markers for non-model species using reference mapping against a model species' genome. AB - This corrects the article DOI: 10.1038/srep23087. PMID- 28627510 TI - Glycogen controls Caenorhabditis elegans lifespan and resistance to oxidative stress. AB - A high-sugar diet has been associated with reduced lifespan in organisms ranging from worms to mammals. However, the mechanisms underlying the harmful effects of glucose are poorly understood. Here we establish a causative relationship between endogenous glucose storage in the form of glycogen, resistance to oxidative stress and organismal aging in Caenorhabditis elegans. We find that glycogen accumulated on high dietary glucose limits C. elegans longevity. Glucose released from glycogen and used for NADPH/glutathione reduction renders nematodes and human hepatocytes more resistant against oxidative stress. Exposure to low levels of oxidants or genetic inhibition of glycogen synthase depletes glycogen stores and extends the lifespan of animals fed a high glucose diet in an AMPK-dependent manner. Moreover, glycogen interferes with low insulin signalling and accelerates aging of long-lived daf-2 worms fed a high glucose diet. Considering its extensive evolutionary conservation, our results suggest that glycogen metabolism might also have a role in mammalian aging. PMID- 28627511 TI - Fronts and waves of actin polymerization in a bistability-based mechanism of circular dorsal ruffles. AB - During macropinocytosis, cells remodel their morphologies for the uptake of extracellular matter. This endocytotic mechanism relies on the collapse and closure of precursory structures, which are propagating actin-based, ring-shaped vertical undulations at the dorsal (top) cell membrane, a.k.a. circular dorsal ruffles (CDRs). As such, CDRs are essential to a range of vital and pathogenic processes alike. Here we show, based on both experimental data and theoretical analysis, that CDRs are propagating fronts of actin polymerization in a bistable system. The theory relies on a novel mass-conserving reaction-diffusion model, which associates the expansion and contraction of waves to distinct counter propagating front solutions. Moreover, the model predicts that under a change in parameters (for example, biochemical conditions) CDRs may be pinned and fluctuate near the cell boundary or exhibit complex spiral wave dynamics due to a wave instability. We observe both phenomena also in our experiments indicating the conditions for which macropinocytosis is suppressed. PMID- 28627512 TI - Non-equilibrium steady states in supramolecular polymerization. AB - Living systems use fuel-driven supramolecular polymers such as actin to control important cell functions. Fuel molecules like ATP are used to control when and where such polymers should assemble and disassemble. The cell supplies fresh ATP to the cytosol and removes waste products to sustain steady states. Artificial fuel-driven polymers have been developed recently, but keeping them in sustained non-equilibrium steady states (NESS) has proven challenging. Here we show a supramolecular polymer that can be kept in NESS, inside a membrane reactor where ATP is added and waste removed continuously. Assembly and disassembly of our polymer is regulated by phosphorylation and dephosphorylation, respectively. Waste products lead to inhibition, causing the reaction cycle to stop. Inside the membrane reactor, however, waste can be removed leading to long-lived NESS conditions. We anticipate that our approach to obtain NESS can be applied to other stimuli-responsive materials to achieve more life-like behaviour. PMID- 28627513 TI - A bioinspired and biocompatible ortho-sulfiliminyl phenol synthesis. AB - Synthetic methods inspired by Nature often offer unique advantages including mild conditions and biocompatibility with aqueous media. Inspired by an ergothioneine biosynthesis protein EgtB, a mononuclear non-haem iron enzyme capable of catalysing the C-S bond formation and sulfoxidation, herein, we discovered a mild and metal-free C-H sulfenylation/intramolecular rearrangement cascade reaction employing an internally oxidizing O-N bond as a directing group. Our strategy accommodates a variety of oxyamines with good site selectivity and intrinsic oxidative properties. Combining an O-N bond with an X-S bond generates a C-S bond and an S=N bond rapidly. The newly discovered cascade reaction showed excellent chemoselectivity and a wide substrate scope for both oxyamines and sulfenylation reagents. We demonstrated the biocompatibility of the C-S bond coupling reaction by applying a coumarin-based fluorogenic probe in bacterial lysates. Finally, the C-S bond coupling reaction enabled the first fluorogenic formation of phospholipids, which self-assembled to fluorescent vesicles in situ. PMID- 28627514 TI - Simultaneous overactivation of Wnt/beta-catenin and TGFbeta signalling by miR-128 3p confers chemoresistance-associated metastasis in NSCLC. AB - Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/beta-catenin and TGF-beta pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/beta-catenin and TGF-beta activities. Notably, correlations among miR-128-3p levels, activated beta-catenin and TGF beta signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC. PMID- 28627515 TI - Lipid-mediated PX-BAR domain recruitment couples local membrane constriction to endocytic vesicle fission. AB - Clathrin-mediated endocytosis (CME) involves membrane-associated scaffolds of the bin-amphiphysin-rvs (BAR) domain protein family as well as the GTPase dynamin, and is accompanied and perhaps triggered by changes in local lipid composition. How protein recruitment, scaffold assembly and membrane deformation is spatiotemporally controlled and coupled to fission is poorly understood. We show by computational modelling and super-resolution imaging that phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] synthesis within the clathrin-coated area of endocytic intermediates triggers selective recruitment of the PX-BAR domain protein SNX9, as a result of complex interactions of endocytic proteins competing for phospholipids. The specific architecture induces positioning of SNX9 at the invagination neck where its self-assembly regulates membrane constriction, thereby providing a template for dynamin fission. These data explain how lipid conversion at endocytic pits couples local membrane constriction to fission. Our work demonstrates how computational modelling and super-resolution imaging can be combined to unravel function and mechanisms of complex cellular processes. PMID- 28627516 TI - Cooperative tumour cell membrane targeted phototherapy. AB - The targeted delivery of therapeutics using antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumours have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. Here, we construct a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumour cell membrane selective localization of synthetic receptor-lipid conjugates (SR-lipids) to amplify the subsequent targeting of therapeutics. The SR-lipids are first delivered selectively to tumour cell membranes in the perivascular region using fusogenic liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the SR-lipids are transferred to neighbouring cells and further spread throughout the tumour tissues where the molecular targets are limited. We show that this tumour cell membrane-targeted delivery of SR-lipids leads to uniform distribution and enhanced phototherapeutic efficacy of the targeted photosensitizer. PMID- 28627517 TI - Corrigendum: A proteinaceous organic matrix regulates carbonate mineral production in the marine teleost intestine. AB - This corrects the article DOI: 10.1038/srep34494. PMID- 28627519 TI - Tumour Immunology: LAP targeting reduces tolerogenic cells in cancer. PMID- 28627518 TI - The unique immunological and microbial aspects of pregnancy. AB - The comparison of the immunological state of pregnancy to an immunosuppressed host-graft model continues to lead research and clinical practice to ill-defined approaches. This Review discusses recent evidence that supports the idea that immunological responses at the receptive maternal-fetal interface are not simply suppressed but are instead highly dynamic. We discuss the crucial role of trophoblast cells in shaping not only the way in which immune cells respond to the invading blastocyst but also how they collectively react to external stimuli. We also discuss the role of the microbiota in promoting a tolerogenic maternal immune system and highlight how subclinical viral infections can disrupt this status quo, leading to pregnancy complications. PMID- 28627521 TI - Regulatory T cells: Subset-specific suppression. PMID- 28627523 TI - Pulse wave analysis and diabetes mellitus. A systematic review. AB - Cardiovascular (CV) disease is the primary cause of death in diabetic patients and one of the explanations may be increased arterial stiffness. Arterial stiffness assessment using pulse wave analysis, is a predictive factor of CV events. The aim of this paper is to review the current knowledge of relations between diabetes mellitus and pulse wave analysis. A MEDLINE search was performed to retrieve both original and review articles addressing the relations and influences on arterial stiffness in diabetics. Pulse wave analysis is considered as a gold standard in CV risk evaluation for patients at risk, especially diabetics. Arterial stiffness assessment may be helpful for choosing more aggressive diagnostic and therapeutic strategies, particularly in younger patients to reduce the incidence of CV disease in these patients. PMID- 28627522 TI - DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. AB - Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis. PMID- 28627520 TI - Unique aspects of the perinatal immune system. AB - The early stages of life are associated with increased susceptibility to infection, which is in part due to an ineffective immune system. In the context of infection, the immune system must be stimulated to provide efficient protection while avoiding insufficient or excessive activation. Yet, in early life, age-dependent immune regulation at molecular and cellular levels contributes to a reduced immunological fitness in terms of pathogen clearance and response to vaccines. To enable microbial colonization to be tolerated at birth, epigenetic immune cell programming and early life-specific immune regulatory and effector mechanisms ensure that vital functions and organ development are supported and that tissue damage is avoided. Advancement in our understanding of age-related remodelling of immune networks and the consequent tuning of immune responsiveness will open up new possibilities for immune intervention and vaccine strategies that are designed specifically for early life. PMID- 28627524 TI - Screening for mutations in two exons of FANCG gene in Pakistani population. AB - BACKGROUND: Fanconi anemia is a rare autosomal recessive disorder of genetic instability. It is both molecularly and clinically, a heterogeneous disorder. Its incidence is 1 in 129,000 births and relatively high in some ethnic groups. Sixteen genes have been identified among them mutations in FANCG gene are most common after FANCA and FANCC gene mutations. OBJECTIVE: To study mutations in exon 3 and 4 of FANCG gene in Pakistani population. METHODS: Thirty five patients with positive Diepoxybutane test were included in the study. DNA was extracted and amplified for exons 3 and 4. Thereafter Sequencing was done and analyzed for the presence of mutations. RESULTS: No mutation was detected in exon 3 whereas a carrier of known mutation c.307+1 G>T was found in exon 4 of the FANCG gene. CONCLUSION: Absence of any mutation in exon 3 and only one heterozygous mutation in exon 4 of FANCG gene points to a different spectrum of FA gene pool in Pakistan that needs extensive research in this area. PMID- 28627525 TI - Inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue as an essential part of the local immune system. AB - BACKGROUND: The innate and adaptive immune systems in lungs are maintained not only by immune cells but also by non-immune tissue structures, locally providing wide intercellular communication networks and regulating the local tissue immune response. AIMS: The aim of this study was to determine the appearance and distribution of inflammatory, anti-inflammatory and regulatory cytokines in relatively healthy lung tissue samples. MATERIAL AND METHODS: We evaluated lung tissue specimens obtained from 49 patients aged 9-95 years in relatively healthy study subjects. Tissue samples were examined by hematoxylin and eosin staining. Interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-7 (IL-7), and interleukin-10 (IL-10) were detected by an immunohistochemistry (IMH) method. The number of positive structures was counted semiquantitatively by microscopy. Non-parametric tests were used to analyse the data. RESULTS: IL-1 positive cells were mostly found in the bronchial cartilage and alveolar epithelium. Immunoreactive lung macrophages were also found. The numbers of IL-4, IL-6, IL-7, and IL-10 containing cells were also found in the bronchial epithelium (in addition to those previously listed). The number of positive structures varied from occasional to moderate, but was graded higher in cartilage. Overall, fewer IL-1-positive cells and more IL-10-positive cells were found. Almost no positive structures for all examined cytokines were found in connective tissue and bronchial glands. CONCLUSIONS: Relatively healthy lung tissue exhibits anti-inflammatory response patterns. The cytokine distribution and appearance suggest persistent stimulation of cytokine expression in lung tissue and indicate the presence of local regulatory and modulating patterns. The pronounced cytokine distribution in bronchial cartilage suggests the involvement of a compensatory local immune response in the supporting tissue. PMID- 28627526 TI - Polymeric carbon nitride for solar hydrogen production. AB - If solar hydrogen production from water is to be a realistic candidate for industrial hydrogen production, the development of photocatalysts, which avoid the use of expensive and/or toxic elements is highly desirable from a scalability, cost and environmental perspective. Metal-free polymeric carbon nitride is an attractive material that can absorb visible light and produce hydrogen from water. This article reviews recent developments in polymeric carbon nitride as used in photocatalysis and then develops the discussion focusing on the three primary processes of a photocatalytic reaction: light-harvesting, carrier generation/separation/transportation and surface reactions. PMID- 28627527 TI - Non-fullerene acceptors based on central naphthalene diimide flanked by rhodanine or 1,3-indanedione. AB - Through the combination of central naphthalene diimide and terminal rhodanine or 1,3-indanedione functionalities, two new non-fullerene electron acceptors, coded as N3 and N4, were designed, synthesized and characterized. Both of the materials exhibited good solubility, thermal stability, and displayed energy levels matching those of the conventional and routinely used donor polymer poly(3-hexyl thiophene) (P3HT). A high power conversion efficiency of 4.76% was obtained in simple, solution-processable bulk-heterojunction devices (P3HT : N3 1 : 1.2) which is the best result for central NDI-based small molecular non-fullerene acceptors. PMID- 28627528 TI - Novel chemical probes for the investigation of nonribosomal peptide assembly. AB - Chemical probes were devised and evaluated for the capture of biosynthetic intermediates involved in the bio-assembly of the nonribosomal peptide echinomycin. Putative intermediate peptide species were isolated and characterised, providing fresh insights into pathway substrate flexibility and paving the way for novel chemoenzymatic approaches towards unnatural peptides. PMID- 28627529 TI - The effect of Y3+ substitution on the structural, optical band-gap, and magnetic properties of cobalt ferrite nanoparticles. AB - In this study we investigated the structural, optical band-gap, and magnetic properties of CoYxFe2-xO4 (0 <= x <= 0.04) nanoparticles (NPs) synthesized using a combustion reaction method without the need for subsequent heat treatment or the calcing process. The particle size measured from X-ray diffraction (XRD) patterns and transmission electron microscope (TEM) images confirms the nanostructural character in the range of 16-36 nm. The optical band-gap (Eg) values increase with the Y3+ ion (x) concentration being 3.30 and 3.58 eV for x = 0 and x = 0.04, respectively. The presence of yttrium in the cobalt ferrite (Y doped cobalt ferrite) structure affects the magnetic properties. For instance, the saturation magnetization, Ms and remanent magnetization, Mr, decrease from 69 emu g-1 to 33 and 28 to 12 emu g-1 for x = 0 and x = 0.04, respectively. On the other hand the coercivity, Hc, increases from 1100 to 1900 Oe for x = 0 and x = 0.04 at room temperature. Also we found that Ms, Mr, and Hc decreased with increasing temperature up to 773 K. The cubic magnetocrystalline constant, K1, determined by using the "law of approach" (LA) to saturation decreases with Y3+ ion concentration and temperature. K1 values for x = 0 (x = 0.04) were 3.3 * 106 erg cm-3 (2.0 * 106 erg cm-3) and 0.4 * 106 erg cm-3 (0.3 * 106 erg cm-3) at 300 K and 773 K, respectively. The results were discussed in terms of inter-particle interactions induced by thermal fluctuations, and Co2+ ion distribution over tetrahedral A-sites and octahedral B-sites of the spinel structure due to Y3+ ion substitution. PMID- 28627530 TI - Ionic liquids containing tricyanomethanide anions: physicochemical characterisation and performance as electrochemical double-layer capacitor electrolytes. AB - We investigated the use of fluorine free ionic liquids (ILs) containing the tricyanomethanide anion ([C(CN)3]) as an electrolyte in electrochemical double layer capacitors (EDLCs). Three cations were used; 1-butyl-3-methylimidazolium ([Im1,4]), N-butyl-N-methylpyrrolidinium ([Pyr1,4]) and N-butyl-N methylpiperidinium ([Pip1,4]). Their physicochemical properties are discussed alongside with their performance as electrolytes. We found that the cyano-based ILs present higher ionic conductivity (9.4, 8.7 and 4.2 mS cm-1 at 25 degrees C for [Im1,4], [Pyr1,4] and [Pip1,4], respectively) than the widely studied IL containing the bis(trifluoromethylsulfonyl)imide anion, namely [Pyr1,4][Tf2N] (2.7 mS cm-1 at 25 degrees C). Of the three ILs investigated, [Pip1,4][C(CN)3] presents the widest electrochemical stability window, 3.0 V, while [Pyr1,4][C(CN)3] is stable up to 2.9 V and its [Tf2N] analogue can operate at 3.5 V. Despite operating at a lower voltage, [Pyr1,4][C(CN)3] EDLC is capable of delivering up to 4.5 W h kg-1 when operating at high specific power of 7.2 kW kg 1, while its [Pyr1,4][Tf2N] counterpart only delivered 3.0 W h kg-1 when operated at similar power. PMID- 28627532 TI - Phenanthroline-based metal-organic frameworks for Fe-catalyzed Csp3-H amination. AB - We report here the synthesis of a robust and highly porous Fe-phenanthroline based metal-organic framework (MOF) and its application in catalyzing challenging inter- and intramolecular C-H amination reactions. For the intermolecular amination reactions, a FeBr2-metalated MOF selectively functionalized secondary benzylic and allylic C-H bonds. The intramolecular amination reactions utilizing organic azides as the nitrene source required the reduction of the FeBr2 metalated MOF with NaBHEt3 to generate the active catalyst. For both reactions, Fe or Zr leaching was less than 0.1%, and MOFs could be recycled and reused with no loss in catalytic activity. Furthermore, MOF catalysts were significantly more active than the corresponding homogeneous analogs. This work demonstrates the great potential of MOFs in generating highly active, recyclable, and reusable earth abundant metal catalysts for challenging organic transformations. PMID- 28627533 TI - Time-resolved X-ray scattering by electronic wave packets: analytic solutions to the hydrogen atom. AB - Modern pulsed X-ray sources permit time-dependent measurements of dynamical changes in atoms and molecules via non-resonant scattering. The planning, analysis, and interpretation of such experiments, however, require a firm and elaborated theoretical framework. This paper provides a detailed description of time-resolved X-ray scattering by non-stationary electronic wave packets in atomic systems. A consistent application of the Waller-Hartree approximation is discussed and different contributions to the total differential scattering signal are identified and interpreted. Moreover, it is demonstrated how the scattering signal of wave packets in the hydrogen atom can be expressed analytically. This permits simulations without numerical integration and establishes a benchmark for both efficiency and accuracy. Based on that, scattering patterns of an exemplary wave packet in the hydrogen atom are computed for different points in time. In doing so, distinct features of time-resolved X-ray scattering by non-stationary electronic wave packets are illustrated and accentuated in greater detail than it has been done before. PMID- 28627534 TI - Encapsulation of a {Cu16} cluster containing four [Cu4O4] cubanes within an isopolyoxometalate {W44} cluster. AB - We report a {Cu16} embedded within a {W44} cluster containing four cubane-like [Cu4O4] units within an isopolyoxotungstate (isoPOT) in a {Na4Cu4[(H2W11O38) (CH3COO)(OH)3]}4.88H2O (1) and a polyanion Cu-linked {W11} chain Na6Cu2[(H2W11O38)(CH3COO)(OH)].26H2O (2). Electronically, the redox properties show that both compounds 1 and 2 undergo irreversible reductions resulting in the demetalation of the compounds, whilst the magnetic behavior of 1 and 2 shows a weak antiferromagnetic and a stronger ferromagnetic coupling, respectively. PMID- 28627535 TI - A first-principles study on the adsorption of ethylenediamine on Ge(100). AB - We have performed density functional theory (DFT) calculations of the atomic and electronic structures of ethylenediamine on Ge(100). The two amine groups in ethylenediamine can interact with germanium surface atoms through a N-H dissociative nucleophilic reaction and/or N-dative bonding with an electron deficient down Ge atom. Of the monodentate and row-bridged bidentate structures that formed, the dative-bonded configurations were found to be more stable than the NH dissociative adsorption structures. The formation of row-bridged bidentate, structures is more favorable than that of on-top or end-bridged structures. In simulated STM images, the three types of row-bridged adsorption structure have characteristic features, and the row-bridged dative-bonded configuration gives rise to features due to both adsorbed ethylenediamine molecules and the underlying Ge atoms. PMID- 28627540 TI - Mixing scheme of an aqueous solution of tetrabutylphosphonium trifluoroacetate in the water-rich region. AB - We have studied the mixing scheme of an aqueous solution of ionic liquid tetrabutylphosphonium trifluoroacetate, [P4,4,4,4]CF3COO, in the water-rich region. The mixture shows phase separation with a lower critical solution temperature. To learn how the solute [P4,4,4,4]CF3COO species interact with each other in the dilute region, the third derivative quantities of Gibbs energy in terms of enthalpy, H, and volume, V, are evaluated. In the present study using up to the third derivative quantities, we conclude that [P4,4,4,4]CF3COO turns out to be an extremely strong hydrophobe. This finding may hint that the present IL is not dissociated in this water-rich region, despite the large dielectric permittivity of solvent water and as such it works as an extremely strong hydrophobe. An earlier 1-propanol (1P) probing study showed that [P4,4,4,4]+ is a significant amphiphile with a strong hydrophobicity and an equally strong hydrophilicity, and CF3COO- is a modest amphiphile. However, the 1-propanol (1P) probing methodology effectively uses the fourth derivative of G, and is capable of providing deeper information on the effect of the test solute on H2O. To reconcile the present conclusion with the earlier observations described above, we propose to conduct the 1P-probing of the ionic liquid salt, [P4,4,4,4]CF3COO. PMID- 28627541 TI - Amino acid functionalisation using the 2-phosphaethynolate anion. A facile route to (phosphanyl)carbonyl-amino acids. AB - We describe the reactivity of the 2-phosphaethynolate anion (PCO-) towards enantiomerically pure alpha-amino acids (AAs) resulting in the formation of novel salts of phosphinecarboxamides bearing chiral functionalities. These transformations occurred quantitatively with all but one of the amino acids trialled (the basic amino acid arginine was found to be unreactive). The resulting ionic species can be readily protonated to afford N (phosphanyl)carbonyl-amino acids, a novel group of amino acids bearing primary phosphine functionalities. PMID- 28627542 TI - Gas-phase vibrational spectroscopy of triphenylamine: the effect of charge on structure and spectra. AB - The effect of ionization by oxidation and protonation on the structure and IR spectrum of isolated, gas-phase triphenylamine (TPA) has been investigated by infrared multiple photon dissociation (IRMPD) spectroscopy in the fingerprint range from 600 cm-1 to 1800 cm-1 using an infrared free electron laser. IR spectra calculated using density functional theory (DFT) convincingly reproduce the experimental data. Spectral and structural differences are identified among neutral TPA, TPA+ and protonated TPA and qualitatively related to effects of resonance delocalization. As a consequence of electron delocalization, computed structural parameters for TPA remain virtually unchanged upon removal of an electron. Nonetheless, CC and CN stretching vibrations in the IR spectra of TPA+ undergo a red shift of up to 52 cm-1 as compared to those in TPA. Since ionization also strongly influences the relative band intensities, a vibrational projection analysis was used to correlate vibrational modes of TPA with those of TPA+. The experimental IR spectrum of gas-phase protonated TPA indicates that protonation occurs on the nitrogen atom, despite delocalization of the lone electron pair. Upon protonation, the structure changes from the nearly planar geometry to a near-tetrahedral configuration. PMID- 28627543 TI - Potential energy construction in the diabatic picture for quantum mechanical rate constants of intermolecular proton transfer. AB - We propose a simple method for potential construction in the diabatic picture and the estimation of thermal rate constants for intermolecular proton transfer reactions using quantum dynamics simulations carried out on the constructed potentials. For symmetrical and asymmetrical proton transfer pairs, the obtained potentials and rate constants were in good agreement with the reference values. Furthermore, our method is used for the analysis of proton transfer in crystalline imidazolium succinate and discusses the proton conductivity in terms of intermolecular proton transfer. This approach can be used to estimate proton transfer rate constants for large molecular systems, even when the calculation of the transition state is impossible. PMID- 28627544 TI - Anchoring ceria nanoparticles on graphene oxide and their radical scavenge properties under gamma irradiation environment. AB - Polymer networks such as those of epoxy resin, as common protection materials, possess radiolytic oxidation degradation effects under gamma irradiation environment, which have a great accelerating effect on the ageing rate and severely limit their potential applications for metal protection in the nuclear industry. To overcome this, we report a simple scheme of anchoring crystalline ceria nanoparticles onto graphene sheets (CG) and incorporate it into the epoxy resin, followed by thermal polymerization to obtain CeO2/graphene-epoxy nanocomposite coating (CGNS). We had proven that graphene might act as "interwalls" in the epoxy matrix, which will result in space location-obstruct effect as well as absorb the radicals induced by gamma-ray irradiation. Moreover, owing to the interconversion of cerium ions between their +3 and +4 states coupled with the formation of oxygen vacancy defects, electron spin resonance (ESR) detection shows that CeO2/graphene (CG) could act as a preferable radical scavenger and achieve better performance in trapping radicals than single graphene based composite. Electrochemical data strongly demonstrate that CeO2/graphene is capable of maintaining the anti-corrosion properties under gamma irradiation environment. Therefore, the designed hybrid CeO2/graphene-epoxy composite can be considered as potential candidates for protective coatings in nuclear industry. PMID- 28627545 TI - Three-component reactions of isocyanoacetates, amines and 3-formylchromones initiated by an unexpected aza-Michael addition. AB - We present herein a new mode of three-component reactions between isocyanoacetates, amines and 3-formylchromones. Both experimental and DFT studies revealed that this Ag-catalyzed unusual transformation is initiated by a facile aza-Michael addition instead of the conventional imine condensation. This catalytic method enables an efficient synthesis of polysubstituted pyrroles. PMID- 28627547 TI - Probing the electronic structure of a copper(ii) complex by CW- and pulse-EPR spectroscopy. AB - Nucleophilic attack by the carbanion -:CH2COCH3 at the carbonyl group of di-2 pyridyl ketone, (py)2CO, in the presence of CuII under moderately basic conditions has yielded the cationic mononuclear complex [Cu{(py)2C(CH2COCH3)(OH)}2](NO3)2.2H2O (1.2H2O) in ~40% yield, where (py)2C(CH2COCH3)(OH) is the ligand bis(2-pyridine-2-yl)butane-1-ol-3-one. The CuII atom of the cation sits on a crystallographically imposed inversion center. The neutral molecule is coordinated to the metal ion as a tridentate fac chelating ligand through the hydroxyl oxygen atom and two 2-pyridyl nitrogen atoms. The pyridyl nitrogens are strongly coordinated to the metal ion, while the hydroxyl oxygen atoms form weak bonds with CuII. The coordination geometry at the CuII center is elongated octahedral. Various interactions build the crystal structure of the complex and Hirshfeld surface analysis was applied to evaluate the magnitude of interactions between the different chemical species in the crystal of 1.2H2O. IR, Raman and UV/VIS data of the solid complex are discussed in terms of the coordination mode of (py)2C(CH2COCH3)(OH), the ionic nature of nitrates and the stereochemistry at copper(ii). The complex was studied in a frozen solution (MeOH-toluene, 1 : 1 v/v) by CW-EPR spectroscopy and advanced EPR methods such as ENDOR and HYSCORE. The results show that the low symmetry of the cation is retained in solution, with the four nitrogen atoms arranged in a square planar configuration and the unpaired electron residing in an orbital pointing towards them. The bonding parameters in the first coordination sphere and the spin density distribution have been fully analyzed based on the ligand hyperfine coupling constants. PMID- 28627546 TI - Theoretical study of gas and solvent phase stability and molecular adsorption of noncanonical guanine bases on graphene. AB - The gas and solvent phase stability of noncanonical (Gua)n nucleobases is investigated in the framework of dispersion-corrected density functional theory (DFT). The calculated results strongly support the high tendency for the dimerization of (Gua)n bases in both gas and solvent phases. An interplay between intermolecular and bifurcated H-bonds is suggested to govern the stability of (Gua)n bases which bears a correlation with the description of dispersion correction terms employed in the DFT calculations. For example, a higher polarity is predicted for (Gua)n bases by the dispersion-corrected DFT in contrast to the non-polar nature of (Gua)3 and (Gua)4 predicted by the hybrid meta-GGA calculations. This distinct variation becomes significant under physiological conditions as polar (Gua)n is likely to exhibit greater stabilization in the gas phase compared to solvated (Gua)n. Graphene acting as a substrate induces modification in base configurations via maximization of pi-orbital overlap between the base and substrate. In solvent, the substrate-induced effects are further heightened with lowering of the dipole moments of (Gua)n as also displayed by the corresponding isosurface of the electrostatic potential. The graphene-induced stability in both gas and solvent phases appears to fulfill one of the prerequisite criteria for molecular self-assembly. The DFT results therefore provide atomistic insights into the stability and molecular assembly of free-standing noncanonical (Gua)n nucleobases which can be extended to understanding the self-assembly process of functional biomolecules on 2D materials for potential biosensing applications. PMID- 28627548 TI - Tunable photoluminescence and room temperature ferromagnetism of In2S3:Dy3+,Tb3+ nanoparticles. AB - Trivalent lanthanide-doped luminescent nanomaterials have unique spectral and magnetic properties, which have been extensively investigated due to their potential application prospects in a number of new technologies. The rare earth Dy3+ and Tb3+ ions co-doped beta-In2S3 dilute nanoparticles with different doping concentrations were successfully synthesized by a gas-liquid phase chemical deposition method. The band gap energy could be tuned by varying the doping concentration from 3.17 to 3.51 eV. The In2S3:Dy3+,Tb3+ nanoparticles exhibited strong photoluminescence emission peaks and room temperature ferromagnetism. Under excitation at 352 nm, the intrinsic emission and transitions of 5D4 -> 7F6 for Tb3+ and 4F9/2 -> 6H13/2 for Dy3+ were observed. The saturation magnetizations presented an increasing trend and then decreased as the doping concentration increased. This can be ascribed to the fact that the enhanced antiferromagnetic interaction suppresses the ferromagnetic behavior after the doping concentration reaches a certain value. In addition, VASP first-principles calculations were used to further shed light on the magnetic origin and chemical bonding mechanism of the as-prepared samples. It was found that the magnetism could be attributed to In vacancies and the co-doped system is in favor of the formation of In vacancies. This study provides experimental and theoretical guidance for the design and synthesis of promising candidates for optical, magnetic, and spintronic applications. PMID- 28627549 TI - Self-assembly of silver(i)-based high-energy metal-organic frameworks (HE-MOFs) at ambient temperature and pressure: synthesis, structure and superior explosive performance. AB - Two new high-energy metal-organic frameworks (HE-MOFs), {Ag2(DNMAF)(H2O)2}n (1) and {Ag2(DNMAF)}n (2) were prepared using potassium 4,4'-bis(dinitromethyl)-3,3' azofurazanate (K2DNMAF) in a self-assembly strategy. Compound 1 exhibits a 3D HE MOF structure with coordinated water molecules. Compound 2 exhibits compact solvent-free 3D HE-MOFs. Both compounds show good thermostability (decomposition temperature (Td) of 211 and 218 degrees C) and superior detonation velocities (D) of 9673 m s-1 and 10 242 m s-1, detonation pressures (P) of 50.01 GPa and 58.30 GPa, and heat of detonation (Q) of 1.95 kcal g-1 and 2.19 kcal g-1, respectively, which are even higher than those of RDX and HMX. PMID- 28627550 TI - A novel universal colorimetric sensor for simultaneous dual target detection through DNA-directed self-assembly of graphene oxide and magnetic separation. AB - A novel universal colorimetric sensor for simultaneous dual target detection through DNA-directed self-assembly of graphene oxide and magnetic separation has been designed for the first time. PMID- 28627551 TI - Gold-loaded nanoporous iron oxide nanocubes: a novel dispersible capture agent for tumor-associated autoantibody analysis in serum. AB - Autoantibodies are produced against tumor associated antigens (TAAs) long before the appearance of any symptoms and thus can serve as promising, non-invasive biomarkers for early diagnosis of cancer. Current conventional methods for autoantibody detection are highly invasive and mostly provide diagnosis in the later stages of cancer. Herein we report a new electrochemical method for early detection of p53 autoantibodies against colon cancer using a strategy that combines the strength of gold-loaded nanoporous iron oxide nanocube (Au@NPFe2O3NC)-based capture and purification while incorporating the inherent simplicity, inexpensive, and portable nature of the electrochemical and naked-eye colorimetric readouts. After the functionalisation of Au@NPFe2O3NC with p53 antigens, our method utilises a two-step strategy that involves (i) magnetic capture and isolation of autoantibodies using p53/Au@NPFe2O3NC as 'dispersible nanocapture agents' in serum samples and (ii) subsequent detection of autoantibodies through a peroxidase-catalyzed reaction on a commercially available disposable screen-printed electrode or naked-eye detection in an Eppendorf tube. This method has demonstrated a good sensitivity (LOD = 0.02 U mL 1) and reproducibility (relative standard deviation, %RSD = <5%, for n = 3) for detecting p53 autoantibodies in serum and has also been successfully applied to analyse a small cohort of clinical samples obtained from colorectal cancer. We believe that the highly inexpensive, rapid, sensitive, and specific nature of our assay could potentially aid in the development of an early diagnostic tool for cancer and related diseases. PMID- 28627552 TI - Graphite exfoliation in cellulose solutions. AB - Shaking graphite powder dispersed in an aqueous alkaline cellulose solution produces stable dispersions of hydrophilic, thin graphite sheets with lateral dimensions reaching many micrometers. The X-ray diffractogram and Raman spectrum of the exfoliated graphite differ from the well-known graphite patterns. Analytical transmission electron micrographs show cellulose bound to the surface of thin lamellae and this is confirmed by scanning probe micrographs. The dispersant properties of dissolved cellulose are assigned to its adsorption on graphite by juxtaposition of the hydrophobic planes on both substances, forming hydrophilic particles. This method uses only simple and easily accessible chemicals, processed under mild conditions. The resulting nanographite-cellulose dispersions are suitable for making conductive lignocellulosic nanocomposites and coatings. PMID- 28627553 TI - Evans-Showell-type polyoxometalate constructing novel 3D inorganic architectures with alkaline earth metal linkers: syntheses, structures and catalytic properties. AB - Four new architectures containing [Co2Mo10H4O38]6- polyoxoanions, (C2N2H10)2[Sr(H2O)5][Co2Mo10H4O38].2H2O 1, (C2N2H10)2[Ba(H2O)3][Co2Mo10H4O38].3H2O 2, (C3N2H12)2[Sr(H2O)5][Co2Mo10H4O38].3H2O 3 and (C3N2H12)[Ba(H2O)4][Ba(H2O)4][Co2Mo10H4O38].2H2O 4 (C2N2H10 = ethylenediamine; C3N2H12 = 1,3-propanediamine) have been synthesized and characterized by elemental analysis, IR spectroscopy, solid diffuse reflective spectroscopy, TG analysis, powder X-ray diffraction and single crystal X-ray diffraction. Compounds 1 and 2 obtained in the presence of ethylenediamine, are made of Evans Showell-type anions [Co2Mo10H4O38]6-, linked by Sr2+ or Ba2+ cations to form 3D frameworks. To our knowledge, compound 1(2) represents the first example of 3D architecture in which the Evans-Showell anions [Co2Mo10H4O38]6- were linked by pure alkaline earth cations. When propanediamine was used instead of ethylenediamine, compounds 3 and 4 with 2D networks were obtained. This phenomenon indicates that the organic cations, which adjust the reaction pH values, can induce different dimensional inorganic frameworks. As heterogeneous catalysts, compounds 1-4 show excellent catalytic performance in the cyanosilylation of carbonyl compounds. Furthermore, these catalytic reactions were performed under solvent-free conditions using only a low amount of the catalysts, and these catalysts can be recovered and reused without displaying any significant loss of activity. As far as we know, compounds 1-4 represent the first examples of cyanosilylation catalyzed by POM-based species containing alkaline earth metal cations. PMID- 28627554 TI - Group 2 metal (Mg, Ca, Sr) silylamides supported by a cyclen-derived macrocyclic polyamine. AB - Heteroleptic bis(silyl)amides of magnesium and calcium [(L)M{N(SiMe3)2}] [M = Mg, Ca; LH = 1,4,7-trimethyl-1,4,7,10-tetraazacyclododecane; (Me3TACD)H] were previously synthesized from LH and [M{N(SiMe3)2}2]. Strontium bis(silyl)amides [Sr{N(SiMe3)2}2(thf)2] and [Sr{N(SiHMe2)2}2(thf)2/3] reacted with LH to give different types of products, depending on the presence of the beta-SiH function. While the former underwent protonolysis to give the amido-bridged dimer [(L)Sr{N(SiMe3)2}]2 (1), the latter gave the adduct [(LH)Sr{N(SiHMe2)2}2] (2) as a stable solid. 2 slowly underwent an intramolecular Si-H/H-N dehydrocoupling in solution to give [{(L)SiMe2N(SiHMe2)}Sr{N(SiHMe2)2}] (3) by liberating H2. The results of transamination of 1 with HN(SiHMe2)2 depended on the relative stoichiometric ratio. A 1 : 1 mixture in n-pentane gave [{(L)SiMe2N(SiHMe2)}Sr{N(SiMe3)2}] (4) and H2, while excess HN(SiHMe2)2 gave the adduct 2 under similar conditions. Compounds 2 and 3 exhibit Sr?H-Si interactions according to X-ray crystallography, NMR, and IR spectroscopy. Lighter congeners of elusive [(L)Sr{N(SiHMe2)2}] were isolable for Mg (5) and Ca (6). PMID- 28627555 TI - Nanopatterning of GeTe phase change films via heated-probe lithography. AB - The crystallization of amorphous germanium telluride (GeTe) thin films is controlled with nanoscale resolution using the heat from a thermal AFM probe. The dramatic differences between the amorphous and crystalline GeTe phases yield embedded nanoscale features with strong topographic, electronic, and optical contrast. The flexibility of scanning probe lithography enables the width and depth of the features, as well as the extent of their crystallization, to be controlled by varying probe temperature and write speed. Together, these technologies suggest a new approach to nanoelectronic and opto-electronic device fabrication. PMID- 28627556 TI - Copper(i)-catalyzed asymmetric exo-selective [3+2] cycloaddition of azomethine ylides with beta-trifluoromethyl beta,beta-disubstituted enones. AB - The employment of beta,beta-disubstituted enones as dipolarophiles poses a considerable challenge due to their steric hindrance and low reactivity. A copper catalyzed asymmetric exo-selective dipolar cycloaddition of beta-trifluoromethyl beta,beta-disubstituted enones with azomethine ylides was developed, which provides an efficient access to valuable pyrrolidines bearing a trifluoromethylated all-carbon quaternary stereocenter. Up to quantitative yields with up to >20 : 1 dr and 99% ee were delivered. A broad substrate scope, good functional group tolerance, high stereoselectivity, as well as diverse synthetically valuable transformations of the products make this approach highly attractive. PMID- 28627557 TI - Towards the photophysical studies of humin by-products. AB - Biomass conversion into chemicals, materials and fuels emerged in the past decade as the most promising alternative to the current petroleum-based industry. However, the chemocatalytic conversion of biomass and bio-derived sugars often leads to numerous side-products, such as humins. The limited characterization of humin materials restricts their study for possible future applications. Thus, herein photophysical studies on humins and separated humin fractions were carried out using steady-state and time-resolved fluorescence techniques. This paper aims to add to the literature important information for scientists involved in the photophysical studies. PMID- 28627558 TI - Triplet sensitization by perovskite nanocrystals for photon upconversion. AB - The potential of three-dimensional (3D) metal-halide perovskites to sensitize organic triplets is unveiled. Nanocrystals of surface-modified inorganic cesium lead halide perovskites (CsPbX3, X = Br/I) are found to work as efficient triplet sensitizers for photon upconversion based on triplet-triplet annihilation (TTA UC) at low excitation intensity. PMID- 28627559 TI - A luminescent lanthanide approach towards direct visualization of primary cilia in living cells. AB - We report a direct imaging tool, HGEu001, for primary cilia in living cells, which is specific, and based on the UV light or near infrared laser (via two photon excitation) induced long-lived europium luminescence. PMID- 28627560 TI - Asymmetric tandem conjugate addition-protonation to forge chiral secondary C-O bonds for quaternary carbon stereocenters at the nonadjacent beta-position. AB - A direct strategy to construct chiral secondary C-O bonds for quaternary carbon stereocenters at the nonadjacent beta-position is described. Methylene 1,3 oxazolidine-2,4-diones were for the first time employed in an asymmetric reaction as viable electrophiles undergoing a tandem conjugate addition-protonation process. Using an l-amino acid-based urea-tertiary amine catalyst, the reaction with 3-substituted oxindoles gave valuable protonation adducts featuring 1,3 quaternary-tertiary (C-O) nonadjacent stereocenters in high yields and excellent stereoselectivities. The method was successfully extended to sulphur nucleophiles for synthesizing chiral 1,3-sulfur-tertiary alcohol derivatives with bioactive importance. PMID- 28627561 TI - A promising single atom catalyst for CO oxidation: Ag on boron vacancies of h-BN sheets. AB - Single atom catalysts (SACs) have attracted broad research interest in recent years due to their importance in various fields, such as environmental protection and energy conversion. Here, we discuss the mechanisms of CO oxidation to CO2 over single Ag atoms supported on hexagonal boron-nitride sheets (Ag1/BN) through systematic van der Waals inclusive density functional theory (DFT-D) calculations. The Ag adatom can be anchored onto a boron defect (VB), as suggested by the large energy barrier of 3.12 eV for Ag diffusion away from the VB site. Three possible mechanisms (i.e., Eley-Rideal, Langmuir-Hinshelwood, and termolecular Eley-Rideal) of CO oxidation over Ag1/BN are investigated. Due to "CO-Promoted O2 Activation", the termolecular Eley-Rideal (TER) mechanism is the most relevant one for CO oxidation over Ag1/BN and the rate-limiting reaction barrier is only 0.33 eV. More importantly, the first principles molecular dynamics simulations confirm that CO oxidation via the TER mechanism may easily occur at room temperature. Analyses with the inclusion of temperature and entropy effects further indicate that the CO oxidation via the TER mechanism over Ag1/BN is thermodynamically favorable in a broad range of temperatures. PMID- 28627562 TI - A novel combined chemical kinetic and trapping method for probing the relationships between chemical reactivity and interfacial H2O, Br- and H+ ion molarities in CTAB/C12E6 mixed micelles. AB - A delicate balance-of-forces governs the interactions responsible for surfactant self-assembly and chemical reactivity within them. Chemical reactions in micellar media generally occur in the interfacial region of micelles that is a complex mixture of: water, headgroups, counterions, co-ions, acids or bases, organic solvents, and the reactants themselves. We have carried out a detailed study of a complex chemical reaction in mixed CTAB/C12E6 micelles by using the chemical kinetic (CK) and chemical trapping (CT) methods. The results provide a detailed quantitative treatment of the reaction of the anion of the antioxidant t butylhydroquinone, TBHQ-, with 4-hexadecylbenzenediazonium, 16-ArN2+, within the interfacial region of the mixed micelles in the C12E6 mole fraction range of 0 to 1 at three different total surfactant concentrations. CK experiments showed that this reaction is monophasic in C12E6 micelles, but biphasic in mixed micelles. The results were fully consistent with a complex mechanism in which TBHQ- reacts with 16-ArN2+ to give a transient diazoether intermediate that competitively breaks down into products and or reverts to starting materials. The kinetics are the same in mixed micelles of CTAB/C12E6 (grow) and CTAB/C12E8 (don't grow) showing that the rates only depend on micelle composition, not shape. CT results provided estimates of interfacial molarities of H2O are approximately constant at ca. 39 and Br- decreases from ca. 2.75 to 0.05 moles per liter of interfacial volume as C12E6 mole fraction increases from 0 to 1. Combined CK/CT results provided values for interfacial pH, ranging from ca. 4.25 in cationic micelles to 1.5 in nonionic micelles despite a constant bulk pH of 1.5 and the TBHQ interfacial pKa = 3.8 at all C12E6 molar fractions. In totality, these results yielded an extraordinary amount of quantitative information about the relationships between the chemical reactivity and interfacial compositions of the mixed micelles. PMID- 28627563 TI - Highly efficient visible-light-driven photocatalytic degradation of tetracycline by a Z-scheme g-C3N4/Bi3TaO7 nanocomposite photocatalyst. AB - Spatial separation of photogenerated electron-hole pairs is one of the most important factors that determine the efficiency of a photocatalyst. It is well acknowledged that the fabrication of heterogeneous photocatalysts with two different inorganic semiconductors is a good strategy to effectively improve the charge separation of electrons and holes. This study describes a novel visible light-induced g-C3N4/Bi3TaO7 composite photocatalyst with superior photocatalytic properties toward the degradation of tetracycline (TC) by visible light irradiation. The formation of heterojunctions significantly improves the separation efficiency of photogenerated carriers, which is confirmed by the photocurrent density and electrochemical impedance spectroscopy. Electron spin resonance examination and trapping experiments confirm that the photoinduced active species (OH and O2-) are responsible for the degradation of tetracycline. Based on the experimental results, a possible Z-scheme system reaction mechanism for the g-C3N4/Bi3TaO7 composite towards the degradation of TC under visible light was proposed. PMID- 28627564 TI - Methanol-methanol and methanol-water systems: the intermolecular interactions controlling the transition from small clusters to the liquid phase. AB - The present paper focuses on the characterization of the properties of methanol and water molecules in gas and liquid environments. A force field for methanol methanol and methanol-water interactions, useful to be applied in Molecular Dynamics (MD) simulations, is proposed. The electrostatic interaction contributions, arising from permanent charge and/or from anisotropic charge distributions originating from permanent electric multipoles (Vel), different in gas and in liquid phases, are combined with the non electrostatic ones (Vnel), defined by means of Improved Lennard-Jones (ILJ) functions [F. Pirani et al., Phys. Chem. Chem. Phys., 2008, 10, 5489-5503]. Interestingly, the relevant parameters of the ILJ functions are not fitted to reproduce the selected properties of the systems but calculated from the molecular polarizability, which is considered the key property to define size (or Pauli) repulsion and dispersion and induction attractions. The constructed force field predicts binding energies and geometries of the methanol-methanol and methanol-water dimers, in good agreement with available data. On the other hand, several bulk and structural properties of liquid methanol, such as densities, vaporization enthalpies, diffusion coefficients, coefficients of cubic thermal expansion, heat capacities at constant pressure and some relevant radial distribution functions, calculated considering 2744 molecules and different conditions of pressure and temperature, have also been found to be in good agreement with experimental data. The study has been completed by calculating the density values at 298 K and 1 bar of some methanol-water mixtures, which have also been found to be in good agreement with experimental data. PMID- 28627565 TI - A stable gold(i)-enyne species obtained by alkyne carboauration in a complex rearrangement. AB - An unprecedented tetranuclear gold derivative with unusual gold-enyne moieties is prepared by a mild and neat rearrangement of a dinuclear gold complex with a bridging bis(diphenylphosphino)alkyne and terminal alkynyl ligands. The complex originates as a consequence of an intramolecular addition of the AuC[triple bond, length as m-dash]CTol fragment to the internal diphosphine triple bond Ph2PC[triple bond, length as m-dash]CPPh2. The crystal structure of the tetranuclear complex shows a dinuclear metallacycle with a very short AuAu bond interaction and bridging phosphino-enyne ligands. This disposition clearly stabilises the elusive vinyl gold species omnipresent as intermediates in gold catalysed reactions. PMID- 28627566 TI - Theoretical study of one-electron-oxidized salen complexes of group 7 (Mn(iii), Tc(iii), and Re(iii)) and group 10 metals (Ni(ii), Pd(ii), and Pt(ii)) with the 3D-RISM-GMC-QDPT method: localized vs. delocalized ground and excited states in solution. AB - One-electron oxidized salen complexes of Mn(iii) and Ni(ii) were recently reported to be unique mixed-valence compounds. Their electronic structures are sensitive to the salen ligand and solvation. We systematically investigated a series of one-electron oxidized salen complexes of group 7 metals (Mn(iii), Tc(iii), and Re(iii)) and their group 10 analogues (Ni(ii), Pd(ii), and Pt(ii)) using the general multi-configuration reference quasi-degenerate perturbation theory (GMC-QDPT) which was combined with the three-dimensional reference interaction site model self-consistent field theory (3D-RISM-SCF) to incorporate the solvation effect. The calculated absorption spectra and electronic structures agree with the experimental observation. The one-electron oxidized salen complexes of group 10 metals with a symmetrical salen ligand have a delocalized electronic structure belonging to class III (Robin-Day classification) in weakly polar solvents. The tendency for taking a delocalized electronic structure increases in the order Pd(ii) < Ni(ii) < Pt(ii). When the salen ligand is asymmetrical, the one-electron oxidized complexes have a localized electronic structure belonging to class II. The group 7 analogues of Mn(iii) and Tc(iii) have a localized electronic structure belonging to class II even in weakly polar solvents and even with a symmetrical salen ligand. However, the one-electron oxidized Re(iii) complex has no mixed-valence nature because one-electron oxidation occurs on the Re center. Theoretical study shows that the solvation effect plays a crucial role in determining the mixed-valence character, class II or III, and thereby its incorporation in the calculation is indispensable for correctly describing geometries, electronic structures, and the inter-valence absorption spectra of these complexes. The d orbital energy is one of the most important factors for determining the localization/delocalization electronic structures in these complexes. Detailed discussion of these factors is presented. PMID- 28627567 TI - Dissecting binding of a beta-barrel membrane protein by phage display. AB - Membrane proteins (MPs) constitute a third of all proteomes, and contribute to a myriad of cellular functions including intercellular communication, nutrient transport and energy generation. For example, TonB-dependent transporters (TBDTs) in the outer membrane of Gram-negative bacteria play an essential role transporting iron and other nutrients into the bacterial cell. The inherently hydrophobic surfaces of MPs complicates protein expression, purification, and characterization. Thus, dissecting the functional contributions of individual amino acids or structural features through mutagenesis can be a challenging ordeal. Here, we apply a new approach for the expedited protein characterization of the TBDT ShuA from Shigella dysenteriae, and elucidate the protein's initial steps during heme-uptake. ShuA variants were displayed on the surface of an M13 bacteriophage as fusions to the P8 coat protein. Each ShuA variant was analyzed for its ability to display on the bacteriophage surface, and functionally bind to hemoglobin. This technique streamlines isolation of stable MP variants for rapid characterization of binding to various ligands. Site-directed mutagenesis studies targeting each extracellular loop region of ShuA demonstrate no specific extracellular loop is required for hemoglobin binding. Instead two residues, His420 and His86 mediate this interaction. The results identify a loop susceptible to antibody binding, and also a small molecule motif capable of disrupting ShuA from S. dysenteriae. The approach is generalizable to the dissection of other phage-displayed TBDTs and MPs. PMID- 28627568 TI - Synthesis and temperature-dependent studies of a perovskite-like manganese formate framework templated with protonated acetamidine. AB - We report the synthesis, crystal structure, thermal, dielectric, phonon and magnetic properties of the [CH3C(NH2)2][Mn(HCOO)3] (AceMn) compound. Our results show that this compound crystallizes in the perovskite-like orthorhombic structure, space group Imma. It undergoes a structural phase transition at 304 K into a monoclinic structure, space group P21/n. X-ray diffraction, dielectric, IR and Raman studies show that the ordering of the acetamidinium cations triggers the phase transition. Low-temperature magnetic studies show that this compound exhibits weak ferromagnetic properties below 9.0 K. PMID- 28627569 TI - Porphyrin-based photosensitizers and their DNA conjugates for singlet oxygen induced nucleic acid interstrand crosslinking. AB - The development of methods for the generation of site-selective interstrand crosslinks (ICLs) in synthetic oligonucleotides provides a platform for the study of ICL repair mechanisms and the stabilisation of DNA-based materials. Our group has previously reported on the use of a furan moiety as a masked reactive functionality for ICL generation and recently introduced the use of 1O2 as an efficient light-induced oxidant. Here, the use of porphyrin-based photosensitizers (PSs) has been explored for ICL generation. The efficiency of the ICL reaction has been investigated using PSs added into solution as well as attached to oligonucleotide probes. Interestingly, even a highly hydrophobic phthalocyanine was able to produce ICLs. Either in solution or conjugated to an ON, chlorin e6 was the most efficient ICL generator for the current purpose. PMID- 28627571 TI - The fractal correlation between relaxation dynamics and atomic-level structures observed in metallic glasses by computer simulation. AB - In the present study, atomistic simulation reveals that the microscopic mechanism of the relaxation dynamics in amorphous materials is governed by the activating atoms that jump more than half of the average nearest neighbor distance within a given time. Based on the unsupervised machine-learning algorithm, hierarchical clustering analysis shows that the activating atoms are excited in a cooperative and avalanche-like model to form activating units. Correlation analysis suggests that large free volumes facilitate the formation of activating atoms. Interestingly, a fractal correlation is found between the number and size of the activating units, indicating that when the maturation temperature, i.e. percolation threshold, is reached the activating units form a complicated and connected body in space. PMID- 28627570 TI - Determination of bending rigidity and tilt modulus of lipid membranes from real space fluctuation analysis of molecular dynamics simulations. AB - We have recently developed a novel computational methodology (termed RSF for Real Space Fluctuations) to quantify the bending rigidity and tilt modulus of lipid membranes from real-space analysis of fluctuations in the tilt and splay degrees of freedom as sampled in molecular dynamics (MD) simulations. In this article, we present a comprehensive study that combines results from the application of the RSF method to a wide range of lipid bilayer systems that encompass membranes of different fluidities and sizes, including lipids with saturated and unsaturated lipid tails, single and multi-component lipid systems, as well as non-standard lipids such as the four-tailed cardiolipin. By comparing the material properties calculated with the RSF method to those obtained from experimental data and from other computational methodologies, we rigorously demonstrate the validity of our approach and show its robustness. This should allow for future applications of even more complex lipidic assemblies, whose material properties are not tractable by other computational techniques. In addition, we discuss the relationship between different definitions of the tilt modulus appearing in current literature to address some important unresolved discrepancies in the field. PMID- 28627572 TI - A general strategy to add diversity to ruthenium arene complexes with bioactive organic compounds via a coordinated (4-hydroxyphenyl)diphenylphosphine ligand. AB - Esterification of (4-hydroxyphenyl)diphenylphosphine, coordinated to the [Ru(eta6 p-cymene)Cl2] fragment, allows a series of bioactive carboxylic acids to be introduced directly into the organometallic molecule. Evaluation of the compounds on human ovarian cancer cells reveals synergistic enhancements in their antiproliferative activity relative to their bioactive organic and organometallic precursors. PMID- 28627573 TI - Surface-specific vibrational spectroscopy of the water/silica interface: screening and interference. AB - Surface-specific vibrational sum-frequency generation spectroscopy (V-SFG) is frequently used to obtain information about the molecular structure at charged interfaces. Here, we provide experimental evidence that not only screening of surface charges but also interference limits the extent to which V-SFG probes interfacial water at sub-mM salt concentrations. As a consequence, V-SFG yields information about the ~single monolayer interfacial region not only at very high ionic strength, where the surface charge is effectively screened, but also for pure water due to the particularly large screening length at this low ionic strength. At these low ionic strengths, the large screening lengths cause destructive interference between contributions in the surface region. A recently proposed theoretical framework near-quantitatively describes our experimental findings by considering only interference and screening. However, a comparison between NaCl and LiCl reveals ion specific effects in the screening efficiency of different electrolytes. Independent of electrolyte, the hydrogen bonding strength of water right at the interface is enhanced at high electrolyte concentrations. PMID- 28627574 TI - Knockout driven fragmentation of porphyrins. AB - We have studied collisions between tetraphenylporphyrin cations and He or Ne at center-of-mass energies in the range 50-110 eV. The experimental results were interpreted in view of density functional theory calculations of dissociation energies and classical molecular dynamics simulations of how the molecules respond to the He/Ne impact. We demonstrate that prompt atom knockout strongly contributes to the total destruction cross sections. Such impulse driven processes typically yield highly reactive fragments and are expected to be important for collisions with any molecular system in this collision energy range, but have earlier been very difficult to isolate for biomolecules. PMID- 28627575 TI - Label-free detection of aggregated platelets in blood by machine-learning-aided optofluidic time-stretch microscopy. AB - According to WHO, about 10 million new cases of thrombotic disorders are diagnosed worldwide every year. Thrombotic disorders, including atherothrombosis (the leading cause of death in the US and Europe), are induced by occlusion of blood vessels, due to the formation of blood clots in which aggregated platelets play an important role. The presence of aggregated platelets in blood may be related to atherothrombosis (especially acute myocardial infarction) and is, hence, useful as a potential biomarker for the disease. However, conventional high-throughput blood analysers fail to accurately identify aggregated platelets in blood. Here we present an in vitro on-chip assay for label-free, single-cell image-based detection of aggregated platelets in human blood. This assay builds on a combination of optofluidic time-stretch microscopy on a microfluidic chip operating at a high throughput of 10 000 blood cells per second with machine learning, enabling morphology-based identification and enumeration of aggregated platelets in a short period of time. By performing cell classification with machine learning, we differentiate aggregated platelets from single platelets and white blood cells with a high specificity and sensitivity of 96.6% for both. Our results indicate that the assay is potentially promising as predictive diagnosis and therapeutic monitoring of thrombotic disorders in clinical settings. PMID- 28627576 TI - 1,2-Diaza-4-phosphaferrocenes: synthesis, structural characterization, 57Fe Mossbauer spectrum analysis, and DFT calculation. AB - Two 1,2-diaza-4-phosphaferrocenes [(eta5-3,5-R2dp)Fe(eta5-CpMe5)] (R = tBu (3), Ph (4)) with a single eta5 ring containing two nitrogen atoms are prepared. Mossbauer spectroscopic, electrochemical, and density functional theory (DFT) studies have provided a more detailed understanding of the electronic structures and stabilities of these complexes. PMID- 28627577 TI - Facile access to 2,2-disubstituted indolin-3-ones via a cascade Fischer indolization/Claisen rearrangement reaction. AB - An efficient approach for the synthesis of 2,2-disubstituted indolin-3-ones is described. From readily accessible aryl hydrazines and allyloxyketones, 2,2 disubstituted indolin-3-ones could be obtained in good to excellent yields under mild reaction conditions via a cascade Fischer indolization/Claisen rearrangement process. This protocol provides a facile entry to 2,2-disubstituted indolin-3 ones, which have been applied in the construction of the benzofuroindoline framework related to Phalarine. PMID- 28627578 TI - A two-dimensional porous framework: solvent-induced structural transformation and selective adsorption towards malachite green. AB - A two-dimensional porous framework SHU-1 could undergo solvent-induced structural transformations to SHU-1a in methanol and SHU-1b in water. SHU-1, SHU-1a and SHU 1b showed selective adsorption towards malachite green. PMID- 28627579 TI - Correlation analysis of protein quality characteristics with gluten-free bread properties. AB - The interest in gluten-free cereal products has increased significantly over the last number of years and there is still a high demand for high quality products. This study aims to establish possible connections between protein properties and dough and bread quality which could advance the knowledge for gluten-free product development. The objective of the present study was to correlate protein properties with bread characteristics. Therefore, a wide range of tests (solubility, emulsifying, foaming, water hydration properties) was performed to characterize a range of food proteins (potato, pea, carob, lupin and soy). Furthermore, the performance of these proteins in a dough matrix (pasting, rheology) and bread formulation (volume, structure, and texture) was analysed. Statistical analysis showed significant (p < 0.05) correlations between protein properties, dough properties and final bread characteristics. The addition of the proteins to the gluten-free bread formulation affected pasting rheological and bread characteristics such as crumb density, crumb hardness and specific volume. The addition of potato and soy protein resulted in the lowest volume with a dense crumb structure and a low consumer acceptance score. However, lupin, pea and carob containing gluten-free breads had a higher specific volume and softer and less dense crumb structure. The protein solubility (r, 0.89; p < 0.01) and its foaming properties (r, 0.97; p < 0.05) were found to be the most important protein properties with correlations significantly with dough properties and bread quality. PMID- 28627580 TI - Cation distribution and vacancies in nickel cobaltite. AB - Samples of nickel cobaltite, a mixed oxide occurring in the spinel structure which is currently extensively investigated because of its prospective application as ferromagnetic, electrocatalytic, and cost-effective energy storage material were prepared in the form of nanocrystals stabilized in a highly porous silica aerogel and as unsupported nanoparticles. Nickel cobaltite nanocrystals with average size 4 nm are successfully grown for the first time into the silica aerogel provided that a controlled oxidation of the metal precursor phases is carried out, consisting in a reduction under H2 flow followed by mild oxidation in air. The investigation of the average oxidation state of the cations and of their distribution between the sites within the spinel structure, which is commonly described assuming the Ni cations are only located in the octahedral sites, has been carried out by X-ray absorption spectroscopy providing evidence for the first time that the unsupported nickel cobaltite sample has a Ni : Co molar ratio higher than the nominal ratio of 1 : 2 and a larger than expected average overall oxidation state of the cobalt and nickel cations. This is achieved retaining the spinel structure, which accommodates vacancies to counterbalance the variation in oxidation state. PMID- 28627581 TI - Controlled self-assembly of alginate microgels by rapidly binding molecule pairs. AB - Controlled self-assembly of cell-encapsulating microscale polymeric hydrogels (microgels) could be advantageous in a variety of tissue engineering and regenerative medicine applications. Here, a method of assembly by chemical modification of alginate polymer with binding pair molecules (BPM) was explored. Alginate was modified with several types of BPM, specifically biotin and streptavidin and click chemistry compounds, and fabricated into 25-30 MUm microgels using a microfluidic platform. These microgels were demonstrated to self-assemble under physiological conditions. By combining complementary microgels at a high ratio, size-defined assemblages were created, and the effects of BPM type and assembly method on the number of microgels per assemblage and packing density were determined. Furthermore, a magnetic process was developed to separate assemblages from single microgels, and allow formation of multilayer spheroids. Finally, cells were singly encapsulated into alginate microgels and assembled using BPM-modified alginate, suggesting potential applications in regenerative medicine. PMID- 28627582 TI - miR-27 inhibits the NF-kappaB signaling pathway by targeting leptin in osteoarthritic chondrocytes. AB - Osteoarthritis (OA) is a chronic degenerative joint disease. An increasing number of studies point to the role of microRNAs (miRNAs or miRs) in the pathogenesis of OA. An earlier study suggested that miR-27b was associated with OA; however, the precise mechanisms regarding the involvement of the miR-27 in the progression of OA remain unclear. In the present study, we first analyzed the effects of miR-27 on OA. In vitro, the degree of miR-27 expression was decreased in chondrocytes obtained from patients with OA. Transfection with miR-27 mimic increased the viability of CH8 cells and induced the expression of type-II collagen, type-X collagen, glycosaminoglycan (GAG) and aggrecan (ACAN). The results of luciferase activity assay revealed that miR-27 directly targeted the 3'-untranslated region (3'-UTR) of leptin. The results of western blot analysis and ELISA indicated that the concentration of leptin was decreased after the CH8 cells were transfected with miR-27 mimic. In vivo, a rat model of OA was established by anterior cruciate ligament transection (ACLT). When the rats with OA were injected with miR-27 lentiviral overexpression vector, the results of ELISA revealed that the levels of interleukin (IL)-6 and IL-8 were decreased. The results of western blot analysis revealed that matrix metalloproteinase (MMP)-9 and MMP-13 expression levels were decreased, and the nuclear factor-kappaB (NF-kappaB) pathway was inhibited. On the whole, our results suggest that the upregulation of miR-27 inhibits the pathogenesis of OA by targeting leptin and inhibiting the NF-kappaB signaling pathway. Thus, miR-27 exerts protective effects against OA. PMID- 28627583 TI - Deoxyactein protects pancreatic beta-cells against methylglyoxal-induced oxidative cell damage by the upregulation of mitochondrial biogenesis. AB - Methylglyoxal (MG) is one of the major precursors of advanced glycation end products (AGEs), which are considered to be one of the causes of diabetes and its complications. The root and rhizomes of black cohosh (Cimicifuga racemosa) have long been used medicinally, and deoxyactein is one of its major constituents. In the present study, the protective effects of deoxyactein against MG-induced oxidative cell damage were investigated in insulin-producing pancreatic beta cells. We found that deoxyactein protected the pancreatic beta-cells against MG induced cell death. Pre-treatment with deoxyactein significantly reduced the levels of intracellular reactive oxygen species (ROS), interleukin-1beta (IL 1beta), cardiolipin peroxidation, and protein adduct accumulation induced by MG. Pre-treatment of the cells with deoxyactein restored glyoxalase I activity and insulin secretion which were reduced by MG, and increased the mRNA expression of insulin 2 (INS2) and pancreatic and duodenal homeobox protein-1 (PDX-1). It also increased the levels of endogenous antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX). Furthermore, treatment with deoxyactein increased the levels of sirtuin 1 (SIRT1) and peroxisome proliferator activated receptor-gamma co-activator-1alpha (PGC-1alpha). These findings indicate that deoxyactein may exert beneficial effects on pancreatic beta-cells via the upregulation of mitochondrial biogenesis. Taken together, these results suggest that deoxyactein may be used for the prevention of pancreatic beta-cell damage. PMID- 28627584 TI - Gastric electrical stimulation improves enteric neuronal survival. AB - Research and clinical experience with vagotomy have confirmed that damage to the central nervous system severely affects physiological movement in the gastrointestinal system. The aim of this study was to investigate the effects of synchronized dual-pulse gastric electrical stimulation (SGES) on the apoptosis of enteric neurons and the possible pathways involved in these effects in vagotomized rats. For this purpose, Male Sprague-Dawley (SD) rats were randomized into a control group, an early subdiaphragmatic vagotomized group (ESDV group), an early subdiaphragmatic vagotomized group with short-term SGES (ESDV + SSGES group), a terminal subdiaphragmatic vagotomized group (TSDV group) and a terminal subdiaphragmatic vagotomized group with long-term SGES (TSDV + LSGES group). The expression levels of connexin 43 (Cx43), glial cell line-derived neurotrophic factor (GDNF), p-Akt, pan-Akt and PGP9.5 were assessed by RT-qPCR, western blot analysis and immunofluorescence staining. Apoptosis was determined by terminal deoxynucleoitidyl transferase-mediated nick-end labeling (TUNEL) assay. We found that Cx43 expression was decreased in the ESDV and TSDV groups, but was significantly upregulated in the SSGES and LSGES groups. In addition, the GDNF and PGP9.5 expression levels were significantly decreased in the ESDV group compared with the control and TSDV groups and were upregulated in both the SSGES and LSGES groups. The LSGES group exhibited a clear increase in p-Akt expression compared with the TSDV group. Fewer TUNEL-positive cells were observed in the SSGES and LSGES groups than in the ESDV and TSDV groups. More TUNEL-positive cells were found in the stomach of rats subjected to subdiaphragmatic vagotomy. On the whole, our data indicate that SGES improved enteric neuronal survival, possibly through GDNF and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways. PMID- 28627586 TI - Hsp70 acetylation prevents caspase-dependent/independent apoptosis and autophagic cell death in cancer cells. AB - Cancer cells are continuously challenged by adverse environmental factors including hypoxia, metabolite restriction, and immune reactions, and must adopt diverse strategies to survive. Heat shock protein (Hsp) 70 plays a central role in protection against stress-induced cell death by maintaining protein homeostasis and interfering with the process of programmed cell death. Recent findings have suggested that Hsp70 acetylation is a key regulatory modification required for its chaperone activity, but its relevance in the process of programmed cell death and the underlying mechanisms involved are not well understood. In this study, we sought to investigate mechanisms mediated by Hsp70 acetylation in relation to apoptotic and autophagic programmed cell death. Upon stress-induced apoptosis, Hsp70 acetylation inhibits apoptotic cell death, mediated by Hsp70 association with apoptotic protease-activating factor (Apaf)-1 and apoptosis-inducing factor (AIF), key modulators of caspase-dependent and independent apoptotic pathways, respectively. Hsp70 acetylation also attenuated autophagic cell death associated with upregulation of autophagy-related genes and autophagosome induction. Collectively, these results suggest that the acetylation of Hsp70 plays key regulatory roles in cell death pathways as well as in its function as a chaperone, together enabling cellular protection in response to stress. PMID- 28627585 TI - Role of metadherin in estrogen-regulated gene expression. AB - The disruption of estrogen signaling is widely associated with the development of breast, endometrial and ovarian cancers. As a multifunctional mediator of carcinogenesis, metadherin (MTDH)/astrocyte elevated gene-1 (AEG-1) overexpression has been associated with numerous types of cancer, with reported roles in tumor initiation, proliferation, invasion, metastasis and chemoresistance. At the molecular level, MTDH has been shown to interact with proteins that drive tumorigenesis, including nuclear factor-kappaB (NF-kappaB), promyelocytic leukaemia zinc finger (PLZF), BRCA2- and CDKN1A (p21Cip1/Waf-1/mda 6)-interacting protein alpha (BCCIPalpha) and staphylococcal nuclease and tudor domain containing 1 (SND1). Through the analysis of the Cancer Genome Atlas (TCGA) datasets for estrogen receptor (ER)-positive endometrial and breast cancers, we found that over 25% of all gene expression correlated with MTDH. Using Affymetrix microarrays, we characterized the differences in gene expression between estrogen-treated parental and MTDH-deficient endometrial and breast cancer cells. We also explored a possible interaction between MTDH and ER by immunoprecipitation, and found that MTDH and ER associated in both breast and endometrial cancer cells in response to estrogen. Reciprocal co immunoprecipitation analysis demonstrated that acute estrogen stimulation promoted the interaction of MTDH with ER in the nucleus. These data, to the best of our knowledge, provide the first evidence that MTDH and ERalpha interact in the nucleus with estrogen treatment to regulate gene expression. PMID- 28627588 TI - IL-22 expression is increased variedly in the initial phase, onset and chronic phase of a pristane-induced arthritis rat model. AB - The aim of the present study was to investigate the expression pattern of T helper (Th) 17 and Th22 cell-related factors in a pristane-induced arthritis (PIA) rat model. PIA rats were divided into the initial phase group [day (D) 6 post-pristane injection], the onset of clinical arthritis group (D12), the acute arthritis group (D26) and the chronic arthritis group (D70). Rats injected with saline alone were used as the control group. The mRNA expression levels of interleukin (IL)-17A, IL-17F, interferon (IFN)-gamma, IL-22, IL-22 receptor (R) 1, IL-22 binding protein (BP) and RAR-related orphan receptor alpha were examined in the spleen and/or synovium of the various phases of PIA rats by reverse transcription-quantitative polymerase chain reaction analysis. The results demonstrated that, in the spleen, IL-22 exhibited an increasing trend in both the initial phase and the onset of disease, while the ratio of IL-22R1/IL-22BP increased in both phases, compared with the control group. During the acute arthritis phase, IL-17F and IFN-gamma were significantly increased and IL-17A exhibited an increasing tendency in the synovium, compared with the control group. In the chronic phase, IL-22, IL-22R1 and IFN-gamma were increased in the spleen, while IL-22 exhibited an increasing trend in the synovium. In addition, immunohistochemistry analysis was used to evaluate the expression of IL-17A, IL 21, IL-22 and IL-22R1 in the ankle joints of D26 PIA rats. IL-17A was mainly expressed in infiltrated inflammatory cells in the synovium. IL-21 and IL-22 were both expressed in the inflammatory cells and in the articular chondrocyte of the proliferative zone. IL-22R1 was expressed in proliferating synovial cells. In conclusion, Th17 and Th22-related factor expression varied in different disease progression phases and in different tissues in PIA rats. IL-22 expression exhibited an increasing trend in the initial phase and the onset phase of arthritis and increased significantly with progression to chronic arthritis in the PIA rat model. It is thought that IL-22 may serve an important role in the pathological process of PIA, particularly in the chronic fluctuation phase. Therefore, it may be a candidate molecule for the treatment of rheumatoid arthritis. PMID- 28627587 TI - Effects of salinomycin and 17-AAG on proliferation of human gastric cancer cells in vitro. AB - The aim of the present study was to investigate the effects and mechanisms of 17 AAG combined with salinomycin treatment on proliferation and apoptosis of the SGC 7901 gastric cancer cell line. An MTT assay was used to detect the proliferation of SGC-7901 cells. Morphological alterations of cells were observed under inverted phase-contrast and fluorescence microscopes. Cell cycle and apoptosis were assessed by flow cytometry analysis. The protein expression of nuclear factor (NF)-kappaB p65 and Fas-ligand (L) were evaluated by immunocytochemistry. Salinomycin with a concentration range of 1-32 umol/l was demonstrated to inhibit growth of SGC-7901 cells effectively, affect the morphology and apoptosis rate of cells, and arrest SGC-7901 cells in S phase. Furthermore, salinomycin significantly increased the protein expression of Fas-L and decreased the protein expression of NF-kappaB p65. The alterations in SGC-7901 cells co-treated with salinomycin and 17-AAG were more significant compared with cells treated with one drug only. In conclusion, the individual use of salinomycin and combined use with 17-AAG may significantly inhibit SGC-7901 gastric cancer cell proliferation and induce cell apoptosis. The potential mechanisms may be associated with upregulation of Fas-L and downregulation of NF-kappaB. These results provide a basis for the potential use of salinomycin in gastric cancer treatment. PMID- 28627589 TI - Effect of the spinal apelin-APJ system on the pathogenesis of chronic constriction injury-induced neuropathic pain in rats. AB - Apelin is hypothesized to serve a dual function in pain processing. Spinal administration of apelin induces hyperalgesia, while opioid receptors are implicated in the antinociceptive effects of apelin in acute nociceptive models. However, whether the apelin-apelin receptor (APJ) system is involved in neuropathic pain remains to be elucidated. The present study aimed to evaluate the impact and mechanism of the spinal apelin-APJ system in neuropathic pain. Chronic constriction injury (CCI) of the sciatic nerve produced sustained spinal apelin and APJ upregulation, which was associated with mechanical allodynia and heat hyperalgesia development in the hind-paw plantar surface. Immunofluorescence demonstrated that apelin and APJ were localized to the superficial dorsal horns. In order to further clarify the function of the apelin-APJ system, a single intrathecal administration of ML221, an APJ antagonist, was used; this transiently reduced CCI-induced pain hypersensitivity. However, apelin-13 (the isoform which binds most strongly to APJ) exhibited no effect on the nociceptive response, suggesting an essential role for the spinal apelin-APJ system in neuropathic pain sensitization. The present study demonstrated that a single application of ML221 alleviated mechanical allodynia and heat hyperalgesia 7 days following CCI, in a dose-dependent manner. Intraspinal delivery of ML221, at the onset of and in fully-established neuropathic pain, persistently attenuated CCI induced pain hypersensitivity, indicating that the apelin-APJ system was involved in initiating and maintaining pain. It was demonstrated, using immunoblotting, that intrathecal ML221 downregulated phosphorylated extracellular signal-related kinase (ERK) in the rat spinal cord dorsal horn, suggesting that the effect of apelin on neuropathic pain may be mediated via ERK signaling. The results of the present study suggested that the spinal apelin-APJ system may drive neuropathic pain. Inhibition of APJ may provide novel pharmacological interventions for neuropathic pain. PMID- 28627590 TI - Activation of Sonic hedgehog signal by Purmorphamine, in a mouse model of Parkinson's disease, protects dopaminergic neurons and attenuates inflammatory response by mediating PI3K/AKt signaling pathway. AB - In Parkinson's disease (PD), microglial activation-mediated neuroinflammation is associated with dopaminergic neurons degeneration in the substantia nigra pars compacta. Previous studies that have investigated this neurodegenerative disease have reported that the Sonic hedgehog (SHH) signaling pathway, through inhibiting the inflammatory processes, exerts a beneficial neuroprotective effect. However, the mechanisms underlying the anti-inflammatory and neuroprotective effects of this signaling pathway remain poorly understood. The present study aimed to further investigate these mechanisms in vitro and in vivo. At first, BV2 microglial cells treated with lipopolysaccharide (LPS) were used to induce an inflammatory response. It was observed that the activation of SHH signaling by Purmorphamine attenuated the LPS-induced inflammatory response, increased the expression of transforming growth factor-beta1 through the phosphatidylinositol 3 kinase (PI3K)/AKT serine/threonine kinase (Akt) intracellular signaling pathway and inhibited nuclear receptor subfamily 4 group A member 2, independently of the PI3K/Akt signaling pathway. Furthermore, the blockade of the PI3K/Akt signaling pathway by intranasal administration of LY294002, significantly reduced the SHH associated neuroprotective effects on dopaminergic neurons, improved motor functions, and increased the microglial activation and inflammatory response in a mouse model of PD induced using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In conclusion, the data of the present study reported that anti-inflammatory and neuroprotective effects can be obtained in BV2 microglial cells and in a mouse model of PD by successive activation of the SHH and PI3K/Akt signaling pathways. PMID- 28627591 TI - Chinese herbal medicine Xinji pill protects the heart from ischemia/reperfusion injury through the Akt/Nrf2 pathway. AB - The cardioprotective drugs used for treatment against ischemia/reperfusion (MI/R) injury have been well evaluated and are considered inadequate. The Chinese herbal medicine formula, Xinji pill (XJP) has been used traditionally for the prevention and treatment of ischemic heart diseases for decades. In the present study, the cardioprotective effects of XJP against MI/R injury were assessed in vivo and its possible mechanism was examined. Male Sprague-Dawley rats were selected for establishing an MI/R model, which was induced by ischemia for 30 min followed by 24 h reperfusion. Drugs and saline were administered intragastrically from day 14 prior to MI/R. Blood samples were collected for biochemical detection. The rats were then sacrificed and cardiac muscle tissues were harvested. The mRNA expression levels of antioxidant genes were measured by reverse transcription quantitative polymerase chain reaction and the protein levels were measured by western blotting. Pretreatment with XJP for 14 days protected the heart against I/R-induced myocardial function disorder, protected against heart injury, as demonstrated by normalized serum levels of lactate dehydrogenase and creatine kinase, and suppressed oxidative stress. XJP markedly upregulated the expression of antioxidant genes, including superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase, and promoted the protein expression of heme oxygenase-1 and NFE2-related factor 2 (Nrf2) in the heart tissues. Furthermore, Akt kinase was confirmed to be upstream of Nrf2 in the XJP treatment. LY294002, a specific inhibitor of Akt, significantly eliminated the cardioprotective effects of XJP. In conclusion, these results demonstrated that XJP exhibited notable cardioprotective properties, in which the Akt/Nrf2 signaling pathway may be involved. PMID- 28627593 TI - Suppressive effect of an aqueous extract of Diospyros kaki calyx on dust mite extract/2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions. AB - Atopic dermatitis (AD) is a common chronic inflammatory skin disease, affecting 10-20% of individuals worldwide. Therefore, the discovery of drugs for treating AD is an attractive subject and important to human health. Diospyros kaki and Diospyros kaki (D. kaki) folium exert beneficial effects on allergic inflammation. However, the effect of D. kaki calyx on AD remains elusive. The present study evaluated the effects of an aqueous extract of D. kaki calyx (AEDKC) on AD-like skin lesions using mouse and keratinocyte models. We used a mouse AD model by the repeated skin exposure of house dust mite extract [Dermatophagoides farinae extract (DFE)] and 2,4-dinitrochlorobenzene (DNCB) to the ears. In addition, to determine the underlying mechanism of its operation, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) activated keratinocytes (HaCaT) were used. Oral administration of AEDKC decreased AD-like skin lesions, as demonstrated by the reduced ear thickness, serum immunoglobulin E (IgE), DFE-specific IgE, IgG2a, histamine level and inflammatory cell infiltration. AEDKC inhibited the expression of pro-inflammatory cytokines and a chemokine via downregulation of nuclear factor-kappaB and signal transducer and activator of transcription 1 in HaCaT cells. On examination of the AD-related factors in vivo and in vitro, it was confirmed that AEDKC decreased AD-like skin lesions. Taken together, the results suggest that AEDKC is a potential drug candidate for the treatment of AD. PMID- 28627594 TI - MicroRNA-320 inhibits cell proliferation, migration and invasion in retinoblastoma by targeting specificity protein 1. AB - Research into the expression and function of microRNAs (miRNAs/miR) in human cancer has provided novel insights into the molecular mechanisms underlying carcinogenesis and cancer progression. Aberrant miRNA expression has been reported in retinoblastoma (RB) and several other types of human cancer. The present study demonstrated that miR-320 is significantly downregulated in RB tissues and cell lines. Furthermore, overexpression of miR-320 was demonstrated to inhibit proliferation, migration and invasion of RB cells. Bioinformatic analysis identified specificity protein 1 (SP1) as a potential target gene of miR 320. Luciferase reporter assay confirmed that the SP1 3'-untranslated region contains a direct binding site for miR-320, and restoration of miR-320 expression decreased the mRNA and protein expression levels of SP1. Notably, SP1 silencing induced a similar effect on the proliferation, migration and invasion of RB cells as that observed with miR-320 overexpression, further supporting the hypothesis that SP1 is a direct functional target of miR-320 in RB. In conclusion, these findings indicate that miR-320 may be an effective therapeutic target for the treatment of RB. PMID- 28627592 TI - Triptolide exerts protective effects against fibrosis following ileocolonic anastomosis by mechanisms involving the miR-16-1/HSP70 pathway in IL-10-deficient mice. AB - Surgeries, particularly ileocecal resection (ICR), are often required in the treatment of Crohn's disease (CD). However, recurrences are common for patients who undergo ICR, and anastomotic fibrosis is the main cause of re-operation. The present study aimed to investigate the therapeutic effects of triptolide (TPL) in ameliorating fibrosis following ileocolonic anastomosis. A model of IL-10-/- mice undergoing ICR was used to study postsurgical inflammation and fibrosis of anastomosis. For this purpsose, interleukin (IL)-10-/- mice were randomly divided into 3 groups as follows: the control group, the saline-treated group subjected to ICR (ST-ICR) and the TPL-treated group subjected to ICR (TT-ICR). Wild-type (WT) mice of matching ages were assigned to the WT group. The effects of TPL treatment on ileocolonic anastomosis were determined by histopathological evaluation, western blot analysis and ELISA. The analysis of the effects of TPL treatment on microRNA-16-1 (miR-16-1) and heat shock protein 70 (HSP70) expression was carried out by RT-qPCR and western blot analysis. Compared with the control group, significantly higher inflammation scores following anastomosis were observed in the ST-ICR group (P<0.05), although reversion was observed in the TT-ICR group, which was consistent with changes in the area of CD4+ cell infiltration. The elevated fibrosis scores and the overexpression of procollagen I and III in the ST-ICR group were all inhibited by TPL. With an increase in the severity of inflammation and fibrosis, the levels of IL-6, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) increased; however, a significant decrease in these levels was observed following treatment with TPL (P<0.05). The results of RT-qPCR revealed that the upregulated miR-16-1 levels in the ST-ICR group were significantly reduced by TPL. HSP70, which can be inhibited by miR-16-1, ameliorates anastomotic inflammation and fibrosis. Thus, the present study demonstrates that TPL exerts a protective effect against fibrosis following anastomosis in CD. The miR-16-1/HSP70 signaling pathway, which can be regulated by TPL, may thus represent a novel therapeutic option in CD that deserves further investigation. PMID- 28627595 TI - Elevated expression of transient receptor potential vanilloid type 1 in dorsal root ganglia of rats with endometriosis. AB - Pain is the most pronounced complaint of women with endometriosis, however the underlying mechanism is still poorly understood. In the present study, the authors evaluate the effect of transient receptor potential vanilloid type 1 (TRPV1) of dorsal root ganglia (DRG) on endometriosis-associated pain. A total of 36 SD rats were randomly divided into a sham group (n=9) and a Model group (n=27), accepted auto-transplanted pieces of fat or uterus to the pelvic cavity. At 4 weeks, the Model group was randomly subdivided into the following groups: ENDO group (no treatment, n=9), BCTC group (Model + BCTC, an antagonist of TRPV1, n=9), Vehicle group (Model + cyclodextrin, the vehicle of BCTC, n=9). Tail-flick test was performed prior to surgery, 1 h prior to and following treatment of BCTC or cyclodextrin. The expression of TRPV1, substance P (SP), calcitonin gene related peptide (CGRP) in L1-L6 DRG was measured via immunohistochemistry, western blotting and RT-qPCR. The results indicated that the Model group exhibited a significant decrease in tail flick latency compared to pre-surgical baseline, and the expression of TRPV1, SP, CGRP protein and mRNA in L1-L6 DRG significantly increased compared to the sham group. BCTC significantly improved tail flick latency, and downregulated the expression of TRPV1, SP and CGRP protein and mRNA levels in L1-L6 DRG compared to ENDO group. However, there were no significant differences of those in Vehicle group compared with the ENDO group. Taken together, the current study provides evidence that TRPV1 expressed in DRG may serve an important role in endometriosis-associated pain. PMID- 28627596 TI - Regulation of type II collagen, matrix metalloproteinase-13 and cell proliferation by interleukin-1beta is mediated by curcumin via inhibition of NF kappaB signaling in rat chondrocytes. AB - Curcumin possesses strong anti-inflammatory, anti-rheumatoid and anti-oxidative activities, and has the potential to inhibit nuclear factor-kappaB (NF-kappaB) signaling. Cartilage damage in osteoarthritis (OA) is largely mediated by interleukin-1beta (IL-1beta) via activation of various transcription factors, including NF-kappaB and activator protein-1. The aim of the present study was to determine whether IL-1beta induces matrix metalloproteinase-13 (MMP-13) expression and inhibits type II collagen expression, as well as to examine whether cell proliferation may be inhibited by curcumin through the inhibition of NF-kappaB signaling. The effects of curcumin were investigated in rat articular chondrocyte cell cultures treated with IL-1beta in the presence or absence of curcumin or the NF-kappaB inhibitor pyrrolidine dithiocarbamate. Western blotting and reverse transcription-quantitative polymerase chain reaction were conducted to evaluate protein and mRNA expression levels of type II collagen, MMP-13, NF kappaB inhibitor alpha (IkappaBalpha), phosphorylated-IkappaBalpha and NF-kappaB subunit p65/RelA. Western blotting and immunofluorescence were performed to examine the effects of curcumin on the expression, phosphorylation and nuclear translocation of NF-kappaB-associated proteins. The effects of curcumin on cell proliferation were evaluated by Cell Counting Kit-8 (CCK-8). Curcumin was demonstrated to inhibit the IL-1beta-induced activation of NF-kappaB by suppressing IkappaBalpha phosphorylation and p65/RelA nuclear translocation. These events were associated with the downregulation of MMP-13 expression and the upregulation of type II collagen expression, both of which are considered to be NF-kappaB targets. CCK-8 assays revealed that co-treatment with curcumin resulted in increased proliferation in IL-1beta-treated chondrocytes. These findings implicated curcumin as a naturally occurring anti-inflammatory agent for the treatment of OA via inhibition of NF-kappaB signaling. PMID- 28627597 TI - Significance of dynamic changes in gastric smooth muscle cell apoptosis, PI3K-AKT mTOR and AMPK-mTOR signaling in a rat model of diabetic gastroparesis. AB - The aim of the present study was to investigate the significance of cell apoptosis, the phosphoinositide-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, and the 5' adenosine monophosphate-activated protein kinase (AMPK)-mTOR pathways in the process of diabetic gastroparesis. Changes in gastric smooth muscle cells of diabetic rats with induced gastroparesis were examined. The diabetic rat model was established by dividing animals into a normal control group and diabetic model groups examined at 2, 4 and 6 weeks. Diabetic gastroparesis was evaluated by examining the rates of gastric residual pigment, whereas flow cytometry was used to detect the apoptosis of gastric smooth muscle cells. The expression levels of PI3K and phosphorylated (p-) AKT, AMPK, mTOR, tuberous sclerosis complex 2, p70 ribosomal S6 kinase, and eukaryotic translation initiation factor 4-binding protein 1 were determined in gastric muscles using western blot analysis. Diabetic gastroparesis was confirmed in models at 6 weeks. The apoptosis of gastric smooth muscle cells gradually increased in all diabetic groups, and significant changes were observed in key proteins involved in PI3K-AKT-mTOR and AMPK-mTOR signaling. The results indicated that apoptosis was important in the occurrence of diabetic gastroparesis, and the PI3K-AKT-mTOR and AMPK-mTOR pathways were activated during the apoptotic processes, but were incapable of regulating apoptosis. PMID- 28627599 TI - HMOX-1 inhibits TGF-beta-induced epithelial-mesenchymal transition in the MCF-7 breast cancer cell line. AB - Epithelial-mesenchymal transition (EMT) is a key mechanism underlying metastatic breast cancer. Reactive oxygen species (ROS) play an important role in EMT. Heme oxygenase-1 (HMOX-1) can reduce oxidative stress. However, the effect of HMOX-1 on the EMT process in breast cancer cells is unknown. We treated the MCF-7 breast cancer cell line with the HMOX-1 inducer hemin and observed that hemin induced HMOX-1 expression and inhibited migration, invasion and ROS generation in transforming growth factor-beta (TGF-beta)-treated MCF-7 cells using quantitative RT-qPCR, western blotting, wound-healing and cell invasion assays as well as fluorescent probe DCFDA. Hemin inhibited TGF-beta-induced EMT in the MCF-7 cells, whereas HMOX-1 siRNA attenuated the suppressive effect of hemin as determined by the expression and cellular distribution of selected EMT markers. In summary, our results revealed that hemin treatment increased HMOX-1 expression and inhibited TGF-beta-induced EMT in MCF-7 cells. PMID- 28627598 TI - Curcumin exerts its tumor suppressive function via inhibition of NEDD4 oncoprotein in glioma cancer cells. AB - Glioblastoma is the most common brain cancer in adults. It represents one of the top ten malignant tumors with an average survival time of nine months despite treatments with surgery, radiotherapy and chemotherapy. Curcumin is a phytochemical turmeric isolated from root of the Curcuma longa plant. Accumulating evidence have proved that curcumin targets numerous cancer signaling pathways. The E3 ubiquitin ligase NEDD4, neural precursor cell expressed developmentally downregulated protein 4, is frequently overexpressed in various cancers. However, whether curcumin regulates NEDD4 expression has not been described in human cancers. Therefore, in this study, we explored the roles of NEDD4 in glioma cell proliferation, apoptosis and mobility. We further investigated whether curcumin exerts its antitumor activities via suppressing NEDD4 expression. We found that curcumin reduced the expression of NEDD4 and Notch1 and pAKT, leading to glioma cell growth inhibition, apoptosis, and suppression of migration and invasion. Moreover, deletion of NEDD4 expression enhanced the sensitivity of glioma cells to curcumin treatment. Thus, inactivation of NEDD4 by curcumin could be a promising approach for therapeutic intervention. PMID- 28627600 TI - MicroRNA-7-5p regulates the expression of TFF3 in inflammatory bowel disease. AB - Trefoil factor 3 (TFF3) serves an important role in intestinal mucosal damage and healing, and contributes to the pathogenesis and treatment of inflammatory bowel disease (IBD). The aim of the present study was to determine the association between TFF3 and microRNA-7-5p (miR-7-5p) in IBD. Tissue immunohistochemistry was applied to evaluate the relative expression of TFF3, and reverse transcription quantitative polymerase chain reaction was performed to determine the expression of miR-7-5p in lesional tissue obtained from patients with IBD and healthy control tissues. A dual-luciferase reporter assay was used to investigate whether TFF3 was a target of miR-7-5p, and western blotting was performed to determine the expression of TFF3 when miR-7-5p was overexpressed or suppressed. The protein expression levels of TFF3 were decreased and miR-7-5p was overexpressed in the lesional tissue of patients with IBD compared with in healthy control tissues. TFF3 was identified as a target of miR-7-5p, and TFF3 protein expression was negatively regulated by miR-7-5p in human colonic epithelial LS174T cells. The present study demonstrated a negative association between the expression of miR-7 5p and TFF3 in IBD lesional tissues and normal tissues. In conclusion, TFF3 was identified as a novel target of miR-7-5p and miR-7-5p may serve as a promising therapeutic target for IBD. PMID- 28627601 TI - An in vitro study on the effects of the combination of salinomycin with cisplatin on human gastric cancer cells. AB - The present study aimed to investigate the anticancer effects of cisplatin (DDP) combined with salinomycin (SAL) on the gastric cancer cell line SGC-7901, as well as to explore the mechanisms underlying their actions. An MTT assay was used to evaluate the inhibitory effects of SAL, DDP and their combination on gastric cancer cell proliferation. Morphological alterations of cancer cells following treatment were observed under an inverted phase-contrast microscope and a fluorescence microscope. Cell cycle progression and apoptosis were analyzed using flow cytometry. The expression of nuclear factor (NF)-kappaB p65 and Fas protein ligand (L) in cancer cells was assessed using immunocytochemistry. The present results demonstrated that the combination of SAL and DDP significantly inhibited the proliferation (P<0.05) and altered the morphological characteristics of SGC 7901 cells, thus suggesting that SAL may enhance the susceptibility of gastric cancer cells to DDP. In addition, treatment with a combination of SAL and DDP resulted in S phase-arrest and increased the apoptotic rate of SGC-7901 cells. Furthermore, marked FasL upregulation and NF-kappaB p65 downregulation were observed in cancer cells treated with the combination of SAL and DDP. The results of the present study demonstrated that the combination of SAL and DDP induced the apoptosis of human gastric cancer cells, and suggested that the underlying mechanism may involve the upregulation of FasL and downregulation of NF-kappaB p65. PMID- 28627602 TI - Molecular profiling of locally-advanced rectal adenocarcinoma using microRNA expression (Review). AB - Treatment for locally-advanced rectal cancer (LARC) typically consists of neoadjuvant chemoradiation followed by total mesorectal excision. Recently, there has been growing interest in non-operative management for patients who are medically-inoperable or wish to avoid surgical morbidity and permanent colostomy. Approximately 50% of patients who receive pre-operative neoadjuvant chemoradiation develop some degree of pathologic response. Approximately 10-20% of patients are found to have a complete pathologic response, a finding which has frequently been shown to predict better clinical outcomes, including local regional control, distant metastasis and survival. Many recent studies have evaluated the role of molecular biomarkers in predicting response to neoadjuvant therapy. MicroRNAs (miRNAs) are an emerging class of biomarkers that have the potential to predict which patients are most likely to benefit from pre-operative therapy and from a selective surgical approach. Here, we review the published literature on microRNAs as prognostic and predictive biomarkers in rectal cancer after pre-operative therapy. In the future, the development of prospectively validated miRNA signatures will allow clinical implementation of miRNAs as prognostic and predictive signatures in LARC. PMID- 28627603 TI - Role of stem cell factor in the regulation of ICC proliferation and detrusor contraction in rats with an underactive bladder. AB - Stem cell factor (SCF) is critical in regulating the proliferation, differentiation and function of the interstitial cells of Cajal (ICCs), which are closely associated with smooth muscle dysfunction. The present study aimed to examine the effect of SCF on ICC proliferation and detrusor contraction in rats with an underactive bladder. Sprague-Dawley rats were divided into four groups comprising control, control+SCF, detrusor underactivity (DU), and DU+SCF groups. The ICC count was determined using immunofluorescence; serum levels of SCF were determined using an enzyme-linked immunosorbent assay; mRNA and protein levels of c-kit and SCF in tissues were assessed using reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. Detrusor contractility was determined using muscle strips, based on the contraction amplitude and frequency determined in each specimen. Significantly fewer ICCs were observed in the DU group, in addition to decreased expression levels of SCF and c-kit, compared with the control group. In addition, the detrusor contraction frequency and amplitude were markedly reduced. However, the administration of SCF significantly increased the number of ICCs, and the levels of SCF and c-kit in animals with DU, and resulted in markedly amplified detrusor contraction frequency and amplitude. Similarly, the number of ICCs and levels of SCF and c kit were higher in the control+SCF group, compared with the control group. Overall, these findings suggested that exogenous SCF improved the organ dysfunction caused by reduced ICC number, providing a novel approach for organ repair. PMID- 28627604 TI - The C-terminus domain of the hepatitis B virus x protein stimulates the proliferation of mouse foetal hepatic progenitor cells, although it is not required for the formation of spheroids. AB - The hepatitis B virus X (HBx) protein is an important factor in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). The C-terminal region of HBx plays a major role in the replication of HBV. Notably, HBx promotes the expansion and tumourigenesis of hepatic progenitor cells (HPCs) in mice. However, it remains unclear as to whether the C-terminal region of HBx is required for the stimulation fo the proliferation of mouse foetal HPCs (FHPCs). In our study, we used EpCAM+, CD133+ and CD49f+ FHPCs, which are bipotential clonogenic cells. These FHPCs transformed into mature hepatocytes and cholangiocytes when cultured under conditions that facilitate differentiation. Compared with the FHPCs grown as monolayers, spherical cell proliferation occurred more rapidly. Furthermore, spherically cultured FHPCs can grow in semi-solid agar and tend to maintain the morphology and characteristics of stem cells compared with growth in rat tail collagen. Notably, we also demonstrate that the C-terminus of HBx stimulates the proliferation of FHPCs, but is not required for the formation of spheroids, similar to hepatic cancer stem cells. These findings enhance our understanding of the HBx-induced tumourigenicity of FHPCs and may aid in the treatment of HCC. PMID- 28627605 TI - Mesenchymal stem cells promote endothelial progenitor cell proliferation by secreting insulin-like growth factor-1. AB - Bone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) interact with each other. EPCs are able to promote the self-renewal of MSCs as niche cells in murine bone marrow, and MSCs are able to promote EPC proliferation in vitro in a co-culture system. It has previously been reported that MSCs can secrete insulin-like growth factor-1 (IGF-1), which serves critical functions in EPC proliferation. However, the mechanism underlying the IGF-1-mediated proliferation of EPCs remains unclear. The aim of the present study was to reveal the molecular mechanisms regulating this process. The effects of IGF-1, which is secreted by MSCs, on EPC proliferation via the PI3K/Akt signaling pathway were examined by MTT assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis. The present study treated EPCs with various concentrations of IGF-1. The results demonstrated that IGF-1 significantly induced the proliferation of cultured EPCs. However, this effect was offset by treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. These results indicated that the pro-proliferative effects of IGF-1 are mediated in response to the PI3K/protein kinase B signaling pathway. PMID- 28627606 TI - Effects of ischemic preconditioning on PDGF-BB expression in the gerbil hippocampal CA1 region following transient cerebral ischemia. AB - Ischemic preconditioning (IPC) is induced by exposure to brief durations of transient ischemia, which results in ischemic tolerance to a subsequent longer or lethal period of ischemia. In the present study, the effects of IPC (2 min of transient cerebral ischemia) were examined on immunoreactivity of platelet derived growth factor (PDGF)-BB and on neuroprotection in the gerbil hippocampal CA1 region following lethal transient cerebral ischemia (LTCI; 5 min of transient cerebral ischemia). IPC was subjected to a 2-min sublethal ischemia and a LTCI was given 5-min transient ischemia. The animals in all of the groups were given recovery times of 1, 2 and 5 days and change in PDGF-BB immunoreactivity was examined as was the neuronal damage/death in the hippocampus induced by LTCI. LTCI induced a significant loss of pyramidal neurons in the hippocampal CA1 region 5 days after LTCI, and significantly decreased PDGF-BB immunoreactivity in the CA1 pyramidal neurons from day 1 after LTCI. Conversely, IPC effectively protected the CA1 pyramidal neurons from LTCI and increased PDGF-BB immunoreactivity in the CA1 pyramidal neurons post-LTCI. In conclusion, the results demonstrated that LTCI significantly altered PDGF-BB immunoreactivity in pyramidal neurons in the hippocampal CA1 region, whereas IPC increased the immunoreactivity. These findings indicated that PDGF-BB may be associated with IPC-mediated neuroprotection. PMID- 28627607 TI - Inactivation of AKT, ERK and NF-kappaB by genistein derivative, 7 difluoromethoxyl-5,4'-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity. AB - Cancer stem cells (CSCs) have central functions in cancer formation and development. Aberrant expression of AKT, ERK and NF-kappaB signaling pathways have been reported in several types of CSCs. Phytochemicals from dietary compounds possess anti-CSC properties, and have been characterized as promising therapeutic agents for the prevention and treatment of many types of cancers. We previously showed that the newly synthesized genistein derivative, 7 difluoromethoxyl-5,4'-di-n-octylygenistein (DFOG), can inhibit the self-renewal ability of ovarian cancer stem cells (OVCSLCs). In the present study, we further assessed whether various signaling pathways are regulated by DFOG. We found that spheroids derived from the SKOV3 cell line possessed OVCSLC properties and DFOG efficiently inhibited the stemness of the OVCSLCs. In addition, the suppression of spheroid and colony formation by DFOG was associated with inhibition of AKT and ERK1/2 protein phosphorylation, and NF-kappaB activity in OVCSLCs from the SKOV3 cells. Importantly, DFOG inhibited the oncogenicity of the OVCSLCs by activation of FoxO3a and/or inactivation of FoxM1 by the targeting of multiple pro-survival (AKT and ERK1/2) and proinflammatory (NF-kappaB) pathways, providing a new avenue for the treatment of ovarian carcinoma in humans. PMID- 28627608 TI - Silencing of LSD1 gene modulates histone methylation and acetylation and induces the apoptosis of JeKo-1 and MOLT-4 cells. AB - Lysine-specific demethylase 1 (LSD1) has been identified and biochemically characterized in epigenetics; however, the pathological roles of its dysfunction in mantle cell lymphoma (MCL) and T-cell acute lymphoblastic leukemia remain to be elucidated. In this study, we evaluated LSD1, and histone H3 lysine 4 (H3K4)me1 and H3K4me2 expression in patients with MCL and silenced LSD1 in JeKo-1 and MOLT-4 cells, in order to define its role in JeKo-1 and MOLT-4 cell proliferation and apoptosis. We retrospectively analyzed the protein expression of LSD1, and mono- and dimethylated H3K4 (H3K4me1 and H3K4me2), and cyclin D1 and Ki67 in 30 cases of MCL by immunohistochemistry. The correlation of LSD1, H3K4me1 and H3K4me2 with Ki67 was determined by statistical analysis. LSD1 was silenced by small interfering RNA (siRNA). Cell apoptosis and cell proliferation were detected by flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The protein expression levels of LSD1, histone methylated H3K4, histone acetylated H3, cyclin D1, apoptotic proteins, p15 and DNA methyltransferase 1 (DNMT1) were examined by western blot analysis. We demonstrated that LSD1 was upregulated, and that H3K4me1 and H3K4me2 were downregulated in the cases with MCL, compared to those with proliferative lymphadenitis (p<0.05). LSD1 positively correlated with Ki67 in MCL [Cohen's kappa (kappa)=0.667, p<0.01]. There was no significant correlation between H3K4me1 and H3K4me2, and Ki67 (kappa=-0.182, p>0.05, kappa=-0.200, p>0.05). The silencing of LSD1 decreased the levels of the apoptosis-related proteins, Bcl-2, pro-caspase-3 and C-myc, and decreased those of DNMT1 and increased p15, and resulted in the loss of cell viability and the induction apoptosis. The silencing of LSD1 increased the expression of H3K4me1 and H3K4me2, and histone acetylated H3 in the JeKo-1 and MOLT-4 cells. LSD1 siRNA also decreased cyclin D1 expression in the JeKo-1 cells. On the whole, our findings demonstrate that the overexpression of LSD1 may be associated with the pathogenesis in MCL. We demonstrated that the silencing of LSD1 is capable of removing the mono- and dimethyl groups from H3K4, and upregulating the histone acetylation of H3 in JeKo 1 and MOLT-4 cells. The silencing of LSD1 inhibited cell growth and induced cell apoptosis. Of note, in JeKo-1 cells, the silencing of LSD1 decreased cyclin D1 expression, which is one of the genes that contribute to the pathogenesis of MCL. LSD1 may thus be a possible therapeutic target in MCL and acute lymphoblastic leukemia MOLT-4 cells. PMID- 28627609 TI - MicroRNA-149 contributes to scarless wound healing by attenuating inflammatory response. AB - A fibrotic or pathological scar is an undesired consequence of skin wound healing and may trigger a series of problems. An attenuated inflammatory response is a significant characteristic of fetal skin wound healing, which can contribute to the scarless healing of fetal skin. According to deep sequencing data, microRNA 149 (miR-149) expression was increased in mid-gestational compared with that in late-gestational fetal skin keratinocytes. It was demonstrated that overexpression of miR-149 in HaCaT cells can downregulate the expression of pro inflammatory cytokines interleukin (IL)-1alpha, IL-1beta, and IL-6 at basal levels and in inflammatory conditions. Furthermore, miR-149 was revealed to indirectly accelerate transforming growth factor-beta3 and collagen type III expression in fibroblasts, which are essential cells in extracellular matrix remodeling. In a rat skin wound model, miR-149 improved the quality of the arrangement of collagen bundles and reduced inflammatory cell infiltration during skin wound healing. These results indicate that miR-149 may be a potential regulator in improving the quality of skin wound healing. PMID- 28627610 TI - Silencing DEK downregulates cervical cancer tumorigenesis and metastasis via the DEK/p-Ser9-GSK-3beta/p-Tyr216-GSK-3beta/beta-catenin axis. AB - Cervical cancer is the second most common gynecological malignancy. The mechanisms of the genesis and progression of cervical cancer are complicated and not thoroughly understood. DEK is reported as an oncogene in various cancers, such as acute myeloid leukemia, bladder cancer, breast cancer and hepatocellular cancer. However, its role in cervical cancer has not been well studied. In our study, we confirmed the DEK protein as an oncoprotein in cervical cancer tissues which is correlated to cervical cancer FIGO staging and tumor type. Moreover, in vitro loss of DEK inhibited cervical cancer cell proliferation, migration and invasion. We proved that silencing DEK downregulated Wnt/beta-catenin and MMP-9, and silencing DEK increased GSK-3beta activity via regulating its phosphorylation instead of translation. Silencing DEK reduced p-Ser9-GSK-3beta and increased p Tyr216-GSK-3beta, which resulted in beta-catenin degradation. Finally, the xenograft model in nude mice proved that silencing DEK impaired cervical cancer cell tumorigenicity. This research unveiled the function of DEK in tumorigenesis and metastasis via the DEK/p-Ser9-GSK-3beta/p-Tyr216-GSK-3beta/beta-catenin axis in cervical cancer and gave insights into DEK-targeting therapy for patients suffering from cervical cancer. PMID- 28627611 TI - Epithelial-mesenchymal transition and cancer stem cell-like phenotype induced by Twist1 contribute to acquired resistance to irinotecan in colon cancer. AB - Inherent and acquired chemoresistance reduce the effectiveness of irinotecan in the treatment of metastatic colorectal cancer (CRC). However, the molecular mechanisms underlying this resistance process are still unclear. Twist1 is one of the master transcription factors of epithelial-mesenchymal transition (EMT). Our previous study indicated that Twist1 is overexpressed in colon cancer tissues, and demonstrated that Twist1 plays a crucial role in the chemoresistance of CRC. In the present study, we further investigated how Twist1 contribute to acquired resistance to irinotecan in colon cancer. The irinotecan-resistant cells were established by gradual adaptation of increasing irinotecan concentrations in LoVo cells, named LoVo/CPT-11R cells. Results showed that cell viabilities to different anticancer drugs were markedly increased in LoVo/CPT-11R cells compared to LoVo cells. Moreover, LoVo/CPT-11R cells displayed EMT, CSC-like cellular morphology and relative biomarkers were also significantly increased. In addition, overexpressed Twist1 LoVo cells were established by lentivirus transfection assay, named LoVo/Twist1 cells. Results showed that the LoVo/Twist1 cells perform a distinctly decreased sensitivity to irinotecan, downregulated expression of E-cadherin, upregulated expression of cluster of differentiation 44 (CD44), and a significant enhancement of invasion and migration potential by regulation of MMP2 compared with control cells. In contrast, the inhibition of Twist1 transfected with siRNA could enhance the irinotecan sensitivity in LoVo/CPT-11R cells and downregulate the expression of vimentin and CD44. Our data provide evidence that EMT and CSC-like phenotype induced by Twist1 contribute to acquire resistance to irinotecan and enhanced migration and invasion in colon cancer. PMID- 28627612 TI - Targeted inhibition of endoplasmic reticulum stress: New hope for renal fibrosis (Review). AB - Chronic kidney disease (CKD) has a very high mortality rate and remains a global health challenge. Inhibiting renal fibrosis is one of the most promising therapeutic strategies for CKD. Recent studies have indicated that endoplasmic reticulum stress (ERS) serves an active role in the development of acute and chronic kidney disease, especially with regards to renal fibrosis. In the current review, the authors summarize the latest understanding of the role of ERS during the onset of renal fibrosis. ERS promotes renal fibrosis through multiple signaling pathways, such as transforming growth factor-beta, epithelial mesenchymal transition and oxidative stress. In addition, ERS also causes podocyte damage, leading to increased proteinuria and the development of renal fibrosis in rat models. In conclusion, targeted inhibition of ERS may become a promising therapeutic strategy for renal fibrosis. PMID- 28627613 TI - Translocation of enterohemorrhagic Escherichia coli effector Tir to the plasma membrane via host Golgi apparatus. AB - The translocated intimin receptor (Tir) is a canonical type III secretion system effector, secreted by the enterohemorrhagic Escherichia coli (E. coli). This receptor alters the regular cellular processing of host cells, to promote intracellular bacterial replication and evasion of the host immune system. Tir is translocated and integrated into the host cell plasma membrane, a process required for its pathogenic activity in these cells, however, the underlying mechanisms of how this occurs remain to be elucidated. The present study used immunofluorescence and immunoelectron microscopy to demonstrate that the Tir of enterohemorrhagic E. coli was localized to the plasma membrane and colocalized with the 58K Golgi protein of the host cells. Treatment with brefeldin A destroyed the Golgi structure, inhibited the formation of actin pedestal and blocked the localization of Tir on the host cell plasma membrane. The results of the present study suggested that Tir is translocated to the host plasma membrane in a Golgi-dependent manner. It may mimic the activities of eukaryotic secretory proteins in order to make use of the Golgi apparatus for transportation and integration into the plasma membrane. These findings reveal a novel trafficking pathway for the translocation of bacterial secretory effectors to their specific subcellular compartments. PMID- 28627614 TI - CagA promotes proliferation and inhibits apoptosis of GES-1 cells by upregulating TRAF1/4-1BB. AB - Cytotoxin-associated gene A (CagA) is one of the most important virulence factors of Helicobacter pylori, and serves a role in H. pylori-mediated tumorigenesis in gastric cancer. However, the underlying molecular mechanism remains to be elucidated. The present study aimed to investigate the effects of CagA on the proliferation and apoptosis of GES-1 cells, and the underlying mechanism. A CagA eukaryotic expression plasmid was constructed and transfected into GES-1 cells. The mRNA and protein levels of CagA, tumor necrosis factor receptor-associated factor 1 (TRAF1) and tumor necrosis factor receptor superfamily member 9 (4-1BB) were determined using the reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Western blot and ELISA analysis was used to detect the release of interleukin (IL)-8. An MTT assay and flow cytometric analysis was used to assess cell viability and apoptosis, respectively. Ectopic expression of CagA markedly increased TRAF1 and 4-1BB mRNA and protein levels in GES-1 cells. CagA increased the expression and release of IL-8 in GES-1 cells. The expression of CagA significantly promoted the proliferation (P<0.05) and inhibited the apoptosis (P<0.05) of GES-1 cells. In conclusion, CagA upregulated TRAF1/4-1BB, thereby promoting the proliferation and inhibiting the apoptosis of GES-1 cells. PMID- 28627615 TI - Synthesis of folate-chitosan nanoparticles loaded with ligustrazine to target folate receptor positive cancer cells. AB - In addition to its vasodilatory effect, ligustrazine (LZ) improves the sensitivity of multidrug resistant cancer cells to chemotherapeutic agents. To enhance the specificity of LZ delivery to tumor cells/tissues, folate-chitosan nanoparticles (FA-CS-NPs) were synthesized by combination of folate ester with the amine group on chitosan to serve as a delivery vehicle for LZ (FA-CS-LZ-NPs). The structure of folate-chitosan and characteristics of FA-CS-LZ-NPs, including its size, encapsulation efficiency, loading capacity and release rates were analyzed. MCF-7 (folate receptor-positive) and A549 (folate receptor-negative) cells cultured with or without folate were treated with FA-CS-LZ-NPs, CS-LZ-NPs or LZ to determine cancer-targeting specificity of FA-CS-LZ-NPs. Fluorescence intensity of intracellular LZ was observed by laser scanning confocal microscopy, and concentration of intracellular LZ was detected by HPLC. The average size of FA-CS-LZ-NPs was 182.7+/-0.56 nm, and the encapsulation efficiency and loading capacity was 59.6+/-0.23 and 15.3+/-0.16% respectively. The cumulative release rate was about 95% at pH 5.0, which was higher than that at pH 7.4. There was higher intracellular LZ accumulation in MCF-7 than that in A549 cells and intracellular LZ concentration was not high when MCF-7 cells were cultured with folate. These results indicated that the targeting specificity of FA-CS-LZ-NPs was mediated by folate receptor. Therefore, the FA-CS-LZ-NPs may be a potential folate receptor-positive tumor cell targeting drug delivery system that could possibly overcome multidrug resistance during cancer therapy. PMID- 28627616 TI - Distinct cellular phenotype linked to defective DNA interstrand crosslink repair and homologous recombination. AB - Repair of DNA interstrand crosslinks (ICLs) predominantly involves the Fanconi anemia (FA) pathway and homologous recombination (HR). The HR repair system eliminates DNA double strand breaks (DSBs) that emerge during ICLs removal. The current study presents a novel cell line, CL-V8B, representing a new complementation group of Chinese hamster cell mutants hypersensitive to DNA crosslinking factors. CL-V8B exhibits increased sensitivity to various DNA damaging agents, including compounds leading to DSBs formation (bleomycin and 6 thioguanine), and is extremely sensitive to poly (ADP-ribose) polymerase inhibitor (>400-fold), which is typical for HR-defective cells. In addition, this cell line exhibits a reduced number of spontaneous and induced sister chromatid exchanges, which suggests likely impairment of HR in CL-V8B cells. However, in contrast to other known HR mutants, CL-V8B cells do not show defects in Rad51 foci induction, but only slight alterations in the focus formation kinetics. CL V8B is additionally characterized by a considerable chromosomal instability, as indicated by a high number of spontaneous and MMC-induced chromosomal aberrations, and a twice as large proportion of cells with abnormal centrosomes than that in the wild type cell line. The molecular defect present in CL-V8B does not affect the efficiency and stabilization of replication forks. However, stalling of the forks in response to replication stress is observed relatively rarely, which suggests an impairment of a signaling mechanism. Exposure of CL-V8B to crosslinking agents results in S-phase arrest (as in the wild type cells), but also in larger proportion of G2/M-phase cells and apoptotic cells. CL-V8B exhibits similarities to HR- and/or FA-defective Chinese hamster mutants sensitive to DNA crosslinking agents. However, the unique phenotype of this new mutant implies that it carries a defect of a yet unidentified gene involved in the repair of ICLs. PMID- 28627617 TI - Sorafenib controls the epithelial-mesenchymal transition of ovarian cancer cells via EGF and the CD44-HA signaling pathway in a cell type-dependent manner. AB - Cluster of differentiation (CD) 44 and epidermal growth factor (EGF) are closely involved in cellular migration and have been used as stem cell markers. Although the hyaluronan (HA)-binding CD44 is responsible for enhanced cellular motility, the mechanism underlying its actions in various cell types and clinical conditions have yet to be elucidated. In the present study, the multikinase inhibitor sorafenib was used to investigate the diverse effects of EGF stimulation on epithelial-mesenchymal transition (EMT) in ovarian cancer cells using immunoblotting and reverse transcription-polymerase chain reaction. In addition, the association between EGF and CD44/HA signaling pathways in the control of mesenchymal phenotype was determined by gene silencing with small interfering RNA transfection. EGF stimulation of ovarian cancer cells increased cellular migration, mesenchymal transition, CD44 expression and the activation of matrix metalloproteinase (MMP)-2 and MMP-9. Sorafenib effectively suppressed the loss of epithelial characteristics in EGF-treated SK-OV-3 ovarian cancer cells, via targeting the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) pathway. Although treatment of Caov-3 ovarian cancer cells with sorafenib blocked the expression of mesenchymal phenotypes following EGF stimulation, EGF-activated Caov-3 cells exhibited reduced MAPK/ERK signaling. Furthermore, EGF-activated Caov-3 cells increased the expression of hyaluronan synthase 2 and HA-CD44 ligation in EGF-exposed Caov-3 cells, which resulted in the activation of the Ras/Raf/MEK signaling pathway, amplification of migratory activity and the expression of mesenchymal markers, including N-cadherin and vimentin. Furthermore, silencing EGFR in SK-OV-3 cells and CD44 in Caov-3 cells suppressed their migratory activity, through inhibition of the MAPK/ERK pathway. The present results suggested that EGF-mediated signaling may regulate metastasis and invasion of ovarian cancer cells, in a cancer cell type-dependent manner. PMID- 28627618 TI - Hypoxia inducible factor-1alpha regulates autophagy via the p27-E2F1 signaling pathway. AB - Autophagy is a highly conserved process by which the cell contents are delivered to lysosomes for degradation, or are used to provide macromolecules for energy generation under conditions of nutritional starvation. It has previously been demonstrated that cancer cells in hypoxic regions, with an oxygen concentration below the normal physiological level, express hypoxia inducible factor (HIF) 1alpha, in order to adapt and survive. HIF-1alpha is important in the regulation of oxygen homeostasis and the transcription of hundreds of genes in response to conditions of hypoxia, hence maintaining energy and redox homeostasis. To determine if HIF-1alpha modulates autophagy and the underlying molecular mechanisms regulating this process, the human esophageal cancer EC109 and IMR90 human diploid fibroblast cell lines were exposed to normoxic or hypoxic conditions and the expression levels of various proteins subsequently examined. Small interfering RNA was used to silence p27, in order to investigate its role in the process of HIF-1alpha regulated autophagy. Hypoxia induced autophagy in IMR90 cells and it was revealed that immature IMR90 cells demonstrated an increased rate of autophagy compared with mature cells. HIF-1alpha promoted EC109 cell autophagy via positively modulating p27, whereas silencing of p27 abolished the autophagy induced by hypoxia. The present study identified the primary components of the p27-E2F1 signaling pathway by which HIF-1alpha regulates autophagy. A previously unidentified mechanism is here presented, via which cancer cells may generate energy, or obtain macromolecules for survival. PMID- 28627619 TI - Expression of Dicer in rheumatoid arthritis is associated with disease activity and balances the production of TNF-alpha. AB - Gene expression can be altered through RNA interference (RNAi), including microRNA (miRNA) or small interfering RNA. Alterations of miRNAs in rheumatoid arthritis (RA) have been reported, however, the components of the RNAi machinery in RA remain to be fully elucidated. The aim of the present study was to detect the levels of Dicer, Argonaute2 and Drosha, components of the RNAi machinery, in the peripheral blood mononuclear cells of patients with RAusingreverse transcription-quantitative polymerase chain reaction, and to compare the results with disease activity and clinical features. Disease activity was assessed using the Disease Activity Score 28 (DAS28). Transfection and stimulation of cultured cells were conducted to determine the biological function of Dicer. ELISA was used to test tumor necrosis factor (TNF)-alpha protein levels. It was found that the mRNA expression levels of Dicer and Drosha were upregulated in patients with RA, and that the increased level of Dicer was correlated with disease activity in patients with RA. Dicer and TNF-alpha were activated in the serum of patients with RA. The activation of Dicer suppressed the production of TNF-alpha. These results suggested that Dicer can balance the production of TNF-alpha, and thus may serve as a regulator of the immune response in patients with RA. PMID- 28627620 TI - Protective effect of human serum amyloid P on CCl4-induced acute liver injury in mice. AB - Human serum amyloid P (hSAP), a member of the pentraxin family, inhibits the activation of fibrocytes in culture and inhibits experimental renal, lung, skin and cardiac fibrosis. As hepatic inflammation is one of the causes of liver fibrosis, in the present study, we investigated the hepatoprotective effects of hSAP against carbon tetrachloride (CCl4)-induced liver injury. Our data indicated that hSAP attenuated hepatic histopathological abnormalities and significantly decreased inflammatory cell infiltration and pro-inflammatory factor expression. Moreover, CCl4-induced apoptosis in the mouse liver was inhibited by hSAP, as measured by terminal-deoxynucleotidyl transferase mediated nick-end labeling (TUNEL) assay and cleaved caspase-3 expression. hSAP significantly restored the expression of B cell lymphoma/leukemia (Bcl)-2 and suppressed the expression of Bcl-2-associated X protein (Bax) in vivo. The number of hepatocytes in early apoptosis stained with Annexin V was significantly reduced by 28-30% in the hSAP treatment group compared with the CCl4 group, and the expression of Bcl-2 was increased, whereas the expression of Bax and cleaved caspase-3 were significantly inhibited in the hSAP pre-treatment group compared with the CCl4 group. hSAP administration also inhibited the migration and activation of hepatic stellate cells (HSCs) in CCl4-injured liver and suppressed the activation of isolated primary HSCs induced by transforming growth factor (TGF)-beta1 in vitro. Collectively, these findings suggest that hSAP exerts a protective effect againts CCl4-induced hepatic injury by suppressing the inflammatory response and hepatocyte apoptosis, potentially by inhibiting HSC activation. PMID- 28627621 TI - Identification of different macrophage subpopulations with distinct activities in a mouse model of oxygen-induced retinopathy. AB - The aim of the present study was to characterize the phenotypic shift, quantity and role changes in different subgroups of retinal macrophages in a mouse model of oxygen-induced retinopathy (OIR). The mRNA expression levels of macrophage M1 and M2 subgroup marker genes and polarization-associated genes were analyzed by RT-qPCR. The number of M1 and M2 macrophages in our mouse model of OIR was analyzed by flow cytometry at different time points during the progression of OIR. Immunofluorescence whole mount staining of the retinas of mice with OIR was performed at different time points to examine the influx of macrophages, as well as the morphological characteristics and roles of M1 and M2 macrophages. An increased number of macrophages was recruited during the progression of angiogenesis in the retinas of mice with OIR due to the pro-inflammatory microenvironment containing high levels of cell adhesion and leukocyte transendothelial migration molecules. RT-qPCR and flow cytometric analysis at different time points revealed a decline in the number of M1 cells from a significantly high level at post-natal day (P)13 to a relatively normal level at P21, as well as an increase in the number of M2 cells from P13 to P21 in the mice with OIR, implicating a shift of macrophage polarization towards the M2 subtype. Immunofluorescence staining suggested that the M1 cells interacted with endothelial tip cells at the vascular front, while M2 cells embraced the emerging vessels and bridged the neighboring vessel sprouts. Thus, our data indicate that macrophages play an active role in OIR by contributing to the different steps of neovascularization. Our findings indicate that tissue macrophages may be considered as a potential target for the anti-angiogenic therapy of ocular neovascularization disease. PMID- 28627622 TI - Human amnion-derived mesenchymal stem cells protect against UVA irradiation induced human dermal fibroblast senescence, in vitro. AB - The aim of the present study was to determine if human amnion-derived mesenchymal stem cells (HAMSCs) exert a protective effect on ultraviolet A (UVA) irradiation induced human dermal fibroblast (HDF) senescence. A senescence model was constructed as follows: HDFs (104-106 cells/well) were cultured in a six-well plate in vitro and then exposed to UVA irradiation at 9 J/cm2 for 30 min. Following the irradiation period, HDFs were co-cultured with HAMSCs, which were seeded on transwells. A total of 72 h following the co-culturing, senescence associated beta-galactosidase staining was performed and reactive oxygen species (ROS) content and mitochondrial membrane potential (Deltapsim) were detected in the HDFs via flow cytometric analysis. The results demonstrated that the percentage of HDFs, detected via staining with X-gal, were markedly decreased when co-cultured with human HAMSCs, compared with the group that were not co cultured. The ROS content was decreased and the mitochondrial membrane potential (Deltapsim) recovered in cells treated with UVA and HAMSCs, compared with that of cells treated with UVA alone. Reverse transcription-quantitative polymerase chain reaction revealed the significant effects of HAMSCs on the HDF senescence marker genes p53 and matrix metalloproteinase-1 mRNA expression. In addition to this, western blot analysis verified the effects of HAMSCs on UVA induced senescence, providing a foundation for novel regenerative therapeutic methods. Furthermore, the results suggested that activation of the extracellular-signal regulated kinase 1/2 mitogen activated protein kinase signal transduction pathway, is essential for the HAMSC-mediated UVA protective effects. The decrease in ROS content additionally indicated that HAMSCs may exhibit the potential to treat oxidative stress-mediated UVA skin senescence in the future. PMID- 28627623 TI - P18 peptide, a functional fragment of pigment epithelial-derived factor, inhibits angiogenesis in hepatocellular carcinoma via modulating VEGF/VEGFR2 signalling pathway. AB - The P18 peptide is a functional fragment of pigment epithelial-derived factor (PEDF), which is an endogenic angiogenesis inhibitor. This study sought to determine the anti-angiogenic bioactivity of the P18 peptide in hepato-cellular carcinoma (HCC) and to elucidate the underlying mechanism. Xenograft tumour growth assays demonstrated the P18 peptide suppressed angiogenesis of HCC in vivo. Wound healing, Transwell and Matrigel-culture assays indicated that the P18 peptide inhibited the cell migration and tube formation of endothelial cells (ECs) in vitro. Cell viability and apoptosis assessed by Cell Counting Kit-8 (CCK 8) and flow cytometry assays suggested that the P18 peptide inhibited angiogenesis by inducing apoptosis of ECs. Angiogenesis- and signal transduction associated molecules analysed by western blot demonstrated that the P18 peptide targets vascular endothelial cell growth factor receptor 2 (VEGFR2) on ECs. In conclusion, by inhibiting the phosphorylation of VEGFR2, the P18 peptide modulates signalling transduction between VEGF/VEGFR2 and suppresses activation of the PI3K/Akt cascades, leading to an increase in mitochondrial-mediated apoptosis and anti-angiogenic activity. This bioactivity of the P18 peptide may represent a novel therapeutic strategy for the treatment of HCC. PMID- 28627624 TI - Pro-oxidant activity of sulforaphane and cisplatin potentiates apoptosis and simultaneously promotes autophagy in malignant mesothelioma cells. AB - Sulforaphane (SFN) is an isothiocyanate compound derived from glucoraphanin, which is found in cruciferous vegetables, and has been heralded as a chemopreventive and/or chemotherapeutic agent. The present study investigated the effects of SFN on enhancing the anticancer role of cisplatin (cis dichlorodiammineplatinum; CDDP) in H-28 malignant mesothelioma cells. At concentrations demonstrating limited toxicity in MeT-5A normal human mesothelial cells, combination treatment with the two compounds exhibited synergistic growth inhibiting and apoptosis-promoting activities, as demonstrated by a series of proapoptotic events, including reactive oxygen species accumulation, loss of mitochondrial membrane potential, upregulation of p53 expression, increased B cell lymphoma 2 (Bcl-2) associated X protein/Bcl-2 ratio, activation of caspase 3, the occurrence of a sub-G0/G1 peak and an increase in cells with pyknotic and fragmented nuclei, Annexin V-phycoerythrin-positive staining and G2/M phase transition delay in the cell cycle. The phosphorylation levels of Akt and mammalian target of rapamycin were reduced by the combination treatment, which was accompanied by a significant increase in the level of autophagosomal marker protein microtubule-associated protein 1 light chain 3B-II and the accumulation of acidic vesicular organelles. Pretreatment with the antioxidant N acetylcysteine attenuated both apoptosis and autophagy, whereas inhibition of autophagy by bafilomycin A1 potentiated apoptotic cell death following the combination treatment with SFN and CDDP. Considering the pro-oxidant-based combinational approach, the results of the present study provide a rationale for targeting cytoprotective autophagy as a potential therapeutic strategy for malignant mesothelioma. PMID- 28627625 TI - Effects of metal ions on the structure and activity of a human anti-cyclin D1 single-chain variable fragment AD5. AB - Cyclin D1 has become a potential target for anti-tumor therapy. Recently, a novel human anti-cyclin D1 single-chain variable fragment (AD5) was identified, which demonstrated specific binding activity to cyclin D1 and exhibited anti-tumor effects. However, the detailed characteristics of AD5 remain unclear. In the present study, the structure and activity of AD5 in the presence of copper II (Cu2+) or iron III (Fe3+) metal ions was investigated by fluorescence spectroscopy, synchronous fluorescence and enzyme-linked immunosorbent assay. Cu2+ and Fe3+ were able to bind to AD5 and quench the fluorescence intensity of AD5 primarily by static quenching, which slightly altered the conformation of AD5 at temperatures of 293, 298 and 303 K; however, these temperatures demonstrated different effects on the activity of AD5. These results may be of value for the clinical application of anti-cyclin D1 single chain antibodies in the future. PMID- 28627626 TI - HMGB1 regulates P-glycoprotein expression in status epilepticus rat brains via the RAGE/NF-kappaB signaling pathway. AB - Overexpression of P-glycoprotein (P-gp) in the brain is an important mechanism involved in drug-resistant epilepsy (DRE). High-mobility group box 1 (HMGB1), an inflammatory cytokine, significantly increases following seizures and may be involved in upregulation of P-gp. However, the underlying mechanisms remain elusive. The aim of the present study was to evaluate the role of HMGB1 and its downstream signaling components, receptor for advanced glycation end-product (RAGE) and nuclear factor-kappaB (NF-kappaB), on P-gp expression in rat brains during status epilepticus (SE). Small interfering RNA (siRNA) was administered to rats prior to induction of SE by pilocarpine, to block transcription of the genes encoding HMGB1 and RAGE, respectively. An inhibitor of NF-kappaB, pyrrolidinedithiocarbamic acid (PDTC), was utilized to inhibit activation of NF kappaB. The expression levels of HMGB1, RAGE, phosphorylated-NF-kappaB p65 (p p65) and P-gp were detected by western blotting. The relative mRNA expression levels of the genes encoding these proteins were measured using reverse transcription-quantitative polymerase chain reaction and the cellular localization of the proteins was determined by immunofluorescence. Pre-treatment with HMGB1 siRNA reduced the expression levels of RAGE, p-p65 and P-gp. PDTC reduced the expression levels of P-gp. These findings suggested that overexpression of P-gp during seizures may be regulated by HMGB1 via the RAGE/NF kappaB signaling pathway, and may be a novel target for treating DRE. PMID- 28627627 TI - Stromal antigen 2 functions as a tumor suppressor in bladder cancer cells. AB - Stromal antigen 2 (STAG2) is a subunit of the cohesion complex that plays an important role in the normal segregation of sister chromatids during mitosis or meiosis. However, the effect of STAG2 on the bladder cancer cell proliferation, migration, and invasion has not yet been fully clarified. In this study, we aimed to characterize STAG2 expression and functional significance in BC and adjacent normal tissue. Notably, STAG2 expression was markedly lower in BC cells and tumor tissues than their normal counterparts at the gene and protein levels. Moreover, clinicopathological analysis showed that the low STAG2 expression is associated with TNM stage. Functional analysis demonstrated that STAG2 overexpression attenuated cell proliferation via G1-phase arrest, invasion, and migration, and promoted apoptosis in BC cell lines, while the opposite was observed with STAG2 knockdown cells. Furthermore, STAG2 overexpression upregulated E-cadherin, caspase-3, and caspase-7 and downregulated vimentin, matrix metalloproteinase (MMP)2, and MMP9. Collectively, these data suggest that STAG2 acts as a tumor suppressor gene in bladder cancer and may be a potential therapeutic target in BC. PMID- 28627628 TI - Phosphorothioate-modified antisense oligonucleotides against human telomerase reverse transcriptase sensitize cancer cells to radiotherapy. AB - Emergence of resistance, unavoidable systemic toxicity and unsatisfactory efficacy arethe main obstacles for traditional cancer therapy. Combination with phosphorothioate modified antisense oligonucleotides (PS-ASODN) against human telomerase reverse transcriptase (hTERT) may enhance the therapeutic effect of irradiation. However, the effect of PS-ASODN against hTERT on the anti-tumor effects of irradiation in liver cancer remain unclear. In the current study, Walker 256 cells were transfected with hTERT PS-ASODN. Cell proliferation and cell viability were measured using the MTT assay and cell senescence was examined by SA-beta-gal staining. Telomerase activity was determined by telomeric repeat amplification protocol-polymerase chain reaction-ELISA. Cell apoptosis was assayed by flow cytometry and DNA damage was determined by the comet assay.The PS ASODN was demonstrated to have an inhibitory effect on cell proliferation and accelerated effect on cell senescence by inhibiting telomerase activity. PS-ASODN promoted the irradiation-induced inhibition of cell viability and telomerase activity, and irradiation-induced DNA damage and cell apoptosis via the activation of apoptosis-associated proteins. Taken together, these results indicated that combined treatment of PS-ASODN with irradiation significantly enhanced tumor inhibition. Therefore, PS-ASODN provides an experimental foundation for gene therapy and is proposed for application in clinical treatment of liver cancer combined with radiotherapy. PMID- 28627629 TI - Reducing autophagy and inducing G1 phase arrest by aloperine enhances radio sensitivity in lung cancer cells. AB - Aloperine (ALO), an isolated alkaloid from the leaves of Sophora alopecuroides (S. alopecuroides), has been suggested to exhibit anti-inflammatory and antitumor properties, and has been traditionally used to treat various diseases, including cancers. However, little is known about the effects of ALO on the radio sensitivity of lung cancer cells. In the present study, we confirmed that agent ALO inhibits cell growth, promotes cell aopotosis and induces G1 phase arrest and consequently enhanced the radio-sensitivity in radio-resistant lung cancer cells A549/IR. Mechanically, ALO markedly down-regulates the G1/S transition regulators, CDK4/6 and cyclin D1. Moreover, ALO decreases cell autophagy signaling, which is characterized by downregulated Beclin1 and upregulated p62, two key autophagy-associated proteins. We also observed that autophagy inhibitors, bafilomycin A1 (BafA) and chloroquine (CQ), could sensitize the radio resistant cells to the ionizing radiation (IR) treatment, which is similar to the effect of ALO. Taken together, the findings from the present study suggest that inhibition of cell autophagy by ALO shows marked results in radio-resistant lung cancer cells, and is shown to enhance the effect of IR. PMID- 28627631 TI - Effect of OATP1B1 genetic polymorphism on the uptake of tamoxifen and its metabolite, endoxifen. AB - Overexpression lentivirus platform was established of OATP1B1 (organic anion transporting polypeptides 1B1) wild-type and mutant type genetic polymorphism in vitro, and using this platform we investigated and compared the uptake of tamoxifen and its metabolites by mutating the 388 and the 521 bases. The overexpression lentivirus cell platforms were successfully constructed, including OATP1B1*1a-HEK293T and OATP1B1*1b-HEK293T and OATP1B1*5-HEK293T cell model, the infection efficiency is not less than 80%. It shows a high level of gene expression at the mRNA and protein level. The tamoxifen and endoxifen can be taken up into the cells through organic anion transporter polypeptide 1B1, and OATP1B1521T>C inhibits the function of the transport protein, resulting in the content of drug in cell lysis liquid in OATP1B1*5-HEK293T group is lower than in OATP1B1*1a-HEK293T group (tamoxifen or endoxifen), with statistical significance. The content of the drug in cell lysis liquid in OATP1B1*1b-HEK293T group and the OATP1B1*1a-HEK293T group, similar with no statistical significance. These results suggest that tamoxifen and endoxifen can be transported by OATP1B1. However, OATP1B1 521T>C can inhibit the effects of OATP1B1 on tamoxifen and endoxifen in the cells. PMID- 28627630 TI - Gene expression profiling of human blastocysts from in vivo and 'rescue IVM' with or without melatonin treatment. AB - To evaluate the effect of melatonin supplementation in maturation medium for human 'rescue IVM' and investigate differences in transcriptomic profile of blastocysts developed from oocytes matured in vitro with/without melatonin treatment and in vivo, a total of 314 GV oocytes and 320 MI oocytes were collected from 200 patients younger than 35 years old undergoing ICSI cycle. The oocytes were randomly distributed in the control group (no melatonin) and four other groups of varying melatonin concentrations (10-11, 10-9, 10-7, 10-5 mol/l). Gene profiling was performed on blastocysts developed from in vivo maturation oocytes (in vivo group), and in vitro maturation (IVM) oocytes with an optimal concentration of melatonin treatment (IVM-anti group) or without melatonin (IVM group). The ratio of high quality blastocysts was significantly higher in the groups treated with 10-5 mol/l melatonin compared with others groups. The large scale analysis of the transcriptome revealed significant differences in mRNA expression levels. In each group, nine blastocysts were selected for gene expression profiling. The differentially expressed genes were involved in cysteine and methionine metabolism, regulation of apoptotic process, mineral absorption, steroid hormone biosynthesis, Wnt signaling, p53 signaling pathway and other functions. The findings indicated that the IVM procedure may potentially affect DNA methylation and the canonical Wnt signaling pathway. Exogenous melatonin positively influenced quality of blastocysts, which may be mediated via upregulation of p53 signaling and correcting DNA methylation changes caused by 'rescue IVM'. However, this study reflected what was generally referred to as 'rescue IVM' and was not a true reflection of clinical IVM techniques. Therefore, melatonin required further investigation as a promising supplement for use in IVM. PMID- 28627632 TI - Association of single nucleotide polymorphisms in the 5' upstream region of the C4BPA gene with essential hypertension in a northeastern Han Chinese population. AB - A previous study of the authors using microarray analysis indicated that the expression of complement component 4 binding protein (C4BP)A is upregulated in essential hypertension (EH) patients, but the association between C4BPA variations and EH has not yet been clearly demonstrated. Since the 5' upstream region is known to serve important roles in the gene expression regulation, the present study aimed to identify and analyze the association of single nucleotide polymorphisms (SNPs) in the 5' upstream region between the C4BPA gene with EH in a case-control study among a northeastern Han Chinese population through direct sequencing as well as genotype detection. A total of 822 unrelated participants were included. The higher expression level of C4BPA in the peripheral blood of patients with EH was verified through reverse transcription-quantitative polymerase chain reaction and ELISA. A total of four SNPs, rs73079108, rs74148971, rs77660718 and rs11120211 were identified in the 5' upstream region of C4BPA. Association analysis demonstrated that the genotypic frequencies of rs73079108 were significantly different between EH and the control groups (P=0.011), and A allelic frequency was lower in EH (P<0.001). Logistic regression analysis indicated that the rs73079108 polymorphism was closely associated with EH (AA:GA:GG genetic model: P=0.007, odds ratio (OR)=0.604, 95% confidence interval (CI) [0.418-0.873]; AA+GA:GG genetic model: P=0.005, OR=0.806, 95% CI[0.382-0.841]), and the A allele may be a protective factor. Subgroup analysis by sex and BMI presented concordant conclusions in female and non-obese samples. Further analysis indicated that rs73079108 was associated with systolic blood pressure (P<0.001), diastolic blood pressure (P=0.001) and fast blood glucose (FBG) (P=0.021). In addition, rs73079108 GA and GG carriers reported a significant increase in the level of the protein encoded by C4BPA than those of AA carriers. The rs73079108 polymorphism in the 5' upstream region of C4BPA was associated with EH, and rs73079108-A may be an independent predictor. PMID- 28627633 TI - Robust cancer-specific gene expression by a novel cassette with hTERT and CMV promoter elements. AB - We developed and validated a novel hTERT/CMV promoter element-driven gene expression cassette that can robustly enhance cancer-specific gene expression. The following gene expressional elements were located in tandem within the plasmid construct: [hTERT core promoter, cytomegalovirus (CMV) minimized promoter, RU5' sequence, an inserted gene, BGH polyA, hTERT enhancer]; this is hereafter referred to as the hT/Cm-R-hT construct. Using various human cancer cell lines and normal cells, the cancer-specific transcription of the green fluorescent protein (GFP) gene was examined by western blotting and fluorescence microscopy. Cancer-specific gene expression was robustly achieved in the hT/Cm-R hT plasmid in comparison to the other control hT/Cm-driven construct. Notably, the expression level of GFP observed in the hT/Cm-R-hT-driven construct was superior to that of the control plasmid with the conventional CMV promoter in HEK293 cells, which are known to possess higher hTERT activity than normal cells. We next examined the availability of hT/Cm-R-hT in detecting the target GFP expressing cancer cells from human peripheral blood mononuclear cells (PBMCs). The hT/Cm-R-hT plasmid successfully induced cancer-specific gene expression; the robust expression of GFP was observed in target HeLa cancer cells, whereas GFP was not visibly expressed in normal PBMCs. The plasmid allowed for the selective visualization of viable HeLa cancer cells in mixed cell cultures containing up to 10000-fold more PBMCs. These findings indicate that the hT/Cm-R-hT expressional system is a valuable tool for detecting viable cancer cells mixed with normal cells. The current system can therefore be applied to the in vitro detection of cancer cells that are disseminated in the blood and other types of body fluid in vivo. Since the current system can also be applied to other types of vectors, including virus vectors, this approach using the hTERT promoter-based construct is expected to become a valuable tool for enhancing cancer-specific gene expression. PMID- 28627634 TI - DTX3L is upregulated in glioma and is associated with glioma progression. AB - Gliomas are the most common primary brain tumors of the central nervous system (CNS). Due to the poor prognosis of glioma patients, it is urgent to develop more effective therapies. Deltex-3-like (DTX3L), also known as B-lymphoma and BAL associated protein (BBAP), has been reported to play an important role in the progression of many tumors. This study aimed to investigate the clinical significance and biological function of DTX3L in human glioma. Clinically, the protein expression level of DTX3L is increased in glioma tissues compared with that observed in normal brain tissues. Immunohistochemical analysis demonstrated that DTX3L was highly expressed in the glioma tissues and its level was correlated with the grade of malignancy. Multivariate analysis revealed the association between high expression of DTX3L and the poor prognosis of glioma patients. In addition, knockdown of DTX3L by siRNA transfection increased glioma cell apoptosis. Moreover, suppression of DTX3L expression was shown to significantly inhibit the migration and invasion of glioma cells. These data indicate that DTX3L plays an important role in the pathogenic process of glioma, suggesting that DTX3L could be a potential prognostic biomarker for glioma. PMID- 28627635 TI - Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development. AB - Lung cancer is the most common malignancy in humans. An increased population of CD4+Foxp3+ regulatory T cells (Tregs) in the tumor-associated microenvironment plays an important role in cancer immune evasion. The exact role and the involved mechanisms of concomitant H37Rv infection in non-small cell lung cancer (NSCLC) development are still not clear. Here, we showed that H37Rv infection promoted NSCLC cell growth with a higher percentage of Tregs found in draining lymph nodes. We also determined in vitro that H37Rv infection induced macrophage maturation and PD-L1 expression, which promoted Treg proportion, with enhanced proliferation suppression function. Mechanism analysis revealed that AKT-mTORC1 signal was important for PD-L1 expression induced by H37Rv infection. Suppressing of AKT-mTORC1 signal by rapamycin or raptor deficiency showed decreased PD-L1 levels which further reduced Treg proportion in a co-culture system. Finally, tumor-bearing mice injected with H37Rv plus rapamycin enhance the immune response of lung cancer compared with injected with H37Rv alone. This study demonstrated that concomitant H37Rv infection promote NSCLC tumor immune eacape through enhancing Treg proportion. PMID- 28627637 TI - Lentiviral vector-mediated co-overexpression of VEGF and Bcl-2 improves mesenchymal stem cell survival and enhances paracrine effects in vitro. AB - Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for ischemic heart disease; however, the low survival rate of transplanted cells limits their therapeutic efficacy. The aim of this study was to investigate whether the dual genetic modification of vascular endothelial growth factor (VEGF) and B-cell lymphoma-2 (Bcl-2) confers a higher expression level of the target genes, better survival and a stronger paracrine effect in MSCs in an adverse environment than the modification of the individual genes. For this purpse, a lentiviral vector was constructed by using a self-cleaving T2A peptide sequence to link and achieve the co-overexpression of VEGF and Bcl-2. Rat MSCs were transfected to obtain cell lines that exhibited a stable overexpression. An in vitro model of oxygen glucose deprivation (OGD) was applied to mimic the ischemic microenvironment, and cell apoptosis, autophagy and the paracrine effects were then determined. Compared with the MSCs in which individual genes were modified and the control MSCs, the MSCs which were subjected to dual genetic modification had a higher expression level of the target genes, a more rapid proliferation, reduced apoptosis, decreased autophagy and an enhanced paracrine effect. Furthermore, the suppression of autophagy was found to contribute to the inhibition of apoptosis in this in vitro OGD model. On the whole, these data indicate that the co-overexpression of VEGF and Bcl-2 protects MSCs in an ischemic environment by inhibiting apoptosis, suppressing autophagy and enhancing the paracrine effects. PMID- 28627636 TI - Formulation and characterization of EGCG for the treatment of superficial bladder cancer. AB - In the United States, the annual incidence of bladder cancer is approximately 70,000 new cases, with a mortality rate of approximately 15,000/year. The most common subtype (70%) of bladder cancer is superficial, namely hte non-muscle invasive disease form limited to the urothelium. The rate of progression and recurrence is up to 40 and 70%, respectively. Urothelial cell carcinoma of the bladder is typically treated with transurethral resection. The cancerous cells can float onto the adjacent epithelium, increasing the risk of recurrence. The standard of care is to offer adjuvant intravesical agents to reduce the risk of progression and recurrence. Current intravesical treatments are costly and are associated with special biohazard handling protocols. Patients are treated with intravesical therapy with bacillus Calmetter-Guerin (BCG) bacterium, or mitomycin C (MMC) following resection, both of which can cause moderate to severe side effects which are rarely life-threatening. We previously examined the efficacy of epigallocatechin-3-gallate (EGCG) in comparison with MMC to prevent tumor cell implantation/growth in an animal model of superficial bladder cancer. Experiments revile that EGCG is slightly more effective than MMC at decreasing tumor cell implantation and consequent cancer growth in a bladder. This treatment requires the stringent sterile requirement of EGCG. EGCG can be unstable when sterilized at high temperatures. Thus, we evaluated two low temperature sterilization methods, such as ionizing radiation or the filtration method followed by freeze drying. Both methods ensure the sterility of the sample; however, infrared and HPLC analysis revealed a slightly better stability of irradiated EGCG over the filtration method. The concentration of stable free radicals following irradiation was low, which are unlikely to exert any damaging effects to EGCG. Therefore, we consider that radiation will be the preferred method of EGCG sterilization, and that this may prove useful for the effective use of EGCG in the treatment of bladder cancer. PMID- 28627639 TI - MicroRNA-187 inhibits tumor growth and metastasis via targeting of IGF-1R in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the primary and most frequently occurring type of malignant liver cancer, accounting for 70-85% of total liver cancer cases worldwide. It has previously been demonstrated that the aberrant expression of microRNAs (miR) contributes to carcinogenesis and progression of various human malignancies, including HCC. However, mechanisms underlying the differential expression and specific roles of miR-187 in HCC remain to be elucidated, particularly regarding how the modulation of malignant phenotypes in HCC cells occurs. The present study demonstrated that miR-187 was significantly downregulated in HCC tissues and cell lines. Restoration of miR-187 expression inhibited cell proliferation, migration and invasion in HCC. Furthermore, insulin like growth factor 1 receptor (IGF-1R) was demonstrated to act as a direct target gene of miR-187 in HCC. IGF-1R knockdown mimicked the effects of miR-187 overexpression in HCC, resulting in a significant inhibition of cell proliferation, migration and invasion. The results of the present study demonstrated that miR-187 acted as a tumor suppressor in HCC progression via direct targeting of IGF-1R. miR-187 may therefore exhibit the potential to act as a novel and therapeutic target for HCC treatment in the future. PMID- 28627638 TI - Meiotic defects and decreased expression of genes located around the chromosomal breakpoint in the testis of a patient with a novel 46,X,t(Y;1)(p11.3;p31) translocation. AB - Balanced translocations are known to be associated with infertility, spontaneous abortions and birth defects in mammals. Spermatocyte spreading and immunostaining were applied to detect meiotic prophase I progression, homologous chromosome pairing, synapsis and recombination in an azoospermic reciprocal translocation 46,X,t(Y;1)(p11.3;p31) carrier. Histological examination of testicular sections revealed a severely reduced number of germ cells with no spermatids or sperm in the carrier. A significant reduction in XY recombination was observed in the patient. The number of MLH1 foci on autosomes that are not involved in the translocation per cell was also significantly decreased in our patient as compared to the controls, which indicates an inter-chromosomal effect (ICE) of the translocation on recombination. An increase in leptotene (P<0.001) and zygotene (P<0.001) and a decrease in pachytene spermatocytes (P<0.001) were observed in the carrier when compared with the controls, indicating disturbed meiotic progression in the patient. Increased RAD51 foci during pachytene (P=0.02) in the spermatocytes of the patient were noted. A decreased expression of the genes (USP1, INSL5, LEPR and MSH4) critical for meiosis/spermatogenesis and located around the breakpoint region of chromosome 1 was observed in the 46,X,t(Y;1) carrier, which may further exacerbate the meiotic failure such as reduced recombination on autosomes and ultimately cause spermatogenesis arrest. In summary, we report a series of events that may have caused infertility in our 46,X,t(Y;1) carrier. To the best of our knowledge, this is the first report shedding light on how, possibly, a reciprocal translocation affects meiosis at the molecular level in azoospermia patients. PMID- 28627640 TI - The function of miRNAs in hepatocarcinogenesis induced by hepatitis B virus X protein (Review). AB - MicroRNAs are short RNAs that play a crucial role in all biological processes through post-transcriptional regulation for protein-coding genes and inducing mRNA degradation. Hepatitis B virus infection has been considered as a major risk factor in hepatocellular carcinoma, further research indicates that hepatitis B virus X protein (HBx) is one of the critical links of hepatocarcinogenesis. HBx takes part in hepatocarcinogenesis via regulating transcription, signal transduction, apoptosis, protein degradation and DNA repair. miRNA is the important target gene of HBx, their interaction impacts many tumor processes, such as proliferation, apoptosis, invasion, metastasis, differentiation and adipogenesis. In the present study we reviewed the current state of knowledge of regulation pathway of HBx acting on miRNAs, and focused on the role of their interplay in hepatocarcinogenesis. PMID- 28627641 TI - Osteopontin deficiency protects mice from cholesterol gallstone formation by reducing expression of intestinal NPC1L1. AB - Homeostasis of cholesterol is regulated by absorption in the intestine and synthesis in the liver. The authors previously demonstrated that OPN (osteopontin) exhibits the ability to alter hepatic cholesterol metabolism, thus affecting cholesterol gallstone formation in mice. The present study investigated the role of OPN in cholesterol gallstone formation, focusing on its effect on intestinal absorption of cholesterol. OPN gene knockout (OPN-/-) mice and wild type mice were respectively fed with a chow or lithogenic diet (LD) for 8 weeks. Following an 8-week LD period, the incidence of gallstone, bile composition, level of serum and fecal lipids and the expression of intestinal associated genes were analyzed. OPN-/- mice were protected from gallstone formation induced by 8 weeks' LD-feeding. This protective effect from OPN deficiency was associated with alterations in bile composition, including a reduced concentration of biliary cholesterol. Additionally, plasma cholesterol level was decreased in LD-fed OPN-/ mice. The alterations primarily resulted from the decreased expression of intestinal Niemann-Pick C1-like (NPC1 L) 1, which is important in the intestinal absorption of cholesterol. The present study demonstrated that OPN deficiency reduced intestinal absorption of cholesterol by suppressing the expression of NPC1L1, thus protecting mice from cholesterol gallstone formation. PMID- 28627642 TI - Effect of retinoid X receptor-alpha nuclear export inhibition on apoptosis of neurons in vivo and in vitro. AB - Alzheimer's disease (AD), which is characte-rized by excessive apoptosis of neurons, is considered to be a global public health crisis. Retinoid-induced apoptosis is dependent on the orphan nuclear receptor Nur77, a transcription factor that is expressed predominantly in brain tissues. Nur77 nuclear export requires retinoid X receptor-alpha (RXRalpha) as a carrier. However, the involvement of Nur77 in mediating beta-amyloid (Abeta)-induced neuronal apoptosis has not yet been elucidated. The primary aim of the present study was to investigate the potential of Nur77 in Abeta-induced neuron apoptosis, and to evaluate the effect of RXRalpha nuclear export inhibition on neuronal apoptosis. Mouse neuroblastoma Neuro-2a (N2a) cells and mouse hippocampi were treated with Abeta25-35 or Abeta25-35 combined with a RXRalpha ligand, 9-cis-retinoid acid (9 cis-RA), while untreated cells and mice served as controls. The expression of RXRalpha and Nur77 was determined using western blotting and reverse transcription-quantitative polymerase chain reaction analyses, and the translocation of RXRalpha and Nur77 was detected using confocal microscopy. In addition, the apoptosis and viability of N2a cells was detected using flow cytometry and MTT assays, respectively, and the expression of B cell lymphoma 2 (Bcl-2) and Bcl-2 associated X (Bax) was quantified by western blotting. No significant alterations in the protein or mRNA expression levels of RXRalpha and Nur77 in N2a cells or mouse hippocampi among the three groups were observed. Abeta25-35 treatment resulted in elevated cytoplasmic protein ratios of RXRalpha and Nur77 in N2a cells when compared with controls, while combined treatment with Abeta25-35 and 9-cis-RA reduced cytoplasmic protein ratios of RXRalpha and Nur77 to 6.67 and 5.44% in N2a cells, respectively. The MTT assay results revealed a significant reduction in the viability of N2a cells following treatment with Abeta25-35 for 24 h when compared with the controls, while the viability of N2a cells treated with Abeta25-35 plus 9-cis-RA significantly increased from 53.65 to 84.10%. Western blotting revealed elevated Bax expression and reduced Bcl-2 expression in Abeta25-35-treated N2a cells when compared with controls, while combined treatment with Abeta25-35 and 9-cis-RA recovered Bcl-2 expression from 0.46-fold in cells treated with Abeta25-35 alone to 2.44-fold (relative to the control) and decreased Bax expression from 2.52-fold in cells treated with Abeta25-35 alone to 0.99-fold (relative to the control). Flow cytometry analysis revealed that the apoptotic rate of untreated N2a cells was 4.36%, while a 15.1% apoptotic rate was detected in cells exposed to Abeta25-35 for 24 h and a ~5.31% apoptotic rate was observed in N2a cells treated with Abeta25-35 plus 9-cis-RA. In conclusion, treatment with Abeta25-35 or Abeta25-35 plus 9-cis-RA demonstrated no significant effect on the protein and mRNA expression levels of RXRalpha and Nur77. In addition, inhibition of RXRalpha nuclear export reduced neuronal apoptosis. The results of the present study may provide novel insight into the development of novel anti-AD agents. PMID- 28627643 TI - Niclosamide attenuates inflammatory cytokines via the autophagy pathway leading to improved outcomes in renal ischemia/reperfusion injury. AB - Renal ischemia/reperfusion (I/R) injury is a debilitating condition that leads to loss renal function and damage to kidney tissue in the majority of patients with acute kidney disease. Previous studies have indicated that autophagy serves a protective function in renal I/R injury. In the present study, the effect of the anthelmintic niclosamide in the regulation of inflammatory responses in kidney I/R was investigated. A total of 40 Sprague-Dawley rats were randomly divided into the following 5 groups (n=8 in each group): Sham group; renal I/R injury; renal I/R injury plus 3-methyladenine (3-MA) treatment (15 mg/kg); renal I/R injury plus niclosamide (25 mg/kg); and renal I/R injury plus rapamycin (10 mg/kg). The expression levels of autophagy-associated proteins in kidney samples obtained from rats with I/R injury were examined using reverse transcription quantitative polymerase chain reaction and western blotting techniques. In addition, histopathological alterations, the expression of cytokines and renal function were evaluated. Treatment with niclosamide was associated with induction of autophagy and an overall improvement in renal function. There was an increased expression of autophagosome-associated proteins, suggesting a strong correlation between autophagy and improvement of renal function. The increased levels of anti inflammatory cytokines and decreased levels of pro-inflammatory cytokines provided additional evidence that niclosamide may be effective for the treatment of renal I/R injury. Clinical studies are required to further validate the results of the present study. PMID- 28627644 TI - 5-aza-2'-deoxycytidine promotes migration of acute monocytic leukemia cells via activation of CCL2-CCR2-ERK signaling pathway. AB - 5-aza-2'-deoxycytidine (5-Aza) has been approved for clinical use in the treatment of myelodysplastic syndrome and acute myeloid leukemia (AML). It inhibits cell proliferation and induces cell differentiation by demethylating various genes, including tumor suppressor genes, transcription factors, and genes encoding cell cycle inhibitors. Although it has demonstrated efficacy in the clinic, drug resistance following 5-Aza treatment occurs. Cell migration and invasion following 5-Aza treatment are considered to be the key factors underlying drug resistance; however, there is currently limited information regarding the detailed mechanisms involved. In the present study, the THP-1 monocytic leukemia cell line was employed. The anti-leukemic functions of 5-Aza in THP-1 cells were first investigated. The results demonstrated that 5-Aza induced differentiation and inhibited THP-1 cell growth. Notably, 5-Aza significantly promoted THP-1 cell migration. Using reverse transcription polymerase chain reaction, Western blot and enzyme-linked immunosorbent assay analyses, 5-Aza treatment was observed to upregulate the expression of chemokine (C-C motif) ligand 2 (CCL2) and C-C chemokine receptor type 2 (CCR2) in THP-1 cells. In addition, the results demonstrated that CCL2 induced extracellular signal-regulated kinase (ERK) phosphorylation by CCR2 in 5-Aza-treated THP-1 cells. Treatment with a CCR2 or ERK inhibitor inhibited the 5-Aza-induced increase in THP-1 cell migration. In conclusion, the results of the present study provide an insight into the molecular mechanism underlying the 5-Aza-induced increase in THP-1 cell migration, as well as a potential strategy to overcome drug resistance in AML therapy. PMID- 28627645 TI - Therapeutic strategies for alcoholic liver disease: Focusing on inflammation and fibrosis (Review). AB - Excessive alcohol consumption is the most common cause of liver disease in the world. Chronic alcohol abuse leads to liver damage, liver inflammation, fibrosis and hepatocellular carcinoma. Inflammatory cytokines, such as tumor necrosis factor-alpha and interferon-gamma, induce liver injury, which leads to the develo pment of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as interleukin (IL)-6 and IL-10, are also associated with ALD. IL-6 improves ALD via the activation of STAT3 and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. Alcohol consumption promotes liver inflammation by incre-asing the translocation of gut-derived endotoxins to the portal circulation and by activating Kupffer cells through the lipopolysaccharide/Toll-like receptor 4 pathways. Oxidative stress and microflora products are also associated with ALD. Hepatic stellate cells play an important role in angiogenesis and liver fibrosis. Anti-angiogenic therapy has been found to be effective in the prevention of fibrosis. This suggests that blocking angiogenesis could be a promising therapeutic option for patients with advanced fibrosis. This review discusses the main pathways associated with liver inflammation and liver fibrosis as well as new therapeutic strategies. PMID- 28627646 TI - Unifying mechanism in the initiation of breast cancer by metabolism of estrogen (Review). AB - Excessive exposure to estrogen is associated with increased risk of breast cancer. The mechanisms of carcinogenesis in the breast caused by estrogen metabolism include formation of depurinating adducts which are released from DNA to generate apurinic sites, and production of reactive oxygen species (ROS). Excess ROS not only exerts genotoxicity by indirectly increasing genomic instability, but also stimulates progression of mammary carcinogenicity by inducing a redox-associated signaling pathway. Estrogen metabolism enzymes serve an important role in estrogen metabolism. Alterations in the expression and activity of estrogen metabolism enzymes may influence estrogen metabolism homeostasis. The present review discusses the process of estrogen metabolism, the role of estrogen metabolites and ROS in breast carcinogenesis, and the effect of metabolism enzyme polymorphisms on generation of pro-carcinogens and breast cancer susceptibility. PMID- 28627647 TI - Differences in telomerase activity and the effects of AZT in aneuploid and euploid cells in colon cancer. AB - Telomerase-targeted treatments for cancer have received a great deal of attention because telomerase is detected in nearly all cancer cells but is not expressed in most normal tissues. Aneuploidy refers to a chromosome number that is not a multiple of the base chromosome number and can indicate either hypo- or hyperploid chromosome numbers. Most solid tumors are aneuploid. In the present study, we sought to determine whether there are differences in telomerase activity and hTERT gene expression between aneuploid and euploid cells. Furthermore, we investigated telomerase inhibitor 3'-azido-3'-deoxythymidine (AZT)-induced cell apoptosis using the p53-Puma/Noxa/Bax pathway and cell cycle arrest using the p53-p21 pathway in both aneuploid and euploid cells. Our results demonstrate that telomerase activity and hTERT gene expression were higher in aneuploid than in euploid cells. In addition, AZT exerted time- and dose dependent cytotoxic effects on both aneuploid and euploid cells, and aneuploid cells were more sensitive to AZT-induced cytotoxicity. In addition, both the p53 Puma/Noxa/Bax pathway and the cell cycle arrest-associated p53-p21 pathway were involved in the AZT-induced suppression of tumor cells. Importantly, aneuploid cells were more sensitive to AZT-induced cell cycle arrest (p53-p21) and DNA double-strand breaks (gamma-H2AX), while euploid cells were more sensitive to AZT induced apoptosis (p53-Puma/Bax/Noxa). PMID- 28627648 TI - Characterization of a blaNDM-1-harboring plasmid from a Salmonella enterica clinical isolate in China. AB - The plasmid-mediated transmission of antibiotic resistance genes has been reported to be involved in the development of antibiotic resistance in bacteria, and poses a serious threat for the success of bacterial infection treatment and human health worldwide. The present study used a 454 GS-FLX pyrosequencing system to determine the ~140 kb nucleotide sequence of plasmid pHS36-NDM, which was identified in a Salmonella Stanley isolate from the stool sample of an 11-month old girl at Lishui Central Hospital, China, and which contains a New Delhi metallo-beta-lactamase-1 (NDM-1) carbapenem resistance gene (blaNDM-1). The 181 open reading frames encode proteins with functions including replication, stable inheritance, antibiotic resistance and mobile genetic elements. Both horizontal transfer and passage stability-related genes were identified in pHS36-NDM, including a conserved type 4 secretion system and stbA (stable plasmid inheritance protein A). Two multidrug resistance gene islands were identified: The ISEcp1-blaCMY transposition unit which contains a CMY-6 beta-lactamase gene (blaCMY-6) and a quaternary ammonium compound resistance gene (sugE); and the intI1-ISCR27 accessory region, which contained a trimethoprim resistance gene (dfrA12), two aminoglycoside resistance genes (aadA2 and rmtC), a truncated quaternary ammonium compound resistance gene (qacE?1), a sulfonamide resistance gene (sul1), the blaNDM-1 carbapenemase and a bleomycin resistance gene (bleMBL). pHS36-NDM shared high homology with other blaNDM-1-containing plasmids reported in Sweden, Italy and Japan. However, no previous international travel history was documented for the patient and her family, even to neighboring cities. Furthermore, pHS36-NDM is of a different incompatibility group to other published blaNDM-1-carrying plasmids reported in China, with low homology in the surrounding structure of blaNDM-1. The present study will facilitate the understanding of the underlying resistance and dispersal mechanism of pHS36-NDM, and will deepen our recognition of the ongoing spread of the blaNDM-1-containing plasmids. PMID- 28627650 TI - The inhibitory effects of deep-sea water on doxorubicin-induced epithelial mesenchymal transition. AB - It has been revealed that the induction of epithelial-mesenchymal transition (EMT) is associated with drug resistance, leading to tumor recurrence and metastasis. Recent studies have shown that chemotherapeutic agents, besides their therapeutic effects, can induce EMT and enhance invasive and metastatic properties of tumor cells. Previously, we revealed that deep-sea water (DSW) exhibited antimetastatic effects in several human cancer cell lines. In the present study, we investigated the effects of DSW on doxorubicin-induced EMT in MCF-7 human breast cancer cells. When treated with doxorubicin, MCF-7 cells displayed characteristics of EMT, such as, mesenchymal markers (vimentin and fibronectin) and EMT-related transcription factors (Slug and Snail-1) in their RNA expression. However, DSW efficiently inhibited doxorubicin-induced EMT, revealing the decreased expression of vimentin, fibronectin, Slug and Snail-1. Moreover, treatment of MCF-7 cells with DSW significantly suppressed their increased migratory ability by doxorubicin as determined by wound-healing assay. We further demonstrated that the inhibitory effects of DSW on doxorubicin-induced EMT appeared to be mediated by inhibition of the ERK1/2, p38 MAPK and PI3K/AKT signaling pathways. Collectively, our data revealed that DSW has the potential to abolish undesired side-effects of doxorubicin by targeting EMT. PMID- 28627649 TI - Hypoxia serves a key function in the upregulated expression of vascular adhesion protein-1 in vitro and in a rat model of hemorrhagic shock. AB - Hemorrhagic shock following major trauma results in mortality, but the function of vascular adhesion protein-1 (VAP-1), implicated in intracranial hemorrhage, remains unknown. This study aimed to determine whether expression of the AOC3 gene and its encoded protein, VAP-1, is altered by hypoxia. Rat hepatic sinusoidal endothelial cells (RHSECs) and rat intestinal microvascular endothelial cells (RIMECs) were transduced with a viral vector carrying AOC3, and AOC3 mRNA expression levels were measured by reverse transcription-quantitative polymerase chain reaction. VAP-1 protein expression levels were measured by western blot analysis and compared between normoxic and hypoxic conditions. Following this, AOC3 mRNA and VAP-1 protein expression levels in hepatic and intestinal tissues were assessed in a rat model of hemorrhagic shock with or without fluid resuscitation; and serum semicarbazide-sensitive amine oxidase (SSAO) activity was measured by fluorometric assays. The effects of 2 bromoethylamine (2-BEA) on AOC3/VAP-1 levels and 24 h survival were investigated. AOC3 mRNA and VAP-1 protein levels were increased in RHSECs and RIMECs by hypoxia, and in hepatic and intestinal tissues from rats following hemorrhagic shock. Hypoxia increased serum SSAO activity in these animals. 2-BEA reduced AOC3 mRNA and VAP-1 protein levels in hepatic and intestinal tissues from rats following hemorrhagic shock, and appeared to improve survival in animals not receiving resuscitation following hemorrhagic shock. In conclusion, hemorrhagic shock upregulates AOC3/VAP-1 expressions, and this potentially occurs via hypoxia. Therefore, inhibition of VAP-1 may be beneficial in the setting of hemorrhagic shock. Further studies are required to confirm these findings and to establish whether VAP-1 may be a valid target for the development of novel therapies for hemorrhagic shock. PMID- 28627651 TI - SOX4 promotes melanoma cell migration and invasion though the activation of the NF-kappaB signaling pathway. AB - SOX4 has been reported to be abnormally expressed in many types of cancer, including melanoma. However, its role in cell proliferation and metastasis remains controversial. In this study, SOX4 was downregulated or overexpressed in A375, A2058 and A875 melanoma cells by siRNA or lentivirus transfection, respectively. Cell metastasis was observed by Transwell assay. In an aim to elucidate the underlying mechanisms, we determined the expression of nuclear factor-kappaB (NF-kappaB) by real-time PCR assay and western blot analysis. Our data indicated that SOX4 knockdown inhibited melanoma cell migration and invasion. In the melanoma cells in which SOX4 was downregulated, the expression levels of NF-kappaB/p65, matrix metalloproteinase (MMP)2 and MMP9 were suppressed at both the mRNA and protein levels. Conversely, the overexpression of SOX4 promoted melanoma cell migration and invasion. In the melanoma cells in which SOX4 was overexpressed, the expression levels of NF-kappaB/p65, MMP2 and MMP9 were increased at both the mRNA and protein level. On the whole, our findings indicate that SOX4 promotes melanoma cell migration and invasion through the activation of the NF-kappaB/p65 signaling pathway. Thus, SOX4 may prove to be a potential therapeutic target for the treatment of melanoma. PMID- 28627652 TI - Eriodictyol 7-O-beta-D glucopyranoside from Coreopsis tinctoria Nutt. ameliorates lipid disorders via protecting mitochondrial function and suppressing lipogenesis. AB - Coreopsis tinctoria (snow chrysanthemum) has been reported to exert antihyperlipidemic effects. The present study aimed to identify the active compounds of Coreopsis tinctoria and to investigate the molecular mechanisms underlying its effects on lipid dysregulation by measuring lipid levels, reactive oxygen species, lipid peroxidation and fatty acid synthesis. The present results demonstrated that snow chrysanthemum aqueous extracts significantly reduced serum lipid levels and oxidative stress in vivo. The main compounds that were isolated were identified as flavanomarein (compound 1) and eriodictyol 7-O-beta-D glucopyranoside (compound 2). Compounds 1 and 2 demonstrated potent antioxidative properties, including free radical scavenging activity, inhibition of lipid peroxidation, as well as lipid-lowering effects in human HepG2 hepatocellular carcinoma cells treated with free fatty acids (FFAs). Compound 2 was revealed to suppress the elevation of triglyceride levels and inhibit lipid peroxidation following FFA treatment. In addition, it was demonstrated to significantly reduce intracellular levels of reactive oxygen species and improve the mitochondrial membrane potential and adenosine triphosphate levels, thus protecting mitochondrial function in FFA-treated HepG2 cells. Furthermore, compound 2 markedly suppressed the protein expression levels of disulfide-isomerase A3 precursor and fatty acid synthase, thus suppressing FFA-induced lipogenesis in HepG2 cells. In conclusion, the present study identified compound 2 as one of the main active compounds in Coreopsis tinctoria responsible for its lipid-lowering effects. Compound 2 was revealed to possess antihyperlipidemic properties, exerted via reducing oxidative stress, protecting mitochondrial function and suppressing lipogenesis. PMID- 28627653 TI - miR-543 functions as a tumor suppressor in glioma in vitro and in vivo. AB - Gliomas are the most common primary central nervous system tumors and account for approximately 80% of malignant brain tumors. MicroRNAs (miRNAs) are a class of small non-coding, regulatory RNA molecules that mediate the expression levels of specific proteins. As a member of the miRNA family, miR-543 plays a tumor suppressive or an oncogenic role in different types of tumors. However, the expression and role of miR-543 in glioma remain unknown. In the present study, the expression level of miR-543 in glioma cell lines and tissues was investigated. A series of in vitro and in vivo experiments was then performed to elucidate the function of miR-543 in glioma. Moreover, proteomic profiling was applied in this study to determine the landscape of differentially expressed proteins associated with miR-543-mediated carcinogenesis in glioma. We found that the expression level of miR-543 was greatly downregulated in glioma cell lines and tissues. Furthermore, the expression level of miR-543 was negatively associated with high-grade glioma. Functional studies demonstrated that miR-543 in glioma cells induced apoptosis and inhibited growth, the cell cycle, migration and invasion. In addition, the in vivo study showed that miR-543 suppressed tumorigenicity of glioma cells. In the present study, a label-free quantitative proteomic approach was performed and 339 proteins were identified as dysregulated after miR-543 was overexpressed. Among these dysregulated proteins, 165 were upregulated and 174 were downregulated. Moreover, multiple pathways were significantly enriched and were probably involved in miR-543-mediated tumorigenesis, including RNA degradation and the inositol phosphate metabolism pathway. In conclusion, miR-543 may function as a tumor suppressor in glioma and may serve as a future therapeutic target in therapy for patients with glioma. PMID- 28627654 TI - Bioinformatics analysis of transcription profiling of solid pseudopapillary neoplasm of the pancreas. AB - Solid pseudopapillary neoplasm (SPN) of the pancreas is a low-grade malignant neoplasm that accounts for ~5% of cystic pancreatic tumors and ~0.9-2.7% of exocrine pancreatic tumors. The transcription profiling data (GSE43795) of 14 SPN and 6 control samples were downloaded from the Gene Expression Omnibus (GEO) database. Using the Limma package, Student's t-tests were performed to identify differentially expressed genes (DEGs) between SPN and control samples [with the following criterion: False discovery rate (FDR)<0.01 and log2 fold-change (FC)>=3]. Pathway and functional enrichment analyses were performed to investigate the biological processes that the DEGs were involved in. Protein protein interaction (PPI) network and sub-network analyses were conducted to comprehensively understand the interactions between DEGs. The screened DEGs were further annotated according to information relating to transcription factors and tumor associated genes (TAGs). A total of 710 upregulated and 710 downregulated DEGs were observed, including 74 transcriptional factors and 124 TAGs. Membrane metallo-endopeptidase (MME), matrix metalloproteinase (MMP)-2 and MMP-9 were also identified as key TAGs. Following PPI network analysis, hub nodes of epidermal growth factor receptor (EGFR), proto-oncogene tyrosine protein kinase Fyn (FYN), c-JUN (JUN), glucagon (GCG), c-Myc (MYC) and CD44 were identified, the majority of which participate in the epidermal growth factor receptor (ErbB) and gonadotropin-releasing hormone (GnRH) signaling pathways. A sub-network involving 70 gene nodes was also identified, with EGFR as the central gene. MME, MMP-2 and MMP-9 contribute to proliferative diabetic retinopathy and also involved in SPN. The genes EGFR, FYN, JUN, GCG, MYC and CD44 may therefore be key genes in SPN, and the ErbB and GnRH signaling pathways may be an important contributor to SPN progression. PMID- 28627655 TI - Elevated expression of miR-155 is associated with the differentiation of CD8+ T cells in patients with HIV-1. AB - The differentiation and response ofCD8+ T cells is vital in host defense against human immunodeficiency virus type 1 (HIV-1). MicroRNA (miR)-155 is an important regulator of T cell differentiation. However, the profile of miR-155 in HIV-1 infected individuals and its association with CD8+ T cell differentiation remain to be fully elucidated. The present cross-sectional study was performed involving 63 HIV-1-infected patients undergoing highly active antiretroviral therapy (HAART), 31 HAART-naive patients and 35 healthy controls. The levels of miR-155 in CD8+ T cells were detected using reverse transcription-quantitative polymerase chain reaction analysis. Subsets of CD8+ T cell differentiation were detected using flow cytometry. The results revealed that the discord controllers and HAART naive patients showed higher percentages of effector and effector memory cells, and lower percentages of naive cells (P<0.05). The levels of miR-155 in CD8+ T cells from the HIV-1-infected patients were higher, particularly in the discord controllers and HAART naive patients (P<0.01). The expression levels of miR-155 were positively correlated with the percentages of effector and effector memory CD8+ T cells, and negatively correlated with the percentages of naive and central memory CD8+ T cells (P<0.01). Taken together, these findings suggested that the levels of miR-155 in CD8+ T cells of patients with HIV-1 were increased and asso ciated with CD8+ T cell differentiation. PMID- 28627656 TI - Adipokines and free fatty acids regulate insulin sensitivity by increasing microRNA-21 expression in human mature adipocytes. AB - Obesity is a global public health concern and may lead to a variety of complications. Previous studies have indicated that adipokines and energy-source materials contribute to obesity and obesity-associated insulin resistance. MicroRNAs (miRs) are endogenous 20- to 25-nucleotide non-coding RNAs associated with fat metabolism. It has been indicated that miR-21 is associated with adipogenesis and metabolic syndrome. In the present study, the expression of miR 21 in human mature adipocytes was analyzed using reverse transcription quantitative-polymerase chain reaction following treatment with adipokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, leptin, resistin and energy source materials, including free fatty acids (FFAs) and glucose. The current study demonstrated that the expression of miR-21 in human mature adipocytes was upregulated following treatment with TNF-alpha, IL-6, leptin, resistin and FFAs. However, low- and high-glucose did not have an effect on miR 21 expression. These results confirmed that TNF-alpha, IL-6, leptin, resistin and FFAs may contribute to obesity and obesity-associated insulin resistance via upregulating miR-21 in human mature adipocytes. Therefore, miR-21 may be a key regulatory factor of obesity and obesity-associated insulin resistance, and represents a potential therapeutic target for the treatment of these disorders. PMID- 28627657 TI - shRNA-mediated NP knockdown inhibits the apoptosis of cardiomyocytes induced by H1N1pdm2009 influenza virus. AB - Acute influenza-associated myocarditis varies in clinical severity ranging between asymptomatic and fulminant varieties. The most severe cases can result in impaired cardiac function-associated mortality; however, the mechanism underlying the development of viral myocarditis has yet to be fully elucidated. The present study investigated the apoptosis induced in H9C2 cardiomyocytes by infection with the H1N1pdm2009 virus. The H9C2 cells were transfected with nucleoprotein (NP) specific short hairpin (sh) RNA, and viral replication was re-evaluated in H9C2 cells infected with the H1N1pdm2009 virus, as was the apoptosis induced by the virus. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to measure the expression of NP and apoptosis associated molecules. A plaque forming assay was used to quantify viral replication in H9C2 cells. An MTT assay and flow cytometric analysis were performed to determine the virus-associated alterations in cellular viability and apoptosis, respectively. Results demonstrated that the H1N1pdm2009 virus replicated effectively in H9C2 cells and promoted apoptosis in association with the viral infection. The expression levels of apoptosis-associated markers, including released cytochrome c and activated caspase-3 were markedly promoted in the H1N1pdm2009-infected H9C2 cells. However, the NP-specific shRNA-mediated NP knockdown significantly inhibited viral infection in the cells. The virus-induced apoptosis of the H9C2 cells was also significantly reduced by the shRNA, which occurred via a decrease in the number of apoptotic cells through downregulating the levels of apoptosis-associated markers. Taken together, the present study demonstrated the key pathogenic role of NP in H1N1pdm2009-induced apoptosis of cardiomyocytes, and this marker of the influenza virus may be important in influenza virus-associated acute myocarditis. In addition, NP-specific shRNA may be an effective agent for inhibiting influenza virus-induced apoptosis in cardiomyocytes or in influenza virus-associated acute myocarditis. PMID- 28627658 TI - Shikonin promotes adriamycin-induced apoptosis by upregulating caspase-3 and caspase-8 in osteosarcoma. AB - Osteosarcoma is the most common primary malignant bone tumor. Cancer cells employ a host of mechanisms to develop resistance to adriamycin (ADM) or other chemotherapeutic drugs. Shikonin (SK), an active constituent extracted from a Chinese medicinal herb, has been shown to cooperate with ADM in the treatment of osteosarcoma and certain other types of cancer by contributing to the response rate of chemotherapy and the side effects. The aim of the present study was to investigate the role and underlying mechanism of SK in chemotherapy for osteosarcoma. In the present study, a CCK-8 assay was performed to assess cell survival rate in vitro. Western blot analysis was performed to determine the expression levels of B-cell lymphoma 2-associated X protein (Bax), caspase-3, caspase-8, and poly (ADP-ribose) polymerase (PARP). Flow cytometry was used to analyze cell cycle and cell death. The survival rate of cells decreased significantly in a dose- and time-dependent manner when treated with a combination of SK and ADM. Western blot analysis revealed increased expression levels of Bax, caspase-3, caspase-8 and PARP in U2OS and MG63 cells 48 h following treatment with SK and ADM. Flow cytometric analysis showed that the combined treatment of SK and ADM significantly induced apoptosis in the osteosarcoma cells. Taken together SK cooperated with ADM to promote apoptosis, possibly by inducing caspase-3- and caspase-8-dependent apoptosis. SK may be a potential enhancer in the treatment of drug-resistant primary osteosarcoma. PMID- 28627659 TI - Effects of Saikosaponin D on apoptosis in human U87 glioblastoma cells. AB - Saikosaponin D (SSd) is a type of Saponin derivative, which is a component extracted from Bupleurum falactum. SSd has been reported to exert anticancer activities. However, the effects of SSd on gliomas have not been elucidated. The aim of the present study was to investigate the pharmacological functions and potential molecular mechanisms of SSd in human U87 glioblastoma cells. The cells were treated with SSd at various concentrations for 48 h, the cell viability was assessed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay, and the activation of Akt, extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK) and caspase-3 was assessed by western blotting. In addition, apoptosis levels were analyzed with Hoechst 33258 and Annexin V staining. The results demonstrated that treatment of the U87 glioma cells with SSd markedly suppressed cell proliferation in a dose-dependent manner. Meanwhile, SSd treatment enhanced apoptosis in the U87 cells. Furthermore, SSd significantly inhibited the phosphorylation of Akt and ERK, and promoted phosphorylated-JNK and cleaved caspase-3 expression. The present study revealed the potential therapeutic effects of SSd in the treatment of gliomas, and the cytotoxic effects of SSd in U87 cells were at least partly attributed to the depression of phosphatidylinositol 3-kinase/Akt and ERK protein expression levels, and activation of JNK and caspase-3 expression. PMID- 28627660 TI - Inhibition of autophagy by berberine enhances the survival of H9C2 myocytes following hypoxia. AB - Hypoxia may induce apoptosis and autophagy to promote cardiomyocyte injury. The present study investigated the effect of berberine, a natural extract of Rhizoma Coptidis, on hypoxia-induced autophagy and apoptosis in the H9c2 rat myocardial cell line. Expression levels of apoptosis and autophagy markers were upregulated in H9c2 myocytes during hypoxia and cell viability was reduced. However, berberine significantly reduced hypoxia-induced autophagy in H9c2 myocytes, as demonstrated by the ratio of microtubule-associated proteins 1A/1B light chain 3 I/II and the expression levels of B-cell lymphoma 2 (Bcl-2)/adenovirus E1B 19 kDa protein-interacting protein 3, and promoted cell viability. In addition, expression levels of the Bcl-2 anti-apoptotic protein were significantly downregulated, and expression levels of pro-apoptotic proteins Bcl-2-associated X protein and cleaved caspase-3 were upregulated during hypoxia injury in cardiac myocytes. This was reversed by treatment with berberine or the autophagy inhibitor 3-methyladenine, whereas the autophagy agonist rapamycin had the opposite effects, suggesting that berberine reduces myocyte cell death via inhibition of autophagy and apoptosis during hypoxia. In addition, Compound C, a 5' adenosine monophosphate-activated protein kinase (AMPK) inhibitor, reduced apoptosis and autophagy in hypoxic myocytes, suggesting that the activation of the AMPK signaling pathway may be involved in this process. These findings suggested that berberine protects cells from hypoxia-induced apoptosis via inhibition of autophagy and suppression of AMPK activation. Therefore, berberine may be a potential therapeutic agent for the treatment of patients with cardiac myocyte injury and ischemia. PMID- 28627662 TI - MicroRNA-363-3p is downregulated in hepatocellular carcinoma and inhibits tumorigenesis by directly targeting specificity protein 1. AB - microRNAs exhibit important regulatory roles in tumorigenesis and tumor development, such as in hepatocellular carcinoma (HCC). The present study aimed to investigate the expression and functional roles of microRNA (miR)-363-3p in HCC. miR-363-3p expression levels in a number of HCC tissues and cell lines were measured by reverse transcription-quantitative PCR (RT-qPCR). The effects of miR 363-3p expression on HCC cell proliferation, migration and invasion were exa mined by MTT assay, Transwell migration and invasion assay, respectively. The effects of miR-363-3p on its downstream target gene, specificity protein 1 (SP1), were examined by bioinformatics analysis, luciferase reporter assay, RT-qPCR and western blotting. An SP1 overexpression vector was subsequently transfected into HCC cells to assess any selective effects on miR-363-3p in modulating HCC. The results revealed that miR-363-3p expression levels were downregulated in both HCC tissues and cell lines, and this low expression level was correlated with tumor size, tumor-node-metastasis stage and venous infiltration in patients with HCC. Upregulation of miR-363-3p inhibited cell proliferation, migration and invasion in HCC cell cultures. In HCC cells transfected with an SP1 expression vector the miR-363-3p-induced tumor suppressive roles on cell proliferation, migration and invasion were reversed. In conclusion, results from the present study indicated that miR-363-3p is a tumor suppressor in HCC and functions through a mechanism involving SP1, suggesting that miR-363-3p may be a potential new therapeutic target for the treatment of HCC. PMID- 28627661 TI - Altered expression of PPAR-gamma and TRPC in neonatal rats with persistent pulmonary hypertension. AB - Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening disease that is commonly observed in the neonatal intensive care unit. PPHN is pathologically characterized by pulmonary vascular remodeling and, in particular, pulmonary artery smooth muscle cell (PASMC) proliferation. Decreased expression levels of peroxisome proliferator-activated receptor gamma (PPAR-gamma), which is a member of the nuclear receptor hormone superfamily, in combination with elevated expressions of transient receptor potential cation channel, subfamily C, member 1 (TRPC1) and TRPC6 contributes to the PASMC proliferation and excessive pulmonary vascular remodeling in adult pulmonary hypertension (PH). Whether PPAR gamma, TRPC1 and TRPC6 affect the development of vascular remodeling in PPHN model rats remains unknown. The aim of the present study was to investigate the roles of PPAR-gamma, TRPC1 and TRP6 on the pathogenesis of PPHN in rats. The rat model of PPHN was established by exposure to hypoxic conditions and indomethacin treatment. Lung tissues, hearts and blood from PPHN model and Control rats were collected and examined. Parameters, including the percentage of medial wall thickness (WT %), the percentage of medial wall area (WA %), right ventricular hypertrophy (RVH) and the plasma concentration of B-type natriuretic peptide (BNP) were used to estimate the development of PPHN. The expression levels of PPAR-gamma, TRPC1 and TRPC6 in lung tissues were detected by immunohistochemistry, western blotting and reverse transcription-quantitative polymerase chain reaction. Significant increases were observed in the WT %, WA %, RVH and plasma BNP in the PPHN group compare with the Control group (P<0.01). In addition, the mRNA and protein expression levels of PPAR-gamma were markedly downregulated (P<0.05 vs. Control). In the PPHN group, the protein expression levels of TRPC1 and TRPC6 were higher compared to the control group; however, there was no difference in the mRNA expression levels (P>0.05). In conclusion, the present study successfully established a PPHN rat model, and the altered expressions of PPAR-gamma, TRPC1 and TRPC6 in the pulmonary artery located in the lungs of newborn rats with PPHN suggested that these proteins may be important mediators of PPHN. PMID- 28627663 TI - Chondromodulin-I expression and correlation with angiogenesis in human osteoarthritic cartilage. AB - The present study aimed to evaluate the expression and localization of chondromodulin-I (ChM-I) in human osteoarthritic cartilage and its correlation with vascular invasion during osteoarthritis (OA) progression. Osteochondral specimens were collected from patients with OA, as well as from young and aged donors without joint diseases. The grade and the number of vascular channels terminating in non-calcified cartilage of these collected specimens were assessed by Safranin-O/Fast green staining. ChM-I expression in articular cartilage was examined by immunohistochemistry, western blotting and reverse transcription quantitative polymerase chain reaction analyses. ChM-I protein and mRNA levels in articular cartilage appeared to be consistent between the normal young and aged groups (P>0.05). In mildly degene-rated cartilage, ChM-I expression decreased in the extracellular matrix (ECM) of the superficial zone and in the cytoplasm of the superficial and middle zone compared with normal cartilage (P<0.05). In moderately degenerated cartilage, ChM-I protein expression was reduced in the ECM of all zones of articular cartilage, but the immunostaining intensity in the cytoplasm was increased. In severely degenerated cartilage, ChM-I expression was detected primarily in the cytoplasm of the cluster-forming chondrocytes. The density of vascular channels was correlated with the ChM-I expression levels in cartilage ECM. ChM-I expression was reduced in OA cartilage matrix, compared with normal cartilage (both young and aged), and correlated with angiogenesis, indicating that loss of ChM-I may promote angiogenesis in OA cartilage. Expression of ChM-I protein in the cytoplasm was decreased in mildly degenerated cartilage, whereas ChM-I expression increased in moderately degenerated cartilage accompanied by chondrocyte proliferation. These findings suggested that attenuation of ChM-I in the cartilage ECM may be due to decreased expression of ChM-I in cytoplasm of early stage OA and increased depletion of ChM-I in the ECM of advanced stage OA. PMID- 28627664 TI - Sodium tanshinone IIA sulfonate suppresses heat stress-induced endothelial cell apoptosis by promoting NO production through upregulating the PI3K/AKT/eNOS pathway. AB - Heat shock is a life-threatening disease involving systematic inflammation that is closely related to endothelial injury and can lead to multiple organ dysfunction syndrome. Sodium tanshinone IIA sulfonate (STS) has various functions in the vascular endothelium. In the present study, STS is presented to suppress heat stress-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and high ambient temperature-induced systematic inflammation in Sprague Dawley rats. In addition, the STS apoptosis-suppression mechanism was explored. The results presented in the present study demonstrated that the PI3K/AKT pathway was stimulated by STS treatment and that eNOS phosphorylation at Ser-1177 was also upregulated, resulting in increased nitric oxide production in HUVECs under heat stress. Using specific inhibitors, the authors confirmed that STS-induced endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177 was activated by protein kinase B phosphorylation at Ser-473, involving activation of phosphatidylinositol-3 kinase (PI3K). The results suggested that STS suppresses heat stress-induced apoptosis of HUVECs via the PI3K/AKT/eNOS pathway and may be used in heat shock treatment as a vascular endothelial protection mechanism. PMID- 28627665 TI - N-acetylcysteine ameliorates repetitive/stereotypic behavior due to its antioxidant properties without activation of the canonical Wnt pathway in a valproic acid-induced rat model of autism. AB - N-acetylcysteine (NAC) is widely used as an antioxidant, and previous studies have suggested that it may have potential as an alternative therapeutic strategy for the treatment of patients with autism. However, the exact effects of NAC administration on the development of autism, as well as the molecular mechanisms underlying its actions, have yet to be fully elucidated. The present study aimed to investigate the effects of NAC on the oxidative status of rats in a valproic acid (VPA)-induced model of autism, and to examine the involvement of the canonical Wnt signaling pathway in the actions of NAC. Rats exposed to VPA were monitored for behavioral changes, and oxidative stress indicators and key molecules of the canonical Wnt pathway were investigated using colorimetric and western blot analysis, respectively. The present results demonstrated that NAC ameliorated repetitive and stereotypic activity in autism model rats. Furthermore, NAC was revealed to relieve oxidative stress, as demonstrated by the increased glutathione and reduced malondialdehyde levels compared with VPA treated rats. However, NAC did not appear to affect the activity of the canonical Wnt signaling pathway. The present findings suggested that the beneficial effects of NAC in autism may be associated with its antioxidative properties, and may not be mediated by the canonical Wnt pathway. However, it may be hypothesized that the canonical Wnt pathway can be indirectly regulated by NAC through the activation of other signaling pathways or upstream factors. Taken together, the present study has contributed to the elucidation of the molecular mechanisms that underlie the actions of NAC in autism, suggesting its potential for the development of novel therapeutic strategies for the treatment of patients with autism. PMID- 28627666 TI - Expression pattern of Zinc finger protein 185 in mouse testis and its role in regulation of testosterone secretion. AB - Zinc finger protein 185 (ZNF185) belongs to the ZNF family and is involved in cell proliferation and differentiation. To the best of our knowledge, the association between ZNF185 and male reproduction is unknown. In the present study, the expression and localization of ZNF185 in mouse testis, as well as its role in testosterone secretion, cell cycle progression and apoptosis of mouse Leydig cells were investigated. The results of the immunofluorescence analysis indicated that ZNF185 was highly expressed in Leydig cells of the mouse testis, and primarily localized in the cytoplasm. The results of quantitative polymerase chain reaction and western blot analyses further validated that ZNF185 expression was significantly higher in Leydig cells and sperm compared with that in Sertoli cells. Subsequently, the expression pattern of ZNF185 in mouse testis was determined at different developmental stages. The results demonstrated that the expression of ZNF185 was highest in the testis of 10-week-old mice and lowest in 2-week-old mice. Furthermore, the role of ZNF185 in Leydig cells of the mouse testis was investigated. Different concentrations of luteinizing hormone (LH) were used to stimulate the Leydig cells and subsequently the expression of ZNF185, and testosterone concentration was detected. The results revealed that LH upregulated the expression of ZNF185 and testosterone secretion, and ZNF185 expression was significantly positively correlated with testosterone secretion. To further validate whether ZNF185 was involved in testosterone secretion, lentiviral-mediated RNA interference was used to knock down ZNF185 expression in Leydig cells. The results demonstrated that ZNF185 expression and testosterone secretion of Leydig cells were decreased significantly. In addition, the results demonstrated that the knockdown of ZNF185 expression did not significantly affect cell cycle progression or apoptosis. Taken together, the results of the present study revealed that ZNF185 was highly expressed in Leydig cells of the testis and involved in the secretion of testosterone. These results have contributed to the elucidation of the mechanism underlying male reproduction and may provide a novel target for the treatment of infertility, and the development of a contraceptive vaccine. PMID- 28627667 TI - Loss of miR-449a-caused PrLZ overexpression promotes prostate cancer metastasis. AB - Distant metastasis is the worst prognostic factor for PCa patients. It has been reported that miR-449a enhances radiosensitivity of prostate cancer cells, but the function of miR449a in metastasis of prostate cancer is mainly unknown. In the present study, we strove to investigate the function and diagnostic value of miR-449a in metastasis of prostate cancer. qRT-PCR was used to quantify the expression of miR449a and PrLZ in PCa cell lines and tissues. we found that miR449a expression was decreased in PCa cell lines. Moreover, miR-449a was downregulated in PCa tissues, especially in primary lesion tissues of metastatic PCa patients. CCK8, FACS, transwell and tube formation assay were performed to assess growth and metastasis of PCa cells in vitro. Lentivirus mediated miR-449a overexpression suppressed proliferation of LNcap and PC-3, and miR-449a also significantly inhibited invasion and angiogenesis ability of LNcap and PC-3. IHC showed that PrLZ was upregulated in PCa tissues. Luciferase assay and western blotting verified that miR-449a targeted PrLZ expression. Moreover, PrLZ shRNA also significantly suppressed proliferation and metastasis of LNcap and PC-3. In addition, western blotting revealed that miR-449a overexpression and PrLZ shRNA all remarkably inhibited the stemness features in LNcap and PC-3. Furthermore, BALB/c nude mouse subcutaneous xenograft model was uesd to verify the function of miR-449a and PrLZ. Our results showed that miR-449a and PrLZ shRNA significantly suppressed PC-3 tumorigenesis and metastasis in vivo. Our studies suggested that miR-449a decreased in malignant process of PCa and was accompanied by excess expression of PrLZ. The loss of miR-449a caused PrLZ overexpression regulated prostate cancer progression and metastasis via regulating the stemness features of prostate cancer cells. The diagnostic value of miR-449a as a distant metastasis predictor of PCa needs further investigation. PMID- 28627668 TI - Potential genetic damage to nematode offspring following exposure to triclosan during pregnancy. AB - Triclosan (TCS) is widely used as broad-spectrum antibacterial agent. However, it may threaten the health of human offspring if the mother is exposed to TCS during pregnancy. The present study aimed to identify potential mechanisms behind the toxic effect of TCS on the offspring of Caenorhabditis elegans (C. elegans), using this nematode as a suitable animal model. The results of the current study demonstrated that the locomotory behavior and reproductive capacity of C. elegans offspring was severely affected by prenatal exposure to different concentrations of TCS. A high-throughput gene microarray was performed to investigate molecular alterations in C. elegans offspring following TCS exposure during pregnancy. Microarray results indicated that 113 genes were differentially expressed following TCS treatment compared with the control group. Gene ontology analysis demonstrated that these dysregulated genes were primarily associated with neuron development, muscular strength and reproduction. Pathway analysis results demonstrated that differentially expressed genes participated in several signaling pathways, including arginine, proline, and purine metabolism, progesterone-mediated oocyte maturation and neuroactive ligand-receptor interaction. Finally, 7 TCS toxicity-associated genes were confirmed by reverse transcription-quantitative polymerase chain reaction. The present study indicates that TCS exposure during pregnancy may disturb the locomotory behavior and reproductive capacity of C. elegans offspring, primarily through 7 TCS toxicity associated genes, which merits further study from an environmental health perspective. PMID- 28627669 TI - Recovery of spinal cord injury following electroacupuncture in rats through enhancement of Wnt/beta-catenin signaling. AB - Electroacupuncture (EA) has been demonstrated to promote the functional recovery of neurons following spinal cord injury (SCI); however, the mechanisms underlying its effects have yet to be elucidated. The Wnt/beta-catenin signaling pathway has been implicated in the regulation of the balance between growth, proliferation and differentiation of neural precursor cells. The present study aimed to investigate the effects of EA therapy on Wnt/beta-catenin-regulated gene expression and neuronal recovery in rats with SCI. The Allen method was used to establish SCI in rats, and alterations in Wnt1 and Nestin mRNA and protein expression levels in response to SCI were determined on days 1, 3, 7 and 14 post injury using reverse transcription-quantitative polymerase chain reaction and western blot analysis. To evaluate the effects of EA treatment on SCI, the following four treatment groups were employed: SCI, SCI + EA, SCI + lithium chloride (LiCl) and SCI + LiCl + EA. The protein expression levels of Wnt1, Nestin and nuclear beta-catenin were evaluated on day 3 post-treatment, and neuronal nuclear antigen (NeuN) protein expression levels were evaluated on day 21 post-treatment using western blot analysis. The Basso, Beattie and Bresnahan scoring method was used to evaluate spinal cord recovery on day 28 post-treatment across the four treatment groups. EA therapy at the Dazhui and Mingmen acupuncture points significantly increased the expression levels of Wnt1, Nestin, beta-catenin and NeuN, thus suggesting that EA therapy may promote spinal cord recovery following injury. The underlying mechanism was demonstrated to involve enhanced Wnt/beta-catenin signaling, which may promote the proliferation and differentiation of neural stem cells. However, further studies are required to elucidate the detailed effects and underlying molecular mechanisms of EA therapy on SCI. PMID- 28627671 TI - Downregulation of Notch1 inhibits the invasion and metastasis of human gastric cancer cells SGC7901 and MKN74 in vitro through PTEN activation and dephosphorylation of Akt and FAK. AB - Migration and invasion are both vital causes of mortality in patients with gastric cancer. Therefore, the inhibition of these tumour cell processes is of great importance in gastric cancer therapy. Activation of Notch has been reported in many cancers. The critical role of Notch and its regulation in tumourigenesis has been noted. Although the studies on Notch in the field of cancer have been performed extensively, the role of Notch1 signalling in gastric cancer requires further study. Inactivation of PTEN has been observed in the development of many malignant tumors, and loss of PTEN function has been implicated in tumorigenic processes. Notch acts as an upstream signalling pathway that regulates PTEN activities. However, the effect of Notch on invasion and metastasis in gastric cancer and the regulation of PTEN during this process remain poorly understood. In the present study, small interfering RNA (siRNA) was used to knock down Notch1 expression in gastric cancer cell lines SGC7901 and MKN74. The mRNA and protein expression of Notch1, PTEN, Akt and FAK were measured upon depletion of Notch1. phospho-PTEN, phospho-Akt and phospho-FAK expression were measured using western blot analysis. Migration and invasion assays were also used after Notch1 depletion. Our results showed that the knockdown of Notch1 leads to the inhibition of cell invasion and metastasis of human gastric cancer cells SCG7901 and MKN74 in vitro. Compared to control and mock groups, PTEN activities were significantly promoted following depletion of Notch1, and the expression of Phospho-Akt and Phospho-FAK were downregulated. Taken together, our findings suggest that Notch1 could be used as a therapeutic target to inhibit cell invasion and migration in gastric cancer. PMID- 28627670 TI - Intermedin improves cardiac function and sympathetic neural remodeling in a rat model of post myocardial infarction heart failure. AB - Emerging evidence has suggested that intermedin (IMD), a novel member of the calcitonin gene-related peptide (CGRP) family, has a wide range of cardioprotective effects. The present study investigated the effects of long-term administration of IMD on cardiac function and sympathetic neural remodeling in heart failure (HF) rats, and studied potential underlying mechanism. HF was induced in rats by myocardial infarction (MI). Male Sprague Dawley rats were randomly assigned to either saline or IMD (0.6 ug/kg/h) treatment groups for 4 weeks post-MI. Another group of sham-operated rats served as controls. Cardiac function was assessed by echocardiography, cardiac catheterization and plasma level of B-type natriuretic peptide (BNP). Cardiac sympathetic neural remodeling was assessed by immunohistochemistical study of tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) immunoreactive nerve fibers. The protein expression levels of nerve growth factor (NGF), TH and GAP43 in the ventricular myocardium were studied by western blotting. Ventricular fibrillation threshold (VFT) was determined to evaluate the incidence of ventricular arrhythmia. Oxidative stress was assessed by detecting the activity of superoxide dismutase and the level of malondialdehyde. Compared with rats administrated with saline, IMD significantly improved cardiac function, decreased the plasma BNP level, attenuated sympathetic neural remodeling, increased VFT and suppressed oxidative stress. In conclusion, these results indicated that IMD prevents ventricle remodeling and improves the performance of a failing heart. In addition, IMD attenuated sympathetic neural remodeling and reduced the incidence of ventricular arrhythmia, which may contribute to its anti-oxidative property. These results implicate IMD as a potential therapeutic agent for the treatment of HF. PMID- 28627672 TI - Inhibition of Skp2 suppresses the proliferation and invasion of osteosarcoma cells. AB - Osteosarcoma (OS) is a common bone tumor that mainly affects children and young adults. S-phase kinase-associated protein 2 (Skp2) has been characterized to play a critical oncogenic role in a variety of human malignancies. However, the biological function of Skp2 in OS remains largely obscure. In the present study, we elucidated the role of Skp2 in cell growth, cell cycle, apoptosis and migration in OS cells. We found that depletion of Skp2 inhibited cell growth in both MG-63 and SW 1353 cells. Moreover, we observed that depletion of Skp2 triggered cell apoptosis in two OS cell lines. Furthermore, downregulation of Skp2 induced cell cycle arrest in the G0/G1 phase in OS cells. Notably, our wound healing assay results revealed that inhibition of Skp2 suppressed cell migration in OS cells. Invariably, our western blot results demonstrated that depletion of Skp2 in OS cells inhibited activation of pAkt and increased p27 expression in OS cells, suggesting that Skp2 exerted its oncogenic function partly through the regulation of Akt and p27. Our findings revealed that targeting Skp2 could be a promising therapeutic strategy for the treatment of OS. PMID- 28627673 TI - Release characteristics of bone-like hydroxyapatite/poly amino acid loaded with rifapentine microspheres in vivo. AB - Bone-like hydroxyapatite/poly amino acid (BHA/PAA) is a potential bone repair material. Rifapentine-loaded poly(lactic-co-glycolic acid) microspheres (RPMs) are bioactive and efficient controlled-release delivery systems used in vitro. The aim of the present study was to investigate the in vivo drug release characteristics of RPM-loaded BHA/PAA on a rabbit model of bone defect. RPM was combined with BHA/PAA to obtain the drug-loaded, slow-releasing bioactive material. Bone defects were generated in New Zealand white rabbits and the rabbits were then implanted with RPM-loaded BHA/PAA. High-performance liquid chromatography (HPLC) was used to determine the concentrations of rifapentine in the plasma and the local muscle tissues of the treated rabbits. Hematoxylin and eosin (H&E) staining and biochemical analyses were performed to elucidate potential side effects of RPM-loaded BHA/PAA on the heart, liver and kidney histopathology and functions of the treated rabbits. The biocompatibility and osteogenic ability of RPM-loaded BHA/PAA was evaluated by H&E staining. The results demonstrated that the material was completely degraded and absorbed at 12 weeks following implantation and new trabecular bone and cartilage tissues had formed. The in vivo release tests revealed that RPM-loaded BHA/PAA exhibited sustained release profiles of rifapentine and the drug concentration in the muscle tissues remained higher than the minimum inhibitory concentration of rifapentine against Mycobacterium tuberculosis for as long as 12 weeks. In addition, RPM-loaded BHA/PAA had no long-term side effects to the heart, liver and kidney of the treated rabbits. In conclusion, the present study demonstrated that RPM-loaded BHA/PAA slowly and continuously released rifapentine in vivo and exhibited no side effects on heart, liver and kidney tissues and function. Furthermore, RPM-loaded BHA/PAA promoted new bone formation, while it was gradually degraded and absorbed. The present study provided a theoretical basis for the potential advancement in developing novel treatments for osteoarticular tuberculosis. PMID- 28627674 TI - miR-200c serves an important role in H5V endothelial cells in high glucose by targeting Notch1. AB - Diabetic vasculopathy is the leading cause of impairment and death in diabetic patients, a variety of factors are involved in its underlying pathological process, however, endothelial cell (EC) dysfunction serves a significant role in the process. MicroRNAs (miRNAs) have emerged as potential therapeutic candidates, due to their ability to regulate multiple targets involved in ECs. The aim of the present study was to investigate the role of miR-200c in regulating ECs in high glucose condition. To investigate the role of miR-200c in regulating hyperglycemia induced ECs by targeting Notch1, ECs H5V cells were cultured in high sugar conditions to initiate the inhibition of Notch1, the same cells in normal medium as the control. H5V cells were transfected with miR-200c mimics, miR-200c inhibitors or scrambled oligonucleotide controls, respectively. Notch1 and Hes1 mRNA and protein expression level were detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. The present study reported that miR-200c was highly expressed by high glucose stimulation in H5V cells, however Notch1 was inhi-bited by high glucose, and it was also depressed by miR-200c in high glucose conditions. Notch1 was identified as the target gene of miR-200c, luciferase reporter assays confirmed the biochemical relationship for miR-200c decreasing Notch1. The current findings revealed that miR-200c may inhibit Notch1 expression in high glucose conditions, which suggested that miR-200c mediating Notch1/Hes1 may involve in the process of vascular damage caused by hyperglycemia. PMID- 28627675 TI - Distinctive crypt shape in a sessile serrated adenoma/polyp: Distribution of Ki67 , p16INK4a-, WNT5A-positive cells and intraepithelial lymphocytes. AB - Serrated lesions in the colorectum are currently predominantly classified as hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs) according to their morphology. However, the histological morphology and the molecular changes in the serrated lesions are still unclear. We performed immunohistochemistry for Ki67, p16INK4a, and WNT5A in human HPs (n=22), SSA/Ps (n=41), and TSAs (n=19). The distribution of Ki67 and p16INK4a positive cells in TSAs was different from that in HPs and SSA/Ps. Co expression of Ki67 and P16INK4a was infrequent in HPs and SSA/Ps; p16INK4a positive cells were found in the crypt cleft and stromal WNT5A-positive stromal cells were localized near the cleft in SSA/Ps, while intraepithelial lymphocytes (IELs) in SSA/Ps were more abundant than HPs. In conclusion, our study provides evidence that HPs branch because of the increase in and patchy distribution of senescent and proliferative cells, with increased and misdistributed stromal and inflammatory cells, which might contribute to creation of L- and/or T-shaped crypts, which are of distinctive shapes in SSA/Ps. Our findings may facilitate better understanding and therapy in the serrated lesions. PMID- 28627676 TI - Luteolin inhibits angiogenesis by blocking Gas6/Axl signaling pathway. AB - Growth arrest-specific protein 6 (Gas6) induces the activation of Axl receptor tyrosine kinase (Axl), which plays an important role in angiogenic processes, including proliferation, migration, invasion, tube formation and pericyte recruitment of endothelial cells. The inhibition of Gas6/Axl pathway has been demonstrated to be an effective anti-angiogenic therapy. Luteolin, which is a natural active flavonoid, has been reported to possess anti-angiogenic effects. However, the underlying mechanism of luteolin in anti-angiogenesis is not fully understood. Herein, we report that luteolin significantly inhibited the Gas6 induced proliferation, migration, invasion and tube formation of human microvascular endothelial cells (HMEC-1s) in vitro, and suppressed the Gas6 induced recruitment of human brain vascular pericytes (HBVPs) to the endothelial tubes. Luteolin also suppressed Gas6-induced microvessel sprouting in aortic ring assay and neovascularization in chick chorioallantoic membrane assay. The anti angiogenic effect of luteolin may be associated with the inhibition of the Gas6/Axl pathway and its downstream phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways. Taken together, the present study provides new evidence regarding an anti-angiogenic mechanism of luteolin, and supports the notion that the dietary intake of luteolin contributes to the treatment of pathological angiogenesis. PMID- 28627677 TI - Integrated analysis of the potential roles of miRNA-mRNA networks in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) is a type of breast cancer where the tumor cells are negative for the estrogen, progesterone and human epidermal growth factor 2 receptors. To date, expression profiling of microRNA (miRNA/miR) and mRNA sequences have been widely applied for the diagnosis of TNBC. In the present study, an integrated analysis of miRNA-mRNA profiling arrays was performed. A total of five dysregulated miRNAs in patients with TNBC were identified, including upregulated miR-558 expression and downregulated miR-320d-1, miR-548v, miR-99a and miR-21 expression. In addition, 49 potential target mRNA sequences were identified. Bioinformatics analyses were performed on the identified miRNAs and mRNAs, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway and miRNA-mRNA network analyses. A total of 31 GO terms and three signaling pathways were identified. The results indicated that the differentially expressed miRNAs and their potential target mRNAs may affect the pathogenesis of TNBC, and may therefore be considered as promising biomarkers for the early diagnosis and targeted therapy of patients with TNBC. PMID- 28627678 TI - Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model. AB - Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), shows superior efficacy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations (EGFR Mut+). However, almost all tumors eventually develop resistance to erlotinib. Recently, the Phase II JO25567 study reported significant prolongation of progression-free survival (PFS) by erlotinib plus bevacizumab combination compared with erlotinib in EGFR Mut+ NSCLC. Herein, we established a preclinical model which became refractory to erlotinib after long-term administration and elucidated the mode of action of this combination. In this model, tumor regrowth occurred after remarkable shrinkage by erlotinib; regrowth was successfully inhibited by erlotinib plus bevacizumab. Tumor vascular endothelial growth factor (VEGF) was greatly reduced by erlotinib in the erlotinib-sensitive phase but significantly increased in the erlotinib-refractory phase despite continued treatment with erlotinib. Although EGFR phosphorylation remained suppressed in the erlotinib-refractory phase, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) were markedly higher than in the erlotinib-sensitive phase; among these, pERK was suppressed by erlotinib plus bevacizumab. MVD was decreased significantly more with erlotinib plus bevacizumab than with each drug alone. In conclusion, the erlotinib plus bevacizumab combination demonstrated promising efficacy in the B901L xenograft model of EGFR Mut+ NSCLC. Re-induction of VEGF and subsequent direct or indirect VEGF-dependent tumor growth was suggested as a major mechanism of erlotinib resistance, and erlotinib plus bevacizumab achieved remarkably prolonged antitumor activity in this model. PMID- 28627680 TI - BMP-7 suppresses excessive scar formation by activating the BMP-7/Smad1/5/8 signaling pathway. AB - Scarring is the inevitable consequence of wound repair, which may cause significant physical and mental pain to patients when excessive. Bone morphogenetic protein-7 (BMP-7) has been proved to inhibit TGF-beta-induced fibrosis in various tissues including dermal papilla cells. However, the effect of BMP-7 on hypertrophic scarring, a common proliferative disorder of dermal fibroblasts, has not been determined. To overcome this problem, the present study established a mouse model of thermal injury to investigate the inhibitory effects of BMP-7 on scar formation. The histological analysis of scar tissues was performed by H&E and Masson's trichrome staining. Western blot assay was used to determine the level changes of related proteins and TUNEL assay was performed to assess the apoptosis of scar tissues. The results demonstrated that BMP-7 promoted wound healing and inhibited scar formation when compared with untreated mice. Collagen deposition and the expression of fibrotic proteins were suppressed in the scar tissues of mice treated with BMP-7. In addition, BMP-7 induced fibroblast apoptosis in scar tissues. Furthermore, activation of the BMP 7/Smad1/5/8 signaling pathway may have been involved in the inhibitory effects of BMP-7 on scar formation. In conclusion, the results of the present study indicate that BMP-7 may inhibit excessive scar formation via activation of the BMP 7/Smad1/5/8 signaling pathway. The results present a potential alternative therapeutic strategy for the treatment of hypertrophic scarring. PMID- 28627681 TI - B7-H3 promotes the proliferation, migration and invasiveness of cervical cancer cells and is an indicator of poor prognosis. AB - B7-H3 is an immune regulatory molecule whose aberrant expression in tumors is associated with adverse outcomes. Upregulation of B7-H3 may promote tumor cell proliferation and metastasis in vitro, but the role of B7-H3 in cervical cancer has not yet been investigated. We measured B7-H3 expression in 90 cervical cancer patient and 20 non-cervical lesion patient tissues using immunohistochemistry and in 30 cervical cancer patient and 30 healthy donor blood samples using ELISA. The association of B7-H3 expression and the prognosis of cervical cancer patients was investigated. B7-H3 knockdown in CaSki and SiHa cell lines was performed using small hairpin (sh)RNA lentiviral transfection and B7-H3 overexpression in CaSki and HeLa cell lines was performed using plasmid-vector lentivirus transduction. Cell proliferation, invasion and migration were then measured using MTT and Transwell assays in vitro. B7-H3 expression was significantly higher in the cervical cancer tissues compared to that noted in the normal cervical tissues (mean 72.22 vs. 15.00%; p<0.001). Using Kaplan-Meier and Cox analyses, our data revealed that patients with strong intensity staining were significantly more likely to have a worse prognosis. The B7-H3 level in cervical cancer patient blood was significantly higher than that in the normal donors (13.41+/-6.12 vs. 9.90+/-3.16 ng/ml; p=0.007). MTT assay revealed that high expression of B7-H3 promoted cervical cancer cell proliferation. Transwell assay data revealed that high expression of B7-H3 enhanced cervical cancer cell migration and invasion (CaSki, p=0.003; HeLa, p=0.03). In conclusion, expression of B7-H3 was significantly higher in cervical cancer tissues compared to normal cervical tissues, and this high expression was associated with worse prognosis for cervical cancer patients. In addition, B7-H3 promoted proliferation, invasion and migration of cervical cancer and may be a potential target for treating cervical cancer. PMID- 28627679 TI - Exosomes: New players in cancer (Review). AB - The past decade has witnessed an exponential increase in research on exosomes. For many years considered to be extracellular debris, exosomes are now considered important mediators in intercellular communication. The capability of exosomes to transfer proteins, DNA, mRNA, as well as non-coding RNAs has made them an attractive focus of research into the pathogenesis of different diseases, including cancer. Increasing evidence suggests that tumor cells release a large sum of exosomes, which may not only influence proximal tumor cells and stromal cells in local microenvironment, but also can exert systemic effects when participating in blood circulation. In this study, we review the current understanding on this topic. The literature outlines two broad facets of exosomes in cancer: 1) promotion of tumor growth, tumorigenesis, tumor angiogenesis, tumor immune escape, drug resistance, and metastasis and 2) their role as promising biomarkers for cancer diagnosis and even as potential treatment targets for cancer patients. PMID- 28627682 TI - Microvesicles released from human embryonic stem cell derived-mesenchymal stem cells inhibit proliferation of leukemia cells. AB - Human embryonic stem cell derived-mesenchymal stem cells (hESC-MSCs) are able to inhibit proliferation of leukemia cells. Microvesicles released from human embryonic stem cell derived-mesenchymal stem cells (hESC-MSC-MVs) might play an important part in antitumor activity. Microvesicles were isolated by ultracentrifugation and identified under a scanning electron microscopy and transmission electron microscope separately. After 48-h cocultured with hESC-MSCs and hESC-MSC-MVs, the number of K562 and HL60 was counted and tumor cell viability was measured by CCK8 assay. The expression of proteins Bcl-2 and Bax were estimated by western blotting. Transmission electron microscope and western blot analysis were adopted to evaluate the autophagy level. Results showed that both hESC-MSCs and hESC-MSC-MVs inhibited proliferation of leukemia cells in a concentration-dependent manner. hESC-MSC-MVs reduced the ratio of Bcl/Bax, enhanced the protein level of Beclin-1 and LC3-II conversion, thus upregulating autophagy and apoptosis. In conclusion, microvesicles released from human embryonic stem cell derived-mesenchymal stem cells inhibited tumor growth and stimulated autophagy and excessive autophagy might induce apoptosis. PMID- 28627683 TI - Regulatory role of tumor necrosis factor receptor-associated factor 6 in breast cancer by activating the protein kinase B/glycogen synthase kinase 3beta signaling pathway. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an endogenous adaptor of innate and adaptive immune responses, and serves a crucial role in tumor necrosis factor receptor and toll-like/interleukin-1 receptor signaling. Although studies have demonstrated that TRAF6 has oncogenic activity, its potential contributions to breast cancer in human remains largely uninvestigated. The present study examined the expression levels and function of TRAF6 in breast carcinoma (n=32) and adjacent healthy (n=25) tissue samples. Compared with adjacent healthy tissues, TRAF6 protein expression levels were significantly upregulated in breast cancer tissues. Reverse transcription-quantitative polymerase chain reaction analysis revealed a significant upregulation of the cellular proliferative marker Ki-67 and proliferation cell nuclear antigen expression levels in breast carcinoma specimens. Furthermore, protein expression levels of the accessory molecule, transforming growth factor beta-activated kinase 1 (TAK1), were significantly increased in breast cancer patients, as detected by western blot analysis. As determined by MTT assay, TRAF6 exerted profoundly proliferative effects in the MCF-7 breast cancer cell line; however, these detrimental effects were ameliorated by TAK1 inhibition. Notably, protein kinase B (AKT)/glycogen synthase kinase (GSK)3beta phosphorylation levels were markedly upregulated in breast cancer samples, compared with adjacent healthy tissues. In conclusion, an altered TRAF6-TAK1 axis and its corresponding downstream AKT/GSK3beta signaling molecules may contribute to breast cancer progression. Therefore, TRAF6 may represent a potential therapeutic target for the treatment of breast cancer. PMID- 28627684 TI - Beneficial effects of Huaiqihuang on hyperglycemia-induced MPC5 podocyte dysfunction through the suppression of mitochondrial dysfunction and endoplasmic reticulum stress. AB - The present study was performed to investigate the effect of Huaiqihuang (HQH) on hyperglycemia (HG)-induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress in MPC5 podocytes. The effects of HQH and HG on cell viability were assessed using an MTT assay. mRNA and protein expression levels were evaluated using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Cell apoptosis was assessed using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling, whereas reactive oxygen species production and alterations in mitochondrial membrane potential were assessed using flow cytometry. DNA damage was evaluated using a comet assay. The results demonstrated that treatment of podocytes with HQH markedly suppressed the HG-induced generation of reactive oxygen species. HQH also significantly improved mitochondrial membrane potential in podocytes exposed to HG. When the podocytes were treated with HG, Ca2+ levels were significantly increased, compared with those in the control group, whereas treatment of the podocytes with HQH significantly reversed the HG-induced upregulation of Ca2+ secretion. Treatment of the podocytes with HQH significantly reversed the HG induced upregulation of glucose-related protein 78 (GRP78) and C/EBP-homologous protein, which were used as indicators of ER stress. Furthermore, GRP78 loss-of function attenuated HG-induced podocyte dysfunction, including cell apoptosis and DNA damage. In conclusion, beneficial effects of HQH on HG-induced MPC5 podocyte dysfunction were observed, and occurred through the suppression of mitochondrial dysfunction and ER stress. PMID- 28627685 TI - Metabolomic analysis based on 1H-nuclear magnetic resonance spectroscopy metabolic profiles in tuberculous, malignant and transudative pleural effusion. AB - Pleural effusion is a common clinical manifestation with various causes. Current diagnostic and therapeutic methods have exhibited numerous limitations. By involving the analysis of dynamic changes in low molecular weight catabolites, metabolomics has been widely applied in various types of disease and have provided platforms to distinguish many novel biomarkers. However, to the best of our knowledge, there are few studies regarding the metabolic profiling for pleural effusion. In the current study, 58 pleural effusion samples were collected, among which 20 were malignant pleural effusions, 20 were tuberculous pleural effusions and 18 were transudative pleural effusions. The small molecule metabolite spectrums were obtained by adopting 1H nuclear magnetic resonance technology, and pattern-recognition multi-variable statistical analysis was used to screen out different metabolites. One-way analysis of variance, and Student Newman-Keuls and the Kruskal-Wallis test were adopted for statistical analysis. Over 400 metabolites were identified in the untargeted metabolomic analysis and 26 metabolites were identified as significantly different among tuberculous, malignant and transudative pleural effusions. These metabolites were predominantly involved in the metabolic pathways of amino acids metabolism, glycometabolism and lipid metabolism. Statistical analysis revealed that eight metabolites contributed to the distinction between the three groups: Tuberculous, malignant and transudative pleural effusion. In the current study, the feasibility of identifying small molecule biochemical profiles in different types of pleural effusion were investigated reveal novel biological insights into the underlying mechanisms. The results provide specific insights into the biology of tubercular, malignant and transudative pleural effusion and may offer novel strategies for the diagnosis and therapy of associated diseases, including tuberculosis, advanced lung cancer and congestive heart failure. PMID- 28627686 TI - Hypoxia- and acidosis-driven aberrations of secreted microRNAs in endometrial cancer in vitro. AB - Due to their post-transcriptional regulatory impact on gene expression, microRNAs (miRNA, miRs) influence decisively cellular processes of differentiation, proliferation and apoptosis. In oncogenic pathways various miRNAs exert either oncogenic or tumor suppressor activities in a stage-specific manner. Dysregulation of miRNA expression pattern has been associated with several human cancers including endometrial cancer (EC). In the present study, expression profile alterations of EC associated secreted miRNAs were determined under the microenvironmental stress situations hypoxia and acidosis occurring in tumor progression and metastasis. The potential influence of hypoxia and acidosis vs. control conditions on the expression levels of 24 EC-relevant miRNA types was quantitatively accessed via real-time PCR in three established EC in vitro models. Expression data were analyzed statistically. In vitro application of hypoxia resulted in downregulation of miR-15a, miR-20a, miR-20b and miR-128-1 in Ishikawa cells (type I EC) and upregulation of miR-21 in EFE-184 cells (type I EC). Acidosis triggered upregulation of tumor promoting miR-125b in AN3-CA cell (type II EC), whereas in Ishikawa cells (type I EC) miRNAs with tumor suppressive function were found altered in divergent directions, both up- (let-7a) and down- (miR-22) regulated. Our current findings emphasize the functional importance of secreted miRNAs in the immediate response of EC cells to exogenic stress situations such as the typical tumor epiphenomena hypoxia and acidosis. Focusing on the specific potential of secreted, thus circulating miRNA molecules, alterations in expression levels not only influence intracellular gene expression and signaling cascades, but also transfer the induction of (tumor)biological cellular changes to adjacent cells. PMID- 28627687 TI - microRNA-205 acts as a tumor suppressor and directly targets YAP1 in glioma. AB - Glioma is the most common form of primary malignant tumor that occurs in the central nervous system. The underlying molecular mechanism of the carcinogenesis and progression of glioma remains to be elucidated. It is well-established that microRNAs (miRs) are associated with the regulation of glioma initiation and progression, and may represent a novel effective therapeutic strategy for the treatment of glioma. In the present study, the expression, roles and molecular mechanisms of miR-205 in glioma were investigated. The expression levels of miR 205 in glioma tissues, normal brain tissues, human glioma and normal HEB glial cell lines were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To explore the functional roles of miR-205 in glioma cells, a Cell Counting kit 8 assay, and Transwell migration and invasion assays were employed. The molecular mechanisms underlying the roles of miR-205 in glioma cells were investigated using bioinformatics analysis, a luciferase reporter assay, RT-qPCR and western blot analysis. The results of the present study demonstrated that miR-205 expression was markedly low in glioma tissues and cell lines compared with normal brain tissue and a glial cell line. Upregulation of miR-205 in vitro decreased cell viability, migration and invasion in glioma. Further investigation of the potential molecular mechanism demonstrated that the tumor suppressive functions of miR-205 in regulating the proliferation, migration and invasion of glioma cells were mediated by a direct target gene, yes associated protein 1 (YAP1). The results of the present study suggested that miR 205 inhibited glioma growth and metastasis by directly targeting YAP1, and that miR-205 should be investigated as a novel therapeutic target for anti-cancer treatment. PMID- 28627688 TI - Danger-recognizing proteins, beta-defensin-128 and histatin-3, as potential biomarkers of recurrent coronary events. AB - Conventional risk factors have limited ability to predict recurrent events in subjects with first-time coronary artery disease (CAD). This aim of this study was to identify novel biomarkers using comparative global proteome analysis to improve the risk assessment for recurrent coronary events. We used samples from phase-I of the Indian Atherosclerosis Research Study (IARS), consisting of 2,332 subjects, of whom 772 were CAD-affected subjects, including 152 with recurrent events identified during a 5-year follow-up period. Global proteome analysis was performed on serum samples of 85 subjects with recurrent coronary events and 85 age- and gender-matched subjects with first-time CAD using surface-enhanced laser desorption ionization time-of-flight mass spectrometry with CM10 arrays. TagIdent was used for protein identification followed by validation by western blot analysis and ELISA. Data were analyzed by logistic analysis, Cox-regression, hazards ratio, C-statistics and combined-marker risk score using SPSS version-17 and R-package version-2.13.0 software. We identified 16 significantly differentially expressed protein peaks. Of these, 2 peaks corresponding to m/z 8588 and 1864 were identified as beta-defensin-128 and histatin-3, belonging to the danger-recognizing peptide family, which exhibited a significant independent association with recurrent events (odds ratios of 7.49 and 1.4, respectively). C statistics improved significantly from 0.677 for conventional risk factors alone to 0.800 (p-value=0.001) in combination with beta-defensin-128 and histatin-3 with a hazards ratio of 1.833. A combined risk score of beta-defensin-128 and histatin-3 could reclassify 112 out of the 170 subjects into intermediate- and high-risk groups. On the whole, our data indicate that beta-defensin-128 and histatin-3 may be potential biomarkers whch may be used to improve risk the stratification for recurrent coronary events. PMID- 28627689 TI - Expression of cell cycle-related proteins in oropharyngeal squamous cell carcinoma based on human papilloma virus status. AB - The molecular association between human papilloma virus (HPV) and cell cycle related (CCR) proteins is not fully understood in oropharyngeal squamous cell carcinoma (OPSCC). Herein, we examined the expression levels of CCRs in OPSCCs based on HPV status. In situ hybridization (ISH)- and polymerase chain reaction (PCR)-based assays were used to detect HPV status in 98 OPSCCs, and CCRs were detected by immunostaining. Of 98 tumors, 47 had HPV-positive tumors by either ISH- or PCR-based assays. Concordance analysis between ISH- and PCR-based tests showed a good agreement in OPSCC. Expression of p16 was moderate, consistent with HPV positivity as determined by ISH-based analysis. High p53-, phospho (p)-Rb-, SKP2-, cyclin D1-, and p-c-myc-positive rates were correlated with HPV-negative tumors, whereas high p16- and p27-positive rates were associated with HPV positive tumors. The positive rates for p21 and cyclin A did not differ between HPV-positive and HPV-negative tumors. Finally, Ki-67 positivity was commonly observed for both types of OPSCCs. Although expression of p16 is thought to be a marker of HPV infection, ISH- or PCR-based tests should be used for HPV detection. In addition, our results regarding CCRs may be helpful for understanding the carcinogenesis of OPSCC. PMID- 28627690 TI - Data mining and pathway analysis of glucose-6-phosphate dehydrogenase with natural language processing. AB - Human glucose-6-phosphate dehydrogenase (G6PD) is a crucial enzyme in the pentose phosphate pathway, and serves an important role in biosynthesis and the redox balance. G6PD deficiency is a major cause of neonatal jaundice and acute hemolyticanemia, and recently, G6PD has been associated with diseases including inflammation and cancer. The aim of the present study was to conduct a search of the National Center for Biotechnology Information PubMed library for articles discussing G6PD. Genes that were identified to be associated with G6PD were recorded, and the frequency at which each gene appeared was calculated. Gene ontology (GO), pathway and network analyses were then performed. A total of 98 G6PD-associated genes and 33 microRNAs (miRNAs) that potentially regulate G6PD were identified. The 98 G6PD-associated genes were then sub-classified into three functional groups by GO analysis, followed by analysis of function, pathway, network, and disease association. Out of the 47 signaling pathways identified, seven were significantly correlated with G6PD-associated genes. At least two out of four independent programs identified the 33 miRNAs that were predicted to target G6PD. miR-1207-5P, miR-1 and miR-125a-5p were predicted by all four software programs to target G6PD. The results of the present study revealed that dysregulation of G6PD was associated with cancer, autoimmune diseases, and oxidative stress-induced disorders. These results revealed the potential roles of G6PD-regulated signaling and metabolic pathways in the etiology of these diseases. PMID- 28627691 TI - Scutellaria baicalensis Georgi induces caspase-dependent apoptosis via mitogen activated protein kinase activation and the generation of reactive oxygen species signaling pathways in MCF-7 breast cancer cells. AB - Scutellaria baicalensis Georgi extract (SBGE) is used in traditional herbal medicine and has also been used clinically to ameliorate the symptoms of various inflammatory diseases and cancer. In women, breast cancer is one of the most common diseases and numerous women succumb to it. The present study was undertaken to investigate the mechanism responsible for the SBGE-induced apoptosis of MCF-7 human breast cancer cells. SBGE was administered to cells at concentrations between 100 and 500 mg/ml, and cell viabilities were identified using an MTT assay. B-cell lymphoma 2 (Bcl-2) and Bcl-2 X-associated protein (Bax) family members were identified by western blotting, and the mRNA expression levels of the pro-apoptosis genes Fas, Fas ligand (FasL) and tumor necrosis factor (TNF)-alpha were assessed by reverse transcription-polymerase chain reaction. It was identified that SBGE treatment for 24 h inhibited MCF-7 proliferation and increased the sub-G1 phase ratio. SBGE suppressed mitochondrial membrane potentials and SBGE-induced apoptotic cell death was identified to be associated with downregulation of Bcl-2, but upregulation of Bax. SBGE-activated caspases 3 and 9, and increased reactive oxygen species generation. However, SBGE had no effect on the expression levels of Fas, FasL or TNF-alpha. Furthermore, mitogen-activated protein kinase and C-Jun N-terminal kinase inhibitors inhibited SBGE-induced cell death. These results suggested that SBGE be considered as an agent for the treatment of breast cancer. PMID- 28627692 TI - The role of intestinal endotoxemia in a rat model of aluminum neurotoxicity. AB - The present study aimed to investigate the effects of intestinal endotoxemia (IETM) in a rat model of aluminum neurotoxicity established by D-galactose and aluminum trichloride (AlCl3). Adult Wistar rats were administered D-galactose and AlCl3 to create the aluminum neurotoxicity model. The learning and memory abilities of the rats were subsequently observed using a Morris water maze test and the serum levels of lipopolysaccharide (LPS), tumor necrosis factor (TNF) alpha, interleukin (IL)-1, diamine oxidase (DAO), glutamine (Gln) and glutaminase were measured. The expression of S-100beta in the serum was detected using an enzyme-linked immunosorbent assay. The expression levels of the amyloid beta protein (Abeta) precursor (APP), presenilin 1 (PS1), beta-site APP-cleaving enzyme (BACE), zona occludens protein (ZO)-1 and Abeta 1-40 in the brain of rats were detected via reverse-transcription polymerase chain reaction, western blotting and immunohistochemistry. The levels of LPS, TNF-alpha, IL-1, DAO, Gln and S-100beta in serum and the mRNA and protein expression levels of APP, PS1, BACE and Abeta1-40 in the brain were markedly increased in the model rats compared with controls. The level of glutaminase in the serum and the expression of ZO-1 in the brain were decreased in the model rats compared with controls. IETM was present in the rat model of aluminum neurotoxicity established by D galactose and AlCl3 and may be important in the development of this neurotoxicity. PMID- 28627693 TI - Renal denervation attenuates cardiac hypertrophy in spontaneously hypertensive rats via regulation of autophagy. AB - It has been suggested that renal denervation (RD) may attenuate left ventricular (LV) hypertrophy. However, the role that autophagy serves in this process is currently unclear. In the present study, utilizing a model of hypertension induced cardiac hypertrophy in spontaneous hypertensive rats, it was demonstrated that RD was significantly associated with a reduction in LV hypertrophy. Furthermore, a decrease in the myocardial mRNA of hypertrophy-associated genes was demonstrated in RD rats compared with sham controls. In addition, RD in hypertension-induced LV hypertrophy rats was associated with the attenuation of cellular autophagic response over activation at a physiological level. This was indicated by a reduction in the expression of Beclin-1, autophagy related 9A and microtubule-associated protein 1A/1B-light chain 3 II/I in RD rats to physiological levels that are observed in control rats. Furthermore, the number of autophagosomes was restored to physiological levels in the cardiomyocytes of RD rats. The results of the current study suggest that RD may attenuate LV hypertrophy via the regulation of autophagic responses. PMID- 28627694 TI - Investigation of the neuroprotective effects of a novel synthetic compound via the mitochondrial pathway. AB - The present study aimed to investigate the neuroprotective effect of a novel synthetic compound (5zou) on differentiated PC12 cells against 6-hydroxydopamine (6-OHDA) and L-glutamic acid (L-Glu) neurotoxin-induced cell injury and the potential mechanisms involved. 5zou is a 2, 2-disubstituted 1,2-dihydropyridine. PC12 cells were treated with 6-OHDA and L-Glu to establish neurotoxic cell models. MTT assay, DCFH-DA staining, Fluo-4-AM staining, JC-1 staining and western blotting were used to determine the changes in cell viability, intracellular reactive oxygen species concentration, Ca2+ influx, mitochondrial membrane potential and the protein expressions of B-cell lymphoma-2 (Bcl-2) and B cell lymphoma-extra large (Bcl-xL). Morphological analysis demonstrated the effect of 5zous on neuritogenesis and differentiation in PC12 cells. The results suggested that 5zou rescued the cell viability, intracellular ROS level, Ca2+ influx, mitochondrial membrane potential, and expression of Bcl-2 and Bcl-xL, which were altered by 6-OHDA and L-Glu. The study confirmed that 5zou has neuroprotective effects on neurotoxin-induced differentiated PC12 cells injury, potentially via the mitochondrial apoptosis pathway. PMID- 28627695 TI - Targeted CDX2 expression inhibits aggressive phenotypes of colon cancer cells in vitro and in vivo. AB - Loss of caudal type homeobox 2 (CDX2) is associated with the development of human colorectal cancer, while human telomerase reverse transcriptase (hTERT) frequently occurs in variety of human cancers. We investigated the effects of restoration of CDX2 expression using a hypoxia-inducible hTERT promoter-driven vector (pLVX-5HRE-hTERTp-CDX2-3FLAG) on colon cancer cell viability, cell cycle distribution, apoptosis, colony formation, invasion ability and xenograft tumor growth in nude mice. CDX2 overexpression significantly inhibited viability, colony formation, and the invasion and migration ability of LoVo cells, and induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. Overexpression of CDX2 under normoxic conditions significantly suppressed the expression of TGF-beta, cyclin D1, uPA, MMP-9, MMP 2, and Bcl-2, and stimulated the expression of collagen IV, laminin-1, and Bax. Overexpression of CDX2 reduced colon cancer xenograft tumor formation in nude mice which was associated with downregulation of Ki-67. In conclusion, overexpression of CDX2 using a hypoxia-inducible hTERT promoter-driven vector suppressed malignant progression of colon cancer cells in vitro and in vivo. These results suggest that pLVX-5HRE-hTERTp-CDX2-3FLAG gene therapy may be a promising novel approach to treat colon cancer. PMID- 28627696 TI - Desipramine induces apoptosis in hepatocellular carcinoma cells. AB - Antitumor effects of antidepressants have been reported in many cancer cell lines. However, anti-proliferative effects of desipramine, a tricyclic antidepressant, in hepatocellular carcinoma are currently unknown. In this study, we examined the effects of desipramine in human hepatoma Hep3B cells. To evaluate anti-proliferative effects of desipramine in Hep3B cells, we determined cell viability, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), mitogen-activated protein kinase (MAPK) activity, and intracellular Ca2+ levels after desipramine treatment. Desipramine reduced cell viability, increased ROS production, and decreased MMP activity in Hep3B cells. In addition, desipramine activated MAPKs (ERK 1/2, JNK, and p38) and increased intracellular Ca2+ levels. Pro-apoptotic effects of desipramine were abolished after MAPK inhibitors (PD98059, SB203580, and SP600125) or N-acetyl-L-cysteine (NAC), as a ROS scavenger, treatments. These findings suggest that desipramine shows anti-proliferative effects in Hep3B cells mediated by promotion of apoptosis, activation of MAPK signaling, and increase in intracellular Ca2+ levels. PMID- 28627698 TI - MicroRNA-508-5p suppresses metastasis in human gastric cancer by targeting S phase kinase-associated protein 2. AB - S-phase kinase-associated protein 2 (SKP2), a potent oncogene was revealed to be upregulated in gastric cancer (GC) tissue samples, in which SKP2 was inversely correlated with microRNA (miR)-508-5p transcripts. In present study, the functional effect of miR-508-5p on SKP2 and its metastatic potential were investigated in SGC-7901 GC cells. Significant downregulation of the miR-508-5p transcript was associated with the progression of GC. Furthermore, the overexpression of miR-508-5p was demonstrated to inhibit the proliferation, migration and invasion of SGC-7901 cells, as well as induced cell apoptosis and cell cycle arrest at the G0/G1 phase in vitro. The overexpression of miR-508-5p was able to downregulate the expression of the SKP2 oncogene, through a mechanism by which miR-508-5p directly targeted the SKP2 gene. Thus, regulating transcriptional and post-transcriptional SKP2 expression, as demonstrated using luciferase reporter assays, reverse transcription-quantitative polymerase chain reaction analysis and immunoblotting assays. The results of the present study identified that miR-508-5p functionally affects the SKP2 gene and reduces metastatic potential in GC, suggesting a novel role of miR-508-5p in the regulation of SKP2 and cell cycle. PMID- 28627699 TI - miR-30a inhibits glioma progression and stem cell-like properties by repression of Wnt5a. AB - miR-30a has been found to be dysregulated in diverse cancers and involved in the regulation of tumor progression. However, there is scarce research on the role of miR-30a in glioma. In the present study, we assessed the expression level of miR 30a in glioma tissues and cell lines. The microRNA microarray analysis revealed low expression of miR-30a in glioma tissues and cells vs. the control. Furthermore, we found that stable miR-30a inhibited cell proliferation, G1 phase arrest and stem cell-like formation in glioma. Moreover, to investigate the molecular mechanism of miR-30a on glioma cell phenotypes, we identified Wnt5a as a new direct target gene for miR-30a by bioinformatic assay, luciferase assay and western blot analysis. Further functional studies suggested that miR-30a suppressed metastasis, sphere formation and glioma growth by targeting Wnt5a signal pathway. Collectively, our findings suggested for the first time that miR 30a may function as a tumor suppressor in glioma by targeting Wnt5a. PMID- 28627697 TI - Cancer drug delivery in the nano era: An overview and perspectives (Review). AB - Nanomaterials are increasingly used as drug carriers for cancer therapy. Nanomaterials also appeal to researchers in the areas of cancer diagnosis and biomarker discovery. Several antitumor nanodrugs are currently being tested in preclinical and clinical trials and show promise in therapeutic and other settings. We review the development of nanomaterial drug carriers, including liposomes, polymer nanoparticles, dendritic polymers, and nanomicelles, for the diagnosis and treatment of various cancers. The prospects of nanomaterials as drug carriers for future clinical applications are also discussed. PMID- 28627700 TI - Isolation of rat Schwann cells based on cell sorting. AB - The present study presented a protocol that can be used to obtain rapidly a high purity of proliferating rat Schwann cells from freshly dissociated rat peripheral nerves. The sciatic nerves of newborn rats (1-3 day old) were dissociated, and the Schwann cells (SCs) were purified using fluorescence-activated cell sorting (FACS) based on the SC membrane-specific expression of the low-affinity nerve growth factor receptor, p75NGFR and oligodendrocyte marker 4. Following sorting, the cells were plated on poly-l-lysine-coated dishes in SC culture medium containing DMEM with 10% FBS, 1% penicillin/streptomycin, 2 uM forskolin and 10 ng/ml HRG. The purified rat SCs were propagated for passaging until confluent. This protocol resulted in SC cultures, which were >98% pure. This FACS-based protocol can be used to facilitate future investigations of general SC biology. PMID- 28627702 TI - Lentivirus-mediated knockdown of chondroitin polymerizing factor inhibits glioma cell growth in vitro. AB - Glioma is the most common primary tumor in the central nervous system, characterized by rapid progression, aggressive behavior, frequent recurrence and poor prognosis. In the present study we demonstrated that chondroitin polymerizing factor (CHPF) is highly expressed in human glioma tissues and 4 glioma cell lines. To explore the role of CHPF in glioma, a lentiviral vector expressing CHPF shRNA was constructed and transfected into the glioma U251 cells, which stably downregulated the expression levels of the CHPF gene in U251 cells in vitro. U251 cell proliferation inhibition rates were determined by MTT assay. The effect of survivin shRNA on U251 cell cycle distribution and cell apoptosis was determined by flow cytometry. Compared to the shRNA-Ctrl group of cells, the shRNA-CHPF group of cells exhibited decreased proliferation and a significant increase in the proportion of cells in the G0/G1 phase. In addition, we found that knockdown of the expression of CHPF increased apoptosis in glioma U251 cells. Therefore, our results confirmed that CHPF promotes growth and inhibits apoptosis in glioma U251 cells. Thus, by in vivo and in vitro data, the present study suggests that CHPF could be a new potential therapeutic target for glioma. PMID- 28627701 TI - Mangiferin positively regulates osteoblast differentiation and suppresses osteoclast differentiation. AB - Mangiferin is a polyphenolic compound present in Salacia reticulata. It has been reported to reduce bone destruction and inhibit osteoclastic differentiation. This study aimed to determine whether mangiferin directly affects osteoblast and osteoclast proliferation and differentiation, and gene expression in MC3T3-E1 osteoblastic cells and osteoclast-like cells derived from primary mouse bone marrow macrophage cells. Mangiferin induced significantly greater WST-1 activity, indicating increased cell proliferation. Mangiferin induced significantly increased alkaline phosphatase staining, indicating greater cell differentiation. Reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that mangiferin significantly increased the mRNA level of runt-related transcription factor 2 (RunX2), but did not affect RunX1 mRNA expression. Mangiferin significantly reduced the formation of tartrate-resistant acid phosphatase positive multinuclear cells. RT-PCR demonstrated that mangiferin significantly increased the mRNA level of estrogen receptor beta (ERbeta), but did not affect the expression of other osteoclast-associated genes. Mangiferin may inhibit osteoclastic bone resorption by suppressing differentiation of osteoclasts and promoting expression of ERbeta mRNA in mouse bone marrow macrophage cells. It also has potential to promote osteoblastic bone formation by promoting cell proliferation and inducing cell differentiation in preosteoblast MC3T3-E1 cells via RunX2. Mangiferin may therefore be useful in improving bone disease outcomes. PMID- 28627703 TI - Overexpression of microRNA-495 suppresses the proliferation and invasion and induces the apoptosis of osteosarcoma cells by targeting high-mobility group nucleosome-binding domain 5. AB - It has been suggested that microRNAs (miRNAs) act as critical regulators in tumorigenesis. MicroRNA-495 (miR-495) has been suggested as a cancer-associated miRNA in various types of cancers; however, the role of miR-495 in osteosarcoma is unknown. The aim of the present study was to determine whether miR-495 is involved in osteosarcoma, and to investigate the potential molecular mechanism of its involvement. We found that miR-495 was significantly downregulated in osteosarcoma tissues and cell lines, as detected by real-time quantitative polymerase chain reaction (RT-qPCR). Overexpression of miR-495 inhibited osteosarcoma cell proliferation in 3-(4,5-dimethylthiazol-2-yl)- ,5 diphenyltetrazolium bromide, colony formation and cell cycle assays. Overexpression of miR-495 induced osteosarcoma cell apoptosis. Moreover, miR-495 overexpression also inhibited osteosarcoma cell invasion. Bioinformatics and luciferase reporter assays demonstrated that miR-495 targets the 3'-untranslated region of high-mobility group nucleosome-binding domain 5 (HMGN5), a potential oncogene in various types of cancers. Overexpression of miR-495 inhibited the expression of HMGN5, cyclin B1, Bcl-2 and matrix metalloproteinase 9. In addition, restoration of HMGN5 protein expression abrogated the miR-495-induced effects. Taken together, the present study indicated that miR-495 suppresses the proliferation and invasion and induces the apoptosis of osteosarcoma cells by targeting HMGN5, providing a novel insight into the molecular pathogenesis of osteosarcoma and suggesting a potential molecular target for the development of an miRNA-targeted therapeutic strategy for osteosarcoma. PMID- 28627704 TI - Matrix metalloproteinase-2 and -9 contribute to functional integrity and noise induced damage to the blood-labyrinth-barrier. AB - The cochlear blood-labyrinth barrier (BLB), located in the stria vascularis, is critical for the homeostasis of cochlear solutes and ion transport. Significant disruption to the BLB occurs early during noise-induced hearing loss. Matrix metalloproteinase (MMP)-2 and -9 are important molecules known to be capable of degrading tight junction (TJ) proteins. The TJ proteins are important components of the extracellular matrix (ECM), required to maintain BLB integrity and permeability. Previous studies have demonstrated that MMP-2 and -9, rich in healthy cochlea, serve an essential role in regulating the cochlear response to acoustic trauma. The present study investigated the localization and function of MMP-2 and -9 in the BLB by determining their associated gene expression and activity under normal conditions and after noise exposure. Analysis of gene expression by RNA-sequencing (RNA-seq) revealed expression of 15 MMP-associated genes, including genes for MMP-2 and -9, in healthy stria vascularis. Expression of these MMP genes was dynamically regulated by noise trauma to the cochlea, and accompanied by alterations in tissue inhibitors of metalloproteinases (TIMPs) and the TJ protein zona-occludens 1 (ZO-1). These alterations suggested that MMP-2 and -9 serve an important role in maintaining the integrity of BLB and in response to acoustic trauma. MMP-2, MMP-9 and ZO-1 protein expression levels in the stria vascularis by immunofluorescence, and observed that the stable expression of MMP-2 and -9 in healthy stria was markedly increased following noise exposure, consistent with the RNA-seq results. The compact structure of ZO 1 in the BLB loosened, and strial capillaries exhibited markedly increased leakage of Evans blue dye following acoustic trauma. These data indicated that mediation of MMP-2 and -9 in structural damage to TJ proteins, including ZO-1, may be an important mechanism in the breakdown of the BLB following acoustic trauma. Additionally, these results indicated that MMPs are involved in regulating the integrity and permeability of the BLB, which may provide a theoretical basis for the prevention of noise-induced hearing loss. PMID- 28627706 TI - The Wnt inhibitor LGK-974 enhances radiosensitivity of HepG2 cells by modulating Nrf2 signaling. AB - Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of antioxidant and detoxification activities that can eliminate reactive oxygen species (ROS) produced via irradiation. However, Nrf2 overexpression in liver cancer cells may cause both radioresistance and chemoresistance. Reducing Nrf2 levels can enhance the radiosensitivity of HepG2 cells. Wingless/int-3A (Wnt3A) is a Wnt family protein that mainly activates the canonical Wnt signaling pathway. Recent studies showed that the Axin1-GSK-3beta protein complex, a component of the canonical Wnt signaling pathway, can capture Nrf2 and facilitate its ubiquitination and proteasomal degradation in the cytoplasm. This protein complex is degraded upon activation of the Wnt signaling pathway. In the present study, we treated HepG2 cells with the Wnt3A inhibitor LGK-974, an effective and specific PORCN inhibitor that can prevent the formation of a proper folding of the Wnt protein in the endoplasmic reticulum. We found that HepG2 cells became more sensitive to radiation with increasing LGK-974 concentrations. Upon 2 Gy or 4 Gy irradiation, the cells treated with LGK-974 more frequently underwent apoptosis and grew less rapidly. PCR and western blot results showed that inhibiting the secretion of Wnt3A blocked the Wnt signaling pathway and prevented Nrf2 signaling. Notably, the Wnt inhibitor may serve as a radiosensitizing drug. PMID- 28627705 TI - Targeting the PD-L1/DNMT1 axis in acquired resistance to sorafenib in human hepatocellular carcinoma. AB - Molecule-targeted therapy, such as sorafenib, is one of the effectively therapeutic options for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib has been found in some HCC patients, resulting in poor prognosis. It is reported that PD-L1 and DNA methyltransferases (DNMTs) contribute to drug resistance. In this study, by inducing sorafenib-resistant HCC cell lines, we investigated their molecular and functional characteristics. Our data indicated that highly upregulated DNMT1 was positively correlated with PD-L1 overexpression in sorafenib-resistant HCC cells. We demonstrate that PD-L1 regulate DNMT1 through STAT3 signaling pathway. Knockdown of PD-L1 induced DNMT1 dependent DNA hypomethylation and restored the expression of methylation-silenced CDH1. Moreover, inactivation of NFkappaB blocked PD-L1/STAT3/DNMT1 pathway in sorafenib-resistant HCC cells. Functionally, genetic or pharmacological disruption of PD-L1 or/and DNMT1 sensitize HCC resistance to sorafenib. Importantly, dual inactivation of PD-L1 and DNMT1 by their inhibitor synergistically disrupts the colony formation of sorafenib-resistant HCC cells. These results demonstrate that targeting NFkappaB/PDL1/STAT3/DNMT1 axis is a new therapeutic strategy for preventing or overcoming the acquired resistance to sorafenib in HCC patients. PMID- 28627707 TI - Tremella fuciformis polysaccharide suppresses hydrogen peroxide-triggered injury of human skin fibroblasts via upregulation of SIRT1. AB - Tremella fuciformis polysaccharide (TFPS), which is the extract of Tremella fuciformis Berk, has previously been demonstrated to exhibit potent anti oxidative, anti-inflammatory and anti-aging effects. However, the mechanisms underlying these protective and therapeutic effects remain to be elucidated. The aim of the present study was to investigate the protective effects of TFPS on hydrogen peroxide-induced injury of human skin fibroblasts and to elucidate the aforementioned underlying mechanisms. A hydrogen peroxide-induced human skin fibroblast injury model was firstly established. MTT and reactive oxygen species (ROS) production assays, in addition to terminal deoxynucleotidyl transferase dUTP nick end labeling, reverse transcription-quantitative polymerase chain reaction and western blotting, were performed to investigate the protective effects of TFPS. Hydrogen peroxide decreased human skin fibroblast viability with a concurrent increase in ROS generation and cell apoptosis. Treatment with 0-400 ug/ml TFPS alone for up to 48 h did not result in alteration in cell viability. Notably, TFPS pre-treatment reduced oxidative stress and cell apoptosis in hydrogen peroxide-treated skin fibroblasts. In addition, there was profound inhibition of p16, p21, p53 and caspase-3 expression, and activation of extracellular-signal regulated kinase and Akt serine/threonine kinase 1, following TFPS pre-treatment. Furthermore, it was revealed that TFPS additionally protected fibroblasts via the upregulation of SIRT1 expression, and this was abrogated by the SIRT1 inhibitor niacinamide. These results indicated that TFPS alleviated hydrogen peroxide-induced oxidative stress and apoptosis in skin fibroblasts via upregulation of SIRT1 expression, indicating that TFPS may act as a potential therapeutic agent for oxidative-stress-associated skin diseases and aging. PMID- 28627708 TI - Alterations in AQP4 expression and polarization in the course of motor neuron degeneration in SOD1G93A mice. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons. The disease progression is associated with the astrocytic environment. Aquaporin-4 (AQP4) water channels are the most abundant AQPs expressed in astrocytes, exerting important influences on central nervous system homeostasis. The present study aimed to characterize the alterations in AQP4 expression and loca-lization in superoxide dismutase 1 (SOD1) G93A transgenic mice. SOD1G93A mice were sacrificed during the presymptomatic, disease onset and end stages and immunostaining was performed on spinal cord sections to investigate neuronal loss, glial activation and AQP4 expression in the spinal cord. It was observed that global AQP4 expression increased in the spinal cord of SOD1G93A mice as the disease progressed. However, AQP4 polarization decreased as the disease progressed, and AQP4 polarized localization at the endfeet of astrocytes was decreased in the spinal ventral horn of SOD1G93A mice at the disease onset and end stages. Meanwhile, motor neuron dege-neration and decreased glutamate transporter 1 expression in astrocytes in SOD1G93A mice were observed as the disease progressed. The results of the present study demonstrated that AQP4 depolarization is a widespread pathological condition and may contribute to motor neuron degeneration in ALS. PMID- 28627709 TI - The homologous recombination protein RAD51 is a promising therapeutic target for cervical carcinoma. AB - RAD51 is one of the pivotal enzymes for DNA double-strand break (DSB) repair by the homologous recombination (HR) pathway, which implies it as a promising and novel target for cancer therapy. Recent findings have indicated RAD51 protein is overexpressed in a variety of tumors. The high-expression of RAD51 is related to poor prognosis. RAD51 is involved in the repair of DNA damage and the generation of genetic diversity by an evolutionarily conserved mechanism. However, the exact mechanism of Rad51 in the progression of cervical cancer remains unclear. RI-1 is a small molecule that inhibits the central recombination protein RAD51. In this study, we found that RAD51 was highly expressed in invasive squamous cervical cancer (SCC). The administration of RI-1 inhibited cell growth in vitro and reduced growth of tumor xenografts in vivo with cervical cancer cells (HeLa and SiHa). Further investigation suggested that RAD51 protein significantly promoted the cell cycle transition from the G0/G1 to S phase. In addition, the inhibition of RAD51 reduced the level of the cell cycle related protein cyclin D1, but increased the levels of p21 mRNA and protein. As a DNA DSB repair enzyme, the expression of RAD51 in tumor cells possibly affects their sensitivity to anti cancer agents. Additionally, in experiments using cisplatin and ionizing radiation, RI-1 treated cervical cancer cells, HeLa and SiHa, were sensitized to a greater extent than the untreated control. Thus, HR inhibition of RAD51 may provide yet another mechanism of therapeutic target for the chemosensitization and radiosensitization of cervical cancer with RI-1. Collectively, our data demonstrated for the first time that inhibition of RAD51 suppressed the cervical cancer cell proliferation and the growth of cervical cancer xenografts by attenuating cell cycle transition, which could be a functional link between RAD51 and cyclin D1 and p21. PMID- 28627710 TI - Oil and eicosapentaenoic acid production by the diatom Phaeodactylum tricornutum cultivated outdoors in Green Wall Panel (GWP(r)) reactors. AB - Phaeodactylum tricornutum is a widely studied diatom and has been proposed as a source of oil and polyunsaturated fatty acids (PUFA), particularly eicosapentaenoic acid (EPA). Recent studies indicate that lipid accumulation occurs under nutritional stress. Aim of this research was to determine how changes in nitrogen availability affect productivity, oil yield, and fatty acid (FA) composition of P. tricornutum UTEX 640. After preliminary laboratory trials, outdoor experiments were carried out in 40-L GWP(r) reactors under different nitrogen regimes in batch. Nitrogen replete cultures achieved the highest productivity of biomass (about 18 g m-2 d-1 ) and EPA (about 0.35 g m-2 d-1 ), whereas nitrogen-starved cultures achieved the highest FA productivity (about 2.6 g m-2 d-1 ). The annual potential yield of P. tricornutum grown outdoors in GWP(r) reactors is 730 kg of EPA per hectare under nutrient-replete conditions and 5,800 kg of FA per hectare under nitrogen starvation. Biotechnol. Bioeng. 2017;114: 2204-2210. (c) 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. PMID- 28627711 TI - Fermentation strategy for second generation ethanol production from sugarcane bagasse hydrolyzate by Spathaspora passalidarum and Scheffersomyces stipitis. AB - Alcoholic fermentation of released sugars in pretreatment and enzymatic hydrolysis of biomass is a central feature for second generation ethanol (E2G) production. Saccharomyces cerevisiae used industrially in the production of first generation ethanol (E1G) convert sucrose, fructose, and glucose into ethanol. However, these yeasts have no ability to ferment pentose (xylose). Therefore, the present work has focused on E2G production by Scheffersomyces stipitis and Spathaspora passalidarum. The fermentation strategy with high pitch, cell recycle, fed-batch mode, and temperature decrease for each batch were performed in a hydrolyzate obtained from a pretreatment at 130 degrees C with NaOH solution (1.5% w/v) added with 0.15% (w/w) of anthraquinone (AQ) and followed by enzymatic hydrolysis. The process strategy has increased volumetric productivity from 0.35 to 0.38 g . L-1 . h-1 (first to third batch) for S. stipitis and from 0.38 to 0.81 g . L-1 . h-1 for S. passalidarum (first to fourth batch). Mass balance for the process proposed in this work showed the production of 177.33 kg ethanol/ton of sugar cane bagasse for S. passalidarum compared to 124.13 kg ethanol/ton of sugar cane bagasse for S. stipitis fermentation. The strategy proposed in this work can be considered as a promising strategy in the production of second generation ethanol. Biotechnol. Bioeng. 2017;114: 2211-2221. (c) 2017 Wiley Periodicals, Inc. PMID- 28627712 TI - Acral dermatofibrosarcoma protuberans with myoid differentiation: A report of 2 cases. AB - Dermatofibrosarcoma protuberans (DFSP) is a low-grade mesenchymal neoplasm with a tendency for local recurrence; it is rarely metastatic. Dermatofibrosarcoma protuberans typically arises in the trunk and proximal extremities. However, it can arise in unusual sites such as the hands and feet. Several variants have been described, including DFSP with myoid differentiation, which is very uncommon. This variant tends to be observed more with the fibrosarcomatous variant, and it can be either in the form of myoid bundles and nodules with no vascular relationship or represent hyperplastic blood vessels within the tumor. Here, we report 2 cases of DFSP with myoid differentiation (ordinary and fibrosarcomatous) on the foot. To the best of our knowledge, these cases represent the first 2 cases of acral DFSP with myoid differentiation. PMID- 28627713 TI - Process development of human multipotent stromal cell microcarrier culture using an automated high-throughput microbioreactor. AB - Microbioreactors play a critical role in process development as they reduce reagent requirements and can facilitate high-throughput screening of process parameters and culture conditions. Here, we have demonstrated and explained in detail, for the first time, the amenability of the automated ambr15 cell culture microbioreactor system for the development of scalable adherent human mesenchymal multipotent stromal/stem cell (hMSC) microcarrier culture processes. This was achieved by first improving suspension and mixing of the microcarriers and then improving cell attachment thereby reducing the initial growth lag phase. The latter was achieved by using only 50% of the final working volume of medium for the first 24 h and using an intermittent agitation strategy. These changes resulted in >150% increase in viable cell density after 24 h compared to the original process (no agitation for 24 h and 100% working volume). Using the same methodology as in the ambr15, similar improvements were obtained with larger scale spinner flask studies. Finally, this improved bioprocess methodology based on a serum-based medium was applied to a serum-free process in the ambr15, resulting in >250% increase in yield compared to the serum-based process. At both scales, the agitation used during culture was the minimum required for microcarrier suspension, NJS . The use of the ambr15, with its improved control compared to the spinner flask, reduced the coefficient of variation on viable cell density in the serum containing medium from 7.65% to 4.08%, and the switch to serum free further reduced these to 1.06-0.54%, respectively. The combination of both serum-free and automated processing improved the reproducibility more than 10-fold compared to the serum-based, manual spinner flask process. The findings of this study demonstrate that the ambr15 microbioreactor is an effective tool for bioprocess development of hMSC microcarrier cultures and that a combination of serum-free medium, control, and automation improves both process yield and consistency. Biotechnol. Bioeng. 2017;114: 2253-2266. (c) 2017 Wiley Periodicals, Inc. PMID- 28627715 TI - Transition and Alkali Metal Complex Ternary Amides for Ammonia Synthesis and Decomposition. AB - A new complex ternary amide, Rb2 [Mn(NH2 )4 ], which simultaneously contains both transition and alkali metal catalytic sites, is developed. This is in line with the recently reported TM-LiH composite catalysts, which have been shown to effectively break the scaling relations and achieve ammonia synthesis under mild conditions. Rb2 [Mn(NH2 )4 ] can be facilely synthesized by mechanochemical reaction at room temperature. It exhibits two temperature-dependent polymorphs, that is, a low-temperature orthorhombic and a high-temperature monoclinic structure. Rb2 [Mn(NH2 )4 ] decomposes to N2 , H2 , NH3 , Mn3 N2 , and RbNH2 under inert atmosphere; whereas it releases NH3 at a temperature as low as 80 degrees C under H2 atmosphere. Those unique behaviors enable Rb2 [Mn(NH2 )4 ], and its analogue K2 [Mn(NH2 )4 ], to be excellent catalytic materials for ammonia decomposition and synthesis. Experimental results show both ammonia decomposition onset temperatures and conversion rates over Rb2 [Mn(NH2 )4 ] and K2 [Mn(NH2 )4 ] are similar to those of noble metal Ru-based catalysts. More importantly, these ternary amides exhibit superior capabilities in catalyzing NH3 synthesis, which are more than 3 orders of magnitude higher than that of Mn nitride and twice of that of Ru/MgO. The in situ SR-PXD measurement shows that manganese nitride, synergistic with Rb/KH or Rb/K(NH2 )x H1-x , are likely the active sites. The chemistry of Rb2 /K2 [Mn(NH2 )x ] and Rb/K(NH2 )x H1-x with H2 /N2 and NH3 correlates closely with the catalytic performance. PMID- 28627714 TI - Migraine Subclassification via a Data-Driven Automated Approach Using Multimodality Factor Mixture Modeling of Brain Structure Measurements. AB - BACKGROUND: The current subclassification of migraine is according to headache frequency and aura status. The variability in migraine symptoms, disease course, and response to treatment suggest the presence of additional heterogeneity or subclasses within migraine. OBJECTIVE: The study objective was to subclassify migraine via a data-driven approach, identifying latent factors by jointly exploiting multiple sets of brain structural features obtained via magnetic resonance imaging (MRI). METHODS: Migraineurs (n = 66) and healthy controls (n = 54) had brain MRI measurements of cortical thickness, cortical surface area, and volumes for 68 regions. A multimodality factor mixture model was used to subclassify MRIs and to determine the brain structural factors that most contributed to the subclassification. Clinical characteristics of subjects in each subgroup were compared. RESULTS: Automated MRI classification divided the subjects into two subgroups. Migraineurs in subgroup #1 had more severe allodynia symptoms during migraines (6.1 +/- 5.3 vs. 3.6 +/- 3.2, P = .03), more years with migraine (19.2 +/- 11.3 years vs 13 +/- 8.3 years, P = .01), and higher Migraine Disability Assessment (MIDAS) scores (25 +/- 22.9 vs 15.7 +/- 12.2, P = .04). There were not differences in headache frequency or migraine aura status between the two subgroups. CONCLUSIONS: Data-driven subclassification of brain MRIs based upon structural measurements identified two subgroups. Amongst migraineurs, the subgroups differed in allodynia symptom severity, years with migraine, and migraine-related disability. Since allodynia is associated with this imaging based subclassification of migraine and prior publications suggest that allodynia impacts migraine treatment response and disease prognosis, future migraine diagnostic criteria could consider allodynia when defining migraine subgroups. PMID- 28627716 TI - A Cherry Seed-Derived Spice, Mahleb, is Recognized by Anti-Almond Antibodies Including Almond-Allergic Patient IgE. AB - There are a number of examples of immunologic cross-reactivity elicited by pollens, fruits, seeds, and nuts of closely related plant species. Such cross reactivity is of particular concern for patients with food allergies. In this report, we investigated a spice (mahleb) that is prepared from the kernel of the St. Lucie cherry, Prunus mahaleb, for cross-reactivity with almond (Prunus dulcis), using enzyme-linked immunosorbent assay (ELISA) and Western blot. Almond and mahleb are members of the same genus. Cross-reactivity between the mahleb and almond was demonstrated by reaction of cherry and almond kernel protein extracts with antibodies raised against almond proteins. Almond-specific murine monoclonal IgG, rabbit polyclonal IgG, and almond-allergic serum IgE each exhibited cross reactivity with cherry kernel protein. Because of the demonstrated cross reactivity between almond and mahleb, these findings should be of special concern to almond-allergic patients and attending medical personnel. PMID- 28627717 TI - Direction-dependent contraction forces on cell boundaries induce collective migration of epithelial cells within their sheet. AB - During early embryonic development, epithelial cells form a monolayer sheet and migrate in a definite direction. This phenomenon, called epithelial cell migration, is an important topic in developmental biology. A characteristic feature of this process is attachment to adjacent cells during migration, which is necessary for maintaining the integrity of the sheet. However, it is unclear how these cohesive cells migrate without breaking their attachments. A mechanism for this phenomenon was recently proposed, in which direction-dependent contraction forces acting on cell boundaries induce unidirectional epithelial migration. In this review, we examine this proposed mechanism from various aspects and provide theoretical background for the collective migration of epithelial cells. This information may be helpful for investigators to realize the basic principles underlying collective epithelial migration and devise new mechanisms for it. PMID- 28627718 TI - Motor performance in children with Noonan syndrome. AB - Although problems with motor performance in daily life are frequently mentioned in Noonan syndrome, the motor performance profile has never been systematically investigated. The aim of this study was to examine whether a specific profile in motor performance in children with Noonan syndrome was seen using valid norm referenced tests. The study assessed motor performance in 19 children with Noonan syndrome (12 females, mean age 9 years 4 months, range 6 years 1 month to 11 years and 11 months, SDS 1 year and 11 months). More than 60% of the parents of the children reported pain, decreased muscle strength, reduced endurance, and/or clumsiness in daily functioning. The mean standard scores on the Visual Motor Integration (VMI) test and Movement Assessment Battery for Children 2, Dutch version (MABC-2-NL) items differed significantly from the reference scores. Grip strength, muscle force, and 6 min Walking Test (6 MWT) walking distance were significantly lower, and the presence of generalized hypermobility was significantly higher. All MABC-2-NL scores (except manual dexterity) correlated significantly with almost all muscle strength tests, VMI total score, and VMI visual perception score. The 6 MWT was only significantly correlated to grip strength. This is the first study that confirms that motor performance, strength, and endurance are significantly impaired in children with Noonan syndrome. Decreased functional motor performance seems to be related to decreased visual perception and reduced muscle strength. Research on causal relationships and the effectiveness of interventions is needed. Physical and/or occupational therapy guidance should be considered to enhance participation in daily life. PMID- 28627719 TI - The frontal assessment battery in clinical practice: a systematic review. AB - BACKGROUND: The frontal assessment battery (FAB) is a brief tool designed to evaluate executive function. Some studies have particularly focused on assessing its applicability addressing two issues: first, on detecting the brain regions responsible for the FAB performance, and second, on determining its capability for differential diagnosis. Our aim was to summarize and analyze critically the studies that assessed the neuroanatomical correspondence and the differential diagnostic value of the FAB in several study populations suffering from different pathologies. METHODS: We completed a literature search in MEDLINE (via PubMed) database by using the term "frontal assessment battery" and the combination of this term with "applicability" or "use" or "usefulness". The search was limited to articles in English or Spanish languages, published between 1 September 2000 and 30 September 2016, human studies, and journal articles. RESULTS: A total of 32 studies met inclusion criteria. Seventeen studies were aimed at identifying the brain regions or the neural substrates involved in executive functions measured by the FAB and 15 studies at verifying that the FAB was an appropriate tool for the differential diagnosis in neurological diseases. CONCLUSION: Our study showed that the FAB may be an adequate assessment tool for executive function and may provide useful information for differential diagnosis in several diseases. Given that the FAB takes short time and is easy to administer, its usage may be of great interest as part of a full neuropsychological assessment in clinical settings. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28627720 TI - The concept of medicalisation reassessed: a rejoinder. PMID- 28627721 TI - Making sense: further studies of living with chronic illness. PMID- 28627722 TI - Pterostilbene Inhibits Lipogenic Activity similar to Resveratrol or Caffeine but Differently Modulates Lipolysis in Adipocytes. AB - The anti-obesity effects of resveratrol shown in rodents are not transposed into an efficient therapy of human obesity. Consequently, the search for molecules mimicking or surpassing resveratrol actions is ongoing. The natural phenolic compound pterostilbene exhibits beneficial health effects and has the capacity to limit fat mass in animal models. In this study, we tested whether pterostilbene modulates triacylglycerol accumulation/breakdown. Prolonged exposure to pterostilbene or resveratrol inhibited adipocyte differentiation in 3T3-F442A preadipocytes. Acute effects on lipolysis, antilipolysis and lipogenesis were determined for pterostilbene in mouse adipocytes, and compared with resveratrol. Pterostilbene was also tested on glycerol release and glucose uptake in subcutaneous human adipocytes. Dose-response analyses did not reveal a clear lipolytic effect in both species. The antilipolytic effect of insulin was improved by pterostilbene at 1-10 MUM in mouse fat cells only, while at 1 mM, the phenolic compound was antilipolytic in human fat cells in a manner not additive to insulin. Pterostilbene dose-dependently inhibited glucose incorporation into lipids similarly to resveratrol and caffeine. However, only the former did not inhibit insulin-stimulated glucose uptake. Indeed, pterostilbene abolished the insulin lipogenic effect without inhibiting its antilipolytic action and rapid activation of glucose uptake. Pterostilbene therefore exhibits a unique panel of direct interactions with adipocytes that relies on its reported anti-obesity and antidiabetic properties. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28627723 TI - Vitamin D enhances omega-3 polyunsaturated fatty acids-induced apoptosis in breast cancer cells. AB - Breast cancer is a leading type of cancer in women and generally classified into three subtypes of ER+ /PR+ , HER2+ and triple negative. Both omega-3 polyunsaturated fatty acids and vitamin D3 play positive role in the reduction of breast cancer incidence. However, whether combination of omega-3 polyunsaturated fatty acids and vitamin D3 has stronger protective effect on breast carcinogenesis still remains unknown. In this study, we show that the combination of omega-3 free fatty acids (omega-3 FFAs) and 1alpha, 25-dihydroxy-vitamin D3 (VD3 ) dramatically enhances cell apoptosis among three subtypes of breast cancer cell lines. Bcl-2 and total PARP protein levels are decreased in combined treatment MCF-7 and SK-BR-3 cells. Caspase signals play a vital role in cell apoptosis induced by combination. Moreover, Raf-MAPK signaling pathway is involved in the apoptosis induction by combination of omega-3 FFAs+VD3 . These results demonstrate that the induction of cell apoptosis by combined treatment is dependent on different signaling pathways in three subtypes of breast cancer cell lines. PMID- 28627724 TI - Comparative Echogenicity of an Epidural Catheter and 2 New Catheters Designed for Ultrasound-Guided Continuous Peripheral Nerve Blocks. AB - Visualization of the catheter during ultrasound-guided continuous nerve block performance may be difficult but is an essential skill for regional anesthesiologists. The objective of this in vitro study was to evaluate 2 newer catheters designed for enhanced echogenicity and compare them to a widely used catheter not purposely designed for ultrasound guidance. Outcomes were the numbers of first-place rankings among all 3 catheters and scores on individual echogenicity criteria as assessed by 2 blinded reviewers. Catheters designed for echogenicity are not superior to an older regional anesthesia catheter, and results suggest that catheter preference for ultrasound-guided placement may be subjective. PMID- 28627725 TI - Proteomic analysis of host cell protein dynamics in the supernatant of Fc-fusion protein-producing CHO DG44 and DUKX-B11 cell lines in batch and fed-batch cultures. AB - Chinese hamster ovary (CHO) cells are the most widely used host cell lines for the commercial production of therapeutic proteins including Fc-fusion proteins. During the culture of recombinant CHO (rCHO) cells, host cell proteins (HCPs), secreted from viable cells and released from dead cells, accumulate extracellularly, potentially impairing product quality. In this study, the HCPs that accumulated extracellularly in batch and fed-batch cultures of Fc-fusion protein-producing rCHO cell lines (DG-Fc and DUKX-Fc) were identified and quantified using nanoflow liquid chromatography-tandem mass spectrometry (LC MS/MS), followed by gene ontology and functional analysis. When the proteome database of Cricetulus griseus was used as a reference to identify the HCPs, more HCPs were identified for DG-Fc (1632 HCPs in batch culture and 1733 HCPs in fed batch culture) than for DUKX-Fc (1114 HCPs in batch culture and 1002 HCPs in fed batch culture). Clustering analysis of HCPs, which were classified into four clusters according to their concentration profiles during culture, showed that the concentration profiles of HCPs affecting the quality of Fc-fusion proteins correlated with changes in Fc-fusion protein quality. Taken together, the dataset of HCPs obtained in this study using the two different rCHO cell lines provides insights into the determination of appropriate target proteins to be removed during the culture and purification steps so as to ensure good Fc-fusion protein quality. Biotechnol. Bioeng. 2017;114: 2267-2278. (c) 2017 Wiley Periodicals, Inc. PMID- 28627726 TI - The Arl3 and Arl1 GTPases co-operate with Cog8 to regulate selective autophagy via Atg9 trafficking. AB - The Arl3-Arl1 GTPase cascade plays important roles in vesicle trafficking at the late Golgi and endosomes. Subunits of the conserved oligomeric Golgi (COG) complex, a tethering factor, are important for endosome-to-Golgi transport and contribute to the efficient functioning of the cytoplasm-to-vacuole targeting (Cvt) pathway, a well-known selective autophagy pathway. According to our findings, the Arl3-Arl1 GTPase cascade co-operates with Cog8 to regulate the Cvt pathway via Atg9 trafficking. arl3cog8Delta and arl1cog8Delta exhibit profound defects in aminopeptidase I maturation in rich medium. In addition, the Arl3-Arl1 cascade acts on the Cvt pathway via dynamic nucleotide binding. Furthermore, Atg9 accumulates at the late Golgi in arl3cog8Delta and arl1cog8Delta cells under normal growth conditions but not under starvation conditions. Thus, our results offer insight into the requirement for multiple components in the Golgi-endosome system to determine Atg9 trafficking at the Golgi, thereby regulating selective autophagy. PMID- 28627727 TI - Development of HGF-binding aptamers with the combination of G4 promoter-derived aptamer selection and in silico maturation. AB - We describe the selection of aptamers based on bioinformatics-based approaches without Systematic Evolution of Ligands by EXponential enrichment (SELEX). SELEX is a potent method; however, it is time intensive and the PCR-amplification step, which is essential step for SELEX, leads to the loss of good aptamers. We have developed an aptamer-screening method, G4 promoter-derived aptamer selection (G4PAS), and an aptamer-improving method, in silico maturation (ISM). They are based on in silico sequence selection and computer assisted directed evolution, respectively. In this study, we succeeded in identifying new aptamers against hepatocyte growth factor (HGF) by G4PAS as well as improving the specificity of the HGF aptamers by ISM. Using ISM improved the specificity of the aptamer for HGF by up to 45-fold in comparison with the original aptamer. These methods enable easy and efficient identification of good aptamers, and the combination of G4PAS with ISM can thus serve as a potent approach for aptamer identification. Biotechnol. Bioeng. 2017;114: 2196-2203. (c) 2017 Wiley Periodicals, Inc. PMID- 28627728 TI - Can atrophic-erosive oral lichen planus promote cardiovascular diseases? A population-based study. AB - OBJECTIVE: Lichen planus has been recently associated with an increased risk of cardiovascular diseases (CVDs). The oral manifestations can be divided into white hyperkeratotic lesions (WL) and atrophic and erosive lesions (RL). The aim of this report was to compare the presence of CVDs between patients affected by WL or RL, to test the hypothesis that RL are associated with an increased incidence of CVDs. SUBJECTS AND METHODS: Patients were analysed through a complete collection of all the risk factors for CVDs. The primary endpoint was the occurrence of a cardiovascular event-acute coronary syndrome (ACS), any revascularization or stroke/TIA. A multivariable logistic regression model, adjusted for age at diagnosis, body mass index, smoking, alcohol consumption, diabetes, hypertension, CVDs familiarity and periodontitis, was performed. RESULTS: A prospective cohort of 307 patients has been evaluated; 185 (60.3%) had WL and 122 RL (39.7%). Twenty-four patients had a CVD. ACS occurred more frequently in RL (adjusted odds ratio 5.83; 95% CI: 1.16-29.39), mainly due to the higher risk of it after the histological diagnosis of Oral lichen planus OLP (odds ratio 4.23; 95% CI: 0.66-27.23). CONCLUSION: Patients with RL could possibly have a higher risk of developing ACS. Further analysis on larger cohort is however warranted. PMID- 28627729 TI - The immune deficiency of chromosome 22q11.2 deletion syndrome. AB - The syndrome originally described by Dr. Angelo DiGeorge had immunodeficiency as a central component. When a 22q11.2 deletion was identified as the cause in the majority of patients with DiGeorge syndrome, the clinical features of 22q11.2 deletion syndrome became so expansive that the immunodeficiency became less prominent in our thinking about the syndrome. This review will focus on the immune system and the changes in our understanding over the past 50 years. Initially characterized as a pure defect in T cell development, we now appreciate that many of the clinical features related to the immunodeficiency are well downstream of the limitation imposed by a small thymus. Dysfunctional B cells presumed to be secondary to compromised T cell help, issues related to T cell exhaustion, and high rates of atopy and autoimmunity are aspects of management that require consideration for optimal clinical care and for designing a cogent monitoring approach. New data on atopy are presented to further demonstrate the association. PMID- 28627730 TI - Does involvement of local NGOs enhance public service delivery? Cautionary evidence from a malaria-prevention program in India. AB - Partnerships between government and non-state actors that aim to enhance the quality or efficiency of service delivery are increasingly common in today's development policy landscape. We investigate the impacts of such an approach using data from an experimental supportive intervention to India's malaria control program that leveraged local non-state capacity in order to promote mosquito net usage and recommended fever care-seeking patterns. The supportive activities were conducted simultaneously by 3 NGOs, contracted out by the Indian government, in 2 endemic districts in the state of Odisha. We find that program impact significantly varied by location. Examining 3 potential sources of this variation (differential population characteristics, differential health worker characteristics, and differential implementer characteristics), we provide evidence that both population and NGO characteristics significantly affected the success of the program. Specifically, the results suggest that the quality and effort of the local implementer played a key role in the differential effectiveness. We discuss these findings as they relate to the external validity of development policy evaluations and, specifically, for the ability of health and other service delivery systems to benefit from limited non-state capacity in underresourced areas. PMID- 28627731 TI - Cell migration analysis: A low-cost laboratory experiment for cell and developmental biology courses using keratocytes from fish scales. AB - Cell and developmental processes are complex, and profoundly dependent on spatial relationships that change over time. Innovative educational or teaching strategies are always needed to foster deep comprehension of these processes and their dynamic features. However, laboratory exercises in cell and developmental biology at the undergraduate level do not often take into account the time dimension. In this article, we provide a laboratory exercise focused in cell migration, aiming to stimulate thinking in time and space dimensions through a simplification of more complex processes occurring in cell or developmental biology. The use of open-source tools for the analysis, as well as the whole package of raw results (available at http://github.com/danielprieto/keratocyte) make it suitable for its implementation in courses with very diverse budgets. Aiming to facilitate the student's transition from science-students to science practitioners we propose an exercise of scientific thinking, and an evaluation method. This in turn is communicated here to facilitate the finding of common caveats and weaknesses in the process of producing simple scientific communications describing the results achieved. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 45(6):475-482, 2017. PMID- 28627732 TI - The Acute Effect of Loperamide on Ileostomy Output: A Randomized, Double-Blinded, Placebo-Controlled, Crossover Study. AB - High stoma output is a common problem in patients with ileostomy and can lead to dehydration and electrolyte disturbances. The first drug of choice to reduce stoma output is often loperamide. The aim was to assess the acute effect of loperamide on (a) ileostomy output in g/day, (b) gastrointestinal transit time and (c) patient-reported effects. A total of 12 patients completed this double blinded, randomized, placebo-controlled, crossover study, consisting of a 3-day treatment period with loperamide 12 mg/day or placebo followed by the reverse after a washout period of 5-7 days. Patients collected stoma output and noted food and fluid intake over 48 hr and swallowed a capsule with radiopaque markers for the determination of gastrointestinal transit time over 24 hr. At the end of the study, patients were asked to report their treatment sequence. Ileostomy output was significantly reduced during loperamide treatment (p < 0.02) with a median of 16.5% (range -5% to 46%). Transit time was reduced significantly for the passage of 10% of the markers (p = 0.02), but not for 50% and 100% of the markers. Fifty-eight per cent (N = 7) of the patients reported the correct treatment sequence (p = 0.41). Loperamide 12 mg/day reduced ileostomy output statistically significantly, but with varying effects among patients and without reaching the clinical significance of 20% set-up by this study. Dose-response studies should be performed, and standard treatment doses of loperamide should be reassessed. The study was registered at ClinicalTrials.gov - NCT02266849. PMID- 28627733 TI - Response of renal tubular cells to differential types and doses of calcium oxalate crystals: Integrative proteome network analysis and functional investigations. AB - We have previously identified changes in the cellular proteome of renal tubular cells induced by low-dose (100 MUg/mL) and high-dose (1000 MUg/mL) calcium oxalate monohydrate (COM) and dihydrate (COD) crystals. However, the functional significance of such expression data remained unclear. In this study, we performed comparative analyses and functional investigations of four proteomic datasets to define potential mechanisms by which renal tubular cells responded to differential crystal types and doses. The data showed that high-dose induced greater changes than low-dose, whereas COM induced more changes than COD. Luciferin-luciferase ATP assay revealed increased intracellular ATP level by high dose of both COM and COD. OxyBlot assay and Western blotting showed accumulated intracellular oxidized proteins but decreased ubiquitinated proteins by high-dose of both crystals. Flow cytometric analysis of cell death showed that high-dose of both crystals, particularly COM, significantly increased cell death. Also, crystal adhesion assay showed higher degree of cell-crystal adhesion in high-dose and COM when compared to low-dose and COD, respectively. Finally, pretreatment of epigallocatechin-3-gallate revealed a protective effect on COM/COD crystals induced oxidative stress and cell-crystal adhesion. Collectively, these data may provide a better understanding of cellular responses of renal tubular cells to COM/COD crystals in kidney stone disease. PMID- 28627734 TI - Role of cytoskeletal mechanics and cell membrane fluidity in the intracellular delivery of molecules mediated by laser-activated carbon nanoparticles. AB - Exposure of cells and nanoparticles to near-infrared nanosecond pulsed laser light can lead to efficient intracellular delivery of molecules while maintaining high cell viability by a photoacoustic phenomenon known as transient nanoparticle energy transduction (TNET). Here, we examined the influence of cytoskeletal mechanics and plasma membrane fluidity on intracellular uptake of molecules and loss of cell viability due to TNET. We found that destabilization of actin filaments using latrunculin A led to greater uptake of molecules and less viability loss caused by TNET. Stabilization of actin filaments using jasplakinolide had no significant effect on uptake or viability loss caused by TNET. To study the role of plasma membrane fluidity, we increased fluidity by depletion of membrane cholesterol using methyl-beta-cyclodextrin and decreased fluidity by enrichment of the membrane with cholesterol using water-soluble cholesterol. Neither of these membrane fluidity changes significantly altered cellular uptake or viability loss caused by TNET. We conclude that weakening mechanical integrity of the cytoskeleton can increase intracellular uptake and decrease loss of cell viability, while plasma membrane fluidity does not appear to play a significant role in uptake or viability loss caused by TNET. The positive effects of cytoskeletal weakening may be due to an enhanced ability of the cell to recover from the effects of TNET and maintain viability. Biotechnol. Bioeng. 2017;114: 2390-2399. (c) 2017 Wiley Periodicals, Inc. PMID- 28627735 TI - Genetic alterations in adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis. It is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. A long latency period from HTLV-1 infection to ATL onset suggests that not only HTLV-1 proteins, such as Tax and HBZ, but also additional genetic and/or epigenetic events are required for ATL development. Although many studies have demonstrated the biological functions of viral genes, alterations of cellular genes associated with ATL have not been fully investigated. Recently, a large-scale integrated genetic analysis revealed the entire landscape of somatic aberrations in ATL. This neoplasm is characterized by frequent gain-of-function alterations in components of the T-cell receptor/NF-kappaB signaling pathway, including activating mutations in the PLCG1, PRKCB, CARD11 and VAV1 genes, and CTLA4-CD28 and ICOS-CD28 fusions. Importantly, molecules associated with immune surveillance, such as HLA-A/B, CD58 and FAS, are affected recurrently. Among them, one notable lesion occurs as frequent structural variations that truncate the PD-L1 3'-untranslated region, leading to its overexpression. Other genetic targets include transcription factors (IRF4, IKZF2, and GATA3) and chemokine receptors (CCR4, CCR7 and GPR183), which are functionally relevant in normal T cells. A substantial proportion of ATL cases show widespread accumulation of repressive epigenetic changes, such as trimethylation of histone H3 lysine 27 and DNA hypermethylation of CpG islands, which coordinately modulate multiple pathways, including Cys2-His2 zinc finger genes involved in silencing retroelements. Here we review the current understanding of the genetic/epigenetic aberrations in ATL, focusing on their relevance in its molecular pathogenesis. PMID- 28627736 TI - Enzyme-free cell detachment mediated by resonance vibration with temperature modulation. AB - Cell detachment is an essential process in adherent cell culture. However, trypsinization, which is the most popular detachment technique used in culture, damages cellular membranes. Reducing cellular membrane damage during detachment should improve the quality of cell culture. In this article, we propose an enzyme free cell detachment method based on resonance vibration with temperature modulation. We developed a culture device that can excite a resonance vibration and control temperature. We then evaluated the cell detachment ratio and the growth response, observed the morphology, and analyzed the cellular protein of the collected cells-mouse myoblast cell line (C2C12). With the temperature of 10 degrees C and the maximum vibration amplitude of 2 MUm, 77.9% of cells in number were successfully detached compared with traditional trypsinization. The 72-h proliferation ratio of the reseeded cells was similar to that with trypsinization, whereas the proliferation ratio of proposed method was 12.6% greater than that of trypsinization after freezing and thawing. Moreover, the cells can be collected relatively intact and both intracellular and cell surface proteins in the proposed method were less damaged than in trypsinization. These results show that this method has definite advantages over trypsinization, which indicates that it could be applied to subcultures of cells that are more susceptible to trypsin damage for mass culture of sustainable clinical use. Biotechnol. Bioeng. 2017;114: 2279-2288. (c) 2017 Wiley Periodicals, Inc. PMID- 28627737 TI - Caries treatment decisions among undergraduate and postgraduate students supported by visual detection systems. AB - BACKGROUND: The difficulties of caries diagnosis and the level of examiner's experience may influence the treatment decision, resulting excessive and inefficient intervention. AIM: This randomized experimental study evaluated caries treatment decisions made by undergraduate (UG) and postgraduate (PG) students when examination was performed through conventional visual clinical examination (CVCE) and when supported by ICDAS (IC) or Nyvad's (NY) criteria. DESIGN: Four UG and four PG initially analyzed, by CVCE, 300 primary incisors and molars surfaces of 25 children aged 5-12 years, and choose between no treatment, non-operative, and operative treatment. Students were randomized between IC (2UG; 2PG) and NY (2UG; 2PG) and, after one week of receiving training, repeated evaluations and treatment suggestions. Reference standard was established by two researchers' consensus. Sensitivity, specificity, ROC analysis, and kappa were calculated. Treatment decisions were analyzed by means of contingency tables. RESULTS: Only sensitivity showed statistical difference (P < 0.05). Operative treatment had high percentage for initial lesions at first evaluation for both criteria; second evaluation showed higher percentage of non-operative treatments for the same lesions. CONCLUSIONS: IC and NY present satisfactory performance in primary teeth by UG and PG, and their use may assistance UG to adopt a less interventionist approach for initial enamel lesions. PMID- 28627738 TI - Systematic review on the proteomic profile of Mycobacterium tuberculosis exposed to drugs. AB - The authors present an overview about proteomics studies in Mycobacterium tuberculosis exposed to some anti-tuberculosis drugs and new candidates, using two-dimensional gel electrophoresis and mass spectrometry. To date, that the authors have knowledge, this is the first studies that was performed specifically in M. tuberculosis using systematic review on electronic literature conducted in three databases using the following search terms: tuberculosis OR mycobacterium tuberculosis, proteome OR proteomics, and mass spectrometry electrospray ionization OR matrix-assisted laser desorption ionization OR two-dimensional gel electrophoresis. By electronic search, 622 abstracts of the original articles published from November 2003 to March 2016 were selected. After the selection, four articles fulfill proposed criteria and were included in this study. The studies reported changes in the protein profile of M. tuberculosis after exposure to isoniazid, ethambutol, streptomycin, ofloxacin, moxifloxacin and two new drugs candidates, SQ109 and ATB107. In conclusion, the proteins changes were related to the synthesis of mycolic acids, cellular metabolism pathways, bacterial stress and starvation. PMID- 28627739 TI - Use of a protein engineering strategy to overcome limitations in the production of "Difficult to Express" recombinant proteins. AB - Certain recombinant proteins are deemed "difficult to express" in mammalian expression systems requiring significant cell and/or process engineering to abrogate expression bottlenecks. With increasing demand for the production of recombinant proteins in mammalian cells, low protein yields can have significant consequences for industrial processes. To investigate the molecular mechanisms that restrict expression of recombinant proteins, naturally secreted model proteins were analyzed from the tissue inhibitors of metalloproteinase (TIMP) protein family. In particular, TIMP-2 and TIMP-3 were subjected to detailed study. TIMP proteins share significant sequence homology (~50% identity and ~70% similarity in amino acid sequence). However, they show marked differences in secretion in mammalian expression systems despite this extensive sequence homology. Using these two proteins as models, this study characterized the molecular mechanisms responsible for poor recombinant protein production. Our results reveal that both TIMP-2 and TIMP-3 are detectable at mRNA and protein level within the cell but only TIMP-2 is secreted effectively into the extracellular medium. Analysis of protein localization and the nature of intracellular protein suggest TIMP-3 is severely limited in its post translational processing. To overcome this challenge, modification of the TIMP-3 sequence to include a furin protease-cleavable pro-sequence resulted in secretion of the modified TIMP-3 protein, however, incomplete processing was observed. Based on the TIMP-3 data, the protein engineering approach was optimized and successfully applied in combination with cell engineering, the overexpression of furin, to another member of the TIMP protein family (the poorly expressed TIMP 4). Use of the described protein engineering strategy resulted in successful secretion of poorly (TIMP-4) and non-secreted (TIMP-3) targets, and presents a novel strategy to enhance the production of "difficult" recombinant targets. Biotechnol. Bioeng. 2017;114: 2348-2359. (c) 2017 Wiley Periodicals, Inc. PMID- 28627740 TI - Biofabrication of soft tissue templates for engineering the bone-ligament interface. AB - Regenerating damaged tissue interfaces remains a significant clinical challenge, requiring recapitulation of the structure, composition, and function of the native enthesis. In the ligament-to-bone interface, this region transitions from ligament to fibrocartilage, to calcified cartilage and then to bone. This gradation in tissue types facilitates the transfer of load between soft and hard structures while minimizing stress concentrations at the interface. Previous attempts to engineer the ligament-bone interface have utilized various scaffold materials with an array of various cell types and/or biological cues. The primary goal of this study was to engineer a multiphased construct mimicking the ligament bone interface by driving differentiation of a single population of mesenchymal stem cells (MSCs), seeded within blended fibrin-alginate hydrogels, down an endochondral, fibrocartilaginous, or ligamentous pathway through spatial presentation of growth factors along the length of the construct within a custom developed, dual-chamber culture system. MSCs within these engineered constructs demonstrated spatially distinct regions of differentiation, adopting either a cartilaginous or ligamentous phenotype depending on their local environment. Furthermore, there was also evidence of spatially defined progression toward an endochondral phenotype when chondrogenically primed MSCs within this construct were additionally exposed to hypertrophic cues. The study demonstrates the feasibility of engineering spatially complex soft tissues within a single MSC laden hydrogel through the defined presentation of biochemical cues. This novel approach represents a new strategy for engineering the ligament-bone interface. Biotechnol. Bioeng. 2017;114: 2400-2411. (c) 2017 Wiley Periodicals, Inc. PMID- 28627741 TI - Proteomics approach to identify novel metastatic bone markers from the secretome of PC-3 prostate cancer cells. AB - Prostate cancer is the leading type of cancer diagnosed, and the most frequent cause of worldwide male cancer-related deaths annually. The limitations of current prostate cancer screening tests demand the identification of novel biomarkers for the early diagnosis of prostate cancer bone metastasis. In the present study, we performed a proteomic analysis of secreted proteins from the prostate cancer bone metastasis cell line, PC-3, and the normal prostate cell line, RWPE-1. We thus quantified 917 proteins, of which 68 were found to be secreted at higher levels by PC-3 than by RWPE-1 cells via LC-MS/MS. To characterize the highly secreted proteins in the PC-3 cell line and thereby identify biomarker proteins, we divided the quantifiable proteins into four quantitative categories (Q1-Q4). The KEGG lysine degradation and osteoclast differentiation pathways were demonstrated to be enriched in the highly secreted Q4 protein group. Transforming growth factor (TGF) beta family proteins related to osteoclast differentiation were identified as key regulators of PC-3 cell proliferation. Immunoblotting was used to confirm the observed high level of pentraxin, follistatin, TGF-beta family members, and serpin B3 secretion by PC-3 cells. From the collective results of the present study, we suggest that serpin B3 is a promising novel biomarker candidate for the diagnosis of prostate cancer bone metastasis. PMID- 28627742 TI - Fabrication of single-walled carbon nanohorns incorporated a monolithic column for capillary electrochromatography. AB - Single-walled carbon nanohorns have received great interest for their unique properties and diverse potential applications. Herein, we demonstrated the feasibility of single-walled carbon nanohorns incorporated poly(styrene divinylbenzene) monolith as the stationary phase for capillary electrochromatography, which were prepared by one-step in situ copolymerization. Single-walled carbon nanohorns were dispersed in styrene to give a stable and homogeneous suspension. The monolithic column gave effective separation for a wide range of aromatic compounds, which was based on hydrophobicity and pi-pi electrostatic stacking of single-walled carbon nanohorns. The precisions of migration time and peak area varied in the ranges of 1.4-1.9% for intraday trials and 1.7-3.5% for interday trials, and 3.2-6.7% for intraday trials and 4.1-7.4% for interday trials, and 3.6-7.2% for inter-column trials and 5.2-21.3% for inter column trials, respectively, indicating the good reproducibility of single-walled carbon nanohorns embedded monolithic columns. PMID- 28627743 TI - Polygenic scores for schizophrenia and educational attainment are associated with behavioural problems in early childhood in the general population. AB - BACKGROUND: Genome-wide association studies in adults have identified numerous genetic variants related to psychiatric disorders and related traits, such as schizophrenia and educational attainment. However, the effects of these genetic variants on behaviour in the general population remain to be fully understood, particularly in younger populations. We investigated whether polygenic scores of five psychiatric disorders and educational attainment are related to emotional and behaviour problems during early childhood. METHODS: From the Generation R Study, we included participants with available genotype data and behavioural problems measured with the Child Behavior Checklist (CBCL) at the age of 3 (n = 1,902), 6 (n = 2,202) and 10 years old (n = 1,843). Polygenic scores were calculated for five psychiatric disorders and educational attainment. These polygenic scores were tested for an association with the broadband internalizing and externalizing problem scales and the specific CBCL syndrome scale scores. RESULTS: Analysis of the CBCL broadband scales showed that the schizophrenia polygenic score was associated with significantly higher internalizing scores at 3, 6 and 10 years and higher externalizing scores at age 3 and 6. The educational attainment polygenic score was associated with lower externalizing scores at all time points and lower internalizing scores at age 3. No associations were observed for the polygenic scores of bipolar disorder, major depressive disorder and autism spectrum disorder. Secondary analyses of specific syndrome scores showed that the schizophrenia polygenic score was strongly related to the Thought Problems scores. A negative association was observed between the educational attainment polygenic score and Attention Problems scores across all age groups. CONCLUSIONS: Polygenic scores for adult psychiatric disorders and educational attainment are associated with variation in emotional and behavioural problems already at a very early age. PMID- 28627744 TI - Femtosecond Charge-Injection Dynamics at Hybrid Perovskite Interfaces. AB - With a power conversion efficiency (PCE) exceeding 22 %, perovskite solar cells (PSCs) have thrilled photovoltaic research. However, the interface behavior is still not understood and is a hot topic of research: different processes occur over a hierarchy of timescales, from femtoseconds to seconds, which makes perovskite interface physics intriguing. Herein, through femtosecond transient absorption spectroscopy with spectral coverage extending into the crucial IR region, the ultrafast interface-specific processes at standard and newly molecularly engineered perovskite interfaces in state-of-the-art PSCs are interrogated. Ultrafast interfacial charge injection occurs with a time constant of 100 fs, resulting in hot transfer from energetic charges and setting the timescale for the first step involved in the complex charge-transfer process. This is also true for 20 % efficient devices measured under real operation, for which the femtosecond injection is followed by a slower picosecond component. These findings provide compelling evidence for the femtosecond interfacial charge injection step and demonstrate a robust method for the straightforward identification of interfacial non-equilibrium processes on the ultrafast timescale. PMID- 28627745 TI - 16-Year follow-up of an avulsed maxillary central incisor after replantation following 10-h storage: An unusual case. AB - Tooth avulsion is a type of dental injury defined as the complete displacement of a tooth out of the alveolar socket, and the lack of prompt treatment measures can result in the loss of function, poor quality of life, and psychological and social problems. However, several factors may not permit the immediate replantation of an avulsed tooth; therefore, delayed replantation has emerged as an alternative to meet the esthetic, functional, and psychological demands of patients. Here it was described that the successful replantation of an avulsed maxillary central incisor in a 9-year-old boy who presented at the clinic with the tooth stored in unfavorable conditions as dry and then in olive oil-milk mixture almost 10 h after the event. The tooth has remained in its socket healthy for 16 years after treatment. The patient was satisfied with both esthetics and function. PMID- 28627746 TI - Hepatic perivascular mesenchymal stem cells with myogenic properties. AB - Pericytes are multipotent mesenchymal stem cells located on the walls of blood vessels in various organs and are characterized as CD146+ cells. In this study, we first immunohistochemically detected pericytes in the perivascular regions of liver from two mouse genotypes, namely wild-type (WT) and myostatin null (Mstn-/- ). We further isolated pericytes using sorting as CD146+ CD34- CD56- CD45- cells. The main finding of this study involves the contrasting fibrogenic vs. myogenic behaviour of liver pericytes from WT and Mstn-/- mice, respectively. Sorted CD146+ liver pericytes (WT and Mstn-/- ) expressed PDGFRbeta, NG2, vimentin, adult stem cell markers CD73, CD105, CD44 and could be readily differentiated into adipogenic, osteogenic and chondrogenic lineages. Furthermore, these CD146+ cells from WT and Mstn-/- livers did not express myostatin, in contrast to the total liver tissue of WT. The absence of alphaSMA and GFAP made these cells easily distinguishable from hepatic stellate cells. When subjected to standard myogenic differentiation with low serum the CD146+ cells from WT liver differentiated into myofibroblasts (fibrogenic) and the CD146+ cells from Mstn-/- liver differentiated into multinucleated myotubes (myogenic). Finally, we transplanted CD146+ pericytes into tibialis anterior muscle of dystrophic mice and established the generation of novel myofibres, thereby proving their cell therapy potential. The liver tissue microenvironment with myostatin in WT and the absence of myostatin in Mstn-/- conditions might exert a paracrine effect in determining the fate of pericyte-like cells in the liver. PMID- 28627747 TI - Spontaneous intercostal artery bleeding in a hemodialysis patient. AB - Spontaneous rupture of an intercostal artery (ICA) is a rare but could be a life threatening emergency requiring prompt diagnosis and intervention for optimal outcome. We report a patient presented with swelling in his right-side back which started immediately after scheduled hemodialysis and continued to increase in size. Contrast computed tomography scan revealed soft tissue attenuated lesion with internal enhancing dots which suggested expanding hematoma with active bleeding. Arteriography detected focal contrast extravasation from seventh ICA, and transcatheter arterial embolization was successfully done. To the best of our knowledge, this is the first report describing spontaneous bleeding of ICA in a hemodialysis patient. PMID- 28627748 TI - On-line reaction monitoring by mass spectrometry, modern approaches for the analysis of chemical reactions. AB - The application of on-line mass spectrometry for direct analysis of chemical and other types of process continues to grow in importance and impact. The ability of the technique to characterize many aspects of a chemical reaction such as product and impurity formation, along with reactant consumption in a single experiment is key to its adoption and development. Innovations in ionization techniques and mass spectrometry instrumentation are enabling this adoption. An increasing range of ambient ionization techniques make on-line mass spectrometry applicable to a large range of chemistries. The academic development and commercialization of small footprint portable/transportable mass spectrometers is providing technology that can be positioned with any process under investigation. These developments, coupled with research into new ways of sampling representatively from both the condensed and gaseous phases, are positioning mass spectrometry as an essential technology for on-line process optimization, understanding and intelligent control. It is recognized that quantitative capability of mass spectrometry in this application can cause some resistance to its adoption, but research activities to tackle this limitation are on-going. PMID- 28627749 TI - Determining the impact of cell mixing on signaling during development. AB - Cell movement and intercellular signaling occur simultaneously to organize morphogenesis during embryonic development. Cell movement can cause relative positional changes between neighboring cells. When intercellular signals are local such cell mixing may affect signaling, changing the flow of information in developing tissues. Little is known about the effect of cell mixing on intercellular signaling in collective cellular behaviors and methods to quantify its impact are lacking. Here we discuss how to determine the impact of cell mixing on cell signaling drawing an example from vertebrate embryogenesis: the segmentation clock, a collective rhythm of interacting genetic oscillators. We argue that comparing cell mixing and signaling timescales is key to determining the influence of mixing. A signaling timescale can be estimated by combining theoretical models with cell signaling perturbation experiments. A mixing timescale can be obtained by analysis of cell trajectories from live imaging. After comparing cell movement analyses in different experimental settings, we highlight challenges in quantifying cell mixing from embryonic timelapse experiments, especially a reference frame problem due to embryonic motions and shape changes. We propose statistical observables characterizing cell mixing that do not depend on the choice of reference frames. Finally, we consider situations in which both cell mixing and signaling involve multiple timescales, precluding a direct comparison between single characteristic timescales. In such situations, physical models based on observables of cell mixing and signaling can simulate the flow of information in tissues and reveal the impact of observed cell mixing on signaling. PMID- 28627750 TI - Emergent Low-Symmetry Phases and Large Property Enhancements in Ferroelectric KNbO3 Bulk Crystals. AB - The design of new or enhanced functionality in materials is traditionally viewed as requiring the discovery of new chemical compositions through synthesis. Large property enhancements may however also be hidden within already well-known materials, when their structural symmetry is deviated from equilibrium through a small local strain or field. Here, the discovery of enhanced material properties associated with a new metastable phase of monoclinic symmetry within bulk KNbO3 is reported. This phase is found to coexist with the nominal orthorhombic phase at room temperature, and is both induced by and stabilized with local strains generated by a network of ferroelectric domain walls. While the local microstructural shear strain involved is only ~0.017%, the concurrent symmetry reduction results in an optical second harmonic generation response that is over 550% higher at room temperature. Moreover, the meandering walls of the low symmetry domains also exhibit enhanced electrical conductivity on the order of 1 S m-1 . This discovery reveals a potential new route to local engineering of significant property enhancements and conductivity through symmetry lowering in ferroelectric crystals. PMID- 28627751 TI - Synthesis of gem-Dinitromethylated and Fluorodinitromethylated Derivatives of 5,5'-Dinitro-bis-1,2,4-triazole as Promising High-Energy-Density Materials. AB - gem-Dinitromethylated and fluorodinitromethylated 5,5'-dinitro-3,3'-bis-1,2,4 triazole (DNBT) (2 and 3) along with seven ionic derivatives 4-9, were synthesized and characterized by NMR and IR spectroscopies, elemental analysis, single-crystal X-ray diffraction (XRD), and differential scanning calorimetry (DSC). XRD revealed that compounds 2 and 3 crystallized in the monoclinic P21 /n space group and compound 5 crystallized in the monoclinic P21 /c space group. The physicochemical properties of the as-synthesized compounds 2-9 were investigated and the results indicated that compounds 3, 6, and 7 exhibited a good balance between high energy and low sensitivity, demonstrating their potential as new high-energy-density materials (HEDMs). The proposed synthetic strategy for introducing gem-dinitromethyl and fluorodinitromethyl groups into the DNBT framework to prepare materials with high energy and low sensitivity suitable for HEDMs looks promising. PMID- 28627752 TI - Patterning on Topography for Generation of Cell Culture Substrates with Independent Nanoscale Control of Chemical and Topographical Extracellular Matrix Cues. AB - The cell microenvironment plays an important role in many biological processes, including development and disease progression. Key to this is the extracellular matrix (ECM), a complex biopolymer network serving as the primary insoluble signaling network for physical, chemical, and mechanical cues. In vitro, the ability to engineer the ECM at the micro- and nanoscales is a critical tool to systematically interrogate the influence of ECM properties on cellular responses. Specifically, both topographical and chemical surface patterning has been shown to direct cell alignment and tissue architecture on biomaterial surfaces, however, it has proven challenging to independently control these surface properties. This protocol describes a method termed Patterning on Topography (PoT) to engineer 2D nanopatterns of ECM proteins onto topographically complex substrates, which enables independent control of physical and chemical surface properties. Applications include interrogation of fundamental cell-surface interactions and engineering interfaces that can direct cell and/or tissue function. (c) 2017 by John Wiley & Sons, Inc. PMID- 28627753 TI - Traction Force Microscopy in 3-Dimensional Extracellular Matrix Networks. AB - Cell migration through a three-dimensional (3-D) matrix depends strongly on the ability of cells to generate traction forces. To overcome the steric hindrance of the matrix, cells need to generate sufficiently high traction forces but also need to distribute these forces spatially in a migration-promoting way. This unit describes a protocol to measure spatial maps of cell traction forces in 3-D biopolymer networks such as collagen, fibrin, or Matrigel. Traction forces are computed from the relationship between measured force-induced matrix deformations surrounding the cell and the known mechanical properties of the matrix. The method does not rely on knowledge of the cell surface coordinates and takes nonlinear mechanical properties of the matrix into account. (c) 2017 by John Wiley & Sons, Inc. PMID- 28627754 TI - Labeling and Magnetic Resonance Imaging of Exosomes Isolated from Adipose Stem Cells. AB - Adipose stem cells (ASC) represent a promising therapeutic approach for neurodegenerative diseases. Most biological effects of ASC are probably mediated by extracellular vesicles, such as exosomes, which influence the surrounding cells. Current development of exosome therapies requires efficient and noninvasive methods to localize, monitor, and track the exosomes. Among imaging methods used for this purpose, magnetic resonance imaging (MRI) has advantages: high spatial resolution, rapid in vivo acquisition, and radiation-free operation. To be detectable with MRI, exosomes must be labeled with MR contrast agents, such as ultra-small superparamagnetic iron oxide nanoparticles (USPIO). Here, we set up an innovative approach for exosome labeling that preserves their morphology and physiological characteristics. We show that by labeling ASC with USPIO before extraction of nanovesicles, the isolated exosomes retain nanoparticles and can be visualized by MRI. The current work aims at validating this novel USPIO-based exosome labeling method by monitoring the efficiency of the labeling with MRI both in ASC and in exosomes. (c) 2017 by John Wiley & Sons, Inc. PMID- 28627755 TI - Labeling DNA Replication Foci to Visualize Chromosome Territories In Vivo. AB - While a detailed understanding of chromatin dynamics is needed to explain how higher-order chromatin organization influences nuclear function, the molecular principles that regulate chromatin mobility in mammalian nuclei remain largely unknown. Here we describe experimental tools to follow chromatin dynamics by labeling DNA during S phase. Using these methods, we have found that foci labeled during early and mid/late S phase have significantly different dynamic behavior. Spatially constrained heterochromatic foci restrict long-range transformations of the chromosome territory (CT) structure while providing a structural framework on which highly mobile euchromatic foci undergo positional oscillations that drive local changes in the chromosome shape. Despite often dramatic mobility, we have demonstrated a preservation of structural integrity which ensures that DNA from neighboring CTs is not able to mix freely within the same nuclear space. Finally, other potential applications of the presented protocols are discussed. (c) 2017 by John Wiley & Sons, Inc. PMID- 28627756 TI - Microcontact Peeling: A Cell Micropatterning Technique for Circumventing Direct Adsorption of Proteins to Hydrophobic PDMS. AB - Microcontact printing (MUCPr) is one of the most popular techniques used for cell micropatterning. In conventional MUCPr, a polydimethylsiloxane (PDMS) stamp with microfeatures is used to adsorb extracellular matrix (ECM) proteins onto the featured surface and transfer them onto particular areas of a cell culture substrate. However, some types of functional proteins other than ECM have been reported to denature upon direct adsorption to hydrophobic PDMS. Here we describe a detailed protocol of an alternative technique--microcontact peeling (MUCPe)- that allows for cell micropatterning while circumventing the step of adsorbing proteins to bare PDMS. This technique employs microfeatured materials with a relatively high surface energy such as copper, instead of using a microfeatured PDMS stamp, to peel off a cell-adhesive layer present on the surface of substrates. Consequently, cell-nonadhesive substrates are exposed at the specific surface that undergoes the physical contact with the microfeatured material. Thus, although MUCPe and MUCPr are apparently similar, the former does not comprise a process of transferring biomolecules through hydrophobic PDMS. (c) 2017 by John Wiley & Sons, Inc. PMID- 28627757 TI - Super-Resolution Microscopy and Single-Protein Tracking in Live Bacteria Using a Genetically Encoded, Photostable Fluoromodule. AB - Visualization of dynamic protein structures in live cells is crucial for understanding the mechanisms governing biological processes. Fluorescence microscopy is a sensitive tool for this purpose. In order to image proteins in live bacteria using fluorescence microscopy, one typically genetically fuses the protein of interest to a photostable fluorescent tag. Several labeling schemes are available to accomplish this. Particularly, hybrid tags that combine a fluorescent or fluorogenic dye with a genetically encoded protein (such as enzymatic labels) have been used successfully in multiple cell types. However, their use in bacteria has been limited due to challenges imposed by a complex bacterial cell wall. Here, we describe the use of a genetically encoded photostable fluoromodule that can be targeted to cytosolic and membrane proteins in the Gram negative bacterium Caulobacter crescentus. Additionally, we summarize methods to use this fluoromodule for single protein imaging and super-resolution microscopy using stimulated emission depletion. (c) 2017 by John Wiley & Sons, Inc. PMID- 28627758 TI - Spectral library-based glycopeptide analysis-detection of circulating galectin-3 binding protein in pancreatic cancer. AB - PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease characterized by its late diagnosis, poor prognosis and rapid development of drug resistance. Using the data-independent acquisition (DIA) technique, the authors applied a spectral library-based proteomic approach to analyze N-glycosylated peptides in human plasma, in the context of pancreatic cancer study. EXPERIMENTAL DESIGN: The authors extended the application of DIA to the quantification of N glycosylated peptides enriched from plasma specimens from a clinically well defined cohort that consists of patients with early stage PDAC, chronic pancreatitis and healthy subjects. RESULTS: The analytical platform was evaluated in light of its robustness for quantitative analysis of large-scale clinical specimens. The authors analysis indicated that the level of N-glycosylated peptides derived from galectin-3 binding proteins (LGALS3BP) were frequently elevated in plasma from PDAC patients, concurrent with the altered N glycosylation of LGALS3BP observed in the tumor tissue. CONCLUSION AND CLINICAL RELEVANCE: The glycosylation form of LGALS3BP influences its function in the galectin network, which profoundly involves in cancer progression, immune response and drug resistance. As one of the major binding ligands of galectin network, discovery of site specific N-glycosylation changes of LGALS3BP in association of PDAC may provide useful clues to facilitate cancer detection or phenotype stratification. PMID- 28627759 TI - Vibrational biospectroscopy characterizes biochemical differences between cell types used for toxicological investigations and identifies alterations induced by environmental contaminants. AB - The use of cell-based assays is essential in reducing the number of vertebrates used in the investigation of chemical toxicities and in regulatory toxicology assessment. An important factor in obtaining meaningful results that can be accurately extrapolated is the use of biologically appropriate cell lines. In the present preliminary study, attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy with multivariate analysis was used to assess the fundamental biomolecular differences between a commonly used cell line, MCF-7 cells, and an environmentally relevant cell line derived from mallard (Anas platyrhynchos) dermal fibroblasts. To better understand differences in basic cell biochemistry, the cells were analyzed in the untreated state or post exposure to polychlorinated biphenyl (PCB) and polybrominated diphenyl ester (PBDE) congeners. The main spectral peaks in spectra from both cell types were associated with cellular macromolecules, particularly proteins and lipids, but the spectra also revealed some cell-specific differences. Spectra from untreated mallard fibroblasts spectra contained a large peak associated with lipids. The cell-related differences in lipids and deoxyribonucleic acid (DNA) were also identified as regions of spectral alteration induced by PBDE and PCB exposure. Although lipid alterations were observed in post treatment spectra from both cell types, these may be of more significance to mallard fibroblasts, which may be the result of increased intracellular lipid as determined by Nile red staining. Untreated MCF-7 cell spectra contained unique peaks related to DNA and nucleic acids. The DNA-associated spectral regions were also identified as areas of considerable alteration in MCF-7 cells exposed to some congeners including PBDE 47 and PCB 153. The findings indicate that in their native state, MCF-7 and mallard cells have unique biochemical differences, which can be identified using ATR-FTIR spectroscopy. Such differences in biochemical composition may influence cell susceptibility to environmental contaminants and therefore influence the choice of cell type used in toxicology experiments. To our knowledge, the present study is the first study to analyze the biochemistry of a mallard dermal fibroblast cell line and to use ATR-FTIR spectroscopy for this purpose. Thus ATR FTIR spectroscopy is demonstrated to be a useful tool for exploration of biomolecular variation at the cellular level and with further development, it could be used as part of a panel of cell-based assays to indicate when different results might be seen in environmental species compared with currently used cell lines. Environ Toxicol Chem 2017;36:3127-3137. (c) 2017 SETAC. PMID- 28627760 TI - Reproductive phenology of Melastomataceae species with contrasting reproductive systems: contemporary and historical drivers. AB - Flowering and fruiting are key events in the life history of plants, and both are critical to their reproductive success. Besides the role of evolutionary history, plant reproductive phenology is regulated by abiotic factors and shaped by biotic interactions with pollinators and seed dispersers. In Melastomataceae, a dominant Neotropical family, the reproductive systems vary from allogamous with biotic pollination to apomictic, and seed dispersal varies from dry (self-dispersed) to fleshy (animal-dispersed) fruits. Such variety in reproductive strategies is likely to affect flowering and fruiting phenologies. In this study, we described the reproductive phenology of 81 Melastomataceae species occurring in two biodiversity hotspots: the Atlantic rain forest and the campo rupestre. We aim to disentangle the role of abiotic and biotic factors defining flowering and fruiting times of Melastomataceae species, considering the contrasting breeding and seed dispersal systems, and their evolutionary history. In both vegetation types, pollinator-dependent species had higher flowering seasonality than pollinator-independent ones. Flowering patterns presented phylogenetic signal regardless of vegetation type. Fruiting of fleshy-fruited species was seasonal in campo rupestre but not in Atlantic rain forest; the fruiting of dry-fruited species was also not seasonal in both vegetation types. Fruiting showed a low phylogenetic signal, probably because the influence of environment and dispersal agents on fruiting time is stronger than the phylogenetic affinity. Considering these ecophylogenetic patterns, our results indicate that flowering may be shaped by the different reproductive strategies of Melastomataceae lineages, while fruiting patterns may be governed mainly by the seed dispersal strategy and flowering time, with less phylogenetic influence. PMID- 28627762 TI - Quantitative NMR Approach to Optimize the Formation of Chemical Building Blocks from Abundant Carbohydrates. AB - The future role of biomass-derived chemicals relies on the formation of diverse functional monomers in high yields from carbohydrates. Recently, it has become clear that a series of alpha-hydroxy acids, esters, and lactones can be formed from carbohydrates in alcohol and water solvents using tin-containing catalysts such as Sn-Beta. These compounds are potential building blocks for polyesters bearing additional olefin and alcohol functionalities. An NMR approach was used to identify, quantify, and optimize the formation of these building blocks in the Sn-Beta-catalyzed transformation of abundant carbohydrates. Record yields of the target molecules can be achieved by obstructing competing reactions through solvent selection. PMID- 28627761 TI - Biological effects of hydrogen peroxide administered intratumorally with or without irradiation in murine tumors. AB - Despite insufficient laboratory data, radiotherapy after intratumoral injection of hydrogen peroxide (H2 O2 ) is increasingly being used clinically for radioresistant tumors. Especially, this treatment might become an alternative definitive treatment for early and advanced breast cancer in patients who refuse any type of surgery. The purpose of this study was to investigate the biological effects and appropriate combination methods of irradiation and H2 O2 in vivo. SCCVII tumor cells transplanted into the legs of C3H/HeN mice were used. Chronological changes of intratumoral distribution of oxygen bubbles after injection of H2 O2 were investigated using computed tomography. The effects of H2 O2 alone and in combination with single or five-fraction irradiation were investigated using a growth delay assay. The optimal timing of H2 O2 injection was investigated. Immunostaining of tumors was performed using the hypoxia marker pimonidazole. Oxygen bubbles decreased gradually and almost disappeared after 24 h. Administration of H2 O2 produced 2-3 days' tumor growth delay. Tumor regrowth was slowed further when H2 O2 was injected before irradiation. The group irradiated immediately after H2 O2 injection showed the longest tumor growth delay. Dose-modifying factors were 1.7-2.0 when combined with single irradiation and 1.3-1.5 with fractionated irradiation. Pimonidazole staining was weaker in tumors injected with H2 O2 . H2 O2 injection alone had modest antitumor effects. Greater tumor growth delays were demonstrated by combining irradiation and H2 O2 injection. The results of the present study could serve as a basis for evaluating results of various clinical studies on this treatment. PMID- 28627763 TI - Suspected Methadone Toxicity: from Hospital to Autopsy Bed. AB - High mortality rates have been reported for methadone in both adults and children. We aimed to determine the pattern of toxicity, possible underlying diseases and treatment challenges in patients referred to our centre with early diagnosis of methadone toxicity and who later died. Medical files of all methadone-poisoned patients who had been admitted to a referral centre of toxicology between March 2011 and March 2016, died during the hospital stay and sent for autopsy to Legal Medicine Organization were retrospectively evaluated. In a total of 94 patients, autopsy findings and laboratory evaluations showed that cause of death was pure methadone toxicity in 57 (60.6%). Other causes of death were ischaemic heart disease in ten, co-ingestions (toxicities including methadone) in eight, brain haemorrhage, multi-organ failure and pneumosepsis (each in four), meningitis/encephalitis in three and head trauma and other toxicities (other than methadone but including an opioid, each in two) patients. Time of cardiopulmonary arrest was significantly different between those with pure methadone toxicity and those who died due to other causes (p = 0.01). Patients who had died due to co-ingestions and other toxicities were younger (p = 0.029) and took more bolus doses of naloxone (p = 0.042). In methadone users, especially in older ages and those with trivial response to naloxone administration, loss of consciousness should not be strictly attributed to methadone toxicity. In such patients, thorough evaluation for other possible causes of loss of consciousness is mandatory. PMID- 28627764 TI - A Simple Route to Strong Carbon-13 NMR Signals Detectable for Several Minutes. AB - Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) suffer from low sensitivity and limited nuclear spin memory lifetimes. Although hyperpolarization techniques increase sensitivity, there is also a desire to increase relaxation times to expand the range of applications addressable by these methods. Here, we demonstrate a route to create hyperpolarized magnetization in 13 C nuclear spin pairs that last much longer than normal lifetimes by storage in a singlet state. By combining molecular design and low field storage with para-hydrogen derived hyperpolarization, we achieve more than three orders of signal amplification relative to equilibrium Zeeman polarization and an order of magnitude extension in state lifetime. These studies use a range of specifically synthesized pyridazine derivatives and dimethyl p-tolyl phenyl pyridazine is the most successful, achieving a lifetime of about 190 s in low field, which leads to a 13 C-signal that is visible for 10 minutes. PMID- 28627765 TI - Measurement of surface topography and stiffness distribution on cross-section of Xenopus laevis tailbud for estimation of mechanical environment in embryo. AB - The stress distribution inside a Xenopus laevis tailbud embryo was estimated to examine the cause of the straightening and elongation. The embryos were cut in the middle, yielding a cross-section perpendicular to the body axis. The section was not flat, owing to the residual stress relief. The stress needed to restore the flatness corresponded to the stress inside the embryo and was calculated using the surface topography and Young's-moduli in the section. We found the areas of the notochord (Nc), neural tube (NT), and abdominal tissue (AT) bulged in the cross-section, which revealed that compressive forces acted in these tissues. The moduli of the Nc, NT, and AT were in the order of several thousand, hundred, and tens of pascals, respectively. In the Nc, the compressive force was largest and increased with the development, suggesting Nc playing a central role in the elongation. The bending moment generated by the AT was 10 times higher than that by the Nc in the early stages of the tailbud formation, and the two were similar in the latter stages, suggesting that the compressive force in the AT was the major cause of the straightening during the early stage. The straightening and elongation could be orchestrated by changes in the compressive forces acting on the Nc, NT, and AT over time. For the sake of simplicity, we calculated the compressive force only and neglected the tensile force. Thus, it should be noted that the amount of the compressive force was somewhat overestimated. PMID- 28627766 TI - Recent applications of metal-organic frameworks in sample pretreatment. AB - Metal-organic frameworks are promising materials in diverse analytical applications especially in sample pretreatment by virtue of their diverse structure topology, tunable pore size, permanent nanoscale porosity, high surface area, and good thermostability. According to hydrostability, metal-organic frameworks are divided into moisture-sensitive and water-stable types. In the actual applications, both kinds of metal-organic frameworks are usually engineered into hybrid composites containing magnetite, silicon dioxide, graphene, or directly carbonized to metal-organic frameworks derived carbon. These metal-organic frameworks based materials show good extraction performance to environmental pollutants. This review provides a critical overview of the applications of metal-organic frameworks and their composites in sample pretreatment modes, that is, solid-phase extraction, magnetic solid-phase extraction, micro-solid-phase extraction, solid-phase microextraction, and stir bar solid extraction. PMID- 28627767 TI - Clinical significance of post-progression survival in lung cancer. AB - Progression-free survival (PFS) and overall survival (OS) are two common endpoints in cancer trials. OS is usually preferred, because it is reliable, precise, meaningful, and can easily be documented. However, subsequent lines of therapy might confound the effects of first-line treatment on OS. Whether PFS or OS is the more appropriate endpoint in clinical trials of metastatic cancer remains controversial. Previous reports on lung cancer have shown that an increase in PFS does not necessarily result in an increase in OS; however, post progression survival (PPS) is strongly associated with OS after early-line treatment. The significance of PPS after first and second-line therapy at the individual level in patients with advanced lung cancer has also recently been reported. Findings of previous reports indicate that PPS is highly associated with OS after first and second-line chemotherapy in patients with advanced non small cell lung cancer and small cell lung cancer, whereas PFS is only moderately associated with OS. Therefore, subsequent treatment after disease progression following early-line treatments may greatly influence OS. This review demonstrates that even in advanced lung cancer, PPS, rather than PFS, has become more strongly associated with OS over the years, potentially because of intensive post-study treatments. As a result of the increasing impact of PPS on OS, a PFS related advantage does not necessarily indicate an OS-related advantage. Thus, the prolongation of PPS might limit the classical role of OS for assessing true efficacy derived from early-line chemotherapy in future clinical trials. PMID- 28627768 TI - Spatially Resolved Large Magnetization in Ultrathin BiFeO3. AB - Here, a quantitative magnetic depth profile across the planar interfaces in BiFeO3 /La0.7 Sr0.3 MnO3 (BFO/LSMO) superlattices using polarized neutron reflectometry is obtained. An enhanced magnetization of 1.83 +/- 0.16 MUB /Fe in BFO layers is observed when they are interleaved between two manganite layers. The enhanced magnetic order in BFO persists up to 200 K. The depth dependence of magnetic moments in BFO/LSMO superlattices as a function of the BFO layer thickness is also explored. The results show the enhanced net magnetic moment in BFO from the LSMO/BFO interface extends 3-4 unit cells into BFO. The interior part of a thicker BFO layer has a much smaller magnetization, suggesting it still keeps the small canted AFM state. The results exclude charge transfer, intermixing, epitaxial strain, and octahedral rotations/tilts as dominating mechanisms for the large net magnetization in BFO. An explanation-one suggested by others previously and consistent with the observations-attributes the temperature dependence of the net magnetization of BFO to strong orbital hybridization between Fe and Mn across the interfaces. Such orbital reconstruction would establish an upper temperature limit for magnetic ordering of BFO. PMID- 28627769 TI - Corneal ring infiltrate secondary to Staphylococcus aureus-induced endogenous endophthalmitis: a case report. PMID- 28627770 TI - Electrochemically Powered, Energy-Conserving Carbon Nanotube Artificial Muscles. AB - While artificial muscle yarns and fibers are potentially important for many applications, the combination of large strokes, high gravimetric work capacities, short cycle times, and high efficiencies are not realized for these fibers. This paper demonstrates here electrochemically powered carbon nanotube yarn muscles that provide tensile contraction as high as 16.5%, which is 12.7 times higher than previously obtained. These electrochemical muscles can deliver a contractile energy conversion efficiency of 5.4%, which is 4.1 times higher than reported for any organic-material-based artificial muscle. All-solid-state parallel muscles and braided muscles, which do not require a liquid electrolyte, provide tensile contractions of 11.6% and 5%, respectively. These artificial muscles might eventually be deployed for a host of applications, from robotics to perhaps even implantable medical devices. PMID- 28627771 TI - Clinical Experience with the Integrase Inhibitors Dolutegravir and Elvitegravir in HIV-infected Patients: Efficacy, Safety and Tolerance. AB - Two integrase inhibitors (INSTIs), dolutegravir (DTG) and elvitegravir/cobicistat (EVG/COBI), have joined recently the pharmacotherapy arsenal against HIV. This study evaluated the efficacy and tolerability of these INSTIs in the last two years. A retrospective observational study in patients who started DTG or EVG/COBI from January 2015 to January 2017 at a reference hospital in north western Spain was done. Epidemiological, clinical and immunovirological data were recorded. A statistical analysis was performed with SPSS software. A total of 542 DTG (n = 275)- or EVG/COBI (n = 267)-based therapies were initiated during the study period. Overall, more than 90% of naive and pre-treated patients had virological suppression in both groups after 48 weeks of initiation of treatment per-protocol snapshot analysis. During follow-up, 10.2% of patients were treated with DTG and 4.5% of those treated with EVG discontinued due to adverse events (AE). In the case of DTG mainly related to neuropsychiatric disturbances (70.4%) and for EVG/COBI with gastrointestinal discomfort (50%). Female sex [HR 2.255 (95%CI 1.121-4.535), p = 0.023] and DTG treatment [HR 2.453 (95%CI 1.221-4.931), p = 0.012] were associated with AE discontinuations. Specifically for neuropsychiatric events, DTG treatment [HR 5.906 (95%CI 1.954-17.846), p = 0.002] and receiving abacavir/lamivudine/DTG [HR 4.380 (95%CI 1.348-14.233), p = 0.014] were identified as predictive risk factors for treatment discontinuations in two different multivariate analyses. A high percentage of AE discontinuations not previously described in clinical trials has been observed, especially with DTG. Female gender and DTG treatment were identified as risk factors for AE discontinuation. DTG-based therapies, especially in combination with abacavir/lamivudine, were associated with an increased risk of treatment discontinuation due to neuropsychiatric AE. PMID- 28627772 TI - Bactericidal Effect of Calcium Oxide (Scallop-Shell Powder) Against Pseudomonas aeruginosa Biofilm on Quail Egg Shell, Stainless Steel, Plastic, and Rubber. AB - The aim of this study was to evaluate the bactericidal effect of calcium oxide (CaO) against Pseudomonas aeruginosa biofilms on quail eggshells and major egg contacting surfaces (stainless steel, plastic, and rubber). The samples were subjected to CaO treatments (0%, 0.01%, 0.05%, 0.10%, 0.15%, 0.20%, 0.25%, and 0.30%) for 1 min. All the CaO treatments significantly reduced P. aeruginosa biofilms on all tested surfaces as compared to controls. In comparison of biofilm stability, the strongest and most resistant biofilm was formed on eggshell against the CaO treatment, followed by rubber, stainless steel, and plastic. In evaluation of bactericidal effect, the largest reduction (3.16 log CFU) was observed in plastic even at the lowest concentration of CaO (0.01%), whereas the least reduction was found in eggshells, regardless of CaO concentration. In addition, stainless steel showed a significant reduction in biofilm formation at all concentrations except 0.10% to 0.15% CaO. At 0.30% CaO, the reduction of P. aeruginosa in biofilms on stainless steel, plastic, rubber, and eggshell were 5.48, 6.37, 4.87, and 3.14 log CFU/cm2 (CFU/egg), respectively. Biofilm reduction after CaO treatment was also observed by field emission scanning electron microscopy (FE-SEM). Based on the FE-SEM images, we observed that P. aeruginosa biofilms formed compact aggregations on eggshell surfaces with CaO treatments up to 0.30%. More specifically, a 0.20% CaO treatment resulted in the reductions of 3 to 6 log CFU in all materials. PMID- 28627774 TI - Decreased expression of WNT2 in villi of unexplained recurrent spontaneous abortion patients may cause trophoblast cell dysfunction via downregulated Wnt/beta-catenin signaling pathway. AB - WNT2 has been reported to be important for placental development, especially for the proper vascularization of the placenta. However, its precise role in first trimester trophoblast cells is still unknown. WNT2 expression in the villous tissues of unexplained recurrent spontaneous abortion (URSA) patients was compared with that of healthy women by Western blot. The function of WNT2 in HTR 8/SVneo trophoblast cells was evaluated by altering the cellular WNT2 level through overexpression and shRNA knockdown. The molecular mechanism of the effect of WNT2 on trophoblast cells was investigated. The association of WNT2 with the Wnt/beta-catenin signaling pathway was studied through Western blot and immunofluorescence. Results showed that WNT2 protein expression was significantly decreased in villi of the URSA group compared with the control group. In vitro studies showed that WNT2 could promote human trophoblast cell proliferation and migration through activating the Wnt/beta-catenin signaling pathway. Moreover, upon the knockdown of WNT2, trophoblast cell proliferation and migration were significantly suppressed. In conclusion, our study indicated that WNT2 plays an important role in trophoblast function. WNT2 insufficiency might cause impaired trophoblast cell proliferation and migration via downregulation of Wnt/beta catenin signaling pathway. PMID- 28627773 TI - Oleanolic acid derivative DKS26 exerts antidiabetic and hepatoprotective effects in diabetic mice and promotes glucagon-like peptide-1 secretion and expression in intestinal cells. AB - BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) is an important target for diabetes therapy based on its key role in maintaining glucose and lipid homeostasis. This study was designed to investigate antidiabetic and hepatoprotective effects of a novel oleanolic acid derivative DKS26 in diabetic mice and elucidate its underlying GLP-1 related antidiabetic mechanisms in vitro and in vivo. EXPERIMENTAL APPROACH: The therapeutic effects of DKS26 were investigated in streptozotocin (STZ)-induced and db/db diabetic mouse models. Levels of plasma glucose, glycosylated serum protein (GSP), lipid profiles, insulin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), oral glucose tolerance (OGT), pancreatic islets and hepatic histopathological morphology, liver lipid levels and expression of pro-inflammatory cytokines were assessed. Intestinal NCI-H716 cells and diabetic models were used to further validate its potential GLP-1-related antidiabetic mechanisms. KEY RESULTS: DKS26 treatment (100 mg.kg-1 .day-1 ) decreased plasma levels of glucose, GSP, ALT and AST; ameliorated OGT and plasma lipid profiles; augmented plasma insulin levels; alleviated islets and hepatic pathological morphology; and reduced liver lipid accumulation, inflammation and necrosis in vivo. Furthermore, DKS26 enhanced GLP 1 release and expression, accompanied by elevated levels of cAMP and phosphorylated PKA in vitro and in vivo. CONCLUSION AND IMPLICATIONS: DKS26 exerted hypoglycaemic, hypolipidaemic and islets protective effects, which were associated with an enhanced release and expression of GLP-1 mediated by the activation of the cAMP/PKA signalling pathway, and alleviated hepatic damage by reducing liver lipid levels and inflammation. These findings firmly identified DKS26 as a new viable therapeutic option for diabetes control. PMID- 28627775 TI - Ensemble Architecture for Prediction of Enzyme-ligand Binding Residues Using Evolutionary Information. AB - Enzyme interactions with ligands are crucial for various biochemical reactions governing life. Over many years attempts to identify these residues for biotechnological manipulations have been made using experimental and computational techniques. The computational approaches have gathered impetus with the accruing availability of sequence and structure information, broadly classified into template-based and de novo methods. One of the predominant de novo methods using sequence information involves application of biological properties for supervised machine learning. Here, we propose a support vector machines-based ensemble for prediction of protein-ligand interacting residues using one of the most important discriminative contributing properties in the interacting residue neighbourhood, i. e., evolutionary information in the form of position-specific- scoring matrix (PSSM). The study has been performed on a non redundant dataset comprising of 9269 interacting and 91773 non-interacting residues for prediction model generation and further evaluation. Of the various PSSM-based models explored, the proposed method named ROBBY (pRediction Of Biologically relevant small molecule Binding residues on enzYmes) shows an accuracy of 84.0 %, Matthews Correlation Coefficient of 0.343 and F-measure of 39.0 % on 78 test enzymes. Further, scope of adding domain knowledge such as pocket information has also been investigated; results showed significant enhancement in method precision. Findings are hoped to boost the reliability of small-molecule ligand interaction prediction for enzyme applications and drug design. PMID- 28627777 TI - Cation-Driven Self-Assembly of a Gold(I)-Based Metallo-Tweezer. AB - A combination of self-complementary pi-pi-stacking interactions and metallophilic interactions triggered the self-assembly of a new digold(I) metallo-tweezer in the presence of several types of M+ ions. Titrations by fluorescence spectroscopy enabled the determination of the association constants of the resulting inclusion duplex complexes. PMID- 28627776 TI - The Catechol-O-methyltransferase Val(108/158)Met Genetic Polymorphism cannot be Recommended as a Biomarker for the Prediction of Venlafaxine Efficacy in Patients Treated in Psychiatric Settings. AB - The antidepressant venlafaxine is known to increase the turnover of cerebral monoamines, which are catabolized by the catechol-O-methyltransferase (COMT). The COMT (Val(108/158)Met, rs4680) genetic polymorphism affects the cerebral COMT activity. But whether this genetic polymorphism is associated with response to venlafaxine remains unclear. We assessed the impact of the COMT Val(108/158)Met, rs4680 genetic polymorphism on the efficacy of venlafaxine in depressed patients. This study was nested in the METADAP cohort, a real-world naturalistic treatment study in psychiatric settings. A total of 206 Caucasian patients with a unipolar major depressive episode (DSM-IVTR) treated with venlafaxine and evaluated with the Hamilton Depression Rating Scale (HDRS) were studied. One hundred and eighty patients were genotyped for the COMT Val(108/158)Met, rs4680 genetic polymorphism and classified into three genotype subgroups: Val/Val, Val/Met and Met/Met. The COMT genotype was the explanatory variable, and the variables to be explained were HDRS score, HDRS score improvement over time, response rate and remission rate. Venlafaxine had a trend to higher efficacy in the Val/Val patients as compared to Met/Met carriers, as shown by the HDRS score improvement after 3 months of treatment, but this result was not significant in mixed models [Val/Val: 59.78% (+/-22.4); Val/Met: 51.64% (+/-26.3); Met/Met: 39.52% (+/ 27.6)]. The percentage of responders and remitters after 3 months of treatment was not significantly different in the three genotype groups, although coherent trends were shown. The COMT Val(108/158)Met, rs4680 genetic polymorphism cannot be recommended as a biomarker for the prediction of venlafaxine efficacy in patients treated in psychiatric settings. PMID- 28627778 TI - Engineering CHO cells with an oncogenic KIT improves cells growth, resilience to stress, and productivity. AB - An optimized biomanufacturing process in mammalian cells is contingent on the ability of the producing cells to reach high viable cell densities. In addition, at the peak of growth, cells need to continue producing the biological entity at a consistent quality. Thus, engineering cells with robust growth performance and resilience to variable stress conditions is highly desirable. The tyrosine kinase receptor, KIT, plays a key role in cell differentiation and the survival of several immune cell types. Its oncogenic mutant, D816V, endows cells with high proliferation capacity, and resistance to kinase inhibitors. Importantly, this onco-KIT mutant when introduced into various cell types is arrested in the endoplasmic reticulum in a constitutively active form. Here, we investigated the effect of oncogenic D816V KIT on the performance of CHO-K1 cells under conventional tissue culture growth settings and when adapted, to shaking conditions. The onco-KIT promoted global protein synthesis, elevated the expression of a secretable transgene, enhanced proliferation, and improved the overall titers of a model glycoprotein. Moreover, the expression of the onco-KIT endowed the cells with a remarkable resistance to various stress conditions. Our data suggest that the introduction of onco-KIT can serve as a strategy for improving glycoprotein biomanufacturing. Biotechnol. Bioeng. 2017;114: 2560-2570. (c) 2017 Wiley Periodicals, Inc. PMID- 28627779 TI - New horizon for breast cancer biomarker discoveries: What might the liquid biopsy of nipple aspirate fluid hold? AB - The existence of cellular, molecular and biochemical heterogeneity of human breast cancers reveals the intricacy of biomarkers complexity, stimulating studies on new approaches (like "liquid biopsies") for the improvements in precision medicine. Breast cancer is recognized as a leading cause of morbidity and mortality worldwide with tumors significantly diverse and containing many types of cells showing different genetic and epigenetic profiles. In this field, the technology of liquid biopsy (applied to a fluid produced by breast gland, named nipple aspirate fluids, NAF) highlights the power of combining basic and clinical research. NAF is the mirror of the entire ductal/alveolar breast tree providing almost complete proteomic profile and a valuable source for biomarker discovery, in non-invasive manner than tissue biopsies. The liquid biopsy technology using NAF may represent the outstanding breakthrough of proteomic cancer research revealing novel diagnostic and prognostic applications. In conjunction to metabolomic and degradome profiling, the use of NAF as liquid biopsy approach will improve the detection of changes in the cellular microenvironment of the breast tumors, understanding molecular and biochemical mechanisms which drive breast tumor initiation, maintenance and progression, and finally enhancing the development of novel drug targets and new treatment strategies. PMID- 28627781 TI - Retraction: 'Early hominin biogeography in Island Southeast Asia' by Roy Larick and Russell L. Ciochon. PMID- 28627780 TI - From Lithium-Ion to Sodium-Ion Batteries: Advantages, Challenges, and Surprises. AB - Mobile and stationary energy storage by rechargeable batteries is a topic of broad societal and economical relevance. Lithium-ion battery (LIB) technology is at the forefront of the development, but a massively growing market will likely put severe pressure on resources and supply chains. Recently, sodium-ion batteries (SIBs) have been reconsidered with the aim of providing a lower-cost alternative that is less susceptible to resource and supply risks. On paper, the replacement of lithium by sodium in a battery seems straightforward at first, but unpredictable surprises are often found in practice. What happens when replacing lithium by sodium in electrode reactions? This review provides a state-of-the art overview on the redox behavior of materials when used as electrodes in lithium ion and sodium-ion batteries, respectively. Advantages and challenges related to the use of sodium instead of lithium are discussed. PMID- 28627782 TI - Elwyn LaVerne Simons: 1930-2016. PMID- 28627783 TI - Elwyn Simons: Opening windows into Madagascar's past. PMID- 28627784 TI - Dr. Elwyn LaVerne Simons: Leader in Lemur Conservation. PMID- 28627785 TI - Species, genera, and phylogenetic structure in the human fossil record: a modest proposal. AB - Because of the greater morphological distances among them, genera should be more robustly recognizable in the fossil record than species are. But there are clearly upper as well as lower bounds to their species inclusivity. Currently, the vast majority of fossils composing the large and rapidly expanding paleoanthropological record are crammed into one of two genera (Australopithecus vs Homo), expanding the latter, especially, far beyond any reasonable morphological or phylogenetic limits. This excessive inclusivity obscures both diversity and the complexities of phylogenetic structure within the hominid family. PMID- 28627786 TI - The North African Middle Stone Age and its place in recent human evolution. AB - The North African Middle Stone Age (NAMSA, ~300-24 thousand years ago, or ka) features what may be the oldest fossils of our species as well as extremely early examples of technological regionalization and 'symbolic' material culture (d'Errico, Vanhaeren, Barton, Bouzouggar, Mienis, Richter, Hublin, McPherron, Louzouet, & Klein, ; Scerri, ; Richter, Grun, Joannes-Boyau, Steele, Amani, Rue, Fernandes, Raynal, Geraads, Ben-Ncer Hublin, McPherron, ). The geographic situation of North Africa and an increased understanding of the wet-dry climatic pulses of the Sahara Desert also show that North Africa played a strategic role in continental-scale evolutionary processes by modulating human dispersal and demographic structure (Drake, Blench, Armitage, Bristow, & White, ; Blome, Cohen, Tryon, Brooks, & Russell, ). However, current understanding of the NAMSA remains patchy and subject to a bewildering array of industrial nomenclatures that mask underlying variability. These issues are compounded by a geographic research bias skewed toward non-desert regions. As a result, it has been difficult to test long established narratives of behavioral and evolutionary change in North Africa and to resolve debates on their wider significance. In order to evaluate existing data and identify future research directions, this paper provides a critical overview of the component elements of the NAMSA and shows that the timing of many key behaviors has close parallels with others in sub-Saharan Africa and Southwest Asia. PMID- 28627787 TI - Psychiatric and cognitive characteristics of individuals with Danon disease (LAMP2 gene mutation). AB - Danon disease (DD) is a rare X-linked disorder caused by loss-of-function mutations in the LAMP2 gene, which encodes lysosome-associated membrane protein. It is characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Whereas the molecular and pathophysiological mechanisms underlying this disorder have been previously reported and continue to be explored, the cognitive deficits and psychiatric comorbidities manifested in DD remain an understudied topic. We systematically assessed cognitive abilities and psychiatric comorbidities in 13 males and females. Most of the participants in our cohort (n = 9; 75%) had an IQ score within the normal range, while only one participant had intellectual disability. Participants' performance on the Cognitive Neuropsychiatric Battery (CNB) showed only mildly impaired cognitive abilities in most modules, except in the executive functioning test, which was low compared to healthy controls. Of note, 69% of the participants met criteria for at least one psychiatric disorder, mainly mood and anxiety disorders, occurring alone or in combination in the same patient. The results of the present study challenge earlier reports suggesting that mental retardation is a core constituent in DD. Of importance, it underscores the need to refer Danon patients to psychiatric assessment. PMID- 28627788 TI - Risk factors associated with treatment refusal in lung cancer. AB - BACKGROUND: The incidence of lung cancer is increasing with longer life expectancy. Refusal of active treatment for cancer is prone to cause patients to experience more severe symptoms and shorten survival. The purpose of this study was to define the factors related to refusal or abandonment of active therapy in lung cancer. METHODS: We retrospectively reviewed the data of 617 patients from medical records from 2010 to 2014. Two groups were formed: 149 patients who refused anti-cancer treatment and allowed only palliative care were classified into the non-treatment group, while the remaining 468 who received anti-cancer treatment were classified into the treatment group. RESULTS: The groups differed significantly in age, employment, relationship status, number of offspring, educational status, body mass index, presence of chest and systemic symptoms, Charlson Comorbidity Index, Eastern Cooperative Oncology Group score, and tumor node metastasis stage ( P < 0.05). In logistic regression analysis, age (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.07-1.13), educational status lower than high school (OR 1.95, 95% CI 1.2-3.2), no history of surgery (OR 2.29, 95% CI 1.4-3.7), body mass index < 18.5 (OR 2.49, 95% CI 1.3-4.7), and a high Eastern Cooperative Oncology Group score of 3 or 4 (OR 5.02, 95% CI 2.3-10.8) were significant factors for refusal of cancer treatment. CONCLUSION: Individual factors, such as old age, low educational status, low weight, and poor performance status can influence refusal of cancer treatment in patients with lung cancer, and should be considered prior to consultation with patients. PMID- 28627789 TI - gamma-Functionalizations of Amines through Visible-Light-Mediated, Redox-Neutral C-C Bond Cleavage. AB - Cleavage of unstrained C-C bonds under mild, redox-neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible-light-mediated, gamma-functionalization of amines. In situ generated C centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp3 )-C(sp3 ), C(sp3 )-H and C(sp3 )-Br bonds, respectively. PMID- 28627790 TI - Regional cerebral blood flow in opiate dependence relates to substance use and neuropsychological performance. AB - Neuroimaging of opiate-dependent individuals indicates both altered brain structure and function. Magnetic resonance-based arterial spin labeling has been used to measure noninvasively cerebral blood flow (i.e. perfusion) in alcohol, tobacco and stimulant dependence; only one arterial spin labeling paper in opiate dependent individuals demonstrated frontal and parietal perfusion deficits. Additional research on regional brain perfusion in opiate dependence and its relationship to cognition and self-regulation (impulsivity, risk taking and decision making) may inform treatment approaches for opiate-dependent individuals. Continuous arterial spin labeling magnetic resonance imaging at 4 T and neuropsychological measures assessed absolute brain perfusion levels, cognition and self-regulation in 18 cigarette smoking opiate-dependent individuals (sODI) stable on buprenorphine maintenance therapy. The sODI were compared with 20 abstinent smoking alcohol-dependent individuals (a substance dependent control group), 35 smoking controls and 29 nonsmoking controls. sODI had lower perfusion in several cortical and subcortical regions including regions within the brain reward/executive oversight system compared with smoking alcohol dependent individuals and nonsmoking controls. Perfusion was increased in anterior cingulate cortex and globus pallidus of sODI. Compared with all other groups, sODI had greater age-related declines in perfusion in most brain reward/executive oversight system and some other regions. In sODI, lower regional perfusion related to greater substance use, higher impulsivity and weaker visuospatial skills. Overall, sODI showed cortical and subcortical hypoperfusion and hyperperfusion. Relating to neuropsychological performance and substance use quantities, the frontal perfusion alterations are clinically relevant and constitute potential targets for pharmacological and cognitive-based therapeutic interventions to improve treatment outcome in opiate dependence. PMID- 28627791 TI - No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct-acting antivirals for hepatitis C in a large real-world cohort. AB - BACKGROUND: Hepatitis B virus (HBV) reactivation has been observed following interferon (IFN)-based treatment in HBV/hepatitis C virus (HCV) co-infected patients. Recent reports suggest that reactivation may also occur in both hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative patients during HCV treatment with direct-acting antivirals (DAAs). AIM: To investigate the rate of patients with HBV reactivation during IFN-based and IFN-free HCV treatment in a large real-world cohort. METHODS: A total of 848 patients with chronic hepatitis C were treated with different combinations of DAAs. Among patients with available outcome and HBV data, there were 272 patients hepatitis B core antibody (HBcAb)-positive (HBsAg-positive, n=9; HBsAg-negative, n=263), and 536 were HBcAb negative. All HBcAb-positive patients were tested for HBV DNA at the end of DAA therapy and alanine transaminase (ALT) levels were frequently measured during therapy and follow-up. RESULTS: Seventy-three percent (n=192/263) of HBsAg negative/HBcAb-positive patients had elevated ALT levels at baseline, which declined to normal values in all but 18 patients, and no HBV reactivation was observed. Eight patients had detectable but not quantifiable HBV DNA (<20 IU/mL) at end of treatment, but none were associated with elevated ALT. Five of nine HBsAg-positive/HBcAb-positive patients experienced transient or permanent HBV reactivation, three of whom required nucleos(t)ide treatment during (n=1) or after (n=2) DAA therapy. CONCLUSIONS: HBV reactivation was not observed in HBsAg negative/HBcAb-positive patients but common in HBsAg-positive/HBcAb-positive patients treated with different combinations of DAAs for HCV. PMID- 28627795 TI - Keynote Speaker. PMID- 28627793 TI - Increased Sympathetic Outflow Induces Adaptation to Acute Experimental Pain. AB - BACKGROUND: There are interrelationships between the autonomic nervous system and pain. This study aims to explore the effect of different autonomic manipulations on pain perception and modulation. METHODS: Twenty healthy subjects (10 men and 10 women, mean age 25 +/- 3 years) participated in this single-blinded, semi randomized, controlled study, which included 2 study visits. Warm detection thresholds, heat pain thresholds, conditioned pain modulation (CPM), and pain adaptation were tested before and after administration of phenylephrine, clonidine, yohimbine, and saline. RESULTS: Changes in heart rate and blood pressure were found after all the pharmacological interventions. The only effect on pain measures was that yohimbine enhanced pain adaptation capacity while phenylephrine reduced it (P = 0.032). Several significant correlations were found between autonomic and pain parameters; greater decreases in heart rate after phenylephrine were associated with reduced pain ratings (r2 = 0.288, P = 0.018). In addition, enhanced pain adaptation was associated with higher total vascular resistance (r2 = 0.442, P = 0.01). CONCLUSIONS: Different effects of acute autonomic manipulations on experimental pain were found: an increase in sympathetic tone induced by yohimbine led to reduced pain sensitivity; a decrease in sympathetic tone with no effect on vagal-parasympathetic tone induced by phenylephrine led to reduction in pain adaptation capacity; and a decrease in sympathetic tone and increase in vagal parasympathetic tone by clonidine led to no change in pain adaptation capacity. While increased sympathetic outflow does facilitate pain adaptation, activation of either the sympathetic or parasympathetic limbs of the autonomic nervous system does not affect pain thresholds or CPM. Finally, a correlation exists between nociception and cardiovascular parameters only due to baroreflex activation. PMID- 28627792 TI - beta-Catenin in desmoid-type fibromatosis: deep insights into the role of T41A and S45F mutations on protein structure and gene expression. AB - Desmoid-type fibromatosis (DF) is a rare mesenchymal lesion with high risk of local recurrence. Specific beta-catenin mutations (S45F) appeared to be related to this higher risk compared to T41A-mutated or wild-type (WT). We explored the influence of both mutations and WT on structure stability and affinity of beta catenin for alpha-catenin and the pattern of gene expression that may influence DF behavior. Using 33 surgically resected primary DFs harboring T41A (n = 14), S45F (n = 10), or WT (n = 9), we performed a comparative molecular analysis by protein/protein interaction modeling, gene expression by DASL microarrays, human inflammation gene panel, and assessment of immune system-based biomarkers by immunohistochemistry. Mutated proteins were more stable than WT and formed a weaker complex with alpha-catenin. Consensus unsupervised gene clustering revealed the presence of two DF group-mutated (T41A + S45F) and WT (P = 0.0047). The gene sets 'Inflammatory-Defense-Humoral Immune Response' and 'Antigen Binding' were significantly enriched in T41A. The deregulation of 16 inflammation related genes was confirmed. Low numbers of T cells and tumor-associated macrophages (TAM) infiltrating the tumors and low/absent PD-1/PD-L1 expression were also identified. We demonstrated that mutated DFs (T41A or S45F) and WT are two distinct molecular subgroups with regard to beta-catenin stability, alpha catenin affinity, and gene expression profiling. A different inflammation signature characterized the two mutated groups, suggesting mediation either by T41A or by S45F. Finally, all mutated cases showed a low number of TIL and TAM cells and a low or absent expression of PD-1 and PD-L1 consistent with beta catenin activation insensitive to checkpoint blockade. PMID- 28627796 TI - Foreword. PMID- 28627798 TI - II. Topic Sessions. PMID- 28627799 TI - IV. Posters. PMID- 28627800 TI - I. Plenary Sessions. PMID- 28627801 TI - III. Young Investigator Oral Communications. PMID- 28627802 TI - The length of patient and primary care time interval in the pathways to treatment in symptomatic oral cancer. A quantitative systematic review. AB - OBJECTIVES: To examine the relative length of the patient and primary care intervals in symptomatic oral cancer. DESIGN: Quantitative systematic review. SEARCH STRATEGY: Oral cancer OR oral squamous cell carcinoma OR oropharyngeal cancer AND time interval OR diagnostic delay. SETTING: Primary and secondary care. PARTICIPANTS: Oral and oropharyngeal cancer patients. MAIN OUTCOME MEASURES: We computed five measures (patient, primary care, diagnosis, total diagnosis and total treatment intervals). Most studies did not provide any dispersion measure. We then used the sample size of each study to compute a weighted average of the mean intervals. When the median was provided, we assumed normality of the distribution of the means and used the median as a proxy of the mean. RESULTS: A total of 1089 articles were identified, and 22 met the inclusion criteria, reporting on 2710 patients from Europe, USA, India, Australia, Japan, Argentina and Iran. The weighted average of patient interval was 80.3 days. Primary care interval was five times shorter: 15.8 days. The diagnostic interval was appreciably shorter (47.9 days) when compared with the patient interval during symptomatic period. CONCLUSIONS: Patient interval represents the major component of waiting times since the detection of the first signs/symptoms to the definitive diagnosis of oral cancer. Thus, strategies focused on high-risk patients should be prioritised. Interventions aimed at optimising the health systems should be implemented by monitoring and facilitating diagnostic and treatment pathways of patients with oral cancer. PMID- 28627803 TI - Base-Mediated Generation of Ketenimines from Ynamides: Direct Access to Azetidinimines by an Imino-Staudinger Synthesis. AB - Ynamides were used as precursors for the in situ generation of highly reactive ketenimines that could be trapped with imines in a [2+2] cycloaddition. This imino-Staudinger synthesis led to a variety of imino-analogs of beta-lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations. PMID- 28627806 TI - Improving the Quantum Yields of Perylene Diimide Aggregates by Increasing Molecular Hydrophobicity in Polar Media. AB - Here we report the quantum yield of four aggregated perylene diimide (PDI) species that vary by the length of the branched side chains attached at the N,N' imide positions. The PDI molecules were dissolved in binary water:methanol solvents as a means to vary the solvent polarity and control the degree of aggregation in solution. By performing spectroscopy, kinetics, and light scattering experiments, the nature of the molecular interactions in the solutions was determined. The maximum quantum yield of the aggregated molecules increased from 0.04 for the shortest chain molecule (B2) to 0.20 for the largest chain molecule (B13). The higher quantum yield of B13 compared with B2 correlates well with an increase in the fluorescence lifetime. The monomer emission lifetime was 4.8 ns whereas a lifetime as high as 21.2 ns was measured for the B13 aggregate fluorescence. A shorter sub-nanosecond lifetime was also measured for suspended colloids in B5, B9, and B13. The enhanced quantum yield is attributed to an increase of disorder in the B13 aggregates. As the polarity of the solution increases, the hydrophobic effect further enhances the disorder, and, therefore, the quantum yields in these particles. PMID- 28627804 TI - The Effect of Genetic Polymorphisms in SLCO2B1 on the Lipid-Lowering Efficacy of Rosuvastatin in Healthy Adults with Elevated Low-Density Lipoprotein. AB - Rosuvastatin is an HMG-CoA reductase inhibitor widely used for treating hypercholesterolaemia. We investigated whether genetic polymorphisms in solute carrier organic anion transporter 2B1 (SLCO2B1) affect the lipid-lowering effect of rosuvastatin in healthy adults with elevated low-density lipoprotein (LDL). This study included 18 volunteers with LDL levels above 130 mg/dL. Rosuvastatin (20 mg) was administered once a day for 8 weeks. Blood samples were drawn before and after the 8-week treatment to measure changes in lipid levels. The presence of single nucleotide polymorphisms (SNPs) of SLCO2B1 (c.935G>A and c.1457C>T), SLCO1B1 (c.521C>T, c.388A>G and c.-11187G>A) and ABCG2 (c.421C>A) was determined by genotyping. Responses to rosuvastatin were compared between wild-type and variant genotypes using permutation test on each polymorphism. In volunteers with SLCO2B1 c.935G>A (rs12422149) variant, rosuvastatin was less effective at lowering LDL (mean % decrease: GG 62.8% GA 50.6% AA 49.3%, p = 0.012) and apoprotein B (mean % decrease: GG 52.1% GA 42.8% AA 42.8%, p = 0.036). Regarding SLCO2B1 c.1457C>T (rs2306168) SNP, there was no significant difference between wild-type and variant genotypes. This study demonstrated that SLCO2B1 c.935G>A (rs12422149) polymorphism influenced the lipid-lowering effects of rosuvastatin in volunteers with hypercholesterolaemia. PMID- 28627805 TI - Predicting the Enzymatic Hydrolysis Half-lives of New Chemicals Using Support Vector Regression Models Based on Stepwise Feature Elimination. AB - The enzymatic hydrolysis of chemicals, which is important for in vitro drug metabolism assays, is an important indicator of drug stability profiles during drug discovery and development. Herein, we employed a stepwise feature elimination (SFE) method with nonlinear support vector machine regression (SVR) models to predict the in vitro half-lives in human plasma/blood of various esters. The SVR model was developed using public databases and literature reported data on the half-lives of esters in human plasma/blood. In particular, the SFE method was developed to prevent over fitting and under fitting in the nonlinear model, and it provided a novel and efficient method of realizing feature combinations and selections to enhance the prediction accuracy. Our final developed model with 24 features effectively predicted an external validation set using the time-split method and presented reasonably good R2 values (0.6) and also predicted two completely independent validation datasets with R2 values of 0.62 and 0.54; thus, this model performed much better than other prediction models. PMID- 28627807 TI - Catalytic Oxidation of Alcohol to Carboxylic Acid with a Hydrophobic Cobalt Catalyst in Hydrocarbon Solvent. AB - A hydrophobic cobalt catalyst was synthesized and proved to be effective in alcohol oxidation under the assistance of hydrocarbon solvent with oxygen as the terminal oxidant. A series of catalysts with different water contact angles was applied to investigate the hydrophobic effect. Further insight into the reaction process was gained by reaction kinetics, isotopic effect, etc. It showed that the hydrocarbon solvent participated in the alcohol oxidation, and with the aid of the in situ generated free radicals, the alpha-C-H bond was smoothly activated and the alcohol was converted to carbonyl compounds. The hydrophobic effect promoted the alcohol oxidation by affecting the solvent oxidation. PMID- 28627808 TI - Evaluation of a pharmaceutical risk-sharing agreement when patients are screened for the probability of success. AB - We analyze a game-theoretic model of a risk-sharing agreement between a payer and a pharmaceutical firm. The drug manufacturer chooses the price while the payer sets the rebate rate and decides which patients are eligible for treatment. The manufacturer provides the payer with a rebate for nonresponding patients. We generalize on the existing literature, by making both price and rebate rate decision variables, allowing the rebate rate to be different from 100%, and incorporating 2 types of administrative costs. We identify a threshold for the expected probability of response for classifying the drug as a mass-market or niche type and investigate the optimal solutions for both types. We also identify a threshold for the rebate rate at which the net benefits become equal for responding and nonresponding patients. Through numerical examples, we examine how various parameters impact the drug manufacturer's and the payer's optimal solution. PMID- 28627810 TI - Development of emotional and behavioral problems in neurofibromatosis type 1 during young childhood. AB - This retrospective longitudinal study in young children with neurofibromatosis type 1 (NF1) aimed to identify if, and how early problems in behavior, intelligence, and language development are associated with later behavioral problems. At the first assessment at preschool age, we evaluated language skills, intelligence, and emotional and behavioral problems as reported by parents. The second assessment at school-age we evaluated intelligence, and emotional and behavioral problems as reported by parents and teachers. Association of baseline assessments with secondary assessment was evaluated using multivariable linear regression analysis. Of the 61 patients (25 males, 36 females; mean age 4;5 years [SD 1;1 years]) with NF1 who had a first assessment, 38 children (21 males, 17 females; mean age 7;11 years [SD 2;1 years]) had a second assessment after a mean period of 3;5 years. Longitudinal data on behavioral problems were collected for 23 of these children. Intelligence and language development were not associated with internalizing problems. Parent-rated internalizing behavioral problems significantly increased with age in this subgroup. Baseline internalizing problems predicted later internalizing problems (adjusted R2 = 0.33, p = 0.003). The presence of these problems at pre-school age may be predictive of internalizing problems at a later age. PMID- 28627809 TI - Ivabradine Reduces Digitalis-induced Ventricular Arrhythmias. AB - The I(f) channel inhibitor ivabradine is recommended for treatment of heart failure but also affects potassium currents and thereby prolongs ventricular repolarization. The aim of this study was to examine the electrophysiological effects of ivabradine on digitalis-induced ventricular arrhythmias. Thirteen rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, the digitalis glycoside ouabain was infused (0.2 MUM). Monophasic action potentials and ECG showed a significant abbreviation of QT interval (-34 ms, p < 0.05) and action potential duration (APD90 ; -27 ms, p < 0.05). The shortening of ventricular repolarization was accompanied by a reduction in effective refractory period (ERP; -27 ms, p < 0.05). Thereafter, hearts were additionally treated with ivabradine (5 MUM). Of note, this did not exert significant effects on QT interval (-4 ms, p = ns) or APD90 (-15 ms, p = ns) but resulted in an increase in ERP (+17 ms, p < 0.05). This led to a significant increase in post-repolarization refractoriness (PRR, +32 ms, p < 0.01) as compared with sole ouabain treatment. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in four of 13 hearts (31%; 15 episodes). After application of 0.2 MUM ouabain, eight of 13 hearts were inducible (62%, 49 episodes). Additional infusion of 5 MUM ivabradine led to a significant suppression of VF. Only four episodes could be induced in two of 13 hearts (15%). In this study, ivabradine reduced digitalis-induced ventricular arrhythmias. Ivabradine did not affect ventricular repolarization in the presence of digitalis treatment but demonstrated potent anti-arrhythmic properties based on an increase in both ERP and PRR. The study further characterizes the beneficial electrophysiological profile of ivabradine. PMID- 28627811 TI - Energy-based Neural Networks as a Tool for Harmony-based Virtual Screening. AB - In Energy-Based Neural Networks (EBNNs), relationships between variables are captured by means of a scalar function conventionally called "energy". In this article, we introduce a procedure of "harmony search", which looks for compounds providing the lowest energies for the EBNNs trained on active compounds. It can be considered as a special kind of similarity search that takes into account regularities in the structures of active compounds. In this paper, we show that harmony search can be used for performing virtual screening. The performance of the harmony search based on two types of EBNNs, the Hopfield Networks (HNs) and the Restricted Boltzmann Machines (RBMs), was compared with the performance of the similarity search based on Tanimoto coefficient with "data fusion". The AUC measure for ROC curves and 1 %-enrichment rates for 20 targets were used in the benchmarking. Five different scores were computed: the energy for HNs, the free energy and the reconstruction error for RBMs, the mean and the maximum values of Tanimoto coefficients. The performance of the harmony search was shown to be comparable or even superior (significantly for several targets) to the performance of the similarity search. Important advantages of using the harmony search for virtual screening are very high computational efficiency of prediction, the ability to reveal and take into account regularities in active structures, flexibility and interpretability of models, etc. PMID- 28627812 TI - Genetics of alcohol consumption in Drosophila melanogaster. AB - Individual variation in alcohol consumption in human populations is determined by genetic, environmental, social and cultural factors. In contrast to humans, genetic contributions to complex behavioral phenotypes can be readily dissected in Drosophila, where both the genetic background and environment can be controlled and behaviors quantified through simple high-throughput assays. Here, we measured voluntary consumption of ethanol in ~3000 individuals of each sex from an advanced intercross population derived from 37 lines of the Drosophila melanogaster Genetic Reference Panel. Extreme quantitative trait loci mapping identified 385 differentially segregating allelic variants located in or near 291 genes at P < 10-8 . The effects of single nucleotide polymorphisms associated with voluntary ethanol consumption are sex-specific, as found for other alcohol related phenotypes. To assess causality, we used RNA interference knockdown or P{MiET1} mutants and their corresponding controls and functionally validated 86% of candidate genes in at least one sex. We constructed a genetic network comprised of 23 genes along with a separate trio and a pair of connected genes. Gene ontology analyses showed enrichment of developmental genes, including development of the nervous system. Furthermore, a network of human orthologs showed enrichment for signal transduction processes, protein metabolism and developmental processes, including nervous system development. Our results show that the genetic architecture that underlies variation in voluntary ethanol consumption is sexually dimorphic and partially overlaps with genetic factors that control variation in feeding behavior and alcohol sensitivity. This integrative genetic architecture is rooted in evolutionarily conserved features that can be extrapolated to human genetic interaction networks. PMID- 28627813 TI - Effect of the Oxidant-Antioxidant System in Seminal Plasma on Varicocele and Idiopathic Infertility in Male Humans. AB - BACKGROUND: The aim of this study was to investigate seminal oxidant-antioxidant activity in idiopathic and varicocele infertility in men. METHODS: Total anti oxidant capacity (TAC), total oxidant status (TOS), paraoxonase (PON1), aryl esterase (ARE), and total thiol levels (TTL) were measured in seminal plasma with an autoanalyzer. The TOS/TAC ratio was determined as the oxidative stress index (OSI). A histopathological evaluation of the sperm was performed in the andrology laboratory of the hospital. Number, motility, morphology, volume, pH, and leukocytes were evaluated in all samples according to World Health Organization criteria. The three study groups were as follows: G1, males with idiopathic infertility; G2, males with varicocele infertility; and G3, normal healthy males (had fathered a child in the last 2 years). Each group was composed of 36 men (age, 25 - 40 years). The Rel Assay Diagnostics kit was used to determine the levels of the parameters. The study was conducted according to the principles of the declaration of Helsinki and was approved by Sakarya University Medicine Faculty Ethic Committee (e.n: 16214662/050.01.04/07). Statistical significance was assumed if p < 0.05. All statistical evaluations were performed using SPSS (version 20.0 for Windows; SPSS, Inc., Chicago, IL, USA). RESULTS: No differences were detected between the mean values of antioxidant parameters among the three groups (Kruskal-Wallis test). The p-values of the test parameters (TAC, TOS, PON1, ARE, TTL, OSI) are respectively: 0.494, 0.548, 0.068, 0.151, 0.202, 0.873. The antioxidant parameters of all subjects were compared using the MannWhitney U test in both groups as fertile (G3) and infertile (G1 + G2). The PON1 levels in infertile subjects were significantly higher than those in fertile subjects. There was a statistically significant difference (p = 0.042). The other antioxidant parameters had no statistically significant difference (p > 0.05). The ARE was not performed in group 3 (control) due to a methodological problem. CONCLUSIONS: PON1 levels in infertile subjects were significantly higher than those of fertile subjects. PMID- 28627814 TI - Prognostic Role of Circulating Soluble uPAR in Various Cancers: a Systematic Review and Meta-Analysis. AB - BACKGROUND: Soluble uPAR (suPAR) is a soluble fraction of uPAR which is an important cell surface receptor. Recent evidence suggests that circulating suPAR levels are elevated in multiple malignancies and associated with prognosis of patients, although the results are not consistent. This study aimed to analyze the effect of suPAR on the prognosis in various carcinomas through a systematic review and meta-analysis. METHODS: Eligible studies were searched in PubMed and EMBASE. Data were extracted from studies investigating the relationship between circulating suPAR and survival in patients with cancers. A meta-analysis of the hazard ratio (HR) was then performed to evaluate the prognostic role of suPAR in various carcinomas. Pooled HRs of suPAR for overall survival (OS) were calculated to measure the effect of circulating suPAR level on prognosis. RESULTS: After the literature search and systematic review, 12 articles regarding suPAR (I - III + II - III) including 2878 patients were included in a meta-analysis, which indicated a significantly poor OS in patients with high expression levels of circulating suPAR in subgroups of colorectal cancer (CRC), ovarian cancer, breast cancer, and prostate cancer (total HR 1.63, 95% CI 1.46 - 1.81) , and this effect is most obvious in patients with CRC (HR 1.67, 95% CI 1.47 - 1.89). No evidence of heterogeneity and publication bias was present. CONCLUSIONS: Our results suggested that suPAR is a promising biomarker in the prediction of prognosis in patients with cancers. However, further studies are warranted to validate its clinical application and biological implication with tumor development. PMID- 28627815 TI - The Levels of Serum Irisin as a Predictor of Insulin Resistance in Han Chinese Adults with Metabolically Healthy Obesity. AB - BACKGROUND: The aim of this study was to evaluate serum irisin levels and analyze its related factors in Han adults with metabolically healthy obesity. METHODS: This cross-sectional study included 75 metabolically healthy, non-obese adults and 51 metabolically healthy, obese adults. Anthropometric measurements, including height, weight, waist circumference (WC), and blood pressure, were performed. All patients underwent an oral glucose tolerance test (OGTT) after 8 hours of fasting, and the levels of glucose, insulin, lipids, and serum irisin were measured. RESULTS: The levels of serum irisin (5.40 +/- 1.69 vs. 6.46 +/- 1.37 ug/mL) were significantly lower in the metabolically healthy obese group (p < 0.05). Irisin correlated positively with high density lipoprotein cholesterol (HDL-C) (r = 0.303) and correlated negatively with body mass index (BMI) (r = 0.389), WC (r = -0.324), fasting plasma glucose (FPG) (r = -0.441), HOMA-IR (r = 0.429), triglycerides (TG) (r = -0.185), total cholesterol (TC) (r = -0.209), low density lipoprotein cholesterol (LDL-C) (r = -0.157) (p < 0.05). Multiple regression analysis revealed that FPG (beta = -1.720, p = 0.001) and HOMA-IR (beta = -0.399, p = 0.006) were still significantly associated with irisin. Serum irisin (beta = -0.246, p = 0.005) and BMI (beta = 0.078, p = 0.043) were significant independent predictors for HOMAIR. CONCLUSIONS: Serum irisin levels were reduced in metabolically healthy, obese Han adults. Irisin reduction appears to be associated with elevated FPG and insulin resistance but not obesity. In additional, falling irisin may increase the occurrence of insulin resistance in metabolically healthy Han adults and should be examined in future studies. PMID- 28627816 TI - Spectrophotometric Determination of Selenium Through Triiodide Anion. AB - BACKGROUND: Selenium is a chemical element found in the human body that plays a crucial role in its regulation. Depending on the concentration, it may have beneficial or have toxic effects. Selenium is incorporated as selenocysteine amino acid residue in selenoproteins which play an important role in many biological functions: anti-oxidant defense, regulation of the immune function and of the inflammatory response, metabolism of thyroid hormones, functioning of the central nervous system, biosynthesis of DNA and RNA, fertility, and reproduction. Excess selenium, altough less common than selenium deficiency, has equally important negative effects. METHODS: Given the importance of selenium quantification in various samples, the study proposes a simple and direct spectrophotometric determination of selenium using triiodide anions. The method is based on the oxidation of iodide in acidic medium by selenium (IV) contained in the sample, to form elemental iodine which, in turn, reacts with the excess iodide to form the triiodide anions, the most stable soluble species in aqueous solution. Triiodide is colored from yellow to brown, depending on the concentration. The coloured compound has maximum absorbance at specific wavelengths and thus, the stage of interaction with a chromogenic agent is eliminated. Due to the sensitivity of the reaction, the detection limit of triiodide, and therefore selenium, is extended toward lower values. RESULTS: The optimal conditions for the measurements were established: lambda = 290 nm, pH = 1.0 - 1.5, reaction time = 15 minutes. Two areas of selenium detection were determined from the samples: 0.025 - 0.100 ppm, and 0.1 - 4.0 ppm. The detection limit of selenium was lowered at 0.100 ppm and even at 0.025 ppm, which significantly improves the sensitivity of the determination. Types of samples were specified which are suitable for analysis using the proposed method and explained why, in case of biological fluids, it must be used only accompanied by an adequate digestion method of the samples. CONCLUSIONS: Selenium can be measured by direct spectrophotometric determination of the triiodide anion resulting from the oxidation of iodide by selenium (IV) compounds from the sample. In this regard, a simple, direct, and sensitive determination method of selenium from the samples by UV-Vis spectrophotometry, without the use of chromogenic agents has been optimized. PMID- 28627817 TI - Turbidimetric Determination of Fecal Calprotectin Using Two Table Top Chemistry Analyzers: Mindray BS-200E and Cobas(r) c111. AB - BACKGROUND: Fecal calprotectin assays are widely used in diagnosis and monitoring of inflammatory bowel disease (IBD) in patients with suspected IBD. The most frequently used technique is ELISA and microtiter plates. Turbidimetric assays for analysis of fecal calprotectin can significantly reduce turnaround time. Many laboratories may be reluctant to run fecal samples on their large chemistry analyzers. The aim of this study was to evaluate fecal calprotectin particle enhanced turbidimetric immunoassay (PETIA) on smaller chemistry analyzers that could be dedicated for fecal samples. METHODS: The BUHLMANN fCAL(r) turbo assay was validated on two table top chemistry analyzers, Mindray BS-200E and cobas(r) c111. RESULTS: The assay was linear in the range between 20 and 1,900 ug/g with a limit of quantification around 20 ug/g on both instruments. The total coefficient of variation was < 7% in the range between 50 and 1,300 ug/g on both instruments. No antigen excess hook effect was observed up to 18,000 ug/g on the Mindray BS 200E and up to 20,000 ug/g on cobas(r) c111. The BUHLMANN fCAL(r) turbo assay showed a high correlation with the BUHLMANN fCAL(r) ELISA. CONCLUSIONS: Running the BUHLMANN fCAL(r) turbo on Mindray BS-200E or cobas(r) c111 chemistry analyzers can provide rapid test results without exposing large routine chemistry analyzers to stool samples. PMID- 28627818 TI - Maternal Serum PLGF, PAPPA, beta-hCG and AFP Levels in Early Second Trimester as Predictors of Preeclampsia. AB - BACKGROUND: Identifying women at risk of preeclampsia (PE) by maternal serum screening is conducive to prompt gestational management and thereby improve both maternal and perinatal outcomes. The purpose of the present study was to evaluate the association between the concentrations of maternal serum placental growth factor (PLGF), pregnancy associated plasma protein-A (PAPPA), free beta-human chorionic gonadotropin (beta-hCG), and alphaFetoprotein (AFP) and the development of preeclampsia early in the second trimester. METHODS: Forty pregnant women subsequently developed mild PE, 21 pregnant women subsequently developed severe PE, and 61 cases of normotensive controls were included. Maternal serum concentrations of PLGF, PAPPA, beta-hCG, and AFP were measured at 15 - 20 weeks of gestation. RESULTS: Serum PLGF level was lower in women who subsequently developed PE than in normotensive controls. However, the significant difference was only found between the severe PE and control groups (p = 0.015). Serum PAPPA, beta-hCG, and AFP levels were not significantly different between the PE and control groups. CONCLUSIONS: Serum PLGF level was lower in women who subsequently developed severe PE early in the second trimester, suggesting its role in prediction of PE. PMID- 28627819 TI - Analysis of Respiratory Viral Infections Detected Using Multiplex Real-Time PCR in Hwaseong, Korea from 2013 to 2015. AB - BACKGROUND: We investigated the incidences and age-related/seasonal variations of respiratory virus infections in a regional area in Korea. METHODS: A total of 3,467 respiratory specimens from patients with acute respiratory infection symptoms in a teaching hospital were tested for respiratory viruses during 2013 - 2015. RESULTS: At least one virus was detected in 2,561 of the 3,467 specimens (73.9%), and 706 patients (20.4%) were positive for two or more viruses. The most frequently detected viruses were rhinovirus (23.9%), respiratory syncytial virus B (15.5%), and adenovirus (12.5%). Most of the patients (with and without a detected virus) were children. Young children (< 5 years old) were significantly more likely to have two or more viruses compared to older individuals (p < 0.0001). Most viruses exhibited seasonal variations. CONCLUSIONS: This study revealed the incidence of respiratory virus infections. These findings can enhance our understanding of the distribution of respiratory viruses according to patient age and season. PMID- 28627820 TI - Performance of the Liaison(r) XL Murex recHTLV-I/II Immunoassay in the Detection of HTLV-1/2 Antibodies in Serum. AB - BACKGROUND: Human T-cell lymphotropic virus type 1 and 2 (HTLV-1/2) immunoassays are used for blood screen- ing from blood products, milk, and organ donors. METHODS: We assessed the performance of the DiaSorin Liaison(r) XL murex recHTLV I/II immunoassay relative to the Abbott Architect(r) rHTLV-I/II immunoassay and with the Innogenetics immunoblot as confirmation. RESULTS: A panel of HTLV positive (n = 66) and negative (n = 30) sera was tested in both techniques within the same freeze/thaw cycle. The specificity and sensitivity of DiaSorin immunoassay were 100% and 78.8%, respectively. Abbott and DiaSorin immunoassays showed a correlation in chemiluminiscent signals to cutoff (S/CO) (Pearson r = 0.92). Half of the samples (34/66) from the seropositive panel were not confirmed by immunoblot (S/CO < 5 in both techniques). CONCLUSIONS: Our data confirmed that the DiaSorin Liaison(r) XL murex recHTLV-I/II immunoassay is an effective platform for HTLV screening. Due to false-positive reaction, especially for samples with low S/CO, each seropositive sample should be confirmed by immunoblot. PMID- 28627821 TI - The Value of Serum Complement C1q in the Diagnosis of Acute Ischemic Stroke. AB - BACKGROUND: To investigate the relationship between the levels of serum complement C1q and the risk and severity of acute ischemic stroke, a total of 154 patients with acute ischemic stroke and 42 healthy volunteers as normal controls were enrolled in the present study. METHODS: According to the onset time of stroke, patients were divided into three groups. Using an immune transmission turbidity method, the levels of serum complement C1q were detected to investigate the relationship between the level of serum complement C1q and the incidence and severity of acute ischemic stroke. The risk factors of these groups were calculated using a conditional logistic regression model. The assessment of neurological function impairment was carried out according to the National Institute of Health Stroke Scale. Then correlation anal- ysis was carried out between the level of serum complement C1q among patients with acute ischemic stroke and the degree of neurological function impairment. RESULTS: The results showed that the level of serum complement C1q was higher in the ischemic stroke group than in the control group. Using a conditional logistic regression model it was discovered that serum complement C1q was the independent pathogenic factor of cerebral infarction. There also was a decreasing trend in the level of serum complement C1q with the extension of the onset time and an increasing trend in the level of serum complement C1q with the increase in the maximum diameter of infarction volume. CONCLUSIONS: Serum complement C1q is an independent risk factor for acute outbreak of ischemic stroke, whose level is closely related to the outbreak and infarct size and neurological function impairment. PMID- 28627822 TI - Development of a One Step Reverse Transcription-Loop-Mediated Isothermal Amplification System for a Highly Sensitive Detection of Rabbit Hepatitis E Virus. AB - BACKGROUND: Hepatitis E virus (HEV) is a major cause of acute viral hepatitis in areas with poor sanitation. Rabbit is one of important animal reservoirs of the virus. Reverse transcription-loop-mediated isothermal amplification (RT-LAMP) system is a novel nucleic acid amplification assay, for which the specificity and sensitivity are much higher than that of conventional PCR. However, previously reported RT-LAMP system cannot detect rabbit HEV, which was identified recently and seems to be another potential source of human HEV infection. METHODS: In this study, genotype 4 HEV strains and rabbit HEV strains were used to verify the applicability of the previously reported HEV RT-LAMP. A new specific one step RT LAMP system was developed and evaluated to amplify rabbit HEV RNA. In order to test the sensitivity of the newly-developed assay, serial dilutions (from 5 x 103 to 5 x 10-1/uL) of the rabbit HEV RNA were used as template to be detected by RT LAMP, real-time RTPCR, and nested RT-PCR. Specificity of the new assay was further evaluated using HAV, HBV, and HCV. With this new assay, 46 rabbit fecal samples were retrospectively investigated with real-time RT-PCR and nested RTPCR in parallel. RESULTS: The detection limit of this newly-developed RT-LAMP assay reached as low as 10 copies/reaction and no cross-reactivity was observed with other hepatitis viruses including hepatitis A, B, and C virus, which indicated that this assay has much higher sensitivity and specificity than that of nested RT-PCR and real time RT-PCR. Furthermore, among 46 rabbit fecal samples, there were four positive samples determined by those three assays and one positive sample only detected by HEV RT-LAMP and real-time RT-PCR. CONCLUSIONS: Using a combination of sensitivity, specificity, and evaluation of clinical samples, this study provides the first data on the usefulness of RT-LAMP in the diagnosis of rabbit HEV RNA. PMID- 28627823 TI - Hepatitis C: an Overview of Various Laboratory Assays with their Mode of Diagnostic Cooperation. AB - BACKGROUND: This review describes in chronological order the different assays for hepatitis C virus (HCV) antibodies, for the core antigen and for the HCV-RNA. METHODS: By ascending chronological order, the enzyme-linked immunosorbent assay (ELISA), rapid diagnostic tests (RDTs), HCV-Ab IgG avidity index (HCV AI), and Cy3-labeled microarray assay have been described for HCV antibodies in addition to ELISA for the total HCV core antigen (Ag). RESULTS: The recombinant immunoblot assay (RIBA) is a confirmatory test for HCV-Ab in blood, which is no longer needed due to the use of the sensitive third and fourth generation ELISA in addition to HCV-RNA detection by the Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). ELISA and RIBA measure current and prior exposure to HCV infection, but cannot discriminate between the two. RT-PCR is performed after ELISA for the diagnosis of HCV infection whether acute, chronic, false positive or false negative ELISA. CONCLUSIONS: The cooperation between ELISA and RT-PCR in the diagnosis of HCV infection has been tabulated and discussed. HCV genotyping and subtyping testing is essential in pre-treatment evaluation of the patients for setting valuable treatment strategies and in understanding the epidemiology of the virus. PMID- 28627824 TI - Clinical Utility of Thiol/Disulfide Homeostasis. AB - BACKGROUND: Recently, the usefulness of thiol/disulfide homeostasis (TDH) in various diseases is being widely investigated. In this mini-review, our aim is to clarify the role of TDH in clinical practice in the light of current literature. METHODS: We performed a systematic review of the existing literature describing the clinical utility of TDH in the clinical setting. MEDLINE, EMBASE, and CINAHL were used as data sources. Two reviewers conducted independent screening and data extraction. Use of TDH in each system was investigated separately. RESULTS: A total of 35 studies were detected in this mini-review. Our results revealed the protective role of TDH and its utility as a diagnostic marker in many common diseases in clinical practice. CONCLUSIONS: Maintenance of TDH as a crucial part of antioxidant defense system is critical in diagnosis and prognosis of potentially lethal diseases. PMID- 28627825 TI - The Comparison of Urinary Stones Between She Minority and Han Nationality in East Fujian, China. AB - BACKGROUND: The purpose of the study was to compare the incidence of urinary stones of She minority and Han nationality and analyze the composition of urinary stones. METHODS: The study was performed in 381 cases with 181 She minority and 200 Han nationality. The composition of stones was mainly analyzed by infrared absorption spectrum. The incidence of urinary stones at different ages, different gender and different parts was compared between She minority and Han nationality. RESULTS: The urinary stone incidence of males was about twice as high as in women in She minority and Han nationality, and the incidence reached its maximum between the ages of 41 and 60, but the incidence decreased after 60 years of age. The distribution characteristics of urethra stones between She minority and Han nationality showed a significant difference (p < 0.05). The differences of carbonate apatite and struvite in male and female were statistically significant between She minority and Han nationality (p < 0.05). The level of Ca2+ and HPO42- in serum showed significant difference between She minority and Han nationality (p < 0.05). CONCLUSIONS: According to these results, we put forward corresponding preventive measures of urinary stones in She minority. PMID- 28627826 TI - Automated Hematology Analyzer for Cell Counting in Body Fluid. PMID- 28627827 TI - A Case of Waldenstrom Macroglobulinemia with Temporary Appearance of 7S IgM Half Molecule. AB - BACKGROUND: We encountered a rare case of Waldenstrom macroglobulinemia with temporary appearance of 7S IgM half molecule and with monoclonal proteins binding to agarose gel. METHODS: The patient's serum and urine were analyzed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. The N terminal amino acid sequences of the IgM with abnormal mass (68 kDa) were determined and compared with those of known immunoglobulin. RESULTS: The 68 kDa IgM consisted of a defective MU chain (36 kDa) and an intact kappa chain. N terminal amino acid sequence analysis demonstrated that the defective MU chain had the variable region of IgM. The agarose gel-binding ability of the IgM-kappa M-protein was lost after reduction or alkaline treatment of serum. CONCLUSIONS: The 7S half molecule IgM in the present case may miss a large part of the constant region of the u chain. PMID- 28627829 TI - MiR-29a and Messenger RNA Expression of Bone Turnover Markers in Canonical Wnt Pathway in Patients with Ankylosing Spondylitis. AB - BACKGROUND: Recent studies showed that the canonical Wnt pathway and miR-29a play important roles in the pathogenesis of bone formation. We studied the levels of miR-29a and messenger RNA (mRNA) of bone turnover markers in the canonical Wnt pathway in ankylosing spondylitis (AS). METHODS: The levels of miR-29a and mRNA of bone turnover markers in canonical Wnt pathway from peripheral blood mononuclear cells were determined by real-time quantitative polymerase chain reaction in 38 patients with AS and 32 healthy controls. Correlation analysis was conducted between the levels of miR-29a and mRNA and clinical measurements using Spearman's correlation test. RESULTS: Compared to healthy controls, the levels of miR-29a, Dickkopf (DKK)-1, beta-catenin and Runx2 mRNA were significantly higher in AS patients (p < 0.05). In contrast, the levels of Gsk-3beta mRNA was significantly lower in AS patients than that in healthy controls (p < 0.05). Gsk 3beta mRNA was positively correlated with beta-catenin mRNA expression (p < 0.05) and no other correlation was observed between any other markers (p > 0.05). Only DKK-1 mRNA expression was negatively correlated with disease course (p < 0.05) and no other correlation was observed between markers and clinical measurements (p > 0.05). CONCLUSIONS: The osteoblastic marker miR-29a and downstream mRNA of canonical Wnt signaling was upregulated in AS, suggesting their possible role in new bone formation in AS. PMID- 28627828 TI - The Relationship Between the MTHFR C677T Genotypes to Serum Anti-Mullerian Hormone Concentrations and In Vitro Fertilization/Intracytoplasmic Sperm Injection Outcome. AB - BACKGROUND: The expression of the 5,10-methylentetrahydrofolate reductase (MTHFR) gene in human oocytes and preimplantation embryos suggests that the MTHFR gene is involved in folliculogenesis and female reproduction. Considering the importance of the MTHFR gene on female reproduction, the aim of this study was to evalu- ate the influence of MTHFR C677T polymorphism on ovarian marker reserve, particularly serum anti-Mullerian hormone (AMH) levels, and ovarian response as well as clinical pregnancy rates after in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI). METHODS: A total of 137 women who underwent ART treatment due to male factor infertility enrolled in this study. Genotyping of MTHFR C677T polymorphism and serum AMH concentrations were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and an ultrasensitive enzymelinked immunosorbent assay (ELISA). RESULTS: Women with the TT genotype showed significantly higher AMH levels (4.5 +/- 3.2 ng/mL) compared to carriers of other genotypes after ovarian stimulation. We observed a nonsignificant trend towards lower clinical pregnancy rates in patients with the TT (23.1%) versus CT (48.4%) genotypes (p = 0.2). No significant differences existed in terms of miscarriage and live birth rates among the groups. Multivariable logistic regression revealed that the duration of infertility and AFC were important predictive variables for the live birth rate. CONCLUSIONS: Our results confirmed that the presence of the T mutant allele of the 677 polymorphism in the MTHFR gene led to an increased trend in AMH levels. Interestingly, we observed that the numbers of oocytes retrieved decreased in the mutated genotypes. We have not observed this trend in relation to oocyte maturity. The influence of the MTHFR C677T polymorphism on embryo quality and pregnancy rate after ART cycles remains unclear. PMID- 28627830 TI - FLT3-ITD Mutations in Egyptian Patients of Acute Myeloid Leukemia: Correlation with Cytogenetic, FAB Subgroups and Prognosis. AB - BACKGROUND: FLT3-ITD mutations are common in AML subgroups, particularly in Acute Promyelocytic Leukemia (APL). It infers poor prognosis in AML patients; however, its prognostic value in APL is still controversial. We aimed to assess the distribution and prognostic value of FLT3-ITD mutation within AML subgroups, focusing on APL. METHODS: In NCI, Cairo University, 346 newly diagnosed AML patients were included. Morphological, immunophenotypic and cytogenetic analysis were done at presentation and fixed follow-up points with monitoring in follow up visits of patients. FLT3-ITD mutations were detected using RT-PCR. RESULTS: FLT3 ITD mutations were detected in 18.5% of AML patients with significant higher incidence in M3 patients (35.5%, p = 0.027) in comparison to other types. There was significant negative association between FLT3ITD mutations and CD34 expression (p = 0.026). FLT3 wild patients had a significantly better response on Day 35 than the mutant group (p = 0.046). Overall Survival (OS) of the wild group was significantly better than that of the mutant group (p = 0.003). In APL patients, OS of wild-FLT3 patients was significantly better than of those with mutant FLT3 (p = 0.018). In non-APL patients, favorable cytogenetic changes - t(8;21) and inv(16) - are more common in FLT3 wild group (12.8%) than in FLT3 mutant group (6.3%). In non-APL patients, FLT3-ITD mutation retained its adverse prognostic effect (p = 0.016). CD34 expression affected survival in both FLT3 mutant and wild groups. CONCLUSIONS: We conclude that FLT3-ITD mutations infer poor prognostic effects both in AML patients generally and in the APL group specifically. CD34 may have a prognostic impact in FLT3-ITD mutant patients, which is to be further investigated. PMID- 28627831 TI - Whole-Blood Thiopurine S-Methyltransferase Genotype and Phenotype Concordance in Iranian Kurdish Ulcerative Colitis (UC) Patients. AB - BACKGROUND: Thiopurine methyl transferase (TPMT), a drug-metabolizing enzyme, catalyzes methylation and consequently, the metabolism of thiopurine compounds used for treatment of inflammatory bowel disease (IBD). Individuals who are homozygous recessive or have extremely low TPMT activity need to avoid thiopurines because of concern for significant leukopenia. The aim of this research was to determine TPMT phenotypes and genotypes in IBD patients to predict the risk of thiopurine toxicity before treatment. METHODS: The present case-control study consisted of 210 ulcerative colitis patients and 212 unrelated healthy controls from the population of western Iran. TPMT phenotype and genotype were determined by HPLC and allele specific PCR and PCR-RFLP, respectively. RESULTS: TPMT phenotyping and genotyping were compatible and demonstrated no frequency for deficient, 2.2% for low, and 97.8% for normal-activity which is different compared with the results of other studies. There was a significant negative correlation between TPMT activities as calculated based on nmol6MTG/gHb/h and the Hb levels in both UC (r = -0.54, p < 0.001) and control groups (r = -0.27, p < 0.001). Interestingly, a significant positive correlation between Hb levels and TPMT activities was seen when the enzyme activity was calculated in mU/L in both UC patients (r = 0.14, p = 0.05) and in control subjects (r = 0.43, p < 0.001). The overall concordance rate between TPMT phenotypes and genotypes of mutants to alleles (9 out of 422), based on receiver operating characteristic (ROC) curve, yielded a sensitivity of 94.7% and specificity of 90% for mU/L and a sensitivity of 85.6% and specificity of 90% for nmol6MTG/gHb/h. CONCLUSIONS: The use of mU/L is more appropriate than nmol6MTG/gHb/h for expressing TPMT activity, and there is better correlation between genotypes and phenotypes of TPMT based on mU/L. The frequency of known mutant TPMT alleles in western Iran (Kurd population) is low suggesting low risk of thiopurine drug toxicity in IBD patients from this region. PMID- 28627832 TI - Molecular Epidemiological Traits of Group A Rotaviruses in Japanese Children During Transitional Period of Rotavirus Vaccine Implementation, 2011 - 2014. AB - BACKGROUND: Group A rotavirus (RVA) vaccines have been introduced in Japan since 2011. To investigate the molecular epidemiological traits of RVA during the transitional period of rotavirus vaccine implementation in Japan, this study was undertaken by following up three-decade long surveillance conducted in the same regions. METHODS: RVA were screened and genotyped by RT-PCR from diarrheal samples collected from non-hospitalized patients in six localities (Hokkaido, Tokyo, Shizuoka, Osaka, Kyoto, and Saga) during 2011 - 2014. Selected samples were sequenced to elucidate the evolutionary trend. RESULTS: Among 1858 specimens, the detection rate of RVA declined to 4.0% in 2013 - 2014 from 17.9% in 2011 - 2012 and 22.1% in 2012 - 2013. G1P[8] was the most predominant genotype in the first two years accounting for more than half, and G9P[8] showed the highest detection rate as 35.0% in the last year. Interestingly, the proportional rate of G2 strains in the studied period increased from 0% to 25%. VP6 genotyping revealed that DS-1 like reassortant G1P[8] strains were detected all over Japan and their prevalence fluctuated greatly from 35.0% to 89.5%. Sequence analysis of VP6 showed that strains in the current strains were closely related but distinct from the original reference strains, namely Wa and DS-1. CONCLUSIONS: The detection rates of RVA, their GP combinations, prevalence of reassortant strains varied greatly after the introduction of rotavirus vaccines in Japan. Continuous monitoring is warranted to refine future vaccine strategy. PMID- 28627833 TI - Comparison of the Analytical Performance Between cobas EGFR Assay and PCR-Clamp Method in the Detection of EGFR Mutations in Japanese Non-Small Cell Lung Cancer Patients. AB - BACKGROUND: EGFR, a tyrosine-kinase, plays an important role in the progression of lung cancer. Since genetic abnormality of EGFR alters the effects of tyrosine kinase inhibitors targeting EGFR, molecular analyses of EGFR have recently gained more attention in the treatment of lung cancer. However, several different techniques are available and which method is superior has not been determined. In this study, we compared two recently developed PCR-based techniques, PCR-clamp method and cobas EGFR assay. METHODS: Ninety-four surgical samples and 58 biopsy samples from patients suffering from non-small cell lung cancers (NSCLCs) were included in the study. Samples with positive and negative genetic abnormalities, 66 and 28 respectively, were chosen for PCR-Clamp methods. Those same samples were reanalyzed with cobas EGFR assay. RESULTS: The concordance between PCR-Clamp and cobas EGFR methods was 95.7%. PCR-Clamp failed to detect four mutations that were detected with cobas EGFR assay. These two methods were further tested by analyzing 58 random biopsy samples. The concordance for the biopsy samples was 93.1%, and PCR-Clamp, again, failed to detect three mutations that were detected with cobas EGFR assay. CONCLUSIONS: Our results showed both methods detected most of the known EGFR mutations and the concordance was similar to those previously reported in different ethnicities. However, in our study, PCR-Clamp method failed to detect a total of seven mutations that were detected with cobas EGFR assay. Thus, we concluded that cobas EGFR assay is an easier and more accurate screening assay than PCR-Clamp method in detecting EGFR genetic abnormalities. PMID- 28627834 TI - Characteristics and Distribution of Penile Lesions in Croatian Men with Laboratory-Confirmed Low-Risk and High-Risk Human Papillomavirus (HPV) Infection. AB - BACKGROUND: Studies that compare penoscopic evaluation with the results of molecular human papillomavirus (HPV) testing are scarce. This study assessed and compared both type and distribution of various penile lesions using penoscopy (peniscopy) technique in Croatian men with different, laboratory-confirmed HPV status. METHODS: From a large cohort of men attending an outpatient STD clinic for HPV testing, a total of 120 patients were randomly selected and grouped into those positive for low-risk HPV, high-risk HPV, both low-risk and highrisk HPV, and those with negative results. Samples for HPV-DNA detection were taken by penile brushing and tested with the hc2 HPV DNA Test using Hybrid Capture 2 technology. Lesions were observed by photocolposcope after the application of aqueous 5% acetic acid, and classified as flat (macular), papular, papillary, classical condyloma, PIN-suspicious and non-specific lesions. RESULTS: The results have shown that flat and non-specific acetowhite lesions were the most common overall. All groups differed significantly with respect to papular and papillary lesions. A combination of heterogeneous lesions (i.e., a mixed penoscopic pattern) was commonly observed in all HPV-positive groups, but was significantly lower in the HPV-negative group. A majority of lesions were located in the coronal sulcus, and the four groups differed with respect to the location only considering the lesions of the penile shaft. Distribution of lesions in different sites did not appear to be significantly different with respect to the group, although differences within the high-risk HPV group and the group with both low-risk and high-risk HPV were detected. CONCLUSIONS: Penoscopy is relevant, but not a conclusive diagnostic tool for differentiating HPV from non HPV findings in men - thus combining it with an HPV DNA test represents a more reliable approach. PMID- 28627835 TI - Clinical and Molecular Delineation of a Novel Cys1050Phe Missense Mutation in the ABCC9 Gene in a Korean Patient with Cantu Syndrome. AB - Cantu syndrome is characterized by congenital hypertrichosis, cardiomegaly, and osteochondrodysplasia and is recognized as a rare syndrome. Although it has previously been reported that the majority of affected individuals have a relatively good prognosis, there are no reports on long-term follow up. Here we report the first case of Cantu syndrome in Korea and the associated changes in overall development with rehabilitation over several months. PMID- 28627836 TI - DNA-Based Identification of a Carbonized Victim by Kinship Analysis. AB - BACKGROUND: Our study will present the DNA identification of a carbonized victim using the DNA genotyping and by comparing the victim's DNA genotype with his parents' genotypes. METHODS: Blood obtained from the heart chambers was used for the identification of the carbonized body's genotype. Biological samples were also obtained by buccal swabs from his biological parents. We used an ABI 7500 real-time PCR system for quantification and a ProFlex PCR System to amplify. PCR products were separated on an ABI 3500 genetic analyser and identified using GeneMapper ID-X vers. 1.4 software. RESULTS: We obtained the three DNA genotypes (mother, father, and carbonized victim). Using maternity and paternity DNA testing we established that the victim's genetic profile matched the DNA profiles of his biological parents. The probability of maternity (PM) and probability of paternity (PP) were of 99.99999% for each of the parents. CONCLUSIONS: Body fluids (blood, saliva) represent a better source for DNA compared to hard tissue, and its processing times are shorter than those for bone or teeth. PMID- 28627837 TI - Natural Antioxidant Vitamins Status in Pregnancies Complicated with Intrauterine Growth Restriction. AB - BACKGROUND: The weight of the infant at birth is a powerful predictor of infant growth and survival and is dependent on maternal health and nutrition during pregnancy. Pregnant women have a defense mechanism against increased oxidative stress composed of antioxidant enzymes and natural antioxidant vitamins like vitamin C and E. Therefore, we evaluated whether differences exist in serum levels of vitamin C and E in pregnant women complicated with intrauterine growth restriction (IUGR). METHODS: This study was done in 180 pregnant women admitted in hospital for delivery. Blood samples were collected and stored at -70 degrees C until analysis. Among 180 pregnant women 150 were identified as IUGR pregnant women according to the weight of the infant and the remaining 30 normal healthy pregnant women as controls. Blood hemoglobin and serum vitamin C and E levels were measured in both groups. RESULTS: The mean hemoglobin concentration was significantly decreased (p< 0.001) in IUGR pregnant women (8.92 +/- 1.35 g/dL) as compared to the normal healthy pregnant women (10.51 +/- 1.04 g/dL) in our study. The serum concentration of vitamin C in the group of pregnant women with IUGR was 0.54 +/- 0.15 mg/dL, whereas in the group of normal healthy pregnant women it was 0.91 +/- 0.23 mg/dL. The serum vitamin E level in the normal healthy pregnant women group was 1.22 +/- 0.35 mg/dL and 0.65 +/- 0.24 mg/dL in IUGR pregnant women group. The serum vitamin C and E level in IUGR pregnant women group was found to be significantly decreased as compared to the normal healthy pregnant women group. CONCLUSIONS: The study indicates the importance of natural antioxidants vitamin C and E against increased oxidative stress in pregnancies complicated with IUGR. Therefore, it may be useful to measure serum vitamin C and E levels in IUGR pregnant women. This study suggests further research to investigate the role of these natural antioxidant vitamins in fetal growth at various gestation stages. PMID- 28627838 TI - Residual Negative Pressure in Vacuum Tubes Might Increase the Risk of Spurious Hemolysis. AB - BACKGROUND: We planned a study to establish whether spurious hemolysis may occur when negative pressure remains in vacuum tubes. METHODS: Four tubes with different vacuum levels (-54, -65, -74, and -86 kPa) were used to examine blood drawn from one healthy volunteer; the tubes were allowed to stand for different times (1, 2, 3, and 4 hours). The plasma was separated and immediately tested for free hemoglobin (FHb). Thirty patients were enrolled in a verification experiment. RESULTS: The degree of hemolysis observed was greater when the remaining negative pressure was higher. Significant differences were recorded in the verification experiment. CONCLUSIONS: The results suggest that residual negative pressure might increase the risk of spurious hemolysis. PMID- 28627839 TI - ? PMID- 28627840 TI - Teaching clinical reasoning is more like detective work than you might imagine. AB - When supervising a medical student or a doctor in training, it is useful to know the different stages of clinical reasoning in order to identify at what stage the learner encounters a difficulty in making the right decision. Is he having trouble characterizing the clinical problem ? Is he generating the right hypotheses that are adapted to the data collection ? Is it a problem of verification of assumptions ? Of interpreting the data ? Of presumptive diagnosis or a poor choice of an intervention plan ? By making a pedagogical diagnosis, the supervisor will be more effective in adapting his recommendations in a more targeted way to the specific difficulties of the student or young colleague. PMID- 28627841 TI - Clinical decision making : from theory to practice... and backward. AB - Being able to analyze all the successive steps of decision making from the first contact with the patient to the final diagnosis is complex because it refers sometimes to intuitive elements proper to each clinician. However, understanding how they integrate probabilities of diseases into their clinical practice and manage diagnostic uncertainties is crucial. This allows a more rational practice of medicine and identifying factors related to the patient, physician or context that may modify the clinical decision making. Furthermore, the use of tools such as clinical scores has taken an important place with the evidence based medicine. Given the fact that they are partly theoretical, it is necessary to assess whether these recommendations are in line with clinical practice. PMID- 28627842 TI - Ultrasonography : an useful diagnostic tool for the general practitioner. AB - The ultrasound has become an increasingly popular tool in the clinical assessment of patients, not least in the field of general medicine. The technical evolution as well as the recent changes of the application of ultrasounds allows for rapid and targeted exams that has the potential to improve the care of patients. With the help of recent articles regarding ultrasound (US) in general medical practice, this article presents several useful indications for the primary care physician as well as shows today's training in Switzerland and demonstrates the need of an adapted training to better respond to today's need. PMID- 28627843 TI - Using the HEADSSS guide to teach students diagnostic skills in adolescent health Views from students participating in interprofessional courses. AB - Over the past few years, an interprofessional team of lecturers in Geneva has developed courses entitled " adolescent health and development ". These courses are open to students in medicine, nursing and nutrition, as well as to other interested health professionals. Using vignettes, students who participated in the courses present their thoughts on the use of the HEADSSS interview guide in the diagnostic approach with adolescents. These optional courses provide an opportunity to explore infrequently taught domains of the curriculum in a creative way. They give students the chance to develop common practice skills providing the basis for improved inter-professional collaborations in the future. PMID- 28627844 TI - Patient care in family medicine : what's new in the 2016 literature findings ? AB - During the last two decades in Europe, the scope of activities regarding chronic diseases management in family medicine has increased while technical activities and preventative care have decreased. A new literature review and meta-analysis confirms that the use of electronic health records improves the quality of care. In the field of interprofessionnality, the task delegation in chronic care management to nurses or medical assistants is a source of satisfaction for these professionals. At the same time, this could improve patients' quality of life. Finally, a systematic literature review reports the major assets according to the family physicians regarding their occupation i.e. freedom to organize and manage their own work, good balance between workload and income and high intellectual stimulation. PMID- 28627845 TI - Efficacy of interprofessionnality : evidence and challenges. AB - Skillmix is often proposed as a measure to address the growing needs of an aging population with its expected increase in chronic diseases. This article reports on a symposium on interprofessional collaboration which took place in the canton of Valais in Switzerland. Reviews of the literature on interprofessional collaboration show evidence in favor of the effectiveness of having interactions between physicians, nurses, pharmacists and physiotherapists. A critical analysis of different forms of coordinated care within family medicine supports the effectiveness of these approaches. However, these approaches now need to be tested in Switzerland. PMID- 28627846 TI - Drug-induced myopathies. AB - Drug myopathies are frequent and their identification important because of their potential morbidity. Apart from statins, the drugs most often involved are glucocorticoids, antimalarials, colchicine, and antiretrovirals. These myopathies are largely preventable, particularly those that occur in combinations of treatments or in the presence of comorbidities. Their relatively specific presentation often makes it possible to approach the diagnosis and to target the possible molecule to be interrupted. In general, they are spontaneously and rapidly reversible upon discontinuation of the drug, with the exception of statin induced autoimmune necrotizing myopathy ; however, the latter is reversible under immunosuppressants, when initiated early enough. PMID- 28627847 TI - ? PMID- 28627848 TI - ? PMID- 28627849 TI - ? PMID- 28627850 TI - To prevent and deal with medical problems on board. AB - As more and more quality of life becomes a goal of personnel and sustainable development, long-distance travel is becoming more widespread. Sailing around the world is an example of this evolution. The keys to a successful journey are rigorous preparation and adherence to some prevention rules. Medical or surgical emergencies are rare, and can often be dealt with by remote medical contact. New communication technologies such as satellite phones make it possible to seek medical advice from professionals, or even for sailers to treat themselves with very short prior training, provided that the required equipment and medicines have been embarked before leaving. Sophisticated rescue can also be organized. These technological innovations have changed the security and lives of sailors and explorers in remote areas of the world. PMID- 28627851 TI - Zika virus: practical guidelines. AB - Zika virus suddenly emerged in Latin America in 2015-2016. Congenital malformations have been observed in infected pregnant women, causing a major public health impact in affected countries, particularly in Brazil. In addition, sexual transmission of Zika virus has been well documented. This led to the development of prevention strategies and recommendations for travellers visiting at risk countries. These documents are regularly amended depending on the evolution of scientific knowledge, the epidemiologic trends and the national and international guidelines. Through practical cases, we present here the guidelines developed by the Geneva University Hospitals. PMID- 28627852 TI - Multidrug-resistant bacteria and travel. AB - Antimicrobial resistance is a global problem which affects also tropical countries. Travelers to these regions expose themselves to the risk of being colonised and infected with multidrug-resistant bacteria. The region visited, the occurrence of diarrhoea and the use of antibiotics are the principal risk factors leading to colonisation with multidrug-resistant Enterobacteriaceae, which can affect up to 80% of travellers. Colonisation with meticillin resistant Staphylococcus aureus and vancomycin resistant enterococci are often due to contacts with the health care system of the visited country. For the practitioner evaluating a patient returning from abroad it is important to consider the risk of infection with multidrug-resistant bacteriae. Screening for these bacteriae in the stool or by mucocutaneous swabs can be discussed in certain situations. PMID- 28627853 TI - Determinants of outbreaks of emerging infectious diseases : the case of Chikungunya in Indian ocean, 2004-2007. AB - Emerging outbreaks of arboviroses are most often tied to the convergence of a set of factors which have physical and environmental, genetic and biological, ecological, social, political and economic origins. Thirteen out of these factors are known as main determinants of emerging infectious disease outbreaks. This paper assesses the role of these factors from exploring the Chikungunya outbreak which occurred in Indian Ocean in 2004-2007, as case study. Chikungunya is an alphavirus borne and transmitted by Aedes aegypti and Aedes albopictus. PMID- 28627854 TI - Swiss and tropical snakebites: the clinical management. AB - With increasing trips to tropical areas, as well as a high number of venomous snake holders in the country, the frequency of snake bites is likely to increase. Even if in 50 % of cases, the bites do not lead to clinical envenoming, rapid and effective management is essential to successful treatment, which includes supply with the polyvalent or specific antivenom and recognition of the signs and symptoms justifying its administration. We will deal here mainly with local and tropical snake envenoming that Swiss practitioners could encounter in their offices or the emergency rooms and propose scenarios according to the syndromes. PMID- 28627856 TI - ? PMID- 28627855 TI - Multiplex PCR gastro-intestinal panels for the management of traveller's diarrhea : are they accurate and useful? AB - Until recently, the search for enteropathogens causing travellers' diarrhea was based on stool culture (Campylobacter spp., Salmonella spp. and Shigella spp.), direct microscopy with (Cryptosporidium spp.) or without specific staining (Giardia lamblia, Entamoeba histolytica) or specific antigen detection (Giardia lamblia, Entamoeba histolytica). Molecular analyses are progressively replacing traditional diagnostic methods but their clinical usefulness remains to be better defined. This article attempts to describe the advantages and disadvantages of these new molecular methods and to illustrate situations where they could be useful using clinical cases frequently encountered in the practice of travel medicine. PMID- 28627857 TI - ? PMID- 28627858 TI - ? PMID- 28627859 TI - Use of dynamic movement orthoses to improve gait stability and trunk control in ataxic patients. AB - BACKGROUND: Patients with cerebellar ataxia show increased upper body movements, which have an impact on balance and walking. AIM: In this study, we investigated the effect of using dynamic movement orthoses (DMO), designed as elastic suits, on trunk motion and gait parameters. DESIGN: Longitudinal uncontrolled study. SETTING: Outpatient rehabilitation unit. POPULATION: Eleven patients (7 men, 4 women; mean age: 49.9+/-9.5 years) with degenerative cerebellar ataxia were enrolled in this study. METHODS: Linear overground gait of patients was recorded by means of an optoelectronic gait analysis system before DMO use (DMO-) and during DMO use (DMO+). Time-distance parameters, lower limb joint kinematics, body sway, trunk oscillations, and gait variability (coefficient of variation [CV]) were recorded. Patient satisfaction with DMO device was measured using Quebec user evaluation of satisfaction with assistive technology. RESULTS: When using the DMO, patients showed a significant decrease in stance phase duration, double support phase duration, swing phase CV, pelvic range of motion (ROM), body sway, and trunk ROMs. A significant increase was observed in the swing phase duration and knee joint ROM. Out of 11 patients, 10 were either quite satisfied (8 points) or very satisfied (2 points) with the assistive device. CONCLUSIONS: The DMO reduce the upper body motion and in improve balance-related gait parameters. CLINICAL REHABILITATION IMPACT: We propose use of DMO as an assistive/rehabilitative device in the neurorehabilitation of cerebellar ataxia to improve the trunk control and gait stability. DMO may be considered a prototype that can be modified in terms of material characteristics, textile layers, elastic components, and diagonal and lateral seams. PMID- 28627860 TI - The World Health Organization Disability Assessment Schedule 2.0 can predict the institutionalization of patients with stroke. AB - BACKGROUND: The World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) is a well-known questionnaire used to evaluate disability. We can not only evaluate disability but also obtain additional information by using the standardized WHODAS 2.0 scores. AIM: To predict the institutionalization of the patients with stroke by using the standardized WHODAS 2.0 scores. DESIGN: Observational study. SETTING: The data of 10,255 patients with stroke were acquired from the Data Bank of Persons with Disabilities (TDPD) in Taiwan. POPULATION: Patients with either ischemic or hemorrhagic stroke during chronic stage. METHODS: For the patients with stroke, we used a chi2 analysis for the categorical variables, and an independent Student's t test to compare the standardized WHODAS 2.0 scores in the six domains between different groups. We also generated a receiver operating characteristic curve using the standardized WHODAS 2.0 scores, and applied Youden Index to calculating the optimal cut-off point on the ROC curve. Then, we used a binary logistic regression analysis to determine risk factors for the institutionalization. RESULTS: All WHODAS 2.0 domains had higher scores in the institution group than in the community group. The ROC curve used to predict the institutionalization of patients with stroke revealed that all WHODAS 2.0 domains were statistically significant. The cognition, and mobility domains and the sum of WHODAS 2.0 scores were more accurate for predicting the risk of institutionalization in a long-term care facility. In a logistic regression analysis, standardized WHODAS 2.0 scores >=69, residence in an urban area, and severity of impairment were factors for predicting the institutionalization of the patients with stroke. CONCLUSIONS: WHODAS 2.0 scores, urbanization level, and severity of impairment were positive factors for the institutionalization of patients with stroke in long-term care facilities, whereas the female sex and an age of >=85 years were negative factors. The cognition and mobility domains and standardized WHODAS 2.0 scores were more accurate for predicting the institutionalization of patients with stroke. CLINICAL REHABILITATION IMPACT: Proper analysis of the functioning status and risk factors, as well as prediction of discharge destination for the patients with stroke can help the healthcare system reduce unnecessary expenditures and make the allocation of social resources more efficient. PMID- 28627861 TI - Effectiveness of aquatic therapy for the control of pain and increased functionality in people with Parkinson's disease: a randomized clinical trial. AB - BACKGROUND: Gait, balance disorders and pain associated with Parkinson's disease represent important therapeutic challenges, as they are related with an increased risk of falls, together with disability and physical decline. AIM: To compare the effects of an aquatic ai chi training program on the perception of pain, the maintenance of balance and the functional independence of patients with Parkinson's disease. DESIGN: A single-blind randomized controlled trial. SETTING: Parkinson's associations and municipal pools. POPULATION: Thirty individuals from two Parkinson's associations in Spain participated in the study. INCLUSION CRITERIA: individuals diagnosed with Parkinson's disease in stages 1 to 3 (Hoehn and Yahr Scale), older than 40 years, in the off phase (not medicated) and with a score greater or equal to 24 on the Mini-Mental State Examination Scale, without any medical contraindications and who accepted the study norms. METHODS: The experimental group (N.=15 patients) participated in a program of aquatic ai chi. The control group (N.=15) received therapy on dry land. The intervention lasted 10 weeks with sessions held twice weekly. The pain VAS, Tinetti, Berg, Test Get Up and Go, Five Times Test and Unified Parkinson's Disease Rating Scale were used. RESULTS: Significant differences were found between the baseline and one month follow up assessments in pain perception values (F=26.89, P<0.001), and the Tinetti Test (F=21.57, P<0.001) in the experimental group compared to the control group (P<0.05) with the exception of the FTSTS (P=0.006). In the control group, improvements were only seen on the VAS Pain Scale (F=8.3, P=0.004) and these were less significant than the changes found in the experimental group. Regarding the scores obtained on the UPDRS scale in the experimental group, there were significant differences in activities of daily living and motor examination, with the exception of mentation, behavior and mood. CONCLUSIONS: An aquatic ai chi program appears to be a valid treatment option for patients diagnosed with mild to moderate Parkinson's disease for the treatment of pain, balance and functional capacity. CLINICAL REHABILITATION IMPACT: Physical exercise performed in water has positive effects on some of the necessary elements that contribute towards improved biomechanical gait patterns in our patients with Parkinson's disease. PMID- 28627862 TI - Feasibility and efficacy of wearable devices for upper limb rehabilitation in patients with chronic stroke: a randomized controlled pilot study. AB - BACKGROUND: Wearable devices based on inertial measurement units through wireless sensor networks have many applications such as real-time motion monitoring and functional outcome assessment of stroke rehabilitation. However, additional investigations are warranted to validate their clinical value, particularly in detecting the synergy patterns of movements after stroke. AIM: The aim of this study was to explore the feasibility and efficacy of wearable devices for upper limb rehabilitation in patients with chronic stroke and to compare the intervention effects (e.g., neurological recovery, active range of motion, and deviation angle) with those in a control group. DESIGN: A single-blind, randomized-controlled pilot study. SETTING: Rehabilitation ward. METHODS: A total of 18 patients with chronic stroke were randomly distributed into a device group and control group. Both groups received conventional rehabilitation; nevertheless, the device group was additionally subjected to 15 daily sessions at least three times a week for 5 weeks. The outcome measures included the upper extremity subscores of the Fugl-Meyer assessment, active range of motion, and deviation angle. These measurements were performed pre- and post-treatment. RESULTS: All five Fugl-Meyer assessment subscores improved in both the device and control groups after intervention; in particular, the "shoulder/elbow/forearm" subscore (P=0.02, 0.03) and "total score" (P=0.03, 0.03) substantially improved. The active range of motion of shoulder flexion and abduction substantially improved at pre-post treatment in both the device (P=0.02, 0.03) and control (P=0.02, 0.03) groups. The deviation angle of shoulder external rotation during shoulder abduction substantially improved in the device group (P=0.02), but not in the control group. CONCLUSIONS: The designed wearable devices are practical and efficient for use in chronic patients with stroke. CLINICAL REHABILITATION IMPACT: Wearable devices are expected to be useful for future internet-of-things rehabilitation clinical trials at home and in long-term care institutions. PMID- 28627863 TI - Endovascular treatment of mycotic aortic aneurysms: a paradigm shift. AB - Treatment of mycotic aortic aneurysms (MAAs) composes a particularly difficult challenge. Open repair has been considered the gold standard, despite lack of evidence supporting its superiority compared with the emerging alternative endovascular aortic repair (EVAR). This review discusses the pros and cons of EVAR for MAAs by dissecting the three largest publications on MAAs, and concludes that there has been a paradigm shift in treatment of MAAs for the benefit of EVAR. PMID- 28627864 TI - Type II endoleaks: when and how. AB - Although most type II endoleaks are self-limiting, the most common indication for secondary intervention after endovascular aneurysm repair (EVAR) is type II endoleak. However, it is still debatable when to treat them. Furthermore, different intervention techniques are available to treat type II endoleaks. The aim of this review is to look at current evidence and updates on type II endoleaks after EVAR for abdominal aortic aneurysm and their management. PMID- 28627865 TI - The value of color Doppler ultrasound in the diagnosis of lower extremity vascular disease in type 2 diabetes and an analysis of related factors. AB - BACKGROUND: The aim of this paper is to explore the application and clinical significance of color Doppler ultrasound (CDU) in diagnosing lower extremity vascular disease in type 2 diabetes mellitus (T2DM) patients. METHODS: The lower extremity arteries of 81 patients with T2DM and 50 control patients were examined by CDU for blood vessel diameter, intima-media thickness, plaque on the vessel wall, lumen stenosis and filling defect in blood flow. The occurrence of diabetes mellitus was investigated in additional T2DM patients of various ages. RESULTS: Left popliteal artery, left and right dorsal artery of the foot; the incidence of atherosclerotic plaque, stenosis and occlusion of the lower extremity vascular lumen of T2DM patients was significantly higher than that in the control group. Vascular disease in the lower extremities was mainly small and medium vascular disease (lower than popliteal artery), especially the dorsal artery of the foot, for which the difference was statistically significant (P<0.05). The elder patients had a greater chance of lower extremity arterial disease. CONCLUSIONS: CDU is the examination method of preference for T2DM patients with lower extremity vascular disease. It has a very important clinical significance for early diagnosis, prevention and treatment. PMID- 28627866 TI - Cardiovascular disease in PCOS is related to severe insulin resistance, not mild. PMID- 28627867 TI - Two-Dimensional Imine-Linked Covalent Organic Frameworks as a Platform for Selective Oxidation of Olefins. AB - Two-dimensional imine-linked covalent organic frameworks with hydroxyl groups, TAPT-DHTA-COFHX and TAPT-DHTA-COFDMF, were respectively constructed by the condensation of 1,3,5-tris-(4-aminophenyl)triazine and 2,5-dihydroxyl terephthalaldehyde under solvothermal and reflux conditions. Both COFs possess excellent thermal stability and a similar eclipsed stacking structure verified by XRD patterns. However, TAPT-DHTA-COFHX presented a larger surface area (2238 m2/g) and higher crystallinity than TAPT-DHTA-COFDMF. Significantly, copper ions are efficiently incorporated into the pores of these two COFs via the coordination interaction with hydroxyl groups and imine linkers. The obtained copper-containing COFs (Cu-COFHX and Cu-COFDMF) were employed in the selective oxidation of styrene to benzaldehyde. Cu-COFHX with superior surface area (1886 m2/g) and pore volume (1.11 cm3/g) exhibited excellent catalytic performance and recyclability. This strategy not only provides a convenient approach to design imine-linked 2D COFs with hydroxyl groups, but also develops their novel application for catalysis. PMID- 28627868 TI - Alkaline Phosphatase-Instructed Self-Assembly of Gadolinium Nanofibers for Enhanced T2-Weighted Magnetic Resonance Imaging of Tumor. AB - Alkaline phosphatase (ALP) is an important enzyme but using ALP-instructed self assembly of gadolinium nanofibers for enhanced T2-weighted magnetic resonance imaging (MRI) of tumor has not been reported. In this work, we rationally designed a hydrogelator Nap-FFFYp-EDA-DOTA(Gd) (1P) which, under the catalysis of ALP, was able to self-assemble into gadolinium nanofibers to form hydrogel Gel I for enhanced T2-weighted MR imaging of ALP activity in vitro and in tumor. T2 phantom MR imaging indicated that the transverse relaxivity (r2) value of Gel I was 33.9% higher than that of 1P and both of them were 1 order of magnitude higher than that of Gd-DTPA. In vivo T2-weighted MR imaging showed that, at 9.4 T, ALP-overexpressing HeLa tumors of 1P-injected mice showed obviously enhanced T2 contrast. We anticipate that, by replacing ALP with other enzymes, our approach could be applied for MR diagnosis of other diseases in the future. PMID- 28627869 TI - Effects of Detergent Micelles on Lipid Binding to Proteins in Electrospray Ionization Mass Spectrometry. AB - A wide variety of biological processes rely upon interactions between proteins and lipids, ranging from molecular transport to the organization of the cell membrane. It was recently established that electrospray ionization mass spectrometry (ESI-MS) is capable of capturing transient interactions between membrane proteins and their lipid environment, and a detailed understanding of the underlying processes is therefore of high importance. Here, we apply ESI-MS to investigate the factors that govern complex formation in solution and gas phases by comparing nonselective lipid binding with soluble and membrane proteins. We find that exogenously added lipids did not bind to soluble proteins, suggesting that lipids have a low propensity to form electrospray ionization adducts. The presence of detergents at increasing micelle concentrations, on the other hand, resulted in moderate lipid binding to soluble proteins. A direct ESI MS comparison of lipid binding to the soluble protein serum albumin and to the integral membrane protein NapA shows that soluble proteins acquire fewer lipid adducts. Our results suggest that protein-lipid complexes form via contacts between proteins and mixed lipid/detergent micelles. For soluble proteins, these complexes arise from nonspecific contacts between the protein and detergent/lipid micelles in the electrospray droplet. For membrane proteins, lipids are incorporated into the surrounding micelle in solution, and complex formation occurs independently of the ESI process. We conclude that the lipids in the resulting complexes interact predominantly with sites located in the transmembrane segments, resulting in nativelike complexes that can be interrogated by MS. PMID- 28627870 TI - Encapsulation of Autoinducer Sensing Reporter Bacteria in Reinforced Alginate Based Microbeads. AB - Quorum sensing, in which bacteria communities use signaling molecules for inter- and intracellular communication, has been intensively studied in recent decades. In order to fabricate highly sensitive easy-to-handle point of care biosensors that detect quorum sensing molecules, we have developed, as is reported here, reporter bacteria loaded alginate-methacrylate (alginate-MA) hydrogel beads. The alginate-MA beads, which were obtained by electrostatic extrusion, were reinforced by photo-cross-linking to increase stability and thereby to reduce bacteria leaching. In these beads the genetically engineered fluorescent reporter bacterium Escherichia coli pTetR-LasR-pLuxR-GFP (E. coli pLuxR-GFP) was encapsulated, which responds to the autoinducer N-(3-oxododecanoyl)homoserine lactone secreted by Pseudomonas aeruginosa. After encapsulation in alginate-MA hydrogel beads with diameters in the range of 100-300 MUm that were produced by an electrostatic extrusion method and rapid photo-cross-linking, the E. coli pLuxR-GFP were found to possess a high degree of viability and sensing activity. The encapsulated bacteria could proliferate inside the hydrogel beads, when exposed to bacteria culture medium. In media containing the autoinducer N-(3 oxododecanoyl)homoserine lactone, the encapsulated reporter bacteria responded with a strong fluorescence signal due to an increased green fluorescent protein (GFP) expression. A prototype dipstick type sensor developed here underlines the potential of encapsulation of viable and functional reporter bacteria inside reinforced alginate-methacrylate hydrogel beads for whole cell sensors for bacteria detection. PMID- 28627871 TI - The Sulfur-Linked Analogue of O-GlcNAc (S-GlcNAc) Is an Enzymatically Stable and Reasonable Structural Surrogate for O-GlcNAc at the Peptide and Protein Levels. AB - Synthetic proteins bearing site-specific posttranslational modifications have revolutionized our understanding of their biological functions in vitro and in vivo. One such modification, O-GlcNAcylation, is the dynamic addition of beta-N acetyl glucosamine to the side chains of serine and threonine residues of proteins, yet our understanding of the site-specific impact of O-GlcNAcylation remains difficult to evaluate in vivo because of the potential for enzymatic removal by endogenous O-GlcNAcase (OGA). Thioglycosides are generally perceived to be enzymatically stable structural mimics of O-GlcNAc; however, in vitro experiments with small-molecule GlcNAc thioglycosides have demonstrated that OGA can hydrolyze these linkages, indicating that S-linked beta-N-acetyl glucosamine (S-GlcNAc) on peptides or proteins may not be completely stable. Here, we first develop a robust synthetic route to access an S-GlcNAcylated cysteine building block for peptide and protein synthesis. Using this modified amino acid, we establish that S-GlcNAc is an enzymatically stable surrogate for O-GlcNAcylation in its native protein setting. We also applied nuclear magnetic resonance spectroscopy and computational modeling to find that S-GlcNAc is an good structural mimic of O-GlcNAc. Finally, we demonstrate that site-specific S GlcNAcylation results in biophysical characteristics that are the same as those of O-GlcNAc within the context of the protein alpha-synuclein. While this study is limited in focus to two model systems, these data suggest that S-GlcNAc broadly resembles O-GlcNAc and that it is indeed a stable analogue in the context of peptides and proteins. PMID- 28627873 TI - Ni and NiO Nanoparticles Decorated Metal-Organic Framework Nanosheets: Facile Synthesis and High-Performance Nonenzymatic Glucose Detection in Human Serum. AB - Ni-MOF (metal-organic framework)/Ni/NiO/carbon frame nanocomposite was formed by combing Ni and NiO nanoparticles and a C frame with Ni-MOF using an efficient one step calcination method. The morphology and structure of Ni-MOF/Ni/NiO/C nanocomposite were characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and energy disperse spectroscopy (EDS) mapping. Ni-MOF/Ni/NiO/C nanocomposites were immobilized onto glassy carbon electrodes (GCEs) with Nafion film to construct high-performance nonenzymatic glucose and H2O2 electrochemical sensors. Cyclic voltammetric (CV) study showed Ni-MOF/Ni/NiO/C nanocomposite displayed better electrocatalytic activity toward glucose oxidation as compared to Ni-MOF. Amperometric study indicated the glucose sensor displayed high performance, offering a low detection limit (0.8 MUM), a high sensitivity of 367.45 mA M-1 cm-2, and a wide linear range (from 4 to 5664 MUM). Importantly, good reproducibility, long-time stability, and excellent selectivity were obtained within the as-fabricated glucose sensor. Furthermore, the constructed high-performance sensor was utilized to monitor the glucose levels in human serum, and satisfactory results were obtained. It demonstrated the Ni-MOF/Ni/NiO/C nanocomposite can be used as a good electrochemical sensing material in practical biological applications. PMID- 28627872 TI - Xanthohumol Blocks Proliferation and Migration of Vascular Smooth Muscle Cells in Vitro and Reduces Neointima Formation in Vivo. AB - Xanthohumol (1) is a principal prenylated chalcone found in hops. The aim of this study was to examine its influence on platelet-derived growth factor (PDGF)-BB triggered vascular smooth muscle cell (VSMC) proliferation and migration in vitro and on experimentally induced neointima formation in vivo. Quantification of resazurin conversion indicated that 1 can inhibit PDGF-BB-induced VSMC proliferation concentration-dependently (IC50 = 3.49 MUM). Furthermore, in a wound-healing assay 1 potently suppresses PDGF-BB-induced VSMC migration at 15 MUM. Tested in a mouse femoral artery cuff model, 1 significantly reduces neointima formation. Taken together, we show that 1 represses PDGF-BB-induced VSMC proliferation and migration in vitro as well as neointima formation in vivo. This novel activity suggests 1 as an interesting candidate for further studies addressing a possible therapeutic application to counteract vascular proliferative disease. PMID- 28627874 TI - Impact of Postsynthetic Modification on the Electrical and Magnetic Properties of Materials. AB - Postsynthetic modification is a promising tool for introducing multifunctional properties in metal-organic frameworks (MOFs). The effects of postsynthetic metal addition/exchange in a barium-based MOF have been well examined toward their magnetic and electrical properties. The rattling motion of the extraframework organic cation is responsible for the ferroelectric behavior. The strong magnetic frustration in Tb@1 is found to arise from the nearly triangular arrangement of Tb3+ ions in its secondary building unit along the chain direction. PMID- 28627875 TI - Preparation of Gemini Surfactant/Conjugated Polymer Aggregates for Enhanced Fluorescence and Bioimaging Application. AB - Conjugated polymers have great potential applications in bioimaging. However, the aggregation of conjugated polymers driven by electrostatic and hydrophobic interactions in aqueous media results in the reduction of photoluminescence quantum efficiency. In present work we synthesized a carboxylate gemini surfactant [sodium 2,6-didodecyl-4-hydroxy-2,6-diaza-1,7-heptanedicarboxylate (SDHC)] to adjust the aggregation behaviors and fluorescence properties of conjugated polymers [anionic poly(2-methoxy-5-propyloxy sulfonate phenylene vinylene) (MPS-PPV) and cationic poly(3-alkoxy-4-methylthiophene) (PMNT)]. This gemini surfactant shows very low critical micellar concentration (CMC) in aqueous solution and forms vesicles above CMC. In neutral and acidic conditions, MPS-PPV combines with the SDHC vesicles mainly via hydrophobic interactions and forms the aggregates in which the photoluminescence quantum efficiency of MPS-PPV is highly enhanced from 0.1% to 27%. As to PMNT, the molecules are located in the bilayer of SDHC vesicles through both electrostatic and hydrophobic interactions, and this structure prevents the production and release of reactive oxygen species. Moreover, SDHC is nontoxic and can effectively decrease the dark- and photocytotoxicity of MPS-PPV and PMNT, laying a good foundation for their bioimaging application. The living cell imaging indicates that the surfactant/conjugated polymer aggregates can stain the MCF-7 cells with main location in the lysosome. This work provides insight into how to improve the fluorescence properties and bioimaging applications of conjugated polymers by surfactants. PMID- 28627876 TI - Graphene Decorated by Indium Sulfide Nanoparticles as High-Performance Anode for Sodium-Ion Batteries. AB - We report a highly performing anode material for sodium-ion batteries (SIBs) composed of graphene decorated by indium sulfide (In2S3). The composite is synthesized by a facile hydrothermal pathway with subsequent annealing and is characterized by defined structure and well-tailored morphology, as is indeed demonstrated by X-ray diffraction and spectroscopy as well as high-resolution microscopy. These optimal characteristics allow the electrode to perform remarkably in sodium cell by achieving a maximum specific capacity as high as 620 mAh g-1 and the still-relevant value of 335 mAh g-1 at an extremely high current (i.e., 5 A g-1). The high storage capacity, the long cycle life, and the impressive rate capability of the composite may be attributed to the synergetic effect between uniform In2S3 nanoparticles and the graphene matrix. These features suggest that the In2S3-graphene is a viable choice for application as an anode material in high-performance SIBs. PMID- 28627878 TI - Tilted Two-Dimensional Array Multifocus Confocal Raman Microspectroscopy. AB - A simple and efficient two-dimensional multifocus confocal Raman microspectroscopy featuring the tilted-array technique is demonstrated. Raman scattering from a 4 * 4 square foci array passing through a 4 * 4 confocal pinhole array is tilted with a periscope. The tilted array of Raman scattering signals is dispersed by an imaging spectrograph onto a CCD detector, giving 16 independent Raman spectra formed as 16 bands with different heights on the sensor. Use of a state-of-the-art imaging spectrograph enables high-precision wavenumber duplicability of the 16 spectra. This high duplicability makes the simultaneously obtained spectra endurable for multivariate spectral analyses, which is demonstrated by a singular value decomposition analysis for Raman spectra of liquid indene. Although the present implementation attains only 16 measurement points, the number of points can be extended to larger than 100 without any technical leaps. Limit of parallelization depends on the interval of measurement points as well as the performance of the optical system. Criteria for finding the maximum feasible number are discussed. PMID- 28627877 TI - Detection and Quantification of Hydrogen Peroxide in Aqueous Solutions Using Chemical Exchange Saturation Transfer. AB - The development of new analytical methods to accurately quantify hydrogen peroxide is of great interest. In the current study, we developed a new magnetic resonance (MR) method for noninvasively quantifying hydrogen peroxide (H2O2) in aqueous solutions based on chemical exchange saturation transfer (CEST), an emerging MRI contrast mechanism. Our method can detect H2O2 by its specific CEST signal at ~6.2 ppm downfield from water resonance, with more than 1000 times signal amplification compared to the direct NMR detection. To improve the accuracy of quantification, we comprehensively investigated the effects of sample properties on CEST detection, including pH, temperature, and relaxation times. To accelerate the NMR measurement, we implemented an ultrafast Z-spectroscopic (UFZ) CEST method to boost the acquisition speed to 2 s per CEST spectrum. To accurately quantify H2O2 in unknown samples, we also implemented a standard addition method, which eliminated the need for predetermined calibration curves. Our results clearly demonstrate that the presented CEST-based technique is a simple, noninvasive, quick, and accurate method for quantifying H2O2 in aqueous solutions. PMID- 28627879 TI - The beta1'-beta2' Motif of the RNase H Domain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Is Responsible for Conferring Open Conformation to the p66 Subunit by Displacing the Connection Domain from the Polymerase Cleft. AB - The heterodimeric human immunodeficiency virus type 1 reverse transcriptase is composed of p66 and p51 subunits. While in the p51 subunit, the connection domain is tucked in the polymerase cleft; it is effectively displaced from the cleft of the catalytically active p66 subunit. How is the connection domain relocated from the polymerase cleft of p66? Does the RNase H domain have any role in this process? To answer this question, we extended the C-terminal region of p51 by stepwise addition of N-terminal motifs of RNase H domain to generate p54, p57, p60, and p63 derivatives. We found all of the C-terminal extended derivatives of p51 assume open conformation, bind to the template-primer, and catalyze the polymerase reaction. Glycerol gradient ultracentrifugation analysis showed that only p54 sedimented as a monomer, while other derivatives were in a homodimeric conformation. We proposed a model to explain the monomeric conformation of catalytically active p54 derivative carrying additional 21-residues long beta1' beta2' motif from the RNase H domain. Our results indicate that the beta1'-beta2' motif of the RNase H domain may be responsible for displacing the connection domain from the polymerase cleft of putative monomeric p66. The unstable elongated p66 molecule may then readily dimerize with p51 to assume a stable dimeric conformation. PMID- 28627881 TI - Defining Cancer Cell Bioenergetic Profiles Using a Dual Organelle-Oriented Chemosensor Responsive to pH Values and Electropotential Changes. AB - Cell fate is largely shaped by combined activity of different types of organelles, which often feature functionally critical parameters that succumb to pathological inducers. We herein report the analysis of cell bioenergetic profiles with a dual organelle-oriented chemosensor (RC-AMI), partitioning in mitochondria to give blue fluorescence and in lysosomes to give red fluorescence. Responsive to lysosomal pH and mitochondrial transmembrane potential (DeltaPsim), two parameters crucial to cell bioenergetics, RC-AMI enables dual colored reporting of lysosomal acidity and DeltaPsim, revealing upregulated DeltaPsim and imbalance dramatically shifted favoring DeltaPsim over lysosomal acidity in cancer cells whereas the tendency is reversed in starved cells. Complementing classical homo-organelle-specific sensors, this dual organelle-oriented and fluorescently responsive probe offers a new tool to detect imbalance between lysosomal acidity and mitochondrial DeltaPsim, an index critical for cancer bioenergetics. PMID- 28627880 TI - Site-Specific Fucosylation Analysis Identifying Glycoproteins Associated with Aggressive Prostate Cancer Cell Lines Using Tandem Affinity Enrichments of Intact Glycopeptides Followed by Mass Spectrometry. AB - Fucosylation (Fuc) of glycoproteins plays an important role in regulating protein function and has been associated with the development of several cancer types including prostate cancer (Pca). Therefore, the research of Fuc glycoproteins has attracted increasing attention recently in the analytical field. Herein, a strategy based on lectin affinity enrichments of intact glycopeptides followed by mass spectrometry has been established to evaluate the specificities of various Fuc-binding lectins for glycosite-specific Fuc analysis of nonaggressive (NAG) and aggressive (AG) Pca cell lines. The enrichment specificities of Fuc glycopeptides using lectins (LCA, PSA, AAL, LTL, UEA I, and AOL) and MAX extraction cartridges alone, or in tandem, were evaluated. Our results showed that the use of lectin enrichment significantly increased the ratio of fucosylated glycopeptides to total glycopeptides compared to MAX enrichment. Furthermore, tandem use of lectin followed by MAX increased the number of identifications of Fuc glycopeptides compared to using lectin enrichment alone. LCA, PSA, and AOL showed stronger binding capacity than AAL, LTL, and UEA I. Also, LCA and PSA bound specifically to core Fuc, whereas AOL, AAL, and UEA I showed binding to both core Fuc and branch Fuc. The optimized enrichment method with tandem enrichment of LCA followed by MAX (LCA-MAX) was then applied to examine the Fuc glycoproteomes in two NAG and two AG Pca cell lines. In total, 973 intact Fuc glycopeptides were identified and quantified from 252 Fuc proteins by using the tandem-mass-tags (TMT) labeling and nanoliquid chromatography-mass spectrometry (nanoLC-MS/MS) analysis. Further data analysis revealed that 51 Fuc glycopeptides were overexpressed more than 2-fold in AG cell lines compared to NAG cells. The analysis of protein core fucosylation has great potential for aiding our understanding of invasive activity of AG Pca and may lead to the development of diagnostic approaches for AG Pca. PMID- 28627882 TI - Switching between Anion-Binding Catalysis and Aminocatalysis with a Rotaxane Dual Function Catalyst. AB - The "off" state for aminocatalysis by a switchable [2]rotaxane is shown to correspond to an "on" state for anion-binding catalysis. Conversely, the aminocatalysis "on" state of the dual-function rotaxane is inactive in anion binding catalysis. Switching between the different states is achieved through the stimuli-induced change of position of the macrocycle on the rotaxane thread. The anion-binding catalysis results from a pair of triazolium groups that act together to CH-hydrogen-bond to halide anions when the macrocycle is located on an alternative (ammonium) binding site, stabilizing the in situ generation of benzhydryl cation and oxonium ion intermediates from activated alkyl halides. The aminocatalysis and anion-binding catalysis sites of the dual-function rotaxane catalyst can be sequentially concealed or revealed, enabling catalysis of both steps of a tandem reaction process. PMID- 28627883 TI - Mechanism of Vanadium Leaching during Surface Weathering of Basic Oxygen Furnace Steel Slag Blocks: A Microfocus X-ray Absorption Spectroscopy and Electron Microscopy Study. AB - Basic oxygen furnace (BOF) steelmaking slag is enriched in potentially toxic V which may become mobilized in high pH leachate during weathering. BOF slag was weathered under aerated and air-excluded conditions for 6 months prior to SEM/EDS and MUXANES analysis to determine V host phases and speciation in both primary and secondary phases. Leached blocks show development of an altered region in which free lime and dicalcium silicate phases were absent and Ca-Si-H was precipitated (CaCO3 was also present under aerated conditions). MUXANES analyses show that V was released to solution as V(V) during dicalcium silicate dissolution and some V was incorporated into neo-formed Ca-Si-H. Higher V concentrations were observed in leachate under aerated conditions than in the air excluded leaching experiment. Aqueous V concentrations were controlled by Ca3(VO4)2 solubility, which demonstrate an inverse relationship between Ca and V concentrations. Under air-excluded conditions Ca concentrations were controlled by dicalcium silicate dissolution and Ca-Si-H precipitation, leading to relatively high Ca and correspondingly low V concentrations. Formation of CaCO3 under aerated conditions provided a sink for aqueous Ca, allowing higher V concentrations limited by kinetic dissolution rates of dicalcium silicate. Thus, V release may be slowed by the precipitation of secondary phases in the altered region, improving the prospects for slag reuse. PMID- 28627885 TI - Absolute Quantification of Water in Microporous Solids with 1H Magic Angle Spinning NMR and Standard Addition. AB - Zeolites are microporous materials driving industrial scale adsorption, ion exchange, and catalytic processes. Their water content dramatically impacts their properties, but its quantification with Karl Fisher titration or thermal gravimetric analysis is problematic. When standard addition of water is combined with 1H magic angle spinning (MAS) NMR detection, absolute quantification of water in microporous materials becomes possible. The method was demonstrated on five different, commercially available zeolites. PMID- 28627884 TI - Hydrogen-Deuterium Exchange Mass Spectrometry Reveals Calcium Binding Properties and Allosteric Regulation of Downstream Regulatory Element Antagonist Modulator (DREAM). AB - Downstream regulatory element antagonist modulator (DREAM) is an EF-hand Ca2+ binding protein that also binds to a specific DNA sequence, downstream regulatory elements (DRE), and thereby regulates transcription in a calcium-dependent fashion. DREAM binds to DRE in the absence of Ca2+ but detaches from DRE under Ca2+ stimulation, allowing gene expression. The Ca2+ binding properties of DREAM and the consequences of the binding on protein structure are key to understanding the function of DREAM. Here we describe the application of hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis to investigate the Ca2+ binding properties and the subsequent conformational changes of full length DREAM. We demonstrate that all EF-hands undergo large conformation changes upon calcium binding even though the EF-1 hand is not capable of binding to Ca2+. Moreover, EF-2 is a lower-affinity site compared to EF-3 and -4 hands. Comparison of HDX profiles between wild-type DREAM and two EF-1 mutated constructs illustrates that the conformational changes in the EF-1 hand are induced by long range structural interactions. HDX analyses also reveal a conformational change in an N-terminal leucine-charged residue-rich domain (LCD) remote from Ca2+ binding EF-hands. This LCD domain is responsible for the direct interaction between DREAM and cAMP response element-binding protein (CREB) and regulates the recruitment of the co-activator, CREB-binding protein. These long-range interactions strongly suggest how conformational changes transmit the Ca2+ signal to CREB-mediated gene transcription. PMID- 28627886 TI - Experimentally Validated Model Enables Debottlenecking of in Vitro Protein Synthesis and Identifies a Control Shift under in Vivo Conditions. AB - Cell-free (in vitro) protein synthesis (CFPS) systems provide a versatile tool that can be used to investigate different aspects of the transcription translation machinery by reducing cells to the basic functions of protein formation. Recent improvements in reaction stability and lysate preparation offer the potential to expand the scope of in vitro biosynthesis from a research tool to a multifunctional and versatile platform for protein production and synthetic biology. To date, even the best-performing CFPS systems are drastically slower than in vivo references. Major limitations are imposed by ribosomal activities that progress in an order of magnitude slower on the mRNA template. Owing to the complex nature of the ribosomal machinery, conventional "trial and error" experiments only provide little insight into how the desired performance could be improved. By applying a DNA-sequence-oriented mechanistic model, we analyzed the major differences between cell-free in vitro and in vivo protein synthesis. We successfully identified major limiting elements of in vitro translation, namely the supply of ternary complexes consisting of EFTu and tRNA. Additionally, we showed that diluted in vitro systems suffer from reduced ribosome numbers. On the basis of our model, we propose a new experimental design predicting 90% increased translation rates, which were well achieved in experiments. Furthermore, we identified a shifting control in the translation rate, which is characterized by availability of the ternary complex under in vitro conditions and the initiation of translation in a living cell. Accordingly, the model can successfully be applied to sensitivity analyses and experimental design. PMID- 28627888 TI - Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes. AB - Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO-) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO- and Rhod-ONOO-) for ONOO- through a novel and universally applicable mechanism: ONOO--mediated deprotection of alpha-keto caged fluorophores. Among them, Rhod-ONOO- can selectively accumulate and react in mitochondria, one of the main sources of ONOO-, with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod ONOO- and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO- generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity. PMID- 28627887 TI - Controlling the Catalytic Functions of DNAzymes within Constitutional Dynamic Networks of DNA Nanostructures. AB - Mimicking complex cellular dynamic chemical networks being up-regulated or down regulated by external triggers is one of the challenges in systems chemistry. Constitutional dynamic networks (CDNs), composed of exchangeable components that respond to environmental triggers by self-adaption, provide general means to mimic biosystems. We use the structural and functional information encoded in nucleic acid nanostructures to construct effector (input)-triggered constitutional dynamic networks that reveal adaptable catalytic properties. Specifically, CDNs composed of four exchangeable constituents, AA', BA', AB', and BB', are constructed. In the presence of an effector (input) that controls the stability of one of the constituents, the input-guided up-regulation or down regulation of the CDN's constituents proceeds. As effectors we apply the fuel strand stabilization of one of the CDN constituents by the formation of the T-A.T triplex structure, or by the K+-ion-induced stabilization of one of the CDN constituents, via the formation of a K+-ion-stabilized G-quadruplex. Energetic stabilization of one of the CDN constituents leads to a new dynamically adapted network composed of up-regulated and down-regulated constituents. By applying counter triggers to the effector units, e.g., an antifuel strand or 18-crown-6 ether, reconfiguration to the original CDNs is demonstrated. The performance of the CDNs is followed by the catalytic activities of the constituents and by complementary quantitative gel electrophoresis experiments. The orthogonal triggered and switchable operation of the CDNs is highlighted. PMID- 28627889 TI - Measuring Spatially Resolved Collective Ionic Transport on Lithium Battery Cathodes Using Atomic Force Microscopy. AB - One of the main challenges in improving fast charging lithium-ion batteries is the development of suitable active materials for cathodes and anodes. Many materials suffer from unacceptable structural changes under high currents and/or low intrinsic conductivities. Experimental measurements are required to optimize these properties, but few techniques are able to spatially resolve ionic transport properties at small length scales. Here we demonstrate an atomic force microscope (AFM)-based technique to measure local ionic transport on LiFePO4 to correlate with the structural and compositional analysis of the same region. By comparing the measured values with density functional theory (DFT) calculations, we demonstrate that Coulomb interactions between ions give rise to a collective activation energy for ionic transport that is dominated by large phase boundary hopping barriers. We successfully measure both the collective activation energy and the smaller single-ion bulk hopping barrier and obtain excellent agreement with values obtained from our DFT calculations. PMID- 28627891 TI - Effect of Deep Eutectic Solvent Nanostructure on Phospholipid Bilayer Phases. AB - Phospholipids are shown by solvent penetration experiments to form lamellar phases and spontaneously spawn vesicles in a wide range of deep eutectic solvents (DESs) composed of alkylammonium halide salts and glycerol or ethylene glycol, which are shown to be nanostructured by X-ray scattering. In contrast with molecular solvents, the chain melting temperature of each phospholipid, which determines the stability of the swellable bilayer phase, depends on the structure of the cation, anion, and molecular H-bond donor that constitute the DES. Chain melting is most sensitive to the length of the alkyl chain of the cation, which is partitioned between apolar domains in the bulk, nanostructured DES and those within the lipid bilayer. This is moderated by the structures of the anion and the molecular hydrogen bond donor, which determine the extent of polar/apolar segregation in the bulk liquid. PMID- 28627890 TI - Improved Description of Sulfur Charge Anisotropy in OPLS Force Fields: Model Development and Parameterization. AB - The atomic point-charge model used in most molecular mechanics force fields does not represent well the electronic anisotropy that is featured in many directional noncovalent interactions. Sulfur participates in several types of such interactions with its lone pairs and sigma-holes. The current study develops a new model, via the addition of off-atom charged sites, for a variety of sulfur compounds in the OPLS-AA and OPLS/CM5 force fields to address the lack of charge anisotropy. Parameter optimization is carried out to reproduce liquid-state properties, torsional and noncovalent energetics from reliable quantum mechanical calculations, and electrostatic potentials. Significant improvements are obtained for computed free energies of hydration, reducing the mean unsigned errors from ca. 1.4 to 0.4-0.7 kcal/mol. Enhanced accuracy in directionality and energetics is also obtained for molecular complexes with sulfur-containing hydrogen and halogen bonds. Moreover, the new model reproduces the unusual conformational preferences of sulfur-containing compounds with 1,4-intramolecular chalcogen bonds. Transferability of the new force field parameters to cysteine and methionine is verified via molecular dynamic simulations of blocked dipeptides. The study demonstrates the effectiveness of using off-atom charge sites to address electronic anisotropy, and provides a parametrization methodology that can be applied to other systems. PMID- 28627892 TI - Approach to Fabricating a Compact Gold Nanoparticle Film with the Assistance of a Surfactant. AB - We report a facile method to fabricate a compact Au nanoparticle film with the assistance of surfactants. First, the dodecanethiol-coated Au nanoparticles were floated on the surface of the toluene/acetonitrile solvent mixture and adjusted to an expanded dispersion by changing the mixture ratio. Silicone oil was then added as a surfactant to compress the floating nanoparticles from the original loose status to a closely packed arrangement that produced a compact nanoparticle film. The relationship of the compressed film area to the silicone oil concentration was plotted and compared to the surface tension curve of silicone oil. The results were quite consistent, suggesting that the surface location of the surfactant induced the nanoparticles' compression. The resulting nanoparticle film was uniform and sufficiently robust to be transferred to the solid substrate. Moreover, it could be applied to catalyze the reduction of 4 nitrophenol. Our study indicated that the utilization of surfactants to compress the well-dispersed nanoparticles on the liquid surface is a simple, fast, and adaptable method of fabricateing compact nanoparticle films with great promise for future applications. PMID- 28627893 TI - Green and Facile Esterification Procedure Leading to Crystalline-Functionalized Graphite Oxide. AB - A simple and eco-friendly procedure of esterification of graphite oxide (GO), which uses acetic anhydride as a model reagent and ethyl acetate as a green solvent, is reported. The procedure leads to high functionalization degrees (at least up to 4.5 mol % of acetyl groups, referred to as graphitic C atoms) and it is much more effective than the literature method based on pure acetic anhydride. Surprisingly, our acetylation procedure does not destroy or reduce GO crystallinity but, irrespective of a substantial increase of distance between GO layers (from 0.84 nm up to 0.95 nm), leads to an increased order in the direction perpendicular to the graphitic planes. This phenomenon indicates that acetyl groups of acetylated GO (AcGO) are easily accommodated between graphitic layers, even improving interlayer order. The esterification procedure is generally applicable with various anhydrides providing differently functionalized graphite oxide. Dispersion of crystalline functionalized GO in volatile organic solvents followed by solvent fast removal, can easily lead to complete exfoliation. PMID- 28627894 TI - Surface Functionalization of Black Phosphorus via Potassium toward High Performance Complementary Devices. AB - Two-dimensional black phosphorus configured field-effect transistor devices generally show a hole-dominated ambipolar transport characteristic, thereby limiting its applications in complementary electronics. Herein, we demonstrate an effective surface functionalization scheme on few-layer black phosphorus, through in situ surface modification with potassium, with a view toward high performance complementary device applications. Potassium induces a giant electron doping effect on black phosphorus along with a clear bandgap reduction, which is further corroborated by in situ photoelectron spectroscopy characterizations. The electron mobility of black phosphorus is significantly enhanced to 262 (377) cm2 V-1 s-1 by over 1 order of magnitude after potassium modification for two terminal (four-terminal) measurements. Using lithography technique, a spatially controlled potassium doping technique is developed to establish high-performance complementary devices on a single black phosphorus nanosheet, for example, the p n homojunction-based diode achieves a near-unity ideality factor of 1.007 with an on/off ratio of ~104. Our findings coupled with the tunable nature of in situ modification scheme enable black phosphorus as a promising candidate for further complementary electronics. PMID- 28627895 TI - Electroanalytical Assessment of the Effect of Ni:Fe Stoichiometry and Architectural Expression on the Bifunctional Activity of Nanoscale NiyFe1-yOx. AB - Electrocatalysis of the oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) was assessed for a series of Ni-substituted ferrites (NiyFe1-yOx, where y = 0.1 to 0.9) as expressed in porous, high-surface-area forms (ambigel and aerogel nanoarchitectures). We then correlate electrocatalytic activity with Ni:Fe stoichiometry as a function of surface area, crystallite size, and free volume. In order to ensure in-series comparisons, calcination at 350 degrees C/air was necessary to crystallize the respective NiyFe1-yOx nanoarchitectures, which index to the inverse spinel structure for Fe-rich materials (y <= 0.33), rock salt for the most Ni-rich material (y = 0.9), and biphasic for intermediate stoichiometry (0.5 <= y <= 0.67). In the intermediate Ni:Fe stoichiometric range (0.33 <= y <= 0.67), the OER current density at 390 mV increases monotonically with increasing Ni content and increasing surface area, but with different working curves for ambigels versus aerogels. At a common stoichiometry within this range, ambigels and aerogels yield comparable OER performance, but do so by expressing larger crystallite size (ambigel) versus higher surface area (aerogel). Effective OER activity can be achieved without requiring supercritical fluid extraction as long as moderately high surface area, porous materials can be prepared. We find improved OER performance (eta decreases from 390 to 373 mV) for Ni0.67Fe0.33Ox aerogel heat-treated at 300 degrees C/Ar, owing to an increase in crystallite size (2.7 to 4.1 nm). For the ORR, electrocatalytic activity favors Fe-rich NiyFe1-yOx materials; however, as the Ni-content increases beyond y = 0.5, a two-electron reduction pathway is still exhibited, demonstrating that bifunctional OER and ORR activity may be possible by choosing a nickel ferrite nanoarchitecture that provides high OER activity with sufficient ORR activity. Assessing the catalytic activity requires an appreciation of the multivariate interplay among Ni:Fe stoichiometry, surface area, crystallographic phase, and crystallite size. PMID- 28627896 TI - Multifaceted alpha-Enaminone: Adaptable Building Block for Synthesis of Heterocyclic Scaffolds Through Conceptually Distinct 1,2-, 1,3-, 1,4-, and C-O Bond Forming Annulations. AB - The new reactivity of alpha,beta-unsaturated enaminones driven by their "dual electronic attitude" is reported. We introduce unexplored, alpha-enaminone synthones and reveal the unusual functionalities of these building blocks. The feasibility of this new concept is demonstrated in the direct functionalization of enaminone precursors, such as alkylation; 1,2- 1,3-, or 1,4-addition; and C-O bond formation. The general and potential applicability is presented through the collective synthesis of several important classes of heterocycles via controlled cyclizations of easily accessible common precursors. The rapid composition of novel key alpha-enaminone synthones yields an assembly of oxazines, azaspirones, quinolinones, and quinolinols in a regio- and chemoselective fashion. PMID- 28627897 TI - Multicolour Electrochromic Film Based on a TiO2@poly[Ni(salen)] Nanocomposite with Excellent Electrochemical Stability. AB - We report the electrochromic properties of a polymeric nanocomposite prepared by potentiodynamic deposition of transition-metal complex [Ni(3-Mesalen)], designated as [1], in the presence of TiO2 nanoparticles (NPs) with an average size of 9.7 +/- 1.1 nm. Entrapment of TiO2 NPs in the poly[1] matrix was confirmed by several techniques. The nanocomposite TiO2@poly[1] films showed similar electrochemical responses to the original (nanoparticle-free) poly[1] films, but with higher electroactive surface coverages (Gamma), showing the advantage of the nanocomposite preparation. The results indicated that the electronic structure of poly[1] was retained in the nanocomposite; nonetheless, a lower epsilon value was obtained for the charge-transfer band of the former, revealing superior stability of the nanocomposite for ligand high oxidation states. The TiO2@poly[1] nanocomposite showed interesting color changes, from yellow (reduced state) to green and russet (oxidized states), with enhanced electrochemical stability, demonstrated by a charge loss of only 7.3% over ca. 10 000 redox cycles surpassing the original polymer film stability: the loss of electroactivity is a factor of ca. 2 less than for pristine poly[1]. Furthermore, an enhancement of 16.7% in the optical modulation (DeltaOD = 0.48) was also observed for the nanocomposite, confirming the benefit of TiO2 incorporation into the EC properties of the original polymer film. PMID- 28627898 TI - Subjective Reactions to International Research Participation: An Illustration of Ethical Considerations With Women Heading Households in Sri Lanka. AB - here are unique ethical considerations in conducting international research with war and disaster-affected populations that are important for ensuring adequate protection of participants. Of particular importance is the distress that participants may experience as a result of being asked about traumatic stressors, psychological symptoms, and life problems. In this study, trauma-affected Tamil women in Eastern Sri Lanka were asked to report on their research-participation experience after taking part in a larger study on risk and resiliency. Results indicated that most participants experienced emotional upset as a result of taking part in the study. However, the degree of distress was generally not more than they anticipated, and most participants reported they would have participated had they known in advance how they would feel. Most participants perceived some benefit as a result of participating and agreed that items were personally relevant. Emotional distress from participation positively correlated with culturally specific symptoms of anxiety and depression. Contextual stressors and social support were not associated with participation-related distress. We discuss these findings as well as general issues that might arise in international research with trauma-affected populations. (PsycINFO Database Record PMID- 28627899 TI - Parenting stress as a mediator of trauma exposure and mental health outcomes in young children. AB - Exposure to potentially traumatic events (PTEs) significantly impacts outcomes for children in behavioral health systems of care (SOCs). The present study built on previous research that found parenting stress influences outcomes for children exposed to PTEs. The sample included 184 young children and their families who were enrolled in an early childhood SOC. Path analyses demonstrated that parenting stress mediated the relationship between the number of PTEs a child experienced and caregiver-reported internalizing/externalizing problem behaviors at baseline. Parenting stress also mediated PTEs and internalizing problem behaviors at 6 months. In response to the culmination of these studies, we discuss ways SOCs can support parents to help alleviate parenting stress. (PsycINFO Database Record PMID- 28627900 TI - Individual versus peer grit: Influence on later individual literacy achievement of dual language learners. AB - The objective of this short-term longitudinal study was to examine individual versus classroom peer effects of grit on later individual literacy achievement in elementary school. The dual language learner, largely Latina/o sample included students from the 3rd through the 5th grades. Participants completed a literacy achievement performance task at 3 time points over 4 months, in addition to student-reported grit at the first time point. Classroom peer grit, not individual grit, was a strong, significant predictor of an individual's later literacy achievement, adjusting for previous literacy achievement, age, gender, home language, and classroom clusters. (PsycINFO Database Record PMID- 28627901 TI - Cone of gaze in positive schizotypy: Relationship to referential thinking and social functioning. AB - Eye contact is an essential means of nonverbal communication, providing information about attention, emotion, mental state, facial expressions, and identity/gender (Itier & Batty, 2009). Although studies suggest that patients with schizophrenia endorse direct gaze more often than controls in ambiguous gaze circumstances, gaze perception in schizotypy remains unstudied. This study investigated whether individuals with positive schizotypic features incorrectly perceive that others are looking at them and whether this is related to referential thinking and psychosocial functioning. Schizotypic individuals (n = 33) and controls (n = 29) completed a newly developed measure of gaze perception, a cone of gaze task (Gamer & Hecht, 2007). Results reveal that individuals in the schizotypy group report feeling as though they are being looked at across a wider range of angles than controls. Consistent with our hypotheses, this wider cone of gaze is associated with increased referential thinking and poorer psychosocial functioning. (PsycINFO Database Record PMID- 28627902 TI - Responses to dominance challenge are a function of psychopathy level: A multimethod study. AB - This study assesses the relationship between psychopathy and dominance, both as a trait level and in 2 interpersonal contexts. Following the interpersonal circumplex model, we expected that interacting with a dominant interviewer would reduce dominance displays by low psychopathy participants (interpersonal complementarity) but might increase such displays in those with higher psychopathy (anticomplementarity). Psychopathic traits and dominance were assessed in a community sample (N = 91) using multiple dominance indicators: self reported overall dominance level, job preference, dominance displays observed during identical interviews with a subordinate and dominant interviewer, and baseline and postinterview measures of personal space and testosterone level. Psychopathic traits were positively related to dominance on both trait measures and in the interviews. As a trait, higher self-reported psychopathy scores were associated with higher levels of self-reported dominance and preference for supervisory job positions. Higher Factor 1 psychopathy scores were associated with increased dominance display in interaction with the dominant interviewer. Higher Factor 2 scores were associated with allowing the dominant interviewer to approach more closely (reduced physical distancing). Psychopathy was partly related to a delayed increase in testosterone levels after interaction. Psychopathic traits may include a general tendency to dominate, a tendency which increases when interacting with a dominant other. The emotional/interpersonal psychopathy factor is specifically related to increased dominance displays when interacting with a dominant individual, while the behavioral factor of psychopathy is related to reduced physical distancing of a dominant partner. At higher psychopathy levels the general rule of dominant-subordinate reciprocity during social interaction is reversed. (PsycINFO Database Record PMID- 28627903 TI - Predictors of substance use in youth with borderline personality disorder. AB - Concomitant substance misuse in adults with borderline personality disorder (BPD) is associated with a more severe course of illness and poorer outcomes. Previous research has found an association between the number of borderline personality features and substance misuse in community samples. This study examined the relationship between substance use and severity of BPD in youth presenting for the first time for treatment (first presentation) of BPD. Participants were 117 help-seeking youth aged 15-25 years (93 females; Mage = 19.0 years, SD = 2.8) with BPD. Hierarchical logistic regression was used to investigate whether the severity of BPD predicted substance use. After adjusting for demographic factors and concurrent mental state pathology, BPD independently predicted alcohol dependence, amphetamine use in the previous month, or use of 2 or more illicit substances in the previous month but not daily tobacco use or cannabis use in the previous month. BPD might increase the probability that an individual will engage in higher-risk behaviors, such as amphetamine and polysubstance use, or problematic alcohol use. These findings support the need for assessment of youth with BPD for alcohol, amphetamine, and polysubstance use along with the need for routine screening in drug and alcohol services for BPD features. (PsycINFO Database Record PMID- 28627904 TI - The development of real-time stability supports visual working memory performance: Young children's feature binding can be improved through perceptual structure. AB - Working memory is a basic cognitive process that predicts higher-level skills. A central question in theories of working memory development is the generality of the mechanisms proposed to explain improvements in performance. Prior theories have been closely tied to particular tasks and/or age groups, limiting their generalizability. The cognitive dynamics theory of visual working memory development has been proposed to overcome this limitation. From this perspective, developmental improvements arise through the coordination of cognitive processes to meet demands of different behavioral tasks. This notion is described as real time stability, and can be probed through experiments that assess how changing task demands impact children's performance. The current studies test this account by probing visual working memory for colors and shapes in a change detection task that compares detection of changes to new features versus swaps in color-shape binding. In Experiment 1, 3- to 4-year-old children showed impairments specific to binding swaps, as predicted by decreased real-time stability early in development; 5- to 6-year-old children showed a slight advantage on binding swaps, but 7- to 8-year-old children and adults showed no difference across trial types. Experiment 2 tested the proposed explanation of young children's binding impairment through added perceptual structure, which supported the stability and precision of feature localization in memory-a process key to detecting binding swaps. This additional structure improved young children's binding swap detection, but not new-feature detection or adults' performance. These results provide further evidence for the cognitive dynamics and real-time stability explanation of visual working memory development. (PsycINFO Database Record PMID- 28627906 TI - Evidence of a goal-directed process in human Pavlovian-instrumental transfer. AB - Cues that signal rewards can motivate reward-seeking behaviors, even for outcomes that are not currently desired. Three experiments examined this phenomenon, using an outcome-selective Pavlovian-instrumental transfer (PIT) design and an outcome devaluation procedure. In Experiment 1, participants learned to perform one response to earn crisps points and another response to earn popcorn points. One outcome was then devalued by adulterating it to make it taste unpleasant. On test, overall response choice was biased toward the outcome that had not been devalued, indicating goal-directed control. Stimuli that signaled crisps and popcorn also biased instrumental response choice toward their respective outcomes (a PIT effect). Most importantly, the strength of this bias was not influenced by the devaluation manipulation. In contrast, Experiment 2 demonstrated that when stimuli signaled equal probability of the two outcomes, cue-elicited response choice was sensitive to the devaluation manipulation. Experiment 3 confirmed this conclusion by demonstrating a selective avoidance of the cued, devalued outcome. Together, these data support a goal-directed model of PIT in which expected outcome probability and value make independent contributions to response choice. (PsycINFO Database Record PMID- 28627905 TI - Mind-wandering in healthy aging and early stage Alzheimer's disease. AB - OBJECTIVE: The frequency of mind-wandering (MW) decreases as a function of age in healthy individuals. One possible explanation is that MW is a resource-dependent process, and cognitive resources decline with age. The present study provides the first investigation of MW in the earliest stages of Alzheimer's disease (AD) to further examine the resource model and discontinuities between healthy aging and AD. METHOD: Three large cohorts completed the Sustained Attention to Response Task (SART): a healthy middle-aged group (mean age = 61.79 +/- 5.84 years; N = 270), a healthy older adult group (mean age = 76.58 +/- 5.27 years; N = 282), and a group with early stage AD (mean age = 76.08 +/- 7.17; N = 77), comparable in age to the second group. RESULTS: Self-reports of MW during the SART decreased as a function of age, and there was a further decrease in the AD group. All 3 groups produced faster responses on trials before No-Go errors, suggesting MW occurred in all cohorts. After No-Go errors, healthy older adults slowed disproportionately compared with middle-aged adults. This was not evident in AD individuals who showed posterror slowing comparable with that in the middle-aged group. CONCLUSIONS: The decreased self-reported MW in older adults and the further decline in AD are consistent with the cognitive resource account of MW. Behavioral indices suggest that AD is on a continuum with healthy aging, with the exception of posterror slowing that may suggest performance monitoring deficits in early AD individuals (e.g., lack of error awareness). (PsycINFO Database Record PMID- 28627907 TI - The role of empathy in experiencing vicarious anxiety. AB - With depictions of others facing threats common in the media, the experience of vicarious anxiety may be prevalent in the general population. However, the phenomenon of vicarious anxiety-the experience of anxiety in response to observing others expressing anxiety-and the interpersonal mechanisms underlying it have not been fully investigated in prior research. In 4 studies, we investigate the role of empathy in experiencing vicarious anxiety, using film clips depicting target victims facing threats. In Studies 1 and 2, trait emotional empathy was associated with greater self-reported anxiety when observing target victims, and with perceiving greater anxiety to be experienced by the targets. Study 3 extended these findings by demonstrating that trait empathic concern-the tendency to feel concern and compassion for others-was associated with experiencing vicarious anxiety, whereas trait personal distress the tendency to experience distress in stressful situations-was not. Study 4 manipulated state empathy to establish a causal relationship between empathy and experience of vicarious anxiety. Participants who took an empathic perspective when observing target victims, as compared to those who took an objective perspective using reappraisal-based strategies, reported experiencing greater anxiety, risk-aversion, and sleep disruption the following night. These results highlight the impact of one's social environment on experiencing anxiety, particularly for those who are highly empathic. In addition, these findings have implications for extending basic models of anxiety to incorporate interpersonal processes, understanding the role of empathy in social learning, and potential applications for therapeutic contexts. (PsycINFO Database Record PMID- 28627908 TI - First evidence for "The backup plan paradox". AB - This research is a first test of the backup plan paradox. We hypothesized that investing in a backup plan may facilitate the conditions that it was developed to address: Plan A's insufficiency. Five studies provide initial, primarily correlative support for the undermining effect of investing in a backup plan. Study 1 (n= 160) demonstrated that the more participants perceived they had invested in developing a backup plan (preparing a "crib sheet"), the more likely they were to use it, although greater investments were unrelated to backup plan utility. Studies 2-4 used a simulated negotiation task. Study 2 (n = 247) demonstrated that when goal-relevant resources are limited, investing in developing backup plans and perceiving them as highly instrumental can decrease goal performance through the indirect effect of increased means replacing. Study 3 (n = 248) replicated this effect when goal-relevant resources were plentiful. Study 4 (n = 204) used an experimental variant of the simulated negotiation task and demonstrated that simply having a backup plan is not detrimental, but perceiving backup plans to be highly instrumental decreased goal performance, again through the indirect effect of increased means replacing. Study 5 (n = 160) replicated findings from Studies 1-4 using a lab-based motor task (throwing a ball). Together, these results provide first evidence that backup plans can introduce costs that may jeopardize goal performance. (PsycINFO Database Record PMID- 28627909 TI - Thought-control difficulty motivates structure seeking. AB - Struggling to control one's mind can change how the world appears. In prior studies testing the compensatory control theory, reduced control over the external environment motivated the search for perceptual patterns and other forms of structured knowledge, even in remote domains. Going further, the current studies test whether difficulty controlling thoughts similarly predicts structure seeking. As hypothesized, thought-control difficulty positively predicted perceptions of causal connections between remote events (Study 1a) and nonexistent objects in visual noise (Study 1b). This effect was mediated by aversive arousal (Study 2) and caused specifically by thought-control difficulty as distinct from general difficulty (Study 3). Study 4 replicated the effect with a sample of meditators learning to control their thoughts, showing that thought control difficulty was a powerful predictor of structure seeking. These findings reveal a novel form of motivated perception. (PsycINFO Database Record PMID- 28627910 TI - At-home partner sleep functioning over the course of military deployment. AB - Although the negative effects of deployment on the health of military spouses have been studied, research on sleep disruptions remains limited. This study investigates trajectories of sleep complaints over the course of deployment and predictors of these changes among a cohort of at-home partners. Data were drawn from the Readiness and Resilience in National Guard Soldiers (RINGS-2) project, a prospective, longitudinal study of National Guard soldiers deployed to Iraq/Kuwait (2011-2012) and their intimate partners. Spouses or cohabiting partners (N = 686) of soldiers completed assessments of risk/protective factors 2 to 5 months before their partners' deployment (Time 1), 4 months (Time 2) and 8 months (Time 3) into the deployment, and 2 to 3 months following the soldiers' return (Time 4). Latent class growth analyses (LCGA) revealed quadratic change in partners' sleep over the deployment cycle, characterized by 4 distinct trajectories: resilient (61%), deployment-onset sleep problems (22%), deployment improvement (10%), and chronic (7%) groups. Predeployment and during deployment predictors of partners' sleep complaints varied by group and included negative emotionality, depression symptoms, alcohol use, low negative communication, and family stressors. Understanding the course of sleep complaints and potentially modifiable risk-factors among at-home partners during deployment may be useful for prevention and targeted intervention efforts. (PsycINFO Database Record PMID- 28627911 TI - Ethnic differences in mothering qualities and relations to academic achievement. AB - Although qualities of mothering behavior have been consistently linked with children's academic outcomes, mothers from different ethnic groups may emphasize different dimensions with their children. The present investigation aims to evaluate and compare the dimensionality of mothering in low-income African American (n = 151) and Mexican American (n = 182) mothers during early childhood and its predictive utility for children's academic achievement. Video-recorded mother-child interactions with children at 21/2 and 31/2 years of age were rated using 6 mothering quality items from a widely used global rating system. A bifactor measurement model of these 6 items yielded a general sensitive support factor and a specific intrusive-insensitive factor. The bifactor model fit the data significantly better at both time points than either a single-factor or a 2 factor model. Invariance testing supported the stability of the measurement model across the 2 time points. Invariance testing by ethnicity indicated differences in factor loadings as well as mean levels of the specific factor of intrusive insensitivity. The specific factor reflecting intrusive-insensitive mothering at age 21/2 years was associated with poorer subsequent reading achievement for African American but not Mexican American children, suggesting the specific factor reflected qualitatively different parenting constructs for the 2 ethnic groups. Critical examination of what constitutes more optimal parenting yielded both similar and dissimilar characteristics and their relations across culturally different groups of families. Such knowledge should contribute to the development of more effective interventions for ethnically diverse families. (PsycINFO Database Record PMID- 28627912 TI - Cognitive-behavioral versus psychodynamic therapy for major depression: Secondary outcomes of a randomized clinical trial. AB - OBJECTIVE: In a randomized clinical trial, we compared the efficacy of cognitive behavioral therapy (CBT) and psychodynamic therapy for adult outpatient depression on measures of psychopathology, interpersonal functioning, pain, and quality of life. METHOD: There were 341 Dutch adults (70.1% female, mean age = 38.9, SD = 10.3) meeting Diagnostic and Statistical Manual for Mental Disorders Fourth Edition (DSM-IV) criteria for a major depressive episode and with a Hamilton Depression Rating Scale (HAM-D) score >=14, who were randomized to 16 sessions of individual manualized CBT or short-term psychodynamic supportive psychotherapy. Severely depressed patients (HAM-D >24) received additional antidepressant medication according to a protocol. Outcome measures included the Brief Symptom Inventory, Beck Anxiety Inventory, Outcome Questionnaire, a visual analogue scale for pain, and EuroQol. Data were analyzed with mixed model analyses using intention-to-treat samples. Noninferiority margins were prespecified as Cohen's d = -0.30. RESULTS: Across treatment conditions, 45-60% of the patients who completed posttreatment assessment showed clinically meaningful change for most outcome measures. We found no significant differences between the treatment conditions on any of the outcome measures at both posttreatment and follow-up. Noninferiority of psychodynamic therapy to CBT was shown for posttreatment and follow-up anxiety measures as well as for posttreatment pain and quality of life measures, but could not be consistently demonstrated for the other outcomes. CONCLUSIONS: This is the first study that shows that psychodynamic therapy can be at least as efficacious as CBT for depression on important aspects of patient functioning other than depressive symptom reduction. These findings extend the evidence-base of psychodynamic therapy for depression, but replication is needed by means of rigorously designed noninferiority trials. (PsycINFO Database Record PMID- 28627913 TI - Effect of attentional retraining on cognition, craving, and smoking in African American smokers. AB - African American cigarette smokers have lower rates of cessation than Whites and live in communities with a higher number of tobacco advertisements. Exposure to smoking cues may promote smoking and undermine cessation. It may be possible to reduce attention to smoking cues ("attentional bias"). In this study, we investigated the effect of attentional retraining (AR) on attentional bias and smoking in African American smokers. Nontreatment- seeking African American smokers (N = 64) were randomly assigned to an AR or control condition. Participants were given a mobile device for 2 weeks and prompted to complete up to 3 AR (or control) trainings per day. Participants completed assessments of attentional bias, craving, and smoking both in the lab and in the field. Participants in the AR and control conditions completed an average of 29.07 AR (SD = 12.48) and 30.61 control training tasks (SD = 13.07), respectively. AR reduced attentional bias assessed in the laboratory, F(1, 126) = 9.20, p = .003, and field, F(1, 374) = 6.18, p = .01. This effect generalized to new stimuli, but not to new tasks. AR did not significantly reduce craving or biological measures of smoking. Smoking assessed on the mobile device declined over days in the AR group, F(1, 26) = 10.95, p = .003, but not in the control group, F(1, 27) = 0.02, p = .89. Two weeks of AR administered on a mobile device reduced attentional bias in African American smokers and had mixed effects on smoking. (PsycINFO Database Record PMID- 28627916 TI - Individual differences in reliance on intuition predict harsher moral judgments. AB - The notion that intuition guides moral judgment is widely accepted. Yet, there is a dearth of research examining whether individual differences in reliance on intuition influence moral judgment. Five studies provided evidence that faith in intuition (FI) predicts higher condemnation of moral transgressions. Studies 1 and 2 (combined N = 543) demonstrated that FI predicted higher moral condemnation of strange actions characterized by ambiguous harm. This association maintained controlling for a host of relevant ideological and emotional "third" variables. Three experiments demonstrated this relationship to be robust in the face of manipulations. In Study 3 (N = 320), participants rated whether moral scenarios involved harm or victims prior to (vs. after) moral judgments. Although considering harm and victims prior to judgments lowered condemnation toward these actions, the manipulation did not moderate the association between FI and condemnation. FI related to moral condemnation of unconventional actions even after consideration of harm and victims. In Study 4 (N = 236), a manipulation designed to enhance deliberation lowered overall moral condemnation (vs. control group), but did not attenuate the relationship between FI and moral condemnation. In Study 5 (N = 204), participants quickly categorized actions according to whether or not they were immoral, harmful, or involved victims. FI predicted higher condemnation of ambiguously harmful actions even when these judgments were made rapidly. Implications for examining individual differences in intuition in the context of dominant theories in moral psychology (dyadic morality, Moral Foundations Theory) are addressed. (PsycINFO Database Record PMID- 28627914 TI - Group motivational interviewing for homeless young adults: Associations of change talk with substance use and sexual risk behavior. AB - Homeless young adults exhibit high rates of alcohol and other drug (AOD) use and sexual risk behaviors. This study is a secondary analysis of data collected in a randomized clinical trial of AWARE, a new 4 session group motivational interviewing intervention. AWARE mainly focused on alcohol use and sexual risk behavior given focus group feedback. We used sequential coding to analyze how the group process affected both AOD use and sexual risk behavior at 3-month follow up among homeless young adults by examining facilitator behavior and participant change talk (CT) and sustain talk (ST). We analyzed 57 group session digital recordings of 100 youth (69% male, 74% heterosexual, 28% non-Hispanic white, 23% African American, 26% Hispanic, 23% multiracial/other; mean age 21.75). Outcomes included importance and readiness to change AOD use and risky sexual behavior, AOD use and consequences, number of partners and unprotected sex, and condom self efficacy. Sequential analysis indicated that facilitator open-ended questions and reflections of CT increased Group CT. Group CT was associated with a lower likelihood of being a heavy drinker 3 months later; Group ST was associated with decreased readiness and confidence to change alcohol use. There were no associations with CT or ST for drug use or risky sexual behavior. Facilitator speech and peer responses were related to CT and ST during the group sessions with this high risk population, which were then associated with individual changes for alcohol use. Further research is needed to explore associations with drug use and sexual risk behavior. (PsycINFO Database Record PMID- 28627915 TI - Long-term classroom functioning and its association with neuropsychological and academic performance following traumatic brain injury during early childhood. AB - OBJECTIVE: The present study utilized ecobehavioral assessment to examine classroom functioning several years following early childhood traumatic brain injury (TBI) or orthopedic injury (OI) and its association with injury factors, neuropsychological abilities, and academic performance. METHOD: Participants included 39 children with moderate to severe TBI and 51 children with OI sustained between ages 3 and 7 years. At 7.2 (+/- 1.3) years post injury, ecobehavioral assessment was used to examine classroom functioning. Additional outcomes included neuropsychological tests, parent and teacher ratings of dysexecutive behavior, and teacher ratings of academic performance. Groups were compared on measures controlling for demographic characteristics, and associations among outcomes were examined using linear regression. RESULTS: Children with TBI showed lower academic engagement relative to children with OI, as well as more frequent individual teacher attention for children with more severe injuries. For children with TBI, difficulties in classroom functioning were associated with lower cognitive flexibility and higher parent and teacher ratings of dysexecutive behavior. Lower scores on a test of fluid reasoning and a greater frequency of individual teacher attention were also associated with lower academic performance in children with TBI. CONCLUSIONS: Difficulties in classroom functioning are evident several years after early childhood TBI and were associated with greater injury severity, neuropsychological weaknesses, and poorer academic performance. Children with impaired cognitive flexibility and fluid reasoning skills were at greatest risk for these difficulties and associated weaknesses in academic performance. Instructional interactions may be a potential target for intervention to promote academic progress in at-risk children. (PsycINFO Database Record PMID- 28627917 TI - Functional intimacy: Needing-But not wanting-The touch of a stranger. AB - Intimacy is often motivated by love, but sometimes it is merely functional. For example, disrobing and being touched at an airport security check serves the goal of catching a flight, not building a relationship. We propose that this functional intimacy induces discomfort, making people prefer greater social distance from their interaction partner. Supporting this prediction, participants who considered (Experiments 1 and 2) or experienced (Experiment 3) more physically intimate medical procedures preferred a health provider who is less social. Increased psychological intimacy also led people to prefer social distance from cleaning and health providers (Experiments 4-5), a preference revealed by nonverbal behavior (e.g., turning away and looking away, Experiments 6-7). These patterns of distancing are unique to functional (vs. romantic) intimacy (Experiment 7). Although creating social distance may be an effective strategy for coping with functional intimacy, it may have costs for service providers. (PsycINFO Database Record PMID- 28627918 TI - Development and validation of the Circumplex Scales of Interpersonal Problems. AB - The interpersonal circumplex (IPC) is a well-established model of social behavior that spans basic personality and clinical science. Although several measures are available to assess interpersonal functioning (e.g., motives, traits) within an IPC framework, researchers studying interpersonal difficulties have relied primarily on a single measure, the Inventory of Interpersonal Problems-Circumplex Scales (IIP-C; Horowitz, Alden, Wiggins, & Pincus, 2000). Although the IIP-C is a widely used measure, it is currently the only measure specifically designed to assess maladaptive interpersonal behavior using the IPC framework. The purpose of the current study is to describe a new 64-item measure of interpersonal problems, called the Circumplex Scales of Interpersonal Problems (CSIP). Interpersonal problems derived from a pool of 400 personality-related problems were assessed in two large university samples. In the scale development sample (N = 1,197), items that best characterized each sector of the IPC were identified, and a set of eight 8-item circumplex scales was developed. Psychometric properties of the resulting measure were then examined in the validation sample (N = 757). Results from confirmatory circumplex structural analyses indicated that the CSIP fit well to a quasi-circumplex model. The CSIP converged with the IIP-C and the Revised Interpersonal Adjective Scales (Wiggins, 1995), and associated in theoretically expected ways with broader assessments of adaptive- and maladaptive-range personality traits and symptoms of psychological distress. The CSIP augments the IIP-C with additional content, thereby helping to extend the underlying constructs, and provides an alternative means for studying the interpersonal consequences of personality and psychopathology. (PsycINFO Database Record PMID- 28627919 TI - The association between parent-reported and observed parenting: A multi-level meta-analysis. AB - The purpose of the present meta-analysis was to investigate the strength of the association between parent-reported and observed parenting, and to investigate which specific characteristics of participants, questionnaires, or observational procedures moderate this association. A systematic search of relevant peer reviewed articles published between January 2000 and December 2014 yielded 36 articles (N = 8,510) and 89 effect sizes. Results from a 3-level random-effects meta-analysis demonstrated a weak, yet significant, overall association of r = .17 between parent-reported and observed parenting. The magnitude of the effect size depended on questionnaire length (larger effect for more items) and the type of parenting investigated (largest effects for negative parent behaviors, next largest effects for positive parent behaviors, and smallest effect for controlling parent behaviors). In conclusion, this study shows that the strength of the association between parent-reported and observed parenting is small but significant. (PsycINFO Database Record PMID- 28627920 TI - Reliability and validity of a Spanish language assessment of children's social emotional learning skills. AB - Few Spanish language tools are available for assessing important social-emotional learning (SEL) skills. The present study presents evidence of the psychometric properties of a Spanish-language version of SELweb (SELweb-S), a web-based system for assessing children's ability to recognize others' emotions and perspectives, solve social problems, and engage in self-control. With a sample of 524 students in Grades K to 3, we examined the reliability and validity of SELweb-S. This study provided evidence that (a) individual assessment modules exhibited moderate to high internal consistency and moderate 6-month temporal stability, (b) composite assessment scores exhibited high reliability, (c) assessment module scores fit a theoretically coherent factor structure, and (d) performance on SELweb-S assessment modules was positively related to teacher-reported SEL skills. Findings are discussed in terms of the importance of direct assessments of SEL skills in languages other than English. In addition, we highlight the importance of abiding by rigorous recommendations in the literature for the translation and cultural adaptation of assessments. (PsycINFO Database Record PMID- 28627921 TI - Risk factors for concurrent suicidal ideation and violent impulses in military veterans. AB - Suicide and violence are significant problems in a subset of Iraq/Afghanistan-era veterans. This study investigates how posttraumatic stress disorder (PTSD) and resilience in veterans are associated with suicidal ideation and violent impulses while controlling for known covariates of both adverse outcomes. Structured clinical interviews were conducted of N = 2,543 Iraq/Afghanistan-era U.S. veterans. Compared with veterans denying suicidal ideation or violent impulses (n = 1,927), veterans endorsing both (n = 171) were more likely to meet diagnostic criteria for PTSD, report childhood abuse, combat exposure, physical pain symptoms, and drug misuse, and less likely to endorse self-direction/life purpose. Veterans reporting concurrent suicidal ideation and violent impulses had higher odds of misusing drugs and reporting pain symptoms relative to veterans reporting suicidal ideation only (n = 186) and had lower odds of endorsing self direction/life purpose compared with veterans reporting violent impulses only (n = 259). The findings underscore the importance of examining drug abuse, physical pain symptoms, and self-direction/life purpose, as well as PTSD and history of trauma, in the context of clinical assessment and empirical research aimed at optimizing risk management of suicide and violence in military veterans. (PsycINFO Database Record PMID- 28627922 TI - Inconsistent responding on the MMPI-2-RF and uncooperative attitude: Evidence from cognitive performance validity measures. AB - It is generally well understood that possible reasons for inconsistent responding on the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2 RF), as measured by the Variable Response Inconsistency (VRIN-r) and True Response Inconsistency (TRIN-r) scales, include reading or language limitations, cognitive impairment, and intentional random responding; however, the interpretive recommendations for the test suggest that higher scores on these scales can also result from an uncooperative test-taking approach. This study utilized a sample of 3,457 predominately non-head injury disability claimants to examine the association between inconsistent responding on the MMPI-2-RF and performance on cognitive tests as well performance validity tests (PVTs), an independent indicator of uncooperative test-taking attitude. Analysis of variance found that both VRIN-r and TRIN-r were associated with statistically lower cognitive test scores. These analyses also supported that TRIN-r was associated with poor performance on collaterally administered PVTs in a subsample of individuals with average reading levels. Illustrating the practical effects of these results, in follow-up relative risk ratio analyses, individuals with elevations on TRIN-r were at up to five times greater risk of PVT failure than those without elevations. Overall, the results of this study provide some support for the interpretation that inconsistent responding on the MMPI-2-RF is associated not only with cognitive/reading problems or limitations but also an uncooperative test-taking approach, particularly for elevated TRIN-r scores. (PsycINFO Database Record PMID- 28627923 TI - Examination of the Triarchic Assessment Procedure for Inconsistent Responding in six non-English language samples. AB - The Triarchic Assessment Procedure for Inconsistent Responding (TAPIR; Mowle et al., 2016) was recently developed to identify inattentiveness or comprehension difficulties that may compromise the validity of responses on the Triarchic Psychopathy Measure (TriPM; Patrick, 2010). The TAPIR initially was constructed and cross-validated using exclusively English-speaking participants from the United States; however, research using the TriPM has been increasingly conducted internationally, with numerous foreign language translations of the measure emerging. The present study examined the cross-language utility of the TAPIR in German, Dutch, Swedish, and Italian translations of the TriPM using 6 archival samples of community members, university students, forensic psychiatric inpatients, forensic detainees, and adolescents residing outside the United States (combined N = 5,404). Findings suggest that the TAPIR effectively detects careless responding across these 4 translated versions of the TriPM without the need for language-specific modifications. The TAPIR total score meaningfully discriminated genuine participant responses from both fully and partially randomly generated data in every sample, and demonstrated further utility in detecting fixed "all true" or "all false" response patterns. In addition, TAPIR scores were reliably associated with inconsistent responding scores from another psychopathy inventory. Specificity for a range of tentative cut scores for assessing profile validity was modestly reduced among our samples relative to rates previously obtained with the English version of the TriPM; however, overall the TAPIR appears to demonstrate satisfactory cross-language generalizability. (PsycINFO Database Record PMID- 28627924 TI - Clusters of financially incentivized chronic pain patients using the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF). AB - The Minnesota Multiphasic Personality Inventory (MMPI)-2 Restructured Form (MMPI 2-RF) has been shown to have clinical utility in the assessment of individuals with chronic pain (e.g., predicting surgical outcomes). The purpose of this study was to explore the ability of the MMPI-2-RF Validity Scales in profiling patients with chronic pain who had external financial incentive (e.g., workers' compensation claims) and determine the associations between Validity Scale response patterns and important outcomes. Cluster analysis identified 2 similarly sized clusters of patients with very different MMPI-2-RF profiles. Cluster 1 was characterized by valid responding and showed mean elevations on the somatic and low positive emotion Restructured Clinical scales. Cluster 2 was characterized by patients overreporting on the MMPI-2-RF Validity Scales, who also demonstrated elevations on 7 of the 9 RC scales. Cluster membership was differentially associated with clinical variables: patients in Cluster 2 had greater self reported pain and disability, were less likely to have spine-related findings on imaging and were more likely to be classified as probable or definite malingerers. These results support the utility of the MMPI-2-RF Validity scales in distinguishing between credible and noncredible responses from patients with chronic pain seen within a medico-legal context. (PsycINFO Database Record PMID- 28627925 TI - Will delay discounting predict intention to quit smoking? AB - Intention to quit cigarette smoking is significantly associated with making quitting attempts and actual quitting. Delay discounting is significantly associated with smoking initiation and success in quitting. To our knowledge, no studies have investigated the relationship between delay discounting and intention to quit smoking. In 2 separate observational, cross-sectional studies, the current investigation examines the relationship between delay discounting and intention to quit smoking within groups of smokers. Experiment 1 used data collected online and an adjusting-delay discounting task; Experiment 2 used data collected in the laboratory and an adjusting-amount discounting task. A total of 242 participants and 142 participants completed the online and on laboratory experiments, respectively. In both studies, participants with higher intention to quit smoking had significantly lower rates of discounting. These associations between intention to quit smoking and rates of delay discounting further support recent characterizations of delay discounting as a candidate behavioral marker of addiction. Understanding cognitive factors affecting treatment initiation such as intention to change, and the effects of delay discounting on these factors, in addition to the mechanisms by which they influence treatment outcomes might be essential to developing, disseminating, and implementing treatment interventions. (PsycINFO Database Record PMID- 28627926 TI - Using crowdsourcing to examine behavioral economic measures of alcohol value and proportionate alcohol reinforcement. AB - Online crowdsourcing websites such as Amazon's Mechanical Turk (MTurk) are increasingly being used in addictions research. However, there is a relative paucity of such research examining the validity of administering behavioral economic alcohol-related measures, via an online crowdsourcing platform. This study sought to validate an alcohol purchase task (APT) for assessing demand and a questionnaire measure of proportionate alcohol reinforcement, using an online sample of participants recruited via MTurk. Participants (N = 865, 59% female) were recruited via MTurk to complete the APT, proportionate alcohol reinforcement questionnaire, Alcohol Use Disorders Identification Test (AUDIT), and demographics. Responses on the APT were highly systematic (<3% nonsystematic data) and conformed to prototypical demand curves. Correlation analyses revealed significant associations among AUDIT total scores with a majority of the alcohol demand indices (r values .08-53, p values < .05) as well as proportionate alcohol reinforcement, r = .43, p < .001. Regression analyses controlling for relevant covariates indicated that intensity, BP, Omax, elasticity, and reinforcement ratio predicted significant variance in AUDIT scores. This study further supports the use of online crowdsourcing websites for investigating behavioral economic determinants of alcohol misuse. (PsycINFO Database Record PMID- 28627928 TI - Craving and acute effects of alcohol in youths' daily lives: Associations with alcohol use disorder severity. AB - Identifying factors associated with the progression from recreational to pathological drinking in youth holds high clinical and theoretical importance. The present study tested cross-sectional associations of alcohol use disorder (AUD) severity with putative mechanisms of AUD progression among youth ages 15-24 years, namely acute subjective effects of alcohol and craving. Male (n = 44) and female (n = 42) youth completed ecological momentary assessments when not drinking, just before drinking, and while drinking in the natural environment via handheld wireless devices. Youth were recruited from the community and were frequent and heavy drinkers, the majority (93%) with at least 1 AUD symptom (M = 3.4, SD = 2.4). Findings from youths' daily lives suggested that how youth feel while they drink depends, in part, on their severity of AUD pathology. In support of hypotheses, youths with more progressed drinking pathology (i.e., those with more symptoms of AUD) reported greater reductions in craving and tension while drinking, relative to nondrinking times. In partial support of hypotheses, males with greater AUD symptomatology reported marginally attenuated increases in stimulatory states while drinking; however, contrary to hypotheses, females with greater AUD symptomatology reported enhanced increases in stimulation while drinking. This research leveraged ecological momentary assessment methods to study subjective responses to alcohol and craving in youths' daily lives and to cross-sectionally test putative associations with AUD etiology. This work adds to literature supporting subjective responses to alcohol in the pathogenesis of alcoholism, specifically by highlighting their importance during the period in life when alcohol problems typically first emerge. (PsycINFO Database Record PMID- 28627927 TI - A reinforcement sensitivity model of affective and behavioral dysregulation in marijuana use and associated problems. AB - This study tested a model linking sensitivity to punishment (SP) and reward (SR) to marijuana use and problems via affect lability and poor control. A 6-month prospective design was used in a sample of 2,270 young-adults (64% female). The hypothesized SP * SR interaction did not predict affect lability or poor control, but did predict use likelihood at baseline. At low levels of SR, SP was associated with an increased likelihood of abstaining, which was attenuated as SR increased. SP and SR displayed positive main effects on both affect lability and poor control. Affect lability and poor control, in turn, mediated effects on the marijuana outcomes. Poor control predicted both increased marijuana use and, controlling for use level, greater intensity of problems. Affect lability predicted greater intensity of problems, but was not associated with use level. There were few prospective effects. SR consistently predicted greater marijuana use and problems. SP however, exhibited both risk and protective pathways. Results indicate that SP is associated with a decreased likelihood of marijuana use. However, once use is initiated SP is associated with increased risk of problems, in part, due to its effects on both affect and behavioral dysregulation. (PsycINFO Database Record PMID- 28627930 TI - Randomized comparative efficacy and safety study of intermittent simvastatin versus fenofibrate in hemodialysis. AB - AIM: Compare the safety and efficacy of intermittent fenofibrate versus simvastatin in chronic hemodialysis patients. PATIENTS & METHODS: Sixty patients received either fenofibrate 100 mg or simvastatin 20 mg after their dialysis session (parallel study). The safety and efficacy of drugs on lipid profile, oxidized low-density lipoprotein (Ox-LDL), glutathione peroxidase and C-reactive protein were compared before and after 16-week treatment. RESULTS: After treatment, significant increase in glutathione peroxidase, significant decrease in total cholesterol, triglycerides, low density lipoprotein (LDL) and ox-LDL (p < 0.05) and no significant changes in C-reactive protein (p > 0.05) were observed in both groups. Both drugs were well tolerated with no serious side effects reported by the patients. CONCLUSION: Both drugs have comparable efficacy and safety when used as intermittent low dose regimen in hemodialysis. Larger studies with longer follow-up periods are needed to confirm our new findings. PMID- 28627931 TI - Hyperacoustic hypoacusis: A new pontine syndrome-Case report. AB - We herein report a unique case of a lateral pontine demyelinating lesion presenting with unilateral sensorineural hearing loss and paradoxical ipsilateral hyperacusis. The association of unilateral hearing loss and ipsilateral hyperacusis is a rare manifestation of a central nervous system lesion. The paradoxical combination of these symptoms strongly suggests pontine dysfunction and prompts urgent neurological evaluation. PMID- 28627932 TI - Short-term prognostic effect of prior cerebrovascular and peripheral artery disease in patients with acute coronary syndrome: Can we do better? AB - BACKGROUND: We sought to evaluate the impact of prior cerebrovascular and/or peripheral arterial disease (PAD) on in-hospital outcomes in patients with acute coronary syndromes. METHODS: From 1 October 2010 to 26 February 2016, 13,904 acute coronary syndrome patients were enrolled in a national multicentre registry. They were divided into four groups: prior stroke/transient ischaemic attack (stroke/TIA); prior PAD; prior stroke/TIA and PAD; none. The endpoints included in-hospital mortality and a composite endpoint of death, re-infarction and stroke during hospitalization. RESULTS: 6.3% patients had prior stroke/TIA, 4.2% prior PAD and 1.4% prior stroke/TIA and PAD. Prior stroke/TIA and/or PAD patients were less likely to receive evidence-based medical therapies (dual antiplatelet therapy: stroke/TIA= 88.6%, PAD= 86.6%, stroke/TIA+PAD= 85.7%, none= 92.2%, p<0.001; beta-blockers: stroke/TIA= 77.1%, PAD= 72.1%, stroke/TIA+PAD= 71.9%, none= 80.8%, p<0.001; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers: stroke/TIA= 86.3%, PAD= 83.6%, stroke/TIA+PAD= 83.2%, none= 87.1%, p=0.030) and to undergo percutaneous revascularization (stroke/TIA= 52.8%, PAD= 45.6%, stroke/TIA+PAD= 43.7%, none= 67.9%, p<0.001), despite more extensive coronary artery disease (three-vessel disease: stroke/TIA= 29.1%, PAD= 38.3%, stroke/TIA+PAD= 38.3%, none= 20.2%, p<0.001). In a multivariable analysis, prior stroke/TIA+PAD was a predictor of in-hospital mortality (odds ratio= 2.828, 95% confidence interval 1.001-7.990) and prior stroke/TIA (odds ratio= 1.529, 95% confidence interval 1.056-2.211), prior PAD (odds ratio= 1.618, 95% confidence interval 1.034-2.533) and both conditions (odds ratio= 3.736, 95% confidence interval 2.002-6.974) were associated with the composite endpoint. CONCLUSION: A prior history of stroke/TIA and/or PAD was associated with lower use of medical therapy and coronary revascularization and with worst short-term prognosis. An individualized management may improve their poor prognosis. PMID- 28627929 TI - Design of the HPTN 065 (TLC-Plus) study: A study to evaluate the feasibility of an enhanced test, link-to-care, plus treat approach for HIV prevention in the United States. AB - Background/Aims HIV continues to be a major public health threat in the United States, and mathematical modeling has demonstrated that the universal effective use of antiretroviral therapy among all HIV-positive individuals (i.e. the "test and treat" approach) has the potential to control HIV. However, to accomplish this, all the steps that define the HIV care continuum must be achieved at high levels, including HIV testing and diagnosis, linkage to and retention in clinical care, antiretroviral medication initiation, and adherence to achieve and maintain viral suppression. The HPTN 065 (Test, Link-to-Care Plus Treat [TLC-Plus]) study was designed to determine the feasibility of the "test and treat" approach in the United States. Methods HPTN 065 was conducted in two intervention communities, Bronx, NY, and Washington, DC, along with four non-intervention communities, Chicago, IL; Houston, TX; Miami, FL; and Philadelphia, PA. The study consisted of five components: (1) exploring the feasibility of expanded HIV testing via social mobilization and the universal offer of testing in hospital settings, (2) evaluating the effectiveness of financial incentives to increase linkage to care, (3) evaluating the effectiveness of financial incentives to increase viral suppression, (4) evaluating the effectiveness of a computer-delivered intervention to decrease risk behavior in HIV-positive patients in healthcare settings, and (5) administering provider and patient surveys to assess knowledge and attitudes regarding the use of antiretroviral therapy for prevention and the use of financial incentives to improve health outcomes. The study used observational cohorts, cluster and individual randomization, and made novel use of the existing national HIV surveillance data infrastructure. All components were developed with input from a community advisory board, and pragmatic methods were used to implement and assess the outcomes for each study component. Results A total of 76 sites in Washington, DC, and the Bronx, NY, participated in the study: 37 HIV test sites, including 16 hospitals, and 39 HIV care sites. Between September 2010 and December 2014, all study components were successfully implemented at these sites and resulted in valid outcomes. Our pragmatic approach to the study design, implementation, and the assessment of study outcomes allowed the study to be conducted within established programmatic structures and processes. In addition, it was successfully layered on the ongoing standard of care and existing data infrastructure without disrupting health services. Conclusion The HPTN 065 study demonstrated the feasibility of implementing and evaluating a multi-component "test and treat" trial that included a large number of community sites and involved pragmatic approaches to study implementation and evaluation. PMID- 28627933 TI - The impact of child and family stressors on the self-rated health of mothers of children with autism spectrum disorder: Associations with depressed mood over a 12-year period. AB - Employing a cohort sequential design and multilevel modeling, the effects of child and family stressors and maternal depressed mood on the self-rated health of 110 mothers of children with autism spectrum disorder were assessed over a 12 year period when children in the study were 7-19 years old. Findings indicate a significant decline in self-rated health over time. In addition, child and family stressors, as well as maternal depressed mood, exerted significant between persons effects on self-rated health such that mothers who reported more stressors and depressed mood across the study period were less likely to rate themselves in better health across that period. In addition, a significant within person relationship between maternal depressed mood and self-rated health was found, indicating that at times when mothers reported higher levels of depressed mood than usual (their personal average across the study), they were significantly less likely to report better self-rated health. Finally, maternal depressed mood partially mediated the between-persons effects of child and family stressors on self-rated health such that increased stressors led to increased maternal depressed mood which, in turn, led to poorer maternal self-rated health. Findings suggest that chronic stressors erode maternal health over time and that depression may be an important mechanism linking stressors to decreased maternal health. PMID- 28627934 TI - Adult patient decision-making regarding implantation of complex cardiac devices: a scoping review. AB - BACKGROUND: Complex cardiac rhythm management device (CRMD) therapy provides an important treatment option for people at risk of sudden cardiac death. Despite the survival benefit, device implantation is associated with significant physical and psychosocial concerns presenting considerable challenges for the decision making process surrounding CRMD implantation for patients and physicians. AIMS: The purpose of this scoping review was to explore what is known about how adult (>16 years) patients make decisions regarding implantation of CRMD therapy. METHODS: Published, peer reviewed, English language studies from 2000 to 2016 were identified in a search across eight healthcare databases. Eligible studies were concerned with patient decision-making for first time device implantation. Quality assessment was completed using the mixed methods appraisal tool for all studies meeting the inclusion criteria. RESULTS: The findings of eight qualitative and seven quantitative studies, including patients who accepted or declined primary or secondary sudden cardiac death prevention devices, were clustered into two themes: knowledge acquisition and the process of decision making, exposing similarities and distinctions with the treatment decision-making literature. CONCLUSION: The review revealed some insight in to the way patients approach decision-making but also exposed a lack of clarity and research activity specific to CRMD patients. Further research is recommended to support the development and application of targeted decision support mechanisms. PMID- 28627935 TI - Interactions between primary sclerosing cholangitis and inflammatory bowel disease: implications in the adult liver transplant setting. AB - INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease which is associated with inflammatory bowel disease (IBD) in most cases. As there is currently no medical therapy which alters the natural history of PSC, liver transplantation may be required. Areas covered: We searched for articles in PubMed and critically reviewed current literature on the interrelationship between PSC and IBD with a specific focus on considerations for patients in the liver transplant setting. Expert commentary: PSC is an uncommon disease which limits available studies to be either retrospective or contain relatively small numbers of patients. Based on observations from these studies, the behavior and complications of PSC and IBD impact on each other both before and after a liver transplant. Both these autoimmune conditions and their associated cancer risk also influence patient selection for transplantation and may be impacted by immunosuppression use post-transplant. Hence, a complex interplay exists between PSC, IBD and liver transplantation which requires clarification with ongoing research. PMID- 28627936 TI - The Microorganisms on Nurses' and Health Care Workers' Uniforms in the Intensive Care Units. AB - The objective of this study was to identify the types of microorganisms present on uniforms of nurses, physicians, respiratory therapist, students, and housekeepers in intensive care units (ICUs). A convenience sampling was used to recruit the participants ( N = 115) who work at military hospital in Jordan. Environmental cultures ( N = 305) were taken from the participants who were nurses, physicians, students, respiratory therapists, and housekeepers. The number of participating nurses was 58 (50.43%). There were 24 types of microorganisms found on the participants' uniforms. Staphylococcus epidermidis was found 59 times (61.3%) on the three areas of uniform culture. High level of contamination was found among all the participants, and it was the highest in physicians (85%) followed by nurse (79.3%) (chi2 = 24.87, p < .001). None of the participants' characteristics have correlated significantly with the uniform contamination. High percentages of uniform's contamination among all those who work in the ICUs were found. PMID- 28627937 TI - The safety of intra-articular injections for the treatment of knee osteoarthritis: a critical narrative review. AB - INTRODUCTION: International guidelines recommend that the management of knee osteoarthritis (OA) combine both nonpharmacological and pharmacological interventions. Intra-articular (IA) therapies are considered part of this multimodal approach and are well-established Food and Drug Administration (FDA) and European Medicines Agency (EMA)-approved treatments. Areas covered: Safety data for knee OA, including IA corticosteroids, hyaluronic acid, platelet-rich plasma and botulinum toxin are critically reviewed, and evidence- and pratice based measures to improve safety of IA therapies are discussed. Expert opinion: The incidence of AEs attributable to IA therapies across clinical trials in knee OA is very low, and barely reaches significance when compared to the incidence of AEs in the comparator group. These events are exceptionally serious. Mild differences between products have been inconsistently reported mainly for IA HA. One can distinguish self-limited AEs such as post-injection pain and swelling that are the most frequently reported AEs, from AEs that are not self-limited but rare such as septic arthritis. The safety of IA therapies can be improved by applying simple measures designed to prevent AEs. However, even though no specific safety concerns have been raised to date about IA therapies, the quality of evidence is low, and there is a need to improve the monitoring and reporting of safety data from clinical trials and post-marketing surveillance. PMID- 28627938 TI - "I've got somebody there, someone cares": what support is most valued following a stroke? AB - PURPOSE: There is often a need for increased support following a stroke. This study explored what types of support are provided by different network members and what support functions are most valued. METHODS: Adults with first stroke were recruited from a stroke unit and participated in in-depth interviews 8-15 months poststroke. Framework Analysis was used to build thematic and explanatory accounts of the data. RESULTS: Twenty-nine participants took part. Main themes to emerge were as follows: the spouse was the most important provider of support; children were a relatively stable source of support, although many participants expressed reservations about worrying a child; relatives and friends typically provided social companionship and emotional support rather than on-going practical support. The only universally valued support function was the sense that someone was concerned and cared. Other valued functions were as follows: social companionship including everyday social "chit chat"; practical support provided sensitively; and, for many, sharing worries and sensitive encouragement. The manner and context in which support was provided was important: support was easiest to receive when it communicated concern, and was part of a reciprocal, caring relationship. CONCLUSIONS: As well as measuring supportive acts, researchers and clinicians should consider the manner and context of support. Implications for rehabilitation The manner in which support was provided mattered: support was easier to receive when it communicated concern. The spouse was the most important source of all support functions; children, relatives and friends were important providers of emotional and social companionship support. Researchers and clinicians should not only focus on what support is received, but also the context (e.g., contribution, reciprocity, quality of relationship) and manner (e.g., responsiveness, sensitivity) of the support. PMID- 28627939 TI - Off-label prescribing for children with chronic diseases in Nigeria; findings and implications. AB - BACKGROUND: Prescribing medicines in an off-label manner for children with chronic conditions is sparsely documented, even more so among developing countries. This needs addressing. The objective of this research was to investigate the extent of off-label prescribing among children with epilepsy, asthma, and sickle cell anaemia in Nigeria. METHODS: Prescriptions for children <=16 years documented in their case files that attended paediatric clinics in Lagos, Nigeria, for these three conditions between January and October 2015, were reviewed retrospectively to extract data on the medicines prescribed. British National Formulary for children and American Hospital Formulary Service Drug information were used as references. RESULTS: 477 patients received 1746 prescriptions. Off-label prescriptions were seen in 7.7% of prescriptions, related to dose (93; 68.9%), indication (22; 16.3%), and age (20; 14.8%). Nervous system (525; 30.1%) and anti-infective (441; 25.2%) medicines were the most prescribed but only 9.5% and 8.2% of the respective prescriptions were off-label. Children with epilepsy received the most number (94; 69.6%) of off-label prescriptions. The three chronic conditions did not associate significantly with the category of off-label medicine prescribed (p = 0.925). CONCLUSION: Off-label prescribing for children with epilepsy, asthma and sickle cell anaemia occurs. Encouragingly, the overall rate appears low in Nigeria. PMID- 28627940 TI - Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease. PMID- 28627941 TI - Detecting social-cognitive deficits after traumatic brain injury: An ALE meta analysis of fMRI studies. AB - PURPOSE: Traumatic brain injury (TBI) can result in significant social dysfunction, which is represented by impairment to social-cognitive abilities (i.e. social cognition, social attention/executive function and communication). This study is aimed to explore brain networks mediating the social dysfunction after TBI and its underlying mechanisms. METHODS: We performed a quantitative meta-analysis using the activation likelihood estimation (ALE) approach on functional magnetic resonance imaging (fMRI) studies of social-cognitive abilities following TBI. Sixteen studies fulfilled the inclusion criteria resulting in a total of 190 patients with TBI and 206 controls enrolled in the ALE meta-analysis. RESULTS: The temporoparietal junction (TPJ) and the medial prefrontal cortex (mPFC) were the specific regions that social cognition predominantly engaged. The cingulate gyrus, frontal gyrus and inferior parietal lobule were the main regions related to social attention/executive functions. Communication dysfunction, especially related to language deficits, was found to show greater activation of the temporal gyrus and fusiform gyrus in TBI. CONCLUSION: The current ALE meta-analytic findings provide evidence that patients have significant social-cognitive disabilities following TBI. The relatively limited pool of literature and the varied fMRI results from published studies indicate that social-cognitive abilities following TBI is an area that would greatly benefit from further investigation. PMID- 28627943 TI - The efficacy and safety of adjuvant interferon-alfa therapy in the evolving treatment landscape for resected high-risk melanoma. AB - INTRODUCTION: Patients with resected stage II or III melanoma are at high risk of recurrence, with 5-year mortality rate of 40-60%. Adjuvant interferon-alfa has demonstrated a small RFS and OS benefit versus observation in this patient population. However, the adjuvant treatment landscape is evolving rapidly. Areas covered: This review aims to summarize the safety and efficacy profiles of adjuvant IFNalpha/PEG-IFNalpha, revisit the controversy surrounding its application, and reappraise its position in the rapidly changing treatment landscape of resected melanoma. A literature search using PubMed database was undertaken using search words melanoma, interferon-alfa, pegylated interferon alfa, adjuvant therapy. Expert opinion: Currently, there is no international consensus regarding the optimal dosing schedule for adjuvant IFNalpha, but HD IFNalpha-2b remains the most widely used regimen. The AEs of HD IFNalpha-2b are substantial; however, toxicity management experience amassed over the past 2 decades has significantly improved safety. Many exciting studies are ongoing to examine the roles of immune checkpoint inhibitors and BRAF-targeted therapies in the adjuvant setting and will further delineate the role of adjuvant IFNalpha. PMID- 28627942 TI - Diffusion imaging of mild traumatic brain injury in the impact accelerated rodent model: A pilot study. AB - PRIMARY OBJECTIVE: There is a need to understand pathologic processes of the brain following mild traumatic brain injury (mTBI). Previous studies report axonal injury and oedema in the first week after injury in a rodent model. This study aims to investigate the processes occurring 1 week after injury at the time of regeneration and degeneration using diffusion tensor imaging (DTI) in the impact acceleration rat mTBI model. RESEARCH DESIGN: Eighteen rats were subjected to impact acceleration injury, and three rats served as sham controls. Seven days post injury, DTI was acquired from fixed rat brains using a 7T scanner. Group comparison of Fractional Anisotropy (FA) values between traumatized and sham animals was performed using Tract-Based Spatial Statistics (TBSS), a method that we adapted for rats. MAIN OUTCOMES AND RESULTS: TBSS revealed white matter regions of the brain with increased FA values in the traumatized versus sham rats, localized mainly to the contrecoup region. Regions of increased FA included the pyramidal tract, the cerebral peduncle, the superior cerebellar peduncle and to a lesser extent the fibre tracts of the corpus callosum, the anterior commissure, the fimbria of the hippocampus, the fornix, the medial forebrain bundle and the optic chiasm. CONCLUSION: Seven days post injury, during the period of tissue reparation in the impact acceleration rat model of mTBI, microstructural changes to white matter can be detected using DTI. PMID- 28627945 TI - [Model concept of the health economic evaluation of low-dose CT lung cancer screening in Hungary]. AB - INTRODUCTION: Lung cancer is a rapidly progressing, often life-threatening disease that constitutes a huge societal burden. Because of the scarce resources of the Hungarian health care system, the cost-effectiveness of introducing low dose computed tomography screening is a relevant health policy matter. AIM: The aim of this study is to design a model concept for assessing the cost effectiveness of low-dose computed tomography lung cancer screening in Hungary, and to define the required steps for performing the analysis. METHOD: A targeted literature review was conducted to identify and synthesize the evidence on efficacy and effectiveness of screening, and results were evaluated based on adaptability to Hungarian settings. We also summarized the available Hungarian scientific evidence and reconstructed the potential patient pathways. RESULTS: In accordance with these findings, we recommend to perform the full health-economic evaluation of low-dose computed tomography lung cancer screening using a complex model structure that consists of several sub-models and is capable to follow the population at risk on life-time horizon. CONCLUSIONS: The proposed cost effectiveness model will be suitable to provide data for further analyses that support decision-making on introducing low-dose computed tomography lung cancer screening as public health program. Orv Hetil. 2017; 158(25): 963-975. PMID- 28627947 TI - [The standardized mortality numbers of patients with gastrointestinal tumors and cardiovascular diseases in four wine regions and in one not-wine region of Hungary between 2000-2010]. AB - INTRODUCTION: Eating habits act on mortalities from gastrointestinal tumors and cardiovascular diseases. AIM: To investigate the role of wine drinking on these mortalities in Hungary. METHOD: The standardized mortality data of people from 206,159 subjects died of gastrointestinal tumors and cardiovascular diseases between 2000-2010 were compared in four wine regions: Tokaj (white), Eger (red), Balaton (white), Szekszard/Villany (red) and in Hodmezovasarhely (not-wine region). RESULTS: The significantly smallest number of tumors (664) occurred in Tokaj, but the cardiovascular mortality here was the highest (5955). On the other hand, the fewest cardiovascular mortality occurred in Szekszard/Villany (3907), but showing here (831) and in Eger (934) the highest values of tumor death. CONCLUSIONS: The protective effect of red wine on cardiovascular mortality was verified. Surprisingly, the low value of gastrointestinal mortality in "Tokaj" - besides the higher level of selenium in tap water - shows some hidden features of these white wines. Orv Hetil. 2017; 158(25): 992-998. PMID- 28627946 TI - [The connection between maltreatment and preterm birth - in the light of psychomotor development at 2 years old]. AB - INTRODUCTION: Preterm children' development and harmful affecting factors to development are important aspects of public health, because in our country the number of preterm birth is very high. AIM: Description of psychomotor development of preterm children (Brunet-Lezine; Bayley-III) and connection between psychomotor development and maternal abuse history (own questionnaire). METHOD: Extremely (<1000 g) and very low (1000-1500 g) birth weight preterm children at 23-30 months (n = 35) and their mothers' abuse history were measured. RESULTS: Lower birth weight was associated with lower psychomotor development quotients and higher development risk. Strong associations were found between maternal history of childhood abuse and the development quotients. CONCLUSIONS: We would like to draw attention to the importance of assessing preterm children, as well as to the importance of maltreatment and the severity of its consequences. With the early recognition of necessity for developmental interventions we can prevent problems in the future. Orv Hetil. 2017; 158(25): 976-983. PMID- 28627950 TI - The association between supportive relatives and lower occurrence of anxiety and depression in heart patients: Results from a nationwide survey. AB - BACKGROUND: Approximately 30-40% of heart patients develop anxiety and/or depression, which might influence recovery and long-term survival. Research has suggested that support from relatives may decrease anxiety and depression among heart patients; however, the results are inconsistent and often based on small study populations. AIM: The paper aimed to investigate the association between having supportive relatives and the occurrence of anxiety and depression in heart patients. METHODS: A population-based cross-sectional study among Danish patients diagnosed with ischemic heart disease, atrial fibrillation, heart failure, or heart valve disease. Presence of supportive relatives was measured as the degree to which the patients felt that they had relatives they could count on, while symptoms of anxiety and depression were measured by the Hospital Anxiety and Depression Scale (HADS). Multiple logistic regression analyses accounting for confounders were used to examine the association between supportive relatives and anxiety/depression. RESULTS: The questionnaire was answered by 2496 heart patients, corresponding to 50% of the invited population. Patients with low or some degree of supportive relatives had a higher odds ratio (OR) of anxiety than patients with a high degree (OR = 2.20, 95% confidence interval (CI): 1.28-2.37; OR = 1.75, 95% CI: 1.57-3.08, respectively). Likewise, patients with low or some degree of supportive relatives had a higher OR of depression than patients with a high degree (OR = 1.96, 95% CI: 1.40-2.66; OR = 1.93, 95% CI: 1.37-2.60, respectively). CONCLUSIONS: The presence of supportive relatives was found to be associated with lower occurrence of anxiety and depression. Health professionals should focus on including relatives in the treatment and rehabilitation of heart patients. PMID- 28627948 TI - [Renal transplantations in the Centre for Nephrology in Szombathely, 1976-2016]. AB - INTRODUCTION: The organized nephrological care in Szombathely commenced its activities in 1976. AIM: Follow-up of our patients who has undergone a kidney transplantation. METHOD: We used the local and national databases. RESULTS: 213 patients (7 preemptive, 206 dialyzed) had 240 renal transplantations. Only 11 of them were living organ donation. Between 69 transplantations (Tx) were carried out between 1976-1995, and 163 Tx were done in the second 20 years. 122 patients (57%) are still alive (the average survival of these patients in renal replacement therapy - RRT - are 11.4 years), and 7 of them had transplantation between 1976-1995. The longest survival time was 35.1 years. Prevalence of patients on RRT at the end of 2016 was 1367 pmp in our county (32.5% living with functioning graft). CONCLUSIONS: Number of transplanted patients has grown in the last decade. Proportion of living organ donation was minimal. Orv Hetil. 2017; 158(25): 984-991. PMID- 28627951 TI - The safety of Bruton's tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia. AB - INTRODUCTION: The approval of ibrutinib has revolutionized the therapeutic landscape of chronic lymphocytic leukemia (CLL). Currently ibrutinib is indicated for patients that are both treatment naive as well as those with relapsed CLL. Ibrutinib is generally well-tolerated with durable responses that improve over time in most patients. Important toxicities include atrial fibrillation and bleeding. Areas cover: This review covers the pharmacokinetics, pharmacodynamics, safety and efficacy of ibrutinib in the treatment of CLL. We also compare ibrutinib with other kinase inhibitors and chemoimmunotherapy regimens using data from clinical trials. A literature search utilized the PubMed database. Expert opinion: Despite the efficacy and tolerability of ibrutinib, important questions remain, which include selection of patients receiving ibrutinib in the first and subsequent lines of treatment, optimal dosing, sequential use of ibrutinib versus other kinase inhibitors and combination therapy. Prospective studies should incorporate minimal residual disease (MRD) status as a clinical endpoint to determine whether patients can be taken off kinase inhibitors. PMID- 28627952 TI - Clinical efficacy of piperacillin/tazobactam in the treatment of complicated skin and soft tissue infections. AB - INTRODUCTION: Complicated skin and soft tissue infections (cSSTIs) are skin and soft tissue infections (SSTIs) that involve deep soft tissue. cSSTIs often require surgical intervention and/or hospitalization. cSSTIs are associated with significant mortality and morbidity, and carry a significant burden on health care systems. Piperacillin/tazobactam has been regarded as a standard treatment for cSSTIs because of its antibiotic spectrum, safety and clinical efficacy. Several antibiotics, as compared to piperacillin/tazobactam, have been evaluated in the treatment of cSSTIs. Areas covered: This review summarizes randomized controlled trials (RCTs) evaluating the clinical efficacy of piperacillin/tazobactam for the treatment of cSSTIs. Expert opinion: Piperacillin/tazobactam, which covers most causative organisms in cSSTIs, is the drug of choice for the treatment of cSSTIs. Other options such as ertapenem and moxifloxacin may be reasonable where multiple daily dosing or intravenous administration is inappropriate. But in general, they should be avoided as an empirical treatment because of their highly association with resistant bacteria, which are becoming a global threat. Therefore, piperacilin/tazobactam is appropriate as an empirical therapy for the treatment of SSTIs and should be de escalated as soon as causative organisms are identified, their drug-sensitivity results are available, and clinical condition becomes stable. PMID- 28627953 TI - Role of diffusion-weighted imaging in head and neck lesions: Pictorial review. AB - Head and neck cancers are very common worldwide, causing significant morbidity and mortality. Squamous cell carcinoma originating from the epithelial lining of the upper aerodigestive tract is the most common histology. Many patients with head and neck cancers present with advanced stage disease requiring aggressive treatment consisting of extensive surgery and chemo-radiation. Appropriate treatment planning as well as prognosis of tumors depends to a large extent on accurate histological diagnosis and differentiation of malignant from benign lesions. Routine imaging modalities such as computed tomography and magnetic resonance imaging give volumetric and morphologic information. However, these modalities cannot be reliably used as a substitute for biopsy in treatment planning. However, diffusion-weighted imaging has shown promise in tissue characterization for primary tumors and nodal metastases, differentiation of recurrent tumor from post therapeutic changes, prediction and monitoring of treatment response, and many other clinical scenarios as described later in this article. In this review article, we describe the imaging findings in applications of diffusion-weighted imaging in the head and neck lesions and discuss their added value over anatomic imaging. PMID- 28627954 TI - Reliability analysis of Cobb measurement in degenerative lumbar scoliosis using endplate versus pedicle as bony landmarks. AB - OBJECTIVES: Degenerative changes of endplates in older patients and tilting of vertebral body in lumbosacral lordosis could make an accurate identification of endplates for the Cobb measurement difficult. Pedicles have been proposed as alternative landmarks because they are usually better visualized, and offer similar clinical validity to the endplates. The objective of this study was to investigate the reliability of the pedicle method of Cobb measurement in degenerative lumbar scoliosis and compare it with the traditional endplate method. METHODS: Two hundred and eighty-four radiographs of degenerative lumbar scoliosis were evaluated. The radiographs were classified into groups based on the patient's age (< 60 years, 60 to 80 years, and > 80 years), level of lower end vertebra (LEV) (LEV at L5, and LEV at or above L4), and curve severity (< 20 degrees , 20 degrees to 40 degrees , and > 40 degrees ). Three observers independently measured the radiographs using the endplate and pedicle methods twice with an interval of 1 week. The intra- and interobserver reliabilities were calculated using intraclass correlation coefficients (ICC). RESULTS: The intra- and interobserver ICC values were better for all observers in the > 80 years age group using the pedicle method. The intraobserver ICC values of pedicle method were also better in the LEV at L5 group, and the interobserver ICC values showed a slightly better consistency with the pedicle method. For patients with > 40 degrees curves, the intraobserver ICC values for all observers as well as interobserver ICC values were better using the endplate method. CONCLUSION: The reliabilities of the endplate and pedicle methods for degenerative lumbar scoliosis were both excellent. The pedicle method might be better in older patients (> 80 years) and those with LEV at L5; while the endplate method could have some strength in severe cases (> 40 degrees ). PMID- 28627955 TI - Herpes simplex encephalitis with thalamic, brainstem and cerebellar involvement. AB - Herpes simplex virus encephalitis is a common and treatable cause of acute encephalitis in all age groups. Certain radiological features such as temporal parenchymal involvement facilitate the diagnosis. The use of herpes simplex virus polymerase chain reaction has expanded the clinical and imaging spectrum. We report the case of a young patient who presented with a movement disorder and predominant involvement of thalami, brainstem and cerebellum on magnetic resonance imaging, and was diagnosed with herpes simplex virus encephalitis. Differentiation from Japanese encephalitis may be difficult in these patients, especially in endemic areas, and may necessitate the use of relevant investigations in all patients. PMID- 28627956 TI - Evaluating the effects of Botulinum Toxin A on tear metrics in patients with hemifacial spasm. AB - Hemifacial spasm has been previously shown to result in dry eye and ocular surface diseases. This study was performed to assess the impact of chemodenervation with botulinum toxin on clinically-relevant metrics of tears. Tear osmolarity and lipid layer thickness were measured in patients with hemifacial spasm after they achieved relief from hemifacial spasm via botulinum toxin injections. Twelve eyes of 6 patients with hemifacial spasm (2 men and 4 women; mean age 55.5 years) were assessed in accordance with the Declaration of Helsinki and IRB approval. The mean tear osmolarities were 300.8 mOsm (standard deviation = 7.44 mOsm) and 293.0 mOsm (standard deviation = 7.01 mOsm) for treated and untreated eyes, respectively, and this difference was not statistically significant (p = 0.097). The mean lipid layer thicknesses of the tear film were 78.7 nm (standard deviation = 18.0 nm) and 71.5 nm (standard deviation = 25.2 nm) for treated and untreated eyes, respectively, and these values were not statistically significantly different (p = 0.671). Although previous investigations have demonstrated significant dry eye disease in patients with hemifacial spasm, successful chemodenervation with botulinum toxin appears to result in tear osmolarities and lipid layer thicknesses that were comparable in treated and untreated eyes. This finding may represent an additional benefit to treatment of hemifacial spasm. PMID- 28627957 TI - Fronto-striatal network activation leads to less fatigue in multiple sclerosis. AB - BACKGROUND: The fronto-striatal network has been implicated in both fatigue, a common multiple sclerosis (MS) symptom, and goal attainment, which has been shown to reduce fatigue in healthy individuals. OBJECTIVES: To investigate whether stimulation of the fronto-striatal network through goal attainment (potential monetary gain) leads to fatigue reduction in MS and healthy control (HC) participants. METHODS: In all, 14 healthy and 19 MS participants performed a gambling task during functional magnetic resonance imaging (fMRI). Participants were presented with an opportunity to receive monetary reward during the outcome condition of the task but not during the no outcome condition. Self-reported fatigue measures were obtained after each condition and outside of the scanner. Structural alterations were also examined. RESULTS: A significant decrease in fatigue was observed after the outcome condition compared to the no outcome condition in both groups. Significantly greater activation was observed in the ventral striatum in association with the outcome condition compared to the no outcome condition in both groups. Ventromedial prefrontal cortex showed significantly greater activation during the no outcome condition compared to the outcome condition with greater difference between conditions in the HC group. CONCLUSION: This is the first functional neuroimaging study showing that stimulation of the fronto-striatal network through goal attainment leads to decreased on-task fatigue in MS and healthy participants. PMID- 28627958 TI - Pushed monocanalicular intubation versus probing for the treatment of simple and incomplete complex types of congenital nasolacrimal duct obstruction in children older than 18 months old. AB - This article compares the success rate of pushed monocanalicular intubation (Masterka) versus probing for the treatment of congenital nasolacrimal duct obstruction (CNLDO) in children older than 18 months. In a non-random comparative study, 90 eyes with CNLDO underwent either Masterka (45 eyes) or probing (45 eyes). All procedures were performed by one oculoplastic surgeon. The tubes were removed 2 months after the operation. Complete resolution was defined as complete absence of clinical signs and symptoms of CNLDO at 6 months after the procedure. The mean age at the time of treatment was 28 +/- 18.2 months for Masterka and 26.7 +/- 18.6 months for probing group. Treatment success was achieved in 33 of 45 eyes (73.3%) in the Masterka group compared with 22 of 45 eyes (48.9%) in the probing group. The difference between the two groups was statistically significant (p = 0.017). For the treatment of CNLDO, Masterka might be more effective than probing in children older than 18 months. PMID- 28627959 TI - Two cases of primary leptomeningeal melanomatosis mimicking subacute meningitis. AB - Primary involvement of leptomeninges with melanocytic tumours is rarely seen and its diagnosis is challenging. Here we summarise two cases of primary leptomeningeal melanomatosis presenting as subacute meningitis. Both cases have pleocytosis and high protein on cerebrospinal fluid analysis, and demonstrated atypical cells on cytology. On magnetic resonance imaging, there is diffuse leptomeningal thickening and avid enhancement of intracranial and intraspinal leptomeninges. One of them demonstrates T1 shortening due to magnetic effects of melanin, the other case is amelanotic and shows hypointensity on precontrast T1 weighted images. Both cases can be diagnosed with biopsy. In conclusion, these cases highlight the importance of the correct interpretation of cytological and magnetic resonance imaging findings in patients with atypical findings. PMID- 28627960 TI - Lack of functional normalisation of tumour vessels following anti-angiogenic therapy in glioblastoma. AB - Neo-angiogenesis represents an important factor for the delivery of oxygen and nutrients to a growing tumour, and is considered to be one of the main pathodiagnostic features of glioblastomas (GBM). Anti-angiogenic therapy by vascular endothelial growth factor (VEGF) blocking agents has been shown to lead to morphological vascular normalisation resulting in a reduction of contrast enhancement as seen by magnetic resonance imaging (MRI). Yet the functional consequences of this normalisation and its potential for improved delivery of cytotoxic agents to the tumour are not known. The presented study aimed at determining the early physiologic changes following bevacizumab treatment. A time series of perfusion MRI and hypoxia positron emission tomography (PET) scans were acquired during the first week of treatment, in two human GBM xenograft models treated with either high or low doses of bevacizumab. We show that vascular morphology was normalised over the time period investigated, but vascular function was not improved, resulting in poor tumoural blood flow and increased hypoxia. PMID- 28627961 TI - Microsomal prostaglandin E2 synthase-1 inhibitors: a patent review. AB - INTRODUCTION: Microsomal prostaglandin E2 synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) generation. It is strongly upregulated in inflamed tissues and overexpressed in tumors and it has been recognized as a key enzyme in inflammatory diseases such as arthritis, atherosclerosis, stroke and cancer. Thus, a great effort has been devoted in developing synthetic mPGES-1 inhibitors as novel anti-inflammatory agents. Areas covered: This review article summarizes the mPGES-1 inhibitors presented in patent literature from 2000 to August 2016 and their biological evaluation, discussing their activities in vitro and in vivo. Expert opinion: The side effects of NSAIDs and COX-2 inhibitors on the gastrointestinal tract and the cardiovascular system showcase the urgent need for the discovery of novel potent and safe anti-inflammatory drugs. mPGES-1 inhibitors may present superior safety in comparison to existing anti inflammatory drugs. The first synthetic inhibitor of mPGES-1 was reported in 2001 and up to now a variety of structurally different inhibitors has been developed. However, only recently two inhibitors entered clinical trials and none has reached yet the market. More preclinical and clinical studies on mPGES-1 inhibitors are needed to realize if indeed they may become novel agents for the treatment of inflammation and cancer. PMID- 28627962 TI - Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod. AB - BACKGROUND: Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS). OBJECTIVE: To determine the correlation of NFL in CSF and serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod. METHODS: A first cohort consisted of MS patients ( n = 39) and neurological disease controls ( n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort ( n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (SimoaTM) technology (detection threshold 1.95 pg/mL). RESULTS: Mean NFL pg/mL (standard deviation ( SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated ( n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod ( n = 243), mean NFL pg/mL ( SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 * 10 6), and levels remained stable at 24 months (13.2 (6.2)). CONCLUSION: NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response. PMID- 28627963 TI - The natural history of recovery of elbow flexion after obstetric brachial plexus injury managed without nerve repair. AB - : In this study, we report the outcome for spontaneous recovery of elbow flexion in obstetric brachial plexus injury managed without nerve reconstruction. Excluding those with transient paralysis, our records revealed 152 children with obstetric brachial plexus injury born before our unit routinely offered brachial plexus reconstruction. Five had had nerve repairs. Of the remainder, only one patient had insufficient flexion to reach their mouth. Elbow flexion started to recover clinically at a mean age of 4 months for Narakas Group 1, 6 months for Group 2, 8 months for Group 3 and 12 months for Group 4. The mean active range of elbow flexion, in 44 cases, was 138 degrees . The mean isometric elbow flexion strength, in 39 patients, was 63% (range 23%-100%) of the normal side. It appears to be rare for elbow flexion not to recover spontaneously, although recovery occurs later in more severe injuries. It is doubtful if nerve reconstruction can improve elbow flexion above the likely spontaneous recovery in babies with obstetric brachial plexus injuries. LEVEL OF EVIDENCE: II. PMID- 28627964 TI - Comparison of the success rate between monocanalicular and bicanalicular intubations in incomplete complex congenital nasolacrimal duct obstruction. AB - This article compares the success rate between monocanalicular (MCI) and bicanalicular intubations (BCI) in incomplete complex congenital nasolacrimal duct obstruction (CNLDO) and evaluate the factors responsible for the success of intubation. First, 99 patients with incomplete complex CNLDO underwent MCI (Monoka) or BCI (Crawford). Therapeutic success was defined as dye disappearance test grade 0-1 and complete resolution of previous symptoms at 12 months' follow up. The success rates were compared between two groups. In all cases, the correlation of the age, gender, history of probing, and the presence of purulent discharges with the improvement in CNLDO symptoms were evaluated. 52 cases in the MCI and 47 cases in the BCI group were included. Then, 48 patients (48.5%) had history of probing. 26 patients (26.3%) had purulent discharges. The patients in the MCI group had lower success rate (59.6%) than the patients in the BCI group (74.4%) but the difference was not significant (p = 0.11). No complication occurred in the BCI group. In 4 cases (7.6%) in the MCI group, the tubes were lost before time of planned removal. In all cases, only preoperative absence of the pus was significantly correlated with success (p = 0.09 and OR = 0.39). BCI may be a better treatment for the patients with incomplete complex CNLDO. In silicone intubation for these cases, preoperative absence of purulent discharges could increase the success rate. PMID- 28627965 TI - Role of angiopoietin-2, endoglin, and placental growth factor in HIV-associated preeclampsia. AB - OBJECTIVE: The factors angiopoeitin-2 (Ang-2), endoglin (Eng), and placental growth factor (PlGF) have been implicated in the pathophysiology of preeclampsia (PE). This study assessed their serum levels in HIV-negative and HIV-positive pregnant normotensive and pre-eclamptic women. METHODS: Participants were recruited at the antenatal clinic, serum samples were evaluated using the Bioplex Human Cancer Biomarker (panel 2). RESULTS: Ang-2 and Eng levels were higher, whilst PlGF levels were lower in the PE compared with the normotensive group. Pregnancy type had no significant effect on Ang-2 and showed a significant interaction with Eng (p < 0.0001) and PlGF (p = 0.0033). HIV status had no significant effect on angiopoeitin-2 (p = 0.4), Eng (p = 0.4), and PlGF (p = 0.7) but the levels were slightly higher in the HIV-negative cohort. CONCLUSIONS: This study demonstrates an elevation of Ang-2 and Eng in pre-eclamptic compared with normotensive pregnant women implicating their role in its pathogenesis. PMID- 28627966 TI - Further Evidence of Cucurbit Host Specificity among Acidovorax citrulli Groups Based on a Detached Melon Fruit Pathogenicity Assay. AB - Bacterial fruit blotch, caused by the gram-negative bacterium Acidovorax citrulli, is a serious economic threat to cucurbit crop production worldwide. A. citrulli strains can be divided into two genetically distinct groups, with group I strains infecting a range of cucurbit species and group II strains being predominantly associated with watermelon. Group I and II A. citrulli strains differ in their arsenal of type III secreted (T3S) effector proteins and we hypothesize that these effectors are critical for cucurbit host preference. However, the pathogenicity or virulence assays used for A. citrulli, including infiltration of seedling cotyledons and mature fruit rind tissues with cell suspensions and spray inoculation of seedlings, lack the sensitivity to consistently distinguish strains of the two groups. Here, we describe an immature, detached melon fruit assay based on 'Joaquin Gold' melon (Syngenta, Rogers Brand) that clearly indicates differences in host specificity between group I and II A. citrulli strains. Using this assay, four group I strains (M6, AAC213-52, AAC213-55, and XJL12) induced typical water-soaked lesions in melon fruit rind tissue 7 to 10 days after pinprick inoculation. In contrast, four group II strains (AAC00-1, AAC213-44, AAC213-47, and AAC213-48) did not induce water-soaked lesions on detached melon fruit rinds during the same period. These data suggest that group I A. citrulli strains have a specific capacity to infect immature Joaquin Gold melon fruit, whereas group II strains do not. Interestingly, this differential pathogenicity phenotype was not observed on foliar seedling tissues of the same melon cultivar, suggesting that host preference of A. citrulli strains is specific to immature fruit tissues. Using the immature melon fruit inoculation assay, a T3S system mutant of the group I A. citrulli strain, M6 (M6DeltahrcV), failed to induce water soaking. This indicates that T3S effectors are involved in A. citrulli cucurbit host preference, and that this assay is suitable for future studies of unique T3S effectors that distinguish group I and II strains. PMID- 28627967 TI - Novel region of interest interrogation technique for diffusion tensor imaging analysis in the canine brain. AB - Purpose We describe a novel technique for measuring diffusion tensor imaging metrics in the canine brain. We hypothesized that a standard method for region of interest placement could be developed that is highly reproducible, with less than 10% difference in measurements between raters. Methods Two sets of canine brains (three seven-week-old full-brains and two 17-week-old single hemispheres) were scanned ex-vivo on a 7T small-animal magnetic resonance imaging system. Strict region of interest placement criteria were developed and then used by two raters to independently measure diffusion tensor imaging metrics within four different white-matter regions within each specimen. Average values of fractional anisotropy, radial diffusivity, and the three eigenvalues (lambda1, lambda2, and lambda3) within each region in each specimen overall and within each individual image slice were compared between raters by calculating the percentage difference between raters for each metric. Results The mean percentage difference between raters for all diffusion tensor imaging metrics when pooled by each region and specimen was 1.44% (range: 0.01-5.17%). The mean percentage difference between raters for all diffusion tensor imaging metrics when compared by individual image slice was 2.23% (range: 0.75-4.58%) per hemisphere. Conclusion Our results indicate that the technique described is highly reproducible, even when applied to canine specimens of differing age, morphology, and image resolution. We propose this technique for future studies of diffusion tensor imaging analysis in canine brains and for cross-sectional and longitudinal studies of canine brain models of human central nervous system disease. PMID- 28627969 TI - Identification of potential inhibitors of Fasciola gigantica thioredoxin1: computational screening, molecular dynamics simulation, and binding free energy studies. AB - Fasciola gigantica is the causative organism of fascioliasis and is responsible for major economic losses in livestock production globally. F. gigantica thioredoxin1 (FgTrx1) is an important redox-active enzyme involved in maintaining the redox homeostasis in the cell. To identify a potential anti-fasciolid compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,740) against the FgTrx1 structure. The ligands were docked against FgTrx1 and 309 ligands were found to have better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 30 compounds were found to fit well for re-docking studies. After refinement by molecular docking and drug-likeness analysis, three potential inhibitors (ZINC15970091, ZINC9312362, and ZINC9312661) were identified. These three ligands were further subjected to molecular dynamics simulation (MDS) to compare the dynamics and stability of the protein structure after binding of the ligands. The binding free energy analyses were calculated to determine the intermolecular interactions. The results suggested that the two compounds had a binding free energy of -82.237, and -109.52 kJ.mol-1 for compounds with IDs ZINC9312362 and ZINC9312661, respectively. These predicted compounds displayed considerable pharmacological and structural properties to be drug candidates. We concluded that these two compounds could be potential drug candidates to fight against F. gigantica parasites. PMID- 28627968 TI - Severe myelinopathy in 49,XXXXY syndrome. AB - 49,XXXXY is a rare aneuploidy with neuroanatomic findings scarcely reported in the literature. Given the fact that many of its phenotypic characteristics are similar to Klinefelter patients, 49,XXXXY has been treated as a variant of Klinefelter syndrome in the past. Newer studies have shown that intellectual disabilities and cardiac sequelae are more common in 49,XXXXY making the need for more precise characterization of the disorder essential. Prior case studies have demonstrated focal (and to a lesser extent confluent) white abnormalities as well as enlarged perivascular cysts (often in clustered arrangements) in the brains of these patients, but high resolution magnetic resonance images of severe myelinopathy are infrequently documented. Presented here is an exceptional manifestation of this rare disease with substantial findings in the brain exhibiting both confluent white matter changes and diffuse perivascular cysts. Cases such as this one serve to expand the differential considerations for confluent dysmyelinating disease and improve diagnostic efficacy. PMID- 28627970 TI - Genome-wide codon usage profiling of ocular infective Chlamydia trachomatis serovars and drug target identification. AB - Chlamydia trachomatis (C.t) is a Gram-negative obligate intracellular bacteria and is a major causative of infectious blindness and sexually transmitted diseases. Among the varied serovars of this organism, A, B and C are reported as prominent ocular pathogens. Genomic studies of these strains shall aid in deciphering potential drug targets and genomic influence on pathogenesis. Hence, in this study we performed deep statistical profiling of codon usage in these serovars. The overall base composition analysis reveals that these serovars are over biased to AU than GC. Similarly, relative synonymous codon usage also showed preference towards A/U ending codons. Parity Rule 2 analysis inferred unequal distribution of AT and GC, indicative of other unknown factors acting along with mutational pressure to influence codon usage bias (CUB). Moreover, absolute quantification of CUB also revealed lower bias across these serovars. The effect of natural selection on CUB was also confirmed by neutrality plot, reinforcing natural selection under mutational pressure turned to be a pivotal role in shaping the CUB in the strains studied. Correspondence analysis (COA) clarified that, C.t C/TW-3 to show a unique trend in codon usage variation. Host influence analysis on shaping the codon usage pattern also inferred some speculative relativity. In a nutshell, our finding suggests that mutational pressure is the dominating factor in shaping CUB in the strains studied, followed by natural selection. We also propose potential drug targets based on cumulative analysis of strand bias, CUB and human non-homologue screening. PMID- 28627971 TI - Moving on: Factors associated with caregivers' bereavement adjustment using a random population-based face-to-face survey. AB - BACKGROUND: Providing care at end of life has consequences for caregivers' bereavement experience. 'Difficulty moving on with life' is an informative and unbiased symptom of prolonged grief disorder. Predictors of bereaved caregivers' ability to 'move on' have not been examined across the population. AIM: To identify the characteristics of bereaved hands-on caregivers who were, and were not, able to 'move on' 13-60 months after the 'expected' death of someone close. DESIGN: The South Australian Health Omnibus is an annual, random, cross-sectional community survey. From 2000 to 2007, respondents were asked about providing care for someone terminally ill and their subsequent ability to 'move on'. Multivariable logistic regression models explored the characteristics moving on and not moving on. SETTING: Respondents were aged ?15 years and lived in households within South Australia. They had provided care to someone who had died of terminal illness in the preceding 5 years. RESULTS: A total of 922 people provided hands-on care. In all, 80% of caregivers (745) had been able to 'move on'. Closeness of relationship to the deceased, increasing caregiver age, caregiver report of needs met, increasing time since loss, sex and English speaking background were significantly associated with 'moving on'. A closer relationship to the deceased, socioeconomic disadvantage and being male were significantly associated with not 'moving on'. CONCLUSION: These results support the relevance of 'moving on' as an indicator of caregivers' bereavement adjustment. Following the outcomes of bereaved caregivers longitudinally is essential if effective interventions are to be developed to minimise the risk of prolonged grief disorder. PMID- 28627972 TI - Immunomodulatory effects of cigarette smoke condensate in mouse macrophage cell line. AB - Increasing evidence has demonstrated that the secretion of cytokines may be associated with cigarette smoke-induced immunomodulatory effects, but a comprehensive analysis of the cytokine profile for cigarette smoke condensate (CSC) exposure is lacking. The aims of this study were to (1) examine the release of 20 cytokines induced by CSC from 12 brands of cigarettes in macrophages cells (Ana-1) and (2) to investigate the general characteristics of the immunomodulatory effects of CSC. Luminex technology was used to simultaneously determine the levels of 20 cytokines (interleukin (IL)-1alpha, IL-1beta, IL-2, IL 4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), keratinocyte-derived Chemokine (KC), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1alpha (MIP-1alpha), induced protein 10 (IP-10), tumor necrosis factor alpha (TNF-alpha), vascular endothelial growth factor (VEGF), monkine inducible by gamma interferon (MIG), and fibroblast growth factor (FGF) basic) in the supernatants from Ana-1 cells treated with the CSC. The results showed that the release of eight cytokines was altered (IL-5, IL-6, IL-12, TNF alpha, VEGF, IP-10, MCP-1, and MIP-1alpha) compared with the control. These cytokines fall into two major subtypes: proinflammatory cytokines, including IL 5, IL-6, IL-12, TNF-alpha, and VEGF, and chemokines, including IP-10, MCP-1, and MIP-1alpha. Compared with control, the remaining 12 cytokines were not significantly affected by CSC from the 12 brands of cigarettes. As a general characteristic, CSC exerts potently suppressive immunomodulatory effects on cytokine production of Ana-1 cells. Proinflammatory cytokines and chemokines may account for or contribute to the immunosuppressive properties of CSC. PMID- 28627973 TI - Profile of gene expression of TLR-signaling pathways in colorectal cancer tissues. AB - Toll-like receptors (TLRs) are involved in transduction of molecular signals in immune process such as induction and regulation of immunity, production of cytokines, and recognition of specific molecular patterns on the surface of microorganisms, but also in cancer development-which was partially proven in previous studies. There is a lack of detailed research on differentiating levels of TLR expression in colorectal cancer at different stages of its advancement, so in our study we want to determine whether there is such a difference of TLRs and TLR-connected protein expression. In this study, 83 samples of colorectal adenocarcinoma (varying clinical degrees) and 40 slices of healthy colon tissue have been analyzed. The delivered material was subjected to homogenization and extraction of total RNA. The isolated RNA was subsequently purified and valued quantitatively and qualitatively. Quantification was performed using a spectrophotometer GeneQuant II. The RNA concentration in the tested samples was determined spectrophotometrically. A qualitative assessment was performed by performing electrophoresis on a 1% agarose gel stained with ethidium bromide. The expression profile of the genes encoding the TLRs was determined using oligonucleotide microarray HG-U133A. To determine the mRNA (messenger RNA), differentiate cancerous tissue from normal colon using PL-Grid Infrastructure. The results were analyzed statistically, taking a significance level P < 0.05. In the study were found three proteins, DUSP2, IFNgamma, EIF4A1, associated with TLR system, that differentiate early stages of colorectal cancer of healthy tissue, moreover eleven, inter alia: vascular endothelial growth factor (VEGF), which differentiate high stage of cancer of healthy tissues. The results emphasize the role of pathways associated with TLR activation in the pathogenesis of colorectal cancer. In summary, molecular studies on the development of colorectal cancer will enable the introduction of minimally invasive genetic diagnosis of early forms of cancer. In addition, identification of new signaling pathways can provide the basis for developing new therapeutic methods. PMID- 28627974 TI - MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation induced apoptosis. AB - Hypoxic-ischemic brain injury (HIBI) results in death or long-term neurologic impairment in both adults and children. In this study, we investigated the effects of microRNA-132 (miR-132) dysregulation on oxygen-glucose deprivation (OGD)-induced apoptosis in fetal rat hippocampal neurons, in order to reveal the therapeutic potential of miR-132 on HIBI. MiR-132 dysregulation was induced prior to OGD exposure by transfection of primary fetal rat hippocampal neurons with miR 132 mimic or miR-132 inhibitor. The effects of miR-132 overexpression and suppression on OGD-stimulated hippocampal neurons were evaluated by detection of cell viability, apoptotic cells rate, and the expression of apoptosis-related proteins. Besides, TargetScan database and dual luciferase activity assay were used to seek a target gene of miR-132. As a result, miR-132 was highly expressed in hippocampal neurons following 2 h of OGD exposure. MiR-132 overexpression significantly increased OGD-diminished cell viability and reduced OGD-induced apoptosis at 12, 24, and 48 h post-OGD. MiR-132 overexpression significantly down regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2. Caspase-3 activity was also significantly decreased by miR-132 overexpression. Furthermore, FOXO3 was a direct target of miR-132, and it was negatively regulated by miR-132. To conclude, our results provide evidence that miR-132 protects hippocampal neurons against OGD injury by inhibiting apoptosis. PMID- 28627976 TI - Administration of rocuronium based on real body weight versus fat-free mass in patients with lymphedema. AB - Objective To compare the clinical pharmacokinetics of rocuronium when applied according to fat-free mass versus real body weight during anesthetic induction of patients with lymphedema. Methods Sixty patients with lymphedema (age, 18-60 years; American Society of Anesthesiologists physical status, I-II) undergoing elective surgery with general anesthesia were randomly divided into two groups. Rocuronium was administered based on the fat-free mass in 30 patients and real body weight in 30 patients. General anesthesia was induced with propofol and remifentanil by target-controlled infusion. Intubation was attempted when the onset time (T1) (time from end of bolus injection to 100% twitch depression) reached maximal inhibition, and respiratory support with mechanical ventilation was then applied. The T1, clinical duration (time from end of bolus injection to recovery of twitch tension to 25% of control), recovery index (time from 25% to 75% of recovery of T1), and dosage were recorded. Results Complete data were recorded for 59 patients, and there were no significant differences in the general condition, intubation condition, or median duration of action of rocuronium between the two groups. However, the median T1, recovery index, and dosage of rocuronium were significantly different. Conclusion Good intubation conditions and a shortened clinical duration can be obtained for patients with lymphedema when induction with rocuronium is based on the fat-free mass. PMID- 28627977 TI - Masquerading bundle branch block as a presenting manifestation of complete atrioventricular block that caused syncope. AB - A 59-year-old male patient was admitted with the main complaints of stuffiness and shortness of breath. An ECG from precordial leads on admission showed masquerading bundle branch block. Syncope frequently occurred after admission. During syncope episodes, ECG telemetry showed that the syncope was caused by intermittent complete atrioventricular block, with the longest RR interval lasting for 4.36 s. At the gap of syncope, ECG showed complete right bundle branch block accompanied by alternation of left anterior fascicular block and left posterior fascicular block. The patient was implanted with a dual-chamber permanent pacemaker. Follow-up of 9 months showed no reoccurrence of syncope. PMID- 28627978 TI - Scarf pin-related hijab syndrome: A new name for an unusual type of foreign body aspiration. AB - Background Foreign body aspiration refers to the inhalation of an object into the respiratory system and is a serious and potentially fatal event. A distinct group of patients has recently been recognized among Muslim nations. These patients include women who wear headscarves and place the safety pin in their mouth prior to securing the veils, leading to accidental foreign body aspiration. The aim of this study was to analyze the main presentation, diagnosis, treatment, and outcome of patients with scarf pin aspiration. Methods This prospective study involved patients with a history of scarf pin aspiration admitted to a single center during an 18-month period. Their main presentation, diagnosis, treatment, and outcome were analyzed. Results In total, 27 patients were included. The needle was extracted by flexible bronchoscopy in 12 (44.4%) patients, rigid bronchoscopy in 13 (48.1%), and thoracotomy in 2 (74%). One patient died during rigid bronchoscopy. All remaining 26 patients were satisfied with the postsurgical outcome at a mean follow-up of 1 week. Conclusions Scarf pin aspiration differs from other types of foreign body aspiration considering the specific population affected, and its management algorithm may thus differ from that of other foreign bodies. The left main bronchus is the most common site of pin impaction. Rigid bronchoscopy is the most commonly performed procedure for successful retrieval. PMID- 28627979 TI - Association between transforming growth factor-beta 1 gene single nucleotide polymorphisms and knee osteoarthritis susceptibility in a Chinese Han population. AB - Objective To investigate associations between single polymorphisms (SNPs) rs1800469 and rs1982073 in the transforming growth factor-beta1 gene ( TGF-beta1) and knee osteoarthritis (OA) susceptibility in a Chinese Han population. Methods TGF-beta1 rs1800469 and rs1982073 were genotyped in patients with knee OA and age and sex-matched OA-free controls from a Chinese Han population. The association was further analyzed according to gender and age. Results A total of 765 patients with knee OA and 780 controls were included. CT and CT + CC genotypes of rs1982073, and variant C, were associated with a significantly increased risk of knee OA. Stratification analysis showed that the association between the OA risk and rs1982073 CT heterozygotes compared with TT homozygotes was stronger in females and those aged >65 years. In contrast, CT, TT, and CT + TT genotypes of rs1800469 were not significantly associated with the risk of knee OA, even after further stratification analysis for gender and age. Conclusions The TGF-beta1 rs1982073 T to C change and the variant C genotype may contribute to knee OA risk in the Chinese Han population. PMID- 28627980 TI - Long-term follow-up of a hospital-based, multi-intervention programme in type 2 diabetes mellitus: impact on cardiovascular events and death. AB - Objective To report the long-term impact on cardiovascular (CV) outcomes and mortality of a 2-year hospital-based multi-interventional care programme as compared with general practitioner (GP)-provided standard care. Methods Patients with type 2 diabetes with >= 1 additional CV risk factor were randomized to 2 years of specialist-based, multi-intervention comprising lifestyle modification and specific pharmacological treatment, or GP-based standard care. After the 2 year intervention period, all participants returned to pre-study care, but were followed up for CV outcomes and mortality. The primary outcome was time to any first severe CV event or death. Results A total of 120 patients (31 women) were enrolled in the study. During the mean +/- SD observational period of 8.7 +/- 2.0 years, 27 patients (16 and 11 in the multi-intervention and standard care groups, respectively) experienced at least one primary outcome event, with a hazard ratio (HR) if allocated to the multi-intervention group of 1.73 (95% confidence interval (CI) 0.80, 3.75). The HR for total mortality was 1.82 (95% CI 0.66, 5.01). Conclusions Hospital-based multi-intervention in patients with type 2 diabetes mellitus improved long-term glycaemic control, but failed to reduce CV outcomes and deaths. Clinical trials.gov id: NCT00133718. PMID- 28627981 TI - Early vitrectomy for dense vitreous hemorrhage in adults with non-traumatic and non-diabetic retinopathy. AB - Objective To evaluate the etiologies for dense vitreous hemorrhage in adults with non-traumatic and reveal management of early vitrectomy for the disease. Methods Study included 105 eyes from 105 patients. Outcome measures were etiologies of vitreous hemorrhage, formation of retinal and/or disk neovascular membrane (NVM), incidence of retinal tear and detachment, visual acuity (VA) and postoperative complications. Results Mean time between presentation and surgery was 7.1 days. The most common etiologies were retinal vein occlusion (RVO) (58.1%), retinal tear (22.9%) and retinal vasculitis (10.4%). Most RVO (77.0%) and retinal vasculitis (72.7%) eyes were associated with retinal and/or disk NVM. Retinal tear and retinal detachment was found in 24 and 48 eyes, respectively. VA improved significantly from 1/70 to 0.6 following vitrectomy. The most common postoperative complication was cataract (28.6%). Conclusion RVO, retinal tear and retinal vasculitis were the most common causes of dense vitreous hemorrhage. Early vitrectomy has a good outcome with acceptable complication rates in this setting. PMID- 28627982 TI - miRNAs as potential therapeutic targets and diagnostic biomarkers for cardiovascular disease with a particular focus on WO2010091204. AB - INTRODUCTION: A number of miRNAs have been reported to be critically involved in the regulation of cardiovascular disease (CVDs). Therefore, the development of potent analogues/inhibitors for miRNAs have thus become a key focus in the present drug discovery. In this review, we discuss the basic research and clinical use of miRNAs as the early diagnosis and therapeutic targets for CVD. We have also focused on the efficiency of therapeutically targeting miR-499, which is considered as one of the most promising molecules for treating CVDs. Areas covered: In this review, we have discussed the patents and patent applications related to miRNAs detected in CVD patients published in recent years. This review also covers the expression pattern of miR-499, as well as it highlights functions of its inhibitors in CVD. We used Google and Pubmed search engines to find relevant patents. Expert opinion: Although a massive number of miRNAs are patented as CVD biomarkers, further work is absolutely required to evaluate the reliable diagnostic values and therapeutic potential of these candidates. Overall, targeting miRNAs is definitely a promising strategy to be investigated for diagnosis and treatment of CVDs in future, however, the delivery system and off-targets effects are still a difficult challenge need to be elucidated. PMID- 28627983 TI - Susceptibility weighted imaging - a problem-solving tool in differentiation of cerebellopontine angle schwannomas and meningiomas. AB - Background and purpose Vestibular schwannomas and meningiomas of the cerebellopontine angle can be differentiated by the presence of foci of blooming on susceptibility weighted imaging. Materials and methods In this retrospective study, magnetic resonance imaging with susceptibility weighted imaging sequence in addition to other routine sequences was done in 73 patients. All the cases were studied for the presence of foci of blooming within the tumor on susceptibility weighted imaging. Histopathological examination confirmed the diagnosis in all cases. Results There were 59 patients in the vestibular schwannoma group and 14 in the meningioma group. Susceptibility weighted imaging showed presence of blooming (due to microhemorrhages) in all the cases of cerebellopontine angle schwannomas. In the meningioma group, 13 cases showed no blooming within the lesion; one case showed blooming which was confirmed to be due to calcification on computed tomography study. For the detection of foci of blooming and predicting histopathologic diagnosis of schwannoma pre-operatively, susceptibility weighted imaging showed a sensitivity of 100%, specificity of 92%, positive predictive value of 98.3%, and negative predictive value of 100%. The Fisher exact test showed a statistically significant difference in the differentiation of vestibular schwannoma from meningioma on the basis of detection of blooming on susceptibility weighted imaging ( p < 0.0001). Conclusion Susceptibility weighted imaging is a problem-solving tool in making accurate pre-operative differentiation of vestibular schwannoma from meningioma. PMID- 28627984 TI - Diagnostic accuracy of proton magnetic resonance spectroscopy and perfusion weighted imaging in brain gliomas follow-up: a single institutional experience. AB - Objectives The objective of this study was to evaluate whether proton magnetic resonance spectroscopy and perfusion magnetic resonance imaging (MRI) are able to increase diagnostic accuracy in the follow-up of brain gliomas, identifying the progression of disease before it becomes evident in the standard MRI; also to evaluate which of the two techniques has the best diagnostic accuracy. Methods Eighty-three patients with cerebral glioma (50 high-grade gliomas (HGGs), 33 low grade gliomas (LGGs)) were retrospectively enrolled. All patients underwent standard MRI, H spectroscopic and perfusion echo-planar imaging MRI. For spectroscopy variations of choline/creatine, choline/N-acetyl-aspartate ratio, and lipids and lactates peak were considered. For perfusion 2.0 was considered the cerebral blood volume cut-off for progression. The combination of functional parameters gave a multiparametric score (0-2) to predict outcome. Diagnostic performance was determined by the receiver operating characteristic curve, with sensitivity, specificity, positive predictive and negative predictive values. Results In patients with LGGs a combined score of at least 1 was the best predictor for progression (odds ratio (OR) 3.91) with 8.4 months median anticipation of diagnosis compared to standard MRI. The individual advanced magnetic resonance technique did not show a diagnostic accuracy comparable to the combination of the two. Overall diagnostic accuracy area under the curve (AUC) was 0.881. In patients with HGGs the multiparametric score did not improve diagnostic accuracy significantly. Perfusion MRI was the best predictor of progression (OR 3.65), with 6.7 months median anticipation of diagnosis. Overall diagnostic accuracy AUC was 0.897. Then spectroscopy and perfusion MRI are able to identify tumour progression during follow-up earlier than standard MRI. Conclusion In patients with LGGs the combination of the functional parameters seems to be the best method for diagnosis of progression. In patients with HGGs perfusion is the best diagnostic method. PMID- 28627986 TI - Obituary. PMID- 28627985 TI - Diagnostic performance of reformatted isotropic thin-section helical CT images in the detection of superior semicircular canal dehiscence. AB - Purpose The purpose of this article is to assess the diagnostic performance of computed tomography (CT) reformatted images for detection of superior semicircular canal (SSC) dehiscence. Material and methods Forty-two patients, with sound- and/or pressure-induced vestibular symptoms, and 42 control participants underwent helical CT examination with a highly collimated beam (0.5 mm). Reformatted images of the vestibular labyrinth were obtained in the standard axial and coronal planes (group A images), and in a plane parallel and perpendicular to the SSC (group B images). Diagnostic performance obtained by evaluating the group A images alone and the group B images alone was analyzed by using the area under the receiver operating characteristic curve (AUC). Results The diagnostic performance of group A images was AUC = 0.929 with an overall accuracy of 92.9%. The diagnostic performance of group B images was AUC = 0.988 with an overall accuracy of 98.8%. The evaluation of group B images alone showed an improved diagnostic performance over the group A images alone. Conclusion Thin section 0.5-mm collimation CT with reformatted images oriented in the plane parallel and perpendicular to the SSC improves diagnostic accuracy in assessing for SSC dehiscence in comparison to CT images with reconstructions limited to traditional axial and coronal planes. PMID- 28627987 TI - Computerised tomography and magnetic resonance imaging of laryngeal squamous cell carcinoma: A practical approach. AB - Squamous cell carcinoma is the most common head and neck cancer. This review describes the state-of-the-art computerised tomography and magnetic resonance imaging protocols of the neck and the normal larynx anatomy, and provides a practical approach for the diagnosis and staging of laryngeal squamous cell carcinoma. PMID- 28627988 TI - Pharyngeal amyloidomas: Variable appearance on imaging. AB - Amyloidomas are rare tumor-like depositions of abnormally folded, insoluble proteins that may be seen in the setting of systemic amyloidosis or as isolated tumoral deposits. Focal, isolated amyloidomas carry an excellent prognosis whereas systemic amyloidoses do not. The ability to identify or suggest amyloidoma on imaging studies may help direct laboratory testing and eventual diagnosis. Amyloidomas involving the head and neck have been variably described from homogeneously T2 hypointense to iso-slightly hyperintense relative to skeletal muscle. Herein we present two patients with pharyngeal submucosal amyloidomas of differing sizes and imaging characteristics to emphasize their potential widely variable imaging appearance and broaden our knowledge of these rare lesions. PMID- 28627989 TI - Computed tomography detection of extracapsular spread of squamous cell carcinoma of the head and neck in metastatic cervical lymph nodes. AB - Background and purpose In patients with squamous cell carcinoma of the head and neck (HNSCC), extracapsular spread (ECS) of metastases in cervical lymph nodes affects prognosis and therapy. We assessed the accuracy of intravenous contrast enhanced computed tomography (CT) and the utility of imaging criteria for preoperative detection of ECS in metastatic cervical lymph nodes in patients with HNSCC. Materials and methods Preoperative intravenous contrast-enhanced neck CT images of 93 patients with histopathological HNSCC metastatic nodes were retrospectively assessed by two neuroradiologists for ECS status and ECS imaging criteria. Radiological assessments were compared with histopathological assessments of neck dissection specimens, and interobserver agreement of ECS status and ECS imaging criteria were measured. Results Sensitivity, specificity, positive predictive value, and accuracy for overall ECS assessment were 57%, 81%, 82% and 67% for observer 1, and 66%, 76%, 80% and 70% for observer 2, respectively. Correlating three or more ECS imaging criteria with histopathological ECS increased specificity and positive predictive value, but decreased sensitivity and accuracy. Interobserver agreement for overall ECS assessment demonstrated a kappa of 0.59. Central necrosis had the highest kappa of 0.74. Conclusion CT has moderate specificity for ECS assessment in HNSCC metastatic cervical nodes. Identifying three or more ECS imaging criteria raises specificity and positive predictive value, therefore preoperative identification of multiple criteria may be clinically useful. Interobserver agreement is moderate for overall ECS assessment, substantial for central necrosis. Other ECS CT criteria had moderate agreement at best and therefore should not be used individually as criteria for detecting ECS by CT. PMID- 28627991 TI - APA Annual Convention Division 40 Society for Clinical Neuropsychology Program Summary - August 3-6, 2017; Washington, D.C. PMID- 28627993 TI - Essays on rising mortality in England and Wales - a MEDLINE search is not infallible. PMID- 28627990 TI - Systemic metastases from central nervous system ependymoma: case report and review of the literature. AB - Ependymal tumours in adults are rare, accounting for less than 4% of primary tumours of the central nervous system, and exceptionally metastasise outside the nervous system. In this study, we present a case of anaplastic ependymoma, which developed metastases outside the nervous system less than a year after its clinical onset. A healthy 65-year-old woman suddenly presented with drowsiness of unknown origin, accompanied by ingravescent fatigue, inability to maintain the upright posture, headache, nausea and vomiting. Computed tomography study performed in the emergency department showed the presence of an inhomogeneously hypodense area, with temporoparietal extension and median line deviation. After surgical excision, performed after two days, the bioptic examination demonstrated an anaplastic ependymoma with multiple areas of necrosis. The patient was submitted to adjuvant radiation therapy. At magnetic resonance imaging follow-up, performed three months after surgery, neither local recurrences nor typical 'drop metastases' to the spinal area were observed. Three months later, magnetic resonance imaging control revealed bone metastases and recurrences in the left insula and at the ipsilateral cerebellar hemisphere. Total body computed tomography examination showed metastases in the liver, vertebrae and pelvic bones, and involvement of paratracheal lymph nodes. PMID- 28627994 TI - We're training robots: we need humans. PMID- 28627996 TI - Metastasectomy for colorectal cancer: are there clothes on the emperor? PMID- 28627997 TI - Events. PMID- 28627998 TI - Improving reports of research by more informative abstracts: a personal reflection. PMID- 28627999 TI - Heritability and genome-wide associations studies of cerebral blood flow in the general population. AB - Cerebral blood flow is an important process for brain functioning and its dysregulation is implicated in multiple neurological disorders. While environmental risk factors have been identified, it remains unclear to what extent the flow is regulated by genetics. Here we performed heritability and genome-wide association analyses of cerebral blood flow in a population-based cohort study. We included 4472 persons free of cortical infarcts who underwent genotyping and phase-contrast magnetic resonance flow imaging (mean age 64.8 +/- 10.8 years). The flow rate, cross-sectional area of the vessel, and flow velocity through the vessel were measured in the basilar artery and bilateral carotids. We found that the flow rate of the basilar artery is most heritable (h2 (SE) = 24.1 (9.8), p-value = 0.0056), and this increased over age. The association studies revealed two significant loci for the right carotid artery area (rs12546630, p value = 2.0 * 10-8) and velocity (rs2971609, p-value = 1.4 * 10-8), with the latter showing a concordant effect in an independent sample (N = 1350, p-value = 0.057, meta-analyzed p-value = 2.5 * 10-9). These loci were also associated with other cerebral blood flow parameters below genome-wide significance, and rs2971609 lies in a known migraine locus. These findings establish that cerebral blood flow is under genetic control with potential relevance for neurological diseases. PMID- 28628001 TI - Can Copper-Coated Surfaces Prevent Healthcare-Associated Infections? PMID- 28628002 TI - "Bundle" Practices and Ventilator-Associated Events: Not Enough - ERRATUM. PMID- 28628000 TI - Epigenetics, inflammation and metabolism in right heart failure associated with pulmonary hypertension. AB - Right ventricular failure (RVF) is the most important prognostic factor for both morbidity and mortality in pulmonary arterial hypertension (PAH), but also occurs in numerous other common diseases and conditions, including left ventricle dysfunction. RVF remains understudied compared with left ventricular failure (LVF). However, right and left ventricles have many differences at the morphological level or the embryologic origin, and respond differently to pressure overload. Therefore, knowledge from the left ventricle cannot be extrapolated to the right ventricle. Few studies have focused on the right ventricle and have permitted to increase our knowledge on the right ventricular specific mechanisms driving decompensation. Here we review basic principles such as mechanisms accounting for right ventricle hypertrophy, dysfunction, and transition toward failure, with a focus on epigenetics, inflammatory, and metabolic processes. PMID- 28628003 TI - Clinical effectiveness and cost-effectiveness results from the randomised, Phase IIB trial in previously untreated patients with chronic lymphocytic leukaemia to compare fludarabine, cyclophosphamide and rituximab with fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab: the Attenuated dose Rituximab with ChemoTherapy In Chronic lymphocytic leukaemia (ARCTIC) trial. AB - BACKGROUND: The conventional frontline therapy for fit patients with chronic lymphocytic leukaemia (CLL) is fludarabine, cyclophosphamide and rituximab (FCR). Rituximab (Mabthera(r), Roche Products Ltd) targets the CD20 antigen, which is expressed at low levels in CLL. The standard dose of rituximab in CLL (375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2-6) was selected based on toxicity data only. Small doses of rituximab (as low as 20 mg) have biological activity in CLL, with an immediate reduction in circulating CLL cells and down-regulation of CD20. Phase II trials had suggested improved efficacy with the addition of mitoxantrone to FCR. The key assumption for the Attenuated dose Rituximab with ChemoTherapy In CLL (ARCTIC) trial was that the addition of mitoxantrone to fludarabine, cyclophosphamide and low-dose rituximab would be more effective than conventional FCR. OBJECTIVES: To assess whether fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab (FCM-miniR) (100 mg of rituximab per cycle) was non inferior to FCR in frontline CLL. Complete response (CR) rate was the primary end point, with the secondary end points being progression-free survival (PFS), overall survival (OS), overall response rate, eradication of minimal residual disease (MRD), safety and cost-effectiveness. DESIGN: ARCTIC was a UK multicentre, randomised, controlled, open, Phase IIB non-inferiority trial in previously untreated CLL. A total of 206 patients with previously untreated CLL who required treatment, according to the International Workshop on Chronic Lymphocytic Leukaemia criteria, were to be randomised to FCR or FCM-miniR. There was an independent Data Monitoring and Ethics Committee (DMEC) with a pre-planned interim efficacy assessment on 103 participants. RESULTS: The DMEC's interim analysis led to early trial closure. Although the response rates in both arms were higher than anticipated, FCM-miniR had a lower CR rate than FCR. This was partly attributable to the higher toxicity associated with mitoxantrone. A total of 100 participants completed FCR, 79 completed FCM-miniR and 21 commenced FCM miniR but switched to FCR following DMEC recommendations. The CR rate for participants receiving FCR was 76%, compared with 55% for FCM-miniR (adjusted odds ratio 0.37; 95% confidence interval 0.19 to 0.73). Key secondary end points also showed that FCR was superior, with more participants achieving MRD negativity (57% for FCR vs. 46% for FCM-miniR). More participants experienced a serious adverse reaction with FCM-miniR compared with FCR (50% vs. 41%). At a median of 37.3 months' follow-up, the PFS and OS rates are good compared with previous studies, with no significant difference between the treatment arms. The economic analysis indicates that because FCM-miniR is less effective than FCR, FCM-miniR is not expected to be cost-effective over a lifetime horizon, producing a mean cost-saving of -L7723, a quality-adjusted life-year loss of -0.73 and a resulting incremental net monetary loss of -L6780. CONCLUSIONS: FCM-miniR is less well tolerated, with poorer response rates, than FCR, partly owing to the additional toxicity associated with mitoxantrone. In view of this, FCM-miniR will not be taken forward into a larger definitive Phase III trial. The trial demonstrated that oral FCR yields extremely high response rates compared with historical series with intravenous chemotherapy. FUTURE WORK: We shall compare the results of ARCTIC with those of the ADMIRE (Does the ADdition of Mitoxantrone Improve Response to FCR chemotherapy in patients with CLL?) trial, which compared FCR with FCM-R to assess the efficacy of low- versus standard-dose rituximab, allowing for the toxicity associated with mitoxantrone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16544962. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 28. See the NIHR Journals Library website for further project information. PMID- 28628004 TI - Visual field map clusters in human frontoparietal cortex. AB - The visual neurosciences have made enormous progress in recent decades, in part because of the ability to drive visual areas by their sensory inputs, allowing researchers to define visual areas reliably across individuals and across species. Similar strategies for parcellating higher-order cortex have proven elusive. Here, using a novel experimental task and nonlinear population receptive field modeling, we map and characterize the topographic organization of several regions in human frontoparietal cortex. We discover representations of both polar angle and eccentricity that are organized into clusters, similar to visual cortex, where multiple gradients of polar angle of the contralateral visual field share a confluent fovea. This is striking because neural activity in frontoparietal cortex is believed to reflect higher-order cognitive functions rather than external sensory processing. Perhaps the spatial topography in frontoparietal cortex parallels the retinotopic organization of sensory cortex to enable an efficient interface between perception and higher-order cognitive processes. Critically, these visual maps constitute well-defined anatomical units that future studies of frontoparietal cortex can reliably target. PMID- 28628006 TI - Live tracking of moving samples in confocal microscopy for vertically grown roots. AB - Roots navigate through soil integrating environmental signals to orient their growth. The Arabidopsis root is a widely used model for developmental, physiological and cell biological studies. Live imaging greatly aids these efforts, but the horizontal sample position and continuous root tip displacement present significant difficulties. Here, we develop a confocal microscope setup for vertical sample mounting and integrated directional illumination. We present TipTracker - a custom software for automatic tracking of diverse moving objects usable on various microscope setups. Combined, this enables observation of root tips growing along the natural gravity vector over prolonged periods of time, as well as the ability to induce rapid gravity or light stimulation. We also track migrating cells in the developing zebrafish embryo, demonstrating the utility of this system in the acquisition of high-resolution data sets of dynamic samples. We provide detailed descriptions of the tools enabling the easy implementation on other microscopes. PMID- 28628005 TI - Emergence of visually-evoked reward expectation signals in dopamine neurons via the superior colliculus in V1 lesioned monkeys. AB - Responses of midbrain dopamine (DA) neurons reflecting expected reward from sensory cues are critical for reward-based associative learning. However, critical pathways by which reward-related visual information is relayed to DA neurons remain unclear. To address this question, we investigated Pavlovian conditioning in macaque monkeys with unilateral primary visual cortex (V1) lesions (an animal model of 'blindsight'). Anticipatory licking responses to obtain juice drops were elicited in response to visual conditioned stimuli (CS) in the affected visual field. Subsequent pharmacological inactivation of the superior colliculus (SC) suppressed the anticipatory licking. Concurrent single unit recordings indicated that DA responses reflecting the reward expectation could be recorded in the absence of V1, and that these responses were also suppressed by SC inactivation. These results indicate that the subcortical visual circuit can relay reward-predicting visual information to DA neurons and integrity of the SC is necessary for visually-elicited classically conditioned responses after V1 lesion. PMID- 28628008 TI - Basophil Histamine Release Induced by Amoxicilloyl-poly-L-lysine Compared With Amoxicillin in Patients With IgE-Mediated Allergic Reactions to Amoxicillin. AB - BACKGROUND: Amoxicillin (AX) is the beta-lactam most often involved in IgE mediated reactions. Diagnosis is based mainly on skin testing, although sensitivity is not optimal. We produced a new AX derivative, amoxicilloyl-poly-L lysine (APL), and analyzed its recognition of IgE using the passive histamine release test (pHRT). METHODS: The study population comprised patients (n=19) with confirmed AX allergy and specific IgE to AX and controls (n=10) with good tolerance to AX. pHRT was performed using "IgE-stripped" blood from a single donor that was sensitized in vitro by patient sera and incubated with AX or APL. Histamine release was determined and expressed as nanograms of histamine released per milliliter of blood. RESULTS: The clinical symptoms were anaphylaxis (n=9), urticaria (n=7), erythema (n=2), and nondefined immediate reactions (n=1). The median (IQR) time interval between reaction and study was 90 (60-240) days and between drug intake and development of symptoms 24 (10-60) minutes. The median sIgE level was 3.37 (0.95-5.89) kUA/L. The sensitivity of pHRT to APL was 79% and the specificity 100%, which were higher than data obtained with pHRT to AX (63% sensitivity and 90% specificity). There was a positive correlation between maximal histamine release levels obtained with AX and APL (r=0.63). CONCLUSIONS: In patients with immediate hypersensitivity reactions to AX, APL showed higher sensitivity and specificity than the culprit drug, AX, when tested in vitro by pHRT. This indicates that APL can improve the in vitro diagnostic accuracy of allergic reactions to AX. Further assessment of skin testing is necessary. PMID- 28628007 TI - Direct measurement of conformational strain energy in protofilaments curling outward from disassembling microtubule tips. AB - Disassembling microtubules can generate movement independently of motor enzymes, especially at kinetochores where they drive chromosome motility. A popular explanation is the 'conformational wave' model, in which protofilaments pull on the kinetochore as they curl outward from a disassembling tip. But whether protofilaments can work efficiently via this spring-like mechanism has been unclear. By modifying a previous assay to use recombinant tubulin and feedback controlled laser trapping, we directly demonstrate the spring-like elasticity of curling protofilaments. Measuring their mechanical work output suggests they carry ~25% of the energy of GTP hydrolysis as bending strain, enabling them to drive movement with efficiency similar to conventional motors. Surprisingly, a beta-tubulin mutant that dramatically slows disassembly has no effect on work output, indicating an uncoupling of disassembly speed from protofilament strain. These results show the wave mechanism can make a major contribution to kinetochore motility and establish a direct approach for measuring tubulin mechano-chemistry. PMID- 28628009 TI - [IMMUNOREHABILITOLOGY: A LOOK FROM THE SOURCES TO THE FUTURE. FROM IMMUNOTHERAPY TO PERSONALIZED TARGETED IMMUNOREHABLITATION]. AB - Development and introduction of modern clinical diagnostic tests (that allow to evaluate the functional system of immune homeostasis) into medical practice, a huge body of evidence on the leading role of the immune system in pathogenesis most acute and chronic diseases and even identification of specific nosological forms of immune-mediated diseases forced the scientists to search and develop new tools and techniques that have therapeutic effects on the impaired immune homeostasis and restore it to the normal state. The introduction of a new concept - immunorehabilitation - was an impetus for the accumulation of new knowledge and a catalyst for research in clinical immunology. It was Revaz Sepiashvili who breathed life into the concept of immunorehabilitation. He was lucky to be at its origi. He became not only the founder of the brand new scientific field - immunorehabilitation, but also the founder of a new medical science - immunorehablitology. In this paper, the author returns to the roots and recalls the way that medical science has gone before coming to understand immunorehablitology and tells readers about current successes and its development prospects. PMID- 28628010 TI - [THE MAIN STAGES OF THE PREPARATION OF VIABLE TUMOR CELLS OF BLADDER CANCER: FROM ISOLATION OF THE TUMOR MATERIAL TILL CRYOPRESERVATION OF CELL LINES]. AB - The development of personalized autologous dendritic cell anti-tumor vaccines (PDPW) against bladder cancer (BC) is a relevant issue that covers many aspects required for its standardization. The article presents personal experimental studies related to development of optimal conditions of transportation of biological material; temperature and temporary modes for the storage of the samples; the materials about the optimal method of disaggregation of the biomaterial; there has been shown a comparative analysis of different methods of tumor disaggregation; the selection of nutritious growth mediums and growth factors for urothelial carcinoma cells (UCC), the conditions of cryopreservation of tumor cells for maximum UCC viability, potentially suitable for creating PDPW against BC. PMID- 28628011 TI - [CRITERIA FOR SELECTION OF TUMOR CELLS AND PROSPECTS FOR SPECIFIC IMMUNOTHERAPY FOR BLADDER CANCER]. AB - Specific antitumor immunotherapy with autologous dendritic cell vaccines is one of the new approaches of modern medicine. For activation of dendritic cells highly immunogenic antigens are used, however optimal antigens in case of bladder cancer (BC) are still not researched. Cancer-testis antigens (CTA) are the most promising target in the context of creation of antitumor vaccines, because they are distinguished by pronounced immunogenicity, they are detected in different types of tumors and have limited pattern of expression in healthy tissues of grown-up organism. Regarding the level of mutational load, bladder cancer (BC) holds the third position among all malignant growths, which creates particular opportunities for use of immunotherapy in case of this disease. At chromosomal level most times the following cytogenetic anomalies specific for BC are detected: hyperploidies at 3, 7 and 17 chromosomes and deletion of 9p 21 locus. Besides, in the literature there is information about possible monosomy at 2, 3, 6, 8, 13, 14, 17 and frequent loss of Y chromosome in case of BC. Development of personified dendritic cell antitumor vaccines (PDAV) against bladder cancer (BC) is a relevant problem, which covers many aspects, necessary for its standardization. In particular, in case of cultivation of tumor cells under in vitro conditions their transformation goes at higher pace in comparison with in vivo tumor development. Moreover, the article presents the results of the study of molecular-genetic features of BC of tumor cultures in case of long-term cultivation, the level of expression of CTA (MAGE, NY-ESO-1, GAGE, BAGE) by urothelial carcinoma cells (UCC). There has been described the karyotypes of cells of urothelial low differentiated carcinoma of high malignant potential at various passages with prolonged cultivation, as well as the correlation between cytogenetic profile and expression of tumor-specific cancer-testis antigens has been identified. There have been developed two verified cell line cultures of muscle invasive and muscle-non-invasive urothelial carcinoma, that are potentially useful for the producing of tumor-associated vaccines against BC. PMID- 28628012 TI - CURATIVE TREATMENT OF COLORECTAL CANCER SOLITARY METASTASIS TO LIVER SUBCAPSULE BY PERCUTANEOUS US GUIDED RADIOFREQUENCY ABLATION USING HYDRODISSECTION (CASE REPORT). AB - Case report presents the successful treatment of solitary liver metastasis in a patient with resected colon cancer. A 39-year-old male underwent left hemicolectomy with colostomy formation followed by chemotherapy for a moderately differentiated adenocarcinoma of the colon. Two years later, a liver metastatic lesion was detected. Patient received chemotherapy; the mass remained stable in size, measuring up to 3 cm in diameter. Low-invasive percutaneous curative treatment by Radiofrequency ablation was conducted using hydrodissection by dielectric fluid intraperitoneal introduction for hydrodissection. The follow-up imaging showed the complete response to treatment. The ablation technique including peritoneal hydrodissection, described in paper avoids capsular breach and appears safe and technically effective in subcapsular lesions treatment. PMID- 28628014 TI - [SELECTION OF MINI-INVASIVE PALLIATIVE DECOMPRESSION METHOD IN PATIENTS WITH MALIGNANT OBSTRUCTION OF BILIARY DUCTS BASED ON THE STUDY OF BIOCHEMICAL BILE INDEXES]. AB - The article gives our own experience in the determination and study of additional laboratory criteria (total lipids, cholesterol, maximum and area chemiluminescence, antioxidant activity) at the local level (in bile) in patients with bile duct obstruction of malignant etiology. Constellation of metabolic disorders allowed to propose an original method for determining the lithogenicity of bile (integral indicator of lithogenicity). The obtained data made it possible to justify the need to assess the degree of metabolic disturbances in bile, on the basis of which it is possible to predict the risk of lithogenesis and the duration of stent operation, which in turn helped optimize the algorithm for choosing the method of bile ducts decompression aimed at preventing early obturation of endoprostheses. PMID- 28628013 TI - MODULATION OF ANTITUMOR IMMUNE RESPONSE IN MOUSE PROSTATE CANCER MODEL. AB - Aim of study - prostate cancer is second most common cancer in men worldwide, and fifth leading cause of death from cancer in men (6.6% of the total men deaths). Unfortunately, once cancer spreads outside of prostate, it becomes incurable. Androgen deprivation can provide some relief, but resistance will develop eventually, and at that time no effective treatment options are left to the patient. Therefore, the search of alternative treatment modalities is paramount. In this article we evaluated the role of epigenetic modifier 5-azacitidine (5 AzaC) and immunomodulator - Lenalidomide and their possible impact on the immune response in the murine prostate cancer model. We studied their impact on murine prostate cancer cells and on dendritic cells (DC), the most potent antigen presenting cells known. RM-1 is a murine prostate cancer cell line, resembling hormone-independent model, which is a lethal variant of this disease in humans. Dendritic cells were obtained from murine bone marrow. Cell proliferation assays were performed to evaluate the effect of 5-AzaC and lenalidomide on prostate cancer and DC. Flow cytometry, ELISA and real-time PCR was performed to evaluate the effect of these compounds on DC and prostate cancer cells. 5-AzaC treatment of RM-1 prostate cancer cells and DC resulted in the decreased proliferation for both, while lenalidomide had no effect. DC were treated with lenalidomide and the expression of surface markers MHC Class I, MHC Class II, CD80, CD86, CD 205, and CD40 was increased. Secretion of IL-12 and IL-15 by DC increased significantly with addition of 5-AzaC. There was also the change in the expression of endothelin receptors on DC, which can affect their function. 5-AzaC also resulted in the increased expression of cancer-testis antigen, P1A, by prostate cancer cells. Combination of epigenetic modifications and immunomodulation by 5-AzaC and lenalidomide should increase tumor immunogenicity and it enhanced DC function. Therefore, these compounds might have a role in the treatment of advanced prostate cancer. PMID- 28628015 TI - LATENT TUBERCULOSIS POTENTIAL BIOMARKERS: REACTIVATION OF INFECTION. AB - Tuberculosis continues to be one of the most important infectious causes of death worldwide. Despite substantial investments and progress made in expansion of directly observed therapy short course (DOTS) strategy, improved treatment completion rates and inadequate case detection remains a major obstacle for global control of Tuberculosis. The global case detection rate has increased from 28% to 60%. However, it is estimated that approximately 50% of patients with tuberculosis are still not diagnosed or treated appropriately. The current diagnostics tests (tuberculin skin test and interferon-gamma release assays) poorly predict who will develop active disease and the therapeutic options available are not optimal for the scale of the intervention that may be required. In this article, we discuss a basis of current understanding of latent TB and highlight their biomarkers. We conclude that the identification new biomarkers which can distinguish various stages within latency are urgently needed in order to prioritize those LTB individuals with the highest risk to reactivate the infection. PMID- 28628016 TI - [ANTIRETROVIRAL THERAPY AND THE RISK OF LIVER FIBROSIS PROGRESSION IN HIV/HCV COINFECTED PATIENTS]. AB - The purpose of the study is to determine the nature of the impact of antiretroviral therapy on the development of liver fibrosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), depending on the order of pathogens acquisition. The fact is that the HIV/HCV coinfection is one of the most common pathological conditions worldwide and liver disease is a major cause of death for these patients. We have previously described the phenomenon, according to which the order of viral pathogens acquisition in HIV/HCV coinfected patients has a significant impact on the degree of progression of liver fibrosis. Introduction to clinical practice of antiretroviral therapy greatly increased the life expectancy of HIV-infected patients, however, the impact of ART on a progressive course of liver fibrosis in HIV/HCV coinfected patients have not yet been definitively established. PMID- 28628017 TI - [COMBINED IMMUNOTHERAPY OF RECONDITIONAL CHRONIC NON-SPECIFIC VULVOVAGINITIS IN IMMUNOCOMPROMISED GIRLS]. AB - Nonspecific chronic vulvovaginitis (CNV) is often a clinical indicator of immune deficiency, especially in young girls. The established violations of the functioning of various parts of the immune system (IS) in this pathology dictate the need to include in the complex of immunomodulatory therapy. The developed program of combined immunotherapy for immunocompromised girls allows to reduce the severity and duration of exacerbation of CNV, their frequency against the background of a significant reduction in the incidence of ARVI. Positive clinical effects were observed against the background of the restoration of the functioning of the IS. A protective effect was obtained (observation in a catamnesis for 1 year) - the duration of a clinically safe period increased from 6 to 11-11,5 months per year. PMID- 28628018 TI - AUTOIMMUNE LIMBIC ENCEPHALITIS (CASE REPORTS). AB - Limbic encephalitis (LE) is an autoimmune or paraneoplastic disease that affects the medial temporal lobes. The patient will usually present with cognitive impairment, psychiatric changes, and seizures. Autoimmune limbic encephalitis (LE) is a challenging diagnosis as it is not always included in the typical paraneoplastic/autoimmune panels. Anti-GAD antibodies are associated with various disease including type I diabetes mellitus, various autoimmune processes, some neoplastic and infectious diseases. Thus, it is not as specific as some of the antibodies causing LE. We are presenting two cases of isolated anti-GAD antibody associated limbic encephalitis. Both patients were adults who developed status epilepticus and refractory seizures, cognitive impairment and mood instability. Patients' cerebrospinal fluid (CSF) and serum anti- GAD antibodies were elevated and after treatment returned to normal reference range. The diagnosis for both patients was delayed (by over one month following hospitalization), both patients required prolonged hospitalization and rehabilitation after discharge. Patient's condition improved only after immunotherapy, but required several antiepileptic drugs for seizure control. The diagnosis was more difficult in the first patient, who had numerous other medical problems including ESRD and moderately severe microvascular changes on brain imaging. In this particular patient, it was hard to appreciate any signal changes on MRI in the mesial temporal lobes given the underlying white matter disease. We recommend inclusion of anti- GAD antibody in the paraneoplastic/encephalopathy panels in order to decrease missed cases of this important cause of LE as well as to hasten the diagnosis. This is a treatable disease, and timely diagnosis is imperative to improve outcomes. PMID- 28628020 TI - [STUDY OF CYTOTOXIC ACTIVITY OF METHANOL EXTRACTS OF THE ENDEMIC PLANT OF THE GENUS ERYSIMUM OF THE ADJARIAN FLORISTIC DISTRICT OF GEORGIA]. AB - According to the results, investigated methanolic extracts of endemic plant from Adjarian floristic region of Georgia do not have specific cytotoxicity against the cell lines of breast adenocarcinoma MCF-7 human, which is typical, e.g., for plant pigment curcumin. At the same time, the high specific cytotoxicity of 2 and 3 fractions towards keratinocytes gives reason for considering endemic plant extracts, of Adjarian floristic region of Georgia, as a potential pharmacological means for topical treatment of pathologies caused by increased proliferation of keratinocytes, such as psoriasis. PMID- 28628019 TI - [STUDY OF LIPIDS OF THE FRUITS OF USUAL HAZEL-NUT CORYLUS AVELLANA L., GROWING IN GEORGIA]. AB - The aim of this investigation was the study of lipids from the fruits of usual hazel-nut Corylus avellana L, growing in Georgia. Ripe fruits was collected in the West Georgia, just in Imereti. From the powdered fruits was obtained the sums of neutral and pollar lipids. Qualitatively there were established classes entered in them. By using High performance liquid chromatography qualitatively and quantitatively were identified ten fatty acids, which time of deduction hesitate from 4,01 min to 13,00 min. By the analyses there were determined unsaturated fatty acids C12:0 to C24:0. The content of unsaturated fatty acids considerably is distinquished from the content of the oil from the hazel-nut, growing in the other eco-geographical conditions. In the oil of the hazel-nut growing in Georgia content of hexadecanoic acid is by far exceled (surpassed) than of the oil from the nut growing in the other natural conditions. In the other matters dominant acid is octadecanoic acid. The oil from the fruits of hazel-nut content physiologically active compounds, which desirably correlation is interesting not only for receiving (obtaining) cosmetic means, not is important for usage in practical medicine. PMID- 28628021 TI - CORRELATION BETWEEN SPIROMETRY DATES AND SPECIAL ALLERGEN- SPECIFIC IGE IN PATIENTS WITH BRONCHIAL ASTHMA IN WEST GEORGIA. AB - The study aimed to establish correlation between airway obstruction and specific IgE specificity, managing future treatment in the patients with bronchial asthma, among the population of west Georgia. In the study have been involved 56 patients (among them 24 males and 32 females) of different ages, with diagnostic bronchial asthma (according to GINA recommendation). On the ground of the aim the study included the following steps of allegro-diagnostics: I step - Computerized spirometry by apparatus ,,SPIROLAB 3". II step - To detect allergenization degree, total serum IgE levels, specific IgE and concentration of Phadiatop, using modern automated system - "Immuno CAP 100", were estimated in the patients. III step- future treatment recommendations. All 56 patients were undergone the spirometry measurement. Our results show that of 56 patient 21 (38%) had very severe obstruction by spiromatry: Pretest: FEV 1 - 28%; FEF-45%; FEV1/FVC ratio 55% on average. Post test: significant bronchodilatation was revealed FEV1> +12%( >200 mL) after the inhalation of four puffs of a short - acting beta2 sympathomimetic agent, e.r., 400 ug of salbutamol. In 19 (33%) patients severe bronchoobstruction was established. By spiromometry was revealed: Pre test: FEV 1 - 42%; FEF-55%; FEV1/FVC ratio -67% on average. Post test: significant bronchodilatation was revealed FEV1> +12%( >200 mL) In 14 (25%) patients moderate bronchoobstruction was diagnosed, the spiromatry results were. Pretest: FEV 1 - 52%; FEF-65%; FEV1/FVC ratio - 67% on average. Post test: It was revealed significant bronchodilatation FEV1> +12%( >200 mL). Only in 2 (4%) patients were diagnosed the normal spiromatry. In the patients with bronchial asthma of a specific positivity of specific IgE to the weeds (Wx2) - ambrosia, plantain, clasp/tarragon, atriplex - in 23 (53%) on average; tree dust (Tx9) - alder, lactarius piperatus, nuts, oak, willow - 11 (19%); and cereals (Gx1) - festuca pratensis, lolium temulentum, timoti grass, poa - 9 (16%); Mx2 -Penicillium notatum, Cladosporium herbarum, Aspergillus fumigatus, Candida albicans, Alternaria alternate- 15 (21%) was revealed, only in 5 (9%) patients we cannot established the allergy specific IgE. It was established the correlation between spiromatry dates and special allergen specific IgE in patient with bronchial asthma. The latter is of great importance for providing the effective and safe allegro-specific immunotherapy (ASIT) and successful preventive measures. PMID- 28628022 TI - [ESTIMATION OF PARAMETERS OF EXTERNAL RESPIRATION OF STUDENTS]. AB - The close relationship of the respiratory system with other systems and organs, its significant participation in the processes of metabolism once again proves the exceptional role of the study of respiratory function. On the other hand, the health of students is one of the most important social tasks of modern society. The aim of the study was detection of parameters of external respiration in students of Georgia. 235 students 18 to 21 of ages, were involved in the study, who underwent computer spirometry with Spiro lab 3 to achieve the aim of study. The research among Georgian students has shown the external respiration function with the following characteristics: Pretest (females n=103) - VC=109.5+/-4.5%; FVC=99+/-5.25%; FEV1=104+/-3.60%; FEV1/VC=114.5+/-7.5%; PEF=74.5+/-0.79%; MEF 25% 75%=84+/-7,0%. Males (n=132) VC=99+/-5.25%; FVC=98+/-10.20%; FEV1=100+/-8.38%; FEV1/VC=104+/-1.41%; PEF=90+/-2.16; MEF 25%-75%=98+/-7.0%. Therefore, based on the research of Georgian students on computer spirometry external respiration function revealed the peculiarities of physiological parameters according to gender. The study, showed the need for the similar study among the variety of population in all age categories. It is really an actual issue for modern clinical medicine. PMID- 28628023 TI - [RAGWEED ALLERGY IN THE SOUTH OF RUSSIA - IN THE CHECHEN REPUBLIC]. AB - Allergy to ragweed pollen and other weeds is a global problem due to the rapid spread of these grasses around the world. In addition, pollen of short ragweed (Ambrosia, Amb) and mugwort (Artemisia, Art) - one of the main causes of respiratory allergy - seasonal allergic rhinoconjunctivitis (hay fever) with/without bronchial asthma patients living in the South of Russia. Epidemiological studies on the prevalence of Allergy to Amb and Art among patients living in Chechen Republic, absent. Aim - of this retrospective study was to investigate the prevalence of sensitization to weed pollen in patients of Chechnya. We surveyed allergy (skin prick tests with 13 inhalant allergens) from 845 patients aged 4-68 years, in Urus-Martan for the period 2013-2016 yrs. Polisensitization was defined as the presence of positive skin tests to 2 or more extracts of different groups of allergens. ~26% and 21% of patients in the Chechen Republic have an allergy to Amb and Art, respectively. Further studies at the molecular level will help to establish the geographical variation of the sensitization profile to the major component of Amb and Art, which could have clinical significance in the proper selection of specific immunotherapy. PMID- 28628024 TI - [EVALUATION OF DYNAMIC TELOMERE LENGTH SHORTENING OF LYMPHOCYTES IN IMMUNOCOMPROMISED CHILDREN WITH CHRONIC DISEASES OF THE RESPIRATORY]. AB - Nowadays it is common to observe the growth of viral-viral and viral-bacterial co infections in children of different ages, due to dysfunction of lymphocytes (DL), which can be connected with the process of the accelerated shortening of the end structures of chromosomal telomeres, telomere length changes are described in lymphocytes of children with chronic mono-infections. The conducted study has shown the shortening of telomere lymphocytes in children with CDRT seropositive for mixed-herpes viral infections (herpes simplex virus, virus, Epstein-Barr virus and cytomegalovirus in various combinations) and for bacterial co infections - Chlamydia trachomatis and (or) Mycoplasma pneumoniae. The use of regression analysis and attribute analysis (in percent) made possible to neutralize age-groups differences of seropositive and seronegative children. Thus showed that children, who suffer from chronic diseases of the respiratory tract associated with mixed-herpes viral and bacterial co-infections, have more pronounced telomere shortening of lymphocytes than seronegative children of the same age. PMID- 28628025 TI - [PHENOTYPE FACILITIES OF LYMPHOCYTES IN HEMORRHAGIC FEVER WITH RENAL SYNDROME]. AB - Hemorrhagic fever with renal syndrome (HFRS) is a feral herd disease caused by hantaviruses. HERS may be severe and its manifestations include acute renal failure, intoxication, hemorrhages and pain syndrome. Hantaviruses as pathogen of HFRS wield considerable influence on the character of the immune response, in particular, is capable of lymphocytic cytolysis suppressing. It was found that cytotoxic T lymphocytes along with NKT and CD8 + regulatory T cells play the key role in the immune mechanisms of hemorrhagic fever with renal syndrome. This reduces of the activation of lymphocytes with cytotoxic properties are closely related to the expression of NKG2D lectin receptors. Immunological signs of heavy currents HFRS can serve as a lack of growth on the part of natural killer and a significant drop in the number of b-lymphocytes in the blood, correlative related to the increase in CD8 + regulatory T cells. PMID- 28628026 TI - [DYNAMICS OF OCCURRENCE AND REGRESSION OF NEUTROPHIL EXTRACELLULAR TRAPS IN THE EXPERIMENTAL MODEL OF THE WOUND INFECTIOUS-INFLAMMATORY PROCESS]. AB - The dynamics of the appearance and regression of neutrophilic extracellular traps (NETs) in the experimental model of the wound infectious-inflammatory process that was caused by infection of open wounds by microbes surrounding environment, was studied. It was established that on the second day from the start of the experiment a significant number of mature neutrophilic granulocytes show the ability to form NETs. The number of NETs was reached its maximum by the 2th and 4th days from the beginning of the experiment, that was associated with maximum occurrence of symptoms of inflammation in the wound. The regression of the wound inflammatory process was associated with decreasing of the number of NETs to 7th day and the complete disappearance of NETs to 14th day of the experiment, which coincided with the healing of wounds. PMID- 28628027 TI - Evolution of the topologically protected surface states in superconductor beta Bi2Pd from the three-dimensional to the two-dimensional limit. AB - The recent discovery of topologically protected surface states in the noncentrosymmetric alpha-BiPd and the centrosymmetric beta-[Formula: see text]Pd has renewed the interest in the Bi-Pd family of superconductors. We employ first principles calculations to investigate the electronic structure and topological features of beta-[Formula: see text]Pd, in bulk and in thin films of various thicknesses. We find that films of nine or more triple layers could harbor topological surface states with Dirac- and Rashba-like band dispersion. PMID- 28628028 TI - Electron transport in stepped Bi2Se3 thin films. AB - We analyse the electron transport in a 16 quintuple layer thick stepped Bi2Se3 film grown on Si(1 1 1) by means of scanning tunnelling potentiometry (STP) and multi-point probe measurements. Scanning tunnelling microscopy images reveal that the local structure of the Bi2Se3 film is dominated by terrace steps and domain boundaries. From a microscopic study on the nm scale by STP, we find a mostly linear gradient of the voltage on the Bi2Se3 terraces which is interrupted by voltage drops at the position of the domain boundaries. The voltage drops indicate that the domain boundaries are scatterers for the electron transport. Macroscopic resistance measurements (2PP and in-line 4PP measurement) on the um scale support the microscopic results. An additional rotational square 4PP measurement shows an electrical anisotropy of the sheet conductance parallel and perpendicular to the Bi2Se3 steps of about 10%. This is a result of the anisotropic step distribution at the stepped Bi2Se3 surface while domain boundaries are distributed isotropically. The determined value of the conductivity of the Bi2Se3 steps of about 1000 S cm-1 verifies the value of an earlier STP study. PMID- 28628029 TI - Thermopower and thermal conductivity in the Weyl semimetal NbP. AB - The Weyl semimetal NbP exhibits an extremely large magnetoresistance and an ultra high mobility. The large magnetoresistance originates from a combination of the nearly perfect compensation between electron- and hole-type charge carriers and the high mobility, which is relevant to the topological band structure. In this work we report on temperature- and field-dependent thermopower and thermal conductivity experiments on NbP. Additionally, we carried out complementary heat capacity, magnetization, and electrical resistivity measurements. We found a giant adiabatic magnetothermopower with a maximum of [Formula: see text] at 50 K in a field of 9 T. Such large effects have been observed rarely in bulk materials. We further observe pronounced quantum oscillations in both thermal conductivity and thermopower. The obtained frequencies compare well with our heat capacity and magnetization data. PMID- 28628030 TI - A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve. AB - OBJECTIVE: Neural reflexes regulate immune responses and homeostasis. Advances in bioelectronic medicine indicate that electrical stimulation of the vagus nerve can be used to treat inflammatory disease, yet the understanding of neural signals that regulate inflammation is incomplete. Current interfaces with the vagus nerve do not permit effective chronic stimulation or recording in mouse models, which is vital to studying the molecular and neurophysiological mechanisms that control inflammation homeostasis in health and disease. We developed an implantable, dual purpose, multi-channel, flexible 'microelectrode' array, for recording and stimulation of the mouse vagus nerve. APPROACH: The array was microfabricated on an 8 um layer of highly biocompatible parylene configured with 16 sites. The microelectrode was evaluated by studying the recording and stimulation performance. Mice were chronically implanted with devices for up to 12 weeks. MAIN RESULTS: Using the microelectrode in vivo, high fidelity signals were recorded during physiological challenges (e.g potassium chloride and interleukin-1beta), and electrical stimulation of the vagus nerve produced the expected significant reduction of blood levels of tumor necrosis factor (TNF) in endotoxemia. Inflammatory cell infiltration at the microelectrode 12 weeks of implantation was limited according to radial distribution analysis of inflammatory cells. SIGNIFICANCE: This novel device provides an important step towards a viable chronic interface for cervical vagus nerve stimulation and recording in mice. PMID- 28628031 TI - Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis. AB - The mechanisms that regulate cell death and inflammation play an important role in liver disease and cancer. Receptor-interacting protein kinase 1 (RIPK1) induces apoptosis and necroptosis via kinase-dependent mechanisms and exhibits kinase-independent prosurvival and proinflammatory functions. Here, we have used genetic mouse models to study the role of RIPK1 in liver homeostasis, injury, and cancer. While ablating either RIPK1 or RelA in liver parenchymal cells (LPCs) did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatocyte apoptosis and developed spontaneous chronic liver disease and cancer that were independent of TNF receptor 1 (TNFR1) signaling. In contrast, mice with LPC-specific knockout of Ripk1 showed reduced diethylnitrosamine-induced (DEN-induced) liver tumorigenesis that correlated with increased DEN-induced hepatocyte apoptosis. Lack of RIPK1 kinase activity did not inhibit DEN-induced liver tumor formation, showing that kinase-independent functions of RIPK1 promote DEN-induced hepatocarcinogenesis. Moreover, mice lacking both RIPK1 and TNFR1 in LPCs displayed normal tumor formation in response to DEN, demonstrating that RIPK1 deficiency decreases DEN-induced liver tumor formation in a TNFR1-dependent manner. Therefore, these findings indicate that RIPK1 cooperates with NF-kappaB signaling to prevent TNFR1-independent hepatocyte apoptosis and the development of chronic liver disease and cancer, but acts downstream of TNFR1 signaling to promote DEN-induced liver tumorigenesis. PMID- 28628032 TI - Osteocyte-specific WNT1 regulates osteoblast function during bone homeostasis. AB - Mutations in WNT1 cause osteogenesis imperfecta (OI) and early-onset osteoporosis, identifying it as a key Wnt ligand in human bone homeostasis. However, how and where WNT1 acts in bone are unclear. To address this mechanism, we generated late-osteoblast-specific and osteocyte-specific WNT1 loss- and gain of-function mouse models. Deletion of Wnt1 in osteocytes resulted in low bone mass with spontaneous fractures similar to that observed in OI patients. Conversely, Wnt1 overexpression from osteocytes stimulated bone formation by increasing osteoblast number and activity, which was due in part to activation of mTORC1 signaling. While antiresorptive therapy is the mainstay of OI treatment, it has limited efficacy in WNT1-related OI. In this study, anti-sclerostin antibody (Scl-Ab) treatment effectively improved bone mass and dramatically decreased fracture rate in swaying mice, a model of global Wnt1 loss. Collectively, our data suggest that WNT1-related OI and osteoporosis are caused in part by decreased mTORC1-dependent osteoblast function resulting from loss of WNT1 signaling in osteocytes. As such, this work identifies an anabolic function of osteocytes as a source of Wnt in bone development and homoeostasis, complementing their known function as targets of Wnt signaling in regulating osteoclastogenesis. Finally, this study suggests that Scl-Ab is an effective genotype-specific treatment option for WNT1-related OI and osteoporosis. PMID- 28628033 TI - Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis. AB - BACKGROUND: The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD cirrhosis. METHODS: This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). RESULTS: The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8-126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1-146.1, P = 0.0438). CONCLUSION: Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. TRIAL REGISTRATION: UCSD IRB: 140084. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH. PMID- 28628034 TI - Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells. AB - HIV-1 causes a chronic, incurable disease due to its persistence in CD4+ T cells that contain replication-competent provirus, but exhibit little or no active viral gene expression and effectively resist combination antiretroviral therapy (cART). These latently infected T cells represent an extremely small proportion of all circulating CD4+ T cells but possess a remarkable long-term stability and typically persist throughout life, for reasons that are not fully understood. Here we performed massive single-genome, near-full-length next-generation sequencing of HIV-1 DNA derived from unfractionated peripheral blood mononuclear cells, ex vivo-isolated CD4+ T cells, and subsets of functionally polarized memory CD4+ T cells. This approach identified multiple sets of independent, near full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4+ T cells harboring intact HIV 1. Intact, near-full-genome HIV-1 DNA sequences that were derived from such clonally expanded CD4+ T cells constituted 62% of all analyzed genome-intact sequences in memory CD4 T cells, were preferentially observed in Th1-polarized cells, were longitudinally detected over a duration of up to 5 years, and were fully replication- and infection-competent. Together, these data suggest that clonal proliferation of Th1-polarized CD4+ T cells encoding for intact HIV-1 represents a driving force for stabilizing the pool of latently infected CD4+ T cells. PMID- 28628035 TI - The brains of the bones: how osteocytes use WNT1 to control bone formation. AB - WNT proteins drive the development and maintenance of many tissues, including bone. It is less clear which of the many WNT proteins act on bone or where these WNTs act in the skeleton; however, loss-of-function mutations in WNT1 cause bone fragility in children and adults. In this issue of the JCI, Joeng and colleagues demonstrate that bone formation is under the control of WNT1 produced by osteocytes, the cells that reside deep in the bone matrix and form dendritic networks. The implication of WNT1 in the control of bone formation identifies a potential new target for the treatment of low bone mass disorders, such as osteoporosis. PMID- 28628036 TI - Arcuate neuropeptide Y inhibits sympathetic nerve activity via multiple neuropathways. AB - Obesity increases sympathetic nerve activity (SNA) via activation of proopiomelanocortin neurons in the arcuate nucleus (ArcN), and this action requires simultaneous withdrawal of tonic neuropeptide Y (NPY) sympathoinhibition. However, the sites and neurocircuitry by which NPY decreases SNA are unclear. Here, using designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate or inhibit ArcN NPY neurons expressing agouti-related peptide (AgRP) in mice, we have demonstrated that this neuronal population tonically suppresses splanchnic SNA (SSNA), arterial pressure, and heart rate via projections to the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH). First, we found that ArcN NPY/AgRP fibers closely appose PVN and DMH presympathetic neurons. Second, nanoinjections of NPY or an NPY receptor Y1 (NPY1R) antagonist into PVN or DMH decreased or increased SSNA, respectively. Third, blockade of DMH NPY1R reversed the sympathoinhibition elicited by selective, DREADD-mediated activation of ArcN NPY/AgRP neurons. Finally, stimulation of ArcN NPY/AgRP terminal fields in the PVN and DMH decreased SSNA. Considering that chronic obesity decreases ArcN NPY content, we propose that the ArcN NPY neuropathway to the PVN and DMH is pivotal in obesity-induced elevations in SNA. PMID- 28628037 TI - Alloimmune T cells in transplantation. AB - Alloimmune T cells are central mediators of rejection and graft-versus-host disease in both solid organ and hematopoietic stem cell transplantation. Unique among immune responses in terms of its strength and diversity, the T cell alloresponse reflects extensive genetic polymorphisms between allogeneic donors and recipients, most prominently within the major histocompatibility complex (MHC), which encodes human leukocyte antigens (HLAs) in humans. The repertoire of alloreactive T cell clones is distinct for every donor-recipient pair and includes potentially thousands of unique HLA/peptide specificities. The extraordinary magnitude of the primary alloresponse and diversity of the T cell population mediating it have presented technical challenges to its study in humans. High-throughput T cell receptor sequencing approaches have opened up new possibilities for tackling many fundamental questions about this important immunologic phenomenon. PMID- 28628038 TI - CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease. AB - Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy. Here, we report that permanent suppression of endogenous mHTT expression in the striatum of mHTT expressing mice (HD140Q-knockin mice) using CRISPR/Cas9-mediated inactivation effectively depleted HTT aggregates and attenuated early neuropathology. The reduction of mHTT expression in striatal neuronal cells in adult HD140Q-knockin mice did not affect viability, but alleviated motor deficits. Our studies suggest that non-allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion-mediated neuronal toxicity in the adult brain. PMID- 28628039 TI - ChREBP refines the hepatic response to fructose to protect the liver from injury. AB - Overconsumption of fructose and other sugars has been linked to nonalcoholic fatty liver disease (NAFLD); however, the sugar-associated effects that lead to disease are poorly defined. In this issue of the JCI, Zhang and colleagues show that the carbohydrate response element-binding protein (ChREBP) coordinates an adaptive response to a high-fructose diet in mice and that loss of this transcription factor leads to hepatic inflammation and early signs of fibrosis. Intriguingly, ChREBP-dependent effects were due to an exaggerated activation of the proapoptotic arms of the endoplasmic reticulum stress response that is probably secondary to inappropriate derepression of cholesterol biosynthesis. These findings suggest that a previously unknown link exists between ChREBP and the regulation of cholesterol synthesis that affects liver injury. PMID- 28628040 TI - Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity. AB - Epidemiologic and animal studies implicate overconsumption of fructose in the development of nonalcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remain largely unknown. Here, we have presented evidence supporting the essential function of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP) in mediating adaptive responses to fructose and protecting against fructose-induced hepatotoxicity. In WT mice, a high-fructose diet (HFrD) activated hepatic lipogenesis in a ChREBP-dependent manner; however, in Chrebp-KO mice, a HFrD induced steatohepatitis. In Chrebp-KO mouse livers, a HFrD reduced levels of molecular chaperones and activated the C/EBP homologous protein-dependent (CHOP dependent) unfolded protein response, whereas administration of a chemical chaperone or Chop shRNA rescued liver injury. Elevated expression levels of cholesterol biosynthesis genes in HFrD-fed Chrebp-KO livers were paralleled by an increased nuclear abundance of sterol regulatory element-binding protein 2 (SREBP2). Atorvastatin-mediated inhibition of hepatic cholesterol biosynthesis or depletion of hepatic Srebp2 reversed fructose-induced liver injury in Chrebp-KO mice. Mechanistically, we determined that ChREBP binds to nuclear SREBP2 to promote its ubiquitination and destabilization in cultured cells. Therefore, our findings demonstrate that ChREBP provides hepatoprotection against a HFrD by preventing overactivation of cholesterol biosynthesis and the subsequent CHOP mediated, proapoptotic unfolded protein response. Our findings also identified a role for ChREBP in regulating SREBP2-dependent cholesterol metabolism. PMID- 28628041 TI - HIV persistence: clonal expansion of cells in the latent reservoir. AB - While antiretroviral therapy (ART) can reduce HIV-1 to undetectable levels, the virus generally reappears if treatment is stopped. Resurgence of the virus is due to the reactivation of T cells harboring latent integrated provirus, and recent studies indicate that proliferation of these latently infected cells helps maintain the HIV-1 reservoir. In this issue of the JCI, Lee et al. evaluated CD4+ T cell subsets to determine whether certain populations are more likely to harbor full-length, replication-competent provirus. The authors identified an enrichment of clonally expanded Th1 cells containing intact HIV-1 proviruses, suggesting that this polarized subset contributes to the persistence of the reservoir. Strategies to target these provirus-harboring cells need to be considered for future therapies aimed toward HIV-1 cure. PMID- 28628042 TI - A therapeutic T cell receptor mimic antibody targets tumor-associated PRAME peptide/HLA-I antigens. AB - Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen that is expressed in many cancers and leukemias. In healthy tissue, PRAME expression is limited to the testes and ovaries, making it a highly attractive cancer target. PRAME is an intracellular protein that cannot currently be drugged. After proteasomal processing, the PRAME300-309 peptide ALYVDSLFFL (ALY) is presented in the context of human leukocyte antigen HLA-A*02:01 molecules for recognition by the T cell receptor (TCR) of cytotoxic T cells. Here, we have described Pr20, a TCR mimic (TCRm) human IgG1 antibody that recognizes the cell surface ALY peptide/HLA-A2 complex. Pr20 is an immunological tool and potential therapeutic agent. Pr20 bound to PRAME+HLA-A2+ cancers. An afucosylated Fc form (Pr20M) directed antibody-dependent cellular cytotoxicity against PRAME+HLA-A2+ leukemia cells and was therapeutically effective against mouse xenograft models of human leukemia. In some tumors, Pr20 binding markedly increased upon IFN-gamma treatment, mediated by induction of the immunoproteasome catalytic subunit beta5i. The immunoproteasome reduced internal destructive cleavages within the ALY epitope compared with the constitutive proteasome. The data provide rationale for developing TCRm antibodies as therapeutic agents for cancer, offer mechanistic insight on proteasomal regulation of tumor-associated peptide/HLA antigen complexes, and yield possible therapeutic solutions to target antigens with ultra-low surface presentation. PMID- 28628044 TI - Perioperative Auto-titrated Continuous Positive Airway Pressure Treatment in Surgical Patients with Obstructive Sleep Apnea: A Randomized Controlled Trial: Erratum. PMID- 28628043 TI - Immunotherapy for transplantation-associated viral infections. AB - Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections following allogeneic hematopoietic stem cell transplantation (HSCT) are a major cause of morbidity and mortality. Early clinical trials demonstrate that adoptive transfer of donor-derived virus-specific T cells to restore virus-specific immunity is an effective strategy to control CMV and EBV infection after HSCT, conferring protection in 70%-90% of patients. The field has evolved rapidly to develop solutions to some of the manufacturing challenges identified in early clinical studies, such as prolonged in vitro culture, optimization of the purity of the virus-specific T cell product, the potential limitations of targeting a single viral antigen, and how to manage the patient with a virus-naive donor. This Review both discusses the seminal early studies and explores cutting-edge novel technologies that broaden the feasibility of and the scope for delivering virus specific T cells to patients after HSCT. PMID- 28628046 TI - Exploring Organizational Smoking Policies and Employee Vaping Behavior. AB - OBJECTIVES: Cigarette consumption has become global threat to both smokers and organizations. However, little is known about organizational smoking and vaping policies, and their influence to employees' smoking and vaping behavior. METHODS: We collected data from 456 employed smokers, vapers, and/or dual users. Smoking and/or vaping behavior, along with perceived organizational smoking/vaping policies were examined. RESULTS: Vapers reported perceiving more stringent smoking policy, while vapers who reported having workplace vaping policies perceived having generally more stringent vaping policy. Most smokers and vapers are well informed about smoking policy; however, a considerable portion of them do not have a good understanding about organizational vaping policy. CONCLUSIONS: Organizations should not consider smoking and vaping to be the same when setting policy. Employers should ensure that organizational vaping policies are present and clear to all employees. PMID- 28628045 TI - Cardio-Respiratory Effects of Air Pollution in a Panel Study of Outdoor Physical Activity and Health in Rural Older Adults. AB - OBJECTIVE: To examine cardio-respiratory effects of air pollution in rural older adults exercising outdoors. METHODS: Adults 55 and over completed measurements of blood pressure, peak expiratory flow and oximetry daily, and of heart rate variability, endothelial function, spirometry, fraction of exhaled nitric oxide and urinary oxidative stress markers weekly, before and after outdoor exercise, for 10 weeks. Data were analyzed using linear mixed effect models. RESULTS: Pooled estimates combining 2013 (n = 36 participants) and 2014 (n = 41) indicated that an interquartile increase in the air quality health index (AQHI) was associated with a significant (P < 0.05) increase in heart rate (2.1%) and significant decreases in high frequency power (-19.1%), root mean square of successive differences (-9.5%), and reactive hyperemia index (-6.5%). CONCLUSIONS: We observed acute subclinical adverse effects of air pollution in rural older adults exercising outdoors. PMID- 28628047 TI - Improving Body Composition May Reduce the Immune and Inflammatory Responses of Firefighters Working in the Heat. AB - OBJECTIVE: We hypothesized that different body composition and fitness of firefighters would affect immune and inflammatory activity after working in the heat. METHODS: Forty-two firefighters worked in the heat (100 +/- 5 degrees C). Changes in leukocytes, platelets, tumor necrosis factor (TNF-alpha), and C reactive protein (CRP) were analyzed based on body composition (DXA) and aerobic fitness (VO2max). RESULTS: Higher baseline leukocytes were observed for high body fat (P = 0.002) and low lean mass (P = 0.023) resulting in the highest peak values. Additionally, significantly lower values for TNF-alpha were observed with high lean mass at all time points. Platelets were unaffected by fitness or body composition. Furthermore, body mass index (BMI) and VO2max played no role. CONCLUSIONS: Minimizing body fat and increasing lean mass may reduce immune and inflammatory activity of firefighters in the heat. PMID- 28628048 TI - Impact of Daily Rest Period on Resting Blood Pressure and Fatigue: A One-Month Observational Study of Daytime Employees. AB - OBJECTIVE: We aimed to examine the effects of the daily rest period (DRP) on resting blood pressure (BP) and fatigue and determine the optimal DRP for daytime workers. METHODS: Fifty-four daytime employees participated in a 1-month observational study. BP was measured thrice at the workplace. Employees underwent a pre- and post-survey to determine the usual DRP and assess subjective health outcomes. To determine the optimal DRP, DRP criteria were set as 11, 12, 13, and 14 hours. RESULTS: Workers with a shorter DRP had high diastolic BP and fatigue. Diastolic BP was higher in the short group than in the long group for the 14-hour DRP criteria alone. CONCLUSIONS: Shorter DRP was associated with high diastolic BP. We recommend a longer DRP (>=14 hours) for improving workers' cardiovascular health. PMID- 28628049 TI - Early Access to Physical Therapy and Specialty Care Management for American Workers With Musculoskeletal Injuries. AB - OBJECTIVE: The aim of this study was to investigate the effect of very early access to physical therapy and specialty care management in a workers' compensation population. METHODS: A prospective pilot (n = 75) was conducted from 2012 to 2013 in which injured workers with musculoskeletal complaints received physical therapy and started care management during their initial occupational medicine clinic visit. Two retrospective comparator groups with workers' compensation claims from 2009 and 2012 were included in this study. RESULTS: When comparing 2009 data with the 2012 to 2013 prospective pilot study, statistically significant differences were noted in favor of the prospective pilot for total costs per claim, cost of indemnity, number of therapy visits, and time to access physical therapy. When compared with the 2012 nonpilot cohort, differences were not statistically significant. CONCLUSIONS: Expedited access to physical therapy and care management can reduce duration of care, cost of claims, and therapy visits. PMID- 28628050 TI - Arizona Hospital Discharge and Emergency Department Database: Implications for Occupational Health Surveillance. AB - OBJECTIVES: The objective of the project was to identify trends in emergency department visits and inpatient admissions for occupational injury and disease frequency and describe the financial impact from specific clinical groups known to have occupational risk factors. METHODS: Workers compensation cases among 19 million records in the Arizona statewide hospital discharge database (HDD) were assessed for seven clinical groups from 2008 to 2014, including back, cardiac, carpal tunnel syndrome, heat-related, psychiatric, pulmonary, and trauma. RESULTS: Cases with cardiac, psychiatric, and pulmonary diagnoses were both frequent and expensive. Although incidence was generally stable, charges per case rose significantly over the time period. IMPLICATIONS: Inpatient and emergency department records provide valuable data that complement other surveillance approaches for both occupational illnesses and injuries. Tracking charge as well as incidence data is useful. PMID- 28628053 TI - Heart Rate and Blood Pressure Responses to Gear Weight Under a Controlled Workload. AB - OBJECTIVE: To compare the effects of personal protective equipment (PPE) weight on blood pressure (BP) and heart rate (HR), between volunteer firefighters (FF) and athletes. METHODS: Athletes and FF were matched by body size and came to the lab twice for two treadmill tests. The "Regular" test was completed in normal fitness clothing, and PPE test was completed in full structural PPE with monitoring of HR assessment every minute and BP each stage. RESULTS: In the FF cohort, all submaximal HR and BP levels were different. HRmax and VO2max were also different (all P < 0.05). In athletes, HRmax was higher in Regular test than PPE. CONCLUSIONS: Future research should examine the effect of different PPE weights on HR and BP responses. PMID- 28628054 TI - Personal and Workplace Environmental Factors Associated With Reduced Worker Productivity Among Older Workers With Chronic Knee Pain: A Cross-Sectional Survey. AB - OBJECTIVES: The aim of this study was to explore personal and workplace environmental factors as predictors of reduced worker productivity among older workers with chronic knee pain. METHODS: A questionnaire-based survey was conducted among 129 older workers who had participated in a randomized clinical trial evaluating dietary supplements. Multivariable analyses were used to explore predictors of reduced work productivity among older workers with chronic knee pain. RESULTS: The likelihood of presenteeism was higher in those reporting knee pain (>=3/10) or problems with other joints, and lower in those reporting job insecurity. The likelihood of work transitions was higher in people reporting knee pain (>=3/10), a high comorbidity score or low coworker support, and lower in those having an occupation involving sitting more than 30% of the day. CONCLUSION: Allowing access to sitting and promoting positive affiliations between coworkers are likely to provide an enabling workplace environment for older workers with chronic knee pain. PMID- 28628056 TI - Time for Self-Care: Downtime Recovery as a Buffer of Work and Home/Family Time Pressures. AB - OBJECTIVE: Opportunities for people to recover from stress are insufficient, because demanding and excessive life activities leave little time for recovery. Downtime is a self-care behavior that can occur in any life domain (ie, work, home/family, leisure). METHODS: Using survey data from a cross-section of 422 U.S. workers, we tested hypotheses regarding downtime as a buffer of the effects of time pressure and whether downtime's benefits were related to the domain in which it was taken, or influenced by perceived time control. RESULTS: In situations of high time pressure, work and home/family downtime were beneficial when time control was high, while relaxing leisure was beneficial when time control was low. CONCLUSIONS: Downtime is available whenever people recognize their need for recovery and respond by entering a state of physical relaxation and psychological detachment from stressors. PMID- 28628055 TI - Workplace Violence and Training Required by New Legislation Among NJ Nurses. AB - OBJECTIVE: The aim of this study was to examine nurses' knowledge of the state of New Jersey (NJ) Violence Prevention in Health Care Facilities Act, workplace violence training, and experience with workplace violence. METHODS: In 2013, 309 (22.5% response rate) nurses returned a mailed survey. Univariate and multivariate analyses were conducted. RESULTS: Ninety percent of respondents were female. When the perpetrator was a patient or a family member, the respondents experienced verbal abuse the most (57.8%), followed by threats (52.3%), and physical assault (38.3%). Respondents who had heard of the regulation (89.6%) received a higher proportion of training than those who had not heard of the regulation (57.9%) (P < 0.0001). CONCLUSIONS: Nurses who received at least 80% of the required training components were more likely to feel more secure at work, suggesting that training is an important tool to address workplace violence. PMID- 28628057 TI - Advancing Value-Based Medicine: Why Integrating Functional Outcomes With Clinical Measures Is Critical to Our Health Care Future. PMID- 28628058 TI - JOEM 2016 Reviewers-Thank you and Perspectives. PMID- 28628059 TI - Response to "Lung Cancer Risk Among Non-Smoking Firefighters". PMID- 28628060 TI - Lung Cancer Risk Among Non-Smoking Firefighters. PMID- 28628061 TI - Strengthening the Coal Workers' Health Surveillance Program. PMID- 28628063 TI - The Relocation of a Health Care Department's Impact on Staff: A Cross-Sectional Survey: Erratum. PMID- 28628065 TI - Effect of Exercise Intensity and Duration on Postexercise Executive Function Erratum. PMID- 28628064 TI - Exercise Training Reduces Intrathoracic Fat Regardless of Defective Glucose Tolerance. AB - PURPOSE: Epicardial (EAT) and pericardial (PAT) fat masses and myocardial triglyceride content (MTC) are enlarged in obesity and insulin resistance. We studied whether the high-intensity interval training (HIIT) and moderate intensity continuous training (MICT) similarly decrease ectopic fat in and around the heart and whether the decrease is similar in healthy subjects and subjects with defective glucose tolerance (DGT). METHODS: A total of 28 healthy men (body mass index = 20.7-30.0 kg.m, age = 40-55 yr) and 16 men with DGT (body mass index = 23.8-33.5 kg.m, age = 43-53 yr) were randomized into HIIT and MICT interventions for 2 wk. EAT and PAT were determined by computed tomography and MTC by H-MRS. RESULTS: At baseline, DGT subjects had impaired aerobic capacity and insulin sensitivity and higher levels of whole body fat, visceral fat, PAT, and EAT (P < 0.05, all) compared with healthy subjects. In the whole group, HIIT increased aerobic capacity (HIIT = 6%, MICT = 0.3%; time * training P = 0.007) and tended to improve insulin sensitivity (HIIT = 24%, MICT = 8%) as well as reduce MTC (HIIT = -42%, MICT = +23%) (time * training P = 0.06, both) more efficiently compared with MICT, and without differences in the training response between the healthy and the DGT subjects. However, both training modes decreased EAT (-5%) and PAT (-6%) fat (time P < 0.05) and not differently between the healthy and the DGT subjects. CONCLUSION: Whole body fat, visceral fat, PAT, and EAT masses are enlarged in DGT. Both HIIT and MICT effectively reduce EAT and PAT in healthy and DGT subjects, whereas HIIT seems to be superior as regards improving aerobic capacity, whole-body insulin sensitivity, and MTC. PMID- 28628066 TI - Mortality Risk Reductions from Substituting Screen Time by Discretionary Activities: Erratum. PMID- 28628067 TI - Identifying and Describing Nurse Faculty Workload Issues: A Looming Faculty Shortage. AB - AIM: The purpose of this project was to address factors contributing to the nurse faculty shortage. BACKGROUND: There is a demonstrated need to sustain and stabilize faculty currently in the workforce to avoid exacerbating the current and future faculty shortage in nursing. Recommendations of previous studies focus on strategies for recruitment, retention, and ongoing faculty development. METHOD: A survey was employed to identify and describe the workload of nurse faculty and identify the impact of retirement and other retention issues. RESULTS: Findings showed an aging and nondiverse nursing faculty with increased and variable workload. There was no standard means of calculating workload. With identification of increased workload, faculty are considering retirement at a higher than projected rate. CONCLUSION: Four primary areas to address the nursing faculty shortage include focus on diversity balance, development of collaborative positions (joint appointments), and clear identification of nursing faculty workload. PMID- 28628068 TI - Exploring Nurse Faculty Incivility and Resonant Leadership. AB - AIM: The purpose of this quantitative correlational study was to explore the relationship between the frequency of interfaculty incivility among nurses in academia and observed levels of resonant leadership of immediate supervisors. BACKGROUND: Despite mandates to address incivility in health care, nurse faculty report high levels of horizontal incivility among their peers. No known quantitative research has measured the relationship between nurse faculty-to faculty incivility and resonant leadership traits of leaders. METHOD: Nursing faculty from 17 universities (n = 260) were emailed an anonymous link to answer survey questions about horizontal peer incivility and leaders' management styles. RESULTS: There was a significant inverse relationship (Pearson's r, -.560) between the frequency of experienced faculty-to-faculty incivility and the level of observed resonant leadership behaviors of participants' immediate supervisors. CONCLUSION: Resonant supervisory behaviors inversely correlated with nurse faculty peer incivility, with potential to impact satisfaction, recruitment, and retention. PMID- 28628069 TI - Sitting Time: An Increasing Heath Risk Among Nurse Educators. AB - Prolonged sitting time (ST) is a distinct risk factor for early mortality and cardiovascular disease. The purpose of this descriptive correlational study was to examine ST and health of Kentucky nurse educators. The written survey included demographic items, general health items, and ST. Total average ST was 10.8 hours (workdays) and 8 hours (non-workdays). There was no relationship between body mass index and ST; however, the medication used to treat hypertension and hypercholesterolemia was associated with increased ST. Nurse educators are at risk for negative health effects of prolonged ST, and effective interventions are imperative. PMID- 28628070 TI - Nursing Doctoral Faculty Perceptions Related to the Effect of Increasing Enrollments on Productivity. AB - Nursing faculty teaching in research and clinical doctoral programs participated in a national survey study to examine the impact of expanded doctoral enrollments on the doctoral faculty's scholarly productivity. They were invited to respond to an open-ended question soliciting information not already addressed in the survey. Results of the analysis are reported here. Findings corroborated the review of literature and results of the survey and focus groups that provided the basis for the survey's development. Current workloads may be unsustainable, jeopardizing the profession's response to Institute of Medicine recommendations. PMID- 28628071 TI - Reflective Responses Following a Role-play Simulation of Nurse Bullying. AB - A qualitative exploratory design was used for this study to evaluate role-play simulation as an active learning strategy. The context for the role-play was bullying in nursing practice. Following a simulation, 333 students from five college campuses of three universities completed a reflection worksheet. Qualitative thematic findings were personal responses, nonverbal communications exhibited, actions taken by participants, and the perceived impact of bullying during the simulation. Role-play simulation was a highly effective pedagogy, eliciting learning at both the cognitive and affective domains. PMID- 28628072 TI - Retention of Content Utilizing a Flipped Classroom Approach. AB - The flipped classroom experience promotes retention and accountability for learning. The authors report their evaluation of a flipped classroom for accelerated second-degree nursing students during their primary medical-surgical nursing course. Standardized HESI(r) scores were compared between a group of students who experienced the flipped classroom and a previous group who had traditional teaching methods. Short- and long-term retention was measured using standardized exams 3 months and 12 months following the course. Results indicated that short-term retention was greater and long- term retention was significantly great in the students who were taught using flipped classroom methodology. PMID- 28628073 TI - Evaluating the Need for Organ Donation and Transplant-Related Education in Nursing Curricula. AB - Transplant education has been historically unstructured and inconsistent. The purpose of this study was to measure nursing students' knowledge and attitudes toward organ donation, allocation, and preparation for practice using a modified version of the Organ Donation Attitude Questionnaire II-Student Version. Scores were low, particularly regarding brain death and organ allocation. Preparedness for practice was related to knowledge of brain death (z = 2.05, p = .04); knowledge (t = 2.24, p = .03) and attitude (t = 7.55, p < .0001) were related to signing a driver's license. Results support including organ donation and transplant education in nursing curricula. PMID- 28628074 TI - When the Nursing Student Also Wears Cleats: Successful Nursing Student Athletes. AB - Being a nursing student athlete carries both rewards and challenges. There is a dearth of nursing literature addressing the subset of nursing student athletes. This article offers the characteristics of successful nursing student athletes; the challenges they encounter; the advantages of having student athletes in the nursing student body; and the student-centered, program-centered, and institution centered strategies that need to be in place for their success. PMID- 28628075 TI - Using the NLN Faculty Preparation for Global Experiences Toolkit for Successful Application for the Fulbright Scholar Award. AB - With an increasingly global world and the migration of diverse populations, nurse faculty have opportunities to learn and share varied perspectives through involvement internationally in research, teaching, and practice. The National League for Nursing (NLN) joins with the World Health Organization and the International Council of Nurses to promote international nursing standards. One way in which nursing faculty can contribute to this goal is by pursuing international education, research, and service as a Fulbright scholar. The NLN Faculty Preparation for Global Experiences Toolkit complements resources offered through the Fulbright program in the preparation of a competitive Fulbright application. PMID- 28628076 TI - Promoting Simulation Globally: Networking with Nursing Colleagues Across Five Continents. AB - Simulation education is gaining momentum internationally and may provide the opportunity to enhance clinical education while disseminating evidence-based practice standards for clinical simulation and learning. There is a need to develop a cohesive leadership group that fosters support, networking, and sharing of simulation resources globally. The Frances Payne Bolton School of Nursing at Case Western Reserve University has had the unique opportunity to establish academic exchange programs with schools of nursing across five continents. Although the joint and mutual simulation activities have been extensive, each international collaboration has also provided insight into the innovations developed by global partners. PMID- 28628077 TI - Using YouTube in Teaching Pharmacology to Nursing Students. AB - Nursing pharmacology can pose a challenge to nursing students as they learn about different disease processes and interventions. Having students engage in their own learning process aids in the retention of information and gives positive reinforcement for exams. Using YouTube as a part of student group presentations helps students engage in the learning process and learn difficult pharmacological concepts in an alternative classroom setting. PMID- 28628078 TI - Nociceptor interleukin 10 receptor 1 is critical for muscle analgesia induced by repeated bouts of eccentric exercise in the rat. AB - Delayed-onset muscle soreness is typically observed after strenuous or unaccustomed eccentric exercise. Soon after recovery, blunted muscle soreness is observed on repeated eccentric exercise, a phenomenon known as repeated bout effect (RBE). Although regular physical activity decreases muscle hyperalgesia, likely because of increased production of the anti-inflammatory cytokine interleukin-10 (IL-10) in the skeletal muscle, whether IL-10 also contributes to the antinociceptive effect of RBE is unknown. Furthermore, whether IL-10 attenuates muscle hyperalgesia by acting on muscle nociceptors remains to be established. Here, we explored the hypothesis that blunted muscle nociception observed in RBE depends on a local effect of IL-10, acting on IL-10 receptor 1 (IL-10R1) expressed by muscle nociceptors. Results show that after a second bout of eccentric exercise, rats exhibited decreased muscle hyperalgesia, indicative of RBE, and increased expression of IL-10 in the exercised gastrocnemius muscle. Although knockdown of IL-10R1 protein in nociceptors innervating the gastrocnemius muscle by intrathecal antisense oligodeoxynucleotide did not change nociceptive threshold in naive rats, it unveiled latent muscle hyperalgesia in rats submitted to eccentric exercise 12 days ago. Furthermore, antisense also prevented the reduction of muscle hyperalgesia observed after a second bout of eccentric exercise. These data indicate that recovery of nociceptive threshold after eccentric exercise and RBE-induced analgesia depend on a local effect of IL 10, acting on its canonical receptor in muscle nociceptors. PMID- 28628079 TI - Neutralization of mobile antiviral small RNA through peroxisomal import. AB - In animals, certain viral proteins are targeted to peroxisomes to dampen the antiviral immune response mediated by these organelles1-3. In plants, RNA interference (RNAi) mediated by small interfering (si)RNA is the main antiviral defence mechanism. To protect themselves against the cell- and non-cell autonomous effects of RNAi, viruses produce viral suppressors of RNA silencing (VSR)4, whose study is crucial to properly understand the biological cycle of plant viruses and potentially find new solutions to control these pathogens. By combining biochemical approaches, cell-specific inhibition of RNAi movement and peroxisome isolation, we show here that one such VSR, the peanut clump virus (PCV)-encoded P15, isolates siRNA from the symplasm by delivering them into the peroxisomal matrix. Infection with PCV lacking this ability reveals that piggybacking of these VSR-bound nucleic acids into peroxisomes potentiates viral systemic movement by preventing the spread of antiviral siRNA. Collectively, these results highlight organellar confinement of antiviral molecules as a novel pathogenic strategy that may have its direct counterpart in other plant and animal viruses. PMID- 28628080 TI - Viral suppressors: Combatting RNA silencing. PMID- 28628081 TI - O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency. AB - Chromatin-associated fumarase (FH) affects histone methylation via its metabolic activity. However, whether this effect is involved in gene transcription remains to be clarified. In this study, we show that under glucose deprivation conditions, AMPK phosphorylates FH at Ser75, which in turn forms a complex with ATF2 and participates in promoter activation. FH-catalysed fumarate in promoter regions inhibits KDM2A demethylase activity, and thus maintains the H3K36me2 profile and facilitates gene expression for cell growth arrest. On the other hand, FH is found to be O-GlcNAcylated at the AMPK phosphorylation site; FH-ATF2 mediated downstream events are impeded by FH O-GlcNAcylation, especially in cancer cells that display robust O-GlcNAc transferase (OGT) activity. Consistently, the FH-Ser75 phosphorylation level inversely correlates with the OGT level and poor prognosis in pancreatic cancer patients. These findings uncover a previously uncharacterized mechanism underlying transcription regulation by FH and the linkage between dysregulated OGT activity and growth advantage of cancer cells under glucose deficiency. PMID- 28628082 TI - Quantifying forces in cell biology. AB - Cells exert, sense, and respond to physical forces through an astounding diversity of mechanisms. Here we review recently developed tools to quantify the forces generated by cells. We first review technologies based on sensors of known or assumed mechanical properties, and discuss their applicability and limitations. We then proceed to draw an analogy between these human-made sensors and force sensing in the cell. As mechanics is increasingly revealed to play a fundamental role in cell function we envisage that tools to quantify physical forces may soon become widely applied in life-sciences laboratories. PMID- 28628083 TI - Molecular basis of selective mitochondrial fusion by heterotypic action between OPA1 and cardiolipin. AB - Mitochondria are highly dynamic organelles that undergo frequent fusion and fission. Optic atrophy 1 (OPA1) is an essential GTPase protein for both mitochondrial inner membrane (IM) fusion and cristae morphology. Under mitochondria-stress conditions, membrane-anchored L-OPA1 is proteolytically cleaved to form peripheral S-OPA1, leading to the selection of damaged mitochondria for mitophagy. However, molecular details of the selective mitochondrial fusion are less well understood. Here, we showed that L-OPA1 and cardiolipin (CL) cooperate in heterotypic mitochondrial IM fusion. We reconstituted an in vitro membrane fusion reaction using purified human L-OPA1 protein expressed in silkworm, and found that L-OPA1 on one side of the membrane and CL on the other side are sufficient for fusion. GTP-independent membrane tethering through L-OPA1 and CL primes the subsequent GTP-hydrolysis-dependent fusion, which can be modulated by the presence of S-OPA1. These results unveil the most minimal intracellular membrane fusion machinery. In contrast, independent of CL, a homotypic trans-OPA1 interaction mediates membrane tethering, thereby supporting the cristae structure. Thus, multiple OPA1 functions are modulated by local CL conditions for regulation of mitochondrial morphology and quality control. PMID- 28628084 TI - Long-term imaging of cellular forces with high precision by elastic resonator interference stress microscopy. AB - Cellular forces are crucial for many biological processes but current methods to image them have limitations with respect to data analysis, resolution and throughput. Here, we present a robust approach to measure mechanical cell substrate interactions in diverse biological systems by interferometrically detecting deformations of an elastic micro-cavity. Elastic resonator interference stress microscopy (ERISM) yields stress maps with exceptional precision and large dynamic range (2 nm displacement resolution over a >1 MUm range, translating into 1 pN force sensitivity). This enables investigation of minute vertical stresses (<1 Pa) involved in podosome protrusion, protein-specific cell-substrate interaction and amoeboid migration through spatial confinement in real time. ERISM requires no zero-force reference and avoids phototoxic effects, which facilitates force monitoring over multiple days and at high frame rates and eliminates the need to detach cells after measurements. This allows observation of slow processes such as differentiation and further investigation of cells, for example, by immunostaining. PMID- 28628085 TI - OPA1 and cardiolipin team up for mitochondrial fusion. AB - Fusion between the inner membranes of two mitochondria requires the GTPase optic atrophy 1 (OPA1), but the molecular mechanism is poorly understood. A study now shows that fusion of two liposomes can be performed by OPA1 tethered to just one liposome, through an interaction with the phospholipid cardiolipin on the opposing liposome. PMID- 28628086 TI - Nitrate signalling: Calcium bridges the nitrate gap. PMID- 28628088 TI - An individualised risk-adapted protocol of pre- and post transplant zoledronic acid reduces bone loss after allogeneic stem cell transplantation: results of a phase II prospective trial. AB - Bone loss occurs frequently following allogeneic haematopoietic stem cell transplantation (alloSCT). The Australasian Leukaemia and Lymphoma Group conducted a prospective phase II study of pretransplant zoledronic acid (ZA) and individualised post-transplant ZA to prevent bone loss in alloSCT recipients. Patients received ZA 4 mg before conditioning. Administration of post-transplant ZA from days 100 to 365 post alloSCT was determined by a risk-adapted algorithm based on serial bone density assessments and glucocorticoid exposure. Of 82 patients enrolled, 70 were alive and without relapse at day 100. A single pretransplant dose of ZA prevented femoral neck bone loss at day 100 compared with baseline (mean change -2.6+/-4.6%). Using the risk-adapted protocol, 42 patients received ZA between days 100 and 365 post alloSCT, and this minimised bone loss at day 365 compared with pretransplant levels (mean change -2.9+/ 5.3%). Femoral neck bone loss was significantly reduced in ZA-treated patients compared with historical untreated controls at days 100 and 365. This study demonstrates that a single dose of ZA pre-alloSCT prevents femoral neck bone loss at day 100 post alloSCT, and that a risk-adapted algorithm is able to guide ZA administration from days 100 to 365 post transplant and minimise further bone loss. PMID- 28628089 TI - Elevated bone marrow eosinophil count is associated with high incidence of severe acute GvHD after allogeneic hematopoietic stem cell transplantation. AB - Predicting severe acute GvHD (aGvHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is challenging but critical. Mild aGvHD may have a favorable impact on relapse, whereas severe aGvHD is associated with poor outcomes. The aim of this study was to evaluate whether elevated eosinophil count in the bone marrow (BM) at 1 month after HSCT is associated with a high incidence of new and severe aGvHD. We enrolled 101 consecutive patients; median age was 50 years, and 50.5% patients were male. The median eosinophil concentration in BM at 1 month after HSCT was 1.1% (quartile 0.4-2.2%). The adjusted hazards ratio at 95% confidence interval for severe aGvHD was 1.26 (1.12-1.42, P<0.001), per 1% increase in eosinophil concentration, and 3.76 (1.41-10.05, P=0.008) for the high risk group at a cutoff value of 4.0%. In addition, the predictive accuracy described by area under the curve of receiver operating characteristics, increased from 0.784 to 0.866 (P=0.033) with the increasing concentration of eosinophils. In conclusion, elevated concentration of eosinophils in BM was associated with high incidence and predictive accuracy of severe aGvHD. BM eosinophil concentration can be one of the key markers to predict aGvHD. PMID- 28628087 TI - Chromatin-enriched lncRNAs can act as cell-type specific activators of proximal gene transcription. AB - We recently described a new class of long noncoding RNAs (lncRNAs) that are distinguished by especially tight chromatin association and whose presence is strongly correlated to expression of nearby genes. Here, we examine the cis enhancer mechanism of this class of chromatin-enriched RNA (cheRNA) across multiple human cell lines. cheRNAs are largely cell type specific and provide the most reliable chromatin signature to predict cis-gene transcription in every human cell type examined. Targeted depletion of three cheRNAs decreases expression of their neighboring genes, indicating potential co-activator function, and single-molecule fluorescence in situ hybridization (smFISH) of one cheRNA-distal target gene pair suggests a spatial overlap consistent with a role in chromosome looping. Additionally, the cheRNA HIDALGO stimulates the fetal hemoglobin subunit gamma 1 (HBG1) gene during erythroid differentiation by promoting contacts to a downstream enhancer. Our results suggest that multiple cheRNAs activate proximal lineage-specific gene transcription. PMID- 28628090 TI - Against the odds: haplo-cord grafts protect from GvHD and relapse. PMID- 28628091 TI - The BTG2-PRMT1 module limits pre-B cell expansion by regulating the CDK4-Cyclin D3 complex. AB - Developing pre-B cells in the bone marrow alternate between proliferation and differentiation phases. We found that protein arginine methyl transferase 1 (PRMT1) and B cell translocation gene 2 (BTG2) are critical components of the pre B cell differentiation program. The BTG2-PRMT1 module induced a cell-cycle arrest of pre-B cells that was accompanied by re-expression of Rag1 and Rag2 and the onset of immunoglobulin light chain gene rearrangements. We found that PRMT1 methylated cyclin-dependent kinase 4 (CDK4), thereby preventing the formation of a CDK4-Cyclin-D3 complex and cell cycle progression. Moreover, BTG2 in concert with PRMT1 efficiently blocked the proliferation of BCR-ABL1-transformed pre-B cells in vitro and in vivo. Our results identify a key molecular mechanism by which the BTG2-PRMT1 module regulates pre-B cell differentiation and inhibits pre B cell leukemogenesis. PMID- 28628093 TI - A heme-dependent enzyme forms the nitrogen-nitrogen bond in piperazate. AB - Molecules containing a nitrogen-nitrogen (N-N) linkage have a variety of structures and biological activities; however, no enzyme has yet been demonstrated to catalyze N-N bond formation in an organic molecule. Here we report that the heme-dependent enzyme KtzT from Kutzneria sp. 744 catalyzes N-N bond formation in the biosynthesis of piperazate, a building block for nonribosomal peptides. PMID- 28628092 TI - Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. AB - Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3. Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (TRM cells), such as CD103, and CTLs from CD103hi tumors displayed features of enhanced cytotoxicity. A greater density of TRM cells in tumors was predictive of a better survival outcome in lung cancer, and this effect was independent of that conferred by CTL density. Here we define the 'molecular fingerprint' of tumor infiltrating CTLs and identify potentially new targets for immunotherapy. PMID- 28628094 TI - A water-soluble DsbB variant that catalyzes disulfide-bond formation in vivo. AB - Escherichia coli DsbB is a transmembrane enzyme that catalyzes the reoxidation of the periplasmic oxidase DsbA by ubiquinone. Here, we sought to convert membrane bound DsbB into a water-soluble biocatalyst by leveraging a previously described method for in vivo solubilization of integral membrane proteins (IMPs). When solubilized DsbB variants were coexpressed with an export-defective copy of DsbA in the cytoplasm of wild-type E. coli cells, artificial oxidation pathways were created that efficiently catalyzed de novo disulfide-bond formation in a range of substrate proteins, in a manner dependent on both DsbA and quinone. Hence, DsbB solubilization was achieved with preservation of both catalytic activity and substrate specificity. Moreover, given the generality of the solubilization technique, the results presented here should pave the way to unlocking the biocatalytic potential of other membrane-bound enzymes whose utility has been limited by poor stability of IMPs outside of their native lipid-bilayer context. PMID- 28628095 TI - A scaffold protein that chaperones a cysteine-sulfenic acid in H2O2 signaling. AB - In Saccharomyces cerevisiae, Yap1 regulates an H2O2-inducible transcriptional response that controls cellular H2O2 homeostasis. H2O2 activates Yap1 by oxidation through the intermediary of the thiol peroxidase Orp1. Upon reacting with H2O2, Orp1 catalytic cysteine oxidizes to a sulfenic acid, which then engages into either an intermolecular disulfide with Yap1, leading to Yap1 activation, or an intramolecular disulfide that commits the enzyme into its peroxidatic cycle. How the first of these two competing reactions, which is kinetically unfavorable, occurs was previously unknown. We show that the Yap1 binding protein Ybp1 brings together Orp1 and Yap1 into a ternary complex that selectively activates condensation of the Orp1 sulfenylated cysteine with one of the six Yap1 cysteines while inhibiting Orp1 intramolecular disulfide formation. We propose that Ybp1 operates as a scaffold protein and as a sulfenic acid chaperone to provide specificity in the transfer of oxidizing equivalents by a reactive sulfenic acid species. PMID- 28628096 TI - Nucleation and growth of a bacterial functional amyloid at single-fiber resolution. AB - Curli are functional amyloids produced by proteobacteria like Escherichia coli as part of the extracellular matrix that holds cells together into biofilms. The molecular events that occur during curli nucleation and fiber extension remain largely unknown. Combining observations from curli amyloidogenesis in bulk solutions with real-time in situ nanoscopic imaging at the single-fiber level, we show that curli display polar growth, and we detect two kinetic regimes of fiber elongation. Single fibers exhibit stop-and-go dynamics characterized by bursts of steady-state growth alternated with periods of stagnation. At high subunit concentrations, fibers show constant, unperturbed burst growth. Curli follow a one-step nucleation process in which monomers contemporaneously fold and oligomerize into minimal fiber units that have growth characteristics identical to those of the mature fibrils. Kinetic data and interaction studies of curli fibrillation in the presence of the natural inhibitor CsgC show that the inhibitor binds curli fibers and predominantly acts at the level of fiber elongation. PMID- 28628097 TI - Cpf1 proteins excise CRISPR RNAs from mRNA transcripts in mammalian cells. AB - Cpf1 is a CRISPR effector protein that has greater specificity than Streptococcus pyogenes Cas9 (SpCas9) in genome-editing applications. Here we show that Lachnospiraceae bacterium (Lb) and Acidaminococus sp. (As) Cpf1 orthologs have RNase activities that can excise multiple CRISPR RNAs (crRNAs) from a single RNA polymerase II-driven RNA transcript expressed in mammalian cells. This property simplifies modification of multiple genomic targets and can be used to increase the efficiency of Cpf1-mediated editing. PMID- 28628098 TI - Short-chain alkanes fuel mussel and sponge Cycloclasticus symbionts from deep-sea gas and oil seeps. AB - Cycloclasticus bacteria are ubiquitous in oil-rich regions of the ocean and are known for their ability to degrade polycyclic aromatic hydrocarbons (PAHs). In this study, we describe Cycloclasticus that have established a symbiosis with Bathymodiolus heckerae mussels and poecilosclerid sponges from asphalt-rich, deep sea oil seeps at Campeche Knolls in the southern Gulf of Mexico. Genomic and transcriptomic analyses revealed that, in contrast to all previously known Cycloclasticus, the symbiotic Cycloclasticus appears to lack the genes needed for PAH degradation. Instead, these symbionts use propane and other short-chain alkanes such as ethane and butane as carbon and energy sources, thus expanding the limited range of substrates known to power chemosynthetic symbioses. Analyses of short-chain alkanes in the environment of the Campeche Knolls symbioses revealed that these are present at high concentrations (in the MUM to mM range). Comparative genomic analyses revealed high similarities between the genes used by the symbiotic Cycloclasticus to degrade short-chain alkanes and those of free living Cycloclasticus that bloomed during the Deepwater Horizon oil spill. Our results indicate that the metabolic versatility of bacteria within the Cycloclasticus clade is higher than previously assumed, and highlight the expanded role of these keystone species in the degradation of marine hydrocarbons. PMID- 28628099 TI - Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection. AB - Globally, nearly 2 billion people are infected with the intracellular protozoan Toxoplasma gondii1. This persistent infection can cause severe disease in immunocompromised people and is epidemiologically linked to major mental illnesses2 and cognitive impairment3. There are currently no options for curing this infection. The lack of effective therapeutics is due partly to a poor understanding of the essential pathways that maintain long-term infection. Although it is known that Toxoplasma replicates slowly within intracellular cysts demarcated with a cyst wall, precisely how it sustains itself and remodels organelles in this niche is unknown. Here, we identify a key role for proteolysis within the parasite lysosomal organelle (the vacuolar compartment or VAC) in turnover of autophagosomes and persistence during neural infection. We found that disrupting a VAC-localized cysteine protease compromised VAC digestive function and markedly reduced chronic infection. Death of parasites lacking the VAC protease was preceded by accumulation of undigested autophagosomes in the parasite cytoplasm. These findings suggest an unanticipated function for parasite lysosomal degradation in chronic infection, and identify an intrinsic role for autophagy in the T. gondii parasite and its close relatives. This work also identifies a key element of Toxoplasma persistence and suggests that VAC proteolysis is a prospective target for pharmacological development. PMID- 28628101 TI - Dynamic illumination of spatially restricted or large brain volumes via a single tapered optical fiber. AB - Optogenetics promises precise spatiotemporal control of neural processes using light. However, the spatial extent of illumination within the brain is difficult to control and cannot be adjusted using standard fiber optics. We demonstrate that optical fibers with tapered tips can be used to illuminate either spatially restricted or large brain volumes. Remotely adjusting the light input angle to the fiber varies the light-emitting portion of the taper over several millimeters without movement of the implant. We use this mode to activate dorsal versus ventral striatum of individual mice and reveal different effects of each manipulation on motor behavior. Conversely, injecting light over the full numerical aperture of the fiber results in light emission from the entire taper surface, achieving broader and more efficient optogenetic activation of neurons, compared to standard flat-faced fiber stimulation. Thus, tapered fibers permit focal or broad illumination that can be precisely and dynamically matched to experimental needs. PMID- 28628100 TI - Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. AB - Although de novo missense mutations have been predicted to account for more cases of autism than gene-truncating mutations, most research has focused on the latter. We identified the properties of de novo missense mutations in patients with neurodevelopmental disorders (NDDs) and highlight 35 genes with excess missense mutations. Additionally, 40 amino acid sites were recurrently mutated in 36 genes, and targeted sequencing of 20 sites in 17,688 patients with NDD identified 21 new patients with identical missense mutations. One recurrent site substitution (p.A636T) occurs in a glutamate receptor subunit, GRIA1. This same amino acid substitution in the homologous but distinct mouse glutamate receptor subunit Grid2 is associated with Lurcher ataxia. Phenotypic follow-up in five individuals with GRIA1 mutations shows evidence of specific learning disabilities and autism. Overall, we find significant clustering of de novo mutations in 200 genes, highlighting specific functional domains and synaptic candidate genes important in NDD pathology. PMID- 28628102 TI - Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1. AB - Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity. PMID- 28628104 TI - Active dendritic integration as a mechanism for robust and precise grid cell firing. AB - Understanding how active dendrites are exploited for behaviorally relevant computations is a fundamental challenge in neuroscience. Grid cells in medial entorhinal cortex are an attractive model system for addressing this question, as the computation they perform is clear: they convert synaptic inputs into spatially modulated, periodic firing. Whether active dendrites contribute to the generation of the dual temporal and rate codes characteristic of grid cell output is unknown. We show that dendrites of medial entorhinal cortex neurons are highly excitable and exhibit a supralinear input-output function in vitro, while in vivo recordings reveal membrane potential signatures consistent with recruitment of active dendritic conductances. By incorporating these nonlinear dynamics into grid cell models, we show that they can sharpen the precision of the temporal code and enhance the robustness of the rate code, thereby supporting a stable, accurate representation of space under varying environmental conditions. Our results suggest that active dendrites may therefore constitute a key cellular mechanism for ensuring reliable spatial navigation. PMID- 28628103 TI - A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. AB - A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function. PMID- 28628105 TI - Identification of liver-specific enhancer-promoter activity in the 3' untranslated region of the wild-type AAV2 genome. AB - Vectors based on adeno-associated virus type 2 (AAV2) are powerful tools for gene transfer and genome editing applications. The level of interest in this system has recently surged in response to reports of therapeutic efficacy in human clinical trials, most notably for those in patients with hemophilia B (ref. 3). Understandably, a recent report drawing an association between AAV2 integration events and human hepatocellular carcinoma (HCC) has generated controversy about the causal or incidental nature of this association and the implications for AAV vector safety. Here we describe and functionally characterize a previously unknown liver-specific enhancer-promoter element in the wild-type AAV2 genome that is found between the stop codon of the cap gene, which encodes proteins that form the capsid, and the right-hand inverted terminal repeat. This 124-nt sequence is within the 163-nt common insertion region of the AAV genome, which has been implicated in the dysregulation of known HCC driver genes and thus offers added insight into the possible link between AAV integration events and the multifactorial pathogenesis of HCC. PMID- 28628106 TI - Variants in the fetal genome near FLT1 are associated with risk of preeclampsia. AB - Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 * 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes. PMID- 28628107 TI - Identification of sequence variants influencing immunoglobulin levels. AB - Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 * 10-55, beta = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 * 10-8, beta = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity. PMID- 28628108 TI - Germline hypomorphic CARD11 mutations in severe atopic disease. AB - Few monogenic causes for severe manifestations of common allergic diseases have been identified. Through next-generation sequencing on a cohort of patients with severe atopic dermatitis with and without comorbid infections, we found eight individuals, from four families, with novel heterozygous mutations in CARD11, which encodes a scaffolding protein involved in lymphocyte receptor signaling. Disease improved over time in most patients. Transfection of mutant CARD11 expression constructs into T cell lines demonstrated both loss-of-function and dominant-interfering activity upon antigen receptor-induced activation of nuclear factor-kappaB and mammalian target of rapamycin complex 1 (mTORC1). Patient T cells had similar defects, as well as low production of the cytokine interferon gamma (IFN-gamma). The mTORC1 and IFN-gamma production defects were partially rescued by supplementation with glutamine, which requires CARD11 for import into T cells. Our findings indicate that a single hypomorphic mutation in CARD11 can cause potentially correctable cellular defects that lead to atopic dermatitis. PMID- 28628109 TI - Truncating mutations in RBM12 are associated with psychosis. AB - Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T (P = 2.2 * 10-4), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis (P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile (P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease. PMID- 28628110 TI - Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. AB - With the goal of modeling human disease of the large intestine, we sought to develop an effective protocol for deriving colonic organoids (COs) from differentiated human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs). Extensive gene and immunohistochemical profiling confirmed that the derived COs represent colon rather than small intestine, containing stem cells, transit-amplifying cells, and the expected spectrum of differentiated cells, including goblet and endocrine cells. We applied this strategy to iPSCs derived from patients with familial adenomatous polyposis (FAP-iPSCs) harboring germline mutations in the WNT-signaling-pathway-regulator gene encoding APC, and we generated COs that exhibit enhanced WNT activity and increased epithelial cell proliferation, which we used as a platform for drug testing. Two potential compounds, XAV939 and rapamycin, decreased proliferation in FAP-COs, but also affected cell proliferation in wild-type COs, which thus limits their therapeutic application. By contrast, we found that geneticin, a ribosome-binding antibiotic with translational 'read-through' activity, efficiently targeted abnormal WNT activity and restored normal proliferation specifically in APC-mutant FAP-COs. These studies provide an efficient strategy for deriving human COs, which can be used in disease modeling and drug discovery for colorectal disease. PMID- 28628111 TI - Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. AB - Central nervous system (CNS) injury transforms naive astrocytes into reactive astrocytes, which eventually become scar-forming astrocytes that can impair axonal regeneration and functional recovery. This sequential phenotypic change, known as reactive astrogliosis, has long been considered unidirectional and irreversible. However, we report here that reactive astrocytes isolated from injured spinal cord reverted in retrograde to naive astrocytes when transplanted into a naive spinal cord, whereas they formed astrocytic scars when transplanted into injured spinal cord, indicating the environment-dependent plasticity of reactive astrogliosis. We also found that type I collagen was highly expressed in the spinal cord during the scar-forming phase and induced astrocytic scar formation via the integrin-N-cadherin pathway. In a mouse model of spinal cord injury, pharmacological blockade of reactive astrocyte-type I collagen interaction prevented astrocytic scar formation, thereby leading to improved axonal regrowth and better functional outcomes. Our findings reveal environmental cues regulating astrocytic fate decisions, thereby providing a potential therapeutic target for CNS injury. PMID- 28628114 TI - Oncoprotein ZNF322A transcriptionally deregulates alpha-adducin, cyclin D1 and p53 to promote tumor growth and metastasis in lung cancer. AB - This corrects the article DOI: 10.1038/onc.2015.296. PMID- 28628113 TI - MicroRNA-20a-mediated loss of autophagy contributes to breast tumorigenesis by promoting genomic damage and instability. AB - Gene expression analysis of The Cancer Genome Atlas (TCGA) breast cancer data set show that miR-20a is upregulated in human breast cancer, especially in triple negative subtype. Gene Set Enrichment Analysis suggests that miR-20a expression negatively correlates with the autophagy/lysosome pathway. We report here that miR-20a inhibits the basal and nutrient starvation-induced autophagic flux and lysosomal proteolytic activity, increases intracellular reactive oxygen species levels and DNA damage response by targeting several key regulators of autophagy, including BECN1, ATG16L1 and SQSTM1. Re-introduction of exogenous BECN1, ATG16L1 or SQSTM1 reverses the inhibitory effect of miR-20a on autophagy and decreases DNA damage. A negative correlation between miR-20a and its target genes is observed in breast cancer tissues. Lower levels of BECN1, ATG16L1 and SQSTM1 are more common in triple-negative cancers than in other subtypes. High levels of miR 20a also associate with higher frequency of copy-number alterations and DNA mutations in breast cancer patients. Further studies in a xenograft mouse model show that miR-20a promotes tumor initiation and tumor growth. Collectively, these findings suggest that miR-20a-mediated autophagy defect might be a new mechanism underlying the oncogenic function of miRNA during breast tumorigenesis. PMID- 28628115 TI - Stearoyl-CoA-desaturase 1 regulates lung cancer stemness via stabilization and nuclear localization of YAP/TAZ. AB - This corrects the article DOI: 10.1038/onc.2017.75. PMID- 28628112 TI - Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention. AB - Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota. PMID- 28628117 TI - A large-scale RNAi screen identifies LCMR1 as a critical regulator of Tspan8 mediated melanoma invasion. AB - This corrects the article DOI: 10.1038/onc.2016.219. PMID- 28628116 TI - Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis. AB - During epithelial ovarian cancer (EOC) progression, intraperitoneally disseminating tumor cells and multicellular aggregates (MCAs) present in ascites fluid adhere to the peritoneum and induce retraction of the peritoneal mesothelial monolayer prior to invasion of the collagen-rich submesothelial matrix and proliferation into macro-metastases. Clinical studies have shown heterogeneity among EOC metastatic units with respect to cadherin expression profiles and invasive behavior; however, the impact of distinct cadherin profiles on peritoneal anchoring of metastatic lesions remains poorly understood. In the current study, we demonstrate that metastasis-associated behaviors of ovarian cancer cells and MCAs are influenced by cellular cadherin composition. Our results show that mesenchymal N-cadherin-expressing (Ncad+) cells and MCAs invade much more efficiently than E-cadherin-expressing (Ecad+) cells. Ncad+ MCAs exhibit rapid lateral dispersal prior to penetration of three-dimensional collagen matrices. When seeded as individual cells, lateral migration and cell cell junction formation precede matrix invasion. Neutralizing the Ncad extracellular domain with the monoclonal antibody GC-4 suppresses lateral dispersal and cell penetration of collagen gels. In contrast, use of a broad spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) to block endogenous membrane type 1 matrix metalloproteinase (MT1-MMP) activity does not fully inhibit cell invasion. Using intact tissue explants, Ncad+ MCAs were also shown to efficiently rupture peritoneal mesothelial cells, exposing the submesothelial collagen matrix. Acquisition of Ncad by Ecad+ cells increased mesothelial clearance activity but was not sufficient to induce matrix invasion. Furthermore, co-culture of Ncad+ with Ecad+ cells did not promote a 'leader-follower' mode of collective cell invasion, demonstrating that matrix remodeling and creation of invasive micro-tracks are not sufficient for cell penetration of collagen matrices in the absence of Ncad. Collectively, our data emphasize the role of Ncad in intraperitoneal seeding of EOC and provide the rationale for future studies targeting Ncad in preclinical models of EOC metastasis. PMID- 28628118 TI - OncoPPi-informed discovery of mitogen-activated protein kinase kinase 3 as a novel binding partner of c-Myc. AB - Mitogen-activated protein kinase kinase 3 (MKK3) is a dual threonine/tyrosine protein kinase that regulates inflammation, proliferation and apoptosis through specific phosphorylation and activation of the p38 mitogen-activated protein kinase. However, the role of MKK3 beyond p38-signaling remains elusive. Recently, we reported a protein-protein interaction (PPI) network of cancer-associated genes, termed OncoPPi, as a resource for the scientific community to generate new biological models. Analysis of the OncoPPi connectivity identified MKK3 as one of the major hub proteins in the network. Here, we show that MKK3 interacts with a large number of proteins critical for cell growth and metabolism, including the major oncogenic driver MYC. Multiple complementary approaches were used to demonstrate the direct interaction of MKK3 with MYC in vitro and in vivo. Computational modeling and experimental studies mapped the interaction interface to the MYC helix-loop-helix domain and a novel 15-residue MYC-binding motif in MKK3 (MBM). The MBM in MKK3 is distinct from the known binding sites for p38 or upstream kinases. Functionally, MKK3 stabilized MYC protein, enhanced its transcriptional activity and increased expression of MYC-regulated genes. The defined MBM peptide mimicked the MKK3 effect in promoting MYC activity. Together, the exploration of OncoPPi led to a new biological model in which MKK3 operates by two distinct mechanisms in cellular regulation through its phosphorylation of p38 and its activation of MYC through PPI. PMID- 28628119 TI - Differential expression of miR16 in glioblastoma and glioblastoma stem cells: their correlation with proliferation, differentiation, metastasis and prognosis. AB - The function of miR16 in multiforme glioblastoma multiforme (GBM) and its stem cells (GSCs) remains elusive. To this end, we investigated the patterns of miR16 expression in these cells and their correlation with malignant behaviors and clinical outcomes. The levels of miR16 and its targeted genes in tumor tissue of GBM and GBM SGH44, U87, U251 cells as well as their stem cell counterparts were measured by qRT-PCR or western blot or immunohistochemistry. Luciferase reporter assay was used to confirm the binding of miR16 to 3'-UTR of its target genes. The effects of miR16 on malignant behaviors were investigated, including tumor cell viability, soft-agar colony formation, GSCs Matrigel colony forming and migration and invasion as well as nude mice xenograft model. Differentially expression patterns of miR16 in glioblastoma cells and GSCs cells were found in this study. Changes of miR16 targeted genes, Bcl2 (B cell lymphoma 2), CDK6 (Cyclin-dependent kinase 6), CCND1 (cyclin D1), CCNE1 (cyclin E1) and SOX5 were confirmed in glioblastoma cell lines and tissue specimens. In vitro and in vivo studies showed that tumor cell proliferation was inhibited by miR16 mimic, but enhanced by miR16 inhibitor. The expression level of miR16 positively correlates with GSCs differentiation, but negatively with the abilities of migration, motility, invasion and colony formation in glioblastoma cells. The inhibitory effects of miR16 on its target genes were also found in nude mice xenograft model. Our findings revealed that the miR16 functions as a tumor suppressor in GSCs and its association with prognosis in GBM. PMID- 28628121 TI - Universal quinone electrodes for long cycle life aqueous rechargeable batteries. AB - Aqueous rechargeable batteries provide the safety, robustness, affordability, and environmental friendliness necessary for grid storage and electric vehicle operations, but their adoption is plagued by poor cycle life due to the structural and chemical instability of the anode materials. Here we report quinones as stable anode materials by exploiting their structurally stable ion coordination charge storage mechanism and chemical inertness towards aqueous electrolytes. Upon rational selection/design of quinone structures, we demonstrate three systems that coupled with industrially established cathodes and electrolytes exhibit long cycle life (up to 3,000 cycles/3,500 h), fast kinetics (>=20C), high anode specific capacity (up to 200-395 mAh g-1), and several examples of state-of-the-art specific energy/energy density (up to 76-92 Wh kg-1/ 161-208 Wh l-1) for several operational pH values (-1 to 15), charge carrier species (H+, Li+, Na+, K+, Mg2+), temperature (-35 to 25 degrees C), and atmosphere (with/without O2), making them a universal anode approach for any aqueous battery technology. PMID- 28628120 TI - Intestinal cancer progression by mutant p53 through the acquisition of invasiveness associated with complex glandular formation. AB - Tumor suppressor TP53 is frequently mutated in colorectal cancer (CRC), and most mutations are missense type. Although gain-of-functions by mutant p53 have been demonstrated experimentally, the precise mechanism for malignant progression in in vivo tumors remains unsolved. We generated ApcDelta716 Trp53LSL*R270H villin CreER compound mice, in which mutant p53R270H was expressed in the intestinal epithelia upon tamoxifen treatment, and examined the intestinal tumor phenotypes and tumor-derived organoids. Mutant Trp53R270H, but not Trp53-null mutation accelerated submucosal invasion with generation of desmoplastic microenvironment. The nuclear accumulation of p53 was evident in ApcDelta716 Trp53R270H/R270H homozygous tumors like human CRC. Although p53 was distributed to the cytoplasm in ApcDelta716 Trp53+/R270H heterozygous tumors, it accumulated in the nuclei at the invasion front, suggesting a regulation mechanism for p53 localization by the microenvironment. Importantly, mutant p53 induced drastic morphological changes in the tumor organoids to complex glandular structures, which was associated with the acquisition of invasiveness. Consistently, the branching scores of human CRC that carry TP53 mutations at codon 273 significantly increased in comparison with those of TP53 wild-type tumors. Moreover, allografted ApcDelta716 Trp53R270H/R270H organoid tumors showed a malignant histology with an increased number of myofibroblasts in the stroma. These results indicate that nuclear accumulated mutant p53R270H induces malignant progression of intestinal tumors through complex tumor gland formation and acquisition of invasiveness. Furthermore, RNA sequencing analyses revealed global gene upregulation by mutant p53R270H, which was associated with the activation of inflammatory and innate immune pathways. Accordingly, it is possible that mutant p53R270H induces CRC progression, not only by a cell intrinsic mechanism, but also by the generation or activation of the microenvironment, which may synergistically contribute to the acceleration of submucosal invasion. Therefore, the present study indicates that nuclear-accumulated mutant p53R270H is a potential therapeutic target for the treatment of advanced CRCs. PMID- 28628122 TI - Semiconducting polymers: Probing the solid-liquid interface. PMID- 28628123 TI - Electrochemical strain microscopy probes morphology-induced variations in ion uptake and performance in organic electrochemical transistors. AB - Ionic transport phenomena in organic semiconductor materials underpin emerging technologies ranging from bioelectronics to energy storage. The performance of these systems is affected by an interplay of film morphology, ionic transport and electronic transport that is unique to organic semiconductors yet poorly understood. Using in situ electrochemical strain microscopy (ESM), we demonstrate that we can directly probe local variations in ion transport in polymer devices by measuring subnanometre volumetric expansion due to ion uptake following electrochemical oxidation of the semiconductor. The ESM data show that poly(3 hexylthiophene) electrochemical devices exhibit voltage-dependent heterogeneous swelling consistent with device operation and electrochromism. Our data show that polymer semiconductors can simultaneously exhibit field-effect and electrochemical operation regimes, with the operation modality and its distribution varying locally as a function of nanoscale film morphology, ion concentration and potential. Importantly, we provide a direct test of structure function relationships by correlating strain heterogeneity with local stiffness maps. These data indicate that nanoscale variations in ion uptake are associated with local changes in polymer packing that may impede ion transport to different extents within the same macroscopic film and can inform future materials optimization. PMID- 28628124 TI - Emergence of an enslaved phononic bandgap in a non-equilibrium pseudo-crystal. AB - Material systems that reside far from thermodynamic equilibrium have the potential to exhibit dynamic properties and behaviours resembling those of living organisms. Here we realize a non-equilibrium material characterized by a bandgap whose edge is enslaved to the wavelength of an external coherent drive. The structure dynamically self-assembles into an unconventional pseudo-crystal geometry that equally distributes momentum across elements. The emergent bandgap is bestowed with lifelike properties, such as the ability to self-heal to perturbations and adapt to sudden changes in the drive. We derive an exact analytical solution for both the spatial organization and the bandgap features, revealing the mechanism for enslavement. This work presents a framework for conceiving lifelike non-equilibrium materials and emphasizes the potential for the dynamic imprinting of material properties through external degrees of freedom. PMID- 28628125 TI - Enhanced insulin sensitivity in successful, long-term weight loss maintainers compared with matched controls with no weight loss history. AB - BACKGROUND: Weight gain is associated with deterioration in metabolic health, whereas weight loss improves insulin sensitivity. This study assesses the impact of long-term, successfully maintained weight loss and weight-loss relapse on measures of insulin sensitivity and identifies factors that explain variability in insulin sensitivity. METHODS: Women (20-45 years) were recruited into four groups: reduced-overweight/obese (RED, n=15); body mass index (BMI)-matched controls (stable low-weight, n=19), BMI?27 kg m-2; relapsed-overweight/obese subjects (REL, n=11); and BMI-matched controls (obese stable weight, n=11), BMI?27 kg m-2. A 75 g oral glucose tolerance test determined fasting and 2 h plasma glucose and insulin. Homeostatic Model Assessment (HOMA-IR) and insulin sensitivity index (ISI(0,120)) assessed insulin sensitivity. Anthropometric measurements, fasting resting metabolic rate (RMR) and respiratory quotient (RQ) were measured. Questionnaires and dietary intake were recorded, and physical activity was measured using accelerometers. RESULTS: RED were more insulin sensitive, characterised by lower fasting (P=0.001) and 2 h insulin (P=0.003) levels compared with all other groups. There were no significant differences in dietary intake, sedentary, light and moderate activity, RMR or RQ in the RED compared with the other three groups. % Body weight (BW) lost (P<0.001), % BW regained (P<0.05), body fat %, light activity (P<0.05, only log HOMA), vigorous activity (P<0.05) and RQ (P<0.01) predicted 61.4% and 59.7% of variability in log HOMA and log ISI(0,120), respectively, in multiple linear regression models. CONCLUSION: This study showed sustained enhanced insulin sensitivity in successful weight loss maintainers compared with BMI-matched controls with no weight loss history. Weight-loss-relapsed individuals were indistinguishable from controls. Weight loss itself was the strongest predictor of improved insulin sensitivity, whereas weight regain significantly predicted reduced insulin sensitivity. Weight-loss maintenance programs are essential to retaining metabolic benefits acquired through weight loss. Being physically active, reducing sedentary behaviour and, in particular, including small amounts of vigorous physical activity significantly predicted improved insulin sensitivity. PMID- 28628126 TI - Consumption of sugar-sweetened beverages and type 2 diabetes incidence in Thai adults: results from an 8-year prospective study. AB - BACKGROUND: The global prevalence of type 2 diabetes mellitus (T2DM) is high and is increasing in countries undergoing rapid socio-economic development, including Thailand. Sugar-sweetened beverage (SSB) intake may contribute to the risk of developing T2DM. However, few studies have assessed this association in Asian populations, and the results have been inconsistent. We aimed to assess that association in a prospective study of Thai adults. METHODS: Data were from Thai Cohort Study participants surveyed in 2005, 2009 and 2013. The nation-wide sample included adult cohort members who were free of diabetes in 2005 and who were followed-up in 2013 (n=39 175). We used multivariable logistic regression to assess associations between SSB intake and eight-year T2DM incidence. We used a counterfactual mediation analysis to explore potential mediation of the SSB intake and T2DM-risk relationship. RESULTS: In women (but not men) consuming SSBs once or more per day (versus rarely) was associated with increased T2DM incidence at the 8-year follow-up (odds ratio (OR)=2.4, 95% confidence interval (CI) 1.5 3.9). Obesity in 2009 was found to mediate ~23% of the total association between SSB intake in 2005 and T2DM risk in 2013 (natural indirect effect 1.15, 95% CI (1.02, 1.31). CONCLUSIONS: Frequent SSB consumption associated with higher T2DM incidence in women but not men. We found that a moderate proportion of the SSB T2DM relationship was mediated through body mass index (BMI). Our findings suggest that targeting SSB consumption can help prevent a national rise in the incidence of T2DM. PMID- 28628127 TI - RosettaES: a sampling strategy enabling automated interpretation of difficult cryo-EM maps. AB - Accurate atomic modeling of macromolecular structures into cryo-electron microscopy (cryo-EM) maps is a major challenge, as the moderate resolution makes accurate placement of atoms difficult. We present Rosetta enumerative sampling (RosettaES), an automated tool that uses a fragment-based sampling strategy for de novo model completion of macromolecular structures from cryo-EM density maps at 3-5-A resolution. On a benchmark set of nine proteins, RosettaES was able to identify near-native conformations in 85% of segments. RosettaES was also used to determine models for three challenging macromolecular structures. PMID- 28628128 TI - Adaptive optics improves multiphoton super-resolution imaging. AB - We improve multiphoton structured illumination microscopy using a nonlinear guide star to determine optical aberrations and a deformable mirror to correct them. We demonstrate our method on bead phantoms, cells in collagen gels, nematode larvae and embryos, Drosophila brain, and zebrafish embryos. Peak intensity is increased (up to 40-fold) and resolution recovered (up to 176 +/- 10 nm laterally, 729 +/- 39 nm axially) at depths ~250 MUm from the coverslip surface. PMID- 28628131 TI - A CRISPR-Cpf1 system for efficient genome editing and transcriptional repression in plants. AB - This corrects the article DOI: 10.1038/nplants.2017.18. PMID- 28628129 TI - High-speed fixed-target serial virus crystallography. AB - We report a method for serial X-ray crystallography at X-ray free-electron lasers (XFELs), which allows for full use of the current 120-Hz repetition rate of the Linear Coherent Light Source (LCLS). Using a micropatterned silicon chip in combination with the high-speed Roadrunner goniometer for sample delivery, we were able to determine the crystal structures of the picornavirus bovine enterovirus 2 (BEV2) and the cytoplasmic polyhedrosis virus type 18 polyhedrin, with total data collection times of less than 14 and 10 min, respectively. Our method requires only micrograms of sample and should therefore broaden the applicability of serial femtosecond crystallography to challenging projects for which only limited sample amounts are available. By synchronizing the sample exchange to the XFEL repetition rate, our method allows for most efficient use of the limited beam time available at XFELs and should enable a substantial increase in sample throughput at these facilities. PMID- 28628132 TI - Resilience potential of the Ethiopian coffee sector under climate change. AB - Coffee farming provides livelihoods for around 15 million farmers in Ethiopia and generates a quarter of the country's export earnings. Against a backdrop of rapidly increasing temperatures and decreasing rainfall, there is an urgent need to understand the influence of climate change on coffee production. Using a modelling approach in combination with remote sensing, supported by rigorous ground-truthing, we project changes in suitability for coffee farming under various climate change scenarios, specifically by assessing the exposure of coffee farming to future climatic shifts. We show that 39-59% of the current growing area could experience climatic changes that are large enough to render them unsuitable for coffee farming, in the absence of significant interventions or major influencing factors. Conversely, relocation of coffee areas, in combination with forest conservation or re-establishment, could see at least a fourfold (>400%) increase in suitable coffee farming area. We identify key coffee growing areas that are susceptible to climate change, as well as those that are climatically resilient. PMID- 28628130 TI - Lipid production in Nannochloropsis gaditana is doubled by decreasing expression of a single transcriptional regulator. AB - Lipid production in the industrial microalga Nannochloropsis gaditana exceeds that of model algal species and can be maximized by nutrient starvation in batch culture. However, starvation halts growth, thereby decreasing productivity. Efforts to engineer N. gaditana strains that can accumulate biomass and overproduce lipids have previously met with little success. We identified 20 transcription factors as putative negative regulators of lipid production by using RNA-seq analysis of N. gaditana during nitrogen deprivation. Application of a CRISPR-Cas9 reverse-genetics pipeline enabled insertional mutagenesis of 18 of these 20 transcription factors. Knocking out a homolog of fungal Zn(II)2Cys6 encoding genes improved partitioning of total carbon to lipids from 20% (wild type) to 40-55% (mutant) in nutrient-replete conditions. Knockout mutants grew poorly, but attenuation of Zn(II)2Cys6 expression yielded strains producing twice as much lipid (~5.0 g m-2 d-1) as that in the wild type (~2.5 g m-2 d-1) under semicontinuous growth conditions and had little effect on growth. PMID- 28628134 TI - [Effects of silver nanoparticle on hemichannel activation and anti-proliferation in HaCaT cells]. AB - OBJECTIVE: To investigate the effect of silver nanoparticles (AgNPs) on hemichannel activity in human skin keratinocytes (HaCaT) and to explore the role of hemichannel in AgNP-induced anti-proliferative effect on HaCaT cells. METHODS: HaCaT cells were exposed to 0, 0.1, 0.2, 1.0, 5.0, 10.0, 15.0 and 20.0 MUg/cm2 of AgNPs for 24 h and cell viability was assessed by propidium iodide (PI) staining with flow cytometry. Hemichannel activity was examined by ethidium bromide (EB) uptake experiments in cells exposed to AgNPs with and without hemichannel inhibitor carbenoxolone (CBX). Afterward, HaCaT cells were seeded at a low density of 1*104/supcell /cm2 or a normal density of 4*104/supcell /cm2 and cultured for 24 h. Cell proliferation was measured by cell counting kit-8 (cck-8) in low- or normal-density cultured cells exposed to AgNPs for 24 h with and without 100 MUmol/L CBX. RESULTS: Cell viability showed no significant differences between the control and AgNP-exposed groups with the concentration less than 10 MUg/cm2. Exposure to AgNPs increased EB uptake in a time- and dose dependent manner in HaCaT cells and EB fluoresce density was increased to 116.67%, 124.85% and 139.53% of the control after exposure to 10 MUg/cm2 AgNPs for 2 h, 12 h and 24 h. After being treated with 25, 50 and 100 MUmol/L CBX, 10 MUg/cm2 AgNP-induced increase in EB uptake was significantly reduced in HaCaT cells (P<0.01). The cellular proliferation rate was increased in low- and normal density cultured cells after AgNPs exposure with 100 MUmol/L CBX. After being treated with 100 MUmol/L CBX, 10 MUg/cm2 AgNP-induced anti-proliferation in low density cultured cells was significantly restrained (P<0.01). CONCLUSION: AgNPs could enhance hemichannel activity of HaCaT cells. Hemichannel activation was involved in AgNP-induced anti-proliferative effect. PMID- 28628133 TI - HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly. AB - Formation of the hepatitis B virus nucleocapsid is an essential step in the viral lifecycle, but its assembly is not fully understood. We report the discovery of sequence-specific interactions between the viral pre-genome and the hepatitis B core protein that play roles in defining the nucleocapsid assembly pathway. Using RNA SELEX and bioinformatics, we identified multiple regions in the pre-genomic RNA with high affinity for core protein dimers. These RNAs form stem-loops with a conserved loop motif that trigger sequence-specific assembly of virus-like particles (VLPs) at much higher fidelity and yield than in the absence of RNA. The RNA oligos do not interact with preformed RNA-free VLPs, so their effects must occur during particle assembly. Asymmetric cryo-electron microscopy reconstruction of the T = 4 VLPs assembled in the presence of one of the RNAs reveals a unique internal feature connected to the main core protein shell via lobes of density. Biophysical assays suggest that this is a complex involving several RNA oligos interacting with the C-terminal arginine-rich domains of core protein. These core protein-RNA contacts may play one or more roles in regulating the organization of the pre-genome during nucleocapsid assembly, facilitating subsequent reverse transcription and acting as a nucleation complex for nucleocapsid assembly. PMID- 28628135 TI - [Effect of nano-TiO2 on intestinal glucose absorption in young rat on the everted gut sac model]. AB - OBJECTIVE: To study the effect of titanium dioxide (TiO2) nanoparticles on intestinal glucose absorption in young rats and its size effect. METHODS: In the study, 63 small intestine segments were isolated from 63 Sprague-Dawley rats (SD rats, 4-week-old) to prepare the everted gut sac model. In the first part of our work, the everted sacs were exposed to 0, 50 mg/L TiO2 nanoparticles (24 nm) for 2 h with the presence of a series of glucose concentrations (10, 25, 50, 100, 200, 400, and 800 mmol/L), and the glucose absorbing function of the everted sacs were assessed in the process. On the basis of the work, utilizing the same method, further study was carried out to compare the effects of TiO2 nanoparticles (24 nm) and fine-particles (120 nm) on intestinal glucose absorbing function with the presence of 400 mmol/L glucose and 0, 10, 50, 200 mg/L TiO2. 3 intestine segments were used in each group. RESULTS: The cumulative glucose absorption increased with time extension and increased glucose concentration. In the first part of our work, with the presence of 400 mmol/L glucose, the group treated with 50 mg/L TiO2 nanoparticles showed significantly lower cumulative glucose absorption and glucose absorbing rate than the control group at the exposure time of 30 min (tcumulative absorption=3.254, P<0.05; tglucose absorbing rate=3.958, P<0.05), 90 min (tcumulative absorption=3.323, P<0.05; tglucose absorbing rate=3.063, P<0.05) and 120 min (tcumulative absorption=2.834, P<0.05; tglucose absorbing rate=3.002, P<0.05). At other glucose concentrations, statistically significant differences in cumulative glucose absorption or glucose absorbing rates were not found between the TiO2 nanoparticle exposed group and the control group. In the second part of our work, when compared with the control group, no significant downregulations in cumulative glucose absorption or glucose absorbing rates were observed in both TiO2 nano-particle treated group and TiO2 fine particle treated group. Differences between the TiO2 nanoparticle treated group and the TiO2 fine particle treated group were not statistically significant. CONCLUSION: Short-term exposure to TiO2 nanoparticles may downregulate the intestinal glucose absorbing function in young rats, and the difference with TiO2 fine particlesis is not obvious. PMID- 28628136 TI - [Effects of equol on colon cancer cell proliferation]. AB - OBJECTIVE: To investigate the effect of equol on the proliferation of colom cancer cells and to explore the mechanisms. METHODS: Colon cancer cells (DLD1,HCT15,COLO205,LOVO,SW480) were incubated, the cell proliferation was identified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay. Reverse transcription PCR and Western blot were used to measure the mRNA and the protein expression of estrogen receptor and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)in the colon cancer cells, respectively. Moreover, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay was used to investigate the effect of estrogen receptor(ER) inhibitor,ERalpha agonist, and estrogen receptor ERbetaagonist on the cell proliferation. RESULTS: ERalpha was faintly expressed in the DLD-1 and HCT-15 cells. However, ERbeta expression in DLD1, HCT15, COLO205, LOVO, and SW480 colon cancer cells. Different concentrations of equol (0, 0.5, 1, 5, 10 MUmol/L) significantly inhibited the growth of HCT-15 cell with the expression of ERalpha and ERbeta.More-over, different concentrations of equol (0, 0.5, 1, 5, 10 MUmol/L) significantly inhibited the growth of LOVO, and SW480 cells with the ERbeta expression in a dose-dependent manner as demonstrated with a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay. mRNA expressions of ERalpha and ERbeta in HCT-15 were stimulated significantly. Western blotting proved that the protein expressions of ERalpha and ERbeta increased with the increasing of equol dose. Moreover we found significant difference of Nrf2 protein expression in HCT-15 cell stimulated by different concentrationss of equol. After the similation of estrogen receptor inhibitor, ERalpha agonist, or ERbeta agonist, we found that only dif-ferent concentrations of ERbeta agonist(0, 1, 10, 100, 1 000, 10 000 nmol/L) significantly inhibited the growth of HCT-15, LOVO, and SW480 in adose-dependent manner. Estrogen receptor inhibitor and ERalpha agonistdid not present significant effect on the cell proliferation of HCT-15, LOVO, and SW480. CONCLUSION: Equol inhibited the colon cancer cell proliferation by its estrogenic activities and antioxidant activities. PMID- 28628137 TI - [Antagonistic effect of quercetin on PM2.5 toxicity in the rat's embryonic development in vitro]. AB - OBJECTIVE: To explore the antagonistic effect of quercetin on fine particulate matter (PM2.5)-induced embryonic developmental toxicity in vitro. METHODS: PM2.5 was collected on glass fiber filters by PM2.5 samplers during the heating period of Dec. 2015 to Mar. 2016 in an area of Haidian District, Beijing City. The sampled filters were cut into 1 cm*3 cm pieces followed by sonication. The PM2.5 suspension was filtered into a 10 cm glass dish through 8 layers of sterile carbasus and stored at -80 degrees C until freeze drying. Frozen PM2.5 suspension was dried by vacuum freeze-drying. In vitro post-implantation whole embryo culture was used in this study. Pregnant rats with 9.5 gestation days (GD) were killed by cervical dislocation and the uteri were removed into sterile Hank's solution. The embryos with intact yolk sacs and ecto placental cones were induced by PM2.5, and then subjected to intervention of quercetin at the doses of 0.1 MUmol/L, 0.5 MUmol/L, 1.0 MUmol/L and 5.0 MUmol/L, respectively. At the end of the 48 h culture period, the cultures were terminated, and all embryos were removed from the culture bottles and placed in prewarmed Hank's solution for evaluation. Morphological evaluation of the embryos was conducted under a stereomicroscope using the morphologic scoring system by Brown and Fabro. The mitochondrial reactive oxygen species (ROS) level was detected by FACSCalibur flow cyto-metry using MitoSOXTM Red staining. RESULTS: An obvious antagonistic effect was achieved through quercetin at the dose of 1.0 MUmol/L, which could result in an increase of visceral yolk sac (VYS) diameter, crown-rump length and head length, somite number, and the differentiation of visceral yolk sac vascular vessels. The scores of allantois, flexion, heart, hind brain, midbrain, forebrain, auditory system, visual system, olfactory system, branchialarch, maxillary process, forelimb bud and hindlimb bud also revealed a significant increase and the relative mitochondrial ROS level of embryonic cells was significantly decreased when compared with PM2.5 group. Although quercetin at the doses of 0.1 MUmol/L, 0.5 MUmol/L, 5.0 MUmol/L also exhibited protective effects against PM2.5-induced embryonic developmental toxicity, the protective effect was weaker when compared with the dose of 1.0 MUmol/L. CONCLUSION: Quercetin at proper dose may be of great benefit for the development of embryos exposed to PM2.5 in the uterus of the rats. Quercetin provides an effective strategy for the prevention of PM2.5-induced embryonic developmental toxicity. Clearance of mitochondrial ROS may be one of its mechanisms. PMID- 28628138 TI - [Effects of exposure to ambient particulate matter and polycyclic aromatic hydrocarbons on oxidative stress biomarkers in the patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To investigate the effects of exposure to ambient particulate matter (PM) and polycyclic aromatic hydrocarbons (PAHs) on systemic oxidative stress biomarkers in chronic obstructive pulmonary disease (COPD) patients. METHODS: A panel of forty-five diagnosed and stable COPD patients, whose residences were within 5 kilometers from Peking University Health Science Center (PKUHSC), were recruited and followed up twice between November 2014 and May 2015. The lung function index percentage of forced expiratory volume in 1 second (FEV1) to predicted value (FEV1%pred), was measured to reflect the severity of COPD patients. The systemic oxidative stress biomarkers malondialdehyde (MDA) and 8 hydroxy-2'-deoxyguanosine (8-OHdG) in their urine samples were measured using high performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA), respectively. Concentrations of ambient air pollutants and levels of meteorological factors were measured continuously through the air pollution monitoring station located in PKUHSC. PM2.5 samples, which were used for measuring the concentrations of PAHs, were collected by PM2.5 high volume air sampler. We constructed linear mixed-effects models, including single-pollutant model, 2-pollutant models and stratification analysis, to estimate the effects of air pollutants on urinary MDA and 8-OHdG after adjusting for confounding factors. RESULTS: In our COPD-patient panel, the associations between ultrafine particles (UFP) and PAHs and urinary MDA were statistically significant at lag2 (P<0.05). For an interquartile range (IQR) increase in UFP and PAHs, respective increases of 28% (95%CI: 4%-57%) and 36% (95%CI: 4%-77%) in urinary MDA were observed, and the effects became stronger after adjusting for the concentration of black carbon (BC). The COPD patients were divided into 2 groups stratified by FEV1%pred. Most air pollutants had stronger effects of systemic oxidative stress in the COPD patients of FEV1%pred>=50%. In this group, we observed that an IQR increase in UFP was associated with a 98% (95%CI: 38%-186%) increase in urinary MDA, and an IQR increase in BC, UFP and PAHs were associated with respective increases of 87% (95%CI: 32%-166%), 69% (95%CI: 24%-130%) and 156% (95%CI: 66%-294%) in urinary 8 OHdG. We didn't find significant associations between fine particulate matter (PM2.5) and urinary oxidative stress biomarkers. CONCLUSION: Our results suggested that exposure to air pollutants, especially UFP and PAHs, was responsible for exacerbation of systemic oxidative stress in COPD patients. Most air pollutants had stronger effects of systemic oxidative stress in mild to moderate COPD patients. PMID- 28628139 TI - [Effect of particulate air pollution on hospital admissions for acute exacerbation of chronic obstructive pulmonary disease in Beijing]. AB - OBJECTIVE: To assess the association between particulate air pollution and hospital admissions for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Beijing, and to evaluate the differences of association among different subgroups. METHODS: Hospital admissions to intertiary hospitals for AECOPD from January 1, 2014, through December 31, 2015 were obtained from the electronic hospitalization summary reports (HSRs).We obtained the data on air pollution during the study period from the national air pollution monitoring system. The data on meteorological variables were obtained from the Chinese meteorological bureau. A poison generalized additive model was used to assess the effects of particulate pollution on AECOPD with adjustment for the long term trend, day of week, holiday effect and meteorological variables. Subgroup analyses were also conducted by age and gender, which would help identify higher risk groups. RESULTS: A total of 7 884 hospitalizations from 15 tertiary hospitals were recorded during the study period, and 69.3% were male patients, 37.1% were >=80 years of age, 45.5% were 65-79 years of age, and 17.4% were younger than 65. The mean (SD) daily concentrations of PM2.5, PM10 were 77.1 (66.6) MUg/m3, 111.9 (75.8) MUg/m3. Every 10 MUg/m3 increase in particulate pollution concentration for a lag of 4 d was associated with an increase in hospital admissions for AECOPD as follows: 0.53% (95% CI: 0.01%-1.06%, P=0.0478) of PM2.5, 0.53% (95% CI: 0.07%-1.00%, P=0.0250) of PM10, respectively. We found differences in risk for AECOPD admissions among the different subgroups. For every 10 MUg/m3 increase in PM2.5, PM10 exposure in the female group there was a 1.13% (95% CI: 0.19%-2.07%, P=0.018 3) increase, 1.06% (95% CI: 0.22%-1.91%, P=0.013 6) increase in admissions, respectively, while in the male group, the association was non-significant. The patients of 80 years of age and older demonstrated a higher risk of AECOPD, 1.25% (95% CI: 0.40%-2.11%, P=0.004 0) increase of PM2.5, 1.18% (95% CI: 0.42%-1.95%, P=0.002 4) increase of PM10, respectively, while other subgroups didn't find significant association. CONCLUSION: Our findings showed that particulate air pollution was significantly associated with hospital admissions for AECOPD in Beijing. The susceptibility to particulate pollution varied by gender and age. PMID- 28628140 TI - [Correlation study between respiratory death and airborne particles in Beijing: Spatiotemporal analysis based on satellite remote sensing data]. AB - OBJECTIVE: To use vertical and humidity correcting method to calibrate aerosol optical depth (AOD), and to explore the feasibility of calibrated-AOD as exposure index to measure the level of air pollutants from the ground and to establish the exposure-response relationship between calibrated-AOD and people's health outcomes. METHODS: First of all, we interpolated AOD, PM2.5, relative humidity and planetary boundary layer height using Kriging method to obtain data at different locations and matched different data with respiratory death in Beijing by geographical coordinates. Then, the planetary boundary layer height and aerosol hygroscopic growth factor calculated based on relative humidity was used to calbrate the AOD. To compare the effects of calibrated-AOD and PM2.5, we used standardization method to get non dimensionless calibrated-AOD and PM2.5. At last, we used the generalized additive mixed model (GAMM) to estimate the acute effects of calibrated-AOD and PM2.5 on respiratory death and chronic obstructive pulmonary disease (COPD) death, after controlling the time trend, temperature and humidity effects, days of the week effect and holiday effects. RESULTS: The correlation coefficient between calibrated-AOD and PM2.5 was 0.72. The effects of calibrated-AOD on respiratory death and COPD death was the strongest at lag 0-3, one unit of calibrated-AOD increases was associated with 3.64% (95%CI: 0.58% 6.78%) increase of respiratory death and 4.92% (95%CI: 1.81%-8.14%) increase of COPD death. As for PM2.5, the strongest effects appeared at lag 0-1, one unit of PM2.5 (about 155 MUg/m3) increases was associated with excess risks of 3.96% (95%CI: 0.82%-7.19%) and 6.12% (95%CI: 1.44%-11.02%) for respiratory death and COPD death respectively. Compared with PM2.5, the effects of calibrated-AOD on respiratory death and COPD death had narrower confidence intervals. The calibrated-AOD was sensitive to capture the lag effects, and the cumulative lag effects of calibrated-AOD were all significant on multiple lag days which indicated that the calibrated-AOD was sensitive to capture cumulative lag effects of air pollutants on respiratory death and COPD death as well. CONCLUSION: We believe that calibrated-AOD can be used as an index to reflect the effects of air pollutants on respiratory death in Beijing. In the absence of ground monitoring, calibrated-AOD can be used to mea-sure the relationship between air pollutants and some health outcomes. PMID- 28628141 TI - [Associations of sedentary behavior and physical activity with dyslipidemia]. AB - OBJECTIVE: To analyze associations of sedentary behavior and physical activity with dyslipidemia among residents in Wuhai city. METHODS: Data about social demographic characteristics, life style, health status and other covariate required for analysis in this study was obtained from a cross-sectional study on a total of 11 497 18-79 years old residents in Wuhai City by questionnaire, body mea-surement and laboratory examination. In this study, sedentary behavior and physical activity were evaluated using international physical activity questionnaire long version (IPAQ). IPAQ is widely used all over the world, and its reliability and validity have been tested in Chinese population. 2016 Chinese Guideline for the Management of Dyslipidemia in Adults was used to define dyslipidemia in this study. RESULTS: According to IPAQ scoring protocol, 124 participants were excluded as a result of reporting more than 960 min of physical activity per day. 50.58% of 11 373 participants included in the analysis reported more than 4 hours of sedentary behavior per day in this study, thus 49.42% participants reported no more than 4 hours of sedentary behavior per day; the proportions of these 11 373 participants who reached Low level physical activity, Moderate level physical activity and high level physical activity were 23.43%, 37.29% and 39.28% respectively; and the detection ratios of new cases and prevalent cases of dyslipidemia in Wuhai City were 20.46% and 16.13% respectively. After controlling for confounders in this study, we found out that sedentary behavior increased the risk of new cases of dyslipidemia in women (OR=1.17, 95% CI: 1.00-1.36), and increased the risk of prevalent cases of dyslipidemia in both men (OR=1.21, 95% CI: 1.02-1.44) and women (OR=1.24, 95% CI: 1.04-1.48); as for association of physical activity with dyslipidemia, association was found between high level physical activity and prevalent cases of dyslipidemia in men in this study (OR=0.78, 95% CI: 0.62-0.98), suggested that high level physical activity may help to reduce the risk of prevalent cases of dyslipidemia in men. CONCLUSION: Our results from this cross-sectional study in Wuhai City suggested that sedentary behavior increased the risk of dyslipidemia; by contrast, physical activity may help to reduce the risk of dyslipidemia. PMID- 28628142 TI - [Epidemic status and secular trends of malnutrition among children and adolescents aged 7-18 years from 2005 to 2014 in China]. AB - OBJECTIVE: To understand and analyze the current situation and secular trends for prevalence of malnutrition among Chinese children and adolescents aged 7-18 years from 2005 to 2014, and to provide important scientific basis for students' nutrition improvement. METHODS: All the subjects aged 7-18 years in both sexes were sampled from 2005, 2010 and 2014 Chinese National Surveys on Students Constitution and Health. According to the new students' health standard of "Screening Standard for Malnutrition of school-age children and adolescents"(WS/T456-2014) in 2014 of China, the nutritional status of children in 31 provinces (autonomous regions and municipalities, excluding Hong Kong, Macao and Taiwan province) were analyzed and compared in different ages, genders, regions and provinces from 2005 to 2014. The Tibetan students was used with the data of Tibetan minority and all the other students from 30 provinces (autonomous regions, municipalities) were Han minority. RESULTS: The prevalence of malnutrition of children and adolescents of Han minority aged 7-18 years in 2014 was 10.0%. The prevalence of malnutrition components, including stunting, mild wasting and moderate severe wasting, were 0.8%, 3.7%, and 5.5%. Compared with 2005 and 2010, the prevalence of malnutrition of Han children and adolescents in 2014 had declined with 5.0 and 2.6 percentage points, respectively, and its components had declined with 1.0, 1.8, 2.2 and 0.4, 1.1, 1.2 percentage points, respectively. The prevalence of malnutrition of 2014 in boys was higher than in girls (11.1% vs.8.9%), the rural was higher than the urban (11.0% vs.9.1%) and the west (11.7%) was higher than the east (9.0%) and the middle (9.2%). Mild wasting of Chinese children and adolescents aged 7-18 years was the main component in malnutrition and the stunting in the Han and Tibetan children and adolescents only accounted for 8.0% and 7.5%, respectively. Compared with 2005 and 2010, the prevalence of malnutrition for Chinese children and adolescents aged 7-18 years in 2014 had declined with various extents constantly, and there was a statistically significant difference among three surveys (P<0.05). Provinces (autonomous regions, municipalities) with high prevalence of malnutrition mainly concentrated in the southwest of China from 2005 to 2014. Compared with 2005 and 2010, the prevalence of malnutrition declined in 31 provinces (autonomous regions, municipalities) of China in 2014. The number of provinces (autonomous regions, municipalities) with high prevalence of malnutrition decreased constantly and increased for the number of province (autonomous regions, municipalities) with low prevalence. CONCLUSION: The prevalence of malnutrition among Chinese children and adolescents aged 7-18 years had declined from 2005 to 2014, but the total prevalence of malnutrition was still high. Mild wasting was the main component in malnutrition and the prevalence of stunting was low. Provinces (autonomous regions, municipalities) with high prevalence of malnutrition mainly concentrated in the southwest of China. PMID- 28628143 TI - [Prevalence of reduced visual acuity among Chinese Han students in 2014]. AB - OBJECTIVE: To analyze the prevalence of reduced visual acuity (VA) and to examine the association between reduced visual acuity and influencing factors among Chinese Han students, so as to provide bases for the prevention and treatment of reduced visual acuity. METHODS: Subjects were from 2014 Chinese National Surveys on Students' Constitution and Health (CNSSCH). In this survey, 261 832 Han students aged 7-22 years participated. Unaided distance VA was measured using a retro-illuminated lgMAR chart with tumbling-E optotypes. Ametropia was determined by using serial bronchoscopy. Logistic regression was used to assess the association between reduced visual acuity and influencing factors. ArcMap 10 was used to map the regional distribution of reduced visual acuity. RESULTS: Nationwide, the overall prevalence of reduced visual acuity was 66.6%, and was highest among the urban girls (73.5%). The prevalence of myopia was 60.8% and accounted for more than 90% among the students with reduced visual acuity. Compared with 2010 CNSSCH, the increments of reduced visual acuity were highest in the students aged 13-15 years (6.8 percentage points). The prevalence of reduced visual acuity ranged from 50.6% to 76.2% in each province (autonomous region, municipality) in 2014 CNSSCH. The top three of the prevalence of reduced visual acuity were Jiangsu (76.2%), Zhejiang (76.0%) and Shandong (75.9%), and the lowest three were Hainan (50.6%), Guizhou (53.9%) and Xinjiang (57.6%). Logistic regression showed that the girls, urban students, and students who spent >=2 h per day in their after school homework were more likely to develop reduced visual acuity, but the students with physical activity time >=2 h per day were less likely to develop reduced visual acuity. CONCLUSION: Although the situation was different in each province (autonomous region, municipality), reduced visual acuity has become a public concern affecting the health of students in China. Based on the intervention on the key populations, such as urban girls and pre adolescent students, we should also continue to strengthen the prevention and control for reduced visual acuity among all students. PMID- 28628144 TI - [Application of the China-PAR risk prediction model for atherosclerotic cardiovascular disease in a rural northern Chinese population]. AB - OBJECTIVE: To validate five-year risk prediction models for atherosclerotic cardiovascular disease (ASCVD) in a contemporary rural Northern Chinese population. METHODS: Totally 6 489 rural adults aged 40 to 79 years without clinical ASCVD were enrolled at baseline between June and August 2010, and followed up through January 2017. Expected prediction risk using the China-PAR (prediction for ASCVD risk in China) model was compared with the pooled cohort equations (PCE) reported in the American College of Cardiology/American Heart Association guideline. Kaplan-Meier analysis was used to obtain the observed ASCVD event (including nonfatal myocardial infarction, coronary heart disease death, nonfatal or fatal stroke) rate at 5 years, and the expected-observed ratios were calculated to eva-luate overestimation or underestimation in the cohort. The participants in the cohort were divided into 4 categories (<5.0%, 5.0%-7.4%, 7.5%-9.9%, and >=10.0%) for comparisons based on ASCVD prediction risk. The models were assessed by discrimination C statistic, calibration chi2, and calibration charts and plots for illustration as well. RESULTS: Over an average 5.82 years of follow-up in this validation cohort with 6 489 rural Chinese participants, 955 subjects developed a first ASCVD event. Recalibrated China-PAR model overestimated ASCVD events by 22.2% in men and 33.1% in women, while the overestimations were much higher for recalibrated PCE as 67.3% in men and 53.1% in women. Gender-specific China-PAR model had C statistics of 0.696 (95%CI, 0.669-0.723) for men and 0.709 (95%CI, 0.690-0.728) for women, which were similar to those of 0.702 (95%CI, 0.675-0.730) for men and 0.714 (95%CI, 0.695 0.733) for women in the PCE. Calibration chi2 values in China-PAR were 17.2 and 54.2 for men and women, respectively; however, the PCE showed poorer ca-libration (chi2=192.0 for men and chi2=181.2 for women). In addition, the calibration charts and plots illustrated good agreement between the observations and the predictions only in the China-PAR model, especially for men. CONCLUSION: In this validation cohort of rural Northern Chinese adults, the China-PAR model had better performance of five-year ASCVD risk prediction than the PCE, indicating that recalibrated China-PAR model might be an appropriate tool for risk assessment and primary prevention of ASCVD in China. PMID- 28628146 TI - [Influence of awareness on the behaviors of Chinese adults with diabetes mellitus]. AB - OBJECTIVE: To explore the influence of awareness on the behaviors of Chinese adults with diabetes mellitus, so as to provide scientific evidence for developing relevant policies and strategies in the prevention and control of diabetes. METHODS: Data from the 2013 China Chronic Disease Risk Factor Surveillance were used, covering 297 surveillance counties (districts). The variables involved in this cross-sectional study included: the prevalence of diabetes, the awareness situation, demographic characteristics, behaviors, and other information. The study used descriptive analysis to analyze diabetes status and chi-square test to determine the difference in the distribution of behaviors between patients who were aware of their disease and those who were not. Logistic analysis was performed to examine the influence of diabetes awareness on patients' behaviors with adjustment for potential confounders. RESULTS: A total of 175 670 subjects were involved. The prevalence of self-reported diabetes in China in 2013 was 3.9%, while the awareness rate was 38.6%. The percentage of current smokers or current drinkers among the patients who were aware of their disease (20.2%, 25.0%) was less than that among the patients who were not aware (25.8%, 35.0%). The proportion of those who often exercised among the patients who were aware of their disease (83.4%) was higher than that among the patients who were not aware (79.0%). There was slightly higher proportion of the subjects who had insufficient intake of vegetables and fruits or over intake of red meat among the patients who were aware of their disease (49.4%, 28.0%) than that among the patients who were not aware (48.4%, 26.1%). After controlling urban and rural areas, regions, age, gender, nationality, marital status, educational level, occupation, and income factors, the possibility of current smoking (OR=0.79) or drinking (OR=0.58) among the patients who were aware of their disease was lower than among those who were not; the possibility of more than 150-minute physical activity per week (OR=1.30) among the patients who were aware of their disease was higher than among those who were not. CONCLUSION: The awareness rate of diabetes in China still remains low. Kno-wing whether they have diabetes or not has an effect on individual choice of behaviors, including smoking, drinking and physical activities. Therefore, health education and health examination for diabetes should be further expanded with wide cooperation from all relevant departments, thus forming an integrated environment involving individuals, health systems and socioeconomic policies to prevent and control diabetes. PMID- 28628145 TI - [Relationship between glycemic control and visceral adiposity index among the patients with type 2 diabetes mellitus]. AB - OBJECTIVE: To explore the relationship between glycemic control and visceral adiposity index (VAI) among type 2 diabetes mellitus (T2DM) patients. METHODS: A community-based epidemiological field study for patients with T2DM aged >= 40 years was conducted in China.Every participant underwent physical examinations, biochemical tests of fasting glucose, glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL C), low density lipoprotein cholesterol (LDL-C) and so on, and a questionnaire, including anthropometric characteristics, lifestyle, disease history, family history, and medication use. Those participants with HbA1c >=7.0% were classified as the poorly controlled in our analysis of relationship between glycemic control and VAI. Anthropometric characteristics, lifestyle, and biochemical indexes of the participants were compared among the groups of different VAI levels. Logistic models were applied in multiple analysis adjusting for possible confounders. RESULTS: A total of 1 607 patients with T2DM were recruited in our analysis with a mean age of (59.4+/-8.1) years and an average T2DM duration of (7.0+/-6.4) years. Among them, 78.3% were on hypoglycemic therapy. The cutoff points of quartiles of VAI were calculated for the males and females, respectively. According to the ascending order of the quartiles of VAI, the participants were divided into four groups, i.e. Q1, Q2, Q3, and Q4. The poor glycemic control rate for these groups were 60.6%, 65.7%, 70.1%, and 71.0%, respectively (Trend chi2=12.20, P<0.001). After adjustment for age, gender, systolic blood pressure (SBP), diastolic blood pressure (DBP), LDL-C, smoking, cardio-cerebral vascular disease (CVD) history, hypoglycemic therapy, T2DM duration, and family history of diabetes, the Logistic regression models showed that the glycemic control rate was significantly associated with VAI levels among the patients with T2DM. Compared with the participants in group Q1, the ORs of poor glycemic control for those in groups Q2, Q3, and Q4 were 1.239 (95%CI 0.918 to 1.672), 1.513 (95%CI 1.117 to 2.050), and 1.535 (95%CI 1.128 to 2.088), respectively (trend P=0.003). With each quartile increase in VAI, the OR of poor glycemic control was 1.162 (95%CI 1.054 to 1.282). CONCLUSION: The glycemic control among the patients with T2DM is significantly associated with VAI. High level of VAI is an indicator of poor glycemic control. PMID- 28628147 TI - [Association between social support and self-management behaviors among patients with diabetes in community]. AB - OBJECTIVE: To study the status quo of directive and nondirective support from family or friends among patients with diabetes in community and to explore the association between directive, nondirective support from family or friends and self-management behaviors. METHODS: The data of the subjects were from the "Community Diagnosis in Tongzhou District, Beijing" survey. Questionnaire-based investigation, physical examination and glycated hemoglobin test were conducted on 474 eligible patients in community. The summary of diabetes self-care activities measure (SDSCA) was adopted to investigate the self-management behaviors, and directive and nondirective support scale among patients with diabetes (DNSS-PD) was adopted to measure the directive and nondirective support among patients with diabetes. RESULTS: A total of 452 patients with diabetes were included in the analysis. The average score of directive support was 2.53+/-1.07, and only 27.6% patients had high level directive support. The average score of nondirective support was 3.13+/-1.12 and 50.8% patients had high level nondirective support. The average SDSCA total score was 35.38+/-14.21 and the corresponding scoring percentage was 45.95%. Only 20.6% patients had optimal self management. The total score, score of diet and physical activity, general self management situation, diet self-management situation and physical activity self management situation of the patients in high level directive support group were significantly better than in low level directive support group. The total score, score of self-management behaviors in five aspects (diet, physical activity, blood glucose self-monitoring, foot care and smoking), general self-management situation, self-management situation of five aspects of patients in high level nondirective support group were significantly better than in low level nondirective support group. Gender (OR=2.729), nondirective support level (OR=4.890), age (OR=0.969) and body mass index (BMI) (OR=0.819) were important influencing factors of self-management behavior. CONCLUSION: The status quo of self-management among patients with diabetes is not optimistic. Patients obtain more nondirective support than directive support from family and friends. However, the support level of both nondirective and directive support should be improved in the future.Both high level directive support and high level nondirective support had positive correlation with better self-management behaviors. Nondirective support had positive correlation with five aspects of self-management behavior, while directive support had positive relation with self management behavior in aspects of diet and physical activity. In addition, more consideration and support of self-management should be provided for older obese male patients with diabetes in community, especially nondirective support. PMID- 28628148 TI - [Changes of acquired immune deficiency syndrome related knowledge, attitudes, behaviors and their influencing factors among college students in Beijing]. AB - OBJECTIVE: To compare acquired immune deficiency syndrome (AIDS) related knowledge, attitudes, behaviors and their influencing factors among college students in different years in Beijing, and to provide evidence for targeted health education among college students in future. METHODS: College students were selected by the stratified cluster sampling method, and a questionnaire survey was conducted among college students in year 2006 and 2016 in Beijing. The sample sizes were 1 800 and 3 001 college students, respectively. The contents of the questionnaire included: socio-demographic characteristics, AIDS related knowledge, AIDS related attitude, sex intercourse and its related risk behaviors, condom use intension, and AIDS related health education. RESULTS: Compared with the year 2006, the average AIDS knowledge scores of college students in year 2016 dropped from 12.78+/-1.95 to 11.90+/-2.56 (t=12.91, P<0.05), and the correct answer rates of questions in the knowledge part were decreased, too. Except for belief on condom use, the college students were more negative on AIDS related attitude and self-efficacy in year 2016 than in year 2006. Among the students who had sex experience, the rates of commercial sex [17.65% (33/187) vs. 6.53% (16/245), chi2=13.003, P<0.001] and the rates of homo-sexual intercourse [15.43% (29/188) vs. 4.13% (10/242), chi2=16.356, P<0.001] were higher in year 2016 than in year 2006. The main way for the students seeking pornographic information was changed from books to internet (41.15%) in 2016 compared with the year 2016. In 2016, the influencing factors of intention on condom use were male (OR=0.713), self-efficacy of condom purchase (OR=0.876), never received sex education before college (OR=0.752), self-efficacy of condom use (OR=1.135), belief of condom use (OR=1.775), and attitude towards AIDS patients (OR=1.136). CONCLUSION: AIDS related knowledge, attitudes and behaviors among college students have been changed, AIDS related health education should be designed and improved based on new characteristics of college students. AIDS health education in colleges should pay more attention to sex attitude and sex responsibility and self-protection awareness among college students as well. PMID- 28628149 TI - [Present situation of awareness of acquired immune deficiency syndrome (AIDS) knowledge and AIDS-related behaviors among youth students in gay dating sites]. AB - OBJECTIVE: To investigate the awareness of acquired immune deficiency syndrome (AIDS) knowledge and AIDS-related behaviors among youth students in gay dating sites, and to provide evidences for AIDS prevention education through the internet. METHODS: The students in gay dating sites, selected by a snowball sampling, were interviewed by questionnaires. Chi-square tests were used to analyze the awareness of AIDS knowledge among the students of different characteristics. The Logistic regression was used to analyze the factors associated with ever testing for HIV. RESULTS: In the study, 469 youth students in gay dating sites filled in the questionnaires, and a total of 442 (94.2%) valid samples were collected. The awareness of HIV/AIDS knowledge for the public among the youth students in gay dating sites was 83.9% (371).The awareness of HIV/AIDS knowledge for the youth students was 77.1% (341), and the rate of ever testing for HIV was 52.0% (230). The awareness of HIV/AIDS knowledge for the public in the students were different in different age groups (P=0.001), different marital statuses (P<0.001), different sexual orientations (P<0.001), and different genders of the first sexual partner (P<0.001). The awareness of HIV/AIDS knowledge for the youth students were different in different age groups (P=0.010), different marital status (P=0.004), different sexual orientations (P<0.001), and different genders of the first sexual partner (P<0.001). The rate of ever having sexual intercourse among the youth students in gay dating sites was 75.1% (332), and the rate of multiple sexual partnerships among the youth students was 41.3% (137). Compared with homosexual orientation, sexual orientation as heterosexual (OR=0.282, 95%CI: 0.151 to 0.528) and not sure (OR=0.175, 95%CI: 0.035 to 0.885) were risk factors of ever testing for HIV. Multiple sexual partnerships (OR=2.103, 95%CI: 1.278 to 3.462) were promoting factors of ever testing for HIV. CONCLUSION: The rate of high-risk behaviors among the youth students in gay dating sites was high. The concern should be raised to heterosexual male students who had tendency to homosexual behavior. The AIDS prevention education should be developed in gay dating sites, to improve the self-protection awareness of the youth students. PMID- 28628150 TI - [Analysis on status and determinants of outpatient service utilization of rural floating population in Beijing at different residence time]. AB - OBJECTIVE: To study the status and identify the determinants of outpatient service utilization of rural floating population in Beijing who have different accumulated residence time. METHODS: The survey data of rural floating population health and health care services in Beijing in 2014 were used, and the migrant population aged 18 years and above were taken as the research object. Whether to use outpatient service within two weeks was taken as dependent variable, gender, age, education level, self-assessment score of socioeconomic status, accumulated residence time in Beijing, health insurance, average household income, suffering from high blood pressure or diabetes as independent variables. Logistic regression model was used to analyze the influencing factors. RESULTS: The average age of the research object was 36.7 years, with mostly secondary education. The average accumulated residence time in Beijing was 8.4 years. The two-week prevalence rate was 10.3%, the two-week visiting rate calculated by person-time was 6.0%. The Logistic regression model suggested that, socioeconomic status, accumulated residence time and suffering from high blood pressure or diabetes were statistically significant determinants of outpatient service utilization. CONCLUSION: The research object is a younger and less educated population, their health status is better and outpatient service utilization is lower. It is found that people who have longer accumulated residence time in Beijing have lower outpatient service utilization. This is because people with longer residence time have lower age-adjusted two-week prevalence rate. This is also because people with longer residence time have larger proportion of taking continuous measures under doctor's advice. It does not mean people with longer residence time have lower utilization of medical service. The residence time variable plays the role of proxy variable. It can solve the problem of variables' endoge-neity. At the same time, it can reflect the influence to outpatient services utilization of some determinants, which are not included in the model but varies with residence time. PMID- 28628151 TI - [Assessment and comparison of hospital operating efficiency under different management systems]. AB - OBJECTIVE: To assess and analyze the operation efficiency of 8 commission general public hospitals managed directly by National Health and Family Planning Commission and 8 municipal general hospitals managed directly by Beijing Municipal Administration of Hospitals in Beijing and to provide suggestions on improving service capacity and designing relevant health policy. METHODS: Input and output data of 8 commission hospitals and 8 municipal hospitals were obtained from Beijing Direct-Reported Health Statistics data from 2011 to 2014. Data envelopment analysis was used as the hospital operation efficiency measurement tool. The CCR and BCC models were built to calculate technical efficiency (TE), pure technical efficiency (PTE), scale efficiency (SE) and the status of scale efficiency of 16 hospitals in 2011 and 2014; the Malmquist index model was built to analyze the total factor productivity change (TFPC), technological change (TC), technical efficiency change, pure technical efficiency change and scale efficiency change of the 16 hospitals from 2011 to 2014. RESULTS: In 2011, the TE, PTE and SE of the commission hospitals were higher than those of the municipal hospitals, and the TEs of the commission hospitals and the municipal hospitals were 0.918 and 0.873 respectively. In 2014, the TE, PTE and SE of commission hospitals were lower than those of the municipal hospitals, and the TE of the commission hospitals and the municipal hospitals were 0.906 and 0.951, respectively, which was contrary to the results in 2011. According to the Malmquist index model, the average of TFPC of the municipal hospitals was larger than that of the commission hospitals, the former increased 5.9% and the latter increased 2.8% per year; the average of TC was greater than the one in both the municipal hospitals and the commission hospitals, with a growth of 3.2% and 2.9% per year, respectively; the average growth of PTE in the commission hospitals was lower than that of the municipal hospitals, and the average descent of SE in the commission hospitals was larger than that in the municipal hospitals. CONCLUSION: There are significant differences in the operation efficiency between different management systems and the main factors associated with operation efficiency are the technological and management level. Given scale efficiency status and macroeconomic medical policies, the commission hospitals and the municipal hospitals require further adjusting the distribution of medical resources, and it is of great significance for all the commission hospitals and the municipal hospitals to improve the management level and resource integration capability. PMID- 28628152 TI - [Relationship between macrophage capping protein and gastric cancer cell's proliferation and migration ability]. AB - OBJECTIVE: To investigate the effect of macrophage-capping protein (CapG) on migration and proliferation of human gastric cancer cell line. METHODS: Real-time PCR method was used to detect the expression of CapG gene in four gastric cancer cell lines, and AGS cells with low expression and transfection were selected as the research objects. Specific primers were designed for CapG and recombinant plasmids synthesized. A lentivirus packaging system which could express CapG was constructed, and a cell line stably expressing CapG was established by infecting human gastric cancer cell line AGS cells. The effect of overexpression of CapG gene on the growth and proliferation of AGS cells was analyzed by CCK8 assay. Cells cratch and Transwell assay were used to analyze the effect of overexpression of CapG gene on AGS cell migration. RESULTS: After the overexpression of CapG, the growth rate of AGS cells was slightly lower than that of the control group, but there was no significant difference between the two groups (t=2.424, P=0.073). Scratch test showed that the average narrowing distance of the scratches in the CapG experimental group was significantly reduced compared with the control group, the average narrowing distance of the CapG experimental group and the control group was 336.99 MUm and 45.54 MUm, the difference was statistically significant (t=14.97, P=0.004). The average number of cell penetra-ting membrane in the CapG experimental group and the eGFP control group was 176 and 70, the number of the cells in the CapG experimental group was significantly higher than that of the control group (t=40.00, P<0.001). CONCLUSION: The overexpression of CapG gene has no significant effect on the growth and proliferation of AGS cells of gastric cancer cell line. Overexpression of CapG gene can promote the migration of AGS cells of gastric cancer cell lines. PMID- 28628153 TI - [13 cases of littoral cell angioma in spleens]. AB - OBJECTIVE: To investigate the clinicopathological features, morphological characteristics, immunophenotypes of littoral cell angioma (LCA) in spleen, and to provide new evidence for making diagnosis and avoiding misdiagnosis. METHODS: Clinicopathological data, histological characteristics of 13 cases of LCA were retrospectively studied and immunohistochemical staining was imposed on the paraffi-nembedded specimens, and 5 cases of cavernous hemangioma, 4 cases of normal littoral cells of spleens were used as control groups, simultaneously. RESULTS: All the 13 LCA patients included 7 males and 6 females, aged from 39 to 70 years with an average of 54. 2 years and a median age of 55 years. Among these tumor patients, 6 cases were accompanied by malignances, benign tumors or inflammation states at abdominal cavities, and 7 cases were accidentally discovered by physical examinations. Grossly, spleens contained solitary or multiple gray red nodules ,which ranged from 0.5 to 6.2 cm in diameter. Histologically, tumors were composed by anastomosing vascular spaces which were lining by plump, rounded to cuboidal littoral cells that extended into vascular lumens. Usually, papillary frameworks that were covered by these cells were also seen extending into the lumens in some areas. Other types of histiocytoid cells were identified in lumens and the sizes were larger than the littoral cells. Both types of cells absented cytologic atypia. Immunohistochemical study demonstrated that the littoral cells in all cases were positive for vascular endothelial and histiocyte markers, such as CD21, CD31, CD68, polyclone FVIII RAg and ERG, while these cells were negative for CD8, CD34, and WT-1. These findings manifested that immunophenotype of littoral cell in LCA distinctive from that in controls. CONCLUSION: LCA is a benign lesion, which frequently occurs in the elderly. Its etiology remains confusion, however, immune dysregulation may associate with it because of the concomitance with other tumor or inflammation in some cases. The littoral cells in LCA show a hybrid endothelial-histiocytic phenotype on immunohistochemistry, therefore these cells may have features that intermediate between those of endotheliocytes and histiocytes. Emphasizing the histological findings and immunophenotypes is significant for diagnosis and differential diagnosis. PMID- 28628154 TI - [Morphological changes on cochlear hair cells of rats in simulated weightlessness and inboard noise]. AB - OBJECTIVE: To observe the morphological changes on cochlear hair cells of rats in simulated weightlessness and inboard noise and to investigate the different changes in three turns of hair cells. METHODS: Thirty-two healthy SD rats, all males, were randomly divided into four groups: control group, weightlessness group, noise group and weightlessness+noise groups (n=8). Then rats were exposed to -30 degrees head down tilt as simulated weightlessness and inboard noise including steady-state noise which was (72+/-2) dB SPL and impulse noise up to 160 dB SPL in spaceship environment. The control group was kept in normal condition for 8 weeks. Bilateral auditory brainstem response (ABR) thresholds were tested before and after exposure respectively, and immunofluorescence staining and scanning electron microscopy (SEMs) of basilar membrane were applied after exposure. RESULTS: ABR threshold shifts of each group were higher after exposure. There was difference between ABRs of the experiment groups before and after exposure (P<0.05). IF showed that the inner hair cells (IHCs) missing was the main damage in the basal turn of weightlessness group, the hair cells in the middle turn were swell and in the top turn, the hair cells were not clear. In noise group, the main loss happened in the outer hair cells (OHCs) of the outermost layer. In weightlessness+noise group, the nuclear missing in the basal turn was apparent, and mainly happened at the outermost layer. Meanwhile, the missing of hair cells in the middle turn and top turn was seen at the innermost layer. SEM showed that the cilia in the basal turn of weightlessness group were serious lodging, and occasional absence. Furthermore, the basal cilia in noise group became lodged and absent, and the other two turns were seriously missing. And in weightlessness+noise group, the cilia missing in the basal turn was apparently seen. The damage degree of the four groups: weightlessness+noise group>noise group>weightlessness group>control group and the damage degree of the four turns of hair cells: basal turn>mid turn>top turn. CONCLUSION: The rats exposed to the above environment for 2 weeks displayed obvious changes in cochlea morphology, and the weightlessness +noise group had the most obvious damage. PMID- 28628156 TI - [Atlantoaxial reduction and fixation guided by the intraoperative CT]. AB - OBJECTIVE: To evaluate the clinical result of atlantoaxial reduction and fixation guided by the intraoperative CT. METHODS: Sixteen cases were retrospectively studied, including seven males and nine females, with the mean age of 49.9 years. Twelve cases were diagnosed as chronic atlantoaxial instability or dislocation, while four cases as acute odontoid fracture and dislocation. Among the sixteen cases, fourteen underwent atlantoaxial fusion, while two underwent temporary atlantoaxial fixation without fusion. The intraoperative CT was used in the setting of: 1. Evaluating the atlantoaxial reduction before the screw insertion; 2. Guiding the C1 and C2 pedicle drilling (two cases using additional three dimensional printing drilling template); 3. Evaluating the position of the screws and reduction after the atlantoaxial fixation. In addition, three-dimensional drilling template combined with intraoperative CT was used in two cases. CT scanning frequency was calculated. To evaluate the accuracy rate of screw fixation under the intraoperative CT, 19 cases without the intraoperative CT were studied as the control group. RESULTS: Averaged CT scanning frequency was 1.4 times (Once in eleven cases, twice in four and three times in one). Among the sixteen cases, mal-positioned C1 screws were found and revised in two cases. No spinal cord injury or vertebral artery injury occurred. The follow-up ranged from three to ten months, with the mean of 6.7 months. Fourteen cases achieved solid osseous fusion, and two with temporary fixation had odontoid fracture union. Anatomic reduction was achieved in all the cases. Eleven cases with preoperative myelopathy had postoperative improvement and their mean JOA scores improved from 12.1 to 14.4. To the last follow-up, no hardware complications were found including screw broken, rod broken or fixation loosening. All the screws of intraoperative CT group had good positions. For 19 cases of the control group, there were two cases of mal-positioned screws (10.5%). CONCLUSION: Advantages of atlantoaxial reduction and fixation guided by the intraoperative CT included: improving the accuracy of the atlantoaxial screws, exactly evaluating the reduction of the atlantoaxial joint, immediately discovering the mal-positioned screws and avoiding the revision surgery. A good clinical result was found in the preliminary study. PMID- 28628155 TI - [3D printed template-assisted and computed tomography image-guided 125-iodine seed implantation for supraclavicular metastatic tumor: a dosimetric study]. AB - OBJECTIVE: To compare the dosimetric data between the preoperative plans and postoperative verification in personalized 3D printed template-assisted and computed tomography (CT) image-guided 125-iodine seed implantation for supraclavicular metastatic tumor, and to evaluate the accuracy and feasibility at the dosimetry level. METHODS: A total of 14 patients with supraclavicular metastatic tumor (including 15 lesions) who received 3D printed template assisted and CT image-guided 125-iodine seed implantation in Department of Radiation Oncology of Peking University Third Hospital from January to September 2016 were enrolled. There were 8 males and 6 females, aged from 46 to 79 years (mean age: 59.9 years). The Karnofsky performance score (KPS) was from 60 to 90 (median of 80). There were one patient who had not received radiotherapy before, and one patient had received radiotherapy, but the dose was unknown. The remaining 12 patients had received radiotherapy, with the median of 60 Gy (20-70 Gy), and one of them with the dose unknown. All the patients underwent preoperative enhanced CT scan, preoperative planning design, 3D printing template, puncture and particle implantation, the prescription dose from 110 Gy to 150 Gy. Comparisons of the dosimetric parameters between the postoperative verification and preoperative plans were made by paired t-test. The dose parameters inclu-ded D90, V100, V150, V200, matched peripheral dose (mPD), conformal index (CI), and external index (EI). The agreement was evaluated between the preoperative planning and postoperative actual dose parameters using Bland-Altman analysis. Bland-Altman plot showed the difference against the average of preoperative planning and postoperative actual dose parameters with limits of agreement (LoA) (broken lines). RESULTS: The difference of all the data between pre- and postoperation, included D90, V100, V150, V200, mPD, and CI, which was not statistically significant (P>0.05). EI was statistically significant (P<0.05). There was poor consistency of D90, V100, V150, V200, and mPD, but better consistency of CI and EI. CONCLUSION: Personalized 3D printed template-assisted and CT image-guided 125-iodine seed implantation for supraclavicular metastatic tumor is accurate and feasible. PMID- 28628157 TI - [Biomechanical analysis of the deep radioulnar ligaments stabilizing the distal radioulnar joint]. AB - OBJECTIVE: To evaluate the role of the deep radioulnar ligament in the stability of the distal radioulnar joint (DRUJ). METHODS: In the study, 14 fresh cadaver upper extremities were randomly divided into two groups. After exposuring the palmar and dorsal deep distal radioulnar ligament, one group was marked as palmar deep radioulnar ligament, and the other group was marked as dorsal deep radioulnar ligament. The pronator teres and the supinator were exposed. A Kirschner wire perpendicular to the bone on Lister tubercle of radius was inserted, then another Kirschner wire on the same level of ulnar inserted when the forearm was in neural position, which was kept parallel to the first Kirschner wire. These specimens were mounted on a specially designed jig which held the limb rigidly, keeping the elbow flexion and the ulnar fixation. The radius could freely rotate around the ulnar. Then 50 N force on the pronator teres was applied to simulate the active pronation, and 60 N force on the supinator to simulate the active supination. The active pronation was stimulated, and the displacement of the distal radius was measured with respect to the ulna. The active supination was atimulated, and the displacement of the distal radius was measured with respect to the ulna. The palmar deep radioulnar ligament in one group was cut, then the displacement of the distal radius measured with respect to the ulna when the forearm was in pronation and supination. The dorsal deep radioulnar ligament in the other group was cut, and the displacement of the distal radius measured with respect to the ulna when the forearm was in pronation and supination. RESULTS: After resection of the palmar deep radioulnar ligament, the displacement of the distal radius with respect to the ulna was statistically significantly different when the forearm was in pronation (t=5.591, P=0.001), but there was no difference when the forearm was in supination (t=0.433, P=0.680). After resection of the dorsal deep radioulnar ligament, the displacement of the distal radius with respect to the ulna was not different when the forearm was in pronation (t=1.000, P=0.356), but there was statistically significant difference when the forearm was in supination (t=6.225, P=0.001). CONCLUSION: DRUJ is unstable when the forearm is in pronation after resection of the palmar deep ra dioulnar ligament, and DRUJ is unstable when the forearm is in supination after resection of the dorsal deep radioulnar ligament. PMID- 28628158 TI - [Effects of PTCH1 mutations on the epithelial proliferation derived from keratocystic odontogenic tumour]. AB - OBJECTIVE: To explore the relationship between the PTCH1 mutation and the expression of bcl-2, filaggrin, and loricrin in the keratocystic odontogenic tumour (KCOT), as well as the effects of the mutated PTCH1 on the epithelial proliferation and differentiation. METHODS: The samples were collected from 20 cases of KCOT with mutated PTCH1, as well as 20 cases without mutation. All the samples were analyzed with immunohistochemical staining, for the purpose of investigating the expression of bcl-2, filaggrin, and loricrin. RESULTS: In the samples with mutated PTCH1, the epithelia of 60% (12/20) cases expressed intensively positive bcl-2 staining, 20% (4/20) expressed moderate staining, and 20% (4/20) weak staining, but no negative bcl-2 staining samples were investigated; it was significantly different from the samples without PTCH1 mutation, in which 20% (4/20) expressed intensive staining, no moderate staining, 50% (10/20) weak staining, and 30% (6/20) negative staining were investigated (U=72, P=0.001). For the expression of filaggrin, 55% (11/20) of samples with PTCH1 mutations were stained weakly and 45% (9/20) showed negative staining, while in the samples not harboring PTCH1 mutations, 30% (6/20) cases showed moderate positive staining, 40% (8/20) weak staining and 30% (6/20) negative staining, no intensive staining was investigated (U=182, P=0.48). The loricrin expressed in all the layer of the epithelia in all the samples, while the filaggrin was mainly loca-lized within 1-4 layer cells of the epithelia. The differences of the expression of filaggrin and loricrin between the samples with mutated PTCH1 and without mutated PTCH1 displayed no significance. CONCLUSION: In the epithelia of KCOT, the bcl-2 expression was significantly associated with the PTCH1 mutation, which suggested that the mutated PTCH1 gene perhaps promotes the proliferation of KCOT epithelium. PMID- 28628159 TI - [Diagnosis accuracy of fine-needle aspiration cytology for vascular anomalies]. AB - OBJECTIVE: To evaluate the feasibility of fine-needle aspiration cytology (FNAC) in diagnosing vascular abnormality in oral and maxillofacial region. METHODS: The method of retrospective study was used. The data from the patients who underwent FNAC from 2011 to 2014 in Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology were collected. All the included patients were divided into surgery group and non-surgery group. The patients in surgery group underwent lesion resection and the postoperative pathological results were gained. The patients in non-surgery group underwent periodical sclerotherapy. The accuracy of FNAC was identified by histopathologic diagnosis in surgery group and the effect of sclerotherapy in non-surgery group. RESULTS: In this study, 93 patients were involved, including 51 males and 42 females. The median age was 2.5 years. Among them, 67 cases were judged as vascular abnormality by FNAC, and 63 cases were in consistent with final diagnosis and 4 cases were not. Among the other 26 cases which were diagnosed as other diseases by FNAC, 5 cases were accorded with final diagnosis. Therefore, the sensitivity of FNAC on diagnosis of vascular abnormity was 93% and its specificity was 84%. Among them, there were 29 cases in the surgery group and 64 cases in the non-surgery group. FNAC results were in consistent with the postoperative pathological results in 20 cases in surgery group (69%), and not consistent with pathological results in 9 cases . The pathological diagnoses included vascular malformations (3 cases), neurofibromas (2 cases), hamartoma (1 case), sebaceous cyst (1 case), adenolymphoma (1 case), and descriptive diagnosis (1 case). In non-surgery group, FNAC results were in consistent with the clinical effect of sclerotherapy in 61 cases (95%). There were 3 misdiagnosed cases. The coincident rate between the result of FNAC and that of pathological or clinical diagnosis was 86%. CONCLUSION: FNAC is a feasible and minimal invasive method to diagnose vascular abnormality in oral and maxillofacial region. PMID- 28628160 TI - [Evaluation of the correction of the skeletal class III malocclusion by distalization of the whole mandible dentition with micro-implant anchorage]. AB - OBJECTIVE: To evaluate the clinical effect of distalizing mandibular dentition with micro-implant in patients with skeletal class III malocclusion. METHODS: In the study, 20 patients with skeletal class IIImalocclusion were selected. They are consist of 8 males and 12 female with an age range from 16 to 38 years old and an average age of (21.5+/-5.6) years.They were treated with straight wire technique and the implant were inserted into the mandibular external oblique line to distlize the lower dentition to a class I molar relationships. Cephalometrics films were taken before and after treatment. The changes of hard tissue and soft tissue were analyzed by evaluating 26 measurement measurements. RESULTS: Class I molar relationships were achieved, and the profile were improved after treatment. ANB increased by (0.80+/-1.02) degrees ,Wits increased by (1.67+/-1.74) mm,after treatment (P<0.05). The lower dentition were significantly retracted after treatment with L1-NB distance decreased by(2.64+/-1.50) mm, P<0.05; the mesial buccal cusp and mesial root of the lower first molars were retracted by (3.26+/ 1.95) mm and (0.79+/-1.27) mm respectively (P<0.05); the mesial buccal cusp of the lower second molars were retracted by (3.06+/-1.80) mm (P<0.05). After treatment, mandibular teeth got up-righted distally. From incisors to molar, L1/MP, L5/MP, L6/MP, L7/MP angle decreased by (6.37+/-8.53) degrees , (10.59+/ 8.50) degrees , (11.48+/-7.22) degrees , (15.72+/-7.16) degrees on average respectively (P<0.05), all of those changes had the statically significant effects. Soft tissue change after treatment, the distance from lower lip to esthetic plane were decreased by (1.70+/-1.59) mm on average (P<0.05). CONCLUSION: Distalizing mandibular dentition with micro-implant can get an satisfying result in patients with skeletal class III malocclusion, the lower teeth were retracted by controlled tipping movement. PMID- 28628161 TI - [Detection and management of the vascular paths in the lateral sinus wall using cone beam computed tomography]. AB - OBJECTIVE: To detect the vascular paths in the lateral wall of maxillary sinus using cone beam computer tomography (CBCT), and to retrospect the surgical managements of avoiding bleeding complication during the lateral approach maxillary sinus elevation. METHODS: The documents of 71 consecutive patients with 81 sides maxillary sinus elevation surgery were collected. The vascular paths in the lateral wall of maxillary sinus were detected by the preoperative CBCT, and the messages about the vascular in surgical records were analyzed. RESULTS: The paths of the vascular could be detected in 77 (95.1%) sides maxillary sinus in the reconstruction panoramic images of CBCT. At the position of the first molar, the paths of the vascular of the lateral maxillary sinus walls could be detected in 54 sides (66.7%) in the reconstruction coronal images of CBCT, and the other 27 sides (33.3%) could not be detected. Two approximately parallel paths of the vascular were found in 3 sides (3.7%) of the lateral maxillary sinus walls. The different diagnoses occurred in 6 sinuses between two observers. The kappa of diagnostic consistency of the two observers was 0.842 (P<0.001). The mean distance between the lower border of the vascular path to the plane of the alveolar crest of 54 sides maxillary sinuses was about (13.0+/-4.7) mm. The mean distance between lower border of vascular path to the plane of the floor of the sinus was (9.3+/-4.8) mm. The vascular path was located in the floor wall in 1 sinus. During the lateral approach maxillary sinus elevation operation, intraosseous vessels were dissected in 4 sides sinus lateral wall, the vascular path was avoided consciously in 3 sides, and the sinus elevation surgery had to be given up in 1 side for the vessel was torn and bleeding. There were no vascular related messages in 73 sides of the lateral approach maxillary sinus elevation operation records. CONCLUSION: The vascular paths of maxillary sinus wall could be detected by CBCT in most cases. Preoperative CBCT examination was proved to be reliable. The vascular paths of maxillary sinus wall should be examined carefully. It was helpful to make the surgical design perfectible and reduce the risk of tearing the vessel in operation. PMID- 28628162 TI - [Distant metastases of malignant salivary gland carcinoma after treated by 125I]. AB - OBJECTIVE: To investigate clinical features of distant metastases from malignant salivary gland carcinomas after treated by 125I internal brachy therapy alone. METHODS: Between 2002 and 2010, 43 patients with locally advanced unresectable or recurrent malignant salivary gland carcinomas were treated by 125I internal brachy therapy alone at Peking University School and Hospital of Stomatology. All of them had been follow-up at least 2 years. The primary sites of malignant salivary gland carcinomas were the parotid for 12 patients, infratemporal fossa for 9 patients, tongue for 7 patients, maxilla for 6 patients, parapharyngeal for 4 patients, floor of months for 3 patients, submandibular gland for 1 patient, and lip for 1 patient. The overall survival rate, local control rate, and distant metastases were retrospectively reviewed. RESULTS: Distant metastases occurred in 23 of the 43 patients (53.5%). Distant metastases developed from 5 to 96 months, with an average interval of (27.0+/-23.7) months from the time of initial diagnosis, the mean interval was 21 months. The commonest site of distant metastases overall was the lung 69.6%(16/23). The most common pathological types of distant metastases were adenoid cystic carcinoma (14/23, 60.9%) and nonspecific adenocarcinoma (7/23, 30.4%). At the time of the last follow-up, 26 patients died, and 18 of them due to distant metastases (69.2%, 18/26). In the study, 27 patients got complete remission(CR), 12 got partial remission(PR) more than 50%, 2 less than 50%, and 2 patients were invalid. The effective rate (CR+ PR) was 90.7%. The 3 year loco-regional control rate and survival rate were 60.1%, 82.6%, respectively, and the 5 year's 53.4% and 56.0%. CONCLUSION: The 125I brachy therapy is a feasible and effective modality for the treatment of locally advanced unresectable or recurrent malignant salivary gland carcinomas. However, further studies are needed with larger numbers of patients and for a longer follow-up assessment. Distant metastasis was the main cause of treatment failure, and the lung was the most common site of distant metastases. PMID- 28628163 TI - [Quantitative structure-activity relationship model for prediction of cardiotoxicity of chemical components in traditional Chinese medicines]. AB - OBJECTIVE: Some quantitative structure-activity relationship (QSAR) models have been developed to predict cardiac toxicity of drugs, which have limited predictive power due to based on hERG channel inhibition. The objective of this study was try to develop a QSAR model based on all kinds of cardiac adverse effects, and to predict the potential cardiotoxicity of chemical components in traditional Chinese medicines (TCM). METHODS: In this study, the compounds data of all kinds of cardiac adverse reactions were selected as the training set. The QSAR models were constructed based on 1 109 compounds with cardiotoxicity and 789 compounds without cardiotoxicity, which were available from the Toxicity Reference Database (ToxRefDB) and Side Effect Resource (SIDER) database. The ADMET Predictor software was applied to calculate and to screen the molecular descriptors, and to construct the QSAR models using support vector machine (SVM) and artificial neural networks (ANN) algorithm, respectively. The models were optimized using compound-based 10-fold cross validation. Then, the predictive performance for the potential cardiotoxicity of chemical components in TCM were assessed using external validation by 19 components in TCM with cardiotoxicity and 10 components in TCM without cardiotoxicity. RESULTS: A total of 220 molecular descriptors were selected for modeling, and the best model using SVM algorithm contained 87 molecular descriptors. The internal validation results showed that the predictive sensitivity, specificity, the Youden's index (YI) and the Matthews correlation coefficient (MCC) were 71%, 70%, 0.41, and 0.41, respectively. The best model constructed using ANN algorithm contained 13 neurons and 87 molecular descriptors. The internal validation results showed that the predictive sensitivity, specificity, the YI and the MCC were 78%, 77%, 0.54, and 0.54, respectively. Both models were validated using external validation by the same set of 29 chemical components in TCM with or without cardiotoxicity, which were not included in the training set. The predictive performances of SVM or ANN model were as follows, respectively: sensitivity 95%, 95%; specificity 40%, 60%; and accuracy 76%, 83%. CONCLUSION: The predictive performance of the QSAR model using ANN algorithm was better than that of the model using SVM algorithm. The external validation study of 29 chemical components in TCM illustrated that the QSAR model was applicable for screening and predicting the potential cardiotoxicity of chemical components in TCM. PMID- 28628164 TI - Long alkyl side-chains impede exciton interaction in organic light harvesting crystals. AB - Side-chains at the imidic position of naphthalimide rendered a firm control over (i) the degrees of pi-pi overlap and (ii) distances between the perylenimide units in a crystalline naphthalimide-perylenimide dyad as determined using single crystal XRD and Hirshfeld surface analyses. Steady-state and time-resolved electronic spectroscopy in addition to DFT calculations revealed a decline in intermolecular excitonic interaction due to interfering alkyl chains. PMID- 28628165 TI - Practical in situ-generation of phosphinite ligands for palladium-catalyzed carbonylation of (hetero)aryl bromides forming esters. AB - An effective method for alkoxycarbonylation of (hetero)aryl bromides is developed in the presence of in situ-generated phosphinite ligands tBu2POR (R = nBu, nPr, Et or Me). For this purpose commercially available tBu2PCl was used as the pre ligand in the presence of different alcohols. For the first time cross coupling reactions with two alcohols - one generating the ligand, the other used as substrate - were developed. Through this method, ligand optimization can be performed in a more efficient manner and the desired products could be obtained with good yields and selectivity. PMID- 28628166 TI - Nucleopolypeptides with DNA-triggered alpha helix-to-beta sheet transition. AB - Synthetic polypeptides are versatile polymers outstandingly relevant to prepare bioinspired materials. In this work, we present a new class of smart polypeptide polymers, called nucleopolypeptides, having lateral chains functionalized with thymidine nucleobases. Structural studies performed by circular dichroism have revealed that the secondary structure of the polymers was influenced by nucleotide interaction and DNA sequence variation affording a selective helix-to beta sheet transition with oligo(AAAAA)6. PMID- 28628167 TI - A theoretical study on the morphological phase diagram of supported lipid bilayers. AB - Supported lipid bilayers (SLBs) have been widely used in drug delivery, biosensors and biomimetic membranes. The microscopic mechanism of SLB formation and stability depends on a number of factors underlying solvent-mediated lipid lipid and lipid-substrate interactions. Whereas recent years have witnessed remarkable progress in understanding the kinetics of SLB formation, relatively little is known about the lipid phase behavior controlling the SLB stability under diverse solution conditions. In this work, we examine the structure of SLBs using classical density functional theory (CDFT) in the context of a coarse grained model that accounts for ion-explicit electrostatic interactions, surface hydrophobicity, as well as the molecular characteristics of the lipid tails. A morphological phase diagram is constructed in terms of various intrinsic properties of lipid molecules (such as the lipid tail length, size and charge of the lipid head segments), substrate conditions (such as the surface charge density and hydrophobicity), and solution parameters (such as the ion concentration and ion type). The morphological phase diagram provides useful insights into the rational design and broader application of SLB membranes as different types of nano-devices. PMID- 28628168 TI - Fracture toughness of wet and dry particulate materials comprised of colloidal sized particles: role of plastic deformation. AB - This work demonstrates a method of measuring the fracture toughness of particulate materials comprised of colloidal sized particles over a wide range of saturation. Diametral compression of cylinders containing flaws of controlled length was used to measure the mode I fracture toughness. The effect of degree of saturation on the fracture toughness of slip cast ceramic grade alumina (d50 = 0.7 MUm) was investigated. Dry powder compacts have significantly lower fracture toughness than when the powder compact is nearly fully saturated. All observations are consistent with the fracture mechanism being predominantly brittle for the dry samples but predominantly ductile in the nearly saturated samples. The additional dissipation that occurs during the ductile fracture of the nearly saturated samples is due to plastic deformation in front of the crack tip. This well-known mechanism for toughening in metals has been quantified for the first time in soft matter. Analysis of the results indicates that the size of the plastic dissipation zone is more than an order of magnitude larger in the nearly saturated materials compared to the dry material. Understanding the fracture mechanisms that control the propagation of cracks through saturated, partially saturated and dry particulate materials comprised of colloidal sized particles provides additional insight into understanding drying cracks in paint, other coatings, ceramics and water treatment sludge. PMID- 28628169 TI - Avoiding the pull-in instability of a dielectric elastomer film and the potential for increased actuation and energy harvesting. AB - Pull-in instability often occurs when a film of a dielectric elastomer is subjected to an electric field. In this work, we concoct a set of simple, experimentally implementable, conditions that render the dielectric elastomer film impervious to pull-in instability for all practical loading conditions. We show that a uniaxially pre-stretched film has a significantly large actuation stretch in the direction perpendicular to the pre-stretch and find that the maximal specific energy of a dielectric elastomer generator can be increased from 6.3 J g-1 to 8.3 J g-1 by avoiding the pull-in instability. PMID- 28628170 TI - Recent advances and perspectives in the design and development of polymyxins. AB - Covering: 1947-early 2017, particularly from 2005-early 2017The rise of bacterial pathogens with acquired resistance to almost all available antibiotics is becoming a serious public health issue. Polymyxins, antibiotics that were mostly abandoned a few decades ago because of toxicity concerns, are ultimately considered as a last-line therapy to treat infections caused by multi-drug resistant Gram-negative bacteria. This review surveys the progress in understanding polymyxin structure, and their chemistry, mechanisms of antibacterial activity and nephrotoxicity, biomarkers, synergy and combination with other antimicrobial agents and antibiofilm properties. An update of recent efforts in the design and development of a new generation of polymyxin drugs is also discussed. A novel approach considering the modification of the scaffold of polymyxins to integrate metabolism and detoxification issues into the drug design process is a promising new line to potentially prevent accumulation in the kidneys and reduce nephrotoxicity. PMID- 28628171 TI - Continuous and discontinuous transitions between two types of capillary bridges on a beaded chain pulled out from a liquid. AB - Capillary bridges can be used for fabricating new materials and structures. Here, we describe theoretically and validate experimentally the mechanism of formation of capillary bridges during a process in which a beaded chain is being pulled out from a liquid with a planar surface. There are two types of capillary bridges present in this system, namely the sphere-planar liquid surface bridge initially formed between the spherical bead leaving the liquid bath and the initially planar liquid surface, and the sphere-sphere capillary bridge formed between neighbouring beads in the part of the chain above the liquid surface. During the process of pulling the chain out of the liquid, the sphere-planar liquid surface bridge transforms into the sphere-sphere bridge. We show that for monodisperse spherical beads comprising the chain, this transition can be either continuous or discontinuous. The transition is continuous when the diameter of the spherical beads is larger than the capillary length. Otherwise, the transition is discontinuous, likewise the capillary force acting on the chain. PMID- 28628172 TI - Trichomes as a natural biophysical barrier for plants and their bioinspired applications. AB - Nature has inspired mankind to create novel inventions with biomimetic structures and materials, where plants provide a significant source of inspiration. Plants have evolved a range of effective appendages, among which trichomes have attracted extensive research interest due to their enormous functions. It is important to understand trichome functions and corresponding mechanisms for their bioinspired applications. In this review, we provide a comprehensive overview of the diverse functions of trichomes, with emphasis placed upon their roles as biophysical barriers that can create a complex three-dimensional (3D) network to help the plant adapt to severe environments. Moreover, we also summarize the bioinspired applications of four typical trichomes, including needle-like, hook like, foliar-like, and antenna-like trichomes. This review offers a new perspective of interdisciplinary research on both trichome functions and their biomimetic applications. PMID- 28628174 TI - Ranking REACH registered neutral, ionizable and ionic organic chemicals based on their aquatic persistency and mobility. AB - The contaminants that have the greatest chances of appearing in drinking water are those that are mobile enough in the aquatic environment to enter drinking water sources and persistent enough to survive treatment processes. Herein a screening procedure to rank neutral, ionizable and ionic organic compounds for being persistent and mobile organic compounds (PMOCs) is presented and applied to the list of industrial substances registered under the EU REACH legislation as of December 2014. This comprised 5155 identifiable, unique organic structures. The minimum cut-off criteria considered for PMOC classification herein are a freshwater half-life >40 days, which is consistent with the REACH definition of freshwater persistency, and a log Doc < 4.5 between pH 4-10 (where Doc is the organic carbon-water distribution coefficient). Experimental data were given the highest priority, followed by data from an array of available quantitative structure-activity relationships (QSARs), and as a third resort, an original Iterative Fragment Selection (IFS) QSAR. In total, 52% of the unique REACH structures made the minimum criteria to be considered a PMOC, and 21% achieved the highest PMOC ranking (half-life > 40 days, log Doc < 1.0 between pH 4-10). Only 9% of neutral substances received the highest PMOC ranking, compared to 30% of ionizable compounds and 44% of ionic compounds. Predicted hydrolysis products for all REACH parents (contributing 5043 additional structures) were found to have higher PMOC rankings than their parents, due to increased mobility but not persistence. The fewest experimental data available were for ionic compounds; therefore, their ranking is more uncertain than neutral and ionizable compounds. The most sensitive parameter for the PMOC ranking was freshwater persistency, which was also the parameter that QSARs performed the most poorly at predicting. Several prioritized drinking water contaminants in the EU and USA, and other contaminants of concern, were identified as PMOCs. This identification and ranking procedure for PMOCs can be part of a strategy to better identify contaminants that pose a threat to drinking water sources. PMID- 28628175 TI - Base-catalyzed cascade synthesis of 2,3-dihydrofuro[2,3-b]pyridines and 2,3 dihydro-1H-pyrrolo[2,3-b]pyridines from N-propargylic beta-enaminones. AB - A novel protocol to prepare multi-substituted dihydrofuropyridine and dihydropyrrolopyridine derivatives from KOH-catalyzed reactions between readily available N-propargylic beta-enaminones and arylaldehydes or N-sulfonyl imines has been developed in moderate to good yields. PMID- 28628178 TI - Jumping drops on hydrophobic surfaces, controlling energy transfer by timed electric actuation. AB - Aqueous sessile drops are launched from a super-hydrophobic surface by electric actuation in an electrowetting configuration with a voltage pulse of variable duration. We show that the jump height, i.e. the amount of energy that is transferred from surface energy to the translational degree of freedom, depends not only on the applied voltage but also in a periodic manner on the duration of the actuation pulse. Specifically, we find that the jump height for a pulse of optimized duration is almost twice as high as the one obtained upon turning off the voltage after equilibration of the drop under electrowetting. Representing the drop by a simple oscillator, we establish a relation between the eigenfrequency of the drop and the optimum actuation time required for most efficient energy conversion. From a general perspective, our experiments illustrate a generic concept how timed actuation in combination with inertia can enhance the flexibility and efficiency of drop manipulation operations. PMID- 28628179 TI - Nucleated dewetting in supported ultra-thin liquid films with hydrodynamic slip. AB - This study reveals the influence of the surface energy and solid/liquid boundary condition on the breakup mechanism of dewetting ultra-thin polymer films. Using silane self-assembled monolayers, SiO2 substrates are rendered hydrophobic and provide a strong slip rather than a no-slip solid/liquid boundary condition. On undergoing these changes, the thin-film breakup morphology changes dramatically - from a spinodal mechanism to a breakup which is governed by nucleation and growth. The experiments reveal a dependence of the hole density on film thickness and temperature. The combination of lowered surface energy and hydrodynamic slip brings the studied system closer to the conditions encountered in bursting unsupported films. As for unsupported polymer films, a critical nucleus size is inferred from a free energy model. This critical nucleus size is supported by the film breakup observed in the experiments using high speed in situ atomic force microscopy. PMID- 28628180 TI - Enhancing the biofuel upgrade performance for Pd nanoparticles via increasing the support hydrophilicity of metal-organic frameworks. AB - In this work, the influence of the hydrophilic/hydrophobic nature of metal organic framework (MOF) materials on the catalytic performance of supported Pd nanoparticles for biofuel upgrade was studied. We show that the introduction of hydrophilic groups on a MOF can greatly enhance the performance of the resultant catalyst. Specifically, Pd nanoparticles supported on MIL-101-SO3Na with superhydrophilicity (Pd/MIL-101-SO3Na) far outperforms pristine MIL-101 and the benchmark catalyst Pd/C in the hydrodeoxygenation reaction of vanillin, a model component of pyrolysis oil derived from the lignin fraction. This is attributed to a favorable mode of adsorption of the highly water soluble reactants on the more hydrophilic support in the vicinity of the catalytically active Pd nanoparticles, thereby promoting their transformation. PMID- 28628181 TI - Synthesis and antiviral evaluation of base-modified deoxythreosyl nucleoside phosphonates. AB - l-alpha-2'-Deoxythreosyl nucleoside phosphonates and their phosphonodiamidate prodrugs with a hypoxanthine, 2,6-diaminopurine, 2-amino-6 cyclopropylaminopurine, 7-deazaadenine, 5-fluorouracil and 5-methylcytosine heterocycle as a nucleobase were synthesized and evaluated for their inhibitory activity against HIV and HBV. The 2,6-diaminopurine modified analogue 23a displayed the most potent activity against HIV, with an EC50 value of 11.17 MUM against HIV-1 (IIIB) and an EC50 value of 8.15 MUM against HIV-2 (ROD). The application of the prodrug strategy on nucleoside phosphonate 23a led to a 200 fold boost in anti-HIV potency. None of the compounds showed any activity against HBV at the highest concentration tested. PMID- 28628182 TI - Prodigiosenes conjugated to tamoxifen and estradiol. AB - We report the synthesis of the first click-appended prodigiosene conjugates. Four prodigiosene conjugates of estradiol functionalised at the 7alpha-position were prepared, as were three prodigiosene conjugates of tamoxifen. The coupling between a prodigiosene and an 11-hydroxy estradiol derivative via an ether linkage was investigated, as was the 11- and 7-functionalisation of the estradiol core. The robustness of estradiol protecting groups was severely challenged by reactions typically used to equip such frameworks for 11- and 7 functionalisation. Specifically, and important to synthesis involving estradiol, TBS, TMS and THP are not useful protecting groups for the functionalisation of this core. When the chemical features of the therapeutic agent limit the choice of protecting group (in this case, prodigiosenes bearing aryl, NH, alkenyl and ester groups), click chemistry becomes an attractive synthetic strategy. The anti cancer activity of the seven click prodigiosene conjugates was evaluated. PMID- 28628183 TI - An unprecedented stereoselective base-induced trimerization of an alpha bromovinylsulfone. AB - A unprecedented base-induced trimerization of bromovinylsulfone 1 afforded the cyclohexene 6 as a single diastereoisomer. Optimization of this reaction gave the adduct 6 in 49% yield. A mechanistic rationale for the trimerization involving consecutive SN2' additions and [3,3]-rearrangements and a final stereoselective intramolecular conjugate addition is proposed and supported by M06-2X density functional theory calculations. PMID- 28628184 TI - Trends of intramolecular hydrogen bonding in substituted alcohols: a deeper investigation. AB - Intramolecular hydrogen bonding (IAHB) is one of the most important intramolecular interactions and a critical element in adopted molecular arrangements. Moreover, slight substitution in a molecule can affect its strength to a great extent. It is well established that alkyl groups play a positive role in IAHB strength. However, the effects that drive it are specific to each system. To investigate the influence of IAHB and its strength dependency on different acyclic compounds, the conformational preferences of propane-1,3-diol, 3 methoxypropan-1-ol, 3-ethoxypropan-1-ol, 3-isopropoxypropan-1-ol, 3-(tert butoxy)propan-1-ol, butane-1,3-diol, 3-methoxybutan-1-ol, 3-methylbutane-1-diol, and 3-methoxy-3-methylbutan-1-ol were evaluated experimentally using infrared spectroscopy theoretically supported by topological and natural bond orbital analyses. The most stable conformation of each compound exhibited IAHB and these conformers are more populated in the equilibrium for all studied compounds. Experimental infrared and topological data suggest that the strength of IAHB increases for each methyl group addition. NBO analyses indicate that methyl groups in different positions related to an OH moiety affect the charge transfer energy involved in intramolecular hydrogen bonding. This occurs mostly due to an increase in the spn-hybridized lone pair (LP1O) contribution to the charge transfer , which is a result of changes in s-character and orbital energy caused by geometrical rearrangements, rehybridization, and/or electronic effects. PMID- 28628185 TI - Epidemiology and prevention of influenza in children in Argentina and Brazil. AB - A group of influenza experts from Argentina and Brazil got together to discuss the burden of influenza in children, review current vaccine coverage rates in both countries, analyze vaccine effectiveness, and discuss strategies to improve prevention. Active surveillance of respiratory viruses is carried out nationwide in both countries. Years 2014 and 2015 were mild influenza seasons; influenza virus type A/H3N2 prevailed, whereas type B represented less than 30% of isolates. Trivalent inactivated influenza vaccine is included in National Immunization Programs for 1) children 6 months to 2 years old in Argentina; 2) children 6 months to 5 years old in Brazil; and 3) all high-risk individuals. Coverage rates in both countries were about 80% (albeit lower for the second dose). Experts from both countries proposed the following strategies to improve prevention: 1) increase surveillance; 2) assess effectiveness and long-term safety of influenza vaccines; 3) reinforce vaccination programs in order to increase coverage rates; and 4) consider introducing more effective vaccines, such as adjuvanted trivalent vaccines. In Argentina, estimating case-fatality rates was also recommended. Other proposed actions included enhancing education of health professionals and the lay community, and better use of communication resources to raise awareness of the burden of influenza and promote vaccine uptake. PMID- 28628186 TI - Knockdown of homeobox containing 1 increases the radiosensitivity of cervical cancer cells through telomere shortening. AB - Homeobox containing 1 (HMBOX1) modulates telomere length in various types of tumor cells by binding to double-stranded telomeric DNA. There is a negative correlation between telomere length and radiosensitivity in tumor cells. In the present study, we aimed to investigate the relationship among HMBOX1, telomere and radiosensitivity in cervical cancer cells. Lentivirus-based shRNAs were used to establish stable transfected cell lines in which protein and mRNA levels of HMBOX1 were notably decreased. Knockdown of HMBOX1 increased the radiosensitivity of HeLa and C33A cells. TERT protein was also decreased while HMBOX1 was downregulated. Knockdown of HMBOX1 shortened telomere length in the HeLa cells, while TERT overexpression rescued telomere shortening in the HeLa-HMBOX1 cells. Knockdown of HMBOX1 increased the apoptosis rate, decreased radiation-induced DNA damage foci, and inhibited the expression of ATM, ATR, p-ATM, p-ATR and BRCA1 in the homologous recombination repair pathway. Our data suggest a possible role of HMBOX1 in regulating radiosensitivity in cervical cancer cells. Moreover, HMBOX1 may be a potential factor in the radiotherapy of cervical cancer. PMID- 28628187 TI - KLF2 inhibits cell growth via regulating HIF-1alpha/Notch-1 signal pathway in human colorectal cancer HCT116 cells. AB - The transcription factor Kruppel-like factor 2 (KLF2) has been shown to function as a tumor suppressor and regulate biological processes of cancer cells, such as cell growth, cell apoptosis and angiogenesis. However, the function and mechanism of KLF2 in colorectal cancer (CRC) is still unknown. In the present study, we show that the expression of KLF2 is diminished in a cohort of CRC cell lines. Also, KLF2 overexpression remarkably inhibits HCT116 and SW480 cell survival and proliferation. Moreover, cell death detection ELISA plus assay showed that KLF2 overexpression increased HCT116 cell proliferation. Caspase-3/7 activity also increased in HCT116 cells transfected with PcDNA3.1-KLF2. Further studies showed that KLF2 significantly suppresses the expression of Notch-1 and is dependent on the decline of the HIF-1alpha level. Most importantly, silencing Notch-1 expression or HIF-1alpha level both impair the action of KLF2 overexpression in CRC cells. Collectively, we demonstrated that KLF2 mediates CRC cell biological processes including cell growth and apoptosis via regulating the HIF-1alpha/Notch 1 signal pathway. These results indicated that KLF2 plays an important role in CRC and provided novel insight on the function of KLF2 in tumor progression. PMID- 28628188 TI - Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy. AB - Ovarian cancer is the most lethal disease among all gynecological malignancies. Interval cytoreductive surgery and cisplatin-based chemotherapy are the recommended therapeutic strategies. However, acquired resistance to cisplatin remains a big challenge for the overall survival and prognosis in ovarian cancer. Complicated molecular mechanisms are involved in the process. At present, increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy. In the present study, as a novel autophagy regulator, BCL2-associated athanogene 3 (BAG3) was investigated to study its role in cisplatin sensitivity in epithelial ovarian cancer. However, whether BAG3 participates in cisplatin sensitivity by inducing autophagy and the underlying mechanism in ovarian cancer cells remain to be clarified. Through the use of quantitative real-time PCR, western blot analysis, CCK-8 and immunofluorescence assays our data revealed that cisplatin-induced autophagy protected ovarian cancer cells from the toxicity of the drug and that this process was regulated by BAG3. Silencing of BAG3 increased cisplatin-induced apoptosis. The results also revealed BAG3 as a potential therapeutic target which enhanced the efficacy of cisplatin in ovarian cancer. PMID- 28628189 TI - [A statement the Polish Cardiac Society Working Group on Pulmonary Circulation on screening for CTEPH patients after acute pulmonary embolism]. AB - Both pharmacological and invasive treatment of chronic thromboembolic pulmonary hypertension (CTEPH) is now available in Poland and the awareness of the disease among physicians is growing. Thus, the Polish Cardiac Society's Working Group on Pulmonary Circulation in cooperation with independent experts in this field, have launched the statement on algorithm to guide a CTEPH diagnosis in patients with previous acute pulmonary embolism (APE). In Poland, every year this disease affects about 250 patients. CTEPH should be suspected in individuals after APE with dyspnea, despite at least 3 months period of effective anticoagulation, particularly when specified risk factors are present. Echocardiography is a main screening tool. The authors suggest that a diagnostic process of patients with significant clinical suspicion of CTEPH and right ventricle overload in echocardiography should be performed in reference centres. The document contains a list of Polish centres diagnosing patients with suspected CTEPH. Pulmonary scintigraphy is a safe and highly sensitive screening test for CTEPH. Multi detector computed tomography with precise detection of thromboembolic residues in pulmonary circulation is important for planning of pulmonary endarterectomy. Right heart catheterisation definitely confirms the presence of pulmonary hypertension and direct pulmonary angiography allows for identification of lesions suitable for thromboendarterectomy or pulmonary balloon angioplasty. In this document a diagnostic algorithm in patients with suspected CTEPH is also proposed. With individualised sequential diagnostic strategy each patient can be finally qualified for a particular mode of therapy by dedicated CTEPH Heart Team. Moreover the document contains short information for the primary care physician about the management of patients after APE. PMID- 28628190 TI - Response to the letter concerning the article: "Atrial electromechanical delay analysed by tissue Doppler echocardiography...". PMID- 28628191 TI - Abiotic and biotic factors modulate carrion fate and vertebrate scavenging communities. AB - Carrion is a valuable nutrient resource used by a diversity of vertebrates across the globe. However, vertebrate scavenging ecology remains an understudied area of science, especially in regards to how biotic and abiotic factors influence scavenging community composition. Here we elucidate how fundamental biotic and abiotic factors interact to modulate the efficiency and composition of vertebrate scavengers by investigating scavenging dynamics across a large gradient in carcass sizes and habitat types representative of many temperate ecosystems, as well as between two seasons reflecting differences in invertebrate activity. We found carcass size and season influenced carcass fate and persistence, as well as the richness and composition of vertebrate scavenger communities utilizing carrion resources. Species richness, which increased as carcass size increased and was higher during the cool season, had a significant effect on carcass persistence. In addition, habitat type influenced carcass detection times by vertebrates, and we observed relatively distinct scavenging communities associated with carcasses of differing sizes. This research highlights a pervasive limitation to the interpretation of results of previous studies as research failing to incorporate carcass size and habitat type could result in the over or underrepresentation of vertebrate scavengers in food web dynamics. PMID- 28628192 TI - Psychiatric disorders with systemic retinoids: a systematic review of case reports. PMID- 28628195 TI - Heterogeneity of tight junctions in the thick ascending limb. AB - Renal tubular transport mechanisms are optimized to be energy efficient and tailored to local gradients and transport rates. The combined transcellular action of ion channels, transporters, and pumps, together with the paracellular pathway, enables kidney function. Monogenetic diseases and mouse models indicate that both trans- and paracellular proteins can become disease-causing candidates and may be targets for future therapeutic approaches. Recent advances in tight junction research have provided new insights into their structure, function, and regulation. The thick ascending limb (TAL) is a nephron segment with specific requirements for the paracellular pathway. It has to fuel the generation of the corticomedullary concentration gradient, to be watertight, and to provide a highly selective permeability for Na+ and divalent cations. Tight junction composition and function in the TAL is organized along the corticomedullary axis. Even on the level of a seemingly homogeneous tubular epithelium like the TAL, there is a separation of tight junction protein expression in the strands between the respective tricellular nexus of the junctional network. Here, we highlight some new insights from our recent work and that of others in this context. In addition, we provide some perspectives for the further study of paracellular transport mechanisms. PMID- 28628193 TI - Modulation of epithelial cell polarity by bacterial pathogens. AB - Epithelial cells constitute a physical barrier that aids in protecting the host from microbial pathogens. Polarized epithelial cells contain distinct apical and basolateral membrane domains separated by intercellular junctions, including tight junctions (TJs), which contribute to the maintenance of apical-basal polarity. Polarity complexes also contribute to the establishment of TJ formation. Several pathogens perturb epithelial TJ barrier function and structure in addition to causing a loss of apical-basal polarity. Here, we review the impact of pathogenic bacteria on the disruption of cell-cell junctions and epithelial polarity. PMID- 28628194 TI - Signals that drive T follicular helper cell formation. AB - T follicular helper (Tfh) cells are a distinct type of CD4+ T cell specialized in providing help to B cells during the germinal centre (GC) reaction. As such, they are critical determinants of the quality of an antibody response following antigen challenge. Excessive production of Tfh cells can result in autoimmunity whereas too few can result in inadequate protection from infection. Hence, their differentiation and maintenance must be tightly regulated to ensure appropriate but limited help to B cells. Unlike the majority of other CD4+ T-cell subsets, Tfh cell differentiation occurs in three phases defined by their anatomical location. During each phase of differentiation the emerging Tfh cells express distinct patterns of co-receptors, which work together with the T-cell receptor (TCR) to drive Tfh differentiation. These signals provided by both TCR and co receptors during Tfh differentiation alter proliferation, survival, metabolism, cytokine production and transcription factor expression. This review will discuss how engagement of TCR and co-receptors work together to shape the formation and function of Tfh cells. PMID- 28628197 TI - Vesicular acetylcholine transporter (VAChT) over-expression induces major modifications of striatal cholinergic interneuron morphology and function. AB - Striatal cholinergic interneurons (CIN) are pivotal for the regulation of the striatal network. Acetylcholine (ACh) released by CIN is centrally involved in reward behavior as well as locomotor or cognitive functions. Recently, BAC transgenic mice expressing channelrhodopsin-2 (ChR2) protein under the control of the choline acetyltransferase (ChAT) promoter (ChAT-ChR2) and displaying almost 50 extra copies of the VAChT gene were used to dissect cholinergic circuit connectivity and function using optogenetic approaches. These mice display over expression of the vesicular acetylcholine transporter (VAChT) and increased cholinergic tone. Consequently, ChAT-ChR2 mice are a valuable model to investigate hypercholinergic phenotypes. Previous experiments established that ChAT-ChR2 mice display an increased sensitivity to amphetamine induced-locomotor activity and stereotypes. In the present report, we analyzed the impact of VAChT over-expression in the striatum of ChAT-ChR2 mice. ChAT-ChR2 mice displayed increased locomotor sensitization in response to low dose of cocaine. In addition, we observed a dramatic remodeling of the morphology of CIN in ChAT-ChR2 transgenic mice. VAChT immunolabeling was markedly enhanced in the soma and terminal of CIN from ChAT-ChR2 mice as previously shown (Crittenden et al. 2014). Interestingly, the number of cholinergic varicosities was markedly reduced (-87%) whereas their size was significantly increased (+177%). Moreover, VAChT over expression dramatically modified its trafficking along the somatodendritic and axonal arbor. These findings demonstrate that ChAT-ChR2 mice present major alterations of CIN neuronal morphology and increased behavioral sensitization to cocaine, supporting the notion that the increased levels of VAChT observed in these mice make them fundamentally different from wild-type mice. PMID- 28628196 TI - Molecular mechanisms of experience-dependent maturation in cortical GABAergic inhibition. AB - Critical periods (CP) in early post-natal life are periods of plasticity during which the neuronal circuitry is most receptive to environmental stimuli. These early experiences translate to a more permanent and sophisticated neuronal connection in the adult brain systems. Multiple studies have pointed to the development of inhibitory circuitry as one of the central factors for the onset of critical periods. We discuss several molecular mechanisms regulating inhibitory circuit maturation and CP, from gene transcription level to protein signaling level. Also, beyond the level of gene sequences, we briefly consider recent information on dynamic epigenetic regulation of gene expression through histone methylation and acetylation and their implication on timed development of the inhibitory circuitry for the onset of CP. PMID- 28628198 TI - Pulse frequency and soil-litter mixing alter the control of cumulative precipitation over litter decomposition. AB - Macroclimate has traditionally been considered the predominant driver of litter decomposition. However, in drylands, cumulative monthly or annual precipitation typically fails to predict decomposition. In these systems, the windows of opportunity for decomposer activity may rather depend on the precipitation frequency and local factors affecting litter desiccation, such as soil-litter mixing. We used a full-factorial microcosm experiment to disentangle the relative importance of cumulative precipitation, pulse frequency, and soil-litter mixing on litter decomposition. Decomposition, measured as litter carbon loss, saturated with increasing cumulative precipitation when pulses were large and infrequent, suggesting that litter moisture no longer increased and/or microbial activity was no longer limited by water availability above a certain pulse size. More frequent precipitation pulses led to increased decomposition at high levels of cumulative precipitation. Soil-litter mixing consistently increased decomposition, with greatest relative increase (+194%) under the driest conditions. Collectively, our results highlight the need to consider precipitation at finer temporal scale and incorporate soil-litter mixing as key driver of decomposition in drylands. PMID- 28628199 TI - Measuring Cancer Drug Sensitivity and Resistance in Cultured Cells. AB - Measuring the potencies of small-molecule drugs in cell lines is a critical aspect of preclinical pharmacology. Such experiments are also prototypical of high-throughput experiments in multi-well plates. The procedure is simple in principle, but many unrecognized factors can affect the results, potentially making data unreliable. The procedures for measuring drug response described here were developed by the NIH LINCS program to improve reproducibility. Key features include maximizing uniform cell growth during the assay period, accounting for the effects of cell density on response, and correcting sensitivity measures for differences in proliferation rates. Two related protocols are described: one involves an endpoint measure well-suited to large-scale studies and the second is a time-dependent measurement that reveals changes in response over time. The methods can be adapted to other types of plate-based experiments. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628200 TI - Local Generation and Imaging of Hydrogen Peroxide in Living Cells. AB - Described here is a localized H2 O2 generation-detection system consisting of a yeast D-amino acid oxidase (DAAO) and two spectrally distinct variants of biosensor, HyPer2 and HyPerRed based on circularly permutated yellow and red fluorescent proteins, respectively, which enables spatiotemporal production and examination of the intracellular H2 O2 dynamics. The protocol describes using this system in a simple cell culture model. We provide detailed instructions on imaging of H2 O2 generated by the activated DAAO. The system can be easily optimized for various combinations of cell types, conditions and DAAO/sensor subcellular localizations. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628202 TI - Paper-based Invasion Assays for Quantifying Cellular Movement in Three dimensional Tissue-like Structures. AB - To elucidate the chemical and environmental conditions that promote invasion of cancer cells, an assay is needed in which the chemical landscape of a tumor-like environment can be experimentally manipulated and probed. The three-dimensional paper-based invasion assays described here simulate poorly vascularized tissue and allow the invasion of cancerous cells to be visualized and quantified. These cultures are easy to assemble and allow multiple invasion assays to be performed in parallel. By using different materials to control gradients formed across the culture, the chemotactic potential of small molecules can be evaluated in a more representative tissue microenvironment. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628201 TI - Designing Drug-Response Experiments and Quantifying their Results. AB - We developed a Python package to help in performing drug-response experiments at medium and high throughput and evaluating sensitivity metrics from the resulting data. In this article, we describe the steps involved in (1) generating files necessary for treating cells with the HP D300 drug dispenser, by pin transfer or by manual pipetting; (2) merging the data generated by high-throughput slide scanners, such as the Perkin Elmer Operetta, with treatment annotations; and (3) analyzing the results to obtain data normalized to untreated controls and sensitivity metrics such as IC50 or GR50 . These modules are available on GitHub and provide an automated pipeline for the design and analysis of high-throughput drug response experiments, that helps to prevent errors that can arise from manually processing large data files. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628203 TI - Photoactivated In Vivo Proximity Labeling. AB - Identification of molecular interactions is paramount to understanding how cells function. Most available technologies rely on co-purification of a protein of interest and its binding partners. Therefore, they are limited in their ability to detect low-affinity interactions and cannot be applied to proteins that localize to difficult-to-solubilize cellular compartments. In vivo proximity labeling (IPL) overcomes these obstacles by covalently tagging proteins and RNAs based on their proximity in vivo to a protein of interest. In IPL, a heterobifunctional probe comprising a photoactivatable moiety and biotin is recruited by a monomeric streptavidin tag fused to a protein of interest. Following UV irradiation, candidate interacting proteins and RNAs are covalently biotinylated with tight spatial and temporal control and subsequently recovered using biotin as an affinity handle. Here, we describe experimental protocols to discover novel protein-protein and protein-RNA interactions using IPL. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628204 TI - A High-Throughput Process for the Solid-Phase Purification of Synthetic DNA Sequences. AB - An efficient process for the purification of synthetic phosphorothioate and native DNA sequences is presented. The process is based on the use of an aminopropylated silica gel support functionalized with aminooxyalkyl functions to enable capture of DNA sequences through an oximation reaction with the keto function of a linker conjugated to the 5'-terminus of DNA sequences. Deoxyribonucleoside phosphoramidites carrying this linker, as a 5'-hydroxyl protecting group, have been synthesized for incorporation into DNA sequences during the last coupling step of a standard solid-phase synthesis protocol executed on a controlled pore glass (CPG) support. Solid-phase capture of the nucleobase- and phosphate-deprotected DNA sequences released from the CPG support is demonstrated to proceed near quantitatively. Shorter than full-length DNA sequences are first washed away from the capture support; the solid-phase purified DNA sequences are then released from this support upon reaction with tetra-n-butylammonium fluoride in dry dimethylsulfoxide (DMSO) and precipitated in tetrahydrofuran (THF). The purity of solid-phase-purified DNA sequences exceeds 98%. The simulated high-throughput and scalability features of the solid phase purification process are demonstrated without sacrificing purity of the DNA sequences. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628205 TI - Stereoselective Synthesis of 4'-Selenonucleosides via the Seleno-Michael Reaction. AB - 5'-Homo-4'-selenonucleosides, a class of next-generation nucleosides, are synthesized from D-ribose via a 4-selenosugar intermediate. The key step in synthesizing this intermediate is a seleno-Michael reaction. 5'-Homo-4' selenouridine and -adenosine are prepared using Pummerer-type and Vorbruggen condensation, respectively. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628206 TI - Water-Medium Synthesis of Nucleoside 5'-Polyphosphates. AB - This unit describes a one-pot, two step synthesis of ribonucleoside 5'-di- and 5' triphosphates, as well as their purification. The first step of the synthesis involves the activation of an unprotected ribonucleoside 5'-monophosphate with 2 chloro-1,3-dimethylimidazolinium hexafluorophosphate and imidazole, in a mixture of water/acetonitrile. The resulting phosphorimidazolate intermediate is then treated with inorganic phosphate or pyrophosphate to afford the corresponding nucleoside 5'-di- or 5'-triphosphates. The attractive features of this strategy include the absence of protecting groups on the starting material and convenient set up (i.e., use of water, non-dry solvents and reagents, commercially available sodium salts). (c) 2017 by John Wiley & Sons, Inc. PMID- 28628207 TI - Engineered Polymerases with Altered Substrate Specificity: Expression and Purification. AB - Polymerase engineering is making it possible to synthesize xeno-nucleic acid polymers (XNAs) with diverse backbone structures and chemical functionality. The ability to copy genetic information back and forth between DNA and XNA has led to a new field of science known as synthetic genetics, which aims to study the genetic concepts of heredity and evolution in artificial genetic polymers. Since many of the polymerases needed to synthesize XNA polymers are not available commercially, researchers must express and purify these enzymes as recombinant proteins from E. coli. This unit details the steps needed to express, purify, and evaluate the activity of engineered polymerases with altered substrate recognition properties. The protocol requires 6 days to complete and will produce ~20 mg of pure, nuclease-free polymerase per liter of E. coli bacterial culture. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628208 TI - Carbocyclic C-C Bond Formation: Intramolecular Radical Ring Closure to Yield Diastereomerically Pure (7'S-Me- or 7'R-Me-) Carba-LNA Nucleotide Analogs. AB - In light of the impressive gene-silencing properties of carba-LNA modified oligo DNA and RNA, both in antisense RNA and siRNA approaches, which have been confirmed as proof-of-concept for biochemical applications in post transcriptional gene silencing, we envision the true potential of carba-LNA modifications to be revealed soon. Herein we provide detailed protocols for synthesis of carba-LNA-A, -G, -5-Me C, and -T nucleosides on a medium/large scale (gram scale), as well as important guidelines for incorporation of these modified carba-LNAs into DNA or RNA oligonucleotides. Creation of a stereoselective C-C bond during the 5-exo radical intramolecular cyclization involves trapping of a C2' radical intermediate intramolecularly by the vicinal double bond of a C4' tethered ?CH2 -CH?CH2 group. All diastereomers of substituted carba-LNAs are now available in pure form. The present procedure allows carba-LNA to be commercialized for medicinal or biotechnological purposes. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628209 TI - Nucleobase Protection of Deoxyribo- and Ribonucleosides. AB - Oligonucleotides carrying a variety of chemical modifications including conjugates are finding increasing applications in therapeutics, diagnostics, functional genomics, proteomics, and as research tools in chemical and molecular biology. The successful synthesis of oligonucleotides primarily depends on the use of appropriately protected nucleoside building blocks including the exocyclic amino groups of the nucleobases, the hydroxyl groups at the 2'-, 3'-, and 5' positions of the sugar moieties, and the internucleotide phospho-linkage. This unit is a thoroughly revised update of the previously published version and describes the recent development of various protecting groups that facilitate reliable oligonucleotide synthesis. In addition, various protecting groups for the imide/lactam function of thymine/uracil and guanine, respectively, are described to prevent irreversible nucleobase modifications that may occur in the presence of reagents used in oligonucleotide synthesis. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628210 TI - Synthesis of Oligodeoxynucleotides Containing a C8-2'-Deoxyguanosine Adduct Formed by the Carcinogen 3-Nitrobenzanthrone. AB - This unit describes the detailed procedure in five parts for the synthesis of the C8-2'-deoxyguanosine-3-aminobenzanthrone adduct located in a desired site in an oligonucleotide. The synthesis of the protected 2'-deoxyguanosine, O6 -benzyl-N2 DMTr-3'-5'-bisTBDMS-C8-Br-2'-deoxyguanosine, is described in the first part. The synthesis of the reduced carcinogen 3-aminobenzanthrone is detailed in part two. The third part outlines the key step of the adduct formation between the reduced carcinogen and the protected nucleoside by a palladium-catalyzed cross coupling reaction. The final two parts describe phosphoramidite synthesis from the nucleoside-carcinogen adduct followed by its site-specific incorporation into DNA by solid-phase oligonucleotide synthesis. The adducted oligonucleotides are purified by reversed-phase HPLC and characterized by mass spectrometry. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628211 TI - Germination phenology determines the propensity for facilitation and competition. AB - A single plant can interact both positively and negatively with its neighbors through the processes of facilitation and competition, respectively. Much of the variation in the balance of facilitation and competition that individuals experience can be explained by the degree of physical stress and the sizes or ages of plants during the interaction. Germination phenology partly controls both of these factors, but its role in defining the facilitation-competition balance has not been explicitly considered. I performed an experiment in a population of the winter annual Arabidopsis thaliana (Brassicaceae) to test whether germinating during physically stressful periods leads to facilitation while germinating during periods that promote growth and reproduction leads to competition. I manipulated germination and neighbor presence across two years in order to quantify the effects of the local plant community on survival, fecundity, and total fitness as a function of germination phenology. Neighbors increased survival when germination occurred under conditions that were unsuitable for survival, but they reduced fecundity in germinants that were otherwise the most fecund. Later germination was associated with facilitation in the first year but competition in the second year. These episodes of facilitation and competition opposed each other, leading to no net effect of neighbors when averaged over all cohorts. These results indicate that variation in germination timing can explain some of the variation in the facilitation-competition balance in plant communities. PMID- 28628212 TI - Disturbance-mediated facilitation by an intertidal ecosystem engineer. AB - Ecosystem engineers facilitate communities by providing a structural habitat that reduces abiotic stress or predation pressure for associated species. However, disturbance may damage or move the engineer to a more stressful environment, possibly increasing the importance of facilitation for associated communities. In this study, we determined how disturbance to intertidal boulders (i.e., flipping) and the subsequent movement of a structural ecosystem engineer, the tube-forming serpulid worm Galeolaria caespitosa, from the bottom (natural state, low abiotic stress) to the top (disturbed state, high abiotic stress) surface of boulders influenced the importance of facilitation for intertidal communities across two intertidal zones. Theory predicts stronger relative facilitation should occur in the harsher environments of the top of boulders and the high intertidal zone. To test this prediction, we experimentally positioned boulders with the serpulids either face up or face down for 12 months in low and high zones in an intertidal boulder field. There were very different communities associated with the different boulders and serpulids had the strongest facilitative effects on the more stressful top surface of boulders with approximately double the species richness compared to boulders lacking serpulids. Moreover, within the serpulid matrix itself there was also approximately double the species richness (both zones) and abundance (high zone only) of small invertebrates on the top of boulders compared to the bottom. The high relative facilitation on the top of boulders reflected a large reduction in temperature by the serpulid matrix on that surface (up to 10 degrees C) highlighting a key role for modification of the abiotic environment in determining the community-wide facilitation. This study has demonstrated that disturbance and subsequent movement of an ecosystem engineer to a more stressful environment increased the importance of facilitation and allowed species to persist that would otherwise be unable to survive in that environment. PMID- 28628213 TI - Changes in kynurenine pathway metabolism in Parkinson patients with L-DOPA induced dyskinesia. AB - L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective drug in the symptomatic treatment of Parkinson's disease, but chronic use is associated with L-DOPA-induced dyskinesia in more than half the patients after 10 years of treatment. L-DOPA treatment may affect tryptophan metabolism via the kynurenine pathway. Altered levels of kynurenine metabolites can affect glutamatergic transmission and may play a role in the development of L-DOPA-induced dyskinesia. In this study, we assessed kynurenine metabolites in plasma and cerebrospinal fluid of Parkinson's disease patients and controls. Parkinson patients (n = 26) were clinically assessed for severity of motor symptoms (UPDRS) and L-DOPA induced dyskinesia (UDysRS). Plasma and cerebrospinal fluid samples were collected after overnight fasting and 1-2 h after intake of L-DOPA or other anti Parkinson medication. Metabolites were analyzed in plasma and cerebrospinal fluid of controls (n = 14), Parkinson patients receiving no L-DOPA (n = 8), patients treated with L-DOPA without dyskinesia (n = 8), and patients with L-DOPA-induced dyskinesia (n = 10) using liquid chromatography-mass spectrometry. We observed approximately fourfold increase in the 3-hydroxykynurenine/kynurenic acid ratio in plasma of Parkinson's patients with L-DOPA-induced dyskinesia. Anthranilic acid levels were decreased in plasma and cerebrospinal fluid of this patient group. 5-Hydroxytryptophan levels were twofold increased in all L-DOPA-treated Parkinson's patients. We conclude that a higher 3-hydroxykynurenine/kynurenic acid ratio in plasma may serve as a biomarker for L-DOPA-induced dyskinesia. Longitudinal studies including larger patients cohorts are needed to verify whether the changes observed here may serve as a prognostic marker for L-DOPA induced dyskinesia. PMID- 28628214 TI - Unconventional role of voltage-gated proton channels (VSOP/Hv1) in regulation of microglial ROS production. AB - It has been established that voltage-gated proton channels (VSOP/Hv1), encoded by Hvcn1, support reactive oxygen species (ROS) production in phagocytic activities of neutrophils (El Chemaly et al. ) and antibody production in B lymphocytes (Capasso et al. ). VSOP/Hv1 is a potential therapeutic target for brain ischemia, since Hvcn1 deficiency reduces microglial ROS production and protects brain from neuronal damage (Wu et al. ). In the present study, we report that VSOP/Hv1 has paradoxical suppressive role in ROS production in microglia. Extracellular ROS production was lower in neutrophils of Hvcn1-/- mice than WT mice as reported. In contrast, it was drastically enhanced in isolated Hvcn1-/- microglia as compared with cells from WT mice. Actin dynamics was altered in Hvcn1-/- microglia and intracellular distribution of cytosolic NADPH oxidase subunit, p67, was changed. When expression levels of oxidative stress responsive antioxidant genes were compared between WT and Hvcn1-/- in cerebral cortex at different ages of animals, they were slightly decreased in Hvcn1-/- mice at younger stage (1 day, 5 days, 3 weeks old), but drastically increased at aged stage (6 months old), suggesting that the regulation of microglial ROS production by VSOP/Hv1 is age-dependent. We also performed brain ischemic stroke experiments and found that the neuroprotective effect of VSOP/Hv1deficiency on infarct volume depended on the age of animals. Taken together, regulation of ROS production by VSOP/Hv1 is more complex than previously thought and significance of VSOP/Hv1 in microglial ROS production depends on age. PMID- 28628215 TI - Monitoring Pathogen-Induced Sickness in Mice and Rats. AB - Sickness behavior monitoring, a technique for examining the development of sickness symptomatology following infection, is necessary in experiments studying neurochemical and physiological changes associated with pathogen-induced immune activation. However, the results of sickness behavior monitoring are difficult to reconcile due to inconsistencies in protocol methods and rater bias. The protocol described herein offers a non-invasive and unbiased approach to assess the progression of pathogen-induced sickness behaviors. This simple, straightforward method uses a five-point scale to assess animals for the presence of four sickness behaviors (i.e., '"0" = no sickness behaviors; "4" = four sickness behaviors) at various time points following exposure to a pathogen. This approach removes the ambiguity and bias inherent to other methods of sickness behavior monitoring that rely on subjective ratings of severity for individual symptoms. This protocol has been successfully applied to male and female rodents injected intraperitoneally with lipopolysaccharide and polyinosinic:polycytidylic acid, and has been effective in pubertal and adult populations. Protocols for changes in body temperature and weight are also provided as physiological markers of sickness. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628216 TI - A Fast, Easy, and Customizable Eight-Color Flow Cytometric Method for Analysis of the Cellular Content of Bronchoalveolar Lavage Fluid in the Mouse. AB - The cell composition of bronchoalveolar lavage fluid (BAL) is an important indicator of airway inflammation. It is commonly determined by cytocentrifuging leukocytes on slides, then staining, identifying, and counting them as eosinophils, neutrophils, macrophages, or lymphocytes according to morphological criteria under light microscopy, where it is not always easy to distinguish macrophages from lymphocytes. We describe here a one-step, easy-to-use, and easy to-customize 8-color flow cytometric method for performing differential cell count and comparing it to morphological counts on stained cytospins. This method identifies BAL cells by a simultaneous one-step immunolabeling procedure using antibodies to identify T cells, B cells, neutrophils, eosinophils, and macrophages. Morphological analysis of flow-sorted cell subsets is used to validate this protocol. An important advantage of this basic flow cytometry protocol is the ability to customize it by the addition of antibodies to study receptor expression at leukocyte cell surfaces and identify subclasses of inflammatory cells as needed. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628217 TI - Mouse Model of Burn Wound and Infection: Thermal (Hot Air) Lesion-Induced Immunosuppression. AB - The immunosuppression induced by thermal injury renders the burned victim susceptible to infection. A mouse model was developed to examine the immunosuppression, which was possible to induce even at a minor thermal insult of 6% total body surface area. After induction of the burn (48 hr) a depression of leukocytes in the peripheral blood was found of the burned mice. This depression was due to a reduction in the polymorphonuclear cells. The burned mice were not able to clear a Pseudomonas aeruginosa wound infection, since the infection spread to the blood as compared to mice only infected with P. aeruginosa subcutaneously. The burn model offers an opportunity to study infections under these conditions. The present model can also be used to examine new antibiotics and immune therapy. Our animal model resembling the clinical situation is useful in developing new treatments of burn wound victims. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628218 TI - Microbiota Analysis Using an Illumina MiSeq Platform to Sequence 16S rRNA Genes. AB - The microbiota have been shown to play an important role in diverse biological processes including immunity, metabolism, and digestion. Assessing the exact composition of the microbiota has proven challenging due to the often unknown growth specificities of its members, and culture-based approaches typically fail to capture the complete diversity of microorganisms present. Next Generation Sequencing (NGS) methods provide an efficient means to gather information about cultured and uncultured members of the microbiota. This article provides a method to characterize bacterial communities in terms of species composition using high throughput sequencing. Briefly, by extracting the entire DNA content of a microbiota sample and performing a targeted high-throughput sequencing of the 16S rRNA gene, a phylogenetic marker for prokaryotes, prediction of the composition of the entire bacterial community is made possible. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628219 TI - Application of SWATH Proteomics to Mouse Biology. AB - The quantitative measurement of the proteome has been shown to yield new insights into physiology and cell biology that cannot be determined from the genome and transcriptome because the quantitative relationship between transcriptome and proteome is complex. MS-based proteomics techniques, such as SWATH-MS, have recently advanced to the point at which they may be reliably applied by biologists who are not specialists in mass spectrometry. Here we provide standard protocols for preparation of tissue samples for input into the SWATH-MS analytical pipeline. These protocols are designed for high-throughput processing of tissues with >=5 mg of sample available for analysis. Studies with extremely limited amounts of tissue should consider PCT-SWATH. An experienced single user should be able to process 48 samples per day for injection into the mass spectrometer, or up to 144 samples a week. The machine time necessary for running these samples with SWATH is approximately 1.5 hr per sample. Data acquisition protocols are also provided. (c) 2017 by John Wiley & Sons, Inc. PMID- 28628220 TI - Importance of endothelial dysfunction biomarkers in patients with Crimean-Congo hemorrhagic fever. AB - The pathogenesis of the Crimean-Congo hemorrhagic fever (CCHF) and the cause of the hemorrhage are not yet fully understood. However, the endothelium plays a key role in the pathogenesis. The purpose of this study was to investigate endothelial dysfunction markers (asymmetrical dimethyl arginine [ADMA], endothelin 1[ET-1], thrombomodulin [TM], von Willebrand factor [vWf], and intercellular adhesion molecule [ICAM-1]) in serum in patients with CCHF and their associations with hemorrhage. Seventy-three patients with CCHF were included in the study. All patients' endothelial dysfunction markers were studied using routine biochemical and hematological tests. The data obtained were then subjected to statistical analysis. Statistically significant differences were determined between the patients and healthy control groups at time of presentation to hospital in terms of ADMA (P < 0.001), ET-1 (P < 0.001), TM (P = 0.039), vWf (P < 0.001), and ICAM-1 (P < 0.001) levels. Only the differences in TM and vWf were significant between the hemorrhagic and non-hemorrhagic groups (P < 0.05). Both serum ADMA and TM levels were significantly higher in the hemorrhage and non-hemorrhage CCHF groups on the 5th day compared to the 1st day (P < 0.05). Levels of endothelial dysfunction markers in CCHF vary in proportion to the damage occurring in the endothelium. ADMA and TM levels were lower in periods with mild endothelial injury. They were increased in line with severity endothelial injury. They may be an early marker in showing hemorrhage. Elevation in ADMA levels and low nitric oxide levels lead to endothelial injury and hemorrhage. Soluble TM that entered the circulation in line with the increased endothelial injury in hemorrhagic patients has been compromised the coagulation cascade. PMID- 28628221 TI - Influence of radiofrequency-electromagnetic waves from 3rd-generation cellular phones on fertilization and embryo development in mice. AB - The purpose of this study was to evaluate the effects of 3rd-generation (3G) cellular phone radiofrequency-electromagnetic wave (RF-EMW) exposure on fertilization and embryogenesis in mice. Oocytes and spermatozoa were exposed to 3G cellular phone RF-EMWs, 1.95 GHz wideband code division multiple access, at a specific absorption rate of 2 mW/g for 60 min, or to sham exposure. After RF-EMW exposure, in vitro fertilization and intracytoplasmic sperm injection were performed. Rates of fertilization, embryogenesis (8-cell embryo, blastocyst), and chromosome aberration were compared between the combined spermatozoa and oocyte groups: both exposed, both non-exposed, one exposed, and the other non-exposed. Rates of fertilization, embryogenesis, and blastocyst formation did not change significantly across the four groups. Considering that the degree of exposure in the present study was >=100 times greater than daily exposure of human spermatozoa and even greater than daily exposure of oocytes, the present results indicate safety of RF-EMW exposure in humans. Bioelectromagnetics. 38:466-473, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28628222 TI - The value of electrocardiography in prognosticating clinical deterioration and mortality in acute pulmonary embolism: A systematic review and meta-analysis. AB - The role of electrocardiography (ECG) in prognosticating pulmonary embolism (PE) is increasingly recognized. ECG is quickly interpretable, noninvasive, inexpensive, and available in remote areas. We hypothesized that ECG can provide useful information about PE prognostication. We searched MEDLINE, EMBASE, Google Scholar, Web of Science, abstracts, conference proceedings, and reference lists through February 2017. Eligible studies used ECG to prognosticate for the main outcomes of death and clinical deterioration or escalation of therapy. Two authors independently selected studies; disagreement was resolved by consensus. Ad hoc piloted forms were used to extract data and assess risk of bias. We used a random-effects model to pool relevant data in meta-analysis with odds ratios (ORs) and 95% confidence intervals (CIs); all other data were synthesized qualitatively. Statistical heterogeneity was assessed using the I 2 value. We included 39 studies (9198 patients) in the systematic review. There was agreement in study selection (kappa: 0.91, 95% CI: 0.86-0.96). Most studies were retrospective; some did not appropriately control for confounders. ECG signs that were good predictors of a negative outcome included S1Q3T3 (OR: 3.38, 95% CI: 2.46-4.66, P < 0.001), complete right bundle branch block (OR: 3.90, 95% CI: 2.46 6.20, P < 0.001), T-wave inversion (OR: 1.62, 95% CI: 1.19-2.21, P = 0.002), right axis deviation (OR: 3.24, 95% CI: 1.86-5.64, P < 0.001), and atrial fibrillation (OR: 1.96, 95% CI: 1.45-2.67, P < 0.001) for in-hospital mortality. Several ischemic patterns also were significantly predictive. Our conclusion is that ECG is potentially valuable in prognostication of acute PE. PMID- 28628223 TI - Unsuccessful treatment of methicillin-resistant Staphylococcus aureus endocarditis with dalbavancin. AB - WHAT IS KNOWN AND OBJECTIVE: Limited evidence describes dalbavancin use in infective endocarditis (IE). CASE DESCRIPTION: A 27-year-old pregnant female received 4 weeks of dalbavancin for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia and tricuspid valve IE after conventional therapy was no longer an option due to non-compliance. Despite having a smaller cardiac vegetation following dalbavancin, she was bacteraemic <2 weeks later with vancomycin-intermediate (VISA) and telavancin-non-susceptible S. aureus. WHAT IS NEW AND CONCLUSION: This is the first report of unsuccessful IE treatment with dalbavancin. Blood cultures grew VISA and lipoglycopeptide-non-susceptible S. aureus <2 weeks following dalbavancin. Both outcomes raise concerns about using dalbavancin for IE. PMID- 28628224 TI - Human exposure to power frequency magnetic fields up to 7.6 mT: An integrated EEG/fMRI study. AB - We assessed the effects of power-line frequency (60 Hz in North America) magnetic fields (MF) in humans using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Twenty-five participants were enrolled in a pseudo-double-blind experiment involving "real" or "sham" exposure to sinusoidal 60 Hz MF exposures delivered using the gradient coil of an MRI scanner following two conditions: (i) 10 s exposures at 3 mT (10 repetitions); (ii) 2 s exposures at 7.6 mT (100 repetitions). Occipital EEG spectral power was computed in the alpha range (8-12 Hz, reportedly the most sensitive to MF exposure in the literature) with/without exposure. Brain functional activation was studied using fMRI blood oxygen level-dependent (BOLD, inversely correlated with EEG alpha power) maps. No significant effects were detected on occipital EEG alpha power during or post-exposure for any exposure condition. Consistent with EEG results, no effects were observed on fMRI BOLD maps in any brain region. Our results suggest that acute exposure (2-10 s) to 60 Hz MF from 3 to 7.6 mT (30,000 to 76,000 times higher than average public exposure levels for 60 Hz MF) does not induce detectable changes in EEG or BOLD signals. Combined with previous findings in which effects were observed on the BOLD signal after 1 h exposure to 3 mT, 60 Hz MF, this suggests that MF exposure in the low mT range (<10 mT) might require prolonged durations of exposure to induce detectable effects. Bioelectromagnetics. 38:425-435, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28628225 TI - Utilization of the Bridging Strategy for the Development of New Drugs in Oncology to Avoid Drug Lag. AB - Global trial (GT) strategy and bridging (BG) strategy are currently the main clinical development strategies of oncology drugs in Japan, but the relationship between development style and drug lag and how the bridging strategy has contributed to the solution of drug lag have not been clear. We investigated the potential factors that influenced submission lag (SL), and also compared the differences in SL among early-initiation BG strategy, late-initiation BG strategy, and GT strategy. A stepwise linear regression analysis identified the potential factors that shorten SL: development start lag and development style. Comparison of the differences in SL among the strategies also indicated that the SL in the GT strategy and that in the early-initiation BG strategy were significantly shorter than that in the late-initiation BG strategy. The findings in our study suggest that the late-initiation BG strategy may not contribute to shortening drug lag. Because the number of late-initiation BG studies has not decreased, we propose first that pharmaceutical companies should initiate clinical development as early as possible in Japan so that they can choose the GT strategy as a first option at the next step, and second when they cannot choose the GT strategy after investigating differences in exposure between Japanese and non-Japanese in a phase 1 study, they should select the early BG strategy to avoid future drug lag. It is also important for the regulatory authorities to provide reasonable guidance to have a positive impact on strategic decisions, even for foreign-capital companies. PMID- 28628226 TI - The future of dream science. AB - This article describes the future prospects of scientific dream research. Three frontiers of investigation hold special promise: neuroscientific studies of the brain-mind system's activities during sleep (such as during lucid dreaming); systematic analyses of large collections of dream reports from diverse populations of people; and psychotherapeutic explorations of the multiple dimensions of personal and collective meaning woven into the dream experiences of each individual. Several helpful books on the science of sleep and dreaming are mentioned for further study. PMID- 28628227 TI - MicroRNA-mediated drug resistance in ovarian cancer. AB - The development of intrinsic or acquired resistance to chemotherapeutic agents used in the treatment of various human cancers is a major obstacle for the successful abolishment of cancer. The accumulated efforts in the understanding the exact mechanisms of development of multidrug resistance (MDR) have led to the introduction of several unique and common mechanisms. Recent studies demonstrate the regulatory role of small noncoding RNA or miRNA in the several parts of cancer biology. Practically all aspects of cell physiology under normal and disease conditions are reported to be controlled by miRNAs. In this review, we discuss how the miRNA profile is changed upon MDR development and the pivotal regulatory role played by miRNAs in overcoming resistance to chemotherapeutic agents. It is hoped that further studies will support the use of these differentially expressed miRNAs as prognostic and predictive markers, as well as novel therapeutic targets to overcome resistance in ovarian cancer. PMID- 28628229 TI - Troxerutin with copper generates oxidative stress in cancer cells: Its possible chemotherapeutic mechanism against hepatocellular carcinoma. AB - Troxerutin (TXER) a rutin derivative is known for its anticancer effect against hepatocellular carcinoma (HCC). As part of large study, recently we have shown TXER interact with genetic material and its anti-mutagenic property. In the present study we have explored its possible mode of action in HCC. Since TXER alone did not show significant anticancer effect on Huh-7 cells, in vitro biochemical assays were performed for determining anticancer efficacy of TXER + metal complex using transition metals such as Cu, Zn, and Fe. The anticancer efficacy of TXER + Cu on Huh-7 cells were evaluated using MTT assay, DCFDA, JC-1 staining, comet assay, cell cycle analysis, immunocytochemistry, and Western blotting. Non-toxic nature of TXER was analyzed on primary rat hepatocytes. The in vivo efficacy of TXER was tested in N-nitrosodiethylamine initiated and gamma benzene hexachloride and partial hepatectomy promoted rat liver cancer. Liver markers, transition metal levels, histopathological examination, and expression levels of GST-P, 8-OHdG and Ki-67 were studied to assess the in vivo anticancer effect of TXER. We observed that TXER + Cu induced extensive cellular death on Huh-7 cells through generating free radicals and did not possess any toxic effect on normal hepatocytes. The in vivo studies revealed that TXER possess significant anti-cancer effect as assessed through improved liver markers and suppressed GST P, 8-OHdG, and Ki-67 expression. TXER treatment reduced the hepatic Cu level in cancer bearing animals. Current study brings the putative mechanism involved in anti-cancer effect of TXER, further it will help to formulate phytoconstituents coupled anti-cancer drug for effective treatment of HCC. PMID- 28628228 TI - Epigenetic mechanisms underlying NMDA receptor hypofunction in the prefrontal cortex of juvenile animals in the MAM model for schizophrenia. AB - Schizophrenia (SCZ) is characterized not only by psychosis, but also by working memory and executive functioning deficiencies, processes that rely on the prefrontal cortex (PFC). Because these cognitive impairments emerge prior to psychosis onset, we investigated synaptic function during development in the neurodevelopmental methylazoxymethanol (MAM) model for SCZ. Specifically, we hypothesize that N-methyl-D-aspartate receptor (NMDAR) hypofunction is attributable to reductions in the NR2B subunit through aberrant epigenetic regulation of gene expression, resulting in deficient synaptic physiology and PFC dependent cognitive dysfunction, a hallmark of SCZ. Using western blot and whole cell patch-clamp electrophysiology, we found that the levels of synaptic NR2B protein are significantly decreased in juvenile MAM animals, and the function of NMDARs is substantially compromised. Both NMDA-mEPSCs and synaptic NMDA-eEPSCs are significantly reduced in prelimbic PFC (plPFC). This protein loss during the juvenile period is correlated with an aberrant increase in enrichment of the epigenetic transcriptional repressor RE1-silencing transcription factor (REST) and the repressive histone marker H3K27me3 at the Grin2b promoter, as assayed by ChIP-quantitative polymerase chain reaction. Glutamate hypofunction has been a prominent hypothesis in the understanding of SCZ pathology; however, little attention has been given to the NMDAR system in the developing PFC in models for SCZ. Our work is the first to confirm that NMDAR hypofunction is a feature of early postnatal development, with epigenetic hyper-repression of the Grin2b promoter being a contributing factor. The selective loss of NR2B protein and subsequent synaptic dysfunction weakens plPFC function during development and may underlie early cognitive impairments in SCZ models and patients. Read the Editorial Highlight for this article on page 264. PMID- 28628230 TI - Thread-Like CMOS Logic Circuits Enabled by Reel-Processed Single-Walled Carbon Nanotube Transistors via Selective Doping. AB - The realization of large-area electronics with full integration of 1D thread-like devices may open up a new era for ultraflexible and human adaptable electronic systems because of their potential advantages in demonstrating scalable complex circuitry by a simply integrated weaving technology. More importantly, the thread like fiber electronic devices can be achieved using a simple reel-to-reel process, which is strongly required for low-cost and scalable manufacturing technology. Here, high-performance reel-processed complementary metal-oxide semiconductor (CMOS) integrated circuits are reported on 1D fiber substrates by using selectively chemical-doped single-walled carbon nanotube (SWCNT) transistors. With the introduction of selective n-type doping and a nonrelief photochemical patterning process, p- and n-type SWCNT transistors are successfully implemented on cylindrical fiber substrates under air ambient, enabling high-performance and reliable thread-like CMOS inverter circuits. In addition, it is noteworthy that the optimized reel-coating process can facilitate improvement in the arrangement of SWCNTs, building uniformly well-aligned SWCNT channels, and enhancement of the electrical performance of the devices. The p- and n-type SWCNT transistors exhibit field-effect mobility of 4.03 and 2.15 cm2 V 1 s-1 , respectively, with relatively narrow distribution. Moreover, the SWCNT CMOS inverter circuits demonstrate a gain of 6.76 and relatively good dynamic operation at a supply voltage of 5.0 V. PMID- 28628231 TI - Gene therapy decreases seizures in a model of Incontinentia pigmenti. AB - OBJECTIVE: Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. METHODS: In a mouse model of IP, we administered a single intravenous dose of the adeno associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood brain barrier (BBB) were monitored. RESULTS: The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. INTERPRETATION: The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104. PMID- 28628232 TI - Sensory mapping of pelvic dermatomes in women with interstitial cystitis/bladder pain syndrome. AB - AIM: To describe a sensory map of pelvic dermatomes in women with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). We hypothesized that if IC/BPS involves changes in central processing, then women with IC/BPS will exhibit sensory abnormalities in neurologic pelvic dermatomes. METHODS: Women with IC/BPS and healthy controls underwent neurologic examination that included evaluation of sharp pain sensitivity and vibration in dermatomes T12, L1, L2, S1-5. Peripheral nervous system sensitivity to pressure, vibration, and pinprick were scored using numeric rating scales (NRS). Bilateral comparisons were made with Wilcoxon signed rank test and comparisons between groups were made by the Mann-Whitney U-test. RESULTS: Total of 74 women with IC/BPS and 36 healthy counterparts were included. IC/BPS and control groups had similar age (43.0 +/- 14.1 and 38.6 +/- 15.3 years, P = 0.14) and BMI (28.9 +/- 8.0 kg/m2 and 26.9 +/- 8.4 kg/m2 , P = 0.24), respectively. Women with IC/BPS reported hyperalgesia (elevated bilateral NRS pain intensity) in all pelvic dermatomes compared to healthy controls. S4-S5 region had the highest pain intensity in all participants. All IC/BPS participants exhibited vibration sensation hypoesthesia, at least unilaterally, in all of the pelvic dermatomes except L1 compared to healthy controls. CONCLUSION: This detailed map of neurologic pelvic dermatomes in women with IC/BPS found hyperalgesia in all pelvic dermatomes, and some evidence of vibration sensation hypoesthesia, compared to healthy controls. These findings support the hypothesis that IC/BPS may involve changes in central signal processing biased towards nociception. PMID- 28628233 TI - Spatial and temporal trends of poly- and perfluoroalkyl substances in fish fillets and water collected from pool 2 of the Upper Mississippi River. AB - In 2011, poly- and perfluoroalkyl substances (PFASs) were analyzed in surface water and fish fillet samples taken from Pool 2 of the Upper Mississippi River, a 33-mile stretch inclusive of the Minneapolis/St. Paul, Minnesota (USA) metropolitan area. Approximately 100 each of bluegill, freshwater drum, smallmouth bass, and white bass were sampled within the study area. Surface water samples were also collected from each of the 10 sampling reaches established for the study. Water and fillet samples were analyzed for perfluorinated carboxylic acids (C4-C12), perfluorinated sulfonic acids (C4, C6, and C8), and perfluorooctane sulfonamide. Perfluorooctane sulfonate (PFOS) was observed with the greatest frequency in fish fillets and ranged from 3.0 to 760 ng/g wet weight. Mean (geometric) PFOS concentrations in bluegill, freshwater drum, smallmouth bass, and white bass were 20, 28, 29, and 58 ng/g wet weight, respectively. When compared with fish data collected in 2009, a significant reduction (p < 0.05) in PFOS concentrations was noted. This finding was confirmed based on data from studies conducted in 2012 and 2013. Overall, between 2009 and 2013, PFOS concentrations decreased by 65, 76, and 50% for bluegill, freshwater drum, and white bass, respectively (44% decrease for smallmouth bass from 2009 to 2012). These declines in fish PFOS concentrations are consistent with ongoing efforts to effectively control sources of PFASs to the Mississippi River. Environ Toxicol Chem 2017;36:3138-3147. (c) 2017 SETAC. PMID- 28628234 TI - Tumor-Targeting Salmonella typhimurium A1-R Promotes Tumoricidal CD8+ T Cell Tumor Infiltration and Arrests Growth and Metastasis in a Syngeneic Pancreatic Cancer Orthotopic Mouse Model. AB - The present study determined the effect of the tumor-targeting strain Salmonella typhimurium A1-R (S. typhimurium A1-R) on CD8+ tumor-infiltrating lymphocytes (TILs) in a syngeneic pancreatic-cancer orthotopic mouse model. The effect of tumor-targeting S. typhimurium A1-R on CD8+ TILs was determined on the Pan02 murine pancreatic-adenocarcinoma implanted orthotopically in the pancreatic tail of C57BL/6 immunocompromised mice. Three weeks after orthotopic implantation, mice were randomized as follows G1: untreated control group (n = 8); and G2: S. typhimurium A1-R-treatment group (n = 8, 1 * 107 colony forming units [CFU]/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor-volume ratio was defined as ratio of tumor volume on the 22nd day relative to the 1st day. The tumor volume ratio was significantly lower in the S. typhimurium A1-R-treated group (G2) (3.0 +/- 2.8) than the untreated control (G1) (39.9 +/- 30.7, P < 0.01). Hematoxylin and easin (H&E) staining on tumor sections was performed to evaluate tumor destruction which was classified according to the Evans grading system and found to be much greater in the S. typhimurium A1-R-treated mice (G2). Six mice in G1 had peritoneal dissemination, whereas no mice showed peritoneal dissemination in G2 (P < 0.01). Immunohistochemical staining with anti-mouse CD8+ antibody was performed in order to detect TILs determined by calculating the average number of CD8+ cells in three high power fields (200*) in the treated and untreated tumors. The TIL score was significantly higher in G2 (133.5 +/- 32.2) than G1 (45.1 +/- 19.4, P < 0.001). The present study demonstrates that S. typhimurium A1-R promotes CD8+ T cell infiltration and inhibition of tumor growth and metastasis. J. Cell. Biochem. 119: 634-639, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28628235 TI - Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients. AB - OBJECTIVE: To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1-IgG-seropositive and/or CASPR2-IgG-seropositive patients. METHODS: Patients were identified through service neural autoantibody evaluation. Ninety five had longitudinal follow-up (7-456 months; median = 35). RESULTS: Among 3,910 patients tested, 196 were LGI1-IgG positive, 51 were CASPR2-IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1-IgG-positive and 5 of 6 (83%) CASPR2 IgG-positive patients. LGI1-IgG-positive specimens had higher voltage-gated potassium channel-IgG immunoprecipitation values (0.33nmol/l, range = 0.02-5.14) than CASPR2-IgG-positive specimens (0.10nmol/l, range = 0.00-0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1-IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1-IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2-mesiotemporal hyperintensity was more common in LGI1-IgG-positive (41%) than in CASPR2-IgG-positive patients (p = 0.033). T1-bright basal ganglia were confined to LGI1-IgG-positive patients with faciobrachial-dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1 IgG/CASPR2-IgG dual seropositive patients (one-third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1-5) at onset and 1.74 (range = 0-6) at last follow-up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication. INTERPRETATION: Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2 IgG or LGI1-IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1-IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long-term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79-92. PMID- 28628236 TI - Blastomyces dermatitidis peritonitis complicating peritoneal dialysis. AB - Fungal peritonitis is an uncommon complication in peritoneal dialysis patients. We report a case of blastomyces dermatitis peritonitis in a nonimmunocompromised peritoneal dialysis patient, who initially presented with symptoms of lower extremity weakness and altered mental status. Peritoneal blastomycosis is rare condition and not previously reported in end stage renal disease patients on peritoneal dialysis. Fungal peritonitis can present with subtle clinical findings so a high index of suspicion is needed as early detection and treatment may decrease mortality and morbidity. PMID- 28628237 TI - Wing phosphorylation is a major functional determinant of the Lrs14-type biofilm and motility regulator AbfR1 in Sulfolobus acidocaldarius. AB - In response to a variety of environmental cues, prokaryotes can switch between a motile and a sessile, biofilm-forming mode of growth. The regulatory mechanisms and signaling pathways underlying this switch are largely unknown in archaea but involve small winged helix-turn-helix DNA-binding proteins of the archaea specific Lrs14 family. Here, we study the Lrs14 member AbfR1 of Sulfolobus acidocaldarius. Small-angle X-ray scattering data are presented, which are consistent with a model of dimeric AbfR1 in which dimerization occurs via an antiparallel coiled coil as suggested by homology modeling. Furthermore, solution structure data of AbfR1-DNA complexes suggest that upon binding DNA, AbfR1 induces deformations in the DNA. The wing residues tyrosine 84 and serine 87, which are phosphorylated in vivo, are crucial to establish stable protein-DNA contacts and their substitution with a negatively charged glutamate or aspartate residue inhibits formation of a nucleoprotein complex. Furthermore, mutation abrogates the cellular abundance and transcription regulatory function of AbfR1 and thus affects the resulting biofilm and motility phenotype of S. acidocaldarius. This work establishes a novel wHTH DNA-binding mode for Lrs14 like proteins and hints at an important role for protein phosphorylation as a signal transduction mechanism for the control of biofilm formation and motility in archaea. PMID- 28628238 TI - A genome-wide association study of 23 agronomic traits in Chinese wheat landraces. AB - Uncovering the genetic basis of agronomic traits in wheat landraces is important for ensuring global food security via the development of improved varieties. Here, 723 wheat landraces from 10 Chinese agro-ecological zones were evaluated for 23 agronomic traits in six environments. All accessions could be clustered into five subgroups based on phenotypic data via discriminant function analysis, which was highly consistent with genotypic classification. A genome-wide association study was conducted for these traits using 52 303 DArT-seq markers to identify marker-trait associations and candidate genes. Using both the general linear model and the mixed linear model, 149 significant markers were identified for 21 agronomic traits based on best linear unbiased prediction values. Considering the linkage disequilibrium decay distance in this study, significant markers within 10 cM were combined as a quantitative trait locus (QTL), with a total of 29 QTL identified for 15 traits. Of these, five QTL for heading date, flag leaf width, peduncle length, and thousand kernel weight had been reported previously. Twenty-five candidate genes associated with significant markers were identified. These included the known vernalization genes VRN-B1 and vrn-B3 and the photoperiod response genes Ppd and PRR. Overall, this study should be helpful in elucidating the underlying genetic mechanisms of complex agronomic traits and performing marker-assisted selection in wheat. PMID- 28628239 TI - Recent Progress on Advanced Materials for Solid-Oxide Fuel Cells Operating Below 500 degrees C. AB - Solid-oxide fuel cells (SOFCs) are electricity generators that can convert the chemical energy in various fuels directly to the electric power with high efficiency. Recent advances in materials and related key components for SOFCs operating at ~500 degrees C are summarized here, with a focus on the materials, structures, and techniques development for low-temperature SOFCs, including the analysis of most of the critical parameters affecting the electrochemical performance of the electrolyte, anode, and cathode. New strategies, such as thin film deposition, exsolution of nanoparticles from perovskites, microwave plasma heating, and finger-like channeled electrodes, are discussed. These recent developments highlight the need for electrodes with higher activity and electrolytes with greater conductivity to generate a high electrochemical performance at lower temperatures. PMID- 28628240 TI - Comparative transcriptome analysis of nodules of two Mesorhizobium-chickpea associations with differential symbiotic efficiency under phosphate deficiency. AB - Phosphate (Pi) deficiency is known to be a major limitation for symbiotic nitrogen fixation (SNF), and hence legume crop productivity globally. However, very little information is available on the adaptive mechanisms, particularly in the important legume crop chickpea (Cicer arietinum L.), which enable nodules to respond to low-Pi availability. Thus, to elucidate these mechanisms in chickpea nodules at molecular level, we used an RNA sequencing approach to investigate transcriptomes of the nodules in Mesorhizobium mediterraneum SWRI9-(MmSWRI9) chickpea and M. ciceri CP-31-(McCP-31)-chickpea associations under Pi-sufficient and Pi-deficient conditions, of which the McCP-31-chickpea association has a better SNF capacity than the MmSWRI9-chickpea association during Pi starvation. Our investigation revealed that more genes showed altered expression patterns in MmSWRI9-induced nodules than in McCP-31-induced nodules (540 vs. 225) under Pi deficiency, suggesting that the Pi-starvation-more-sensitive MmSWRI9-induced nodules required expression change in a larger number of genes to cope with low Pi stress than the Pi-starvation-less-sensitive McCP-31-induced nodules. The functional classification of differentially expressed genes (DEGs) was examined to gain an understanding of how chickpea nodules respond to Pi starvation, caused by soil Pi deficiency. As a result, more DEGs involved in nodulation, detoxification, nutrient/ion transport, transcriptional factors, key metabolic pathways, Pi remobilization and signalling were found in Pi-starved MmSWRI9 induced nodules than in Pi-starved McCP-31-induced nodules. Our findings have enabled the identification of molecular processes that play important roles in the acclimation of nodules to Pi deficiency, ultimately leading to the development of Pi-efficient chickpea symbiotic associations suitable for Pi deficient soils. PMID- 28628241 TI - Aberrant expression of CD10 and BCL6 in mantle cell lymphoma. AB - AIMS: Mantle cell lymphoma (MCL) is characterized by distinctive histological and molecular features. Aberrant expression of BCL6 and CD10 has been reported occasionally, but the biological features of such cases are largely unknown. This study aimed to define the epidemiological, histological and cytogenetic characteristics of BCL6 and CD10-positive MCLs, also investigating possible biological features. METHODS AND RESULTS: A total of 165 cases of cyclin D1 and t(11;14)(q13;q34)-positive MCLs were studied for CD10 and BCL6 immunohistochemical expression, which was documented in 26 of 165 (15.8%) cases (BCL6 17 of 165; CD10 11 of 165; BCL6 and CD10 co-expression two of 165). CD10 positivity was significantly more frequent in females (63.3%; P < 0.01). Either expression correlated significantly with higher mean proliferation index and higher prevalence of MUM1 positivity (P < 0.05). Fluorescence in-situ hybridization (FISH) for BCL6 (3q27) gene derangements was performed on the BCL6- and CD10-positive cases and 98 matched controls: amplifications were documented more frequently in BCL6-positive than -negative cases (50.0% versus 19.4% of cases) (P < 0.05). The mutational status of the variable immunoglobulin heavy chain genes (IGVH) was investigated by Sanger sequencing: five of the six successfully tested cases (83.3%) showed no somatic hypermutations. CONCLUSIONS: Aberrant CD10 and BCL6 expression defines a subset of MCLs with higher mean Ki-67 index and higher prevalence of MUM1 expression. BCL6 protein positivity correlates with cytogenetic aberrations involving the BCL6 gene. Although examined successfully in few cases, the high prevalence of unmutated IGVH genes also points at a pregerminal cell origin for these phenotypically aberrant cases. PMID- 28628242 TI - Lead-Free Antiferroelectric Silver Niobate Tantalate with High Energy Storage Performance. AB - Antiferroelectric materials that display double ferroelectric hysteresis loops are receiving increasing attention for their superior energy storage density compared to their ferroelectric counterparts. Despite the good properties obtained in antiferroelectric La-doped Pb(Zr,Ti)O3 -based ceramics, lead-free alternatives are highly desired due to the environmental concerns, and AgNbO3 has been highlighted as a ferrielectric/antiferroelectric perovskite for energy storage applications. Enhanced energy storage performance, with recoverable energy density of 4.2 J cm-3 and high thermal stability of the energy storage density (with minimal variation of <=+/-5%) over 20-120 degrees C, can be achieved in Ta-modified AgNbO3 ceramics. It is revealed that the incorporation of Ta to the Nb site can enhance the antiferroelectricity because of the reduced polarizability of B-site cations, which is confirmed by the polarization hysteresis, dielectric tunability, and selected-area electron diffraction measurements. Additionally, Ta addition in AgNbO3 leads to decreased grain size and increased bulk density, increasing the dielectric breakdown strength, up to 240 kV cm-1 versus 175 kV cm-1 for the pure counterpart, together with the enhanced antiferroelectricity, accounting for the high energy storage density. PMID- 28628243 TI - Using ultrahigh-resolution mass spectrometry and toxicity identification techniques to characterize the toxicity of oil sands process-affected water: The case for classical naphthenic acids. AB - Previous assessments of oil sands process-affected water (OSPW) toxicity were hampered by lack of high-resolution analytical analysis, use of nonstandard toxicity methods, and variability between OSPW samples. We integrated ultrahigh resolution mass spectrometry with a toxicity identification evaluation (TIE) approach to quantitatively identify the primary cause of acute toxicity of OSPW to rainbow trout (Oncorhynchus mykiss). The initial characterization of OSPW toxicity indicated that toxicity was associated with nonpolar organic compounds, and toxicant(s) were further isolated within a range of discrete methanol fractions that were then subjected to Orbitrap mass spectrometry to evaluate the contribution of naphthenic acid fraction compounds to toxicity. The results showed that toxicity was attributable to classical naphthenic acids, with the potency of individual compounds increasing as a function of carbon number. Notably, the mass of classical naphthenic acids present in OSPW was dominated by carbon numbers <=16; however, toxicity was largely a function of classical naphthenic acids with >=17 carbons. Additional experiments found that acute toxicity of the organic fraction was similar when tested at conductivities of 400 and 1800 MUmhos/cm and that rainbow trout fry were more sensitive to the organic fraction than larval fathead minnows (Pimephales promelas). Collectively, the results will aid in developing treatment goals and targets for removal of OSPW toxicity in water return scenarios both during operations and on mine closure. Environ Toxicol Chem 2017;36:3148-3157. (c) 2017 SETAC. PMID- 28628245 TI - Effects of resistance training using known vs unknown loads on eccentric-phase adaptations and concentric velocity. AB - The aims of this study were to compare both eccentric- and concentric-phase adaptations in highly trained handball players to 4 weeks of twice-weekly rebound bench press throw training with varying loads (30%, 50% and 70% of one-repetition maximum [1-RM]) using either known (KL) or unknown (UL) loads and to examine the relationship between changes in eccentric- and concentric-phase performance. Twenty-eight junior team handball players were divided into two experimental groups (KL or UL) and a control group. KL subjects were told the load prior each repetition, while UL were blinded. For each repetition, the load was dropped and then a rebound bench press at maximum velocity was immediately performed. Both concentric and eccentric velocity as well as eccentric kinetic energy and musculo articular stiffness prior to the eccentric-concentric transition were measured. Results showed similar increases in both eccentric velocity and kinetic energy under the 30% 1-RM but greater improvements under 50% and 70% 1-RM loads for UL than KL. UL increased stiffness under all loads (with greater magnitude of changes). KL improved concentric velocity only under the 30% 1-RM load while UL also improved under 50% and 70% 1-RM loads. Improvements in concentric movement velocity were moderately explained by changes in eccentric velocity (R2 =.23 .62). Thus, UL led to greater improvements in concentric velocity, and the improvement is potentially explained by increases in the speed (as well as stiffness and kinetic energy) of the eccentric phase. Unknown load training appears to have significant practical use for the improvement of multijoint stretch-shortening cycle movements. PMID- 28628244 TI - Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72 associated amyotrophic lateral sclerosis. AB - As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146. PMID- 28628246 TI - Heterogeneous Catalysis in Zeolites, Mesoporous Silica, and Metal-Organic Frameworks. AB - Crystalline porous materials are important in the development of catalytic systems with high scientific and industrial impact. Zeolites, ordered mesoporous silica, and metal-organic frameworks (MOFs) are three types of porous materials that can be used as heterogeneous catalysts. This review focuses on a comparison of the catalytic activities of zeolites, mesoporous silica, and MOFs. In the first part of the review, the distinctive properties of these porous materials relevant to catalysis are discussed, and the corresponding catalytic reactions are highlighted. In the second part, the catalytic behaviors of zeolites, mesoporous silica, and MOFs in four types of general organic reactions (acid, base, oxidation, and hydrogenation) are compared. The advantages and disadvantages of each porous material for catalytic reactions are summarized. Conclusions and prospects for future development of these porous materials in this field are provided in the last section. This review aims to highlight recent research advancements in zeolites, ordered mesoporous silica, and MOFs for heterogeneous catalysis, and inspire further studies in this rapidly developing field. PMID- 28628247 TI - Scalable Synthesis of 2D Si Nanosheets. AB - 2D Si nanomaterials have attracted tremendous attention due to their novel properties and a wide range of potential applications from electronic devices to energy storage and conversion. However, high-quality and large-scale fabrication of 2D Si remains challenging. This study reports a room-temperature and one-step synthesis technique that leads to large-scale and low-cost production of Si nanosheets (SiNSs) with thickness ~4 nm and lateral size of several micrometers, based on the intrinsic delithiation process of chemically leaching lithium from the Li13 Si4 alloy. Together with experimental results, a combination of theoretical modeling and atomistic simulations indicates that the formation of single SiNS arises from spontaneous delamination of nanosheets from their substrate due to delithiation-induced mismatch. Subsequently, the synthesized Si nanosheets evolve from amorphous to nanocrystalline to crystalline structures during annealing at different temperatures. It is demonstrated that these SiNSs possess unique mechanical properties, in particular ultralow friction, in contrast to their bulk counterparts. PMID- 28628248 TI - Kinetic Selectivity and Thermodynamic Features of Competitive Imine Formation in Dynamic Covalent Chemistry. AB - The kinetic and thermodynamic selectivities of imine formation have been investigated for several dynamic covalent libraries of aldehydes and amines. Two systems were examined, involving the reaction of different types of primary amino groups (aliphatic amines, alkoxy-amines, hydrazides and hydrazines) with two types of aldehydes, sulfobenzaldehyde and pyridoxal phosphate in aqueous solution at different pD (5.0, 8.5, 11.4) on one hand, 2-pyridinecarboxaldehyde and salicylaldehyde in organic solvents on the other hand. The reactions were performed separately for given amine/aldehyde pairs as well as in competitive conditions between an aldehyde and a mixture of amines. In the latter case, the time evolution of the dynamic covalent libraries generated was followed, taking into consideration the operation of both kinetic and thermodynamic selectivities. The results showed that, in aqueous solution, the imine of the aliphatic amine was not stable, but oxime and hydrazone formed well in a pH dependent way. On the other hand, in organic solvents, the kinetic product was the imine derived from an aliphatic amine and the thermodynamic products were oxime and hydrazone. The insights gained from these experiments provide a basis for the implementation of imine formation in selective derivatization of mono-amines in mixtures as well as of polyfunctional compounds presenting different types of amino groups. They may in principle be extended to other dynamic covalent chemistry systems. PMID- 28628249 TI - Defining a temporal order of genetic requirements for development of mycobacterial biofilms. AB - Most mycobacterial species spontaneously form biofilms, inducing unique growth physiologies and reducing drug sensitivity. Biofilm growth progresses through three genetically programmed stages: substratum attachment, intercellular aggregation and architecture maturation. Growth of Mycobacterium smegmatis biofilms requires multiple factors including a chaperonin (GroEL1) and a nucleoid associated protein (Lsr2), although how their activities are linked remains unclear. Here it is shown that Lsr2 participates in intercellular aggregation, but substratum attachment of Lsr2 mutants is unaffected, thereby genetically distinguishing these developmental stages. Further, a suppressor mutation in a glycopeptidolipid synthesis gene (mps) that results in hyperaggregation of cells and fully restores the form and functions of Deltalsr2 mutant biofilms was identified. Suppression by the mps mutation is specific to Deltalsr2; it does not rescue the maturation-deficient biofilms of a DeltagroEL1 mutant, thereby differentiating the process of aggregation from maturation. Gene expression analysis supports a stepwise process of maturation, highlighted by temporally separated, transient inductions of iron and nitrogen import genes. Furthermore, GroEL1 activity is required for induction of nitrogen, but not iron, import genes. Together, the findings begin to define molecular checkpoints during development of mycobacterial biofilms. PMID- 28628250 TI - Grain subproteome responses to nitrogen and sulfur supply in diploid wheat Triticum monococcum ssp. monococcum. AB - Wheat grain storage proteins (GSPs) make up most of the protein content of grain and determine flour end-use value. The synthesis and accumulation of GSPs depend highly on nitrogen (N) and sulfur (S) availability and it is important to understand the underlying control mechanisms. Here we studied how the einkorn (Triticum monococcum ssp. monococcum) grain proteome responds to different amounts of N and S supply during grain development. GSP composition at grain maturity was clearly impacted by nutrition treatments, due to early changes in the rate of GSP accumulation during grain filling. Large-scale analysis of the nuclear and albumin-globulin subproteomes during this key developmental phase revealed that the abundance of 203 proteins was significantly modified by the nutrition treatments. Our results showed that the grain proteome was highly affected by perturbation in the N:S balance. S supply strongly increased the rate of accumulation of S-rich alpha/beta-gliadin and gamma-gliadin, and the abundance of several other proteins involved in glutathione metabolism. Post-anthesis N supply resulted in the activation of amino acid metabolism at the expense of carbohydrate metabolism and the activation of transport processes including nucleocytoplasmic transit. Protein accumulation networks were analyzed. Several central actors in the response were identified whose variation in abundance was related to variation in the amounts of many other proteins and are thus potentially important for GSP accumulation. This detailed analysis of grain subproteomes provides information on how wheat GSP composition can possibly be controlled in low-level fertilization condition. PMID- 28628251 TI - A Network Meta-Analysis of Short and Long-Term Efficacy of Targeted Therapy With Single or Double-Drug Regimens in the Treatment of Stage III/IV Malignant Melanoma Based on 16 Randomized Controlled Trials. AB - For the treatment of stage III/IV malignant melanoma (MM), a network meta analysis (NMA) was conducted to compare the short and long-term efficacy of targeted therapy with single or double-drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double-drug regimens for treatment of stage III/IV MM were also analyzed. To group the treatments according to their similarity with regards to both outcomes, cluster analyses were performed. Ultimately, 16 RCTs were incorporated for this NMA. The NMA revealed that the overall response rate (ORR) values of single-drug regimens (Vemurafenib [Vem], Dabrafenib [Dab], and Nivolumab [Niv]) were higher than those of Dacarbazine (Dac). Also the ORR values of double-drug regimens (Dab + Trametinib [Dab + Tra], Niv + Ipilimumab [Niv + Ipi], and Vem + Cobimetinib [Vem + Cob]) were moderately higher than those of Dac. The results of the SUCRA showed that short-term efficacy of single-drug regimens (Vem and Dab) were better, while the short-term efficacy of double-drug regimens (Dab + Tra and Vem + Cob) were relatively better. It was determined that Vem, Dab, and Niv might be the best choice in evaluating the treatment of stage III/IV MM among different single-drug targeted therapy regimens, while Dab + Tra, Niv + Ipi, and Vem + Cob might have better short-term efficacy among different double-drug targeted therapy regimens. J. Cell. Biochem. 119: 640-649, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28628252 TI - Microstructural Engineering and Architectural Design of Metal-Organic Framework Membranes. AB - In the past decade, a huge development in rational design, synthesis, and application of molecular sieve membranes, which typically included zeolites, metal-organic frameworks (MOFs), and graphene oxides, has been witnessed. Owing to high flexibility in both pore apertures and functionality, MOFs in the form of membranes have offered unprecedented opportunities for energy-efficient gas separations. Reports on the fabrication of well-intergrown MOF membranes first appeared in 2009. Since then there has been tremendous growth in this area along with an exponential increase of MOF-membrane-related publications. In order to compete with other separation and purification technologies, like cryogenic distillation, pressure swing adsorption, and chemical absorption, separation performance (including permeability, selectivity, and long-term stability) of molecular sieve membranes must be further improved in an attempt to reach an economically attractive region. Therefore, microstructural engineering and architectural design of MOF membranes at mesoscopic and microscopic levels become indispensable. This review summarizes some intriguing research that may potentially contribute to large-scale applications of MOF membranes in the future. PMID- 28628253 TI - 3D Atomic-Scale Insights into Anisotropic Core-Shell-Structured InGaAs Nanowires Grown by Metal-Organic Chemical Vapor Deposition. AB - III-V ternary InGaAs nanowires have great potential for electronic and optoelectronic device applications; however, the 3D structure and chemistry at the atomic-scale inside the nanowires remain unclear, which hinders tailoring the nanowires for specific applications. Here, atom probe tomography is used in conjunction with a first-principles simulation to investigate the 3D structure and chemistry of InGaAs nanowires, and reveals i) the nanowires form a spontaneous core-shell structure with a Ga-enriched core and an In-enriched shell, due to different growth mechanisms in the axial and lateral directions; ii) the shape of the core evolves from hexagon into Reuleaux triangle and grows larger, which results from In outward and Ga inward interdiffusion occurring at the core-shell interface; and iii) the irregular hexagonal shell manifests an anisotropic growth rate on {112}A and {112}B facets. Accordingly, a model in terms of the core-shell shape and chemistry evolution is proposed, which provides fresh insights into the growth of these nanowires. PMID- 28628254 TI - Thermal Light Emission from Monolayer MoS2. AB - Layered transition metal dichalcogenide semiconductors, such as MoS2 and WSe2 , exhibit a range of fascinating properties and are being currently explored for a variety of electronic and optoelectronic devices. These properties include a low thermal conductivity and a large Seebeck coefficient, which make them promising for thermoelectric applications. Moreover, transition metal dichalcogenides undergo an indirect-to-direct bandgap transition when thinned down in thickness, leading to strong excitonic photo- and electroluminescence in monolayers. Here, it is demonstrated that a MoS2 monolayer sheet, freely suspended in vacuum over a distance of 150 nm, emits visible light as a result of Joule heating. Due to the poor transfer of heat to the contact electrodes, as well as the suppressed heat dissipation through the underlying substrate, the electron temperature can reach ~1500-1600 K. The resulting narrow-band light emission from thermally populated exciton states is spatially located to an only ~50 nm wide region in the center of the device and goes along with a negative differential electrical conductance of the channel. PMID- 28628255 TI - Still a reasonable goal: Targeting cholesterol in dialysis and advanced chronic kidney disease patients. AB - Chronic kidney disease (CKD) patients have a high burden of cardiovascular disease. In the general population, lipid metabolism disorders, which cause the initiation and progression of atherosclerotic vascular changes, are major targets for preventive and therapeutic strategies in cardiovascular medicine. However, data from large cohort studies and from clinical trials suggest that the treatment guidelines on cardiovascular disease prevention and therapy cannot uncritically be transferred from individuals with intact renal function to CKD patients. Thus, unlike in the general population, neither plasma levels of HDL cholesterol, nor the key parameter of HDL-cholesterol function-that is, cholesterol efflux capacity-predicts future cardiovascular events. Therefore, HDL cholesterol should presently not be considered as therapeutic target in CKD patients. In contrast, lowering of LDL-cholesterol has been shown to reduce cardiovascular events at least among nondialysis CKD patients. The cardiovascular benefit of targeting LDL-cholesterol among dialysis CKD patients is less evident. We strongly believe that at least some subgroups of dialysis patients may profit from such treatment, particularly those with highest baseline LDL-cholesterol. Finally, as CKD patients have been characterized to have rather high intestinal cholesterol absorption, and relatively low hepatic cholesterol synthesis, substituting combined statin/ezetimibe treatment for statin monotherapy may be of particular benefit for nephrologic patients. PMID- 28628256 TI - Cutaneous involvement in luteinized thecomas with sclerosing peritonitis (LTSP)-A new finding in a rare syndrome. AB - Luteinized thecomas with sclerosing peritonitis (LTSP) is a rare disease characterized by ovarian luteinized thecomas and associated fibrosing peritonitis. Cutaneous involvement has never been reported. We report a case of classical LTSP with skin involvement, outlining the clinical and histopathologic features of this novel presentation of a rare syndrome. PMID- 28628257 TI - Contrasting gene expression programs correspond with predator-induced phenotypic plasticity within and across generations in Daphnia. AB - Research has shown that a change in environmental conditions can alter the expression of traits during development (i.e., "within-generation phenotypic plasticity") as well as induce heritable phenotypic responses that persist for multiple generations (i.e., "transgenerational plasticity", TGP). It has long been assumed that shifts in gene expression are tightly linked to observed trait responses at the phenotypic level. Yet, the manner in which organisms couple within- and TGP at the molecular level is unclear. Here we tested the influence of fish predator chemical cues on patterns of gene expression within- and across generations using a clone of Daphnia ambigua that is known to exhibit strong TGP but weak within-generation plasticity. Daphnia were reared in the presence of predator cues in generation 1, and shifts in gene expression were tracked across two additional asexual experimental generations that lacked exposure to predator cues. Initial exposure to predator cues in generation 1 was linked to ~50 responsive genes, but such shifts were 3-4* larger in later generations. Differentially expressed genes included those involved in reproduction, exoskeleton structure and digestion; major shifts in expression of genes encoding ribosomal proteins were also identified. Furthermore, shifts within the first generation and transgenerational shifts in gene expression were largely distinct in terms of the genes that were differentially expressed. Such results argue that the gene expression programmes involved in within- vs. transgeneration plasticity are fundamentally different. Our study provides new key insights into the plasticity of gene expression and how it relates to phenotypic plasticity in nature. PMID- 28628258 TI - Tankyrase inhibition regulates corpus luteum development and luteal function in gonadotropin-treated rats. AB - Tankyrases are physiological regulators of Axin, a protein involved in several cellular processes, including Wnt signaling. Here, we investigated the effect of a specific Tankyrase inhibitor (XAV939) in follicular-luteal dynamics, and its possible relationship with ovarian vascular development. Studies were designed to analyze the effect of intrabursa administration of XAV939 in gonadotropin-treated prepubertal rats. In particular, we examined follicle and corpus luteum development, steroidogenesis, angiogenic markers, and apoptotic parameters. We found that in vivo inhibition of Wnt signaling impaired corpus luteum development, with a decrease in the number of corpora lutea balanced by a high number of cysts; decreased circulating progesterone levels, likely due to a decrease in Steroidogenic acute regulatory protein content in the corpus luteum; and increased pro-apoptotic parameters. In addition, Extracellular signal regulated kinase phosphorylation, Vascular endothelium growth factor 120 content, and endothelial cell area were diminished in corpora lutea of inhibitor-treated ovaries. Thus, Wnt/beta-catenin signaling appears to participate in the regulation of corpus luteum development and luteal cell function. PMID- 28628260 TI - Society for Academic Emergency Medicine Statement on Plagiarism. AB - The integrity of the research enterprise is of the utmost importance for the advancement of safe and effective medical practice for patients and for maintaining the public trust in health care. Academic societies and editors of journals are key participants in guarding scientific integrity. Avoiding and preventing plagiarism helps to preserve the scientific integrity of professional presentations and publications. The Society for Academic Emergency Medicine (SAEM) Ethics Committee discusses current issues in scientific publishing integrity and provides a guideline to avoid plagiarism in SAEM presentations and publications. PMID- 28628259 TI - Exercise prior to, but not concomitant with, stress reverses stress-induced delayed skin wound healing. AB - Stress-induced prolonged inflammation impairs cutaneous wound healing. Exercise may inhibit this effect via an anti-inflammatory mechanism. Our aim was to investigate the effect of moderate exercise on skin wound healing in chronically stressed mice. Mice were trained five times per week on a treadmill or received no training. Mice underwent daily rotational stress from the 6th week until euthanasia. During the 8th week, two wounds were created in the dorsum and collected 10 days later. A control group only received wounds. Exercise was performed prior to and simultaneous with stress for 2 weeks or only prior to stress. Stress increased normetanephrine levels 10 days after wounding, resulting in an increased amount of inflammatory cells and reduced expression of inflammatory cytokines as well as angiogenesis, myofibroblast differentiation and matrix deposition. Concomitant exercise and stress potentiated these effects, intensifying the delayed wound contraction. When exercise was performed only prior to stress, however, the mice showed reduced inflammatory cells in granulation tissue 10 days after wounding and improved wound healing compared with animals with exercise and concomitant stress. Moderate exercise in association with stress potentiates the stress effect; however, when exercise was performed prior to stress, wound healing was improved. PMID- 28628261 TI - Studying the Conformation of a Receptor Tyrosine Kinase in Solution by Inhibitor Based Spin Labeling. AB - The synthesis of a spin label based on PD168393, a covalent inhibitor of a major anticancer drug target, the epidermal growth factor receptor (EGFR), is reported. The label facilitates the analysis of the EGFR structure in solution by pulsed electron paramagnetic resonance (EPR) spectroscopy. For various EGFR constructs, including near-full-length EGFR, we determined defined distance distributions between the two spin labels bound to the ATP binding sites of the EGFR dimer. The distances are in excellent agreement with an asymmetric dimer of the EGFR. Based on crystal structures, this dimer had previously been proposed to reflect the active conformation of the receptor but structural data demonstrating its existence in solution have been lacking. More generally, our study provides proof of-concept that inhibitor-based spin labeling enables the convenient introduction of site-specific spin labels into kinases for which covalent or tight-binding small-molecule modulators are available. PMID- 28628262 TI - Catalytic Enantioselective Reaction of Allenylnitriles with Imines Using Chiral Bis(imidazoline)s Palladium(II) Pincer Complexes. AB - The first highly enantioselective reaction of allenylnitriles with imines has been developed. Excellent yields and enantioselectivities were observed for the reaction with various imines using chiral Phebim-PdII complexes. This process offers a simple and efficient synthetic route for various functionalized alpha vinylidene-beta-aminonitriles and their derivatives. PMID- 28628263 TI - Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with non-alcoholic fatty liver disease. AB - AIM: Type 2 diabetes mellitus (T2DM) is a major complication of patients with non alcoholic fatty liver disease (NAFLD). The aim of this retrospective study is to determine the risk factors for development of T2DM in patients with biopsy-proven NAFLD. METHODS: One hundred and sixty two consecutive patients with biopsy-proven NAFLD who received a 75-g oral glucose tolerance test were enrolled as the total cohort. Among them, we analyzed 89 patients without T2DM diagnosed by oral glucose tolerance test to estimate the cumulative rate for development of T2DM as the follow-up cohort. RESULTS: Of 162 patients, the glucose tolerance pattern were DM in 45 patients (27.8%), impaired glucose tolerance in 68 (42.0%), and normal glucose tolerance in 49 (30.2%). Patients with NAFL tended to be more likely to have normal glucose tolerance than those with non-alcoholic steatohepatitis (NASH). The serum levels of pre- and post-load insulin were significantly higher in the NASH group. Of 89 patients without T2DM, 13 patients newly developed T2DM during a follow-up period of 5.2 years. The cumulative rate of T2DM incidence was 8.8% at the end of the 5th year and 23.4% at the end of the 10th year. Multivariate analysis identified homeostasis model of assessment - insulin resistance (>=3.85, hazard ratio 40.1, P = 0.033) as an independent risk factor for development of T2DM. CONCLUSIONS: Patients with NASH have an underlying potential of glucose intolerance. In NAFLD patients, insulin resistance is the most important risk factor for the incidence of T2DM. Appropriate therapy against insulin resistance could be needed for patients with NAFLD to prevent development of T2DM. PMID- 28628264 TI - Controlling lactation oestrus: The final frontier for breeding herd management. AB - Lactation anoestrus limits the flexibility of modern pig production systems such that any increase in lactation length reduces farrowing frequency, and thus profit. This review focuses on post-partum development of the sow's reproductive system, the physiology of lactation anoestrus and how it can be overcome, as well as the fertility of sows mated while lactating. The propensity for sows to ovulate spontaneously while lactating is high (24-31%), and a high proportion of sows will ovulate rapidly and synchronously in response to combinations of altered suckling (split weaning, interrupted suckling), daily boar contact, exogenous gonadotrophins, and group housing. The apparent ease with which lactation anoestrus can be overcome represents an opportunity to uncouple sow mating from weaning, thus reducing the impact of lactation length on productivity. This is especially true when considering the benefits of the described stimulation methods on the reproductive performance (i.e., shorter weaning to oestrus intervals and higher litter sizes) of the low proportion of sows that maintain lactation anoestrus. PMID- 28628265 TI - Improving preventive locust management: insights from a multi-agent model. AB - BACKGROUND: Preventive management of locust plagues works in some cases but still fails frequently. The role of funding institution awareness was suggested as a potential facilitating factor for cyclic locust plagues. We designed a multi agent system to represent the events of locust plague development and a management system with three levels: funding institution, national control unit and field teams. A sensitivity analysis identified the limits and improvements of the management system. RESULTS: The model generated cyclic locust plagues through a decrease in funding institution awareness. The funding institution could improve its impact by increasing its support by just a few percent. The control unit should avoid hiring too many field teams when plagues bring in money, in order to ensure that surveys can be maintained in times of recession. The more information the teams can acquire about the natural system, the more efficient they will be. CONCLUSION: We argue that anti-locust management should be considered as a complex adaptive system. This not only would allow managers to prove to funders the random aspect of their needs, but would also enable funders and decision-makers to understand and integrate their own decisions into the locust dynamics that still regularly affect human populations. (c) 2017 Society of Chemical Industry. PMID- 28628266 TI - Embryo-maternal dialogue during pregnancy establishment and implantation in the pig. AB - Porcine conceptuses secrete pregnancy-recognition signals (estrogens, including estradiol-17beta) that inhibit luteolysis, thereby prolonging progesterone production by corpora lutea. The supportive mechanism by which the conceptus also inhibits luteolysis is by shifting endometrial prostaglandin (PG) synthesis to luteoprotective PGE2. Progesterone stimulates endometrial production of factors that are essential for conceptus development. Priming the uterus by progesterone and loss of progesterone receptors from the uterine epithelium by D1ay 10-12 after estrus are key for achieving endometrial receptivity for implantation. Conceptus implantation involves a series of events, many resembling the inflammatory reaction, that are greatly influenced by cytokines, growth factors, and prostaglandins. We herein present a novel, dual role for PGF2alpha in corpora lutea that depends on the acquisition of luteolytic sensitivity, based on the knowledge that PGF2alpha triggers pathways involved in luteolysis during the estrous cycle or/and may have an alternative function in maintaining progesterone synthesis during pregnancy. We also point out a new role for PGF2alpha that, together with PGE2, can act as embryonic signal mediators. PGF2alpha, which until recently was considered undesirable for promoting pregnancy, is now known to stimulate conceptus-maternal interactions and angiogenesis in the endometrium. This function is in line with other important prostaglandin functions, such as stimulating adhesion of trophoblasts (PGE2, PGI2) as well as endometrial vascular functions and trophoblast cell proliferation (PGI2). Finally, microRNAs have emerged as important post-transcriptional regulators of gene function, adding a new area of investigation that may enhance understanding of conceptus-endometrial interactions. PMID- 28628267 TI - Opto-electrochemical In Situ Monitoring of the Cathodic Formation of Single Cobalt Nanoparticles. AB - Single-particle electrochemistry at a nanoelectrode is explored by dark-field optical microscopy. The analysis of the scattered light allows in situ dynamic monitoring of the electrodeposition of single cobalt nanoparticles down to a radius of 65 nm. Larger sub-micrometer particles are directly sized optically by super-localization of the edges and the scattered light contains complementary information concerning the particle redox chemistry. This opto-electrochemical approach is used to derive mechanistic insights about electrocatalysis that are not accessible from single-particle electrochemistry. PMID- 28628268 TI - NiCo2 S4 Materials for Supercapacitor Applications. AB - Cobalt-nickel sulfide (NiCo2 S4 ) shows extensive potential for innovative photoelectronic and energetic materials owing to distinctive physical and chemical properties. In this review, representative strategies for the fabrication and application of NiCo2 S4 and composite nanostructures are outlined for supercapacitors, with the aim of promoting the development of NiCo2 S4 and their composites in the supercapacitor field through an analysis and comparison of diverse nanostructures. A brief introduction into the structures, properties, and morphologies are presented. Further prospects and promising developments of the materials in the supercapacitor field are also proposed. PMID- 28628269 TI - Effect of Food Intake on the Pharmacokinetics of a Novel Methylphenidate Extended Release Oral Suspension for Attention Deficit Hyperactivity Disorder. AB - We conducted an open-label, single-dose, randomized, crossover study in healthy adults to assess the impact of food on the bioavailability of 60 mg methylphenidate extended-release oral suspension (MEROS; Quillivant XRTM)-a long acting stimulant for the treatment of attention deficit hyperactivity disorder-by comparing the pharmacokinetic parameters under fed and fasting conditions. When MEROS 60 mg was administered under fed conditions compared with fasting conditions, the exposure of methylphenidate (d enantiomer) was higher, with a mean area under the plasma concentration-vs-time curve (AUC)0-t of 160.2 ng.h/mL vs 140.4 ng.h/mL, and a mean AUC0-inf of 163.2 ng.h/mL vs 143.7 ng.h/mL, respectively. The ratios of the ln-transformed geometric means for methylphenidate for AUC0-t and AUC0-inf were 119.5% (90%CI, 115.7% to 123.5%) and 119.0% (90%CI, 115.2% to 122.8%), respectively, within the standard 80% to 125% bioequivalence acceptance range indicating no food effect on the overall exposure (rate and extent). There was a small increase in the peak plasma concentration (127.6% [90%CI, 119.9% to 135.8%]). However, this effect was small and not likely to be clinically significant. Overall, MEROS 60 mg was safe in both the fed and fasting condition when administered to healthy volunteers in this study. PMID- 28628270 TI - Serum Klotho, vitamin D, and homocysteine in combination predict the outcomes of Chinese patients with multiple system atrophy. AB - AIMS: Neuroinflammation contributed to the pathogenesis of multiple system atrophy (MSA). We aimed to detect the correlation between inflammatory mediators, such as Klotho (Klt), vitamin D (25(OH)D) and homocysteine (Hcy), and disease severity among MSA patients. METHODS: A total of 53 MSA patients, 65 PD patients, and 62 normal subjects were recruited in our cross-sectional study. Serum Klotho (Klt), vitamin D (25(OH)D), and homocysteine (Hcy) levels were measured. Several scales were undertaken to assess the motor/nonmotor function and cognitive impairment of MSA. RESULTS: Decreased Serum Klt and 25(OH)D levels and increased Hcy levels were found in patients with MSA, compared with healthy controls. These results were more pronounced in male patients. The three biomarkers also displayed differences between MSA and PD subgroups based on genders. Interestingly, Klt, 25(OH)D and Hcy levels associated with cognition impairment, motor dysfunction, mood/cardiovascular disorder among MSA patients. In addition, the combination of Klt, 25(OH)D and Hcy had a better diagnostic ability for distinguishing MSA patients from healthy subjects, as well as distinguishing male MSA patients from male PD patients. CONCLUSION: This study suggested that Klt, 25(OH)D and Hcy levels could be a potential predictor for MSA severity evaluation. PMID- 28628272 TI - Ruthenium-Catalyzed [2+2+2] Cycloaddition of 1,6-Enynes and Unactivated Alkynes: Access to Ring-Fused Cyclohexadienes. AB - The [2+2+2] intermolecular carbocyclization reactions between 1,6-enynes and alkynes catalyzed by [RuCl(cod)(Cp*)] (cod=1,5-cyclooctadiene, Cp*=pentamethylcyclopentadienyl) are reported to provide bicyclohexa-1,3-dienes. The presented reaction conditions are compatible with internal and terminal alkynes and the chemo- and regioselectivity issues are controlled by the presence of substituents at the propargyl carbon center of the alkyne(s) partner(s). PMID- 28628271 TI - Surgical treatment of trans-sphincteric anal fistulas with the Fat GRAFT technique: a minimally invasive procedure. AB - AIM: Anal fistulas are common pathologies with a significant social impact; however, their treatment is often complex and the recurrence rate can be significant. Some surgical treatments for fistula are also associated with the risk of sphincter injury. In this technical note, we aim to evaluate the feasibility and efficacy of the Fat GRAFT technique (Fat Grafting in Anal Fistula Treatment) in the treatment of recurrent anal fistulas. METHOD: All patients presenting with recurrent trans-sphincteric anal fistulas over an 18-month period were included. After abdominal fat harvesting and fat preparation, fat grafting was performed in the track and peripheral area of the fistula. The internal and external openings of the fistula were closed to maximally preserve the retention of the adipocyte graft in the fistula. RESULTS: Eleven patients underwent the Fat GRAFT procedure (seven men, four women). The average re-injected volume for each fistula was 21 ml (range 10-30 ml). The postoperative course was uneventful. At 6 months three patients developed recurrence (73% healed). There were no postoperative complications. CONCLUSION: The Fat GRAFT technique appears to be a promising technique with a low risk of anal incontinence, in contrast to other techniques. This method was effective in > 70% of patients in a single session. PMID- 28628273 TI - Exposure of Induced Pluripotent Stem Cell-Derived Vascular Endothelial and Smooth Muscle Cells in Coculture to Hemodynamics Induces Primary Vascular Cell-Like Phenotypes. AB - Human induced pluripotent stem cells (iPSCs) can be differentiated into vascular endothelial (iEC) and smooth muscle (iSMC) cells. However, because iECs and iSMCs are not derived from an intact blood vessel, they represent an immature phenotype. Hemodynamics and heterotypic cell:cell communication play important roles in vascular cell phenotypic modulation. Here we tested the hypothesis that hemodynamic exposure of iECs in coculture with iSMCs induces an in vivo-like phenotype. iECs and iSMCs were cocultured under vascular region-specific blood flow hemodynamics, and compared to hemodynamic cocultures of blood vessel-derived endothelial (pEC) and smooth muscle (pSMC) cells. Hemodynamic flow-induced gene expression positively correlated between pECs and iECs as well as pSMCs and iSMCs. While endothelial nitric oxide synthase 3 protein was lower in iECs than pECs, iECs were functionally mature as seen by acetylated-low-density lipoprotein (LDL) uptake. SMC contractile protein markers were also positively correlated between pSMCs and iSMCs. Exposure of iECs and pECs to atheroprone hemodynamics with oxidized-LDL induced an inflammatory response in both. Dysfunction of the transforming growth factor beta (TGFbeta) pathway is seen in several vascular diseases, and iECs and iSMCs exhibited a transcriptomic prolife similar to pECs and pSMCs, respectively, in their responses to LY2109761-mediated transforming growth factor beta receptor I/II (TGFbetaRI/II) inhibition. Although there are differences between ECs and SMCs derived from iPSCs versus blood vessels, hemodynamic coculture restores a high degree of similarity in their responses to pathological stimuli associated with vascular diseases. Thus, iPSC-derived vascular cells exposed to hemodynamics may provide a viable system for modeling rare vascular diseases and testing new therapeutic approaches. Stem Cells Translational Medicine 2017;6:1673-1683. PMID- 28628274 TI - New technology for using meteorological information in forest insect pest forecast and warning systems. AB - BACKGROUND: Near surface air temperature and rainfall are major weather factors affecting forest insect dynamics. The recent developments in remote sensing retrieval and geographic information system spatial analysis techniques enable the utilization of weather factors to significantly enhance forest pest forecasting and warning systems. The current study focused on building forest pest digital data structures as a platform of correlation analysis between weather conditions and forest pest dynamics for better pest forecasting and warning systems using the new technologies. RESULTS: The study dataset contained 3 353 425 small polygons with 174 defined attributes covering 95 counties of Guangxi province of China currently registering 292 forest pest species. Field data acquisition and information transfer systems were established with four software licences that provided 15-fold improvement compared to the systems currently used in China. Nine technical specifications were established including codes of forest districts, pest species and host tree species, and standard practices of forest pest monitoring and information management. Attributes can easily be searched using ArcGIS9.3 and/or the free QGIS2.16 software. CONCLUSIONS: Small polygons with pest relevant attributes are a new tool of precision farming and detailed forest insect pest management that are technologically advanced. (c) 2017 Society of Chemical Industry. PMID- 28628275 TI - Design of a Tunable Self-Oscillating Polymer with Ureido and Ru(bpy)3 Moieties. AB - An upper critical solution temperature (UCST)-type self-oscillating polymer was designed that exhibited rhythmic soluble-insoluble changes induced by the Belousov-Zhabotinsky (BZ) reaction. The target polymers were prepared by conjugating Ru(bpy)3 , a catalyst for the BZ reaction, to ureido-containing poly(allylamine-co-allylurea) (PAU) copolymers. The Ru(bpy)3 -conjugated PAUs exhibited a UCST-type phase-transition behavior, and the solubility of the polymer changed in response to the alternation in the valency of Ru(bpy)3 . The ureido content influences the temperature range of self-oscillation, and the oscillation occurred at higher temperatures than conventional LCST-type self oscillating polymers. Furthermore, the self-oscillating behavior of the Ru-PAU could be regulated by addition of urea, which is a unique tuning strategy. We envision that novel self-oscillating polymers with widely tunable soluble insoluble behaviors can be rationally designed based these UCST-type polymers. PMID- 28628276 TI - Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse. AB - BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-alpha in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT. PMID- 28628277 TI - Twelve-month use of herbal medicines as a remedy for mental health problems in Japan: A cross-national analysis of World Mental Health Survey data. AB - AIM: The purpose of this study was to clarify the frequencies and sociodemographic and other characteristics around use of herbal medicine as a remedy for mental health problems in Japan. METHODS: Data from the World Mental Health Japan (WMHJ) Survey and US National Comorbidity Survey Replications were analyzed. The WMHJ was conducted in 2002 to 2006, with 4129 respondents. National Comorbidity Survey Replications was conducted in 2002 to 2003, with 9282 respondents. The interview asked the respondents about their use of several types of herbs for mental health problems. Frequencies of use of herbal medicine were compared between Japan and the United States. Multiple logistic regression analyses were conducted to determine sociodemographic and mental health-related correlates of 12-month herbal medicine use. Relevant sampling weights were used to adjust for the sampling designs. RESULTS: The proportion for use of herbal medicines as a remedy for mental health problems in the past 12 months was lower (0.4%) in Japan than that in the United States (3.7%). Low education in both countries (P < .05) was significantly associated with nonuse of herbal medicine. Any anxiety disorder in Japan was significantly associated with herbal medicine use (P < .01), while any mental disorder categories were significantly associated in the United States (P < .01). DISCUSSION: The frequency for use of herbal medicine among patients with mental health problems in the past 12 months was much lower in Japan compared to the United States. Persons with high educational attainment and anxiety disorders used herbal medicine as a remedy for mental health problems more frequently in Japan. PMID- 28628278 TI - Interfacial Charge Engineering in Ferroelectric-Controlled Mott Transistors. AB - Heteroepitaxial coupling at complex oxide interfaces presents a powerful tool for engineering the charge degree of freedom in strongly correlated materials, which can be utilized to achieve tailored functionalities that are inaccessible in the bulk form. Here, the charge-transfer effect between two strongly correlated oxides, Sm0.5 Nd0.5 NiO3 (SNNO) and La0.67 Sr0.33 MnO3 (LSMO), is exploited to realize a giant enhancement of the ferroelectric field effect in a prototype Mott field-effect transistor. By switching the polarization field of a ferroelectric Pb(Zr,Ti)O3 (PZT) gate, nonvolatile resistance modulation in the Mott transistors with single-layer SNNO and bilayer SNNO/LSMO channels is induced. For the same channel thickness, the bilayer channels exhibit up to two orders of magnitude higher resistance-switching ratio at 300 K, which is attributed to the intricate interplay between the charge screening at the PZT/SNNO interface and the charge transfer at the SNNO/LSMO interface. X-ray absorption spectroscopy and X-ray photoelectron spectroscopy studies of SNNO/LSMO heterostructures reveal about 0.1 electron per 2D unit cell transferred between the interfacial Mn and Ni layers, which is corroborated by first-principles density functional theory calculations. The study points to an effective strategy to design functional complex oxide interfaces for developing high-performance nanoelectronic and spintronic applications. PMID- 28628279 TI - Acyclic Nucleoside Phosphonates Containing 9-Deazahypoxanthine and a Five Membered Heterocycle as Selective Inhibitors of Plasmodial 6-Oxopurine Phosphoribosyltransferases. AB - Acyclic nucleoside phosphonates (ANPs) are an important class of therapeutic drugs that act as antiviral agents by inhibiting viral DNA polymerases and reverse transcriptases. ANPs containing a 6-oxopurine unit instead of a 6 aminopurine or pyrimidine base are inhibitors of the purine salvage enzyme, hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT). Such compounds, and their prodrugs, are able to arrest the growth of Plasmodium falciparum (Pf) in cell culture. A new series of ANPs were synthesized and tested as inhibitors of human HGPRT, PfHGXPRT, and Plasmodium vivax (Pv) HGPRT. The novelty of these compounds is that they contain a five-membered heterocycle (imidazoline, imidazole, or triazole) inserted between the acyclic linker(s) and the nucleobase, namely, 9-deazahypoxanthine. Five of the compounds were found to be micromolar inhibitors of PfHGXPRT and PvHGPRT, but no inhibition of human HGPRT was observed under the same assay conditions. This demonstrates selectivity of these types of compounds for the two parasitic enzymes compared to the human counterpart and confirms the importance of the chemical nature of the acyclic moiety in conferring affinity/selectivity for these three enzymes. PMID- 28628280 TI - Combination antimicrobial susceptibility testing for acute exacerbations in chronic infection of Pseudomonas aeruginosa in cystic fibrosis. AB - BACKGROUND: Antibiotic therapy for acute pulmonary exacerbations in people with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility testing of individual drugs. Combination antimicrobial susceptibility testing assesses the efficacy of drug combinations including two or three antibiotics in vitro and can often demonstrate antimicrobial efficacy against bacterial isolates even when individual antibiotics have little or no effect. Therefore, choosing antibiotics based on combination antimicrobial susceptibility testing could potentially improve response to treatment in people with cystic fibrosis with acute exacerbations. This is an updated version of a previously published review. OBJECTIVES: To compare antibiotic therapy based on conventional antimicrobial susceptibility testing to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis and chronic infection with Pseudomonas aeruginosa. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 19 December 2016.We also searched ongoing trials registries. Date of latest search: 08 March 2017. SELECTION CRITERIA: Randomised and quasi-randomised controlled studies of antibiotic therapy based on conventional antimicrobial susceptibility testing compared to antibiotic therapy based on combination antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in cystic fibrosis due to chronic infection with Pseudomonas aeruginosa. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies, assessed their quality and extracted data from eligible studies. Additionally, the authors contacted the study investigators to obtain further information. MAIN RESULTS: The search identified one multicentre study eligible for inclusion in the review. This study prospectively assessed whether the use of multiple combination bactericidal antibiotic testing improved clinical outcomes in participants with acute pulmonary exacerbations of cystic fibrosis who were infected with multiresistant bacteria. A total of 132 participants were randomised in the study. The study investigators provided data specific to the 82 participants who were only infected with Pseudomonas aeruginosa for their primary outcome of time until next pulmonary exacerbation. For participants specifically infected with only Pseudomonas aeruginosa, the hazard ratio of a subsequent exacerbation was 0.82, favouring the control group (95% confidence interval 0.44 to 1.51) (P = 0.52). No further data for any of this review's outcomes specific to participants infected with Pseudomonas aeruginosa were available. The risk of bias for the included study was deemed to be low. The quality of the evidence was moderate for the only outcome providing data solely for individuals with infection due to Pseudomonas aeruginosa. For other outcomes, we were unable to judge the quality of the evidence as no data were available for the relevant subset of participants. AUTHORS' CONCLUSIONS: The current evidence, limited to one study, shows that there is insufficient evidence to determine effect of choosing antibiotics based on combination antimicrobial susceptibility testing compared to choosing antibiotics based on conventional antimicrobial susceptibility testing in the treatment of acute pulmonary exacerbations in people with cystic fibrosis with chronic Pseudomonas aeruginosa infection. A large international and multicentre study is needed to further investigate this issue.The only study included in the review was published in 2005, and we have not identified any further relevant studies up to March 2017. We therefore do not plan to update this review until new studies are published. PMID- 28628281 TI - Genomic analysis of melanoma evolution following a 30-year disease-free interval. AB - Ultra-late melanoma recurrence is infrequent, poorly understood and, in most cases, difficult to unambiguously distinguish from a new primary melanoma. We identified a patient with a second melanoma diagnosed after a 30-year disease free interval, and sought to determine if this new lesion was a recurrence of the original melanoma. Here we report the genomic sequence analysis of the exomes of 2 melanoma lesions isolated from the same individual in 1985 and 2015, and their comparison to each other and to the germline DNA of the patient. Identification of many shared somatic mutations between these lesions proves a lineal relationship spanning 30 years. Unlike prior reports of ultra-late melanoma recurrence, the availability of the original tumor and the use of comprehensive genomic analysis allowed us to confirm that the second lesion is truly a recurrence. We demonstrate the acquisition of numerous additional mutations during the 3 decade asymptomatic period. These data highlight the low but very long-lasting risk of recurrence in this patient population. PMID- 28628282 TI - [Image of the month. A case of cement pulmonary embolism.] PMID- 28628283 TI - [Case report. Pulmonary embolism complicated by angioneurotic edema.] AB - Although angioneurotic oedema (AE) is a rare entity, it sometimes leads to devastating consequences. We report the case of an oro-pharyngeal angioneurotic attack following the initiation of a fibrinolysis therapy by alteplase and relay by heparin in a patient with severe acute pulmonary embolism. In view of this original case, we propose to highlight the most recent elements concerning the physiopathology of this disease. PMID- 28628284 TI - [Coronary artery disease and sport practice]. AB - Cardiovascular diseases are responsible for many deaths in our western societies. Practice of sport activities can decrease their occurrence and improve the prognosis of the patients already affected. The practice of a sport, however, presents an increased cardiovascular risk during its realization (sudden death, myocardial infarction, etc.). An assessment of the risk of complication is necessary before allowing patients with ischemic heart disease to practice a sport activity. Sport activities in competitions are discouraged for most patients, but for the majority, recreational activities should be encouraged. A regular medical follow-up is necessary as well as a respect of instructions of good sport practice. PMID- 28628285 TI - [Fibromyalgia : state of the issue in 2017]. AB - Fibromyalgia (FM), whose diagnostic criteria were originally established in 1990 and updated in 2010, consists of a syndrome characterized by the presence of deep and diffuse musculoskeletal pain associated with other subjective manifestations (sleep, mood, cognitive problems). The prevalence is assessed in the general population at 2.2 %. Various risk factors were identified: age, gender, level of education and socio-economic status. Various etiological hypotheses have been explored, whether in neuroimaging or from the point of view of possible neuroendocrine and cytokine perturbations. In addition, various potential pathogenic mechanisms have been identified: genetic predisposition, central amplification, diffuse inhibitory control failure, muscle as peripheral nociceptive afferents. Finally, with regard to treatment and clinical course, the first will be multidisciplinary and the second will not be marked by real remission. In addition, patients tend to reduce their activities (professional, physical or leisure), which degrades and perpetuates the situation, while they must remain as active as possible. PMID- 28628286 TI - [Contribution of continuous glucose measurement in the management of gestational diabetes : a pilot study]. AB - The prevalence of gestational diabetes increases as a result of universal screening, but also because of more stringent diagnostic criteria due to decreased set points. This diabetes can lead to severe complications for the offspring and / or for the mother. The management of a patient suffering from gestational diabetes is based on healthy diet and lifestyle advices. Iterative control of capillary glycemia is the usual way to monitor daily blood glucose. Continuous blood glucose measurement (CGM) provides reliable and comprehensive data over several days. Observing and interpreting the continuously recorded glucose concentration values should help to better understand the kinetics of glucose and to personalize the treatment. This preliminary study reports the results of 12 women with gestational diabetes and describes fluctuations of blood glucose levels all day long, particularly in the postprandial period. The CGM analysis shows that the maximum concentration of postprandial glucose is reached approximately 70 minutes after the morning and midday meals and 110 minutes after the evening meal. PMID- 28628287 TI - [Professional fatigue syndrome (burnout) : Part 2 : from therapeutic management]. AB - Burnout or professional fatigue syndrome is the result of exposure to a situation in which the strategies of the subject who are supposed to manage the stresses of the environment become outdated and inoperative. An imbalance is created between the demands and the material, operational and psychological resources to cope with them. Many health professions are confronted with the challenge of managing burnout, but the general practitioner is very often on the front line. After a first article devoted to the epidemiology, diagnosis, causes and consequences of the burnout, this second article is focusing on its therapeutic management, through listening, sick leave, dietary supplements, antidepressants, behavioural and cognitive therapy, professional coaching and multidisciplinary approach. PMID- 28628288 TI - [The Mosan Study Group of Pigmented Tumours facing toward the oligometastatic cutaneous melanoma]. AB - The oligometastatic melanoma is a peculiar stage of cancer progression which is initially restricted to the initial body area. In most instances, only a small number of metastases are simultaneously present. The oligometastatic stage is synchronous when metastases are disclosed at the time of initial diagnosis of the primary cancer. Metastases are metachronous when they are detected after the initial treatment of the primary neoplasm. A variant of the disease is called the smouldering disease when cutaneous metastases grow or regress in unison. The smouldering disease is granted to a condition when some metastases keep grooving when other metastases regress. PMID- 28628289 TI - [Neuropsychiatric syndroms in seropositive population]. AB - The Acquired ImmunoDeficiency Syndrome (AIDS) is a chronic infectious disease. By its complexity and the importance of psychiatric syndromes observed among HIV patients, the common contribution of somatic and psychiatric health specialists is often mandatory. Conversely, more or less 20 % of psychiatric patients are infected by the AIDS' virus. Moreover, these troubles would be their second reason of hospitalization. These psychiatric symptoms, so caused by HIV, may occur before its serological discovery. Thereby, it will be interesting for the psychiatrist to acquire enough knowledge about this disease to establish preventing actions and strategies of psychoeducation. PMID- 28628290 TI - [Pain complaints in a patient with schizophrenia]. AB - Schizophrenia is a complex pathology. Its prevalence reaches almost 1 %. Its semiology can be diversified. Sensorial perception can be altered included pain perception. Most of the studies conclude that psychotic patients have a hypoalgesia. It's important to consider this fact to avoid missing potentially grave somatic disease. PMID- 28628292 TI - Environment-Sensitive Turn-On Fluorescent Polyamino Acid: Fingerprinting Protein Populations with Post-Translational Modifications. AB - The identification of post-translational modifications (PTMs) in proteins has been of particular interest in the elucidation of human diseases and the improvement of therapeutic proteins. Herein, we report a novel strategy toward the construction of fingerprint-based PTM-sensing systems as an alternative to conventional specific recognition tools. Our strategy is based on poly-l-lysine (PLL) derivatives with two distinct properties suitable to fingerprint-based protein-sensing: (i) a turn-on fluorescent signal upon binding to proteins and (ii) condition-dependent cross-reactivity toward proteins and PTMs. One type of PLL derivative under varying solution properties (pH value and ionic strength) was sufficient to construct a sensing array that produces unique fluorescence fingerprints for structurally similar mammalian albumins with/without a wide variety of chemical modifications corresponding to PTMs. This approach was also applicable for the recognition of deviations in physicochemical properties of proteins as a result of realistic glycation and phosphorylation events. Multivariate analyses of the thus obtained fingerprints successfully identified analytes with 100% accuracy (qualitatively and quantitatively) in all cases. This study thus demonstrates for the first time a fingerprint-based sensing of proteins with/without PTMs using a single, highly accessible, and tunable synthetic polymer, and accordingly offers a powerful platform for simple high throughput sensing of PTMs in proteins. PMID- 28628293 TI - One-Step Device Fabrication of Phosphorene and Graphene Interdigital Micro Supercapacitors with High Energy Density. AB - Rational engineering and simplified fabrication of high-energy micro supercapacitors (MSCs) using graphene and other 2D nanosheets are of great value for flexible and integrated electronics. Here we develop one-step mask-assisted simplified fabrication of high-energy MSCs (PG-MSCs) based on the interdigital hybrid electrode (PG) patterns of stacking high-quality phosphorene nanosheets and electrochemically exfoliated graphene in ionic liquid electrolyte. The hybrid PG films with interdigital patterns were directly manufactured by layer-by-layer deposition of phosphorene and graphene nanosheets with the assistance of a customized interdigital mask, and directly transferred onto a flexible substrate. The resultant patterned PG films present outstanding uniformity, flexibility, conductivity (319 S cm-1), and structural integration, which can directly serve as binder- and additive-free flexible electrodes for MSCs. Remarkably, PG-MSCs deliver remarkable energy density of 11.6 mWh cm-3, outperforming most nanocarbon based MSCs. Moreover, our PG-MSCs show outstanding flexibility and stable performance with slight capacitance fluctuation even under highly folded states. In addition, our simplified mask-assisted strategy for PG-MSCs is highly flexible for simplified production of parallelly and serially interconnected modular power sources, without need of conventional metal-based interconnects and contacts, for designable integrated circuits with high output current and voltage. PMID- 28628294 TI - Fused Deposition Modeling 3D Printing for (Bio)analytical Device Fabrication: Procedures, Materials, and Applications. AB - In this work, the use of fused deposition modeling (FDM) in a (bio)analytical/lab on-a-chip research laboratory is described. First, the specifications of this 3D printing method that are important for the fabrication of (micro)devices were characterized for a benchtop FDM 3D printer. These include resolution, surface roughness, leakage, transparency, material deformation, and the possibilities for integration of other materials. Next, the autofluorescence, solvent compatibility, and biocompatibility of 12 representative FDM materials were tested and evaluated. Finally, we demonstrate the feasibility of FDM in a number of important applications. In particular, we consider the fabrication of fluidic channels, masters for polymer replication, and tools for the production of paper microfluidic devices. This work thus provides a guideline for (i) the use of FDM technology by addressing its possibilities and current limitations, (ii) material selection for FDM, based on solvent compatibility and biocompatibility, and (iii) application of FDM technology to (bio)analytical research by demonstrating a broad range of illustrative examples. PMID- 28628295 TI - Cross-Linked Protein Nanofilter with Antibacterial Properties for Multifunctional Air Filtration. AB - Development of high-performance nanomaterials with not only strong ability to trap the pollutants but also good structure stability under varying environmental conditions is a critical need for air-filtration applications. However, it has been very challenging for a filtering material to simultaneously realize multifunctional air filtration and good environmental stability. Here, based on our previous studies on protein-based nanofilters, we report a cross-linked protein nanofabric to address this challenging issue. It is found that cross linked protein nanofabrics can significantly improve the structure stability against different moisture levels and temperatures, while maintaining the multifunctional filtration performance. Moreover, it is demonstrated that the cross-linked protein nanomaterials also possess antibacterial properties, such as Shewanella oneidensis bacteria, further improving the environmental stability. The effects of cross-linking with different loadings of cross-linking agent on the structure stability and filtration performance are further investigated at different humidity levels and temperatures. This study provides a cost-effective solution for advanced "green" nanomaterials with excellent performance in both filtration functions and structure stability under varying environment. PMID- 28628296 TI - Enhanced Antibacterial Properties of Self-Assembling Peptide Amphiphiles Functionalized with Heparin-Binding Cardin-Motifs. AB - The emergence of antibiotic resistance in bacteria has caused many healthcare problems and social burdens. In this study, a type of self-assembled peptide amphiphiles (PA) functionalized with a heparin-binding Cardin-motif peptide (sequence (AKKARK)2) has been designed to combat bacterial drug resistance. Above the critical micelle concentration (CMC) at 45 MUM, these amphiphilic Cardin antimicrobial peptide (ACA-PA) can self-assemble into cylindrical supramolecular structures (7-10 nm in diameter) via hydrophobic interactions and beta-sheet secondary conformation. The ACA-PA displays excellent antibacterial properties against both Gram-positive and Gram-negative bacteria. This work also demonstrates the effects of molecular self-assembly on antibacterial activity of peptide amphiphiles. The ACA-PA exhibits antibacterial activity on Gram-positive bacteria in a dose-dependent manner, but in the case of Gram-negative bacteria, the antibacterial potency of ACA-PA is remarkably enhanced at concentrations above the CMC. The ACA-PA has been shown to cause bacterial cytoplasmic leakage, causing localized membrane disruption in Gram-positive bacteria and blisters on disorganized membranes of Gram-negative bacteria. Therefore, these peptide-based nanoparticles have promising potential as antimicrobial agents without resorting to the use of antibiotics, and, thus, should be further studied for a wide range of biomaterial applications. PMID- 28628297 TI - Organic Carbon Amendments for Enhanced Biological Attenuation of Trace Organic Contaminants in Biochar-Amended Stormwater Biofilters. AB - This study sought to evaluate how dissolved organic carbon (DOC) affects attenuation of trace organic contaminants (TOrCs) in biochar-amended stormwater biofilters. It was hypothesized that (1) DOC-augmented runoff would demonstrate enhanced TOrC biodegradation and (2) biochar-amended sand bearing DOC-cultivated biofilms would achieve enhanced TOrC attenuation due to sorptive retention and biodegradation. Microcosm and column experiments were conducted utilizing actual runoff, DOC from straw and compost, and a suite of TOrCs. Biodegradation of TOrCs in runoff was more enhanced by compost DOC than straw DOC (particularly for atrazine, prometon, benzotriazole, and fipronil). 16S rRNA gene quantification and sequencing revealed that growth-induced microbial community changes were, among replicates, most consistent for compost-augmented microcosms and least consistent for raw runoff microcosms. Compost DOC most robustly enhanced utilization of TOrCs as carbon substrates, possibly due to higher residual nutrient levels upon TOrC exposure. Sand columns containing just 0.5 wt % biochar maintained sorptive TOrC retention in the presence of compost-DOC-cultivated biofilms, and TOrC removal was further enhanced by biological activity. Overall, these results suggest that coamendment with biochar and compost may robustly enhance TOrC attenuation in stormwater biofilters, a finding of significance for efforts to mitigate the impacts of runoff on water quality. PMID- 28628298 TI - Selective Electrocatalytic Degradation of Odorous Mercaptans Derived from S-Au Bond Recongnition on a Dendritic Gold/Boron-Doped Diamond Composite Electrode. AB - To improve selectivity of electrocatalytic degradation of toxic, odorous mercaptans, the fractal-structured dendritic Au/BDD (boron-doped diamond) anode with molecular recognition is fabricated through a facile replacement method. SEM and TEM characterizations show that the gold dendrites are single crystals and have high population of the Au (111) facet. The distinctive structure endows the electrode with advantages of low resistivity, high active surface area, and prominent electrocatalytic activity. To evaluate selectivity, the dendritic Au/BDD is applied in degrading two groups of synthetic wastewater containing thiophenol/2-mercaptobenzimidazole (targets) and phenol/2-hydroxybenzimidazole (interferences), respectively. Results show that targets removals reach 91%/94%, while interferences removals are only 58%/48% in a short time. The corresponding degradation kinetic constants of targets are 3.25 times and 4.1 times that of interferences in the same group, demonstrating modification of dendritic gold on BDD could effectively enhance electrocatalytic target-selectivity. XPS and EXAFS further reveal that the selective electrocatalytic degradation derives from preferential recognition and fast adsorption to thiophenol depending on strong Au S bond. The efficient, selective degradation is attributed to the synergetic effects between accumulative behavior and outstanding electrochemical performances. This work provides a new strategy for selective electrochemical degradation of contaminants for actual wastewater treatment. PMID- 28628300 TI - Application of Struvite Alters the Antibiotic Resistome in Soil, Rhizosphere, and Phyllosphere. AB - Struvite recovered from wastewater is a renewable source of phosphorus and nitrogen and can be used as fertilizer for plant growth. However, antibiotics and resistome can be enriched in the struvite derived from wastewater. Robust understanding of the potential risks after struvite application to soils has remained elusive. Here, we profiled antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in struvite, soil, rhizosphere and phyllosphere of Brassica using high-throughput quantitative PCR. A total of 165 ARGs and 10 MGEs were detected. Application of struvite was found to increase both the abundance and diversity of ARGs in soil, rhizosphere and phyllosphere. In addition, ARGs shared exclusively between Brassica phyllosphere and struvite were identified, indicating that struvite was an important source of ARGs found in phyllosphere. Furthermore, OTUs shared between rhizosphere and phyllosphere were found to significantly correlate with ARGs, suggesting that microbiota in leaf and root could interconnect and ARGs might transfer from struvite to the surface of plants via rhizosphere using bacteria as spreading medium. These findings demonstrated that struvite as an organic fertilizer can facilitate the spread of antibiotic resistance into human food chain and this environment-acquired antibiotic resistance should be put into human health risk assessment system. PMID- 28628299 TI - Dihydropyrimidine-Thiones and Clioquinol Synergize To Target beta-Amyloid Cellular Pathologies through a Metal-Dependent Mechanism. AB - The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by beta-amyloid (Abeta), the peptide implicated in Alzheimer's disease. Rescue of Abeta toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Abeta toxicity by reducing Abeta levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Abeta in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Abeta peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Abeta toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies. PMID- 28628301 TI - The Effect of Fluorine Substitution on the Molecular Interactions and Performance in Polymer Solar Cells. AB - Fluorine (F) substitution on conjugated polymers in polymer solar cells (PSCs) has a diverse effect on molecular properties and device performance. We present a series of three D-A type conjugated polymers (PBT, PFBT, and PDFBT) based on dithienothiophene and benzothiadiazole units with different numbers of F atoms to explain the influence of F substitution by comparing the molecular interactions of the polymers and the recombination kinetics in PSCs. The preaggregation behavior of PFBT and PDFBT in o-DCB at the UV-vis absorption spectra proves that both polymers have strong intermolecular interactions. Besides, more closely packed structures and change into face-on orientation of fluorinated polymers are observed in polymer:PC71BM blends by GIXD which is beneficial for charge transport and, ultimately, for current density in PSCs (4.3, 13.0, and 14.5 mA cm 2 for PBT, PFBT, and PDFBT, respectively). Also, the introduction of F atoms on conjugated backbones affects the recombination kinetics by suppressing bimolecular recombination, thereby improving the fill factor (0.41, 0.68, and 0.69 for PBT, PFBT, and PDFBT, respectively). Consequently, the PCE of PSCs reached 7.3% without any additional treatment (annealing, solvent additive, etc.) in the polymer containing difluorinated BT (PDFBT) that is much higher than nonfluorinated BT (PBT ~ 1%) and monofluorinated BT (PFBT ~ 6%). PMID- 28628302 TI - Highly Fe3+-Selective Fluorescent Nanoprobe Based on Ultrabright N/P Codoped Carbon Dots and Its Application in Biological Samples. AB - Measuring the levels of Fe3+ in human body has attracted considerable attention for health monitoring as it plays an essential role in many physiological processes. In this work, we reported a selective fluorescent nanoprobe for Fe3+ detection in biological samples based on ultrabright N/P codoped carbon dots. By employing adenosine 5'-triphosphate (ATP) as the carbon, nitrogen, and phosphorus source, the N/P codoped carbon dots could be simply prepared through hydrothermal treatment. The obtained carbon dots exhibited high quantum yields up to 43.2%, as well as excellent photostability, low toxicity, and water solubility. Because of the Fe-O-P bonds formed between Fe3+ and the N/P codoped carbon dots, this nanoprobe showed high selectivity toward Fe3+ against various potential interfering substances in the presence of EDTA. The fluorescence quenching of as fabricated carbon dots was observed with the increasing Fe3+ concentration, and the calibration curve displayed a wide linear region over the range of 1-150 MUM with a detection limit of 0.33 MUM. The satisfactory accuracy was further confirmed with the river samples and ferrous sulfate tablets, respectively. With the above outstanding properties, these N/P codoped carbon dots were successfully applied for direct detection of Fe3+ in biological samples including human blood serum and living cells. As compared to the most reported carbon dots-based Fe3+ sensors, this nanoprobe showed high fluorescence, good accuracy, and excellent selectivity, which presents the potential practical application for diagnosis of Fe3+ related disease. PMID- 28628303 TI - Folate and Heptamethine Cyanine Modified Chitosan-Based Nanotheranostics for Tumor Targeted Near-Infrared Fluorescence Imaging and Photodynamic Therapy. AB - Folate (FA) and heptamethine cyanine (Cy7)-modified chitosan (CF7) was synthesized by click chemistry and its self-assembled nanoparticles (CF7Ns) were developed for tumor-specific imaging and photodynamic therapy. The characterization spectrum confirmed CF7 had a good FA and Cy7 conjugation efficacy. The diameter of CF7Ns measured by DLS was about 291.6 nm, and the morphology observed with AFM showed filamentous clusters of particles. The results of targeting ability of CF7Ns demonstrated enhanced targeting behaviors of CF7Ns compared with non-FA-modified nanoparticles C7Ns in FA receptor-positive HeLa cells. The cytotoxicity and cell apoptosis assay showed that CF7Ns under near-infrared light irradiation led to more apoptotic cell death in HeLa cells to improve the therapeutic efficacy. The mechanisms of the photodynamic effects of CF7Ns were demonstrated through measurement of intracellular reactive oxygen species and the apoptosis-related cytokines. These results suggested that CF7Ns are promising tumor targeting carriers for simultaneous fluorescence imaging and photodynamic therapy. PMID- 28628304 TI - Secondary Organic Aerosol (SOA) from Nitrate Radical Oxidation of Monoterpenes: Effects of Temperature, Dilution, and Humidity on Aerosol Formation, Mixing, and Evaporation. AB - Nitrate radical (NO3) oxidation of biogenic volatile organic compounds (BVOC) is important for nighttime secondary organic aerosol (SOA) formation. SOA produced at night may evaporate the following morning due to increasing temperatures or dilution of semivolatile compounds. We isothermally dilute the oxidation products from the limonene+NO3 reaction at 25 degrees C and observe negligible evaporation of organic aerosol via dilution. The SOA yields from limonene+NO3 are approximately constant (~174%) at 25 degrees C and range from 81 to 148% at 40 degrees C. Based on the difference in yields between the two temperatures, we calculated an effective enthalpy of vaporization of 117-237 kJ mol-1. The aerosol yields at 40 degrees C can be as much as 50% lower compared to 25 degrees C. However, when aerosol formed at 25 degrees C is heated to 40 degrees C, only about 20% of the aerosol evaporates, which could indicate a resistance to aerosol evaporation. To better understand this, we probe the possibility that SOA from limonene+NO3 and beta-pinene+NO3 reactions is highly viscous. We demonstrate that particle morphology and evaporation is dependent on whether SOA from limonene is formed before or during the formation of SOA from beta-pinene. This difference in particle morphology is present even at high relative humidity (~70%). PMID- 28628305 TI - Variation in Methane Emission Rates from Well Pads in Four Oil and Gas Basins with Contrasting Production Volumes and Compositions. AB - Atmospheric methane emissions from active natural gas production sites in normal operation were quantified using an inverse Gaussian method (EPA's OTM 33a) in four major U.S. basins/plays: Upper Green River (UGR, Wyoming), Denver-Julesburg (DJ, Colorado), Uintah (Utah), and Fayetteville (FV, Arkansas). In DJ, Uintah, and FV, 72-83% of total measured emissions were from 20% of the well pads, while in UGR the highest 20% of emitting well pads only contributed 54% of total emissions. The total mass of methane emitted as a percent of gross methane produced, termed throughput-normalized methane average (TNMA) and determined by bootstrapping measurements from each basin, varied widely between basins and was (95% CI): 0.09% (0.05-0.15%) in FV, 0.18% (0.12-0.29%) in UGR, 2.1% (1.1-3.9%) in DJ, and 2.8% (1.0-8.6%) in Uintah. Overall, wet-gas basins (UGR, DJ, Uintah) had higher TNMA emissions than the dry-gas FV at all ranges of production per well pad. Among wet basins, TNMA emissions had a strong negative correlation with average gas production per well pad, suggesting that consolidation of operations onto single pads may reduce normalized emissions (average number of wells per pad is 5.3 in UGR versus 1.3 in Uintah and 2.8 in DJ). PMID- 28628306 TI - Lysine Deacetylation by HDAC6 Regulates the Kinase Activity of AKT in Human Neural Progenitor Cells. AB - The AKT family of serine-threonine kinases functions downstream of phosphatidylinositol 3-kinase (PI3K) to transmit signals by direct phosphorylation of a number of targets, including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3beta (GSK3beta), and beta-catenin. AKT binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated by PI3K activation, which results in its membrane localization and subsequent activation through phosphorylation by phosphoinositide-dependent protein kinase 1 (PDK1). Together, the PI3K-AKT signaling pathway plays pivotal roles in many cellular systems, including in the central nervous system where it governs both neurodevelopment and neuroplasticity. Recently, lysine residues (Lys14 and Lys20) on AKT, located within its pleckstrin homology (PH) domain that binds to membrane bound PIP3, have been found to be acetylated under certain cellular contexts in various cancer cell lines. These acetylation modifications are removed by the enzymatic action of the class III lysine deacetylases, SIRT1 and SIRT2, of the sirtuin family. The extent to which reversible acetylation regulates AKT function in other cell types remains poorly understood. We report here that AKT kinase activity is modulated by a class IIb lysine deacetylase, histone deacetylase 6 (HDAC6), in human neural progenitor cells (NPCs). We find that HDAC6 and AKT physically interact with each other in the neuronal cells, and in the presence of selective HDAC6 inhibition, AKT is acetylated at Lys163 and Lys377 located in the kinase domain, two novel sites distinct from the acetylation sites in the PH domain modulated by the sirtuins. Measurement of the functional effect of HDAC6 inhibition on AKT revealed decreased binding to PIP3, a correlated decrease in AKT kinase activity, decreased phosphorylation of Ser552 on beta-catenin, and modulation of neuronal differentiation trajectories. Taken together, our studies implicate the deacetylase activity of HDAC6 as a novel regulator of AKT signaling and point to novel mechanisms for regulating AKT activity with small-molecule inhibitors of HDAC6 currently under clinical development. PMID- 28628307 TI - Present Perspectives of Advanced Characterization Techniques in TiO2-Based Photocatalysts. AB - TiO2 is the most investigated photocatalyst because of its nontoxicity, low cost, chemical stability, and strong photooxidative ability. Because of the morphology- and structure-dependent photocatalytic properties of TiO2, accurate characterization of the crystal and electronic structures of TiO2-based materials and their performance during the photocatalytic process is crucial not only for understanding the photocatalytic mechanism but also for providing experimental guidelines as well as a theoretical framework for the synthesis of high performance photocatalysts. In this review, we focused on the advanced characterization techniques that are utilized in the studies on the TiO2 structures and photocatalytic performance of TiO2 and TiO2-based materials. It is therefore anticipated that this review can provide a novel perspective to understand the fundamental aspects of photocatalysis and inspire the development of new photocatalysts with superior performances. PMID- 28628308 TI - Molecular Insights into the Transformation of Dissolved Organic Matter in Landfill Leachate Concentrate during Biodegradation and Coagulation Processes Using ESI FT-ICR MS. AB - Landfill leachate concentrate is a type of refractory organic wastewater with high environmental risk. Identification of refractory components and insights into the molecular transformations of the organics are essential for the development of efficient treatment process. In this report, molecular compositions of dissolved organic matter (DOM) in leachate concentrate, as well as changes after anaerobic/aerobic biodegradation and coagulation with salts, were characterized using electrospray ionization (ESI) coupled with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). DOM in leachate concentrate were more saturated and less oxidized with more nitrogen and sulfur containing substances (accounting for 50.0%), comparing with natural organic matter in Suwannee River. Selectivity for different classes of organics during biodegradation and coagulation processes was observed. Substances with low oxidation degree (O/C < 0.3) were more reactive during biodegradation process, leading to the formation of highly oxidized molecules (O/C > 0.5). Unsaturated (H/C < 1.0) and oxidized (O/C > 0.4) substances containing carboxyl groups were preferentially removed after coagulation with Al or Fe sulfate. The complementary functions of biodegradation and coagulation in the treatment of DOM in leachate concentrate were verified at the molecular level. Lignin-derived compounds and sulfur-containing substances in leachate concentrate were resistant to biodegradation and coagulation treatments. To treat leachate concentrate more effectively, processes aimed at removal of such DOM should be developed. PMID- 28628309 TI - Dissecting Orthosteric Contacts for a Reverse-Fragment-Based Ligand Design. AB - Orthosteric sites on proteins are formed typically from noncontiguous interacting sites in three-dimensional space where the composite binding interaction of a biological ligand is mediated by multiple synergistic interactions of its constituent functional groups. Through these multiple interactions, ligands stabilize both the ligand binding site and the local secondary structure. However, relative energetic contributions of the individual contacts in these protein-ligand interactions are difficult to resolve. Deconvolution of the contributions of these various functional groups in natural inhibitors/ligand would greatly aid in iterative fragment-based drug discovery (FBDD). In this study, we describe an approach of progressive unfolding of a target protein using a gradient of denaturant urea to reveal the individual energetic contributions of various ligand-functional groups to the affinity of the entire ligand. Through calibrated unfolding of two protein-ligand systems: cAMP-bound regulatory subunit of Protein Kinase A (RIalpha) and IBMX-bound phosphodiesterase8 (PDE8), monitored by amide hydrogen-deuterium exchange mass spectrometry, we show progressive disruption of individual orthosteric contacts in the ligand binding sites, allowing us to rank the energetic contributions of these individual interactions. In the two cAMP-binding sites of RIalpha, exocyclic phosphate oxygens of cAMP were identified to mediate stronger interactions than ribose 2'-OH in both the RIalpha-cAMP binding interfaces. Further, we have also ranked the relative contributions of the different functional groups of IBMX based on their interactions with the orthosteric residues of PDE8. This strategy for deconstruction of individual binding sites and identification of the strongest functional group interaction in enzyme orthosteric sites offers a rational starting point for FBDD. PMID- 28628310 TI - Furoxan Nitric Oxide Donors Disperse Pseudomonas aeruginosa Biofilms, Accelerate Growth, and Repress Pyoverdine Production. AB - The use of nitric oxide (NO) as a signal for biofilm dispersal has been shown to increase the susceptibility of many biofilms to antibiotics, promoting their eradication. The delivery of NO to biofilms can be achieved by using NO donors with different kinetics and properties of NO release that can influence their efficacy as biofilm control agents. In this study, the kinetics of three furoxan derivatives were evaluated. The effects of these NO donors, which have an advantageous pharmacological profile of slower onset with an extended duration of action, on Pseudomonas aeruginosa growth, biofilm development, and dispersal were also characterized. Compound LL4254, which showed a fast rate of NO release, induced biofilm dispersal at approximately 200 MUM. While LL4212 and LL4216 have a slower rate of NO release, both compounds could induce biofilm dispersal, under the same treatment conditions, when used at higher concentrations. In addition, LL4212 and LL4216 were found to promote P. aeruginosa growth in iron-limited minimal medium, leading to a faster rate of biofilm formation and glucose utilization, and ultimately resulted in early dispersal of biofilm cells through carbon starvation. High concentrations of LL4216 also repressed production of the siderophore pyoverdine by more than 50-fold, via both NOx-dependent and NOx independent mechanisms. The effects on growth and pyoverdine levels exerted by the furoxans appeared to be mediated by NO-independent mechanisms, suggesting functional activities of furoxans in addition to their release of NO and nitrite. Overall, this study reveals that secondary effects of furoxans are important considerations for their use as NO-releasing dispersal agents and that these compounds could be potentially redesigned as pyoverdine inhibitors. PMID- 28628311 TI - Pushing the Limits of Oxygen Balance in 1,3,4-Oxadiazoles. AB - Gem-trinitromethyl groups were introduced into a 1,3,4-oxadiazole ring to give the first example of a bifunctionalized single five-membered ring with six nitro groups. 2,5-Bis(trinitromethyl)-1,3,4-oxadiazole (12) has a high calculated crystal density of 2.007 g cm-3 at 150 K (1.941 g cm-3 at 293 K) and a very high positive oxygen balance (39.12%), which makes it a strong candidate as a high energy dense oxidizer. The dihydroxylammonium and dihydrazinium salts of bis(trinitromethyl)-1,3,4-oxadiazole (5 and 6) exhibit excellent calculated detonation properties (5, vD = 9266 m s-1, P = 38.9 GPa; 6, vD = 8900 m s-1, P = 36.3 GPa) and acceptable impact sensitivities (5 20 J, 6 19 J), which are superior to those of RDX (7.4 J) and HMX (7.4 J). Such attractive features support the application potential of the gem-polynitromethyl group in the design of advanced energetic materials. Surprisingly, 2,5-bis(trinitromethyl)-1,3,4 oxadiazole (12) is more thermally stable and less sensitive than its bis(dinitromethyl) analogue, 8. PMID- 28628312 TI - A Mononuclear Nonheme Iron(V)-Imido Complex. AB - Mononuclear nonheme iron(V)-oxo complexes have been reported previously. Herein, we report the first example of a mononuclear nonheme iron(V)-imido complex bearing a tetraamido macrocyclic ligand (TAML), [(TAML)FeV(NTs)]- (1). The spectroscopic characterization of 1 revealed an S = 1/2 Fe(V) oxidation state, an Fe-N bond length of 1.65(4) A, and an Fe-N vibration at 817 cm-1. The reactivity of 1 was demonstrated in C-H bond functionalization and nitrene transfer reactions. PMID- 28628313 TI - Tunneling Kinetics and Nonadiabatic Proton-Coupled Electron Transfer in Proteins: The Effect of Electric Fields and Anharmonic Donor-Acceptor Interactions. AB - A proper description of proton donor-acceptor (D-A) distance fluctuations is crucial for understanding tunneling in proton-coupled electron transport (PCET). The typical harmonic approximation for the D-A potential results in a Gaussian probability distribution, which does not appropriately reflect the electronic repulsion forces that increase the energetic cost of sampling shorter D-A distances. Because these shorter distances are the primary channel for thermally activated tunneling, the analysis of tunneling kinetics depends sensitively on the inherently anharmonic nature of the D-A interaction. Thus, we have used quantum chemical calculations to account for the D-A interaction and developed an improved model for the analysis of experimental tunneling kinetics. Strong internal electric fields are also considered and found to contribute significantly to the compressive forces when the D-A distance distribution is positioned below the van der Waals contact distance. This model is applied to recent experiments on the wild type (WT) and a double mutant (DM) of soybean lipoxygenase-1 (SLO). The compressive force necessary to prepare the tunneling active distribution in WT SLO is found to fall in the ~ nN range, which greatly exceeds the measured values of molecular motor and protein unfolding forces. This indicates that ~60-100 MV/cm electric fields, aligned along the D-A bond axis, must be generated by an enzyme conformational interconversion that facilitates the PCET tunneling reaction. Based on the absolute value of the measured tunneling rate, and using previously calculated values of the electronic matrix element, the population of this tunneling-active conformation is found to lie in the range 10-5-10-7, indicating this is a rare structural fluctuation that falls well below the detection threshold of recent ENDOR experiments. Additional analysis of the DM tunneling kinetics leads to a proposal that a disordered (high entropy) conformation could be tunneling-active due to its broad range of sampled D-A distances. PMID- 28628314 TI - Benchmarking the Fundamental Electronic Properties of small TiO2 Nanoclusters by GW and Coupled Cluster Theory Calculations. AB - We study the vertical and adiabatic ionization potentials and electron affinities of bare and hydroxylated TiO2 nanoclusters, as well as their fundamental gap and exciton binding energy values, to understand how the clusters' electronic properties change as a function of size and hydroxylation. In addition, we have employed a range of many-body methods; including G0W0, qsGW, EA/IP-EOM-CCSD, and DFT (B3LYP, PBE), to compare the performance and predictions of the different classes of methods. We demonstrate that, for bare clusters, all many-body methods predict the same trend with cluster size. The highest occupied and lowest unoccupied DFT orbitals follow the same trends as the electron affinity and ionization potentials predicted by the many-body methods, but are generally far too shallow and deep respectively in absolute terms. In contrast, the DeltaDFT method is found to yield values in the correct energy window. However, its predictions depend upon the functional used and do not necessarily follow trends based on the many-body methods. Adiabatic potentials are predicted to be similar to their vertical counterparts and holes found to be trapped more strongly than excess electrons. The effect of hydroxylation on the clusters is to open up both the optical and fundamental gap. Finally, a simple microscopic explanation for the observed trends with cluster size and upon hydroxylation is proposed in terms of the onsite electrostatic potential. PMID- 28628315 TI - A Pseudohypervalent Sulfur Intermediate as an Oxidative Protective Mechanism in the Archaea Peroxiredoxin Enzyme ApTPx. AB - Peroxiredoxins (Prxs) are a ubiquitous class of enzymes that have central roles in a number of important physiological processes. Using a multiscale computational approach, we have investigated the mechanism by which the active site cysteine (Cys50) in the typical 2-Cys Prx from Archaea (ApTPx) is oxidized by H2O2 to sulfenic acid. In addition, its further oxidation to give a sulfinic acid and its possible alternate intramolecular reaction to form an experimentally proposed hypervalent sulfurane were examined. Oxidation of Cys50 by H2O2 to give the sulfenic acid intermediate occurs in one step with a barrier of 82.1 kJ mol 1. A two-step pathway is proposed with a very low barrier of 16.5 kJ mol-1 by which it can subsequently react with an adjacent histidyl (His42) to form the pseudohypervalent sulfurane. This pathway also involves an adjacent aspartyl (Asp45), which helps alternate the protonation state of His42. The sulfurane's Cys50S...NdeltaHis42 interaction was characterized using QTAIM, NCI, and NBO analyses and found to be a noncovalent interaction. Notably, this bond helps orient the Cys50SOH moiety such that it is less susceptible to oxidation by H2O2 to sulfinic acid. Significantly, sulfurane formation is energetically favored to further H2O2 oxidation of Cys50SOH to a sulfinic acid, providing a mechanism by which the active-site Cys50 is protected against overoxidation. PMID- 28628316 TI - Soft-Sphere Continuum Solvation in Electronic-Structure Calculations. AB - We present an implicit solvation approach where the interface between the quantum mechanical solute and the surrounding environment is described by a fully continuous permittivity built up with atomic-centered "soft" spheres. This approach combines many of the advantages of the self-consistent continuum solvation model in handling solutes and surfaces in contact with complex dielectric environments or electrolytes in electronic-structure calculations. In addition it is able to describe accurately both neutral and charged systems. The continuous function, describing the variation of the permittivity, allows to compute analytically the nonelectrostatic contributions to the solvation free energy that are described in terms of the quantum surface. The whole methodology is computationally stable, provides consistent energies and forces, and keeps the computational efforts and runtimes comparable to those of standard vacuum calculations. The capabilitiy to treat arbitrary molecular or slab-like geometries as well as charged molecules is key to tackle electrolytes within mixed explicit/implicit frameworks. We show that, with given, fixed atomic radii, two parameters are sufficient to give a mean absolute error of only 1.12 kcal/mol with respect to the experimental aqueous solvation energies for a set of 274 neutral solutes. For charged systems, the same set of parameters provides solvation energies for a set of 60 anions and 52 cations with an error of 2.96 and 2.13 kcal/mol, respectively, improving upon previous literature values. To tackle elements not present in most solvation databases, a new benchmark scheme on wettability and contact angles is proposed for solid-liquid interfaces and applied to the investigation of the stable terminations of a CdS (1120) surface in an electrochemical medium. PMID- 28628317 TI - Controllability of Polymer Crystal Orientation Using Heterogeneous Nucleation of Deformed Polymer Loops Grafted on Two-Dimensional Nanofiller. AB - Nowadays, it is a research hotspot to realize the controllability of polymer crystal structure in polymer nanocomposites. However, polymer crystals induced by two-dimensional filler always exhibit random orientation, which somewhat limit the improvement of physical properties of polymer materials. In the current paper, dynamic Monte Carlo simulations were performed to explore the methods preparing crystals with uniform orientation. Heterogeneous nucleation of deformed polymer loops grafted on two-dimensional filler can induce the appearance of a special nanohybrid shish-kebab (NHSK) structure, in which the two-dimensional filler acts as "shish" and induces the formation of crystals with uniform orientation. The grafted deformed chains are first heterogeneously nucleated on filler surface, and then free chains participate in crystallization, resulting in the formation of the NHSK structure. The NHSK structure can only be formed in the systems with high interfacial interactions at high temperatures or moderate interfacial interactions at moderate temperatures or low interfacial interactions at low temperatures. The method proposed here can be used to achieve the controllability of polymer crystal orientation in experiments. PMID- 28628319 TI - Mechanism of Phenol Alkylation in Zeolite H-BEA Using In Situ Solid-State NMR Spectroscopy. AB - The reaction mechanism of solid-acid-catalyzed phenol alkylation with cyclohexanol and cyclohexene in the apolar solvent decalin has been studied using in situ 13C MAS NMR spectroscopy. Phenol alkylation with cyclohexanol sets in only after a majority of cyclohexanol is dehydrated to cyclohexene. As phenol and cyclohexanol show similar adsorption strength, this strict reaction sequence is not caused by the limited access of phenol to cyclohexanol, but is due to the absence of a reactive electrophile as long as a significant fraction of cyclohexanol is present. 13C isotope labeling demonstrates that the reactive electrophile, the cyclohexyl carbenium ion, is directly formed in a protonation step when cyclohexene is the coreactant. In the presence of cyclohexanol, its protonated dimers at Bronsted acid sites hinder the adsorption of cyclohexene and the formation of a carbenium ion. Thus, it is demonstrated that protonated cyclohexanol dimers dehydrate without the formation of a carbenium ion, which would otherwise have contributed to the alkylation in the kinetically relevant step. Isotope scrambling shows that intramolecular rearrangement of cyclohexyl phenyl ether does not significantly contribute to alkylation at the aromatic ring. PMID- 28628318 TI - Third-Generation Light-Driven Symmetric Molecular Motors. AB - Symmetric molecular motors based on two overcrowded alkenes with a notable absence of a stereogenic center show potential to function as novel mechanical systems in the development of more advanced nanomachines offering controlled motion over surfaces. Elucidation of the key parameters and limitations of these third-generation motors is essential for the design of optimized molecular machines based on light-driven rotary motion. Herein we demonstrate the thermal and photochemical rotational behavior of a series of third-generation light driven molecular motors. The steric hindrance of the core unit exerted upon the rotors proved pivotal in controlling the speed of rotation, where a smaller size results in lower barriers. The presence of a pseudo-asymmetric carbon center provides the motor with unidirectionality. Tuning of the steric effects of the substituents at the bridgehead allows for the precise control of the direction of disrotary motion, illustrated by the design of two motors which show opposite rotation with respect to a methyl substituent. A third-generation molecular motor with the potential to be the fastest based on overcrowded alkenes to date was used to visualize the equal rate of rotation of both its rotor units. The autonomous rotational behavior perfectly followed the predicted model, setting the stage for more advanced motors for functional dynamic systems. PMID- 28628320 TI - Dynamics of Charge Injection and Charge Recombination in DNA Mini-Hairpins. AB - Steady state spectroscopy, femtosecond transient absorption spectroscopy (fsTA), and femtosecond stimulated Raman spectroscopy (FSRS) of DNA mini-hairpins possessing a diphenylacetylenedicarboxamide (DPA) linker and 1-3 adenine-thymine (A-T) or guanine-cytosine (G-C) base pairs have been investigated. Ultraviolet and circular dichroism (UV and CD) spectra are consistent with ground state conformations that are predominantly base-paired and pi-stacked for conjugates possessing two or three base pairs; however, they offer no information concerning the conformation of conjugates possessing a single base pair. fsTA spectra are indicative of pi-stacked structures excepted in the case of the conjugate possessing a single G-C base pair. All of the conjugates display transient absorption bands characteristic of the DPA-. anion radical. Conjugates possessing two or three G-C base pairs display a transient absorption band characteristic of the short-lived G+* cation radical. The mini-hairpins with 1-3 A-T base pairs do not display the transient absorption band characteristic of the (An+*) polaron. This implies that an A-tract with three base pairs is too short to support polaron formation. PMID- 28628321 TI - Manganese-Catalyzed Aminomethylation of Aromatic Compounds with Methanol as a Sustainable C1 Building Block. AB - This study represents the first example of a manganese-catalyzed environmentally benign, practical three-component aminomethylation of activated aromatic compounds including naphtols, phenols, pyridines, indoles, carbazoles, and thiophenes in combination with amines and MeOH as a C1 source. These reactions proceed with high atom efficiency via a sequence of dehydrogenation and condensation steps which give rise to selective C-C and C-N bond formations, thereby releasing hydrogen and water. A well-defined hydride Mn(I) PNP pincer complex, recently developed in our laboratory, catalyzes this process in a very efficient way, and a total of 28 different aminomethylated products were synthesized and isolated yields of up to 91%. In a preliminary study, a related Fe(II) PNP pincer complex was shown to catalyze the methylation of 2-naphtol rather than its aminomethylation displaying again the divergent behavior of isoelectronic Mn(I) and Fe(II) PNP pincer systems. PMID- 28628322 TI - Applying Mondrian Cross-Conformal Prediction To Estimate Prediction Confidence on Large Imbalanced Bioactivity Data Sets. AB - Conformal prediction has been proposed as a more rigorous way to define prediction confidence compared to other application domain concepts that have earlier been used for QSAR modeling. One main advantage of such a method is that it provides a prediction region potentially with multiple predicted labels, which contrasts to the single valued (regression) or single label (classification) output predictions by standard QSAR modeling algorithms. Standard conformal prediction might not be suitable for imbalanced data sets. Therefore, Mondrian cross-conformal prediction (MCCP) which combines the Mondrian inductive conformal prediction with cross-fold calibration sets has been introduced. In this study, the MCCP method was applied to 18 publicly available data sets that have various imbalance levels varying from 1:10 to 1:1000 (ratio of active/inactive compounds). Our results show that MCCP in general performed well on bioactivity data sets with various imbalance levels. More importantly, the method not only provides confidence of prediction and prediction regions compared to standard machine learning methods but also produces valid predictions for the minority class. In addition, a compound similarity based nonconformity measure was investigated. Our results demonstrate that although it gives valid predictions, its efficiency is much worse than that of model dependent metrics. PMID- 28628323 TI - Double Diastereoselective Approach to Chiral syn- and anti-1,3-Diol Analogues through Consecutive Catalytic Asymmetric Borylations. AB - Homoallylic boronate carboxylate esters derived from unsaturated aldehydes via an imination, beta-borylation, imine hydrolysis, and Wittig trapping sequence, were subjected to a second boryl addition to give 1,3-diborylated carboxylate esters. Control of the absolute and relative stereochemistry of the two new 1,3 stereogenic centers was achieved through: (1) direct chiral catalyst controlled asymmetric borylation of the first stereocenter on the unsaturated imine with high e.e.; and (2) a double diastereoselectively controlled borylation of an unsaturated ester employing a chiral catalyst to largely overcome directing effects from the first chiral boryl center to give poor (mismatched) to good (matched) diastereocontrol. Subsequently, the two C-B functions were transformed into C-O systems to allow unambiguous stereochemical assignment of the two borylation reactions involving oxidation and acetal formation. PMID- 28628324 TI - Activation Parameters of Self-Diffusion of Aromatic Chiral Molecules in External Magnetic Fields. AB - The mobility of aromatic chiral molecules 1-phenylethanol and 1-phenyl-1-propanol in liquids was studied by 1H NMR spectroscopy depending on the strength of the external magnetic field, temperature, and concentration ratio of enantiomers. The data obtained were analyzed using Arrhenius law. The activation parameters were found to depend on the applied field. This effect is caused by the induced magnetic moments in aromatic molecules. The use of strong magnetic fields seems to be promising for investigation of intermolecular interactions of chiral molecules. PMID- 28628325 TI - Tuning Optical Signatures of Single- and Few-Layer MoS2 by Blown-Bubble Bulge Straining up to Fracture. AB - Emerging atomic layer semiconducting crystals such as molybdenum disulfide (MoS2) are promising candidates for flexible electronics and strain-tunable devices due to their ultrahigh strain limits (up to ~20-30%) and strain-tunable bandgaps. However, high strain levels, controllable isotropic and anisotropic biaxial strains in single- and few-layer MoS2 on device-oriented flexible substrates permitting convenient and fast strain tuning, remain unexplored. Here, we demonstrate a "blown-bubble" bulge technique for efficiently applying large strains to atomic layer MoS2 devices on a flexible substrate. As the strain increases via bulging, we achieve continuous tuning of Raman and photoluminescence (PL) signatures in single- and few-layer MoS2, including splitting of Raman peaks. With proper clamping of the MoS2 crystals, we apply up to ~9.4% strain in the flexible substrate, which causes a doubly clamped single layer MoS2 to fracture at 2.2-2.6% strain measured by PL and 2.9-3.5% strain measured by Raman spectroscopy. This study opens new pathways for exploiting 2D semiconductors on stretchable substrates for flexible electronics, mechanical transducers, tunable optoelectronics, and biomedical transducers on curved and bulging surfaces. PMID- 28628326 TI - Improved Sodium-Ion Storage Performance of Ultrasmall Iron Selenide Nanoparticles. AB - Sodium-ion batteries are potential low-cost alternatives to current lithium-ion technology, yet their performances still fall short of expectation due to the lack of suitable electrode materials with large capacity, long-term cycling stability, and high-rate performance. In this work, we demonstrated that ultrasmall (~5 nm) iron selenide (FeSe2) nanoparticles exhibited a remarkable activity for sodium-ion storage. They were prepared from a high-temperature solution method with a narrow size distribution and high yield and could be readily redispersed in nonpolar organic solvents. In ether-based electrolyte, FeSe2 nanoparticles exhibited a large specific capacity of ~500 mAh/g (close to the theoretical limit), high rate capability with ~250 mAh/g retained at 10 A/g, and excellent cycling stability at both low and high current rates by virtue of their advantageous nanosizing effect. Full sodium-ion batteries were also constructed from coupling FeSe2 with NASICON-type Na3V2(PO4)3 cathode and demonstrated impressive capacity and cycle ability. PMID- 28628327 TI - Impact of the Niemann-Pick c1 Gene Mutation on the Total Cellular Glycomics of CHO Cells. AB - Niemann-Pick disease type C (NPC) is an autosomal recessive lipid storage disorder, and the majority of cases are caused by mutations in the NPC1 gene. In this study, we clarified how a single gene mutation in the NPC1 gene impacts the cellular glycome by analyzing the total glycomic expression profile of Chinese hamster ovary cell mutants defective in the Npc1 gene (Npc1 KO CHO cells). A number of glycomic alterations were identified, including increased expression of lactosylceramide, GM1, GM2, GD1, various neolacto-series glycosphingolipids, and sialyl-T (O-glycan), which was found to be the major sialylated protein-bound glycan, as well as various N-glycans, which were commonly both fucosylated and sialylated. We also observed significant increases in the total amounts of free oligosaccharides (fOSs), especially in the unique complex- and hybrid-type fOSs. Treatment of Npc1 KO CHO cells with 2-hydroxypropyl-beta-cyclodextrin (HPBCD), which can reduce cholesterol and glycosphingolipid (GSL) storage, did not affect the glycomic alterations observed in the GSL-, N-, and O-glycans of Npc1 KO CHO cells. However, HPBCD treatment corrected the glycomic alterations observed in fOSs to levels observed in wild-type cells. PMID- 28628328 TI - pH-Switchable Interaction of a Carboxybetaine Ester-Based SAM with DNA and Gold Nanoparticles. AB - We describe a self-assembled monolayer (SAM) on a gold surface with a carboxybetaine ester functionality to control the interaction between DNA and gold nanoparticles via pH. The negatively charged phosphate backbone of DNA interacts with and adsorbs to the positively charged carboxybetaine esters on the SAM. DNA release can be achieved by the hydrolysis of carboxybetaine ester (CBE) to a zwitterionic carboxybetaine state. Furthermore, the adsorption of negatively charged citrate-capped gold nanoparticles to a SAM-modified plain gold surface can be controlled by the pH. The SAM based on carboxybetaine ester allows for the homogeneous adsorption of particles, whereas the SAM after hydrolysis at high pH repels AuNP adsorption. The antifouling surface properties of the surface modified with carboxybetaine were investigated with protein samples. PMID- 28628329 TI - Exploring the Formation of Symmetric Gold Nanostars by Liquid-Cell Transmission Electron Microscopy. AB - The shape-dependent properties of gold nanostars (NSs) have motivated massive research efforts in the field of colloidal chemistry to gain a better control over the morphology of these promising nanostructures. Nevertheless, this challenge requires a better understanding of the atomic-scale processes leading to the formation of stellated nanoparticles. We hereby report an unprecedented in situ study focused on the seed-mediated synthesis of symmetric gold NSs performed by radiolysis in methanol. We take advantage of the spatial and temporal resolutions of liquid-cell transmission electron microscopy to unravel the key effects of the growth speed, seed-crystal morphology, and dimethylamine functionalization on the formation mechanisms, shape, and stability of NSs enclosed by high-index facets. Surprisingly, the stellation processes transforming icosahedral nanoparticles into NSs with 20 sharp arms entails a continuous restructuring of NS facets driven by surface diffusion, which provide a fresh look at faceting mechanisms. PMID- 28628330 TI - Quantum Spin Hall Effect and Tunable Spin Transport in As-Graphane. AB - Tunable spin transport in nanodevices is highly desirable to spintronics. Here, we predict existence of quantum spin Hall effects and tunable spin transport in As-graphane, based on first-principle density functional theory and tight binding calculations. Monolayer As-graphane is constituted by using As adsorbing on graphane with honeycomb H vacancies. Owing to the surface strain, monolayer As graphane nanoribbons will self-bend toward the graphane side. The naturally curved As-graphane nanoribbons then exhibit unique spin transport properties, distinctively different from the flat ones, which is a two-dimensional topological insulator. Under external stress, one can realize tunable spin transport in curved As-graphane nanoribon arrays. Such intriguing mechanical bending induced spin flips can offer promising applications in the future nanospintronics devices. PMID- 28628331 TI - Quantum Cascade Laser Spectral Histopathology: Breast Cancer Diagnostics Using High Throughput Chemical Imaging. AB - Fourier transform infrared (FT-IR) microscopy coupled with machine learning approaches has been demonstrated to be a powerful technique for identifying abnormalities in human tissue. The ability to objectively identify the prediseased state and diagnose cancer with high levels of accuracy has the potential to revolutionize current histopathological practice. Despite recent technological advances in FT-IR microscopy, sample throughput and speed of acquisition are key barriers to clinical translation. Wide-field quantum cascade laser (QCL) infrared imaging systems with large focal plane array detectors utilizing discrete frequency imaging have demonstrated that large tissue microarrays (TMA) can be imaged in a matter of minutes. However, this ground breaking technology is still in its infancy, and its applicability for routine disease diagnosis is, as yet, unproven. In light of this, we report on a large study utilizing a breast cancer TMA comprised of 207 different patients. We show that by using QCL imaging with continuous spectra acquired between 912 and 1800 cm-1, we can accurately differentiate between 4 different histological classes. We demonstrate that we can discriminate between malignant and nonmalignant stroma spectra with high sensitivity (93.56%) and specificity (85.64%) for an independent test set. Finally, we classify each core in the TMA and achieve high diagnostic accuracy on a patient basis with 100% sensitivity and 86.67% specificity. The absence of false negatives reported here opens up the possibility of utilizing high throughput chemical imaging for cancer screening, thereby reducing pathologist workload and improving patient care. PMID- 28628332 TI - Watson-Crick Base Pair Radical Cation as a Model for Oxidative Damage in DNA. AB - The deleterious cellular effects of ionizing radiation are well-known, but the mechanisms causing DNA damage are poorly understood. The accepted molecular events involve initial oxidation and deprotonation at guanine sites, triggering hydrogen atom abstraction reactions from the sugar moieties, causing DNA strand breaks. Probing the chemistry of the initially formed radical cation has been challenging. Here, we generate, spectroscopically characterize, and examine the reactivity of the Watson-Crick nucleobase pair radical cation in the gas phase. We observe rich chemistry, including proton transfer between the bases and propagation of the radical site in deoxyguanosine from the base to the sugar, thus rupturing the sugar. This first example of a gas-phase model system providing molecular-level details on the chemistry of an ionized DNA base pair paves the way toward a more complete understanding of molecular processes induced by radiation. It also highlights the role of radical propagation in chemistry, biology, and nanotechnology. PMID- 28628333 TI - Coupling Targeted and Untargeted Mass Spectrometry for Metabolome-Microbiome-Wide Association Studies of Human Fecal Samples. AB - Increasing appreciation of the gut microbiome's role in health motivates understanding the molecular composition of human feces. To analyze such complex samples, we developed a platform coupling targeted and untargeted metabolomics. The approach is facilitated through split flow from one UPLC, joint timing triggered by contact closure relays, and a script to retrieve the data. It is designed to detect specific metabolites of interest with high sensitivity, allows for correction of targeted information, enables better quantitation thus providing an advanced analytical tool for exploratory studies. Procrustes analysis revealed that untargeted approach provides a better correlation to microbiome data, associating specific metabolites with microbes that produce or process them. With the subset of over one hundred human fecal samples from the American Gut project, the implementation of the described coupled workflow revealed that targeted analysis using combination of single transition per compound with retention time misidentifies 30% of the targeted data and could lead to incorrect interpretations. At the same time, the targeted analysis extends detection limits and dynamic range, depending on the compounds, by orders of magnitude. A software application has been developed as a part of the workflow to allows for quantitative assessments based on calibration curves. Using this approach, we detect expected microbially modified molecules such as secondary bile acids and unexpected microbial molecules including Pseudomonas-associated quinolones and rhamnolipids in feces, setting the stage for metabolome-microbiome wide association studies (MMWAS). PMID- 28628334 TI - Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents. AB - We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8-37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L, and K103N-Y181C HIV-1 strains. Six racemic mixtures, 8, 23-25, 31, and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (alpha methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31, and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers. Compound 23 protected hippocampal neuronal cells from the excitotoxic insult, while efavirenz (EFV) did not contrast the neurotoxic effect of glutamate. The present results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV 1 strains and reduced neurotoxic effects. PMID- 28628335 TI - Molecular Dipole-Driven Electronic Structure Modifications of DNA/RNA Nucleobases on Graphene. AB - The emergence of graphene in recent years provides exciting avenues for achieving fast, reliable DNA/RNA sensing and sequencing. Here we explore the possibility of enhancing electronic fingerprints of nucleobases adsorbed on graphene by tuning the surface coverage and modifying molecular dipoles using first-principles calculations. We demonstrate that intermolecular interactions have a strong influence on the adsorption geometry and the electronic structure of the nucleobases, resulting in tilted configurations and a considerable modification of their electronic fingerprints in graphene. Our analysis reveals that the molecular dipole of the nucleobase molecules plays a dominant role in the electronic structure of graphene-nucleobase systems, inducing significant changes in the work functions and energy level alignments at the interface. These results highlight tunable control of the measured molecular signals in graphene by optimizing the surface contact between nucleobases and graphene. Our findings have important implications for identification and understanding of molecular fingerprints of DNA/RNA nucleobases in graphene-based sensing and sequencing methods. PMID- 28628336 TI - Effect of Salt Concentration on the pH Responses of Strong and Weak Polyelectrolyte Brushes. AB - Strong polyelectrolyte brushes (SPB) and weak polyelectrolyte brushes (WPB) have different origins with response to pH, which makes their pH-responsive properties sensitive to salt concentration in different ways. Herein, we have employed poly[2-(methacryloyloxy)ethyl trimethylammonium chloride] (PMETAC) and poly[2 (dimethylamino)ethyl methacrylate] (PDMAEMA) brushes as model systems for SPB and WPB, respectively, to investigate the effect of salt concentration on the pH responses of SPB and WPB using several surface-sensitive techniques. The pH responsive properties of the PMETAC brushes are governed by the reorganization of the interchain hydrogen bonds between the grafted chains, whereas the pH response of the PDMAEMA brushes is controlled by the charge of the grafted chains. The response of the properties of the PMETAC brushes including hydration, conformation, and surface wettability becomes weaker with increasing salt concentration induced by the competitive adsorption of counterions to the brushes between OH- and Cl-. The weakening of the pH response of the PMETAC brushes is more remarkable at the relatively high pH values. The pH response of the PDMAEMA brushes also exhibits a salt-concentration dependence. As the salt concentration increases, the weakening of the pH response of the PDMAEMA brushes is attributed to the decrease in osmotic pressure within the brushes at relatively low pH values. PMID- 28628337 TI - Buckling Under Pressure: Curvature-Based Lipid Segregation and Stability Modulation in Cardiolipin-Containing Bilayers. AB - Mitochondrial metabolic function is affected by the morphology and protein organization of the mitochondrial inner membrane. Cardiolipin (CL) is a unique tetra-acyl lipid that is involved in the maintenance of the highly curved shape of the mitochondrial inner membrane as well as spatial organization of the proteins necessary for respiration and oxidative phosphorylation. Cardiolipin has been suggested to self-organize into lipid domains due to its inverted conical molecular geometry, though the driving forces for this organization are not fully understood. In this work, we use coarse-grained molecular dynamics simulations to study the mechanical properties and lipid dynamics in heterogeneous bilayers both with and without CL, as a function of membrane curvature. We find that incorporation of CL increases bilayer deformability and that CL becomes highly enriched in regions of high negative curvature. We further show that another mitochondrial inverted conical lipid, phosphatidylethanolamine (PE), does not partition or increase the deformability of the membrane in a significant manner. Therefore, CL appears to possess some unique characteristics that cannot be inferred simply from molecular geometry considerations. PMID- 28628338 TI - Community-acquired Tsukamurella pneumonia in a young immunocompetent adult: a case misdiagnosed as pulmonary tuberculosis and literature review. AB - This report describes a case of Tsukamurella pneumonia in a 24-year-old immunocompetent woman. The patient was diagnosed as having pulmonary tuberculosis and was treated for nearly 9 months. The correct diagnosis was suspected only when the results of mycobacteria nucleic acid amplification tests on cultural colonies were negative. Tsukamurella was identified from the patient's sputum and bronchoalveolar lavage fluid by using 16S rRNA sequence analysis. Here, the clinical presentation, diagnosis, and treatment strategies of Tsukamurella pneumonia are discussed, along with a literature review. Tsukamurella pneumonia may be highly underdiagnosed owing to its similarity with pulmonary tuberculosis and the habitual thinking of doctors in countries with a high tuberculosis burden. Tsukamurella should be carefully considered in the etiology of tuberculosis-like lung diseases. PMID- 28628339 TI - Picornavectors. Viruses That Spread Bacteria. PMID- 28628340 TI - The Role of QuantiFERON(r)-TB Gold and Tuberculin Skin Test as Diagnostic Tests for Intraocular Tuberculosis in HIV-Positive and HIV-Negative Patients in South Africa. AB - PURPOSE: To compare QuantiFERON(r)-TB Gold and tuberculin skin testing as diagnostic tests for intraocular tuberculosis in HIV positive and negative patients. METHODS: A prospective study evaluating two different tests to help diagnose intraocular tuberculosis. RESULTS: Thirty-five of 106 patients (33.0%) were diagnosed with intraocular tuberculosis including 11 (31.4%) with HIV infection. Patients were 6.95 times more likely to have intraocular tuberculosis if TST alone was positive (p < 0.001) versus 2.19 times more likely if Quantiferon alone was positive (p = 0.04). Tuberculin skin testing showed superior specificity (60.3% vs 33.3%) (p = 0.001) but similar sensitivity (90.3% vs 85.7%), positive (54.9% vs 40.5%) and negative predictive values (92.1% vs 81.5%) compared to Quantiferon. Specificity did not increase significantly if both skin testing and Quantiferon were positive. CONCLUSIONS: In South Africa, with its high HIV burden and limited public health resources, Quantiferon testing should not replace tuberculin skin testing as it provides little additional diagnostic information. PMID- 28628341 TI - Observational Study of Neural Respiratory Drive During Sleep at High Altitude. AB - : Steier, Joerg, Nic Cade, Ben Walker, John Moxham, and Caroline Jolley. Observational study of neural respiratory drive during sleep at high altitude. High Alt Med Biol. 18:242-248, 2017. AIMS: Ventilation at altitude changes due to altered levels of pO2, pCO2 and the effect on blood pH. Nocturnal ventilation is particularly exposed to these changes. We hypothesized that an increasing neural respiratory drive (NRD) is associated with the severity of sleep-disordered breathing at altitude. METHODS: Mountaineers were studied at sea level (London, United Kingdom), and at altitude at the Aconcagua (Andes, Argentina). NRD was measured as electromyogram of the diaphragm (EMGdi) overnight by a transesophageal multi-electrode catheter; results were reported for sea level, 3,380 m, 4,370 m, and 5,570 m. RESULTS: Four healthy subjects (3 men, age 31(3)years, body mass index 23.6(0.9)kg/m2, neck circumference 37.0(2.7)cm, forced expiratory volume in 1 second 111.8(5.1)%predicted, and forced vital capacity 115.5(6.3)%predicted) were studied. No subject had significant sleep abnormalities at sea level. Time to ascent to 3,380 m was 1 day, to 4,370 m was 5 days, and the total nights at altitude were 21 days. The oxygen desaturation index (4% oxygen desaturation index [ODI] 0.8(0.4), 22.0 (7.2), 61.4 (26.9), 144.9/hour, respectively) and the EMGdi (5.2 (1.9), 12.8 (5.1), 14.1 (3.4), 18.5%, respectively) increased with the development of periodic breathing at altitude, whereas the average SpO2 declined (97.5 (1.3), 84.8 (0.5), 81.0 (4.1), 68.5%, respectively). The average EMGdi correlated well with the 4%ODI (r = 0.968, p = 0.032). CONCLUSION: NRD sleep increases at altitude in relation to the severity of periodic breathing. PMID- 28628342 TI - Effect of Green Tea Polyphenol Epigallocatechin-3-gallate on the Aggregation of alphaA(66-80) Peptide, a Major Fragment of alphaA-crystallin Involved in Cataract Development. AB - PURPOSE: Crystallin is a major protein present in eye lens. Peptide fragment alphaA(66-80) derived from alphaA-crystallin possesses high aggregation propensity and forms amyloid-like structures. alphaA(66-80) aggregates are known to interact with soluble crystallins and destabilize native structures that subsequently undergo aggregation. Crystallin aggregation in eye lens leads to reduction in lens opacity, the condition generally referred to as a cataract. Thus, alphaA(66-80) aggregation appears to be an important event during cataract development, and therefore, inhibition of alphaA(66-80) aggregation may be an attractive strategy to intervene in cataract development. MATERIALS AND METHODS: alphaA(66-80) peptide derived from alphaA-crystallin possesses high aggregation potential and has a crucial role in cataract development. In order to inhibit the aggregation of alphaA(66-80) peptide, epigallocatechin-3-gallate (EGCG), a major active constituent of green tea, was employed. The inhibitory effect was assessed by Congo Red (CR) spectral shift assay, Thioflavin-T binding assay, transmission electron microscopy and fluorescence microscopy. RESULTS: The inhibitory potential of EGCG toward alphaA-crystallin was clearly observed as in the presence of EGCG, the alphaA(66-80) aggregation was considerably inhibited and the pre-formed fibrillary aggregates of alphaA(66-80) were found to be disassembled. CONCLUSION: In the present study, we are able to successfully demonstrate that EGCG efficiently blocks the aggregation of alphaA(66-80) peptide in a concentration-dependent manner. Furthermore, it is also evident that EGCG is able to disaggregate pre-formed alphaA(66-80) aggregates. The study suggests that EGCG can be a potential molecule that can prevent the initiation of cataract as well as be helpful in the disease reversal. PMID- 28628344 TI - Rituximab Induction and Maintenance Treatment in Patients with Scleritis and Granulomatosis with Polyangiitis (Wegener's). AB - AIMS: To evaluate the efficacy and safety of rituximab (RTX) induction and maintenance treatment for patients with scleritis and granulomatosis with polyangiitis (GPA), Wegener's. METHODS: Nine patients (12 eyes) with scleritis with GPA who did not respond to corticosteroids and more than one immunosuppressive agent who received ongoing maintenance RTX treatment were identified. Demographics and outcome measures were recorded. RESULTS: Median follow-up time of 30 months (range, 15 to 87 months). All 12 eyes achieved remission during the RTX maintenance period with a median time in remission of 14 months (range, 5-76 months), and median interval between RTX initiation and inactive disease of 5 months (range, 2-8 months). Two eyes in two patients relapsed. One received steroid eye drops, and the other received a short-term increased dose of intravenous corticosteroids. CONCLUSIONS: RTX was effective as an induction and maintenance treatment in our small cohort of patients with GPA associated scleritis. PMID- 28628343 TI - Chronic Herpetic Retinitis: Clinical Features and Long-Term Outcomes. AB - INTRODUCTION: Chronic uveitis treated with immunosuppressive agents may have unfavorable outcomes due to delays in diagnosis. The aim of this study was to review initial data from clinical and ocular assessments and patient outcomes following specific treatments for atypical herpes virus ocular infections. METHODS: The records of four consecutive patients with recurrent uveitis for at least five years treated in our department between 2001 and 2016 were retrospectively reviewed. They had atrophic retinal lesions resulting in an unfavorable outcome with lesion progression and vision loss under immunosuppressive treatment. Varicella zoster virus (1 case) and herpes simplex virus type 2 (3 cases) were detected in ocular samples. RESULTS: Uveitis was granulomatous and bilateral (3 cases) or unilateral (1 case). Immunosuppressive treatments worsened the clinical situation whereas antiherpetic treatments improved the control of intraocular inflammation. CONCLUSION: This description should be added to the broad repertoire of clinical polymorphisms associated with herpes virus infections. Recognizing these cases should be useful due to their sensitivity to antiherpetic treatments. PMID- 28628345 TI - Personalizing antiplatelet therapies: What have we learned from recent trials? AB - Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is currently the standard of care for the prevention of ischemic events in patients with acute coronary syndrome or undergoing percutaneous coronary intervention. Several studies have shown that not all patients benefit from the treatment to the same degree and demonstrated that high on-treatment platelet reactivity may be associated with an increased risk of thrombotic events, while low on-treatment platelet reactivity may be linked to a higher risk of bleeding. Personalized antiplatelet treatment strategies based on platelet function monitoring and genetic testing constitute a promising tool for the prevention of both stent thrombosis and bleeding events, but conclusive evidence that such approaches can improve clinical outcomes is lacking. This review presents the most recent studies on tailored antiplatelet therapy in the management of coronary heart disease, with a focus on the prognosis value of platelet function testing. PMID- 28628346 TI - Physician Review Portals Do Not Favor Highly Cited US Ophthalmologists. AB - PURPOSE: Physician review portals are becoming increasingly popular among patients and often serve as a primary advisory tool during the search for a doctor. However, it has not been established whether these platforms favor leaders of the field; i.e., physicians with high academic rank. Here, we assessed online ratings of US ophthalmologists, selected for their outstanding scientific performance. METHODS: This cross-sectional, Internet-based study was performed in September 2016. First, we selected US ophthalmologists who published at least one manuscript or conference abstract that reached at least 100 citations from 2006 to 2016. Second, academic impact of preselected physicians, measured by overall number of citations or Hirsch index, was correlated with their ratings on two physician review portals: healthgrades.com and zocdoc.com. RESULTS: We selected 105 ophthalmologists who met established criteria. A total of 78 were rated on healthgrades.com, but only two were rated on zocdoc.com. The average rating on healthgrades.com was 4.2 +/-0.9, similar to the previously reported US mean for a physician (~4). The rating did not correlate with the number of citations or with Hirsh index. CONCLUSIONS: Highly cited ophthalmologist are not rated proportionately to their scientific achievements. Their reviews are positive, but do not stand out in comparison to other physicians. Additionally, we found that this group of ophthalmologists might be significantly underrepresented on particular review websites. PMID- 28628347 TI - Preventive treatment with atorvastatin ameliorates endothelial dysfunction of small pulmonary arteries in monocrotaline-induced pulmonary hypertensive rats. AB - This study examined the effects of preventive atorvastatin (Ator) treatment on vasodilatation of small pulmonary arteries (SPAs) in monocrotaline (MCT)-induced pulmonary hypertensive rats. SD rats were randomly assigned to: normal control (Ctr), pulmonary arterial hypertension (PAH), PAH treated with 5 mg/kg/d Ator (LAtor), or 10 mg/kg/d Ator (HAtor). PAH was induced by MCT injection (40 mg/kg, i.p.). Mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index (RVHI%), endothelium-dependent relaxations (EDdRs), and endothelium-independent relaxations (EDiRs) were determined. Four weeks after MCT injection, mPAP was higher in PAH group compared to that in Ctr group, and this effect was suppressed by Ator treatment (PAH: 32.19 +/- 0.91 mm Hg vs. LAtor: 19.13 +/- 1.01 mm Hg, HAtor: 17.55 +/- 0.20 mm Hg, p < 0.05). Similar trend of changes in RVHI% was found in the same way. EDdRs of SPA rings in PAH group were markedly decreased 2 and 4 weeks after MCT injection, while in Ator treated groups, the impairment can only be detected 4 weeks after MCT injection. There were no differences in EDiRs among all groups 1 week after MCT injection. However, 2 weeks and 4 weeks after MCT injection, EDiRs were significantly impaired, while in HAtor and LAtor groups, EDiR was only impaired 4 weeks but not 2 weeks after MCT injection. Preventive treatment with atorvastatin for 2 weeks ameliorated endothelium dependent and endothelium-independent vasodilative dysfunction in small pulmonary artery rings of MCT-induced PAH rats. It suggests that MCT-induced damage of endothelial function was progressing, and Ator was only beneficial in the early stage of MCT-induced PAH. PMID- 28628348 TI - Relation between peak knee flexion angle and knee ankle kinetics in single-leg jump landing from running: a pilot study on male handball players to prevent ACL injury. AB - OBJECTIVES: The relationship between knee kinematics and knee-ankle kinetics during the landing phase of single leg jumping has been widely studied to identify proper strategies for preventing non-contact ACL injury. However, there is a lack of study on knee-ankle kinetics at peak knee flexion angle during jumping from running. Hence, the purpose of this study is to establish the relationship between peak knee flexion angle, knee extension moment, ankle plantar flexion moment and ground reaction force in handball players in order to protect ACL from excessive stress during single leg jumping. In addition, the study also clarifies the role of calf muscles in relieving part of ACL stresses with different knee flexion angles during landing. METHODS: Fifteen active male elite handball players of Saudi Arabia have participated in this study (Age = 22.6 +/- 3.5years, Height = 182 +/- 3.7 cm, Weight = 87.5 +/- 10.2 kg). The players performed three successful landings of single-leg jump following running a fixed distance of about 450cm. The data were collected using a 3D motion capture and analysis system (VICON). RESULTS: Pearson product moment correlation coefficients showed that greater peak knee flexion angle is related significantly to both lesser knee extension moment (r = -.623, P = .013) and vertical component of ground reaction force (VGRF) (r = -.688, P = .005) in landing phase. Moreover, increasing the peak knee flexion angle in landing phase tends to increase the ankle plantar flexion moment significantly (r = .832, P = .000). CONCLUSION: With an increase of the peak knee flexion angle during single leg jump landing from running, there would be less knee extension moment, low impact force and more plantar flexion moment. As such, the clinical implication of this study is that there may be a possible protective mechanism by increasing the knee flexion angle during landing phase, which tends to protect the ACL from vigorous strain and injuries. PMID- 28628349 TI - Evaluation of a Client-Centered Linkage Intervention for Patients Newly Diagnosed with HIV at an Urban United States LGBT Center: The Linkage to Care Specialist Project. AB - Linkage to care (LTC) is a key element of the HIV care continuum, and a crucial bridge from testing and diagnosis to receipt of antiretroviral therapies and viral suppression. In 2012, the Los Angeles LGBT Center hired a full-time LTC specialist (LTC-S), who developed a unique client-centered approach to LTC. This single-arm demonstration project was designed to systematically evaluate the LTC S intervention. Individuals who were newly diagnosed with HIV between March 2014 and September 2015 were eligible for enrollment. The LTC-S draws heavily from principles of motivational interviewing and strengths-based case management, helping to normalize fears while guiding clients at a pace that reflects individual needs and resources. These tailored, targeted methods facilitate the rapid development of rapport, enabling the LTC-S to help clients address particular reactions and barriers to care more effectively. Of the 118 newly HIV diagnosed individuals who enrolled, 111 (94.1%) saw an HIV primary care provider within 3 months of diagnosis; the LTC-S spent an average of 2.1 h working with each participant. Enrolled clients were a racially diverse, urban group composed primarily of young men who have sex with men. The LTC-S intervention was effective in promoting LTC among this sample. Our results demonstrate that client centered, resiliency-based LTC services can be seamlessly integrated into an existing HIV testing program, thereby increasing the chances that newly diagnosed individuals will link to care. PMID- 28628350 TI - Custom Cast Ball Attachments Used on Outdated Implants to Restore a Maxillary Implant-Supported Overdenture. AB - The lack of compatible prosthetic components can be a complication during oral rehabilitation using outdated implants. The aim of the present clinical report was to describe an alternative technique for the fabrication of a maxillary implant-supported overdenture in a patient with 20-year-old dental implants using castable spherical patterns and ball attachments. The patient had been wearing a relined bar/clip overdenture in the mandible on 4 external-hexagon dental implants and a relined complete denture in the maxilla on 4 internal-hexagon implants due to abutment screw fracture inside of the implants, losing the attachment system. The remaining maxillary dental implants did not possess attachments compatible with current systems due to configuration changes by the manufacturer in the dental implant's platform and the components over time. Therefore, castable spherical patterns and cast ball attachments were used to fabricate a maxillary implant-supported overdenture. The mandible rehabilitation was performed using 4 osseointegrated dental implants with a fixed implant supported prosthesis. The use of cast ball attachments on the maxillary dental implants avoided invasive procedures on the remaining implants. Considering the lack of available compatible prosthetic components for the osseointegrated implants, this technique was considered a viable and satisfactory treatment option. PMID- 28628351 TI - Sleep in Adolescents and Young Adults in the Year After Cancer Treatment. AB - PURPOSE: Adolescents and young adults (AYA) with cancer are a vulnerable group facing more intense treatments, higher symptom burden, and poorer treatment outcomes relative to younger children. Sleep disruption is common during cancer treatment and sleep problems persist into adulthood for some survivors of AYA cancer. The developmental period of adolescence/emerging adulthood confers greater biological and behavioral risk for insufficient sleep relative to older or younger ages. Thus, understanding AYA sleep disturbances shortly after completing treatment can inform interventions to manage cancer-related symptoms and improve quality of life. METHODS: Sixty-one AYA (ages 12-25) within 1 year of finishing cancer treatment completed the Pittsburgh Sleep Quality Index (PSQI) and the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form. Treatment variables were extracted from electronic medical records. RESULTS: Forty-seven percent of participants were classified as "poor sleepers," 41% reported prolonged sleep onset latency (>30 minutes), 31% reported sleep efficiency suggestive of insomnia, and 33% slept <8 hours nightly. Age moderated the relationship between time off treatment and PSQI total score: for younger AYA the relationship was positive and for older AYA the relationship was negative. Better sleep and higher quality of life were strongly related (r = -0.57, p < 0.001). CONCLUSIONS: For almost half of AYA cancer survivors studied, sleep is disrupted as indicated by long sleep-onset latencies, sleep efficiency suggestive of insomnia, and inadequate total sleep time. Screening for sleep disturbances after AYA complete cancer therapy may reduce the impact of sleep on quality of life and identify those at risk for insomnia. PMID- 28628353 TI - Effect of Early vs Late Start of Oral Intake on Anastomotic Leakage Following Elective Lower Intestinal Surgery: A Systematic Review. AB - BACKGROUND: Experimental and clinical studies have demonstrated a beneficial effect of early enteral nutrition (EN) on anastomotic leakage following colorectal surgery. Early oral intake is a common form of early EN with various clinical benefits, but the effect on anastomotic leakage is unclear. This systematic review investigates the effect of early vs late start of oral intake on anastomotic leakage following lower intestinal surgery. METHODS: A systematic literature search was performed using the PubMed, Embase, Medline, and Cochrane databases. Randomized controlled trials were included that compared early (within 24 hours) vs late start of oral intake following elective surgery of the small bowel, colon, or rectum. Meta-analysis was performed for anastomotic leakage, overall complications, length of stay, and mortality. Sensitivity analysis was performed in which studies of inferior methodological quality were excluded. RESULTS: Nine studies including 879 patients met eligibility criteria. Early start of oral intake significantly reduced overall complications (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.46-0.93; P = .02), length of stay (mean difference, -0.89; 95% CI, -1.22 to -0.57; P < .001), and anastomotic leakage (OR, 0.40; 95% CI, 0.17-0.95; P = .04) compared with late start of oral intake. However, in the sensitivity analysis only the overall reduction of length of stay remained significant. CONCLUSION: The effect of early oral intake on anastomotic leakage is unclear as existing studies are heterogeneous and at risk of bias. High-quality studies are needed to study the potential benefit of EN on anastomotic healing. PMID- 28628352 TI - Characteristics of Hospitalized Cancer Patients Referred for Inpatient Palliative Care Consultation. AB - BACKGROUND: Palliative care is associated with improved patient and family outcomes and lower cost of care, but studies estimate that <50% of hospitalized adults in the United States who are appropriate for palliative care receive it. Few studies have addressed demographic and clinical factors associated with receipt of palliative care. OBJECTIVE: Our aim was to identify characteristics of hospitalized advanced cancer patients that are associated with referral to an interdisciplinary hospital-based palliative care team. METHODS: The data are from a prospective observational study of hospitalized advanced cancer patients in five hospitals. We used multivariable logistic regression to estimate the relationship between patient characteristics and palliative care referral. RESULTS: The sample includes 3096 patients; 81% received usual care and 19% were referred to palliative care. Advanced cancer patients were twice as likely to receive palliative care referral if, at admission, they needed assistance with transfer from bed (p = 0.002) and about 1.5 times as likely if they were taking medication for pain (p = 0.002), nausea (p = 0.04), or constipation (p = 0.04). Patients with more comorbidities (p = 0.001) and higher symptom burden (p = 0.001) were more likely to be referred. CONCLUSION: Advanced cancer patients were more likely to be referred to the palliative care consultation team if they had high symptom burden at hospital admission. Overall a minority of advanced cancer patients were referred. Standardized screening for palliative care may be needed to ensure that advanced cancer patients receive the highest quality of evidence based care. PMID- 28628355 TI - Adjacent Dental Implants Classification Based on Restorative Design. AB - There is controversy in the literature regarding the indicated retentive mechanism for implant-supported crowns. When adjacent implants are restored, the restoration can be screw retained, cement retained, or a combination of cement and screw retained. Adjacent implant-supported crowns can be restored as individual implant supported crowns or can be splinted. A classification system is proposed when adjacent implants are restored. The classification system describes currently available options to restore adjacent implants. Six types of prosthetic design options are proposed as Class I through Class VI. In Class I design, individual cement-retained crowns are made. In Class II, individual screw retained crowns are fabricated. Class III involves fabrication of individual screw-retrievable/cement-retained crowns. Class IV prosthetic design involves splinted cement-retained implant crowns. Class V prosthetic design involves splinted screw-retained crowns, and Class VI involves splinted screw retrievable/cement-retained implant supported crowns. PMID- 28628354 TI - Soft Tissue Enhancement and Implant Placement Following Partial Mandibulectomy Due to Squamous Cell Carcinoma. AB - Many dental procedures allow for implant placement in partially or totally edentulous patients. Despite the availability of various implant and abutment types on the market, it often becomes quite challenging to achieve the biological and esthetic goals in a patient who has ridge deficiencies. Problems arise from the lack of adequate bone quality and quantity. 1 , 2 Soft tissue form and maintenance is also a consideration to evaluate. 3 Primary reconstructive techniques following segmental mandibulectomy is evolving and improves quality of life. A seldom encountered complication is the discovery and treatment of a malignant process (for example, squamous cell carcinoma). Oral squamous cell carcinoma (OSCC) is one of the most aggressive malignancies worldwide and accounts for more than 90% of all oral cancers. 4 It is ranked as the sixth leading cause of cancer mortality worldwide. The most common sites of OSCC are the lateral ventral surface of the tongue, the floor of the mouth and buccal mucosa. For most oral cavity cancers, surgery is the initial treatment of choice (often involving the full or partial removal of bony jaw structure). 5 Radiation or chemoradiation is added postoperatively if disease is more advanced or has high-risk features. Successful cancer therapy can affect the quantity and quality of soft tissue in areas where implants are planned, thus affecting the initial placement and the long-term success of the implants. Complications can be numerous; especially difficult is implant treatment in the mandibular anterior area where inadequate alveolar height results in the lingual floor and the vestibule becoming contiguous. 6 Further complicating treatment is the presence of scar tissue (often found following cancer surgery and radiotherapy). The present case is a report of the combination of a soft tissue enhancement and implant placement following partial mandibulectomy resulting from the treatment of oral squamous cell carcinoma. A video abstract is available for viewing at https://youtu.be/dZ9t3j4ufOc?list=PLvRxNhB9EJqbqjcYMbwKbwi8Xpbb0YuHI . PMID- 28628356 TI - Clips vs Resilient Liners Used With Bilateral Posterior Prefabricated Bars for Retaining Four Implant-Supported Mandibular Overdentures. AB - The objective of this research was to clinically compare peri-implant tissue health of bar-clips vs silicone-resilient liners used with bilateral posterior bars for retaining 4 implant-supported mandibular overdentures. Thirty completely edentulous male patients (mean age, 65 years) were randomly assigned into 2 equal groups. Each patient received 4 implants in the canine and first molar regions of the mandible using a flapless surgical technique. Mandibular overdentures were immediately connected to the implants with bilateral prefabricated instant adjusting bars. According to the method of retention to the bar, 1 group was retained with clips (GI), whereas the other group was retained with a silicone resilient soft liner (GII). Peri-implant tissue health was evaluated clinically in terms of plaque scores (MPI), bleeding scores (MBI), probing depth (PD), and implant stability (IS). MPI, MBI, and PD were measured at mesial, distal, buccal, and lingual surfaces of each implant. Evaluations were performed 2 weeks (T0), 6 months (T6), and 12 months (T12) after overdenture insertion. Implants of GI with clips demonstrated significant increase in plaque, bleeding, and PD scores compared with those of GII with silicone-resilient liner at all observation times. Implants in GI demonstrated a significant decrease in implant stability compared with those of GII at T6 and T12 anteriorly and at T12 posteriorly. Resilient liners are considered better than bar-clips when used with bilateral posterior bars for retaining implant-supported mandibular overdentures in terms of peri-implant soft tissue health. Bilateral posterior ready-made bars cannot be proposed as a promising design for supporting implant-assisted mandibular overdentures. PMID- 28628357 TI - Continuous Periosteal Strapping Sutures for Stabilization of Osseous Grafts With Resorbable Membranes for Buccal Ridge Augmentation: A Technique Report. AB - Alveolar bone loss occurs after extraction with loss of a premolar or anterior tooth; the residual supporting alveolar bone loss averages 1.53 mm of crestal bone height and 3.87 mm of buccolingual width, with most of the bone loss occurring at the facial plate. Socket preservation does not completely preserve the original ridge contours but can be an effective means of reducing bone loss following extraction. Attempts to rebuild the alveolar ridge structure after tooth loss often employ the concept of guided bone regeneration, a technique sensitive procedure that routinely involves placement of particulate bone with or without fixation screws and either a resorbable or a nonresorbable membrane. We present a novel technique for stabilizing a resorbable membrane and underlying particulate graft allowing for predictable bone grafting across multiple edentulous sites. PMID- 28628358 TI - H2B ubiquitination: Conserved molecular mechanism, diverse physiologic functions of the E3 ligase during meiosis. AB - RNF20/Bre1 mediated H2B ubiquitination (H2Bub) has various physiologic functions. Recently, we found that H2Bub participates in meiotic recombination by promoting chromatin relaxation during meiosis. We then analyzed the phylogenetic relationships among the E3 ligase for H2Bub, its E2 Rad6 and their partner WW domain-containing adaptor with a coiled-coil (WAC) or Lge1, and found that the molecular mechanism underlying H2Bub is evolutionarily conserved from yeast to mammals. However, RNF20 has diverse physiologic functions in different organisms, which might be caused by the evolutionary divergency of their domain/motif architectures. In the current extra view, we not only elucidate the evolutionarily conserved molecular mechanism underlying H2Bub, but also discuss the diverse physiologic functions of RNF20 during meiosis. PMID- 28628360 TI - Genetic Risk Factors for Folate-Responsive Neural Tube Defects. AB - Neural tube defects (NTDs) are the most severe congenital malformations of the central nervous system. The etiology is complex, with both genetic and environmental factors having important contributions. Researchers have known for the past two decades that maternal periconceptional use of the B vitamin folic acid can prevent many NTDs. Though this finding is arguably one of the most important recent discoveries in birth defect research, the mechanism by which folic acid exerts this benefit remains unknown. Research to date has focused on the hypothesis that an underlying genetic susceptibility interacts with folate sensitive metabolic processes at the time of neural tube closure. Little progress has been made searching for risk-causative variants in candidate genes; therefore, more complex genetic and epigenetic methodologies are now being considered. This article reviews the research to date that has been targeted on this important gene-nutrient locus. PMID- 28628361 TI - Lipocalin 2: An Emerging Player in Iron Homeostasis and Inflammation. AB - Lipocalin 2 (Lcn2), an innate immune protein, has emerged as a critical iron regulatory protein during physiological and inflammatory conditions. As a bacteriostatic factor, Lcn2 obstructs the siderophore iron-acquiring strategy of bacteria and thus inhibits bacterial growth. As part of host nutritional immunity, Lcn2 facilitates systemic, cellular, and mucosal hypoferremia during inflammation, in addition to stabilizing the siderophore-bound labile iron pool. In this review, we summarize recent advances in understanding the interaction between Lcn2 and iron, and its effects in various inflammatory diseases. Lcn2 exerts mostly a protective role in infectious and inflammatory bowel diseases, whereas both beneficial and detrimental functions have been documented in neurodegenerative diseases, metabolic syndrome, renal disorders, skin disorders, and cancer. Further animal and clinical studies are necessary to unveil the multifaceted roles of Lcn2 in iron dysregulation during inflammation and to explore its therapeutic potential for treating inflammatory diseases. PMID- 28628362 TI - Weight Loss Surgery in Adolescents. AB - Childhood obesity continues to be a national health problem, with growing numbers of adolescents (8.7%) affected by severe obesity and its associated cardiometabolic risks. Since current nonsurgical methods for treating these adolescents have only modest effects, weight loss surgery (WLS) is an alternative treatment. An overview of the literature was conducted describing the selection, management, and outcomes of adolescents undergoing WLS. Adolescent guidelines require physical and emotional maturity as well as serious comorbidities associated with body mass index cutoffs higher than those used for adults. Medium term to long-term outcomes are similar to those of adults undergoing WLS. Such outcomes depend on management by a multidisciplinary team with expertise in caring for adolescents who are still developing psychosocially and who are relatively more dependent on family supports for continued care. Future exploration is needed to elucidate optimal surgical indications for adolescents, improved adherence to postoperative care, and the impact of WLS on life expectancy. Resulting evidence can better inform the direction for healthcare delivery and policy directed toward this at-risk population. PMID- 28628359 TI - Genetic Basis for Sex Differences in Obesity and Lipid Metabolism. AB - Men and women exhibit significant differences in obesity, cardiovascular disease, and diabetes. To provide better diagnosis and treatment for both sexes, it is important to identify factors that underlie the observed sex differences. Traditionally, sex differences have been attributed to the differential effects of male and female gonadal secretions (commonly referred to as sex hormones), which substantially influence many aspects of metabolism and related diseases. Less appreciated as a contributor to sex differences are the fundamental genetic differences between males and females, which are ultimately determined by the presence of an XX or XY sex chromosome complement. Here, we review the mechanisms by which gonadal hormones and sex chromosome complement each contribute to lipid metabolism and associated diseases, and the current approaches that are used to study them. We focus particularly on genetic approaches including genome-wide association studies in humans and mice, -omics and systems genetics approaches, and unique experimental mouse models that allow distinction between gonadal and sex chromosome effects. PMID- 28628365 TI - To The Last Drop. PMID- 28628364 TI - Time to Stop Saying Geriatric Assessment Is Too Time Consuming. PMID- 28628363 TI - Efficacy of a Weight Loss Intervention for African American Breast Cancer Survivors. AB - Purpose African American women with breast cancer have higher cancer-specific and overall mortality rates. Obesity is common among African American women and contributes to breast cancer progression and numerous chronic conditions. Weight loss interventions among breast cancer survivors positively affect weight, behavior, biomarkers, and psychosocial outcomes, yet few target African Americans. This article examines the effects of Moving Forward, a weight loss intervention for African American breast cancer survivors (AABCS) on weight, body composition, and behavior. Patients and Methods Early-stage (I-III) AABCS were randomly assigned to a 6-month interventionist-guided (n = 125) or self-guided (n = 121) weight loss program supporting behavioral changes to promote a 5% weight loss. Anthropometric, body composition, and behavioral data were collected at baseline, postintervention (6 months), and follow-up (12 months). Descriptive statistics and mixed models analyses assessed differences between groups over time. Results Mean (+/- standard deviation) age, and body mass index were 57.5 (+/- 10.1) years and 36.1 (+/- 6.2) kg/m2, respectively, and 82% had stage I or II breast cancer. Both groups lost weight. Mean and percentage of weight loss were greater in the guided versus self-guided group (at 6 months: 3.5 kg v 1.3kg; P < .001; 3.6% v 1.4%; P < .001, respectively; at 12 months: 2.7 kg v 1.6 kg; P < .05; 2.6% v 1.6%; P < .05, respectively); 44% in the guided group and 19% in the self-guided group met the 5% goal. Body composition and behavioral changes were also greater in the interventionist-guided group at both time points. Conclusion The study supports the efficacy of a community-based interventionist-guided weight loss program targeting AABCS. Although mean weight loss did not reach the targeted 5%, the mean loss of > 3% at 6 months is associated with improved health outcomes. Affordable, accessible health promotion programs represent a critical resource for AABCS. PMID- 28628366 TI - Culex Flavivirus During West Nile Virus Epidemic and Interepidemic Years in Chicago, United States. AB - Culex flavivirus (CxFV) is an insect-specific flavivirus infecting Culex mosquitoes, which are important vectors of West Nile virus (WNV). CxFV and WNV cocirculate in nature and coinfect Culex mosquitoes, including in a WNV "hotspot" in suburban Chicago. We previously identified a positive association between CxFV and WNV in mosquito pools collected from suburban Chicago in 2006. To further investigate this phenomenon, we compared the spatial and temporal distribution of CxFV during an interepidemic year (2011) and an epidemic year (2012) for WNV. Both viruses were more prevalent in mosquito pools in 2012 compared to 2011. During both years, the CxFV infection status of mosquito pools was associated with environmental factors such as habitat type and precipitation frequency rather than coinfection with WNV. These results support the idea that WNV and CxFV are ecologically associated, perhaps because both viruses respond to similar environmental drivers of mosquito populations. PMID- 28628367 TI - Learning to spell: Phonology and beyond. AB - An understanding of the nature of writing systems and of the typical course of spelling development is an essential foundation for understanding the problems of children who have serious difficulties in learning to spell. The present article seeks to provide that foundation. It argues that the dual-route models of spelling that underlie much existing research and practice are based on overly simple assumptions about how writing systems work and about how spelling skills develop. Many writing systems include not only context-free links from phonemes to letters but also context-sensitive phonological patterns, morphological influences, and graphotactic patterns. According to an alternative framework, IMP (integration of multiple patterns), spellers acquire multiple sources of information through use of their statistical-learning skills and through direct instruction. Children learn the spelling of a word most easily when different patterns converge on the spelling, and they have difficulty when patterns conflict. Implications of these ideas for assessment and instruction are considered. PMID- 28628368 TI - Dietitians' Perspectives on Teaching Nutrition to Medical Students. AB - OBJECTIVES: The provision of nutrition care by health professionals can facilitate improved patient nutrition behaviors. Some education institutions include nutrition in their medical curriculum; however, doctors and medical students continue to lack competence in providing nutrition care. Dietitians are increasingly teaching nutrition to medical students, yet evidence on the topic remains anecdotal. It is important to understand the experiences of these dietitians to support improvements in undergraduate medical nutrition education. The aim of this study was to explore dietitians' perspectives of teaching nutrition to medical students. METHODS: A qualitative study was conducted in collaboration with the Need for Nutrition Education/Innovation Programme (NNEdPro). Twenty-four dietitians who had provided nutrition education to medical students participated in individual semistructured interviews. Participants were from Australia (n = 5), New Zealand (n = 1), the United States (n = 6), Canada (n = 5), the United Kingdom (n = 5), Germany (n = 1), and Finland (n = 1). Data analysis was conducted using a constant comparative approach to thematic analysis. RESULTS: The dietitians expressed confidence in their ability to teach medical students and believed that they were the most appropriate professionals to administer the education. However, they were not confident that medical students graduate with sufficient nutrition competence and attributed this to poor curriculum planning for nutrition. Dietitians had access to useful resources and tools to support education, with opportunity to contribute further to integration of nutrition throughout medical curricula. CONCLUSION: This study suggests that dietitians are likely appropriate nutrition teachers in medical education. However, optimizing dietitians' role requires their further involvement in curriculum planning and development. Including dietitians as members of medical faculty would facilitate their input on nutrition throughout the curriculum, which could enhance the nutrition education of medical students. PMID- 28628369 TI - Premier League academy soccer players' experiences of competing in a tournament bio-banded for biological maturation. AB - Individual differences in the growth and maturation have been shown to impact player performance and development in youth soccer. This study investigated Premier League academy players' experiences of participating in a tournament bio banded for biological maturation. Players (N = 66) from four professional soccer clubs aged 11 and 14 years and between 85-90% of adult stature participated in a tournament. Players competed in three 11 vs 11 games on a full size pitch with 25 min halves. Sixteen players participated in four 15-min focus groups and were asked to describe their experiences of participating in the bio-banded tournament in comparison to age group competition. All players described their experience as positive and recommended the Premier League integrate bio-banding into the existing games programme. In comparison to age-group competitions, early maturing players described the bio-banded games more physically challenging, and found that they had to adapt their style of play placing a greater emphasis on technique and tactics. Late maturing players considered the games to be less physically challenging, yet appreciated the having more opportunity to use, develop and demonstrate their technical, physical, and psychological competencies. Bio-banding strategies appear to contribute positively towards the holistic development of young soccer players. PMID- 28628370 TI - Multiple-joint exercises using elastic resistance bands vs. conventional resistance-training equipment: A cross-over study. AB - Previous studies indicate that elastic resistance bands (ERB) can be a viable option to conventional resistance-training equipment (CRE) during single-joint resistance exercises, but their efficacy has not been established for several commonly used multiple-joint resistance exercises. Thus, we compared muscular activation levels in four popular multiple-joint exercises performed with ERB (TheraBand(r)) vs. CRE (Olympic barbell or cable pulley machines). In a cross over design, men and women (n = 29) performed squats, stiff-legged deadlifts, unilateral rows and lateral pulldown using both modalities. Multilevel mixed effects linear regression analyses of main and interaction effects, and subsequent post hoc analyses were used to assess differences between the two resistance-training modalities. CRE induced higher levels of muscle activation in the prime movers during all exercises (p < .001 for all comparisons), compared to muscle activation levels induced by ERB. The magnitude of the differences was marginal in lateral pulldown and unilateral rows and for the erector spinae during stiff-legged deadlifts. In squats the quadriceps femoris activations were substantially lower for ERB. The differences between ERB and CRE were mostly observed during the parts of the contractions where the bands were relatively slack, whilst the differences were largely eliminated when the bands became elongated in the end ranges of the movements. We conclude that ERB can be a feasible training modality for lateral pulldowns, unilateral rows and to some extent stiff-legged deadlifts, but not for the squat exercise. PMID- 28628371 TI - Sexual Desire Among an Online Sample of Men Sexually Attracted to Children. AB - Sexual attraction to children occurs in roughly 3 to 9 percent of the population. However, most knowledge about such desires comes from forensic samples, and most studies fail to assess preferred sexual activity and sexual partner. A new multimodal assessment of sexual desire was used to investigate interest in consensual and nonconsensual sex with adults and children in an online sample of men sexually attracted to children (n = 101). Desires were compared across history of sex offending behavior and preferred gender of child victim. Men who have and have not acted on their sexual attractions to children reported similar levels of sexual desire. Men primarily attracted to girls reported greater desire for sex with adults than did men primarily attracted to boys. Results highlight the heterogeneity of men sexually attracted to children as well as possible distinctions across gender of children to whom they are primarily attracted. PMID- 28628372 TI - Suicide intervention training for college staff: Program evaluation and intervention skill measurement. AB - OBJECTIVE: Suicide remains a pressing issue for college communities. Consequently, gatekeeper trainings are often provided for staff. This study examines the effect of one such program, Applied Suicide Intervention Skills Training (ASIST). PARTICIPANTS: 51 college employees received ASIST in August of 2014 and were compared to 30 wait-list control participants. METHODS: Repeated Measures ANOVA were used to analyze pre- and post-training: (a) skills at responding to students-at-risk; (b) attitudes toward suicide; (c) knowledge about suicide; and (d) comfort/competence/confidence at helping a student-at-risk. RESULTS: Significant positive training effects were observed for ASIST on self report measures and also for objectively assessed skill at responding, after adjusting for a potential scoring limitation of the Suicide Intervention Response Inventory, Revised (SIRI-2). CONCLUSIONS: ASIST improved the self-perception of college staff at working with students-at-risk of suicide and also their skills at performing an intervention. Further, analysis of SIRI-2 data provides support for a potential instrument revision. PMID- 28628373 TI - Association between Urinary Phytoestrogens and C-reactive Protein in the Continuous National Health and Nutrition Examination Survey. AB - OBJECTIVE: A reduced risk of some cancers and cardiovascular disease associated with phytoestrogen intake may be mediated through its effect on serum C-reactive protein (CRP; an inflammation biomarker). Therefore, this study examined the associations between urinary phytoestrogens and serum CRP. METHODS: Urinary phytoestrogen and serum CRP data obtained from 6009 participants aged >= 40 years in the continuous National Health and Nutrition Examination Survey during 1999 2010 were analyzed. RESULTS: After adjustment for confounders, urinary concentrations of total and all individual phytoestrogens were inversely associated with serum concentrations of CRP (all p < 0.004). The largest reductions in serum CRP (mg/L) per interquartile range increase in urinary phytoestrogens (ng/mL) were observed for total phytoestrogens (beta = -0.18; 95% confidence interval [CI], -0.22, -0.15), total lignan (beta = -0.15; 95% CI, 0.18, -0.12), and enterolactone (beta = -0.15; 95% CI, -0.19, -0.12). A decreased risk of having high CRP concentrations (>=3.0 mg/L) for quartile 4 vs quartile 1 was also found for total phytoestrogens (OR = 0.63; 95% CI, 0.53, 0.73), total lignan (OR = 0.64; 95% CI, 0.54, 0.75), and enterolactone (OR = 0.59; 95% CI, 0.51, 0.69). CONCLUSION: Urinary total and individual phytoestrogens were significantly inversely associated with serum CRP in a nationally representative sample of the U.S. POPULATION: PMID- 28628375 TI - Integrating Microbiome and Metabolome Data to Understand Infectious Airway Disease. PMID- 28628374 TI - Effects of a Multispecies Probiotic Supplement on Bone Health in Osteopenic Postmenopausal Women: A Randomized, Double-blind, Controlled Trial. AB - OBJECTIVE: The development of alternative approaches to prevent and/or treat osteoporosis, as a chronic progressive bone disease, is being considered currently. Among dietary supplements, probiotics may have favorable effects on bone metabolism. Therefore, the aim of this study was to evaluate the effects of a multispecies probiotic supplementation on bone biomarkers and bone density in osteopenic postmenopausal women. METHODS: This randomized double-blind placebo controlled clinical trial was performed on 50 patients with osteopenia aged 50-72 years. Participants were randomly assigned to take either a multispecies probiotic supplement (GeriLact; n = 25) or placebo (n = 25) for 6 months. GeriLact contains 7 probiotic bacteria species. Participants received 500 mg Ca plus 200 IU vitamin D daily. Bone mineral density (BMD) of lumbar spine and total hip and blood biomarkers including bone-specific alkaline phosphatase (BALP), osteocalcin (OC), collagen type 1 cross-linked C-telopeptide (CTX), deoxypyridinoline (DPD), parathyroid hormone (PTH), 25-OH vitamin D, and serum pro-inflammatory cytokines (tumor necrosis factor [TNF]-alpha and interleukin [IL]-1beta) were assessed at baseline and at the end of the study. RESULTS: The multispecies probiotic significantly decreased BALP (p = 0.03) and CTX (p = 0.04) levels in comparison with the control group but had no effect on BMD of the spine and total hip. Moreover, there was a statistically significant decrease in serum PTH (p = 0.01) and TNF-alpha (p = 0.02) in the intervention group compared to the placebo group. CONCLUSIONS: These results may suggest the favorable effects of the multispecies probiotic supplementation for 6 months on bone health in postmenopausal women due to slowing down the rate of bone turnover. PMID- 28628376 TI - Becoming a mother: perspectives and experiences of young women in a South African Township. AB - There has been growing interest in the high levels of pregnancy among young women in South Africa. This study aimed to explore a range of perspectives and experiences of early motherhood among young women in a township in KwaZulu-Natal, South Africa. This was done using in-depth interviews from a small sample of young mothers aged 18-24 years. All the young mothers reported that they had had their first child while still at school. None of them had intended or planned to have a child, and were therefore not ready for motherhood. Limited information on pregnancy prevention methods plays a key role in influencing early childbearing. Young mothers in the study wanted to assume financial responsibility for their children but they were finding it difficult to do so. Many faced numerous obstacles as they were no longer in a relationship with the father of their child and depended on their own parents for support. Participants described how the difficulties they faced in their daily lives and their new roles as mothers impacted negatively on their education and career aspirations. The study recommends greater involvement of schools and community in addressing the challenges of early childbearing. PMID- 28628377 TI - Environmental Effects of Intensive Livestock Farming. PMID- 28628378 TI - Knowledge and Behavioral Impact of Adult Participation in Child Sexual Abuse Prevention: Evaluation of the Protecting God's Children Program. AB - This article presents findings from an evaluation of a popular adult training program (Protecting God's Children) used in Catholic institutions, including schools, churches, and social service agencies. The study explores knowledge and behavior change based on pretest/posttest questionnaires administered to over 500 adults and follow-up questionnaires sent six months after the training. The participants in the training were compared to a control group of adults who did not participate in the program. The results indicate that participants arrive at the training with fairly high rates of preexisting knowledge but that the program increases knowledge across demographic groups. Follow-up surveys suggest that the new knowledge is retained over six months. The study indicates that the program is associated with an increase in participants talking to their own children about child sexual abuse. Participants also report sharing information with other adults and monitoring behavior around children more closely. PMID- 28628379 TI - Visuomotor behaviors and performance in a dual-task paradigm with and without vibrotactile feedback when using a myoelectric controlled hand. AB - Prosthesis users allocate visual attention to their prosthetic hand while performing activities of daily living (ADLs), due to absence of sensory feedback. Dual-task assignments present competition for visual attention and may affect the performance of ADLs. Vibrotactile feedback (VTF) is a frequently-used method to provide prosthesis users with tactile feedback. However, the effect of adding VTF on visual attention and performance in a motor dual-task paradigm has not been investigated. Our aim was to compare visual attention and performance during ADLs in a motor dual-task paradigm when using binary VTF and without using VTF. Forty three able-bodied subjects (age 26 +/- 6.6 years) had a myoelectric-controlled hand attached to their right hand. The dual task comprised of a computer game played with the left hand, while manipulating objects with the artificial hand. This was performed with and without VTF in a counter-balanced order of two conditions. An eye-tracker monitored visual attention, while time to complete each task and the time the virtual car went off-road were recorded. No significant differences were found in visual attention or in performance time between the two conditions. Further examination of adding VTF to prosthesis users is recommended, with disrupted visual feedback and basic grasping tasks. PMID- 28628380 TI - Low-frequency noise effects on the rat parotid gland: A transmission electron microscopy study. AB - INTRODUCTION: Low-frequency noise (LFN) is a ubiquitous physical stressor known to cause degenerative cellular changes and organ alterations with functional repercussions both in humans and animals. MATERIALS AND METHODS: After acceptance of the study protocol by a local ethics committee, 20 Wistar rats were randomly divided into two equal groups. One group was kept in silence and the other continuously exposed to LFN during 13 weeks. The rats had unlimited access to water and were fed standard rat chow. After exposure, the animals were sacrificed and the parotid glands were excised and prepared for transmission electron microscopy. RESULTS: The acinar cells showed marked ultrastructural alterations, such as intracellular vacuolization, loss of cell polarity, increased heterochromatin, cytoplasmic inclusions, and oncocytic transformation. CONCLUSIONS: LFN induces ultrastructural changes in the rat parotid gland that correlate with previously described functional changes. PMID- 28628381 TI - Monoclonal immunoglobulin-associated proliferative glomerulonephritis characterized by organized deposits of striated ultra-substructures: A case report. AB - We herein report the case of a 64-year-old male who presented with progressive glomerulonephritis notable for organized and striated ultra-substructures. The patient was diagnosed with hypertension and proteinuria 3 years prior to admission and subsequently developed nephrotic syndrome and impairment of renal function. Laboratory tests did not reveal any evidence of infections or autoimmune diseases. Monoclonal gammopathy was not detected in serum or urine, although a small population of abnormal plasma cell clones was detected by flow cytometry. A renal biopsy showed mesangial and endocapillary proliferative glomerulonephritis with lobular accentuation, accompanied with focal and segmental double-contour formation. Additionally, moderate tubulointerstitial scarring and arteriosclerosis were noted. Immunofluorescence staining revealed positive staining for IgG, IgM, C3, C1q, and fibrinogen. IgG subclass and light chain staining showed restricted positivity for IgG1kappa. Electron microscopy demonstrated massive amounts of subendothelial deposits with a fibrillary and branching profile. At higher magnification, a periodic striated pattern was observed within the microfilament-like structures. Immunohistochemical staining was negative for myoglobin, laminin, and collagens (type III and IV). Steroid and antihypertensive therapy did not show improvement in renal function. The second biopsy performed 2 years later revealed a similar lobular proliferative glomerulonephritis pattern with more extensive tubulointerstitial damage, indicating poor response to immunosuppressive therapy. The patient progressed to end-stage renal disease and required hemodialysis. We discuss the possible origins of the deposits with unusual substructures observed in this case. PMID- 28628382 TI - UnPAKing RUNX3 functions-Both sides of the coin. AB - Post translational modifications of RUNX3 have been shown to play an important role in directing RUNX3 functions. In this review we highlight the phosphorylation dependent functions of RUNX3 as regulated by PAK1 and its implications on tumorigenesis. PMID- 28628383 TI - Cardiovascular Response of an Acute Exergame Session in Prepubertal Obese Children. AB - PURPOSE: We aimed to analyze the acute autonomic response of obese and eutrophic prepubertal boys to an exergame (EXG) session. MATERIALS AND METHOD: Nine eutrophic (8.89 +/- 2.71 years of age and 16.42% +/- 6.30% body fat) and nine obese boys (8.70 +/- 1.16 years of age and 40.76% +/- 4.2% body fat) participated. Nutritional state was determined using World Health Organization guidelines. Variables were collected at rest, immediately post (IP), and 60 minutes after a 20 minutes EXG session. Autonomic nervous system (ANS) activity was assessed using heart rate variability in time and frequency domains, and data were analyzed using Shapiro-Wilk and ANOVA tests with Tukey post hoc. RESULTS: The obese group demonstrated an increased sympathetic activity at rest when compared with the eutrophic group (P < 0.05). The obese group also demonstrated an increased parasympathetic activity 60 minutes after the EXG session when compared with the eutrophic group (P < 0.05). CONCLUSION: We concluded that an acute session of EXG promoted ANS super compensation. We encourage research on chronic ANS response to EXG. PMID- 28628384 TI - "Pokemon Go!" May Promote Walking, Discourage Sedentary Behavior in College Students. AB - OBJECTIVE: To assess self-reported walking and sedentary behavior in young adults before and after downloading "Pokemon Go!". MATERIALS AND METHODS: In September 2016, a sample of 358 (19.8 +/- 2.1 years old, n = 187 females) college students who had downloaded "Pokemon Go!" on their cellular telephones (i.e., cell phones) were surveyed for weekly walking and sedentary behavior via the International Physical Activity Questionnaire. A single interview was administered to participants who estimated their walking and sedentary behavior at three time points: the week immediately preceding their download of "Pokemon Go!" (Baseline), the first week after downloading the game (Time 1), and the week the survey was completed (Time 2). Differences in self-reported physical activity and sedentary behavior across the three time points and across the two genders were compared via analyses of variance. RESULTS: There was a significant main effect of time (F >= 49.3, P <= 0.001) for walking and sedentary behavior. Participants reported greater (t >= 9.5, P < 0.001) daily walking during Time 1 (218.6 +/- 156.3 minutes) and Time 2 (182.7 +/- 172.1 minutes) versus the baseline (108.5 +/ 110.8 minutes). Walking behavior was also significantly greater (t = 4.1, P < 0.001) at Time 1 versus Time 2. Participants reported greater (t >= 6.5, P < 0.001) daily sedentary behavior during baseline (346.6 +/- 201.3 minutes) versus both Time 1 (261.7 +/- 172.4 minutes) and Time 2 (284.3 +/- 175.4 minutes). Sedentary behavior was also significantly greater (t = 2.6, P = 0.03) at Time 2 versus Time 1. There were no effects of gender (F <= 1.8, P >= 0.17). CONCLUSION: Playing "Pokemon Go!" was associated with increased self-reported walking and decreased sedentary behavior. Such games hold promise as technology that may promote physical activity and discourage sedentary behavior. PMID- 28628385 TI - Serious Games for Psychotherapy: A Systematic Review. AB - INTRODUCTION: In the evolving digital age, media applications are increasingly playing a greater role in the field of psychotherapy. While the Internet is already in the phase of being established when it comes to the care of mental disorders, experimentation is going on with other modern media such as serious games. A serious game is a game in which education and behavior change is the goal, alongside with entertainment. OBJECTIVE: The objective of the present article was to provide a first empirical overview of serious games applied to psychotherapy and psychosomatic rehabilitation. METHOD: Therefore, a systematic literature search, including the terms "serious game" or "computer game" and "psychotherapy" or "rehabilitation" or "intervention" or "mental disorders" in the databases Medline and PsycINFO, was performed. Subsequently, an Internet search was conducted to identify studies not published in journals. Publications not providing empirical data about effectiveness were excluded. RESULTS: On the basis of this systematic literature review, the results of N = 15 studies met inclusion criteria. They utilized primarily cognitive behavioral techniques and can be useful for treating a range of mental disorders. Serious games are effective both as a stand-alone intervention or part of psychotherapy and appeal to patients independent of age and sex. CONCLUSION: Included serious games proved to be an effective therapeutic component. Nonetheless, findings are not conclusive and more research is needed to further investigate the effectiveness of serious games for psychotherapeutic purposes. PMID- 28628386 TI - Comparison of Path Length and Ranges of Movement of the Center of Pressure and Reaction Time and Between Paired-Play and Solo-Play of a Virtual Reality Game. AB - AIMS: To test whether paired-play will induce longer path length and ranges of movement of the center of pressure (COP), which reflects on balance performance and stability, compared to solo-play and to test the difference in the path length and ranges of movement of the COP while playing the virtual reality (VR) game with the dominant hand compared to playing it with the nondominant hand. METHODS: In this cross-sectional study 20 children (age 6.1 +/- 0.7 years old) played an arm movement controlled VR game alone and with a peer while each of them stood on a pressure measuring pad to track the path length and ranges of movement of the COP. RESULTS: The total COP path was significantly higher during the paired-play (median 295.8 cm) compared to the COP path during the solo-play (median 189.2 cm). No significant differences were found in the reaction time and the mediolateral and anterior-posterior COP ranges between solo-play and paired play. No significant differences were found between the parameters extracted during paired-play with the dominant or nondominant hand. DISCUSSION: Our findings imply that the paired-play is advantageous compared to solo-play since it induces a greater movement for the child, during which, higher COP velocities are reached that may contribute to improving the balance control of the child. Apart from the positive social benefits of paired-play, this positive effect on the COP path length is a noteworthy added value in the clinical setting when treating children with balance disorder. PMID- 28628387 TI - A Questionnaire-Based Study on the Perceptions of Canadian Seniors About Cognitive, Social, and Psychological Benefits of Digital Games. AB - OBJECTIVE: This study explored the perceptions of seniors who play digital games on the potential benefits of these games and on the factors associated with these perceptions. MATERIALS AND METHODS: We developed and administered a questionnaire to a sample of 590 Canadian seniors in British Columbia and Quebec that addressed demographics, digital game practices, and perceived benefits. RESULTS: Results of administering the questionnaire showed that cognitive benefits were reported more frequently than social or psychological benefits. First language and gender were associated with the benefits reported, with fewer Francophones and women reporting benefits. The most important factor found was whether or not they played online, as playing online was associated with greater perceptions of social, as well as cognitive, benefits. CONCLUSION: Social and cognitive benefits are reported by seniors from playing digital games and should be investigated through future experimental and quasi-experimental research. PMID- 28628388 TI - Coordination of AMPA receptor trafficking by Rab GTPases. AB - Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPA-type glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD). We highlight the importance of the tight spatio temporal control of Rab activity and suggest that this is critical for proper neuronal functions. We also discuss how abnormal AMPA receptor trafficking and malfunctioning of Rabs can lead to neurologic disorders or memory problems. PMID- 28628389 TI - "An Ounce of Prevention . . . ": Will This Be the Future for Idiopathic Pulmonary Fibrosis? PMID- 28628390 TI - Influence of Screw Surface Treatment on Retention of Implant-Supported Fixed Partial Dentures. AB - The aim of this study was to assess the effect of a diamond-like carbon (DLC) coating on the removal torque of prefabricated implant screws after cyclic loading. Four groups with two crowns supported by two implants (n = 5) were obtained according to splinted and nonsplinted prosthesis, using titanium or DLC screws (splinted crowns with titanium screw [STi], splinted crowns with DLC screw [SC], nonsplinted crowns and titanium screw [NSTi], and nonsplinted crowns and DLC screw [NSC]). The prosthetic screws were tightened at 32 Ncm and retightened, and the specimens were submitted to 106 mechanical cycles (4 Hz/98 N). After cyclic loading, loosening torque was evaluated, and the final measurements were performed. Data were analyzed by two-way analysis of variance and Tukey's test (alpha = .005). There was statistically significance in the interaction of screw * splinting (P = .003). For the group that used titanium screws, NSTi showed smaller removal torque compared with STi. It was concluded that the use of the DLC coating screws in nonsplinted prosthesis maintain the torque after cyclic loading. PMID- 28628391 TI - Interest and Attitudes of Patients With Advanced Cancer With Regard to Secondary Germline Findings From Tumor Genomic Profiling. AB - PURPOSE: Tumor genomic profiling (TGP) can reveal secondary findings about inherited disease risks in a patient with cancer. Little is known about how patients with advanced cancer, currently the primary users of TGP, perceive the benefits and harms of secondary germline findings. METHODS: We conducted semistructured interviews with 40 patients with advanced breast, bladder, colorectal, or lung cancer who had TGP. Qualitative interview data were evaluated by using a thematic content analysis approach. RESULTS: Most participants expressed interest in the prospect of learning their secondary germline findings (57%), although a minority was equivocal (29%) or disinterested (14%). Reasons for these preferences varied but were influenced by participants' perceptions of diverse benefits and harms of this information, which they regarded as relevant to themselves; their families; and other patients with cancer, medical science, and society. These attitudes were uniquely shaped by participants' personal disease experiences and health status. CONCLUSION: Many patients with advanced cancer are interested in learning secondary germline findings and hold optimistic and perhaps unrealistic beliefs about the potential health benefits. Patients also have important concerns about clinical and emotional implications of this information. These perceptions are necessary to address to ensure that patients make informed decisions about learning secondary germline findings. PMID- 28628392 TI - Potential Drug-Drug and Herb-Drug Interactions in Patients With Cancer: A Prospective Study of Medication Surveillance. AB - PURPOSE: Patients with cancer frequently use herbal supplements and concomitant medications along with antineoplastic agents. These patients are at high risk of herb-drug interactions (HDIs) and drug-drug interactions (DDIs). We aimed to determine clinically relevant DDIs and HDIs leading to pharmaceutical intervention. METHODS: Patients starting a new anticancer therapy were asked to complete a questionnaire to identify concomitant use of any over-the-counter drug or herbal supplement. Potential DDIs and HDIs were identified using two different databases. If a potentially clinically relevant DDI was recognized by the clinical pharmacist, a notification was sent to the prescribing oncologist, who decided whether to carry out a suggested intervention. Regression analyses were performed to identify variables associated with clinically relevant DDIs. RESULTS: A total of 149 patients were included in this study, with 36 potentially clinically relevant DDIs identified in 26 patients (17.4%; 95% CI, 11.3% to 23.5%), all of them leading to therapy modifications. In total, four patients (2.7%; 95% CI, 0.1% to 5.3%) had experienced clinical consequences from DDIs at the time of pharmacist notification. Additionally, 84 patients (56.4%; 95% CI, 48.4% to 64.4%) reported using concurrent herbal supplements, and 122 possible HDIs were detected. Concomitant use of two or more drugs was independently associated with high risk of a clinically significant DDI (odds ratio, 2.53; 95% CI, 1.08 to 5.91; P = .03). CONCLUSION: Potentially clinically relevant DDIs and possible HDIs were frequently detected in this prospective study. A multidisciplinary approach is required to identify and avoid potentially harmful combinations with anticancer therapy. PMID- 28628393 TI - Early National Dissemination of Abiraterone and Enzalutamide for Advanced Prostate Cancer in Medicare Part D. AB - INTRODUCTION: Abiraterone and enzalutamide were approved by the Food and Drug Administration in 2011 and 2012 to treat men with metastatic castration-resistant prostate cancer (mCRPC). Most men with mCRPC are > 65 years of age and thus eligible for Medicare Part D. We conducted a study to better understand the early dissemination of these drugs across the United States using national Medicare Part D data. METHODS: We evaluated the number of prescriptions for abiraterone and enzalutamide by provider specialty and hospital referral region (HRR) using Medicare Part D and Dartmouth Atlas data. We categorized HRRs by abiraterone and enzalutamide prescriptions, adjusted for prostate cancer incidence, and examined factors associated with regional variation using multilevel regression models. RESULTS: Among providers who wrote the majority of prescriptions for abiraterone or enzalutamide in 2013 (n = 2,121), 87.5% were medical oncologists, 3.3% were urologists, and 9.2% were other provider specialties. Among prescribers, approximately 30% were responsible for three quarters of the claims for abiraterone and 20% were responsible for more than half the claims for enzalutamide. Some HRRs demonstrated low-prescribing rates despite average medical oncology and urology physician workforce density. Our multilevel model demonstrated that regional factors potentially influenced variation in care. CONCLUSION: The majority of prescriptions written for abiraterone and enzalutamide through Medicare Part D in 2013 were written by a minority of providers, with marked regional variation across the United States. Better understanding of the early national dissemination of these effective but expensive drugs can help inform strategies to optimize introduction of new, evidence-based mCRPC treatments. PMID- 28628394 TI - Nutritional Routine of Tae Kwon Do Athletes Prior to Competition: What Is the Impact of Weight Control Practices? AB - OBJECTIVE: The purpose of the present study was to investigate and assess the common dietary and weight management strategies of Tae Kwon Do (TKD) athletes prior to national competitions, as well as to examine the relationships between these strategies and body weight reduction and sensation of physical condition. METHODS: Sixty (n = 60) TKD athletes, 23 women (19.4 +/- 2.9 years) and 37 men (20.4 +/- 3.6 years), with at least 12.1 +/- 3.1 years of experience, participated in the present study. The athletes recorded their dietary intake and physical activity for 3 training days and on a competition day. Bioelectrical impedance was used for body composition estimation. RESULTS: Male athletes consumed 1918 +/- 685 kcal/24 hours and 1974 +/- 669 kcal/24 hours on training and competition days, respectively, and women 1814 +/- 446 kcal/24 hours and 1700 +/- 439 kcal/24 hours. TKD athletes had significant negative energy balance (48.6% +/- 17.8% to 60.3% +/- 26.9%; p < 0.05), with the majority of macro- and micronutritional elements being lower than the recommended values, with significant differences between them, as well as within groups, between weekdays and weekend days (p < 0.05). Females lost most of their weight 2 weeks before the games (3.50 +/- 1.00 kg), and males lost most of their weight 3 weeks before (3.16 +/- 2.48 kg). The majority of TKD athletes were guided by their coaches for weight management strategies. No significant correlations were found between any body composition variable, weight loss, and any nutritional intake at any time point (p > 0.05). CONCLUSIONS: These data suggest that the methods of TKD athletes for rapid weight loss are guided by unspecialized professionals, leading to significant malnutrition, because certain deficiencies in both macro- and micronutrient content are present, with no guaranteed specific reduction of their body mass. PMID- 28628395 TI - Evaluation of a companion robot based on field tests with single older adults in their homes. AB - The growing number of older adults places insurmountable load on family members and professional caregivers. Assistive technology with the aid of robots can present a possible solution. The goal of this article was to test a companion robot supporting older adults in their home environments. Eight senior volunteers were involved in the field test. They all lived alone and were self-supporting. The robot was capable of providing cognitive assistance to manage the user's daily routine. Each participant used the robot for 94.9 +/- 19.6 days. The primary communication modality was voice communication in their natural language, while the touch screen display was also available for interaction with the robot. The assistance given in daily living was evaluated by subjective (the user's opinion) and objective (logged data) criteria. The most useful and the least reliable robot functions according to the users were the navigation and the verbal communication. Entertainment, locomotion, and weather forecast were the most frequently used functions, while the shopping list was the least popular. The companion robot used in the test was accepted enthusiastically by the senior subjects. Specific robot functions (mainly navigation in the apartment and the speech recognition) require improvement to better accommodate real circumstances. PMID- 28628396 TI - Differential in Maximal Aerobic Capacity by Sex in Collegiate Endurance Athletes Consuming a Marginally Low Carbohydrate Diet. AB - PURPOSE: Although current sports nutrition recommendations advocate for a high carbohydrate (CHO) intake among endurance athletes, recent research has suggested that training with low CHO availability may augment adaptations to aerobic training. The purpose of this study was to observe the dietary habits of collegiate distance runners and to investigate the effects of habitual CHO intake on aerobic performance [VO2max(post)] during a competitive season. METHODS: During an 8-week trial period, 12 (N = 12) collegiate track athletes recorded their self-selected dietary intake via 24-hour recall. Analysis of CHO intake was conducted by a registered dietitian. Pre [VO2max (pre)] and post [VO2max (post)] season aerobic capacity assessments were performed using a one-way analysis of covariance (ANCOVA) with 2 covariates controlling for VO2max (pre) and CHO intake compared to the variance in VO2max (pre) and VO2max (post) by sex. RESULTS: The average CHO was 4.11 +/- 1.03 g/kg body mass (BM), with only one female athlete meeting dietary recommendations, consuming >= 6 g/kg BM. Male distance runners on average had a lower CHO than females. After adjusting for VO2max (pre) and CHO, there were statistically significant differences between VO2max (post) group means by sex with a difference of 12.62 ml/kg/min (95% confidence interval [CI], 2.12-23.12, p = 0.02), with CHO accounting for 18% of the variance in VO2max (post). CONCLUSION: Collegiate distance runners exhibited marked improvements in maximal aerobic capacity during the in-season while consuming a marginally low CHO diet, with a predominant effect in males. Therefore, CHO intakes below current recommendations for endurance athletes might not be detrimental to aerobic training adaptations. PMID- 28628397 TI - Culturally-Informed Interventions for Substance Abuse Among Indigenous Youth in the United States: A Review. AB - PURPOSE: Given the disproportionately high levels of alcohol and other drug abuse among Indigenous youth in the United States, the purpose of this systematic review was to explicate the current state of empirically-based and culturally informed substance abuse prevention and intervention programs for Indigenous youth (ages 9-18). METHOD: The 14 articles that met inclusion criteria for this review were analyzed both in terms of the cultural intervention itself (primary population, intervention, core tenants, focus of intervention, intervention goals, location, intervention location, and program length) and their evaluation approach. RESULTS: Results indicate variable integration of cultural components with the majority of interventions taking place in schools and treatment facilities, targeting primarily individuals. DISCUSSION: There is a current gap in research on culturally-informed substance abuse interventions for Indigenous youth, which this review begins to address. Promising areas of future research and interventions include bringing communities and families into treatment and prevention. PMID- 28628398 TI - Skill level changes the coordination and variability of standing posture and movement in a pistol-aiming task. AB - The study investigated the coordination and variability of posture and pistol motion for skilled pistol shooters and novices in a pistol-aiming task. The participants stood on a force platform and held a pistol with the preferred arm to aim for accuracy to a target on 30 s trials. The results revealed that the amount of the centre of pressure (COP) and pistol motion was lower for the expert than novice group. The time-varying structure of COP as indexed by multiscale entropy (MSE) and detrended fluctuation analysis (DFA) was also lower for the expert than the novice group. The relative phase between the COP in the anterior posterior (AP) and pistol in the AP and between the COP in the medial-lateral (ML) and pistol in AP was close to inphase for the both groups. However, for the novice group the coordination patterns of posture and pistol motion were more variable with the pistol motion leading the posture motion while it was lagging in the skilled group. The findings show different qualitative and quantitative dynamics in pistol-aiming as a function of skill level with postural control foundational to supporting the reduced dispersion and complexity of the skilled arm-pistol motion. PMID- 28628399 TI - Polymorphisms in Lep and Lepr Genes in Infants: Correlation with Serum Leptin Values in the First 6 Months of Life. AB - OBJECTIVE: Because several studies indicate that polymorphisms in leptin (Lep) and leptin receptor (Lepr) genes play a central role in determining obesity, we analyzed 2 single nucleotide polymorphisms (SNPs) in the Lep gene (Lep G2548A and A19G) and one in the Lepr gene (Lepr A668G) to verify the effect of the 3 SNPs on leptin concentrations in infancy. METHODS: We enrolled 80 healthy Caucasian infants under 6 months of age, who were genotyped for the 3 SNPs with amplification refractory mutation system-mismatch amplification mutation assay (ARMS-MAMA) real-time polymerase chain reaction (PCR). Serum leptin values were measured with a radioimmunoassay method. Statistical significance was set at p < 0.05. RESULTS: There were no significant differences between individually analyzed leptin polymorphisms Lep G2548A and A19G and serum leptin levels (p > 0.05). Because we found that Lep G2548A and A19G are in linkage disequilibrium on chromosome 7, we performed the haplotype analysis for Lep G2548A and Lep A19G. We obtained higher serum leptin levels in infants with the GG/GG haplotype (p < 0.05). Regarding receptor, we found higher leptin levels in GG-genotype infants for Lepr A668G (p < 0.001). Considering the 3 SNPs together, we found higher serum leptin values in GG/GG-GG infants (LepG2548A/A19G-Lepr A668G; p < 0.001). CONCLUSION: We obtained higher serum leptin levels in infants with the GG genotype for Lepr A668G, with haplotype GG/GG for Lep G2548A/A19G, and with GG/GG GG (LepG2548A/A19G-Lepr A668G); thus, it seems that the genotype GG could be a protector against obesity development in infancy and adulthood. Moreover, these data confirm that not variations in the Lep gene as well as in the Lepr gene could play a role in weight gain. Further studies are needed to evaluate the role of genetics and the environment in a predisposition toward obesity later in life. PMID- 28628400 TI - West Nile Virus: Seroprevalence in Animals in Palestine and Israel. AB - West Nile virus (WNV) epidemiological situation in Israel and Palestine, due to their unique location, draws attention following to the global spread of West Nile fever (WNF). Although much information is available from Israel on clinical cases and prevalence of WNV, clinical cases are rarely reported in Palestine, and prevalence is not known. The objectives of this study were to determine WNV seroprevalence in various domestic animals in Palestine and to reevaluate current seroprevalence, force of infection, and risk factors for WNV exposure in horses in Israel. Sera samples were collected from 717 animals from Palestine and Israel (460 horses, 124 donkeys, 3 mules, 50 goats, 45 sheep, and 35 camels). Two hundred and ten horses were sampled twice. The level of WNV antibodies was determined using commercial Enzyme-linked Immunosorbent Assay (ELISA) Kit. Seroprevalence in equids was 73%. Seroprevalence in Israel (84.6%) was significantly higher than in Palestine (48.6%). Seroprevalence in horses (82.6%) was significantly higher than in donkeys and mules (39.3%). Multivariable statistical analysis showed that geographical area, landscape features (altitude), environmental factors (land surface temperature during the day [LSTD]), species, and age significantly influenced WNV seroprevalence. Fourteen of 95 (14.7%) sheep and goats and 14/35 camels (40%) sampled in Palestine were seropositive for WNV. Of the horses that were sampled twice, 82.8% were seropositive for WNV at the first sampling, and all remained seropositive. Three of the seronegative horses, all from Palestine, converted to positive when resampled (8.5%). The results indicate that domestic animals in Palestine were infected with WNV in the past, and the seroconversion indicates that WNV was circulating in Palestine in the summer of 2014. Control measures to prevent human infection should be implemented in Palestine. Anti WNV antibodies in domestic animals suggest that those species can be used as sentinels for WNV activity in areas where most horses are either seropositive or vaccinated. PMID- 28628401 TI - Dietary Red and Processed Meat Intake and Markers of Adiposity and Inflammation: The Multiethnic Cohort Study. AB - OBJECTIVE: The potential influence of dietary factors on inflammation is important for cancer prevention. Utilizing data from control participants (312 men, 911 women) in 2 nested case-control studies of cancer within the Multiethnic Cohort, we examined the associations of red and processed meat intake with serum levels of leptin, adiponectin, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 and the mediator effect of body mass index (BMI) on the above associations (if present). METHODS: Multivariable linear models were applied to assess the association between red and processed meat intake at cohort entry and serum biomarker levels measured 9.1 years later after adjusting for covariates and to determine the mediator effect of BMI. RESULTS: Overall red and processed meat intake was positively associated with serum leptin levels in men (beta = 0.180, p = 0.0004) and women (beta = 0.167, p < 0.0001). In women, higher red and processed meat consumption was significantly associated with higher CRP (beta = 0.069, p = 0.03) and lower adiponectin levels (beta = 0.082, p = 0.005). In mediation analyses with red and processed meat intake and BMI as predictors, the associations of red and processed meat with biomarkers decreased substantially (as indicated by percentage change in effect: leptin in men, 13.4%; leptin in women, 13.7%; adiponectin in women, -4.7%; CRP in women, 7.4%) and were no longer significant (p > 0.05), whereas BMI remained significantly associated with serum leptin (men: beta = 3.209, p < 0.0001; women: beta = 2.891, p < 0.0001), adiponectin (women: beta = -1.085, p < 0.0001), and CRP (women: beta = 1.581, p < 0.0001). CONCLUSION: The current data suggest that the amount of excess body weight or the degree of adiposity may mediate the relations between dietary red and processed meat intake and serum biomarkers associated with obesity and inflammation. PMID- 28628402 TI - Calcium Bioavailability from Mineral Waters with Different Mineralization in Comparison to Milk and a Supplement. AB - OBJECTIVE: The aim of the present study was to compare the bioavailability of calcium from 3 mineral waters with different concentrations of minerals with that of milk and a calcium supplement. METHODS: A single-center, randomized controlled trial with a crossover design with 21 healthy men and women was conducted at the Institute of Food Science and Human Nutrition, Leibniz University Hannover. The participants consumed the 5 test products providing 300 mg of calcium each on 5 examination days with 1-week wash-out phases in between. Primary outcome variables were the area under the curve of serum calcium levels for 10-hour (AUC0 10h) and 24-hour urinary calcium excretion. RESULTS: In all groups, no significant differences in the AUC0-10h of serum calcium levels as well as in the 24-hour urinary calcium excretion were observed. Likewise, mean changes in serum phosphate and urinary phosphate, as well as serum parathormone, showed no differences between the groups. CONCLUSION: Given an equivalent bioavailability of calcium in all test products, neither a high concentration of SO42- or of HCO3 influenced the bioavailability of calcium. Accordingly, the use of mineral water with high concentrations of calcium constitutes a calorie-free calcium source that can improve calcium supply. PMID- 28628403 TI - Old and New MR Tools to Measure Hepatic Steatosis: Is Their Diagnostic Accuracy the Same? PMID- 28628404 TI - Case 247. PMID- 28628405 TI - Further Implications of Off-Label Use of Acetazolamide in the Management of Moyamoya Disease in Japan. PMID- 28628406 TI - Is the Genetic Paradigm of Cancer Complete? PMID- 28628409 TI - Impact of Measurement Time on Clinical Workflow in Different Manual Methods of Region of Interest Positioning for ADC Quantification. PMID- 28628411 TI - Sports and the Growing Musculoskeletal System: Sports Imaging Series. AB - Increased youth participation in sports has resulted in increased injury tolls due to shifts toward participation in competitive sports at earlier ages, increased training intensity and competition schedules, as well as specialization into one sport. The physiology of the growing musculoskeletal system makes the growing athlete particularly vulnerable to specific types of injuries. Radiologists must understand the differences between pediatric and adult athletes to recognize the particular injuries to which these young athletes are prone. Imaging and pertinent clinical details of major representative acute and overuse injuries characteristic to pediatric athletes will be discussed. (c) RSNA, 2017. PMID- 28628412 TI - Stratification, Imaging, and Management of Acute Massive and Submassive Pulmonary Embolism. AB - While pulmonary embolism (PE) causes approximately 100 000-180 000 deaths per year in the United States, mortality is restricted to patients who have massive or submassive PEs. This state of the art review familiarizes the reader with these categories of PE. The review discusses the following topics: pathophysiology, clinical presentation, rationale for stratification, imaging, massive PE management and outcomes, submassive PE management and outcomes, and future directions. It summarizes the most up-to-date literature on imaging, systemic thrombolysis, surgical embolectomy, and catheter-directed therapy for submassive and massive PE and gives representative examples that reflect modern practice. (c) RSNA, 2017. PMID- 28628413 TI - Sir Peter Mansfield, PhD. PMID- 28628414 TI - Paraspinal Fat Pad Changes as a Valuable Indicator of Posterior Ligamentous Complex Injury in Upper Cervical Spine Trauma. PMID- 28628415 TI - Signal Intensity Increase in the Central Nervous System after Previous Gadoxetic Acid-enhanced MR Imaging. PMID- 28628416 TI - Case 243: Extramedullary Hematopoiesis in an Adrenal Myelolipoma. AB - History A 30-year-old man presented to the emergency department with epigastric pain. He was vomiting and in distress, and he had a history of thalassemia. Physical examination findings were unremarkable. Pertinent blood results were a hemoglobin level of 10.5 g/dL (6.52 mmol/L) (normal range, 13.5-18.0 g/dL [8.38 11.17 mmol/L]) and a bilirubin level of 62 umol/L (normal range, 3-17 umol/L). The remaining hematologic and biochemical results were normal. Aortic dissection was suspected clinically, so the patient was referred for imaging. Unenhanced and arterial phase computed tomographic (CT) images were acquired initially. Ultrasonography (US) (images not shown) and magnetic resonance (MR) imaging were performed subsequently. Because of the imaging findings, the patient was referred for surgery. PMID- 28628417 TI - Motherhood challenges and well-being along with the studentship role among Iranian women: A qualitative study. AB - This study purposed to explore and describe the experiences of Iranian female students with the role of motherhood. This 2015 qualitative study used purposeful sampling to select 20 student mothers aged 24-50 who were studying at a state or non-state university in an urban area in northwest Iran. Data was collected through individual semi-structured interviews and analysed using a qualitative content analysis approach. Three main themes were developed during data analysis: "simultaneous management", "facilities", and "barriers". The management of maternal and family affairs by female students in universities where motherhood is not supported is a challenge. The significance of mother-student roles must be emphasized and support and education provided for women to gain skills useful in playing these roles. Policy makers should devise strategies for bringing change to the traditional perspective that motherhood and educational responsibilities cannot be met at the same time by one person. PMID- 28628418 TI - Erratum. PMID- 28628419 TI - Association of Competition Volume, Club Sports, and Sport Specialization With Sex and Lower Extremity Injury History in High School Athletes. AB - BACKGROUND: High school athletes are increasingly encouraged to participate in 1 sport year-round to increase their sport skills. However, no study has examined the association of competition volume, club sport participation, and sport specialization with sex and lower extremity injury (LEI) in a large sample of high school athletes. HYPOTHESIS: Increased competition volume, participating on a club team outside of school sports, and high levels of specialization will all be associated with a history of LEI. Girls will be more likely to engage in higher competition volume, participate on a club team, and be classified as highly specialized. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: High school athletes completed a questionnaire prior to the start of their competitive season regarding their sport participation and previous injury history. Multivariable logistic regression analyses were used to investigate associations of competition volume, club sport participation, and sport specialization with history of LEI, adjusting for sex. RESULTS: A cohort of 1544 high school athletes (780 girls; grades 9-12) from 29 high schools completed the questionnaire. Girls were more likely to participate at high competition volume (23.2% vs 11.0%, chi2 = 84.7, P < 0.001), participate on a club team (61.2% vs 37.2%, chi2 = 88.3, P < 0.001), and be highly specialized (16.4% vs 10.4%, chi2 = 19.7, P < 0.001). Athletes with high competition volume, who participated in a club sport, or who were highly specialized had greater odds of reporting a previous LEI than those with low competition volume (odds ratio [OR], 2.08; 95% CI, 1.55-2.80; P < 0.001), no club sport participation (OR, 1.50; 95% CI, 1.20 1.88; P < 0.001), or low specialization (OR, 2.58; 95% CI, 1.88-3.54; P < 0.001), even after adjusting for sex. CONCLUSION: Participating in high sport volume, on a club team, or being highly specialized was associated with history of LEI. Girls were more likely to participate at high volumes, be active on club teams, or be highly specialized, potentially placing them at increased risk of injury. CLINICAL RELEVANCE: Youth athletes, parents, and clinicians should be aware of the potential risks of intense, year-round participation in organized sports. PMID- 28628420 TI - Value of Multiparametric US in the Assessment of Intratesticular Lesions. AB - Purpose To evaluate the diagnostic accuracy of multiparametric ultrasonography (US) consisting of gray-scale US, color Doppler US, strain elastography, and contrast agent-enhanced US in the assessment of intratesticular lesions. Materials and Methods Institutional review board approval was obtained for this retrospective study. From January 2012 to December 2015, 55 focal testicular lesions that were indeterminate on gray-scale US scans were further characterized with color Doppler US, strain elastography, and contrast-enhanced US. Strain elastography was performed to assess tissue elasticity, and hard lesions were defined as malignant. Color Doppler US and contrast-enhanced US were performed to determine the absence or presence of vascularization. Avascular lesions were defined as benign. Histopathologic results or follow-up examinations served as reference standards. Correct classification rate, sensitivity, specificity, and likelihood ratio were calculated. Results Of 55 testicular lesions, 43 (78.2%) were benign and 12 (21.8%) were malignant. Single-modality sensitivities and specificities were 66.7% and 88.4% for color Doppler US, 100% and 76.7% for contrast-enhanced US, and 100% and 72.1% for strain elastography, respectively. Among 12 malignant lesions, color Doppler US failed to demonstrate vascularization in four (33.3%) lesions, which were positive for cancer at contrast-enhanced US. By combining strain elastography and contrast-enhanced US, a sensitivity of 100% and specificity of 93.0% were achieved in differentiating benign and malignant focal testicular lesions. Positive likelihood ratio was 5.7 for color Doppler US, 4.3 for contrast-enhanced US, 3.6 for strain elastography, 14.3 for strain elastography combined with color Doppler US, and 14.3 for strain elastography combined with contrast-enhanced US. Conclusion Multiparametric US allows for a reliable differentiation of benign and malignant intratesticular lesions and can potentially be useful in deciding whether orchiectomy can be replaced with follow-up or less invasive organ-sparing strategies. (c) RSNA, 2017. PMID- 28628421 TI - High-Grade Serous Ovarian Cancer: Associations between BRCA Mutation Status, CT Imaging Phenotypes, and Clinical Outcomes. AB - Purpose To investigate the associations between BRCA mutation status and computed tomography (CT) phenotypes of high-grade serous ovarian cancer (HGSOC) and to evaluate CT indicators of cytoreductive outcome and survival in patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. Materials and Methods This HIPAA-compliant, institutional review board-approved retrospective study included 108 patients (33 with BRCA mutant and 75 with BRCA wild-type HGSOC) who underwent CT before primary debulking. Two radiologists independently reviewed the CT findings for various qualitative CT features. Associations between CT features, BRCA mutation status, cytoreductive outcome, and progression-free survival (PFS) were evaluated by using logistic regression and Cox proportional hazards regression, respectively. Results Peritoneal disease (PD) pattern, presence of PD in gastrohepatic ligament, mesenteric involvement, and supradiaphragmatic lymphadenopathy at CT were associated with BRCA mutation status (multiple regression: P < .001 for each CT feature). While clinical and CT features were not associated with cytoreductive outcome for patients with BRCA-mutant HGSOC, presence of PD in lesser sac (odds ratio [OR] = 2.40) and left upper quadrant (OR = 1.19), mesenteric involvement (OR = 7.10), and lymphadenopathy in supradiaphragmatic (OR = 2.83) and suprarenal para-aortic (OR = 4.79) regions were associated with higher odds of incomplete cytoreduction in BRCA wild-type HGSOC (multiple regression: P < .001 each CT feature). Mesenteric involvement at CT was associated with significantly shorter PFS for both patients with BRCA mutant HGSOC (multiple regression: hazard ratio [HR] = 26.7 P < .001) and those with BRCA wild-type HGSOC (univariate analysis: reader 1, HR = 2.42, P < .001; reader 2, HR = 2.61; P < .001). Conclusion Qualitative CT features differed between patients with BRCA-mutant HGSOC and patients with BRCA wild-type HGSOC. CT indicators of cytoreductive outcome varied according to BRCA mutation status. Mesenteric involvement at CT was an indicator of significantly shorter PFS for both patients with BRCA-mutant HGSOC and those with BRCA wild-type HGSOC. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28628422 TI - T1rho-weighted Dynamic Glucose-enhanced MR Imaging in the Human Brain. AB - Purpose To evaluate the ability to detect intracerebral regions of increased glucose concentration at T1rho-weighted dynamic glucose-enhanced (DGE) magnetic resonance (MR) imaging at 7.0 T. Materials and Methods This prospective study was approved by the institutional review board. Nine patients with newly diagnosed glioblastoma and four healthy volunteers were included in this study from October 2015 to July 2016. Adiabatically prepared chemical exchange-sensitive spin-lock imaging was performed with a 7.0-T whole-body unit with a temporal resolution of approximately 7 seconds, yielding the time-resolved DGE contrast. T1rho-weighted DGE MR imaging was performed with injection of 100 mL of 20% d-glucose via the cubital vein. Glucose enhancement, given by the relative signal intensity change at T1rho-weighted MR imaging (DGErho), was quantitatively investigated in brain gray matter versus white matter of healthy volunteers and in tumor tissue versus normal-appearing white matter of patients with glioblastoma. The median signal intensities of the assessed brain regions were compared by using the Wilcoxon rank-sum test. Results In healthy volunteers, the median signal intensity in basal ganglia gray matter (DGErho = 4.59%) was significantly increased compared with that in white matter tissue (DGErho = 0.65%) (P = .028). In patients, the median signal intensity in the glucose-enhanced tumor region as displayed on T1rho-weighted DGE images (DGErho = 2.02%) was significantly higher than that in contralateral normal-appearing white matter (DGErho = 0.08%) (P < .0001). Conclusion T1rho-weighted DGE MR imaging in healthy volunteers and patients with newly diagnosed, untreated glioblastoma enabled visualization of brain glucose physiology and pathophysiologically increased glucose uptake and may have the potential to provide information about glucose metabolism in tumor tissue. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28628423 TI - Current Considerations for Low-Level Laser Therapy/Photobiomodulation Therapy in the Management of Side Effects of Chemoradiation Therapy for Cancer. PMID- 28628424 TI - Agaricus blazei extract abrogates rotenone-induced dopamine depletion and motor deficits by its anti-oxidative and anti-inflammatory properties in Parkinsonic mice. AB - Neuroinflammation and oxidative damage are the two main malfactors that play an important role in the pathogenesis of experimental and clinical Parkinson's disease (PD). The current study was aimed to study the possible anti-oxidant and anti-inflammatory effects of the methanolic extract of Agaricus blazei (A. blazei) against rotenone-induced PD in mice. Male Albino mice were randomized and divided into the following groups: control, treated with rotenone (1 mg/kg/day), co-treated with rotenone and A. blazei (50, 100, and 200 mg/kg b.w.), and treated with A. blazei alone (200 mg/kg b.w.). After the end of the experimental period, behavioral studies, biochemical estimations, and protein expression patterns of inflammatory markers were studied. Rotenone treatment exhibited enhanced motor impairments, neurochemical deficits, oxidative stress, and inflammation, whereas oral administration of A. blazei extract attenuated the above-said indices. Even though further research is needed to prove its efficacy in clinical studies, the results of our study concluded that A. blazei extract offers a promising and new therapeutic lead for treatment of PD. PMID- 28628425 TI - Fighting the reflux reflex. PMID- 28628426 TI - The USPSTF and screening for obstructive sleep apnea: Dispelling misconceptions. PMID- 28628428 TI - ERAAs for menopause treatment: Welcome the 'designer estrogens'. AB - Estrogen receptor agonist-antagonists (ERAAs) selectively inhibit or stimulate estrogen-like action in targeted tissues. This review summarizes how ERAAs can be used in combination with an estrogen or alone to treat menopausal symptoms (vasomotor symptoms, genitourinary syndrome of menopause), breast cancer or the risk of breast cancer, osteopenia, osteoporosis, and other female midlife concerns. PMID- 28628427 TI - Is there a doctor on board? In-flight medical emergencies. AB - Although not legally required to render assistance in the event of a medical emergency aboard an airplane, physicians have an ethical obligation to do so and should be prepared. PMID- 28628429 TI - Apps and fitness trackers that measure sleep: Are they useful? AB - Consumers have become increasingly interested in using fitness trackers and smartphone applications to quantify sleep. The devices claim to measure various sleep parameters, with the result that patients are now showing the data from their devices to their clinicians with concerns about their quantity or quality of sleep. In general, these devices have major shortcomings and limited utility, as they have not been thoroughly evaluated in clinical populations. PMID- 28628430 TI - Autosomal dominant polycystic kidney disease and the heart and brain. AB - Autosomal dominant polycystic kidney disease (ADPKD) has numerous systemic manifestations and complications. This article gives an overview of hypertension, cardiac complications, and intracranial aneurysms in ADPKD, their pathophysiology, and recent developments in their management. PMID- 28628431 TI - A man with progressive dysphagia. PMID- 28628432 TI - Black hairy tongue cured concurrently with respiratory infection. PMID- 28628433 TI - A 68-year-old man with a blue toe. PMID- 28628434 TI - A dermatosis of pregnancy. PMID- 28628435 TI - To the Editor: Fungal organisms in the brain. PMID- 28628436 TI - Contaminated Stream Water as Source for Escherichia coli O157 Illness in Children. AB - In May 2016, an outbreak of Shiga toxin-producing Escherichia coli O157 infections occurred among children who had played in a stream flowing through a park. Analysis of E. coli isolates from the patients, stream water, and deer and coyote scat showed that feces from deer were the most likely source of contamination. PMID- 28628437 TI - Nontuberculous Mycobacteria Infections at a Provincial Reference Hospital, Cambodia. AB - Prevalence of nontuberculous mycobacteria (NTM) disease is poorly documented in countries with high prevalence of tuberculosis (TB). We describe prevalence, risk factors, and TB program implications for NTM isolates and disease in Cambodia. A prospective cohort of 1,183 patients with presumptive TB underwent epidemiologic, clinical, radiologic, and microbiologic evaluation, including >12-months of follow-up for patients with NTM isolates. Prevalence of NTM isolates was 10.8% and of disease was 0.9%; 217 (18.3%) patients had TB. Of 197 smear-positive patients, 171 (86.8%) had TB confirmed (167 by culture and 4 by Xpert MTB/RIF assay only) and 11 (5.6%) had NTM isolates. HIV infection and past TB were independently associated with having NTM isolates. Improved detection of NTM isolates in Cambodia might require more systematic use of mycobacterial culture and the use of Xpert MTB/RIF to confirm smear-positive TB cases, especially in patients with HIV infection or a history of TB. PMID- 28628438 TI - Haemophilus influenzae Type a Meningitis in Immunocompetent Child, Oman, 2015. AB - Meningitis caused by Haemophilus influenzae type b (Hib) was eliminated in Oman after the introduction of Hib vaccine in 2001. However, a case of H. influenzae type a meningitis was diagnosed in a child from Oman in 2015, which highlights the need to monitor the incidence of invasive non-Hib H. influenzae disease. PMID- 28628439 TI - Locally Acquired mcr-1 in Escherichia coli, Australia, 2011 and 2013. AB - We identified discrete importation events of the mcr-1 gene on incompatibility group IncI2 plasmids in Escherichia coli isolated from patients in New South Wales, Australia, in 2011 and 2013. mcr-1 is present in a small minority of colistin-resistant Enterobacteriaceae and appears not to be established locally. PMID- 28628440 TI - Norovirus GII.17 as Major Epidemic Strain in Italy, Winter 2015-16. AB - In winter 2015-16, norovirus GII.17 Kawasaki 2014 emerged as a cause of sporadic gastroenteritis in children in Italy. Median patient age was higher for those with GII.17 than GII.4 infection (55 vs. 24 months), suggesting limited cross protection for older children. PMID- 28628441 TI - Novel Retinal Lesion in Ebola Survivors, Sierra Leone, 2016. AB - We conducted a case-control study in Freetown, Sierra Leone, to investigate ocular signs in Ebola virus disease (EVD) survivors. A total of 82 EVD survivors with ocular symptoms and 105 controls from asymptomatic civilian and military personnel and symptomatic eye clinic attendees underwent ophthalmic examination, including widefield retinal imaging. Snellen visual acuity was <6/7.5 in 75.6% (97.5% CI 63%-85.7%) of EVD survivors and 75.5% (97.5% CI 59.1%-87.9%) of controls. Unilateral white cataracts were present in 7.4% (97.5% CI 2.4%-16.7%) of EVD survivors and no controls. Aqueous humor from 2 EVD survivors with cataract but no anterior chamber inflammation were PCR-negative for Zaire Ebola virus, permitting cataract surgery. A novel retinal lesion following the anatomic distribution of the optic nerve axons occurred in 14.6% (97.5% CI 7.1%-25.6%) of EVD survivors and no controls, suggesting neuronal transmission as a route of ocular entry. PMID- 28628442 TI - Phylogeography of Burkholderia pseudomallei Isolates, Western Hemisphere. AB - The bacterium Burkholderia pseudomallei causes melioidosis, which is mainly associated with tropical areas. We analyzed single-nucleotide polymorphisms (SNPs) among genome sequences from isolates of B. pseudomallei that originated in the Western Hemisphere by comparing them with genome sequences of isolates that originated in the Eastern Hemisphere. Analysis indicated that isolates from the Western Hemisphere form a distinct clade, which supports the hypothesis that these isolates were derived from a constricted seeding event from Africa. Subclades have been resolved that are associated with specific regions within the Western Hemisphere and suggest that isolates might be correlated geographically with cases of melioidosis. One isolate associated with a former World War II prisoner of war was believed to represent illness 62 years after exposure in Southeast Asia. However, analysis suggested the isolate originated in Central or South America. PMID- 28628443 TI - Novel Avulaviruses in Penguins, Antarctica. AB - We identified 3 novel and distinct avulaviruses from Gentoo penguins sampled in Antarctica. We isolated these viruses and sequenced their complete genomes; serologic assays demonstrated that the viruses do not have cross-reactivity between them. Our findings suggest that these 3 new viruses represent members of 3 novel avulavirus species. PMID- 28628444 TI - Case of Nigeria-Acquired Human African Trypanosomiasis in United Kingdom, 2016. AB - Human African trypanosomiasis has not been reported in Nigeria since 2012. Nevertheless, limitations of current surveillance programs mean that undetected infections may persist. We report a recent case of stage 2 trypanosomiasis caused by Trypanosoma brucei gambiense acquired in Nigeria and imported into the United Kingdom. PMID- 28628445 TI - Mycobacterium gordonae in Patient with Facial Ulcers, Nosebleeds, and Positive T SPOT.TB Test, China. AB - Mycobacterium gordonae is often regarded as a weak pathogen that only occasionally causes overt disease. We report a case of M. gordonae infection in the facial skin, nasal mucosa, and paranasal sinus in an immunocompetent patient and review previous cases. The T-SPOT.TB test might be useful in diagnosing such cases. PMID- 28628446 TI - Diphtheria in Mayotte, 2007-2015. AB - Epidemiology of diphtheria in the southwestern Indian Ocean is poorly documented. We analyzed 14 cases of infection with toxigenic Corynebacterium diphtheriae reported during 2007-2015 in Mayotte, a French department located in this region. Local control of diphtheria is needed to minimize the risk for importation of the bacterium into disease-free areas. PMID- 28628447 TI - Environmental Factors as Key Determinants for Visceral Leishmaniasis in Solid Organ Transplant Recipients, Madrid, Spain. AB - During a visceral leishmaniasis outbreak in an area of Madrid, Spain, the incidence of disease among solid organ transplant recipients was 10.3% (7/68). Being a black person from sub-Saharan Africa, undergoing transplantation during the outbreak, and residing <1,000 m from the epidemic focus were risk factors for posttransplant visceral leishmaniasis. PMID- 28628448 TI - Case-Control Study of Risk Factors for Meningococcal Disease in Chile. AB - An outbreak of meningococcal disease with a case-fatality rate of 30% and caused by predominantly serogroup W of Neisseria meningitidis began in Chile in 2012. This outbreak required a case-control study to assess determinants and risk factors for infection. We identified confirmed cases during January 2012-March 2013 and selected controls by random sampling of the population, matched for age and sex, resulting in 135 case-patients and 618 controls. Sociodemographic variables, habits, and previous illnesses were studied. Analyses yielded adjusted odds ratios as estimators of the probability of disease development. Results indicated that conditions of social vulnerability, such as low income and overcrowding, as well as familial history of this disease and clinical histories, especially chronic diseases and hospitalization for respiratory conditions, increased the probability of illness. Findings should contribute to direction of intersectoral public policies toward a highly vulnerable social group to enable them to improve their living conditions and health. PMID- 28628449 TI - Porcine Hemagglutinating Encephalomyelitis Virus and Respiratory Disease in Exhibition Swine, Michigan, USA, 2015. AB - Acute outbreaks of respiratory disease in swine at agricultural fairs in Michigan, USA, in 2015 raised concern for potential human exposure to influenza A virus. Testing ruled out influenza A virus and identified porcine hemagglutinating encephalomyelitis virus as the cause of influenza-like illness in the affected swine. PMID- 28628450 TI - Zika Virus Screening among Spanish Team Members After 2016 Rio de Janeiro, Brazil, Olympic Games. AB - We evaluated the risk for the Spanish Olympic Team acquiring Zika virus in Rio de Janeiro, Brazil, during 2016. We recruited 117 team members, and all tested negative for Zika virus. Lack of cases in this cohort supports the minimum risk estimates made before the Games. PMID- 28628451 TI - Detection and Genetic Characterization of Adenovirus Type 14 Strain in Students with Influenza-Like Illness, New York, USA, 2014-2015. AB - During the 2014-15 influenza season, 13/168 respiratory samples from students with influenza-like illness (ILI) at a college in New York, USA, were positive for human adenovirus (HAdV); 4/13 samples were positive for HAdV-B14p1. During influenza season, HAdV should be included in the differential diagnostic panel used to determine the etiology of ILI. PMID- 28628452 TI - Rabbit Hepatitis E Virus Infections in Humans, France. AB - Hepatitis E virus (HEV) has been detected in rabbits, but whether rabbit HEV strains can be transmitted to humans is not known. Of 919 HEV-infected patients in France during 2015-2016, five were infected with a rabbit HEV strain. None of the patients had direct contact with rabbits, suggesting foodborne or waterborne infections. PMID- 28628453 TI - Mycobacterium chimaera Isolates from Heater-Cooler Units, United Kingdom. PMID- 28628454 TI - Disseminated Mycobacterium genavense Infection in Patient with Adult-Onset Immunodeficiency. AB - We report a case of disseminated Mycobacterium genavense infection resulting from neutralizing anti-interferon-gamma autoantibodies in the patient. We identified M. genavense targeting the hsp65 gene in an aspiration specimen of the lymph node. Adult-onset immunodeficiency caused by neutralizing anti-interferon-gamma autoantibodies, in addition to HIV infection, can lead to disseminated nontuberculous mycobacterial infection. PMID- 28628455 TI - Concurrent Infection with Hepatitis C Virus and Streptococcus pneumoniae. AB - Little is known about concurrent infection with hepatitis C virus (HCV) and Streptococcus pneumoniae, which causes invasive pneumococcal disease (IPD). We hypothesized that co-infection with HCV and S. pneumoniae would increase risk for death and complications. We captured sociodemographic and serologic data for adults with IPD in a population-based cohort study in northern Alberta, Canada, during 2000-2014. IPD patients infected with HCV were compared with IPD patients not infected with HCV for risk of in-hospital deaths and complications by using multivariable logistic regression. A total of 355 of 3,251 patients with IPD were co-infected with HCV. The in-hospital mortality rate was higher for IPD patients infected with HCV. Prevalence of most IPD-related complications (e.g., cellulitis, acute kidney injury, mechanical ventilation) was also higher in HCV infected patients. Infection with HCV is common in patients with IPD, and HCV is independently associated with an increased risk for serious illness and death. PMID- 28628456 TI - Novel Pestivirus Species in Pigs, Austria, 2015. AB - A novel pestivirus species was discovered in a piglet-producing farm in Austria during virologic examinations of congenital tremor cases. The emergence of this novel pestivirus species, provisionally termed Linda virus, in domestic pigs may have implications for classical swine fever virus surveillance and porcine health management. PMID- 28628457 TI - Clonal Clusters and Virulence Factors of Group C and G Streptococcus Causing Severe Infections, Manitoba, Canada, 2012-2014. AB - The incidence of group C and G Streptococcus (GCGS) bacteremia, which is associated with severe disease and death, is increasing. We characterized clinical features, outcomes, and genetic determinants of GCGS bacteremia for 89 patients in Winnipeg, Manitoba, Canada, who had GCGS bacteremia during 2012-2014. Of the 89 patients, 51% had bacteremia from skin and soft tissue, 70% had severe disease features, and 20% died. Whole-genome sequencing analysis was performed on isolates derived from 89 blood samples and 33 respiratory sample controls: 5 closely related genetic lineages were identified as being more likely to cause invasive disease than non-clade isolates (83% vs. 57%, p = 0.002). Virulence factors cbp, fbp, speG, sicG, gfbA, and bca clustered clonally into these clades. A clonal distribution of virulence factors may account for severe and fatal cases of bacteremia caused by invasive GCGS. PMID- 28628458 TI - Rickettsia sibirica mongolitimonae Infection, Turkey, 2016. AB - In 2016, Rickettsia sibirica mongolitimonae was diagnosed for a man in Turkey. He had been bitten by a Hyalomma marginatum tick, from which PCR detected rickettsial DNA. Sequence analysis of the DNA identified R. sibirica mongolitimonae. Immunofluorescence assay of patient serum indicated R. conorii, which cross-reacts. PCR is recommended for rickettsiosis diagnoses. PMID- 28628459 TI - Francisella tularensis ssp. holarctica in Ringtail Possums, Australia. AB - The occurrence of Francisella tularensis outside of endemic areas, such as North America and Eurasia, has been enigmatic. We report the metagenomic discovery and isolation of F. tularensis ssp. holarctica biovar japonica from diseased ringtail possums in Sydney, Australia. This finding confirms the presence of F. tularensis in the Southern Hemisphere. PMID- 28628460 TI - Risk Factors for Legionella longbeachae Legionnaires' Disease, New Zealand. AB - Legionella longbeachae, found in soil and compost-derived products, is a globally underdiagnosed cause of Legionnaires' disease. We conducted a case-control study of L. longbeachae Legionnaires' disease in Canterbury, New Zealand. Case-patients were persons hospitalized with L. longbeachae pneumonia, and controls were persons randomly sampled from the electoral roll for the area served by the participating hospital. Among 31 cases and 172 controls, risk factors for Legionnaires' disease were chronic obstructive pulmonary disease, history of smoking >10 years, and exposure to compost or potting mix. Gardening behaviors associated with L. longbeachae disease included having unwashed hands near the face after exposure to or tipping and troweling compost or potting mix. Mask or glove use was not protective among persons exposed to compost-derived products. Precautions against inhaling compost and attention to hand hygiene might effectively prevent L. longbeachae disease. Long-term smokers and those with chronic obstructive pulmonary disease should be particularly careful. PMID- 28628461 TI - Measles Outbreak with Unique Virus Genotyping, Ontario, Canada, 2015. AB - The province of Ontario continues to experience measles virus transmissions despite the elimination of measles in Canada. We describe an unusual outbreak of measles in Ontario, Canada, in early 2015 that involved cases with a unique strain of virus and no known association among primary case-patients. A total of 18 cases of measles were reported from 4 public health units during the outbreak period (January 25-March 23, 2015); none of these cases occurred in persons who had recently traveled. Despite enhancements to case-patient interview methods and epidemiologic analyses, a source patient was not identified. However, the molecular epidemiologic analysis, which included extended sequencing, strongly suggested that all cases derived from a single importation of measles virus genotype D4. The use of timely genotype sequencing, rigorous epidemiologic investigation, and a better understanding of the gaps in surveillance are needed to maintain Ontario's measles elimination status. PMID- 28628462 TI - Attributable Fraction of Influenza Virus Detection to Mild and Severe Respiratory Illnesses in HIV-Infected and HIV-Uninfected Patients, South Africa, 2012-2016. AB - The attributable fraction (AF) of influenza virus detection to illness has not been described for patients in different age groups or with different HIV infection statuses. We compared the age group-specific prevalence of influenza virus infection among patients with influenza-like illness (ILI) or severe acute or chronic respiratory illness (SARI and SCRI, respectively) with that among controls, stratified by HIV serostatus. The overall AF for influenza virus detection to illness was 92.6% for ILI, 87.4% for SARI, and 86.2% for SCRI. Among HIV-uninfected patients, the AF for all syndromes was highest among persons <1 and >65 years of age and lowest among persons 25-44 years of age; this trend was not observed among HIV-infected patients. Overall, influenza viruses when detected in patients with ILI, SARI, or SCRI are likely attributable to illness. This finding is particularly likely among children and the elderly irrespective of HIV serostatus and among HIV-infected persons irrespective of age. PMID- 28628464 TI - Early Evidence for Zika Virus Circulation among Aedes aegypti Mosquitoes, Rio de Janeiro, Brazil. AB - During 2014-2016, we conducted mosquito-based Zika virus surveillance in Rio de Janeiro, Brazil. Results suggest that Zika virus was probably introduced into the area during May-November 2013 via multiple in-country sources. Furthermore, our results strengthen the hypothesis that Zika virus in the Americas originated in Brazil during October 2012-May 2013. PMID- 28628463 TI - Operational Research during the Ebola Emergency. AB - Operational research aims to identify interventions, strategies, or tools that can enhance the quality, effectiveness, or coverage of programs where the research is taking place. Medecins Sans Frontieres admitted ~5,200 patients with confirmed Ebola virus disease during the Ebola outbreak in West Africa and from the beginning nested operational research within its emergency response. This research covered critical areas, such as understanding how the virus spreads, clinical trials, community perceptions, challenges within Ebola treatment centers, and negative effects on non-Ebola healthcare. Importantly, operational research questions were decided to a large extent by returning volunteers who had first-hand knowledge of the immediate issues facing teams in the field. Such a method is appropriate for an emergency medical organization. Many challenges were also identified while carrying out operational research across 3 different countries, including the basic need for collecting data in standardized format to enable comparison of findings among treatment centers. PMID- 28628465 TI - Cardiopulmonary involvement in Takayasu's arteritis. AB - OBJECTIVES: To evaluate cardiopulmonary (CP) involvement in patients with Takayasu's arteritis (TAK) and assess the impact on disease outcomes. METHODS: A retrospective cohort of patients with newly diagnosed TAK from 1984 to 2009 was assembled. Demographics, baseline disease characteristics, relapse events, surgeries and mortality were abstracted from direct medical record review. Angiograms, advanced imaging and cardiac studies were reviewed for evidence of CP involvement. Cox models with time-dependent covariates were used to assess the association between CP involvement and outcomes. RESULTS: A total of 124 patients with TAK were identified. Forty-five (36%) patients had at least one objective CP abnormality observed within 6 months of TAK diagnosis. Age at diagnosis was higher in those with CP involvement than those without (34.6 vs 30.1 yrs; p=0.04). Baseline characteristics and symptoms were similar, except shortness of breath, which was more frequently observed at TAK diagnosis in patients with CP involvement compared to those without (53% vs 21%; p=0.001). Composite CP involvement was not associated with risk of first surgery [Hazard ratio (95% CI): 1.21 (0.64-2.30); p=0.56]. However, pulmonary hypertension (PH) on echocardiogram was significantly associated with risk of first surgery [HR (95% CI): 12.9 (1.86- 89.14); p=0.01]. CP involvement was not significantly associated with mortality [HR (95% CI): 2.51 (0.45- 14.02); p=0.29]. CONCLUSIONS: Cardiopulmonary abnormalities in TAK are common at the time of initial presentation. In this population, the presence of PH predicted a 13-fold increased risk for vascular or valvular surgery. In this cohort, the presence of CP involvement did not increase mortality. PMID- 28628466 TI - Evaluation of cancer-associated myositis and scleroderma autoantibodies in breast cancer patients without rheumatic disease. AB - OBJECTIVES: Systemic sclerosis (scleroderma) and dermatomyositis are two prototypic autoimmune diseases that are strongly associated with malignancy. While specific autoantibodies in these diseases are markers of an increased risk of cancer at scleroderma and dermatomyositis onset, it is not known whether these autoantibodies are biomarkers of cancer risk in patients without rheumatic disease. METHODS: In a matched case-control study of women without rheumatic disease, identified from a familial breast cancer cohort, 50 breast cancer cases and 50 controls were assayed for 3 autoantibodies that are known markers of cancer-associated scleroderma and dermatomyositis: anti-RNA polymerase III, anti NXP2, and anti-TIF1gamma. RESULTS: No subject had moderate or strong autoantibody positivity. Eleven women were borderline positive for at least one autoantibody. The prevalence of borderline autoantibody positivity did not differ between cases and controls. CONCLUSIONS: Our results suggest that scleroderma and dermatomyositis autoantibodies are cancer biomarkers only in patients with clinical manifestations of specific rheumatic diseases and are unlikely to improve risk stratification for cancer in the general population. However, prospective studies are needed to examine whether scleroderma and dermatomyositis autoantibodies are markers of malignancy in other cancer types. PMID- 28628467 TI - Juvenile- and adult-onset systemic lupus erythematosus: a comparative study in a large cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER). AB - OBJECTIVES: We aimed to describe juvenile-onset systemic lupus erythematosus (jSLE) features and to establish its differences compared to adult-onset SLE (aSLE) from a large national database. METHODS: Data from patients (>=4 ACR criteria) included in Spanish Society of Rheumatology Lupus Registry (RELESSER) were analysed. Sociodemographic, clinical, serological, activity, treatment, cumulative damage, comorbidities and severity data were collected. Patients with disease onset <18 years were described and compared to those with disease onset >=18 years. RESULTS: We reviewed 3,428 aSLE patients (89.6% women) and 484 jSLE patients (89.8% girls), 93% Caucasian (both groups). Mean age at diagnosis was 38.1+/-14 and 16.6+/-6.3 years (p<0.001) and mean age at the end of follow-up was 48.8+/-14.3 and 31.5+/-30 years (p<0.001), respectively. jSLE showed significantly more clinical (including lymphadenopathy, fever, malar rash, mucosal ulcers, pericarditis, pleuritis, Raynaud's phenomenon, lupus nephritis, recurrent nephritis, histologic nephritis changes, thrombocytopenia, haemolytic anaemia, thrombotic thrombocytopenic purpura, seizures, lupus headache and organic brain syndrome) and immunological (a-dsDNA and a-Sm antibodies, hypocomplementaemia) involvement than did aSLE, except for secondary Sjogren's syndrome, a-Ro antibodies, fibromyalgia and osteoporosis. jSLE also showed more SLE family history, longer diagnosis delay, higher SLEDAI and Katz scores, but lower Charlson scores than aSLE. Several specific domains were more frequently involved in SLICC/ACR DI in jSLE. jSLE patients more frequently underwent all SLE related treatment and procedures, as well as dialysis and kidney transplantations. CONCLUSIONS: jSLE shares many clinical and serological features with aSLE. However, jSLE patients typically manifested more activity, severity, cumulative damage in certain areas, than their aSLE counterparts. PMID- 28628468 TI - DAPSA, DAS28 and MDA predict long-term treatment regime in psoriatic arthritis. The Swedish Early Psoriatic Arthritis Cohort. AB - OBJECTIVES: To describe treatment patterns in the Swedish early psoriatic arthritis cohort (SwePsA) of the mono-/oligo-arthritic (M/O) and polyarthritis (P) and identify early predictive factors for treatment with disease-modifying anti-rheumatic (DMARD), non-steroidal anti-inflammatory drugs (NSAID), and tumour necrosis factor inhibition (TNFi) after 5 years. METHODS: Data for 198 M/O and P PsA were obtained within the programme for SwePsA. Multinomial and binary logistic regression analyses were used to assess the association between early predictive factors and treatment after 5 years adjusted for age at inclusion. The analysis of DMARD/NSAID was adjusted for medication at inclusion. RESULTS: After inclusion visit, DMARD was prescribed in 30% of M/O and 56% of P PsA; mainly methotrexate. TNFi was not prescribed at inclusion, but 23 patients were treated at 5-year follow-up. The adjusted OR (95% CI) for treatment with both DMARD and NSAID after 5 years was 3.65 (1.34 - 9.89) (p=0.010) for Disease Activity Score 28 (DAS28) >3.2 and 2.90 (1.20-6.99) (p=0.038) for Disease Activity Index in Psoriatic Arthritis (DAPSA) >14 at inclusion. TNFi treatment was, after adjusting for age, associated with high erythrocyte sedimentation rate (p=0.0043), high C reactive protein (p=0.013), DAPSA (p<0.001), not reaching minimal disease activity (p=0.001) high health assessment questionnaire (p=0.001), patient's overall assessment on the visual analogue scale (VAS) (p=0.009), high pain VAS (p=0.007), and high number of tender and swollen joints (p=0.031) at inclusion. CONCLUSIONS: Disease activity in early M/O and P PsA is to be considered in deciding the level of health care assessment and future pharmacological treatment. DAS28 >3.2 and DAPSA>14 early in the disease predict subsequent treatment with DMARD. For prediction of biological treatment, not reaching MDA at onset of disease, would be the composite index of choice. PMID- 28628469 TI - Six-joint ultrasound in rheumatoid arthritis: a feasible approach for implementing ultrasound in remission. AB - OBJECTIVES: Subclinical disease activity in rheumatoid arthritis (RA) detected by imaging methods is predictive for flares and damage. Lack of time is the major limitation for not screening for subclinical disease in routine practice. We aimed to determine the most feasible protocol to screen patients with no clinical disease activity by ultrasound (US). METHODS: A hundred consecutive RA patients with no clinical activity according to the physician had an US scan for 38 joints. The prevalence of power Doppler (PD) signal in each joint was determined and different combinations of joints were assessed for their ability to capture this information. The most practical combination with a good sensitivity was tested in another group of 50 RA patients. RESULTS: Having any PD signal was not linked to the disease activity parameters whereas presence of PD of >=2 was associated with higher DAS28CRP. Sixty patients had at least one joint with PD of grade >=2 (60%). A combination of the wrists and 2nd-3rd MCP joints bilaterally (PD-6 joints) was able to detect 45/60 (75%) cases with PD signals and 45% of the whole patient population. The correlation between PD-38 and PD-6 joints was excellent (r=0.820, p<0.0001). PD-6 joints in the 2nd cohort was also able to detect 22/50 (44%) of the whole group. CONCLUSIONS: Subclinical disease activity could be detected in 60% of RA patients when 38 joints screened by US. Limiting the screening to wrists, 2nd-3rd MCPs bilaterally was acceptable as it detected 75% of cases with subclinical disease and increased the feasibility. PMID- 28628470 TI - Vascularity of nail bed by ultrasound to discriminate psoriasis, psoriatic arthritis and healthy controls. PMID- 28628471 TI - Haematological involvement associated with a mild autoinflammatory phenotype, in two patients carrying the E250K mutation of PSTPIP1. AB - OBJECTIVES: Hyperzincaemia/hypercalprotectinemia (Hz/Hc) syndrome is a recently described condition caused by a specific de novo mutation (E250K) affecting PSTPIP1 gene. It has a phenotype distinct from classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome that includes severe systemic and cutaneous inflammation, hepatosplenomegaly, arthritis without sequelae, pancytopenia and failure to thrive. METHODS: We describe an 8-year-old boy who presented recurrent right knee swelling mimicking septic arthritis and persistent bone marrow involvement, without cutaneous involvement. RESULTS: Molecular analysis of the PSTPIP1 gene revealed the presence of a heterozygous E250K mutation. No growth failure was detected nor in the patient neither in his mother, carrying the same variant. Blood zinc and calprotectin MRP8/14 concentrations of the patient were found to be markedly increased. Therapy with anakinra was started with rapid disappearance of clinical symptoms and normalization of CRP levels in 24 hours, but persistence of bone marrow involvement. CONCLUSIONS: The patient described has a milder phenotype, with no skin features, minor episodes of arthritis with no sequelae and normal growth. Compared to the patients with de novo mutations described in the literature, familial cases seem to have a milder phenotype. Our case further confirms the lack of efficacy of anakinra on bone marrow involvement. PMID- 28628472 TI - IFN-gamma, CXCL16, uPAR: potential biomarkers for systemic lupus erythematosus. AB - OBJECTIVES: IFN-gamma, CXCL16 and uPAR have recently been regarded as potential biomarkers in systemic lupus erythematosus (SLE). However, few researches have focused on the comparison of these three markers in SLE. We conducted this study to evaluate their role as biomarkers of disease activity and renal damage. METHODS: We enrolled 50 SLE patients with or without lupus nephritis (LN) and 15 healthy control subjects. The levels of IFN-gamma, CXCL16, uPAR in serum, urine and renal tissues were detected by ELISA or immunohistochemistry. Relevant clinical and laboratory features were recorded. RESULTS: Serum and urine IFN gamma, CXCL16 and suPAR levels in SLE patients were significantly higher than that in healthy controls. Moreover, LN patients had higher levels than non-LN patients. A positive correlation was observed between these markers, and disease activity and suPAR had a stronger association with disease activity. The expression of these biomarkers in renal tissues was significantly higher in LN patients and was also associated with the activity of pathological lesions. CONCLUSIONS: IFN-gamma, CXCL16 and uPAR are promising as effective biomarkers of disease activity, renal damage, and the activity of pathological lesions in SLE. PMID- 28628473 TI - Viruses and cancer: molecular relations and perspectives. PMID- 28628474 TI - Prediction of human iron bioavailability using rapid c-ELISAs for human plasma hepcidin. AB - BACKGROUND: Hepcidin is the central systemic regulator of iron metabolism, but its quantification in biological fluids is challenging. Rapid, accurate and user friendly methods are needed. Our aim was to assess the ability of hepcidin as measured by three different c-ELISA assays to predict iron bioavailability in humans. METHODS: The three assays used were commercially available DRG and Peninsula assays and the c-ELISA method performed at Radboud University Medical Centre, Nijmegen, The Netherlands (Hepcidinanalysis.com), validated by comparative measurements with time-of-flight mass spectrometry. We analyzed plasma samples (n=37) selected to represent a broad range of hepcidin concentrations from a subgroup of healthy, iron-depleted women in a study assessing fractional absorption from iron supplements. RESULTS: In single regressions, all three c-ELISA assays were predictors of fractional iron absorption: R2=0.363 (DRG), R2=0.281 (Peninsula) and R2=0.327 (Hepcidinanalysis.com). In multiple regressions, models including hepcidin measured with either DRG-, Peninsula or Hepcidinanalysis.com explained 55.7%, 44.5% and 52.5% of variance in fractional absorption, and hepcidin was a strong predictor of fractional absorption irrespective of the hepcidin assays used. However, we found significant differences in absolute values for hepcidin between different methods. Both the DRG assay's (y=0.61x+0.87; R2=0.873) and the Peninsula assay's measurements (y=1.88x+0.62; R2=0.770) were correlated with Hepcidinanalysis.com. CONCLUSIONS: The biological variability in plasma hepcidin, (inter-sample CV) was 5-10-fold higher for both the Peninsula and DRG assay than the analytical variably (inter-run within-sample CV) suggesting substantial discriminatory power to distinguish biological hepcidin variation. Between methods, prediction of iron bioavailability in generally healthy iron depleted subjects appears comparable. PMID- 28628475 TI - Predictive autoimmunity using autoantibodies: screening for anti-nuclear antibodies. PMID- 28628476 TI - Differences in physical activity, eating habits and risk of obesity among Kuwaiti adolescent boys and girls: a population-based study. AB - The study aimed to assess gender differences among Kuwaiti adolescents in healthy living choices that impact the risk of obesity. A cross-sectional multistage cluster design was employed with a representative sample of 2672 students aged 13 15 years who completed a self-administered Global School-based Student Health (GSHS) survey. The study found that around 48.0% of adolescents were overweight and obese. More boys than girls were obese (28.2% vs. 22.3%, p < 0.0001). However, boys were more likely than girls to report healthy food choices regarding fruit (38.1% vs. 33.2%), and vegetables (21.8% vs. 16.7%). Only 20.7% of adolescents reported physical activity for more than 60 min/day, predominately by boys rather than girls (30.8% vs. 10.5%, respectively, p < 0.0001). Multivariate analysis revealed that male gender, skipping breakfast and physical inactivity were significantly correlated with the risk of overweight and obesity among adolescents. These results suggest that lifestyle education for promoting healthy body masses targeting adolescents should take gender into account. PMID- 28628477 TI - Is age of menarche among school girls related to academic performance? AB - Background There is strong evidence that the mean age of menarche has declined over the last few decades in developed and developing countries. This is of a major concern because of its enormous public health implications. This study aimed to estimate the age of menarche in Kuwait and investigate the association between menarcheal age and academic performance among high school girls in Kuwait. Methods A cross-sectional study was conducted on randomly selected female high school students from private and public high schools in all governorates in Kuwait. Data on the age of menarche were collected by self-administered questionnaire from the students, while data on academic performance were extracted from the students' academic records. Results Of the 907 students we selected, 800 (88.2%) responded. The mean age of menarche was 12.33 [95% confidence interval (CI) 12.18-12.49] years. There was no evidence for significant association between age of menarche and students' academic performance before or after adjusting for potential confounders. Conclusion The calculated age of menarche among contemporary girls in Kuwait is similar to that of the girls in industrialized countries. Early menarcheal age is unlikely to lead to adverse behavior that may affect academic performance in our setting. PMID- 28628478 TI - Reducing barriers to primary school education for girls in rural Kenya: reusable pads' intervention. AB - Purpose The current study explored girls' perceptions of the impact of sanitary pads' intervention on their school attendance and grades. Methods Participants included 150 girls in 6th, 7th, and 8th grade in two rural schools in Kenya. Participants completed a questionnaire on menstrual health issues and the perceived impact on school attendance and academic performance. Results Results indicated that of all participants (150), those who had passed menarche and had cloth pads had similar comfort levels at school as those who had not yet had their period. Of those who had reached menarche (with pads n = 34, without pads n = 91), they answered questions about how much their period interfered with their attendance and grades. Those who had received the pads reported significantly less negative influence on their attendance and schoolwork than those who did not have pads. They also reported significantly lower levels of wanting to hide their menstrual cycle from friends and family. In addition, they reported significantly higher levels of comfort at home and school than those who did not have pads. Finally, those with pads reported significantly lower levels of fear during their period. Conclusion These findings suggest providing girls with pads minimizes the barriers to successful schooling. PMID- 28628479 TI - Chronic pain in high school students is associated with physical activity and sleeping hours but not with screen time. AB - Background Existing studies on the association between physical activity (PA), screen based time and sleeping show conflicting results. Objective This study investigates the association between chronic pain at different body regions and self-reported PA, screen based time and sleeping hours in high school students. Subjects A total of 969 students aged 13-19 years old. Methods Participants completed a questionnaire on chronic pain, time spent in moderate and vigorous PA, screen based time watching televivsion (TV)/digital versatile discs (DVD), playing, using mobile phones and computers and sleeping hours. Univariate and multivariate associations between pain and PA, screen based time and sleeping hours were investigated. Results In the univariate model time spent in moderate and vigorous PA, in screen based activities and sleeping were associated with pain in at least one body site. In the multivariate model, screen based activities were not associated with pain; sleeping 7 h or less and increased time in moderate PA were associated with pain at almost all body sites [odds ratio (OR) between 2.69-3.66 and 1.06-1.10, respectively]. Conclusion Time spent in PA and sleeping increased the risk of chronic pain in almost all body regions and might confound the association between screen based time and pain. PMID- 28628480 TI - Kernel-Based Measure of Variable Importance for Genetic Association Studies. AB - The identification of genetic variants that are associated with disease risk is an important goal of genetic association studies. Standard approaches perform univariate analysis where each genetic variant, usually Single Nucleotide Polymorphisms (SNPs), is tested for association with disease status. Though many genetic variants have been identified and validated so far using this univariate approach, for most complex diseases a large part of their genetic component is still unknown, the so called missing heritability. We propose a Kernel-based measure of variable importance (KVI) that provides the contribution of a SNP, or a group of SNPs, to the joint genetic effect of a set of genetic variants. KVI can be used for ranking genetic markers individually, sets of markers that form blocks of linkage disequilibrium or sets of genetic variants that lie in a gene or a genetic pathway. We prove that, unlike the univariate analysis, KVI captures the relationship with other genetic variants in the analysis, even when measured at the individual level for each genetic variable separately. This is specially relevant and powerful for detecting genetic interactions. We illustrate the results with data from an Alzheimer's disease study and show through simulations that the rankings based on KVI improve those rankings based on two measures of importance provided by the Random Forest. We also prove with a simulation study that KVI is very powerful for detecting genetic interactions. PMID- 28628481 TI - Strengthening Distance Nursing Laboratory Courses Through Application of Theoretical Foundations: A Literature Review. AB - A literature review was conducted to assess study results and theoretical foundations regarding distance nursing lab courses. A variety of education and nursing-specific theories were utilized during curriculum development. No two studies applied the same theoretical foundations. Further research and integration of theoretical foundations, including the synthesis of multiple theories regarding the distance teaching of psychomotor skills, will strengthen distance nursing lab courses and allow for more effective and evidence-based learning of psychomotor skills. PMID- 28628482 TI - The Relationship Between Levels of Fidelity in Simulation, Traditional Clinical Experiences and Objectives. AB - The purpose of this study was to explore the relationship of baccalaureate nursing students' (BSN) perceived learning effectiveness using the Clinical Learning Environments Comparison Survey of different levels of fidelity simulation and traditional clinical experiences. A convenience sample of 103 first semester BSN enrolled in a fundamental/assessment clinical course and 155 fifth semester BSN enrolled in a leadership clinical course participated in this study. A descriptive correlational design was used for this cross-sectional study to evaluate students' perceptions after a simulation experience and the completion of the traditional clinical experiences. The subscales measured were communication, nursing leadership, and teaching-learning dyad. No statistical differences were noted based on the learning objectives. The communication subscale showed a tendency toward preference for traditional clinical experiences in meeting students perceived learning for communication. For student perceived learning effectiveness, faculty should determine the appropriate level of fidelity in simulation based on the learning objectives. PMID- 28628483 TI - SiGe layer thickness effect on the structural and optical properties of well organized SiGe/SiO2 multilayers. AB - In this work, we report on the production of regular (SiGe/SiO2)20 multilayer structures by conventional RF-magnetron sputtering, at 350 degrees C. Transmission electron microscopy, scanning transmission electron microscopy, raman spectroscopy, and x-ray reflectometry measurements revealed that annealing at a temperature of 1000 degrees C leads to the formation of SiGe nanocrystals between SiO2 thin layers with good multilayer stability. Reducing the nominal SiGe layer thickness (t SiGe) from 3.5-2 nm results in a transition from continuous SiGe crystalline layer (t SiGe ~ 3.5 nm) to layers consisting of isolated nanocrystals (t SiGe ~ 2 nm). Namely, in the latter case, the presence of SiGe nanocrystals ~3-8 nm in size, is observed. Spectroscopic ellipsometry was applied to determine the evolution of the onset in the effective optical absorption, as well as the dielectric function, in SiGe multilayers as a function of the SiGe thickness. A clear blue-shift in the optical absorption is observed for t SiGe ~ 2 nm multilayer, as a consequence of the presence of isolated nanocrystals. Furthermore, the observed near infrared values of n = 2.8 and k = 1.5 are lower than those of bulk SiGe compounds, suggesting the presence of electronic confinement effects in the nanocrystals. The low temperature (70 K) photoluminescence measurements performed on annealed SiGe/SiO2 nanostructures show an emission band located between 0.7-0.9 eV associated with the development of interface states between the formed nanocrystals and surrounding amorphous matrix. PMID- 28628484 TI - Battling bacterial infection with hexamethylene diisocyanate cross-linked and Cefaclor-loaded collagen scaffolds. AB - Implant infections remain a major healthcare problem due to the prolonged hospitalisation period required to disrupt and treat bacterial biofilm formation, and the need for additional surgery to remove/replace the infected implant, which if not removed in a timely manner may lead to sepsis. Although localised drug administration, via an implanted scaffold, has shown promise in a clinical setting, the ideal scaffold cross-linking (to initially withstand the aggressive infection environment) and drug (to be effective against infection) have yet to be identified. In this work, in the first instance, the biochemical, biophysical, and biological properties of collagen sponges as a function of various concentrations (0.625%, 1.0%, 2.5%, 5.0%, and 10.0%) of hexamethylene diisocyanate were assessed. Data presented illustrate that hexamethylene diisocyanate at 0.625% concentration was able to effectively stabilise collagen scaffolds, as judged by the reduction in free amines, adequate resistance to collagenase digestion, reduction in swelling, increase in denaturation temperature, suitable mechanical properties, and appropriate cytocompatibility. Subsequently, collagen scaffolds stabilised with 0.625% hexamethylene diisocyanate were loaded with variable concentrations (0, 10, 100, and 500 MUg ml 1) of Cefaclor and Ranalexin. Both drugs exhibited similar loading efficiency, release profile, and cytocompatibility. However, only collagen scaffolds loaded with 100 MUg ml-1 Cefaclor exhibited adequate antibacterial properties against both 106 and 108 colony-forming units per ml of both Escherichia coli and Staphylococcus epidermidis. PMID- 28628485 TI - Free-standing Ag triangle arrays a configurable vertical gap for surface enhanced Raman spectroscopy. AB - Large-area ordered arrays with dense hotspots are highly desirable substrates for surface enhanced Raman scattering (SERS). In this paper, we present a quasi-3D SERS substrate of free-standing Ag triangle arrays (FATA) which was fabricated by nanosphere lithography incorporated with photolithography and Ag covering. A significant SERS effect arises from a strongly enhanced local electric field within the tiny gaps between the suspended Ag triangle and the Ag baseplate. The SERS intensity relative standard deviation is less than 7.6%, leading to excellent reliability for Raman detection. The simple fabrication of the Ag film covering FATA nanostructures provides a practical solution for large-area, highly efficient and reproducible SERS substrates. PMID- 28628486 TI - Inactivation of bacterial biofilms using visible-light-activated unmodified ZnO nanorods. AB - Various zinc oxide (ZnO) nanostructures are widely used for photocatalytic antibacterial applications. Since ZnO possesses a wide bandgap, it is believed that only UV light may efficiently assist bacterial inactivation, and diverse crystal lattice modifications should be applied in order to narrow the bandgap for efficient visible-light absorption. In this work we show that even unmodified ZnO nanorods grown by an aqueous chemical growth technique are found to possess intrinsic defects that can be activated by visible light (lambda = 405 nm) and successfully applied for total inactivation of various highly resistant bacterial biofilms rather than more sensitive planktonic bacteria. Time-resolved fluorescence analysis has revealed that visible-light excitation creates long lived charge carriers (tau > 1 MUs), which might be crucial for destructive biochemical reactions achieving significant bacterial biofilm inactivation. ZnO nanorods covered with bacterial biofilms of Enterococcus faecalis MSCL 302 after illumination by visible light (lambda = 405 nm) were inactivated by 2 log, and Listeria monocytogenes ATCL3C 7644 and Escherichia coli O157:H7 biofilms by 4 log. Heterogenic waste-water microbial biofilms, consisting of a mixed population of mesophilic bacteria after illumination with visible light were also completely destroyed. PMID- 28628487 TI - Do toddler's fractures of the tibia require evaluation and management by an orthopaedic surgeon routinely? AB - OBJECTIVE: The majority of uncomplicated toddler fractures of the tibia (toddler's fractures) do not need an orthopaedic surgeon's intervention or follow up. However, inexperienced emergency room physicians, general practitioners and orthopaedic trainees and surgeons understandably defer to a cautious approach of referral and subsequent frequent clinical and radiographic follow-up. An evidence based pathway can help prevent this overtreatment, reduce unnecessary radiation exposure and decrease the financial burden on families and the healthcare system. PATIENTS AND METHODS: A retrospective analysis of patients who presented for management of toddler's fractures to The Hospital for Sick Children (SickKids) was performed. RESULTS: A total of 184 (113 boys, 72 girls) patients, of a mean age of 1.99 (range: 0.2-3.9) years, were included for review. The included patients had attended 2.00+/-1.0 clinic visits and had had 5.86+/-2.7 radiographs taken on average. No complications such as cast injuries, nonunion, refracture or subsequent deformity needing assessment or intervention were identified. CONCLUSION: Toddler's fractures do not require routine orthopaedic surgeon assessment, intervention or follow-up. If diagnosed and managed correctly at initial presentation, patients with toddler's fractures may be discharged safely without the need for further clinician contact. We developed a toddler's fracture clinical care pathway to reduce unnecessary orthopaedic surgeon referral and clinical and radiographic follow-up, thereby decreasing radiation exposure and costs to families and the healthcare system without risking patient outcomes. PMID- 28628488 TI - Falls and Physical Activity in Persons With Mild to Moderate Dementia Participating in an Intensive Motor Training: Randomized Controlled Trial. AB - BACKGROUND: Physical activity is beneficial in people with dementia. As physical activity increases risk exposure for falls, safety concerns arise. Prior exercise trials in people with dementia have not measured physical activity. Falls in relation to exposure time rather than person-years as outcome measure has been promoted but not investigated in people with dementia. METHODS: Patients with mild to moderate dementia (n=110) were randomized to an intensive, progressive strength and functional training intervention or to a low-intensity group training for 12 weeks each. Physical activity was measured with a standardized questionnaire. Falls were documented prospectively by calendars for 12 months. RESULTS: During the intervention, physical activity was significantly higher in the intervention group (P<0.001) without an increased fall rate (intervention group vs. CONTROL GROUP: 2.89 vs. 1.94; incidence rate ratio, 1.49; 95% confidence interval, 0.66-3.36; P=0.333). In the subgroup of multiple fallers, the number of falls per 1000 hours of activity was significantly lower in the intervention group (8.85 vs. 18.67; P=0.017). CONCLUSIONS: Increased physical activity during exercise intervention was safe in people with mild to moderate dementia. Fall rate adjusted for physical activity is a useful and sensitive outcome measure in addition to fall rate per person-years. PMID- 28628489 TI - Shifting of the Line of Sight in Tilted Disk Syndrome. AB - OBJECTIVES: To investigate the shifting of the line of sight (LoS) and the refractive, topographic, and aberrometric parameters that may be associated with the shifting of the LoS in eyes with tilted disk syndrome (TDS). METHODS: Eighty left eyes of 80 subjects with TDS (Study Group) and 70 left eyes of 70 subjects with myopia and astigmatism (Control Group) were included in this study. Line-of sight coordinates on the horizontal (x) and vertical (y) axes, refractive, topographic, and aberrometric parameters were evaluated. All parameters were compared between groups, and correlations were analyzed for the study group. RESULTS: In the study group, the LoS significantly shifted to the superotemporal direction compared with the control group (P=0.022 and P=0.008 respectively). The shift on y-axis was correlated with mean cylindrical refractive error (r=-0.283, P=0.011), total root mean square (RMS) (r=0.321, P=0.004), higher-order aberration RMS (r=0.300, P=0.007), vertical coma (r=0.430, P<0.001), and vertical trefoil values (r=-0.455, P<0.001). CONCLUSIONS: Results demonstrated a superotemporal shifting of the LoS in eyes with TDS. As eyes with TDS have an important place among candidates for refractive and multifocal intraocular lens implantation surgeries, this shift must be accounted for to prevent decentralization and provide satisfactory outcomes. PMID- 28628490 TI - Comparison of Efficacy of Difluprednate 0.05% and Loteprednol Gel 0.5% After Cataract Surgery. AB - PURPOSE: To compare the outcomes and complications of topical difluprednate 0.05% and loteprednol gel 0.5% after routine cataract surgery. METHODS: Subjects received either difluprednate emulsion 0.05% (n=30 eyes) or loteprednol gel 0.5% (n=30 eyes) after routine cataract surgery. Topical steroid drops were initiated 3 days before cataract surgery and continued for 2 weeks postoperatively. Anterior chamber (AC) cell grade, corneal edema, corneal pachymetry, visual acuity, ocular surface quality (Oxford scale), and intraocular pressure (IOP) were evaluated at 1 day, 1 week, and 1 month postoperatively. RESULTS: Patients treated with difluprednate or loteprednol had statistically similar resolution of their AC cell grade and corneal edema at 1 day, 1 week, and 1 month postoperatively (P>0.05 at each study visit). Difluprednate-treated and loteprednol-treated eyes achieved a mean best-corrected visual acuity of at least 20/25 by 1 week postoperatively (0.055 and 0.061 logarithm of the minimum angle of resolution, respectively; P=0.82). The nasal ocular surface quality at 1 week had improved in loteprednol-treated eyes compared with difluprednate-treated eyes (1.0 vs. 1.9 Oxford score, respectively; P<0.001), but similar at all other visits. There was no statistical difference between IOP levels between both treatment groups (P>0.05). In the difluprednate-treated group, one patient developed rebound inflammation and two patients developed cystoid macular edema at their 1-month postoperative visit. CONCLUSIONS: The anti-inflammatory effect, visual recovery, and IOP of patients using topical difluprednate or loteprednol gel after cataract surgery are equivalent. There may be an additional short-term benefit of loteprednol gel in protecting the ocular surface after cataract surgery. PMID- 28628491 TI - Calcein-acetoxymethy ester enhances the antitumor effects of doxorubicin in nonsmall cell lung cancer by regulating the TopBP1/p53RR pathway. AB - Calcein acetoxymethyl ester (calcein-AM) treatment has been reported to exert antitumor effects in certain cancer cells; however, the detailed mechanism of action of calcein-AM in cancers remains unclear, especially in nonsmall cell lung cancer (NSCLC). This study focused on the function and mechanism of action of calcein-AM in NSCLC. We used cell viability assays, western blotting, and EdU proliferation assay combined with calcein-AM treatment or siRNA interference to investigate the role of topoisomerase IIbeta binding protein 1 (TopBP1) and p53 in NSCLC chemotherapy. We found that calcein-AM has antitumor effects in lung cancer and enhances the antitumor effects of doxorubicin in NSCLC. Furthermore, we found that TopBP1, which we previously showed was involved in doxorubicin resistance through upregulation of aberrant p53, was involved in calcein-AM mediated increased doxorubicin sensitivity. Doxorubicin upregulated the expression of aberrant p53. Calcein-AM repressed the expression of TopBP1, which resulted in reduced expression of aberrant p53 and disrupted the antiapoptotic activity mediated by the TopBP1/mutp53 pathway in NSCLC. Together, our findings show that calcein-AM, the cell-permeable derivative of calcein, exerts significant antitumor effects in NSCLC, and can enhance the antitumor effect of doxorubicin by regulating the TopBP1/mutp53 pathway. These findings provide novel insight into lung cancer treatment. PMID- 28628493 TI - The opioid crisis. PMID- 28628492 TI - Complete remission of intrathecal metastases with lorlatinib therapy in a heavily pretreated ALK-positive lung cancer patient. AB - Patients with lung cancer who show EML4-ALK translocation are routinely treated with ALK tyrosine kinase inhibitors, although in the majority of cases, these patients develop resistance over time. The central nervous system is a common of site of recurrence in this population, which calls for next-generation drugs that can penetrate into the brain and achieve clinically meaningful central nervous system activity. Here, I report the case of a female patient diagnosed with adenocarcinoma of the lung in 2005, at the age of 46 years, who underwent lobectomy and then experienced a series of progression episodes 6 years later. Local recurrence was managed by chemotherapy and crizotinib after the patient was included in a named patient use programme in 2012. Over the following years, the patient repeatedly developed lesions at different sites in the brain and spinal cord. Partial remission was obtained twice with local irradiation. When the next generation ALK tyrosine kinase inhibitors became available, her treatment was switched to brigatinib, which again induced partial remission. Another episode of intrathecal progression prompted the prescription of the third-generation ALK tyrosine kinase inhibitor lorlatinib. This treatment has resulted in complete remission in the patient. PMID- 28628495 TI - Congress of the International Intestinal Rehabilitation and Transplantation Association (CIRTA) Abstracts. PMID- 28628494 TI - Funneling evidence into practice. PMID- 28628496 TI - Proton pump inhibitor and selective serotonin reuptake inhibitor therapy for the management of noncardiac chest pain. AB - INTRODUCTION: Although gastroesophageal reflux disease is the main cause of noncardiac chest pain (NCCP), proton pump inhibitors (PPIs) benefit a minority of patients. Our prospective study evaluated the effect of PPI and selective serotonin reuptake inhibitors on the different subtypes of NCCP characterized by impedance-pH monitoring. METHODS: All NCCP patients underwent impedance-pH monitoring and on the basis of the results, those with abnormal distal esophageal acid exposure received PPIs twice daily (group A), those with a positive symptom index for chest pain received citalopram 20 mg and PPI once daily (group B), and those with a negative symptom index for chest pain received citalopram 20 mg once daily (group C). Therapy was administered for 12 weeks and treatment success was defined as complete disappearance of chest pain. RESULTS: From March 2015 to March 2016, 63 patients were included (group A=9, group B=18, group C=36). After 12 weeks of therapy, complete resolution of chest pain was noted in 8/9 (88.9%) group A, 13/18 (72.2%) group B, and 24/36 (66.7%) group C patients. CONCLUSION: Combined impedance-pH monitoring identifies different subtypes of NCCP patients who can receive tailored management. Targeted therapy with PPIs and/or citalopram offers complete symptom relief in the great majority of them. PMID- 28628497 TI - Predicting short-term and long-term mortality of hospitalized Portuguese patients with alcoholic hepatitis. AB - BACKGROUND: Alcohol abuse can result in a spectrum of liver injury that ranges from mild fatty infiltration to alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma. The present study aimed to evaluate current scoring systems in predicting short-term and long-term mortality because of AH. PATIENTS AND METHODS: Records of 170 consecutive patients with AH admitted to a tertiary center between January 2005 and October 2015 were reviewed. Clinical and biochemical parameters were retrieved for the assessment of AH scores for the day of admission (D1) and for the seventh day of hospitalization (D7). Endpoints included admission to the ICU, and 30-day, 90-day, and 1-year mortality. RESULTS: The Maddrey discriminant function and the Model of End-Stage Liver Disease (MELD) were modest predictors of the need for ICU admission. In-hospital, 30-day, 90 day, and 1-year mortality were 15.9, 18.2, 21.8, and 30.0%, respectively. There was a numerical, albeit nonsignificant, trend for higher accuracy using D7 scores, especially the MELD, in predicting 30-day and 1-year mortality. Overall, all scores showed high negative predictive values (30 day: 91.2-98.7% and 1 year: 78.8-93.7%), but modest positive predictive values (30 day: 30.6-70.8% and 1 year: 42.1-61.2%). Survival rates were the highest among patients showing a decrease in the MELD, Glasgow Alcoholic Hepatitis Score, and Age, serum Bilirubin, International normalized ratio, and serum Creatinine score over the first week of admission. DISCUSSION: AH scores were comparable in identifying patients at low risk of mortality up to 1 year following admission. Reassessment of the MELD, Glasgow Alcoholic Hepatitis Score, and Age, serum Bilirubin, International normalized ratio, and serum Creatinine score scores after 1 week further improved mortality prediction. PMID- 28628498 TI - Earlier Physical Therapy Input Is Associated With a Reduced Length of Hospital Stay and Reduced Care Needs on Discharge in Frail Older Inpatients: An Observational Study. AB - BACKGROUND AND PURPOSE: Pressures on hospital bed occupancy in the English National Health Service have focused attention on enhanced service delivery models and methods by which physical therapists might contribute to effective cost savings, while retaining a patient-centered approach. Earlier access to physical therapy may lead to better outcomes in frail older inpatients, but this has not been well studied in acute National Health Service hospitals. Our aim was to retrospectively study the associations between early physical therapy input and length of hospital stay (LOS), functional outcomes, and care needs on discharge. METHODS: This was a retrospective observational study in a large tertiary university National Health Service hospital in the United Kingdom. We analyzed all admission episodes of people admitted to the department of medicine for the elderly wards for more than 3 months in 2016. Patients were categorized into 2 groups: those examined by a physical therapist within 24 hours of admission and those examined after 24 hours of admission.The outcome variables were as follows: LOS (days), functional measures on discharge (Elderly Mobility Scale and walking speed over 6 m), and the requirement of formal care on discharge. Characterization variables on admission were age, gender, existence of a formal care package, preadmission abode, the Clinical Frailty Scale, Charlson Comorbidity Index, the Emergency Department Modified Early Warning Score, C reactive protein level on admission, and the 4-item version of the Abbreviated Mental Test.The association between the delay to physical therapy input and LOS before discharge home was evaluated using a Cox proportional hazards regression model. RESULTS AND DISCUSSION: There were 1022 hospital episodes during the study period. We excluded 19 who were discharged without being examined by a physical therapist. Of the remaining 1003, 584 (58.2%) were examined within 24 hours of admission (early assessment) and 419 (41.8%) after 24 hours of admission (late assessment).The median (interquartile range) LOS of the early assessment group was 6.7 (3.1-13.7) versus 10.0 (4.2-20.1) days in the late assessment group, P < .001. The early assessment group was less likely to require formal care on discharge: n = 110 (20.3%) versus n = 105 (27.0%), P = .016. No other statistically significant differences were seen between the 2 groups.In the unadjusted Cox proportional hazards model, the hazard ratio for early assessment compared with late assessment was 1.29 (95% confidence interval: 1.12-1.48, P < .001). Early assessment was associated with a 29% higher probability of discharge to usual residence within the first 21 days after admission than the late assessment. Adjustment for possible confounding variables increased the hazard ratio: 1.34 (1.16-1.55), P < .001. CONCLUSIONS: Early physical therapy input was associated with a shorter LOS and lower odds of needing care on discharge. This may be due to the beneficial effect of early physical therapy in preventing hospital-related deconditioning in frail older adults. However, causality cannot be inferred and further research is needed to investigate causal mechanisms. PMID- 28628499 TI - Psychometric Validation of the Mandarin Version Control Attitudes Scale-Revised Questionnaire in Taiwanese Patients With Heart Failure. AB - BACKGROUND: Perceived control is an important construct in patients with heart failure (HF) and related to improved health outcomes. There is no reliable and valid instrument available for the measurement of perceived control in Taiwan, limiting the practical application of the construct in research and clinical practice. PURPOSE: The aim of this study was to translate, culturally adapt, and validate the Mandarin version of the Control Attitudes Scale-Revised (Mandarin CAS-R) in Taiwanese patients with HF. METHODS: The Mandarin CAS-R was developed using a translation/back-translation process and semantic equivalence; importantly, conceptual equivalence was also examined. Reliability was assessed using Cronbach's alpha to determine internal consistency, and item homogeneity was assessed using item-total and interitem correlations. Construct validity was examined using exploratory factor analysis and hypothesis testing for known associations. RESULTS: Three hundred forty-eight patients with HF were included, and 5-item Mandarin CAS-R was validated in the study. The model performance was acceptable with all factor loadings greater than 0.70, a variance explained of 55.2%, and a Cronbach's alpha of .79. The 5-item Mandarin CAS-R was associated with higher levels of self-care maintenance (beta = 0.395, P < .001), management (beta = 0.219, P < .01), and confidence (beta = 0.524, P < .001); perceived social support (beta = 0.246, P < .001); and depression (beta = -0.125, P < .05). CONCLUSIONS: This study provided evidence of the reliability and validity of the 5-item Mandarin CAS-R as a measure of perceived control in Taiwanese patients with HF. PMID- 28628500 TI - Atrial Fibrillation Symptoms and Sex, Race, and Psychological Distress: A Literature Review. AB - BACKGROUND: Atrial fibrillation (AF) symptoms are a major component of treatment decisions for patients with AF and impact quality of life and functional ability yet are poorly understood. OBJECTIVE: This review aimed to determine what is known about the prevalence of symptoms and the association of symptoms to AF characteristics, psychological distress, sex, and race. METHODS: We performed a structured review of AF symptoms as of March 2016 using PubMed, EMBASE, and CINAHL and reference searches of retrieved articles. Full-text, published, peer reviewed, English-language articles were examined. Articles were included if they reported original research data on symptom prevalence and type among patients with AF. RESULTS: The 3 most common symptoms were dyspnea, palpitations, and fatigue. The results suggested that, although AF characteristics are not a significant predictor of symptoms, tachycardia, female sex, race, and psychological distress have a positive association to symptoms. CONCLUSIONS: There is a scarcity of research examining symptoms in AF. Furthermore, the inconsistency in measurement methods and the failure to include diverse populations in AF research make it difficult to draw definitive conclusions from the current literature. Given the prevalence of AF in the United States and the impact of symptoms on quality of life and healthcare use, further research examining predictors of symptoms and interventions to alleviate symptoms is crucial. PMID- 28628501 TI - Comparison of Donor Site Drainage Duration and Seroma Rate Between Latissimus Dorsi Musculocutaneous Flaps and Thoracodorsal Artery Perforator Flaps. AB - INTRODUCTION: Donor site seroma formation and prolonged drainage duration are common complications of using latissimus dorsi musculocutaneous (LDMC) flaps. The present retrospective study aimed to investigate the effect of types of back flap harvest on drainage duration and seroma formation rates. METHODS: Adult patients (n = 155) who underwent reconstruction with a latissimus dorsi flap from January 2010 to October 2015 were included in the study, of which 54 patients underwent breast reconstruction with a pedicled LDMC flap (LD breast group), 80 patients underwent an LDMC flap transfer for purposes other than breast reconstruction (LD nonbreast group), and 21 patients underwent soft tissue reconstruction with a thoracodorsal artery perforator (TAP) flap (TAP group). Flap size, drainage durations, and seroma formation rates at donor sites were compared among the 3 groups. RESULTS: Flap sizes significantly differed between the LD nonbreast group (median value, 185.5 cm) and the other 2 groups (119 cm in the LD breast group. 127.5 cm in the TAP group), with no significant difference observed between the LD breast and TAP groups. The mean drainage duration was 11.6 days for the LD breast group. 9.82 days for the LD nonbreast group, and 4.81 days for the TAP group. Drainage durations significantly differed among the groups. Seroma formation rate of the LD breast group (42.6%) was significantly higher than those of the other groups. CONCLUSIONS: The type of back flap harvest used significantly affected drainage duration and seroma formation rate in the present study. Lumbar fat extension with the use of a LDMC flap for breast reconstruction may lead to seroma formation. Thoracodorsal artery perforator flaps are associated with minimal risks of seroma formation and significantly shortened drainage duration compared with LDMC flaps. PMID- 28628502 TI - Placebo response in trichotillomania. AB - Trichotillomania is a functionally impairing, often overlooked disorder with no Food and Drug Administration-approved medications indicated for its treatment. The ability of clinical trials to detect the beneficial effects of pharmacologic treatment in trichotillomania has been hampered by the high placebo response rate. Very little is known about baseline demographic and clinical characteristics that may be predictive of placebo response in such patients. Overall, 104 participants assigned to placebo were pooled from five double-blind trials conducted at three sites in the USA and Canada. Participants were classified as placebo responders or nonresponders on the basis of a cutoff of a 35% reduction in symptom severity on the Massachusetts General Hospital Hair Pulling Scale. Baseline group differences were characterized using t-tests and equivalent nonparametric tests as appropriate. Thirty-one percent of individuals assigned to placebo treatment showed a significant clinical response to placebo. Placebo responders (n=32) and nonresponders (n=72) did not differ significantly on any demographic or clinical variable. Predictors of placebo response for trichotillomania remain elusive and do not appear to be similar to those reported for other mental health disorders. PMID- 28628503 TI - Influence of Refractive Status on the Higher-Order Aberration Pattern After Small Incision Lenticule Extraction Surgery. AB - PURPOSE: To study the effect of myopia on the pattern change in higher-order aberrations after small incision lenticule extraction. METHODS: Sixty eyes of 60 patients were included: low myopia (<=-3.00 D), moderate myopia (-3.00 D to -6.00 D), and high myopia (>=-6.00 D). Total higher-order aberrations (tHOA), vertical coma ((Equation is included in full-text article.)), horizontal coma ((Equation is included in full-text article.)), and spherical aberration ((Equation is included in full-text article.)) were measured preoperatively and at postoperative 3 months. RESULTS: At the end of 3 months, tHOA changed significantly compared with the preoperative values (P < 0.05), except for (Equation is included in full-text article.)and (Equation is included in full text article.)in the low myopia group. The change in (Equation is included in full-text article.), (Equation is included in full-text article.), and (Equation is included in full-text article.)in the moderate group (-0.299, -0.175, and 0.108 MUm) was 2.020, 4.861, and 4.696 times higher than the low group (-0.148, 0.036, 0.023 MUm) (P = 0.002, 0.001, 0.001), respectively. The value in the high group (-0.331, -0.192, 0.154 MUm) was 1.107, 1.097 (P = 0.478, 0.665), and 1.426 times (P = 0.047) higher than the moderate group. The degree of myopia was positively correlated with Delta(Equation is included in full-text article.)(r = 0.447; P < 0.001) and Delta(Equation is included in full-text article.)(r = 0.496; P < 0.001), and negatively correlated with DeltatHOA (r = -0.363, P = 0.004) and Delta(Equation is included in full-text article.)(r = -0.599; P < 0.001). CONCLUSIONS: The study showed a different pattern of change in ocular aberrations after small incision lenticule extraction in patients with varying degrees of myopia. In patients with low myopia, there was no increase in (Equation is included in full-text article.)or (Equation is included in full-text article.). In high myopia, however, (Equation is included in full-text article.)increased with the degree of myopia, whereas the rising rate of coma was slowing. PMID- 28628504 TI - Morphology and Function of Meibomian Glands and Other Tear Film Parameters in Junior High School Students. AB - PURPOSE: We measured tear film parameters, including the morphology and function of meibomian glands, in junior high school students at 15 years of age. METHODS: A total of 111 eyes of 111 students (56 males and 55 females) were enrolled in the study. The ocular symptom score (0-14), after-school study time, lipid layer thickness (LLT) of the tear film, partial blink rate, lid margin abnormalities (0 4), tear film breakup time, corneal and conjunctival epithelial damage (fluorescein staining score, 0-9), meiboscore as determined by noncontact meibography (0-6), Schirmer test value, and meibum grade (0-3) were determined. The relationships between parameters were evaluated with the Spearman correlation coefficient (rho). RESULTS: The meiboscore was 2.8 +/- 1.2, and the meibum grade was 1.8 +/- 1.2. The meiboscore significantly correlated with the meibum grade (rho = 0.272, P = 0.004), Schirmer test value (rho = -0.220, P = 0.021), and LLT (rho = -0.264, P = 0.005). The breakup time significantly correlated with LLT (rho = 0.261, P = 0.006), meibum grade (rho = -0.338, P < 0.001), and fluorescein staining score (rho = -0.214, P = 0.025). The partial blink rate significantly correlated with the Schirmer test value (rho = -0.240, P = 0.011). The meiboscore (P < 0.001) and meibum grade (P = 0.032) were significantly greater in males than in females. CONCLUSIONS: The morphology and function of meibomian glands are altered even at 15 years of age, with the changes being more prominent in males than in females. PMID- 28628505 TI - Central Connections of the Lacrimal Functional Unit. AB - PURPOSE: To study the contribution of each eye to the reflex tear response, after unilateral and bilateral topical anesthesia. METHOD: A closed-eye, modified Schirmer test was performed bilaterally in 8 normal subjects, in a controlled environment chamber set to 23 degrees C, 45% relative humidity, and 0.08 m/s airflow. Eye drops were instilled into each eye 10 minutes before the Schirmer test. Experiments were as follows: 1) bilateral saline (control), 2) unilateral anesthesia (ipsilateral anesthetic; contralateral saline), and 3) bilateral anesthesia. RESULTS: There was no difference in between-eye wetting lengths in the saline control eyes (P = 0.394) or the bilaterally anesthetized eyes (P = 0.171). The wetting length was reduced in both eyes after bilateral anesthesia compared with saline controls (P = 0.001; P <= 0.0005). After unilateral anesthesia, the wetting length was reduced in the anesthetized eye compared with its saline control by 51.4% (P <= 0.0005) and compared with its fellow, unanesthetized eye (P = 0.005). The fellow eye value was also reduced compared with its saline control (P = 0.06). CONCLUSIONS: The wetting length was reduced by topical anesthesia, when instilled bilaterally and ipsilaterally. The latter response implies an ipsilateral, reflex sensory drive to lacrimal secretion. In the unanesthetized fellow eye, the reduction compared with its saline control was not quite significant. This implies a relative lack of central, sensory, reflex cross-innervation, although the possibility cannot entirely be ruled out. These results are relevant to the possibility of reflex lacrimal compensation from a normal fellow eye, in cases of unilateral corneal anesthesia. PMID- 28628506 TI - Why we need to research with children, not on children. PMID- 28628507 TI - Patient-reported outcomes following neoadjuvant chemotherapy or chemoradiotherapy treatment for esophageal cancer: a scoping review protocol. AB - REVIEW OBJECTIVE: The objective of this scoping review is to identify, describe and compare studies investigating patient-reported outcomes (PROs) in esophageal cancer patients following neoadjuvant (preoperative) chemotherapy (CT) and surgery or neoadjuvant chemoradiotherapy (CRT) and surgery.After preliminary searching of the literature and consultation with experts in the fields of esophageal cancer surgery, behavioral science, information systems and scoping review methodology, the following research objectives were defined as follows. PMID- 28628508 TI - Efficacy of a respiratory physiotherapy intervention for intubated and mechanically ventilated adults with community acquired pneumonia: a systematic review protocol. AB - REVIEW OBJECTIVES: The objective of the review is to map evidence on the efficacy of a respiratory physiotherapy intervention for intubated and mechanically ventilated adults with community acquired pneumonia (CAP). Specifically, the review seeks to investigate if respiratory physiotherapy interventions can achieve the following for intubated and mechanically ventilated adults with CAP. PMID- 28628509 TI - Medication safety programs in primary care: a scoping review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objective of this scoping review is to examine the characteristics of medication safety programs in the primary care setting and to map evidence on the outcome measures used to assess the effectiveness of medication safety programs in improving patient safety.The current review will be guided by the following research questions. PMID- 28628510 TI - Effectiveness of vocational rehabilitation on work participation in adults with musculoskeletal disorders: an umbrella review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this umbrella review is to determine the effectiveness of vocational rehabilitation on work participation in working age adults with musculoskeletal disorders (MSDs). More specifically the review will address the following questions. PMID- 28628511 TI - Absolute clinical skill decay in the medical, nursing and allied health professions: a scoping review protocol. AB - REVIEW QUESTIONS/OBJECTIVES: The objective of this scoping review is to examine and map absolute clinical skill decay in the medical, nursing and allied health professions and to map the range of approaches used to address decay of clinical skills in these professions.Specifically, the review questions are: which clinical skills, performed by which professional groups, are reported to be most susceptible to absolute clinical skill decay, and what approaches have been reported for addressing absolute clinical skill decay in the medical, nursing and allied health professions?In addressing the review questions, the following sub questions will also be addressed:It is anticipated that this scoping review will inform further systematic review/s on the topic of addressing clinical skill decay in the medical, nursing and allied health professions, as well as identify gaps in the research knowledge base that will inform further primary research. PMID- 28628512 TI - The impact of the Helping Babies Survive program on neonatal outcomes and health provider skills: a systematic review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objective of this review is to evaluate the impact of the Helping Babies Survive program on neonatal outcomes and healthcare provider knowledge and skills. This quantitative review will aim to answer the following question: What is the impact of the Helping Babies Survive modules (Helping Babies Breathe, Essential Care for Every Baby and Essential Care for Small Babies) on neonatal outcomes and health provider knowledge and skills? PMID- 28628513 TI - Indicators to measure pre-hospital care quality: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The current scoping review seeks to locate, examine and describe international literature on indicators used to measure pre-hospital care quality. Specifically, the review will. PMID- 28628514 TI - Effects of dexamethasone on sugammadex reversal times of rocuronium: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of the review is to identify the effect of dexamethasone on reversal times of rocuronium when utilizing sugammadex as the reversal agent. The incidence of the prolonged time to extubation in patients who have received concurrent dexamethasone and sugammadex therapies as opposed to those who have not received dexamethasone will also be examined.The proposed PICO question is as follows: In patients undergoing reversal of aminosteroidal neuromuscular blockade with rocuronium, does dexamethasone administration affect sugammadex reversal times, as compared to patients who have not received dexamethasone? PMID- 28628515 TI - Effectiveness of self-administered decision aids for people invited to participate in colorectal cancer screening: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective is to assess the effectiveness of self administered decision aids for people invited to participate in colorectal cancer screening. We will evaluate effects on informed choice, decisional conflict, knowledge, and participation in colorectal cancer screening. PMID- 28628516 TI - Risk factors for readmission to hospital in adult patients with heart failure and reduced ejection fraction: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this systematic review is to identify and synthesize the best available evidence on risk factors associated with hospital readmission at different time points within the first year after heart failure (HF) hospitalization in patients suffering from HF with reduced ejection fraction (EF).More specifically, the question is: what are the risk factors for the prediction of hospital readmission within seven, 15, 30, 60, 90, 180 and 365 days of discharge in hospitalized patients with HF with reduced EF aged 18 years or older? PMID- 28628517 TI - Experiences of stigma among family members of persons living with schizophrenia: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The aim of this qualitative systematic review is to explicate the experiences of stigma among family members of persons living with schizophrenia in any setting where they receive care. More specifically, the review will: (i) describe the experiences of stigma among family members of persons living with schizophrenia, (ii) describe the factors that influence the experiences of stigma, and (iii) describe the strategies and approaches used to cope with the stigma. PMID- 28628518 TI - Identifying predictors of change in the severity of untreated lower urinary tract symptoms in men: a systematic review protocol. AB - REVIEW OBJECTIVE: The objective of this systematic review is to synthesize the best available evidence on the predictors of change in the severity of untreated lower urinary tract symptoms in men in a non-hospital setting. PMID- 28628519 TI - Comparative efficacy of lifestyle intervention strategies on weight outcomes in people with psychosis: a systematic review and network meta-analysis protocol. AB - REVIEW QUESTION/OBJECTIVE:: (i) To systematically review and rank the efficacy of different types of lifestyle intervention strategies on weight outcomes (weight, body mass index [BMI], waist circumference and waist-to-hip ratio) in people with psychosis. (The efficacy of different types of lifestyle intervention strategies will be ranked by comparing the effect size on weight outcomes in people with psychotic disorders.) (ii) To stratify lifestyle interventions that target weight outcomes (weight, BMI, waist circumference and waist-to-hip ratio) in people with psychosis, according to their inclusion of dietary information that adheres with Australian Dietary Guidelines (National Health and Medical Research Council. Eat for Health, Australian Dietary Guidelines Canberra National Health and Medical Research Council; 2013).Specifically, the review question is: What lifestyle intervention strategies targeting weight outcomes (weight, BMI, waist circumference and waist-to-hip ratio) in people with psychosis compared to no treatment or various control conditions have the best efficacy? PMID- 28628520 TI - Effectiveness of teaching strategies to improve critical thinking in nurses in clinical practice: a systematic review protocol. AB - OBJECTIVES: The aim of this review is to identify and synthesize the best available evidence on the effectiveness of teaching strategies aimed at improving critical thinking (CT) in registered nurses who provide direct patient care. Specifically, the research question is: What are the best teaching strategies to improve CT skills in registered nurses who provide direct patient care? PMID- 28628521 TI - Experiences of acute pain in children who present to a healthcare facility for treatment: a systematic review of qualitative evidence. AB - BACKGROUND: Pain is a universal and complex phenomenon that is personal, subjective and specific. Despite growing knowledge in pediatric pain, management of children's pain remains sub-optimal and is linked to negative behavioral and physiological consequences later in life. As there is no synthesis of these studies, it was timely to undertake a systematic review. OBJECTIVES: To identify, evaluate and synthesize the existing qualitative evidence on children's experiences of acute pain, including pain management, within a healthcare facility. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Children aged four to 18 years (inclusive) attending a healthcare facility who experienced acute pain associated with any injury, medical condition or treatment. PHENOMENA OF INTEREST: Children's experiences and perceptions of their acute pain, pain management and expectations of others in managing their pain. Studies on children's experiences of pain in the postoperative context were excluded as a systematic review exploring this phenomenon had previously been published. Studies reporting on children's experiences of chronic pain were also excluded. CONTEXT: Any healthcare facility including general practitioners' surgeries, hospitals, emergency departments and outpatient clinics. TYPES OF STUDIES: Qualitative studies including phenomenology, grounded theory, ethnography, action research and feminist research designs. SEARCH STRATEGY: Using a three-step search strategy, databases were searched in December 2015 to identify both published and unpublished articles from 2000 to 2015. Studies published in languages other than English were excluded. METHODOLOGICAL QUALITY: All studies that met the inclusion criteria were assessed by at least two independent reviewers for methodological quality using a standardized critical appraisal tool from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI). DATA EXTRACTION: Data were extracted from the papers included in the review using standardized data extraction tool from JBI-QARI. DATA SYNTHESIS: Findings were pooled using JBI-QARI. Findings were rated according to their level of credibility and categorized based on similarity in meaning and then were subjected to a meta-synthesis. RESULTS: Four studies were included in this review. Two meta-syntheses were generated from five categories based on 21 findings: first, children can express their pain experiences in terms of cause, location, meaning and quality. Children's pain experiences include both physical and psychological dimensions. Children's pain experiences are influenced by their previous pain experiences, pain expectations and sociocultural factors. Second, children use a range of cognitive/behavioral and sensory/physical self-soothing strategies not only to help manage their pain, but also rely on the actions and presence of others as helpers when they are in pain. CONCLUSION: Children's pain is a multi-dimensional complex phenomenon relying upon a multi-modal approach to management. Children as young as four years are capable of articulating their pain in terms of location, intensity and depth. The way children perceive, express and respond to pain is shaped by sociocultural factors, previous pain experiences and their expectations of pain. Children, parents and healthcare professionals play an important role in managing children's pain experiences. PMID- 28628522 TI - Patient experiences of partnering with healthcare professionals for hand hygiene compliance: a systematic review. AB - BACKGROUND: Healthcare-associated infections pose a significant risk to patients in acute healthcare settings such as hospitals. Increasingly, patients are encouraged to be active participants and partner with healthcare professionals to positively influence their own safety and overall experience throughout their healthcare journey. Patient-focused safety initiatives include the empowerment of patients to be active partners with healthcare professionals in order to influence the hand hygiene behaviors and compliance of the healthcare professionals providing care to them. Partnering within the context of healthcare, and between the patient and healthcare professional, can be considered as a general concept that involves the empowerment of patients to participate in their care. Terms used to describe patient partnering within healthcare vary and include patient participation, patient-centeredness, patient empowerment and patient engagement. Although patients appear generally to have positive attitudes and intentions about engaging in their safety and partnering in the healthcare setting, their intentions and actual behaviors vary considerably. Patients appear less likely to engage in behaviors that require questioning of the perceived or real authority of healthcare professionals. A patient's intention and subsequent act of partnering with healthcare professionals for hand hygiene compliance by the healthcare professional are influenced by complex internal, external and social factors as well as cultural, behavioral and systematic factors. OBJECTIVES: To determine the best available evidence in relation to the experiences of the patient partnering with healthcare professionals for hand hygiene compliance. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review considered qualitative (critical or interpretive) papers that included adult in-patients and healthcare professionals (medical and nursing staff), in the acute hospital-care setting. Adult was considered to be any person aged 18 years or over. It should be noted that consumers in this context were patients and vice versa; the term patient is therefore used throughout this report for consistency. PHENOMENA OF INTEREST: The current review considered studies that investigated the experience of partnership between patients and healthcare professionals in relation to hand hygiene compliance. This review investigated the phenomena of partnering from both the perspectives of the patient and the healthcare professional. TYPES OF STUDIES: The current review considered studies that focused on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research. As qualitative studies were identified and on appraisal found to be of sufficient quality for inclusion, this review did not seek alternate forms of evidence such as text and opinion. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished studies from 1990 to May 2015. Studies published in English were considered for inclusion in this review. METHODOLOGICAL QUALITY: Qualitative papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI QARI). DATA EXTRACTION: Qualitative data were extracted from papers included in the review using the standardized data extraction tool from JBI-QARI. DATA SYNTHESIS: Qualitative research findings were pooled using JBI-QARI. RESULTS: Following the systematic search and critical appraisal process, three studies were included in the review for data extraction and synthesis of findings. The review process resulted in 29 study findings that were aggregated into seven categories. The categories generated two meta-synthesized findings. The two final synthesized findings were as follows. Synthesized finding 1: Organizational structures enable partnering between healthcare professionals and patients for hand hygiene compliance; however, the culture, beliefs and behaviors of healthcare professionals and patients do not fully support this partnership. Synthesized finding 2: Patients have differing levels of knowledge and balance partnering in hand hygiene against possible detrimental impacts on the caring relationship provided by healthcare professionals, out of concern for their own wellbeing, health outcomes, treatment and/or recovery. CONCLUSION: The current review highlights the complexity of the patient's experience of partnering with healthcare professionals for hand hygiene compliance. The experiences reported indicated that there is a possible disparity between the healthcare facility and healthcare professionals' promotion and intention of partnering for hand hygiene compliance, and the actual patient's acceptance, participation, partnership, experience and implementation of this initiative. This disconnect between intent and action appears to be influenced by a number of factors including organizational structures as well as drivers such as cultural beliefs and behavior. PMID- 28628523 TI - Effectiveness of surgery for adults with hallux valgus deformity: a systematic review. AB - BACKGROUND: Hallux valgus (HV) is a common foot deformity. In severe stages of this condition, surgery is often necessary. Currently, there is no systematic review comparing the effectiveness of surgery over conservative treatment. OBJECTIVES: The objective of this review was to establish the effectiveness of surgery compared to conservatory management for adults with HV. INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review included adults (18 years or over) with HV deformity, excluding adults with neurological problems causing foot deformities, for example, cerebral palsy, neuropathy, stroke and multiple sclerosis. TYPES OF INTERVENTIONS: The review included any type of HV surgery compared to no surgery, conservative treatment or different types of HV surgeries. OUTCOMES: The primary outcome was gait measurement, and secondary outcomes included quality of life, patient satisfaction, pain assessed using any validated assessment tool and adverse events. TYPES OF STUDIES: The review included randomized controlled trials. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished studies. A three-step search strategy was utilized in 16 databases without language and date limitations. METHODOLOGICAL QUALITY: Papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments developed by the Joanna Briggs Institute (JBI). DATA EXTRACTION: Data were extracted from papers included in the review using the standardized data extraction tool developed by the JBI. DATA SYNTHESIS: Quantitative data were, where possible, pooled in statistical meta-analysis using RevMan5 (Copenhagen: The Nordic Cochrane Centre, Cochrane). Effect sizes expressed as risk ratio (for categorical data) and mean differences (MD) or standardized MD (for continuous data) and their 95% confidence intervals were calculated for analysis. Where statistical pooling was not possible, the findings have been presented in narrative form. RESULTS: Searching identified 2412 citations. After removal of duplicates, paper retrieval and critical appraisal, 25 studies were included in the review. The included trials were of medium-to poor quality.Twenty-four trials compared the effectiveness of different types of surgeries. Meta-analysis revealed no difference in level of pain between distal chevron-type osteotomy and other surgical procedures (standard mean difference [SMD] 0.02, 95% confidence interval [CI] -0.24 to 0.28). One single trial reported that distal chevron osteotomy is more effective than Lindgren osteotomy in terms of walking speed (MD -0.24, 95% CI -0.43 to -0.05).One medium quality trial assessed the effectiveness of HV surgery compared to conservative or no treatment. This trial showed that surgery, specifically distal chevron osteotomy of the first metatarsal, is a more effective procedure for pain compared to conservative treatment (MD -15.00, 95% CI -22.79 to -7.21) and also no treatment in the first year (MD -18.00, 95% CI -25.62 to -10.38). CONCLUSION: The current systematic review showed that differences between various types of surgical procedures, specifically osteotomies of the first metatarsal on clinical outcomes, are minimal. There is evidence from one study, that surgery, specifically distal chevron osteotomy of the first metatarsal is a more effective procedure than conservative or no treatment in reducing pain in the first year following surgery. However, this systematic review has identified that there is a lack of high-quality studies comparing similar types of HV treatments that assess the same outcomes. PMID- 28628524 TI - Experiences of non-specialist nurses caring for patients and their significant others undergoing transitions during palliative end-of-life cancer care: a systematic review. AB - BACKGROUND: Non-specialist nurses, who are providing palliative end-of-life cancer care to patients and significant others undergoing psychosocial and existential transitions, may experience dissatisfaction, frustration and sorrow. On the other hand, they may also experience happiness, increased knowledge and personal growth. OBJECTIVE/QUESTION: What are non-specialist nurses' experiences when providing palliative end-of-life cancer care that involves the psychosocial and existential transitions of their patients and significant others? INCLUSION CRITERIA TYPES OF PARTICIPANTS: The current review considered studies that included a description of the experiences of non-specialist trained registered nurses (RNs) working in non-specialist wards. PHENOMENA OF INTEREST: The current review considered studies that investigated experiences of RNs when providing palliative end-of-life cancer care that involves the psychosocial and existential transitions of their patients and significant others. CONTEXT: The contact and care for patients and their significant others during palliative end-of-life cancer care. TYPES OF STUDIES: The current review considered studies that focused on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research. SEARCH STRATEGY: The search aimed at finding both published and unpublished studies in English, Danish, Norwegian, Swedish and German, and was unrestricted by time. Eleven electronic databases and seven websites were searched. METHODOLOGICAL QUALITY: Methodological validity of the qualitative papers was assessed independently by two reviewers using the standardized critical appraisal instruments from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI). DATA EXTRACTION: Data were extracted from papers included in the review using the standardized data extraction tool from the JBI-QARI. DATA SYNTHESIS: Qualitative research findings were synthesized using the JBI-QARI. RESULTS: A total of 81 findings were extracted from the three studies and allocated to five categories and merged into a meta-synthesis with the overarching synthesized finding related to the challenges that non-specialist nurses faced when providing palliative end-of-life cancer care. The summary of findings is illustrated below. CONCLUSION: The studies in this review provided useful and credible statements from non-specialist nurses working in non specialist wards about their challenges when providing palliative end-of-life cancer care to patients and their significant others undergoing psychosocial and existential transitions. PMID- 28628525 TI - Assessing sensitivity and specificity of the Manchester Triage System in the evaluation of acute coronary syndrome in adult patients in emergency care: a systematic review. AB - BACKGROUND: Triage is the first assessment and sorting process used to prioritize patients arriving in the emergency department (ED). As a triage tool, the Manchester Triage System (MTS) must have a high sensitivity to minimize the occurrence of under-triage, but must not compromise specificity to avoid the occurrence of overtriage. Sensitivity and specificity of the MTS can be calculated using the frequency of appropriately assigned clinical priority levels for patients presenting to the ED. However, although there are well established criteria for the prioritization of patients with suspected acute coronary syndrome (ACS), several studies have reported difficulties when evaluating patients with this condition. OBJECTIVE: The objective of this review was to synthesize the best available evidence on assessing the sensitivity and specificity of the MTS for screening high-level priority adult patients presenting to the ED with ACS. METHOD: The current review considered studies that evaluated the use of the MTS in the risk classification of adult patients in the ED. In this review, studies that investigated the priority level, as established by the MTS to screen patients under suspicion of ACS or the sensitivity and specificity of the MTS, for screening patients before the medical diagnosis of ACS were included. This review included both experimental and epidemiological study designs. RESULTS: The results were presented in a narrative synthesis. Six studies were appraised by the independent reviewers. All appraised studies enrolled a consecutive or random sample of patients and presented an overall moderate methodological quality, and all of them were included in this review. A total of 54,176 participants were included in the six studies. All studies were retrospective. Studies included in this review varied in content and data reporting. Only two studies reported sensitivity and specificity values or all the necessary data to calculate sensitivity and specificity. The remaining four studies presented either a sensitivity analysis or the number of true positives and false negatives. However, these four studies were conducted considering only data from patients diagnosed with ACS. Sensitivity values were relatively uniform among the studies: 0.70-0.80. A specificity of 0.59 was reported in the study including only patients with non-traumatic chest pain. On the other hand, in the study that included patients with any complaint, the specificity of MTS to screen patients with ACS was 0.97. CONCLUSION: The current review demonstrates that the MTS has a moderate sensitivity to evaluate patients with ACS. This may compromise time to treatment in the ED, an important variable in the prognosis of ACS. Atypical presentation of ACS, or high specificity, may also explain the moderate sensitivity demonstrated in this review. However, because of minimal data, it is not possible to confirm this hypothesis. It is difficult to determine the acceptable level of sensitivity or specificity to ensure that a certain triage system is safe. PMID- 28628526 TI - Determinants of HIV-1 CD4-Independent Brain Adaptation. AB - BACKGROUND: HIV-1 is known to adapt to the local environment in its usage of receptors, and it can become CD4 independent in the brain where the receptor is scarce. This adaptation is through amino acid variations, but the patterns of such variation are not yet well understood. Given that infection of long-lived CD4-low and CD4-negative cells in anatomical compartments such as the brain expands cell tropism in vivo and may serve as potential viral reservoirs that pose challenge for HIV eradication, understanding the evolution to CD4 independence and envelope conformation associated with infection in the absence of CD4 will not only broaden our insights into HIV pathogenesis but may guide functional cure strategies as well. METHODS: We characterize, by site-directed mutagenesis, neutralization assay, and structural analysis, a pair of CD4 dependent (cl2) and CD4-independent (cl20) envelopes concurrently isolated from the cerebral spinal fluid of an SHIV-infected macaque with neurological AIDS and with minimum sequence differences. RESULTS: Residues different between cl2 and cl20 are mapped to the V1V2 and surrounding regions. Mutations of these residues in cl2 increased its CD4 independence in infection, and the effects are cumulative and likely structural. CONCLUSIONS: Our data suggested that the determinants of CD4 independence in vivo mapped principally to V1V2 of gp120 that can destabilize the apex of the envelope spike, with an additional change in V4 that abrogated a potential N-linked glycan to facilitate movement of the V1V2 domain and further expose the coreceptor-binding site. PMID- 28628527 TI - Antiretroviral Prescription and Viral Suppression in a Representative Sample of HIV-Infected Persons in Care in 4 Large Metropolitan Areas of the United States, Medical Monitoring Project, 2011-2013. AB - BACKGROUND: Comparisons of antiretroviral therapy (ART) prescription and viral suppression among people in HIV care across US metropolitan areas are limited. Medical Monitoring Project, 2011-2013, data were used to describe and compare associations between sociodemographics and ART prescription and viral suppression for persons receiving HIV care. SETTING: Chicago, Los Angeles County (LAC), Philadelphia, and San Francisco in the United States. METHODS: Bivariate and multivariable methods were used. RESULTS: The proportion of patients prescribed ART (91%-93%) and virally suppressed (79%-88%) was consistent although more persons were virally suppressed in San Francisco compared with the other areas, and a smaller proportion was virally suppressed in Philadelphia compared with Chicago. In the combined cohort, persons aged 30-49 years were less likely than persons 50+ (adjusted prevalence ratio (aPR) -0.97, confidence interval (CI): 0.94 to 0.99); persons reporting non-injection drug use were less likely than non users (aPR = 0.94, CI: 0.90 to 0.98); and Hispanics were more likely than whites (aPR - 1.04, CI: 1.01 to 1.08) to be prescribed ART. Blacks (aPR = 0.93; CI: 0.87 to 0.99) and homeless persons (aPR = 0.87; CI: 0.80 to 0.95) were less likely to be virally suppressed in the combined cohort. In LAC, persons aged 30-49 years were less likely than those 50+ to be prescribed ART (aPR = 0.94, CI: 0.90 to 0.98). Younger persons (18-29) (aPR = 0.77; CI: 0.60 to 0.99) and persons with less than a high school education (aPR = 0.80; CI: 0.67 to 0.95) in Philadelphia, blacks (aPR = 0.90; CI: 0.83 to 0.99) and men who have sex with women only (aPR = 0.89; CI: 0.80 to 0.99) in Chicago, and homeless individuals in LAC (aPR = 0.80; CI: 0.67 to 0.94) were less likely to be virally suppressed. CONCLUSION: Data highlight the need to increase ART prescription to achieve viral suppression among younger persons, noninjection drug users, blacks, and homeless persons in US metropolitan areas and underscores the importance of region-specific strategies for affected subgroups. PMID- 28628528 TI - Increased Persistence of Initial Treatment for HIV Infection With Modern Antiretroviral Therapy. AB - BACKGROUND: Initiating antiretroviral therapy (ART) early improves clinical outcomes and prevents transmission. Guidelines for first-line therapy have changed with the availability of newer ART agents. In this study, we compared persistence and virologic responses with initial ART according to the class of anchor agent used. SETTING: An observational clinical cohort study in the Southeastern United States. METHODS: All HIV-infected patients participating in the UNC Center for AIDS Research Clinical Cohort (UCHCC) and initiating ART between 1996 and 2014 were included. Separate time-to-event analyses with regimen discontinuation and virologic failure as outcomes were used, including Kaplan Meier survival curves and adjusted Cox proportional hazards models. RESULTS: One thousand six hundred twenty-four patients were included (median age of 37 years at baseline, 28% women, 60% African American, and 28% white). Eleven percent initiated integrase strand transfer inhibitor (INSTI), 33% non-nucleoside reverse transcriptase inhibitor (NNRTI), 20% boosted protease inhibitor, 27% other, and 9% NRTI only regimens. Compared with NNRTI-containing regimens, INSTI-containing regimens had an adjusted hazard ratio of 0.49 (95% confidence interval, 0.35 to 0.69) for discontinuation and 0.70 (95% confidence interval, 0.46 to 1.06) for virologic failure. All other regimen types were associated with increased rates of discontinuation and failure compared with NNRTI. CONCLUSIONS: Initiating ART with an INSTI-containing regimen was associated with lower rates of regimen discontinuation and virologic failure. PMID- 28628531 TI - Costs and Length of Stay for the Acute Care of Patients with Motor-Complete Spinal Cord Injury Following Cervical Trauma: The Impact of Early Transfer to Specialized Acute SCI Center. AB - OBJECTIVE: Acute spinal cord injury (SCI) centers aim to optimize outcome following SCI. However, there is no timeframe to transfer patients from regional to SCI centers in order to promote cost-efficiency of acute care. Our objective was to compare costs and length of stay (LOS) following early and late transfer to the SCI center. DESIGN: A retrospective cohort study involving 116 individuals was conducted. Group 1 (n = 87) was managed in an SCI center promptly after the trauma, whereas group 2 (n = 29) was transferred to the SCI center only after surgery. Direct comparison and multivariate linear regression analyses were used to assess the relationship between costs, LOS, and timing to transfer to the SCI center. RESULTS: Length of stay was significantly longer for group 2 (median, 93.0 days) as compared with group 1 (median, 40.0 days; P < 10), and average costs were also higher (median, Canadian $17,920.0 vs. $10,521.6; P = 0.004) for group 2, despite similar characteristics. Late transfer to the SCI center was the main predictive factor of longer LOS and increased costs. CONCLUSIONS: Early admission to the SCI center was associated with shorter LOS and lower costs for patients sustaining tetraplegia. Early referral to an SCI center before surgery could lower the financial burden for the health care system. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Determine the optimal timing for transfer of individuals with cervical traumatic spinal cord injury (SCI) in order to decrease acute care resource utilization; (2) Determine benefits of a complete perioperative management in a specialized SCI center; and (3) Identify factors that may influence resource utilization for acute care following motor-complete tetraplegia. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 28628529 TI - Brief Report: Appraising Viral Load Thresholds and Adherence Support Recommendations in the World Health Organization Guidelines for Detection and Management of Virologic Failure. AB - BACKGROUND: The World Health Organization defines HIV virologic failure as 2 consecutive viral loads >1000 copies/mL, measured 3-6 months apart, with interval adherence support. We sought to empirically evaluate these guidelines using data from an observational cohort. SETTING: The Uganda AIDS Rural Treatment Outcomes study observed adults with HIV in southwestern Uganda from the time of antiretroviral therapy (ART) initiation and monitored adherence with electronic pill bottles. METHODS: We included participants on ART with a detectable HIV RNA viral load and who remained on the same regimen until the subsequent measurement. We fit logistic regression models with viral resuppression as the outcome of interest and both initial viral load level and average adherence as predictors of interest. RESULTS: We analyzed 139 events. Median ART duration was 0.92 years, and 100% were on a nonnucleoside reverse-transcriptase inhibitor-based regimen. Viral resuppression occurred in 88% of those with initial HIV RNA <1000 copies/mL and 42% if HIV RNA was >1000 copies/mL (P <0.001). Adherence after detectable viremia predicted viral resuppression for those with HIV RNA <1000 copies/mL (P = 0.011) but was not associated with resuppression for those with HIV RNA >1000 copies/mL (P = 0.894; interaction term P = 0.077). CONCLUSIONS: Among patients on ART with detectable HIV RNA >1000 copies/mL who remain on the same regimen, only 42% resuppressed at next measurement, and there was no association between interval adherence and viral resuppression. These data support consideration of resistance testing to help guide management of virologic failure in resource limited settings. PMID- 28628530 TI - Effects of salt loading and potassium supplement on the circadian blood pressure profile in salt-sensitive Chinese patients. AB - BACKGROUND AND OBJECTIVE: Salt-sensitive (SS) patients more frequently showed a nondipper blood pressure pattern and were associated with more serious target organ damage than non-SS patients. We aimed to investigate whether potassium supplement can improve the blunted nocturnal blood pressure fall in SS patients exposed to a high-salt diet. PATIENTS AND METHODS: Approximately 49 normotensive and mildly hypertensive Chinese patients received a study protocol of a 3 days of baseline examination, 7 days of a low-salt diet (3 g NaCl/day), 7 days of a high salt diet (18 g NaCl/day), and 7 days of a high-salt diet with a potassium supplement (18 g NaCl and 4.5 g KCl/day). The 24 h ambulatory blood pressure was determined at the end of each period. RESULTS: A total of 14 patients were classified as SS according to the at least 10% increase in their 24-h mean arterial pressure after high-salt loading. The night-to-day blood pressure ratio was significantly higher in SS patients than in non-SS patients during the high salt loading period (systolic 0.96+/-0.01 vs. 0.89+/-0.01, P<0.01; diastolic 0.96+/-0.01 vs. 0.92+/-0.01, P<0.05). Compared with the high-salt loading period, the night-to-day blood pressure ratio was significantly reversed by potassium supplement in SS patients (systolic 0.91+/-0.01 vs. 0.96+/-0.01, P<0.05; diastolic 0.91+/-0.01 vs. 0.96+/-0.01, P<0.05). CONCLUSION: Potassium supplement can improve the blunted nocturnal blood pressure fall in SS patients exposed to a high-salt diet, but the related mechanism needs to be studied further. PMID- 28628532 TI - Evaluation of the Effectiveness and Safety of Ultrasound-Guided Percutaneous Carpal Tunnel Release: A Cadaveric Study. AB - OBJECTIVE: The looped thread carpal tunnel release (TCTR) procedure is a minimally invasive percutaneous technique performed under ultrasound (US) to transect the transverse carpal ligament in patients with carpal tunnel syndrome. Study objectives were to evaluate the accuracy of identifying key US landmarks, safety, effectiveness, and technical difficulty of TCTR. DESIGN: Fourteen lightly embalmed cadaveric distal forearm-hand specimens were subject to US identification of key landmarks, TCTR procedure, and post-TCTR dissection. Outcome measures of interest were (1) correspondence between key landmarks (median nerve and 4 bony pillars of transverse carpal ligament) identified on US and anatomical structures exposed by dissection, (2) percentage of the transverse carpal ligament transected and location of the transection, (3) frequency of damage to adjacent structures, (4) time to complete procedure, and (5) operator assessment of technical difficulty of each TCTR procedure (0 = extremely easy, 10 = extremely difficult). RESULTS: (1) Skin markings delineating the position of US visualized landmarks corresponded almost perfectly to anatomical dissection. (2) Nine (64.2%) of 14 specimens had complete division of the transverse carpal ligament. In the remaining 5 specimens, an average of 68.8% of the ligament was transected. (3) No adjacent structures were damaged. (4) Time to complete the procedure was on average 9.9 +/- 4.6 minutes. (5) Average procedural difficulty was 4.3/10. CONCLUSIONS: Thread carpal tunnel release is potentially a safe, quick, and effective procedure to transect the transverse carpal ligament. Future clinical investigation is recommended. PMID- 28628533 TI - The Association Between Activity Limitation Stages and Admission to Facilities Providing Long-term Care Among Older Medicare Beneficiaries. AB - OBJECTIVE: This study aimed to examine whether activity limitation stages are associated with admission to facilities providing long-term care (LTC). DESIGN: Cohort study using Medicare Current Beneficiary Survey data from the 2005-2009 entry panels. A total of 14,580 community-dwelling Medicare beneficiaries 65 years or older were included. Proportional subhazard models examined associations between activity limitation stages and time to first LTC admission, adjusting for baseline sociodemographics and health conditions. RESULTS: The weighted annual rate of LTC admission was 1.1%. In the adjusted model, compared to activity of daily living (ADL) stage 0, the hazard ratios (95% confidence intervals [CIs]) were 2.0 (1.5-2.7), 3.9 (2.9-5.4), 3.6 (2.5-5.3), and 4.7 (2.5-9.0) for ADL stage I (mild limitation), ADL stage II (moderate limitation), ADL stage III (severe limitation), and ADL stage IV (complete limitation), respectively. Compared to instrumental ADL (IADL) stage 0, the hazard ratios, and 95% CIs for IADL stages I to IV were 2.0 (1.4-2.7), 3.7 (2.6-5.4), 4.6 (3.3-6.5), and 7.6 (4.6-12.3), respectively. CONCLUSIONS: Activity limitation stages are strongly associated with future admission to LTC and may therefore be useful in identifying specific supportive care needs among vulnerable older community-dwelling adults, which may reduce or the delay need for admission to LTC. PMID- 28628534 TI - Daily Physical Activity in Total Hip Arthroplasty Patients Undergoing Different Surgical Approaches: A Cohort Study. AB - OBJECTIVE: Muscle weakness due to trauma from the surgical approach is anticipated to affect the ability of the patient to undertake daily physical activity early after total hip arthroplasty (THA). The objective of this study was to compare daily physical activity on days 1 to 4 after discharge, in patients following THA performed by 1 of 3 surgical approaches. DESIGN: A cohort study included 60 hip osteoarthritis patients, scheduled for THA, allocated to direct lateral approach, posterior approach, or anterior approach. Daily physical activity was measured by an accelerometer, with upright time per 24 hours as primary outcome and walking time, number of steps, and number of upright events per 24 hours as secondary outcomes. RESULTS: There were no statistically significant group differences in any of the measures of daily physical activity (P > 0.290) or between days of follow-up (P > 0.155). Overall, the median participant had 3.50 hours (interquartile range, 2.85-4.81 hours) of upright time, and participants showed wide variation in all outcomes of daily physical activity. CONCLUSIONS: There were no differences in daily physical activity between THA patients undergoing different surgical approaches. The surgical approach may not be a limiting factor for daily physical activity early after surgery in a fast-track treatment course. PMID- 28628535 TI - Community-Based Rehabilitation to Improve Stroke Survivors' Rehabilitation Participation and Functional Recovery. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of a community based rehabilitation appropriate technique (CRAT) intervention program in increasing rehabilitation participation and improving functional recovery of stroke survivors. DESIGN: This study followed a quasi-experimental design. In each of 5 centers servicing approximately 50,000 individuals, 2 communities were designated as either the intervention or control community. A CRAT intervention program, including 2-year rehabilitation education and 3-month CRAT treatment, was regularly implemented in the intervention communities, whereas there was no special intervention in the control community. Two sampling surveys, at baseline and after intervention, were administered to evaluate the rehabilitation activity undertaken. In intervention communities, stroke survivor's motor function, daily activity, and social activity were evaluated pretreatment and posttreatment, using the Fugl-Meyer Motor Function Assessment, Barthel index, and Social Functional Activities Questionnaire. RESULTS: The proportion of individuals participating in rehabilitation-related activity was increased significantly (P < 0.05) in intervention communities, as compared with control communities. In intervention communities, the patients' Fugl-Meyer Motor Function Assessment, Barthel index, and Social Functional Activities Questionnaire scores were significantly improved after rehabilitation (P < 0.05) across all ages and disease courses, except for the FAQ scores in patients younger than 50 years (P > 0.05). CONCLUSIONS: Community-based rehabilitation appropriate technique increases rehabilitation participation rates and enhances motor function, daily activity, and social activity of stroke survivors. PMID- 28628536 TI - Forging Alliances in Interdisciplinary Rehabilitation Research (FAIRR): A Logic Model. AB - In a patient-centered care era, rehabilitation can benefit from researcher clinician collaboration to effectively and efficiently produce the interdisciplinary science that is needed to improve patient-centered outcomes. The authors propose the use of the Forging Alliances in Interdisciplinary Rehabilitation Research (FAIRR) logic model to provide guidance to rehabilitation scientists and clinicians who are committed to growing their involvement in interdisciplinary rehabilitation research. We describe the importance and key characteristics of the FAIRR model for conducting interdisciplinary rehabilitation research. PMID- 28628538 TI - Memory Rehabilitation Strategies in Nonsurgical Temporal Lobe Epilepsy: A Review. AB - People with temporal lobe epilepsy (TLE) who have not undergone epilepsy surgery often complain of memory deficits. Cognitive rehabilitation is employed as a remedial intervention in clinical settings, but research is limited and findings concerning efficacy and the criteria for choosing different approaches have been inconsistent. We aimed to appraise existing evidence on memory rehabilitation in nonsurgical individuals with temporal lobe epilepsy and to ascertain the effectiveness of specific strategies. A scoping review was preferred given the heterogeneous nature of the interventions. A comprehensive literature search using MEDLINE, EMBASE, CINAHL, AMED, Scholars Portal/PSYCHinfo, Proceedings First, and ProQuest Dissertations and Theses identified articles published in English before February 2016. The search retrieved 372 abstracts. Of 25 eligible studies, six were included in the final review. None included pediatric populations. Strategies included cognitive training, external memory aids, brain training, and noninvasive brain stimulation. Selection criteria tended to be general. Overall, there was insufficient evidence to make definitive conclusions regarding the efficacy of traditional memory rehabilitation strategies, brain training, and noninvasive brain stimulation. The review suggests that cognitive rehabilitation in nonsurgical TLE is underresearched and that there is a need for a systematic evaluation in this population. PMID- 28628537 TI - Needs of Stroke Survivors as Perceived by Their Caregivers: A Scoping Review. AB - OBJECTIVE: Caregivers usually are not involved while planning the stroke survivor's medical and rehabilitation goals and interventions. This review aimed to identify the needs of stroke survivors as perceived by their caregivers. DESIGN: A literature search from 2003 to 2014 was conducted using Medline, CINAHL, PsychINFO, and Google Scholar. Sixty-six studies were included. Most studies excluded did not encompass caregivers' perspectives. Four reviewers screened the titles, abstracts, and full texts of the articles for inclusion. The data extracted from these studies were synthetized into metathemes. RESULTS: Fifty-two qualitative, ten quantitative survey, and four mixed-methods studies were included in the final synthesis. The studies came from 11 countries. The data synthesis produced following three metathemes: (a) body functional needs, including psychological function, physical function, cognitive function, and uncertainty related to function; (b) activity and participatory needs, including healthy lifestyle, physical activities, speech, independence, cognitive activities, and uncertainty related to activities and participation; and (c) environmental needs, encompassing support, services, safety, accommodation and accessibility, and uncertainty related to environmental factors. CONCLUSIONS: This scoping review identified a range of needs of stroke survivors as perceived by their caregivers. Incorporating the caregiver's preferences and values into clinical decisions may improve outcomes among stroke survivors. PMID- 28628539 TI - Effects of an Off-Axis Pivoting Elliptical Training Program on Gait Function in Persons With Spastic Cerebral Palsy: A Preliminary Study. AB - This preliminary study examined the effects of off-axis elliptical training on reducing transverse-plane gait deviations and improving gait function in 8 individuals with cerebral palsy (CP) (15.5 +/- 4.1 years) who completed an training program using a custom-made elliptical trainer that allows transverse plane pivoting of the footplates during exercise. Lower-extremity off-axis control during elliptical exercise was evaluated by quantifying the root-mean square and maximal angular displacement of the footplate pivoting angle. Lower extremity pivoting strength was assessed. Gait function and balance were evaluated using 10-m walk test, 6-minute-walk test, and Pediatric Balance Scale. Toe-in angles during gait were quantified. Participants with CP demonstrated a significant decrease in the pivoting angle (root mean square and maximal angular displacement; effect size, 1.00-2.00) and increase in the lower-extremity pivoting strength (effect size = 0.91-1.09) after training. Reduced 10-m walk test time (11.9 +/- 3.7 seconds vs. 10.8 +/- 3.0 seconds; P = 0.004; effect size = 1.46), increased Pediatric Balance Scale score (43.6 +/- 12.9 vs. 45.6 +/- 10.8; P = 0.042; effect size = 0.79), and decreased toe-in angle (3.7 +/- 10.5 degrees vs. 0.7 +/- 11.7 degrees; P = 0.011; effect size = 1.22) were observed after training. We present an intervention to challenge lower-extremity off-axis control during a weight-bearing and functional activity for individuals with CP. Our preliminary findings suggest that this intervention was effective in enhancing off-axis control, gait function, and balance and reducing in-toeing gait in persons with CP. PMID- 28628540 TI - Evaluating Disability Insurance Assistance as a Specific Intervention by Physiatrists at a Cancer Center. AB - Because of their expertise, physiatrists provide disability insurance assistance for cancer survivors. In this brief report, we perform a descriptive retrospective analysis of all new (354) outpatient physiatry consultations from January 1, 2009, to December 31, 2013, at a National Cancer Institute Comprehensive Cancer Center. Disability and/or work accommodations were brought up at some point with the physiatrist during the duration of their care for 131 (37%) of 354 patients. More than 90% of the discussions took place during the first visit. Of those patients who had a documented disability/employment discussion, 58 (44.3%) of 131 patients were originally referred for disability assistance specifically, and 58 (44.3%) of 131 also had disability insurance paperwork completed by the physiatrist. Outcomes of initial physiatry disability insurance assistance were 45 (77.6%) of 58 approved/renewed, 5 (8.6%) of 58 denied, and 8 (13.8%) of 58 unknown/died during the disability application process. The median form size was 33 (SD, 25.95) items. This study is the first of its kind and provides an initial look at work-related discussions and support with disability insurance paperwork as a specific intervention provided by physiatrists at a cancer center. The results are compelling and demonstrate that physiatrists frequently provide these interventions. These interventions take considerable time and effort but are generally successful. PMID- 28628541 TI - Apathy Due to Injury of the Prefrontocaudate Tract Following Mild Traumatic Brain Injury. AB - In this study, we report on a patient who developed apathy resulting from injury to the prefrontocaudate tract following mild traumatic brain injury (TBI), which was observed on diffusion tensor tractography (DTT). A 46-year-old female patient was involved in a bus accident. Her history included intracerebral hemorrhage (ICH) in the left putamen 4 years ago before the head trauma, and her family reported that she had fully recovered. She developed apathy after the TBI, worsening over time. Decreased neural connectivity of the left caudate nucleus (CN) to the left upper medial prefrontal cortex (PFC) resulting from the ICH was observed on the pre-TBI-DTT, whereas on the post-TBI-DTT (28 months after TBI), the neural connectivity of the left CN to the left upper medial PFC was increased, whereas that to the left lower medial PFC and orbitofrontal cortex was decreased. In the right hemisphere, decreased neural connectivity of the CN to the medial PFC and orbitofrontal cortex was observed on the post-TBI-DTT compared with the pre-TBI-DTT. Injury of the prefrontocaudate tract was observed in a patient with old ICH who developed apathy following mild TBI, using DTT. PMID- 28628542 TI - A Rare Intramedullary Spinal Cord Metastasis from a Retroperitoneal Leiomyosarcoma Presenting as a Non-Traumatic Spinal Cord Injury. AB - Leiomyosarcoma (LMS) is a rare but well-recognized malignant soft tissue sarcoma of smooth muscle origin. Metastases commonly occur in the lungs, liver, kidney, brain, and bone. Cases of metastatic osseous lesions or other extradural space occupying masses secondary to LMS leading to neurologic compromise are relatively commonplace in the literature. Conversely, cases of intramedullary spinal cord metastasis (ISCM), an unusual entity as a sequela of any cancer, are exceedingly rare as a consequence of LMS. Only 2 cases of an ISCM from LMS are currently documented in the literature, and to the best of our knowledge, no case is described in the rehabilitation literature. This case report presents a patient with a history of longstanding metastatic LMS presenting with incomplete paraplegia, neurogenic bowel and bladder, and neuropathic pain. The patient was found to have an ISCM of the thoracic spinal cord. She made functional gains with concurrent inpatient rehabilitation and radiation but was unable to perform her own intermittent catheterization program, bowel program, or transfers and was unable to discharge home independently. Intramedullary spinal cord metastasis is a rare and potentially devastating consequence of LMS or any primary cancer, but can be amenable to common interventions in the acute inpatient rehabilitation setting. PMID- 28628543 TI - Bilateral Rectus Femoris Muscle Rupture Following Statin Medication. PMID- 28628544 TI - Sciatic Nerve Schwannoma in the Gluteal Region Mimicking Sciatica. PMID- 28628545 TI - Salbutamol Therapy for Food Impaction in Eosinophilic Oesophagitis. PMID- 28628547 TI - Complex Cases: A Force for Change. PMID- 28628546 TI - The Impact of Multiple Viral Respiratory Infections on Outcomes for Critically Ill Children. AB - OBJECTIVE: Advances in molecular diagnosis have led to increased testing for single and multiviral respiratory infection in routine clinical practice. This study compares outcomes between single and multiviral respiratory infections in children younger than 5 years old admitted to the PICU with respiratory failure. DESIGN: Retrospective, single-center, cohort study. SETTING: Tertiary-care, freestanding children's hospital. PATIENTS: Children younger than 5 years old admitted to the PICU with respiratory failure and positive respiratory molecular panel. Children with comorbidity or history of similar infections were excluded. After exclusions, the children were divided into single or multiviral groups. Their demographics and PICU outcomes were compared and analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four hundred seventy-seven children with respiratory failure tested positive on respiratory panel, out of which 432 had single and 45 had multiple viruses. Children with multiple viruses had a longer PICU stay (4.5 d) compared with the single viral group (3 d; p < 0.002). Multiviral infections were associated with higher utilization of central line (odds ratio, 2.4; 95% CI, 1.3-4.6; p = 0.008) but not with the need of invasive ventilation requirement or cardiovascular dysfunction. Further analysis among invasively ventilated patients showed multiviral infections resulted in higher association of prolonged ventilation (> 7 d) (odds ratio, 3.4; 95% CI, 1.2-9.4; p = 0.01) and bacterial lower respiratory tract infection confirmed by quantitative bronchoalveolar lavage (odds ratio, 2.1; 95% CI, 1.1-11.2; p = 0.03). Infections with human rhinovirus/Enterovirus, Adenovirus, parainfluenza, and influenza formed a significantly larger proportions of cases (p = 0.00089) as multiviral infections compared with individual infections. CONCLUSIONS: Multiviral infections were associated with longer PICU stay, with prolonged mechanical ventilation, with bacterial lower respiratory infections, and with central line requirement. Certain common viruses resulted in higher percentages of PICU admission as multiviral infections. PMID- 28628548 TI - Clinical Outcome Measures for Lateropulsion Poststroke: An Updated Systematic Review. AB - BACKGROUND AND PURPOSE: Contraversive Lateropulsion, also referred to as contraversive pushing, pusher behavior, and pusher syndrome, can be associated with increased hospital length of stay, increased health care costs, and delayed outcomes in persons with stroke. The purpose of this updated systematic review was to identify scales used to classify contraversive lateropulsion, investigate literature that addresses their clinimetric properties, and create a resource for clinicians recommending use in clinical practice. METHODS: Three databases were searched for articles from inception to March 2017. The search strategy followed Cochrane Collaboration guidelines. The Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was applied to evaluate methodological quality. RESULTS: Four hundred three records were screened. Seven studies met inclusion criteria. Four scales were identified: the Scale for Contraversive Pushing (SCP), the Modified Scale for Contraversive Pushing (M-SCP), the Burke Lateropulsion Scale (BLS), and the Swedish Scale for Contraversive Pushing (S-SCP). Psychometric property investigation was most robust for the SCP and the BLS. Cross-cultural validity has not been fully investigated in scales used outside of their country of origin. DISCUSSION AND CONCLUSIONS: The BLS is recommended for identifying contraversive lateropulsion. The scale assesses the presence of contraversive lateropulsion across several functional tasks, from rolling to walking, and is the only scale originally written in English. The BLS is the only tool to receive ratings greater than poor for reliability and responsiveness. The BLS should be implemented as soon as contraversive lateropulsion is suspected to guide frontline clinicians' initial plan of care, allow objective identification of change over time, and facilitate easier investigation of interventional efficacy.Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A177). PMID- 28628549 TI - A Classification System to Guide Physical Therapy Management in Huntington Disease: A Case Series. AB - BACKGROUND AND PURPOSE: Individuals with Huntington disease (HD), a rare neurological disease, experience impairments in mobility and cognition throughout their disease course. The Medical Research Council framework provides a schema that can be applied to the development and evaluation of complex interventions, such as those provided by physical therapists. Treatment-based classifications, based on expert consensus and available literature, are helpful in guiding physical therapy management across the stages of HD. Such classifications also contribute to the development and further evaluation of well-defined complex interventions in this highly variable and complex neurodegenerative disease. The purpose of this case series was to illustrate the use of these classifications in the management of 2 individuals with late-stage HD. CASE DESCRIPTION: Two females, 40 and 55 years of age, with late-stage HD participated in this case series. Both experienced progressive declines in ambulatory function and balance as well as falls or fear of falling. Both individuals received daily care in the home for activities of daily living. INTERVENTION: Physical therapy Treatment Based Classifications for HD guided the interventions and outcomes. Eight weeks of in-home balance training, strength training, task-specific practice of functional activities including transfers and walking tasks, and family/carer education were provided. OUTCOMES: Both individuals demonstrated improvements that met or exceeded the established minimal detectible change values for gait speed and Timed Up and Go performance. Both also demonstrated improvements on Berg Balance Scale and Physical Performance Test performance, with 1 of the 2 individuals exceeding the established minimal detectible changes for both tests. Reductions in fall risk were evident in both cases. DISCUSSION: These cases provide proof-of-principle to support use of treatment-based classifications for physical therapy management in individuals with HD. Traditional classification of early-, mid-, and late-stage disease progression may not reflect patients' true capabilities; those with late-stage HD may be as responsive to interventions as those at an earlier disease stage.Video Abstract available for additional insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A172). PMID- 28628550 TI - Visual and Motor Recovery After "Cognitive Therapeutic Exercises" in Cortical Blindness: A Case Study. AB - BACKGROUND AND PURPOSE: Spontaneous visual recovery is rare after cortical blindness. While visual rehabilitation may improve performance, no visual therapy has been widely adopted, as clinical outcomes are variable and rarely translate into improvements in activities of daily living (ADLs). We explored the potential value of a novel rehabilitation approach "cognitive therapeutic exercises" for cortical blindness. CASE DESCRIPTION: The subject of this case study was 48-year old woman with cortical blindness and tetraplegia after cardiac arrest. Prior to the intervention, she was dependent in ADLs and poorly distinguished shapes and colors after 19 months of standard visual and motor rehabilitation. Computed tomographic images soon after symptom onset demonstrated acute infarcts in both occipital cortices. INTERVENTION: The subject underwent 8 months of intensive rehabilitation with "cognitive therapeutic exercises" consisting of discrimination exercises correlating sensory and visual information. OUTCOMES: Visual fields increased; object recognition improved; it became possible to watch television; voluntary arm movements improved in accuracy and smoothness; walking improved; and ADL independence and self-reliance increased. Subtraction of neuroimaging acquired before and after rehabilitation showed that focal glucose metabolism increases bilaterally in the occipital poles. DISCUSSION: This study demonstrates feasibility of "cognitive therapeutic exercises" in an individual with cortical blindness, who experienced impressive visual and sensorimotor recovery, with marked ADL improvement, more than 2 years after ischemic cortical damage.Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A173). PMID- 28628551 TI - A Clinical Framework for Functional Recovery in a Person With Chronic Traumatic Brain Injury: A Case Study. AB - BACKGROUND AND PURPOSE: This case study describes a task-specific training program for gait walking and functional recovery in a young man with severe chronic traumatic brain injury. CASE DESCRIPTION: The individual was a 26-year old man 4 years post-traumatic brain injury with severe motor impairments who had not walked outside of therapy since his injury. He had received extensive gait training prior to initiation of services. His goal was to recover the ability to walk. INTERVENTION: The primary focus of the interventions was the restoration of walking. A variety of interventions were used, including locomotor treadmill training, electrical stimulation, orthoses, and specialized assistive devices. A total of 79 treatments were delivered over a period of 62 weeks. OUTCOMES: At the conclusion of therapy, the client was able to walk independently with a gait trainer for approximately 1km (over 3000 ft) and walked in the community with the assistance of his mother using a rocker bottom crutch for distances of 100m (330 ft). DISCUSSION: Specific interventions were intentionally selected in the development of the treatment plan. The program emphasized structured practice of the salient task, that is, walking, with adequate intensity and frequency. Given the chronicity of this individual's injury, the magnitude of his functional improvements was unexpected.Video Abstract available for additional insights from the Authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A175). PMID- 28628552 TI - A Case Study of High-Velocity, Persistent Geotropic Nystagmus: Is This BPPV? AB - BACKGROUND AND PURPOSE: Deciphering the cause for a persistent, direction changing geotropic nystagmus can be difficult. Migraine and light cupula are two possible causes, though can be confused with benign paroxysmal positional vertigo (BPPV) affecting the horizontal semicircular canal. In migraine, the persistent geotropic nystagmus tends to be slow; in light cupula, the nystagmus has been illustrated to beat in the direction opposite that of prone positioning. CASE DESCRIPTION: Here we describe a patient with initial occurrence then recurrence of a high velocity (>=30 deg/sec), persistent direction-changing geotropic nystagmus and vertigo with an intensity variable based on head position, which was difficult to manage. This patient did not have migraine. The case presented uniquely as it was unlikely due to canalithiasis of the horizontal semicircular canal yet the presentation was not clearly related to the light cupula phenomena either. INTERVENTION: In this case, the physical therapist attempted to use the barbeque roll canalith repositioning maneuver (CRM) even though the direction changing geotropic nystagmus was persistent. The nystagmus did not resolve during the clinic visit. OUTCOMES AND DISCUSSION: The persistent, high velocity geotropic nystagmus resolved within 1 week, however, this resolution was likely spontaneous and not due to the CRM intervention. Our case suggests that physical therapists assessing persistent geotropic nystagmus should wait long enough for the nystagmus to stop (~2 minutes), test for fatigue by repeating the positional nystagmus tests, incorporate a head flexion component as part of the positional testing, and attempt to identify a null point.Video Abstract available for additional insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A178). PMID- 28628553 TI - Single-Case Design, Analysis, and Quality Assessment for Intervention Research. AB - BACKGROUND AND PURPOSE: The purpose of this article is to describe single-case studies and contrast them with case studies and randomized clinical trials. We highlight current research designs, analysis techniques, and quality appraisal tools relevant for single-case rehabilitation research. SUMMARY OF KEY POINTS: Single-case studies can provide a viable alternative to large group studies such as randomized clinical trials. Single-case studies involve repeated measures and manipulation of an independent variable. They can be designed to have strong internal validity for assessing causal relationships between interventions and outcomes, as well as external validity for generalizability of results, particularly when the study designs incorporate replication, randomization, and multiple participants. Single-case studies should not be confused with case studies/series (ie, case reports), which are reports of clinical management of a patient or a small series of patients. RECOMMENDATIONS FOR CLINICAL PRACTICE: When rigorously designed, single-case studies can be particularly useful experimental designs in a variety of situations, such as when research resources are limited, studied conditions have low incidences, or when examining effects of novel or expensive interventions. Readers will be directed to examples from the published literature in which these techniques have been discussed, evaluated for quality, and implemented. PMID- 28628554 TI - JNPT Thanks Retiring Editorial Board Members & Welcomes New Editorial Board Members. PMID- 28628555 TI - JNPT Congratulates APTA Award Winners. PMID- 28628556 TI - Real-time imaging of epileptic seizures in rats using electrical impedance tomography. AB - The presence of multiple or diffuse lesions on imaging is a contraindication to surgery for patients with intractable epilepsy. Theoretically, as a functional imaging technique, electrical impedance tomography (EIT) can accurately image epileptic foci. However, most current studies are limited to examining epileptic spikes and few studies use EIT for real-time imaging of seizure activity. Moreover, little is known about changes in electrical impedance during seizures. In this study, we used EIT to monitor seizure progression in real time and analyzed changes in electrical impedance during seizures. EIT and electroencephalography data were recorded simultaneously in rats. Sixty-three seizures were recorded from the cortices of eight rats. During 54 seizures, the average impedance decreased by between 4.86 and 9.17% compared with the baseline. Compared with the control group, the average impedance of the experimental group decreased significantly (P=0.004). Our results indicate that EIT can be used to detect and image electrical impedance reduction within lesions during epileptic seizures. PMID- 28628557 TI - Excessive hemodynamic activity in the superior frontal cortex during the flanker task in children with attention deficit hyperactivity disorder. AB - Near-infrared spectroscopy studies in children with attention deficit hyperactivity disorder (ADHD) have shown excessive prefrontal activity responsible for coping with interference. However, it is possible that the previous results were influenced by verbal, reading, and memory developments. The flanker task is an interference task that does not require a verbal response, reading, or memorization. We examined activity in the superior frontal cortex (SFC) during the flanker task in 12 children with ADHD and 14 children with typical development using near-infrared spectroscopy. SFC activity was significantly greater in children with ADHD than in those with typical development. The results showed excessive interference coping activity in children with ADHD irrespective of verbal, reading, and memory development. Moreover, SFC activity was positively correlated with the inattention subscale score of the ADHD rating scale. We suggest that children with ADHD need greater SFC activation to cope with interference, and the inefficient mechanism is demanding and hard to sustain, which causes inattention symptoms of children with ADHD. PMID- 28628558 TI - Genetics of pleiotropic effects of dexamethasone. AB - OBJECTIVES: Glucocorticoids such as dexamethasone have pleiotropic effects, including desired antileukemic, anti-inflammatory, or immunosuppressive effects, and undesired metabolic or toxic effects. The most serious adverse effects of dexamethasone among patients with acute lymphoblastic leukemia are osteonecrosis and thrombosis. To identify inherited genomic variation involved in these severe adverse effects, we carried out genome-wide association studies (GWAS) by analyzing 14 pleiotropic glucocorticoid phenotypes in 391 patients with acute lymphoblastic leukemia. PATIENTS AND METHODS: We used the Projection Onto the Most Interesting Statistical Evidence integrative analysis technique to identify genetic variants associated with pleiotropic dexamethasone phenotypes, stratifying for age, sex, race, and treatment, and compared the results with conventional single-phenotype GWAS. The phenotypes were osteonecrosis, central nervous system toxicity, hyperglycemia, hypokalemia, thrombosis, dexamethasone exposure, BMI, growth trajectory, and levels of cortisol, albumin, and asparaginase antibodies, and changes in cholesterol, triglycerides, and low density lipoproteins after dexamethasone. RESULTS: The integrative analysis identified more pleiotropic single nucleotide polymorphism variants (P=1.46*10( 215), and these variants were more likely to be in gene-regulatory regions (P=1.22*10(-6)) than traditional single-phenotype GWAS. The integrative analysis yielded genomic variants (rs2243057 and rs6453253) in F2RL1, a receptor that functions in hemostasis, thrombosis, and inflammation, which were associated with pleiotropic effects, including osteonecrosis and thrombosis, and were in regulatory gene regions. CONCLUSION: The integrative pleiotropic analysis identified risk variants for osteonecrosis and thrombosis not identified by single-phenotype analysis that may have importance for patients with underlying sensitivity to multiple dexamethasone adverse effects. PMID- 28628559 TI - The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. AB - Five-year survival rates of pediatric acute lymphoblastic leukemia (ALL) have reached 90% in the developed countries. However, toxicity because of methotrexate (MTX) occurs frequently. Variety in the occurrence of toxicity is partly determined by single nucleotide polymorphisms (SNPs) in coding regions. Recently, five SNPs in non-coding pre-microRNAs and microRNA processing (miRNA) genes were identified in association with MTX-induced oral mucositis. This study aimed to replicate the association of these miRNA variants in relation to MTX-induced oral mucositis in a prospective childhood ALL cohort. Three out of five SNPs with a minor allele frequency more than 0.15 [CCR4-NOT transcription complex (CNOT4) rs3812265, miR-1206 rs2114358, miR-2053 rs10505168] were analyzed in 117 pediatric ALL patients treated with 5 g/m MTX (DCOG ALL-10). Oral mucositis was defined as grade more than or equal to 3 according to the National Cancer Institute criteria. rs2114358 in miR-1206 was associated with oral mucositis [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.1-11.5], whereas we did not confirm the association of CNOT4 rs3812265 (OR: 0.69; 95% CI: 0.27-1.80) and miR-2053 rs10505168 (OR: 2.50; 95% CI: 0.76-8.24). Our results replicate the association between rs2114358 in miR-1206 and MTX-induced oral mucositis in childhood ALL. Genetic variation in miR-1206 has potential as a novel biomarker to predict MTX-induced toxicity. PMID- 28628561 TI - The Surgeon Volume-outcome Relationship: Not Yet Ready for Policy. AB - OBJECTIVE: Increasing surgeon volume may improve outcomes for index operations. We hypothesized that there may be surrogate operative experiences that yield similar outcomes for surgeons with a low-volume experience with a specific index operation, such as esophagectomy. BACKGROUND: The relationship between surgeon volume and outcomes has potential implications for credentialing of surgeons. Restrictions of privileges based on surgeon volume are only reasonable if there is no substitute for direct experience with the index operation. This study was aimed at determining whether there are valid surrogates for direct experience with a sample index operation-open esophagectomy. METHODS: The Nationwide Inpatient Sample (2003-2009) was utilized. Surgeons were stratified into low and high-volume groups based on annual volume of esophagectomy. Surrogate volume was defined as the aggregate annual volume per surgeon of upper gastrointestinal operations including excision of esophageal diverticulum, gastrectomy, gastroduodenectomy, and repair of diaphragmatic hernia. RESULTS: In all, 26,795 esophagectomies were performed nationwide (2003-2009), with a crude inhospital mortality rate of 5.2%. Inhospital mortality decreased with increasing volume of esophagectomies performed annually: 7.7% and 3.8% for low and high-volume surgeons, respectively (P < 0.0001). Among surgeons with a low-volume esophagectomy experience, increasing volume of surrogate operations improved the outcomes observed for esophagectomy: 9.7%, 7.1%, and 4.3% for low, medium, and high-surrogate-volume surgeons, respectively (P = 0.016). CONCLUSIONS: Both operation-specific volume and surrogate volume are significant predictors of inhospital mortality for esophagectomy. Based on these observations, it would be premature to limit hospital privileges based solely on operation-specific surgeon volume criteria. PMID- 28628560 TI - Genetic coding variants in the niacin receptor, hydroxyl-carboxylic acid receptor 2, and response to niacin therapy. AB - OBJECTIVE: Niacin has been used for seven decades to modulate plasma lipids, but its mechanism of action is still unclear. We sought to determine whether variants in the niacin receptor gene, hydroxyl-carboxylic receptor 2 (HCAR2), are associated with lipid response to treatment. PARTICIPANTS AND METHODS: Coding variants, rs7314976 (p.R311C) and rs2454727 (p.M317I), were genotyped in 2067 participants from the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial. AIM-HIGH was a randomized, placebo-controlled trial that was conducted to assess the effect of extended-release niacin in patients with cardiovascular disease aggressively treated with low-density lipoprotein cholesterol-lowering therapy. RESULTS: There was no association of p.R311C or p.M317I with changes in low density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol at 1 year in groups receiving placebo or extended-release niacin. In White patients, the reduction in lipoprotein (a) [Lp(a)] in response to niacin was greater in homozygous carriers of the major 317M allele (-22.7%; P=0.005) compared with minor allele carriers (-15.3%). This was directionally consistent in the Black participants. Upon combining both groups, the reduction in Lp(a) in response to niacin was significantly greater in the homozygous major allele carriers (-23.0%; P=0.003) compared with minor allele carriers (-15.2%). CONCLUSION: Understanding the genetic contribution toward variation in response to niacin therapy, including Lp(a) reduction, could uncover mechanisms by which niacin decreases Lp(a), an important independent risk factor for cardiovascular disease. PMID- 28628562 TI - Robotic Versus Video-assisted Lobectomy/Segmentectomy for Lung Cancer: A Meta analysis. AB - : : Objective: To compare the safety/efficacy of the robotic-assisted lobectomy/segmentectomy (RAL/S) with the video-assisted lobectomy/segmentectomy (VAL/S) for radical lung cancer resection. BACKGROUND: It remains uncertain whether the newly developed RAL/S is comparable with the VAL/S. METHODS: A comprehensive search of online databases was performed. Perioperative outcomes were synthesized. Cumulative meta-analysis was performed to evaluate the temporal trend of pooled outcomes. Specific subgroups (propensity score matching studies, pure lobectomy studies) were examined. RESULTS: Analysis of 14 studies including a total of 7438 patients was performed. RAL/S was performed on 3239 patients, whereas the other 4199 patients underwent VAL/S. The 30-day mortality [0.7% vs 1.1%; odds ratio (OR) 0.53, P = 0.045] and conversion rate to open surgery (10.3% vs 11.9%; OR 0.57, P < 0.001) were significantly lower in patients who underwent RAL/S than VAL/S. Meanwhile, the postoperative complications (27.5% vs 28.2%; OR 0.95, P = 0.431), operation time [176.63 vs 162.74 min; standardized mean difference (SMD) 0.30, P = 0.086], duration of hospitalization (4.90 vs 5.23 days; SMD -0.08, P = 0.292), days to tube removal (4.10 vs 3.53 days; SMD 0.25, P = 0.120), retrieved lymph node (11.96 vs 10.67; SMD 0.46, P = 0.381), and retrieved lymph node station (4.98 vs 4.32; SMD 0.83, P = 0.261) were similar between the 2 groups. The cumulative meta-analyses suggested that the relative effects between 2 groups have already stabilized. All outcomes of subgroup and overall analyses were similar. CONCLUSIONS: This up-to-date meta-analysis confirms that RAL/S is a feasible and safe alternative to VAL/S for radical resection of lung cancer. Future studies should focus on the long-term benefits and cost effectiveness of RAL/S compared with VAL/S. PMID- 28628563 TI - Recurrence Risk Stratification After Preoperative Chemoradiation of Esophageal Adenocarcinoma. AB - OBJECTIVE: To discern recurrence risk stratification and investigate its influence on postoperative surveillance in patients with esophageal adenocarcinoma (EAC) after neoadjuvant chemoradiotherapy (CRT). BACKGROUND: Reports documenting recurrence risk stratification in EAC after neoadjuvant CRT are scarce. METHODS: Between 1998 and 2014, 601 patients with EAC who underwent neoadjuvant CRT followed by esophagectomy were included for analysis. The pattern, site, timing, and frequency of the first recurrence and potential prognostic factors for developing recurrences were analyzed. This cohort was used as the training set to propose a recurrence risk stratification system, and the stratification was further validated in another cohort of 172 patients. RESULTS: A total of 150 patients (25.0%) achieved pathologic complete response (pCR) after neoadjuvant CRT and the rest were defined as the non-pCR group (n = 451) in the training cohort. After a median follow-up of 63.6 months, the pCR group demonstrated a significantly lower locoregional (4.7% vs 19.1%) and distant recurrence rate (22.0% vs.44.6%) than the non-pCR group (P < 0.001). Based on independent prognostic factors, patients were stratified into 4 recurrence risk categories: pCR with clinical stage I/II, pCR with clinical stage III, non-pCR with pN0, and non-pCR with pN+, with corresponding 5-year recurrence-free survival rates of 88.7%, 65.8%, 55.3%, and 33.0%, respectively (P < 0.001). The risk stratification was reproducible in the validation cohort. CONCLUSIONS: We proposed a recurrence risk stratification system for EAC patients based on pathologic response and pretreatment clinical stage. Risk-based postoperative surveillance strategies could be developed for different risk categories. PMID- 28628564 TI - Risk of Post-transplant Hepatocellular Carcinoma Recurrence Is Higher in Recipients of Livers From Male Than Female Living Donors. AB - OBJECTIVE: To evaluate the relationship between donor sex and hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation. BACKGROUND: HCC shows a male predominance in incidence and recurrence after tumor resection due to sex differences in hepatic sex hormone receptors. There have been no studies evaluating the importance of donor sex on post-transplant HCC recurrence. METHODS: Of 384 recipients of livers, from living donors, for HCC: 104/120 who received grafts from female donors were matched with 246/264 who received grafts from male donors using propensity score matching, with an unfixed matching ratio based on factors like tumor biology. Survival analysis was performed with death as a competing risk event. The primary outcome was overall HCC recurrence. RESULTS: The median follow-up time was 39 months. Before matching, recurrence probability at 1/2/5 years after transplantation was 6.1/9.7/12.7% in recipients with female donors and 11.7/19.2/25.3% in recipients with male donors. Recurrence risk was significantly higher with male donors in univariable analysis (hazard ratio [HR] = 2.04 [1.15-3.60], P = 0.014) and multivariable analysis (HR=2.10 [1.20-3.67], P = 0.018). In the matched analysis, recurrence risk was also higher with male donors (HR=1.92 [1.05-3.52], P = 0.034): both in intrahepatic recurrence (HR=1.92 [1.05-3.51], P = 0.034) and extrahepatic recurrence (HR=1.93 [1.05-3.52], P = 0.033). Multivariable analysis confirmed the significance of donor sex (HR=2.08 [1.11-3.91], P = 0.023). Interestingly, the significance was lost when donor age was >40 years. Two external cohorts validated the significance of donor sex. CONCLUSIONS: Donor sex appears to be an important graft factor modulating HCC recurrence after living donor liver transplantation. PMID- 28628565 TI - Open versus Laparoscopic Surgery for Advanced Low Rectal Cancer: A Large, Multicenter, Propensity Score Matched Cohort Study in Japan. AB - BACKGROUND: Laparoscopic surgery for rectal cancer is widely performed all over the world and several randomized controlled trials have been reported. However, the usefulness of laparoscopic surgery compared with open surgery has not been demonstrated sufficiently, especially for the low rectal area. OBJECTIVE: The aim of this study was to investigate the hypothesis that laparoscopic primary tumor resection is safe and effective when compared with the open approach for locally advanced low rectal cancer. PATIENTS AND METHODS: Data from patients with clinical stage II to III low rectal cancer below the peritoneal reflection were collected and analyzed. The operations were performed from 2010 to 2011. Short term outcomes and long-term prognosis were analyzed with propensity score matching. RESULTS: Of 1608 cases collated from 69 institutes, 1500 cases were eligible for analysis. The cases were matched into 482 laparoscopic and 482 open cases. The mean height of the tumor from the anal verge was 4.6 cm. Preoperative treatment was performed in 35% of the patients. The conversion rate from laparoscopic to open surgery was 5.2%. Estimated blood loss during laparoscopic surgery was significantly less than that during open surgery (90 vs 625 mL, P < 0.001). Overall, the occurrence of complications after laparoscopic surgeries was less than that after open surgeries (30.3% vs 39.2%, P = 0.005). Three-year overall survival rates were 89.9% [95% confidence interval (95% CI) 86.7-92.4] and 90.4% (95% CI 87.4-92.8) in the laparoscopic and open groups, respectively, and no significant difference was seen between the 2 groups. No significant difference was observed in recurrence-free survival (RFS) between the 2 groups (3 year RFS: 70.9%, 68.4 to 74.2 vs 71.8%, 67.5 to 75.7). CONCLUSION: Laparoscopic surgery could be considered as a treatment option for advanced, low rectal cancer below the peritoneal reflection, based on the short-term and long-term results of this large cohort study (UMIN-ID: UMIN000013919). PMID- 28628566 TI - Immediate Impact of Centralization on Abdominal Aortic Aneurysm Repair Outcomes for a Vascular Network in the South West of England: A Retrospective Cohort Study. AB - OBJECTIVE: Our aim was to assess the short-term impact of centralization on the outcomes of patients undergoing abdominal aortic aneurysm repair in a vascular network in the South West of England. BACKGROUND: The centralization of vascular services has been implemented nationally across the National Health Service to improve patient outcomes. The full impact of these major changes has not yet been fully analyzed. METHODS: A retrospective cohort study examining outcomes of patients undergoing abdominal aortic aneurysm repair, based on prospectively entered National Vascular Registry data, pre and post centralization in the South West of England. The primary outcome was mortality at 30 days. Secondary measures included 30-day morbidity, length of hospital stay, and length of intensive care unit stay. RESULTS: The 30-day mortality was unchanged pre and post centralization (11% vs 12%, P = 0.84). The 30-day morbidity rate was also unchanged (24% vs 25%, P = 0.83), as was length of intensive care unit stay (3 vs 3 days, P = 0.74). Overall length of stay was not significantly different (8 vs 6 days, P = 0.76). Subgroup analysis of patients with elective, ruptured, and symptomatic aneurysm repair demonstrated no differences in 30-day mortality. There was a significantly shorter stay post-centralization for patients with symptomatic aneurysms (6 vs 12 days pre-centralization, P = 0.012). CONCLUSIONS: The process of centralization of abdominal aortic aneurysm repair in a vascular network was safe for patients and had no immediate impact on outcomes. Longer term outcome measures and financial data will be required to further assess the benefit of centralization. PMID- 28628567 TI - The Checklist Paradox. PMID- 28628568 TI - Irregular Outcomes: Predictors of New Atrial Fibrillation After Noncardiac Surgery. PMID- 28628569 TI - Estimated Blood Loss: In the Equation of the Beholder. PMID- 28628570 TI - Ensuring Optimal Anesthetic Care for Children: A Call to Action. PMID- 28628571 TI - Is Experience a Surrogate for Expertise? PMID- 28628572 TI - Multimodal Analgesia and the Vigilance of Heimdall. PMID- 28628573 TI - Postoperative Atrial Fibrillation. PMID- 28628574 TI - Estimating Blood Loss. PMID- 28628575 TI - The Analgesia Nociception Index: Tailoring Opioid Administration. PMID- 28628576 TI - The Insight From Foresight: Near-Infrared Spectroscopy in Cyanotic Congenital Heart Disease. PMID- 28628577 TI - Part of the Steamroller and Not Part of the Road: Better Blood Pressure Management Through Automation. PMID- 28628578 TI - Neuraxial Anesthesia in Obstetric Patients Receiving Thromboprophylaxis With Unfractionated or Low-Molecular-Weight Heparin: A Systematic Review of Spinal Epidural Hematoma. AB - Venous thromboembolism remains a major source of morbidity and mortality in obstetrics with an incidence of 29.8/100,000 vaginal delivery hospitalizations; cesarean delivery confers a 4-fold increased risk of thromboembolism when compared with vaginal delivery. Revised national guidelines now stipulate that the majority of women delivering via cesarean and women at risk for ante- or postpartum venous thromboembolism receive mechanical or pharmacological thromboprophylaxis. This practice change has important implications for obstetric anesthesiologists concerned about the risk of spinal epidural hematoma (SEH) among anticoagulated women receiving neuraxial anesthesia. We conducted a systematic review of published English language studies (1952-2016) and of the US Anesthesia Closed Claims Project Database (1990-2013) to identify cases of SEH associated with neuraxial anesthesia and thromboprophylaxis. We also report on SEH in obstetric patients receiving thromboprophylaxis and neuraxial anesthesia without adherence to the American Society of Regional Anesthesia (ASRA) recommendations. In our review, we initially identified 736 publications of which 10 met inclusion criteria; these were combined with the 5 cases of SEH identified in 546 obstetric Anesthesia Closed Claims reviews. None of these publications revealed SEH associated with neuraxial anesthesia and thromboprophylaxis with unfractionated heparin or low-molecular-weight heparin in obstetric patients. Based on data from 6 reports, 28 parturients had their neuraxial blockade before the minimum ASRA recommended time interval between the last anticoagulant dose and the neuraxial procedure. Based on data from 2 reports, 52 parturients received neuraxial anesthesia without their low-molecular-weight heparin dose being discontinued during the intrapartum period. Although the very low level of evidence and high heterogeneity in these reports make it difficult to draw quantitative conclusions from this systematic review, it is encouraging that this comprehensive search did not identify a single case of SEH in an obstetric patient receiving thromboprophylaxis and neuraxial anesthesia. Analysis of large scale registries (eg, the Anesthesia Incident Reporting System of the Anesthesia Quality Institute) with more granular clinical and pharmacological data is needed to assess the impact of these practice changes on obstetric SEH incidence. In the interim, optimal care of obstetric patients depends on multidisciplinary planning of anticoagulation dosing to facilitate neuraxial anesthesia and thoughtful weighing of the relative risks and benefits of providing versus withholding neuraxial in favor of general anesthesia. PMID- 28628579 TI - Distal humeral flexion osteotomy for the treatment of supracondylar extension type malunions in children. AB - Distal humeral extension-type malunions may occur as a complication following improper reduction of supracondylar humerus fractures. We evaluated results after distal humeral flexion osteotomies for sagittal realignment of the humeral condyle in children. Medical records and radiographs of all patients younger than 18 years of age, who underwent this procedure because of a clinically relevant lack of elbow flexion, were evaluated. In a cohort of 18 children with a mean age of 8 years at the time of surgery and a mean follow-up duration of 1 year, elbow flexion increased significantly from a mean of 101 degrees preoperatively to 126 degrees at the final follow-up; established radiographic parameters (e.g. anterior humeral line, humerocondylar angle) were normalized as well. The distal humeral flexion osteotomy is a reliable method to efficiently correct extension type malunions and improve impaired elbow flexion in children. PMID- 28628580 TI - Scoliosis severity does not impact the risk of scoliosis in family members. AB - Does scoliosis severity increase scoliosis risk or severity in relatives? In a cohort of 1257 severe idiopathic scoliosis patients, the percentage with at least one affected relative was compared across the categories of patient sex, major curve severity (Cobb angle), and treatment method. In total, 138 (11%) of 1257 patients had at least one affected first-degree relative and 59 (5%) had at least one affected second-degree relative. As expected, males were more likely to have affected first-degree relatives than females (18 vs. 10% with a risk difference of -0.0864) [95% confidence interval (CI): -0.14 to -0.03; P=0.0002]. However, the major curve severity of the patient (<25 degrees , 25 degrees -49 degrees , and >=50 degrees ) did not impact the prevalence of having at least one affected relative (P=0.69). Surgically treated patients had no greater risk than nonsurgically treated patients of having either an affected relative or a surgically treated relative [11 vs. 11% (odds ratio: 0.912; 95% CI: 0.640-1.299, P=0.61), 6 vs. 5% (OR: 0.788; 95% CI: 0.485-1.280, P=0.34), respectively]. Therefore, our data suggest that scoliosis severity does not independently influence the risk of either scoliosis or its severity in family members. PMID- 28628581 TI - A Collaborative Approach to Childhood Obesity Surveillance From a Local Health Department. AB - DuPage County Health Department collected de-identified data from health forms submitted by participating schools for academic years 2011-2015 for kindergarten, sixth-, and ninth-grade students to determine the prevalence of obesity and elevated blood pressure among public school students. The prevalence of obesity in students for the 2014-2015 school year was 15.1%, and the prevalence of elevated blood pressure was 22.8%. Students in the "obese" body mass index percentile category had an elevated blood pressure prevalence of 44.2%, which was higher than students in the "nonobese" category (P < .001). Significant differences were also observed both by sex and by grade. The results identify the need to support implementation and evaluation of policies to reduce childhood obesity and improve health outcomes. By partnering with schools to obtain preexisting health data, state or local health departments with limited resources may replicate these methods to develop a childhood obesity surveillance system. PMID- 28628582 TI - Revolving Loan Fund: A Novel Approach to Increasing Access to Long-Acting Reversible Contraception Methods in Community Health Centers. AB - OBJECTIVE: The aim of this study was to assess the impact of a revolving loan fund (RLF) on timing of device insertion and long-acting reversible contraception (LARC) access among a high-risk urban population at 3 Boston community health centers. DESIGN: Three health centers were identified to implement a RLF. Each clinic received $5000 from the RLF to purchase LARC devices. Data collected through medical record review retrospectively 1 year prior to start of the RLF and prospectively for 1 year thereafter included patient demographics, type of LARC selected, patient's date of documented interest in a LARC device, and date of insertion. The effect of a RLF on delay to LARC insertion was tested using negative binomial regression, controlling for site and potential confounding variables between the pre- and post-RLF periods. SETTING: Three urban community health centers. PARTICIPANTS: Reproductive-aged women who received family planning services at the 3 participating health centers. MAIN OUTCOME MEASURES: Increasing access to LARC and decreasing wait times to LARC insertion after implementation of the RLF. RESULTS: Data on 133 patients in the pre-RLF group and 205 in the post-RLF group were collected. There were no statistically significant differences in demographic or clinical characteristics between the 2 time periods. LARC uptake increased significantly from the pre- to post-RLF period, specifically among implant users. There was a statistically significant decrease in the mean number of days in delay from interest to insertion from the pre- to post-RLF period (pre-RLF: 31.3 +/- 50.6 days; post-RLF: 13.6 +/- 16.7 days, adjusted P < .001). The reasons for the delay did not differ significantly between the 2 time periods. CONCLUSION: The RLF decreased wait time for the devices and increased overall insertion rates. This may serve as a promising solution to improve LARC access in community health centers. This project could be expanded to include more health centers, creating a city wide RLF. This expansion could allow for further data analysis, including unintended pregnancy rates with LARC delay, LARC continuation rates, and sustainability of a RLF. PMID- 28628583 TI - Improving Hypertension Control Population-wide in Minnesota. AB - CONTEXT: Hypertension is a common and costly risk factor for cardiovascular disease, but just over half of all adults with hypertension have their blood pressure controlled nationally. In Minneapolis-St Paul, Minnesota, the rate of hypertension control is approximately 70% despite a rate of hypertension control similar to the national average as recently as the first half of the 1990s. OBJECTIVE: The purposes of this study were to identify factors in Minneapolis-St Paul and state-level policies and programs in Minnesota that may have contributed to the more rapid increase in blood pressure control there than that in the rest of the nation and to identify factors that can potentially be replicated in other jurisdictions. DESIGN, SETTING, PARTICIPANTS: The study included analysis of trends in hypertension control since 1980 based on the Minnesota Heart Survey and the National Health and Nutrition Examination Survey, as well as interviews with health care and public health leaders in Minnesota. MAIN OUTCOME MEASURE: Prevalence of hypertension control. RESULTS: Probable contributing factors identified include a focus on collaborative and continuous quality improvement; a forum for setting statewide clinical guidelines and measures; the willing participation from the largest health systems, purchasers, and nonprofit health plans; and the use of widely accepted mechanisms for providing feedback to clinicians and reporting performance. The relatively high rate of insurance coverage and socioeconomic status may have contributed but do not fully explain the difference in hypertension control as compared with the rest of the United States. CONCLUSIONS: The experience in Minnesota demonstrates that it is possible to dramatically increase hypertension control at the population level, across health systems, and health plans in a relatively short period of time. Lessons learned may be helpful to informing local, state, and national efforts to improve hypertension control. PMID- 28628584 TI - Distributed Data Networks That Support Public Health Information Needs. AB - INTRODUCTION: Data networks, consisting of pooled electronic health data assets from health care providers serving different patient populations, promote data sharing, population and disease monitoring, and methods to assess interventions. Better understanding of data networks, and their capacity to support public health objectives, will help foster partnerships, expand resources, and grow learning health systems. METHODS: We conducted semistructured interviews with 16 key informants across the United States, identified as network stakeholders based on their respective experience in advancing health information technology and network functionality. Key informants were asked about their experience with and infrastructure used to develop data networks, including each network's utility to identify and characterize populations, usage, and sustainability. RESULTS: Among 11 identified data networks representing hundreds of thousands of patients, key informants described aggregated health care clinical data contributing to population health measures. Key informant interview responses were thematically grouped to illustrate how networks support public health, including (1) infrastructure and information sharing; (2) population health measures; and (3) network sustainability. CONCLUSION: Collaboration between clinical data networks and public health entities presents an opportunity to leverage infrastructure investments to support public health. Data networks can provide resources to enhance population health information and infrastructure. PMID- 28628585 TI - Building Data and Information Capacity in Environmental Public Health: A Best Worst Scaling Experiment. AB - CONTEXT: Environmental public health practitioners rely on information technology (IT) to maintain and improve environmental health. However, current systems have limited capacity. A better understanding of the importance of IT features is needed to enhance data and information capacity. OBJECTIVE: (1) Rank IT features according to the percentage of respondents who rated them as essential to an information management system and (2) quantify the relative importance of a subset of these features using best-worst scaling. DESIGN: Information technology features were initially identified from a previously published systematic review of software evaluation criteria and a list of software options from a private corporation specializing in inspection software. Duplicates and features unrelated to environmental public health were removed. The condensed list was refined by a working group of environmental public health management to a final list of 57 IT features. The essentialness of features was electronically rated by environmental public health managers. Features where 50% to 80% of respondents rated them as essential (n = 26) were subsequently evaluated using best-worst scaling. SETTING: Ontario, Canada. PARTICIPANTS: Environmental public health professionals in local public health. MAIN OUTCOME MEASURE: Importance scores of IT features. RESULTS: The majority of IT features (47/57) were considered essential to an information management system by at least half of the respondents (n = 52). The highest-rated features were delivery to printer, software encryption capability, and software maintenance services. Of the 26 features evaluated in the best-worst scaling exercise, the most important features were orientation to all practice areas, off-line capability, and ability to view past inspection reports and results. CONCLUSIONS: The development of a single, unified environmental public health information management system that fulfills the reporting and functionality needs of system users is recommended. This system should be implemented by all public health units to support data and information capacity in local environmental public health. This study can be used to guide vendor evaluation, negotiation, and selection in local environmental public health, and provides an example of academia-practice partnerships and the use of best-worst scaling in public health research. PMID- 28628586 TI - Building a Pediatric Oral Health Training Curriculum for Community Health Workers. AB - OBJECTIVES: Community health workers (CHWs) are a promising approach to oral health promotion in high-risk populations. This article describes the process of creating a pediatric oral health CHW training curriculum. DESIGN: Existing curricula were identified through outreach efforts to experts in the oral health and CHW fields, as well as PubMed and Google searches. After coding basic information, curricula were mapped to define oral health domains. Then group discussion was employed to determine final curriculum contents. SETTING: United States. INCLUSION CRITERIA: Curricula were included if they addressed oral health, were in English or Spanish, involved US populations, did not target dental clinicians, and whether sufficient data could be obtained. MAIN OUTCOME MEASURES: Curricula were evaluated for delivery format, number of hours, target audience, inclusion of CHWs, completeness, and oral health content. RESULTS: Eighteen unique curricula were identified; 14 (78%) were CHW specific. Pathologic factors, caries formation, toothbrushing basics, flossing, nutrition, sugar sweetened beverages, oral health recommendations, baby bottle tooth decay, fluoride treatments, and fluoride were covered to some extent in 75% of curricula. More than half did not mention types of teeth, oral health during pregnancy, antifluoride, cultural humility, and special needs populations. After comparing CHW curricula with non-CHW curricula, the original 26 oral health domains were condensed into 10 CHW training domains. CONCLUSION: Using existing evidence and expert insight, an oral health CHW training curriculum outline was created that emphasizes behaviors, social support, and navigation assistance to promote preventive oral health behaviors in families of young children. This has implications beyond oral health. CHW programs are expanding to address the social determinants of health. The process of creating this curriculum and its basic elements can be applied to other disease areas. Clearly defined trainings that are made publicly available, such as this one, support efforts to standardize the CHW field in preparation for CHW certification and reimbursement in the future. PMID- 28628587 TI - The Who, What, How, and Why of Estimating Public Health Activity Spending. PMID- 28628588 TI - Youth Sports and Physical Activity: Innovative Perspectives on the Role of Health Care Professionals. PMID- 28628589 TI - Next Steps: The Evolution of Neurologic Physical Therapy Practice and Research. PMID- 28628590 TI - The Past, Present, and Future of Neurorehabilitation: From NUSTEP Through IV STEP and Beyond. AB - PURPOSES: To present the history and aims of the STEP conferences; describe the interdependence of prevention, prediction, plasticity, and participation; reflect on where we stand today regarding those 4 Ps; and discuss how future neurorehabilitation should look for individuals with movement disorders. KEY POINTS: Physical therapists have focused primarily on tertiary prevention, emphasizing primary/secondary prevention far less. Predicting optimal response to intervention is essential for primary prevention. Research examining neurorehabilitation effects mediated by brain plasticity is evolving from an emphasis on impairment outcomes toward examination of participation outcomes. CLINICAL PRACTICE RECOMMENDATIONS:: (1) Capitalize on primary and secondary prevention. (2) Administer simple, environmentally relevant predictive measures. (3) Partner with researchers to examine exercise-induced brain plasticity effects via neuroimaging. (4) Encourage physical activity to promote secondary prevention of lifestyle-related diseases and enhance participation. (5) Integrate psychological/social sciences with physiological sciences to move forward with advances in mindful health and patient-centered practices. PMID- 28628591 TI - Movement System Diagnosis. AB - BACKGROUND AND PURPOSE: This article presents the concept of movement system diagnoses (MSDxs), including an examination of the evolution of the ideas that are shaping the development of MSDxs. SUMMARY OF KEY POINTS: Ideas leading to development of the need for MSDxs are traced, and an overview of Diagnosis Dialog and points of consensus are provided. Four examples from areas of neurologic and pediatric practice where additional work is needed on movement system diagnosis are highlighted. CLINICAL PRACTICE: The development and use of MSDxs are deemed critical to the future development of practice in pediatric and neurologic physical therapy. The prediction of treatment outcomes through research is dependent on homogeneous groups of patients with similar signs and symptoms of movement system disorders. Only by investigating homogeneous groups with refined MSDxs will it be possible to carefully examine and identify interventions that are appropriate to a specific diagnosis. Further, our ability to identify disordered movements, including inactivity and over-activity that could lead across time to disabling conditions presents a strong argument for establishing movement system diagnoses that forewarn of the risk of disordered movement poses to health. Such movement system diagnoses would guide interventions that deter the development of disabling conditions rooted in disordered movement. PMID- 28628592 TI - Genetic Variation and Neuroplasticity: Role in Rehabilitation After Stroke. AB - BACKGROUND AND PURPOSE: In many neurologic diagnoses, significant interindividual variability exists in the outcomes of rehabilitation. One factor that may impact response to rehabilitation interventions is genetic variation. Genetic variation refers to the presence of differences in the DNA sequence among individuals in a population. Genetic polymorphisms are variations that occur relatively commonly and, while not disease-causing, can impact the function of biological systems. The purpose of this article is to describe genetic polymorphisms that may impact neuroplasticity, motor learning, and recovery after stroke. SUMMARY OF KEY POINTS: Genetic polymorphisms for brain-derived neurotrophic factor (BDNF), dopamine, and apolipoprotein E have been shown to impact neuroplasticity and motor learning. Rehabilitation interventions that rely on the molecular and cellular pathways of these factors may be impacted by the presence of the polymorphism. For example, it has been hypothesized that individuals with the BDNF polymorphism may show a decreased response to neuroplasticity-based interventions, decreased rate of learning, and overall less recovery after stroke. However, research to date has been limited and additional work is needed to fully understand the role of genetic variation in learning and recovery. RECOMMENDATIONS FOR CLINICAL PRACTICE: Genetic polymorphisms should be considered as possible predictors or covariates in studies that investigate neuroplasticity, motor learning, or motor recovery after stroke. Future predictive models of stroke recovery will likely include a combination of genetic factors and other traditional factors (eg, age, lesion type, corticospinal tract integrity) to determine an individual's expected response to a specific rehabilitation intervention. PMID- 28628593 TI - Consideration of Dose and Timing When Applying Interventions After Stroke and Spinal Cord Injury. AB - BACKGROUND AND PURPOSE: Nearly 4 decades of investigation into the plasticity of the nervous system suggest that both timing and dose could matter. This article provides a synopsis of our lectures at the IV STEP meeting, which presented a perspective of current data on the issues of timing and dose for adult stroke and spinal cord injury motor rehabilitation. SUMMARY OF KEY POINTS: For stroke, the prevailing evidence suggests that greater amounts of therapy do not result in better outcomes for upper extremity interventions, regardless of timing. Whether or not greater amounts of therapy result in better outcomes for lower extremity and mobility interventions needs to be explicitly tested. For spinal cord injury, there is a complex interaction of timing postinjury, task-specificity, and the microenvironment of the spinal cord. Inflammation appears to be a key determinant of whether or not an intervention will be beneficial or maladaptive, and specific retraining of eccentric control during gait may be necessary. RECOMMENDATIONS FOR CLINICAL PRACTICE: To move beyond the limitations of our current interventions and to effectively reach nonresponders, greater precision in task-specific interventions that are well-timed to the cellular environment may hold the key. Neurorehabilitation that ameliorates persistent deficits, attains greater recovery, and reclaims nonresponders will decrease institutionalization, improve quality of life, and prevent multiple secondary complications common after stroke and spinal cord injury. PMID- 28628594 TI - Telehealth, Wearable Sensors, and the Internet: Will They Improve Stroke Outcomes Through Increased Intensity of Therapy, Motivation, and Adherence to Rehabilitation Programs? AB - BACKGROUND AND PURPOSE: Stroke, predominantly a condition of older age, is a major cause of acquired disability in the global population and puts an increasing burden on health care resources. Clear evidence for the importance of intensity of therapy in optimizing functional outcomes is found in animal models, supported by neuroimaging and behavioral research, and strengthened by recent meta-analyses from multiple clinical trials. However, providing intensive therapy using conventional treatment paradigms is expensive and sometimes not feasible because of social and environmental factors. This article addresses the need for cost-effective increased intensity of practice and suggests potential benefits of telehealth (TH) as an innovative model of care in physical therapy. SUMMARY OF KEY POINTS: We provide an overview of TH and present evidence that a web supported program, used in conjunction with constraint-induced therapy (CIT), can increase intensity and adherence to a rehabilitation regimen. The design and feasibility testing of this web-based program, "LifeCIT," is presented. We describe how wearable sensors can monitor activity and provide feedback to patients and therapists. The methodology for the development of a wearable device with embedded inertial and mechanomyographic sensors, algorithms to classify functional movement, and a graphical user interface to present meaningful data to patients to support a home exercise program is explained. RECOMMENDATIONS FOR CLINICAL PRACTICE: We propose that wearable sensor technologies and TH programs have the potential to provide most-effective, intensive, home-based stroke rehabilitation. PMID- 28628595 TI - Activity-Based Therapy: From Basic Science to Clinical Application for Recovery After Spinal Cord Injury. AB - BACKGROUND AND PURPOSE: Collaboration between scientists and clinicians effectively accelerated translation of scientific evidence for activity-based therapies (ABTs) into rehabilitation. This article addresses the basic scientific findings of activity-dependent plasticity that led to locomotor training, an ABT, and its principles to advance recovery in adult and pediatric populations with spinal cord injury (SCI). Expansion to new therapies based on these common principles is highlighted, for example, epidural stimulation. The article also describes a recently developed measure, the Neuromuscular Recovery Scale (NRS), and its psychometric properties. SUMMARY OF KEY POINTS: Locomotor training has led to recovery of walking in some individuals with motor-incomplete SCI even years after injury. Recent studies resulted in individuals with motor-complete SCI regaining some voluntary movements and standing in the presence of epidural stimulation. The level of success for locomotor training and epidural stimulation appears dependent on spinal networks maintaining the appropriate central state of excitability for the desired task. As these new advances in restorative therapies required an outcome measure that measured performance without compensation, the NRS was developed. The NRS has strong psychometric properties in adults, and a pediatric version is under development. Application of locomotor training in children is still novel. Preliminary evidence suggests that locomotor training can improve trunk control and also foster participation in children with chronic SCI. RECOMMENDATIONS FOR CLINICAL PRACTICE: ABTs may effectively promote neuromuscular recovery and improve function and participation in adults and children post-SCI. Evaluation of outcomes with valid measures, such as the NRS, is necessary to document the ability to perform functional tasks and to assess progress as function improves. PMID- 28628597 TI - Integrating Health Promotion Into Physical Therapy Practice to Improve Brain Health and Prevent Alzheimer Disease. AB - BACKGROUND AND PURPOSE: Alzheimer disease is the most common cause of dementia, and brain pathology appears years before symptoms are evident. Primary prevention through health promotion can incorporate lifestyle improvement across the lifespan. Risk factor assessment and identifying markers of disease might also trigger preventive measures needed for high-risk individuals and groups. SUMMARY OF KEY POINTS: Many potential risk factors are modifiable through exercise, and may be responsive to early intervention strategies to reduce the downward slope toward disability. Through the use of common clinical tests to identify cognitive and noncognitive functional markers of disease, detection and intervention can occur at earlier stages, including preclinical stages of disease. Physical activity and exercise interventions to address modifiable risk factors and impairments can play a pivotal role in the prevention and delay of functional decline, ultimately reducing the incidence of dementia. This article discusses prevention, prediction, plasticity, and participation in the context of preserving brain health and preventing Alzheimer disease and related dementias in aging adults. RECOMMENDATIONS FOR CLINICAL PRACTICE: Rehabilitation professionals have opportunities to slow disease progression through research, practice, and education initiatives. From a clinical perspective, interventions that target brain health through lifestyle changes and exercise interventions show promise for preventing stroke and associated neurovascular diseases in addition to dementia. Physical therapists are well positioned to integrate primary health promotion into practice for the prevention of dementia and other neurological conditions in older adults. PMID- 28628598 TI - Stepping Up to Rethink the Future of Rehabilitation: IV STEP Considerations and Inspirations. AB - BACKGROUND AND PURPOSE: The IV STEP conference challenged presenters and participants to consider the state of science in rehabilitation, highlighting key area of progress since the previous STEP conference related to prediction, prevention, plasticity, and participation in rehabilitation. KEY POINTS: Emerging from the thought-provoking discussions was recognition of the progress we have made as a profession and a call for future growth. In this summary article, we present a recap of the key points and call for action. We review the information presented and the field at large as it relates to the 4 Ps: prediction, prevention, plasticity, and participation. RECOMMENDATIONS FOR PRACTICE: Given that personalized medicine is an increasingly important approach that was clearly woven throughout the IV STEP presentations, we took the liberty of adding a fifth "P," Personalized, in our discussion of the future direction of the profession. PMID- 28628596 TI - From Disease to Health: Physical Therapy Health Promotion Practices for Secondary Prevention in Adult and Pediatric Neurologic Populations. AB - BACKGROUND AND PURPOSE: Over the last decade there has been a substantial increase in efforts to better understand how targeted physical activity and exercise interventions can be used to minimize secondary consequences arising from neurological damage in both adult and pediatric populations. This article offers an overview of contemporary research that addresses mediators of functional and neuroplastic adaptations associated with physical activity and exercise. We emphasize the important role that physical therapists can play to increase participation and improve well-being in adults and children with neurological disorders. We further highlight potential strategies to foster translation of evidence-based findings for use by clinicians and consumers. SUMMARY OF KEY POINTS: Engagement in physical activity can serve as a powerful promoter of health and well-being in adults and youth with neurologic disease, and has the potential to alter the course of disease processes. Physical therapists can play a key role in promoting fitness and wellness by encouraging active living, providing early diagnosis of disease and prescribing targeted activity interventions to improve fitness and participation, and helping individuals overcome personal and environmental barriers to an active lifestyle. RECOMMENDATIONS FOR CLINICAL PRACTICE: Physical therapists must adopt a model of rehabilitation that emphasizes secondary prevention in adults and youth with neurologic diseases. Physical therapists have a unique role in developing forward thinking approaches in using innovative health and wellness strategies to promote positive changes in activity and exercise behaviors. PMID- 28628599 TI - Combat casualty care research for the multidomain battlefield. PMID- 28628600 TI - Alterations in brain-derived neurotrophic factor and insulin-like growth factor-1 protein levels after penetrating ballistic-like brain injury in rats. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) are essential for neuroplasticity and neuronal survival. Despite the importance of these endogenous factors in mediating posttraumatic recovery, little is known about their response after penetrating type traumatic brain injury. The objective of this study was to quantify the expression levels BDNF and IGF-1, two well-known neuroplasticity mediators, after penetrating ballistic like brain injury (PBBI). METHODS: Rats were randomly assigned to receive unilateral sham or PBBI injuries. Using enzyme-linked immunosorbent assay and immunohistochemistry, we performed a comprehensive evaluation of BDNF and IGF-1 expression at acute (1 hour, 6 hours, 1 day) and subacute (2, 3, 7, and 14 days) timepoints after injury. RESULTS: BDNF and IGF-1 expression was transiently upregulated in both cortex and hippocampus after PBBI. Although BDNF levels increased at acute timepoints, IGF-1 expression peaked at 3 days in cortical homogenates. Although there was loss of staining in cells bordering the cavity, increased BDNF and IGF-1 immunoreactivity was observed in scattered neurons away from the contusion site. Glial upregulation of both growth factors was observed at early timepoints in the hippocampus. CONCLUSION: Our findings demonstrate that PBBI results in a brief upregulation of BDNF and IGF-1 during early posttraumatic period, providing critical information for interventions aiming to enhance neuronal survival and brain plasticity. PMID- 28628601 TI - The Damage Control Surgery in Austere Environments Research Group (DCSAERG): A dynamic program to facilitate real-time telementoring/telediagnosis to address exsanguination in extreme and austere environments. AB - Hemorrhage is the most preventable cause of posttraumatic death. Many cases are potentially anatomically salvageable, yet remain lethal without logistics or trained personnel to deliver diagnosis or resuscitative surgery in austere environments. Revolutions in technology for remote mentoring of ultrasound and surgery may enhance capabilities to utilize the skill sets of non-physicians. Thus, our research collaborative explored remote mentoring to empower non physicians to address junctional and torso hemorrhage control in austere environments. Major studies involved using remote-telementored ultrasound (RTMUS) to identify torso and junctional exsanguination, remotely mentoring resuscitative surgery for torso hemorrhage control, understanding and mitigating physiological stress during such tasks, and the technical practicalities of conducting damage control surgery (DCS) in austere environments. Iterative projects involved randomized guiding of firefighters to identify torso (RCT) and junctional (pilot) hemorrhage using RTMUS, randomized remote mentoring of MedTechs conducting resuscitative surgery for torso exsanguination in an anatomically realistic surgical trainer ("Cut Suit") including physiological monitoring, and trained surgeons conducting a comparative randomized study for torso hemorrhage control in normal (1g) versus weightlessness (0g). This work demonstrated that firefighters could be remotely mentored to perform just-in-time torso RTMUS on a simulator. Both firefighters and mentors were confident in their abilities, the ultrasounds being 97% accurate. An ultrasound-naive firefighter in Memphis could also be remotely mentored from Hawaii to identify and subsequently tamponade an arterial junctional hemorrhage using RTMUS in a live tissue model. Thereafter, both mentored and unmentored MedTechs and trained surgeons completed resuscitative surgery for hemorrhage control on the Cut-Suit, demonstrating practicality for all involved. While remote mentoring did not decrease blood loss among MedTechs, it increased procedural confidence and decreased physiologic stress. Therefore, remote mentoring may increase the feasibility of non physicians conducting a psychologically daunting task. Finally, DCS in weightlessness was feasible without fundamental differences from 1g. Overall, the collective evidence suggests that remote mentoring supports diagnosis, noninvasive therapy, and ultimately resuscitative surgery to potentially rescue those exsanguinating in austere environments and should be more rigorously studied. PMID- 28628602 TI - Procoagulant activity of human mesenchymal stem cells. AB - BACKGROUND: Allogeneic mesenchymal stem cells (MSCs) show great potential for the treatment of military and civilian trauma based on their reduced immunogenicity and ability to modulate inflammation and immune function in the recipient. Although generally considered to be safe, MSCs express tissue factor (TF), a potent activator of coagulation. In the current study, we evaluated multiple MSC populations for tissue factor expression and procoagulant activity to characterize safety considerations for systemic use of MSCs in trauma patients who may have altered coagulation homeostasis. METHODS: Multiple MSC populations derived from either human adipose tissue or bone marrow were expanded in the recommended stem cell media. Stem cell identity was confirmed using a well characterized panel of positive and negative markers. Tissue factor expression on the cell surface was evaluated by flow cytometry with anti-CD142 antibody. Effects on blood coagulation were determined by thromboelastography and calibrated automated thrombogram assays using platelet-poor plasma or whole blood. RESULTS: Mesenchymal stem cells express tissue factor on their surfaces and are procoagulant in the presence of blood or plasma. The adipose-derived MSCs (Ad-MSC) evaluated were more procoagulant and expressed more tissue factor than bone marrow MSCs (BM-MSCs), which showed a greater variability in TF expression. Bone marrow MSCs were identified that exhibited low procoagulant activity, whereas all Ad-MSCs examined exhibited high procoagulant activity. The percentage of cells in a given population expressing surface tissue factor correlates roughly with functional procoagulant activity. Mesenchymal stem cell tissue factor expression and procoagulant activity change over time in culture. CONCLUSIONS: All MSC populations are not equivalent; care should be taken to select cells for clinical use that minimize potential safety problems and maximize chance of patient benefit. Adipose-derived MSCs seem more consistently procoagulant than BM-MSCs, presenting a potential safety concern for systemic administration in coagulopathic patients. Donor variation exists between different cell populations, and culture handling conditions may also determine coagulation activity. Cells must be routinely monitored during preparation to ensure that they retain the desired characteristics before patient administration. PMID- 28628603 TI - Field and en route resuscitative endovascular occlusion of the aorta: A feasible military reality? AB - BACKGROUND: Severe noncompressible torso hemorrhage remains a leading cause of potentially preventable death in modern military conflicts. Resuscitative endovascular occlusion of the aorta (REBOA) has demonstrated potential as an effective adjunct to the treatment of noncompressible torso hemorrhage in the civilian early hospital and even prehospital settings-but the application of this technology for military prehospital use has not been well described. We aimed to assess the feasibility of both field and en route prehospital REBOA in the military exercise setting, simulating a modern armed conflict. METHODS: Two adult male Sus Scrofa underwent simulated junctional combat injury in the context of a planned military training exercise. Both underwent zone I REBOA in conjunction with standard tactical combat casualty care interventions-one during point of injury care and the other during en route flight care. Animals were sequentially evacuated to two separate forward surgical teams by rotary wing platform where the balloon position was confirmed by chest x-ray. Animals then underwent different damage control thoracic and abdominal procedures before euthanasia. RESULTS: The first swine underwent immediate successful REBOA at the point of injury 7 minutes and 30 seconds after the injury. It required 6 minutes total from initiation of procedure to effective aortic occlusion. Total occlusion time was 60 minutes. In the second animal, the REBOA placement procedure was initiated immediately after take off (17 minutes and 40 seconds after the injury). Although the movements and vibration of flight were not significant impediments, we only succeeded to put a 6-French (Fr) sheath into a femoral artery during the 14 minutes flight due to lighting and visualization challenges. After the sheath had been upsized in the forward surgical team, the REBOA catheter was primarily placed in zone I followed by its replacement to zone III. Both animals survived to study completion and the termination of training. No complications were observed in either animal. CONCLUSION: Our study demonstrates the potential feasibility of REBOA for use during tactical field and en route (flight) care of combat casualties. Further study is needed to determine the optimal training and utilization protocols required to facilitate the effective incorporation of REBOA into military prehospital care capabilities. PMID- 28628604 TI - Correlations of Complete Blood Count with Alanine and Aspartate Transaminase in Chinese Subjects and Prediction Based on Back-Propagation Artificial Neural Network (BP-ANN). AB - BACKGROUND The complete blood count (CBC) is the most common examination used to monitor overall health in clinical practice. Whether there is a relationship between CBC indexes and alanine transaminase (ALT) and aspartate aminotransferase (AST) has been unclear. MATERIAL AND METHODS In this study, 572 normal-weight and 346 overweight Chinese subjects were recruited. The relationship between CBC indexes with ALT and AST were analyzed by Pearson and Spearman correlations according to their sex, then we conducted colinearity diagnostics and multiple linear regression (MLR) analysis. A prediction model was developed by a back propagation artificial neural network (BP-ANN). RESULTS ALT was related to 4 CBC indexes in the male normal-weight group and 3 CBC indexes in the female group. In the overweight group, ALT had a similar relationship with the normal group, but there was only 1 index related with AST in the normal-weight group and male overweight groups. The ALT regression models were developed in normal-weight and overweight people, which had better correlation coefficient (R>0.3). After training 1000 epochs, the BP-ANN models of ALT achieved higher correlations than MLR models in normal-weight and overweight people. CONCLUSIONS ALT is a more suitable index than AST for developing a regression model. ALT can be predicted by CBC indexes in normal-weight and overweight individuals based on a BP-ANN model, which was better than MLR analysis. PMID- 28628605 TI - Corrigendum: Reevaluation of Performance of Electric Double-layer Capacitors from Constant-current Charge/Discharge and Cyclic Voltammetry. AB - This corrects the article DOI: 10.1038/srep38568. PMID- 28628606 TI - Splicing stimulates siRNA formation at Drosophila DNA double-strand breaks. AB - DNA double-strand breaks trigger the production of locus-derived siRNAs in fruit flies, human cells and plants. At least in flies, their biogenesis depends on active transcription running towards the break. Since siRNAs derive from a double stranded RNA precursor, a major question is how broken DNA ends can generate matching sense and antisense transcripts. We performed a genome-wide RNAi-screen in cultured Drosophila cells, which revealed that in addition to DNA repair factors, many spliceosome components are required for efficient siRNA generation. We validated this observation through site-specific DNA cleavage with CRISPR-cas9 followed by deep sequencing of small RNAs. DNA breaks in intron-less genes or upstream of a gene's first intron did not efficiently trigger siRNA production. When DNA double-strand breaks were induced downstream of an intron, however, this led to robust siRNA generation. Furthermore, a downstream break slowed down splicing of the upstream intron and a detailed analysis of siRNA coverage at the targeted locus revealed that unspliced pre-mRNA contributes the sense strand to the siRNA precursor. Since splicing factors are stimulating the response but unspliced transcripts are entering the siRNA biogenesis, the spliceosome is apparently stalled in a pre-catalytic state and serves as a signaling hub. We conclude that convergent transcription at DNA breaks is stimulated by a splicing dependent control process. The resulting double-stranded RNA is converted into siRNAs that instruct the degradation of cognate mRNAs. In addition to a potential role in DNA repair, the break-induced transcription may thus be a means to cull improper RNAs from the transcriptome of Drosophila melanogaster. Since the splicing factors identified in our screen also stimulated siRNA production from high copy transgenes, it is possible that this surveillance mechanism serves in genome defense beyond DNA double-strand breaks. PMID- 28628607 TI - Host gene expression analysis in Sri Lankan melioidosis patients. AB - BACKGROUND: Melioidosis is a life threatening infectious disease caused by the gram-negative bacillus Burkholderia pseudomallei predominantly found in southeast Asia and northern Australia. Studying the host transcription profiles in response to infection is crucial for understanding disease pathogenesis and correlates of disease severity, which may help improve therapeutic intervention and survival. The aim of this study was to analyze gene expression levels of human host factors in melioidosis patients and establish useful correlation with disease biomarkers, compared to healthy individuals and patients with sepsis caused by other pathogens. METHODS: The study population consisted of 30 melioidosis cases, 10 healthy controls and 10 sepsis cases caused by other pathogens. Total RNA was extracted from peripheral blood mononuclear cells (PBMC's) of study subjects. Gene expression profiles of 25 gene targets including 19 immune response genes and 6 epigenetic factors were analyzed by real time quantitative polymerase chain reaction (RT-qPCR). PRINCIPAL FINDINGS: Inflammatory response genes; TLR4, late onset inflammatory mediator HMGB1, genes associated with antigen presentation; MICB, PSMB2, PSMB8, PSME2, epigenetic regulators; DNMT3B, HDAC1, HDAC2 were significantly down regulated, whereas the anti-inflammatory gene; IL4 was up regulated in melioidosis patients compared to sepsis cases caused by other pathogens. Septicaemic melioidosis cases showed significant down regulation of IL8 compared to sepsis cases caused by other pathogens. HMGB1, MICB, PSMB8, PSMB2, PSME2, HDAC1, HDAC2 and DNMT3B showed consistent down regulation of gene expression in melioidosis patients compared to other sepsis infection, irrespective of comorbidities such as diabetes, duration of clinical symptoms and antibiotic treatment. SIGNIFICANCE: Specific immune response genes and epigenetic regulators are differentially expressed among melioidosis patients and patients with sepsis caused by other pathogens. Therefore, these genes may serve as biomarkers for disease diagnosis to distinguish melioidosis from cases of sepsis due to other infections and therapeutic intervention for melioidosis. PMID- 28628610 TI - Outcome of cardiac surgery in patients with congenital heart disease in England between 1997 and 2015. AB - BACKGROUND: The number of patients with congenital heart disease (CHD) is increasing worldwide and most of them will require cardiac surgery, once or more, during their lifetime. The total volume of cardiac surgery in CHD patients at a national level and the associated mortality and predictors of death associated with surgery are not known. We aimed to investigate the surgical volume and associated mortality in CHD patients in England. METHODS: Using a national hospital episode statistics database, we identified all CHD patients undergoing cardiac surgery in England between 1997 and 2015. RESULTS: We evaluated 57,293 patients (median age 11.9years, 46.7% being adult, 56.7% female). There was a linear increase in the number of operations performed per year from 1,717 in 1997 to 5,299 performed in 2014. The most common intervention at the last surgical event was an aortic valve procedure (9,276; 16.2%), followed by repair of atrial septal defect (9,154; 16.0%), ventricular septal defect (7,746; 13.5%), tetralogy of Fallot (3,523; 6.1%) and atrioventricular septal defect (3,330; 5.8%) repair. Associated mortality remained raised up to six months following cardiac surgery. Several parameters were predictive of post-operative mortality, including age, complexity of surgery, need for emergency surgery and socioeconomic status. The relationship of age with mortality was "U"-shaped, and mortality was highest amongst youngest children and adults above 60 years of age. CONCLUSIONS: The number of cardiac operations performed in CHD patients in England has been increasing, particularly in adults. Mortality remains raised up to 6-months after surgery and was highest amongst young children and seniors. PMID- 28628608 TI - TCP4-dependent induction of CONSTANS transcription requires GIGANTEA in photoperiodic flowering in Arabidopsis. AB - Photoperiod is one of the most reliable environmental cues for plants to regulate flowering timing. In Arabidopsis thaliana, CONSTANS (CO) transcription factor plays a central role in regulating photoperiodic flowering. In contrast to posttranslational regulation of CO protein, still little was known about CO transcriptional regulation. Here we show that the CINCINNATA (CIN) clade of class II TEOSINTE BRANCHED 1/ CYCLOIDEA/ PROLIFERATING CELL NUCLEAR ANTIGEN FACTOR (TCP) proteins act as CO activators. Our yeast one-hybrid analysis revealed that class II CIN-TCPs, including TCP4, bind to the CO promoter. TCP4 induces CO expression around dusk by directly associating with the CO promoter in vivo. In addition, TCP4 binds to another flowering regulator, GIGANTEA (GI), in the nucleus, and induces CO expression in a GI-dependent manner. The physical association of TCP4 with the CO promoter was reduced in the gi mutant, suggesting that GI may enhance the DNA-binding ability of TCP4. Our tandem affinity purification coupled with mass spectrometry (TAP-MS) analysis identified all class II CIN-TCPs as the components of the in vivo TCP4 complex, and the gi mutant did not alter the composition of the TCP4 complex. Taken together, our results demonstrate a novel function of CIN-TCPs as photoperiodic flowering regulators, which may contribute to coordinating plant development with flowering regulation. PMID- 28628609 TI - A multidimensional integration analysis reveals potential bridging targets in the process of colorectal cancer liver metastasis. AB - Approximately 9% of cancer-related deaths are caused by colorectal cancer. Liver metastasis is a major factor for the high colorectal cancer mortality rate. However, the molecular mechanism underlying colorectal cancer liver metastasis remains unclear. Using a global and multidimensional integration approach, we studied sequencing data, protein-protein interactions, and regulation of transcription factor and non-coding RNAs in primary tumor samples and liver metastasis samples to unveil the potential bridging molecules and the regulators that functionally link different stages of colorectal cancer liver metastasis. Primary tumor samples and liver metastasis samples had modules with significant overlap and crosstalk from which we identified several bridging genes (e.g. KNG1 and COX5B), transcription factors (e.g. E2F4 and CDX2), microRNAs (e.g. miR-590 3p and miR-203) and lncRNAs (e.g. lincIRX5 and lincFOXF1) that may play an important role in the process of colorectal cancer liver metastasis. This study enhances our understanding of the genetic alterations and transcriptional regulation that drive the metastatic process, but also provides the methodology to guide the studies on other metastatic cancers. PMID- 28628611 TI - Effects of salinity on gonadal development, osmoregulation and metabolism of adult male Chinese mitten crab, Eriocheir sinensis. AB - As a catadromous species, salinity is a key parameter that affects gonadal development of Chinese mitten crab Eriocheir sinensis during reproductive migration. It is however unclear the effects of salinity on the gonadal development of male E. sinensis as well as their physiological responses to salinity during reproductive migration. This study investigated the effects of four salinities (0 0/00, 6 0/00, 12 0/00 and 18 0/00) on gonadal development, osmoregulation and metabolism of adult male E. sinensis over a 40-day period. The results showed that elevating salinity promote gonadal development, increase hemolymph osmolality and K+ and Mg2+ concentrations (P < 0.05). The 12 0/00 salinity resulted in the highest contents of taurine and arginine in the hemolymph while the highest contents of threonine, phenylalanine, lysine, beta alanine, tryptophan, ornithine and total free amino acids were found for 0 0/00 treatment (P < 0.05). A decreasing trend was detected for the Na+/K+-ATPase activity and its mRNA expression level in the posterior gills with salinity (P < 0.05). Total saturated fatty acids in the anterior gills decreased with increasing salinity (P < 0.05); the 0 0/00 treatment had the highest total polyunsaturated fatty acids in the posterior gills while total n-6 polyunsaturated fatty acids increased with salinity (P < 0.05). The hemolymph glucose and uric acid showed a decreasing trend as salinity while an increasing trend was found for the hemolymph triglyceride and high-density lipoprotein cholesterol (P < 0.05). The 12 0/00 treatment had the highest levels of hemolymph malonaldehyde and hepatopancreatic gamma-glutamyltranspeptidase (P < 0.05). In conclusion, these results suggested that the brackish water promote gonadal development of male E. sinensis, and increase osmolality and ionic concentrations in hemolymph while reduced the activity of Na+ /K+- ATPase and its mRNA expression in the posterior gills as well as metabolism. PMID- 28628612 TI - Novel interplay between JNK and Egfr signaling in Drosophila dorsal closure. AB - Dorsal closure (DC) is a developmental process in which two contralateral epithelial sheets migrate to seal a large hole in the dorsal ectoderm of the Drosophila embryo. Two signaling pathways act sequentially to orchestrate this dynamic morphogenetic process. First, c-Jun N-terminal kinase (JNK) signaling activity in the dorsal-most leading edge (LE) cells of the epidermis induces expression of decapentaplegic (dpp). Second, Dpp, a secreted TGF-beta homolog, triggers cell shape changes in the adjacent, ventrally located lateral epidermis, that guide the morphogenetic movements and cell migration mandatory for DC. Here we uncover a cell non-autonomous requirement for the Epidermal growth factor receptor (Egfr) pathway in the lateral epidermis for sustained dpp expression in the LE. Specifically, we demonstrate that Egfr pathway activity in the lateral epidermis prevents expression of the gene scarface (scaf), encoding a secreted antagonist of JNK signaling. In embryos with compromised Egfr signaling, upregulated Scaf causes reduction of JNK activity in LE cells, thereby impeding completion of DC. Our results identify a new developmental role for Egfr signaling in regulating epithelial plasticity via crosstalk with the JNK pathway. PMID- 28628613 TI - Immunosuppressive and angiogenic cytokine profile associated with Bartonella bacilliformis infection in post-outbreak and endemic areas of Carrion's disease in Peru. AB - Analysis of immune responses in Bartonella bacilliformis carriers are needed to understand acquisition of immunity to Carrion's disease and may allow identifying biomarkers associated with bacterial infection and disease phases. Serum samples from 144 healthy subjects from 5 villages in the North of Peru collected in 2014 were analyzed. Four villages had a Carrion's disease outbreak in 2013, and the other is a traditionally endemic area. Thirty cytokines, chemokines and growth factors were determined in sera by fluorescent bead-based quantitative suspension array technology, and analyzed in relation to available data on bacteremia quantified by RT-PCR, and IgM and IgG levels measured by ELISA against B. bacilliformis lysates. The presence of bacteremia was associated with low concentrations of HGF (p = 0.005), IL-15 (p = 0.002), IL-6 (p = 0.05), IP-10 (p = 0.008), MIG (p = 0.03) and MIP-1alpha (p = 0.03). In multi-marker analysis, the same and further TH1-related and pro-inflammatory biomarkers were inversely associated with infection, whereas angiogenic chemokines and IL-10 were positively associated. Only EGF and eotaxin showed a moderate positive correlation with bacteremia. IgM seropositivity, which reflects a recent acute infection, was associated with lower levels of eotaxin (p = 0.05), IL-6 (p = 0.001), and VEGF (p = 0.03). Only GM-CSF and IL-10 concentrations were positively associated with higher levels of IgM (p = 0.01 and p = 0.007). Additionally, IgG seropositivity and levels were associated with high levels of angiogenic markers VEGF (p = 0.047) and eotaxin (p = 0.006), respectively. Our findings suggest that B. bacilliformis infection causes immunosuppression, led in part by overproduction of IL-10. This immunosuppression probably contributes to the chronicity of asymptomatic infections favoring B. bacilliformis persistence in the host, allowing the subsequent transmission to the vector. In addition, angiogenic markers associated with bacteremia and IgG levels may be related to the induction of endothelial cell proliferation in cutaneous lesions during chronic infections, being possible candidate biomarkers of asymptomatic infections. PMID- 28628615 TI - Flipping chromosomes in deep-sea archaea. AB - One of the major mechanisms driving the evolution of all organisms is genomic rearrangement. In hyperthermophilic Archaea of the order Thermococcales, large chromosomal inversions occur so frequently that even closely related genomes are difficult to align. Clearly not resulting from the native homologous recombination machinery, the causative agent of these inversions has remained elusive. We present a model in which genomic inversions are catalyzed by the integrase enzyme encoded by a family of mobile genetic elements. We characterized the integrase from Thermococcus nautili plasmid pTN3 and showed that besides canonical site-specific reactions, it catalyzes low sequence specificity recombination reactions with the same outcome as homologous recombination events on DNA segments as short as 104bp both in vitro and in vivo, in contrast to other known tyrosine recombinases. Through serial culturing, we showed that the integrase-mediated divergence of T. nautili strains occurs at an astonishing rate, with at least four large-scale genomic inversions appearing within 60 generations. Our results and the ubiquitous distribution of pTN3-like integrated elements suggest that a major mechanism of evolution of an entire order of Archaea results from the activity of a selfish mobile genetic element. PMID- 28628614 TI - LAMPhimerus: A novel LAMP assay for detecting Amphimerus sp. DNA in human stool samples. AB - BACKGROUND: Amphimeriasis is a fish-borne disease caused by the liver fluke Amphimerus spp. that has recently been reported as endemic in the tropical Pacific side of Ecuador with a high prevalence in humans and domestic animals. The diagnosis is based on the stool examination to identify parasite eggs, but it lacks sensitivity. Additionally, the morphology of the eggs may be confounded with other liver and intestinal flukes. No immunological or molecular methods have been developed to date. New diagnostic techniques for specific and sensitive detection of Amphimerus spp. DNA in clinical samples are needed. METHODOLOGY/PRINCIPAL FINDINGS: A LAMP targeting a sequence of the Amphimerus sp. internal transcribed spacer 2 region was designed. Amphimerus sp. DNA was obtained from adult worms recovered from animals and used to optimize the molecular assays. Conventional PCR was performed using outer primers F3-B3 to verify the proper amplification of the Amphimerus sp. DNA target sequence. LAMP was optimized using different reaction mixtures and temperatures, and it was finally set up as LAMPhimerus. The specificity and sensitivity of both PCR and LAMP were evaluated. The detection limit was 1 pg of genomic DNA. Field testing was done using 44 human stool samples collected from localities where fluke is endemic. Twenty-five samples were microscopy positive for Amphimerus sp. eggs detection. In molecular testing, PCR F3-B3 was ineffective when DNA from fecal samples was used. When testing all human stool samples included in our study, the diagnostic parameters for the sensitivity and specificity were calculated for our LAMPhimerus assay, which were 76.67% and 80.77%, respectively. CONCLUSIONS/SIGNIFICANCE: We have developed and evaluated, for the first time, a specific and sensitive LAMP assay for detecting Amphimerus sp. in human stool samples. The procedure has been named LAMPhimerus method and has the potential to be adapted for field diagnosis and disease surveillance in amphimeriasis-endemic areas. Future large-scale studies will assess the applicability of this novel LAMP assay. PMID- 28628616 TI - Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques. AB - Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections. PMID- 28628617 TI - Comparative analysis of European bat lyssavirus 1 pathogenicity in the mouse model. AB - European bat lyssavirus 1 is responsible for most bat rabies cases in Europe. Although EBLV-1 isolates display a high degree of sequence identity, different sublineages exist. In individual isolates various insertions and deletions have been identified, with unknown impact on viral replication and pathogenicity. In order to assess whether different genetic features of EBLV-1 isolates correlate with phenotypic changes, different EBLV-1 variants were compared for pathogenicity in the mouse model. Groups of three mice were infected intracranially (i.c.) with 102 TCID50/ml and groups of six mice were infected intramuscularly (i.m.) with 105 TCID50/ml and 102 TCID50/ml as well as intranasally (i.n.) with 102 TCID50/ml. Significant differences in survival following i.m. inoculation with low doses as well as i.n. inoculation were observed. Also, striking variations in incubation periods following i.c. inoculation and i.m. inoculation with high doses were seen. Hereby, the clinical picture differed between general symptoms, spasms and aggressiveness depending on the inoculation route. Immunohistochemistry of mouse brains showed that the virus distribution in the brain depended on the inoculation route. In conclusion, different EBLV-1 isolates differ in pathogenicity indicating variation which is not reflected in studies of single isolates. PMID- 28628618 TI - Solving the influence maximization problem reveals regulatory organization of the yeast cell cycle. AB - The Influence Maximization Problem (IMP) aims to discover the set of nodes with the greatest influence on network dynamics. The problem has previously been applied in epidemiology and social network analysis. Here, we demonstrate the application to cell cycle regulatory network analysis for Saccharomyces cerevisiae. Fundamentally, gene regulation is linked to the flow of information. Therefore, our implementation of the IMP was framed as an information theoretic problem using network diffusion. Utilizing more than 26,000 regulatory edges from YeastMine, gene expression dynamics were encoded as edge weights using time lagged transfer entropy, a method for quantifying information transfer between variables. By picking a set of source nodes, a diffusion process covers a portion of the network. The size of the network cover relates to the influence of the source nodes. The set of nodes that maximizes influence is the solution to the IMP. By solving the IMP over different numbers of source nodes, an influence ranking on genes was produced. The influence ranking was compared to other metrics of network centrality. Although the top genes from each centrality ranking contained well-known cell cycle regulators, there was little agreement and no clear winner. However, it was found that influential genes tend to directly regulate or sit upstream of genes ranked by other centrality measures. The influential nodes act as critical sources of information flow, potentially having a large impact on the state of the network. Biological events that affect influential nodes and thereby affect information flow could have a strong effect on network dynamics, potentially leading to disease. Code and data can be found at: https://github.com/gibbsdavidl/miergolf. PMID- 28628619 TI - South African Ebola diagnostic response in Sierra Leone: A modular high biosafety field laboratory. AB - BACKGROUND: In August 2014, the National Institute for Communicable Diseases (NICD) in South Africa established a modular high-biosafety field Ebola diagnostic laboratory (SA FEDL) near Freetown, Sierra Leone in response to the rapidly increasing number of Ebola virus disease (EVD) cases. METHODS AND FINDINGS: The SA FEDL operated in the Western Area of Sierra Leone, which remained a "hotspot" of the EVD epidemic for months. The FEDL was the only diagnostic capacity available to respond to the overwhelming demand for rapid EVD laboratory diagnosis for several weeks in the initial stages of the EVD crisis in the capital of Sierra Leone. Furthermore, the NICD set out to establish local capacity amongst Sierra Leonean nationals in all aspects of the FEDL functions from the outset. This led to the successful hand-over of the FEDL to the Sierra Leone Ministry of Health and Sanitation in March 2015. Between 25 August 2014 and 22 June 2016, the laboratory tested 11,250 specimens mostly from the Western Urban and Western Rural regions of Sierra Leone, of which 2,379 (21.14%) tested positive for Ebola virus RNA. CONCLUSIONS: The bio-safety standards and the portability of the SA FEDL, offered a cost-effective and practical alternative for the rapid deployment of a field-operated high biocontainment facility. The SA FEDL teams demonstrated that it is highly beneficial to train the national staff in the course of formidable disease outbreak and accomplished their full integration into all operational and diagnostic aspects of the laboratory. This initiative contributed to the international efforts in bringing the EVD outbreak under control in Sierra Leone, as well as capacitating local African scientists and technologists to respond to diagnostic needs that might be required in future outbreaks of highly contagious pathogens. PMID- 28628620 TI - Prevalence and determinants of online-sex use in the German population. AB - INTRODUCTION: The unlimited access to sexual features in the World Wide Web has raised concerns about excessive and problematic online-sex use. However, little is known about antecedents of internet-sex use of different intensity. Based on a representative German sample of 2,522 participants between the ages of 14 and 97 years, the aims of the present study were (1) to determine the prevalence rates of online-sex users with the short version (ISSTGSV) of the Internet Sex Screening Test and (2) to associate online-sex use with anxious vs. avoidant partner attachment patterns and "Big Five" personality traits as potential antecedents. RESULTS: The ISST is a brief, one-dimensional and reliable measure of online-sex activities (rtt = .69). Overall, 14.7% of respondents reported occasional and 4.2% intensive online-sex use. In multivariate analysis, online sex use was significantly positively associated with male sex, younger age, unemployment and an anxious partner attachment pattern and negatively with conscientiousness and agreeableness. CONCLUSIONS: Arousal and satisfaction by virtual enactment of sexual phantasies may be attractive for anxiously attached persons who find it difficult to commit to a real life relationship due to fear of rejection or low self-esteem. More knowledge about the individual antecedents of intensive online-sex use may also be helpful for the development of consultation and treatment strategies for excessive and addictive online-sex use. PMID- 28628621 TI - Time course of VCAM-1 expression in reperfused myocardial infarction in swine and its relation to retention of intracoronary administered bone marrow-derived mononuclear cells. AB - BACKGROUND: Intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC), after acute myocardial infarction (AMI), has been shown to improve myocardial function. However, therapeutic efficacy is limited, possibly because cell retention rates are low, suggesting that optimization of cell retention might increase therapeutic efficacy. Since retention of injected BMMNC is observed only within infarcted, but not remote, myocardium, we hypothesized that adhesion molecules on activated endothelium following reperfusion are essential. Consequently, we investigated the role of vascular cell adhesion molecule 1 (VCAM 1) in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion. METHODS AND RESULTS: VCAM-1 expression in the infarct and remote region was quantified at 1, 3, 7, 14, and 35 days, post-reperfusion (n>=6 swine per group). Since expression levels were significantly higher at 3 days (2.41+/-0.62%) than at 7 days (0.98+/-0.28%; p<0.05), we compared the degree of cell retention at those time points in a follow-up study, in which an average of 43.106 autologous BMMNCs were infused intracoronary at 3, or 7 days, post-reperfusion (n = 6 swine per group) and retention was histologically quantified one hour after intracoronary infusion of autologous BMMNCs. Although VCAM-1 expression correlated with retention of BMMNC within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3+/-1.3% vs. 3.1+/-1.4%, p = 0.72). This was not due to the composition of infused bone marrow cell fractions (analyzed with flow cytometry; n = 5 per group), as cell composition of the infused BMMNC fractions was similar. CONCLUSION: These findings suggest that VCAM-1 expression influences to a small degree, but is not the principal determinant of, BMMNC retention. PMID- 28628622 TI - Urinary catheter-associated microbiota change in accordance with treatment and infection status. AB - The use of long-term catheterisation to manage insensate bladders, often associated with spinal cord injury (SCI), increases the risk of microbial colonisation and infection of the urinary tract. Urinary tract infection (UTI) is typically diagnosed and treated based on the culturing of organisms from the urine, although this approach overlooks low titer, slow growing and non traditional pathogens. Here, we present an investigation of the urinary tract microbiome in catheterised SCI individuals, using T-RFLP and metagenomic sequencing of the microbial community. We monitored three neurogenic patients over a period of 12 months, who were part of a larger study investigating the efficacy of probiotics in controlling UTIs, to determine how their urinary tract microbial community composition changed over time and in relation to probiotic treatment regimens. Bacterial biofilms adherent to urinary catheters were examined as a proxy for bladder microbes. The microbial community composition of the urinary tract differed significantly between individuals. Probiotic therapy resulted in a significant change in the microbial community associated with the catheters. The community also changed as a consequence of UTI and this shift in community composition preceded the clinical diagnosis of infection. Changes in the microbiota due to probiotic treatment or infection were transient, resolving to microbial communities similar to their pre-treatment communities, suggesting that the native community was highly resilient. Based on these results, we propose that monitoring a patient's microbial community can be used to track the health of chronically catheterized patients and thus, can be used as part of a health-status monitoring program. PMID- 28628623 TI - Use of the DEKA Arm for amputees with brachial plexus injury: A case series. AB - OBJECTIVE: Patients with upper limb amputation and brachial plexus injuries have high rates of prosthesis rejection. Study purpose is to describe experiences of subjects with transhumeral amputation and brachial plexus injury, who were fit with, and trained to use, a DEKA Arm. METHODS: This was a mixed-methods study utilizing qualitative (e.g. interview, survey) and quantitative data (e.g. self report and performance measures). Subject 1, a current prosthesis user, had a shoulder arthrodesis. Subject 2, not a prosthesis user, had a subluxed shoulder. Both were trained in laboratory and participated in a trial of home use. Descriptive analyses of processes and outcomes were conducted. RESULTS: Subject 1 was fitted with the transhumeral configuration (HC) DEKA Arm using a compression release stabilized socket. He had 12 hours of prosthetic training and participated in all home study activities. Subject 1 had improved dexterity and prosthetic satisfaction with the DEKA Arm and reported better quality of life (QOL) at the end of participation. Subject 2 was fit with the shoulder configuration (SC) DEKA Arm using a modified X-frame socket. He had 30 hours of training and participated in 3 weeks of home activities. He reported less functional disability at the end of training as compared to baseline, but encountered personal problems and exacerbation of PTSD symptoms and withdrew from home use portion at 3 weeks. Both subjects reported functional benefits from use, and expressed a desire to receive a DEKA Arm in the future. DISCUSSION: This paper reported on two different strategies for prosthetic fitting and their outcomes. The advantages and limitations of each approach were discussed. CONCLUSION: Use of both the HC and SC DEKA Arm for patients with TH amputation and brachial plexus injury was reported. Lessons learned may be instructive to clinicians considering prosthetic choices for future cases. PMID- 28628624 TI - Heterogeneity of miRNA expression in localized prostate cancer with clinicopathological correlations. AB - INTRODUCTION: In the last decade microRNAs (miRNAs) have been widely investigated in prostate cancer (PCa) and have shown to be promising biomarkers in diagnostic, prognostic and predictive settings. However, tumor heterogeneity may influence miRNA expression. The aims of this study were to assess the impact of tumor heterogeneity, as demonstrated by a panel of selected miRNAs in PCa, and to correlate miRNA expression with risk profile and patient outcome. MATERIAL AND METHODS: Prostatectomy specimens and matched, preoperative needle biopsies from a retrospective cohort of 49 patients, who underwent curatively intended surgery for localized PCa, were investigated with a panel of 6 miRNAs (miRNA-21, miRNA 34a, miRNA-125b, miRNA-126, miRNA-143, and miRNA-145) using tissue micro-array (TMA) and in situ hybridization (ISH). Inter- and intra-patient variation was assessed using intra-class correlation (ICC). RESULTS: Four miRNAs (miRNA-21, miRNA-34a, miRNA-125, and miRNA-126) were significantly upregulated in PCa compared to benign prostatic hyperplasia (BPH), and except for miRNA-21 these miRNAs documented a positive correlation between the expression level in PCa cores and their matched BPH cores, (r > 0.72). The ICC varied from 0.451 to 0.764, with miRNA-34a showing an intra-tumoral heterogeneity accounting for less than 50% of the total variation. Regarding clinicopathological outcomes, only miRNA-143 showed potential as a prognostic marker with a higher expression correlating with longer relapse-free survival (p = 0.016). CONCLUSION: The present study documents significant upregulation of the expression of miRNA-21, miRNA-34a, miRNA-125, and miRNA-126 in PCa compared to BPH and suggests a possible prognostic value associated with the expression of miRNA-143. The results, however, document intra-tumoral heterogeneity in the expression of various miRNAs calling for caution when using these tumor tissue biomarkers in prognostic and predictive settings. PMID- 28628625 TI - Neural progenitor cell proliferation in the hypothalamus is involved in acquired heat tolerance in long-term heat-acclimated rats. AB - Constant exposure to moderate heat facilitates progenitor cell proliferation and neuronal differentiation in the hypothalamus of heat-acclimated (HA) rats. In this study, we investigated neural phenotype and responsiveness to heat in HA rats' hypothalamic newborn cells. Additionally, the effect of hypothalamic neurogenesis on heat acclimation in rats was evaluated. Male Wistar rats (5 weeks old) were housed at an ambient temperature (Ta) of 32 degrees C for 6 days (STHA) or 40 days (LTHA), while control (CN) rats were kept at a Ta of 24 degrees C for 6 days (STCN) or 40 days (LTCN). Bromodeoxyuridine (BrdU) was intraperitoneally injected daily for five consecutive days (50 mg/kg/day) after commencing heat exposure. The number of hypothalamic BrdU-immunopositive (BrdU+) cells in STHA and LTHA rats was determined immunohistochemically in brain samples and found to be significantly greater than those in respective CN groups. In LTHA rats, approximately 32.6% of BrdU+ cells in the preoptic area (POA) of the anterior hypothalamus were stained by GAD67, a GABAergic neuron marker, and 15.2% of BrdU+ cells were stained by the glutamate transporter, a glutamatergic neuron marker. In addition, 63.2% of BrdU+ cells in the POA were immunolabeled with c-Fos. Intracerebral administration of the mitosis inhibitor, cytosine arabinoside (AraC), interfered with the proliferation of neural progenitor cells and acquired heat tolerance in LTHA rats, whereas the selected ambient temperature was not changed. These results demonstrate that heat exposure generates heat responsive neurons in the POA, suggesting a pivotal role in autonomic thermoregulation in long-term heat-acclimated rats. PMID- 28628626 TI - Is normal-tension glaucoma a risk factor for stroke?-A 10-year follow-up study. AB - OBJECTIVES: To investigate whether patients with normal-tension glaucoma (NTG) have a higher incidence of stroke. DESIGN: A population-based retrospective cohort study based on data from the Taiwan National Health Insurance Research Database (NHIRD) from January 1, 2001, to December 31, 2010. METHODS: Data were retrospectively collected from the NHIRD. A total of 245 (20.1%) patients with a history of stroke at the time of glaucoma diagnosis were excluded, and 1,218 patients with NTG who were 20 years of age and older were identified. Patients' age, gender and pre-existing comorbidities, including hypertension, diabetes, congestive heart failure, ischemic heart disease, atrial fibrillation and disorders of lipid metabolism, were recorded. The propensity score method with a 1:5 matching ratio was used to minimize selection bias. Cox regression with robust variance estimation was used to estimate the hazard ratio (HR) of developing stroke between the NTG and control groups. RESULTS: After adjusting for patient age, gender, and pre-existing comorbidities, the HR was 6.34, indicating that the incidence of stroke was significantly higher in patients with NTG than in controls. Furthermore, a higher risk of stroke was also found in most subgroups with the above-mentioned comorbidities. CONCLUSION: NTG is a significant risk factor for subsequent stroke in most of the described comorbidity subgroups. Early interventions for stroke prevention should be provided to newly diagnosed patients with NTG. PMID- 28628627 TI - The current status of phlebotomine sand flies in Albania and incrimination of Phlebotomus neglectus (Diptera, Psychodidae) as the main vector of Leishmania infantum. AB - The incidence of visceral leishmaniasis (VL) in Albania is higher than in other countries of southern Europe, however the role of local sand fly species in the transmission of Leishmania infantum was not addressed conclusively. In 2006, a country-wide collection of sand flies performed in 14 sites selected based on recent occurrence of VL cases showed that Phlebotomus neglectus was by far the most prevalent species (95.6%). Furthermore, 15% of pools made from 422 P. neglectus females tested positive for Leishmania sp. genomic DNA. In the same year, Culicoides trapping was performed for bluetongue disease surveillance in 91 sites of southern Albania, targeting livestock farms regardless recent occurrence of VL in the surveyed areas. In 35 sites where sand flies were collected along with midges, Phlebotomus perfiliewi was the most prevalent among the Phlebotomus species identified, however search for leishmanial DNA in females of this species was unsuccessful. In 2011, sand flies were trapped in 4 sites of north Albania characterized by high VL incidence, and females were dissected to search for Leishmania infections. Both P. neglectus and P. tobbi were collected at high densities. Two positive specimens were detected from a sample of 64 P. neglectus trapped in one site (3.1%). Parasites were successfully cultured from one specimen and characterized as belonging to Leishmania infantum zymodeme MON-1, the only zymodeme so far identified as the agent of human and canine leishmaniasis in the country. Altogether our studies indicate that P. neglectus is the main leishmaniasis vector in Albania. PMID- 28628629 TI - Understanding mSOS: A qualitative study examining the implementation of a text messaging outbreak alert system in rural Kenya. AB - Outbreaks of epidemic diseases pose serious public health risks. To overcome the hurdles of sub-optimal disease surveillance reporting from the health facilities to relevant authorities, the Ministry of Health in Kenya piloted mSOS (mobile SMS based disease outbreak alert system) in 2013-2014. In this paper, we report the results of the qualitative study, which examined factors that influence the performances of mSOS implementation. In-depth interviews were conducted with 11 disease surveillance coordinators and 32 in-charges of rural health facilities that took part in the mSOS intervention. Drawing from the framework analysis, dominant themes that emerged from the interviews are presented. All participants voiced their excitement in using mSOS. The results showed that the technology was well accepted, easy to use, and both health workers and managers unanimously recommended the scale-up of the system despite challenges encountered in the implementation processes. The most challenging components were the context in which mSOS was implemented, including the lack of strong existing structure for continuous support supervision, feedback and response action related to disease surveillance. The study revealed broader health systems issues that should be addressed prior to and during the intervention scale-up. PMID- 28628630 TI - Bird sound spectrogram decomposition through Non-Negative Matrix Factorization for the acoustic classification of bird species. AB - Feature extraction for Acoustic Bird Species Classification (ABSC) tasks has traditionally been based on parametric representations that were specifically developed for speech signals, such as Mel Frequency Cepstral Coefficients (MFCC). However, the discrimination capabilities of these features for ABSC could be enhanced by accounting for the vocal production mechanisms of birds, and, in particular, the spectro-temporal structure of bird sounds. In this paper, a new front-end for ABSC is proposed that incorporates this specific information through the non-negative decomposition of bird sound spectrograms. It consists of the following two different stages: short-time feature extraction and temporal feature integration. In the first stage, which aims at providing a better spectral representation of bird sounds on a frame-by-frame basis, two methods are evaluated. In the first method, cepstral-like features (NMF_CC) are extracted by using a filter bank that is automatically learned by means of the application of Non-Negative Matrix Factorization (NMF) on bird audio spectrograms. In the second method, the features are directly derived from the activation coefficients of the spectrogram decomposition as performed through NMF (H_CC). The second stage summarizes the most relevant information contained in the short-time features by computing several statistical measures over long segments. The experiments show that the use of NMF_CC and H_CC in conjunction with temporal integration significantly improves the performance of a Support Vector Machine (SVM)-based ABSC system with respect to conventional MFCC. PMID- 28628628 TI - Transcriptional mechanisms associated with seed dormancy and dormancy loss in the gibberellin-insensitive sly1-2 mutant of Arabidopsis thaliana. AB - While widespread transcriptome changes were previously observed with seed dormancy loss, this study specifically characterized transcriptional changes associated with the increased seed dormancy and dormancy loss of the gibberellin (GA) hormone-insensitive sleepy1-2 (sly1-2) mutant. The SLY1 gene encodes the F box subunit of an SCF E3 ubiquitin ligase needed for GA-triggered proteolysis of DELLA repressors of seed germination. DELLA overaccumulation in sly1-2 seeds leads to increased dormancy that can be rescued without DELLA protein destruction either by overexpression of the GA receptor, GA-INSENSITIVE DWARF1b (GID1b-OE) (74% germination) or by extended dry after-ripening (11 months, 51% germination). After-ripening of sly1 resulted in different transcriptional changes in early versus late Phase II of germination that were consistent with the processes known to occur. Approximately half of the transcriptome changes with after-ripening appear to depend on SLY1-triggered DELLA proteolysis. Given that many of these SLY1/GA-dependent changes are genes involved in protein translation, it appears that GA signaling increases germination capacity in part by activating translation. While sly1-2 after-ripening was associated with transcript-level changes in 4594 genes over two imbibition timepoints, rescue of sly1-2 germination by GID1b-OE was associated with changes in only 23 genes. Thus, a big change in sly1-2 germination phenotype can occur with relatively little change in the global pattern of gene expression during the process of germination. Most GID1b-OE-responsive transcripts showed similar changes with after-ripening in early Phase II of imbibition, but opposite changes with after-ripening by late Phase II. This suggests that GID1b-OE stimulates germination early in imbibition, but may later trigger negative feedback regulation. PMID- 28628631 TI - Computational explanation for bioactivation mechanism of targeted anticancer agents mediated by cytochrome P450s: A case of Erlotinib. AB - EGFR inhibitors, even with therapeutics superiorities in anticancer, can cause idiosyncratic pulmonary and hepatic toxicities that are associated with the reactive electrophile bioactivated by Cytochrome P450s (P450s). Until now, neither has the electrophilic intermediate been caught experimentally, nor has the subtle mechanism been declared. Herein, the underlying mechanism of bioactivation mediated by P450s was explored by DFT calculations for a case of EGFR inhibitor, Erlotinib. Based on the calculation and analysis, we suggest that with other metabolites, reactive electrophiles of Erlotinib: epoxide and quinine imine, can be generated by several steps along the oxidative reaction pathway. The generation of epoxide needs two steps: (1) the addition of Erlotinib to Compound I (Cpd I) and (2) the rearrangement of protons. Whereas, quinine-imine needs a further oxidation step (3) via which quinone is generated and ultimately turns into quinine-imine. Although both reactive electrophiles can be produced for either face-on or side-on pose of Erlotinib, the analysis of energy barriers indicates that the side-on path is preferred in solvent environment. In the rate determining step, e.g. the addition of Erlotinib to the porphyrin, the reaction barrier for side-on conformation is decreased in aqueous and protein environment compared with gas phase, whereas, the barrier for face-on pose is increased in solvent environment. The simulated mechanism is in good agreement with the speculation in previous experiment. The understanding of the subtle mechanism of bioactivation of Erlotinib will provide theoretical support for toxicological mechanism of EGFR inhibitors. PMID- 28628632 TI - Increasing procaspase 8 expression using repurposed drugs to induce HIV infected cell death in ex vivo patient cells. AB - HIV persists because a reservoir of latently infected CD4 T cells do not express viral proteins and are indistinguishable from uninfected cells. One approach to HIV cure suggests that reactivating HIV will activate cytotoxic pathways; yet when tested in vivo, reactivating cells do not die sufficiently to reduce cell associated HIV DNA levels. We recently showed that following reactivation from latency, HIV infected cells generate the HIV specific cytotoxic protein Casp8p41 which is produced by HIV protease cleaving procaspase 8. However, cell death is prevented, possibly due to low procaspase 8 expression. Here, we tested whether increasing procaspase 8 levels in CD4 T cells will produce more Casp8p41 following HIV reactivation, causing more reactivated cells to die. Screening 1277 FDA approved drugs identified 168 that increased procaspase 8 expression by at least 1.7-fold. Of these 30 were tested for anti-HIV effects in an acute HIVIIIb infection model, and 9 drugs at physiologic relevant levels significantly reduced cell-associated HIV DNA. Primary CD4 T cells from ART suppressed HIV patients were treated with one of these 9 drugs and reactivated with alphaCD3/alphaCD28. Four drugs significantly increased Casp8p41 levels following HIV reactivation, and decreased total cell associated HIV DNA levels (flurbiprofen: p = 0.014; doxycycline: p = 0.044; indomethacin: p = 0.025; bezafibrate: P = 0.018) without effecting the viability of uninfected cells. Thus procaspase 8 levels can be increased pharmacologically and, in the context of HIV reactivation, increase Casp8p41 causing death of reactivating cells and decreased HIV DNA levels. Future studies will be required to define the clinical utility of this or similar approaches. PMID- 28628633 TI - Pro-inflammatory immune responses are associated with clinical signs and symptoms of human anaplasmosis. AB - Human anaplasmosis (HA) is an emerging tick-borne disease that may present as a mild flu-like illness or a life threatening, sepsis-like condition. Although disease severity is hypothesized to relate to immunopathology and immune dysfunction in humans, studies to directly measure immune responses in infected humans have been very limited. We quantified cytokines in 80 confirmed HA patients using a multiplex chemiluminescence immunoassay system and compared similarly measured responses in 1000 control subjects. Pro-inflammatory cytokines were significantly elevated in HA patients (all seven p<0.0001). Interferon gamma (IFN-gamma) concentrations were particularly high, with average concentrations 7.8 times higher in the HA patients than the controls. A subset of cytokines consisting of IL-1beta, IL-8, IL-6, TNF-alpha, and IL-10 was also coordinately high and significantly associated with severity of thrombocytopenia in HA patients. Patients with infections in the very acute stage (<= 4 days ill) tended to have the highest IFN-gamma, IL-12p70, and IL-2 levels. Higher concentrations of IL-13 and IL-5 were associated with diarrhea and vomiting. Our findings support a pathophysiological role for a pro-inflammatory response in HA, especially with regard to the modulation of hematopoiesis and subsequent hematopoietic complications. PMID- 28628634 TI - Protein signature in cerebrospinal fluid and serum of Alzheimer's disease patients: The case of apolipoprotein A-1 proteoforms. AB - In the diagnosis of Alzheimer's disease (AD) total tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), and the 42 amino acid isoform of alpha beta-amyloid (Abeta) are well established surrogate CSF markers. However, there is a constant need for new diagnostic markers to identify the disease at a very early stage. The identification of new molecules for AD diagnosis and monitoring in CSF is hampered by several "confounding" factors including intra- and inter-individual, pre-analytical and analytical variabilities. In an attempt to partially overcome patient's variability and to determine new molecules significantly dysregulated in CSF, we assessed the proteome profile of low molecular weight protein species in CSF and serum of the same patients. CSFs and sera from 36 ADs, 32 iNPHs (idiopathic normal pressure hydrocephalus) and 12 controls were compared by MALDI profiling (non-parametric statistics, CV<20%, AUC>0.750). After protein identification by mass spectrometry, the proteoform composition was assessed by 2-D DIGE/MS. Results indicated that CSF of iNPH can be used as control. Serum and CSF of AD patients shows a specific protein profile compared to iNPH samples. A variation (p<0.01) of Apo A-1 levels in AD, together with a specific dysregulation of Apo A-1 proteoforms was observed. The profiling of CSF and serum of the same patients, suggests that the decrement of total Apo A 1 occurs specifically in CSF. Serum and CSF of AD shows a characteristic Apo A-1 proteoform pattern suggesting it as potential marker which can support the clinical workflow adopted for AD diagnosis and progression. PMID- 28628635 TI - Cross-resistance and synergism bioassays suggest multiple mechanisms of pyrethroid resistance in western corn rootworm populations. AB - Recently, resistance to the pyrethroid bifenthrin was detected and confirmed in field populations of western corn rootworm, Diabrotica virgifera virgifera LeConte from southwestern areas of Nebraska and Kansas. As a first step to understand potential mechanisms of resistance, the objectives of this study were i) to assess adult mortality at diagnostic concentration-LC99 to the pyrethroids bifenthrin and tefluthrin as well as DDT, ii) estimate adult and larval susceptibility to the same compounds as well as the organophosphate methyl parathion, and iii) perform synergism experiments with piperonyl butoxide (PBO) (P450 inhibitor) and S,S,S-tributyl-phosphorotrithioate (DEF) (esterase inhibitor) in field populations. Most of the adult field populations exhibiting some level of bifenthrin resistance exhibited significantly lower mortality to both pyrethroids and DDT than susceptible control populations at the estimated LC99 of susceptible populations. Results of adult dose-mortality bioassays also revealed elevated LC50 values for bifenthrin resistant populations compared to the susceptible control population with resistance ratios ranging from 2.5 to 5.5 fold for bifenthrin, 28 to 54.8-fold for tefluthrin, and 16.3 to 33.0 for DDT. These bioassay results collectively suggest some level of cross-resistance between the pyrethroids and DDT. In addition, both PBO and DEF reduced the resistance ratios for resistant populations although there was a higher reduction in susceptibility of adults exposed to PBO versus DEF. Susceptibility in larvae varied among insecticides and did not correlate with adult susceptibility to tefluthrin and DDT, as most resistance ratios were < 5-fold when compared to the susceptible population. These results suggest that both detoxifying enzymes and target site insensitivity might be involved as resistance mechanisms. PMID- 28628636 TI - Weight change across the start of three consecutive pregnancies and the risk of maternal morbidity and SGA birth at the second and third pregnancy. AB - BACKGROUND: Weight-change across parities and/or current BMI may influence maternal and fetal morbidity and requires to be differentiated to better inform weight-management guidance. METHODS: Direction, pattern and magnitude of weight change across three consecutive parities and thereby two inter-pregnancy periods was described in 5079 women. The association between inter-pregnancy weight change versus current BMI and adverse maternal events, SGA-birth and preterm delivery at second and third pregnancy were investigated by logistic regression. RESULTS: More women gained weight across the defined childbearing period than lost it, with ~35% of normal and overweight women gaining sufficient weight to move up a BMI-category. Nine patterns of weight-change were defined across two inter-pregnancy periods and 50% of women remained weight-stable throughout (within 2BMI units/period). Women who were overweight/obese at first pregnancy had higher risk of substantial weight-gain and loss (>10kg) during each of two inter-pregnancy periods. Inter-pregnancy weight-gain (> 2BMI units) between first and second pregnancy increased the risk of maternal morbidity (1or more event of hypertensive disease, caesarean-section, thromboembolism) at second pregnancy, while weight-loss (>2BMI units) increased the risk of SGA-birth. Similarly, increased risk of maternal morbidity at the third pregnancy was influenced by weight-gain during both inter-pregnancy periods but not by current BMI-category. Both weight-gain between first and second pregnancy, and being overweight/obese by third pregnancy protected the fetus against SGA-birth whereas weight-loss between second and third pregnancy doubled the SGA risk. CONCLUSION: Half the women studied exhibited significant weight-fluctuations. This influenced their risk of maternal morbidity and SGA-birth at second and third pregnancy. PMID- 28628637 TI - Survival, bacterial clearance and thrombocytopenia are improved in polymicrobial sepsis by targeting nuclear transport shuttles. AB - The rising tide of sepsis, a leading cause of death in the US and globally, is not adequately controlled by current antimicrobial therapies and supportive measures, thereby requiring new adjunctive treatments. Severe microvascular injury and multiple organ failure in sepsis are attributed to a "genomic storm" resulting from changes in microbial and host genomes encoding virulence factors and endogenous inflammatory mediators, respectively. This storm is mediated by stress-responsive transcription factors that are ferried to the nucleus by nuclear transport shuttles importins/karyopherins. We studied the impact of simultaneously targeting two of these shuttles, importin alpha 5 (Imp alpha5) and importin beta 1 (Imp beta1), with a cell-penetrating Nuclear Transport Modifier (NTM) in a mouse model of polymicrobial sepsis. NTM reduced nuclear import of stress-responsive transcription factors nuclear factor kappa B, signal transducer and activator of transcription 1 alpha, and activator protein 1 in liver, which was also protected from sepsis-associated metabolic changes. Strikingly, NTM without antimicrobial therapy improved bacterial clearance in blood, spleen, and lungs, wherein a 700-fold reduction in bacterial burden was achieved while production of proinflammatory cytokines and chemokines in blood plasma was suppressed. Furthermore, NTM significantly improved thrombocytopenia, a prominent sign of microvascular injury in sepsis, inhibited neutrophil infiltration in the liver, decreased L-selectin, and normalized plasma levels of E-selectin and P selectin, indicating reduced microvascular injury. Importantly, NTM combined with antimicrobial therapy extended the median time to death from 42 to 83 hours and increased survival from 30% to 55% (p = 0.022) as compared to antimicrobial therapy alone. This study documents the fundamental role of nuclear signaling mediated by Imp alpha5 and Imp beta1 in the mechanism of polymicrobial sepsis and highlights the potential for targeting nuclear transport as an adjunctive therapy in sepsis management. PMID- 28628638 TI - Temperature and concentration calibration of aqueous polyvinylpyrrolidone (PVP) solutions for isotropic diffusion MRI phantoms. AB - To use the "apparent diffusion coefficient" (Dapp) as a quantitative imaging parameter, well-suited test fluids are essential. In this study, the previously proposed aqueous solutions of polyvinylpyrrolidone (PVP) were examined and temperature calibrations were obtained. For example, at a temperature of 20 degrees C, Dapp ranged from 1.594 (95% CI: 1.593, 1.595) MUm2/ms to 0.3326 (95% CI: 0. 3304, 0.3348) MUm2/ms for PVP-concentrations ranging from 10% (w/w) to 50% (w/w) using K30 polymer lengths. The temperature dependence of Dapp was found to be so strong that a negligence seems not advisable. The temperature dependence is descriptively modelled by an exponential function exp(c2 (T - 20 degrees C)) and the determined c2 values are reported, which can be used for temperature calibration. For example, we find the value 0.02952 K-1 for 30% (w/w) PVP concentration and K30 polymer length. In general, aqueous PVP solutions were found to be suitable to produce easily applicable and reliable Dapp-phantoms. PMID- 28628640 TI - Birds of a feather flock together: Insights into starling murmuration behaviour revealed using citizen science. AB - Pre-roost murmuration displays by European starlings Sturnus vulgaris are a spectacular example of collective animal behaviour. To date, empirical research has focussed largely on flock movement and biomechanics whereas research on possible causal mechanisms that affect flock size and murmuration duration has been limited and restricted to a small number of sites. Possible explanations for this behaviour include reducing predation through the dilution, detection or predator confusion effects (the "safer together" hypotheses) or recruiting more birds to create larger (warmer) roosts (the "warmer together" hypothesis). We collected data on size, duration, habitat, temperature and predators from >3,000 murmurations using citizen science. Sightings were submitted from 23 countries but UK records predominated. Murmurations occurred across a range of habitats but there was no association between habitat and size/duration. Size increased significantly from October to early February, followed by a decrease until the end of the season in March (overall mean 30,082 birds; maximum 750,000 birds). Mean duration was 26 minutes (+/- 44 seconds SEM). Displays were longest at the start/end of the season, probably due to a significant positive relationship with day length. Birds of prey were recorded at 29.6% of murmurations. The presence of predators including harrier Circus, peregrine Falco peregrinus, and sparrowhawk Accipiter nisus was positively correlated with murmuration size (R2 = 0.401) and duration (R2 = 0.258), especially when these species were flying near to, or actively engaging with, starlings. Temperature was negatively correlated with duration but the effect was much weaker than that of day length. When predators were present, murmurations were statistically more likely to end with all birds going down en masse to roost rather than dispersing from the site. Our findings suggest that starling murmurations are primarily an anti-predator adaptation rather than being undertaken to attract larger numbers of individuals to increase roost warmth. PMID- 28628639 TI - Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes. AB - Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response. This sensitivity is due to a synthetic lethal interaction between FEN1 and MRE11A, which is often mutated in MSI cancers through instabilities at a poly(T) microsatellite repeat. Disruption of ATM is similarly synthetic lethal with FEN1 inhibition, suggesting that disruption of FEN1 function leads to the accumulation of DNA double-strand breaks. These are likely a result of the accumulation of aberrant replication forks, that accumulate as a consequence of a failure in Okazaki fragment maturation, as inhibition of FEN1 is toxic in cells disrupted for the Fanconi anemia pathway and post-replication repair. Furthermore, RAD51 foci accumulate as a consequence of FEN1 inhibition and the toxicity of FEN1 inhibitors increases in cells disrupted for the homologous recombination pathway, suggesting a role for homologous recombination in the resolution of damage induced by FEN1 inhibition. Finally, FEN1 appears to be required for the repair of damage induced by olaparib and cisplatin within the Fanconi anemia pathway, and may play a role in the repair of damage associated with its own disruption. PMID- 28628641 TI - Hypersensitivity pneumonitis onset and severity is regulated by CD103 dendritic cell expression. AB - BACKGROUND: Pulmonary dendritic cells drive lung responses to foreign antigens, including Saccharopolyspora rectivirgula, a causative agent of hypersensitivity pneumonitis. While the airway inflammatory mechanisms involved in hypersensitivity pneumonitis are well described, the mechanisms leading to the break in homeostasis and hypersensitivity pneumonitis onset are not well described, and could involve CD103+ dendritic cells, which are found at baseline and during inflammatory responses in the lung. However, recent demonstration of the ability of CD103+ dendritic cells to induce inflammatory responses starkly contrasts with their classically described role as regulatory cells. These discrepancies may be attributable to the lack of current information on the importance of CD103 expression and modulation on these cells during inflammatory episodes. METHODS: To verify the importance of CD103 expression in the regulation of hypersensitivity pneumonitis, wild-type and Cd103-/- mice were exposed intranasally to S. rectivirgula and airway inflammation was quantified. Surface expression of CD103 in response to S. rectivirgula exposure was studied and cell transfers were used to determine the relative importance of CD103 expression on dendritic cells and T cells in regulating the inflammation in hypersensitivity pneumonitis. RESULTS: Cd103-/- mice developed an exacerbated inflammatory response as early as 18h following S. rectivirgula exposure. CD103 expression on dendritic cells was downregulated quickly following S. rectivirgula exposure, and cell transfers demonstrated that CD103 expression on dendritic cells specifically (and not T cells) regulates the onset and severity of this response. CONCLUSION: All in all, we demonstrate that CD103 expression by dendritic cells, but not T cells, is crucial for homeostasis maintenance and the regulation of the TH17 airway inflammatory response in hypersensitivity pneumonitis. PMID- 28628642 TI - Nanoscale quantification of the biophysical characterization of combretastatin A 4-treated tumor cells using atomic force microscopy. AB - As an inhibitor of microtubule assembly, combretastatin A-4 (CA-4)-induced biological responses in tumor cells have been well known, but the corresponding changes in nano-biophysical properties were not investigated given the lack of an ideal tool. Using AFM technique, we investigated the alteration of nano biophysical properties when CA-4-treated tumor cells underwent the different biological processes, including cell cycle arrest, apoptosis and autophagy. We found that CA-4-resistant cells were rougher with the presence of characteristic "ridges", indicating that the development of "ridge" structure may be a determinant of the sensitivity of cells to CA-4 compounds. CA-4 induced G2/M arrest and apoptosis in sensitive cells but triggered anti-apoptotic autophagy in resistant cells. CA-4 treatment caused an increase in stiffness in both sensitive and resistant cells. However, these cells exhibited different changes in cell surface roughness. CA-4 decreased Ra and Rq values in sensitive cells but increased these values in resistant cells. The reorganization of F-actin might contribute to the different changes of nano-biophysical properties in CA-4 sensitive and-resistant cells. Our results suggest that cellular nano-biophysical properties, such as "ridges", roughness and stiffness, could be applied as potential biomarkers for evaluating CA-4 compounds, and knowledge regarding how biological alterations cause changes in cellular nano-biophysical properties is helpful to develop a new high-resolution screening tool for anti-tumor agents. PMID- 28628643 TI - Mis-targeting of the mitochondrial protein LIPT2 leads to apoptotic cell death. AB - Lipoyl(Octanoyl) Transferase 2 (LIPT2) is a protein involved in the post translational modification of key energy metabolism enzymes in humans. Defects of lipoic acid synthesis and transfer start to emerge as causes of fatal or severe early-onset disease. We show that the first 31 amino acids of the N-terminus of LIPT2 represent a mitochondrial targeting sequence and inhibition of the transit of LIPT2 to the mitochondrion results in apoptotic cell death associated with activation of the apoptotic volume decrease (AVD) current in normotonic conditions, as well as over-activation of the swelling-activated chloride current (IClswell), mitochondrial membrane potential collapse, caspase-3 cleavage and nuclear DNA fragmentation. The findings presented here may help elucidate the molecular mechanisms underlying derangements of lipoic acid biosynthesis. PMID- 28628644 TI - Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells. AB - Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses. PMID- 28628645 TI - Effect of horizontal rectus surgery for the correction of intermittent exotropia on sub-A or sub-V pattern. AB - We evaluated effect of horizontal rectus surgery on sub-A or sub-V pattern intermittent exotropia. We enrolled patients with sub-A or sub-V pattern intermittent exotropia. The sub-A pattern was diagnosed when the eyes diverged less than 10 prism diopters (PD) from upgaze to downgaze, and sub-V pattern when the divergence was 14 PD or less from downgaze to upgaze. Patients had undergone horizontal rectus surgery without vertical transposition of horizontal rectus muscle or oblique muscle weakening. The patients were divided into two groups: sub-A pattern (group A) and sub-V pattern (group V). The outcome measures were change of amount of pattern and rate of collapse of pattern postoperatively. The amount of pattern (vertical incomitance) was amount of difference in exodeviation between upgaze and downgaze. Collapse of pattern was defined as disappearance of difference in exodeviation between upgaze and downgaze. In groups A and V, preoperative amounts of pattern were 4.9 PD and 6.8 PD, respectively. A significant reduction in amount of pattern was observed in both groups throughout the follow-up period (p<0.05). At postoperative 6 months, the amounts of pattern were 1.0 PD and 1.2 PD and the extents of reduction in amount of pattern were 4.4 PD and 5.9 PD. The rates of collapse of pattern at postoperative 6 months were 77.8 and 60.0%, respectively. In the patients with sub-A or sub-V pattern exotropia, horizontal rectus surgery without vertical transposition or oblique muscle weakening can successfully collapse the pattern. PMID- 28628646 TI - The impact of glycemic status on radiological manifestations of pulmonary tuberculosis in diabetic patients. AB - SETTING: Diabetes mellitus (DM) may increase risk of pulmonary tuberculosis (PTB) and influence its radiological manifestations. OBJECTIVE: To evaluate the impact of glycemic status on radiological findings of PTB in diabetic patients. METHODS: Between January 2010 and December 2015, chest radiographs (CXRs) in consecutive 214 DM patients with culture-proved PTB and 123 available thoracic computed tomography (CT) scans were enrolled. An equal number of non-DM patients with similar demographics was included as the control group. Glycemic status was assessed by glycosylated hemoglobin (HbA1c), and a cutoff of 8% was used to further investigate radiological features of diabetic PTB. Two radiologists and one pulmonologist reviewed the chest images independently. RESULTS: Compared with non-DM patients, primary PTB pattern and extensive disease on CXRs as well as primary PTB pattern, large non-cavitary nodule, more than one cavity in a single lesion, unusual location, and all lobe involvement of lesions on thoracic CT scans were more common in DM patients. Furthermore, diabetics with HbA1c > 8% were more likely to exhibit unusual findings (P < 0.001), far advanced extensive lesions (P < 0.001) on CXRs, lymphadenopathy (P = 0.028), more than one cavity in a single lesion (P < 0.001) and all lobe involvement (P = 0.041) on thoracic CT scans. CONCLUSIONS: Glycemic status influenced radiological manifestations of diabetic PTB. Given an increased risk of atypical radiological presentations of PTB in DM patients, physicians should be alert and pay more attention to those with poor glycemic control. PMID- 28628647 TI - An efficient coding theory for a dynamic trajectory predicts non-uniform allocation of entorhinal grid cells to modules. AB - Grid cells in the entorhinal cortex encode the position of an animal in its environment with spatially periodic tuning curves with different periodicities. Recent experiments established that these cells are functionally organized in discrete modules with uniform grid spacing. Here we develop a theory for efficient coding of position, which takes into account the temporal statistics of the animal's motion. The theory predicts a sharp decrease of module population sizes with grid spacing, in agreement with the trend seen in the experimental data. We identify a simple scheme for readout of the grid cell code by neural circuitry, that can match in accuracy the optimal Bayesian decoder. This readout scheme requires persistence over different timescales, depending on the grid cell module. Thus, we propose that the brain may employ an efficient representation of position which takes advantage of the spatiotemporal statistics of the encoded variable, in similarity to the principles that govern early sensory processing. PMID- 28628648 TI - The adenovirus major core protein VII is dispensable for virion assembly but is essential for lytic infection. AB - The Adenovirus (Ad) genome within the capsid is tightly associated with a virus encoded, histone-like core protein-protein VII. Two other Ad core proteins, V and X/MU, also are located within the virion and are loosely associated with viral DNA. Core protein VII remains associated with the Ad genome during the early phase of infection. It is not known if naked Ad DNA is packaged into the capsid, as with dsDNA bacteriophage and herpesviruses, followed by the encapsidation of viral core proteins, or if a unique packaging mechanism exists with Ad where a DNA-protein complex is simultaneously packaged into the virion. The latter model would require an entirely new molecular mechanism for packaging compared to known viral packaging motors. We characterized a virus with a conditional knockout of core protein VII. Remarkably, virus particles were assembled efficiently in the absence of protein VII. No changes in protein composition were evident with VII virus particles, including the abundance of core protein V, but changes in the proteolytic processing of some capsid proteins were evident. Virus particles that lack protein VII enter the cell, but incoming virions did not escape efficiently from endosomes. This greatly diminished all subsequent aspects of the infectious cycle. These results reveal that the Ad major core protein VII is not required to condense viral DNA within the capsid, but rather plays an unexpected role during virus maturation and the early stages of infection. These results establish a new paradigm pertaining to the Ad assembly mechanism and reveal a new and important role of protein VII in early stages of infection. PMID- 28628649 TI - Insights into the binding mode of MEK type-III inhibitors. A step towards discovering and designing allosteric kinase inhibitors across the human kinome. AB - Protein kinases are critical drug targets for treating a large variety of human diseases. Type-III kinase inhibitors have attracted increasing attention as highly selective therapeutics. Thus, understanding the binding mechanism of existing type-III kinase inhibitors provides useful insights into designing new type-III kinase inhibitors. In this work, we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors. We hypothesize that the helix-folding activation loop is a hallmark allosteric binding site for type-III inhibitors. Subsequently, we screened and predicted allosteric binding sites across the human kinome, suggesting other kinases as potential targets suitable for type-III inhibitors. PMID- 28628651 TI - The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes. AB - To elucidate the etiology of type 1 diabetes, the affected pancreas needs to be thoroughly characterized. Pancreatic innervation has been suggested to be involved in the pathology of the disease and a reduction of sympathetic innervation of the islets was recently reported. In the present study, we hypothesized that parasympathetic innervation would be altered in the type 1 diabetes pancreas. Human pancreatic specimens were obtained from a unique cohort of individuals with recent onset or long standing type 1 diabetes. Density of parasympathetic axons was assessed by immunofluorescence and morphometry. Our main finding was a reduced density of parasympathetic axons in the exocrine, but not endocrine compartment of the pancreas in individuals with recent onset type 1 diabetes. The reduced density of parasympathetic axons in the exocrine compartment could have functional implications, e.g. be related to the exocrine insufficiency reported in type 1 diabetes patients. Further studies are needed to understand whether reduced parasympathetic innervation is a cause or consequence of type 1 diabetes. PMID- 28628650 TI - The human cytomegalovirus glycoprotein pUL11 acts via CD45 to induce T cell IL-10 secretion. AB - Human Cytomegalovirus (HCMV) is a widespread pathogen, infection with which can cause severe disease for immunocompromised individuals. The complex changes wrought on the host's immune system during both productive and latent HCMV infection are well known. Infected cells are masked and manipulated and uninfected immune cells are also affected; peripheral blood mononuclear cell (PBMC) proliferation is reduced and cytokine profiles altered. Levels increase of the anti-inflammatory cytokine IL-10, which may be important for the establishment of HCMV infections and is required for the development of high viral titres by murine cytomegalovirus. The mechanisms by which HCMV affects T cell IL-10 secretion are not understood. We show here that treatment of PBMC with purified pUL11 induces IL-10 producing T cells as a result of pUL11 binding to the CD45 phosphatase on T cells. IL-10 production induced by HCMV infection is also in part mediated by pUL11. Supernatants from pUL11 treated cells have anti inflammatory effects on untreated PBMC. Considering the mechanism, CD45 can be a positive or negative regulator of TCR signalling, depending on its expression level, and we show that pUL11 also has concentration dependent activating or inhibitory effects on T cell proliferation and on the kinase function of the CD45 substrate Lck. pUL11 is therefore the first example of a viral protein that can target CD45 to induce T cells with anti-inflammatory properties. It is also the first HCMV protein shown to induce T cell IL-10 secretion. Understanding the mechanisms by which pUL11-induced changes in signal strength influence T cell development and function may provide the basis for the development of novel antiviral treatments and therapies against immune pathologies. PMID- 28628652 TI - MicroRNA-433-3p promotes osteoblast differentiation through targeting DKK1 expression. AB - Dickkopf-1 (DKK1) is a powerful antagonist of canonical WNT signaling pathway, and is regarded as a biomarker for osteoporosis. Its expression is highly correlated with bone mass and osteoblasts maturation. In this study, mouse primary bone marrow cells and osteoblast cell lines were used. Luciferase reporter assay and western blotting methods were employed to validate if miRNA 433-3p epigenetically regulated DKK1 translation. Rat bone marrow derived osteoblasts were infected with lentivirus vector in which miR-433-3p was constructed. The authors constructed lentivirus mediated miRNA-433-3p stable expression and examined the alkaline phosphatase (ALP) activity and mineral deposition level in vitro. In situ hybridization method was used to observe miR 433-3p in primary osteoblasts. We built up an OVX rat model to mimic postmenopausal osteoporosis, and found aberrant circulating miR-433-3p and miR 106b, which were not reported previously. Results showed that miR-433-3p potentially regulated DKK1 mRNA, Furthermore, the correlation of serum DKK1 with circulating miR-433-3p level was significant (r = 0.7520, p = 0.046). In the luciferase reporter assay, we found that miR-433-3p siRNA decreased luminescence signal, indicating direct regulation of miR-433-3p on DKK1 mRNA. When the miR-433 3p binding site in DKK1 3'UTR was mutant, such reduction was prohibited. Western blotting result validated that miR-433-3p inhibited over 90% of DKK1 protein expression. Similarly, the change of protein expression was not observed in mutant group. The stable expression of lentivirus mediated miR-433-3p increased ALP activity and mineralization both in human and rat derived immortalized cells. We found that primary osteoblasts had higher miR-433-3p level compared with immortal cells through real-time PCR, as well as in situ hybridization experiment. Conclusively, our findings further emphasized the vital role of miR 433-3p in DKK1/WNT/beta-catenin pathway through decreasing DKK1 expression and inducing osteoblasts differentiation. PMID- 28628653 TI - Esperanza Window Traps for the collection of anthropophilic blackflies (Diptera: Simuliidae) in Uganda and Tanzania. AB - There is an increasing need to evaluate the impact of chemotherapeutic and vector based interventions as onchocerciasis affected countries work towards eliminating the disease. The Esperanza Window Trap (EWT) provides a possible alternative to human landing collections (HLCs) for the collection of anthropophilic blackflies, yet it is not known whether current designs will prove effective for onchocerciasis vectors throughout sub-Saharan Africa. EWTs were deployed for 41 days in northern Uganda and south eastern Tanzania where different Simulium damnosum sibling species are responsible for disease transmission. The relative efficacy of EWTs and HLCs was compared, and responses of host-seeking blackflies to odour baits, colours, and yeast-produced CO2 were investigated. Blue EWTs baited with CO2 and worn socks collected 42.3% (2,393) of the total S. damnosum s.l. catch in northern Uganda. Numbers were comparable with those collected by HLCs (32.1%, 1,817), and higher than those collected on traps baited with CO2 and BG-Lure (25.6%, 1,446), a synthetic human attractant. Traps performed less well for the collection of S. damnosum s.l. in Tanzania where HLCs (72.5%, 2,432) consistently outperformed both blue (16.8%, 563) and black (10.7%, 360) traps baited with CO2 and worn socks. HLCs (72.3%, 361) also outperformed sock-baited (6.4%, 32) and BG-Lure-baited (21.2%, 106) traps for the collection of anthropophilic Simulium bovis in northern Uganda. Contrasting blackfly distributions were observed on traps in Uganda and Tanzania, indicating differences in behaviour in each area. The success of EWT collections of S. damnosum s.l. in northern Uganda was not replicated in Tanzania, or for the collection of anthropophilic S. bovis. Further research to improve the understanding of behavioural responses of vector sibling species to traps and their attractants should be encouraged. PMID- 28628654 TI - The ApaH-like phosphatase TbALPH1 is the major mRNA decapping enzyme of trypanosomes. AB - 5'-3' decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5'-3' exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5'-3' degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding. A fraction of ALPH1 co-localises exclusively with the trypanosome 5'-3' exoribonuclease XRNA to a special granule at the posterior pole of the cell, indicating a connection between the two enzymes. RNAi depletion of ALPH1 is lethal and causes a massive increase in total mRNAs that are deadenylated, but have not yet started 5'-3' decay. These data suggest that ALPH1 acts downstream of deadenylation and upstream of mRNA degradation, consistent with a function in mRNA decapping. In vitro experiments show that recombinant, N-terminally truncated ALHP1 protein, but not a catalytically inactive mutant, sensitises the capped trypanosome spliced leader RNA to yeast Xrn1, but only if an RNA 5' polyphosphatase is included. This indicates that the decapping mechanism of ALPH1 differs from the decapping mechanism of Dcp2 by leaving more than one phosphate group at the mRNA's 5' end. This is the first reported function of a eukaryotic ApaH-like phosphatase, a bacterial-derived class of enzymes present in all phylogenetic super-groups of the eukaryotic kingdom. The substrates of eukaryotic ApaH-like phosphatases are unknown. However, the substrate of the related bacterial enzyme ApaH, diadenosine tetraphosphate, is highly reminiscent of a eukaryotic mRNA cap. PMID- 28628655 TI - MoEnd3 regulates appressorium formation and virulence through mediating endocytosis in rice blast fungus Magnaporthe oryzae. AB - Eukaryotic cells respond to environmental stimuli when cell surface receptors are bound by environmental ligands. The binding initiates a signal transduction cascade that results in the appropriate intracellular responses. Studies have shown that endocytosis is critical for receptor internalization and signaling activation. In the rice blast fungus Magnaporthe oryzae, a non-canonical G protein coupled receptor, Pth11, and membrane sensors MoMsb2 and MoSho1 are thought to function upstream of G-protein/cAMP signaling and the Pmk1 MAPK pathway to regulate appressorium formation and pathogenesis. However, little is known about how these receptors or sensors are internalized and transported into intracellular compartments. We found that the MoEnd3 protein is important for endocytic transport and that the DeltaMoend3 mutant exhibited defects in efficient internalization of Pth11 and MoSho1. The DeltaMoend3 mutant was also defective in Pmk1 phosphorylation, autophagy, appressorium formation and function. Intriguingly, restoring Pmk1 phosphorylation levels in DeltaMoend3 suppressed most of these defects. Moreover, we demonstrated that MoEnd3 is subject to regulation by MoArk1 through protein phosphorylation. We also found that MoEnd3 has additional functions in facilitating the secretion of effectors, including Avr-Pia and AvrPiz-t that suppress rice immunity. Taken together, our findings suggest that MoEnd3 plays a critical role in mediating receptor endocytosis that is critical for the signal transduction-regulated development and virulence of M. oryzae. PMID- 28628656 TI - Ultrasound-guided cable-free 13-gauge vacuum-assisted biopsy of non-mass breast lesions. AB - PURPOSE: To compare the outcomes of ultrasound-guided core biopsy for non-mass breast lesions by the novel 13-gauge cable-free vacuum-assisted biopsy (VAB) and by the conventional 14-gauge semi-automated core needle biopsy (CCNB). MATERIALS AND METHODS: Our institutional review board approved this prospective study, and all patients provided written informed consent. Among 1840 ultrasound-guided percutaneous biopsies performed from August 2013 to December 2014, 145 non-mass breast lesions with suspicious microcalcifications on mammography or corresponding magnetic resonance imaging finding were subjected to 13-gauge VAB or 14-gauge CCNB. We evaluated the technical success rates, average specimen numbers, and tissue sampling time. We also compared the results of percutaneous biopsy and final surgical pathologic diagnosis to analyze the rates of diagnostic upgrade or downgrade. RESULTS: Ultrasound-guided VAB successfully targeted and sampled all lesions, whereas CCNB failed to demonstrate calcification in four (10.3%) breast lesions with microcalcification on specimen mammography. The mean sampling time were 238.6 and 170.6 seconds for VAB and CCNB, respectively. No major complications were observed with either method. Ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH) lesions were more frequently upgraded after CCNB (8/23 and 3/5, respectively) than after VAB (2/26 and 0/4, respectively P = 0.028). CONCLUSION: Non-mass breast lesions were successfully and accurately biopsied using cable-free VAB. The underestimation rate of ultrasound-detected non-mass lesion was significantly lower with VAB than with CCNB. TRIAL REGISTRATION: CRiS KCT0002267. PMID- 28628657 TI - Reported family burden of schizophrenia patients in rural China. AB - We aim to assess the level of family burden of schizophrenia patients and identify its predicting factors in a rural community sample of China. A sample of 327 primary caregivers was recruited through a one-stage cluster sampling in Ningxiang County of Hunan province, China. Family burden was assessed using the Family Burden Interview Schedule (FBIS) of Pai and Kapur. Our results showed that the mean score of FBIS was 23.62+/-9.76 (range, 0-48), with over half (52%) caregivers reported their family burden being moderate and severe. Among the six domains of family burden, financial burden (76%) was the commonest burden, while disruption of family interactions (37%) was the least mentioned. A multivariate analysis of family burden revealed that patient being admitted for over 3 times, caregiver being female, having a middle school education, and with additional dependents, as well as higher care network function were positive predictors of family burden, while higher patient function and family function, and increasing patient age were negative predictors of family burden. Intervention to decrease family burden may be best served by improving family function and exploring alternative care model instead of hospitalization. PMID- 28628659 TI - Wave intensity of aortic root pressure as diagnostic marker of left ventricular systolic dysfunction. AB - BACKGROUND: Systolic left ventricular function strongly influences the blood pressure waveform. Therefore, pressure-derived parameters might potentially be used as non-invasive, diagnostic markers of left ventricular impairment. The aim of this study was to investigate the performance of pressure-based parameters in combination with electrocardiography (ECG) for the detection of left ventricular systolic dysfunction defined as severely reduced ejection fraction (EF). METHODS AND RESULTS: Two populations, each comprising patients with reduced EF and pressure-matched controls, were included for the main analysis (51/102 patients) and model testing (44/88 patients). Central pressure was derived from radial readings and used to compute blood flow. Subsequently, pulse wave analysis and wave intensity analysis were performed and the ratio of the two peaks of forward intensity (SDR) was calculated as a novel index of ventricular function. SDR was significantly decreased in the reduced EF group (2.5 vs. 4.4, P<0.001), as was central pulse pressure, augmentation index and ejection duration (ED), while the QRS-duration was prolonged. SDR and ED were independent predictors of ventricular impairment and when combined with QRS in a simple decision tree, a reduced EF could be detected with a sensitivity of 92% and a specificity of 80%. The independent power of ED, SDR and QRS to predict reduced EF was furthermore confirmed in the test population. CONCLUSION: The detection or indication of reduced ejection fraction from pressure-derived parameters seems feasible. These parameters could help to improve the quality of cardiovascular risk stratification or might be used in screening strategies in the general population. PMID- 28628658 TI - Effects of obesogenic diet and estradiol on dorsal raphe gene expression in old female macaques. AB - The beneficial effects of bioidentical ovarian steroid hormone therapy (HT) during the perimenopause are gaining recognition. However, the positive effects of estrogen (E) plus or minus progesterone (P) administration to ovariectomized (Ovx) lab animals were recognized in multiple systems for years before clinical trials could adequately duplicate the results. Moreover, very large numbers of women are often needed to find statistically significant results in clinical trials of HT; and there are still opposing results being published, especially in neural and cardiovascular systems. One of the obvious differences between human and animal studies is diet. Laboratory animals are fed a diet that is low in fat and refined sugar, but high in micronutrients. In the US, a large portion of the population eats what is known as a "western style diet" or WSD that provides calories from 36% fat, 44% carbohydrates (includes 18.5% sugars) and 18% protein. Unfortunately, obesity and diabetes have reached epidemic proportions and the percentage of obese women in clinical trials may be overlooked. We questioned whether WSD and obesity could decrease the positive neural effects of estradiol (E) in the serotonin system of old macaques that were surgically menopausal. Old ovo-hysterectomized female monkeys were fed WSD for 2.5 years, and treated with placebo, Immediate E (ImE) or Delayed E (DE). Compared to old Ovx macaques on primate chow and treated with placebo or E, the WSD-fed monkeys exhibited greater individual variance and blunted responses to E-treatment in the expression of genes related to serotonin neurotransmission, CRH components in the midbrain, synapse assembly, DNA repair, protein folding, ubiquitylation, transport and neurodegeneration. For many of the genes examined, transcript abundance was lower in WSD-fed than chow-fed monkeys. In summary, an obesogenic diet for 2.5 years in old surgically menopausal macaques blunted or increased variability in E-induced gene expression in the dorsal raphe. These results suggest that with regard to function and viability in the dorsal raphe, HT may not be as beneficial for obese women as normal weight women. PMID- 28628660 TI - Systematic review of emergency medicine clinical practice guidelines: Implications for research and policy. AB - INTRODUCTION: Over 25 years, emergency medicine in the United States has amassed a large evidence base that has been systematically assessed and interpreted through ACEP Clinical Policies. While not previously studied in emergency medicine, prior work has shown that nearly half of all recommendations in medical specialty practice guidelines may be based on limited or inconclusive evidence. We sought to describe the proportion of clinical practice guideline recommendations in Emergency Medicine that are based upon expert opinion and low level evidence. METHODS: Systematic review of clinical practice guidelines (Clinical Policies) published by the American College of Emergency Physicians from January 1990 to January 2016. Standardized data were abstracted from each Clinical Policy including the number and level of recommendations as well as the reported class of evidence. Primary outcomes were the proportion of Level C equivalent recommendations and Class III equivalent evidence. The primary analysis was limited to current Clinical Policies, while secondary analysis included all Clinical Policies. RESULTS: A total of 54 Clinical Policies including 421 recommendations and 2801 cited references, with an average of 7.8 recommendations and 52 references per guideline were included. Of 19 current Clinical Policies, 13 of 141 (9.2%) recommendations were Level A, 57 (40.4%) Level B, and 71 (50.4%) Level C. Of 845 references in current Clinical Policies, 67 (7.9%) were Class I, 272 (32.3%) Class II, and 506 (59.9%) Class III equivalent. Among all Clinical Policies, 200 (47.5%) recommendations were Level C equivalent, and 1371 (48.9%) of references were Class III equivalent. CONCLUSIONS: Emergency medicine clinical practice guidelines are largely based on lower classes of evidence and a majority of recommendations are expert opinion based. Emergency medicine appears to suffer from an evidence gap that should be prioritized in the national research agenda and considered by policymakers prior to developing future quality standards. PMID- 28628661 TI - Elimination of persistent vaccine bacteria of Salmonella enterica serovar Typhimurium in the guts of immunized mice by inducible expression of truncated YncE. AB - Orally administered vaccine bacteria usually persist for a period of time in the intestinal tracts of immunized individuals, and are excreted in feces to the environment resulting in a potential biosafety issue. The releasing risk can be minimized by immediate elimination of the persistent vaccine bacteria once adequate protective immune responses have been elicited by the vaccine bacteria. In a previous study, inducible expression of truncated yncE gene (yncE*) was found lethal to host bacteria. This feature has an application potential in biosafety control. Here, we assessed the efficacy of YncE* in eliminating an attenuated strain of Salmonella enterica serovar Typhimurium in a mouse model. To this end, a pBAD-derived plasmid containing yncE* under the control of the Ara promoter was transformed into a DeltaphoPQ mutant of S. Typhimurium. Our data show that the induced expression of yncE* in the presence of arabinose eliminated the vaccine bacteria both in vitro and in vivo. BALB/c mice with or without streptomycin-pretreatment were used to assess the efficacy of YncE* in vivo. Oral administration of 500 MUl of 20% arabinose at 24 h postvaccination removed the vaccine bacteria from the guts of the tested mice without streptomycin pretreatment. For streptomycin-pretreated mice, which were colonized with higher levels of Salmonella, an additional gavage of arabinose was required to completely eliminate the vaccine bacteria in the guts of the tested mice. The orally administered arabinose did not affect the persistence of bacteria that had penetrated the intestinal mucosa of the immunized mice. Furthermore, there was no significant difference in the protection rate between the routine immunization and the immunization with the arabinose treatment. The results indicate that the yncE* element improves the biosafety of the bacterial vaccine, and can be taken in consideration in future design of live bacterial vaccines. PMID- 28628662 TI - Quantitative analysis of retinal layers on three-dimensional spectral-domain optical coherence tomography for pituitary adenoma. AB - PURPOSE: To quantitatively investigate the characteristics of eyes with pituitary adenoma presented by three-dimensional (3D) spectral-domain optical coherence tomography (SD-OCT) using three common indices, including thickness, optical intensity ratio, and optical intensity attenuation coefficient (OIAC). METHODS: The SD-OCT database of 38 patients with pituitary adenoma and 39 normal controls were included in the study. Quadrantal and average measurements of thickness, optical intensity ratio, and OIAC were calculated for macular retinal nerve fiber layer (mRNFL), ganglion cell layer (GCL) combined with inner plexiform layer (IPL) (GCIPL) and/or the collective ganglion cell complex (GCC). The parameters of patients and controls were compared by unpaired t-test and Mann-Whitney U test. The relationships between the optical intensity ratio and the thickness of mRNFL and GCIPL were evaluated by Pearson's correlation. Diagnostic performances of these indices were assessed using receiver operating characteristic (ROC) analysis. RESULTS: Significant decreases in thickness existed in the mRNFL and nasal GCC of patients compared with controls (p-values of 0.000 to 0.039). Optical intensity ratios in the relevant retinal layers of patients were almost all lower than those of controls. In patients, optical intensities were increased in the mRNFL but decreased in the GCIPL along with an increase of retinal thicknesses. The OIAC measurements were significantly higher in the upper quadrants and global average of the mRNFL in patients. The areas under the ROC curves (AUC) obtained by global average mRNFL thickness was significantly greater than that of the global average OIAC in the mRNFL (p = 0.0265). CONCLUSIONS: Thicknesses of the mRNFL and nasal GCC were significantly decreased in the retinas of patients with pituitary adenoma compared with controls. The differences of the optical intensity ratio and OIAC between patients and controls were not all statistically significant. Thickness was more sensitive than optical characteristics indices in distinguishing pituitary adenoma from controls. PMID- 28628663 TI - Survival and medical utilization of children and adolescents with prolonged ventilator-dependent and associated factors. AB - Over the course of a year, more than 20,000 patients in Taiwan require prolonged mechanical ventilation (PMV). Data from the National Health Insurance Research Database for patients between 2005 and 2011 were used to conduct a retrospective analysis on ventilator dependence. The study subjects were PMV patients aged <17 years in Taiwan. A multiple regression model employing general estimating equations was applied to investigate the factors affecting the use of medical resources by children and adolescent PMV patients. A Cox proportional hazard model was incorporated to explore the factors affecting the survival of these patients. Data were collected for a total of 1,019 children and adolescent PMV patients in Taiwan. The results revealed that the average number of outpatient visits per subject was 32.1 times per year, whereas emergency treatments averaged 1.56 times per year per subject and hospitalizations averaged 160.8 days per year per subject. Regarding average annual medical costs, hospitalizations accounted for the largest portion at NT$821,703 per year per subject, followed by outpatient care at NT$123,136 per year per subject and emergency care at NT$3,806 per year per subject. The demographic results indicated that the patients were predominately male (61.24%), with those under 1 year of age accounting for the highest percentage (36.38%). According to the Kaplan-Meier curve, the 1-year and 5-year mortality rates of the patients were approximately 32% and 47%, respectively. The following factors affecting the survival rate were considered: age, the Charlson Comorbidity Index (CCI), diagnosis type necessitating ventilator use, and whether an invasive ventilator was used. This study investigated the use of medical resources and the survival rates of children and adolescent PMV patients. The findings of this study can serve as a reference for the National Health Insurance Administration in promoting its future integrated pilot projects on ventilator dependency. PMID- 28628664 TI - Effects of diesel exhaust particle exposure on a murine model of asthma due to soybean. AB - BACKGROUND: Exposure to soybean allergens has been linked to asthma outbreaks. Exposure to diesel exhaust particles (DEP) has been associated with an increase in the risk of asthma and asthma exacerbation; however, in both cases the underlying mechanisms remain poorly understood, as does the possible interaction between the two entities. OBJECTIVE: To investigate how the combination of soybean allergens and DEP can affect the induction or exacerbation of asthma in a murine model. METHODS: BALB/c mice received intranasal instillations of saline, 3 or 5 mg protein/ml soybean hull extract (SHE), or a combination of one of these three solutions with DEP. Airway hyperresponsiveness (AHR), pulmonary inflammation in bronchoalveolar lavage, total serum immunoglobulin E and histological studies were assessed. RESULTS: A 5 mg protein/ml SHE solution was able by itself to enhance AHR (p = 0.0033), increase eosinophilic inflammation (p = 0.0003), increase levels of IL-4, IL-5, IL-13, IL-17A, IL-17F and CCL20, and reduce levels of IFN-gamma. The combination of 5 mg protein/ml SHE with DEP also produced an increase in AHR and eosinophilic inflammation, but presented a slightly different cytokine profile with higher levels of Th17-related cytokines. However, while the 3 mg protein/ml SHE solution did not induce asthma, co exposure with DEP resulted in a markedly enhanced AHR (p = 0.002) and eosinophilic inflammation (p = 0.004), with increased levels of IL-5, IL-17F and CCL20 and decreased levels of IFN-gamma. CONCLUSIONS & CLINICAL RELEVANCE: The combination of soybean allergens and DEP is capable of triggering an asthmatic response through a Th17-related mechanism when the soybean allergen concentration is too low to promote a response by itself. DEP monitoring may be a useful addition to allergen monitoring in order to prevent new asthma outbreaks. PMID- 28628665 TI - A chromosome 5q31.1 locus associates with tuberculin skin test reactivity in HIV positive individuals from tuberculosis hyper-endemic regions in east Africa. AB - One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an "experiment of nature" design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease. PMID- 28628666 TI - The effector AvrRxo1 phosphorylates NAD in planta. AB - Gram-negative bacterial pathogens of plants and animals employ type III secreted effectors to suppress innate immunity. Most characterized effectors work through modification of host proteins or transcriptional regulators, although a few are known to modify small molecule targets. The Xanthomonas type III secreted avirulence factor AvrRxo1 is a structural homolog of the zeta toxin family of sugar-nucleotide kinases that suppresses bacterial growth. AvrRxo1 was recently reported to phosphorylate the central metabolite and signaling molecule NAD in vitro, suggesting that the effector might enhance bacterial virulence on plants through manipulation of primary metabolic pathways. In this study, we determine that AvrRxo1 phosphorylates NAD in planta, and that its kinase catalytic sites are necessary for its toxic and resistance-triggering phenotypes. A global metabolomics approach was used to independently identify 3'-NADP as the sole detectable product of AvrRxo1 expression in yeast and bacteria, and NAD kinase activity was confirmed in vitro. 3'-NADP accumulated upon transient expression of AvrRxo1 in Nicotiana benthamiana and in rice leaves infected with avrRxo1 expressing strains of X. oryzae. Mutation of the catalytic aspartic acid residue D193 abolished AvrRxo1 kinase activity and several phenotypes of AvrRxo1, including toxicity in yeast, bacteria, and plants, suppression of the flg22 triggered ROS burst, and ability to trigger an R gene-mediated hypersensitive response. A mutation in the Walker A ATP-binding motif abolished the toxicity of AvrRxo1, but did not abolish the 3'-NADP production, virulence enhancement, ROS suppression, or HR-triggering phenotypes of AvrRxo1. These results demonstrate that a type III effector targets the central metabolite and redox carrier NAD in planta, and that this catalytic activity is required for toxicity and suppression of the ROS burst. PMID- 28628667 TI - Characterization of HIV-1 CRF90_BF1 and putative novel CRFs_BF1 in Central West, North and Northeast Brazilian regions. AB - The Brazilian AIDS epidemic has been characterized by an increasing rate of BF1 recombinants and so far eight circulating recombinant forms/CRFs_BF1 have been described countrywide. In this study, pol sequences (protease/PR, reverse transcriptase/RT) of 87 BF1 mosaic isolates identified among 828 patients living in six Brazilian States from three geographic regions (Central West, North, Northeast) were analyzed. Phylogenetic and bootscan analyses were performed to investigate the evolutionary relationship and mosaic structure of BF1 isolates. Those analyses showed that 20.7% of mosaics (18 out of 87) were CRFs-like isolates, mostly represented by CRF28/CRF29_BF-like viruses (14 out of 18). We also identified five highly supported clusters that together comprise 42 out of 87 (48.3%) BF1 sequences, each cluster containing at least five sequences sharing a similar mosaic structure, suggesting possible new unidentified CRFs_BF1. The divergence time of these five potential new CRFs_BF1 clusters was estimated using a Bayesian approach and indicate that they probably originated between the middle 1980s and the middle 1990s. DNA was extracted from whole blood and four overlapping fragments were amplified by PCR providing full/near full length genomes (FLG/NFLG) and partial genomes. Eleven HIV-1 isolates from Cluster # 5 identified in epidemiologically unlinked individuals living in Central West and North regions provided FLG/NFLG/partial genome sequences with identical mosaic structure. These viruses differ from any known CRF_BF1 reported to date and were named CRF90_BF1 by the Los Alamos National Laboratory. This is the 9th CRF_BF1 described in Brazil and the first one identified in Central West and North regions. Our results highlight the importance of continued molecular screening and surveillance studies, especially of full genome sequences to understand the evolutionary dynamics of the HIV-1 epidemic in a country of continental dimensions as Brazil. PMID- 28628668 TI - Dose-dependent effects of gamma radiation on the early zebrafish development and gene expression. AB - Ionizing radiation from natural sources or anthropogenic activity has the potential to cause oxidative stress or genetic damage in living organisms, through the ionization and excitation of molecules and the subsequent production of free radicals and reactive oxygen species (ROS). The present work focuses on radiation-induced biological effects using the zebrafish (Danio rerio) vertebrate model. Changes in developmental traits and gene expression in zebrafish were assessed after continuous external gamma irradiation (0.4, 3.9, 15 and 38 mGy/h) with corresponding controls, starting at 2.5 hours post fertilization (hpf) and lasting through embryogenesis and the early larval stage. The lowest dose rate corresponded to recommended benchmarks at which adverse effects are not expected to occur in aquatic ecosystems (2-10 mGy/day). The survival observed at 96 hours post fertilization (hpf) in the 38 mGy/h group was significantly lower, while other groups showed no significant difference compared to controls. The total hatching was significantly lower from controls in the 15 mGy/h group and a delay in hatching onset in the 0.4 mGy/h group was observed. The deformity frequency was significantly increased by prolonged exposure duration at dose rates >= 0.4 mGy/h. Molecular responses analyzed by RNA-seq at gastrulation (5.5 hpf transcriptome) indicate that the radiation induced adverse effects occurred during the earliest stages of development. A dose-response relationship was found in the numbers of differentially regulated genes in exposure groups compared to controls at a total dose as low as 1.62 mGy. Ingenuity Pathway Analysis identified retinoic acid receptor activation, apoptosis, and glutathione mediated detoxification signaling as the most affected pathways in the lower dose rate (0.54 mGy/h), while eif2 and mTOR, i.e., involved in the modulation of angiogenesis, were most affected in higher dose rates (5.4 and 10.9 mGy/h). By comparing gene expression data, myc was found to be the most significant upstream regulator, followed by tp53, TNF, hnf4a, TGFb1 and cebpa, while crabp2b and vegfab were identified as most frequent downstream target genes. These genes are associated with various developmental processes. The present findings show that continuous gamma irradiation (>= 0.54 mGy/h) during early gastrula causes gene expression changes that are linked to developmental defects in zebrafish embryos. PMID- 28628669 TI - The Global Fund in China: Multidrug-resistant tuberculosis nationwide programmatic scale-up and challenges to transition to full country ownership. AB - China has the world's second largest burden of multidrug-resistant tuberculosis (MDR-TB; resistance to at least isoniazid and rifampicin), with an estimated 57,000 cases (range, 48,000-67,000) among notified pulmonary TB patients in 2015. During October 1, 2006-June 30, 2014, China expanded MDR-TB care through a partnership with the Global Fund to Fight AIDS, Tuberculosis, and Malaria (Global Fund). We analyzed data on site expansion, patient enrolment, treatment outcomes, cost per patient, and overall programme expenditure. China expanded MDR-TB diagnostic and treatment services from 2 prefectures in 2006 to 92 prefectures, covering 921 of the country's 3,000 counties by June 2014. A total of 130,910 patients were tested for MDR-TB, resulting in 13,744 laboratory-confirmed cases, and 9,183 patients started on MDR-TB treatment. Treatment success was 48.4% (2011 cohort). The partnership between China and the Global Fund resulted in enormous gains. However, changes to health system TB delivery and financing coincided with the completion of the Global Fund Programme, and could potentially impact TB and MDR-TB control. Transition to full country financial ownership is proving difficult, with a decline in enrollment and insufficient financial coverage. Given needed improvement to the current treatment success rates, these factors jeopardise investments made for MDR-TB control and care. China now has a chance to cement its status in TB control by strengthening future financing and ensuring ongoing commitment to quality service delivery. PMID- 28628670 TI - Combining ability, heritability and genotypic relations of different physiological traits in cacao hybrids. AB - Selecting parents and evaluating progenies is a very important step in breeding programs and involves approaches such as understanding the initial stages of growth and characterizing the variability among genotypes for different parameters, such as physiological, growth, biomass partitioning and nutrient translocation to the aerial part. In these cases, facilitating tools can be used to understand the involved gene dynamics, such as diallel crosses and genetic and phenotypic correlations. Our main hypothesis is that the contrasting phenotypes of these parental genotypes of cocoa used are due to genetic factors, and progenies derived from crosses of these parental genotypes are useful for breeding programs related to plant architecture, physiological parameters and translocation of mineral nutrients. We aimed to evaluate the combining abilities in progenies of cacao (Theobroma cacao L) originating from contrasting parents for canopy vigor. Emphasis was given to the evaluation of morphological and physiological parameters and the phenotypic and genotypic correlations to understand the dynamics of the action of the genes involved, as well as in expression profile from genes of gibberellins biosynthesis pathway in the parents. Fifteen F1 progenies were obtained from crosses of six clones (IMC 67, P4B, PUCALA, SCA 6, SCA 24 and SJ 02) that were evaluated in a randomized complete block design with four replicates of 12 plants per progeny, in a balanced half table diallel scheme. It is possible to identify and select plants and progenies of low, medium and high height, as there is expressive genetic variability for the evaluated parameters, some of these on higher additive effects, others on larger nonadditive effects and others under a balance of these effects. Most physiological parameters evaluated show that for selection of plants with the desired performance, no complex breeding methods would be necessary due to the high and medium heritability observed. Strong genetic components were observed from many of the correlations, which indicate the possibility to formulate selection indices for multi-traits, such as dwarfism or semidwarfism, tolerance to increase of leaf sodium concentrations and maintenance of the photosynthetic apparatus integrity under these conditions. Additionally, plants with higher carbon fixation, better water use, higher carboxylation efficiency and greater magnesium accumulation in leaves can be selected. PMID- 28628671 TI - Correction: A novel intraperitoneal metastatic xenograft mouse model for survival outcome assessment of esophageal adenocarcinoma. AB - [This corrects the article DOI: 10.1371/journal.pone.0171824.]. PMID- 28628672 TI - Low-dose exposure to bisphenols A, F and S of human primary adipocyte impacts coding and non-coding RNA profiles. AB - Bisphenol A (BPA) exposure has been suspected to be associated with deleterious effects on health including obesity and metabolically-linked diseases. Although bisphenols F (BPF) and S (BPS) are BPA structural analogs commonly used in many marketed products as a replacement for BPA, only sparse toxicological data are available yet. Our objective was to comprehensively characterize bisphenols gene targets in a human primary adipocyte model, in order to determine whether they may induce cellular dysfunction, using chronic exposure at two concentrations: a "low-dose" similar to the dose usually encountered in human biological fluids and a higher dose. Therefore, BPA, BPF and BPS have been added at 10 nM or 10 MUM during the differentiation of human primary adipocytes from subcutaneous fat of three non-diabetic Caucasian female patients. Gene expression (mRNA/lncRNA) arrays and microRNA arrays, have been used to assess coding and non-coding RNA changes. We detected significantly deregulated mRNA/lncRNA and miRNA at low and high doses. Enrichment in "cancer" and "organismal injury and abnormalities" related pathways was found in response to the three products. Some long intergenic non-coding RNAs and small nucleolar RNAs were differentially expressed suggesting that bisphenols may also activate multiple cellular processes and epigenetic modifications. The analysis of upstream regulators of deregulated genes highlighted hormones or hormone-like chemicals suggesting that BPS and BPF can be suspected to interfere, just like BPA, with hormonal regulation and have to be considered as endocrine disruptors. All these results suggest that as BPA, its substitutes BPS and BPF should be used with the same restrictions. PMID- 28628673 TI - Multiple tolerance defects contribute to the breach of B cell tolerance in New Zealand Black chromosome 1 congenic mice. AB - Lupus is characterized by a loss of B cell tolerance leading to autoantibody production. In this study, we explored the mechanisms underlying this loss of tolerance using B6 congenic mice with an interval from New Zealand Black chromosome 1 (denoted c1(96-100)) sufficient for anti-nuclear antibody production. Transgenes for soluble hen egg white lysozyme (sHEL) and anti-HEL immunoglobulin were crossed onto this background and various tolerance mechanisms examined. We found that c1(96-100) mice produced increased levels of IgM and IgG anti-HEL antibodies compared to B6 mice and had higher proportions of germinal center B cells and long-lived plasma cells, suggesting a germinal center dependent breach of B cell anergy. Consistent with impaired anergy induction, c1(96-100) double transgenic B cells showed enhanced survival and CD86 upregulation. Hematopoietic chimeric sHEL mice with a mixture of B6 and c1(96 100) HEL transgenic B cells recapitulated these results, suggesting the presence of a B cell autonomous defect. Surprisingly, however, there was equivalent recruitment of B6 and c1(96-100) B cells into germinal centers and differentiation to splenic plasmablasts in these mice. In contrast, there were increased proportions of c1(96-100) T follicular helper cells and long-lived plasma cells as compared to their B6 counterparts, suggesting that both B and T cell defects are required to breach germinal center tolerance in this model. This possibility was further supported by experiments showing an enhanced breach of anergy in double transgenic mice with a longer chromosome 1 interval with additional T cell defects. PMID- 28628675 TI - Interleukin-10/lymphocyte ratio predicts mortality in severe septic patients. AB - BACKGROUND: Immunosuppression is common even in the early stage of severe sepsis. Interleukin-10 (IL-10) secretion and lymphocyte exhaustion are the main features of sepsis-induced immunosuppression. However, the relationship between IL-10 and the lymphocyte is still unclear. We investigated if IL-10/lymphocyte ratio (IL10LCR) were associated with mortality in severe septic patients. METHODS: Adult patients with severe sepsis admitted to ICU of the First Affiliated Hospital of Guangzhou Medical University were identified from October 2012 to August 2013. Within 24 hours of ICU admission, peripheral whole blood was collected for the measurement of IL-10 using commercial multiplex bead-based assay kits and determination of lymphocyte count from laboratory data. The primary outcome was 28-day mortality. RESULTS: A total of 63 severe sepsis patients were identified. There were 20 (32%) patients died within 28 days. IL10LCR in non-survival patients was significantly higher than survival patients (median (IQR) 36.78 (12.34-79.63) ng/ml2 versus 11.01(5.41-27.50) ng/ml2, P = 0.002). Correlation analysis showed that IL10LCR was significantly correlated with APACHE II score (Spearman's rho = 0.424, P<0.001). The receiver operating characteristic (ROC) curves showed the area under the curve was 0.749 for IL10LCR level to predict 28-day mortality with sensitivity and specificity at 70.0% and 74.4%, respectively. At an optimal cutoff of 23.39ng/ml2, Kaplan-Meier curve showed survival in patients with IL10LCR level above 23.39ng/ml2 was significantly lower than in patients with IL10LCR level less than 23.39ng/ml2 (P = 0.001 by log-rank test). CONCLUSION: IL10LCR level is significantly associated with the severity and outcome of severe septic patients. It may serve as a biomarker for sepsis-induced immunosuppression. PMID- 28628674 TI - Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease. AB - BACKGROUND: This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD). METHODS: In Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs. RESULTS: Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver. CONCLUSION: The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD. PMID- 28628677 TI - Impact of a 31-gene Expression Profiling Test for Cutaneous Melanoma on Dermatologists' Clinical Management Decisions. AB -

Importance: Current guidelines for cutaneous malignant melanoma (CMM) provide general recommendations regarding surveillance while indicating that management should be tailored to patients' individual probability of recurrence. A 31-gene expression profile (31-GEP) test to predict metastatic risk has been previously validated, and classifies patients as either Class 1 (low risk) or Class 2 (high risk).

Objective: To determine the impact of the 31-GEP test's result on clinical decision-making.

Design, Setting, and Participants: Dermatology residents who attended a national educational conference were presented with clinical validity evidence for the 31-GEP. Respondents were given six CMM patient vignettes with descriptions of clinical features and answered questions about their willingness to recommend sentinel lymph node biopsy (SLNBx) or imaging based on each scenario. Additionally, respondents were asked to provide the Breslow thickness (BT), ranging from 0.7-1.5mm in 0.1mm increments, at which they would recommend SLNBx, imaging, or oncology referral.

Main Outcomes and Measures: The number of respondents who would recommend each management modality based upon three outcomes (no result, Class 1, or Class 2) was quantified. Differences between response groups were assessed using Fisher's exact test.

Results: The majority of respondents (62%, 57%, and 55%, respectively) indicated a 1.0mm BT as the guiding modality, reflecting adherence to current guidelines. After inclusion of a Class 2 result, the BT used to guide SLNBx, oncology referral, and imaging was changed in 47%, 50% and 47% of the responses, respectively, with 95%, 84% and 97% of the cases, respectively, changed in a risk appropriate direction (decreased BT). Based on a 31-GEP Class 1 or Class 2 result, risk appropriate recommendations were more likely to be made for each management modality tested in five of the six patient vignettes (P less than 0.05).

Conclusions and Relevance: The 31-GEP test had a significant and appropriate impact on management while remaining within the context of established guidelines.

J Drugs Dermatol. 2017;16(5):428 431.

. PMID- 28628676 TI - A human-scale perspective on global warming: Zero emission year and personal quotas. AB - This article builds on the premise that human consumption of goods, food and transport are the ultimate drivers of climate change. However, the nature of the climate change problem (well described as a tragedy of the commons) makes it difficult for individuals to recognise their personal duty to implement behavioural changes to reduce greenhouse gas emissions. Consequently, this article aims to analyse the climate change issue from a human-scale perspective, in which each of us has a clearly defined personal quota of CO2 emissions that limits our activity and there is a finite time during which CO2 emissions must be eliminated to achieve the "well below 2 degrees C" warming limit set by the Paris Agreement of 2015 (COP21). Thus, this work's primary contribution is to connect an equal per capita fairness approach to a global carbon budget, linking personal levels with planetary levels. Here, we show that a personal quota of 5.0 tons of CO2 yr-1 p-1 is a representative value for both past and future emissions; for this level of a constant per-capita emissions and without considering any mitigation, the global accumulated emissions compatible with the "well below 2 degrees C" and 2 degrees C targets will be exhausted by 2030 and 2050, respectively. These are references years that provide an order of magnitude of the time that is left to reverse the global warming trend. More realistic scenarios that consider a smooth transition toward a zero-emission world show that the global accumulated emissions compatible with the "well below 2 degrees C" and 2 degrees C targets will be exhausted by 2040 and 2080, respectively. Implications of this paper include a return to personal responsibility following equity principles among individuals, and a definition of boundaries to the personal emissions of CO2. PMID- 28628678 TI - Assessment of Efficacy and Irritation of Ingenol Mebutate Gel 0.015% Used With or Without Dimethicone Lotion for Treatment of Actinic Keratosis on the Face. AB -

Background: Ingenol mebutate gel 0.015% provides high clearance rates for actinic keratosis (AK) on the face and scalp but causes transient local skin responses (LSRs).

Objective: This study sought to determine whether the application of 1% dimethicone would decrease ingenol mebutate-associated LSRs and/or affect efficacy during the treatment of multiple AKs on the face.

Methods: Ingenol mebutate gel 0.015% was applied for 3 days to two 25 cm2 areas, each containing 3 to 8 AKs on the face of each subject, followed by application of 1% dimethicone lotion in an investigator-blinded manner to one randomly selected AK-containing area until LSRs were no longer present.

Results: In total, 20 subjects were enrolled and completed the study. Topical 1% dimethicone lotion applied during and after treatment of facial AK with ingenol mebutate gel 0.015% reduced mean total LSR scores at days 8 and 15 compared with ingenol mebutate gel only, although the difference was not statistically significant. Efficacy was equivalent between the two treatment arms.

Limitations: The study evaluated a relatively small number of subjects, all of whom were white.

Conclusions: The application of 1% dimethicone following ingenol mebutate gel 0.015% produced a trend toward lower severity of some LSRs, with no difference in efficacy.

J Drugs Dermatol. 2017;16(5):432-436.

. PMID- 28628679 TI - Safety and Efficacy of Escalating Doses of Ingenol Mebutate for Field Treatment of Actinic Keratosis on the Full Face, Full Balding Scalp, or Chest. AB -

Background: Actinic keratosis (AK) can affect large skin areas. Ingenol mebutate (IngMeb) gel (0.015% and 0.05%) is approved for topical treatment of AK in a single contiguous area of ~25 cm2.

Objective: The study sought to determine the maximum tolerated dose (MTD), efficacy, and tolerability of IngMeb applied to AK on a contiguous area less than equal to 250 cm2.

Methods: Part 1 determined the MTD of IngMeb at 7 concentrations for 2 or 3 days. Part 2 assessed efficacy and tolerability at the MTD and one dose lower for 2 or 3 days vs vehicle.

Results: Four dosing regimens with an acceptable benefit-to risk ratio were identified: 0.018% and 0.027% once daily for 2 or 3 days. Complete clearance at 8 weeks was achieved by 21.3% to 39.1% of IngMeb-treated patients vs 0% to 3.2% treated with vehicle. Composite local skin response scores peaked on the day after the last application, rapidly declined, and were near baseline at 2 weeks. Adverse events were predominantly mild or moderate.

Limitations: The study evaluated a limited number of doses in a population of only white patients.

Conclusion: IngMeb gel was effective and well tolerated as field treatment of AK on the full face, full scalp, and up to 250 cm2 on the chest.

J Drugs Dermatol. 2017;16(5):438-444.

. PMID- 28628680 TI - Current Perspectives Among U.S. Dermatologists on Chemoprevention of Nonmelanoma Skin Cancer: A Survey-Based Study. AB -

Introduction: Nonmelanoma skin cancer (NMSC) is the most common malignancy in the US Primary prevention of NMSC with physical photoprotective measures are often not sufficient to impact skin cancer incidence in high-risk individuals. Chemoprevention is the use of agents to prevent, suppress, and reverse carcinogenic progression. Many agents have been investigated, but preclinical and clinical studies are often inconsistent.

Methods: A cross-sectional study was designed to assess current practices, perceptions, and general knowledge of U.S. dermatologists pertaining to chemopreventive strategies. This voluntary online survey was distributed to practicing dermatologists via dermatology society electronic mailing lists. Software from SurveyGizmo.com was used for survey implementation and anonymous data collection. Stata 12.0 statistical analysis software (StataCorp, LP) was used to perform nonparametric Spearman correlation tests.

Results: Approximately half of the 156 responding dermatologists reported being in practice 16 years or more (47.3%) and working in urban communities (48.7%). 59.3% reported "frequently" using topical therapies, while only 13.7% reported frequent use of systemic chemopreventive therapies. Dermatologists practicing in urban settings were more likely to indicate they believe knowledge has increased substantially (P=0.047) as compared to colleagues in other communities. Respondents also reported varying degrees of confidence in selecting appropriate chemopreventive regimens: most feel comfortable determining which agents to use in patients, but 29.1% answered "neutral" or "disagree" when asked if they felt comfortable. More experienced dermatologists were more likely to recommend diet modifications such as increased dietary vitamin D (P=0.014), low fat diet (P=0.022), and tea polyphenols (P=0.04) as methods of chemoprevention.

Discussion: Efforts to identify effective, minimally toxic chemopreventive agents have long been underway, but conflicting reports in the literature make formulation of validated guidelines challenging. Our study suggests differing perceptions, comfort levels, and practice strategies among U.S. dermatologists. This serves to identify areas of research requiring additional contributions from clinical investigators and reveals a need to broaden understanding of available evidence-based techniques.

J Drugs Dermatol. 2017;16(5):449-452.

. PMID- 28628681 TI - Changes in Self-Perceptions of Photoaging Severity and Skin Cancer Risk After Objective Facial Skin Quality Analysis. AB -

Background: Despite public education efforts, many people at risk for skin cancer do not practice safe sun behaviors.

Objective: To determine whether machine-based evaluation of UV-induced alterations (VISIA scan) changes self assessment of facial photoaging, skin cancer risk, and willingness to improve sun protective habits. In addition, to determine whether VISIA scan analysis reveals differences between those with versus without a history of skin cancer, men versus women, those older than 50 versus less than 50 years of age, and Fitzpatrick skin types I-III versus IV-VI.

Methods: Volunteers attending a health expo were recruited and queried about their perceived risk of skin cancer and degree of skin photoaging. All participants underwent facial skin quality analysis of both sides of the face, and then completed a follow-up survey.

Results: Participants' scored self-perceptions of overall skin aging were all statistically significantly worse after VISIA scan analysis. There was no change in perceived skin cancer risk, but most participants expressed intent to improve their sun protection habits.

Limitations: Limitations to this study include selection bias, recall-misclassification bias, and social desirability bias.

Conclusion: Intervention with facial skin analysis can positively affect subjects' stated intent to use sun protection, indicating the importance of appearance in these health decisions.

J Drugs Dermatol. 2017;16(5):453-459.

. PMID- 28628682 TI - Radiation Therapy in Dermatology: Non-Melanoma Skin Cancer. AB -

Background: Dermatologists were historically well versed in the use of radiation therapy for the management of non-melanoma skin cancers and various inflammatory dermatologic conditions. With the advent of Mohs micrographic surgery and therapeutic discoveries for treating inflammatory dermatoses, radiotherapy assumed loss of a role in the clinical repertoire of the dermatologist. In recent years, its importance has again been realized for the management of non-melanoma skin cancers not amenable to surgical treatment or as adjuvant or palliative therapy.

Objective: To review the evolving use of radiation therapy in the treatment of non-melanoma skin cancer.

Methods and Materials: All published literature regarding the applications of radiotherapy for the treatment of non-melanoma skin cancer were analyzed and collated.

Results: A comprehensive review of radiotherapy for the treatment of non-melanoma skin cancer was outlined.

Conclusion: Dermatologists should be well versed in radiation therapy in order to deliver the best possible care for patients, as radiotherapy is an important adjuvant tool for the treatment of non-melanoma skin cancer.

J Drugs Dermatol. 2017;16(5):464-469.

. PMID- 28628683 TI - Understanding the Shape of Forehead Lines. AB - :

Background: Individualized neuromodulator injections of the forehead are increasingly important to maximize patient safety and satisfaction and to yield the best aesthetic outcome. To assess the location of maximal muscle contraction, it would beneficial to relate the shape and location of the forehead lines to the morphology of the underlying frontalis muscle.

Materials and Methods: We investigated the shape of forehead lines and their relationship to the morphology of the underlying frontalis muscle using anatomic dissection in a sample of 31 human body donors, with a mean age at death of 77.2 +/- 13.2 years (range, 47-93) of which n=29 (93.5%) were of Caucasian and n=2 (6.5%) of African-American ethnicity and of which n=16 (51.6%) were females (n=15 males; 48.4%).

Results: Horizontal forehead lines were classified into straight n=13 (41.9%) and wavy n=18 (58.1%) lines. The presence of wavy forehead lines (as compared to straight lines) was significantly related to the presence of a midline aponeurosis (r = 0.69; P less than 0.001) and to a greater muscle fascicle angle (12.67 +/- 2.60 degrees vs 10.18 +/- 2.12 degrees ) (r = 0.47; P less than 0.001), but was not statistical significantly influenced by age, gender, or ethnicity (all P greater than 0.05).

Conclusion: According to the shape of the forehead lines, physicians can appreciate the morphology of the underlying frontalis muscle. This understanding will facilitate more accurate neuromodulator injections and a better aesthetic outcome. It may also result in decreased dosages and increased injection intervals for maximal patient safety. LEVEL OF EVIDENCE: IV

J Drugs Dermatol. 2017;16(5):471-477.

. PMID- 28628684 TI - Megasessions: Efficacy of Fewer, Longer Treatment Sessions for Fat Reduction in Noninvasive Body Contouring Using a Radiofrequency Based Device. AB -

While the field of noninvasive body contouring is booming, many patients still note a lesser result than they might achieve with a single session of liposuction or dermolipectomy. The duration of a noninvasive fat reduction treatment series can be daunting. Patients have questioned the worth of these procedures when the expected benefit is modest and the time they devote to the project is significant. An eight-patient mini-study was performed to see if two or three "megasessions" could be substituted for eight weekly sessions of bipolar radiofrequency based fat reduction treatments. Patients were randomized into a two session or three session group by drawing straws. The device used was the BodyFX bipolar RF device by InMode. This device employs a suction coupled vacuum that heats a section of skin and soft tissue in the treatment region and delivers a high voltage pulse. Each patient was treated for 2 hours per session, using the Body FX, more superficial Mini FX, and the Deep FX device in an effort to treat on a multilevel basis. Preoperative 2D and 3D Vectra photos were taken, and were repeated at 1 month and 3 months post-treatment. Volumetric analysis and patient assessment showed similar results with a two or three treatment "megasession" protocol when compared with the traditional protocol of eight weekly sessions. While the cohort number was not statistically significant, the photographs and measurements are compelling enough to warrant further investigation into this treatment protocol.

J Drugs Dermatol. 2017;16(5):478-480.

. PMID- 28628685 TI - A Systematic Review of Light Emitting Diode (LED) Phototherapy for Treatment of Psoriasis: An Emerging Therapeutic Modality. AB -

Background: Psoriasis is a chronic, inflammatory skin condition. The economic burden of psoriasis is approximately $35.2 billion in the United States per year, and treatment costs are increasing at a higher rate than general inflation. Light emitting diode (LED) phototherapy may represent a cost-effective, efficacious, safe, and portable treatment modality for psoriasis.

Objective: The goal of our manuscript is to review the published literature and provide evidence based recommendations on LED phototherapy for the treatment of psoriasis.

Methods & Materials: A search of the databases Pubmed, EMBASE, Web of Science, and CINAHL was performed on April 5, 2016. Key search terms were related to psoriasis and LED-based therapies.

Results: A total of 7,793 articles were generated from the initial search and 5 original articles met inclusion criteria for our review. Grade of recommendation: B for LED-blue light. Grade of recommendation: C for LED-ultraviolet B, LED-red light, and combination LED-near infrared and LED-red light.

Conclusion: We envision further characterizing the effects of LED phototherapy to treat psoriasis in patients may increase adoption of LED-based modalities and provide clinicians and patients with new therapeutic options that balance safety, efficacy, and cost.

J Drugs Dermatol. 2017;16(5):482-488.

. PMID- 28628686 TI - Off Face Usage of Poly-L-Lactic Acid for Body Rejuvenation. AB -

Injectable soft-tissue augmentation agents have become popular alternatives to surgical procedures for the aging face and body. In contrast to temporary, space occupying replacement fillers such as collagen-based and hyaluronic acid products, poly-l-lactic acid (PLLA) has been demonstrated to gradually promotes deposition of collagen via a biostimulatory response, with therapeutic effects lasting approximately two years. In 2004, the FDA approved its use for rejuvenation of facial contours secondary to lipoatrophy associated with antiretroviral therapy for HIV infection. By 2009 PLLA was FDA-approved for the correction of nasolabial fold contour deficiencies and other lines and wrinkles. There have since been limited but promising results with off-label use of PLLA for nonfacial volumization as well, including the hands, neck/decollete, abdomen, and gluteal area. The objective of this article is to review clinical evidence, current trends, and technical considerations for the use of PLLA for nonfacial, body rejuvenation.

J Drugs Dermatol. 2017;16(5):489-494.

. PMID- 28628687 TI - The Infatuation With Biotin Supplementation: Is There Truth Behind Its Rising Popularity? A Comparative Analysis of Clinical Efficacy versus Social Popularity. AB -

Biotin, also known as Vitamin B7 or vitamin H, is a water-soluble B vitamin that acts as an essential cofactor for several carboxylases involved in the cellular metabolism of fatty acids, amino acids, and gluconeogenesis. Although there exists an incredible amount of social media hype and market advertising touting its efficacy for the improvement of hair quantity and quality, biotin's efficacy for hair remains largely unsubstantiated in scientific literature. We reviewed all pertinent scientific literature regarding the efficacy of biotin supplementation for hair growth and quality improvement, and we also investigated its popularity in society defined as a function of market analytics. To date, there have been no clinical trials conducted to investigate the efficacy of biotin supplementation for the treatment of alopecia of any kind, nor has there been any randomized controlled trial to study its effect on hair quality and quantity in human subjects. Because of the lack of clinical evidence, its use to improve hair quantity or quality is not routinely recommended. However, societal infatuation with biotin supplementation is not only propagated by its glamorization in popular media, its popularity is vastly disproportionate to the insufficient clinical evidence supporting it's efficacy in hair improvement. In other words, biotin supplements are quite "in vogue", without there being any real reason to be so.

J Drugs Dermatol. 2017;16(5):496-500.

. PMID- 28628688 TI - Effectiveness of a Nutraceutical During Non-Ablative 1927 nm Fractional Laser on Patients With Facial Hyperpigmentation and Photoaging. AB -

Background: Fractional lasers have been proven to treat hyperpigmentation and photoaging. Little research has been done on the effects of supplements on healing post-laser resurfacing. A nutraceutical could offer the benefit of faster healing of the skin and fewer side effects.

Objective: Evaluate the effectiveness of a nutraceutical associated with fractional 1927 nm laser in healing time and effectiveness on hyperpigmentation and photoaging.

Methods & Materials: A prospective, randomized, evaluator-blinded, pilot study included Fitzpatrick skin types I-III patients with hyperpigmentation and photoaging randomly assigned to two groups. Group 1 was laser treatment and Group 2 was laser treatment and nutraceutical. Results were compared with objective biometric TEWL (transepidermal water loss), mexameter, corneometer, and cutometer parameters. A blinded physician-evaluator and the subjects completed questionnaires to evaluate skin improvements.

Results: Twenty women were included. Eight in Group 1 and 10 in Group 2 completed the study. Group 2 presented a faster recovery of the skin barrier function post procedure. Three months after the procedure, Group 2 presented with significantly improved skin glossiness, hydration, and melanin rebound levels. Group 2 presented more overall aesthetic improvement determined by the patient and the blinded physician evaluator.

Conclusion: The nutraceutical improved the results of the laser treatment.

J Drugs Dermatol. 2017;16(5):501-506.

. PMID- 28628689 TI - Aggressive Skin Cancers Occurring in Patients Treated With the Janus Kinase Inhibitor Ruxolitinib. AB -

The Food and Drug Administration approved Ruxolitinib in 2011 for the treatment of primary myelofibrosis. Five-year safety data showed a higher incidence of skin cancer in patients treated with Ruxolitinib compared to best available therapy for myelofibrosis. This report presents a series of five patients with history of myelofibrosis treated with Ruxolitinib who subsequently developed numerous skin cancers with aggressive biological behavior. Each patient in this report was treated by a Mohs surgeon affiliated with an academic institution. All patients had a history of myelofibrosis and were exposed to Ruxolitinib. Some patients were exposed to other immunomodulatory medications such as Hydroxyurea and Rituximab. The total number of skin cancers and skin cancers with particularly aggressive behavior were noted. All five patients in this series developed numerous skin cancers with aggressive biological behavior during or after therapy with Ruxolitinib. Also, one patient developed lentigo maligna melanoma and another developed metastatic undifferentiated pleomorphic sarcoma. The repeat observation of skin cancers with aggressive features during JAK inhibitor treatment suggests that these medications may promote cutaneous malignant transformation in at risk patients. Further surveillance and testing of JAK kinases regarding the risk of skin cancers is indicated.

J Drugs Dermatol. 2017;16(5):508-511.

. PMID- 28628690 TI - Case Report of Multiple Keratoacanthomas and Squamous Cell Carcinomas in a Patient Receiving Pembrolizumab. AB -

PD-1 is expressed on antigen-stimulated T cells and induces a downstream signaling pathway that works by negative feedback to inhibit T cell proliferation, cytokine release, and cytotoxicity. PD-1 antibodies increase tumor cell killing peripherally and have a role in advanced melanoma treatment. We describe a case of an 84 year old female with stage 4 metastatic melanoma in a trial of the PD-1 inhibitor pembrolizumab who developed multiple keratoacanthomas after several months of treatment. While keratoacanthomas have been reported in patients taking BRAF inhibitors, no such reports exist for those on pembrolizumab, making this the first case report to point out this association for further investigative studies.

J Drugs Dermatol. 2017;16(5):513 515.

. PMID- 28628691 TI - Eruptive Melanocytic Acral Nevi in the Setting of 6-mercaptopurine Therapy. AB -

Eruptive melanocytic nevi (EMN) are a rare clinical finding characterized by sudden-onset nevi that often present in a grouped distribution. They have been associated with chemotherapy, immunosuppression, bullous diseases, and medications including multikinase and BRAF inhibitors. It is important for dermatologists to be able to identify patients with sudden development of new melanocytic nevi secondary to particular medications. Herein, we describe a case of eruptive melanocytic acral nevi secondary to 6-mercaptopurine therapy.

J Drugs Dermatol. 2017;16(5):516-518.

. PMID- 28628692 TI - A Novel Technology: Sunscreen With Actinic Damage Repair. AB - . PMID- 28628693 TI - Understanding the Role of Photolyases: Photoprotection and Beyond. AB -

The limitations of photoprotection modalities have been the inability to arrest the progression of photodamage. Chemoprevention strategies involving a sunscreen has been incomplete because of the need to induce sustained repair of mutations and slow carcinogenesis. Photolyases, or photoreactivation enzymes, serve the role of repairing mutations and damage to DNA induced by ultraviolet (UV) radiation and therefore influence the initiation phases of carcinogenesis. As these enzymes are absent in humans, exogenous forms have been manufactured and are now utilized in topical agents to supplement and augment the innate repair mechanisms that are mostly inefficient.

J Drugs Dermatol. 2017;16(5 Suppl):61-66.

. PMID- 28628694 TI - Fecal Immunochemical Tests in Patients at Increased Risk for Colorectal Cancer-Is It Prime Time Yet? PMID- 28628695 TI - Efficiency and Interpretability of Text Paging Communication for Medical Inpatients: A Mixed-Methods Analysis. PMID- 28628696 TI - JAMA Pediatrics Annual Contest for Trainees. PMID- 28628697 TI - Pediatric Migraine Prevention-First, Do No Harm. PMID- 28628698 TI - Pagers and Beyond in an Era of Microcommunications-What Is Old Is New Again. PMID- 28628699 TI - Closing the Medication-Assisted Treatment Gap for Youth With Opioid Use Disorder. PMID- 28628700 TI - Emergent or Urgent Appendectomy?-A Changing Perspective. PMID- 28628701 TI - Trends in Receipt of Buprenorphine and Naltrexone for Opioid Use Disorder Among Adolescents and Young Adults, 2001-2014. AB - Importance: Opioid use disorder (OUD) frequently begins in adolescence and young adulthood. Intervening early with pharmacotherapy is recommended by major professional organizations. No prior national studies have examined the extent to which adolescents and young adults (collectively termed youth) with OUD receive pharmacotherapy. Objective: To identify time trends and disparities in receipt of buprenorphine and naltrexone among youth with OUD in the United States. Design, Setting, and Participants: A retrospective cohort study was conducted using deidentified data from a national commercial insurance database. Enrollment and complete health insurance claims of 9.7 million youth, aged 13 to 25 years were analyzed, identifying individuals who received a diagnosis of OUD between January 1, 2001, and June 30, 2014, with final follow-up date December 31, 2014. Analysis was conducted from April 25 to December 31, 2016. Time trends were identified and multivariable logistic regression was used to determine sociodemographic factors associated with medication receipt. Exposures: Sex, age, race/ethnicity, neighborhood education and poverty levels, geographic region, census region, and year of diagnosis. Main Outcomes and Measures: Dispensing of a medication (buprenorphine or naltrexone) within 6 months of first receiving an OUD diagnosis. Results: Among 20 822 youth diagnosed with OUD (0.2% of the 9.7 million sample), 13 698 (65.8%) were male and 17 119 (82.2%) were non-Hispanic white. Mean (SD) age was 21.0 (2.5) years at the first observed diagnosis. The diagnosis rate of OUD increased nearly 6-fold from 2001 to 2014 (from 0.26 per 100 000 person-years to 1.51 per 100 000 person-years). Overall, 5580 (26.8%) youth were dispensed a medication within 6 months of diagnosis, with 4976 (89.2%) of medication-treated youth receiving buprenorphine and 604 (10.8%) receiving naltrexone. Medication receipt increased more than 10-fold, from 3.0% in 2002 (when buprenorphine was introduced) to 31.8% in 2009, but declined in subsequent years (27.5% in 2014). In multivariable analyses, younger individuals were less likely to receive medications, with adjusted probability for age 13 to 15 years, 1.4% (95% CI, 0.4%-2.3%); 16 to 17 years, 9.7% (95% CI, 8.4%-11.1%); 18 to 20 years, 22.0% (95% CI, 21.0%-23.0%); and 21 to 25 years, 30.5% (95% CI, 30.0% 31.5%) (P < .001 for difference). Females (7124 [20.3%]) were less likely than males (13 698 [24.4%]) to receive medications (P < .001), as were non-Hispanic black (105 [14.8%]) and Hispanic (1165 [20.0%]) youth compared with non-Hispanic white (17 119 [23.1%]) youth (P < .001). Conclusions and Relevance: In this first national study of buprenorphine and naltrexone receipt among youth, dispensing increased over time. Nonetheless, only 1 in 4 commercially insured youth with OUD received pharmacotherapy, and disparities based on sex, age, and race/ethnicity were observed. PMID- 28628702 TI - Financial Incentives for Linkage to Care and Viral Suppression Among HIV-Positive Patients: A Randomized Clinical Trial (HPTN 065). AB - Importance: Achieving linkage to care and viral suppression in human immunodeficiency virus (HIV)-positive patients improves their well-being and prevents new infections. Current gaps in the HIV care continuum substantially limit such benefits. Objective: To evaluate the effectiveness of financial incentives on linkage to care and viral suppression in HIV-positive patients. Design, Setting, and Participants: A large community-based clinical trial that randomized 37 HIV test and 39 HIV care sites in the Bronx, New York, and Washington, DC, to financial incentives or standard of care. Interventions: Participants at financial incentive test sites who had positive test results for HIV received coupons redeemable for $125 cash-equivalent gift cards upon linkage to care. HIV-positive patients receiving antiretroviral therapy at financial incentive care sites received $70 gift cards quarterly, if virally suppressed. Main Outcomes and Measures: Linkage to care: proportion of HIV-positive persons at the test site who linked to care within 3 months, as indicated by CD4+ and/or viral load test results done at a care site. Viral suppression: proportion of established patients at HIV care sites with suppressed viral load (<400 copies/mL), assessed at each calendar quarter. Outcomes assessed through laboratory test results reported to the National HIV Surveillance System. Results: A total of 1061 coupons were dispensed for linkage to care at 18 financial incentive test sites and 39 359 gift cards were dispensed to 9641 HIV positive patients eligible for gift cards at 17 financial incentive care sites. Financial incentives did not increase linkage to care (adjusted odds ratio, 1.10; 95% CI, 0.73-1.67; P = .65). However, financial incentives significantly increased viral suppression. The overall proportion of patients with viral suppression was 3.8% higher (95% CI, 0.7%-6.8%; P = .01) at financial incentive sites compared with standard of care sites. Among patients not previously consistently virally suppressed, the proportion virally suppressed was 4.9% higher (95% CI, 1.4%-8.5%; P = .007) at financial incentive sites. In addition, continuity in care was 8.7% higher (95% CI, 4.2%-13.2%; P < .001) at financial incentive sites. Conclusions and Relevance: Financial incentives, as used in this study (HPTN 065), significantly increased viral suppression and regular clinic attendance among HIV-positive patients in care. No effect was noted on linkage to care. Financial incentives offer promise for improving adherence to treatment and viral suppression among HIV-positive patients. Trial Registration: clinicaltrials.gov Identifier: NCT01152918. PMID- 28628703 TI - Marketing Claims for Infant Formula Additives and Infant Formula. PMID- 28628704 TI - Can the Spot Sign Identify Who Benefits From Aggressive Blood Pressure Reduction in Intracerebral Hemorrhage? PMID- 28628705 TI - Time to Appendectomy and Risk of Complicated Appendicitis and Adverse Outcomes in Children. AB - Importance: Management of appendicitis as an urgent rather than emergency procedure has become an increasingly common practice in children. Controversy remains as to whether this practice is associated with increased risk of complicated appendicitis and adverse events. Objective: To examine the association between time to appendectomy (TTA) and risk of complicated appendicitis and postoperative complications. Design, Setting, and Participants: In this retrospective cohort study using the Pediatric National Surgical Quality Improvement Program appendectomy pilot database, 2429 children younger than 18 years who underwent appendectomy within 24 hours of presentation at 23 children's hospitals from January 1, 2013, through December 31, 2014, were studied. Exposures: The main exposure was TTA, defined as the time from emergency department presentation to appendectomy. Patients were further categorized into early and late TTA groups based on whether their TTA was shorter or longer than their hospital's median TTA. Exposures were defined in this manner to compare rates of complicated appendicitis within a time frame sensitive to each hospital's existing infrastructure and diagnostic practices. Main Outcomes and Measures: The primary outcome was complicated appendicitis documented at operation. The association between treatment delay and complicated appendicitis was examined across all hospitals by using TTA as a continuous variable and at the level of individual hospitals by using TTA as a categorical variable comparing outcomes between late and early TTA groups. Secondary outcomes included length of stay (LOS) and postoperative complications (incisional and organ space infections, percutaneous drainage procedures, unplanned reoperation, and hospital revisits). Results: Of the 6767 patients who met the inclusion criteria, 2429 were included in the analysis (median age, 10 years; interquartile range, 8-13 years; 1467 [60.4%] male). Median hospital TTA was 7.4 hours (range, 5.0-19.2 hours), and 574 patients (23.6%) were diagnosed with complicated appendicitis (range, 5.2%-51.1% across hospitals). In multivariable analyses, increasing TTA was not associated with risk of complicated appendicitis (odds ratio per 1-hour increase in TTA, 0.99; 95% CI, 0.97-1.02). The odds ratios of complicated appendicitis for late vs early TTA across hospitals ranged from 0.39 to 9.63, and only 1 of the 23 hospitals had a statistically significant increase in their late TTA group (odds ratio, 9.63; 95% CI, 1.08-86.17; P = .03). Increasing TTA was associated with longer LOS (increase in mean LOS for each additional hour of TTA, 0.06 days; 95% CI, 0.03-0.08 days; P < .001) but was not associated with increased risk of any of the other secondary outcomes. Conclusions and Relevance: Delay of appendectomy within 24 hours of presentation was not associated with increased risk of complicated appendicitis or adverse outcomes. These results support the premise that appendectomy can be safely performed as an urgent rather than emergency procedure. PMID- 28628706 TI - Diagnostic Accuracy of Fecal Immunochemical Test in Patients at Increased Risk for Colorectal Cancer: A Meta-analysis. AB - Importance: The potential role of the fecal immunochemical test (FIT) for screening patients at increased risk for colorectal cancer (CRC) has not yet been elucidated. Objective: To assess the diagnostic accuracy of FIT for CRC or advanced neoplasia (AN) in asymptomatic patients at above-average risk. Data Sources: MEDLINE, EMBASE, Cochrane Library, and gray literature sources through August 2016. Study Selection: Diagnostic studies evaluating the accuracy of FIT for CRC or AN in patients with a personal or familial history of CRC using colonoscopy as the reference standard. Data Extraction and Synthesis: Two authors (A.K. and P.P.) independently extracted data and evaluated study quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, and evaluated the quality of the body of evidence by means of GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Hierarchical models were used to synthesize available evidence. Main Outcomes and Measures: The primary outcome was the diagnostic performance of FIT for detecting CRC or AN. Results: We included 12 studies (6204 participants). Seven studies were deemed at high or unclear risk of bias. The average sensitivity of FIT for CRC was 93% (95% CI, 53% 99%), and the average specificity was 91% (95% CI, 89%-92%), yielding a positive likelihood ratio (LR+) of 10.30 (CI 7.7-13.9) and a negative likelihood ratio (LR ) of 0.08 (95% CI, 0.01-0.75) (GRADE: very low). The average sensitivity of FIT for AN was 48% (95% CI, 39%-57%); and the average specificity was 93% (95% CI, 91%-94%), yielding an LR+ of 6.55 (95% CI, 5.0-8.5) and an LR- of 0.57 (95% CI, 0.48-0.67) (GRADE: very low). Subgroup analyses indicated that FIT cutoff values between 15- and 25-MUg/g feces provided the best combination of sensitivity and specificity for the diagnosis of CRC (93% and 94%, respectively). Quantitative and 1-sample FIT showed adequate test performance, but data on other FIT brands and multiple samples were insufficient. Conclusions and Relevance: The FIT has high overall diagnostic accuracy for CRC but moderate accuracy for AN in patients at above-average personal or familial risk. Heterogeneity and wide confidence intervals limit the trustworthiness of our findings. PMID- 28628708 TI - Brain Calcifications in Adult-Onset Genetic Leukoencephalopathies: A Review. AB - Importance: Adult-onset genetic leukoencephalopathies and leukodystrophies are increasingly recognized as a heterogeneous group of disorders with new diagnostic approaches and potential treatments. In the new era of genomics, the challenging interpretation of individual genetic variations requires an accurate phenotypic description and classification. Clinical and magnetic resonance imaging (MRI) based approaches have been proposed to improve the diagnostic process of adult onset leukoencephalopathies. Cerebral calcifications, when associated with white matter hyperintensities, are of major importance in the decision-making process to focus the diagnosis among the diversity of rare causes. Observations: This literature review demonstrated that the morphologic features and topography of the calcifications observed in a careful combined analysis of computed tomographic and MRI scans may help indicate the diagnosis of adult-onset genetic leukoencephalopathies. Vascular genetic leukoencephalopathies are an important cause of leukoencephalopathy with calcifications. Among them, COL4A1-related disorders are frequently associated with spotlike calcifications in the basal ganglia. Adult-onset leukoencephalopathy with axonal spheroids, a probably underestimated disorder, is associated with a specific pattern of calcifications: small, symmetric, sparing the basal ganglia, and a stepping stone appearance in the frontal pericallosal region. Moreover, disorders primarily associated with basal ganglia calcifications, such as primary familial brain calcifications, can be associated with marked leukoencephalopathy. Conclusions and Relevance: The number of identified causes of adult-onset genetic leukoencephalopathies has recently increased. A diagnostic algorithm should take into account the pattern of calcifications to better target the genetic analyses. PMID- 28628707 TI - Intensive Blood Pressure Reduction and Spot Sign in Intracerebral Hemorrhage: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: The computed tomographic angiography (CTA) spot sign is associated with intracerebral hemorrhage (ICH) expansion and may mark those patients most likely to benefit from intensive blood pressure (BP) reduction. Objective: To investigate whether the spot sign is associated with ICH expansion across a wide range of centers and whether intensive BP reduction decreases hematoma expansion and improves outcome in patients with ICH and a spot sign. Design, Setting, and Participants: SCORE-IT (Spot Sign Score in Restricting ICH Growth) is a preplanned prospective observational study nested in the Antihypertensive Treatment of Acute Cerebral Hemorrhage II (ATACH-II) randomized clinical trial. Participants included consecutive patients with primary ICH who underwent a CTA within 8 hours from onset at 59 sites from May 15, 2011, through December 19, 2015. Data were analyzed for the present study from July 1 to August 31, 2016. Main Outcomes and Measures: Patients in ATACH-II were randomized to intensive (systolic BP target, <140 mm Hg) vs standard (systolic BP target, <180 mm Hg) BP reduction within 4.5 hours from onset. Expansion of ICH was defined as hematoma growth of greater than 33%, and an unfavorable outcome was defined as a 90-day modified Rankin Scale score of 4 or greater (range, 0-6). The association among BP reduction, ICH expansion, and outcome was investigated with multivariable logistic regression. Results: A total of 133 patients (83 men [62.4%] and 50 women [37.6%]; mean [SD] age, 61.9 [13.1] years) were included. Of these, 53 (39.8%) had a spot sign, and 24 of 123 without missing data (19.5%) experienced ICH expansion. The spot sign was associated with expansion with sensitivity of 0.54 (95% CI, 0.34-0.74) and specificity of 0.63 (95% CI, 0.53-0.72). After adjustment for potential confounders, intensive BP treatment was not associated with a significant reduction of ICH expansion (relative risk, 0.83; 95% CI, 0.27 2.51; P = .74) or improved outcome (relative risk of 90-day modified Rankin Scale score >=4, 1.24; 95% CI, 0.53-2.91; P = .62) in spot sign-positive patients. Conclusions and Relevance: The predictive performance of the spot sign for ICH expansion was lower than in prior reports from single-center studies. No evidence suggested that patients with ICH and a spot sign specifically benefit from intensive BP reduction. Trial Registration: clinicaltrials.gov Identifier: NCT01176565. PMID- 28628709 TI - Maximizing Benefits and Minimizing Harms of Lung Cancer Screening: A Teachable Moment. PMID- 28628710 TI - Marketing Claims for Infant Formula Additives and Infant Formula-Reply. PMID- 28628711 TI - Antiplatelet Therapy in Patients With Coronary Stents Undergoing Elective Noncardiac Surgery: Continue, Stop, or Something in Between? PMID- 28628712 TI - Hyperthermic intraperitoneal chemoperfusion as a component of multimodality therapy for ovarian and primary peritoneal cancer. AB - BACKGROUND AND OBJECTIVES: The role of hyperthermic intraperitoneal chemoperfusion (HIPEC) in the multimodality treatment of ovarian peritoneal metastases (OPM) and primary peritoneal cancer (PPC) remains controversial. We hypothesized that cytoreductive surgery (CRS) and HIPEC would provide meaningful survival benefit without excessive morbidity. METHODS: We reviewed clinicopathologic and perioperative data following 96 CRS-HIPEC procedures for primary or recurrent OPM and PPC. Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. RESULTS: CRS-HIPEC was mostly performed for recurrent disease (56.3%) and high grade serous carcinoma (72.9%). Platinum-based systemic chemotherapy was administered to 89.5% of patients, with 75.5% having platinum-sensitive disease at CRS-HIPEC. Complete macroscopic resection was achieved in 70.8% of patients. Clavien-Dindo grade 3/4 morbidity occurred in 23.4% of patients; three patients died within 60-days postoperatively. Median overall survival from diagnosis of peritoneal metastases and CRS-HIPEC was 78 and 38 months, respectively. Completeness of cytoreduction, pathologic subtype, and 30-day morbidity were independent predictors of survival in multiple regression analysis. CONCLUSIONS: Our study demonstrates promising survival data and supports the role of HIPEC in the multimodality treatment algorithm for primary or recurrent OPM and PPC. However definite indications and timing of HIPEC need to be clarified by prospective studies. PMID- 28628713 TI - Robotic versus laparoscopic distal pancreatectomy: A propensity score-matched study. AB - BACKGROUND: Robotic distal pancreatectomy (RDP) is considered a safe and feasible alternative to laparoscopic distal pancreatectomy (LDP). However, previous studies have some limitations including small sample size and selection bias. This study aimed to evaluate whether the robotic approach has advantages over laparoscopic surgery in distal pancreatectomy. METHODS: Demographics and perioperative outcomes among patients undergoing RDP (n = 102) and LDP (n = 102) between January 2011 and December 2015 were reviewed. A 1:1 propensity score matched analysis was performed between both groups. RESULTS: Both groups displayed no significant differences in perioperative outcomes including operative time, blood loss, transfusion rate, and rates of overall morbidities and pancreatic fistula. Robotic approach reduced the rate of conversion to laparotomy (2.9% vs 9.8%, P = 0.045), especially in patients with large tumors (0% vs 22.2%, P = 0.042). RDP improved spleen (SP) and splenic vessels preservation (SVP) rates in patients with moderate tumors (60.0% vs 35.5%, P = 0.047; 37.1% vs 12.9%, P = 0.025), especially in patients without malignancy (95.5% vs 52.4%, P = 0.001; 59.1% vs 19.0%, P = 0.007). RDP also reduced postoperative hospital stay (PHS) significantly (7.67% vs 8.58, P = 0.032). CONCLUSIONS: RDP is associated with less rate of conversion to laparotomy, shorter PHS, and improved SP and SVP rates in selected patients than LDP. PMID- 28628714 TI - Advanced real-time multi-display educational system (ARMES): An innovative real time audiovisual mentoring tool for complex robotic surgery. AB - INTRODUCTION: The recent scientific and technologic advances have profoundly affected the training of surgeons worldwide. We describe a novel intraoperative real-time training module, the Advanced Robotic Multi-display Educational System (ARMES). METHODS: We created a real-time training module, which can provide a standardized step by step guidance to robotic distal subtotal gastrectomy with D2 lymphadenectomy procedures, ARMES. The short video clips of 20 key steps in the standardized procedure for robotic gastrectomy were created and integrated with TileProTM software to delivery on da Vinci Surgical Systems (Intuitive Surgical, Sunnyvale, CA). RESULTS: We successfully performed the robotic distal subtotal gastrectomy with D2 lymphadenectomy for patient with gastric cancer employing this new teaching method without any transfer errors or system failures. Using this technique, the total operative time was 197 min and blood loss was 50 mL and there were no intra- or post-operative complications. CONCLUSIONS: Our innovative real-time mentoring module, ARMES, enables standardized, systematic guidance during surgical procedures. PMID- 28628715 TI - Overcoming the resistance of pancreatic cancer to immune checkpoint inhibitors. AB - Immunotherapy has become a new modality of cancer treatment, but has had a limited success in treating PDAC. A combination approach to immunotherapy, using both immune checkpoint inhibitors and immune activating agonists, is needed, as PDAC does not respond to single-agent checkpoint inhibitors. Studies have also supported using vaccine-based therapies to prime the tumor microenvironment of PDAC with effector T-cells. Other therapeutic strategies including epigenetic agents, stroma modulators, radiotherapy, and T-cell transfer therapies may also prime the tumor microenvironment to overcome resistance to immune checkpoint inhibitors. PMID- 28628716 TI - Imprinted Photonic Hydrogels for the Size- and Shell-Selective Recognition of Nanoparticles. AB - Sensors based on responsive photonic hydrogels have recently attracted considerable attention for visual medical diagnostics, pharmaceutical bioassays, and environmental monitoring. However, the use of these promising materials for the detection of nanoparticles (NPs) has never been explored so far, although the sensing of nanoobjects is a rapidly evolving area of research. To address this issue, we have combined the concepts of inverse-opal hydrogels and nanoparticle imprinted polymers. In this way, we could obtain a NP-imprinted photonic hydrogel consisting of a three-dimensional, highly ordered poly(methacrylic acid) macroporous array, in which nanocavities complementary to the target NPs, in this case colloidal quantum dots, are distributed. This novel type of NP-imprinted photonic hydrogel sensor was shown to display high sensitivity and selectivity, thus opening new prospects for the development of equipment-free and cost efficient sensing devices for NPs. PMID- 28628717 TI - Implications of extra nodal extension in differentiated thyroid cancer. PMID- 28628718 TI - A better method for assessment of hepatic function in hepatocellular carcinoma patients treated with radiofrequency ablation: Usefulness of albumin-bilirubin grade. AB - AIM: To evaluate the efficacy of the newly proposed albumin-bilirubin (ALBI) grade for therapy selection, clinical features of patients treated with radiofrequency ablation (RFA) were elucidated. METHODS: From 2000 to 2015, 1101 patients with HCC (<3 cm, <=3 tumors) treated with RFA were enrolled, with the following clinical features: 734 men and 367 women; 779 with hepatitis C virus, 153 with hepatitis B virus, 5 with hepatitis C and B, and 164 others; and Child Pugh classification (CP) A : B ratio of 842:259. Liver damage classification (LD) using the indocyanine green retention rate at 15 min and ALBI-grade were compared in regard to the prognoses of those patients. RESULTS: Median tumor size was 1.7 cm (interquartile range, 1.4-2.2 cm) and single tumors were found in 802 cases (72.8%) (tumor-node-metastasis stage of the Liver Cancer Study Group of Japan I : II : III = 536:454:111). In the LD-A group, the number of cases with ALBI-grade 1, 2, and 3 were 294, 224, and 1, respectively, while those in the LD-B group were 47, 490, and 12, respectively. In the LD-C group, 19 and 14 patients were ALBI-2 and -3, respectively. Akaike Information Criterion values for CP, LD grade, and ALBI-grade were 6015.4, 5988.8, and 5990.7, respectively. However, there was no significant difference regarding prognosis between LD-A/B (n = 228) and C (n = 31) (median survival time, 4.8 vs. 3.9 years, P = 0.0818) in CP-B, whereas a significant difference was observed regarding prognosis for ALBI-1/2 (n = 232) and ALBI-3 (n = 27) (median survival time, 4.8 vs. 2.7 years, P = 0.0168). CONCLUSION: Albumin-bilirubin grade showed an assessment ability similar to that of LD-grade. Furthermore, there was a small improvement in prognosis following RFA in patients with an ALBI-grade of 3. Although only two serological parameters, albumin and total bilirubin, are used, assessment with ALBI-grade may be more useful than with LD-grade for avoiding a non-beneficial RFA procedure. PMID- 28628719 TI - Surgical innovation. PMID- 28628720 TI - Cost-effective teaching of radiology with preclinical anatomy. AB - Graduating physicians in all subspecialties have an increased need for competency in radiology, particularly since the use of diagnostic imaging continues to grow. To integrate the teaching of radiology with anatomy during the first year of medical school at Howard University, a novel approach was developed to overcome the limitations of resources including funding, faculty, and curricular time. The resulting program relies on self-study and peer-to-peer interactions to develop proficiency at manipulating free versions of medical image viewer software (using the DICOM standard), identifying normal anatomy in medical images, and applying critical thinking skills to understand common clinical conditions. An effective collaborative relationship between a radiologist and anatomist was necessary to develop and implement the program of anatomic-radiographic instruction which consists of five tiers: (1) initial exposure to anatomy through dissection which provides a foundation of knowledge; (2) study of annotated radiographs from atlases; (3) a radiology quiz open to group discussions; (4) small group study of clinical cases with diagnostic images; and (5) radiographic tests. Students took all quizzes and tests by working from image datasets preloaded on their personal computers, mimicking the approach by which radiologists analyze medical images. In addition to stimulating student support of a new teaching initiative, the strengths of Howard's program are that it can be introduced into an existing preclinical curriculum in almost any medical school with minimal disruption, it requires few additional resources to implement and run, and its design is consistent with the principles of modern education theory. Anat Sci Educ 11: 196 206. (c) 2017 American Association of Anatomists. PMID- 28628721 TI - Protonation of Nitramines: Where Does the Proton Go? AB - The reactions of nitramine, N-methyl nitramine, and N,N-dimethyl nitramine with anhydrous HF and the superacids HF/MF5 (M=As, Sb) were investigated at temperatures below -40 degrees C. In solution, exclusive O-protonation was observed by multinuclear NMR spectroscopy. Whereas no solid product could be isolated from the neat HF solutions even at -78 degrees C, in the HF/MF5 systems, protonated nitramine MF6- salts were isolated for the first time as moisture-sensitive solids that decompose at temperatures above -40 degrees C. In the solid state, depending on the counterion, O-protonated or N-protonated cations can be formed, in accord with theoretical calculations which show that the energy differences between O-protonation and N-protonation are very small. The salts [H2 N-NO2 H][AsF6 ], [H3 N-NO2 ][SbF6 ], [MeHNNO2 H][SbF6 ], and [Me2 NNO2 H][SbF6 ] were characterized by their X-ray crystal structures. PMID- 28628722 TI - Microscopic lymphovascular invasion is an independent predictor of survival in resected pancreatic ductal adenocarcinoma. AB - Background and Objectives Despite routine inclusion of lymphovascular invasion (LVI) status in pathologic reports of resected pancreatic ductal adenocarcinomas (PDA), the clinical implications of LVI have not been well characterized. Methods This study is a retrospective review of 2640 patients who underwent a pancreatectomy for PDA at Thomas Jefferson University Hospital, Massachusetts General Hospital, or Johns Hopkins Hospital (2003-2014). Clinical and pathologic records were extracted from institutional databases. Results The median post resection survival for the total cohort was 19.2 months with a 5-year survival rate of 15.2%. In a multivariate Cox proportional hazards model including conventional pathologic features, LVI was an independent predictor of survival (HR = 1.14, P = 0.017). In a stratified Kaplan-Meier survival analysis, patients with N0, LVI- PDA had a significantly improved overall survival compared to those with N0, LVI+ PDA (median 31 vs 24 mo, P = 0.020). Similarly, patients with N1, LVI- PDA had superior survival to patients with N1, LVI+ disease (18.6 vs 16.5 mo, P = 0.001). Conclusions As the first large scale study focused on the clinical impact of LVI status in PDA, these data indicate that this routinely reported pathologic feature is a bona fide and independent adverse prognostic factor. PMID- 28628723 TI - A Multifunctional Radiotheranostic Agent for Dual Targeting of Breast Cancer Cells. AB - A straightforward synthetic route for a new multifunctional 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivative is described. To demonstrate the versatility of this pro-chelator for the preparation of radiolabeled hybrid compounds containing two different biological targeting moieties, an antitumor agent (e.g., a DNA-intercalating agent) and an estrogen receptor (ER) ligand (e.g., LXXLL-based peptide) were regiospecifically conjugated to the DOTA derivative. The bifunctional probe was radiolabeled with the auger electron emitter indium-111, and the resulting radioconjugate was demonstrated to induce DNA damage in vitro, which, along with the nuclear internalization exhibited in breast cancer cells, might enhance its therapeutic activity. This favorable in vitro performance suggests that these hybrid compounds could be attractive probes for theranostic applications. PMID- 28628724 TI - Bifunctional Boron Phosphate as an Efficient Catalyst for Epoxide Activation to Synthesize Cyclic Carbonates with CO2. AB - Development of inexpensive, easily prepared, non-toxic, and efficient catalysts for the cycloaddition of CO2 with epoxides to synthesize five-membered cyclic carbonates is a very attractive topic in the field of CO2 transformation. In this work, we conducted the first work on the cycloaddition of CO2 with epoxides to produce cyclic carbonates catalyzed by a binary catalyst system consisting of KI and boron phosphate (BPO4 ), which are both inexpensive and non-toxic, and various corresponding cyclic carbonates could be produced with high yields (93-99 %) at 110 degrees C with a CO2 pressure of 4 MPa under solvent-free conditions. In the BPO4 /KI catalyst system, BPO4 , a Bronsted and Lewis acid hybrid, played the role of activating the epoxy ring through the formation of hydrogen bonds with Bronsted acidic sites and the interaction with Lewis acidic sites simultaneously, and thus enhanced the activity of KI for the cycloaddition of CO2 with epoxides significantly. Additionally, the activity of the BPO4 /KI catalyst system showed no noticeable decrease after being reused five times, indicating that the BPO4 was stable under the reaction conditions. PMID- 28628725 TI - Dendronized Semiconducting Polymer as Photothermal Nanocarrier for Remote Activation of Gene Expression. AB - Regulation of transgene systems is needed to develop innovative medicines. However, noninvasive remote control of gene expression has been rarely developed and remains challenging. We herein synthesize a near-infrared (NIR) absorbing dendronized semiconducting polymer (DSP) and utilize it as a photothermal nanocarrier not only to efficiently deliver genes but also to spatiotemporally control gene expression in conjunction with heat-inducible promoter. DSP has a high photothermal conversion efficiency (44.2 %) at 808 nm, permitting fast transduction of NIR light into thermal signals for intracellular activation of transcription. Such a DSP-mediated remote activation can rapidly and safely result in 25- and 4.5-fold increases in the expression levels of proteins in living cells and mice, respectively. This study thus provides a promising approach to optically regulate transgene systems for on-demand therapeutic transgene dosing. PMID- 28628726 TI - Coinage Metal Superatomic Cores: Insights into Their Intrinsic Stability and Optical Properties from Relativistic DFT Calculations. AB - Coinage-metal atomically precise nanoclusters are made of a well-defined metallic core embedded in a ligand-protecting outer shell. Whereas gold derivatives are particularly well documented, examples of silver nanoclusters are somewhat limited and copper species remain particularly scare. Our DFT relativistic calculations on superatomic metallic cores indicate that copper species are almost as stable as gold clusters and more stable than their silver counterparts. Thus, for silver superatomic cores, the role of the stabilizing ligands is more crucial in the stabilization of the overall structure, in comparison to copper and gold. Hence, the chemistry of the earlier counterparts of gold, especially copper, should grow quickly with at least characterizations of species related to that found in the heavier elements in the triad, which requires tackling synthetic challenges. Time-dependent (TD)-DFT calculations show that with an increase of the cluster core nuclearity, the absorption bands are redshifted, allowing us to differentiate between the clusters types. Moreover, the optical properties of the silver cores are fairly different from that of their Cu and Au relatives. PMID- 28628727 TI - Bone resection for facial cutaneous malignancies. AB - BACKGROUND AND OBJECTIVES: The aim of this study is to analyze the clinical outcomes of patients who underwent bone resection for cutaneous malignancy of the face and scalp. METHODS: We retrospectively collected patient data from 62 patients who underwent bone resection for craniofacial cutaneous malignancy of the face and scalp over the last 10 years. We investigated risk factors for disease progression and assessed the utility of pre-operative imaging to predict bone, dura, and brain infiltration. RESULTS: Out of all factors analyzed, brain invasion, surgical margin involvement, and dural margin involvement were found to significantly reduce survival. CT and MRI correctly predicted bone infiltration in 88% and 89% of cases. MRI correctly predicted dura invasion in 89% but grossly underestimated the amount of dural invasion in 23% of reports. CONCLUSIONS: Our data indicate that the resection of bone is a reasonable surgical option in the treatment of patients with advanced cutaneous malignancies of the face and scalp. Brain invasion and positive margins reduced the probability of survival. PMID- 28628728 TI - Characterizing the detection threshold for optical imaging in surgical oncology. AB - BACKGROUND AND OBJECTIVES: Optical imaging to guide cancer resections is rapidly transitioning into the operating room. However, the sensitivity of this technique to detect subclinical disease is yet characterized. The purpose of this study was to determine the minimum range of cancer cells that can be detected by antibody based fluorescence imaging. METHODS: 2LMP (breast), COLO-205 (colon), MiaPaca-2 (pancreas), and SCC-1 (head and neck) cells incubated in vitro with cetuximab IRDye800CW (dose range 8.6-86 nM) were implanted subcutaneously in mice (n = 3 mice, 5 tumors/mouse). Following incubation with 8.6 * 10-2 uM of cetuximab IRDye800CW in vitro, serial dilutions of each cell type (1 * 103 -1 * 106 ) were implanted subcutaneously (n = 3, 5 tumors/mouse). Tumors were imaged with Pearl Impulse and Xenogen IVIS 100 imaging systems. Scatchard analysis was performed to determine receptor density and kinetics for each cell line. RESULTS: Under conditions of minimal cetuximab-IRDye800CW exposure to low cellular quantity, closed-field fluorescence imaging theoretically detected a minimum of 4.2 * 104 9.5 * 104 2LMP cells, 1.9 * 105 -4.5 * 105 MiaPaca-2 cells, and 2.4 * 104 -6.7 * 104 SCC-1 cells; COLO-205 cells could not be identified. Higher EGFR-mediated uptake of cetuximab correlated with sensitivity of detection. CONCLUSION: This study supports the clinical utility of cetuximab-IRDye800CW to sensitively localize subclinical disease in the surgical setting. PMID- 28628729 TI - Pre- and post-operative HBsAg levels may predict recurrence and survival after curative resection in patients with HBV-associated hepatocellular carcinoma. AB - PURPOSE: To investigate pre- and post-operative levels of HBsAg influence prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. METHODS: Medical records were retrospectively analyzed for 881 patients with HBV-related HCC treated by curative resection. Patients were classified as having high or low serum HBsAg levels (>=200 or <200 ng/mL) pre- or post-operatively. RESULTS: OS and RFS were better for patients with low pre-operative serum levels of HBsAg than for those with high levels. Similarly, OS was better among patients with low post-operative serum levels of HBsAg than among those with high levels. RFS, in contrast, was similar between these two groups. After generating propensity score-matched pairs of patients, OS was higher in patients with falling post-operative HBsAg levels than in those with rising levels. In contrast, RFS was similar between these two groups. Antiviral nucleoside analog therapy prolonged OS in patients with high pre-operative HBsAg levels. CONCLUSIONS: Low pre- and post-operative levels of HBsAg may be associated with better long-term survival in patients with HBV related HCC. Pre-operative serum levels of HBsAg >=200 ng/mL may identify patients more likely to benefit from antiviral treatment. PMID- 28628730 TI - Comparative study on ambient ionization methods for direct analysis of navel orange tissues by mass spectrometry. AB - It is of sustainable interest to improve the sensitivity and selectivity of the ionization process, especially for direct analysis of complex samples without matrix separation. Herein, four ambient ionization methods including desorption atmospheric pressure chemical ionization (DAPCI), heat-assisted desorption atmospheric pressure chemical ionization (heat-assisted DAPCI), microwave plasma torch (MPT) and internal extractive electrospray ionization (iEESI) were employed for comparative analysis of the navel orange tissue samples by mass spectrometry. The volatile organic compounds (e.g. ethanol, vanillin, leaf alcohol and jasmine lactone) were successfully detected by non-heat-assisted DAPCI-MS, while semi volatile organic compounds (e.g. 1-nonanol and ethyl nonanoate) together with low abundance of non-volatile organic compounds (e.g. sinensetin and nobiletin) were obtained by heat-assisted DAPCI-MS. Typical nonvolatile organic compounds [e.g. 5 (hydroxymethyl)furfural and glucosan] were sensitively detected with MPT-MS. Compounds of high polarity (e.g. amino acids, alkaloids and sugars) were easily profiled with iEESI-MS. Our data showed that more analytes could be detected when more energy was delivered for the desorption ionization purpose; however, heat sensitive analytes would not be detected once the energy input exceeded the dissociation barriers of the analytes. For the later cases, soft ionization methods such as iEESI were recommended to sensitively profile the bioanalytes of high polarity. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28628731 TI - Response to HER2 status might be independent determinant associated with no residual disease at surgical resection in patients with DCIS. PMID- 28628733 TI - Size Matters: Chemical Synthesis of a Homogenous Arabinogalactan 92-mer. AB - 31+30+31: Ye and colleagues have synthesized a branched 92-mer of arabinogalactan a major component of the cell wall of M. tuberculosis-by linking a linear oligogalactan 30-mer with two d-arabinofuranose 31-mers. Their approach capitalizes on sequential, one-pot glycosylation reactions that result in a rapid increase in molecular complexity and efficient synthesis of a branched oligosaccharide. PMID- 28628732 TI - Understanding neurophobia: Reasons behind impaired understanding and learning of neuroanatomy in cross-disciplinary healthcare students. AB - Recent studies have highlighted a fear or difficulty with the study and understanding of neuroanatomy among medical and healthcare students. This has been linked with a diminished confidence of clinical practitioners and students to manage patients with neurological conditions. The underlying reasons for this difficulty have been queried among a broad cohort of medical, dental, occupational therapy, and speech and language sciences students. Direct evidence of the students' perception regarding specific difficulties associated with learning neuroanatomy has been provided and some of the measures required to address these issues have been identified. Neuroanatomy is perceived as a more difficult subject compared to other anatomy topics (e.g., reproductive/pelvic anatomy) and not all components of the neuroanatomy curriculum are viewed as equally challenging. The difficulty in understanding neuroanatomical concepts is linked to intrinsic factors such as the inherent complex nature of the topic rather than outside influences (e.g., lecture duration). Participants reporting high levels of interest in the subject reported higher levels of knowledge, suggesting that teaching tools aimed at increasing interest, such as case-based scenarios, could facilitate acquisition of knowledge. Newer pedagogies, including web-resources and computer assisted learning (CAL) are considered important tools to improve neuroanatomy learning, whereas traditional tools such as lecture slides and notes were considered less important. In conclusion, it is suggested that understanding of neuroanatomy could be enhanced and neurophobia be decreased by purposefully designed CAL resources. This data could help curricular designers to refocus attention and guide educators to develop improved neuroanatomy web resources in future. Anat Sci Educ 11: 81-93. (c) 2017 American Association of Anatomists. PMID- 28628734 TI - Effect of abdominopelvic sepsis on cancer outcome in patients undergoing sphincter saving surgery for rectal cancer. AB - BACKGROUND: In rectal cancer, the significance of abdominopelvic sepsis (APS) on metastatic tumor growth remains uncertain. We aimed to analyze the effect of abdominopelvic sepsis on long-term survival in patients undergoing restorative rectal cancer surgery. METHODS: Data were used from the Belgian PROCARE rectal cancer registry. The effect of abdominopelvic infection on survival was assessed in uni- and multivariable Cox regression models. The effect of clinical and pathological covariates was controlled by propensity score-based matching of cases with controls. The effect of abdominopelvic sepsis on the rate of local and metastatic recurrence was evaluated using crosstabulation and the Pearson chi2 test. RESULTS: In univariable analysis, the presence of APS was associated with significantly worse overall survival (HR 1.3, P = 0.025). After propensity score matching including age, BMI, tumor level, pTstage, pN stage, CRM, tumor grade, number of lymph nodes, and presence of lymphovascular invasion, the association of APS with OS was no longer significant (HR 1.26, 95%CI 0.92-1.74, P = 0.15). No differences were observed in the risk of local or metastatic recurrence (3.6% vs 2.9% and 13% vs 16.5%). CONCLUSIONS: In this analysis APS after rectal cancer resection was not significantly associated with OS, metastatic, or local recurrence. PMID- 28628735 TI - Effect of shade, opacity and layer thickness on light transmission through a nano hybrid dental composite during curing. AB - OBJECTIVE: The aim of this study was to investigate the effect of shade and opacity on the change in light transmission through different thicknesses of a nano-hybrid composite during curing. MATERIALS AND METHODS: Twelve different shades of Venus Diamond (Heraeus Kulzer) were placed in disk shaped molds with thickness of 1, 2, and 3 mm (n = 3 per group) and cured with an LED light-curing unit. Initial, final and average irradiance, and the total amount of energy passing through the specimen were measured using the MARC Resin Calibrator at every 10s for a total of 40s. The translucency parameter and the contrast ratio were obtained using a chromameter. Results were analyzed with ANOVA/Tukey's test (alpha = 0.05). RESULTS: All shades and all thicknesses (up to 3 mm) experienced an increase in light transmittance during curing. The majority of the increase occurred during the initial 10s exposure, with significant increase occurring from subsequent exposures only in thicker specimens (i.e., 3 mm). The increase in irradiance at the bottom during curing was dependent on shade, with darker shades and greater depths of material showing less increase. CONCLUSIONS: For one specific resin composite formulation, an increase in translucency occurs as cure progresses, and the increase is enhanced for composites with greater lightness and lower contrast ratio. CLINICAL SIGNIFICANCE: Composites demonstrate increased light transmittance as curing progress, which may improve depth of cure. The thicker composite showed the least increase in light transmission within the same shade. The increase in translucency is enhanced for composites with great lightness and lower contrast ratio. PMID- 28628736 TI - 'It's definitely not Alzheimer's': Perceived benefits and drawbacks of a mild cognitive impairment diagnosis. AB - OBJECTIVES: To understand the perceived benefits and drawbacks of a mild cognitive impairment (MCI) diagnosis from the perspective of those living with the label. METHODS: Participants were included if they had recently (within 6 months) received a MCI diagnosis. We also recruited close family members to gain their perspectives. Each was interviewed separately with a semi-structured topic guide covering three areas: (1) experience of cognitive impairments and changes in the individual; (2) impact of cognitive impairment(s) on daily activities and social relationships; and (3) experience of the diagnosis process and living with the label. Transcribed interviews were stored in Nvivo(r) . Grounded theory procedures of memo writing, open coding, constant comparison, and focused coding were used to derive conceptual themes. RESULTS: Eighteen dyads were interviewed. The overarching themes surrounding diagnosis benefits and drawbacks were as follows: (1) emotional impact of the diagnosis; (2) practical benefits and limitations of the diagnosis, in terms of (a) understanding one's symptoms and (b) access to clinical support. Although participants were glad to have clinical support in place, they expressed frustration at the lack of clarity, and the lack of available treatments for MCI. Consequently, living with MCI can be characterized as an ambivalent experience. CONCLUSION: As a clinical label, MCI appears to have little explanatory power for people living with cognitive difficulties. Work is needed to clarify how clinicians and patients communicate about MCI, and how people can be helped to live well with the label. Despite an emerging body of prognostic studies, people with MCI are likely to continue living with significant uncertainty. Statement of contribution What is already known on this subject? Mild cognitive impairment is a state of cognitive decline between normal cognitive ageing and dementia. This clinical category has been an important domain of academic debate over recent years. From a clinical perspective, diagnosing MCI is a helpful way to enable communication between health professionals, and a diagnosis can be important for patients in need of support and education. However, diagnosis can be fraught with difficulties, while patients have reported significant uncertainty about the label. This study aimed to examine the perceived benefits and drawbacks of receiving a MCI diagnosis. What does this study add? The emotional impact of a MCI diagnosis is complex and raised conflicting and fluctuating emotions in our participants' accounts - most notably worry and relief. Participants were glad to have clinical support available to call on; however, they were frustrated at the lack of 'treatments' available for MCI and were often anxious to slow any cognitive decline down Health psychologists will have an important role to play in understanding and improving clinical communication about MCI. PMID- 28628737 TI - Analysis of Structure-Activity Relationships Based on the Hepatitis C Virus SLIIb Internal Ribosomal Entry Sequence RNA-Targeting GGHYRFK?Cu Complex. AB - New therapeutics for targeting the hepatitis C virus (HCV) have been released in recent years. Although they are less prone to resistance, they are still administered in cocktails as a combination of drugs targeting various aspects of the viral life cycle. Herein, we aim to contribute to an arsenal of new HCV therapeutics by targeting the HCV internal ribosomal entry sequence (IRES) RNA through the development of catalytic metallodrugs that function to degrade rather than inhibit the target molecule. Based on a previously characterized HCV IRES stem-loop IIb RNA-targeting metallopeptide Cu-GGHYrFK (1?Cu), an all-l analogue (3?Cu) and a series of additional complexes with single alanine substitutions in the targeting domain were prepared and screened to determine the influence each amino acid side chain on RNA localization and recognition, and catalytic reactivity toward the RNA. Additional substitutions of the tyrosine position in complex 3?Cu were also investigated. Good agreement between calculated and measured binding affinities provided support for in silico modeling of the SLIIb RNA binding site and correlations with RNA cleavage sites. Examination of the cleavage products from reaction of the Cu complexes with SLIIb provided mechanistic insights, with the first observation of the 5'-geminal diol and 5' phosphopropenal as products through the use of a Cu?ATCUN catalytic motif. Together, the data yielded insights into structure-function relationships that will guide future optimization efforts. PMID- 28628738 TI - HER2 status might be independent determinant associated with no residual disease at surgical resection in patients with DCIS. PMID- 28628739 TI - Predictive validity of body fat percentage by bioimpedance compared with deuterium oxide dilution in Costa Rican schoolchildren. AB - OBJECTIVE: The purpose of this study was to verify the validity of body fat percentage (BF%) by bioelectrical impedance analysis (BIA) in a sample of Costa Rican schoolchildren. METHODS: The sample consisted of 52 male (mean age 8.1 +/- 0.9 years) and 49 female (mean age 7.5 +/- 1.0 years) schoolchildren. Deuterium oxide dilution was the reference method used as the "gold standard" to determine the fat mass (FM) expressed as BF%. Linear regression analyses and paired sample t-tests were used to test the association and mean differences between BIA and deuterium oxide dilution BF%. Concordance between BIA and deuterium oxide dilution BF% was determined by Lin's concordance correlation coefficient. Measurement of agreement between the two methods was analyzed using the Bland Altman procedure. RESULTS: Significant associations between BIA and deuterium oxide dilution BF% were found in males (R = 0.97, R2 = 0.95, P < .0001) and in females (R = 0.98, R2 = .96, P < .0001). The measurements of BF% (mean +/- SD) were not significantly different between males (BIA 31.1 +/- 7.6% vs. deuterium oxide dilution 31.0 +/- 7.4%) and females (BIA 25.9 +/- 7.9% vs. deuterium oxide dilution 26.3 +/- 7.8%) by t-test. Lin's concordance correlation coefficient identified an almost perfect strength of agreement between males and females. Bland-Altman plots showed that the Bodystat measured similar BF% compared to the deuterium oxide dilution in both males and females. CONCLUSIONS: BIA Bodystat presented high agreement with BF% measured by deuterium oxide dilution; therefore BIA Bodystat is recommended for estimating BF% in Costa Rican schoolchildren. PMID- 28628740 TI - Stuck in the spin cycle: Avoidance and intrusions following breast cancer diagnosis. AB - OBJECTIVES: Theories and research regarding cognitive and emotional processing during the experience of profound stressors suggest that the presence of intrusive thoughts and feelings predicts greater use of avoidance and that the use of avoidance paradoxically predicts more intrusions. However, empirical investigations of their purported bidirectional relationship are limited. DESIGN: This study presents a longitudinal investigation of the reciprocal relationship between intrusions and avoidance coping over a 6-month period in the year following breast cancer diagnosis. METHODS: Breast cancer patients (N = 460) completed measures of cancer-related intrusions and avoidance at study entry, 3 months, and 6 months later (i.e., an average of 2, 5, and 8 months after diagnosis, respectively). RESULTS: Cross-lagged panel analyses revealed that intrusive thoughts, feelings, and images at study entry predicted greater avoidance 3 months later, and avoidance coping at study entry predicted intrusions 3 months later, controlling for the stability of intrusions and avoidance as well as time since diagnosis. Findings were not statistically significant for avoidance predicting intrusions, or vice versa, between the 3 month and the 6-month assessment period, during which they declined. CONCLUSIONS: These findings provide empirical support for the theoretical contention that avoidance and intrusive thoughts and emotions reciprocally influence one another following stressful events. Additionally, in the months shortly after breast cancer diagnosis, intrusions and avoidance are positively related. However, the relationships attenuate over time, which could indicate resolved cognitive and emotional processing of the cancer experience. Statement of contribution What is already known on this subject? Following stressful life events, individuals often experience intrusive thoughts and feelings related to the event and they report avoidance of such reminders. Many studies demonstrate that greater intrusions predict more subsequent use of avoidance coping, and other studies show that greater use of avoidance predicts more intrusions. Their reciprocal relation has not been examined, however. What does this study add? This is the first examination of the concurrent, reciprocal influence of intrusions and avoidance. Findings suggest that accounting for the bidirectional influence of avoidance and intrusions best estimates hypothesized models. Higher intrusions and avoidance predicted each other for the first 3 months after study entry, but the relationship diminished 6 months after study entry, perhaps due to productive mental processing of the stress of breast cancer diagnosis and treatment. PMID- 28628742 TI - Acceleration of Semiempirical QM/MM Methods through Message Passage Interface (MPI), Hybrid MPI/Open Multiprocessing, and Self-Consistent Field Accelerator Implementations. AB - The strategy and implementation of scalable and efficient semiempirical (SE) QM/MM methods in CHARMM are described. The serial version of the code was first profiled to identify routines that required parallelization. Afterward, the code was parallelized and accelerated with three approaches. The first approach was the parallelization of the entire QM/MM routines, including the Fock matrix diagonalization routines, using the CHARMM message passage interface (MPI) machinery. In the second approach, two different self-consistent field (SCF) energy convergence accelerators were implemented using density and Fock matrices as targets for their extrapolations in the SCF procedure. In the third approach, the entire QM/MM and MM energy routines were accelerated by implementing the hybrid MPI/open multiprocessing (OpenMP) model in which both the task- and loop level parallelization strategies were adopted to balance loads between different OpenMP threads. The present implementation was tested on two solvated enzyme systems (including <100 QM atoms) and an SN2 symmetric reaction in water. The MPI version exceeded existing SE QM methods in CHARMM, which include the SCC-DFTB and SQUANTUM methods, by at least 4-fold. The use of SCF convergence accelerators further accelerated the code by ~12-35% depending on the size of the QM region and the number of CPU cores used. Although the MPI version displayed good scalability, the performance was diminished for large numbers of MPI processes due to the overhead associated with MPI communications between nodes. This issue was partially overcome by the hybrid MPI/OpenMP approach which displayed a better scalability for a larger number of CPU cores (up to 64 CPUs in the tested systems). PMID- 28628741 TI - Amplicon Competition Enables End-Point Quantitation of Nucleic Acids Following Isothermal Amplification. AB - It is inherently difficult to quantitate nucleic acid analytes with most isothermal amplification assays. We developed loop-mediated isothermal amplification (LAMP) reactions in which competition between defined numbers of "false" and "true" amplicons leads to order of magnitude quantitation by a single endpoint determination. These thresholded LAMP reactions were successfully used to directly and quantitatively estimate the numbers of nucleic acids in complex biospecimens, including directly from cells and in sewage, with the values obtained closely correlating with qPCR quantitations. Thresholded LAMP reactions are amenable to endpoint readout by cell phone, unlike other methods that require continuous monitoring, and should therefore prove extremely useful in developing one-pot reactions for point-of-care diagnostics without needing sophisticated material or informatics infrastructure. PMID- 28628743 TI - Preparation of Blatter Radicals via Aza-Wittig Chemistry: The Reaction of N Aryliminophosphoranes with 1-(Het)aroyl-2-aryldiazenes. AB - Reacting N-aryliminophosphoranes with 1-(het)aroyl-2-aryldiazenes in preheated diphenyl ether at ca. 150-250 degrees C for 5-25 min affords in most cases the 1,3-diaryl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yls (aka Blatter radicals) in moderate to good yields. All new compounds are fully characterized, including EPR and CV studies for the radicals. Single-crystal X-ray structures of 1-benzoyl-2 (perfluorophenyl)diazene and 1-(perfluorophenyl)-3-phenyl-1,4 dihydrobenzo[e][1,2,4]triazinyl are also presented. PMID- 28628744 TI - General Approach of Stimuli-Induced Aggregation for Monitoring Tumor Therapy. AB - Intracellular construction of nanoaggregates from synthetic molecules to mimic natural ordered superstructures has gained increasing attention recently. Here, we develop an endogenous stimuli-induced aggregation (eSIA) approach to construct functional nanoaggregates for sensing and monitoring cellular physiological processes in situ. We design a series of thermosensitive polymer-peptide conjugates (PPCs), which are capable of constructing nanoaggregates in cells based on their isothermal phase transition property. The PPCs are composed of three moieties (i.e., a thermoresponsive polymer backbone, a grafted peptide, and a signal-molecule label). The bioenvironment-associated phase transition behavior of PPCs are carefully studied by consideration of various crucial parameters such as chain length, hydrophilicity, ratio of grafted peptides, and concentration. Intriguingly, under the specific intracellular stimulus, the PPCs are tailored and simultaneously form nanoaggregates exhibiting long-term retention effect, which enables specific identification and quantification of endogenous factors. This general approach is expected for high-performance in situ sensing and dynamic monitoring of disease progression in living subjects. PMID- 28628745 TI - Significant Enhancement of Photocatalytic Reduction of CO2 with H2O over ZnO by the Formation of Basic Zinc Carbonate. AB - Electron-hole pair separation efficiency and adsorption performance of photocatalysts to CO2 are the two key factors affecting the performance of photocatalytic CO2 reduction with H2O. Distinct from conventional promoter addition, this study proposed a novel approach to address these two issues by tuning the own surface features of semiconductor photocatalyst. Three ZnO samples with different morphologies, surface area, and defect content were fabricated by varying preparation methods, characterized by XRD, TEM, and room-temperature PL spectra, and tested in photoreduction of CO2 with H2O. The results show that the as-prepared porous ZnO nanosheets exhibit a much higher activity for photoreduction of CO2 with H2O when compared to ZnO nanoparticles and nanorods attributed to the existence of more defect sites, that is, zinc and oxygen vacancies. These defects would lower the combination rate of electron-hole pair as well as promote the formation of basic zinc carbonate by Lewis acid-base interaction, which is the active intermediate species for photoreduction of CO2. ZnO nanoparticles and ZnO nanorods with few defects show weak adsorption for CO2 leading to the inferior photocatalytic activities. This work provides new insight on the CO2 activation under light irradiation. PMID- 28628746 TI - Core-Shell Microgel-Based Surface Coatings with Linear Thermoresponse. AB - We study the swelling and shrinking behavior of core-shell microgels adsorbed on silicon wafers. In these systems, the core is made of cross-linked poly(N isopropylmethacrylamide) and the shell consists of cross-linked poly(N-n propylacrylamide). In suspension, these particles exhibit an extended linear swelling behavior in the temperature interval between the lower critical solution temperatures of the two polymers. Using ellipsometry and atomic force microscopy, we show that this linear response is also observed in the adsorbed state. PMID- 28628747 TI - Laser Ablation of Silver in Liquid Organic Monomer: Influence of Experimental Parameters on the Synthesized Silver Nanoparticles/Graphite Colloids. AB - During the past decade, synthesizing silver nanoparticles (Ag NPs) by liquid phase-pulsed laser ablation (LP-PLA) has attracted a lot of attention. Basically, this technique allows producing various metallic nanoparticles with controlled size, shape, composition, or surroundings in several liquids (i.e., water, ethanol, acetone, toluene, and so forth). Recently, such processes have been studied in liquid organic monomer such as methyl methacrylate (MMA). However, the influence of the laser parameters on the materials synthesized in such reactive liquid and their features were not fully investigated so far. Here we investigate the LP-PLA of silver in two different but rather similar acrylate monomers: dodecyl acrylate (DOCA) and 1H,1H,2H,2H perfluorodecyl acrylate (PFDA). The influence of the fluence and the number of pulses on the production, size, and morphology of the materials has been examined. First, factorial design experiments have been achieved in order to determine the weight of the laser parameters in each precursor. This study shows two highly different behaviors in function of the monomer where the process took place. This has been explained by the plasma plume confinement and/or the "interpulses" self-absorption of the particles by the laser beam. The formation of graphite around the synthesized AgNPs has been highlighted by Raman spectroscopy at low number of pulses. Nevertheless, increasing the number of pulses could lead to three phenomenon depending on the fluence and the used monomer: degradation of the matrix, conservation of the matrix with changes in AgNPs size and distribution, or sustainment of the matrix with any changes in the particles properties. So the surrounding, the size, and stability could be triggered by adjusting these parameters. This paper does highlight that LP-PLA is a powerful technique to provide AgNPs in acrylate monomer with a good control of their features. PMID- 28628748 TI - Does young age really put the heart at risk? AB - Despite significant advances in the management and treatment of heart disease in children, there continue to be patients who have worse outcomes than might be expected. A number of risk factors that could be responsible have been identified. Evidence-based findings will be reviewed, including whether young age and (or) reduced body weight exacerbate these responses. For example, newborn children undergoing congenital cardiac surgery are known to have worse outcomes than older children. Evidence exists that newborn hearts do not tolerate ischemia as well as adult hearts, developing irreversible injury sooner and exhibiting at risk metabolic profiles. As well, in response to the administration of heparin, elevations in free fatty acids occur during congenital heart surgery in children, which can have detrimental effects on the heart. Furthermore, myocardial energetic state has also been suggested to impact outcomes. Unfavourable energetic profiles were correlated to lower body weights in the same age healthy newborn piglet model. Newborn children suffering from congenital heart disease, with lower body weights, also had lower myocardial energetic state and this correlated with longer postoperative ventilatory support as well as a trend to longer intensive care unit stay. These findings imply that unfavourable myocardial metabolic profiles could contribute to postoperative complications. PMID- 28628749 TI - Acupuncture-Related Techniques for Psoriasis: A Systematic Review with Pairwise and Network Meta-Analyses of Randomized Controlled Trials. AB - OBJECTIVE: There has be a large body of evidence on the pharmacological treatments for psoriasis, but whether nonpharmacological interventions are effective in managing psoriasis remains largely unclear. This systematic review conducted pairwise and network meta-analyses to determine the effects of acupuncture-related techniques on acupoint stimulation for the treatment of psoriasis and to determine the order of effectiveness of these remedies. METHODS: This study searched the following databases from inception to March 15, 2016: Medline, PubMed, Cochrane Central Register of Controlled Trials, EBSCO (including Academic Search Premier, American Doctoral Dissertations, and CINAHL), Airiti Library, and China National Knowledge Infrastructure. Randomized controlled trials (RCTs) on the effects of acupuncture-related techniques on acupoint stimulation as intervention for psoriasis were independently reviewed by two researchers. RESULTS: A total of 13 RCTs with 1,060 participants were included. The methodological quality of included studies was not rigorous. Acupoint stimulation, compared with nonacupoint stimulation, had a significant treatment for psoriasis. However, the most common adverse events were thirst and dry mouth. Subgroup analysis was further done to confirm that the short-term treatment effect was superior to that of the long-term effect in treating psoriasis. Network meta-analysis identified acupressure or acupoint catgut embedding, compared with medication, and had a significant effect for improving psoriasis. It was noted that acupressure was the most effective treatment. CONCLUSIONS: Acupuncture-related techniques could be considered as an alternative or adjuvant therapy for psoriasis in short term, especially of acupressure and acupoint catgut embedding. This study recommends further well-designed, methodologically rigorous, and more head-to-head randomized trials to explore the effects of acupuncture-related techniques for treating psoriasis. PMID- 28628750 TI - Ergonomic Benefits From a Laparoscopic Instrument With Rotatable Handle Piece Depend on the Area of the Operating Field and Working Height. AB - Objective To evaluate the effect of a laparoscopic instrument with a 360 degrees rotatable handle piece (rot-HP) on biomechanical stress and precision in different areas of a simulated operating field at two working heights. Background Surgeons performing laparoscopic procedures are exposed to biomechanical stress and have an increased risk of musculoskeletal complaints. Method Fifty-seven healthy subjects (27 men, median age 26) without experience in laparoscopy performed a precision task in four quadrants (A-D) of the operating field using the rot-HP or a common fixed handle piece (fixed-HP) at an individually adjusted lower or higher working height. Biomechanical stress was assessed by surface EMG, wrist joint angles, and arm postures and precision by the number of mistakes. Results Using the rot-HP reduced muscle activity of the biceps brachii and flexor carpi radialis muscle. An interaction of flexor activity and area of the operating field occurred with the lowest activity in Quadrant C. Wrist joint angles were more neutral using the rot-HP, especially when the lower working height was applied and in Quadrants B and C. However, increased wrist dorsal flexion occurred in Quadrant A while using the rot-HP. Arm postures and precision were less affected. Conclusion The rot-HP allows some reductions of stresses in the arm and hand region, whereas the stress in the shoulder neck region is not modified. Application The instrument's position and the working height may have to be considered as mediatory factors when describing the effectiveness of an ergonomic handle design for laparoscopic instruments. PMID- 28628751 TI - Comparison between line and surface mesh models to represent the rotator cuff muscle geometry in musculoskeletal models. AB - Accurate muscle geometry (muscle length and moment arm) is required to estimate muscle function when using musculoskeletal modelling. In shoulder, muscles are often modelled as a collection of independent line segments, leading to non physiological muscles trajectory, especially for the rotator cuff muscles. To prevent this, a surface mesh model was developed and validated against 7 MRI positions in one participant. Mean moment arm errors was 11.4% for the line vs. 8.8% for the mesh model. While the model with independent lines led to some non physiological trajectories, the mesh model gave lower misestimations of muscle lengths and moment arms. PMID- 28628753 TI - Computer Vision Syndrome. AB - With the increased use of electronic devices with visual displays, computer vision syndrome is becoming a major public health issue. Improving the visual status of workers using computers results in greater productivity in the workplace and improved visual comfort. PMID- 28628754 TI - The Association Between Skin Rashes and Work Environment, Personal Protective Equipment, and Hygiene Practices Among Female Farmworkers. AB - The objective of this study was to assess work-related hygiene practices and the frequency and location of skin rashes due to cutaneous contact with crop associated materials (e.g., pesticides) for female nursery and fernery workers in Central Florida. A cross-sectional, community-based participatory research study of 237 female nursery and fernery workers between the ages of 19 and 43 years with significant cutaneous contact with foliage crops was conducted using a self report questionnaire and a skin rash chart assessment tool. Of the 237 farmworkers surveyed, 37.1% ( n = 88) reported a rash on at least one area of their bodies. Women who were pregnant during the study were 4.7 times more likely to report more than 30% total body surface area (TBSA) covered by rash compared with non-pregnant fernery workers ( p = .045; 95% confidence interval [CI] [1.04, 21.35]). Further research is needed to better understand the development of skin rashes among farmworkers, to generate effective prevention strategies. PMID- 28628752 TI - High Prevalence of Resistance to Fluoroquinolones and Tetracycline Campylobacter Spp. Isolated from Poultry in Poland. AB - Campylobacter spp. is a major cause of foodborne diseases in humans, particularly when transmitted by the handling or consumption of undercooked poultry meat. Most Campylobacter infections are self-limiting, but antimicrobial treatment (e.g., fluoroquinolones and macrolides) is necessary in severe or prolonged cases. The indiscriminate use of these drugs, both in clinical medicine and animal production, has a major impact on public health. The aim of the present study was to identify Campylobacter strains, isolated from turkey and broilers, using both PCR and the matrix-assisted laser desorption-ionization time-of-flight (MALDI TOF) methods to reveal the accuracy of identification, as well to evaluate the antimicrobial and genetic resistance of the investigated strains. MALDI-TOF and PCR methods were used to show differences, if any, in the specificity of that test. In this study, MALDI-TOF mass spectrometry gave the same results as multiplex PCR, in all cases. The highest rate of resistance (i.e., 100% of turkey and broiler strains) was detected against ciprofloxacin, whereas 58.1% of turkey and 78.6% of broiler strains were resistant to tetracycline. Multidrug-resistant isolates were not found in the study. All ciprofloxacin-resistant strains had a mutation in the gyrA gene, at the Thr-86 position. The presence of the tetO gene was found in 71% of turkey and in 100% of broiler strains. All resistant to tetracycline strains included tetO gene. Additionally, in five turkey and three broiler strains, susceptible to tetracycline, tetO gene was present. These results indicate the high prevalence of Campylobacter strains, which are phenotypically and genetically resistant to fluoroquinolones and tetracycline. PMID- 28628757 TI - Editorial Comment. PMID- 28628756 TI - Atypical sympathomimetic drug lerimazoline mediates contractile effects in rat aorta predominantly by 5-HT2A receptors. AB - Lerimazoline is a sympathomimetic drug that belongs to the imidazoline class of compounds, and is used as a nasal decongestant. Studies on lerimazoline are rare, and its pharmacological profile is not completely understood. Here, we analyzed the affinity of lerimazoline for dopamine receptor D2, serotonin 5-HT1A and 5 HT2A receptors and alpha1-adrenoceptor, and investigated lerimazoline contractile effects in isolated rat thoracic aorta. We also determined the effect of several antagonists on the contractile response to lerimazoline, including prazosin (alpha1-adrenoceptor antagonist), RX 821002 and rauwolscine (alpha2-adrenoceptor antagonists), JP 1302 (alpha2C-adrenoceptor antagonist), methiothepin (non selective 5-HT receptor antagonist), SB 224289 (5-HT1B receptor antagonist), BRL 15572 (5-HT1D receptor antagonist), and ketanserin (5-HT2A receptor antagonist). Lerimazoline displayed high affinity for the 5-HT1A receptor (Ki = 162.5 nM), similar to the previously reported affinity for the 5-HT1D receptor. Binding affinity estimates (Ki) for alpha1, 5-HT2A, and D2 receptors were 6656, 4202 and 3437.5 nM, respectively (the literature reported Ki for 5-HT1B receptor is 3480 nM). Lerimazoline caused concentration-dependent contractions in 70% of preparations, varying in the range between 40% and 55% of the maximal contraction elicited by phenylephrine. While prazosin reduced the maximum contractile response to lerimazoline, rauwolscine showed a non-significant trend in reduction of the response. Both ketanserin (10 nM and 1 uM) and methiothepin strongly suppressed the maximum response to lerimazoline. Overall, our results suggest that 5-HT2A and, less distinctly, alpha1-adrenergic receptors are involved in the lerimazoline-induced contractions, which makes lerimazoline an "atypical" decongestant. PMID- 28628758 TI - Intermediate Risk Prostate Cancer and Active Surveillance: Maximize Utilization while Minimizing Failure. PMID- 28628759 TI - Do infants with cow's milk protein allergy have inadequate levels of vitamin D? AB - OBJECTIVE: To verify whether infants with cow's milk protein allergy have inadequate vitamin D levels. METHODS: This cross-sectional study included 120 children aged 2 years or younger, one group with cow's milk protein allergy and a control group. The children were recruited at the pediatric gastroenterology, allergology, and pediatric outpatient clinics of a university hospital in the Northeast of Brazil. A questionnaire was administered to the caregiver and blood samples were collected for vitamin D quantification. Vitamin D levels <30ng/mL were considered inadequate. Vitamin D level was expressed as mean and standard deviation, and the frequency of the degrees of sufficiency and other variables, as proportions. RESULTS: Infants with cow's milk protein allergy had lower mean vitamin D levels (30.93 vs.35.29ng/mL; p=0.041) and higher deficiency frequency (20.3% vs.8.2; p=0.049) than the healthy controls. Exclusively or predominantly breastfed infants with cow's milk protein allergy had higher frequency of inadequate vitamin D levels (p=0.002). Regardless of sun exposure time, the groups had similar frequencies of inadequate vitamin D levels (p=0.972). CONCLUSIONS: Lower vitamin D levels were found in infants with CMPA, especially those who were exclusively or predominantly breastfed, making these infants a possible risk group for vitamin D deficiency. PMID- 28628760 TI - Tuberculosis incidence among people living with HIV/AIDS with virological failure of antiretroviral therapy in Salvador, Bahia, Brazil. AB - Antiretroviral therapy for HIV has led to increased survival of HIV-infected patients. However, tuberculosis remains the leading opportunistic infection and cause of death among people living with HIV/AIDS. Tuberculosis has been shown to be a good predictor of virological failure in this group. This study aimed to evaluate the incidence of tuberculosis and its consequences among individuals diagnosed with virological failure of HIV. This was a retrospective cohort study involving people living with HIV/AIDS being followed-up in an AIDS reference center in Salvador, Bahia, Brazil. Individuals older than 18 years with HIV infection on antiretroviral therapy for at least six months, diagnosed with virological failure (HIV-RNA greater than or equal to 1000copies/mL), from January to December 2013 were included. Tuberculosis was diagnosed according to the criteria of the Brazilian Society of Pneumology. Fourteen out of 165 (8.5%) patients developed tuberculosis within two years of follow-up (incidence density=4.1 patient-years). Death was directly related to tuberculosis in 6/14 (42.9%). A high incidence and tuberculosis-related mortality was observed among patients with virological failure. Diagnosis of and prophylaxis for tuberculosis in high-incidence countries such as Brazil is critical to decrease morbidity and mortality in people living with HIV/AIDS. PMID- 28628761 TI - Loss of Function of P2X7 Receptor Scavenger Activity in Aging Mice: A Novel Model for Investigating the Early Pathogenesis of Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7 null mice had thickening of Bruchs membrane and retinal pigment epithelium dysfunction. By 18 months of age, P2X7-null mice displayed phenotypic characteristics consistent with early AMD, including Bruchs membrane thickening, retinal pigment epithelium cell loss, retinal functional deficits, and signs of subretinal inflammation. Our present study shows that loss of function of the P2X7 receptor in mice induces retinal changes representing characteristics of early AMD, providing a valuable model for investigating the role of scavenger receptor function and the immune system in the development of this age-related disease. PMID- 28628762 TI - White matter microstructure in boys with persistent depressive disorder. AB - BACKGROUND: Persistent depressive symptoms in children and adolescents are considered a risk factor for the development of major depressive disorder (MDD) later in life. Previous research has shown alterations in white matter microstructure in pediatric MDD but discrepancies exist as to the specific tracts affected. The current study aimed to improve upon previous methodology and address the question whether previous findings of lower fractional anisotropy (FA) replicate in a sample of children with persistent depressive disorder characterized by mild but more chronic symptoms of depression. METHODS: White matter microstructure was examined in 25 boys with persistent depressive disorder and 25 typically developing children. Tract specific analysis implemented with the Diffusion Tensor Imaging - ToolKit (DTI-TK) was used to probe fractional anisotropy (FA) in eleven major white matter tracts. RESULTS: Clusters within the left uncinate, inferior fronto-occipital and cerebrospinal tracts showed lower FA in the clinical group. FA in the left uncinate showed a negative association with self-reported symptoms of depression. CONCLUSIONS: The results demonstrate lower FA in several white matter tracts in children with persistent depressive disorder. These findings support the contention that early onset depression is associated with altered white matter microstructure, which may contribute to the maintenance and recurrence of symptoms. PMID- 28628763 TI - Patients' perspectives on treatment with Metacognitive Training for Depression (D MCT): Results on acceptability. AB - BACKGROUND: Our understanding of how patients perceive and evaluate treatment for depression is scarce. Because dropout rates are high among individuals in treatment for depression, it is necessary to expand the focus of research to patients' perspectives on the treatment they receive. The aim of the two studies presented was to evaluate patient acceptance of Metacognitive Training for Depression (D-MCT), a highly standardized group intervention. METHODS: Acceptability was evaluated in an open case series (Study 1, N = 70) and a randomized controlled trial (RCT; Study 2, N = 84). In both studies, participants rated their subjective appraisal on a 15-item questionnaire after administration of eight D-MCT modules. In Study 1, a subsample of patients also evaluated modules individually after each session. In Study 2, ratings were compared to an active control intervention (walking and psychoeducation sessions), and assessment was repeated at 6-months follow-up. RESULTS: High rates of acceptance of the D-MCT were demonstrated in both studies immediately after treatment (post assessment). In addition, the RCT showed better evaluations for the D-MCT than for the control condition at post-assessment as well as at 6-months follow-up. Weekly session evaluations in Study 1 indicated good acceptance for individual modules. LIMITATIONS: Evaluations could only be obtained from completers; blinding of patients and therapists was not possible. CONCLUSIONS: Results of the two studies suggest that D-MCT represents a promising group treatment in terms of patient acceptance and provide an example of how patients' feedback may be used to improve treatment. PMID- 28628764 TI - Psychiatric disorders moderate the relationship between insomnia and cognitive problems in military soldiers. AB - BACKGROUND: There has been a great deal of research on the comorbidity of insomnia and psychiatric disorders, but much of the existing data is based on small samples and does not assess the full diagnostic criteria for each disorder. Further, the exact nature of the relationship between these conditions and their impact on cognitive problems are under-researched in military samples. METHOD: Data were collected from the All Army Study of the Army Study to Assess Risk and Resilience in Service members (unweighted N = 21, 449; weighted N = 674,335; 18 61 years; 13.5% female). Participants completed the Brief Insomnia Questionnaire to assess for insomnia disorder and a self-administered version of the Composite International Diagnostic Interview Screening Scales to assess for psychiatric disorders and cognitive problems. RESULTS: Military soldiers with current major depressive episode (MDE) had the highest prevalence of insomnia disorder (INS; 85.0%), followed by current generalized anxiety disorder (GAD; 82.6%) and current posttraumatic stress disorder (PTSD; 69.7%), respectively. Significant interactions were found between insomnia and psychiatric disorders; specifically, MDE, PTSD, and GAD status influenced the relationship between insomnia and memory/concentration problems. LIMITATIONS: Cross-sectional nature of the assessment and the absence of a comprehensive neurocognitive battery. CONCLUSION: Psychiatric disorders moderated the relationship between insomnia and memory/concentration problems, suggesting that psychiatric disorders contribute unique variance to cognitive problems even though they are associated with insomnia disorder. Results highlight the importance of considering both insomnia and psychiatric disorders in the diagnosis and treatment of cognitive deficits in military soldiers. PMID- 28628765 TI - Emotional blunting with antidepressant treatments: A survey among depressed patients. AB - BACKGROUND: Emotional blunting is regularly reported in depressed patients on antidepressant treatment but its actual frequency is poorly understood. We have previously used qualitative methods to develop an appropriate scale, the Oxford Questionnaire on the Emotional Side-Effects of Antidepressants (OQESA). METHODS RESULTS: Six hundred and sixty nine depressed patients on treatment and 150 recovered (formerly depressed) controls (aged >=18 years) participated in this internet-based survey. The rate of emotional blunting in treated depressed patients was 46%, slightly more frequent in men than women (52% versus 44%) and in those with higher Hospital Anxiety and Depression (HAD) scale scores. There was no difference according to antidepressant agent, though it appeared less frequent with bupropion. Depressed patients with emotional blunting had much higher total blunting scores on OQESA than controls (42.83 +/- 14.73 versus 25.73 +/- 15.00, p < 0.0001) and there was a correlation between total blunting score and HAD-Depression score (r = 0.521). Thus, those with HAD-D score >7 (n = 170) had a higher total questionnaire score, 49.23+/-12.03, than those with HAD-D score <=7 (n = 140), 35.07 +/- 13.98, and the difference between the two groups was highly significant. However, patients with HAD-D score <=7 (n = 140) had a higher total score (35.07 +/- 13.98) than the recovered controls (n = 150) (25.73 +/- 15.00), and the difference between the two groups was significant. Among the patients with emotional blunting, 37% had a negative perception of their condition and 38% positive. Men reported a more negative perception than women (p=0.008), and patients with a negative perception were more likely to have higher HAD scores. Higher levels of emotional blunting are associated with a more negative perception of it by the patient (r = -0.423). LIMITATIONS: Include self evaluation and the modest size of the sample for detection of differences between antidepressants. CONCLUSIONS: Emotional blunting is reported by nearly half of depressed patients on antidepressants. It appears to be common to all monoaminergic antidepressants. The OQESA scores are highly correlated with HAD depression score; emotional blunting cannot be described simply as a side-effect of antidepressants, but also as a symptom of depression. A higher degree of emotional blunting is associated with a poorer quality of remission. The OQESA scale allows the detection of this phenomenon. PMID- 28628766 TI - Multimorbidity and depression: A systematic review and meta-analysis. AB - BACKGROUND: Multimorbidity, the presence of two or more chronic conditions, is increasingly common and complicates the assessment and management of depression. The aim was to investigate the relationship between multimorbidity and depression. METHOD: A systematic literature search was conducted using the databases; PsychINFO, Medline, Embase, CINAHL and Cochrane Central. Results were meta-analysed to determine risk for a depressive disorder or depressive symptoms in people with multimorbidity. RESULTS: Forty articles were identified as eligible (n = 381527). The risk for depressive disorder was twice as great for people with multimorbidity compared to those without multimorbidity [RR: 2.13 (95% CI 1.62-2.80) p<0.001] and three times greater for people with multimorbidity compared to those without any chronic physical condition [RR: 2.97 (95% CI 2.06-4.27) p<0.001]. There was a 45% greater odds of having a depressive disorder with each additional chronic condition compared to the odds of having a depressive disorder with no chronic physical condition [OR: 1.45 (95% CI 1.28 1.64) p<0.001]. A significant but weak association was found between the number of chronic conditions and depressive symptoms [r = 0.26 (95% CI 0.18-0.33) p <0.001]. LIMITATIONS: Although valid measures of depression were used in these studies, the majority assessed the presence or absence of multimorbidity by self report measures. CONCLUSIONS: Depression is two to three times more likely in people with multimorbidity compared to people without multimorbidity or those who have no chronic physical condition. Greater knowledge of this risk supports identification and management of depression. PMID- 28628767 TI - Multi-modal neuroimaging of adolescents with non-suicidal self-injury: Amygdala functional connectivity. AB - BACKGROUND: Non-suicidal self-injury (NSSI) is a significant mental health problem among adolescents. Research is needed to clarify the neurobiology of NSSI and identify candidate neurobiological targets for interventions. Based on prior research implicating heightened negative affect and amygdala hyperactivity in NSSI, we pursued a systems approach to characterize amygdala functional connectivity networks during rest (resting-state functional connectivity [RSFC)]) and a task (task functional connectivity [TFC]) in adolescents with NSSI. METHOD: We examined amygdala networks in female adolescents with NSSI and healthy controls (n = 45) using resting-state fMRI and a negative emotion face-matching fMRI task designed to activate the amygdala. Connectivity analyses included amygdala RSFC, amygdala TFC, and psychophysiological interactions (PPI) between amygdala connectivity and task conditions. RESULTS: Compared to healthy controls, adolescents with NSSI showed atypical amygdala-frontal connectivity during rest and task; greater amygdala RSFC in supplementary motor area (SMA) and dorsal anterior cingulate; and differential amygdala-occipital connectivity between rest and task. After correcting for depression symptoms, amygdala-SMA RSFC abnormalities, among others, remained significant. LIMITATIONS: This study's limitations include its cross-sectional design and its absence of a psychiatric control group. CONCLUSIONS: Using a multi-modal approach, we identified widespread amygdala circuitry anomalies in adolescents with NSSI. While deficits in amygdala-frontal connectivity (driven by depression symptoms) replicates prior work in depression, hyperconnectivity between amygdala and SMA (independent of depression symptoms) has not been previously reported. This circuit may represent an important mechanism underlying the link between negative affect and habitual behaviors. These abnormalities may represent intervention targets for adolescents with NSSI. PMID- 28628769 TI - Complex psychotropic polypharmacy in bipolar disorder across varying mood polarities: A prospective cohort study of 2712 inpatients. AB - BACKGROUND: It is common for patients with bipolar disorder (BP) to receive multiple psychotropics, but few studies have assessed demographic and clinical features associated with risk for receiving complex psychotropic polypharmacy. METHODS: This longitudinal cohort study examined 2712 inpatients with a DSM-IV clinical diagnosis of BP to assess associations between complex polypharmacy (defined as >=4 psychotropics) and demographic and clinical features; associations with risk of rehospitalization were also examined. Logistic regressions were performed with the sample as a whole and with each of four DSM IV BP subtypes individually. RESULTS: Complex polypharmacy was present in 21.0%. BP-I depressed patients were more likely to receive complex regimens than BP-I manic, BP-I mixed or BP-II patients. In the sample as a whole, variables significantly associated with complex polypharmacy included female, white, psychotic features and a co-diagnosis of borderline personality, post-traumatic stress or another anxiety disorder. The only examined medication not significantly associated with complex polypharmacy was lithium, although only in BP-I depressed and BP-I mixed. Complex polypharmacy was associated with rehospitalization in BP-I mania within 15 and 30days post index hospitalization. LIMITATIONS: All data were from one clinical facility; results may not generalize to other settings and patient populations. CONCLUSIONS: BP-I depression may pose a greater treatment challenge than the other BP subtypes. Lithium may confer an overall advantage compared to other medications in BP-I depressed and BP-I mixed. Further research is needed to guide pharmacotherapy decisions in BP patients. PMID- 28628768 TI - Internet delivered cognitive behavior therapy for antenatal depression: A randomised controlled trial. AB - : Major depression occurs in 5-10% of pregnancies and is associated with many negative effects for mother and child, yet treatment options are scarce. To our knowledge, this is the first published randomised controlled trial on Internet delivered Cognitive Behavior Therapy (ICBT) for this group. OBJECTIVE: To test the efficacy of a pregnancy adapted version of an existing 10-week ICBT-program for depression as well as assessing acceptability and adherence DESIGN: Randomised controlled trial. SETTING: Online and telephone. POPULATION OR SAMPLE: Self-referred pregnant women (gestational week 10-28 at intake) currently suffering from major depressive disorder. METHODS: 42 pregnant women (gestational week 12-28) with major depression were randomised to either treatment as usual (TAU) provided at their antenatal clinic or to ICBT as an add-on to usual care. MAIN OUTCOME MEASURES: The primary outcome was depressive symptoms measured with the Montgomery-Asberg depression rating scale-self report (MADRS-S). The Edinburgh Postnatal Depression Scale and measures of anxiety and sleep were used. Credibility, satisfaction, adherence and utilization were also assessed. RESULTS: The ICBT group had significantly lower levels of depressive symptoms post treatment (p < 0.001, Hedges g =1.21) and were more likely to be responders (i.e. achieve a statistically reliable improvement) (RR = 0.36; p = 0.004). Measures of treatment credibility, satisfaction, utilization, and adherence were comparable to implemented ICBT for depression. LIMITATIONS: Small sample size and no long term evaluation. CONCLUSION: Pregnancy adapted ICBT for antenatal depression is feasible, acceptable and efficacious. These results need to be replicated in larger trials to validate these promising findings. PMID- 28628770 TI - A comparative analysis between proteasome and immunoproteasome inhibition in cellular and humoral alloimmunity. AB - Triggered by the successful administration of the proteasome inhibitor bortezomib in kidney transplant recipients with acute or chronic antibody-mediated rejection, we evaluated the effect of the proteasome inhibitor CEP-18770 and of the selective immunoproteasome inhibitor ONX-0914 on cellular and humoral alloimmunity. Cellular alloimmunity was assessed by cell proliferation in a two way mixed lymphocyte reaction (MLR) with human peripheral blood mononuclear cells (PBMC). For assessing humoral alloimmunity we developed a method, where humoral alloimmunity was induced in one-way MLR. The de novo production of alloantibodies was measured with an antibody-mediated complement-dependent cytotoxicity assay, in which supernatants from the above MLRs were used against resting PBMC similar to the stimulator cells of the forementioned MLRs. In two-way MLRs ONX-0914 inhibited cell proliferation more than CEP-18770. In one-way MLRs CEP-18770 and ONX-0194 decreased alloantibody production to the same extent. Inhibition of the immunoproteasome is superior to inhibition of the proteasome in suppressing cellular alloimmunity, and equally effective as regards to humoral alloimmunity. Considering the selective expression of the immunoproteasome in immune cells and the expected restrictive toxicity of its inhibitors, these results render immunoproteasome an excellent target for the development of new immunosuppressive medications in the field of transplantation. PMID- 28628771 TI - Lentinan diminishes apoptotic bodies in the ileal crypts associated with S-1 administration. AB - S-1 is an oral agent containing tegafur (a prodrug of 5-fluorouracil) that is used to treat various cancers, but adverse effects are frequent. Two pilot clinical studies have suggested that lentinan (LNT; beta-1,3-glucan) may reduce the incidence of adverse effects caused by S-1 therapy. In this study, we established a murine model for assessment of gastrointestinal toxicity associated with S-1 and studied the effect of LNT. S-1 was administered orally to BALB/c mice at the effective dose (8.3mg/kg, as tegafur equivalent) once daily (5days per week) for 3weeks. Stool consistency and intestinal specimens were examined. We investigated the effect of combined intravenous administration of LNT at 0.1mg, which is an effective dose in murine tumor models. We also investigated the effect of a single administration of S-1. During long-term administration of S-1, some mice had loose stools and an increase in apoptotic bodies was observed in the ileal crypts. An increase in apoptotic bodies was also noted after a single administration of S-1 (15mg/kg). Prior or concomitant administration of LNT inhibited the increase in apoptotic bodies in both settings. Administration of LNT also increased the accumulation of CD11b+TIM-4+ cells in the ileum, while depletion of these cells by liposomal clodronate diminished the inhibitory effect of LNT on S-1 toxicity. Combined administration of LNT with S-1 led to a decrease in apoptotic bodies in the ileal crypts, possibly because LNT promoted phagocytosis of damaged cells by CD11b+TIM-4+ cells. PMID- 28628772 TI - Prognostic impact of proliferation for resected early stage 'pure' invasive lobular breast cancer: Cut-off analysis of Ki67 according to histology and clinical validation. AB - INTRODUCTION: The intent of this analysis was to investigate and validate the prognostic potential of Ki67 in a multi-center series of patients affected by early stage 'pure' invasive lobular carcinoma (ILC). METHODS: Clinical pathological data of patients affected by ILC were correlated with overall survival and disease-free survival (OS/DFS); data from a parallel invasive ductal carcinoma (IDC) patients' cohort were gathered as well. The maximally selected Log-Rank statistics analysis was applied to Ki67 continuous variable to estimate the appropriate cut-off. The Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was performed as well. RESULTS: Data from overall 1097 (457/222 ILC: training/validation set; 418 IDC) patients were gathered. The identified optimal Ki67 cut-offs were 4% and 14% for DFS in ILC and IDC cohort, respectively. In ILC patients, the Ki67 cut-off was an independent OS predictor. Ten-years OS and DFS were 89.9% and 77.2% (p = 0.007) and 79.4% and 69.2% (p = 0.03) for patients with Ki67 <= 4% and >4%, respectively. In IDC patients, 10-years OS was 93.8% and 71.7%, p = 0.02, DFS was 84.0% and 52.6%, p = 0.0003, for patients with Ki67 <= 14% and >14%, respectively. In the validation set, the optimal Ki67 OS cut-off was 5%. The STEPP analysis showed that in the presence of low Ki67 values, IDC patients have a better DFS than ILC patients, while with the increase of values the prognosis tends to overlap. CONCLUSIONS: Despite the retrospective design of the study, the prognostic relevance of Ki67 (as well as its optimal cut-off) seems to significantly differ according to breast cancer histology. PMID- 28628773 TI - Temperament and behavior in toddlers born preterm with related clinical problems. AB - OBJECTIVE: The aim of this study was to compare temperament and behavior profiles among groups of preterm toddlers differentiated by level of prematurity and the presence of bronchopulmonary dysplasia (BPD) or retinopathy of prematurity (ROP), controlling for neonatal clinical conditions and chronological age. METHOD: The sample comprised 100 preterm toddlers segregated according to level of prematurity (75 very preterm and 25 moderate/late preterm) and presence of BPD (n=36) and ROP (n=63). Temperament was assessed by the Early Childhood Behavior Questionnaire and behavior by the Child Behavior Checklist. The MANOVA was performed with a post-hoc univariate test. RESULTS: The level of prematurity and the presence of BPD and ROP did not affect temperament and behavioral problems in toddlers born preterm. However, the covariates age and length of stay in NICU (Neonatal Intensive Care Unit) affected temperament and behavioral problems, respectively. The older toddlers showed higher inhibitory control and lower activity levels than younger toddlers (range of 18-36months-old). Additionally, toddlers who stayed in the NICU longer showed more pervasive development and emotionally reactive problems than toddlers who stayed in NICU for less time. CONCLUSION: The level of prematurity and the presence of bronchopulmonary dysplasia and retinopathy of prematurity did not affect temperament and behavioral problems in toddlers born preterm. However, a longer stay in the NICU increased the risk for behavioral problems, and age enhanced the regulation of temperament at toddlerhood. PMID- 28628774 TI - A segmentation method for myocardial ischemia/infarction applicable in heart photos. AB - The myocardial infarction, known as heart attack, is the ultimate result of a prolonged/untreated cardiac ischemia. The accurate segmentation of the myocardial infarction or ischemia in images obtained from diversified sources, such as Magnetic Resonance Images or Echocardiograph, is worthwhile for the medical area or the animal experimentation. An alternative image source for ischemia/infarction segmentation is the photo, which can depict the actual heart image. This work presents a method for ischemia segmentation in rat heart photos. The method applicability was tested in pictures of human hearts available in public databases from the Internet. At first, heart images were separated from the background using GrabCut method. Secondly, the segmentation of the cardiac ischemia region was performed by using Fuzzy Clustering method. Finally, a sequence of image processing (including morphological operations to remove small components and to fill the holes) was performed to obtain the final segmentation image. All resulting images were compared with the corresponding images containing contours of cardiac ischemia drawn manually by specialists. The mean accuracy was 83.24% +/- 04.16%. As for the intrinsically human errors (tracing error between two specialists: 18.94% +/- 05.30%), the average accuracy is within the inter-operator variability. As for the human heart pictures obtained from public libraries, the algorithm segmented the infarction areas correctly. The results show that the algorithm effectively helps the visualization of the cardiac ischemia/infarction region and has the potential to be applied to heart images of animals or humans, representing a versatile tool to assist advances in cardiomyopathology studies. PMID- 28628775 TI - Developing new PET tracers to image the growth hormone secretagogue receptor 1a (GHS-R1a). AB - INTRODUCTION: 'The growth hormone secretagogue receptor 1a (GHS-R1a) is the orphan G-protein-coupled receptor, and its endogenous ligand is ghrelin. GHS-R1a contributes to regulation of glucose homeostasis, memory and learning, food addiction, and neuroprotection. Several PET tracers for GHS-R1a have been developed, but none have been reported to be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHS-R1a: 18F labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o tolyl)quinazolin-4(3H)-one (1), 11C-labeled 6-(4-chlorophenyl)-3-((1-(2 methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3H)-one (2), and 11C labeled (S)-(4-(1H-indole-6-carbonyl)-3-methylpiperazin-1-yl)(4'-methoxy-[1,1' biphenyl]-4-yl)methanone (3). METHODS: [18F]1 was synthesized by the 18F fluoroethylation; [11C]2 or [11C]3 was synthesized by the 11C-methylation. Biodistribution studies and PET studies were conducted in mice. RESULTS: We successfully radiosynthesized [18F]1, [11C]2, and [11C]3 with appropriate radioactivity for the animal study. In the ex vivo biodistribution study, 60min following injection, the radioactivity level of [18F]1 was relatively high in the small intestine, that of [11C]2 was high in the liver, and that of [11C]3 was high in the pancreas. The radioactivity levels of the three PET tracers were relatively low in the brain. Under pretreatment with YIL781 (a selective and high affinity antagonist for GHS-R1a), the pancreas radioactivity level at 30min following [11C]3 injection was significantly reduced to 55% of control, but the radioactivity in the brain was not changed. In the PET study under control conditions, high radioactivity levels in the liver and pancreas were observed following [11C]3 injection. With YIL781 pretreatment, the accumulated radioactivity in the pancreas 15-60min after [11C]3 injection was significantly decreased to 78% of control. CONCLUSION: [11C]3 exhibited relatively high uptake and in vivo specific binding to GHS-R1a in the mouse pancreas. [11C]3 may be a useful PET tracers for in vivo imaging of GHS-R1a in the pancreas. PMID- 28628776 TI - 3D printed lattices as an activation and expansion platform for T cell therapy. AB - One of the most significant hurdles to the affordable, accessible delivery of cell therapy is the cost and difficulty of expanding cells to clinically relevant numbers. Immunotherapy to prevent autoimmune disease, tolerate organ transplants or target cancer critically relies on the expansion of specialized T cell populations. We have designed 3D-printed cell culture lattices with highly organized micron-scale architectures, functionalized via plasma polymerization to bind monoclonal antibodies that trigger cell proliferation. This 3D technology platform facilitate the expansion of therapeutic human T cell subsets, including regulatory, effector, and cytotoxic T cells while maintaining the correct phenotype. Lentiviral gene delivery to T cells is enhanced in the presence of the lattices. Incorporation of the lattice format into existing cell culture vessels such as the G-Rex system is feasible. This cell expansion platform is user friendly and expedites cell recovery and scale-up, making it ideal for translating T cell therapies from bench to bedside. PMID- 28628777 TI - Effects of adipose stem cell sheets on colon anastomotic leakage in an experimental model: Proof of principle. AB - The most dreaded complication of colorectal surgery is anastomotic leakage. Adipose tissue-derived stem cell sheets (ASC sheets) prepared from temperature responsive culture surfaces can be easily transplanted onto tissues. These sheets are proposed to improve cell transplant efficiency and enhance wound healing. The aim of this study was to investigate whether application of ASC sheets could prevent leakage of sutured colorectal anastomoses. Insufficient suturing of colorectal anastomoses was performed in Wistar rats to create a colorectal anastomotic leakage model. Rats were randomized to ASC sheet application or control group. Leakage, abscess formation, adhesion formation, anastomotic bursting pressure (ABP), and histology were evaluated on postoperative day 3 or 7. ASC sheet application significantly reduced anastomotic leakage compared to controls, without increased adhesion formation. ASC sheet transplantation resulted in more CD3+ T-cells and CD163+ anti-inflammatory macrophages at the anastomotic site than the control group. ABP, vessel density and collagen deposition were not different between groups. Using cell sheet technology, we generated ASC sheets that prevented disruption of sutured colorectal anastomoses as shown by reduced leakage. Increased numbers of anti-inflammatory macrophages and T-cells might have contributed to this positive effect. PMID- 28628778 TI - Effects of incubation time and filtration method on Kd of indigenous selenium and iodine in temperate soils. AB - In this study, the effects of incubation time and the method of soil solution extraction and filtration on the empirical distribution coefficient (Kd) obtained by de-sorbing indigenous selenium (Se) and iodine (I) from arable and woodland soils under temperate conditions were investigated. Incubation time had a significant soil- and element-dependent effect on the Kd values, which tended to decrease with the incubation time. Generally, a four-week period was sufficient for the desorption Kd value to stabilise. Concurrent solubilisation of soil organic matter (OM) and release of organically-bound Se and I was probably responsible for the observed decrease in Kd with time. This contrasts with the conventional view of OM as a sink for Se and I in soils. Selenium and I Kd values were not significantly affected by the method of soil solution extraction and filtration. The results suggest that incubation time is a key criterion when selecting Se and I Kd values from the literature for risk assessments. Values derived from desorption of indigenous soil Se and I might be most appropriate for long-term assessments since they reflect the quasi-equilibrium state of their partitioning in soils. PMID- 28628779 TI - On the presence of plutonium in Madagascar following the SNAP-9A satellite failure. AB - This study examined the 238Pu and 239+240Pu activity concentration and the 240Pu/239Pu atomic ratio in peat bogs sampled in 2012 from marshlands in central Madagascar. The purpose was to investigate the presence of plutonium isotopes, 238, 239, 240Pu, from the 1964 satellite failure carrying a SNAP-9A radiothermal generator. With an average 238Pu/239+240Pu activity ratio of 0.165 +/- 0.02 (decay corrected to 1964), the peat bogs in Madagascar exhibit similar values as the ones found in the southeastern African continent, except they are one order of magnitude higher than expected (0.025) from global fallout in the Southern Hemisphere. The 240Pu/239Pu atomic ratio showed a distinct decrease for layers dating back to the mid-1960s (down to 0.069 compared with an anticipated ratio of 0.17 for global fallout), indicating that the SNAP-9A failure also resulted in an elevated deposition of 239Pu. The obtained results demonstrate that further Pu analysis in Madagascar and in southeastern continental Africa is necessary to fully account for the regional Pu deposition from the SNAP-9A event. PMID- 28628780 TI - BrainAGE score indicates accelerated brain aging in schizophrenia, but not bipolar disorder. AB - BrainAGE (brain age gap estimation) is a novel morphometric parameter providing a univariate score derived from multivariate voxel-wise analyses. It uses a machine learning approach and can be used to analyse deviation from physiological developmental or aging-related trajectories. Using structural MRI data and BrainAGE quantification of acceleration or deceleration of in individual aging, we analysed data from 45 schizophrenia patients, 22 bipolar I disorder patients (mostly with previous psychotic symptoms / episodes), and 70 healthy controls. We found significantly higher BrainAGE scores in schizophrenia, but not bipolar disorder patients. Our findings indicate significantly accelerated brain structural aging in schizophrenia. This suggests, that despite the conceptualisation of schizophrenia as a neurodevelopmental disorder, there might be an additional progressive pathogenic component. PMID- 28628781 TI - Young children have social worries too: Validation of a brief parent report measure of social worries in children aged 4-8 years. AB - This study investigated the psychometric properties of the Social Worries Anxiety Index for Young children (SWAIY), adapted from the Social Worries Questionnaire Parent version (SWQ-P; Spence, 1995), as a measure of social anxiety in young children. 169 parents of children aged four to eight years from a community sample completed the SWAIY and a standardized measure of anxiety; the SWAIY was completed again two weeks later. Parents deemed the items appropriate and relevant to children of this age. The SWAIY demonstrated excellent (>0.80) internal consistency and a one-factor model. Test-retest reliability was strong (r=0.87) and evidence of convergent validity (r>.50) was found. The study provides initial evidence for the validation of SWAIY as a measure of social anxiety in children aged four to eight years old. This questionnaire is ideal for investigating social anxiety over early childhood and the relationship between early social worries and later anxiety disorders. PMID- 28628782 TI - Incorporation of a health economic modelling tool into public health commissioning: Evidence use in a politicised context. AB - This paper explores how commissioners working in an English local government authority (LA) viewed a health economic decision tool for planning services in relation to diabetes. We conducted 15 interviews and 2 focus groups between July 2015 and February 2016, with commissioners (including public health managers, data analysts and council members). Two overlapping themes were identified explaining the obstacles and enablers of using such a tool in commissioning: a) evidence cultures, and b) system interdependency. The former highlighted the diverse evidence cultures present in the LA with politicians influenced by the 'soft' social care agendas affecting their local population and treating local opinion as evidence, whilst public health managers prioritised the scientific view of evidence informed by research. System interdependency further complicated the decision making process by recognizing interlinking with departments and other disease groups. To achieve legitimacy within the commissioning arena health economic modelling needs to function effectively in a highly politicised environment where decisions are made not only on the basis of research evidence, but on grounds of 'soft' data, personal opinion and intelligence. In this context decisions become politicised, with multiple opinions seeking a voice. The way that such decisions are negotiated and which ones establish authority is of importance. We analyse the data using Larson's (1990) discursive field concept to show how the tool becomes an object of research push and pull likely to be used instrumentally by stakeholders to advance specific agendas, not a means of informing complex decisions. In conclusion, LA decision making is underpinned by a transactional business ethic which is a further potential 'pull' mechanism for the incorporation of health economic modelling in local commissioning. PMID- 28628783 TI - Automatic retrieval of shoeprint images using blocked sparse representation. AB - Shoe marks are regarded as remarkable clues which can be usually detected in crime scenes where forensic experts use them for investigating crimes and identifying the criminals. Hence, developing a robust method for matching shoeprints with one another is of critical significance which can be used for recognizing criminals. In this paper, a promising method is proposed for retrieving shoe marks by means of developing blocking sparse representation technique. In the proposed method, the queried image was divided into two blocks. Then, two sparse representations are extracted for each queried image through approximate l1 minimizing method. Also, the referenced database is categorized into two parts and two separate dictionaries are developed via them. Next, using the blocks, the total errors of classes are measured by resetting the coefficients related to other classes into zero. The performance of the proposed method was evaluated via the following methods Wright's sparse representation, extracting shoeprint image local and global features by Fourier transform, extracting shoeprint image features by Gabor transform after the image is rotated and extracting the corners of shoeprint image by Hessian and Harris' multi-scale detectors and SIFT descriptors. Accurate detection score was obtained in terms of the ratio of the number of accurately detected images to the total test images. The results of simulations indicated that the proposed method was highly effective and efficient in retrieving shoe marks, whole shoeprints, partial toe and heel shoeprints. Furthermore, it was found that the proposed method had better performance than the other methods with which it was compared. Accurate identification rate according to cumulative match score for the first n matches was measured. That is to say, the proposed method accurately recognized 99.47% of whole shoeprints, 80.53% of partial toe shoeprints and 79.47% of partial heel shoeprints in the first rank. Also, the proposed method was compared with the other methods in terms of rotation and scale distortions. The results indicated that the proposed method was resistant to these distortions. PMID- 28628785 TI - Looking at a contrast object before speaking boosts referential informativeness, but is not essential. AB - Variation in referential form has traditionally been accounted for by theoretical frameworks focusing on linguistic and discourse features. Despite the explosion of interest in eye tracking methods in psycholinguistics, the role of visual scanning behaviour in informative reference production is yet to be comprehensively investigated. Here we examine the relationship between speakers' fixations to relevant referents and the form of the referring expressions they produce. Overall, speakers were fully informative across simple and (to a lesser extent) more complex displays, providing appropriately modified referring expressions to enable their addressee to locate the target object. Analysis of contrast fixations revealed that looking at a contrast object boosts but is not essential for full informativeness. Contrast fixations which take place immediately before speaking provide the greatest boost. Informative referring expressions were also associated with later speech onsets than underinformative ones. Based on the finding that fixations during speech planning facilitate but do not fully predict informative referring, direct visual scanning is ruled out as a prerequisite for informativeness. Instead, pragmatic expectations of informativeness may play a more important role. Results are consistent with a goal-based link between eye movements and language processing, here applied for the first time to production processes. PMID- 28628784 TI - Identifying populations sensitive to environmental chemicals by simulating toxicokinetic variability. AB - The thousands of chemicals present in the environment (USGAO, 2013) must be triaged to identify priority chemicals for human health risk research. Most chemicals have little of the toxicokinetic (TK) data that are necessary for relating exposures to tissue concentrations that are believed to be toxic. Ongoing efforts have collected limited, in vitro TK data for a few hundred chemicals. These data have been combined with biomonitoring data to estimate an approximate margin between potential hazard and exposure. The most "at risk" 95th percentile of adults have been identified from simulated populations that are generated either using standard "average" adult human parameters or very specific cohorts such as Northern Europeans. To better reflect the modern U.S. population, we developed a population simulation using physiologies based on distributions of demographic and anthropometric quantities from the most recent U.S. Centers for Disease Control and Prevention National Health and Nutrition Examination Survey (NHANES) data. This allowed incorporation of inter-individual variability, including variability across relevant demographic subgroups. Variability was analyzed with a Monte Carlo approach that accounted for the correlation structure in physiological parameters. To identify portions of the U.S. population that are more at risk for specific chemicals, physiologic variability was incorporated within an open-source high-throughput (HT) TK modeling framework. We prioritized 50 chemicals based on estimates of both potential hazard and exposure. Potential hazard was estimated from in vitro HT screening assays (i.e., the Tox21 and ToxCast programs). Bioactive in vitro concentrations were extrapolated to doses that produce equivalent concentrations in body tissues using a reverse dosimetry approach in which generic TK models are parameterized with: 1) chemical-specific parameters derived from in vitro measurements and predicted from chemical structure; and 2) with physiological parameters for a virtual population. For risk-based prioritization of chemicals, predicted bioactive equivalent doses were compared to demographic-specific inferences of exposure rates that were based on NHANES urinary analyte biomonitoring data. The inclusion of NHANES-derived inter individual variability decreased predicted bioactive equivalent doses by 12% on average for the total population when compared to previous methods. However, for some combinations of chemical and demographic groups the margin was reduced by as much as three quarters. This TK modeling framework allows targeted risk prioritization of chemicals for demographic groups of interest, including potentially sensitive life stages and subpopulations. PMID- 28628786 TI - BTEX- and naphthalene-degrading bacterium Microbacterium esteraromaticum strain SBS1-7 isolated from estuarine sediment. AB - In this study, a non-pathogenic, BTEX-degrading Microbacterium esteraromaticum SBS1-7 was isolated from estuarine sediment in Thailand via an enrichment technique. M. esteraromaticum SBS1-7 was able to degrade all six BTEX components, in both liquid medium and soil slurry system, when BTEX was supplied as an individual component or a mixture. It exhibited a high level of tolerance towards a wide range of hydrocarbons and also utilized alkanes and naphthalene. Detection of metabolites produced during BTEX and naphthalene degradation revealed highly extensive biodegradation pathways used by M. esteraromaticum SBS1-7. Toluene was metabolized via activities of both monooxygenase (toluene 4-monooxygenase or T4MO) and dioxygenases (toluene dioxygenase or TDO and naphthalene 1,2 dioxygenase or NDO). Benzene was metabolized via phenol, possibly by an activity of T4MO. Ethylbenzene was converted into styrene and 1-phenethyl alcohol by a well-documented activity of NDO. Dioxidation of ethylbenzene, possibly by ethylbenzene dioxygenase or EBDO, was also found. All xylene isomers were converted into their corresponding alcohols via an activity of NDO while naphthalene was metabolized via dioxidation reaction by the same enzyme. This study is, by far, the first direct evidence of BTEX biodegradation by a non pathogenic, rhizosphere bacterium M. esteraromaticum. PMID- 28628787 TI - Biological welfare and the commons: A natural experiment in the Alps, 1765-1845. AB - In the late 18th century hundreds self-governing alpine communities in Northern Italy came under the direct control of centralized states (Austria and France) at different times. We exploit the timing and location of these interventions in a DD type design to investigate the effects of removing CPR institutions on biological welfare. We find a significant and persistent increase in infant mortality rates and a more modest decrease in birth rates as a result of state centralization. We provide evidence that these demographic changes reflect a critical loss of natural resource income caused by the disruption of communal institutions. Impacts are most severe in communities that have no prior experience with formal institutions. PMID- 28628788 TI - Cryo-EM structures of human gamma-secretase. AB - gamma-secretase, a membrane-embedded aspartate protease, catalyzes peptide bond hydrolysis of a large variety of type I integral membrane proteins exemplified by amyloid precursor protein (APP). Cleavage of APP leads to formation of beta amyloid plaque, which is a hallmark of Alzheimer's disease (AD). Over 200 AD associated mutations are mapped to presenilin 1 (PS1), the catalytic component of gamma-secretase. In the past three years, several cryo-electron microscopy (cryo EM) structures of human gamma-secretase have been determined at near atomic resolutions. Here we summarize the methods involved and discuss structural features of gamma-secretase and the associated functional insights. PMID- 28628789 TI - Challenges and opportunities in the high-resolution cryo-EM visualization of microtubules and their binding partners. AB - As non-crystallizable polymers, microtubules have been the target of cryo electron microscopy (cryo-EM) studies since the technique was first established. Over the years, image processing strategies have been developed that take care of the unique, pseudo-helical symmetry of the microtubule. With recent progress in data quality and data processing, cryo-EM reconstructions are now reaching resolutions that allow the generation of atomic models of microtubules and the factors that bind them. These include cellular partners that contribute to microtubule cellular functions, or small ligands that interfere with those functions in the treatment of cancer. The stage is set to generate a family portrait for all identified microtubule interacting proteins and to use cryo-EM as a drug development tool in the targeting of tubulin. PMID- 28628790 TI - Associated illness severity in schizophrenia and diabetes mellitus: A systematic review. AB - OBJECTIVE: We aimed to elucidate whether schizophrenia and type II diabetes mellitus may present with associated illness severity, in light of accumulating evidence to suggest both conditions have important shared inflammatory components with many shared inflammatory genetic factors. METHODS: We conducted a systematic review employing PRISMA criteria, searching EMBASE, Ovid MEDLINE, PsychInfo, Web of Science and Google Scholar to February 1st, 2017, for clinical studies assessing schizophrenia severity alongside dysglycaemia. A narrative synthesis was employed to discuss and compare findings between studies. RESULTS: Eleven observational studies were included in the analysis. Ten presented evidence in support of an association between schizophrenia severity and dysglycaemia. This association appeared particularly strong regarding negative symptomatology and impaired cognitive function, between which there may be some overlap. Studies examining positive symptomatology returned mixed results. CONCLUSION: Whilst study design varied amongst the included studies, the results suggest that further work examining the effect of hyperglycaemia on schizophrenia severity may be relevant, particularly longitudinal studies assessing negative symptomatology and cognitive function. To the authors' knowledge, this is the first systematic review conducted to address this question. PMID- 28628791 TI - Recent life events and psychosis: The role of childhood adversities. AB - Life events are commonly reported to be related to psychosis. However, less attention has been given to the role that recent events play on psychosis, in relation to exposure to childhood adversity. The current study aimed to evaluate the relationship between recent events and psychosis, taking into account the role of early adversities. 78 psychotic patients and 156 controls were enrolled. Childhood adversity was evaluated using a validated semi-structured interview and the Childhood Experience of Care and Abuse Questionnaire. Recent events were recorded using a semi-structured interview with a normative and contextual approach. The diagnosis of psychosis was made according to Jablenski's criteria. Chi-square, t-test, odds ratio, and binary logistic regression statistical analyses were performed. Psychotic patients reported an excess of recent events. The occurrence of more than one recent event increased the risk of psychosis; there was a cumulative effect between recent and childhood events on psychosis. Recent events were significantly related to psychosis, even in the absence of childhood adversity or when adjusted for it. Our findings suggested that the effect of recent events on psychosis may be amplified by previous exposure to early adversity. Recent events alone, could be also linked to psychosis independently of childhood adversity. PMID- 28628792 TI - Sleep disturbances as predictors of prolonged exposure therapy effectiveness among veterans with PTSD. AB - Sleep disturbances (SD) are pronounced in Veterans with posttraumatic stress disorder (PTSD). In clinical trials, SD have been shown to limit the effectiveness of evidence-based treatments for non-PTSD disorders. The purpose of this study was to investigate the relationships between pretreatment SD and the effectiveness of Prolonged Exposure (PE) therapy for Veterans with PTSD. Twenty one Veterans completed the Pittsburgh Sleep Quality Index (PSQI) and the Clinician Administered PTSD Scale upon presenting to a PTSD specialty clinic. Veterans completed the PTSD Symptom Checklist-Civilian (PCL-C) at the initiation of PE and biweekly thereafter for the duration of treatment (96 total assessments). Correlations and hierarchical linear modeling were utilized to examine the potential impact of baseline sleep variables on the slope and magnitude of treatment outcomes. Higher PSQI total scores, and higher sleep latency and sleep medication use subscale scores were associated with higher PCL C scores at baseline. Veterans evidenced significant reductions in PTSD symptoms during the course of the treatment study. Total PSQI scores and composites were not associated with reduced effectiveness of PE treatment or the slope of PTSD symptom changes. Sleep disturbances do not preclude Veterans from benefits derived from engagement in this gold standard PTSD intervention. PMID- 28628793 TI - The reliability, concurrent validity and association with salivary oxytocin of the self-report version of the Inventory of Callous-Unemotional Traits in adolescents with conduct disorder. AB - The present study evaluated the self-report version of the Inventory of Callous Unemotional Traits (ICU-SR) in terms of reliability, concurrent validity, and correlation with salivary oxytocin levels, a potential biomarker of CU traits. 67 socially at-risk male adolescents (mean 16.2 years) completed the ICU-SR, ICU teacher-version (ICU-TR), Strengths and Difficulties Questionnaire, and their medical files were coded for previous antisocial acts using Brown-Goodwin Lifetime Aggression Scale. Salivary samples were assayed for oxytocin. The reliability of ICU-SR was lower (alpha = 0.71) than ICU-TR (alpha = 0.86). ICU-SR mean score was significantly lower than ICU-TR (M = 25.29, SD = 8.02; M = 33.14, SD = 9.47). ICU-TR but not ICU-SR, significantly correlated with history of antisocial acts (r = 0.40). Two-way analysis of variance showed a significant effect of conduct disorder and oxytocin on ICU-TR but not ICU-SR [F(1,59) = 6.53; F(1,59) = 6.08], and a significant interaction only for ICU-TR [F(1,59) = 2.89]. Subjective self-reports of CU traits may be less reliable and valid than teachers' reports. PMID- 28628794 TI - Neurological soft signs, but not theory of mind and emotion recognition deficit distinguished children with ADHD from healthy control. AB - Attention Deficit Hyperactivity Disorder (ADHD) is associated with social cognition impairment, executive dysfunction and motor abnormalities, consisting in the persistence of neurological soft signs (NSS). Theory of mind (ToM) and emotion recognition (ER) deficit of children with ADHD have been interpreted as a consequence of their executive dysfunction, particularly inhibitory control deficit. To our knowledge, there are not studies that evaluate the possible correlation between the ToM and ER deficit and NSS in the population with ADHD, while this association has been studied in other psychiatric disorders, such as schizophrenia. Therefore, the aim of this study was to evaluate ToM and ER and NSS in a sample of 23 drug-naive children with ADHD and a sample of 20 healthy children and the possible correlation between social cognition dysfunction and NSS in ADHD. Our findings suggest that ToM and ER dysfunction is not a constant feature in the population with ADHD, while NSS confirmed as a markers of atypical neurodevelopment and predictors of the severity of functional impairment in children with ADHD. PMID- 28628796 TI - Evaluation of Cd, Cr, Cu, Ni, and Pb in selected cosmetic products from Jordanian, Sudanese, and Syrian markets. AB - OBJECTIVES: There is no sufficient data that evaluate heavy metal content in cosmetic products in Jordan as well as Sudan and Syria. This study aims to assess metal levels which include Cadmium (Cd), Chromium (Cr), Copper (Cu), Nickel (Ni), and Lead (Pb) in cosmetic products. These elements have draft limits because they are identified as potential impurities and are known to be toxic. This study aims to provide information to the population that may be beneficial to public health. STUDY DESIGN: Samples were collected from different brands obtained from markets in Jordan, Sudan, and Syria. Some of the selected cosmetic products were eyeliner, eye pencil, mascara, lipstick, powder, face cream, body cream, sun block, Vaseline, and the traditional eye cosmetic (kohl). The heavy metal content in these samples were determined by atomic absorption spectrometry (AAS). Based on analysis of variance analysis, a significant difference in heavy metal levels was found for samples obtained from Jordanian and Sudanese markets. METHODS: The acid digestion method used in this study was based on procedures recommended by Nnorom et al. with some modifications as follows. (i) A weight of 2.0 g of cosmetic sample was dissolved in a mixture of 6 mL of high quality concentrated 69% nitric acid (HNO3; Merck, Darmstadt, Germany) and 4 mL of concentrated 37% hydrochloric acid (Scharlau, Spain) in a porcelain crucible and heated on a hotplate to near dryness. (ii) An aliquot of 15 mL HNO3 (1.00 M) was added to the digested sample and filtered through a Whatman No. 40 filter paper. (iii) The digested sample was transferred quantitatively into a 25 mL volumetric flask and then diluted with deionized water. (iv) Each digested sample was evaporated at 70 degrees C to about 1 mL and transferred into a polyethylene flask and diluted with 25 mL deionized water. (v) Blank was treated in the same procedure. RESULTS: In Jordan the concentration ranges of heavy metals in the collected samples were: Cd (0.03-0.10 MUg/g), Cr (0.0-1.00 MUg/g), Cu (0.60-7.40 MUg/g), Ni (0.50-3.60 MUg/g), and Pb (0.30-15.4 MUg/g). Whereas, in Sudanese market the concentration ranges were: Cd (0.01-0.15 MUg/g), Cr (0.00-27.9 MUg/g), Cu (0.60-10.10 MUg/g), Ni (0.00-5.70 MUg/g), and Pb (0.02-3.80 MUg/g). Also, the concentration ranges of heavy metals in Syrian market were: Cd (0.04-0.056 MUg/g), Cr (0.24-0.83 MUg/g), Cu (0.61-1.27 MUg/g), Ni (0.73-1.41 MUg/g), and Pb (4.85-27.70 MUg/g). Results revealed that kohl samples have the highest concentration of most of the studied metals, particularly Pb. CONCLUSIONS: Based on the results obtained, it is likely to conclude the following: (i) It is not possible to completely eliminate the presence of heavy metals from cosmetic products after manufacturing. However, the quality of the products can be improved by careful selection of raw materials, taking in consideration heavy metal levels. (ii) Heavy metal concentration in lipstick differs with different manufacturers' colors and shade. Statistically significant associations between Pb level and the cosmetic type were found. (iii) Heavy metals levels including Cd, Cr, Cu, Ni, and Pb may impose risk in daily use and repeated application as well as in ingestion through the mouth even at concentration below the allowed limits. (iv) It is the manufacturers' responsibility to ensure that the finished cosmetic product contains the lowest levels possible of heavy metals. So it does not exceed the limits set by health authorities. PMID- 28628797 TI - Attenuated error-related potentials in amyotrophic lateral sclerosis with executive dysfunctions. AB - OBJECTIVE: Executive dysfunctions affect up to 50% of the patients with amyotrophic lateral sclerosis (ALS). Executive dysfunctions have been identified as negative prognostic factor and can affect quality of life in patients and their caregivers. Assessment of executive dysfunction may be impeded by the patients' motor impairments. Event-related potentials (ERP) have been proposed as a tool to overcome these assessment difficulties. The error(-related) negativity (Ne/ERN) is an ERP which can be recorded with minimal motor requirements for the patient. METHODS: We compared response-synchronized ERP amplitudes of 18 ALS patients and 19 healthy controls (HC) obtained on error trials on a flanker task. We also evaluated the relation between Ne/ERN amplitudes and executive functions as assessed by standardized neuropsychological measures. RESULTS: While response synchronized ERP amplitudes were generally unaffected by ALS, we found an ALS associated relation between Ne/ERN amplitudes and executive functions. ALS patients with poorer executive functioning showed attenuated Ne/ERN amplitudes. CONCLUSIONS: Our data suggest that Ne/ERN amplitudes reflect ALS-associated impairment of executive functions, potentially due to disturbances in neural networks that involve the anterior cingulate cortex. SIGNIFICANCE: Assessment of Ne/ERN amplitudes might provide a cost-efficient and non-invasive marker for executive dysfunction in ALS. PMID- 28628795 TI - Knockout of the Nogo-B Gene Attenuates Tumor Growth and Metastasis in Hepatocellular Carcinoma. AB - Human hepatocellular carcinoma (HCC) is a malignant cancer. It is a challenge to develop anti-HCC drugs due to HCC's extreme aggressiveness and with the sensitivity of the liver to show severe adverse effects. More importantly, the precise mechanisms causing HCC pathogenicity are not known. Our previous study disclosed Nogo-B as a reticulon 4 (Rtn4) family member. In the present study, we first identified that Nogo-B played a critical role in HCC progression. We found, via in vitro and in vivo assays, that Nogo-B was expressed aberrantly in primary HCC tumor tissues and immortal HCC cells but was relatively scarce in the normal liver tissues or cells. Nogo-B knockout, via the CRISPR-Cas9 technique, resulted in significant suppression of HCC cell proliferation and tumor growth. Next generation sequencing analysis showed that Nogo-B knockout have effects on interleukin-6 (IL-6) signaling pathway. Furthermore, we observed that IL-6 induced phosphorylation of STAT3 (pSTAT3) in wild-type HCC cells, but Nogo-B knockout could reduce IL-6-induced increase of pSTAT3, supporting that Nogo-B affects HCC tumor progression possibly via regulating the IL-6/STAT3 signaling pathway. In conclusion, Nogo-B is expressed aberrantly in HCCs and plays an oncogenic role. These findings support that Nogo-B may be a novel anti-HCC therapeutic target. PMID- 28628798 TI - Maternal liver docosahexaenoic acid (DHA) stores are increased via higher serum unesterified DHA uptake in pregnant long Evans rats. AB - Maternal docosahexaenoic acid (DHA, 22:6n-3) supplies the developing fetus during pregnancy; however, the mechanisms are unclear. We utilized pregnant rats to determine rates of DHA accretion, tissue unesterified DHA uptake and whole-body DHA synthesis-secretion. Female rats maintained on a DHA-free, 2% alpha-linolenic acid diet were either:1) sacrificed at 56 days for baseline measures, 2) mated and sacrificed at 14-18 days of pregnancy or 3) or sacrificed at 14-18 days as age-matched virgin controls. Maternal brain, adipose, liver and whole body fatty acid concentrations was determined for balance analysis, and kinetic modeling was used to determine brain and liver plasma unesterified DHA uptake and whole-body DHA synthesis-secretion rates. Total liver DHA was significantly higher in pregnant (95+/-5 MUmol) versus non-pregnant (49+/-5) rats with no differences in whole-body DHA synthesis-secretion rates. However, liver uptake of plasma unesterified DHA was 3.8-fold higher in pregnant animals compared to non-pregnant controls, and periuterine adipose DHA was lower in pregnant (0.89+/-0.09 MUmol/g) versus non-pregnant (1.26+/-0.06) rats. In conclusion, higher liver DHA accretion during pregnancy appears to be driven by higher unesterified DHA uptake, potentially via DHA mobilization from periuterine adipose for delivery to the fetus during the brain growth spurt. PMID- 28628799 TI - A novel 2-stage approach that detects complement activation in patients with antiphospholipid antibody syndrome. AB - INTRODUCTION: The antiphospholipid syndrome (APS) is marked by autoantibodies that recognize anionic phospholipids in a cofactor-dependent manner. A role for complement has been implicated in the pathophysiology, however, elevations of complement activation markers have not been consistently demonstrated in clinical studies. We therefore designed a proof-of-principle study to determine whether complement activation might be detectable in APS by first exposing plasmas to phospholipid vesicles. METHODS: We examined complement activation markers in patients with APS, non-APS thrombosis, systemic lupus erythematosus, cancer, patients with antiphospholipid antibodies without thrombosis (APL) and healthy controls. Direct measurements of plasma C5a and sC5b-9 levels were compared to levels that were generated in normal serum by phospholipid vesicles that had been pre-incubated with the same plasmas. We then determined the effects of the C5 inhibitor, eculizumab, examined the complement pathways involved, and determined whether the effects could be reproduced with purified IgGs and beta2-glycoprotein I (beta2GPI). RESULTS: Plasma levels of C5a and sC5b-9 were higher, but not significantly increased in APS patients compared to healthy controls. In contrast, phospholipid vesicles pre-incubated with APS plasmas generated significantly higher levels than healthy controls and the other groups, except for APL patients. Complement activation was abrogated by addition of eculizumab. The results with substrate sera indicated that the alternative and classical/lectin pathways were involved. The results were reproducible with purified IgGs and beta2GPI. CONCLUSION: This proof-of-principle study confirms a role for complement in APS and opens the possibility of monitoring complement activation by including phospholipid vesicles in assay systems. PMID- 28628800 TI - Increased internal femoral torsion can be regarded as a risk factor for patellar instability - A biomechanical study. AB - BACKGROUND: Increased internal femoral torsion is regarded as a risk factor for patellar instability. Biomechanical investigations confirming this hypothesis are missing. METHODS: Eight fresh-frozen cadaver knees were tested on a specially designed simulator. Patellar motion and patellofemoral pressure were evaluated for 0 degrees , 10 degrees , and 20 degrees of increased internal and external femoral torsion with native and with transected medial patellofemoral ligaments used to simulate patellar instability. A regression analysis was used for statistical analysis. FINDINGS: In native medial patellofemoral ligaments, there were no significant changes in mean or peak pressures for any torsional states (P>=0.07). At 20 degrees increased internal femoral torsion, there was a significant center of force shift towards the lateral side (P=0.01). Patellar shift was directed laterally at low knee flexion angles up to 30 degrees . Lateral patellar tilt increased significantly at 10 degrees and 20 degrees of increased internal femoral torsion (P<=0.004). In transected medial patellofemoral ligaments, mean pressure (P<=0.005) and peak pressure (P<=0.02) decreased significantly for all torsional states. There was a significantly greater lateral center of force shift with increased internal femoral torsion (P<=0.04). Lateral patellar tilt increased significantly (P<0.001). Patellar shift did not change significantly with increased internal femoral torsion (P>=0.30). INTERPRETATION: In a native medial patellofemoral ligament, 20 degrees of increased internal femoral torsion can be regarded as a significant risk factor for patellar instability. With an insufficient medial patellofemoral ligament, 10 degrees of increased internal femoral torsion already represents a significant risk factor. PMID- 28628801 TI - Evaluation of midcarpal capitate contact mechanics in normal, injured and post operative wrists. AB - BACKGROUND: Scapholunate ligament injury is a commonly occurring carpal ligament injury. Pathology associated with scapholunate ligament injury depends on several factors such as the time after injury, type of injury (instability) and the development of osteoarthritis. The aim of this study was to investigate and compare contact mechanics in the lunocapitate and scaphocapitate joints in the normal, injured (scapholunate dissociation) and repaired (postoperative) wrist. METHODS: Four human subjects with scapholunate ligament dissociation participated in this study. MR images of normal (contralateral), injured and postoperative wrists were obtained during relaxed condition and during active light grasp. Relaxed MR images were used to construct model geometry (bones with cartilage) for the capitate, lunate and scaphoid. Kinematic transformations were obtained by using image registration between the unloaded and functionally loaded image sets. Joint surface contact mechanics were then calculated. FINDINGS: All contact measures (contact force, pressure, mean pressure and area) tended to increase with injury in both articulations. A significantly higher contact area was found in the injured scaphocapitate joint compared to normal. A significant increase in peak pressure was observed in the postoperative state compared to normal. INTERPRETATION: Injury to the scapholunate ligament increased contact measures, suggesting a risk for onset of osteoarthritis in both the scaphocapitate and lunocapitate joints. Surgical repair appeared to restore most measures of contact mechanics to near normal values, more so for the lunocapitate joint when compared to scaphocapitate joint. The elevated postoperative peak pressures indicate the difficulty to fully restore joint mechanics. PMID- 28628802 TI - Metabolic control and periodontal treatment decreases elevated oxidative stress in the early phases of type 1 diabetes onset. AB - OBJECTIVE: Recently, increasing concern has been focused on the contribution of oxidative stress in the pathology of periodontal disease and diabetes mellitus. Firstly, the present study aimed to analyze gingival crevicular fluid (GCF), salivary, and serum oxidative status in children with type 1 diabetes mellitus (T1DM) at diagnosis and systemically healthy children with and without gingivitis. Additionally, the diabetic patients were reevaluated after diabetes and periodontal treatment. DESIGN: The study groups were composed of 32 T1DM patients at diagnosis, and age- and gender-matched thirty-six systemically healthy children with (G) and without (H) gingivitis. The diabetic patients who took insulin therapy (1.5 units/kg/day totally) and periodontal treatment (oral hygiene education with professional scaling) were reevaluated after 3 months. The levels of total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were recorded. RESULTS: GCF, salivary, and serum OSI were elevated in group T1DM compared to the other groups at baseline (p<0.05), and decreased in group T1DM at reevaluation compared to baseline (p<0.05). GCF OSI was positively correlated with periodontal clinical parameters (p<0.05). Glycated hemoglobin was positively correlated with GCF TOS (r=0.302, p=0.007), GCF OSI (r=0.346, p=0.002), salivary TOS (r=0.326, p=0.046), and serum TOS (r=0.239, p=0.044). CONCLUSION: The instability in the oxidative status that accompanies diabetes may be considered a significant pathogenic factor of diabetes-related periodontal inflammation. PMID- 28628803 TI - Mucoepidermoid carcinoma-associated expression of MUC5AC, MUC5B and mucin-type carbohydrate antigen sialyl-Tn in the parotid gland. AB - OBJECTIVES: The aberrant expression of mucins and mucin-type carbohydrates has been described in many types of cancer, including mucoepidermoid carcinoma (MEC), a malignant salivary gland tumor. In this study, we examined the aberrant expression patterns of mucins (MUC1, MUC4, MUC5AC and MUC5B), simple mucin-type carbohydrate antigens (Tn, sialyl-Tn and T) and mature carbohydrate antigens (Lewisa and sulfo-Lewisa antigens) in MEC originating from the parotid gland, which normally does not secrete mucins. DESIGN: We conducted an immunohistochemical study to investigate the presence of mucins and carbohydrates in 24 MEC samples originating from the parotid gland and in surrounding normal tissue of the same gland in comparison 6 samples of normal salivary glands. The expression levels were compared with respect to the histological grading. Furthermore, 24 MEC samples from non-parotid salivary glands were included. RESULTS: We observed loss of topology of membrane-bound MUC1 and MUC4, and de novo expression of MUC5AC, MUC5B and sialyl-Tn in MEC that originated in the parotid gland. Furthermore, mucins MUC1, MUC4 and carbohydrate antigens Tn, sialyl-Tn, T, Lewisa and sulfo-Lewisa were overexpressed in MEC samples compared to surrounding normal salivary gland tissues. MUC1 was expressed in both low- and high grade MECs, whereas MUC4 was not expressed in high grade MECs of the parotid gland. CONCLUSION: During the development of MEC in the parotid gland, the genes for gel-forming secretory mucins are switched on. Besides these MEC tissues overexpress short oligosaccharides, suggesting that the glycosylation machinery is altered. PMID- 28628805 TI - Erratum to 'Adverse events in a chiropractic spinal manipulative therapy single blinded, placebo, randomized controlled trial for migraineurs' [Musculoskeletal. Ther. and Pract. 29C (2017) 66-71]. PMID- 28628804 TI - Neuronal substrates of sleep homeostasis; lessons from flies, rats and mice. AB - Sleep homeostasis is a fundamental property of vigilance state regulation that is highly conserved across species. Neuronal systems and circuits that underlie sleep homeostasis are not well understood. In Drosophila, a neuronal circuit involving neurons in the ellipsoid body and in the dorsal Fan-shaped body is a candidate for both tracing sleep need during waking and translating it to increased sleep drive and expression. Sleep homeostasis in rats and mice involves multiple neuromodulators acting on multiple wake- and sleep-promoting neuronal systems. A functional central homeostat emerges from A1 receptor mediated actions of adenosine on wake-promoting neurons in the basal forebrain and hypothalamus, and A2A adenosine receptor-mediated actions on sleep-promoting neurons in the preoptic hypothalamus and nucleus accumbens. PMID- 28628806 TI - Resilience and spirituality in patients with depression and their family members: A cross-sectional study. AB - OBJECTIVE: The degree and quality of resilience in patients with depression have never been investigated in the context of remission status, spirituality/religiosity, and family members' resilience levels, which was addressed in this study. METHODS: This cross-sectional study recruited Japanese outpatients with depressive disorder according to ICD-10 and cohabitant family members who were free from psychiatric diagnoses. Resilience was assessed using the 25-item Resilience Scale (RS). Other assessments included the Montgomery Asberg Depression Rating Scale (MADRS); the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT) and Kasen et al.'s (2012) scale for spirituality/religiosity; and the Rosenberg Self-Esteem Scale (RSES). RESULTS: One hundred outpatients with depression (mean+/-SD age, 50.8+/ 14.5years; 44 men; MADRS total score 9.8+/-9.0) and 36 healthy family members (mean+/-SD age, 56.5+/-15.0years; 18 men) were included. Symptom severity, attendance at religious/spiritual services, and self-esteem were significantly associated with RS scores in the patient group. RS total scores were significantly higher in remitted patients compared to non-remitted patients (mean+/-SD, 112.3+/-17.1 vs. 84.8+/-27.7, p<0.001). No correlation was found in RS total scores between patients and their family members (p=0.265), regardless of patients' remission status. CONCLUSIONS: Resilience may be influenced by individual characteristics rather than familial environment; furthermore, self esteem or spirituality/religiosity may represent reinforcing elements. While caution is necessary in extrapolating these findings to other patient populations, our results suggest that resilience may be considered a state marker in depression. PMID- 28628807 TI - The role of family financial socialization and financial management skills on youth saving behavior. PMID- 28628808 TI - Quantitative image analysis of the shape and size of circular wound sites generated by vertically stamped scratches. AB - A protocol for quantitative image analysis of wound generation is important to better understand the integrative process of wound healing and the closure mechanism. Here, we present a method for quantitative analysis of microscopic images of circular wound sites generated by vertically stamped scratches. To demonstrate proof-of-concept validation, we used two types of mechanical stamping tools, a mechanical pencil lead (type 1; brittle) and polydimethylsiloxane (PDMS) pillars (type 2; ductile), to create circular wound sites. We also present a method for analysis of microscopic images of the generated wound sites by suggesting new parameters, such as controlled area transfer ratio, modified shape factor, and roundness index, specifically to investigate the shape and size of wounds via house-coded image processing. We believe that this approach can be potentially useful by providing a better way of studying vertical wound generation for future skin wound generation and care applications compared with its counterpart, conventional horizontal wound generation. PMID- 28628809 TI - Distrust of the senses and its association with obsessive-compulsive symptoms. AB - BACKGROUND AND OBJECTIVES: Leading cognitive theories of OCD suggests that despite prevalent and persistent doubt, individuals with OCD do not have perceptual deficits. An alternate cognitive theory, the Seeking Proxies for Internal States hypothesis (SPIS), proposes that sensory distrust in OCD stems from actual deficits in accessing internal states. Consistent with the SPIS, previous research has found that high-OC individuals were less accurate than low OC individuals in producing target levels of muscle tension in a biofeedback task and that OC symptoms were positively associated with reliance on an external proxy. METHODS: The current study aimed to replicate and extend the SPIS hypothesis in two experiments using a modified version of the biofeedback-aided muscle tensing task using grip strength as the sensory input and a distance perception task. We contrasted the performance of undergraduate students self reporting high- and low-OC symptoms. RESULTS: Overall, our findings failed to substantially support the SPIS hypothesis such that OC symptoms were not associated with deficient access to internal states of grip strength and distance perception or increased reliance on feedback. LIMITATIONS: As this study was conducted in a non-clinical sample, we were unable to generalise our findings to a clinical population. CONCLUSIONS: Findings are commensurate with the wider OCD literature suggesting the absence of cognitive and perceptual deficits in OCD individuals. PMID- 28628810 TI - GH administration decreases subcutaneous abdominal adipocyte size in men with abdominal obesity. AB - OBJECTIVE: To investigate the effects of short-term GH administration on abdominal subcutaneous adipocyte size and CT attenuation in men with abdominal obesity. DESIGN: 6-week, randomized, double-blind, placebo-controlled study of GH (starting dose 2MUg/kg/d) vs placebo of 15 abdominally obese men (mean age: 34+/ 6years; mean BMI: 37.7+/-6.1kg/m2, mean IGF-1 SDS: -1.9+/-0.5) who underwent abdominal subcutaneous adipose tissue (SAT) aspirations to determine adipocyte size, CTs for body composition and measures of glucose tolerance at baseline and 6weeks. GH dosing was titrated to target IGF-1 levels in the upper normal age appropriate range. RESULTS: GH administration decreased subcutaneous abdominal adipocyte size compared to placebo. Adipocyte size was positively associated with 120-min glucose and HOMA-IR and inversely associated with peak-stimulated GH and CT attenuation. CT attenuation of SAT was inversely associated with 120-min glucose and HOMA-IR and increased following GH administration. CONCLUSION: In men with abdominal obesity, subcutaneous abdominal adipocyte size is positively associated with measures of impaired glucose tolerance and administration of GH at doses that raise IGF-1 levels within the normal range, decreases abdominal subcutaneous adipocyte size, suggesting that GH administration improves the health of adipose tissue. Clinical trials number: NCT00131378. PMID- 28628811 TI - Evaluating pedestrian behavior at crosswalks: Validation of a pedestrian behavior questionnaire for the U.S. population. AB - The aim of this study was to develop and validate a self-reporting Pedestrian Behavior Questionnaire (PBQ) for the U.S. population to measure frequency of risky behaviors among pedestrians. The PBQ includes 50 survey items that allow respondents to rate the frequency with which they engage in different types of road-using behaviors as pedestrians. The validation study was conducted on 425 participants (228 males and 197 females) between the ages of 18 and 71. Confirmatory factor analysis differentiated pedestrian behaviors into five factor categories: violations, errors, lapses, aggressive behaviors, and positive behaviors. A short version of the PBQ with 20 items was also created by selecting four items with high factor loadings from each of the five factor categories. Regression analyses investigated associations with scenario-based survey behavioral responses to validate the five-factor PBQ subscale scores and composite score. For both long and short versions, each of these five individual factor scales were found to be reliable (0.70.99), and the lower limits of quantification (LLOQ) were 0.66-46.88ng/mL. The intra- and inter-day precisions ranged 1.24-12.45% and 2.49-13.24% for all the analytes. The mean extraction recoveries of the analytes were in the range of 73.10-93.71% and the average matrix effects were within 82.39-93.18%. The validated method has been fully applied to compare the pharmacokinetic parameters of ten components in rat plasma after oral administration of NXEO, NXEO+beta cyclodextrin (beta-CD), NXEO+XEO, and NXEO+beta-XEO (the inclusion of XEO by beta CD). It was found that the area under the concentration curves (AUC0-t) of ten constituents in group NXEO+beta-CD increased compared with group NXEO especially Paeoniflorin, Tetrahydropalmatine and Tetrahydrocolumbamine (p <0.05). The maximum concentration (Cmax) and AUC0-t of ten compounds in group NXEO+XEO and NXEO+beta-XEO had varying degree of increasing in comparison with group NXEO. The growth of group NXEO+beta-XEO ran higher than group NXEO+XEO. As can be seen from above-mentioned results, beta-CD could remarkably increase the absorption of Paeoniflorin, Tetrahydropalmatine and Tetrahydrocolumbamine. Both of XEO and beta XEO could improve the absorption and bioavailability of all the ten non-volatile compositions. The promotion effect of beta-XEO was stronger than XEO due to the double functions of XEO and beta-CD. PMID- 28628838 TI - Validated UPLC-MS/MS method for simultaneous quantification of eight saikosaponins in rat plasma: Application to a comparative pharmacokinetic study in depression rats after oral administration of extracts of raw and vinegar-baked Bupleuri Radix. AB - A sensitive and efficient UPLC-MS/MS method was developed and validated for simultaneous quantification of eight saikosaponins (SSa, SSb1, SSb2, SSb3, SSb4, SSc, SSd and SSf) in rat plasma. Furthermore, comparative pharmacokinetic profiles of these sakosaponins were investigated, following oral administration of extracts of raw and vinegar-baked Bupleuri Radix to depression rats. Biosamples were processed with liquid-liquid extraction technique using ethyl acetate. Chromatographic separation was accomplished on Waters BEH C18 UPLC column. 0.05% formic acid in water and acetonitrile as mobile phase was used at a flow rate of 0.40mL/min. The analytes and internal standard, digoxin, were detected using negative ion electrospray ionization in multiple reaction monitoring mode. The lower limit of quantification was less than 0.62ng/mL for the each analyte. The validation parameters investigated, which were specificity, precision, accuracy, matrix effect, recovery and stability, were well within acceptable limits. Results showed that for some of analytes, AUC0-t and Cmax were significantly different after oral administration of extracts of raw and vinegar baked Bupleuri Radix. Moreover, the pharmacokinetic study in pathological state could provide more useful information to guide the clinical usage of Bupleuri Radix. PMID- 28628839 TI - A simple and fast LC-MS/MS method with a very high sensitivity for the measurement of raltitrexed in human plasma. AB - Raltitrexed is a thymidylate synthase inhibitor that can be administered safely to patients with cardiovascular disease or dihydropyrimidine dehydrogenase deficiency, as opposed to 5FU. The recommended dose of 3mg/m2 every 3 weeks often leads to toxicity. Interestingly, the 2mg/m2 every 2 weeks dose appears to be less toxic. A pharmacokinetic trial was then performed by our team to investigate such phenomenon. However, there are currently, two main methods for RTX measurement described in the literature: a radioimmunoassay (RIA) and chromatographic-based methods with either UV or mass spectrometry detections. The RIA methods: display a low limit of quantification (below 1MUg/L), but also a low extent of linearity for the calibration curve. The chromatographic-based methods: include high level of calibrators, but have poor sensitivity (>2MUg/mL). If a high sensitivity is essential to satisfactorily describe the elimination of RTX, high concentrations in the calibration curve are also needed to avoid bias linked to the dilutions of the samples. A new LC-MS/MS method was then developed that allows to simultaneously measure very low (0.1MUg/L) and very high (3000MUg/L) concentrations in the same run. Moreover, the extraction steps are very simple and fast with mainly a precipitation and a filtration steps. This method was validated following the EMA recommendations. In view of the extent of the calibration curve, the carry-over effect was more deeply investigated. With this method, it was possible to measure RTX in samples taken 3 weeks after the administration. Taken together, this method allows to simply and quickly measure RTX in plasma of patients. PMID- 28628840 TI - Nasal epithelium injury by chlorination products and other stressors predicts persistent sensitization to aeroallergens in young schoolchildren. AB - BACKGROUND: Allergic sensitization during childhood is a dynamic process with a substantial rate of remission. Factors influencing this process are largely unknown. METHODS: We conducted a two-year prospective study among 121 schoolchildren (mean age, 5.8 years; 64 boys). We measured urea, club cell protein (CC16), beta2-microglobulin and albumin in nasal lavage fluid (NALF) and IgE to cat, pollen or house dust mite (HDM) in nasal mucosa fluid. RESULTS: Odds of persistent sensitization to any aeroallergen increased across baseline ascending tertiles of urea-adjusted beta2-microglobulin or albumin and descending tertiles of albumin- or beta2-microglobulin-adjusted CC16 (P-trend = 0.006, 0.02, 0.044 and 0.006, respectively). Persistent HDM sensitization also increased with baseline descending tertiles of raw or urea-adjusted CC16 (both P-trend = 0.007). Such strong associations were not observed with new-onset or remitted sensitization to any aeroallergen or with raw NALF concentrations of urea, albumin or beta2-microglobulin. At baseline, house cleaning with bleach and chlorinated pool attendance emerged among the strongest and most consistent determinants of NALF biomarkers, being both associated with higher urea and lower CC16 in NALF. CONCLUSION: In young children, a defective nasal epithelium attributable to immaturity or stressors such as chlorination products is predictive of more persistent aeroallergen sensitization. PMID- 28628841 TI - Mitochondrial dysfunction in Autism Spectrum Disorder: clinical features and perspectives. AB - Autism Spectrum Disorder (ASD) is a prototypic pervasive developmental disorder characterized by social interaction, and communication deficits, repetitive, stereotypic patterns of behavior, and impairments in language and development. Clinical studies have identified mitochondrial disturbances at the levels of DNA, activity, complexes, oxidative stress, and metabolites in blood and urine of ASD patients. However, these observations from postmortem brains or peripheral tissues do not provide a direct link between autism and mitochondria. The synaptic abnormality of autistic patients has not been investigated yet. Here we review the findings of clinical studies investigating mitochondrial involvement in ASD patients, focusing particularly on the brain and the limitations and future directions needed in order to fully understand the role of mitochondria in ASD pathology. PMID- 28628842 TI - Matching genomic molecular aberrations with molecular targeted agents: Are biliary tract cancers an ideal playground? AB - Biliary tract cancers (BTCs) are a heterogeneous group of tumours with geographical discrepancies in terms of incidence and risk factors. However, a convergent genomic and epigenetic mutational landscape emerges from the genome wide screens of BTCs in South East Asia, Latin America and in the Western World. Specificities are observed for some alterations and anatomical subtypes: frequent fibroblast growth factor receptor 2 (FGFR2) and isocitrate dehydrogenase 1/2 (IDH1/2) alterations are specific to intrahepatic cholangiocarcinomas (ICCs), whereas frequent ERBB2 oncogene alterations are specific to extrahepatic cholangiocarcinomas (ECCs) and gallbladder carcinomas (GBCs). Until now, the outcome of patients with BTCs treated by molecular targeted agents (MTAs) alone or in combination with conventional chemotherapy in non-biology driven trials remains poor and does not exceed the outcome of patients treated with chemotherapy alone. Encouraging reports of biology-driven therapeutic approaches should accelerate the clinical development of MTAs in BTCs. Additionally, frequent epigenetic aberrations such as IDH1/2 mutations and switch/sucrose non fermenting (SWI/SNF) complex dysfunctions suggest that epidrugs must also be considered. In this review, we expose the rationale and feasibility to biologically drive the treatment of BTC patients. PMID- 28628843 TI - Preoperative chemotherapy versus chemoradiotherapy in locally advanced adenocarcinomas of the oesophagogastric junction (POET): Long-term results of a controlled randomised trial. AB - BACKGROUND: Results of the PreOperative therapy in Esophagogastric adenocarcinoma Trial (POET) showed some benefits when including radiotherapy into the preoperative treatment. This article is reporting long-term results of this phase III study. PATIENTS AND METHODS: Patients with locally advanced adenocarcinomas of the oesophagogastric junction (Siewert types I-III) were eligible. Randomisation was done to chemotherapy (group A) or induction chemotherapy and chemoradiotherapy (CRT; group B) followed by surgery. RESULTS: The primary end point of the study was overall survival at 3 years. The study was closed early after 119 patients having been randomised and were eligible. Local progression free survival after tumour resection was significantly improved by CRT (hazard ratio [HR] 0.37; 0.16-0.85, p = value 0.01) and 20 versus 12 patients were free of local tumour progression at 5 years (p = 0.03). Although the rate of postoperative in-hospital mortality was somewhat higher with CRT (10.2% versus 3.8%, p = 0.26), more patients were alive at 3 and 5 years after CRT (46.7% and 39.5%) compared with chemotherapy (26.1% and 24.4%). Thus, overall survival showed a trend in favour of preoperative CRT (HR 0.65, 95% confidence interval [CI] 0.42-1.01, p = 0.055). CONCLUSION: Although the primary end-point overall survival of the study was not met, our long-term follow-up data suggest a benefit in local progression-free survival when radiotherapy was added to preoperative chemotherapy in patients with locally advanced adenocarcinoma of the oesophagogastric junction. PMID- 28628844 TI - Serum microRNAs in buffalo cows: Potential biomarkers of pregnancy. AB - MiRNAs (microRNA) constitute a large family of single-stranded, non-coding small RNAs. Although the functions and target genes of most miRNAs are still unknown, it has been well established that they are involved in embryogenesis, organogenesis and neonatal birth. In recent decades, interest in buffalo breeding has largely increased worldwide thus focusing the attention on this species as a dairy purpose animal. Problems related to long calving interval, late puberty and seasonal anestrus hamper reproductive efficiency in this species. Early pregnancy diagnosis is important to shorten the calving interval and increase lifetime production on dairy animals. MicroRNAs have recently emerged as key molecules in fertilization of several species even though in buffalo, few previous studies have investigated miRNAs. The aim of this research was to identify the best miRNA reference in serum among miR-191, miR-25-3p, SNORD44, and SNORD48. Consequently, assess the expression levels of miR-103, miR-200b, miR-301a, miR-423-5p, miR-375, miR-451 and miR-452 involved in buffalo progesterone-maturation oocyte and pregnancy. Interestingly, we found that all the miRNAs analyzed at 40days after artificial insemination were differentially expressed among pregnant and non pregnant buffalo. Our research may be a first step for gain further insight in the biological function of circulating miRNAs in this species. PMID- 28628845 TI - Serum antioxidant capacity and oxidative damage in clinical and subclinical canine ehrlichiosis. AB - The objective of this study was to evaluate and compare the antioxidant response and the products of oxidative damage analysed by various assays in clinical and subclinical canine monocytic ehrlichiosis (CME). For this purpose, four assays to measure the total serum antioxidant capacity (TAC), such as the cupric reducing antioxidant capacity (CUPRAC), ferric reducing ability of plasma (FRAP), trolox equivalent antioxidant capacity (TEAC) using acidic medium (TEACA), and the TEAC using the horseradish peroxidase (TEACH) were used. In addition, the serum thiol concentrations were analysed. Reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and ferrous oxidation-xylenol orange (FOX) were measured to determine the concentrations of free radical and the products of oxidative damage as result of the disease. All antioxidant markers were significantly lower in the dogs on clinical ehrlichiosis when compared with healthy dogs; however only the CUPRAC, FRAP and thiol were significantly lower in subclinical CME compared with healthy dogs. TBARS and FOX showed no significant differences between dogs with CME and healthy dogs; however, a significant increased ROS concentration was observed in dogs with clinical and subclinical CME when compared with healthy dogs. Results showed that in CME there is a state of oxidative stress with significant changes in markers of antioxidant defence and in concentrations of free radicals. However, the detection of these changes would depend of the assay used. PMID- 28628847 TI - The importance of declining insulin requirements during pregnancy in patients with pre-gestational gestational diabetes mellitus. AB - OBJECTIVE: In patients with pre-gestational and gestational diabetes mellitus (GDM), insulin requirements often increase during the third trimester of pregnancy in order to maintain proper glycemic control. However, a fraction of patients demonstrate a significant decrease in insulin requirements in late gestation. We aimed to evaluate the clinical significance of decreasing insulin requirements in patients with pre-gestational diabetes and GDM with respect to fetal wellbeing and pregnancy outcome. STUDY DESIGN: We performed a retrospective cohort study in a single referral center for gestational diabetes between 1/2010 and 12/2014. Healthy pregnant women with pre-gestational diabetes and GDMA2 and a decrease of at least 30% in insulin requirements over a period of two weeks during the third trimester (group A) were compared to women with stable or increasing insulin requirements (group B). The primary outcome was a composite of situations associated with feto-placental dysfunction (fetal growth restriction, oligohydramnios and cesarean section due to category 2-3 monitor). Secondary outcomes were maternal oral glucose tolerance test (OGTT) results 6 weeks postpartum, neonatal intensive care unit (NICU) admission rates, Apgar scores <=7 at 5min, arterial blood pH<=7.1, macrosomia, neonatal hypoglycemia and a composite adverse neonatal outcomes (defined as one or more of the following: respiratory morbidity, cerebral morbidity, phototherapy, need for blood transfusion, necrotizing enterocolitis or death). RESULTS: Group A consisted of 101 women and group B - of 203 women. There were no differences between the groups in demographic characteristics or diagnostic characteristics of diabetes. The frequency of conditions related to feto-placental dysfunction did not differ between the groups (7.9% vs. 8.4%, p=0.61). Secondary outcome measures also did not differ between the groups, regardless of insulin requirements. CONCLUSION: Decreasing insulin requirements during the third trimester are not associated with adverse perinatal outcome related to placental dysfunction. PMID- 28628846 TI - Substance P and the neurokinin-1 receptor expression in dog ileum with and without inflammation. AB - In the gastrointestinal tract, the tachykinin Substance P (SP) is involved in motility, fluid and electrolyte secretion, and blood flow and regulation of immunoinflammatory response. SP exerts its biological activity on target cells by interacting mainly with the neurokinin-1 receptor (NK1R). The present study aims to quantify the percentage of SP-immunoreactive (SP-IR) enteric neurons and the density of SP-IR nerve fibers in the ileum of control dogs (CTRL-dogs; n=7) vs dogs with spontaneous ileal inflammation (INF-dogs; n=8). In addition, the percentage of enteric neurons bearing NK1R, and nitrergic neurons (nNOS-IR) expressing NK1R immunoreactivity were evaluated in both groups. The percentages of SP-IR neurons were similar in CTRL- and INF-dogs, in either the myenteric (MP) (15+/-8% vs. 16+/-7%, respectively) and submucosal plexus (SMP) (26+/-7% vs. 24+/ 14%, respectively). In INF-dogs, the density of SP-IR mucosal nerve fibers showed a trend to decrease (P=0.07). Myenteric neurons of CTRL- and INF-dogs expressed similar percentages of NK1R-immunoreactivity (39+/-5% vs. 38+/-20%, respectively). Submucosal NK1R-IR neurons were occasionally observed in a CTRL dog. MP nitrergic neurons bearing NK1R showed a trend to decrease in INF-dogs vs. CTRL- dogs (41+/-22% vs. 65+/-10%, respectively; P=0.11). In INF-dogs, muscle cells and immune cells overexpressed NK1R immunoreactivity. These findings should be taken as a warning for possible intestinal motility disorders, which might occur during administration of NK1R-antagonist drugs. Conversely, the strong expression of NK1R immunoreactivity observed in muscle and mucosal immune cells of inflamed tissues may provide a rationale for the use of NK1R antagonist drugs in the treatment of intestinal inflammation. PMID- 28628848 TI - Sexual dysfunction in infertile women: A systematic review and meta-analysis. AB - OBJECTIVE: This study aimed to assess the prevalence of sexual dysfunction and Female Sexual Function Index (FSFI) score in women with infertility. STUDY DESIGN: A systematic search of the literature was conducted using PubMed, EMBASE, IBECS, and LILACS. The search was limited to articles published from January 2000 to September 2016, without language restriction. Data were analyzed using Stata 12.0. Random effects meta-analyses in weighted mean difference (WMD) were performed for six comparative studies (infertility versus fertility). Heterogeneity was estimated using I2. Moreover, to explore the heterogeneity sources among the studies, meta-regression analyses were also performed. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation guidelines, and risk of bias, with a graphic funnel. RESULTS: Meta-analysis was performed in 11 of 13 comparative studies. The result indicated a significant association between an increase in sexual dysfunction and infertility in women (WMD=-0.16, 95% confidence interval=-0.254 to -0.084, p<0.001), and high heterogeneity between studies was noted (I2=98.6%, p<0.000). Meta-regression analysis did not indicate heterogeneity (I2=0.00%). We also performed a meta-analysis of individual FSFI domains in 10 studies. Infertile women had problems with lubrication, orgasm, and satisfaction. Meta-regression analysis also showed that heterogeneity had no influence on the final results of all the analyses. CONCLUSIONS: Infertility was associated with an increase in female sexual dysfunction. The most affected areas of sexual function were lubrication, orgasm, and satisfaction. PMID- 28628849 TI - Kinematic patterns underlying disguised movements: Spatial and temporal dissimilarity compared to genuine movement patterns. AB - This study examined the kinematic characteristics of disguised movements by applying linear discriminant (LDA) and dissimilarity analyses to the motion data from 788 disguised and 792 non-disguised 7-m penalty throws performed by novice and expert handball field players. Results of the LDA showed that discrimination between type of throws (disguised vs. non-disguised) was more error-prone when throws were performed by experts (spatial: 4.6%; temporal: 29.6%) compared to novices (spatial: 1.0%; temporal: 20.2%). The dissimilarity analysis revealed significantly smaller spatial dissimilarities and variations between type of throws in experts compared to novices (p<0.001), but also showed that these spatial dissimilarities and variations increased significantly in both groups the closer the throws came to the moment of (predicted) ball release. In contrast, temporal dissimilarities did not differ significantly between groups. Thus, our data clearly demonstrate that expertise in disguising one's own action intentions results in an ability to perform disguised penalty throws that are highly similar to genuine throws. We suggest that this expertise depends mainly on keeping spatial dissimilarities small. However, the attempt to disguise becomes a challenge the closer one gets to the action outcome (i.e., ball release) becoming visible. PMID- 28628850 TI - Indoline derivatives mitigate liver damage in a mouse model of acute liver injury. AB - BACKGROUND: Exposure of mice to D-galactosamine (GalN) and lipopolysaccharide (LPS) induces acute liver failure through elevation of TNF-alpha, which causes liver damage resembling that in humans. The current study evaluated in this model the effect of two indoline derivatives, which have anti-inflammatory activity in macrophages. METHODS: AN1297 and AN1284 (0.025-0.75mg/kg) or dexamethasone (3mg/kg), were injected subcutaneously, 15min before intraperitoneal injection of GalN (800mg) plus LPS (50MUg) in male Balb/C mice. After 6h, their livers were evaluated histologically by staining with hematoxylin and eosin for tissue damage and by cleaved caspase 3 for apoptosis. Activity of liver enzymes, alanine transaminase (ALT) and aspartate aminotransferase (AST) and levels of TNF-alpha and IL-6 were measured in plasma, and those of TNF-alpha and IL-6, in the liver. RESULTS: AN1297 (0.075-0.75mg/kg) and AN1284 (0.25-0.75mg/kg) maximally reduced ALT by 51% and 80%, respectively. Only AN1284 (0.25 and 0.75mg/kg) reduced AST by 41% and 48%. AN1297 and AN1284 (0.25mg/kg) decreased activation of caspase 3 (a sign of apoptosis) by 80% and plasma TNF-alpha by 75%. AN1297 and AN1284 (0.075mg/kg) prevented the rise in TNF-alpha and IL-6 in the liver. AN1284 (0.25mg/kg) reduced mortality from 90% to 20% (p<0.01) and AN1297, to 60% (p=0.121). Both indoline derivatives inhibited the phosphorylation of MAPK p38 and DNA binding of the transcription factor, AP-1. CONCLUSION: While both compounds are highly potent anti-inflammatory agents, AN1284 is more effective in mitigating the underlying causes of GalN/LPS-induced acute liver failure in mice. PMID- 28628851 TI - Spinal 5-HT4 and 5-HT6 receptors contribute to the maintenance of neuropathic pain in rats. AB - BACKGROUND: Nerve injury promotes release of 5-HT at the spinal cord. Once released, 5-HT may produce antinociceptive or pronociceptive effects depending of the nature of 5-HT receptors. The purpose of this study was to investigate the participation of spinal 5-HT4 and 5-HT6 receptors in the maintenance of neuropathic pain in rats. METHODS: Tactile allodynia was measured using von Frey hairs in male Wistar rats subjected to L5-L6 spinal nerve injury. Selective 5-HT4 (GR-113808, 0.01-10nmol/rat) and 5-HT6 (SB-258585, 1-1000nmol/rat) receptor antagonists were administered intrathecally to nerve injured rats. Likewise, the most effective dose of 5-HT4 (1nmol/rat) and 5-HT6 (100 nmol/rat) antagonists were co-administered with their respective agonists (ML-10302, 10-100nmol/rat and WAY-208466, 100-1000nmol/rat, respectively). Spinal cord protein expression of both receptors was determined by western blot. RESULTS: Intrathecal administration of 5-HT4 or 5-HT6 receptor antagonists, but not vehicle, decreased in a dose-dependent manner tactile allodynia in neuropathic rats. Moreover, intrathecal co-administration with the agonists prevented in a dose-dependent manner the antagonists-induced antiallodynic effect. Both 5-HT4 and 5-HT6 receptors were expressed in the spinal cord of naive, sham and neuropathic rats. Nerve injury did not modify expression of any receptor. CONCLUSIONS: Data suggests that spinal 5-HT4 and 5-HT6 receptors are expressed in dorsal spinal cord and they participate in the maintenance of neuropathic pain in rats. In this regard, blockade of these receptors could be a useful strategy to treat neuropathic pain states. PMID- 28628852 TI - Skin regeneration in three dimensions, current status, challenges and opportunities. AB - Skin regeneration is a life-saving need for many patients, whom list is stretched from burn victims to motor-car accidents. Spraying cells, either keratinocytes or stem cells, were associated with variable results and, in many cases, unfavorable outcomes. As the spatial configuration of the skin is distinctive, many trials investigated the bio-printing or the construction of three dimensional skin models where different layers of the skin were preserved. Although some of these models showed the histological configuration of the skin, their acceptance by the wound was questionable as a consequence of delayed vascularization. In this mini review, different models for three dimensional regeneration of the skin will be discussed with their main points of strength and challenges as well as their possible opportunities. PMID- 28628853 TI - Willingness to pay for opioid agonist treatment among opioid dependent people who inject drugs in Ukraine. AB - BACKGROUND: In the context of decreasing external and limited Ukrainian governmental funding for opioid agonist treatments (OAT) for opioid dependent people who inject drugs in Ukraine, information on sustainable financial models is needed. METHODS: Data on 855 opioid dependent people who inject drugs (PWID) were drawn from a cross-sectional nationwide survey of 1613 PWID. They comprised 434 participants who were receiving OAT and 421 who were on OAT in the past or have never been on OAT and were interested in receiving the treatment. Multivariate logistic regression was used to examine factors associated with willingness-to-pay (WTP) for OAT, stratified by OAT experience. Variation in the price which respondents were willing to pay for OAT and its effect on their monthly income among PWID with different OAT experience were assessed as a continuous variable using one-way ANOVA and Kruskal-Wallis test. RESULTS: Overall, 378 (44%) expressed WTP for OAT. Factors independently associated with WTP differed by OAT experience. Among those using OAT, independent predictors of WTP included: city (Dnipro - aOR=1.9; 95%CI=1.1-4.8 and Lviv - (aOR=2.2; 95%CI=1.1-4.8) compared to those elsewhere in Ukraine), higher income (aOR=1.8; 95%CI=1.2-2.7) and receiving psychosocial counseling (aOR=1.8; 95%CI=1.2-2.7). Among those who had previously been on OAT, positive attitude towards OAT (aOR=1.3; 95%CI=1.1-1.6) and family support of OAT (aOR=2.5; 95%CI=1.1-5.7) were independently associated with WTP. Among PWID who had never been on OAT, being male (aOR=2.2; 95%CI=1.1-4.2), younger age (aOR=1.9; 95%CI=1.2-3.2), higher income (aOR=2.0; 95%CI=1.2-3.4) and previous unsuccessful attempts to enter OAT (aOR=2.3; 95%CI=1.1-4.7) were independently associated with WTP. PWID were willing to commit a large percentage of their monthly income for OAT, which, however, varied significantly based on OAT experience: current OAT: 37% of monthly income, previous OAT: 53%, and never OAT: 60% (p-value=0.0009). CONCLUSIONS: WTP for OAT was substantial among PWID in Ukraine, supporting the implementation of self-pay or co-payment programs. Such strategies, however, must remain affordable, provide better access to OAT, and consider specific needs of PWID. PMID- 28628855 TI - Progress in programming spatiotemporal patterns and machine-assembly in cell-free protein expression systems. AB - Building biological systems outside the cell is an emerging interdisciplinary research field aimed to study design principles, and to emulate biological functions for technology. Reconstructing programmable cellular functions, from assembly of protein/nucleic-acid machines to spatially distributed systems, requires implementing minimal systems of molecular interactions encoded in genes, source-sink protein expression dynamics, and materials platforms for reaction diffusion scenarios. Here, we first review how molecular turnover mechanisms, combined with nonlinear interactions and feedback in cell-free gene networks enable programmable dynamic expression patterns in various compartments. We then describe recent work on spatially distributed protein expression reactions. Finally, we discuss progress and challenges in the study of programmable protein/nucleic-acid complexes. PMID- 28628854 TI - Prevalence and predictors of HCV among a cohort of opioid treatment patients in Dar es Salaam, Tanzania. AB - BACKGROUND: The government of Tanzania launched an opioid treatment program (OTP), using methadone, in Dar es Salaam in February of 2011. Hepatitis C virus (HCV) is a leading cause of morbidity and mortality globally, especially among people who inject drugs (PWID). We conducted a cross-sectional study among PWID engaged in OTP in Dar es Salaam to describe the prevalence and predictors of HCV antibody serostatus. METHODS: Routine programmatic data on patients enrolled in Muhimbili National Hospital's OTP clinic from February 2011 to January 2013 were utilized. Multivariable Poisson regression was used to examine factors associated with HCV antibody serostatus. RESULTS: A total of 630 PWID enrolled into the OTP clinic during the study period, seven percent of which were women. The overall seroprevalence of HCV antibody was 57% (95% Confidence interval: 53-61%). In adjusted analysis, methadone patients who used heroin for 5-10 years (adjusted prevalence ratio; aPR=1.41; 95% CI: 1.10-1.81) and >10years (aPR=1.48; 95% CI: 1.17-1.88) were more likely to be HCV antibody positive, compared to patients who used heroin for <5years. Patients who reported sharing needles or other equipment at their last injection (aPR=1.20; 95% CI: 1.01-1.41; p=0.022), being arrested (aPR=1.20; 95% CI: 1.04-1.40; p=0.012) and who were HIV-positive (aPR=1.84; 95% CI: 1.56-2.16; p<0.001) were also more likely to be HCV antibody positive than their counterparts. CONCLUSION: Our observed HCV antibody prevalence among PWID engaged in OTP is higher than previously reported estimates in Dar es Salaam. Predictors of HCV antibody serostatus in this sample were similar to those found among PWID in many other settings. Integrating HCV care and treatment into OTP clinics should be considered, leveraging lessons learned from the integration of HIV services into OTP. Global efforts to develop HCV care and treatment programs in low and middle-income countries are critical, especially among PWID who have a high burden of HCV. PMID- 28628856 TI - Mammalian synthetic biology in the age of genome editing and personalized medicine. AB - The recent expansion of molecular tool kits has propelled synthetic biology toward the design of increasingly sophisticated mammalian systems. Specifically, advances in genome editing, protein engineering, and circuitry design have enabled the programming of cells for diverse applications, including regenerative medicine and cancer immunotherapy. The ease with which molecular and cellular interactions can be harnessed promises to yield novel approaches to elucidate genetic interactions, program cellular functions, and design therapeutic interventions. Here, we review recent advancements in the development of enabling technologies and the practical applications of mammalian synthetic biology. PMID- 28628857 TI - Identification of B and T cell epitope based peptide vaccine from IGF-1 receptor in breast cancer. AB - The insulin-like growth factor-1 receptor (IGF-1R) plays a key role in proliferation, growth, differentiation, and development of several human malignancies including breast and pancreatic adenocarcinoma. IGF-1R targeted immunotherapeutic approaches are particularly attractive, as they may potentially elicit even stronger antitumor responses than traditional targeted approaches. Cancer peptide vaccines can produce immunologic responses against cancer cells by triggering helper T cell (Th) or cytotoxic T cells (CTL) in association with Major Histocompatibility Complex (MHC) class I or II molecules on the cell surface of antigen presenting cells. In our previous study, we set a technique based on molecular docking in order to find the best MHC class I and II binder peptides using GOLD. In the present work, molecular docking analyses on a library consisting of 30 peptides mimicking discontinuous epitopes from IGF-1R extracellular domain identified peptides 249 and 86, as the best MHC binder peptides to both MHC class I and II molecules. The receptors most often targeted by peptide 249 are HLA-DR4, HLA-DR3 and HLA-DR2 and those most often targeted by peptide 86 are HLA-DR4, HLA-DP2 and HLA-DR3. These findings, based on bioinformatics analyses, can be conducted in further experimental analyses in cancer therapy and vaccine design. PMID- 28628858 TI - Unravelling the structural interactions between PKR kinase domain and its small molecule inhibitors using computational approaches. AB - The RNA-dependent protein kinase (PKR), an eIF2alpha kinase plays an important role in anti-viral response, apoptosis and cell survival. It is also implicated to play a role in several cancers, metabolic and neurodegenerative disorders. A few ATP competitive inhibitors of the PKR have been reported in the literature with promising results in vitro and in vivo. The aim of this study was to unravel the structural interactions between these inhibitors and the PKR kinase domain using molecular simulations and docking. Our study reveals that the reported inhibitors bind in the adenine pocket and form hydrogen bonds with the hinge region and vdW interactions with non-polar residues in the binding site. The most potent inhibitor has several favorable interactions with the binding site and induces the P-loop to fold inward, creating a significant hydrophobic enclosure for itself. The computed binding free energies of these inhibitors are in accord with experimental data (IC50). Strategies to design potent and selective PKR inhibitors are discussed to overcome the reported promiscuity. PMID- 28628859 TI - Structural and functional effects of nucleotide variation on the human TB drug metabolizing enzyme arylamine N-acetyltransferase 1. AB - The human arylamine N-acetyltransferase 1 (NAT1) enzyme plays a vital role in determining the duration of action of amine-containing drugs such as para aminobenzoic acid (PABA) by influencing the balance between detoxification and metabolic activation of these drugs. Recently, four novel single nucleotide polymorphisms (SNPs) were identified within a South African mixed ancestry population. Modeling the effects of these SNPs within the structural protein was done to assess possible structure and function changes in the enzyme. The use of molecular dynamics simulations and stability predictions indicated less thermodynamically stable protein structures containing E264K and V231G, while the N245I change showed a stabilizing effect. Coincidently the N245I change displayed a similar free energy landscape profile to the known R64W amino acid substitution (slow acetylator), while the R242M displayed a similar profile to the published variant, I263V (proposed fast acetylator), and the wild type protein structure. Similarly, principal component analysis indicated that two amino acid substitutions (E264K and V231G) occupied less conformational clusters of folded states as compared to the WT and were found to be destabilizing (may affect protein function). However, two of the four novel SNPs that result in amino acid changes: (V231G and N245I) were predicted by both SIFT and POLYPHEN-2 algorithms to affect NAT1 protein function, while two other SNPs that result in R242M and E264K substitutions showed contradictory results based on SIFT and POLYPHEN-2 analysis. In conclusion, the structural methods were able to verify that two non synonymous substitutions (E264K and V231G) can destabilize the protein structure, and are in agreement with mCSM predictions, and should therefore be experimentally tested for NAT1 activity. These findings could inform a strategy of incorporating genotypic data (i.e., functional SNP alleles) with phenotypic information (slow or fast acetylator) to better prescribe effective treatment using drugs metabolized by NAT1. PMID- 28628860 TI - In silico modeling on ADME properties of natural products: Classification models for blood-brain barrier permeability, its application to traditional Chinese medicine and in vitro experimental validation. AB - In silico modeling of blood-brain barrier (BBB) permeability plays an important role in early discovery of central nervous system (CNS) drugs due to its high throughput and cost-effectiveness. Natural products (NP) have demonstrated considerable therapeutic efficacy against several CNS diseases. However, BBB permeation property of NP is scarcely evaluated both experimentally and computationally. It is well accepted that significant difference in chemical spaces exists between NP and synthetic drugs, which calls into doubt on suitability of available synthetic chemical based BBB permeability models for the evaluation of NP. Herein poor discriminative performance on BBB permeability of NP are first confirmed using internal constructed and previously published drug derived computational models, which warrants the need for NP-oriented modeling. Then a quantitative structure-property relationship (QSPR) study on a NP dataset was carried out using four different machine learning methods including support vector machine, random forest, Naive Bayes and probabilistic neural network with 67 selected features. The final consensus model was obtained with approximate 90% overall accuracy for the cross-validation study, which is further taken to predict passive BBB permeability of a large dataset consisting of over 10,000 compounds from traditional Chinese medicine (TCM). For 32 selected TCM molecules, their predicted BBB permeability were evaluated by in vitro parallel artificial membrane permeability assay and overall accuracy for in vitro experimental validation is around 81%. Interestingly, our in silico model successfully predicted different BBB permeation potentials of parent molecules and their known in vivo metabolites. Finally, we found that the lipophilicity, the number of hydrogen bonds and molecular polarity were important molecular determinants for BBB permeability of NP. Our results suggest that the consensus model proposed in current work is a reliable tool for prioritizing potential CNS active NP across the BBB, which would accelerate their development and provide more understanding on their mechanisms, especially those with pharmacologically active metabolites. PMID- 28628861 TI - Enhancement in recovery of drugs with high protein binding efficiency from human plasma using magnetic nanoparticles. AB - In this paper, we propose an alternate method for bioanalytical extraction of drugs from human plasma samples using bare magnetic nanoparticles. The magnetic nanoparticles (MNPs) were used for deproteination of biological samples that further assist in extraction of plasma bound drugs for bioanalytical studies. The method uses basic solvents (ethanol, methanol, etc.) rather than the expensive and toxic solvents. The MNPs provide several advantages like avoiding the use of centrifuge machine, and making extraction time effective. The average time involved for the sample preparation is around 30-40min. The developed method was examined for seven different drugs having moderate (40-70%) to high (>80%) plasma protein binding efficiency. The present study focuses on the principle of magnetic nanoparticle based extraction of drug that binds with the plasma protein. In calcitriol (protein binding efficiency >99%), it was observed that the drug extraction efficiency could be enhanced by 16% using the present method. However, we assume that still there is a scope for improving the extraction efficiency by optimizing proper solvent for the specific drug. The use of magnetic nanoparticles makes the extraction cost effective and quick with improved efficiency. PMID- 28628862 TI - Characterization and inhibition studies of tissue nonspecific alkaline phosphatase by aminoalkanol derivatives of 1,7-dimethyl-8,9-diphenyl-4 azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione, new competitive and non competitive inhibitors, by capillary electrophoresis. AB - The article describes the inhibitory effect of two new aminoalkanol derivatives on the enzymatic kinetic of tissue non-specific alkaline phosphatase with use of capillary zone electrophoresis to evaluate the inhibitory effect. This technique allows to investigate of the enzymatic kinetic by the measure of the amounts of the substrate and product in the presence of compound (I) or (II) in the reaction mixture. The separation process was conducted using an eCAP fused-silica capillary. The detector was set at 200nm. The best parameters for the analysis were: 25mM sodium dihydrogen phosphate adjusted to pH=2.5, temperature 25 degrees C, and voltage -15kV. Lineweaver-Burk plots were constructed and determined by comparison of the Km, of alkaline phosphatase in the presence of inhibitor (I) or (II) with the Km in a solution without inhibitor. The influence of replacement the propylamine group by the dimethylamine group on tissue non-specific alkaline phosphatase inhibition activity of new derivatives (I) and (II) was investigated. The tested compounds (I) and (II) were found to be tissue non-specific alkaline phosphatase inhibitors. Detailed kinetic studies indicated a competitive mode of inhibition against tissue non-specific alkaline phosphatase for compound (I) and non-competitive mode of inhibition for compound (II). PMID- 28628863 TI - Simultaneous quantification of endothelin receptor antagonists and phosphodiesterase 5 inhibitors currently used in pulmonary arterial hypertension. AB - Combination treatment with endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitors (PDE5I) improved efficacy of pulmonary arterial hypertension (PAH) therapy. However, drug-drug interactions, variable exposure, non-adherence can influence plasma levels. For these reasons, drug quantification may be advantageous particularly in patients with poor treatment responses. We developed, validated, and applied an assay for the simultaneous quantification of ambrisentan, bosentan, macitentan, sildenafil, and tadalafil as well as their main (and partly active) metabolites in human plasma. This method is based on LC MS/MS separation for a rapid and sensitive quantification with stable isotopically labelled analogues as internal standards for each drug and metabolite. Sample preparation was carried out using a solid phase extraction protocol based on Oasis HLB material. The separation was achieved on a Kinetex C18 column and multiple reaction monitoring in negative ionization mode was used for sensitive detection. The calibrations were linear for all analytes with correlation coefficients >0.99 within the concentration range observed under a therapeutic PAH dosing scheme with lower limits of quantification between 0.34ng/mL (OH-ambrisentan) and 10ng/mL (despropyl-macitentan). Intra- and inter day precision at LLOQ and QC levels ranged between 2.03% and 19.8%, and 0.65% and 14.0%, respectively. The sample turnover time was 12min. The applicability of this versatile LC/MS/MS assay was verified by the successful analysis of clinical routine samples of patients on PAH medication. This new method allows for the first time to assess trough drug and metabolite levels of the currently approved PDE5I and ERAs in PAH patients, thus enabling for measurement of samples in clinical routine. PMID- 28628864 TI - Polybrominated diphenyl ethers (PBDEs) and thyroid hormones in cord blood. AB - Human exposure to polybrominated diphenyl ethers (PBDEs) has been increasing over the last three decades in China and around the world. Animal studies suggest that PBDEs could reduce blood levels of thyroid hormones, but it is unclear whether PBDEs disrupt thyroid function in humans. We used data from a prospective birth cohort of 123 pregnant women who were enrolled between September 2010 and March 2011 in Shandong, China. We measured the concentrations of eight PBDE congeners (n = 106) and five thyroid hormones (n = 107) in cord serum samples. We examined the relationship between prenatal exposure to PBDEs and thyroid function (n = 90). Median concentrations of BDEs 47, 99, 100, and 153 (detection frequencies > 75%) were 3.96, 8.27, 3.31, and 1.89 ng/g lipid, respectively. A 10-fold increase in BDE-99 and Sigma4 PBDEs (the sum of BDEs 47, 99, 100, and 153) concentrations was associated with a 0.41 MUg/dL (95% confidence interval [CI]: 0.10 to 0.72) and 0.37 MUg/dL (95% CI: 0.06 to 0.68) increase in total thyroxine levels (TT4), respectively. No associations were found between other individual congeners and any of the five thyroid hormones. Our study suggests that prenatal exposure to PBDEs may be associated with higher TT4 in cord blood. Given the inconsistent findings across existing studies, our results need to be confirmed in additional studies. PMID- 28628865 TI - Urban emissions hotspots: Quantifying vehicle congestion and air pollution using mobile phone GPS data. AB - On-road emissions vary widely on time scales as short as minutes and length scales as short as tens of meters. Detailed data on emissions at these scales are a prerequisite to accurately quantifying ambient pollution concentrations and identifying hotspots of human exposure within urban areas. We construct a highly resolved inventory of hourly fluxes of CO, NO2, NOx, PM2.5 and CO2 from road vehicles on 280,000 road segments in eastern Massachusetts for the year 2012. Our inventory integrates a large database of hourly vehicle speeds derived from mobile phone and vehicle GPS data with multiple regional datasets of vehicle flows, fleet characteristics, and local meteorology. We quantify the 'excess' emissions from traffic congestion, finding modest congestion enhancement (3-6%) at regional scales, but hundreds of local hotspots with highly elevated annual emissions (up to 75% for individual roadways in key corridors). Congestion-driven reductions in vehicle fuel economy necessitated 'excess' consumption of 113 million gallons of motor fuel, worth ~ $415M, but this accounted for only 3.5% of the total fuel consumed in Massachusetts, as over 80% of vehicle travel occurs in uncongested conditions. Across our study domain, emissions are highly spatially concentrated, with 70% of pollution originating from only 10% of the roads. The 2011 EPA National Emissions Inventory (NEI) understates our aggregate emissions of NOx, PM2.5, and CO2 by 46%, 38%, and 18%, respectively. However, CO emissions agree within 5% for the two inventories, suggesting that the large biases in NOx and PM2.5 emissions arise from differences in estimates of diesel vehicle activity. By providing fine-scale information on local emission hotspots and regional emissions patterns, our inventory framework supports targeted traffic interventions, transparent benchmarking, and improvements in overall urban air quality. PMID- 28628866 TI - Anticancer drugs: Consumption trends in Spain, prediction of environmental concentrations and potential risks. AB - This study presents the occurrence and impact of 78 anticancer drugs in Spanish river basins based on consumption data in pharmacies during the period 2010-2015 and calculation of the predicted environmental concentrations (PEC). The total consumption of anticancer drugs in Spanish pharmacies was of 23.4 tons in 2015, being mycophenolic acid and hydroxycarbamide the drugs with the highest prescription. Their PECs in river at national scale were up to 80 ng/L. However, the use of different dilution factors revealed major differences between hydrographic basins, and PECriver rose up to 68,014 ng/L in highly populated rivers with low flows. Concerning acute toxicity, there was no expected risk for the aquatic environment. However, chronic toxicity tests revealed possible long term mutagenic effects for aquatic organisms. This study provides the tools for the estimation of PEC at river basin scale using time trend consumption data compilation. This information is very useful for prioritization of compounds of concern and permit to focus resources in environmental monitoring and risk evaluation. PMID- 28628867 TI - The improvement of multi-contaminated sandy loam soil chemical and biological properties by the biochar, wood ash, and humic substances amendments. AB - Nowadays trace metal contamination of soils represents an important environmental hazard. Nevertheless, the use of some secondary waste products as amendments may restore the common soil functions. This paper focuses on the chemical and biological influence of wood biochar (BC), wood ash (WA) and humic substances (HS), alone and in the mixtures, on a heavily multi-contaminated sandy loam soil. The soil was amended by above-mentioned materials to follow a pH-increasing design (pHCa from 6.0 to 6.5, 7.0 and 7.5); soil samples were analyzed after 3, 30, and 60 days using a set of variables, namely the plant-available trace element concentrations (Cu, Cd, and Zn), microbial biomass carbon (Cmic), and microbial quotient (qCO2), as well as toxicity to Sinapis alba and Daphnia magna. Wood ash and WA + HS were the most efficient treatments to decrease mobile Cd and Zn concentrations in the soil, while HS, BC, and BC + HS combinations were the most effective in reducing the Cu mobility. The effect of BC and WA on the Cmic and qCO2 was mostly negative, whereas adding HS markedly increased Cmic and reduced qCO2 in soil. After amendment applications, the root elongation of mustard was significantly increased in HS and combined treatments (BC + HS, WA + HS). Additionally, BC + HS, WA + HS and WA 8.4% significantly decreased the toxicity of leachates to D. magna to the low-, or non-toxic levels. Our results suggest that the combination of amendments with HS can be a suitable remediation strategy for heavily contaminated soils. PMID- 28628868 TI - An overview on exploration and environmental impact of unconventional gas sources and treatment options for produced water. AB - Rising global energy demands associated to unbalanced allocation of water resources highlight the importance of water management solutions for the gas industry. Advanced drilling, completion and stimulation techniques for gas extraction, allow more economical access to unconventional gas reserves. This stimulated a shale gas revolution, besides tight gas and coalbed methane, also causing escalating water handling challenges in order to avoid a major impact on the environment. Hydraulic fracturing allied to horizontal drilling is gaining higher relevance in the exploration of unconventional gas reserves, but a large amount of wastewater (known as "produced water") is generated. Its variable chemical composition and flow rates, together with more severe regulations and public concern, have promoted the development of solutions for the treatment and reuse of such produced water. This work intends to provide an overview on the exploration and subsequent environmental implications of unconventional gas sources, as well as the technologies for treatment of produced water, describing the main results and drawbacks, together with some cost estimates. In particular, the growing volumes of produced water from shale gas plays are creating an interesting market opportunity for water technology and service providers. Membrane-based technologies (membrane distillation, forward osmosis, membrane bioreactors and pervaporation) and advanced oxidation processes (ozonation, Fenton, photocatalysis) are claimed to be adequate treatment solutions. PMID- 28628869 TI - Integrated electrocoagulation-electrooxidation process for the treatment of soluble coffee effluent: Optimization of COD degradation and operation time analysis. AB - Soluble coffee production generates wastewater containing complex mixtures of organic macromolecules. In this work, a sequential Electrocoagulation Electrooxidation (EC-EO) process, using aluminum and graphite electrodes, was proposed as an alternative way for the treatment of soluble coffee effluent. Process operational parameters were optimized, achieving total decolorization, as well as 74% and 63.5% of COD and TOC removal, respectively. The integrated EC-EO process yielded a highly oxidized (AOS = 1.629) and biocompatible (BOD5/COD ~ 0.6) effluent. The Molecular Weight Distribution (MWD) analysis showed that during the EC-EO process, EC effectively decomposed contaminants with molecular weight in the range of 10-30 kDa. In contrast, EO was quite efficient in mineralization of contaminants with molecular weight higher than 30 kDa. A kinetic analysis allowed determination of the time required to meet Colombian permissible discharge limits. Finally, a comprehensive operational cost analysis was performed. The integrated EC-EO process was demonstrated as an efficient alternative for the treatment of industrial effluents resulting from soluble coffee production. PMID- 28628870 TI - Affective disorders and completed suicide by self-poisoning, trend of using antidepressants as a method of self-poisoning. AB - The aim of this research was to study the role and trend of antidepressant use as a method of suicide in completed self-poisoning suicides in patients with affective disorders during a 23-year follow up period. The data consisted of 483 completed self-poisoning suicides from 1988 to 2011 in the province of Oulu in Northern Finland (286 men and 197 women). Of the self-poisoning victims, 26.9% (n=130) had hospital-treated unipolar depression and 3.1% (n=15) hospital-treated bipolar disorder. Further, 53.8% (n=70) of those with unipolar depression and 53.3% (n=8) of those with bipolar depression died by suicide using antidepressants. During the 23-year follow-up period, the proportion of those using antidepressants doubled among all self-poisoning victims of suicide. A significant decline was observed in the use of tricyclic antidepressants in self- poisoning suicides while a linear increase was found in the use of SSRIs (selective serotonin reuptake inhibitors) and other antidepressants. During recent years one in five self-poisoning suicides involved the use of antiepileptics. A limitation of our study was that the psychiatric diagnoses only include hospital inpatient episodes. In conclusion, the use of new antidepressants has increased rapidly, but the risk of their use in self poisoning suicide has perhaps been underestimated. PMID- 28628872 TI - Ag nanowire/ZnO nanobush hybrid structures for improved photocatalytic activity. AB - Reverse-engineered Ag nanowire/ZnO nanobush hybrid structures have been synthesized for the first time by a combination of polyol method and low temperature solution method. Through the elaborate control of Ag-to-ZnO weight ratio, vertically aligned ZnO nanobushes grew on the surface of well-faceted Ag nanowires. The Ag/ZnO hybrid nanostructures showed the crystal features of both Ag nanowires and wurtzite ZnO nanostructures. They exhibited strong UV absorption, whereas their photoluminescence spectra were much weaker than pure ZnO nanostructures due to the inhibited carrier recombination. The photocatalytic activity of Ag/ZnO hybrid nanostructures was greatly improved compared to pure ZnO nanostructures. Furthermore, they showed good cyclic performance and easy recovery from the test solution, demonstrating the possibility of their practical use. PMID- 28628873 TI - Complexation thermodynamics of alpha-cyclodextrin with ionic surfactants in water. AB - The interaction of alpha-cyclodextrin (alpha-CD) with ten ionic surfactants (S) in water was systematically examined using isothermal titration calorimetry. The S comprised cationic and anionic head groups while the hydrocarbon alkyl chain length varied from eight to fourteen carbon atoms. The heat data were measured at five temperatures ranging from 283.15K to 318.15K and were treated simultaneously allowing the estimation of a thermodynamically consistent temperature dependence of the equilibrium constant, as well as the enthalpy and heat capacity for the sequential formation of the [alpha-CD.S] and the [alpha-CD2.S] inclusion complexes. All attempts to fit the data assuming that only [alpha-CD.S] complexes are present failed. It was found that the thermodynamic footprint of the [alpha CD.S] complexes does not depend importantly on the head group, while the formation and stabilization of the [alpha-CD2.S] complexes is strongly influenced by the chemical nature of the polar head group. Several contributions to the thermodynamic parameters are discussed in detail. Among the studied surfactants, the decyl- and octylsulfates were identified as those with a predominant content of [alpha-CD2.S] complexes and hence they are promising candidates to form viscoelastic films at the liquid/air interface, as it was found previously for the dodecylsulfate surfactant. PMID- 28628871 TI - Patterns of high-intensity drinking among young adults in the United States: A repeated measures latent class analysis. AB - OBJECTIVE: Using a national sample of young adults, this study identified latent classes of alcohol use including high-intensity drinking (10+ drinks) from ages 18 to 25/26, and explored associations between time-invariant covariates measured at age 18 and class membership. METHOD: Longitudinal data from the national Monitoring the Future study were available for 1078 individuals (51% female) first surveyed as 12th grade students in 2005-2008, and followed through modal age 25/26. Repeated measures latent class analysis was used to identify latent classes based on self-reported alcohol use: no past 30-day drinking, 1-9 drinks per occasion in the past 2weeks, and 10+ drinks per occasion. RESULTS: Four latent classes of alcohol use from ages 18 to 25/26 were identified: (1) Non Drinkers (21%); (2) Legal Non-High-Intensity Drinkers (23%); (3) Persistent Non High-Intensity Drinkers (40%); and (4) High-Intensity Drinkers (16%). Membership in the High-Intensity Drinkers class was characterized by higher than average probabilities of high-intensity drinking at all ages, with the probability of high-intensity drinking increasing between ages 18 and 21/22. Both gender and race/ethnicity significantly differentiated class membership, whereas neither parental education (a proxy for socioeconomic status) nor college plans at 12th grade showed significant associations. CONCLUSIONS: More than one in seven individuals who were seniors in high school experienced a long-term pattern of high-intensity drinking lasting into middle young adulthood. Young adult high intensity drinking is often preceded by high-intensity drinking in high school, suggesting the importance of screening and prevention for high-intensity drinking during adolescence. PMID- 28628874 TI - A building blocks strategy for preparing photocatalytically active anatase TiO2/rutile SnO2 heterostructures by hydrothermal annealing. AB - Effective heterostructures for photocatalysis need to present good electron-hole mobility among phases, a feature that is only attained with satisfactory interface quality. For very small sizes and with a stable colloidal state, the oriented attachment mechanism can be used to prepare suitable structures by means of a building blocks strategy, whereby preformed nanoparticles are used to control the desired amount of each phase in the heterostructure. Here, we show the success of this strategy for anatase TiO2/rutile SnO2 heterostructures, applying conventional hydrothermal annealing, where successive collisions among particles increase the probability of oriented attachment. The photodegradation of Rhodamine B in water under UV radiation was used as a probe reaction to evaluate formation of the heterostructure, as indicated by an increase in photoactivity. Increased heterostructure photoactivity was related to heterojunction formation and charge separation. The increased lifetimes of the photogenerated charges, due to heterojunction formation, enabled them to reach the oxides surface and promote photocatalytic reactions. The insights presented here may be used in a rationalized synthesis method to obtain heterostructures from preformed nanocrystals. PMID- 28628875 TI - Bioindicator value of flagellates in urban wastewater treatment using membrane bioreactors. AB - Two experimental submerged membrane bioreactors (MBR) at the industrial scale with different membranes (microfiltration and ultrafiltration) were used to analyse the influence of the small flagellates on the lack of significance of the sludge biotic index (SBI). Also, with these systems, flagellates were analysed as bioindicators in the activated sludge of MBRs. Both facilities were operated in parallel with a pre-denitrification system for a period of nearly two years and fed with real pretreated urban wastewater. During the experimental period, the sludge-retention time in the facilities was from 16.5 to 36.5 days, the organic loading ranged between 1.8 Kg COD/d m3 and 0.14 Kg COD/d m3, and the temperature of the activated sludge was between 32.8 and 12.8 degrees C. Under these conditions, the concentrations of total solids in the activated sludge reached 21.6 and 0.3 g/L, and the ratio of food:microrganims (F:M) remained stable at around 0.1 Kg BOD5/Kg VSS day, while the trans-membrane pressure (TMP) followed an increasing trend. Both facilities presented a high capacity for organic matter elimination and complete nitrification. The small flagellates were present throughout the experimental period in the activated sludge and showed no significant bioindicator role in the MBR systems which limited the application of SBI. Of the large flagellates studied, only Peranema sp. could be considered to be a bioindicator of MBR systems, indicating the effectiveness of denitrification for systems with complete nitrification and correlating with the time course of the TMP. PMID- 28628876 TI - Column study of enhanced Cr(VI) removal and longevity by coupled abiotic and biotic processes using Fe0 and mixed anaerobic culture. AB - In this study, Fe0 and mixed anaerobic culture were integrated in one column to investigate the coupled abiotic and biotic effects on hexa-valent chromium (Cr(VI)) removal and column longevity with an abiotic Fe0 column in the control experiments. According to the breakthrough study, a slower Cr(VI) breakthrough rate of 0.19 cm/PV was observed in the biotic Fe0 column whereas the value in the abiotic Fe0 column was 0.30 cm/PV, resulting in 64% longer life-span and 62% higher Cr(VI) removal capacity in the biotic Fe0 column than the abiotic one. The solid phase characterization by scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and X-ray diffraction (XRD) confirmed that this enhancement was attributed to the higher consumption of iron and greater production of diverse reactive minerals (e.g., green rust, magnetite and lepidocrocite) induced by the synergistic interaction of Fe0 and anaerobic culture, providing more reactive sites for Cr(VI) adsorption, reduction and co precipitation. Furthermore, the decreasing breakthrough rates and growing iron corrosion along the biotic Fe0 column demonstrated an inhomogeneous distribution of reactive zones in the column and its latter 3/5 section was considered to be the most reactive area for Cr(VI) removal. These results indicate that the inoculation of microorganisms in Fe0-based permeable reactive barriers will enable this technology a higher removal capacity and longer life-span for the remediation of Cr(VI)-contaminated groundwater. PMID- 28628877 TI - Remediation of groundwater contaminated with arsenic through enhanced natural attenuation: Batch and column studies. AB - Batch and column laboratory experiments were conducted on natural sediment and groundwater samples from a contaminated site in Maine, USA with the aim of lowering the dissolved arsenate [As(V)] concentrations through chemical enhancement of natural attenuation capacity. In batch factorial experiments, two levels of treatment for three parameters (pH, Ca, and Fe) were studied at different levels of phosphate to evaluate their impact on As(V) solubility. Results illustrated that lowering pH, adding Ca, and adding Fe significantly increased the sorption capacity of sediments. Overall, Fe amendment had the highest individual impact on As(V) levels. To provide further evidence for the positive impact of Ca on As(V) adsorption, isotherm experiments were conducted at three different levels of Ca concentrations. A consistent increase in adsorption capacity (26-37%) of sediments was observed with the addition of Ca. The observed favorable effect of Ca on As(V) adsorption is likely caused by an increase in the surface positive charges due to surface accumulation of Ca2+ ions. Column experiments were conducted by flowing contaminated groundwater with elevated pH, As(V), and phosphate through both uncontaminated and contaminated sediments. Potential in-situ remediation scenarios were simulated by adding a chemical amendment feed to the columns injecting Fe(II) or Ca as well as simultaneous pH adjustment. Results showed a temporary and limited decrease in As(V) concentrations under the Ca treatment (39-41%) and higher levels of attenuation in Fe(II) treated columns (50-91%) but only after a certain number of pore volumes (18-20). This study illustrates the importance of considering geochemical parameters including pH, redox potential, presence of competing ions, and sediment chemical and physical characteristics when considering enhancing the natural attenuation capacity of sediments to mitigate As contamination in natural systems. PMID- 28628878 TI - Pretreatment of a primary and secondary sludge blend at different thermal hydrolysis temperatures: Impacts on anaerobic digestion, dewatering and filtrate characteristics. AB - A study was performed to evaluate the effect of thermal hydrolysis pretreatment (THP) temperature on subsequent digestion performance and operation, as well as downstream parameters such as dewatering and cake quality. A blend of primary and secondary solids from the Blue Plains treatment plant in Washington, DC was dewatered to about 16% total solids (TS), and thermally hydrolyzed at five different temperatures 130, 140, 150, 160, 170 degrees C. The thermally hydrolyzed solids were then fed to five separate, 10 L laboratory digesters using the same feed concentration, 10.5% TS and a solids retention time (SRT) of 15 days. The digesters were operated over a six month period to achieve steady state conditions. The higher thermal hydrolysis temperatures generally improved the solids reduction and methane yields by about 5-6% over the temperature range. The increased temperature reduced viscosity of the solids and increased the cake solids after dewatering. The dissolved organic nitrogen and UV absorbance generally increased at the higher THP temperatures. Overall, operating at a higher temperature improved performance with a tradeoff of higher dissolved organic nitrogen and UV adsorbing materials in the return liquor. PMID- 28628879 TI - Development of a method for the characterization and operation of UV-LED for water treatment. AB - Tremendous improvements in semiconductor technology have made ultraviolet light emitting diodes (UV-LEDs) a viable alternative to conventional UV sources for water treatment. A robust and validated experimental protocol for studying the kinetics of microorganism inactivation is key to the further development of UV LEDs for water treatment. This study proposes a protocol to operate UV-LEDs and control their output as a polychromatic radiation source. In order to systematically develop this protocol, the results of spectral power distribution, radiation profile, and radiant power measurements of a variety of UV-LEDs are presented. A wide range of UV-LEDs was selected for this study, covering various UVA, UVB, and UVC wavelengths, viewing angles from 3.5 degrees to 135 degrees , and a variety of output powers. The effects of operational conditions and measurement techniques were investigated on these UV-LEDs using a specially designed and fabricated setup. Operating conditions, such as the UV-LED electrical current and solder temperature, were found to significantly affect the power and peak wavelength output. The measurement techniques and equipment, including the detector size, detector distance from the UV-LED, and potential reflection from the environment, were shown to influence the results for many of the UV-LEDs. The results obtained from these studies were analyzed and applied to the development of a protocol for UV-LED characterization. This protocol is presented as a guideline that allows the operation and control of UV-LEDs in any structure, as well as accurately measuring the UV-LED output. Such information is essential for performing a reliable UV-LED assessment for the inactivation of microorganisms and for obtaining precise kinetic data. PMID- 28628880 TI - Forward osmosis for oily wastewater reclamation: Multi-charged oxalic acid complexes as draw solutes. AB - Forward osmosis (FO) has demonstrated its merits in hybrid FO seawater desalination. However, FO may have a potential for other applications if suitable draw solutes are available. In this study, a series of novel draw solutes based on oxalic acid (OA)-transitional metal complexes are presented. Influential factors of FO performance have been systematically investigated by varying the transitional metals, cations of the complex draw solutes as well as the experimental conditions. Compared to NaCl and other recently synthesized draw solutes, the OA complexes show superior FO performance in terms of high water fluxes up to 27.5 and 89.1 LMH under the respective FO and PRO (pressure retarded osmosis) modes, both with negligible reverse solute fluxes. The features of octahedral geometry, abundant hydrophilic groups and ionic species are crucial for the OA complexes as appropriate draw solutes with satisfactory FO performance. Among the synthesized OA complexes, the ammonium salt of chromic complex (NH4-Cr-OA) outperforms others due to the presence of more ionic species in its complex system. NH4-Cr-OA also performs better than the typical NaCl draw solute in FO oily wastewater treatment with higher water recovery and negligible reverse fluxes. Dilute solutions of OA complexes have been reconcentrated through membrane distillation (MD) and reused to new round of FO processes. The OA complexes have demonstrated their suitability and superiority as a novel class of draw solutes for the FO process in this study. PMID- 28628882 TI - Effective biotransformation and detoxification of anthraquinone dye reactive blue 4 by using aerobic bacterial granules. AB - Treatment of textile wastewater containing anthraquinone dye is quite a huge challenge due to its complex aromatic structure and toxicity. Present study deals with the degradation and detoxification of anthraquinone dye reactive blue 4 using aerobic bacterial granules. Bacterial granules effectively decolorized reactive blue 4 at wide range of pH (4.0-11.0) and temperature (20-55 degrees C) as well as decolorized and tolerated high concentration of reactive blue 4 dye upto 1000 mg l-1 with Vmax 6.16 +/- 0.82 mg l-1 h-1 and Km 227 +/- 41 mg l-1. Metagenomics study evaluates important role of Clostridia, Actinobacteria, and Proteobacterial members in biotransformation and tolerance of high concentrations of reactive blue 4 dye. Up-regulation of xenobiotic degradation and environmental information processing pathways during dye exposure signifies their noteworthy role in dye degradation. Biotransformation of dye was confirmed by significant decrease in the values of total suspended solids, biological and chemical oxygen demand. The metabolites formed after biotransformation was characterized by FT-IR and GC-MS analysis. The reactive blue 4 dye was found to be phytotoxic, cytotoxic and genotoxic whereas its biotransformed product were non-toxic. This study comprehensively illustrates that, bacterial aerobic granules can be used for eco friendly remediation and detoxification of wastewater containing high organic load of anthraquinone dye. PMID- 28628881 TI - Photodegradation and ecotoxicology of acyclovir in water under UV254 and UV254/H2O2 processes. AB - The photochemical and ecotoxicological fate of acyclovir (ACY) through UV254 direct photolysis and in the presence of hydroxyl radicals (UV254/H2O2 process) were investigated in a microcapillary film (MCF) array photoreactor, which provided ultrarapid and accurate photochemical reaction kinetics. The UVC phototransformation of ACY was found to be unaffected by pH in the range from 4.5 to 8.0 and resembled an apparent autocatalytic reaction. The proposed mechanism included the formation of a photochemical intermediate (phiACY = (1.62 +/- 0.07).10-3 mol ein-1) that further reacted with ACY to form by-products (k' = (5.64 +/- 0.03).10-3 M-1 s-1). The photolysis of ACY in the presence of hydrogen peroxide accelerated the removal of ACY as a result of formation of hydroxyl radicals. The kinetic constant for the reaction of OH radicals with ACY (kOH/ACY) determined with the kinetic modeling method was (1.23 +/- 0.07).109 M-1 s-1 and with the competition kinetics method was (2.30 +/- 0.11).109 M-1 s-1 with competition kinetics. The acute and chronic effects of the treated aqueous mixtures on different living organisms (Vibrio fischeri, Raphidocelis subcapitata, D. magna) revealed significantly lower toxicity for the samples treated with UV254/H2O2 in comparison to those collected during UV254 treatment. This result suggests that the addition of moderate quantity of hydrogen peroxide (30-150 mg L-1) might be a useful strategy to reduce the ecotoxicity of UV254 based sanitary engineered systems for water reclamation. PMID- 28628883 TI - Pros and cons of rituximab maintenance in follicular lymphoma. AB - Follicular lymphoma (FL) is the most prevalent indolent non-Hodgkin lymphoma. Most patients present with advanced disease and are incurable with current therapy. The approval of rituximab has revolutionized the treatment of follicular lymphoma when administered in the induction setting for high-tumor burden disease, but the use of rituximab as a maintenance therapy (MR) continues to be a point of controversy. In this article, we review the main data and arguments in favor and against MR in FL. In summary, most studies have demonstrated a significant benefit in progression-free or event-free survival in this notoriously recurrent disease; however, long-term outcomes could not consistently demonstrate to be improved with this intervention. In a meta-analysis of randomized trials overall survival (OS) showed a tendency to improvement when given to patients in relapse, but no single study reached a significant OS advantage. The risk of high-grade transformation does not seem to be reduced in prospective trials. On the other hand, MR clearly increases toxicity without an improvement in quality of life. Finally, MR is expensive, and it is not proven that the delayed relapse time can compensate for these costs. In conclusion, despite the proven increase in progression-free survival, MR can't be recommended as a standard for the treatment of FL. PMID- 28628884 TI - Proteomics profiling reveals inflammatory biomarkers of antidepressant treatment response: Findings from the CO-MED trial. AB - Animal and human studies suggest an association between depression and aberrant immune response. Further, common inflammatory markers may change during the course of antidepressant treatment in patients. The objective of this study was to evaluate changes in inflammatory markers and clinical outcomes from subjects enrolled in the Combining Medications to Enhance Depression Outcome (CO-MED) trial. At baseline and week 12 (treatment completion), plasma samples of 102 participants were analyzed via a multiplex assay comprised of inflammatory markers using a 27-plex standard assay panel plus a 4-plex human acute phase xMAP technology based platform. We carried out analyses in two steps. First, t-tests were used to identify inflammatory marker levels that changed between baseline and week 12. For markers that were altered, logistic regression models were then conducted to look for associated changes in remission at week 12. Among the 31 inflammatory markers analyzed, several cytokines (IL-5, IFN-gamma, IL-13), two chemokines (Eotaxin-1/CCL11, RANTES) and an acute-phase reactant (serum amyloid P component) showed change from baseline to week 12. However, only two indicated differential remission responses. Interestingly, increased levels of Eotaxin 1/CCL11 correlated with remission at week 12, whereas decreased levels of IFN gamma correlated with non-remission at week 12. Results suggest that these inflammatory proteins may serve as predictors of treatment response. PMID- 28628885 TI - Use of antidepressants and risk of hospitalization for acute myocardial infarction: A nationwide case-crossover study. AB - BACKGROUND: We aimed to investigate the association between antidepressant use and the risk of hospitalization for acute myocardial infarction (AMI). METHODS: A case-crossover study was conducted using a nationwide population-based sample from Taiwan's National Health Insurance Research Database. A total of 18,631 patients with incident AMI were included in this study. The effects of antidepressant use as well as that of various classes (including tricyclic or tetracyclic antidepressants; selective serotonin reuptake inhibitors; or serotonin norepinephrine reuptake inhibitors), doses, and receptor-binding profiles of the antidepressants on AMI were assessed. Conditional logistic regression models with adjustment for potential confounding factors were applied to determine the effects of antidepressant use on the risk of AMI during case and control time periods of 15, 30, and 60 days, respectively. The modifiable effects of age, gender, and comorbidity were evaluated by stratified analysis. RESULTS: Antidepressant use was not associated with the risk of AMI (adjusted odds ratio [AOR] = 1.04; 95% confidence interval (CI): 0.88-1.24). Likewise, neither the class, dose, nor the binding affinity of serotonin transporter or norepinephrine transporter was associated with AMI risks, and there was no modifying effect of age, gender, or comorbid medical condition on the association between antidepressant use and AMI. CONCLUSIONS: Use of antidepressant drugs was not associated with the risk of AMI. PMID- 28628886 TI - Estimation of the production of medical Ac-225 on thorium material via proton accelerator. AB - In the present study, we aimed at estimating the production of medical Ac-225 radionuclide via proton accelerator in the energy range Eproton=1000 ->1MeV under certain conditions, on thorium target material instead of uranium due to the low abundant of uranium in nature. Hence, to produce the medical Ac-225, cross section, separation energy was calculated by taking into account the proton induced reaction processes that were simulated to estimate activity and, yield of the product up to 1000MeV. Moreover, the calculated integral yields of reactions were presented. For achieving the aim, we have put forward the X-PMSP program to derive mass stopping power from a new perspective. PMID- 28628887 TI - Determining concentrations of elements with different reaction channels in photon activation. AB - In photon activation, same element may be activated by the bremsstrahlung beam through different nuclear reaction channels and produce different radioisotopes. These radioisotopes follow their own decay schemes and generate characteristic gamma rays. This phenomenon usually is an interference in spectra analysis, but it also offers a theoretical feasibility to determine the concentration of one element through different reaction channels. To realize this theoretical feasibility, we conducted series of photon activation experiments with sample and reference of known concentrations. Irradiation of the samples and the references were conducted with electronic LINAC with different photon converters at a peak energy around 30MeV. Several elements and their corresponding reaction channels were chosen to validate this procedure. Calculations of PAA were based on the internal monitor method. Our results have confirmed the advantages of current PAA reaction channel selection, and show that it might be beneficial to calculate the concentration of same elements with different reaction channels in some certain occasions. N-values, which indicate the relative intensity of reaction channels, were calculated and compared with those values generated from the photon activation at the Federal Institute for Materials Research and Testing in Germany (BAM). Results suggested that N values are impacted by several parameters of electron beam, and the design of electron-gamma converter may play a dominant role in determining N values. PMID- 28628888 TI - An algorithm for filtering detector instabilities in search of novel non exponential decay and in conventional half-life determinations. AB - Recent reports of Solar modulation of beta-decay have reignited interest in whether or not radioactive half-lives are constants. A numerical approach for filtering instrumental effects on residuals is developed, using correlations with atmospheric conditions recorded while counting 204Tl emissions with a Geiger Muller counter. Half-life oscillations and detection efficiency oscillations can be separated provided their periods are substantially different. A partial uncertainty budget for the 204Tl half-life shows significant decreases to medium frequency instabilities correlated with pressure and temperature, which suggests that further development may aid general improvements in half-life determinations. PMID- 28628890 TI - Interleukin-6 induced activation of a non-selective outward cation conductance in human cardiac fibroblasts. AB - BACKGROUND: It has been demonstrated that cardiac fibroblasts of the human heart have several myocyte-like features, induced by inflammation. OBJECTIVES: This study analyzed the changes of the expressed currents in the basal condition and in the presence of interleukin-6 in cultured human cardiac fibroblasts. METHODS: Human cardiac fibroblasts were cultured as monolayers from earlier passages (2 4). Whole-cell voltage clamp experiments were performed on single culture human cardiac fibroblasts. RESULTS: The cultured human cardiac fibroblasts had a membrane resistance of Rm of 412+/-91MOmega, and a resting membrane potential of 68.1+/-3.2mV. Among different cells, we have been analyzed these at which depolarizing clamp steps induced outward currents that reached peak within approx. 20ms and then slowly decayed. Gd3+ decreased the current amplitudes at depolarizing steps. Superfusion with interleukin-6 caused increasing of the outward membrane currents. The changes in the membrane currents continued up to 6min of interleukin-6 perfusion, by reaching their maximum at 3min and slowly decreasing to the level of control recordings at 6min. In the presence of 8MUmol/l Gd3+, interleukin-6 does not modify the membrane currents. CONCLUSION: The involvement of mechano sensitive channels in interleukin-6 induced electrical property of fibroblast was proposed. This report presents one particular model of action of interleukin-6, that can open new insights for a deeper understanding of the relationships between interleukin-6 and different ion channels into the fibroblast. PMID- 28628889 TI - The innate immune response to lower respiratory tract E. Coli infection and the role of the CCL2-CCR2 axis in neonatal mice. AB - : Neonates have greater morbidity/mortality from lower respiratory tract infections (LRTI) compared to older children. Lack of conditioning of the pulmonary immune system due to limited environmental exposures and/or infectious challenges likely contributes to the increase susceptibility in the neonate. In this study, we sought to gain insights into the nature and dynamics of the neonatal pulmonary immune response to LRTI using a murine model. METHODS: Wildtype (WT) and Ccr2-/- C57BL/6 neonatal and juvenile mice received E. coli or PBS by direct pharyngeal aspiration. Flow cytometry was used to measure immune cell dynamics and identify cytokine-producing cells. Real-time PCR and ELISA were used to measure cytokine/chemokine expression. RESULTS: Innate immune cell recruitment in response to E. coli-induced LRTI was delayed in the neonatal lung compared to juvenile lung. Lung clearance of bacteria was also significantly delayed in the neonate. Ccr2-/- neonates, which lack an intact CCL2-CCR2 axis, had higher mortality after E. coli challenged than Ccr2+/+ neonates. A greater percentage of CD8+ T cells and monocytes from WT neonates challenged with E. coli produced TNF compared to controls. CONCLUSION: The pulmonary immune response to E. coli-induced LRTI differed significantly between neonatal and juvenile mice. Neonates were more susceptible to increasing doses of E. coli and exhibited greater mortality than juveniles. In the absence of an intact CCL2-CCR2 axis, susceptibility to LRTI-induced mortality was further increased in neonatal mice. Taken together these findings underscore the importance of age-related differences in the innate immune response to LRTI during early stages of postnatal life. PMID- 28628891 TI - Synthesis and antimicrobial activity of 6-sulfo-6-deoxy-D-glucosamine and its derivatives. AB - 6-Sulfo-6-deoxy-D-glucosamine (GlcN6S), 6-sulfo-6-deoxy-D-glucosaminitol (ADGS) and their N-acetyl and methyl ester derivatives have been synthesized and tested as inhibitors of enzymes catalyzing reactions of the UDP-GlcNAc pathway in bacteria and yeasts. GlcN6S and ADGS at micromolar concentrations inhibited glucosamine-6-phosphate (GlcN6P) synthase of microbial origin. The former was also inhibitory towards fungal GlcN6P N-acetyl transferase, but at millimolar concentrations. Both compounds and their N-acetyl derivatives exhibited antimicrobial in vitro activity, with MICs in the 0.125-2.0 mg mL-1 range. Antibacterial but not antifungal activity of GlcN6S was potentiated by D glucosamine and a synergistic antibacterial effect was observed for combination of ADGP and a dipeptide Nva-FMDP. PMID- 28628892 TI - Structural characterization of wall and lipidated polysaccharides from Clostridium perfringens ATCC 13124. AB - Cell surface polysaccharides produced by C. perfringens ATCC 13124 were analyzed using NMR, chemical and immunological methods. Two distinct polymers were identified. The more abundant PS1 had a structure based on a polymer of beta mannosamine with a number of modifications, including varying levels of substitution at O-6 with PEtN, N-acetylation, and different linkages between monosaccharides. The shortest variant of PS1 represented a lipoteichoic acid. It contained only 1-4-linkages between ManNAc residues, minor branching alpha-Ribf, and glucosyl-glycerol at the reducing end, which was acylated with linear saturated fatty acids C16, C18, and C20 (dominant). Other non-lipidated variants of PS1 contained less PEtN, no alpha-Ribf, up to 50% 1-3-linkages, and up to 25% ManN with the free amino group. The minor polysaccharide PS2 had a linear regular structure with a -4-alpha-Rha-3-beta-Gal-4-beta-GalNAc3PCho- repeating unit, where PCho indicates phosphocholine. PMID- 28628893 TI - One-year mortality after hip fracture in older individuals: the effects of delirium and dementia. AB - BACKGROUND: Delirium is common in older hip fracture patients, yet its association with mortality after hip fracture remains uncertain. This study aimed to determine whether delirium was associated with all-cause one-year mortality after hip fracture in older patients and whether the effect of delirium was independent of dementia status. METHOD: A retrospective analysis of linked hospitalisation and mortality data for patients aged >=65 years with a hip fracture during 1 January 2010 to 30 June 2014 in New South Wales, Australia. The association between delirium and mortality after a hip fracture was assessed using Cox proportional hazard regression. RESULTS: There were 4,065 (14.6%) of 27,888 hip fracture hospitalisations identified with delirium during hospitalisation. Individuals with delirium had a higher age-adjusted rate of all cause one-year mortality after hip fracture compared to individuals without delirium (35.3% versus 23.9%). After adjusting for covariates, the risk of all cause mortality was increased at one-year post-admission for older individuals compared to those aged 65-69 years, for individuals with multiple comorbidities, dementia (Hazard Ratio (HR): 1.14; 95%CI:1.08-1.20), delirium (HR: 1.19; 95%CI:1.12-1.26), and who had an Intensive Care Unit admission (HR: 1.44; 95%CI:1.31-1.59). Comorbid delirium did not add additional mortality risk for individuals with a hip fracture who have dementia. CONCLUSIONS: Delirium identified in hospital was associated with all-cause one-year mortality after hip fracture in older Australians without dementia. As delirium is potentially preventable, better systematic assessment and documentation of a hip fracture patient's cognitive state is warranted to select the most effective strategies to prevent and manage delirium. PMID- 28628895 TI - A composite polynomial approach for analyzing the indefinite self-association of macromolecules studied by sedimentation equilibrium. AB - A different approach is described for analyzing sedimentation equilibrium experiments of indefinitely self-associating systems. The procedure involves application of conservation of mass criteria, along with local evaluation of the weight average molar mass, to generate a polynomial based on a composite pseudo independent variable. The outlined method does not depend upon non-linear regression to generate a solution, but instead requires evaluation of the roots of a high-order polynomial. PMID- 28628894 TI - Small molecule probes for cellular death machines. AB - The past decade has witnessed a significant expansion of our understanding about the regulated cell death mechanisms beyond apoptosis. The application of chemical biological approaches had played a major role in driving these exciting discoveries. The discovery and use of small molecule probes in cell death research has not only revealed significant insights into the regulatory mechanism of cell death but also provided new drug targets and lead drug candidates for developing therapeutics of human diseases with huge unmet need. Here, we provide an overview of small molecule modulators for necroptosis and ferroptosis, two non apoptotic cell death mechanisms, and discuss the molecular pathways and relevant pathophysiological mechanisms revealed by the judicial applications of such small molecule probes. We suggest that the development and applications of small molecule probes for non-apoptotic cell death mechanisms provide an outstanding example showcasing the power of chemical biology in exploring novel biological mechanisms. PMID- 28628896 TI - Cholinergic neuron gene expression differences captured by translational profiling in a mouse model of Alzheimer's disease. AB - Cholinergic neurotransmission is impaired in Alzheimer's disease (AD), and loss of basal forebrain cholinergic neurons is a key component of disease pathogenicity and symptomatology. To explore the molecular basis of this cholinergic dysfunction, we paired translating ribosome affinity purification (TRAP) with RNA sequencing (TRAP-Seq) to identify the actively translating mRNAs in anterior forebrain cholinergic neurons in the TgCRND8 mouse model of AD. Bioinformatic analyses revealed the downregulation of 67 of 71 known cholinergic related transcripts, consistent with cholinergic neuron dysfunction in TgCRND8 mice, as well as transcripts related to oxidative phosphorylation, neurotrophins, and ribosomal processing. Upregulated transcripts included those related to axon guidance, glutamatergic synapses and kinase activity and included AD-risk genes Sorl1 and Ptk2b. In contrast, the total transcriptome of the anterior forebrain showed upregulation in cytokine signaling, microglia, and immune system pathways, including Trem2, Tyrobp, and Inpp5d. Hence, TRAP-Seq clearly distinguished the differential gene expression alterations occurring in cholinergic neurons of TgCRND8 mice compared with wild-type littermates, providing novel candidate pathways to explore for therapeutic development in AD. PMID- 28628897 TI - Diverted medications and new psychoactive substances-A chemical network analysis of discarded injecting paraphernalia in Hungary. AB - BACKGROUND: Until about 2010, people who inject drugs (PWIDs) injected almost exclusively heroin and amphetamines in Hungary. After 2010, self-reported studies have indicated a dominance of new psychoactive substances on the drug market for injectable drugs. METHODS: Between March 2015 and February 2016, we collected used and discarded injecting paraphernalia. We utilized chemical analysis to assess and UCINet to visualize the connections between the most prevalent main substances and their respective co-occurring additional components at 7 locations in Hungary. RESULTS: The samples (n=2977) contained a mean of 4.5 components (SD=3.1, range: 1-18); 422 contained only one component. We found that the most common main components were the diverted substitution medication methadone (32%) and cathinones: pentedrone (18%), mephedrone (13%), alpha-PHP (8%), and alpha-PEP (5%). While these main substances also occurred among the top co-occurring additional components, caffeine and benzoic acid (a preservative) also frequently co-occurred. CONCLUSION: A large number of co-occurring additional components indicate either common reuse of injecting paraphernalia or the common addition of additives or both. While caffeine may indeed be an adulterant, the high prevalence of benzoic acid may be difficult to explain. The preference of methadone despite the availability of a wide array of drugs may indicate a preference for opioids during the current heroin drought and/or a true demand for opioid substitution therapy. PMID- 28628898 TI - "Talking about child sexual abuse would have helped me": Young people who sexually abused reflect on preventing harmful sexual behavior. AB - Harmful sexual behavior carried out by children and young people accounts for about half of all child sexual abuse perpetration. The aim of this study was to draw on the insights of young people who had been sexually abusive to enhance the current prevention agenda. The study involved semi-structured interviews with 14 young people and six treatment-providing workers. Sampling was purposive and the young people had previously completed a treatment program for harmful sexual behaviour in Victoria, Australia. The young people were approached as experts based on their previous experience of engaging in harmful sexual behavior. At the same time, their past abusive behavior was not condoned or minimised. Constructivist Grounded Theory was used to analyse the qualitative data. Opportunities for preventing harmful sexual behavior were the focus of the interviews with young people and workers. The research identified three opportunities for prevention, which involved acting on behalf of children and young people to: reform their sexuality education; redress their victimization experiences; and help their management of pornography. These opportunities could inform the design of initiatives to enhance the prevention agenda. PMID- 28628899 TI - Correlates of child abuse potential among African American and latina mothers: A developmental-ecological perspective. AB - The child victimization rate in the US has rapidly grown over the past five years. Today, nine out of every 1000 children are victims of some type of child maltreatment, and lifetime costs of child victimization exceed $100 billion per year. Effective policies promoting fairness and child safety must target the most salient indicators of child maltreatment. In this study, we examined three groups of risk factors for child abuse potential with the goal of identifying the most prominent indicators in a sample of 170 African-American and Latina mothers. Specifically, we analyzed the effect of socio-demographic variables (e.g., SES), child-specific behaviors, maternal trauma and corresponding psychological sequelae on child abuse potential. Variables from all three groups were significantly associated with child abuse potential with maternal SES, alexithymia, depression, and child self-control as well as internalizing behaviors having the largest effects. All factors combined captured over 50% of the variation in child abuse potential. The results highlight the need for programs that not only address the financial needs of low SES mothers, but also the mental health outcomes correlated with low SES. Particular emphasis should also be placed on interventions that address children's social needs, specifically their socio-emotional functioning. PMID- 28628900 TI - Evaluation of the InnoTyper(r) 21 genotyping kit in multi-ethnic populations. AB - We report the findings of the evaluation of the InnoTyper(r) 21 genotyping kit for the use of human identification (HID) and paternity testing in South Africa. This novel forensic kit evaluates 20 retrotransposable elements (AC4027, MLS26, ALU79712, NBC216, NBC106, RG148, NBC13, AC2265, MLS09, AC1141, TARBP, AC2305, HS4.69, NBC51, ACA1766, NBC120, NBC10, NBC102, SB19.12 and NBC148) and the Amelogenin locus for sex determination. The evaluation of the genotyping performance showed no significant spectral pull-up for peak heights between 100 and 30,000 RFUs. All loci presented biallelic patterns except the triallelic RG148 locus resulting from a variant insertion allele, named RG148I-1, observed exclusively in the Bantu. The InnoTyper(r) 21 kit was found to be highly discriminatory between the 507 unrelated individuals of the Afrikaaner, Asian Indian, Coloured, amaXhosa and amaZulu groups. The HID parameters: the CPD ranged between 0.99999987 and 0.9999999845, and the CMP between 1.0335*10-7 and 1.5506*10-8. The paternity parameters: the CPI ranged between 0.0202 and 0.3177, and the CPE between 0.9161 and 0.9749. There were no significant signs of deviations from HWE or linkage disequilibrium (LD) after applying a Bonferroni correction. This kit also showed minor levels of population structure which could differentiate between the African and non-African population groups. Finally, in challenging casework with severely degraded biological material, the InnoTyper(r) 21 genotyping kit was compatible with GlobalFiler(r) and Investigator DIPplex(r) to increase the HID parameters. PMID- 28628901 TI - Characterisation of artefacts and drop-in events using STR-validator and single cell analysis. AB - There is a need to understand the occurrence of drop-in and their peak height distributions to further improve existing models to interpret complex DNA results. The necessary data is usually very time-consuming to collect. Here we present a practical approach for simultaneous characterisation of reproducible artefacts and drop-in contamination from negative controls. As an alternative to the traditional approach we demonstrate the use of the DEPArray system as a source of single molecules for amplification to infer the peak height distribution of drop-in events. Though signal detection is often confounded by noise and artefact, single molecule contamination, or allele drop-in, is also regularly detected as demonstrated by the overlap in signal intensities between suspected drop-in events and signal obtained from single-cells. PMID- 28628902 TI - Recycling stabilised/solidified drill cuttings for forage production in acidic soils. AB - Stabilisation/solidification (S/S), which involves fixation and immobilisation of contaminants using cementitious materials, is one method of treating drill cuttings before final fate. This work considers reuse of stabilised/solidified drill cuttings for forage production in acidic soils. It sought to improve the sustainability of S/S technique through supplementation with the phytoremediation potential of plants, eliminate the need for landfill disposal and reduce soil acidity for better plant growth. Drill cuttings with an initial total petroleum hydrocarbon (TPH) concentration of 17,125 mg kg-1 and low concentrations of metals were treated with 5%, 10%, and 20% cement dosages. The treated drill cuttings were reused in granular form for growing a forage, elephant grass (Pennisetum purpureum), after mixing with uncontaminated soil. The grasses were also grown in uncontaminated soil. The phytoremediation and growth potential of the plants was assessed over a 12-week period. A mix ratio of one part drill cuttings to three parts uncontaminated soil was required for active plant growth. The phytoremediation ability of elephant grass (alongside abiotic losses) reduced the TPH level (up to 8795 mg kg-1) in the soil-treated-drill cuttings mixtures below regulatory (1000 mg kg-1) levels. There were also decreased concentrations of metals. The grass showed better heights and leaf lengths in soil containing drill cuttings treated with 5% cement dosage than in uncontaminated soil. The results suggest that recycling S/S treated drill cuttings for forage production may be a potential end use of the treated waste. PMID- 28628903 TI - Functional kaolin supported nanoscale zero-valent iron as a Fenton-like catalyst for the degradation of Direct Black G. AB - Kaolin supported nanoscale zero-valent iron (K-nZVI) is synthesized and applied as the Fenton-like oxidation catalyst to degrade a model azo dye, Direct Black G (DBG). The characterization of K-nZVI by the high resolution transmission electronmicroscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), Energy Diffraction Spectrum (EDS) and X-ray diffraction (XRD) show that kaolin as a support material not only reduces the aggregation of zero-valent iron (nZVI) but also facilitates the Fenton-like oxidation by increasing the local concentration of DBG in the vicinity of nZVI. Pseudo first-order and pseudo second-order kinetic models are employed to reveal the adsorption and degradation of the DBG using K-nZVI as the catalyst. A better fit with pseudo second-order model for the adsorption process and equal excellent fits with pseudo first-order and pseudo second-order models for the degradation process are observed; the adsorption process is found to be the rate limiting step for overall reactions. The adsorption, evaluated by isotherms and thermodynamic parameters is a spontaneous and endothermic process. High performance liquid chromatography-mass spectrometry (LC-MS) analysis was used to test degraded products in the degradation of DGB by K-nZVI. A removal mechanism based on the adsorption and degradation is proposed, including (i) prompt adsorption of DBG onto the K-nZVI surface, and (ii) oxidation of DBG by hydroxyl radicals at the K-nZVI surface. The application of K-nZVI to treat real wastewater containing azo dyes shows excellent degradation efficiency. PMID- 28628904 TI - Geochemical characteristics of rare earth elements in different types of soil: A chemometric approach. AB - Rare earth elements (REEs) are becoming significant due to their huge applications in many industries, large-scale mining and refining activities. Increasing usage of such metals pose negative environmental impacts. In this research ICP-MS has been used to analyze soil samples collected from former ex mining areas in the depths of 0-20 cm, 21-40 cm, and 41-60 cm of residential, mining, natural, and industrial areas of Perak. Principal component analysis (PCA) revealed that soil samples taken from different mining, industrial, residential, and natural areas are separated into four clusters. It was observed that REEs were abundant in most of the samples from mining areas. Concentration of the rare elements decrease in general as we move from surface soil to deeper soils. PMID- 28628905 TI - A ROS-mediated mitochondrial pathway and Nrf2 pathway activation are involved in BDE-47 induced apoptosis in Neuro-2a cells. AB - Our previous study showed that 2,2'-,4,4'-tetrabromodiphenyl ether (BDE-47) is cytotoxic and induces apoptosis in Neuro-2a cells. In the present study, we aimed to investigate whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcriptional regulator of oxidative stress and apoptosis, is involved in this process. The results of toxicological experiments showed that BDE-47 decreased the cellular mitochondrial membrane potential (MMP) and increased cytochrome c release to the cytoplasm, followed by an increase in intracellular caspase-9 and caspase-3 activity, suggesting that a mitochondrial pathway was involved in the apoptotic process. Intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) contents as well as the oxidized/reduced glutathione (GSSG/GSH) ratio were elevated simultaneously in a concentration dependent manner, indicating that BDE-47 induced oxidative stress. The ROS scavenger N-acetyl-l-cysteine (NAC) not only alleviated the oxidative stress but also blocked apoptosis and the decrease in MMP induced by BDE-47, indicating that the overproduction of ROS participates in a mitochondria-mediated apoptotic pathway. Moreover, BDE-47 stimulated the transcriptional induction of the Nrf-2 gene and induced mRNA expression of the main antioxidant response genes in the Nrf-2 pathway, including heme oxygenase 1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase modifier (GCLM) and glutathione peroxidase (GPX). Additionally, NAC and the p38 mitogen activated protein kinase (MAPK) signaling pathway inhibitor SB 203580 greatly reduced Nrf2 and HO-1 induction. We hypothesized that the ROS mediated mitochondrial pathway is involved in the BDE 47-induced apoptosis in Neuro-2a cells and that the Nrf2 pathway helps protect Neuro-2a cells from BDE-47-induced apoptosis. PMID- 28628906 TI - Quadrupolar nutation NMR to discriminate central and satellite transitions: Spectral assignments for a Ziegler-Natta catalyst. AB - In this contribution we used solid state 35Cl (I=3/2) quadrupolar NMR to study a MgCl2/2,2-dimethyl-1,3-dimethoxypropane (DMDOMe) adduct that serves as a model system for Ziegler-Natta catalysis. Employing large Radio-Frequency (RF) field strengths we observe three spectral features with strongly varying line widths. The assignment of the spectra is complicated because of the large difference in quadrupolar interactions experienced by the different sites in the system. The satellite transitions (ST) of relatively well-defined bulk Cl sites are partially excited and may overlap with the central transition (CT) resonances of more distorted surface sites. We show that nutation NMR of the ST of I=3/2 spins yields a unique pattern that makes a clear distinction between an extensively broadened central transition and the satellite transitions of a component with a smaller quadrupolar interaction. This allows us to unambiguously unravel the spectra of the MgCl2 adduct showing that we observe CT and ST of the bulk phase of MgCl2-nanoparticles with a CQ of 4.6MHz together with the CT of surface sites displaying an average CQ of ~10MHz. PMID- 28628907 TI - Whispering Gallery mode ESR spectroscopy and parameters measurement in single crystal SrLaAlO4 at millikelvin temperature. AB - A cylindrical single crystal SrLaAlO4 Whispering Gallery mode dielectric resonator was cooled to millikelvin temperature using a dilution refrigerator. By controlling a DC-magnetic field, impurity ions' spins were coupled to a variety of modes allowing the measurement of hybrid spin-photon systems. This Electron Spin Resonance mapping technique allowed us to detect Cu2+,Fe3+ and Mn4+ impurity ions (at the level of parts per million (ppm) to parts per billion (ppb)), verified by the measurement of the spin parameters along with their site symmetry. Whispering Gallery modes exhibited Q-factors ?105 at a temperature less than 20mK, allowing sensitive spectroscopy with high precision. Measured hyperfine line constants of the Cu2+ ion shows different parallel g-factors, g||Cu, of 2.526,2.375,2.246 and 2.142. The spin-orbit coupling constant of the Cu2+ ion was determined to be lambda?-635cm-1. The low-spin state Fe3+ ion's measured parallel g-factor, g||Fe, of 2.028 reveals tetragonal anisotropy. The Mn4+ ion is identified in the lattice, producing hyperfine structure with high valued g-factors,g||Mn, of 7.789,7.745,7.688,7.613,7.5304 and 7.446. The hyperfine structures of the Cu2+ and Mn4+ ions show broadening of about 79G between 9.072GHz and 10.631GHz, and 24.5G broadening between 9.072GHz and 14.871GHz, respectively. PMID- 28628908 TI - Design of a shielded coil element of a matrix gradient coil. AB - The increasing interest in spatial encoding with non-linear magnetic fields has intensified the need for coils that generates such fields. Matrix coils consisting of multiple coil elements appear to offer a high flexibility in generating customized encoding fields and are particularly promising for localized high resolution imaging applications. However, coil elements of existing matrix coils were primarily designed and constructed for better shimming and therefore are not expected to achieve an optimal performance for local spatial encoding. Moreover, eddy current properties of such coil elements were not fully explored. In this work, an optimization problem is formulated based on the requirement of local non-linear encoding and eddy current reduction that results in novel designs of coil elements for an actively-shielded matrix gradient coil. Two metrics are proposed to assess the performance of different coil element designs. The results are analyzed to reveal new insights into coil element design. PMID- 28628909 TI - Nonalcoholic fatty liver disease impairs the cytochrome P-450-dependent metabolism of alpha-tocopherol (vitamin E). AB - This study aims to investigate in in vivo and in vitro models of nonalcoholic fatty liver disease (NAFLD) the enzymatic metabolism of alpha-tocopherol (vitamin E) and its relationship to vitamin E-responsive genes with key role in the lipid metabolism and detoxification of the liver. The experimental models included mice fed a high-fat diet combined or not with fructose (HFD+F) and HepG2 human hepatocarcinoma cells treated with the lipogenic agents palmitate, oleate or fructose. CYP4F2 protein, a cytochrome P-450 isoform with proposed alpha tocopherol omega-hydroxylase activity, decreased in HFD and even more in HFD+F mice liver; this finding was associated with increased hepatic levels of alpha tocopherol and decreased formation of the corresponding long-chain metabolites alpha-13-hydroxy and alpha-13-carboxy chromanols. A decreased expression was also observed for PPAR-gamma and SREBP-1 proteins, two vitamin E-responsive genes with key role in lipid metabolism and CYP4F2 gene regulation. A transient activation of CYP4F2 gene followed by a repression response was observed in HepG2 cells during the exposure to increasing levels of the lipogenic and cytotoxic agent palmitic acid; such gene repression effect was further exacerbated by the co treatment with oleic acid and alpha-tocopherol and was also observed for PPAR gamma and the SREBP isoforms 1 and 2. Such gene response was associated with increased uptake and omega-hydroxylation of alpha-tocopherol, which suggests a minor role of CYP4F2 in the enzymatic metabolism of vitamin E in HepG2 cells. In conclusion, the liver metabolism and gene response of alpha-tocopherol are impaired in experimental NAFLD. PMID- 28628910 TI - The Efficacy of Trimodal Chemoradiotherapy with Cisplatin as a Bladder-Preserving Strategy for the Treatment of Muscle-Invasive Bladder Cancer. AB - INTRODUCTION: Open radical cystectomy (ORC) is currently the standard treatment for muscle-invasive bladder cancer (MIBC) without metastasis, while many patients with MIBC are not always appropriate candidates due to multiple comorbidities. To evaluate the bladder-preservation strategy, we compared the results with those obtained by ORC. PATIENTS AND METHODS: We retrospectively analyzed the data of 50 patients with MIBC treated by trimodal chemoradiotherapy with cisplatin (CDDP radiation [CDDP-R]). Transurethral resection of the bladder tumor (TURBT) was performed before treatment to confirm pathological stage >=T2. Extensive TURBT was performed after chemoradiotherapy to evaluate the pathological response to treatment. We compared the survival outcomes of our CDDP-R with those of ORC (retrospective cohort, n = 205) by propensity score matching analysis. RESULTS: The 2- and 5-year progression-free survival, bladder-intact survival, cancer specific survival, and overall survival (OS) rates after treatment were 70.8 and 63.9%, 64.0 and 49.8%, 86.7 and 71.8%, and 84.3 and 64.8%, respectively. The 2- and 5-year OS rates after CDDP-R were 90.5 and 74.3%, respectively, and those after ORC were 71.8 and 59.9%, respectively, indicating a significant survival advantage conferred by CDDP-R over ORC (p < 0.05, HR 0.45, 95% CI 0.21-0.94). CONCLUSIONS: In selected patients, CDDP-R for MIBC may provide comparative oncological outcomes as ORC. PMID- 28628911 TI - A CARASIL Patient from Americas with Novel Mutation and Atypical Features: Case Presentation and Literature Review. AB - OBJECTIVE: Reporting a novel mutation in the HTRA1 gene in a CARASIL patient from Americas. METHODS: Clinical presentation and neuroimaging were consistent with CARASIL. HTRA1 DNA sequencing was performed using advanced ("next generation") sequencing technology. The results revealed a homozygous missense mutation as c.616G>A (p.Gly206Arg) in the HTRA1 gene. RESULTS: A 24-year-old man with a history of chronic back pain presented with recurrent ischemic strokes. A diagnosis of CARASIL was made with the finding of a novel homozygous missense mutation c.616G>A in HTRA1 gene, resulting in change from Glycine to Arginine in the Serine Protease HTRA1. Brain imaging showed multiple lacunar infarcts with extensive abnormalities of the white matter that spared the external capsules. He also had unilateral decreased hearing with craniofacial asymmetry. None of the above features have been previously described in known CARASIL patients. Both parents of the proband were heterozygous for the same missense mutation. CONCLUSION: We discovered a novel missense mutation (c.616G>A) associated with a phenotype of CARASIL. This is the first genetically backed case of CARASIL in the new world. The patient's craniofacial abnormalities, including asymmetry of the head, may be related to impaired modulation of transforming growth factor-beta1, the result of loss of proteolytic activity of HTRA1. External capsules remained unaffected, despite findings of advanced changes in the rest of the cerebral white matter. Literature is briefly reviewed. The patient's history, neurological exam, neuroimaging, and genetic testing are included. PMID- 28628912 TI - Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice. AB - BACKGROUND/AIMS: Sepsis is a common disease that continues to increase in prevalence worldwide, and diabetes mellitus may make the situation worse. This study was designed to determine the role of Liver Kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in diabetic mice complicated with systemic endotoxemia. METHODS: The effects of LKB1/AMPK signaling pathway activation on endotoxemia were investigated in streptozotocin induced diabetic mice (STZ-mice) and db/db diabetic mice. Primary peritoneal macrophages and human umbilical vein endothelial cells (HUVECs) monolayers were simultaneously stimulated by both high glucose and LPS and used as a model to investigate the potential molecular mechanisms in vitro. RESULTS: After treatment with LPS, high glucose or both LPS and high glucose, phosphor-AMPK expression was decreased, and moreover, AMPK activation by metformin treatment alleviated the decrease in phosphor-AMPK expression in HUVECs and macrophages as well as in lung tissue. Furthermore, both LPS and high glucose co-treatment decreased LKB1 and phosphor-AMPK expression via enhanced oxidative stress response, and importantly, LKB1 overexpression mediated by adenovirus inhibited the decrease in phosphor AMPK expression in macrophages and HUVECs. AMPK activation by metformin administration improved the survival of STZ-induced diabetic mice and db/db diabetic mice, which was associated with reduced lung endothelial hyperpermeability and systemic inflammatory response. Furthermore, the permeability of HUVECs monolayers induced by both high glucose and LPS stimulation was also alleviated by AMPK activation, which was partly via suppression of VE-cadherin phosphorylation. CONCLUSION: These data demonstrated that LKB1/AMPK signaling pathway activation improved the survival of diabetic mice complicated with endotoxemia. Thus, LKB1/AMPK signaling pathway may serve as a potentially useful therapeutic target for severe infection in diabetic patients. PMID- 28628913 TI - Age-Dependent Effects of ALK5 Inhibition and Mechanism of Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury. AB - Neonatal encephalopathy due to hypoxic-ischemic (HI) brain injury triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the initial insult. In a recent set of studies, we evaluated the therapeutic efficacy of a small molecule antagonist for ALK5 (activin-like kinase 5 ), TGF-beta receptor in a rat model of moderate perinatal HI and found significant improvements in neurologic outcomes. Here, we have extended those studies to evaluate the efficacy of delayed TGF-beta receptor antagonism on postnatal day (P) 6 and P9 HI rat pups with and without hypothermia. The ALK5 receptor antagonist SB505124 was administered systemically by osmotic pump beginning 3 days following HI. Extending our earlier data set that showed protection of the hippocampus in P6 pups treated with SB505124, these animals sustained less damage to their hippocampi and had improved performance on the Morris water maze (MWM) when tested on P60 versus vehicle-treated HI animals. By contrast, SB505124 did not improve sensorimotor deficits and exacerbated hippocampal and thalamic volume loss when administered 3 days after HI to P9 pups. SB505124-treated rats injured on P9 tended to perform worse than their vehicle-treated counterparts on MWM, and SB505124 treatment did not preserve hippocampal or thalamic neurons in P9 pups when combined with hypothermia. To elucidate the mechanism whereby ALK5 inhibition reduced neuronal death in the P6 HI model, we assessed levels of autophagy markers in neurons of the neocortex, hippocampus, and thalamus, and in the subcortical white matter, and found that SB505124 increased numbers of autophagosomes and levels of lipidated LC3 (light chain 3), a key protein known to mediate autophagy. Altogether, our results demonstrate that there is a dynamic switch in the CNS response to TGF-beta1 that occurs around P9 in rats where TGF-beta signaling inhibition worsens functional outcomes. This response is similar to the outcome of antagonizing TGF-beta signaling in adult stroke and other CNS disease models. We conclude that attenuating TGF-beta1 signaling will likely be an effective treatment for HI related encephalopathy in moderately preterm infants, offering protection of the neocortex, hippocampus, and thalamus with enhanced cerebral autophagy contributing to the decrease in the extent of progressive neuronal cell death. PMID- 28628914 TI - Efficacy and Safety of Tadalafil Once-a-Day versus Tadalafil On-Demand in Patients with Erectile Dysfunction: A Systematic Review and Meta-Analyses. AB - INTRODUCTION: To compare the efficacy and safety between tadalafil once-a-day and tadalafil on-demand dosing regimen in patients with ED. MATERIALS AND METHODS: A systematic search of Medline, Embase, and Cochrane Library was performed to identify all randomized controlled trials (RCTs) that compared tadalafil used a once-a-day with an on-demand dosing regimen for erectile dysfunction. A secondary hand-search was performed in relevant journals, references, and the grey literature. Meta-analyses were performed using Review Manager version 5.3.0. RESULTS: Six RCTs involving a total of 1,534 patients were included in this review. All studies reported the International Index of Erectile Function Erectile Function domain score and the results of the meta-analysis showed no difference between the groups. The overall pooled estimated weighted mean differences (WMD) was 0.97 (95% CI -0.37 to 2.32; p = 0.16). Meta-analyses of Sexual Encounter Profile questions 2 and 3 (SEP-2 and SEP-3) showed that the once a-day dosing regimen was superior to the on-demand regimen with statistical significance. The WMD of SEP-2 and SEP-3 were 10.32 (95% CI 3.16-17.48; p = 0.005) and 11.07 (95% CI 2.57-19.56; p = 0.01), respectively. Both dosing regimens of tadalafil showed similar complication rates. The meta-analyses of adverse events showed no significant differences. CONCLUSIONS: The efficacy rates of tadalafil once-a-day and on-demand were similar. No significant difference in safety was found between the 2 dose regimens of tadalafil. PMID- 28628915 TI - MiR-495 Promotes Senescence of Mesenchymal Stem Cells by Targeting Bmi-1. AB - BACKGROUND/AIMS: Mesenchymal stem cells (MSCs) play an important role in regulating angiogenesis and immune balance. Abnormal proliferation and function of MSCs were reported at maternal fetal interface in patients with pre-eclampsia (PE). Micro-RNA-495 was known to be upregulated in the MSCs derived from patients with PE. However, it is not clear whether the up-regulated miR-495 is related to the pathogenesis of PE. METHODS: We analyzed the expression of miR-495 in MSCs and umbilical cords derived from healthy pregnancies (NC) and PE, then we upregulated or downregulated the expression of miR-495 in MSCs derived from NC and tested the proliferation, apoptosis, migration, invasion, tube formation and senescence. RESULTS: In the current study, we found that the expression of miR 495 was significantly increased in both umbilical cord tissues and MSCs in patients with severe PE. Overexpressing miR-495 arrested cell cycle in S phase and promoted cell apoptosis. The supernatants from miR-495-overexpressed-MSCs inhibited the migration of MSCs and HTR-8/SVneo, invasion of HTR-8/SVneo and tube formation of HUVEC, while si-miR-495 had the opposite effects. Furthermore, we analyzed the senescence related beta-galactosidase activity and CD146 and found that miR-495 induced the senescence of MSCs. Molecular mechanism studies confirmed that Bmi-1 mediated these effects of miR-495 on MSCs. CONCLUSION: Taken together, our data demonstrated that miR-495 induced senescence of MSCs may be involved in the pathogenesis of PE. PMID- 28628916 TI - Comprehensive Biomarker Analyses in Patients with Advanced or Metastatic Non Small Cell Lung Cancer Prospectively Treated with the Polo-Like Kinase 1 Inhibitor BI2536. AB - BACKGROUND: Polo like kinase 1 (PLK1) is frequently upregulated in tumors and is thus viewed as a promising therapeutic target in various cancers. Several PLK1 inhibitors have recently been developed and clinically tested in solid cancers, albeit with limited success. So far, no predictive biomarkers for PLK1 inhibitors have been established. To this end, we conducted a post-hoc biomarker analysis of tumor samples from non-small cell lung cancer (NSCLC) patients treated with the PLK1 inhibitor BI2536 in a phase II study. METHODS: We analyzed formalin-fixed paraffin-embedded surplus tumor tissue from 47 study patients using immunohistochemistry (IHC) and DNA sequencing of KRAS, EGFR, BRAF, and PIK3CA. RESULTS: KRAS-mutated patients showed numerically prolonged progression-free survival, but statistical significance was not established. Interestingly, when pathways rather than single genes were analyzed, a positive correlation between IHC staining of activated ERK (p-ERK) and mutated KRAS was detected, whereas KRAS mutation status was found to be negatively correlated with activated AKT (p-AKT). CONCLUSION: With this hypothesis-generating study in BI2531-treated patients, we could not establish a correlation between KRAS mutations and relevant clinical endpoints. Future clinical trials with concomitant systematic biosampling and comprehensive molecular analyses are required to identify biomarkers predictive for response to PLK1 inhibitors. PMID- 28628917 TI - Anatomical Characteristics of Facial Nerve and Cochlea Interaction. AB - OBJECTIVE: The aim was to study the relationship between the labyrinthine portion (LP) of the facial canal and the cochlea in human inner ear molds and temporal bones using micro-CT and 3D rendering. A reduced cochlea-facial distance may spread electric currents from the cochlear implant to the LP and cause facial nerve stimulation. Influencing factors may be the topographic anatomy and otic capsule properties. METHODS: An archival collection of human temporal bones underwent micro-CT and 3D reconstruction. In addition, cochlea-facial distance was assessed in silicone and polyester resin molds, and the association between the LP and upper basal turn of the cochlea was analyzed. RESULTS: Local thinning of the otic capsule and local anatomy may explain the development of cochlea facial dehiscence, which was found in 1.4%. A reduced cochlea-facial distance was noted in 1 bone with a superior semicircular canal dehiscence but not in bones with superior semicircular canal "blue line." The otic capsule often impinged upon the LP and caused narrowing. CONCLUSION: Micro-CT with 3D rendering offers new possibilities to study the topographic anatomy of the human temporal bone. The varied shape of the cross-section of the LP could often be explained by an "intruding" cochlea. PMID- 28628918 TI - Bifidobacterium-Rich Fecal Donor May Be a Positive Predictor for Successful Fecal Microbiota Transplantation in Patients with Irritable Bowel Syndrome. AB - BACKGROUND/AIMS: Dysbiosis is associated with various systemic disorders including irritable bowel syndrome (IBS). Fecal microbiota transplantation (FMT) might restore intestinal microbial balance. The study aimed to determine the safety and efficacy of FMT in IBS patients, as well as also positive predictors for FMT. METHODS: This was a single-arm, open-label study. Eligible patients were diagnosed based on Rome III Diagnostic Criteria. Fecal materials were administered to the patient via colonoscopy. The primary end point was a change in the Bristol stool form scale at 4 weeks after FMT. Recovery to types 3-4 was considered a clinical response. The secondary end point was a change in intestinal microbiota and psychological status using the Hamilton Rating Scale. RESULTS: Ten patients were enrolled. Six patients achieved a clinical response. The diversity of patients 4 weeks after FMT increased significantly compared with patients before FMT, and that of responding patients was significantly higher than non-responder patients. The abundance of Bifidobacterium in effective donors was significantly higher than in ineffective donors and patients. Psychological status of all patients was significantly improved after FMT. CONCLUSIONS: FMT for patients with IBS is safe, and relatively effective. Bifidobacterium-rich fecal donor may be a positive predictor for successful FMT. Key Summary: (1) Dysbiosis is associated with various gastrointestinal disorders including IBS. (2) FMT has potential to restore intestinal microbial balance. (3) We showed that FMT improved stool form and psychological status of IBS patients. (4) Bifidobacterium rich donor efficiently induced symbiosis in IBS patients. PMID- 28628919 TI - Effect of Influenza Vaccination on Risk of Stroke: A Systematic Review and Meta Analysis. AB - BACKGROUND: Despite the presence of a strong association between influenza infection and stroke, whether influenza vaccination reduces the risk of stroke is yet a matter of controversy. We conducted a meta-analysis to determine whether influenza vaccination protects against stroke. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from database inception date to November 18, 2016, without language restrictions, to identify studies investigating the effect of influenza vaccination on subsequent risk of stroke. We conducted a meta analysis to quantify the risk of stroke in overall and subgroup analyses and calculated a pooled OR for developing stroke with a 95% CI. Publication bias was assessed by Begg's rank correlation test. RESULTS: Eleven studies fulfilled our inclusion criteria. In a random-effects model, vaccinated individuals had a decreased risk of stroke compared with unvaccinated individuals (OR 0.82; 95% CI 0.75-0.91; p < 0.001). The relationship between influenza vaccination and stroke risk remained robust in subgroup analyses. The significant effect of influenza vaccination was associated with ascertainment of vaccination status and stage of prevention. CONCLUSION: Vaccination against influenza is associated with a lower risk of stroke. Well-designed prospective studies are needed to provide stronger evidence of the protective effect of influenza vaccination against stroke. PMID- 28628920 TI - Predictive Effects of Circulating miR-221, miR-130a and miR-155 for Coronary Heart Disease: A Multi-Ethnic Study in China. AB - BACKGROUND: Differences in microRNA (miRNA) profiles between patients with and without coronary heart disease (CHD)have not been fully determined. The purpose of the study was to evaluate in a multi-ethnic population in China the predictive value of miRNAs previously suggested to have a role in CHD. SUBJECT AND METHOD: 932 participants were included, and plasma samples obtained. A quantitative reverse-transcription PCR(RT-qPCR) assay was conducted to confirm the concentration of plasma miRNAs. Circulating levels of miRNAs were quantified using the 2-Deltact method. The severity of coronary atherosclerosis was evaluated via Gensini Scores. RESULT: The circulating levels of the nine proposed miRNAs were not different among the five main ethnicities examined (all p > 0.05). The Spearman correlation analyses indicated that miR-221 and miR-130a were negatively associated with the severity of CHD as indicated by Gensini Scores (r = -0.106, p = 0.001;r = -0.073, p = 0.026). Results of the univariate analysis showed that lower circulating miR-221 (OR, 1.663; 95 % CI, 1.255-2.202, p = <0.001), miR-155 (OR, 1.520; 95 % CI, 1.132-2.042, p = 0.005), and miR-130a (OR, 1.943; 95% CI, 1.410-2.678, p = <0.001) were potential risk factors for CHD. Moreover, miR-130a (OR, 2.405; 95 % CI, 1.691-3.421, p = <0.001) remained independently associated with the risk of CHD after adjusting for potential confounding factors. The analysis of the possible positive/negative associations between miR-221, miR-155 and miR-130awere conducted. A positive association between miR-130a and miR-155 was found (SI = 1.60, SIM = 1.21 and AP = 0.22), and in these groups, the proportion of CHD attributable to the interaction between miR-130a and miR-155 was as high as 22 %. A negative interaction was found between miR-221 and miR-130a (SI = 0.68, SIM = 0.60 and AP = 0.27). CONCLUSION: Plasma levels of miR-221, miR-130a and miR-155 decreased in patients with CHD, and miR-130a may be an independent predictor for CHD. PMID- 28628921 TI - Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury. AB - BACKGROUND/AIMS: The activation of NOD-like receptor family, pyrin domain containing3 (NLRP3) inflammasome has been shown to be positively correlated with the severity of proteinuria in chronic kidney disease (CKD) patients. Prostaglandin E2 (PGE2), an important inflammatory mediator, is also involved in various kidney injuries. The aim of the present study was to investigate the involvement of NLRP3 inflammasome and PGE2 synthetic pathway in albumin-induced renal tubular injury. METHODS: Murine proximal tubular cells (mPTCs) were treated with albumin to induce cell injury. NLRP3 siRNA and specific COX-2 inhibitor NS398 were used to define their roles in mediating albumin-induced mPTC injury or the activation of COX-2/mPGES-1/PGE2 cascade. RESULTS: In mPCTs, inhibition of NLRP3 by a small interfering RNA (siRNA) blocked albumin-induced kidney injury molecule 1 (KIM-1) upregulation, inflammatory response, and cell apoptosis. Albumin markedly activated cyclooxygenase-2 (COX-2)/ microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway in this cell line, an effect largely abolished by NLRP3 silencing at both mRNA and protein levels. More interestingly, blockade of COX-2 using a specific COX-2 inhibitor NS398 markedly inhibited the upregulation of KIM-1 and inflammatory cytokines, and attenuated cell apoptosis in line with blunted PGE2 release following albumin treatment. CONCLUSIONS: The findings suggest that COX-2/mPGES-1/PGE2 axis could be activated by albumin in the proximal tubular cells via a NLRP3 inflammasome-mediated mechanism and could thus contribute to proteinuria-related renal tubular cell injury. PMID- 28628923 TI - Cremophor EL Alters the Plasma Protein Binding and Pharmacokinetic Profile of Valspodar in Rats. AB - Cremophor EL is a nonionic surfactant widely used in pharmaceutical formulations. Nonetheless, there are several reports on the influence of this excipient on the protein binding, pharmacokinetics, and pharmacodynamics of drugs. Valspodar is an investigational non-immunosuppressive derivative of cyclosporine A, used in clinical trials for treatment of multidrug resistant tumors. The formulation of valspodar (Amdray(r)) contains cremophor EL and ethanol as solubilizing agents. The main aim of the current study was to assess the plasma protein binding (in vitro) and the pharmacokinetic profile of valspodar in the cremophor EL-based formulation in comparison to a cremophor EL-free formulation following intravenous (i. v.) administration to rats. Valspodar dissolved in PEG 400/ethanol (diluted in Dextrose 5%) was used as the cremophor EL-free formulation. The in vitro plasma unbound fraction (f u) of valspodar in the cremophor EL formulation was 2.3-fold higher than the PEG 400/ethanol formulation. Following a single i. v. dose of 5 mg/kg, valspodar in the cremophor EL-based formulation had around 50% lower plasma AUC compared to the PEG 400/ethanol formulation. Moreover, the cremophor EL formulation had significantly higher volume of distribution and clearance in comparison to the PEG 400-based formulation. The results highlight the significance of excipient-drug interaction that should not be overlooked during the early stages of drug development. PMID- 28628922 TI - Observation of three-component fermions in the topological semimetal molybdenum phosphide. AB - In quantum field theory, Lorentz invariance leads to three types of fermion Dirac, Weyl and Majorana. Although the existence of Weyl and Majorana fermions as elementary particles in high-energy physics is debated, all three types of fermion have been proposed to exist as low-energy, long-wavelength quasiparticle excitations in condensed-matter systems. The existence of Dirac and Weyl fermions in condensed-matter systems has been confirmed experimentally, and that of Majorana fermions is supported by various experiments. However, in condensed matter systems, fermions in crystals are constrained by the symmetries of the 230 crystal space groups rather than by Lorentz invariance, giving rise to the possibility of finding other types of fermionic excitation that have no counterparts in high-energy physics. Here we use angle-resolved photoemission spectroscopy to demonstrate the existence of a triply degenerate point in the electronic structure of crystalline molybdenum phosphide. Quasiparticle excitations near a triply degenerate point are three-component fermions, beyond the conventional Dirac-Weyl-Majorana classification, which attributes Dirac and Weyl fermions to four- and two-fold degenerate points, respectively. We also observe pairs of Weyl points in the bulk electronic structure of the crystal that coexist with the three-component fermions. This material thus represents a platform for studying the interplay between different types of fermions. Our experimental discovery opens up a way of exploring the new physics of unconventional fermions in condensed-matter systems. PMID- 28628924 TI - Chrysin Alters microRNAs Expression Levels in Gastric Cancer Cells: Possible Molecular Mechanism. AB - Background Gastric carcinoma still remains the second most common cause of cancer mortality in the world. Chrysin, as a flavone, has showed cancer chemopreventive activity. The cellular and molecular mechanisms of chrysin in cancer cells have not been fully understood. Objective In this study, we investigate expression levels of let-7a, miR-9, mir-18a, miR-21, miR-22, miR-34a, miR-126 and mir-221 to describe the anti-cancer effects of chrysin. Materials and Methods The cytotoxic effects of chrysin were assessed using MTT assay. The effect of chrysin on the microRNAs expression was determined by qRT-PCR. Results The MTT results for different concentrations of chrysin at different times on the Gastric carcinoma cells showed that IC50 for chrysin was 68.24 uM after 24 h of treatment. Expression analysis identified that miR-18, miR-21 and miR-221 were down regulated whereas let-7a, miR-9, miR-22, miR-34a and miR-126 were up regulated in Gastric carcinoma cell line (p<0.05). Conclusion Treatment with chrysin can alter the miRNAs expression and these findings might be an explanation for molecular mechanism of chrysin effect on gastric cancer. PMID- 28628925 TI - Apoptosis and Caspase 3 Pathway Role on Anti-Proliferative Effects of Scrophulariaoxy Sepala Methanolic Extract on Caco-2 Cells. AB - Colorectal cancer is one the most important malignancies worldwide and finding new treatment option for this cancer is of high priority. Natural compounds are common source of drugs for treatment of various diseases including cancers. The aim of this study was to investigate the effects of Scrophularia oxysepala extract on Caco-2 cells and explore the possible role of caspase 3 pathway in inducing cell death in this cancer cells in compare with chemotherapy agents of cisplatin and capecitabine. The methanolic extract of Scrophularia oxysepala (SO) was prepared by drench method. The IC50 of extract, cisplatin and capecitabine on Caco-2 cells were determined by MTT assay. The effect of SO extract on caspase 3 expression and inducing apoptosis were determined using TUNEL assay and caspase 3 ELISA methods, respectively. The IC50 of SO extract, cisplatin and capecitabine were 300, 195 and 80 ug/ml, respectively. Analysis for apoptosis revealed that SO methanolic extract increased apoptosis significantly (P<0.001) compared with control group. The effect of high doses of SO extract on apoptosis induction were comparable to cisplatin but significantly were higher than capecitabine. Only high doses of SO methanolic extract showed significant effects (P<0.05) on increasing caspase 3 compared to control group. The methanolic extract of SO showed inhibitory effect on Caco-2 cells and induced apoptosis in a dose dependent manner comparable to cisplatin and higher than capecitabine 2 commonly used chemotherapeutic agent for various cancers. PMID- 28628926 TI - Synthesis, Characterisation, Molecular Docking, Anti-microbial and Anti-diabetic Screening of Substituted 4-indolylphenyl-6-arylpyrimidine-2-imine Derivatives. AB - The purpose of the research is to synthesise a novel series of (E)-2-(4-(1H-indol 3-yl)-6-p-substituted phenylpyrimidin-2-yl)dimethylguanidine derivatives since 3 (1H-indol-3-yl)-1-p-substituted phenylprop-2-en-1-one and evaluate their molecular docking studies, antimicrobial, and anti-diabetic activities. Among all the synthesized compounds (11a-g), compound 11a exhibits excellent CDOCKER energy (-11.36 kcal/mol). The entire compounds (11a-g) confirm very good antimicrobial activity towards the tested microorganisms. In the in vitro anti-diabetic studies, compounds (11a, 11c, and 11g) confirm higher alpha-amylase and alpha glucosidase inhibition activity. In the in vivo anti-diabetic activities, the synthesized compounds (11a-g) (10 mg/kg, p.o.) investigated by the streptozotocin (60 mg/kg, ip) -nicotinamide (120 mg/kg, p.o.) - induced model in adult male albino Wistar rat and these derivatives show considerable fasting blood glucose level when compared to metformin hydrochloride a potent and well-known anti diabetic drug as a reference. PMID- 28628927 TI - Curcumin Promotes Apoptosis of Activated Hepatic Stellate Cells by Inhibiting Protein Expression of the MyD88 Pathway. AB - Activation and proliferation of hepatic stellate cells (HSC) play an important role in the progress of liver fibrosis. HSC activation occurs in response to inflammatory cytokines, cellular interactions with immune cells, and morphogenetic signals. The literature hints to a role of the adaptor protein MyD88 in fibrosis. Although curcumin has been shown to exert inhibitory effects on the proliferation of HSC in vitro, its influence on the MyD88 pathway in HSC has remained unclear. Here, we investigated whether curcumin accelerates apoptosis of HSC through the MyD88 pathway. HSC (rat HSC T6) were divided into a control group, MyD88 small interfering RNA (siRNA) group, curcumin group, and curcumin + MyD88 siRNA group. The MyD88 siRNA groups were exposed to siRNA for 48 h. The curcumin groups were cultured in the presence of curcumin for 24 h. Apoptosis was detected by flow cytometry. For Toll-like receptor (TLR) 2 and 4 as well as MyD88 and the dependent factors NF-kappaB, TNF-alpha, and IL-1beta, mRNA expression was detected by reverse transcription polymerase chain reaction (RT PCR). For MyD88, protein expression was further observed by Western Blot. Both curcumin and MyD88 siRNA inhibited the mRNA expression of MyD88 pathway-related effectors (TLR2, TLR4, NF-kappaB, TNF-alpha, IL-1beta) in HSC. Furthermore, both treatments reduced the expression of MyD88 protein in HSC and promoted their apoptosis. These effects were more obvious in the curcumin + MyD88 siRNA group. This study demonstrates that curcumin promotes apoptosis of activated HSC by inhibiting the expression of cytokines related to the MyD88 pathway. It elucidates the possible mechanisms of curcumin in inducing apoptosis of HSC through the MyD88 pathway. PMID- 28628928 TI - [Accurate OCT-angiography Interpretation - Detection and Exclusion of Artifacts]. AB - Background Optical coherence tomography angiography (OCTA) provides, non invasively, a three-dimensional visualization of the microvasculature of the retina and choroid. However, image artifacts may occur in OCTA and have an impact on clinical interpretation. The aim of this article is to describe image artifacts of OCTA and to present a nomenclature. Methods OCTA examinations were performed with the AngioPlexTM OCTA-technology in combination with the CIRRUS HD OCT 5000 (Carl Zeiss Meditec, Inc., Dublin, USA) as well as with the PlexElite 9000 (Carl Zeiss Meditec, Inc., Dublin, USA). Typical artifacts identified in the OCTA images are described and their causes are explained. Results There are three main groups of artifacts that can be distinguished: (a) artifacts that are inherent in the OCTA technology and occur with all types of devices (projection artifacts, masking, unmasking, loss of signal); (b) artifacts caused by data and image processing algorithms and whose frequency or severity may depend on the device type used (segmentation artifacts, duplications of vessels); (c) motion artifacts that vary in frequency and severity depending on the type of device used, as different methods (e.g., eye tracker) are used to reduce them. The occurrence of artifacts is also dependent on patient cooperation, the clarity of the optical media, and the pathology of the retina. Conclusion As in any other imaging method, artifacts also occur in OCTA images. Nevertheless, qualitative assessment of OCTA images is almost always possible and provides indispensable findings on the morphology and perfusion status of the retina and choroid. A good knowledge of possible artifacts, and a critical analysis of the complete OCTA data set, allows a correct interpretation and is essential for making a precise clinical diagnosis. PMID- 28628929 TI - [Who Should Provide Persons with Familial Risk of Colorectal Cancer with Information on Early Detection? - The View of those Affected]. AB - BACKGROUND: Colonoscopy is recommended for persons with a familial risk of colorectal cancer (CRC) before they reach 55 years of age. The aim of this analysis was to ask affected persons aged 40-54 years whether they had found out about early detection of CRC and from which institutions and media they would like to obtain such information. METHODS: Analysis of data from a cross-sectional study: In a general practice setting, those with a positive family history of CRC were asked to provide written information. RESULTS: In total, 191 persons with a positive family history of CRC participated in the study: 59.6% had already found out about early detection of CRC. Out of this, 67.0% had received information from their physicians. Most of the participants wanted information on early detection of CRC to be provided by the general practitioner (98.9% completely or mostly agree), and by health insurers (74.5% completely or mostly agree). The participants would rather not prefer to receive information from public institutions such as the public health department (69.5% not or mostly not agree) and private organizations such as self-help groups (80.9% not or mostly not agree). Approximately half would prefer to receive such information via TV. More men than women would prefer to source such information from the internet (completely or mostly agree: 66.7 vs. 43.8%), or newspapers and magazines (completely or mostly agree: 53.6 vs. 41.8%). CONCLUSION: A survey in a general practice setting found that more than half of persons with familial risk of CRC had already obtained information on early detection. The setting of the survey on preferred information sources possibly encouraged participants to put general practitioners in the first place. Furthermore, the results of this nationwide unique cohort of persons aged 40-54 with a familial risk of CRC show that their information-seeking behavior was not more pronounced than average and that men and women can be provided with information in different ways. PMID- 28628930 TI - [Rational Use of Antibiotics Data form a Survey from 2014 within the mrdo Network Compared to Nationwide Data from 2009]. AB - Introduction To combat multi-resistant gram-negative bacteria as the cause of life-threatening infections, antibiotic stewardship activities are of great importance. Objective To detect weaknesses when prescribing antibiotics in hospitals and compare the situation between 2009 and 2014. Methods In 2014, a questionnaire was sent to all 380 physicians employed in 7 hospitals. Primary, secondary and tertiary care hospitals were included. Investigated were: demographic data, position, certified specialization, presence of antibiotic prescription rules and behavior to follow them. 119 completed questionnaires of 2014 were compared to 3 613 obtained in 2009. Results31% of the questionnaires were returned. 53.8% were interns. Half of these had a certified specialization. 32.8% were consultants and 12.6% were chief physicians. 22.6% were internists, 18.4% surgeons, 10.9% urologists and 9.2% anesthetists. The majority prescribed antibiotics on a daily routine, among the interns 66%. 23% of interns reported they would advise colleagues daily and 61% at least once a week. The most common indications for antibiotic use were antibiotic prophylaxis in surgery (35), urinary tract infection (32) and pneumonia (29). Standard duration of antibiotic therapy reported were 7 days for pneumonia, 5 days for urinary tract infections and 1 day for antibiotic prophylaxis in surgery, while almost 50% of surgeons widened the antibiotic prophylaxis to 3, 5, 7,8 and 10 days. 93.3% physicians reported the use of therapeutic guidelines either from their own hospital or from medical societies. Only 59.3% were provided with the antimicrobial resistance data of their hospital. 52.1% would not ask a consultant for advice before prescribing a broadband antibiotic. Compared to 2009, lack of knowledge about antimicrobial resistance, use of guidelines, and advice from a consultant improved about 5%-points each. Conclusion Despite improvement compared to 2009, 38.9% of all physicians asked did not know their regional antibiotic resistant data and half of all surgeons still used surgical prophylaxis longer than 24 h. As the compliance to use guidelines is high with 93.3%, maintenance and development of antibiotic guidelines adjusted to the resistance data is of the greatest importance. Furthermore, antibiotic prophylaxis in surgery longer than 1 day adds to the risks of antibiotics without giving more benefit and must be critically analyzed. PMID- 28628931 TI - [The Probabilistic Efficiency Frontier: A Value Assessment of Treatment Options in Hepatitis C]. AB - Background The German Institute for Quality and Efficiency in Health Care (IQWiG) recommends the concept of the efficiency frontier to assess health care interventions. The efficiency frontier supports regulatory decisions on reimbursement prices for the appropriate allocation of health care resources. Until today this cost-benefit assessment framework has only been applied on the basis of individual patient-relevant endpoints. This contradicts the reality of a multi-dimensional patient benefit. Objective The objective of this study was to illustrate the operationalization of multi-dimensional benefit considering the uncertainty in clinical effects and preference data in order to calculate the efficiency of different treatment options for hepatitis C (HCV). This case study shows how methodological challenges could be overcome in order to use the efficiency frontier for economic analysis and health care decision-making. Method The operationalization of patient benefit was carried out on several patient relevant endpoints. Preference data from a discrete choice experiment (DCE) study and clinical data based on clinical trials, which reflected the patient and the clinical perspective, respectively, were used for the aggregation of an overall benefit score. A probabilistic efficiency frontier was constructed in a Monte Carlo simulation with 10000 random draws. Patient-relevant endpoints were modeled with a beta distribution and preference data with a normal distribution. The assessment of overall benefit and costs provided information about the adequacy of the treatment prices. The parameter uncertainty was illustrated by the price acceptability-curve and the net monetary benefit. Results Based on the clinical and preference data in Germany, the interferon-free treatment options proved to be efficient for the current price level. The interferon-free therapies of the latest generation achieved a positive net cost-benefit. Within the decision model, these therapies showed a maximum overall benefit. Due to their high additional benefit and approved prices, the therapies lie above of the extrapolated efficiency frontier, which suggests that these options have efficient reimbursement prices. Considering uncertainty, even a higher price would have resulted in a positive cost-benefit ratio. Conclusion IQWiG's efficiency frontier was used to assess the value of different treatment options in HCV. This study demonstrates that the probabilistic efficiency frontier, price acceptability-curve and the net monetary benefit can contribute essential information to reimbursement decisions and price negotiations. PMID- 28628932 TI - [European Collaboration in Medical Device Assessment: One Step Towards Cross Border Health Care]. AB - AIM: The aim of this paper was to present the legal framework as well as previous experience in transnational collaboration regarding the assessment of medical devices for reimbursement decisions. Furthermore, the possible benefit of transnational collaboration for various stakeholders will be discussed. METHODS: Experiences gathered with the compilation of overall 6 joint rapid assessments of medical devices within the completed European Network for Health Technology Assessment (EUnetHTA) Joint Action 2 (JA2) are summarised and discussed. Benefits, aims and opportunities of the ongoing EUnetHTA Joint Action 3 (JA3) are described. RESULTS: Challenges in joint European assessment of medical devices encompass the choice of topics and the time point of assessments, the non transparency of the medical devices market as well as the lack of European standards for systematic patient involvement. Characteristics of medical devices such as incremental changes and learning curves call for monitoring of medical devices through their whole lifecycle. The concrete benefit of European collaboration for stakeholders is manifold: uncertainties with regard to the actual added value of a technology, caused by a lack of evidence, may be reduced by Early Dialogues; harmonized and transparent assessment processes throughout Europe increase the reproducibility and quality of reports; the division of work among the health technology assessment (HTA) organisations allows a resource efficient assessment of a larger amount of technologies; patient involvement facilitates consideration of patient-relevant endpoints. The importance of cross border collaboration in the field of HTA is shown in the continuation of the EUnetHTA project, which aims to further strengthen international collaboration even after expiration of EU funding. CONCLUSION: A sustainable transnational collaboration in the assessment of medical devices can ensure cross-border health care as well as efficient collaboration of national health systems. The focus should be on a wide implementation of jointly established methods and quality standards. The European collaboration can lead to a concrete benefit for patients, physicians, HTA organisations and national decision makers. PMID- 28628933 TI - Early Markers of Angiogenesis and Ischemia during Bowel Conduit Neovascularization. PMID- 28628934 TI - Accelerated Lymph Flow in Early-Stage Secondary Lymphedema Detected by Indocyanine Green Fluorescence Lymphography. PMID- 28628935 TI - Proximal Left Main Bronchus Resection-Reconstruction through Left Thoracotomy with Tracheal Traction. AB - Surgical approach for resection-reconstruction of the proximal left main bronchus has been a matter of discussion. Through standard left thoracotomy, the proximal main bronchus close to the carina is not easily exposed. Accordingly, median sternotomy or right thoracotomy may be commonly employed, but the exposure and management of the distal left main bronchus may be difficult through the approach. Here, we present a left thoracotomy approach with traction of the trachea, which may easily allow excellent exposure of the proximal end of the left main bronchus and the carina. PMID- 28628936 TI - Vacuum-Assisted Closure Therapy for the Treatment of Poststernotomy Wound Dehiscence in Neonates and Infants. PMID- 28628938 TI - Outcome after Robotic-Assisted Thymectomy in Children and Adolescents with Acetylcholine Receptor Antibody-Positive Juvenile Myasthenia Gravis. PMID- 28628939 TI - Expanding Phenotype of De Novo Mutations in GNAO1: Four New Cases and Review of Literature. PMID- 28628940 TI - Clinical Neurophysiology in Neuromuscular Disorders: Old Fashioned or Still Relevant? PMID- 28628941 TI - A novel cause of chronic viral meningoencephalitis: Cache Valley virus. AB - OBJECTIVE: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients. METHODS: We present the case of a 34-year-old man with X-linked agammaglobulinemia from Australia suffering from 3 years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen. RESULTS: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue. INTERPRETATION: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in 3 immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multiorgan failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. Ann Neurol 2017;82:105-114. PMID- 28628942 TI - Increasing burden of liver cancer despite extensive use of antiviral agents in a hepatitis B virus-endemic population. AB - : Most mortalities from liver disease and liver cancer worldwide are attributable to hepatitis B virus (HBV) and hepatitis C virus. Despite remarkable advances in the treatment of HBV over past decades, limited population-level data are available regarding its impact on burden of liver disease and liver cancer. Mortality data from liver disease and liver cancer were obtained from the national death certificate database of Korea, an HBV-endemic country, between 1999 and 2013, and were analyzed by Joinpoint analysis. For liver disease, number of annual deaths decreased by 62.3% (95% confidence interval [CI], 62.0-62.6), crude death rate (CDR) decreased by 64.6% (95% CI, 64.3-64.9) from 21.2 to 7.5 per 100,000 population, and age-standardized death rate (ADR) declined by 75.0% (95% CI, 74.7-75.3), between 1999 and 2013. In contrast, for liver cancer, number of annual deaths increased by 17.8% (95% CI, 17.6-18.0) and CDR increased by 10.2% (95% CI, 10.0-10.4) from 20.5 to 22.6, although ADR decreased by 26.9% (95% CI, 26.6-27.2). The annual number of patients receiving oral antiviral agents against HBV increased from 1,716 to 187,226 during the study period. The increase in mean age at death from liver disease was significantly greater than that from liver cancer (8.8 vs. 6.1 years: P = 0.02). CONCLUSION: Marked reduction in liver disease mortality by widespread use of antiviral treatments against HBV may increase the life expectancy and number of patients at risk of developing liver cancer, inadvertently leading to increased burden of liver cancer in an HBV endemic population. The competing nature between death from liver disease and that from liver cancer should be carefully considered in establishing a health care policy. (Hepatology 2017;66:1454-1463). PMID- 28628943 TI - Antimony Complexes for Electrocatalysis: Activity of a Main-Group Element in Proton Reduction. AB - Main-group complexes are shown to be viable electrocatalysts for the H2 evolution reaction (HER) from acid. A series of antimony porphyrins with varying axial ligands were synthesized for electrocatalysis applications. The proton reduction catalytic properties of TPSb(OH)2 (TP=5,10,15,20-tetra(p tolyl)porphyrin) with two axial hydroxy ligands were studied in detail, demonstrating catalytic H2 production. Experiments, in conjunction with quantum chemistry calculations, show that the catalytic cycle is driven via the redox activity of both the porphyrin ligand and the Sb center. This study brings insight into main group catalysis and the role of redox-active ligands during catalysis. PMID- 28628944 TI - Bistable Solid-State Fluorescence Switching in Photoluminescent, Infinite Coordination Polymers. AB - Photo-functional infinite coordinated polymers (ICPs) were synthesized that consist of the photochromic dithienylethene (DTE) and a luminescent bridging unit to give enhanced fluorescence in the solid state. We could fabricate well-ordered micropatterns of these ICPs by a soft-lithographic method, which repeatedly showed high contrast on-off fluorescence switching. PMID- 28628945 TI - Precise spike timing dynamics of hippocampal place cell activity sensitive to cholinergic disruption. AB - New memory formation depends on both the hippocampus and modulatory effects of acetylcholine. The mechanism by which acetylcholine levels in the hippocampus enable new encoding remains poorly understood. Here, we tested the hypothesis that cholinergic modulation supports memory formation by leading to structured spike timing in the hippocampus. Specifically, we tested if phase precession in dorsal CA1 was reduced under the influence of a systemic cholinergic antagonist. Unit and field potential were recorded from the dorsal CA1 of rats as they completed laps on a circular track for food rewards before and during the influence of the systemically administered acetylcholine muscarinic receptor antagonist scopolamine. We found that scopolamine significantly reduced phase precession of spiking relative to the field theta, and that this was due to a decrease in the frequency of the spiking rhythmicity. We also found that the correlation between position and theta phase was significantly reduced. This effect was not due to changes in spatial tuning as tuning remained stable for those cells analyzed. Similarly, it was not due to changes in lap-to-lap reliability of spiking onset or offset relative to either position or phase as the reliability did not decrease following scopolamine administration. These findings support the hypothesis that memory impairments that follow muscarinic blockade are the result of degraded spike timing in the hippocampus. PMID- 28628946 TI - Structural plasticity of the ventral stream and aphasia recovery. AB - Restrengthening of the residual language network is likely to be crucial for speech recovery in poststroke aphasia. Eight participants with chronic aphasia received intensive speech therapy for 3 weeks, with standardized naming tests and brain magnetic resonance imaging before and after therapy. Kurtosis-based diffusion tensor tractography was used to measure mean kurtosis (MK) along a segment of the inferior longitudinal fasciculus (ILF). Therapy-related reduction in the number of semantic but not phonemic errors was associated with strengthening (renormalization) of ILF MK (r = -0.90, p < 0.05 corrected), suggesting that speech recovery is related to structural plasticity of language specific components of the residual language network. Ann Neurol 2017;82:147-151. PMID- 28628947 TI - Meta-analysis of determinants of survival following treatment of recurrent hepatocellular carcinoma. AB - BACKGROUND: Intrahepatic recurrence of hepatocellular carcinoma (HCC) following resection is common. However, no current consensus guidelines exist to inform management decisions in these patients. Systematic review and meta-analysis of survival following different treatment modalities may allow improved treatment selection. This review aimed to identify the optimum treatment strategies for HCC recurrence. METHODS: A systematic review, up to September 2016, was conducted in accordance with MOOSE guidelines. The primary outcome was the hazard ratio for overall survival of different treatment modalities. Meta-analysis of different treatment modalities was carried out using a random-effects model, with further assessment of additional prognostic factors for survival. RESULTS: Nineteen cohort studies (2764 patients) were included in final data analysis. The median 5 year survival rates after repeat hepatectomy (525 patients), ablation (658) and transarterial chemoembolization (TACE) (855) were 35.2, 48.3 and 15.5 per cent respectively. Pooled analysis of ten studies demonstrated no significant difference between overall survival after ablation versus repeat hepatectomy (hazard ratio 1.03, 95 per cent c.i. 0.68 to 1.55; P = 0.897). Pooled analysis of seven studies comparing TACE with repeat hepatectomy showed no statistically significant difference in survival (hazard ratio 1.61, 0.99 to 2.63; P = 0.056). CONCLUSION: Based on these limited data, there does not appear to be a significant difference in survival between patients undergoing repeat hepatectomy or ablation for recurrent HCC. The results also identify important negative prognostic factors (short disease-free interval, multiple hepatic metastases and large hepatic metastases), which may influence choice of treatment. PMID- 28628948 TI - Platelet hyperaggregability is associated with decreased ADAMTS13 activity and enhanced endotoxemia in patients with acute cholangitis. AB - AIM: Insufficient ADAMTS13 activity (ADAMTS13:AC) leads to increased levels of unusually large von Willebrand factor (VWF) multimers and causes microcirculatory disturbance and multiple organ failure (MOF). Endotoxin (Et) triggers the activation of coagulation and cytokine cascades, leading to MOF in severe inflammatory response syndrome. Here, we investigated the potential role of endotoxemia-related ADAMTS13 in acute cholangitis. METHODS: Twenty-four patients with acute cholangitis, including 7 with severe acute cholangitis, were recruited in this study. The levels of ADAMTS13:AC, VWF antigen (VWF:Ag), interleukin (IL) 6, IL-8, and tumor necrosis factor (TNF)-alpha in each patient were determined by enzyme-linked immunosorbent assay, whereas Et levels were determined by Et activity assay (EAA) analysis. RESULTS: The ADAMTS13:AC and VWF:Ag levels were significantly lower and higher, respectively, in patients with acute cholangitis than in controls. The EAA levels were higher in patients with acute cholangitis than in controls, and were inversely correlated with that of ADAMTS13:AC. Patients with severe acute cholangitis had significantly lower ADAMTS13:AC and higher VWF:Ag levels than those with mild to moderate cholangitis. Notably, ADMTS13:AC was directly correlated with platelet counts and inversely correlated with IL-6 levels, and the VWF:Ag/ADAMTS13:AC ratio was directly correlated with IL-8 and TNF-alpha levels. CONCLUSIONS: Imbalance of ADAMTS13:AC and VWF:Ag levels might be associated with severe acute cholangitis, reflecting platelet hyperaggregability. Severe acute cholangitis has severe pathophysiological features and is complicated by endotoxemia and MOF. Notably, this is the first report indicating an association between the levels of ADAMTS13:AC and VWF:Ag and those of EAA and cytokines in acute cholangitis. PMID- 28628949 TI - Photosynthate partitioning to starch in Arabidopsis thaliana is insensitive to light intensity but sensitive to photoperiod due to a restriction on growth in the light in short photoperiods. AB - Photoperiod duration can be predicted from previous days, but irradiance fluctuates in an unpredictable manner. To investigate how allocation to starch responds to changes in these two environmental variables, Arabidopsis Col-0 was grown in a 6 h and a 12 h photoperiod at three different irradiances. The absolute rate of starch accumulation increased when photoperiod duration was shortened and when irradiance was increased. The proportion of photosynthate allocated to starch increased strongly when photoperiod duration was decreased but only slightly when irradiance was decreased. There was a small increase in the daytime level of sucrose and twofold increases in glucose, fructose and glucose 6-phosphate at a given irradiance in short photoperiods compared to long photoperiods. The rate of starch accumulation correlated strongly with sucrose and glucose levels in the light, irrespective of whether these sugars were responding to a change in photoperiod or irradiance. Whole plant carbon budget modelling revealed a selective restriction of growth in the light period in short photoperiods. It is proposed that photoperiod sensing, possibly related to the duration of the night, restricts growth in the light period in short photoperiods, increasing allocation to starch and providing more carbon reserves to support metabolism and growth in the long night. PMID- 28628950 TI - A Flexible, Fused, Azomethine-Boron Complex: Thermochromic Luminescence and Thermosalient Behavior in Structural Transitions between Crystalline Polymorphs. AB - This manuscript reports the multi-functional boron complex presenting aggregation induced emission (AIE), crystallization-induced emission enhancement (CIEE), and thermosalient behavior accompanying thermochromic luminescence during crystal crystal transitions by employing the fused azomethine ligand. In particular, we propose that these properties can be explained by molecular "flexibility" toward external stimuli, including temperature changes and photo-excitation, and two types of crystal polymorphs with different absorption and luminescent properties were obtained. Optical measurements indicated that both polymorphs showed individual AIE and strong CIEE properties. From the investigations, the boron complex showed large structural relaxation and formed the bent structure in the excited state, followed by emission annihilation in the absence of structural restriction. In addition, it was shown that interconversion between these polymorphs could be reversibly induced by heating and cooling. The data from the single-crystal X-ray analyses suggested that alteration of crystal packing and intermolecular interaction should influence the luminescent chromism. Moreover, we also found that the crystals showed unusual mechanical behavior, such as hopping and fragmentation by heating and cooling, respectively, which is called thermosalient behavior. It was suggested that the loosely-fused structure could be responsible for expressing unique optical and mechanical properties. PMID- 28628951 TI - Cranial Indicators Identified for Peak Incidence of Otitis Media. AB - Acute otitis media (AOM) is one of the most common pediatric conditions worldwide. Peak age of occurrence for AOM has been identified within the first postnatal year and it remains frequent until approximately six postnatal years. Morphological differences between adults and infants in the cartilaginous Eustachian tube (CET) and associated structures may be responsible for development of this disease yet few have investigated normal growth trajectories. We tested hypotheses on coincidence of skeletal growth changes and known ages of peak AOM occurrence. Growth was divided into five dental eruption stages ranging from edentulous neonates (Stage 1) to adults with erupted third maxillary molars (Stage 5). A total of 32 three-dimensional landmarks were used and Generalized Procrustes Analysis was performed. Next, we performed principal components analysis and calculated univariate measures. It was found that growth change in Stage 1 was the most rapid and comprised the largest amount of overall growth in upper respiratory tract proportions (where time is represented by the natural logarithmic transformation of centroid size). The analysis of univariate measures showed that Stage 1 humans did indeed possess the relatively shortest and most horizontally oriented CET's with the greatest amount of growth change occurring at the transition to Stage 2 (eruption of deciduous dentition at five postnatal months, commencing peak AOM incidence) and ceasing by Stage 3 (approximately six postnatal years). Skeletal indicators appear related to peak ages of AOM incidence and may contribute to understanding of a nearly ubiquitous human disease. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1721 1740, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28628952 TI - SEEKING COMFORT IN AN UNCOMFORTABLE CHAIR. AB - The author explores the concept of comfort in relation to the setting. The concept of comfort, an unusual word in the psychoanalytic lexicon, describes the intuitive and complex experience of patient and analyst being together in the analytic office. The couch and the chair are not the only tools of the setting, but they are potential instruments with which to study the therapeutic process, both in high-frequency therapy and in lower-frequency treatments. To describe the transformations that an alternative experience of comfort can promote, the author looks at the intersection of this concept with the body-mind relationship and with the Bionian concept of binocular vision. PMID- 28628954 TI - A COMPARATIVE LOOK AT INTERSUBJECTIVE AND OBJECT RELATIONAL APPROACHES TO CLINICAL MATERIAL. AB - The Search for a Relational Home: An Intersubjective View of Therapeutic Action. By Chris Jaenicke. London/New York: Routledge, 2015. 100 pp. PMID- 28628955 TI - RECOVERING THE FATHER IN MIND AND FLESH: HISTORY, TRIADIC FUNCTIONING, AND DEVELOPMENTAL IMPLICATIONS. AB - This paper aims to restore the father and paternal function to their rightful place alongside the mother and maternity in order to counter the prevailing matricentric, dyadic bias in psychoanalytic theory and technique. The author contends that both the symbolic and the actual, flesh-and-blood father are necessary to optimize his child's development. The paternal function inevitably operates in a triadic matrix; thirdness is always psychically in existence-with the father ever present in the mother's unconscious mind-and the paternal third is necessary to open up symbolic space. As an embodied other, the actual father, both as a separating agent and an attracting object, is called upon to recognize his child's otherness throughout the inescapable father-child rivalries, neglect, and desire. PMID- 28628957 TI - AFFECT, SYMPTOM, FANTASY, DREAM: CLINICAL AND THEORETICAL CONSIDERATIONS. AB - A symptom being studied in the process of analysis can be seen as not unlike the unconscious affect it sprang from. The author presents a case in which a symptom, premature ejaculation, was analogous to the unconscious affect of guilt, which itself seemed to be a premature defensive transformation of a deeper current of anger. Guilt was interpreted as if it were a psychic premature ejaculation, a defensive derailment of anger. Fantasy and dream seemed to be engaged in similar transformations, with a fantasy of "premature incarceration" not unlike the symptom itself in its analogous functioning. Analysis of affect, symptom, fantasy, and dream in complex, integrative analytic process led not only to resolution of the symptom itself, but also to a deeper understanding of the mind's complex functioning in general. PMID- 28628959 TI - SHIFTING BETWEEN ALTERNATIVE MODES OF COGNITION: CAN FREE ASSOCIATION, IN AND OF ITSELF, PROVE THERAPEUTIC? AB - From early on in his career, at the time of his treatment of Frau Emmy von N., Freud (Breuer and Freud 1895) recognized the value of listening to the patient's material without attempting to steer it along a particular course. His focus on the method of freie Einfalle (free association), to be presented to the patient as the fundamental rule of analytic treatment, led to his recommendation that the analyst listen with evenly suspended attention (Freud ). But is free association therapeutic in and of itself? The author proposes an affirmative reply to this question based on the contribution of free association to the patient's nascent ability to shift between active and passive modes of cognition. PMID- 28628961 TI - THE STUDY AND TREATMENT OF MOTHERS AND INFANTS, THEN AND NOW: MELANIE KLEIN'S "NOTES ON BABY" IN A CONTEMPORARY PSYCHOANALYTIC CONTEXT. AB - This paper draws on Melanie Klein's (unpublished) observational notes of her infant grandson, written primarily in 1938 and 1939. Apart from moving glimpses into a young family's life, the notes contain astute observations of an infant's behavior and emotions. Compared with Klein's published writings, the style is less theoretical and polemical. Later, in his latency years, Klein's grandson was in analysis with Marion Milner, who in 1952 published a paper drawing on the treatment. The present paper focuses on (1) how observations and treatment of the same child and his family by clinicians in close relationships with each other (Klein, Milner, and Winnicott) fertilized reciprocal influence but also brought into question the validity of Klein's observations, and (2) the relative merits and contributions of various modalities in understanding the infant's psyche, including experimental research, direct observation, parent-infant psychotherapy, and reconstructions from older patients-as occurs, for example, in psychoanalysis. PMID- 28628963 TI - RELATIONAL GROUP AND INDIVIDUAL PSYCHOANALYSIS: CULTURAL ANTECEDENTS AND CLINICAL IMPLICATIONS. AB - The One and the Many: Relational Psychoanalysis and Group Analysis. By Juan Tubert-Oklander. London: Karnac, 2014. 288 pp. PMID- 28628965 TI - HYPOCHONDRIA: A REVIEW OF ITS PLACE IN PSYCHOANALYTIC THEORY. AB - After identifying Freud's fundamental contributions to the concept of hypochondria, the author undertakes a brief review of the term's trajectory within the Anglophone and Francophone psychoanalytic literature. Notions of defense, anxiety, and representation as they relate to corporeal experience are discussed. The author illustrates these main axes with which to read hypochondria with clinical material drawn from the analysis of a woman in whom somatic manifestations were especially pervasive. PMID- 28628967 TI - POST-BIONIAN DEVELOPMENTS IN PSYCHOANALYTIC FIELD THEORY: THE CONTRIBUTIONS OF ANTONINO FERRO AND GIUSEPPE CIVITARESE. AB - The Bi-Personal Field: Experiences in Child Psychoanalysis. By Antonino Ferro. New York: Routledge, 1992 (1999). 232 pp. The Intimate Room: Theory and Technique of the Analytic Field. By Giuseppe Civitarese. New York: Routledge, 2008 (2010). 240 pp. The Necessary Dream: New Theories and Techniques of Interpretation in Psychoanalysis. By Giuseppe Civitarese; translated by Ian Harvey. London: Karnac, 2013 (2014). 246 pp. The Analytic Field and Its Transformations. By Antonino Ferro and Giuseppe Civitarese. London: Karnac, 2015. 224 pp. PMID- 28628968 TI - Performance Trends in Age Group Triathletes in the Olympic Distance Triathlon at the World Championships 2009-2014. AB - Performance trends in elite triathletes competing in age group classes have been investigated forIronman triathlon in 'Ironman Hawaii' but not for short distance triathletes competing at internationallevel in events such as the Olympic distance triathlon at the World Championships. The aim of the presentstudy was to evaluate participation and performance trends of age group triathletes competing in theOlympic distance triathlon at the International Triathlon Union (ITU) World Championships 2009-2014.During this period, the number of participants remained constant. Swimming performance improved inathletes in age groups 25-29 years to 55-59 years, but not in younger (18-24 years) and older (> 60-64years) age groups. Cycling performance improved in athletes in age groups 18-24 years to 70 74years, but not in age group 75-79 years. In running, athletes in age groups 18 24 years, 30-34 years,35-39 years and 65-69 years improved, but not in the other age groups. Overall race time wasimproved by athletes in age groups 18-24 to 65 69 years, but not in age groups 70-74 years and 75-79years. Transition times were improved by all age group athletes. Women were slower than men inswimming, cycling, running and overall race time in age groups 18-24 years to 70-74 years, but not inthe age group 75-79 years. For transition times, women were slower than men in age groups 18-24 yearsto 65-69 years, but not in age groups 70-74 years to 75-79 years. In summary, women and men improvedperformance in most age groups across all years, men were faster than women except in the age group75-79 years and the sex difference between women and men remained constant. This knowledgeshould be considered when future age group triathletes train for and compete in Olympic distancetriathlons at international level. PMID- 28628969 TI - Comparative Induction of Controlled Hypotension by Electroacupuncture at DU20 Acupoint and Remifentanil in Lumbar Laminectomy. AB - Hypotensive anesthesia is utilized to reduce bleeding during orthopedic surgery. One of thevarious drugs that have been used to reduce blood pressure is remifentanil. This study was an attemptto compare the effect of remifentanil with that of electroacupuncture (EA) at DU20 on reducing bloodpressure. In this randomized controlled clinical trial, 54 patients undergoing lumbar laminectomy wereallocated to two groups. Hypotensive anesthesia was performed through infusion of remifentanil 100MUg/kg/min for the control group, and EA at DU20 acupoint with a frequency of 2-10 Hz and intensity of1-5 mA for the intervention group. Blood pressure, pulse rate, volume of blood lost and the quality ofsurgical field were evaluated every 10 min. There were no statistically significant differences betweenthe two groups in terms of the changes in mean arterial pressure (MAP), pulse rate, and the qualityof surgical field (P > 0.05). Therefore, EA can be as effective as remifentanil to reduce blood pressurein the patients undergoing lumbar laminectomy. PMID- 28628970 TI - A Randomized, Double-Blind Clinical Study on Blood Pressure Reduction and Blood Lipid Profile Amelioration on Treatment with Ankascin 568. AB - Hypertension and cardiovascular complications are the leading causes of death worldwide.Antihypertensive drugs often cause various side effects, and improper use of antihypertensivemedications can result in irreparable damage. Edible fungi of the Monascus species have been usedas traditional Chinese medicines in Southeast Asia for several centuries. The fermented products ofMonascus purpureus NTU 568 (ANKASCIN 568) possess a number of functional secondary metabolitesincluding the anti-inflammatory pigments monascin (MS) and ankaflavin (AK). In this study, adouble-blind, placebo-controlled clinical trial was performed in which patients with mild to moderatehypertension were randomly assigned to receive placebo or two 500-mg capsules of Ankascin 568 for8 weeks. The effects of this treatment on the regulation of blood pressure (BP) were then examined.The results showed that systolic blood pressure (SBP) decreased from 141.6 +/- 12.0 to 133.9 +/- 14.4mmHg (P < 0.05), and diastolic blood pressure (DBP) decreased from 91.7 +/- 8.1 to 84.8 +/- 7.4 mmHg(P < 0.05). Moreover, Ankascin 568 treatment effectively reduced serum triglycerides and totalcholesterol (TC), increased high-density lipoprotein cholesterol (HDL-C), and reduced low-densitylipoprotein cholesterol (LDL-C) levels, thereby improving the serum lipid profile. Additionally,administration of Ankascin 568 did not cause significant rhabdomyolysis nor impaired the metabolicor physiological functions of the liver or kidney. In conclusion, patients administered Ankascin 568for 8 weeks exhibited significant in reduction of SBP, serum TC and LDL-C levels, which shouldcontribute to better cardiovascular health. PMID- 28628971 TI - Occurrence of phthalate diesters in indoor air from several Northern cities in Vietnam, and its implication for human exposure. AB - Phthalates are used as plasticizers to impart flexibility of plastics. Because of their toxicity, human exposure to phthalates is a concern. Little is known on the occurrence of and inhalation exposure to phthalates in indoor air. In this study, ten phthalates were measured in 97 indoor air samples collected from Northern Vietnam during September 2016 to January 2017. The mean concentrations of total phthalates (i.e., sum of ten phthalates) in particulate and gas phases ranged from 95.2 to 13,100MUgg-1 and from 57.0 to 14,900ngm-3, respectively. In bulk indoor air samples (i.e., gas plus particulate phase), the mean concentration of total phthalates ranged from 106 to 16,000ngm-3 (mean: 1040ngm-3). Diethyl phthalate (DEP) was found at the highest concentration in indoor air at a concentration range of below the method quantitation limit (MQL) to 12,400ngm-3 (mean: 376). Among various microenvironments, indoor air collected from hair salons contained the highest concentrations of phthalates (range: 596 to 16,000ngm-3). Among the four northern Vietnamese cities studied, the highest concentrations of phthalates were found in indoor air samples from Hanoi. The calculated mean inhalation exposure doses to phthalates for infants, toddlers, children, teenagers, and adults were 780, 485, 416, 292, and 213ngkg-bw-1d-1, respectively. PMID- 28628972 TI - Urinary sexual steroids associated with bisphenol A (BPA) exposure in the early infant stage: Preliminary results from a Daishan birth cohort. AB - BACKGROUND: Many surveys have shown that older children are ubiquitously exposed to bisphenol A (BPA), and many laboratory studies have shown that BPA exposure has adverse effects related to estrogenic disruption, whereas the evidence in infants has not yet been observed. METHODS: Women in early pregnancy were recruited by the Maternal and Child Health and Family Planning Service Center, Daishan, China, from March 2012 to December 2014. After delivery, urine samples were collected from the diapers of 59 infants (0 to 6months of age). Urinary BPA, estradiol (E2), testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and creatinine were analyzed. The partial correlation and multivariable linear regression were applied to assess the associations of BPA with E2, T, FSH, and LH for each of the development stages: at birth, 14days, 28days, 42days, 3months, and 6months. RESULTS: For both genders from birth to 6months, infants showed randomly changed urinary BPA but regularly changed hormones, i.e., the monotonic decreasing E2 and T, the "U" shaping E2/T and upside down "U" shaping FSH and LH with extreme values at approximately the 14 day stage, respectively. However, the creatinine-adjusted FSH for all stages and E2 from 6months were genders different. After adjustment for creatinine, gender, and infant body mass index, BPA was positively associated with E2 both in male (for 14-, 28-, and 42-day stages) and female (for 14-, 28-, 42-day, and 3-month stages) infants; positively associated with E2/T ratio in both male (for 14- and 28-day stages) and female (for 14-day stage) infants; and positively associated with T in female (for 3-month stage) infants. CONCLUSIONS: To the best of our knowledge, this is the first time that associations of BPA with E2, E2/T, and T in infant urine were observed. The results suggested that the infants first demonstrate a surge of steroids after leaving the maternal uterus's steroidogenic environment (i.e., mini-puberty) and may be affected by BPA; this pollution may disrupt the premature gonad function at some important developmental windows. PMID- 28628973 TI - A baseline survey of dissolved methane in aquifers of Great Britain. AB - Interest in dissolved methane (CH4) concentrations in aquifers in England, Scotland and Wales ('Great Britain' or GB) has grown concurrently with interest in the exploitation of unconventional gas sources (UGS). Experience, mainly from North America, has shown the importance of a pre-production baseline against which changes possibly due to UGS extraction can be compared. The British Geological Survey, aided by water utilities, private users and regulators, has compiled a unique dataset for CH4 in groundwaters of GB. This focuses principally on areas where UGS exploration is considered more likely, as indicated by the underlying geology. All the main water supply aquifers (Principal aquifers) were targeted, plus Secondary aquifers where locally important. The average dissolved CH4 concentration across GB in the aquifers sampled was 45MUg/l. Out of a total of 343 sites, 96% showed dissolved CH4 concentrations <100MUg/l, 80% <10MUg/l, and 43%<1MUg/l. No site had a CH4 concentration above the US Department of the Interior suggested risk action level of 10,000MUg/l. While most sites were sampled only once, a subset was monitored quarterly to determine the magnitude of seasonal or other variations. Generally these variations were minor, with 84% of sites showing variations within the range 0.5-37MUg/l, but some aquifers where the porosity was primarily fracture-related showed larger changes (0.5-264MUg/l). This may have been due to the nature of sampling at these sites which, unlike the others, did not have installed pumps. Since the regulatory compliance monitoring attending UGS operations will include the measurement of parameters such as dissolved CH4, it is essential that sampling methods are tested to ensure that reliable and comparable datasets can be obtained. PMID- 28628974 TI - The influence of climate change on the accumulation of polycyclic aromatic hydrocarbons, black carbon and mercury in a shrinking remote lake of the southern Tibetan Plateau. AB - A sediment core from a remote lake, Pumoyum Co, located in the southern TP, was analyzed for polycyclic aromatic hydrocarbons (PAHs), black carbon (BC) and mercury. Concentrations ranged from 30 to 229ng/g for PAHs, 0.46 to 1.48mg/g for BC and 10 to 30ng/g for mercury. Significant correlations were found among the concentrations of PAHs, BC and mercury, suggesting the sources of these pollutants to be similar; mainly from combustion processes. Further diagnosis of the likely sources of BC and PAHs suggested that petroleum combustion has been one of the increasing sources in the last few decades, but biomass burning remains the dominant source of these pollutants. The historic trends of the three pollutants closely followed historic BC emission trends from Europe (before 1970) and southern Asia (after 2000). With economic development in southern Asia, concentrations of pollutants in the sediments of Pumoyum Co have increased during the past decade. However, the accumulation fluxes of the pollutants during that period remained stable, which may be due to the recent low precipitation and less catchment erosion of Pumoyum Co (experienced a drier climate and shrinking of lake area). PMID- 28628975 TI - Highly expressed long non-coding RNA NNT-AS1 promotes cell proliferation and invasion through Wnt/beta-catenin signaling pathway in cervical cancer. AB - BACKGROUND: Cervical cancer is the most common gynecological malignancies in women worldwide. The previous study showed that lncRNA NNT-AS1 could play an important role in tumor development and metastasis of colorectal cancer. However, little is known about the function of NNT-AS1 in cervical cancer. The aim of this study was to investigate the expression profile of NNT-AS1 in cervical cancer and assess its possible molecular mechanism. METHODS: Relative expression levels of NNT-AS1 in cervical cancer tissues were determined by qRT-PCR. The biologic functions of NNT-AS1 in cervical cancer were explored by MTT assay, transwell assay and flow cytometric analysis in vitro. The influence of NNT-AS1 on tumorigenesis was measured by mice xenograft model. In addition, we evaluated the activation of Wnt/beta-catenin signaling pathway by luciferase assay and western blot. RESULTS: Our results showed that NNT-AS1 expression in cervical cancer tissues compared with adjacent non-tumor tissues the overexpression of NNT-AS1 was positively associated with advanced FIGO stage, lymph node metastasis, depth of cervical invasion and poorer overall survival. Function assays showed that NNT AS1 inhibition could suppress cervical cancer cells proliferation and invasion ability in vitro as well as the activation of Wnt/beta-catenin signaling pathway. In vivo mice xenograft model revealed that silencing NNT-AS1 could reduce tumor growth in nude mice. CONCLUSIONS: The results of the current study suggested that NNT-AS1 might play an important role in cervical carcinogenesis and might serve as a potentially therapeutic target and prognostic marker in the treatment of cervical cancer. PMID- 28628976 TI - Effective enzymatic in situ saccharification of bamboo shoot shell pretreated by dilute alkalic salts sodium hypochlorite/sodium sulfide pretreatment under the autoclave system. AB - In this study, dilute alkali salts (0.6% NaClO, 0.067% Na2S) pretreatment at 10% sulfidity under the autoclave system at 120 degrees C for 40min was used for pretreating bamboo shoot shell (BSS). Furthermore, FT-IR, XRD and SEM were employed to characterize the changes in the cellulose structural characteristics (porosity, morphology, and crystallinity) of the pretreated BSS solid residue. After 72h, the reducing sugars and glucose from the enzymatic in situ hydrolysis of 50g/L pretreated BSS in dilute NaClO/Na2S media could be obtained at 31.11 and 20.32g/L, respectively. Finally, the obtained BSS-hydrolysates containing alkalic salt NaClO/Na2S resulted in slightly negative effects on the ethanol production. Glucose in BSS-hydrolysates was fermented from 20.0 to 0.17g/L within 48h, and an ethanol yield of 0.41g/g glucose, which represents 80.1% of the theoretical yield, was obtained. This study provided an effective strategy for potential utilization of BSS. PMID- 28628977 TI - Enhanced performance of microbial fuel cell with in situ preparing dual graphene modified bioelectrode. AB - This study proposed a three-step method to prepare dual graphene modified bioelectrode (D-GM-BE) by in situ microbial-induced reduction of GO and polarity reversion in microbial fuel cell (MFC). Both graphene modified bioanode (GM-BA) and biocathode (GM-BC) were of 3D graphene/biofilm architectures; the viability and thickness of microbial biofilm decreased compared with control bioelectrode (C-BE). The coulombic efficiency (CE) of GM-BA was 2.1 times of the control bioanode (C-BA), which demonstrated higher rate of substrates oxidation; the relationship between peak current and scan rates data meant that GM-BC was of higher efficiency of catalyzing oxygen reduction than the control biocathode (C BC). The maximum power density obtained in D-GM-BE MFC was 122.4+/-6.9mWm-2, the interfacial charge transfer resistance of GM-BA and GM-BC were decreased by 79% and 75.7%. The excellent electrochemical performance of D-GM-BE MFC was attributed to the enhanced extracellular electron transfer (EET) process and catalyzing oxygen reduction. PMID- 28628978 TI - A high-throughput dye-reducing photometric assay for evaluating microbial exoelectrogenic ability. AB - Exoelectrogenic bacteria (EEB) can transfer electrons to extracellular electron acceptors and have wide applications in environmental bioremediation and bioenergy generation. Thus, methods for effectively probing the exoelectrogenic ability of EEB are highly desirable. In this work, a simple but efficient photometric assay based on the extracellular reduction of high polar dyes was developed to evaluate the microbial exoelectrogenic ability. Methyl orange were proven to be used as a probe for evaluating the exoelectrogenic ability of EEB. Through monitoring the extracellular dye decolorization under anaerobic conditions, this plate-based photometric assay could rapidly measure the exoelectrogenic ability of various EEB. This approach was also able to evaluate the exoelectrogenic capacity of Shewanella oneidensis MR-1 wild-type strain and its Mtr mutants. Furthermore, the exoelectrogenic ability of mixed cultures in microbial fuel cells was correlated with the extracellular dye decolorization. Thus, this work is useful for the practical implementation of microbial exoelectrogenic ability evaluation. PMID- 28628979 TI - The short- and long-term effects of Mn2+ on biogranule-based anaerobic ammonium oxidation (anammox). AB - The short- and long-term effects of Mn2+ on the performance of anaerobic ammonium oxidation (anammox) granules were investigated in the present study. Anammox activity was determined at various Mn2+ concentrations in batch assays, and the 50% inhibition concentration value was determined to be 7.33mgL-1. However, no obvious deterioration of reactor performance was observed during the 150-day continuous-flow operation, and the nitrogen removal efficiency of the test reactor (R1) fluctuated between 91% and 92% as the Mn2+ concentration was increased from 1 to 200mgL-1. Additionally, the specific anammox activity, heme c content and the amounts of extracellular polymeric substances in the anammox biomass increased and then subsequently decreased. The results demonstrated that short-term exposure to Mn2+ has a negative effect on anammox biomass, but the biomass could tolerate Mn2+ stress after acclimation to a high concentration of 200mgL-1 at the end of the continuous-flow experiment. PMID- 28628980 TI - Depolymerization of cellulose into high-value chemicals by using synergy of zinc chloride hydrate and sulfate ion promoted titania catalyst. AB - Experiments for cellulose depolymerization by synergy of zinc chloride hydrate (ZnCl2.RH2O) and sulfated titania catalyst (SO42-/TiO2) were investigated in this study. The results showed the introduction of sulfate into the TiO2 significantly enhanced the catalyst acid amount, especially for Bronsted acid site, which is beneficial for subsequent cellulose depolymerization. ZnCl2.RH2O hydrate, only a narrow composition range of water, specifically 3.0<=R<=4.0, can dissolve cellulose, which finally resulted the cellulose with low crystallinity and weak intrachain and interchain hydrogen bond network. Coupling of ZnCl2.RH2O hydrate and SO42-/TiO2 catalyst as a mixed reaction system promoted cellulose depolymerization, and the products can be adjusted by the control of reaction conditions, the low temperature (80-100 degrees C) seemed beneficial for glucose formation (maximal yield 50.5%), and the high temperature (120-140 degrees C) favored to produce levulinic acid (maximal yield 43.1%). Besides, the addition of organic co-solvent making HMF as the main product (maximal yield 38.3%). PMID- 28628981 TI - Biodiesel synthesis from Calophyllum inophyllum oil with different supercritical fluids. AB - Biodiesel or fatty acid methyl esters (FAMEs) is primarily synthesized using edible vegetable oils and methanol with a catalyst. However, in the present study, FAMEs were synthesized from a non-edible oil (Calophyllum inophyllum also called as sura honne, Punnagam, Alexandrian Laurel) in different supercritical fluids: methanol (MeOH), methyl tert-butyl ether (MTBE), methyl acetate (MeOAc) and dimethyl carbonate (DMC) non-catalytically. Reactions were performed from 523K to 673K at 30MPa with a molar ratio of 40:1 with times varying from 3min to 3h. Conversions higher than 80% were obtained within 30min for oil reaction with MeOH and DMC at 623K and conversions of 60% and 70% were obtained at 673K with MeOAc and MTBE, respectively. Pseudo first order kinetics was used to obtain the rate constants and the activation energies followed the order: EMeOH90% and CO2 mitigation >99%. They also gave the biomass and lipid production of 1.300+/-0.050g/L and 0.356+/-0.097g/L, respectively. The repeated batch cultivation improved the biomass and lipid production by 2.66 folds and 1.41 folds, respectively. The scale up in 3L-fluidized bed photobioreactor gave the maximum biomass of 3.280+/-0.049g/L and lipid production of 0.362+/-0.010g/L. Fatty acid compositions of Nannochloropsis sp. lipids showed their suitability as biodiesel feedstocks. This system not only contributes as tertiary treatment of industrial effluent and CO2 mitigation but also low-cost production of renewable energy. PMID- 28628984 TI - High-level expression of recombinant thermostable beta-glucosidase in Escherichia coli by regulating acetic acid. AB - In the fermentation progress, fermentation parameters including the feed rate, induction temperature, and induction pH evidently regulate the accumulation of acetic acid generated by recombinant E. coli in the medium. The production of thermostable beta-glucosidase (Tpebgl3) was increased by optimizing the parameters mentioned step by step. The optimal conditions were obtained with the highest enzyme expression (560.4U/mL) and the maximum DCW (65g/L) at the pre induction specific growth rate of 0.2h-1 followed by a post-induction specific growth rate (0.18h-1); induction temperature is 39 degrees C; the pH is 7.2; the concentration of acetic acid was maintained all along below 0.9g/L. Results show it is necessary for the synthesis of Tpebgl3 to regulate the accumulation of acetic acid at the premise of feeding to meet the normal growth of E. coli. The production of Tpebgl3 by recombinant E. coli is the highest reported to date. PMID- 28628985 TI - Enhanced polyhydroxyalkanoate production by mixed microbial culture with extended cultivation strategy. AB - Low biomass output is a crucial reason for low polyhydroxyalkanoate (PHA) production in mixed microbial cultures (MMCs) PHA process. In this research, an extended cultivation strategy was proposed to rapidly expand the biomass yield of PHA accumulating MMCs and conserve the PHA accumulating ability simultaneously. High PHA content of the cultivated MMCs of 71.4% and 66.7% (higher than 62.1% of the seed biomass) in batch assays and biomass magnification of 43 and 52 were obtained after 10days of extended cultivation with and without sludge discharge, respectively. By embedding the extended cultivation process into the production process, a highly competitive PHA production performance in terms of overall PHA storage yield (0.49g CODPHA/gCODVFA) and volumetric productivity (1.21gPHA/L/d with final cell density of 17.22g/L) was achieved. The proposed PHA production process based on the extended cultivation can be a promising choice in industrial scale practice. PMID- 28628986 TI - Acetate production and electron utilization facilitated by sulfate-reducing bacteria in a microbial electrosynthesis system. AB - The aim of this study is to investigate the effect of sulfate-reducing bacteria on performance of a mixed culture microbial electrosynthesis system (MES). The two-chamber MESs were operated under different cathode potentials (-0.5, -0.6, 0.7, and -0.8V) with or without addition of 6mM sulfate. At -0.7V, acetate production and electrons harvesting in the MES with the sulfate addition were 31.81mM and 5152C, respectively, which improved by 2.7 and 2.4times compared to that without sulfate. With sulfate, the biomass, proportion of live cells, and electrochemical activity of cathode biofilm were enhanced at all the potentials. At -0.7V, the relative abundance of Acetobacterium and Desulfovibrionaceae was 14.2% and 36.7% with sulfate, respectively, compared to 17.4% and 7.3% without sulfate. At -0.7 and -0.8V, the sulfate-reducing bacteria can promote the electron transfer of cathode biofilm and enhance the acetate production. PMID- 28628987 TI - A long-term study on the effect of magnetite supplementation in continuous anaerobic digestion of dairy effluent - Magnetic separation and recycling of magnetite. AB - Promotion of direct interspecies electron transfer (DIET) between exoelectrogenic bacteria and electron-utilizing methanogens has recently been discussed as a new method for enhanced biomethanation. This study evaluated the effect of magnetite promoted DIET in continuous anaerobic digestion of dairy effluent and tested the magnetic separation and recycling of magnetite to avoid continuous magnetite addition. The applied magnetite recycling method effectively supported enhanced DIET activity and biomethanation performance over a long period (>250days) without adding extra magnetite. DIET via magnetite particles as electrical conduits was likely the main mechanism for the enhanced biomethanation. Magnetite formed complex aggregate structures with microbes, and magnetite recycling also helped retain more biomass in the process. Methanosaeta was likely the major methanogen group responsible for DIET-based methanogenesis, in association with Proteobacteria and Chloroflexi populations as syntrophic partners. The recycling approach proved robust and effective, highlighting the potential of magnetite recycling for high-rate biomethanation. PMID- 28628988 TI - Enhanced power generation and wastewater treatment in sustainable biochar electrodes based bioelectrochemical system. AB - Corn-straw biochar (BC500 and BC900) and KOH modified biochar (BAC) were used as the electrode materials of bioelectrochemical system (BES). Compared to carbon felt (CF) electrodes BES, the maximum power density of BC500, BC900 and BAC anodes BES increased by 10.7%, 56.0% and 92.0%, and that of BC500, BC900 and BAC cathodes BES increased by 3.1, 5.2 and 4.8 times, respectively. The CF electrodes BES was optimized to decolor the AO7 simulated wastewater and 97% of AO7 was quickly degraded within 2h. When using biochar anodes, the decoloration rates were enhanced. The apparent rate constant (kapp) increased from 2.93h-1 for CF anode BES to 3.58, 4.35 and 5.33h-1 for BC500, BC900 and BAC anode system, respectively. AO7 could also be effectively decolored in biochar cathode systems, which was mainly due to adsorption. PMID- 28628989 TI - Pollutant removal and microorganism evolution of activated sludge under ofloxacin selection pressure. AB - An activated sludge sequencing batch reactor (SBR) was fed with synthetic wastewater containing ofloxacin (OFL) for 52days to study the overall performance of the SBR, the characteristics of extracellular polymeric substances (EPS) and the bacterial community shift. Removal efficiencies of chemical oxygen demand, ammonia nitrogen, phosphorus and OFL were maintained at 90%, 96%, 80% and 65%, respectively. The EPS contents increased with increasing OFL concentration because more EPS was secreted to protect cells from OFL damage. Moreover, the EPS compositions shifted. For denitrifying bacteria, the read number of Pseudomonas and Bacillus sharply decreased initially (p<0.05) and increased from Day 25 to Day 50, which agreed with the tendency of Nitrosomonadaceae (ammonia oxidizer), while Paracoccus significantly decreased (p<0.05). The read number of Rhodocyclaceae, a phosphorus-accumulating bacterium, increased. Other functional microbes such as Nitrospirales (nitrite oxidizer) and Planctomyces (anammox) sharply decreased under OFL pressure (p<0.05). PMID- 28628990 TI - Kinetic modelling of starch and lipid formation during mixotrophic, nutrient limited microalgal growth. AB - Microalgal starch and lipids, carbon-based storage molecules, are useful as potential biofuel feedstocks. In this work, cultivation strategies maximising starch and lipid formation were established by developing a multi-parameter kinetic model describing microalgal growth as well as starch and lipid formation, in conjunction with laboratory-scale experiments. Growth dynamics are driven by nitrogen-limited mixotrophic conditions, known to increase cellular starch and lipid contents whilst enhancing biomass growth. Model parameters were computed by fitting model outputs to a range of experimental datasets from batch cultures of Chlamydomonas reinhardtii. Predictive capabilities of the model were established against different experimental data. The model was subsequently used to compute optimal nutrient-based cultivation strategies in terms of initial nitrogen and carbon concentrations. Model-based optimal strategies yielded a significant increase of 261% for starch (0.065gCL-1) and 66% for lipid (0.08gCL-1) production compared to base-case conditions (0.018gCL-1 starch, 0.048gCL-1 lipids). PMID- 28628991 TI - Bacterial community composition in rainwater associated with synoptic weather in an area downwind of the Asian continent. AB - Bacteria are abundant in atmospheric waters and can be disseminated by precipitation to the surface of the Earth, potentially influencing ecosystems, public health and climate. However, data on bacterial communities in rainwater, especially on the association with weather, are very limited. In this study, rainwater was collected at the coastal city Kumamoto, southwestern Japan, in 2015. The bacterial communities in fourteen samples were identified using 16S rRNA sequencing and compared according to the rain types at the synoptic scale, i.e., cyclones, Meiyu and non-Meiyu stationary fronts, and typhoons. Diverse bacterial communities were present in all four types of rainwater and were dominated by the phyla Proteobacteria (37%), Bacteroidetes (16%), Cyanobacteria (14%), Actinobacteria (9%), Acidobacteria (8%) and Firmicutes (5%). Approximately half of the phyla (16 out of 33) were common among the rain types. The operational taxonomic units (OTUs) common among the four types of rainwater represented the majority (averagely 74%) of the sequences, indicating the predominance of common bacterial OTUs regardless of rain type. On the other hand, the synoptic weather systems and the origins of air masses associated with the rain likely resulted in distinct bacterial communities. High fractions of bacterial soil indicator taxa signified the large contribution of bacteria from soils. Genera containing ice nucleation-active bacteria were identified in all samples except one typhoon rain sample. Marine bacterial taxa, e.g., Pseudoalteromonas, Synechococcus and Marinobacter, were detected in several samples, indicating the dispersal of marine bacteria via clouds and rainwater. Fecal indicator bacteria were also detected in all samples. Thus, the bacteria in the four types of rainwater were characterized by largely overlapping communities with some differences in community composition, indicating that rain is an efficient pathway for the dissemination of bacterial communities in nature and links continental, marine and island ecosystems. PMID- 28628992 TI - Estimating linkages between forest structural variables and rainfall interception parameters in semi-arid deciduous oak forest stands. AB - An understanding of the relationship between canopy structure and the water balance is needed for predicting how forest structure changes affect rainfall partitioning and, consequently, water resources. The objective of this study was to predict rainfall interception (I) and canopy storage capacity (S) using canopy structure variables and to investigate how seasonal changes influence their relationship. The study was conducted in twelve 50m*50m plots in the Zagros forest in the western Iranian state of Ilam, protected forests of Dalab region. Average cumulative I was 84.2mm, accounting for 10.2% of cumulative gross precipitation (GP) over a 1-year period. Using a regression based method, S averaged ~1mm and 0.1mm in the leafed and leafless periods, respectively. There were no relationships between tree density and I:GP or S, but I:GP and S increased with leaf area index, canopy cover fraction, basal area, tree height, and diameter at breast height in the leafed period. In addition, wood area index and canopy cover fraction were related to I:GP or S in the leafless period. PMID- 28628993 TI - The impact of silver nanoparticles on marine plankton dynamics: Dependence on coating, size and concentration. AB - During this study, three microcosm experiments were carried out with natural coastal seawater, collected in the Eastern Mediterranean Sea, in order to assess the effect of silver nanoparticle (AgNP) exposure to natural plankton communities. The impact of coating (branched-polyethyleneimine: BPEI vs. poly vinylpyrrolidone: PVP), size (40 vs. 60nm), concentration (200, 500, 2000, 5000 and 10,000ng Ag L-1) and silver form (dissolved Ag+ vs. AgNPs) were tested. The results of chlorophyll a concentration revealed that PVP AgNPs caused a higher toxicity than BPEI AgNPs, and this was possibly related to the measured higher dissolution rate. Additionally, toxicity of BPEI AgNPs was size-dependent, with 40 being more toxic than 60 nm AgNPs, which was nevertheless not seen clearly for PVP AgNPs. Interestingly, community composition altered in response to AgNP exposure: cyanobacterial abundance was negatively affected at concentrations >=200ng Ag L-1, and dinoflagellate abundance and composition were altered at a 2000ng Ag L-1 concentration. Specifically, dinoflagellate (Gymnodinium, Prorocentrum and Gyrodinium) and diatom (Nitzschia, Navicula and Climacosphenia) genera either increased or decreased, highlighting taxa-specific effects, with some of them being able to tolerate, compensate or even benefit from AgNPs. Silver in either form (dissolved Ag+ or in NPs) caused almost identical results in the plankton community, further indicating that Ag+ release is the primary cause of AgNP toxicity. This study employed for the first time environmentally relevant AgNP concentrations (minimum 200ng Ag L-1) in natural seawater without pre-filtration steps and showed that community changes were driven by the exposure but were largely dependent on ambient physico-chemical characteristics and should be further investigated. PMID- 28628994 TI - TiO2 surfaces support neuron growth during electric field stimulation. AB - TiO2 is proposed here for the first time as a substrate for neural prostheses that involve electrical stimulation. Several characteristics make TiO2 an attractive material: Its electrochemical behaviour as an insulator prevents surface changes during stimulation. Hydration creates -OH groups at the surface, which aid cell adhesion by interaction with inorganic ions and macromolecules in cell membranes. Its ability to neutralize reactive oxygen and nitrogen species that trigger inflammatory processes confers biocompatibility properties in dark conditions. Here, physicochemical characterization of TiO2 samples and their surfaces was carried out by X-ray diffraction, X-ray photoelectronic emission spectroscopy, scanning electron microscopy, atomic force microscopy and by contact angle measurements. Its properties were related to the growth parameters and morphology of amphibian spinal neurons cultured on TiO2 samples. Neurons adhered to and extended neurites directly on TiO2 surfaces without pre-coating with adhesive molecules, indicating that the material permits intimate neuron surface interactions. On TiO2 surfaces the distal tips of each extending neurite and the neurite shafts themselves showed more complex filopodial morphology compared with control cultures on glass. Importantly, the ability of TiO2 to support neuron growth during electric field exposure was also tested. The extent of growth and the degree of neurite orientation relative to the electric field on TiO2 approximated that on glass control substrates. Collectively, the data suggest that TiO2 materials support neuron growth and that they have potential utility for neural prosthetic applications incorporating electric field stimulation, especially where intimate contact of neurons with the material is beneficial. PMID- 28628995 TI - In simulated body fluid performance of polymorphic apatite coatings synthesized by pulsed electrodeposition. AB - Surface modification is to modify biological responses through changing surface properties without reducing the mechanical properties of the implant. Specifically bioactive coatings, such as hydroxyapatite, carbonate apatite and dicalcium phosphate dehydrate, have been deposited on carbon/carbon (C/C) composites to change the bio-inert surface state. This work focused on the effects of voltages and electrolyte concentrations of pulsed electrodeposition on apatite layer. The apatite coatings thus synthesized were then structurally, morphologically and chemically characterized using X-ray diffraction, scanning electron microscopy, Transmission electron microscopy and Fourier-transform infrared spectroscopy. Remarkably, the voltages and electrolyte concentrations changed the structure, morphology and crystallinity of the obtained coatings. In vitro bioactivity evaluation of polymorphic apatite coatings was performed by soaking the apatite layer coated C/C composites in simulated body fluid (SBF). The corrosion behavior was investigated via the potentiodynamic polarization test in SBF solution. The results confirmed that the increasing deposition voltage and concentration of electrolyte resulted in promoting bioactivity and corrosion resistance by altering the morphologies and phases. PMID- 28628996 TI - PVP and PEG doped CuO nanoparticles are more biologically active: Antibacterial, antioxidant, antidiabetic and cytotoxic perspective. AB - Search for biologically active nanoparticles is prerequisite for biomedical applications. CuO nanoparticles synthesized by co-precipitation method are capped by polyethylene-glycol (PEG) and polyvinyl-pyrrolidone (PVP) on the surface by simple adsorption. Physical and chemical properties carried out by SEM, XRD and FTIR confirm nanometer in size and efficient capping of PVP and PEG on CuO NPs. Biological assays reveal higher activities of CuO-PEG and CuO-PVP as compared to the uncapped CuO nanoparticles. CuO-PEG shows better antitumor activity against Streptomyces as compared with CuO-PVP and CuO NPs. Both the capped NPs are significantly active for alpha-amylase inhibition assay. CuO-PVP demonstrates significantly better activity against bacterial strains followed by CuO-PEG and uncapped CuO. PVP coated CuO NPs also shows strong DPPH based free radical scavenging activity, total reducing power potential, total antioxidative potential and also carries flavonoid and phenolics properties determines to querecetin and gallic acid equivalence, respectively. It can be concluded that PVP and PEG capped CuO NPs are more capable to be used in biomedical applications as drug and diagnostic carrier molecules. PMID- 28628997 TI - Preparations of hyperbranched polymer nano micelles and the pH/redox controlled drug release behaviors. AB - Hyperbranched polymer nano micelles (NMs) were prepared through a nucleophilic ring opening polymerization between cystamine and polyethylene glycol diglycidyl ether, followed by a reaction of amino groups and dimethyl maleic anhydride. The NMs showed spheric morphologies with hydrodynamic diameters of 106-120nm. Doxorubicin was loaded in the NMs with loading rate as high as 15.38wt%; The NMs possessed negative zeta potentials in aqueous solutions of pH7.4 due to the carboxyl ions on the particle surfaces, but the zeta potentials were converted to positive ones due to the hydrolysis of amide bonds at pH5.0-6.5, leading to the leaving of carboxyl groups and remaining of amino groups. The disulfide bonds in cystamine were designed in the hyperbranched polymer structures of the NMs, and bonds could be broken by a reducing agent l-glutathione (GSH) (10mM), resulting in a targeted drug release. The smart NMs displayed good biodegradability and biocompatibility, and they could be potentially used in drug controlled release field. PMID- 28628998 TI - A facile fabrication of silk/MoS2 hybrids for Photothermal therapy. AB - Photothermal therapy, due to its safety and effectiveness, has attracted tremendous interest in the area of cancer treatment in recent few decades. The emerging of two-dimensional transition metal dichalcogenides has provided this promising therapy with a novel genus of nanomaterials. Herein, we present a facile one-step way to prepare a hybrid of regenerated silk fibroin (RSF) and molybdenum disulfide (MoS2) nanosheets simply by directly adding MoS2 dispersion into RSF aqueous solution to induce the self-assembly of silk protein on the surface of MoS2 flakes. The produced RSF/MoS2 hybrids demonstrate better photothermal performance and less cytotoxicity than the pristine MoS2. In the meantime, the RSF/MoS2 hybrids show a good photothermal stability. Finally and importantly, the RSF/MoS2 hybrids display a satisfying photothermal capability on ablating HeLa cells in vitro, which imply that such a protein/inorganic hybrid material holds a great promise as a photothermal agent in future cancer treatment. PMID- 28628999 TI - Synthesis, characterisation and phase transition behaviour of temperature responsive physically crosslinked poly (N-vinylcaprolactam) based polymers for biomedical applications. AB - Poly (N-vinylcaprolactam) (PNVCL) is a polymer which offers superior characteristics for various potential medical device applications. In particular it offers unique thermoresponsive capabilities, which fulfils the material technology constraints required in targeted drug delivery applications. PNVCL phase transitions can be tailored in order to suit the requirements of current and next generation devices, by modifying the contents with regard to the material composition and aqueous polymer concentration. In this study, physically crosslinked Poly (N-vinylcaprolactam)-Vinyl acetate (PNVCL-VAc) copolymers were prepared by photopolymerisation. The structure of the polymers was established by Fourier transform infrared spectroscopy, nuclear magnetic resonance and gel permeation chromatography. The polymers were further characterised using differential scanning calorimetry and swelling studies. Determination of the LCST of the polymers in aqueous solution was achieved by employing four techniques; cloud point, UV-spectrometry, differential scanning calorimetry and rheometry. Sol-gel transition was established using tube inversion method and rheological analysis. This study was conducted to determine the characteristics of PNVCL with the addition of VAc, and to establish the effects on the phase transition. The PNVCL based polymers exhibited a decrease in the LCST as the composition of VAc increased. Sol-gel transition could be controlled by altering the monomeric feed ratio and polymer concentration in aqueous milieu. Importantly all copolymers (10wt% in solution) underwent gelation between 33.6 and 35.9 degrees C, and based on this and the other materials properties recorded in this study, these novel copolymers have potential for use as injectable in situ forming drug delivery systems for targeted drug delivery. PMID- 28629000 TI - Formulation and in-vitro efficacy of antifungal mucoadhesive polymeric matrices for the delivery of miconazole nitrate. AB - Oral candidiasis is the most common opportunistic infection affecting patients with the human immunodeficiency virus. Miconazole buccal tablets or miconazole gel are approved for the treatment of oropharyngeal candidiasis. However, buccal films present more flexibility and also offer protection for the wounded mucosa, reducing pain. Due to their small size and thickness, buccal films may improve patients' compliance, compared to tablets. Additionally, they may increase the relatively short residence time on the mucosa of oral gels, which are easily removed by saliva. Polymeric films loaded with miconazole nitrate were prepared by a casting/solvent evaporation methodology using chitosan, carbopol, gelatin, gum arabic, and alginate to form the polymeric matrices. The morphology of films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity by differential thermal analysis and X-ray diffraction. Films were characterized in terms of thickness, folding endurance, tensile properties, swelling, adhesiveness, and drug release. Finally, the antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. The more appropriate formulations were those based on chitosan gelatin and chitosan-carbopol which showed good mechanical properties and adhesiveness, a relative low swelling index, improved drug release, and showed better in vitro activity against Candida cultures than miconazole nitrate raw material. Thus, it will be possible to produce a new pharmaceutical form based on polymeric films containing chitosan and miconazole nitrate, which could be loaded with low drug concentration producing the same therapeutic effect against Candida cultures. PMID- 28629001 TI - Biomimetic electrospun scaffolds from main extracellular matrix components for skin tissue engineering application - The role of chondroitin sulfate and sulfated hyaluronan. AB - Incorporation of bioactive components like glycosaminoglycans (GAGs) into tissue engineering scaffolds, is a promising approach towards developing new generation functional biomaterial. Here, we have designed electrospun nanofibrous scaffolds made of gelatin and different concentrations of chemically sulfated or non sulfated hyaluronan (sHA or HA) and chondroitin sulfate (CS). Evenly distributed fiber morphology was observed with no differences between varying concentrations and types of GAGs. In vitro release kinetics revealed that GAGs release is driven by diffusion. The effects of these scaffolds were analyzed on human keratinocyte (HaCaT), fibroblast (Hs27) and mesenchymal stem cells (hMSCs) adhesion and proliferation. A significant increase in cell number (~5 fold) was observed when cultivating all three cell types alone on scaffolds containing sHA and CS. These findings suggest that sulfated GAG-containing electrospun nanofibrous scaffolds might be beneficial for the development of effective skin tissue engineered constructs by stimulating cellular performance and therefore accelerate epidermal dermal regeneration processes. PMID- 28629002 TI - A facile synthesis method of hydroxyethyl cellulose-silver nanoparticle scaffolds for skin tissue engineering applications. AB - Green porous and ecofriendly scaffolds have been considered as one of the potent candidates for tissue engineering substitutes. The objective of this study is to investigate the biocompatibility of hydroxyethyl cellulose (HEC)/silver nanoparticles (AgNPs), prepared by the green synthesis method as a potential host material for skin tissue applications. The substrates which contained varied concentrations of AgNO3 (0.4%-1.6%) were formed in the presence of HEC, were dissolved in a single step in water. The presence of AgNPs was confirmed visually by the change of color from colorless to dark brown, and was fabricated via freeze-drying technique. The outcomes exhibited significant porosity of >80%, moderate degradation rate, and tremendous value of water absorption up to 1163% in all samples. These scaffolds of HEC/AgNPs were further characterized by SEM, UV-Vis, ATR-FTIR, TGA, and DSC. All scaffolds possessed open interconnected pore size in the range of 50-150MUm. The characteristic peaks of Ag in the UV-Vis spectra (417-421nm) revealed the formation of AgNPs in the blend composite. ATR FTIR curve showed new existing peak, which implies the oxidation of HEC in the cellulose derivatives. The DSC thermogram showed augmentation in Tg with increased AgNO3 concentration. Preliminary studies of cytotoxicity were carried out in vitro by implementation of the hFB cells on the scaffolds. The results substantiated low toxicity of HEC/AgNPs scaffolds, thus exhibiting an ideal characteristic in skin tissue engineering applications. PMID- 28629003 TI - A simple semi-quantitative approach studying the in vivo degradation of regenerated silk fibroin scaffolds with different pore sizes. AB - The biocompatibility and in vivo degradation rate of biomaterials represent critical control points in the long-term success of scaffolds for tissue restoration. In this study, new three-dimensional (3D) regenerated silk fibroin scaffolds (RSFs) were prepared by the freezing-defrosting procedure, and then were implanted beneath the dorsal skin of rats. This study aims to develop a kinetic semi-quantitative approach to assess in vivo degradation rate and biocompatibility of this kind of RSFs with different pore sizes for the first time, and to evaluate the relationship between the biodegradation and tissue responses by measuring the thickness of residual scaffolds, fibrous capsules and infiltrated tissues through integrated techniques of histology, optical imaging and image analysis. Our results showed that scaffolds with both pore sizes (74.35+/-10.84MUm and 139.23+/-44.93MUm, respectively) were well tolerated by host animals and pore size was found to be the rate limiting factor to the biodegradation in the subcutaneous implantation model. In addition, the biodegradation of RSFs was inflammation-mediated to a certain degree and fibroblasts may play a critical role in this process. Overall, such semi quantitative approach was demonstrated to be a simple and effective method to assess the in vivo degradation rate, and the prepared RSFs were presented to have promising potential in tissue engineering applications. PMID- 28629004 TI - Performance evaluation of non-ionic surfactant based tazarotene encapsulated proniosomal gel for the treatment of psoriasis. AB - The study aims to explore the potential of non-ionic surfactant based proniosomal gel (PNG) in improving the topical delivery of tazarotene by in vitro and in vivo studies. The PNG was prepared using coacervation phase separation method composed of span, stearylamine, cholesterol, and lecithin. The PNG demonstrated favorable vesicle size (3.26+/-0.22MUm) and percent encapsulation efficiency (49.50+/ 2.3%). The PNG was evaluated for viscosity which indicated that the ratio of span:cholesterol:stearylamine (64.5:30.5:5mM) demonstrated no any fluctuations in viscosity. The scanning electron micrographs exhibited spherical vesicles with sharp boundaries. The in vitro drug release through cellulose membrane and rat's skin were found to be in the following order of the formulation code A2>A4>A3>A5 and A4>A2>A3>A5, respectively, which showed the prolonged release of entrapped tazarotene. Further, in vitro drug permeation and retention studies revealed that formulations A2 and A4 showed the higher percent of drug permeation whereas formulations A3 and A5 showed the higher percent of drug retention through rat's skin. Moreover, PNG A2 and A4 formulations demonstrated good stability characteristics at different temperature conditions. The stability in the presence of detergent revealed that no any abrupt change in turbidity. The skin irritation studies performed with formulations A2 and A4 showed no erythema compared with the plain PNG. The male Albino NMRI mice tail model was used to performed in vivo skin histological examination which revealed that an increase in the orthokeratosis strengthened. Thus, all the results concluded that surfactant, Span 60 based PNG formulations have shown a good ability to increase drug accumulation in the various skin layers and more potential carrier for topical delivery of tazarotene for an effective therapy of psoriasis. PMID- 28629005 TI - Laser surface structuring of Ti6Al4V substrates for adhesion enhancement in Ti6Al4V-PEEK joints. AB - PEEK is a promising polymer possessing high mechanical strength and biocompatibility and therefore it can be associated to titanium for biomedical applications. This study aimed at producing Ti6Al4V-PEEK joints with enhanced adhesion through laser-structuring Ti6Al4V treatments. Ti6Al4V cylindrical substrates were prepared by two types of surface treatments: alumina blasting and laser structuring. The holes number and size in laser-structured surfaces was varied. PEEK was then hot pressed against the metallic substrate to completely filling the surface cavities. The adhesion of the PEEK/Ti6Al4V joint was assessed by a shear bond strength test. Fracture surfaces and interfaces were investigated by SEM/EDS. Significant differences were found in the shear bond strength between alumina blasted and laser-structured samples. Bond strength improvement (exceeding 300%) was registered for the laser-structured specimens relative to grit-blasted ones. The laser-structuring technique showed to be very promising in the production of specifically designed surfaces for high strength and mechanically stable Ti6Al4V/PEEK joints. PMID- 28629006 TI - A colon targeted drug delivery system based on alginate modificated graphene oxide for colorectal liver metastasis. AB - A major problem associated with colon cancer is liver metastasis. A colon targeted drug delivery system is one way to address this problem after the resection of colorectal cancer. However, traditional drug delivery systems face many challenges, such as an inability to control the release rate, inaccurate targeting, susceptibility to the microenvironment and poor stability. Here, we report the development of a graphene oxide (GO)-based, sodium alginate (ALG) functionalized colon-targeting drug delivery system, that is loaded with 5 fluorouracil (5-FU) as the anti-cancer drug (denoted as GO-ALG/5-FU). Our results demonstrate that the as-prepared drug delivery system possesses a much lower toxicity and better colon-targeting controlled-release behaviours. We show that GO-ALG/5-FU significantly inhibited tumour growth and liver metastasis and prolonged the survival time of mice. We anticipate that our assay will help improve basic research of colon-targeted drug delivery systems and provide a new way to treat colon cancer liver metastasis. PMID- 28629007 TI - Upconverting and persistent luminescent nanocarriers for accurately imaging guided photothermal therapy. AB - The fluorescence-guided photothermal therapy (FPTT) has great potential in cancer treatment. However, the conventional FPTT has to be stimulated by external light, which tends to increase background noise and leads to the inaccurate infrared light irradiation for PTT. In this study, upconverting and persistent luminescent nanocarriers (UPLNs) loaded mesoporous silica nanoparticles (UPLNs@mSiO2) were first designed to solve the problem mentioned above. The UPLNs cores can effectively reduce the short-lived autofluorescence interference by exerting the delay time between signal acquisition and pulsed excitation light. For testing the luminescence properties, the indotcyanine green (ICG) as photothermal agent was encapsulated into the UPLNs@mSiO2. The experimental results showed that the UPLNs@mSiO2 nanoparticles could significantly reduce the short-lived autofluorescence interference and improve signal-to-noise ratio during FPTT. Our data suggest that UPLNs@mSiO2 may be a promising tool for improving the accuracy of PTT in vivo. PMID- 28629008 TI - Multi-walled carbon nanotubes/graphene oxide hybrid and nanohydroxyapatite composite: A novel coating to prevent dentin erosion. AB - To date is emergent the development of novel coatings to protect erosion, especially to preventive dentistry and restorative dentistry. Here, for the first time we report the effectiveness of multi-walled carbon nanotube/graphene oxide hybrid carbon-base material (MWCNTO-GO) combined with nanohydroxyapatite (nHAp) as a protective coating for dentin erosion. Fourier transform Raman spectroscopy (FT-Raman), scanning electron (SEM), and transmission electron (TEM) microscopy were used to investigated the coatings and the effect of acidulated phosphate fluoride gel (APF) treatment on bovine teeth root dentin before and after erosion. The electrochemical corrosion performance of the coating was evaluated. Raman spectra identified that: (i) the phosphate (nu1PO43-) content of dentin was not significantly affected by the treatments and (ii) the carbonate (nu1CO32-) content in dentin increased when nHAp was used. However, the nHAp/MWCNTO-GO composite exposited lower levels of organic matrix (CH bonds) after erosion compared to other treatments. Interesting, SEM micrographs identified that the nHAp/MWCNTO-GO formed layers after erosive cycling when associate with APF treatment, indicating a possible chemical bond among them. Treatments of root dentin with nHAp, MWCNTO-GO, APF_MWCNTO-GO, and APF_nHAp/MWCNTO-GO increased the carbonate content, carbonate/phosphate ratio, and organic matrix band area after erosion. The potentiodynamic polarization curves and Nyquist plot showed that nHAp, MWCNT-GO and nHAp/MWCNT-GO composites acted as protective agents against corrosion process. Clearly, the nHAp/MWCNTO-GO composite was stable after erosive cycling and a thin and acid-resistant film was formed when associated to APF treatment. PMID- 28629009 TI - Surgical suture braided with a diclofenac-loaded strand of poly(lactic-co glycolic acid) for local, sustained pain mitigation. AB - In this work, we propose a surgical suture that can sustainably release diclofenac (DF) for the local pain relief of surgical wounds. We separately fabricated a DF-loaded strand composed of a biodegradable polymer, poly(lactic-co glycolic acid) (PLGA), which was then braided with a surgical suture already in clinical use, i.e., VICRYLTM. In this way, the drug-delivery suture presented herein could release DF in a sustained manner for 10days while maintaining the mechanical strength needed for wound closure. According to the in vivo results of an induced-pain animal model, the drug-delivery suture mitigated pain throughout the period of persistent pain. The histological analysis of tissue around the sutures showed that the drug-delivery suture exhibited biocompatibility comparable to that of the VICRYLTM suture in clinical use. PMID- 28629010 TI - Fabrication of DNA nanotubes with an array of exterior magnetic nanoparticles. AB - Described here a methodology for arraying of magnetic nanoparticles (MNPs) on the surface of DNA nanotubes (DNTs). Positioning of magnetic nanoparticles at exterior surface of DNTs were shaped after self-assembling of oligonucleotide staples within an M13mp18 DNA scaffold via an origami process. The staples were partially labeled with biotin to be arrayed at the surface of DNTs. Gel retardation assay of the DNTs carrying magnetic nanoparticles indicated a reversely behavioral electrophoretic movement in comparison to the nanotubes have been demonstrated previously. Also, high resolution transmission electron microscopy confirmed positioning magnetic nanoparticles at the exterior surface of DNTs, correctly. Ultrastructural characteristics of these DNA nanotubes using atomic force microscopy demonstrated topographic heights on their surfaces formed through positioning of magnetic nanoparticles outside the tubules. This nanoarchitecture would be potential for multiple arraying of nanoparticles that those be useful as functionalized chimeric nanocarriers for developing novel nanodrugs and nanobiosensors. PMID- 28629011 TI - Chitosan nanoparticles as alternative anti-staphylococci agents: Bactericidal, antibiofilm and antiadhesive effects. AB - Chitosan is a biocompatible, bioactive, non-toxic polymer that due to these characteristics has been widely used as a carrier for targeted delivery of bioactive molecules. In recent years, and considering that chitosan has a strong antimicrobial potential, the scientific community's focus has shifted onto the possible antimicrobial activity of chitosan nanoparticles. With this in mind, the aim of this work was to produce low molecular weight chitosan nanoparticles, through the ionic gelation method and characterize their potential biological activity against three staphylococci (MSSA, MRSA and MRSE) in planktonic and sessile environments. The chitosan nanoparticles produced had an average size of 244+/-12nm, an average charge of 17.3+/-1.4mV and had a MIC of 1.25mg/mL for all tested microorganisms. Bactericidal activity was only registered for MSSA and MRSA with the time-inhibition curves showing bactericidal activity within 1h. Assays regarding chitosan nanoparticles' impact upon sessile populations showed that they were effective in preventing MRSE adhesion and highly effective in reducing MRSA and MSSA biofilm formation. PMID- 28629012 TI - Equilibrium, kinetics and mechanism of Au3+, Pd2+ and Ag+ ions adsorption from aqueous solutions by graphene oxide functionalized persimmon tannin. AB - In this study, a novel bio-adsorbent (PT-GO) was prepared by functionalization persimmon tannin (PT) with graphene oxide (GO) and the effective adsorption behaviors of Au3+, Pd2+ and Ag+ ions from aqueous solution was investigated. The PT-GO was characterized by Fourier transform infrared spectrometer (FTIR), scanning electronic microscope (SEM), thermogravimetric analysis (TGA) and Zeta potential. Many influence factors such as pH value, bio-adsorbent dosage, initial concentration of metal ions and contact time were optimized. The maximum adsorption capacity for Au3+, Pd2+ and Ag+ was 1325.09mg/g, 797.66mg/g and 421.01mg/g, respectively. The equilibrium isotherm for the adsorption of Au3+ and Ag+ on PT-GO were found to obey the Langmuir model, while the Freundlich model fitted better for Pd2+. The adsorption process of Au3+, Pd2+ presented relatively fast adsorption kinetics with pseudo-second-order equation as the best fitting model, while the pseudo-first-order kinetic model was suitable for describing the adsorption of Ag+. Combination of ion exchange, electrostatic interaction and physical adsorption was the mechanism for adsorption of Au3+, Pd2+ and Ag+ onto PT-GO bio-adsorbent. Therefore, the PT-GO bio-adsorbent would be an ideal adsorbent for removal of precious metal ions and broaden the potential applications of persimmon tannin in environmental research. PMID- 28629013 TI - A novel bioactive vaterite-containing tricalcium silicate bone cement by self hydration synthesis and its biological properties. AB - A novel bioactive vaterite-containing tricalcium silicate bone cement (V5) was successfully synthesized through self hydration and carbonization, by introducing CO2 into the hydration process of Ca3SiO5 (C3S). The purpose of this work is to reduce the adverse effect of the hydration products Ca(OH)2 on the C3S bone cement, and improve further the bioactivity of the C3S bone cement. XRD and FT-IR analysis indicated that vaterite was successfully formed in tricalcium silicate bone cement. The in vitro bioactivity of V5 was investigated by soaking in simulated body fluid (SBF) for various periods (1, 3, 7days), in addition to setting time, compressive strength and cell behavior. The results showed that the V5 could rapidly induce hydroxyapatite (HA) formation. The bio-effects of V5 on MC3T3-E1 osteoblast-like cells were evaluated by studying cell viability, adhesion and proliferation. The CCK-8 assay shows that cell viability on the resulting V5 is improved obviously after through hydration and carbonization. The V5 cement enhanced the higher expression of cell attachment, proliferation and differentiation as compared to V50 cement. SEM results present significant improvement on the cell adhesion and proliferation for cells cultured on the V5. Experimental results demonstrated that, C3S bone cement of containing vaterite has more excellent bioactivity and medium setting time too, suggesting their potential applications in areas such as MC3T3-E1 cell stimulation and bone tissue engineering. PMID- 28629014 TI - Physicochemical properties of liposomal modifiers that shift macrophage phenotype. AB - Liposomes are one of the most widely studied drug carriers due to their relative biocompatibility, lack of immune system stimulation, ability to be cell specific, and serve as a protective drug carrier. Due to several physicochemical properties such as size and charge, liposomes naturally target the phagocytic capabilities of macrophages. In the tumor microenvironment, macrophages strongly influence growth and progression, making them an appealing target for drug delivery. Using the natural capability of liposomes to target macrophages, and the knowledge that material properties can alter cellular responses, this work aims to influence macrophage phenotype with arginine-like surface modified DOPE:DOPC liposomes. These liposomes were incubated with interleukin-4 (IL-4) or lipopolysaccharide (LPS) stimulated macrophages and naive RAW 264.7 macrophages. Macrophage phenotype was determined through arginase activity, tumor necrosis factor (TNF) alpha secretion, and nitrite production. With significant variations in the molecular profiles of each activated cell type, these findings suggest that macrophage responses could be altered with small variations in surface functionality of liposomes. PMID- 28629015 TI - Poly(N-isopropylacrylamide)/poly(l-lactic acid-co-E-caprolactone) fibers loaded with ciprofloxacin as wound dressing materials. AB - In this work, we aimed to develop new materials to reduce the secondary injuries which can be imparted when replacing wound dressings. Electrospun fibers based on the thermoresponsive polymer poly(N-isopropylacrylamide) (PNIPAAm), poly(l-lactic acid-co-E-caprolactone) (PLCL), and the antibiotic ciprofloxacin (CIF) were prepared. The water contact angle of fibers made from a blend of PNIPAAm and PLCL changed dramatically when the temperature was increased above 32 degrees C. Sustained release of CIF from the formulations was observed over >200h. Moreover, L929 fibroblasts could proliferate on the fibers, indicating their biocompatibility. The CIF-loaded fibers were found to have potent antibacterial activity against E. coli and S. aureus. In vivo tests on rats indicated that CIF loaded thermosensitive fibers have enhanced healing performance compared to CIF loaded PLCL fibers or a commercial gauze. Electrospun PNIPAAm/PLCL fibers loaded with CIF thus have great promise in the development of new wound dressing materials. PMID- 28629016 TI - Effect of stearic acid modified HAp nanoparticles in different solvents on the properties of Pickering emulsions and HAp/PLLA composites. AB - Stearic acid (Sa) was used to modify the surface properties of hydroxyapatite (HAp) in different solvents (water, ethanol or dichloromethane(CH2Cl2)). Effect of different solvents on the properties of HAp particles (activation ratio, grafting ratio, chemical properties), emulsion properties (emulsion stability, emulsion type, droplet morphology) as well as the cured materials (morphology, average pore size) were studied. FT-IR and XPS results confirmed the interaction occurred between stearic acid and HAp particles. Stable O/W and W/O type Pickering emulsions were prepared using unmodified and Sa modified HAp nanoparticles respectively, which indicated a catastrophic inversion of the Pickering emulsion happened possibly because of the enhanced hydrophobicity of HAp particles after surface modification. Porous materials with different structures and pore sizes were obtained using Pickering emulsion as the template via in situ evaporation solvent method. The results indicated the microstructures of cured samples are different form each other when HAp was surface modified in different solvents. HAp particles fabricated using ethanol as solvent has higher activation ratio and grafting ratio. Pickering emulsion with higher stability and cured porous materials with uniform morphology were obtained compared with samples prepared using water and CH2Cl2 as solvents. In conclusion, surface modification of HAp in different solvents played a very important role for its stabilized Pickering emulsion as well as the microstructure of cured samples. It is better to use ethanol as the solvent for Sa modified HAp particles, which could increase the stability of Pickering emulsion and obtain cured samples with uniform pore size. PMID- 28629017 TI - Design of a new nanocomposite between bismuth nanoparticles and graphene oxide for development of electrochemical sensors. AB - This study describes a new route for preparation of a nanocomposite between graphene oxide (GO) and bismuth nanoparticles (BiNPs) and its evaluation as modifier electrode for development of electrochemical sensors. BiNPs were synthesized under ultrasound conditions using Bi(NO3)3 as metal precursor and ascorbic acid (AA) as reducing agent/passivating. Some experimental parameters of BiNPs synthesis such as Bi3+:AA molar ratio and reaction time were conducted aiming the best voltammetric performance of the sensor. Glassy carbon electrodes (GCE) were modified by drop-casting with the BiNPs dispersions and anodic stripping voltammetry measurements were performed and revealed an improvement in the sensitivityfor determination of Cd(II) and Pb(II) compared to an unmodified electrode. The best electrochemical response was obtained for a BiNPs synthesis with Bi3+:AA molar ratio of 1:6 and reaction time of 10min, which yielded Bi metallic nanoparticles with average size of 5.4nm confirmed by XRD and TEM images, respectively. GO was produced by graphite oxidation using potassium permanganate and exfoliated with an ultrasound tip. GO-BiNPs nanocomposite was obtained by a simple mixture of GO and BiNPs dispersions in water and kept under ultrasonic bath for 1h. GCE were modified with a nanocomposite suspension containing 0.3 and 1.5mgmL-1 of GO and BiNPs in water, respectively. Under optimized conditions, the proposed nanocomposite was evaluated on the voltammetric determination of Pb (II) and Cd (II), leading to a linear response range between 0.1 and 1.4MUmolL-1 for both cations, with limit of detection of 30 and 27nmolL-1, respectively. These results indicate the great potential of the GO BiNPs nanocomposite for improving the sensitivity of voltammetric procedures. PMID- 28629019 TI - Methotrexate-loaded nitrogen-doped graphene quantum dots nanocarriers as an efficient anticancer drug delivery system. AB - Graphene quantum dots (GQDs) are new efficient nanomaterials used in therapeutic applications. In this study, blue fluorescent nitrogen-doped GQDs (N-GQDs) were synthesized by a hydrothermal method via pyrolisis of citric acid as the carbon source and urea as the nitrogen source. The existence of doped nitrogen in GQDs was confirmed by FTIR characterization. Here, for the first time, the N-GQDs were loaded with the anticancer drug, methotrexate (MTX), to prepare MTX-(N-GQDs) as an efficient drug delivery system. The establishment of the strong pi-pi stacking interaction between MTX and N-GQDs was confirmed by FTIR and UV-vis spectroscopies indicating successful loading of MTX to N-GQDs. The in-vitro cytotoxicity of MTX-(N-GQDs) on human breast cancer cells investigated through MTT assay suggested that the drug-free N-GQDs nanocarriers are highly biocompatible, whereas the MTX-loaded ones are more cytotoxic than the free MTX. PMID- 28629018 TI - The Bone Building Blues: Self-hardening copper-doped calcium phosphate cement and its in vitro assessment against mammalian cells and bacteria. AB - A blue calcium phosphate cement with optimal self-hardening properties was synthesized by doping whitlockite (beta-TCP) with copper ions. The mechanism and the kinetics of the cement solidification process were studied using energy dispersive X-ray diffraction and it was found out that hardening was accompanied by the phase transition from TCP to brushite. Reduced lattice parameters in all crystallographic directions resulting from the rather low (1:180) substitution rate of copper for calcium was consistent with the higher ionic radius of the latter. The lower cationic hydration resulting from the partial Ca->Cu substitution facilitated the release of constitutive hydroxyls and lowered the energy of formation of TCP from the apatite precursor at elevated temperatures. Addition of copper thus effectively inhibited the formation of apatite as the secondary phase. The copper-doped cement exhibited an antibacterial effect, though exclusively against Gram-negative bacteria, including E. coli, P. aeruginosa and S. enteritidis. This antibacterial effect was due to copper ions, as demonstrated by an almost negligible antibacterial effect of the pure, copper free cement. Also, the antibacterial activity of the copper-containing cement was significantly higher than that of its precursor powder. Since there was no significant difference between the kinetics of the release of copper from the precursor TCP powder and from the final, brushite phase of the hardened cement, this has suggested that the antibacterial effect was not solely due to copper ions, but due to the synergy between cationic copper and a particular phase and aggregation state of calcium phosphate. Though inhibitory to bacteria, the copper doped cement increased the viability of human glial E297 cells, murine osteoblastic K7M2 cells and especially human primary lung fibroblasts. That this effect was also due to copper ions was evidenced by the null effect on viability increase exhibited by the copper-free cements. The difference in the mechanism of protection of dehydratases in prokaryotes and eukaryotes was used as a rationale for explaining the hereby evidenced selectivity in biological response. It presents the basis for the consideration of copper as a dually effective ion when synergized with calcium phosphates: toxic for bacteria and beneficial for the healthy cells. PMID- 28629020 TI - A comparative in vivo evaluation of bioactive glasses and bioactive glass-based composites for bone tissue repair. AB - In this work a set of novel materials for bone tissue regeneration have been tested in vivo in an animal model. In fact, despite many studies have been devoted to amorphous 45S5 Bioglass(r), there is lack in the literature of works aimed to study the in vivo performance of heat-treated - and thus partially crystallized - 45S5. As widely reported, crystallization limits the bioactivity of 45S5 and is the main reason that prevents a broader use of this material. Thus, in the present work, a recently developed bioactive glass (BG_Ca/Mix) is tested, since previous investigations demonstrated that BG_Ca/Mix is particularly promising by virtue of both its high bioactivity and lower tendency to crystallize with respect to 45S5. BG_Ca/Mix sintered powders and two composites, which contain BG_Ca/Mix and an increasing percentage (20wt% or 70wt%) of hydroxyapatite (HA), were considered. As a term of comparison, 45S5 sintered powders were also studied. The samples were implanted in rabbits' femurs and harvested after 8weeks. The histological analysis demonstrated that BG_Ca/Mix has an osteoconductive ability slightly higher than that of 45S5 glass-ceramics, followed by that of the composites, which may represent the starting point for obtaining systems with degradation rate tailored for a given clinical application. Moreover, the 45S5 samples were locally cracked, probably because of a non-uniform dissolution in the physiological environment. On the contrary such cracks, which could lead to implant instability and unsuitable mechanical performance, were not observed in BG_Ca/Mix. PMID- 28629021 TI - Novel hiPSC-based tri-culture for pre-vascularization of calcium phosphate scaffold to enhance bone and vessel formation. AB - Vascularization of tissue-engineered bone is a critical step in maintaining cell viability and advancing cell performance in vivo. In this study, a novel tri culture system was developed to elicit pre-vascularization of calcium phosphate cement (CPC) scaffold in which human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSMSCs) were seeded together with human umbilical vein endothelial cells (HUVECs) and pericytes. In a two-step methodology design, we first performed osteoinduction of the seeded hiPSMSCs on the CPC scaffold and then incorporated HUVECs and pericytes to the hiPSMSC-colonized CPC scaffold under a favorable culturing condition, with an objective to form a stable and functional capillary-like vascular network that sustained the engineered osseous tissue. The angiogenic and osteogenic effects of various culture strategies were studied and compared in nude rat model with cranial bone defects: (1) CPC scaffold alone (CPC control); (2) Pericyte-seeded CPC (CPC-pericytes); (3) HUVEC seeded CPC (CPC-HUVECs); (4) hiPSMSC-seeded CPC (CPC-hiPSMSCs); (5) HUVECs co cultured with hiPSMSCs on CPC (bi-culture group) and (6) HUVECs and pericytes co cultured with hiPSMSCs on CPC (tri-culture group). After 12weeks, tri-culture group showed the highest amount of new bone (new bone area fraction of (45.3+/ 2.7) %, p<0.05) and vessel formation (new blood vessel density of (50.7+/-3.8) vessels/mm2, p<0.05) in all groups. Our results demonstrated that the tri-culture strategy was effective in promoting angiogenesis and osteogenesis for bone tissue engineering. PMID- 28629022 TI - A novel functionalization method for carbon nanotubes to repel ox-LDL in treatments after stent placement. AB - Carbon nanotubes (CNT) can be chemically modified by doping or functionalization to change the chemical and surface properties. These characteristic makes to CNT candidates for multiple applications including medical field in cardiovascular area. A novel method to CNT functionalization by formation of two compounds: alpha-bromoacid and the organic compound 2-(methacryloyloxy) ethyl phosphorylcholine (MPC), will be discussed in this article. According to results, CNT are suggested like candidates to repel oxidized low-density lipoproteins (ox LDL) to prevent restenosis. The electronegative character on surface of functionalized CNT (F-CNT) is shown by wettability analysis observing a repellent behaviour in contact with ox-LDL after functionalization route. Here we analyse the toxicity of CNT and F-CNT on HepG2 cell line and find no damage to the cell membrane of HepG2 cells in concentration at doses below 1mg/ml. PMID- 28629024 TI - Electrospun silk fibroin scaffolds coated with reduced graphene promote neurite outgrowth of PC-12 cells under electrical stimulation. AB - Novel approaches to neural research require biocompatible materials capable to act as electrode structures or scaffolds for tissue engineering in order to stimulate or restore the functionality of damaged tissues. This work offers promising results that indicate the potential use of electrospun silk fibroin (SF) scaffolds coated with reduced graphene oxide (rGO) in this sense. The coated material becomes conductor and electroactive. A complete characterisation of SF/rGO scaffolds is provided in terms of electrochemistry, mechanical behaviour and chemical conformation of fibroin. The excellent biocompatibility of this novel material is proved with cultures of PC-12 cells. The coating with rGO improved the adhesion of cells in comparison with cells growing onto the surface of pure SF scaffolds. Also, the use of SF/rGO scaffolds combined with electrical stimulation promoted the differentiation into neural phenotypes reaching comparable or even superior levels to those obtained by means of the traditional treatment with neural growth factor (NGF). PMID- 28629023 TI - Heparin/DNA aptamer co-assembled multifunctional catecholamine coating for EPC capture and improved hemocompatibility of vascular devices. AB - Good hemocompatibility and rapid endothelialization are two key factors in the success of stent interventional therapy. In this study, aptamers with the ability to capture endothelial progenitors and anticoagulant molecular heparin were successfully immobilized on the surface of dopamine/polyethylenimine (PDA/PEI) copolymer coating via electrostatic interaction. The results of X-ray spectroscopy (XPS), water contact angle (WCA), and immunofluorescence staining tests confirmed the successful introduction of heparin and aptamers. Platelet adhesion and whole blood experiments demonstrated that the hemocompatibility of the co-modified surface was improved. Dynamic endothelial progenitor cell (EPC) capture experiments showed that the modified surfaces could effectively capture the endothelial progenitor in dynamic conditions. More importantly, ex vivo experiments revealed that the modified surfaces could regulate the distribution of CD34/vWF-positive cells on stent surfaces, and this was beneficial for the endothelialization of vascular stents. These results suggested that heparin and aptamer co-modified stents could capture EPCs and promote endothelialization. This surface co-modification strategy has great potential for enhancing stent development. PMID- 28629025 TI - Polycaprolactone- and polycaprolactone/ceramic-based 3D-bioplotted porous scaffolds for bone regeneration: A comparative study. AB - : One of the critical challenges that scaffolding faces in the organ and tissue regeneration field lies in mimicking the structure, and the chemical and biological properties of natural tissue. A high-level control over the architecture, mechanical properties and composition of the materials in contact with cells is essential to overcome such challenge. Therefore, definition of the method, materials and parameters for the production of scaffolds during the fabrication stage is critical. With the recent emergence of rapid prototyping (RP), it is now possible to create three-dimensional (3D) scaffolds with the essential characteristics for the proliferation and regeneration of tissues, such as porosity, mechanical strength, pore size and pore interconnectivity, and biocompatibility. In this study, we employed 3D bioplotting, a RP technology, to fabricate scaffolds made from (i) pure polycaprolactone (PCL) and (ii) a composite based on PCL and ceramic micro-powder. The ceramics used for the composite were bovine bone filling Nukbone(r) (NKB), and hydroxyapatite (HA) with 5%, 10% or 20% wt. CONTENT: The scaffolds were fabricated in a cellular lattice structure (i.e. meshing mode) using a 0/90 degrees lay down pattern with a continuous contour filament in order to achieve interconnected porous reticular structures. We varied the temperature, as well as injection speed and pressure during the bioplotting process to achieve scaffolds with pore size ranging between 200 and 400MUm and adequate mechanical stability. The resulting scaffolds had an average pore size of 323MUm and an average porosity of 32%. Characterization through ATR-FTIR revealed the presence of the characteristic bands of hydroxyapatite in the PCL matrix, and presented an increase of the intensity of the phosphate and carbonyl bands as the ceramic content increased. The bioplotted 3D scaffolds have a Young's modulus (E) in the range between 0.121 and 0.171GPa, which is compatible with the modulus of natural bone. PCL/NKB scaffolds, particularly 10NKBP (10% NKB wt.) exhibited the highest proliferation optical density, demonstrating an evident osteoconductive effect when cultured in Dulbecco's Modified Eagle Medium (DMEM). Scanning electron microscopy (SEM) confirmed osteoblast anchorage to all composite scaffolds, but a low adhesion to the all-PCL scaffold, as well as cell proliferation. The results from this study demonstrate the potential of PCL/NKB 3D bioplotted scaffolds as viable platforms to enable osseous tissue formation, which can be used in several tissue engineering applications, including improvement of bone tissue regeneration. PMID- 28629026 TI - Multistate proteinous biomemory device based on redox controllable hapten cross linker. AB - A multistate biomemory device consisting of cytochrome c (Cyt-c) photosensitively cross-linked by MACys-Ru(bipyr)2-MACys hapten molecules, which have memory effect through a charge transfer mechanism, has been developed. In this study, it has suggested a highly resolute surface-confined switch composed a signal-enhanced electro-active protein (Cyt-c) co-polymerized on the gold substrates that can be controlled by redox property through Ruthenium based cysteine monomer hapten, MACys-Ru(bipyr)2-MACys as an ANADOLUCA photosensitive cross-linker. The photosensitive cross-linking of the Cyt-c protein on the gold surface topography has been determined by the scanning electron microscopy (SEM). Two state memory functions, writing and erasing of the developed biomemory device, have been investigated by the chronoamperometry (CA) and open-circuit potential amperometry (OCPA). The polymeric proteinous memory device, p(MACys-Ru(bipyr)2-MACys-co-Cyt c) layer, on the gold electrode is stable and repeatable up to with 104 times continuous cycle. PMID- 28629027 TI - Electrophoretic deposition of hydroxyapatite-hexagonal boron nitride composite coatings on Ti substrate. AB - In this study, commercial pure titanium samples were coated with nano hydroxyapatite-nano hexagonal boron nitride (nano HA-nano hBN) composite by electrophoretic deposition (EPD). The effect of process parameters (applied voltage, deposition time and solid concentration) on the coating morphology, thickness and the adhesion behavior were studied systematically and crack free nano hBN-nano HA composite coating production was achieved for developing bioactive coatings on titanium substrates for orthopedic applications. For the examination of structural and morphological characteristics of the coating surfaces, various complementary analysis methods were performed. For the structural characterization, XRD and Raman Spectroscopy were used while, Scanning Electron Microscopy (SEM) equipped with an energy dispersive spectrometer (EDS) and Transmission Electron Microscopy (TEM) techniques were carried out for revealing the morphological characterization. The results showed that nano HA nano hBN were successfully deposited on Ti surface with uniform, crack-free coating by EPD. The amounts of hBN in suspension are considered to have no effect on coating thickness. By adding hBN into HA, the morphology of HA did not change and hBN has no significant effect on porous structure. These nanostructured surfaces are expected to be suitable for proliferation of cells and have high potential for bioactive materials. PMID- 28629028 TI - Physicochemical and biological assessment of PEEK composites embedding natural amorphous silica fibers for biomedical applications. AB - The main aim of this study was to assess the physicochemical and biological properties of a novel poly(ether ether ketone) (PEEK) composite containing 30%wt natural amorphous silica fibers (NASF). PEEK and NASF powders were previously functionalized by atomization and citric acid in order to enhance adhesion between polymeric matrix and fillers. Then, composites were produced by cold compression molding technique at 350 degrees C for 3h. Materials were characterized by chemical, microstructural, thermophysical, mechanical and cytotoxic analysis. The results of the mechanical assays showed that the incorporation fibers increased the elastic modulus of the resultant PEEK composite in 56% while its microhardness increased in 26.7%. Chemical and microscopic analyses detected a good interfacial adhesion between PEEK and NASF. The results of the cytotoxicity assays indicated that PEEK/NASF composites stimulated the metabolic activity of fibroblasts and therefore a high cytocompatibility was noticed. PEEK composites embedding natural amorphous silica fibers revealed a high potential to be used in medicine and dentistry replacing several polymeric and composite materials. PMID- 28629029 TI - Chitosan-coated amyloid fibrils increase adipogenesis of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have the potential to revolutionize medicine due to their ability to differentiate into specific lineages for targeted tissue repair. Development of materials and cell culture platforms that improve differentiation of either autologous or allogenic stem cell sources into specific lineages would enhance clinical utilization of MCSs. In this study, nanoscale amyloid fibrils were evaluated as substrate materials to encourage viability, proliferation, multipotency, and differentiation of MSCs. Fibrils assembled from the proteins lysozyme or beta-lactoglobulin, with and without chitosan coatings, were deposited on planar mica surfaces. MSCs were cultured and differentiated on fibril-covered surfaces, as well as on unstructured controls and tissue culture plastic. Expression of CD44 and CD90 proteins indicated that multipotency was maintained for all fibrils, and osteogenic differentiation was similarly comparable among all tested materials. MSCs grown for 7days on fibril-covered surfaces favored multicellular spheroid formation and demonstrated a >75% increase in adipogenesis compared to tissue culture plastic controls, although this benefit could only be achieved if MSCs were transferred to TCP for the final differentiation step. The largest spheroids and greatest tendency to undergo adipogenesis was evidenced among MSCs grown on fibrils coated with the positively charged polysaccharide chitosan, suggesting that spheroid formation is prompted by both topography and cell-surface interactivity and that there is a connection between multicellular spheroid formation and adipogenesis. PMID- 28629030 TI - High degradation rate of Fe-20Mn-based bio-alloys by accumulative cryo-rolling and annealing. AB - A new strategy of accumulative cryo-rolling (ACR) at liquid nitrogen temperature and annealing was performed to improve degradation rate of Fe-Mn-based implants. Differing from as-cast and ACRed Fe-Mn-based alloys with single-phase austenite, ACRed-annealed sample mainly consists of austenite and non-equilibrium Fe5C2 precipitate. ACR-annealed sample shows a degradation rate of 0.0388mA.cm-2, which is 4.6 times higher than as-cast alloy. Pitting corrosion plays a dominant role in both as-cast and ACRed samples. Conversely, some micro-batteries are prone to form among different phase interfaces for ACR-annealed sample, resulting in general corrosion. It reveals that phase optimization is a possible strategy to achieve bio-Fe implants. PMID- 28629031 TI - Near-infrared persistent luminescence phosphors ZnGa2O4:Cr3+ as an accurately tracker to photothermal therapy in vivo for visual treatment. AB - The photothermal therapy agents induced by 808 nm near infrared light laser have good potential for photothermal therapy (PTT) in vivo, with the advantages of harmless treatment, minimally invasion, high efficiency and deep tissue penetration. For the traditional photothermal therapy agents, however, it was impossible to track them in vivo because of the low signal-to-noise ratio, so we cannot conduct the extra near infrared light laser to radiate tumors sites accurately. Herein, we introduce a new complex: indocyanine green (ICG), near infrared persistent luminescence (PL) phosphors ZnGa2O4:Cr3+ (ZGC) and mesoporous silica nanoparticles (MSNs) (ICG@mZGC nanoparticles) were assembled for long lasting optical imaging to guide PTT. The results revealed that the novel nanoparticle, ICG@mZGC, could lower signal-to-noise ratio, enable highly sensitive optical detection during optical imaging-guided PTT and perform a good effect of photothermal therapy in vivo, and thus providing possibilities for mZGC to improve the localization precision of tumor sites in photothermal therapy in the body. PMID- 28629032 TI - Effects of silane-modified fillers on properties of dental composite resin. AB - The effect of silanization on the mechanical, chemical, and physical properties of dental composites was investigated. Silica fillers were obtained from colloidal silica solution, Ludox(r) HS-40 and they were silanized by using 3 methacryloxypropyl trimethoxysilane (MPTMS) in an acidic media. Mineralogical and chemical structures of unsilanized and silanized fillers were determined by using XRD and FT-IR analyses. The modification of unsilanized/silanized fillers were investigated by performing XPS and TGA analyses. The morphological evaluations, surface area, and particle size measurements were performed by using SEM, BET, and Zeta-Sizer, respectively. Eventually, pure and amorphous silica fillers were obtained. Furthermore, the weight percentage of the silane in silica/silane structure was compatible with theoretical values. SEM images, surface area, and particle size measurements showed that agglomeration tendencies of silanized fillers were lower compared to silanized fillers because of the MPTMS addition. Experimental composites (5/10/10/5BisGMA/HEMA/UDMA/TEGDMA resin reinforced with 70wt% silanized/unsilanized SiO2) were fabricated into 4mm diameter*6mm thick discs for compressive strength (CS), angular flexural strength (AFS), curing depth (CD), and polymerization shrinkage (PS) on a 25*2*2mm rectangular Teflon mold for flexural strength (FS) and modulus of elasticity (E) tests. The curing depth (CD) and degree of polymerization percentage (DP) of composites were determined. Consequently, results showed that mechanical properties and DP of composite resins can be greatly influenced by silanization as a result of the organic matrix-inorganic filler interface bonding formed by silane structures. Despite of these findings, silanization of the SiO2 was not effected DC and PS values. PMID- 28629033 TI - A new finding on the in-vivo crevice corrosion damage in a CoCrMo hip implant. AB - A detailed investigation was performed to characterize the fretting wear and corrosion damage to the neck component of a CoCrMo stem from a metal-on polyethylene implant retrieved after 99months. The stem was a low-carbon (0.07wt%) wrought Co-28Cr-6Mo alloy with no secondary carbide phases in the matrix (gamma-phase). The original design of the neck surface contained an intentionally fabricated knurled profile with a valley-to-peak range of approximately 11MUm. Roughness measurements indicated that the tip of the knurled profile was significantly damaged, especially in the distal medial region of the neck, with up to a 22% reduction in the mean peak-to-valley height (Ra) compared to the original profile. As a new finding, the channels between the peaks of the profile created an additional crevice site in the presence of stagnant body fluid within the head-neck taper junction. These channels were observed to contain the most severe corroded areas and surface oxide layers with micro-cracks. SEM/EDS, XRD and XPS evaluations identified the formation of Cr2O3 as a corrosion product. Also, decobaltification was found to occur in these corroded areas. The findings of this work indicate the important role of the knurled profile in inducing additional crevice corrosion. PMID- 28629034 TI - Icariin immobilized electrospinning poly(l-lactide) fibrous membranes via polydopamine adhesive coating with enhanced cytocompatibility and osteogenic activity. AB - In this study, icariin (ICA), one of the main active ingredients of Herba Epimedii for osteogenesis, was applied to functionalize electrospinning poly(l lactide) (PLLA) fibrous membrane via an intermediate layer of polydopamine (PDA) to obtain enhanced cytocompatibility and osteogenic activity. For this purpose, an array of PDA-coated PLLA fibrous membranes (PLLA-0.5PDA, PLLA-1PDA, PLLA-2PDA, PLLA-5PDA) and ICA-modified PLLA-2PDA fibrous membranes (PLLA-2PDA-10ICA, PLLA 2PDA-20ICA, PLLA-2PDA-40ICA) were successively prepared. Successful modification of PDA and ICA onto PLLA fibrous membranes was verified by field emission scanning electron microscope (FESEM), thermogravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS). Besides, the hydrophilicity as well as tensile properties of PLLA fibrous membrane were improved after surface modified with PDA and ICA. In vitro cells culture experiments revealed that the adhesion, proliferation and osteogenic differentiation of MC3T3-E1 cells on the PLLA fibrous membrane were significantly improved by successively immobilized with PDA and ICA. Moreover, the concentration of ICA immobilized on the fibrous membranes has the complicated effects on the MC3T3-E1 cells behavior. The PLLA-2PDA-ICA fibrous membranes with low ICA concentration promoted the cell adhesion and proliferation, but on the contrary, those with high ICA concentration were more beneficial to the enhancement in ALP activity and calcium deposition. PMID- 28629035 TI - Sodium alginate-polyvinyl alcohol-bovin serum albumin coated Fe3O4 nanoparticles as anticancer drug delivery vehicle: Doxorubicin loading and in vitro release study and cytotoxicity to HepG2 and L02 cells. AB - The challenging part of this work was to research the potential aspects of sodium alginate (SA)-polyvinyl alcohol (PVA)-bovin serum albumin (BSA) coated Fe3O4 nanoparticles (Fe3O4-SA-PVA-BSA) as a drug delivery system for doxorubicin (DOX). The anticancer drug doxorubicin was selected as a model drug which is powerful for numerous cancer treatments. Superparamagnetic Fe3O4 nanoparticles were prepared by co-precipitation method. The mixture solution of Fe3O4-sodium alginate (SA) - doxorubicin (DOX) was crosslinked with Ca2+ to form (Fe3O4-SA DOX) nanoparticles and addition of PVA and BSA with (Fe3O4-SA-DOX) nanoparticles was prepared by coating procedure. Doxorubicin drug loaded NPs were prepared by a simple crosslinking method by calcium chloride solution. The prepared polymer coated magnetic nanoparticles (Fe3O4-SA-PVA-BSA) were characterized by using SEM, AFM, FT-IR, XRD and VSM. The mean sizes of the obtained drug loaded nanoparticles (Fe3O4-SA-DOX, Fe3O4-SA-DOX-PVA and Fe3O4-SA-DOX-PVA-BSA) were between 240+/-8.3 and 460+/-8.7nm and zeta potential of the particles also was evaluated using Malvern Zetasizer which ranged between -48.1+/-2.3 and -22.4+/-4.1mV. The encapsulation efficiency, was between 36.2+/-0.01 and 96.45+/-2.12. Moreover drug loading and drug release properties of the polymer coated magnetic nanoparticles loaded with doxorubicin (Fe3O4-SA-DOX-PVA-BSA) were also studied. In addition, the cytotoxicity of the created nanoparticles was performed by using MTT assay analysis which showed that DOX loaded nanoparticles (Fe3O4-SA-DOX-PVA-BSA) were toxic to HepG2 cell lines and non-toxic to L02 cell lines. The in-vitro drug release was studied by using UV-Visible spectrophotometer at acidic environment (pH5.0) and basic environment (pH7.4) as well as at different temperatures (37 degrees C and 42 degrees C). It was found that DOX drug is released much faster in acidic environment (pH5.0) than in the basic environment (pH7.4). The results propose that prepared polymer coated magnetic (Fe3O4-SA-PVA-BSA) nanoparticles are suitable for controlled and targeted release of anticancer drugs reducing side effects and attaining higher efficacy. PMID- 28629036 TI - Intestine-targeted delivery potency of the O-carboxymethyl chitosan-gum Arabic coacervate: Effects of coacervation acidity and possible mechanism. AB - The potential of the glutaraldehyde-crosslinked O-carboxymethyl chitosan (O-CMC) gum Arabic (GA) coacervate as an intestine-targeted delivery system for hydrophobic compounds was concerned. OCMC-GA coacervates and emulsified bovine serum albumin (BSA)-loaded microcapsules were prepared in pH3.0, 4.5, and 6.0 and their swelling behaviors as well as BSA release profiles in simulated gastrointestinal fluids were measured. All the coacervates showed higher swelling ratios in the simulated gastric solution than in the simulated intestine and colon solutions and the values increased as the coacervation pH increased from 3.0 to 6.0, but a reversed trend was observed for the BSA release profile. SEM, TEM, and CLSM analysis revealed that the coacervation acidity influenced the swelling and BSA release behavior by changing the matrix density and O-CMC content of the coacervates. It was concluded that the O-CMC-GA coacervate could be used to deliver hydrophobic compounds to the intestine and its delivery performance could be tailored by selecting appropriate coacervation acidity and crosslinking degree. PMID- 28629037 TI - Regenerated egg white/silk fibroin composite films for biomedical applications. AB - Protein-based composites have always been desirable biomaterials as they can be fabricated into a wide range of biomaterials with tunable properties, including modulation of mechanical properties and control of cell responses. Both egg white protein (EW) and silk fibroin (SF) are biocompatible, biodegradable, non-toxic and naturally abundant biopolymers. In order to obtain biocompatible composite films with tunable performance, EW and SF were blended at various ratios. Raising the SF ratio in the composite films significantly increased breaking strength, but impaired flexibility. Conversely, increasing the EW ratio remarkably enhanced elasticity of the composite films. Furthermore, the biological assays based on endothelial cells showed that the incorporation of EW promoted cell viability. These make them potential materials with controllable mechanical property and enhanced bioactivity, providing useful options for the fabrication of tissue engineering scaffolds. PMID- 28629038 TI - Electrospinning of PVA/sericin nanofiber and the effect on epithelial-mesenchymal transition of A549 cells. AB - This research aims to investigate the cell-nanomaterial interaction between epithelial-mesenchymal transition of A549 cell and electrospinning nanofibers composed of polyvinyl alcohol (PVA)/silk sericin (SS). The electrospinning of regenerated nanofiber was performed with water as a spinning solvent and glutaraldehyde as a chemical cross-linker. Solution concentration, applied voltage and spin distances as well as other parameters were optimized to generate fine nanofibers with smooth surface in good homogeneity. From the scanning electron microscopy (SEM) analysis, the nanofibers had an average diameter of 200nm. Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells lose their cell polarity to become mesenchymal stem cells. This transition is affected by multiple biochemical and physical factors in cell metabolism cascade. Herein, we investigate the biophysical effect on A549 EMT by culturing cells on nanofibrous mats with different topography and composition. The cell viability was evaluated by biochemical assay and its morphology was observed with SEM. The results demonstrate that cells appropriately attached to the surface of the nanofibrous mats with extended morphology by their filopodia. Gene expression analysis was conducted by real-time PCR using multiple markers for detecting EMT: N-cadherin (NCad), Vimentin (Vim), Fibronectin (Fib) and Matrix metallopeptidase (MMP9). An increasing expression pattern was observed on NCad, Vim, Fib, with respect to a negative control as cell cultured on polystyrene dish. This result indicates the 200nm PVA/SS nanofibers may induce A549 cells to process epithelial mesenchymal transition during the culturing. PMID- 28629039 TI - Time-dependent subcellular structure injuries induced by nano-/micron-sized calcium oxalate monohydrate and dihydrate crystals. AB - Comparative studies were conducted to investigate the time effect of cell injury induced by nano-sized (50nm) and micron-sized (10MUm) calcium oxalate monohydrate (COM) and dihydrate (COD) crystals in African green monkey renal epithelial (Vero) cells. The effects of nano-/micron-sized COM and COD exposure on Vero cells were investigated by detecting the cell viability, cell morphology, LDH release, reactive oxygen species, mitochondrial membrane potential, cell cycle, and cell apoptosis, as well as the intracellular and extracellular crystal distribution. Nano-/micron-sized COM and COD exposure lead to subcellular organelle injury in varying degrees, but the injury sequence of various organelles differed. The time sequence of organelle injury presenting significant variation was described as follows: cell membrane injury (1h)500MUg/mL). In particular, the percentage of necrotic cells decrease in a statistically significant manner for the functionalized particles at lower doses than 100MUg/mL. This study concludes that the proposed surface functionalization of MSNs particles does not compromise their viability on H9c2 cells, and therefore they could potentially be used for biomedical purposes. Fourier transform infrared, Raman, TGA/DSC, N2 adsorption-desorption, and TEM techniques were used to characterize the as-prepared materials. Confocal microscopy and flow cytometry analyses were carried out to measure the histograms of cell complexity and the half maximal inhibitory concentration, respectively. Reactive oxygen species generation was accessed using assays with MitoSOX and Amplex Red fluoroprobes. PMID- 28629087 TI - A novel candidate for wound dressing: Transparent porous maghemite/cellulose nanocomposite membranes with controlled release of doxorubicin from a simple approach. AB - The aim of this study is to develop transparent maghemite/cellulose nanocomposite membranes with high porosity, high adsorption capacity and controlled release of doxorubicin to be used as a candidate for wound dressing. The membranes were fabricated by a tape casting method through blending a homogeneous dispersion of citrate coated maghemite nanoparticles and cellulose in the NaOH/urea aqueous solution system. The prepared membranes were characterized by Light transmittance measurements, Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray Diffractometry (XRD), Differential scanning calorimetry (DSC), Tensile tests and Vibrating sample magnetometer (VSM). Furthermore, porosity, swelling behavior, water loss ratio and Bovine serum albumin adsorption capacity were evaluated. Drug loading and release was investigated using doxorubicin hydrochloride as a model drug. In vitro cytotoxicity and cells morphology assays of cells growth and proliferation were also studied. This study served as a demonstration of the feasibility of maghemite/cellulose nanocomposite membranes for loading and release of bioactive compounds as a candidate for wound dressing. PMID- 28629089 TI - Assembly of chitosan support matrix with gallic acid-functionalized nanoparticles. AB - The incorporation of gallic acid (GA) in a direct way or into nanoparticles included in chitosan edible films appears as a suitable approach to increase its preservation upon adverse conditions. The addition of nanoparticles to chitosan based matrices resulted in improvements in their solubility, swelling, and mechanical properties. It is worth noting that by means of the nanoencapsulation, the release process can be modulated in relation to the delivery of GA included directly in the matrix, releasing the agent at a lower rate for a longer time. Films containing functionalized nanoparticles are promising as a means to develop tailor-made support matrices for improving the shelf stability of the included active compound. From the point of view of the antimicrobial activity, all studied films showed bacteriostatic activity against Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 25922, Salmonella spp. and Candida vinaria. The results suggest that active films with nanoparticles could be a potential candidate for the support and controlled release of active compounds such as gallic acid. PMID- 28629088 TI - Encapsulation of methotrexate and cyclophosphamide in interpolymer complexes formed between poly acrylic acid and poly ethylene glycol on multi-walled carbon nanotubes as drug delivery systems. AB - By combining the advantage of multi-walled carbon nanotubes (MWCNTs) and interpolymer complexes, we synthesis a new carrier system consist of poly(acrylic acid)/poly(ethylene glycol)/carbon nanotube (PAA/PEG/CNT). Then, Methotrexate (MTX) and Cyclophosphamide (CPP) were loaded on PAA/PEG/CNT, and the physicochemical properties of nanoparticles characterized by Infrared spectroscopy (IR), Scanning Electron Microscopy (SEM), Thermo Gravimetric Analysis (TGA) and Nuclear Magnetic Resonance (NMR). In the second part after efficiency determination of loaded drugs, in vitro drug release study was examined with ultra violet spectroscopy (UV) in pH=7.4 buffer (human body range) and pH=4 buffer (pH of cancer cells), and fever temperature drug release kinetic was studied by different mathematical models. PMID- 28629090 TI - Low-temperature direct heterogeneous bonding of polyether ether ketone and platinum. AB - Direct heterogeneous bonding between polyether ether ketone (PEEK) and Pt was realized at the temperatures lower than 150 degrees C. In order to create sufficient bondability to diverse materials, the surface was modified by vacuum ultraviolet (VUV) irradiation, which formed hydrate bridges. For comparison, direct bonding between surfaces atomically cleaned via Ar fast atom bombardment (FAB) was conducted in a vacuum. The VUV irradiation was found to be effective for creating an ultrathin hydrate bridge layer from the residual water molecules in the chamber. Tight bonds were formed through dehydration of the hydrate bridges by heating at 150 degrees C, which also contributed to enhancing interdiffusion across the interface. The VUV-modified surfaces showed bondability as good as that of the FAB-treated surfaces, and the VUV-modified samples had shear strengths at the same level as those of FAB-treated surfaces. This technology will be of practical use in the packaging of lightweight, flexible biomedical devices. PMID- 28629091 TI - Polyurethane-silica hybrid foams from a one-step foaming reaction, coupled with a sol-gel process, for enhanced wound healing. AB - Polyurethane (PU)-based dressing foams have been widely used due to their excellent water absorption capability, optimal mechanical properties, and unequaled economic advantage. However, the low bioactivity and poor healing capability of PU limit the applications of PU dressings in complex wound healing cases. To resolve this problem, this study was carried out the hybridization of bioactive silica nanoparticles with PU through a one-step foaming reaction that is coupled with the sol-gel process. The hybridization with silica did not affect the intrinsically porous microstructure of PU foams with silica contents of up to 10wt% and where 5-60nm silica nanoparticles were well dispersed in the PU matrix, despite slight agglomerations. The incorporated silica enhanced the mechanical performance of PU by proffering better flexibility and durability as well as maintaining good water absorption capabilities and the WVTR characteristics of pure PU foam. The silica of PU-10wt% Si foams was gradually dissolved and released under physiological conditions during a 14-day immersion period. The in vitro cell attachment and proliferation tests showed significant improvements in terms of the biocompatibility of PU-Si hybrid foams and demonstrated the effects of silica on cell growth. More significantly, the superior healing capability of PU-Si as a wound dressing in comparison to PU-treated wounds was verified through in vivo animal tests. Full-thickness wounds treated with PU-Si foams exhibited faster wound closure rates as well as accelerated collagen and elastin fiber regeneration in newly formed dermis, which was ultimately completely covered by a new epithelial layer. It is clear that PU-Si hybrid foams have considerable potential as a wound dressing material geared for accelerated, superior wound healing. PMID- 28629092 TI - Binary functional porous multi mineral-substituted apatite nanoparticles for reducing osteosarcoma colonization and enhancing osteoblast cell proliferation. AB - We investigated the use of combined nanoparticles in bone replacement for patients with bone cancer. Bismuth (Bi) is known to have antitumor effects, and the inclusion of Bi in bioactive mineral (M)-substituted hydroxyapatite (M-HAP) may provide anti-cancer properties implant resources. A series of Bi-substituted M-HAP (Bi-M-HAP) nanoparticles with various Bi concentrations was synthesized via the ultrasound irradiation method. The nanoparticles were examined using physicochemical strategies. The cell-substance interface of the nanoparticles was observed in vitro with human osteosarcoma cells and cell multiplication was measured at 1, 3, and 7days of incubation and in vivo in rats after 3weeks of implantation. The nanoparticles promoted osseous proliferation, improved mechanical strength, and repressed the development of cancerous cells. Overall, Bi-M-HAP nanoparticles show promise for treatment of bone cancer and advance the field of embedded biomaterials. PMID- 28629093 TI - Novel Pemulen/Pullulan blended hydrogel containing clotrimazole-loaded cationic nanocapsules: Evaluation of mucoadhesion and vaginal permeation. AB - In this work, hydrogels containing clotrimazole-loaded nanocapsules were developed through the innovative association of two mucoadhesive polymers: Pemulen(r) TR1 and Pullulan. Furthermore, the hydrogels macroscopic characteristics, pH and spreadability were evaluated. The formulations showed homogeneous appearance and pH compatible with vaginal application (around 5.0). Similar spreadability profiles were found in hydrogels containing clotrimazole loaded nanocapsules and in the free drug as well. Hydrogels were evaluated considering their mucoadhesive potential by the falling liquid film method and the permeation/penetration capacity through cow vaginal mucosa in Franz cell. The results showed that the concentration of 3% Pullulan was important to increase the adhesive strength on the layer used (mucin gel or animal mucosa). The results of the permeation/penetration study showed that the hydrogel containing clotrimazole-loaded nanocapsules remained on the vaginal mucosa surface, what is ideal for the treatment of superficial vaginal infections. This way, the Pemulen/Pullulan blended hydrogel is a promising alternative for the treatment of vulvovaginal candidiasis. PMID- 28629094 TI - Study on the injectability of a novel glucose modified magnesium potassium phosphate chemically bonded ceramic. AB - A novel magnesium potassium phosphate chemically bonded ceramic (MKPCBC) was prepared as a byproduct of boron-containing magnesium oxide (B-MgO) after extracting Li2CO3 from salt lakes. In this work, the influence of glucose on the properties of MKPCBC, such as the setting time, compressive strength and hydration heat, was investigated. In addition, we studied the effect of the magnesium-phosphate ratio (M/P) and liquid-solid ratio (L/S) on the injectability of MKPCBC. The pH change in glucose modified MKPCBC paste was also investigated. The phase composition and microstructure were studied in detail by using X-ray diffraction (XRD) and scanning electron microscopy-energy dispersive spectrometry (SEM-EDS). The results show that the optimal content of glucose is 6wt%. The optimum proportions of M/P and L/S for MKPCBC are 1.5 and 0.25, respectively. The properties of the novel MPCBC can meet the requirements of biomaterials. In addition, the retardation mechanism of glucose on MKPCBC and the hydration mechanism of novel MKPCBC were studied in detail through the continuous monitoring of the phase composition and microstructure. PMID- 28629095 TI - Solvothermal synthesis of hydroxyapatite nanorods with assistance of green polymer. AB - Development of low cost, environmental friendly crystal growth modifying reagents that are effective to HAp's microstructure regulation is highly crucial. Herein, sodium lignin sulfonate (SS), a byproduct of the pulp process, was used for preparing HAp nanorods. Results showed that both stirring time of reaction solution and the concentration of SS affected crystals' structure and aspect ratio. The growth mechanism was discussed on the basis of the results. And we hope this new synthetic strategy will offer an attractive route for the design of functional HAp nano-/micro- materials with fine structure. PMID- 28629096 TI - Synthesis of magnetic nanoparticles and their dispersions with special reference to applications in biomedicine and biotechnology. AB - Biomedical and biotechnological applications of magnetic nanoparticles and their dispersions in liquids are found to be potentially useful. An exponential growth in publications of papers, reviews and patents has been observed. Possibilities of their indiscriminate use on individual as well as environmental health hazards are also investigated. Still, there appears to be a good scope for further research work in the field. Even a small improvement either in preparation method or development of novel nanoparticles may prove to be beneficial in longer run. With this aim in mind, the present review discussed the work carried out in author's laboratory on synthesis and characterization of certain biomagnetic particles and biocompatible fluids composed of these particles. Modified methods were used to synthesize these particles. Notable amongst these are direct binding of biomolecules or drug on magnetic nano particles, low Curie point functionalized magnetic particles, targeted drug delivery system, photodyne therapy, anti-bacterial activity and bioremediation of marine fungi. Advantages and limitations of these work in light of recent work is also discussed. PMID- 28629097 TI - Emerging bone tissue engineering via Polyhydroxyalkanoate (PHA)-based scaffolds. AB - Polyhydroxyalkanoates (PHAs) are a class of biodegradable polymers derived from microorganisms. On top of their biodegradability and biocompatibility, different PHA types can contribute to varying mechanical and chemical properties. This has led to increasing attention to the use of PHAs in numerous biomedical applications over the past few decades. Bone tissue engineering refers to the regeneration of new bone through providing mechanical support while inducing cell growth on the PHA scaffolds having a porous structure for tissue regeneration. This review first introduces the various properties PHA scaffold that make them suitable for bone tissue engineering such as biocompatibility, biodegradability, mechanical properties as well as vascularization. The typical fabrication techniques of PHA scaffolds including electrospinning, salt-leaching and solution casting are further discussed, followed by the relatively new technology of using 3D printing in PHA scaffold fabrication. Finally, the recent progress of using different types of PHAs scaffold in bone tissue engineering applications are summarized in intrinsic PHA/blends forms or as composites with other polymeric or inorganic hybrid materials. PMID- 28629098 TI - Carbon nanotube ensembled hybrid nanocomposite electrode for direct electrochemical detection of epinephrine in pharmaceutical tablets and urine. AB - An efficient electrochemical sensor for selective detection of the neurotransmitter, epinephrine (Epn), has been fabricated with the aid of a functionalized multiwall carbon nanotube-chitosan biopolymer nanocomposite (Chit fCNT) electrode. Multiwall carbon nanotubes (CNT) were successfully functionalized with the aid of nitric acid and confirmed by the Raman spectral data. Functionalized carbon nanotubes (fCNT) were dispersed in chitosan solution and the resulting bio-nanocomposite was used for the fabrication of sensor surface by drop and cast method. Electrochemical characteristics of the fabricated sensor were understood using cyclic, differential pulse voltammetry (CV, DPV) and electrochemical impedance analysis for the detection of Epn in phosphate buffer (pH7.4). CV and impedance analysis revealed that the Chit-fCNT modified electrode enhances the electrodic reaction of Epn and facilitated the electron transfer more readily compared to that of bare electrode. Applying DPV for the detection of Epn, achieved 30nM as the lowest detection limit in the determination range of 0.05-10MUM and the analytical time as low as 10s. Selective determination of Epn against the coexistence of a number of biological electroactive interferents and reproducible results for the determination of Epn were demonstrated. The present biosensor has been found efficient for successful direct determination of Epn from pharmaceutical adrenaline formulations and urine samples. PMID- 28629099 TI - Instrumental methods and techniques for structural and physicochemical characterization of biomaterials and bone tissue: A review. AB - A review of recent advances in instrumental methods and techniques for structural and physicochemical characterization of biomaterials and bone tissue is presented in this paper. In recent years, biomaterials attracted great attention primarily because of the wide range of biomedical applications. This paper focuses on the practical aspects of instrumental methods and techniques that were most often applied (X-ray methods, vibrational spectroscopy (IR and Raman), magnetic resonance spectroscopy (NMR and ESR), mass spectrometry (MS), atomic absorption spectrometry (AAS) and inductively coupled plasma-atomic emission spectrometry (ICP-AES), thermogravimetry (TG), differential thermal analysis (DTA) and differential scanning calorimetry (DSC), scanning electron microscopy (SEM), transmission electron microscopy (TEM)) in the structural investigation and physicochemical characterization of biomaterials and bone tissue. The application of some other physicochemical methods was also discussed. Hands-on information is provided about these valuable research tools, emphasizing practical aspects such as typical measurement conditions, their limitations and advantages, interpretation of results and practical applications. PMID- 28629100 TI - Biomaterials and cells for cardiac tissue engineering: Current choices. AB - The major purpose of cardiac tissue engineering is to engineer cells on scaffolds and use it as a substitute to infarcted cardiac cells. With an ever-increasing risk of cardiac diseases there is an increasing need to have a stable and sustainable approach to cure such ailments. This review provides a comprehensive update on the cell sources and biomaterials essential for cardiac tissue engineering, ensuring their biocompatibility under a variety of conditions. Cells can be obtained from allogenic or autologous sources. The cells sources described in this paper are cardiomyocytes, a variety of stem cells, fibroblasts and parthenogenetic cells. Scaffolds to seed the cells should fulfill various criteria, the most important ones being non-immunogenicity, biodegradability and native tissue mimicking. There are several kinds of scaffolds including hydrogels, prefabricated matrices, decellularized scaffolds and cell sheets. Using this knowledge of cell sources and scaffold fabrication, production of various tissue engineered products is possible. PMID- 28629101 TI - A mini review on hydrogels classification and recent developments in miscellaneous applications. AB - Hydrogels are composed of three-dimensional smart and/or hungry networks, which do not dissolve in water but swell considerably in an aqueous medium, demonstrating an extraordinary ability to absorb water into the reticulated structure. Such inherent feature is a subject of considerable scientific research interest which leads to a dominating path in extending their potential in hi-tech applications. Over the past decades, significant progress has been made in the field of hydrogels. Further, explorations are continuously being made in all directions at an accelerated pace for their extensive usage. In view of this, the present review discusses the subject on the miscellaneous hydrogels with regard to their raw materials, methods of fabrication and applications. In addition, this article summarizes the classification of hydrogels, based on their cross linking and physical states. Lately, a brief outlook on the future prospects of hydrogels is also presented. PMID- 28629102 TI - Bioelectrochemical approach for control of methane emission from wetlands. AB - To harvest electricity and mitigate methane emissions from wetlands, a novel microbial fuel cell coupled constructed wetland (MFC-CW) was assembled with an anode placing in the rhizosphere and a cathode on the water surface. Plant mediated methane accounted for 71-82% of the total methane fluxes. The bioanode served as an inexhaustible source of electron acceptors and resulted in reduced substantial methane emissions owing to electricigens outcompeting methanogens for carbon and electrons when substrate was deficient. However, when supplying sufficient organic carbon, both electricity and methane increased, indicating that electrogenesis and methanogenesis could co-exist in harmony. Direct methane emission (diffusion/ebullition) and plant-mediated methane emission were affected by operating conditions. Methanogenesis was significantly suppressed (~98%) at HRT of 96h and with external resistance of 200Omega, accompanied with improved coulombic efficiency of 14.9% and current density of 187mA/m2. Contrarily, change of electrode polarity in the rhizosphere led to more methane efflux. PMID- 28629103 TI - Lignocentric analysis of a carbohydrate-producing lignocellulosic biorefinery process. AB - A biologically-based lignocellulosic biorefinery process for obtaining carbohydrates from raw biomass was investigated across six diverse biomasses (three hardwoods & three nonwoods) for the purpose of decoding lignin's influence on sugar production. Acknowledging that lignin could positively alter the economics of an entire process if valorized appropriately, we sought to correlate the chemical properties of lignin within the process to the traditional metrics associated with carbohydrate production-cellulolytic digestibility and total sugar recovery. Based on raw carbohydrate, enzymatic recovery ranged from 40 to 64% w/w and total recovery ranged from 70 to 87% w/w. Using nitrobenzene oxidation to quantify non-condensed lignin structures, it was found that raw hardwoods bearing increasing non-condensed S/V ratios (2.5-5.1) render increasing total carbohydrate recovery from hardwood biomasses. This finding indicates that the chemical structure of hardwood lignin influences the investigated biorefinery process' ability to generate carbohydrates from a given raw hardwood feedstock. PMID- 28629104 TI - Efficient 2,4-dichloronitrobenzene removal in the coupled BES-UASB reactor: Effect of external voltage mode. AB - In this study, bioelectrochemical-upflow anaerobic sludge blanket (BES-UASB) system was developed for treatment of 2,4-dichloronitrobenzen (DClNB) containing wastewater to investigate the effect of external voltage with different supplying modes. Results showed that 2,4-dichloroaniline (DClAN) was under detection limit in R1 (applied with intermittent voltage) and R2 (applied with continuous voltage) when the DClNB loading increased from 25 to 100gm3d-1 (hydraulic retention time (HRT) was decreased from 24 to 6h) while sudden accumulation of DClAN (1.7mgL-1) was observed in R0 (control). Dechlorination efficiency (DE) decreased to 32.7%, 45.0% and 45.3% in R0, R1 and R2 when HRT was further shortened to 4h. Microbial community analysis indicated the significant enrichment of dechlorination-related species in R1 and R2 compared with R0, e.g., Dehalobacter and Dehalococcoides. In summary, the BES-UASB system with intermittent voltage is an alternative process for efficient treatment of DClNB containing wastewater, and the energy input was reduced markedly. PMID- 28629105 TI - Indispensable role of biochar-inherent mineral constituents in its environmental applications: A review. AB - Biochar typically consists of both carbon and mineral fractions, and the carbon fraction has been generally considered to determine its properties and applications. Recently, an increasing body of research has demonstrated that mineral components inherent in biochar, such as alkali or alkaline earth metals in the form of carbonates, phosphates, or oxides, could also influence the properties and thus the applications. The review articles published thus far have mainly focused on multiple environmental and agronomic applications of biochar, including carbon sequestration, soil improvement, environmental remediation, etc. This review aims to highlight the indispensable role of the mineral fraction of biochar in these different applications, especially in environmental applications. Specifically, it provides a critical review of current research findings related to the mineral composition of biochar and the effect of the mineral fraction on the physicochemical properties, contaminant sorption, carbon retention and stability, and nutrient bioavailability of biochar. Furthermore, the role of minerals in the emerging applications of biochar, as a precursor for fuel cells, supercapacitors, and photoactive components, is also summarized. Overall, inherent minerals should be fully considered while determining the most appropriate application for any given biochar. A thorough understanding of the role of biochar-bound minerals in different applications will also allow the design or selection of the most suitable biochar for specific applications based on the consideration of feedstock composition, production parameters, and post treatment. PMID- 28629106 TI - Tannin extraction pretreatment and very high gravity fermentation of acorn starch for bioethanol production. AB - The bioethanol production from a novel non-grain feedstock, acorn starch, was studied in this work. The inhibition of tannin in strain growth was investigated, and the effect of tannin was negligible when the tannin concentration was lower than 1g/L in medium. Therefore, the extraction of tannin was performed using 40% (v/v) ethanol-water solution as the solvent for three times under the conditions of solid/liquid ratio 1:20, 60 degrees C, 3h, by which more than 80% of tannin in acorn was extracted and the content of tannin in acorn decreased from 7.4% (w/w) to 1.5% (w/w). Very high gravity (VHG) fermentation technology was subsequently carried out to achieve a high ethanol concentration at 86.4g/L. A comprehensive process for bioethanol production from acorn starch was designed and a preliminary economic assessment was then performed revealing that this process appeared technically and economically justified. PMID- 28629107 TI - Reducing the bioavailability and leaching potential of lead in contaminated water hyacinth biomass by phosphate-assisted pyrolysis. AB - For the purpose of safe disposal of biomass contaminated by biosorption of heavy metals, phosphate-assisted pyrolysis of water hyacinth biomass contaminated by lead (Pb) was tried to reduce the bioavailability and leaching potential of Pb, using direct pyrolysis without additive as a control method. Direct pyrolysis of the contaminated biomass at low temperatures (300 and 400 degrees C) could reduce the bioavailability of Pb, but the leaching potential of Pb was increased with the rising pyrolysis temperature. While phosphate-assisted pyrolysis significantly enhanced the recovery and stability of Pb in the char. Specifically, the percentages of bioavailable Pb and leachable Pb in the chars obtained by phosphate-assisted pyrolysis at low temperatures were reduced to less than 5% and 7%, respectively. The sequential extraction test indicated the transformation of Pb into more stable fractions after phosphate-assisted pyrolysis, which was related to the formation of Pb phosphate minerals including pyromorphite and lead-substituted hydroxyapatite. PMID- 28629108 TI - Lactic acid production from Sophora flavescens residues pretreated with sodium hydroxide: Reutilization of the pretreated liquor during fermentation. AB - The feasibility of lactic acid production from Sophora flavescens residues (SFRs) pretreated with sodium hydroxide with the reutilization of the pretreated liquor during fermentation was investigated. After sodium hydroxide pretreatment, 67.5% of the lignin was removed, and hydrolysis efficiency increased from 37.3% to 79.2%. The reutilization of pretreated liquor at 50% loading during open fermentation of unwashed SFR increased lactic acid production by 34.1%. The pretreated liquor acted as pH buffer and resulted in stable pH and high cellulase activity during fermentation. Inhibitors in the pretreated liquor did not affect the growth of lactic acid bacteria but severely inhibited the growth of ethanol producing yeast. Consequently, lactic acid production increased and ethanol production was zero at 50% loading. Water consumption during pretreatment and fermentation with 50% pretreated liquor was 1.341L per 100g SFR, which was 67.6% lower than that during fermentation with washed SFR. PMID- 28629109 TI - Biological methanol production by immobilized Methylocella tundrae using simulated biohythane as a feed. AB - Biohythane may be used as an alternative feed for methanol production instead of costly pure methane. In this study, methanol production potential of Methylocella tundrae immobilized through covalent immobilization, adsorption, and encapsulation was evaluated. Cells covalently immobilized on groundnut shells and chitosan showed a relative methanol production potential of 83.9 and 91.6%, respectively, compared to that of free cells. The maximum methanol production by free cells and cells covalently immobilized on groundnut shells and chitosan was 6.73, 6.20, and 7.23mM, respectively, using simulated biohythane as a feed. Under repeated batch conditions of eight cycles, cells covalently immobilized on chitosan and groundnut shells, and cells encapsulated in sodium-alginate resulted in significantly higher cumulative methanol production of 37.76, 31.80, and 25.58mM, respectively, than free cells (18.57mM). This is the first report on immobilization of methanotrophs on groundnut shells and its application in methanol production using biohythane as a feed. PMID- 28629110 TI - Recycling the liquid fraction of alkaline hydrogen peroxide in the pretreatment of corn stover. AB - The aim of this study was to evaluate the influence of recycling the liquid fraction of pretreatment with alkaline hydrogen peroxide (AHP) on the hydrolysis of corn stover. Corn stover was pretreated in the traditional condition with 7.5% v/v H2O2. After pretreatment, the solids were separated from the liquid fraction and five successive reuse cycles of the liquid fraction were tested. The solid fraction from pretreatment in each recycle was submitted to enzymatic hydrolysis. The number of recycles had a linear negative effect (R2=0.98) on biomass delignification efficiency and also affected negatively the enzymatic conversion efficiency. Despite the decrease in efficiency after each recycling step, reuse of the liquid fraction leads to reduction in water, H2O2 and NaOH consumption of up to 57.6%, 59.6% and 57.6%, respectively. These findings point to an efficient recycling technology, which may reduce costs and save water. PMID- 28629111 TI - Volatile fatty acid production dynamics during the acidification of pretreated olive mill wastewater. AB - This study focuses on the dynamics of VFA production from pretreated olive mill wastewater (OMW). Acidogenic anaerobic sequencing batch reactors (AcASBR) were operated with the pretreated OMW at hydraulic retention time (HRT) of 2days and pH of 5,5 for different organic loading rates (OLRs) ranging from 5gCOD/L.d to 40gCOD/L.d. VFA production reached to the highest value of about 27,000mg/L with the increase in the organic load applied (20gCOD/L.d). The highest acidification rate was calculated as 68%. Acetic acid was found to be as the dominant VFA compound for all stage of the study. At steady state, VFA production during a day cycle period (24th hour) in AcASBR is also monitored, VFA production gradually increased after the 3rd and 6th hours (about 20%) and a rapid increase (about 40%) was observed reaching the maximum at the end of the cycle (24th hour). PMID- 28629112 TI - European demonstration program on the effect-based and chemical identification and monitoring of organic pollutants in European surface waters. AB - Growing concern about the adverse environmental and human health effects of a wide range of micropollutants requires the development of novel tools and approaches to enable holistic monitoring of their occurrence, fate and effects in the aquatic environment. A European-wide demonstration program (EDP) for effect based monitoring of micropollutants in surface waters was carried out within the Marie Curie Initial Training Network EDA-EMERGE. The main objectives of the EDP were to apply a simplified protocol for effect-directed analysis, to link biological effects to target compounds and to estimate their risk to aquatic biota. Onsite large volume solid phase extraction of 50 L of surface water was performed at 18 sampling sites in four European river basins. Extracts were subjected to effect-based analysis (toxicity to algae, fish embryo toxicity, neurotoxicity, (anti-)estrogenicity, (anti-)androgenicity, glucocorticoid activity and thyroid activity), to target analysis (151 organic micropollutants) and to nontarget screening. The most pronounced effects were estrogenicity, toxicity to algae and fish embryo toxicity. In most bioassays, major portions of the observed effects could not be explained by target compounds, especially in case of androgenicity, glucocorticoid activity and fish embryo toxicity. Estrone and nonylphenoxyacetic acid were identified as the strongest contributors to estrogenicity, while herbicides, with a minor contribution from other micropollutants, were linked to the observed toxicity to algae. Fipronil and nonylphenol were partially responsible for the fish embryo toxicity. Within the EDP, 21 target compounds were prioritized on the basis of their frequency and extent of exceedance of predicted no effect concentrations. The EDP priority list included 6 compounds, which are already addressed by European legislation, and 15 micropollutants that may be important for future monitoring of surface waters. The study presents a novel simplified protocol for effect-based monitoring and draws a comprehensive picture of the surface water status across Europe. PMID- 28629113 TI - Correction: p63alpha modulates c-Myc activity via direct interaction and regulation of MM1 protein stability. PMID- 28629114 TI - Correction: Th1high in tumor microenvironment is an indicator of poor prognosis for patients with NSCLC. PMID- 28629115 TI - Osthole Enhances Osteogenesis in Osteoblasts by Elevating Transcription Factor Osterix via cAMP/CREB Signaling In Vitro and In Vivo. AB - Anabolic anti-osteoporotic agents are desirable for treatment and prevention of osteoporosis and fragility fractures. Osthole is a coumarin derivative extracted from the medicinal herbs Cnidium monnieri (L.) Cusson and Angelica pubescens Maxim.f. Osthole has been reported with osteogenic and anti-osteoporotic properties, whereas the underlying mechanism of its benefit still remains unclear. The objective of the present study was to investigate the osteopromotive action of osthole on mouse osteoblastic MC3T3-E1 cells and on mouse femoral fracture repair, and to explore the interaction between osthole-induced osteopromotive effect and cyclic adenosine monophosphate (cAMP) elevating effect. Osthole treatment promoted osteogenesis in osteoblasts by enhancing alkaline phosphatase (ALP) activity and mineralization. Oral gavage of osthole enhanced fracture repair and increased bone strength. Mechanistic study showed osthole triggered the cAMP/CREB pathway through the elevation of the intracellular cAMP level and activation of the phosphorylation of the cAMP response element-binding protein (CREB). Blockage of cAMP/CREB downstream signals with protein kinase A (PKA) inhibitor KT5720 partially suppressed osthole-mediated osteogenesis by inhibiting the elevation of transcription factor, osterix. In conclusion, osthole shows osteopromotive effect on osteoblasts in vitro and in vivo. Osthole-mediated osteogenesis is related to activation of the cAMP/CREB signaling pathway and downstream osterix expression. PMID- 28629116 TI - Systematic Review of Chemical Constituents in the Genus Lycium (Solanaceae). AB - The Lycium genus is widely used as a traditional Chinese medicine and functional food. Many of the chemical constituents of the genus Lycium were reported previously. In this review, in addition to the polysaccharides, we have enumerated 355 chemical constituents and nutrients, including 22 glycerogalactolipids, 29 phenylpropanoids, 10 coumarins, 13 lignans, 32 flavonoids, 37 amides, 72 alkaloids, four anthraquinones, 32 organic acids, 39 terpenoids, 57 sterols, steroids, and their derivatives, five peptides and three other constituents. This comprehensive study could lay the foundation for further research on the Lycium genus. PMID- 28629117 TI - Alpha- and Gamma-Tocopherol and Telomere Length in 5768 US Men and Women: A NHANES Study. AB - Antioxidants have a number of potential health benefits. The present investigation was designed to determine the relationship between serum alpha- and gamma-tocopherol levels (powerful antioxidants), and leukocyte telomere length (a biomarker of biological aging). A cross-sectional design was employed to study 5768 adults from the National Health and Nutrition Examination Survey (NHANES). DNA was obtained via blood samples. Telomere length was assessed using the quantitative polymerase chain reaction method. Serum concentrations of alpha- and gamma-tocopherol were measured using high performance liquid chromatography (HPLC). Results showed that for each one-year increase in age, telomeres were 15.6 base pairs shorter (F = 410.4, p < 0.0001). After adjusting for differences in the demographic covariates, for each ug/dL higher level of gamma-tocopherol, telomeres were 0.33 base pairs shorter (F = 7.1, p = 0.0126). Telomeres were approximately 1 year shorter (15.6 base pairs) for each increment of 47.3 to 55.7 ug/dL of gamma-tocopherol in the blood, depending on the variables controlled. Adults at the 75th percentile of gamma-tocopherol had 2.8-3.4 years greater cellular aging than those at the 25th percentile, depending on the covariates in the model. However, alpha-tocopherol was not related to telomere length. Evidently, gamma-tocopherol levels, but not alpha-tocopherol, account for meaningful increases in biological aging. PMID- 28629118 TI - Long-Term Dexamethasone Exposure Down-Regulates Hepatic TFR1 and Reduces Liver Iron Concentration in Rats. AB - Exposure to stress is known to cause hepatic iron dysregulation, but the relationship between prolonged stress and liver iron metabolism is not yet fully understood. Thirty 13-week-old female Sprague-Dawley rats were randomly divided into two groups, as follows: the control group (saline-injection) and the dexamethasone group (Dexamethasone (Dex)-injection 0.1 mg/kg/day). After the 21 day stress trial, the results showed that chronic Dex administration not only impaired serum corticosterone (p = 0.00) and interleukin-6 (IL-6) (p = 0.01) levels, but also decreased white blood cell counts (p = 0.00), and reduced blood lymphocyte counts (p = 0.00). The daily Dex-injection also significantly reduced body weight (p < 0.01) by inhibiting food intake. Consecutive Dex administration resulted in decreased iron intake (p = 0.00), enhanced serum iron levels (p = 0.01), and increased the serum souble transferrin receptor (sTfR) content (p = 0.00) in rats. Meanwhile, long-term Dex exposure down-regulated duodenal cytochrome b (DCYTB) (p = 0.00) and the divalent metal transporter 1 (DMT1) (p = 0.04) protein expression, but up-regulated ferroportin (FPN) protein expression (p = 0.04). Chronic Dex administration reduced liver iron concentration (p = 0.02) in rats. Hepatic transferrin receptor 1 (TFR1) expression was lowered at the protein level (p = 0.03), yet with uncoupled mRNA abundance in Dex-treated rats. Enhanced iron-regulatory protein (IRP)/iron-responsive element (IRE) binding activity was observed, but did not line up with lowered hepatic TFR1 protein expression. This study indicates that long-term Dex exposure reduces liver iron content, which is closely associated with down-regulated hepatic TFR1 protein expression. PMID- 28629119 TI - Cholinesterase Inhibitory Activities of Adamantyl-Based Derivatives and Their Molecular Docking Studies. AB - Adamantyl-based compounds are clinically important for the treatments of type 2 diabetes and for their antiviral abilities, while many more are under development for other pharmaceutical uses. This study focused on the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities of adamantyl-based ester derivatives with various substituents on the phenyl ring using Ellman's colorimetric method. Compound 2e with a 2,4-dichloro electron-withdrawing substituent on the phenyl ring exhibited the strongest inhibition effect against AChE, with an IC50 value of 77.15 uM. Overall, the adamantyl-based ester with the mono-substituent at position 3 of the phenyl ring exhibited good AChE inhibition effects with an ascending order for the substituents: Cl < NO2 < CH3 < OCH3. Furthermore, compounds with electron-withdrawing groups (Cl and NO2) substituted at position 3 on their phenyl rings demonstrated stronger AChE inhibition effects, in comparison to their respective positional isomers. On the other hand, compound 2j with a 3-methoxyphenyl ring showed the highest inhibition effect against BChE, with an IC50 value of 223.30 uM. Molecular docking analyses were conducted for potential AChE and BChE inhibitors, and the results demonstrated that the peripheral anionic sites of target proteins were predominant binding sites for these compounds through hydrogen bonds and halogen interactions instead of hydrophobic interactions in the catalytic active site. PMID- 28629120 TI - Metabolomics Characterization of Two Apocynaceae Plants, Catharanthus roseus and Vinca minor, Using GC-MS and LC-MS Methods in Combination. AB - Catharanthus roseus (C. roseus) and Vinca minor (V. minor) are two common important medical plants belonging to the family Apocynaceae. In this study, we used non-targeted GC-MS and targeted LC-MS metabolomics to dissect the metabolic profile of two plants with comparable phenotypic and metabolic differences. A total of 58 significantly different metabolites were present in different quantities according to PCA and PLS-DA score plots of the GC-MS analysis. The 58 identified compounds comprised 16 sugars, eight amino acids, nine alcohols and 18 organic acids. We subjected these metabolites into KEGG pathway enrichment analysis and highlighted 27 metabolic pathways, concentrated on the TCA cycle, glycometabolism, oligosaccharides, and polyol and lipid transporter (RFOS). Among the primary metabolites, trehalose, raffinose, digalacturonic acid and gallic acid were revealed to be the most significant marker compounds between the two plants, presumably contributing to species-specific phenotypic and metabolic discrepancy. The profiling of nine typical alkaloids in both plants using LC-MS method highlighted higher levels of crucial terpenoid indole alkaloid (TIA) intermediates of loganin, serpentine, and tabersonine in V. minor than in C. roseus. The possible underlying process of the metabolic flux from primary metabolism pathways to TIA synthesis was discussed and proposed. Generally speaking, this work provides a full-scale comparison of primary and secondary metabolites between two medical plants and a metabolic explanation of their TIA accumulation and phenotype differences. PMID- 28629121 TI - Creating a Registry for Patients with Thoracic Outlet Syndrome. AB - The creation of any patient database requires substantial planning. In the case of thoracic outlet syndrome, which is a rare disease, the Society for Vascular Surgery has defined reporting standards to serve as an outline for the creation of a patient registry. Prior to undertaking this task, it is critical that designers understand the basics of registry planning and a priori establish plans for data collection and analysis. PMID- 28629122 TI - Age-Related Changes in Immunological and Physiological Responses Following Pulmonary Challenge. AB - This review examines the current status of knowledge of sepsis and pneumonia in the elderly population and how the dynamics of the pulmonary challenge affects outcome and consequences. Led by an unprecedented shift in demographics, where a larger proportion of the population will reach an older age, clinical and experimental research shows that aging is associated with certain pulmonary changes, but it is during infectious insult of the lungs, as in the case of pneumonia, that the age-related differences in responsiveness and endurance become obvious and lead to a worse outcome than in the younger population. This review points to the neutrophil, and the endothelium as important players in understanding age-associated changes in responsiveness to infectious challenge of the lung. It also addresses how the immunological set-point influences injury repair phases, remote organ damage and how intake of drugs may alter the state of responsiveness in the users. Further, it points out the importance of considering age as a factor in inclusion criteria in clinical trials, in vitro/ex vivo experimental designs and overall interpretation of results. PMID- 28629123 TI - Sensory Characteristics and Volatile Components of Dry Dog Foods Manufactured with Sorghum Fractions. AB - Descriptive sensory analysis and gas chromatography-mass spectrometry (GC-MS) with a modified headspace solid-phase microextraction (SPME) method was performed on three extruded dry dog food diets manufactured with different fractions of red sorghum and a control diet containing corn, brewer's rice, and wheat as a grain source in order to determine the effect of sorghum fractions on dry dog food sensory properties. The aroma compounds and flavor profiles of samples were similar with small differences, such as higher toasted aroma notes, and musty and dusty flavor in the mill-feed sample. A total of 37 compounds were tentatively identified and semi-quantified. Aldehydes were the major group present in the samples. The total volatile concentration was low, reflecting the mild aroma of the samples. Partial least squares regression was performed to identify correlations between sensory characteristics and detected aroma compounds. Possible relationships, such as hexanal and oxidized oil, and broth aromatics were identified. Volatile compounds were also associated with earthy, musty, and meaty aromas and flavor notes. This study showed that extruded dry dog foods manufactured with different red sorghum fractions had similar aroma, flavor, and volatile profiles. PMID- 28629125 TI - Metabolomic Profiling of Bile Acids in Clinical and Experimental Samples of Alzheimer's Disease. AB - Certain endogenous bile acids have been proposed as potential therapies for ameliorating Alzheimer's disease (AD) but their role, if any, in the pathophysiology of this disease is not currently known. Given recent evidence of bile acids having protective and anti-inflammatory effects on the brain, it is important to establish how AD affects levels of endogenous bile acids. Using LC MS/MS, this study profiled 22 bile acids in brain extracts and blood plasma from AD patients (n = 10) and age-matched control subjects (n = 10). In addition, we also profiled brain/plasma samples from APP/PS1 and WT mice (aged 6 and 12 months). In human plasma, we detected significantly lower cholic acid (CA, p = 0.03) in AD patients than age-matched control subjects. In APP/PS1 mouse plasma we detected higher CA (p = 0.05, 6 months) and lower hyodeoxycholic acid (p = 0.04, 12 months) than WT. In human brain with AD pathology (Braak stages V-VI) taurocholic acid (TCA) were significantly lower (p = 0.01) than age-matched control subjects. In APP/PS1 mice we detected higher brain lithocholic acid (p = 0.05) and lower tauromuricholic acid (TMCA; p = 0.05, 6 months). TMCA was also decreased (p = 0.002) in 12-month-old APP/PS1 mice along with 5 other acids: CA (p = 0.02), beta-muricholic acid (p = 0.02), Omega-muricholic acid (p = 0.05), TCA (p = 0.04), and tauroursodeoxycholic acid (p = 0.02). The levels of bile acids are clearly disturbed during the development of AD pathology and, since some bile acids are being proposed as potential AD therapeutics, we demonstrate a method that can be used to support work to advance bile acid therapeutics. PMID- 28629127 TI - Lower Physical Performance in Colder Seasons and Colder Houses: Evidence from a Field Study on Older People Living in the Community. AB - The aim of this paper was to explore the effect of seasonal temperature differences and cold indoor environment in winter on the physical performance of older people living in the community based on a field study. We recruited 162 home-dwelling older people from a rehabilitation facility in the Osaka prefecture, Japan; physical performance data were available from 98/162 (60.5%). At the same time, for some participants, a questionnaire survey and a measurement of the indoor temperature of individual houses were conducted. The analysis showed that there were seasonal trends in the physical performance of older people and that physical performance was worse in the winter compared with the autumn. Furthermore, people living in colder houses had worse physical performance. The findings indicate that keeping the house warm in the winter can help to maintain physical performance. PMID- 28629126 TI - Differentiated Thyroid Cancer-Treatment: State of the Art. AB - Differentiated thyroid cancer (DTC) is a rare malignant disease, although its incidence has increased over the last few decades. It derives from follicular thyroid cells. Generally speaking, the prognosis is excellent. If treatment according to the current guidelines is given, cases of recurrence or persistence are rare. DTC requires special expertise by the treating physician. In recent years, new therapeutic options for these patients have become available. For this article we performed a systematic literature review with special focus on the guidelines of the American Thyroid Association, the European Association of Nuclear Medicine, and the German Society of Nuclear Medicine. For DTC, surgery and radioiodine therapy followed by levothyroxine substitution remain the established therapeutic procedures. Even metastasized tumors can be cured this way. However, in rare cases of radioiodine-refractory tumors, additional options are to be discussed. These include strict suppression of thyroid-stimulating hormone (also known as thyrotropin, TSH) and external local radiotherapy. Systemic cytostatic chemotherapy does not play a significant role. Recently, multikinase or tyrosine kinase inhibitors have been approved for the treatment of radioiodine-refractory DTC. Although a benefit for overall survival has not been shown yet, these new drugs can slow down tumor progression. However, they are frequently associated with severe side effects and should be reserved for patients with threatening symptoms only. PMID- 28629124 TI - Microbial Diseases of Bivalve Mollusks: Infections, Immunology and Antimicrobial Defense. AB - A variety of bivalve mollusks (phylum Mollusca, class Bivalvia) constitute a prominent commodity in fisheries and aquacultures, but are also crucial in order to preserve our ecosystem's complexity and function. Bivalve mollusks, such as clams, mussels, oysters and scallops, are relevant bred species, and their global farming maintains a high incremental annual growth rate, representing a considerable proportion of the overall fishery activities. Bivalve mollusks are filter feeders; therefore by filtering a great quantity of water, they may bioaccumulate in their tissues a high number of microorganisms that can be considered infectious for humans and higher vertebrates. Moreover, since some pathogens are also able to infect bivalve mollusks, they are a threat for the entire mollusk farming industry. In consideration of the leading role in aquaculture and the growing financial importance of bivalve farming, much interest has been recently devoted to investigate the pathogenesis of infectious diseases of these mollusks in order to be prepared for public health emergencies and to avoid dreadful income losses. Several bacterial and viral pathogens will be described herein. Despite the minor complexity of the organization of the immune system of bivalves, compared to mammalian immune systems, a precise description of the different mechanisms that induce its activation and functioning is still missing. In the present review, a substantial consideration will be devoted in outlining the immune responses of bivalves and their repertoire of immune cells. Finally, we will focus on the description of antimicrobial peptides that have been identified and characterized in bivalve mollusks. Their structural and antimicrobial features are also of great interest for the biotechnology sector as antimicrobial templates to combat the increasing antibiotic-resistance of different pathogenic bacteria that plague the human population all over the world. PMID- 28629128 TI - Interactions between a Heparin Trisaccharide Library and FGF-1 Analyzed by NMR Methods. AB - FGF-1 is a potent mitogen that, by interacting simultaneously with Heparan Sulfate Glycosaminoglycan HSGAG and the extracellular domains of its membrane receptor (FGFR), generates an intracellular signal that finally leads to cell division. The overall structure of the ternary complex Heparin:FGF-1:FGFR has been finally elucidated after some controversy and the interactions within the ternary complex have been deeply described. However, since the structure of the ternary complex was described, not much attention has been given to the molecular basis of the interaction between FGF-1 and the HSGAG. It is known that within the complex, the carbohydrate maintains the same helical structure of free heparin that leads to sulfate groups directed towards opposite directions along the molecular axis. The precise role of single individual interactions remains unclear, as sliding and/or rotating of the saccharide along the binding pocket are possibilities difficult to discard. The HSGAG binding pocket can be subdivided into two regions, the main one can accommodate a trisaccharide, while the other binds a disaccharide. We have studied and analyzed the interaction between FGF-1 and a library of trisaccharides by STD-NMR and selective longitudinal relaxation rates. The library of trisaccharides corresponds to the heparin backbone and it has been designed to interact with the main subsite of the protein. PMID- 28629131 TI - A Hybrid Scheme for Fine-Grained Search and Access Authorization in Fog Computing Environment. AB - In the fog computing environment, the encrypted sensitive data may be transferred to multiple fog nodes on the edge of a network for low latency; thus, fog nodes need to implement a search over encrypted data as a cloud server. Since the fog nodes tend to provide service for IoT applications often running on resource constrained end devices, it is necessary to design lightweight solutions. At present, there is little research on this issue. In this paper, we propose a fine grained owner-forced data search and access authorization scheme spanning user fog-cloud for resource constrained end users. Compared to existing schemes only supporting either index encryption with search ability or data encryption with fine-grained access control ability, the proposed hybrid scheme supports both abilities simultaneously, and index ciphertext and data ciphertext are constructed based on a single ciphertext-policy attribute based encryption (CP ABE) primitive and share the same key pair, thus the data access efficiency is significantly improved and the cost of key management is greatly reduced. Moreover, in the proposed scheme, the resource constrained end devices are allowed to rapidly assemble ciphertexts online and securely outsource most of decryption task to fog nodes, and mediated encryption mechanism is also adopted to achieve instantaneous user revocation instead of re-encrypting ciphertexts with many copies in many fog nodes. The security and the performance analysis show that our scheme is suitable for a fog computing environment. PMID- 28629129 TI - Dietary Management of Skin Health: The Role of Genistein. AB - In women, aging and declining estrogen levels are associated with several cutaneous changes, many of which can be reversed or improved by estrogen supplementation. Two estrogen receptors-alpha and beta-have been cloned and found in various tissue types. Epidermal thinning, declining dermal collagen content, diminished skin moisture, decreased laxity, and impaired wound healing have been reported in postmenopausal women. Experimental and clinical studies in postmenopausal conditions indicate that estrogen deprivation is associated with dryness, atrophy, fine wrinkling, and poor wound healing. The isoflavone genistein binds to estrogen receptor beta and has been reported to improve skin changes. This review article will focus on the effects of genistein on skin health. PMID- 28629130 TI - Optimization of Polyplex Formation between DNA Oligonucleotide and Poly(L Lysine): Experimental Study and Modeling Approach. AB - The polyplexes formed by nucleic acids and polycations have received a great attention owing to their potential application in gene therapy. In our study, we report experimental results and modeling outcomes regarding the optimization of polyplex formation between the double-stranded DNA (dsDNA) and poly(L-Lysine) (PLL). The quantification of the binding efficiency during polyplex formation was performed by processing of the images captured from the gel electrophoresis assays. The design of experiments (DoE) and response surface methodology (RSM) were employed to investigate the coupling effect of key factors (pH and N/P ratio) affecting the binding efficiency. According to the experimental observations and response surface analysis, the N/P ratio showed a major influence on binding efficiency compared to pH. Model-based optimization calculations along with the experimental confirmation runs unveiled the maximal binding efficiency (99.4%) achieved at pH 5.4 and N/P ratio 125. To support the experimental data and reveal insights of molecular mechanism responsible for the polyplex formation between dsDNA and PLL, molecular dynamics simulations were performed at pH 5.4 and 7.4. PMID- 28629132 TI - Effects of Vitamin D Supplementation on IGF-1 and Calcitriol: A Randomized Controlled Trial. AB - Increasing evidence suggests a possible interaction between vitamin D and insulin like growth factor-1 (IGF-1). We aimed to investigate effects of vitamin D supplementation on IGF-1 (primary outcome) and calcitriol (1,25(OH)2D) concentrations (secondary outcome). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial-a single-center, double-blind, randomized, placebo controlled trial (RCT) conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two-hundred subjects with arterial hypertension and 25(OH)D concentrations <30 ng/mL were randomized to either receive 2800 IU of vitamin D daily or placebo for eight weeks. A total of 175 participants (mean +/- standard deviation age, 60 +/- 11 years; 49% women) with available IGF-1 concentrations were included in the present analysis. At baseline, IGF-1 concentrations were significantly correlated with 1,25(OH)2D (r = 0.21; p = 0.005) but not with 25(OH)D (r = -0.008; p = 0.91). In the RCT, vitamin D had no significant effect on IGF-1 (mean treatment effect 3.1; 95% confidence interval -5.6 to 11.9 ng/mL; p = 0.48), but it increased 1,25(OH)2D concentrations (mean treatment effect 9.2; 95% confidence interval 4.4 to 13.9 pg/mL; p <= 0.001). In this RCT, in hypertensive patients with low 25(OH)D concentrations, there was no significant effect of vitamin D supplementation on IGF-1 concentrations. However, we observed a cross-sectional correlation between 1,25(OH)2D and IGF-1 and an increase of 1,25(OH)2D after vitamin D supplementation. PMID- 28629134 TI - Fabrication of Circuits on Flexible Substrates Using Conductive SU-8 for Sensing Applications. AB - This article describes a new low-cost rapid microfabrication technology for high density interconnects and passive devices on flexible substrates for sensing applications. Silver nanoparticles with an average size of 80 nm were used to create a conductive SU-8 mixture with a concentration of wt 25%. The patterned structures after hard baking have a sheet resistance of 11.17 Omega /?. This conductive SU-8 was used to pattern planar inductors, capacitors and interconnection lines on flexible Kapton film. The conductive SU-8 structures were used as a seed layer for a subsequent electroplating process to increase the conductivity of the devices. Examples of inductors, resistor-capacitor (RC) and inductor-capacitor (LC) circuits, interconnection lines and a near-field communication (NFC) antenna are presented as a demonstration. As an example of high-resolution miniaturization, we fabricated microinductors having line widths of 5 MU m. Mechanical bending tests were successful down to a 5 mm radius. To the best of the authors' knowledge, this is the first report of conductive SU-8 used to fabricate such planar devices and the first on flexible substrates. This is a proof of concept that this fabrication approach can be used as an alternative for microfabrication of planar passive devices on flexible substrates. PMID- 28629133 TI - Propolis Diterpenes as a Remarkable Bio-Source for Drug Discovery Development: A Review. AB - Propolis is one of the complex, but valuable, bio-sources for discovering therapeutic compounds. Diterpenes are organic compounds composed of four isoprene units and are known for their biological and pharmacological characteristics, such as antibacterial, anticancer, and anti-inflammatory activities. Recently, advancements have been made in the development of antibacterial and anticancer leads from propolis-isolated diterpenes, and scrutiny of these compounds is being pursued. Thus, this review covers the progress in this arena, with a focus on the chemistry and biological activities of propolis diterpenes. It is anticipated that important information, in a comprehensive and concise manner, will be delivered here for better understanding of natural product drug discovery research. PMID- 28629135 TI - Unequal Probability Marking Approach to Enhance Security of Traceback Scheme in Tree-Based WSNs. AB - Fog (from core to edge) computing is a newly emerging computing platform, which utilizes a large number of network devices at the edge of a network to provide ubiquitous computing, thus having great development potential. However, the issue of security poses an important challenge for fog computing. In particular, the Internet of Things (IoT) that constitutes the fog computing platform is crucial for preserving the security of a huge number of wireless sensors, which are vulnerable to attack. In this paper, a new unequal probability marking approach is proposed to enhance the security performance of logging and migration traceback (LM) schemes in tree-based wireless sensor networks (WSNs). The main contribution of this paper is to overcome the deficiency of the LM scheme that has a higher network lifetime and large storage space. In the unequal probability marking logging and migration (UPLM) scheme of this paper, different marking probabilities are adopted for different nodes according to their distances to the sink. A large marking probability is assigned to nodes in remote areas (areas at a long distance from the sink), while a small marking probability is applied to nodes in nearby area (areas at a short distance from the sink). This reduces the consumption of storage and energy in addition to enhancing the security performance, lifetime, and storage capacity. Marking information will be migrated to nodes at a longer distance from the sink for increasing the amount of stored marking information, thus enhancing the security performance in the process of migration. The experimental simulation shows that for general tree-based WSNs, the UPLM scheme proposed in this paper can store 1.12-1.28 times the amount of stored marking information that the equal probability marking approach achieves, and has 1.15-1.26 times the storage utilization efficiency compared with other schemes. PMID- 28629137 TI - Coarse Alignment Technology on Moving base for SINS Based on the Improved Quaternion Filter Algorithm. AB - Initial alignment of the strapdown inertial navigation system (SINS) is intended to determine the initial attitude matrix in a short time with certain accuracy. The alignment accuracy of the quaternion filter algorithm is remarkable, but the convergence rate is slow. To solve this problem, this paper proposes an improved quaternion filter algorithm for faster initial alignment based on the error model of the quaternion filter algorithm. The improved quaternion filter algorithm constructs the K matrix based on the principle of optimal quaternion algorithm, and rebuilds the measurement model by containing acceleration and velocity errors to make the convergence rate faster. A doppler velocity log (DVL) provides the reference velocity for the improved quaternion filter alignment algorithm. In order to demonstrate the performance of the improved quaternion filter algorithm in the field, a turntable experiment and a vehicle test are carried out. The results of the experiments show that the convergence rate of the proposed improved quaternion filter is faster than that of the tradition quaternion filter algorithm. In addition, the improved quaternion filter algorithm also demonstrates advantages in terms of correctness, effectiveness, and practicability. PMID- 28629136 TI - Zinc in Infection and Inflammation. AB - Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps (NET) formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors of differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B (NF-kappaB), a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli. PMID- 28629139 TI - Novel Descattering Approach for Stereo Vision in Dense Suspended Scatterer Environments. AB - In this paper, we propose a model-based scattering removal method for stereo vision for robot manipulation in indoor scattering media where the commonly used ranging sensors are unable to work. Stereo vision is an inherently ill-posed and challenging problem. It is even more difficult in the case of images of dense fog or dense steam scenes illuminated by active light sources. Images taken in such environments suffer attenuation of object radiance and scattering of the active light sources. To solve this problem, we first derive the imaging model for images taken in a dense scattering medium with a single active illumination close to the cameras. Based on this physical model, the non-uniform backscattering signal is efficiently removed. The descattered images are then utilized as the input images of stereo vision. The performance of the method is evaluated based on the quality of the depth map from stereo vision. We also demonstrate the effectiveness of the proposed method by carrying out the real robot manipulation task. PMID- 28629138 TI - Alcohol Warnings and Moderate Drinking Patterns among Italian University Students: An Exploratory Study. AB - The introduction of health warnings on labels to correct externalities associated with alcohol consumption is heavily debated and has been explored from different perspectives. The current paper aims to analyse the interest and attitudes of Italian university students regarding health warnings on alcoholic beverages and to verify the existence of segments that differ in terms of attitudes towards such warnings. Our results show that young consumers consider health warnings quite important, although the degree of perceived utility differs in relation to the type of warning. Cluster analysis shows the existence of three groups of young consumers with different degrees of attention and perceived utility of warnings on alcoholic beverages, but also in relation to drinking behaviour and awareness of social and health risks related to alcohol consumption. In brief, Italian young adults with moderate consumption behaviour view label warnings positively, while this attitude is weaker among younger adults and those with riskier consumption behaviours. Our findings, albeit limited and based on stated and not revealed data, support the need for appropriate tools to improve the availability of information among young adults on the risks of excessive alcohol consumption and increased awareness of the importance of moderate drinking. PMID- 28629140 TI - 3D Imaging Millimeter Wave Circular Synthetic Aperture Radar. AB - In this paper, a new millimeter wave 3D imaging radar is proposed. The user just needs to move the radar along a circular track, and high resolution 3D imaging can be generated. The proposed radar uses the movement of itself to synthesize a large aperture in both the azimuth and elevation directions. It can utilize inverse Radon transform to resolve 3D imaging. To improve the sensing result, the compressed sensing approach is further investigated. The simulation and experimental result further illustrated the design. Because a single transceiver circuit is needed, a light, affordable and high resolution 3D mmWave imaging radar is illustrated in the paper. PMID- 28629141 TI - Graph-Based Cooperative Localization Using Symmetric Measurement Equations. AB - Precise localization is a key requirement for the success of highly assisted or autonomous vehicles. The diminishing cost of hardware has resulted in a proliferation of the number of sensors in the environment. Cooperative localization (CL) presents itself as a feasible and effective solution for localizing the ego-vehicle and its neighboring vehicles. However, one of the major challenges to fully realize the effective use of infrastructure sensors for jointly estimating the state of a vehicle in cooperative vehicle-infrastructure localization is an effective data association. In this paper, we propose a method which implements symmetric measurement equations within factor graphs in order to overcome the data association challenge with a reduced bandwidth overhead. Simulated results demonstrate the benefits of the proposed approach in comparison with our previously proposed approach of topology factors. PMID- 28629142 TI - A Source Anonymity-Based Lightweight Secure AODV Protocol for Fog-Based MANET. AB - Fog-based MANET (Mobile Ad hoc networks) is a novel paradigm of a mobile ad hoc network with the advantages of both mobility and fog computing. Meanwhile, as traditional routing protocol, ad hoc on-demand distance vector (AODV) routing protocol has been applied widely in fog-based MANET. Currently, how to improve the transmission performance and enhance security are the two major aspects in AODV's research field. However, the researches on joint energy efficiency and security seem to be seldom considered. In this paper, we propose a source anonymity-based lightweight secure AODV (SAL-SAODV) routing protocol to meet the above requirements. In SAL-SAODV protocol, source anonymous and secure transmitting schemes are proposed and applied. The scheme involves the following three parts: the source anonymity algorithm is employed to achieve the source node, without being tracked and located; the improved secure scheme based on the polynomial of CRC-4 is applied to substitute the RSA digital signature of SAODV and guarantee the data integrity, in addition to reducing the computation and energy consumption; the random delayed transmitting scheme (RDTM) is implemented to separate the check code and transmitted data, and achieve tamper-proof results. The simulation results show that the comprehensive performance of the proposed SAL-SAODV is a trade-off of the transmission performance, energy efficiency, and security, and better than AODV and SAODV. PMID- 28629144 TI - n+ GaAs/AuGeNi-Au Thermocouple-Type RF MEMS Power Sensors Based on Dual Thermal Flow Paths in GaAs MMIC. AB - To achieve radio frequency (RF) power detection, gain control, and circuit protection, this paper presents n+ GaAs/AuGeNi-Au thermocouple-type RF microelectromechanical system (MEMS) power sensors based on dual thermal flow paths. The sensors utilize a conversion principle of RF power-heat-voltage, where a thermovoltage is obtained as the RF power changes. To improve the heat transfer efficiency and the sensitivity, structures of two heat conduction paths are designed: one in which a thermal slug of Au is placed between two load resistors and hot junctions of the thermocouples, and one in which a back cavity is fabricated by the MEMS technology to form a substrate membrane underneath the resistors and the hot junctions. The improved sensors were fabricated by a GaAs monolithic microwave integrated circuit (MMIC) process. Experiments show that these sensors have reflection losses of less than -17 dB up to 12 GHz. At 1, 5, and 10 GHz, measured sensitivities are about 63.45, 53.97, and 44.14 uV/mW for the sensor with the thermal slug, and about 111.03, 94.79, and 79.04 uV/mW for the sensor with the thermal slug and the back cavity, respectively. PMID- 28629143 TI - Nutrients and Other Environmental Factors Influence Virus Abundances across Oxic and Hypoxic Marine Environments. AB - Virus particles are highly abundant in seawater and, on average, outnumber microbial cells approximately 10-fold at the surface and 16-fold in deeper waters; yet, this relationship varies across environments. Here, we examine the influence of a suite of environmental variables, including nutrient concentrations, salinity and temperature, on the relationship between the abundances of viruses and prokaryotes over a broad range of spatial and temporal scales, including along a track from the Northwest Atlantic to the Northeast Pacific via the Arctic Ocean, and in the coastal waters of British Columbia, Canada. Models of varying complexity were tested and compared for best fit with the Akaike Information Criterion, and revealed that nitrogen and phosphorus concentrations, as well as prokaryote abundances, either individually or combined, had significant effects on viral abundances in all but hypoxic environments, which were only explained by a combination of physical and chemical factors. Nonetheless, multivariate models of environmental variables showed high explanatory power, matching or surpassing that of prokaryote abundance alone. Incorporating both environmental variables and prokaryote abundances into multivariate models significantly improved the explanatory power of the models, except in hypoxic environments. These findings demonstrate that environmental factors could be as important as, or even more important than, prokaryote abundance in describing viral abundance across wide-ranging marine environments. PMID- 28629145 TI - Synthesis and Evaluation of Phenylxanthine Derivatives as Potential Dual A2AR Antagonists/MAO-B Inhibitors for Parkinson's Disease. AB - The aim of this research was to prove the speculation that phenylxanthine (PX) derivatives possess adenosine A2A receptor (A2AR)-blocking properties and to screening and evaluate these PX derivatives as dual A2AR antagonists/MAO-B inhibitors for Parkinson's disease. To explore this hypothesis, two series of PX derivatives were prepared and their antagonism against A2AR and inhibition against MAO-B were determined in vitro. In order to evaluate further the antiparkinsonian properties, pharmacokinetic and haloperidol-induced catalepsy experiments were carried out in vivo. The PX-D and PX-E analogues acted as potent A2AR antagonists with Ki values ranging from 0.27 to 10 MUM, and these analogues displayed relatively mild MAO-B inhibition potencies, with inhibitor dissociation constants (Ki values) ranging from 0.25 to 10 MUM. Further, the compounds PX-D-P6 and PX-E-P8 displayed efficacious antiparkinsonian properties in haloperidol induced catalepsy experiments, verifying that these two compounds were potent A2AR antagonists and MAO-B inhibitors. We conclude that PX-D and PX-E analogues are a promising candidate class of dual-acting compounds for treating Parkinson's disease. PMID- 28629146 TI - Emerging Disparities in Dietary Sodium Intake from Snacking in the US Population. AB - BACKGROUND: The US population consumes dietary sodium well in excess of recommended levels. It is unknown how the contribution of snack foods to sodium intake has changed over time, and whether disparities exist within specific subgroups of the US population. OBJECTIVE: To examine short and long term trends in the contribution of snack food sources to dietary sodium intake for US adults and children over a 37-year period from 1977 to 2014. METHODS: We used data collected from eight nationally representative surveys of food intake in 50,052 US children aged 2-18 years, and 73,179 adults aged 19+ years between 1977 and 2014. Overall, patterns of snack food consumption, trends in sodium intake from snack food sources and trends in food and beverage sources of sodium from snack foods across race-ethnic, age, gender, body mass index, household education and income groups were examined. RESULTS: In all socio-demographic subgroups there was a significant increase in both per capita sodium intake, and the proportion of sodium intake derived from snacks from 1977-1978 to 2011-2014 (p < 0.01). Those with the lowest household education, Non-Hispanic Black race-ethnicity, and the lowest income had the largest increase in sodium intake from snacks. While in 1977-1978 Non-Hispanic Blacks had a lower sodium intake from snacks compared to Non-Hispanic Whites (p < 0.01), in 2011-2014 they had a significantly higher intake. Conclusions: Important disparities are emerging in dietary sodium intake from snack sources in Non-Hispanic Blacks. Our findings have implications for future policy interventions targeting specific US population subgroups. PMID- 28629148 TI - Involvement of CD36 in Modulating the Decrease of NPY and AgRP Induced by Acute Palmitic Acid Stimulation in N1E-115 Cells. AB - Central nervous system (CNS) fatty acid sensing plays an important role in the regulation of food intake, and palmitic acid (PA) is the most important long chain fatty acid (LCFA) in the mammalian diet. To explore the effect of PA on central neuropeptide expression and the role of the cluster of the differentiation of 36 (CD36) in the process, N1E-115 cells were cultured with PA in the presence or absence of sulfosuccinimidyl-oleate (SSO), a CD36 inhibitor. Results showed that 10 MUmol/L PA significantly reduced NPY and AgRP mRNA expression after 20 min of exposure, while the expression of CD36 was upregulated. The presence of SSO significantly attenuated the decrease of NPY and AgRP expression that was induced by PA alone, although no notable effect on PA- induced CD36 gene expression was observed. In conclusion, our study suggests the involvement of CD36 in the PA-induced decrease of NPY and AgRP in N1E-115 cells. PMID- 28629147 TI - Proteomic High Affinity Zn2+ Trafficking: Where Does Metallothionein Fit in? AB - The cellular constitution of Zn-proteins and Zn-dependent signaling depend on the capacity of Zn2+ to find specific binding sites in the face of a plethora of other high affinity ligands. The most prominent of these is metallothionein (MT). It serves as a storage site for Zn2+ under various conditions, and has chemical properties that support a dynamic role for MT in zinc trafficking. Consistent with these characteristics, changing the availability of zinc for cells and tissues causes rapid alteration of zinc bound to MT. Nevertheless, zinc trafficking occurs in metallothionein-null animals and cells, hypothetically making use of proteomic binding sites to mediate the intracellular movements of zinc. Like metallothionein, the proteome contains a large concentration of proteins that strongly coordinate zinc. In this environment, free Zn2+ may be of little significance. Instead, this review sets forth the basis for the hypothesis that components of the proteome and MT jointly provide the platform for zinc trafficking. PMID- 28629149 TI - Impact of Second Trimester Maternal Dietary Intake on Gestational Weight Gain and Neonatal Birth Weight. AB - Poor maternal nutrition is a major contributor to the high incidence of low birth weight deliveries in developing countries. This study aimed to assess the impact of second trimester maternal dietary intake on gestational weight gain and neonatal birth weight. A longitudinal study was conducted in a tertiary care hospital in Sri Lanka. Participants were 141 pregnant women at 18-24 weeks gestation who were followed up until delivery. Maternal dietary intake was assessed using a validated Food Frequency Questionnaire at 21.1 +/- 1.8 gestational weeks. Gestational weight gain was examined at the end of 28 weeks gestation and at the end of pregnancy. Energy and nutrient intakes were calculated using NutriSurvey 2007 (EBISpro, Willstaett, Germany) nutrient analysis software, modified for Sri Lankan foods. The mean total gestational weight gain of women with low carbohydrate intake (229-429 g/day) was 2.2 kg less than that of women with moderate carbohydrate intake (430-629 g/day) (95% confidence interval (CI) 0.428-4.083 kg; p = 0.016). Similarly, babies of women with low carbohydrate intake were 312 g lighter compared with those of women with a moderate carbohydrate intake (95% CI 91-534 g; p = 0.006). Our results suggest that second trimester maternal carbohydrate intake has significant impacts on total gestational weight gain and neonatal birth weight. PMID- 28629150 TI - Role of Nigella sativa and Its Constituent Thymoquinone on Chemotherapy-Induced Nephrotoxicity: Evidences from Experimental Animal Studies. AB - BACKGROUND: Most chemotherapeutic drugs are known to cause nephrotoxicity. Therefore, new strategies have been considered to prevent chemotherapy-induced nephrotoxicity. It is of note that Nigella sativa (NS), or its isolated compound Thymoquinone (TQ), has a potential role in combating chemotherapy-induced nephrotoxicity. AIM: To analyze and report the outcome of experimental animal studies on the protective effects of NS/TQ on chemotherapy-associated kidney complications. DESIGN: Standard systematic review and narrative synthesis. DATA SOURCES: MEDLINE, EMBASE databases were searched for relevant articles published up to March 2017. Additionally, a manual search was performed. Criteria for a study's inclusion were: conducted in animals, systematic reviews and meta analysis, containing data on nephroprotective effects of NS/TQ compared to a placebo or other substance. All strains and genders were included. RESULTS: The database search yielded 71 studies, of which 12 (cisplatin-induced nephrotoxicity 8; methotrexate-induced nephrotoxicity 1; doxorubicin-induced nephrotoxicity 2; ifosfamide-induced nephrotoxicity 1) were included in this review. CONCLUSIONS: Experimental animal studies showed the protective effect of NS, or TQ, on chemotherapy-induced nephrotoxicity. These effects are caused by decreasing lipid peroxidation and increasing activity of antioxidant enzymes in renal tissue of chemotherapy-treated animals. PMID- 28629151 TI - Structured Additive Quantile Regression for Assessing the Determinants of Childhood Anemia in Rwanda. AB - Childhood anemia is among the most significant health problems faced by public health departments in developing countries. This study aims at assessing the determinants and possible spatial effects associated with childhood anemia in Rwanda. The 2014/2015 Rwanda Demographic and Health Survey (RDHS) data was used. The analysis was done using the structured spatial additive quantile regression model. The findings of this study revealed that the child's age; the duration of breastfeeding; gender of the child; the nutritional status of the child (whether underweight and/or wasting); whether the child had a fever; had a cough in the two weeks prior to the survey or not; whether the child received vitamin A supplementation in the six weeks before the survey or not; the household wealth index; literacy of the mother; mother's anemia status; mother's age at the birth are all significant factors associated with childhood anemia in Rwanda. Furthermore, significant structured spatial location effects on childhood anemia was found. PMID- 28629152 TI - The Association between Pediatric NAFLD and Common Genetic Variants. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of obesity. Several studies have shown that genetic predisposition probably plays an important role in its pathogenesis. In fact, in the last few years a large number of genetic studies have provided compelling evidence that some gene variants, especially those in genes encoding proteins regulating lipid metabolism, are associated with intra-hepatic fat accumulation. Here we provide a comprehensive review of the gene variants that have affected the natural history of the disease. PMID- 28629154 TI - Two Novel Two-Stage Direction of Arrival Estimation Algorithms for Two Dimensional Mixed Noncircular and Circular Sources. AB - This paper addresses the two-dimensional (2D) direction-of-arrival (DOA) estimation problem with two novel methods for mixed noncircular and circular signals. The first proposed method is named the two-stage direction-of-arrival matrix (TSDOAM) method, and the other is called the two-stage rank reduction (TSRARE) method. The proposed methods utilize both the circularity and the direction-of-arrival differences between the noncircular and circular sources to estimate the 2D directions-of-arrival (DOAs). The maximum detectable 2D angle parameters of the TSDOAM and TSRARE methods are twice those of the existing methods. Moreover, the TSRARE method can detect more incident signals than the TSDOAM method due to the array aperture of two parallel uniform linear arrays (ULAs) being fully utilized. Simulation results show that compared to the existing methods for the small angle separation of 2D directions-of-arrival, the two proposed methods perform well in terms of the signal-to-noise ratio (SNR) and snapshots. PMID- 28629153 TI - Compositional Characteristics and In Vitro Evaluations of Antioxidant and Neuroprotective Properties of Crude Extracts of Fucoidan Prepared from Compressional Puffing-Pretreated Sargassum crassifolium. AB - Fucoidan, a fucose-containing sulfated polysaccharide with diverse biological functions, is mainly recovered from brown algae. In this study, we utilized a compressional-puffing process (CPP) to pretreat Sargassum crassifolium (SC) and extracted fucoidans from SC by warm water. Three fucoidan extracts (SC1: puffing at 0 kg/cm2; SC2: puffing at 1.7 kg/cm2; and SC3: puffing at 6.3 kg/cm2) were obtained, and their composition, and antioxidant and neuroprotective activities were examined. The results suggest that CPP decreased the bulk density of algal samples, expanded the algal cellular structures, and eliminated the unpleasant algal odor. The extraction yields of fucoidans were increased and impurities of fucoidans were decreased by increasing the pressures used in CPP. The SC1-SC3 extracts displayed various characteristics of fucoidan as illustrated by the analyses of composition, Fourier transform infrared (FTIR) spectroscopy, and molecular weight. All three extracts SC1-SC3 showed antioxidant activity dose dependently. Although both SC1 and SC2 possessed high and similar neuronal protective properties, SC2 showed a higher extraction yield, higher efficacy in the reversion of H2O2-induced cytotoxicity in rat pheochromocytoma PC-12 cells, and lower impurities compared with SC1, and thus SC2 is suggested as a good candidate for a therapeutic agent in the preventive treatment of neurodegenerative diseases. PMID- 28629156 TI - Spatial Indexing for Data Searching in Mobile Sensing Environments. AB - Data searching and retrieval is one of the fundamental functionalities in many Web of Things applications, which need to collect, process and analyze huge amounts of sensor stream data. The problem in fact has been well studied for data generated by sensors that are installed at fixed locations; however, challenges emerge along with the popularity of opportunistic sensing applications in which mobile sensors keep reporting observation and measurement data at variable intervals and changing geographical locations. To address these challenges, we develop the Geohash-Grid Tree, a spatial indexing technique specially designed for searching data integrated from heterogeneous sources in a mobile sensing environment. Results of the experiments on a real-world dataset collected from the SmartSantander smart city testbed show that the index structure allows efficient search based on spatial distance, range and time windows in a large time series database. PMID- 28629155 TI - Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies. AB - Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three beta-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC50 range 15.8-26.1 MUg/mL) in comparison with benznidazole and nifurtimox (LC50 range 33.1-46.7 MUg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90-60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents. PMID- 28629157 TI - Wuhan Ionospheric Oblique Backscattering Sounding System and Its Applications-A Review. AB - For decades, high-frequency (HF) radar has played an important role in sensing the Earth's environment. Advances in radar technology are providing opportunities to significantly improve the performance of HF radar, and to introduce more applications. This paper presents a low-power, small-size, and multifunctional HF radar developed by the Ionospheric Laboratory of Wuhan University, referred to as the Wuhan Ionospheric Oblique Backscattering Sounding System (WIOBSS). Progress in the development of this radar is described in detail, including the basic principles of operation, the system configuration, the sounding waveforms, and the signal and data processing methods. Furthermore, its various remote sensing applications are briefly reviewed to show the good performance of this radar. Finally, some suggested solutions are given for further improvement of its performance. PMID- 28629158 TI - Contribution of the Degeneration of the Neuro-Axonal Unit to the Pathogenesis of Multiple Sclerosis. AB - Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. In recent years, it has become more evident that neurodegeneration, including neuronal damage and axonal injury, underlies permanent disability in MS. This manuscript reviews some of the mechanisms that could be responsible for neurodegeneration and axonal damage in MS and highlights the potential role that dysfunctional heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and antibodies to hnRNP A1 may play in MS pathogenesis. PMID- 28629159 TI - Intercomparison of Unmanned Aerial Vehicle and Ground-Based Narrow Band Spectrometers Applied to Crop Trait Monitoring in Organic Potato Production. AB - Vegetation properties can be estimated using optical sensors, acquiring data on board of different platforms. For instance, ground-based and Unmanned Aerial Vehicle (UAV)-borne spectrometers can measure reflectance in narrow spectral bands, while different modelling approaches, like regressions fitted to vegetation indices, can relate spectra with crop traits. Although monitoring frameworks using multiple sensors can be more flexible, they may result in higher inaccuracy due to differences related to the sensors characteristics, which can affect information sampling. Also organic production systems can benefit from continuous monitoring focusing on crop management and stress detection, but few studies have evaluated applications with this objective. In this study, ground based and UAV spectrometers were compared in the context of organic potato cultivation. Relatively accurate estimates were obtained for leaf chlorophyll (RMSE = 6.07 ug.cm-2), leaf area index (RMSE = 0.67 m2.m-2), canopy chlorophyll (RMSE = 0.24 g.m-2) and ground cover (RMSE = 5.5%) using five UAV-based data acquisitions, from 43 to 99 days after planting. These retrievals are slightly better than those derived from ground-based measurements (RMSE = 7.25 ug.cm-2, 0.85 m2.m-2, 0.28 g.m-2 and 6.8%, respectively), for the same period. Excluding observations corresponding to the first acquisition increased retrieval accuracy and made outputs more comparable between sensors, due to relatively low vegetation cover on this date. Intercomparison of vegetation indices indicated that indices based on the contrast between spectral bands in the visible and near infrared, like OSAVI, MCARI2 and CIg provided, at certain extent, robust outputs that could be transferred between sensors. Information sampling at plot level by both sensing solutions resulted in comparable discriminative potential concerning advanced stages of late blight incidence. These results indicate that optical sensors, and their integration, have great potential for monitoring this specific organic cropping system. PMID- 28629160 TI - Structural Characterization of a Rhamnogalacturonan I Domain from Ginseng and Its Inhibitory Effect on Galectin-3. AB - A rhamnogalacturonan I domain, named RG-I-3A, was prepared from ginseng pectin by pectinase digestion and chromatography separation. Monosaccharide composition analysis revealed that it was mainly composed of galacturonic acid, rhamnose, galactose, and arabinose in a molar ratio of 32.5:11.2:31.9:16.5, with a molecular weight of 50 kDa. Partial acid hydrolysis, monoclonal antibody detection, and NMR spectra analysis suggested RG-I-3A was composed of ->4)-alpha GalpA-(1->2)-alpha-Rhap-(1->disaccharide repeating units as backbone, with beta 1,4-galactan, alpha-1,5-arabinan, AG-I, and AG-II side chains substituted via the O-4 of Rhap. Galectin-3-mediated hemagglutination and biolayer interferometry assay indicated that RG-I-3A had inhibitory activity on galectin-3. These findings suggest the potential use of this ginseng RG-I domain as a galectin-3 inhibitor in drug development applications. PMID- 28629163 TI - beta-Cyanoalanine Synthases and Their Possible Role in Pierid Host Plant Adaptation. AB - Cyanide is generated in larvae of the glucosinolate-specialist Pieris rapae (Lepidoptera:Pieridae) upon ingestion of plant material containing phenylalanine derived glucosinolates as chemical defenses. As these glucosinolates were widespread within ancient Brassicales, the ability to detoxify cyanide may therefore have been essential for the host plant shift of Pierid species from Fabales to Brassicales species giving rise to the Pierinae subfamily. Previous research identified beta-cyanoalanine and thiocyanate as products of cyanide detoxification in P. rapae larvae as well as three cDNAs encoding the beta cyanoalanine synthases PrBSAS1-PrBSAS3. Here, we analyzed a total of eight species of four lepidopteran families to test if their cyanide detoxification capacity correlates with their feeding specialization. We detected beta cyanoalanine synthase activity in gut protein extracts of all six species tested, which included Pierid species with glucosinolate-containing host plants, Pierids with other hosts, and other Lepidoptera with varying food specialization. Rhodanese activity was only scarcely detectable with the highest levels appearing in the two glucosinolate-feeding Pierids. We then amplified by polymerase chain reaction (PCR) 14 cDNAs encoding beta-cyanoalanine synthases from seven species. Enzyme characterization and phylogenetic analysis indicated that lepidopterans are generally equipped with one PrBSAS2 homolog with high affinity for cyanide. A second beta-cyanoalanine synthase which grouped with PrBSAS3 was restricted to Pierid species, while a third variant (i.e., homologs of PrBSAS1), was only present in members of the Pierinae subfamily. These results are in agreement with the hypothesis that the host shift to Brassicales was associated with the requirement for a specialized cyanide detoxification machinery. PMID- 28629161 TI - Cancer Chemoprevention by Resveratrol: The p53 Tumor Suppressor Protein as a Promising Molecular Target. AB - Increasing epidemiological and experimental evidence has demonstrated an inverse relationship between the consumption of plant foods and the incidence of chronic diseases, including cancer. Microcomponents that are naturally present in such foods, especially polyphenols, are responsible for the benefits to human health. Resveratrol is a diet-derived cancer chemopreventive agent with high therapeutic potential, as demonstrated by different authors. The aim of this review is to collect and present recent evidence from the literature regarding resveratrol and its effects on cancer prevention, molecular signaling (especially regarding the involvement of p53 protein), and therapeutic perspectives with an emphasis on clinical trial results to date. PMID- 28629162 TI - Promotion of Tumor Invasion by Tumor-Associated Macrophages: The Role of CSF-1 Activated Phosphatidylinositol 3 Kinase and Src Family Kinase Motility Signaling. AB - Macrophages interact with cells in every organ to facilitate tissue development, function and repair. However, the close interaction between macrophages and parenchymal cells can be subverted in disease, particularly cancer. Motility is an essential capacity for macrophages to be able to carry out their various roles. In cancers, the macrophage's interstitial migratory ability is frequently co-opted by tumor cells to enable escape from the primary tumor and metastatic spread. Macrophage accumulation within and movement through a tumor is often stimulated by tumor cell production of the mononuclear phagocytic growth factor, colony-stimulating factor-1 (CSF-1). CSF-1 also regulates macrophage survival, proliferation and differentiation, and its many effects are transduced by its receptor, the CSF-1R, via phosphotyrosine motif-activated signals. Mutational analysis of CSF-1R signaling indicates that the major mediators of CSF-1-induced motility are phosphatidyl-inositol-3 kinase (PI3K) and one or more Src family kinase (SFK), which activate signals to adhesion, actin polymerization, polarization and, ultimately, migration and invasion in macrophages. The macrophage transcriptome, including that of the motility machinery, is very complex and highly responsive to the environment, with selective expression of proteins and splice variants rarely found in other cell types. Thus, their unique motility machinery can be specifically targeted to block macrophage migration, and thereby, inhibit tumor invasion and metastasis. PMID- 28629164 TI - Cataract Surgery Performed by High Frequency LDV Z8 Femtosecond Laser: Safety, Efficacy, and Its Physical Properties. AB - BACKGROUND: The aim of our study was to investigate the safety and efficacy of the LDV Z8 femtosecond laser in cataract surgery compared to the conventional procedure. METHODS: This prospective study was performed at the Swiss Eye Research Foundation, Eye Clinic ORASIS, Reinach, Switzerland. The study included 130 eyes from 130 patients: 68 treated with femtosecond laser-assisted cataract surgery (FLACS) using the FEMTO LDV Z8 and 62 treated with conventional phacoemulsification. Capsulotomy and lens fragmentation in the laser group were performed with the FEMTO LDV Z8 femtosecond laser system, which employs a new, low-energy, high repetition rate laser process for cataract surgery. In the conventional group, the capsulotomy was performed by a cystotome, and lens fragmentation was achieved by the stop-and-chop. RESULTS: Ease of phacoemulsification (on a 4-point scale), the completeness of capsulotomy (on a 10-point scale), effective phacoemulsification time (seconds), uncorrected distance visual acuity (UCVA), best spectacle-corrected distance visual acuity (BSCVA), spherical equivalent (SE), and safety of the procedure were evaluated. The total follow-up time was three months. CONCLUSIONS: FLACS with the FEMTO LDV Z8 system was characterized by complete and reproducible capsulotomy and highly effective lens fragmentation. Postoperative visual outcomes were excellent, and the safety of the procedure was optimal. PMID- 28629165 TI - A Cost-Effective Vehicle Localization Solution Using an Interacting Multiple Model-Unscented Kalman Filters (IMM-UKF) Algorithm and Grey Neural Network. AB - In this paper, we propose a cost-effective localization solution for land vehicles, which can simultaneously adapt to the uncertain noise of inertial sensors and bridge Global Positioning System (GPS) outages. First, three Unscented Kalman filters (UKFs) with different noise covariances are introduced into the framework of Interacting Multiple Model (IMM) algorithm to form the proposed IMM-based UKF, termed as IMM-UKF. The IMM algorithm can provide a soft switching among the three UKFs and therefore adapt to different noise characteristics. Further, two IMM-UKFs are executed in parallel when GPS is available. One fuses the information of low-cost GPS, in-vehicle sensors, and micro electromechanical system (MEMS)-based reduced inertial sensor systems (RISS), while the other fuses only in-vehicle sensors and MEMS-RISS. The differences between the state vectors of the two IMM-UKFs are considered as training data of a Grey Neural Network (GNN) module, which is known for its high prediction accuracy with a limited amount of samples. The GNN module can predict and compensate position errors when GPS signals are blocked. To verify the feasibility and effectiveness of the proposed solution, road-test experiments with various driving scenarios were performed. The experimental results indicate that the proposed solution outperforms all the compared methods. PMID- 28629166 TI - Mechanistic Explanation of the Weak Carbonic Anhydrase's Esterase Activity. AB - In order to elucidate the elementary mechanism of the promiscuous esterase activity of human carbonic anhydrase (h-CA), we present an accurate theoretical investigation on the hydrolysis of fully-acetylated d-glucose functionalized as sulfamate. This h-CA's inhibitor is of potential relevance in cancer therapy. The study has been performed within the framework of three-layer ONIOM (QM-high:QM' medium:MM-low) hybrid approach. The computations revealed that the hydrolysis process is not energetically favored, in agreement with the observed weak carbonic anhydrase's esterase activity. PMID- 28629167 TI - IgG Avidity Test in Congenital Toxoplasmosis Diagnoses in Newborns. AB - The goal of this study was to investigate the importance of IgG avidity testing in newborns (NBs) diagnosed with early congenital toxoplasmosis. We collected samples from 88 puerperae infected by Toxoplasma gondii (T. gondii) and their NBs (48 acutely-infected puerperae (AIP) and 40 chronically-infected puerperae (CIP)), from two public maternity hospitals in Goiania city, Goias, Brazil, from 2010 to 2015. Specific anti-T. gondii IgM and IgG serum levels and IgG avidity tests were evaluated using chemiluminescence. Congenital toxoplasmosis was observed in 66.66% (n = 32) of NBs with AIP, 94.1% presenting low avidity (LA) and 51.61% presenting high avidity (HA) test results. The IgG and IgM levels of NBs with LA and their puerperae were higher in comparison with HA NBs and puerperae (p = 0.0001). The avidity tests showed 100% specificity and 50% sensitivity (p = 0.0001). NBs with LA had a 15-fold increased risk of developing congenital toxoplasmosis in comparison with HA NBs. The IgG avidity test could be used to assist in early congenital toxoplasmosis diagnoses in NBs and LA, identifying a greater probability of vertical transmission. PMID- 28629168 TI - Assessing Statistically Significant Heavy-Metal Concentrations in Abandoned Mine Areas via Hot Spot Analysis of Portable XRF Data. AB - To develop appropriate measures to prevent soil contamination in abandoned mining areas, an understanding of the spatial variation of the potentially toxic trace elements (PTEs) in the soil is necessary. For the purpose of effective soil sampling, this study uses hot spot analysis, which calculates a z-score based on the Getis-Ord Gi* statistic to identify a statistically significant hot spot sample. To constitute a statistically significant hot spot, a feature with a high value should also be surrounded by other features with high values. Using relatively cost- and time-effective portable X-ray fluorescence (PXRF) analysis, sufficient input data are acquired from the Busan abandoned mine and used for hot spot analysis. To calibrate the PXRF data, which have a relatively low accuracy, the PXRF analysis data are transformed using the inductively coupled plasma atomic emission spectrometry (ICP-AES) data. The transformed PXRF data of the Busan abandoned mine are classified into four groups according to their normalized content and z-scores: high content with a high z-score (HH), high content with a low z-score (HL), low content with a high z-score (LH), and low content with a low z-score (LL). The HL and LH cases may be due to measurement errors. Additional or complementary surveys are required for the areas surrounding these suspect samples or for significant hot spot areas. The soil sampling is conducted according to a four-phase procedure in which the hot spot analysis and proposed group classification method are employed to support the development of a sampling plan for the following phase. Overall, 30, 50, 80, and 100 samples are investigated and analyzed in phases 1-4, respectively. The method implemented in this case study may be utilized in the field for the assessment of statistically significant soil contamination and the identification of areas for which an additional survey is required. PMID- 28629169 TI - Association between Six CETP Polymorphisms and Metabolic Syndrome in Uyghur Adults from Xinjiang, China. AB - OBJECTIVE: To explore the association between CETP gene polymorphisms and metabolic syndrome (MS), as well as the relationship between the CETP gene polymorphisms and each component of MS. METHODS: A total of 571 individuals which were randomly selected from 5692 Uyghur adults were subdivided into two groups, including 280 patients with MS and 291 control subjects, using the group-matching method after matching for gender. We detected CETP polymorphisms (rs5882, rs1800775, rs3764261, rs12149545, rs711752, and rs708272) by using the Snapshot method. RESULTS: (1) Significant differences were found involving the frequency distribution of genotypes and alleles of rs1800775, rs3764261, rs12149545, rs711752, and rs708272 between the control and MS groups (all p < 0.05). (2) rs1800775, rs3764261, rs12149545, rs711752, and rs708272 polymorphisms were significantly related to the risk of MS (all p < 0.05). (3) The rs1800775 polymorphism was associated with high fasting blood glucose levels and low high density lipoprotein cholesterol (HDL-C); rs3764261 and rs12149545 polymorphisms were associated with all components of MS except high blood pressure; rs711752 and rs708272 polymorphisms were associated with low HDL-C (all p < 0.05). (4) Complete linkage disequilibrium (LD) was identified for two pairs of single nucleotide polymorphisms (SNPs) (rs3764261 and rs12149545 (D' = 1.000, r2 = 0.931), rs711752 and rs708272 (D' = 1.000, r2 = 0.996)). (5) The A-G-G-G-C (p = 0.013, odds ratio [OR] = 0.622, 95% confidence interval [95% CI] = 0.427-0.906) and A-T-A-A-T (p < 0.001, OR = 0.519, 95% CI = 0.386-0.697) haplotypes were more frequent in the control group than in the case group. Conclusions: The rs1800775, rs3764261, rs12149545, rs711752, and rs708272 polymorphisms of CETP were associated with MS and its components among the Uyghur ethnic group. Complete LD was found between two pairs of SNPs (rs3764261 and rs12149545, rs711752, and rs708272). The A-G-G-G-C and A-T-A-A-T haplotypes might be protective factors for MS. PMID- 28629170 TI - EGFR and EGFRvIII Promote Angiogenesis and Cell Invasion in Glioblastoma: Combination Therapies for an Effective Treatment. AB - Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related angiogenesis and their upregulation correlates with the poor prognosis of glioma patients. Glioma cell invasion and increased angiogenesis share mechanisms of the degradation of the extracellular matrix (ECM) through upregulation of ECM-degrading proteases as well as the activation of aberrant signaling pathways. This review describes the role of EGFR and EGFRvIII in those mechanisms which might offer new combined therapeutic approaches targeting EGFR or EGFRvIII together with drug treatments against proteases of the ECM or downstream signaling to increase the inhibitory effects of mono-therapies. PMID- 28629172 TI - The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence. AB - Embryo implantation is a complex process involving continuous molecular cross talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes. PMID- 28629171 TI - Cutaneous Manifestations of Human and Murine Leishmaniasis. AB - The leishmaniases are diseases caused by pathogenic protozoan parasites of the genus Leishmania. Infections are initiated when a sand fly vector inoculates Leishmania parasites into the skin of a mammalian host. Leishmania causes a spectrum of inflammatory cutaneous disease manifestations. The type of cutaneous pathology is determined in part by the infecting Leishmania species, but also by a combination of inflammatory and anti-inflammatory host immune response factors resulting in different clinical outcomes. This review discusses the distinct cutaneous syndromes described in humans, and current knowledge of the inflammatory responses associated with divergent cutaneous pathologic responses to different Leishmania species. The contribution of key hematopoietic cells in experimental cutaneous leishmaniasis in mouse models are also reviewed and compared with those observed during human infection. We hypothesize that local skin events influence the ensuing adaptive immune response to Leishmania spp. infections, and that the balance between inflammatory and regulatory factors induced by infection are critical for determining cutaneous pathology and outcome of infection. PMID- 28629174 TI - Using Coexpression Protein Interaction Network Analysis to Identify Mechanisms of Danshensu Affecting Patients with Coronary Heart Disease. AB - Salvia miltiorrhiza, known as Danshen, has attracted worldwide interest for its substantial effects on coronary heart disease (CHD). Danshensu (DSS) is one of the main active ingredients of Danshen on CHD. Although it has been proven to have a good clinical effect on CHD, the action mechanisms remain elusive. In the current study, a coexpression network-based approach was used to illustrate the beneficial properties of DSS in the context of CHD. By integrating the gene expression profile data and protein-protein interactions (PPIs) data, two coexpression protein interaction networks (CePIN) in a CHD state (CHD CePIN) and a non-CHD state (non-CHD CePIN) were generated. Then, shared nodes and unique nodes in CHD CePIN were attained by conducting a comparison between CHD CePIN and non-CHD CePIN. By calculating the topological parameters of each shared node and unique node in the networks, and comparing the differentially expressed genes, target proteins involved in disease regulation were attained. Then, Gene Ontology (GO) enrichment was utilized to identify biological processes associated to target proteins. Consequently, it turned out that the treatment of CHD with DSS may be partly attributed to the regulation of immunization and blood circulation. Also, it indicated that sodium/hydrogen exchanger 3 (SLC9A3), Prostaglandin G/H synthase 2 (PTGS2), Oxidized low-density lipoprotein receptor 1 (OLR1), and fibrinogen gamma chain (FGG) may be potential therapeutic targets for CHD. In summary, this study provided a novel coexpression protein interaction network approach to provide an explanation of the mechanisms of DSS on CHD and identify key proteins which maybe the potential therapeutic targets for CHD. PMID- 28629173 TI - Autophagic Mechanism in Anti-Cancer Immunity: Its Pros and Cons for Cancer Therapy. AB - Autophagy, a self-eating machinery, has been reported as an adaptive response to maintain metabolic homeostasis when cancer cells encounter stress. It has been appreciated that autophagy acts as a double-edge sword to decide the fate of cancer cells upon stress factors, molecular subtypes, and microenvironmental conditions. Currently, the majority of evidence support that autophagy in cancer cells is a vital mechanism bringing on resistance to current and prospective treatments, yet whether autophagy affects the anticancer immune response remains unclear and controversial. Accumulated studies have demonstrated that triggering autophagy is able to facilitate anticancer immunity due to an increase in immunogenicity, whereas other studies suggested that autophagy is likely to disarm anticancer immunity mediated by cytotoxic T cells and nature killer (NK) cells. Hence, this contradiction needs to be elucidated. In this review, we discuss the role of autophagy in cancer cells per se and in cancer microenvironment as well as its dual regulatory roles in immune surveillance through modulating presentation of tumor antigens, development of immune cells, and expression of immune checkpoints. We further focus on emerging roles of autophagy induced by current treatments and its impact on anticancer immune response, and illustrate the pros and cons of utilizing autophagy in cancer immunotherapy based on preclinical references. PMID- 28629175 TI - The Instrumentation of a Microfluidic Analyzer Enabling the Characterization of the Specific Membrane Capacitance, Cytoplasm Conductivity, and Instantaneous Young's Modulus of Single Cells. AB - This paper presents the instrumentation of a microfluidic analyzer enabling the characterization of single-cell biophysical properties, which includes seven key components: a microfluidic module, a pressure module, an imaging module, an impedance module, two LabVIEW platforms for instrument operation and raw data processing, respectively, and a Python code for data translation. Under the control of the LabVIEW platform for instrument operation, the pressure module flushes single cells into the microfluidic module with raw biophysical parameters sampled by the imaging and impedance modules and processed by the LabVIEW platform for raw data processing, which were further translated into intrinsic cellular biophysical parameters using the code developed in Python. Based on this system, specific membrane capacitance, cytoplasm conductivity, and instantaneous Young's modulus of three cell types were quantified as 2.76 +/- 0.57 MUF/cm2, 1.00 +/- 0.14 S/m, and 3.79 +/- 1.11 kPa for A549 cells (ncell = 202); 1.88 +/- 0.31 MUF/cm2, 1.05 +/- 0.16 S/m, and 3.74 +/- 0.75 kPa for 95D cells (ncell = 257); 2.11 +/- 0.38 MUF/cm2, 0.87 +/- 0.11 S/m, and 5.39 +/- 0.89 kPa for H460 cells (ncell = 246). As a semi-automatic instrument with a throughput of roughly 1 cell per second, this prototype instrument can be potentially used for the characterization of cellular biophysical properties. PMID- 28629176 TI - Fortifying Horticultural Crops with Essential Amino Acids: A Review. AB - To feed the world's growing population, increasing the yield of crops is not the only important factor, improving crop quality is also important, and it presents a significant challenge. Among the important crops, horticultural crops (particularly fruits and vegetables) provide numerous health compounds, such as vitamins, antioxidants, and amino acids. Essential amino acids are those that cannot be produced by the organism and, therefore, must be obtained from diet, particularly from meat, eggs, and milk, as well as a variety of plants. Extensive efforts have been devoted to increasing the levels of essential amino acids in plants. Yet, these efforts have been met with very little success due to the limited genetic resources for plant breeding and because high essential amino acid content is generally accompanied by limited plant growth. With a deep understanding of the biosynthetic pathways of essential amino acids and their interactions with the regulatory networks in plants, it should be possible to use genetic engineering to improve the essential amino acid content of horticultural plants, rendering these plants more nutritionally favorable crops. In the present report, we describe the recent advances in the enhancement of essential amino acids in horticultural plants and possible future directions towards their bio fortification. PMID- 28629177 TI - ExNOTic: Should We Be Keeping Exotic Pets? AB - There has been a recent trend towards keeping non-traditional companion animals, also known as exotic pets. These pets include parrots, reptiles, amphibians and rabbits, as well as small species of rodent such as degus and guinea pigs. Many of these exotic pet species are not domesticated, and often have special requirements in captivity, which many owners do not have the facilities or knowledge to provide. Keeping animals in settings to which they are poorly adapted is a threat to their welfare. Additionally, owner satisfaction with the animal may be poor due to a misalignment of expectations, which further impacts on welfare, as it may lead to repeated rehoming or neglect. We investigate a range of commonly kept exotic species in terms of their suitability as companion animals from the point of view of animal welfare and owner satisfaction, and make recommendations on the suitability of various species as pets. PMID- 28629178 TI - Active2Gether: A Personalized m-Health Intervention to Encourage Physical Activity. AB - Lack of physical activity is an increasingly important health risk. Modern mobile technology, such as smartphones and digital measurement devices, provides new opportunities to tackle physical inactivity. This paper describes the design of a system that aims to encourage young adults to be more physically active. The system monitors the user's behavior, uses social comparison and provides tailored and personalized feedback based on intelligent reasoning mechanisms. As the name suggests, social processes play an important role in the Active2Gether system. The design choices and functioning of the system are described in detail. Based on the experiences with the development and deployment of the system, a number of lessons learnt are provided and suggestions are proposed for improvements in future developments. PMID- 28629179 TI - Epidermal Growth Factor Enhances Cellular Uptake of Polystyrene Nanoparticles by Clathrin-Mediated Endocytosis. AB - The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies to assess the influence of cellular factors, such as growth factor responses, on the cellular uptake efficiency of nanoparticles. The aim of this study was to clarify the effects of epidermal growth factor (EGF) on the uptake efficiency of polystyrene nanoparticles (PS NPs) by A431 cells, a human carcinoma epithelial cell line. The results showed that EGF enhanced the uptake efficiency of A431 cells for PS NPs. In addition, inhibition and localization studies of PS NPs and EGF receptors (EGFRs) indicated that cellular uptake of PS NPs is related to the binding of EGF EGFR complex and PS NPs. Different pathways are used to enter the cells depending on the presence or absence of EGF. In the presence of EGF, cellular uptake of PS NPs is via clathrin-mediated endocytosis, whereas, in the absence of EGF, uptake of PS NPs does not involve clathrin-mediated endocytosis. Our findings indicate that EGF enhances cellular uptake of PS NPs by clathrin-mediated endocytosis. This result could be important for developing safe nanoparticles and their safe use in medical applications. PMID- 28629181 TI - Knockout of Murine Mamld1 Impairs Testicular Growth and Daily Sperm Production but Permits Normal Postnatal Androgen Production and Fertility. AB - MAMLD1 has been implicated in testicular function in both human and mouse fetuses. Although three patients with MAMLD1 mutations were reported to have hypergonadotropic hypogonadism in their teens, the functional significance of MAMLD1 in the postnatal testis remains unclear. Here, we analyzed the phenotype of Mamld1 knockout (KO) male mice at reproductive ages. The reproductive organs of KO male mice were morphologically unremarkable, except for relatively small testes. Seminiferous tubule size and number of proliferating spermatogonia/spermatocytes were reduced in the KO testis. Daily sperm production of KO mice was mildly attenuated, whereas total sperm counts in epididymal semen remained normal. Sperm motility and morphology, as well as androgen levels in serum and testicular tissues and the number of pups born from cross-mated wildtype (WT) female mice, were comparable between WT and KO male mice. These results indicate that MAMLD1 contributes to the maintenance of postnatal testicular growth and daily sperm production but is dispensable for androgen biosynthesis and fertility. MAMLD1 likely plays supporting roles in multiple and continuous steps of male reproduction. PMID- 28629180 TI - Bioavailability of Dietary Omega-3 Fatty Acids Added to a Variety of Sausages in Healthy Individuals. AB - A low Omega-3 Index (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocytes) is associated with cardiac, cerebral, and other health issues. Intake of EPA and DHA, but not of alpha-linolenic acid (ALA), increases the Omega 3 Index. We investigated bioavailability, safety, palatability and tolerability of EPA and DHA in a novel source: a variety of sausages. We screened 96 healthy volunteers, and recruited 44 with an Omega-3 Index <5%. Participants were randomly assigned to receive a variety of sausages enriched with approximately 250 mg EPA and DHA per 80 g (n = 22) daily for 8 weeks, or matching placebo sausages (n = 22). All sausages contained approximately 250 mg ALA/80 g. In the verum group, the mean Omega-3 Index increased from 4.18 +/- 0.54 to 5.72 +/- 0.66% (p < 0.001), while it remained unchanged in the placebo group. While ALA levels increased only in the placebo group, DPA levels increased in both groups. Inter-individual variability in the response was large. The mean increase of the Omega-3 Index per intake of EPA and DHA we observed was higher than for other sources previously studied, indicating superior bioavailability. As increasing production of EPA and DHA is difficult, improvements of bioavailability can facilitate reaching the target range for the Omega-3 Index (8-11%). PMID- 28629182 TI - Magnetic Resonance Spectroscopy for Detection of 2-Hydroxyglutarate as a Biomarker for IDH Mutation in Gliomas. AB - Mutations in the isocitrate dehydrogenase (IDH)1/2 genes are highly prevalent in gliomas and have been suggested to play an important role in the development and progression of the disease. Tumours harbouring these mutations exhibit a significant alteration in their metabolism resulting in the aberrant accumulation of the oncometabolite 2-hydroxygluarate (2-HG). As well as being suggested to play an important role in tumour progression, 2-HG may serve as a surrogate indicator of IDH status through non-invasive detection using magnetic resonance spectroscopy (MRS). In this review, we describe the recent efforts in developing MRS methods for detection and quantification of 2-HG in vivo and provide an assessment of the role of the 2-HG in gliomagenesis and patient prognosis. PMID- 28629183 TI - An Amyloidogenic Sequence at the N-Terminus of the Androgen Receptor Impacts Polyglutamine Aggregation. AB - The human androgen receptor (AR) is a ligand inducible transcription factor that harbors an amino terminal domain (AR-NTD) with a ligand-independent activation function. AR-NTD is intrinsically disordered and displays aggregation properties conferred by the presence of a poly-glutamine (polyQ) sequence. The length of the polyQ sequence as well as its adjacent sequence motifs modulate this aggregation property. AR-NTD also contains a conserved KELCKAVSVSM sequence motif that displays an intrinsic property to form amyloid fibrils under mild oxidative conditions. As peptide sequences with intrinsic oligomerization properties are reported to have an impact on the aggregation of polyQ tracts, we determined the effect of the KELCKAVSVSM on the polyQ stretch in the context of the AR-NTD using atomic force microscopy (AFM). Here, we present evidence for a crosstalk between the amyloidogenic properties of the KELCKAVSVSM motif and the polyQ stretch at the AR-NTD. PMID- 28629184 TI - Determination of Structural Requirements of N-Substituted Tetrahydro-beta Carboline Imidazolium Salt Derivatives Using in Silico Approaches for Designing MEK-1 Inhibitors. AB - Novel N-substituted tetrahydro-beta-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-beta-carboline-imidazolium salt derivative moieties. In the case of Topomer CoMFA, all the compounds were split into two fragments which were used to generate a 3D invariant representation, the statistical results of the Topomer CoMFA model: q2 value of 0.700; r2 value of 0.954; with 5 optimum components. The database alignment was utilized for building the CoMSIA model, and the CoMSIA model had q2 and r2 values of 0.615 and 0.897, with 4 optimum components. Target fishing of the PharmMapper platform was utilised for finding potential targets, the human mitogen-activated protein kinase 1 (MEK-1) was found to be the primary potential target for the three compounds with the fit scores of 6.288, 5.741, and 6.721. The molecular docking technique of MOE 2015 was carried out to identify the interactions of amino acids surrounding the ligand, and correlating QASR contour maps were used to identify structural requirements of N-substituted tetrahydro-beta-carboline imidazolium salt moieties. Molecular dynamics and simulation studies proved that the target protein was stable for 0.8-5 ns. The pivotal moieties of N-substituted tetrahydro beta-carboline imidazolium salt derivatives and its potential targets were verified by the QASR study, PharmMapper, and the molecular docking study which would be helpful to design novel MEK-1 inhibitors for anticancer drugs. PMID- 28629185 TI - Leptadenia reticulata (Retz.) Wight & Arn. (Jivanti): Botanical, Agronomical, Phytochemical, Pharmacological, and Biotechnological Aspects. AB - Leptadenia reticulata (Retz.) Wight & Arn. (Apocynaceae), is a traditional medicinal plant species widely used to treat various ailments such as tuberculosis, hematopoiesis, emaciation, cough, dyspnea, fever, burning sensation, night blindness, cancer, and dysentery. In Ayurveda, it is known for its revitalizing, rejuvenating, and lactogenic properties. This plant is one of the major ingredients in many commercial herbal formulations, including Speman, Envirocare, Calshakti, Antisept, and Chyawanprash. The therapeutic potential of this herb is because of the presence of diverse bioactive compounds such as alpha amyrin, beta-amyrin, ferulic acid, luteolin, diosmetin, rutin, beta-sitosterol, stigmasterol, hentricontanol, a triterpene alcohol simiarenol, apigenin, reticulin, deniculatin, and leptaculatin. However, most biological studies on L. reticulata are restricted to crude extracts, and many biologically active compounds are yet to be identified in order to base the traditional uses of L. reticulata on evidence-based data. At present, L. reticulata is a threatened endangered plant because of overexploitation, unscientific harvesting, and habitat loss. The increased demand from pharmaceutical, nutraceutical, and veterinary industries has prompted its large-scale propagation. However, its commercial cultivation is hampered because of the non-availability of genuine planting material and the lack of knowledge about its agronomical practices. In this regard, micropropagation techniques will be useful to obtain true-to-type L. reticulata planting materials from an elite germplasm to meet the current demand. Adopting other biotechnological approaches such as synthetic seed technology, cryopreservation, cell culture, and genetic transformation can help conservation as well as increased metabolite production from L. reticulata. The present review summarizes scientific information on the botanical, agronomical, phytochemical, pharmacological, and biotechnological aspects of L. reticulata. This comprehensive information will certainly allow better utilization of this industrially important herb towards the discovery of lead drug molecules. PMID- 28629186 TI - Design and Performance of a Portable and Multichannel SPR Device. AB - A portable multichannel surface plasmon resonance (SPR) biosensor device is presented in this study. As an optical biosensor device, the core component of its light path is a semi-cylindrical prism, which is used as the coupling unit for the excitation of the SPR phenomena. Based on this prism, a wedge-shaped incident light beam including a continuous angle range (10 degrees ) is chosen to replace the commonly-used parallel light beam in traditional SPR devices, in which the incident angle is adjusted by a sophisticated mechanical system. Thus, complicated, cumbersome, and costly mechanical structures can be avoided in this design. Furthermore, the selection of a small and high-stability semiconductor laser and matrix CCD detector as well as a microfluidic system aids in the realization of a miniaturized and multichannel device. Several different samples were used to test the performance of this new device. For ethanol with different concentrations, the sensing response was of good linear relativity with the concentration (Y = 3.17143X + 2.81518, R2 = 0.97661). Mouse IgG and goat anti mouse IgG were used as biological samples for immunological analysis, and BSA as the control group. Good specific recognition between mouse IgG and goat anti mouse IgG has been achieved. The detection limit of antibody to antigen coated on the sensing surface was about 25 mg/L without surface modification. PMID- 28629187 TI - Suppression of Ghrelin Exacerbates HFCS-Induced Adiposity and Insulin Resistance. AB - High fructose corn syrup (HFCS) is widely used as sweetener in processed foods and soft drinks in the United States, largely substituting sucrose (SUC). The orexigenic hormone ghrelin promotes obesity and insulin resistance; ghrelin responds differently to HFCS and SUC ingestion. Here we investigated the roles of ghrelin in HFCS- and SUC-induced adiposity and insulin resistance. To mimic soft drinks, 10-week-old male wild-type (WT) and ghrelin knockout (Ghrelin-/-) mice were subjected to ad lib. regular chow diet supplemented with either water (RD), 8% HFCS (HFCS), or 10% sucrose (SUC). We found that SUC-feeding induced more robust increases in body weight and body fat than HFCS-feeding. Comparing to SUC fed mice, HFCS-fed mice showed lower body weight but higher circulating glucose and insulin levels. Interestingly, we also found that ghrelin deletion exacerbates HFCS-induced adiposity and inflammation in adipose tissues, as well as whole-body insulin resistance. Our findings suggest that HFCS and SUC have differential effects on lipid metabolism: while sucrose promotes obesogenesis, HFCS primarily enhances inflammation and insulin resistance, and ghrelin confers protective effects for these metabolic dysfunctions. PMID- 28629189 TI - Localization Framework for Real-Time UAV Autonomous Landing: An On-Ground Deployed Visual Approach. AB - [-5]One of the greatest challenges for fixed-wing unmanned aircraft vehicles (UAVs) is safe landing. Hereafter, an on-ground deployed visual approach is developed in this paper. This approach is definitely suitable for landing within the global navigation satellite system (GNSS)-denied environments. As for applications, the deployed guidance system makes full use of the ground computing resource and feedbacks the aircraft's real-time localization to its on-board autopilot. Under such circumstances, a separate long baseline stereo architecture is proposed to possess an extendable baseline and wide-angle field of view (FOV) against the traditional fixed baseline schemes. Furthermore, accuracy evaluation of the new type of architecture is conducted by theoretical modeling and computational analysis. Dataset-driven experimental results demonstrate the feasibility and effectiveness of the developed approach. PMID- 28629188 TI - Serum Biomarkers for Discrimination between Hepatitis C-Related Arthropathy and Early Rheumatoid Arthritis. AB - In the present study, we aimed to estimate the concentrations of cytokines (interleukin 6, IL-6, tumor necrosis factor-alpha, TNF-alpha) and auto-antibodies (rheumatoid factor IgM isotype, IgM-RF, antinuclear auto-antibodies, ANA, anti cyclic citrullinated peptide antibodies IgG isotype, IgG anti-CCP3.1, anti cardiolipin IgG isotype, IgG anti-aCL) in serum of patients with eRA (early rheumatoid arthritis) and HCVrA (hepatitis C virus-related arthropathy) and to assess the utility of IL-6, TNF-alpha together with IgG anti-CCP and IgM-RF in distinguishing between patients with true eRA and HCVrA, in the idea of using them as differential immunomarkers. Serum samples were collected from 54 patients (30 diagnosed with eRA-subgroup 1 and 24 with HCVrA-subgroup 2) and from 28 healthy control persons. For the evaluation of serum concentrations of studied cytokines and auto-antibodies, we used immunoenzimatique techniques. The serum concentrations of both proinflammatory cytokines were statistically significantly higher in patients of subgroup 1 and subgroup 2, compared to the control group (p < 0.0001). Our study showed statistically significant differences of the mean concentrations only for ANA and IgG anti-CCP between subgroup 1 and subgroup 2. We also observed that IL-6 and TNF-alpha better correlated with auto-antibodies in subgroup 1 than in subgroup 2. In both subgroups of patients, ROC curves indicated that IL-6 and TNF-alpha have a higher diagnostic utility as markers of disease. In conclusion, we can say that, due to high sensitivity for diagnostic accuracy, determination of serum concentrations of IL-6 and TNF-alpha, possibly in combination with auto-antibodies, could be useful in the diagnosis and distinguishing between patients with true eRA and HCV patients with articular manifestation and may prove useful in the monitoring of the disease course. PMID- 28629191 TI - A New Filtering and Smoothing Algorithm for Railway Track Surveying Based on Landmark and IMU/Odometer. AB - High-accuracy railway track surveying is essential for railway construction and maintenance. The traditional approaches based on total station equipment are not efficient enough since high precision surveying frequently needs static measurements. This paper proposes a new filtering and smoothing algorithm based on the IMU/odometer and landmarks integration for the railway track surveying. In order to overcome the difficulty of estimating too many error parameters with too few landmark observations, a new model with completely observable error states is established by combining error terms of the system. Based on covariance analysis, the analytical relationship between the railway track surveying accuracy requirements and equivalent gyro drifts including bias instability and random walk noise are established. Experiment results show that the accuracy of the new filtering and smoothing algorithm for railway track surveying can reach 1 mm (1sigma) when using a Ring Laser Gyroscope (RLG)-based Inertial Measurement Unit (IMU) with gyro bias instability of 0.03 degrees /h and random walk noise of 0.005 degrees h while control points of the track control network (CPIII) position observations are provided by the optical total station in about every 60 m interval. The proposed approach can satisfy at the same time the demands of high accuracy and work efficiency for railway track surveying. PMID- 28629190 TI - Biotechnological Potential of Cold Adapted Pseudoalteromonas spp. Isolated from 'Deep Sea' Sponges. AB - The marine genus Pseudoalteromonas is known for its versatile biotechnological potential with respect to the production of antimicrobials and enzymes of industrial interest. We have sequenced the genomes of three Pseudoalteromonas sp. strains isolated from different deep sea sponges on the Illumina MiSeq platform. The isolates have been screened for various industrially important enzymes and comparative genomics has been applied to investigate potential relationships between the isolates and their host organisms, while comparing them to free living Pseudoalteromonas spp. from shallow and deep sea environments. The genomes of the sponge associated Pseudoalteromonas strains contained much lower levels of potential eukaryotic-like proteins which are known to be enriched in symbiotic sponge associated microorganisms, than might be expected for true sponge symbionts. While all the Pseudoalteromonas shared a large distinct subset of genes, nonetheless the number of unique and accessory genes is quite large and defines the pan-genome as open. Enzymatic screens indicate that a vast array of enzyme activities is expressed by the isolates, including beta-galactosidase, beta-glucosidase, and protease activities. A beta-glucosidase gene from one of the Pseudoalteromonas isolates, strain EB27 was heterologously expressed in Escherichia coli and, following biochemical characterization, the recombinant enzyme was found to be cold-adapted, thermolabile, halotolerant, and alkaline active. PMID- 28629192 TI - Effects of Sulfate, Chloride, and Bicarbonate on Iron Stability in a PVC-U Drinking Pipe. AB - In order to describe iron stability in plastic pipes and to ensure the drinking water security, the influence factors and rules for iron adsorption and release were studied, dependent on the Unplasticized poly (vinyl chloride) (PVC-U) drinking pipes employed in this research. In this paper, sulfate, chloride, and bicarbonate, as well as synthesized models, were chosen to investigate the iron stability on the inner wall of PVC-U drinking pipes. The existence of the three kinds of anions could significantly affect the process of iron adsorption, and a positive association was found between the level of anion concentration and the adsorption rate. However, the scaling formed on the inner surface of the pipes would be released into the water under certain conditions. The Larson Index (LI), used for a synthetic consideration of anion effects on iron stability, was selected to investigate the iron release under multi-factor conditions. Moreover, a well fitted linear model was established to gain a better understanding of iron release under multi-factor conditions. The simulation results demonstrated that the linear model was better fitted than the LI model for the prediction of iron release. PMID- 28629194 TI - Adhesive Defect Monitoring of Glass Fiber Epoxy Plate Using an Impedance-Based Non-Destructive Testing Method for Multiple Structures. AB - The emergence of composite materials has revolutionized the approach to building engineering structures. With the number of applications for composites increasing every day, maintaining structural integrity is of utmost importance. For composites, adhesive bonding is usually the preferred choice over the mechanical fastening method, and monitoring for delamination is an essential factor in the field of composite materials. In this study, a non-destructive method known as the electromechanical impedance method is used with an approach of monitoring multiple areas by specifying certain frequency ranges to correspond to a certain test specimen. Experiments are conducted using various numbers of stacks created by attaching glass fiber epoxy composite plates onto one another, and two different debonding damage types are introduced to evaluate the performance of the multiple monitoring electromechanical impedance method. PMID- 28629193 TI - Telomere Biology-Insights into an Intriguing Phenomenon. AB - Bacteria and viruses possess circular DNA, whereas eukaryotes with typically very large DNA molecules have had to evolve into linear chromosomes to circumvent the problem of supercoiling circular DNA of that size. Consequently, such organisms possess telomeres to cap chromosome ends. Telomeres are essentially tandem repeats of any DNA sequence that are present at the ends of chromosomes. Their biology has been an enigmatic one, involving various molecules interacting dynamically in an evolutionarily well-trimmed fashion. Telomeres range from canonical hexameric repeats in most eukaryotes to unimaginably random retrotransposons, which attach to chromosome ends and reverse-transcribe to DNA in some plants and insects. Telomeres invariably associate with specialised protein complexes that envelop it, also regulating access of the ends to legitimate enzymes involved in telomere metabolism. They also transcribe into repetitive RNA which also seems to be playing significant roles in telomere maintenance. Telomeres thus form the intersection of DNA, protein, and RNA molecules acting in concert to maintain chromosome integrity. Telomere biology is emerging to appear ever more complex than previously envisaged, with the continual discovery of more molecules and interplays at the telomeres. This review also includes a section dedicated to the history of telomere biology, and intends to target the scientific audience new to the field by rendering an understanding of the phenomenon of chromosome end protection at large, with more emphasis on the biology of human telomeres. The review provides an update on the field and mentions the questions that need to be addressed. PMID- 28629195 TI - Candida albicans Impairments Induced by Peppermint and Clove Oils at Sub Inhibitory Concentrations. AB - Members of Candida species cause significant health problems, inducing various types of superficial and deep-seated mycoses in humans. In order to prevent from Candida sp. development, essential oils are more and more frequently applied, due to their antifungal activity, low toxicity if used appropriately, and biodegrability. The aim of the study was to characterize the early alterations in Candida albicans metabolic properties in relation to proteins and chromosomal DNA profiles, after treatment with peppermint and clove oils at sub-inhibitory concentrations. The yeasts were affected by the oils even at a concentration of 0.0075% v/v, which resulted in changes in colony morphotypes and metabolic activities. Peppermint and clove oils at concentrations ranging from 0.015* MIC (minimal inhibitory concentration) to 0.5* MIC values substantially affected the enzymatic abilities of C. albicans, and these changes were primarily associated with the loss or decrease of activity of all 9 enzymes detected in the untreated yeast. Moreover, 29% isolates showed additional activity of N-acetyl-beta glucosaminidase and 14% isolates-alpha-fucosidase in comparison to the yeast grown without essential oils addition. In response to essential oils at 0.25-0.5* MIC, extensive changes in C. albicans whole-cell protein profiles were noted. However, the yeast biochemical profiles were intact with the sole exception of the isolate treated with clove oil at 0.5* MIC. The alterations were not attributed to gross chromosomal rearrangements in C. albicans karyotype. The predominantly observed decrease in protein fractions and the yeast enzymatic activity after treatment with the oils should be considered as a phenotypic response of C. albicans to the essential oils at their sub-inhibitory concentrations and may lead to the reduction of this yeast pathogenicity. PMID- 28629196 TI - Letter to the Editor: "Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy". AB - n/a. PMID- 28629197 TI - Reply to the Letter to the Editor by C. Nicolazzo et al.: "Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy". AB - n/a. PMID- 28629198 TI - Rapid Global Calibration Technology for Hybrid Visual Inspection System. AB - Vision-based methods for product quality inspection are playing an increasingly important role in modern industries for their good performance and high efficiency. A hybrid visual inspection system, which consists of an industrial robot with a flexible sensor and several stationary sensors, has been widely applied in mass production, especially in automobile manufacturing. In this paper, a rapid global calibration method for the hybrid visual inspection system is proposed. Global calibration of a flexible sensor is performed first based on the robot kinematic. Then, with the aid of the calibrated flexible sensor, stationary sensors are calibrated globally one by one based on homography. Only a standard sphere and an auxiliary target with a 2D planar pattern are applied during the system global calibration, and the calibration process can be easily re-performed during the system's periodical maintenance. An error compensation method is proposed for the hybrid inspection system, and the final accuracy of the hybrid system is evaluated with the deviation and correlation coefficient between the measured results of the hybrid system and Coordinate Measuring Machine (CMM). An accuracy verification experiment shows that deviation of over 95% of featured points are less than +/-0.3 mm, and the correlation coefficients of over 85% of points are larger than 0.7. PMID- 28629199 TI - Association of Education and Smoking Status on Risk of Diabetes Mellitus: A Population-Based Nationwide Cross-Sectional Study. AB - Background: Exposure to smoke, including environmental tobacco smoke (ETS), is a well-known risk factor for diabetes. Low socioeconomic status, especially lack of education, is also a risk factor for diabetes. Therefore, we assessed the association of demographic, socioeconomic, clinical, and behavior risk factor related variables and smoking status, including ETS exposure, with the prevalence of diabetes. Methods: Data were from the 2007-2013 Korea National Health and Nutritional Evaluation Survey (KNHANES). Multivariable logistic regression examined associations between various lifestyle and health factors and the prevalence of diabetes while controlling for potential confounding variables. Subgroup analysis was performed according to smoking status to determine factors associated with diabetes. Results: Of 19,303 individuals analyzed, 1325 (11.4%) had diabetes. Greater average age, male sex, lower educational level, unemployment, and coexisting health problems were significantly associated with diabetes. Individuals with only elementary, middle, or high school level education had significantly greater odds ratios (p < 0.05) compared to college graduates; smokers and nonsmokers exposed to ETS had significantly greater OR (p < 0.05) than nonsmokers unexposed to ETS. Subgroup analysis of diabetics according to smoking status revealed significant associations (p < 0.05) for diabetic nonsmokers exposed to ETS with female sex, single status, elementary level education, urban residence, National Health Insurance (NHI), hypertension, a lack of alcohol intake, and a lack of moderate physical activity. For diabetic smokers, there were significant associations (p < 0.05) with elementary education, urban residence, a lack of moderate physical activity, a lack of alcohol intake, and NHI. Conclusions: The results suggested that smoking status, as well as ETS exposure, was associated with a higher prevalence of diabetes, especially in populations with less education. Thus, we should direct efforts for controlling diabetes toward individuals with lower levels of education and those who are smokers and nonsmokers exposed to ETS. PMID- 28629200 TI - Level of Sedentary Behavior and Its Associated Factors among Saudi Women Working in Office-Based Jobs in Saudi Arabia. AB - Research in Saudi Arabia has revealed a shocking level of insufficiently physically active adults, particularly women. The risk of sedentary behavior will likely increase as the number of women with office-based jobs increases. The aim of this study is to determine the level of sedentary behavior, and its associated factors, among Saudi women working office-based jobs in the city of Riyadh. A cross-sectional study of 420 Saudi female employees at 8 office-based worksites were measured to determine body mass index and were given a self-administered survey to evaluate their level of physical activity and sedentary behavior. Median sitting time on work days was 690 min per day (interquartile range, IQR 541-870), with nearly half accumulated during work hours, and 575 min per day (IQR 360-780) on non-work days. Predictors of work day sitting time were level of education, number of children, and working in the private sector. Number of children, whether they were single, and whether they lived in a small home were found to predict non-work day sitting time. This study identifies Saudi women in office-based jobs as a high-risk group for sedentary behavior. There is a need to promote physical activity at worksites and reduce prolonged sitting. PMID- 28629201 TI - Systemic Induction of the Defensin and Phytoalexin Pisatin Pathways in Pea (Pisum sativum) against Aphanomyces euteiches by Acetylated and Nonacetylated Oligogalacturonides. AB - Oligogalacturonides (OGs) are known for their powerful ability to stimulate the plant immune system but little is known about their mode of action in pea (Pisum sativum). In the present study, we investigated the elicitor activity of two fractions of OGs, with polymerization degrees (DPs) of 2-25, in pea against Aphanomyces euteiches. One fraction was nonacetylated (OGs - Ac) whereas the second one was 30% acetylated (OGs + Ac). OGs were applied by injecting the upper two rachises of the plants at three- and/or four-weeks-old. Five-week-old roots were inoculated with 105 zoospores of A. euteiches. The root infection level was determined at 7, 10 and 14 days after inoculation using the quantitative real time polymerase chain reaction (qPCR). Results showed significant root infection reductions namely 58, 45 and 48% in the plants treated with 80 ug OGs + Ac and 59, 56 and 65% with 200 ug of OGs - Ac. Gene expression results showed the upregulation of genes involved in the antifungal defensins, lignans and the phytoalexin pisatin pathways and a priming effect in the basal defense, SA and ROS gene markers as a response to OGs. The reduction of the efficient dose in OGs + Ac is suggesting that acetylation is necessary for some specific responses. Our work provides the first evidence for the potential of OGs in the defense induction in pea against Aphanomyces root rot. PMID- 28629202 TI - A Novel Extreme Learning Machine Classification Model for e-Nose Application Based on the Multiple Kernel Approach. AB - A novel classification model, named the quantum-behaved particle swarm optimization (QPSO)-based weighted multiple kernel extreme learning machine (QWMK ELM), is proposed in this paper. Experimental validation is carried out with two different electronic nose (e-nose) datasets. Being different from the existing multiple kernel extreme learning machine (MK-ELM) algorithms, the combination coefficients of base kernels are regarded as external parameters of single-hidden layer feedforward neural networks (SLFNs). The combination coefficients of base kernels, the model parameters of each base kernel, and the regularization parameter are optimized by QPSO simultaneously before implementing the kernel extreme learning machine (KELM) with the composite kernel function. Four types of common single kernel functions (Gaussian kernel, polynomial kernel, sigmoid kernel, and wavelet kernel) are utilized to constitute different composite kernel functions. Moreover, the method is also compared with other existing classification methods: extreme learning machine (ELM), kernel extreme learning machine (KELM), k-nearest neighbors (KNN), support vector machine (SVM), multi layer perceptron (MLP), radical basis function neural network (RBFNN), and probabilistic neural network (PNN). The results have demonstrated that the proposed QWMK-ELM outperforms the aforementioned methods, not only in precision, but also in efficiency for gas classification. PMID- 28629203 TI - The Consumption of Dairy Products Is Associated with Reduced Risks of Obesity and Metabolic Syndrome in Korean Women but not in Men. AB - We aimed to investigate the association between dairy product consumption and the risk of obesity and metabolic syndrome (MetS) in Korean adults. Data from 13,692 Korean adults aged >=19 years from the KNHANES 2010-2013 were used. The study participants were divided into three groups according to the serving size of dairy products they consumed based on a single 24-h recall. About 58% of the Korean adults did not consume any dairy products in one day. In both the sexes, only those who adhered to the recommendation for dairy products (>=1 serving/day) achieved the daily requirement of calcium. Women who consumed >=1 serving/day of dairy products had lower risks of obesity (body mass index >= 25 kg/m2) (adjusted odds ratio (AOR), 0.77; 95% confidence interval (CI), 0.66-0.89; p for trend < 0.01) and MetS (AOR, 0.67; 95% CI, 0.56-0.80; p for trend < 0.01) than women who did not consume dairy products. However, these significant associations were not observed in men. In conclusion, consuming >= 1 serving/day of dairy products could be an easy and efficient strategy for meeting daily calcium requirement as well as lowering risks of obesity and MetS among Korean women. PMID- 28629204 TI - Paternal Risk Factors for Oral Clefts in Northern Africans, Southeast Asians, and Central Americans. AB - While several studies have investigated maternal exposures as risk factors for oral clefts, few have examined paternal factors. We conducted an international multi-centered case-control study to better understand paternal risk exposures for oral clefts (cases = 392 and controls = 234). Participants were recruited from local hospitals and oral cleft repair surgical missions in Vietnam, the Philippines, Honduras, and Morocco. Questionnaires were administered to fathers and mothers separately to elicit risk factor and family history data. Associations between paternal exposures and risk of clefts were assessed using logistic regression adjusting for potential confounders. A father's personal/family history of clefts was associated with significantly increased risk (adjusted OR: 4.77; 95% CI: 2.41-9.45). No other significant associations were identified for other suspected risk factors, including education (none/primary school v. university adjusted OR: 1.29; 95% CI: 0.74-2.24), advanced paternal age (5-year adjusted OR: 0.98; 95% CI: 0.84-1.16), or pre pregnancy tobacco use (adjusted OR: 0.96; 95% CI: 0.67-1.37). Although sample size was limited, significantly decreased risks were observed for fathers with selected occupations. Further research is needed to investigate paternal environmental exposures as cleft risk factors. PMID- 28629205 TI - Attachment Style Is Related to Quality of Life for Assistance Dog Owners. AB - Attachment styles have been shown to affect quality of life. Growing interest in the value of companion animals highlights that owning a dog can also affect quality of life, yet little research has explored the role of the attachment bond in affecting the relationship between dog ownership and quality of life. Given that the impact of dog ownership on quality of life may be greater for assistance dog owners than pet dog owners, we explored how anxious attachment and avoidance attachment styles to an assistance dog affected owner quality of life (n = 73). Regression analysis revealed that higher anxious attachment to the dog predicted enhanced quality of life. It is suggested that the unique, interdependent relationship between an individual and their assistance dog may mean that an anxious attachment style is not necessarily detrimental. Feelings that indicate attachment insecurity in other relationships may reflect more positive aspects of the assistance dog owner relationship, such as the level of support that the dog provides its owner. PMID- 28629206 TI - An enhanced vector-free allele exchange (VFAE) mutagenesis protocol for genome editing in a wide range of bacterial species. AB - Vector-free allele exchange (VFAE) is a newly developed protocol for genome editing in Pseudomonas species. Although several parameters have been determined to optimize the procedures for obtaining a stable and high-frequency mutation, numerous false-positive clones still appear on the plate, which increases the difficulty of finding the desired mutants. It has also not been established whether this protocol can be used for genome editing in other bacterial species. In the current study, the protocol was modified to dramatically decrease the occurrence of false-positive colonies using Pseudomonas stutzeri A1501 as a model strain. This improvement was reached by increasing the occurrence of circular-DNA cassettes of the correct size. Furthermore, the enhanced protocol was used to construct mutants in both the gram-negative Escherichia coli BL21 and gram positive Bacillus subtilis 168 strains. The protocol works well in both strains, yielding ideal results with a low percentage of false-positive colonies. In summary, the enhanced VFAE mutagenesis protocol is a potential tool for use in bacterial genome editing. PMID- 28629207 TI - H2O2 as a candidate bottleneck for MnP activity during cultivation of Agaricus bisporus in compost. AB - Degradation of lignin by fungi enhances availability of cellulose and hemicellulose in plant waste and thereby increases the amount of carbon source available to these microorganisms. The button mushroom Agaricus bisporus degrades only about half of the lignin in compost and about 40% of the carbohydrates remain unutilized during mushroom cultivation. Here it was assessed whether over expression of the manganese peroxidase gene mnp1 improves lignin degradation and, as a consequence, carbohydrate breakdown by A. bisporus. Transformants expressing mnp1 under the control of actin regulatory sequences produced MnP activity in malt extract medium, while the parental strain A15 did not. MnP activity was increased 0.3- and 3-fold at casing and after the 2nd flush of a semi-commercial cultivation, respectively, when compared to strain A15. Pyrolysis-GC-MS showed that overexpression of MnP decreased phenylmethane and phenylethane type lignin relative to the phenylpropane type after the 2nd flush. However, it neither affected the syringyl/guaiacyl derived residue ratio nor the ratio of oxidized to non-oxidized lignin residues. Moreover, the carbohydrate content and accessibility was not affected in compost. Notably, the capacity of compost extract to consume the MnP co-factor H2O2 was 4- to 8-fold higher than its production. This may well explain why over-expression of mnp1 did not improve carbohydrate degradation in compost. In fact, availability of H2O2 may limit lignin degradation by wild-type A. bisporus. PMID- 28629208 TI - Breaking Through the Multi-Mesa-Channel Width Limited of Normally Off GaN HEMTs Through Modulation of the Via-Hole-Length. AB - We present new normally off GaN high-electron-mobility transistors (HEMTs) that overcome the typical limitations in multi-mesa-channel (MMC) width through modulation of the via-hole-length to regulate the charge neutrality screen effect. We have prepared enhancement-mode (E-mode) GaN HEMTs having widths of up to 300 nm, based on an enhanced surface pinning effect. E-mode GaN HEMTs having MMC structures and widths as well as via-hole-lengths of 100 nm/2 MUm and 300 nm/6 MUm, respectively, exhibited positive threshold voltages (V th) of 0.79 and 0.46 V, respectively. The on-resistances of the MMC and via-hole-length structures were lower than those of typical tri-gate nanoribbon GaN HEMTs. In addition, the devices not only achieved the E-mode but also improved the power performance of the GaN HEMTs and effectively mitigated the device thermal effect. We controlled the via-hole-length sidewall surface pinning effect to obtain the E mode GaN HEMTs. Our findings suggest that via-hole-length normally off GaN HEMTs have great potential for use in next-generation power electronics. PMID- 28629209 TI - Fabrication of Nanoshell-Based 3D Periodic Structures by Templating Process using Solution-derived ZnO. AB - Fabrication methods for a 3D periodic nanostructure with excellent and unique properties for various applications, such as photonic and phononic crystals, have attracted considerable interest. Templating processes using colloidal crystals have been proposed to create nanoshell-based 3D structures over a large area with ease. However, there are technical limitations in structural design, resulting in difficulties for structural flexibility. Here, we demonstrate a combination of proximity field nanopatterning and infiltration processes using solution-derived ZnO for a nanoshell-based 3D periodic structure with high structural flexibility and controllability. A unique process of infiltration of a solution-derived material into a polymeric template prepared by a proximity field nanopatterning process achieves the fabrication of a pre-formed layer that works as a protective layer for the template and framework for the inverse structure. Subsequently, this process shows the controllability of nanoshell thickness and significant improvement in the structure height shrinkage factor (16%) compared to those of a previous non-vacuum infiltration method (34%). The proposed method offers high controllability and flexibility in the design of structural sizes, leading to further development toward nanoshell-based 3D structures for various applications including energy devices and sensors. PMID- 28629210 TI - Activation of IGF-I Survival Signaling and Its Compensative Inhibition of the Cardiac Apoptosis on Carotid Arteries Balloon-Injured Rat Hearts. AB - In this study, a rat carotid balloon injury-animal model was used to elucidate the temporal relationof hypertrophy in the progression of cardiac damage and the role of insulin-like growth factor (IGF)-Isurvival pathway on course of the cardiac damage. Rats were subjected to carotid balloon-injuryand examined at different time points. We further studied the heart-weight/body-weight ratio,histology and protein expression to understand the pathological events associated with percutaneoustransluminal coronary angioplasty (PTCA) induced damages. Protein expression analysis showedincreased levels of IGF-I signaling pathway and mitogen-activated protein kinase (MAPK) signalingpathway after 2 h and after 2 d of carotid balloon injury. On the other hand, apoptosis signalingpathways were enhanced after 14 d of carotid balloon injury. According to the results, rat carotidballoon injury significantly induced IGF-I survival signaling and compensated hypertrophy pathwayduring the initial period of injury however after 14 d the proteins involved in apoptotic cell deathwere elevated and the proteins of the survival pathway and compensatory hypertrophy weresignificantly reduced. PMID- 28629211 TI - Effect of Methoxsalen on Ca2+ Homeostasis and Viability in Human Osteosarcoma Cells. AB - Methoxsalen is a natural compound found in many seed plants. The effect of methoxsalen on Ca2+-related physiology in human osteosarcoma is unclear. This study investigated the effect of methoxsalenon cytosolic free Ca2+ concentrations ([Ca2+]i) in MG63 human osteosarcoma cells. Methoxsalen induced[Ca2+]i rises concentration-dependently. Methoxsalen-induced Ca2+ entry was confirmed by Mn2+ inducedquench of fura-2 fluorescence. This Ca2+ entry was suppressed by nifedipine, econazole, and SKF96365.In Ca2+-free medium, incubation with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone(BHQ) inhibited methoxsalen-evoked [Ca2+]i rises by 96%. In contrast, incubationwith methoxsalen abolished BHQ-evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122abolished methoxsalen-induced [Ca2+]i rises. Methoxsalen was cytotoxic at 300-700 MUM in a concentration-dependentfashion. Chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraaceticacid/acetoxymethyl ester (BAPTA/AM) did not prevent methoxsalen-induced cytotoxicity. Collectively, our data suggestthat in MG63 cells, methoxsalen induced [Ca2+]i rises by evoking PLC-dependent Ca2+ release from theendoplasmic reticulum, and Ca2+ entry via store-operated Ca2+ entry. Methoxsalen also induced Ca2+-disassociated cell death. PMID- 28629212 TI - A Study of the Modulating Action of Quercetin on Biochemical and Histological Alterations Induced by Lead Exposure in the Liver and Kidney of Rats. AB - Lead is a highly toxic metal and a very potent poison. Lead poisoning is a serious condition butcan be treated. Quercetin is a flavonoid with many beneficial uses. The aim of the present study wasto investigate the possible modulating action of quercetin as a model of an antioxidant against the toxiceffects of lead acetate on liver and kidneys of rats. Rats were randomly divided into four groups: (i)saline group (control); (ii) lead group received i.p. lead acetate (20 mg/kg b.w.); (iii) quercetin groupreceived i.p. quercetin (50 mg/kg b.w.); (iv) lead and quercetin group received i.p. lead acetate (20 mg/kg b.w.)followed by i.p. quercetin (50 mg/kg b.w.) for 4 weeks. The lead concentrations were determined in the liverand kidney tissues. Liver marker enzymes, bilirubin, albumin, total protein, creatinine, uric acid andurea, were assessed in the serum and light microscopic studies were performed. The results showed thatlead acetate administration was associated with an increase in serum alkaline phosphatase (ALP), alanineaminotransferase (ALT), aspartate aminotransferase (AST) activities, total bilirubin, creatinine, uricacid, urea levels. Lead accumulation in kidneys and liver tissues was also found, but were associated withdecrease in albumin and total protein in comparison with the respective mean values of the control. Leadacetate caused numerous histological alterations in the liver, including chronic inflammation, bilaryhyperplasia, edema, congestion, Kupffer cells hyperplasia and hemosiderosis, and in the kidney, includingtubular dilation, atrophy of glomerular tuft, widening of urinary space and mild fibroblast. Incontrary, administration of lead acetate along with quercetin partially restored the studied parametersto normal values and improved structure of liver and kidney with significant decreases in the severity ofhistopathological changes when compared with the lead acetate group. In conclusion, treatment withquercetin may provide a modulating action against the toxic effects induced by lead acetate in the liverand kidney of male rats. PMID- 28629214 TI - Infrared Studies of the Symmetry Changes of the 28SiH4 Molecule in Low Temperature Matrixes. Fundamental, Combination, and Overtone Transitions. AB - Infrared spectra of 28SiH4 in argon and nitrogen matrixes at low temperature 6.5 20 K in the region of overtone and combination transitions were recorded for the first time. Additionally, the high-resolution spectra were obtained in the fundamental region. The frequencies and the relative intensities of all bands were determined. The set of experimental data suggests that the symmetry of molecules studied in the matrixes is different from the symmetry of the free molecules because of an interaction with the environment. The symmetry of 28SiH4 changes from Td to C3v on transition from the gas phase to a nitrogen matrix and to D2d on transition to an argon matrix. A modeling of SiH4 molecule force fields explains the experimental data as a change of a force constant of the selected SiH bond in the case of SiH4 in the nitrogen matrix or force constants of two opposite angles in the case of SiH4 in the argon matrix. In spite of small values of these changes, they result in noticeable spectroscopic effects: the band splitting and appearance of new bands in matrix spectra compared with spectra of free SiH4. The interpretation of transitions in the fundamental and combination regions was performed. PMID- 28629215 TI - Unusual Interfacial Freezing Phenomena in Hexacontane/Silica Composites. AB - The crystallization behaviors of n-hexacontane (C60H122)/Stober silica (SiO2) composites with various compositions were investigated by a combination of differential scanning calorimetry (DSC), solid-state 13C nuclear magnetic resonance (solid-state 13C NMR), and proton NMR relaxation experiments. By means of DSC, C60H122 molecules in C60H122/silica composites were observed to be involved in the interfacial freezing not present in the free bulk C60H122. The orientation of C60H122 molecules, being preferentially normal to silica surface, was confirmed by grazing incidence X-ray diffraction experiments on thin n hexacontane film adsorbed on the silicon wafer with a native SiO2 layer. Inferred from the solid 13C NMR data, the interfacial monolayer is in orthorhombic phase with certain chain disorders. It is speculated that the "interfacial freezing" of C60H122 formed in the presence of silica particles is driven by the combination of the strong attraction between the molecules and the enhanced number of interfacial molecules on the silica surface. PMID- 28629216 TI - Amphiphilic Antifogging/Anti-Icing Coatings Containing POSS-PDMAEMA-b-PSBMA. AB - Highly transparent antifogging/anti-icing coatings were developed from amphiphilic block copolymers of polyhedral oligomeric silsesquioxane-poly[2 (dimethylamino)ethyl methacrylate]-block-poly(sulfobetaine methacrylate) (POSS PDMAEMA-b-PSBMA) with a small amount of ethylene glycol dimethacrylate (EGDMA) via UV-curing. The excellent antifogging properties of the prepared coatings were originated from the hygroscopicity of both PDMAEMA and PSBMA blocks in the semi interpenetrating polymer network (SIPN) with polymerization of EGDMA and hydrophobic POSS clusters aggregated on the surface. PDMAEMA with a lower critical solution temperature and PSBMA with an upper critical solution temperature in the block copolymers facilitated dispersion and absorption of water molecules into the SIPN coatings, fulfilling the enhanced antifogging function. Analysis of differential scanning calorimetry further confirmed that there was bond water and nonfreezable bond water in the SIPN coatings. The amphiphilic SIPN coatings exhibited the anti-icing ability with a freezing delay time of more than 2 min at -15 degrees C, owing to the aggregation of hydrophobic POSS groups and the self-lubricating aqueous layer generated by nonfreezable bond water on the surface. The prepared transparent antifogging/anti icing coatings could have novel potential applications in practice. PMID- 28629217 TI - Ultrasensitive Pressure Sensor Based on an Ultralight Sparkling Graphene Block. AB - Herein, we develop a supersensitive pressure sensor based on a fully air-bubbled ultralight graphene block through a simple sparkling strategy. The obtained sparkling graphene block (SGB) exhibits excellent elasticity even at 95% compressive strain and rebounds a steel ball with an ultrafast recovery speed (~1085 mm s-1). Particularly, the SGB-based sensor reveals a record pressure sensitivity of 229.8 kPa-1, much higher than other graphene materials, because of the highly cavity-branched internal structure. Impressively, the pressure sensor can detect the extremely gentle pressures even beyond the real human skin and hence are promising for ultrasensitive sensing applications. PMID- 28629218 TI - Two-Dimensional Plasmonic Nanoparticle as a Nanoscale Sensor to Probe Polymer Brush Formation. AB - Conventional analysis and characterization of polymer brush formation relies on laborious methods that use a quartz crystal microbalance, atomic force microscope, microcantilever, or other tools that measure the concentration change of solutions. Herein we develop a simple and easy method that utilizes intrinsically flat two-dimensional (2D) plasmonic nanoparticles as sensors for unveiling the mechanism of polymer brush formation on surfaces. Via ultraviolet visible spectroscopy, the plasmonic nanoparticles can be used to determine the amount of polymers near the surface in situ. As the amount of polymers increases near the surface, the nanoparticle characteristic localized surface plasmon resonance wavelength redshifts, and the shift amount corresponds linearly to the polymer density near the surface. By functionalizing the nanoparticles in solutions of thiolated polyethylene glycol (PEG-SH) with or without PEG disulfide (PEG-S-S-PEG), the three-regime kinetics of the polymer brush formation is confirmed. The fast adsorption and slow chain rearrangement in the first regime are found to be the causes of the latent regime. In the latent regime, the adsorbed polymer chains rearrange to anchor their ends onto the surface and contract to liberate space so that other polymer chains can graft onto the surface until saturation. The fundamental understanding gained herein enables the design of surfaces with complex chemistries and properties, which can find broad applications in responsive sensors, films, and coatings. Moreover, the novel analytical method of using 2D plasmonic nanoparticle as a sensor to understand the polymer brush formation is applicable to investigating the grafting of other molecules such as self-assembled monolayers, protein, and DNA. PMID- 28629219 TI - Thermally Induced Generation of Desirable Aroma-Active Compounds from the Glucosinolate Sinigrin. AB - Glucosinolates are the most abundant secondary sulfur-containing plant metabolites in the plant family of Brassicaceae. These phytochemicals are well known for their enzymatic degradation induced by the enzyme myrosinase, resulting in pungent odor impressions derived from their respective degradation products. However, up to now, only little attention has been paid to non-enzymatic thermal degradation and the release of additional aroma-active compounds. Thermal treatment is particularly important in the processing of Brassica vegetables, and thereby, glucosinolates as precursors can act as a natural source of odorants. Application of gas chromatography-olfactometry to the volatile fractions obtained after heat treatment of sinigrin (2-propenyl glucosinolate) in different matrices (phosphate buffer at a pH value of 5, 7, or 9, silicon oil, silica gel (7% water), sea sand, and glycerol) showed a high potential to generate aroma-active compounds, mainly revealing onion- and garlic-like odor impressions deriving from sulfur-containing odorants. A clear dependency of the formation of desired aroma active compounds upon the respective matrix was found, indicating the need of detailed investigations to obtain knowledge for the best use of glucosinolates as a source of natural aroma compositions. For example, the distillate obtained from sinigrin heat-processed in buffer solution at pH 7 led to the identification of 17 odorants. PMID- 28629220 TI - Ring Polymer Surface Hopping: Incorporating Nuclear Quantum Effects into Nonadiabatic Molecular Dynamics Simulations. AB - We apply a recently proposed ring polymer surface hopping (RPSH) approach to investigate the real-time nonadiabatic dynamics with explicit nuclear quantum effects. The nonadibatic electronic transitions are described through Tully's fewest-switches surface hopping algorithm and the motion of the nuclei are quantized through the ring polymer Hamiltonian in the extended phase space. Applying the RPSH method to simulate Tully's avoided crossing models, we demonstrate the critical role of the nuclear tunneling effect and zero-point energy for accurately describing the transmission and reflection probabilities with low initial momenta. In addition, in Tully's extended coupling model, we show that the ring polymer quantization effectively captures decoherence, yielding more accurate reflection probabilities. These promising results demonstrate the potential of using RPSH as an accurate and efficient method to incorporate nuclear quantum effects into nonadiabatic dynamics simulations. PMID- 28629221 TI - Extracted apocarotenoids from saffron stigmas and evaluated the quality of saffron. AB - Saffron is a kind of expensive spice and therapeutic agent. In order to establish a set of methods to evaluate the quality of saffron, High Performance Liquid Chromatography/Mass Spectrometry (HPLC/MS) were used to identify the apocarotenoids extracted from saffron stigmas. TOPSIS method was applied to evaluate the qualities of saffron. The conditions of HPLC/MS and chemical fingerprints of saffron had been established. The 14 chromatographic peaks and 13 main apocarotenoids of saffron with high reproducibility, stability and specificity were confirmed. The qualities of 40 kinds of saffron from different countries and regions were ranked. PMID- 28629222 TI - Associations of Parental Self-Efficacy With Diet, Physical Activity, Body Composition, and Cardiorespiratory Fitness in Swedish Preschoolers: Results From the MINISTOP Trial. AB - BACKGROUND: High parental self-efficacy (PSE) has been associated with healthy diets and higher levels of physical activity (PA) in children; however, data on PSE in relation to body weight and body composition are scarce. The objective of this study was to investigate associations of PSE with measures of diet, PA, body composition, and physical fitness in early childhood. METHOD: We used baseline data from the MINISTOP trial in healthy Swedish children ( n = 301; 4.5 +/- 0.15 years). PSE was assessed using a questionnaire, dietary data were collected using a mobile technology-assisted methodology, and PA was obtained (sedentary behavior and moderate-to-vigorous) by accelerometry. Body composition was measured using the pediatric option for BodPod and cardiorespiratory fitness by the 20 m shuttle run. Linear regression was conducted to evaluate cross-sectional associations of the outcomes in relation to total PSE and scores computed for the individual PSE factors: (1) diet, (2) limit setting of unhealthful behaviors, and (3) PA. RESULTS: Higher scores of total PSE and the diet factor were associated with higher fruit intake (beta = 0.82 g/point and 1.99 g/point; p = .014 and .009, respectively) and lower consumption of unhealthy snacks (beta = -0.42 g/point and -0.89 g/point; p = .012 and .020, respectively) after adjustment for parental body mass index and education, respondent, and child's sex and age. No associations were observed between PSE and PA, body composition, or cardiorespiratory fitness. CONCLUSIONS: Our study noted that PSE should be considered in conjunction with other strategies for a sustainable impact on childhood obesity. PMID- 28629223 TI - Essential oil composition of Erica spiculifolia Salisb - first report. AB - The essential oil isolated from Erica spiculifolia Salisb. by hydrodistillation was analysed by GC-MS. One hundred compounds representing 92.6% of total oil were identified. Among the detected compounds 38 were monoterpenoids (46.2%), 30 were sesquiterpenoids (31.7%), 2 diterpene (0.4%) and 30 compounds (14.3%) were with various non-terpenoid structures. Oxygenated monoerpenes were by far the main class (45.3%) with alpha-terpineol (7.5%) endo-borneol (7.2%), pinocarveol (5.9%) and thymol (3.7%) as the major compounds. The predominant components of sesquiterpenes were caryophyllene oxide (5.0%), caryophyllene (4.2%), tau murrolol (3.5%), spathulenol (2.9) and alpha-cadinol (2.3%). PMID- 28629224 TI - "It's not my business": Exploring heteronormativity in young people's discourses about lesbian, gay, bisexual, transgender, and queer issues and their implications for youth health and wellbeing. AB - In Canada, the issue of creating safe and inclusive school environments for lesbian, gay, bisexual, transgender, and queer students has been in the spotlight. Several researchers and advocates have pointed out the positive effects of lesbian, gay, bisexual, transgender, and queer-positive policy frameworks on the health and wellbeing of all young people. In this article, we take a critical approach to analyzing narrative findings from qualitative interviews conducted with youth in three communities in British Columbia, Canada: "the North," Vancouver, and Abbotsford. Using a Foucauldian Discourse Analytic Approach and Butler's concept of Citationality, our analysis suggested that although explicit homophobia was largely absent from youth discussions, young people discursively constructed lesbian, gay, bisexual, transgender, and queer identities and "communities" in ways that reified heteronormativity. Youth made references to sociopolitical discourses of libertarianism and liberalism and to homonormative stereotypes regarding gay masculinity. A few young people also alluded to egalitarian, queer-positive discourses, which appeared to interrogate structures of heteronormativity. Since studies suggest a connection between the existence of institutional supports for lesbian, gay, bisexual, transgender, and queer students in schools and their mental and physical wellbeing, we conclude by considering the limitations and possibilities of these sociopolitical discourses in the struggle for sexual and gender equity, and how they might help frame future health-related, anti-homophobia policy frameworks in educational settings. PMID- 28629226 TI - No significant impact of Foxf1 siRNA treatment in acute and chronic CCl4 liver injury. AB - Chronic liver injury of any etiology is the main trigger of fibrogenic responses and thought to be mediated by hepatic stellate cells. Herein, activating transcription factors like forkhead box f1 are described to stimulate pro fibrogenic genes in hepatic stellate cells. By using a liver-specific siRNA delivery system (DBTC), we evaluated whether forkhead box f1 siRNA treatment exhibit beneficial effects in murine models of acute and chronic CCl4-induced liver injury. Systemic administration of DBTC-forkhead box f1 siRNA in mice was only sufficient to silence forkhead box f1 in acute CCl4 model, but was not able to attenuate liver injury as measured by liver enzymes and necrotic liver cell area. Therapeutic treatment of mice with DBTC-forkhead box f1 siRNA upon chronic CCl4 exposition failed to inhibit forkhead box f1 expression and hence lacked to diminish hepatic stellate cells activation or fibrosis development. As a conclusion, DBTC-forkhead box f1 siRNA reduced forkhead box f1 expression in a model of acute but not chronic toxic liver injury and showed no positive effects in either of these mice models. Impact statement As liver fibrosis is a worldwide health problem, antifibrotic therapeutic strategies are urgently needed. Therefore, further developments of new technologies including validation in different experimental models of liver disease are essential. Since activation of hepatic stellate cells is a key event upon liver injury, the activating transcription factor forkhead box f1 (Foxf1) represents a potential target gene. Previously, we evaluated Foxf1 silencing by a liver-specific siRNA delivery system (DBTC), exerting beneficial effects in cholestasis. The present study was designed to confirm the therapeutic potential of Foxf1 siRNA in models of acute and chronic CCl4-induced liver injury. DBTC-Foxf1 siRNA was only sufficient to silence Foxf1 in acute CCl4 model and did not ameliorate liver injury or fibrogenesis. This underlines the significance of the experimental model used. Each model displays specific characteristics in the pathogenic nature, time course and severity of fibrosis and the optimal time point for starting a therapy. PMID- 28629228 TI - Use of Provider Debriefing to Improve Fast-Track Extubation Rates Following Cardiac Surgery at an Academic Medical Center. AB - When used in appropriate patient populations, fast-track extubation (FTE) anesthetic techniques and intensive care unit (ICU) protocols safely reduce intubation times, ICU length of stay, and resource utilization. The authors hypothesized that perioperative provider debriefing on success or failure of FTE would improve FTE success. This retrospective observational study included consecutive patients undergoing elective coronary artery bypass graft (CABG), valve, or combined CABG/valve surgery between February 2015 and May 2016 (N = 313). Throughout the intervention period, a briefing was distributed on postoperative day 1 to the anesthesiology providers responsible for operative care of the patient detailing success or failure of FTE and perioperative characteristics. The preintervention FTE success rate of 55.6% significantly improved to 72.8% in the intervention group ( P = .022). When combined with a continuous interdepartmental review process, provider debriefing improved FTE success. Perioperative provider debriefing requires minimal resources for implementation and can easily be replicated in other cardiac surgery centers. PMID- 28629227 TI - Chemical and biological studies on Cichorium intybus L. AB - Cichorium intybus L. (Asteraceae family) is a world-wide grown plant known as chicory. In traditional medicine, this plant is used as diuretic, anti inflammatory, digestive, cardiotonic and liver tonic. Chromatographic purification of the supercritical fluid extract of aerial parts of C. intybus on silica gel column led to isolation of three compounds: new compound, 28beta hydroxytaraxasterol (I), and two known compounds usnic acid (II) and beta sitosterol (III). Purification of the ethanolic extract of aerial parts of this plant on silica gel column chromatography yielded four compounds: 1,3 dioleylglycerate (IV), sitoindoside II (V), 11beta-13-dihydrolactucin (VI) and beta-sitosterol-3-O-glucoside (VII). The structures of the isolated compounds were determined by their 1D, 2D NMR and MS spectral data. All the fractions and isolated compounds were tested for cannabinoid and opioid receptor binding, as well as antibacterial, antifungal and antimalarial activities. Compound I showed moderate activity (60.5% displacement) towards CB1 receptor. PMID- 28629225 TI - Cortical Plasticity in Depression. AB - Neural plasticity is considered the neurophysiological correlate of learning and memory, although several studies have also noted that it plays crucial roles in a number of neurological and psychiatric diseases. Indeed, impaired brain plasticity may be one of the pathophysiological mechanisms that underlies both cognitive decline and major depression. Moreover, a degree of cognitive impairment is frequently observed throughout the clinical spectrum of mood disorders, and the relationship between depression and cognition is often bidirectional. However, most evidence for dysfunctional neural plasticity in depression has been indirect. Transcranial magnetic stimulation has emerged as a noninvasive tool for investigating several parameters of cortical excitability with the aim of exploring the functions of different neurotransmission pathways and for probing in vivo plasticity in both healthy humans and those with pathological conditions. In particular, depressed patients exhibit a significant interhemispheric difference in motor cortex excitability, an imbalanced inhibitory or excitatory intracortical neurochemical circuitry, reduced postexercise facilitation, and an impaired long-term potentiation-like response to paired-associative transcranial magnetic stimulation, and these symptoms may indicate disrupted plasticity. Research aimed at disentangling the mechanism by which neuroplasticity plays a role in the pathological processes that lead to depression and evaluating the effects of modulating neuroplasticity are needed for the field to facilitate more powerful translational research studies and identify novel therapeutic targets. PMID- 28629229 TI - Colistin resistance associated with outer membrane protein change in Klebsiella pneumoniae and Enterobacter asburiae. AB - In this study, outer membrane proteins (OMPs) of colistin-resistant Klebsiella pneumoniae and Enterobacter asburiae were analyzed. One colistin-susceptible and three colistin-resistant K. pneumoniae sequence type 258 strains as well as one colistin-susceptible E. asburiae and its colistin-heteroresistant counterpart strain were involved in the study. OMP analysis of each strain was performed by microchip method. Matrix-assisted laser desorption ionization time of flight/mass spectrometry (MALDI-TOF/MS) investigation was carried out after separation of OMPs by two-dimensional gel electrophoresis and in-gel digestion. The MALDI TOF/MS analysis of OMPs in the colistin-susceptible K. pneumoniae found 16 kDa proteins belonging to the LysM domain/BON superfamily, as well as DNA starvation proteins, whereas OmpX and OmpW were detected in the colistin-resistant counterpart strains. OmpC and OmpW were detected in the colistin-susceptible E. asburiae, whereas OmpA and OmpX were identified in the colistin-resistant counterpart. This study demonstrated that OMP differences were between colistin susceptible and -resistant counterpart strains. The altered Gram-negative cell wall may contribute to acquired colistin resistance in Enterobacteriaceae. PMID- 28629213 TI - Survival of cancer patients in Italy. AB - OBJECTIVES: Population-based survival statistics are fundamental to assess the efficacy of services offered to improve cancer patients' prognosis. This study aims to update cancer survival estimates for the Italian population, as well as provide new measures, such as the crude probability of death, which takes into account the possibility of dying from causes other than cancer, and the change in life expectancy after a cancer diagnosis, to properly address various questions. RESULTS: The study includes 1,932,450 cancer cases detected by the Network of Italian Cancer Registries (AIRTUM) from 1994 to 2011 and provides estimates for 38 cancer sites and for allsites cancer. For most common cancers diagnosed from 2005 to 2009, age-standardized 5-year net survival was: colon-rectum - males 65%, females 65%; lung - males 15%, females 19%; breast 87%; prostate 91%. For cancer sites such as stomach, colon, rectum, lung, skin melanoma, breast, cervix, prostate, and kidney, 5-year net survival is consistent between Central and Northern Italy, while it is a few percentage points lower in Southern Italy. Funnel plots expose these differences more in detail by showing the survival estimates in 13 Italian regions. For all sites but skin, 5- and 10-year net survival increased by about 10 percentage points in men and 7 points in women from 1994 to 2011. DISCUSSION: Specific articles deal with results on solid and haematological malignancies, international comparisons and analysis of time trends of incidence, mortality, and survival in combination for key cancer sites, aiming to interpret overall progress in the control of cancer in Italy. PMID- 28629230 TI - Association between Toxoplasma gondii types and outcomes of human infection: A meta-analysis. AB - The virulence and pathogenicity of various types of Toxoplasma gondii differ considerably in mice. Recent studies have claimed that similar phenomenon was observed in humans, but no relevant studies have been performed to validate this finding. In addition, reports showing association between a given T. gondii type and outcomes of human infection yielded conflicting results. To provide a more precise estimation of the association and a more reliable conclusion on this subject, we performed this meta-analysis. Relevant literatures were identified in multiple databases and selected based on strict screening. T. gondii-type proportions among different severities of infection were calculated and compared using Fisher's exact test. Pooled odds ratios (OR) were calculated. Our results showed that the difference among T. gondii-type proportions was significant (p < 0.0001). In addition, significant associations were detected between Type I strains infection and congenital toxoplasmosis (OR: 1.91, p = 0.0009), Type III strains infection and pulmonary toxoplasmosis (OR: 5.15, p = 0.04). In our subgroup analysis, Type I strains were significantly associated with cerebral toxoplasmosis in offspring (OR: 1.81, p = 0.02). This result indicated that different types of T. gondii exhibited different virulence and caused different outcomes in humans. PMID- 28629231 TI - Comment on Paranasal sinus opacification in headache sufferers: A population based imaging study (the HUNT study-MRI). PMID- 28629232 TI - Latent Profile Analysis of the Five Facet Mindfulness Questionnaire in a Sample With a History of Recurrent Depression. AB - BACKGROUND: Extending previous research, we applied latent profile analysis in a sample of adults with a history of recurrent depression to identify subgroups with distinct response profiles on the Five Facet Mindfulness Questionnaire and understand how these relate to psychological functioning. METHOD: The sample was randomly divided into two subsamples to first examine the optimal number of latent profiles (test sample; n = 343) and then validate the identified solution (validation sample; n = 340). RESULTS: In both test and validation samples, a four-profile solution was revealed where two profiles mapped broadly onto those previously identified in nonclinical samples: "high mindfulness" and "nonjudgmentally aware." Two additional subgroups, "moderate mindfulness" and "very low mindfulness," were observed. "High mindfulness" was associated with the most adaptive psychological functioning and "very low mindfulness" with the least adaptive. CONCLUSIONS: In most people with recurrent depression, mindfulness skills are expressed evenly across different domains. However, in a small minority a meaningful and replicable uneven profile indicating nonjudgmental awareness is observable. Current findings require replication and future research should examine the extent to which profiles change from periods of wellness to illness in people with recurrent depression and how profiles are influenced by exposure to mindfulness-based intervention. PMID- 28629233 TI - A new antibiotic produced by the cyanobacterium-symbiotic fungus Simplicillium lanosoniveum. AB - The culture broth of the cyanobacterium-symbiotic fungus Simplicillium lanosoniveum var. Tianjinienss Q. L. Dong exhibited unanticipated antibacterial activities against the Gram-positive bacteria, particularly the pathogenic bacterium Staphylococcus aureus, indicating the secretion of antibiotic-like metabolite, for which the modified Sabouraud medium was the suitable medium. The antibiotic-like metabolite was separated with macroporous resins CT-12 (absorption) and 95% ethanol (desorption), purified by ion-exchange resins D301T and displayed a characteristic absorption peak at 228 nm, suggesting the presence of nitrogen. The negative biuret and ninhydrin tests confirmed the absence of NH2 and -COOH groups. Further, HPLC and mass spectrometry analyses showed that the retention time and molecular weight of the antibiotic-like metabolite were 4.1031 min and 163.0182 (Delta +/- 2.3 ppm), respectively. Taking together, we speculated that the antibiotic-like metabolite was a new antibiotic structurally similar to alkaloid, which was the first one isolated from the species of Simplicillium genus. PMID- 28629234 TI - Healing of Osteochondral Defects via Endochondral Ossification in an Ovine Model. AB - OBJECTIVE: The objective of this study was to describe the mechanism of healing of osteochondral defects of the distal femur in the sheep, a commonly used translational model. Information on the healing mechanism be useful to inform the design of tissue engineering devices for joint surface defect repair. DESIGN: A retrospective study was conducted examining 7-mm diameter osteochondral defects made in the distal medial femoral condyle of 40 adult female sheep, comprising control animals from 3 separate structures. The healing of the defects was studied at post mortem at up to 26 weeks. RESULTS: Osteochondral defects of the distal femur of the sheep heal through endochondral ossification as evidenced by chondrocyte hypertrophy and type X collagen expression. Neocartilage is first formed adjacent to damaged cartilage and then streams over the damaged underlying bone before filling the defect from the base upward. No intramembranous ossification or isolated mesenchymal stem cell aggregates were detected in the healing tissue. No osseous hypertrophy was detected in the defects. CONCLUSIONS: Osteochondral defects of the medial femoral condyle of the sheep heal via endochondral ossification, with neocartilage first appearing adjacent to damaged cartilage. Unlike the mechanism of healing in fracture repair, neocartilage is eventually formed directly onto damaged bone. There was most variability between animals between 8 and 12 weeks postsurgery. These results should be considered when designing devices to promote defect healing. PMID- 28629235 TI - Atrial fibrillation as a complication of ibrutinib therapy: clinical features and challenges of management. AB - Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor finding increasingly widespread use in non-Hodgkin lymphoma. Evidence of an increased risk of atrial fibrillation (AF) emerged in Phase III studies with a median incidence of approximately 6%. The mechanism remains unknown, but inhibition of a cardioprotective pathway has been proposed. Ibrutinib induces a platelet function defect, increasing the bleeding risk of anticoagulation for AF stroke prophylaxis. Multiple potential drug interactions are an added complication. In this review we examine the characteristics and management of the reported cases of AF with ibrutinib and where possible make recommendations. The evidence suggests dose reduction or temporary suspension of drug, are feasible alternative to discontinuation. The optimum choice of thromboprophylaxis has not been determined, but we propose the use of novel anticoagulants (NOACs) and avoidance of anti-platelet agents where possible. Further research and consensus guidelines are required. PMID- 28629236 TI - Advances in new psychoactive substances identification: the U.R.I.To.N. Consortium. AB - Identification of new psychoactive substances (NPS) in biological and non biological samples represents a hard challenge for forensic toxicologists. Their great chemical variety and the speed with which new NPS are synthesised and spread make stringent the need of advanced tools for their detection based on multidisciplinary approaches. For this reason, in August 2016, the "Unit of Research and Innovation in Forensic Toxicology and Neuroscience of Addiction" (U.R.I.To.N.) was founded by the Forensic Toxicology Division of the University of Florence. In this Research Unit, various professionals (i.e. forensic toxicologists, chemists, physicians) collaborate to study all the aspects of drugs of abuse, especially NPS. Herein, we describe the multidisciplinary approach comprising liquid chromatography coupled to tandem mass spectrometry (LC MS/MS), gas chromatography hyphenated to mass spectrometry (GC-MS) and solution nuclear magnetic resonance analysis that allowed the identification of three NPS such as 1-(benzofuran-5-yl)-N-methylpropan-2-amine, 2-amino-1-(4-bromo-2,5 dimethoxyphenyl)ethan-1-one (bk-2C-B), and 3-(2-aminopropyl)indole (alpha methyltryptamine) in seized materials. PMID- 28629237 TI - Improved pregnancy outcome following earlier splenectomy in women with immune thrombocytopenia: a 5-year observational study. AB - OBJECTIVE: To assess prospectively the maternal and fetal outcome in women with immune thrombocytopenic purpura (ITP) who undergone earlier splenectomy compared to women on medical therapy. METHODS: A 5-year observational study included pregnant women in the first trimester previously diagnosed with primary ITP with 74 patients underwent splenectomy before pregnancy and 86 patients on medical therapy. Patients were followed throughout pregnancy and labour to record their obstetric outcome. Data were collected and tabulated. RESULTS: There was a higher platelet count in the splenectomy group at enrollment (p < .05) and at delivery (p < .001). Higher number of patients in the medical group experienced bleeding episodes (p < .001), severe thrombocytopenia (p < .001), need for therapy (p < .001), complications of steroid therapy (p < .05), postpartum hemorrhage (p < .05), and defective lactation (p < .001) compared to patients in the splenectomy group. Higher rates of small for gestational age, preterm labour, and admission to neonatal intensive care unit (NICU) were observed in patients in the medical group (p < .05) compared to patients in the splenectomy group. CONCLUSION: Earlier splenectomy in patients with ITP may have a beneficial impact on obstetric outcome and should be explained to patients wishing to get pregnant. Further larger multicenter studies are warranted to confirm or refute our findings. PMID- 28629238 TI - US trends in abortion and preterm birth. AB - BACKGROUND: A recent large meta-analysis concluded that prior surgical abortion was an independent risk factor for spontaneous preterm birth (PTB), while they found no significant correlation between PTB and medical abortion. OBJECTIVE: To evaluate the potential impact of changes in US abortion rates and practices on US incidence of PTB rate. STUDY DESIGN: This was an epidemiologic analysis of legal abortion and PTB data in the USA from 2003 to 2012. Birth data (annual total birth, annual number and incidence of PTB, defined as PTB <37 weeks) are from National Vital Statistics Reports from the National Center for Health Statistics, Center of Disease Control and Prevention (CDC). Abortion data were collected using Abortion Surveillance provided by the CDC. Abortion incidence was reported overall, and by type: surgical, medical method and procedures reported as "other" such as intrauterine instillation and hysterectomy/hysterotomy. To test for the trend of abortion and of PTB over time, we used the chi-squared test for trend. The primary outcome of our study was the correlation trend analysis between abortion rate and PTB rate. Pearson correlation test was used. A two-tailed p value of 0.05 or less was considered significant. RESULTS: From 2003 to 2012 there were 41 206 315 births in USA, of which 5 042 982 (12.2%) were <37 weeks. The PTB rate declined significantly from 12.3% in 2003 to 11.5% in 2012 (p value test for trend <.04). Out of the 6 122 649 legal abortions, reported by type of procedure, performed from 2003 to 2012 in USA, 5 132 789 were surgical abortion (82.8%) and 860 288 (14.0%) were medical. Chi-squared test for trend showed that the rate of surgical abortion significantly decreased from 88.9 to 78.0% (p < .01) while the rate of medical abortion significantly increased from 7.9 to 21.9% (p < .01) from 2003 to 2012, respectively. The rate of PTB was correlated with the rate of medical abortion (p = .01) and of surgical abortion (p = .02) over time. The higher the surgical abortion rate, the higher the incidence of PTB (Pearson correlation 0.712); the higher the medical abortion rate, the lower the incidence of PTB (Pearson correlation -0.731). CONCLUSION: Recent changes in abortion practices may be associated with the current decrease in US incidence of PTB. Further study on the effect of surgical versus medical abortion is warranted regarding a possible effect on the incidence of PTB. PMID- 28629239 TI - Cortisol precursors in neonates with vasopressor-resistant hypotension in relationship to demographic characteristics. AB - OBJECTIVE: To correlate between cortisol precursors in neonates with vasopressor resistant hypotension and demographic characteristics. METHODS: We investigated 48 neonates with vasopressor-resistant hypotension. Gestation at birth ranged from 34 to 42 weeks and postnatal age from 4 to 14 days. Cortisol and precursor steroids were measured soon after the onset of volume expansion and inotropes for treatment of shock. Their concentrations were determined using liquid chromatography/mass spectrometry. RESULTS: In neonates with vasopressor-resistant hypotension, the serum levels of cortisol were within normal nonstress range. There was a strong negative linear association between postnatal age and dehydroepiandrosterone level (r = -0.50, p < .01), which decreased with neonatal age. In addition, there was a significant positive association between gestational age at birth and 17-hydroxy-pregnenolone (r = 0.33, p = .02). No further significant associations were evident between the neonatal weight, duration of gestation or gender and of the levels of cortisol or the other steroids (p > .05). The cause of therapy-resistant hypotension did not appear to influence the steroid levels. CONCLUSIONS: Cortisol stress response is absent in these severely ill late preterm and term infants. This may be due to inhibition of the distal pathway of cortisol synthesis. PMID- 28629240 TI - Foetoscopic endotracheal occlusion (FETO) for severe isolated left-sided congenital diaphragmatic hernia: single center Polish experience. AB - OBJECTIVE: To present early experience with foetoscopic endotracheal occlusion (FETO) for congenital diaphragmatic hernia (CDH) in a new center in Poland. METHODS: This was a prospective study in singleton pregnancies with CDH treated by FETO between 2014 and 2016 in the Medical University of Warsaw, Poland. FETO was carried out at 25.6-30.1 (median 27.7) weeks' gestation in 28 consecutive cases of isolated left-sided CDH with observed over expected lung area to head circumference ratio (o/e LHR) of 20.7-22.6 (median 18.9). RESULTS: Neonatal survival rate was 46.4% (13/28) at the time of discharge. The median o/e LHR the day before balloon removal was 33.4 (19.7-57.5) and median gestational age at delivery was 34.7 (29.0-38.1) weeks. Comparison of the survivors and perinatal deaths showed no significant differences in median gestational age at FETO or median o/e LHR before FETO, but higher median gestational age at delivery (35.9, range 32.7-38.1 weeks vs. 33.2, range 29.0-37.7 weeks; p = .007) and o/e LHR before balloon removal (33.7, range 28.3-57.5 vs. 30.9, range 19.7-37.5; p = .017). CONCLUSIONS: FETO was implemented successfully in Poland and the survival rate (46.4%) is similar to that reported in other centers. Important determinants of survival were gestational age at delivery and pulmonary response to FETO. The rate of preterm prelabor rupture of membranes (PPROM) in our series is similar to the larger series treated with FETO in the pioneering centers of this technique. PMID- 28629241 TI - A model to predict risk of postpartum infection after Caesarean delivery. AB - PURPOSE: The purpose of this study is to build and validate a statistical model to predict infection after caesarean delivery (CD). METHODS: Patient and surgical variables within 30 d of CD were collected on 2419 women. Postpartum infection included surgical site infection, urinary tract infection, endomyometritis and pneumonia. The data were split into model development and internal validation (1 January-31 August; N = 1641) and temporal validation subsets (1 September-31 December; N = 778). Logistic regression models were fit to the data with concordance index and calibration curves used to assess accuracy. Internal validation was performed with bootstrapping correcting for bias. RESULTS: Postoperative infection occurred in 8% (95% CI 7.3-9.9), with 5% meeting CDC criteria for surgical site infections (SSI) (95% CI 4.1-5.8). Eight variables were predictive for infection: increasing BMI, higher number of prior Caesarean deliveries, emergent Caesarean delivery, Caesarean for failure to progress, skin closure using stainless steel staples, chorioamnionitis, maternal asthma and lower gestational age. The model discriminated between women with and without infection on internal validation (concordance index = 0.71 95% CI 0.67-0.76) and temporal validation (concordance index = 0.70, 95% CI 0.62, 0.78). CONCLUSIONS: Our model accurately predicts risk of infection after CD. Identification of patients at risk for postoperative infection allows for individualized patient care and counseling. PMID- 28629242 TI - Differential effect of p38 and MK2 kinase inhibitors on the inflammatory and toxicity biomarkers in vitro. AB - BACKGROUND: Many inflammatory responses including chemotaxis, production of nitric oxide, and modulation of pro-inflammatory cytokines in immunological cells are mediated by p38MAPK. Due to its pivotal role, p38MAPK has been extensively explored as a molecular target for inhibition of chronic inflammation; however, it has not been successful so far due to serious toxicity issues. Among several downstream substrates of p38, mitogen-activated protein kinase-activated protein kinase 2 (MK2) has been reported to be a direct and essential downstream component in regulation of innate immune and inflammatory responses. Thus, in this study, we aimed to understand relative molecular differences between p38 and MK2 kinase inhibition in terms of a comparative anti-inflammatory potential along with molecular regulation of toxicity biomarkers such as Phospho c-Jun N-Terminal Kinase (pJNK), caspase-3, and hepatic enzyme levels in relevant human cells in vitro. RESULTS: Both p38 and MK2 inhibitors attenuated lipopolysaccharide-induced pro-inflammatory biomarkers expression. In addition, both these kinase inhibitors inhibited release of Th1 and Th17 cytokines in phytohemagglutinin-induced cells with MK2 inhibitor showing a better potency for inhibition of Th1 cytokine release, interferon-gamma. In the mechanistic differentiation studies, p38 inhibitors displayed an increase in pJNK and caspase-3 activity in U937 cells and elevation in aspartate transaminase enzyme in HepG2 cells, whereas MK2 inhibitor did not show such adverse toxic effects. CONCLUSION: Taken together, inhibition of MK2 kinase can be a relatively preferred strategy as an anti-inflammatory therapy over direct inhibition of p38 kinase in p38MAPK pathway. PMID- 28629243 TI - Effect of therapeutic hypothermia on myocardial dysfunction in term neonates with perinatal asphyxia - a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of therapeutic hypothermia on myocardial dysfunction in term neonates with perinatal asphyxia. MATERIAL AND METHODS: This randomized controlled trial (RCT) conducted in a tertiary care teaching hospital, south India included 120 newborns with perinatal asphyxia that were randomized to two groups (therapeutic hypothermia and normothermia). Cardiac enzyme profile changes between groups were assessed at 0, 24, 72 h CPK-MB and troponin I levels were estimated by immune inhibition and quantitative immunochromatography methods, respectively. Electrocardiography (ECG) and Echocardiography (ECHO) were done at 0 and 72 h to evaluate the cardiac function and pulmonary hypertension. Neurodevelopment was assessed at 6 months of age in both groups using Developmental Assessment Scales for Indian Infants. RESULTS: The median values of CPK-MB in the normothermia and hypothermia groups at 0, 24, and 72 h were 198, 127, and 92 IU/L and 202, 111 and 64 IU/L, respectively. The median values of troponin I in normothermia and hypothermia groups at 0, 24, and 72 hrs were 2.45, 1.53, and 0.9 ng/mL and 1.97, 0.93, and 0.01 ng/mL, respectively. ECG and ECHO findings also suggest lesser myocardial dysfunction in therapeutic hypothermia group compared with the normothermia group. CONCLUSIONS: Therapeutic hypothermia significantly decreases the myocardial damage in term asphyxiated neonates. PMID- 28629244 TI - Will we be able to afford a cure in multiple myeloma? PMID- 28629245 TI - Obstetric risk factors for poor neonatal adaptation at birth. AB - PURPOSE: To identify obstetric risk factors of delivering a neonate with poor neonatal adaptation at birth. MATERIAL AND METHODS: Nested case-control study. Poor neonatal adaptation was defined for presence of at least: umbilical cord artery pH <7.10, base deficit >=12 mmol/L, Apgar score at 1' <=5. Controls were selected from the same population and matched with cases. The association between clinical parameters and poor neonatal adaptation was analyzed by logistic regression. RESULTS: One hundred and thirty three women (2.1% of all live births) with a neonate presenting a poor neonatal adaptation were matched with 133 subsequent controls. Significant contributions for the prediction of poor neonatal adaptation were provided by maternal age >=35 years (p <= .001, odds ratio (OR) 3.9 [95%CI: 2.3-6.8]), nulliparity (p <= .001, OR 3.3 [95%CI: 1.8-6]), complications during pregnancy (p = .032, OR 2.2 [95%CI: 1.1-4.4]), gestational age at delivery <37 weeks (p = .008, OR 5.2 [95%CI: 1.5-17.8]) and cardiotocography category II or III (p <= .001, OR 36.3 [95%CI: 16.5-80.1]). The receiver operative characteristic curve was 0.91 [95%CI: 0.87-0.95], and detection rates 82.7% and 89.5% at 10% and 20% of false positive rates, respectively. CONCLUSIONS: Several obstetric risk factors before and during labor can identify a subgroup of newborns at higher risk of a poor neonatal adaptation at birth. PMID- 28629246 TI - Clinical significance of primary symptoms in women with placental abruption. AB - BACKGROUND: To evaluate the clinical significance of primary symptoms in women with placental abruption. METHODS: A retrospective study of 273 cases of placental abruption was performed. The subjects were classified into two groups according to primary symptoms: 210 cases of the vaginal bleeding group and 63 cases of the abdominal pain group. The clinical features, maternal and neonatal outcomes were compared between two groups. RESULTS: The incidence of preeclampsia and preterm birth in the vaginal bleeding group was significantly lower than abdominal pain group, while the incidence of premature rupture of membrane (PROM) in the former group was higher than that in the latter group. Both fetal and maternal outcomes were significantly poorer in the abdominal pain group than in the vaginal bleeding group in terms of rate of abnormal fetal heart monitoring (FHR), concealed abruption, abruption area over 50%, uteroplacental apoplexy, volume of postpartum hemorrhage, rate of blood transfusion, neonatal asphyxia and acidemia. CONCLUSIONS: Primary symptoms of placental abruption were associated with preterm birth, preeclampsia and PROM, which could predict pregnancy outcomes effectively. PMID- 28629247 TI - Obstetric practice patterns in pregnancies complicated by fetal trisomy 13 or 18. AB - PURPOSE: Describe practice patterns among obstetrician/gynecologists (OB/GYNs) when caring for women with pregnancy complicated by fetal trisomy 13 (T13) or 18 (T18) and compare these between maternal-fetal medicine (MFM) and non-MFM providers. MATERIALS AND METHODS: We conducted an electronic survey using the American College of Obstetricians and Gynecologists database. Using simple statistics, we describe demographics and practice patterns among respondents and compare those of MFM practitioners with non-MFM providers. RESULTS: The survey was sent to 300 individuals, 161 individuals verified email receipt, and 105 had complete response and were included. The median age was 58 (IQR 53,62). Sixty percent were female, 69% were private practice, and 38% were MFM. All providers were more likely to offer than to recommend antenatal and intrapartum interventions. MFMs were more likely to offer growth ultrasounds and neonatal hospice consults (53% vs. 29%, p = .02; 88% vs. 60%, p < .01). During labor, MFMs were more likely offer no fetal heart rate monitoring, (90% vs. 52%, p < .01), 60% of all providers offer breech vaginal delivery; 32% offer cesarean delivery for fetal distress. CONCLUSION: Many providers offer antepartum and intrapartum interventions for pregnancies complicated by T13/18. We recommend that providers elicit each woman's goals for pregnancies complicated by T13/18 and tailor management options to meet these goals. PMID- 28629248 TI - The relationship of maternal-fetal attachment and depression with social support in pregnant women referring to health centers of Tabriz-Iran, 2016. AB - PURPOSE: The objective of this study was to determine the relationship of maternal-fetal attachment and depression during pregnancy with social support. METHODS: This cross-sectional study was done on 287 primipara women. The data collection tools used included a demographic characteristics questionnaire, Maternal-Fetal Attachment Scale, the Edinburgh Postnatal Depression Scale and the Social Support Scale. Pearson's correlation test and general linear model were used for data analysis. RESULTS: The mean maternal-fetal attachment score was 90.0 (SD: 10.3). The highest score was obtained in the "role taking" domain and the lowest in the "interaction with the fetus" domain. The mean depression score was 8.5 (SD: 4.0). The score of perceived social support was 135.5 (SD: 15.6). Pearson's correlation test showed a significant positive correlation between social support and maternal-fetal attachment (r = 0.36, p < .001) and a significant negative correlation between social support and depression (r= -0.14, p = .018). CONCLUSION: The present study found a significant relationship between maternal-fetal attachment, depression and social support. It is recommended to devise plans for increasing the support given to women and to improve the society's and families' awareness about these issues in the attempt to have healthy mothers and thereby healthy families and communities. PMID- 28629249 TI - Increase of neuronal injury markers Tau and neurofilament light proteins in umbilical blood after intrapartum asphyxia. AB - AIM: Compare the levels of the brain injury biomarkers Tau and neurofilament light protein (NFL) in cases of asphyxia with those in controls. MATERIALS AND METHODS: We analyzed the neuronal proteins Tau and NFL in umbilical blood of 10 cases of severe-moderate intrapartum asphyxia and in 18 control cases. RESULTS: The levels of both Tau and neurofilament were significantly higher after asphyxia and it appeared to be a correlation between the levels of the biomarkers and the severity of the insult. DISCUSSION: Future studies are warranted to support or refute the value of Tau/NFLin clinical practice. CONCLUSION: Fetal asphyxia remains a clinical problem resulting in life-long neurological disabilities. We urgently need more accurate early predictive markers to direct the clinician when to provide neuroprotective therapy. PMID- 28629250 TI - A comparison between the effects of ginger, pyridoxine (vitamin B6) and placebo for the treatment of the first trimester nausea and vomiting of pregnancy (NVP). AB - INTRODUCTION: Nausea and vomiting of pregnancy (NVP) are one of the most common complains of the early pregnancy period and are bothersome for pregnant women. Some prefer to use herbal medicine instead of chemical agents. OBJECTIVE: The purpose of the present study was to compare the effects of ginger, pyridoxine (vitamin B6), and placebo for the treatment of NVP. METHOD: The study was performed as a triple blind clinical trial on pregnant women suffering mild to moderate NVP between 6 and 16 weeks of pregnancy. In these women ginger, 500 mg twice daily, vitamin B6 40 mg twice daily and placebo twice daily were administered for 4 d. Rhodes questionnaire was used for evaluation of the severity of symptoms. The severity of NVP was evaluated 24 h before entering the study and up to 4 d after using medications and results were compared among the three groups. RESULTS: Seventy-seven women finished the study (28 in the Ginger group, 26 in the B6 group, and 23 in the placebo group). The women of the three groups did not have significant differences according to age, gestational age, parity, and severity of each symptom before treatment and educational status. Total score of Rhodes questionnaire for nausea was decreased significantly in three groups after treatment. (p < .001, p = .012, and p = .03 for ginger, vitamin B6, and placebo, respectively.) Also total score of Rhodes questionnaire for vomiting was decreased in three groups (p = .03 for ginger, p = .02 for B6, and p = .04 for placebo). Ginger and vitamin B6 could reduce the severity of all items of Rhodes questionnaire significantly; however, placebo was significantly effective only on the frequency of nausea, intensity of vomiting and frequency of retching. Ginger and vitamin B6 were more effective than placebo (p = .039 and p = .007, respectively); however, total score of Rhodes did not show significant difference between ginger and vitamin B6 (p = .128). Ginger was more effective for nausea (intensity and distress) and distress of vomit. CONCLUSION: Ginger is more effective than placebo for the treatment of mild to moderate NVP and is comparable with vitamin B6. Trial registration number and registry website: IRCT2015020320923N1. PMID- 28629251 TI - Neonatal complications among 596 infants delivered by vacuum extraction (in relation to characteristics of the extraction). AB - OBJECTIVE: To investigate the association between complicated vacuum extraction (VE) deliveries and neonatal complications. METHODS: Observational study including data on the management of 596 consecutive VE-deliveries at 6 different birth clinics in Sweden in 2013. We used logistic regression to examine the association between a complicated VE and: extracranial bleeding, severe neonatal complication (intracranial hemorrhage and/or asphyxia/low Apgar score and/or convulsions, and/or encephalopathy), and brachial plexus injury. VE was considered complicated if duration exceeded 15 min, and/or more than six pulls were used, and/or more than one cup detachment occurred. Uncomplicated VE served as the reference group. RESULTS: Ten percent of the infants were diagnosed with at least one of the investigated complications. Cephalohematoma occurred in 5.2% of the infants and 1.5% had a subgaleal hematoma. Altogether 24 (4.0%) infants were diagnosed with a severe complication; low Apgar score, neonatal convulsions, encephalopathy or intracranial hemorrhages. Brachial plexus injury occurred in eight (1.3%) infants. The crude odds ratio for extracranial hemorrhages was 2.6 (95% CI 1.17-5.77), 4.07 (1.67-9.92) for severe neonatal complications, and 4.63 (1.08-19.76) for brachial plexus injury. CONCLUSIONS: Extraction time >15 min, >6 pulls and >1 cup detachment is associated with increased risk of neonatal complications. These results support compliance with guidelines and recommendations for VE deliveries. PMID- 28629252 TI - Study of composite vascular scaffold combining with differentiated VSMC- and VEC like cells in vitro and in vivo. AB - Although research into the tissue engineering of vessels has proceeded at a tremendous pace, many deficiencies still need to be resolved. A well-adopted constructed vessel requires both functional and structural properties to stimulate the native vessel and resist stress and tension in vivo. In the present study, we developed a novel three-layer composite vascular scaffold consisting of differentiated vascular smooth muscle cell-, vascular endothelial cell-like cells, and a rabbit acellular vascular matrix (ACVM)-0.25% HLC-I scaffold. HE staining, immunohistochemical assays, immunofluorescence assays (IFAs), and scanning electron microscopy were performed to monitor the growth status of cells on the scaffold material in vitro. After the vascular endothelial cell -vascular smooth muscle cell-scaffold was implanted into nude mice for three, six, and nine weeks, samples were harvested from the implanted mice and observed visually or by HE staining and IFAs for cell viability and morphology. Additionally, burst pressure resistance experiments were used to assess the maximal pressure that the engineered vessel could resist. We found that the engineered vascular endothelial cell-vascular smooth muscle cell-scaffold vessel possessed favorable biocompatibility and considerable strength, matching native vessels in vivo and in vitro, and may be significant in the future clinical implantation of tissue engineered vasculature. PMID- 28629253 TI - Insights into the Management of Papillary Microcarcinoma of the Thyroid. AB - BACKGROUND: Rapid increases in the incidence of thyroid carcinoma with stable mortality rates from thyroid carcinoma have been reported from many countries, and these increases are thought to be due mostly to the increased detection of small papillary thyroid carcinomas (PTCs), including papillary microcarcinomas (PMCs; i.e., PTCs <=10 mm). Some researchers have suggested that small PTCs have been overdiagnosed and overtreated. In Japan, the active surveillance of patients with low-risk PMCs was initiated by Kuma Hospital (1993) and Tokyo's Cancer Institute Hospital (1995) based on the extremely higher incidences of both latent thyroid carcinomas in autopsy studies and small PTCs detected in mass screening studies using ultrasound examinations compared to the prevalence of clinical thyroid carcinomas. METHODS: The above two institutions' data are summarized regarding the active surveillance of low-risk PMCs, and future prospects for their management are discussed. RESULTS: At 10-year observations in the Kuma Hospital series of 1235 patients, only 8% and 3.8% of the PMC patients showed size enlargement by >=3 mm and the novel appearance of node metastasis, respectively. In contrast to clinical PTC, PMCs are most unlikely to grow in older patients (>=60 years). In the Kuma Hospital series, the 974 patients who underwent immediate surgery had significantly higher incidences of unfavorable events than the 1179 patients who chose active surveillance. The total cost of immediate surgery, including the costs for salvage surgery and postoperative care for 10 years, was 4.1 times the total cost of 10-year management by active surveillance. Only 8% of the 51 PMC patients showed tumor enlargement during pregnancy, and the rescue surgeries after delivery were successful. In the Cancer Institute Hospital series of 230 patients with 300 lesions, only 7% and 1% of the patients showed size enlargement and novel node metastasis, respectively, and that institution's analysis also revealed that macroscopic or rim calcification and poor vascularity were correlated with non-progressing disease. In both series, none of the patients who underwent rescue surgery after progression signs were detected showed significant recurrence or died of PTC. CONCLUSION: Active surveillance of low-risk PMC can be the first-line management. Interestingly, older patients with low-risk PMCs are the best candidates for active surveillance. PMID- 28629254 TI - The "yin and yang" of the adrenal and gonadal systems in elite military men. AB - We recently established daily, free-living profiles of the adrenal hormone cortisol, the (primarily adrenal) anabolic precursor dehydroepiandrosterone (DHEA) and the (primarily gonadal) anabolic hormone testosterone in elite military men. A prevailing view is that adrenal and gonadal systems reciprocally modulate each other; however, recent paradigm shifts prompted the characterization of these systems as parallel, cooperative processes (i.e. the "positive coupling" hypothesis). In this study, we tested the positive coupling hypothesis in 57 elite military men by evaluating associations between adrenal and gonadal biomarkers across the day. Salivary DHEA was moderately and positively coupled with salivary cortisol, as was salivary testosterone. Anabolic processes (i.e. salivary DHEA and testosterone) were also positively and reliably coupled across the day. In multivariate models, salivary DHEA and cortisol combined to account for substantial variance in salivary testosterone concentrations across the day, but this was driven almost exclusively by DHEA. This may reflect choreographed adrenal release of DHEA with testicular and/or adrenal release of testosterone, systemic conversion of DHEA to testosterone, or both. DHEA and testosterone modestly and less robustly predicted cortisol concentrations; this was confined to the morning, and testosterone was the primary predictor. Altogether, top-down co-activation of adrenal and gonadal hormone secretion may complement bottom-up counter-regulatory functions to foster anabolic balance and neuronal survival; hence, the "yin and yang" of adrenal and gonadal systems. This may be an adaptive process that is amplified by stress, competition, and/or dominance hierarchy. PMID- 28629255 TI - Hemophagocytic lymphohistiocytosis associated to Haemophilus parainfluenzae endocarditis- a case report. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe and potentially fatal syndrome that is characterized by increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system. This syndrome is classified as primary (genetic) or secondary when acquired in the context of infections (usually viral), malignancies, rheumatologic and metabolic diseases. CASE SUMMARY: We report a case of HLH complicating a Haemophilus parainfluenzae mitral valve endocarditis and resolving under antibiotic and surgical treatment alone. We also review other case reports of infective endocarditis associated with HLH. CONCLUSION: The syndrome is probably underdiagnosed. To our knowledge, this is the first report of a HLH syndrome associated with H. parainfluenzae endocarditis. PMID- 28629256 TI - Managing menopause in women living with HIV: A survey of primary care practitioners. AB - Objective One in three women living with HIV (WLHIV) in the UK is aged 45-56, and therefore of potentially menopausal age. Little is known about the management of menopause in WLHIV in primary care. We aim to describe current knowledge and practice in the management of menopause in WLWH among primary care practitioners (PCPs). Methods A questionnaire-based study of 88 PCPs attending two sexual and reproductive health conferences. Results Almost all respondents (n = 87, 99%) routinely managed women with menopause-related symptoms; however, only 18 (20%) reported having managed menopause in WLHIV. Over 95% (n = 85) reported being confident in managing menopause in general, whereas less than half (n = 40) reported confidence in managing menopause in WLHIV ( p < 0.001). The majority of respondents (n = 84) felt that menopause should be routinely managed in primary care, whereas just over half thought that menopause in WLHIV should be managed in primary care (n = 50, p < 0.001). Almost all respondents (n = 85) reported concerns about managing menopause in WLHIV. Conclusion PCPs reported limited experience of and low levels of confidence in managing menopause-related symptoms in WLHIV. Nearly all PCPs had concerns about managing menopause-related symptoms in WLHIV, many stating that this should be managed outside primary care. Development of national guidance and specialised training, coupled with good liaison between HIV services and PCPs, may improve confidence in this area. PMID- 28629257 TI - Risk stratification of diffuse large B-cell lymphoma with interim PET-CT based on different cutoff Deauville scores. AB - We evaluated the usefulness of interim 18F-FDG PET/CT for risk stratification using different cutoff values of the Deauville 5-point scale (5-DS) in DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). One hundred and fifty patients underwent interim (I-) and end of treatment (EOT-) PET/CT scans. Applying the conventional 5-DS cutoff value of scores 4 to 5 at interim, there was no significant difference in progression free survival (PFS) between I-PET negative and I-PET positive patients. In comparison, PFS was inferior in patients with a score of 5 on I-PET scan compared with those with a score in between 1 to 4 (28.6% vs. 78.7%, p < .0001), and positive predictive value (71.4%) was improved compared to that obtained using cutoff value of scores 4 to 5 (34.9%). Our study shows that a cutoff score of 5 at interim has an alternative clinical implication for identifying patients at a significant risk. PMID- 28629258 TI - Implementation and preliminary evaluation of 'C-tone': A novel algorithm to improve lexical tone recognition in Mandarin-speaking cochlear implant users. AB - OBJECTIVES: Because of limited spectral resolution, Mandarin-speaking cochlear implant (CI) users have difficulty perceiving fundamental frequency (F0) cues that are important to lexical tone recognition. To improve Mandarin tone recognition in CI users, we implemented and evaluated a novel real-time algorithm (C-tone) to enhance the amplitude contour, which is strongly correlated with the F0 contour. METHODS: The C-tone algorithm was implemented in clinical processors and evaluated in eight users of the Nurotron NSP-60 CI system. Subjects were given 2 weeks of experience with C-tone. Recognition of Chinese tones, monosyllables, and disyllables in quiet was measured with and without the C-tone algorithm. Subjective quality ratings were also obtained for C-tone. RESULTS: After 2 weeks of experience with C-tone, there were small but significant improvements in recognition of lexical tones, monosyllables, and disyllables (P < 0.05 in all cases). Among lexical tones, the largest improvements were observed for Tone 3 (falling-rising) and the smallest for Tone 4 (falling). Improvements with C-tone were greater for disyllables than for monosyllables. Subjective quality ratings showed no strong preference for or against C-tone, except for perception of own voice, where C-tone was preferred. DISCUSSION: The real-time C tone algorithm provided small but significant improvements for speech performance in quiet with no change in sound quality. Pre-processing algorithms to reduce noise and better real-time F0 extraction would improve the benefits of C-tone in complex listening environments. CONCLUSIONS: Chinese CI users' speech recognition in quiet can be significantly improved by modifying the amplitude contour to better resemble the F0 contour. PMID- 28629259 TI - Bayesian analysis of longitudinal dyadic data with informative missing data using a dyadic shared-parameter model. AB - Analyzing longitudinal dyadic data is a challenging task due to the complicated correlations from repeated measurements and within-dyad interdependence, as well as potentially informative (or non-ignorable) missing data. We propose a dyadic shared-parameter model to analyze longitudinal dyadic data with ordinal outcomes and informative intermittent missing data and dropouts. We model the longitudinal measurement process using a proportional odds model, which accommodates the within-dyad interdependence using the concept of the actor-partner interdependence effects, as well as dyad-specific random effects. We model informative dropouts and intermittent missing data using a transition model, which shares the same set of random effects as the longitudinal measurement model. We evaluate the performance of the proposed method through extensive simulation studies. As our approach relies on some untestable assumptions on the missing data mechanism, we perform sensitivity analyses to evaluate how the analysis results change when the missing data mechanism is misspecified. We demonstrate our method using a longitudinal dyadic study of metastatic breast cancer. PMID- 28629260 TI - Risk of Dementia in Adults With ADHD: A Nationwide, Population-Based Cohort Study in Taiwan. AB - OBJECTIVE: This study aimed to investigate the association between adults with ADHD and the risk of developing dementia. METHOD: Utilizing National Health Insurance Research Database of Taiwan, ADHD patients were identified and compared with age- and gender-matched controls (1:3). RESULTS: Of the study participants, 37 (5.48%) developed dementia compared with 81 (4.0%) in the control group. Cox proportional hazards regression analysis revealed that the study participants were more likely to develop dementia. The crude hazard ratio (HR) is 3.418 (95% confidence interval [CI] = [2.289, 5.106], p < .001), and adjusted HR is 4.008 (95% CI = [2.526, 6.361], p < .001) in risk of developing dementia after adjusted for age, gender, comorbidities, geographical area of residence, urbanization level of residence, and monthly income. CONCLUSION: Adults with ADHD have a 3.4 fold risk of developing dementia, and other large or national data sets should be explored to support the current findings. PMID- 28629261 TI - Assessment of leakage pressure following enterotomy closure reinforced by tissue adhesive in a caprine cadaver model. AB - AIMS: To compare the combination of suture and tissue adhesive with suture alone for closure of enterotomy incisions in an ex vivo caprine jejunal model, by measuring the intraluminal pressure at which leakage occurred and the proportion of closures that leaked at intraluminal pressures <40 mmHg. METHODS: Jejunal tissue was harvested from a goat following euthanasia, and enterotomy incisions (4 mm in length) were made in each of 24 isolated jejunal segments. The enterotomies were randomly assigned to be closed using a single interrupted suture alone (n=12) or in combination with biopolymer tissue adhesive (n=12). The jejunal segments were infused with saline containing fluorescent dye and leakage pressure was defined as the peak pressure attained when visible leakage of saline solution occurred. The number of enterotomies that did or did not exhibit leakage at <40 mmHg intraluminal pressure was also recorded. RESULTS: Enterotomies closed using a combination of suture and tissue adhesive leaked at higher intraluminal pressure (58.2 (SD 4.7) mmHg) than those closed with suture alone (29.8 (SD 4.2) mmHg; p<0.001). The proportion of enterotomy closures in which the intraluminal pressure failed to reach 40 mmHg before leakage occurred was higher in enterotomies closed using suture alone (9/12, 75%) compared to those closed using both suture and tissue adhesive (3/12, 25%; p=0.002). CONCLUSIONS AND CLINICAL RELEVANCE: Use of tissue adhesive in addition to sutures increased the intraluminal pressure achieved before leakage occurred, compared to sutures alone, following enterotomy closure in a caprine cadaver model. In vivo studies are indicated to further assess the value of supplementing intestinal suture lines with tissue adhesive. PMID- 28629262 TI - Dynamic modelling of n-of-1 data: powerful and flexible data analytics applied to individualised studies. AB - N-of-1 studies are based on repeated observations within an individual or unit over time and are acknowledged as an important research method for generating scientific evidence about the health or behaviour of an individual. Statistical analyses of n-of-1 data require accurate modelling of the outcome while accounting for its distribution, time-related trend and error structures (e.g., autocorrelation) as well as reporting readily usable contextualised effect sizes for decision-making. A number of statistical approaches have been documented but no consensus exists on which method is most appropriate for which type of n-of-1 design. We discuss the statistical considerations for analysing n-of-1 studies and briefly review some currently used methodologies. We describe dynamic regression modelling as a flexible and powerful approach, adaptable to different types of outcomes and capable of dealing with the different challenges inherent to n-of-1 statistical modelling. Dynamic modelling borrows ideas from longitudinal and event history methodologies which explicitly incorporate the role of time and the influence of past on future. We also present an illustrative example of the use of dynamic regression on monitoring physical activity during the retirement transition. Dynamic modelling has the potential to expand researchers' access to robust and user-friendly statistical methods for individualised studies. PMID- 28629264 TI - A comparative study of subgroup identification methods for differential treatment effect: Performance metrics and recommendations. AB - Subgroup identification with differential treatment effects serves as an important step towards precision medicine, as it provides evidence regarding how individuals with specific characteristics respond to a given treatment. This knowledge not only supports the tailoring of treatment strategies but also prompts the development of new treatments. This manuscript provides a brief overview of the issues associated with the methodologies aimed at identifying subgroups with differential treatment effects, and studies in depth the operational characteristics of five data-driven methods that have appeared recently in the literature. The performance of the methods under study to identify correctly the covariates affecting treatment effects is evaluated via simulation and under various conditions. Two clinical trial data sets are also used to illustrate the application of these methods. Discussion and recommendations pertaining to the use of these methods are provided, with emphasis on the relative performance of the methods under the conditions studied. PMID- 28629263 TI - Mass spectrometry-based analysis of murine bronchoalveolar lavage fluid following respiratory exposure to 4,4'-methylene diphenyl diisocyanate aerosol. AB - 1. Diisocyanates are highly reactive electrophiles utilized in the manufacture of a wide range of polyurethane products and have been identified as causative agents of occupational allergic respiratory disease. However, in spite of the significant occupational health burden associated with diisocyanate-induced asthma, the mechanism of disease pathogenesis remains largely unknown. 2. To better understand the fate of inhaled diisocyanates, a nose-only aerosol exposure system was constructed and utilized to expose a BALB/c mouse model to an aerosol generated from 4,4'-methylene diphenyl diisocyanate (MDI). Tissue and bronchoalveolar lavage samples were evaluated 4 and 24 h post-exposure for evidence of diisocyanate-protein haptenation, and a label-free quantitative proteomics strategy was employed to evaluate relative changes to the protein content of the cellular fraction of the lavage fluid. 3. Following MDI aerosol exposure, expression of the number of proteins with immunological or xenobiotic metabolism relevance is increased, including endoplasmin, cytochrome P450 and argininosuccinate synthase. Western blot analysis indicated MDI-conjugated protein in the lavage fluid, which was identified as serum albumin. 4. Tandem mass spectrometry analysis of MDI-albumin revealed MDI conjugation occurs at a dilysine motif at Lys525, as well as at a glutamine-lysine motif at Lys414, in good agreement with previously published in vitro data on diisocyanate-conjugated serum albumin. PMID- 28629265 TI - The comparative analysis of postural and biomechanical parameters of preschool teachers pre- and post-intervention within the ErgoKiTa study. AB - The ErgoKiTa study aimed to determine the musculoskeletal strain of preschool teachers and to identify and evaluate suitable prevention measures to reduce this strain. A comprehensive work analysis using objective and subjective methods was performed to determine the present work situation in preschools in Germany, and the results were used to derive suitable intervention measures. The musculoskeletal strain was determined by means of a comprehensive analysis of postures, forces and movements using the CUELA system and calculated as cumulative shift workloads. The intervention measures were evaluated in a pre- and post-intervention assessment for 12 participants. Significant alterations in the duration of postures were determined, specifically for the daily duration of knee-straining postures as well as the degree of trunk flexion between 60 degrees and 90 degrees , which were reduced from 8.4 to 3.1% and from 3.7 to 2.4%, respectively, following the intervention. Practitioner Summary: Research has shown that preschool teachers are at risk of developing musculoskeletal disorders. The effects of a situation-orientated and behaviour-orientated intervention approach were assessed with regard to awkward working postures. Significant alterations in the duration of postures following the intervention were found, specifically for knee-straining postures. PMID- 28629266 TI - Polygonatum Sibiricum Polysaccharide Promotes Osteoblastic Differentiation Through the ERK/GSK-3beta/beta-Catenin Signaling Pathway In Vitro. AB - Natural compound polygonatum sibiricum polysaccharide (PSP) has a variety of biological actions such as reducing blood fat, antitumor and antioxidant activities, and enhancing immune function. Our previous study has revealed that PSP can promote osteoblastic (OB) differentiation in bone mesenchymal stem cells by increasing nuclear accumulation of beta-catenin. This study was designed to investigate that PSP can upregulate nuclear beta-catenin, which was prevented by inhibiting the glycogen synthase kinase 3beta (GSK-3beta) activity, by effectively activating Wnt signaling independent of low-density lipoprotein receptor-related protein 5 (LRP5). We showed that PSP reduced the level of GSK 3beta, which phosphorylates and destabilizes nuclear beta-catenin through extracellular signal-regulated kinase (ERK) signaling pathway. Taken together, these findings demonstrate that PSP promotes OB differentiation and mineralization in vitro through the ERK/GSK-3beta/beta-catenin signaling pathways. This study may aid in the development of a therapeutic approach utilizing PSP for the enhancement of bone health and prevention of osteoporosis. PMID- 28629267 TI - Adsorption of sodium dodecyl sulfate onto precipitate in treatment of vat dark blue BO by dissolved air flotation. AB - Vat dark blue BO-simulated wastewater was treated by dissolved air flotation (DAF). In this process, the interactions of sodium dodecyl sulfate (SDS) and resulting DAF process precipitates were investigated by infrared spectroscopy and kinetic methods. Fourier transform infrared analysis revealed that gamma values (cm-1) for asymmetric and symmetric stretching vibrations of CH2 groups for SDS treated precipitation shifted toward higher in comparison to pure SDS, showing strong SDS and precipitate interactions. This showed the chemical adsorption of SDS onto precipitate surfaces. Adsorption data were well described by a pseudo second-order model, with an adsorption activation energy of 42.602 kJ mol-1, further predicting an SDS chemisorption uptake process by the precipitate. SDS could be considered as one of the most efficient flotation agents for the removal of vat dark blue BO in DAF processing. PMID- 28629268 TI - Comparing the effect of Cawthorne-Cooksey and Frenkel exercises on balance in patients with multiple sclerosis: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of Cawthorne-Cooksey and Frenkel exercises on balance in patients with multiple sclerosis. DESIGN: It was a three-arm parallel randomized controlled trial study. SETTING: Outpatient clinic. SUBJECTS: Patients with multiple sclerosis. INTERVENTIONS: Subjects in the intervention groups completed a 12-week program consisted of Cawthorne-Cooksey or Frenkel exercises. The control group only received routine care. MAIN MEASURES: The outcome measure was the Berg Balance Scale. RESULTS: Seventy-two patients completed the study. At the end of the intervention, there was a statistically significant improvement in Berg Balance Scale in the Cawthorne-Cooksey group ( n = 24) in comparison with the other two groups ( P = 0.001). In the Frenkel group ( n = 23), the improvement was statistically greater than the changes in the control group ( n = 25), but it did not appear to be clinically significant. The Berg Balance Scale score increased to 8.9 in the Cawthorne-Cooksey group and 2.3 in the Frenkel group, while it decreased to 1.2 in the control group. When comparing inter-group changes, Berg Balance Scale showed significant improvements in favor of the Cawthorne-Cooksey group after the intervention ( P < 0.05). CONCLUSION: This study demonstrated that in comparison with Frenkel and the control groups, a program of Cawthorne-Cooksey exercise is more effective in improving balance in patients with multiple sclerosis. PMID- 28629269 TI - Aquatic obstacle training improves freezing of gait in Parkinson's disease patients: a randomized controlled trial. AB - OBJECTIVE: Our aim was to evaluate the effect of aquatic obstacle training on balance parameters in comparison with a traditional aquatic therapy in patients with Parkinson's disease. DESIGN: A randomized single-blind controlled trial. SETTING: Outpatients in the rehabilitation department. SUBJECTS: A total of 46 patients with Parkinson's disease in Hoehn-Yahr stage 2-3. INTERVENTIONS: Participants were randomly assigned to (1) aquatic therapy or (2) obstacle aquatic therapy. All participants undertook aquatic therapy for 30 minutes, five times per week for six weeks. MAIN MEASURES: The Freezing of Gait Questionnaire, Functional Reach Test, Timed Up and Go test and Berg Balance Scale were assessed at baseline, posttreatment and at six-month follow-up. RESULTS: Both groups of patients had improved primary outcomes after the training program. A between group comparison of the changes revealed that obstacle aquatic therapy was significantly higher for the Freezing of Gait Questionnaire (after treatment: 8.7 +/- 3.3 vs 6.2 +/- 2.1, P = 0.004; posttest: 7.7 +/- 3.1 vs 5.3 +/- 2.0, P = 0.003) and Timed Up and Go test (after treatment: 17.1 +/- 2.9 vs 13.8 +/- 1.9, P < 0.001; posttest: 16.3 +/- 2.8 vs 12.9 +/- 1.4, P < 0.001). CONCLUSION: Obstacle aquatic therapy in this protocol seems to be more effective than traditional protocols for gait and balance in patients with Parkinson's disease, and the effect lasts for six months. PMID- 28629270 TI - A randomized controlled trial of a modified wheelchair arm-support to reduce shoulder pain in stroke patients. AB - OBJECTIVE: To evaluate the effect of modified wheelchair arm-support to mitigate hemiplegic shoulder pain and reduce pain frequency in stroke patients. DESIGN: A single-blind randomized controlled trial using computer-generated simple randomization. SETTING: Participants recruited from inpatients at the Guangdong Provincial Hospital of Chinese Medicine. SUBJECTS: A total of 120 patients with stroke were divided into two groups. INTERVENTIONS: All subjects underwent basic rehabilitation training and wheelchair assistance with eight weeks follow-up period. Patients in the treatment group additionally received modified wheelchair arm-support for at least 60 minutes a day, six days a week, for four weeks. OUTCOME MEASURES: Primary outcome was measured by the Visual Analogue Pain Scale or Numeric Pain Rating Scale. Secondary outcome was measured using the Upper Extremity Fugl-Meyer Assessment scale, Modified Barthel Index and Quality of Life Index. Measurements were made at 4 weeks and 12 weeks, following the intervention. RESULTS: Patients age from 21 to 83 years (mean +/- SD = 62.41 +/- 12.26). The average duration of disease was 1.9 +/- 1.3 months. At four weeks, the median of pain intensity was higher in the control group (median, interquartile range = 3, 5.75 vs. 2, 3.75; P = 0.059). At 12 weeks, the median of pain intensity was higher in the control group (median, interquartile range = 3, 5.00 vs. 0, 1.00; P < 0.001). At 12 weeks, patients with shoulder pain were higher in the control group (6 vs. 1; P < 0.05). CONCLUSION: Using the modified wheelchair arm-support could lead to the mitigation of hemiplegic shoulder pain and reduction in pain incidence in stroke patients. It may also improve the patients' quality of life. PMID- 28629271 TI - Expression of Interleukin-1 and temporomandibular disorder: Contemporary review of the literature. AB - OBJECTIVE: Temporomandibular disorders (TMD) are a group of conditions affecting the temporomandibular joint (TMJ), leading to jaw dysfunction, joint and muscle pain, and a decrease in quality of life. A communication network of pro- and anti inflammatory mediators called cytokines maintains the homeostasis of the TMJ. This review will focus on the Interleukin (IL) family of cytokines, which have been quantified in TMJ synovial fluids in a variety of studies. IL-1alpha and IL 1beta have pro-inflammatory effects, while the endogenous receptor antagonist (IL 1RA) inhibits the pro-inflammatory effects of IL-1. METHODS: A literature search (2006-2016) to identify eligible studies was completed using the PubMed database. Studies identified used saline irrigation to quantify cytokine profiles in synovial fluid of healthy and/or dysfunctional joints. RESULTS: The initial search yielded 111 articles, 5 of which met the inclusion criteria after inter reviewer discussion. CONCLUSIONS: Articles that compared IL-1 concentrations in TMD vs. control groups found significant differences. PMID- 28629272 TI - Treating Suicidal Thoughts and Behaviors Within an Emotional Disorders Framework: Acceptability and Feasibility of the Unified Protocol in an Inpatient Setting. AB - We provide a theoretical rationale for applying a transdiagnostic, shared mechanism treatment (the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders [UP]) to suicidal thoughts and behaviors. We also present results from a proof of concept study examining the feasibility and acceptability of adding a modified UP to treatment as usual (TAU) in an inpatient setting for individuals reporting a recent suicide attempt or active suicidal ideation. Participants ( N = 12) were randomly assigned to receive UP + TAU or TAU alone. Findings indicate good feasibility and acceptability of the adjunctive intervention. Among participants who were responsive to contact attempts postdischarge ( n = 6), there were no observable differences in suicidal thoughts or behaviors during a 6-month follow-up. This application represents a promising initial extension of a cognitive-behavioral, emotion-focused treatment to suicidal individuals within an inpatient setting. Future studies adequately powered to speak to efficacy of the modified UP intervention are warranted. PMID- 28629273 TI - The association between maternal race and adverse outcomes in twin pregnancies with similar healthcare access. AB - OBJECTIVE: To compare twin pregnancy outcomes between white and nonwhite women with similar access to health care. METHODS: Retrospective cohort study of all twin pregnancies delivered by a single maternal-fetal medicine practice from 2005 2016. All patients had private health insurance and equal access to physician care. Outcomes were compared between white and nonwhite women using logistic regression to adjust for differences at baseline. RESULTS: Of the 858 women included, 730 (85.1%) were white and 128 (14.9%) were nonwhite. Univariate analysis demonstrated that nonwhite women had higher rates of preterm birth <32 weeks (12.5 versus 6.7%, p = .022), cesarean delivery (78.1% versus 61.4% of all women, p < .001 and 43.5% versus 16.1% of women who attempted labor, p < .001), preeclampsia (22.4% versus 14.5%, p = .029) and gestational diabetes (23.2% versus 7.3%, p < .001). On adjusted analysis, nonwhite race remained significantly associated with cesarean delivery in women who attempted labor (aOR 2.27, 95% CI: 1.09, 4.71) and gestational diabetes (aOR 2.61, 95% CI: 1.53, 4.45). CONCLUSIONS: Nonwhite women with twin pregnancies have an increased risk of adverse outcomes that cannot be explained by access to care. Although improving access to care is an important goal for health care systems, our data suggest that this alone will not eliminate all disparities in health care outcomes between women of different races. PMID- 28629274 TI - Investigation of serum thiol/disulphide homeostasis in patients with abortus imminens. AB - AIM: The aim of our study is to compare serum thiol/disulphide homeostasis of women diagnosed with abortus imminens (AI) and healthy pregnant women, and to determine whether it has a role in the pathogenesis of the disease or not. MATERIALS AND METHODS: A total of 100 pregnant women were included in the study. The study group consisted of 50 patients with AI whereas 50 healthy pregnant women were chosen as the control group. All of the patients in the two groups were matched for age, gestational age, and body mass index. Thiol/disulphide levels were analyzed with a newly developed automated spectrophotometric method. RESULTS: We found significantly reduced levels of native thiol (SH) (370.2 +/- 35.2 MUmol/l versus 397.6 +/- 29.3 MUmol/l) and total thiol (406 +/- 37.1 MUmol/l versus 434.5 +/- 29.9 MUmol/l), in the sera of the study group compared to the control group (p < .001). But serum levels of disulphide (SS) were statistically insignificant between the two groups (17.9 +/- 5.9 MUmol/l versus 18.4 +/- 4.9 MUmol/l, p: .612). Similarly, no significant differences were observed between the two groups in terms of SS/SH, SS/total thiol and SH/total thiol ratios (all p > .05). CONCLUSIONS: We found a decrease in thiol levels which have antioxidant properties in patients with AI. Decreased antioxidant level in the body is thought to play a role in the etiology of AI. In this regard, further studies are needed to elucidate the potential role of dynamic thiol/disulphide homeostasis in the pathogenesis of AI. PMID- 28629275 TI - Applying Learning Theory to Safety and Health Training for Hispanic Immigrant Dairy Workers. AB - We designed a safety and health curriculum for dairy immigrant workers aiming to increase knowledge, encourage safe behavior, and reduce worker communication inequalities to prevent occupational injury and diseases. The design is largely based on the Taxonomy of Significant Learning and incorporated behavioral and adult learning theories and principles of occupational hazard control. Trainings were implemented with 836 Spanish-speaking workers from 67 farms in Wisconsin. Sixty-seven percent of workers reported never being trained before in dairy safety, 65% of these worked in dairy for 5 or fewers years, and 26% of workers reported being ever injured while working on dairy. Quantitative and qualitative evaluation of the trainings suggest that our curriculum successfully increased worker knowledge and promoted contemplation of safe practices. The overall knowledge gain of 25% was statistically significant ( p < .01). Workers recalled at least one key concept, expressed confidence of adopting at least one safety behavior, and mentioned their intention to communicate safety concerns to farmers. To our knowledge, this is the first Taxonomy of Significant Learning application to occupational safety and health education. Our curriculum can support dairy farmers' compliance with Occupational Safety and Health Administration's annual training requirements by providing our basic safety and health training to workers at early job stages. PMID- 28629277 TI - Addressing Tobacco Use Among Consumers and Staff at Behavioral Health Treatment Facilities Through Comprehensive Workplace Programming. AB - Tobacco use is the leading cause of death and disability in the United States; cigarette smoking is the most common form of tobacco use. Smoking has become increasingly concentrated among individuals with behavioral health needs (e.g., persistent mental illness) and has led to increased morbidity and mortality in this group relative to the general population. Comprehensive tobacco-free workplace programs are effective in reducing tobacco use and cigarette smoke exposure among behavioral health consumers and the individuals who serve them. Taking Texas Tobacco-Free (TTTF) represents an academic-community partnership formed to address tobacco use among consumers and employees at behavioral health clinics across Texas via the dissemination of an evidence-based, multicomponent tobacco-free workplace program. Program components of TTTF include tobacco-free campus policy implementation and enforcement, staff education about tobacco use hazards, provider training to regularly screen for and address tobacco dependence via intervention, and community outreach. These components, the nature of the academic-community partnership, the process of behavioral health facility involvement and engagement, and the benefits and challenges of implementation from the perspectives of the project team and participating clinic leaders are described. This information can guide similar academic and community partnerships and inform the implementation of other statewide tobacco-free workplace programming. PMID- 28629279 TI - Understanding Determinants of Cardiovascular Health in a Mexican American Community. AB - Cardiovascular disease (CVD) is the leading cause of death in Hispanic Americans. Social and physical determinants of health unique to this community must be understood before interventions can be designed and implemented. This article describes a CVD risk assessment conducted in a primarily Mexican American community, using Healthy People 2020 as a model. Social (language, culture, awareness of CVD, and socio-economic status) and physical (presence and use of recreation areas, presence of grocery stores, public transportation, and environmental pollution) determinants of health as well as access to health services were assessed. Fifteen community leaders were interviewed using guided interviews. Database searches and direct observations were conducted. Using these methods provided comprehensive assessment of social and physical determinants of health, and access issues that were unique to the community studied. Findings demonstrated greater awareness of diabetes than CVD as a health problem, with little knowledge of CVD risk factors. Lack of access to health services (lack of insurance, lack of a medical home) and presence of cultural and socioeconomic barriers such as language, unemployment, low income, and lack of insurance were identified. The physical determinants such as environment presented fewer barriers, with adequate access to fruits and vegetables, transportation, and parks. Results revealed target areas for intervention. PMID- 28629280 TI - Absent ductus venosus: case series from two tertiary centres. AB - INTRODUCTION: Congenital absence of the ductus venosus (ADV) is a rare vascular anomaly often associated with fetal cardiac and extracardiac anomalies, aneuploidies, and hydrops. The prognosis depends on the patterns of abnormal venous circulation, on the associated malformations and on chromosomal aberrations. METHODS: We performed a retrospective audit of all consecutive cases with ADV referred in our centres and analysed the outcomes. RESULTS: A total of six cases with prenatally diagnosed ADV were identified. The gestational age at diagnosis ranged from 15 to 35 weeks. Karyotyping was performed in all cases. Normal karyotype was found in five out of the six cases. Overall, four neonates survived at 28 days follow-up. The other two died 48 h after delivery: both of them had extrahepatic ADV. DISCUSSION: Absence of the ductus venosus may be compatible with normal fetal development without relevant disturbance of circulation and oxygenation independently from type of abnormal venous circulation. PMID- 28629281 TI - Noninvasive Quantitative Assessment of Hepatic Steatosis by Proton Magnetic Resonance Spectroscopy Among Adult Patients Receiving Home Parenteral Nutrition. AB - BACKGROUND: Intestinal failure-associated liver disease is a frequent complication in patients with chronic intestinal failure (CIF), with steatosis as a dominant feature in adults. Proton magnetic resonance spectroscopy (1H-MRS) is a noninvasive method to quantify liver fat content (LFC). In this study, LFC was assessed with 1H-MRS, taking into account the possible accumulation of paramagnetic components of home parenteral nutrition (HPN) that may disturb these measurements. METHODS: LFC was measured in 15 adult CIF patients who had been receiving HPN for >6 months. 1H-MR spectra were obtained with a 3 Tesla magnetic resonance (MR) system, with a method correcting for the presence of paramagnetic ions. Patients with low (<5%) versus high (>=5%, steatosis) LFC were compared with nonparametric statistical tests. RESULTS: 1H-MRS analysis revealed steatosis in 5 patients (median, 10.3%), while 10 patients had normal LFC (median, 0.9%). In all patients, the 1H-MRS results indicated the presence of various amounts of paramagnetic constituents in the liver. Patients with steatosis had higher alanine aminotransferase values than patients without steatosis (median, 60 vs 28 U/L). Unexpectedly, in the steatosis group, the frequency of HPN use was lower, with significant lower total HPN and carbohydrate calories. In 1 patient, MR spectra were of inferior quality, with broadened resonances after infusion with a ferric compound. CONCLUSION: 1H-MRS enables reliable noninvasive assessment of LFC in patients receiving long-term HPN, if correcting for possible accumulation of paramagnetic components in the liver. However, LFC determination by 1H-MRS is not recommended after a recent ferric compound infusion. PMID- 28629282 TI - Emotional intelligence, trauma severity, and emotional expression. AB - This study investigated Emotional Intelligence (EI) as a moderator for the association between emotional expression and adaptive trauma processing, as measured by depressive symptoms. Using Pennebaker's written emotional expression paradigm, 105 participants were assigned to either a conventional trauma-writing or religious trauma-writing condition. Depressive symptoms were assessed at baseline and again at one-month post writing. No significant association between EI and religiousness was found at baseline. Results indicated a three-way interaction among EI, trauma severity, and writing condition on depressive symptoms at follow-up. For the religious trauma-writing condition only, there was a significant difference between high- versus low-EI participants who experienced more severe trauma in depressive symptoms at follow-up, such that low-EI participants registered less depressive symptoms than high-EI participants; while there was no significant difference between low versus high EI for participants with less severe trauma. These findings encourage further investigation of the conditions under which religion may be a beneficial factor in trauma adaptation. PMID- 28629283 TI - Prevalence and correlates of major depression among Nigerian adults with sickle cell disease. AB - Objective To ascertain the current and lifetime prevalence of depression among adults with sickle cell disease and identify relevant socio-demographic and clinical correlates. Method A cross-sectional study of 205 stable adult out patient attendees at a treatment center in southern Nigeria between April and September, 2014. A socio-demographic questionnaire, the depression module of Mini International Neuropsychiatric Interview, and the eight-item Morisky Medication Adherence Scale were administered. Categorical and continuous variables associated with a diagnosis of depression were tested using chi-squared and t tests respectively. Level of significance was set a priori at P < 0.05. Results Prevalence of current depression was 16.6%, while lifetime prevalence was 29.8%. Current depression was significantly associated with frequent analgesic use ( P < 0.03), unemployment ( P = 0.04), low income ( P < .04), low educational status ( P < 0.01), and subjective pain ( P < 0.001). Subjective pain was nearly twice as likely to predict a current depressive episode (AOR: 1.81, 95%CI: 1.42-2.02, P < 0.03). Conclusions Depression is common among adults with sickle cell disease and is significantly associated with severity of subjective pain. PMID- 28629284 TI - Anxiety leads to up-regulation of CD36 on the monocytes of chronic hepatitis B infected patients. AB - Introduction It has been hypothesized that mental disorders including depression and anxiety can affect immune responses. The study was done to evaluate the relation between depression and anxiety and expression levels of CD36, CD68, and CD9 on peripheral blood monocytes of chronic hepatitis B (CHB) patients. Methods Sixty CHB patients were selected with various ranges of depression and anxiety. Depression and anxiety were evaluated using a standard questionnaire by an expert psychiatrist according to BECK's Depression Inventory II and Hamilton Anxiety Rating Scale, respectively. The levels of CD36, CD68, and CD9 on the peripheral blood monocytes have been performed using flow cytometry technique. Results The results demonstrated that levels of CD36 were significantly increased on the peripheral blood monocytes of CHB patients when compared with CHB patients with no anxiety. Expression levels of CD68 and CD9 were not significantly altered on the CHB patients with various ranges of anxiety. Expression levels of CD36, CD68, and CD9 were also not significantly altered on the CHB patients with various ranges of depression. Discussion It seems that anxiety induces inflammation in the CHB patients by induction of alteration in several molecules including up regulation of CD36. CD36 plays important roles in the induction of tissue damage; hence, it may be hypothesized that anxiety may participate in the induction of some hepatitis B complications. PMID- 28629285 TI - Acute movement disorders in the medical setting. AB - Objective Psychosomatic medicine psychiatrists are often tasked with the evaluation and treatment of complex neuropsychiatric states which may be motoric in phenotype. Little energy has been dedicated to understanding acute movement disorders in the hospital environment. Method Recognizing the importance of frontal-subcortical (corticostriatothalamocortical) circuitry and basal ganglia structures, we present a case series of acute movement disorder phenotypes resulting from underlying medical conditions, commonly-administered medications, or the interaction of both. We organize these scenarios into neurodegenerative disorders, primary psychiatric disorders, neuroinflammation, and polypharmacy, demonstrating a clinical example of each followed by background references on a variety of clinical states and medications contributing to acute movement disorders. In addition, we offer visual illustration of implicated neurocircuitry as well as proposed neurotransmitter imbalances involving glutamate, gamma aminobutyric acid, and dopamine. Furthermore, we review the various clinical syndromes and medications involved in the development of acute movement disorders. Results Acute movement disorder's involve complex interactions between frontal-subcortical circuits and acute events. Given the complexity of interactions, psychopharmacological considerations become critical, as some treatments may alleviate acute movement disorders while others will exacerbate them. Conclusion Integrating underlying medical conditions and acutely administered (or discontinued) pharmacological agents offers an interactional, neuromedical approach to acute movement disorders that is critical to the work of psychosomatic medicine. PMID- 28629286 TI - Psychotherapy for cancer patients. AB - Objective Psychotherapy is a common non-pharmacological approach to help cancer patients in their psychological distress. The benefit of psychotherapies was documented, but the types of psychotherapies proposed are varied. Given that the previous literature review was a decade ago and no quantitative analysis was done on this topic, we again critically and systematically reviewed all published trials on psychotherapy in cancer patients. Method We identified 17 clinical trials on six types of psychotherapy for cancer patients by searching PubMed and EMBASE. Result There were four trials involved adjunct psychological therapy which were included in quantitative analysis. Each trial demonstrated that psychotherapy improved the quality of life and coping in cancer patients. There was also a reduction in distress, anxiety, and depression after a psychological intervention. However, the number and quality of clinical trials for each type of psychotherapy were poor. The meta-analysis of the four trials involved adjunct psychological therapy showed no significant change in depression, with only significant short-term improvement in anxiety but not up to a year-the standardized mean differences were -0.37 (95% confidence interval (CI) = -0.57, 0.16) at 2 months, -0.21 (95% CI = -0.42, -0.01) at 4 months, and 0.03 (95 % CI = -0.19, 0.24) at 12 months. Conclusion The evidence on the efficacy of psychotherapy in cancer patients is unsatisfactory. There is a need for more rigorous and well-designed clinical trials on this topic. PMID- 28629288 TI - P53 Mutation and Epigenetic Imprinted IGF2/H19 Gene Analysis in Mesenchymal Stem Cells Derived from Amniotic Fluid, Amnion, Endometrium, and Wharton's Jelly. AB - Mesenchymal stem cells (MSC) are promising cells for medical therapy. In in vitro expansion, MSC can give rise to progeny with genomic and epigenomic alterations, resulting in senescence, loss of terminal differentiation, and transformation to cancer. However, MSC genome protects its genetic instability by a guardian function of the P53 tumor suppressor gene and epigenetic balance system during MSC culture. Mutations of P53 and epigenetic alterations have been reported to disrupt the quality and quantity of MSC and initiate tumorigenesis. We monitor P53 and epigenetic changes in MSC derived from amniotic fluid (AF-MSC), amnion membrane (AM-MSC), endometrium (EM-MSC), and Wharton's jelly (WJ-MSC) by the missense mutation analysis of the P53 gene and the expression levels of P53, and epigenetic insulin-like growth factor 2 (IGF2) and H19-imprinted genes. Our work demonstrates a variation of P53 expression among different MSC types. AF-MSC has a high P53 expression level with retaining a stability of P53 expression throughout a long culture period, whereas EM-MSC and WJ-MSC showed variation of P53 gene expression during culture. Epigenetic analysis showed a stable H19 expression pattern in AF-MSC, AM-MSC, and EM-MSC culture, whereas H19 expression fluctuated in WJ-MSC culture. We conclude that gene instability can be found during in vitro MSC expansion. With awareness to MSC quality and safety in MSC transformation risk, P53 mutation and IGF2 and H19-imprinted gene analysis should be applied to monitor in therapeutic-grade MSC. We also demonstrated that AF-MSC is one of the most interesting MSC for medical therapy because of its high genomic stability and epigenetic fidelity. PMID- 28629287 TI - Anti-acetylcholinesterase activity and antioxidant properties of extracts and fractions of Carpolobia lutea. AB - CONTEXT: There is an unmet need to discover new treatments for Alzheimer's disease. This study determined the anti-acetylcholinesterase (AChE) activity, DPPH free radical scavenging and antioxidant properties of Carpolobia lutea G. Don (Polygalaceae). OBJECTIVE: The objective of this study is to quantify C. lutea anti-AChE, DPPH free radical scavenging, and antioxidant activities and cell cytotoxicity. MATERIALS AND METHODS: Plant stem, leaves and roots were subjected to sequential solvent extractions, and screened for anti-AChE activity across a concentration range of 0.02-200 MUg/mL. Plant DPPH radical scavenging activity, reducing power, and total phenolic and flavonoid contents were determined, and cytotoxicity evaluated using human hepatocytes. RESULTS: Carpolobia lutea exhibited concentration-dependent anti-AChE activity. The most potent inhibitory activity for the stem was the crude ethanol extract and hexane stem fraction oil (IC50 = 140 MUg/mL); for the leaves, the chloroform leaf fraction (IC50 = 60 MUg/mL); and for roots, the methanol, ethyl acetate and aqueous root fractions (IC50 = 0.3-3 MUg/mL). Dose-dependent free radical scavenging activity and reducing power were observed with increasing stem, leaf or root concentration. Total phenolic contents were the highest in the stem: ~632 mg gallic acid equivalents/g for a hexane stem fraction oil. Total flavonoid content was the highest in the leaves: ~297 mg quercetin equivalents/g for a chloroform leaf fraction. At 1 MUg/mL, only the crude ethanol extract oil was significantly cytotoxic to hepatocytes. DISCUSSION AND CONCLUSIONS: Carpolobia lutea possesses anti-AChE activity and beneficial antioxidant capacity indicative of its potential development as a treatment of Alzheimer's and other diseases characterized by a cholinergic deficit. PMID- 28629289 TI - Mania induced by adalimumab in a patient with ankylosing spondylitis. AB - Objectives Monoclonal antibodies such as antagonists of tumor necrosis factor alpha have been shown to have beneficial effects on the well-being of patients with inflammatory illnesses. However, mood episodes triggered by such agents have been reported. We herein report the case of mania induced by adalimumab treatment in an adult with ankylosing spondylitis, which later resolved once adalimumab was discontinued and mood stabilizers were initiated. Methods A 25-year-old man, with prior history of dysthymia, was diagnosed with ankylosing spondylitis and started on adalimumab. He gradually developed manic symptoms over seven to eight months, while maintained on adalimumab. As his condition did not improve with outpatient management, the patient was admitted to the Psychiatry inpatient unit. Results Valproate and aripiprazole were initiated, and adalimumab was substituted with non-steroidal anti-inflammatory agents. Mood symptoms resolved within days, and the patient was discharged. Upon follow-up, the patient was euthymic and compliant to his psychotropic medications. He was started on certolizumab, a different immunomodulatory, for his ankylosing spondylitis. Conclusions Immunological modulation might be a key factor in triggering, maintaining, or treating mood symptoms. Further research in this field is warranted to better understand the pathophysiology of mania. To our knowledge, manic symptoms induced by adalimumab have not been previously reported in the literature, which is why our case report can have an impact in recognizing this important clinical adverse effect. PMID- 28629290 TI - Functional foods: How functional are they? A case report of supplement-induced psychosis. AB - There is rising evidence of patients' use of alternative and complementary medicine. The percentage of the U.S. population who used at least one dietary supplement increased from 42% in 1988-1994 to 53% in 2003-2006. We present a case of an Asian female in her 40s, with no previous psychiatric illness, who presented to the emergency room following a brief psychotic episode, during which she self-amputated the tips of her fingers, after using multivitamins and herbal supplements including ginseng, gui yuan rou (Chinese herb), astaxanthin, goji (Chinese fruit), selenium, saw palmetto, grape seed extract, citrus bioflavanoid, lutein (zeaxantin), resvexatrol, sun chlorella, spirulina powder, phytoceramides, phytoestrogen, glucosatrin, bromelain plus, and American bee pollen. Comprehensive laboratory workup, drug screening, and diagnostic imaging were negative. Vital signs were stable. Other than the amputated finger tips, the remainder of her physical examination was unremarkable. Her mental status improved significantly after treatment with risperidone 1 mg twice daily, during a five-day psychiatric hospitalization. This case draws attention to the fact that supplements have the potential of producing frank psychosis and require close monitoring and study by physicians. PMID- 28629292 TI - Increased blood pressures in veterans with post traumatic stress disorder. AB - Objective Veterans of war affected by posttraumatic stress disorder (PTSD) are at increased risk for cardiovascular diseases. We aimed to compare brachial and central blood pressures between veterans with PTSD and controls. Method In this case-control study on veterans of Iran-Iraq war, 50 veterans with PTSD and 50 veterans as controls were selected from an outpatient clinic and matched for age +/-3 years. Exclusion criteria were malignancies, severe anatomical defects such as amputated extremities, history of PTSD before serving in war, comorbid psychiatric disorders other than anxiety or depressive disorders. Detailed history was taken concerning medical and social aspects. Beck Depression Inventory was used for depressive symptoms. Brachial blood pressures were measured using both auscultatory and oscillometric devices. Measures of central hemodynamics were estimated accordingly. Data on lipid profile were collected either through medical records or newly required lab tests. Results Brachial systolic, diastolic, and pulse pressures as well as estimated central systolic and diastolic pressures were significantly higher in the PTSD group. Beck Depression Inventory scores, frequency of diabetes mellitus, and hypertension were significantly higher in the PTSD group. PTSD status was an independent predictor of both brachial and central systolic and diastolic pressures. Conclusions We demonstrated increased measures of blood pressure in veterans with PTSD independent of depression and other risk factors. Further research is warranted to confirm our results. PMID- 28629291 TI - Chronic pain care. AB - Objective Experiencing pain not only affects patients' biopsychosocial functioning but also the existential domain. Attention to the existential, in addition to the biopsychosocial domains, might thus be important in chronic pain care. Therefore, we investigated: (a) how satisfied patients were with the attention of their practitioners to the impact of pain on biological, psychological, social, and existential life domains, and (b) how satisfaction with each domain was related to patient functioning. Method Pain patients ( N = 163) were questioned on their satisfaction with the attention of their practitioners to biological, psychological, social, and existential life domains, and on pain intensity, pain disability, life satisfaction, and depressive symptoms. Results Patients reported low satisfaction with the attention of their practitioners to the social and existential domains. Satisfaction with each domain was negatively related with pain intensity, pain disability, and depressive symptoms and positively related with life satisfaction. Only satisfaction with the existential domain was able to predict all functional outcomes above and beyond all other satisfaction variables modeled simultaneously. Conclusions Patients reported not feeling satisfied with the attention to the social and existential life domains. Furthermore, practitioners' attention to the existential domain seems highly important for patient functioning. Openness to existential concerns of pain patients might thus be an important aspect of chronic pain care. PMID- 28629293 TI - Clinical efficacy and safety of the Shugan Jieyu capsule in patients with acute myocardial infarction and depression. AB - Objective The aim is to comparatively study Shugan Jieyu capsule and sertraline for non-inferiority in the treatment of patients with acute myocardial infarction and depression (observing the curative effects and safety) by the randomized controlled experiment. Methods A total of 149 patients with acute myocardial infarction and depression were randomly divided into two groups, the Shugan Jieyu group (76 cases) and the sertraline group (73 cases), and received treatments for 24 weeks. Depression states were assessed by the rote diagnostic checklist, and effects were evaluated by the Hamilton depression scale. Drug safety for heart was assessed by left ventricular ejection fraction (reduced by 5%), blood pressure, heart rate, P-wave and R wave interval, Q-R-S complex wave, and corrected Q-T interval after 12 weeks of treatment. Results There were no significant differences in the effective rates of Shugan Jieyu and sertraline groups. Significantly lower adverse event rate was observed in the Shugan Jieyu group. Two groups had a similar cardiac safety. Conclusion Shugan Jieyu capsule has a reliable effect and high safety in patients with acute myocardial infarction and depression. PMID- 28629294 TI - Prevalence of insomnia and related impact. AB - Background Sleep problem is a common geriatric condition that can result in various outcomes, both physical and mental, that reduce quality of life. The studies regarding the prevalence and impact of insomnia on daily activities in Thailand in pre-elderly and elderly adults are few. Objectives The primary objective of this study was to determine the prevalence of insomnia among pre elderly and elderly populations and the secondary objective was to study the impact of insomnia on their daily lives. Methods This study included the participants from the urban middle class in the pre-retirement age of 50 years or older adults who worked for Khon Kaen University (KKU), Khon Kaen, Thailand, and their elderly relatives. Information on baseline characteristics, sleep problems, and outcomes were collected. Descriptive analytical statistics were used to analyze baseline data. Multivariate analysis was used to analyze associated factors of the impact of insomnia. Results A total of 491 participants were recruited. The prevalence of insomnia was 60%. The significant consequences related to insomnia were feeling unrefreshed (adjusted odds ratio (AOD) 2.22, 95% confidence interval (CI) 1.44-3.04), daytime sleepiness (AOD 2.04, 95% CI 1.29 3.22), need for a sedative drug (AOD 4.23, 95% CI 2.09-8.55), depression (AOD 4.74, 95% CI 1.73-13), and impaired attention (AOD 2.29, 95% CI 1.52-3.45). Conclusions Insomnia was found in the majority of pre-elderly and elderly participants and resulted in several poor outcomes. Early detection of insomnia may prevent some inevitable outcomes. PMID- 28629295 TI - Reliability and validity of Somali version of the PHQ-9 in primary care practice. AB - Objectives Depression is one of the common mental health problems noticed in immigrants because of the experiences related to their resettlement which is the case for Somali population. Depression increases mortality, morbidity, disability, and costs of health care which can be controlled by screening depression in the primary care setting using a culturally and linguistically congruent screening tool. The aim of the current study is to translate the English PHQ-9 into Somali language using evidence-based translational methodology and establish psychometric properties of the Somali PHQ-9. Methods The initial validation of the Somali PHQ-9 was studied by comparing the original and back translation versions using the comparability and interpretability tool in a sample of 56 monolingual health care professionals. The reliability and validity of the Somali version were established by psychometric analysis in a sample of 47 bilingual health-care workers. Results Cronbach's alpha was 0.79 for the Somali version with the inter-item correlation mean of 0.33 and item-to-total correlation mean in the range of 0.40-0.80 ( p < 0.01). Pearson correlation for the item-to-item correlation between English and Somali version was between 0.70 and 0.93 ( p < 0.01) with the paired t-test showing no significant difference between the item means. Conclusions The Somali PHQ-9 showed a good reliability, homogeneity, and internal consistency. The construct validity for the Somali PHQ 9 was also established showing that the Somali PHQ-9 has similar reliability and validity like the other translated versions of PHQ-9. PMID- 28629296 TI - Atypical antipsychotic use and outcomes in an urban maternal mental health service. AB - Objective Despite many women suffering from psychosis in their childbearing years, limited data exist about the use of atypical antipsychotic agents in pregnancy. Atypical antipsychotic agents are often used to treat bipolar disorder, instead of lithium or valproate because of the known teratogenicity of those agents. As well, atypical antipsychotics are often prescribed in anxiety disorders and depression. This study sought to describe pregnancy outcomes for women prescribed atypical antipsychotics during pregnancy. Methods This retrospective review included all cases treated by Auckland Maternal Mental Health services in which atypical antipsychotic agents were utilized during pregnancy over three years. Results Over the three years, 45 pregnant women were prescribed atypical antipsychotic agents, most commonly quetiapine or olanzapine. Two-fifths (40%) were diagnosed with bipolar disorder and almost one-third (31%) with a psychotic disorder. Two-thirds (64%) were prescribed multiple psychotropic medications during their pregnancy. Instrumental delivery rates were elevated at 38%. A minority (13%) of the women developed gestational diabetes mellitus. Although 7% of infants were born premature, all were born after 35 weeks. Two major malformations were noted, similar to baseline community rates. Conclusions This naturalistic study adds to the limited literature about treatment with atypical antipsychotic agents in pregnancy, though not adequately powered to detect small differences in malformations or obstetrical outcomes. It also highlights the myriad of indications for which pregnant women are prescribed atypical antipsychotics, and the multiple other risk factors seen in this population. PMID- 28629297 TI - Correlates of waterpipe smoking among Iranian university students and the role of religiosity. AB - Waterpipe smoking among youth and adolescents in Iran has gained in popularity. The aim of this study was to investigate the relationship between waterpipe smoking and different dimensions of religiosity in a sample of students attending two major universities in South East Iran. A total of 682 students completed a waterpipe and cigarette smoking questionnaire along with the Duke University Religion Index. The lifetime prevalence of dual cigarette and waterpipe use was 48.3%, with prevalence of current use (within the last 30 days) of 24.9%. The proportions of lifetime and current waterpipe-only users were 27.0% and 18.8%, respectively. Students who participated more often in private religious activities were less likely to report engaging in waterpipe smoking (odds ratio: 0.82; 95% confidence interval: 0.71-0.98). A higher level of attendance of religious services was negatively associated with dual cigarette and waterpipe smoking (odds ratio: 0.71; 95% confidence interval: 0.54-0.93). Waterpipe-only use was significantly higher among males, students who had lower grade point averages, those who reported having a close friend or a family member who was a waterpipe smoker. To conclude, it is possible that religious observance may have a protective role in lowering waterpipe usage among Iranian university students. PMID- 28629298 TI - Anxiety and depression are improved by continuous positive airway pressure treatments in obstructive sleep apnea. AB - Background Obstructive sleep apnea involves repeated nocturnal desaturation and sleep fragmentation that leads to poor sleep quality, anxiety, and depression. This study aimed to investigate short- and long-term improvements in the anxiety and depression of patients with different obstructive sleep apnea treatments. Methods This is a prospective, non-randomized hospital-based study evaluated 55 patients (46 male, 9 female) with obstructive sleep apnea. The patients were divided into three groups based on different treatment: uvulopalatopharyngoplasty group, continuous positive airway pressure group, and no treatment group (by their own decision). They completed the Beck Depression Inventory II, Beck Anxiety Inventory, and Pittsburgh Sleep Quality Index before treatment and at one and six months after treatment. Results Compared to the no treatment group, the surgery and continuous positive airway pressure groups had higher body mass index, AHI, and Epworth sleepiness scale, but no difference in Pittsburgh Sleep Quality Index, Chinese Health Questionnaire-12, Beck Depression Inventory II, and Beck Anxiety Inventory. The continuous positive airway pressure and surgery groups still had no improvements in Pittsburgh Sleep Quality Index, Chinese Health Questionnaire-12, Beck Depression Inventory II, and Beck Anxiety Inventory scores one month after treatment. At six months after treatment, the continuous positive airway pressure group had significantly decreased Pittsburgh Sleep Quality Index, Chinese Health Questionnaire-12, Beck Depression Inventory II, and Beck Anxiety Inventory, whereas the surgery group had significant difference in Beck Anxiety Inventory only and the no treatment group still had no significant difference in any of the parameters. Conclusions Continuous positive airway pressure can improve the sleep quality, quality of life, depression, and anxiety of obstructive sleep apnea patients after six months of treatment. However, surgery can significantly improve anxiety only in the same period. PMID- 28629299 TI - Farm and cow-level prevalence of bovine digital dermatitis on dairy farms in Taranaki, New Zealand. AB - AIMS: The aims of this cross-sectional study were to investigate the herd and cow level prevalence of bovine digital dermatitis (BDD) in dairy farms in the northern Taranaki region of New Zealand, and to identify whether there was any spatial clustering of herds with the disease. METHODS: A survey of 224 dairy farms in the northern Taranaki region of New Zealand was undertaken from September 2014 to February 2015. Following training in robust criteria to confirm BDD visually, a technician inspected the rear feet of every milking cow on the farms during milking. The identity of cows with lesions and the feet involved were recorded. The proportion of cows affected among the inspected population (cow-level prevalence), the proportion of a herd affected (farm-level prevalence), and proportion of farms with >=1 cow with lesions, were calculated. A bivariate K function analysis was then used to assess whether farms with >=1 cow with lesions were clustered, after accounting for the distribution of the farms involved in the study. RESULTS: Bovine digital dermatitis lesions were observed on 143/224 (63.8 (95% CI=57.5-70.1)%) farms. Within-farm prevalence was 0% on 81 (36.2%) farms, between >0 and <3% on 120 (53.5%) farms, with a maximum prevalence of 12.7% on one farm. Overall, cow-level prevalence was 707/60,455 (1.2 (95% CI=0.9-3.0)%), and on affected farms was 707/41,116 (1.7 (95% CI=1.4 2.1)%). In affected cows, 268/707 (37.9%) had a lesion on left foot only, 262/707 (37.1%) on the right foot only and 177/707 (25.0%) on both feet. The K function analysis showed no evidence of clustering of farms with BDD. CONCLUSIONS: Bovine digital dermatitis was widespread among the survey farms, but there was no evidence that there was any clustering of herds with BDD. The cow-level prevalence on affected farms was much lower than reported elsewhere. CLINICAL RELEVANCE: Although the prevalence at the cow level was low, if these data are representative of other regions of New Zealand, BDD could easily become a major problem on dairy farms in New Zealand, as has been observed in other countries. PMID- 28629300 TI - Dynamic Interplay of Pharmacy Learners During a Solid Organ Transplantation Learning Experience. AB - Institutions with established clinical pharmacy services have the ability to offer focused patient care learning experiences, often led by a clinical specialist, for pharmacy residents and pharmacy students. Since all parties are continually involved in professional development and lifelong learning, the aforementioned groups can all be considered "pharmacy learners." By utilizing the dynamic interplay and collaboration between pharmacy learners through direct and nondirect patient care activities, experiential and educational opportunities may be improved and enhanced for each learner. A tiered learning approach engages individuals in areas such as direct patient care, patient education, presentations, research projects, career development, and the feedback process. We describe our experience during a solid organ transplantation learning experience using a layered learning practice model that included a clinical pharmacy specialist, a postgraduate year 2 specialty pharmacy resident, a postgraduate year 1 pharmacy resident, and a pharmacy student. PMID- 28629301 TI - Discrepancies Identified Through a Telephone-Based, Student-Led Initiative for Medication Reconciliation in Ambulatory Psychiatry. AB - PURPOSE: To identify the number of medication discrepancies following establishment of a telephone-based, introductory pharmacy practice experience student-driven, medication reconciliation service for new patients in an ambulatory psychiatry clinic. Secondarily, to identify factors impacting medication discrepancies to better target medication profiles to reconcile and to evaluate whether the implementation of a call schedule effected clinic no-show rates. METHODS: This was a retrospective analysis of a telephone-based medication reconciliation service from June 2014 to January 2016. RESULTS: At least 1 medication discrepancy was identified among 84.7% of medication profiles (N = 438), with a total of 1416 medication discrepancies reconciled (3.2 discrepancies per patient). Of the 1416 discrepancies, 38.6% were deletions, 38.9% were additions, and 22.5% were changes in dosage strength or frequency. Discrepancies pertaining to prescription medications totaled 57.8%. Student pharmacists were critical team members in the service. Patient's age, number of medications on the patient's list, and number of days since the last medication reconciliation were not clinically significant determinants for targeting medication profiles. There was a statistically significant reduction in the clinic no-show rates following implementation of a call schedule compared with no-show rates prior to call schedule implementation. CONCLUSION: This student pharmacist-led telephone medication reconciliation service demonstrated the importance of medication reconciliation in ambulatory psychiatry by identifying numerous discrepancies within this population. Further, we demonstrated pharmacy students across various levels of education can assist in this process under the supervision of a pharmacist. PMID- 28629302 TI - "Pimping" in Pharmacy Education: A Survey and Comparison of Student and Faculty Views. AB - BACKGROUND: "Pimping" is an informal teaching technique that is widely used in medical education. Pimping is characterized by questioning the learner with the intent of reinforcing clinical hierarchy. To date, there are no studies of the use of pimping in pharmacy education. OBJECTIVES: To describe the use of pimping as a teaching method in pharmacy education and to compare student and faculty perceptions of this technique. METHODS: Faculty and fourth-year PharmD (P4) students from 2 colleges of pharmacy were invited to participate in a survey about experiences and perceptions of pimping. Faculty and P4 surveys each contained up to 17 items to assess personal experiences, utilization, perceived risks and benefits, and preferences regarding the role of the technique in pharmacy education. RESULTS: The response rate was 49.5% (159 of 321). Of faculty, 74.1% reported they had been pimped in their training, but less than half (45.8%) use pimping themselves. Similarly, 73.7% of students reported that they had been pimped at some time in their pharmacy education. Students nearly equally viewed their experiences as positive (35.3%) versus negative (38.2%). Responses were similar between faculty and students recommending that the method should be avoided entirely ( P = .259), used sparingly ( P = .072), or used consistently ( P = .309). Perceived benefits and risks of pimping were similar between faculty and students, but there were many differences in rationales offered by faculty versus students' perceived rationales. CONCLUSION: Pimping is common in pharmacy education and its use is controversial. The perceived rationale for use of pimping differs, which may undermine student/faculty relationships. PMID- 28629303 TI - Dual Antiplatelet Therapy Beyond One Year in Patients After Stent Placement: A Review. AB - PURPOSE: To review the evidence on the safety and efficacy of the continued use of dual antiplatelet therapy (DAPT) beyond 12 months after stent placement in patients following an acute coronary syndrome (ACS) event. SUMMARY: Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released a focused update on the duration of DAPT in patients with coronary artery disease (CAD). The update makes new recommendations about the duration of DAPT in light of recently performed studies investigating this topic. In regard to patients after an ACS event, the update states it is reasonable to continue DAPT beyond 1 year if these patients are not at a high risk of bleeding and had no overt bleeding while on DAPT. Several trials have been released which aim to provide information about the correct duration of DAPT after an ACS event. CONCLUSION: Recent trials have shown a benefit of prolonged (beyond 12 months) DAPT in preventing recurrent cardiovascular (CV) events in patients, mostly in patients who have had a previous myocardial infarction (MI). These benefits must be weighed with the elevated risks of bleeding. PMID- 28629304 TI - Board of Pharmacy Practices Related to Medication Errors and Their Potential Impact on Patient Safety. AB - State boards of pharmacy are generally responsible for the governance of the practice of pharmacy. While the regulatory process and methods for accomplishing this task may vary by state, all boards of pharmacy must address medication errors committed by pharmacists. The National Association of Boards of Pharmacy (NABP) has recommended that state boards of pharmacy implement best practices and enforcement actions that are aimed to promote patient safety and reduce medication errors. The current study was designed to identify and compare current corrective action practices among boards of pharmacy in response to medication errors. An electronic survey regarding board policies and anticipated board actions in response to hypothetical medication error scenarios was sent to boards of pharmacy for completion. Approximately 45% of pharmacy boards responded. Survey responses demonstrated that corrective actions and consequences were levied against pharmacists inconsistently among state boards. Corrective action plans and process improvement components were lacking in a majority of state board of pharmacy practices. Medication safety education for pharmacists and for members on boards of pharmacy was insufficient in many states. Responses to hypothetical error scenarios indicated that most board actions are educational and punitive in nature, rather than focusing on systems improvement. PMID- 28629305 TI - Evaluation of cost and length of stay, linked to complications associated with major surgical procedures. AB - INTRODUCTION: A lot of studies have demonstrated the possibility of reducing the number of post-operative complications in the domain of major surgical procedures with the use of medical preventive techniques. However, complications following surgical procedures are unfortunately frequent and are a major problem, not only because of the impact for the patient, but also because of economic consequences that they provoke. The aim of the present study is to evaluate the extra length of stay and the extra cost, born by the hospital and the social security, linked to complications, incurring after major surgical procedures. MATERIAL AND METHODS: Study based on the data from 13 Belgian hospitals for the year 2012. Complications were extracted through medical discharge summaries. The cost born by the social security was assessed on the basis of the billing data, hospital cost are taken from cost accounting studies. RESULTS: The rate of complication for all the hospitals is 6.6%. About 30.3% of inpatient stays having a major or extreme severity of index had a complication during the stay, 1.8% of stays with a minor or moderate severity of index had a complication. The extra length of stay is 19.38 days when the stay has had a complication (p < 0.001). The additional mean cost borne from the hospital perspective is ?21 353.07 and ?8 026.65 for the social security. This additional mean cost varies greatly from one hospital to another. DISCUSSION/CONCLUSION: The present study has shown that the actual financing do not cover real hospital costs in the field of major surgical procedures having caused complications. Results should encourage Belgian authorities to propose and finance preventive measures in order to reduce these complications, which represent major economic impacts, not only for authorities but also for hospitals. PMID- 28629306 TI - beta-CA-specific inhibitor dithiocarbamate Fc14-584B: a novel antimycobacterial agent with potential to treat drug-resistant tuberculosis. AB - Inhibition of novel biological pathways in Mycobacterium tuberculosis (Mtb) creates the potential for alternative approaches for treating drug-resistant tuberculosis. In vitro studies have shown that dithiocarbamate-derived beta carbonic anhydrase (beta-CA) inhibitors Fc14-594 A and Fc14-584B effectively inhibit the activity of Mtb beta-CA enzymes. We screened the dithiocarbamates for toxicity, and studied the in vivo inhibitory effect of the least toxic inhibitor on M. marinum in a zebrafish model. In our toxicity screening, Fc14-584B emerged as the least toxic and showed minimal toxicity in 5-day-old larvae at 300 uM concentration. In vitro inhibition of M. marinum showed that both compounds inhibited growth at a concentration of 75 uM. In vivo inhibition studies using 300 uM Fc14-584B showed significant (p > .05) impairment of bacterial growth in zebrafish larvae at 6 days post infection. Our studies highlight the therapeutic potential of Fc14-584B as a beta-CA inhibitor against Mtb, and that dithiocarbamate compounds may be developed into potent anti-tuberculosis drugs. PMID- 28629307 TI - Tumor Reversion: Mesenchymal-Epithelial Transition as a Critical Step in Managing the Tumor-Microenvironment Cross-Talk. AB - Tumour reversion represents a promising field of investigation. The occurrence of cancer reversion both in vitro and in vivo has been ascertained by an increasing number of reports. The reverting process may be triggered in a wide range of different cancer types by both molecular and physical cues. This process encompasses mandatorily a change in the cell-stroma interactions, leading to profound modification in tissue architecture. Indeed, cancer reversion may be obtained by only resetting the overall burden of biophysical cues acting on the cell-stroma system, thus indicating that conformational changes induced by cell shape and cytoskeleton remodelling trigger downstream the cascade of molecular events required for phenotypic reversion. Ultimately, epigenetic regulation of gene expression (chiefly involving presenilin-1 and translationally controlled tumour protein) and modulation of a few critical biochemical pathways trigger the mesenchymal-epithelial transition, deemed to be a stable cancer reversion. As cancer can be successfully 'reprogrammed' by modifying the dynamical cross-talk with its microenvironment thus the cell-stroma interactions must be recognized as targets for pharmacological intervention. Yet, understanding cancer reversion remains challenging and refinement in modelling such processes in vitro as well as in vivo is urgently warranted. This new approach bears huge implications, from both a theoretical and clinical perspective, as it may facilitate the design of a novel anticancer strategy focused on mimicking or activating the tumour reversion pathway. PMID- 28629308 TI - Comments from Editor-in-Chief, CPPS. PMID- 28629309 TI - Editorial: Conventional, Traditional and Alternative Therapies for Cardiovascular Disorders. Part 2: Traditional Therapy. PMID- 28629310 TI - Editorial: Identification of Lead Compounds Using Metabolomic Analysis in Drug Discovery. PMID- 28629312 TI - Editorial: Advanced Big-Data Analysis Methods and Tools for High-Throughput Omics Technologies. PMID- 28629311 TI - Cell Cycle Arrest and Apoptosis Induction Activity of Nitidine Chloride on Acute Myeloid Leukemia Cells. AB - BACKGROUND: Acute myeloid leukemia (AML) is the most common hematological malignancy in adults, characterized by distorted proliferation and development of myeloid cells and their precursors in the bone marrow. Nitidine chloride, a naturally occurring alkaloid, has been identified to possess antitumor activity. However, the effects of nitidine chloride on acute myeloid leukemia cells and its underlying mechanisms have not been elucidated. Here we investigated the cellular and molecular mechanism of the anti-leukemic effects of nitidine chloride. METHODS AND RESULTS: Nitidine chloride treatment for 48 consecutive hours exhibited a timedependent and dose-dependent growth inhibition activity against AML cells by inducing cell cycle arrest and apoptosis. Moreover, nitidine chloride downregulated Cyclin B1, CDK1 and Bcl-2, upregulated p27 and Bax, inactivated PARP, activated Caspase-3 in AML cells. We further demonstrated that growth inhibition activity of nitidine chloride in AML cells is partially via inhibiting the phosphorylation of AKT and ERK. CONCLUSION: In conclusion, our data suggest that nitidine chloride could be an effective therapeutic agent against AML via cell cycle arrest and apoptosis. PMID- 28629313 TI - EDITORIAL: Spicing Up the Management of Type 2 Diabetes with Cinnamon. PMID- 28629314 TI - Erratum to: Standardizing effect size from linear regression models with log transformed variables for meta-analysis. PMID- 28629315 TI - Erratum to: Life and living in advanced age: a cohort study in New Zealand -Te Puawaitanga o Nga Tapuwae Kia Ora Tonu, LiLACS NZ: study protocol. PMID- 28629316 TI - A multiplex primer design algorithm for target amplification of continuous genomic regions. AB - BACKGROUND: Targeted Next Generation Sequencing (NGS) assays are cost-efficient and reliable alternatives to Sanger sequencing. For sequencing of very large set of genes, the target enrichment approach is suitable. However, for smaller genomic regions, the target amplification method is more efficient than both the target enrichment method and Sanger sequencing. The major difficulty of the target amplification method is the preparation of amplicons, regarding required time, equipment, and labor. Multiplex PCR (MPCR) is a good solution for the mentioned problems. RESULTS: We propose a novel method to design MPCR primers for a continuous genomic region, following the best practices of clinically reliable PCR design processes. On an experimental setup with 48 different combinations of factors, we have shown that multiple parameters might effect finding the first feasible solution. Increasing the length of the initial primer candidate selection sequence gives better results whereas waiting for a longer time to find the first feasible solution does not have a significant impact. CONCLUSIONS: We generated MPCR primer designs for the HBB whole gene, MEFV coding regions, and human exons between 2000 bp to 2100 bp-long. Our benchmarking experiments show that the proposed MPCR approach is able produce reliable NGS assay primers for a given sequence in a reasonable amount of time. PMID- 28629317 TI - Surface hypothermia predicts murine mortality in the intragastric Vibrio vulnificus infection model. AB - BACKGROUND: The Gram-negative bacterium Vibrio vulnificus can cause severe disease in humans who consume undercooked, contaminated seafood. To study food borne V. vulnificus disease in the laboratory, mouse virulence studies predominantly use death as the primary experimental endpoint because behaviorally based moribund status does not consistently predict lethality. This study assessed ventral surface temperature (VST) and its association with mouse survival during V. vulnificus virulence studies as an efficacious, humane alternative. METHODS: VST of mice intragastrically inoculated with V. vulnificus was measured every 2-h for 24 h and data for minimal VST analyzed for prediction of lethal outcome. RESULTS: In contrast to the relatively stable VST of mock infected control animals, mice infected with V. vulnificus exhibited hypothermia with minima occurring 8 to 12 h post-inoculation. The minimum VST of mice that proceeded to death was significantly lower than that of surviving mice. VST <= 23.5 degrees C was predictive of subsequent death with a sensitivity of 68% and specificity of 95%. CONCLUSIONS: Use of VST <= 23.5 degrees C as an experimental endpoint during V. vulnificus infection has potential to reduce suffering of nearly 70% of mice for a mean of 10 h per mouse, without compromising experimental efficacy. Temperature cutoff of 23.5 degrees C exhibited 93% positive and 77% negative predictive value. For future V. vulnificus virulence studies requiring only binary comparison (e.g., LD50 assays), we find that VST can be applied as a humane endpoint. However, use of VST is not recommended when detailed survival kinetics are desired. PMID- 28629318 TI - The effect of a daily application of a 0.05% chlorhexidine oral rinse solution on the incidence of aspiration pneumonia in nursing home residents: a multicenter study. AB - BACKGROUND: Dysphagia and potential respiratory pathogens in the oral biofilm are risk factors for aspiration pneumonia in nursing home residents. The aim of the study was to examine if the daily application of 0.05% chlorhexidine oral rinse solution is effective in reducing the incidence of aspiration pneumonia in nursing home residents with dysphagia. Associations between background variables (age, gender, dysphagia severity, care dependency, medication use, number of medical diagnoses, teeth and dental implants, and wearing removable dentures) and the incidence of aspiration pneumonia were also examined. METHODS: This study is a multicenter study in which for 1 year participants with dysphagia in the intervention group received the usual oral hygiene care with the addition of a 0.05% chlorhexidine oral rinse solution, whereas participants in the control group received only oral hygiene care. RESULTS: Data of 103 participants in 17 nursing homes were analyzed. Survival analysis showed no significant difference in the incidence of pneumonia between both groups (Cox regression, HR = 0.800; 95% CI [0.368-1.737], p = 0.572). Cox regression analysis for Functional Oral Intake Scale (FOIS)-level showed a significant risk of the incidence of pneumonia (HR = 0.804; 95% CI [0.656-0.986], p = 0.036). After adjustment for Group and FOIS-level, Cox multivariate proportional hazard regression analysis showed that the variables age, gender, Care-dependency Scale-score (CDS) number of diseases, medication use, number of teeth, and the presence of dental implants or removable dentures were not significantly associated with the incidence of pneumonia. CONCLUSIONS: Chlorhexidine oral rinse solution 0.05% as an adjunctive intervention in daily oral hygiene care was not found to reduce incidence of aspiration pneumonia. The requested number of participants to achieve sufficient power was not established and high drop-out rate and non-structural compliance was present. The power was considered to be sufficient to analyze the associations between the background variables and the incidence of pneumonia in the included nursing home residents with dysphagia. Dysphagia was found to be a risk factor for aspiration pneumonia. TRIAL REGISTRATION: Registration in The Netherlands National Trial Register: TC = 3515. Approval for the study was obtained from the Medical Ethical Committee of the Radboud University Medical Center (NL. nr:41,990.091.12). PMID- 28629319 TI - Polymorphism in asparagine synthetase is associated with overall survival of hepatocellular carcinoma patients. AB - BACKGROUND: Recently, it is reported that asparagine synthetase (ASNS) is an independent predictor of surgical survival in hepatocellular carcinoma (HCC) patients. It is also reported that activating transcription factor 6 (ATF6) expression is decreased in HCC patients. So in the present study, we explored the relationship between ASNS and ATF6, and whether ASNS expression was associated with HCC. METHODS: ATF6 was over expressed in 3 HCC cell lines (HepG2, HepG2.2.15 and SMMC-7721). We then examined the mRNA levels of ASNS and ATF6 in 90 HCC patients, 77 chronic hepatitis B patients and 70 controls. We also genotyped 2 functional polymorphisms in ASNS in a case-control study. RESULTS: The expression of ASNS was significantly elevated when ATF6 was over expressed. The expressions of these 2 genes were both decreased in HCC patients, and it was more significantly with ASNS. The mRNA levels of ASNS and ATF6 were positively correlated with each other. rs34050735 was associated with HCC in the case control study (P = 0.003) and also an independent predictor of overall survival of HCC patients (P = 0.001). CONCLUSIONS: Taken together, these findings indicated that rs34050735 in ASNS may associate with HCC and may be a promising biomarker of HCC. PMID- 28629320 TI - Transcriptomic changes reveal gene networks responding to the overexpression of a blueberry DWARF AND DELAYED FLOWERING 1 gene in transgenic blueberry plants. AB - BACKGROUND: Constitutive expression of the CBF/DREB1 for increasing freezing tolerance in woody plants is often associated with other phenotypic changes including dwarf plant and delayed flowering. These phenotypic changes have been observed when Arabidopsis DWARF AND DELAYED FLOWERING 1 (DDF1) was overexpressed in A. thaliana plants. To date, the DDF1 orthologues have not been studied in woody plants. The aim of this study is to investigate transcriptomic responses to the overexpression of blueberry (Vaccinium corymbosum) DDF1 (herein, VcDDF1-OX). RESULTS: The VcDDF1-OX resulted in enhanced freezing tolerance in tetraploid blueberry plants and did not result in significant changes in plant size, chilling requirement, and flowering time. Comparative transcriptome analysis of transgenic 'Legacy-VcDDF1-OX' plants containing an overexpressed VcDDF1 with non transgenic highbush blueberry 'Legacy' plants revealed the VcDDF1-OX derived differentially expressed (DE) genes and transcripts in the pathways of cold response, plant flowering, DELLA proteins, and plant phytohormones. The increase in freezing tolerance was associated to the expression of cold-regulated genes (CORs) and the ethylene pathway genes. The unchanged plant size, dormancy and flowering were due to the minimal effect of the VcDDF1-OX on the expression of DELLA proteins, flowering pathway genes, and the other phytohormone genes related to plant growth and development. The DE genes in auxin and cytokinin pathways suggest that the VcDDF1-OX has also altered plant tolerance to drought and high salinity. CONCLUSION: A DDF1 orthologue in blueberry functioned differently from the DDF1 reported in Arabidopsis. The overexpression of VcDDF1 or its orthologues is a new approach to increase freezing tolerance of deciduous woody plant species with no obvious effect on plant size and plant flowering time. PMID- 28629321 TI - The biocontrol agent Pseudomonas chlororaphis PA23 primes Brassica napus defenses through distinct gene networks. AB - BACKGROUND: The biological control agent Pseudomonas chlororaphis PA23 is capable of protecting Brassica napus (canola) from the necrotrophic fungus Sclerotinia sclerotiorum via direct antagonism. While we have elucidated bacterial genes and gene products responsible biocontrol, little is known about how the host plant responds to bacterial priming on the leaf surface, including global changes in gene activity in the presence and absence of S. sclerotiorum. RESULTS: Application of PA23 to the aerial surfaces of canola plants reduced the number of S. sclerotiorum lesion-forming petals by 91.1%. RNA sequencing of the host pathogen interface showed that pretreatment with PA23 reduced the number of genes upregulated in response to S. sclerotiorum by 16-fold. By itself, PA23 activated unique defense networks indicative of defense priming. Genes encoding MAMP triggered immunity receptors detecting flagellin and peptidoglycan were downregulated in PA23 only-treated plants, consistent with post-stimulus desensitization. Downstream, we observed reactive oxygen species (ROS) production involving low levels of H2O2 and overexpression of genes associated with glycerol 3-phosphate (G3P)-mediated systemic acquired resistance (SAR). Leaf chloroplasts exhibited increased thylakoid membrane structures and chlorophyll content, while lipid metabolic processes were upregulated. CONCLUSION: In addition to directly antagonizing S. sclerotiorum, PA23 primes the plant defense response through induction of unique local and systemic defense networks. This study provides novel insight into the effects of biocontrol agents applied to the plant phyllosphere. Understanding these interactions will aid in the development of biocontrol systems as an alternative to chemical pesticides for protection of important crop systems. PMID- 28629322 TI - Construction of high-density genetic map and QTL mapping of yield-related and two quality traits in soybean RILs population by RAD-sequencing. AB - BACKGROUND: One of the overarching goals of soybean breeding is to develop lines that combine increased yield with improved quality characteristics. High-density marker QTL mapping can serve as an effective strategy to identify novel genomic information to facilitate crop improvement. In this study, we genotyped a recombinant inbred line (RIL) population (Zhonghuang 24 * Huaxia 3) using a restriction-site associated DNA sequencing (RAD-seq) approach. A high-density soybean genetic map was constructed and used to identify several QTLs that were shown to influence six yield-related and two quality traits. RESULTS: A total of 47,472 single-nucleotide polymorphisms (SNPs) were detected for the RILs that were integrated into 2639 recombination bin units, with an average distance of 1.00 cM between adjacent markers. Forty seven QTLs for yield-related traits and 13 QTLs for grain quality traits were found to be distributed on 16 chromosomes in the 2 year studies. Among them, 18 QTLs were stable, and were identified in both analyses. Twenty six QTLs were identified for the first time, with a single QTL (qNN19a) in a 56 kb region explaining 32.56% of phenotypic variation, and an additional 10 of these were novel, stable QTLs. Moreover, 8 QTL hotpots on four different chromosomes were identified for the correlated traits. CONCLUSIONS: With RAD-sequencing, some novel QTLs and important QTL clusters for both yield related and quality traits were identified based on a new, high-density bin linkage map. Three predicted genes were selected as candidates that likely have a direct or indirect influence on both yield and quality in soybean. Our findings will be helpful for understanding common genetic control mechanisms of co localized traits and to select cultivars for further analysis to predictably modulate soybean yield and quality simultaneously. PMID- 28629323 TI - Fetal death in utero and miscarriage in a patient with Crohn's disease under therapy with ustekinumab: case-report and review of the literature. AB - BACKGROUND: Ustekinumab is a fully human monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 which is involved in the pathogenesis of several inflammatory diseases. Ustekinumab is approved for psoriasis and psoriatic arthritis treatment and has been successfully evaluated in phase II and III trials for patients with Crohn's disease (CD). CASE PRESENTATION: We report here the case of a patient who became pregnant during treatment with ustekinumab for a refractory CD and which ended in miscarriage. CONCLUSION: Ustekinumab is a relatively new pharmacotherapy and in addition to this clinical case, we reviewed the published literature concerning the use of this treatment during pregnancy and its consequences on pregnancy and fetus outcome. PMID- 28629324 TI - Residual transpiration as a component of salinity stress tolerance mechanism: a case study for barley. AB - BACKGROUND: While most water loss from leaf surfaces occurs via stomata, part of this loss also occurs through the leaf cuticle, even when the stomata are fully closed. This component, termed residual transpiration, dominates during the night and also becomes critical under stress conditions such as drought or salinity. Reducing residual transpiration might therefore be a potentially useful mechanism for improving plant performance when water availability is reduced (e.g. under saline or drought stress conditions). One way of reducing residual transpiration may be via increased accumulation of waxes on the surface of leaf. Residual transpiration and wax constituents may vary with leaf age and position as well as between genotypes. This study used barley genotypes contrasting in salinity stress tolerance to evaluate the contribution of residual transpiration to the overall salt tolerance, and also investigated what role cuticular waxes play in this process. Leaves of three different positions (old, intermediate and young) were used. RESULTS: Our results show that residual transpiration was higher in old leaves than the young flag leaves, correlated negatively with the osmolality, and was positively associated with the osmotic and leaf water potentials. Salt tolerant varieties transpired more water than the sensitive variety under normal growth conditions. Cuticular waxes on barley leaves were dominated by primary alcohols (84.7-86.9%) and also included aldehydes (8.90-10.1%), n-alkanes (1.31 1.77%), benzoate esters (0.44-0.52%), phytol related compounds (0.22-0.53%), fatty acid methyl esters (0.14-0.33%), beta-diketones (0.07-0.23%) and alkylresorcinols (1.65-3.58%). A significant negative correlation was found between residual transpiration and total wax content, and residual transpiration correlated significantly with the amount of primary alcohols. CONCLUSIONS: Both leaf osmolality and the amount of total cuticular wax are involved in controlling cuticular water loss from barley leaves under well irrigated conditions. A significant and negative relationship between the amount of primary alcohols and a residual transpiration implies that some cuticular wax constituents act as a water barrier on plant leaf surface and thus contribute to salinity stress tolerance. It is suggested that residual transpiration could be a fundamental mechanism by which plants optimize water use efficiency under stress conditions. PMID- 28629325 TI - Quasi-linear score for capturing heterogeneous structure in biomarkers. AB - BACKGROUND: Linear scores are widely used to predict dichotomous outcomes in biomedical studies because of their learnability and understandability. Such approaches, however, cannot be used to elucidate biodiversity when there is heterogeneous structure in target population. RESULTS: Our study was focused on describing intrinsic heterogeneity in predictions. Because heterogeneity can be captured by a clustering method, integrating different information from different clusters should yield better predictions. Accordingly, we developed a quasi linear score, which effectively combines the linear scores of clustered markers. We extended the linear score to the quasi-linear score by a generalized average form, the Kolmogorov-Nagumo average. We observed that two shrinkage methods worked well: ridge shrinkage for estimating the quasi-linear score, and lasso shrinkage for selecting markers within each cluster. Simulation studies and applications to real data show that the proposed method has good predictive performance compared with existing methods. CONCLUSIONS: Heterogeneous structure is captured by a clustering method. Quasi-linear scores combine such heterogeneity and have a better predictive ability compared with linear scores. PMID- 28629327 TI - Female begging calls reflect nutritional need of nestlings in the hen harrier Circus cyaneus. AB - BACKGROUND: Most birds exhibit bi-parental care with both sexes providing food for their young. Nestling signal food needs through begging. However, for some species, males rarely visit the nest, so have limited opportunity for gaining information directly from the chicks. Instead, females beg when males deliver food. We tested whether this calling signalled nutritional need and specifically the needs of the female (Breeder Need hypothesis) or that of their chicks (Offspring Need hypothesis). RESULTS: We observed begging and provisioning rates at 42 nests of hen harrier (Circus cyaneus) in Scotland, explored the factors associated with variation in begging rate and the relationship between begging and provisioning. We also tested the impact of food on begging and provisioning through a feeding experiment. Female begging rate increased up to a chick age of 3 weeks and then tailed off. In addition, begging increased when broods were large. CONCLUSIONS: Our data provided support for the Offspring Need hypothesis. At nests where adlib food was provided females reduced their begging rate. These patterns suggested that female begging was an honest signal of need. However, begging continued even with adlib food and was only weakly associated with greater provisioning by males, suggesting that these calls may also play an additional role, possibly reflecting sexual or parent-offspring conflict. PMID- 28629326 TI - Cardiac tissue oxidative stress and inflammation after vitamin D administrations in high fat- diet induced obese rats. AB - BACKGROUND: Obesity is associated with numerous metabolic and inflammatory disorders. The current study was aimed to evaluate the effects of vitamin D administration on the markers of oxidative stress and inflammation in the cardiac tissue of high-fat diet induced obese rats. METHODS: In the beginning of the study, 40 male Wistar rats were divided into two groups: normal diet (ND) and high fat diet (HFD) for 16 weeks; then each group subdivided into two groups including: ND, ND + vitamin D, HFD and HFD + vitamin D. Vitamin D supplementation was done for 5 weeks at 500 IU/kg dosage. Tumor necrosis factor (TNF)-alpha concentration and markers of oxidative stress including glutathione peroxidase (GPx), superoxide dismutase (SOD), malondialdehyde (MDA) and catalase (CAT) concentrations in the cardiac tissue and serum concentrations of lipids in rats were determined using ELISA kits and spectrophotometry methods respectively. RESULTS: According to our results, GPx activity in ND and ND + vitamin D group was significantly higher compared with HFD group. Similarly, SOD activity was also significantly increased in ND + vitamin D group compared with ND and HFD groups. Moreover, vitamin D administration, significantly reduced catalase activity in ND + vitamin D and HFD + vitamin D groups (P < 0.05). TNF-alpha concentration in heart tissue in ND + vitamin D group significantly reduced compared with ND group. Cardiac tissue MDA concentration in baseline or after vitamin D administration did not changed significantly. CONCLUSION: Vitamin D improved cardiac oxidative stress and inflammatory markers in HFD induced obese rats. Further studies in human models are needed to further confirm the use of this nutrient in daily clinical practice. PMID- 28629328 TI - Impact of systematic capacity building on cataract surgical service development in 25 hospitals. AB - BACKGROUND: This study measured the effectiveness and cost of a capacity building intervention in 25 eye hospitals in South Asia, East Africa and Latin America over 4 years. The intervention involved eye care non-governmental organizations or high-performing eye hospitals acting as "mentors" to underperforming eye hospitals- "mentees" in 10 countries. Intervention activities included systematic planning and support for training and key equipment purchases as well as hospital specific mentoring which focused on strengthening leadership, increasing the volume and equity of community outreach, improving surgical quality and volume, strengthening organizational and financial management and streamlining operational processes. METHODS: This is a before and after observational study of the impact of this multi-dimensional process on hospital and individual productivity and financial sustainability after 4 years. Mentee hospitals reported data monthly using a standardized template. Key indicators included cataract surgery volume, cataract operations per surgeon, the proportion of direct paying cataract surgical patients, intervention program costs per additional surgery and cost per mentor. RESULTS: By the end of the study period, the hospitals experienced a 69% average increase (range: -63% to 690%) in cataract surgical volume over baseline with 12 hospitals showing increases over 100%. Twenty-three hospitals experienced a 59% average increase in the number of cataract surgeries per surgeon with 10 hospitals showing increases over 100%. The proportion of paying patients increased in 8 of the 14 hospitals reporting this data. The average mentoring cost per additional surgery for these 25 hospitals was $5.39. An average of $36,489.99 was spent per mentor per year to support their work with mentees. CONCLUSIONS: The intervention resulted in proportionally similar increases in cataract surgical volume and productivity across diverse settings in three distinct geographic regions. Its wide applicability and moderate cost make it an attractive means to rapidly and substantially increase eye care services to meet VISION2020 goals. PMID- 28629329 TI - Personalised informed choice on evidence and controversy on mammography screening: study protocol for a randomized controlled trial. AB - BACKGROUND: In Italy women aged 50-69 are invited for a population-based breast cancer (BC) screening. Physicians, policy makers and patients associations agree on the need to inform women about the benefits and harms in order to permit an informed decision. Decision aids (DA) are an effective way to support people in their decisions about health. This trial aims to assess women's informed choices, according to their health literacy and values, on participating or not in BC screening for the first time. Benefits, harms and controversies are presented. METHODS/DESIGN: The impact of the DA will be evaluated in a randomized controlled trial with a two-week follow-up. Women will be randomized via web to DA or a standard brochure. We will invite 8160 women, to obtain a final sample of 816 women. The primary outcome will be informed choice, measured on the basis of knowledge, attitudes and intentions on BC screening. Secondary outcomes are participation rate, satisfaction on information and decisional conflict. DISCUSSION: The web DA will be open-source and implemented on BC screenings and its efficacy for increasing informed choice will be tested. This model could be applied to other healthcare settings, cancer screenings, and public health programs. TRIAL REGISTRATION: The protocol for this trial was registered with the Clinicaltrials.gov registry on March 16, 2017: NCT03097653 . PMID- 28629330 TI - Breast cancer patient delay in Fukushima, Japan following the 2011 triple disaster: a long-term retrospective study. AB - BACKGROUND: Little information is available concerning how patient delay may be affected by mass disasters. The main objectives of the present study are to identify whether there was a post-disaster increase in the risk of experiencing patient delay among breast cancer patients in an area affected by the 2011 triple disaster in Fukushima, Japan, and to elucidate factors associated with post disaster patient delay. Sociodemographic factors (age, employment status, cohabitant status and evacuation status), health characteristics, and health access- and disaster-related factors were specifically considered. METHODS: Records of symptomatic breast cancer patients diagnosed from 2005 to 2016 were retrospectively reviewed to calculate risk ratios (RRs) for patient delay in every year post-disaster compared with the pre-disaster baseline. Total and excessive patient delays were respectively defined as three months or more and twelve months or more from symptom recognition to first medical consultation. Logistic regression analysis was conducted for pre- and post-disaster patient delay in order to reveal any factors potentially associated with patient delay, and changes after the disaster. RESULTS: Two hundred nineteen breast cancer patients (122 pre-disaster and 97 post-disaster) were included. After adjustments for age, significant post-disaster increases in RRs of experiencing both total (RR: 1.66, 95% Confidence Interval (CI): 1.02-2.70, p < 0.05) and excessive patient delay (RR: 4.49, 95% CI: 1.73-11.65, p < 0.01) were observed. The RRs for total patient delay peaked in the fourth year post-disaster, and significant increases in the risk of excessive patient delay were observed in the second, fourth, and fifth years post-disaster, with more than five times the risk observed pre-disaster. A family history of any cancer was the only factor significantly associated with total patient delay post-disaster (odds ratio: 0.38, 95% CI: 0.15-0.95, p < 0.05), while there were no variables associated with delay pre-disaster. CONCLUSIONS: The triple disaster in Fukushima appears to have led to an increased risk of patient delay among breast cancer patients, and this trend has continued for five years following the disaster. PMID- 28629332 TI - An exploratory study of men's companionship, perceptions and experiences during pregnancy and delivery in Uganda. AB - BACKGROUND: Globally, low involvement of men in maternal health care services remains a problem to health care providers and policy makers. Men's support is essential for making women's world better. There are increasing debates among policymakers and researchers on the role of men in maternal health programs, which is a challenge in patriarchal societies like Uganda. The aim of the study was to assess companionship during delivery; men's perception and experiences during pregnancy and delivery. METHODS: This was a descriptive exploratory study using a qualitative approach. This study involved 16 male participants who were present in the labor room during the delivery of their child. In-depth interviews (IDIs) were the main data collection methods used in the study. Purposive sampling was used to select participants who share particular characteristics with the potential of providing rich, relevant, and diverse data. The interviews were tape-recorded with the permission of the participants; in addition, the interviewer took notes. Each interview lasted between 30 and 45 min. The transcripts were entered into ATLAS.ti for analysis. Manifest content analysis was used. RESULTS: The major themes were; feelings about attending child birth, responsibilities during child birth, positive experiences and negative experiences about child birth. Men are willing to participate in child birth and should be encouraged as many are the decision makers in the family. Admission of men into the delivery room, improves family togetherness. The women felt loved and treasured. The men reported bondage to their partners and new born. CONCLUSIONS: Men's involvement in the child birth process was associated with a more perceived bondage with the partner and the newborn. Their presence helped to promote a calm and successful child birth process. Hospitals should work on measures encouraging male involvement. PMID- 28629331 TI - Depletion of p21-activated kinase 1 up-regulates the immune system of APC?14/+ mice and inhibits intestinal tumorigenesis. AB - BACKGROUND: P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC?14/+ mice. METHODS: The PAK1 KO APC?14/+ mice were generated by cross-breeding of PAK1 KO mice with APC?14/+ mice. Splenic lymphocytes were analysed by flow cytometry, and immunohistochemical staining. The numbers of intestinal tumours were counted. Blood cells were also counted. RESULTS: Compared to APC+/+ mice, the numbers of both T- and B- lymphocytes were reduced in the spleen of APC?14/+ mice. Depletion of PAK1 in APC?14/+ mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC?14/+ mice with PF-3758309, a PAK inhibitor reduced the numbers of intestinal tumours and increased the numbers of blood lymphocytes. CONCLUSION: Depletion of active PAK1 up-regulates the immune system of APC?14/+ mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours. PMID- 28629333 TI - Efficacy of ultra-short course chemotherapy for new smear positive drug susceptible pulmonary tuberculosis: study protocol of a multicenter randomized controlled clinical trial. AB - BACKGROUND: Shortening the standard 6-month treatment for drug-susceptible pulmonary tuberculosis (DS-PTB) would be a major improvement for TB case management and disease control. METHODS: We are conducting a randomized, open label, controlled, non-inferiority trial involving patients with smear-positive, newly diagnosed DS-PTB cases nationwide to assess the efficacy and safety of two 4.5- month regimens in comparison to the standard 6-month WHO recommended regimen. The regimen used in one experiment group is a 4.5-month fluoroquinolone containing regimen, which consists of full course of levofloxacin, isoniazid (H), rifampin (R), parazinamid (Z) and ethambutol (E). Regimen used in the second experiment group includes 4.5-month full course of H, R, Z, E with levofloxacin removed. Patients in the control group, receive H, R, Z and E for 2 months, followed by 4 months of H and R. The primary endpoint is treatment failure or relapse within 24 month after treatment completion. DISCUSSION: Results from this trial along with other studies will contribute to the science of constructing a shorter, effective and safe regiment for TB patients. TRIAL REGISTRATION: The protocol has been registered on ClinicalTrials.gov on 2 September,2016 with identifier NCT02901288 . PMID- 28629334 TI - Protein kinase C-alpha (PKCalpha) modulates cell apoptosis by stimulating nuclear translocation of NF-kappa-B p65 in urothelial cell carcinoma of the bladder. AB - BACKGROUND: The protein kinase C (PKC) family comprises central regulators of multiple signal transduction processes and is involved in the progression of many cancers. Nuclear factor Kappa-B (NF-kappaB) is constitutively expressed in cancer tissues and stimulates the transcription of various tumor-related genes. The present study aims to investigate the clinical significance of PKCalpha and NF kappaB p65 in bladder cancer tissues and the mechanism underlying PKCalpha induction of bladder cancer cell apoptotic resistance through stimulation of p65 nuclear translocation. METHODS: Expression of PKCalpha and NF-kappaB subunit p65 was detected in seven bladder cancer cell lines by western blot and in 30 bladder cancer tissue specimens by immunostaining. Immunofluorescence was performed to evaluate p65 nuclear translocation induced by Phorbol 12-myristate 13-acetate (PMA). PKCalpha/beta selective inhibitor Go6976, PKC pan-inhibitor sotrastaurin, and the PKC siRNA were employed to conduct PKC inhibition/knockdown in bladder cancer cells. Luciferase reporter assays were performed to measure the activity of NF-kappaB. Flow cytometry and TUNEL analysis were used to assess cell apoptosis. RESULTS: Expression of PKCalpha and NF-kappaB was found to positively correlate with tumor progression in 30 tumor tissue specimens. Furthermore, a Pearson's correlation coefficient analysis revealed a positive correlation between PKCalpha and NF-kappaB expression. Among the PKC inhibitors, the PKCalpha/beta selective inhibitor Go6976 yielded the most significant block of PKCalpha and NF-kappaB activation by PMA. Knockdown of NF-kappaB p65 remarkably induced cell apoptosis, but PMA restored p65 expression and significantly suppressed cell apoptosis that was otherwise induced by the p65 knockdown alone. CONCLUSION: Our study showed that PKCalpha modulated cell resistance to apoptosis by stimulating NF-kappaB activation and thus promoted the tumorigenesis of bladder cancer. PMID- 28629335 TI - Utility of the sentinel node concept for detection of lateral pelvic lymph node metastasis in lower rectal cancer. AB - BACKGROUND: There are two lymphatic flows in lower rectal cancer; one along the inferior mesenteric artery and another towards the internal iliac artery. The benefit of dissection of lateral pelvic (LP) lymph nodes (LPLN) remains controversial. This study aimed to clarify the possibility of detecting the sentinel node (SN) of the LP region (LPSN) and examine metastasis, including micrometastasis, using a radio isotope (RI) method. METHODS: In total, 62 patients with clinical (c)T1-T4 rectal cancer were enrolled in this study (11, 16 and 35 patients had tumor located in the upper, middle and lower rectal third, respectively). LPSNs were detected using a radio-isotope method in which 99 m technetium-tin colloid was endoscopically injected into the submucosa in patients with cT1, and into the muscularis propria in patients with cT2, cT3 and cT4. All patients underwent curative resection with lymphadenectomy. LPSN metastases were diagnosed by HE staining, immunohistochemical staining using AE1/AE3 as a primary antibody and by RT-PCR using CEA as a marker. RESULTS: Of the lower rectal (c)T2 4 tumors, 38.4% had lateral pelvic lymphatic flow that was significantly greater than that of cT1 tumors in the upper and middle thirds of the rectum (p = 0.0074). HE and immunohistochemical staining did not detect LPSN metastases but RT-PCR detected micrometastasis of three SNs. The remaining half of LPSNs were immunohistochemically re-examined; in all three cases, isolated tumor cells were detected. CONCLUSION: The SN concept may be useful for detecting lateral pelvic lymphatic flow and LPSN metastases, including micrometastasis in lower rectal cancer. PMID- 28629336 TI - Erratum to: Incidence of influenza virus infection among pregnant women: a systematic review. PMID- 28629337 TI - Validity and reliability of electroacoustic probe for diagnosis of developmental dysplasia of the hip. AB - BACKGROUND: Sound transmission is used in the diagnosis of hip dysplasia since the end of the 80's. Aim of this study is to quantify the validity and reliability of electroacoustic probe for the diagnosis of hip dysplasia in neonates. METHODS: Diagnostic study included neonates aged 4-28 days, whose parents signed an informed consent. The probe was used three times for comparative sound transmission and with extension/flexion; hip ultrasound was performed with Graf technique as gold standard. Kappa was determined for intraobserver and interobserver reliability; validity was calculated with sensitivity, specificity, and predictive values. RESULTS: 100 neonates were included. For the comparative sound transmission, 0.80 and 0.81 Kappa were obtained for the intraobserver and interobserver respectively; with extension/flexion, Kappa 0.98 and 0.95 were obtained for the intraobserver and interobserver respectively. With comparative sound transmission, 44.8%, 97.7%, 76.5% and 91.3% for sensitivity, specificity, positive and negative predictive values, respectively; with extension/flexion test, the sensitivity, specificity, positive and negative predictive values: 82.8%, 99.4%, 96.0%, and 97.1%, respectively. CONCLUSION: The electroacoustic probe is moderate valid and reliable for the diagnosis of developmental dysplasia of the hip. TRIAL REGISTRATION: Open Science framework https://osf.io/kpf5s/?view_only=0a9682c6w1c842ad8e1d9a66e8dcf038. PMID- 28629339 TI - Droplet digital PCR for detection and quantification of circulating tumor DNA in plasma of head and neck cancer patients. AB - BACKGROUND: During posttreatment surveillance of head and neck cancer patients, imaging is insufficiently accurate for the early detection of relapsing disease. Free circulating tumor DNA (ctDNA) may serve as a novel biomarker for monitoring tumor burden during posttreatment surveillance of these patients. In this exploratory study, we investigated whether low level ctDNA in plasma of head and neck cancer patients can be detected using Droplet Digital PCR (ddPCR). METHODS: TP53 mutations were determined in surgically resected primary tumor samples from six patients with high stage (II-IV), moderate to poorly differentiated head and neck squamous cell carcinoma (HNSCC). Subsequently, mutation specific ddPCR assays were designed. Pretreatment plasma samples from these patients were examined on the presence of ctDNA by ddPCR using the mutation-specific assays. The ddPCR results were evaluated alongside clinicopathological data. RESULTS: In all cases, plasma samples were found positive for targeted TP53 mutations in varying degrees (absolute quantification of 2.2-422 mutational copies/ml plasma). Mutations were detected in wild-type TP53 background templates of 7667-156,667 copies/ml plasma, yielding fractional abundances of down to 0.01%. CONCLUSIONS: Our results show that detection of tumor specific TP53 mutations in low level ctDNA from HNSCC patients using ddPCR is technically feasible and provide ground for future research on ctDNA quantification for the use of diagnostic biomarkers in the posttreatment surveillance of HNSCC patients. PMID- 28629340 TI - Hospital readmission within 10 years post stroke: frequency, type and timing. AB - BACKGROUND: The aim of this study was to examine the hospital readmissions in a 10 year follow-up of a stroke cohort previously studied for acute and subacute complications and to focus on their frequency, their causes and their timing. METHODS: The hospital records of 243 patients, 50% of a cohort of 489 patients acutely and consecutively admitted to our stroke unit in 2002/3, were subjected to review 10 years after the incidental stroke and all acute admissions were examined. The main admitting diagnoses were attributed to one of 18 predefined categories of illness. Additionally, the occurrence of death was registered. RESULTS: After 10 years 68.9% of patients had died and 72.4% had been readmitted to the hospital with a mean number of readmissions of 3.4 (+15.1 SD). 20% of the readmissions were due to a vascular cause, 17.3% were caused by infection, 9.3% by falls with (6.1%) and without fracture, 5.7% by a hemorrhagic event. The readmission rate was highest in the first 6 months post stroke with a rate of 116.2 admissions/100 live patient-years. Falls with fractures occurred maximally 3-5 years post stroke. CONCLUSIONS: Hospital readmissions over the 10 years following stroke are caused by vascular events, infections, falls and hemorrhagic events, where the first 6 months are a period of particular vulnerability. The magnitude and the spectrum of these long-term complications suggest the need for a more comprehensive approach to post stroke prophylaxis. PMID- 28629338 TI - A phase 2 randomized trial to evaluate the impact of a supervised exercise program on cardiotoxicity at 3 months in patients with HER2 overexpressing breast cancer undergoing adjuvant treatment by trastuzumab: design of the CARDAPAC study. AB - BACKGROUND: The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer is a poor prognosis. Trastuzumab improves overall survival but is associated with cardiotoxicity, especially a decline in left ventricular ejection fraction (LVEF). In addition, chemotherapy and radiotherapy increase fatigue and pain, decrease physical capacity and health-related quality of life. To date, no study has evaluated the benefits of physical activity on the side effects of treatment in patients with HER2 positive breast cancer. The aim of this study is to evaluate the impact of 3 months' exercise intervention on myocardial function and in particular on the rate of cardiotoxicity. METHODS: This multicenter, randomized clinical trial will include 112 patients treated by adjuvant trastuzumab for HER2 positive breast cancer to investigate the effects of a 3 months' supervised exercise program (intermittent exercise, combining moderate and high intensities; 55 minutes duration, 3 times per week), on the rate of cardiotoxicity [defined by either a decrease of the LVEF under 50% or an absolute drop of LVEF of 10%] between baseline and at 3 months and on strength, aerobic capacity, metabolic, inflammatory and hormonal parameters. Health-related quality of life, fatigue, pain and level of physical activity will also be assessed. Participants are randomly allocated to one of the two groups ("training group" vs "standard oncological care"). Performance-based and self-reported outcomes are assessed at baseline, at the end of supervised exercise program and at six months follow-up. DISCUSSION: Although physical exercise is recommended to reduce the side effects of adjuvant treatments in breast cancer patients, no randomized study has been conducted to assess the benefits of a physical training program in patients with HER2 overexpressing breast cancer. Cardiac toxicity of trastuzumab may be minimized with an exercise program combining high and moderate intensities. This type of program may be safe, feasible and effective but also increase cardiorespiratory fitness and improve health-related quality of life. If these benefits are confirmed, this exercise intervention could be systematically proposed to patients during the course of treatment by trastuzumab in addition to standard oncological care. TRIAL REGISTRATION: National Clinical Trials Number ( NCT02433067 ); Registration 28 april 2015. PMID- 28629341 TI - Protective effects of Cynara scolymus leaves extract on metabolic disorders and oxidative stress in alloxan-diabetic rats. AB - BACKGROUND: Diabetes mellitus (DM) is associated with hyperglycemia, inflammatory disorders and abnormal lipid profiles, currently the extracts from leaves of cynara scolymus has been discovered to treat metabolic disorders and has been stated by multitudinous scientists according to a good source of polyphenols compounds. The present study aimed to evaluate the protective effect of the ethanol leaves extract of C. scolymus in alloxan induced stress oxidant, hepatic kidney dysfunction and histological changes in liver, kidney and pancreas of different experimental groups of rats. METHODS: We determinate the antioxidant activity by ABTS .+ and antioxidant total capacity (TAC) of all extracts of C. scolymus leaves, the inhibition of alpha-amylase activity in vitro was also investigated. Forty male Wistar rats were induced to diabetes with a single dose intraperitoneal injection (i.p.) of alloxan (150 mg/kg body weight (b.w.)). Diabetic rats were orally and daily administrated of ethanol extract from C. scolymus at two doses (200-400 mg/kg, b.w) or (12 mg/kg, b.w) with anti-diabetic reference drug, Acarbose for one month. Ethanol extract of C. scolymus effect was confirmed by biochemical analysis, antioxidant activity and histological study. RESULTS: The results indicated that the ethanol extract from leaves of C. scolymus showed the highest antioxidant activity by ABTS .+ (499.43g+/- 39.72 Trolox/g dry extract) and (128.75 +/- 8.45 mg VC /g dry extract) for TAC and endowed the powerful inhibition in vitro of alpha-amylase activity with IC50=72,22 ug/uL. In vivo, the results showed that ethanol extract from the leaves of C. scolymus (200-400 mg/kg) decreased significantly (p < 0.001) the alpha-amylase levels in serum of diabetic rats, respectively associated with significant reduction (p < 0.001) in blood glucose rate of 42,84% and 37,91% compared to diabetic groups after 28 days of treatment, a significant lowered of plasma total cholesterol (T-Ch) by 18,11% and triglyceride (TG) by 60,47%, significantly and low-density lipoproteins (LDL-C) by 37,77%, compared to diabetic rats, moreover, the administration of ethanol extract appears to exert anti-oxidative activity demonstrated by the increase of CAT, SOD and GSH activities in liver, kidney and pancreas of diabetic rats. This positive effect of the ethanol extract from C. scolymus was confirmed by histological study. CONCLUSION: These observed strongly suggest that ethanol extract from the leaves of C. scolymus has anti-hyperglycemic properties, at least partly mediated by antioxidant and hypolipidemic effects. PMID- 28629342 TI - Hypnosis in patients with perceived stress - a systematic review. AB - BACKGROUND: Although hypnosis and hypnotherapy have become more popular in recent years, the evidence for hypnosis to influence perceived stress is unclear. In this systematic review we searched and evaluated randomized clinical studies investigating the effect of hypnosis on perceived stress reduction and coping. METHODS: The Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Review of Effects, EMBASE, Medline, PsycINFO, PSYNDEX and PubMed were systematically screened from their inception until December 2015 for randomized controlled trials (RCTs) reporting about hypnosis or hypnotherapy for stress reduction in healthy participants. Risk of Bias was assessed according the Cochrane Collaboration recommendations. RESULTS: Nine RCTs with a total of 365 participants met the inclusion criteria and were included in this review. Most included participants were medical students, predominantly female (n = 211). Mean age of participants ranged in most studies between 20 and 25 years, in three studies the mean ages were between 30 and 42 years. Perceived stress was measured by a wide range of psychological questionnaires including Face Valid Stress Test, Stress Thermometer, and immunological data was collected. All nine included studies used explorative designs and showed a high risk of bias. Six out of nine studies reported significant positive effects of hypnosis for stress reduction in the main outcome parameter compared to control groups (3 active controls, 3 no therapy controls). Immunological outcomes were assessed in six studies, the results were inconclusive. CONCLUSIONS: Due to exploratory designs and high risk of bias, the effectiveness of hypnosis or hypnotherapy in stress reduction remains still unclear. More high quality clinical research is urgently needed. PMID- 28629343 TI - Comparative effectiveness research: what to do when experts disagree about risks. AB - BACKGROUND: Ethical issues related to comparative effectiveness research, or research that compares existing standards of care, have recently received considerable attention. In this paper we focus on how Ethics Review Committees (ERCs) should evaluate the risks of comparative effectiveness research. MAIN TEXT: We discuss what has been a prominent focus in the debate about comparative effectiveness research, namely that it is justified when "nothing is known" about the comparative effectiveness of the available alternatives. We argue that this focus may be misleading. Rather, we should focus on the fact that some experts believe that the evidence points in favor of one intervention, whereas other experts believe that the evidence favors the alternative(s). We will then introduce a case that illustrates this point, and based on that, discuss how ERCs should deal with such cases of expert disagreement. CONCLUSION: We argue that ERCs have a duty to assess the range of expert opinions and based on that assessment arrive at a risk judgment about the study under consideration. We also argue that assessment of expert disagreement is important for the assignment of risk level to a clinical trial: what is the basis for expert opinions, how strong is the evidence appealed to by various experts, and how can clinical trial monitoring affect the possible increased risk of clinical trial participation. PMID- 28629344 TI - Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis. AB - BACKGROUND: ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. METHODS: Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX levels was obtained in our previous study. RESULTS: The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX inhibition at 300 mg QD was maintained at >=82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study. CONCLUSION: The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO-5334 over 24 h and allowed prediction of BMD gain due to ONO-5334. TRIAL REGISTRATION: The registration number in The European Union Clinical Trials Register is 2007 002417-39 . The date of registration was August 31, 2007. PMID- 28629345 TI - Prevalence and incidence of overweight and obesity among Vietnamese preschool children: a longitudinal cohort study. AB - BACKGROUND: A plateau in childhood overweight and obesity has been reported in some developed countries while in almost all developing countries this problem is on the rise. The aim of this paper is to describe the changes in prevalence of overweight and obesity within a cohort of preschool children followed for 3 years, and to estimate and compare the incidences in urban and rural children of Hanoi, Vietnam. METHODS: A longitudinal study of a cohort of 2677 children aged 3 to 6 years old at the beginning of the study was conducted in urban DodaLab and rural FilaBavi, Hanoi, Vietnam. Overall, 2602 children, 1311 urban and 1291 rural, were followed for 3 years with identical measurements of weight and height in 2013, 2014 and 2016. Standard methods were used to estimate prevalence and incidence as well as confidence intervals. RESULTS: During the three-year follow up, the overall estimated prevalence of overweight increased from 9.1% to 16.7%. For the urban children, the increase was considerably higher. The overall prevalence of obesity decreased from 6.4% to 4.5% with less decrease in the urban children. In the group of children who were overweight and obese at the start of the study, 41.4% and 30.7%, respectively, remained in the same state three years later. The incidence of overweight and obesity during the three years were 12.4% and 2.7%, respectively. Boys were more likely to develop obesity than girls. CONCLUSIONS: Already in preschool age, the prevalence of overweight is high and it continues to increase with age, especially in the urban area. Prevention and intervention programs need to start at early preschool age and actions in urban areas deserve priority. PMID- 28629346 TI - A hyper-thermostable alpha-amylase from Pyrococcus furiosus accumulates in Nicotiana tabacum as functional aggregates. AB - BACKGROUND: Alpha amylase hydrolyzes alpha-bonds of polysaccharides such as starch and produces malto-oligosaccharides. Its starch saccharification applications make it an essential enzyme in the textile, food and brewing industries. Commercially available alpha-amylase is mostly produced from Bacillus or Aspergillus. A hyper-thermostable and Ca 2++ independent alpha-amylase from Pyrococcus furiosus (PFA) expressed in E.coli forms insoluble inclusion bodies and thus is not feasible for industrial applications. RESULTS: We expressed PFA in Nicotiana tabacum and found that plant-produced PFA forms functional aggregates with an accumulation level up to 3.4 g/kg FW (fresh weight) in field conditions. The aggregates are functional without requiring refolding and therefore have potential to be applied as homogenized plant tissue without extraction or purification. PFA can also be extracted from plant tissue upon dissolution in a mild reducing buffer containing SDS. Like the enzyme produced in P. furiosus and in E. coli, plant produced PFA preserves hyper-thermophilicity and hyper-thermostability and has a long shelf life when stored in lyophilized leaf tissue. With tobacco's large biomass and high yield, hyper-thermostable alpha-amylase was produced at a scale of 42 kg per hectare. CONCLUSIONS: Tobacco may be a suitable bioreactor for industrial production of active hyperthermostable alpha amylase. PMID- 28629347 TI - International validation of quality indicators for evaluating priority setting in low income countries: process and key lessons. AB - BACKGROUND: While there have been efforts to develop frameworks to guide healthcare priority setting; there has been limited focus on evaluation frameworks. Moreover, while the few frameworks identify quality indicators for successful priority setting, they do not provide the users with strategies to verify these indicators. Kapiriri and Martin (Health Care Anal 18:129-147, 2010) developed a framework for evaluating priority setting in low and middle income countries. This framework provides BOTH parameters for successful priority setting and proposes means of their verification. Before its use in real life contexts, this paper presents results from a validation process of the framework. METHODS: The framework validation involved 53 policy makers and priority setting researchers at the global, national and sub-national levels (in Uganda). They were requested to indicate the relative importance of the proposed parameters as well as the feasibility of obtaining the related information. We also pilot tested the proposed means of verification. RESULTS: Almost all the respondents evaluated all the parameters, including the contextual factors, as 'very important'. However, some respondents at the global level thought 'presence of incentives to comply', 'reduced disagreements', 'increased public understanding,' 'improved institutional accountability' and 'meeting the ministry of health objectives', which could be a reflection of their levels of decision making. All the proposed means of verification were assessed as feasible with the exception of meeting observations which would require an insider. These findings results were consistent with those obtained from the pilot testing. CONCLUSIONS: These findings are relevant to policy makers and researchers involved in priority setting in low and middle income countries. To the best of our knowledge, this is one of the few initiatives that has involved potential users of a framework (at the global and in a Low Income Country) in its validation. The favorable validation of all the parameters at the national and sub-national levels implies that the framework has potential usefulness at those levels, as is. The parameters that were disputed at the global level necessitate further discussion when using the framework at that level. The next step is to use the validated framework in evaluating actual priority setting at the different levels. PMID- 28629348 TI - Applying the Plan-Do-Study-Act (PDSA) approach to a large pragmatic study involving safety net clinics. AB - BACKGROUND: The Plan-Do-Study-Act (PDSA) cycle is a commonly used improvement process in health care settings, although its documented use in pragmatic clinical research is rare. A recent pragmatic clinical research study, called the Strategies and Opportunities to STOP Colon Cancer in Priority Populations (STOP CRC), used this process to optimize the research implementation of an automated colon cancer screening outreach program in intervention clinics. We describe the process of using this PDSA approach, the selection of PDSA topics by clinic leaders, and project leaders' reactions to using PDSA in pragmatic research. METHODS: STOP CRC is a cluster-randomized pragmatic study that aims to test the effectiveness of a direct-mail fecal immunochemical testing (FIT) program involving eight Federally Qualified Health Centers in Oregon and California. We and a practice improvement specialist trained in the PDSA process delivered structured presentations to leaders of these centers; the presentations addressed how to apply the PDSA process to improve implementation of a mailed outreach program offering colorectal cancer screening through FIT tests. Center leaders submitted PDSA plans and delivered reports via webinar at quarterly meetings of the project's advisory board. Project staff conducted one-on-one, 45-min interviews with project leads from each health center to assess the reaction to and value of the PDSA process in supporting the implementation of STOP CRC. RESULTS: Clinic-selected PDSA activities included refining the intervention staffing model, improving outreach materials, and changing workflow steps. Common benefits of using PDSA cycles in pragmatic research were that it provided a structure for staff to focus on improving the program and it allowed staff to test the change they wanted to see. A commonly reported challenge was measuring the success of the PDSA process with the available electronic medical record tools. CONCLUSION: Understanding how the PDSA process can be applied to pragmatic trials and the reaction of clinic staff to their use may help clinics integrate evidence-based interventions into their everyday care processes. TRIAL REGISTRATION: Clinicaltrials.gov NCT01742065 . Registered October 31, 2013. PMID- 28629349 TI - Relationships between dental personnel and non-dental primary health care providers in rural and remote Queensland, Australia: dental perspectives. AB - BACKGROUND: Collaboration between dental practitioners and non-dental primary care providers has the potential to improve oral health care for people in rural and remote communities, where access to oral health services is limited. However, there is limited research on collaboration between these professional disciplines. The purpose of this paper was to explore the relationships between dental practitioners and non-dental primary care providers from rural and remote areas of Queensland and to identify strategies that could improve collaboration between these disciplines from the perspective of dental participants. METHODS: Semi-structured interviews were conducted between 2013 and 2015 with visiting, local and regional dental practitioners (n = 12) who had provided dental services to patients from eight rural and remote Queensland communities that did not have a resident dentist. Participants were purposely recruited through a snow ball sampling technique. Interview data were analysed using thematic analysis with the assistance of QSR Nvivo v.10. RESULTS: Four major themes emerged from the data: (1) Communication between dental practitioners and rural primary care providers; (2) Relationships between dental and primary care providers; (3) Maintenance of professional dualism; (4) Strategies to improve interprofessional relationships (with subthemes: face to face meetings; utilisation of technology; oral health training for primary care providers; and having a community based oral health contact person). Participants observed that there was a lack of communication between the dental providers who saw patients from these rural communities and the primary care providers who worked in each community. This was attributed to poor communication, the high turnover of staff and the siloed behaviours of some practitioners. Visiting dental practitioners were likely to have stronger professional relationships with hospital nursing, administrative and allied health care staff who were often long term residents of the community. CONCLUSIONS: The findings suggest that there was little relationship between the dental personnel and primary care providers. Interprofessional collaboration between dental care providers and non-dental rural primary care providers in the rural and remote communities sampled could be improved by having regular face to face meetings between practitioners from across the health disciplines, providing oral health education to primary care providers, establishing and maintaining effective communication and referral pathways, and exploring a greater role for tele-dentistry. PMID- 28629350 TI - The utility of the hematoxylin and eosin staining in patients with suspected Hirschsprung disease. AB - BACKGROUND: While immunohistochemistry (IHC) methods have been widely conducted for the diagnosis of Hirschsprung disease (HSCR) in developed countries, there are very few studies on their use in developing countries where hematoxylin and eosin (HE) staining is a key element of the diagnosis of HSCR. We aimed to determine the accuracy of HE staining in the diagnosis of HSCR using S100 IHC as the reference standard in Indonesia. METHODS: All histopathology performed for the suspicion of HSCR patients from January 2013 to August 2015 in Dr. Sardjito Hospital, Yogyakarta, Indonesia, were retrospectively reviewed. RESULTS: Our study included 23 HSCR patients: 9 males and 14 females. The HE staining revealed 14 negative (absence of ganglion cells) cases (61%) and 9 positive (presence of ganglion cells) cases (39%). In S100 IHC, out of the 9 positive cases by HE staining, 6 (67%) were confirmed for having ganglion cells; and out of the 14 negative cases by HE staining, 12 (86%) were reported negative and 2 (14%) were positive by S100 IHC staining. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rates of the HE staining were 80% (95% CI: 0.51-0.95), 75% (95% CI: 0.36-0.96), 85.7% (95% CI: 0.56-0.98), 66.7% (95% CI: 0.31-0.91), and 78.3% (95% CI: 0.58-0.90), respectively. CONCLUSIONS: Our study showed that HE staining has relatively moderate accuracy for the diagnosis of HSCR. The use of HE staining is still recommended for the diagnosis of HSCR given the limitation of resource allocation for more expensive IHC technologies in developing countries. PMID- 28629351 TI - Assessing health-related quality of life in urology - a survey of 4500 German urologists. AB - BACKGROUND: Urological diseases and their treatment may negatively influence continence, potency, and health-related quality of life (HRQOL). Although current guidelines recommend HRQOL assessment in clinical urology, specific guidance on how to assess HRQOL is frequently absent. We evaluated whether and how urologists assess HRQOL and how they determine its practicality. METHODS: A random sample of 4500 (from 5200 identified German urologists) was drawn and invited to participate in a postal survey (an initial letter followed by one reminder after six weeks). The questionnaire included questions on whether and how HRQOL is assessed, general attitudes towards the concept of HRQOL, and socio-demographics. Due to the exploratory character of the study we produced mainly descriptive statistics. Chi2-tests and logistic regression were used for subgroup-analysis. RESULTS: 1557 urologists (85% male, with a mean age of 49 yrs.) participated. Most of them (87%) considered HRQOL assessment as 'important' in daily work, while only 7% reported not assessing HRQOL. Patients with prostate carcinoma, incontinence, pain, and benign prostate hyperplasia were the main target groups for HRQOL assessment. The primary aim of HRQOL assessment was to support treatment decisions, monitor patients, and produce a 'baseline measurement'. Two thirds of urologists used questionnaires and interviews to evaluate HRQOL and one quarter assessed HRQOL by asking: 'How are you?'. The main barriers to HRQOL assessment were anticipated questionnaire costs (77%), extensive questionnaire length (52%), and complex analysis (51%). CONCLUSIONS: The majority of German urologists assess HRQOL as part of their clinical routine. However, knowledge of HRQOL assessment, analysis, and interpretation seems to be limited in this group. Therefore, urologists may benefit from a targeted education program. TRIAL REGISTRATION: The clinical trial was registered with the code VfD_13_003629 at the German Healthcare Research Registry ( www.versorgungsforschung-deutschland.de ). PMID- 28629352 TI - Male suicide among construction workers in Australia: a qualitative analysis of the major stressors precipitating death. AB - BACKGROUND: Suicide rates among those employed in male-dominated professions such as construction are elevated compared to other occupational groups. Thus far, past research has been mainly quantitative and has been unable to identify the complex range of risk and protective factors that surround these suicides. METHODS: We used a national coronial database to qualitatively study work and non work related influences on male suicide occurring in construction workers in Australia. We randomly selected 34 cases according to specific sampling framework. Thematic analysis was used to develop a coding structure on the basis of pre-existing theories in job stress research. RESULTS: The following themes were established on the basis of mutual consensus: mental health issues prior to death, transient working experiences (i.e., the inability to obtain steady employment), workplace injury and chronic illness, work colleagues as a source of social support, financial and legal problems, relationship breakdown and child custody issues, and substance abuse. CONCLUSION: Work and non-work factors were often interrelated pressures prior to death. Suicide prevention for construction workers needs to take a systematic approach, addressing work-level factors as well as helping those at-risk of suicide. PMID- 28629353 TI - Lipid emulsion mitigates impaired pulmonary function induced by limb I/R in rats through attenuation of local cellular injury and the subsequent systemic inflammatory response/inflammation. AB - BACKGROUND: Limb ischemia/reperfusion causes inflammation and elicits oxidative stress that may lead to local tissue damage and remote organ such as lung injury. This study investigates pulmonary function after limb ischemia/reperfusion and the protective effect of a lipid emulsion (Intralipid). METHODS: Twenty-four rats were divided into three groups: sham operation group (group S), ischemia/reperfusion group (group IR), and lipid emulsion treatment group (group LE). limb ischemia/reperfusion was induced through occlusion of the infrarenal abdominal aorta for 3 h. The microvascular clamp was removed carefully and reperfusion was provided for 3 h. RESULTS: The mean arterial pressure in group LE was higher than group IR during the reperfusion period (P = 0.024). The heart rate of both group LE and IR are significantly higher than group S during the ischemia period(P < 0.001, P < 0.001, respectively). The arterial oxygen pressure of group LE was significantly higher than group IR (P = 0.003), the arterial carbon dioxide pressure of group LE were lower than that of group IR (P = 0.005). The concentration of plasma interleukin-6, tumor necrosis factor-alpha and malondialdehyde in group LE were significantly lower than group IR (P < 0.001, P = 0.009 and 0.029, respectively). The plasma superoxide dismutase activity in group LE was significantly higher than group IR (P = 0.029). The myeloperoxidase activity in lung tissues of group LE was significantly less than group IR (P = 0.046). Both muscle and lung in group IR were damaged seriously, whereas lipid emulsion (Intralipid) effectively reversed the damage. In summary, Intralipid administration resulted in several beneficial effects as compared to group IR, such as the pulmonary gas exchange and inflammatory. CONCLUSIONS: The ischemic/reperfusion injury of limb muscles with resultant inflammatory damage to lung tissue can be mitigated by administration of a lipid emulsion (Intralipid, 20%, 5 ml/kg). The mechanisms attenuating such a physiological may be attributed to reduction of the degree of limb injury through a decrease in the release of local inflammatory mediators, a reduction of lipid peroxidation, and a blunting of the subsequent remote inflammatory response. PMID- 28629354 TI - Acetone leaf extracts of some South African trees with high activity against Escherichia coli also have good antimycobacterial activity and selectivity index. AB - BACKGROUND: Tuberculosis is a world-wide problem affecting humans and animals. There is increasing development of resistance of the pathogens to current antimycobacterial agents. Many authors have investigated activities of extracts and isolated compounds from plants. The traditional uses of plants have frequently been the criterion to select plants investigated. In this contribution, we investigate whether plant extracts with very good activity against Escherichia coli may also be active against mycobacteria. METHODS: The antimycobacterial activity of eight South African tree leaf extracts with high activity against Escherichia coli were determined in vitro against Mycobacterium smegmatis, M. fortuitum and M. aurum, using a serial microdilution method. The cellular cytotoxicity was also determined by the MTT assay using Vero monkey kidney cells. The selectivity index was determined by dividing the cytotoxicity of extracts by MIC. RESULTS: The antimycobacterial activity of the extracts ranged from 0.02 to 2.5 mg/ml. Mycobacterium smegmatis was more sensitive to the extracts (Average MIC = 0.96 mg/ml) and Mycobacterium aurum was comparatively resistant (Average MIC = 2.04 mg/ml). The extracts of Cremaspora triflora had strong antimycobacterial activity with a MIC of 0.05 mg/ml that compared reasonably well with that of streptomycin (0.01 mg/ml) and rifampicin (0.03 mg/ml), p > 0.05. Cremaspora triflora had the best selectivity index of 2.87 against Mycobacterium fortuitum. CONCLUSION: The high activity of C. triflora extracts against the fast-growing mycobacteria and good cellular safety is promising. It may be interesting to investigate extracts against pathogenic M. tuberculosis, M. bovis and M. avium cultures and to isolate active antimycobacterial compounds. PMID- 28629355 TI - Biologically constrained optimization based cell membrane segmentation in C. elegans embryos. AB - BACKGROUND: Recent advances in bioimaging and automated analysis methods have enabled the large-scale systematic analysis of cellular dynamics during the embryonic development of Caenorhabditis elegans. Most of these analyses have focused on cell lineage tracing rather than cell shape dynamics. Cell shape analysis requires cell membrane segmentation, which is challenging because of insufficient resolution and image quality. This problem is currently solved by complicated segmentation methods requiring laborious and time consuming parameter adjustments. RESULTS: Our new framework BCOMS (Biologically Constrained Optimization based cell Membrane Segmentation) automates the extraction of the cell shape of C. elegans embryos. Both the segmentation and evaluation processes are automated. To automate the evaluation, we solve an optimization problem under biological constraints. The performance of BCOMS was validated against a manually created ground truth of the 24-cell stage embryo. The average deviation of 25 cell shape features was 5.6%. The deviation was mainly caused by membranes parallel to the focal planes, which either contact the surfaces of adjacent cells or make no contact with other cells. Because segmentation of these membranes was difficult even by manual inspection, the automated segmentation was sufficiently accurate for cell shape analysis. As the number of manually created ground truths is necessarily limited, we compared the segmentation results between two adjacent time points. Across all cells and all cell cycles, the average deviation of the 25 cell shape features was 4.3%, smaller than that between the automated segmentation result and ground truth. CONCLUSIONS: BCOMS automated the accurate extraction of cell shapes in developing C. elegans embryos. By replacing image processing parameters with easily adjustable biological constraints, BCOMS provides a user-friendly framework. The framework is also applicable to other model organisms. Creating the biological constraints is a critical step requiring collaboration between an experimentalist and a software developer. PMID- 28629356 TI - Lifestyle and Income-related Inequality in Health in South Africa. AB - BACKGROUND: Many low- and middle-income countries are experiencing an epidemiological transition from communicable to non-communicable diseases. This has negative consequences for their human capital development, and imposes a growing economic burden on their societies. While the prevalence of such diseases varies with socioeconomic status, the inequalities can be exacerbated by adopted lifestyles of individuals. Evidence suggests that lifestyle factors may explain the income-related inequality in self-reported health. Self-reported health is a subjective evaluation of people's general health status rather than an objective measure of lifestyle-related ill-health. METHOD: The objective of this paper is to expand the literature by examining the contribution of smoking and alcohol consumption to health inequalities, incorporating more objective measures of health, that are directly associated with these lifestyle practices. We used the National Income Dynamic Study panel data for South Africa. The corrected concentration index is used to measure inequalities in health outcomes. We use a decomposition technique to identify the contribution of smoking and alcohol use to inequalities in health. RESULTS: We find significant smoking-related and income-related inequalities in both self-reported and lifestyle-related ill health. The results suggest that smoking and alcohol use contribute positively to income-related inequality in health. Smoking participation accounts for up to 7.35% of all measured inequality in health and 3.11% of the inequality in self reported health. The estimates are generally higher for all measured inequality in health (up to 14.67%) when smoking duration is considered. Alcohol consumption accounts for 27.83% of all measured inequality in health and 3.63% of the inequality in self-reported health. CONCLUSION: This study provides evidence that inequalities in both self-reported and lifestyle-related ill-health are highly prevalent within smokers and the poor. These inequalities need to be explicitly addressed in future programme planning to reduce health inequalities in South Africa. We suggest that policies that can influence poor individuals to reduce tobacco consumption and harmful alcohol use will improve their health and reduce health inequalities. PMID- 28629357 TI - XuefuZhuyu decoction protected cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy. AB - BACKGROUND: XuefuZhuyu decoction (XFZY) is a well-known traditional Chinese herbal medicine for the treatment of various cardiovascular diseases, such as unstable angina pectoris and myocardial ischemia-reperfusion injury. However, the mechanism by which XFZY contributes to the amelioration of cardiac injury remains unclear. METHODS: H9C2 cells were cultured under the hypoxic condition for 10 h and reoxygenated for 2 h. In the presence of various concentrations of XFZY for 12 h, the cell viability was measured by MTT assay. The protective effect of XFZY in hypoxia/reoxygenation (H/R) cell model was confirmed by measuring the amount of LDH released into the extracellular fluid. Cell apoptosis was measured by western blotting. The autophagy level of H9C2 cells and the correlative pathway were determined by transmission electron microscopy, Cyto-ID(r) Autophagy Detection Kit, and western blotting. RESULTS: In this study, we investigated the effects of XFZY on H/R induced cardiac injury. The results showed that treatment with XFZY significantly inhibited autophagy induced by H/R, with decreased formation of autophagosomes as well as the expression of LC3-II/LC3-I ratio and Beclin 1 after H/R. Importantly, inhibition of autophagy by XFZY resulted in enhanced cell viability and decreased apoptosis. XFZY also inhibited the activation of AMPK and upregulated the phosphorylation of mammalian target of Rapamycin (mTOR). CONCLUSIONS: The cardioprotective effects of XFZY during H/R were mediated by inhibiting autophagy via regulating AMPK-mTOR signaling pathways. PMID- 28629358 TI - Inequities in utilization of reproductive and maternal health services in Ethiopia. AB - BACKGROUND: Disparities in health services utilization within and between regional states of countries with diverse socio-cultural and economic conditions such as Ethiopia is a frequent encounter. Understanding and taking measures to address unnecessary and avoidable differences in the use of reproductive and maternal health services is a key concern in Ethiopia. The aim of the study was to examine degree of equity in reproductive and maternal health services utilization in Ethiopia. METHOD: Data from Ethiopia demographic health survey 2014 was analyzed. We assessed inequities in utilization of modern contraceptive methods, antenatal care, facility based delivery and postnatal checkup. Four standard equity measurement methods were used; equity gaps, rate-ratios, concertation curve and concentration index. RESULTS: Inequities in service utilization were exhibited favoring women in developed regions, urban residents, most educated and the wealthy. Antenatal care by skilled provider was three times higher among women with post-secondary education than mothers with no education. Women in the highest wealth quantile had about 12 times higher skilled birth attendance than those in lowest wealth quantile. The rate of postnatal care use among urban resident was about 6 times that of women in rural area. Use of modern contraceptive methods was more equitably utilized service while, birth at health facility was less equitable across all economic levels, favoring the wealthy. CONCLUSION: Considerable inequity between and within regions of Ethiopia in the use of maternal health services was demonstrated. Strategically targeting social determinants of health with special emphasis to women education and economic empowerment will substantially contribute for altering the current situation favorably. PMID- 28629359 TI - Forced expiration measurements in mouse models of obstructive and restrictive lung diseases. AB - BACKGROUND: Pulmonary function measurements are important when studying respiratory disease models. Both resistance and compliance have been used to assess lung function in mice. Yet, it is not always clear how these parameters relate to forced expiration (FE)-related parameters, most commonly used in humans. We aimed to characterize FE measurements in four well-established mouse models of lung diseases. METHOD: Detailed respiratory mechanics and FE measurements were assessed concurrently in Balb/c mice, using the forced oscillation and negative pressure-driven forced expiration techniques, respectively. Measurements were performed at baseline and following increasing methacholine challenges in control Balb/c mice as well as in four disease models: bleomycin-induced fibrosis, elastase-induced emphysema, LPS-induced acute lung injury and house dust mite-induced asthma. RESULTS: Respiratory mechanics parameters (airway resistance, tissue damping and tissue elastance) confirmed disease-specific phenotypes either at baseline or following methacholine challenge. Similarly, lung function defects could be detected in each disease model by at least one FE-related parameter (FEV0.1, FEF0.1, FVC, FEV0.1/FVC ratio and PEF) at baseline or during the methacholine provocation assay. CONCLUSIONS: FE-derived outcomes in four mouse disease models behaved similarly to changes found in human spirometry. Routine combined lung function assessments could increase the translational utility of mouse models. PMID- 28629360 TI - Conceptualisation of job-related wellbeing, stress and burnout among healthcare workers in rural Ethiopia: a qualitative study. AB - BACKGROUND: Wellbeing of healthcare workers is important for the effective functioning of health systems. The aim of this study was to explore the conceptualisations of wellbeing, stress and burnout among healthcare workers in primary healthcare settings in rural Ethiopia in order to inform the development of contextually appropriate interventions. METHODS: A qualitative study was conducted in a rural zone of southern Ethiopia. A total of 52 frontline primary healthcare workers participated in in-depth interviews (n = 18) or Focus Group Discussions (FGDs) (4 groups, total n = 34). There were 35 facility based healthcare professionals and 17 community-based health workers. Data were analysed using thematic analysis. RESULTS: Most participants conceptualised wellbeing as absence of stress rather than as a positive state. Many threats to wellbeing were identified. For facility-based workers, the main stressors were inadequate supplies leading to fears of acquiring infection and concerns about performance evaluation. For community health workers, the main stressor was role ambiguity. Workload and economic self-sufficiency were a concern for both groups. Burnout and its symptoms were recognised and reported by most as a problem of other healthcare workers. Derogatory and stigmatising terms, such as "chronics", were used to refer to those who had served for many years and who appeared to have become drained of all compassion. Most participants viewed burnout as inevitable if they continued to work in their current workplace without career progression. Structural and environmental aspects of work emerged as potential targets to improve wellbeing, combined with tackling stigmatising attitudes towards mental health problems. An unmet need for intervention for healthcare workers who develop burnout or emotional difficulties was identified. CONCLUSION: Ethiopian primary healthcare workers commonly face job-related stress and experience features of burnout, which may contribute to the high turnover of staff and dissatisfaction of both patients and providers. Recent initiatives to integrate mental healthcare into primary care provide an opportunity to promote the wellbeing of healthcare workers and intervene to address burnout and emotional problems by creating a better understanding of mental health. PMID- 28629362 TI - Long-term exposure to ambient ultrafine particles and respiratory disease incidence in in Toronto, Canada: a cohort study. AB - BACKGROUND: Little is known about the long-term health effects of ambient ultrafine particles (<0.1 MUm) (UFPs) including their association with respiratory disease incidence. In this study, we examined the relationship between long-term exposure to ambient UFPs and the incidence of lung cancer, adult-onset asthma, and chronic obstructive pulmonary disease (COPD). METHODS: Our study cohort included approximately 1.1 million adults who resided in Toronto, Canada and who were followed for disease incidence between 1996 and 2012. UFP exposures were assigned to residential locations using a land use regression model. Random-effect Cox proportional hazard models were used to estimate hazard ratios (HRs) describing the association between ambient UFPs and respiratory disease incidence adjusting for ambient fine particulate air pollution (PM2.5), NO2, and other individual/neighbourhood-level covariates. RESULTS: In total, 74,543 incident cases of COPD, 87,141 cases of asthma, and 12,908 cases of lung cancer were observed during follow-up period. In single pollutant models, each interquartile increase in ambient UFPs was associated with incident COPD (HR = 1.06, 95% CI: 1.05, 1.09) but not asthma (HR = 1.00, 95% CI: 1.00, 1.01) or lung cancer (HR = 1.00, 95% CI: 0.97, 1.03). Additional adjustment for NO2 attenuated the association between UFPs and COPD and the HR was no longer elevated (HR = 1.01, 95% CI: 0.98, 1.03). PM2.5 and NO2 were each associated with increased incidence of all three outcomes but risk estimates for lung cancer were sensitive to indirect adjustment for smoking and body mass index. CONCLUSIONS: In general, we did not observe clear evidence of positive associations between long term exposure to ambient UFPs and respiratory disease incidence independent of other air pollutants. Further replication is required as few studies have evaluated these relationships. PMID- 28629361 TI - Decoy receptor 3: an endogenous immunomodulator in cancer growth and inflammatory reactions. AB - Decoy receptor 3 (DcR3), also known as tumor necrosis factor receptor (TNFR) superfamily member 6b (TNFRSF6B), is a soluble decoy receptor which can neutralize the biological functions of three members of tumor necrosis factor superfamily (TNFSF): Fas ligand (FasL), LIGHT, and TL1A. In addition to 'decoy' function, recombinant DcR3.Fc is able to modulate the activation and differentiation of dendritic cells (DCs) and macrophages via 'non-decoy' action. DcR3-treated DCs skew T cell differentiation into Th2 phenotype, while DcR3 treated macrophages behave M2 phenotype. DcR3 is upregulated in various cancer cells and several inflammatory tissues, and is regarded as a potential biomarker to predict inflammatory disease progression and cancer metastasis. However, whether DcR3 is a pathogenic factor or a suppressor to attenuate inflammatory reactions, has not been discussed comprehensively yet. Because mouse genome does not have DcR3, it is not feasible to investigate its physiological functions by gene-knockout approach. However, DcR3-mediated effects in vitro are determined via overexpressing DcR3 or addition of recombinant DcR3.Fc fusion protein. Moreover, CD68-driven DcR3 transgenic mice are used to investigate DcR3-mediated systemic effects in vivo. Upregulation of DcR3 during inflammatory reactions exerts negative-feedback to suppress inflammation, while tumor cells hijack DcR3 to prevent apoptosis and promote tumor growth and invasion. Thus, 'switch-on' of DcR3 expression may be feasible for the treatment of inflammatory diseases and enhance tissue repairing, while 'switch-off' of DcR3 expression can enhance tumor apoptosis and suppress tumor growth in vivo. PMID- 28629363 TI - Fibroblast paracrine TNF-alpha signaling elevates integrin A5 expression in idiopathic pulmonary fibrosis (IPF). AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis. Inflammatory cytokines play a significant role in IPF pathology. However, the fibroblast itself is also believed to be the primary effector in IPF. We hypothesized that the fibroblasts themselves secrete pro inflammatory cytokines that could propagate IPF by affecting normal neighboring cells. Thus, we explored the effects of IPF fibroblast derived media on normal fibroblast characteristics. METHODS: Primary IPF/normal tissue derived fibroblast cultures were established and their supernatants were collected (IPF/N-SN, respectively). These supernatants were added to normal fibroblasts. Cell death (caspase-3, western blot), proliferation, viability (WST-1), migration (scratch test) and cell detachment (crystal violet and fibronectin adhesion assays) were tested. 10 inflammatory cytokines were measured by ELISA-based quantitative array. Integrin alpha5 (ITGA5), pIkappaBalpha, p/total STAT3 levels were measured by western blot/IHC. TNF-alpha involvement was confirmed using Infliximab (r), anti-TNF-alpha mAb. RESULTS: The IPF-SN facilitated fibroblast cell detachment and reduced cell migration (p < 0.05). Nevertheless, these effects were reversed when cells were seeded on fibronectin. The exposure to the IPF-SN also elevated ITGA5 levels, the fibronectin receptor, in addition to NFkappaB pathway activation (pIkappaBalpha? 150%, p < 0.05). In accordance, IPF derived fibroblasts were found to express higher ITGA5 than the normal cells (44%?, p < 0.05). ITGA5 was also expressed in the fibroblastic foci. The IPF-SN contained high TNF-alpha levels (3-fold, p < 0.05), and Infliximab pretreatment successfully reversed all the above observations. CONCLUSION: We suggest a possible mechanism in which IPF fibroblast secreted TNF-alpha modifies neighboring fibroblast cell behavior. PMID- 28629364 TI - Changes in concentrations of haemostatic and inflammatory biomarkers in synovial fluid after intra-articular injection of lipopolysaccharide in horses. AB - BACKGROUND: Septic arthritis is a common and potentially devastating disease characterized by severe intra-articular (IA) inflammation and fibrin deposition. Research into equine joint pathologies has focused on inflammation, but recent research in humans suggests that both haemostatic and inflammatory pathways are activated in the joint compartment in arthritic conditions. The aim of this study was to characterize the IA haemostatic and inflammatory responses in horses with experimental lipopolysaccharide (LPS)-induced joint inflammation. Inflammation was induced by IA injection of LPS into one antebrachiocarpal joint of six horses. Horses were evaluated clinically with subjective grading of lameness, and blood and synovial fluid (SF) samples were collected at post injection hours (PIH) -120, -96, -24, 0, 2, 4, 8, 16, 24, 36, 48, 72 and 144. Total protein (TP), white blood cell counts (WBC), serum amyloid A (SAA), haptoglobin, iron, fibrinogen, thrombin-antithrombin (TAT) and d-dimer concentrations were assessed in blood and SF. RESULTS: Intra-articular injection of LPS caused local and systemic signs of inflammation including increased rectal temperature, lameness and increased joint circumference and skin temperature. Most of the biomarkers (TP, WBC, haptoglobin, fibrinogen and TAT) measured in SF increased quickly after LPS injection (at PIH 2-4), whereas SAA and d-dimer levels increased more slowly (at PIH 16 and 144, respectively). SF iron concentrations did not change statistically significantly. Blood WBC, SAA, haptoglobin and fibrinogen increased and iron decreased significantly in response to the IA LPS injection, while TAT and d-dimer concentrations did not change. Repeated pre-injection arthrocenteses caused significant changes in SF concentrations of TP, WBC and haptoglobin. CONCLUSION: Similar to inflammatory joint disease in humans, joint inflammation in horses was accompanied by an IA haemostatic response with changes in fibrinogen, TAT and d-dimer concentrations. Inflammatory and haemostatic responses were induced simultaneously and may likely interact. Further studies of interactions between the two responses are needed for a better understanding of pathogenesis of joint disease in horses. Knowledge of effects of repeated arthrocenteses on levels of SF biomarkers may be of value when markers are used for diagnostic purposes. PMID- 28629365 TI - Evaluation and improvement of the regulatory inference for large co-expression networks with limited sample size. AB - BACKGROUND: Co-expression has been widely used to identify novel regulatory relationships using high throughput measurements, such as microarray and RNA-seq data. Evaluation studies on co-expression network analysis methods mostly focus on networks of small or medium size of up to a few hundred nodes. For large networks, simulated expression data usually consist of hundreds or thousands of profiles with different perturbations or knock-outs, which is uncommon in real experiments due to their cost and the amount of work required. Thus, the performances of co-expression network analysis methods on large co-expression networks consisting of a few thousand nodes, with only a small number of profiles with a single perturbation, which more accurately reflect normal experimental conditions, are generally uncharacterized and unknown. METHODS: We proposed a novel network inference methods based on Relevance Low order Partial Correlation (RLowPC). RLowPC method uses a two-step approach to select on the high-confidence edges first by reducing the search space by only picking the top ranked genes from an intial partial correlation analysis and, then computes the partial correlations in the confined search space by only removing the linear dependencies from the shared neighbours, largely ignoring the genes showing lower association. RESULTS: We selected six co-expression-based methods with good performance in evaluation studies from the literature: Partial correlation, PCIT, ARACNE, MRNET, MRNETB and CLR. The evaluation of these methods was carried out on simulated time-series data with various network sizes ranging from 100 to 3000 nodes. Simulation results show low precision and recall for all of the above methods for large networks with a small number of expression profiles. We improved the inference significantly by refinement of the top weighted edges in the pre-inferred partial correlation networks using RLowPC. We found improved performance by partitioning large networks into smaller co-expressed modules when assessing the method performance within these modules. CONCLUSIONS: The evaluation results show that current methods suffer from low precision and recall for large co-expression networks where only a small number of profiles are available. The proposed RLowPC method effectively reduces the indirect edges predicted as regulatory relationships and increases the precision of top ranked predictions. Partitioning large networks into smaller highly co-expressed modules also helps to improve the performance of network inference methods. The RLowPC R package for network construction, refinement and evaluation is available at GitHub: https://github.com/wyguo/RLowPC . PMID- 28629366 TI - Molecular characterization of clinical IMP-producing Klebsiella pneumoniae isolates from a Chinese Tertiary Hospital. AB - BACKGROUND: IMP-producing Klebsiella pneumoniae (IMPKpn) exhibits sporadic prevalence in China. The mechanisms related to the spread of IMPKpn remain unclear. METHODS: Carbapenem non-susceptible K. pneumoniae isolates were collected from our hospital. The genetic relatedness, antimicrobial susceptibility, as well as sequence types (ST) were analyzed by pulsed-field gel electrophoresis (PFGE), VITEK 2 AST test Kit, and multilocus sequence typing (MLST), respectively. S1-PFGE, Southern blot analysis and multiple PCR amplification were used for plasmid profiling. RESULTS: Between October 2009 and June 2016, 25 non-repetitive IMPKpn isolates were identified. PFGE results showed that these isolates belonged to 20 genetically unrelated IMPKpn strains. Diverse STs were identified by MLST. Most strains carried bla IMP-4, followed by bla IMP 1. Four incompatibility types of bla IMP-carrying plasmids were identified, which included A/C (n = 2), B/O (n = 2), L/M (n = 1) and N (n = 14), while type of other one plasmid failed to be determined. CONCLUSIONS: The IMPKpn isolates exhibited sporadic prevalence in our hospital. IncN types of plasmids with various sizes have emerged as the main platform mediating the spread of the bla IMP genes in our hospital. PMID- 28629367 TI - African-American esophageal squamous cell carcinoma expression profile reveals dysregulation of stress response and detox networks. AB - BACKGROUND: Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is largely unresponsive to therapy. African-Americans have an increased risk for esophageal squamous cell carcinoma (ESCC), the subtype that shows marked variation in geographic frequency. The molecular architecture of African-American ESCC is still poorly understood. It is unclear why African American ESCC is more aggressive and the survival rate in these patients is worse than those of other ethnic groups. METHODS: To begin to define genetic alterations that occur in African-American ESCC we conducted microarray expression profiling in pairs of esophageal squamous cell tumors and matched control tissues. RESULTS: We found significant dysregulation of genes encoding drug-metabolizing enzymes and stress response components of the NRF2- mediated oxidative damage pathway, potentially representing key genes in African-American esophageal squamous carcinogenesis. Loss of activity of drug metabolizing enzymes would confer increased sensitivity of esophageal cells to xenobiotics, such as alcohol and tobacco smoke, and may account for the high incidence and aggressiveness of ESCC in this ethnic group. To determine whether certain genes are uniquely altered in African-American ESCC we performed a meta-analysis of ESCC expression profiles in our African-American samples and those of several Asian samples. Down-regulation of TP53 pathway components represented the most common feature in ESCC of all ethnic groups. Importantly, this analysis revealed a potential distinctive molecular underpinning of African-American ESCC, that is, a widespread and prominent involvement of the NRF2 pathway. CONCLUSION: Taken together, these findings highlight the remarkable interplay of genetic and environmental factors in the pathogenesis of African-American ESCC. PMID- 28629368 TI - Identification and characterization of long intergenic noncoding RNAs in bovine mammary glands. AB - BACKGROUND: Mammary glands of dairy cattle produce milk for the newborn offspring and for human consumption. Long intergenic noncoding RNAs (lincRNAs) play various functions in eukaryotic cells. However, types and roles of lincRNAs in bovine mammary glands are still poorly understood. RESULTS: Using computational methods, 886 unknown intergenic transcripts (UITs) were identified from five RNA-seq datasets from bovine mammary glands. Their non-coding potentials were predicted by using the combination of four software programs (CPAT, CNCI, CPC and hmmscan), with 184 lincRNAs identified. By comparison to the NONCODE2016 database and a domestic-animal long noncoding RNA database (ALDB), 112 novel lincRNAs were revealed in bovine mammary glands. Many lincRNAs were found to be located in quantitative trait loci (QTL). In particular, 36 lincRNAs were found in 172 milk related QTLs, whereas one lincRNA was within clinical mastitis QTL region. In addition, targeted genes for 10 lincRNAs with the highest fragments per kilobase of transcript per million fragments mapped (FPKM) were predicted by LncTar for forecasting potential biological functions of these lincRNAs. Further analyses indicate involvement of lincRNAs in several biological functions and different pathways. CONCLUSION: Our study has provided a panoramic view of lincRNAs in bovine mammary glands and suggested their involvement in many biological functions including susceptibility to clinical mastitis as well as milk quality and production. This integrative annotation of mammary gland lincRNAs broadens and deepens our understanding of bovine mammary gland biology. PMID- 28629369 TI - Erratum to: Relationships between parental sleep quality, fatigue, cognitions about infant sleep, and parental depression pre and post-intervention for infant behavioral sleep problems. PMID- 28629370 TI - Pharmacogenetic testing through the direct-to-consumer genetic testing company 23andMe. AB - BACKGROUND: Rapid advances in scientific research have led to an increase in public awareness of genetic testing and pharmacogenetics. Direct-to-consumer (DTC) genetic testing companies, such as 23andMe, allow consumers to access their genetic information directly through an online service without the involvement of healthcare professionals. Here, we evaluate the clinical relevance of pharmacogenetic tests reported by 23andMe in their UK tests. METHODS: The research papers listed under each 23andMe report were evaluated, extracting information on effect size, sample size and ethnicity. A wider literature search was performed to provide a fuller assessment of the pharmacogenetic test and variants were matched to FDA recommendations. Additional evidence from CPIC guidelines, PharmGKB, and Dutch Pharmacogenetics Working Group was reviewed to determine current clinical practice. The value of the tests across ethnic groups was determined, including information on linkage disequilibrium between the tested SNP and causal pharmacogenetic variant, where relevant. RESULTS: 23andMe offers 12 pharmacogenetic tests to their UK customers, some of which are in standard clinical practice, and others which are less widely applied. The clinical validity and clinical utility varies extensively between tests. The variants tested are likely to have different degrees of sensitivity due to different risk allele frequencies and linkage disequilibrium patterns across populations. The clinical relevance depends on the ethnicity of the individual and variability of pharmacogenetic markers. Further research is required to determine causal variants and provide more complete assessment of drug response and side effects. CONCLUSION: 23andMe reports provide some useful pharmacogenetics information, mirroring clinical tests that are in standard use. Other tests are unspecific, providing limited guidance and may not be useful for patients without professional interpretation. Nevertheless, DTC companies like 23andMe act as a powerful intermediate step to integrate pharmacogenetic testing into clinical practice. PMID- 28629371 TI - Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. AB - PURPOSE: MDM2 and CDK4 are frequently co-amplified in well differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. EXPERIMENTAL DESIGN: DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting. Xenograft mouse models were used to assess tumour growth and survival. Treatment efficacy was assessed by Western blotting, histopathology and tumour volume. RESULTS: RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone, with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib. The combination treatment significantly increased apoptosis compared to the single agents. We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS. The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival. CONCLUSIONS: Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting. PMID- 28629372 TI - Novel NBAS mutations and fever-related recurrent acute liver failure in Chinese children: a retrospective study. AB - BACKGROUND: Underlying causes in Chinese children with recurrent acute liver failure (RALF), including liver crises less than full acute liver failure, are incompletely understood. We sought to address this by searching for genes mutated in such children. METHODS: Five unrelated Chinese boys presenting between 2012 and 2015 with RALF of unexplained etiology were studied. Results of whole exome sequencing were screened for mutations in candidate genes. Mutations were verified in patients and their family members by Sanger sequencing. All 5 boys underwent liver biopsy. RESULTS: NBAS was the only candidate gene mutated in more than one patient (biallelic mutations, 3 of 5 patients; 5 separate mutations). All NBAS mutations were novel and predictedly pathogenic (frameshift insertion mutation c.6611_6612insCA, missense mutations c.2407G > A and c.3596G > A, nonsense mutation c.586C > T, and splicing-site mutation c.5389 + 1G > T). Of these mutations, 3 lay in distal (C-terminal) regions of NBAS, a novel distribution. Unlike the 2 patients without NBAS mutations, the 3 patients with confirmed NBAS mutations all suffered from a febrile illness before each episode of liver crisis (fever-related RALF), with markedly elevated alanine aminotransferase and aspartate aminotransferase activities 24-72 h after elevation of body temperature, succeeded by severe coagulopathy and mild to moderate jaundice. CONCLUSIONS: As in other countries, so too in China; NBAS disease is a major cause of fever-related RALF in children. The mutation spectrum of NBAS in Chinese children seems different from that described in other populations. PMID- 28629373 TI - Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia. AB - BACKGROUND: T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are important inhibitory receptors that associate with T cell exhaustion in acute myeloid leukemia (AML). In this study, we aimed to determine the underlying transcriptional mechanisms regulating these inhibitory pathways. Specifically, we investigated the role of transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) in T cell response and transcriptional regulation of TIGIT and PD-1 in AML. METHODS: Peripheral blood samples collected from patients with AML were used in this study. Blimp-1 expression was examined by flow cytometry. The correlation of Blimp-1 expression to clinical characteristics of AML patients was analyzed. Phenotypic and functional studies of Blimp-1-expressing T cells were performed using flow cytometry-based assays. Luciferase reporter assays and ChIP assays were applied to assess direct binding and transcription activity of Blimp-1. Using siRNA to silence Blimp-1, we further elucidated the regulatory role of Blimp-1 in the TIGIT and PD-1 expression and T cell immune response. RESULTS: Blimp-1 expression is elevated in T cells from AML patients. Consistent with exhaustion, Blimp-1+ T cells upregulate multiple inhibitory receptors including PD-1 and TIGIT. In addition, they are functionally impaired manifested by low cytokine production and decreased cytotoxicity capacity. Importantly, the functional defect is reversed by inhibition of Blimp-1 via siRNA knockdown. Furthermore, Blimp-1 binds to the promoters of PD-1 and TIGIT and positively regulates their expression. CONCLUSIONS: Our study demonstrates an important inhibitory effect of Blimp-1 on T cell response in AML; thus, targeting Blimp-1 and its regulated molecules to improve the immune response may provide effective leukemia therapeutics. PMID- 28629374 TI - Multi-purpose ECG telemetry system. AB - BACKGROUND: The Electrocardiogram ECG is one of the most important non-invasive tools for cardiac diseases diagnosis. Taking advantage of the developed telecommunication infrastructure, several approaches that address the development of telemetry cardiac devices were introduced recently. Telemetry ECG devices allow easy and fast ECG monitoring of patients with suspected cardiac issues. Choosing the right device with the desired working mode, signal quality, and the device cost are still the main obstacles to massive usage of these devices. METHODS: In this paper, we introduce design, implementation, and validation of a multi-purpose telemetry system for recording, transmission, and interpretation of ECG signals in different recording modes. The system consists of an ECG device, a cloud-based analysis pipeline, and accompanied mobile applications for physicians and patients. The proposed ECG device's mechanical design allows laypersons to easily record post-event short-term ECG signals, using dry electrodes without any preparation. Moreover, patients can use the device to record long-term signals in loop and holter modes, using wet electrodes. In order to overcome the problem of signal quality fluctuation due to using different electrodes types and different placements on subject's chest, customized ECG signal processing and interpretation pipeline is presented for each working mode. RESULTS: We present the evaluation of the novel short-term recorder design. Recording of an ECG signal was performed for 391 patients using a standard 12-leads golden standard ECG and the proposed patient-activated short-term post-event recorder. In the validation phase, a sample of validation signals followed peer review process wherein two experts annotated the signals in terms of signal acceptability for diagnosis.We found that 96% of signals allow detecting arrhythmia and other signal's abnormal changes. Additionally, we compared and presented the correlation coefficient and the automatic QRS delineation results of both short term post-event recorder and 12-leads golden standard ECG recorder. CONCLUSIONS: The proposed multi-purpose ECG device allows physicians to choose the working mode of the same device according to the patient status. The proposed device was designed to allow patients to manage the technical requirements of both working modes. Post-event short-term ECG recording using the proposed design provide physicians reliable three ECG leads with direct symptom-rhythm correlation. PMID- 28629375 TI - Diagnostic performance of multi-organ ultrasound with pocket-sized device in the management of acute dyspnea. AB - BACKGROUND: The availability of ultra-miniaturized pocket ultrasound devices (PUD) adds diagnostic power to the clinical examination. Information on accuracy of ultrasound with handheld units in immediate differential diagnosis in emergency department (ED) is poor. The aim of this study is to test the usefulness and accuracy of lung ultrasound (LUS) alone or combined with ultrasound of the heart and inferior vena cava (IVC) using a PUD for the differential diagnosis of acute dyspnea (AD). METHODS: We included 68 patients presenting to the ED of "Maurizio Bufalini" Hospital in Cesena (Italy) for AD. All patients underwent integrated ultrasound examination (IUE) of lung-heart-IVC, using PUD. The series was divided into patients with dyspnea of cardiac or non cardiac origin. We used 2 * 2 contingency tables to analyze sensitivity, specificity, positive predictive value and negative predictive value of the three ultrasonic methods and their various combinations for the diagnosis of cardiogenic dyspnea (CD), comparing with the final diagnosis made by an independent emergency physician. RESULTS: LUS alone exhibited a good sensitivity (92.6%) and specificity (80.5%). The highest accuracy (90%) for the diagnosis of CD was obtained with the combination of LUS and one of the other two methods (heart or IVC). CONCLUSIONS: The IUE with PUD is a useful extension of the clinical examination, can be readily available at the bedside or in ambulance, requires few minutes and has a reliable diagnostic discriminant ability in the setting of AD. PMID- 28629376 TI - Radiation therapy for older patients with brain tumors. AB - The incidence of brain tumors in the elderly population has increased over the last few decades. Current treatment includes surgery, radiotherapy and chemotherapy, but the optimal management of older patients with brain tumors remains a matter of debate, since aggressive radiation treatments in this population may be associated with high risks of neurological toxicity and deterioration of quality of life. For such patients, a careful clinical status assessment is mandatory both for clinical decision making and for designing randomized trials to adequately evaluate the optimal combination of radiotherapy and chemotherapy.Several randomized studies have demonstrated the efficacy and safety of chemotherapy for patients with glioblastoma or lymphoma; however, the use of radiotherapy given in association with chemotherapy or as salvage therapy remains an effective treatment option associated with survival benefit. Stereotactic techniques are increasingly used for the treatment of patients with brain metastases and benign tumors, including pituitary adenomas, meningiomas and acoustic neuromas. Although no randomized trials have proven the superiority of SRS over other radiation techniques in older patients with brain metastases or benign brain tumors, data extracted from recent randomized studies and large retrospective series suggest that SRS is an effective approach in such patients associated with survival advantages and toxicity profile similar to those observed in young adults. Future trials need to investigate the optimal radiation techniques and dose/fractionation schedules in older patients with brain tumors with regard to clinical outcomes, neurocognitive function, and quality of life. PMID- 28629377 TI - Quantitative phosphoproteome on the silkworm (Bombyx mori) cells infected with baculovirus. AB - BACKGROUND: Bombyx mori has become an important model organism for many fundamental studies. Bombyx mori nucleopolyhedrovirus (BmNPV) is a significant pathogen to Bombyx mori, yet also an efficient vector for recombinant protein production. A previous study indicated that acetylation plays many vital roles in several cellular processes of Bombyx mori while global phosphorylation pattern upon BmNPV infection remains elusive. METHOD: Employing tandem mass tag (TMT) labeling and phosphorylation affinity enrichment followed by high-resolution LC MS/MS analysis and intensive bioinformatics analysis, the quantitative phosphoproteome in Bombyx mori cells infected by BmNPV at 24 hpi with an MOI of 10 was extensively examined. RESULTS: Totally, 6480 phosphorylation sites in 2112 protein groups were identified, among which 4764 sites in 1717 proteins were quantified. Among the quantified proteins, 81 up-regulated and 25 down-regulated sites were identified with significant criteria (the quantitative ratio above 1.3 was considered as up-regulation and below 0.77 was considered as down-regulation) and with significant p-value (p < 0.05). Some proteins of BmNPV were also hyperphosphorylated during infection, such as P6.9, 39 K, LEF-6, Ac58-like protein, Ac82-like protein and BRO-D. CONCLUSION: The phosphorylated proteins were primary involved in several specific functions, out of which, we focused on the binding activity, protein synthesis, viral replication and apoptosis through kinase activity. PMID- 28629378 TI - MicroRNA-130b is involved in bovine granulosa and cumulus cells function, oocyte maturation and blastocyst formation. AB - BACKGROUND: Oocyte maturation and preimplantation embryo development are controlled by array of genes that are post-transcriptionally regulated by microRNAs. With respect to this, previously, we identified altered expression of microRNA-130b (miR-130b) during oocyte maturation. Here, we aimed to investigate the role of miR-130b in bovine granulosa and cumulus cell function, oocyte maturation and preimplantation embryo development using gain- and loss-of- function approach. METHODS: For this study, the granulosa cells, cumulus cells and the oocytes were collected from ovaries obtained from slaughterhouse. The genes targeted by miR-130b were identified using dual-luciferase reporter assay. The role of miR-130b in granulosa and cumulus cell function was investigated by increasing and inhibiting its expression in in vitro cultured cells using miR 130b precursor and inhibitor, respectively while the role of miR-130b on oocyte development, immature oocytes were microinjected with miR-130b precursor and inhibitor and the polar body extrusion, the proportion of oocytes reaching to metaphase II stage and the mitochondrial were determined in each oocyte group 22 h after microinjection. Moreover, to investigate the role of miR-130b during preimplantation embryo development, zygote stage embryos were microinjected with miR-130b precursor or inhibitor and the cleavage rate, morula and blastocyst formation was analyzed in embryos derived from each zygote group after in vitro culture. RESULTS: The luciferase assay showed that SMAD5 and MSK1 genes were identified as the direct targets of miR-130b. Overexpression of miR-130b increased the granulosa and cumulus cell proliferation, while inhibition showed the opposite phenotype. Apart from these, modulation of miR-130b altered the lactate production and cholesterol biosynthesis in cumulus cells. Furthermore, inhibition of miR-130b expression during oocyte in vitro maturation reduced the first polar body extrusion, the proportion of oocytes reaching to metaphase II stage and the mitochondrial activity, while inhibition of miR-130b during preimplantation embryo development significantly reduced morula and blastocyst formation. CONCLUSION: This study demonstrated that in vitro functional modulation of miR-130b affected granulosa and cumulus cell proliferation and survival, oocyte maturation, morula and blastocyst formation suggesting that miR 130b is involved in bovine oocyte maturation and preimplantation embryo development. PMID- 28629380 TI - Retinal and vitreous metastases from hepatocholangiocarcinoma. AB - BACKGROUND: To report a case of metastatic hepatocholangiocarcinoma to the vitreous and retina. CASE PRESENTATION: A 70-year-old male, who was recently diagnosed with hepatocholangiocarcinoma, was complaining of floaters in his right eye over the past 5 months and was referred to the Liverpool Ocular Oncology Centre. On presentation, his visual acuity in the right eye was 6/24. Fundus exam revealed a whitish, unilateral, full-thickness retinal lesion at the inferotemporal arcade of his right eye, with vitreous infiltration and subretinal fluid. The patient underwent 25G pars plana vitrectomy with biopsy, resection of the lesion and intravitreal bevacizumab injection. Histopathology testing of the surgical specimens confirmed the diagnosis of metastatic carcinoma to the eye. Two months postoperatively his visual acuity had improved to 6/7.5 and there was no sign of active disease in his right eye, while 9 months postoperatively his visual acuity decreased to 6/9.5 due to developing nuclear sclerotic cataract in his right eye. CONCLUSION: The current report presents the first case of a hepatocholangiocarcinoma metastasis to the vitreous and retina. PMID- 28629379 TI - Laparoscopic gastrectomy in obese gastric cancer patients: a comparative study with non-obese patients and evaluation of difference in laparoscopic methods. AB - BACKGROUND: Obesity is a growing epidemic around the world, and obese patients are generally regarded as high risk for surgery compared with normal weight patients. The purpose of this study was to evaluate the influence of obesity on the surgical outcomes of laparoscopic gastrectomy (LG) for gastric cancer. METHODS: We reviewed data for all patients undergoing LG for gastric cancer at our institute between October 2004 and December 2016. Patients were divided into non-obese and obese groups and the perioperative outcomes were compared. Furthermore, a subgroup analysis was conducted to evaluate which of the two commonly used methods of LG, laparoscopic-assisted gastrectomy (LAG) and totally laparoscopic gastrectomy (TLG), is more suitable for obese patients. RESULTS: A total of 1691 patients, 1255 non-obese and 436 obese or overweight patients, underwent LG during the study period. The mean operation time was significantly longer in the obese group than in the non-obese group (209.9 +/- 29.7 vs. 227.2 +/- 25.7 min, P < 0.01), and intraoperative blood loss was significantly lower in the non-obese group (113.4 +/- 34.1 vs. 136.9 +/- 36.7 ml, P < 0.01). Time to first flatus, time to oral intake, and postoperative hospital stay were significantly shorter in the non-obese group than in the obese group (3.3 +/- 0.8 vs. 3.6 +/- 0.9 days; 4.3 +/- 1.0 vs. 4.6 +/- 1.0 days; and 9.0 +/- 2.2 vs. 9.6 +/- 2.2 days, respectively; P < 0.01). 119 (9.5%) of the non-obese patients had postoperative complications as compared to 44 (10.1%) of the obese patients (P = 0.71). In the subgroup analysis of all patients, TLG showed improved results for early surgical outcomes compared to LAG, mainly due to its advantages in obese patients. CONCLUSIONS: Obesity is associated with long operation time, increased blood loss, and slow recovery after laparoscopic gastric resection but does not affect intraoperative security or effectiveness. TLG may have less negative results in obese patients than LAG due to a variety of reasons. Our analysis shows that TLG is more advantageous, with regard to early surgical outcomes, for obese patients. PMID- 28629382 TI - Community first responders and responder schemes in the United Kingdom: systematic scoping review. AB - BACKGROUND: Community First Responder (CFR) schemes support lay people to respond to medical emergencies, working closely with ambulance services. They operate widely in the UK. There has been no previous review of UK literature on these schemes. This is the first systematic scoping review of UK literature on CFR schemes, which identifies the reasons for becoming a CFR, requirements for training and feedback and confusion between the CFR role and that of ambulance service staff. This study also reveals gaps in the evidence base for CFR schemes. METHODS: We conducted a systematic scoping review of the published literature, in the English language from 2000 onwards using specific search terms in six databases. Narrative synthesis was used to analyse article content. RESULTS: Nine articles remained from the initial search of 15,969 articles after removing duplicates, title and abstract and then full text review. People were motivated to become CFRs through an altruistic desire to help others. They generally felt rewarded by their work but recognised that the help they provided was limited by their training compared with ambulance staff. There were concerns about the possible emotional impact on CFRs responding to incidents. CFRs felt that better feedback would enhance their learning. Ongoing training and support were viewed as essential to enable CFRs to progress. They perceived that public recognition of the CFR role was low, patients sometimes confusing them with ambulance staff. Relationships with the ambulance service were sometimes ambivalent due to confusion over roles. There was support for local autonomy of CFR schemes but with greater sharing of best practice. DISCUSSION: Most studies dated from 2005 and were descriptive rather than analytical. In the UK and Australia CFRs are usually lay volunteers equipped with basic skills for responding to medical emergencies, whereas in the US they include other emergency staff as well as lay people. CONCLUSION: Opportunities for future research include exploring experiences and perceptions of patients who have been treated by CFRs and other stakeholders, while also evaluating the effectiveness and costs of CFR schemes. PMID- 28629381 TI - The era of bioengineering: how will this affect the next generation of cancer immunotherapy? AB - BACKGROUND: Immunotherapy consists of activating the patient's immune system to fight cancer and has the great potential of preventing future relapses thanks to immunological memory. A great variety of strategies have emerged to harness the immune system against tumors, from the administration of immunomodulatory agents that activate immune cells, to therapeutic vaccines or infusion of previously activated cancer-specific T cells. However, despite great recent progress many difficulties still remain, which prevent the widespread use of immunotherapy. Some of these limitations include: systemic toxicity, weak immune cellular responses or persistence over time and most ultimately costly and time-consuming procedures. MAIN BODY: Synthetic and natural biomaterials hold great potential to address these hurdles providing biocompatible systems capable of targeted local delivery, co-delivery, and controlled and/or sustained release. In this review we discuss some of the bioengineered solutions and approaches developed so far and how biomaterials can be further implemented to help and shape the future of cancer immunotherapy. CONCLUSION: The bioengineering strategies here presented constitute a powerful toolkit to develop safe and successful novel cancer immunotherapies. PMID- 28629383 TI - Epitope mapping and characterization of a novel Nsp10-specific monoclonal antibody that differentiates genotype 2 PRRSV from genotype 1 PRRSV. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV), the causative agent of PRRS, has two distinct and highly diverse genotypes (genotype 1 and genotype 2) in the field. Accurate diagnosis and differentiation of the two genotypes of PRRSV are critical to the effective prevention and control of PRRS. The non-structural protein 10 (Nsp10) plays a vital role in viral replication and is one of the most conserved proteins of PRRSV, thus constituting a good candidate for PRRSV diagnosis. RESULTS: In this study, we generated a monoclonal antibody (mAb) 4D9 against Nsp10 by immunizing BALB/c mice with purified recombinant Nsp10 expressed by an Escherichia coli system. Through fine epitope mapping of mAb 4D9 using a panel of eukaryotic expressed polypeptides with GFP tags, we identified the motif 286AIQPDYRDKL295 as the minimal unit of the linear B-cell epitope recognized by mAb 4D9. Protein sequence alignment indicated that 286AIQPDYRDKL295 was highly conserved in genotype 2 PRRSV strains, whereas genotype 1 PRRSV strains had variable amino acids in this motif. Furthermore, a mutant of the motif carrying two constant amino acids of genotype 1 PRRSV, Cys290 and Glu293, failed to react with mAb 4D9. More importantly, the mAb 4D9 could differentiate genotype 2 PRRSV strains from genotype 1 PRRSV strains using Western blotting and immunofluorescence analysis. CONCLUSION: Our findings suggest that Nsp10-specific mAb generated in this study could be a useful tool for basic research and may facilitate the establishment of diagnostic methods to discriminate between genotype 1 and genotype 2 PRRSV infection. PMID- 28629384 TI - Involvement of the glutamate/glutamine cycle and glutamate transporter GLT-1 in antidepressant-like effects of Xiao Yao san on chronically stressed mice. AB - BACKGROUND: Xiao Yao San (XYS) is an herbal prescription which is used in the treatment of depression for thousands of years from Song dynasty in China (960 1127 A.D.), and is the bestselling and most popular herb formula for treating major depression. This study aimed to assess the chronic antidepressant effects of XYS and fluoxetine in depressed mice induced by chronic unpredictable mild stress (CUMS) and its association with alterations in glutamate/glutamine cycle and glutamate transporters. METHODS: Mice in the control and model group were given 0.5 ml physiological saline by intragastric administration. Mice in two treatment groups were given XYS (0.25 g/kg/d) and fluoxetine (2.6 mg/kg/d), respectively. The depressive-like behaviors such as forced swim test (FST), sucrose preference test (SPT) and novelty-suppressed feeding (NSF) test were measured after mice exposed to CUMS for 21 days. Body weight, contents of glutamate and glutamine, glutamine/glutamate ratio that is usually thought to reflect glutamate/glutamine cycle, and the protein and mRNA expressions of glutamate transporters (excitatory amino acid transporter 1-2,GLAST/EAAT1 and GLT 1/EAAT2) were measured. The immunoreactivities of GLAST and GLT-1 in the hippocampus were also investigated. RESULTS: After CUMS exposure, mice exhibited depressive-like behaviors, body weight loss, increased glutamate level, decreased glutamine level, elevated glutamine/glutamate ratio, decreased GLT-1 protein expression and mRNA level, and decreased average optical density (AOD) of GLT-1 in the CA1, CA3 and DG in the hippocampus. These abnormalities could be effectively reversed by XYS or fluoxetine treatment. In addition, the study also found that GLAST expression in the hippocampus could not be altered by 21-d CUMS. CONCLUSION: The studies indicated that XYS may have therapeutic actions on depression -like behavior s induced by CUMS in mice possibly mediated by modulation of glutamate/glutamine cycle and glutamate transporter GLT-1 in the hippocampus. PMID- 28629385 TI - Administrative Algorithms to identify Avascular necrosis of bone among patients undergoing upper or lower extremity magnetic resonance imaging: a validation study. AB - BACKGROUND: Studies of the epidemiology and outcomes of avascular necrosis (AVN) require accurate case-finding methods. The aim of this study was to evaluate performance characteristics of a claims-based algorithm designed to identify AVN cases in administrative data. METHODS: Using a centralized patient registry from a US academic medical center, we identified all adults aged >=18 years who underwent magnetic resonance imaging (MRI) of an upper/lower extremity joint during the 1.5 year study period. A radiologist report confirming AVN on MRI served as the gold standard. We examined the sensitivity, specificity, positive predictive value (PPV) and positive likelihood ratio (LR+) of four algorithms (A D) using International Classification of Diseases, 9th edition (ICD-9) codes for AVN. The algorithms ranged from least stringent (Algorithm A, requiring >=1 ICD-9 code for AVN [733.4X]) to most stringent (Algorithm D, requiring >=3 ICD-9 codes, each at least 30 days apart). RESULTS: Among 8200 patients who underwent MRI, 83 (1.0% [95% CI 0.78-1.22]) had AVN by gold standard. Algorithm A yielded the highest sensitivity (81.9%, 95% CI 72.0-89.5), with PPV of 66.0% (95% CI 56.0 75.1). The PPV of algorithm D increased to 82.2% (95% CI 67.9-92.0), although sensitivity decreased to 44.6% (95% CI 33.7-55.9). All four algorithms had specificities >99%. CONCLUSION: An algorithm that uses a single billing code to screen for AVN among those who had MRI has the highest sensitivity and is best suited for studies in which further medical record review confirming AVN is feasible. Algorithms using multiple billing codes are recommended for use in administrative databases when further AVN validation is not feasible. PMID- 28629386 TI - Strain elastography imaging for early detection and prediction of tumor response to concurrent chemo-radiotherapy in locally advanced cervical cancer: feasibility study. AB - BACKGROUND: To investigate the feasibility of strain elastography imaging in early detecting and predicting treatment response in patients receiving concurrent chemo-radiotherapy (CCRT) for locally advanced cervical cancer. METHODS: Between January 2015 and June 2016, 47 patients with locally advanced cervical cancer were enrolled in a feasibility study approved by the institutional review board. All patients underwent CCRT and received strain elastography examinations at 4 time points: pre-therapy (baseline), 1 week and 2 weeks during, as well as immediately post CCRT. Treatment response was evaluated by MRI at the time of diagnosis and immediately after CCRT. Based on the MRI findings, the treatment outcome was characterized as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Strain ratio of the normal parametrial tissue vs. cervical tumor was calculated and compared with the clinical outcome. RESULTS: Out of the 47 patients, 36 patients who completed all 4 examinations were included in the analyses: 25 were classified as CR, 11 as PR, and 0 in the SD/PD groups. Strain ratios were significantly different among the time points in both the CR group (F = 87.004, p < 0.001) and PR group (F = 38.317, p < 0.001). Strain ratios were significantly difference between the CR and PR groups (F = 7.203 p = 0.011). Strain ratios between the CR group and PR group were significantly different at 1 week after treatment initiation (p < 0.05). Compared to the baseline, a significant decrease in the CR group was observed at week 1, week 2 and post treatment (all p < 0.001), while a significant decrease in the PR group was shown in week 2 and post treatment (both p < 0.05), but not at week 1 during CCRT (p = 0.084). CONCLUSIONS: We have conducted a prospective longitudinal study to evaluate tumor response in women receiving CCRT for cervical cancers. This study has demonstrated the potential of strain elastography imaging in monitoring and early predicting tumor response induced by CCRT. PMID- 28629387 TI - An updated assessment of microglia depletion: current concepts and future directions. AB - Microglia are the principal resident immune cells in the central nervous system and are believed to be versatile players in both inflammatory and physiological contexts. On the one hand, in order to safeguard the microenvironment microglia can be rapidly activated by contact with microbial products or cell debris, thereby exerting the functions of innate immunity via phagocytosis and secretion of cytokines and chemokines. Conversely, microglia can also assist in brain development, synaptic plasticity and neural repair through the production of neurotrophic factors and clearance of myelin debris. It is now well accepted that the dysfunction of microglia and microglia-induced neuroinflammation are implicated in the occurrence and progression of many neurological diseases. Although the past decade has witnessed major progress in understanding of multi tasking microglia, what remains largely enigmatic is the relative importance of microglia at different disease stages and how microglia should be targeted for optimal therapeutic efficacy. Notably, microglia depletion through genetic targeting or pharmacological therapies can be viewed as effective tools to stimulate new microglia to repopulate the central nervous system. Microglia depletion and subsequent repopulation at defined stages in various experimental animal model disorders allow us to extend our knowledge of molecular mechanisms, thus holding promise for designing strategies to resolve neuroinflammation and promote recovery. Herein we highlight the highly plastic and diverse phenotypes of microglia and outline the lessons learned from microglia depletion approaches. PMID- 28629388 TI - The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and beta-cell function in spontaneous diabetic KKAy mice. AB - BACKGROUND: E2HSA is a genetic fusion protein that consists of two tandem exendin 4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker. Previous studies have demonstrated that E2HSA significantly decreased blood glucose levels, improved beta-cell function and promoted beta cell proliferation in diabetic db/dB mice. This study aimed to evaluate the benefits of E2HSA on glucose and lipid metabolism in a spontaneous diabetes animal model, KKAy mice. METHODS: E2HSA was acutely administered at doses of 1, 3 and 9 mg/kg by subcutaneous injection in diabetic KKAy mice with exendin-4 (2 MUg/kg) as a positive reference, and then the non-fasting blood glucose and food intake levels were dynamically monitored. In addition, different doses of E2HSA were injected once daily, as well as with exendin-4 twice daily, for 7 weeks to evaluate the effect on glucose and lipid metabolism, as well as the body weight, food and water intake. RESULTS: Single injection of E2HSA decreased non-fasting blood glucose and food intake levels in a dose-dependent manner for 4 days and 2 days, respectively. Repeated injections with E2HSA significantly decreased variations in blood glucose levels with a reduction of HbA1c levels by 1.6% at a 9 mg/kg dose, simultaneously increased fasting blood insulin levels, inhibited fasting blood glucagon levels, improved the impaired oral glucose tolerance and enhanced glucose infusion rate, which is the gold standard for evaluating beta cell function. Moreover, repeated injections with E2HSA also ameliorated the dyslipidemia and reduced body weight, food and water intake in diabetic KKAy mice. CONCLUSIONS: E2HSA significantly reduced blood glucose levels over a prolonged duration, enhanced beta-cell function, and ameliorated dyslipidemia and obesity in diabetic KKAy mice. Thus, E2HSA may be a new candidate for the treatment of type 2 diabetes. PMID- 28629390 TI - Results of the first interim analysis of the RAPPER II trial in patients with spinal cord injury: ambulation and functional exercise programs in the REX powered walking aid. AB - BACKGROUND: The RAPPER II study investigates the feasibility, safety and acceptability of using the REX self-stabilising robotic exoskeleton in people with spinal cord injury (SCI) who are obligatory wheelchair users. Feasibility is assessed by the completion of transfer into the REX device, competency in achieving autonomous control and completion of upper body exercise in an upright position in the REX device. Safety is measured by the occurrence of serious adverse events. Device acceptability is assessed with a user questionnaire. METHODS: RAPPER II is a prospective, multi-centre, open label, non-randomised, non-comparative cohort study in people with SCI recruited from neurological rehabilitation centres in the United Kingdom, Australia and New Zealand. This is the planned interim report of the first 20 participants. Each completed a transfer into the REX, were trained to achieve machine control and completed Timed Up and Go (TUG) tests as well as upper body exercises in standing in a single first time session. The time to achieve each task as well as the amount of assistance required was recorded. After finishing the trial tasks a User Experience questionnaire, exploring device acceptability, was completed. RESULTS: All participants could transfer into the REX. The mean transfer time was 439 s. Nineteen completed the exercise regime. Eighteen could achieve autonomous control of the REX, 17 of whom needed either no assistance or the help of just one therapist. Eighteen participants completed at least one TUG test in a mean time of 313 s, 15 with the assistance of just one therapist. The questionnaire demonstrated high levels of acceptability amongst users. There were no Serious Adverse Events. CONCLUSIONS: This first interim analysis of RAPPER II shows that it is feasible and safe for people with SCI to use the REX powered assisted walking device to ambulate and exercise in. Participants with tetraplegia and paraplegia could walk and perform a functional exercise program when standing needing only modest levels of assistance in most cases. User acceptability was high. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02417532 . Registered 11 April 2015. PMID- 28629391 TI - Anterior lens capsule and epithelium thickness measurements using spectral-domain optical coherence tomography. AB - BACKGROUND: To investigate the anterior lens capsule and epithelium thickness (defined as anterior lens capsular complex: ALCC) in normal Chinese subjects using spectral-domian optical coherence tomography (SD-OCT) and examine the factors that may influence the ALCC, such as age, gender, pupil diameter (PD) and signal strength index (SSI). METHODS: A prospective observational case series. One-hundred-thirty-four normal subjects (134 eyes) were included. The ALCCs were determined manually via SD-OCT. Using the pupil center as a reference position, the central ALCC (CALCC), nasal 1-mm ALCC (NALCC), temporal 1-mm ALCC (TALCC) and PD were measured manually. RESULTS: The mean CALCC, NALCC and TALCC were 33 +/- 6 MUm, 36 +/- 7 MUm and 34 +/- 6 MUm, respectively. The NALCC was significantly thicker than the CALCC (P < .001) and TALCC (P < .001). Moreover, CALCC was significantly thinner than TALCC (P = 0.013). Age was positively correlated with the CALCC (r = 0.292, P < .001), NALCC (r = 0.400, P < .001) and TALCC (r = 0.521, P < .001). PD, gender and SSI were not significantly correlated with the three ALCC parameters. CONCLUSIONS: The SD-OCT can be used to demonstrate the ALCC thickness, and age is positively correlated with the ALCC in the central, nasal and temporal sides. PMID- 28629389 TI - Cancer chemoprevention through dietary flavonoids: what's limiting? AB - Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e.g., bioavailability, drug-drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and efforts that are being made to surmount these challenges. PMID- 28629392 TI - Do investors value the FDA orphan drug designation? AB - BACKGROUND: The Orphan Drug Act is an important piece of legislation that uses financial incentives to encourage the development of drugs that treat rare diseases. This analysis studies the effects of a portion of the Orphan Drug Act, the orphan drug designation. Specifically, it studies the value that investors place on the orphan drug designation, by investigating how investors react to companies' announcing that their product has received the designation. RESULTS: The results, on average, show that the stock price of a company increases by 3.36% after the announcement of the designation, increasing the value of the company. The results are more pronounced for oncology drugs, and drugs being developed by the smallest companies. CONCLUSION: The orphan designation appears to be successful at generating positive value for companies, as seen by the positive and significant average increases in stock price. PMID- 28629393 TI - The effect of an elective cesarean section on maternal request on peripartum anxiety and depression in women with childbirth fear: a systematic review. AB - BACKGROUND: Obstetricians are often reluctant to grant requests for an elective cesarean section (ECS) due to childbirth fear. To date, it is unknown if an ECS on request improves mental well-being in the mother in the peripartum period and if possible beneficial effects on anxiety and depression could outweigh the increased risk of complications associated with a surgical delivery. A systematic review was conducted to explore the effect of ECS on request on peripartum anxiety and depression. METHODS: We searched on PubMed, PsychoInfo and Embase. Studies were included with primary data on anxiety and/or depression postpartum in women with childbirth fear who had requested an ECS. After full-text evaluation of 65 papers and quality analysis of four papers, three papers were included. Of one paper additional and yet unpublished data were provided. Studies varied in outcome measures, hence no meta-analysis was performed. RESULTS: Women who requested an ECS had higher antepartum depression and anxiety levels but no different postpartum depression levels than women who delivered vaginally. One study of good quality examined the effect of vaginal delivery in women preferring ECS: These women had significantly higher symptom levels of post-traumatic stress disorder (PTSD) and depression than women with normal vaginal delivery. CONCLUSIONS: The prospect of an ECS does not lower antepartum anxiety and/or depression levels in women requesting an ECS. If women resolutely persist in wishing an ECS despite adequate counselling and/or psychiatric treatment, the risk of developing depressive and PTSD symptoms in case of vaginal delivery should be taken into account, and an ECS may be considered as a valid alternative. PMID- 28629394 TI - Validating the WHO maternal near miss tool: comparing high- and low-resource settings. AB - BACKGROUND: WHO proposed the WHO Maternal Near Miss (MNM) tool, classifying women according to several (potentially) life-threatening conditions, to monitor and improve quality of obstetric care. The objective of this study is to analyse merged data of one high- and two low-resource settings where this tool was applied and test whether the tool may be suitable for comparing severe maternal outcome (SMO) between these settings. METHODS: Using three cohort studies that included SMO cases, during two-year time frames in the Netherlands, Tanzania and Malawi we reassessed all SMO cases (as defined by the original studies) with the WHO MNM tool (five disease-, four intervention- and seven organ dysfunction-based criteria). Main outcome measures were prevalence of MNM criteria and case fatality rates (CFR). RESULTS: A total of 3172 women were studied; 2538 (80.0%) from the Netherlands, 248 (7.8%) from Tanzania and 386 (12.2%) from Malawi. Total SMO detection was 2767 (87.2%) for disease-based criteria, 2504 (78.9%) for intervention-based criteria and 1211 (38.2%) for organ dysfunction-based criteria. Including every woman who received >=1 unit of blood in low-resource settings as life-threatening, as defined by organ dysfunction criteria, led to more equally distributed populations. In one third of all Dutch and Malawian maternal death cases, organ dysfunction criteria could not be identified from medical records. CONCLUSIONS: Applying solely organ dysfunction-based criteria may lead to underreporting of SMO. Therefore, a tool based on defining MNM only upon establishing organ failure is of limited use for comparing settings with varying resources. In low-resource settings, lowering the threshold of transfused units of blood leads to a higher detection rate of MNM. We recommend refined disease-based criteria, accompanied by a limited set of intervention- and organ dysfunction-based criteria to set a measure of severity. PMID- 28629395 TI - Early experiences from one of the first treatment programs for chronic hepatitis B in sub-Saharan Africa. AB - BACKGROUND: Treatment for chronic hepatitis B (CHB) is virtually absent in sub Saharan Africa. Here we present early experiences from a pilot program for treatment of CHB in Ethiopia. METHODS: Adults (>=18 years) with CHB were included in a cohort study at St. Paul's Hospital Millennium Medical College, Addis Ababa, from February 2015. The baseline assessment included liver function tests, viral markers and transient elastography (Fibroscan 402, Echosense, France). Logistic regression models were used to identify predictors of fibrosis. Tenofovir disoproxil fumarate (TDF) was initiated based on the European Association for the Study of the Liver (EASL) criteria, with some modifications. The initial 300 patients underwent a more comprehensive evaluation and are presented here. RESULTS: One-hundred-and-thirty-eight patients (46.0%) were women and median age was 30 years (interquartile range 26-40). Co-infections were rare: four patients (1.3%) were anti-HCV positive, 11 (3.7%) were anti-HDV positive, whereas 5 (1.7%) had HIV-infection. The majority were hepatitis B e-antigen (HBeAg) negative (n = 262; 90.7%) and had a normal (<=40 U/L) alanine aminotransferase (ALT) (n = 245; 83.1%). Of 268 patients with a valid Fibroscan result, 79 (29.5%) had significant fibrosis (>7.9 kPa). Independent predictors of fibrosis were male sex, age > 35 years and viral load >20,000 IU/ml. In total, 74 patients (24.7%) started TDF therapy, of whom 46 (62.2%) had cirrhosis. CONCLUSIONS: The majority were HBeAg negative and had normal ALT. However, one quarter of the patients were in need of antiviral treatment, underscoring the need to scale up CHB treatment on the African continent. TRIAL REGISTRATION: NCT02344498 ( ClinicalTrials.gov identifier). Registered 16 January 2015. PMID- 28629396 TI - Identifying approaches for assessing methodological and reporting quality of systematic reviews: a descriptive study. AB - BACKGROUND: The methodological quality and completeness of reporting of the systematic reviews (SRs) is fundamental to optimal implementation of evidence based health care and the reduction of research waste. Methods exist to appraise SRs yet little is known about how they are used in SRs or where there are potential gaps in research best-practice guidance materials. The aims of this study are to identify reports assessing the methodological quality (MQ) and/or reporting quality (RQ) of a cohort of SRs and to assess their number, general characteristics, and approaches to 'quality' assessment over time. METHODS: The Cochrane Library, MEDLINE(r), and EMBASE(r) were searched from January 1990 to October 16, 2014, for reports assessing MQ and/or RQ of SRs. Title, abstract, and full-text screening of all reports were conducted independently by two reviewers. Reports assessing the MQ and/or RQ of a cohort of ten or more SRs of interventions were included. All results are reported as frequencies and percentages of reports. RESULTS: Of 20,765 unique records retrieved, 1189 of them were reviewed for full-text review, of which 76 reports were included. Eight previously published approaches to assessing MQ or reporting guidelines used as proxy to assess RQ were used in 80% (61/76) of identified reports. These included two reporting guidelines (PRISMA and QUOROM) and five quality assessment tools (AMSTAR, R-AMSTAR, OQAQ, Mulrow, Sacks) and GRADE criteria. The remaining 24% (18/76) of reports developed their own criteria. PRISMA, OQAQ, and AMSTAR were the most commonly used published tools to assess MQ or RQ. In conjunction with other approaches, published tools were used in 29% (22/76) of reports, with 36% (8/22) assessing adherence to both PRISMA and AMSTAR criteria and 26% (6/22) using QUOROM and OQAQ. CONCLUSIONS: The methods used to assess quality of SRs are diverse, and none has become universally accepted. The most commonly used quality assessment tools are AMSTAR, OQAQ, and PRISMA. As new tools and guidelines are developed to improve both the MQ and RQ of SRs, authors of methodological studies are encouraged to put thoughtful consideration into the use of appropriate tools to assess quality and reporting. PMID- 28629397 TI - Optimal timing of renal replacement therapy initiation in acute kidney injury: the elephant felt by the blindmen? AB - Renal replacement therapy (RRT) is a key component in the management of severe acute kidney injury (AKI) in critically ill patients. Many cohort studies, meta analyses, and two recent large randomized prospective trials which evaluated the relationship between the timing of RRT initiation and patient outcome remain inconclusive due to substantial differences in study design, patient population, AKI definition, and RRT indication. A cause-specific diagnosis of AKI based on current staging criteria plus a sensitive biomarker (panel) that allows creating a homogeneous study population is definitely needed to assess the impact of early versus late initiation of RRT on patient outcome. PMID- 28629398 TI - Anaplastic astrocytoma mimicking progressive multifocal leucoencephalopathy: a case report and review of the overlapping syndromes. AB - BACKGROUND: Co-occurrence of multiple sclerosis (MS) and glial tumours (GT) is uncommon although occasionally reported in medical literature. Interpreting the overlapping radiologic and clinical characteristics of glial tumours, MS lesions, and progressive multifocal leukoencephalopathy (PML) can be a significant diagnostic challenge. CASE PRESENTATION: We report a case of anaplastic astrocytoma mimicking PML in a 27-year-old patient with a 15-year history of MS. She was treated with interferon, natalizumab and finally fingolimod due to active MS. Follow-up MRI, blood and cerebrospinal fluid examinations, and biopsy were conducted, but only the latter was able to reveal the cause of progressive worsening of patient's disease. CONCLUSIONS: Anaplastic astrocytoma misdiagnosed as PML has not yet been described. We suppose that the astrocytoma could have evolved from a low grade glioma to anaplastic astrocytoma over time, as the tumour developed adjacent to typical MS plaques. The role of the immunomodulatory treatment as well as other immunological factors in the malignant transformation can only be hypothesised. We discuss clinical, laboratory and diagnostic aspects of a malignant GT, MS lesions and PML. The diagnosis of malignant GT must be kept in mind when an atypical lesion develops in a patient with MS. PMID- 28629399 TI - Epigenomics: dissecting hybridization and polyploidization. AB - Epigenetic profiling in diploid, allopolyploid, and domesticated cotton shows that despite most DNA methylation being conserved and stably inherited, alterations likely due to hybridization and domestication affect gene expression. PMID- 28629400 TI - Characteristics of syphilitic uveitis in northern China. AB - BACKGROUND: To describe the characteristics of patients with syphilitic uveitis in northern China. METHODS: A case series of 21 patients (33 eyes) diagnosed with syphilitic uveitis from 2011 to 2016 at a tertiary center in northern China was retrospectively analyzed. RESULTS: Twenty-one patients (33 eyes) were diagnosed as syphilitic uveitis. Posterior segment involvement was found in 32 eyes (97.0%). Vitreous haze, neuroretinitis, and posterior placoid chorioretinitis were mainly found in patients with a relatively short duration of the disease, while diffuse chorioretinitis, pseudoretinitis pigmentosa, cystoid macular edema, and epiretinal membrane were found in patients with relatively long duration of ocular involvement. A low best-corrected visual acuity (P = 0.022) and a delay of syphilis treatment (P < 0.001) were associated with a significantly worse visual outcome. CONCLUSIONS: Syphilitic uveitis should be included in the differential diagnosis of any form of posterior ocular inflammation. The pattern of ocular involvement may change with the disease progression. PMID- 28629401 TI - Odontogenic orbital cellulitis associated with cavernous sinus thrombosis and pulmonary embolism: a case report. AB - BACKGROUND: This case illustrates the importance of prompt assessment and treatment of orbital cellulitis. In fact the ocular signs and symptoms may be associated with systemic complications which should be investigated and identified as soon as possible to avoid a poor prognosis. CASE PRESENTATION: A 46 year-old white woman presented to our emergency room with proptosis, ophthalmoplegia, and conjunctival chemosis of her left eye. An ophthalmologist, having diagnosed orbital cellulitis in her left eye, suspected a cavernous sinus thrombosis. Hematochemical and radiological examinations confirmed the cavernous sinus thrombosis and also showed septic pulmonary embolism. A blood culture indicated Streptococcus constellatus, which is a member of the Peptostreptococcus family, a saprophyte of the oral mucosa that can be pathogenic in immunocompromised persons. The odontogenic origin was then confirmed by dental radiography which showed a maxillary abscess. Her eye signs regressed after antibiotic and anticoagulant therapy. CONCLUSIONS: This complex case shows the importance of a multidisciplinary approach for the management of orbital cellulitis, for the prompt diagnosis and treatment of eye injuries and possible complications, so as to avoid serious and permanent sequelae. PMID- 28629402 TI - Erratum to: Social capital-a mixed blessing for women? A cross-sectional study of different forms of social relations and self-rated depression in Moscow. PMID- 28629403 TI - Factors influencing professional life satisfaction among neurologists. AB - BACKGROUND: Predicted shortages in the supply of neurologists may limit patients' access to and quality of care for neurological disorders. Retaining neurologists already in practice provides one opportunity to support the overall supply of practicing neurologists. Understanding factors associated with professional life satisfaction (and dissatisfaction) and implementing policies to enhance satisfaction may encourage neurologists to remain in clinical practice. In this paper, we present results from the first study examining factors associated with professional life satisfaction among a large sample of U.S, neurologists. METHODS: We collaborated with the AAN to survey a sample of U.S. neurologists about their professional life satisfaction. Analyses examined the association of physician and practice characteristics with aspects of professional life satisfaction, including satisfaction with their career in medicine, medical specialty, current position, relationship with colleagues, relationship with patients, work/life balance, and pay. RESULTS: The study population consisted of 625 neurologists. In multivariate regression analyses, no single group or population stratum indicated high (or low) responses to all aspects of satisfaction. Older neurologists reported higher satisfaction with career, specialty, and relationship with patients than younger neurologists. Female neurologists had significantly lower satisfaction with pay than male neurologists. Neurologists who spent more time in research and teaching had greater satisfaction with specialty, relationship with colleagues, and relationship with patients than those spending no time in research. Neurologists who practiced in small cities/rural areas reported lower satisfaction across multiple dimensions than those practicing in large urban areas. Neurologists in solo practice had greater satisfaction with the relationship with their patients, but lower satisfaction with pay. CONCLUSIONS: Satisfaction is a multidimensional construct that is associated with physician and practice characteristics. Enhancing professional life satisfaction among neurologists requires multiple strategies, such as promoting comparable wages for men and women, providing collaboration and research opportunities, and providing resources for small and rural practices. PMID- 28629404 TI - White matter lesions characterise brain involvement in moderate to severe chronic obstructive pulmonary disease, but cerebral atrophy does not. AB - BACKGROUND: Brain pathology is relatively unexplored in chronic obstructive pulmonary disease (COPD). This study is a comprehensive investigation of grey matter (GM) and white matter (WM) changes and how these relate to disease severity and cognitive function. METHODS: T1-weighted and fluid-attenuated inversion recovery images were acquired for 31 stable COPD patients (FEV1 52.1% pred., PaO2 10.1 kPa) and 24 age, gender-matched controls. T1-weighted images were segmented into GM, WM and cerebrospinal fluid (CSF) tissue classes using a semi-automated procedure optimised for use with this cohort. This procedure allows, cohort-specific anatomical features to be captured, white matter lesions (WMLs) to be identified and includes a tissue repair step to correct for misclassification caused by WMLs. Tissue volumes and cortical thickness were calculated from the resulting segmentations. Additionally, a fully-automated pipeline was used to calculate localised cortical surface and gyrification. WM and GM tissue volumes, the tissue volume ratio (indicator of atrophy), average cortical thickness, and the number, size, and volume of white matter lesions (WMLs) were analysed across the whole-brain and regionally - for each anatomical lobe and the deep-GM. The hippocampus was investigated as a region-of-interest. Localised (voxel-wise and vertex-wise) variations in cortical gyrification, GM density and cortical thickness, were also investigated. Statistical models controlling for age and gender were used to test for between-group differences and within-group correlations. Robust statistical approaches ensured the family wise error rate was controlled in regional and local analyses. RESULTS: There were no significant differences in global, regional, or local measures of GM between patients and controls, however, patients had an increased volume (p = 0.02) and size (p = 0.04) of WMLs. In patients, greater normalised hippocampal volume positively correlated with exacerbation frequency (p = 0.04), and greater WML volume was associated with worse episodic memory (p = 0.05). A negative relationship between WML and FEV1 % pred. approached significance (p = 0.06). CONCLUSIONS: There was no evidence of cerebral atrophy within this cohort of stable COPD patients, with moderate airflow obstruction. However, there were indications of WM damage consistent with an ischaemic pathology. It cannot be concluded whether this represents a specific COPD, or smoking-related, effect. PMID- 28629405 TI - Erratum to: Comparative evaluation of the diagnosis, reporting and investigation of malaria cases in China, 2005-2014: transition from control to elimination for the national malaria programme. PMID- 28629406 TI - Geospatial and temporal associations of Getah virus circulation among pigs and horses around the perimeter of outbreaks in Japanese racehorses in 2014 and 2015. AB - BACKGROUND: We studied a recent epizootic of Getah virus infection among pigs in the southern part of Ibaraki Prefecture and the northern part of Chiba Prefecture, Japan, focusing on its possible association with outbreaks in racehorses in 2014 and 2015. The genomic sequence of a Getah virus strain from an infected pig was analyzed to evaluate the degree of identity with the strains from horses. RESULTS: Sera were collected from pigs from September to December 2012 to 2015 in south Ibaraki (380 pigs in 29 batches), and from September to December 2010 to 2015 in north Chiba (538 pigs in 104 batches). They were examined by using a virus-neutralizing test for Getah virus. Seropositivity rates in 2012-2013 in south Ibaraki and 2010-2012 in north Chiba ranged from 0% to 1.6%. In south Ibaraki, seropositivity rates in 2014 (28.8%) and 2015 (65.0%) were significantly higher than those in the previous years (P < 0.01); 4/5 batches had positive sera in 2014 and 7/7 in 2015. In north Chiba, seropositivity rates in 2013 (14.1%), 2014 (17.8%), and 2015 (48.0%) were significantly higher than those in the previous years (P < 0.01); 6/27 batches had positive sera in 2013, 3/9 in 2014, and 5/5 in 2015. Complete genome analysis revealed that the virus isolated from an infected pig had 99.89% to 99.94% nucleotide identity to the strains isolated from horses during the outbreaks in 2014 and 2015. CONCLUSIONS: Serological surveillance of Getah virus in pigs revealed that the virus was circulating in south Ibaraki and north Chiba in 2014 and 2015; this was concomitant with the outbreaks in racehorses. The Getah virus strain isolated from a pig was closely related to the ones from horses during the 2014 and 2015 outbreaks. To our knowledge, this is the first convincing case of simultaneous circulation of Getah virus both among pigs and horses in specific areas. PMID- 28629407 TI - Antibacterial activity of crude extracts of some South African medicinal plants against multidrug resistant etiological agents of diarrhoea. AB - BACKGROUND: This study evaluated the antibacterial activity of some plants used in folklore medicine to treat diarrhoea in the Eastern Cape Province, South Africa. METHODS: The acetone extracts of Acacia mearnsii De Wild., Aloe arborescens Mill., A. striata Haw., Cyathula uncinulata (Schrad.) Schinz, Eucomis autumnalis (Mill.) Chitt., E. comosa (Houtt.) Wehrh., Hermbstaedtia odorata (Burch. ex Moq.) T.Cooke, Hydnora africana Thunb, Hypoxis latifolia Wight, Pelargonium sidoides DC, Psidium guajava L and Schizocarphus nervosus (Burch.) van der Merwe were screened against Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, multi-resistant Salmonella enterica serovar Isangi, S. typhi, S. enterica serovar Typhimurium, Shigella flexneri type 1b and Sh. sonnei phase II. A qualitative phytochemical screening of the plants extracts was by thin layer chromatography. Plants extracts were screened for antibacterial activity using serial dilution microplate technique and bioautography. RESULTS: The TLC fingerprint indicated the presence of terpenoids and flavonoids in the herbs. Most of the tested organisms were sensitive to the crude acetone extracts with minimum inhibitory concentration (MIC) values ranging from 0.018-2.5 mg/ml. Extracts of A. striata, C. uncinulata, E. autumnalis and P. guajava were more active against enteropathogens. S. aureus and Sh. flexneri were the most sensitive isolates to the crude extracts but of significance is the antibacterial activity of A. arborescens and P. guajava against a confirmed extended spectrum betalactamase positive S. enterica serovar Typhimurium. CONCLUSION: The presence of bioactive compounds and the antibacterial activity of some of the selected herbs against multidrug resistant enteric agents corroborate assertions by traditional healers on their efficacies. PMID- 28629408 TI - Biochemical characterization of an enantioselective esterase from Brevundimonas sp. LY-2. AB - BACKGROUND: Lactofen, a member of the diphenylether herbicides, has high activity and is commonly used to control broadleaf weeds. As a post-emergent herbicide, it is directly released to the environment, and easily caused the pollution. This herbicide is degraded in soil mainly by microbial activity, but the functional enzyme involved in the biodegradation of lactofen is still not clear now. RESULTS: A novel esterase gene lacH, involved in the degradation of lactofen, was cloned from the strain Brevundimonas sp. LY-2. The gene contained an open reading frame of 921 bp, and a putative signal peptide at the N-terminal was identified with the most likely cleavage site between Ala 28 and Ala 29. The encoded protein, LacH, could catalyze the hydrolysis of lactofen to form acifluorfen. Phylogenetic analysis showed that LacH belong to family V of bacterial lipolytic enzymes. Biochemical characterization analysis showed that LacH was a neutral esterase with an optimal pH of 7.0 and an optimal temperature of 40 degrees C toward lactofen. Besides, the activity of LacH was strongly inhibited by Hg2+ and Zn2+. LacH preferred short chain p-nitrophenyl esters (C2-C6), exhibited maximum activity toward p-nitrophenyl acetate. Furthermore, the enantioselectivity of LacH during lactofen hydrolysis was also studied, and the results show that R-(-) lactofen was degraded faster than S-(+)-lactofen, indicating the occurrence of enantioselectivity in the enzymatic reaction. CONCLUSIONS: Our studies characterized a novel esterase involved in the biodegradation of diphenylether herbicide lactofen. The esterase showed enantioselectivity during lactofen degradation, which revealed the occurrence of enzyme-mediated enantioselective degradation of chiral herbicides. PMID- 28629409 TI - Correlation between knowledge on transmission and prevention of HIV/STI and proficiency in condom use among male migrants from Africa and Middle East evaluated by a Condom Use Skills score using a wooden penile model. AB - BACKGROUND: Migrants in Italy are prevalently young adults, with a higher risk of sexual transmitted infections (STI) and HIV infection. Promoting consistent as well as correct use of condoms could reduce failure rate due to their improper use. The aim of our study was to evaluate Condom Use Skills among a migrant population recently landed in Italy, hosted in a government center for asylum seekers. METHODS: The study sample was composed of 80 male migrants. Sanitary trained interviewers submitted a questionnaire to participants to investigate age, provenience, marital status, educational level and knowledge about transmission and prevention of HIV/STI. Then, we assessed participants' level of condom use skill with the Condom Use Skills (CUS) measure by using a wooden penile model. The interviewer filled in a checklist and assigned 1 point for correct demonstration of each behavior that may prevent condom failure during sex. RESULTS: Participants' median age was 26 years and the sample was composed of 54 migrants from sub-Saharan Africa and 26 from Middle East. Most of them were married, with a lower middle level of education, up to 8 or 5 years. Half of the sample achieved the highest score in the questionnaire and our CUS showed a large number of people with middle high score classes. The Spearman's rho was 0.30, therefore answers to the questionnaire and CUS score appeared correlated (p < 0.05). In the multivariate model, to have a higher CUS score resulted to be associated to be older than 26 years (p < 0.05), with a higher level of education (p = 0.001), and a higher score in the questionnaire (p < 0.05). There were no significant differences in the level of CUS between single or married men and between African and Middle Asian migrants of the sample. CONCLUSIONS: Our study shows that educational level influences the quality of knowledge and awareness about STI/AIDS and contribute to correct condom use. Since the half of participants had a low educational level and linguistic problems, the risk of missing campaigns messages or misunderstanding informative materials increases. Direct observation of condom-application on penile model may offer realistic assessment of application skills in these individuals. PMID- 28629410 TI - He's just content to sit: a qualitative study of mothers' perceptions of infant obesity and physical activity. AB - BACKGROUND: Rates of obesity among children ages zero to five are rapidly increasing. Greater efforts are needed to promote healthy behaviors of young children. Mothers are especially important targets for promoting health as mothers' views play a vital role in helping their children foster healthy habits from an early age. Research has found parents' views of infants' weight may influence their feeding practices; however, limited research has explored mothers' view of infants' weight in relation to the promotion of physical activity. Therefore, the purpose of this study was to explore the perceptions of mothers of normal weight infants and overweight infants about their infant's weight and physical activity. METHODS: Semi-structured interviews were conducted with mothers of normal weight (n = 18) and of overweight (n = 11) infants (6.5 +/ 0.5 month) in a Midwestern city in the United States. A thematic analysis was used to analyze the data. RESULTS: A majority of mothers thought infants could be overweight. However, no mothers referenced their own infant as overweight. Mothers most commonly noted infants could be overweight only if they were formula fed and/or were overfed, not if they were breastfed. Mothers views were not negatively influenced by others who mentioned that their child was either "big" or "small" and only one mother had been told her infant was overweight. A majority of mothers thought an infant could be physically active. When discussing infant activity, mothers primarily referred to it in terms of general mobility and a few thought activity level was related to a personality characteristic. Mothers intended to promote physical activity in the future either through outdoor play or specific organized activities such as sports. Despite a majority of mothers stating they were currently physically active themselves, only a few talked about interacting with their infant to promote their infant's physical activity. CONCLUSIONS: Efforts are needed by healthcare professionals and other public health professionals to inform mothers about the dangers of increased weight during infancy as well as the importance of interacting with infants to promote physical activity. PMID- 28629411 TI - Prevalence and predictors of complementary and alternative medicine use among people with coronary heart disease or at risk for this in the sixth Tromso study: a comparative analysis using protection motivation theory. AB - BACKGROUND: Engagement in healthy lifestyle behaviors, such as healthy diet and regular physical activity, are known to reduce the risk of developing coronary heart disease (CHD). Complementary and alternative medicine (CAM) is known to be associated with having a healthy lifestyle. The primary aim of this study was to examine the prevalence and predictors of CAM use in CHD patients, and in those without CHD but at risk for developing CHD, using Protection Motivation Theory (PMT) as a guiding conceptual framework. METHOD: Questionnaire data were collected from 12,981 adult participants in the cross-sectional sixth Tromso Study (2007-8). Eligible for analyses were 11,103 participants who reported whether they had used CAM or not. Of those, 830 participants reported to have or have had CHD (CHD group), 4830 reported to have parents, children or siblings with CHD (no CHD but family risk), while 5443 reported no CHD nor family risk of CHD. We first compared the patterns of CAM use in each group, and then examined the PMT predictors of CAM use. Health vulnerability from the threat appraisal process of PMT was assessed by self-rated health and expectations for future health. Response efficacy from the coping appraisal process of PMT was assessed as preventive health beliefs and health behavior frequency. RESULTS: Use of CAM was most commonly seen in people with no CHD themselves, but family risk of developing CHD (35.8%), compared to people already diagnosed with CHD (30.2%) and people with no CHD nor family risk (32.1%). All four of the PMT factors; self rated health, expectations for future health, preventive health beliefs, and the health behavior index - were predictors for CAM use in the no CHD but family risk group. CONCLUSION: These findings suggest that people use CAM in response to a perceived risk of developing CHD, and to prevent disease and to maintain health. PMID- 28629412 TI - Cross-cultural validation of health literacy measurement tools in Italian oncology patients. AB - BACKGROUND: The aim of this study was to assess the psychometric characteristics of four Health Literacy (HL) measurement tools, viz. Newest Vital Sign (NVS), Short Test of Functional Health Literacy in Adults (STOFHLA), Single Item Literacy Screener (SILS) and Single question on Self-rated Reading Ability (SrRA) among Italian oncology patients. METHODS: The original version of the tools were translated from the English language into Italian using a standard forward backward procedure and according to internationally recognized good practices. Their internal consistency (reliability) and validity (construct, convergent and discriminative) were tested in a sample of 245 consecutive cancer patients recruited from seven Italian health care centers. RESULTS: The internal consistency of the STOFHLA-I was Chronbach's alpha=0.96 and that of NVS-I was alpha=0.74. The STOFHLA-I, NVS-I, SILS-I and SrRA-I scores were in a good relative correlation and in all tools the discriminative known-group validity was confirmed. The reliability and validity values were similar to those obtained from other cultural context studies. CONCLUSION: The psychometric characteristics of the Italian version of NVS, STHOFLA, SILS and SrRA were found to be good, with satisfactory reliability and validity. This indicates that they could be used as a screening tool in Italian patients. Moreover, the use of the same cross cultural tools, validated in different languages, is essential for implementing multicenter studies to measure and compare the functional HL levels across countries. PMID- 28629413 TI - Progressive disability in elderly population among tribals of Telangana: a cross sectional study. AB - BACKGROUND: The tribal population of Telangana, India, lives in remote and difficult conditions. This study was carried out to find out estimate, the prevalence and progression of disability in elderly population among tribals of Khammam District, Telangana state, India. METHODS: A population based cross sectional survey was conducted in villages of Tribal Sub Plan area. Elderly people who are 60 years or older were chosen with a two stage sampling procedure: (1) probability proportion to size was used to select clusters and (2) in each selected cluster households were selected by systematic random sampling. The participants were interviewed with the 36 item Telugu version of the World Health Organization Disability Assessment Schedule (WHODAS 2.0) questionnaire. Socio- demographic information, behavioral measurements, health and social benefit indicators were also assessed. Descriptive analytical methods were used for prevalence estimation and logistic regression was used to examine the associations of progressive age over disability among elderly. RESULTS: A total of 506 elderly people from 1349 households in 20 villages across 31mandals of Khammam were interviewed. Majority of elderly population among tribals were illiterate (men 88.94%; women 99.33%), used tobacco (men 81.25%; women 57.72%), consumed alcohol (men 80.77%; women 47.32%) and were hypertensive (men 53.85%; women 63.42%). The prevalence of disability was higher in women. Maximum disability in the interviewed elderly population was seen in domains of performing house hold activities, and mobility. In comparison with men, women expressed more disability for majority of domains. As age progressed, the disability for self-care domain increased to a maximum of 2.6 times in men and 6.6 times in women and for mobility domain increased to a maximum of 9.7 times in men and 7.2 times in women. CONCLUSIONS: Although present disability modifying mobility Assistive Devices (AD) can help elderly in overcoming disability, these are primarily designed for built environments. As the needs, cultural sensitivities, and living environment of elderly population in tribals are unique, newer innovative assistive devices should be designed and developed. PMID- 28629414 TI - Fibrinogen deficiency in a dog - a case report. AB - BACKGROUND: Among coagulation disorders, primary fibrinogen deficiency is very rare in dogs. It is divided into hypofibrinogenemia, afibrinogenemia and dysfibrinogenemia. Afibrinogenemia has been described in three dogs. There are, however, no published case reports of primary hypofibrinogenemia in dogs. CASE PRESENTATION: A 1.5 year-old male German Pointer dog was evaluated for a locked jaw syndrome associated with eye protrusion which appeared after a minor head trauma. Three months before the trauma, a persistent increase in coagulation times was detected by the referring veterinarian after a strong suspicion of snake envenomation. Apart for the primary complaint, physical examination was normal. A complete hemostatic profile revealed a moderately increased prothrombin time, activated partial thromboplastin times and a dramatically decreased fibrinogen concentration (0.34 g/L, reference interval [1.3-4.8 g/L]). Platelet count, plasma D-dimers and antithrombin, were all within the reference intervals and not consistent with a disseminated intravascular coagulation. Other possible causes of hypofibrinogenemia such as chronic hemorrhage and liver failure were excluded by laboratory work-up and imaging studies. Finally, antifibrinogen circulating anticoagulants were excluded using a dilution of citrated plasma from the pooled plasma of healthy dogs. These results supported a diagnosis of congenital fibrinogen deficiency and secondary retrobulbar hematoma and/or cellulitis. The dog's condition improved rapidly after symptomatic treatment with corticosteroids and antibiotics. At the 1 year follow-up, the dog was clinically normal but a persistent hypofibrinogenemia (<= 0.8 g/L) remained. CONCLUSIONS: Various clinical presentations may occur in canine primary hypofibrinogenemia which should be included in the list of coagulation disorders. Diagnosis should include fibrinogen determination by coagulometric and non-coagulometric methods to differentiate from dysfibrinogenemia. There is no specific treatment but care should be taken to prevent bleeding and trauma. Emergency management of bleeding episodes with cryoprecipitate is the treatment of choice. PMID- 28629416 TI - CT texture features are associated with overall survival in pancreatic ductal adenocarcinoma - a quantitative analysis. AB - BACKGROUND: To assess whether CT-derived texture features predict survival in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). METHODS: Thirty patients with pre-operative CT from 2007 to 2012 for PDAC were included. Tumor size and five texture features namely uniformity, entropy, dissimilarity, correlation, and inverse difference normalized were calculated. Mann-Whitney rank sum test was used to compare tumor with normal pancreas. Receiver operating characteristics (ROC) analysis, Cox regression and Kaplan Meier tests were used to assess association of texture features with overall survival (OS). RESULTS: Uniformity (p < 0.001), entropy (p = 0.009), correlation (p < 0.001), and mean intensity (p < 0.001) were significantly different in tumor regions compared to normal pancreas. Tumor dissimilarity (p = 0.045) and inverse difference normalized (p = 0.046) were associated with OS whereas tumor intensity (p = 0.366), tumor size (p = 0.611) and other textural features including uniformity (p = 0.334), entropy (p = 0.330) and correlation (p = 0.068) were not associated with OS. CONCLUSION: CT-derived PDAC texture features of dissimilarity and inverse difference normalized are promising prognostic imaging biomarkers of OS for patients undergoing curative intent surgical resection. PMID- 28629415 TI - KAPS (kinematic assessment of passive stretch): a tool to assess elbow flexor and extensor spasticity after stroke using a robotic exoskeleton. AB - BACKGROUND: Spasticity is a common sequela of stroke. Traditional assessment methods include relatively coarse scales that may not capture all characteristics of elevated muscle tone. Thus, the aim of this study was to develop a tool to quantitatively assess post-stroke spasticity in the upper extremity. METHODS: Ninety-six healthy individuals and 46 individuals with stroke participated in this study. The kinematic assessment of passive stretch (KAPS) protocol consisted of passive elbow stretch in flexion and extension across an 80 degrees range in 5 movement durations. Seven parameters were identified and assessed to characterize spasticity (peak velocity, final angle, creep (or release), between arm peak velocity difference, between-arm final angle, between-arm creep, and between-arm catch angle). RESULTS: The fastest movement duration (600 ms) was most effective at identifying impairment in each parameter associated with spasticity. A decrease in peak velocity during passive stretch between the affected and unaffected limb was most effective at identifying individuals as impaired. Spasticity was also associated with a decreased passive range (final angle) and a classic 'catch and release' as seen through between-arm catch and creep metrics. CONCLUSIONS: The KAPS protocol and robotic technology can provide a sensitive and quantitative assessment of post-stroke elbow spasticity not currently attainable through traditional measures. PMID- 28629417 TI - Use of mobile and cordless phones and change in cognitive function: a prospective cohort analysis of Australian primary school children. AB - BACKGROUND: Some previous studies have suggested an association between children's use of mobile phones (MPs)/cordless phones (CPs) and development of cognitive function. We evaluated possible longitudinal associations between the use of MPs and CPs in a cohort of primary school children and effects on their cognitive function. METHODS: Data on children's socio-demographics, use of MPs and CPs, and cognitive function were collected at baseline (2010-2012) and follow up (2012-2013). Cognitive outcomes were evaluated with the CogHealthTM test battery and Stroop Color-Word test. The change in the number of MP/CP voice calls weekly from baseline to follow-up was dichotomized: "an increase in calls" or a "decrease/no change in calls". Multiple linear regression analyses, adjusting for confounders and clustering by school, were performed to evaluate the associations between the change in cognitive outcomes and change in MP and CP exposures. RESULTS: Of 412 children, a larger proportion of them used a CP (76% at baseline and follow-up), compared to a MP (31% at baseline and 43% at follow-up). Of 26 comparisons of changes in cognitive outcomes, four demonstrated significant associations. The increase in MP usage was associated with larger reduction in response time for response inhibition, smaller reduction in the number of total errors for spatial problem solving and larger increase in response time for a Stroop interference task. Except for the smaller reduction in detection task accuracy, the increase in CP usage had no effect on the changes in cognitive outcomes. CONCLUSION: Our study shows that a larger proportion of children used CPs compared to MPs. We found limited evidence that change in the use of MPs or CPs in primary school children was associated with change in cognitive function. PMID- 28629418 TI - Prenatal brain disruption in isolated sulfite oxidase deficiency. AB - BACKGROUND: Isolated sulfite oxidase deficiency (ISOD) is a very rare autosomal recessive inherited neurometabolic disease. The most striking postnatal neuroimaging finding is multicystic encephalomalacia, which occurs rapidly within days to weeks after birth and mimics severe hypoxic-ischemic encephalopathy. The aim of this study was to describe the prenatal neuroimaging features in a neonate and a fetus diagnosed with ISOD. RESULTS: We report an 11-day-old female neonate who presented with feeding difficulties, decreased activity, neonatal seizures, and movement disorders within a few days after birth. Brain MRI at 9 days of age showed cystic lesions over the left frontal and temporal areas, diffuse and evident T2 high signal intensity of bilateral cerebral cortex, and increased T2 signal intensity of the globus pallidi. A pronounced low level of plasma cysteine and normal level of plasma uric acid were noted. Mutation analysis of SUOX revealed homozygous c.1200C > G mutations, resulting in an amino acid substitution of tyrosine to a stop codon (Y400X). The diagnosis of ISOD was made. The brain MRI of a prenatally diagnosed ISOD fetus of the second pregnancy of the mother of the index case showed poor gyration and differentiation of cortical layers without formation of cystic lesions at gestational age 21 weeks. CONCLUSION: Cystic brain destruction might occur prenatally and neurodevelopment of gyration and differentiation of the cortical layers in the developing brain could be affected by sulfite accumulation early during the second trimester in ISOD patients. This is the first description of the prenatal neurodevelopment of brain disruption in ISOD. PMID- 28629419 TI - Effect of beta-blockers on exacerbation rate and lung function in chronic obstructive pulmonary disease (COPD). AB - BACKGROUND: Beta-blockers are commonly prescribed for patients with cardiovascular disease. Providers have been wary of treating chronic obstructive pulmonary disease (COPD) patients with beta-blockers due to concern for bronchospasm, but retrospective studies have shown that cardio-selective beta blockers are safe in COPD and possibly beneficial. However, these benefits may reflect symptom improvements due to the cardiac effects of the medication. The purpose of this study is to evaluate associations between beta-blocker use and both exacerbation rates and longitudinal measures of lung function in two well characterized COPD cohorts. METHODS: We retrospectively analyzed 1219 participants with over 180 days of follow up from the STATCOPE trial, which excluded most cardiac comorbidities, and from the placebo arm of the MACRO trial. Primary endpoints were exacerbation rates per person-year and change in spirometry over time in association with beta blocker use. RESULTS: Overall 13.9% (170/1219) of participants reported taking beta-blockers at enrollment. We found no statistically significant differences in exacerbation rates with respect to beta-blocker use regardless of the prevalence of cardiac comorbidities. In the MACRO cohort, patients taking beta-blockers had an exacerbation rate of 1.72/person-year versus a rate of 1.71/person-year in patients not taking beta blockers. In the STATCOPE cohort, patients taking beta-blockers had an exacerbation rate of 1.14/person-year. Patients without beta-blockers had an exacerbation rate of 1.34/person-year. We found no detrimental effect of beta blockers with respect to change in lung function over time. CONCLUSION: We found no evidence that beta-blocker use was unsafe or associated with worse pulmonary outcomes in study participants with moderate to severe COPD. PMID- 28629420 TI - Comparison of the effects of platelet-rich or growth factor-rich plasma on intestinal anastomosis healing in pigs. AB - BACKGROUND: The use of autologous platelet-rich plasma (PRP) and plasma rich in growth factors (PRGF) has been proposed for the treatment of several acute and chronic syndromes, such as corneal epithelial defects and dry eye syndrome, gum bleeding during oral surgery, and in orthopaedic surgery. We hypothesized that PRGF, rather than PRP, could be more effective because of its intrinsic characteristics in promoting the healing of intestinal anastomosis. The purpose of the present study was to evaluate and compare the effects of PRP and PRGF on various parameters of anastomotic healing in a swine model. METHODS: Eight female pigs were randomly assigned to two groups and subjected to hand sewn jeujuno jejunal appositional extramucosal anastomoses. For each animal, a total of six anastomoses were performed: two were considered controls and received no treatment, while the remaining four anastomoses were treated with PRP or PRGF of which both were prepared at a platelet concentration that was respectively 3.4 fold and 2.81-fold higher than the original platelet count. In each animal, either PRP or PRGF was used as a treatment, to avoid interference among products. Animals were euthanized after 8 days and the anastomoses were evaluated and compared for the presence of adhesions, anastomotic leakage, bursting pressure, and histological appearance. RESULTS: The concentration of platelets in PRP was 3.41-fold higher (range, 3.20-4.24) that the concentration in whole blood, while the concentration in PRGF was 2.81-fold higher (range, 2.89-4.88). The results obtained from the present study highlighted that there are no differences between anastomotic samples treated with either PRP or PRGF preparations, except for a significant increase in epithelization of the intestinal mucosa at the anastomotic site in the PRGF group. CONCLUSIONS: Both PRP and PRGF suspensions should be considered a safe strategy and represent a relatively low-cost technology that is flexible enough to be applied in several therapeutic fields. No true benefit could be proven in our study compared to the no treatment following anastomoses formation, with the exception of enhanced epithelization of the mucosa in the PRGF group. PMID- 28629421 TI - Erratum to: Imatinib relaxes the pulmonary venous bed of guinea pigs. PMID- 28629422 TI - Erratum to: Ozone and childhood respiratory disease in three US cities: evaluation of effect measure modification by neighborhood socioeconomic status using a Bayesian hierarchical approach. PMID- 28629423 TI - Understanding consumer and clinician preferences and decision making for rehabilitation following arthroplasty in the private sector. AB - BACKGROUND: To understand private consumer and clinician preferences towards different rehabilitation modes following knee or hip arthroplasty, and identify factors which influence the chosen rehabilitation pathway. METHODS: Mixed methods cross-sectional study involving 95 semi-structured interviews of consumers (patients and carers) and clinicians (arthroplasty surgeons, physiotherapists and rehabilitation physicians) in Sydney, Australia, during 2014-2015. Participants were asked about the acceptability of different modes of rehabilitation provision, and factors influencing their chosen rehabilitation pathway. Interviews were in person or via the telephone. Qualitative analysis software was used to electronically manage qualitative data. An analytical approach guided data analysis. RESULTS: Pre-operative preferences strongly influenced the type of rehabilitation chosen by consumers. Key factors that influenced this were both intrinsic and extrinsic, including; the previous experience of self or known others, the perceived benefits of the chosen mode, a sense of entitlement, the role of orthopaedic surgeons and influence of patient preference, a patient's clinical status post-surgery, the private hospital business model and insurance provider involvement. The acceptability of rehabilitation modes varied between clinician groups. CONCLUSIONS: No one rehabilitation mode provided following arthroplasty is singularly preferred by stakeholders. Factors other than the belief that a particular mode was more effective than another appear to dominate the pathway followed by private arthroplasty consumers, indicating evidence-based policies around rehabilitation provision may have limited appeal in the private sector. PMID- 28629425 TI - Screening for chronic kidney disease of uncertain aetiology in Sri Lanka: usability of surrogate biomarkers over dipstick proteinuria. AB - BACKGROUND: The use of dipstick proteinuria to screen Chronic Kidney Disease of uncertain aetiology (CKDu) in Sri Lanka is a recently debated matter of dispute. The aim of this study was to assess the suitability of biomarkers: serum creatinine, cystatin C and urine albumin to creatinine ratio (ACR) for screening CKDu in Sri Lanka. METHODS: Forty-four male CKDu patients and 49 healthy males from a CKDu-endemic region were selected. Meanwhile, 25 healthy males from a non endemic region were selected as an absolute control. The diagnostic accuracy of each marker was compared using the above three study groups. RESULTS: In receiver operating characteristics (ROC) plots for creatinine, cystatin C and ACR, values of area under the curve (AUC) were 0.926, 0.920 and 0.737 respectively when CKDu was compared to non-endemic control. When CKDu was compared to endemic control, AUCs of above three analytes were distinctly lower as 0.718, 0.808 and 0.678 respectively. Cystatin C exhibited the highest sensitivity for CKDu when analyzed against both control groups where respective sensitivities were 0.75 against endemic control and 0.89 against non-endemic control. ROC-optimal cutoff limits of creatinine, cystatin C and ACR in CKDu vs non-endemic control were 89.0 MUmol/L, 1.01 mg/L and 6.06 mg/g-Cr respectively, whereas in CKDu vs endemic control the respective values were 111.5 MUmol/L, 1.22 mg/L and 12.66 mg/g-Cr. CONCLUSIONS: Amongst the three biomarkers evaluated in this study, our data suggest that Cystatin C is the most accurate functional marker in detecting CKDu in endemic regions, yet the high cost hinders its usability on general population. Creatinine is favorable over dipstick proteinuria owing to its apparent accuracy and cost efficiency, while having the ability to complement the kidney damage marker (ACR) in screening. ACR may not be favorable as a standalone screening marker in place of dipstick proteinuria due to its significant decline in sensitivity against the CKDu-endemic population. However, creatinine and ACR in a complementary manner could overcome current shortcomings of dipstick proteinuria and such a dual marker tool could be commodious in screening CKDu type tubulointerstital diseases. Furthermore, use of ACR may also increase the ability to clinically discriminate CKDu from other glomerular nephropathies. PMID- 28629424 TI - Evaluation of the international standardized 24-h dietary recall methodology (GloboDiet) for potential application in research and surveillance within African settings. AB - BACKGROUND: Collection of reliable and comparable individual food consumption data is of primary importance to better understand, control and monitor malnutrition and its related comorbidities in low- and middle-income countries (LMICs), including in Africa. The lack of standardised dietary tools and their related research support infrastructure remains a major obstacle to implement concerted and region-specific research and action plans worldwide. Citing the magnitude and importance of this challenge, the International Agency for Research on Cancer (IARC/WHO) launched the "Global Nutrition Surveillance initiative" to pilot test the use of a standardized 24-h dietary recall research tool (GloboDiet), validated in Europe, in other regions. In this regard, the development of the GloboDiet-Africa can be optimised by better understanding of the local specific methodological needs, barriers and opportunities. The study aimed to evaluate the standardized 24-h dietary recall research tool (GloboDiet) as a possible common methodology for research and surveillance across Africa. METHODS: A consultative panel of African and international experts in dietary assessment participated in six e-workshop sessions. They completed an in-depth e questionnaire to evaluate the GloboDiet dietary methodology before and after participating in the e-workshop. RESULTS: The 29 experts expressed their satisfaction on the potential of the software to address local specific needs when evaluating the main structure of the software, the stepwise approach for data collection and standardisation concept. Nevertheless, additional information to better describe local foods and recipes, as well as particular culinary patterns (e.g. mortar pounding), were proposed. Furthermore, food quantification in shared-plates and -bowls eating situations and interviewing of populations with low literacy skills, especially in rural settings, were acknowledged as requiring further specific considerations and appropriate solutions. CONCLUSIONS: An overall positive evaluation of the GloboDiet methodology by both African and international experts, supports the flexibility and potential applicability of this tool in diverse African settings and sets a positive platform for improved dietary monitoring and surveillance. Following this evaluation, prerequisite for future implementation and/or adaptation of GloboDiet in Africa, rigorous and robust capacity building as well as knowledge transfer will be required to roadmap a stepwise approach to implement this methodology across pilot African countries/regions. PMID- 28629426 TI - Development and validation of a prognostic scoring model for Mycobacterium avium complex lung disease: an observational cohort study. AB - BACKGROUND: Patients with Mycobacterium avium complex (MAC) lung disease (LD) have a heterogeneous prognosis. This study aimed to develop and validate a prognostic scoring model for these patients using independent risk factors for survival. METHODS: We retrospectively analyzed the data of patients with MAC-LD from two hospitals (cohort 1, n = 368; cohort 2, n = 118). Cohort 1 was evaluated using a multivariate Cox proportional hazards model to identify independent risk factors for overall survival (OS). A prognostic scoring model composed of these factors was developed, and cohort 1 was stratified into three groups according to risk using the log-rank test. Finally, the prognostic scoring model was validated using the data of cohort 2. RESULTS: Seven independent risk factors for OS were selected from cohort 1, including the male sex, age >= 70 years, the presence of a malignancy, body mass index <18.5 kg/m2, lymphocyte count <1000 cells/MUL, serum albumin levels <3.5 g/dL, and fibrocavitary disease. The areas under the receiver operating characteristic curves for the prognostic scoring model were 0.84 [95% confidence interval (CI), 0.80 - 0.89] for cohort 1 and 0.84 (95% CI, 0.75 - 0.92) for cohort 2. The 5-year OS rates of patients stratified into low risk, intermediate-risk, and high-risk groups were 97.6, 76.6, and 30.8%, respectively (P < 0.001), in cohort 1, and 97.2, 82.3, and 45.4%, respectively (P < 0.001), in cohort 2. CONCLUSIONS: This study is the first to develop and validate a prognostic scoring model for patients with MAC-LD. This model may prove useful in clinical settings and practical in estimating the prognosis. PMID- 28629427 TI - Targeting VEGFR-3/-2 signaling pathways with AD0157: a potential strategy against tumor-associated lymphangiogenesis and lymphatic metastases. AB - BACKGROUND: Lymphatic metastasis is one of the leading causes of death in patients with different types of cancer and is the main prognostic factor for the disease survival. The formation of new lymphatic vessels (lymphangiogenesis) in primary tumors facilitates tumor cell dissemination to regional lymph nodes and correlates with distant metastases. Lymphangiogenesis has thus emerged as a suitable therapeutic target to block metastases, but no anti-lymphangiogenic compounds have been approved for clinical use to date. Therefore, new or improved therapies blocking lymphatic metastases are urgently required. METHODS: We established murine breast tumors to assess the effect of AD0157 on tumor growth, lymphangiogenesis, and lymphatic dissemination. Then, a battery of in vivo (mouse corneal neovascularization and ear sponges), ex vivo (mouse lymphatic rings and rat mesentery explants), and in vitro (proliferation, tubulogenesis, wound healing, Boyden chambers, and spheroids) assays was used to give insight into the lymphangiogenic steps affected by AD0157. Finally, we investigated the molecular pathways controlled by this drug. RESULTS: AD0157 was found to inhibit the growth of human breast cancer xenografts in mice, to strongly reduce tumor-associated lymphangiogenesis and to block metastatic dissemination to both lymph nodes and distant organs. The high anti-lymphangiogenic potency of AD0157 was further supported by its inhibitory activity at low micromolar range in two in vivo pathological models and in two ex vivo assays. In addition, AD0157 inhibited lymphatic endothelial cell proliferation, migration and invasion, cellular sprouting, and tube formation. Mechanistically, this compound induced apoptosis in lymphatic endothelial cells and decreased VEGFR-3/-2, ERK1/2, and Akt phosphorylations. CONCLUSIONS: These findings demonstrate the suitability of AD0157 to suppress tumor-associated lymphangiogenesis. Beyond discovering a new potent anti-lymphangiogenic drug that is worth considering in future clinical settings, our study supports the interest of designing anti-lymphangiogenic therapies to avoid distant metastatic processes. PMID- 28629428 TI - Study protocol: evaluation of an online, father-inclusive, universal parenting intervention to reduce child externalising behaviours and improve parenting practices. AB - BACKGROUND: Parenting interventions that focus on enhancing the quality and consistency of parenting are effective for preventing and reducing externalising problems in children. There has been a recent shift towards online delivery of parenting interventions in order to increase their reach and impact on the population prevalence of child externalising problems. Parenting interventions have low rates of father participation yet research suggests that father involvement may be critical to the success of the intervention. Despite this, no online parenting interventions have been specifically developed to meet the needs and preferences of fathers, as well as mothers. This paper describes the protocol of a study examining the effectiveness of an online, father-inclusive parenting intervention called 'ParentWorks', which will be delivered as a universal intervention to Australian families. METHODS/DESIGN: A single group clinical trial will be conducted to examine the effectiveness of ParentWorks for reducing child externalising problems and improving parenting, as well as to explore the impact of father engagement (in two-parent families) on child outcomes. Australian parents/caregivers with a child aged 2-16 years will be recruited. Participants will provide informed consent, complete pre-intervention measures and will then complete the intervention, which consists of five compulsory video modules and three optional modules. The primary outcomes for this study are changes in child externalising behaviour, positive and dysfunctional parenting practices and parental conflict, and the secondary outcome is changes in parental mental health. Demographic information, satisfaction with the intervention, and measures of parental engagement will also be collected. Questionnaire data will be collected at pre-intervention, post-intervention and three-month follow-up, as well as throughout the program. DISCUSSION: This paper describes the study protocol of a single group clinical trial of a national, online, father-inclusive parenting intervention. The results from this study could be used to inform public policy about providing support to parents of children with behaviour problems, and enhancing the engagement of fathers in parenting interventions. TRIAL REGISTRATION: ACTRN12616001223426 , registered 05/09/2016. PMID- 28629429 TI - Linked read sequencing resolves complex genomic rearrangements in gastric cancer metastases. AB - BACKGROUND: Genome rearrangements are critical oncogenic driver events in many malignancies. However, the identification and resolution of the structure of cancer genomic rearrangements remain challenging even with whole genome sequencing. METHODS: To identify oncogenic genomic rearrangements and resolve their structure, we analyzed linked read sequencing. This approach relies on a microfluidic droplet technology to produce libraries derived from single, high molecular weight DNA molecules, 50 kb in size or greater. After sequencing, the barcoded sequence reads provide long range genomic information, identify individual high molecular weight DNA molecules, determine the haplotype context of genetic variants that occur across contiguous megabase-length segments of the genome and delineate the structure of complex rearrangements. We applied linked read sequencing of whole genomes to the analysis of a set of synchronous metastatic diffuse gastric cancers that occurred in the same individual. RESULTS: When comparing metastatic sites, our analysis implicated a complex somatic rearrangement that was present in the metastatic tumor. The oncogenic event associated with the identified complex rearrangement resulted in an amplification of the known cancer driver gene FGFR2. With further investigation using these linked read data, the FGFR2 copy number alteration was determined to be a deletion-inversion motif that underwent tandem duplication, with unique breakpoints in each metastasis. Using a three-dimensional organoid tissue model, we functionally validated the metastatic potential of an FGFR2 amplification in gastric cancer. CONCLUSIONS: Our study demonstrates that linked read sequencing is useful in characterizing oncogenic rearrangements in cancer metastasis. PMID- 28629430 TI - Bangladesh policy on prevention and control of non-communicable diseases: a policy analysis. AB - BACKGROUND: This paper is aimed at critically assessing the extent to which Non Communicable Disease NCD-related policies introduced in Bangladesh align with the World Health Organization's (WHO) 2013-2020 Action Plan for the Global Strategy for the Prevention and Control of NCDs. METHODS: The authors reviewed all relevant policy documents introduced by the Government of Bangladesh since its independence in 1971. The literature review targeted scientific and grey literature documents involving internet-based search, and expert consultation and snowballing to identify relevant policy documents. Information was extracted from the documents using a specific matrix, mapping each document against the six objectives of the WHO 2013-2020 Action Plan for the Global Strategy for the Prevention and Control of NCDs. RESULTS: A total of 51 documents were identified. Seven (14%) were research and/or surveys, nine were on established policies (17%), while seventeen (33%) were on action programmes. Five (10%) were related to guidelines and thirteen (25%) were strategic planning documents from government and non-government agencies/institutes. The study covered documents produced by the Government of Bangladesh as well as those by quasi-government and non-government organizations irrespective of the extent to which the intended policies were implemented. CONCLUSIONS: The policy analysis findings suggest that although the government has initiated many NCD-related policies or programs, they lacked proper planning, implementation and monitoring. Consequently, Bangladesh over the years had little success in effectively addressing the growing burden of non-communicable diseases. It is imperative that future research critically assess the effectiveness of national NCD policies by monitoring their implementation and level of population coverage. PMID- 28629431 TI - MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway. AB - BACKGROUND: Brain metastasis (BM) is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Recent studies demonstrated that microRNA-330-3p (miR-330-3p) was involved in NSCLC brain metastasis (BM). However, the exact parts played by miR-330-3p in BM of NSCLC remain unknown. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. Here, we evaluated the expression and biological effects of miR-330-3p in NSCLC cells and explored the underlying mechanism of miR-330-3p in promoting cell migration and invasion in NSCLC. METHODS: Stable over-expression and knockdown of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical, and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330 3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay. The correlation between GRIA3 and DNA methyltransferase (DNMT) 1 and DNMT3A was tested by RT-PCR, western blotting, and co-immunoprecipitation (IP). RESULTS: miR-330-3p was significantly up-regulated in NSCLC cell lines. MTT assay, transwell migration, and invasion assays showed that miR-330-3p promoted the growth, migration, and invasion of NSCLC cells in vitro and induced tumor growth and metastasis in vivo. Luciferase reporter assays showed that GRIA3 was a target of miR-330-3p. qRT-PCR and western blotting exhibited that miR-330-3p promoted the growth, invasion, and migration of NSCLC cells by activating mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinases (ERK) signaling pathway. Furthermore, miR-330-3p up regulated the total DNA methylation in NSCLC cells, and co-IP-demonstrated GRIA3 was directly related with DNMT1 and DNMT3A. CONCLUSIONS: miR-330-3p promoted the progression of NSCLC and might be a potential target for the further research of NSCLC brain metastasis. PMID- 28629432 TI - Imaging of alphavbeta3 integrin expression in experimental myocardial ischemia with [68Ga]NODAGA-RGD positron emission tomography. AB - BACKGROUND: Radiolabeled RGD peptides detect alphavbeta3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased alphavbeta3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether alphavbeta3 integrin is expressed in viable ischemic or injured myocardium. METHODS: We studied 8 Finnish landrace pigs 13 +/- 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 +/- 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology. RESULTS: Stent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 +/- 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of alphavbeta3 integrin that was expressed in the injured myocardial areas. CONCLUSIONS: Cardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial alphavbeta3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects alphavbeta3 integrin expression associated with repair of recent myocardial injury. PMID- 28629433 TI - Smoking and timing of cessation on postoperative pulmonary complications after curative-intent lung cancer surgery. AB - BACKGROUND: Smoking is a risk factor for postoperative pulmonary complications (PPC) following non-small cell lung cancer (NSCLC) surgery. The optimal timing for preoperative smoking cessation has not been identified. Our study aimed to observe the impact of preoperative smoking cessation on PPC incidence and other postoperative outcomes including long-term survival. METHODS: A prospective study included consecutive patients following resection for NSCLC in a regional thoracic centre over a 4-year period (2010-2014). Patients were stratified according to self-reported preoperative smoking status. The primary endpoint was PPC incidence, which was assessed from postoperative day one onwards using the Melbourne Group Scale. Secondary endpoints included short-term outcomes (hospital length of stay [LOS], intensive therapy unit [ITU] admission, 30-day hospital readmission rate) and long-term survival. RESULTS: Four hundred and sixty-two patients included 111 (24%) current smokers, 55 (12%) ex-smokers <6 weeks, 245 (53%) ex-smokers >=6 weeks and 51 (11%) never smokers. PPC occurred in 60 (13%) patients in total. Compared to never smokers, current smokers had a higher frequency of PPC (22% vs. 2%, p = 0.004), higher frequency of ITU admission (14% vs. 0%; p = 0.001) and a longer median (IQR) hospital LOS (6 [5] vs. 5 [2]; p = 0.001). In the ex-smokers there was a trend for a lower frequency of PPC (<6 weeks, 10.9% vs. >=6 weeks, 11.8%) and ITU admission (<6 weeks, 5.5% vs. >=6 weeks, 4.5%), but there was no difference between the <6 weeks or >=6 weeks ex smoking groups prior to surgery. There was no significant difference in long-term survival found between the groups of differing smoking status (median follow-up 29.8 months, 95%CI 28.4-31.1). CONCLUSION: Current smokers have higher postoperative morbidity; this risk reduces following smoking cessation but 6 weeks does not appear to identify a time-point where differences in outcomes are noted. PMID- 28629434 TI - Reduction of breathing irregularity-related motion artifacts in low-pitch spiral 4D CT by optimized projection binning. AB - BACKGROUND: Respiration-correlated CT (4D CT) is the basis of radiotherapy treatment planning of thoracic and abdominal tumors. Current clinical 4D CT images suffer, however, from artifacts due to unfulfilled assumptions concerning breathing pattern regularity. We propose and evaluate modifications to existing low-pitch spiral 4D CT reconstruction protocols to counteract respective artifacts. METHODS: The proposed advanced reconstruction (AR) approach consists of two steps that build on each other: (1) statistical analysis of the breathing signal recorded during CT data acquisition and extraction of a patient-specific reference breathing cycle for projection binning; (2) incorporation of an artifact measure into the reconstruction. 4D CT data of 30 patients were reconstructed by standard phase- and local amplitude-based reconstruction (PB, LAB) and compared with images obtained by AR. The number of artifacts was evaluated and artifact statistics correlated to breathing curve characteristics. RESULTS: AR reduced the number of 4D CT artifacts by 31% and 27% compared to PB and LAB; the reduction was most pronounced for irregular breathing curves. CONCLUSIONS: We described a two-step optimization of low-pitch spiral 4D CT reconstruction to reduce artifacts in the presence of breathing irregularity and illustrated that the modifications to existing reconstruction solutions are effective in terms of artifact reduction. PMID- 28629436 TI - Disease Compass- a navigation system for disease knowledge based on ontology and linked data techniques. AB - BACKGROUND: Medical ontologies are expected to contribute to the effective use of medical information resources that store considerable amount of data. In this study, we focused on disease ontology because the complicated mechanisms of diseases are related to concepts across various medical domains. The authors developed a River Flow Model (RFM) of diseases, which captures diseases as the causal chains of abnormal states. It represents causes of diseases, disease progression, and downstream consequences of diseases, which is compliant with the intuition of medical experts. In this paper, we discuss a fact repository for causal chains of disease based on the disease ontology. It could be a valuable knowledge base for advanced medical information systems. METHODS: We developed the fact repository for causal chains of diseases based on our disease ontology and abnormality ontology. This section summarizes these two ontologies. It is developed as linked data so that information scientists can access it using SPARQL queries through an Resource Description Framework (RDF) model for causal chain of diseases. RESULTS: We designed the RDF model as an implementation of the RFM for the fact repository based on the ontological definitions of the RFM. 1554 diseases and 7080 abnormal states in six major clinical areas, which are extracted from the disease ontology, are published as linked data (RDF) with SPARQL endpoint (accessible API). Furthermore, the authors developed Disease Compass, a navigation system for disease knowledge. Disease Compass can browse the causal chains of a disease and obtain related information, including abnormal states, through two web services that provide general information from linked data, such as DBpedia, and 3D anatomical images. CONCLUSIONS: Disease Compass can provide a complete picture of disease-associated processes in such a way that fits with a clinician's understanding of diseases. Therefore, it supports user exploration of disease knowledge with access to pertinent information from a variety of sources. PMID- 28629435 TI - Eculizumab treatment: stochastic occurrence of C3 binding to individual PNH erythrocytes. AB - BACKGROUND: C5 blockade by eculizumab prevents complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). However, C3-bound PNH red blood cells (RBCs), arising in almost all treated patients, may undergo extravascular hemolysis reducing clinical benefits. Despite the uniform deficiency of CD55 and of CD59, there are always two distinct populations of PNH RBCs, with (C3+) and without (C3-) C3 binding. METHODS: To investigate this paradox, the phenomenon has been modeled in vitro by incubating RBCs from eculizumab untreated PNH patients with compatible sera containing eculizumab, and by assessing the C3 binding after activation of complement alternative pathway. RESULTS: When RBCs from untreated patients were exposed in vitro to activated complement in the context of C5-blockade, there was the prompt appearance of a distinct C3+ PNH RBC population whose size increased with time and also with the rate of complement activation. Eventually, all PNH RBCs become C3+ to the same extent, without differences between old and young (reticulocytes) PNH RBCs. CONCLUSIONS: This study indicates that the distinct (C3+ and C3-) PNH RBC populations are not intrinsically different; rather, they result from a stochastic all-or-nothing phenomenon linked to the time-dependent cumulative probability of each individual PNH red cell to be exposed to levels of complement activation able to trigger C3 binding. These findings may envision novel approaches to reduce C3 opsonization and the subsequent extravascular hemolysis in PNH patients on eculizumab. PMID- 28629437 TI - Evaluation of a low-cost, low-power syringe pump to deliver magnesium sulfate intravenously to pre-eclamptic women in a Malawian referral hospital. AB - BACKGROUND: Magnesium sulfate is an affordable and effective treatment for pre eclampsia and eclampsia. In settings where infusion pumps are not available to regulate the flow rate of intravenous delivery, healthcare providers must administer magnesium sulfate (MgSO4) via time-consuming and painful, large-volume intramuscular injections. As an alternative to costly commercially available syringe pumps, we developed AutoSyp, an accurate, low-cost, and low-powered syringe pump designed to meet the needs and constraints these low-resource settings. This paper describes results of a pilot study to evaluate the feasibility of using AutoSyp to administer MgSO4 intravenously to women suffering from pre-eclampsia at a referral hospital in Blantyre, Malawi. METHODS: AutoSyp was programmed to deliver MgSO4 following the Zuspan regimen to pregnant and post partum women suffering from pre-eclampsia at Queen Elizabeth Central Hospital in Blatnyre, Malawi. Given the selection of either loading or maintenance dose on AutoSyp's user interface, the flow rate was automatically programmed to dispense 60 mL/h or 5 mL/h of 20% MgSO4 solution, respectively. During each treatment, the dispensed volume was automatically calculated by the device based on the plunger position and stored on a computer for accuracy analysis of the mean flow rate and total volume delivered. The clinical results for both the loading and maintenance dose administrations were compared to the device's accuracy during tests performed in the laboratory setting. RESULTS: Twenty-two women were enrolled in this study. In both the clinical and laboratory settings, the mean flow rate errors for the loading and maintenance dose infusions were under 2%. During 466 h of testing, the device sounded 129 occlusion alarms across 14 subjects. Of these, 71 alarms were false positives. CONCLUSION: Results of this study support the use of AutoSyp as a less painful and accurate means of MgSO4 administration in clinical environments that lack infusion systems. There were a large number of false alarms in the current system which will be addressed in future designs. AutoSyp maintains the comfort of intravenous MgSO4 administration, but unlike commercially available syringe pumps, it is capable of operating with a variety of syringe brands and sizes and requires no additional consumables. AutoSyp's appropriate design will benefit its implementation and sustained use in low resource settings. TRIAL REGISTRATION: Trial registered prospectively on November 18, 2014 with ClinicalTrials.gov ( NCT02296931 ). PMID- 28629438 TI - An output evaluation of a health research foundation's enhanced grant review process for new investigators. AB - BACKGROUND: We assessed the ability of the Manitoba Medical Service Foundation (MMSF, a small not-for-profit foundation affiliated with Manitoba Blue Cross) to determine the best candidates for selection to receive research funding support among new researchers applying to the Research Operating Grants Programme (ROGP). METHODS: Using bibliometric and grants funding analyses, we retrospectively compared indices of academic outputs from five cohorts of MMSF-funded and not MMSF-funded applicants to the annual MMSF ROGP over 2008 to 2012, from 1 to 5 years after having received evaluation decisions from the MMSF enhanced grant review process. RESULTS: Those researchers funded by the MMSF competition (MMSF funded) had a statistically significant greater number of publications, a higher h-index and greater national Tri-Council (TC) funding, versus those not selected for funding (not MMSF-funded). MMSF-funded applicants and the Manitoba research community have created a strong and rapid (within 1 to 5 years of receiving the MMSF grant) local economic return on investment associated with the MMSF ROGP that supports new investigators, of approximately nine-fold for TC grants by the principal investigator, and of 34-fold for the principal investigator on collaborative (total) TC grants. CONCLUSIONS: The use of small amounts of seed money for competitive research grants at early stages of an MMSF-funded applicant's career correlates with future short-term success of that applicant. The ability to correctly select promising candidates who subsequently demonstrate greater academic performance after the MMSF funding shows the selection process and the ROGP to be of merit. Multiple components may have contributed to this outcome, including a direct presentation and interview process of the candidate with five-person selection subcommittees, plus an assessment by an external reviewer (the enhanced grant review process). The selection methods used here may add value to the research grant selection processes of new researchers. PMID- 28629440 TI - Incidence, management and outcome of women requiring massive transfusion after childbirth in the Netherlands: secondary analysis of a nationwide cohort study between 2004 and 2006. AB - BACKGROUND: Postpartum hemorrhage remains the leading cause of maternal morbidity and mortality worldwide. Few population-based studies have examined the epidemiology of massive transfusion for postpartum hemorrhage. The aim of this study was to determine the incidence, management, and outcomes of women with postpartum hemorrhage who required massive transfusion in the Netherlands between 2004 and 2006. METHODS: Data for all women from a gestational age of 20 weeks onwards who had postpartum hemorrhage requiring eight or more red blood cell concentrates were obtained from a nationwide population-based cohort study including all 98 hospitals with a maternity unit in the Netherlands. RESULTS: Three hundred twenty-seven women who had postpartum hemorrhage requiring massive transfusion were identified (massive transfusion rate 91 per 100,000 deliveries (95% confidence interval: 81-101)). The median blood loss was 4500 mL (interquartile range 3250-6000 mL) and the median number of red blood cell concentrates transfused was 11 units (interquartile range 9-16 units). Among women receiving massive transfusion, the most common cause of hemorrhage was uterine atony. Eighty-three women (25%) underwent hysterectomy, 227 (69%) were admitted to an intensive care unit, and three women died (case fatality rate 0,9%). CONCLUSION: The number of women in the Netherlands who had postpartum hemorrhage treated with massive transfusion was relatively high compared to other comparable settings. Evidence-based uniform management guidelines are necessary. PMID- 28629441 TI - Erratum to: Noticing cigarette health warnings and support for new health warnings among non-smokers in China: findings from the International Tobacco Control project (ITC) China survey. PMID- 28629439 TI - MSM HIV testing following an online testing intervention in China. AB - BACKGROUND: Scaling up HIV testing is the first step in the HIV treatment continuum which is important for controlling the HIV epidemic among men who have sex with men (MSM). Following an online HIV testing intervention among MSM, we aim to examine sociodemographic and spatial factors associated with HIV testing. METHODS: We conducted a secondary analysis on data from an online HIV testing intervention among MSM who had never-tested for HIV. The survey was distributed through online networks connected to all provinces and regions of China. Univariate and multivariable analyses were performed to examine factors associated with testing three weeks post-intervention. RESULTS: At three weeks after the intervention, 36% of 624 followed-up MSM underwent HIV testing, 69 men reported positive HIV test results. Having money for sex, ever tested for sexually transmitted infections and intimate partner violence experience were significant factors of post-intervention HIV testing. Students were less likely to undergo HIV testing at follow-up compared to others (adjusted odds ratio=0.69, 95% C.I.=0.47-0.99), adjusted by age and type of intervention. Moderate provincial spatial variation of testing was observed. CONCLUSIONS: While high risk men generally had higher HIV testing rates, some MSM like students had lower testing rates, suggesting the need for further ways to enhance HIV testing in specific MSM communities. PMID- 28629442 TI - Treatment patterns, healthcare resource utilization, and costs following first line antidepressant treatment in major depressive disorder: a retrospective US claims database analysis. AB - BACKGROUND: Although the symptoms of major depressive disorder (MDD) are often manageable with pharmacotherapy, response to first-line antidepressant treatment is often less than optimal. This study describes long-term treatment patterns in MDD patients in the United States and quantifies the economic burden associated with different treatment patterns following first-line antidepressant therapy. METHODS: MDD patients starting first-line antidepressant monotherapy and having continuous enrollment >=12 months before and >=24 months following the index date (i.e., the first documented prescription fill) were selected from the Truven Health Analytics MarketScan (2003-2014) database. Based on the type of first treatment change following initiation, six treatment cohorts were defined a priori ("persistence"; "discontinuation"; "switch"; "dose escalation"; "augmentation"; and "combination"). Treatment patterns through the fourth line of therapy within each cohort, healthcare resource utilization (HCRU), and cost analyses were restricted to patients with adequate treatment duration (defined as >=42 days) in each line (analysis sub-sample, N = 21,088). HCRU and costs were described at the cohort and pattern levels. Treatment cohorts representing <5% of the analysis sub-sample were decided a priori not to be analyzed due to limited sample size. RESULTS: 39,557 patients were included. Mean age was 42.1 years, 61.1% of patients were female, and mean follow-up was 4.1 years. Among the analysis sub-sample, the discontinuation (49.1%), dose escalation (37.4%), and switch (6.6%) cohorts were the most common of all treatment cohorts. First-line antidepressant discontinuation without subsequent MDD pharmacotherapy (22.9%) and cycling between discontinuation and resumption (11.2%) were the two most common treatment patterns. Median time to discontinuation was 23 weeks. The switch cohort exhibited the highest HCRU (18.9 days with medical visits per-patient-per year) and greatest healthcare costs ($11,107 per-patient-per-year) following the index date. Treatment patterns representing a cycling on and off treatment in the switch cohort were associated with the greatest healthcare costs overall. CONCLUSION: A high proportion of patients discontinue first-line antidepressant shortly after initiation. Patterns representing a cycling on and off treatment in the switch cohort were associated with the highest healthcare costs. These findings underscore challenges in effectively treating patients with MDD and a need for personalized patient management. PMID- 28629443 TI - Parents' and guardians' perceptions on availability and pricing of medicines and healthcare for children in eThekwini, South Africa - a qualitative study. AB - BACKGROUND: Inadequate access to affordable essential medicines poses a challenge to achieving Universal Health Coverage. Access to essential medicines for children has been in the spotlight in recent research. However, information from the end users of medicines, i.e. patients is scarce. Obtaining information at a household level is integral to understanding how people access, obtain and use medicines. This study aimed to gather opinions and perceptions from parents/guardians on availability, affordability and quality of medicines and healthcare for children in SA. METHODS: Eight Focus group discussions were held with 41 individuals in eThekwini, South Africa (SA), from September-November 2016. Participants were parents/guardians of children up to 12 years from different ethnicities, ages, gender, and socio-economic backgrounds. Key informants identified by the principal researcher recruited participants using snowball sampling. Focus group discussions were recorded, transcribed verbatim, coded by the first author, verified by the second author, reconciled for consensus and imported into NVIVO for data analysis. RESULTS: Medicines and healthcare facilities are accessible in urban and peri-urban areas in eThekwini. Medicines may not always be available in public sector facilities due to medicine shortages, compelling parents to purchase medicines from private sector pharmacies. Common medicines were perceived as affordable for most socio-economic groups except the 'Poor' group. Quality of medicines was perceived as 'good' especially if obtained from the private sector but sometimes perceived as 'poor' and viewed with suspicion when received from public sector clinics. Quality of healthcare was perceived as 'good' but requires improvement for both sectors. CONCLUSIONS: This is the first study in SA to report on parent/guardian perceptions on availability, affordability and quality of medicines and healthcare for children. It has the potential to be up-scaled to a country-wide investigation to paint a national picture of parents' opinions of healthcare for children. This will allow for patient input into pharmaceutical and healthcare policy governing access to and availability of essential medicines and services within the country. The study recommends that patient input be sought to assess impact of policies on the intended target group in the country to ensure that the policy objectives are achieved. PMID- 28629444 TI - MicroRNA-98 inhibits the cell proliferation of human hypertrophic scar fibroblasts via targeting Col1A1. AB - BACKGROUND: Hypertrophic scarring (HS) is a severe disease, and results from unusual wound healing. Col1A1 could promote the hypertrophic scar formation, and the expression of Col1A1 in HS tissue was markedly higher than that in the normal. In present study, we aimed to identify miRNAs as post-transcriptional regulators of Col1A1 in HS. METHODS: MicroRNA-98 was selected as the key miRNA comprised in HS. The mRNA levels of miR-98 in HS tissues and the matched normal skin tissues were determined by qRT-PCR. MTT and flow cytometry were used to determine the influence of miR-98 on cell proliferation and apoptosis of HSFBs, respectively. Col1A1 was found to be the target gene of miR-98 using luciferase reporter assay. Luciferase assay was performed to determine the relative luciferase activity in mimic NC, miR-98 mimic, inhibitor NC and miR-98 inhibitor with Col1A13'-UTR wt or Col1A13'-UTR mt reporter plasmids. The protein expression of Col1A1 in HSFBs after transfection with mimic NC, miR-98 mimic, inhibitor NC and miR-98 inhibitor were determined by western blotting. RESULTS: The mRNA level of miR-98 in HS tissues was much higher than that in the control. Transfection of HSFBs with a miR-98 mimic reduced the cell viability of HSFBs and increased the apoptosis portion of HSFBs, while inhibition of miR-98 increased cell viability and decreased apoptosis portion of HSFBs. miR-98 inhibitor increased the relative luciferase activity significantly when cotransfected with the Col1A1-UTR reporter plasmid, while the mutant reporter plasmid abolished the miR-98 inhibitor mediated increase in luciferase activity. Western blotting revealed that overexpression of miR-98 decreased the expression of Col1A1. CONCLUSIONS: Overexpression of miR-98 repressed the proliferation of HSFBs by targeting Col1A1. PMID- 28629445 TI - Effects of perioperative statin use on cardiovascular complications in patients submitted to non-cardiac surgery: protocol for a systematic review, meta analysis, and trial sequential analysis. AB - BACKGROUND: Preliminary evidence suggests statins may reduce major perioperative vascular events. However, evidence is limited to observational studies, underpowered trials, and non-comprehensive systematic reviews. This review aims to assess the effects of perioperative statin use on cardiovascular complications in patients submitted to non-cardiac surgery. METHODS: We will search MEDLINE/PubMed, EMBASE, LILACS, CENTRAL, Web of Science, and CINAHL for randomized controlled trials assessing the effects of perioperative statin use in adults undergoing non-cardiac surgery and reporting cardiovascular complications. For patients already using statins for hyperlipidemia, a preoperative loading dose of statin is required in the experimental group. We will place no language or publication restriction on our search. Teams of two reviewers will independently assess eligibility and risk of bias, and will extract data from the included trials. Our primary outcome is a combination of cardiovascular mortality or non-fatal myocardial infarction. We will also assess the following outcomes: individual components of the primary outcome, all-cause mortality, total myocardial infarction, elevated troponin in the first seven postoperative days, total stroke, total venous thromboembolism, postoperative atrial fibrillation, elevation of creatine phosphokinase or liver enzymes, and rates of myalgia or rhabdomyolysis. We will conduct meta-analyses using random-effects model and will use trial sequential analysis to establish monitoring boundaries to limit global type I error due to repetitive testing for our primary outcome. We will rate the quality of evidence using the GRADE system. DISCUSSION: The results of this systematic review may help to inform clinical practice and also the design of future large-scale randomized trials. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016035987. PMID- 28629446 TI - Increasing mapping precision of genome-wide association studies: to genotype and impute, sequence, or both? AB - Fine-mapping to identify causal variants in genome-wide association studies remains challenging. A recent study provides guidance for future research. PMID- 28629447 TI - Transcranial direct current stimulation for depression in Alzheimer's disease: study protocol for a randomized controlled trial. AB - BACKGROUND: Patients with Alzheimer's disease frequently elicit neuropsychiatric symptoms as well as cognitive deficits. Above all, depression is one of the most common neuropsychiatric symptoms in Alzheimer's disease but antidepressant drugs have not shown significant beneficial effects on it. Moreover, electroconvulsive therapy has not ensured its safety for potential severe adverse events although it does show beneficial clinical effect. Transcranial direct current stimulation can be the safe alternative of neuromodulation, which applies weak direct electrical current to the brain. Although transcranial direct current stimulation has plausible evidence for its effect on depression in young adult patients, no study has explored it in older subjects with depression in Alzheimer's disease. Therefore, we present a study protocol designed to evaluate the safety and clinical effect of transcranial direct current stimulation on depression in Alzheimer's disease in subjects aged over 65 years. METHOD: This is a two-arm, parallel-design, randomized controlled trial, in which patients and assessors will be blinded. Subjects will be randomized to either an active or a sham transcranial direct current stimulation group. Participants in both groups will be evaluated at baseline, immediately, and 2 weeks after the intervention. DISCUSSION: This study investigates the safety and effect of transcranial direct current stimulation that may bring a significant impact on both depression and cognition in patients with Alzheimer's disease, and may be useful to enhance their quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02351388 . Registered on 27 January 2015. Last updated on 30 May 2016. PMID- 28629448 TI - Azithromycin for idiopathic acute exacerbation of idiopathic pulmonary fibrosis: a retrospective single-center study. AB - BACKGROUND: Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition without an established pharmaceutical treatment. Most patients are treated with high-dose corticosteroids and broad-spectrum antibiotics. Azithromycin is a macrolide with immunomodulatory activity and may be beneficial for treatment of acute lung injury. The objective of this study was to determine the effect of azithromycin on survival of patients with idiopathic AE of IPF. METHODS: We evaluated 85 consecutive patients hospitalized in our department for idiopathic AE of IPF from April 2005 to August 2016. The initial 47 patients were treated with a fluoroquinolone-based regimen (control group), and the following 38 consecutive patients were treated with azithromycin (500 mg/day) for 5 days. Idiopathic AE of IPF was defined using the criteria established by the 2016 International Working Group. RESULTS: Mortality in patients treated with azithromycin was significantly lower than in those treated with fluoroquinolones (azithromycin, 26% vs. control, 70%; p < 0.001). Multivariate analysis revealed that the two variables were independently correlated with 60-day mortality as determined by the Acute Physiology and Chronic Health Evaluation II score (p = 0.002) and azithromycin use (p < 0.001). CONCLUSION: Azithromycin may improve survival in patients with idiopathic AE of IPF. PMID- 28629449 TI - Delineating the genetic heterogeneity of OCA in Hungarian patients. AB - BACKGROUND: Oculocutaneous albinism (OCA) is a clinically and genetically heterogenic group of pigmentation abnormalities characterized by variable hair, skin, and ocular hypopigmentation. Six known genes and a locus on human chromosome 4q24 have been implicated in the etiology of isolated OCA forms (OCA 1 7). METHODS: The most frequent OCA types among Caucasians are OCA1, OCA2, and OCA4. We aimed to investigate genes responsible for the development of these OCA forms in Hungarian OCA patients (n = 13). Mutation screening and polymorphism analysis were performed by direct sequencing on TYR, OCA2, SLC45A2 genes. RESULTS: Although the clinical features of the investigated Hungarian OCA patients were identical, the molecular genetic data suggested OCA1 subtype in eight cases and OCA4 subtype in two cases. The molecular diagnosis was not clearly identifiable in three cases. In four patients, two different heterozygous known pathogenic or predicted to be pathogenic mutations were present. Seven patients had only one pathogenic mutation, which was associated with non pathogenic variants in six cases. In two patients no pathogenic mutation was identified. CONCLUSIONS: Our results suggest that the concomitant screening of the non-pathogenic variants-which alone do not cause the development of OCA, but might have clinical significance in association with a pathogenic variant-is important. Our results also show significant variation in the disease spectrum compared to other populations. These data also confirm that the concomitant analysis of OCA genes is critical, providing new insights to the phenotypic diversity of OCA and expanding the mutation spectrum of OCA genes in Hungarian patients. PMID- 28629450 TI - Interaction with adipocyte stromal cells induces breast cancer malignancy via S100A7 upregulation in breast cancer microenvironment. AB - BACKGROUND: Breast adipocytes play important roles in both the development and function of mammary epithelial cells. Therefore, carcinoma-adipose stromal cell (ASC) interactions have been considered pivotal in supporting tumor growth in breast cancer. In addition, it has been demonstrated that the biological features of cancer-associated adipocytes differ from those of normal ASCs. Therefore, we investigated an interaction between ASCs and carcinoma cell lines to identify genes associated with ASC invasion of carcinoma cells. METHODS: 3T3-L1 ASC derived conditioned medium (CM) was treated to measure the proliferation rate of breast cancer cells. To further examine the effect of ASCs, breast cancer cells were cocultivated with either primary human or 3T3-L1 ASCs for migration assays, DNA microarrays, quantitative real-time polymerase chain reactions, and Western blotting experiments. Furthermore, immunoreactivity of S100A7, the most upregulated gene in MCF7, after coculture with ASCs was evaluated for 150 breast cancer tissues to statistically analyze its association with clinicopathological parameters. RESULTS: We first confirmed that ASC-derived CM treatment enhanced the cell proliferation rate of MCF7, T47D, SK-BR-3, and ZR-75-1 cell lines, whereas the migration rate of breast cancer cells was promoted by coculture with ASCs. We identified that a small calcium-binding protein, S100A7, was markedly upregulated (by 5.8-fold) in MCF7 cells after coculture with primary human ASCs. Knockdown of S100A7 significantly suppressed ASC-stimulated cell proliferation and migration rate, indicating a possible involvement of S100A7 in the carcinoma ASC interaction in breast tumors. Furthermore, strong S100A7 immunoreactivity was detected at the invasive front of adipose stromal tissues compared with that at the intratumoral area. The status of S100A7 was also significantly correlated with adverse pathological parameters, and multivariate analysis revealed that S100A7 could be an independent prognostic marker for a poor relapse-free survival rate. Moreover, induction of oncostatin M was detected in cancer-stimulated ASCs, whereas the downstream S100A7 binding proteins/receptor for advanced glycation endproducts were significantly upregulated in correspondence with S100A7 expression in breast cancer cells after coculture with ASCs. CONCLUSIONS: The results of our study suggest that paracrine production of cytokines from ASCs stimulates breast carcinoma cell growth via upregulation of S100A7 expression in breast cancer cell lines. PMID- 28629451 TI - Metabolic response to three different diets in lean cats and cats predisposed to overweight. AB - BACKGROUND: The existence of a genetic predisposition to obesity is commonly recognized in humans and rodents. Recently, a link between genetics and overweight was shown in cats. The goal of this study was to identify the effect of diet composition on plasma levels of glucose, insulin, free fatty acids and triglycerides in cats receiving different diets (high-carbohydrate, high-fat and high-protein diets). RESULTS: Insulin and leptin concentrations were significantly correlated with phenotype. Insulin levels were lower, whereas leptin levels were higher in cats predisposed to overweight. The other blood parameters were not correlated with phenotype. Intake of the high-carbohydrate diet resulted in higher insulin concentrations compared with the two other diets. Insulin levels were within the values described for non-obese cats in previous studies. CONCLUSIONS: There was no difference in metabolic response between the two groups. As the high-carbohydrate diet led to the highest insulin blood concentrations, it might be useful to avoid such diets in cats predisposed to overweight. In addition, even cats with genetically linked obesity can regain insulin sensitivity after weight loss. PMID- 28629453 TI - Three-dimensional substructure measurements for the differential diagnosis of ground glass nodules. AB - BACKGROUND: We analyzed the differences between maximum and peak computed tomography (CT) numbers (M-P), respectively representing the densities of the solid center and the main periphery of ground-glass nodules (GGNs), and the average change in M-P velocity (V(M-P)) during follow-up to differentiate between pre-invasive (PIA) and invasive adenocarcinoma (IAC). METHODS: Data of 102 patients were retrospectively collected and analyzed in our study including 43 PIAs and 59 IACs. Diameters, total volumes, and the maximum and peak CT numbers in CT number histograms were measured and followed for at least 3 months. This study was registered retrospectively. RESULTS: The M-P values for IACs were higher than those for PIAs (p = 0.001), with an area under the curve (AUC) of 0.810 and a threshold of 489.5 Hounsfield units (HU) in ROC analysis. The V(M-P) values for IACs were smaller than those for PIAs (p = 0.04), with an AUC of 0.805 and a threshold of 11.01 HU/day. CONCLUSIONS: M-P and V(M-P) values may help distinguish IACs from PIAs by representing the changes in the sub-structural densities of GGNs during follow-up. PMID- 28629452 TI - Inhibitory brainstem reflexes under external emotional-stimuli in bipolar I and II disorders. AB - BACKGROUND: Bipolar disorder types I (BD I) and II (BD II) might present different dysfunctions of the cortex and brainstem, as reflected by the second exteroceptive suppression period of temporalis muscle activity (ES2) under different stimuli of external emotions. METHODS: This study included 30 BD I and 20 BD II patients, and 40 healthy volunteers. All participants were invited to answer the Mood Disorder Questionnaire, the Hypomania Checklist-32, and the Plutchik-van Praag Depression inventory, as well as to undergo the ES2 test under external emotional-stimuli (emotional pictures plus sounds) of Disgust, Erotica, Fear, Happiness, and Sadness. RESULTS: The scale scores were elevated in both patient groups, but were not correlated with ES2 parameters. Compared to healthy controls, BD I showed prolonged ES2 latency under Erotica, and their perceived happiness and sadness intensities were negatively correlated with the respective ES2 durations, while BD II showed prolonged ES2 latencies under Disgust and Happiness, and shortened ES2 durations under Disgust, Happiness and Sadness. Moreover, ES2 duration under Sadness was significantly shorter in BD II than that in BD I. CONCLUSIONS: The cortico-brainstem inhibitory dysfunctions in BD I and BD II was different, and this difference was independent of the patient's ongoing emotions. Our study thus provides some hints to distinguish the two types of bipolar disorders. PMID- 28629455 TI - An investigation of the relationship between autonomy, childbirth practices, and obstetric fistula among women in rural Lilongwe District, Malawi. AB - BACKGROUND: Obstetric fistula is a childbirth injury caused by prolonged obstructed labor that results in destruction of the tissue wall between the vagina and bladder. Although obstetric fistula is directly caused by prolonged obstructed labor, many other factors indirectly increase fistula risk. Some research suggests that many women in rural Malawi have limited autonomy and decision-making power in their households. We hypothesize that women's limited autonomy may play a role in reinforcing childbirth practices that increase the risk of obstetric fistula in this setting by hindering access to emergency care and further prolonging obstructed labor. METHODS: A medical student at Baylor College of Medicine partnered with a Malawian research assistant in July 2015 to conduct in-depth qualitative interviews in Chichewa with 25 women living within the McGuire Wellness Centre's catchment area (rural Central Lilongwe District) who had received obstetric fistula repair surgery. RESULTS: This study assessed whether women's limited autonomy in rural Malawi reinforces childbearing practices that increase risk of obstetric fistula. We considered four dimensions of autonomy: sexual and reproductive decision-making, decision-making related to healthcare utilization, freedom of movement, and discretion over earned income. We found that participants had limited autonomy in these domains. For example, many women felt pressured by their husbands, families, and communities to become pregnant within three months of marriage; women often needed to seek permission from their husbands before leaving their homes to visit the clinic; and women were frequently prevented from delivering at the hospital by older women in the community. CONCLUSIONS: Many of the obstetric fistula patients in our sample had limited autonomy in several or all of the aforementioned domains, and their limited autonomy often led both directly and indirectly to an increased risk of prolonged labor and fistula. Reducing the prevalence of fistula in Malawi requires a broad understanding of the causes of fistula, so we recommend that the relationship between women's autonomy and fistula risk undergo further investigation. PMID- 28629454 TI - Impact of pharmacy channel on adherence to oral oncolytics. AB - BACKGROUND: Oral chemotherapy is increasingly prescribed to treat cancer. Despite its benefits, concerns have been raised regarding adherence to therapy. The study objective was to compare and measure adherence, persistence, and abandonment in patients filling prescriptions in traditional retail (TR) versus specialty pharmacy (SP) channels. METHODS: Using a retrospective cohort design, we selected newly treated patients aged >=18 years with a prescription for erlotinib, capecitabine, or imatinib during 2007-2011 from a Medco population of both United States commercial and Medicare health plans. Patients were classified according to pharmacy channel providing the medication. Abandonment was defined as a reversal following initial approval of the index prescription claim with no additional paid claims for agent within 90 days of reversal. Patients were considered adherent if the proportion of days covered between the date of the first and last oral prescription was >=80%. RESULTS: In our retrospective cohort, 11,972 filled their prescriptions within the SP channel, and 30,394 filled their prescriptions within the TR channels, respectively. The SP channel had the highest proportion of adherent patients compared with TR (71.6% vs. 56.4%, P < .001). Abandonment of the initial prescription was low with overall rates of only 1.7%. In multivariate models controlling for demographic characteristics, index oncolytic, days of supply, and copay, SP channel (relative to TR) was significantly associated with lower rates of abandonment and increased adherence. CONCLUSIONS: Pharmacy channel may be influential on abandonment and adherence. Lower rates of abandonment and higher rates of adherence were observed among SP patients versus TR. PMID- 28629456 TI - Comparison of the effects of 7.2% hypertonic saline and 20% mannitol on whole blood coagulation and platelet function in dogs with suspected intracranial hypertension - a pilot study. AB - BACKGROUND: Hyperosmolar therapy with either mannitol or hypertonic saline (HTS) is commonly used in the treatment of intracranial hypertension (ICH). In vitro data indicate that both mannitol and HTS affect coagulation and platelet function in dogs. The aim of this study was to compare the effects of 20% mannitol and 7.2% HTS on whole blood coagulation using rotational thromboelastometry (ROTEM(r)) and platelet function using a platelet function analyzer (PFA(r)) in dogs with suspected ICH. Thirty client-owned dogs with suspected ICH needing osmotherapy were randomized to receive either 20% mannitol (5 ml/kg IV over 15 min) or 7.2% HTS (4 ml/kg IV over 5 min). ROTEM(r) (EXTEM(r) and FIBTEM(r) assays) and PFA(r) analyses (collagen/ADP cartridges) were performed before (T0), as well as 5 (T5), 60 (T60) and 120 (T120) minutes after administration of HTS or mannitol. Data at T5, T60 and T120 were analyzed as a percentage of values at T0 for comparison between groups, and as absolute values for comparison between time points, respectively. RESULTS: No significant difference was found between the groups for the percentage change of any parameter at any time point except for FIBTEM(r) clotting time. Within each group, no significant difference was found between time points for any parameter except for FIBTEM(r) clotting time in the HTS group, and EXTEM(r) and FIBTEM(r) maximum clot firmness in the mannitol group. Median ROTEM(r) values lay within institutional reference intervals in both groups at all time points, whereas median PFA(r) values were above the reference intervals at T5 (both groups) and T60 (HTS group). CONCLUSIONS: Using currently recommended doses, mannitol and HTS do not differ in their effects on whole blood coagulation and platelet function in dogs with suspected ICH. Moreover, no relevant impairment of whole blood coagulation was found following treatment with either solution, whereas a short-lived impairment of platelet function was found after both solutions. PMID- 28629457 TI - Molecular imaging biomarkers for cell-based immunotherapies. AB - While many decades of scientific research studies have gone into harnessing the power of the immune system to fight cancer, only recently have cancer immunotherapeutic approaches begun to show robust clinical responses in patients with a variety of cancers. These treatments are adding to the current arsenal of cancer treatments; surgery, radiation and chemotherapy, and increasing the therapeutic options for cancer patients. Despite these advances, issues associated with these therapies include that not all patients respond to these therapies, and some patients who respond experience varying degrees of toxicities. One of the major issues affecting immunotherapy is the inability to evaluate trafficking of activated T-cells into sites of tumor. The current diagnostic imaging based on conventional anatomic imaging, which is the mainstay to monitor response to cytotoxic chemotherapy or radiation, is not adequate to assess initial response to immunotherapy or disease evolution. Patients' prognosis by histological analysis has limited use in regards to immunotherapy. Thus, there is a crucial need for noninvasive biomarkers for screening patients that show long term response to therapy. Here, we provide a brief account of emerging molecular magnetic resonance imaging biomarkers that have potential to exploit the metabolism and metabolic products of activated T cells. PMID- 28629458 TI - Methotrexate-induced nausea in the treatment of juvenile idiopathic arthritis. AB - BACKGROUND: Methotrexate is the most commonly used disease modifying antirheumatic drug in the treatment of juvenile idiopathic arthritis and can be effective in controlling disease in many patients. MAIN BODY: A significant proportion of patients experience nausea and vomiting induced by methotrexate therapy, which can lead to decreased quality of life and discontinuation of treatment with methotrexate. Many strategies have been employed in attempts to reduce methotrexate-induced nausea, including folate supplementation, switching from oral to subcutaneous methotrexate, anti-emetic therapy, behavioral therapy, and others. Anticipatory nausea can be difficult to treat, making primary prevention of nausea with anti-emetics an attractive approach. CONCLUSION: Understanding the prevalence and impact of methotrexate-induced nausea, as well as potentially effective interventions, may help maximize the therapeutic benefits of methotrexate. PMID- 28629459 TI - Antiretroviral therapy initiation within seven days of enrolment: outcomes and time to undetectable viral load among children at an urban HIV clinic in Uganda. AB - BACKGROUND: Viral suppression is a critical indicator of HIV treatment success. In the era of test-and-start, little is known about treatment outcomes and time to undetectable viral loads. This study compares treatment outcomes, median times to achieve undetectable viral loads and its predictors under different antiretroviral (ART) treatment initiation schedules (i.e. within seven days of enrolment or later). METHODS: A retrospective cohort of 367 patients <18 years who enrolled in care between January 2010 and December 2015 with a baseline viral load of >5000 copies/ml were followed up for 60 months. Undetectable viral load measurements were based on both Roche (<20copies/ml) and Abbot (<75copies/ml). Clinical treatment outcomes were compared using chi-squared test. Survival experiences between the two cohorts were assessed through incidence rates and Kaplan Meier curves. A cox model with competing risks was used to assess predictors for time to undetectable viral load. RESULTS: Of the 367 patients, 180 (49.1%) initiated ART within seven days from enrolment, 192 (52.3%) attained undetectable viral load of which 133 (69.3%) were children below six years and 101 (52.6%) were females. Among those who initiated ART within seven days 15 (8.3%) died and 6 (3.3%) were lost to follow-up compared to 27 (14.4%) and 16 (8.6%) respectively in the later initiators. The median time to undetectable viral load was 24.9 months (95% CI: 19.7, 28.5) among early ART initiators and 38.5 months (95% CI: 31.1, 44.5) among those initiating beyond seven days. There was a significant difference in failure estimates between those initiating within seven and those that deferred (log rank, p = 0.001). Significant predictors for time to undetectable viral load were; starting ART within seven days (SHR = 2.02, 95% CI: 1.24, 3.28), baseline WHO stage I or II (SHR = 1.59, 95% CI: 1.06, 2.28), inconsistent adherence on three consecutive clinic visits (SHR = 0.44, 95% CI: 0.28, 0.67), and baseline weight (SRH = 1.04, 95% CI: 1.01, 1.07). CONCLUSION: Prompt initiation of ART within the first week of enrolment is associated with better treatment outcomes. Early timing, baseline WHO clinical stage and adherence rates should be major considerations while managing HIV among children. PMID- 28629460 TI - Interaction between Pasteurella multocida B:2 and its derivatives with bovine aortic endothelial cell (BAEC). AB - BACKGROUND: Pasteurella multocida B:2 causes bovine haemorrhagic septicaemia (HS), leading to rapid fatalities in cattle and buffaloes. An attenuated derivative of P. multocida B:2 GDH7, was previously constructed through mutation of the gdhA gene and proved to be an effective live attenuated vaccine for HS. Currently, only two potential live attenuated vaccine candidates for HS are being reported; P. multocida B:2 GDH7 and P. multocida B:2 JRMT12. This study primarily aims to investigate the potential of P. multocida B:2 GDH7 strain as a delivery vehicle for DNA vaccine for future multivalent applications. RESULTS: An investigation on the adherence, invasion and intracellular survival of bacterial strains within the bovine aortic endothelial cell line (BAEC) were carried out. The potential vaccine strain, P. multocida B:2 GDH7, was significantly better (p <= 0.05) at adhering to and invading BAEC compared to its parent strain and to P. multocida B:2 JRMT12 and survived intracellularly 7 h post treatment, with a steady decline over time. A dual reporter plasmid, pSRGM, which enabled tracking of bacterial movement from the extracellular environment into the intracellular compartment of the mammalian cells, was subsequently transformed into P. multocida B:2 GDH7. Intracellular trafficking of the vaccine strain, P. multocida B:2 GDH7 was subsequently visualized by tracking the reporter proteins via confocal laser scanning microscopy (CLSM). CONCLUSIONS: The ability of P. multocida B:2 GDH7 to model bactofection represents a possibility for this vaccine strain to be used as a delivery vehicle for DNA vaccine for future multivalent protection in cattle and buffaloes. PMID- 28629461 TI - Cost-effectiveness of lung cancer screening and treatment methods: a systematic review of systematic reviews. AB - BACKGROUND: Due to extensive literature in the field of lung cancer and their heterogeneous results, the aim of this study was to systematically review of systematic reviews studies which reviewed the cost-effectiveness of various lung cancer screening and treatment methods. METHODS: In this systematic review of systematic reviews study, required data were collected searching the following key words which selected from Mesh: "lung cancer", "lung oncology", "lung Carcinoma", "lung neoplasm", "lung tumors", "cost- effectiveness", "systematic review" and "Meta-analysis". The following databases were searched: PubMed, Cochrane Library electronic databases, Google Scholar, and Scopus. Two reviewers (RA and A-AS) evaluated the articles according to the checklist of "assessment of multiple systematic reviews" (AMSTAR) tool. RESULTS: Overall, information of 110 papers was discussed in eight systematic reviews. Authors focused on cost effectiveness of lung cancer treatments in five systematic reviews. Targeted therapy options (bevacizumab, Erlotinib and Crizotinib) show an acceptable cost effectiveness. Results of three studies failed to show cost-effectiveness of screening methods. None of the studies had used the meta-analysis method. The Quality of Health Economic Studies (QHES) tool and Drummond checklist were mostly used in assessing the quality of articles. Most perspective was related to the Payer (64 times) and the lowest was related to Social (11times). Most cases referred to Incremental analysis (82%) and also the lowest point of referral was related to Discounting (in 49% of the cases). The average quality score of included studies was calculated 9.2% from 11. CONCLUSIONS: Targeted therapy can be an option for the treatment of lung cancer. Evaluation of the cost effectiveness of computerized tomographic colonography (CTC) in lung cancer screening is recommended. The perspective of the community should be more taken into consideration in studies of cost-effectiveness. Paying more attention to the topic of Discounting will be necessary in the studies. PMID- 28629462 TI - Treatment decisions for older adults with advanced chronic kidney disease. AB - Dialysis initiation rates among older adults, aged 75 years or greater, are increasing at a faster rate than for younger age groups. Older adults with advanced CKD (eGFR < 30 ml/min/1.73 m2) typically lose renal function slowly, often suffer from significant comorbidity and thus may die from associated comorbidities before they require dialysis.A patient's pattern of renal function loss over time in relation to their underlying comorbidities can serve as a guide to the probability of a future dialysis requirement. Most who start dialysis, initiate treatment "early", at an estimated glomerulofiltration rate (eGFR) >10 ml/min/1.73 m2 and many initiate dialysis in hospital, often in association with an episode of acute renal failure. In the US older adults start dialysis at a mean e GFR of 12.6 ml/min/1.73 m2 and 20.6% die within six months of dialysis initiation. In both the acute in hospital and outpatient settings, many older adults appear to be initiating dialysis for non-specific, non-life threatening symptoms and clinical contexts. Observational data suggests that dialysis does not provide a survival benefit for older adults with poor mobility and high levels of comorbidity. To optimize the care of this population, early and repeat shared decision making conversations by health care providers, patients, and their families should consider the risks, burdens, and benefits of dialysis versus conservative management, as well as the patient specific symptoms and clinical situations that could justify dialysis initiation. The potential advantages and disadvantages of dialysis therapy should be considered in conjunction with each patient's unique goals and priorities.In conclusion, when considering the morbidity and quality of life impact associated with dialysis, many older adults may prefer to delay dialysis until there is a definitive indication or may opt for conservative management without dialysis. This approach can incorporate all CKD treatments other than dialysis, provide psychosocial and spiritual support and active symptom management and may also incorporate a palliative care approach with less medical monitoring of lab parameters and more focus on the use of drug therapies directed to relief of a patient's symptoms. PMID- 28629463 TI - How understanding and application of drug-related legal instruments affects harm reduction interventions in Cambodia: a qualitative study. AB - BACKGROUND: Harm reduction interventions in Cambodia face numerous obstacles because of conflicting understanding and interests and inconsistencies in the implementation by law enforcement officials. This study aims to examine how understanding and application of Drug Control Law (DCL) and Village/Commune Safety Policy (VCSP) affects harm reduction interventions in Cambodia from the standpoints of law enforcement officials, people who inject drugs and people who use drugs (PWID/PWUD), as well as other key stakeholders. METHODS: This qualitative study was conducted in the capital city of Phnom Penh in 2015. We held five focus group discussions (FGDs) with groups of PWID/PWUD, police officers, Sangkat/commune officers, and local non-governmental organization (NGO) field staff. We also conducted ten key informant interviews (KIIs) with representatives from government agencies, donor agencies, and NGOs. FGDs and KIIs with Cambodian participants were transcribed in Khmer and translated into English. KIIs with foreign participants were transcribed in English. Transcripts were read and re-read to identify emerging themes, which were reviewed and refined to develop common and divergent patterns. RESULTS: There was a huge gap between what the DCL and VCSP say and how law enforcement officers and PWID/PWUD understood them. The gap was also evident in how law enforcement officers implemented the DCL and VCSP. Harm reduction services, including health- and non health-related interventions, were limited and challenged by unsupportive attitudes, misinterpretation of the DCL and VCSP, and the lack of full engagement with NGOs in the development of these instruments. The needs of PWID/PWUD in accessing health care services were not met due to misconduct of authorities while practicing the DCL and VCSP. Further, the misconduct and enforcement of the law and policy lead to increased social discrimination and physical abuses against PWID/PWUD. CONCLUSIONS: There is a lack of common understanding of the drug-related law and policy and their implications to harm reduction services among both law enforcement officers and PWID/PWUD. Thus, there is a need to mainstream and simplify the law and policy for better comprehension among these actors. To improve the quality and coverage of harm reduction interventions, the gap of understanding and enforcement of laws and policies should be narrowed, and coordination between the government and NGOs and other key stakeholders should be strengthened. PMID- 28629464 TI - miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of triple-negative breast cancer. AB - BACKGROUND: Different breast cancer subtypes show distinct tropisms for sites of metastasis. Notably, the lung is the most common site for the first distant recurrence in triple-negative breast cancer (TNBC). The identification of novel biomarkers for lung metastasis is of great importance to improving the outcome of TNBC. In this study, we sought to identify a microRNA (miRNA)-based biomarker and therapeutic target for lung metastasis of TNBC. METHODS: A total of 669 patients without de novo stage IV TNBC were recruited for this study. miRNA profiling was conducted in the discovery cohort. Diagnostic accuracy and prognostic values of candidate miRNAs were evaluated in the training and validation cohorts, respectively. The biological functions of candidate miRNAs, as well as potential targets, were further evaluated through bioinformatic analysis as well as by performing in vitro and in vivo assays. RESULTS: In the discovery set, we found that miR-629-3p was specifically upregulated in both metastatic foci (fold change 144.16, P < 0.0001) and primary tumors (fold change 74.37, P = 0.004) in patients with lung metastases. In the training set, the ROC curve showed that miR-629-3p yielded high diagnostic accuracy in discriminating patients with lung metastasis from patients without recurrence (AUC 0.865, 95% CI 0.800-0.930, P < 0.0001). Although miR-629-3p predicted poor overall survival and disease-free survival in the validation set, it failed to show significance after multivariate analysis. Notably, logistic regression analyses confirmed that miR-629-3p was an independent risk factor for lung metastasis (OR 4.1, 95% CI 2.5-6.6, P < 0.001). Inhibition of miR-629-3p drastically attenuated the viability and migration of TNBC cells, and it markedly suppressed lung metastasis in vivo. Furthermore, we identified the leukemia inhibitory factor receptor (LIFR), a well-known metastatic suppressive gene, to be a direct target of miR-629-3p. CONCLUSIONS: miR-629-3p may serve as a novel biomarker and potential therapeutic target for lung metastases of TNBC mediated via LIFR. PMID- 28629465 TI - Natural IgM antibodies that bind neoepitopes exposed as a result of spinal cord injury , drive secondary injury by activating complement. AB - BACKGROUND: Natural IgM antibodies (Abs) function as innate immune sensors of injury via recognition of neoepitopes expressed on damaged cells, although how this recognition systems function following spinal cord injury (SCI) exposes various neoepitopes and their precise nature remains largely unknown. Here, we investigated the role of two natural IgM monoclonal Abs (mAbs), B4 and C2, that recognize post-ischemic neoepitopes following ischemia and reperfusion in other tissues. METHODS: Identification of post-SCI expressed neoepitopes was examined using previously characterized monoclonal Abs (B4 and C2 mAbs). The role of post SCI neoepitopes and their recognition by natural IgM Abs in propagating secondary injury was examined in Ab-deficient Rag1-/- or wild type C57BL/6 mice using Ab reconstitution experiments and neoepitope-targeted therapeutic studies, respectively. RESULTS: Administration of B4 or C2 mAb following murine SCI increased lesion size and worsened functional outcome in otherwise protected Ab deficient Rag1-/- mice. Injury correlated with colocalized deposition of IgM and C3d in injured spinal cords from both mAb reconstituted Rag1-/- mice and untreated wild-type mice. Depletion of peritoneal B1 B cells, a source of natural Abs, reduced circulating levels of IgM with B4 (annexin-IV) and C2 (subset of phospholipids) reactivity, reduced IgM and complement deposition in the spinal cord, and protected against SCI. We therefore investigated whether the B4 neoepitope represents a therapeutic target for complement inhibition. B4-Crry, a fusion protein consisting of a single-chain Ab derived from B4 mAb, linked to the complement inhibitor Crry, significantly protected against SCI. B4-Crry exhibited a dual function in that it inhibited both the binding of pathogenic IgM and blocked complement activation in the spinal cord. CONCLUSIONS: This study identifies important neoepitopes expressed within the spinal cord after injury. These neoepitopes are recognized by clonally specific natural IgM Abs that activate complement and drive pathology. We demonstrate that these neoepitopes represent novel targets for the therapeutic delivery of a complement inhibitor, and possibly other payload, to the injured spinal cord. PMID- 28629466 TI - Intra-articular injection in the knee of adipose derived stromal cells (stromal vascular fraction) and platelet rich plasma for osteoarthritis. AB - BACKGROUND: Stromal vascular fraction (SVF) can easily be obtained from a mini lipoaspirate procedure of fat tissue and platelet rich plasma (PRP) can be obtained from peripheral blood. We evaluated the safety and preliminary efficacy of administering SVF and PRP intra-articularly into patients with osteoarthritis grade 1 and 2. METHODS: A total of ten patients underwent a local tumescent liposuction procedure to remove approximately 100 ml of fat tissue from the abdomen. SVF was isolated using an enzyme digestion and resuspended in PRP for intra-articular injection in the knee. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and six-minute walk distance (6MWD) were used to evaluate clinical effects and included measure of patient's subjective assessment of pain, joint mobility, and physical disability. WOMAC score, 6MWD and laboratory tests were repeated at 3 and 6 months and 1, 1.5 and 2 years. XRAY and MRI were completed at 1 year. RESULTS: The average total WOMAC score was 64 at baseline and significantly reduced to 52 at 3 months, 46 at 6 months, 42 at 1 year, 38 at 1.5 years, and 41 at 2 years. Patients walked an average of 1310 feet at baseline and demonstrated a statistically significant improvement at 3 and 6 months and 1, 1.5, and 2 years post treatment. Cartilage thickness as determined by MRI improved by at least 0.2 mm in six patients, was unchanged in two patients and decreased by at least 0.2 mm in two patients. CONCLUSIONS: Overall, all of the patients were pleased with the treatment results. They reported a reduction in pain levels, especially after 3 months. More importantly, the procedure demonstrated a strong safety profile with no severe adverse events or complications reported. Trial registration NCT03089762; Name of registry: http://www.clinicaltrials.gov. PMID- 28629467 TI - Chromatin marks and ambient temperature-dependent flowering strike up a novel liaison. AB - A distinct chromatin mark, H3K36me3, has been found to engage in temperature dependent alternative splicing and ambient temperature-dependent flowering-time control in Arabidopsis. PMID- 28629468 TI - Improving detection and initial management of gestational diabetes through the primary level of care in Morocco: protocol for a cluster randomized controlled trial. AB - BACKGROUND: Morocco is facing a growing prevalence of diabetes and according to latest figures of the World Health Organization, already 12.4% of the population are affected. A similar prevalence has been reported for gestational diabetes (GDM) and although it is not yet high on the national agenda, immediate and long term complications threaten the health of mothers and future generations. A situational analysis on GDM conducted in 2015 revealed difficulties in access to screening and delays in receiving appropriate care. This implementation study has as objective to evaluate a decentralized GDM detection and management approach through the primary level of care and assess its potential for scaling up. METHODS: We will conduct a hybrid effectiveness-implementation research using a cluster randomized controlled trial design in two districts of Morocco. Using the health center as unit of randomization we randomly selected 20 health centers with 10 serving as intervention and 10 as control facilities. In the intervention arm, providers will screen pregnant women attending antenatal care for GDM by capillary glucose testing during antenatal care. Women tested positive will receive nutritional counselling and will be followed up through the health center. In the control facilities, screening and initial management of GDM will follow standard practice. Primary outcome will be birthweight with weight gain during pregnancy, average glucose levels and pregnancy outcomes including mode of delivery, presence or absence of obstetric or newborn complications and the prevalence of GDM at health center level as secondary outcomes. Furthermore we will assess the quality of life /care experienced by the women in both arms. Qualitative methods will be applied to evaluate the feasibility of the intervention at primary level and its adoption by the health care providers. DISCUSSION: In Morocco, gestational diabetes screening and its initial management is fragmented and coupled with difficulties in access and treatment delays. Implementation of a strategy that enables detection, management and follow-up of affected women at primary health care level is expected to positively impact on access to care and medical outcomes. TRIAL REGISTRATION: The trial has been registered on clininicaltrials.gov ; identifier NCT02979756 ; retrospectively registered 22 November 2016. PMID- 28629469 TI - A putative molecular network associated with colon cancer metastasis constructed from microarray data. AB - BACKGROUND: This study aimed to identify the potential molecular network associated with colon cancer metastasis. METHODS: A gene expression profile dataset (GSE40367) downloaded from Gene Expression Omnibus was used to identify and compare differentially expressed genes (DEGs) between primary colon adenocarcinoma tissues and matched tissue samples of liver metastases of colon adenocarcinoma. After the functional analysis of the DEGs, their protein-protein interactions (PPIs) were analyzed, and the transcription factors (TFs) and microRNAs (miRNAs) that regulated these DEGs were predicted. The data were used to construct an integrated network of DEGs, TFs, and miRNAs. Finally, the GSE68468 dataset was used to validate the DEGs associated with liver metastasis of colon adenocarcinoma identified in the GSE40367 dataset. RESULTS: Compared with the primary colon adenocarcinoma sample, 262 DEGs were upregulated and 216 were downregulated in the liver metastasis sample. The DEGs were primarily involved in functions associated with cell junctions and cell adhesion. The DEGs included 17 genes encoding TFs, and 39 miRNAs that regulated DEGs were predicted. Further analysis of the DEGs led to the identification of 490 PPIs. The data were used to construct an integrated network consisting of DEGs, TFs, and miRNAs. DEGs with a high degree of connectivity in the network included FGF2, ERBB4, PTPRC, CXCR4, CCL2, and CCL4. The network also revealed that FGF2 interacted with ERBB4, PTPRC, and CXCR4 and that PTPRC interacted with CXCR4. Furthermore, LCP2 and APBB1IP were predicted to target several other DEGs, including PTPRC, and miR-30a 3p and miR-30e-3p were predicted to regulate ERBB4 and several other DEGs. Notably, FGF2, ERBB4, PTPRC, LCP2, CCL2, and CCL4 were also identified as DEGs in the GSE68468 dataset. CONCLUSION: The DEGs, TFs, and miRNAs identified in this study might play key roles in colon cancer metastasis. PMID- 28629470 TI - Policy lessons from health taxes: a systematic review of empirical studies. AB - BACKGROUND: Taxes on alcohol and tobacco have long been an important means of raising revenues for public spending in many countries but there is increasing interest in using taxes on these, and other unhealthy products, to achieve public health goals. We present a systematic review of the research on health taxes, and aim to generate insights into how such taxes can: (i) reduce consumption of targeted products and related harms; (ii) generate revenues for health objectives and distribute the tax burden across income groups in an efficient and equitable manner; and (iii) be made politically sustainable. METHODS: Six scientific and four grey-literature databases were searched for empirical studies of 'health taxes' - defined as those intended to increase the costs of manufacturing, distributing, retailing and/or consuming health-damaging products. Since reviews already exist of the evidence relating to traditional alcohol and tobacco excise taxes, we focus on other taxes such as taxes on retailers and manufacturers of unhealthy products, and consumer taxes targeting unhealthy foods, such as sugar sweetened beverages. RESULTS: Ninety-one peer-reviewed and 11 grey-literature studies met our inclusion criteria. The review highlights a recent, rapid rise in research in this area, most of which focuses on high-income countries and on taxes on food products or nutrients. Findings demonstrate that high tax rates on sugar-sweetened beverages are likely to have a positive impact on health behaviours and outcomes, and, while taxes on products reduce demand, they add to fiscal revenues. Common concerns about health taxes are also discussed. CONCLUSIONS: If the primary policy goal of a health tax is to reduce consumption of unhealthy products, then evidence supports the implementation of taxes that increase the price of products by 20% or more. However, where taxes are effective in changing health behaviours, the predictability of the revenue stream is reduced. Hence, policy actors need to be clear about the primary goal of any health tax and frame the tax accordingly - not doing so leaves taxes vulnerable to hostile lobbying. Conversely, earmarking health taxes for health spending tends to increase public support so long as policymakers follow through on specified spending commitments. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42016048603. PMID- 28629471 TI - Improving child nutrition and development through community-based childcare centres in Malawi - The NEEP-IE study: study protocol for a randomised controlled trial. AB - BACKGROUND: The Nutrition Embedded Evaluation Programme Impact Evaluation (NEEP IE) study is a cluster randomised controlled trial designed to evaluate the impact of a childcare centre-based integrated nutritional and agricultural intervention on the diets, nutrition and development of young children in Malawi. The intervention includes activities to improve nutritious food production and training/behaviour-change communication to improve food intake, care and hygiene practices. This paper presents the rationale and study design for this randomised control trial. METHODS: Sixty community-based childcare centres (CBCCs) in rural communities around Zomba district, Malawi, were randomised to either (1) a control group where children were attending CBCCs supported by Save the Children's Early Childhood Health and Development (ECD) programme, or (2) an intervention group where nutritional and agricultural support activities were provided alongside the routine provision of the Save the Children's ECD programme. Primary outcomes at child level include dietary intake (measured through 24-h recall), whilst secondary outcomes include child development (Malawi Development Assessment Tool (MDAT)) and nutritional status (anthropometric measurements). At household level, primary outcomes include smallholder farmer production output and crop-mix (recall of last production season). Intermediate outcomes along theorised agricultural and nutritional pathways were measured. During this trial, we will follow a mixed-methods approach and undertake child-, household-, CBCC- and market-level surveys and assessments as well as in-depth interviews and focus group discussions with project stakeholders. DISCUSSION: Assessing the simultaneous impact of preschool meals on diets, nutrition, child development and agriculture is a complex undertaking. This study is the first to explicitly examine, from a food systems perspective, the impact of a preschool meals programme on dietary choices, alongside outcomes in the nutritional, child development and agricultural domains. The findings of this evaluation will provide evidence to support policymakers in the scale-up of national programmes. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN96497560 . Registered on 21 September 2016. PMID- 28629472 TI - Protein S100 as outcome predictor after out-of-hospital cardiac arrest and targeted temperature management at 33 degrees C and 36 degrees C. AB - BACKGROUND: We aimed to investigate the diagnostic performance of S100 as an outcome predictor after out-of-hospital cardiac arrest (OHCA) and the potential influence of two target temperatures (33 degrees C and 36 degrees C) on serum levels of S100. METHODS: This is a substudy of the Target Temperature Management after Out-of-Hospital Cardiac Arrest (TTM) trial. Serum levels of S100 were measured a posteriori in a core laboratory in samples collected at 24, 48, and 72 h after OHCA. Outcome at 6 months was assessed using the Cerebral Performance Categories Scale (CPC 1-2 = good outcome, CPC 3-5 = poor outcome). RESULTS: We included 687 patients from 29 sites in Europe. Median S100 values were higher in patients with a poor outcome at 24, 48, and 72 h: 0.19 (IQR 0.10-0.49) versus 0.08 (IQR 0.06-0.11) MUg/ml, 0.16 (IQR 0.10-0.44) versus 0.07 (IQR 0.06-0.11) MUg/L, and 0.13 (IQR 0.08-0.26) versus 0.06 (IQR 0.05-0.09) MUg/L (p < 0.001), respectively. The ability to predict outcome was best at 24 h with an AUC of 0.80 (95% CI 0.77-0.83). S100 values were higher at 24 and 72 h in the 33 degrees C group than in the 36 degrees C group (0.12 [0.07-0.22] versus 0.10 [0.07-0.21] MUg/L and 0.09 [0.06-0.17] versus 0.08 [0.05-0.10], respectively) (p < 0.02). In multivariable analyses including baseline variables and the allocated target temperature, the addition of S100 improved the AUC from 0.80 to 0.84 (95% CI 0.81 0.87) (p < 0.001), but S100 was not an independent outcome predictor. Adding S100 to the same model including neuron-specific enolase (NSE) did not further improve the AUC. CONCLUSIONS: The allocated target temperature did not affect S100 to a clinically relevant degree. High S100 values are predictive of poor outcome but do not add value to present prognostication models with or without NSE. S100 measured at 24 h and afterward is of limited value in clinical outcome prediction after OHCA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01020916 . Registered on 25 November 2009. PMID- 28629474 TI - Q&A: Expansion microscopy. AB - Expansion microscopy (ExM) is a recently invented technology that uses swellable charged polymers, synthesized densely and with appropriate topology throughout a preserved biological specimen, to physically magnify the specimen 100-fold in volume, or more, in an isotropic fashion. ExM enables nanoscale resolution imaging of preserved samples on inexpensive, fast, conventional microscopes. How does ExM work? How good is its performance? How do you get going on using it? In this Q&A, we provide the answers to these and other questions about this new and rapidly spreading toolbox. PMID- 28629473 TI - Emergency treatment with levetiracetam or phenytoin in status epilepticus in children-the EcLiPSE study: study protocol for a randomised controlled trial. AB - BACKGROUND: Convulsive status epilepticus (CSE) is the most common life threatening neurological emergency in childhood. These children are also at risk of significant morbidity, with acute and chronic impact on the family and the health and social care systems. The current recommended first-choice, second-line treatment in children aged 6 months and above is intravenous phenytoin (fosphenytoin in the USA), although there is a lack of evidence for its use and it is associated with significant side effects. Emerging evidence suggests that intravenous levetiracetam may be effective as a second-line agent for CSE, and fewer adverse effects have been described. This trial therefore aims to determine whether intravenous phenytoin or levetiracetam is more effective, and safer, in treating childhood CSE. METHODS/DESIGN: This is a phase IV, multi-centre, parallel group, randomised controlled, open-label trial. Following treatment for CSE with first-line treatment, children with ongoing seizures are randomised to receive either phenytoin (20 mg/kg, maximum 2 g) or levetiracetam (40 mg/kg, maximum 2.5 g) intravenously. The primary outcome measure is the cessation of all visible signs of CSE as determined by the treating clinician. Secondary outcome measures include the need for further anti-seizure medications or rapid sequence induction for ongoing CSE, admission to critical care areas, and serious adverse reactions. Patients are recruited without prior consent, with deferred consent sought at an appropriate time for the family. The primary analysis will be by intention-to-treat. The primary outcome is a time to event outcome and a sample size of 140 participants in each group will have 80% power to detect an increase in CSE cessation rates from 60% to 75%. Our total sample size of 308 randomised and treated participants will allow for 10% loss to follow-up. DISCUSSION: This clinical trial will determine whether phenytoin or levetiracetam is more effective as an intravenous second-line agent for CSE, and provide evidence for management recommendations. In addition, this trial will also provide data on which of these therapies is safer in this setting. TRIAL REGISTRATION: ISRCTN identifier, ISRCTN22567894 . Registered on 27 August 2015 EudraCT identifier, 2014-002188-13 . Registered on 21 May 2014 NIHR HTA Grant: 12/127/134. PMID- 28629475 TI - Can formalizing links among community health workers, accredited drug dispensing outlet dispensers, and health facility staff increase their collaboration to improve prompt access to maternal and child care? A qualitative study in Tanzania. AB - BACKGROUND: In Tanzania, progress toward achieving the 2015 Millennium Development Goals for maternal and newborn health was slow. An intervention brought together community health workers, health facility staff, and accredited drug dispensing outlet (ADDO) dispensers to improve maternal and newborn health through a mechanism of collaboration and referral. This study explored barriers, successes, and promising approaches to increasing timely access to care by linking the three levels of health care provision. METHODS: The study was conducted in the Kibaha district, where we applied qualitative approaches with in depth interviews and focus group discussions. In-depth interview participants included retail drug shop dispensers (36), community health workers (45), and health facility staff members (15). We conducted one focus group discussion with district officials and four with mothers of newborns and children under 5 years old. RESULTS: Relationships among the three levels of care improved after the linkage intervention, especially for ADDO dispensers and health facility staff who previously had no formal communication pathway. The study participants perceptions of success included improved knowledge of case management and relationships among the three levels of care, more timely access to care, increased numbers of patients/customers, more meetings between community health workers and health facility staff, and a decrease in child and maternal mortality. Reported challenges included stock-outs of medicines at the health facility, participating ADDO dispensers who left to work in other regions, documentation of referrals, and lack of treatment available at health facilities on the weekend. The primary issue that threatens the sustainability of the intervention is that local council health management team members, who are responsible for facilitating the linkage, had not made any supervision visits and were therefore unaware of how the program was running. CONCLUSION: The study highlights the benefits of approaches that link different levels of care providers to improve access to maternal and child health care. To strengthen this collaboration further, health campaign platforms should include retail drug dispensers as a type of community health care provider. To increase linkage sustainability, the council health management team needs to develop feasible supervision plans. PMID- 28629476 TI - Stromal vascular fraction cells for the treatment of critical limb ischemia: a pilot study. AB - BACKGROUND: Cell-based therapy is being explored as an alternative treatment option for critical limb ischemia (CLI), a disease associated with high amputation and mortality rates and poor quality of life. However, therapeutic potential of uncultured adipose-derived stromal vascular fraction (SVF) cells has not been evaluated as a possible treatment. In this pilot study, we investigated the efficacy of multiple injections of autologous uncultured adipose-derived SVF cells to treat patients with CLI. METHODS: This study included 15 patients, from 35 to 77 years old, with rest pain and ulceration. SVF cells were injected once or twice in the ischemic limb along the arteries. Digital subtraction angiography was performed before and after cell therapy. The clinical follow up was carried out for the subsequent 12 months after the beginning of the treatment. RESULTS: Multiple intramuscular SVF cell injections caused no complications during the follow-up period. Clinical improvement occurred in 86.7% of patients. Two patients required major amputation, and the amputation sites healed completely. The rest of patients achieved a complete ulcer healing, pain relief, improved ankle-brachial pressure index and claudication walking distance, and had ameliorated their quality of life. Digital subtraction angiography performed before and after SVF cell therapy showed formation of numerous vascular collateral networks across affected arteries. CONCLUSION: Results of this pilot study demonstrate that the multiple intramuscular SVF cell injections stimulate regeneration of injured tissue and are effective alternative to achieve therapeutic angiogenesis in CLI patients who are not eligible for conventional treatment. Trial registration number at ISRCTN registry, ISRCTN13001382. Retrospectively registered at 26/04/2017. PMID- 28629477 TI - Identification of EGF-NF-kappaB-FOXC1 signaling axis in basal-like breast cancer. AB - BACKGROUND: The pathogenesis of human basal-like breast cancer (BLBC) is not well understood and patients with BLBC have a poor prognosis. Expression of the epidermal growth factor receptor (EGFR) and nuclear factor-kappaB (NF-kappaB) is well-known to be upregulated in BLBC. The forkhead box C1 (FOXC1) transcription factor, an important prognostic biomarker specific for BLBC, has been shown to be induced by EGF and is critical for EGF effects in breast cancer cells. How FOXC1 is transcriptionally activated in BLBC is not clear. METHODS: Luciferase reporter assays were performed to show that NF-kappaB-p65 enhances FOXC1 promoter activity in BLBC cells (MDA-MB-468). Electrophoretic mobility shift assay, biotinylated oligonucleotide precipitation assay, and chromatin immunoprecipitation assay were used to show that NF-kappaB interacts and binds to the promoter region of FOXC1. RESULTS: In this study, we demonstrate that NF-kappaB is a pivotal mediator of the EGF/EGFR regulation of FOXC1 expression by binding to the FOXC1 promoter to activate FOXC1 transcription. Loss or inhibition of NF-kappaB diminished FOXC1 expression. CONCLUSION: Collectively, our findings reveal a novel EGFR-NF-kappaB FOXC1 signaling axis that is critical for BLBC cell function, supporting the notion that intervention in the FOXC1 pathway may provide potential modalities for BLBC treatment. PMID- 28629479 TI - Evaluation of invasive breast cancer samples using a 12-chemokine gene expression score: correlation with clinical outcomes. AB - BACKGROUND: A unique 12-chemokine gene expression score (CS) accurately predicted the presence of tumor-localized, ectopic lymph node-like structures (TL-ELNs) and improved overall survival (OS) in primary colorectal cancer and metastatic melanoma. We analyzed the correlation between CS, clinicopathological variables, molecular data, and 366 survival in Moffitt Cancer Center's Total Cancer Care (TCC) patients with non-metastatic breast cancer. METHODS: Affymetrix gene expression profiles were used to interrogate the CS by the principal component method. Breast tumors were classified as high or low score based on median split, and correlations between clinicopathologic variables, PAM50 molecular subtype, and ELN formation were analyzed using the TCC dataset. Differences in overall survival (OS) and recurrence-free survival (RFS) in the larger KM Plot breast cancer public datasets were compared using Kaplan-Meier curves. RESULTS: We divided the Total Cancer Care (TCC) breast cancer patients into two groups of high or low CS. Mean CS was 0.24 (range, 2.2-2.1). Patients with higher CS were more likely to be white (172 vs. 159; p = 0.03), had poorly differentiated tumors (112 vs. 59; p <0.0001), ER/PR negative (41 vs. 26) and HER2 positive (36 vs. 19; p = 0.001), and contain TL-ELNs. Higher CS scores were also seen in the basal and HER2+ molecular subtypes. In the KM Plot breast cancer datasets higher CS patients demonstrated superior OS (HR = 0.73, p = 0.008) and RFS (HR 0.76, p = <0.0001), especially in basal and HER2+ patients. CONCLUSIONS: High CS breast tumors tend to be higher grade, basal or HER2+, and present more frequently in Caucasians. However, this group of patients also shows the presence of TL-ELNs within the tumor microenvironment and has better survival outcomes. The CS is a novel tool that can identify breast cancer patients with tumors of a unique intratumoral immune composition and better prognosis. Whether or not the CS is a predictive response marker in breast cancer patients undergoing immunotherapy remains to be determined. PMID- 28629480 TI - A Bifactor and item response analysis of the geriatric anxiety inventory. AB - BACKGROUND: Due to previously reported mixed findings, there is a need for further empirical research on the factorial structure of the commonly used Geriatric Anxiety Inventory (GAI). Therefore, the psychometric properties of the GAI and its short form version (GAI-SF) were evaluated in a psychogeriatric mixed in-and-out patient sample (n = 543). METHODS: Unidimensionality was tested using a bifactor analysis. Rasch modeling was used to assess scale properties. Sex, cognitive functioning and depressive symptoms were tested for differential item functioning (DIF). RESULTS: The bifactor analysis identified an essential unidimensional (general) factor structure but also specific local factors. The general factor comprises all the 20 items as one factor, and the results showed that the variance in the general and specific factors (subscale) scores is best explained by the single general factor. These findings were demonstrated for both versions of the GAI. Furthermore, the Rasch models identified extensive item overlap, indicating redundant items in the full version of the GAI. The GAI-SF also seems to extract much of the same information as the full form. Test scores and items have the same meaning for older adults across different demographic status. CONCLUSION: The findings support the use of a total sum score for both GAI and GAI-SF. Notably, when using the GAI-SF, no information is lost, in comparison with the full scale, thus, supporting the option of choosing the short form (version) when considered most appropriate in demanding clinical contexts. PMID- 28629478 TI - Genetic-epigenetic interactions in cis: a major focus in the post-GWAS era. AB - Studies on genetic-epigenetic interactions, including the mapping of methylation quantitative trait loci (mQTLs) and haplotype-dependent allele-specific DNA methylation (hap-ASM), have become a major focus in the post-genome-wide association-study (GWAS) era. Such maps can nominate regulatory sequence variants that underlie GWAS signals for common diseases, ranging from neuropsychiatric disorders to cancers. Conversely, mQTLs need to be filtered out when searching for non-genetic effects in epigenome-wide association studies (EWAS). Sequence variants in CCCTC-binding factor (CTCF) and transcription factor binding sites have been mechanistically linked to mQTLs and hap-ASM. Identifying these sites can point to disease-associated transcriptional pathways, with implications for targeted treatment and prevention. PMID- 28629481 TI - Depression, inflammation, and memory loss among Mexican Americans: analysis of the HABLE cohort. AB - BACKGROUND: This study explored the combined impact of depression and inflammation on memory functioning among Mexican-American adults and elders. METHODS: Data were analyzed from 381 participants of the Health and Aging Brain study among Latino Elders (HABLE). Fasting serum samples were collected and assayed in duplicate using electrochemiluminesce on the SECTOR Imager 2400A from Meso Scale Discovery. Positive DepE (depression endophenotype) was codified as any score >1 on a five-point scale based on the GDS-30. Inflammation was determined by TNFalpha levels and categorized by tertiles (1st, 2nd, 3rd). WMS III LMI and LMII as well as CERAD were utilized as measures of memory. ANOVAs examined group differences between positive DepE and inflammation tertiles with neuropsychological scale scores as outcome variables. Logistic regressions were used to examine level of inflammation and DepE positive status on the risk for MCI. RESULTS: Positive DepE as well as higher inflammation were both independently found to be associated with lower memory scores. Among DepE positive, those who were high in inflammation (3rd tertile) were found to perform significantly worse on WMS-III LM I (F = 4.75, p = 0.003), WMS-III LM II (F = 8.18, p < 0.001), and CERAD List Learning (F = 17.37, p < 0.001) when compared to those low on inflammation (1st tertile). The combination of DepE positive and highest tertile of inflammation was associated with increased risk for MCI diagnosis (OR = 6.06; 95% CI = 3.9-11.2, p < 0.001). CONCLUSION: Presence of elevated inflammation and positive DepE scores increased risk for worse memory among Mexican-American older adults. Additionally, the combination of DepE and high inflammation was associated with increased risk for MCI diagnosis. This work suggests that depression and inflammation are independently associated with worse memory among Mexican-American adults and elders; however, the combination of both increases risk for poorer memory beyond either alone. PMID- 28629482 TI - Dementia Care Mapping in long-term care settings: a systematic review of the evidence. AB - BACKGROUND: This systematic review identifies and reports the extent and nature of evidence to support the use of Dementia Care Mapping as an intervention in care settings. METHODS: The review was limited to studies that used Dementia Care Mapping as an intervention and included outcomes involving either care workers and/or people living with dementia. Searches were conducted in PubMed, Web of Knowledge, CINAHL, PsychINFO, EBSCO, and Scopus and manually from identified articles reference lists. Studies published up to January 2017 were included. Initial screening of identified papers was based on abstracts read by one author; full-text papers were further evaluated by a second author. The quality of the identified papers was assessed independently by two authors using the Cochrane Risk of Bias Tool. A narrative synthesis of quantitative findings was conducted. RESULTS: We identified six papers fulfilling predefined criteria. Studies consist of recent, large scale, good quality trials that had some positive impacts upon care workers' stress and burnout and benefit people with dementia in terms of agitated behaviors, neuropsychiatric symptoms, falls, and quality of life. CONCLUSION: Available research provides preliminary evidence that Dementia Care Mapping may benefit care workers and people living with dementia in care settings. Future research should build on the successful studies to date and use other outcomes to better understand the benefits of this intervention. PMID- 28629483 TI - The challenges of control groups, placebos and blinding in clinical trials of dietary interventions. AB - High-quality placebo-controlled evidence for food, nutrient or dietary advice interventions is vital for verifying the role of diet in optimising health or for the management of disease. This could be argued to be especially important where the benefits of dietary intervention are coupled with potential risks such as compromising nutrient intake, particularly in the case of exclusion diets. The objective of the present paper is to explore the challenges associated with clinical trials in dietary research, review the types of controls used and present the advantages and disadvantages of each, including issues regarding placebos and blinding. Placebo-controlled trials in nutrient interventions are relatively straightforward, as in general placebos can be easily produced. However, the challenges associated with conducting placebo-controlled food interventions and dietary advice interventions are protean, and this has led to a paucity of placebo-controlled food and dietary advice trials compared with drug trials. This review appraises the types of controls used in dietary intervention trials and provides recommendations and nine essential criteria for the design and development of sham diets for use in studies evaluating the effect of dietary advice, along with practical guidance regarding their evaluation. The rationale for these criteria predominantly relate to avoiding altering the outcome of interest in those delivered the sham intervention in these types of studies, while not compromising blinding. PMID- 28629484 TI - Outbreak of non-tuberculous mycobacteria skin or soft tissue infections associated with handling fish - New York City, 2013-2014. AB - Mycobacterium marinum, a bacterium found in freshwater and saltwater, can infect persons with direct exposure to fish or aquariums. During December 2013, the New York City Department of Health and Mental Hygiene learned of four suspected or confirmed M. marinum skin or soft tissue infections (SSTIs) among persons who purchased whole fish from Chinese markets. Ninety-eight case-patients with non tuberculous mycobacteria (NTM) SSTIs were identified with onset June 2013-March 2014. Of these, 77 (79%) were female. The median age was 62 years (range 30-91). Whole genome sequencing of clinical isolates revealed two main clusters and marked genetic diversity. Environmental samples from distributors yielded NTM though not M. marinum. We compared 56 case-patients with 185 control subjects who shopped in Chinese markets, frequency-matched by age group and sex. Risk factors for infection included skin injury to the finger or hand (odds ratio [OR]: 15.5; 95% confidence interval [CI]: 6.9-37.3), hand injury while preparing fish or seafood (OR 8.3; 95% CI 3.8-19.1), and purchasing tilapia (OR 3.6; 95% CI 1.1 13.9) or whiting (OR 2.7; 95% CI 1.1-6.6). A definitive environmental outbreak source was not identified. PMID- 28629485 TI - Characterisation of vitamin and mineral supplement users differentiated according to their motives for using supplements: results of the German National Nutrition Monitoring (NEMONIT). AB - OBJECTIVE: To characterise German vitamin and mineral supplement users differentiated by their motives for supplement use. DESIGN: Data were obtained from the German National Nutrition Monitoring (2010/11) via two 24 h dietary recalls and a telephone interview. Motive-based subgroups of supplement users were identified by factor and cluster analysis. Sociodemographic, lifestyle, health and dietary characteristics and supplement use were examined. Differences were analysed using chi 2 tests, logistic and linear regression models. SETTING: Germany, nationwide. SUBJECTS: Individuals (n 1589) aged 18-80 years. RESULTS: Three motive-based subgroups were identified: a 'Prevention' subgroup (n 324), characterised by the motive to prevent nutrient deficiencies; a 'Prevention and additional benefits' subgroup (n 166), characterised by motives to prevent health problems and improve well-being and performance; and a 'Treatment' subgroup (n 136), characterised by motives to treat nutrient deficiencies or diseases. Members of the two prevention subgroups had a higher Healthy Eating Index score and tended to be more physically active than non-users. Those in the 'Prevention and additional benefits' subgroup supplemented with a greater number of micronutrients. Members of the 'Treatment' subgroup tended to be older and have a lower self-reported health status than non-users, and supplemented with a smaller number of micronutrients. CONCLUSIONS: The majority of supplement users take supplements for preventive purposes and they are more health conscious than non users of supplements due to their concerns about developing health problems. Those supplementing for treatment purposes may have underlying health indications and may be more likely to benefit from supplementation than those supplementing for preventive purposes. PMID- 28629486 TI - The collaboration of general practitioners and nurses in primary care: a comparative analysis of concepts and practices in Slovenia and Spain. AB - : Aim A comparative analysis of concepts and practices of GP-nurse collaborations in primary health centres in Slovenia and Spain. BACKGROUND: Cross-professional collaboration is considered a key element for providing high-quality comprehensive care by combining the expertise of various professions. In many countries, nurses are also being given new and more extensive responsibilities. Implemented concepts of collaborative care need to be analysed within the context of care concepts, organisational structures, and effective collaboration. METHODS: Background review of primary care concepts (literature analysis, expert interviews), and evaluation of collaboration in 'best practice' health centres in certain regions of Slovenia and Spain. Qualitative content analysis of expert interviews, presentations, observations, and group discussions with professionals and health centre managers. Findings In Slovenian health centres, the collaboration between GPs and nurses has been strongly shaped by their organisation in separate care units and predominantly case-oriented functions. Conventional power structures between professions hinder effective collaboration. The introduction of a new cross-professional primary care concept has integrated advanced practice nurses into general practice. Conventional hierarchies still exist, but a shared vision of preventive care is gradually strengthening attitudes towards team-oriented care. Formal regulations or incentives for teamwork have yet to be implemented. In Spain, health centres were established along with a team-based care concept that encompasses close physician-nurse collaboration and an autonomous role for nurses in the care process. Nurses collaborate with GPs on more equal terms with conflicts centring on professional disagreements. Team development structures and financial incentives for team achievements have been implemented, encouraging teams to generate their own strategies to improve teamwork. CONCLUSION: Clearly defined structures, shared visions of care and team development are important for implementing and maintaining a good collaboration. Central prerequisites are advanced nursing education and greater acceptance of advanced nursing practice. PMID- 28629487 TI - Learning and Memory in Adolescents With Critical Biventricular Congenital Heart Disease. AB - OBJECTIVES: Although evidence exists of broadly defined memory impairment among adolescents with critical congenital heart disease (CHD), nuanced investigations of declarative memory in this at-risk population have not been conducted. This study had two primary aims: (1) to conduct a fine-grained analysis of a range of relevant learning and memory processes in adolescents with critical biventricular CHD, and (2) to identify risk, odds, and predictors of memory impairment. METHODS: Data were combined from two single-center studies of neurodevelopmental outcomes in critical CHD. Two-hundred seven adolescents (M age =15.61+/-1.0 years) with critical CHD (139 with dextro-transposition of the great arteries and 68 with tetralogy of Fallot without an identified genetic condition), as well as 61 healthy referents (M age =15.27+/-1.1 years) completed a neuropsychological evaluation which included the Children's Memory Scale. RESULTS: Whereas visual spatial memory deficits were found in both CHD subgroups, verbal memory abilities were relatively preserved. Adolescents with CHD demonstrated stronger memory for Stories than Word Pairs, t (203)=2.63, p=.009, and for Dot Locations than Faces, t(204)=-2.57, p=.01. CHD subgroup, socioeconomic status, sex, and seizure history were among the most frequent significant predictors of memory impairment. Seizure history, in particular, was associated with a 2 to 3 times greater odds of impaired performance on learning and memory tasks. CONCLUSIONS: Adolescents with critical biventricular CHD are at risk for deficits in aspects of declarative memory. Independent risk factors for worse outcome include history of seizures. (JINS, 2017, 23, 627-639). PMID- 28629488 TI - Supporting in an existential crisis: A mixed-methods evaluation of a training model in palliative care. AB - BACKGROUND: Palliative care staff often report that they lack the skills and confidence to provide support during an existential crisis. Consequently, there is a definite need for a training program in this area. OBJECTIVE: Our aim was to investigate whether a training model could give palliative care staff increased knowledge, awareness, and preparedness-all useful tools for providing support. METHODS: A mixed-methods research design was used. Data were collected in four hospital-based palliative homecare teams in the Stockholm area. In total, 34 staff participated, representing different palliative care team professions. Before and after the intervention, a questionnaire with a 9-point Likert-type scale was completed (n = 34). Qualitative focus group discussions were conducted a month after the intervention (25 participants). These were recorded, transcribed, and analyzed using qualitative content analysis with a manifest focus. RESULTS: In the quantitative part of our study, the participants showed significantly increased perceived knowledge, awareness, and preparedness in every aspect (p < 0.001 for all items). The focus group discussions revealed a process that made it possible to apply new knowledge and insight. The process began with theoretical knowledge and, through care-related reflection and self-reflection, the knowledge base gradually developed and provided useful skills and increased job satisfaction. SIGNIFICANCE OF RESULTS: The team-based "TrainingModel Sand/TER" can be performed without excessive effort and contribute to improved competence in providing support during an existential crisis. It is particularly useful for staff working in clinical palliative care. PMID- 28629489 TI - Eating down or simply eating less? The diet and health implications of these practices during pregnancy and postpartum in rural Bangladesh. AB - OBJECTIVE: To: (i) determine the prevalence of self-reported eating less and eating down during early and late pregnancy and postpartum, and explore risk factors associated with eating less; (ii) examine the association between eating less and diet quality; and (iii) determine the association between eating less and weight gain during pregnancy. DESIGN: Data were collected longitudinally from a cohort of women participating in a community health programme. Diet was assessed at three time points (<=20 weeks' gestation, 36 weeks' gestation, 6 months' postpartum), body weight was measured during study enrolment (<=20 weeks' gestation) and at 36 weeks' gestation, and information about the woman and her household was collected at enrolment. SETTING: The Rang-Din Nutrition Study in the Rangpur and Dinajpur districts of Bangladesh. SUBJECTS: Women (n 4011). RESULTS: The prevalence of self-reported eating less differed by time point (75.9 % in early pregnancy, 38.8 % in late pregnancy, 7.4 % postpartum; P<0.001). The most common reason for eating less across all time periods was food aversion or loss of appetite. Women who reported eating less in late pregnancy had consumed animal-source foods less frequently in the preceding week than women who reported eating more (mean (sd): 11.7 (7.4) v. 14.8 (9.2) times/week; P<0.001) and had lower weekly weight gain than women who reported eating more (mean (se): 0.27 (0.004) v. 0.33 (0.004) kg/week; P<0.001). CONCLUSIONS: Eating less has negative implications with respect to diet quality and pregnancy weight gain in this context. PMID- 28629490 TI - Precipitation of (Si2-xAlx)Hf in an Al-Si-Mg-Hf Alloy. AB - The morphology, composition, and structure of precipitates in an Al-Si-Mg-Hf alloy after heat treatment at 560 degrees C for 20 h were studied by means of C s -corrected high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), energy dispersive X-ray spectrometry (EDS), high resolution transmission electron microscopy (HRTEM), and first-principle calculations. Precipitates with three kinds of morphologies were observed. The rectangular and square precipitates were predominantly (Si2-x Al x )Hf phases, while the nanobelt-like precipitate is the Si2Hf phase. First-principle calculations were used to show that the Si6 and Si8 sites were the most favorable sites for Al incorporation in the orthorhombic Si2Hf phase. PMID- 28629491 TI - Sphingobacterium alkalisoli sp. nov., isolated from a saline-alkaline soil. AB - A Gram-staining-negative, non-motile, non-spore-forming bacterium designated Y3L14T was isolated from the saline-alkaline soil of a farmland, Inner Mongolia, northern China. Strain Y3L14T could grow at 10-40 degrees C (optimally at 30 degrees C), pH 6.0-10.0 (optimally at pH 8.0), and in the presence of 0-6.0 % (w/v) NaCl (optimally with 0-2.0 %). Phylogenetic analysis based on the 16S rRNA gene and DNA gyrase subunit B (gyrB) gene sequences revealed that strain Y3L14T clustered with strains belonging to the genus Sphingobacterium, sharing the highest 16S rRNA gene sequence similarity with Sphingobacterium lactis WCC 4512T (94.99 %). Its major cellular fatty acids contained iso-C15 : 0, C16 : 0, iso-C17 : 0 3-OH and summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1omega7c). Menaquinone-7 (MK-7) was the only isoprenoid quinone. Strain Y3L14T contained phosphatidylethanolamine, sphingophospholipid, two unknown phospholipids and three unknown lipids as the major polar lipids. The genomic DNA G+C content of strain Y3L14T was 36.0 mol%. Based on the phenotypic, phylogenetic and genotypic characteristics, strain Y3L14T represents a novel species within the genus Sphingobacterium, for which Sphingobacterium alkalisoli sp. nov. is proposed; the type strain is Y3L14T (=CGMCC 1.15782T=KCTC 52379T). PMID- 28629492 TI - Calidifontibacter terrae sp. nov., an actinomycete isolated from soil, with potential applications in cosmetics. AB - An aerobic, Gram-stain-positive, oxidase- and catalase-positive, non-motile, non spore-forming, coccoid, creamish-white-coloured bacterium, designated strain R161T, was isolated from soil in Hwaseong, South Korea. The cell-wall peptidoglycan contained glycine, glutamic acid, alanine, aspartic acid, serine and lysine, and whole-cell sugars were galactose, rhamnose, glucose and ribose. Strain R161T showed antibacterial and enzyme inhibitory activities. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain R161T formed a lineage within the family Dermacoccaceae, and showed highest sequence similarity with type strains of Calidifontibacter indicus PC IW02T (97.71 % sequence similarity) and Yimella lutea YIM 45900T (97.58 %). The sequence similarity of strain R161T with type strains of members of the genus Dermacoccus was less than 96.5 %. The major menaquinone was MK-8(H4). The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannosides. The major cellular fatty acids were iso-C16 : 0, anteiso-C17 : 0, iso-C16 : 1 H, anteiso-C17 : 1omega9c, summed feature 9 (iso-C17 : 1omega9c and/or C16 : 0 10-methyl) and iso-C15 : 0. The DNA G+C content of strain R161T was 73.9 mol%. The DNA-DNA hybridization value between strain R161T and C. indicus JCM 16038T was 52.1 %. On the basis of phenotypic, genotypic, chemotaxonomic and phylogenetic analysis, strain R161T represents a novel species of genus Calidifontibacter, for which the name Calidifontibacter terrae sp. nov. is proposed. The type strain of Calidifontibacter terrae sp. nov. is R161T (=KEMB 9005-404T=KACC 18906T=JCM 31558T). PMID- 28629493 TI - Naumannella huperziae sp. nov., an endophytic actinobacterium isolated from Huperzia serrata (Thunb.). AB - An endophytic, short rod-shaped, non-motile and non-spore-forming actinobacterium, designated strain CPCC 204135T, was isolated from a surface sterilized medicinal plant, Huperzia serrata (Thunb.), collected from Sichuan Province, south-west China. Strain CPCC 204135T was observed to grow at temperatures between 20 and 37 degrees C (optimum, 28-32 degrees C), at pH 6.0 9.0 (optimum, pH 7.0-8.0) and in the presence of 0-9.0 % (w/v) NaCl (optimum, 0-3 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CPCC 204135T belonged to the genus Naumannella, showing the highest level of 16S rRNA gene sequence similarity with Naumannella halotolerans DSM 24323T (97.2 %), the only species of the genus Naumannella in the family Propionibacteriaceaewith avalidly published name. The DNA-DNA hybridization value between strain CPCC 204135T and N. halotolerans DSM 24323T was 20.1+/-1.8 %, which is far below the accepted 70 % threshold for species delineation. The cell-wall hydrolysates contained ll-diaminopimelic acid, alanine, glycine and glutamic acid, with the peptidoglycan type of A3gamma. Diphosphatidylglycerol, phosphatidylglycerol, an unidentified phospholipid, one unidentified aminolipid, one unidentified polar lipid and several kinds of glycolipids were detected in the polar lipids profile. MK-9(H4) was identified as the predominant menaquinone. The major cellular fatty acids (>10 %) were anteiso-C15 : 0 and iso-C16 : 0. The G+C content of the genomic DNA of strain CPCC 204135T was determined to be 71.8 mol%. On the basis of phylogenetic analysis, and phenotypic and chemotaxonomic characteristics, we concluded that strain CPCC 204135T represents a novel species of the genus Naumannella, for which the name Naumannella huperziae sp. nov. is proposed, with strain CPCC 204135T (=DSM 101717T=NBRC 111773T) as the type strain. PMID- 28629494 TI - Shewanella intestini sp. nov., isolated from the intestine of abalone, Haliotis diversicolor. AB - A Gram-stain-negative, rod-shaped bacterium with a singular polar flagellum, designated as strain XMDDZSB0408T, was isolated from the intestine of adult abalone, Haliotis diversicolor. Activity of oxidase was positive and catalase activity was negative. It could grow at salinities from 3 to 6 % NaCl (w/v), and pH 7-9. It had the highest sequence similarity of <96.0 % with all previously established species for the complete 16S rRNA gene (1531 bp). The results of phylogenetic analysis indicated that the strain was affiliated to the genus Shewanella and closely related to Shewanella gaetbuli TF-27T and Shewanella japonica KMM 3299T (95.8 % sequence similarity), Shewanella electrodiphila MAR441T (95.6 %), Shewanella pacifica KMM 3597T (95.4 %), Shewanella donghaensis LT17T (95.3 %) and Shewanella olleyana ACEM 9T (94.7 %). The respiratory quinones were MK-7, Q-8, Q-7, MK-8, Q-7 (H4) and Q-6. The predominant fatty acids consisted of C16:0, summed feature 3 (comprised of C16 : 1omega7c/C16 : 1omega6c), C18 : 0, summed feature 8 (comprised of C18 : 1omega7c/C18 : 1omega6c), C12 : 0 and C14 : 0. The polar lipids were identified as phosphatidylethanolamine (PE), a glycolipid (GL), a phospholipid (PL) and one unidentified lipid (L). The DNA G+C content was 41.4 mol% calculated from the draft genome sequence. On the basis of its polyphasic taxonomic properties, strain XMDDZSB0408T represented a novel species, for which the name Shewanella intestini sp. nov. was proposed, with the type strain XMDDZSB0408T (=KCTC 52125T=MCCC 1A01895T). PMID- 28629495 TI - Noviherbaspirillum denitrificans sp. nov., a denitrifying bacterium isolated from rice paddy soil and Noviherbaspirillum autotrophicum sp. nov., a denitrifying, facultatively autotrophic bacterium isolated from rice paddy soil and proposal to reclassify Herbaspirillum massiliense as Noviherbaspirillum massiliense comb. nov. AB - Thirty-nine denitrifying bacterial strains closely related to one another, represented by strains TSA40T and TSA66T, were isolated from rice paddy soils. Strains TSA40T and TSA66T were Gram-stain-negative, slightly curved rod-shaped, and motile by means of polar flagella. They were able to reduce nitrate, nitrite and nitrous oxide, but unable to fix atmospheric N2. While strain TSA66T was able to grow autotrophically by H2-dependent denitrification, strain TSA40T could not. Phylogenetic analysis suggested that they belong to the family Oxalobacteraceae, the order Burkholderiales in the class Betaproteobacteria. Major components in the fatty acids (C16 : 0, C17 : 0 cyclo, C18 : 1omega7c and summed feature 3) and quinone (Q-8) also supported the affiliation of strains TSA40T and TSA66T to the family Oxalobacteraceae. Based on 16S rRNA gene sequence comparisons, strains TSA40T and TSA66T showed the greatest degree of similarity to Herbaspirillum massiliense JC206T, Noviherbaspirillum malthae CC-AFH3T, Noviherbaspirillum humi U15T, Herbaspirillum seropedicae Z67T and Paucimonas lemoignei LMG 2207T, and lower similarities to the members of other genera. Average nucleotide identity values between the genomes of strain TSA40T, TSA66T and H. massiliense JC206T were 75-77 %, which was lower than the threshold value for species discrimination (95-96 %). Based on the 16S rRNA gene sequence analysis in combination with physiological, chemotaxonomic and genomic properties, strains TSA40T (=JCM 17722T=ATCC TSD-69T) and TSA66T (=JCM 17723T=DSM 25787T) are the type strains of two novel species within the genus Noviherbaspirillum, for which the names Noviherbaspirillum denitrificans sp. nov. and Noviherbaspirillum autotrophicum sp. nov. are proposed, respectively. We also propose the reclassification of Herbaspirillum massiliense as Noviherbaspirillum massiliense comb. nov. PMID- 28629496 TI - Delftia rhizosphaerae sp. nov. isolated from the rhizosphere of Cistus ladanifer. AB - A bacterial strain, designated RA6T, was isolated from the rhizosphere of Cistus ladanifer. Phylogenetic analyses based on 16S rRNA gene sequence placed the isolate into the genus Delftia within a cluster encompassing the type strains of Delftia lacustris, Delftia tsuruhatensis, Delftia acidovorans and Delftia litopenaei, which presented greater than 97 % sequence similarity with respect to strain RA6T. DNA-DNA hybridization studies showed average relatedness ranging from of 11 to 18 % between these species of the genus Delftia and strain RA6T. Catalase and oxidase were positive. Casein was hydrolysed but gelatin and starch were not. Ubiquinone 8 was the major respiratory quinone detected in strain RA6T together with low amounts of ubiquinones 7 and 9. The major fatty acids were those from summed feature 3 (C16 : 1omega7c/C16 : 1 omega6c) and C16 : 0. The predominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Phylogenetic, chemotaxonomic and phenotypic analyses showed that strain RA6T should be considered as a representative of a novel species of genus Delftia, for which the name Delftia rhizosphaerae sp. nov. is proposed. The type strain is RA6T (=LMG 29737T= CECT 9171T). PMID- 28629497 TI - Hannaella dianchiensis sp. nov., a basidiomycetous yeast species isolated from lake water. AB - Three strains (YIM-HL1107T, YIM-HL1045, YIM-HL1112) representing a novel yeast species were isolated from surface water samples collected from the Caohai region of Dianchi Lake in Yunnan, south-western China. On the basis of morphological, physiological and biochemical characteristics and sequence analysis of the D1/D2 region of the LSU rRNA gene and the internal transcribed spacer (ITS) region, they were assigned to a novel species of the genus Hannaella. The closest relative to the novel species was Hannaella pagnoccae, but it showed 6.3 % nucleotide differences (34 nt substitutions out of 541 nt) in the D1/D2 region of the LSU rRNA gene and 9.3-9.6 % nucleotide differences (40-41 substitutions and 7 8 gaps out of 430 nt) in the ITS region. The name Hannaella dianchiensis sp. nov. is proposed. The type strain is YIM-HL1107T (=CBS 14191T=CCTCC AY 2015009T), and the MycoBank number is MB 816297. PMID- 28629498 TI - Rodentibacter gen. nov. including Rodentibacter pneumotropicus comb. nov., Rodentibacter heylii sp. nov., Rodentibacter myodis sp. nov., Rodentibacter ratti sp. nov., Rodentibacter heidelbergensis sp. nov., Rodentibacter trehalosifermentans sp. nov., Rodentibacter rarus sp. nov., Rodentibacter mrazii and two genomospecies. AB - Rodentibacter gen. nov. is proposed based on isolation and phenotypic characterization of strains, predominantly from rodents. The strains showed 86 % or higher rpoB gene sequence similarity and indicated a genus-level relationship within Pasteurellaceae. The strains compared at 16S rRNA gene sequence level showed 93.8 % or higher similarity, and their genus-level relationship within Pasteurellaceae was confirmed by phenotypic analysis. The type species Rodentibacter pneumotropicus comb. nov. is reclassified from [Pasteurella] pneumotropica with type strain NCTC 8141T (=CCUG 12398T). Whole genomic comparison allowed the estimation of DNA-DNA renaturation. Rodentibacter heylii sp. nov. was proposed for a group that included the biovar Heyl of [Pasteurella] pneumotropica with the type strain ATCC 12555T (=CCUG 998T). A group was proposed as Rodentibacter ratti sp. nov., which included the taxon 22 of Bisgaard; the type strain is F75T (=CCUG 69665T=DSM 103977T). Taxon 41 of Bisgaard was proposed as Rodentibacter myodis sp. nov. with type strain Ac151T (=CCUG 69666T=DSM 103994T). Rodentibacter heidelbergensis sp. nov. included the type strain 1996025094T (=Ac69T) (=CCUG 69667T=DSM 103978T). A group strains of was proposed as Rodentibacter trehalosifermentans sp. nov. with type strain H1987082031T (=CCUG 69668T=DSM 104075T). Two strains including the reference strain of taxon 17 of Bisgaard that showed 16S rRNA gene similarity of 97.3 % were proposed as Rodentibacter rarus sp. nov. 2325/79T (=CCUG 17206T=DSM 103980T). Rodentibacter mrazii sp. nov. was proposed with type strain Ppn418T (Bisgaard taxon 21) (=CCUG 69669T=DSM 103979T). The eight species could be separated based on phenotypic characteristics such as NAD requirement, ornithine decarboxylase and indole formation, alpha-glucosidase, beta-galactosidase and in acid formation from (+)-l arabinose, (-)-d-ribose, (+)-d-xylose, myo-inositol, (-)-d-mannitol, lactose, melibiose and trehalose. Forty-six strains including taxon 48 of Bisgaard formed a monophyletic group by rpoB and 16S rRNA gene sequence analysis, but could not be separated phenotypically from R. pneumotropicus and R. heylii, and it was left as an unnamed genomospecies 1 of Rodentibacter with reference strain Ppn416. Another taxon that included 13 strains, mainly isolated from Apodemus sylvaticus, could not be separated phenotypically from R. pneumotropicus or R. heylii and was designated as genomospecies 2. Strain Ppn85 with 95 % or less rpoB gene sequence similarity and with 16S rRNA gene sequence similarity of 97 % or less to the other members of Rodentibacter was left as an unnamed singleton. PMID- 28629499 TI - Agrobacterium salinitolerans sp. nov., a saline-alkaline-tolerant bacterium isolated from root nodule of Sesbania cannabina. AB - Two Gram-staining-negative, aerobic bacteria (YIC 5082T and YIC4104) isolated from root nodules of Sesbania cannabina grown in a high-salt and alkaline environment were identified as a group in the genus Agrobacterium because they shared 100 and 99.7 % sequence similarities of 16S rRNA and recA+atpD genes, respectively. These two strains showed 99.2/100 % and 93.9/95.4 % 16S rRNA and recA+atpD gene sequence similarities to Agrobacterium radiobacter LMG140T and Agrobacterium. pusense NRCPB10T, respectively. The average nucleotide identities (ANI) of genome sequences were 89.95 % or lower between YIC 5082T and the species of the genus Agrobacterium examined. Moreover, these two test strains formed a unique nifH lineage deeply separated from other rhizobia. Although the nodC gene was not detected in YIC 5082T and YIC4104, they could form effective root nodules on S. cannabina plants. The main cellular fatty acids in YIC 5082T were summed feature 8 (C18 : 1omega7c/C18 : 1omega6c), C19 : 0cyclo omega8c, summed feature 2 (C12 : 0 aldehyde/unknown equivalent chain length 10.9525) and C16 : 0. The DNA G+C content of YIC 5082T was 59.3 mol%. The failure to utilize d-sorbitol as a carbon source distinguished YIC 5082T from the type strains of related species. YIC 5082T could grow in presence of 5.0 % (w/v) NaCl and at a pH of up to 10.0. Based on results regarding the genetic and phenotypic properties of YIC 5082T and YIC4104 the name Agrobacterium salinitolerans sp. nov. is proposed and YIC 5082T (=HAMBI 3646T=LMG 29287T) is designed as the type strain. PMID- 28629500 TI - Imhoffiella gen. nov., a marine phototrophic member of the family Chromatiaceae including the description of Imhoffiella purpurea sp. nov. and the reclassification of Thiorhodococcus bheemlicus Anil Kumar et al. 2007 as Imhoffiella bheemlica comb. nov. AB - A coccoid-shaped phototrophic purple sulfur bacterium, strain AK35T, was isolated from a coastal surface water sample collected from Visakhapatnam, India. Cells were Gram-stain-negative, motile and purple, containing bacteriochlorophyll a and the carotenoid rhodopinal as major photosynthetic pigments. Strain AK35T was able to grow photoheterotrophically and could utilize a number of organic substrates. It was unable to grow photoautotrophically. Strain AK35T was able to utilize sulfide and thiosulfate as electron donors. The main fatty acids present were identified as C16 : 0, C18 : 1omega7c, and C16 : 1omega7c and/or iso-C15 : 0 2OH (summed feature 3). Strain AK35T contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and six unidentified lipids as polar lipids. The G+C content of the DNA of strain AK35T was 63.1 mol%. 16S rRNA gene sequence comparisons indicated that the isolate represented a member of the family Chromatiaceae. 16S rRNA gene sequence analysis indicated that strain AK35T is phylogenetically distinctly positioned outside the groups of most members of the genus Thiorhodococcus, clustered with members of the genera Marichromatium and Phaeochromatium, but was most closely related to Thiorhodococcus bheemlicus with a pairwise sequence similarity of 98.75 %. Based on DNA-DNA hybridization between strain AK35T and Thiorhodococcus bheemlicus MTCC 8120T a relatedness of 39.46 % was established. Distinct morphological, physiological and genotypic differences from these previously described taxa supported the classification of the new isolate as a representative of a novel species in a new genus, for which the name Imhoffiella purpurea gen. nov., sp. nov. is proposed. The type strain of Imhoffiella purpurea is AK35T (=JCM 18851T=KCTC 15575T=MTCC 12304T). In addition, Thiorhodococcus bheemlicus is recognized as another species of this genus and transferred to Imhoffiella bheemlica comb. nov. PMID- 28629501 TI - Mycobacterium persicum sp. nov., a novel species closely related to Mycobacterium kansasii and Mycobacterium gastri. AB - Four strains isolated in Iran from pulmonary specimens of unrelated patients are proposed as representative of a novel Mycobacterium species. Similarity, at the phenotypic level, with Mycobacterium kansasii is remarkable with the photochromogenic yellow pigmentation of the colonies being the salient feature. They differ, however, genotypically from this species and present unique sequences in 16S rRNA, hsp65 and rpoB genes. The average nucleotide identity and the genome-to-genome distance fully support the status of an independent species. The name proposed for this species is Mycobacterium persicum sp. nov. with AFPC 000227T (=DSM 104278T=CIP 111197T) as the type strain. PMID- 28629502 TI - Transfer of Pseudomonas pictorum Gray and Thornton 1928 to genus Stenotrophomonas as Stenotrophomonas pictorum comb. nov., and emended description of the genus Stenotrophomonas. AB - A polyphasic taxonomic approach including analysis of phenotypic, physiological and genotypic characteristics, 16S rRNA gene sequence and DNA-DNA hybridization analysis was used to determine the most consistent affiliation of Pseudomonas pictorum. Pseudomonas pictorum ATCC 23328T exhibited phenotypic traits of members of the genus Stenotrophomonas including cellular fatty acid composition, quinone and limited range of substrates that could be used. Antibiotic susceptibility and physiological characteristics were determined. The DNA G+C content was 65.7 mol%. Phylogenetic analysis revealed that the type strains of Stenotrophomonas terrae, Stenotrophomonashumi, Stenotrophomonasnitritireducens and Stenotrophomonasacidaminiphila were the nearest relatives (16S rRNA gene sequence similarity of 98.0 to 98.8 %). All the other type strains of species of the genus Stenotrophomonas showed high 16S rRNA gene sequence similarities (96.8 to 97.2 %). DNA-DNA hybridizations revealed 31.0, 32.0, 43.3 and 43.6 % reassociation between Pseudomonas pictorum ATCC 23328T and the type strains of S. terrae, S. humi, S. nitritireducens and S. acidaminiphila, respectively. Our overall results indicate that Pseudomonas pictorum should be transferred to the genus Stenotrophomonas as a novel species of this genus, Stenotrophomonas pictorum comb. nov. Since the original description of the genus Stenotrophomonaswas made with only one species (Stenotrophomonasmaltophilia), an emendation of the genus description is proposed in order to match better with the characteristics of the eleven novel species assigned to this genus since then. PMID- 28629503 TI - Red-pink pigmented Hymenobacter coccineus sp. nov., Hymenobacter lapidarius sp. nov. and Hymenobacter glacialis sp. nov., isolated from rocks in Antarctica. AB - Four rod-shaped and Gram-stain-negative bacterial strains, CCM 8647, CCM 8649T, CCM 8643T and CCM 8648T, were isolated from rock samples collected on James Ross Island, Antarctica. Extensive biotyping, fatty acid profiling, chemotaxonomy, 16S rRNA gene sequencing and whole-genome sequencing was applied to isolates to clarify their taxonomic position. Phylogenetic analysis based on 16S rRNA gene sequencing indicated that all four isolates belonged to the genus Hymenobacter. Strains CCM 8649T and CCM 8647 were most closely related to Hymenobacter arizonensis OR362-8T (94.4 % 16S rRNA gene sequence similarity), strain CCM 8643T to Hymenobacter terrae DG7AT (96.3 %) and strain CCM 8648T to Hymenobacter glaciei VUG-A130T (96.3 %). The predominant fatty acids of CCM 8649T and CCM 8647 were summed feature 3 (C16 : 1omega7c/C16 : 1omega6c), C16 : 1omega5c and iso-C15 : 0, whereas those of CCM 8643T and CCM 8648T were summed feature 3 (C16 : 1omega7c/C16 : 1omega6c) and C16 : 1omega5c. The quinone systems contained exclusively menaquinone MK-7. The major polyamine was sym-homospermidine. All four strains contained the major polar lipid phosphatidylethanolamine. The G+C content of genomic DNA ranged from 60-63 mol%. Whole-genome sequencing data supported the finding that isolates represented distinct species of the genus Hymenobacter. On the basis of the results obtained, three novel species are proposed for which the names Hymenobacter coccineus sp. nov., Hymenobacter lapidarius sp. nov. and Hymenobacter glacialis sp. nov. are suggested, with the type strains CCM 8649T (=LMG 29441T=P5239T), CCM 8643T (=LMG 29435T=P3150T) and CCM 8648T (=LMG 29440T=P5086T), respectively. PMID- 28629504 TI - Sulfodiicoccus acidiphilus gen. nov., sp. nov., a sulfur-inhibited thermoacidophilic archaeon belonging to the order Sulfolobales isolated from a terrestrial acidic hot spring. AB - A novel thermoacidophilic archaeon, strain HS-1T, was isolated from the Hakone Ohwaku-dani hot spring in Japan. Cells of strain HS-1T in exponential phase were cocci to irregular cocci with a diameter of 0.8-1.5 um. The strain grew within a temperature range of 50-70 degrees C (optimal: 65-70 degrees C), a pH range of pH 1.4-5.5 (optimal: pH 3.0-3.5) and a NaCl concentration range of 0-2.5 % (w/v). The novel strain grew in aerobic conditions but did not grow anaerobically. Moreover, this strain utilized various complex substrates (beef extract, casamino acids, peptone, tryptone and yeast extract) and sugars (arabinose, xylose, galactose, glucose, maltose, sucrose, raffinose and lactose) as sole carbon sources. No chemolithoautotrophic growth occurred on elemental sulfur, pyrite, K2S4O6, Na2S2O3 or FeSO4 . 7H2O; however, growth by the oxidation of hydrogen occurred weakly. The core lipids were calditoglycerocaldarchaeol (CGTE) and caldarchaeol (DGTE). The DNA G+C content of the strain was 52.0 mol%, which was remarkably higher than those of known species of the order Sulfolobales(31-46.2 %). The growth of the strain was significantly inhibited in the presence of elemental sulfur. Analyses of 16S rRNA and 23S rRNA gene sequences showed that HS 1T belonged to the order Sulfolobales; however, it was distantly related to all known species of the order Sulfolobales (less than 89 % sequence similarity). On the basis of these results, we propose the novel genus, Sulfodiicoccus, in the order Sulfolobales (in the family Sulfolobaceae). The type species of the genus is Sulfodiicoccus acidiphilus sp. nov., and the type strain of the species is HS 1T (=JCM 31740T=InaCC Ar79T). PMID- 28629505 TI - Micromonospora fulva sp. nov., isolated from forest soil. AB - A novel actinobacterium, designated strain UDF-1T, was isolated from forest soil in Chungnam, South Korea, and its taxonomic position was investigated using a polyphasic approach. Strain UDF-1T formed a branched brownish-orange substrate mycelium with spherical or oval spores. No aerial mycelium was formed. Comparative 16S rRNA gene sequence analysis indicated that strain UDF-1T belongs to the genus Micromonospora, showing the highest sequence similarity to Micromonospora palomenae NEAU-CX1T (99.2 % 16S rRNA gene sequence similarity), 'Micromonospora maoerensis' NEAU-MES19 (99.0 %), Micromonospora endolithica DSM 44398T (98.8 %) and Micromonospora matsumotoense IMSNU 22003T (98.8 %). The predominant menaquinones of strain UDF-1T were MK-10 (H4) and MK-10 (H6). The cell wall contained meso-diaminopimelic acid and the whole-cell sugars were arabinose and xylose. The major polar lipids were phosphatidylinositol, diphosphatidylglycerol and phosphatidylethanolamine. The major cellular fatty acids were iso-C16 : 0, anteiso-C15 : 0 and iso-C15 : 0. The genomic DNA G+C content was 73.1 mol%. DNA-DNA relatedness between strain UDF-1T and closely related type strains in the genus Micromonospora was below 30 %. On the basis of the polyphasic analysis conducted in this study, strain UDF-1T represents a novel species of the genus Micromonospora, for which the name Micromonospora fulva sp. nov. is proposed. The type strain is UDF-1T (=KACC 18696T=NBRC 111826T). PMID- 28629506 TI - Actinomyces liubingyangii sp. nov. isolated from the vulture Gypaetus barbatus. AB - Two strains (VUL4_1T and VUL4_2) of Gram-staining-positive, catalase-negative, non-spore-forming short rods were isolated from rectal swabs of Old World vultures (Gypaetus barbatus) in the Tibet-Qinghai Plateau, China. Analysis of morphological characteristics and biochemical tests indicated that the two strains closely resembled each other but were distinct from other species of the genus Actinomyces previously described. Based on the results of 16S rRNA gene sequence comparison and genome analysis, strains were determined to be members of the genus Actinomyces, closely related to the type strains of Actinomyces marimammalium (96.4 % 16S rRNA gene sequence similarity), Actinomyceshongkongensis (92.4 %), Actinomyceshordeovulneris (92.3 %) and Actinomycesnasicola (92.2 %), respectively. Optimal growth conditions were 37 degrees C, pH 6-7, with 1 % (w/v) NaCl. Strain VUL4_1T contained C18 : 1omega9c and C16 : 0 as the major cellular fatty acids and diphosphatidylglycerol as the major component of the polar lipids. The genomic DNA G+C content of VUL4_1T was 54.9 mol%. Strain VUL4_1T showed less than 70 % DNA-DNA relatedness with other species of the genus Actinomyces, further supporting strain VUL4_1T as a representative of a novel species. Based on the phenotypic data and phylogenetic inference, a novel species, Actinomyces liubingyangii sp. nov., is proposed with VUL4_1T (=CGMCC 4.7370T=DSM 104050T) as the type strain. PMID- 28629507 TI - Oceanisphaera marina sp. nov., isolated from a deep-sea seamount. AB - A Gram-stain-negative, rod-shaped, strictly aerobic, motile bacterial strain, designated YM319T, was isolated from a seamount near the Yap Trench in the tropical western Pacific. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YM319T was related to the genus Oceanisphaera and had highest 16S rRNA gene sequence similarities with the type strains Oceanisphaera profunda SM1222T (97.4 %), Oceanisphaera sediminis TW92T (97.3 %) and Oceanisphaera ostreae T-w6T (97.1 %). The predominant cellular fatty acids were summed feature 3 (composed of iso-C15 : 0 2-OH and/or C16 : 1 omega7c), C16 : 0 and C18 : 1omega7c. Strain YM319T had Q-8 as the predominant ubiquinone. The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid and four unidentified lipids. The genomic DNA G+C content of strain YM319T was 54.8 mol%. On the basis of the evidence presented in this study, strain YM319T represents a novel species of the genus Oceanisphaera, for which we propose the name Oceanisphaera marina sp. nov. (type strain YM319T=KACC 18564T=CGMCC 1.15923T). PMID- 28629508 TI - Campylobacter pinnipediorum sp. nov., isolated from pinnipeds, comprising Campylobacter pinnipediorum subsp. pinnipediorum subsp. nov. and Campylobacter pinnipediorum subsp. caledonicus subsp. nov. AB - During independent diagnostic screenings of otariid seals in California (USA) and phocid seals in Scotland (UK), Campylobacter-like isolates, which differed from the established taxa of the genus Campylobacter, were cultured from abscesses and internal organs of different seal species. A polyphasic study was undertaken to determine the taxonomic position of these six isolates. The isolates were characterized by 16S rRNA gene and AtpA sequence analysis and by conventional phenotypic testing. The whole-genome sequences were determined for all isolates, and the average nucleotide identity (ANI) was determined. The isolates formed a separate phylogenetic clade, divergent from all other taxa of the genus Campylobacter and most closely related to Campylobactermucosalis. Although all isolates showed 100 % 16S rRNA gene sequence homology, AtpA and ANI analyses indicated divergence between the otariid isolates from California and the phocid isolates from Scotland, which warrants subspecies status for each clade. The two subspecies could also be distinguished phenotypically on the basis of catalase activity. This study shows clearly that the isolates obtained from pinnipeds represent a novel species within the genus Campylobacter, for which the name Campylobacter pinnipediorum sp. nov. is proposed. Within this novel species, the Californian isolates represent a separate subspecies, for which the name C. pinnipediorum subsp. pinnipediorum subsp. nov. is proposed. The type strain for both this novel species and subspecies is RM17260T (=LMG 29472T=CCUG 69570T). The Scottish isolates represent another subspecies, for which the name C. pinnipediorum subsp. caledonicus subsp. nov. is proposed. The type strain of this subspecies is M302/10/6T (=LMG 29473T=CCUG 68650T). PMID- 28629509 TI - Actinomyces vulturis sp. nov., isolated from Gyps himalayensis. AB - Two strains of Gram-stain-positive, facultatively anaerobic, non-spore-forming short rods (VUL7T and VUL8) were isolated from rectal swabs of Old World vultures, namely Gyps himalayensis, in Tibet-Qinghai Plateau, China. Optimal growth occurred at 37 degrees C, pH 6-7, with 1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences classified the two strains to the genus Actinomyces, with highest 16S rRNA gene sequence similarity (95 %) to type strains of Actinomyces haliotis, Actinomyces radicidentis and Actinomyces urogenitalis. The major cellular fatty acids were C18 : 1omega9c and C16 : 0. MK 10(H4) was the major respiratory quinone. The genomic DNA G+C content of the isolate was 54.4 mol%. DNA-DNA hybridization values with the most closely related species ofthe genusActinomyces was 24.6 %. The two strains can be differentiated from the most closely related species such as A. haliotis, A. radicidentis, A. graevenitzii and A. urogenitalis by a list of carbohydrate fermentations and enzyme activities. On the basis of physiological, biochemical and phylogenetic analysis, strains VUL7T and VUL8 represent novel species of the genus Actinomyces, for which the name Actinomyces vulturis sp. nov. is proposed. The type strain is VUL7T (=CGMCC 4.7366T=DSM 103437T). PMID- 28629510 TI - Screening strategies for atrial fibrillation: a systematic review and cost effectiveness analysis. AB - BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia that increases the risk of thromboembolic events. Anticoagulation therapy to prevent AF-related stroke has been shown to be cost-effective. A national screening programme for AF may prevent AF-related events, but would involve a substantial investment of NHS resources. OBJECTIVES: To conduct a systematic review of the diagnostic test accuracy (DTA) of screening tests for AF, update a systematic review of comparative studies evaluating screening strategies for AF, develop an economic model to compare the cost-effectiveness of different screening strategies and review observational studies of AF screening to provide inputs to the model. DESIGN: Systematic review, meta-analysis and cost-effectiveness analysis. SETTING: Primary care. PARTICIPANTS: Adults. INTERVENTION: Screening strategies, defined by screening test, age at initial and final screens, screening interval and format of screening {systematic opportunistic screening [individuals offered screening if they consult with their general practitioner (GP)] or systematic population screening (when all eligible individuals are invited to screening)}. MAIN OUTCOME MEASURES: Sensitivity, specificity and diagnostic odds ratios; the odds ratio of detecting new AF cases compared with no screening; and the mean incremental net benefit compared with no screening. REVIEW METHODS: Two reviewers screened the search results, extracted data and assessed the risk of bias. A DTA meta-analysis was perfomed, and a decision tree and Markov model was used to evaluate the cost-effectiveness of the screening strategies. RESULTS: Diagnostic test accuracy depended on the screening test and how it was interpreted. In general, the screening tests identified in our review had high sensitivity (> 0.9). Systematic population and systematic opportunistic screening strategies were found to be similarly effective, with an estimated 170 individuals needed to be screened to detect one additional AF case compared with no screening. Systematic opportunistic screening was more likely to be cost effective than systematic population screening, as long as the uptake of opportunistic screening observed in randomised controlled trials translates to practice. Modified blood pressure monitors, photoplethysmography or nurse pulse palpation were more likely to be cost-effective than other screening tests. A screening strategy with an initial screening age of 65 years and repeated screens every 5 years until age 80 years was likely to be cost-effective, provided that compliance with treatment does not decline with increasing age. CONCLUSIONS: A national screening programme for AF is likely to represent a cost-effective use of resources. Systematic opportunistic screening is more likely to be cost effective than systematic population screening. Nurse pulse palpation or modified blood pressure monitors would be appropriate screening tests, with confirmation by diagnostic 12-lead electrocardiography interpreted by a trained GP, with referral to a specialist in the case of an unclear diagnosis. Implementation strategies to operationalise uptake of systematic opportunistic screening in primary care should accompany any screening recommendations. LIMITATIONS: Many inputs for the economic model relied on a single trial [the Screening for Atrial Fibrillation in the Elderly (SAFE) study] and DTA results were based on a few studies at high risk of bias/of low applicability. FUTURE WORK: Comparative studies measuring long-term outcomes of screening strategies and DTA studies for new, emerging technologies and to replicate the results for photoplethysmography and GP interpretation of 12-lead electrocardiography in a screening population. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013739. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28629512 TI - Erythropoietin Receptor Structural Domains. AB - Erythropoietin (EPO) is a hormone that is important for regulating red blood cell production. It is functional through binding to its receptor-EpoR. EpoR is a single-span membrane protein. It contains an extracellular region, a transmembrane domain, and a C-terminus. The extracellular region is important for binding to EPO, and its conformation is critical for signal transduction. The transmembrane domain contains 21 residues forming a helix which plays an important role in transferring ligand-induced conformational changes of the extracellular domain across the cell membrane. The C-terminal region contains the Janus kinase 2-binding sites and eight tyrosine residues that can be phosphorylated to become binding sites for transcription factors to active the downstream pathways. This chapter focuses on structural description of the domains of the EpoR. The recent progress in the structural determination of these domains is summarized, which will be useful for understanding their function in signal transduction. PMID- 28629511 TI - Microbiota regulates visceral pain in the mouse. AB - The perception of visceral pain is a complex process involving the spinal cord and higher order brain structures. Increasing evidence implicates the gut microbiota as a key regulator of brain and behavior, yet it remains to be determined if gut bacteria play a role in visceral sensitivity. We used germ-free mice (GF) to assess visceral sensitivity, spinal cord gene expression and pain related brain structures. GF mice displayed visceral hypersensitivity accompanied by increases in Toll-like receptor and cytokine gene expression in the spinal cord, which were normalized by postnatal colonization with microbiota from conventionally colonized (CC). In GF mice, the volumes of the anterior cingulate cortex (ACC) and periaqueductal grey, areas involved in pain processing, were decreased and enlarged, respectively, and dendritic changes in the ACC were evident. These findings indicate that the gut microbiota is required for the normal visceral pain sensation. PMID- 28629513 TI - Erythropoietin and Hypothalamic-Pituitary Axis. AB - Erythropoietin (EPO), known primarily for its erythropoietic activity, is commonly used clinically to treat anemia of chronic kidney disease. However, the expression of EPO receptor (EpoR) beyond erythroid tissue provides for potential extrahematopoietic effects of EPO, including EPO regulation of metabolic homeostasis (Zhang et al., 2014). Small clinical studies have shown that EPO treatment in patients with end-stage renal disease improved glycemic control and insulin sensitivity. Studies in animal models have shown that EPO regulation of metabolism is mainly attributed to its response in fat, and the hypothalamus pituitary axis (Dey et al., 2016; Dey, Scullen, & Noguchi, 2015; Teng, Gavrilova, et al., 2011; Wang et al., 2013) and is not dependent on its hematopoietic activity. EpoR expression in the hypothalamus is localized to the neurons expressing proopiomelanocortin (POMC) in the arcuate nucleus region, the most important site in the brain for the regulation of physiological energy expenditure. EPO treatment increases POMC production in anorexigenic POMC neurons in the hypothalamus. In the pituitary, EPO modulates the secretion of the POMC derived peptide, adrenocorticotropic hormone (ACTH) that regulates physiological and metabolic stress response. With EPO produced by cells in the brain, such as astrocytes, and with EPO-stimulated POMC expression in the hypothalamus and EPO inhibited ACTH secretion in the pituitary, EPO signaling contributes to the hypothalamic-pituitary axis as a major regulator of glucose metabolism and energy homeostasis. PMID- 28629514 TI - Erythropoietin-Mediated Regulation of Central Respiratory Command. AB - Erythropoietin (Epo) is a cytokine expressed throughout the body, including in the central nervous system where it can act as a breathing modulator in the central respiratory network. In vitro, Epo allows maintaining the activity of respiratory neurons during acute hypoxia, resulting in inhibition of the hypoxia induced rhythm depression. In vivo, Epo action on the central respiratory command results in enhancement of the acute hypoxic ventilatory response, allowing a better oxygenation of the body by improvement of gases exchanges in the lungs. Importantly, this effect of Epo is age-dependent, being observed at adulthood and at both early and late postnatal ages, but not at middle postnatal ages, when an important setup of the central respiratory command occurs. Epo regulation of the central respiratory command involves at least two intracellular signaling pathways, PI3K-Akt and MEK-ERK pathways. However, the exact mechanism underlying the action of Epo on the central respiratory control remains to be deciphered, as well as the exact cell types and nuclei involved in this control. Epo-mediated effect on the central respiratory command is regulated by several factors, including hypoxia, sex hormones, and an endogen antagonist. Although more knowledge is needed before reaching the clinical trial step, Epo seems to be a promising therapeutic treatment, notably against newborn breathing disorders. PMID- 28629515 TI - Mutual Cross Talk Between Iron Homeostasis and Erythropoiesis. AB - Iron is necessary for physiological processes essential for the activity of all cells, but the erythropoietic compartment is a privileged iron consumer. In fact, a considerable amount of iron is daily required for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The iron needed for hemoglobin synthesis is mainly ensured by inhibiting hepcidin expression, thereby increasing both ferroportin mediated iron export from the duodenal absorptive cells and iron release from the reticuloendothelial cells that process old and/or damaged red blood cells. This mechanism makes certain that sufficient iron availability to the erythropoietic compartment occurs. Recent studies established that hypoxia and/or hypoxia induced erythropoietin are not direct regulators of hepcidin, which is indirectly inhibited by erythropoietic drive, in particular under pathological conditions characterized by expanded but ineffective erythropoiesis, such as beta thalassemia. Among the number of factors proposed as mediators linking erythropoiesis with liver hepcidin suppression, erythroferrone, a hormone produced and secreted by erythroid precursors, appears the best candidate. PMID- 28629516 TI - Context-Dependent Skeletal Effects of Erythropoietin. AB - Erythropoietin (Epo) is the main hormone that regulates the production of red blood cells (hematopoiesis), by stimulating their progenitors. Beyond this vital function, several emerging roles have been noted for Epo in other tissues, including neurons, heart, and retina. The skeletal system is also affected by Epo; however, its actions on bone are, as yet, controversial. Here, we review the seemingly contradicting evidence regarding Epo effects on bone remodeling. We also discuss the evidence pointing to a direct vs indirect effect of Epo on the osteoblastic and osteoclastic cell lineages. The current controversy may derive from a context-dependent mode of function of Epo, namely, opposite skeletal actions during bone regeneration and steady-state bone remodeling. Differences in conclusions deriving from the published in vitro studies may thus relate to the different experimental conditions. Taken together, the current state-of-the-art indicates definite Epo effects on bone cells and points to the complexity of the mode of function. PMID- 28629517 TI - Erythropoietin-Mediated Neuroprotection in Insects Suggests a Prevertebrate Evolution of Erythropoietin-Like Signaling. AB - The cytokine erythropoietin (Epo) mediates protective and regenerative functions in mammalian nervous systems via activation of poorly characterized receptors that differ from the "classical" homodimeric Epo receptor expressed on erythroid progenitor cells. Epo genes have been identified in vertebrate species ranging from human to fish, suggesting that Epo signaling evolved earlier than the vertebrate lineage. Studies on insects (Locusta migratoria, Chorthippus biguttulus, Tribolium castaneum) revealed Epo-mediated neuroprotection and neuroregeneration. Recombinant human Epo (rhEpo) prevents apoptosis by binding to a janus kinase-associated receptor, stimulation of STAT transcription factors, and generation of factors that prevent the activation of proapoptotic caspases. Insect neurons were also protected by a neuroprotective but nonerythropoietic Epo splice variant, suggesting similarity with mammalian neuroprotective but not with homodimeric "classical" Epo receptors. Additionally, rhEpo promotes the regeneration of neurites in primary cultured insect brain neurons and after nerve crush in an in vivo preparation. In contrast to neuroprotective and regenerative effects shared with mammalian species, no evidence for a role of Epo signaling in the regulation of neuro- or gliogenesis was found in insects. Similar structural and functional characteristics of the Epo binding receptors, partly shared transduction pathways that prevent apoptosis and the functional implication in neuroprotective and neuroregenerative processes in both mammalian and insect species, suggest that Epo-like signaling was already established in their last common ancestor. Originally functioning as a tissue-protective response to unfavorable physiological situations, cell injury, and pathogen invasion, Epo was later adapted as a humoral regulator of erythropoiesis in the vertebrate lineage. PMID- 28629518 TI - Analysis of the Asymmetry of Activated EPO Receptor Enables Designing Small Molecule Agonists. AB - Amgen solved the high-resolution cocrystal structure of erythropoietin (EPO) bound to the extracellular part of the receptor (EPOR) in 1998, which reveals that the EPO-EPOR interaction surface is formed by 11 salt bridges, 17 H-bonds, and 2 hydrophobic clusters centered at a pair of crucial phenylalanines (F93). The EPOR has two domains, one that penetrates the membrane and a second extracellular domain that forms one arm of the binding site for the EPO ligand. The complete competent receptor-binding site is a homodimer of EPOR with the two arms forming a funnel-shaped cup where EPO binds. The two binding arms of the EPOR dimer meet at the membrane at a 120 degree angle, which Amgen characterizes as, "erythropoietin imposes a unique angular relationship and orientation that is responsible for optimal signaling." They come to this conclusion, because the EPOR cocrystallized with 2 equivalents of a 20 residue EPO mimetic peptide created at Robert Wood Johnson (RWJ) activates the receptor with a 3 order of magnitude reduction in potency, and the binding arms are forced to meet at the membrane with an angle of 180 degrees. The vast interaction surface between EPO and EPOR forms a singularly important three-dimensional structure responsible for hematopoietic stem cell proliferation and differentiation-this is Amgen's conclusion. This goal of this work is to present experimental and computational evidence that the Amgen structure is a postsignaling off-state and that the RWJ structure with the partially active peptide mimetics is an on-state. A detailed side-by-side comparison of the two structures will be presented along with literature evidence that calls into question the Amgen claim that their structure is a unique on-state. A computational fragment-based drug discovery method applied to the RWJ structure was used to locate and characterize a new predicted small molecule binding site and a fragment analysis was performed based on theories of asymmetry to create a proposed agonist with MW<300. When this molecule was experimentally tested, it displaced radiolabeled EPO with nanomolar potency and transformed human hematopoietic stem cells into red blood cells with subnanomolar potency. Obviously, this small molecule makes none of the EPO-EPOR interactions that Amgen stated were essential for fully turning on the receptor and provides strong evidence that stabilizing receptor asymmetry, not specific interactions, is the critical factor needed for activating signal transduction. Finally, when the agonist was altered to remove the asymmetric component, it still was able to displace radiolabeled EPO in competition binding experiments, but it no longer activated the receptor. PMID- 28629519 TI - Erythropoietin: Endogenous Protection of Ischemic Brain. AB - The human brain requires uninterrupted delivery of blood-borne oxygen and nutrients to sustain its function. Focal ischemia, particularly, ischemic stroke, and global ischemia imposed by cardiac arrest disrupt the brain's fuel supply. The resultant ATP depletion initiates a complex injury cascade encompassing intracellular Ca2+ overload, glutamate excitotoxicity, oxido-nitrosative stress, extracellular matrix degradation, and inflammation, culminating in neuronal and astroglial necrosis and apoptosis, neurocognitive deficits, and even death. Unfortunately, brain ischemia has proven refractory to pharmacological intervention. Many promising treatments afforded brain protection in animal models of focal and global ischemia, but failed to improve survival and neurocognitive recovery of stroke and cardiac arrest patients in randomized clinical trials. The culprits are the blood-brain barrier (BBB) that limits transferral of medications to the brain parenchyma, and the sheer complexity of the injury cascade, which presents a daunting array of targets unlikely to respond to monotherapies. Erythropoietin is a powerful neuroprotectant capable of interrupting multiple aspects of the brain injury cascade. Preclinical research demonstrates erythropoietin's ability to suppress glutamate excitotoxicity and intracellular Ca2+ overload, dampen oxidative stress and inflammation, interrupt the apoptotic cascade, and preserve BBB integrity. However, the erythropoietin dosages required to traverse the BBB and achieve therapeutically effective concentrations in the brain parenchyma impose untoward side effects. Recent discoveries that hypoxia induces erythropoietin production within the brain and that neurons, astroglia, and cerebrovascular endothelium harbor membrane erythropoietin receptors, raise the exciting prospect of harnessing endogenous erythropoietin to protect the brain from the ravages of ischemia-reperfusion. PMID- 28629520 TI - The Erythropoietin System Protects the Heart Upon Injury by Cardiac Progenitor Cell Activation. AB - Erythropoietin (EPO) is a growth hormone, widely known for its role in erythropoiesis. The broad expression of erythropoietin receptor (EPOR) in adult organs suggested that EPO may also affect other cells besides late erythroid progenitors. In the embryonic heart, EPOR is expressed in all cells including the immature proliferating cardiomyocytes. In contrast to the embryonic heart in adulthood, EPOR expression is decreased and mainly detected in immature proliferating cells (i.e., resident cardiac progenitor cells) rather than in terminally differentiated cells (i.e., cardiomyocytes). Since cardiac progenitor cells are considered a regenerative cell source upon cardiac injury, the protective action of the EPO system was tested by creating an erythroid-rescued EPOR knockout mouse model. Although these mice appear to have less immature proliferating myocytes during embryogenesis, they reach adulthood without apparent morphological defects. However, upon ischemia reperfusion, these animals show a greater infarct size, suggesting that the EPO/EPOR protects the heart upon injury. Indeed preclinical studies showed that EPO administration postinfarction improves cardiac function via neoangiogenesis, antiapoptotic mechanisms, and/or CPC activation. Despite the promising preclinical data, large cohort clinical studies in humans failed to show a significant amelioration in cardiac function upon systemic injection of EPO in patients with myocardial infarctions. The discrepancy between preclinical and clinical trials may be due to differences between the doses, the way of delivery, the homogeneity of the cohorts, and last but not least the species differences. These data pinpoint the importance of carrying out preclinical studies in human models of disease as engineered human cardiac tissue that will provide a better understanding of the expression pattern of EPOR and the role of its ligand in human cardiac cells. Such studies may be able to bridge the gap between preclinical rodent data and human clinical trials and thus lead to the design of more successful clinical studies. PMID- 28629521 TI - Erythropoietin Promotes Glioblastoma via miR-451 Suppression. AB - Erythropoietin (EPO) is an erythropoiesis stimulating growth factor and hormone. EPO has been widely used in the treatment of chronic renal failure, cancer, and chemotherapy-related anemia for three decades. However, many clinical trials showed that EPO treatment may be associated with tumorigenesis and cancer progression. EPO is able to cross blood-brain barriers, and this may lead to an increased possibility of central nervous system tumors such as glioblastoma. Indeed, EPO promotes glioblastoma growth and invasion in animal studies. Additionally, EPO increases glioblastoma cell survival, proliferation, migration, invasion, and chemoresistancy in vitro. However, the exact mechanisms of cancer progression induced by EPO treatment are not fully understood. Posttranscriptional gene regulation through microRNAs may contribute to EPO's cellular and biological effects in tumor progression. Here, we aimed to study whether tumor suppressive microRNA, miR-451, counteracts the positive effects of EPO on U87 human glioblastoma cell line. Migration and invasion were evaluated by scratch assay and transwell invasion assay, respectively. We found that EPO decreased basal miR-451 expression and increased cell proliferation, migration, invasion, and cisplatin chemoresistancy in vitro. miR-451 overexpression by transfection of its mimic significantly reversed these effects. Furthermore, ectopic expression of miR-451 inhibited expression of its own target genes, such as metalloproteinases-2 and -9, which are stimulated by EPO treatment and involved in carcinogenesis processes, especially invasion. These findings suggest that miR-451 mimic delivery may be useful as adjuvant therapy in addition to chemotherapy and anemia treatment by EPO and should be tested in experimental glioblastoma models. PMID- 28629522 TI - Erythropoietin, Stem Cell Factor, and Cancer Cell Migration. AB - Cell migration of normal cells is tightly regulated. However, tumor cells are exposed to a modified microenvironment that promotes cell migration. Invasive migration of tumor cells is stimulated by receptor tyrosine kinases (RTKs) and is regulated by growth factors. Erythropoietin (Epo) is a glycoprotein hormone that regulates erythropoiesis and is also known to be a potent chemotactic agent that induces cell migration by binding to its receptor (EpoR). Expression of EpoR has been documented in tumor cells, and the potential of Epo to induce cell migration has been explored. Stem cell factor (SCF) is a cytokine that synergizes the effects of Epo during erythropoiesis. SCF is the ligand of c-Kit, a member of the RTKs family. Molecular activity of RTKs is a primary stimulus of cell motility. Thus, expression of the SCF/c-Kit axis is associated with cell migration. In this chapter, we summarize data describing the potential effect of Epo/EpoR and SCF/c Kit as promoters of cancer cell migration. We also integrate recent findings on molecular mechanisms of Epo/EpoR- and SCF/c-Kit-mediated migration described in various cancer models. PMID- 28629523 TI - Significance of Erythropoietin Receptor Antagonist EMP9 in Cancers. AB - We have clarified that cancer cells express their own erythropoietin (Epo) and its receptor (EpoR) mRNA levels, and the respective proteins, which are under the control of Epo-EpoR signaling. Then we explored to inhibit the Epo-EpoR signaling with an EpoR antagonist Epo mimetic peptide 9 (EMP9) that is a derivative of an Epo-mimicking peptide EMP1. In the study of the cancer cell lines in vitro, rhEpo accelerated the cancer cell growth, whereas the EMP9 inhibited the cell growth along with the inhibition of STAT5 tyrosine phosphorylation. Moreover, in vitro study of surgically resected histoculture of lung cancers revealed that EMP9 diminishes the expression of myoglobin in the cancer cells and destroys the feeding vessels. Additionally, in the xenografts of lung cancer histoculture, the EMP9 destroyed the xenografts by inducing apoptosis and suppressing proliferation of cancer cells in concomitant with macrophage accumulation. Furthermore, two types of perforations were detected in their cytoplasm: the one is mediated by nNOS in the cancer cells and the other one is by iNOS in the innate immune cells. These findings suggest that the inhibition of the Epo-EpoR signaling by EMP9 induces the cancer cell death that is mediated by the apoptosis and calcification of the cancer cells as well as the oxygen deficiency through the feeding vessels. Taken together, EMP9-based therapy may be a promising strategy to treat cancer patients. PMID- 28629524 TI - Endogenous Erythropoietin. AB - We sought to briefly describe current models of endogenous erythropoietin (EPO) pleiotropic properties to make four points clear. First, endogenous EPO regulates erythroid cell apoptosis so that red blood cell production is balanced against the number of cells destroyed in order to maintain optimal tissue oxygen levels (i.e., consistent with provision of homeostatic functional signaling information). Second, preclinical and clinical studies alike provide additional evidence of other (i.e., extraerythropoietic) immune-related and growth/trophic properties. Third, EPO might also be increased as an antiinflammatory response to other proinflammatory cytokines, and not because it is an inflammatory protein, in which case, it would make the association between EPO and these other proteins an epiphenomenon. Fourth, on the other hand, EPO might also act as a tissue protector or it could reflect immaturity/vulnerability of the brain or of the systems responsible for protecting it. Each of these scenarios is plausible, and all are probably true in certain circumstances. PMID- 28629525 TI - Erythropoietin Regulation by Angiotensin II. AB - The renin-angiotensin system (RAS) is a key regulator of blood pressure and blood volume homeostasis. The RAS is primarily comprised of the precursor protein angiotensinogen and the two proteases, renin and angiotensin-converting enzyme (ACE). Angiotensin I (Ang I) is derived from angiotensinogen by renin, but appears to have no biological activity. In contrast, angiotensin II (Ang II) that has a variety of biological functions in the cells is converted from Ang I through removal of two-C-terminal residues by ACE. The physiological effects of Ang II are due to Ang II signaling through specific receptor binding, resulting in muscle contraction leading to increased blood pressure and volume. To modulate RAS, three classes of drugs have been developed: (1) renin inhibitors to prevent angiotensinogen conversion to Ang I, (2) ACE inhibitors, to prevent Ang I processing to Ang II and (3) angiotensin receptor blockers, to inhibit Ang II signaling through its receptor. Studies using the RAS inhibitors and Ang II demonstrated that RAS signaling mediates actions of Ang II in the regulation of proliferation and differentiation of specific hematopoietic cell types, especially in the red blood cell lineage. Accumulating evidence indicates that RAS regulates EPO, an essential mediator of red cell production, for human anemia and erythropoiesis in vivo and in vitro. The regulation of EPO expression by Ang II may be responsible for maintaining red blood cell homeostasis. This review highlights the biological roles of RAS for blood cell and EPO homeostasis through Ang II signaling. The molecular mechanism for Ang II-induced EPO production of the cell or tissue type-specific expression is discussed. PMID- 28629526 TI - Erythropoietin Receptor Signaling and Lipid Rafts. AB - Erythropoiesis is tightly regulated by the growth factor erythropoietin (Epo). Signal activation begins when Epo engages its cognate receptor, Epo-R, triggering receptor homodimerization, and recruitment of signaling intermediates including Jak2 that phosphorylates both the receptor cytoplasmic tail and downstream effectors including the transcription factor, STAT5. Transcription factors subsequently activate transcription of prosurvival and prodifferentiation genes responsible for red blood cell production. The fidelity of Epo-R signaling is dependent upon residence within detergent insoluble membrane lipid raft fractions. Lipid rafts are membrane microdomains that serve as signaling scaffolds composed of densely packed sphingolipids and cholesterol where receptors and intermediate signaling proteins are recruited and interact to execute stimuli. Disruption of lipid rafts is detrimental to Epo signaling, a phenomenon that may be utilized to design novel therapeutics for conditions in which Epo signaling is deficient. Here, we review the Epo signaling cascade, particularly, as it relates to localization and dependence on lipid rafts, and discuss considerations for novel therapeutic design. PMID- 28629527 TI - Preface. PMID- 28629528 TI - Foreword. PMID- 28629529 TI - A brief introduction to early forms of non-verbal social cognition. PMID- 28629530 TI - Novel natural product therapeutics targeting both inflammation and cancer. AB - Inflammation is recently recognized as one of the hallmarks of human cancer. Chronic inflammatory response plays a critical role in cancer development, progression, metastasis, and resistance to chemotherapy. Conversely, the oncogenic aberrations also generate an inflammatory microenvironment, enabling the development and progression of cancer. The molecular mechanisms of action that are responsible for inflammatory cancer and cancer-associated inflammation are not fully understood due to the complex crosstalk between oncogenic and pro inflammatory genes. However, molecular mediators that regulate both inflammation and cancer, such as NF-kappaB and STAT have been considered as promising targets for preventing and treating these diseases. Recent works have further demonstrated an important role of oncogenes (e.g., NFAT1, MDM2) and tumor suppressor genes (e.g., p53) in cancer-related inflammation. Natural products that target these molecular mediators have shown anticancer and anti-inflammatory activities in preclinical and clinical studies. Sesquiterpenoids (STs), a class of novel plant-derived secondary metabolites have attracted great interest in recent years because of their diversity in chemical structures and pharmacological activities. At present, we and other investigators have found that dimeric sesquiterpenoids (DSTs) may exert enhanced activity and binding affinity to molecular targets due to the increased number of alkylating centers and improved conformational flexibility and lipophilicity. Here, we focus our discussion on the activities and mechanisms of action of STs and DSTs in treating inflammation and cancer as well as their structure-activity relationships. PMID- 28629531 TI - Survey of traditional Dai medicine reveals species confusion and potential safety concerns: a case study on Radix Clerodendri Japonicum. AB - The adulteration of herbal products is a threat to consumer safety. In the present study, we surveyed the species composition of commercial Radix Clerodendri Japonicum products using DNA barcoding as a supervisory method. A reference database for plant-material DNA-barcode was successfully constructed with 48 voucher samples from 12 Clerodendrum species. The database was used to identify 27 Radix Clerodendri Japonicum decoction piece samples purchased from drug stores and hospitals. The DNA sequencing results revealed that only 1 decoction piece (3.70%) was authentic C. japonicum, as recorded in the Dai Pharmacopeia, whereas the other samples were all adulterants, indicating a potential safety issue. The results indicate that decoction pieces that are available in the market have complex origins and that DNA barcoding is a suitable tool for regulation of Dai medicines. PMID- 28629532 TI - Hypaconitine inhibits TGF-beta1-induced epithelial-mesenchymal transition and suppresses adhesion, migration, and invasion of lung cancer A549 cells. AB - Epithelial-mesenchymal transition (EMT) has been implicated in tumor invasion and metastasis and provides novel strategies for cancer therapy. Hypaconitine (HpA), a diester-diterpenoid alkaloid isolated from the root of the Aconitum species, exhibits anti-inflammatory, analgesic, and especially, cardiotoxic activities. Here, we reported the anti-metastatic potentials of HpA in transforming growth factor-beta1 (TGF-beta1)-induced EMT in lung cancer A549 cells. The cytotoxic effect of HpA was determined by MTT assay. A549 cells were treated with TGF-beta1 with or without HpA co-treatment, and the morphological alterations were observed with a microscopy. The expression of E-cadherin, N-cadherin, and NF-kappaB was determined by both Western blotting and immunofluorescence analyses. The adhesion, migration, and invasion were detected with Matrigel, wound-healing, and transwell assays, respectively. The expression of Snail was determined by Western blotting. The expression of NF-kappaB p65, IkappaBalpha, and p-IkappaBalpha in nuclear and cytosolic extracts was assessed by Western blotting. The results showed that low concentration of HpA (<16 MUmol.L-1) had no obvious cytotoxicity to A549 cells. Morphologically, TGF-beta1 treatment induced spindle-shaped alteration in the cells. The upregulation of N-cadherin, NF-kappaB, and Snail and the downregulation of E-cadherin were detected after TGF-beta1 treatment. The adhesion, migration and invasion abilities were also increased by TGF-beta1. Besides, TGF-beta1 induced expression of Snail in a time-dependent manner. Furthermore, TGF-beta1 induced nuclear translocation of NF-kappaB p65. All these alterations were dramatically inhibited by HpA co-treatment. In addition, the NF kappaB inhibitor PDTC showed similar inhibitory effect. In conclusion, these results showed that HpA inhibited TGF-beta1-induced EMT in A549 cells, which was possibly mediated by the inactivation of the NF-kappaB signaling pathway, providing an evidence for anti-cancer effect of HpA. PMID- 28629533 TI - Design of new traditional Chinese medicine herbal formulae for treatment of type 2 diabetes mellitus based on network pharmacology. AB - In the present study, 28 Chinese medicinal herbs belonging to traditional Chinese medicine (TCM) for the treatment of type 2 diabetes were selected to explore the application of network pharmacology in developing new Chinese herbal medicine formulae for the treatment of type 2 diabetes mellitus (T2DM). These herbs have the highest appearance rate in the literature, and their compounds are listed. The human protein-protein interaction network and the T2DM disease protein interaction network were constructed. Then, the related algorithm for network topology was used to perform interventions on the interaction network of disease proteins and normal human proteins to test different Chinese herbal medicine compound combinations, according to the information on the interaction of compounds-targets in two databases, namely TarNet and the Medicinal Plants Database. Results of the intervention scores indicate that the method proposed in this study can provide new effective combinations of Chinese herbal medicines for T2DM. Network pharmacology can effectively promote the modernization and development of TCM. PMID- 28629534 TI - Heparin-derived oligosaccharide inhibits vascular intimal hyperplasia in balloon injured carotid artery. AB - The aims of the present study were to determine the effects of heparin-derived oligosaccharides (HDOs) on vascular intimal hyperplasia (IH) in balloon-injured carotid artery and to elucidate the underlying mechanisms of action. An animal model was established by rubbing the endothelia within the common carotid artery (CCA) in male rabbits. The rabbits were fed a high-cholesterol diet. Arterial IH was determined by histopathological changes to the CCA. Serum lipids were detected using an automated biochemical analysis. Expressions of mRNAs for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), scavenger receptor class B type I (SR-BI), and ATP-binding cassette transporter A1 (ABCA-1) were analyzed using reverse transcription polymerase chain reaction assays. Expressions of VEGF, VCAM-1, MCP-1, SR-BI and ABCA-1 proteins were analyzed by Western blotting. Enzyme-linked immunosorbent assays were used to quantify expression levels of VEGF and bFGF. Our results showed that administration of HDO significantly inhibited CCA histopathology and restenosis induced by balloon injury. The treatment with HDOs significantly decreased the mRNA and protein expression levels of VEGF, bFGF, VCAM-1, MCP-1, and SR-BI in the arterial wall; however, ABCA-1 expression level was elevated. HDO treatment led to a reduction in serum lipids (total cholesterol, triglycerides, high-density and low-density lipoproteins). Our results from the rabbit model indicated that HDOs could ameliorate IH and underlying mechanism might involve VEGF, bFGF, VCAM 1, MCP-1, SR-BI, and ABCA-1. PMID- 28629535 TI - Enhanced absorption and inhibited metabolism of emodin by 2, 3, 5, 4' tetrahydroxystilbene-2-O-beta-D-glucopyranoside: Possible mechanisms for Polygoni Multiflori Radix-induced liver injury. AB - Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. However, PMR-associated hepatotoxicity is becoming a safety issue. In our previous in vivo study, an interaction between stilbenes and anthraquinones has been discovered and a hypothesis is proposed that the interaction between stilbene glucoside-enriching fraction and emodin may contribute to the side effects of PMR. To further support our previous in vivo results in rats, the present in vitro study was designed to evaluate the effects of 2, 3, 5, 4' tetrahydroxystilbene-2-O-beta-D-glucopyranoside (TSG) on the cellular absorption and human liver microsome metabolism of emodin. The obtained results indicated that the absorption of emodin in Caco-2 cells was enhanced and the metabolism of emodin in human liver microsomes was inhibited after TSG treatment. The effects of the transport inhibitors on the cellular emodin accumulation were also examined. Western blot assay suggested that the depressed metabolism of emodin could be attributed to the down-regulation of UDP-glucuronosyltransferases (UGTs) 1A8, 1A10, and 2B7. These findings definitively demonstrated the existence of interaction between TSG and emodin, which provide a basis for a better understanding of the underlying mechanism for PMR-induced liver injury. PMID- 28629536 TI - Two new diterpenoid lactones isolated from Andrographis paniculata. AB - In the present study, two new diterpenoid lactones, 3-deoxy-andrographoside (1) and 14-deoxy-15-methoxy-andrographolide (2), were isolated from the aerial parts of Andrographis paniculata. Their structures were elucidated by combination of NMR, MS, and chemical methods. The configurations of 1 and 2 were established based on the analysis of ROESY data and single crystal X-ray diffraction experiment. PMID- 28629537 TI - Triterpenoid saponins from the roots of Cyathula officinalis and their inhibitory effects on nitric oxide production. AB - The present study was designed to investigate the chemical constituents of the roots of Cyathula officinalis. Compounds were isolated by silica gel, Sephadex LH 20, ODS column chromatography, and preparative HPLC. Their structures were determined on the basis of 1D and 2D NMR techniques, mass spectrometry, and chemical methods. One new oleanane-type triterpenoid saponin, 28-O-[alpha-L rhamnopyranosyl-(1->3)-beta-D-glucuronopyranosyl-(1->3)-beta-D-glucopyranosyl] hederagenin (1), was isolated from the roots of Cyathula officinalis. The anti inflammatory activities of the isolates were evaluated for their inhibitory effects against LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages cells. Compounds 2, 4, and 6 exhibited moderate anti-inflammatory activities. PMID- 28629538 TI - Bioassay-guided isolation of saikosaponins with agonistic activity on 5 hydroxytryptamine 2C receptor from Bupleurum chinense and their potential use for the treatment of obesity. AB - 5-Hydroxytryptamine 2C (5-HT2C) receptor is one of the major targets of anti obesity agents, due to its role in regulation of appetite. In the present study, the 70% EtOH extract of the roots of Bupleurum chinense was revealed to have agonistic activity on 5-HT2C receptor, and the subsequent bioassay-guided isolation led to identification of several saikosaponins as the active constituents with 5-HT2C receptor agonistic activity in vitro and anti-obesity activity in vivo. The new compound, 22-oxosaikosaponin d (1), was determined by extensive spectroscopic analyses (HR-ESI-MS, IR, and 1D and 2D NMR). The primary structure-activity relationship study suggested that the intramolecular ether bond between C-13 and C-28 and the number of sugars at C-3 position were closely related to the 5-HT2C receptor agonistic activity. Saikosaponin a (3), the main saponin in B. chinense, showed obviously agonistic activity on 5-HT2C receptor with an EC50 value of 21.08 +/- 0.33 MUmol.L-1in vitro and could reduce food intake by 39.1% and 69.2%, and weight gain by 13.6% and 16.4%, respectively, at 3.0 and 6.0 mg.kg-1in vivo. This investigation provided valuable information for the potential use of B. chinense as anti-obesity agent. PMID- 28629539 TI - UPLC/ESI-QTOF-MS-based metabolomics survey on the toxicity of triptolide and detoxication of licorice. AB - Triptolide (TP) from Tripterygium wilfordii has been demonstrated to possess anti inflammatory, immunosuppressive, and anticancer activities. TP is specially used for the treatment of awkward rheumatoid arthritis, but its clinical application is confined by intense side effects. It is reported that licorice can obviously reduce the toxicity of TP, but the detailed mechanisms involved have not been comprehensively investigated. The current study aimed to explore metabolomics characteristics of the toxic reaction induced by TP and the intervention effect of licorice water extraction (LWE) against such toxicity. Obtained urine samples from control, TP and TP + LWE treated rats were analyzed by UPLC/ESI-QTOF-MS. The metabolic profiles of the control and the TP group were well differentiated by the principal component analysis and orthogonal partial least squares discriminant analysis. The toxicity of TP was demonstrated to be evolving along with the exposure time of TP. Eight potential biomarkers related to TP toxicity were successfully identified in urine samples. Furthermore, LWE treatment could attenuate the change in six of the eight identified biomarkers. Functional pathway analysis revealed that the alterations in these metabolites were associated with tryptophan, pantothenic acid, and porphyrin metabolism. Therefore, it was concluded that LWE demonstrated interventional effects on TP toxicity through regulation of tryptophan, pantothenic acid, and porphyrin metabolism pathways, which provided novel insights into the possible mechanisms of TP toxicity as well as the potential therapeutic effects of LWE against such toxicity. PMID- 28629540 TI - Kinetics and Dose Dependency of Intranasal Oxytocin Effects on Amygdala Reactivity. AB - BACKGROUND: Current neuroimaging perspectives on a variety of mental disorders emphasize dysfunction of the amygdala. The neuropeptide oxytocin (OXT), a key mediator in the regulation of social cognition and behavior, accumulates in cerebrospinal fluid after intranasal administration in macaques and humans and modulates amygdala reactivity in both species. However, the translation of neuromodulatory OXT effects to novel treatment approaches is hampered by the absence of studies defining the most effective dose and dose-response latency for targeting the amygdala. METHODS: To address this highly relevant issue, a total of 116 healthy men underwent functional magnetic resonance imaging using a randomized, double-blind, placebo-controlled crossover study design. The experimental rationale was to systematically vary dose-test latencies (15-40, 45 70, and 75-100 minutes) and doses of OXT (12, 24, and 48 international units) in order to identify the most robust effects on amygdala reactivity. During functional magnetic resonance imaging, subjects completed an emotional face recognition task including stimuli with varying intensities ranging from low (highly ambiguous) to high (less ambiguous). RESULTS: Our results indicate that the OXT-induced inhibition of amygdala responses to fear was most effective in a time window between 45 and 70 minutes after administration of a dose of 24 international units. Furthermore, the observed effect was most evident in subjects scoring high on measures of autistic-like traits. Behavioral response patterns suggest that OXT specifically reduced an emotional bias in the perception of ambiguous faces. CONCLUSIONS: These findings provide initial evidence of the most effective dose and dose-test interval for future experimental or therapeutic regimens aimed at targeting amygdala functioning using intranasal OXT administration. PMID- 28629542 TI - Nivolumab-Induced Granulomatous Inflammation of the Pleura. PMID- 28629543 TI - Mutation of MET Y1230 as an Acquired Mechanism of Crizotinib Resistance in NSCLC with MET Exon 14 Skipping. PMID- 28629544 TI - Continued Response to One Dose of Nivolumab Complicated by Myasthenic Crisis and Myositis. PMID- 28629541 TI - Stress and Loss of Adult Neurogenesis Differentially Reduce Hippocampal Volume. AB - BACKGROUND: Hippocampal volume loss is a hallmark of clinical depression. Chronic stress produces volume loss in the hippocampus in humans and atrophy of CA3 pyramidal cells and suppression of adult neurogenesis in rodents. METHODS: To investigate the relationship between decreased adult neurogenesis and stress induced changes in hippocampal structure and volume, we compared the effects of chronic unpredictable restraint stress and inhibition of neurogenesis in a rat pharmacogenetic model. RESULTS: Chronic unpredictable restraint stress over 4 weeks decreased total hippocampal volume, reflecting loss of volume in all hippocampal subfields and in both dorsal and ventral hippocampus. In contrast, complete inhibition of adult neurogenesis for 4 weeks led to volume reduction only in the dentate gyrus. With prolonged inhibition of neurogenesis for 8 or 16 weeks, volume loss spread to the CA3 region, but not CA1. Combining stress and inhibition of adult neurogenesis did not have additive effects on the magnitude of volume loss but did produce a volume reduction throughout the hippocampus. One month of chronic unpredictable restraint stress and inhibition of adult neurogenesis led to atrophy of pyramidal cell apical dendrites in dorsal CA3 and to neuronal reorganization in ventral CA3. Stress also significantly affected granule cell dendrites. CONCLUSIONS: The findings suggest that adult neurogenesis is required to maintain hippocampal volume but is not responsible for stress induced volume loss. PMID- 28629545 TI - EGFR and KRAS Mutations in Triple-Mutated Lung Cancer. PMID- 28629546 TI - Erlotinib Is Effective for Leptomeningeal Carcinomatosis due to Disease Flare after Osimertinib Treatment Failure. PMID- 28629547 TI - Coexistence of the BRAF Mutation and EGFR Exon 20 Insertion in a Patient with Lung Adenocarcinoma. PMID- 28629548 TI - A Case of a Patient with Idiopathic Pulmonary Fibrosis with Lung Squamous Cell Carcinoma Treated with Nivolumab. PMID- 28629549 TI - Intracranial and Systemic Response to Alectinib in a Patient with RET-KIF5B Oncogenic Fusion. PMID- 28629550 TI - A young man with several episodes of tachycardia. PMID- 28629551 TI - The who, how, and why of screening patients for atrial fibrillation: More questions than answers. PMID- 28629552 TI - Comparative Analysis of Four Scores to Stratify Patients With Heart Failure and Reduced Ejection Fraction. AB - There are several prognostic risk scores available for patients with heart failure with reduced ejection fraction (HFrEF) that can aid in the decision of listing candidates for heart transplant (HTx). A direct comparison between these scores has not been performed. Therefore, our objective was to evaluate the calibration and discriminative power of 4 contemporary HF scores. A retrospective analysis of 259 patients with HFrEF who underwent cardiopulmonary exercise test was conducted. The Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta-analysis Global Group in Chronic Heart Failure (MAGGIC), and Metabolic Exercise Cardiac Kidney Index (MECKI) were compared. During the first year, 7 deaths occurred (6 cardiovascular) and 25 patients were submitted to HTx (8 urgent). Over a 2-year period, 14 deaths occurred (10 cardiovascular) and 34 patients received an HTx (8 urgent). Calibration analysis showed that SHFM and HFSS tended to underestimate event occurrence, whereas MAGGIC and MECKI tended to overestimate risk, especially in the highest risk subgroups. Interestingly, MECKI score at 1 year was well calibrated (expected similar to observed events). Overall, the MECKI score consistently showed better discrimination ability for all studied end points (areas under the curve between 0.8 and 0.9). In conclusion, along with HFSS and SHFM, the MECKI score can also be used to aid treatment decisions, such as HTx listing with the advantage of being very well calibrated at 1-year intervals, which might allow us to avoid the pitfalls of under/overestimation of risk. PMID- 28629553 TI - Risk of Death Is Higher After Stent Postdilation in Patients With Acute Coronary Syndrome. PMID- 28629554 TI - Emphysema quantification and lung volumetry in chest X-ray equivalent ultralow dose CT - Intra-individual comparison with standard dose CT. AB - OBJECTIVES: To determine whether ultralow dose chest CT with tin filtration can be used for emphysema quantification and lung volumetry and to assess differences in emphysema measurements and lung volume between standard dose and ultralow dose CT scans using advanced modeled iterative reconstruction (ADMIRE). METHODS: 84 consecutive patients from a prospective, IRB-approved single-center study were included and underwent clinically indicated standard dose chest CT (1.7+/-0.6mSv) and additional single-energy ultralow dose CT (0.14+/-0.01mSv) at 100kV and fixed tube current at 70mAs with tin filtration in the same session. Forty of the 84 patients (48%) had no emphysema, 44 (52%) had emphysema. One radiologist performed fully automated software-based pulmonary emphysema quantification and lung volumetry of standard and ultralow dose CT with different levels of ADMIRE. Friedman test and Wilcoxon rank sum test were used for multiple comparison of emphysema and lung volume. Lung volumes were compared using the concordance correlation coefficient. RESULTS: The median low-attenuation areas (LAA) using filtered back projection (FBP) in standard dose was 4.4% and decreased to 2.6%, 2.1% and 1.8% using ADMIRE 3, 4, and 5, respectively. The median values of LAA in ultralow dose CT were 5.7%, 4.1% and 2.4% for ADMIRE 3, 4, and 5, respectively. There was no statistically significant difference between LAA in standard dose CT using FBP and ultralow dose using ADMIRE 4 (p=0.358) as well as in standard dose CT using ADMIRE 3 and ultralow dose using ADMIRE 5 (p=0.966). In comparison with standard dose FBP the concordance correlation coefficients of lung volumetry were 1.000, 0.999, and 0.999 for ADMIRE 3, 4, and 5 in standard dose, and 0.972 for ADMIRE 3, 4 and 5 in ultralow dose CT. CONCLUSIONS: Ultralow dose CT at chest X ray equivalent dose levels allows for lung volumetry as well as detection and quantification of emphysema. However, longitudinal emphysema analyses should be performed with the same scan protocol and reconstruction algorithms for reproducibility. PMID- 28629555 TI - Evaluating the ability to detect pancreatic lesions using a special ultrasonography examination focusing on the pancreas. AB - PURPOSE: The ability to detect pancreatic cysts was compared between special ultrasonography (US) examination focusing on the pancreas (special pancreatic US) and routine upper abdominal ultrasonography to objectively assess the ability of the former to detect cysts. SUBJECTS AND METHODS: Of 3704 patients who underwent special pancreatic US at our hospital, 186 underwent routine upper abdominal US within six months, had pancreatic cysts, and underwent magnetic resonance imaging (MRI). In these patients, 447 cysts measuring >=5mm were detected via MRI, which was used as the gold standard. The ability and sensitivity of the US modalities to detect each cyst was determined. RESULTS: The sensitivity of special pancreatic US was 92.2% (95% confidence interval [CI], 89.7%-94.7%) and that of routine upper abdominal US was 70.2% (95% CI, 66.0%-74.5%). McNemar test (Stata Version 13.1) revealed a significant difference in the cyst (>=5mm) detection sensitivity between the two modalities (p<0.001). An analysis stratified by patients similarly revealed a significant difference between the two modalities (p<0.001). The cyst detection sensitivity was also analyzed in various parts of the pancreas. The sensitivity of special pancreatic US was 88.7% for the uncinate process and inferior head, 97.5% for the head, 97.1% for the body, 89.0% for the body-tail, and 66.7% for the tail, whereas that of routine upper abdominal US was 74.2% for the uncinate process, 69.5% for the head, 81.0% for the body, 67.0% for the body-tail, and 26.7% for the tail. The McNemar test revealed significant differences in the sensitivity of the two modalities for all pancreatic parts (p<0.001-0.016). CONCLUSION: Compared with routine upper abdominal US, special pancreatic US had higher sensitivity in detecting pancreatic cysts. PMID- 28629556 TI - Drug-eluting balloons for treatment of SFA and popliteal disease - A review of current status. AB - The endovascular treatment of atherosclerotic disease of the infra-inguinal arteries has changed significantly over the last decades. In an attempt to overcome the high restenosis rates that characterize plain balloon angioplasty and stenting using bare mate stents drug-eluting balloon technology has been applied in the treatment of lesions of the superficial femoral and popliteal artery. This paper will give an overview of the rationale and the technology of drug-eluting balloons and will review currently available data from registries and randomized controlled trials. PMID- 28629557 TI - Multiparametric MRI for differentiation of borderline ovarian tumors from stage I malignant epithelial ovarian tumors using multivariate logistic regression analysis. AB - OBJECTIVE: To assess the value of contrast-enhanced MRI, apparent diffusion coefficient (ADC) measurement, and CA-125 measurement for differentiating borderline ovarian tumors (BOTs) from stage I malignant epithelial ovarian tumors (MEOTs). MATERIAL AND METHODS: This retrospective study included 43 patients with BOTs and 43 patients with stage I MEOTs who underwent contrast-enhanced MRI with DWI and CA-125 analysis. Two radiologists evaluated the MRI findings in consensus. Univariate and multivariate analyses were performed to detect the best predictor variables for MEOTs. RESULTS: Mixed cystic/solid and predominantly solid appearances, as well as thickened irregular septa, were more frequent in MEOTs. A papillary architecture and internal branching (PA&IB) pattern was more frequent in BOTs. MEOTs had thicker walls and septa, larger solid components, and higher CA-125 values. The mean ADC value of solid components (ADCmean) and minimum ADC value of whole lesions (ADCmin) were lower in MEOTs. Multivariate analysis revealed that ADCmin and maximum diameter of the solid components were independent indicators of MEOTs with an AUC, sensitivity, and specificity of 0.86, 81%, and 84%, respectively. CONCLUSION: ADCmin and maximum diameter of solid components were useful for differentiating BOTs from MEOTs. PMID- 28629558 TI - Is there a trend in CT scanning scaphoid nonunions for deformity assessment?-A systematic review. AB - PURPOSE: The effect of scaphoid nonunion deformity on wrist function is uncertain due to the lack of reliable imaging tools. Advanced three-dimensional (3-D) computed tomography (CT)-based imaging techniques may improve deformity assessment by using a mirrored image of the contralateral intact wrist as anatomic reference. The implementation of such techniques depends on the extent to which conventional CT is currently used in standard practice. The purpose of this systematic review of medical literature was to analyze the trend in CT scanning scaphoid nonunions, either unilaterally or bilaterally. MATERIALS AND METHODS: Using Medline and Embase databases, two independent reviewers searched for original full-length clinical articles describing series with at least five patients focusing on reconstructive surgery of scaphoid nonunions with bone grafting and/or fixation, from the years 2000-2015. We excluded reports focusing on only nonunions suspected for avascular necrosis and/or treated with vascularized bone grafting, as their workup often includes magnetic resonance imaging. For data analysis, we evaluated the use of CT scans and distinguished between uni- and bilateral, and pre- and postoperative scans. RESULTS: Seventy seven articles were included of which 16 were published between 2000 and 2005, 19 between 2006 and 2010, and 42 between 2011 and 2015. For these consecutive intervals, the rates of articles describing the use of pre- and postoperative CT scans increased from 13%, to 16%, to 31%, and from 25%, to 32%, to 52%, respectively. Hereof, only two (3%) articles described the use of bilateral CT scans. CONCLUSION: There is an evident trend in performing unilateral CT scans before and after reconstructive surgery of a scaphoid nonunion. To improve assessment of scaphoid nonunion deformity using 3-D CT-based imaging techniques, we recommend scanning the contralateral wrist as well. PMID- 28629559 TI - Prospective intra-individual comparison of standard dose versus reduced-dose thoracic CT using hybrid and pure iterative reconstruction in a follow-up cohort of pulmonary nodules-Effect of detectability of pulmonary nodules with lowering dose based on nodule size, type and body mass index. AB - OBJECTIVES: To determine the diagnostic accuracy of lung nodule detection in thoracic CT using 2 reduced dose protocols comparing 3 available CT reconstruction algorithms (filtered back projection-FBP, adaptive statistical reconstruction-ASIR and model-based iterative reconstruction-MBIR) in a western population. MATERIALS AND METHODS: A prospective single-center study recruited 98 patients with written consent. Standard dose (STD) thoracic CT followed by 2 reduced-dose protocols using automatic tube current modulation (RD1) and fixed tube current (RD2) were performed and reconstructed with FBP, ASIR and MBIR with subsequent diagnostic accuracy analysis for nodule detection. RESULTS: 108 solid nodules, 47 subsolid nodules and 89 purely calcified nodules were analyzed. RD1 was superior to RD2 for assessment of solid nodules <=4mm, and subsolid nodules <=5mm (p<0.05). Deterioration of RD2 is correlated to patient's body mass index and least affected by MBIR. For solid nodules <=4mm, MBIR area under curve (AUC) for RD1 was 0.935/0.913 and AUC for RD2 was 0.739/0.739, for rater 1/rater2 respectively. For subsolid nodules <=5mm, MBIR AUC for RD1 was 0.971/0.986 and AUC for RD2 was 0.914/0.914, for rater 1/rater2 respectively. For calcified nodules excellent detection accuracy was maintained regardless of reconstruction algorithms with AUC >0.97 for both readers across all dose and reconstruction algorithms. CONCLUSIONS: Diagnostic performance of lung nodule is affected by nodule size, protocol, reconstruction algorithm and patient's body habitus. The protocol in this study showed that RD1 was superior to RD2 for assessment of solid nodules <=4mm, and subsolid nodules <=5mm and deterioration of RD2 is related to patient's body mass index. PMID- 28629560 TI - CT-based radiomics signature for differentiating Borrmann type IV gastric cancer from primary gastric lymphoma. AB - PURPOSE: To evaluate the value of CT-based radiomics signature for differentiating Borrmann type IV gastric cancer (GC) from primary gastric lymphoma (PGL). MATERIALS AND METHODS: 40 patients with Borrmann type IV GC and 30 patients with PGL were retrospectively recruited. 485 radiomics features were extracted and selected from the portal venous CT images to build a radiomics signature. Subjective CT findings, including gastric wall peristalsis, perigastric fat infiltration, lymphadenopathy below the renal hila and enhancement pattern, were assessed to construct a subjective findings model. The radiomics signature, subjective CT findings, age and gender were integrated into a combined model by multivariate analysis. The diagnostic performance of these three models was assessed with receiver operating characteristics curves (ROC) and were compared using DeLong test. RESULTS: The subjective findings model, the radiomics signature and the combined model showed a diagnostic accuracy of 81.43% (AUC [area under the curve], 0.806; 95% CI [confidence interval]: 0.696-0.917; sensitivity, 63.33%; specificity, 95.00%), 84.29% (AUC, 0.886 [95% CI: 0.809 0.963]; sensitivity, 86.67%; specificity, 82.50%), 87.14% (AUC, 0.903 [95%CI: 0.831-0.975]; sensitivity, 70.00%; specificity, 100%), respectively. There were no significant differences in AUC among these three models (P=0.051-0.422). CONCLUSION: Radiomics analysis has the potential to accurately differentiate Borrmann type IV GC from PGL. PMID- 28629561 TI - Multi-contrast and three-dimensional assessment of the aortic wall using 3T MRI. AB - OBJECTIVES: To develop a 3D-multi-contrast MRI protocol allowing for high resolution imaging of the wall and of atheroma in the thoracic aorta. METHODS: Eleven healthy volunteers and eleven acute stroke patients with aortic plaques detected by TEE underwent MRI at 3T. The MRI-protocol consisted of a T1w-bright blood, a T2w- and a PDw-black-blood sequence (spatial resolution=1.15mm3). Image quality was assessed by two blinded investigators using a 3-point score and intra and inter-rater agreement was tested. In patients, atherosclerotic plaques were graded according to the modified American Heart Association (AHA) classification. RESULTS: Total examination time was 35:42+/-7:48min in volunteers and 41:07+/ 3:15min in patients. Image quality was graded with the highest score in 80-94% of T1w, 89-96% of T2w and 79-86% of PDw datasets. Intra- and inter-rater reliability regarding image quality grading was high. Five stroke patients showed AHA type III lesions, three had AHA type VII and two had type VIII plaques. One patient had a vulnerable appearing AHA VI plaque. CONCLUSIONS: 3D-multi-contrast MR imaging of the aorta was performed with high image quality and in reasonable time. It allows evaluation of atherosclerotic plaque composition throughout the aortic arch and can be used to identify vulnerable plaques in acute stroke patients. PMID- 28629562 TI - 3T MR-defecography-A feasibility study in sensorimotor complete spinal cord injured patients with neurogenic bowel dysfunction. AB - INTRODUCTION: To investigate whether MR-defecography can be employed in sensorimotor complete spinal cord injury (SCI) subjects as a potential diagnostic tool to detect defecational disorders associated with neurogenic bowel dysfunction (NBD) using standard parameters for obstructed defecation. MATERIAL AND METHODS: In a prospective single centre clinical trial, we developed MR defecography in traumatic sensorimotor complete paraplegic SCI patients with upper motoneuron type injury (neurological level of injury T1 to T10) using a conventional 3T scanner. Defecation was successfully induced by eliciting the defecational reflex after rectal filling with ultrasonic gel, application of two lecicarbon suppositories and digital rectal stimulation. Examination was performed with patients in left lateral decubitus position using T2-weighted turbo spin echo sequence in the sagittal plane at rest (TE 89ms, TR 3220ms, FOV 300mm, matrix 512*512, ST 4mm) and ultrafast-T2-weighted-sequence in the sagittal plane with repeating measurements (TE 1.54ms, TR 3.51ms, FOV 400mm, matrix 256*256, ST 6mm). Changes of anorectal angle (ARA), anorectal descent (ARJ) and pelvic floor weakness were documented and measured data was compared to reference values of asymptomatic non-SCI subjects in the literature to assess feasibility. RESULTS: MR-defecography provides evaluable imaging sequences of the induced evacuation phase in SCI patients. Measurement results for ARA, ARJ, hiatal width (H-line) and hiatal descent (M-line) deviate significantly from reference values in the literature in asymptomatic subjects without SCI. The overall mean values in our study for SCI patients were: ARA (rest) 127.3 degrees , ARA (evacuation) 137.6 degrees , ARJ (rest) 2.4cm, ARJ (evacuation) 4.0cm, H-line (rest) 7.6cm, H line (evacuation) 8.1cm, M-line (rest) 2.6cm, M-line (evacuation) 4.2cm. CONCLUSIONS: MR-defecography is feasible in sensorimotor complete SCI patients. Individual MR-defecography findings may help to determine specific therapeutical options for respective patients suffering from severe NBD. PMID- 28629563 TI - Positron emission tomography/computed tomography in patients with hepatocellular carcinoma undergoing liver transplantation. Useful, necessary or irrelevant? AB - Hepatocellular Carcinoma (HCC) is an aggressive tumor entity, with the only curative options being surgical resection or orthotopic liver transplantation (OLT). The presence of one single tumor nodule of less than 5 centimeters diameter or a maximum of 3 nodules, with the largest of these not exceeding 3 centimeters (Milan criteria) constitute the clinical situation in which the best results for OLT in patients with HCC have been achieved. The survival of patients fulfilling the Milan criteria after transplantation is comparable to patients with similar tumor stages without cirrhosis, undergoing hepatic resection. The application of PET in oncology has become increasingly common in the last decade as it is a non-invasive tool that also gathers information about the degree of the biological aggressiveness of the tumor. The objective of this study was to perform a review of the literature, identifying the strengths and weaknesses of the PET as a prognostic tool in patients with HCC after OLT. PMID- 28629564 TI - Computed tomography perfusion imaging for monitoring transarterial chemoembolization of hepatocellular carcinoma. AB - PURPOSE: To prospectively monitor changes in tumor perfusion of hepatocellular carcinoma (HCC) in response to doxorubicin-eluted bead based transarterial chemoembolization (DEB-TACE) using perfusion-CT (P-CT). METHODS AND MATERIALS: 24 patients (54-79 years) undergoing P-CT before and shortly after DEB-TACE of HCC were prospectively included in this dual-center study. Two readers determined arterial-liver-perfusion (ALP, mL/min/100mL), portal-venous-perfusion (PLP, mL/min/100mL) and the hepatic-perfusion-index (HPI, %) by placing matched regions of-interests within each HCC before and after DEB-TACE. Imaging follow-up was used to determine treatment response and to distinguish complete from incomplete responders. Performance of P-CT for prediction and early response assessment was determined using receiver-operating-characteristics curve analysis. RESULTS: Interreader agreement was fair to excellent (ICC, 0.716-0.942). PLP before DEB TACE was significantly higher in pre-treated vs non-treated lesions (P<0.05). Mean changes of ALP, PLP and HPI from before to after DEB-TACE were -55%, +24% and -27%. ALP and HPI after DEB-TACE were correlating with response-grades (r=0.45/0.48; both, p<0.04), showing an area-under-the-curve (AUC) of 0.74 and 0.80 respectively for identification of complete response. CONCLUSION: High arterial and low portal-venous perfusion of HCC early after DEB-TACE indicates incomplete response with good diagnostic accuracy. PMID- 28629565 TI - A tri-exponential model for intravoxel incoherent motion analysis of the human kidney: In silico and during pharmacological renal perfusion modulation. AB - In the kidneys, there is both blood flow through the capillaries and flow of pre urine through the tubuli and collecting ducts. We hypothesized that diffusion weighted (DW) MRI measures both blood and pre-urine flow when using a tri exponential intravoxel incoherent motion (IVIM) model. Our aim was to systematically investigate and optimize tri-exponential IVIM-analysis for the kidney and test its sensitivity to renal perfusion changes in humans. The tri exponential fit probes the diffusion coefficient (D), the intermediate (D*i) and fast (D*f) pseudo-diffusion coefficients, and their signal fractions, fD, fi and ff. First, we studied the effects of fixing the D*-coefficients of the tri exponential fit using in silico simulations. Then, using a 3T MRI scanner, DW images were acquired in healthy subjects (18-24 years) and we assessed the within subject coefficient of variation (wsCV, n=6). Then, renal perfusion was modulated by Angiotensin II infusion during which DW imaging of the kidneys and phase contrast MRI of the renal artery was performed (n=8). Radioisotope clearing tests were used to assess the glomerular filtration rate. Simulations showed that fixing the D*-coefficients - which could potentially increase the fit stability - in fact decreased the precision of the model. Changes in D*-coefficients were translated into the f-parameters instead. Fixing D*-coefficients resulted in a stronger response of the fit parameters to the intervention. Using this model, the wsCVs for D, fD, fi and ff were 2.4%, 0.8%, 3.5%, 19.4% respectively. fi decreased by 14% (p=0.059) and ff increased by 32% (p=0.004) between baseline and maximal Angiotensin II dose. ff inversely correlated to renal plasma flow (R= 0.70, p<0.01) and fi correlated to glomerular filtration rate (R=0.39, p=0.026). We validated a kidney-specific method for IVIM analysis using a tri-exponential model. The model is able to track renal perfusion changes induced by Angiotensin II. PMID- 28629566 TI - PI-RADS version 2: Preoperative role in the detection of normal-sized pelvic lymph node metastasis in prostate cancer. AB - OBJECTIVES: To analyze whether Prostate Imaging Reporting and Data System (PI RADSv2) scores are associated with a risk of normal-sized pelvic lymph node metastasis (PLNM) in prostate cancer (PCa). MATERIALS AND METHODS: A consecutive series of 221 patients who underwent magnetic resonance imaging and radical prostatectomy with pelvic lymph node dissection (PLND) for PCa were retrospectively analyzed under the approval of institutional review board in our institution. No patients had enlarged (>=0.8cm in short-axis diameter) lymph nodes. Clinical parameters [prostate-specific antigen (PSA), greatest percentage of biopsy core, and percentage of positive cores], and PI-RADSv2 score from two independent readers were analyzed with multivariate logistic regression and receiver operating-characteristic curve for PLNM. Diagnostic performance of PI RADSv2 and Briganti nomogram was compared. Weighted kappa was investigated regarding PI-RADSv2 scoring. RESULTS: Normal-sized PLNM was found in 9.5% (21/221) of patients. In multivariate analysis, PI-RADSv2 (reader 1, p=0.009; reader 2, p=0.026) and PSA (reader 1, p=0.008; reader 2, p=0.037) were predictive of normal-sized PLNM. Threshold of PI-RADSv2 was a score of 5, where PI-RADSv2 was associated with high sensitivity (reader 1, 95.2% [20/21]; reader 2, 90.5% [19/21]) and negative predictive value (reader 1, 99.2% [124/125]; reader 2, 98.6% [136/138]). However, diagnostic performance of PI-RADSv2 (AUC=0.786-0.788) was significantly lower than that of Briganti nomogram (AUC=0.890) for normal sized PLNM (p<0.05). The inter-reader agreement was excellent for PI-RADSv2 of 5 or not (weighted kappa=0.804). CONCLUSION: PI-RADSv2 scores may be associated with the risk of normal-sized PLNM in PCa. PMID- 28629567 TI - CT coronary calcium scoring with tin filtration using iterative beam-hardening calcium correction reconstruction. AB - OBJECTIVES: To investigate the diagnostic accuracy of CT coronary artery calcium scoring (CACS) with tin pre-filtration (Sn100kVp) using iterative beam-hardening correction (IBHC) calcium material reconstruction compared to the standard 120kVp acquisition. BACKGROUND: Third generation dual-source CT (DSCT) CACS with Sn100kVp acquisition allows significant dose reduction. However, the Sn100kVp spectrum is harder with lower contrast compared to 120kVp, resulting in lower calcium score values. Sn100kVp spectral correction using IBHC-based calcium material reconstruction may restore comparable calcium values. METHODS: Image data of 62 patients (56% male, age 63.9+/-9.2years) who underwent a clinically indicated CACS acquisition using the standard 120kVp protocol and an additional Sn100kVp CACS scan as part of a research study were retrospectively analyzed. Datasets of the Sn100kVp scans were reconstructed using a dedicated spectral IBHC CACS reconstruction to restore the spectral response of 120kVp spectra. Agatston scores were derived from 120kVp and IBHC reconstructed Sn100kVp studies. Pearson's correlation coefficient was assessed and Agatston score categories and percentile-based risk categorization were compared. RESULTS: Median Agatston scores derived from IBHC Sn100kVp scans and 120kVp acquisition were 31.7 and 34.1, respectively (p=0.057). Pearson's correlation coefficient showed excellent correlation between the acquisitions (r=0.99, p<0.0001). Agatston score categories and percentile-based cardiac risk categories showed excellent agreement (K=1.00 and K=0.99), resulting in a low cardiac risk reclassification of 1.6% with the use of IBHC CACS reconstruction. Image noise was 24.9+/-3.6HU in IBHC Sn100kVp and 17.1+/-3.9HU in 120kVp scans (p<0.0001). The dose-length product was 13.2+/-3.4mGycm with IBHC Sn100kVp and 59.1+/-22.9mGycm with 120kVp scans (p<0.0001), resulting in a significantly lower effective radiation dose (0.19+/-0.07mSv vs. 0.83+/-0.33mSv, p<0.0001) for IBHC Sn100kVp scans. CONCLUSION: Low voltage CACS with tin filtration using a dedicated IBHC CACS material reconstruction algorithm shows excellent correlation and agreement with the standard 120kVp acquisition regarding Agatston score and cardiac risk categorization, while radiation dose is significantly reduced by 75% to the level of a chest x-ray. PMID- 28629568 TI - Repeatability of estimated fetal weight: Comparison between MR imaging versus 2D ultrasound in at- and near-term patients. AB - INTRODUCTION: Our aim was to evaluate the intra- and inter-observer variability and the impact of operator experience on the estimation of fetal weight (EFW) as measured by 2-dimensional ultrasound (2D-US) and magnetic resonance (MR) imaging. MATERIAL AND METHODS: We estimated fetal weight in 46 singleton pregnancies at 35.6-41.4 weeks gestation using 2D-US according to the Hadlock formula and using MR imaging according to the equation developed by Baker. Each examination was performed twice, once by an inexperienced operator and once by an experienced operator. The MR-EFW was derived from the planimetric measurement of fetal body volume (FBV) using an assisted semi-automated method. Intra- and inter-observer variability was evaluated by Bland-Altman analysis. Regression analysis was used to investigate the effect of maternal BMI, delivery weight, diabetes and fetal gender on the differences in US-EFW between the inexperienced and experienced operators. RESULTS: US-EFW showed higher intra-observer variability than MR-EFW, irrespective of operator experience. The 95% limits of agreement of MR were narrower compared with those of the US measurements. Similarly, US-EFW showed higher inter-observer variability than MR-EFW. MR-EFW improvement over 2D-US for the limits of agreement was 77.9% for intra-observer variability and 74.5% for inter-observer variability. Regression analysis showed that the differences between US-EFW measurements were not related to any of the tested variables. CONCLUSIONS: Operator experience has a marginal impact on the variability of US EFW and no impact on MR-EFW variability. The variability in US-EFW measurements is unpredictable. PMID- 28629569 TI - In-depth analysis of interreader agreement and accuracy in categorical assessment of brown adipose tissue in (18)FDG-PET/CT. AB - PURPOSE: To evaluate the interreader agreement of a three-tier craniocaudal grading system for brown fat activation and investigate the accuracy of the distinction between the three grades. MATERIALS AND METHODS: After IRB approval, 340 cases were retrospectively selected from patients undergoing (18)FDG-PET/CT between 2007 and 2015 at our institution, with 85 cases in each grade and 85 controls with no active brown fat. Three readers evaluated all cases independently. Furthermore standardized uptake values (SUV) measurements were performed by two readers in a subset of 53 cases. Agreement between the readers was assessed with Cohen's Kappa (k), the concordance correlation coefficient (CCC) and the intraclass correlation coefficient (ICC). Accuracy was assessed with Bland-Altman and receiver operating characteristics (ROC) analysis. A Bonferroni-corrected two-tailed p<0.016 was considered statistically significant. RESULTS: Agreement for BAT grade was excellent by all three metrics with k=0.83 0.89, CCC=0.83-0.89 and ICC=0.91-0.94. Bland-Altman analysis revealed only slight average over- or underestimation (-0.01-0.14) with the majority of disagreements within one grade. ROC analysis yielded slightly less accurate classification between higher vs. lower grades (Area under the ROC curves 0.78-0.84 vs. 0.88 0.92) but no significant differences between readers. Agreement was also excellent for the maximum SUV and the total brown fat volume (k=0.90 and 0.94, CCC=0.93 and 0.99, ICC=0.96 and 0.99), but Bland-Altman plots revealed a tendency to underestimate activity by one of the readers. CONCLUSION: Grading the activation of brown fat by assessment of the most caudally activated depots results in excellent interreader agreement, comparable to SUV measurements. PMID- 28629570 TI - The association between multiple sclerosis and spondylosis: When and why. AB - OBJECTIVES: To evaluate risk factors for the development of cervical spine spondylosis (CSS) in patients with multiple sclerosis (MS) and to propose a pathogenetic mechanism. METHODS: Forty-two consecutive patients aged 23-66 years with MS and 42 age and sex matched controls were evaluated retrospectively; Clinical disability was evaluated with the expanded disability status scale (EDSS) and spasticity with the Asworth score. Total brain lesion volume (BLV), total grey matter (GM) volume and deep GM volume were assessed. In the cervical spine CSS indices (disk dehydration, disk protrusion, abnormal posture and osteophytosis) and the spinal cord lesion load (SLL) was evaluated. The association of CSS indices with the presence of MS, the clinical scales and the brain and spinal cord imaging measurements were assessed. RESULTS: Presence of MS was positively associated with abnormal posture (P=0.002), disk dehydration at C6 C7 (P=0.049) and posterior disk protrusion at C5-C6 (P=0.033) and C6-C7 (P=0.001). All patients had spasticity. Patients with abnormal posture were younger (37.5+/-11.1years) than those with normal (45.4+/-8.6years), P=0.024. Age (P=0.008), EDSS (P=0.045) and BLV (P=0.084) were significant independent predictors of abnormal posture. Younger age combined with worse EDSS and increased BLV predicted abnormal posture. CONCLUSIONS: Patients with MS present more frequently spondylosis which is associated with younger age, more severe disability and extensive lesions in the brain. Spasticity induced by the brain lesions and abnormal expression of extracellular matrix proteins in the brain and the intervertebral disk constitute a possible pathogenetic mechanism. PMID- 28629571 TI - Detection and characterization of Budd-Chiari syndrome with inferior vena cava obstruction: Comparison of fixed and flexible delayed scan time of computed tomography venography. AB - PURPOSE: To compare the results of computed tomography venography (CTV) with a fixed and a flexible delayed scan time for Budd-Chiari syndrome (BCS) with inferior vena cava (IVC) obstruction. MATERIAL AND METHODS: A total of 209 consecutive BCS patients with IVC obstruction underwent either a CTV with a fixed delayed scan time of 180s (n=87) or a flexible delayed scan time for good image quality according to IVC blood flow in color Doppler ultrasonography (n=122). The IVC blood flow velocity was measured using a color Doppler ultrasound prior to CT scan. Image quality was classified as either good, moderate, or poor. Image quality, surrounding structures and the morphology of the IVC obstruction were compared between the two groups using a chi2-test or paired or unpaired t-tests as appropriate. Inter-observer agreement was assessed using Kappa statistics. RESULTS: There was no significant difference in IVC blood flow velocity between the two groups. Overall image quality, surrounding structures and IVC obstruction morphology delineation on the flexible delayed scan time of CTV images were rated better relative to those obtained by fixed delayed scan time of CTV images (p<0.001). Evaluation of CTV data sets was significantly facilitated with flexible delayed scan time of CTV. There were no significant differences in Kappa statistics between Group A and Group B. CONCLUSION: The flexible delayed scan time of CTV was associated with better detection and more reliable characterization of BCS with IVC obstruction compared to a fixed delayed scan time. PMID- 28629572 TI - 3T diffusion-weighted MRI in the response assessment of colorectal liver metastases after chemotherapy: Correlation between ADC value and histological tumour regression grading. AB - PURPOSE: The purpose of the study was to correlate the apparent diffusion coefficient (ADC) values of diffusion-weighted MR imaging (DW-MRI) by 3T device with the histological tumour regression grading (TRG) analysis of colorectal liver metastases after preoperative chemotherapy. MATERIALS AND METHODS: Our study included thirty-five patients with colorectal liver metastases who had undergone MRI by 3T device (GE DISCOVERY MR750; GE Healthcare) after preoperative chemotherapy. DW-MRI was performed using a single-shot spin-echo echo-planar sequence with multiple b-values (0, 150, 500, 1000, 1500s/mm2), thus obtaining an ADC map. For each liver lesion (more than 1cm in diameter) the fitted ADC values were calculated by two radiologists in conference and three ROIs were drawn: around the entire tumour (ADCe), at the tumour periphery (ADCp) and at the tumour center (ADCc). All ADC values were correlated with histopathological findings after surgery. Hepatic metastases were pathologically classified into five groups on the basis of TRG. Statistical analysis was performed on a per-lesion basis utilizing the one-way analysis of variance (ANOVA). This retrospective study was approved by our institutional review board; written informed consent was obtained from all patients. RESULTS: A total of 106 colorectal liver metastases were included for image analysis. TRG1, TRG2, TRG3, TRG4 and TRG5 were observed in 4, 14, 36, 35 and 17 lesions, respectively. ADCe and ADCp values were significantly higher in lesions classified as TRG1 (2.40+/-0.12*10-9m2/s and 2.28+/-0.26*10 9m2/s, respectively) and as TRG2 (1.40+/-0.31*10-9m2/s and 1.44+/-0.35*10-9m2/s), compared to TRG3 (1.16+/-0.13*10-9m2/s and 1.01+/-0.18*10-9m2/s), TRG4 (1.10+/ 0.26*10-9m2/s and 0.97+/-0.24*10-9m2/s), and TRG5 (0.93+/-0.17*10-9m2/s and 0.82+/-0.28*10-9m2/s). ADCe, ADCp and ADCc values were significantly different in TRG classes (p<0.0001). Statistical correlations were found between the ADCe, ADCp, ADCc values and the TRG classes (Spearman correlation coefficient were 0.568, -0.542 and -0.554, respectively). CONCLUSION: Our study showed a significant correlation between ADC values of 3T DW-MRI and histological TRG of colorectal liver metastases after preoperative chemotherapy. PMID- 28629573 TI - Added value of prone CT in the assessment of honeycombing and classification of usual interstitial pneumonia pattern. AB - OBJECTIVE: To retrospectively investigate whether prone CT improves identification of honeycombing and classification of UIP patterns in terms of interobserver agreement and accuracy using pathological results as a reference standard. MATERIALS AND METHODS: Institutional review board approval with waiver of patients' informed consent requirement was obtained. HRCTs of 86 patients with pathologically proven UIP, NSIP and chronic HP between January 2011 and April 2015 were evaluated by 8 observers. Observers were asked to review supine only set and supine and prone combined set and determine the presence of honeycombing and UIP classification (UIP, possible UIP, inconsistent with UIP). The diagnosis was regarded as correct when UIP pattern on CT corresponded to pathological UIP. RESULTS: Interobserver agreement of honeycombing identification among radiologists was only fair on the supine and combined set (weighted kappa=0.31 and 0.34). Additional review of prone images demonstrated a significant improvement in interobserver agreement (weighted kappa) of UIP classification from 0.25 to 0.33. Prone CT conferred a significant improvement in interobserver agreement of UIP classification for trainee radiologists (from 0.10 to 0.34) while no improvement was found for board-certified radiologists (from 0.35 to 0.31). There were no significant differences in the accuracy of UIP pattern with reference to pathological results between the supine and combined set (78.8% (145/184) and 81.3% (179/220), P=0.612). CONCLUSION: Additional review of prone CT can improve overall interobserver agreement of UIP classification among radiologists with variable experiences, particularly for less experienced radiologists, while no improvement was found in honeycombing identification. PMID- 28629574 TI - Biventricular mechanics in prediction of severe myocardial fibrosis in patients with dilated cardiomyopathy: CMR study. AB - PURPOSE: The purpose of this study was to compare the ability of various parameters of myocardial mechanics to predict large amounts of biventricular fibrosis assessed via T1 mapping in patients with dilated cardiomyopathy (DCM). MATERIAL: Cardiovascular magnetic resonance feature tracking analysis and T1 mapping were performed in 26 patients with DCM [mean age: 34.4+/-9.1years, 15 (57.6%) males]. The values of various parameters of myocardial mechanics at predicting advanced left-ventricle (LV) and right-ventricle (RV) fibrosis were compared using logistic regression analysis and receiver operating characteristic curve (ROC) analysis. RESULTS: There were 7 (26.9%) patients with a large amount of LV fibrosis and 9 (34.6%) patients with severe RV fibrosis. ROC curve analysis revealed that the model of combined LV strain rates (AUC=0.902) offered superb ability at predicting large amounts of LV fibrosis. The models including RV strain rates (AUC=0.974), a combination of RV strains, strain rates and clinical parameters (AUC=0.993) as well as the RV radial strain rate alone model (AUC=0.961) yielded outstanding performance in discriminating large and small amounts of RV fibrosis. In multivariate analysis, the LV circumferential strain (LVCR) and RV radial (RVR) strain rate were the only independent predictors of large amounts of LV and RV fibrosis, respectively. CONCLUSIONS: Indices of myocardial deformation, especially combined with clinical features, offered a superlative ability to differentiate high from low degrees of fibrosis in DCM patients. Among all analyzed parameters of myocardial mechanics, LVCR and RVR rate alone were the independent predictors of high degrees of LV and RV fibrosis, respectively. PMID- 28629575 TI - Outcome of patients with proximal vessel occlusion of the anterior circulation and DWI-PWI mismatch is time-dependent. AB - BACKGROUND AND PURPOSE: Patients with ischemic stroke and large vessel occlusion are assumed to benefit from endovascular therapy (ET) independent of the symptom onset-to-treatment time (OTT) if they present with a mismatch of diffusion- and perfusion-weighted imaging (DWI-PWI mismatch). We aimed at studying the influence of OTT on clinical outcome in these patients. METHODS: Retrospective database review in a tertiary care university hospital. All patients presented with proximal vessel occlusion of the anterior circulation and DWI-PWI mismatch. Primary outcome was the influence of OTT on modified Rankin scale (mRS) score three months after treatment, dichotomized in favourable (0-2) and unfavourable outcome (3-6). Secondary outcome was the effect of OTT on the shift of the mRS score. Patients treated within an early time window (<340min) and a late time window (>=340min) were compared. RESULTS: 139 patients were included. The rate of favourable outcome was significantly higher in patients who were treated in an early compared to those treated in a late time window (31 [49%] vs. 20 patients [27%], p=0.005). Adjusted multivariate logistic regression revealed that late treatment was an independent negative predictor of favourable outcome (odds ratio 0.39, confidence interval [0.18-0.84]; p=0.016). A shift towards higher mRS scores for late treatment was evident (p=0.015). In sensitivity analysis, OTT remained an independent predictor when evaluated as continuous variable. These findings were confirmed in patients with a comparable DWI-PWI mismatch according to the definitions from large trials (DEFUSE 2, DEFUSE 3, SWIFT-PRIME, EXTEND IA). CONCLUSION: Outcome of patients with comparable DWI-PWI mismatch is time dependent. PMID- 28629576 TI - Differentiation of brain tumor-related edema based on 3D T1rho imaging. AB - BACKGROUND AND PURPOSE: Cerebral edema associated with brain tumors is an important source of morbidity. Its type depends largely on the capillary ultra structures of the histopathologic subtype of underlying brain tumor. The purpose of our study was to differentiate vasogenic edema associated with brain metastases and infiltrative edema related to diffuse gliomas using quantitative 3D T1 rho (T1rho) imaging. MATERIALS AND METHODS: Preoperative MR examination including whole brain 3D T1rho imaging was performed in 23 patients with newly diagnosed brain tumors (9 with metastasis, 8 with lower grade glioma, LGG, 6 with glioblastoma, GBM). Mean T1rho values were measured in regions of peritumoral non enhancing T2 signal hyperintensity, excluding both enhancing and necrotic or cystic component, and normal-appearing white matter. RESULTS: Mean T1rho values were significantly elevated in the vasogenic edema surrounding intracranial metastases when compared to the infiltrative edema associated with either LGG or GBM (p=0.02 and <0.01, respectively). No significant difference was noted between T1rho values of infiltrative edema between LGG and GBM (p=0.84 and 0.96, respectively). CONCLUSION: Our study demonstrates the feasibility and potential diagnostic role of T1rho in the quantitative differentiation between edema related to intracranial metastases and gliomas and as a potentially complementary tool to standard MR techniques in further characterizing pathophysiology of vasogenic and infiltrative edema. PMID- 28629577 TI - Comparison of ultrasonography-guided percutaneous microwave ablation for subcapsular and nonsubcapsular hepatocellular carcinoma. AB - PURPOSE: To compare the prognosis of subcapsular and nonsubcapsular hepatocellular carcinoma (HCC) after ultrasonography (US)-guided percutaneous microwave ablation (MWA). MATERIALS AND METHODS: From January 2012 to December 2015, 463 enrollment patients (382 men, 81 women; age range, 24-95 years) with a single HCC underwent US-guided percutaneous MWA. The patients were divided into two groups according to tumor location: subcapsular (n=224) and nonsubcapsular (n=239). Therapeutic efficacy was assessed by contrast enhanced imaging after MWA. The technique effectiveness rate, the local tumor progression (LTP) rate, overall survival (OS) rate and complication were compared between two groups. RESULTS: There were no significant differences in the mean treatment sessions (p=0.105) and the mean number of antenna insertions (p=0.065) between two groups. No significant difference in the technique effectiveness rate was found between subcapsular and nonsubcapsular tumors (95.5% vs 98.3%, p=0.089). The respective 1 , 2-, 3-, and 4-year cumulative LTP rates were 5.0%, 5.5%, 5.5% and 5.5% in subcapsular group and 6.4%, 6.4%, 6.4% and 6.4% in nonsubcapsular group, respectively(p=0.861). The 1-, 2-, 3-, and 4-year OS rates were estimated to be 95.7%, 90.1%, 82.9%, and 71.1% in subcapsular group and 98.5%, 92.8%, 83.2%, and 73.6% in nonsubcapsular group, respectively (p=0.426). There was no significant difference in major complication rates between the subcapsular group (2.2%) and nonsubcapsular group (1.3%) (p=0.653). There was higher postoperative pain rate in subcapsular group (13.4%) than nonsubcapsular group (7.1%) (p=0.025). CONCLUSIONS: There were no significant differences in the technique effectiveness rate, cumulative LTP rate, OS rate and major complication rate between subcapsular and nonsubcapsular group after MWA for HCC. PMID- 28629578 TI - Endobronchial squamous cell carcinoma presenting as localized, long, continuous bronchial thickening on CT. AB - OBJECTIVE: To report pulmonary squamous cell carcinomas presenting as localized, long, continuous, bronchial thickening on computed tomography (CT). MATERIALS AND METHODS: This study comprised five men (mean age, 66 years; range, 60-79 years) with pulmonary squamous cell carcinoma, including two (0.6%) selected from 310 consecutive patients with the diagnosis. Inclusion criteria were as follows: histological diagnosis obtained from thickened bronchi; continuous bronchial thickening >5cm in longitudinal extension on CT. CT scans were retrospectively reviewed, focusing on bronchial abnormalities. They were correlated with histopathological findings in four patients who underwent lobectomy. RESULTS: On initial CT, bronchial thickening was continuous without skip area (n=5), measured 56-114mm in maximum longitudinal length, involved lobar (n=3) or segmental and distal bronchi (n=5) of the right upper (n=4) or lower (n=1) lobe, and was focally bulbous (n=2). Follow-up CT before treatment, available in two, showed progression of bronchial thickening in its thickness and longitudinal length (n=2) and a new bulbous portion (n=1) and peribronchial nodules (n=1) along the thickened bronchi. Cancer recurred after lobectomy in two, one of which manifested as continuous bronchial thickening extending from the bronchial stump on CT. On CT-histopathological correlation, bronchial thickening was mostly due to tumor spreading along the bronchus. A focal or short segmental tumor outgrowth from the thickened bronchi corresponded to a nodule or bulbous portion along thickened bronchi on CT, respectively. CONCLUSION: Pulmonary squamous cell carcinoma may present as localized, long, continuous, bronchial thickening on CT, simulating benign infectious or inflammatory diseases. PMID- 28629579 TI - Role of SOCE architects STIM and Orai proteins in Cell Death. AB - Calcium (Ca2+) signaling plays a critical role in regulating plethora of cellular functions including cell survival, proliferation and migration. The perturbations in cellular Ca2+ homeostasis can lead to cell death either by activating autophagic pathways or through induction of apoptosis. Endoplasmic reticulum (ER) is the major storehouse of Ca2+ within cells and a number of physiological agonists mediate ER Ca2+ release by activating IP3 receptors (IP3R). This decrease in ER Ca2+ levels is sensed by STIM, which physically interacts and activates plasma membrane Ca2+ selective Orai channels. Emerging literature implicates a key role for STIM1, STIM2, Orai1 and Orai3 in regulating both cell survival and death pathways. In this review, we will retrospect the work highlighting the role of STIM and Orai homologs in regulating cell death signaling. We will further discuss the rationales that could explain the dual role of STIM and Orai proteins in regulating cell fate decisions. PMID- 28629580 TI - Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease. AB - Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons. GPR37 also constitutes a core structure of Lewy bodies, demonstrating a more general involvement in PD pathology. However, if folded and matured properly, GPR37 seems to be neuroprotective. Moreover, GPR37 modulates functionality of the dopamine transporter and the dopamine D2 receptor and stimulates dopamine neurotransmission. Here we review the multiple roles of GPR37 with relevance to potential disease modification and symptomatic therapies of PD and highlight unsolved issues in this field. PMID- 28629581 TI - Impact of a TeamSTEPPS Trauma Nurse Academy at a Level 1 Trauma Center. AB - PROBLEM: Nurses are crucial members of the team caring for the acutely injured trauma patient. Until recently, nurses and physicians gained an understanding of leadership and supportive roles separately. With the advent of a multidisciplinary team approach to trauma care, formal team training and simulation has transpired. METHODS: Since 2007, our Level I trauma system has integrated TeamSTEPPS (Team Strategies & Tools to Enhance Performance & Patient Safety; Agency for Healthcare Research and Quality, Rockville, MD) into our clinical care, joint training of nurses and physicians, using simulations with participation of all health care providers. With the increased expectations of a well-orchestrated team and larger number of emergency nurses, our program created the Trauma Nurse Academy. This academy provides a core of experienced nurses with an advanced level of training while decreasing the variability of personnel in the trauma bay. Components of the academy include multidisciplinary didactic education, the Essentials of TeamSTEPPS, and interactive trauma bay learning, to include both equipment and drug use. Once completed, academy graduates participate in the orientation and training of General Surgery and Emergency Medicine residents' trauma bay experience and injury prevention activities. RESULTS: Internal and published data have demonstrated growing evidence linking trauma teamwork training to knowledge and self-confidence in clinical judgment to team performance, patient outcomes, and quality of care. IMPLICATIONS FOR PRACTICE: Although trauma resuscitations are stressful, high risk, dynamic, and a prime environment for error, new methods of teamwork training and collaboration among trauma team members have become essential. PMID- 28629582 TI - A 32-Year-Old Woman with Postpartum Cardiac Arrest. PMID- 28629583 TI - Ex vivo retrieval and cryopreservation of oocytes from oophorectomized specimens for fertility preservation in a BRCA1 mutation carrier with ovarian cancer. AB - OBJECTIVE: To report a case of ex vivo oocyte retrieval from oophorectomized specimens in a BRCA1 mutation carrier undergoing surgical staging for ovarian cancer. DESIGN: Video case report and literature review. SETTING: University affiliated center. PATIENT(S): A 37-year-old single woman, gravida 0, with a known BRCA1 mutation, presented to her oncologist with a complex right ovarian mass and elevated CA-125 level. Ovarian cancer was suspected, and the patient consented to complete surgical staging. Although she desired to cryopreserve oocytes for fertility preservation, conventional oocyte retrieval was deemed unsafe because follicular puncture would compromise the integrity of the ovarian capsule, thereby increasing the risk of malignant cell spillage and cancer upstaging. INTERVENTION(S): Luteal-phase ovarian stimulation with gonadotropins and letrozole was performed. Surgical staging was initiated 34 hours after the administration of the ovulatory trigger. MAIN OUTCOME MEASURE(S): Ex vivo retrieval of oocytes from bilateral oophorectomized specimens under direct visualization at the time of surgical staging. RESULT(S): Seven mature oocytes were retrieved and vitrified. Concomitant surgical staging was completed. CONCLUSION(S): The present case highlights the feasibility of ex vivo or extracorporeal retrieval of mature oocytes from oophorectomized specimens in patients with ovarian cancer. By avoiding follicular puncture within the pelvic cavity, it minimizes the risk of malignant cell spillage and cancer upstaging. PMID- 28629585 TI - Sensory capability of young, middle-aged and elderly Irish assessors to identify beef steaks of varying texture. AB - This study assessed the capability of various Irish assessor age cohorts to identify beef steaks of varying texture. Varying steak textures Moderately Tough (MTH), Moderately Tender (MTR) and Tender (TR) were achieved by aging beef longissimus thoracis et lumborum (LTL) muscle for 2, 7 and 21days respectively. Warner Bratzler Shear Force (WBSF) was measured to standardise the samples. Sensory evaluation was carried using 428 participants; 18-30yrs (years) (n=143), 31-60yrs (n=80), 61-75yrs (n=99) and 76-85yrs old (n=106). Within 6 age cohort categories (18-70), significant positive and negative correlations were observed for TR and MTH tenderness categories respectively. Poor identification of tenderness classification was found in the 71-85 age cohort groupings. Consequently more research is required in this area so that guidelines could be presented for industrial uptake. This study supports the hypothesis that changes in textural perception occur with age in humans. PMID- 28629584 TI - Association of vitamin D intake and serum levels with fertility: results from the Lifestyle and Fertility Study. AB - OBJECTIVE: To evaluate the role of vitamin D intake and serum levels on conception of clinical pregnancy and live birth. DESIGN: Prospective cohort study. SETTING: Academic medical centers. PATIENT(S): Healthy, nulliparous women, age 18-39 years, and their male partners. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy and live birth were compared between those who did or did not meet the vitamin D estimated average requirement (EAR) intake (10 MUg/d) and with serum 25-hydroxyvitamin D (25(OH)D) considered at risk for inadequacy or deficiency (<50 nmol/L) or sufficient (>=50 nmol/L). RESULT(S): Among 132 women, 37.1% did not meet the vitamin D EAR and 13.9% had serum levels at risk for inadequacy or deficiency. Clinical pregnancies were significantly higher among women who met the vitamin D EAR (67.5% vs. 49.0%) and with sufficient serum 25(OH)D (64.3% vs. 38.9%) compared with those who did not. Live births were higher among those who met the vitamin D EAR (59.0% vs. 40.0%). The adjusted odds ratio (AOR) of conceiving a clinical pregnancy was significantly higher among those who met the EAR (AOR = 2.26; 95% confidence interval [CI], 1.05-4.86) and had sufficient serum 25(OH)D (AOR = 3.37; 95% CI, 1.06-10.70). The associations were not significant after controlling for selected nutrients and dietary quality. CONCLUSION(S): Women with vitamin D intake below EAR and serum 25(OH)D levels at risk for inadequacy or deficiency may be less likely to conceive and might benefit from increased vitamin D intake to achieve adequacy. CLINICAL TRIAL REGISTRATION NUMBER: NCT00642590. PMID- 28629587 TI - Microparticles in Chronic Heart Failure. AB - Heart failure (HF) continues to have a sufficient impact on morbidity, mortality, and disability in developed countries. Growing evidence supports the hypothesis that microparticles (MPs) might contribute to the pathogenesis of the HF development playing a pivotal role in the regulation of the endogenous repair system, thrombosis, coagulation, inflammation, immunity, and metabolic memory phenomenon. Therefore, there is a large body of data clarifying the predictive value of MP numerous in circulation among subjects with HF. Although the determination of MP signature is better than measurement of single MP circulating level, there is not yet close confirmation that immune phenotype of cells produced MPs are important for HF prediction and development. The aim of the chapter is to summarize knowledge regarding the role of various MPs in diagnosis and prognosis of HF. The role of MPs as a delivery vehicle for drugs attenuated cardiac remodeling is considered. PMID- 28629586 TI - Re: Maria Carmen Mir, Ithaar Derweesh, Francesco Porpiglia, Homayoun Zargar, Alexandre Mottrie, Riccardo Autorino. Partial Nephrectomy Versus Radical Nephrectomy for Clinical T1b and T2 Renal Tumors: A Systematic Review and Meta analysis of Comparative Studies. Eur Urol. 2017;71:606-17. PMID- 28629588 TI - Human Papillomavirus and Its Testing Assays, Cervical Cancer Screening, and Vaccination. AB - Human papillomavirus (HPV) was found to be the causative agent for cervical cancer in the 1980s with almost 100% of cervical cancer cases testing positive for HPV. Since then, many studies have been conducted to elucidate the molecular basis of HPV, the mechanisms of carcinogenesis of the virus, and the risk factors for HPV infection. Traditionally, the Papanicolaou test was the primary screening method for cervical cancer. Because of the discovery and evolving understanding of the role of HPV in cervical dysplasia, HPV testing has been recommended as a new method for cervical cancer screening by major professional organizations including the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology. In order to detect HPV infections, many sensitive and specific HPV assays have been developed and used clinically. Different HPV assays with various principles have shown their unique advantages and limitations. In response to a clear causative relationship between high-risk HPV and cervical cancer, HPV vaccines have been developed which utilize virus-like particles to create an antibody response for the prevention of HPV infection. The vaccines have been shown in long-term follow up studies to be effective for up to 8 years; however, how this may impact screening for vaccinated women remains uncertain. In this chapter, we will review the molecular basis of HPV, its pathogenesis, and the epidemiology of HPV infection and associated cervical cancer, discuss the methods of currently available HPV testing assays as well as recent guidelines for HPV screening, and introduce HPV vaccines as well as their impact on cervical cancer screening and treatments. PMID- 28629589 TI - Physical Exercise and DNA Injury: Good or Evil? AB - Regular, low-intensity physical activity is currently advocated for lowering the risk of developing many acute and especially chronic diseases. However, several lines of evidence attest that strenuous exercise may enhance inflammation and trigger the generation of free radical-mediated damage, thus overwhelming the undisputable benefits of regular, medium-intensity physical activity. Since reactive oxygen species are actively generated during high-intensity exercise, and these reactive compounds are known to impact DNA stability, we review here the current evidence about strenuous exercise and DNA injury. Despite the outcome of the various studies cannot be pooled due to considerable variation in design, sample population, outcome, and analytical techniques used to assess DNA damage, it seems reasonable to conclude that medium- to high-volume exercise triggers a certain amount of DNA injury, which appears to be transitory and directly proportional to exercise intensity. This damage, reasonably attributable to direct effect of free radicals on nucleic acids, is efficiently repaired in vivo within 24-72h. Therefore, physical exercise should not bear long-term consequences for athlete's health provided that an appropriate time of recovery between volumes of high-intensity exercise is set. Regular exertion, with a step by-step increase of exercise load, also seems to be the most safe approach for eluding DNA instability. PMID- 28629590 TI - Bulky DNA Adducts, Tobacco Smoking, Genetic Susceptibility, and Lung Cancer Risk. AB - The generation of bulky DNA adducts consists of conjugates formed between large reactive electrophiles and DNA-binding sites. The term "bulky DNA adducts" comes from early experiments that employed a 32P-DNA postlabeling approach. This technique has long been used to elucidate the association between adducts and carcinogen exposure in tobacco smoke studies and assess the predictive value of adducts in cancer risk. Molecular data showed increased DNA adducts in respiratory tracts of smokers vs nonsmokers. Experimental studies and meta analysis demonstrated that the relationship between adducts and carcinogens was linear at low doses, but reached steady state at high exposure, possibly due to metabolic and DNA repair pathway saturation and increased apoptosis. Polymorphisms of metabolic and DNA repair genes can increase the effects of environmental factors and confer greater likelihood of adduct formation. Nevertheless, the central question remains as to whether bulky adducts cause human cancer. If so, lowering them would reduce cancer incidence. Pooled and meta analysis has shown that smokers with increased adducts have increased risk of lung cancer. Adduct excess in smokers, especially in prospective longitudinal studies, supports their use as biomarkers predictive of lung cancer. PMID- 28629591 TI - Peptide Antibodies in Clinical Laboratory Diagnostics. AB - Peptide antibodies, with their high specificities and affinities, are invaluable reagents for peptide and protein recognition in biological specimens. Depending on the application and the assay, in which the peptide antibody is to used, several factors influence successful antibody production, including peptide selection and antibody screening. Peptide antibodies have been used in clinical laboratory diagnostics with great success for decades, primarily because they can be produced to multiple targets, recognizing native wildtype proteins, denatured proteins, and newly generated epitopes. Especially mutation-specific peptide antibodies have become important as diagnostic tools in the detection of various cancers. In addition to their use as diagnostic tools in malignant and premalignant conditions, peptide antibodies are applied in all other areas of clinical laboratory diagnostics, including endocrinology, hematology, neurodegenerative diseases, cardiovascular diseases, infectious diseases, and amyloidoses. PMID- 28629593 TI - Preface. PMID- 28629592 TI - Measurement and Clinical Utility of betaCTX in Serum and Plasma. AB - Biochemical markers of bone turnover (BTM) are released during bone remodeling and can be measured in blood or urine as noninvasive surrogate markers for the bone remodeling rate. The C-terminal cross-linked telopeptide of type I collagen (betaCTX) is released during bone resorption and is specific to bone tissue. Assays have been developed to measure betaCTX in blood and in urine; most current use of betaCTX measurement for research and in clinical practice is performed on a blood sample. Method-specific differences for serum and plasma betaCTX have led to initiatives to standardize or harmonize betaCTX commercial assays. betaCTX demonstrates significant biological variation due to circadian rhythm and effect of food which can be minimized by standardized sample collection in the fasting state in the morning. While betaCTX predicts fracture risk independent of bone mineral density, lack of data has precluded its inclusion in fracture risk calculators. The changes seen in betaCTX with antiresorptive therapies have been well characterized and this has led to its widespread use for monitoring therapy in osteoporosis. However, more fracture-based data on appropriate treatment goals for monitoring need to be developed. Evidence is lacking for the use of betaCTX in managing "drug holidays" of bisphosphonate treatment in osteoporosis or risk stratifying those at increased risk of developing osteonecrosis of the jaw. betaCTX is useful as an adjunct to imaging techniques for the diagnosis of Paget's disease of bone and for monitoring therapy and detecting recurrence. betaCTX also shows promise in the management of metastatic bone disease. PMID- 28629594 TI - The discovery of benzoxazine sulfonamide inhibitors of NaV1.7: Tools that bridge efficacy and target engagement. AB - The voltage-gated sodium channel NaV1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss of-function mutations to pain phenotypes. Despite this genetic validation of NaV1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat NaV1.7 versus human NaV1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse NaV1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement. PMID- 28629595 TI - A novel intestinal-restricted FXR agonist. AB - In this study, a new intestinal-restricted FXR agonist named fexaramine-3 (Fex-3) was developed and investigated both in vitro and in vivo. Fex-3 could selectively activate intestinal FXR and promote the expression of BSEP and SHP while suppressing CYP7A1 which is involved in bile acids syntheses better than the reported intestinal-restricted FXR agonist fexaramine (Fex). We demonstrated that Fex-3 targeted on FXR in ileum and has better selectivity than Fex. And the study of utilizing Fex-3 to reduce obesity was undergoing. PMID- 28629596 TI - Attaining precision therapy in prostate cancer: A tall order. PMID- 28629597 TI - Special issue on Gradients in Biomaterials. PMID- 28629598 TI - Is there a genetic support for the Cloninger (type I/II) clinical classification of alcohol addiction? PMID- 28629599 TI - Moral learning: Psychological and philosophical perspectives. AB - The past 15years occasioned an extraordinary blossoming of research into the cognitive and affective mechanisms that support moral judgment and behavior. This growth in our understanding of moral mechanisms overshadowed a crucial and complementary question, however: How are they learned? As this special issue of the journal Cognition attests, a new crop of research into moral learning has now firmly taken root. This new literature draws on recent advances in formal methods developed in other domains, such as Bayesian inference, reinforcement learning and other machine learning techniques. Meanwhile, it also demonstrates how learning and deciding in a social domain-and especially in the moral domain sometimes involves specialized cognitive systems. We review the contributions to this special issue and situate them within the broader contemporary literature. Our review focuses on how we learn moral values and moral rules, how we learn about personal moral character and relationships, and the philosophical implications of these emerging models. PMID- 28629600 TI - Multiple mechanisms of neurodegeneration and progression. PMID- 28629601 TI - A custom-made temporomandibular joint prosthesis for fabrication by selective laser melting: Finite element analysis. AB - A novel and custom-made selective laser melting (SLM) 3D-printed alloplastic temporomandibular joint (TMJ) prosthesis is proposed. The titanium-6aluminium 4vanadium (Ti-6Al-4V) condyle component and ultra-high molecular weight polyethylene (UHMWPE) fossa component comprised the total alloplastic TMJ replacement prosthesis. For the condyle component, an optimized tetrahedral open porous scaffold with combined connection structures, i.e. an inlay rod and an onlay plate, between the prosthesis and remaining mandible was designed. The trajectory of movement of the intact condyle was assessed via kinematic analysis to facilitate the design of the fossa component. The behaviours of the intact mandible and mandible with the prosthesis were compared. The biomechanical behaviour was analysed by assessing the stress distribution on the prosthesis and strain distribution on the mandible. After muscle force was applied, the magnitude of the compressive strain on the condyle neck of the mandible with the prosthesis was lower than that on the condyle neck of the intact mandible, with the exception of the area about the screws; additionally, the magnitude of the strain at the scaffold-bone interface was relatively high. PMID- 28629603 TI - Demographics. PMID- 28629602 TI - Management of dentin hypersensitivity by practitioners in The National Dental Practice-Based Research Network. AB - BACKGROUND: Dentin hypersensitivity (DH) is a condition commonly encountered in clinical dental practice. The authors conduct a study to identify the treatments recommended to manage DH among dentists in the United States. METHODS: The authors conducted a multicenter study of 1,862 patients with DH who received a diagnosis and were treated by 171 dentists with The National Dental Practice Based Research Network. RESULTS: The most common treatment recommended was desensitizing over-the-counter (OTC) potassium nitrate toothpaste (alone or in combination with other treatments) for 924 of 1,862 patients (50%). This was followed by an application of fluoride varnish (FV) for 516 patients (28%) and a prescription for fluoride toothpaste for 314 patients (17%). Restorative treatments were recommended to 151 patients (8%). The most common single treatment recommendation was desensitizing OTC potassium nitrate toothpaste, recommended to 335 patients (18%). The most frequent combination of 2 treatment modalities was FV and desensitizing OTC potassium nitrate toothpaste, recommended to 100 patients (5%). A total of 890 of 1,862 patients (48%) with DH received a recommendation for 1 treatment modality, and 644 of 1,862 patients (35%) received a recommendation for a combination of 2 treatment modalities, most frequently an application of FV along with desensitizing OTC potassium nitrate toothpaste (100/1,862; 5%). CONCLUSIONS: Desensitizing OTC potassium nitrate toothpaste and fluoride products were the most widely recommended products to manage DH in the practice setting. PRACTICAL IMPLICATIONS: Our results suggest that most network clinicians preferred noninvasive treatment modalities when treating DH. PMID- 28629605 TI - CT findings in 11 patients with TAFRO syndrome: a variant of multicentric Castleman's disease. AB - AIM: To assess detailed computed tomography (CT) findings in patients with the recently described thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome, in order to contribute to imaging interpretation in the challenging diagnosis of this disease. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the need for informed consent. Eleven patients (six men, five women; mean age, 52.5 years) with confirmed TAFRO syndrome were included in this study. Chest-to-pelvis CT images were analysed for the presence of anasarca, organomegaly, bone lesions, and lung lesions. RESULTS: Anasarca was present in all patients and involved multiple cavities and tissues; pleural effusion and ascites were found in 100% of patients; pericardial effusion in 64%; periportal collar in 91%; gallbladder wall oedema in 78%; subcutaneous oedema in 91%; retroperitoneal oedema in 100%; and mesenteric oedema in 100%. Organomegaly involved multiple organs: hepatomegaly in 73%, splenomegaly in 82%, lymphadenopathy in 100%, and enlarged anterior mediastinum in 64% (solitary, well-circumscribed mass, 0%; infiltrative mass, 0%; non-mass-forming infiltrative lesion, 64%). Bone lesions were present in 91% patients and all bone lesions had ground-glass density with diffuse distribution. None of the patients had any lesions in their lungs. CONCLUSION: The present study revealed that the findings of anasarca, organomegaly, and diffuse bony ground-glass appearance were observed in detail on CT in patients with TAFRO syndrome. A "matted" appearance of the enlarged anterior mediastinum is the characteristic CT finding of TAFRO syndrome, and it is possible to diagnose TAFRO syndrome from the combination of several CT findings. PMID- 28629604 TI - Novel FKRP mutations in a Japanese MDC1C sibship clinically diagnosed with Fukuyama congenital muscular dystrophy. AB - INTRODUCTION: Fukuyama congenital muscular dystrophy (FCMD), caused by fukutin mutations, is the most common form of Japanese CMD. We followed a Japanese CMD sibship without fukutin mutation, and herein identified new FKRP mutations causing MDC1C rarely reported in Oriental countries. PATIENTS: Two affected siblings, individuals 1 (I-1, male) and 2 (I-2, female), were born uneventfully to unaffected, non-consanguineous parents. Severe hypotonia was soon apparent and serum CK levels were elevated: I-1: 1025 IU/L (normal range <130 IU/L) and I-2: 5350 IU/L. I-1 had neither shown head control, nor said any words until he died of pneumonia at the age of 23months. I-2 learned to sit at 4years and 10months and spoke sentences at 6years and 5months. She had received respiratory support since 9years of age and died at 22years. Both showed a low-density area in the cerebral white matter on CT. MRI of I-2 revealed diffuse hyperintensity in the cerebral white matter on T2-WI, polymicrogyria over the frontal and parietal lobes, and disorganized folia and cysts in the cerebellum. METHODS AND RESULTS: Next generation and Sanger sequencing were performed for I-2. Heterozygous FKRP mutations were identified in exon 4: c.1167_1168delGC, p.Gly391Leufs*72 and c.501_502GT>CC, p.Arg167Ser, p.Cys168Arg. DISCUSSION: Recently, fukutin and FKRP were identified as sequentially acting ribitol 5-phosphate transferases involved in the post-translational modification of alpha-dystroglycan. This may explain the clinical similarities between the two disorders. PMID- 28629606 TI - Evidence for a higher resolution of HLA genotyping by a new NGS-based approach. AB - With more than 16,000 alleles identified, the human leucocyte antigen (HLA) system is one of the most polymorphic regions of the human genome. Regarding the crucial role of HLA compatibility in transplantation and especially in Hematopoietic Stem Cell Transplantation, identification of HLA polymorphisms at a high-resolution level is of major interest. Recently, NGS technology has been proposed which appears to be simpler and more informative than the classical molecular methods such as SSP, SSOr and SBT. In the present report, a new set of NGS reagents and the appropriate associated software for sequence analysis are described. Through different studies, the performances of the system are illustrated and demonstrate that the method herein described overcomes current limitations in performing high-resolution HLA typing in clinical laboratories. PMID- 28629607 TI - Post-operative management of perforated appendicitis: Can clinical pathways improve outcomes? AB - BACKGROUND: We sought to decrease organ space infection (OSI) following appendectomy for perforated acute appendicitis (PAA) by minimizing variation in clinical management. OBJECTIVE: A postoperative treatment pathway was developed and four recommendations were implemented: 1) clear documentation of post operative diagnosis, 2) patients with unknown perforation status to be treated as perforated pending definitive diagnosis, 3) antibiotic therapy to be continued post operatively for 4-7 days after SIRS resolution, and 4) judicious use of abdominal computed tomography (CT) scanning prior to post-operative day 5. Patient demographics and potential clinical predictors of OSI were captured. The primary end point was development of OSI within 30 days of discharge. Secondary endpoints included length of stay (LOS), readmission rate, other complications and secondary procedures performed. RESULTS: A total of 1246 appendectomies were performed and we excluded patients <18 years (n = 205), interval appendectomies (n = 51) or appendectomies for other diagnosis (n = 37). Among the remaining 953 patients, 133 (14.0%) were perforated and 21 of these (15.8%) developed OSI. Comparing pre (n = 91) to post (n = 42) protocol patients, we saw similar rates of OSI (16.5 vs 14.3%, p = 0.75) with a peak in OSI development immediately prior to protocol implementation which dropped to baseline levels 1 year later based on CUSUM analysis. Readmission rates fell by 49.7% (14.3 vs 7.1%, p = 0.39) without increase in LOS (5.3 vs 5.7 days, p = 0.55) comparing patients pre and post protocol, although these results did not reach clinical significance. CONCLUSIONS: The implementation of and compliance with a post-operative protocol status post appendectomy for PAA demonstrated a trend towards diminishing readmission rates and decreased utilization of CT imaging, but did not affect OSI rates. Additional approaches to diminishing OSI following management of perforated appendicitis need to be evaluated. PMID- 28629609 TI - Outcomes after laparoscopic or robotic colectomy and open colectomy when compared by operative duration for the procedure. AB - Laparoscopic colectomy is associated with important early postoperative advantages. These procedures can however increase total operative duration. Our hypothesis is that increased operative duration is associated with post-operative complications that may outweigh the benefits of a minimally invasive approach. We analyzed data from the Michigan Surgical Quality Collaborative (MSQC)R. This is a statewide database of patients who have undergone colon or rectal resections. Colorectal procedures were divided into four groups by surgical approach: open, laparoscopic, robotic and laparoscopic and robotic procedures converted to open. The sample was divided into three groups by operative duration: less than 2 h, between 2 and 4 h and greater than 4 h and compared by selected preoperative variables and outcomes. Small but significant differences in perioperative outcomes were noted in colectomies with a >4 h operative duration. However, laparoscopic procedures exceeding 4 h were not associated with significant differences perioperative outcomes. PMID- 28629608 TI - Laparotomy and intraoperative enteroscopy for obscure gastrointestinal bleeding before and after the era of video capsule endoscopy and deep enteroscopy: A tertiary center experience. AB - BACKGROUND: To evaluate roles of intraoperative endoscopy (IOE) in management of severe obscure GI bleeding (OGIB) before vs. after introduction of video capsule endoscopy (VCE) and deep enteroscopy (DE). METHODS: We retrospectively reviewed prospectively collected data of patients undergoing IOE for severe OGIB in a tertiary referral center. RESULTS: 52 patients had laparotomy/IOE for OGIB, 11 pre and 41 post VCE/DE eras. In the pre VCE/DE era, 36.4% (4/11) had preoperative presumptive diagnoses while in the post VCE/DE era presumptive diagnoses were made in 48.8% (20/41) (p = 0.18). Preoperative evaluation led to correct diagnoses in 18.2% (2/11) in the pre and 51.2% (21/41) in the post VCE/DE era (p = 0.09). Vascular lesions and ulcers were the most common diagnoses, but rebleeding was common. No rebleeding was found among patients with tumors, Meckel's diverticulum, and aortoenteric fistula. CONCLUSIONS: Presumptive diagnoses in the post VCE/DE era were usually accurate. If VCE or DE are negative, the probability of negative IOE is high. Patients with tumors and Meckel's diverticulum were the best candidates for IOE. PMID- 28629611 TI - Sentinel lymph node mapping in minimally invasive surgery: Role of imaging with color-segmented fluorescence (CSF). AB - OBJECTIVE: Sentinel lymph node mapping, alone or in combination with pelvic lymphadenectomy, is considered a standard approach in staging of patients with cervical or endometrial cancer [1-3]. The goal of this video is to demonstrate the use of indocyanine green (ICG) and color-segmented fluorescence when performing lymphatic mapping in patients with gynecologic malignancies. METHODS: Injection of ICG is performed in two cervical sites using 1mL (0.5mL superficial and deep, respectively) at the 3 and 9 o'clock position. Sentinel lymph nodes are identified intraoperatively using the Pinpoint near-infrared imaging system (Novadaq, Ontario, CA). Color-segmented fluorescence is used to image different levels of ICG uptake demonstrating higher levels of perfusion. A color key on the side of the monitor shows the colors that coordinate with different levels of ICG uptake. Color-segmented fluorescence may help surgeons identify true sentinel nodes from fatty tissue that, although absorbing fluorescent dye, does not contain true nodal tissue. It is not intended to differentiate the primary sentinel node from secondary sentinel nodes. The key ranges from low levels of ICG uptake (gray) to the highest rate of ICG uptake (red). RESULTS: Bilateral sentinel lymph nodes are identified along the external iliac vessels using both standard and color-segmented fluorescence. No evidence of disease was noted after ultra-staging was performed in each of the sentinel nodes. CONCLUSION: Use of ICG in sentinel lymph node mapping allows for high bilateral detection rates. Color segmented fluorescence may increase accuracy of sentinel lymph node identification over standard fluorescent imaging. The following are the supplementary data related to this article. PMID- 28629610 TI - A Model for Assessing the Clinical and Economic Benefits of Bone-forming Agents for Reducing Fractures in Postmenopausal Women at High, Near-term Risk of Osteoporotic Fracture. AB - PURPOSE: The goal of this study was to assess and compare the potential clinical and economic value of emerging bone-forming agents using the only currently available agent, teriparatide, as a reference case in patients at high, near-term (imminent, 1- to 2-year) risk of osteoporotic fractures, extending to a lifetime horizon with sequenced antiresorptive agents for maintenance treatment. METHODS: Analyses were performed by using a Markov cohort model accounting for time specific fracture protection effects of bone-forming agents followed by antiresorptive treatment with denosumab. The alternative bone-forming agent profiles were defined by using assumptions regarding the onset and total magnitude of protection against fractures with teriparatide. The model cohort comprised 70-year-old female patients with T scores below -2.5 and a previous vertebral fracture. Outcomes included clinical fractures, direct costs, and quality-adjusted life years. The simulated treatment strategies were compared by calculating their incremental "value" (net monetary benefit). FINDINGS: Improvements in the onset and magnitude of fracture protection (vs the teriparatide reference case) produced a net monetary benefit of $17,000,000 per 10,000 treated patients during the (1.5-year) bone-forming agent treatment period and $80,000,000 over a lifetime horizon that included 3.5 years of maintenance treatment with denosumab. IMPLICATIONS: Incorporating time-specific fracture effects in the Markov cohort model allowed for estimation of a range of cost savings, quality-adjusted life years gained, and clinical fractures avoided at different levels of fracture protection onset and magnitude. Results provide a first estimate of the potential "value" new bone-forming agents (romosozumab and abaloparatide) may confer relative to teriparatide. PMID- 28629612 TI - Structural Basis for Ribosome Rescue in Bacteria. AB - Ribosomes that translate mRNAs lacking stop codons become stalled at the 3' end of the mRNA. Recycling of these stalled ribosomes is essential for cell viability. In bacteria three ribosome rescue systems have been identified so far, with the most ubiquitous and best characterized being the trans-translation system mediated by transfer-messenger RNA (tmRNA) and small protein B (SmpB). The two additional rescue systems present in some bacteria employ alternative rescue factor (Arf) A and release factor (RF) 2 or ArfB. Recent structures have revealed how ArfA mediates ribosome rescue by recruiting the canonical termination factor RF2 to ribosomes stalled on truncated mRNAs. This now provides us with the opportunity to compare and contrast the available structures of all three bacterial ribosome rescue systems. PMID- 28629613 TI - Out of the institution, into the classroom: Legal challenges to the use of restraint and seclusion in school settings in the United States. AB - The issue of restraint and seclusion of children with mental and developmental disabilities in schools has gained greater attention in the United States in recent years as more children with disabilities are attending mainstream schools. This article looks at how cases brought on behalf of children who have been subjected to such treatment fit or fail to fit within a well-developed jurisprudence that provides constitutional protections for the rights of people with mental disabilities to be free from discrimination and from cruel and unusual punishment. It examines this jurisprudence in light of Article 16's emphasis on the provision of age- and gender-appropriate services to protect people with disabilities from exploitation, violence, and abuse.1. PMID- 28629614 TI - Molecular detection methods of resistance to antituberculosis drugs in Mycobacterium tuberculosis. AB - OBJECTIVE: Molecular methods predict drug resistance several weeks before phenotypic methods and enable rapid implementation of appropriate therapeutic treatment. We aimed to detail the most representative molecular tools used in routine practice for the rapid detection of resistance to antituberculosis drugs among Mycobacterium tuberculosis strains. MATERIALS AND METHODS: The molecular diagnosis of resistance to antituberculosis drugs in clinical samples or from in vitro cultures is based on the detection of the most common mutations in the genes involved in the development of resistance in M. tuberculosis strains (encoding either protein targets of antibiotics, or antibiotic activating enzymes) by commercial molecular kits or by sequencing. RESULTS: Three hypotheses could explain the discrepancies between the genotypic results and the phenotypic drug susceptibility testing results: a low percentage of resistant mutants precluding the detection by genotypic methods on the primary culture; a low level of resistance not detected by phenotypic testing; and other resistance mechanisms not yet characterized. DISCUSSION/CONCLUSIONS: Molecular methods have varying sensitivity with regards to detecting antituberculosis drug resistance; that is why phenotypic susceptibility testing methods are mandatory for detecting antituberculosis drug-resistant isolates that have not been detected by molecular methods. The questionable ability of existing phenotypic and genotypic drug susceptibility testing to properly classify strains as susceptible or resistant, and at what level of resistance, was raised for several antituberculosis agents. PMID- 28629615 TI - A simple method to compare firing pin marks using stereomicroscope and Microsoft office (Windows 8) tools. AB - Pertinent marks of fired cartridge cases such as firing pin, breech face, extractor, ejector, etc. are used for firearm identification. A non-standard semiautomatic pistol and four .22rim fire cartridges (head stamp KF) is used for known source comparison study. Two test fired cartridge cases are examined under stereomicroscope. The characteristic marks are captured by digital camera and comparative analysis of striation marks is done by using different tools available in the Microsoft word (Windows 8) of a computer system. The similarities of striation marks thus obtained are highly convincing to identify the firearm. In this paper, an effort has been made to study and compare the striation marks of two fired cartridge cases using stereomicroscope, digital camera and computer system. Comparison microscope is not used in this study. The method described in this study is simple, cost effective, transport to field study and can be equipped in a crime scene vehicle to facilitate immediate on spot examination. The findings may be highly helpful to the forensic community, law enforcement agencies and students. PMID- 28629616 TI - Cytotoxic steroidal saponins from Panicum turgidum Forssk. AB - Three new bidesmosidic cholestane-type steroidal glycosides, 16-O-beta-d glucopyranosyl-cholest-5-en-3beta,16beta-diol-22-one-3-O-alpha-l-rhamnopyranosyl (1->2)-O-[(beta-d-glucopyranosyl(1->4)]-O-beta-d-glucopyranoside (1), 16-O-beta-d glucopyranosylcholest-5-en-3beta,16beta-diol-22-one-3-O-alpha-l-rhamnopyranosyl (1->2)-O-beta-d-glucopyranoside (2), and 16-O-beta-d-glucopyranosylcholestan 3beta,16beta-diol-6,22-dione-3-O-alpha-l-rhamnopyranosyl-(1->2)-O-beta-d glucopyranoside (3) were isolated from a methanolic extract of Panicum turgidum. In addition four known compounds, pennogenin 3beta-O-alpha-l-rhamnopyranosyl-(1 >2)-O-[alpha-l-rhamnopyranosyl-(1->4)-O-alpha-l-rhamnopyranosyl-(1->4)]-O-beta-d glucopyranoside (4), yamogenin 3beta-O-alpha-l-rhamnopyranosyl-(1->2)-O-[alpha-l rhamnopyranosyl-(1->4)]-O-beta-d-glucopyranoside (5), yamogenin 3beta-O-alpha-l rhamnopyranosyl-(1->2)-O-[alpha-l-rhamnopyranosyl-(1->4)-O-alpha-l rhamnopyranosyl-(1->4)]-O-beta-d-glucopyranoside (6), and pennogenin 3beta-O alpha-l-rhamnopyranosyl-(1->2)-O-[alpha-l-rhamnopyranosyl-(1->4)]-O-beta-d glucopyranoside (7) were also isolated and characterized. Their structures were established using extensive spectroscopic methods including 1D and 2D NMR and HRESIMS. The isolated compounds were screened for cytotoxicity towards a panel of mammalian cell lines and 4-7 were found to be cytotoxic. PMID- 28629617 TI - Corrigendum to "Integrative therapy decreases the risk of lupus nephritis in patients with systemic lupus erythematosus: A population-based retrospective cohort study" [J. Ethnopharmacol. 196 (2017) 201-212]. PMID- 28629618 TI - Conditioning and Robustness of RNA Boltzmann Sampling under Thermodynamic Parameter Perturbations. AB - Understanding how RNA secondary structure prediction methods depend on the underlying nearest-neighbor thermodynamic model remains a fundamental challenge in the field. Minimum free energy (MFE) predictions are known to be "ill conditioned" in that small changes to the thermodynamic model can result in significantly different optimal structures. Hence, the best practice is now to sample from the Boltzmann distribution, which generates a set of suboptimal structures. Although the structural signal of this Boltzmann sample is known to be robust to stochastic noise, the conditioning and robustness under thermodynamic perturbations have yet to be addressed. We present here a mathematically rigorous model for conditioning inspired by numerical analysis, and also a biologically inspired definition for robustness under thermodynamic perturbation. We demonstrate the strong correlation between conditioning and robustness and use its tight relationship to define quantitative thresholds for well versus ill conditioning. These resulting thresholds demonstrate that the majority of the sequences are at least sample robust, which verifies the assumption of sampling's improved conditioning over the MFE prediction. Furthermore, because we find no correlation between conditioning and MFE accuracy, the presence of both well- and ill-conditioned sequences indicates the continued need for both thermodynamic model refinements and alternate RNA structure prediction methods beyond the physics-based ones. PMID- 28629619 TI - Slow Interconversion in a Heterogeneous Unfolded-State Ensemble of Outer-Membrane Phospholipase A. AB - Structural and dynamic investigations of unfolded proteins are important for understanding protein-folding mechanisms as well as the interactions of unfolded polypeptide chains with other cell components. In the case of outer-membrane proteins (OMPs), unfolded-state properties are of particular physiological relevance, because these proteins remain unfolded for extended periods of time during their biogenesis and rely on interactions with binding partners to support proper folding. Using a combination of ensemble and single-molecule spectroscopy, we have scrutinized the unfolded state of outer-membrane phospholipase A (OmpLA) to provide a detailed view of its structural dynamics on timescales from nanoseconds to milliseconds. We find that even under strongly denaturing conditions and in the absence of residual secondary structure, OmpLA populates an ensemble of slowly (>100 ms) interconverting and conformationally heterogeneous unfolded states that lack the fast chain-reconfiguration motions expected for an unstructured, fully unfolded chain. The drastically slowed sampling of potentially folding-competent states, as compared with a random-coil polypeptide, may contribute to the slow in vitro folding kinetics observed for many OMPs. In vivo, however, slow intramolecular long-range dynamics might be advantageous for entropically favored binding of unfolded OMPs to chaperones and, by facilitating conformational selection after release from chaperones, for preserving binding competent conformations before insertion into the outer membrane. PMID- 28629620 TI - Effects of Inhibiting VPS4 Support a General Role for ESCRTs in Extracellular Vesicle Biogenesis. AB - Extracellular vesicles (EVs) are proposed to play important roles in intercellular communication. Two classes of EVs can be distinguished based on their intracellular origin. Exosomes are generated within endosomes and released when these fuse with the plasma membrane, whereas ectosomes bud directly from the plasma membrane. Studies of EV function have been hindered by limited understanding of their biogenesis. Components of the endosomal sorting complex required for transport (ESCRT) machinery play essential roles in topologically equivalent processes at both the endosome and the plasma membrane and are consistently recovered in EVs, but whether they are generally required to produce EVs is still debated. Here, we study the effects of inhibiting the ESCRT associated AAA+ ATPase VPS4 on EV release from cultured cells using two methods for EV recovery, differential centrifugation and polyethylene glycol precipitation followed by lectin affinity chromatography. We find that inhibiting VPS4 in HEK293 cells decreases release of EV-associated proteins and miRNA as well as the overall number of EV particles. The tetraspanins CD63 and CD9 are among the most frequently monitored EV proteins, but they differ in their subcellular localization, with CD63 primarily in endosomes and CD9 on the plasma membrane. We find that CD63 and CD9 are enriched in separable populations of EVs that are both sensitive to VPS4 inhibition. Serum stimulation increases release of both types of EVs and is also reduced by inhibiting VPS4. Taken together, our data indicate that VPS4 activity is important for generating exosomes and ectosomes, thereby generally implicating the ESCRT machinery in EV biogenesis. PMID- 28629621 TI - Differential effect of obesity on prevalence of cardiac and carotid target organ damage in hypertension (the Campania Salute Network). AB - BACKGROUND: Whether increasing body mass index (BMI) is independently associated with parallel increased prevalence of hypertensive vascular and cardiac target organ damage (TOD) needs further clarification. METHODS: We analyzed 8815 hypertensive patients without prevalent cardiovascular disease, participating in the Campania Salute Network, grouped into BMI classes (normal 20-24.9kg/m2, overweight 25-29.9kg/m2 and obese >=30kg/m2). Vascular and cardiac TOD was defined as ultrasound plaque (intima-media thickness>1.5mm) in >1 of the common or internal carotid arteries and echocardiographic left ventricular (LV) hypertrophy (LVH) (LV mass/height2.7>47g/m2.7 in women and >50g/m2.7 in men), respectively. RESULTS: A majority of patients were either overweight (49%) or obese (27%). In spite of more use of combination therapy, the obese group had higher blood pressure (BP) and prevalence of TOD. In multivariate logistic analyses, obesity was associated with a 6.9 times higher prevalence of LVH (95% confidence interval [CI] 5.84-8.17, p=0.0001), independent of significant associations with female sex, age, diabetes mellitus, office systolic BP, antihypertensive and antiplatelet treatment. In contrast, only a 17% increased prevalence of carotid plaques (OR=1.17; 95% CI 1.02-1.33, p=0.02) was found in obese patients independent of significant effect of male sex, older age and higher clinic systolic BP, an association that disappeared once effect of metabolic risk factors and related therapy was also considered. CONCLUSIONS: In hypertensive patients participating in the Campania Salute Project, concomitant obesity was associated with a modestly increased prevalence of carotid plaques and a pronounced increase in prevalent LVH. PMID- 28629622 TI - Optical coherence tomography compared with fractional flow reserve guided approach in acute coronary syndromes: A propensity matched analysis. AB - AIM: To compare in patients with ACS (acute coronary syndromes) a PCI (percutaneous coronary intervention) approach based on FFR (fractional flow reserve) vs. one based on OCT (optical coherence tomography). METHODS AND RESULTS: Consecutive patients admitted for ACS and treated with a PCI approach based on OCT or on FFR (recruited in two different studies) were compared and matched with propensity score analysis. Target Lesion revascularization (TLR) was the primary end point, while major adverse cardiovascular events [MACEs defined as the composite of death from cardiac causes, non-fatal MI, clinically driven target vessel revascularization (TVR), or re-hospitalization due to unstable angina] were the secondary ones. Sub-group analysis was performed for patients with FFR/OCT performed on culprit lesions and not. 285 patients were enrolled in the OCT-guided group and 335 in the FFR-guided group, 197 for each being selected after propensity score. After 25months (range: 7-39months), OCT-guided group were exposed to lower incidence of TLR (4.1% vs. 14.2% p<0.01) compared with FFR guided group without impact on MACEs (14.2% vs. 14.2%, p=1) or all-cause death (3.6% vs. 1.1%, p=0.34). At Kaplan-Maier curve analysis for MACEs OCT-guided and FFR-guided groups showed similar outcomes (HR 1.19, CI 0.65-2.2, p=0.54). Subgroup analysis on culprit and not culprit vessel demonstrated consistent results. CONCLUSIONS: An OCT based approach in ACS patients offers a reduction in TLR when compared to a PCI-FFR driven. These findings should be confirmed in randomized controlled trial. PMID- 28629623 TI - Exploring energy loss by vector flow mapping in children with ventricular septal defect: Pathophysiologic significance. AB - BACKGROUND: Vector flow mapping is a novel echocardiographic flow visualization method, and it has enabled us to quantitatively evaluate the energy loss in the left ventricle (intraventricular energy loss). Although intraventricular energy loss is assumed to be a part of left ventricular workload itself, it is unclear what this parameter actually represents. The aim of the present study was to elucidate the characteristics of intraventricular energy loss. METHODS: We enrolled 26 consecutive children with ventricular septal defect (VSD). On echocardiography vector flow mapping, intraventricular energy loss was measured in the apical 3-chamber view. We measured peak energy loss and averaged energy loss in the diastolic and systolic phases, and subsequently compared these parameters with catheterization parameters and serum brain natrium peptide (BNP) level. RESULTS: Diastolic, peak, and systolic energy loss were strongly and positively correlated with right ventricular systolic pressure (r=0.76, 0.68, and 0.56, p<0.0001, = 0.0001, and 0.0029, respectively) and right ventricular end diastolic pressure (r=0.55, 0.49, and 0.49, p=0.0038, 0.0120, and 0.0111, respectively). In addition, diastolic, peak, and systolic energy loss were significantly correlated with BNP (r=0.75, 0.69 and 0.49, p<0.0001, < 0.0001, and=0.0116, respectively). CONCLUSIONS: In children with VSD, elevated right ventricular pressure is one of the factors that increase energy loss in the left ventricle. The results of the present study encourage further studies in other study populations to elucidate the characteristics of intraventricular energy loss for its possible clinical application. PMID- 28629624 TI - The protective role of oestradiol against silent myocardial ischemia and hypertension risk in South African men: The SABPA study. AB - BACKGROUND: Oestradiol has a protective effect on coronary artery health in women but the effect it has on men, is controversial. A translational approach was followed to assess whether sex hormone levels are associated with silent myocardial ischemia (SMI) and hypertension risk over a 3year period. METHODS: Participants included 89 Black and 91 White men (aged 21-63years) participating in both phases of the Sympathetic activity and Ambulatory Blood Pressure in Africans prospective study. Fasting blood samples, ambulatory blood pressure and 2-lead ECG recordings were obtained. RESULTS: No difference in the levels of the various baseline serum T fractions between the two ethnic groups occurred. Oestradiol of the Black men increased by 54.2% compared to a decrease of 24.1% in the White men. Changes in total oestradiol (adjusted R2=0.33, beta=-0.31, p=0.023) and free oestradiol (adjusted R2=0.34, beta=-0.33, p=0.019) were inversely associated with changes in SMI in the Black men but not in White men. Baseline serum nitric oxide metabolites were inversely associated with DeltaSMI in the Blacks only (adjusted R2=0.33, beta=-0.28, p=0.047). Chronic SMI was associated with 24h hypertension in Blacks [cut point 1.5 events: Area under the curve 0.71 (95% CI: 0.60, 0.82); p=0.006; with sensitivity/specificity 44%/94%]. CONCLUSIONS: Chronic SMI events facilitated future ischemic heart disease in Black men. Up-regulated free oestradiol seems to be involved in the protection of the heart against SMI and hypertension risk in Black but not in White men. A similar protective role for testosterone could however not be shown. PMID- 28629625 TI - WITHDRAWN: What exactly, regression of atherosclerosis or foreign body reaction with hyaline arteriosclerosis, drives transient scaffolding of coronary arteries? A pooled analysis of observational ABSORB studies with a serial multimodality imaging substudy of ABSORB cohort B1 trial. PMID- 28629626 TI - Left atrial accessory appendages, diverticula, and left-sided septal pouch in multi-slice computed tomography. Association with atrial fibrillation and cerebrovascular accidents. AB - BACKGROUND: The aim of this study is to provide a morphometric description of the left-sided septal pouch (LSSP), left atrial accessory appendages, and diverticula using cardiac multi-slice computed tomography (MSCT) and to compare results between patient subgroups. METHODS: Two hundred and ninety four patients (42.9% females) with a mean of 69.4+/-13.1years of age were investigated using MSCT. The presence of the LSSP, left atrial accessory appendages, and diverticula was evaluated. Multiple logistic regression analysis was performed to check whether the presence of additional left atrial structures is associated with increased risk of atrial fibrillation and cerebrovascular accidents. RESULTS: At least one additional left atrial structure was present in 51.7% of patients. A single LSSP, left atrial diverticulum, and accessory appendage were present in 35.7%, 16.0%, and 4.1% of patients, respectively. After adjusting for other risk factors via multiple logistic regression, patients with LSSP are more likely to have atrial fibrillation (OR=2.00, 95% CI=1.14-3.48, p=0.01). The presence of a LSSP was found to be associated with an increased risk of transient ischemic attack using multiple logistic regression analysis after adjustment for other risk factors (OR=3.88, 95% CI=1.10-13.69, p=0.03). CONCLUSIONS: In conclusion LSSPs, accessory appendages, and diverticula are highly prevalent anatomic structures within the left atrium, which could be easily identified by MSCT. The presence of LSSP is associated with increased risk for atrial fibrillation and transient ischemic attack. PMID- 28629627 TI - Direct oral anticoagulants in patients with cervical artery dissection and cerebral venous thrombosis. A case series and review of the literature. AB - BACKGROUND: To date, very little is known about the effects of direct oral anticoagulants (DOA) use in patients with cervical artery dissection (CAD) and cerebral venous thrombosis (CVT). We present our initial experience with the use of DOA for CAD and CVT and an overview of the published literature. METHODS: From our database, we identified 4 patients who received DOA after CAD and 4 patients after CVT. Also, we analyzed the data reported for 45 patients who received DOA after CAD and 23 after CVT from review of the literature. RESULTS: Among patients with CAD, resolved or improved arterial stenosis was noted in 27 (55%), and symptomatic recurrent ischemic stroke in 2 (4%). Among patients with CVT, complete or partial recanalization was noted in 25 (90%), and no significant functional disability in 26 (93%). No patient developed intracranial hemorrhage. CONCLUSIONS: Although no statistical conclusions can be drawn from these data, DOA could be an alternative in patients with CAD-related embolic infarct and CVT related hemorrhagic venous infarct. A large-scale clinical trial will be needed to validate these results. PMID- 28629628 TI - Left ventricular outflow tract obstruction and its impact on systolic ventricular function and exercise capacity in adults with a subaortic right ventricle. AB - BACKGROUND: In biventricular hearts the filling and contractility of one ventricle affects the performance of the other. In this study, we compared right ventricular systolic function and exercise capacity in patients with a subaortic right ventricle (RV) in relation to the presence of a left ventricular outflow tract obstruction (LVOTO). METHODS: Retrospective chart review of adults with congenitally corrected transposition of the great arteries (ccTGA) or with a previous atrial switch procedure for complete TGA (D-TGA). A LVOTO was defined by a peak instantaneous systolic gradient>20mmHg. Right and left ventricular ejection fraction (EF) were measured by cardiac magnetic resonance imaging (CMR), and exercise capacity as the predicted peak oxygen consumption (peak VO2) on a cycle ergometer. RESULTS: We identified 79 clinically stable adults (age 33+/ 10years, 70% male). Nine patients (11%) had cc-TGA and 70 patients had (89%) D TGA. Thirteen patients (16%) had a LVOTO with a mean peak instantaneous systolic gradient of 43+/-22mmHg. Patients with a LVOTO had higher left (68+/-7% vs. 60+/ 9%, p=0.01) and right ventricular EF (52+/-8 vs. 46+/-9%, p=0.05) by CMR compared to patients without LVOTO. In a multivariate regression analysis with left ventricular EF and LVOTO as predictors, only left ventricular EF was independently associated with right ventricular EF (correlation coefficient 0.41, p<0.01). The presence of a LVOTO was not associated with improved exercise capacity. CONCLUSIONS: In adults with a subaortic RV, a pressure loaded subpulmonary left ventricle has a beneficial effect on systemic right ventricular EF. PMID- 28629629 TI - Association between Lithium Use and Melanoma Risk and Mortality: A Population Based Study. AB - Laboratory studies show that lithium, an activator of the Wnt/beta-catenin signaling pathway, slows melanoma progression, but to our knowledge no published epidemiologic studies have explored this association. We conducted a retrospective cohort study of adult white Kaiser Permanente Northern California members (n = 2,213,848) from 1997-2012 to examine the association between lithium use and melanoma risk. Lithium exposure (n = 11,317) was assessed from pharmacy databases, serum lithium levels were obtained from electronic laboratory databases, and incident cutaneous melanomas (n = 14,056) were identified from an established cancer registry. In addition to examining melanoma incidence, melanoma hazard ratios and 95% confidence intervals for lithium exposure were estimated using Cox proportional hazards models, adjusted for potential confounders. Melanoma incidence per 100,000 person-years among lithium-exposed individuals was 67.4, compared with 92.5 in unexposed individuals (P = 0.027). Lithium-exposed individuals had a 32% lower risk of melanoma (hazard ratio = 0.68, 95% confidence interval = 0.51-0.90) in unadjusted analysis, but the estimate was attenuated and nonsignificant in adjusted analysis (adjusted hazard ratio = 0.77, 95% confidence interval = 0.58-1.02). No lithium-exposed individuals presented with thick (>4 mm) or advanced-stage melanoma at diagnosis. Among melanoma patients, lithium-exposed individuals were less likely to suffer melanoma-associated mortality (rate = 4.68/1,000 person-years) compared with the unexposed (rate = 7.21/1,000 person-years). Our findings suggest that lithium may reduce melanoma risk and associated mortality. PMID- 28629630 TI - Design, synthesis and tumor cell growth inhibitory activity of 3-nitro-2H cheromene derivatives as histone deacetylaes inhibitors. AB - As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or omega-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or alpha-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10uM, the ortho-aminoanilide series and the d Phe derived alpha-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and 12b, 14 and 15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho aminoanilides 9b, 9c, 10b, 10c, 11b, and the alpha-aminoamides 16a and 16b were potent HADC1 inhibitors with the IC50 values in the nanomolar ranges. The ortho aminoanilides 10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2. PMID- 28629631 TI - Probenecid-treatment reduces demyelination induced by cuprizone feeding. AB - Recent experiments showed that a pannexin-1 inhibitor, probenecid, reduced clinical symptoms in the murine experimental autoimmune encephalomyelitis when applied during the initial phase of neuronal inflammation. An inflammatory component is also present in a toxically induced inflammation and demyelination using cuprizone diet. Probenecid is a pannexin-1 antagonist and a probenecid therapy was investigated. Mice were fed for 10days with a cuprizone diet. In the following, the diet was continued but combined with a daily injection of a low dose of probenecid or solvent for 10days. Electron microscopy revealed demyelination in the optic nerve. The demyelination as measured by the axonal diameter was significantly reduced in the animals treated with 100mg per kg body weight probenecid. In comparison to controls, the number of leukocytes and lymphocytes in the peripheral blood was reduced in all cuprizone groups including the treatment group. In conclusion, early demyelination in the optic nerve was moderately reduced by 10days treatment with a low dose probenecid. This is a hint for the involvement of pannexin-1 modulated inflammation in cuprizone feeding induced toxic demyelination. Thus, probenecid is a candidate for the treatment of neuro-inflammation and multiple sclerosis. PMID- 28629632 TI - Rationale for immunological approaches to breast cancer therapy. AB - Despite great advances in early detection, as well as surgical resection of breast tumours, breast cancer remains the deadliest cancer for women worldwide. Moreover, its incidence is without pair, accounting for twice as many new cancer cases as the second most prevalent cancer, colorectal carcinoma. There is therefore a strong need for new therapeutic approaches to breast cancers. Immunotherapies are novel treatment modalities which aim to use immune mediators to attack cancerous cells. Recent clinical results show that these may not only mediate tumour regressions but also cures in some cases. In this review, we discuss the relevance of the immune system in the development of new carcinomas, as well as its importance in mediating cancer regression. We also dissect the known different approaches to harness the immune system to attack breast tumours. Namely, therapies using the passive transfer of either tumour-specific antibodies or cytotoxic cells have been researched and in some cases are already standard of care. Additionally, therapeutic vaccines and immune checkpoint blockade have recently demonstrated great therapeutic efficacy and have generated great excitement for the development of new treatments. Immunotherapies have the potential to generate tumour specific responses, as well as long-lasting remissions, which is why studying those approaches is crucial for the future of cancer medicine. PMID- 28629633 TI - Atypical pantothenate kinase-associated neurodegeneration: Clinical description of two brothers and a review of the literature. AB - Two clinical forms of pantothenate kinase-associated neurodegeneration (PKAN) have been described: typical PKAN and atypical PKAN. Atypical PKAN has later onset and a slower course of disease. This report describes two siblings with the atypical form of PKAN, combining dystonia, irritability and a dysmorphia syndrome. In addition, a review of the literature was carried out for all published cases of atypical PKAN to gather descriptions of its various clinical presentations, age of onset and MRI findings, and to highlight the different treatments used for PKAN patients. PMID- 28629634 TI - 123I-FP-CIT SPECT imaging in blepharospasm. AB - INTRODUCTION: Blepharospasm is a focal dystonia characterized by involuntary cocontraction of the eyelid protractors, causing spasmodic closure of the eyelids. Apraxia of eyelid opening is caused by an inability to initiate lid opening without paralytic abnormality. Some studies suggest that patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening are more prone to developing Parkinson's disease. METHODS: In our study, 123I-FP-CIT (DAT) SPECT was performed in 24 patients with either pure blepharospasm or blepharospasm associated with apraxia of eyelid opening and no signs of parkinsonism to identify dopaminergic dysfunction. RESULTS: DAT-SPECT was abnormal in 11 (46%) cases (five patients with isolated blepharospasm and six patients with blepharospasm associated with apraxia of eyelid opening) whose mean disease duration was 11 years. CONCLUSION: Our study revealed presynaptic dopaminergic dysfunction, as determined by 123I-FP-CIT or DAT-SPECT, in nearly half of our blepharospasm patients (with or without apraxia of eyelid opening). Thus, the presence of blepharospasm might be an early sign of a parkinsonian syndrome. PMID- 28629635 TI - Primary non-Hodgkin lymphoma of the cranial vault. PMID- 28629636 TI - Nasal high flow oxygen therapy in the ward setting: A prospective observational study. AB - BACKGROUND: Whilst research demonstrates the benefits of nasal high flow oxygen in the intensive care setting, limited literature exists on its benefits in ward patients. OBJECTIVES: This study evaluated the use of nasal high flow oxygen in adult ward patients with respiratory failure or at risk of respiratory deterioration. Primary outcome was an improvement in pulmonary function as indicated by decreases in respiratory and heart rates and an increase in arterial oxygen saturation via pulse oximetry. RESEARCH METHODOLOGY: Using a prospective observational research design, purposeful sampling recruited 67 adult ward patients receiving nasal high flow oxygen between May and July 2015 (inclusive). All recruited patients were included in the data analysis. RESULTS: The median age was 71.0 years (q25, q75=58.0, 78.0) and most patients were medical specialty patients (n=46, 68.7%). After commencing nasal high flow oxygen, respiratory rate (t=2.79, p=<0.01) and heart rate (t=2.23, p=0.03) decreased and arterial oxygen saturation via pulse oximetry increased (t=4.08, p=<0.001). CONCLUSION: Nasal high flow oxygen appears effective in a selective group of ward patients with respiratory failure, or at risk of respiratory deterioration, and may reduce demand on critical care beds; this warrants further research. PMID- 28629638 TI - Editorial overview: Cardiovascular and renal: Putting the brake on heart-breaks: emerging targets and treatment strategies for cardiovascular and renal disorders. PMID- 28629637 TI - Direct medical cost associated with colorectal cancer in north of Jordan. AB - Colorectal cancer (CRC) is mainly characterized as the malignant and impaired growth of rectal cells in the intestinal region. Direct medical cost is related to resources, which are directly used in treating the patient, that mainly includes the cost of drugs, diagnostic, treatment, follow-up, rehabilitation, and hospital admission. The objective of this study is to estimate and analyze direct medical costs attributable to CRC in Jordan. A retrospective analysis of a cohort patients treated for CRC data has been performed to determine direct medical costs attributable to CRC in Jordan. The prevalence-based approach has been used in addition to the "bottom up" approach to accumulate 1-year time costs of CRC. Demographic, clinical, and economic data have been collected and analyzed using SPSS for windows. Costs were estimated by a bottom-up approach, in which each service component was identified and valued at the most detailed level, to provide greater transparency and reliability in economic evaluation of health care services. This study quantified the economic burden associated with CRC by Jordanian patients in King Abdullah University Hospital from the perspective of health care providers (public sector). Total CRC cost in the year 2014 was estimated to JD 695,608, and the most expensive stage for all sites was stage 4 reaching a cost of JD 5147. Advanced disease stages were associated with an increase in total cost and chemotherapy costs. In conclusion, results of this study propose that direct medical costs associated with CRC are considerable. Most of the cost was devoted for medications, primarily chemotherapy. Advanced stages were associated with higher cost and largest number of patients. PMID- 28629639 TI - ATP-synthesis capacity of pulsed light-exposed bacteria. AB - The ability of four different bacteria to synthesize new ATP upon exposure to different doses of pulsed-light (PL) irradiation was investigated. The bacterial cells were PL treated on a gel surface, resuspended in phosphate buffered saline (PBS) and subsequently incubated in Tryptic Soy Broth (TSB) at 37 degrees C. Cellular ATP levels were monitored during a 2h incubation period and compared to the respective colony count data. Although PL affected ATP production in a dose dependent manner, the results showed that bacteria, which had rendered unculturable after PL exposure, are still capable of generating significant quantities of ATP. Escherichia coli and Listeria innocua proved to be more resistant to PL than Salmonella enterica and Staphylococcus aureus, which was supported by the colony count data and the ATP synthesis capacity. These findings underline that bacteria undetectable by culture-based methods may still show cellular activity and synthesize new ATP. PMID- 28629640 TI - Is physical activity a modifier of the association between air pollution and arterial stiffness in older adults: The SAPALDIA cohort study. AB - INTRODUCTION AND OBJECTIVES: Air pollution and insufficient physical activity have been associated with inflammation and oxidative stress, molecular mechanisms linked to arterial stiffness and cardiovascular disease. There are no studies on how physical activity modifies the association between air pollution and arterial stiffness. We examined whether the adverse cardiovascular effects of air pollution were modified by individual physical activity levels in 2823 adults aged 50-81 years from the well-characterized Swiss Cohort Study on Air Pollution and Lung and Heart Diseases (SAPALDIA). METHODS: We assessed arterial stiffness as the brachial-ankle pulse wave velocity (baPWV [m/s]) with an oscillometric device. We administered a self-reported physical activity questionnaire to classify each subject's physical activity level. Air pollution exposure was estimated by the annual average individual home outdoor PM10 and PM2.5 (particulate matter <10MUm and <2.5MUm in diameter, respectively) and NO2 (nitrogen dioxide) exposure estimated for the year preceding the survey. Exposure estimates for ultrafine particles calculated as particle number concentration (PNC) and lung deposited surface area (LDSA) were available for a subsample (N=1353). We used mixed effects logistic regression models to regress increased arterial stiffness (baPWV>=14.4m/s) on air pollution exposure and physical activity while adjusting for relevant confounders. RESULTS: We found evidence that the association of air pollution exposure with baPWV was different between inactive and active participants. The probability of having increased baPWV was significantly higher with higher PM10, PM2.5, NO2, PNC and LDSA exposure in inactive, but not in physically active participants. We found some evidence of an interaction between physical activity and ambient air pollution exposure for PM10, PM2.5 and NO2 (pinteraction=0.06, 0.09, and 0.04, respectively), but not PNC and LDSA (pinteraction=0.32 and 0.35). CONCLUSIONS: Our study provides some indication that physical activity may protect against the adverse vascular effects of air pollution in low pollution settings. Additional research in large prospective cohorts is needed to assess whether the observed effect modification translates to high pollution settings in mega-cities of middle and low-income countries. PMID- 28629641 TI - Multiple Ways of BES1/BZR1 Degradation to Decode Distinct Developmental and Environmental Cues in Plants. PMID- 28629642 TI - Splenic vein reconstruction is unnecessary in pancreatoduodenectomy combined with resection of the superior mesenteric vein-portal vein confluence according to short-term outcomes. AB - BACKGROUND: Superior mesenteric vein-portal vein confluence resection combined with pancreatoduodenectomy (SMPVrPD) is occasionally required for resection of pancreatic head tumors. It remains unclear whether such situations require splenic vein (SV) reconstruction for decompression of left-sided portal hypertension (LSPH). METHODS: The data from 93 of 104 patients who underwent pancreatoduodenectomy (PD) for pancreatic head malignancies were reviewed. Surgical outcomes in three groups-standard PD (control group), PD combined with vascular resection and SV preservation (SVp group), and SMPVrPD with SV resection (SVr group)-were compared. The influence of division and preservation of the two natural confluences (left gastric vein-portal vein and/or inferior mesenteric vein-SV confluences) on portal hemodynamics were evaluated using three dimensional computed tomographic portography. RESULTS: No mortality occurred. The morbidity rates were not significantly different among the three groups (18/43, 8/21, and 7/29, respectively; p = 0.306). In the SVr group, three patients had gastric remnant venous congestion, and three had esophageal varices without hemorrhagic potential. No patients had splenomegaly, or severe or prolonged thrombocytopenia. These LSPH-associated findings were less frequently observed when the two confluences were preserved. CONCLUSIONS: SMPVrPD without SV reconstruction can be safely conducted. Additionally, preservation of these two confluences may reduce the risk of LSPH. PMID- 28629643 TI - Reduced electrode arrays for acute electroencephalography: Can less be more? PMID- 28629644 TI - Need for updating safety recommendations on repetitive transcranial magnetic stimulation in stroke patients. PMID- 28629645 TI - Atypical activation of action-semantic network in adolescents with autism spectrum disorder. AB - In typical adults, fMRI studies have shown activation of primary and pre-motor regions during action word processing. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments. ASD studies have shown atypical semantic processing and motor deficits. The objective of this study was to examine semantic processing of verbs in ASD. 15 ASD adolescents and 19 typically developing adolescents, 11-16years, completed a semantic similarity judgment task during fMRI. There were no differences in task accuracy or reaction time. At the group level, both groups had activation in left language areas; controls, but not ASD, also had activation in the left pre-supplementary motor area (pre-SMA). In ASD, less left frontal activation and reduced left lateralization of activation within these regions was associated with shorter reaction times and better language skills. More left temporal activation was associated with better language abilities in ASD. Differences in pre-SMA activation may relate to motor planning deficits or differences in approach to the semantic task in ASD. Results suggest that left frontal language areas may be less efficient in ASD and those who can compensate by recruiting more right hemisphere homologues may result in better language abilities. PMID- 28629646 TI - Memory and time: Backward and forward telescoping in Alzheimer's disease. AB - Backward and forward telescoping are opposite timing biases. The former refers to misattributing events to earlier dates, whereas the latter refers to misattributing events to later dates. The present study investigated both biases in participants with Alzheimer's Disease (AD) and healthy older adults, matched on age, sex, and education level. Participants were asked to recall the years when five remote and five recent public events had occurred. They were also assessed with a cognitive and clinical battery that included a context memory task on which they had to associate letters and locations. Results showed backward telescoping for recent events and forward telescoping for remote events in AD participants and older adults. Furthermore, poorer context recall was observed in AD participants and older adults displaying backward telescoping than in those displaying forward telescoping. These findings suggest an association between the amount of contextual information recalled and the direction of the timing bias. Backward telescoping can be associated with deficiencies in retrieving context characteristics of events, which have been associated with retrograde amnesia and pathological changes to the hippocampus in AD. PMID- 28629647 TI - The cultures of mathematical economics in the postwar Soviet Union: More than a method, less than a discipline. PMID- 28629648 TI - Ten reasons to embrace scientism. AB - A strong version of scientism, such as that of Alex Rosenberg, says, roughly, that natural science reliably delivers rational belief or knowledge, whereas common sense sources of belief, such as moral intuition, memory, and introspection, do not. In this paper I discuss ten reasons that adherents of scientism have or might put forward in defence of scientism. The aim is to show which considerations could plausibly count in favour of scientism and what this implies for the way scientism ought to be formulated. I argue that only three out of these ten reasons potentially hold water and that the evidential weight is, therefore, on their shoulders. These three reasons for embracing scientism are, respectively, particular empirical arguments to the effect that there are good debunking explanations for certain common sense beliefs, that there are incoherences and biases in the doxastic outputs of certain common sense sources of belief, and that beliefs that issue from certain common sense doxastic sources are illusory. From what I argue, it follows that only a version of scientism that is significantly weaker than many versions of scientism that we find in the literature is potentially tenable. I conclude the paper by stating what such a significantly weaker version of scientism could amount to. PMID- 28629649 TI - Scientists' attitudes on science and values: Case studies and survey methods in philosophy of science. AB - This article examines the relevance of survey data of scientists' attitudes about science and values to case studies in philosophy of science. We describe two methodological challenges confronting such case studies: 1) small samples, and 2) potential for bias in selection, emphasis, and interpretation. Examples are given to illustrate that these challenges can arise for case studies in the science and values literature. We propose that these challenges can be mitigated through an approach in which case studies and survey methods are viewed as complementary, and use data from the Toolbox Dialogue Initiative to illustrate this claim. PMID- 28629650 TI - The directionality of distinctively mathematical explanations. AB - In "What Makes a Scientific Explanation Distinctively Mathematical?" (2013b), Lange uses several compelling examples to argue that certain explanations for natural phenomena appeal primarily to mathematical, rather than natural, facts. In such explanations, the core explanatory facts are modally stronger than facts about causation, regularity, and other natural relations. We show that Lange's account of distinctively mathematical explanation is flawed in that it fails to account for the implicit directionality in each of his examples. This inadequacy is remediable in each case by appeal to ontic facts that account for why the explanation is acceptable in one direction and unacceptable in the other direction. The mathematics involved in these examples cannot play this crucial normative role. While Lange's examples fail to demonstrate the existence of distinctively mathematical explanations, they help to emphasize that many superficially natural scientific explanations rely for their explanatory force on relations of stronger-than-natural necessity. These are not opposing kinds of scientific explanations; they are different aspects of scientific explanation. PMID- 28629651 TI - Science denial as a form of pseudoscience. AB - Science denialism poses a serious threat to human health and the long-term sustainability of human civilization. Although it has recently been rather extensively discussed, this discussion has rarely been connected to the extensive literature on pseudoscience and the science-pseudoscience demarcation. This contribution argues that science denialism should be seen as one of the two major forms of pseudoscience, alongside of pseudotheory promotion. A detailed comparison is made between three prominent forms of science denialism, namely relativity theory denialism, evolution denialism, and climate science denialism. Several characteristics are identified that distinguish science denialism from other forms of pseudoscience, in particular its persistent fabrication of fake controversies, the extraordinary male dominance among its activists, and its strong connection with various forms of right-wing politics. It is argued that the scientific response to science denialism has to be conceived with these characteristics in mind. In particular, it is important to expose the fabricated fake controversies for what they are and to reveal how science denialists consistently use deviant criteria of assent to distort the scientific process. PMID- 28629652 TI - The history of science as the progress of the human spirit: The historiography of astronomy in the eighteenth century. AB - In the eighteenth century, the historiography of astronomy was part of a wider discussion concerning the history of the human spirit. The concept of the human spirit was very popular among Enlightenment authors because it gave the history of human knowledge continuity, unity and meaning. Using this concept, scientists and historians of science such as Montucla, Lalande, Bailly and Laplace could present the history of astronomy in terms of a progress towards contemporary science that was slow and could be interrupted at times, but was still constant, regular, and necessary. In my paper I intend to explain how the originally philosophical concept of the human spirit was transferred to the history of astronomy. I also introduce the basic principles to which the development of the spirit is subject in astronomy, according to historians of astronomy. The third part of the paper describes how historians of astronomy took into account the effect of social and natural factors on the history of astronomy. PMID- 28629654 TI - Activity determination of 60Co and the importance of its beta spectrum. AB - The activity concentration of a 60Co solution was measured by means of two 4pibeta-gamma coincidence counting systems using a liquid scintillation counter and a proportional counter (PC) in the beta channel, respectively. Additional liquid scintillation measurements were carried out and CIEMAT/NIST efficiency tracing as well as the triple-to-double coincidence ratio (TDCR) methods were applied to analyse the data. The last two methods require computed beta spectra to determine the counting efficiencies. The results of both 4pibeta-gamma coincidence counting techniques are in very good agreement and yield a robust reference value. The initial activity concentration determined with liquid scintillation counting was found to be significantly lower than the results from 4pibeta-gamma coincidence counting. In addition, the results from TDCR and CIEMAT/NIST show some inconsistency. The discrepancies were resolved by applying new beta spectrum calculations for the dominant allowed beta transition of 60Co. The use of calculations which take screening effects as well as the atomic exchange effect into account leads to good agreement between all four methods; the combination of these techniques delivers an important validation of beta spectra. PMID- 28629653 TI - Do hepatic-sided tumors require more extensive resection than peritoneal-sided tumors in patients with T2 gallbladder cancer? Results of a retrospective multicenter study. AB - BACKGROUND: Tumor location is a prognostic factor for survival in patients with T2 gallbladder cancer. However, the optimal extent of resection according to tumor location remains unclear. METHODS: We reviewed the records of 192 patients with T2 gallbladder cancer who underwent R0 or R1 resection at 6 institutions. Perioperative and oncologic outcomes were compared according to the extent of resection between hepatic-sided (n = 93) and peritoneal-sided (n = 99) tumors. RESULTS: After a median follow-up of 30 months, the 5-year overall survival (84.9% vs 71.8%, P = .048) and recurrence-free survival (74.6% vs 62.2%, P = .060) were greater in peritoneal-sided T2 patients than in hepatic-sided T2 patients. Among hepatic-sided T2 patients, the 5-year overall survival was greater in patients who underwent radical cholecystectomy including lymph node dissection with liver resection than in patients who underwent lymph node dissection without liver resection (80.3% vs 30.0%, P = .032), and the extent of liver resection was not associated with overall survival (P = .526). Lymph node dissection without liver resection was an independent prognostic factor for overall survival in hepatic-sided T2 gallbladder cancer (hazard ratio 5.009, 95% confidence interval 1.512-16.596, P = .008). In peritoneal-sided T2 patients, the 5-year overall survival was not significantly different between the lymph node dissection with liver resection and the lymph node dissection without liver resection subgroups (70.5% vs 54.8%, P = .111) and the extent of lymph node dissection was not associated with overall survival (P = .395). CONCLUSION: In peritoneal-sided T2 gallbladder cancer, radical cholecystectomy including lymph node dissection without liver resection is a reasonable operative option. Radical cholecystectomy including lymph node dissection with liver resection is suitable for hepatic-sided T2 gallbladder cancer. PMID- 28629655 TI - Protocols for sperm cryopreservation in the domestic cat: A review. AB - The main objectives of sperm cryopreservation in domestic cats are to preserve these gametes for future use, especially in valuable domestic cat breeds and to use knowledge-gained for developing sperm preservation techniques in wild felids that are threatened with extinction. To achieve acceptable quality of post-thaw sperm and results after insemination, sperm samples must be properly handled, cryopreserved and thawed by using appropriate protocols. In this paper, cryopreservation protocols of domestic cat sperm that have been reported previously are described. The subtopics include sources of sperm, freezing extenders, methods of sperm dilution, freezing storage vessels, methods of sperm cryopreservation, thawing temperature, and thawing extenders. In addition, comparisons of sperm quality results for different treatments within the same studies and between different studies are also presented. PMID- 28629656 TI - Clinical practice points for diabetes management during RAMADAN fast. AB - Diabetes management during Ramadan is very crucial from the patient perspective as it can present significant risk of hypoglycemia and death when proper care is not taken. Moreover, managing diabetes in fasting Ramadan patients require different mechanisms than the routine diabetes management and pose significant challenge to the health care practitioners. Here we set forth to review the available literature of various clinical trials and studies on different antidiabetic agents in the context of Ramadan. On the basis of available evidence, we suggest that gliclazide is effective and it could be safely recommended in type 2 diabetic patients fasting during Ramadan. PMID- 28629657 TI - Single-unit implant-supported restoration adjacent to multiple lithium disilicate restorations, an approach to an esthetic challenge: A clinical report. AB - This clinical report describes a method for predictably shade matching a highly opaque yttrium-stabilized tetragonal zirconia polycrystal (Y-TZP) implant restoration adjacent to relatively translucent lithium disilicate veneers in the maxillary anterior region. To achieve a satisfactory outcome, the milled Y-TZP abutment was layered with low-fusing feldspathic porcelain to match the stump shade of the adjacent prepared teeth; this layer subsequently facilitated adhesive bonding of a veneer to the abutment before insertion. PMID- 28629658 TI - Fracture of the femur in a patient with polyostotic Paget's disease. PMID- 28629659 TI - Focal myositis associated to radiculopathy. PMID- 28629660 TI - Characterization and risk factors for aortic dilatation in pediatric patients with bicuspid aortic valve. AB - INTRODUCTION AND OBJECTIVES: Dilatation of the ascending aorta associated with bicuspid aortic valve is a major cause of morbidity and mortality in adults. The main objective was to recognize the aortic involvement in children, its characteristics and risk factors. METHODS: Aortic measures of all pediatric patients with bicuspid aortic valve followed in a tertiary pediatric hospital between 1997 and 2015 were retrospectively taken. Patients with syndromes associated with aortic dilatation were excluded (n=17). RESULTS: Two hundred and six patients were included, 67.9% males. The commonest opening pattern was horizontal: 137 (66.7%). Half of the patients (101) had a history of surgical aortic coarctation, 46 (22.3%) had>=moderate aortic valve stenosis and 13 (6%) had>=moderate aortic insufficiency. Mean follow-up time was 6.1 (4.9) years; diagnosis of aortic dilatation was made during the first year of follow-up. Progression of the dilatation of the ascending aorta was noted in 17.1%, and of the aortic root in 2.5%. More than one-third (80/206) had aortic dilatation (z score>2). The ascending aorta was exclusively affected in 70/80 patients, with sparing of the aortic root. In the multivariate analysis, patients with dilatation of the ascending aorta were associated with absence of coarctation (P=.001) and vertical opening pattern (P=.007). CONCLUSIONS: Pediatric patients with bicuspid aortic valve warrant medical follow-up for the frequent association with valve impairment and/or dilatation of the ascending aorta. PMID- 28629661 TI - Cornelia de Lange syndrome: Congenital heart disease in 149 patients. AB - INTRODUCTION: Cornelia de Lange syndrome (CdLS) is produced by mutations in genes that encode regulatory or structural proteins of the cohesin complex. Congenital heart disease (CHD) is not a major criterion of the disease, but it affects many individuals. The objective of this study was to study the incidence and type of CHD in patients with CdLS. MATERIAL AND METHOD: Cardiological findings were evaluated in 149 patients with CdLS and their possible relationship with clinical and genetic variables. RESULTS: A percentage of 34.9 had CHD (septal defects 50%, pulmonary stenosis 27%, aortic coarctation 9.6%). The presence of CHD was related with neonatal hospitalisation (P=.04), hearing loss (P=.002), mortality (P=.09) and lower hyperactivity (P=.02), it being more frequent in HDAC8+ patients (60%), followed by NIPBL+ (33%) and SMC1A+ (28.5%). While septal defects predominate in NIPBL+, pulmonary stenosis is more common in HDAC8+. CONCLUSIONS: Patients with CdLS have a high incidence of CHD, which varies according to the affected gene, the most frequent findings being septal defects and pulmonary stenosis. Perform a cardiologic study in all these patients is suggested. PMID- 28629662 TI - Pyoderma gangrenosum: Classic and emerging therapies. AB - Pyoderma gangrenosum is an ulceronecrotising dermatosis that represents a challenge for any clinician, not only for its ability to mimic other dermatoses but also for its lack of response to treatment. During the past year, there have been new studies about the efficacy of standard therapies, such as cyclosporine and systemic corticosteroids. These studies showed that classic treatment was comparable, but they are insufficient as monotherapy. That being said, new emerging therapies are becoming important, as the use of corticosteroid-sparing agents, tumour necrosis factor inhibitors or even surgery. This review updates the current evidence for the treatment of pyoderma gangrenosum. PMID- 28629663 TI - Genomic Tests Should be Used to Help Guide Treatment of Prostate Cancer: No. PMID- 28629664 TI - Genomic Tests Should be Used to Help Guide Treatment of Prostate Cancer: Yes. PMID- 28629666 TI - Treating active rheumatoid arthritis with Janus kinase inhibitors. PMID- 28629667 TI - Interchange rotation factors and player characteristics influence physical and technical performance in professional Australian Rules football. AB - OBJECTIVES: To examine the effects of match-related and individual player characteristics on activity profile and technical performance during rotations in professional Australian football. DESIGN: Longitudinal observational study. METHODS: Global positioning system data and player rating scores were collected from 33 professional Australian football players during 15 Australian football League matches. Player rating scores were time aligned with their relative total and high-speed running (HSR) distance (>20kmh-1) for each on ground rotation. Individual players' maximal aerobic running speed (MAS) was determined from a two kilometre trial. A multilevel linear mixed model was used to examine the influence of rotations on physical activity profiles and skill execution during match play. RESULTS: Rotation duration and accumulated distance resulted in a trivial-to-moderate reduction in relative total and HSR distances as well as relative rating points. The number of disposals in a rotation had a small positive effect on relative total and HSR distances and a large positive effect on relative rating points. MAS was associated with a moderate-to-large increase in relative total distance, but had a large negative effect on relative rating points. Previous rotation time, stoppages and the number of rotations in the quarter had a trivial-to-small negative effect on relative total and HSR distances. A greater speed (mmin-1) was associated with a trivial increase in rating points during a rotation, while there was a trivial decrease in relative total distance as rating points increased. CONCLUSION: The complex relationship between factors that influence activity profile and technical performance during rotations in Australian football needs to be considered when interpreting match performance. PMID- 28629668 TI - Underestimating the size of the problem? UK anaesthesia for patients with obesity. AB - We analysed data from 14,000 patients in the 2013 United Kingdom Anaesthesia Activity Survey of the Fifth National Audit Project of the Royal College of Anaesthetists and Association of Anaesthetists of Great Britain and Ireland to examine anaesthetic, organisational and clinical practice for patients with obesity. We compared practice then with current guidance on management of this patient group. Obesity was reported in 22%, mainly Black, Afro-Caribbean and White Caucasian patients. There was minimal variation in surgical timing, anaesthetic seniority, induction location or day-case procedure rates. As BMI increased above 25kgm-2 ASA grade rose and there were modest changes in practice towards that recommended for this patient group. Some practice changes were counter-intuitive. When BMI exceeded 35kgm-2 safety based practice changed markedly. For patients receiving GA there was an increase in immediate (operative) mortality as BMI rose. UK anaesthetic practice in 2013 appears to underestimate patient levels of obesity, does not reflect recent published guidelines for the management of patients with obesity undergoing anaesthesia and, taken with the mortality findings, raises concerns over the reliability of safe management of such patients. PMID- 28629669 TI - Influence of the Mediterranean diet during pregnancy in the development of wheezing and eczema in infants in Pamplona, Spain. AB - BACKGROUND: This study examined the relationship between different food groups and the adherence to a Mediterranean diet during pregnancy and the risk of wheezing and eczema in children aged 12-15 months. METHODS: The study involves 1087 Spanish infants from the International Study of Wheezing in Infants (Estudio Internacional de Sibilancias en Lactantes, EISL). The study of the association of the different food consumption and Mediterranean diet with wheezing, recurrent wheezing and eczema was performed using different models of unconditional logistic regression to obtain adjusted prevalence odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: No association was found between a good adherence to the Mediterranean diet during pregnancy and the development of wheezing (p=0.372), recurrent wheezing (p=0.118) and eczema (p=0.315). The consumption once or twice a week of white fish (OR: 1.95[1.01-3.75]), cooked potatoes (OR: 1.75[1.22-2.51]) and industrial pastry (OR: 1.59[1.13-2.24]), and the consumption more than three times a week of industrial pastry (OR: 1.47 [1.01 2.13]) during pregnancy increases the risk of "wheezing" at 12 months. Instead, high fruit consumption during the pregnancy has a protective effect against "wheezing" in 12-month-old infants (OR: 0.44 [0.20-0.99]). No statistically significant differences were observed between food intake during pregnancy and "recurrent wheezing". No statistically significant differences were observed between the consumption of any food during pregnancy and the presence of eczema at 12 months. CONCLUSIONS: The present study showed that the consumption of Mediterranean diet during pregnancy did not have a protective effect for wheezing, recurrent wheezing or eczema. PMID- 28629670 TI - Trends in prevalence and risk factors of allergic rhinitis symptoms in primary schoolchildren six years apart in Budapest. AB - BACKGROUND: Few data are available concerning the time trends and risk factors associated with allergic rhinitis (AR) in schoolchildren in Hungary. METHODS: At an interval of six years, parents of 6-12-year-old children completed identical ISAAC-based and additional questionnaires related to possible risk factors. RESULTS: Response rate was 62.8% with 6335 questionnaires distributed in 2007, and 52.9% with 6441 questionnaires in 2013. The prevalence of current AR symptoms (subjects presenting clinical symptoms of AR in the past 12 months, but had yet to be diagnosed by physician) increased significantly from 14.9% to 23.5% (p<0.001). There was no significant change in the prevalence of physician diagnosed AR (11.6-11.2%). In multivariate analysis, gender (OR 0.733; CI 0.642 0.931), a family history of atopy (OR 2.017; CI 1.669-2.436), frequent upper respiratory tract infections (OR 2.033; CI 1.659-2.492), long-lasting disease before the appearance of the allergy (OR 2.119; CI 1.311-3.428), feather bedding (OR 0.773; CI 0.599-0.996) and living in a green area (OR 1.367; CI 1.133-1.650) were found to be significant risk factors of cumulative AR in 2013. In both of the groups with (p<0.000) or without (p<0.003) AR the families with a history of atopy used feather bedding less frequently than families without atopy. CONCLUSION: Although the prevalence of physician-diagnosed AR has not shown significant changes during the studied interval, the significant increase of the current AR symptoms suggests growing prevalence of AR among children in Budapest. Our results revealed new aspects of bedding customs in atopic families. PMID- 28629665 TI - Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. AB - BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. METHODS: ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98.34% CI of the difference between comparators was larger than -13.0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. FINDINGS: 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98.34% CI -6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (-6 [-14 to 3]) or tofacitinib and methotrexate (-8 [-16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. INTERPRETATION: Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. FUNDING: Pfizer Inc. PMID- 28629671 TI - Oral immunisation with Taishan Pinus massoniana pollen polysaccharide adjuvant with recombinant Lactococcus lactis-expressing Proteus mirabilis ompA confers optimal protection in mice. AB - BACKGROUND: Proteus mirabilis poses a critical burden on the breeding industry, but no efficient vaccine is available for animals. METHOD: A recombinant Lactococcus lactis expressing the ompA of P. mirabilis was used to develop a vaccine. The mucosal and systemic immune responses of the recombinant vaccine were evaluated in mice after oral immunisation. The inhibition on P. mirabilis colonisation of vaccines was also determined. Moreover, Taishan Pinus massoniana pollen polysaccharides (TPPPS) were used as adjuvants to examine the immunomodulatory effects. RESULTS: The pure recombinant L. lactis vaccine significantly induced the production of specific IgA and IgG, IL-2, IL-4, IFN gamma, and T lymphocyte proliferation, and the immunised mice exhibited significant resistance to P. mirabilis colonisation. Notably, the TPPPS adjuvant vaccines induced higher levels of immune responses than the pure L. lactis. CONCLUSIONS: The L. lactis as a vaccine vehicle combined with TPPPS adjuvant provides a feasible method for preventing P. mirabilis infection. PMID- 28629672 TI - The safety profile of subcutaneous allergen immunotherapy in children with asthma in Hangzhou, East China. AB - BACKGROUND: The aim of the current study is to evaluate the prevalence, severity and possible risk factors of systemic reactions (SRs) to subcutaneous allergen immunotherapy (SCIT) in children and adolescents with asthma in Hangzhou, east China's Zhejiang province. METHODS: From January 2011 to December 2016, this survey analysed the SCIT-related SRs involving 429 patients (265 children and 134 adolescents) affected by allergic asthma. Recorded data included demographics, diagnosis, patient statuses, pulmonary function testing results before and after each injection, allergen dosage, and details of SRs. RESULTS: All patients finished the initial phase and six patients withdrew during the maintenance phase. There were 2.59% (328/12,655) SRs in all injections (3.28% in children and 1.47% in adolescents); 15.62% (67/429) patients experienced SRs (18.49% children and 10.98% adolescents). There were 54.57% SRs of grade 1; 42.37% SRs of grade 2; 3.05% SRs of grade 3; and no grades 4 or grade 5 SRs occurred in patients. Most reactions were mild, and were readily controlled by immediate emergency treatment. There was no need for hospitalisation. The occurrence of SRs was significantly higher in children than that in adolescents (p<0.01). A higher ratio of SRs was found among patients with moderate asthma. CONCLUSION: This retrospective survey showed that properly-conducted SCIT was a safe treatment for children and adolescents with asthma in Hangzhou, East China. Children and patients with moderate asthma may be prone to develop SRs. PMID- 28629673 TI - A comparison of two clinical scores for bronchiolitis. A multicentre and prospective study conducted in hospitalised infants. AB - BACKGROUND: There are a number of clinical scores for bronchiolitis but none of them are firmly recommended in the guidelines. METHOD: We designed a study to compare two scales of bronchiolitis (ESBA and Wood Downes Ferres) and determine which of them better predicts the severity. A multicentre prospective study with patients <12 months with acute bronchiolitis was conducted. Each patient was assessed with the two scales when admission was decided. We created a new variable "severe condition" to determine whether one scale afforded better discrimination of severity. A diagnostic test analysis of sensitivity and specificity was made, with a comparison of the AUC. Based on the optimum cut-off points of the ROC curves for classifying bronchiolitis as severe we calculated new Se, Sp, LR+ and LR- for each scale in our sample. RESULTS: 201 patients were included, 66.7% males and median age 2.3 months (IQR=1.3-4.4). Thirteen patients suffered bronchiolitis considered to be severe, according to the variable severe condition. ESBA showed a Se=3.6%, Sp=98.1%, and WDF showed Se=46.2% and Sp=91.5%. The difference between the two AUC for each scale was 0.02 (95%CI: 0.01-0.15), p=0.72. With new cut-off points we could increase Se and Sp for ESBA: Se=84.6%, Sp=78.7%, and WDF showed Se=92.3% and Sp=54.8%; with higher LR. CONCLUSIONS: None of the scales studied was considered optimum for assessing our patients. With new cut-off points, the scales increased the ability to classify severe infants. New validation studies are needed to prove these new cut-off points. PMID- 28629674 TI - Cystinosis distal myopathy, novel clinical, pathological and genetic features. AB - Nephropathic cystinosis is an autosomal recessive lysosomal disease in which cystine cannot exit the lysosome to complete its degradation in the cytoplasm, thus accumulating in tissues. Some patients develop a distal myopathy involving mainly hand muscles. Myopathology descriptions from only 5 patients are available in the literature. We present a comprehensive clinical, pathological and genetic description of 3 patients from 2 families with nephropathic cystinosis. Intrafamiliar variability was detected in one family in which one sibling developed a severe distal myopathy while the other sibling did not show any signs of skeletal muscle involvement. One of the patients was on treatment with Cysteamine for over 12 years but still developed the usual complications of nephropathic cystinosis in his twenties. Novel pathological findings consisting in sarcoplasmic deposits reactive for slow myosin were identified. Three previously known and one novel mutation are reported. Nephropathic cystinosis should be included in the differential diagnosis of distal myopathies in those with early renal failure. Novel clinical and pathological features are reported here contributing to the characterization of the muscle involvement in nephropathic cystinosis. PMID- 28629675 TI - Misdiagnosis is an important factor for diagnostic delay in McArdle disease. AB - Diagnosis of McArdle disease is frequently delayed by many years following the first presentation of symptoms to a health professional. The aim of this study was to investigate the importance of misdiagnosis in delaying diagnosis of McArdle disease. The frequency of misdiagnosis, duration of diagnostic delay, categories of misdiagnoses and inappropriate medical interventions were assessed in 50 genetically confirmed patients. The results demonstrated a high frequency of misdiagnosis (90%, n = 45/50) most commonly during childhood years (67%; n = 30/45) compared with teenage years and adulthood (teenage: n = 7/45; adult n = 5/45; not known n = 3/45). The correct diagnosis of McArdle disease was rarely made before adulthood (median age of diagnosis 33 years). Thirty-one patients (62%) reported having received more than one misdiagnosis; the most common were "growing pains" (40%, n = 20) and "laziness/being unfit" (46%, n = 23). A psychiatric/psychological misdiagnosis was significantly more common in females than males (females 6/20; males 1/30; p < 0.01). Of the 45 patients who were misdiagnosed, 21 (47%) received incorrect management. This study shows that most patients with McArdle disease received an incorrect explanation of their symptoms providing evidence that misdiagnosis plays an important part in delaying implementation of appropriate medical advice and management to this group of patients. PMID- 28629676 TI - Percutaneous Nephrolithotomy Puncture and Tract Dilation: Evidence on the Safety of Approaches to the Infundibulum of the Middle Renal Calyx. AB - OBJECTIVE: To investigate the anatomical relations of the papillary, infundibular, and pelvic approach to percutaneous nephrolithotomy and evaluate the amount of vascularization at the respective sites. MATERIALS AND METHODS: 99mTc-dimercaptosuccinic acid single-photon emission computed tomography/computed tomography (SPECT/CT) renal scintigraphies or computed tomography perfusion (CTP) was performed in 40 patients (prone n = 20 or supine position n = 20). The angle of approach (AoA) for access tracts and the respective regions of interest to the mid-calyceal papilla and infundibulum as well as renal pelvis were designed and compared. RESULTS: The design of access tracts aiming to the renal pelvis, papilla, and infundibulum of the renal calyx was impossible for the nondilated collecting systems as all these tracts were in close vicinity. In both SPECT/CT and CTP, there was no statistical difference between the AoA for infundibular or pelvic access in comparison with the papillary puncture in either prone or supine position regardless of the degree of dilation of the system. The comparison of the measurements in the regions of interest showed that there was no difference in blood supply between the infundibular and pelvic access in comparison with the papillary approach in both positions regardless of the degree of collecting system dilation. CONCLUSION: The use of SPECT/CT and CTP showed that the punctures to the mid-calyceal renal papilla-fornix and infundibulum as well as the renal pelvis at the same level have similar AoA. The sites of the parenchyma involved in the tract dilation of the respective approaches are not related to significant differences in terms of vascularization. PMID- 28629677 TI - Antibiotic resistance: thinking outside the hospital. PMID- 28629678 TI - History of electromyography and nerve conduction studies: A tribute to the founding fathers. AB - The early development of nerve conduction studies (NCS) and electromyography (EMG) was linked to the discovery of electricity. This relationship had been concluded by observing the effect of applying electricity to the body of an animal and discovering that nerves and muscles themselves could produce electricity. We attempt to review the historical evolution of NCS and EMG over the last three centuries by reviewing the landmark publications of Galvani, Adrian, Denny-Brown, Larrabee, and Lambert. In 1771, Galvani showed that electrical stimulation of animal muscle tissue produced contraction and, thereby, the concept of animal electricity was born. In 1929, Adrian devised a method to record a single motor unit potential by connecting concentric needle electrodes to an amplifier and a loud speaker. In 1938, Denny-Brown described the fasciculation potentials and separated them from fibrillations. Toward the end of World War II, Larrabee began measuring the compound muscle action potential in healthy and injured nerves of war victims. In 1957, Lambert and Eaton described the electrophysiologic features of a new myasthenic syndrome associated with lung carcinoma. Overall, research on this topic was previously undertaken by neurophysiologists and then later by neurologists, with Adrian most likely being the first neurologist to be involved. The field greatly benefited from the invention of equipment that was capable of amplifying small bioelectrical currents by the beginning of the 20th century. Significant scientific and technical advances were later made during and after World War II which provided a large patient population with nerve injuries to study. PMID- 28629679 TI - How to address cerebrospinal fluid leakage following ossification of the posterior longitudinal ligament surgery. AB - BACKGROUND: Primary dural repair in ossification of posterior longitudinal ligament (OPLL) surgery via anterior is challenging because of limited space. Based on several years of our experiences, we present our concept for addressing cerebrospinal fluid (CSF) leakage following dural tear during anterior OPLL surgery. METHODS: We reviewed the medical records of 65 patients who underwent anterior OPLL surgery from 2003 to 2014. We included 7 patients whose operation records described dural tear followed by CSF leakage. Primary dural repair could not be performed in 6 patients because of ragged tear and limited space. We managed them with our own strategy: simple cover with an artificial dura, collagen sponge and/or fibrin glue on defect site; anatomical layer-by-layer repair without either subfascial or CSF drain, and early ambulation. RESULTS: Of 7 patients, wound problems developed in 2 patients. Wound aspiration and antibiotic treatment was done without wound compression in one patient, and simple irrigation followed by anatomical layer-by-layer re-closure was done in the other patient without either bed rest or lumbar drainage. Pseudomeningoceles were detected in 4 patients, including 2 patients who had wound problems. However, all pseudomeningoceles were absorbed spontaneously or stabilized on follow-up images without interventions such as bed rest, lumbar drain or wound compression. CONCLUSIONS: Without interference of pressure equilibrium between intradural and extradural space, the defect site would heal and close. After that, the isolated pseudomeningocele would be spontaneously absorbed after certain period of time. PMID- 28629680 TI - Preoperative embolization in spinal tumour surgery: Enhancing its effectiveness. AB - We conducted a retrospective review of 221 patients, who underwent spinal oncologic surgery at a tertiary university hospital between 2005 and 2014; in order to identify and validate factors that influence the impact of preoperative embolization of spinal tumours on outcome measures of blood loss and transfusion requirements in spinal oncologic surgery. We also focused on primary tumour type and type of spinal surgery performed. Patients' electronic and physical records were reviewed to provide demographic data, tumour characteristics, embolization techniques and surgical procedure details. These data were analysed against recorded outcome measures of blood loss (absolute volume and haemoglobin reduction) and transfusion requirements. Forty eight patients who received preoperative embolization were compared against 173 patients who did not. There was a tendency towards reduced blood loss and transfusion requirements in embolized spinal metastases from HCC and thyroid; as well as primary spine tumours, though the differences were not significant. Total embolization of arterial supply to spinal tumours resulted in significantly less blood loss as compared to partial or subtotal embolization. In addition, median blood loss was lower in patients receiving a more proximal embolization and in patients who underwent surgery between 13 and 24h post-embolization despite the insignificant difference. To conclude, preoperative spinal tumour embolization is likely to be effective in reducing blood loss if a total embolization is performed 13-24h prior to the surgery. Similarly, the impact of embolization is likely to be more profound in metastases from HCC, thyroid and primary spine tumours. PMID- 28629681 TI - Association of ischemic and hemorrhagic strokes hospital admission with extreme temperature in Nanchang, China-A case-crossover study. AB - Despite consistent evidence of a higher short-term risk of stroke mortality associated with ambient temperature, there are no findings on the association between extreme temperature and stroke. A total of 16,264 stroke hospital admissions were observed in three hospitals of Nanchang between 2008 and 2015. The case-crossover design was utilized for our study. Conditional logistic regression models were used to calculate the odds ratios. Extreme high temperature exposure during the 3days before the stroke was associated with both ischemic (OR=1.18; 95% CI: 1.07-1.36) and hemorrhagic stroke admissions (OR=1.34; 95% CI: 1.26-1.42) as compared to 3-day control periods (1-3days last week before the onset of stroke). Extreme low temperature was associated with hemorrhagic stroke admission (OR=1.42; 95% CI: 1.28-1.58) but not ischemic stroke (OR=1.06; 95% CI: 0.93-1.13). This study suggests that extreme high temperature might be a risk factor for both hemorrhagic and ischemic strokes, and that extreme low temperature might be a risk factor of hemorrhagic stroke. Further studies are necessary in order to clarify this relationship and provide evidence for stroke prevention. PMID- 28629682 TI - Aquatic live animal radiotracing studies for ecotoxicological applications: Addressing fundamental methodological deficiencies. AB - The use of live animal gamma radioisotope tracer techniques in the field of ecotoxicology allows laboratory studies to accurately monitor contaminant biokinetics in real time for an individual organism. However, methods used in published studies for aquatic organisms are rarely described in sufficient detail to allow for study replication or an assessment of the errors associated with live animal radioanalysis to be identified. We evaluate the influence of some important methodological deficiencies through an overview of the literature on live aquatic animal radiotracer techniques and through the results obtained from our radiotracer studies on four aquatic invertebrate species. The main factors discussed are animal rinsing, radioanalysis and geometry corrections. We provide examples of three main techniques in live aquatic animal radiotracer studies to improve data quality control and demonstrate why each technique is crucial in interpreting the data from such studies. The animal rinsing technique is also relevant to non-radioisotope tracer studies, especially those involving nanoparticles. We present clear guidance on how to perform each technique and explain the importance of proper reporting of the validation of each technique for individual studies. In this paper we describe methods that are often used in lab-based radioecology studies but are rarely described in great detail. We hope that this paper will act as the basis for standard operating procedures for future radioecology studies to improve study replication and data quality control. PMID- 28629683 TI - The Relationship between Dietary Intake, Growth, and Body Composition in Inborn Errors of Intermediary Protein Metabolism. AB - OBJECTIVES: To examine relationships between dietary intake, growth and body composition patterns in patients with inborn errors of intermediary protein metabolism and to determine a safe protein:energy ratio (P:E ratio) associated with optimal growth outcomes. STUDY DESIGN: Retrospective longitudinal data of growth and dietary intake in patients (n = 75) with isovaleric acidemia (IVA; n = 7), methylmalonic acidemia/propionic acidemia (MMA/PA; n = 14), urea cycle defects (UCD; n = 44), classical maple syrup urine disease (MSUD; n = 10) were collected. Prospective longitudinal data of growth, dietary intake, and body composition from 21 patients: IVA (n = 5), MMA/PA (n = 6), UCD (n = 7), and MSUD (n = 3) were collected at clinic visits. RESULTS: Fifty-two of 75 (66%), 49 of 74 (68%), and 44 of 65 (68%) patients had a z-score of 0 (+/-1) for lifetime weight, height, and body mass index, respectively. Patients with MMA/PA had the lowest median height and weight z-scores, and MSUD patients had highest median body mass index z-score at all ages. In IVA, MMA/PA, and UCD, total natural protein intake met or exceeded the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO)/United Nations University (UNU) recommended safe levels. Median percentage fat mass was 17.6% in IVA, 20.7% in MMA/PA, 19.4% in UCD, and 17.8% in MSUD. There was a significant negative correlation between percentage fat mass and total protein intake in IVA, MMA/PA, and UCD (r = -0.737; P = .010). The correlation between the P:E ratio and growth variables in IVA, MMA/PA, and UCD suggest a safe P:E ratio (>1.5 to < 2.9) g protein:100 kcal/day. CONCLUSION: Growth outcomes in inborn errors of intermediary protein metabolism are not always ideal. Most patients with IVA, MMA/PA, and UCD consume sufficient natural protein to meet FAO/WHO/UNU recommendations. A P:E ratio range of (>1.5 to < 2.9)g protein/100 kcal/day correlates with optimal growth outcomes. PMID- 28629684 TI - United States Medical Licensing Examination and American Board of Pediatrics Certification Examination Results: Does the Residency Program Contribute to Trainee Achievement. AB - OBJECTIVE: To determine whether training site or prior examinee performance on the US Medical Licensing Examination (USMLE) step 1 and step 2 might predict pass rates on the American Board of Pediatrics (ABP) certifying examination. STUDY DESIGN: Data from graduates of pediatric residency programs completing the ABP certifying examination between 2009 and 2013 were obtained. For each, results of the initial ABP certifying examination were obtained, as well as results on National Board of Medical Examiners (NBME) step 1 and step 2 examinations. Hierarchical linear modeling was used to nest first-time ABP results within training programs to isolate program contribution to ABP results while controlling for USMLE step 1 and step 2 scores. Stepwise linear regression was then used to determine which of these examinations was a better predictor of ABP results. RESULTS: A total of 1110 graduates of 15 programs had complete testing results and were subject to analysis. Mean ABP scores for these programs ranged from 186.13 to 214.32. The hierarchical linear model suggested that the interaction of step 1 and 2 scores predicted ABP performance (F[1,1007.70] = 6.44, P = .011). By conducting a multilevel model by training program, both USMLE step examinations predicted first-time ABP results (b = .002, t = 2.54, P = .011). Linear regression analyses indicated that step 2 results were a better predictor of ABP performance than step 1 or a combination of the two USMLE scores. CONCLUSIONS: Performance on the USMLE examinations, especially step 2, predicts performance on the ABP certifying examination. The contribution of training site to ABP performance was statistically significant, though contributed modestly to the effect compared with prior USMLE scores. PMID- 28629685 TI - Sudden Death in Epilepsy: Knowledge among Pediatric Providers. AB - A survey of 146 pediatric care providers (PCPs) revealed that 75.3% were unaware that children with epilepsy were at risk of death, specifically from sudden unexpected (or unexplained) death in epilepsy (SUDEP). PCPs assume that the treating neurologist discusses these risks. Increasing PCPs' knowledge of SUDEP will help address the care gap related to informing families about SUDEP. PMID- 28629686 TI - Is childhood cardiometabolic status a risk factor from early infancy or toddler age? PMID- 28629687 TI - Sensitivity and Specificity of Empiric Treatment for Sexually Transmitted Infections in a Pediatric Emergency Department. AB - OBJECTIVE: To determine test characteristics of provider judgment for empiric antibiotic provision to patients undergoing testing for a sexually transmitted infection. STUDY DESIGN: We conducted a retrospective cross-sectional electronic health record review of all patients aged 13-19 years who had Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) testing sent from an urban, academic pediatric emergency department in 2012. We abstracted data, including patient demographics, chief complaint, sexually transmitted infection test results, and treatment. We calculated test characteristics comparing clinician judgment for presumptive treatment for a sexually transmitted infection with the reference standard of the actual results of testing for a sexually transmitted infection. RESULTS: Of 1223 patient visits meeting inclusion criteria, 284 (23.2%) had a positive GC and/or CT test result. Empiric treatment was provided in 615 encounters (50.3%). Provider judgment for presumptive treatment had an overall sensitivity of 67.6% (95% CI, 61.8-73.0) and a specificity of 55% (95% CI, 51.7-58.2) for accurate GC and/or CT detection. CONCLUSIONS: Many adolescents tested for GC and CT receive empiric treatment at the initial emergency department visit. Provider judgment may lack sufficient sensitivity and specificity for identifying infected patients, resulting in the potential for undertreatment of true disease, overtreatment of uninfected patients, or both. PMID- 28629688 TI - Generalized Pustular Psoriasis. PMID- 28629689 TI - Advanced Power Doppler Technique Increases Synovial Vascularity Detection in Patients with Rheumatoid Arthritis. AB - We compared the diagnostic performance of an advanced power Doppler technique (superb microvascular imaging [SMI]) with that of power Doppler Imaging (PDI) and B-mode ultrasound (US) in patients with early rheumatoid arthritis (RA) and RA under treatment with rituximab. Thirty patients (21 women aged 45 +/- 11 y) affected by RA with remission to moderate disease activity were examined. Both hand joints were evaluated using US, PDI and SMI. Two radiologists reviewed all video clips and evaluated synovial vascularity intensity using a semi quantitative scoring system. SMI revealed the presence of synovial vascularity in a significantly larger number of patients than PDI (p = 0.02). Inter-observer agreement for US, PDI and SMI was moderate (kappa = 0.59), very good (kappa = 0.87) and very good (kappa = 0.82), respectively. We conclude that SMI detects more vessels than PDI in RA patients. This may allow increased sensitivity for early diagnosis of synovial inflammation, monitoring of its dynamic changes under therapy and evaluation of true imaging remission. PMID- 28629690 TI - Axillary Lymph Node Sonographic Features and Breast Tumor Characteristics as Predictors of Malignancy: A Nomogram to Predict Risk. AB - The purpose of this study was to build a mathematical model to predict the probability of axillary lymph node metastasis based on the ultrasonographic features of axillary lymph nodes and the tumor characteristics. We included 74 patients (75 axillae) with invasive breast cancer who underwent axillary ultrasonography ipsilateral to the tumor and fine-needle aspiration of one selected lymph node. Lymph node pathology results from sentinel lymph node biopsy or surgical dissection were correlated with lymph node ultrasonographic data and with the cytologic findings of fine-needle aspiration. Our mathematical model of prediction risk of lymph node metastasis included only pre-surgical data from logistic regression analysis: lymph node cortical thickness (p = 0.005), pre surgical tumor size (p = 0.030), menopausal status (p = 0.017), histologic type (p = 0.034) and tumor location (p = 0.011). The area under the receiver operating characteristic curve of the model was 0.848, reflecting an excellent discrimination of the model. This nomogram may assist in the choice of the optimal axillary approach. PMID- 28629691 TI - Diastolic Carotid Artery Longitudinal Wall Motion Is Sensitive to Both Aging and Coronary Artery Disease Status Independent of Arterial Stiffness. AB - We investigated the ability of systolic and diastolic carotid artery longitudinal wall motion (CALM) to delineate expected differences in arterial health in individuals representing a range of both age and health status. We recruited 161 younger healthy adults (aged 24 +/- 5 y), 51 older healthy adults (aged 70 +/- 5 y) and 14 adults with coronary artery disease (aged 67 +/- 8 y) for resting assessment of CALM and arterial stiffness. All CALM parameters were reduced in the old healthy adults and adults with coronary artery disease compared with the young healthy adults (p < 0.01), with diastolic velocity and maximum diastolic acceleration being further reduced in the adults with coronary artery disease than in the older healthy adults (p < 0.01). Diastolic CALM parameters were more strongly related to age (beta range: -0.46 to -0.53) than systolic CALM parameters (beta range: -0.24 to -0.44). In contrast to previous examinations of a variety of CALM parameters, diastolic CALM may provide superior promise in terms of characterizing arterial wall properties, with additional sensitivity to cardiovascular disease status. PMID- 28629692 TI - Is homeopathy a medicine? PMID- 28629693 TI - Helping ethics committees separate the wheat from the chaff. PMID- 28629694 TI - Interleukin-6 participation in pathology of ocular diseases. AB - Interleukin-6 (IL-6) is a multifunctional cytokine that affects a variety of cells in the body such as osteoclasts, hepatocytes, endothelial cells, epithelial cells, white and red blood cells and etc. Elevated levels of IL-6 have been detected in many ocular diseases. Studies show that IL-6 has a major role in the pathology of glaucoma, CRVO, macular edema, ocular neovascularization, posterior capsule opacity formation, keratitis, dry eye disease, allergic eye disease, ocular autoimmune disease, corneal chemical burn, ocular inflammation and so on. IL-6 does its effects through the classic or trans-signal pathways in cells. Blocking of IL-6 signal pathways via Tocilizumab or other chemicals and therapeutics will help to overcome complications related to ocular diseases. PMID- 28629695 TI - A controlled study of the influence of comorbidity on activities of daily living in elderly cancer survivors (the HUNT-3 survey). AB - OBJECTIVES: To examine the influence of somatic comorbidity on Activity of Daily Living (ADL) problems in cancer survivors >=70years (ECSs) based on data from The Health Study of Nord-Trondelag County (HUNT-3) 2006-08. MATERIAL AND METHODS: Among participants of the HUNT-3 survey, 599 ECSs had a diagnosis of one invasive cancer according to both The Cancer Registry of Norway and self-report. Three controls without cancer aged >=70years for each ECS were drawn from the HUNT-3 sample. We compared personal-ADL (P-ADL) and instrumental-ADL (I-ADL) problems for ECSs and differences between ADL problems for ECSs with and without comorbidity and controls with and without comorbidity. RESULTS: The prevalence of P-ADL problems was 3.5% among ECSs and 2.9% among controls (p=0.97) and for I-ADL 28.5% versus 21.4% (p=0.01), respectively. In bivariate analyses where ECSs versus controls was the dependent variable, presence of I-ADL problems, higher age, being female, paired relationship, poor self-rated health, hospitalization last year, and low level of neuroticism were associated being ECSs. In multivariate analyses, these variables, except I-ADL-problems and paired relationship, remained significantly associated being ECSs. No significant differences were shown for P-ADL problems when comparing ECSs and controls with comorbidity, and ECSs with and without comorbidity. ECSs with comorbidity reported significantly more I-ADL-problems than controls with comorbidity, and ECSs with comorbidity had significantly more I-ADL-problems than ECSs without comorbidity. CONCLUSION: Our results reflect common factors found in ADL studies in the elderly population. Health personnel have to be particularly observant on I-ADL problems among female ECSs, and those reporting poor self-rated health or comorbidity. PMID- 28629696 TI - New criteria to determine the destabilization of the acidogenic anaerobic co digestion of organic fraction of municipal solid waste (OFMSW) with mixed sludge (MS). AB - Effect of hydraulic retention time (HRT) on bio-hydrogen production from co digestion of organic fraction of municipal solid waste (OFMSW) and mixed sludge (MS) in dry thermophilic conditions (55 degrees C and 20% total solids) was investigated. A decreasing sequence of six HRTs, from 2.9 to 0.8-days, was performed to evaluate the stability of the system and the influence of HRT on the organic matter solubilization, the daily hydrogen production (HP) and the specific hydrogen production (SHP). Best results were obtained operating at 1.2 days HRT: HP of 3.67L H2/Lreactor/day, SHP of 33.8mL H2/gVSadded and hydrogen percentage in biogas of 52.4%. However, HRTs lower than 1.2-days induce failure in the system due to an unbalance of the hydrolytic phase. This fact was corroborated through the evaluation of two indirect parameters, "non-solubilized carbon" (NSC) and "acidogenic substrate as carbon" (ASC), and the relationships of NSC/TOC and ASC/TOC. PMID- 28629697 TI - Increase in furfural tolerance by combinatorial overexpression of NAD salvage pathway enzymes in engineered isobutanol-producing E. coli. AB - To reduce the furfural toxicity for biochemical production in E. coli, a new strategy was successfully applied by supplying NAD(P)H through the nicotine amide salvage pathway. To alleviate the toxicity, nicotinamide salvage pathway genes were overexpressed in recombinant, isobutanol-producing E. coli. Gene expression of pncB and nadE respectively showed increased tolerance to furfural among these pathways. The combined expression of pncB and nadE was the most effective in increasing the tolerance of the cells to toxic aldehydes. By comparing noxE- and fdh-harbouring strains, the form of NADH, rather than NAD+, was the major effector of furfural tolerance. Overall, this study is the application of the salvage pathway to isobutanol production in the presence of furfural, and this system seems to be applicable to alleviate furfural toxicity in the production of other biochemical. PMID- 28629698 TI - Cardboard proportions and total solids contents as driving factors in dry co fermentation of food waste. AB - This study evaluated the influence of the co-substrate proportions (0-60% of cardboard in dry basis) and the initial total solid contents (20-40%) on the batch fermentation performance. Maximum hydrogen yields were obtained when mono fermenting food waste at high solids contents (89mlH2.gVS-1). The hydrogen yields were lower when increasing the proportions of cardboard. The lower hydrogen yields at higher proportions of cardboard were translated into higher yields of caproic acid (up to 70.1gCOD.kgCODbio-1), produced by consumption of acetic acid and hydrogen. The highest substrate conversions were achieved at low proportions of cardboard, indicating a stabilization effect due to higher buffering capacities in co-fermentation. Clostridiales were predominant in all operational conditions. This study opens up new possibilities for using the cardboard proportions for controlling the production of high added-value products in dry co fermentation of food waste. PMID- 28629699 TI - Understanding the applicability of results from primary care trials: lessons learned from applying PRECIS-2. AB - OBJECTIVE: To compare two approaches for trial teams to apply PRECIS-2 to pragmatic trials: independent scoring and scoring following a group discussion. STUDY DESIGN AND SETTING: We recruited multidisciplinary teams who were conducting or had conducted trials in primary care in collaboration with the Pragmatic Clinical Trials Unit, Queen Mary University of London. Each team carried out two rounds of scoring on the nine PRECIS-2 domains: first independently using an online version of PRECIS-2 and second following a discussion. RESULTS: Seven teams took part in the study. Before the discussion, within-team agreement in scores was generally poor and not all raters were able to score all domains; agreement improved after the discussion. The PRECIS-2 wheels suggested that the trials were pragmatic, although some domains were more pragmatic than others. CONCLUSION: PRECIS-2 can facilitate information exchange within trial teams. To apply PRECIS-2 successfully, we recommend a discussion between those with detailed understanding of what usual care is for the intervention, the trial's design including operational and technical aspects, and the PRECIS-2 domains. For some cluster-randomized trials, greater insight may be gained by plotting two PRECIS-2 wheels, one at the individual participant level and another at the cluster level. PMID- 28629700 TI - Designing pragmatic trials-what can we learn from lessons learned? AB - Pragmatic trials aim to inform clinical decision making by measuring the effect of a treatment in clinical practice. The purpose of the PRECIS-2 tool is to support in designing a truly pragmatic trial. We comment on a study by Forbes et al., who assessed the applicability of the PRECIS-2 tool. The tool will prove particularly useful when implemented in the process of trial design. However, it is yet unclear how e.g., possible dependencies between PRECIS domains, or conducting a pragmatic trial within an existing data registry (e.g., electronic health records) affect the applicability of the tool. PMID- 28629702 TI - Dopamine and serotonin levels in cerebrospinal fluid during episodes of Kleine Levin syndrome. PMID- 28629701 TI - A polymethoxyflavone mixture extracted from orange peels, mainly containing nobiletin, 3,3',4',5,6,7,8-heptamethoxyflavone and tangeretin, suppresses melanogenesis through the acidification of cell organelles, including melanosomes. AB - BACKGROUND: Skin color is determined by melanin contents and its distribution. Melanin is synthesized in melanosomes of melanocytes, catalyzed by tyrosinase, melanogenic enzymes. Regarding the process of melanin synthesis, melanosomal pH is considered to play an important role, because it has been reported to differ between Caucasian and Black melanocytes. OBJECTIVE: Although polymethoxyflavone (PMF) has many beneficial effects, it has not been reported which PMF suppresses melanogenesis. In this study, we identified the mechanism underlying the effect of PMF on melanogenesis METHODS: We determined the effects of a PMF mixture extracted from orange peels on melanogenesis, on tyrosinase expression, on the localization of tyrosinase and on the acidification of organelles, including melanosomes, in HM3KO human melanoma cells. RESULTS TREATMENT: with the PMF mixture elicited the suppression of melanogenesis, the degradation of tyrosinase in lysosomes and the mislocalization of tyrosinase associated with the acidification of intracellular organelles, including melanosomes. The neutralization of cell organelle pH by ammonium chloride restored melanogenesis and the correct localization of tyrosinase to melanosomes, which had been suppressed by the PMF mixture. CONCLUSION: These results suggest that the PMF mixture suppresses the localization of tyrosinase to melanosomes and consequently inhibits melanogenesis due to the acidification of cell organelles, including melanosomes. PMID- 28629703 TI - Association of food access and neighbor relationships with diet and underweight among community-dwelling older Japanese. AB - BACKGROUND: Food access is important for maintaining dietary variety, which predicts underweight. The aim of this study was to examine the association of food access and neighbor relationships with eating and underweight. METHODS: We analyzed cross-sectional data from 102,869 Japanese individuals aged 65 years or older. The perceived availability of food was assessed using the presence or absence of food stores within 1 km of the home. Level of relationships with neighbors was also assessed. The odds ratios (ORs) and 95% confidence intervals (CIs) for infrequent food intake and underweight were determined using logistic regression analysis. RESULTS: The proportion of men and women having low access to food was 25-30%. Having low food access (OR 1.18; 95% CI, 1.12-1.25 for men and OR 1.26; 95% CI, 1.19-1.33 for women) and a low level of relationship with neighbors (OR 1.38; 95% CI, 1.31-1.45 for men and OR 1.57; 95% CI, 1.48-1.67 for women) was associated with infrequent intake of fruits and vegetables in both sexes. Association between low food access and infrequent intake of fruits and vegetables was higher among men with low levels of neighbor relationship (OR 1.34; 95% CI, 1.23-1.46) than among men with high levels of relationship (OR 1.10; 95% CI, 1.03-1.18). CONCLUSIONS: Low perceived availability of food is a risk factor for low dietary variety among older people. Furthermore, high levels of relationship with neighbors may relieve the harmful effect of low food access. PMID- 28629704 TI - Relationship between 8-year weight change, body size, and health in a large cohort of adults in Thailand. AB - BACKGROUND: Overweight and obesity have been shown to be risk factors for a range of non-communicable diseases, especially cardio-metabolic conditions, worldwide. But less is known about the effects of weight change on adults' overall health and wellbeing, particularly in transitional low- and middle-income countries. This study aimed to assess the relationship between 8-year weight change and measures of self-assessed health among Thai adults. METHODS: Data were collected from Thai adults aged 25-40 years (n = 27,003) enrolled in the Thai cohort Study and surveyed in 2005, 2009, and 2013. We used self-reported weight and height measurements at baseline and 2013, as well as three standard health questions regarding overall health, energy, and emotion asked at the two time points, to investigate the effects of weight change on health. RESULTS: Between 2005 and 2013, 6.0% of participants lost more than 5% of their baseline weight; 38.5% were stable (<5% loss to 5% gain); 23.0% slightly gained weight (>5%-10%); 22.8% gained moderate weight (>10%-20%); and 9.4% had heavy weight gain (>20%). Moderate (>10%-20%) and heavy weight gain (>20%) were both associated with an increased risk of reporting 'poor or very poor' overall health in 2013 among participants who had a normal body mass index (BMI) (adjusted odds ratio [AOR] 1.39; 95% confidence interval [CI], 1.13-1.71 and AOR 1.44; 95% CI, 1.09-1.90, respectively), were overweight (AOR 1.53; 955 CI, 1.01-2.29 and AOR 1.82; 95% CI, 1.04-3.19, respectively) or had obesity (AOR 2.47; 95% CI, 1.74-3.51 and AOR 3.20; 95% CI, 2.00-5.16, respectively) in 2005. Weight gain of over 20% also had a negative impact on energy level among cohort members with a normal BMI in 2005 (AOR 1.36; 95% CI, 1.11-1.65) and among participants with obesity in 2005 (AOR 1.93; 95% CI, 1.38-2.71). For those who were underweight, had a normal BMI, or had obesity at baseline, weight loss of more than 5% was associated with reporting emotional problems. Excessive weight gain adversely impacted participants who were underweight or had obesity at baseline. CONCLUSION: Our study found that weight change, in particular weight gain, was associated with negative health outcomes, and this effect appeared to increase at higher levels of body size. The present findings may be useful to promote weight maintenance and healthy lifestyles. PMID- 28629705 TI - Nursing involvement in risk and patient safety management in Primary Care. AB - Patient safety and quality of care in a highly complex healthcare system depends not only on the actions of professionals at an individual level, but also on interaction with the environment. Proactive risk management in the system to prevent incidents and activities targeting healthcare teams is crucial in establishing a culture of safety in centres. Nurses commonly lead these safety strategies. Even though safety incidents are relatively infrequent in primary care, since the majority are preventable, actions at this level of care are highly effective. Certification of services according to ISO standard 9001:2008 focuses on risk management in the system and its use in certifying healthcare centres is helping to build a safety culture amongst professionals. PMID- 28629706 TI - Disulfide-linked dimerization of the FcRgamma chain is required for positive and negative regulation of mast cell activation via FcepsilonRI. PMID- 28629707 TI - Theoretical investigation of the selective dehydration and dehydrogenation of ethanol catalyzed by small molecules. AB - Catalytic dehydration and dehydrogenation reactions of ethanol have been investigated systematically using the ab initio quantum chemistry methods The catalysts include water, hydrogen peroxide, formic acid, phosphoric acid, hydrogen fluoride, ammonia, and ethanol itself. Moreover, a few clusters of water and ethanol were considered to simulate the catalytic mechanisms in supercritical water and supercritical ethanol. The barriers for both dehydration and dehydrogenation can be reduced significantly in the presence of the catalysts. It is revealed that the selectivity of the catalytic dehydration and dehydrogenation depends on the acidity and basicity of the catalysts and the sizes of the clusters. The acidic catalyst prefers dehydration while the basic catalysts tend to promote dehydrogenation more effectively. The calculated water-dimer catalysis mechanism supports the experimental results of the selective oxidation of ethanol in the supercritical water. It is suggested that the solvent- and catalyst-free self-oxidation of the supercritical ethanol could be an important mechanism for the selective dehydrogenation of ethanol on the theoretical point of view. PMID- 28629708 TI - Comparative use of different emission measurement approaches to determine methane emissions from a biogas plant. AB - A sustainable anaerobic biowaste treatment has to mitigate methane emissions from the entire biogas production chain, but the exact quantification of these emissions remains a challenge. This study presents a comparative measurement campaign carried out with on-site and ground-based remote sensing measurement approaches conducted by six measuring teams at a Swedish biowaste treatment plant. The measured emissions showed high variations, amongst others caused by different periods of measurement performance in connection with varying operational states of the plant. The overall methane emissions measured by ground based remote sensing varied from 5 to 25kgh-1 (corresponding to a methane loss of 0.6-3.0% of upgraded methane produced), depending on operating conditions and the measurement method applied. Overall methane emissions measured by the on-site measuring approaches varied between 5 and 17kgh-1 (corresponding to a methane loss of 0.6 and 2.1%) from team to team, depending on the number of measured emission points, operational state during the measurements and the measurement method applied. Taking the operational conditions into account, the deviation between different approaches and teams could be explained, in that the two largest methane-emitting sources, contributing about 90% of the entire site's emissions, were found to be the open digestate storage tank and a pressure release valve on the compressor station. PMID- 28629709 TI - Energy recovery from one- and two-stage anaerobic digestion of food waste. AB - One- and two-stage anaerobic digestion of food waste aimed at recovering methane (CH4) and hydrogen and methane (H2+CH4), respectively, were compared in order to assess the potential benefits from the two-stage process in terms of overall energy recovery. Results suggest that a two-stage process where the first reactor is properly operated in order to achieve a significant net hydrogen production, may display a 20% comparatively higher energy recovery yield as a result, mainly, of enhanced methane production as well as of the associated hydrogen production. The highest methane production of the two-stage process was due to improved hydrolysis and fermentation of food waste, with increased amounts of volatile fatty acids being readily available to methanogenesis. PMID- 28629710 TI - Anaerobic digestion of tuna waste for the production of volatile fatty acids. AB - Fish canning industries generate a significant amount of solid waste that can be digested anaerobically into volatile fatty acids (VFA). The aim of this research was to study the effect of various pHs, ranging from 5.0 to 10.0, and percentage of total solids on the anaerobic digestion of tuna waste into VFA, both in batch assays and continuous reactor. The production of VFA was affected by pH and was significantly higher under alkaline conditions. At pH 8.0, the VFA production reached 30,611mgCOD/L. The VFA mainly consisted of acetic, propionic, n-butyric and i-valeric acids. Acetic acid was the main product at all the pHs tested. In terms of total solids (TS) the best results were obtained with 2.5% total solids, reaching 0.73gCODVFA/gCODwaste. At higher TS concentrations (5 and 8% TS) lower yields were reached probably due to inhibition at high VFA concentration. PMID- 28629711 TI - Single-step construction of a picornavirus replicon RNA with precise ends. AB - A versatile single-step method is described for constructing a picornavirus replicon RNA with precise ends to facilitate improved understanding of viral genome function and mimic native virus replication in host cells as far as possible. The key innovation in this new approach is the use of a bridge primer to both introduce a ribozyme sequence for cis-cleavage of RNA to generate precise 5' ends of EV71 RNA and also mediate overlapping assembly of two fragments. Using an EV71 replicon as a test case, precise ends for the viral replicon were shown to be important for efficient virus replication. Thus, our work provides a novel efficient way to generating higher efficient viral replicon with precise ends and this novel method can be applied to other picornaviruses' research. PMID- 28629712 TI - Corrigendum to 'Predictors of Shunt Insertion in Aneurysmal Subarachnoid Hemorrhage' [World Neurosurgery 98 (2017) 421-426]. PMID- 28629713 TI - The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders. AB - Approximately 10% of pregnant women are prescribed antidepressant drugs (ADDs), with selective serotonin reuptake inhibitors (SSRIs) the most widely prescribed. SSRIs bind to the serotonin transporter (SERT), blocking the reabsorption of serotonin by the presynaptic neuron and increasing serotonin levels in the synaptic cleft. The serotonergic system regulates a range of brain development processes including neuronal proliferation, migration, differentiation and synaptogenesis. Given the presence of SERT in early brain development, coupled with the ability of SSRIs to cross the placenta and also enter breast milk, concerns have been raised regarding the effects of SSRI exposure on the developing foetus and newborns. In this review, we evaluate preclinical and clinical studies that have examined the effects of maternal SSRI exposure and the risk for altered neurodevelopment and associated behaviours in offspring. While the current body of evidence suggests that maternal SSRI treatment may cause perturbations to the neurobiology, behaviour and ultimately risk for neurodevelopmental disorders in exposed offspring, conflicting findings do exist and the evidence is not conclusive. However, given the increasing incidence of depression and number of women prescribed ADDs during pregnancy, further investigation into this area is warranted. PMID- 28629714 TI - [Clinical observation of newborns with infection risk: A safe practice]. AB - INTRODUCTION: Early-onset neonatal sepsis refers to an infection which starts during the first 72hours of birth, and can lead to significant morbidity and mortality. Scientific evidence shows that infected infants present with symptoms during the first hours after delivery. There has been a significant decrease in this condition with the implementation of guidelines for its prevention. However, International guidelines still recommend the evaluation of these infants using painful tests. MATERIAL AND METHODS: A prospective cohort study was conducted on all asymptomatic infants born at>35 weeks gestation with one or more risk factors in a single tertiary care centre from 2011 to 2015. They were periodically observed in newborn nursery from admission until discharge looking for signs of infection. RESULTS: Out of the 9,424 babies born during this period, 1425 were included in the study. A total of 53 infants were admitted to the neonatal unit, half of them because of sepsis suspicion. Finally, just 7 were discharged with the diagnosis of sepsis. All these 7 presented with symptoms during their first 72hours of life. No sepsis was reported in asymptomatic infants. CONCLUSIONS: Truly infected infants present with symptoms during their first hours of life. This study supports the observation of infants at risk as a safe practice to detect early-onset sepsis. PMID- 28629716 TI - Psychosocial factors, musculoskeletal disorders and work-related fatigue amongst nurses in Brunei: structural equation model approach. AB - INTRODUCTION: Psychosocial factors, musculoskeletal disorders and work-related fatigue have adverse effects on individual nurses and place a substantial financial burden on health care. Evidence of an association has been reported in the literature, but no theoretical explanation has been published to date. AIM: To explore and develop a structural model to provide a theoretical explanation for this relationship. METHODS: A cross-sectional study using data from 201 valid samples of emergency and critical care nurses across public hospitals in Brunei was performed via self-administered questionnaire. The structural equation model was assessed using partial least squares analysis. RESULTS: A valid and robust structural model was constructed. This revealed that 61.5% of the variance in chronic fatigue could be explained by psychosocial factors and musculoskeletal disorders pathways. Among the psychosocial factors, work-family conflict was identified as a key mediator for progression of musculoskeletal problems and subsequent fatigue through stress and burnout. CONCLUSION: This report provides a novel theoretical contribution to understanding the relationship between psychosocial factors, musculoskeletal disorders and work-related fatigue. These preliminary results may be useful for future studies on the development of work related fatigue and musculoskeletal disorders, particularly the central role of work-family conflict. PMID- 28629717 TI - Sarcopenia Screened by the SARC-F Questionnaire and Physical Performances of Elderly Women: A Cross-Sectional Study. AB - OBJECTIVES: Screening for sarcopenia in daily practice can be challenging. Our objective was to explore whether the SARC-F questionnaire is a valid screening tool for sarcopenia (defined by the Foundation for the National Institutes of Health [FNIH] criteria). Moreover, we evaluated the physical performance of older women according to the SARC-F questionnaire. DESIGN: Cross-sectional study. PARTICIPANTS: Data from the Toulouse and Lyon EPIDemiologie de l'OSteoporose study (EPIDOS) on 3025 women living in the community (mean age: 80.5 +/- 3.9 years), without a previous history of hip fracture, were assessed. MEASUREMENTS: The SARC-F self-report questionnaire score ranges from 0 to 10: a score >=4 defines sarcopenia. The FNIH criteria uses handgrip strength (GS) and appendicular lean mass (ALM; assessed by DXA) divided by body mass index (BMI) to define sarcopenia. Outcome measures were the following performance-based tests: knee-extension strength, 6-m gait speed, and a repeated chair-stand test. The associations of sarcopenia with performance-based tests was examined using bootstrap multiple linear-regression models; adjusted R2 determined the percentage variation for each outcome explained by the model. RESULTS: Prevalence of sarcopenia was 16.7% (n = 504) according to the SARC-F questionnaire and 1.8% (n = 49) using the FNIH criteria. Sensibility and specificity of the SARC-F to diagnose sarcopenia (defined by FNIH criteria) were 34% and 85%, respectively. Sarcopenic women defined by SARC-F had significantly lower physical performance than nonsarcopenic women. The SARC-F improved the ability to predict poor physical performance. CONCLUSION: The validity of the SARC-F questionnaire to screen for sarcopenia, when compared with the FNIH criteria, was limited. However, sarcopenia defined by the SARC-F questionnaire substantially improved the predictive value of clinical characteristics of patients to predict poor physical performance. PMID- 28629719 TI - Alpha ketoglutarate nanoparticles: A potentially effective treatment for cyanide poisoning. AB - The purpose of this research work was to prepare nanosized formulation of alpha ketoglutarate as dry powder inhaler for cyanide poisoning. Nanosizing can be approached by solid phase and liquid phase method. The different conditions encountered in both these approaches can greatly affect the particle characteristics. In this study milling and precipitation technique were compared to study their effect on alpha-KG particles characteristics. Differences in choice of stabilizers were observed between the two processing techniques. Sonication processes followed by HPH produced small sized particles in which Pluronic F68 was employed as stabilizing agent. Precipitation approach produced ultrafine drug particles by utilizing combination of stabilizers (PVA+PEG 400). Amongst the two sonication processes, probe sonication process produced well stabilized small sized particles. The designed particles showed 43.13+/-2.36% lung deposition when compared with ultrasonication and precipitation technique that showed 31.69% and 21.67% respirable fraction. The MMAD of the designed particles was found suitable for deep alveolar deposition. Clinical studies (Phase-I trial) showed whole lung deposition of 52.51% for DPI. The P/C ratio was found to be 1.02 suggesting uniform distribution of particles in different lung compartments. PMID- 28629718 TI - Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors. AB - Primary forms of focal and segmental glomerulosclerosis (FSGS) are driven by circulating factors that cause dysfunction or loss podocytes. Rare genetic forms of FSGS can be caused by mutations in TRPC6, which encodes a Ca2+-permeable cationic channel expressed in mesangial cells and podocytes; and NPHS2, which encodes podocin, a TRPC6-binding protein expressed in podocyte slit diaphragm domains. Here we observed that exposing immortalized mouse podocytes to serum or plasma from recurrent FSGS patients for 24h increased the steady-state cell surface abundance of TRPC6, accompanied by an increase in currents through endogenous TRPC6 channels evoked by a hypoosmotic stretch stimulus. These effects were mimicked by the soluble urokinase receptor (suPAR) and by tumor necrosis factor (TNF), circulating factors implicated in nephrotic syndromes. Most but not all of the recurrent FSGS plasma samples that we examined also caused a loss of podocin over a period of several hours. The loss of podocin was also seen following exposure to suPAR but not TNF. However, TNF increased the effects of suPAR on TRPC6 and podocin, and TNF and suPAR are required for the full effects of one of the recurrent FSGS plasma samples. The actions of FSGS plasma, suPAR and TNF on surface abundance of TRPC6 were blocked by cilengitide, an inhibitor of alphavbeta3-integrin signaling. These data suggest that primary FSGS is a heterogeneous condition mediated by multiple circulating factors, and support TRPC6 and alphavbeta3-integrin as potential therapeutic targets. PMID- 28629720 TI - Exploring connectivity with large-scale Granger causality on resting-state functional MRI. AB - BACKGROUND: Large-scale Granger causality (lsGC) is a recently developed, resting state functional MRI (fMRI) connectivity analysis approach that estimates multivariate voxel-resolution connectivity. Unlike most commonly used multivariate approaches, which establish coarse-resolution connectivity by aggregating voxel time-series avoiding an underdetermined problem, lsGC estimates voxel-resolution, fine-grained connectivity by incorporating an embedded dimension reduction. NEW METHOD: We investigate application of lsGC on realistic fMRI simulations, modeling smoothing of neuronal activity by the hemodynamic response function and repetition time (TR), and empirical resting-state fMRI data. Subsequently, functional subnetworks are extracted from lsGC connectivity measures for both datasets and validated quantitatively. We also provide guidelines to select lsGC free parameters. RESULTS: Results indicate that lsGC reliably recovers underlying network structure with area under receiver operator characteristic curve (AUC) of 0.93 at TR=1.5s for a 10-min session of fMRI simulations. Furthermore, subnetworks of closely interacting modules are recovered from the aforementioned lsGC networks. Results on empirical resting state fMRI data demonstrate recovery of visual and motor cortex in close agreement with spatial maps obtained from (i) visuo-motor fMRI stimulation task sequence (Accuracy=0.76) and (ii) independent component analysis (ICA) of resting state fMRI (Accuracy=0.86). COMPARISON WITH EXISTING METHOD(S): Compared with conventional Granger causality approach (AUC=0.75), lsGC produces better network recovery on fMRI simulations. Furthermore, it cannot recover functional subnetworks from empirical fMRI data, since quantifying voxel-resolution connectivity is not possible as consequence of encountering an underdetermined problem. CONCLUSIONS: Functional network recovery from fMRI data suggests that lsGC gives useful insight into connectivity patterns from resting-state fMRI at a multivariate voxel-resolution. PMID- 28629721 TI - A 16-year retrospective surveillance report on the pathogenic features and antimicrobial susceptibility of Pseudomonas aeruginosa isolates from FAHJU in Guangzhou representative of Southern China. AB - Pseudomonas aeruginosa is a major pathogen responsible for nosocomial infections. A 16-year retrospective report from 2000 to 2015 was conducted to assess the antimicrobial resistance of P. aeruginosa in Southern China. A total of 1387 P. aeruginosa were collected from inpatients and outpatients. Susceptibility testing results were interpreted according to the Clinical and Laboratory Standards Institute (CLSI, 2015). Piperacillin, piperacillin-tazobactam, ceftazidime, aminoglycosides and carbapenems remained to be active against P. aeruginosa, with resistance rates ranging from 5.6% to 29.7%. Generally, ampicillin, ampicillin sulbactam, ceftriaxone and trimethoprim-sulfamethoxazole nearly lost the effect on P. aeruginosa, as the resistance rates increase up to 90%. Notably, sputum and blood specimen showed higher resistance rates than other sources in carbapenems, suggesting more caution should be paid on the choice of antibiotic against infections associated with respiratory tract. PMID- 28629722 TI - The manganese efflux system MntE contributes to the virulence of Streptococcus suis serotype 2. AB - Manganese is an essential micronutrient to bacteria and plays an important role in bacterial physiology. However, an excess of manganese is extremely deleterious to the cell. The manganese efflux system is used to control intracellular manganese levels by some bacteria. In this study, we have identified a cation efflux family protein (MntE) that functions as a manganese export system in Streptococcus suis serotype 2. To investigate the role of mntE in S. suis 2, a mntE deletion mutant (DeltamntE) and the corresponding complementation strain (CDeltamntE) were constructed. DeltamntE displayed similar growth compared to the wild-type and complementation strains under normal growth conditions, but was defective in medium supplemented with high concentrations of manganese. In addition, the mutant was more sensitive to oxidative stress conferred by diamide. Using a competitive-infection assay in the murine infection model, we demonstrated for the first time that MntE is involved in the virulence of S. suis 2. Collectively, our data indicate that manganese homeostasis controlled by the manganese efflux system MntE is important for the pathogenesis of S. suis 2. PMID- 28629723 TI - Microbial antioxidant defense enzymes. AB - Free radicals are often described as chemical compounds characterized by unpaired electrons in their outer orbital rendering them highly reactive species. In mammalians, studies on free radicals were focused on reactive oxygen species (ROS) or reactive nitrogen species (RNS) due to their relative importance in physiological as well as in pathological processes. These cellular compounds are produced by different physiological systems such as the aerobic metabolism and play a major role in cell signaling pathways but also in the host immune defenses against pathogenic microorganisms. ROS and RNS are highly reactive species with potentially harmful effects on any cellular components (lipids, proteins and nucleic acids) when produced with a high level. To maintain ROS and RNS at a non toxic concentration, enzymatic and non-enzymatic cellular antioxidants coordinate the balance between their production and their degradation. Superoxide dismutases, catalases, glutathione system, thioredoxin system, peroxidase systems, flavohemoglobins and nitrate or nitrite reductases represent the prominent enzymatic antioxidants used to scavenge excess of internal as well as external ROS and RNS. Bacteria, fungi and parasites also display similar enzymatic activities to escape the host oxidative defenses during the immune response against infectious processes. Here we summarize current knowledge on the enzymatic systems that allow microorganisms to fight against ROS and RNS, and shed light on the role that take some of them in microbial infections. Such microbial protective systems are considered as virulence factors, and therefore represent key targets for diagnosis of the infections or development of anti infectious drugs. PMID- 28629724 TI - In vitro antiviral effects of Peganum harmala seed extract and its total alkaloids against Influenza virus. AB - This research was aimed to evaluate the in vitro antiviral effect and the mechanism of the effect of Peganum. harmala seeds extract against influenza A virus infection using Madin-Darby canine kidney (MDCK) cells. In this research, ethyl alcohol extract of P. harmala seeds and its total alkaloids was prepared. The potential antiviral activity of the extract and its total alkaloids against influenza A/Puerto Rico/8/34 (H1N1; PR8) virus was assessed. The mode of action of the extract to inhibit influenza replication was investigated using virucidal activity, hemagglutination inhibition assay, time of addition assays, RNA replication, western blot analysis and RNA polymerase blocking assay. The crud extract of P. harmala seed and its total alkaloids showed the best inhibitory effect against influenza A virus replication in MDCK cells using MTT assay, TCID50 method and hemagglutination assay. Our results indicated that the extract inhibits viral RNA replication and viral polymerase activity but did not effect on hemagglutination inhibition and virucidal activity. This study showed that, in vitro antiviral activity of P. harmala seed extract against influenza virus is most probably associated with inhibiting viral RNA transcription. Therefore, this extract and its total alkaloid should be further characterized to be developed as anti-influenza A virus agent. PMID- 28629725 TI - Relationship between histopathological status of the Helicobacter pylori infected patients and proteases of H. pylori in isolates carrying diverse virulence genotypes. AB - Helicobacter pylori is the main cause of several gastroduodenal diseases in Humans. Among various virulence factors of H. pylori, proteases may also be involved in its pathogenicity. In this study, relationship between proteolytic activity of H. pylori strains and histopathological changes of the stomach was investigated in the patients infected with strains carrying diverse virulence factors. H. pylori strains were isolated from the biopsies of 116 patients who referred to hospital for their gastroduodenal disorders, in Tehran, Iran. Biopsies were sent to microbiology and pathology laboratories for further analysis. All the suspected grown colonies were characterized by both biochemical tests and polymerase chain reaction (PCR). Presence of seven protease genes, htrA, clpP, hp0169, hp1012, hp0382, hp1350 and hp1435, and distinct allelic variants of H. pylori virulence factors, cagA, vacA, iceA, babA2 and sabA, were analyzed in each strain. Protease activity of the strains was assessed using spectrophotometric assay. Furthermore, association between diversity in protease genes and virulence genes, protease activity, as well as pathological changes was estimated statistically. Proteases genes, htrA, clpP, hp0169, hp1012, hp0382, hp1350, hp1435, were detected among 100%, 100%, 98%, 98%, 98%, 98%, and 8% of fifty H. pylori strains isolated from the patients, respectively. Status of cagA, vacA s1, vacA s2, vacA m1, vacA m2, iceA1, iceA2, babA2 and sabA genes in isolates were 64%, 68%, 30%, 26%, 74%, 48%, 52%, 100%, and 96%, respectively. Predominant (84%) combined status for protease genes was: htrA/clpP/hp0169/hp1012/hp0382/hP1350/hp1435, while the prevalent combined status (16%) for virulence genes was: cagA+/vacA s1m2/iceA1+/sabA+/babA2+. Although most of the strains (91.4%) presented moderate protease activity in vitro, lowest activity was measured in strains isolated from the patients with chronic gastritis (4.25%). Present study provide the new data on diversity of protease genes in H. pylori, as well as the proteolytic activity of these genes in H. pylori strains from the sick patients. Presence of significant association between lower protease activity of the strains and mildness of the pathological changes propose involvement of these proteases in the pathogenesis of H. pylori in vivo. PMID- 28629726 TI - Th2-related immune responses by the Brucella abortus cellular antigens, malate dehydrogenase, elongation factor, and arginase. AB - Brucellosis is an important zoonotic disease caused by Brucella species. The disease is difficult to control due to the intracellular survival of the bacterium and the lack of precise understanding of pathogenesis. Despite of continuous researches on the pathogenesis of Brucella spp. infection, there is still question on the pathogenesis, especially earlier immune response in the bacterial infection. Malate dehydrogenase (MDH), elongation factor (Tsf), and arginase (RocF), which showed serological reactivity, were purified after gene cloning, and their immune modulating activities were then analyzed in a murine model. Cytokine production profiles were investigated by stimulating RAW 264.7 cells and naive splenocytes with the three recombinant proteins. Also, immune responses were analyzed by ELISA and an ELIspot assay after immunizing mice with the three proteins. Only TNF-alpha was produced in stimulated RAW 264.7 cells, whereas Th1-related cytokines, IFN-gamma and IL-2, were induced in naive splenocytes. In contrast, Th2-type immune response was more strongly induced in antigen-secreting cells in the splenocytes obtained 28 days after immunizing mice with the three proteins, as were IgM and IgG. The induction of Th2-related antibody, IgG1, was higher than the Th1-related antibody, IgG2a, in immunized mice. These results suggest that the three proteins strongly induce Th2-type immune response in vivo, even though Th1-related cytokines were produced in vitro. PMID- 28629727 TI - Antigenicity of phage clones and their synthetic peptides for the serodiagnosis of canine and human visceral leishmaniasis. AB - In the Americas, Brazil is responsible by 90% of the cases registered of visceral leishmaniasis (VL), and Leishmania infantum is the most common parasite species responsible by disease in Brazilian dogs and humans. A precise diagnosis may allow to a faster and more effective treatment against the disease, which increases the possibility of cure, as well as to induce less toxic effects, due to a lower time exposition for the chemotherapeutics. In a previous study, two L. infantum mimotopes, B10 and C01 clones, were recognized by antibodies in VL dogs sera by a phage display technology, and were well-successfully evaluated as vaccine candidates against visceral and tegumentary leishmaniasis. In the present work, the diagnostic efficacy of these clones, as well as of their exogenous peptides (B10: LSFPFPG and C01: FTSFSPY), was evaluated to diagnose canine and human VL. ELISA assays were performed with the four antigens, and results showed that both clones, as well as their synthetic peptides; showed high sensitivity and specificity values to identify VL samples, presenting an excellent performance to serologically diagnose VL-developing humans and dogs. On the other hand, a wild-type phage, a random non-specific clone and a L. infantum antigenic preparation were used as controls, and showed worst sensitivity and specificity results. In conclusion, besides their biological action as vaccine, B10 and C01 phages and their synthetic peptides could be considered as new markers for the serodiagnosis of canine and human VL. PMID- 28629728 TI - Antibiotic resistance determinants and clonal relationships among multidrug resistant isolates of Klebsiella pneumoniae. AB - In the present study, we performed PCR based screening to determine the presence of antibiotic resistance genes and sequencing to find mutation in QRDR region among fourteen isolates of K. pneumoniae. Association analysis was conducted to detect the co-resistance among the isolates. Multi-locus sequence analysis was carried out to determine the clonal relationship among them. All the K. pneumoniae isolates showed resistance to multiple antibiotics and exhibited cross resistance to antibiotics. Although few isolates co-harbored variants of beta lactamase genes, others carried qnrB on plasmid and mutations in Quinolone Resistant Determining Region (QRDR). This study thus indicates that clonally unrelated K. pneumoniae isolates exhibited co-resistance, harboured multiple antibiotic resistance genes present on the chromosome, plasmids and/or integron Therefore, the data from this study can provide guidelines for the prudent use of antibiotics to avert the impending danger of losing out on the available antibiotics for therapeutic use. PMID- 28629729 TI - A multicenter study of routine versus selective intraoperative leak testing for sleeve gastrectomy. AB - BACKGROUND: Staple line leaks after sleeve gastrectomy are dreaded complications. Many surgeons routinely perform an intraoperative leak test (IOLT) despite little evidence to validate the reliability, clinical benefit, and safety of this procedure. OBJECTIVES: To determine the efficacy of IOLT and if routine use has any benefit over selective use. SETTING: Eight teaching hospitals, including private, university, and military facilities. METHODS: A multicenter, retrospective analysis over a 5-year period. The efficacy of the IOLT for identifying unsuspected staple line defects and for predicting postoperative leaks was evaluated. An anonymous survey was also collected reflecting surgeons' practices and beliefs regarding IOLT. RESULTS: From January 2010 through December 2014, 4284 patients underwent sleeve gastrectomy. Of these, 37 patients (.9%) developed a postoperative leak, and 2376 patients (55%) received an IOLT. Only 2 patients (0.08%) had a positive finding. Subsequently, 21 patients with a negative IOLT developed a leak. IOLT demonstrated a sensitivity of only 8.7%. There was a nonsignificant trend toward increased leak rates when an IOLT was performed versus when IOLT was not performed. Leak rates were not statistically different between centers that routinely perform IOLT versus those that selectively perform IOLT. CONCLUSIONS: Routine IOLT had very poor sensitivity and was negative in 91% of patients who later developed postoperative leaks. The use of IOLT was not associated with a decrease in the incidence of postoperative leaks, and routine IOLT had no benefit over selective leak testing. IOLT should not be used as a quality indicator or "best practice" for bariatric surgery. PMID- 28629730 TI - Synergistic antinociceptive effect of a calcium channel blocker and a TRPV1 blocker in an acute pain model in mice. AB - AIMS: Extensive evidence supports a role for voltage-gated calcium channels (VGCC) and TRPV1 receptors in pain transmission and modulation. We investigated the profile of analgesic interaction between Phalpha1beta toxin (a VGCC blocker) and SB366791 (selective TRPV1 antagonist) in a model of acute pain induced by capsaicin. Changes in body temperature induced by combination regimens were also evaluated. MAIN METHODS: Isobolographic approach with a fixed dose-ratio of combined drugs was used to determine whether antinociceptive interaction of Phalpha1beta and SB366791 are subadditive, additive or synergic. Body temperature was obtained by thermal infrared imaging. KEY FINDINGS: Phalpha1beta and SB366791 interact in a synergistic manner to cause antinociception. We found an interaction index (alpha) of 0.07 for Phalpha1beta and SB366791 when these drugs were injected together intraplantarly, which indicates that in vivo interaction between these drugs is greater than additive interaction. Synergism also occurred when intraplantar SB366791 was administered simultaneously with intrathecal Phalpha1beta (interaction index alpha=0.06) suggesting a 15 fold rise in potency on the analgesic effect of these drugs when they are added together. It was observed no significant alterations in body temperature of animals treated with this combination regimen. SIGNIFICANCE: Our data reveal that Phalpha1beta toxin potentiates in 15 fold the antinociceptive action of the TRPV1 blocker SB366791. Therefore, lower doses of these drugs are required to achieve antinociceptive effects when these agents are given in combination. PMID- 28629731 TI - Pterostilbene ameliorates insulin sensitivity, glycemic control and oxidative stress in fructose-fed diabetic rats. AB - AIMS: The present investigation was designed to explore the effectiveness of pterostilbene (PT) on insulin resistance, metabolic syndrome and oxidative stress in fructose-fed insulin resistant rats. MAIN METHODS: Age-matched, male Sprague Dawley rats (330+/-30g body weight) were allocated into five groups (n=10). Control (C) group received 65% cornstarch, and the diabetic (D) group received 65% fructose for eight weeks. The third group (D+PT20) received 65% fructose and PT 20mg/kg/day for eight weeks. The fourth group (D+PT40) received 65% fructose and PT 40mg/kg/day for eight weeks. The fifth group (D+M) received 65% fructose and metformin (M) 100mg/kg/day for eight weeks. PT was dissolved in 10% beta cyclodextrin and given orally to rats. Several biochemical parameters were determined to assess the PT efficacy against insulin resistance, metabolic complications, and hepatic oxidative stress. KEY FINDINGS: Significantly high HOMA-IR (p<0.001) values in D group compared to C group indicate the presence of insulin resistance. Significantly high levels of TBARS (p<0.001) and decreased levels of SOD (p<0.001) and GSH (p<0.001) in hepatic tissues of D group indicate oxidative stress associated with insulin resistance. Pterostilbene treatment to fructose-fed diabetic rats significantly decreased HOMA-IR (p<0.001) values. Furthermore, PT treatment significantly decreased hepatic TBARS (p<0.001) and increased SOD (p<0.001) and GSH (p<0.001) levels in fructose-fed diabetic rats. SIGNIFICANCE: Current study reveals that PT is successful in ameliorating glycemic control, insulin sensitivity while diminishing metabolic disturbances and hepatic oxidative stress in a fructose-induced T2DM rat model. PMID- 28629732 TI - Impact of granulocyte contamination on PBMC integrity of shipped blood samples: Implications for multi-center studies monitoring regulatory T cells. AB - In centralized immune monitoring for a multi-center allergen immunotherapy trial, we observed frequent loss of CD4+ T cell integrity following staining of cultured PBMCs with our regulatory T cell flow cytometry panel. Samples were marked by a loss of total cellular events, altered scatter properties, and reduced CD3+CD4+ events. This occurred only in samples that were stained with Foxp3 and were therefore treated with Foxp3 fixation-permeabilization buffer. We identified granulocyte contamination in samples associated with a loss of integrity, and went on to test the impact of granulocyte depletion on day-old blood samples. Granulocyte depletion prevented loss of cell integrity and CD3+CD4+ events, and reduced variability in detection of Foxp3+ cells. Addition of purified neutrophils back to PBMCs altered scatter properties and detection of CD4+ T cells. Implementation of a granulocyte depletion step in our standard operating protocols has reduced assay failure due to loss of sample integrity from 31% to 0%. Routine incorporation of a granulocyte depletion step during PBMC isolation is recommended prior to downstream immune monitoring in blood with next-day processing. PMID- 28629733 TI - An optimized protocol for the generation and functional analysis of human mast cells from CD34+ enriched cell populations. AB - The culture of mast cells from human tissues such a cord blood, peripheral blood or bone marrow aspirates has advanced our understanding of human mast cells (huMC) degranulation, mediator production and response to pharmacologic agents. However, existing methods for huMC culture tend to be laborious and expensive. Combining technical approaches from several of these protocols, we designed a simplified and more cost effective approach to the culture of mast cells from human cell populations including peripheral blood and cryopreserved cells from lymphocytapheresis. On average, we reduced by 30-50 fold the amount of culture media compared to our previously reported method, while the total MC number generated by this method (2.46+/-0.63*106 vs. 2.4+/-0.28*106, respectively, from 1.0*108 lymphocytapheresis or peripheral blood mononuclear blood cells [PBMCs]) was similar to our previous method (2.36+/-0.70*106), resulting in significant budgetary savings. In addition, we compared the yield of huMCs with or without IL 3 added to early cultures in the presence of stem cell factor (SCF) and interlukin-6 (IL-6) and found that the total MC number generated, while higher with IL-3 in the culture, did not reach statistical significance, suggesting that IL-3, often recommended in the culture of huMCs, is not absolutely required. We then performed a functional analysis by flow cytometry using standard methods and which maximized the data we could obtain from cultured cells. We believe these approaches will allow more laboratories to culture and examine huMC behavior going forward. PMID- 28629734 TI - Immunohistochemical and genetic exploration of incompatible A blood group antigen expression in invasive micropapillary breast carcinoma: A case report. AB - INTRODUCTION: Invasive Micropapillary Carcinoma (IMPC) of the breast is a relatively rare subtype of invasive ductal carcinoma and represents the most inherently aggressive form. Expression of incompatible blood group A antigen in cancer of type O patients has been reported in several types of cancer, however, the biosynthetic mechanism and the genetic basis remain unclear until today. The aim of the present case report study was to evaluate the expression of incompatible blood group A antigen and to identify the genetic basis of this expression in IMPC of the breast. MATERIAL AND METHODS: One patient blood group O with Invasive Micropapillary Carcinoma was screened at Pathology Department of University Hospital CHU Ibn Rochd, Casablanca. ABH antigens expression was assessed by immunohistochemistry. ABO genotyping was performed by allele specific primers PCR-ASP and Exon 6 of ABO gene was sequenced with Sanger method. RESULTS: H antigen was expressed in endothelial and epithelial cells of normal tissue. However, H antigen expression was lost in both invasive micropapillary carcinomas. A antigen was expressed in IMPC with approximately 80% of positive cells. Tumor DNA was genotyped as heterozygous A/O. In normal DNA, we identified a single frameshift deletion c.320delA p.(Glu107Glyfs*12), which is removed from tumor DNA. CONCLUSION: Our findings suggest that incompatible A antigen expression in IMPC is due to glycosyltransferase A encoded by an A allele which is derived from O allele with a deletion at the position 320. PMID- 28629735 TI - Chronic fluoxetine treatment enhances sympathetic activities associated with abnormality of baroreflex function in conscious normal rats. AB - Data regarding the effects of selective serotonin reuptake inhibitors (SSRIs), which are a common type of antidepressants, on cardiovascular autonomic function are inconsistent. The present study was conducted to determine the effects of chronic fluoxetine, an SSRI, on blood pressure, cardiac autonomic nervous activities and baroreflex control of heart rate. Male Sprague-Dawley rats were treated with fluoxetine (10mg/kg day, p.o.) or saline for 14 weeks. Baroreflex function was determined by the sigmoid logistic method based on the heart rate responses to changes in blood pressure elicited by phenylephrine or sodium nitroprusside infusions. Cardiac sympathetic and parasympathetic tones were determined after methylatropine and propranolol treatments. Vascular responsiveness to acetylcholine, phenylephrine and sodium nitroprusside, and cardiac responsiveness to isoproterenol were determined after ganglionic blockade. Chronic fluoxetine treatment increased plasma levels of adrenaline and noradrenaline, but not nitric oxide. Elevation of blood pressure and heart rate by chronic fluoxetine was accompanied by baroreflex resetting and depressed baroreflex sensitivity. Elevated heart rate was mediated by enhanced sympathetic and depressed parasympathetic tones. The lowered baroreflex sensitivity might be attributed to attenuation of the parasympathetic component of baroreflex function. Chronic fluoxetine also diminished cardiac and vascular responsiveness to isoproterenol and acetylcholine, respectively. The plasma levels of adrenaline and noradrenaline were highly correlated with blood pressure, heart rate and baroreflex sensitivity. In conclusion, our results demonstrate that chronic fluoxetine treatment in normal rats induced predominant sympathoexcitation and depressed parasympathetic activity leading to mild hypertension, tachycardia, and impairment of baroreflex function. PMID- 28629736 TI - KFP-H008 blocks gastric acid secretion through inhibiting H+-K+-ATPase. AB - 1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (KFP-H008),a novel and potent potassium-competitive acid blocker for the treatment of acid secretion related diseases, has not been reported previously. In this study, we demonstrated that KFP-H008 inhibits basal acid secretion, 2 deoxy-D-glucose- (2DG-) stimulated gastric acid secretion in rats. KFP-H008 blocked histamine-stimulated acid secretion in rats and heidenhain pouch dogs and reversed acid output in isolated gastric perfusion under histamine stimulation. In all the animal experiments, KFP-H008 exerted a more effective, potent and longer-lasting inhibitory action in comparison with lansoprazole, a proton pump inhibitor (PPI) commonly used in clinic. KFP-H008 inhibited H+-K+-ATPase activity both at pH 6.5 and pH 7.5, and was unaffected by pH. The inhibitory action was reversible and was achieved in a K+-competitive manner. Furthermore, KFP-H008 did not affect Na+-K+-ATPase activity, thus exhibiting high selectivity, which is different from PPIs. In all, KFP-H008, a novel potassium-competitive acid blocker, may provide new option for the patients with acid-related diseases and provide longer-lasting inhibitory action than drugs commonly used in clinical treatment. PMID- 28629737 TI - The obligatory role of Activin A in the formation of heterotopic bone in Fibrodysplasia Ossificans Progressiva. AB - Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder that presents at birth with only minor patterning defects, but manifests its debilitating pathology early in life with episodic, yet progressive and cumulative, heterotopic ossification (HO) of ligaments, tendons, and a subset of major skeletal muscles. The resulting HO lesions are endochondral in nature, and appear to be linked to inflammatory stimuli arising in association with known injuries, or from inflammation linked to normal tissue repair. FOP is caused by gain-of-function mutations in ACVR1, which encodes a type I BMP receptor. Initial studies on the pathogenic mechanism of FOP-causing mutations in ACVR1 focused on the enhanced function of this receptor in response to certain BMP ligands, or independently of ligands, but did not directly address the fact that HO in FOP is episodic and inflammation-driven. Recently, we and others demonstrated that Activin A is an obligate factor for the initiation of HO in FOP, signaling aberrantly via mutant ACVR1 to transduce osteogenic signals and trigger heterotopic bone formation (Hatsell et al., 2015; Hino et al., 2015). Subsequently, we identified distinct tissue-resident mesenchymal progenitor cells residing in muscles and tendons that recognize Activin A as a pro-osteogenic signal (solely in the context of FOP-causing mutant ACVR1), and give rise to the cartilaginous anlagen that form heterotopic bone (Dey et al., 2016). During the course of these studies, we also found that the activity of FOP-causing ACVR1 mutations does not by itself explain the triggered or inflammatory nature of HO in FOP, suggesting the importance of other, inflammation-introduced, factors or processes. This review presents a synthesis of these findings with a focus on the role of Activin A and inflammation in HO, and lays out perspectives for future research. PMID- 28629739 TI - Twisting cracks in Bouligand structures. AB - The Bouligand structure, which is found in many biological materials, is a hierarchical architecture that features uniaxial fiber layers assembled periodically into a helicoidal pattern. Many studies have highlighted the high damage-resistant performance of natural and biomimetic Bouligand structures. One particular species that utilizes the Bouligand structure to achieve outstanding mechanical performance is the smashing Mantis Shrimp, Odontodactylus Scyllarus (or stomatopod). The mantis shrimp generates high speed, high acceleration blows using its raptorial appendage to defeat highly armored preys. The load-bearing part of this appendage, the dactyl club, contains an interior region [16] that consists of a Bouligand structure. This region is capable of developing a significant amount of nested twisting microcracks without exhibiting catastrophic failure. The development and propagation of these microcracks are a source of energy dissipation and stress relaxation that ultimately contributes to the remarkable damage tolerance properties of the dactyl club. We develop a theoretical model to provide additional insights into the local stress intensity factors at the crack front of twisting cracks formed within the Bouligand structure. Our results reveal that changes in the local fracture mode at the crack front leads to a reduction of the local strain energy release rate, hence, increasing the necessary applied energy release rate to propagate the crack, which is quantified by the local toughening factor. Ancillary 3D simulations of the asymptotic crack front field were carried out using a J-integral to validate the theoretical values of the energy release rate and the local stress intensity factors. PMID- 28629738 TI - Nitrous oxide versus oral sedation for pain management of first-trimester surgical abortion - a randomized study. AB - OBJECTIVE: The objective of the study was to compare nitrous oxide with oxygen (N2O/O2) to oral hydrocodone/acetaminophen and lorazepam for analgesia during first-trimester surgical abortion. STUDY DESIGN: This double-blind randomized trial assigned women undergoing first-trimester surgical abortion at<11 weeks' gestation to inhaled N2O/O2 vs. oral sedation for pain management. The N2O/O2 group received up to 70:30 ratio during the procedure and placebo pills preprocedure; the oral group received inhaled oxygen during the procedure and oral hydrocodone/acetaminophen 5 mg/325 mg and lorazepam 1 mg preprocedure. The primary outcome was maximum procedural pain, assessed on a 100-mm visual analog scale (VAS; anchors 0=no pain and 100=worst pain) at 2 min postprocedure. A difference of 13 mm on the VAS was considered clinically significant. Satisfaction with pain management was measured on a 100-mm VAS (anchors 0=very unsatisfied, 100=very satisfied). RESULTS: We randomized 140 women, 70 per study arm. Mean age of participants was 26+/-6.6 years; mean gestational age was 7.3+/ 1.5 weeks. Mean maximum procedure pain scores were 52.5+/-26.7 and 60.8+/-24.4 for N2O/O2 and oral groups, respectively (p=.09). Satisfaction with pain management was 69.3+/-28.4 and 61.5+/-30.4 for N2O/O2 and oral groups. respectively (p=.15). CONCLUSION: We found no difference in mean procedural pain scores between women assigned to N2O/O2 vs. those assigned to oral sedation for first-trimester surgical abortion. Satisfaction with both options was high. IMPLICATIONS: Women undergoing early surgical abortion experienced no differences in pain and satisfaction between those who used inhaled nitrous oxide and oral sedation. Nitrous oxide, with side effects limited to the duration of inhalation and no need for a ride home, is a viable alternative to oral sedation for first trimester abortion pain management. PMID- 28629740 TI - Seasonal dynamics, spatial distribution and genetic analysis of Anaplasma species infecting small ruminants from Northern Tunisia. AB - To date, there have been no reports on seasonal variations of Anaplasma spp. in South Mediterranean small ruminants. In this longitudinal field study, single and mixed Anaplasma spp. infections in small ruminants from five different governorates belonging to three bioclimatic zones from the North of Tunisia were evaluated according to seasons. A total of 1685 blood small ruminant samples were collected in spring (355 sheep and 241 goats), summer (249 sheep and 202 goats), autumn (236 sheep and 186 goats) and winter (132 sheep and 84 goats). Molecular survey of A. ovis and A. bovis showed that average prevalence rates were 35.6% (minimum 30.7% in spring and maximum 43.6% in autumn) and 7.4% (minimum 0.9% in spring and maximum 18.1% in summer), respectively, in sheep, and 46% (minimum 21.7% in summer and maximum 65.5% in winter) and 10.1% (minimum 2.2% in autumn and maximum 23.8% in summer), respectively, in goats. A. phagocytophilum was not detected in all investigated animals. The infection profiles of A. ovis and A. bovis show that anaplasmosis caused by A. ovis is endemic in small ruminants from all investigated bioclimatic areas during the four seasons but conversely, A. bovis infection is highly intensified only in the summer. A. ovis and A. bovis infections were validated by sequencing. The comparison of the 16S rRNA sequences of A. bovis variants showed 100% identity between Tunisian variants isolated from goats, sheep and cattle. The analysis of A. ovis msp4 sequences revealed two different genetic variants previously described in Italy. This is the first survey outlining seasonal dynamics of Anaplasma spp. infections in Tunisian small ruminants. This situation should to be taken into account if anaplasmosis control programs in these domesticated animals are envisaged. PMID- 28629741 TI - Establishment of an ideal time window model in hypothermic-targeted temperature management after traumatic brain injury in rats. AB - Although hypothermic-targeted temperature management (HTTM) holds great potential for the treatment of traumatic brain injury (TBI), translation of the efficacy of hypothermia from animal models to TBI patientshas no entire consistency. This study aimed to find an ideal time window model in experimental rats which was more in accordance with clinical practice through the delayed HTTM intervention. Sprague-Dawley rats were subjected to unilateral cortical contusion injury and received therapeutic hypothermia at 15mins, 2 h, 4 h respectively after TBI. The neurological function was evaluated with the modified neurological severity score and Morris water maze test. The brain edema and morphological changes were measured with the water content and H&E staining. Brain sections were immunostained with antibodies against DCX (a neuroblast marker) and GFAP (an astrocyte marker). The apoptosis levels in the ipsilateral hippocampi and cortex were examined with antibodies against the apoptotic proteins Bcl-2, Bax, and cleaved caspase-3 by the immunofluorescence and western blotting. The results indicated that each hypothermia therapy group could improve neurobehavioral and cognitive function, alleviate brain edema and reduce inflammation. Furthermore, we observed that therapeutic hypothermia increased DCX expression, decreased GFAP expression, upregulated Bcl-2 expression and downregulated Bax and cleaved Caspase-3 expression. The above results suggested that HTTM at 2h or even at 4h post-injury revealed beneficial brain protection similarly, despite the best effect at 15min post-injury. These findings may provide relatively ideal time window models, further making the following experimental results more credible and persuasive. PMID- 28629742 TI - Statistical differences in the white matter tracts in subjects with depression by using different skeletonized voxel-wise analysis approaches and DTI fitting procedures. AB - Major depressive disorder (MDD) is one of the most significant contributors to the global burden of illness. Diffusion tensor imaging (DTI) is a procedure that has been used in several studies to characterize abnormalities in white matter (WM) microstructural integrity in MDD. These studies, however, have provided divergent findings, potentially due to the large variety of methodological alternatives available in conducting DTI research. In order to determine the importance of different approaches to coregistration of DTI-derived metrics to a standard space, we compared results from two different skeletonized voxel-wise analysis approaches: the standard TBBS pipeline and the Advanced Normalization Tools (ANTs) approach incorporating a symmetric image normalization (SyN) algorithm and a group-wise template (ANTs TBSS). We also assessed effects of applying twelve different fitting procedures for the diffusion tensor. For our dataset, lower fractional anisotropy (FA) and axial diffusivity (AD) in depressed subjects compared with healthy controls were found for both methods and for all fitting procedures. No group differences were found for radial and mean diffusivity indices. Importantly, for the AD metric, the normalization methods and fitting procedures showed reliable differences, both in the volume and in the number of significant between-groups difference clusters detected. Additionally, a significant voxel-based correlation, in the left inferior fronto-occipital fasciculus, between AD and self-reported stress was found only for one of the normalization procedure (ANTs TBSS). In conclusion, the sensitivity to detect group-level effects on DTI metrics might depend on the DTI normalization and/or tensor fitting procedures used. PMID- 28629743 TI - Association study of childhood food allergy with genome-wide association studies discovered loci of atopic dermatitis and eosinophilic esophagitis. PMID- 28629744 TI - Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p. AB - BACKGROUND: Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glycoallergens, including cockroach allergens. OBJECTIVE: We sought to determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p. METHODS: We examined MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) and Mrc1-/- mice. The role of miR-511-3p in macrophage polarization and cockroach allergen-induced lung inflammation in mice transfected with adeno-associated virus (AAV)-miR-511 3p (AAV-cytomegalovirus-miR-511-3p-enhanced green fluorescent protein) was analyzed. Gene profiling of macrophages with or without miR-511-3p overexpression was also performed. RESULTS: Mrc1-/- lung macrophages showed a significant reduction in cockroach allergen uptake compared with WT mice, and Mrc1-/- mice had an exacerbated lung inflammation with increased levels of cockroach allergen specific IgE and TH2/TH17 cytokines in a cockroach allergen-induced mouse model compared with WT mice. Macrophages from Mrc1-/- mice showed significantly reduced levels of miR-511-3 and an M1 phenotype, whereas overexpression of miR-511-3p rendered macrophages to exhibit a M2 phenotype. Furthermore, mice transfected with AAV-miR-511-3p showed a significant reduction in cockroach allergen-induced inflammation. Profiling of macrophages with or without miR-511-3p overexpression identified 729 differentially expressed genes, wherein expression of prostaglandin D2 synthase (Ptgds) and its product PGD2 were significantly downregulated by miR-511-3p. Ptgds showed a robust binding to miR-511-3p, which might contribute to the protective effect of miR-511-3p. Plasma levels of miR-511 3p were significantly lower in human asthmatic patients compared with nonasthmatic subjects. CONCLUSION: These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation. PMID- 28629745 TI - Exposure to nonmicrobial N-glycolylneuraminic acid protects farmers' children against airway inflammation and colitis. AB - BACKGROUND: Childhood exposure to a farm environment has been shown to protect against the development of inflammatory diseases, such as allergy, asthma, and inflammatory bowel disease. OBJECTIVE: We sought to investigate whether both exposure to microbes and exposure to structures of nonmicrobial origin, such as the sialic acid N-glycolylneuraminic acid (Neu5Gc), might play a significant role. METHODS: Exposure to Neu5Gc was evaluated by quantifying anti-Neu5Gc antibody levels in sera of children enrolled in 2 farm studies: the Prevention of Allergy Risk factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 299) and the Protection Against Allergy Study in Rural Environments (PASTURE) birth cohort (cord blood [n = 836], 1 year [n = 734], 4.5 years [n = 700], and 6 years [n = 728]), and we associated them with asthma and wheeze. The effect of Neu5Gc was examined in murine airway inflammation and colitis models, and the role of Neu5Gc in regulating immune activation was assessed based on helper T-cell and regulatory T-cell activation in mice. RESULTS: In children anti-Neu5Gc IgG levels correlated positively with living on a farm and increased peripheral blood forkhead box protein 3 expression and correlated inversely with wheezing and asthma in nonatopic subjects. Exposure to Neu5Gc in mice resulted in reduced airway hyperresponsiveness and inflammatory cell recruitment to the lung. Furthermore, Neu5Gc administration to mice reduced the severity of a colitis model. Mechanistically, we found that Neu5Gc exposure reduced IL-17+ T-cell numbers and supported differentiation of regulatory T cells. CONCLUSIONS: In addition to microbial exposure, increased exposure to non microbial-derived Neu5Gc might contribute to the protective effects associated with the farm environment. PMID- 28629747 TI - Mitochondrial DNA depletion induces innate immune dysfunction rescued by IFN gamma. PMID- 28629748 TI - Patterns and predictors of atopic dermatitis disease control past childhood: An observational cohort study. PMID- 28629746 TI - Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. AB - BACKGROUND: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IkappaBalpha that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IkappaBalpha have impaired noncanonical NF-kappaB activity and defective lymphorganogenesis. OBJECTIVE: We sought to establish genotype phenotype correlation in patients with AD EDA-ID. METHODS: A disease severity scoring system was devised. Stability of IkappaBalpha mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-kappaB signaling in skin derived fibroblasts. RESULTS: Disease severity was greater in patients with IkappaBalpha point mutations than in those with truncation mutations. IkappaBalpha point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-kappaB-dependent IL 6 secretion and upregulation of the NF-kappaB subunit 2/p100 and RELB proto oncogene, NF-kappaB subunit (RelB) components of the noncanonical NF-kappaB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-kappaB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus alpha-lymphotoxin beta receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS: IkappaBalpha point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-kappaB activity in patients with AD EDA-ID. PMID- 28629749 TI - A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis. AB - BACKGROUND: Clonal mast cell disorders are known to occur in a subset of patients with systemic reactions to Hymenoptera stings. This observation has prompted the question of whether clonal mast cell disorders also occur in patients with idiopathic anaphylaxis (IA). OBJECTIVE: We sought to determine the prevalence of clonal mast cell disorders among patients with IA, criteria to identify those patients who require a bone marrow biopsy, and whether the pathogenesis of IA involves a hyperresponsive mast cell compartment. METHODS: We prospectively enrolled patients with IA (>=3 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, allele-specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination. Mast cells were cultured from peripheral blood CD34+ cells and examined for releasability after FcepsilonRI aggregation. RESULTS: Clonal mast cell disease was diagnosed in 14% of patients referred with IA. ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome. A modified overall clonal prediction model was developed by using clinical findings, a serum tryptase determination, and ASqPCR. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. CONCLUSION: Patients with clonal mast cell disease can present as having IA. Distinct clinical and laboratory features can be used to select those patients more likely to have an underlying clonal mast cell disorder (monoclonal mast cell activation syndrome or systemic mastocytosis) and thus candidates for a bone marrow biopsy. PMID- 28629750 TI - Food protein-induced enterocolitis syndromes with and without bloody stool have distinct clinicopathologic features. PMID- 28629751 TI - Unique influenza A cross-reactive memory CD8 T-cell receptor repertoire has a potential to protect against EBV seroconversion. PMID- 28629752 TI - RNA-containing exosomes in induced sputum of asthmatic patients. PMID- 28629753 TI - Active identification of patients who are methicillin-resistant Staphylococcus aureus colonized is not associated with longer duration of vancomycin therapy. AB - BACKGROUND: Excessive prescribing of vancomycin among patients admitted to inpatient wards is a challenge for antimicrobial stewardship programs, especially in the setting of expanded screening programs for methicillin-resistant Staphylococcus aureus (MRSA). Studies examining factors associated with longer duration of vancomycin use are limited. METHODS: We conducted a retrospective cohort study to assess the impact of universal MRSA admission screening on duration of vancomycin use at the VA Boston Healthcare System during the period from January 2013-November 2015. RESULTS: A total of 2,910 patients were administered intravenous vancomycin during the study period. A clinical culture positive for MRSA was strongly associated with vancomycin administration lasting >72 hours (odds ratio [OR], 2.72; 95% confidence interval [CI], 1.86-3.97; P < .001). After controlling for clinical culture results, admission MRSA colonization was not associated with vancomycin use past 72 hours (OR, 0.94; 95% CI, 0.8-1.1). A negative MRSA nasal swab on admission had a high negative predictive value for all MRSA infections evaluated (99.6% for pneumonia, 99.6% for bloodstream infection, and 98.1% for skin and soft tissue infection). CONCLUSIONS: Admission surveillance for MRSA nasal colonization is not a major driver of prolonged vancomycin use. A negative admission MRSA nasal screen may be a useful tool for antimicrobial stewardship programs to limit vancomycin use, particularly in noncritically ill patients. PMID- 28629754 TI - Improving compliance with surgical antibiotic prophylaxis guidelines: A multicenter evaluation. AB - BACKGROUND: Improving surgical antibiotic prophylaxis (SAP) use is an important element in the control of antimicrobial resistance. However, compliance with SAP guidelines is unsatisfactory. This study investigated the level of compliance with SAP guidelines in neurosurgery, and institutional characteristics associated with compliance. METHODS: This study assessed surgeries in 9 Brazilian hospitals. Medical record reviews and a structured questionnaire were used to assess compliance and to describe institutional characteristics. Six attributes of compliance with SAP guidelines were evaluated; full compliance was defined whenever all these attributes were met. Logistic and linear regressions were used to investigate the association between compliance, patients, and hospital characteristics. RESULTS: Full compliance was 10% and was associated with weekly hours of infection control personnel per intensive care unit bed (95% CI, 0.2 0.1), hospital-wide dissemination of SAP guidelines (95% CI, 1.2-25.1), monitoring (95% CI, 1.2-25.1), and feedback of compliance rates (95% CI, 3.8 25.2). Daytime procedures had greater compliance regarding drug dose (odds ratio [OR], 3.38; 95% confidence interval [CI], 1.72-6.65) and initial time (OR, 2.30; 95% CI, 1.24-4.25). Spinal procedures achieved greater compliance with initial time (OR, 1.83; 95% CI, 1.12-3.01) and duration (OR, 1.59; 95% CI, 1.7-2.16). CONCLUSIONS: A low level of compliance was identified, which pointed out the need for an innovative stewardship approach to improve adherence to SAP guidelines. Targeted training programs need to be developed to ensure dissemination of guidelines among surgeons. Monitoring, feedback, and closer interaction between the infection control personnel and the surgical team are key factors for better compliance rates of SAP. PMID- 28629755 TI - Using inherent and elective behavior to improve hand hygiene monitoring in health care. AB - This study established a method for collecting hand hygiene (HH) performance data based on behavioral drivers (inherent or elective) that can be used by infection preventionists (IPs) to improve practice. Further, we explored the influence that task and setting has on HH behavior. A significant effect was found between task and setting that has implications for improving the usefulness of HH measurement, with positive feedback reported regarding the new measurement method. PMID- 28629756 TI - Nasal colonization of Staphylococcus aureus colonal complex 5: Prevalence, influencing factors, and phenotypic and molecular characteristics in pregnant Chinese women. AB - BACKGROUND: Colonal complex 5 (CC5) has been referred to as the most pandemic community-associated Staphylococcus aureus in most Asian countries. However, few studies have focused on CC5 isolates in pregnant women. The aim of this study was to determine the prevalence and phenotypic and molecular characteristics of S aureus and methicillin-resistant S aureus (MRSA) CC5 nasal colonization in pregnant Chinese women. METHODS: We performed a cross-sectional study between August and November 2015 in 2 hospitals in Shenzhen, China. Pregnant women were asked to complete questionnaires, and nasal swabs were collected. Log-binomial regression models were used to explore factors influencing S aureus and MRSA nasal colonization between the CC5 and non-CC5 or non-S aureus groups. Polymerase chain reaction assays were used to detect the molecular characteristics of isolates. RESULTS: Overall, 2,172 pregnant women were included in this study. The prevalence of S aureus and MRSA was 25.60% (n = 556) and 5.62% (n = 122), respectively. The multilocus sequence typing of S aureus isolates was diversified. A lower frequency of daily handwashing (<7) and weekly bathing (<7) were risk factors for the prevalence of S aureus (adjusted prevalence ratio [aPR], 1.13; 95% confidence interval [CI], 1.03-1.41 and aPR, 1.22; 95% CI, 1.03 1.45) and MRSA (aPR, 1.96; 95% CI, 1.23-3.14 and aPR, 1.47; 95% CI, 1.21-2.44) nasal colonization in the CC5 groups of pregnant women. CONCLUSIONS: The prevalence of S aureus and MRSA nasal colonization was moderate. The molecular characteristics of S aureus and MRSA isolates indicated possible cross transmission among multiple resources. A higher frequency of daily handwashing and weekly bathing significantly decreased the prevalence of S aureus and MRSA CC5 nasal colonization in the pregnant women. PMID- 28629757 TI - Bacterial biofilm-based catheter-associated urinary tract infections: Causative pathogens and antibiotic resistance. AB - BACKGROUND: We sought to determine the incidence of bacterial biofilm-based catheter-associated urinary tract infections, identify variables affecting biofilm formation, and identify etiologic bacterial pathogens and antibiotic resistance patterns associated with biofilm-based catheter-associated urinary tract infections (CAUTIs) in our setup. METHODS: Patients who developed at least 2 symptoms of urinary tract infection after at least 2 days of indwelling urinary catheters were included. Urine was collected aseptically from catheter tubing and processed per standard microbiologic practices. Bacterial pathogens were identified on the basis of gram staining, colony morphology, and biochemical reactions. The detection of the biofilm was done using the tube adherence method. Drug susceptibility testing was done using the Kirby-Bauer disc diffusion method. FINDINGS: Biofilm was detected in 73.4% isolates, whereas 26.6% of isolates were nonbiofilm producers. Mean duration of catheterization after which biofilm was detected was 5.01 +/- 1.31 days. A latex catheter was used in 69.5% of patients, whereas a silicone catheter was used in 30.4% of patients. Escherichia coli was found to be the most common pathogen isolated (52.3%), whereas Enterobacter cloacae exhibited the highest biofilm production (87.5%) among isolated pathogens. Among biofilm producers, the highest resistance was observed with ampicillin (100%). Fosfomycin exhibited the lowest resistance (17.2%). Significant association with biofilm was detected for gender, duration of catheterization, and type of catheter. CONCLUSION: Biofilm-based CAUTI is an emerging problem. E coli was the most frequent isolate. High antibiotic resistance was observed in biofilm-producing strains. Using the variables affecting biofilm formation, tailored intervention strategies can be implemented to reduce biofilm-based CAUTIs. PMID- 28629758 TI - Implications of the gut microbiota in vulnerability to the social avoidance effects of chronic social defeat in male mice. AB - Appreciable evidence suggests that perturbations within the gut microbiome and the immune system may play a key role in the pathogenesis of depression stemming from earlier stressful experiences. In the present investigation we examined whether microbial changes in cecum contents were associated with social avoidance behaviors, a feature of depression, and pro-inflammatory variations among socially stressed mice. Male C57BL/6 mice experienced social defeat or a control condition once a day for 10 consecutive days. Social avoidance behaviors were examined three weeks after the last defeat or control episode and blood, brain, and cecum contents were collected 24h afterward for the determination of corticosterone, pro-inflammatory cytokines, and microbial populations. Mice that were most susceptible to the behavioral effects of chronic social defeat (reflected by severe social avoidance behaviors) displayed the greatest changes within particular sets of bacteria at the phylum and genus taxonomic ranks. Although plasma and brain cytokines were not significantly altered in socially defeated mice, changes in the mRNA expression of interleukin (IL)-1beta and IL-6 within the prefrontal cortex were associated with elevated abundance of Flavobacterium spp. and reduced abundance of Turicibacter spp., which were also strongly correlated to social avoidance severity. Although at this time a causal connection cannot be inferred, these results point to the possibility that specific clusters of bacterial communities in cecum contents may be linked to vulnerability to social deficits stemming from prolonged social stressor experiences. PMID- 28629759 TI - Development holds the key to understanding the interplay of nature versus nurture in shaping the individual. PMID- 28629760 TI - Cardiac overexpression of Epac1 in transgenic mice rescues lipopolysaccharide induced cardiac dysfunction and inhibits Jak-STAT pathway. AB - Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic stimulation leads to coupling of the beta-adrenergic receptor/Gs/adenylyl cyclase, a membrane bound enzyme that catalyzes the conversion of ATP to cAMP, thereby stimulating protein kinase A (PKA) and ultimately compensating for cardiac dysfunction. The mechanism of such compensation by catecholamine has been traditionally understood as PKA-mediated enforcement of cardiac contractility. We hypothesized that exchange protein activated by cyclic AMP (Epac), a new target of cAMP signaling that functions independently of protein kinase A, also plays a key role in protection against acute stresses or changes in hemodynamic overload. Lipopolysaccharide injection induced cytokine release and severe cardiac dysfunction in mouse. In mouse overexpressing Epac1 in the heart, however, the magnitude of such dysfunction was significantly smaller. Epac1 overexpression inhibited the Jak-STAT pathway, as indicated by decreased phosphorylation of STAT3 and increased SOCS3 expression, with subsequent inhibition of iNOS expression. In cultured cardiomyocytes treated with isoproterenol or forskolin, the increase of SOCS3 expression was blunted when Epac1 or PKCalpha was silenced with siRNA. Activation of the cAMP/Epac/PKCalpha pathway protected the heart against cytokine-induced cardiac dysfunction, suggesting a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac1 and its downstream pathways may be novel targets for treating cardiac dysfunction in endotoxemia. PMID- 28629761 TI - Cytokines for the induction of antitumor effectors: The paradigm of Cytokine Induced Killer (CIK) cells. AB - Cytokine-Induced killer (CIK) cells are raising growing interest in cellular antitumor therapy, as they can be easily expanded with a straightforward and inexpensive protocol, and are safe requiring only GMP-grade cytokines to obtain very high amounts of cytotoxic cells. CIK cells do not need antigen-specific stimuli to be activated and proliferate, as they recognize and destroy tumor cells in an HLA-independent fashion through the engagement of NKG2D. In several preclinical studies and clinical trials, CIK cells showed a reduced alloreactivity compared to conventional T cells, even when challenged across HLA barriers; only in a few patients, a mild GVHD occurred after treatment with allogeneic CIK cells. Additionally, their antitumor activity can be redirected and further improved with chimeric antigen receptors, clinical-grade monoclonal antibodies or immune checkpoint inhibitors. The evidence obtained from a growing body of literature support CIK cells as a very promising cell population for adoptive immunotherapy. In this review, all these aspects will be addressed with a particular emphasis on the role of the cytokines involved in CIK cell generation, expansion and functionalization. PMID- 28629762 TI - Targeting the tumor and its associated stroma: One and one can make three in adoptive T cell therapy of solid tumors. AB - Adoptive T cell therapy (ACT) has become a promising immunotherapeutic option for cancer patients. The proof for ACT therapeutic efficacy was first obtained with allogenic T cells and then reproduced with T cells isolated from patients' tumor samples (i.e. tumor-infiltrating lymphocytes). It is now clear that specificity of ACT products can be educated by genetically engineering T cells with classical T Cell Receptors (TCR) or chimeric antigen receptors (CAR). To date a poor accessibility of the tumor mass and a hostile microenvironment, influenced by genetic and epigenetic instability, mainly limit ACT therapeutic efficacy in the case of solid tumors. Available data indicate that these hurdles might be overcome by combinatorial therapeutic strategies targeting the tumor and its associated stroma. Here we review some of the available dual targeting strategies focusing on given combination of TCR/CAR-redirected T cell products and their association with drugs targeting the tumor-vessel and/or epigenetic modifiers, with the ability to sensitize tumors to T cell recognition. Existing data have proven synergistic effects in combined settings (one and one can indeed make three) and suggest that further benefit might be achieved by additional combinatorial therapeutic approaches (could one+one+one make ten?) in ACT of solid tumor. PMID- 28629763 TI - Delayed referral to specialist centre increases morbidity in patients with bile duct injury (BDI) after laparoscopic cholecystectomy (LC). AB - BACKGROUND: There is still a debate regarding the optimal management of bile duct injury following cholecystectomy. Our aim was to ascertain if delayed referral influenced clinical outcomes for patients with BDI treated in our institution. MATERIALS AND METHODS: We interrogated a prospectively maintained database, including all patients with BDI (Bismuth and Strasberg classifications) post LC managed in our unit from 2000-2014. Referrals were arbitrarily defined as early (<96 h from the injury) and delayed (>96 h). RESULTS: 68 patients with BDI were managed. Patient demographics, referral time, level of injury and morbidity data was collected. 50 patients (77%) required a surgical bile duct reconstruction. The Early referral Group included 33 patients (52.4%) and Delayed referral group 30 (47.6%). The patients referred late had a significantly high incidence of right hepatic artery injury (23% vs. 3%) and the overall number of complications (0.0001). The average number of surgical interventions (2.5 vs 1.8, p < 0.05) and invasive procedures (4 vs. 2.5, p < 0.05) per patient was high in the late referral group. There was significant difference in the interval between BDI-to reconstruction (median 3 vs. median 88 days, p < 0.05) and referral-to-hospital discharge (median 9 vs. median days 59, p < 0.05). On multivariate analysis only delayed referral (OR 7.58, 95% CI 2.1-26.6) and Strasberg-E injuries (OR 4.86, 95% CI 1.1-20.9) were significant. CONCLUSION: A late referral was associated with a higher incidence of post-treatment complications, greater need for invasive procedures and a longer recovery period. These observations support the need for early patient transfer to a tertiary institution following BDI. PMID- 28629764 TI - Oral versus topical calcium channel blockers for chronic anal fissure-a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Chemical sphincterotomy with pharmacological agents is recommended as first line therapy for chronic anal fissures (CAF). Calcium channel blockers (CCB) are associated with similar efficacy but fewer side effects compared to nitrates. However, the optimal formulation (oral versus topical) is unknown. We aimed to perform a systematic review and meta-analysis to compare the effectiveness of oral and topical CCB in the treatment of CAF. METHODS: PubMed and Embase online databases were searched for relevant articles. Two independent reviewers performed methodological assessment and data extraction. Random effects models were used to calculate pooled effect size estimates. A sensitivity analysis was also carried out. RESULTS: Four randomized controlled trials describing 279 patients (138 in oral, 141 in topical group) were examined. There was significant heterogeneity among studies. On random effects analysis, topical CCB were associated with a significantly lower rate of unhealed fissure (21.3% vs. 38.4%; OR = 2.65, 95% CI = 1.50 to 4.69, p = 0.0008) when compared to oral therapy. However, there were no significant differences in fissure recurrence (5.4% vs. 5.5%; OR = 1.01, 95% CI = 0.31 to 3.33, p = 0.98) or side effects (15.6% vs. 39.1%; OR = 4.54, 95% CI = 0.46 to 44.3, p = 0.19) between topical and oral CCB. On sensitivity analysis, having excluded the most heavily biased trial, topical CCB were associated with significantly fewer side effects compared to oral therapy (4.3% vs. 38.0%; OR = 13.16, 95% CI = 5.05 to 34.3, p < 0.00001). CONCLUSIONS: Topical CCB are associated with better healing and fewer side effects when compared to oral therapy but there is no difference in recurrence rates. PMID- 28629765 TI - Study on the relationship between vitamin D deficiency and susceptibility to spinal tuberculosis. AB - OBJECTIVE: To investigate the effect of vitamin D deficiency on susceptibility to spinal tuberculosis and its pathological development. METHODS: A case-control design was used in this study. A total of 163 treatment-naive patients with spinal tuberculosis admitted to this institute for an operation from June 2013 to May 2016 were included in the case group, and 170 subjects who received a health examination in the same hospital were included in the control group. Control group patients were frequency-matched with the case group by age, gender, and season. Serum 25-hydroxyvitamin D levels were detected using an enzyme linked immunosorbent assay (ELISA). Pathological classification of patients in the case group was conducted according to intraoperative findings, and definite diagnosis of spinal tuberculosis was confirmed after operation. RESULTS: The serum level of vitamin D [23.99 (20.55, 29.54) nmol/L] in the case group was lower than that in the control group [42.94 (35.68, 51.04) nmol/L], and the difference was statistically significant (Z = -9.048, P < 0.05). Out of the 163 patients with spinal tuberculosis who underwent pathological classification, 107 cases of caseous necrosis and 56 cases of hyperplasia were identified. Based on the vitamin D levels of the patients in the case group, these patients were further divided into a low-level group (<25 nmol/L) and a high-level group (>=25 nmol/L). The proportion of patients with caseous necrosis in the low-level group (79.17%) was higher than that in the high-level group (46.27%), with a statistically significant difference (chi2 = 18.937, P < 0.05). CONCLUSION: Vitamin D deficiency is associated with susceptibility to spinal tuberculosis and its pathological classification, and vitamin D deficiency affects the occurrence and development of spinal tuberculosis. PMID- 28629766 TI - Laparoscopic-assisted approach for penetrating abdominal trauma: A solution for multiple bowel injuries. AB - BACKGROUND: Therapeutic laparoscopy (TL) for penetrating abdominal trauma (PAT) is controversial because the management of multiple bowel injuries is challenging and the conversion rate is high. However, the laparoscopic-assisted approach (LAA) allows easy management of multiple bowel injuries but not investigated in a trauma setting. The aim of this study was to investigate its role in management of multiple bowel injuries and to compare LAA with therapeutic laparoscopy performed fully laparoscopically (FTL). METHODS: All adult patients with PAT managed with TL over four-year period were analyzed. Intraoperative findings, trauma scoring, grading of bowel injuries, related procedures, outcomes and length of hospital stay (LOS) were compared between LAA and FTL groups. RESULTS: Seventy two (53%) patients were in the FTL group and 65 (47%) in the LAA group. The majority of patients presented with stab wounds. Colonic and small bowel injuries were more common in the LAA group (19 versus 17 and 47 versus 8, respectively). The higher number of bowel repairs, resections and anastomosis were performed in the LAA group. The ISS was higher in the FTL group (13 versus 11, p = 0.02), and the PATI was higher in the LAA group (6 versus 10, p < 0.001). Nine patients in the FTL group suffered Clavien-Dindo grade 3 complications and 11 patients in the LAA group. There was one death in each group. No missed injuries were reported. There was no significant difference in LOS between groups. CONCLUSIONS: The LAA is safe in the management of stable patients with PAT. It can used for management of multiple bowel injuries instead of a conversion to laparotomy. It provides benefits of minimally invasive surgery and the speed and versatility of laparotomy. Moreover, the LAA seems not to be inferior to entirely laparoscopic therapeutic procedures. More studies are needed to compare LAA with FTL and laparotomy. PMID- 28629767 TI - Prognostic nomogram for patients with non-B non-C hepatocellular carcinoma after curative liver resection. AB - BACKGROUND: The proportion of the both serum hepatitis B surface antigen and hepatitis C antibody negative hepatocellular carcinoma (NBNC HCC) patients are tended to increase recently. We investigated the characteristics and surgical outcome for those patients after liver resection. METHODS: Four hundred and thirty-five NBNC patients were involved in our study. According to the results of the HBcAb in the serum, those patients were divided into HBcAb-positive subgroup (n = 328) and HBcAb-negative subgroup (n = 107). Based on the multivariate risk factors, the nomogram was constructed for predicting the possibility for over survival (OS) rate. RESULTS: For all of the NBNC HCC patients, the median OS was 57 months with 5-year OS rate 54.0%. The positive HBcAb NBNC patients were associating with a better liver function (p = 0.026), higher AFP (p < 0.001) and more proportion of micro-vascular invasion (p = 0.001). Multivariate analysis revealed that worse liver function (Child-Pugh B, HR = 1.93; 95% CI: 1.23-3.04), vascular invasion (MIVI vs negative, HR = 1.86; 95% CI: 1.21-2.86, MAVI vs negative, HR = 2.05; 95% CI: 1.37-3.06), poorer ES differentiation (HR = 2.34; 95% CI: 1.67-3.30) and larger tumor size (HR = 1.10; 95% CI: 1.06-1.15) were associated with the worse OS. CONCLUSION: We established a novel prognostic nomogram to predict the OS of NBNC HCC patients after liver resection. The prognosis of NBNC HCC was mainly determined by tumor stage and liver function not by the previous etiologies. PMID- 28629768 TI - Does the duration of symptoms of anal fissure impact its response to conservative treatment? A prospective cohort study. AB - BACKGROUND: Conservative treatment is the first line of treatment for anal fissure. The current study aimed to evaluate the impact of symptom duration on the response of anal fissure to conservative treatment. PATIENTS AND METHODS: This prospective study was conducted on sixty patients with acute or chronic anal fissure who were treated conservatively with bulking agents, Sitz baths, and topical glyceryl trinitrate (GTN) 0.2%. Pain and constipation were assessed prior to treatment and at 6 weeks after therapy using visual analogue scale (VAS) and Wexner constipation score. Adverse effects as headache and postural hypotension were also queried. RESULTS: The mean pre-treatment VAS for acute fissure was significantly higher than chronic fissure (8.8 +/- 0.96 Vs 5.8 +/- 1.12), also the post-treatment VAS for acute fissure was significantly lower at 6 weeks of treatment (0.47 +/- 0.8 Vs 2.5 +/- 1.3). The baseline Wexner constipation score was comparable in both groups; however, at six weeks of treatment it declined more significantly in patients with acute fissure. Patients with acute fissure achieved significantly better healing than chronic fissure (80% Vs 40%). Healing rates decreased from 100% in patients with symptoms < one month to 33.3% in patients with symptoms >6 months. CONCLUSION: Conservative treatment including topical GTN 0.2% significantly hastened healing and relieved pain and other symptoms of acute more than chronic anal fissure. Healing rates of anal fissure in response to conservative treatment showed remarkable decrease in proportion to the duration of complaint. PMID- 28629769 TI - The correlation of the morphological changes of ankle point and ankle joint function after surgery on the Ruedi-Allgouer type III Pilon fracture: A case series study. AB - BACKGROUND: To analyze the relationship between imaging findings and postoperative curative effect by measuring the morphology of the ankle mortise in patients with the Ruedi-Allgouer type III Pilon fractures. MATERIAL AND METHODS: Forty-seven patients with Ruedi-Allgouer type III Pilon fractures who underwent surgical treatment from January 2011 to January 2015 were retrospectively analyzed. At the last follow-up, x-rays of the affected ankle and the healthy side were measured. According to the Kitaoka score of ankle joint function at the last follow-up. RESULTS: All patients were followed up for 18-24 months (mean 21 months). This study demonstrated that compared with the healthy side, the index of the width, depth, and coronal/sagittal angles of the ankle mortise were significantly different (P < 0.05) in the 47 patients except for the index of height (P > 0.05). According to the Kitaoka score, the difference between the affected and the healthy sides of each index of the ankle mortise was compared between the 3 groups. That is, the intraoperative treatment of the width and depth of the ankle mortise as well as the coronal and sagittal angles of the ankle mortise were significantly correlated with the postoperative curative effect. CONCLUSION: The intraoperative treatment of ankle mortise width, depth, and ankle coronal/sagittal angle in patients with severe Pilon fractures has a significant impact on postoperative efficacy. In order to prevent the occurrence of traumatic arthritis, the anatomical morphology of the ankle should be restored as much as possible in the course of surgery. PMID- 28629770 TI - Application of the laparoscopic technique in perihilar cholangiocarcinoma surgery. AB - INTRODUCTION: The aim of this study is to investigate the feasibility of the application of the laparoscopic technique in perihilar cholangiocarcinoma. METHODS: A total of nine cases of patients who received laparoscopic perihilar cholangiocarcinoma surgery from January 2007 to May 2014 were retrospectively analyzed. The Bismuth subtypes consisted of one case of type I, three cases of type II, two cases of type IIIb, and three cases type IV. RESULTS: Radical resection was conducted in six cases: two cases (type II) with the caudate lobe resection, and two cases (type IIIb) with the left hepatectomy and caudate lobe resection. The mean operation time was 7.3 h (5.5-8.5 h), the mean blood loss was 503 ml (150-850 ml). The pathological tests showed two cases of poorly differentiated adenocarcinoma, three cases of moderately differentiated adenocarcinoma, and four cases of highly differentiated adenocarcinoma. CONCLUSION: Laparoscopic technology in the surgical treatment of perihilar cholangiocarcinoma is an option for the resection approach. PMID- 28629771 TI - Chemokines play complex roles in cerebral ischemia. AB - Ischemic stroke (IS) is a disease caused by deficiency of blood and oxygen in focal or complete brain, followed by inflammation cascade and other pathological reactions, which finally lead to irreversible damage to the cerebrum. For the inflammation is a key progress at the initiation of ischemia and poststroke, and chemokines work as vital cytokines in inflammation, we focus the roles of chemokines in IS. Studies have shown cerebral ischemia is associated with marked induction of both CXC and CC chemokines which resulting in extensive leukocyte infiltration in the ischemic brain, and neutrophil infiltration may increase cerebral edema inducing injury in the ischemic area. In addition, chemokines also shows other functions such as promote neuroblast migration, hematogenous cell recruitment and functional brain repair. Thus, a similar chemokine ligand/chemokine receptor pair can mediate both beneficial and detrimental effects depending on the window of observation and pathophysiological conditions. This manuscript reviews the studies about chemokine-mediated effects in cerebral ischemia/reperfusion and discusses the potential significance of these interactions in injury and repair of ischemic tissues. We also refer drug development based on the chemokines and clinical applications using chemokines as diagnostic or prognostic biomarkers in ischemic stroke. PMID- 28629772 TI - Impact of the cardiovascular system-associated adipose tissue on atherosclerotic pathology. AB - Cardiac obesity makes an important contribution to the pathogenesis of cardiovascular disease. One of the important pathways of this contribution is the inflammatory process that takes place in the adipose tissue. In this review, we consider the role of the cardiovascular system-associated fat in atherosclerotic cardiovascular pathology and a non-atherosclerotic cause of coronary artery disease, such as atrial fibrillation. Cardiovascular system-associated fat not only serves as the energy store, but also releases adipokines that control local and systemic metabolism, heart/vascular function and vessel tone, and a number of vasodilating and anti-inflammatory substances. Adipokine appears to play an important protective role in cardiovascular system. Under chronic inflammation conditions, the repertoire of signaling molecules secreted by cardiac fat can be altered, leading to a higher amount of pro-inflammatory messengers, vasoconstrictors, profibrotic modulators. This further aggravates cardiovascular inflammation and leads to hypertension, induction of the pathological tissue remodeling and cardiac fibrosis. Contemporary imaging techniques showed that epicardial fat thickness correlates with the visceral fat mass, which is an established risk factor and predictor of cardiovascular disease in obese subjects. However, this correlation is no longer present after adjustment for other covariates. Nevertheless, recent studies showed that pericardial fat volume and epicardial fat thickness can probably serve as a better indicator for atrial fibrillation. PMID- 28629774 TI - Genome instabilities arising from ribonucleotides in DNA. AB - Genomic DNA is transiently contaminated with ribonucleotide residues during the process of DNA replication through misincorporation by the replicative DNA polymerases alpha, delta and epsilon, and by the normal replication process on the lagging strand, which uses RNA primers. These ribonucleotides are efficiently removed during replication by RNase H enzymes and the lagging strand synthesis machinery. However, when ribonucleotides remain in DNA they can distort the DNA helix, affect machineries for DNA replication, transcription and repair, and can stimulate genomic instabilities which are manifest as increased mutation, recombination and chromosome alterations. The genomic instabilities associated with embedded ribonucleotides are considered here, along with a discussion of the origin of the lesions that stimulate particular classes of instabilities. PMID- 28629775 TI - 8-Oxo-7,8-dihydroguanine, friend and foe: Epigenetic-like regulator versus initiator of mutagenesis. AB - A high flux of reactive oxygen species during oxidative stress results in oxidative modification of cellular components including DNA. Oxidative DNA "damage" to the heterocyclic bases is considered deleterious because polymerases may incorrectly read the modifications causing mutations. A prominent member in this class is the oxidized guanine base 8-oxo-7,8-dihydroguanine (OG) that is moderately mutagenic effecting G->T transversion mutations. Recent reports have identified that formation of OG in G-rich regulatory elements in the promoters of the VEGF, TNFalpha, and SIRT1 genes can increase transcription via activation of the base excision repair (BER) pathway. Work in our laboratory with the G-rich sequence in the promoter of VEGF concluded that BER drives a shift in structure to a G-quadruplex conformation leading to gene activation in mammalian cells. More specifically, removal of OG from the duplex context by 8-oxoguanine glycosylase 1 (OGG1) produces an abasic site (AP) that destabilizes the duplex, shifting the equilibrium toward the G-quadruplex fold because of preferential extrusion of the AP into a loop. The AP is bound but inefficiently cleaved by apurinic/apyrimidinic endoDNase I (APE1) that likely allows recruitment of activating transcription factors for gene induction. The ability of OG to induce transcription ascribes a regulatory or epigenetic-like role for this oxidatively modified base. We compare OG to the 5-methylcytosine (5mC) epigenetic pathway including its oxidized derivatives, some of which poise genes for transcription while also being substrates for BER. The mutagenic potential of OG to induce only ~one-third the number of mutations (G->T) compared to deamination of 5mC producing C->T mutations is described. These comparisons blur the line between friendly epigenetic base modifications and those that are foes, i.e. DNA "damage," causing genetic mutations. PMID- 28629776 TI - Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression? AB - The Base Excision Repair (BER) pathway, initially studied as a mere DNA repair pathway, has been later found to be implicated in the expression of cancer related genes in human. For several years, this intricate involvement in apparently different processes represented a mystery, which we now are starting to unveil. The BER handles simple alkylation and oxidative lesions arising from both endogenous and exogenous sources, including cancer therapy agents. Surprisingly, BER pathway involvement in transcriptional regulation, immunoglobulin variability and switch recombination, RNA metabolism and nucleolar function is astonishingly consolidating. An emerging evidence in tumor biology is that RNA processing pathways participate in DNA Damage Response (DDR) and that defects in these regulatory connections are associated with genomic instability of cancers. In fact, many BER proteins are associated with those involved in RNA metabolism, ncRNA processing and transcriptional regulation, including within the nucleolus, proving a substantial role of the interactome network in determining their non-canonical functions in tumor cells. Maybe these new insights of BER enzymes, along with their emerging function in RNA-decay, may explain BER essential role in tumor development and chemoresistance and may explain the long time mystery. Here, we would like to summarize different roles of BER pathway in human cells. First, we will give a short description of the classical BER pathway, which has been covered in detail in recent reviews. We will then outline potential new roles of BER in gene expression and RNA metabolism. Although recent works have provided tremendous amount of data in this field, there are still lot of open questions. PMID- 28629773 TI - BERing the burden of damage: Pathway crosstalk and posttranslational modification of base excision repair proteins regulate DNA damage management. AB - DNA base damage and non-coding apurinic/apyrimidinic (AP) sites are ubiquitous types of damage that must be efficiently repaired to prevent mutations. These damages can occur in both the nuclear and mitochondrial genomes. Base excision repair (BER) is the frontline pathway for identifying and excising damaged DNA bases in both of these cellular compartments. Recent advances demonstrate that BER does not operate as an isolated pathway but rather dynamically interacts with components of other DNA repair pathways to modulate and coordinate BER functions. We define the coordination and interaction between DNA repair pathways as pathway crosstalk. Numerous BER proteins are modified and regulated by post-translational modifications (PTMs), and PTMs could influence pathway crosstalk. Here, we present recent advances on BER/DNA repair pathway crosstalk describing specific examples and also highlight regulation of BER components through PTMs. We have organized and reported functional interactions and documented PTMs for BER proteins into a consolidated summary table. We further propose the concept of DNA repair hubs that coordinate DNA repair pathway crosstalk to identify central protein targets that could play a role in designing future drug targets. PMID- 28629778 TI - Posture and gaze tracking of a vertically moving target reveals age-related constraints in visuo-motor coupling. AB - Previously we have demonstrated that the effect of aging on posture and gaze active tracking of a visual target moving in the horizontal direction is dependent on target's complexity. In this study, we asked whether a similar phenomenon is present when tracking a visual target moving with varying complexity in the vertical direction. Ten young (22.98+/-2.9years) and 10 older adults (72.45+/-4.72years) tracked for 120s, a visual target moving vertically by shifting their bodyweight in the anterior-posterior direction. Three target motions were tested: a simple periodic (sine wave), a more complex (Lorenz attractor) and an ultra-complex random (Surrogated Lorenz attractor) pattern. Cross-spectral analysis revealed lower sway-target coherence as a function of age, regardless of target motion's complexity. This age effect was significant for the sway-target gain but not for the phase index. Gaze-target analysis revealed age related differences only when tracking the more complex targets. Regardless of age, tracking of the complex target was associated with lower cross Approximate Entropy. It is concluded that tracking of visual targets oscillating in the vertical direction reveals age related constraints that are independent of visual motion's complexity. These constraints are evident in the spatial and not temporal aspects of visuo-motor coupling, which suggests the presence of neuromuscular deficiencies in controlling visually guided postural sway in the anterior-posterior direction. PMID- 28629777 TI - Mechanistic insights into transcription coupled DNA repair. AB - Transcription-coupled DNA repair (TCR) acts on lesions in the transcribed strand of active genes. Helix distorting adducts and other forms of DNA damage often interfere with the progression of the transcription apparatus. Prolonged stalling of RNA polymerase can promote genome instability and also induce cell cycle arrest and apoptosis. These generally unfavorable events are counteracted by RNA polymerase-mediated recruitment of specific proteins to the sites of DNA damage to perform TCR and eventually restore transcription. In this perspective we discuss the decision-making process to employ TCR and we elucidate the intricate biochemical pathways leading to TCR in E. coli and human cells. PMID- 28629779 TI - Are dopaminergic genotypes risk factors for eating behavior and obesity in adults? AB - Dopamine (DA) is the main modulator of the brain reward system and significantly regulates food intake. The idea that obesity is a neurobiological disease rather than a metabolic disorder, is the basis of the study. Changes in dopamine neurotransmission affect the brain reward system in a direct way. Furthermore, changes in the reward system influence the eating behavior in human. The enzymes monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) terminate the DA function by metabolizing it. In our study, the control group which included 214 individuals and 234 subjects with obesity were investigated for MAOA-u VNTR and COMT (rs4680) polymorphisms. In our study, statistical analysis has showed that in control group Val/Met COMT genotype was significantly higher compared with the patient group (p=0.04). When the groups were compared in terms of eating behavior, the number of the subjects who ate for reward was significantly higher in patient group (p=0.03). Our findings demonstrated that eating behavior might have an effect on obesity and dopaminergic polymorphisms could be risk factors for the development of obesity in Turkish population. PMID- 28629780 TI - Is bilateral internal thoracic artery grafting a safe option for chronic dialysis patients? AB - BACKGROUND: The use of bilateral internal thoracic artery (BITA) grafting has been proposed for dialysis patients with multivessel coronary artery disease, primarily because of hypothetical long-term survival benefits. AIMS: To investigate the outcome of BITA grafting in dialysis patients. METHODS: This was a retrospective analysis of the use of BITA grafting in 105 consecutive patients with end-stage renal failure on chronic dialysis in three European centres with extensive experience in BITA. Baseline patient characteristics, operative data, early postoperative complications and late survival were reviewed. Outcomes of patients from one of the three centres who underwent either BITA (n=40) or single internal thoracic artery (SITA) grafting (n=19) were also analysed; a one-to-one propensity score (PS)-matched analysis was performed. RESULTS: There were 19 (18.1%) hospital deaths. Despite differences in preoperative patient characteristics and surgical features, in each centre, hospital mortality was greater than the 75th percentile of expected operative risk (EuroSCORE II). Diseased ascending aorta and extracardiac arteriopathy were found to be predictors of hospital death (odds ratio 9.7; P=0.006) and complicated hospital course (odds ratio 2.54; P=0.035), respectively. The 7-year non-parametric estimates of freedom from all-cause death and cardiac or cerebrovascular death were 59% (95% confidence interval: 52.3-65.7%) and 75.6% (95% confidence interval: 71.2-80%), respectively. There were no significant differences in early and late outcomes between BITA and SITA PS-matched groups. CONCLUSIONS: BITA grafting remains a risky operation for chronic dialysis patients, even when performed routinely. No long-term survival benefits for the use of BITA versus SITA were proven. PMID- 28629781 TI - Position paper for the evaluation and management of oral status in patients with valvular disease: Groupe de Travail Valvulopathies de la Societe Francaise de Cardiologie, Societe Francaise de Chirurgie Orale, Societe Francaise de Parodontologie et d'Implantologie Orale, Societe Francaise d'Endodontie et Societe de Pathologie Infectieuse de Langue Francaise. AB - Oral health is of particular importance in patients with heart valve diseases because of the risk of infective endocarditis. Recommendations for antibiotic prophylaxis before dental procedures have been restricted, but the modalities of oral evaluation and dental care are not detailed in guidelines. Therefore, a multidisciplinary working group reviewed the literature to propose detailed approaches for the evaluation and management of buccodental status in patients with valvular disease. Simple questions asked by a non-dental specialist may draw attention to buccodental diseases. Besides clinical examination, recent imaging techniques are highly sensitive for the detection of inflammatory bone destruction directly related to oral or dental infection foci. The management of buccodental disease before cardiac valvular surgery should be adapted to the timing of the intervention. Simple therapeutic principles can be applied even before urgent intervention. Restorative dentistry and endodontic and periodontal therapy can be performed before elective valvular intervention and during the follow-up of patients at high risk of endocarditis. The detection and treatment of buccodental foci of infection should follow specific rules in patients who present with acute endocarditis. Implant placement is no longer contraindicated in patients at intermediate risk of endocarditis, and can also be performed in selected high-risk patients. The decision for implant placement should follow an analysis of general and local factors increasing the risk of implant failure. The surgical and prosthetic procedures should be performed in optimal safety conditions. It is therefore now possible to safely decrease the number of contraindicated dental procedures in patients at risk of endocarditis. PMID- 28629782 TI - TNF phase III signalling in tolerant cells is tightly controlled by A20 and CYLD. AB - Following the acute phase of an inflammatory reaction, a strictly controlled resolution of inflammation is necessary. A dysregulation of this process leads to hyperinflammation, chronic inflammatory disease, or immune paralysis. Different mechanisms participate in the coordinated termination of the inflammatory process, e.g. the expression of antiinflammatory molecules and different forms of tolerance. To better understand the processes which mediate resolution of TNF dependent inflammation and induce tolerance, it is necessary to characterize the signal transduction quality during TNF long-term (pre)incubation. Within a time frame from 12 to 48h, designated as phase III of the TNF response, we measured an ongoing, constitutive activation of TNFR1/NF-kappaB-dependent pathways in monocytic cells. Phase III signalling which was also named "constitutive signaling in TNF tolerant cells" induces the expression of low- and high sensitive target genes including A20 which is differentially regulated by transcriptional and proteolytic events. A20 strictly controls TNF long-term constitutive signalling in an IkappaB kinase complex- and partially RIP-dependent manner supported by adjuvant ABIN1. In addition, CYLD proteins participate in the regulation of this late-phase signal transduction, whereas downstream molecules such as Bcl3 and p50 are not involved. A20 and CYLD are expressed with different mRNA kinetics resulting in a strong or only a modest increase in protein levels, respectively. The identification of mechanisms which contribute to the termination of inflammation will provide additional diagnostic and therapeutic aspects to specifically diagnose certain aspects of inflammation and specifically modulate them. PMID- 28629783 TI - GRP78 plays an integral role in tumor cell inflammation-related migration induced by M2 macrophages. AB - Macrophages are the main immune-competent cells that infiltrate in tumors. Tumor associated macrophages (TAMs), termed M2 macrophages, facilitate tumor progress and promote metastasis. However, M2 macrophages always display an immunosuppressive phenotype, which is not in accordance with the tumor inflammatory microenvironment and inflammation-related metastasis. In this study, we established a macrophage polarization model with human monocytes and found that the conditioned medium from M2 macrophages increased GRP78 expression in tumor cells and facilitated tumor cell migration. Mechanistically, excessive GRP78 formed a protein complex with STAT3 and JAK2 to promote STAT3 phosphorylation. Furthermore, p-STAT3 facilitated the high expression of inflammatory factors IL-1beta and TNF-alpha in tumor cells, which was important in M2 macrophage-induced metastasis. The present data demonstrate that M2 macrophages elevate tumor cell GRP78 expression to trigger an inflammatory response, which further facilitates tumor metastasis. Therefore, our study not only uncovered a new cause of GRP78 overexpression in tumor cell, but also, explained the antinomy of TAMs immunosuppressive properties and inflammation related tumor metastasis. PMID- 28629784 TI - [From paediatric urological care to adult urology. Assessment of a transition consultation for adolescents]. AB - : To provide an adequate lifelong urological care in the complex period of adolescence, a transition consultation conducted by a paediatric surgeon and an urologist was developed in our institution. As a real rite of passage, it allows the follow-up and the adapted care of urological conditions, sometimes complex, and permits the transition between childhood and the world of grown-ups. We reported our experience at the Children Hospital of our institution (paediatric surgery and urology departments). During a 6 months period (January-July 2015), forty-five young adults with a mean age of 17.8+/-3.6 years were seen in transition consultation. Eight patients had neurogenic voiding disorders (4 spina bifida, 1 multiple sclerosis, 1 mitochondrial encephalopathy, 1 metachromic leucodystrophy, 1 paraplegia), 9 patients had idiopathic voiding disorders, 1 patient had a non obstructive malformative uropathy; and 30 patients had surgery during infancy and childhood: hypospadias in 17 young men and malformative uropathy in 13 patients. This consultation occurred within 4.6+/-4.5 years after the last consultation with paediatric surgeon. For 6 patients, the transition consultation was the first for the urological problem. After this consultation, 8 patients stayed in paediatric surgery and 37 patients were referred to adult urologist. Among those 8 patients: 2 patients had cognitive and psychiatric disorders; 4 patients refused to be transferred to adult unit; 2 patients wanted to come back at transition consultation. Among the 37 patients transferred in adult urological care: 6 patients had urological surgery, and one patient was referred to a sexology consultation. The remaining 30 patients have initiated long-term monitoring. All reconvened patients came back at the follow-up visit (at least 12 months follow-up). A 16-year-old patient (spina bifida with polymalformative syndrome) developed a depressive syndrome at the end of the consultation, in the motive of an awareness of the definitive nature of his handicap and the need of medical follow-up throughout his life. Transition consultation makes easier the passage from paediatric care to adult urological care. It allows a smooth change of interlocutors, facilitates subsequent care and improves compliance to medical follow-up. It requires a good collaboration between paediatric and adult care units. Transition responds to an increasing request of adolescents, families, and medical teams, since care rupture during adolescence can have functional and psychological consequences. LEVEL OF PROOF: 4. PMID- 28629785 TI - [Interest using 3D ultrasound and MRI fusion biopsy for prostate cancer detection]. AB - INTRODUCTION: The strategic therapy for prostate cancer depends on histo pronostics data, which could be upgraded by obtaining targeted biopsies (TB) with MRI (magnetic resonance imagery) fusion 3D ultrasound. OBJECTIVES: To compare diagnostic yield of image fusion guided prostate biopsy using image fusion of multi-parametric MRI (mpMRI) with 3D-TRUS. MATERIALS AND METHODS: Between January 2010 and April 2013, 179 consecutive patients underwent outpatient TRUS biopsy using the real-time 3D TRUS tracking system (UrostationTM). These patients underwent MRI-TRUS fusion targeted biopsies (TB) with 3D volume data of the MRI elastically fused with 3D TRUS at the time of biopsy. RESULTS: A hundred and seventy-three patients had TBs with fusion. Mean biopsy core per patient were 11.1 (6-14) for SB and 2.4 (1-6) for TB. SBs were positive in 11% compared to 56% for TB (P<0.001). TB outperformed systematic biopsy(SB) in overall any cancer detection rate, detection of clinically significant cancer (58% vs. 36%), cancer core length (6.8mm vs. 2.8mm), and cancer rate per core (P<0.001). In multivariable logistic regression, with TB we have more chance to find a clinically significant cancer (OR:3.72 [2-6.95]). When both TRUS and MRI are positive, there is 2.73 more chance to find a clinically significant cancer. CONCLUSION: MR/TRUS elastic fusion-guided biopsies outperform systematic random biopsies in diagnosing clinically significant cancer. Ability of interpretation of real-time TRUS is essential to perform the higher level of MR/US fusion and should be use for active surveillance. LEVEL OF PROOF: 4. PMID- 28629787 TI - Oral cancer from the perspective of wide-field optical fluorescence: Diagnosis, tumor evolution and post-treatment follow up. AB - In this communication, we present that wide-field optical fluorescence might be useful for: the screening of oral lesions that are imperceptible to the naked eye, determination of biopsy area, better definition of treatment, and previous and post-treatment follow-up. PMID- 28629786 TI - [Pregnancy and delivery for women with congenital spinal cord defects and neurogenic bladder]. AB - INTRODUCTION: Data are scarce regarding pregnancy and delivery among women with a neurogenic bladder due to congenital spinal cord defects. OBJECTIVE: To report the obstetrical and urological outcomes of women with congenital spinal cord defects and vesico-sphincteric disorders. METHODS: A retrospective multicentric study included all consecutive women with a neurogenic bladder due to congenital spinal defects, who delivered between January 2005 and December 2014. The following data were collected: demographics, neuro-urological disease characteristics, urological and obstetrical history, complications during pregnancy, neonatal outcomes, and changes in urological symptoms. RESULTS: Overall, sixteen women, median age 29,4 years old (IQR 22-36), had a total of 20 pregnancies and 21 births (15 caesareans, 5 vaginal deliveries). Prior to the beginning of their first pregnancy, 12 patients were under intermittent self catheterization. Symptomatic urinary tract infections during pregnancy occurred in 11 pregnancies, including 4 pyelonephritis. In 4 women, stress urinary incontinence had worsened but recovered post-partum. In 3 women, de novo clean intermittent catheterization became necessary and had to be continued post partum. During 3 pregnancies, anticholinergic treatment had been started or increased because of urge urinary incontinence worsened. These changes were maintained after delivery. The median gestational age at birth was 39.0 weeks (IQR 37.8-39.5). There were 15 caesarean sections, of which 9 were indicated to prevent a potential aggravation of vesico-sphincteric disorders. Among the 5 pregnancies with vaginal delivery, there was no post-partum alteration of the sphincter function. CONCLUSION: Successful pregnancy outcome is possible in women with congenital spinal cord defects and vesico-sphincteric disorders but it requires managing an increased risk of urinary tract infections, caesarean section, and occasionally worsened urinary incontinence. LEVEL OF EVIDENCE: 5. PMID- 28629788 TI - The meta-analysis. PMID- 28629789 TI - Undifferentiated high-grade pleomorphic sarcoma of ethmoid sinus: a case report and literature review. PMID- 28629790 TI - Current therapeutic approaches for HBV infected patients. PMID- 28629791 TI - Inositol-phosphate signaling as mediator for growth and sexual reproduction in Podospora anserina. AB - The molecular pathways involved in the development of multicellular fruiting bodies in fungi are still not well known. Especially, the interplay between the mycelium, the female tissues and the zygotic tissues of the fruiting bodies is poorly documented. Here, we describe PM154, a new strain of the model ascomycetes Podospora anserina able to mate with itself and that enabled the easy recovery of new mutants affected in fruiting body development. By complete genome sequencing of spod1, one of the new mutants, we identified an inositol phosphate polykinase gene as essential, especially for fruiting body development. A factor present in the wild type and diffusible in mutant hyphae was able to induce the development of the maternal tissues of the fruiting body in spod1, but failed to promote complete development of the zygotic ones. Addition of myo-inositol in the growth medium was able to increase the number of developing fruiting bodies in the wild type, but not in spod1. Overall, the data indicated that inositol and inositol polyphosphates were involved in promoting fruiting body maturation, but also in regulating the number of fruiting bodies that developed after fertilization. The same effect of inositol was seen in two other fungi, Sordaria macrospora and Chaetomium globosum. Key role of the inositol polyphosphate pathway during fruiting body maturation appears thus conserved during the evolution of Sordariales fungi. PMID- 28629792 TI - Alternative splicing and start sites: Lessons from the Grainyhead-like family. AB - The two main mechanisms that expand the proteomic output of eukaryotic genes are alternative splicing and alternative translation initiation signals. Despite being essential to generate isoforms of gene products that create functional diversity during development, the impact of these mechanisms on fine-tuning regulatory gene networks is still underappreciated. In this review, we use the Grainyhead-like (Grhl) family as a case study to illustrate the importance of isoforms when investigating transcription factor family function during development and disease, and highlight the potential for differential modulation of downstream target genes. We provide insights into the importance of considering alternative gene products when designing, undertaking, and analysing primary research, and the effect that isoforms may have on development. This review also covers known mutations in Grhl family members, and postulates how genetic changes may dictate transcriptional specificity between the Grhl family members. It also contrasts and compares the available literature on the function and importance of the Grhl isoforms, and highlights current gaps in our understanding of their regulatory gene networks in development and disease. PMID- 28629793 TI - The effects of hypoxia on active ionic transport processes in the gill epithelium of hyperregulating crab, Carcinus maneas. AB - Effects of hypoxia on the osmorespiratory functions of the posterior gills of the shore crab Carcinus maenas acclimated to 12ppt seawater (DSW) were studied. Short circuit current (Isc) across the hemilamella (one epithelium layer supported by cuticle) was substantially reduced under exposure to 1.6, 2.0, or 2.5mg O2/L hypoxic saline (both sides of epithelium) and fully recovered after reoxygenation. Isc was reduced equally in the epithelium exposed to 1.6mg O2/L on both sides and when the apical side was oxygenated and the basolateral side solely exposed to hypoxia. Under 1.6mg O2/L, at the level of maximum inhibition of Isc, conductance was decreased from 40.0mScm-2 to 34.7mScm-2 and fully recovered after reoxygenation. Isc inhibition under hypoxia and reduced 86Rb+ (K+) fluxes across apically located K+ channels were caused preferentially by reversible inhibition of basolaterally located and ouabain sensitive Na+,K+ ATPase mediated electrogenic transport. Reversible inhibition of Isc is discussed as decline in active transport energy supply down regulating metabolic processes and saving energy during oxygen deprivation. In response to a 4day exposure of Carcinus to 2.0mg O2/L, hemolymph Na+ and Cl- concentration decreased, i.e. hyperosmoregulation was weakened. Variations of the oxygen concentration level and exposure time to hypoxia lead to an increase of the surface of mitochondria per epithelium area and might in part compensate for the decrease in oxygen availability under hypoxic conditions. PMID- 28629794 TI - Uncoupling effect of palmitate is exacerbated in skeletal muscle mitochondria of sea-acclimatized king penguins (Aptenodytes patagonicus). AB - In king penguin juveniles, the environmental transition from a terrestrial to a marine habitat, occurring at fledging, drastically stimulates lipid catabolism and the remodelling of muscle mitochondria to sustain extensive swimming activity and thermoregulation in the cold circumpolar oceans. However, the exact nature of these mechanisms remains only partially resolved. Here we investigated, in vitro, the uncoupling effect of increasing doses of fatty acids in pectoralis muscle intermyofibrillar mitochondria isolated, either from terrestrial never-immersed or experimentally cold water immersed pre-fledging king penguins or from sea acclimatized fledged penguins. Mitochondria exhibited much greater palmitate induced uncoupling respiration and higher maximal oxidative capacity after acclimatization to marine life. Such effects were not reproduced experimentally after repeated immersions in cold water, suggesting that the plasticity of mitochondrial characteristics may not be primarily driven by cold exposure per se but by other aspects of sea acclimatization. PMID- 28629795 TI - Epidemiological Features and Antibiotic Resistance Patterns of Haemophilus influenzae Originating from Respiratory Tract and Vaginal Specimens in Pediatric Patients. AB - STUDY OBJECTIVE: Haemophilus influenzae (H. influenzae) is a common pathogen of respiratory tract infections in children, however, as a possible cause of vulvovaginitis in prepubertal girls, its epidemiological features, antibiotic resistance patterns, and treatment are seldom noted. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Specimens obtained from patients were inoculated on Haemophilus selective medium; and drug-sensitivities tests were determined using the disk diffusion method. A cefinase disk was used to detect beta-lactamase. RESULTS: A total of 610 H. influenzae strains, 81.6% (498/610) from the respiratory tract and 18.0% (110/610) from the vagina, were identified in the Children's Hospital in 2015. The age of the children with respiratory tract strains were significantly younger than those with vaginal strains (P < .001). The H. influenzae isolation rate in May was the highest. The beta-lactamase positive rate was 51.5% (314/610), and 52.5% (320/610) were resistant to ampicillin. The susceptibilities rates to cefuroxime, ampicillin/sulbactam, cefotaxime, clarithromycin, and sulfamethoxazole trimethoprim were 72.1% (440/610), 95.9%, 96.4% (588/610), 81.8% (499/610), and 36.4% (222/610), respectively. Higher resistance to ampicillin, cefuroxime, clarithromycin, and sulfamethoxazole-trimethoprim were found in respiratory tract strains, compared with vaginal strains (P < .05). All of the patients with H. influenzae in the respiratory tract were cured with oral or intravenous beta lactam antibiotics. Of all patients with vaginal strains, 50% (55/110) were cured with topical ofloxacin gel, and 44.5% (49/110) were cured with oral beta-lactam antibiotics. CONCLUSION: The drug-resistance rates of H. influenzae isolated from vagina were lower than those from the respiratory tract. Topical ofloxacin gel or oral beta-lactam antibiotics are effective treatments to eliminate the H. influenza causing infection in the vagina. PMID- 28629796 TI - Large Omental Cystic Lymphangioma Masquerading as Mucinous Ovarian Neoplasia in an 8-Year-Old Premenarchal Girl: The Findings from Diagnostic Imaging and Laparoscopic-Assisted Excision. AB - BACKGROUND: Omental cystic lymphangioma is an extremely rare abdominal mass caused by congenital malformation. CASE: An 8-year-old premenarchal girl reported abdominal pain. Diagnostic imaging revealed a large multicystic mass measuring 22 cm in diameter, which occupied the entire abdominal cavity with ascites. Emergency laparoscopy revealed a ruptured large cystic mass originating from the greater omentum; this was followed by successful laparoscopic-assisted excision. The pathological diagnosis was omental cystic lymphangioma. SUMMARY AND CONCLUSION: The present findings show that omental cystic lymphangioma masquerading as mucinous ovarian neoplasia was a rare cause of acute abdominal events in a young girl. The present case shows that minimally invasive surgery can be a feasible option, which might achieve a favorable outcome in a young patient with an omental cystic lymphangioma. PMID- 28629797 TI - Diagnosing Inequity in Infectious Disease Control. PMID- 28629798 TI - Proteomic analysis of mesenchymal to Schwann cell transdifferentiation. AB - : While transplantation of Schwann cells facilitates axon regeneration, remyelination and repair after peripheral nerve injury clinical use is limited by cell bioavailability. We posit that such limitation in cell access can be overcome by the use of autologous bone-marrow derived mesenchymal stem cells (MSCs). As MSCs can transdifferentiate to Schwann cell-phenotypes and accelerate nerve regeneration we undertook proteomic evaluation of the cells to uncover the protein contents that affects Schwann cell formulation. Transdifferentiated MSCs secrete significant amounts of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in cell-conditioned media that facilitated neurite outgrowth. MSC proteins significantly regulated during Schwann cell transdifferentiation included, but were not limited to, GNAI2, MYL9, ACTN4, ACTN1, ACTB, CAV-1, HSPB1, PHB2, TBB4B, CTGF, TGFI1, ARF6, EZR, GELS, VIM, WNT5A, RTN4, EFNB1. These support axonal guidance, myelination, neural development and neural growth and differentiation. The results unravel the molecular events that underlie cell transdifferentiation that ultimately serve to facilitate nerve regeneration and repair in support of cell transplantation. SIGNIFICANCE STATEMENT: While Schwann cells facilitate axon regeneration, remyelination and repair after peripheral nerve injury clinical use is limited by cell bioavailability. We posit that such limitation in cell access can be overcome by the use of bone-marrow derived mesenchymal stem cells (MSCs) transdifferentiated to Schwann cell-phenotypes. In the present study, we undertook the first proteomic evaluation of these transdifferentiated cells to uncover the protein contents that affects Schwann cell formulation. Furthermore, these transdifferentiated MSCs secrete significant amounts of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in cell-conditioned media that facilitated neurite outgrowth. Our results demonstrate that a number of MSC proteins were significantly regulated following transdifferentiation of the MSCs supporting roles in axonal guidance, myelination, neural development and differentiation. The conclusions of the present work unravel the molecular events that underlie cell transdifferentiation that ultimately serve to facilitate nerve regeneration and repair in support of cell transplantation. Our study was the first proteomic comparison demonstrating the transdifferentiation of MSCs and these reported results can affect a wide field of stem cell biology, tissue engineering, and proteomics. PMID- 28629799 TI - Self-efficacy and Coping as Correlates of Migrant Safe Sexual Behavior to Prevent HIV. AB - Along the Mexico/United States border, migrants are at increased risk of HIV. The objective of our study was to investigate the relationship between two process indicators (self-efficacy to prevent HIV and coping with sexual risk) and safe sexual behaviors in migrants. A correlational design was used. Migrants were recruited from two cities on the northern border of Mexico. Transition theory informed the measurement of self-efficacy and coping process indicators. Three generalized linear models were built for each safe sexual behavior outcome: (a) partner communication, (b) use of condoms, and (c) safe sex. Of 311 migrants, indicators of self-efficacy and coping with sexual risk were associated with all three outcome measures of safe sexual behavior (p < .05). Process indicators explained 22.5% to 30.6% of the variance in the data. Therefore, self-efficacy to prevent HIV and coping ability are important correlates of migrant sexual risk behavior. PMID- 28629801 TI - Corrigendum to "Binding of alkaloid harmalol to DNA: Photophysical and calorimetric approach" [J. Photochem. Photobiol. B: Biol. 130 (2014) 272-280]. PMID- 28629800 TI - Perspectives of HIV Clinic Staff on the Implementation of a Client Financial Incentives Program Targeting Viral Suppression. AB - We present perspectives of health care providers and clinic staff on the implementation of a financial incentive program for clients living with HIV in three Louisiana clinics. Interviews were conducted in May-June 2015 with 27 clinic staff to assess their perspectives on implementation of the Health Models financial incentive program, which was initiated in September 2013. Many providers and staff welcomed the program, but some were concerned about sustainability and the ethics of a program that paid patients to receive care. Most said they eventually found the program to be helpful for patients and clinic operations in general, by facilitating partnerships between providers and patients, improving appointment keeping, providing opportunities for patient education, engaging patients in care, and helping patients form new prevention habits. The findings can improve understanding of staff and leadership perceptions of incentive programs and can inform planning and implementation of these programs in the future. PMID- 28629802 TI - Interventional rheumatology, an unsettled issue. PMID- 28629803 TI - Development of MPC-DPA polymeric nanoparticle systems for inhalation drug delivery applications. AB - Inhalation of nanoparticles for pulmonary drug delivery offers the potential to harness nanomedicine formulations of emerging therapeutics, such as curcumin, for treatment of lung cancer. Biocompatible nanoparticles composed of poly(2 methacryloyloxyethyl phosphorylcholine)-b-poly(2-(diisopropylamino)ethyl methacrylate) (MPC-DPA) have been shown to be suitable nanocarriers for drugs, whilst N-trimethyl chitosan chloride (TMC) coating of nanoparticles has been reported to further enhance their cellular delivery efficacy; the combination of the two has not been previously investigated. Development of effective systems requires the predictable, controllable, and reproducible ability to prepare nanosystems possessing particle sizes, and drug loading capacities, appropriate for successful airway travel, lung tissue penetration, and tumor suppression. Although a number of MPC-DPA based nanosystems have been described, a complete understanding of parameters controlling nanoparticle formation, size, and morphology has not been reported; in particular the effects of differing solvents phases remains unclear. In this current study a matrix of 31 solvent combinations were examined to provide novel data pertaining to the formation of MPC-DPA nanoparticles, and in doing so afforded the selection of systems with particle sizes appropriate for pulmonary delivery applications to be loaded with curcumin, and coated with TMC. This paper presents the first report of novel data detailing the successful preparation, characterisation, and optimisation of MPC-DPA nanoparticles of circa 150-180nm diameter, with low polydispersity, and a curcumin loading range of circa 2.5-115MUM, tunable by preparation parameters, with and without TMC coating, and thus considered suitable candidates for inhalation drug delivery applications. PMID- 28629804 TI - Zero order controlled release delivery of cholecalciferol from injectable biodegradable microsphere: In-vitro characterization and in-vivo pharmacokinetic studies. AB - Poly(lactic-co-glycolic acid) microspheres loaded with cholecalciferol (CL), more bioactive form of vitamin D was developed as an injectable controlled drug release system and was evaluated for its feasibility of once a month delivery. The CL loaded microspheres (CL-MS) were prepared by simple oil in water (O/W) emulsion-solvent evaporation technique incorporated with a stabilizer, Tocopherol Succinate (TS). Different formulation as well as process parameters were investigated namely concentration of emulsifier, concentration of stabilizer and drug: polymer mass ratios. The prepared CL-MS were evaluated for particle size, drug loading, in-vitro drug release and in-vivo pharmacokinetics in rats. The optimized formulation was found to have a mean particle size of 28.62+/-0.26MUm, Encapsulation Efficiency (EE) of 94.4+/-5.4% and drug loading of 5.19+/-0.29% with CL:TS ratio of 2:1. It was found that the EE drastically decreased (26+/ 5.9%) in the absence of stabilizer (TS) indicating its role in stabilization of CL during formulation. DSC and XRD studies indicated that CL existed in an amorphous structure in the polymer matrix. SEM of the CL-MS revealed the spherical morphology and confirmed the particle size. In-vitro release showed that the CL release from CL-MS followed near zero-order drug release kinetics over nearly 1month. In-vivo pharmacokinetic study of CL-MS showed higher t1/2 (239+/-27.5h) compared to oily CL depot (32.7+/-4.8h) with sustained release of CL plasma concentration for 1month. The labile CL could thus be effectively encapsulated and protected against degradation during microspheres formulation, storage and release in presence of stabilizer. This novel CL loaded PLGA MS is stable and may have great potential for clinical use. PMID- 28629805 TI - Association of Hip Radiograph Findings With Pain and Function in Patients Presenting With Low Back Pain. AB - BACKGROUND: Relationships between low back pain (LBP) and the hip in patient cohorts have been described primarily in patients with moderate to severe hip osteoarthritis (OA). Less is known about the links of LBP with hip radiographic findings of hip deformity and minimal OA. OBJECTIVE: To describe the incidence of radiographic hip deformity or hip OA; to describe and compare spine- and hip related pain and function in the subset of patients who were found to have radiographic hip deformity or hip OA; and to compare patients with evidence of radiographic hip deformity or hip OA to patients without hip radiographic findings. DESIGN: Prospective cohort study with cross-sectional design. SETTING: Tertiary university. PATIENTS: A total of 63 patients (40 women, 23 men) with a mean age of 48.5 +/- 14 years with LBP and a minimum of one positive provocative hip test. METHODS: Hip radiographs were assessed by an independent examiner for hip OA and deformity. MAIN OUTCOME MEASUREMENTS: Comparisons of hip and lumbar spine pain and function were completed for patients with radiographic findings of hip OA or deformity. RESULTS: Moderate to severe hip OA was found in 12 of 60 patients (20.0%). At least one measurement of femoroacetabular impingement (FAI) was found in 14 of 60 patients (23.3%) to 33 of 45 patients (73.3%). At least one measurement of developmental hip dysplasia (DDH) was found in 7 of 60 patients (11.6%) to 11 of 63 patients (17.4%). Greater pain and reduced hip and lumbar spine function were found in the patients with moderate to severe hip OA. Patients with LBP and FAI were found to have significantly greater extremes of pain and reduced lumbar spine function. CONCLUSION: Links between the hip and the spine affecting pain and function may be found in patients with LBP and hip deformity and before the onset of radiographic hip OA, and may be associated with hip deformity. Further investigation is needed to better understand these links and their potential impact on prognosis and treatment of LBP. LEVEL OF EVIDENCE: II. PMID- 28629806 TI - Prevalence of Bleeding Complications Following Ultrasound-Guided Botulinum Toxin Injections in Patients on Anticoagulation or Antiplatelet Therapy. AB - BACKGROUND: Patients receiving anticoagulation or antiplatelet therapy may be at higher risk for bleeding complications following intramuscular chemodenervation injections. Musculoskeletal ultrasound may be able to reduce the risk of bleeding complications by providing real-time visualization of vascular structures and postinjection monitoring. Limited data exist addressing the risk of bleeding complications following ultrasound-guided botulinum neurotoxin intramuscular chemodenervation procedures in the setting of anticoagulation or antiplatelet therapy. OBJECTIVE: To provide initial outcome data regarding bleeding complications in patients on anticoagulation or antiplatelet therapy who have received ultrasound-guided botulinum neurotoxin intramuscular chemodenervation procedures. DESIGN: Retrospective, medical record review. SETTING: Academic institution outpatient spasticity clinic. PARTICIPANTS: Total of 328 ultrasound guided intramuscular botulinum toxin injections performed in 15 patients (mean age 53.8 years) with the predominant indication for chemodenervation being spastic paresis secondary to stroke. METHODS: The medical records of all patients undergoing ultrasound-guided intramuscular chemodenervation procedures performed between July 1, 2011, and October 16, 2015, were reviewed for demographic information, details regarding anticoagulation therapy, procedure specifics, and postinjection bleeding complications. All patients had a postinjection ultrasound to screen for hematoma. MAIN OUTCOME MEASURES: Prevalence of clinically significant bleeding complications and of sonographically documented subclinical bleeding complications following ultrasound-guided chemodenervation procedures in patients on anticoagulation or antiplatelet therapy. RESULTS: Of 328 procedures, only 2 subclinical hematomas were detected, resulting in a bleeding complication rate of 0.61% in this patient population. The target muscles in these cases were tibialis posterior and pronator teres, and both cases were in patients on anticoagulation therapy (as opposed to antiplatelet therapy). CONCLUSIONS: The risk of clinically significant bleeding complication appears to be very small following ultrasound-guided intramuscular chemodenervation procedures in the setting of systemic anticoagulation or antiplatelet therapy. LEVEL OF EVIDENCE: IV. PMID- 28629807 TI - Spike or not a spike? That is the question in a patient with single lead pacemaker. AB - Dual-chamber pacing is feasible via the floating atrial sensor electrodes of a single-pass VDD lead but the atrial lead threshold is higher than the accepted clinical standard. Furthermore, due to the floating nature of the system, atrial sensing and pacing thresholds may vary during the follow up. For these reasons this strategy is seldom considered a common pacing solution in routine clinical practice. Alternatively, this phenomenon is likely to be observed as a result of incorrect generator configuration. As shown in our case, this inadequate setting can be suspected just by the analysis of the surface ECG and the post implantation chest X-ray. PMID- 28629808 TI - Physiological and pathophysiological role of transient receptor potential canonical channels in cardiac myocytes. AB - Transient receptor potential canonical (TRPC) channels constitute a family of seven Ca2+ permeable ion channels, named TRPC1 to 7. These channels are abundantly expressed in the mammalian heart, yet mechanisms underlying activation of TRPC channels and their precise role in cardiac physiology remain poorly understood. In this review, we perused original literature regarding TRPC channels in cardiomyocytes. We first reviewed studies on TRPC channel assembly and sub-cellular localization across multiple species and cell types. Our review indicates that TRPC localization in cardiac cells is still a topic of controversy. We then examined common molecular biology tools used to infer on location and physiological roles of TRPC channels in the heart. We subsequently reviewed pharmacological tools used to modulate TRPC activity in both cardiac and non-cardiac cells. Suggested physiological roles in the heart include modulation of heart rate and sensing of mechanical strain. We examined studies on the contribution of TRPC to cardiac pathophysiology, mainly hypertrophic signaling. Several TRPC channels, particularly TRPC1, 3 and 6 were proposed to play a crucial role in hypertrophic signaling. Finally, we discussed gaps in our understanding of the location and physiological role of TRPC channels in cardiomyocytes. Closing these gaps will be crucial to gain a full understanding of the role of TRPC channels in cardiac pathophysiology and to further explore these channels as targets for treatments for cardiac diseases, in particular, hypertrophy. PMID- 28629809 TI - Theoretical modeling of the subject: Western and Eastern types of human reflexion. AB - The author puts forth the hypothesis that mental phenomena are connected with thermodynamic properties of large neural network. A model of the subject with reflexion and capable for meditation is constructed. The processes of reflexion and meditation are presented as the sequence of heat engines. Each subsequent engine compensates for the imperfectness of the preceding engine by performing work equal to the lost available work of the preceding one. The sequence of heat engines is regarded as a chain of the subject's mental images of the self. Each engine can be interpreted as an image of the self that the engine next to it has, and the work performed by engines as the emotions that the subject and his images are experiencing. Two types of meditation are analyzed: The dissolution in nothingness and union with the Absolute. In the first type, the initial engine is the one that yields heat to the coldest reservoir, and in the second type, the initial engine is the one that takes heat from the hottest reservoir. The main concepts of thermodynamics are reviewed in relation to the process of human reflexion. PMID- 28629810 TI - Spindle cell lesions of the breast - An approach to diagnosis. AB - Spindle cell lesions of the breast are among the less common entities encountered in breast pathology. They encompass a whole spectrum of benign reactive lesions to high grade malignant neoplasms. An accurate diagnosis is important to ensure that the patient receives the appropriate management. While this group of conditions broadly share the same basic morphology of a lesion composed of spindle cells, there are often recognizable differences on histology, which coupled with ancillary studies and correlation with the clinical and imaging findings, can help one to arrive at a specific diagnosis. On core biopsy however, spindle cell lesions pose significant interpretive challenges and a firm diagnosis is often not possible. We share our approach to this group of conditions, with a focus on the more common entities, highlighting their key clinical, imaging and pathological features. PMID- 28629811 TI - TBT and its metabolites in sediments: Survey at a German coastal site and the central Baltic Sea. AB - Since the 1950s the organotin compound tributyltin (TBT) was intensively used in antifouling paints for marine vessels and it became of concern for the marine environment. Herein, we report on a study from 2015 on TBT and its metabolites monobutyltin (MBT) and dibutyltin (DBT) in sediments from the central Baltic Sea and a Baltic Sea coastal site with strong harbor activities (Warnemunde). Sublayers from a sediment core from the Arkona Basin were analyzed to investigate the long term organotin pressure for the Baltic Sea. For the central Baltic Sea total organotin (MBT+DBT+TBT) ranged from 100 to 500ng/g TOC with distinct areas of high organotin content probably due to historical inputs. For the coastal site total organotin ranged from 10,000 to 60,000ng/g TOC. MBT and DBT were the predominant organotin species detected. Overall, the data obtained indicate the progress of TBT degradation at the investigated sites. PMID- 28629812 TI - Benthic foraminifera for heavy metal pollution monitoring: A case study from Burullus Lagoon of Egypt. AB - Sources of heavy metals pollution in the Burullus Lagoon include phosphate fertilizers, sewage and oil spills from fishing boats. The benthic species identified in this lagoon are Adelosina carinata striata (Wiesner), Quinqueloculina bosciana (d'Orbigny), Quinqueloculina seminulum (Linnaeus), Ammonia tepida (Cushman), Elphidium excavatum (Terquem). A. tepida is the most dominant species in the lagoon. It constitutes more than 97% of the total benthic foraminiferal assemblages reflecting tolerance to the very low salinity in the Burullus Lagoon. The intensity of deformation was severe exhibiting a peculiar change in the coiling direction in A. tepida with increase in cadmium concentration. A. tepida exhibited a great morphological variability and the recorded morphological abnormalities show high spire giving the spiroconvex test, additional chamber, aberrant chamber shape and size, twisted tests with elongated axes of rotation and complex deformities, whereas E. excavatum showed additional calcite secretion (tumors). PMID- 28629813 TI - Recruitment failure of scleractinian corals in a subtropical marginal environment: Three-year monitoring in a Hong Kong marine park. AB - Coral recruitment was monitored for three years, using terracotta tiles, in two core coral areas in Tung Ping Chau Marine Park where coral coverage is one of the richest in Hong Kong. Results revealed an extremely low recruitment success of corals, with only 10 recruits recorded on 384 tile pairs, equivalent to 0.19 recruits m-2yr-1 throughout the study period. Recruits of Platygyra acuta pre seeded on tiles that were subsequently grown in situ experienced very high mortality following settlement, with average mortality of 80% within half a month and <0.1% survival through the first four months of deployment. Data suggested that low recruitment of corals may be due to the lack of arrival of competent coral larvae, low larval settlement; and/or low post-settlement survival of recruits due to high sedimentation or intense competition for space with fouling organisms, e.g. algae, oysters, barnacles and bryozoans, which may negatively affect coral recruitment. PMID- 28629814 TI - Abcb1a (P-glycoprotein) limits brain exposure of the anticancer drug candidate seliciclib in vivo in adult mice. AB - Seliciclib displayed limited brain exposure in vivo in adult rats with mature blood-brain barrier (BBB). Selicilib was shown to be a specific substrate of human ABCB1 in vitro. To demonstrate that ABCB1/Abcb1 can limit brain exposure in vivo in mice we are showing that seliciclib is a substrate of mouse Abcb1a, the murine ABCB1 ortholog expressed in the BBB as LLC-PK-Abcb1a cells displayed an efflux ratio (ER) of 15.31+/-3.54 versus an ER of 1.44+/-0.10 in LLC-PK1-mock cells. Additionally, in the presence of LY335979, an ABCB1/Abcb1a specific inhibitor, the observed ER for seliciclib in the LLC-PK1-mMdr1a cells decreased to 1.05+/-0.25. To demonstrate in vivo relevance of seliciclib transport by Abcb1a mouse brain microdialysis experiments were carried out that showed that the AUCbrain/AUCblood ratio of 0.143 in anesthetized mice increased about two fold to 0.279 in the presence of PSC833 another ABCB1/Abcb1a specific inhibitor. PSC833 also increased the brain exposure (AUCbrain) of seliciclib close to 2-fold (136 vs 242) in awake mice. In sum, Abcb1a significantly decreases seliciclib permeability in vitro and is partly responsible for limited brain exposure of seliciclib in vivo in mice. PMID- 28629816 TI - Tinospora species: An overview of their modulating effects on the immune system. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Studies on the effects of natural immunomodulators to heal various diseases related to the immune system have been a growing interest in recent years. Amongst the medicinal plants, Tinospora species (family; Menispermaceae) have been one of the widely investigated plants for their modulating effects on the immune system due to their wide use in ethnomedicine to treat various ailments related to immune-related diseases. However, their ethnopharmacological uses are mainly with limited or without scientific basis. AIM OF THIS REVIEW: In this article, we have reviewed the literature on the phytochemicals of several Tinospora species, which have shown strong immunomodulatory effects and critically analyzed the reports to provide perspectives and instructions for future research for the plants as a potential source of new immunomodulators for use as medicinal agents or dietary supplements. MATERIALS AND METHODS: Electronic search on worldwide accepted scientific databases (Google Scholar, Science Direct, SciFinder, Web of Science, PubMed, Wiley Online Library, ACS Publications Today) was performed to compile the relevant information. Some information was obtained from books, database on medicinal plants used in Ayurveda, MSc dissertations and herbal classics books written in various languages. RESULTS: T. cordifolia, T. crispa, T. sinensis, T. smilacina, T. bakis, and T. sagittata have been reported to possess significant immunomodulatory effects. For a few decades, initiatives in molecular research on the effects of these species on the immune system have been carried out. However, most of the biological and pharmacological studies were carried out using the crude extracts of plants. The bioactive compounds contributing to the bioactivities have not been properly identified, and mechanistic studies to understand the immunomodulatory effects of the plants are limited by many considerations with regard to design, conduct, and interpretation. CONCLUSION: The plant extracts and their active constituents should be subjected to more detail mechanistic studies, in vivo investigations in various animal models including pharmacokinetic and bioavailability studies, and elaborate toxicity study before submission to clinical trials. PMID- 28629815 TI - Resveratrol suppresses pulmonary tumor metastasis by inhibiting platelet-mediated angiogenic responses. AB - BACKGROUND: To explore the impact of Resveratrol (RSV) on the angiogenic potential of activated platelets and to elucidate the underlying mechanism. METHODS: Vascular endothelial growth factor concentrations were measured by enzyme-linked immunosorbent assay. Capillary tube formation assay was used to examine the impact of RSV on the angiogenic potential of activated platelets. The levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP) in the supernatant were evaluated using corresponding enzyme-linked immunosorbent assay kits. Immunoblotting assays were used to determine the expression of vasodilator-stimulated phosphoprotein and Akt phosphorylation. A pulmonary metastasis experiment with male nude mice model was performed to test the effect of RSV on pulmonary metastasis and angiogenesis in vivo. RESULTS: RSV inhibited platelets-mediated angiogenic responses induced by adenosine diphosphate (ADP)ADP through increased cGMP generation and cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation along with reduced intracellular Ca2+ mobilization. In addition, RSV attenuated the platelet secretion and angiogenic responses induced by A549 cells in vitro and suppressed A549 lung cancer metastasis and angiogenesis in nude mice. CONCLUSIONS: RSV is a potential therapeutic drug for the prevention of tumor metastasis by interrupting the platelet-tumor cell amplification loop. PMID- 28629817 TI - The antinociceptive effects of a standardized ethanol extract of the Bidens odorata Cav (Asteraceae) leaves are mediated by ATP-sensitive K+ channels. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bidens odorata Cav (Asteraceae) is used for the empirical treatment of inflammation and pain. AIM OF THE STUDY: This work evaluated the in vitro and in vivo toxicity, antioxidant activity, as well as the anti-inflammatory and antinociceptive effects of an ethanol extract from Bidens odorata leaves (BOE). MATERIALS AND METHODS: The in vitro toxicity of BOE (10 1000ug/ml) was evaluated with the comet assay in PBMC. The in vivo acute toxicity of BOE (500-5000mg/kg) and the effect of BOE (10-1000ug/ml) on the level of ROS in PBMC were determined. The in vivo anti-inflammatory activity of BOE was assessed using the TPA-induced ear edema in mice. The antinociceptive activities of BOE (50-200mg/kg p.o.) were assessed using the acetic acid and formalin tests. The antinociceptive mechanism of BOE was determined using naloxone and glibenclamide. RESULTS: BOE lacked DNA damage, and showed low in vivo toxicity (LD50 > 5000mg/kg p.o.). BOE inhibited ROS production (IC50 = 252.13 +/- 20.54ug/ml), and decreased inflammation by 36.1 +/- 3.66%. In both antinociceptive test, BOE (200mg/kg) exerted activity with similar activity than the reference drugs. CONCLUSION: B. odorata exerts low in vitro and in vivo toxicity, antioxidant effects, moderate in vivo anti-inflammatory activity, and antinociceptive effects mediated by ATP-sensitive K+ channels. PMID- 28629819 TI - Umbilical appearance and patient/parent satisfaction over 5years of follow-up after umbilical hernia repair in children. AB - BACKGROUND/PURPOSE: We evaluated the long-term umbilical appearance and patient/parent satisfaction at follow-up after umbilical hernia repair (UHR). METHODS: In a retrospective review of 128 children who underwent UHR and were followed up for over 5 years, satisfaction was assessed using e-mailed questionnaires and attached photographs of the umbilicus. RESULTS: The survey response rate was 80.3% by parents, 79.5% by patients, and 72.1% using photographs. The median follow-up period was 7.6 (range, 5.3-10.1) years. The satisfaction rate was 78.9% among parents and 91.5% among patients; however, eight patients (8.5%) reported dissatisfaction with the results. The main reason for dissatisfaction was the shallow depth of the umbilicus (parents, 10/20; patients, 5/8). During the follow-up period, satisfaction increased in 14 cases (14.7%) and decreased in 10 cases (10.5%). Superior hooding was considered an ideal shape for the umbilicus. Concomitant laparoscopic surgery and higher age at surgery were significantly associated with dissatisfaction in parents (P = 0.045) and patients (P = 0.046), respectively. Large defect size was significantly associated with decreased satisfaction during the follow-up period (P = 0.030). CONCLUSION: E-mail surveys are useful for long-term follow-up after UHR. Patients with these above risk factors should receive long-term follow-up with careful attention to patient satisfaction. LEVEL OF EVIDENCE: Type of study: prognosis study, level II. PMID- 28629818 TI - Corydalis hendersonii Hemsl. protects against myocardial injury by attenuating inflammation and fibrosis via NF-kappaB and JAK2-STAT3 signaling pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Corydalis hendersonii Hemsl. (CH) with heat clearing and detoxifying effects are well described in Tibetan folk medicine. It has been used for centuries in China largely for the treatment of high altitude polycythemia, a pathophysiological condition referred to "plethora" in Tibetan medicine, hypertension, hepatitis, edema, gastritis, and other infectious diseases. AIM OF THE STUDY: To investigate the cardioprotective effects of Corydalis hendersonii extract in an ICR mouse model of myocardial ischemic injury. MATERIALS AND METHODS: Ethanol [85% (v/v)] extract of CH whole plant was prepared, and their chemical profile was analyzed with use of HPLC-DAD and IT-TOF ESI-MS. A mouse model of AMI was established by ligation of the left ventricular dysfunction (LAD) coronary artery. Mice were randomly divided into six groups (n = 12 per group): sham group, model group, CH groups treated with three doses of CH (100, 200, and 400mg/kg, intragastric), and a positive control group (captopril, 16.67mg/kg, intragastric). Heart function was evaluated by measurement of ejection fraction (EF) and fractional shortening (FS) by echocardiography. Serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), plasma levels of angiotensin II (AngII), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the cardiac tissue homogenate, protein expressions of signal-transduction proteins, p65, IkappaBalpha, JAK2, and STAT3 in heart tissues were measured by ELISA and Western blot analyses. Inflammatory cell infiltration and changes in collagen deposition in the myocardial ischemic heart tissues were observed by histopathological examination. Platelet aggregation in vitro was also assessed. RESULTS: CH treatment showed a dose-dependent cardioprotective effect. It significantly reduced left ventricular end-diastolic diameter (LVEDd) and left ventricular end diastolic diameter (LVEDs), improved EF and FS as compared to those in the model group; attenuated the increase levels of CK-MB and LDH in serum; reduced expressions of AngII, TNF-alpha, IL-6 and IL-1beta in plasma, MMP-2 and MMP-9 expressions in the cardiac tissue homogenate; and down-regulated myocardial expressions of p-p65, p-IkappaBalpha, p-JAK2, p-STAT3, MMP-2, and MMP-9 in AMI mice. Also, an obvious reduction in inflammatory cell infiltration in the myocardial infarct was found in all CH treated groups. Besides, CH also inhibited platelet aggregation induced by THR, ADP, and AA. CONCLUSION: CH extract exerted a protective effect against myocardial ischemic injury via inhibition of inflammation, myocardial fibrosis, and platelet aggregation. This study demonstrates such protection for the first time and provides a basis for development of CH-based drugs for treatment of ischemic heart disease in clinical settings. PMID- 28629820 TI - Urodynamic performance in boys with Y-type urethral duplication. AB - PURPOSE: The aim of this study was to elucidate the urodynamic features of patients with Y-type urethral duplication. METHODS: Patients with Y-type urethral duplication were retrospectively analyzed. Clinical presentation, urodynamic findings, surgical methods, and treatment outcomes were reviewed. RESULTS: From 2014 to 2016, six boys were diagnosed with Y-type urethral duplication at our institution. All patients underwent urodynamic testing. Urodynamic testing in patient 1 and 2 revealed detrusor pressure as 100cmH2O and 88cmH2O in the voiding stage, while urinary flow rate were 0ml/s and 2.8ml/s with volume of residual urine as 300ml and 110ml respectively, which consistent with the typical urodynamic of lower urinary tract obstruction. Patient 1, 3, 4 and 6 showed impaired bladder compliance as 7.5ml/H2O, 12ml/H2O, 6ml/H2O and 6ml/H2O respectively. Patient 5 and 6 also showed maximum urethral pressure as 110cmH2O and 125cmH2O with maximum urethral closure pressure as 103cmH2O and 110cmH2O respectively in the resting state. CONCLUSIONS: Y-type urethral duplication is one potential cause of lower urinary tract obstruction, as seen in the abnormal urodynamic findings in our patients. Further studies are needed to elucidate the characteristics of this rare condition and determine optimal surgical management. TYPE OF STUDY: Retrospective case series. LEVEL OF EVIDENCE: Level 4 observational study without controls. PMID- 28629821 TI - Glycogen Reduction in Myotubes of Late-Onset Pompe Disease Patients Using Antisense Technology. AB - Glycogen storage disease type II (GSDII) is a lysosomal disorder caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme, leading to the accumulation of glycogen within the lysosomes. The disease has been classified in infantile and late-onset forms. Most late-onset patients share a splicing mutation c.-32-13T > G in intron 1 of the GAA gene that prevents efficient recognition of exon 2 by the spliceosome. In this study, we have mapped the splicing silencers of GAA exon 2 and developed antisense morpholino oligonucleotides (AMOs) to inhibit those regions and rescue normal splicing in the presence of the c.-32-13T > G mutation. Using a minigene approach and patient fibroblasts, we successfully increased inclusion of exon 2 in the mRNA and GAA enzyme production by targeting a specific silencer with a combination of AMOs. Most importantly, the use of these AMOs in patient myotubes results in a decreased accumulation of glycogen. To our knowledge, this is the only therapeutic approach resulting in a decrease of glycogen accumulation in patient tissues beside enzyme replacement therapy (ERT) and TFEB overexpression. As a result, it may represent a highly novel and promising therapeutic line for GSDII. PMID- 28629823 TI - Characterization and biological function analysis of the TRIM47 gene from common carp (Cyprinus carpio). AB - The TRIM family protein was known to play an important role in many cellular processes, including potential antiviral activity, which has attracted lots of attention. In this study, a TRIM47 homolog from common carp (Cyprinus carpio) was cloned and the full length coding DNA sequence (CDS) of this gene was analyzed, results showed that there was a 97% similarity between common carp and zebrafish (Danio rerio), but only 18% similarity with that of human (Homo sapiens) and mouse (Mus musculus). The tissue distribution analysis showed TRIM47 had the highest mRNA level in the brain, a few immune related organs such as liver and kidney also had a relatively high level of TRIM47 expression. SVCV infection decreased TRIM47 mRNA level significantly both in vitro and in vivo, but its expression was not affected by the virus at the protein level. The recombinant plasmid pcDNA4-TRIM47-His was constructed, the subcellular localization in FHM cells showed that TRIM47 uniformly distributed in the cytoplasm at the form of tiny spots, and partially localized in the mitochondria. Overexpression TRIM47 in FHM cells significantly decreased the mRNA level of SVCV-G gene, and it was accompanied with the increasing of IFN1, a member of type I IFN, at the case of SVCV stimulation. In summary, our results had first demonstrated that TRIM47 of the common carp played an important role in viral resistance processes as well as the regulation of IFN signaling pathway. PMID- 28629822 TI - Structure-Based Designed Nano-Dysferlin Significantly Improves Dysferlinopathy in BLA/J Mice. AB - Dysferlinopathy is an autosomal recessive muscular dystrophy characterized by the progressive loss of motility that is caused by mutations throughout the DYSF gene. There are currently no approved therapies that ameliorate or reverse dysferlinopathy. Gene delivery using adeno-associated vectors (AAVs) is a leading therapeutic strategy for genetic diseases; however, the large size of dysferlin cDNA (6.2 kB) precludes packaging into a single AAV capsid. Therefore, using 3D structural modeling and hypothesizing dysferlin C2 domain redundancy, a 30% smaller, dysferlin-like molecule amenable to single AAV vector packaging was engineered (termed Nano-Dysferlin). The intracellular distribution of Nano Dysferlin was similar to wild-type dysferlin and neither demonstrated toxicity when overexpressed in dysferlin-deficient patient myoblasts. Intramuscular injection of AAV-Nano-Dysferlin in young dysferlin-deficient mice significantly improved muscle integrity and decreased muscle turnover 3 weeks after treatment, as determined by Evans blue dye uptake and central nucleated fibers, respectively. Systemically administered AAV-Nano-Dysferlin to young adult dysferlin-deficient mice restored motor function and improved muscle integrity nearly 8 months after a single injection. These preclinical data are the first report of a smaller dysferlin variant tailored for AAV single particle delivery that restores motor function and, therefore, represents an attractive candidate for the treatment of dysferlinopathy. PMID- 28629824 TI - Comparison of SHOX and associated elements duplications distribution between patients (Leri-Weill dyschondrosteosis/idiopathic short stature) and population sample. AB - The effect of heterozygous duplications of SHOX and associated elements on Leri Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS) development is less distinct when compared to reciprocal deletions. The aim of our study was to compare frequency and distribution of duplications within SHOX and associated elements between population sample and LWD (ISS) patients. A preliminary analysis conducted on Czech population sample of 250 individuals compared to our previously reported sample of 352 ISS/LWD Czech patients indicated that rather than the difference in frequency of duplications it is the difference in their distribution. Particularly, there was an increased frequency of duplications residing to the CNE-9 enhancer in our LWD/ISS sample. To see whether the obtained data are consistent across published studies we made a literature survey to get published cases with SHOX or associated elements duplication and formed the merged LWD, the merged ISS, and the merged population samples. Relative frequency of particular region duplication in each of those merged samples were calculated. There was a significant difference in the relative frequency of CNE-9 enhancer duplications (11 vs. 3) and complete SHOX (exon1-6b) duplications (4 vs. 24) (p value 0.0139 and p-value 0.000014, respectively) between the merged LWD sample and the merged population sample. We thus propose that partial SHOX duplications and small duplications encompassing CNE-9 enhancer could be highly penetrant alleles associated with ISS and LWD development. PMID- 28629825 TI - ICT1 predicts a poor survival and correlated with cell proliferation in diffuse large B-cell lymphoma. AB - Immature colon carcinoma transcript-1 (ICT1) is a crucial member of the large mitoribosomal subunit in mitochondrial ribosome, which has been shown to be closely related to tumorigenesis. Its expression and function in human diffuse large B-cell lymphoma (DLBCL), however, remained elusive. In this study, analysis of public available Oncomine database suggested that the expression levels of ICT1 mRNA was significantly upregulated in DLBCL tissues. Consistently, we described ICT1 was remarkably upregulated in fresh DLBCL samples compared with the corresponding normal tissues using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. Moreover, ICT1 overexpression was associated with the poor overall survival (OS) of DLBCL patients. Finally, we used DLBCL cell lines to further probe the potential mechanisms, and found shRNA-mediated knockdown of ICT1 significantly suppressed DLBCL cell proliferation, induced cell cycle arrest at G0/G1 phase and apoptosis in vitro. Further verification showed that inhibition of ICT1 gene expression caused the upregulation of the p21, Bad and caspase-3, and downregulation of PCNA, Survivin, CDK4, CDK6 and Cyclin D1. Taken together, this study suggested that ICT1 may play an oncogenic role in human DLBCL by promoting cell proliferation and it might be a biomarker of unfavorable prognosis in DLBCL patients. PMID- 28629826 TI - Silencing of FKBP51 alleviates the mechanical pain threshold, inhibits DRG inflammatory factors and pain mediators through the NF-kappaB signaling pathway. AB - Neuropathic pain is chronic pain caused by lesions or diseases of the somatosensory system, currently available analgesics provide only temporal relief. The precise role of FK506 binding protein 51 (FKBP51) in neuropathic pain induced by chronic constriction injury (CCI) is not clear. The purpose of the present study was to investigate the effects and possible mechanisms of FKBP51 in neuropathic pain in the rat model of CCI. Our results showed that FKBP51 was obviously upregulated in a time-dependent manner in the dorsal root ganglion (DRG) of CCI rats. Additionally, silencing of FKBP51 remarkably attenuated mechanical allodynia and thermal hyperalgesia as reflected by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in CCI rats. Moreover, knockdown of FKBP51 reduced the production of pro-inflammatory cytokines (TNF-alpha, IL 1beta and IL-6), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG of CCI rats. Furthermore, we revealed that inhibition of FKBP51 greatly suppressed the activation of the NF-kappaB (NF kappaB) signaling in the DRG of CCI rats. Interestingly, similar to the FKBP51 siRNA (si-FKBP51), ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF kappaB) also alleviated neuropathic pain and neuro-inflammation, indicating that knockdown of FKBP51 alleviated neuropathic pain development of CCI rats by inhibiting the activation of NF-kappaB signaling pathway. Taken together, our findings indicate that FKBP51 may serve as a novel therapeutic target for neuropathic pain. PMID- 28629827 TI - Debriefing values in high-fidelity simulation. PMID- 28629828 TI - Factors associated with the decision of operative procedure for proximal femoral bone metastasis: Questionnaire survey to institutions participating the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. AB - BACKGROUND: Pathological fracture of the proximal femur is a main cause of cancer patients losing their ability to walk. Although both osteosynthetic devices (predominantly intramedullary nails) and prosthetic replacement have been widely performed for treatment, controversies exist regarding which procedure should be used for the various conditions. In order to decide the eligibility criteria of a planned randomized prospective study about the treatment of pathological fractures of the proximal femur, we assessed the factors affecting the selection of operative procedures using questionnaires sent to the members of the Bone and Soft Tissue Tumor Study Group (BSTTSG) of the Japan Clinical Oncology Group (JCOG). METHODS: Questionnaire surveys to evaluate (1) the priority levels of the factors, (2) the equipoise range of each factor in situations where either procedure could be applied, (3) risk and benefit of each procedure, and (4) the degree of bone destruction affecting the selection of operative procedures, were sent to 26 institutions. RESULTS: Over 80% of the institutions answered. Orthopaedic surgeons of BSTTSG decided on the procedure according to the following factors in descending order: life expectancy, performance status before fracture, the degree of bone destruction, walking ability before fracture, general complications, the number of bone metastases in other sites, and the visceral metastasis status. With regard to bone destruction, (1) the involvement of the head, neck, calcar, and intertrochanteric region, (2) transverse destruction >1/2, and (3) soft-tissue tumor extension, were the factors that led to the choice of prosthesis treatment. CONCLUSIONS: Using these identified factors, the inclusion criteria for the prospective randomized study of the surgical treatment of metastatic bone tumors of the proximal femur were optimized. The evaluation system about the bone destruction of metastases needs to be refined through the following prospective randomized study. PMID- 28629829 TI - Morphological variability and molecular characterization of Pomphorhynchus zhoushanensis sp. nov. (Acanthocephala: Pomphorhynchidae), with comments on the systematic status of Pomphorhynchus Monticelli, 1905. AB - Species of Pomphorhynchus Monticelli, 1905 commonly parasitize the digestive tract of freshwater fishes, and rarely occur in marine fishes and amphibians. In the present study, Pomphorhynchus zhoushanensis sp. nov., collected from the barred knifejaw Oplegnathus fasciatus (Temminck & Schlegel) (Perciformes: Oplegnathidae) in the East China Sea, was described using integrated approaches, including light and scanning electron microscopy, and the sequencing and analysing of ribosomal [small ribosomal DNA (18S) and internal transcribed spacer (ITS)] and mitochondrial [cytochrome c oxidase subunit 1 (cox1)] target regions. The results of the molecular analyses showed that morphological differences in the shape of the neck bulb (symmetrical or asymmetrical) among individuals of P. zhoushanensis sp. nov. are actually intraspecific variations. Moreover, phylogenetic analyses based on the 18S, ITS and cox1 sequences were constructed to evaluate the phylogenetic relationships between the new species and other pomphorhynchid species. The results of the phylogenetic analyses suggested that Pomphorhynchus is not a monophyletic group. Based on the results of the molecular and phylogenetic analyses, the taxonomic importance of the symmetry of the neck bulb for species identification in the genus Pomphorhynchus is questioned. PMID- 28629830 TI - Re: Ipsilateral full-thickness skin grafts to repair the donor site defect of a radial forearm free flap: a reflection on technique. PMID- 28629831 TI - Extracapsular dissection in the parapharyngeal space: benefits and potential pitfalls. AB - The aim of this study was to investigate the benefits and potential pitfalls of transcervical extracapsular dissection in the treatment of parotid gland tumours in the parapharyngeal space. We retrospectively evaluated the records of all patients with parapharyngeal parotid gland lesions treated between 2000 and 2015 by transcervical extracapsular dissection. Patients having revision operations and patients whose records were not complete were excluded, leaving 49 patients in the study. We found acceptable oncological and functional outcomes throughout. Special attention should be paid in cases with multilobular growth of the tumour on magnetic resonance imaging, satellite tumours of pleomorphic adenomas, tumours in broad contact with the inner surface of the deep lobe, and lesions suspected of malignancy. Extracapsular dissection in the parapharyngeal region is associated with acceptable oncological and functional outcomes. These outcomes can be expected only after a thorough assessment of patient's history and preoperative imaging. PMID- 28629832 TI - Evaluation of four designs of short implants placed in atrophic areas with reduced bone height: a three-year, retrospective, clinical and radiographic study. AB - The aim of the present study was to evaluate retrospectively the clinical and radiographic behaviour of four commercially-available short implants with different macrodesigns and microdesigns in areas in which the height of the bone was reduced. We took into account the success and survival, peri-implant crestal bone loss, and the level of probing at which the gum bled. Patients were included if they had been given one or more short implants (<=8.5mm long) in the posterior jaws at least three years earlier. Three hundred and ninety-one short implants were placed in 170 subjects, and were divided in four groups based on the brand of implant. The implants were evaluated one, two, and three years after they had been inserted. Short implants had a three-year survival and success rate of 90% in all groups, and bone loss was acceptable after three years with no significant differences between them. These results support the use of short implants as an effective and safe treatment. However, within the limitations of this study, the design of the implant does seem to influence the behaviour of peri-implant bone at the crestal level. PMID- 28629833 TI - New approach to improve the keratinised peri-implant soft tissues in patients with intraoral osteocutaneous reconstruction using a free flap. PMID- 28629834 TI - Myositis in the head and neck: challenges in diagnosis and management. AB - Myositis in the head and neck may present with non-specific symptoms, and radiographically may mimic malignancy. Multidisciplinary management is often essential, and we describe the challenges in an effort to raise awareness of the condition. PMID- 28629837 TI - "One-stop shop" tumor tattooing and sentinel lymph node mapping: A new paradigm for lung cancer therapy. PMID- 28629836 TI - Opposite effects of catalase and MnSOD ectopic expression on stress induced defects and mortality in the desmin deficient cardiomyopathy model. AB - Oxidative stress has been linked strongly to cell death and cardiac remodeling processes, all hallmarks of heart failure. Mice deficient for desmin (des-/-), the major muscle specific intermediate filament protein, develop dilated cardiomyopathy and heart failure characterized by mitochondrial defects and cardiomyocyte death. The cellular and biochemical alterations in the hearts of these mice strongly suggest that oxidative stress is one of the mechanisms contributing to the pathogenesis of the phenotype. Recently, we showed that indeed the desmin deficient cardiomyocytes are under increased oxidative stress. In order to verify these findings in vivo, we generated transgenic animals overexpressing SOD2 (MnSOD) and/or catalase in the heart and crossed them with des-/- mice, thus allowing us to evaluate the contribution of oxidative injury in inherited cardiomyopathies, as well as the therapeutic potential of antioxidant strategies. Moderate MnSOD and/or catalase overexpression in des-/- hearts leads to a marked decrease in intracellular reactive oxygen species (ROS), ameliorates mitochondrial and other ultrastructural defects, minimizes myocardial degeneration and leads to a significant improvement of cardiac function. Importantly, catalase overexpression increased the 50% survival rate of des-/- mice in an obligatory exercise to 100%. In contrast, MnSOD overexpression enhanced the lethality of des-/- mice, underscoring the importance of a fine balanced cellular redox status. Overall, the present study supports the contribution of oxidative stress in the development of des-/- cardiomyopathy and points to a well-considered antioxidant treatment as therapeutic for cardiomyopathies. PMID- 28629835 TI - Ruthenium complex exerts antineoplastic effects that are mediated by oxidative stress without inducing toxicity in Walker-256 tumor-bearing rats. AB - The present study evaluated the in vivo antitumor effects and toxicity of a new Ru(II) compound, cis-(Ru[phen]2[ImH]2)2+ (also called RuphenImH [RuC]), against Walker-256 carcinosarcoma in rats. After subcutaneous inoculation of Walker-256 cells in the right pelvic limb, male Wistar rats received 5 or 10mgkg-1 RuC orally or intraperitoneally (i.p.) every 3 days for 13 days. A positive control group (2mgkg-1 cisplatin) and negative control group (vehicle) were also used. Tumor progression was checked daily. After treatment, tumor weight, plasma biochemistry, hematology, oxidative stress, histology, and tumor cell respiration were evaluated. RuC was effective against tumors when administered i.p. but not orally. The highest i.p. dose of RuC (10mgkg-1) significantly reduced tumor volume and weight, induced oxidative stress in tumor tissue, reduced the respiration of tumor cells, and induced necrosis but did not induce apoptosis in the tumor. No clinical signs of toxicity or death were observed in tumor-bearing or healthy rats that were treated with RuC. These results suggest that RuC has antitumor activity through the modulation of oxidative stress and impairment of oxidative phosphorylation, thus promoting Walker-256 cell death without causing systemic toxicity. These effects make RuC a promising anticancer drug for clinical evaluation. PMID- 28629838 TI - Optimizing cerebral blood flow: Hitting the sweet spot on cardiopulmonary bypass. PMID- 28629839 TI - Surgery versus percutaneous transcatheter embolization for pulmonary arteriovenous malformation: Analysis of a national inpatient database in Japan. AB - OBJECTIVE: Although the treatment options for pulmonary arteriovenous malformation are surgery and percutaneous transcatheter embolization, no study has compared the outcomes between these 2 treatments. METHODS: From the Japanese Diagnosis Procedure Combination database, the medical records of 996 patients who received treatment for pulmonary arteriovenous malformation between 2010 and 2015 were retrospectively reviewed. We created balanced groups for surgery or percutaneous transcatheter embolization using propensity scoring. The primary outcome was the rate of reintervention for pulmonary arteriovenous malformation, and the secondary outcomes were composite complications and postoperative length of stay. Patients who had any 1 of the complications during hospitalization were considered to have experienced a composite complication. RESULTS: Of the total sample, 211 patients underwent surgery and 785 patients underwent percutaneous transcatheter embolization. By using 1-to-1 propensity score matching, 202 pairs were selected. Compared with percutaneous transcatheter embolization, surgery was associated with a significantly higher proportion of composite complications (6.9% vs 2.0%, P = .027) and longer postoperative length of hospital stay (median, 6 vs 2 days, P < .01). However, surgery resulted in a significantly lower rate of reintervention for pulmonary arteriovenous malformation (2.1% vs 8.3% at 2 years; P < .01). CONCLUSIONS: Percutaneous transcatheter embolization had the advantage in composite complications and shorter postoperative length of stay compared with surgery, but surgery had higher curability than percutaneous transcatheter embolization. Surgery may be considered as a therapeutic option for patients with lesions that can be completely resected and are difficult to treat with percutaneous transcatheter embolization. PMID- 28629840 TI - Recapitulating nature's design: Myocardial repair with cell sheet technology. PMID- 28629841 TI - Circumflex artery injury during mitral valve repair: Not well known, perhaps not so infrequent-lessons learned from a 6-case experience. PMID- 28629842 TI - Indications for sublobar resection of clinical stage IA radiologic pure-solid lung adenocarcinoma. AB - OBJECTIVES: The aim of this study was to identify clinical factors associated with lepidic growth in resected clinical stage IA radiologic pure-solid lung adenocarcinoma for identifying a possible sublobar resection candidate in the population. METHODS: Clinicopathologic data were reviewed for 200 surgically resected clinical stage IA pure-solid lung adenocarcinomas. Radiologic pure-solid tumor was defined as a tumor without a ground-glass opacity component, that is, a consolidation tumor ratio equal to 1.0. Lepidic predominant adenocarcinoma included adenocarcinomas in situ, minimally invasive adenocarcinomas, and lepidic predominant invasive adenocarcinomas. RESULTS: A total of 57 patients (29%) had lepidic predominant adenocarcinoma. The 5-year overall survival of clinical stage IA pure-solid adenocarcinoma was 83.4% and that of lepidic predominant adenocarcinoma and nonlepidic predominant adenocarcinoma was 98.1% versus 76.6% (P = .0012). A multivariate analysis revealed that maximum standardized uptake value was an independently significant variable of lepidic predominant adenocarcinoma (P < .0001) and a significant prognostic factor (P = .034). The predictive criterion of lepidic predominant adenocarcinoma was maximum standardized uptake value 3.3 or less based on a receiver operating characteristic curve, and 77 patients (39%) who met this criterion showed less pathologic invasiveness regarding lymphatic (P = .0012) and vascular (P < .0001) invasions, nodal metastasis (P = .0007), and better overall survival than those who did not (maximum standardized uptake value <=3.3 vs >3.3 rates being 91.7% vs 78.6%, P = .0031). Moreover, the 3-year locoregional recurrence-free survival of the sublobar resection arm was significantly worse than that of the lobectomy arm when the tumor showed maximum standardized uptake value greater than 3.3 (62.7% vs 82.9%, P = .0281). CONCLUSIONS: Higher maximum standardized uptake value may be useful for identifying patients with clinical stage IA radiologic pure-solid lung adenocarcinoma in whom sublobar resection should not be considered, even if technically feasible. PMID- 28629843 TI - Implanting a mechanical valve in the pulmonary position: What's your bias? PMID- 28629844 TI - Circulating tumor DNA: Solid data from liquid biopsies. PMID- 28629845 TI - Role of primary motor cortex in the control of manual dexterity assessed via sequential bilateral lesion in the adult macaque monkey: A case study. AB - From a case study, we describe the impact of unilateral lesion of the hand area in the primary motor cortex (M1) on manual dexterity and the role of the intact contralesional M1 in long-term functional recovery. An adult macaque monkey performed two manual dexterity tasks: (i) "modified Brinkman board" task, assessed simple precision grip versus complex precision grip, the latter involved a hand postural adjustment; (ii) "modified Kluver board" task, assessed movements ranging from power grip to precision grip, pre-shaping and grasping. Two consecutive unilateral M1 lesions targeted the hand area of each hemisphere, the second lesion was performed after stable, though incomplete, functional recovery from the primary lesion. Following each lesion, the manual dexterity of the contralesional hand was affected in a comparable manner, effects being progressively more deleterious from power grip to simple and then complex precision grips. Both tasks yielded consistent data, namely that the secondary M1 lesion did not have a significant impact on the recovered performance from the primary M1 lesion, which took place 5months earlier. In conclusion, the intact contralesional M1 did not play a major role in the long-term functional recovery from a primary M1 lesion targeted to the hand area. PMID- 28629846 TI - Hippocampal GR- and CB1-mediated mGluR5 differentially produces susceptibility and resilience to acute and chronic mild stress in rats. AB - The molecular mechanism of individual response of susceptibility and resilience under psychological stress remains controversial and unclear. The present study aimed to explore the relationship of metabotropic glutamate receptor 5 (mGluR5) with glucocorticoid receptor (GR) or cannabinoid receptor (CB1) and further indicate the molecular mechanism of susceptibility and resilience to acute stress (AS) and chronic mild stress (CMS). Sucrose preference test and open field test were used to evaluate the response of susceptibility and resilience under stress in rats. The mRNA levels and protein expressions of mGluR5, GR, and CB1 were detected. AS induced a 35% reduction in the sucrose intake of rats, and these rats were considered as susceptible to stress; 21% of the rats showed resilience to the stress. Thirty-three percent of rats in the CMS group showed reduced sucrose water intake and were considered susceptible, while 20% of rats were considered resilient. Hippocampal mGluR5 mRNA and protein levels were increased in the susceptible rats. Pharmacological testing showed that GR was positively associated with mGluR5 in susceptible rats in the CMS group, while CB1 was negatively related to mGluR5 in susceptible rats in the AS group. The results suggested that GR and CB1 in the hippocampus might regulate mGluR5 protein and mRNA levels, which might be related to individual responses of susceptibility and resilience under AS and CMS. PMID- 28629848 TI - A novel intrinsic electroretinogram response in isolated mouse retina. AB - Since the discovery of intrinsic photosensitive retinal ganglion cell (ipRGC) was reported in 2002, many features specific to this cell type have been described. However, scare information is available on the retinographic components directly reflecting ipRGC activity. In this study, we identified the electroretinogram (microERG) that reflects the photoresponses by ipRGCs in ex vivo preparations of the mouse retina, in which classical photoreceptors (cones and rods) were ablated mechanically and photochemically. MicroERG consisted of three components: a large transient ON response, a small and lazy hump 19s after the onset of the light, and a large transient OFF response. A complete microERG recording required at least 30s of light exposure. MicroERG showed the highest spectral photosensitivity at 478nm. This wavelength corresponds to the peak wavelength in the ipRGCs' photosensitive curve. The psychophysical test using a blue light emitting diode (LED) light (470nm) revealed that the absolute threshold illuminance for microERG was greater than 12.26 log photons/s/cm2 in both ON and OFF responses, whereas microERG was not adapted for dark. The amplitude of microERG increased linearly with irradiance. The sensitivity of temporal frequency was high in microERG (at least 100Hz), as suggested by the study on melatonin suppression by flickering light in human subjects (Zelter et al., 2014). Melatonin secretion was suppressed by light via ipRGCs and the suprachiasmatic nucleus. These properties of the photoresponse indicate that microERG may reflect the functions of ipRGC as a luminance detector in the mouse retina. PMID- 28629849 TI - Analysis of archived newborn dried blood spots (DBS) identifies congenital cytomegalovirus as a major cause of unexplained pediatric sensorineural hearing loss. AB - PURPOSE: Congenital cytomegalovirus (cCMV) infection is the most common non genetic cause of sensorineural hearing loss (SNHL). However, accurate diagnosis of cCMV as the etiology of SNHL is problematic beyond the neonatal period. This study therefore examined whether cCMV infection could be identified retrospectively in children presenting with unexplained SNHL to a multidisciplinary diagnostic outpatient otolaryngology clinic at an academic medical center in Minnesota. METHODS: Over a 4-year period, 57 patients with an age range of 3months to 10years with unexplained SNHL were recruited to participate in this study. Informed consent was obtained to test the archived dried blood spots (DBS) of these patients for cCMV infection by real-time PCR, targeting a highly conserved region of the CMV UL83 gene. Results were normalized to recovery of an NRAS gene control. Chart review was conducted to identify subjects who underwent genetic testing and/or neurodiagnostic imaging to investigate possible genetic, syndromic, or anatomical causes of SNHL. RESULTS: In total, 15 of the 57 children with unexplained SNHL tested positive for CMV DNA in their DBS (26%). A mean viral load of 8.3*104 (+/-4.1*104) [range, 1*103 6*105] copies/MUg DNA was observed in subjects retrospectively diagnosed with cCMV. No statistically significant correlation was found between viral load and SNHL severity. CONCLUSIONS: A retrospective DBS analysis demonstrated that 26% of patients presenting with unexplained SNHL in childhood had cCMV. DBS testing is useful in the retrospective diagnosis of cCMV, and may provide definitive diagnostic information about the etiology of SNHL. PMID- 28629847 TI - Evidence for M2 muscarinic receptor modulation of axon terminals and dendrites in the rodent basolateral amygdala: An ultrastructural and electrophysiological analysis. AB - The basolateral amygdala receives a very dense cholinergic innervation from the basal forebrain that is important for memory consolidation. Although behavioral studies have shown that both M1 and M2 muscarinic receptors are critical for these mnemonic functions, there have been very few neuroanatomical and electrophysiological investigations of the localization and function of different types of muscarinic receptors in the amygdala. In the present study we investigated the subcellular localization of M2 muscarinic receptors (M2Rs) in the anterior basolateral nucleus (BLa) of the mouse, including the localization of M2Rs in parvalbumin (PV) immunoreactive interneurons, using double-labeling immunoelectron microscopy. Little if any M2R-immunoreactivity (M2R-ir) was observed in neuronal somata, but the neuropil was densely labeled. Ultrastructural analysis using a pre-embedding immunogold-silver technique (IGS) demonstrated M2R-ir in dendritic shafts, spines, and axon terminals forming asymmetrical (excitatory) or symmetrical (mostly inhibitory) synapses. In addition, about one-quarter of PV+ axon terminals and half of PV+ dendrites, localized using immunoperoxidase, were M2R+ when observed in single thin sections. In all M2R+ neuropilar structures, including those that were PV+, about one-quarter to two-thirds of M2R+ immunoparticles were plasma-membrane associated, depending on the structure. The expression of M2Rs in PV+ and PV negative terminals forming symmetrical synapses indicates M2R modulation of inhibitory transmission. Electrophysiological studies in mouse and rat brain slices, including paired recordings from interneurons and pyramidal projection neurons, demonstrated M2R-mediated suppression of GABA release. These findings suggest cell-type-specific functions of M2Rs and shed light on organizing principles of cholinergic modulation in the BLa. PMID- 28629850 TI - Function follows form: When electrophysiology derives from anatomy. PMID- 28629851 TI - Another piece of the puzzle: Assessment of mechanical dispersion by magnetic resonance in long QT syndrome. PMID- 28629852 TI - Bioelectronic block of paravertebral sympathetic nerves mitigates post-myocardial infarction ventricular arrhythmias. AB - BACKGROUND: Autonomic dysfunction contributes to induction of ventricular tachyarrhythmia (VT). OBJECTIVE: To determine the efficacy of charge-balanced direct current (CBDC), applied to the T1-T2 segment of the paravertebral sympathetic chain, on VT inducibility post-myocardial infarction (MI). METHODS: In a porcine model, CBDC was applied in acute animals (n = 7) to optimize stimulation parameters for sympathetic blockade and in chronic MI animals (n = 7) to evaluate the potential for VTs. Chronic MI was induced by microsphere embolization of the left anterior descending coronary artery. At termination, in anesthetized animals and following thoracotomy, an epicardial sock array was placed over both ventricles and a quadripolar carousel electrode positioned underlying the right T1-T2 paravertebral chain. In acute animals, the efficacy of CBDC carousel (CBDCC) block was assessed by evaluating cardiac function during T2 paravertebral ganglion stimulation with and without CBDCC. In chronic MI animals, VT inducibility was assessed by extrasystolic (S1-S2) stimulations at baseline and under >66% CBDCC blockade of T2-evoked sympathoexcitation. RESULTS: CBDCC demonstrated a current-dependent and reversible block without impacting basal cardiac function. VT was induced at baseline in all chronic MI animals. One animal died after baseline induction. Of the 6 remaining animals, only 1 was reinducible with simultaneous CBDCC application (P < .002 from baseline). The ventricular effective refractory period (VERP) was prolonged with CBDCC (323 +/- 26 ms) compared to baseline (271 +/- 32 ms) (P < .05). CONCLUSIONS: Axonal block of the T1-T2 paravertebral chain with CBDCC reduced VT in a chronic MI model. CBDCC prolonged VERP, without altering baseline cardiac function, resulting in improved electrical stability. PMID- 28629853 TI - From trailer parks to the human atria: The meandering path of rotors. PMID- 28629855 TI - CON4EI: Development of serious eye damage and eye irritation testing strategies with respect to the requirements of the UN GHS/EU CLP hazard categories. AB - The main objective of the CON4EI (CONsortium for in vitro Eye Irritation testing strategy) project (2015-2016) was to develop tiered, non-animal testing strategies for serious eye damage and eye irritation assessment in relation to the most important drivers of classification. The serious eye damage and eye irritation potential of a set of 80 chemicals was identified based on existing in vivo Draize eye test data and testing was conducted using the following eight alternative test methods: BCOP (Bovine Corneal Opacity and Permeability)+histopathology, BCOP-LLBO (BCOP Laser Light-Based Opacitometer), ICE (Isolated Chicken Eye)+histopathology, STE (Short Term Exposure), EpiOcularTM EIT (EpiOcular Eye Irritation Test), EpiOcularTM ET-50 (EpiOcularTM Time-to toxicity), SkinEthicTM HCE EIT (SkinEthicTM Human Corneal Epithelial Eye Irritation Test), and SMI (Slug Mucosal Irritation). Project management decided to not include the ICE data in this project since the execution showed relevant, and not predictable, deviations from Organisation for Economic Co-operation and Development (OECD) Test Guideline (TG) 438 and Guidance Document 160. At this stage, the outcome of these deviations has not been fully assessed. In addition to these alternative test methods, the computational models Toxtree and Case Ultra were taken into account. This project assessed the relevance of these test methods, their applicability domains and limitations in terms of 'drivers of classification', and their strengths and weaknesses. In this way, methods were identified that fit into a tiered-testing strategy for serious eye damage/eye irritation assessment to distinguish United Nations Globally Harmonized System of Classification and Labelling of Chemicals (UN GHS) Category 1 (Cat 1) chemicals from non-Cat 1 chemicals and address the gap namely distinguish between Category 2 (Cat 2) and Cat 1 chemicals. PMID- 28629854 TI - Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. AB - Cigarette smoke condensate (CSC) has previously been shown to impair activity and expression of hepatic drug transporters. In the present study, we provided evidence that CSC also hinders activity of organic anion transporters (OATs), notably expressed at the kidney level. CSC thus cis-inhibited OAT substrate uptake in OAT1- and OAT3-transfected HEK293 cells, in a concentration-dependent manner (IC50=72.1MUg/mL for OAT1 inhibition and IC50=27.3MUg/mL for OAT3 inhibition). By contrast, OAT4 as well as the renal organic cation transporter (OCT) 2 were less sensitive to the inhibitory effect of CSC (IC50=351.5MUg/mL and IC50=226.2MUg/mL, for inhibition of OAT4 and OCT2, respectively). OAT3 activity was further demonstrated to be blocked by some single chemicals present in cigarette smoke such as the heterocyclic amines AalphaC (IC50=11.3MUM) and PhIP (IC50=1.9MUM), whereas other major cigarette smoke components used at 100MUM, like nicotine, the nitrosamine NNK and the polycyclic aromatic hydrocarbons benzo(a)pyrene and phenanthrene, were without effect. AalphaC and PhIP however failed to trans-stimulate activity of OAT3, suggesting that they were not substrates for this transporter. Taken together, these data establish OAT1 and OAT3 transporters as targets of cigarette smoke chemicals, which may contribute to smoking-associated pharmacokinetics alterations. PMID- 28629856 TI - Ethnic differences in glucose effectiveness and disposition index in overweight/obese African American and white women with prediabetes: A study of compensatory mechanisms. AB - OBJECTIVE: Prediabetes, a major precursor of type 2 diabetes, varies among ethnic populations. Therefore, we compared the pathophysiologic mechanisms of prediabetes in overweight/obese African American (AA) and White American (WA) women. SUBJECTS AND METHODS: We recruited 95 women (67 AA, 28 WA) with prediabetes. Standard OGTT and FSIVGTT were performed in each subject. Insulin sensitivity (Si), glucose effectiveness (Sg), beta cell function (acute insulin response to glucose (AIRg) and disposition index (DI: Si*AIRg) were calculated using Bergman's Minmod. RESULTS: Mean BMI was greater in AA vs WA with prediabetes (38.3+/-8.2vs 34.6+/-8.5kg/m2, p=0.05). Mean fasting serum glucose, and insulin levels were lower in AA vs WA. Similarly, mean peak serum glucose levels were lower while peak insulin levels were higher at 30 and 60minutes in AA vs WA. In contrast, mean fasting and peak serum c-peptide levels at 60 and 90minutes were significantly lower in AA vs WA. Mean AIRg was higher but not significantly different in AA vs WA (633+/-520.92 vs 414.8+/-246.8, p=0.193). Although, Si (2.93+/-3.25vs 44 2.50+/-1.76 (*10-4*min-1 [MUU/ml]-1), p=0.448) was not different, DI was significantly higher in AA vs WA (1381+/-1126 vs 901.9+/ 477.1, p=0.01). In addition, mean Sg was significantly higher in AAvs WA (2.51+/ 1.17 vs 1.97+/-0.723 (*10-2/min), p=0.02). CONCLUSIONS: We found that in overweight/obese prediabetic AA and WA women with similar Si, the mean Sg and DI were significantly higher in AA. We conclude that the pathophysiologic mechanisms of prediabetes differ in the overweight/obese AA and WA women. PMID- 28629857 TI - Parents' Underestimations of Child Weight: Implications for Obesity Prevention. AB - PURPOSE: Obesity prevention efforts may be ineffective if parents lack awareness of their children's overweight status. This study examined the factors that predicted parents' underestimation of child weight status. DESIGN AND METHODS: Using a cross sectional design, researchers recruited children and parents in a local children's museum. Parents completed a demographic questionnaire, the Newest Vital Sign, and the Child Body Image Scale. Children's height and weight were measured to calculate child BMI. Random effects modeling examined the association between predictor variables (parent race/ethnicity, income, education, and health literacy, and child BMI percentile, gender, and age) and the dependent variable, parent underestimation of child weight status. RESULTS: Participants included 160 parents (213 children aged 7-12years) representing a racially and ethnically diverse sample who were affluent, educated, and with 36.6% of parents assessed with limited health literacy. Although 45.1% of children were overweight/obese, only 7.5% of parents chose this weight status; 80% of parents underestimated the weight of their normal weight children, 96% underestimated their overweight children, and 72% underestimated their obese children. Parents were more likely to underestimate weight of older children and those under 81st percentile of BMI. No other predictors were significant. CONCLUSIONS: Parent underestimation of child weight status appears to be a widespread phenomenon in this sample, regardless of race, ethnicity, income, education, and health literacy. PRACTICE IMPLICATIONS: The consistent underestimation of child weight suggests that parents' misperception of weight status represents a critical pathway for intervention. Methods to improve parents' perception of child weight need be developed and tested. PMID- 28629858 TI - Preparation, characterization and antioxidant activity of silk peptides grafted carboxymethyl chitosan. AB - Free radicals are closely related to the occurrence and development of aging, cancer and inflammation, the ability to scavenge free radicals is an important indicator of the antioxidant activity. In this study, we prepared a water soluble, free radical scavenging and biocompatible copolymer for regenerative therapy. Carboxymethyl chitosan (CMC) was modified with silk peptide (SP) by microbial transglutaminase (MTGase), FT-IR and NMR spectroscopy were used to confirm the successful grafting of SP to CMC. The degree of substitution was determined by ultraviolet spectrophotometry. In vitro antioxidant activity assays demonstrated that, within the scope of study the highest scavenging activity of DPPH was 24.86%, 91% of hydroxyl radical and 36.8% of H2O2. Finally, no relevant cytotoxicity against NIH-3T3 mouse fibroblasts was found for the copolymers. Briefly, our results suggested the potential application of CMC-SP as an antioxidant for regenerative therapy. PMID- 28629860 TI - Hydrogen-Deuterium exchange kinetics in beta-lactoglobulin (-)-epicatechin complexes studied by FTIR spectroscopy. AB - Hydrogen-Deuterium exchange kinetics of beta-lactoglobulin and beta-lactoglobulin (-)-epicatechin solutions has been investigated through the analysis of the amide I absorption band at 1650cm-1 in the FTIR spectrum. H-D substitution in NH amides and residues of the protein results in a slight red-shift and in intensity changes of the amide I components: either these effects have been inspected in the framework of the Principal Components Analysis methods. The present analysis allowed to unveil three H-D kinetics at the timescale of the oligomeric fluctuations of the protein. A fast mechanism (lifetime from 5 to 10min) can be ascribed to the dynamics of protein oligomers and aggregates at the scale of the quaternary structure variations, and it is not observed in the complexes beta lactoglobulin (-)-epicatechin. The other slowest kinetics, whose lifetimes are in the range 1-10h, are here associated to dynamics of high-molecular weight complexes that hamper the proton exchange. The role of (-)-epicatechin as an enhancer of the formation of stable high-molecular weight aggregates from beta lactoglobulin is also discussed by comparison of the lifetimes at different protein concentrations. PMID- 28629859 TI - S-adenosyl-L-homocysteine hydrolase from a hyperthermophile (Thermotoga maritima) is expressed in Escherichia coli in inactive form - Biochemical and structural studies. AB - Thermotoga maritima is a hyperthermophilic bacterium but its genome encodes a number of archaeal proteins including S-adenosyl-L-homocysteine hydrolase (SAHase), which regulates cellular methylation reactions. The question of proper folding and activity of proteins of extremophilic origin is an intriguing problem. When expressed in E.coli and purified (as a homotetramer) at room temperature, the hyperthermophilic SAHase from T.maritima was inactive. ITC study indicated that the protein undergoes heat-induced conformational changes, and enzymatic activity assays demonstrated that these changes are required to attain enzymatic activity. To explain the mechanism of thermal activation, two crystal structures of the inactive form of T. maritima SAHase (iTmSAHase) were determined for an incomplete binary complex with the reduced cofactor (NADH), and in a mixture of binary complexes with NADH and with adenosine. In contrast to active SAHases, in iTmSAHase only two of the four subunits contain a bound cofactor, predominantly in its non-reactive, reduced state. Moreover, the closed-like conformation of the cofactor-containing subunits precludes substrate delivery to the active site. The two other subunits cannot be involved in the enzymatic reaction either; although they have an open-like conformation, they do not contain the cofactor, whose binding site may be occupied by an adenosine molecule. The results suggest that this enzyme, when expressed in mesophilic cells, is arrested in the activity-incompatible conformation revealed by its crystal structures. PMID- 28629861 TI - Flavonoids determine the rate of fibrillogenesis and structure of collagen type I fibrils in vitro. AB - Collagen fibrils are produced from collagen monomers not only in vivo, but also in vitro. The ability to have an influence on the structure and properties of fibrils may find medical application and can be useful for controlling the formation of collagen gels and sheets in tissue engineering. Here we investigated the influence of flavonoids, distinguished by the number of hydroxyl groups in the B-ring, on the formation of collagen fibrils. A correlation was found between the number of hydroxyl groups, lipophilicity of molecules and their ability to influence the fibril formation. The molecules with a smaller number of hydroxyls (flavone and kaempferol) were more lipophilic and accelerated the formation of fibrils, whereas molecules with a larger number of hydroxyls (quercetin, myricetin) were more hydrophilic and prevented the fibril formation. Among the studied substances, an exception was taxifolin, which accelerated the formation of fibrils in spite of the increased hydrophilicity of this compound. However, molecular modeling revealed that all investigated accelerators of the fibril formation, including taxifolin, were distinguished by the increased lipophilicity exactly in the B-ring. This suggests a critical role of the B-ring lipophilicity in the ability of the studied flavonoids to accelerate the formation of collagen fibrils. PMID- 28629862 TI - Sustained delivery of BSA/HSA from biocompatible plant cellulose nanocrystals for in vitro cholesterol release from endothelial cells. AB - Nanocomposites of plant cellulose nanocrystals (CNCs) were developed by binding model proteins BSA and HSA onto CNCs by physical adsorption and chemical conjugation methods The spectroscopy and microscopy studies confirmed the protein binding onto CNCs. Phosphate buffer saline (pH=4.0, 7.4) and simulated gastric and intestinal fluids (SGF/SIF; pH=1.1/6.5) showed maximum protein release of ~62% over a period of time. The released proteins were found to retain both structural integrity as well as>=90% of bioactivity. Further, these cytocompatible nanocomposites showed ~58-85% cholesterol release from HUVEC whereas no selectivity was observed for HCAEC. It is speculated that due to the presence of combination of shuttles (albumins) and sinks (CNCs and albumins), these prepared nanocomposites with increased cholesterol effluxing ability may serve as a potential candidate for future biomedical applications in pharmaceuticals. PMID- 28629863 TI - The unfolding mechanism of monomeric mutant SOD1 by simulated force spectroscopy. AB - Mechanical unfolding of mutated apo, disulfide-reduced, monomeric superoxide dismutase 1 protein (SOD1) has been simulated via force spectroscopy techniques, using both an all-atom (AA), explicit solvent model and a coarse-grained heavy atom Go (HA-Go) model. The HA-Go model was implemented at two different pulling speeds for comparison. The most-common sequence of unfolding in the AA model agrees well with the most-common unfolding sequence of the HA-Go model, when the same normalized pulling rate was used. Clustering of partially-native structures as the protein unfolds shows that the AA and HA-Go models both exhibit a dominant pathway for early unfolding, which eventually bifurcates repeatedly to multiple branches after the protein is about half-unfolded. The force-extension curve exhibits multiple force drops, which are concomitant with jumps in the local interaction potential energy between specific beta-strands in the protein. These sudden jumps in the potential energy coincide with the dissociation of specific pairs of beta-strands, and thus intermediate unfolding events. The most common sequence of beta-strand dissociation in the unfolding pathway of the AA model is beta-strands 5, 4, 8, 7, 1, 2, then finally beta-strands 3 and 6. The observation that beta-strand 5 is among the first to unfold here, but the last to unfold in simulations of loop-truncated SOD1, could imply the existence of an evolutionary compensation mechanism, which would stabilize beta-strands flanking long loops against their entropic penalty by strengthening intramolecular interactions. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28629865 TI - Editorial Commentary: Coronary artery calcification on non-cardiac chest CT: Incidental but impactful. PMID- 28629866 TI - Distributed reconfigurable control strategies for switching topology networked multi-agent systems. AB - In this paper, distributed control reconfiguration strategies for directed switching topology networked multi-agent systems are developed and investigated. The proposed control strategies are invoked when the agents are subject to actuator faults and while the available fault detection and isolation (FDI) modules provide inaccurate and unreliable information on the estimation of faults severities. Our proposed strategies will ensure that the agents reach a consensus while an upper bound on the team performance index is ensured and satisfied. Three types of actuator faults are considered, namely: the loss of effectiveness fault, the outage fault, and the stuck fault. By utilizing quadratic and convex hull (composite) Lyapunov functions, two cooperative and distributed recovery strategies are designed and provided to select the gains of the proposed control laws such that the team objectives are guaranteed. Our proposed reconfigurable control laws are applied to a team of autonomous underwater vehicles (AUVs) under directed switching topologies and subject to simultaneous actuator faults. Simulation results demonstrate the effectiveness of our proposed distributed reconfiguration control laws in compensating for the effects of sudden actuator faults and subject to fault diagnosis module uncertainties and unreliabilities. PMID- 28629864 TI - Structure-function relationships in human d-aspartate oxidase: characterisation of variants corresponding to known single nucleotide polymorphisms. AB - d-Aspartate oxidase (DDO) is a degradative enzyme that is stereospecific for the acidic amino acid d-aspartate, an endogenous agonist of the N-methyl-d-aspartate (NMDA) receptor. Dysregulation of NMDA receptor-mediated neurotransmission has been implicated in the onset of various neuropsychiatric disorders including schizophrenia and in chronic pain. Thus, appropriate regulation of the amount of d-aspartate is believed to be important for maintaining proper neural activity in the nervous system. Herein, the effects of the non-synonymous single nucleotide polymorphisms (SNPs) R216Q and S308N on several properties of human DDO were examined. Analysis of the purified recombinant enzyme showed that the R216Q and S308N substitutions reduce enzyme activity towards acidic d-amino acids, decrease the binding affinity for the coenzyme flavin adenine dinucleotide and decrease the temperature stability. Consistent with these findings, further experiments using cultured mammalian cells revealed elevated d-aspartate in cultures of R216Q and S308N cells compared with cells expressing wild-type DDO. Furthermore, accumulation of several amino acids other than d-aspartate also differed between these cultures. Thus, expression of DDO genes carrying the R216Q or S308N SNP substitutions may increase the d-aspartate content in humans and alter homeostasis of several other amino acids. This work may aid in understanding the correlation between DDO activity and the risk of onset of NMDA receptor-related diseases. PMID- 28629867 TI - Culture shapes nursing practice: Findings from a New Zealand study. AB - OBJECTIVES: This paper reports research undertaken to investigate nurses' and parents' experiences of communication about parental emotions in a hospital setting, with a focus on the environmental and cultural context within which the communication occurs. METHODS: A focused ethnography was employed as the aims were to understand the context within which nurse-parent interaction takes place, by exploring cultural factors, such as ways of living affecting nursing communication. Data collection occurred in a children's unit of a New Zealand hospital, involving 260h of participant observation field work, informal interviews with parents and nurses, followed by 20 formal interviews with nurses and parents. RESULTS: Nurses are cultural brokers, with the potential to be a link between the insider culture, the hospital and the outside, the parents. Parents look to nurses for cultural brokerage, to help them cross the strong cultural boundaries present in a hospital unit. CONCLUSION: The context and culture of a hospital unit influences nurse-parent communication. There is a disconnection between parents' emotional needs in hospital and nurses' ability to meet those needs. PRACTICE IMPLICATIONS: Nurses must be supported to provide effective cultural brokerage for parents. Unit managers need to acknowledge that meeting parents' diverse needs is vital. PMID- 28629868 TI - Reply about letter regarding "Prevalence of graduated compression stocking associated pressure injuries in surgical intensive care units". PMID- 28629869 TI - Evaluation of cell wall damage by dimethyl sulfoxide in Candida species. AB - Studies dealing with the response of microorganisms to oxidative stress require the dissolution of oxidant agents in an appropriate solvent. A commonly used medium is dimethyl sulfoxide, which has been considered as an innocuous polar solvent. However, we have observed significant differences between control, untreated cells and those receiving increasing amounts of the oxidant and hence increasing amounts of DMSO, to the maximum allowed of 1%. Here we show that, while this solvent does not influence yeast cell viability, it does affect expression of cell wall proteins as well as catalase activity. Therefore, its use in future studies of oxidative stress as an innocuous solvent should be reconsidered. PMID- 28629870 TI - Tumor-Stroma Ratio is an independent predictor for overall survival and disease free survival in gastric cancer patients. AB - BACKGROUND: Despite different prognostic factors have been already studied, patients undergoing potentially curative resection for gastric cancer, still have a poor outcome. There is therefore the need to identify novel prognostic factors. Recently, Tumor-Stroma Ratio (TSR) was proven to be associated with prognosis in different types of cancers. Aim of this study was to evaluate the prognostic value of TSR in gastric cancer patients. METHODS: 106 patients underwent gastrectomy between January 2004 and December 2015. Demographics and histopathological characteristics were collected. We considered a 50% TSR cutoff value to divide patients in Stroma-Rich (>=50%) and Stroma-Poor (<50%) groups. RESULTS: Forty-one (38.7%) patients were classified as Stroma-Poor while 65 (61.3%) as Stroma-Rich (61.3%). The Stroma-Rich patients had a higher number of positive lymph-nodes, lymph node ratio (LNR), a higher percentage of T3/T4 local invasion and N2/N3, and a more advanced TNM. Moreover, these patients showed a higher percentage of lymphovascular and perineural invasion. With a median FU of 38 months Stroma-Rich patients had a significantly worse 5-years actuarial overall survival (OS) and disease free survival (DFS) compared to Stroma-Poor patients. Moreover, the multivariate analysis showed that Stroma-Rich was the only independent factor associated with OS and DFS together with TNM-Stage. CONCLUSIONS: TSR is an independent marker of poor prognosis in patients with gastric cancer that should be readily incorporated into routine clinical pathology reporting. Identification of sensitive markers for patients who had undergone curative gastrectomy and who are at high risk of recurrence could provide useful information for planning follow-up after surgery or intensive and or/targeting adjuvant chemotherapy. PMID- 28629871 TI - A review of patterns of practice and clinical guidelines in the palliative radiation treatment of uncomplicated bone metastases. AB - BACKGROUND AND PURPOSE: Single fraction radiation treatment (SFRT) is recommended for its equivalence to multiple-fraction (MF) RT in the palliation of uncomplicated bone metastases (BM). However, adoption of SFRT has been slow. MATERIALS AND METHODS: Literature searches for studies published following 2014 were conducted using online repositories of gray literature, Ovid MEDLINE, Embase and Embase Classic, and the Cochrane Central Register of Controlled Trials databases. RESULTS: A total of 32 articles detailing patterns of practice and clinical practice guidelines were included for final synthesis. The majority of organizations have released high level recommendations for SFRT use in treatment of uncomplicated BM, based on evidence of non-inferiority to MFRT. There are key differences between guidelines, such as varying strengths of recommendation for SFRT use over MFRT; contraindication in vertebral sites for SFRT; and risk estimation of pathologic fractures after SFRT. Differences in guidelines may be influenced by committee composition and organization mandate. Differences in patterns of practice may be influenced by individual center policies, payment modalities and consideration of patient factors such as age, prognosis, and performance status. CONCLUSION: Although there is some variation between groups, the majority of guidelines recommend use of SFRT and others consider it to be a reasonable alternative to MFRT. PMID- 28629872 TI - Sevoflurane Relieves Lung Function Deterioration After Cardiopulmonary Bypass. AB - OBJECTIVE: To investigate sevoflurane's potential to alleviate the detrimental pulmonary changes after cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized clinical investigation. SETTING: University hospital. PARTICIPANTS: One hundred ninety patients undergoing elective cardiac surgery. INTERVENTIONS: Ninety-nine patients under intravenous anesthesia were administered 1 minimal alveolar concentration of sevoflurane for 5 minutes after being weaned from CPB (group SEV); intravenous anesthesia was maintained in the other 91 patients (group CTRL). MEASUREMENTS AND MAIN RESULTS: Measurements were performed with open chest: before CPB, after CPB, and after intervention. The lungs' mechanical impedance and capnogram traces were recorded, arterial and central venous blood samples were analyzed, and lung compliance was documented. Airway resistance, tissue damping, and elastance were obtained from the impedance spectra. The capnogram phase III slope was determined using linear regression. The partial pressure of oxygen in the arterial blood/fraction of inspired oxygen ratio and shunt fraction were calculated from blood gas parameters. After CPB, sevoflurane induced bronchodilation, reflected in marked drops in airway resistance and smaller improvements in lung tissue viscoelasticity indicated by decreases in tissue damping and elastance. These changes were reflected in a decreased capnogram phase III slope and shunt fraction and increased partial pressure of oxygen in the arterial blood/fraction of inspired oxygen ratio and lung compliance. The more severe deteriorations that occurred after CPB, the greater improvements by sevoflurane were observed. CONCLUSIONS: Sevoflurane can alleviate CPB-induced bronchoconstriction, compromised lung tissue mechanics, and enhanced intrapulmonary shunt. This benefit has particular importance in patients with severe CPB-induced lung function deterioration. PMID- 28629873 TI - On the ethics of not supplementing low 25-hydroxyvitamin D levels in a controlled study in relapsing remitting multiple sclerosis. PMID- 28629874 TI - Neural activity during attentional conflict predicts reduction in tinnitus perception following rTMS. AB - BACKGROUND: Subjective idiopathic tinnitus is an intrusive, distracting, and potentially disabling disorder characterized by phantom perception of sounds. Although tinnitus has no approved pharmacologic treatment, recent evidence supports the use of repetitive transcranial magnetic stimulation (rTMS) to alleviate tinnitus symptoms. OBJECTIVE/HYPOTHESIS: Repetitive TMS delivered over the middle superior temporal gyrus (STG) may alter ratings of tinnitus awareness and annoyance more than loudness due to change in attentional processing. STG has reciprocal connections to regions of the prefrontal cortex that mediate attention. To probe the hypothesized influence of STG stimulation on attention, a subset of patients with tinnitus enrolled in an rTMS clinical trial [n = 12, 9 male, mean (sd) age = 49 (15) years] underwent an attentional conflict task before and after rTMS treatment in a repeated-measures functional magnetic resonance imaging (fMRI) study. METHODS: The Multi-Source Interference Task (MSIT), a Stroop-based visual attentional conflict fMRI task, was used to map participants' neural processing of attentional conflict prior to rTMS intervention (Baseline) and after three rTMS intervention arms: Sham, 1 Hz, and 10 Hz (four sessions per arm, 1800 pulses per session, delivered @110% of the motor threshold over the posterior superior temporal gyrus). RESULTS: All measures of tinnitus severity (awareness, loudness, and annoyance) improved with 1 Hz rTMS intervention; however, the greatest and most robust changes were observed for ratings of tinnitus awareness (mean 16% reduction in severity from Baseline, p < 0.01). The MSIT elicited a similar pattern of neural activation among tinnitus participants at Baseline compared to an independent sample of 43 healthy comparison adults (r = 0.801, p = 0.001). Linear regression with bootstrap resampling showed that greater recruitment of bilateral prefrontal and bilateral parietal regions by MSIT at Baseline corresponded with poorer treatment response. Individual regions' activities explained 37-67% variance in participant treatment response, with left dorsolateral prefrontal cortex's MSIT activity at Baseline explaining the greatest reduction in tinnitus awareness following 1 Hz stimulation. Although left dorsolateral prefrontal cortex activity at Baseline also predicted reduction in tinnitus loudness and annoyance (~50% variance explained), these symptoms were more strongly predicted by right middle occipital cortex (~70% variance explained) - suggesting that the neural predictors of symptom-specific treatment outcomes may be dissociable. CONCLUSION: These candidate neural reactivity markers of treatment response have potential clinical value in identifying tinnitus sufferers who would or would not therapeutically benefit from rTMS intervention. PMID- 28629875 TI - Antibiotic stewardship hits a home run for patients. PMID- 28629876 TI - Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. AB - BACKGROUND: Antibiotic stewardship programmes have been shown to reduce antibiotic use and hospital costs. We aimed to evaluate evidence of the effect of antibiotic stewardship on the incidence of infections and colonisation with antibiotic-resistant bacteria. METHODS: For this systematic review and meta analysis, we searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science for studies published from Jan 1, 1960, to May 31, 2016, that analysed the effect of antibiotic stewardship programmes on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infections in hospital inpatients. Two authors independently assessed the eligibility of trials and extracted data. Studies involving long-term care facilities were excluded. The main outcomes were incidence ratios (IRs) of target infections and colonisation per 1000 patient-days before and after implementation of antibiotic stewardship. Meta-analyses were done with random-effect models and heterogeneity was calculated with the I2 method. FINDINGS: We included 32 studies in the meta analysis, comprising 9 056 241 patient-days and 159 estimates of IRs. Antibiotic stewardship programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria (51% reduction; IR 0.49, 95% CI 0.35 0.68; p<0.0001), extended-spectrum beta-lactamase-producing Gram-negative bacteria (48%; 0.52, 0.27-0.98; p=0.0428), and meticillin-resistant Staphylococcus aureus (37%; 0.63, 0.45-0.88; p=0.0065), as well as the incidence of C difficile infections (32%; 0.68, 0.53-0.88; p=0.0029). Antibiotic stewardship programmes were more effective when implemented with infection control measures (IR 0.69, 0.54-0.88; p=0.0030), especially hand-hygiene interventions (0.34, 0.21-0.54; p<0.0001), than when implemented alone. Antibiotic stewardship did not affect the IRs of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant Gram-negative bacteria. Significant heterogeneity between studies was detected, which was partly explained by the type of interventions and co-resistance patterns of the target bacteria. INTERPRETATION: Antibiotic stewardship programmes significantly reduce the incidence of infections and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. These results provide stakeholders and policy makers with evidence for implementation of antibiotic stewardship interventions to reduce the burden of infections from antibiotic resistant bacteria. FUNDING: German Center for Infection Research. PMID- 28629877 TI - The effect of a genetic variant on quantitative real-time PCR in a case of disseminated adenovirus infection. AB - A patient developed disseminated adenovirus infection following bone marrow transplant. TaqMan real-time PCR showed reduced maximum fluorescence in the amplification curve from all plasma samples. Sequencing revealed three single nucleotide mismatches between the TaqMan probe and probe binding region. Real time PCR with probe matching the isolate sequence showed normal amplification and a higher copy number result. PMID- 28629878 TI - Campylobacter bacteremia in London: A 44-year single-center study. AB - PURPOSE: Campylobacter species are a well-recognized but rare cause of bloodstream infection. METHODS: Here we reviewed 41 cases of Campylobacter bloodstream infection occurring at a single center in London over 44years, comprising 0.2% of all recorded episodes during this time period. RESULTS: Patients had a mean age of 46years and, contrasting with previous reports, nearly 50% of our patients did not have significant comorbidities. Ciprofloxacin resistance increased over the study period with 35% of isolates overall being resistant compared with only 3% exhibiting macrolide resistance. Despite a minority of patients receiving appropriate empirical antibiotic therapy, overall mortality was only 7%. CONCLUSION: Campylobacter bacteremia remains a rare but significant cause of morbidity with a low associated mortality. Underlying immunosuppressive conditions are common but by no means universal. In our setting, macrolides would be favored as empirical agents to treat suspected Campylobacter enteritis, including cases with associated bacteremia. PMID- 28629880 TI - A new tool to identify patients with Parkinson's disease at increased risk of dementia. PMID- 28629881 TI - Cell-mediated immune response of postmetamorphic sea urchin juveniles against infectious stages of diatom Cylindrotheca closterium (Bacillariophyceae). AB - In this study, successive infectious stages by diatom Cylindrotheca closterium (Bacillariophyceae) are described for the first time during the early development of sea urchin at low temperature (8 degrees C). Diatom cell-types enclosed or not by typical theca were capable of infection. As an immune response, red spherulocytes and amoebocytes migrated towards infested areas and restrained the infection spreading over shells in 2- and 3-month old urchins. Only amoebocyte cells appeared to be involved in the immune reaction of 1-month old specimens which turned out to be a less effective fence to stop infestation. The effectiveness of the inflammatory process caused by diatoms within sea urchin spines seemed to vary as a function of urchin age, cohort's type and individual cell pool. PMID- 28629882 TI - Quantification of fungal growth and destruxin A during infection of Galleria mellonella larvae by Metarhizium brunneum. AB - Destruxin A is among the major secondary metabolites produced by the entomopathogenic ascomycete Metarhizium sp., and the lack of studies concerning production of destruxin A by the fungus is most likely the biggest obstacle for the registration of new fungal strains. Although several studies focus on the production of destruxin A in culture media, few studies examine destruxin A in vivo during host infection. In the current work, Galleria mellonella was used as an insect model to develop for the first time in vivo real-time PCR- and HPLC-MS based quantification of fungal growth and metabolite production, respectively, during infection by two strains of M. brunneum. Total mortality of sixth instar G. mellonella larvae that were immersed in a suspension of 1.0*108conidiamL-1 of M. brunneum EAMa 01/58-Su or BIPESCO5 strains reached 85.5% and 78.8%, respectively, and the percentage of cadavers with fungal outgrowth was low at 12.2% and 4.4%, respectively. The average survival time of treated larvae was 5.5days for both fungal strains. Using EAMa 01/58-Su and BIPESCO5 specific primer set, real-time PCR showed that the patterns of fungal growth were different for the two strains, whereas no significant differences were detected in the number of fungal sequence copies recovered from the infected larvae. EAMa 01/58-Su and BIPESCO5 strains secreted destruxin A from days 2 to 6 and from days 2 to 5 post treatment, respectively. For EAMa 01/58-Su and BIPESCO5, the maximum titer of destruxin A in the host was on day 4 at 0.369 and 0.06ug/larva, respectively, and throughout the pathogenic process, the total production was 0.6 and 0.09ug/larva, respectively. These results demonstrated that the strains pose a low hazard, if any, to humans and the environment. The methods used in this study to quantify fungal growth and metabolite production provided valuable data to better understand the role of destruxin A during the growth of M. brunneum in the host larvae and to monitor the fate of destruxin A in food chains. PMID- 28629883 TI - Laboratory evaluation of the effect of Beauveria bassiana on the predatory mite Phytoseiulus persimilis (Acari: Phytoseiidae). AB - Tetranychus urticae Koch (Acari: Tetranychidae), a major pest of many agricultural crops, is mainly controlled with chemical acaricides. However, predatory mites and entomopathogens have been proposed as alternative control agents. In this study, the effect of the BotaniGard(r) GHA strain of Beauveria bassiana on the survival, longevity, fecundity, and egg hatch rate of the predatory mite Phytoseiulus persimilis Athias-Henriot (Acari: Phytoseiidae) were studied under laboratory conditions. When B. bassiana was applied directly to P. persimilis eggs at a concentration of 1*108conidia/ml, corrected hatchability was less than 5%, and the corrected mortality of nymphs and adults was not significantly different from control 10days after treatment. Phytoseiulus persimilis nymphs that hatched from treated eggs showed no significant change in their development time, adult female longevity, hatch rate, survival rates over time, or offspring sex ratio. However, significant negative effects on fecundity and life table parameters (net reproductive rate, intrinsic rate of natural increase, mean generation time, finite rate of increase, and doubling time) were found when B. bassiana was applied to the adult stage. Spraying B. bassiana at 1*108conidia/ml on newly emerged adults of P. persimilis caused 44% reduction in the oviposition period, 26% in adult longevity, and 63% in fecundity. Due to these negative effects, B. bassiana should be used with careful adjustment of application timing (first spray B. bassiana and then release P. persimilis) to supplement biological mite control systems using P. persimilis. PMID- 28629884 TI - [Evaluation of mortality after the analysis of the screening history in women diagnosed with infiltrating cervical cancer]. AB - OBJECTIVE: To assess the impact of screening history on the incidence of cervical cancer from 2000 to 2010 in Asturias. DESIGN: Retrospective study. LOCATION: All public hospitals in Asturias. MEAN MEASUREMENTS: From 374 women diagnosed with cervical cancer were retrieved. Clinical information, FIGO stage and all previous cytological data were extracted from clinical and histopathological records. Proportional differences were assessed using chi-square tests. Logistic regression analysis was used to estimate odds ratios and 95% confidence intervals. RESULTS: Women between 25 and 70years had no records of a previous cytology within 5.5years of cancer diagnosis in 65.6%. This proportion was related with older age, presence of symptoms and an advance tumor stage at diagnosis. Women over 70years old had no records of a previous cytology in 83.3%. CONCLUSION: An organized cervical cancer screening program and optimal quality of the system, monitored through audits, could help to reduce cervical cancer incidence and mortality in Asturias. PMID- 28629885 TI - [Prevalence of osteoporosis, estimation of probability of fracture and bone metabolism study in patients with newly diagnosed prostate cancer in the health area of Lugo]. AB - OBJECTIVE: To study the prevalence of osteoporosis and fracture probability in patients diagnosed with prostate cancer. DESIGN: Observational descriptive transversal study. SITE: Study performed from Primary Care of Lugo in collaboration with Rheumatology and Urology Services of our referral hospital. PARTICIPANTS: Patients diagnosed with prostate cancer without bone metastatic disease from January to December 2012. MAIN MEASUREMENTS: Epidemiologic, clinical, laboratory and densitometric variables involved in osteoporosis were collected. The likelihood of fracture was estimated by FRAX(r) Tool. RESULTS: Eighty-three patients met the inclusion criteria. None was excluded. The average age was 67 years. The Body Mass Index was 28.28. Twenty-five patients (30.1%) had previous osteoporotic fractures. Other prevalent risk factors were alcohol (26.5%) and smoking (22.9%). Eighty-two subjects had vitamin D below normal level (98.80%). Femoral Neck densitometry showed that 8.9% had osteoporosis and 54% osteopenia. The average fracture risk in this population, estimated by FRAX(r), was 2.63% for hip fracture and 5.28% for major fracture. Cut level for FRAX(r) major fracture value without DXA >5% and >=7.5% proposed by Azagra et al. showed 24 patients (28.92%) and 8 patients (9.64%) respectively. CONCLUSIONS: The prevalence of osteoporosis in this population was very high. The more frequent risk factors associated with osteoporosis were: previous osteoporotic fracture, alcohol consumption, smoking and family history of previous fracture. The probability of fracture using femoral neck FRAX(r) tool was low. Vitamin D deficiency was very common (98.8%). PMID- 28629879 TI - Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts. AB - BACKGROUND: Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. METHODS: In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] <=25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population. FINDINGS: 3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE <=25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12.8 years (median 2.8, IQR 1.6-4.6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and beta-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8.6 years (median 6.5, IQR 4.1-7.2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0.85 in both the discovery (95% CI 0.82-0.90) and replication (95% CI 0.78-0.91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18.4 [95% CI 9.4-36.1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0.88 (95% CI 0.79-0.94) and a negative predictive value of 0.92 (95% 0.88-0.95) at the predefined cutoff of 0.196. Performance was stable in 10 000 randomly resampled subsets. INTERPRETATION: Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis. FUNDING: National Institutes of Health, US Department of Defense. PMID- 28629886 TI - [Evaluation of the effectiveness of a Mindfulness and Self-Compassion program to reduce stress and prevent burnout in Primary Care health professionals]. AB - OBJECTIVE: To evaluate the effectiveness of a Mindfulness and Self-Compassion Program on the levels of stress and burnout in Primary Care health professionals. DESIGN: Randomised, controlled clinical trial. PARTICIPANTS AND SETTING: Training in Mindfulness was offered to 1,281 health professionals in Navarra (Spain) Primary Care, and 48 of them accepted. The participants were randomly assigned to groups: 25 to the intervention group, and the remaining 23 to the control group. INTERVENTION: The Mindfulness and Self-Compassion training program consisted of sessions of 2.5chours/week for 8 weeks. The participants had to attend at least 75% of the sessions and perform a daily practical of 45minutes. MAIN MEASUREMENTS: The levels of mindfulness, self-compassion, perceived stress, and burnout were measured using four questionnaires before and after the intervention. RESULTS: After the intervention, the scores of the intervention group improved significantly in mindfulness (P<.001); perceived stress (P<.001); self-compassion: self-kindness P<.001, shared humanity P=.004, mindfulness P=.001; and burnout: emotional fatigue (P=.046). The comparison with the control group showed significant differences in mindfulness (P<.001), perceived stress (P<.001), self-kindness (P<.001) and emotional fatigue (P=.032). CONCLUSIONS: This work suggests that it may be beneficial to encourage mindfulness and self compassion practices in the health environment. PMID- 28629887 TI - [Early diagnosis of HIV in Primary Care in Spain. Results of a pilot study based on targeted screening based on indicator conditions, behavioral criteria and region of origin]. AB - OBJECTIVES: To estimate the prevalence of HIV infection in patients diagnosed with an indicator condition (IC) for HIV and/or risk behavior for their acquisition and/or coming from high prevalence countries. To determine the acceptability and feasibility of offering HIV testing based on IC and behavioral and origin criteria in Primary Care (PC). DESIGN: Cross-sectional study in a convenience sample. LOCATION: Six PC centers in Spain. PARTICIPANTS: The inclusion criteria were: patients between 16 and 65years old who presented at least one of the proposed ICs and/or at least one of the proposed behavioral and/or origin criteria. A total of 388 patients participated. INTERVENTION: HIV serology was offered to all patients who met the inclusion criteria. MAIN MEASUREMENTS: Description of IC frequency, behavioral and origin criteria. Prevalence of HIV infection. Level of acceptability and feasibility of the HIV screening based on IC and behavioral and origin criteria. RESULTS: A total of 174 patients had an IC (44.84%). The most common behavioral criterion was: having unprotected sex at some time in life with people who did not know their HIV status (298; 76.8%). Four HIV+ patients (1.03%) were diagnosed. All had an IC and were men who had sex with men. The level of acceptability in PC was high. CONCLUSIONS: Offering HIV testing to patients with IC and behavioral criteria is feasible and effective in PC. PMID- 28629888 TI - Development of novel behavioral interventions in an experimental therapeutics world: Challenges, and directions for the future. AB - Recently, the focus of funding mechanisms associated with clinical trials has changed to be consistent with an experimental therapeutics approach. While this approach holds considerable promise, the paradigm shift has presented challenges for behavioral trials in complex psychiatric illness such as schizophrenia, as molecular targets - the classic focus in experimental therapeutics paradigms - may not represent logical targets for many psychosocial interventions designed to treat multifaceted, multiply determined symptoms. Clear guidelines for alternate models have not been offered, leaving large numbers of clinical trials researchers unclear about how to frame their work. We address some of the challenges for behavioral interventions research, and offer guidance for the development of novel approaches to the application of a target engagement framework to behavioral clinical trials. PMID- 28629889 TI - Comparison of the effectiveness of brand-name and generic antipsychotic drugs for treating patients with schizophrenia in Taiwan. AB - The purpose of this nationwide population-based study is to compare the long-term effectiveness of brand-name antipsychotics with generic antipsychotics for treating schizophrenia. We identified patients with schizophrenia who were prescribed antipsychotics from a random sample of one million records from Taiwan's National Health Insurance database, observed between January 1, 2000 and December 31, 2012. Only those with no prior use of antipsychotics for at least 180days were included. We selected patients who were prescribed brand-name risperidone (N=404), generic risperidone (N=145), brand-name sulpiride (N=334), or generic sulpiride (N=991). The effectiveness of the treatments researched in this study consisted of average daily doses, rates of treatment discontinuation, augmentation therapy, and psychiatric hospitalization. We found that compared to patients treated with generic risperidone, those treated with brand-name risperidone required lower daily doses (2.14mg vs. 2.61mg). However, the two groups demonstrated similar rates of treatment discontinuation, augmentation, and psychiatric hospitalization. On the other hand, in comparison with patients prescribed generic sulpiride, those treated with brand-name sulpiride not only required lower daily doses (302.72mg vs. 340.71mg) but also had lower psychiatric admission rates (adjusted hazard ratio: 0.24, 95% confidence interval: 0.10 0.56). In conclusion, for both risperidone and sulpiride, higher daily doses of the respective generic drugs were prescribed than with brand-name drugs in clinical settings. Furthermore, the brand-name sulpiride is more effective at preventing patients from hospitalization than generic sulpiride. These findings can serve as an important reference for clinical practices and healthcare economics for treating schizophrenic patients. PMID- 28629890 TI - Perceived social stress and symptom severity among help-seeking adolescents with versus without clinical high-risk for psychosis. AB - Research suggests that social stress exposure influences illness presentation and course among youth at clinical high-risk (CHR) for psychosis, though less is known about the extent to which self-reported perceptions of social stress relate to the severity of positive symptoms. Importantly, despite the notion that youth at CHR are especially susceptible to elevations in positive symptoms under conditions of stress, no study has examined this presumption relative to other psychiatric groups. Extending previous work demonstrating that perceived social stress was higher in a CHR group than in a clinical group of non-CHR, help seeking controls, the current study aimed to: (1) examine whether perceived social stress is related to the severity of attenuated positive symptoms in the full sample (N=110); and (2) determine whether CHR status moderates the stress symptom relation. Exploratory analyses examined relations of perceived social stress to negative, disorganized, and general symptoms. Greater perceptions of social stress were associated with more severe positive symptoms in the entire sample; however, although positive symptoms and perceived social stress were higher in the CHR group, the strength of this relation was statistically indistinguishable across groups. No differential effect of perceived social stress was observed for any symptom domain. Results provide some support for the diathesis-stress model of psychosis, while also suggesting that social stress and symptomatology are related independent of clinical vulnerability to psychosis. Future research would benefit from longitudinal studies of stress-symptom relations across CHR and help-seeking control groups. PMID- 28629891 TI - A New Clinical Pain Knowledge Test for Nurses: Development and Psychometric Evaluation. AB - All nurses care for patients with pain, and pain management knowledge and attitude surveys for nurses have been around since 1987. However, no validated knowledge test exists to measure postlicensure clinicians' knowledge of the core competencies of pain management in current complex patient populations. To develop and test the psychometric properties of an instrument designed to measure pain management knowledge of postlicensure nurses. Psychometric instrument validation. Four large Midwestern U.S. hospitals. Registered nurses employed full time and part time August 2015 to April 2016, aged M = 43.25 years; time as RN, M = 16.13 years. Prospective survey design using e-mail to invite nurses to take an electronic multiple choice pain knowledge test. Content validity of initial 36 item test "very good" (95.1% agreement). Completed tests that met analysis criteria, N = 747. Mean initial test score, 69.4% correct (range 27.8-97.2). After revision/removal of 13 unacceptable questions, mean test score was 50.4% correct (range 8.7-82.6). Initial test item percent difficulty range was 15.2% 98.1%; discrimination values range, 0.03-0.50; final test item percent difficulty range, 17.6%-91.1%, discrimination values range, -0.04 to 1.04. Split-half reliability final test was 0.66. A high decision consistency reliability was identified, with test cut-score of 75%. The final 23-item Clinical Pain Knowledge Test has acceptable discrimination, difficulty, decision consistency, reliability, and validity in the general clinical inpatient nurse population. This instrument will be useful in assessing pain management knowledge of clinical nurses to determine gaps in education, evaluate knowledge after pain management education, and measure research outcomes. PMID- 28629892 TI - Engineered myocardium model to study the roles of HIF-1alpha and HIF1A-AS1 in paracrine-only signaling under pathological level oxidative stress. AB - : Studying heart tissue is critical for understanding and developing treatments for cardiovascular diseases. In this work, we fabricated precisely controlled and biomimetic engineered model tissues to study how cell-cell and cell-matrix interactions influence myocardial cell survival upon exposure to pathological level oxidative stress. Specifically, the interactions of endothelial cells (ECs) and cardiomyocytes (CMs), and the role of hypoxia inducible factor-1alpha (HIF 1alpha), with its novel alternative regulator, HIF-1alpha antisense RNA1 (HIF1A AS1), in these interactions were investigated. We encapsulated CMs in photo crosslinkable, biomimetic hydrogels with or without ECs, then exposed to oxidative stress followed by normoxia. With precisely controlled microenvironment provided by the model tissues, cell-cell interactions were restricted to be solely through the secreted factors. CM survival after oxidative stress was significantly improved, in the presence of ECs, when cells were in the model tissues that were functionalized with cell attachment motifs. Importantly, the cardioprotective effect of ECs was reduced when HIF-1alpha expression was knocked down suggesting that HIF-1alpha is involved in cardioprotection from oxidative damage, provided through secreted factors conferred by the ECs. Using model tissues, we showed that cell survival increased with increased cell-cell communication and enhanced cell-matrix interactions. In addition, whole genome transcriptome analysis showed, for the first time to our knowledge, a possible role for HIF1A-AS1 in oxidative regulation of HIF-1alpha. We showed that although HIF1A-AS1 knockdown helps CM survival, its effect is overridden by CM-EC bidirectional interactions as we showed that the conditioned media taken from the CM-EC co-cultures improved CM survival, regardless of HIF1A-AS1 expression. STATEMENT OF SIGNIFICANCE: Cardiovascular diseases, most of which are associated with oxidative stress, is the most common cause of death worldwide. Thus, understanding the molecular events as well as the role of intercellular communication under oxidative stress is upmost importance in its prevention. In this study we used 3D engineered tissue models to investigate the role of HIF 1alpha and its regulation in EC-mediated cardioprotection. We showed that EC mediated protection is only possible when there is a bidirectional crosstalk between ECs and CMs even without physical cell-cell contact. In addition, this protective effect is at least partially related to cell-ECM interactions and HIF 1alpha, which is regulated by HIF1A-AS1 under oxidative stress. PMID- 28629893 TI - A new NIR-triggered doxorubicin and photosensitizer indocyanine green co-delivery system for enhanced multidrug resistant cancer treatment through simultaneous chemo/photothermal/photodynamic therapy. AB - : It is a great challenge to combat multidrug resistant (MDR) cancer effectively. To address this issue, we developed a new near-infrared (NIR) triggered chemotherapeutic agent doxorubicin (DOX) and photosensitizer indocyanine green (ICG) co-release system by aid of NIR induced photothermal effect of gold nanocages (AuNCs) and temperature sensitive phase-change property of 1 tetradecanol at its melting point of 39 degrees C, which could simultaneously exerted chemo/photothermal/photodynamic treatment on MDR human breast cancer MCF 7/ADR cells. This nano-sized system was constructed by filling the interior of AuNCs with DOX, ICG and 1-tetradecanol, and modifying the surface with biotinylated poly (ethylene glycol) via Au-S bonds, termed as DOX/ICG@biotin-PEG AuNC-PCM. The DOX and ICG co-release from DOX/ICG@biotin-PEG-AuNC-PCM was much faster in PBS at 40 degrees C or under 808nm NIR irradiation at 2.5W/cm2 than at 37 degrees C (e.g. 67.27% or 80.31% vs. 5.57% of DOX, 76.08% vs. 3.83% of ICG for 20min). The flow cytometry and confocal laser scanning microscopy (CLSM) results showed, the AuNCs were taken up by MCF-7/ADR cells via endocytosis, thus enhancing DOX uptake; the biotin on AuNCs facilitated this endocytosis; NIR irradiation caused the heating of the AuNCs, triggering the DOX and ICG co release and enhancing the distribution of DOX in nuclei, the released ICG generated ROS to take photodynamic therapy. Due to the above unique properties, DOX/ICG@biotin-PEG-AuNC-PCM exerted excellent anti-tumor effects under NIR irradiation, its IC50 against MCF-7/ADR cells was very low, only 0.48ug/mL, much smaller than that of free DOX (74.51MUg/mL). STATEMENT OF SIGNIFICANCE: A new near-infrared (NIR) triggered chemotherapeutic agent doxorubicin (DOX) and photosensitizer indocyanine green (ICG) co-release system by aid of NIR induced photothermal effect of gold nanocages (AuNCs) and temperature sensitive phase change property of 1-tetradecanol at its melting point of 39 degrees C, was prepared, termed as DOX/ICG@biotin-PEG-AuNC-PCM, which could simultaneously exerted chemo/photothermal/photodynamic treatment on MDR human breast cancer MCF 7/ADR cells. DOX/ICG@biotin-PEG-AuNC-PCM exerted excellent anti-tumor effects under NIR irradiation, its IC50 against MCF-7/ADR cells was very low, only 0.48ug/mL, much smaller than that of free DOX (74.51MUg/mL). PMID- 28629894 TI - Enhanced nutrient transport improves the depth-dependent properties of tri layered engineered cartilage constructs with zonal co-culture of chondrocytes and MSCs. AB - : Biomimetic design in cartilage tissue engineering is a challenge given the complexity of the native tissue. While numerous studies have generated constructs with near-native bulk properties, recapitulating the depth-dependent features of native tissue remains a challenge. Furthermore, limitations in nutrient transport and matrix accumulation in engineered constructs hinders maturation within the central core of large constructs. To overcome these limitations, we fabricated tri-layered constructs that recapitulate the depth-dependent cellular organization and functional properties of native tissue using zonally derived chondrocytes co-cultured with MSCs. We also introduced porous hollow fibers (HFs) and HFs/cotton threads to enhance nutrient transport. Our results showed that tri layered constructs with depth-dependent organization and properties could be fabricated. The addition of HFs or HFs/threads improved matrix accumulation in the central core region. With HF/threads, the local modulus in the deep region of tri-layered constructs nearly matched that of native tissue, though the properties in the central regions remained lower. These constructs reproduced the zonal organization and depth-dependent properties of native tissue, and demonstrate that a layer-by-layer fabrication scheme holds promise for the biomimetic repair of focal cartilage defects. STATEMENT OF SIGNIFICANCE: Articular cartilage is a highly organized tissue driven by zonal heterogeneity of cells, extracellular matrix proteins and fibril orientations, resulting in depth dependent mechanical properties. Therefore, the recapitulation of the functional properties of native cartilage in a tissue engineered construct requires such a biomimetic design of the morphological organization, and this has remained a challenge in cartilage tissue engineering. This study demonstrates that a layer by-layer fabrication scheme, including co-cultures of zone-specific articular CHs and MSCs, can reproduce the depth-dependent characteristics and mechanical properties of native cartilage while minimizing the need for large numbers of chondrocytes. In addition, introduction of a porous hollow fiber (combined with a cotton thread) enhanced nutrient transport and depth-dependent properties of the tri-layered construct. Such a tri-layered construct may provide critical advantages for focal cartilage repair. These constructs hold promise for restoring native tissue structure and function, and may be beneficial in terms of zone-to-zone integration with adjacent host tissue and providing more appropriate strain transfer after implantation. PMID- 28629895 TI - Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma. AB - INTRODUCTION: The upregulation of programmed death ligand 1 (PD-L1) is found in many cancers and contributes to evasion of the host's immune defense. In malignant pleural mesothelioma (MPM), PD-L1 expression is associated with the nonepithelioid histological subtype and poor prognosis, but the pathways involved in control of PD-L1 expression in MPM are poorly understood. To address one possible means of PD-L1 regulation we investigated the relationship between dysregulated microRNA levels and PD-L1 expression. METHODS: PD-L1 expression was analyzed by immunohistochemistry in tissue microarrays prepared from samples from patients undergoing an operation (pleurectomy with or without decortication). MicroRNA expression was analyzed by reverse-transcriptase quantitative polymerase chain reaction. Regulation of PD-L1 expression in cell lines was assessed after transfection with microRNA mimics and small interfering RNAs. Interaction between microRNAs and PD-L1 was analyzed by using argonaute-2 immunoprecipitation and a luciferase reporter assay. RESULTS: In a series of 72 patients with MPM, 18 (25%) had positive PD-L1 staining, and this was more common in patients with the nonepithelioid subtype (p = 0.01). PD-L1 expression was associated with poor survival (median overall survival 4.0 versus 9.2 months with positive versus negative PD-L1 expression [p < 0.001]), and in multivariate analyses, PD-L1 expression remained a significant adverse prognostic indicator (hazard ratio = 2.2, 95% confidence interval: 1.2-4.1, p < 0.01). In the same patient series, PD L1 expression was also associated with downregulation of microRNAs previously shown to have tumor suppressor activity in MPM. The median microRNA expression levels of miR-15b, miR-16, miR-193a-3p, miR-195, and miR-200c were significantly lower in the PD-L1-positive samples. Transfecting MPM cell lines with mimics corresponding to miR-15a and miR-16, both of which are predicted to target PD-L1, led to downregulation of PD-L1 mRNA and protein. In addition, miR-193a-3p, with an alternative G-U-containing target site, also caused PD-L1 downregulation. CONCLUSIONS: Together, these data suggest that tumor suppressor microRNAs contribute to the regulation of PD-L1 expression in MPM. PMID- 28629896 TI - Randomized Phase II Study of Preoperative Chemoradiotherapy +/- Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIa, N2+) Non-Small Cell Lung Cancer: NRG Oncology RTOG 0839. AB - INTRODUCTION: Multimodality therapy has curative potential in locally advanced NSCLC. Mediastinal nodal sterilization (MNS) after induction chemoradiotherapy (CRT) can serve as an intermediate marker for efficacy. NRG Oncology Radiation Therapy Oncology Group (RTOG) 0229 demonstrated the feasibility and efficacy of combining full-dose radiation (61.2 Gy) with chemotherapy followed by resection and chemotherapy. On the basis of that experience and evidence that EGFR antibodies are radiosensitizing, we explored adding panitumumab to CRT followed by resection and consolidation chemotherapy in locally advanced NSCLC with a primary end point of MNS. METHODS: Patients with resectable locally advanced NSCLC were eligible if deemed suitable for trimodality therapy before treatment. Surgeons were required to demonstrate expertise after CRT and adhere to specific management guidelines. Concurrent CRT consisted of weekly carboplatin (area under the curve = 2.0), paclitaxel (50 mg/m2), and 60 Gy of radiation therapy delivered in 30 fractions. There was a 2:1 randomization in favor of panitumumab at 2.5 mg/kg weekly for 6 weeks. The mediastinum was pathologically reassessed before or at the time of resection. Consolidation chemotherapy was weekly carboplatin (area under the curve = 6) and paclitaxel, 200 mg/m2 every 21 days for two courses. The study was designed to detect an improvement in MNS from 52% to 72%. With use of a 0.15 one-sided type 1 error and 80% power, 97 patients were needed. RESULTS: The study was opened in November 2010 and closed in August 2015 by the Data Monitoring Committee after 71 patients had been accrued for futility and excessive toxicity in the experimental arm. A total of 60 patients were eligible: 19 patients (86%) who received CRT and 29 (76%) who received CRT plus panitumumab and underwent an operation. With regard to postoperative toxicity, there were three grade 4 adverse events (13.6%) and no grade 5 adverse events (0%) among those who received CRT versus six grade 4 (15.8%) and four grade 5 adverse events (10.5%) among those who received CRT plus panitumumab. The MNS rates were 68.2% (95% confidence interval: 45.1-86.1) and 50.0% (95% confidence interval: 33.4 66.6) for CRT and CRT plus panitumumab, respectively (p = 0.95). CONCLUSION: The addition of panitumumab to CRT did not improve MNS. There was an unexpectedly high mortality rate in the panitumumab arm, although the relationship to panitumumab is unclear. The control arm had outcomes similar to those in NRG Oncology RTOG 0229. PMID- 28629897 TI - A Unified Pathophysiological Construct of Diabetes and its Complications. AB - Advances in understanding diabetes mellitus (DM) through basic and clinical research have helped clarify and reunify a disease state fragmented into numerous etiologies and subtypes. It is now understood that a common pathophysiology drives the diabetic state throughout its natural history and across its varied clinical presentations, a pathophysiology involving metabolic insults, oxidative damage, and vicious cycles that aggravate and intensify organ dysfunction and damage. This new understanding of the disease requires that we revisit existing diagnostics and treatment approaches, which were built upon outmoded assumptions. 'The Common Pathophysiologic Origins of Diabetes Mellitus and its Complications Construct' is presented as a more accurate, foundational, and translatable construct of DM that helps make sense of the hitherto ambiguous findings of long term outcome studies. PMID- 28629898 TI - Alpha-lipoic acid supplement in obesity treatment: A systematic review and meta analysis of clinical trials. AB - BACKGROUND & AIMS: Previous studies have supported positive roles of antioxidant supplements on weight-loss. One antioxidant supplement is Alpha-lipoic acid. However, recommending ALA as an anti-obesity supplement remains controversial. Accordingly, the purpose of the present study was to perform a meta-analysis on the effects of ALA supplement on anthropometric indices among adult subjects. METHODS: We searched five electronic databases till September 2016. Placebo controlled clinical trials were included. Weighted Mean Difference (WMD) was pooled using a random-effects model. RESULTS: Findings of 12 included trials indicated that ALA supplement reduced body weight (WMD: -0.69 kg; 95% CI: -1.27, 0.10; I2 = 0%) and BMI (WMD: -0.38 kg/m2; 95% CI: -0.53, -0.24; I2 = 0%) significantly compared to the placebo group. However, its effects on Waist Circumference (WC) was not significant (WMD: -0.30 cm; 95% CI: -1.18, 0.58; I2 = 17.8%). Stratification by health status indicated that ALA decreased WC in unhealthy subjects (WMD: -2.00 cm; 95% CI: -4.19, 0.19; I2 = 1.3%) more than healthy individuals (0.03 cm; 95% CI: -0.69, 0.75; I2 = 0%). CONCLUSIONS: The present study revealed that supplementation with ALA slightly but significantly decreased body weight and BMI. Safe dosage for ALA is up to 1200 mg/day. However, it seems that ALA cannot be cost-effective. Further studies are needed to clarify the effects of ALA on metabolic parameter in unhealthy obese individuals. PMID- 28629899 TI - High adherence to a Mediterranean diet and lower risk of frailty among French older adults community-dwellers: Results from the Three-City-Bordeaux Study. AB - BACKGROUND & AIMS: Mediterranean diet (MeDi) is considered as a key component for healthy aging, including prevention of age-related disability, while its association with frailty, independent of disability has never been assessed. Our objective was to investigate the relation between MeDi adherence and frailty incidence among persons aged >=75 years participating at the prospective population-based French Three-City Study. METHODS: The study sample consisted of 560 initially non-frail participants of the Three-City-Bordeaux center, seen at the 2009-2010 follow-up, and re-examined two years later. Adherence to MeDi was computed from a food frequency questionnaire (scored as 0-9). Frailty was defined as having at least three out of the following five slightly modified Fried frailty criteria: involuntary weight loss, exhaustion, slowness, weakness and low physical activity. Logistic regression models adjusted for sociodemographic and clinical covariates, including cognitive performance and depressive symptomatology, were used to assess the association between MeDi score and subsequent frailty risk. RESULTS: Over the 2-year follow-up, 79 participants (14%) became frail. Older adults with the highest MeDi adherence (score 6-9) had a significantly 68% frailty risk reduction (95% CI: 28-86%, p = 0.006) compared to those in the lowest MeDi category (score 0-3). Regarding the frailty criterion separately, the highest MeDi adherence was associated with a significantly reduced risk of incident slowness (OR = 0.45; 95% CI: 0.20-0.99, p = 0.04), poor muscle strength (OR = 0.44; 95% CI: 0.20-0.98, p = 0.04) and low physical activity (OR = 0.39; 95% CI: 0.18-0.82, p = 0.01), compared to the lowest MeDi adherence. CONCLUSION: In addition to its well-documented beneficial effects on health, adherence to MeDi might contribute to prevent the onset of frailty, even at late stages of life. PMID- 28629900 TI - Multiple analyses indicate the specific association of NR1I3, C6 and TNN with low hip BMD risk. PMID- 28629901 TI - Identification of the adenovirus type 2 C-168 protein. AB - A hitherto predicted but undetected protein, C-168, in adenovirus type 2 (Ad2) has been identified using mass spectrometry (MS) based proteomics. The gene of this 17.7kDa protein is located on the forward strand in the major late transcription unit between base pairs 9294 and 9797. A tryptic peptide, derived from the C-terminal part of the protein, was identified with high amino acid sequence coverage. A candidate splice site for the corresponding mRNA is also presented. The protein sequence is unusual with repeats of serine, glycine and arginine. A bioinformatics prediction of protein function and localization is presented. PMID- 28629902 TI - Relationship between vessel diameter and depth measurements within the limbus using ultra-high resolution optical coherence tomography. AB - PURPOSE: To establish a relationship between the diameter and depth position of vessels in the superior and inferior corneo-scleral limbus using ultra-high resolution optical coherence tomography (UHR-OCT). METHODS: Volumetric OCT images of the superior and inferior limbus were acquired from 14 healthy subjects with a research-grade UHR-OCT system. Differences in vessel diameter and depth between superior and inferior limbus were analyzed using repeated measured ANOVA in SPSS and R. RESULTS: The mean (+/- SD) superior and inferior diameters were 29+/-18MUm and 24+/-18MUm respectively, and the mean (+/- SD) superior and inferior depths were 177+/-109MUm and 207+/-132MUm respectively. The superior limbal vessels were larger than the inferior ones (RM-ANOVA, p=0.004), and the inferior limbal vessels were deeper than the superior vessels (RM-ANOVA, p=0.041). There was a positive linear association between limbal vessel depth and size within the superior and inferior limbus with Pearson correlation coefficients of 0.803 and 0.754, respectively. CONCLUSION: This study demonstrated that the UHR-OCT was capable of imaging morphometric characteristics such as the size and depth of vessels in the limbus. The results of this study suggest a difference in the size and depth of vessels across different positions of the limbus, which may be indicative of adaptations to chronic hypoxia caused by the covering of the superior limbus by the upper eyelid. UHR-OCT may be a useful tool to evaluate the effect of contact lenses on the microvascular properties within the limbus. PMID- 28629904 TI - Perioperative Morbidity of Same-Day and Staged Bilateral Total Hip Arthroplasty. AB - BACKGROUND: Management strategies for bilateral hip degenerative disease include same-day or staged bilateral total hip arthroplasty (THA), but information on outcomes remains sparse. We sought to describe in-hospital complications and blood transfusion rates after same-day and staged bilateral THAs at different time intervals and to assess risk factors for these events. METHODS: We retrospectively reviewed administrative data for 3785 patients treated with same day bilateral (n = 1946; group A) and staged bilateral THA within (1) 0-3 months apart (n = 328; group B); (2) 3-6 months apart (n = 703; group C); and (3) 6-12 months apart (n = 808; group D), between 1999 and 2014. We recorded demographics, the Charlson-Deyo comorbidity index and in-hospital local and systemic (minor and major) complications. Complication and blood transfusion rates among groups were compared. A logistic regression model was developed to identify risk factors for major complications. RESULTS: Local complications were rare. Minor complications were less frequent in group A (P < .001). Major complications were more frequent in group D (P = .012). Group A had higher overall (P < .001) and allogeneic blood transfusion rates (P < .001) compared with the staged groups. Staged procedures within 6-12 months apart vs same-day bilateral THA, older age, Charlson-Deyo index >=2 vs 0, and earlier vs recent admission year were associated with higher adjusted odds for major complications. CONCLUSION: Same-day bilateral THA in a high-volume joint replacement center may be a safe option for younger and healthier patients, given the relatively low incidence of adverse events reported in this study. PMID- 28629903 TI - Recording Adverse Events Following Joint Arthroplasty: Financial Implications and Validation of an Adverse Event Assessment Form. AB - BACKGROUND: In Ireland, funding of joint arthroplasty procedures has moved to a pay-by-results national tariff system. Typically, adverse clinical events are recorded via retrospective chart-abstraction methods by administrative staff. Missed or undocumented events not only affect the quality of patient care but also may unrealistically skew budgetary decisions that impact fiscal viability of the service. Accurate recording confers clinical benefits and financial transparency. The aim of this study was to compare a prospectively implemented adverse events form with the current national retrospective chart-abstraction method in terms of pay-by-results financial implications. METHODS: An adverse events form adapted from a similar validated model was used to prospectively record complications in 51 patients undergoing total hip or knee arthroplasties. Results were compared with the same cohort using an existing data abstraction method. Both data sets were coded in accordance with current standards for case funding. RESULTS: Overall, 114 events were recorded during the study through prospective charting of adverse events, compared with 15 events documented by customary method (a significant discrepancy). Wound drainage (15.8%) was the most common complication, followed by anemia (7.9%), lower respiratory tract infections (7.9%), and cardiac events (7%). A total of ?61,956 ($67,778) in missed funding was calculated as a result. CONCLUSION: This pilot study demonstrates the ability to improve capture of adverse events through use of a well-designed assessment form. Proper perioperative data handling is a critical aspect of financial subsidies, enabling optimal allocation of funds. PMID- 28629905 TI - 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons Guideline for the Perioperative Management of Antirheumatic Medication in Patients With Rheumatic Diseases Undergoing Elective Total Hip or Total Knee Arthroplasty. AB - OBJECTIVE: This collaboration between the American College of Rheumatology and the American Association of Hip and Knee Surgeons developed an evidence-based guideline for the perioperative management of antirheumatic drug therapy for adults with rheumatoid arthritis (RA), spondyloarthritis (SpA) including ankylosing spondylitis and psoriatic arthritis, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE) undergoing elective total hip (THA) or total knee arthroplasty (TKA). METHODS: A panel of rheumatologists, orthopedic surgeons specializing in hip and knee arthroplasty, and methodologists was convened to construct the key clinical questions to be answered in the guideline. A multi-step systematic literature review was then conducted, from which evidence was synthesized for continuing versus withholding antirheumatic drug therapy and for optimal glucocorticoid management in the perioperative period. A Patient Panel was convened to determine patient values and preferences, and the Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence and the strength of recommendations, using a group consensus process through a convened Voting Panel of rheumatologists and orthopedic surgeons. The strength of the recommendation reflects the degree of certainty that benefits outweigh harms of the intervention, or vice versa, considering the quality of available evidence and the variability in patient values and preferences. RESULTS: The guideline addresses the perioperative use of antirheumatic drug therapy including traditional disease-modifying antirheumatic drugs, biologic agents, tofacitinib, and glucocorticoids in adults with RA, SpA, JIA, or SLE who are undergoing elective THA or TKA. It provides recommendations regarding when to continue, when to withhold, and when to restart these medications, and the optimal perioperative dosing of glucocorticoids. The guideline includes 7 recommendations, all of which are conditional and based on low- or moderate-quality evidence. CONCLUSION: This guideline should help decision-making by clinicians and patients regarding perioperative antirheumatic medication management at the time of elective THA or TKA. These conditional recommendations reflect the paucity of high-quality direct randomized controlled trial data. PMID- 28629906 TI - Can Bundled Payments Be Successful in the Medicaid Population for Primary Joint Arthroplasty? AB - BACKGROUND: Although some bundled payment models have had success in total joint arthroplasty, concerns exist about access to care for higher cost patients who use more resources. The purpose of this study is to determine whether Medicaid patients have increased hospital costs and more resource utilization in a 90-day episode of care than Medicare or privately insured patients. METHODS: We retrospectively reviewed a consecutive series of 7268 primary hip and knee arthroplasty patients at a single institution. Using a propensity score-matching algorithm for demographic variables, we matched the 92 consecutive Medicaid patients with 184 privately insured and 184 Medicare patients. Hospital-specific costs, discharge disposition, complications, and 90-day readmissions were analyzed. RESULTS: Medicaid patients had higher mean inpatient hospital costs than both of the matched Medicare and privately insured groups ($15,396 vs $12,165 vs $13,864, P < .001) with longer length of stay (3.34 vs 2.49 vs 1.46 days, P < .001). Medicaid and Medicare patients were more likely to be discharged to a rehabilitation facility than privately insured patients (17% vs 21% vs 1%, P < .001). When controlling for demographic factors and comorbidities, Medicaid insurance was a significant independent risk factor for increased hospital costs (odds ratio 3.64, 95% confidence interval 1.80-7.38, P < .001). CONCLUSION: Because of increased hospital costs, current bundled payment models should not include Medicaid patients because of concerns about patient selection and access to care. Further study is needed to determine whether bundling Medicaid arthroplasty costs in a stand-alone program with a separate target price will result in improved outcomes and decreased costs. PMID- 28629907 TI - The role of biosimilar manufacturers in improving access to insulin globally. PMID- 28629908 TI - Use of Underarm Cosmetic Products in Relation to Risk of Breast Cancer: A Case Control Study. AB - BACKGROUND: Previous studies on breast cancer (BC), underarm cosmetic products (UCP) and aluminum salts have shown conflicting results. We conducted a 1:1 age matched case-control study to investigate the risk for BC in relation to self reported UCP application. METHODS: Self-reported history of UCP use was compared between 209 female BC patients (cases) and 209 healthy controls. Aluminum concentration in breast tissue was measured in 100 cases and 52 controls. Multivariable conditional logistic regression analysis was performed to estimate odds ratios (ORs) with 95% confidence intervals (CIs), adjusting for established BC risk factors. FINDINGS: Use of UCP was significantly associated with risk of BC (p=0.036). The risk for BC increased by an OR of 3.88 (95% CI 1.03-14.66) in women who reported using UCP's several times daily starting at an age earlier than 30years. Aluminum in breast tissue was found in both cases and controls and was significantly associated to self-reported UCP use (p=0.009). Median (interquartile) aluminum concentrations were significantly higher (p=0.001) in cases than in controls (5.8, 2.3-12.9 versus 3.8, 2.5-5.8nmol/g). INTERPRETATION: Frequent use of UCPs may lead to an accumulation of aluminum in breast tissue. More than daily use of UCPs at younger ages may increase the risk of BC. PMID- 28629909 TI - ASF1A in Gastric and Colorectal Cancer: On the Hinge Between Genetics and Epigenetics? PMID- 28629910 TI - Memory B Cells, the HLA-B*57 Allele and Natural Control of HIV Infection. PMID- 28629911 TI - Combined Mass Spectrometry Imaging and Top-down Microproteomics Reveals Evidence of a Hidden Proteome in Ovarian Cancer. AB - BACKGROUND: Recently, it was demonstrated that proteins can be translated from alternative open reading frames (altORFs), increasing the size of the actual proteome. Top-down mass spectrometry-based proteomics allows the identification of intact proteins containing post-translational modifications (PTMs) as well as truncated forms translated from reference ORFs or altORFs. METHODS: Top-down tissue microproteomics was applied on benign, tumor and necrotic-fibrotic regions of serous ovarian cancer biopsies, identifying proteins exhibiting region specific cellular localization and PTMs. The regions of interest (ROIs) were determined by MALDI mass spectrometry imaging and spatial segmentation. FINDINGS: Analysis with a customized protein sequence database containing reference and alternative proteins (altprots) identified 15 altprots, including alternative G protein nucleolar 1 (AltGNL1) found in the tumor, and translated from an altORF nested within the GNL1 canonical coding sequence. Co-expression of GNL1 and altGNL1 was validated by transfection in HEK293 and HeLa cells with an expression plasmid containing a GNL1-FLAG(V5) construct. Western blot and immunofluorescence experiments confirmed constitutive co-expression of altGNL1-V5 with GNL1-FLAG. CONCLUSIONS: Taken together, our approach provides means to evaluate protein changes in the case of serous ovarian cancer, allowing the detection of potential markers that have never been considered. PMID- 28629913 TI - Vascular Spasm: A Newly Unraveled Cause for Cardiovascular Adversity of Proteasome Inhibition. PMID- 28629912 TI - Calprotectin and the Magnitude of Antibodies to Infliximab in Clinically-stable Ulcerative Colitis Patients are More Relevant Than Infliximab Trough Levels and Pharmacokinetics for Therapeutic Escalation. AB - Although infliximab (IFX) is an efficient therapy for ulcerative colitis (UC) patients, a considerably high rate of therapeutic failures still occurs. This study aimed at a better understanding of IFX pharmacokinetics and pharmacodynamics among clinically-asymptomatic UC patients. This was a multicentric and prospective study involving 65 UC patients in the maintenance phase of IFX therapy. There were no significant differences between patients with positive and negative clinical, endoscopic and histological outcomes concerning their IFX trough levels (TLs), area under the IFX concentration vs. time curve (AUC), clearance and antibodies to infliximab (ATI) levels. However, the need to undergo therapeutic escalation later in disease development was significantly associated with higher ATI levels (2.62MUg/mL vs. 1.15MUg/mL, p=0.028). Moreover, and after adjusting for disease severity, the HR (hazard ratio) for therapeutic escalation was significantly decreased for patients with an ATI concentration below 3MUg/mL (HR=0.119, p=0.010), and increased for patients with fecal calprotectin (FC) level above 250MUg/g (HR=9.309, p=0.018). In clinically-stable UC patients, IFX pharmacokinetic features cannot predict therapeutic response on a short-term basis. However, high levels of ATIs or FC may be indicative of a future therapeutic escalation. PMID- 28629915 TI - Video Laryngoscopy for Endotracheal Intubation of Critically Ill Adults: A Systemic Review and Meta-Analysis. AB - BACKGROUND: Endotracheal intubation (EI) in ICU patients is associated with an increased risk of life-threatening adverse events due to unstable conditions, rapid deterioration, limited preparation time, and variability in the expertise of operators. The goal of this study was to compare the effect of video laryngoscopy (VL) and direct laryngoscopy (DL) in ICU patients requiring EI. METHODS: We searched for relevant studies in PubMed, Embase, and the Cochrane database from inception through January 30, 2017. Randomized controlled trials were included if they reported data on any of the predefined outcomes in ICU patients requiring EI and managed with VL or DL. Results were expressed as risk ratios (RRs) or mean differences (MDs) with accompanying 95% CIs. RESULTS: Five randomized controlled trials with 1,301 patients were included. Despite better glottic visualization with VL (RR = 1.24; 95% CI, 1.07 to 1.43; P = .003), use of VL did not result in a significant increase in the first-attempt success rate (RR = 1.08; 95% CI, 0.92-1.26; P = .35) compared with DL. In addition, time to intubation (MD = 4.12 s; 95% CI, -15.86-24.09; P = .69), difficult intubation (RR = 0.72; 95% CI, 0.30-1.70; P = .45), mortality (RR = 1.02; 95% CI, 0.84-1.25; P = .83), and most other complications were similar between the VL and DL groups. CONCLUSIONS: The VL technique did not increase the first-attempt success rate during EI in ICU patients compared with DL. These findings do not support routine use of VL in ICU patients. PMID- 28629914 TI - Mortality Risk Prediction in Scleroderma-Related Interstitial Lung Disease: The SADL Model. AB - BACKGROUND: Interstitial lung disease (ILD) is an important cause of morbidity and mortality in patients with scleroderma (Scl). Risk prediction and prognostication in patients with Scl-ILD are challenging because of heterogeneity in the disease course. METHODS: We aimed to develop a clinical mortality risk prediction model for Scl-ILD. Patients with Scl-ILD were identified from two ongoing longitudinal cohorts: 135 patients at the University of California, San Francisco (derivation cohort) and 90 patients at the Mayo Clinic (validation cohort). Using these two separate cohorts, a mortality risk prediction model was developed and validated by testing every potential candidate Cox model, each including three or four variables of a possible 19 clinical predictors, for time to death. Model discrimination was assessed using the C-index. RESULTS: Three variables were included in the final risk prediction model (SADL): ever smoking history, age, and diffusing capacity of the lung for carbon monoxide (% predicted). This continuous model had similar performance in the derivation (C index, 0.88) and validation (C-index, 0.84) cohorts. We created a point scoring system using the combined cohort (C-index, 0.82) and used it to identify a classification with low, moderate, and high mortality risk at 3 years. CONCLUSIONS: The SADL model uses simple, readily accessible clinical variables to predict all-cause mortality in Scl-ILD. PMID- 28629916 TI - A Medical Student Perspective on Physician-Assisted Suicide. AB - Physician-assisted suicide and euthanasia (PAS/E) has been increasingly discussed and debated in the public arena, including in professional medical organizations. However, the medical student perspective on the debate has essentially been absent. We present a medical student perspective on the PAS/E debate as future doctors and those about to enter the profession. We argue that PAS/E is not in line with the core principles of medicine and that the focus should be rather on providing high-quality end-of-life and palliative care. PMID- 28629917 TI - Personalized Management Approach for OSA. AB - OSA is a heterogeneous disorder. If left untreated, it has major health, safety, and economic consequences. In addition to varying levels of impairment in pharyngeal anatomy (narrow/collapsible airway), nonanatomical "phenotypic traits" are also important contributors to OSA for most patients. However, the majority of existing therapies (eg, CPAP, oral appliances, weight loss, positional therapy, upper airway surgery) target only the anatomical cause. These are typically administered as monotherapy according to a trial and error management approach in which the majority of patients are first prescribed CPAP. Despite its high efficacy, CPAP adherence remains unacceptably low, and second-line therapies have variable and unpredictable efficacies. Recent advances in knowledge regarding the multiple causes of OSA using respiratory phenotyping techniques have identified new targets or "treatable traits" to direct therapy. Identification of the traits and development of therapies that selectively target one or more of the treatable traits has the potential to personalize the management of this chronic health condition to optimize patient outcomes according to precision medicine principles. This brief review highlights the latest developments and emerging therapies for personalized management approaches for OSA. PMID- 28629918 TI - Trajectories of Emergent Central Sleep Apnea During CPAP Therapy. AB - BACKGROUND: The emergence of central sleep apnea (CSA) during positive airway pressure (PAP) therapy has been observed clinically in approximately 10% of obstructive sleep apnea titration studies. This study assessed a PAP database to investigate trajectories of treatment-emergent CSA during continuous PAP (CPAP) therapy. METHODS: U.S. telemonitoring device data were analyzed for the presence/absence of emergent CSA at baseline (week 1) and week 13. Defined groups were as follows: obstructive sleep apnea (average central apnea index [CAI] < 5/h in week 1, < 5/h in week 13); transient CSA (CAI >= 5/h in week 1, < 5/h in week 13); persistent CSA (CAI >= 5/h in week 1, >= 5/h in week 13); emergent CSA (CAI < 5/h in week 1, >= 5/h in week 13). RESULTS: Patients (133,006) used CPAP for >= 90 days and had >= 1 day with use of >= 1 h in week 1 and week 13. The proportion of patients with CSA in week 1 or week 13 was 3.5%; of these, CSA was transient, persistent, or emergent in 55.1%, 25.2%, and 19.7%, respectively. Patients with vs without treatment-emergent CSA were older, had higher residual apnea-hypopnea index and CAI at week 13, and more leaks (all P < .001). Patients with any treatment-emergent CSA were at higher risk of therapy termination vs those who did not develop CSA (all P < .001). CONCLUSIONS: Our study identified a variety of CSA trajectories during CPAP therapy, identifying several different clinical phenotypes. Identification of treatment-emergent CSA by telemonitoring could facilitate early intervention to reduce the risk of therapy discontinuation and shift to more efficient ventilator modalities. PMID- 28629920 TI - Pulmonary Hypertension in Parenchymal Lung Diseases: Any Future for New Therapies? AB - Pulmonary hypertension (PH) due to chronic lung disease is associated with a poor prognosis, regardless of the underlying respiratory condition. Updated PH guidelines recommend optimal treatment of the underlying lung disease, including long-term oxygen therapy, in patients with chronic hypoxemia despite the lack of randomized controlled clinical trials supporting this statement. So far, randomized controlled trials of drugs approved for pulmonary arterial hypertension have yielded discouraging results in both interstitial lung diseases and COPD with PH. In some cases, the trials were terminated because of an increase in death and other major adverse events in the active treatment arm vs placebo. In cases of PH due to idiopathic pulmonary fibrosis, new therapies under investigation use a combination of novel antifibrotic treatments and other treatments approved for pulmonary arterial hypertension. The choice of robust end points as well as a target group of patients with specific hemodynamic criteria may help in the selection of innovative therapeutic strategies. The aim of this review is to discuss recent studies and clinical trials for the treatment of PH due to the main chronic respiratory diseases and to discuss possible future scenarios for the evaluation of new therapeutic strategies. PMID- 28629919 TI - Comparing Pulmonary Nodule Location During Electromagnetic Bronchoscopy With Predicted Location on the Basis of Two Virtual Airway Maps at Different Phases of Respiration. AB - BACKGROUND: Electromagnetic navigational bronchoscopy (ENB) is guided bronchoscopy to pulmonary nodules (PN) that relies on a preprocedural chest CT to create a three-dimensional (3D) virtual airway map. The CT is traditionally done at a full inspiratory breath hold (INSP), but the procedure is performed while the patient tidal breaths, when lung volumes are closer to functional residual capacity. Movement of a PN from INSP to expiration (EXP) has been shown to average 17.6 mm. Therefore, the hypothesis of this study is that preprocedural virtual maps built off a CT closer to physiological lung volumes during bronchoscopy may better represent the actual 3D location of a PN. METHODS: Consecutive patients with a PN needing a histological diagnosis were enrolled. A preprocedure INSP and EXP CT scan were obtained to create two virtual maps. During the airway inspection, the system tracked the sensor probe to collect 3D points that were reconstructed into the lumen registration map. This map is thought to best represent the patient's airways during bronchoscopy. Predicted PN location on an EXP and INSP map was compared with lumen registration. RESULTS: Twenty consecutive PN underwent ENB. The predicted PN location, compared with lumen registration, was significantly closer on EXP vs INSP (4.5 mm +/- 3.3 mm vs 14.8 mm +/- 9.7 mm; p < 0.0001). CONCLUSIONS: Predicted 3D nodule location using an EXP scan for ENB is significantly closer to actual nodule location when compared with an INSP scan, but whether this leads to increased yields needs to be determined. PMID- 28629921 TI - The importance of vaccine supply chains to everyone in the vaccine world. AB - While the focus of many in the vaccine world has been on developing new vaccines and measuring their effects on humans, failure to understand and properly address vaccine supply chain issues can greatly reduce the impact of any vaccine. Therefore, everyone involved in vaccine decision-making may want to take into account supply chains when making key decisions. In fact, considering supply chain issues long before a vaccine reaches the market can help design vaccines and vaccine programs that better match the system. We detail how vaccine supply chains may affect the work and decision making of ten examples of different members of the vaccine community: preclinical vaccinologists, vaccine clinical trialists, vaccine package designers, health care workers, epidemiologists and disease surveillance experts, policy makers, storage equipment manufacturers, other technology developers, information system specialists, and funders. We offer ten recommendations to help decision makers better understand and address supply chains. PMID- 28629922 TI - Vaccination with a codon-optimized A27L-containing plasmid decreases virus replication and dissemination after vaccinia virus challenge. AB - Smallpox is a disease caused by Variola virus (VARV). Although eradicated by WHO in 1980, the threat of using VARV on a bioterror attack has increased. The current smallpox vaccine ACAM2000, which consists of live vaccinia virus (VACV), causes complications in individuals with a compromised immune system or with previously reported skin diseases. Thus, a safer and efficacious vaccine needs to be developed. Previously, we reported that our virus-free DNA vaccine formulation, a pVAX1 plasmid encoding codon-optimized VACV A27L gene (pA27LOPT) with and without Imiquimod adjuvant, stimulates A27L-specific production of IFN gamma and increases humoral immunity 7days post-vaccination. Here, we investigated the immune response of our novel vaccine by measuring the frequency of splenocytes producing IFN-gamma by ELISPOT, the TH1 and TH2 cytokine profiles, and humoral immune responses two weeks post-vaccination, when animals were challenged with VACV. In all assays, the A27-based DNA vaccine conferred protective immune responses. Specifically, two weeks after vaccination, mice were challenged intranasally with vaccinia virus, and viral titers in mouse lungs and ovaries were significantly lower in groups immunized with pA27LOPT and pA27LOPT+Imiquimod. These results demonstrate that our vaccine formulation decreases viral replication and dissemination in a virus-free DNA vaccine platform, and provides an alternative towards a safer an efficacious vaccine. PMID- 28629923 TI - Immunogenicity and safety of a fully liquid DTaP-IPV-HB-PRP~T hexavalent vaccine compared with the standard of care in infants in the Republic of Korea. PMID- 28629924 TI - Predicting Health Care Utilization for Children With Respiratory Insufficiency Using Parent-Proxy Ratings of Children's Health-Related Quality of Life. AB - INTRODUCTION: Children with chronic respiratory insufficiency and mechanical ventilation often experience acute illnesses requiring unscheduled hospitalizations. Health-related quality of life (HRQL) may predict future health care utilization. METHODS: Participants were 30 days to 22 years old with chronic respiratory insufficiency (N = 120). Parent-proxies completed global HRQL and general health measures. Outcomes were total health care (emergency department, outpatient, inpatient) and inpatient days over 6 months. Adjusted negative binomial regression estimated the effects of global HRQL and general health on utilization. RESULTS: Three quarters of children had any utilization; 32% had hospitalizations. Children with poor/fair global HRQL had 3.7 times more health care days than those with very good/excellent global HRQL. Children with poor/fair global HRQL had 6.3 times more inpatient days than those with very good/excellent global HRQL. Similar relationships existed between general health and utilization. DISCUSSION: HRQL was associated with health care and inpatient days. Clinical teams can use HRQL as a marker for utilization risk, enabling potentially earlier intervention, better outcomes, and lower costs. PMID- 28629925 TI - A 50% reduction in multiple live birth rate is associated with a 13% cost saving: a real-life retrospective cost analysis. AB - Belgian legislation limiting the number of embryos for transfer has been shown to result in a 50% reduction of the multiple live birth rate (MLBR) per cycle without having a negative impact on the cumulative delivery rate per patient within six cycles or 36 months. The objective of the current study was to evaluate the cost saving associated with a 50% reduction in MLBR. A retrospective cost analysis was performed of 213 couples, who became pregnant and had a live birth after one or more assisted reproductive technology treatment cycles, and their 254 children. The mean cost of a singleton (n = 172) and multiple (n = 41) birth was calculated based on individual hospital invoices. The cost analysis showed a significantly higher total cost (assisted reproductive technology treatment, pregnancy follow-up, delivery, child cost until the age of 2 years) for multiple births (both children: mean ?43,397) than for singleton births (mean: ?17,866) (Wilcoxon-Mann-Whitney P < 0.0001). A 50% reduction in MLBR resulted in a significant cost reduction related to hospital care of 13%. PMID- 28629926 TI - Different functional susceptibilities of mouse retinal ganglion cell subtypes to optic nerve crush injury. AB - In optic neuropathies, the progressive deterioration of retinal ganglion cell (RGC) function leads to irreversible vision loss. Increasing experimental evidence suggests differing susceptibility for RGC functional subtypes. Here with multi-electrode array recordings, RGC functional loss was characterized at multiple time points in a mouse model of optic nerve crush. Firing rate, latency of response and receptive field size were analyzed for ON, OFF and ON-OFF RGCs separately. It was observed that responses and receptive fields of OFF cells were impaired earlier than ON cells after the injury. For the ON-OFF cells, the OFF component of response was also more susceptible to optic nerve injury than the ON component. Moreover, more ON transient cells survived than ON sustained cells post the crush, implying a diversified vulnerability for ON cells. Together, these data support the contention that RGCs' functional degeneration in optic nerve injury is subtype dependent, a fact that needs to be considered when developing treatments of glaucomatous retinal ganglion cell degeneration and other optic neuropathies. PMID- 28629928 TI - Safety and Efficacy of Endovascular Fiducial Marker Insertion for CyberKnife Stereotactic Radiation Therapy Planning in Early-Stage Lung Cancer. AB - PURPOSE: To evaluate the safety and efficacy of endovascular fiducial markers (EVFMs) for CyberKnife stereotactic radiation therapy (RT) of malignant lung neoplasms in patients with contraindications to percutaneous fiducial marker (PTFM) placement. MATERIALS AND METHODS: Between January 2011 and December 2013, 15 patients (7 men and 8 women) aged 59-87 years (mean, 73 y) underwent EVFM placement and 109 patients (54 men and 55 women) aged 55-92 years (mean, 73 y) underwent 114 PTFM placements. All patients who received EVFMs had contraindications to PTFM insertion. Complications were recorded for all 129 procedures. Proportions of markers used for CyberKnife stereotactic RT planning and distance between markers and tumor were assessed in all 15 patients in the EVFM group and in 15 randomly selected patients in the PTFM group. RESULTS: Sixty two EVFMs and 56 PTFMs were inserted in the groups of 15 patients. CyberKnife stereotactic RT was not performed in 2 EVFM recipients (8 EVFMs) and 1 PTFM recipient (4 PTFMs). CyberKnife stereotactic RT was planned with the use of 39 of 54 EVFMs (72%) in 13 patients and 37 of 52 PTFMs (71%) in 14 patients. Mean distances between the tumor and EVFMs and PTFMs were 5.5 mm and 2.7 mm, respectively (P = .0152). No complications occurred in the EVFM group. In the PTFM group, 60 of 114 patients (52.6%) had small or moderate pneumothoraxes, 13 (11.4%) had chest tubes inserted, and 5 (4.4%) had self-limiting hemoptysis. CONCLUSIONS: EVFM is feasible and safe, and may therefore offer an alternative when patients are not candidates for percutaneous marker placement. PMID- 28629929 TI - Interactions between microRNAs and long non-coding RNAs in cardiac development and repair. AB - Non-coding RNAs (ncRNAs) are emerging players in muscle regulation. Based on their length and differences in molecular structure, ncRNAs are subdivided into several categories including small interfering RNAs, stable non-coding RNAs, microRNAs (miRs), long non-coding RNAs (lncRNAs), and circular RNAs. miRs and lncRNAs are able to post-transcriptionally regulate many genes and bring into play several traits simultaneously due to a myriad of different targets. Recent studies have emphasized their importance in cardiac regeneration and repair. As their altered expression affects cardiac function, miRs and lncRNAs could be potential targets for therapeutic intervention. In this context, miR- and lncRNA based gene therapies are an interesting field for harnessing the complexity of ncRNA-based therapeutic approaches in cardiac diseases. In this review we will focus on lncRNA- and miR-driven regulations of cardiac development and repair. Finally, we will summarize miRs and lncRNAs as promising candidates for the treatment of heart diseases. PMID- 28629927 TI - Quick-freeze/deep-etch electron microscopy visualization of the mouse posterior pole. AB - The mouse is one of the most commonly used mammalian systems to study human diseases. In particular it has been an invaluable tool to model a multitude of ocular pathologies affecting the posterior pole. The aim of this study was to create a comprehensive map of the ultrastructure of the mouse posterior pole using the quick-freeze/deep-etch method (QFDE). QFDE can produce detailed three dimensional images of tissue structure and macromolecular moieties, without many of the artifacts introduced by structure-altering post-processing methods necessary to perform conventional transmission electron microscopy (cTEM). A total of 18 eyes from aged C57BL6/J mice were enucleated and the posterior poles were processed, either intact or with the retinal pigment epithelium (RPE) cell layer removed, for imaging by either QFDE or cTEM. QFDE images were correlated with cTEM cross-sections and en face images through the outer retina. Nicely preserved outer retinal architecture was observed with both methods, however, QFDE provided excellent high magnification imaging, with greater detail, of the apical, central, and basal planes of the RPE. Furthermore, key landmarks within Bruch's membrane, choriocapillaris, choroid and sclera were characterized and identified. In this study we developed methods for preparing the outer retina of the mouse for evaluation with QFDE and provide a map of the ultrastructure and cellular composition of the outer posterior pole. This technique should be applicable for morphological evaluation of mouse models, in which detailed visualization of subtle ocular structural changes is needed or in cases where post-processing methods introduce unacceptable artifacts. PMID- 28629930 TI - Dining with dad: Fathers' influences on family food practices. AB - Scholars have documented multiple influences on family food practices. This article examines an overlooked contributor to family diet: fathers. Using 109 in depth interviews with middle and upper-middle class mothers, adolescents, and fathers in the United States, I show how fathers can undermine mothers' efforts to provision a healthy diet. While family members perceive mothers as committed to provisioning a healthy diet, many fathers are seen as, at best, detached and, at worst, a threat to mothers' dietary aspirations. Fathers not only do little foodwork; they are also viewed as less concerned about their own and other family members' dietary health. When tasked with feeding, many fathers often turn to quick, unhealthy options explicitly avoided by mothers. Mothers report efforts to limit fathers' involvement in foodwork to ensure the healthiness of adolescents' diets, with variation across families by mothers' employment status. Fathers' dietary approaches reflect and reinforce traditional gender norms and expectations within families. In highlighting how and why fathers can undermine mothers' efforts to provision a healthy diet, this study deepens our understanding of the myriad dynamics shaping family food practices. PMID- 28629931 TI - Fathers' feeding practices and children's weight status in Mexican American families. AB - Mothers' feeding practices are associated with their children's weight status, but little is known about the associations between fathers' feeding practices and children's weight status. Moreover, there is a dearth of research on Latino fathers' feeding practices and children's weight status, even though Latino children suffer some of the highest obesity rates in the U.S. We examined the associations between fathers' feeding practices and child weight status, conditional on mothers' feeding practices, within 174 Mexican American families with children aged 8-10 years. Parents completed the Parental Feeding Practices Questionnaire, which consists of four subscales: positive involvement in child eating, pressure to eat, use of food to control behavior, and restriction of amount of food. To assess child weight status, body mass index (BMI) was calculated and converted to age- and gender-specific percentile scores (BMI z score). We fit four sets of regression models, one set for each of the four parental feeding practices subscales, with child BMI z-score as the outcome variable. Fathers' pressure to eat (b = -0.20, p = 0.04; 95% CI: -0.39, -0.01) and use of food to control behavior (b = -0.36, p = 0.02; 95% CI: -0.65, -0.07) were associated with lower child BMI z-score, and restriction of amount of food (b = 0.56, p < 0.001; 95% CI: 0.27, 0.84) was associated with higher child BMI z score, after accounting for mothers' feeding practices. Fathers' positive involvement in child eating was not associated with child BMI z-score. These findings provide empirical evidence that fathers' feeding practices are independently associated with children's weight status, even when mothers' feeding practices are taken into account, and suggest that fathers' feeding practices also matter in regard to children's weight status. PMID- 28629932 TI - Systemic antimicrobial prophylaxis in burn patients: systematic review. AB - OBJECTIVE: To review studies of systemic antibiotic prophylaxis in burn patients. METHODS: Electronic databases were searched for human clinical trials performed between 1966 and 2016 that compared prophylactic systemic antibiotics with placebo or no intervention. RESULTS: Nineteen trials met the selection criteria. Early postburn prophylaxis was assessed in non-severe burn patients (six trials) and severe burn patients (seven trials). Antimicrobial prophylaxis showed no effectiveness for the prevention of toxic shock syndrome or burn wound infection (Grade 1C), but could be useful in patients with severe burns and requirement for mechanical ventilation (Grade 2B). Perioperative prophylaxis was assessed in six trials. Antimicrobial prophylaxis during resection of devitalized tissue is of no benefit in most burn patients (Grade 2B); however, there is insufficient evidence to make a recommendation for patients with extensive burns. Antibiotic prophylaxis may also be effective in preventing split-thickness skin graft infections in selected procedures (Grade 2B). CONCLUSIONS: The available evidence does not support the role of systemic antibiotic prophylaxis in the management of the majority of burn patients. Nevertheless, it may be useful in patients with severe burns who require mechanical ventilation, and in selected split-thickness skin grafting procedures. PMID- 28629933 TI - Lignans from the root of Wikstroemia indica and their cytotoxic activity against PANC-1 human pancreatic cancer cells. AB - Six new compounds, wikstronin A (1), wikstronin B (2), wikstresinol (3), acetylwikstresinol (4), bis-5',5'-(+)-matairesinol (5), bis-5,5'-(+)-matairesinol (6), together with 20 known compounds (7-26) were isolated from the CH2Cl2 extract of roots of Wikstroemia indica. Structures of compounds 1-6 were determined by extensive NMR and CD spectroscopic analysis. In vitro preferential cytotoxicity of all the isolates was evaluated against a PANC-1 human pancreatic cell line. Compounds 8 and 12 displayed mild preferential cytotoxicity in the nutrient-deprived medium (NDM) and without causing toxicity in normal nutrient rich conditions. PMID- 28629934 TI - Recent advances in Leishmania reverse genetics: Manipulating a manipulative parasite. AB - In this review we describe the expanding repertoire of molecular tools with which to study gene function in Leishmania. Specifically we review the tools available for studying functions of essential genes, such as plasmid shuffle and DiCre, as well as the rapidly expanding portfolio of available CRISPR/Cas9 approaches for large scale gene knockout and endogenous tagging. We include detail on approaches that allow the direct manipulation of RNA using RNAi and protein levels via Tet or DiCre induced overexpression and destabilization domain mediated degradation. The utilisation of current methods and the development of more advanced molecular tools will lead to greater understanding of the role of essential genes in the parasite and thereby more robust drug target validation, thereby paving the way for the development of novel therapeutics to treat this important disease. PMID- 28629935 TI - A DiCre recombinase-based system for inducible expression in Leishmania major. AB - Here we present the establishment of an inducible system based on the dimerizable Cre recombinase (DiCre) for controlled gene expression in the protozoan parasite Leishmania. Rapamycin-induced DiCre activation promoted efficient flipping and expression of gene products in a time and dose-dependent manner. The DiCre flipping activity induced the expression of target genes from both integrated and episomal contexts broadening the applicability of the system. We validated the system by inducing the expression of both full length and truncated forms of the checkpoint protein Rad9, which revealed that the highly divergent C-terminal domain of Rad9 is necessary for proper subcellular localization. Thus, by establishing the DiCre-based inducible system we have created and validated a robust new tool for assessing gene function in Leishmania. PMID- 28629937 TI - The multi-mode modulator: A versatile fluidic device for two-dimensional gas chromatography. AB - A fluidic device called the multi-mode modulator (MMM) has been developed for use as a comprehensive two-dimensional gas chromatography (GC x GC) modulator. The MMM can be employed in a wide range of capacities including as a traditional heart-cutting device, a low duty cycle GC x GC modulator, and a full transfer GC x GC modulator. The MMM is capable of producing narrow component pulses (widths <50ms) while operating at flows compatible with high resolution chromatography. The sample path of modulated components is confined to the interior of a joining capillary. The joining capillary dimensions and the position of the columns within the joining capillary can be optimized for the selected modulation mode. Furthermore, the joining capillary can be replaced easily and inexpensively if it becomes fouled due to sample matrix components or column bleed. The principles of operation of the MMM are described and its efficacy is demonstrated as a heart cutting device and as a GC x GC modulator. PMID- 28629936 TI - Logit-log evaluation of planar yeast estrogen screens. AB - Receptor assays like the yeast estrogen screen (YES) performed in microtiter plates normally provide dose-response curves with a sigmoidal shape in semi-log plots. Such sigmoidal plots can be linearized by the logit function resulting in logit-log plots, as mainly known for the evaluation of enzyme-linked immunosorbent assays and radioimmunoassays. Since the planar yeast estrogen screen (pYES) represents the transfer of the receptor assay YES to high performance thin-layer chromatography (HPTLC), it was assumed to obtain sigmoidal shaped dose-response curves from the measured signals, which subsequently could be used to generate logit-log plots. However, it was observed that typical sigmoidal curves were not obtained, when peak areas were plotted against the applied amount on a logarithmic scale (log amount). Therefore, peak heights were examined in the present study, which revealed proper dose-response curves when plotted against the log amount. The presence of sigmoidal dose-response curves from HPTLC-pYES made it possible to transform the signals into logits and, therefore, to create logit-log plots with linear correlations. The logit-log plots for the estrogen active compounds (EAC) 17beta-estradiol (E2) and 17alpha ethinylestradiol (EE2) provided a working range up to 500pg/zone. Applying logit log plots, mean recovery rates for E2 and EE2 from spiked water samples (2 20ng/L) were determined to 90% and 108%, respectively, with <=24% RSD. Moreover, the linear graphs allowed an easy determination of the half maximal effect dose (ED50) of EAC, since the intersection of the graph with the abscissa represents the ED50. Additionally, with the knowledge of the ED50 values, the estrogenic potential of EAC in terms of estradiol equivalent factors (EEF) could be determined, resulting in 0.64 for EE2. PMID- 28629938 TI - Poly(glycidyl methacrylate) nanoparticle-coated capillary with oriented antibody immobilization for immunoaffinity in-tube solid phase microextraction: Preparation and characterization. AB - A combination between modification with nanoparticles (NP) and oriented antibody immobilization (OAI) on the inner face of capillary was for the first time developed for immunoaffinity in-tube solid-phase microextraction (SPME) to promise high antigen extraction capacity. beta2-microglobin (beta2MG) and cystatin C (Cys-C) were selected as model antigens. Poly(glycidyl methacrylate) (PGMA) NPs were chemically immobilized onto the capillary by a ring-opening reaction. Antibodies for beta2MG and Cys-C were immobilized on the NPs through OAI. Scanning electron micrograph of the OAI capillary clearly showed that the PGMA NPs were coated onto the inner surface of capillary in a dense monolayer. In addition, random antibody immobilized (RAI) capillaries and OAI capillaries without NP were also prepared as controls. The extraction capacities of OAI capillaries were 2.02 and 2.18mgm-1 for beta2MG and Cys-C, and were about 5 and 6 times as many as RAI capillaries and OAI capillaries without NP, respectively. The resultant capillaries were used as in-tube SPME materials to enrich beta2MG and Cys-C for particle-enhanced turbidimetric immunoassay. When using 1.0mgL-1 standard solutions, the recoveries of OAI capillaries, RAI capillaries and OAI capillaries without NP were 103.6% and 96.8%, 48.5% and 31.5%, and 24.2% and 25.7% for beta2MG and Cys-C, respectively. Furthermore, the method quantitation limit by OAI capillaries was 5 and 10 times lower than that by RAI capillaries and OAI capillaries without NP, respectively. This result indicated that the NP coated capillaries with OAI are more suitable for using as immunoaffinity in-tube SPME materials than that with RAI. PMID- 28629939 TI - Preparation and evaluation of 400MUm I.D. polymer-based hydrophilic interaction chromatography monolithic columns with high column efficiency. AB - The quest for higher column efficiency is one of the major research areas in polymer-based monolithic column fabrication. In this research, two novel polymer based HILIC monolithic columns with 400MUm I.D.*800MUm O.D. were prepared based on the thermally initiated co-polymerization of N,N-dimethyl-N-(3 methacrylamidopropyl)-N-(3-sulfopropyl) ammonium betaine (SPP) and ethylene glycol dimethacrylate (EDMA) or N,N'-methylenebisacrylamide (MBA). In order to obtain a satisfactory performance in terms of column permeability, mechanical stability, efficiency and selectivity, the polymerization parameters were systematically optimized. Column efficiencies as high as 142, 000 plates/m and 120, 000 plates/m were observed for the analysis of neutral compounds at 0.6mm/s on the poly(SPP-co-MBA) and poly(SPP-co-EDMA) monoliths, respectively. Furthermore, the Van Deemter plots for thiourea on the two monoliths were compared with that on a commercial silica based ZIC-HILIC column (3.5MUm, 200A, 150mm*300MUm I.D.) using ACN/H2O (90/10, v/v) as the mobile phase at room temperature. It was noticeable that the Van Deemter curves for both monoliths, particularly the poly(SPP-co-MBA) monolith, are significantly flatter than that obtained for the ZIC-HILIC column, which indicates that in spite of their larger internal diameters, they yield better overall efficiency, with less peak dispersion, across a much wider range of usable linear velocities. A clearly better separation performance was also observed for nucleobases, nucleosides, nucleotides and small peptides on the poly(SPP-co-MBA) monolith compared to the ZIC-HILIC column. It is particularly worth mentioning that these 400MUm I.D. polymer-based HILIC monolithic columns exhibit enhanced mechanical strength owing to the thicker capillary wall of the fused-silica capillaries. PMID- 28629940 TI - Highly informative multiclass profiling of lipids by ultra-high performance liquid chromatography - Low resolution (quadrupole) mass spectrometry by using electrospray ionization and atmospheric pressure chemical ionization interfaces. AB - A simple, fast, and versatile method, using an ultra-high performance liquid chromatography system coupled with a low resolution (single quadrupole) mass spectrometer was optimized to perform multiclass lipid profiling of human plasma. Particular attention was made to develop a method suitable for both electrospray ionization and atmospheric pressure chemical ionization interfaces (sequentially in positive- and negative-ion mode), without any modification of the chromatographic conditions (mobile phase, flow-rate, gradient, etc.). Emphasis was given to the extrapolation of the structural information based on the fragmentation pattern obtained using atmospheric pressure chemical ionization interface, under each different ionization condition, highlighting the complementary information obtained using the electrospray ionization interface, of support for related molecule ions identification. Furthermore, mass spectra of phosphatidylserine and phosphatidylinositol obtained using the atmospheric pressure chemical ionization interface are reported and discussed for the first time. PMID- 28629941 TI - Does patella lowering improve crouch gait in cerebral palsy? Comparative retrospective study. AB - BACKGROUND: Patella lowering aims to improve quadriceps function as a means of correcting crouch gait in patients with cerebral palsy. Few studies have assessed the effects of patella lowering as a component of multilevel surgery. HYPOTHESIS: Including patella lowering into the components of multilevel surgery is beneficial in patients with crouch gait and patella alta. MATERIAL AND METHODS: In 12 lower limbs with patella alta (Caton-Deschamps index>1.4) in 41 children with cerebral palsy, patella lowering was performed, without distal femoral extension osteotomy or hamstring release. Among limbs with similar surgical procedures (e.g., hamstring lengthening, rectus femoris transfer) except for patella lowering, controls were selected retrospectively by matching on a propensity score for patella lowering. The propensity score was computed based on preoperative knee flexion contracture, knee extension lag, and minimum knee flexion at mid-stance. Clinical and 3D kinematic data were compared between the two groups. RESULTS: The improvement in minimum knee flexion at mid-stance was significantly greater in the group with patellar lowering (-24 degrees +/-12 degrees vs. -12 degrees +/-7 degrees ). The Gait Deviation Index improved similarly in the two groups. Knee flexion contracture improved only in the group with patellar lowering. Extension lag did not improve in either group. Peak knee flexion during the swing phase remained unchanged in both groups. DISCUSSION: Patellar lowering is effective in diminishing minimum knee flexion at mid-stance in patients with patella alta and crouch gait due to cerebral palsy. Patellar lowering has not adverse effects on gait. These findings cannot be assumed to apply to patients with normal patellar height. LEVEL OF EVIDENCE: IV (retrospective study). PMID- 28629942 TI - Can a target zone safer than Lewinnek's safe zone be defined to prevent instability of total hip arthroplasties? Case-control study of 56 dislocated THA and 93 matched controls. AB - BACKGROUND: Various factors contribute to instability of total hip arthroplasty (THA), with implant orientation being a major contributor. We performed a case control study with computed tomography (CT) data to determine whether: 1) orientation contributes to THA instability and 2) a safer target zone for stability than Lewinnek's classic safe zone can be defined. MATERIAL AND METHODS: We included prospectively 363 cases of THA dislocation that occurred during the calendar 2013 year in 24 participating hospitals. Of the 128 dislocations that occurred in patients who underwent THA at these centers, 56 (24 anterior, 32 posterior) had CT scans, thus were included in the analysis. The control group was matched 4:1 based on implant type, year of implantation, age, sex, bearing types and THA indication. Of the 428 matched control THA cases, 93 had CT scans. In all, the CT scans from 149 cases (56 unstable, 93 stable) were analyzed to determine the acetabular cup's inclination and anteversion, and the femoral stem's anteversion. RESULTS: In the unstable THA group, cup inclination was 46.9 degrees +/-7.4 degrees , cup anteversion was 20.4 degrees +/-10.8 degrees and stem anteversion was 14.2 degrees +/-9.9 degrees . In the stable THA group, cup inclination was 44.9 degrees +/-5.3 degrees (P=0.057), cup anteversion was 22.1 degrees +/-5.1 degrees (P=0.009) and stem anteversion was 13.4 degrees +/-4.4 degrees (P=0.362). The optimal total anteversion (cup+stem) of 40-60 degrees was achieved in 16.5% of unstable THA cases and 13.9% of stable THA cases, thus this parameter does not predict stability (odds ratio [OR] of 0.40, P=0.144). The cup was positioned in Lewinnek's safe zone in 44.6% of patients in the unstable group and 68.2% of those in the stable group (OR 3.74, P=0.003). A target zone defined as 40-50 degrees inclination and 15-30 degrees anteversion was better able to distinguish between unstable cases (23.2%) and stable cases (71.6%) resulting in an OR of 13.91 (P<0.001). DISCUSSION: Implant positioning was the only risk factor for instability found in this study. Moreover, our findings reinforce the theory put forward by other authors that Lewinnek's safe zone is not specific enough to differentiate between stable and unstable THA implantations. The target zone for acetabular cups proposed here (40-50 degrees inclination and 15 degrees -30 degrees anteversion) is related to a lower risk of instability. This orientation can be used as a guide, but must be combined with other technical elements to optimize stability. By balancing stability and biomechanics, the 40-50 degrees inclination and 15 degrees -30 degrees anteversion target zone redefines the optimal positioning window. LEVEL OF EVIDENCE: III case-control study. PMID- 28629943 TI - Arthroscopically assisted fixation is a reliable option for patellar fractures: A literature review. AB - : Proper reduction and stable fixation of articular fractures is essential for an early recovery and to avoid late complications. Arthroscopically assisted techniques for minimally invasive fixation have been introduced to reduce local morbidity and improve anatomic reduction of the fragments. However up to date no clear indications for surgery have been given. In addition, the precise rates of functional outcomes and complications are controversial. The hypothesis was the systematic analysis of the available literature would provide precise indications, outcomes and complications of arthroscopically assisted techniques for patellar fracture fixation. A comprehensive literature review was performed using the keywords "patellar fracture", "arthroscopy" with no limit regarding the year of publication. All the selected articles were in English language and were evaluated with the Coleman score by three independent surgeons. The interclass correlation coefficient between the three examiners was calculated. Six full text articles were retrieved. The initial cohort included 60 patients with a displaced transverse fracture in the majority of the cases. At an average FU of 27.2 months the Lysholm score was 91.3. The rate of complication was 7%; Average Coleman score for the three observers was 55.8+/-6.5 with an ICC of 0.89, indicating adequate inter-rater agreement. Arthroscopically assisted techniques for minimally invasive fixation of patellar fractures represent a reliable option. The positive clinical outcomes and low rates of complications must be confirmed with further studies including larger series and longer FU. LEVEL OF EVIDENCE: Level IV, systematic review of retrospective series. PMID- 28629944 TI - What are the risk factors for dislocation in primary total hip arthroplasty? A multicenter case-control study of 128 unstable and 438 stable hips. AB - INTRODUCTION: Dislocation after total hip arthroplasty (THA) is a leading reason for surgical revision. The risk factors for dislocation are controversial, particularly those related to the patient and to the surgical procedure itself. The differences in opinion on the impact of these factors stem from the fact they are often evaluated using retrospective studies or in limited patient populations. This led us to carry out a prospective case-control study on a large population to determine: 1) the risk factors for dislocation after THA, 2) the features of these dislocations, and 3) the contribution of patient-related factors and surgery-related factors. HYPOTHESIS: Risk factors for dislocation related to the patient and procedure can be identified using a large case-control study. PATIENTS AND METHODS: A multicenter, prospective case-control study was performed between January 1 and December 31, 2013. Four patients with stable THAs were matched to each patient with a dislocated THA. This led to 566 primary THA cases being included: 128 unstable, 438 stable. The primary matching factors were sex, age, initial diagnosis, surgical approach, implantation date and type of implants (bearing size, standard or dual-mobility cup). RESULTS: The patients with unstable THAs were 67+/-12 [37-73]years old on average; there were 61 women (48%) and 67 men (52%). Hip osteoarthritis (OA) was the main reason for the THA procedure in 71% (91/128) of the unstable group. The dislocation was posterior in 84 cases and anterior in 44 cases. The dislocation occurred within 3 months of the primary surgery in 48 cases (38%), 3 to 12 months after in 23 cases (18%), 1 to 5years after in 20 cases (16%), 5 to 10years after in 17 cases (13%) and more than 10years later in 20 cases. The dislocation recurred within 6 months of the initial dislocation in 23 of the 128 cases (18%). The risk factors for instability were a high ASA score with an odds ratio (OR) of 1.93 (95% CI: 1.4 2.6), neurological disability (cognitive, motor or psychiatric disorders) with an OR of 3.9 (95% CI: 2.15-7.1), history of spinal disease (lumbar stenosis, spinal fusion, discectomy, scoliosis and injury sequelae) with an OR of 1.89 (95% CI: 1.0-3.6), unrepaired joint capsule (all approaches) with an OR of 4.1 (95% CI: 2.3-7.37), unrepaired joint capsule (posterior approach) with an OR of 6.0 (95% CI: 2.2-15.9), and cup inclination outside Lewinnek's safe zone (30 degrees -50 degrees ) with OR of 2.4 (95% CI: 1.4-4.0). DISCUSSION: This large comparative study isolated important patient-related factors for dislocation that surgeons must be aware of. We also found evidence that implanting the cup in 30 degrees to 50 degrees inclination has a major impact on preventing dislocation. LEVEL OF EVIDENCE: Level III; case-control study. PMID- 28629945 TI - Anthropometric and aesthetic outcomes for the nasolabial region in 101 consecutive African children with unilateral cleft lip one year after repair using the anatomical subunit approximation technique. AB - One hundred and one patients with complete or incomplete cleft lip underwent the anatomical subunit approximation technique for repair. The patients were followed up prospectively for 1year. The objective of this study was to determine the outcomes for the nasolabial area through anthropometric measurements and assessment of the Asher-McDade Aesthetic Index and Steffensen's criteria at 1year after surgery. Six assessors (three cleft surgeons and three non-surgeon medical professionals) examined cropped images; reliability was assessed using Cronbach's alpha. The difference in lip length between the healthy and operated sides was 0.61mm and the difference in nostril diameter was 0.37mm (differences not significant). The average scar width was 2.78+/-1.35mm. Hypertrophic scars were observed in 9.9% of cases. The average Asher-McDade Aesthetic Index rating varied between 1.35 and 1.98 for all parameters. Cronbach's alpha coefficient was 0.83, 0.89, 0.98, and 0.89 for nasal form, nasal symmetry, vermilion border, and nasolabial profile, respectively. Steffensen's criteria rated appearance as 'good' in 69.3% to 91.1% of cases. The anatomical subunit approximation technique can be performed in Sub-Saharan Africans for all types of unilateral cleft lip. It significantly improves the length of the medial and lateral lips, leaving an acceptable scar. A study with a larger sample size and longer follow-up is warranted. PMID- 28629946 TI - Phytol-induced pathology in 2-hydroxyacyl-CoA lyase (HACL1) deficient mice. Evidence for a second non-HACL1-related lyase. AB - 2-Hydroxyacyl-CoA lyase (HACL1) is a key enzyme of the peroxisomal alpha oxidation of phytanic acid. To better understand its role in health and disease, a mouse model lacking HACL1 was investigated. Under normal conditions, these mice did not display a particular phenotype. However, upon dietary administration of phytol, phytanic acid accumulated in tissues, mainly in liver and serum of KO mice. As a consequence of phytanic acid (or a metabolite) toxicity, KO mice displayed a significant weight loss, absence of abdominal white adipose tissue, enlarged and mottled liver and reduced hepatic glycogen and triglycerides. In addition, hepatic PPARalpha was activated. The central nervous system of the phytol-treated mice was apparently not affected. In addition, 2OH-FA did not accumulate in the central nervous system of HACL1 deficient mice, likely due to the presence in the endoplasmic reticulum of an alternate HACL1-unrelated lyase. The latter may serve as a backup system in certain tissues and account for the formation of pristanic acid in the phytol-fed KO mice. As the degradation of pristanic acid is also impaired, both phytanoyl- and pristanoyl-CoA levels are increased in liver, and the omega-oxidized metabolites are excreted in urine. In conclusion, HACL1 deficiency is not associated with a severe phenotype, but in combination with phytanic acid intake, the normal situation in man, it might present with phytanic acid elevation and resemble a Refsum like disorder. PMID- 28629947 TI - Temporal microbiota changes of high-protein diet intake in a rat model. AB - Alterations of specific microbes serve as important indicators that link gut health with specific diet intake. Although a six-week high-protein diet (45% protein) upregulates the pro-inflammatory response and oxidative stress in colon of rats, the dynamic alteration of gut microbiota remains unclear. To dissect temporal changes of microbiota, dynamic analyses of fecal microbiota were conducted using a rat model. Adult rats were fed a normal-protein diet or an HPD for 6 weeks, and feces collected at different weeks were used for microbiota and metabolite analysis. The structural alteration of fecal microbiota was observed after 4 weeks, especially for the decreased appearance of bands related to Akkermansia species. HPD increased numbers of Escherichia coli while decreased Akkermansia muciniphila, Bifidobacterium, Prevotella, Ruminococcus bromii, and Roseburia/Eubacterium rectale (P < 0.05), compared to the normal-protein diet. HPD also decreased the copies of genes encoding butyryl-CoA:acetate CoA transferase and Prevotella-associated methylmalonyl-CoA decarboxylase alpha subunit (P < 0.05). The concentrations of acetate, propionate, and butyrate were decreased by HPD (P < 0.05). Additionally, HPD tended to decrease (P = 0.057) the concentration of IgG in the colonic lumen, which was positively correlated with fecal butyrate at week 6 (P < 0.05). Collectively, this study found the temporal alteration of fecal microbiota related to the decreased numbers and activity of propionate- and butyrate-producing bacteria in feces after the HPD. These findings may provide important reference for linking changes of specific fecal microbes with gut health under high-protein diet. PMID- 28629948 TI - Percutaneous Treatment of Early Denegeration of a Sutureless Bioprosthesis. PMID- 28629949 TI - The Diversity of Long Noncoding RNAs and Their Generation. AB - Long noncoding RNAs (lncRNAs) are emerging as potential key regulators in gene expression networks and exhibit a surprising range of shapes and sizes. Several distinct classes of lncRNAs are transcribed from different DNA elements, including promoters, enhancers, and intergenic regions in eukaryotic genomes. Additionally, others are derived from long primary transcripts with noncanonical RNA processing pathways, generating new RNA species with unexpected formats. These lncRNAs can be processed by several mechanisms, including ribonuclease P (RNase P) cleavage to generate mature 3' ends, capping by small nucleolar RNA (snoRNA)-protein (snoRNP) complexes at their ends, or the formation of circular structures. Here we review current knowledge on lncRNAs and highlight the most recent discoveries of the underlying mechanisms related to their formation. PMID- 28629950 TI - Antibiotic-Independent Adaptive Effects of Antibiotic Resistance Mutations. AB - Antibiotic usage selects for the accumulation and spread of antibiotic-resistant bacteria. However, resistance can also accumulate in the absence of antibiotic exposure. Antibiotics are often designed to target widely distributed regulatory housekeeping genes. The targeting of such genes enables these antibiotics to be useful against a wider variety of pathogens. This review highlights work suggesting that regulatory housekeeping genes of the type targeted by many antibiotics function as hubs of adaptation to conditions unrelated to antibiotic exposure. As a result of this, some mutations to the regulatory housekeeping gene targets of antibiotics confer both antibiotic resistance and an adaptive effect unrelated to antibiotic exposure. Such antibiotic-independent adaptive effects of resistance mutations may substantially affect the dynamics of antibiotic resistance accumulation and spread. PMID- 28629951 TI - Immunogenicity of Class I HLA but not preformed low MFI donor specific antibodies correlates with outcomes after first renal transplantation. AB - BACKGROUND: The role of low levels of circulating donor specific antibodies (DSA) producing negative flow cytometry cross match is not completely defined. The purpose of this study was to examine the clinical significance of preexisting low levels of class I DSAs in flow cytometry cross match (FC CM) negative first kidney transplant recipients (KTRs). METHODS: All of the KTRs (n=41) had low levels of anti-class I antibodies only. The kidney transplant outcome was evaluated by the development of a deleterious effect (DE) in recipients in the study cohort (Group 1: DE+, Group 2: DE-). Positivity for DE was determined based on the following criteria: biopsy proven transplant glomerulopathy (TG), de novo development of DSAs, increasing MFI values for preexisting DSAs, and the development of biopsy proven AMR. Anti-HLA antibodies were tested using single antigen Luminex technology. The HLAMatchmaker computer algorithm was used for the immunogenicity analysis of antibody verified (AbVer) mismatched eplets (MME) at the HLA-A and B loci. RESULTS: The results of this study showed that the number of AbVer MME is larger (P=0.03) in the group of KTR who developed DE. We also demonstrated that the number of AbVer MME is a strong predictor of post transplant DE. These results indicate that persistent weakly reactive DSA is not a significant risk factor for the development of post-transplant DE and that recipients with such antibodies can be successfully transplanted. CONCLUSIONS: Immunogenicity of AbVer MME at HLA-A and B loci is strong predictor of post transplant increases of the MFI values of preexisting or de novo developed DSA in the FC CM negative first KTR. Avoiding of transplants with more than eleven Class I AbVer MMEs may be the optimal approach to reduce the risk of kidney graft failure. PMID- 28629952 TI - Analysis of Outcomes Using Hypofractionated Tumor Bed Boost Combined With Hypofractionated Whole Breast Irradiation for Early-stage Breast Cancer. AB - INTRODUCTION: Tumor bed boost improves local control and is an important part of breast-conserving therapy. Data on the use of a hypofractioned tumor bed boost are needed. We performed a retrospective analysis of patients treated with hypofractionated whole breast irradiation (WBI) and hypofractionated boost to examine acute and delayed outcomes. MATERIALS AND METHODS: We examined the records of patients treated with hypofractionated WBI and tumor bed boost after lumpectomy for Stage 0 to II breast cancer. Local control, toxicity, and cosmetic outcome were evaluated. Patient, tumor, and treatment characteristics were evaluated including excision volume, surgical technique, surgical complications, chemotherapy, endocrine therapy administration, radiation dose, fractionation, and technique. RESULTS: A total of 143 patients received hypofractionated WBI with hypofractionated boost between 2010 and 2015. The median follow-up was 16.8 months. The median patient age was 65 years. Patient stage was 0, I, and II in 25%, 68%, and 7%, respectively. All patients received hypofractionated WBI with 42.5 Gy in 16 fractions. Sixty-one percent of women received a boost regimen of 2.66 Gy/fraction for 3 fractions. Boost techniques included noninvasive breast brachytherapy, electrons, 3-dimensional conformal radiation therapy, or a combination of techniques. Acute skin reaction was grade 1 in 65% and grade 2 in 32%. Good or excellent cosmetic outcome was achieved in 94% of patients. Subcutaneous fibrosis was the most common delayed toxicity in 19%, of which 86% was grade 1. There were no local recurrences. CONCLUSIONS: Hypofractionated tumor bed boost is well-tolerated with a low rate of toxicity and high rate of good-to excellent cosmetic outcome. PMID- 28629953 TI - 3D black blood MR angiography of the carotid arteries. A simple sequence for plaque hemorrhage and stenosis evaluation. AB - OBJECTIVES: To evaluate the diagnostic performance of a new three-dimensional T1 weighted turbo-spin-echo sequence (3D T1-w TSE) compared to 3D contrast-enhanced angiography (CE-MRA) for stenosis measurement and compared to 2D T1-w TSE for intra-plaque hemorrhage (IPH) detection. METHODS: Eighty three patients underwent carotid MRI, using a new elliptic-centric phase encoding T1-weighted 3D TSE sequence in addition to the clinical protocol. Two observers evaluated image quality, presence of flow artifacts, and presence of intra-plaque hemorrhage, and computed the NASCET degree of stenosis for CE-MRA and for the new sequence. Inter observer agreement and correlation between 3D TSE and CE-MRA for NASCET stenosis was estimated using Cohen's kappa, and correlation using linear regression and Bland-Altman plots. Histology was performed on endarterectomy samples for 18 patients. Sensitivity and specificity of 2D and 3D TSE for IPH diagnosis were computed. RESULTS: 3D TSE showed better image quality than 2D TSE (p<0.05). Interobserver agreement was good (kappa>=0.86). Correlation between 3D TSE and CE MRA was excellent (R=0.95) for NASCET stenosis. Sensitivity and specificity for IPH diagnosis was 50% and 100% for 2D TSE and 100% and 83% for the 3D TSE. CONCLUSIONS: The new 3D T1-w TSE allows both reliable measures of carotid stenosis, with a slight overestimation compared to CE-MRA (5%), and improved IPH identification, compared to 2D TSE. PMID- 28629954 TI - High resolution myelin water imaging incorporating local tissue susceptibility analysis. AB - Quantitative myelin water imaging (MWI) from signal T2* decay acquired with multiple Gradient-Recalled Echo (mGRE) sequence has been widely used since its first report. A recent study showed that with low resolution data (2mm isotropic voxels), direct application of complex fitting to a three-pool WM model with frequency shift terms could produce more stable parameter estimation for myelin water fraction mapping. MWI maps of higher spatial resolution resulting in more detailed tissue structures and reduced partial volume effects around white matter/gray matter (WM/GM) interface, however, is more desirable. Furthermore, as signal-to-noise ratio (SNR) of original images decreases due to reduced voxel size, the direct complex fitting procedure of myelin water imaging becomes more prone to systematic errors which severely compromised stability and reliability of the result. Instead of using the original part of T2* decay, this work presents a new method based on the WM-induced phase from tissue susceptibility calculated with the same mGRE dataset, in a three-pool WM model (water of myelin, axonal and extracellular water), to improve high resolution MWI. Compared with direct complex fitting for the higher spatial resolution case, the proposed method is shown to provide a more stable and accurate estimation of MWI parameters, and finer details near WM/GM boundaries with greatly reduced partial volume effects. PMID- 28629955 TI - Correlation study between DKI and conventional DWI in brain and head and neck tumors. AB - PURPOSE: To investigate the relationship between the Diffusion Kurtosis Imaging (DKI) parameters and conventional metrics provided by Diffusion-weighted imaging (DWI) in patients affected by Brain or Head and Neck (HN) cancer. METHODS: Ten patients affected by brain tumor and nine patients with HN tumor underwent a pre treatment MR examination at 3 T. The largest tumor section was manually contoured by two expert neuroradiologists. The apparent diffusion coefficient (Dapp) and apparent diffusional kurtosis (Kapp) parameters were determined at the voxel level by using the DKI model, and compared to the apparent diffusion coefficient (ADC) and the tissue diffusion coefficient (Dmono) obtained from mono-exponential fitting methods. The Akaike Information Criteria (AIC) was calculated to assess the quality of the fitting methods. Cross-correlations between all the variables were assessed using the Spearman rank test. RESULTS: Increased Kapp values were found in each lesion. All parameters were strongly related, in particular an inverse relationship emerged between median values of Kapp and Dapp/Dmono/ADC in both patient groups, while Dapp showed positive correlations with Dmono and ADC. From the analysis at the voxel level, significant inverse associations were found between Kapp and Dmono within the lesions, while a weak or moderate association emerged between Kapp and ADC or Dapp. CONCLUSIONS: A significant association between the apparent diffusional kurtosis Kapp and the tissue diffusion coefficient Dmono emerged for both brain and HN tumors at 3 T, suggesting that both variables may consistently reflect deeper insight into the microstructural characteristics of tumors. PMID- 28629956 TI - Effects of fat saturation on short T2 quantification. AB - Ultrashort TE (UTE) sequences have the capability to image tissues with very short T2s that typically appear as low signal in clinical sequences. UTE sequences can also be used in multi-echo acquisitions which allow assessment of the T2s of these tissues. Here we study the accuracy of such T2 measurements when combined with fat saturation (FS). PMID- 28629957 TI - Chemical Hand Warmer Packet Ingestion: A Case of Elemental Iron Exposure. AB - For individuals who work outdoors in the winter or play winter sports, chemical hand warmers are becoming increasingly more commonplace because of their convenience and effectiveness. A 32-year-old woman with a history of chronic pain and bipolar disorder presented to the emergency department complaining of a "warm sensation" in her mouth and epigastrium after reportedly ingesting the partial contents of a chemical hand warmer packet containing between 5 and 8 g of elemental iron. She had been complaining of abdominal pain for approximately 1 month and was prescribed unknown antibiotics the previous day. The patient denied ingestion of any other product or medication other than what was prescribed. A serum iron level obtained approximately 6 hours after ingestion measured 235 micrograms/dL (reference range 40-180 micrograms/dL). As the patient demonstrated no new abdominal complaints and no evidence of systemic iron toxicity, she was discharged uneventfully after education. However, the potential for significant iron toxicity exists depending on the extent of exposure to this or similar products. Treatment for severe iron toxicity may include fluid resuscitation, whole bowel irrigation, and iron chelation therapy with deferoxamine. Physicians should become aware of the toxicity associated with ingestion of commercially available hand warmers. Consultation with a medical toxicologist is recommended. PMID- 28629958 TI - The Provision of Prescription-Only Medicines for Use on UK-based Overseas Expeditions. AB - Expedition teams without accompanying medical professionals traveling overseas from the UK frequently carry medical kits containing prescription-only medicines (POMs). Access to safe, basic POMs whilst on expedition is important, as the quality and availability of medicines in-country may not be acceptable, and delay in treatment may be hazardous. At present, there is no published guidance relating to drug acquisition and administration in these situations. In the UK, a number of different practices are currently in use, with uncertainty and medicolegal concerns currently hampering safe and efficient provision of POMs on overseas expeditions. A guideline is proposed for the management of prescription only medications in an expedition setting. PMID- 28629959 TI - Glycemic Control and Muscle Damage in 3 Athletes With Type 1 Diabetes During a Successful Performance in a Relay Ultramarathon: A Case Report. AB - Ultramarathon races are fairly demanding and impose substantial physiological stress on healthy athletes. These competitions may thus be considerably more challenging for individuals with diabetes. This case study aims to describe glycemic control, muscle damage, inflammation, and renal function in 3 athletes with type 1 diabetes during a successful performance in a relay ultramarathon. The team completed the race in 29 hours and 28 minutes, earning third place. The total distance covered by each athlete was 68.7, 84.5, and 65.1 km. Most blood glucose levels showed that athletes were in a zone where it was safe to exercise (90-250 mg/dL or 5.0-13.9 mmol/L). Creatine kinase, lactate dehydrogenase, and aspartate aminotransferase serum levels increased 1.2- to 50.7-fold prerace to postrace, and were higher than the reference ranges for all the athletes postrace. Blood leukocytes, neutrophils, and serum C-reactive protein (CRP) increased 1.6- to 52-fold prerace to postrace and were higher than the reference ranges for 2 athletes after the race. Serum creatinine increased 1.2-fold prerace to postrace for all the athletes but did not meet the risk criteria for acute kidney injury. In conclusion, our main findings show evidence of satisfactory glycemic control in athletes with type 1 diabetes during a relay ultramarathon. Moreover, elevation of muscle damage and inflammatory biomarkers occurred without affecting renal function and challenging the maintenance of blood glucose among athletes. These findings are novel and provide an initial understanding of the physiological responses in athletes with type 1 diabetes during ultramarathon races. PMID- 28629960 TI - Molecular cloning and mRNA expression pattern of Sox4 in Paramisgurnus dabryanus. AB - Sox4 belonged to the SoxC subfamily of the Sox family, which play important roles in the development of the vertebrate gonad and nervous system. A Sox4 homologue was cloned from brain of Paramisgurnus dabryanus by using homologous cloning and rapid amplification of cDNA ends (RACE), designated as PdSox4. The full-length cDNA was 2163bp, containing the 759bp 5'-untranslated region, 267bp 3' untranslated region and encoding a putative protein of 378 amino acids with a characteristic high mobility group box (HMG-box) DNA-binding domain of 79 amino acids with the specific motif (RPMNAFMVW). Alignment and phylogenetic analyses indicated that PdSox4 shares highly identical sequence with Sox4 homologues from different species. The signal peptide analysis predicted that PdSox4 is a non secretory protein. The hydropathy profile of PdSox4 protein revealed that this protein is hydrophilic in nature. The expression profiles of PdSox4 in different developmental stages and various adult tissues of sexs were analyzed by quantitative real-time RT-PCR (qRT-PCR) and In situ hybridization (ISH). The results showed that PdSox4 was ubiquitously expressed during embryogenesis and various adult tissues, especially in central nervous system. Tissue distribution analyses revealed that PdSox4 was expression in developing germ cells. Taken together, these preliminary findings suggested that PdSox4 is highly conserved during vertebrate evolution and involved in a wide range of developmental processes including embryogenesis, neurogenesis and gonad development. PMID- 28629961 TI - Tortoises in front of mirrors: Brain asymmetries and lateralized behaviours in the tortoise (Testudo hermanni). AB - Brain lateralization in response to social stimuli is well known for its involvement of the right hemisphere in several vertebrate species, including humans. This study aimed to investigate the laterality of the social behavior during the mirror-images inspection in tortoises (Testudo hermanni). In a rectangular apparatus, in presence or in absence of two mirrors as the longer walls, we assessed: 1) the animal's position and 2) the monocular viewing compared to the longer walls, 3) the paw used to start a movement from a resting position. Here we provide the first evidence of lateralization towards social stimuli in tortoises, a reptile that is likely to lead mostly a solitary life, but also able to show a few basic abilities in social cognition. Results revealed a preference to spend significantly more time in peripheral positions, mainly in the presence of mirrors. Moreover, a consistent left-eye preference to inspect the mirrors was observed, especially when close to them. In contrast, a significant right-eye preference appeared in absence of mirrors, when tortoises occupied the central areas. Findings show a significant preference for right-paw use in starting movements, when mirrors were present. Results are discussed with reference to other evidence of brain asymmetry. PMID- 28629962 TI - Pharmacological inhibition of Anaplastic Lymphoma Kinase rescues spatial memory impairments in Neurofibromatosis 1 mutant mice. AB - Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations are found in 90% of patients with neurofibromatosis, a syndrome associated with disabling cognitive impairment. Drosophila studies have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 in cognitive performance. In addition, pharmacologic inhibition of Alk improves cognitive performance in heterozygous NF1 mutant flies. In this study, we tested whether pharmacological inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments. Cognitive impairment of spatial memory retention observed in heterozygous NF1 mutant mice was rescued by the Alk inhibitor. These data support the hypothesis that inhibition of Alk may cognitively benefit patients with Neurofibromatosis 1. PMID- 28629963 TI - Environmental enrichment reduces innate anxiety with no effect on depression-like behaviour in mice lacking the serotonin transporter. AB - Along with being the main target of many antidepressant medications, the serotonin transporter (5-HTT) is known to be involved in the pathophysiology of depression and anxiety disorders. In line with this, mice with varying 5-HTT genotypes are invaluable tools to study depression- and anxiety-like behaviours as well as the mechanisms mediating potential therapeutics. There is clear evidence that both genetic and environmental factors play a role in the aetiology of psychiatric disorders. In that regard, housing paradigms which seek to enhance cognitive stimulation and physical activity have been shown to exert beneficial effects in animal models of neuropsychiatric disorders. In the present study, we examined the effects of environmental enrichment on affective-like behaviours and sensorimotor gating function of 5-HTT knock-out (KO) mice. Using the elevated plus maze and the light-dark box, we found that environmental enrichment ameliorated the abnormal innate anxiety of 5-HTT KO mice on both tests. In contrast, environmental enrichment did not rescue the depression-like behaviour displayed by 5-HTT KO mice in the forced-swim test. Finally, measuring pre-pulse inhibition, we found no effect of genotype or treatment on sensorimotor gating. In conclusion, our data suggest that environmental enrichment specifically reduces innate anxiety of 5-HTT KO mice with no amelioration of the depression like behaviour. This has implications for the current use of clinical interventions for patients with symptoms of both anxiety and depression. PMID- 28629964 TI - A novel heterocyclic compound improves working memory in the radial arm maze and modulates the dopamine receptor D1R in frontal cortex of the Sprague-Dawley rat. AB - A series of compounds have been shown to enhance cognitive function via the dopaminergic system and indeed the search for more active and less toxic compounds is continuing. It was therefore the aim of the study to synthetise and test a novel heterocyclic compound for cognitive enhancement in a paradigm for working memory. Specific and effective dopamine re-uptake inhibition DAT (IC50=4,1+/-0,8MUM) made us test this compound in a radial arm maze (RAM) in the rat. CE-125 (4-((benzhydrylsulfinyl)methyl)-2-cyclopropylthiazole), was tested for dopamine (DAT), serotonin and norepinephrine re-uptake inhibition by a well established system. The working memory index (WMI) was evaluated in male Sprague Dawley rats that were intraperitoneally injected with CE-125 (1 or 10mg/kg body weight). In order to evaluate basic neurotoxicity, the open field, elevated plus maze, rota rod studies and the forced swim test were carried out. Frontal cortex was taken at the last day of the RAM test and dopamine receptors D1R and D2R, DAT and phosphorylated DAT protein levels were determined. On the 10th day both doses were increasing the WMI as compared to the vehicle-treated group. In both, trained and treated groups, D1R levels were significantly reduced while D2R levels were unchanged. DAT levels were comparable between all groups while phosphorylated DAT levels were increased in the trained group treated with 1mg/kg body weight. CE-125 as a probably non-neurotoxic compound and specific reuptake inhibitor was shown to increase performance (WMI) and modulation of the dopaminergic system is proposed as a possible mechanism of action. PMID- 28629965 TI - Cortical Atrophy is Associated with Accelerated Cognitive Decline in Mild Cognitive Impairment with Subsyndromal Depression. AB - OBJECTIVES: To investigate the association between cognitive decline and cortical atrophy in individuals with mild cognitive impairment (MCI) and chronic subsyndromal symptoms of depression (SSD) over a 4-year period. DESIGN: Prospective cohort study. SETTING: Multicenter, clinic-based. PARTICIPANTS: Within the Alzheimer's Disease Neuroimaging Initiative repository, the Neuropsychiatric Inventory was used to identify individuals with MCI and stable endorsement (SSD group N = 32) or no endorsement (non-SSD group N = 69) of depressive symptoms across time points. MEASUREMENTS: Repeated measures of cognitive outcomes, cortical atrophy, and their associations were evaluated with mixed effects models adjusting for age, education, sex, and APOE genotype. RESULTS: The SSD group demonstrated accelerated decline on measures of global cognition (Alzheimer Disease Assessment Scale; df = 421, t = 2.242, p = 0.025), memory (Wechsler Memory Scale-Revised Logical Memory II; df = 244, t = -2.525, p = 0.011), information processing speed (Trail Making Test Parts A [df = 421, t = 2.376, p = 0.018] and B [df = 421, t = 2.533, p = 0.012]), and semantic fluency (Category Fluency; df = 424, t = -2.418, p = 0.016), as well as accelerated frontal lobe (df = 341, t = -2.648, p = 0.008) and anterior cingulate (df = 341, t = -3.786, p < 0.001) atrophy. No group differences were observed for rate of decline on measures of attention, learning, and confrontation naming or for rate of atrophy in any other regions. Accelerated frontal lobe and anterior cingulate atrophy was associated with cognitive decline on measures of global cognition, information processing speed, and semantic fluency (all p < 0.05), but not memory. CONCLUSIONS: Individuals with chronic SSD may represent an MCI subgroup that is highly vulnerable to accelerated cognitive decline, an effect that may be governed by frontal lobe and anterior cingulate atrophy. PMID- 28629966 TI - Pharmacological characterisation and functional roles for egg-laying of a beta adrenergic-like octopamine receptor in the brown planthopper Nilaparvata lugens. AB - Octopamine, the invertebrate counterpart of adrenaline and noradrenaline, controls and modulates many physiological and behavioral processes in protostomes. It mediates its effects by binding to specific receptors belonging to the superfamily of G-protein coupled receptors. We report the cloning of a cDNA from the brown planthopper (Nloa2b2) sharing high similarity with members of the OA2B2 receptor class. Activation of NlOA2B2 by octopamine increased the production of cAMP in a dose-dependent manner (EC50 = 114 nM). Tyramine also activated the receptor but with much less potency than octopamine. Using a series of known agonists and antagonists of octopamine receptors and cAMP measurements, we observed a rather unique pharmacological profile of NlOA2B2. The potency ranking of the tested agonists was naphazoline > clonidine. The activated effect of octopamine is abolished by co-incubation with epinastine, mianserin, phentolamine, methiothepin, butaclamol or methysergide. Nloa2b2 was expressed in different developmental stages and in various tissues including female reproductive regions known to be involved in egg-laying behavior. Using in vivo pharmacology and RNAi methodology, we demonstrated that interference of NlOA2B2 signaling pathway had a strong impact on the egg-laying behavior of female brown planthopper. The data presented here mark the first comprehensive study-from gene to behavior-of a OA2B2 receptor in the rice brown planthopper. PMID- 28629967 TI - Isolation of fungi from dung of wild herbivores for application in bioethanol production. AB - Producing biofuels such as ethanol from non-food plant material has the potential to meet transportation fuel requirements in many African countries without impacting directly on food security. The current shortcomings in biomass processing are inefficient fermentation of plant sugars, such as xylose, especially at high temperatures, lack of fermenting microbes that are able to resist inhibitors associated with pre-treated plant material and lack of effective lignocellulolytic enzymes for complete hydrolysis of plant polysaccharides. Due to the presence of residual partially degraded lignocellulose in the gut, the dung of herbivores can be considered as a natural source of pre-treated lignocellulose. A total of 101 fungi were isolated (36 yeast and 65 mould isolates). Six yeast isolates produced ethanol during growth on xylose while three were able to grow at 42 degrees C. This is a desirable growth temperature as it is closer to that which is used during the cellulose hydrolysis process. From the yeast isolates, six isolates were able to tolerate 2g/L acetic acid and one tolerated 2g/L furfural in the growth media. These inhibitors are normally generated during the pre-treatment step. When grown on pre-treated thatch grass, Aspergillus species were dominant in secretion of endo glucanase, xylanase and mannanase. PMID- 28629968 TI - Inhibitor tolerance of a recombinant flocculating industrial Saccharomyces cerevisiae strain during glucose and xylose co-fermentation. AB - Lignocellulose-derived inhibitors have negative effects on the ethanol fermentation capacity of Saccharomyces cerevisiae. In this study, the effects of eight typical inhibitors, including weak acids, furans, and phenols, on glucose and xylose co-fermentation of the recombinant xylose-fermenting flocculating industrial S. cerevisiae strain NAPX37 were evaluated by batch fermentation. Inhibition on glucose fermentation, not that on xylose fermentation, correlated with delayed cell growth. The weak acids and the phenols showed additive effects. The effect of inhibitors on glucose fermentation was as follows (from strongest to weakest): vanillin>phenol>syringaldehyde>5-HMF>furfural>levulinic acid>acetic acid>formic acid. The effect of inhibitors on xylose fermentation was as follows (from strongest to weakest): phenol>vanillin>syringaldehyde>furfural>5-HMF>formic acid>levulinic acid>acetic acid. The NAPX37 strain showed substantial tolerance to typical inhibitors and showed good fermentation characteristics, when a medium with inhibitor cocktail or rape straw hydrolysate was used. This research provides important clues for inhibitors tolerance of recombinant industrial xylose-fermenting S. cerevisiae. PMID- 28629970 TI - Variation analysis of bacterial polyhydroxyalkanoates production using saturated and unsaturated hydrocarbons. AB - Polyhydroxyalkanoates (PHA) are efficient, renewable and environment friendly polymeric esters. These polymers are synthesized by a variety of microbes under stress conditions. This study was carried out to check the suitability of waste frying oil in comparison to other oils for economical bioplastic production. Six bacterial strains were isolated and identified as Bacillus cereus (KF270349), Klebsiella pneumoniae (KF270350), Bacillus subtilis (KF270351), Brevibacterium halotolerance (KF270352), Pseudomonas aeruginosa (KF270353), and Stenotrophomonas rhizoposid (KF270354) by ribotyping. All strains were PHA producers so were selected for PHA synthesis using four different carbon sources, i.e., waste frying oil, canola oil, diesel and glucose. Extraction of PHA was carried out using sodium hypochlorite method and maximum amount was detected after 72h in all cases. P. aeruginosa led to maximum PHA production after 72h at 37 degrees C and 100rpm using waste frying oil that was 53.2% PHA in comparison with glucose 37.8% and cooking oil 34.4%. B. cereus produced 40% PHA using glucose as carbon source which was high when compared against other strains. A significantly lesser amount of PHA was recorded with diesel as a carbon source for all strains. Sharp Infrared peaks around 1740-1750cm-1 were present in Fourier Transform Infrared spectra that correspond to exact position for PHA. The use of waste oils and production of poly-3hydroxybutyrate-co-3hydroxyvalerate (3HB-co-3HV) by strains used in this study is a good aspect to consider for future prospects as this type of polymer has better properties as compared to PHBs. PMID- 28629969 TI - Prevalence and serotype distribution of Listeria monocytogenes isolated from foods in Montevideo-Uruguay. AB - The aim of this work was to study the prevalence of Listeria monocytogenes in foods obtained in retail shops and food industries located in Montevideo-Uruguay, and to identify the serogroups of the obtained isolates. Three-thousand one hundred and seventy-five food samples (frozen, deli meats, ready-to-eat and cheese) were analyzed. The obtained isolates were serogrouped by multiplex PCR and serotyped by conventional procedure. Genetic comparisons were performed using pulsed-field gel electrophoresis on a sub-set of isolates belonging to the same serotype successively recovered from the same establishment. L. monocytogenes was isolated from 11.2% of samples. The highest prevalence was observed in frozen foods (38%), followed by cheese (10%). 1/2b and 4b were the most frequently identified serotypes. In six of 236 analyzed establishments we successively recovered L. monocytogenes isolates belonging to the same serotype. Most of them corresponded to serotype 1/2b. Pulsed-field gel electrophoresis profiles suggest that at least 33% of L. monocytogenes 1/2b isolates are genetically related and that may remain viable for prolonged periods. The observed prevalence of L. monocytogenes was lower than reported in neighboring countries. Our findings highlight the role that frozen foods may play in the spread of this pathogen, and the relevance of serotypes 1/2b and 4b. PMID- 28629971 TI - Survey of pathogens in threatened wild red-tailed Amazon parrot (Amazona brasiliensis) nestlings in Rasa Island, Brazil. AB - The red-tailed Amazon parrot (Amazona brasiliensis) is a threatened species of psittacine bird that inhabit coastal regions of Brazil. In view of the threat of this species, the aim of this study was to perform a health evaluation in wild nestlings in Rasa Island, determining the prevalence of enterobacteria and infectious agents according to type of nest. Blood samples were collected from 64 birds and evaluated for antibodies of Chlamydia psittaci by commercial dot-blot ELISA. Cloacal and oropharyngeal swabs samples were collected from 23 birds from artificial wooden nests, 15 birds from PVC nests and 2 birds from natural nests for microbiological analysis. Swab samples were collected from 58 parrots for C. psittaci detection by PCR and from 50 nestlings for Avian Influenza, Newcastle Disease and West Nile viruses' detection analysis by real-time RT-PCR. Ten bacterial genera and 17 species were identified, and the most prevalent were Escherichia coli and Klebsiella oxytoca. There was no influence of the type of nest in the nestlings' microbiota. All samples tested by ELISA and PCR were negative. There is currently insufficient information available about the health of A. brasiliensis and data of this study provide a reference point for future evaluations and aid in conservation plans. PMID- 28629972 TI - Characterization of dioxygenases and biosurfactants produced by crude oil degrading soil bacteria. AB - Role of microbes in bioremediation of oil spills has become inevitable owing to their eco friendly nature. This study focused on the isolation and characterization of bacterial strains with superior oil degrading potential from crude-oil contaminated soil. Three such bacterial strains were selected and subsequently identified by 16S rRNA gene sequence analysis as Corynebacterium aurimucosum, Acinetobacter baumannii and Microbacterium hydrocarbonoxydans respectively. The specific activity of catechol 1,2 dioxygenase (C12O) and catechol 2,3 dioxygenase (C23O) was determined in these three strains wherein the activity of C12O was more than that of C23O. Among the three strains, Microbacterium hydrocarbonoxydans exhibited superior crude oil degrading ability as evidenced by its superior growth rate in crude oil enriched medium and enhanced activity of dioxygenases. Also degradation of total petroleum hydrocarbon (TPH) in crude oil was higher with Microbacterium hydrocarbonoxydans. The three strains also produced biosurfactants of glycolipid nature as indicated d by biochemical, FTIR and GCMS analysis. These findings emphasize that such bacterial strains with superior oil degrading capacity may find their potential application in bioremediation of oil spills and conservation of marine and soil ecosystem. PMID- 28629973 TI - alpha-Eleostearic acid-containing triglycerides for a continuous assay to determine lipase sn-1 and sn-3 regio-preference. AB - Lipases are essentially described as sn-1 and sn-3 regio-selective. Actually few methods are available to measure this lipase regio-selectivity, moreover they require chiral chromatography analysis or specific derivations which are discontinuous and time consuming. In this study we describe a new, convenient, sensitive and continuous spectrophotometric method to screen lipases regio selectivity using synthetic triglycerides (TG) containing alpha-eleostearic acid (9Z, 11E, 13E-octadecatrienoic acid) either at the sn-1 position [1-alpha eleostearoyl-2,3-octadecyl-sn-glycerol (sn-EOO)] or at the sn-3 position [1,2 octadecyl-3-alpha-eleostearoyl-sn-glycerol (sn-OOE)] and coated onto the wells of microtiter plates. A non-hydrolysable ether bond, with a non UV-absorbing alkyl chain, was introduced at the other sn positions to prevent acyl chain migration during TG synthesis or lipolysis. The synthesis of TG containing alpha eleostearic acid was performed from S-glycidol in six steps to obtain sn-EOO and in five steps to sn-OOE. The alpha-eleostearic acid conjugated triene constitutes an intrinsic chromophore and, consequently, confers the strong UV absorption properties of this free fatty acid as well as of the TG harboring it. The lipase activity on coated sn-EOO or sn-OOE was measured by the increase in the absorbance at 272nm due to the transition of alpha-eleostearic acid from the adsorbed to the soluble state. Human and porcine pancreatic lipases, guinea pig pancreatic lipase related protein 2, Thermomyces lanuginosus lipase, Candida antarctica lipase A and Candida antarctica lipase B were all used to validate the assay. This continuous high-throughput screening method could determine directly without any processes after lipolysis the regio-selectivity of various lipases. PMID- 28629974 TI - The effects of changes in object location on object identity detection: A simultaneous EEG-fMRI study. AB - Object identity and location are bound together to form a unique integration that is maintained and processed in visual working memory (VWM). Changes in task irrelevant object location have been shown to impair the retrieval of memorial representations and the detection of object identity changes. However, the neural correlates of this cognitive process remain largely unknown. In the present study, we aim to investigate the underlying brain activation during object color change detection and the modulatory effects of changes in object location and VWM load. To this end we used simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings, which can reveal the neural activity with both high temporal and high spatial resolution. Subjects responded faster and with greater accuracy in the repeated compared to the changed object location condition, when a higher VWM load was utilized. These results support the spatial congruency advantage theory and suggest that it is more pronounced with higher VWM load. Furthermore, the spatial congruency effect was associated with larger posterior N1 activity, greater activation of the right inferior frontal gyrus (IFG) and less suppression of the right supramarginal gyrus (SMG), when object location was repeated compared to when it was changed. The ERP-fMRI integrative analysis demonstrated that the object location discrimination-related N1 component is generated in the right SMG. PMID- 28629975 TI - Anatomical and functional properties of the foot and leg representation in areas 3b, 1 and 2 of primary somatosensory cortex in humans: A 7T fMRI study. AB - Primary somatosensory cortex (S1) processes somatosensory information and is composed of multiple subregions. In particular, tactile information from the skin is encoded in three subregions, namely Brodmann areas (BAs) 3b, 1 and 2, with each area representing a complete map of the contralateral body. Although, much is known about the somatotopic organization of the hand in human S1, less research has been carried out regarding the somatotopic maps of the foot and leg in S1. Moreover, a latero-medial S1 organization along the superior part of the postcentral gyrus has been reported when moving from hip to toes, yet to date there is no study investigating leg/foot maps within the different subregions of S1. Using ultra-high field MRI (7T), we mapped six cortical representations of the lower limb (hip to toes) at the single subject level and performed this analysis separately for BAs 3b, 1 and 2. Analyzing the BOLD responses associated with tactile stimulations of the mapped foot and leg regions on each side, we quantified the extent and the strength of activation to determine somatotopic organization. In addition, we investigated whether each mapped representation also responded to the stimulation of other body parts (i.e. response selectivity) and conducted dissimilarity analysis relating these anatomical and functional properties of S1 to the physical structure of the lower limbs. Our data reveal somatotopy for the leg, but not for the foot in all investigated BAs, with large inter-subject variability. We found only minor differences between the properties of the three investigated BAs, suggesting that S1 maps for the lower limbs differ from those described for the hand. We also describe greater extent/strength of S1 activation for the big toe representation (compared to the other mapped representations) within all BAs, suggesting a possible homology between the first digit of upper and lower extremity in humans, and report different patterns of selectivity in the foot representations (i.e. lower selectivity) compared to the other leg representations (i.e. greater selectivity). These data provide a detailed description of human S1 subregions for the foot and leg, highlight the importance of high-resolution mapping studies and of single subject analysis, and indicate potential differences between the lower and the upper limb. PMID- 28629976 TI - MAPBOT: Meta-analytic parcellation based on text, and its application to the human thalamus. AB - Meta-analysis of neuroimaging results has proven to be a popular and valuable method to study human brain functions. A number of studies have used meta analysis to parcellate distinct brain regions. A popular way to perform meta analysis is typically based on the reported activation coordinates from a number of published papers. However, in addition to the coordinates associated with the different brain regions, the text itself contains considerably amount of additional information. This textual information has been largely ignored in meta analyses where it may be useful for simultaneously parcellating brain regions and studying their characteristics. By leveraging recent advances in document clustering techniques, we introduce an approach to parcellate the brain into meaningful regions primarily based on the text features present in a document from a large number of studies. This new method is called MAPBOT (Meta-Analytic Parcellation Based On Text). Here, we first describe how the method works and then the application case of understanding the sub-divisions of the thalamus. The thalamus was chosen because of the substantial body of research that has been reported studying this functional and structural structure for both healthy and clinical populations. However, MAPBOT is a general-purpose method that is applicable to parcellating any region(s) of the brain. The present study demonstrates the powerful utility of using text information from neuroimaging studies to parcellate brain regions. PMID- 28629977 TI - Neural representations of the concepts in simple sentences: Concept activation prediction and context effects. AB - Although it has been possible to identify individual concepts from a concept's brain activation pattern, there have been significant obstacles to identifying a proposition from its fMRI signature. Here we demonstrate the ability to decode individual prototype sentences from readers' brain activation patterns, by using theory-driven regions of interest and semantic properties. It is possible to predict the fMRI brain activation patterns evoked by propositions and words which are entirely new to the model with reliably above-chance rank accuracy. The two core components implemented in the model that reflect the theory were the choice of intermediate semantic features and the brain regions associated with the neurosemantic dimensions. This approach also predicts the neural representation of object nouns across participants, studies, and sentence contexts. Moreover, we find that the neural representation of an agent-verb-object proto-sentence is more accurately characterized by the neural signatures of its components as they occur in a similar context than by the neural signatures of these components as they occur in isolation. PMID- 28629978 TI - Dual roles of TPGS based microemulsion for tacrolimus: Enhancing the percutaneous delivery and anti-psoriatic efficacy. AB - In this study, we demonstrate for the first time the dual roles of Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS) based microemulsion (ME) for tacrolimus (TAC) to enhance TAC percutaneous delivery and anti-psoriatic efficacy. The ME formulation was developed and optimized based on pseudo-ternary phase diagrams combined with in vitro permeation. The result of Fourier transform infrared spectroscopy (FTIR) demonstrated that TAC was completely solubilized in the TPGS ME. In vitro permeation studies showed that TPGS-ME enhanced TAC permeation through and into the skin, and the enhanced deposition of TAC in the normal or psoriatic skin was further confirmed in vivo. The cellular uptake performed with HaCaT cells presented more pronounced uptake of TPGS-ME. Topical TAC-TPGS-ME treated imiquimod-induced psoriasis in mice more efficaciously than the commercial formulation of TAC (Protopic(r)), which is consistent with the enhanced TAC levels by TAC-TPGS-ME in the psoriatic skin. Haematoxylin and Eosin (HE) staining revealed that TAC-TPGS-ME significantly diminished the severity of the psoriasis-like skin inflammation. Moreover, TPGS-ME vehicle exhibited a moderate anti-inflammatory activity, which indicated that TPGS acted as a potential adjuvant in the TAC anti-psoriasis process, and the synergism was identified in anti-proliferation against HaCaT cells. The colloidal nano-carrier combined ME with TPGS is a potential approach for percutaneous delivery of TAC, which exploited both virtues of ME and TPGS to obtain the synergetic effects of enhanced permeability and anti-psoriatic efficacy. PMID- 28629979 TI - Nasal vaccination with poly(beta-amino ester)-poly(d,l-lactide-co-glycolide) hybrid nanoparticles. AB - Mucosal vaccination stimulates both mucosal and systemic immunity. However, mucosal applications of vaccine antigens in their free form generally result in poor systemic immune responses and need adjuvantation. In this study, bovine serum albumin loaded, new hybridised poly(beta-amino ester)-poly(d,l-lactide-co glycolide) nanoparticles were prepared by double emulsion-solvent evaporation method, characterised and evaluated in vivo as nasal vaccine carriers. Cationic spherical particles with a mean size of 240nm, good physical stability and high encapsulation efficiency were obtained. Protein structure was not affected throughout preparation and minimal toxicity was shown in Calu-3 and A549 cells. Nasal vaccination with these nanoparticles revealed markedly higher humoral immune responses compared with free antigen following intranasal and subcutaneous immunisation. Mucosal immune response was also stimulated and cytokine titres indicated that Th1 and Th2 pathways were successfully activated. This study shows that the formulated hybrid nanoparticles can be a promising carrier for nasal immunisation of poor antigenic proteins. PMID- 28629981 TI - Retrospective Quality by Design (rQbD) applied to the optimization of orodispersible films. AB - The study demonstrates the application of QbD based on historical data for a product at a later development stage - retrospective QbD (rQbD). More specifically, it is investigated the root-cause for the observed slower drug release in Orodispersible Films (ODFs) during storage. Risk assessment tools were used to identify parameters affecting ODFs critical quality attributes, namely percent drug release and residual water content. The parameters room temperature, room relative humidity, drying temperature and mixing equipment were used in the statistical modeling of the available data. The estimated models were then used to define the feasible working region. Statistical modeling indicates that initial residual water content of the ODFs is mainly affected by 2nd order interactions of room temperature, room relative humidity and drying temperature, while the stability of drug release profile is mostly influenced by room temperature and an interaction between room relative humidity and drying temperature. Depending on the drying temperature employed the effect of room temperature and room relative humidity change significantly. This work shows that it is possible to apply rQbD to achieve a greater understanding of the manufacturing process of ODFs and to define a proper design space. PMID- 28629980 TI - Polymer nanoassemblies with hydrophobic pendant groups in the core induce false positive siRNA transfection in luciferase reporter assays. AB - Poly(ethylene glycol)-conjugated polyethylenimine (PEG-PEI) is a widely studied cationic polymer used to develop non-viral vectors for siRNA therapy of genetic disorders including cancer. Cell lines stably expressing luciferase reporter protein typically evaluate the transfection efficacy of siRNA/PEG-PEI complexes, however recent findings revealed that PEG-PEI can reduce luciferase expression independent of siRNA. This study elucidates a cause of the false positive effect in luciferase assays by using polymer nanoassemblies (PNAs) made from PEG, PEI, poly-(l-lysine) (PLL), palmitate (PAL), and deoxycholate (DOC): PEG-PEI (2P), PEG PEI-PAL (3P), PEG-PLL (2P'), PEG-PLL-PAL (3P'), and PEG-PEI-DOC (2PD). In vitro transfection and western blot assays of luciferase using a colorectal cancer cell line expressing luciferase (HT29/LUC) concluded that 2P and 2P' caused no luciferase expression reduction while hydrophobically modified PNAs induced a 35 50% reduction (3P'<2PD<3P). Although cell viability remained stagnant, 3P triggered cellular stress responses including increased membrane porosity and decreased ATP and cellular protein concentrations. Raman spectroscopy suggested that hydrophobic groups influence PNA conformation changes, which may have caused over-ubiquitination and degradation of luciferase in the cells. These results indicate that hydrophobically modified PEG-PEI induces cellular distress causing over-ubiquitination of the luciferase protein, producing false positive siRNA transfection in the luciferase assay. PMID- 28629982 TI - Polymeric nanoparticles: Promising platform for drug delivery. AB - Nano medicine had viewed countless breakthroughs in drug delivery implementations. The main objective of nanotechnology application in delivering and carrying many promising therapeutics is to assure drugs carriage to their action sites, to maximize the pharmacological desired influence of remedies and to overcome their limitations and drawbacks that would hinder the required effectiveness. One of these applications was the particulates type of nano-range in size and tremendous impact in achievement. About this specific diversity of particulates, the different elaboration methodologies, mandatory and elementary components for design, and examples of splendid success stories for these particulates were emphasized in this humble review. Challenges such as oral delivery probability for peptide moieties and enhancement the harshly passage process of drugs across the blood brain barriers were accepted and defeated by the almost insurmountable latterly mentioned particulates. Behold, the polymeric nanoparticles. PMID- 28629983 TI - Self-assembly nanostructure controlled sustained release, activity and stability of peptide drugs. AB - Peptides are considered as a new generation of drugs due to their high structural and functional diversity. However, the development of peptide drugs is always limited by their poor stability and short circulation time. Carriers are applied for peptide drug delivery, but there may be problems like poor loading efficiency and undesired xenobiotic toxicity. Peptide self-assembly is an effective approach to improve the stability and control the release of peptide drugs. In this study, two self-assembling anticancer peptides are designed by appending a pair of glutamic acid and asparagine to either the N-terminus or the C-terminus of a lytic peptide. This simple, yet rational sequence modification was made to change the amphiphilic pattern and secondary structural content of the parent peptide, thereby modulating its self-assembly process. It was found that the N-terminus modified peptide favors the formation of nanofibrils and the peptide with C terminal modification formed micelles. Although both nanostructures showed prolonged action profiles and improved serum stability compared to the parent peptide, the morphology of the nanostructures is highly critical to manipulate the release profile of the free peptide from the assembly and regulate their bioactivity. We believe the self-assembly approach demonstrated in this study can be applied to a variety of therapeutic peptide drugs to improve their stability and therapeutic activity for the development of carrier-free drug delivery system. PMID- 28629984 TI - The contribution of the in-vivo fate of an oil depot to drug absorption. AB - Sustained release of lipophilic compounds can be achieved with oil depots. These parenteral formulations are generally injected in the vastus lateralis and deltoid muscle. It is known that the absorption rate differs between these two muscles. The reason for this is not fully understood. The aim of the current study was to investigate the fate of an oil depot in different tissues to elucidate whether the disappearance rate of oil is the cause of observed differences in absorption rate. A study with healthy volunteers was conducted to determine 1.0mL oil depots in the vastus lateralis and deltoid muscle for two weeks. The spatial distribution of the oil depots was determined using MRI. Additionally, a study in rats was conducted to microscopically examine the oil immediately and after 31days of injection. All rats were injected with a 0.1mL oil depot with and without benzyl alcohol (BOH), a commonly used excipient in oil depots. In humans, it was shown that all oil depots were equal in volume and surface area directly after injection. Moreover, the disappearance rate for all oil depots was similar; within one week there was no depot visible anymore by MRI. This in contrast to the depots in rats, which were still microscopically visible after 31days. It is concluded from these observations that the oil is dispersed to small droplets in the course of time. The resulting increase in surface area does not lead to an increase in absorption rate however. The results of this paper show that the variation in drug absorption as found for the two muscles is not caused by a distinction in surface areas or disappearance rates of the oil depots. Therefore, it is argued that the local tissue drainage (e.g. lymph flow) plays a considerable role in drug absorption from oil depots, whereby the lymph flow differs between the muscles. PMID- 28629985 TI - Letter to Editor: "Intra-operative assessment of excised breast tumour margins using clear edge imaging device". PMID- 28629986 TI - Identification of influenza polymerase inhibitors targeting polymerase PB2 cap binding domain through virtual screening. AB - Influenza A virus is the major cause of epidemics and pandemics worldwide. In this study, virtual screening was used to identify compounds interacting with influenza A polymerase PB2 cap-binding domain (CBD). With a database of 21,351 small molecules, 28 candidate compounds were tested and one compound (225) was identified as hit compound. Compound 225 and three of its analogs (225D1, 426 and 426Br) were found to bind directly to PB2 CBD by surface plasmon resonance (SPR). The evaluation of compounds 426Br and 225 indicated that they could bind to PB2 CBD and inhibit influenza virus at low micromolar concentration. They were predicted to bind the cap binding site of the protein by molecular modeling and were confirmed by SPR assay using PB2 CBD mutants. These two compounds have novel scaffolds and could be further developed into lead compound for influenza virus inhibition. PMID- 28629987 TI - Anti-herpes simplex virus type 1 activity of Houttuynoid A, a flavonoid from Houttuynia cordata Thunb. AB - Early events in herpes simplex virus type 1 (HSV-1) infection reactivate latent human immunodeficiency virus, Epstein-Barr virus, and human papillomavirus in the presence of acyclovir (ACV). The common use of nucleoside analog medications, such as ACV and pencyclovir, has resulted in the emergence of drug-resistant HSV 1 strains in clinical therapy. Therefore, new antiherpetics that can inhibit early events in HSV-1 infection should be developed. An example of this treatment is Houttuynia cordata Thunb. water extract, which can inhibit HSV-1 infection through multiple mechanisms. In this study, the anti-HSV-1 activity of Houttuynoid A, a new type of flavonoid isolated from H. cordata, was investigated. Three different assays confirmed that this compound could exhibit strong in vitro anti-HSV-1 activity. One assay verified that this compound could inhibit HSV-1 multiplication and prevent lesion formation in a HSV-1 infection mouse model. Mechanism analysis revealed that this compound could inactivate HSV 1 infectivity by blocking viral membrane fusion. Moreover, Houttuynoid A exhibited antiviral activities against other alpha herpes viruses, such as HSV-2 and varicella zoster virus (VZV). In conclusion, Houttuynoid A may be a useful antiviral agent for HSV-1. PMID- 28629988 TI - 4'-Azidocytidine (R1479) inhibits henipaviruses and other paramyxoviruses with high potency. AB - The henipaviruses Nipah virus and Hendra virus are highly pathogenic zoonotic paramyxoviruses which have caused fatal outbreaks of encephalitis and respiratory disease in humans. Despite the availability of a licensed equine Hendra virus vaccine and a neutralizing monoclonal antibody shown to be efficacious against henipavirus infections in non-human primates, there remains no approved therapeutics or vaccines for human use. To explore the possibility of developing small-molecule nucleoside inhibitors against henipaviruses, we evaluated the antiviral activity of 4'-azidocytidine (R1479), a drug previously identified to inhibit flaviviruses, against henipaviruses along with other representative members of the family Paramyxoviridae. We observed similar levels of R1479 antiviral activity across the family, regardless of virus genus. Our brief study expands the documented range of viruses susceptible to R1479, and provides the basis for future investigation and development of 4'-modified nucleoside analogs as potential broad-spectrum antiviral therapeutics across both positive and negative-sense RNA virus families. PMID- 28629989 TI - Patient-Proxy Agreement on the Health-Related Quality of Life One Year After Traumatic Brain Injury. AB - OBJECTIVE: To examine the level of agreement between patients and their proxies on a measure of health-related quality of life (HRQL) 1 year after traumatic brain injury (TBI). DESIGN: A cross-sectional study. SETTING: Four hospitals in Taipei. PARTICIPANTS: Participants (N=176) were patients with TBI (n=88) identified from discharge records of 4 hospitals in Taiwan and family members or friends (n=88) who could answer questions regarding the patient's health and HRQL 1 year after the injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A health profile of the brief Taiwanese version of the World Health Organization Quality of Life (WHOQOL-BREF) and 2 health utility measures of the time tradeoff (TTO) and standard gamble (SG). RESULTS: Compared with proxy responses, patients provided higher ratings on the domains of the WHOQOL-BREF and lower ratings on the TTO and SG. Intraclass correlation coefficients between patient and proxy ratings varied among the 4 domains of the WHOQOL-BREF, in which levels of agreement were moderate or good for physical capacity (.69) and low for psychological well-being (.45), social relationships (.24), and the environment (.32). Levels of agreement were extremely low for the TTO (0.0) and SG (.10). A profile analysis showed that patients' ratings on the WHOQOL-BREF, on average, were significantly greater than those of their proxies (mean difference, 3.07), with a similar distribution of scatter responses (mean difference, .002) and shape agreement (mean difference, .57). Greater variations in the patient-proxy level of agreement appeared in patients who were younger and had more severe injuries, and also with parent and child proxies. CONCLUSIONS: To assess the HRQL of patients with a TBI, the level of patient-proxy agreement was adequate for the physical domain but was lower for the social and environmental domains, and the agreement was very low for the TTO and SG. Furthermore, a patient's age and injury severity, and the patient-proxy' relationship may affect the agreement. PMID- 28629990 TI - Employment Stability in Veterans and Service Members With Traumatic Brain Injury: A Veterans Administration Traumatic Brain Injury Model Systems Study. AB - OBJECTIVE: To examine incidence and predictors of employment stability in veterans and military service members with traumatic brain injury (TBI) who return to work. DESIGN: Prospective observational cohort study. SETTING: Four rehabilitation centers. PARTICIPANTS: Veterans and military service members (N=110) with mild (26%), moderate (22%), or severe (52%) TBI enrolled in the Department of Veterans Affairs Polytrauma Rehabilitation Centers TBI Model Systems database within 2 years of injury who were discharged between January 2009 and June 2015. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Employment stability as reflected by competitive employment at 1- and/or 2-year follow-up. RESULTS: Over half (n=61, 55%) of the participants had stable employment at the time the first competitive employment date was recorded. Individuals with stable employment were more likely to be white (79%) and to have slightly higher cognitive and motor discharge scores on the FIM. Based on univariate analysis, more severe TBI and higher FIM motor scores at discharge were significantly associated with employment stability. At follow-up, compared with veterans and military service members who had unstable employment, those with stable employment had higher scores on motor and cognitive FIM and lower scores of self-report symptoms on the Neurobehavioral Symptom Inventory, the 9 item Patient Health Questionnaire-Depression, the 7-item Generalized Anxiety Disorder Questionnaire, and the PTSD Checklist-Civilian version. CONCLUSIONS: A number of unique factors affect employment stability in veterans and military service members with TBI. Study findings identify veterans and military service members who have stable employment and predictors of employment stability. PMID- 28629991 TI - Physical Activity and Sedentary Behavior Subsequent to Serious Orthopedic Injury: A Systematic Review. AB - OBJECTIVE: To systematically review and synthesize the evidence on physical activity and sedentary behavior after serious orthopedic injury. DATA SOURCES: Eight electronic databases and reference lists of relevant articles were searched from inception to March 2016. STUDY SELECTION: Studies on physical activity and sedentary behavior measured objectively or via self-report among patients with a serious orthopedic injury (acute bone or soft tissue injury requiring emergency hospital admission and/or nonelective surgery) were included. DATA EXTRACTION: Data extraction and methodological quality assessment were independently performed by 2 reviewers using standardized checklists. DATA SYNTHESIS: Twelve of 2572 studies were included: 8 were on hip fractures and 4 on other orthopedic injuries. Follow-up ranged from 4 days to 2 years postinjury. When measured objectively, physical activity levels were low at all time points postinjury, with individuals with hip fracture achieving only 1% of recommended physical activity levels 7 months postinjury. Studies using objective measures also showed patients to be highly sedentary throughout all stages of recovery, spending 76% to 99% of the day sitting or reclining. For studies using self-report measures, no consistent trends were observed in postinjury physical activity or sedentary behavior. CONCLUSIONS: For studies using objective measures, low physical activity levels and high levels of sedentary behaviors were found consistently after injury. More research is needed not only on the impact of immobility on long-term orthopedic injury outcomes and the risk of chronic disease, but also the potential for increasing physical activity and reducing sedentary behavior in this population. PMID- 28629992 TI - Do Patients With Carpal Tunnel Syndrome Benefit From Low-Level Laser Therapy? A Systematic Review of Randomized Controlled Trials. AB - OBJECTIVE: To systematically review the literature on the effectiveness of low level laser therapy for patients with carpal tunnel syndrome. DATA SOURCES: The Cochrane Library, PubMed, Embase, CINAHL, and Physiotherapy Evidence Database were searched for relevant systematic reviews and randomized controlled trials (RCTs) up to April 8, 2016. STUDY SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted the data and assessed the methodologic quality. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results of the 2 systematic reviews and 17 RCTs that were included. Strong evidence was found for the effectiveness of low-level laser therapy compared with placebo treatment in the very short term (0 to <=5wk). After 5 weeks, the positive effects of low-level laser therapy on pain, function, or recovery diminished over time (moderate and conflicting evidence were found at 7- and 12-wk follow-up, respectively). CONCLUSIONS: In the very short term, low-level laser therapy is more effective as a single intervention than placebo low-level laser therapy in patients with carpal tunnel syndrome, after which the positive effects of low level laser therapy tend to subside. Evidence in the midterm and long term is sparse. PMID- 28629993 TI - Increasing the efficiency of oncology basket trials using a Bayesian approach. AB - With the rapid growth of targeted and immune-oncology therapies, novel statistical design approaches are needed to increase the flexibility and efficiency of early phase oncology trials. Basket trials enroll patients with defined biological deficiencies, but with multiple histologic tumor types (or indications), to discover in which indications the drug is active. In such designs different indications are typically analyzed independently. This, however, ignores potential biological similarities among the indications. Our research provides a statistical methodology to enhance such basket trials by assessing the homogeneity of the response rates among indications at an interim analysis, and applying a Bayesian hierarchical modeling approach in the second stage if the efficacy is deemed reasonably homogenous across indications. This increases the power of the study by allowing indications with similar response rates to borrow information from each other. Via simulations, we quantify the efficiency gain of our proposed approach relative to the conventional parallel approach. The operating characteristics of our method depend on the similarity of the response rates between the different indications. If the response rates are comparable in most or all indications after treatment with the investigational drug, a substantial increase in efficiency as compared to the conventional approach can be obtained as fewer patients are required or a higher power is attained. We also demonstrate that efficacy again decreases if the response rates vary considerably among tumor types but it is still better than the conventional approach. PMID- 28629994 TI - The effect of estrogen on tendon and ligament metabolism and function. AB - Tendons and ligaments are crucial structures inside the musculoskeletal system. Still many issues in the treatment of tendon diseases and injuries have yet not been resolved sufficiently. In particular, the role of estrogen-like compound (ELC) in tendon biology has received until now little attention in modern research, despite ELC being a well-studied and important factor in the physiology of other parts of the musculoskeletal system. In this review we attempt to summarize the available information on this topic and to determine many open questions in this field. PMID- 28629995 TI - Intraosseous compared to intravenous drug resuscitation in out-of-hospital cardiac arrest. AB - AIMS: Although the intraosseous (IO) route is increasingly used for vascular access in out-of-hospital cardiac arrest (OHCA), little is known about its comparative effectiveness relative to intravenous (IV) access. We evaluated clinical outcomes following OHCA comparing drug administration via IO versus IV routes. METHODS: This retrospective cohort study evaluated Emergency Medical Services (EMS)-treated adults with atraumatic OHCA in a large metropolitan EMS system between 9/1/2012-12/31/2014. Access was classified as IO or IV based on the route of first EMS drug administration. Study endpoints were survival to hospital discharge, return of spontaneous circulation (ROSC) and survival to hospital admission. RESULTS: Among 2164 adults with OHCA, 1800 met eligibility criteria, 1525 of whom were treated via IV and 275 principally via tibial-IO routes. Compared to IV, IO-treated patients were younger, more often women, had unwitnessed OHCA, a non-cardiac aetiology, and presented with non-shockable rhythms. IO versus IV-treated patients were less likely to survive to hospital discharge (14.9% vs 22.8%, p=0.003), achieve ROSC (43.6% vs 55.5%, p<0.001) or be hospitalized (38.5% vs 50.0% p<0.001). In multivariable adjusted analyses, IO treatment was not associated with survival to discharge (odds ratio (OR) (95% confidence interval) 0.81 (0.55, 1.21), p=0.31), but was associated with a lower likelihood of ROSC (OR=0.67 (0.50, 0.88), p=0.004) and survival to hospitalization (OR=0.68 (0.51, 0.91), p=0.009). CONCLUSION: Though not independently associated with survival to discharge, principally tibial IO versus IV treatment was associated with a lower likelihood of ROSC and hospitalization. How routes of vascular access influence clinical outcomes after OHCA merits additional study. PMID- 28629996 TI - Production of medically useful nitric monoxide using AC arc discharge. AB - Inhaled nitric monoxide (iNO) is increasingly used as a medical treatment for acute respiratory distress syndrome. A course of the existing nitric monoxide (NO) therapy with gas cylinders could cost up to approximately $15,000 for an average of 30.2 h. Moreover, a gas cylinder containing a mixture of N2 and NO may potentially leak NO. The objective of this study is to develop an efficient and cost-effective on-site iNO generation system. In the present setup, NO was generated by using dry air or mixed oxygen/nitrogen (O2/N2) and an AC power source with an output power level of 5-30 W at atmospheric pressure. The simultaneously produced NO2 was eliminated with an ammonium sulfite ((NH4)2SO3) solution. The effects of the O2/N2 ratio, gas flow rate, discharge gap distance, output energy density and electrode structure on NOx concentration and the NO/NO2 ratio are reported. The concentrations of NO and NO2 reached 62 ppm and 3 ppm, respectively, after absorption and dilution at a gas flow rate of 6 L/min. With the present setup, the AC arc discharge produced NOx at a stable concentration for at least 6 h using dry air. PMID- 28629997 TI - Membrane translocation of transient receptor potential ankyrin 1 induced by inflammatory cytokines in lung cancer cells. AB - Transient receptor potential ankyrin 1 (TRPA1) is known as one of the nociceptors expressed in sensory neurons. It also plays a role in non-neural cells in inflammatory sites. However, the regulatory mechanisms for the reactivity of TRPA1 in these cells under inflammatory conditions are not clear. To clarify these mechanisms, we examined the effects of inflammatory cytokines (interleukin [IL]-1alpha, IL-1beta and tumor necrosis factor alpha [TNFalpha]) on TRPA1 reactivity and expression in the endogenously TRPA1-expressing lung tumor cell line A549. Treatment with IL-1alpha, but not IL-1beta or TNFalpha, increased the number of cells responding to allyl isothiocyanate, a TRPA1 agonist, in a dose- and time-dependent manner. The IL-1alpha-induced increase of TRPA1 responsiveness was inhibited by an extracellular-regulated kinase (Erk) inhibitor (PD98059) but not by inhibitors of c-Jun kinase, p38 mitogen-activated protein kinase or phosphatidylinositol-3 kinase. Phosphorylation of Erk gradually increased at 24 h after its transient induction in cells treated with IL-1alpha. IL-1alpha increased the TRPA1 levels on biotinylated cell surface proteins. These results suggest that IL-1alpha enhances the translocation of TRPA1 to the plasma membrane via the activation of Erk in A549. TRPA1 may have a pathophysiological role in non-neural lung cells under inflammatory conditions. PMID- 28629998 TI - Aloe-emodin (AE) nanoparticles suppresses proliferation and induces apoptosis in human lung squamous carcinoma via ROS generation in vitro and in vivo. AB - Human lung squamous cell carcinoma is a deadly cancer for which present therapeutic strategies are inadequate. And traditional chemotherapy results in severe systemic toxicity. Compounds from living organisms often exert a biological activity, triggering several targets, which may be useful for the improvement of novel pharmaceuticals. Aloe-emodin (AE), a well-known natural compound, is a primary component of anthraquinones in Aloe vera and exhibits anti proliferative and apoptotic effects on various tumor cells. However, the translational and clinical use of AE has been limited owing to its rapid degradation and poor bioavailability. To improve its efficacy, a poly (lactic-co glycolic acid) based AE nanoparticle formulation (NanoAE) was prepared. Our study indicated that compared to the free AE, nanoAE significantly suppressed cancer cell proliferation, induced cell cycle arrest and apoptosis, evidenced by high cleavage of Caspase-3, poly (ADP-ribose) polymerase (PARP), Caspase-8 and Caspase 9. NanoAE enhanced reactive oxygen species (ROS) production, along with Mitogen activated protein kinases (MAPKs) activation and PI3K/AKT inactivation. Cell proliferation, apoptosis and MAPKs and PI3K/AKT were dependent on ROS production in nanoAE-treated groups. In vivo, nanoAE exhibited inhibitory effects on the tumor growth with little toxicity. Together, our results indicated that nanoAE might be an effective treatment for human lung squamous cell carcinoma. PMID- 28629999 TI - Trimethylamine N-oxide prime NLRP3 inflammasome via inhibiting ATG16L1-induced autophagy in colonic epithelial cells. AB - Recently, the intricate relationship between Trimethylamine N-oxide (TMAO) and inflammatory bowel disease (IBD) is of growing interest. The NLRP3 inflammasome plays crucial roles in gut homeostasis and determining the severity of inflammation in IBD, however, the precise roles of the NLRP3 inflammasome in IBD are still debated. ATG16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with IBD. Whether TMAO prime NLRP3 inflammasome via ATG16L1-induced autophagy remains unclear. This study observed the expression of ATG16L1, LC3-II and p62 and activation of NLRP3 inflammasome stimulated by TMAO in fetal human colon cells (FHCs), aiming to elucidate the mechanism by which the TMAO may contribute to colonic epithelial inflammation. Our results demonstrated that TMAO significantly inhibited ATG16L1, LC3-II and p62 expression, and triggered the activated NLRP3 inflammasome and production of ROS in a dose- and time-dependent manner. Furthermore, TMAO-mediated effects were observably reversed by over expression ATG16L1 and siRNA-mediated knockdown NLRP3.The present results support the hypothesis that TMAO may be involved in the pathogenesis of IBD by impacting ATG16L1-induced autophagy and activating NLRP3 inflammasome, suggesting a potential therapeutic targets for the treatment of IBD and TMAO-associated complications. PMID- 28630000 TI - Betaine Aldehyde Dehydrogenase expression during physiological cardiac hypertrophy induced by pregnancy. AB - Betaine Aldehyde Dehydrogenase (betaine aldehyde: NAD(P)+ oxidoreductase, (E.C. 1.2.1.8; BADH) catalyze the irreversible oxidation of betaine aldehyde (BA) to glycine betaine (GB) and is essential for polyamine catabolism, gamma aminobutyric acid synthesis, and carnitine biosynthesis. GB is an important osmolyte that regulates the homocysteine levels, contributing to a vascular risk factor reduction. In this sense, distinct investigations describe the physiological roles of GB, but there is a lack of information about the GB novo synthesis process and regulation during cardiac hypertrophy induced by pregnancy. In this work, the BADH mRNA expression, protein level, and activity were quantified in the left ventricle before, during, and after pregnancy. The mRNA expression, protein content and enzyme activity along with GB content of BADH increased 2.41, 1.95 and 1.65-fold respectively during late pregnancy compared to not pregnancy, and returned to basal levels at postpartum. Besides, the GB levels increased 1.53-fold during pregnancy and remain at postpartum. Our results demonstrate that physiological cardiac hypertrophy induced BADH mRNA expression and activity along with GB production, suggesting that BADH participates in the adaptation process of physiological cardiac hypertrophy during pregnancy, according to the described GB role in cellular osmoregulation, osmoprotection and reduction of vascular risk. PMID- 28630001 TI - Host influence in the genomic composition of flaviviruses: A multivariate approach. AB - Flaviviruses present substantial differences in their host range and transmissibility. We studied the evolution of base composition, dinucleotide biases, codon usage and amino acid frequencies in the genus Flavivirus within a phylogenetic framework by principal components analysis. There is a mutual interplay between the evolutionary history of flaviviruses and their respective vectors and/or hosts. Hosts associated to distinct phylogenetic groups may be driving flaviviruses at different pace and through various sequence landscapes, as can be seen for viruses associated with Aedes or Culex spp., although phylogenetic inertia cannot be ruled out. In some cases, viruses face even opposite forces. For instance, in tick-borne flaviviruses, while vertebrate hosts exert pressure to deplete their CpG, tick vectors drive them to exhibit GC-rich codons. Within a vertebrate environment, natural selection appears to be acting on the viral genome to overcome the immune system. On the other side, within an arthropod environment, mutational biases seem to be the dominant forces. PMID- 28630002 TI - Inhibition of Wnt/beta-catenin signaling by IWR1 induces expression of Foxd3 to promote mouse epiblast stem cell self-renewal. AB - Inhibition of Wnt/beta-catenin signaling facilitates the derivation of mouse epiblast stem cells (EpiSCs), as well as dramatically promotes EpiSC self renewal. The specific mechanism, however, is still unclear. Here, we showed that IWR1, a Wnt/beta-catenin signaling inhibitor, allowed long-term self-renewal of EpiSCs in serum medium in combination with ROCK inhibitor Y27632. Through transcriptome data analysis, we arrived at a set of candidate transcription factors induced by IWR1. Among these, Forkhead box D3 (Foxd3) was most abundant. Forced expression of Foxd3 could recapitulate the self-renewal-promoting effect of IWR1 in EpiSCs. Conversely, knockdown of Foxd3 profoundly compromised responsiveness to IWR1, causing extinction of pluripotency markers and emergence of differentiation phenotype. Foxd3 thus is necessary and sufficient to mediate self-renewal downstream of Wnt/beta-catenin signaling inhibitor. These findings highlight an important role for Foxd3 in regulating EpiSCs and will expand current understanding of the primed pluripotency. PMID- 28630003 TI - Effects of mild calorie restriction on lipid metabolism and inflammation in liver and adipose tissue. AB - Calorie restriction (CR) has been reported to improve lipid metabolism and to decrease inflammatory diseases. However, most existing CR models use 30-50% calorie reduction, which is hard to achieve in humans. We investigated the effects of mild CR on lipid metabolism and inflammatory responses. Male C57BL/6 mice were fed control diet (10% kcal fat, Control) or high fat diet (60% kcal fat, HFD) ad libitum or reduced amount of control diet to achieve 15% CR for 16 wks. Body weights, white adipose tissue weights, liver triacylglycerol levels, and serum fetuin-A levels were lower in CR than in the Control. Serum adiponectin levels were higher in CR and lower in HFD compared with the Control. Liver and adipose tissue Mcp-1 mRNA levels were significantly lower in CR compared with the Control. Adipose tissue mRNA levels of Mcp-1, Il-6, Tnf-alpha and Socs3 were significantly higher in HFD than in the Control and CR, and levels of these negatively correlated with serum adiponectin levels. CR group had the lowest leptin levels and the highest liver Lepr expression, and Lepr mRNA levels positively correlated with liver Socs3 mRNA levels. Our findings showed that mild CR lowered adiposity which resulted in higher adiponectin and lower fetuin-A levels, and might have contributed to alleviation of inflammatory status in the liver and adipose tissue. Furthermore, mild CR might have affected leptin sensitivity by up-regulating Lepr expression. PMID- 28630004 TI - CO-releasing molecules-2 attenuates ox-LDL-induced injury in HUVECs by ameliorating mitochondrial function and inhibiting Wnt/beta-catenin pathway. AB - Oxidized low-density lipoprotein (ox-LDL) is well known to disrupt normal functionality of endothelium, which plays a prominent role in endothelial dysfunction in many cardiovascular diseases. CO-releasing molecule 2 (CORM-2) is a promising candidate for treatment of cardiovascular diseases. However, it has not been defined whether CORM-2 might improve endothelial injury induced by ox LDL. The present study was undertaken to determine the regulatory role of CORM-2 in cell injury of ox-LDL-treated human umbilical vein endothelial cells (HUVECs). Our results showed that ox-LDL inhibited the cell proliferation, but promoted apoptosis and release of cytochrome c (cytc) from mitochondrion into cytoplasm, stimulated the cleavage of caspase-3 and mitochondrial permeability transition pore (MPTP) opening. In addition, ox-LDL-incubated HUVECs exhibited excessive reactive oxygen species (ROS), increased protein levels of NADPH oxidase subunits p22phox, p47phox, NOX-2 and activation of Wnt/beta-catenin signaling pathway. However, pretreatment with CORM-2 significantly reduced cell apoptosis, release of cytc from mitochondrion into cytoplasm, MPTP opening and cleavage of caspase 3, suppressed the superoxide anion generation and Wnt/beta-catenin pathway activation in HUVECs response to ox-LDL. Collectively, we provide the evidence that CORM-2 attenuated ox-LDL-mediated endothelial apoptosis and oxidative stress by recovering the mitochondrial function and blocking Wnt/beta-catenin pathway. PMID- 28630005 TI - Transgenerational effects of proton beam irradiation on Caenorhabditis elegans germline apoptosis. AB - When treating cancer using radiation therapy, it is critical to increase patient survival rates and to reduce side effects. In this respect, proton beam radiation treatment performs better than other radiation treatments because of its high target specificity. However, complications still remain after proton beam radiation treatment. Among them, the risk to progeny after irradiation of their parents is a major concern. In this study, we analyzed the transgenerational effects of proton beam irradiation using the model organism Caenorhabditis. elegans. We found that germline apoptosis increased after proton beam irradiation and its effects were sustained transgenerationally. Moreover, we identified that a germline-specific histone methyltransferase component, SET-2, has a critical role in transmitting the transgenerational effect on germline apoptosis to the next generation after proton beam irradiation. PMID- 28630006 TI - Multiple conformational states of DnaA protein regulate its interaction with DnaA boxes in the initiation of DNA replication. AB - DnaA protein is the initiator of genomic DNA replication in prokaryotes. It binds to specific DNA sequences in the origin of DNA replication and unwinds small AT rich sequences downstream for the assembly of the replisome. The mechanism of activation of DnaA that enables it to bind and organize the origin DNA and leads to replication initiation remains unclear. In this study, we have developed double-labeled fluorescent DnaA probes to analyze conformational states of DnaA protein upon binding DNA, nucleotide, and Soj sporulation protein using Fluorescence Resonance Energy Transfer (FRET). Our studies demonstrate that DnaA protein undergoes large conformational changes upon binding to substrates and there are multiple distinct conformational states that enable it to initiate DNA replication. DnaA protein adopted a relaxed conformation by expanding ~15A upon binding ATP and DNA to form the ATP.DnaA.DNA complex. Hydrolysis of bound ATP to ADP led to a contraction of DnaA within the complex. The relaxed conformation of DnaA is likely required for the formation of the multi-protein ATP.DnaA.DNA complex. In the initiation of sporulation, Soj binding to DnaA prevented relaxation of its conformation. Soj.ADP appeared to block the activation of DnaA, suggesting a mechanism for Soj.ADP in switching initiation of DNA replication to sporulation. Our studies demonstrate that multiple conformational states of DnaA protein regulate its binding to DNA in the initiation of DNA replication. PMID- 28630007 TI - RNA localization: Making its way to the center stage. AB - Cells are highly organized entities that rely on intricate addressing mechanisms to sort their constituent molecules to precise subcellular locations. These processes are crucial for cells to maintain their proper organization and carry out specialized functions in the body, consequently genetic perturbations that clog up these addressing systems can contribute to disease aetiology. The trafficking of RNA molecules represents an important layer in the control of cellular organization, a process that is both highly prevalent and for which features of the regulatory machineries have been deeply conserved evolutionarily. RNA localization is commonly driven by trans-regulatory factors, including RNA binding proteins at the core, which recognize specific cis-acting zipcode elements within the RNA transcripts. Here, we first review the functions and biological benefits of intracellular RNA trafficking, from the perspective of both coding and non-coding RNAs. Next, we discuss the molecular mechanisms that modulate this localization, emphasizing the diverse features of the cis- and trans-regulators involved, while also highlighting emerging technologies and resources that will prove instrumental in deciphering RNA targeting pathways. We then discuss recent findings that reveal how co-transcriptional regulatory mechanisms operating in the nucleus can dictate the downstream cytoplasmic localization of RNAs. Finally, we survey the growing number of human diseases in which RNA trafficking pathways are impacted, including spinal muscular atrophy, Alzheimer's disease, fragile X syndrome and myotonic dystrophy. Such examples highlight the need to further dissect RNA localization mechanisms, which could ultimately pave the way for the development of RNA-oriented diagnostic and therapeutic strategies. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. PMID- 28630008 TI - Contribution of the carbohydrate-binding ability of Vatairea guianensis lectin to induce edematogenic activity. AB - Vatairea guianensis lectin (VGL), Dalbergiae tribe, is a N-acetyl-galactosamine (GalNAc)/Galactose (Gal) lectin previously purified and characterized. In this work, we report its structural features, obtained from bioinformatics tools, and its inflammatory effect, obtained from a rat paw edema model. The VGL model was obtained by homology with the lectin of Vatairea macrocarpa (VML) as template, and we used it to demonstrate the common characteristics of legume lectins, such as the jellyroll motif and presence of a metal-binding site in the vicinity of the carbohydrate-recognition domain (CRD). Protein-ligand docking revealed favorable interactions with N-acetyl-d-galactosamine, d-galactose and related sugars as well as several biologically relevant N- and O-glycans. In vivo testing of paw edema revealed that VGL induces edematogenic effect involving prostaglandins, interleukins and VGL CRD. Taken together, these data corroborate with previous reports showing that VGL interacts with N- and/or O-glycans of molecular targets, particularly in those presenting galactosides in their structure, contributing to the lectin inflammatory effect. PMID- 28630009 TI - Identification of two frataxin isoforms in Zea mays: Structural and functional studies. AB - Frataxin is a ubiquitous protein that plays a role in Fe-S cluster biosynthesis and iron and heme metabolism, although its molecular functions are not entirely clear. In non-photosynthetic eukaryotes, frataxin is encoded by a single gene, and the protein localizes to mitochondria. Here we report the presence of two functional frataxin isoforms in Zea mays, ZmFH-1 and ZmFH-2. We confirmed our previous findings regarding plant frataxins: both proteins have dual localization in mitochondria and chloroplasts. Physiological, biochemical and biophysical studies show some differences in the expression pattern, protection against oxidants and in the aggregation state of both isoforms, suggesting that the two frataxin homologs would play similar but not identical roles in plant cell metabolism. In addition, two specific features of plant frataxins were evidenced: their ability to form dimers and their tendency to undergo conformational change under oxygen exposure. PMID- 28630010 TI - Borrelia burgdorferi infection induces lipid mediator production during Lyme arthritis. AB - Experimental Lyme arthritis provides a mouse model for exploring the development of pathology following infection of C3H mice with Borrelia burgdorferi. Infected mice develop a reliable inflammatory arthritis of the ankle joint with severity that typically peaks around two to three weeks post-infection and then undergoes spontaneous resolution. This makes experimental Lyme arthritis an excellent model for investigating the mechanisms that drive both the development and resolution phases of inflammatory disease. Eicosanoids are powerful lipid mediators of inflammation and are known to regulate multiple aspects of inflammatory processes. While much is known about the role of eicosanoids in regulating immune responses during autoimmune disease and cancer, relatively little is known about their role during bacterial infection. In this review, we discuss the role of eicosanoid biosynthetic pathways in mediating inflammatory responses during bacterial infection using experimental Lyme arthritis as a model system. We point out the critical role eicosanoids play in disease development and highlight surprising differences between sterile autoimmune responses and those occurring in response to bacterial infection. These differences should be kept in mind when designing therapies and treatments for inflammatory diseases. PMID- 28630011 TI - Interplay between hepatitis C virus and lipid metabolism during virus entry and assembly. AB - Hepatitis C virus (HCV) infection is a major public health problem worldwide. In most cases, HCV infection becomes chronic, leading to the development of liver diseases that range from fibrosis to cirrhosis and hepatocellular carcinoma. Due to its medical importance, the HCV life cycle has been deeply characterized, and a unique feature of this virus is its interplay with lipids. Accordingly, all the steps of the virus life cycle are influenced by the host lipid metabolism. Indeed, due to their association with host lipoproteins, HCV particles have a unique lipid composition. Furthermore, the biogenesis pathway of very low density lipoproteins has been shown to be involved in HCV morphogenesis with apolipoprotein E being an essential element for the production of infectious HCV particles. Association of viral components with host cytoplasmic lipid droplets is also central to the HCV morphogenesis process. Finally, due to its close connection with host lipoproteins, HCV particle also uses several lipoprotein receptors to initiate its infectious cycle. In this review, we outline the way host lipoproteins participate to HCV particle composition, entry and assembly. PMID- 28630012 TI - Assessing Passeriformes health in South Texas via select venous analytes. AB - The handheld point of care analyzer is a quick and feasible option to obtain hematology data from individuals. The iSTAT-1(r) was used to evaluate select venous blood analytes obtained via jugular venipuncture from 238 passerine birds from South Texas. These data were used to assess the health of birds in the area while taking into consideration life history (migratory or sedentary), locale, seasonality, sex, and age. We attributed increased values of pO2 and hematocrit, in addition to hemoglobin and glucose concentrations of migratory birds compared to sedentary birds as the increased need of oxygen carrying capacity and energy for long duration flights. Increased glucose and lower ionized calcium concentrations were observed in migratory birds likely based on breakdown of fat deposits in the body to fuel the muscular endurance of migration. During the hotter months of the year, birds' responses to handling were exhibited by relative respiratory acidosis. When sedentary birds sampled from South Texas were compared to a previous study from Central Texas, venous blood analytes differed by locale but were within the ranges of healthy populations. These findings lead us to conclude that sedentary avian communities can be used as ecosystem bioindicators. PMID- 28630013 TI - Receptor mediated endocytosis of vicilin in Callosobruchus maculatus (Coleoptera: Chrysomelidae) larval midgut epithelial cells. AB - The transport of proteins across the intestinal epithelium of insects is still not well understood. There is evidence that vicilin, a major storage protein of cowpea seeds (Vigna unguiculata), is internalized in larvae of the seed-beetle Callosobruchus maculatus. It has been reported that this vicilin interacts with proteins present in the microvillar membranes of columnar cells along the digestive tract of the larvae. In the present work, we studied the cellular pathway involved in endocytosis of vicilin in larval C. maculatus by employing ex vivo experiments. In the ex vivo approach, we incubated FITC-labelled vicilin with isolated midgut wholemounts in the absence or in the presence of endocytosis inhibitors. The fate of labelled or non-labelled globulins was monitored by confocal microscopy and fluorescence measurement. Our results suggest that the internalization of vicilins is due to receptor-mediated endocytosis. Here we report the identity of a microvillar vicilin-binding protein that was purified using affinity chromatography on a vicilin-sepharose column. The putative vicilin receptor showed high homology to proteins with the CRAL-TRIO domain, specifically the Sec14 superfamily member alpha-tocopherol transfer protein. The precise mechanism involved in vicilin internalization was defined through the use of specific inhibitors of the endocytosis pathway. The inhibitors filipin III and nystatin significantly inhibited the endocytosis of vicilin, while chlorpromazine and phenylarsine oxide had a much lower effect on endocytosis, suggesting that the endocytic pathway is predominantly mediated by caveolin. PMID- 28630014 TI - Impact of molecular hydrogen treatments on the innate immune activity and survival of zebrafish (Danio rerio) challenged with Aeromonas hydrophila. AB - Recently, molecular hydrogen has been reported to have a suppressive effect on inflammation in human and rodent models. The aim of this study was to evaluate the preventive effects of hydrogen-rich water (HRW) on zebrafish challenged by A. hydrophila. We have found an increased survival rate of bacteria-challenged zebrafish subjected to the HRW immersion treatment. Furthermore, we have revealed that HRW was able to block multiplication of A. hydrophila in zebrafish. In addition, treatment of zebrafish infected by A. hydrophila with effective concentrations of HRW strongly affected the expression of genes mediating pro inflammatory and anti-inflammatory cytokines. There were down-regulation of selected pro-inflammatory immune response genes (IL-1beta, IL-6, and NF-kappaB), and up-regulation of the anti-inflammatory cytokine gene (IL-10) in the spleen, kidney, and liver. This study is the first one to investigate the effects of HRW on fish infected with bacteria, and might shed new light on hydrogen's antimicrobial effects and further application in aquaculture fish species. PMID- 28630015 TI - Characterization of Japanese flounder (Paralichthys olivaceus) Caspase1 involved in extracellular ATP-mediated immune signaling in fish. AB - Caspase1 is a member of inflammatory Caspases that play important roles in the innate immune system. Although several teleost caspase1 genes have been identified, their partner proteins and implication in extracellular ATP-mediated immune signaling in fish are still very limited. Here we identified and characterized a caspase1 gene, named JfCaspase1, from Japanese flounder Paralichthys olivaceus. JfCaspase1 mRNA was constitutively expressed in all examined normal tissues with high expression in skin and gills and moderate expression in the enriched Japanese flounder head kidney macrophages (HKMs) and peripheral blood leukocytes (PBLs). JfCaspase1 was initially down-regulated but significantly up-regulated at the later stage upon LPS and poly(I:C) challenges in the HKMs. JfCaspase1 was also up-regulated in the Japanese flounder immune related tissues including head kidney, gill and spleen by bacterial challenge with Edwardsiella tarda. JfCaspase1 protein is comprised of 384 amino acid residues with a calculated molecular mass of 43.75 kDa and is phylogenetically close to fish Caspase1 proteins. JfCaspase1 was co-immunopercipitated with Japanese flounder apoptosis-associated speck-like protein (ASC) when co-expressed in HeLa cells, suggesting that there is a potential interaction between the two proteins. In addition, we showed that extracellular ATP, a potent signaling molecule in activating innate immune response, rapidly up-regulates JfCaspase1 expression and enhances its enzymatic activity both in the HKMs and PBLs. Our findings indicated that the inflammatory JfCaspase1 interacted with ASC protein is implicated in the extracellular ATP-mediated immune signaling in fish. PMID- 28630016 TI - Comparative transcriptome analysis of Sinonovacula constricta in gills and hepatopancreas in response to Vibrio parahaemolyticus infection. AB - The razor clam Sinonovacula constricta is an important economic species in China. However, bacterial pathogenic diseases limits S. constricta farming industry for large-scale production. In this study, de novo transcriptome sequencing was performed on S. constricta gills and hepatopancreas under Vibrio parahaemolyticus challenge for 12 h and 48 h, respectively. Transcripts assembly constructed 18,330 sequences, each of which was 500 bp long and functionally annotated, and 1781 and 490 transcripts were differentially expressed in the gills and hepatopancreas, respectively. Host immune factors that respond to Vibrio infection were then identified. These factors included up-regulated transcripts with function in non-self recognition, signal transduction, immune effectors and anti-apoptosis. The comparison between the differentially expressed transcripts of the gills and hepatopancreas indicated that immune responses had tissue specificity. As an important external barrier between the environment and the clam, ATP-binding cassette transporters and other ion transporters contribute to immune response in gills, while, transcripts in complement system, such as complement 1 q protein, IgGFc-binding protein, and low affinity immunoglobulin epsilon Fc receptor, were more active in hepatopancreas and often not expressed in gill tissues. Eleven genes were selected to be validated by qRT-PCR and the expressions were consistent with the results of RNA-seq. Our study is the first attempt to identify molecular features in different tissues of S. constricta in response to V. parahaemolyticus infection. These findings improved our understanding of bivalve immunity and defense mechanisms and revealed more potential immune-related genes. PMID- 28630017 TI - Vesicoureteral reflux is a phenotype, not a disease: A population-centered approach to pediatric urinary tract infection. AB - We performed a review of the recent literature concerning urinary tract infection (UTI) evaluation and management. In modeling options for management, one overriding conclusion became apparent: in most affected children, the presence of vesicoureteral reflux (VUR) is inconsequential since it has no bearing on optimal management or outcome. In fact, knowing that a child does not have reflux might bias the provider to withhold potentially helpful therapeutic modalities to decrease UTI morbidity, such as antibiotic prophylaxis. In this review, we will propose that evaluation for VUR is not necessary or helpful except in the small subset of children whose UTIs have proven refractory to management of their other risk factors. PMID- 28630018 TI - The modified Ulaanbaatar procedure: Reduced complications and enhanced cosmetic outcome for the most severe cases of hypospadias. AB - INTRODUCTION/OBJECTIVE: Proximal hypospadias is one of the most challenging conditions that pediatric urologists have to deal with. Many procedures have been devised over the years, but nothing has been proven to be the best option. Although there have been some attempts at correcting severe hypospadias in one procedure, most have advocated a staged approach. The classic approach - laying penile skin or a graft within a split glans followed by glanuloplasty at the second stage - by definition requires two operations on the glans. In the Ulaanbaatar procedure the distal glanular urethra is constructed at the first stage, allowing for a single glans procedure and thus potentially better cosmetic outcomes. The present study discusses experience with the Ulaanbaatar procedure for severe hypospadias. STUDY DESIGN: The study retrospectively reviewed every child who underwent both stages of this procedure at the present institution. It reviewed age, associated diagnoses, surgical technique and outcomes. SURGICAL TECHNIQUE: The first stage was analogous to a classic first-stage procedure with regard to division of the urethral plate and correction of penile curvature. However, an island flap of preputial skin was mobilized and tubularized to create the glanular urethra. No attempt was made to bridge the native meatus and this reconstructed urethra, and the remaining penile skin was placed between the two. The second stage was performed 6 months later by tubularizing the penile skin between the two meatuses. RESULTS: The series consisted of 34 boys. Mean age at surgery was 18.3 months (range 6-118). Nineteen underwent evaluation for genital ambiguity at birth (56%). Thirty (88%) received pre-operative testosterone or human chorionic gonadotropin (HCG). After urethral plate transection, persistent curvature was addressed during the first stage, with dorsal plication in 12 (35%), urethral plate transection alone in six (18%) or ventral grafting with small intestinal submucosa in 16 (47%). Twenty-three boys (67%) had the neourethra tunneled through the glans, and 11 (33%) had the glans split followed by glanuloplasty. Average time between the two stages was 7 months (range 4.0 13.9). Four patients (12%) developed urethral diverticula that required repair. One developed recurrent epididymitis related to an abnormal ejaculatory duct (no stricture) and underwent vasectomy. No patient developed a fistula. Mean length of follow-up was 15.2 months (range 0.3-55.5). DISCUSSION: This modification of the classic staged hypospadias repair may allow for better cosmetic outcome, since the majority of boys required no formal glanuloplasty. There were reduced complications, perhaps because the urethral defect acted like a controlled fistula, allowing for better tissue healing prior to final urethral reconstruction. PMID- 28630019 TI - Tunica vaginalis pedicle flap for repair of ruptured testis: A single-center experience with four patients. AB - Management of testicular rupture with a large tunical defect may not be feasible without excision of viable tissue. This study describes the use of a vascularized tunica vaginalis flap, without debridement of viable tissue, in four adolescents. Postoperative ultrasound showed good blood flow and 80% volume of the contralateral testis in two cases. Postoperative exam revealed normal exam and ultrasonographic appearance in three patients, the fourth was demonstrated to be small and undescended during evaluation of contralateral testicular torsion. This approach is recommended in cases of large tunical defects, as it avoids the debridement of viable testicular tissue. PMID- 28630020 TI - Transumbilical multi-port laparoscopic pyeloplasty versus transumbilical single site laparoscopic pyeloplasty for ureteropelvic junction obstruction in children: A retrospectively comparative study. AB - INTRODUCTION: Laparoscopic pyeloplasty has achieved good cosmetic and functional outcomes. Both transumbilical single-site and transumbilical multi-port approaches are currently being used. No comparison of transumbilical single-site laparoscopic pyeloplasty (TSLP) and transumbilical multi-port laparoscopic pyeloplasty (TMLP) has been reported in the literature. OBJECTIVES: We present a retrospective comparison study to evaluate clinical outcomes of TSLP and TMLP for children with ureteropelvic junction obstruction (UPJO). STUDY DESIGN: A retrospective study was carried out comparing TSLP and TMLP performed by a single surgeon between July 2012 and June 2014. The patient data of the two groups (90 in each group) were evaluated. All patients underwent urine analysis, ultrasonography, magnetic resonance urography, and diuretic renogram using 99Tc diethylene triamine pentaacetic acid scan preoperative and postoperative follow up. Data were analyzed using the SPSS 20.0 software package. RESULTS: DISCUSSION: To our knowledge, our series is the first report in the literature that compares the outcomes of TSLP and TMLP in children. Our study suggested that there were no significant differences in start of oral feeding, drain removal, hospital stay, postoperative renal pelvic anteroposterior diameter and differential renal function at 6 months, postoperative complications, and success rate between the two groups. It demonstrated that TMLP is as effective and safe as TSLP. Although the cosmetic result of the TSLP group is satisfactory, TMLP requires three 0.5-cm ports around the umbilicus and does not change the shape of the umbilicus. Hence, the cosmetic result of the TMLP group is better than that of the TSLP group. TSLP involves some technical challenges. However, TMLP facilitates the procedure and renders the operation easier. Our findings confirmed that the operative time of TMLP group is shorter than that in TSLP group, and also showed that TMLP is relatively easy to perform compared with TSLP. CONCLUSION: TMLP is a feasible and safe operation for pediatric UPJO. TMLP is shorter in operative time and has a better cosmetic result than TSLP. We propose TMLP as a more viable treatment option for pediatric UPJO. PMID- 28630021 TI - Thyroid hormone signaling and deiodinase actions in muscle stem/progenitor cells. AB - Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development and metabolism of nearly all vertebrate tissues. In skeletal muscle, TH plays a critical role in regulating the function of satellite cells, the bona fide skeletal muscle stem cells. Deiodinases (D2 and D3) have been found to modulate the expression of various TH target genes in satellite cells. Regulation of the expression and activity of the deiodinases constitutes a cell autonomous, pre-receptor mechanism that controls crucial steps during the various phases of myogenesis. Here, we review the roles of deiodinases in skeletal muscle stem cells, particularly in muscle homeostasis and upon regeneration. We focus on the role of T3 in stem cell functions and in commitment towards lineage progression. We also discuss how deiodinases might be therapeutically exploited to improve satellite-cell-mediated muscle repair in skeletal muscle disorders or injury. PMID- 28630022 TI - Lamprey metamorphosis: Thyroid hormone signaling in a basal vertebrate. AB - As one of the most basal living vertebrates, lampreys represent an excellent model system to study the evolution of thyroid hormone (TH) signaling. The lamprey hypothalamic-pituitary-thyroid and reproductive axes overlap functionally. Lampreys have 3 gonadotropin-releasing hormones and a single glycoprotein hormone from the hypothalamus and pituitary, respectively, that regulate both the reproductive and thyroid axes. TH synthesis in larval lampreys takes place in an endostyle that transforms into typical vertebrate thyroid tissue during metamorphosis; both the endostyle and follicular tissue have all the typical TH synthetic components found in other vertebrates. Furthermore, lampreys also have the vertebrate suite of peripheral regulators including TH distributor proteins (THDPs), deiodinases and TH receptors (TRs). Although at the molecular level the components of the lamprey thyroid system are ancestral to other vertebrates, their functions have been largely conserved. TH signaling as it relates to lamprey metamorphosis represents a particularly interesting phenomenon. Unlike other metamorphosing vertebrates, lamprey THs increase throughout the larval period, peak prior to metamorphosis and decline rapidly at the onset of metamorphosis; patterns of deiodinase activity are consistent with these increases and declines. Moreover, goitrogens (which suppress TH levels) initiate precocious metamorphosis, and exogenous TH treatment blocks goitrogen induced metamorphosis and disrupts natural metamorphosis. Despite this clear physiological difference, TH action via TRs is consistent with higher vertebrates. Based on observations that TRs are upregulated in a tissue-specific fashion during morphogenesis and the finding that lamprey TRs upregulate genes via THs in a fashion similar to higher vertebrates, we propose the following hypothesis for further testing. THs have a dual role in lampreys where high TH levels promote larval feeding and growth and then at the onset of metamorphosis TH levels decrease rapidly; at this time the relatively low TH levels function via TRs in a fashion similar to that of other metamorphosing vertebrates. PMID- 28630023 TI - Epigenetics of pheochromocytoma and paraganglioma. AB - Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising in the medullae of the adrenal glands or in paraganglia. The knowledge of the tumor biology of these lesions has increased dramatically during the past two decades and more than a dozen recurrently mutated genes have been identified. Different clusters have been described that share epigenetic signatures. Mutations in the succinate dehydrogenase complex subunit genes play a pivotal role in reprogramming the epigenetic state of these tumors by inhibiting epigenetic regulators such as TET enzymes and histone demethylases. Another subgroup of tumors carries hypomethylated genomes, and overexpression of several micro-RNAs has been described. While much remains to be investigated regarding the epigenetics of PPGLs, it is clear that it plays an important role in PPGL biology. PMID- 28630024 TI - Proteolytic control of Interleukin-11 and Interleukin-6 biology. AB - Interleukin-11 (IL-11) and IL-6 are secreted glycoproteins which fulfill important homeostatic functions. Activation of target cells occurs via membrane bound IL-11 and IL-6 receptors (IL-11R and IL-6R, respectively). Formation of IL 11/IL-11R and IL-6/IL-6R complexes triggers the recruitment of a homodimer of the ubiquitously expressed signal-transducing beta-receptor gp130 (classic signaling). IL-11R and IL-6R can be shed by several proteases, albeit with different preferences and specificities, and these soluble receptors (sIL-11R and sIL-6R) act as agonists and can activate in principle all cells via gp130. We have termed these protease-controlled pathways IL-6 and IL-11 trans-signaling. In this review, we describe the basic biology of both cytokines and summarize the current knowledge how proteases control and shape the trans-signaling pathways of the two cytokines. We will further highlight how the underlying molecular mechanisms can be used to design specific inhibitors that block trans, but not classic signaling of IL-11 and IL-6. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. PMID- 28630025 TI - The clock is ticking. Ageing of the circadian system: From physiology to cell cycle. AB - The circadian system is the responsible to organise the internal temporal order in relation to the environment of every process of the organisms producing the circadian rhythms. These rhythms have a fixed phase relationship among them and with the environment in order to optimise the available energy and resources. From a cellular level, circadian rhythms are controlled by genetic positive and negative auto-regulated transcriptional and translational feedback loops, which generate 24h rhythms in mRNA and protein levels of the clock components. It has been described about 10% of the genome is controlled by clock genes, with special relevance, due to its implications, to the cell cycle. Ageing is a deleterious process which affects all the organisms' structures including circadian system. The circadian system's ageing may produce a disorganisation among the circadian rhythms, arrhythmicity and, even, disconnection from the environment, resulting in a detrimental situation to the organism. In addition, some environmental conditions can produce circadian disruption, also called chronodisruption, which may produce many pathologies including accelerated ageing. Finally, some strategies to prevent, palliate or counteract chronodisruption effects have been proposed to enhance the circadian system, also called chronoenhancement. This review tries to gather recent advances in the chronobiology of the ageing process, including cell cycle, neurogenesis process and physiology. PMID- 28630026 TI - What have we learned on aging from omics studies? AB - Aging is a complex process. Transcriptomic studies of the last decade have identified genes and pathways that are regulated during aging in multiple species and organs. Yet, since a manifold of pathways are regulated and the amplitude of regulation is often small, reproducibility across studies is moderate and disentangling cause-consequence relationships has proven challenging. Here, we review a number of consistent findings in the light of more recent, longitudinal studies and of studies combining transcriptomics and proteomics that identified deregulation of protein biosynthetic pathways as an early event and likely driver of aging. PMID- 28630027 TI - Talking over the extracellular matrix: How do cells communicate mechanically? AB - Communication between cells enables them to coordinate their activity and is crucial for the differentiation, development, and function of tissues and multicellular organisms. Cell-cell communication is discussed almost exclusively as having a chemical or electrical origin. Only recently, a new mode of cell communication was elucidated: mechanical communication through the extracellular matrix (ECM). Cells can communicate mechanically by responding either to mechanical deformations generated by their neighbors or to a change in the mechanical properties of the ECM induced by a neighboring cell. This newly resolved mode of communication possesses unique features that complement the cellular ability to receive and share information, and to consequently act in a cooperative way with surrounding cells. Herein, we review several examples of mechanical communication, discuss their unique properties, and comment on the major challenges facing the field. PMID- 28630028 TI - The effect of enucleation on orbital growth in patients with retinoblastoma. AB - PURPOSE: To measure orbital volume using serial magnetic resonance imaging (MRI) scans to determine the effect of enucleation on orbital growth over time. METHODS: The medical records of patients who underwent unilateral enucleation for retinoblastoma with a minimum of 2 MRIs were retrospectively reviewed. Orbital asymmetry was calculated using MRI measurements. Nonlinear and linear mixed effect regression models were used to predict the effect of age at time of enucleation on degree of orbital asymmetry. RESULTS: A total of 27 patients were included (mean age at enucleation, 2 years; range, 2.5 months to 5 years). Age at scan (P = 0.046) and age at enucleation (P = 0.0006) were found to have a significant effect on orbital asymmetry. Change in orbital asymmetry over time was more pronounced after enucleation in children enucleated at <1 (P < 0.0001) or <2 years of age (P = 0.0109). Younger age at enucleation was associated with a greater degree of asymmetry over time, although this effect was extinguished for patients enucleated after the age of 3 years. CONCLUSIONS: In patients with retinoblastoma, enucleation with orbital implant before 3 years of age has a significant effect on orbital volume asymmetry. After the age of 3, this effect appears to be less detrimental to the degree of orbital asymmetry. PMID- 28630029 TI - Malignant transformation of multifocal tapioca iris nevus in a child. AB - A 31-month-old white boy was evaluated for multiple iris lesions in his left eye, initially suspected to be juvenile xanthogranuloma and later diagnosed as tapioca nevi. Four years later the tumors enlarged. There was invasion throughout the anterior segment into the angle and related secondary elevation in intraocular pressure. Fine-needle aspiration biopsy disclosed spindle-B melanoma. Treatment with custom-designed iodine-125 plaque radiotherapy resulted in tumor regression and stabilization of intraocular pressure. PMID- 28630031 TI - Response to David's article on the use of pellet guns in Kashmir. PMID- 28630030 TI - Alzheimer's brains show inter-related changes in RNA and lipid metabolism. AB - Alzheimer's disease (AD) involves changes in both lipid and RNA metabolism, but it remained unknown if these differences associate with AD's cognition and/or post-mortem neuropathology indices. Here, we report RNA-sequencing evidence of inter-related associations between lipid processing, cognition level, and AD neuropathology. In two unrelated cohorts, we identified pathway-enriched facilitation of lipid processing and alternative splicing genes, including the neuronal-enriched NOVA1 and hnRNPA1. Specifically, this association emerged in temporal lobe tissue samples from donors where postmortem evidence demonstrated AD neuropathology, but who presented normal cognition proximate to death. The observed changes further associated with modified ATP synthesis and mitochondrial transcripts, indicating metabolic relevance; accordingly, mass-spectrometry derived lipidomic profiles distinguished between individuals with and without cognitive impairment prior to death. In spite of the limited group sizes, tissues from persons with both cognitive impairment and AD pathology showed elevation in several drug-targeted genes of other brain, vascular and autoimmune disorders, accompanied by pathology-related increases in distinct lipid processing transcripts, and in the RNA metabolism genes hnRNPH2, TARDBP, CLP1 and EWSR1. To further detect 3'-polyadenylation variants, we employed multiple cDNA primer pairs. This identified variants that showed limited differences in scope and length between the tested cohorts, yet enabled superior clustering of demented and non-demented AD brains versus controls compared to total mRNA expression values. Our findings indicate inter-related cognition-associated differences in AD's lipid processing, alternative splicing and 3'-polyadenylation, calling for pursuing the underlying psychological and therapeutics implications. PMID- 28630032 TI - What Are People Tweeting About Zika? An Exploratory Study Concerning Its Symptoms, Treatment, Transmission, and Prevention. AB - BACKGROUND: In order to harness what people are tweeting about Zika, there needs to be a computational framework that leverages machine learning techniques to recognize relevant Zika tweets and, further, categorize these into disease specific categories to address specific societal concerns related to the prevention, transmission, symptoms, and treatment of Zika virus. OBJECTIVE: The purpose of this study was to determine the relevancy of the tweets and what people were tweeting about the 4 disease characteristics of Zika: symptoms, transmission, prevention, and treatment. METHODS: A combination of natural language processing and machine learning techniques was used to determine what people were tweeting about Zika. Specifically, a two-stage classifier system was built to find relevant tweets about Zika, and then the tweets were categorized into 4 disease categories. Tweets in each disease category were then examined using latent Dirichlet allocation (LDA) to determine the 5 main tweet topics for each disease characteristic. RESULTS: Over 4 months, 1,234,605 tweets were collected. The number of tweets by males and females was similar (28.47% [351,453/1,234,605] and 23.02% [284,207/1,234,605], respectively). The classifier performed well on the training and test data for relevancy (F1 score=0.87 and 0.99, respectively) and disease characteristics (F1 score=0.79 and 0.90, respectively). Five topics for each category were found and discussed, with a focus on the symptoms category. CONCLUSIONS: We demonstrate how categories of discussion on Twitter about an epidemic can be discovered so that public health officials can understand specific societal concerns within the disease-specific categories. Our two-stage classifier was able to identify relevant tweets to enable more specific analysis, including the specific aspects of Zika that were being discussed as well as misinformation being expressed. Future studies can capture sentiments and opinions on epidemic outbreaks like Zika virus in real time, which will likely inform efforts to educate the public at large. PMID- 28630034 TI - Fall Prevention Self-Assessments Via Mobile 3D Visualization Technologies: Community Dwelling Older Adults' Perceptions of Opportunities and Challenges. AB - BACKGROUND: In the field of occupational therapy, the assistive equipment provision process (AEPP) is a prominent preventive strategy used to promote independent living and to identify and alleviate fall risk factors via the provision of assistive equipment within the home environment. Current practice involves the use of paper-based forms that include 2D measurement guidance diagrams that aim to communicate the precise points and dimensions that must be measured in order to make AEPP assessments. There are, however, issues such as "poor fit" of equipment due to inaccurate measurements taken and recorded, resulting in more than 50% of equipment installed within the home being abandoned by patients. This paper presents a novel 3D measurement aid prototype (3D-MAP) that provides enhanced measurement and assessment guidance to patients via the use of 3D visualization technologies. OBJECTIVE: The purpose of this study was to explore the perceptions of older adults with regard to the barriers and opportunities of using the 3D-MAP application as a tool that enables patient self delivery of the AEPP. METHODS: Thirty-three community-dwelling older adults participated in interactive sessions with a bespoke 3D-MAP application utilizing the retrospective think-aloud protocol and semistructured focus group discussions. The system usability scale (SUS) questionnaire was used to evaluate the application's usability. Thematic template analysis was carried out on the SUS item discussions, think-aloud, and semistructured focus group data. RESULTS: The quantitative SUS results revealed that the application may be described as having "marginal-high" and "good" levels of usability, along with strong agreement with items relating to the usability (P=.004) and learnability (P<.001) of the application. Four high-level themes emerged from think-aloud and focus groups discussions: (1) perceived usefulness (PU), (2) perceived ease of use (PEOU), (3) application use (AU) and (4) self-assessment (SA). The application was seen as a useful tool to enhance visualization of measurement guidance and also to promote independent living, ownership of care, and potentially reduce waiting times. Several design and functionality recommendations emerged from the study, such as a need to manipulate the view and position of the 3D furniture models, and a need for clearer visual prompts and alternative keyboard interface for measurement entry. CONCLUSIONS: Participants perceived the 3D-MAP application as a useful tool that has the potential to make significant improvements to the AEPP, not only in terms of accuracy of measurement, but also by potentially enabling older adult patients to carry out the data collection element of the AEPP themselves. Further research is needed to further adapt the 3D-MAP application in line with the study outcomes and to establish its clinical utility with regards to effectiveness, efficiency, accuracy, and reliability of measurements that are recorded using the application and to compare it with 2D measurement guidance leaflets. PMID- 28630033 TI - Trust and Credibility in Web-Based Health Information: A Review and Agenda for Future Research. AB - BACKGROUND: Internet sources are becoming increasingly important in seeking health information, such that they may have a significant effect on health care decisions and outcomes. Hence, given the wide range of different sources of Web based health information (WHI) from different organizations and individuals, it is important to understand how information seekers evaluate and select the sources that they use, and more specifically, how they assess their credibility and trustworthiness. OBJECTIVE: The aim of this study was to review empirical studies on trust and credibility in the use of WHI. The article seeks to present a profile of the research conducted on trust and credibility in WHI seeking, to identify the factors that impact judgments of trustworthiness and credibility, and to explore the role of demographic factors affecting trust formation. On this basis, it aimed to identify the gaps in current knowledge and to propose an agenda for future research. METHODS: A systematic literature review was conducted. Searches were conducted using a variety of combinations of the terms WHI, trust, credibility, and their variants in four multi-disciplinary and four health-oriented databases. Articles selected were published in English from 2000 onwards; this process generated 3827 unique records. After the application of the exclusion criteria, 73 were analyzed fully. RESULTS: Interest in this topic has persisted over the last 15 years, with articles being published in medicine, social science, and computer science and originating mostly from the United States and the United Kingdom. Documents in the final dataset fell into 3 categories: (1) those using trust or credibility as a dependent variable, (2) those using trust or credibility as an independent variable, and (3) studies of the demographic factors that influence the role of trust or credibility in WHI seeking. There is a consensus that website design, clear layout, interactive features, and the authority of the owner have a positive effect on trust or credibility, whereas advertising has a negative effect. With regard to content features, authority of the author, ease of use, and content have a positive effect on trust or credibility formation. Demographic factors influencing trust formation are age, gender, and perceived health status. CONCLUSIONS: There is considerable scope for further research. This includes increased clarity of the interaction between the variables associated with health information seeking, increased consistency on the measurement of trust and credibility, a greater focus on specific WHI sources, and enhanced understanding of the impact of demographic variables on trust and credibility judgments. PMID- 28630035 TI - The Effects of Preoperative Volume Replacement in Diabetic Patients Undergoing Coronary Artery Bypass Grafting Surgery: Protocol for a Randomized Controlled Trial (VeRDiCT Trial). AB - BACKGROUND: Diabetes mellitus is a major risk factor for prolonged hospital stays, renal failure, and mortality in patients having coronary artery bypass grafting (CABG). Complications pose a serious threat to patients and prolong intensive care and hospital stays. Low glomerular filtration rate (GFR) due to existing renal impairment or volume depletion may exacerbate acute renal impairment/failure in these patients. Preoperative volume replacement therapy (VRT) is reported to increase the GFR and we hypothesize that VRT will reduce renal impairment and related complications in diabetic patients. OBJECTIVE: The objective of this study is to establish the efficacy of preoperative VRT in reducing postoperative complications in diabetic patients undergoing CABG surgery. Time to "fit for discharge", incidence of postoperative renal failure, cardiac injury, inflammation, and other health outcomes will be investigated. METHODS: In this open parallel group randomized controlled trial, 170 diabetic patients undergoing elective or urgent CABG surgery received 1 mL/kg/hour of Hartmann's solution for 12 consecutive hours prior to surgery, versus routine care. The primary outcome was time until participants were "fit for discharge", which is defined as presence of: normal temperature, pulse, and respiration; normal oxygen saturation on air; normal bowel function; and physical mobility. Secondary outcomes included: incidence of renal failure; markers of renal function, inflammation, and cardiac damage; operative morbidity; intensive care stay; patient-assessed outcome, including the Coronary Revascularization Outcome Questionnaire; and use of hospital resources. RESULTS: Recruitment started in July 2010. Enrolment for the study was completed in July 2014. Data analysis commenced in December 2016. Study results will be submitted for publication in the summer of 2017. CONCLUSIONS: VRT is a relatively easy treatment to administer in patients undergoing surgical procedures who are at risk of renal failure. This experimental protocol will increase scientific and clinical knowledge of VRT in diabetic patients undergoing elective or urgent CABG surgery. Findings supporting the efficacy of this intervention could easily be implemented in the health care system. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 02159606; http://www.controlled-trials.com/ISRCTN02159606 (Archived by WebCite at http://www.webcitation.org/6rDkSSkkK). PMID- 28630036 TI - Understanding Health Information Seeking on the Internet Among Sexual Minority People: Cross-Sectional Analysis From the Health Information National Trends Survey. AB - BACKGROUND: Individuals who face barriers to health care are more likely to access the Internet to seek health information. Pervasive stigma and heterosexism in the health care setting are barriers to health care for sexual minority people (SMP, ie, lesbian, gay, and bisexual people); therefore, SMP may be more likely to use the Internet as a source of health information compared to heterosexual people. OBJECTIVE: Currently, there is a dearth of published empirical evidence concerning health information seeking on the Internet among SMP; the current project addresses this gap. METHODS: Data from the 2015 Health Information National Trends Survey Food and Drug Administration Cycle were used to describe and summarize health information seeking among SMP (n=105) and heterosexual people (n=3405). RESULTS: Almost all of the SMP in this sample reported having access to the Internet (92.4%, 97/105). SMP were equally as likely as heterosexual people to seek health information on the Internet (adjusted odds ratio [aOR] 0.94, 95% CI 0.56-1.66) and to report incidental exposure to health information online (aOR 1.02, 95% CI 0.66-1.60). SMP were 58% more likely to watch a health-related video on YouTube than heterosexual people (aOR 1.58, 95% CI 1.00-2.47). Incidental exposure to health information was associated with seeking health information for oneself (aOR 3.87, 95% CI 1.16-14.13) and for someone else (aOR 6.30, 95% CI 2.40-17.82) among SMP. CONCLUSIONS: SMP access the Internet at high rates and seek out health information online. Their incidental exposure could be associated with seeking information for self or others. This suggests that online interventions could be valuable for delivering or promoting health information for SMP. PMID- 28630038 TI - NHS pay cap is barrier to recruitment and retention, unions warn. PMID- 28630037 TI - A Mobile App for the Self-Management of Type 1 Diabetes Among Adolescents: A Randomized Controlled Trial. AB - BACKGROUND: While optimal blood glucose control is known to reduce the long-term complications associated with type 1 diabetes mellitus, adolescents often struggle to achieve their blood glucose targets. However, their strong propensity toward technology presents a unique opportunity for the delivery of novel self management interventions. To support type 1 diabetes self-management in this population, we developed the diabetes self-management app bant, which included wireless blood glucose reading transfer, out-of-range blood glucose trend alerts, coaching around out-of-range trend causes and fixes, and a point-based incentive system. OBJECTIVE: The primary objective was to evaluate bant 's effect on hemoglobin A1c (HbA1c) through a randomized controlled trial (RCT). Secondary measures (eg, self-monitoring of blood glucose [SMBG]) were also collected to assess bant 's impact on the self-management behaviors of adolescents with type 1 diabetes. METHODS: We enrolled 92 adolescents into a 12-month RCT, with 46 receiving usual care and 46 receiving usual care plus bant. Clinical outcome data were collected at quarterly research visits via validated tools, electronic chart review, glucometer downloads, and semistructured interviews. App satisfaction was assessed at 6 and 12 months, and at trial end, users ranked bant components based on perceived usefulness. Mobile analytics captured frequency of blood glucose uploads, which were used to categorize participants into high, moderate, low, or very low engagement levels. RESULTS: Linear mixed models showed no changes in primary and secondary clinical outcomes. However, exploratory regression analysis demonstrated a statistically significant association between increased SMBG and improved HbA1c in the intervention group. For a subgroup of bant users taking SMBG >=5 daily, there was a significant improvement in HbA1c of 0.58% (P=.02), while the parallel subgroup in the control arm experienced no significant change in HbA1c (decrease of 0.06%, P=.84). Although app usage did diminish over the trial, on average, 35% (16/46 participants) were classified as moderately or highly engaged (uploaded SMBG >=3 days a week) over the 12 months. CONCLUSION: Although primary analysis of clinical outcomes did not demonstrate differences between the bant and control groups, exploratory analysis suggested that bant may positively impact the use of SMBG data and glycemic control among youth. The next generation of bant will aim to remove barriers to use, such as deploying the app directly to personal devices instead of secondary research phones, and to explore the utility of integrating bant into routine clinical care to facilitate more frequent feedback. Future evaluations of mHealth apps should consider more robust research tools (eg, ResearchKit) and alternative RCT study designs to enable more rapid and iterative evaluations, better suited to the nature of rapidly evolving consumer technology. TRIAL REGISTRATION: ClinicalTrials.gov NCT01899274; https://clinicaltrials.gov/ct2/show/NCT01899274 (Archived by WebCite at http://www.webcitation.org/6qWrqF1yw). PMID- 28630039 TI - Low-level internalization of cystatin E/M affects legumain activity and migration of melanoma cells. AB - The ratio between proteases and their inhibitors is unbalanced in cancer. The cysteine protease inhibitor cystatin C is internalized by some cancer cells, which affects cellular properties. Here we aimed to investigate if uptake of cystatin C and the related inhibitor cystatin E/M occur in melanoma cell lines and to evaluate to what extent the uptake affects the legumain activity that is typically increased in melanoma. First we studied the basic expression, secretion, and intracellular content of all type 2 cystatins as well as expression and activity of their possible target enzymes legumain and cathepsin B in MDA-MB-435S, A375, and C8161 melanoma cells. Legumain activity was measureable in all cell lines, and of the potential legumain inhibitors, cystatin C, E/M, and F, cystatin C was the one mainly produced. All cells internalized cystatin C added to culture media, leading to increased intracellular cystatin C levels by 120-200%. Cystatin E/M was internalized as well but at a modest rate. The effects on intracellular legumain activity were nevertheless pronounced, probably because the cells lacked this inhibitor, and its affinity for legumain is 100-fold higher than that of cystatin C. Likewise, the low-degree uptake resulted in reduced migration and invasion of A375 cells in Matrigel to an extent comparable with the W106F variant of cystatin C with optimal uptake properties and resulting in much higher intracellular levels. Thus, cystatin E/M appears to be a good candidate to efficiently down-regulate the increased legumain activity, possibly important for the malignant phenotype of melanoma cells. PMID- 28630041 TI - Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage. AB - Aberrant Zn2+ homeostasis is associated with dysregulated intracellular Ca2+ release, resulting in chronic heart failure. In the failing heart a small population of cardiac ryanodine receptors (RyR2) displays sub-conductance-state gating leading to Ca2+ leakage from sarcoplasmic reticulum (SR) stores, which impairs cardiac contractility. Previous evidence suggests contribution of RyR2 independent Ca2+ leakage through an uncharacterized mechanism. We sought to examine the role of Zn2+ in shaping intracellular Ca2+ release in cardiac muscle. Cardiac SR vesicles prepared from sheep or mouse ventricular tissue were incorporated into phospholipid bilayers under voltage-clamp conditions, and the direct action of Zn2+ on RyR2 channel function was examined. Under diastolic conditions, the addition of pathophysiological concentrations of Zn2+ (>=2 nm) caused dysregulated RyR2-channel openings. Our data also revealed that RyR2 channels are not the only SR Ca2+-permeable channels regulated by Zn2+ Elevating the cytosolic Zn2+ concentration to 1 nm increased the activity of the transmembrane protein mitsugumin 23 (MG23). The current amplitude of the MG23 full-open state was consistent with that previously reported for RyR2 sub conductance gating, suggesting that in heart failure in which Zn2+ levels are elevated, RyR2 channels do not gate in a sub-conductance state, but rather MG23 gating becomes more apparent. We also show that in H9C2 cells exposed to ischemic conditions, intracellular Zn2+ levels are elevated, coinciding with increased MG23 expression. In conclusion, these data suggest that dysregulated Zn2+ homeostasis alters the function of both RyR2 and MG23 and that both ion channels play a key role in diastolic SR Ca2+ leakage. PMID- 28630040 TI - Endoplasmic reticulum-associated degradation of the renal potassium channel, ROMK, leads to type II Bartter syndrome. AB - Type II Bartter syndrome is caused by mutations in the renal outer medullary potassium (ROMK) channel, but the molecular mechanisms underlying this disease are poorly defined. To rapidly screen for ROMK function, we developed a yeast expression system and discovered that yeast cells lacking endogenous potassium channels could be rescued by WT ROMK but not by ROMK proteins containing any one of four Bartter mutations. We also found that the mutant proteins were significantly less stable than WT ROMK. However, their degradation was slowed in the presence of a proteasome inhibitor or when yeast cells contained mutations in the CDC48 or SSA1 gene, which is required for endoplasmic reticulum (ER) associated degradation (ERAD). Consistent with these data, sucrose gradient centrifugation and indirect immunofluorescence microscopy indicated that most ROMK protein was ER-localized. To translate these findings to a more relevant cell type, we measured the stabilities of WT ROMK and the ROMK Bartter mutants in HEK293 cells. As in yeast, the Bartter mutant proteins were less stable than the WT protein, and their degradation was slowed in the presence of a proteasome inhibitor. Finally, we discovered that low-temperature incubation increased the steady-state levels of a Bartter mutant, suggesting that the disease-causing mutation traps the protein in a folding-deficient conformation. These findings indicate that the underlying pathology for at least a subset of patients with type II Bartter syndrome is linked to the ERAD pathway and that future therapeutic strategies should focus on correcting deficiencies in ROMK folding. PMID- 28630042 TI - The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate. AB - Cancer cells with specific genetic alterations may be highly dependent on certain nutrients for survival, which can inform therapeutic strategies to target these cancer-specific metabolic vulnerabilities. The glutamate/cystine antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT) is overexpressed in several cancers. Contrasting the established pro-survival roles of SLC7A11 under other stress conditions, here we report the unexpected finding that SLC7A11 overexpression enhances cancer cell dependence on glucose and renders cancer cells more sensitive to glucose starvation-induced cell death and, conversely, that SLC7A11 deficiency by either knockdown or pharmacological inhibition promotes cancer cell survival upon glucose starvation. We further show that glucose starvation induces SLC7A11 expression through ATF4 and NRF2 transcription factors and, correspondingly, that ATF4 or NRF2 deficiency also renders cancer cells more resistant to glucose starvation. Finally, we show that SLC7A11 overexpression decreases whereas SLC7A11 deficiency increases intracellular glutamate levels because of SLC7A11-mediated glutamate export and that supplementation of alpha-ketoglutarate, a key downstream metabolite of glutamate, fully restores survival in SLC7A11-overexpressing cells under glucose starvation. Together, our results support the notion that both glucose and glutamate have important roles in maintaining cancer cell survival and uncover a previously unappreciated role of SLC7A11 to promote cancer cell dependence on glucose. Our study therefore informs therapeutic strategies to target the metabolic vulnerability in tumors with high SLC7A11 expression. PMID- 28630044 TI - Single-molecule Forster resonance energy transfer (FRET) analysis discloses the dynamics of the DNA-topoisomerase II (Top2) interaction in the presence of TOP2 targeting agents. AB - Topoisomerases play crucial roles in DNA replication, transcription, and recombination. For instance, topoisomerase II (Top2) is critically important for resolving DNA tangles during cell division, and as such, it is a broad anticancer drug target. Top2 regulates DNA topology by transiently breaking one double stranded DNA molecule (cleavage), allowing a second double strand to pass through the opened DNA gate (opening), and then closing the gate by rejoining the broken ends. Drugs that modulate Top2 catalysis may therefore affect enzymatic activity at several different steps. Previous studies have focused on examining DNA cleavage and ligation; however, the dynamic opening and closing of the DNA gate has been less explored. Here, we used the single-molecule Forster resonance energy transfer (smFRET) method to observe the open and closed state of the DNA gate and to measure dwell times in each state. Our results show that Top2 binds and bends DNA to increase the energy transfer efficiency (EFRET), and ATP treatment further induces the fluctuation of EFRET, representing the gate opening and closing. Additionally, our results demonstrate that both types of Top2 targeting anticancer drugs, the catalytic inhibitor dexrazoxane (ICRF187) and mechanistic poison teniposide (VM26), can interfere with DNA gate dynamics and shorten the dwell time in the closed state. Moreover, Top2 bound to the nonhydrolyzable ATP analog 5'-adenylyl-beta,gamma-imidodiphosphate exhibits altered DNA gate dynamics, but the DNA gate appears to open and close even after N-gate closure. In summary, we have utilized single-molecule detection to unravel Top2 DNA gate dynamics and reveal previously unknown effects of Top2 drugs on these dynamics. PMID- 28630043 TI - The small GTPases K-Ras, N-Ras, and H-Ras have distinct biochemical properties determined by allosteric effects. AB - H-Ras, K-Ras, and N-Ras are small GTPases that are important in the control of cell proliferation, differentiation, and survival, and their mutants occur frequently in human cancers. The G-domain, which catalyzes GTP hydrolysis and mediates downstream signaling, is 95% conserved between the Ras isoforms. Because of their very high sequence identity, biochemical studies done on H-Ras have been considered representative of all three Ras proteins. We show here that this is not a valid assumption. Using enzyme kinetic assays under identical conditions, we observed clear differences between the three isoforms in intrinsic catalysis of GTP by Ras in the absence and presence of the Ras-binding domain (RBD) of the c-Raf kinase protein (Raf-RBD). Given their identical active sites, isoform G domain differences must be allosteric in origin, due to remote isoform-specific residues that affect conformational states. We present the crystal structure of N Ras bound to a GTP analogue and interpret the kinetic data in terms of structural features specific for H-, K-, and N-Ras. PMID- 28630046 TI - Northern Ireland's GPs miss out on L1m of QOF funding. PMID- 28630047 TI - Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease. AB - The treatment of inflammatory bowel disease (IBD)-ulcerative colitis (UC) and Crohn's disease (CD)-has evolved beyond surgery with the introduction of biologic agents, primarily antibodies against mediators of inflammation and cell attraction. Anti-tumor necrosis factor (TNF) agents have been the first line treatment for moderate to severe ulcerative colitis and Crohn's disease for more than 15 years. During that time much has been learnt about how best to use these agents. This review will assess the evidence on how to optimize the use of anti TNF agents; when and how to start treatment; how to monitor treatment and when to de-escalate it; and the potential adverse effects of these drugs. New and emerging treatments such as anti-attractants, anti-interleukins, and Janus kinase (JAK) inhibitors will also be discussed. PMID- 28630045 TI - Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding. AB - Small GTPases are molecular switches that have critical biological roles and are controlled by GTPase-activating proteins and guanine nucleotide exchange factors (GEFs). The smg GDP dissociation stimulator (SmgGDS) protein functions as a GEF for the RhoA and RhoC small GTPases. SmgGDS has various regulatory roles, including small GTPase trafficking and localization and as a molecular chaperone, and interacts with many small GTPases possessing polybasic regions. Two SmgGDS splice variants, SmgGDS-558 and SmgGDS-607, differ in GEF activity and binding affinity for RhoA depending on the lipidation state, but the reasons for these differences are unclear. Here we determined the crystal structure of SmgGDS-558, revealing a fold containing tandem copies of armadillo repeats not present in other GEFs. We also observed that SmgGDS harbors distinct positively and negatively charged regions, both of which play critical roles in binding to RhoA and GEF activity. This is the first report demonstrating a relationship between the molecular function and atomic structure of SmgGDS. Our findings indicate that the two SmgGDS isoforms differ in GTPase binding and GEF activity, depending on the lipidation state, thus providing useful information about the cellular functions of SmgGDS in cells. PMID- 28630048 TI - Implementation of shared medical appointments to offer battlefield acupuncture efficiently to veterans with pain. PMID- 28630049 TI - Comparison of electroacupuncture and medical treatment for functional constipation: a systematic review and meta-analysis. AB - OBJECTIVES: To assess the effectiveness of electroacupuncture (EA) relative to conventional medication in functional constipation (FC). DESIGN: Systematic review and meta-analysis. SETTING: To be included, studies needed to: (1) have been randomised controlled trials; (2) have recruited adult patients diagnosed with FC according to the Rome II/III criteria or the American Gastroenterological Association guideline for chronic FC; and (3) have randomised patients to be treated with EA or anti-constipation medication. We searched Medline, the Cochrane Library and Embase databases for articles published up to 30 June 2016. INTERVENTION: EA or anti-constipation medication. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the change in the number of weekly spontaneous bowel movements. Secondary outcomes were total response rate (or total effective rate), symptom reduction and Cleveland Clinic constipation scores. RESULTS: The pooled results showed significantly more improvement in the frequency of spontaneous bowel movements in the EA treatment group compared with the medicine treated group (pooled SMD 0.244, 95% CI 0.065 to 0.424, P=0.008). Deep-needling EA was significantly more effective than treatment with medication at increasing the frequency of spontaneous bowel movements (p=0.019). Significantly greater improvement was also seen for total response rates (p=0.018) and reductions in symptom score (p<0.001) in EA-treated patients. CONCLUSIONS: EA was more effective than medication at improving spontaneous bowel movements and total response rate, and reducing the symptoms of FC. PMID- 28630050 TI - Effectiveness of computer-aided diagnosis (CADx) of breast pathology using immunohistochemistry results of core needle biopsy samples for synaptophysin, oestrogen receptor and CK14/p63 for classification of epithelial proliferative lesions of the breast. AB - AIMS: The aim of this study was to develop a computer-aided diagnosis (CADx) system for identifying breast pathology. METHODS: Two sets of 100 consecutive core needle biopsy (CNB) specimens were collected for test and validation studies. All 200 CNB specimens were stained with antibodies targeting oestrogen receptor (ER), synaptophysin and CK14/p63. All stained slides were scanned in a whole-slide imaging system and photographed. The photographs were analysed using software to identify the proportions of tumour cells that were positive and negative for each marker. In the test study, the cut-off values for synaptophysin (negative and positive) and CK14/p63 (negative and positive) were decided using receiver operating characteristic (ROC) analysis. For ER analysis, samples were divided into groups with <10% positive or >10% positive cells and decided using receiver operating characteristic (ROC) analysis. Finally, these two groups categorised as ER-low, ER-intermediate (non-low and non-high) and ER-high groups. In the validation study, the second set of immunohistochemical slides were analysed using these cut-off values. RESULTS: The cut-off values for synaptophysin, <10% ER positive, >10% ER positive and CK14/p63 were 0.14%, 2.17%, 77.93% and 18.66%, respectively. The positive predictive value for malignancy (PPV) was 100% for synaptophysin-positive/ER-high/(CK14/p63)-any or synaptophysin positive/ER-low/(CK14/p63)-any. The PPV was 25% for synaptophysin-positive/ER intermediate/(CK14/p63)-positive. For synaptophysin-negative/(CK14/p63)-negative, the PPVs for ER-low, ER-intermediate and ER-high were 100%, 80.0% and 95.8%, respectively. The PPV was 4.5% for synaptophysin-negative/ER intermediate/(CK14/p63)-positive. CONCLUSION: The CADx system was able to analyse sufficient data for all types of epithelial proliferative lesions of the breast including invasive breast cancer. This system may be useful for pathological diagnosis of breast CNB in routine investigations. PMID- 28630052 TI - Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases. AB - ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. As few ETV6-RUNX1 carriers develop precursor B-cell acute lymphocytic leukemia (pB ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor. Here, we present in vivo genetic evidence mechanistically connecting preleukemic ETV6-RUNX1 expression in hematopoetic stem cells/precursor cells (HSC/PC) and postnatal infections for human-like pB-ALL. In our model, ETV6-RUNX1 conferred a low risk of developing pB ALL after exposure to common pathogens, corroborating the low incidence observed in humans. Murine preleukemic ETV6-RUNX1 pro/preB cells showed high Rag1/2 expression, known for human ETV6-RUNX1 pB-ALL. Murine and human ETV6-RUNX1 pB-ALL revealed recurrent genomic alterations, with a relevant proportion affecting genes of the lysine demethylase (KDM) family. KDM5C loss of function resulted in increased levels of H3K4me3, which coprecipitated with RAG2 in a human cell line model, laying the molecular basis for recombination activity. We conclude that alterations of KDM family members represent a disease-driving mechanism and an explanation for RAG off-target cleavage observed in humans. Our results explain the genetic basis for clonal evolution of an ETV6-RUNX1 preleukemic clone to pB ALL after infection exposure and offer the possibility of novel therapeutic approaches. Cancer Res; 77(16); 4365-77. (c)2017 AACR. PMID- 28630051 TI - DNA Damage and Repair Biomarkers of Immunotherapy Response. AB - DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 675-93. (c)2017 AACR. PMID- 28630056 TI - The Relationship of Serum Soluble Receptor for Advanced Glycation End Products (sRAGE) and Carboxymethyl Lysine (CML) to the Incidence of Diabetic Nephropathy in Persons With Type 1 Diabetes. PMID- 28630053 TI - Glucose Catabolism in Liver Tumors Induced by c-MYC Can Be Sustained by Various PKM1/PKM2 Ratios and Pyruvate Kinase Activities. AB - Different pyruvate kinase isoforms are expressed in a tissue-specific manner, with pyruvate kinase M2 (PKM2) suggested to be the predominant isoform in proliferating cells and cancer cells. Because of differential regulation of enzymatic activities, PKM2, but not PKM1, has been thought to favor cell proliferation. However, the role of PKM2 in tumorigenesis has been recently challenged. Here we report that increased glucose catabolism through glycolysis and increased pyruvate kinase activity in c-MYC-driven liver tumors are associated with increased expression of both PKM1 and PKM2 isoforms and decreased expression of the liver-specific isoform of pyruvate kinase, PKL. Depletion of PKM2 at the time of c-MYC overexpression in murine livers did not affect c-MYC induced tumorigenesis and resulted in liver tumor formation with decreased pyruvate kinase activity and decreased catabolism of glucose into alanine and the Krebs cycle. An increased PKM1/PKM2 ratio by ectopic PKM1 expression further decreased glucose flux into serine biosynthesis and increased flux into lactate and the Krebs cycle, resulting in reduced total levels of serine. However, these changes also did not affect c-MYC-induced liver tumor development. These results suggest that increased expression of PKM2 is not required to support c-MYC induced tumorigenesis in the liver and that various PKM1/PKM2 ratios and pyruvate kinase activities can sustain glucose catabolism required for this process. Cancer Res; 77(16); 4355-64. (c)2017 AACR. PMID- 28630054 TI - SLC45A2: A Melanoma Antigen with High Tumor Selectivity and Reduced Potential for Autoimmune Toxicity. AB - Cytotoxic T lymphocyte (CTL)-based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopeptidomes of 55 melanoma patient-derived cell lines, we identified a number of shared HLA class I-bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A*0201- and HLA-A*2402-restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity. Cancer Immunol Res; 5(8); 618-29. (c)2017 AACR. PMID- 28630057 TI - Characteristics of children who do not attend their hospital appointments, and GPs' response: a mixed methods study in primary and secondary care. AB - BACKGROUND: Children who do not attend (DNA) their hospital outpatient appointments are a concern because this potentially compromises the child's health and incurs financial cost. Little is known about children who DNA or the views of GPs to non-attendance. AIM: To describe the characteristics of children who DNA hospital paediatric outpatient appointments, and explore how GPs view and respond to DNAs. DESIGN AND SETTING: A mixed methods study of data from all new referrals to a children's hospital in the South West of England between 1 September and 31 October 2012. METHOD: Data were extracted from patients' hospital and GP records, and Stata was used to analyse the data quantitatively. Analysis focused on describing the characteristics of children who DNA, and the process of care that followed. Practices that had either the highest or lowest number of DNAs were purposefully sampled for GPs who had referred children to secondary care at the study hospital within the previous year. Interviews were held between May 2014 and July 2015, and were analysed thematically. RESULTS: Children who DNA are more likely to be from an area of greater deprivation (adjusted odds ratio [AOR] 1.02, 95% confidence interval [CI] = 1.00 to 1.02, P = 0.04), and with a child protection alert in their hospital notes (AOR 2.72, 95% CI = 1.26 to 5.88, P = 0.01). Non-attendance is communicated poorly to GPs, rarely coded in patients' GP records, and few GP practices have a formal policy regarding paediatric DNAs. CONCLUSION: Non-attendance at hospital outpatient appointments may indicate a child's welfare is at risk. Communication between primary and secondary care needs to be improved, and guidelines developed to encourage GPs to monitor children who DNA. PMID- 28630058 TI - Psychological morbidity and return to work after injury: multicentre cohort study. AB - BACKGROUND: The benefits of work for physical, psychological, and financial wellbeing are well documented. Return to work (RTW) after unintentional injury is often delayed, and psychological morbidity may contribute to this delay. The impact of psychological morbidity on RTW after a wide range of unintentional injuries in the UK has not been adequately quantified. AIM: To quantify the role of psychological factors, including anxiety, depression, and post-traumatic distress, on RTW following unintentional injuries. DESIGN AND SETTING: A longitudinal multicentre prospective study was undertaken in Nottingham, Bristol, Leicester, and Guildford, UK. METHOD: Participants (n = 273) were 16-69-year-olds admitted to hospital following unintentional injury, who were in paid employment prior to injury. They were surveyed at baseline, then at 1, 2, 4, and 12 months following injury; demographic data were collected along with injury characteristics, psychological morbidity, and RTW status. Associations between demographic, injury and psychological factors, and RTW between 2 and 12 months after injury were quantified using random effects logistic regression. RESULTS: The odds of RTW between 2 and 12 months after injury reduced as depression scores early in the recovery period (1 month after injury) increased (odds ratio [OR] 0.87, 95% confidence interval [CI] = 0.79 to 0.95) and as length of hospital stay increased (OR 0.91, 95% CI] = 0.86 to 0.96). For those experiencing threatening life events following injury (OR 0.27, 95% CI = 0.10 to 0.72) and with higher scores on the Crisis Support Scale (OR 0.93, 95% CI] = 0.88 to 0.99), the odds of RTW between 2 and 12 months after injury were lower. Multiple imputation analysis found similar results, but those relating to crisis support did not remain statistically significant. CONCLUSION: Primary care professionals can identify patients at risk of delayed RTW who may benefit from management of psychological morbidity and support to RTW. PMID- 28630060 TI - NHS providers achieve "the impossible" and cut their deficit by two thirds. PMID- 28630059 TI - The role of contraindications in prescribing anticoagulants to patients with atrial fibrillation: a cross-sectional analysis of primary care data in the UK. AB - BACKGROUND: Underuse of anticoagulants in atrial fibrillation (AF) is an international problem, which has often been attributed to the presence of contraindications to treatment. No studies have assessed the influence of contraindications on anticoagulant prescribing in the UK. AIM: To determine the influence of contraindications on anticoagulant prescribing in patients with AF in the UK. DESIGN AND SETTING: Cross-sectional analysis of primary care data from 645 general practices contributing to The Health Improvement Network, a large UK database of electronic primary care records. METHOD: Twelve sequential cross sectional analyses were carried out from 2004 to 2015. Patients with a diagnosis of AF aged >=35 years and registered for at least 1 year were included. Outcome measure was prescription of anticoagulant medication. RESULTS: Over the 12 study years, the proportion of eligible patients with AF with contraindications who were prescribed anticoagulants increased from 40.1% (95% confidence interval [CI] = 38.3 to 41.9) to 67.2% (95% CI = 65.6 to 68.8), and the proportion of those without contraindications prescribed anticoagulants increased from 42.1% (95% CI = 41.6 to 42.6) to 67.7% (95% CI = 67.2 to 68.1). In patients with a recent history of major bleeding or aneurysm, prescribing rates increased from 44.3% (95% CI = 42.2 to 46.5) and 34.8% (95% CI = 29.4 to 40.6) in 2004 to 71.7% (95% CI = 69.9 to 73.5) and 63.2% (95% CI = 58.3 to 67.8) in 2015, respectively, comparable with rates in patients without contraindications. CONCLUSION: The presence or absence of recorded contraindications has little influence on the decision to prescribe anticoagulants for the prevention of stroke in patients with AF. The study analysis suggests that, nationally, 38 000 patients with AF with contraindications are treated with anticoagulants. This has implications for patient safety. PMID- 28630061 TI - Increased Resistance to Intradermal Francisella tularensis LVS Infection by Inactivation of the Sts Phosphatases. AB - The Suppressor of TCR signaling proteins (Sts-1 and Sts-2) are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic lineages, including T lymphocytes. Mice lacking Sts expression are characterized by enhanced T cell responses. Additionally, a recent study demonstrated that Sts-/- mice are profoundly resistant to systemic infection by Candida albicans, with resistance characterized by enhanced survival, more rapid fungal clearance in key peripheral organs, and an altered inflammatory response. To investigate the role of Sts in the primary host response to infection by a bacterial pathogen, we evaluated the response of Sts-/- mice to infection by a Gram-negative bacterial pathogen. Francisella tularensis is a facultative bacterial pathogen that replicates intracellularly within a variety of cell types and is the causative agent of tularemia. Francisella infections are characterized by a delayed immune response, followed by an intense inflammatory reaction that causes widespread tissue damage and septic shock. Herein, we demonstrate that mice lacking Sts expression are significantly resistant to infection by the live vaccine strain (LVS) of F. tularensis Resistance is characterized by reduced lethality following high-dose intradermal infection, an altered cytokine response in the spleen, and enhanced bacterial clearance in multiple peripheral organs. Sts-/- bone marrow-derived monocytes and neutrophils, infected with F. tularensis LVS ex vivo, display enhanced restriction of intracellular bacteria. These observations suggest the Sts proteins play an important regulatory role in the host response to bacterial infection, and they underscore a role for Sts in regulating functionally relevant immune response pathways. PMID- 28630062 TI - The Transcription Factor NFAT1 Participates in the Induction of CD4+ T Cell Functional Exhaustion during Plasmodium yoelii Infection. AB - Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and upregulate cell surface inhibitory molecules such as PD-1 and LAG-3. The molecular events that lead to the induction of this phenotype have, however, not been fully characterized. In T cells, members of the NFAT family of transcription factors not only are responsible for the expression of many activation-induced genes but also are crucial for the induction of transcriptional programs that inhibit T cell activation and maintain tolerance. Here we show that NFAT1 deficient CD4+ T cells maintain higher proliferative capacity and expression of effector cytokines following Plasmodium yoelii infection and are therefore more resistant to P. yoelii-induced exhaustion than their wild-type counterparts. Consequently, gene expression microarray analysis of CD4+ T cells following P. yoelii-induced exhaustion shows upregulation of effector T cell-associated genes in the absence of NFAT1 compared with wild-type exhausted T cells. Furthermore, adoptive transfer of NFAT1-deficient CD4+ T cells into mice infected with P. yoelii results in increased production of antibodies to cognate antigen. Our results support the idea that NFAT1 is necessary to fully suppress effector responses during Plasmodium-induced CD4+ T cell exhaustion. PMID- 28630063 TI - Listeria-vectored vaccine expressing the Mycobacterium tuberculosis 30 kDa major secretory protein via the constitutively active prfA* regulon boosts BCG efficacy against tuberculosis. AB - A potent vaccine against tuberculosis, one of the world's deadliest diseases, is needed to enhance the immunity of people worldwide, most of whom have been vaccinated with the partially effective BCG vaccine. Here we investigate novel live attenuated recombinant Listeria monocytogenes (rLm) vaccines expressing the Mycobacterium tuberculosis (Mtb) 30 kDa major secretory protein (r30/Ag85B) (rLm30) as heterologous booster vaccines in animals primed with BCG. Using three attenuated Lm vectors, rLm DeltaactA (LmI), rLm DeltaactA DeltainlB (LmII), and rLm DeltaactA DeltainlBprfA* (LmIII), we constructed five rLm30 vaccine candidates expressing the r30 linked in-frame to the Lm Listeriolycin O signal sequence and driven by the hly promoter (h30) or linked in-frame to the ActA N terminus and driven by the actA promoter (a30). All five rLm30 vaccines secreted r30 in broth and macrophages; while rLm expressing r30 via a constitutively active prfA* regulon (rLmIII/a30) expressed the greatest amount of r30 in broth culture, all five rLm vaccines expressed equivalent amounts of r30 in infected macrophages. In comparative studies, boosting BCG-immunized mice with rLmIII/a30 induced the strongest antigen-specific T-cell responses, including splenic and lung polyfunctional CD4+ T-cells expressing the three cytokines of interferon gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and interleukin-2 (IL 2) (P < 0.001) and splenic and lung CD8+ T-cells expressing IFN-gamma (P < 0.0001). In mice and guinea pigs, rLmIII/a30 and rLmI/h30 vaccines were generally more potent booster vaccines than r30 in adjuvant and a recombinant adenovirus vaccine expressing r30. In a setting in which BCG alone was highly immunoprotective, boosting mice with rLmIII/a30, the most potent of the vaccines, significantly enhanced protection against aerosolized Mtb (P <0.01). PMID- 28630064 TI - Pneumolysin-Dependent Calpain Activation and Interleukin-1alpha Secretion in Macrophages Infected with Streptococcus pneumoniae. AB - Pneumolysin (PLY), a major virulence factor of Streptococcus pneumoniae, is a pore-forming cytolysin that modulates host innate responses contributing to host defense against and pathogenesis of pneumococcal infections. Interleukin-1alpha (IL-1alpha) has been shown to be involved in tissue damage in a pneumococcal pneumonia model; however, the mechanism by which this cytokine is produced during S. pneumoniae infection remains unclear. In this study, we examined the role of PLY in IL-1alpha production. Although the strains induced similar levels of pro IL-1alpha expression, wild-type S. pneumoniae D39, but not a deletion mutant of the ply gene (Deltaply), induced the secretion of mature IL-1alpha from host macrophages, suggesting that PLY is critical for the maturation and secretion of IL-1alpha during S. pneumoniae infection. Further experiments with calcium chelators and calpain inhibitors indicated that extracellular calcium ions and calpains (calcium-dependent proteases) facilitated the maturation and secretion of IL-1alpha from D39-infected macrophages. Moreover, we found that PLY plays a critical role in calcium influx and calpain activation, as elevated intracellular calcium levels and the degradation of the calpain substrate alpha-fodrin were detected in macrophages infected with D39 but not the Deltaply strain. These results suggested that PLY induces the influx of calcium in S. pneumoniae infected macrophages, followed by calpain activation and subsequent IL-1alpha maturation and secretion. PMID- 28630065 TI - CCR5 Is Involved in Interruption of Pregnancy in Mice Infected with Toxoplasma gondii during Early Pregnancy. AB - Toxoplasmosis can cause abortion in pregnant humans and other animals; however, the mechanism of abortion remains unknown. C-C chemokine receptor type 5 (CCR5) is essential for host defense against Toxoplasma gondii infection. To investigate the relationship between CCR5 and abortion in toxoplasmosis, we inoculated wild type and CCR5-deficient (CCR5-/-) mice with T. gondii tachyzoites intraperitoneally on day 3 of pregnancy (embryonic day 3 [E3]). The pregnancy rate decreased as pregnancy progressed in infected wild-type mice. Histopathologically, no inflammatory lesions were observed in the fetoplacental tissues. Although wild-type mice showed a higher parasite burden at the implantation sites than did CCR5-/- mice at E6 (3 days postinfection [dpi]), T. gondii antigen was detected only in the uterine tissue and not in the fetoplacental tissues. At E8 (5 dpi), the embryos in infected wild-type mice showed poor development compared with those of infected CCR5-/- mice, and apoptosis was observed in poorly developed embryos. Compared to uninfected mice, infected wild-type mice showed increased CCR5 expression at the implantation site at E6 and E8. Furthermore, analyses of mRNA expression in the uterus of nonpregnant and pregnant mice suggested that a lack of the CCR5 gene and the downregulation of tumor necrosis factor alpha (TNF-alpha) and CCL3 expression at E6 (3 dpi) are important factors for the maintenance of pregnancy following T. gondii infection. These results suggested that CCR5 signaling is involved in embryo loss in T. gondii infection during early pregnancy and that apoptosis is associated with embryo loss rather than direct damage to the fetoplacental tissues. PMID- 28630066 TI - Porphyromonas gulae Activates Unprimed and Gamma Interferon-Primed Macrophages via the Pattern Recognition Receptors Toll-Like Receptor 2 (TLR2), TLR4, and NOD2. AB - Porphyromonas gulae is an anaerobic, Gram-negative coccobacillus that has been associated with periodontal disease in companion animals. The aims of this study were to analyze the ligation of pattern recognition receptors by P. gulae and the subsequent activation of macrophages. Exposure of HEK cells transfected with Toll like receptors (TLRs) or NOD-like receptors to P. gulae resulted in the ligation of TLR2, TLR4, and NOD2. The effects of this engagement of receptors were investigated by measuring the synthesis of nitric oxide (NO), CD86 expression, and inflammatory cytokine production by wild-type, TLR2-/-, and TLR4-/- macrophages. The addition of P. gulae to unprimed and gamma interferon (IFN gamma)-primed (M1 phenotype) macrophages significantly increased the surface expression of CD86, but only M1 macrophages produced nitric oxide. P. gulae induced expression of CD86 on unprimed macrophages was dependent on both TLR2 and TLR4, but CD86 expression and NO production in M1 macrophages were only TLR2 dependent. P. gulae induced an increase in secretion of interleukin-1alpha (IL 1alpha), IL-1beta, IL-6, IL-12p70, IL-13, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1alpha (MIP-1alpha) by M1 macrophages compared to that by unprimed controls. Among these cytokines, secretion of IL-6 and TNF-alpha by M1 macrophages was dependent on either TLR2 or TLR4. Our data indicate that TLR2 and TLR4 are important for P. gulae activation of unprimed macrophages and that activation and effector functions induced in M1 macrophages by P. gulae are mainly dependent on TLR2. In conclusion, P. gulae induces a strong TLR2-dependent inflammatory M1 macrophage response which may be important in establishing the chronic inflammation associated with periodontal disease in companion animals. PMID- 28630067 TI - SipA Activation of Caspase-3 Is a Decisive Mediator of Host Cell Survival at Early Stages of Salmonella enterica Serovar Typhimurium Infection. AB - Salmonella invasion protein A (SipA) is a dual-function effector protein that plays roles in both actin polymerization and caspase-3 activation in intestinal epithelial cells. To date its function in other cell types has remained largely unknown despite its expression in multiple cell types and its extracellular secretion during infection. Here we show that in macrophages SipA induces increased caspase-3 activation early in infection. This activation required a threshold level of SipA linked to multiplicity of infection and may be a limiting factor controlling bacterial numbers in infected macrophages. In polymorphonuclear leukocytes, SipA or other Salmonella pathogenicity island 1 effectors had no effect on induction of caspase-3 activation either alone or in the presence of whole bacteria. Tagging of SipA with the small fluorescent phiLOV tag, which can pass through the type three secretion system, allowed visualization and quantification of caspase-3 activation by SipA-phiLOV in macrophages. Additionally, SipA-phiLOV activation of caspase-3 could be tracked in the intestine through multiphoton laser scanning microscopy in an ex vivo intestinal model. This allowed visualization of areas where the intestinal epithelium had been compromised and demonstrated the potential use of this fluorescent tag for in vivo tracking of individual effectors. PMID- 28630068 TI - Ehrlichia chaffeensis TRP120 Moonlights as a HECT E3 Ligase Involved in Self- and Host Ubiquitination To Influence Protein Interactions and Stability for Intracellular Survival. AB - Ehrlichia chaffeensis secretes tandem repeat protein (TRP) effectors that are involved in a diverse array of host cell interactions, some of which directly activate cell signaling pathways and reprogram host gene transcription to promote survival in the mononuclear phagocyte. However, the molecular details of these effector-host interactions and roles in pathobiology are incompletely understood. In this study, we determined that the E. chaffeensis effector TRP120 is posttranslationally modified by ubiquitin (Ub) and that ubiquitination occurs through intrinsic and host-mediated HECT ligase activity. A functional HECT E3 ligase domain with a conserved catalytic site was identified in the C-terminal region of TRP120, and TRP120 autoubiquitination occurred in vitro in the presence of host UbcH5b/c E2 enzymes. TRP120 ubiquitination sites were mapped using a high density microfluidic peptide array and confirmed by ectopic expression of TRP120 lysine mutants in cells. Moreover, we determined that the HECT E3 ubiquitin ligase, Nedd4L, interacts with TRP120 during infection and also mediates TRP120 ubiquitination. Nedd4L knockdown resulted in the reduction of TRP120-Ub, decreased ehrlichial infection, and reduced recruitment of a known TRP120 interacting host protein, PCGF5, to ehrlichial inclusions. TRP120-mediated PCGF5 polyubiquitination was associated with a reduction in PCGF5 levels. Inhibition of ubiquitination with small molecules also significantly decreased ehrlichial infection, indicating that the Ub pathway is critical for ehrlichial intracellular replication and survival. The current study identified a novel E. chaffeensis ubiquitin ligase and revealed an important role for the ubiquitin pathway in effector-host interactions and pathogen-mediated host protein stability in order to promote intracellular survival. PMID- 28630070 TI - Regulation of Type III Secretion of Translocon and Effector Proteins by the EsaB/EsaL/EsaM Complex in Edwardsiella tarda. AB - The type III secretion system (T3SS) plays a crucial role in the pathogenesis of many Gram-negative bacteria, including Edwardsiella tarda, an important fish pathogen. Within the E. tarda T3SS, there are three proteins (EsaB/EsaL/EsaM) that are homologous to proteins present in many other bacteria, including SpiC/SsaL/SsaM in Salmonella, SepD/SepL/CesL in enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC), and YscB/YopN/SycN in Yersinia EsaL was found to interact with both EsaB and EsaM within the bacterial cell, as revealed by a coimmunoprecipitation assay. Moreover, EsaM is required for EsaB stability, and the two proteins interact with each other. EsaB, EsaL, and EsaM are all indispensable for the secretion of the T3SS translocon protein EseC into supernatants under pH 5.5 and pH 7.2 conditions. Unlike EseC, EseG is a T3SS effector whose secretion is suppressed by EsaL at pH 7.2 while it is promoted at pH 5.5 condition. Despite this finding, mutant strains lacking EsaB, EsaL, or EsaM (i.e., the DeltaesaB, DeltaesaL, or DeltaesaM strain, respectively) were all outcompeted by wild-type E. tarda during a coinfection model. These results demonstrate that EsaB/EsaL/EsaM form a ternary complex controlling the secretion of T3SS translocon and effector proteins and contributing to E. tarda pathogenesis. PMID- 28630069 TI - Degradation of Incretins and Modulation of Blood Glucose Levels by Periodontopathic Bacterial Dipeptidyl Peptidase 4. AB - Severe periodontitis is known to aggravate diabetes mellitus, though molecular events related to that link have not been fully elucidated. Porphyromonas gingivalis, a major pathogen of periodontitis, expresses dipeptidyl peptidase 4 (DPP4), which is involved in regulation of blood glucose levels by cleaving incretins in humans. We examined the enzymatic characteristics of DPP4 from P. gingivalis as well as two other periodontopathic bacteria, Tannerella forsythia and Prevotella intermedia, and determined whether it is capable of regulating blood glucose levels. Cell-associated DPP4 activity was found in those microorganisms, which was effectively suppressed by inhibitors of human DPP4, and molecules sized 73 kDa in P. gingivalis, and 71 kDa in T. forsythia and P. intermedia were immunologically detected. The kcat/Km values of recombinant DPP4s ranged from 721 +/- 55 to 1,283 +/- 23 MUM-1s-1 toward Gly-Pro-4-methylcoumaryl-7 amide (MCA), while those were much lower for His-Ala-MCA. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis showed His/Tyr-Ala dipeptide release from the N termini of incretins, glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, respectively, with the action of microbial DPP4. Moreover, intravenous injection of DPP4 into mice decreased plasma active GLP-1 and insulin levels, accompanied by a substantial elevation in blood glucose over the control after oral glucose administration. These results are the first to show that periodontopathic bacterial DPP4 is capable of modulating blood glucose levels the same as mammalian DPP4; thus, the incidence of periodontopathic bacteremia may exacerbate diabetes mellitus via molecular events of bacterial DPP4 activities. PMID- 28630071 TI - Albumin Inhibits Pseudomonas aeruginosa Quorum Sensing and Alters Polymicrobial Interactions. AB - Polymicrobial interactions are complex and can influence the course of an infection, as is the case when two or more species exhibit a synergism that produces a disease state not seen with any of the individual species alone. Cell to-cell signaling is key to many of these interactions, but little is understood about how the host environment influences polymicrobial interactions or signaling between bacteria. Chronic wounds are typically polymicrobial, with Staphylococcus aureus and Pseudomonas aeruginosa being the two most commonly isolated species. While P. aeruginosa readily kills S. aureusin vitro, the two species can coexist for long periods together in chronic wound infections. In this study, we investigated the ability of components of the wound environment to modulate interactions between P. aeruginosa and S. aureus We demonstrate that P. aeruginosa quorum sensing is inhibited by physiological levels of serum albumin, which appears to bind and sequester some homoserine lactone quorum signals, resulting in the inability of P. aeruginosa to produce virulence factors that kill S. aureus These data could provide important clues regarding the virulence of P. aeruginosa in albumin-depleted versus albumin-rich infection sites and an understanding of the nature of friendly versus antagonistic interactions between P. aeruginosa and S. aureus. PMID- 28630072 TI - Pseudomonas Quinolone Signal Induces Oxidative Stress and Inhibits Heme Oxygenase 1 Expression in Lung Epithelial Cells. AB - Pseudomonasaeruginosa causes lung infections in patients with cystic fibrosis (CF). The Pseudomonas quinolone signal (PQS) compound is a secreted P. aeruginosa virulence factor that contributes to the pathogenicity of P. aeruginosa We were able to detect PQS in sputum samples from CF patients infected with P. aeruginosa but not in samples from uninfected patients. We then tested the hypothesis that PQS induces oxidative stress in host cells by determining the ability of PQS to induce the production of reactive oxygen species (ROS) in lung epithelial cells (A549 and primary normal human bronchial epithelial [NHBE]) cells and macrophages (J774A.1 and THP-1). ROS production induced by PQS was detected with fluorescent probes (dichlorodihydrofluorescein diacetate, dihydroethidium, and MitoSOX Red) in conjunction with confocal microscopy and flow cytometry. PQS induced ROS production in lung epithelial (A549 and NHBE) cells and macrophages (J774A.1 and THP-1 cells). NHBE cells were sensitive to PQS concentrations as low as 500 ng/ml. PQS significantly induced early apoptosis (P < 0.05, n = 6) in lung epithelial cells, as measured by annexin/propidium iodide detection by flow cytometry. However, no change in apoptosis upon PQS treatment was seen in J774A.1 cells. Heme oxygenase-1 (HO-1) protein is an antioxidant enzyme usually induced by oxidative stress. Interestingly, incubation with PQS significantly reduced HO 1 and NrF2 expression in A549 and NHBE cells but increased HO-1 expression in J774A.1 cells (P < 0.05, n = 3), as determined by immunoblotting and densitometry. These PQS effects on host cells could play an important role in the pathogenicity of P. aeruginosa infections. PMID- 28630073 TI - New Insights into the Roles of Long Polar Fimbriae and Stg Fimbriae in Salmonella Interactions with Enterocytes and M Cells. AB - Salmonella enterica serovar Typhi causes the systemic disease typhoid fever. After ingestion, it adheres to and invades the host epithelium while evading the host innate immune response, causing little if any inflammation. Conversely, Salmonella enterica serovar Typhimurium causes gastroenteritis in humans and thrives in the inflamed gut. Upon entering the host, S Typhimurium preferentially colonizes Peyer's patches, a lymphoid organ in which microfold cells (M cells) overlay an arrangement of B cells, T cells, and antigen-presenting cells. Both serovars can adhere to and invade M cells and enterocytes, and it has been assumed that S Typhi also preferentially targets M cells. In this study, we present data supporting the alternative hypothesis that S Typhi preferentially targets enterocytes. Using a tissue culture M cell model, we examined S Typhi strains with a deletion in the stg fimbriae. The stg deletion resulted in increased adherence to M cells and, as expected, decreased adherence to Caco-2 cells. Adherence to M cells could be further enhanced by introduction of the long polar fimbriae (Lpf), which facilitate adherence of S Typhimurium to M cells. Deletion of stg and/or introduction of lpf enhanced M cell invasion as well, leading to significant increases in secretion of interleukin 8. These results suggest that S Typhi may preferentially target enterocytes in vivo. PMID- 28630075 TI - Doctors have medical and social responsibilities in the Trump era. PMID- 28630074 TI - The Enterohemorrhagic Escherichia coli Effector EspW Triggers Actin Remodeling in a Rac1-Dependent Manner. AB - Enterohemorrhagic Escherichia coli (EHEC) is a diarrheagenic pathogen that colonizes the gut mucosa and induces attaching-and-effacing lesions. EHEC employs a type III secretion system (T3SS) to translocate 50 effector proteins that hijack and manipulate host cell signaling pathways, which allow bacterial colonization and subversion of immune responses and disease progression. The aim of this study was to characterize the T3SS effector EspW. We found espW in the sequenced O157:H7 and non-O157 EHEC strains as well as in Shigella boydii Furthermore, a truncated version of EspW, containing the first 206 residues, is present in EPEC strains belonging to serotype O55:H7. Screening a collection of clinical EPEC isolates revealed that espW is present in 52% of the tested strains. We report that EspW modulates actin dynamics in a Rac1-dependent manner. Ectopic expression of EspW results in formation of unique membrane protrusions. Infection of Swiss cells with an EHEC espW deletion mutant induces a cell shrinkage phenotype that could be rescued by Rac1 activation via expression of the bacterial guanine nucleotide exchange factor, EspT. Furthermore, using a yeast two-hybrid screen, we identified the motor protein Kif15 as a potential interacting partner of EspW. Kif15 and EspW colocalized in cotransfected cells, while ectopically expressed Kif15 localized to the actin pedestals following EHEC infection. The data suggest that Kif15 recruits EspW to the site of bacterial attachment, which in turn activates Rac1, resulting in modifications of the actin cytoskeleton that are essential to maintain cell shape during infection. PMID- 28630076 TI - What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Is Affinity Maturation a Self Defeating Process for Eliciting Broad Protection? AB - Vaccinations are one of the greatest success stories of modern medicine, saving millions of lives since their widespread adoption. However, several diseases continue to elude highly effective vaccination strategies. Chief among these are human immunodeficiency virus (HIV) and influenza (flu), both of which will require vaccines that can guide the creation of highly mutated, broadly neutralizing antibodies (bnAbs). The generation of bnAbs is hindered by our inability to effectively drive the high levels of affinity maturation required to achieve them in a large number of cells. Major limitations placed on affinity maturation derives from the inherent mutability of immunoglobulin genes, the evolved activation-induced cytidine deaminase (AID) targeting mechanisms that exist within them, and biases in targeting of particular epitope B cells. PMID- 28630077 TI - What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Breaking through Immunity's Glass Ceiling. AB - A key goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs) targeted to the vulnerable regions of the HIV envelope. BnAbs develop over time in ~50% of HIV-1-infected individuals. However, to date, no vaccines have induced bnAbs and few or none of these vaccine-elicited HIV-1 antibodies carry the high frequencies of V(D)J mutations characteristic of bnAbs. Do the high frequencies of mutations characteristic of naturally induced bnAbs represent a fundamental barrier to the induction of bnAbs by vaccines? Recent studies suggest that high frequencies of V(D)J mutations can be achieved by serial vaccination strategies. Rather, it appears that, in the absence of HIV-1 infection, physiologic immune tolerance controls, including a germinal center process termed affinity reversion, may limit vaccine-driven bnAb development by clonal elimination or selecting for mutations incompatible with bnAb activity. PMID- 28630078 TI - What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? A Role for Antibody Feedback. AB - We discuss the impact of antibody feedback on affinity maturation of B cells. Competition from epitope-specific antibodies produced earlier during the immune response leads to immune complex formation, which is essential for transport and deposition of antigen onto follicular dendritic cells (FDCs). It also reduces the concentration of free epitopes into the MUm to nm range, which is essential for B cell receptors (BCRs) to sense affinity-dependent changes in binding capacity. Antibody feedback may also induce epitope spreading, leading to a broader selection of epitopes recognized by newly emerging B-cell clones. This may be exploitable, providing ways to manipulate epitope usage induced by vaccination. PMID- 28630079 TI - What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Lessons from the Antibody Response to HIV-1. AB - Most broadly neutralizing antibodies to HIV-1 have in common an extreme degree of somatic hypermutation (SHM), which correlates with their ability to neutralize multiple viral strains. However, achieving such extreme SHM by immunization remains a challenge. Here, we discuss how antigenic variation during HIV-1 infection may work to exacerbate SHM by permitting multiple iterative cycles of affinity maturation in germinal centers, and speculate on how this could be recapitulated through vaccination. PMID- 28630080 TI - The Potential of Pharmacogenomics to Advance Kidney Disease Treatment. PMID- 28630082 TI - Politicians want the whole NHS to consist of employees. PMID- 28630081 TI - Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis. AB - BACKGROUND AND OBJECTIVES: We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. RESULTS: There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P<=0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P<=0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). CONCLUSIONS: These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics. PMID- 28630083 TI - Are fire safe cigarettes actually fire safe? Evidence from changes in US state laws. AB - OBJECTIVE: To estimate the effects of fire safe cigarette laws on fire mortality and cigarette-related fires in the USA. METHODS: We examined the gradual implementation of the laws to identify their average effects, using difference-in differences analysis to account for common year effects, time-invariant state effects, state-specific trends and observable time-varying state-level covariates. RESULTS: We found no statistically significant effects on all-cause fire mortality, residential fire mortality or cigarette-caused fire rates. The estimates for cigarette-caused fire deaths were significant under some specifications, but were not robust to the inclusion of state-specific trends or comparisons to effects on other cause-determined fires. CONCLUSIONS: Given the mixed state of our results, we conclude that previous claims regarding the effects of fire safe cigarette laws may be premature. PMID- 28630084 TI - Maternal lifestyle and nutritional status in relation to pregnancy and infant health outcomes in Western China: protocol for a prospective cohort study. AB - INTRODUCTION: Improving the health and nutrition of women and children is a priority for Western China, where the economy is less developed. Due to the dynamic nature of lifestyle, modern food habits and nutrition, there is a need to update our limited knowledge and understanding of maternal lifestyle and nutritional status and their impact on pregnancy and infant health outcomes. While breast milk is the preferred feeding option, infant formula use is widespread in China. It is thus necessary to examine the effects of formula consumption on growth and morbidity. METHODS AND ANALYSIS: This is an ongoing prospective cohort study started in 2015 in Chengdu, Sichuan Province. A sample of 1901 pregnant women at 15-20 weeks of gestation were recruited from four maternal and child health hospitals and are followed prospectively to 12 months post partum. Detailed information on maternal lifestyle and nutritional status, obstetric complications, pregnancy outcomes, infant feeding practices, illnesses of the mother and infant and growth trajectory is collected through personal interviews, anthropometric measures and medical records and local health management system records retrieval. Multilevel mixed regression models, adjusted for clustering, will be applied to investigate the association between various exposure variables of interest and the longitudinal outcomes, taking into account the correlated data structure and the nesting of observations. Kaplan-Meier test and Cox regression analysis will be used to analyse the time-to-event data. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the ethics committee of West China School of Public Health, Sichuan University and the Human Research Ethics Committee of Curtin University. Results will be presented at national and international conferences and published in peer-reviewed journals. PMID- 28630085 TI - Risk of allergic conjunctivitis in patients with type 1 diabetes mellitus: a population-based retrospective cohort study. AB - OBJECTIVE: In accordance with the dichotomy between T helper type 1(Th1) and T helper type 2 (Th2) responses, the occurrence of allergic conjunctivitis (AC) and type 1 diabetes mellitus (T1DM) is, in theory, inversely related in the individual. However, recent studies investigating the association between the two diseases are controversial. DESIGN: Population-based cohort study. SETTING: We used claims data of the National Health Insurance Research Database of Taiwan. PARTICIPANTS: We identified 4160 patients aged 1-30 years with newly diagnosed T1DM and no history of AC at baseline. For each patient with T1DM, four non-T1DM controls (n=16,640) were matched by sex. The mean follow-up time was 6 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Multivariate Cox proportional hazards regression analysis was used to evaluate the risk of AC. We additionally evaluated the association between risk of AC and T1DM progression by examining Diabetes Complications Severity Index (aDCSI) changes from the date of diagnosis until the end of follow-up. RESULTS: The overall incidence of allergic conjunctivitis (AC) was higher in the type 1 diabetes mellitus (T1DM) cohort than in the control cohort (23.0 vs 13.5 per 1000 person-years, adjusted incidence rate ratio (aIRR): 1.59, 95% CI 1.47 to 1.71). Relative to that in patients with mildly progressive T1DM, the risk of AC increased as the adapted Diabetes Complications Severity Index (aDCSI) increased (aIRR: 1.68, 3.78 and 18.8, with yearly changes in aDCSI score: 0.51 to 1.00, 1.01 to 2.00, and >2.00 vs <0.51, respectively; for trend <0.001). CONCLUSION: Patients with T1DM are at an elevated risk of developing AC; this risk increases with T1DM progression. The T helper type 1/T helper type 2 hypothesis is an overly simplistic explanation for this association. PMID- 28630086 TI - Psychosocial therapy for Parkinson's-related dementia: study protocol for the INVEST randomised controlled trial. AB - INTRODUCTION: Parkinson's disease (PD) with mild cognitive impairment (MCI-PD) or dementia (PDD) and dementia with Lewy bodies (DLB) are characterised by motor and 'non-motor' symptoms which impact on quality of life. Treatment options are generally limited to pharmacological approaches. We developed a psychosocial intervention to improve cognition, quality of life and companion burden for people with MCI-PD, PDD or DLB. Here, we describe the protocol for a single-blind randomised controlled trial to assess feasibility, acceptability and tolerability of the intervention and to evaluate treatment implementation. The interaction among the intervention and selected outcome measures and the efficacy of this intervention in improving cognition for people with MCI-PD, PDD or DLB will also be explored. METHODS AND ANALYSIS: Dyads will be randomised into two treatment arms to receive either 'treatment as usual' (TAU) or cognitive stimulation therapy specifically adapted for Parkinson's-related dementias (CST-PD), involving 30 min sessions delivered at home by the study companion three times per week over 10 weeks. A mixed-methods approach will be used to collect data on the operational aspects of the trial and treatment implementation. This will involve diary keeping, telephone follow-ups, dyad checklists and researcher ratings. Analysis will include descriptive statistics summarising recruitment, acceptability and tolerance of the intervention, and treatment implementation. To pilot an outcome measure of efficacy, we will undertake an inferential analysis to test our hypothesis that compared with TAU, CST-PD improves cognition. Qualitative approaches using thematic analysis will also be applied. Our findings will inform a larger definitive trial. ETHICS AND DISSEMINATION: Ethical opinion was granted (REC reference: 15/YH/0531). Findings will be published in peer reviewed journals and at conferences. We will prepare reports for dissemination by organisations involved with PD and dementia. TRIAL REGISTRATION NUMBER: ISRCTN (ISRCTN11455062). PMID- 28630087 TI - Paucimannose-Rich N-glycosylation of Spatiotemporally Regulated Human Neutrophil Elastase Modulates Its Immune Functions. AB - Human neutrophil elastase (HNE) is an important N-glycosylated serine protease in the innate immune system, but the structure and immune-modulating functions of HNE N-glycosylation remain undescribed. Herein, LC-MS/MS-based glycan, glycopeptide and glycoprotein profiling were utilized to first determine the heterogeneous N-glycosylation of HNE purified from neutrophil lysates and then from isolated neutrophil granules of healthy individuals. The spatiotemporal expression of HNE during neutrophil activation and the biological importance of its N-glycosylation were also investigated using immunoblotting, cell surface capture, native MS, receptor interaction, protease inhibition, and bacteria growth assays. Site-specific HNE glycoprofiling demonstrated that unusual paucimannosidic N-glycans, particularly Manalpha1,6Manbeta1,4GlcNAcbeta1,4(Fucalpha1,6)GlcNAcbeta, predominantly occupied Asn124 and Asn173. The equally unusual core fucosylated monoantenna complex-type N-sialoglycans also decorated these two fully occupied sites. In contrast, the mostly unoccupied Asn88 carried nonfucosylated paucimannosidic N-glycans probably resulting from low glycosylation site solvent accessibility. Asn185 was not glycosylated. Subcellular- and site-specific glycoprofiling showed highly uniform N-glycosylation of HNE residing in distinct neutrophil compartments. Stimulation induced cell surface mobilization demonstrated a spatiotemporal regulation, but not cell surface-specific glycosylation signatures, of HNE in activated human neutrophils. The three glycosylation sites of HNE were located distal to the active site indicating glycan functions other than interference with HNE enzyme activity. Functionally, the paucimannosidic HNE glycoforms displayed preferential binding to human mannose binding lectin compared with the HNE sialoglycoforms, suggesting a glycoform-dependent involvement of HNE in complement activation. The heavily N-glycosylated HNE protease inhibitor, alpha1-antitrypsin, displayed concentration-dependent complex formation and preferred glycoform-glycoform interactions with HNE. Finally, both enzymatically active HNE and isolated HNE N glycans demonstrated low micromolar concentration-dependent growth inhibition of clinically-relevant Pseudomonas aeruginosa, suggesting some bacteriostatic activity is conferred by the HNE N-glycans. Taken together, these observations support that the unusual HNE N-glycosylation, here reported for the first time, is involved in modulating multiple immune functions central to inflammation and infection. PMID- 28630088 TI - The islet-resident macrophage is in an inflammatory state and senses microbial products in blood. AB - We examined the transcriptional profiles of macrophages that reside in the islets of Langerhans of 3-wk-old non-obese diabetic (NOD), NOD.Rag1-/-, and B6.g7 mice. Islet macrophages expressed an activation signature with high expression of Tnf, Il1b, and MHC-II at both the transcript and protein levels. These features are common with barrier macrophages of the lung and gastrointestinal tract. Moreover, injection of lipopolysaccharide induced rapid inflammatory gene expression, indicating that blood stimulants are accessible to the macrophages and that these macrophages can sense them. In NOD mice, the autoimmune process imparted an increased inflammatory signature, including elevated expression of chemokines and chemokine receptors and an oxidative response. The elevated inflammatory signature indicates that the autoimmune program was active at the time of weaning. Thus, the macrophages of the islets of Langerhans are poised to mount an immune response even at steady state, while the presence of the adaptive immune system elevates their activation state. PMID- 28630089 TI - Dynamic balance between master transcription factors determines the fates and functions of CD4 T cell and innate lymphoid cell subsets. AB - CD4 T cells, including T regulatory cells (Treg cells) and effector T helper cells (Th cells), and recently identified innate lymphoid cells (ILCs) play important roles in host defense and inflammation. Both CD4 T cells and ILCs can be classified into distinct lineages based on their functions and the expression of lineage-specific genes, including those encoding effector cytokines, cell surface markers, and key transcription factors. It was first recognized that each lineage expresses a specific master transcription factor and the expression of these factors is mutually exclusive because of cross-regulation among these factors. However, recent studies indicate that the master regulators are often coexpressed. Furthermore, the expression of master regulators can be dynamic and quantitative. In this review, we will first discuss similarities and differences between the development and functions of CD4 T cell and ILC subsets and then summarize recent literature on quantitative, dynamic, and cell type-specific balance between the master transcription factors in determining heterogeneity and plasticity of these subsets. PMID- 28630091 TI - B-1a Cells Protect Mice from Sepsis: Critical Role of CREB. AB - Bacterial sepsis is a serious life-threatening condition caused by an excessive immune response to infection. B-1 cells differ from conventional B-2 cells by their distinct phenotype and function. A subset of B-1 cells expressing CD5, known as B-1a cells, exhibits innate immune activity. Here we report that B-1a cells play a beneficial role in sepsis by mitigating exaggerated inflammation through a novel mechanism. Using a mouse model of bacterial sepsis, we found that the numbers of B-1a cells in various anatomical locations were significantly decreased. Adoptive transfer of B-1a cells into septic mice significantly attenuated systemic inflammation and improved survival, whereas B-1a cell deficient CD19-/- mice were more susceptible to infectious inflammation and mortality. We also demonstrated B-1a cells produced ample amounts of IL-10 which controlled excessive inflammation and the mice treated with IL-10-deficient B-1a cells were not protected against sepsis. Moreover, we identified a novel intracellular signaling molecule, cAMP-response element binding protein (CREB), which serves as a pivotal transcription factor for upregulating IL-10 production by B-1a cells in sepsis through its nuclear translocation and binding to putative responsive elements on IL-10 promoter. Thus, the benefit of B-1a cells in bacterial sepsis is mediated by CREB and the identification of CREB in B-1a cells reveals a potential avenue for treatment in bacterial sepsis. PMID- 28630092 TI - Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation. AB - CMV reactivation is a major complication after allogeneic stem cell transplantation (SCT). Immune reconstitution of CMV-specific CTLs (CMV-CTLs) is essential for virus control. During CMV-CTL monitoring using mutated HLA/CMV tetramers selectively detecting high-avidity T cells, we observed coappearance of CMV-CTLs with low (CMV tetlow CTLs) and high tetramer binding (CMV tethigh CTLs) in 53/115 CMV IgG+ patients stem cell transplanted from CMV IgG+ donors. However, the relevance of these coappearing differentially tetramer binding ("dual") CMV CTLs was unclear. In this study, we investigated the kinetics, properties, and clinical impact of coappearing CMV tetlow and tethigh CTLs after allogeneic SCT. Patients with dual CMV-CTLs had more CMV tethigh than tetlow CTLs. Chimerism analysis of isolated CMV tetlow and tethigh CTLs revealed their exclusive donor origin. CMV tetlow and tethigh CTLs had an identical effector memory CD45RA-CCR7- and CD45RA+CCR7- T cell distribution, equal differentiation, senescence, and exhaustion marker expression and were negative for regulatory CD8+ T cell markers. Isolated CMV tetlow and tethigh CTLs were equally sensitive to CMV peptides in IFN-gamma release and cytotoxicity assays. However, CMV tethigh CTLs proliferated more in response to low CMV peptide concentrations than tetlow CTLs. TCR repertoire analysis revealed that CMV tetlow and tethigh CTLs use different TCRs. Finally, dual CMV-CTLs were not associated with CMV antigenemia. In conclusion, these data show for the first time, to our knowledge, that both CMV tetlow and tethigh CTLs are functional effector T cells differing by proliferation, numbers in peripheral blood, and probably by their precursors without increasing the CMV reactivation risk after allogeneic SCT. PMID- 28630090 TI - T Cell Transcriptomes from Paroxysmal Nocturnal Hemoglobinuria Patients Reveal Novel Signaling Pathways. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder originating from hematopoietic stem cells and is a life-threating disease characterized by intravascular hemolysis, bone marrow (BM) failure, and venous thrombosis. The etiology of PNH is a somatic mutation in the phosphatidylinositol glycan class A gene (PIG-A) on the X chromosome, which blocks synthesis of the glycolipid moiety and causes deficiency in GPI-anchored proteins. PNH is closely related to aplastic anemia, in which T cells mediate destruction of BM. To identify aberrant molecular mechanisms involved in immune targeting of hematopoietic stem cells in BM, we applied RNA-seq to examine the transcriptome of T cell subsets (CD4+ naive, CD4+ memory, CD8+ naive, and CD8+ memory) from PNH patients and healthy control subjects. Differentially expressed gene analysis in four different T cell subsets from PNH and healthy control subjects showed distinct transcriptional profiles, depending on the T cell subsets. By pathway analysis, we identified novel signaling pathways in T cell subsets from PNH, including increased gene expression involved in TNFR, IGF1, NOTCH, AP-1, and ATF2 pathways. Dysregulation of several candidate genes (JUN, TNFAIP3, TOB1, GIMAP4, GIMAP6, TRMT112, NR4A2, CD69, and TNFSF8) was validated by quantitative real-time RT-PCR and flow cytometry. We have demonstrated molecular signatures associated with positive and negative regulators in T cells, suggesting novel pathophysiologic mechanisms in PNH. These pathways may be targets for new strategies to modulate T cell immune responses in BM failure. PMID- 28630093 TI - Dendritic Cell Sensing of Hydrophobic Di- and Triacylated Lipopeptides Self Assembled within Synthetic Virus-like Particles. AB - Dendritic cells (DCs) play critical roles in developing immune defenses. One important aspect is interaction with pathogen-associated molecular patterns (PAMPs)/danger-associated molecular patterns, including di- and triacylated lipopeptides. Isolated or synthetic lipopeptides are potent vaccine adjuvants, interacting with cell surface TLR2 heterodimers. In contrast, deep embedment within bacteria cell walls would impair lipopeptide interaction with cell surface TLR2, requiring degradation for PAMP recognition. Accordingly, DC processing in the absence of surface TLR2 ligation was defined using synthetic virus-like particles (SVLPs) carrying hydrophobic TLR2 PAMPs within di- and triacylated lipopeptide cores (P2Cys-SVLPs and P3Cys-SVLPs) compared with SVLPs lacking immunomodulatory lipopeptides. DCs rapidly and efficiently internalized SVLPs, which was dominated by slow endocytic processing via macropinocytosis, although some caveolar endocytosis was implicated. This delivered SVLPs primarily into macropinosomes often interacting with EEA-1+ early endosomes. Although endoplasmic reticulum association was occasionally noted, association with recycling/sorting structures was not observed. Involvement of LysoTracker+ structures slowly increased with time, with SVLPs present in such structures ultimately dominating. Only SVLPs carrying di- and triacylated lipopeptide cores induced DC activation and maturation independently of surface TLR2 ligation. Intracellular recognition of SVLP TLR2 ligands was confirmed by observing SVLPs' association with internal TLR2, which had similar kinetics to SVLP association with LysoTracker. This related to inflammatory cytokine induction by SVLP+ DCs, with adaptive immune response activation ex vivo/in vivo. Importantly, particular DCs, not monocytes, recognized intracellular exposure of the TLR2 PAMPs carried by di- and triacylated SVLP cores, which indicates subset-distinct recognition of functional internal TLR2 ligands. Thus, vaccines carrying hydrophobic TLR2 ligands would interact with particular DCs for efficient induction of specific immunity in the absence of additional adjuvant. PMID- 28630096 TI - China vows to clamp down on academic fraud amid medical journal scandal. PMID- 28630094 TI - Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice. AB - During RBC transfusion, production of alloantibodies against RBC non-ABO Ags can cause hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Multiple studies have established that certain inflammatory disorders and inflammatory stimuli promote alloimmune responses to RBC Ags. However, the molecular mechanisms underlying these findings are poorly understood. Type I IFNs (IFN alpha/beta) are induced in inflammatory conditions associated with increased alloimmunization. By developing a new transgenic murine model, we demonstrate that signaling through the IFN-alpha/beta receptor is required for inflammation induced alloimmunization. Additionally, mitochondrial antiviral signaling protein mediated signaling through cytosolic pattern recognition receptors was required for polyinosinic-polycytidylic acid-induced IFN-alpha/beta production and alloimmunization. We further report that IFN-alpha, in the absence of an adjuvant, is sufficient to induce RBC alloimmunization. These findings raise the possibility that patients with IFN-alpha/beta-mediated conditions, including autoimmunity and viral infections, may have an increased risk of RBC alloimmunization and may benefit from personalized transfusion protocols and/or targeted therapies. PMID- 28630095 TI - Antibody-Dependent NK Cell Activation Differentially Targets EBV-Infected Cells in Lytic Cycle and Bystander B Lymphocytes Bound to Viral Antigen-Containing Particles. AB - NK cells have been reported to respond against EBV-infected B cells in the lytic cycle and to control the viral infection involving IFN-gamma secretion. Early reports proposed a role for NK cell Ab-dependent cellular cytotoxicity (ADCC) triggered via FcgammaR-IIIA (CD16) in the response to EBV. In the current study, we revisited this issue, showing that serum from EBV+ individuals triggered vigorous NK cell degranulation and cytokine production (i.e., TNF-alpha and IFN gamma) against EBV-infected cells, enhancing NK cell activation. The effect was preferentially directed against cells in the lytic phase and was associated with surface expression of the gp350/220 envelope Ag. In contrast, binding of gp350+ particles, released by EBV-infected cells, to B cell lines or autologous primary B lymphocytes also promoted specific Ab-dependent NK cell degranulation and TNF alpha production but induced minimal IFN-gamma secretion. In that case, target cell damage appeared marginal compared with the effect of a control anti-CD20 Ab (rituximab) at concentrations that triggered similar NK cell activation, indicating that cell-associated gp350+ particles may divert the cytolytic machinery, impairing its direct action on the plasma membrane. These observations support that Ab-dependent NK cell activation plays an important role in the control of EBV, enhancing NK cell effector functions against infected B cells in the lytic cycle. In contrast, the data reveal that gp350+ particles bound to bystander B cells trigger Ab-dependent NK cell degranulation and TNF-alpha but not cytotoxicity or IFN-gamma production, potentially favoring the progression of viral infection. PMID- 28630097 TI - Fired researcher who shot medical school dean is convicted of attempted murder. PMID- 28630098 TI - Comparative microRNAome analysis of the testis and ovary of the Chinese giant salamander. AB - MicroRNAs (miRNAs) are 18-24 nucleotides non-coding RNAs that regulate gene expression by post-transcriptional suppression of mRNA. The Chinese giant salamander (CGS, Andrias davidianus), which is an endangered species, has become one of the important models of animal evolution; however, no miRNA studies on this species have been conducted. In this study, two small RNA libraries of CGS ovary and testis were constructed using deep sequencing technology. A bioinformatics pipeline was developed to distinguish miRNA sequences from other classes of small RNAs represented in the sequencing data. We found that many miRNAs and other small RNAs such as piRNA and tsRNA were abundant in CGS tissue. A total of 757 and 756 unique miRNAs were annotated as miRNA candidates in the ovary and testis respectively. We identified 145 miRNAs in CGS ovary and 155 miRNAs in CGS testis that were homologous to those in Xenopus laevis ovary and testis respectively. Forty-five miRNAs were more highly expressed in ovary than in testis and 21 miRNAs were more highly expressed in testis than in ovary. The expression profiles of the selected miRNAs (miR-451, miR-10c, miR-101, miR-202, miR-7a and miR-499) had their own different roles in other eight tissues and different development stages of testis and ovary, suggesting that these miRNAs play vital regulatory roles in sexual differentiation, gametogenesis and development in CGS. To our knowledge, this is the first study to reveal miRNA profiles that are related to male and female CGS gonads and provide insights into sex differences in miRNA expression in CGS. PMID- 28630099 TI - KNDy neurone activation prior to the LH surge of the ewe is disrupted by LPS. AB - In the ewe, steroid hormones act on the hypothalamic arcuate nucleus (ARC) to initiate the GnRH/LH surge. Within the ARC, steroid signal transduction may be mediated by estrogen receptive dopamine-, beta-endorphin- or neuropeptide Y (NPY) expressing cells, as well as those co-localising kisspeptin, neurokinin B (NKB) and dynorphin (termed KNDy). We investigated the time during the follicular phase when these cells become activated (i.e., co-localise c-Fos) relative to the timing of the LH surge onset and may therefore be involved in the surge generating mechanism. Furthermore, we aimed to elucidate whether these activation patterns are altered after lipopolysaccharide (LPS) administration, which is known to inhibit the LH surge. Follicular phases of ewes were synchronised by progesterone withdrawal and blood samples were collected every 2 h. Hypothalamic tissue was retrieved at various times during the follicular phase with or without the administration of LPS (100 ng/kg). The percentage of activated dopamine cells decreased before the onset of sexual behaviour, whereas activation of beta endorphin decreased and NPY activation tended to increase during the LH surge. These patterns were not disturbed by LPS administration. Maximal co-expression of c-Fos in dynorphin immunoreactive neurons was observed earlier during the follicular phase, compared to kisspeptin and NKB, which were maximally activated during the surge. This indicates a distinct role for ARC dynorphin in the LH surge generation mechanism. Acute LPS decreased the percentage of activated dynorphin and kisspeptin immunoreactive cells. Thus, in the ovary-intact ewe, KNDy neurones are activated prior to the LH surge onset and this pattern is inhibited by the administration of LPS. PMID- 28630100 TI - NLRP2 and FAF1 deficiency blocks early embryogenesis in the mouse. AB - Nlrp2 is a maternal effect gene specifically expressed by mouse ovaries; deletion of this gene from zygotes is known to result in early embryonic arrest. In the present study, we identified FAF1 protein as a specific binding partner of the NLRP2 protein in both mouse oocytes and preimplantation embryos. In addition to early embryos, both Faf1 mRNA and protein were detected in multiple tissues. NLRP2 and FAF1 proteins were co-localized to both the cytoplasm and nucleus during the development of oocytes and preimplantation embryos. Co immunoprecipitation assays were used to confirm the specific interaction between NLRP2 and FAF1 proteins. Knockdown of the Nlrp2 or Faf1 gene in zygotes interfered with the formation of a NLRP2-FAF1 complex and led to developmental arrest during early embryogenesis. We therefore conclude that NLRP2 interacts with FAF1 under normal physiological conditions and that this interaction is probably essential for the successful development of cleavage-stage mouse embryos. Our data therefore indicated a potential role for NLRP2 in regulating early embryo development in the mouse. PMID- 28630101 TI - Oviduct extracellular vesicles protein content and their role during oviduct embryo cross-talk. AB - Successful pregnancy requires an appropriate communication between the mother and the embryo. Recently, exosomes and microvesicles, both membrane-bound extracellular vesicles (EVs) present in the oviduct fluid have been proposed as key modulators of this unique cross-talk. However, little is known about their content and their role during oviduct-embryo dialog. Given the known differences in secretions by in vivo and in vitro oviduct epithelial cells (OEC), we aimed at deciphering the oviduct EVs protein content from both sources. Moreover, we analyzed their functional effect on embryo development. Our study demonstrated for the first time the substantial differences between in vivo and in vitro oviduct EVs secretion/content. Mass spectrometry analysis identified 319 proteins in EVs, from which 186 were differentially expressed when in vivo and in vitro EVs were compared (P < 0.01). Interestingly, 97 were exclusively expressed in in vivo EVs, 47 were present only in in vitro and 175 were common. Functional analysis revealed key proteins involved in sperm-oocyte binding, fertilization and embryo development, some of them lacking in in vitro EVs. Moreover, we showed that in vitro-produced embryos were able to internalize in vivo EVs during culture with a functional effect in the embryo development. In vivo EVs increased blastocyst rate, extended embryo survival over time and improved embryo quality. Our study provides the first characterization of oviduct EVs, increasing our understanding of the role of oviduct EVs as modulators of gamete/embryo-oviduct interactions. Moreover, our results point them as promising tools to improve embryo development and survival under in vitro conditions. PMID- 28630102 TI - The phenotype and function of preterm infant monocytes: implications for susceptibility to infection. AB - The extreme vulnerability of preterm infants to invasive microbial infections has been attributed to "immature" innate immune defenses. Monocytes are important innate immune sentinel cells critical in the defense against infection in blood. They achieve this via diverse mechanisms that include pathogen recognition receptor- and inflammasome-mediated detection of microbes, migration into infected tissues, and differentiation into Mphis and dendritic cells, initiation of the inflammatory cascade by free radicals and cytokine/chemokine production, pathogen clearance by phagocytosis and intracellular killing, and the removal of apoptotic cells. Relatively little is known about these cells in preterm infants, especially about how their phenotype adapts to changes in the microbial environment during the immediate postnatal period. Overall, preterm monocytes exhibit attenuated proinflammatory cytokine responses following stimulation by whole bacterial or specific microbial components in vitro. These attenuated cytokine responses cannot be explained by a lack of intracellular signaling events downstream of pattern recognition receptors. This hyporesponsiveness also contrasts with mature, term-like phagocytosis capabilities detectable even in the most premature infant. Finally, human data on the effects of fetal chorioamnionitis on monocyte biology are incomplete and inconsistent. In this review, we present an integrated view of human studies focused on monocyte functions in preterm infants. We discuss how a developmental immaturity of these cells may contribute to preterm infants' susceptibility to infections. PMID- 28630103 TI - Up-regulation of EP2 and EP3 receptors in human tolerogenic dendritic cells boosts the immunosuppressive activity of PGE2. AB - Dendritic cells (DCs) are APCs essential in regulating the immune response. PGE2, produced during inflammation, has a pivotal role in the maturation of DCs and, therefore, is vital for the immune response. The large variety of biologic functions governed by PGE2 is mediated by its signaling through 4 distinct E-type prostanoid (EP) receptors. Immunogenic DCs express EP2 and EP4, which mediate the PGE2 signaling. However, the expression and function of EP receptors in human tolerogenic DCs (tol-DCs), which present an inhibitory phenotype, have not yet, to our knowledge, been assessed. To clarify the role of EP receptors in tol-DCs, we examined the expression of different EP receptors and their effect using selective agonists in human cells. We find that EP2 and EP3 expression are up regulated in in vitro-generated tol-DCs compared with mature DCs (mDCs). Activation of EP2-EP4 has a direct effect on the surface expression of costimulatory molecules and maturation receptors, such as CD80, CD83, and CD86 or MHCII and CCR7 in tol-DCs, the latter being exclusively modulated by PGE2-EP4 signaling. Importantly, we find that EP2 and EP3 receptors are involved in tolerance induction through IL-10 production by tol-DCs. These results are in sharp contrast with the inflammatory role of EP4 Moreover, we show that DCs generated in the presence of agonists for EP receptors, induce naive T cell differentiation toward polarized Th1/Th17 cells. Given the differential effects of EP receptors, our results suggest that EP receptor agonist/antagonists might become relevant novel drug templates to modulate immune response. PMID- 28630106 TI - Access Guide to Antigen Receptor Genes. PMID- 28630104 TI - Evidence for Adaptive Introgression of Disease Resistance Genes Among Closely Related Arabidopsis Species. AB - The generation and maintenance of functional variation in the pathogen defense system of plants is central to the constant evolutionary battle between hosts and parasites. If a species is susceptible to a given pathogen, hybridization and subsequent introgression of a resistance allele from a related species can potentially be an important source of new immunity and is therefore expected to be selected for in a process referred to as adaptive introgression. Here, we survey sequence variation in 10 resistance (R-) genes and compare them with 37 reference genes in natural populations of the two closely related and interfertile species: Arabidopsis lyrata and A. halleri The R-genes are highly polymorphic in both species and show clear signs of trans-species polymorphisms. We show that A. lyrata and A. halleri have had a history of limited introgression for the reference genes. For the R-genes, the introgression rate has been significantly higher than for the reference genes, resulting in fewer fixed differences between species and a higher sharing of identical haplotypes. We conclude that R-genes likely cross the species boundaries at a higher rate than reference genes and therefore also that some of the increased diversity and trans specific polymorphisms in R-genes is due to adaptive introgression. PMID- 28630107 TI - Pillars Article: A Role for Histone Acetylation in the Developmental Regulation of V(D)J Recombination. Science. 2000. 287: 495-498. PMID- 28630108 TI - Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems. AB - Mucosal IgA or secretory IgA (SIgA) are structurally equipped to resist chemical degradation in the harsh environment of mucosal surfaces and enzymes of host or microbial origin. Production of SIgA is finely regulated, and distinct T independent and T-dependent mechanisms orchestrate Ig alpha class switching and SIgA responses against commensal and pathogenic microbes. Most infectious pathogens enter the host via mucosal surfaces. To provide a first line of protection at these entry ports, vaccines are being developed to induce pathogen specific SIgA in addition to systemic immunity achieved by injected vaccines. Mucosal or epicutaneous delivery of vaccines helps target the inductive sites for SIgA responses. The efficacy of such vaccines relies on the identification and/or engineering of vaccine adjuvants capable of supporting the development of SIgA alongside systemic immunity and delivery systems that improve vaccine delivery to the targeted anatomic sites and immune cells. PMID- 28630110 TI - Retraction: Adora2b Adenosine Receptor Signaling Protects during Acute Kidney Injury via Inhibition of Neutrophil-Dependent TNF-alpha Release. PMID- 28630109 TI - Macrophage-Mediated Inflammation in Normal and Diabetic Wound Healing. AB - The healing of cutaneous wounds is dependent on the progression through distinct, yet overlapping phases of wound healing, including hemostasis, inflammation, proliferation, and resolution/remodeling. The failure of these phases to occur in a timely, progressive fashion promotes pathologic wound healing. The macrophage (MPhi) has been demonstrated to play a critical role in the inflammatory phase of tissue repair, where its dynamic plasticity allows this cell to mediate both tissue-destructive and -reparative functions. The ability to understand and control both the initiation and the resolution of inflammation is critical for treating pathologic wound healing. There are now a host of studies demonstrating that metabolic and epigenetic regulation of gene transcription can influence MPhi plasticity in wounds. In this review, we highlight the molecular and epigenetic factors that influence MPhi polarization in both physiologic and pathologic wound healing, with particular attention to diabetic wounds. PMID- 28630111 TI - Investigation of Seizure-Susceptibility in a Drosophila melanogaster Model of Human Epilepsy with Optogenetic Stimulation. AB - We examined seizure-susceptibility in a Drosophila model of human epilepsy using optogenetic stimulation of ReaChR (red-activatable channelrhodopsin). Photostimulation of the seizure-sensitive mutant parabss1 causes behavioral paralysis that resembles paralysis caused by mechanical stimulation, in many aspects. Electrophysiology shows that photostimulation evokes abnormal seizure like neuronal firing in parabss1 followed by a quiescent period resembling synaptic failure and apparently responsible for paralysis. The pattern of neuronal activity concludes with seizure-like activity just prior to recovery. We tentatively identify the mushroom body as one apparent locus of optogenetic seizure initiation. The alpha/beta lobes may be primarily responsible for mushroom body seizure induction. PMID- 28630112 TI - Rapid Evolution of Ovarian-Biased Genes in the Yellow Fever Mosquito (Aedes aegypti). AB - Males and females exhibit highly dimorphic phenotypes, particularly in their gonads, which is believed to be driven largely by differential gene expression. Typically, the protein sequences of genes upregulated in males, or male-biased genes, evolve rapidly as compared to female-biased and unbiased genes. To date, the specific study of gonad-biased genes remains uncommon in metazoans. Here, we identified and studied a total of 2927, 2013, and 4449 coding sequences (CDS) with ovary-biased, testis-biased, and unbiased expression, respectively, in the yellow fever mosquito Aedes aegypti The results showed that ovary-biased and unbiased CDS had higher nonsynonymous to synonymous substitution rates (dN/dS) and lower optimal codon usage (those codons that promote efficient translation) than testis-biased genes. Further, we observed higher dN/dS in ovary-biased genes than in testis-biased genes, even for genes coexpressed in nonsexual (embryo) tissues. Ovary-specific genes evolved exceptionally fast, as compared to testis- or embryo-specific genes, and exhibited higher frequency of positive selection. Genes with ovary expression were preferentially involved in olfactory binding and reception. We hypothesize that at least two potential mechanisms could explain rapid evolution of ovary-biased genes in this mosquito: (1) the evolutionary rate of ovary-biased genes may be accelerated by sexual selection (including female female competition or male-mate choice) affecting olfactory genes during female swarming by males, and/or by adaptive evolution of olfactory signaling within the female reproductive system (e.g., sperm-ovary signaling); and/or (2) testis biased genes may exhibit decelerated evolutionary rates due to the formation of mating plugs in the female after copulation, which limits male-male sperm competition. PMID- 28630113 TI - Complex Coding and Regulatory Polymorphisms in a Restriction Factor Determine the Susceptibility of Drosophila to Viral Infection. AB - It is common to find that major-effect genes are an important cause of variation in susceptibility to infection. Here we have characterized natural variation in a gene called pastrel that explains over half of the genetic variance in susceptibility to the Drosophila C virus (DCV) in populations of Drosophila melanogaster We found extensive allelic heterogeneity, with a sample of seven alleles of pastrel from around the world conferring four phenotypically distinct levels of resistance. By modifying candidate SNPs in transgenic flies, we show that the largest effect is caused by an amino acid polymorphism that arose when an ancestral threonine was mutated to alanine, greatly increasing resistance to DCV. Overexpression of the ancestral, susceptible allele provides strong protection against DCV; indicating that this mutation acted to improve an existing restriction factor. The pastrel locus also contains complex structural variation and cis-regulatory polymorphisms altering gene expression. We find that higher expression of pastrel is associated with increased survival after DCV infection. To understand why this variation is maintained in populations, we investigated genetic variation surrounding the amino acid variant that is causing flies to be resistant. We found no evidence of natural selection causing either recent changes in allele frequency or geographical variation in frequency, suggesting that this is an old polymorphism that has been maintained at a stable frequency. Overall, our data demonstrate how complex genetic variation at a single locus can control susceptibility to a virulent natural pathogen. PMID- 28630114 TI - Toward Universal Forward Genetics: Using a Draft Genome Sequence of the Nematode Oscheius tipulae To Identify Mutations Affecting Vulva Development. AB - Mapping-by-sequencing has become a standard method to map and identify phenotype causing mutations in model species. Here, we show that a fragmented draft assembly is sufficient to perform mapping-by-sequencing in nonmodel species. We generated a draft assembly and annotation of the genome of the free-living nematode Oscheius tipulae, a distant relative of the model Caenorhabditis elegans We used this draft to identify the likely causative mutations at the O. tipulae cov-3 locus, which affect vulval development. The cov-3 locus encodes the O. tipulae ortholog of C. elegans mig-13, and we further show that Cel-mig-13 mutants also have an unsuspected vulval-development phenotype. In a virtuous circle, we were able to use the linkage information collected during mutant mapping to improve the genome assembly. These results showcase the promise of genome-enabled forward genetics in nonmodel species. PMID- 28630115 TI - Discovering Complete Quasispecies in Bacterial Genomes. AB - Mobile genetic elements can be found in almost all genomes. Possibly the most common nonautonomous mobile genetic elements in bacteria are repetitive extragenic palindromic doublets forming hairpins (REPINs) that can occur hundreds of times within a genome. The sum of all REPINs in a genome can be viewed as an evolving population because REPINs replicate and mutate. In contrast to most other biological populations, we know the exact composition of the REPIN population and the sequence of each member of the population. Here, we model the evolution of REPINs as quasispecies. We fit our quasispecies model to 10 different REPIN populations from 10 different bacterial strains and estimate effective duplication rates. Our estimated duplication rates range from ~5 * 10-9 to 15 * 10-9 duplications per bacterial generation per REPIN. The small range and the low level of the REPIN duplication rates suggest a universal trade-off between the survival of the REPIN population and the reduction of the mutational load for the host genome. The REPIN populations we investigated also possess features typical of other natural populations. One population shows hallmarks of a population that is going extinct, another population seems to be growing in size, and we also see an example of competition between two REPIN populations. PMID- 28630116 TI - Attitudes Toward Tobacco 21 Among US Youth. AB - BACKGROUND: An important movement in reducing youth smoking is to restrict the supply of cigarettes to youth by raising the minimum age of sales to 21, termed Tobacco 21. This study examined attitudes toward Tobacco 21 among youth and their correlations with tobacco use. METHODS: Data from the 2015 National Youth Tobacco Survey (n = 17 092, the typical age of 11-18 years) were analyzed to examine the prevalence of support toward Tobacco 21 among youth. This study further assessed whether attitudes toward Tobacco 21 were associated with (1) intention to initiate cigarette smoking among never-smoking youth (n = 16 449); and (2) intention to quit tobacco use among current tobacco users (n = 2914). RESULTS: Approximately 63.9% of respondents reported supporting Tobacco 21. Support for Tobacco 21 was higher among middle school students (versus high school students), girls (versus boys), and noncurrent users of cigarettes or electronic cigarettes (versus current users). Youth support attitudes were significantly associated with perceptions of tobacco's danger and tobacco use by household members. Never smokers who supported Tobacco 21 had lower odds of intention to initiate cigarette use (adjusted odds ratio = 0.2, P < .0001). Current tobacco users who supported Tobacco 21 had higher odds of intention to quit tobacco use in the next 12 months (adjusted odds ratio = 2.6, P < .0001). CONCLUSIONS: Tobacco 21 is supported by the majority of youth nationwide and youth attitudes were correlated with smoking behaviors. Education programs about the harm of smoking and nicotine addiction at the early stages of life may help increase support of this policy among young tobacco users. PMID- 28630117 TI - Confronting the Firearm Injury Plague. PMID- 28630118 TI - Childhood Firearm Injuries in the United States. AB - OBJECTIVES: Examine fatal and nonfatal firearm injuries among children aged 0 to 17 in the United States, including intent, demographic characteristics, trends, state-level patterns, and circumstances. METHODS: Fatal injuries were examined by using data from the National Vital Statistics System and nonfatal injuries by using data from the National Electronic Injury Surveillance System. Trends from 2002 to 2014 were tested using joinpoint regression analyses. Incident characteristics and circumstances were examined by using data from the National Violent Death Reporting System. RESULTS: Nearly 1300 children die and 5790 are treated for gunshot wounds each year. Boys, older children, and minorities are disproportionately affected. Although unintentional firearm deaths among children declined from 2002 to 2014 and firearm homicides declined from 2007 to 2014, firearm suicides decreased between 2002 and 2007 and then showed a significant upward trend from 2007 to 2014. Rates of firearm homicide among children are higher in many Southern states and parts of the Midwest relative to other parts of the country. Firearm suicides are more dispersed across the United States with some of the highest rates occurring in Western states. Firearm homicides of younger children often occurred in multivictim events and involved intimate partner or family conflict; older children more often died in the context of crime and violence. Firearm suicides were often precipitated by situational and relationship problems. The shooter playing with a gun was the most common circumstance surrounding unintentional firearm deaths of both younger and older children. CONCLUSIONS: Firearm injuries are an important public health problem, contributing substantially to premature death and disability of children. Understanding their nature and impact is a first step toward prevention. PMID- 28630119 TI - GATA2 haploinsufficiency accelerates EVI1-driven leukemogenesis. AB - Chromosomal rearrangements between 3q21 and 3q26 induce inappropriate EVI1 expression by recruiting a GATA2-distal hematopoietic enhancer (G2DHE) to the proximity of the EVI1 gene, leading to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The acquisition of G2DHE by the EVI1 gene reciprocally deprives this enhancer of 1 of the 2 GATA2 alleles, resulting in a loss-of function genetic reduction in GATA2 abundance. Because GATA2 haploinsufficiency is strongly associated with MDS and AML, we asked whether EVI1 misexpression and GATA2 haploinsufficiency both contributed to the observed leukemogenesis by using a 3q21q26 mouse model that recapitulates the G2DHE-driven EVI1 misexpression, but in this case, it was coupled to a Gata2 heterozygous germ line deletion. Of note, the Gata2 heterozygous deletion promoted the EVI1-provoked leukemic transformation, resulting in early onset of leukemia. The 3q21q26 mice suffered from leukemia in which B220+ cells and/or Gr1+ leukemic cells occupied their bone marrows. We found that the B220+Gr1-c-Kit+ population contained leukemia initiating cells and supplied Gr1+ leukemia cells in the 3q21q26 leukemia. When Gata2 expression levels in the B220+Gr1-c-Kit+ cells were decreased as a result of Gata2 heterozygous deletion or spontaneous phenomenon, myeloid differentiation of the B220+Gr1-c-Kit+ cells was suppressed, and the cells acquired induced proliferation as well as B-lymphoid-primed characteristics. Competitive transplantation analysis revealed that Gata2 heterozygous deletion confers selective advantage to EVI1-expressing leukemia cell expansion in recipient mice. These results demonstrate that both the inappropriate stimulation of EVI1 and the loss of 1 allele equivalent of Gata2 expression contribute to the acceleration of leukemogenesis. PMID- 28630120 TI - Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis. AB - Selinexor is the first oral selective inhibitor of nuclear export compound tested for cancer treatment. Selinexor has demonstrated a safety therapy profile with broad antitumor activity against solid and hematological malignancies in phases 2 and 3 clinical trials (#NCT03071276, #NCT02343042, #NCT02227251, #NCT03110562, and #NCT02606461). Although selinexor shows promising efficacy, its primary adverse effect is high-grade thrombocytopenia. Therefore, we aimed to identify the mechanism of selinexor-induced thrombocytopenia to relieve it and improve its clinical management. We determined that selinexor causes thrombocytopenia by blocking thrombopoietin (TPO) signaling and therefore differentiation of stem cells into megakaryocytes. We then used both in vitro and in vivo models and patient samples to show that selinexor-induced thrombocytopenia is indeed reversible when TPO agonists are administered in the absence of selinexor (drug holiday). In sum, these data reveal (1) the mechanism of selinexor-induced thrombocytopenia, (2) an effective way to reverse the dose-limiting thrombocytopenia, and (3) a novel role for XPO1 in megakaryopoiesis. The improved selinexor dosing regimen described herein is crucial to help reduce thrombocytopenia in selinexor patients, allowing them to continue their course of chemotherapy and have the best chance of survival. This trial was registered at www.clinicaltrials.gov as #NCT01607905. PMID- 28630121 TI - A novel recombinant human thrombopoietin therapy for the management of immune thrombocytopenia in pregnancy. AB - The aim of this study was to determine the safety and efficacy of recombinant human thrombopoietin (rhTPO) for the management of immune thrombocytopenia (ITP) during pregnancy. Pregnant patients with ITP were enrolled in the study if they had a platelet count less than 30 * 109/L, were experiencing bleeding manifestations, had failed to respond to corticosteroids and/or intravenous immunoglobulin (IVIG), and had developed refractoriness to platelet transfusion. Thirty-one patients received rhTPO at an initial dose of 300 U/kg once daily for 14 days. Twenty-three patients responded (74.2%), including 10 complete responders (>100 * 109/L) and 13 responders (30-100 * 109/L). It appears that rhTPO ameliorated the bleeding symptoms remarkably, even in the nonresponders. rhTPO was well tolerated. Dizziness, fatigue, and pain at an injection site were reported in 1 patient each. No congenital disease or developmental delays were observed in the infants in a median follow-up of 53 (range, 39-68) weeks. In conclusion, rhTPO is a potentially safe and effective treatment choice for patients with ITP during pregnancy. Our work has paved the way for further study on the clinical application of rhTPO and other thrombopoietic agents for the management of ITP during pregnancy. This study is registered at www.clinicaltrials.gov as NCT02391272. PMID- 28630122 TI - Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults. AB - Eculizumab, a humanized anti-complement C5 monoclonal antibody (mAb) for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended; whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A, C, W, Y vaccines. Bacterial survival was measured after 3-hour incubation in the presence of eculizumab or control complement factor D inhibitor ACH-4471, which blocks the complement alternative pathway (AP) and is in phase 2 development for treatment of PNH. In the absence of inhibitors, colony formation units (CFUs) per milliliter in blood from all 12 immunized subjects decreased from ~4000 at time 0 to sterile cultures at 3 hours. In the presence of eculizumab, there was a >22-fold increase in geometric mean CFUs per milliliter (90 596 and 114 683 CFU/mL for serogroup B and C strains, respectively; P < .0001 compared with time 0). In the presence of ACH 4471, there was a >12-fold decrease (23 and 331 CFU/mL, respectively; P < .0001). The lack of meningococci killing by blood containing eculizumab resulted from inhibition of release of C5a, a C5 split product needed for upregulation of phagocytosis. The results provide an explanation for the large number of cases of meningococcal disease in immunized patients being treated with eculizumab and suggest that vaccination may provide better protection against meningococcal disease in patients treated with an AP-specific inhibitor. PMID- 28630123 TI - Absence of the Polar Organizing Protein PopZ Results in Reduced and Asymmetric Cell Division in Agrobacterium tumefaciens. AB - Agrobacterium tumefaciens is a rod-shaped bacterium that grows by polar insertion of new peptidoglycan during cell elongation. As the cell cycle progresses, peptidoglycan synthesis at the pole ceases prior to insertion of new peptidoglycan at midcell to enable cell division. The A. tumefaciens homolog of the Caulobacter crescentus polar organelle development protein PopZ has been identified as a growth pole marker and a candidate polar growth-promoting factor. Here, we characterize the function of PopZ in cell growth and division of A. tumefaciens Consistent with previous observations, we observe that PopZ localizes specifically to the growth pole in wild-type cells. Despite the striking localization pattern of PopZ, we find the absence of the protein does not impair polar elongation or cause major changes in the peptidoglycan composition. Instead, we observe an atypical cell length distribution, including minicells, elongated cells, and cells with ectopic poles. Most minicells lack DNA, suggesting a defect in chromosome segregation. Furthermore, the canonical cell division proteins FtsZ and FtsA are misplaced, leading to asymmetric sites of cell constriction. Together, these data suggest that PopZ plays an important role in the regulation of chromosome segregation and cell division.IMPORTANCEA. tumefaciens is a bacterial plant pathogen and a natural genetic engineer. However, very little is known about the spatial and temporal regulation of cell wall biogenesis that leads to polar growth in this bacterium. Understanding the molecular basis of A. tumefaciens growth may allow for the development of innovations to prevent disease or to promote growth during biotechnology applications. Finally, since many closely related plant and animal pathogens exhibit polar growth, discoveries in A. tumefaciens may be broadly applicable for devising antimicrobial strategies. PMID- 28630124 TI - The DNA Repair Repertoire of Mycobacterium smegmatis FenA Includes the Incision of DNA 5' Flaps and the Removal of 5' Adenylylated Products of Aborted Nick Ligation. AB - We characterize Mycobacterium smegmatis FenA as a manganese-dependent 5'-flap endonuclease homologous to the 5'-exonuclease of DNA polymerase I. FenA incises a nicked 5' flap between the first and second nucleotides of the duplex segment to yield a 1-nucleotide gapped DNA, which is then further resected in dinucleotide steps. Initial FenA cleavage at a Y-flap or nick occurs between the first and second nucleotides of the duplex. However, when the template 3' single strand is eliminated to create a 5'-tailed duplex, FenA incision shifts to between the second and third nucleotides. A double-flap substrate with a mobile junction (mimicking limited strand displacement synthesis during gap repair) is preferentially incised as the 1-nucleotide 3'-flap isomer, with the scissile phosphodiester shifted by one nucleotide versus a static double flap. FenA efficiently removes the 5' App(dN) terminus of an aborted nick ligation reaction intermediate, thereby highlighting FenA as an agent of repair of such lesions, which are formed under a variety of circumstances by bacterial NAD+-dependent DNA ligases and especially by mycobacterial DNA ligases D and C.IMPORTANCE Structure specific DNA endonucleases are implicated in bacterial DNA replication, repair, and recombination, yet there is scant knowledge of the roster and catalytic repertoire of such nucleases in Mycobacteria This study identifies M. smegmatis FenA as a stand-alone endonuclease homologous to the 5'-exonuclease domain of mycobacterial DNA polymerase 1. FenA incises 5' flaps, 5' nicks, and 5' App(dN) intermediates of aborted nick ligation. The isolated N-terminal domain of M. smegmatis Pol1 is also shown to be a flap endonuclease. PMID- 28630125 TI - Communal metabolism of methane and the rare Earth element switch. AB - Metabolism of methane is an important part of biogeochemical cycling of carbon. Methane is also a major contributor to climate change. A specialized group of microbes that consume methane, the methanotrophs, represent a natural filter preventing an even faster accumulation of methane in the atmosphere. Methanotrophy can proceed via both anaerobic and aerobic modes. The anaerobic methanotrophs, represented by both archaea and bacteria, all appear to be engaged in syntrophic interdependencies with other species, to overcome the energetic barriers of methane metabolism in the absence of oxygen. In contrast, aerobic methanotrophy can be carried out by pure cultures of bacteria. Nevertheless, a concept of communal function in aerobic methane oxidation has been gaining momentum, based on data from natural cooccurrence of specific functional guilds, and based on results from laboratory manipulations. The mechanistic details are still sparse on how and why the methanotrophs share their carbon with other species, and whether and what they gain in return. In this minireview we highlight recent studies that led to this new concept of community function in aerobic methane oxidation. We first describe the stable isotope probing experiments employing heavy carbon-labeled methane, tracing methane carbon consumption. We then follow up with analysis of data from microcosm community dynamics. We further discuss the role of a synthetic community approach in unraveling the principles of carbon flow and species cooperation in methane consumption. Finally, we touch on the role of lanthanides, which are rare Earth elements, previously thought to be biologically inert, in bacterial metabolism of methane. PMID- 28630126 TI - A Key Enzyme of the NAD+ Salvage Pathway in Thermus thermophilus: Characterization of Nicotinamidase and the Impact of Its Gene Deletion at High Temperatures. AB - NAD (NAD+) is a cofactor related to many cellular processes. This cofactor is known to be unstable, especially at high temperatures, where it chemically decomposes to nicotinamide and ADP-ribose. Bacteria, yeast, and higher organisms possess the salvage pathway for reconstructing NAD+ from these decomposition products; however, the importance of the salvage pathway for survival is not well elucidated, except for in pathogens lacking the NAD+de novo synthesis pathway. Herein, we report the importance of the NAD+ salvage pathway in the thermophilic bacterium Thermus thermophilus HB8 at high temperatures. We identified the gene encoding nicotinamidase (TTHA0328), which catalyzes the first reaction of the NAD+ salvage pathway. This recombinant enzyme has a high catalytic activity against nicotinamide (Km of 17 MUM, kcat of 50 s-1, kcat/Km of 3.0 * 103 s-1 . mM 1). Deletion of this gene abolished nicotinamide deamination activity in crude extracts of T. thermophilus and disrupted the NAD+ salvage pathway in T. thermophilus Disruption of the salvage pathway led to the severe growth retardation at a higher temperature (80 degrees C), owing to the drastic decrease in the intracellular concentrations of NAD+ and NADH.IMPORTANCE NAD+ and other nicotinamide cofactors are essential for cell metabolism. These molecules are unstable and decompose, even under the physiological conditions in most organisms. Thermophiles can survive at high temperatures where NAD+ decomposition is, in general, more rapid. This study emphasizes that NAD+ instability and its homeostasis can be one of the important factors for thermophile survival in extreme temperatures. PMID- 28630128 TI - Identification of a d-Arabinose-5-Phosphate Isomerase in the Gram-Positive Clostridium tetani. AB - d-Arabinose-5-phosphate (A5P) isomerases (APIs) catalyze the interconversion of d ribulose-5-phosphate and d-arabinose-5-phosphate. Various Gram-negative bacteria, such as the uropathogenic Escherichia coli strain CFT073, contain multiple API paralogs (KdsD, GutQ, KpsF, and c3406) that have been assigned various cellular functions. The d-arabinose-5-phosphate formed by these enzymes seems to play important roles in the biosynthesis of lipopolysaccharide (LPS) and group 2 K antigen capsules, as well as in the regulation of the cellular d-glucitol uptake and uropathogenic infectivity/virulence. The genome of a Gram-positive pathogenic bacterium, Clostridium tetani, contains a gene encoding a putative API, C. tetani API (CtAPI), even though C. tetani lacks both LPS and capsid biosynthetic genes. To better understand the physiological role of d-arabinose-5-phosphate in this Gram-positive organism, recombinant CtAPI was purified and characterized. CtAPI displays biochemical characteristics similar to those of APIs from Gram-negative organisms and complements the API deficiency of an E. coli API knockout strain. Thus, CtAPI represents the first d-arabinose-5-phosphate isomerase to be identified and characterized from a Gram-positive bacterium.IMPORTANCE The genome of Clostridium tetani, a pathogenic Gram-positive bacterium and the causative agent of tetanus, contains a gene (the CtAPI gene) that shares high sequence similarity with those of genes encoding d-arabinose-5-phosphate isomerases. APIs play an important role within Gram-negative bacteria in d-arabinose-5-phosphate production for lipopolysaccharide biosynthesis, capsule formation, and regulation of cellular d-glucitol uptake. The significance of our research is in identifying and characterizing CtAPI, the first Gram-positive API. Our findings show that CtAPI is specific to the interconversion of arabinose-5-phosphate and ribulose-5 phosphate while having no activity with the other sugars and sugar phosphates tested. We have speculated a regulatory role for this API in C. tetani, an organism that does not produce lipopolysaccharide. PMID- 28630127 TI - Deciphering function of new gonococcal vaccine antigens using phenotypic microarrays. AB - The function and extracellular location of cell envelope proteins make them attractive candidates for developing vaccines against bacterial diseases, including challenging, drug-resistant pathogens such as Neisseria gonorrhoeae Proteomics-driven reverse vaccinology delivered multiple gonorrhea vaccine candidates; however, the biological functions of many of them remain to be elucidated. Herein, the functions of six gonorrhea vaccine candidates - NGO2121, NGO1985, NGO2054, NGO2111, NGO1205, and NGO1344 - in cell envelope homeostasis were probed using phenotype microarrays with 1,056 conditions and a DeltabamE mutant (Deltango1780) as a reference of perturbed outer membrane integrity. Optimal growth conditions for a N. gonorrhoeae phenotype microarray assay in defined liquid media were developed, which can be useful in other applications, including rapid and thorough antimicrobial susceptibility assessment. Our studies revealed 91 conditions having uniquely positive or negative effects on one of the examined mutants. A cluster analysis of 37 and 57 commonly beneficial and detrimental compounds, respectively, revealed three separate phenotype groups: NGO2121 and NGO1985; NGO1344 and BamE; and the trio of NGO1205, NGO2111 and NGO2054, with the latter protein forming an independent branch of this cluster. Similar phenotypes were associated with loss of these vaccine candidates in the highly antibiotic resistant WHO X strain. Based on their extensive sensitivity phenomes, NGO1985 and NGO2121 appear as the most promising vaccine candidates. This study establishes the principle that phenotype microarrays can be successfully applied to a fastidious bacterial organism such as N. gonorrhoeaeIMPORTANCE Innovative approaches are required to develop vaccines against prevalent and neglected sexually transmitted infections such as gonorrhea. Herein, we have utilized phenotype microarrays in the first such investigation into Neisseria gonorrhoeae to probe the function of proteome derived vaccine candidates in cell envelope homeostasis. Information gained from this screening can feed to the vaccine candidate decision tree by providing insights into the roles these proteins play in membrane permeability, integrity, and overall N. gonorrhoeae physiology. The optimized screening protocol can be applied in investigations into the function of other hypothetical proteins of N. gonorrhoeae discovered in the expanding number of whole genome sequences, in addition to revealing phenotypic differences between clinical and laboratory strains. PMID- 28630129 TI - Polar Organizing Protein PopZ Is Required for Chromosome Segregation in Agrobacterium tumefaciens. AB - Despite being perceived as relatively simple organisms, many bacteria exhibit an impressive degree of subcellular organization. In Caulobacter crescentus, the evolutionarily conserved polar organizing protein PopZ facilitates cytoplasmic organization by recruiting chromosome centromeres and regulatory proteins to the cell poles. Here, we characterize the localization and function of PopZ in Agrobacterium tumefaciens, a genetically related species with distinct anatomy. In this species, we find that PopZ molecules are relocated from the old pole to the new pole in the minutes following cell division. PopZ is not required for the localization of the histidine kinases DivJ and PdhS1, which become localized to the old pole after PopZ relocation is complete. The histidine kinase PdhS2 is temporally and spatially related to PopZ in that it localizes to transitional poles just before they begin to shed PopZ and disappears from the old pole after PopZ relocalization. At the new pole, PopZ is required for tethering the centromere of at least one of multiple replicons (chromosome I), and the loss of popZ results in a severe chromosome segregation defect, aberrant cell division, and cell mortality. After cell division, the daughter that inherits polar PopZ is shorter in length and delayed in chromosome I segregation compared to its sibling. In this cell type, PopZ completes polar relocation well before the onset of chromosome segregation. While A. tumefaciens PopZ resembles its C. crescentus homolog in chromosome tethering activity, other aspects of its localization and function indicate distinct properties related to differences in cell organization.IMPORTANCE Members of the Alphaproteobacteria exhibit a wide range of phenotypic diversity despite sharing many conserved genes. In recent years, the extent to which this diversity is reflected at the level of subcellular organization has become increasingly apparent. However, which factors control such organization and how they have changed to suit different body plans are poorly understood. This study focuses on PopZ, which is essential for many aspects of polar organization in Caulobacter crescentus, but its role in other species is unclear. We explore the similarities and differences in PopZ functions between Agrobacterium tumefaciens and Caulobacter crescentus and conclude that PopZ lies at a point of diversification in the mechanisms that control cytoplasmic organization and cell cycle regulation in Alphaproteobacteria. PMID- 28630131 TI - 'It's a hard conversation to have'. Healthcare professionals' views concerning advance care discussions with young people affected by life-limiting neuromuscular diseases: an interview study. AB - OBJECTIVE: Life-limiting neuromuscular disease, such as some of the muscular dystrophies, are often diagnosed in early childhood: when death comes, commonly in the second or third decade of life, patients rarely have advance care plans in place or documented end-of-life care preferences. There is very limited literature concerning the discussions about end-of-life plans healthcare professionals have with young people affected by life-limiting neuromuscular diseases. The aim of this study was to investigate the views and experiences of healthcare professionals concerning having discussions about advance care plans and end-of-life care with teenagers and young adult patients affected by life limiting neuromuscular diseases. METHODS: Semistructured interviews with a maximum variety sample of nine professionals involved in the care of young people with life-limiting neuromuscular diseases in one region of the UK. RESULTS: While recognising the inevitable progression of the conditions, there was no consensus among interviewees concerning best approaches to discuss end-of-life care plans. Several environmental and personal barriers were identified that lead to avoidance of the emotionally challenging and difficult conversations. CONCLUSIONS: Community-based professionals with well-established relationships with patients and families may be best placed to take the lead and coordinate discussions, but individual case-by-case preferences need to be carefully considered. PMID- 28630130 TI - How a Genetically Stable Extremophile Evolves: Modes of Genome Diversification in the Archaeon Sulfolobus acidocaldarius. AB - In order to analyze in molecular terms how Sulfolobus genomes diverge, damage induced mutations and natural polymorphisms (PMs) were identified in laboratory constructs and wild-type isolates, respectively, of Sulfolobus acidocaldarius Among wild-type isolates drawn from one local population, pairwise nucleotide divergence averaged 4 * 10-6, which is about 0.15% of the corresponding divergence reported for Sulfolobus islandicus The most variable features of wild type S. acidocaldarius genomes were homopolymer (mononucleotide) tracts and longer tandem repeats, consistent with the spontaneous mutations that occur under laboratory conditions. Natural isolates, however, also revealed large insertions/deletions and inversions, which did not occur in any of the laboratory manipulated strains. Several of the large insertions/deletions could be attributed to the integration or excision of mobile genetic elements (MGEs), and each MGE represented a distinct system of site-specific recombination. The mode of recombination associated with one MGE, a provirus related to Sulfolobus turreted icosahedral virus, was also seen in certain chromosomal inversions. Artificially induced mutations, non-MGE insertions/deletions, and small PMs exhibited different distributions over the genome, suggesting that large-scale patterning of Sulfolobus genomes begins early in the divergence process. Unlike induced mutations, natural base pair substitutions occurred in clusters, and one cluster exhibited properties expected of nonreciprocal recombination (gene conversion) between dispersed imperfect repeats. Taken together, the results identify simple replication errors, slipped-strand events promoted by tandem repeats, homologous recombination, and rearrangements promoted by MGEs as the primary sources of genetic variation for this extremely acidophilic archaeon in its geothermal environment.IMPORTANCE The optimal growth temperatures of hyperthermophilic archaea accelerate DNA decomposition, which is expected to make DNA repair especially important for their genetic stability, yet these archaea lack certain broadly conserved types of DNA repair proteins. In this study, the genome of the extreme thermoacidophile Sulfolobus acidocaldarius was found to be remarkably stable, accumulating few mutations in many (though not all) laboratory manipulations and in natural populations. Furthermore, all the genetic processes that were inferred to diversify these genomes also operate in mesophilic bacteria and eukaryotes. This suggests that a common set of mechanisms produces most of the genetic variation in all microorganisms, despite the fundamental differences in physiology, DNA repair systems, and genome structure represented in the three domains of life. PMID- 28630133 TI - Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney. AB - Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1alpha, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs. PMID- 28630134 TI - Correction: Clustering of Ca2+ transients in interstitial cells of Cajal defines slow wave duration. PMID- 28630135 TI - Inhibition of the Cardiac Fibroblast-Enriched lncRNA Meg3 Prevents Cardiac Fibrosis and Diastolic Dysfunction. AB - RATIONALE: Cardiac fibroblasts (CFs) drive extracellular matrix remodeling after pressure overload, leading to fibrosis and diastolic dysfunction. Recent studies described the role of long noncoding RNAs (lncRNAs) in cardiac pathologies. Nevertheless, detailed reports on lncRNAs regulating CF biology and describing their implication in cardiac remodeling are still missing. OBJECTIVE: Here, we aimed at characterizing lncRNA expression in murine CFs after chronic pressure overload to identify CF-enriched lncRNAs and investigate their function and contribution to cardiac fibrosis and diastolic dysfunction. METHODS AND RESULTS: Global lncRNA profiling identified several dysregulated transcripts. Among them, the lncRNA maternally expressed gene 3 (Meg3) was found to be mostly expressed by CFs and to undergo transcriptional downregulation during late cardiac remodeling. In vitro, Meg3 regulated the production of matrix metalloproteinase-2 (MMP-2). GapmeR-mediated silencing of Meg3 in CFs resulted in the downregulation of Mmp-2 transcription, which, in turn, was dependent on P53 activity both in the absence and in the presence of transforming growth factor-beta I. Chromatin immunoprecipitation showed that further induction of Mmp-2 expression by transforming growth factor-beta I was blocked by Meg3 silencing through the inhibition of P53 binding on the Mmp-2 promoter. Consistently, inhibition of Meg3 in vivo after transverse aortic constriction prevented cardiac MMP-2 induction, leading to decreased cardiac fibrosis and improved diastolic performance. CONCLUSIONS: Collectively, our findings uncover a critical role for Meg3 in the regulation of MMP-2 production by CFs in vitro and in vivo, identifying a new player in the development of cardiac fibrosis and potential new target for the prevention of cardiac remodeling. PMID- 28630136 TI - ATP synthase complex and the mitochondrial permeability transition pore: poles of attraction. PMID- 28630137 TI - Structure and function of DHHC protein S-acyltransferases. AB - It has been estimated that 10% of the human genome encodes proteins that are fatty acylated at cysteine residues. The vast majority of these proteins are modified by members of the DHHC protein family, which carry out their enzymatic function on the cytoplasmic face of cell membranes. The biomedical importance of DHHC proteins is underscored by their association with human disease; unique and essential roles for DHHC proteins have been uncovered using DHHC-deficient mouse models. Accordingly, there is great interest in elucidating the molecular mechanisms that underlie DHHC protein function. In this review, we present recent insights into the structure and function of DHHC enzymes. PMID- 28630138 TI - Targeting the Ras palmitoylation/depalmitoylation cycle in cancer. AB - The Ras proteins are well-known drivers of many cancers and thus represent attractive targets for the development of anticancer therapeutics. Inhibitors that disrupt the association of the Ras proteins with membranes by blocking the addition of the farnesyl lipid moiety to the Ras C-terminus failed in clinical trials. Here, we explore the possibility of targeting a second lipid modification, S-acylation, commonly referred to as palmitoylation, as a strategy to disrupt the membrane interaction of specific Ras isoforms. We review the enzymes involved in adding and removing palmitate from Ras and discuss their potential roles in regulating Ras tumorigenesis. In addition, we examine other proteins that affect Ras protein localization and may serve as future drug targets. PMID- 28630139 TI - Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling. AB - Toll-like receptor 4 (TLR4) recognizes lipopolysaccharide (LPS), produces pro inflammatory cytokines and type I interferons, and associates with a trigger of endotoxin shock. TLR4 is interacted with a TIR domain-containing adaptor molecule 2 (TICAM-2)/TRAM [TRIF (TIR domain-containing adaptor-inducing interferon-beta) related adaptor molecule] via its Toll-interleukin-1 receptor homology (TIR) domain. TICAM-2 acts as a scaffold protein and activates TIR domain-containing adaptor molecule-1 (TICAM-1)/TRIF. According to the structural analysis by NMR, TICAM-2 interacts with TICAM-1 by the acidic amino acids motif, E87/D88/D89. The TIR domain of TICAM-2 couples with the dimer of TIR domain of TLR4 beneath the membrane, and TICAM-2 itself also forms dimer and constitutes a binding site with TICAM-1. Endosomal localization of TICAM-2 is essential for TLR4-mediated type I interferon-inducing signal from the endosome. N-terminal myristoylation allows TICAM-2 to anchor to the endosomal membrane. Additionally, we have identified two acidic amino acids, D91/E92, as a functional motif that cooperatively determines endosomal localization of TICAM-2. This structural information of TICAM-2 suggests that the specific structure is indispensable for the endosomal localization and type I interferon production of TICAM-2. Taken together with the knowledge on cytoplasmic sensors for LPS, TICAM-2/TICAM-1 may conform to a signal network on TLR4 to facilitate induction of cytokine disorders. PMID- 28630140 TI - Three-dimensional structure of the 3'X-tail of hepatitis C virus RNA in monomeric and dimeric states. AB - The 3'X domain is a 98-nt region located at the 3' end of hepatitis C virus genomic RNA that plays essential functions in the viral life cycle. It contains an absolutely conserved, 16-base palindromic sequence that promotes viral RNA dimerization, overlapped with a 7-nt tract implicated in a distal contact with a nearby functional sequence. Using small angle X-ray scattering measurements combined with model building guided by NMR spectroscopy, we have studied the stoichiometry, structure, and flexibility of domain 3'X and two smaller subdomain sequences as a function of ionic strength, and obtained a three-dimensional view of the full-length domain in its monomeric and dimeric states. In the monomeric form, the 3'X domain adopted an elongated conformation containing two SL1' and SL2' double-helical stems stabilized by coaxial stacking. This structure was significantly less flexible than that of isolated subdomain SL2' monomers. At higher ionic strength, the 3'X scattering envelope nearly doubled its size, reflecting the formation of extended homodimers containing an antiparallel SL2' duplex flanked by coaxially stacked SL1' helices. Formation of these dimers could initialize and/or regulate the packaging of viral RNA genomes into virions. PMID- 28630142 TI - The WHO joint statement from funders on trials transparency. PMID- 28630141 TI - Temperature-responsive miRNAs in Drosophila orchestrate adaptation to different ambient temperatures. AB - The majority of Drosophila genes are expressed in a temperature-dependent manner, but the way in which small RNAs may contribute to this effect is completely unknown as we currently lack an idea of how small RNA transcriptomes change as a function of temperature. Applying high-throughput sequencing techniques complemented by quantitative real-time PCR experiments, we demonstrate that altered ambient temperature induces drastic but reversible changes in sequence composition and total abundance of both miRNA and piRNA populations. Further, mRNA sequencing reveals that the expression of miRNAs and their predicted target transcripts correlates inversely, suggesting that temperature-responsive miRNAs drive adaptation to different ambient temperatures on the transcriptome level. Finally, we demonstrate that shifts in temperature affect both primary and secondary piRNA pools, and the observed aberrations are consistent with altered expression levels of the involved Piwi-pathway factors. We further reason that enhanced ping-pong processing at 29 degrees C is driven by dissolved RNA secondary structures at higher temperatures, uncovering target sites that are not accessible at low temperatures. Together, our results show that small RNAs are an important part of epigenetic regulatory mechanisms that ensure homeostasis and adaptation under fluctuating environmental conditions. PMID- 28630143 TI - Extracellular vesicles of stromal origin target and support hematopoietic stem and progenitor cells. AB - Extracellular vesicles (EVs) have been recently reported as crucial mediators in cell-to-cell communication in development and disease. In this study, we investigate whether mesenchymal stromal cells that constitute a supportive microenvironment for hematopoietic stem and progenitor cells (HSPCs) released EVs that could affect the gene expression and function of HSPCs. By taking advantage of two fetal liver-derived stromal lines with widely differing abilities to maintain HSPCs ex vivo, we demonstrate that stromal EVs play a critical role in the regulation of HSPCs. Both supportive and nonsupportive stromal lines secreted EVs, but only those delivered by the supportive line were taken up by HSPCs ex vivo and in vivo. These EVs harbored a specific molecular signature, modulated the gene expression in HSPCs after uptake, and maintained the survival and clonogenic potential of HSPCs, presumably by preventing apoptosis. In conclusion, our study reveals that EVs are an important component of the HSPC niche, which may have major applications in regenerative medicine. PMID- 28630144 TI - CRMP-1 enhances EVL-mediated actin elongation to build lamellipodia and the actin cortex. AB - Cells can control actin polymerization by nucleating new filaments or elongating existing ones. We recently identified CRMP-1 as a factor that stimulates the formation of Listeria monocytogenes actin comet tails, thereby implicating it in actin assembly. We now show that CRMP-1 is a major contributor to actin assembly in epithelial cells, where it works with the Ena/VASP family member EVL to assemble the actin cytoskeleton in the apical cortex and in protruding lamellipodia. CRMP-1 and EVL bind to one another and together accelerate actin filament barbed-end elongation. CRMP-1 also stimulates actin assembly in the presence of VASP and Mena in vitro, but CRMP-1-dependent actin assembly in MDCK cells is EVL specific. Our results identify CRMP-1 as a novel regulator of actin filament elongation and reveal a surprisingly important role for CRMP-1, EVL, and actin polymerization in maintaining the structural integrity of epithelial sheets. PMID- 28630145 TI - Activity-dependent trafficking of lysosomes in dendrites and dendritic spines. AB - In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins. PMID- 28630148 TI - Membrane pores: from structure and assembly, to medicine and technology. PMID- 28630146 TI - ER stress causes widespread protein aggregation and prion formation. AB - Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress. PMID- 28630147 TI - A bifurcated signaling cascade of NIMA-related kinases controls distinct kinesins in anaphase. AB - In mitosis, cells undergo a precisely orchestrated series of spatiotemporal changes in cytoskeletal structure to divide their genetic material. These changes are coordinated by a sophisticated network of protein-protein interactions and posttranslational modifications. In this study, we report a bifurcation in a signaling cascade of the NIMA-related kinases (Neks) Nek6, Nek7, and Nek9 that is required for the localization and function of two kinesins essential for cytokinesis, Mklp2 and Kif14. We demonstrate that a Nek9, Nek6, and Mklp2 signaling module controls the timely localization and bundling activity of Mklp2 at the anaphase central spindle. We further show that a separate Nek9, Nek7, and Kif14 signaling module is required for the recruitment of the Rho-interacting kinase citron to the anaphase midzone. Our findings uncover an anaphase-specific function for these effector kinesins that is controlled by specific Nek kinase signaling modules to properly coordinate cytokinesis. PMID- 28630149 TI - Molecular mechanism of pore formation by aerolysin-like proteins. AB - Aerolysin-like pore-forming proteins are an important family of proteins able to efficiently damage membranes of target cells by forming transmembrane pores. They are characterized by a unique domain organization and mechanism of action that involves extensive conformational rearrangements. Although structures of soluble forms of many different members of this family are well understood, the structures of pores and their mechanism of assembly have been described only recently. The pores are characterized by well-defined beta-barrels, which are devoid of any vestibular regions commonly found in other protein pores. Many members of this family are bacterial toxins; therefore, structural details of their transmembrane pores, as well as the mechanism of pore formation, are an important base for future drug design. Stability of pores and other properties, such as specificity for some cell surface molecules, make this family of proteins a useful set of molecular tools for molecular recognition and sensing in cell biology.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630150 TI - Cryo-electron tomography: an ideal method to study membrane-associated proteins. AB - Cryo-electron tomography (cryo-ET) is a three-dimensional imaging technique that makes it possible to analyse the structure of complex and dynamic biological assemblies in their native conditions. The latest technological and image processing developments demonstrate that it is possible to obtain structural information at nanometre resolution. The sample preparation required for the cryo ET technique does not require the isolation of a protein and other macromolecular complexes from its native environment. Therefore, cryo-ET is emerging as an important tool to study the structure of membrane-associated proteins including pores.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630151 TI - Assembly mechanism of the alpha-pore-forming toxin cytolysin A from Escherichia coli. AB - The cytolytic toxin cytolysin A (ClyA) from Escherichia coli is probably one of the best-characterized examples of bacterial, alpha-pore-forming toxins (alpha PFTs). Like other PFTs, ClyA exists in a soluble, monomeric form that assembles to an annular, homo-oligomeric pore complex upon contact with detergent or target membranes. Comparison of the three-dimensional structures of the 34 kDa monomer and the protomer in the context of the dodecameric pore complex revealed that ClyA undergoes one of the largest conformational transitions described for proteins so far, in which 55% of the residues change their position and 16% of the residues adopt a different secondary structure in the protomer. Studies on the assembly of ClyA revealed a unique mechanism that differs from the assembly mechanism of other PFTs. The rate-liming step of pore formation proved to be the unimolecular conversion of the monomer to an assembly-competent protomer, during which a molten globule-like off-pathway intermediate accumulates. The oligomerization of protomers to pore complexes is fast and follows a kinetic scheme in which mixtures of linear oligomers of different size are formed first, followed by very rapid and specific association of pairs of oligomers that can directly perform ring closure to the dodecameric pore complex.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630152 TI - Repurposing a pore: highly conserved perforin-like proteins with alternative mechanisms. AB - Pore-forming proteins play critical roles in pathogenic attack and immunological defence. The membrane attack complex/perforin (MACPF) group of homologues represents, with cholesterol-dependent cytolysins, the largest family of such proteins. In this review, we begin by describing briefly the structure of MACPF proteins, outlining their common mechanism of pore formation. We subsequently discuss some examples of MACPF proteins likely implicated in pore formation or other membrane-remodelling processes. Finally, we focus on astrotactin and bone morphogenetic protein and retinoic acid-induced neural-specific proteins, highly conserved MACPF family members involved in developmental processes, which have not been well studied to date or observed to form a pore-and which data suggest may act by alternative mechanisms.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630153 TI - Membrane-spanning alpha-helical barrels as tractable protein-design targets. AB - The rational (de novo) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of 'scaffolds' for protein design, and the means to garner sequence-to-structure relationships to guide the design process. The alpha helical coiled coil is a protein-structure element found in both globular and membrane proteins, where it cements a variety of helix-helix interactions and helical bundles. Our deep understanding of coiled coils has enabled a large number of successful de novo designs. For one class, the alpha-helical barrels that is, symmetric bundles of five or more helices with central accessible channels-there are both water-soluble and membrane-spanning examples. Recent computational designs of water-soluble alpha-helical barrels with five to seven helices have advanced the design field considerably. Here we identify and classify analogous and more complicated membrane-spanning alpha-helical barrels from the Protein Data Bank. These provide tantalizing but tractable targets for protein engineering and de novo protein design.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630154 TI - Design of self-assembling transmembrane helical bundles to elucidate principles required for membrane protein folding and ion transport. AB - Ion transporters and channels are able to identify and act on specific substrates among myriads of ions and molecules critical to cellular processes, such as homeostasis, cell signalling, nutrient influx and drug efflux. Recently, we designed Rocker, a minimalist model for Zn2+/H+ co-transport. The success of this effort suggests that de novo membrane protein design has now come of age so as to serve a key approach towards probing the determinants of membrane protein folding, assembly and function. Here, we review general principles that can be used to design membrane proteins, with particular reference to helical assemblies with transport function. We also provide new functional and NMR data that probe the dynamic mechanism of conduction through Rocker.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630155 TI - Haemolytic actinoporins interact with carbohydrates using their lipid-binding module. AB - Pore-forming toxins (PFTs) are proteins endowed with metamorphic properties that enable them to stably fold in water solutions as well as in cellular membranes. PFTs produce lytic pores on the plasma membranes of target cells conducive to lesions, playing key roles in the defensive and offensive molecular systems of living organisms. Actinoporins are a family of potent haemolytic toxins produced by sea anemones vigorously studied as a paradigm of alpha-helical PFTs, in the context of lipid-protein interactions, and in connection with nanopore technologies. We have recently reported that fragaceatoxin C (FraC), an actinoporin, engages biological membranes with a large adhesive motif allowing the simultaneous attachment of up to four lipid molecules prior to pore formation. Since actinoporins also interact with carbohydrates, we sought to understand the molecular and energetic basis of glycan recognition by FraC. By employing structural and biophysical methodologies, we show that FraC engages glycans with low affinity using its lipid-binding module. Contrary to other PFTs requiring separate domains for glycan and lipid recognition, the small single domain actinoporins economize resources by achieving dual recognition with a single binding module. This mechanism could enhance the recruitment of actinoporins to the surface of target tissues in their marine environment.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630156 TI - Apoptotic foci at mitochondria: in and around Bax pores. AB - The permeabilization of the mitochondrial outer membrane by Bax and Bak during apoptosis is considered a key step and a point of no return in the signalling pathway. It is always closely related to the reorganization of mitochondrial cristae that frees cytochrome c to the intermembrane space and to massive mitochondrial fragmentation mediated by the dynamin-like protein Drp1. Despite multiple evidence in favour of a functional link between these processes, the molecular mechanisms that connect them and their relevance for efficient apoptosis signalling remain obscure. In this review, we discuss recent progress on our understanding of how Bax forms pores in the context of Drp1-stabilized signalling platforms at apoptotic foci in mitochondria.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630157 TI - Pore formation by dimeric Bak and Bax: an unusual pore? AB - Apoptotic cell death via the mitochondrial pathway occurs in all vertebrate cells and requires the formation of pores in the mitochondrial outer membrane. Two Bcl 2 protein family members, Bak and Bax, form these pores during apoptosis, and how they do so has been investigated for the last two decades. Many of the conformation changes that occur during their transition to pore-forming proteins have now been delineated. Notably, biochemical, biophysical and structural studies indicate that symmetric homodimers are the basic unit of pore formation. Each dimer contains an extended hydrophobic surface that lies on the outer membrane, and is anchored at either end by a transmembrane domain. Membrane remodelling events such as positive membrane curvature have been reported to accompany apoptotic pore formation, suggesting Bak and Bax form lipidic pores rather than proteinaceous pores. However, it remains unclear how symmetric dimers assemble to porate the membrane. Here, we review how clusters of dimers and their lipid-mediated interactions provide a molecular explanation for the heterogeneous assemblies of Bak and Bax observed during apoptosis.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630159 TI - The mystery behind membrane insertion: a review of the complement membrane attack complex. AB - The membrane attack complex (MAC) is an important innate immune effector of the complement terminal pathway that forms cytotoxic pores on the surface of microbes. Despite many years of research, MAC structure and mechanism of action have remained elusive, relying heavily on modelling and inference from biochemical experiments. Recent advances in structural biology, specifically cryo electron microscopy, have provided new insights into the molecular mechanism of MAC assembly. Its unique 'split-washer' shape, coupled with an irregular giant beta-barrel architecture, enable an atypical mechanism of hole punching and represent a novel system for which to study pore formation. This review will introduce the complement terminal pathway that leads to formation of the MAC. Moreover, it will discuss how structures of the pore and component proteins underpin a mechanism for MAC function, modulation and inhibition.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630158 TI - Computational studies of peptide-induced membrane pore formation. AB - A variety of peptides induce pores in biological membranes; the most common ones are naturally produced antimicrobial peptides (AMPs), which are small, usually cationic, and defend diverse organisms against biological threats. Because it is not possible to observe these pores directly on a molecular scale, the structure of AMP-induced pores and the exact sequence of steps leading to their formation remain uncertain. Hence, these questions have been investigated via molecular modelling. In this article, we review computational studies of AMP pore formation using all-atom, coarse-grained, and implicit solvent models; evaluate the results obtained and suggest future research directions to further elucidate the pore formation mechanism of AMPs.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630161 TI - Insertion of proteins and lipopolysaccharide into the bacterial outer membrane. AB - The bacterial outer membrane contains phospholipids in the inner leaflet and lipopolysaccharide (LPS) in the outer leaflet. Both proteins and LPS must be frequently inserted into the outer membrane to preserve its integrity. The protein complex that inserts LPS into the outer membrane is called LptDE, and consists of an integral membrane protein, LptD, with a separate globular lipoprotein, LptE, inserted in the barrel lumen. The protein complex that inserts newly synthesized outer-membrane proteins (OMPs) into the outer membrane is called the BAM complex, and consists of an integral membrane protein, BamA, plus four lipoproteins, BamB, C, D and E. Recent structural and functional analyses illustrate how these two complexes insert their substrates into the outer membrane by distorting the membrane component (BamA or LptD) to directly access the lipid bilayer.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630160 TI - Listeriolysin O: from bazooka to Swiss army knife. AB - Listeria monocytogenes (Lm) is a Gram-positive facultative intracellular pathogen. Infections in humans can lead to listeriosis, a systemic disease with a high mortality rate. One important mechanism of Lm dissemination involves cell-to cell spread after bacteria have entered the cytosol of host cells. Listeriolysin O (LLO; encoded by the hly gene) is a virulence factor present in Lm that plays a central role in the cell-to-cell spread process. LLO is a member of the cholesterol-dependent cytolysin (CDC) family of toxins that were initially thought to promote disease largely by inducing cell death and tissue destruction essentially acting like a 'bazooka'. This view was supported by structural studies showing CDCs can form large pores in membranes. However, it is now appreciated that LLO has many subtle activities during Lm infection of host cells, and many of these likely do not involve large pores, but rather small membrane perforations. It is also appreciated that membrane repair pathways of host cells play a major role in limiting membrane damage by LLO and other toxins. LLO is now thought to represent a 'Swiss army knife', a versatile tool that allows Lm to induce many membrane alterations and cellular responses that promote bacterial dissemination during infection.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630162 TI - Real-time dynamics of carbon nanotube porins in supported lipid membranes visualized by high-speed atomic force microscopy. AB - In-plane mobility of proteins in lipid membranes is one of the fundamental mechanisms supporting biological functionality. Here we use high-speed atomic force microscopy (HS-AFM) to show that a novel type of biomimetic channel-carbon nanotube porins (CNTPs)-is also laterally mobile in supported lipid membranes, mimicking biological protein behaviour. HS-AFM can capture real-time dynamics of CNTP motion in the supported lipid bilayer membrane, build long-term trajectories of the CNTP motion and determine the diffusion coefficients associated with this motion. Our analysis shows that diffusion coefficients of CNTPs fall into the same range as those of proteins in supported lipid membranes. CNTPs in HS-AFM experiments often exhibit 'directed' diffusion behaviour, which is common for proteins in live cell membranes.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630163 TI - Measuring the potential energy barrier to lipid bilayer electroporation. AB - Electroporation is a common tool for gene transfection, tumour ablation, sterilization and drug delivery. Using experimental methods, we explore the temperature dependence of electropore formation in a model membrane system (droplet-interface bilayers), using optical single-channel recording to image the real-time gating of individual electropores. We investigate the influence of the agarose substrate on electropores formed in this system. Furthermore, by examining the temperature-dependent kinetics of pore opening and closure we are able to estimate a barrier to pore opening in 1,2-diphytanoyl-sn-glycero-3 phosphocholine (DPhPC) membranes to be 25.0 +/- 8.3 kBT, in agreement with previous predictions. Overall these measurements help support the toroidal model of membrane electroporation.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630165 TI - The cell adhesion molecule CHL1 interacts with patched-1 to regulate apoptosis during postnatal cerebellar development. AB - The immunoglobulin superfamily adhesion molecule close homolog of L1 (CHL1) plays important roles during nervous system development. Here, we identified the hedgehog receptor patched-1 (PTCH1) as a novel CHL1-binding protein and showed that CHL1 interacts with the first extracellular loop of PTCH1 via its extracellular domain. Colocalization and co-immunoprecipitation of CHL1 with PTCH1 suggest an association of CHL1 with this major component of the hedgehog signaling pathway. The trans-interaction of CHL1 with PTCH1 promotes neuronal survival in cultures of dissociated cerebellar granule cells and of organotypic cerebellar slices. An inhibitor of the PTCH1-regulated hedgehog signal transducer, smoothened (SMO), and inhibitors of RhoA and Rho-associated kinase (ROCK) 1 and 2 prevent CHL1-dependent survival of cultured cerebellar granule cells and survival of cerebellar granule and Purkinje cells in organotypic cultures. In histological sections from 10- and 14-day-old CHL1-deficient mice, enhanced apoptosis of granule, but not Purkinje, cells was observed. The results of the present study indicate that CHL1 triggers PTCH1-, SMO-, RhoA- and ROCK dependent signal transduction pathways to promote neuronal survival after cessation of the major morphogenetic events during mouse cerebellar development. PMID- 28630164 TI - Single-molecule nanopore enzymology. AB - Biological nanopores are a class of membrane proteins that open nanoscale water conduits in biological membranes. When they are reconstituted in artificial membranes and a bias voltage is applied across the membrane, the ionic current passing through individual nanopores can be used to monitor chemical reactions, to recognize individual molecules and, of most interest, to sequence DNA. In addition, a more recent nanopore application is the analysis of single proteins and enzymes. Monitoring enzymatic reactions with nanopores, i.e. nanopore enzymology, has the unique advantage that it allows long-timescale observations of native proteins at the single-molecule level. Here, we describe the approaches and challenges in nanopore enzymology.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'. PMID- 28630167 TI - Successive governments are responsible for GP crisis. PMID- 28630166 TI - Deficiency of PHB complex impairs respiratory supercomplex formation and activates mitochondrial flashes. AB - Prohibitins (PHBs; prohibitin 1, PHB1 or PHB, and prohibitin 2, PHB2) are evolutionarily conserved and ubiquitously expressed mitochondrial proteins. PHBs form multimeric ring complexes acting as scaffolds in the inner mitochondrial membrane. Mitochondrial flashes (mitoflashes) are newly discovered mitochondrial signaling events that reflect electrical and chemical excitations of the organelle. Here, we investigate the possible roles of PHBs in the regulation of mitoflash signaling. Downregulation of PHBs increases mitoflash frequency by up to 5.4-fold due to elevated basal reactive oxygen species (ROS) production in the mitochondria. Mechanistically, PHB deficiency impairs the formation of mitochondrial respiratory supercomplexes (RSCs) without altering the abundance of individual respiratory complex subunits. These impairments induced by PHB deficiency are effectively rescued by co-expression of PHB1 and PHB2, indicating that the multimeric PHB complex acts as the functional unit. Furthermore, downregulating other RSC assembly factors, including SCAFI (also known as COX7A2L), RCF1a (HIGD1A), RCF1b (HIGD2A), UQCC3 and SLP2 (STOML2), all activate mitoflashes through elevating mitochondrial ROS production. Our findings identify the PHB complex as a new regulator of RSC formation and mitoflash signaling, and delineate a general relationship among RSC formation, basal ROS production and mitoflash biogenesis. PMID- 28630168 TI - Incidence and Factors Associated With the Occurrence of Pulmonary Vein Narrowing After Cryoballoon Ablation. AB - BACKGROUND: In contrast with traditional radiofrequency ablation, little is known about the influence of cryoballoon ablation on the morphology of pulmonary veins (PVs). We evaluated the influence of cryoballoon ablation on the PV dimension (PVD) and investigated the factors associated with a reduction of the PVD. METHODS AND RESULTS: Seventy-four patients who underwent cryoballoon ablation for paroxysmal atrial fibrillation were included in the present study. All subjects underwent contrast-enhanced computed tomography both before and at 3 months after the procedure. The PVD (cross-sectional area) was measured using a 3-dimensional electroanatomical mapping system. Each PV was evaluated according to the PVD reduction rate (DeltaPVD), which was calculated as follows: (1-post-PVD/pre PVD)*100 (%). Ninety-two percent of the PVs (271/296) were successfully isolated only by cryoballoon ablation; the remaining 8% of the PVs required touch-up ablation and were excluded from the analysis. Mild (25%-50%), moderate (50%-75%), and severe (>=75%) DeltaPVD values were observed in 87, 14, and 3 PVs, respectively, including 1 case with severe left superior PV stenosis (DeltaPVD: 94%) in a patient who required PV angioplasty. In multivariable analysis, a larger PV ostium and lower minimum freezing temperature during cryoballoon ablation were independently associated with PV narrowing (odds ratio, 1.773; P=0.01; and odds ratio, 1.137; P<0.001, respectively). CONCLUSIONS: A reduction of the PVD was often observed after cryoballoon ablation for atrial fibrillation. A larger PV ostium and lower minimum freezing temperature during cryoballoon ablation were associated with an increased risk of PVD reduction. PMID- 28630170 TI - Characterization of Aortic Valve Closure Artifact During Outflow Tract Mapping: Correlation With Hemodynamics and Mechanical Valves. AB - BACKGROUND: Premature ventricular contractions originating in the left ventricle outflow tract represent a significant subgroup of patients referred for catheter ablation. Mechanical artifacts from aortic valve leaflet motion may be observed during mapping, although the incidence and characteristics have not been reported. METHODS AND RESULTS: Twenty-eight consecutive patients with left ventricle outflow tract premature ventricular contraction were included. Electric signals recorded on the ablation catheter not coincident with atrial or ventricular depolarization were analyzed on the recording system. Correlation with invasive hemodynamic aortic pressure tracings was performed. Additionally, 4 patients with mechanical aortic valves, who underwent scar-related ventricular tachycardia ablation, were analyzed to correlate the timing of the observed artifacts with native aortic valves. Aortic valve artifact was observed while mapping within the coronary cusps in 11 patients (39%; 73% men; age, 41+/-25 years; left ventricular ejection fraction 49+/-16%) with high incidence from the left coronary cusp. This artifact was consistently observed with timing coincident with the terminal portion of the T wave. The average interval between the end of the T wave and the aortic valve artifact was 19+/-37 ms. The duration of the aortic valve artifact was 39+/-8 ms with amplitude of 0.12+/-0.07 mV (range, 0.06-0.36 mV). CONCLUSIONS: In patients referred for left ventricle outflow tract premature ventricular contraction ablation, an aortic valve closure artifact is observed in up to one third of cases during mapping within the aortic cusps. The timing of this artifact correlates with invasive hemodynamics and mechanical aortic valve artifacts. Recognition of this physiological phenomenon is useful when assigning near-field activation. PMID- 28630169 TI - Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia type 2 (CPVT2) results from autosomal recessive CASQ2 mutations, causing abnormal Ca2+-handling and malignant ventricular arrhythmias. We aimed to establish a patient-specific human induced pluripotent stem cell (hiPSC) model of CPVT2 and to use the generated hiPSC-derived cardiomyocytes to gain insights into patient-specific disease mechanism and pharmacotherapy. METHODS AND RESULTS: hiPSC cardiomyocytes were derived from a CPVT2 patient (D307H-CASQ2 mutation) and from healthy controls. Laser-confocal Ca2+ and voltage imaging showed significant Ca2+ transient irregularities, marked arrhythmogenicity manifested by early afterdepolarizations and triggered arrhythmias, and reduced threshold for store overload-induced Ca2+-release events in the CPVT2-hiPSC cardiomyocytes when compared with healthy control cells. Pharmacological studies revealed the prevention of adrenergic-induced arrhythmias by beta-blockers (propranolol and carvedilol), flecainide, and the neuronal sodium-channel blocker riluzole; a direct antiarrhythmic action of carvedilol (independent of its alpha/beta adrenergic blocking activity), flecainide, and riluzole; and suppression of abnormal Ca2+ cycling by the ryanodine stabilizer JTV-519 and carvedilol. Mechanistic insights were gained on the different antiarrhythmic actions of the aforementioned drugs, with carvedilol and JTV-519 (but not flecainide or riluzole) acting primarily through sarcoplasmic reticulum stabilization. Finally, comparable outcomes were found between flecainide and labetalol antiarrhythmic effects in vitro and the clinical results in the same patient. CONCLUSIONS: These results demonstrate the ability of hiPSCs cardiomyocytes to recapitulate CPVT2 disease phenotype and drug response in the culture dish, to provide novel insights into disease and drug therapy mechanisms, and potentially to tailor patient-specific drug therapy. PMID- 28630172 TI - Role of His Refractory Premature Ventricular Complexes in the Differential Diagnosis of a Left Bundle Branch Block Morphology Tachycardia. PMID- 28630171 TI - Distinctive Left Ventricular Activations Associated With ECG Pattern in Heart Failure Patients. AB - BACKGROUND: In contrast to patients with left bundle branch block (LBBB), heart failure patients with narrow QRS and nonspecific intraventricular conduction delay (NICD) display a relatively limited response to cardiac resynchronization therapy. We sought to compare left ventricular (LV) activation patterns in heart failure patients with narrow QRS and NICD to patients with LBBB using high density electroanatomic activation maps. METHODS AND RESULTS: Fifty-two heart failure patients (narrow QRS [n=18], LBBB [n=11], NICD [n=23]) underwent 3 dimensional electroanatomic mapping with a high density of mapping points (387+/ 349 LV). Adjunctive scar imaging was available in 37 (71%) patients and was analyzed in relation to activation maps. LBBB patients typically demonstrated (1) a single LV breakthrough at the septum (38+/-15 ms post-QRS onset); (2) prolonged right-to-left transseptal activation with absence of direct LV Purkinje activity; (3) homogeneous propagation within the LV cavity; and (4) latest activation at the basal lateral LV. In comparison, both NICD and narrow QRS patients demonstrated (1) multiple LV breakthroughs along the posterior or anterior fascicles: narrow QRS versus LBBB, 5+/-2 versus 1+/-1; P=0.0004; NICD versus LBBB, 4+/-2 versus 1+/-1; P=0.001); (2) evidence of early/pre-QRS LV electrograms with Purkinje potentials; (3) rapid propagation in narrow QRS patients and more heterogeneous propagation in NICD patients; and (4) presence of limited areas of late activation associated with LV scar with high interindividual heterogeneity. CONCLUSIONS: In contrast to LBBB patients, narrow QRS and NICD patients are characterized by distinct mechanisms of LV activation, which may predict poor response to cardiac resynchronization therapy. PMID- 28630173 TI - Primary Prevention of Sudden Cardiac Death Early Post-Myocardial Infarction: Root Cause Analysis for Implantable Cardioverter-Defibrillator Failure and Currently Available Options. PMID- 28630174 TI - Experimental, Pathologic, and Clinical Findings of Radiofrequency Catheter Ablation of Para-Hisian Region From the Right Ventricle in Dogs and Humans. AB - BACKGROUND: Ablation of para-Hisian accessory pathway (AP) poses high risks of atrioventricular block. We developed a pacing technique to differentiate the near field (NF) from far-field His activations to avoid the complication. METHODS AND RESULTS: Three-dimensional mapping of the right ventricle was performed in 15 mongrel dogs and 23 patients with para-Hisian AP. Using different pacing outputs, the NF- and far-field His activation was identified on the ventricular aspect. Radiofrequency application was delivered at the NF His site in 8 (group 1) and the far-field His site in 7 dogs (group 2), followed by pathologic examination after 14 days. NF His activation was captured with 5 mA/1 ms in 10 and 10 mA/1 ms in 5 dogs. In group 1, radiofrequency delivery resulted in complete atrioventricular block in 3, right bundle branch block with HV (His-to ventricular) interval prolongation in 1, and only right bundle branch block in 2 dogs, whereas no changes occurred in group 2. Pathologic examination in group-1 dogs showed complete or partial necrosis of the His bundle in 4 and complete necrosis of the right bundle branch in 5 dogs. In group 2, partial necrosis in the right bundle branch was found only in 1 dog. Using this pacing technique, the APs were 5.7+/-1.2 mm away from the His bundle located superiorly in 20 or inferiorly in 3 patients. All APs were successfully eliminated with 1 to 3 radiofrequency applications. No complications and recurrence occurred during a follow-up of 11.8+/-1.4 months. CONCLUSIONS: Differentiating the NF His from far field His activations led to a high ablation success without atrioventricular block in para-Hisian AP patients. PMID- 28630175 TI - Patient-Specific Induced Pluripotent Stem Cell-Based Disease Model for Pathogenesis Studies and Clinical Pharmacotherapy. PMID- 28630176 TI - Diagnostic Perturbations. PMID- 28630178 TI - Efficacy of Cefiderocol against Carbapenem-Resistant Gram-Negative Bacilli in Immunocompetent-Rat Respiratory Tract Infection Models Recreating Human Plasma Pharmacokinetics. AB - Cefiderocol (S-649266), a novel siderophore cephalosporin, shows potent activity against carbapenem-resistant Gram-negative bacilli. In this study, we evaluated the efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli (Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae) in immunocompetent-rat respiratory tract infection models recreating plasma pharmacokinetics (PK) profiles in healthy human subjects. A total of 6 clinical isolates (1 cephalosporin-susceptible P. aeruginosa isolate, 1 multidrug resistant P. aeruginosa isolate, 2 multidrug-resistant A. baumannii isolates, and 2 carbapenem-resistant K. pneumoniae isolates) were evaluated. Four-day treatment with a human exposure of 1 g ceftazidime every 8 h as a 0.5-h infusion showed potent efficacy only against a ceftazidime-susceptible isolate, not against five ceftazidime-resistant isolates harboring carbapenemase. With cefiderocol, a human exposure of 2 g every 8 h as a 3-h infusion for 4 days produced a >3 log10 reduction in the number of viable cells of these carbapenem-resistant isolates in the lungs. When the infusion time was 1 h, bactericidal activity was also observed against all isolates tested, although for 2 of 5 carbapenem-resistant isolates, a 3 log10 reduction was not achieved. The difference in efficacy achieved by changing the infusion period from 1 h to 3 h was considered to be due to the higher percentage of the dosing interval during which free-drug concentrations were above the MIC (%fTMIC), as observed for beta-lactam antibiotics. These results suggest the potential utility of cefiderocol for the treatment of lung infections caused by carbapenem-resistant P. aeruginosa, A. baumannii, and K. pneumoniae strains. PMID- 28630177 TI - Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome. AB - While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation. PMID- 28630179 TI - Antibiotic Resistance as a Stress Response: Recovery of High-Level Oxacillin Resistance in Methicillin-Resistant Staphylococcus aureus "Auxiliary" (fem) Mutants by Induction of the Stringent Stress Response. AB - Studies with methicillin-resistant Staphylococcus aureus (MRSA) strain COL have shown that the optimal resistance phenotype requires not only mecA but also a large number of "auxiliary genes" identified by Tn551 mutagenesis. The majority of auxiliary mutants showed greatly increased levels of oxacillin resistance when grown in the presence of sub-MICs of mupirocin, suggesting that the mechanism of reduced resistance in the auxiliary mutants involved the interruption of a stringent stress response, causing reduced production of penicillin-binding protein 2A (PBP 2A). PMID- 28630180 TI - De Novo Acquisition of Resistance to SCY-078 in Candida glabrata Involves FKS Mutations That both Overlap and Are Distinct from Those Conferring Echinocandin Resistance. AB - SCY-078 is an orally active antifungal whose target is the beta-(1,3)-d-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant Candida glabrata isolates following drug exposure in vitro Resistant isolates were analyzed using broth microdilution methodology and FKS sequencing. The kinetic inhibition parameter IC50 (50% inhibitory concentration) was also determined from GS complexes. The spectrum of resistance mutations found suggested a partially overlapping but independent binding site for SCY-078 relative to echinocandins on GS. PMID- 28630181 TI - In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against a Recent Collection of Clinically Relevant Gram-Negative Bacilli from North America and Europe, Including Carbapenem-Nonsusceptible Isolates (SIDERO-WT-2014 Study). AB - Cefiderocol (formerly S-649266) is an investigational siderophore cephalosporin. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) was prepared according to the Clinical and Laboratory Standards Institute (CLSI) protocol and used to perform broth microdilution testing of cefiderocol against a 2014-2015 collection of clinical isolates of Gram-negative bacilli from North America (n = 4,239) and Europe (n = 4,966). The concentrations of cefiderocol inhibiting 90% of isolates tested (MIC90s) were 0.5 MUg/ml (North America; n = 3,007) and 1 MUg/ml (Europe; n = 3,080) for all isolates of Enterobacteriaceae; 1 MUg/ml (North America; n = 30) and 4 MUg/ml (Europe; n = 139) for meropenem nonsusceptible (MIC >= 2 MUg/ml) isolates of Enterobacteriaceae; 0.5 MUg/ml for both North American (n = 765) and European (n = 765) isolates of Pseudomonas aeruginosa; 0.5 MUg/ml (North America; n = 151) and 1 MUg/ml (Europe; n = 202) for meropenem-nonsusceptible (MIC >= 4 MUg/ml) isolates of P. aeruginosa; 1 MUg/ml for both North American (n = 309) and European (n = 839) isolates of all Acinetobacter baumannii strains as well as for both North American (n = 173) and European (n = 595) isolates of meropenem-nonsusceptible A. baumannii; and 0.5MUg/ml (North America; n = 152) and 0.25 MUg/ml (Europe; n = 276) for isolates of Stenotrophomonas maltophilia MICs of cefiderocol were <=4 MUg/ml for 99.9% (6,078/6,087) of all Enterobacteriaceae, 97.0% (164/169) of meropenem nonsusceptible Enterobacteriaceae, 99.9% (1,529/1,530) of all P. aeruginosa isolates, 100% (353/353) of meropenem-nonsusceptible P. aeruginosa isolates, 97.6% (1,120/1,148) of all A. baumannii isolates, 96.9% (744/768) of meropenem nonsusceptible A. baumannii isolates, 100% of isolates of S. maltophilia (428/428) and 93.8% of isolates of Burkholderia cepecia (11/12). We conclude that cefiderocol demonstrated potent in vitro activity against a recent collection of clinical isolates of commonly encountered Gram-negative bacilli, including carbapenem-nonsusceptible isolates. PMID- 28630182 TI - Biodistribution and In Vivo Antileishmanial Activity of 1,2 Distigmasterylhemisuccinoyl-sn-Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B. AB - 1,2-Distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and in vitro antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in Leishmania major-infected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip- and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in L. major-infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly (P < 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly (P < 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The in vivo activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation. PMID- 28630183 TI - Bioavailability of Lumefantrine Is Significantly Enhanced with a Novel Formulation Approach, an Outcome from a Randomized, Open-Label Pharmacokinetic Study in Healthy Volunteers. AB - The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ~48-fold and ~24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2. PMID- 28630184 TI - Occurrence of Clinically Important Lineages, Including the Sequence Type 131 C1 M27 Subclone, among Extended-Spectrum-beta-Lactamase-Producing Escherichia coli in Wastewater. AB - Contamination of environmental waters by extended-spectrum-beta-lactamase (ESBL) producing Escherichia coli (ESBLEC) is of great concern. Wastewater treatment plants (WWTPs) and hospitals release large amounts of ESBLEC into the environment. In the present study, we isolated ESBLEC strains from wastewater collected from a WWTP and a hospital in Japan and performed whole-genome sequencing to characterize these strains. Genomic analysis of 54 strains (32 from the WWTP and 22 from hospital wastewater) revealed the occurrence of clinically important clonal groups with extraintestinal pathogenic E. coli status in the WWTP and hospital wastewater. Fine-scale phylogenetic analysis was performed to further characterize 15 sequence type 131 (ST131) complex strains (11 from the WWTP and 4 from hospital wastewater). These ST131 complex strains were comprised of the following different subgroups: clade A (n = 2), C1-M27 (n = 8), and C1 (non-C1-M27) (n = 1) for strains from the WWTP and clade A (n = 2), C1-M27 (n = 1), and C1 (non-C1-M27) (n = 1) for strains from hospital wastewater. The results indicate that ESBLEC strains belonging to clinically important lineages, including the C1-M27 clade, may disseminate into the environment through wastewater, highlighting the need to monitor for antibiotic resistance in wastewater. PMID- 28630185 TI - In Vivo Biomarker Analysis of the Effects of Intranasally Dosed PC945, a Novel Antifungal Triazole, on Aspergillus fumigatus Infection in Immunocompromised Mice. AB - PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with A. fumigatus, and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days -7 to +3 or days -7 to 0) were also compared with those of the shorter treatment regimens (days -1 to +3 or days -1 and 0). Early and late interventions with PC945 (2.8 to 350 MUg/mouse; approximately 0.11 to ~14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in BALF (interferon gamma [IFN-gamma], interleukin-17 [IL-17], and malondialdehyde) and serum (tumor necrosis factor alpha [TNF-alpha] and IL-6) in a dose-dependent manner and were >3- and >47-fold more potent than intranasally dosed posaconazole and voriconazole, respectively. Furthermore, extended prophylaxis with low-dose PC945 (0.56 MUg/mouse; 0.022 mg/kg) was found to inhibit fungal loads and to decrease the concentrations biomarkers more potently than did the shorter treatment regimens. Thus, PC945 dosed intranasally once daily showed potent antifungal effects, and the effects of PC945 accumulated upon repeat dosing and were persistent. Therefore, PC945 has the potential to be a novel inhaled therapy for the treatment of A. fumigatus infection in humans. PMID- 28630186 TI - Loss of C-5 Sterol Desaturase Activity Results in Increased Resistance to Azole and Echinocandin Antifungals in a Clinical Isolate of Candida parapsilosis. AB - Among emerging non-albicans Candida species, Candida parapsilosis is of particular concern as a cause of nosocomial bloodstream infections in neonatal and intensive care unit patients. While fluconazole and echinocandins are considered effective treatments for such infections, recent reports of fluconazole and echinocandin resistance in C. parapsilosis indicate a growing problem. The present study describes a novel mechanism of antifungal resistance in this organism affecting susceptibility to azole and echinocandin antifungals in a clinical isolate obtained from a patient with prosthetic valve endocarditis. Transcriptome analysis indicated differential expression of several genes in the resistant isolate, including upregulation of ergosterol biosynthesis pathway genes ERG2, ERG5, ERG6, ERG11, ERG24, ERG25, and UPC2 Whole-genome sequencing revealed that the resistant isolate possessed an ERG3 mutation resulting in a G111R amino acid substitution. Sterol profiles indicated a reduction in sterol desaturase activity as a result of this mutation. Replacement of both mutant alleles in the resistant isolate with the susceptible isolate's allele restored wild-type susceptibility to all azoles and echinocandins tested. Disruption of ERG3 in the susceptible and resistant isolates resulted in a loss of sterol desaturase activity, high-level azole resistance, and an echinocandin intermediate to -resistant phenotype. While disruption of ERG3 in C. albicans resulted in azole resistance, echinocandin MICs, while elevated, remained within the susceptible range. This work demonstrates that the G111R substitution in Erg3 is wholly responsible for the altered azole and echinocandin susceptibilities observed in this C. parapsilosis isolate and is the first report of an ERG3 mutation influencing susceptibility to the echinocandins. PMID- 28630187 TI - Cumulative Effect of an Antimicrobial Stewardship and Rapid Diagnostic Testing Bundle on Early Streamlining of Antimicrobial Therapy in Gram-Negative Bloodstream Infections. AB - The use of rapid diagnostic tests (RDTs) enhances antimicrobial stewardship program (ASP) interventions in optimization of antimicrobial therapy. This quasi experimental cohort study evaluated the combined impact of an ASP/RDT bundle on the appropriateness of empirical antimicrobial therapy (EAT) and time to de escalation of broad-spectrum antimicrobial agents (BSAA) in Gram-negative bloodstream infections (GNBSI). The ASP/RDT bundle consisted of system-wide GNBSI treatment guidelines, prospective stewardship monitoring, and sequential introduction of two RDTs, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and the FilmArray blood culture identification (BCID) panel. The preintervention period was January 2010 through December 2013, and the postintervention period followed from January 2014 through June 2015. The postintervention period was conducted in two phases; phase 1 followed the introduction of MALDI-TOF MS, and phase 2 followed the introduction of the FilmArray BCID panel. The interventions resulted in significantly improved appropriateness of EAT (95% versus 91%; P = 0.02). Significant reductions in median time to de-escalation from combination antimicrobial therapy (2.8 versus 1.5 days), antipseudomonal beta-lactams (4.0 versus 2.5 days), and carbapenems (4.0 versus 2.5 days) were observed in the postintervention compared to the preintervention period (P < 0.001 for all). The reduction in median time to de escalation from combination therapy (1.0 versus 2.0 days; P = 0.03) and antipseudomonal beta-lactams (2.2 versus 2.7 days; P = 0.04) was further augmented during phase 2 compared to phase 1 of the postintervention period. Implementation of an antimicrobial stewardship program and RDT intervention bundle in a multihospital health care system is associated with improved appropriateness of EAT for GNBSI and decreased utilization of BSAA through early de-escalation. PMID- 28630188 TI - Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa. AB - Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and, due to increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells, and elimination of these cells would therefore significantly improve patient outcomes. In this study, a small molecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters compared to the number achieved with treatment with the antibiotic alone. Based on the early structure-activity relationship, 1-((2,4 dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 106-fold in both lab strains and clinical isolates of P. aeruginosa Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel antipersister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections. PMID- 28630189 TI - In Vitro Activity of Delafloxacin and Microbiological Response against Fluoroquinolone-Susceptible and Nonsusceptible Staphylococcus aureus Isolates from Two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections. AB - Delafloxacin is an investigational anionic fluoroquinolone antibiotic with broad spectrum in vitro activity, including activity against Gram-positive organisms, Gram-negative organisms, atypical organisms, and anaerobes. The in vitro activity of delafloxacin and the percent microbiological response in subjects infected with fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus isolates were determined from two global phase 3 studies of delafloxacin versus vancomycin plus aztreonam in patients with acute bacterial skin and skin structure infections (ABSSSI). Patients from 23 countries, predominately the United States but also Europe, South America, and Asia, were enrolled. The microbiological intent-to-treat (MITT) population included 1,042 patients from which 685 S. aureus isolates were submitted for identification and susceptibility testing per CLSI guidelines at the central laboratory (JMI Laboratories, North Liberty, IA). The comparator fluoroquinolone antibiotics included levofloxacin and ciprofloxacin. Nonsusceptibility to these antibiotics was determined using CLSI breakpoints. S. aureus isolates were 33.7% levofloxacin nonsusceptible (LVX NS). The delafloxacin MIC90 values against levofloxacin-nonsusceptible S. aureus, methicillin-resistant S. aureus (MRSA), and methicillin-susceptible S. aureus isolates were all 0.25 MUg/ml. Delafloxacin demonstrated high rates of microbiological response against LVX-NS isolates as well as isolates with documented mutations in the quinolone resistance-determining region (QRDR). S. aureus was eradicated or presumed eradicated in 98.4% (245/249) of delafloxacin treated patients. Similar eradication rates were observed for delafloxacin treated subjects with levofloxacin-nonsusceptible S. aureus isolates (80/81; 98.8%) and MRSA isolates (70/71; 98.6%). Microbiological response rates of 98.6% were observed with delafloxacin-treated subjects with S. aureus isolates with the S84L mutation in gyrA and the S80Y mutation in parC, the most commonly observed mutations in global phase 3 studies. The data suggest that delafloxacin could be a good option for the treatment of infections caused by S. aureus isolates causing ABSSSI, including MRSA isolates, where high rates of ciprofloxacin and levofloxacin nonsusceptibility are observed. (The phase 3 studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT01984684 and NCT01811732.). PMID- 28630190 TI - beta-Lactam Antibiotics with a High Affinity for PBP2 Act Synergistically with the FtsZ-Targeting Agent TXA707 against Methicillin-Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen that poses a significant risk to global health today. We have developed a promising new FtsZ-targeting agent (TXA707) with potent activity against MRSA isolates resistant to current standard-of-care antibiotics. We present here results that demonstrate differing extents of synergy between TXA707 and a broad range of beta-lactam antibiotics (including six cephalosporins, two penicillins, and two carbapenems) against MRSA. To explore whether there is a correlation between the extent of synergy and the preferential antibacterial target of each beta-lactam, we determined the binding affinities of the beta-lactam antibiotics for each of the four native penicillin-binding proteins (PBPs) of S. aureus using a fluorescence anisotropy competition assay. A comparison of the resulting PBP binding affinities with our corresponding synergy results reveals that beta lactams with a high affinity for PBP2 afford the greatest degree of synergy with TXA707 against MRSA. In addition, we present fluorescence and electron microscopy studies that suggest a potential mechanism underlying the synergy between TXA707 and the beta-lactam antibiotics. In this connection, our microscopy results show a disruption of septum formation in TXA707-treated MRSA cells, with a concomitant mislocalization of the PBPs from midcell to nonproductive peripheral sites. Viewed as a whole, our results indicate that PBP2-targeting beta-lactam antibiotics are optimal synergistic partners with FtsZ-targeting agents for use in combination therapy of MRSA infections. PMID- 28630191 TI - Ceftazidime-Avibactam and Aztreonam, an Interesting Strategy To Overcome beta Lactam Resistance Conferred by Metallo-beta-Lactamases in Enterobacteriaceae and Pseudomonas aeruginosa. PMID- 28630192 TI - In Vitro Activity of Aztreonam-Avibactam against Enterobacteriaceae and Pseudomonas aeruginosa Isolated by Clinical Laboratories in 40 Countries from 2012 to 2015. AB - The combination of the monobactam aztreonam and the non-beta-lactam beta lactamase inhibitor avibactam is currently in clinical development for the treatment of serious infections caused by metallo-beta-lactamase (MBL)-producing Enterobacteriaceae, a difficult-to-treat subtype of carbapenem-resistant Enterobacteriaceae for which therapeutic options are currently very limited. The present study tested clinically significant isolates of Enterobacteriaceae (n = 51,352) and Pseudomonas aeruginosa (n = 11,842) collected from hospitalized patients in 208 medical center laboratories from 40 countries from 2012 to 2015 for in vitro susceptibility to aztreonam-avibactam, aztreonam, and comparator antimicrobial agents using a standard broth microdilution methodology. Avibactam was tested at a fixed concentration of 4 MUg/ml in combination with 2-fold dilutions of aztreonam. The MIC90s of aztreonam-avibactam and aztreonam were 0.12 and 64 MUg/ml, respectively, for all Enterobacteriaceae isolates; >99.9% of all isolates and 99.8% of meropenem-nonsusceptible isolates (n = 1,498) were inhibited by aztreonam-avibactam at a concentration of <=8 MUg/ml. PCR and DNA sequencing identified 267 Enterobacteriaceae isolates positive for MBL genes (NDM, VIM, IMP); all Enterobacteriaceae carrying MBLs demonstrated aztreonam avibactam MICs of <=8 MUg/ml and a MIC90 of 1 MUg/ml. Against all P. aeruginosa isolates tested, the MIC90 of both aztreonam-avibactam and aztreonam was 32 MUg/ml; against MBL-positive P. aeruginosa isolates (n = 452), MIC90 values for aztreonam-avibactam and aztreonam were 32 and 64 MUg/ml, respectively. The current study demonstrated that aztreonam-avibactam possesses potent in vitro activity against a recent, sizeable global collection of Enterobacteriaceae clinical isolates, including isolates that were meropenem nonsusceptible, and against MBL-positive isolates of Enterobacteriaceae, for which there are few treatment options. PMID- 28630193 TI - Pyrazinamide Susceptibility and pncA Mutation Profiles of Mycobacterium tuberculosis among Multidrug-Resistant Tuberculosis Patients in Bangladesh. AB - Pyrazinamide (PZA) is a frontline antituberculosis (anti-TB) drug used in both first- and second-line treatment regimens. However, due to complex laboratory requirements, the PZA susceptibility test is rarely performed, leading to a scarcity of data on susceptibility to PZA. Bangladesh is a country with a burden of high rates of both TB and multidrug-resistant TB (MDR-TB), but to our knowledge, published data on rates of PZA susceptibility (PZAs), especially among MDR-TB patients, are limited. We aimed to analyze the PZA susceptibility patterns of Mycobacterium tuberculosis isolates from MDR-TB patients and to correlate the pncA mutation with PZA resistance in Bangladesh. A total of 169 confirmed MDR M. tuberculosis isolates from a pool of specimens collected in a nationwide surveillance study were included in this analysis. All the isolates were tested for phenotypic PZA susceptibility in Bactec mycobacterial growth indicator tube (MGIT) culture medium, and the pncA gene was sequenced. We also correlated different types of clinical information and treatment outcomes with PZA susceptibility. We found that 45% of isolates were phenotypically PZA resistant. Sequencing of the pncA gene revealed a high concordance (82.2%) between the pncA gene sequence and the phenotypic assay results. A total of 64 different mutations were found, and 9 isolates harbored multiple mutations. We detected 27 new pncA mutations. We did not find any significant correlation between the different clinical categories, the genetic lineage, or treatment outcome group and PZA susceptibility. Considering the turnaround time, sequencing would be the more feasible option to determine PZA susceptibility, and further studies to investigate the MIC of PZA should be conducted to determine an effective dose of the drug. PMID- 28630194 TI - Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers. AB - The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters +/- standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (Cmax), 44.3 +/- 7.6 and 370 +/- 61.9 MUg/ml; time to maximum concentration of drug in serum (Tmax), 1.1 +/- 0.05 and 1.08 +/- 0.01 h; volume of distribution (V), 29.7 +/- 5.7 and 31.5 +/- 10.4 liters; clearance (CL), 8.7 +/- 1.7 and 7.8 +/- 1.4 liters/h; renal clearance (CLR), 6.6 +/- 1.9 and 6.3 +/- 1.6 liters/h; area under the concentration-time curve from 0 to infinity (AUC0-infinity), 120 +/- 28.5 and 1,060 +/- 192 MUg.h/ml; and half-life (t1/2), 2.4 +/- 0.4 and 2.8 +/- 0.6 h. After oral administration, the parameters were the following: Cmax, 26.8 +/- 6.4 MUg/ml; Tmax, 2.25 +/- 0.4 h; V/F, 204 +/- 70.7 liters; CL/F, 17 +/- 4.7 liters/h; CLR, 6.5 +/- 1.8 liters/h; AUC0-infinity, 191 +/- 57.6 MUg . h/ml; and t1/2, 9.04 +/- 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1 g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis. PMID- 28630195 TI - Topical Antimicrobial Treatments Can Elicit Shifts to Resident Skin Bacterial Communities and Reduce Colonization by Staphylococcus aureus Competitors. AB - The skin microbiome is a complex ecosystem with important implications for cutaneous health and disease. Topical antibiotics and antiseptics are often employed to preserve the balance of this population and inhibit colonization by more pathogenic bacteria. However, despite their widespread use, the impact of these interventions on broader microbial communities remains poorly understood. Here, we report the longitudinal effects of topical antibiotics and antiseptics on skin bacterial communities and their role in Staphylococcus aureus colonization resistance. In response to antibiotics, cutaneous populations exhibited an immediate shift in bacterial residents, an effect that persisted for multiple days posttreatment. By contrast, antiseptics elicited only minor changes to skin bacterial populations, with few changes to the underlying microbiota. While variable in scope, both antibiotics and antiseptics were found to decrease colonization by commensal Staphylococcus spp. by sequencing- and culture-based methods, an effect which was highly dependent on baseline levels of Staphylococcus Because Staphylococcus residents have been shown to compete with the skin pathogen S. aureus, we also tested whether treatment could influence S. aureus levels at the skin surface. We found that treated mice were more susceptible to exogenous association with S. aureus and that precolonization with the same Staphylococcus residents that were previously disrupted by treatment reduced S. aureus levels by over 100-fold. In all, the results of this study indicate that antimicrobial drugs can alter skin bacterial residents and that these alterations can have critical implications for cutaneous host defense. PMID- 28630196 TI - Antimicrobial Susceptibility Trends among Staphylococcus aureus Isolates from U.S. Hospitals: Results from 7 Years of the Ceftaroline (AWARE) Surveillance Program, 2010 to 2016. AB - We evaluated trends in Staphylococcus aureus antimicrobial susceptibility in U.S. hospitals in the 2010-2016 period. A total of 21,056 clinical isolates from 42 medical centers were tested for susceptibility by broth microdilution methods. Methicillin-resistant S. aureus (MRSA) rates decreased from 50.0% (in 2010) to 42.2% (in 2016). Susceptibility to erythromycin, levofloxacin, and clindamycin increased slightly, whereas susceptibility to ceftaroline, trimethoprim sulfamethoxazole, and tetracycline remained stable. Ceftaroline retained potent activity against methicillin-susceptible S. aureus (MSSA) and MRSA (97.2% susceptible) with no marked variations. PMID- 28630197 TI - Pharmacodynamics of Cefepime Combined with Tazobactam against Clinically Relevant Enterobacteriaceae in a Neutropenic Mouse Thigh Model. AB - The lack of new antibiotics has prompted investigation of the combination of two existing agents-cefepime, a broad-spectrum cephalosporin, and tazobactam-to broaden their efficacy against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae We determined the pharmacokinetic (PK) and pharmacodynamic (PD) properties of the combination in a murine neutropenic thigh model in order to establish its exposure-response relationships (ERRs). The PK of cefepime were determined for five doses; that of tazobactam was determined in earlier studies (Melchers et al., Antimicrob Agents Chemother 59:3373-3376, 2015, https://doi.org/10.1128/AAC.04402-14). The PK were linear for both compounds. The estimated mean (standard deviation [SD]) half-life of cefepime was 0.33 (0.12) h, and that of tazobactam was 0.176 (0.026) h; the volumes of distribution (V) were 0.73 liters/kg and 1.14 liters/kg, respectively. PD studies of cefepime administered every 2 h (q2h) with or without tazobactam, including dose fractionation studies of tazobactam, were performed against six ESBL-producing isolates. A sigmoidal maximum-effect (Emax) model was fitted to the data. In the dose fractionation study, the q2h regimen was more efficacious than the q4h and q6h regimens, indicating time-dependent activity of tazobactam. The threshold concentration (CT ) best correlating with tazobactam efficacy was 0.25 mg/liter, as evidenced by the best fit of the percentage of time above the threshold concentration (%fT>CT ) and response. A mean %fT>CT of 24.6% (range, 11.4 to 36.3%) for a CT of 0.25 mg/liter was required to obtain a bacteriostatic effect. We conclude that tazobactam enhanced the effect of cefepime in otherwise resistant isolates of Enterobacteriaceae and that the %fT>CT of 0.25 mg/liter best correlated with efficacy. These studies provide the basis for the development of human dosing regimens for this combination. PMID- 28630198 TI - Genome Evolution to Penicillin Resistance in Serotype 3 Streptococcus pneumoniae by Capsular Switching. AB - Streptococcus pneumoniae isolates of serotype 3 were collected from cases of invasive pneumococcal disease (n = 124) throughout Japan between April 2010 and March 2013. A penicillin-resistant S. pneumoniae (PRSP) isolate from an adult patient, strain KK0981 of serotype 3, was identified among these strains. Whole genome analysis characterized this PRSP as a recombinant strain derived from PRSP of serotype 23F with the cps locus (20.3 kb) replaced by that of a penicillin susceptible strain of serotype 3. PMID- 28630199 TI - Genomewide Analysis of the Antimicrobial Peptides in Python bivittatus and Characterization of Cathelicidins with Potent Antimicrobial Activity and Low Cytotoxicity. AB - In this study, we sought to identify novel antimicrobial peptides (AMPs) in Python bivittatus through bioinformatic analyses of publicly available genome information and experimental validation. In our analysis of the python genome, we identified 29 AMP-related candidate sequences. Of these, we selected five cathelicidin-like sequences and subjected them to further in silico analyses. The results showed that these sequences likely have antimicrobial activity. The sequences were named Pb-CATH1 to Pb-CATH5 according to their sequence similarity to previously reported snake cathelicidins. We predicted their molecular structure and then chemically synthesized the mature peptide for three putative cathelicidins and subjected them to biological activity tests. Interestingly, all three peptides showed potent antimicrobial effects against Gram-negative bacteria but very weak activity against Gram-positive bacteria. Remarkably, DeltaPb-CATH4 showed potent activity against antibiotic-resistant clinical isolates and also was observed to possess very low hemolytic activity and cytotoxicity. DeltaPb CATH4 also showed considerable serum stability. Electron microscopic analysis indicated that DeltaPb-CATH4 exerts its effects via toroidal pore preformation. Structural comparison of the cathelicidins identified in this study to previously reported ones revealed that these Pb-CATHs are representatives of a new group of reptilian cathelicidins lacking the acidic connecting domain. Furthermore, Pb CATH4 possesses a completely different mature peptide sequence from those of previously described reptilian cathelicidins. These new AMPs may be candidates for the development of alternatives to or complements of antibiotics to control multidrug-resistant pathogens. PMID- 28630200 TI - Pharmacodynamics and Biodistribution of Single-Dose Liposomal Amphotericin B at Different Stages of Experimental Visceral Leishmaniasis. AB - Visceral leishmaniasis is a neglected tropical disease that causes significant morbidity and mortality worldwide. Characterization of the pharmacokinetics and pharmacodynamics of antileishmanial drugs in preclinical models is important for drug development and use. Here we investigated the pharmacodynamics and drug distribution of liposomal amphotericin B (AmBisome) in Leishmania donovani infected BALB/c mice at three different dose levels and two different time points after infection. We additionally compared drug levels in plasma, liver, and spleen in infected and uninfected BALB/c mice over time. At the highest administered dose of 10 mg/kg AmBisome, >90% parasite inhibition was observed within 2 days after drug administration, consistent with drug distribution from blood to tissue within 24 h and a fast rate of kill. Decreased drug potency was observed in the spleen when AmBisome was administered on day 35 after infection, compared to day 14 after infection. Amphotericin B concentrations and total drug amounts per organ were lower in liver and spleen when AmBisome was administered at the advanced stage of infection and compared to those in uninfected BALB/c mice. However, the magnitude of difference was lower when total drug amounts per organ were estimated. Differences were also noted in drug distribution to L. donovani-infected livers and spleens. Taken together, our data suggest that organ enlargement and other pathophysiological factors cause infection- and organ specific drug distribution and elimination after administration of single-dose AmBisome to L. donovani-infected mice. Plasma drug levels were not reflective of changes in drug levels in tissues. PMID- 28630201 TI - Combined Effect of the Cfr Methyltransferase and Ribosomal Protein L3 Mutations on Resistance to Ribosome-Targeting Antibiotics. AB - Several groups of antibiotics inhibit bacterial growth by binding to bacterial ribosomes. Mutations in ribosomal protein L3 have been associated with resistance to linezolid and tiamulin, which both bind at the peptidyl transferase center in the ribosome. Resistance to these and other antibiotics also occurs through methylation of 23S rRNA at position A2503 by the methyltransferase Cfr. The mutations in L3 and the cfr gene have been found together in clinical isolates, raising the question of whether they have a combined effect on antibiotic resistance or growth. We transformed a plasmid-borne cfr gene into a uL3-depleted Escherichia coli strain containing either wild-type L3 or L3 with one of seven mutations, G147R, Q148F, N149S, N149D, N149R, Q150L, or T151P, expressed from plasmid-carried rplC genes. The L3 mutations are well tolerated, with small to moderate growth rate decreases. The presence of Cfr has a very minor influence on the growth rate. The resistance of the transformants to linezolid, tiamulin, florfenicol, and Synercid (a combination of quinupristin and dalfopristin [Q-D]) was measured by MIC assays. The resistance from Cfr was, in all cases, stronger than the effects of the L3 mutations, but various effects were obtained with the combinations of Cfr and L3 mutations ranging from a synergistic to an antagonistic effect. Linezolid and tiamulin susceptibility varied greatly among the L3 mutations, while no significant effects on florfenicol and Q-D susceptibility were seen. This study underscores the complex interplay between various resistance mechanisms and cross-resistance, even from antibiotics with overlapping binding sites. PMID- 28630202 TI - Identifying Spectra of Activity and Therapeutic Niches for Ceftazidime-Avibactam and Imipenem-Relebactam against Carbapenem-Resistant Enterobacteriaceae. AB - We determined imipenem, imipenem-relebactam, ceftazidime, and ceftazidime avibactam MICs against 100 CRE isolates that underwent whole-genome sequencing. Klebsiella pneumoniae carbapenemases (KPCs) were the most common carbapenemases. Forty-six isolates carried extended-spectrum beta-lactamases (ESBLs). With the addition of relebactam, imipenem susceptibility increased from 8% to 88%. With the addition of avibactam, ceftazidime susceptibility increased from 0% to 85%. Neither imipenem-relebactam nor ceftazidime-avibactam was active against metallo beta-lactamase (MBL) producers. Ceftazidime-avibactam (but not imipenem relebactam) was active against OXA-48-like producers, including a strain not harboring any ESBL. Major OmpK36 porin mutations were independently associated with higher imipenem-relebactam MICs (P < 0.0001) and showed a trend toward independent association with higher ceftazidime-avibactam MICs (P = 0.07). The presence of variant KPC-3 was associated with ceftazidime-avibactam resistance (P < 0.0001). In conclusion, imipenem-relebactam and ceftazidime-avibactam had overlapping spectra of activity and niches in which each was superior. Major OmpK36 mutations in KPC-K. pneumoniae may provide a foundation for stepwise emergence of imipenem-relebactam and ceftazidime-avibactam resistance. PMID- 28630203 TI - Bactericidal and Sterilizing Activity of a Novel Regimen with Bedaquiline, Pretomanid, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis. AB - New regimens based on 2 or more novel agents are sought to shorten or to simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) plus pretomanid (PMD) plus pyrazinamide (PZA) and PMD plus moxifloxacin (MXF) plus PZA shortened the treatment duration necessary to prevent relapse by 2 to 3 months and 1 to 2 months, respectively, compared with the current first-line regimen, in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQ+PMD+MXF+PZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored, to identify the optimal regimens and treatment times and to estimate the likelihood of success against drug-resistant strains. BDQ+PMD+MXF+PZA rendered all mice relapse-free after 2 months of treatment. PZA administration could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA, or BDQ administration from the beginning necessitated approximately 0.5, 1, or 2 months, respectively, of additional treatment to attain the same outcome. PMID- 28630204 TI - A Low-Molecular-Weight Alginate Oligosaccharide Disrupts Pseudomonal Microcolony Formation and Enhances Antibiotic Effectiveness. AB - In chronic respiratory disease, the formation of dense, 3-dimensional "microcolonies" by Pseudomonas aeruginosa within the airway plays an important role in contributing to resistance to treatment. An in vitro biofilm model of pseudomonal microcolony formation using artificial-sputum (AS) medium was established to study the effects of low-molecular-weight alginate oligomers (OligoG CF-5/20) on pseudomonal growth, microcolony formation, and the efficacy of colistin. The studies employed clinical cystic fibrosis (CF) isolates (n = 3) and reference nonmucoid and mucoid multidrug-resistant (MDR) CF isolates (n = 7). Bacterial growth and biofilm development and disruption were studied using cell viability assays and image analysis with scanning electron and confocal laser scanning microscopy. Pseudomonal growth in AS medium was associated with increased ATP production (P < 0.05) and the formation (at 48 h) of discrete (>10 MUm) microcolonies. In conventional growth medium, colistin retained an ability to inhibit growth of planktonic bacteria, although the MIC was increased (0.1 to 0.4 MUg/ml) in AS medium compared to Mueller-Hinton (MH) medium. In contrast, in an established-biofilm model in AS medium, the efficacy of colistin was decreased. OligoG CF-5/20 (>=2%) treatment, however, induced dose-dependent biofilm disruption (P < 0.05) and led to colistin retaining its antimicrobial activity (P < 0.05). While circular dichroism indicated that OligoG CF-5/20 did not change the orientation of the alginate carboxyl groups, mass spectrometry demonstrated that the oligomers induced dose-dependent (>0.2%; P < 0.05) reductions in pseudomonal quorum-sensing signaling. These findings reinforce the potential clinical significance of microcolony formation in the CF lung and highlight a novel approach to treat MDR pseudomonal infections. PMID- 28630205 TI - Impact of gyrB and eis Mutations in Improving Detection of Second-Line-Drug Resistance among Mycobacterium tuberculosis Isolates from Georgia. AB - The country of Georgia has a high burden of multi- and extensively drug-resistant tuberculosis (XDR-TB). To evaluate whether mutations in gyrB and eis genes increased the sensitivity of detection of phenotypic resistance to ofloxacin and kanamycin or capreomycin compared to use of the first-generation MTBDRsl assay alone, which tests for mutations in gyrA and rrs genes, a retrospective study of stored Mycobacterium tuberculosis isolates was performed. All isolates underwent DNA sequencing of resistance-determining regions. Among 112 M. tuberculosis isolates with DNA extraction data, targeted sequencing was successfully performed for each gene as follows: for gyrA, 98% sensitivity; for gyrB, 96%; for rrs, 93%; for the eis gene and its promoter, 93%. The specificity and hence the positive predictive value of gyrA and gyrB mutations for detecting ofloxacin resistance were 100%. The addition of gyrB mutations increased the sensitivity of phenotypic ofloxacin resistance detection by 13% (75% to 88%). All rrs resistance-conferring mutations were A1401G, and this mutation had low sensitivity (40% and 18%) and high specificity (95% and 100%) in predicting phenotypic capreomycin and kanamycin resistance, respectively. The eis C-14T mutation increased the sensitivity of phenotypic kanamycin resistance detection by 9% (18% to 27%) and was found solely in kanamycin phenotypic resistance isolates. Our data showed that the inclusion of eis C-14T and gyrB mutations in addition to rrs and gyrA mutations improves the sensitivity of detection of phenotypic ofloxacin and kanamycin resistance, respectively. PMID- 28630207 TI - Of Mice and Man and the Regulation of Aldosterone Secretion. PMID- 28630208 TI - Telomeres and Atherosclerosis: The Intricate Pursuit of Mechanistic Insight Through Epidemiology. PMID- 28630206 TI - Rapid and Consistent Evolution of Colistin Resistance in Extensively Drug Resistant Pseudomonas aeruginosa during Morbidostat Culture. AB - Colistin is a last-resort antibiotic commonly used against multidrug-resistant strains of Pseudomonas aeruginosa To investigate the potential for in situ evolution of resistance against colistin and to map the molecular targets of colistin resistance, we exposed two P. aeruginosa isolates to colistin using a continuous-culture device known as a morbidostat. As a result, colistin resistance reproducibly increased 10-fold within 10 days and 100-fold within 20 days, along with highly stereotypic yet strain-specific mutation patterns. The majority of mutations hit the pmrAB two-component signaling system and genes involved in lipopolysaccharide (LPS) synthesis, including lpxC, pmrE, and migA We tracked the frequencies of all arising mutations by whole-genome deep sequencing every 3 to 4 days to obtain a detailed picture of the dynamics of resistance evolution, including competition and displacement among multiple resistant subpopulations. In 7 out of 18 cultures, we observed mutations in mutS along with a mutator phenotype that seemed to facilitate resistance evolution. PMID- 28630209 TI - Functional TASK-3-Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells. AB - Ca2+ drives aldosterone synthesis in the cytosolic and mitochondrial compartments of the adrenal zona glomerulosa cell. Membrane potential across each of these compartments regulates the amplitude of the Ca2+ signal; yet, only plasma membrane ion channels and their role in regulating cell membrane potential have garnered investigative attention as pathological causes of human hyperaldosteronism. Previously, we reported that genetic deletion of TASK-3 channels (tandem pore domain acid-sensitive K+ channels) from mice produces aldosterone excess in the absence of a change in the cell membrane potential of zona glomerulosa cells. Here, we report using yeast 2-hybrid, immunoprecipitation, and electron microscopic analyses that TASK-3 channels are resident in mitochondria, where they regulate mitochondrial morphology, mitochondrial membrane potential, and aldosterone production. This study provides proof of principle that mitochondrial K+ channels, by modulating inner mitochondrial membrane morphology and mitochondrial membrane potential, have the ability to play a pathological role in aldosterone dysregulation in steroidogenic cells. PMID- 28630210 TI - Short Telomeres, but Not Telomere Attrition Rates, Are Associated With Carotid Atherosclerosis. AB - Short telomeres are associated with atherosclerosis. However, the temporal relationship between atherosclerosis and telomere length is unclear. The objective of this work was to examine the temporal formation and progression of carotid atherosclerotic plaques in relation to telomere dynamics. In a longitudinal study, comprising 154 French men and women (aged 31-76 years at baseline), carotid plaques were quantified by echography, and telomere length on leucocytes was measured by Southern blots at baseline and follow-up examinations. Telomere attrition rates during the 9.5-year follow-up period were not different in individuals with plaques at both baseline and follow-up examinations (23.3+/ 2.0 base pairs/y) than in individuals who developed plaques during the follow-up period (26.5+/-2.0 base pairs/y) and those without plaques at either baseline or follow-up examination (22.5+/-2.3 base pairs/y; P=0.79). At baseline, telomere length was associated with presence of carotid plaques (P=0.02) and with the number of regions with plaques (P=0.005). An interaction (P=0.03) between age and the presence of plaques was observed, such that the association between plaques and telomere length was more pronounced at a younger age. In conclusion, carotid atherosclerosis is not associated with increased telomere attrition during a 9.5 year follow-up period. Short telomere length is more strongly associated with early-onset than late-onset carotid atherosclerosis. Our results support the thesis that heightened telomere attrition during adult life might not explain the short telomeres observed in subjects with atherosclerotic disease. Rather, short telomeres antecedes the clinical manifestation of the disease. PMID- 28630213 TI - Dose-Finding Methods: Moving Away from the 3 + 3 to Include Richer Outcomes. AB - The most commonly used method for dose finding, the 3 + 3, has poor performance. New adaptive designs are more efficient. Nevertheless, they have reached a maximum performance level, and further improvement requires either larger sample sizes or outcomes measures richer than the simplistic severe toxicity measured at cycle 1. Clin Cancer Res; 23(15); 3977-9. (c)2017 AACRSee related article by Yan et al., p. 3994. PMID- 28630211 TI - Recent Advances in Hypertension and Cardiovascular Toxicities With Vascular Endothelial Growth Factor Inhibition. PMID- 28630212 TI - A Pilot Study of Stereotactic Body Radiation Therapy Combined with Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma. AB - Purpose: While stereotactic body radiotherapy (SBRT) can reduce tumor volumes in patients with metastatic renal cell carcinoma (mRCC), little is known regarding the immunomodulatory effects of high-dose radiation in the tumor microenvironment. The main objectives of this pilot study were to assess the safety and feasibility of nephrectomy following SBRT treatment of patients with mRCC and analyze the immunological impact of high-dose radiation.Experimental Design: Human RCC cell lines were irradiated and evaluated for immunomodulation. In a single-arm feasibility study, patients with mRCC were treated with 15 Gray SBRT at the primary lesion in a single fraction followed 4 weeks later by cytoreductive nephrectomy. RCC specimens were analyzed for tumor-associated antigen (TAA) expression and T-cell infiltration. The trial has reached accrual (ClinicalTrials.gov identifier: NCT01892930).Results: RCC cells treated in vitro with radiation had increased TAA expression compared with untreated tumor cells. Fourteen patients received SBRT followed by surgery, and treatment was well tolerated. SBRT-treated tumors had increased expression of the immunomodulatory molecule calreticulin and TAA (CA9, 5T4, NY-ESO-1, and MUC-1). Ki67+ proliferating CD8+ T cells and FOXP3+ cells were increased in SBRT-treated patient specimens in tumors and at the tumor-stromal interface compared with archived patient specimens.Conclusions: It is feasible to perform nephrectomy following SBRT with acceptable toxicity. Following SBRT, patient RCC tumors have increased expression of calreticulin, TAA, as well as a higher percentage of proliferating T cells compared with archived RCC tumors. Collectively, these studies provide evidence of immunomodulation following SBRT in mRCC. Clin Cancer Res; 23(17); 5055-65. (c)2017 AACR. PMID- 28630214 TI - Patient-derived Interstitial Fluids and Predisposition to Aggressive Sporadic Breast Cancer through Collagen Remodeling and Inactivation of p53. AB - Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors.Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells.Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53 mutant knock-in mice, IFHigh promotes spontaneous tumor formation.Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446-59. (c)2017 AACR. PMID- 28630215 TI - Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer. AB - Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors.Results: The FGFR inhibitor-resistant cells were cross resistant and characterized by sustained MAPK pathway activation. In drug resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. Clin Cancer Res; 23(18); 5527-36. (c)2017 AACR. PMID- 28630216 TI - Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates. AB - Purpose: To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBDs) antibody drug conjugates (ADCs) without compromising antitumor activity.Experimental Design: A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models. The exposure-activity relationship was investigated in mouse xenograft models of human prostate cancer, breast cancer, and gastric cancer by comparing antitumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer. The exposure-tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys).Results: Observations of similar antitumor activity in mice treated with single or fractionated dosing suggests that antitumor activity of PBD ADCs is more closely related to total exposure (AUC) than peak drug concentrations (Cmax). In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with Cmax than AUC.Conclusions: We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy. These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further. Clin Cancer Res; 23(19); 5858-68. (c)2017 AACR. PMID- 28630218 TI - Mistaken identity: haemoglobinuria secondary to paravalvular leak masking as haematuria. AB - Haemolytic anaemia caused by a paravalvular leak presenting as progressively worsening red urine. Haemoglobinuria was easily mistaken for gross haematuria, resulting in extensive invasive urological investigation that proved to be futile. Further investigation following an emergency admission led to the realisation that intravascular haemolysis secondary to a paravalvular leaka?"presenting 43 years following metallic valve insertiona?"was the cause of discoloured urine and newly presenting symptomatic anaemia. This case highlights that there remains other causes of what often appears to be haematuria, and further exploration of alternative causes should be considered when no urological cause is found. PMID- 28630219 TI - A Rare Case Of Sigmoid Colon Perforation With Subsequent Psoas Abscess Collection With Extensive Involvement Of The Sartorius Muscle. AB - A middle-aged man was admitted with worsening hip pain, fevers and reduced mobility. These symptoms were preceded by a mechanical fall but despite regular analgesia, symptoms did not resolve. His prior medical history included ischaemic heart disease, hypertension and hypercholesterolaemia. A trauma and orthopaedic review revealed a painful left hip with reduced range of motion. In addition, some mild tenderness in the left iliac fossa was noted. Blood tests revealed markedly raised inflammatory markers. Plain radiographs and ultrasound were normal. MRI scan found a massive left iliopsoas collection secondary to perforated diverticular disease of the sigmoid colon. The patient was managed with intravenous antibiotics and the collection was drained percutaneously. Approximately 500 mL of pus was aspirated. The patient made an excellent recovery with interval imaging showing a reduction in the collection size. PMID- 28630217 TI - Effectiveness of conservative interventions including exercise, manual therapy and medical management in adults with shoulder impingement: a systematic review and meta-analysis of RCTs. AB - OBJECTIVE: To investigate the effectiveness of conservative interventions for pain, function and range of motion in adults with shoulder impingement. DESIGN: Systematic review and meta-analysis of randomised trials. DATA SOURCES: Medline, CENTRAL, CINAHL, Embase and PEDro were searched from inception to January 2017. STUDY SELECTION CRITERIA: Randomised controlled trials including participants with shoulder impingement and evaluating at least one conservative intervention against sham or other treatments. RESULTS: For pain, exercise was superior to non exercise control interventions (standardised mean difference (SMD) -0.94, 95% CI 1.69 to -0.19). Specific exercises were superior to generic exercises (SMD -0.65, 95% CI -0.99 to -0.32). Corticosteroid injections were superior to no treatment (SMD -0.65, 95% CI -1.04 to -0.26), and ultrasound guided injections were superior to non-guided injections (SMD -0.51, 95% CI -0.89 to -0.13). Nonsteroidal anti-inflammatory drugs (NSAIDS) had a small to moderate SMD of 0.29 (95% CI -0.53 to -0.05) compared with placebo. Manual therapy was superior to placebo (SMD -0.35, 95% CI -0.69 to -0.01). When combined with exercise, manual therapy was superior to exercise alone, but only at the shortest follow-up (SMD -0.32, 95% CI -0.62 to -0.01). Laser was superior to sham laser (SMD -0.88, 95% CI -1.48 to -0.27). Extracorporeal shockwave therapy (ECSWT) was superior to sham (-0.39, 95% CI -0.78 to -0.01) and tape was superior to sham (-0.64, 95% CI 1.16 to -0.12), with small to moderate SMDs. CONCLUSION: Although there was only very low quality evidence, exercise should be considered for patients with shoulder impingement symptoms and tape, ECSWT, laser or manual therapy might be added. NSAIDS and corticosteroids are superior to placebo, but it is unclear how these treatments compare to exercise. PMID- 28630220 TI - Beyond cervical lipomas: myoclonus, gait disorder and multisystem involvement leading to mitochondrial disease. AB - Madelung's disease (benign symmetric lipomatosis) is a rare syndrome in which there are multiple lipomas around the neck, upper limbs and trunk in the context of chronic alcoholism. We report on a female patient with lipomas and slightly progressive myoclonus, neuropathy, myopathy, ataxia and respiratory systemic involvement (labelled in the past as Madelung's disease). Multisystem involvement and family history of lipomas led to the development of mitochondrial genetic tests, which can assess two concurrent mitochondrial mutations: the m.8344A>G mutation in MT-TK gene, related MERRF (myoclonic epilepsy with ragged-red fibre) phenotype and m.14484T>C mutation in the MT-ND6 gene responsible for Leber hereditary optic neuropathy phenotype. PMID- 28630221 TI - Retrorectal tumour simulating vaginal birth: an exceptional case of emergency surgery indication. AB - Cystic retrorectal tumours are a very rare entity that pose a problem in differential diagnosis between congenital cyst and other lesions. We present a 49 year-old female patient presenting a perineal bulge which was discovered simulating a vaginal birth associated with prolapsed haemorrhoids grade IV. The interest of this case resides in the surgical indication of a big presacral cyst demonstrated via CT causing acute intense pain due to pelvic organ compression, as no emergent surgery management has been reported up to date. PMID- 28630222 TI - Acute pneumatosis cystoides intestinalis with atrophic desmosis of the colon in a child. AB - Acute pneumatosis cystoides intestinalis (PCI) has been described after bone marrow transplantation (BMT). Several case series have demonstrated successful conservative treatment of PCI in children. We present a child with Fanconi anaemia, who developed severe graft versus host disease of the gastrointestinal tract, skin and liver after BMT and an acute, severe form of PCI. Our case report illustrates the complexity of diagnostic and therapeutic procedures in PCI in immunocompromised children. PMID- 28630223 TI - Imaging findings in Steidele's complex. PMID- 28630224 TI - Successful conservative treatment of severe frostbite lesions in a Greenlandic Inuit. AB - Frostbite may cause lesions. The severity ranges from superficial wounds to severe cases with loss of limbs and tissue. Hence, proper treatment is of utmost importance. We present a case of an 18-year-old man from Arctic Greenland who was admitted with severe frostbite lesions involving both hands. The patient had fallen asleep outside during extreme temperatures. He was treated conservatively with proper wound care, antibiotics and intensive physical therapy. The patient made a full recovery without sequelae. The current report emphasises that non operative treatment should be attempted for frostbite lesions, as conservative treatment often results in good outcomes. PMID- 28630225 TI - Lipoma of right pyriform sinus. AB - We present a case of large mass arising from the right pyriform sinus extending inferiorly to the postcricoid area and superiorly to the right aryepiglottic fold causing a foreign body sensation and obstructive symptoms, its histological examination following the endoscopic surgical excision showed a lipoma. We are also describing the endoscopic, radiological and intraoperative findings with a brief literature review. PMID- 28630226 TI - Thyrotoxic periodic paralysis as an initial presentation of Graves' disease in a Saudi patient. AB - Thyrotoxic periodic paralysis (TPP) is a well-known complication of hyperthyroidism, characterised by recurrent flaccid paralysis with hypokalaemia. To date, only five cases of this rare disorder have been reported in Saudi Arabia. Here, we report an additional case involving a 25-year-old Saudi man who presented with lower limb paralysis and severe hypokalaemia. Clinically, he showed symptoms and signs suggestive of Graves' disease, which was confirmed by laboratory investigations. Carbimazole, a beta-blocker and potassium replacement were administered, resulting in dramatic improvement of the TTP. This case emphasises the importance of considering TPP in patients with acute muscle weakness and the importance of promptly initiating treatment and preventing relapse of TPP. PMID- 28630227 TI - 'Carbuncle in diabetes': a problem even today! PMID- 28630228 TI - The "Achilles' Heel" of Cancer and Its Implications for the Development of Novel Immunotherapeutic Strategies. AB - Over the last century, scientists have embraced the idea of mobilizing antitumor immune responses in patients with cancer. In the last decade, we have seen the rebirth of cancer immunotherapy and its validation in a series of high profile clinical trials following the discovery of several immune-regulatory receptors. Recent studies point toward the tumor mutational load and resulting neoantigen burden as being crucial to tumor cell recognition by the immune system, highlighting a potentially targetable Achilles' heel in cancer. In this review, we explore the key mechanisms that underpin the recognition of cancerous cells by the immune system and discuss how we may advance immunotherapeutic strategies to target the cancer mutanome to stimulate tumor-specific immune responses, ultimately, to improve the clinical outcome for patients with cancer. PMID- 28630229 TI - Observing Clonal Dynamics across Spatiotemporal Axes: A Prelude to Quantitative Fitness Models for Cancer. AB - The ability to accurately model evolutionary dynamics in cancer would allow for prediction of progression and response to therapy. As a prelude to quantitative understanding of evolutionary dynamics, researchers must gather observations of in vivo tumor evolution. High-throughput genome sequencing now provides the means to profile the mutational content of evolving tumor clones from patient biopsies. Together with the development of models of tumor evolution, reconstructing evolutionary histories of individual tumors generates hypotheses about the dynamics of evolution that produced the observed clones. In this review, we provide a brief overview of the concepts involved in predicting evolutionary histories, and provide a workflow based on bulk and targeted-genome sequencing. We then describe the application of this workflow to time series data obtained for transformed and progressed follicular lymphomas (FL), and contrast the observed evolutionary dynamics between these two subtypes. We next describe results from a spatial sampling study of high-grade serous (HGS) ovarian cancer, propose mechanisms of disease spread based on the observed clonal mixtures, and provide examples of diversification through subclonal acquisition of driver mutations and convergent evolution. Finally, we state implications of the techniques discussed in this review as a necessary but insufficient step on the path to predictive modelling of disease dynamics. PMID- 28630230 TI - Urine Ammonium and Preclinical Acidosis in CKD. PMID- 28630231 TI - Understanding Medication Nonadherence after Kidney Transplant. AB - Alloimmunity remains a barrier to long-term graft survival that necessitates lifelong immunosuppressive therapy after renal transplant. Medication nonadherence has been increasingly recognized as a major impediment to achieving effective immunosuppression. Electronic medication monitoring further reveals that nonadherence manifests early after transplant, although the effect is delayed. The etiology of nonadherence is multifactorial, with the strongest risk factors including past nonadherence and being an adolescent or young adult. Other risk factors with smaller but consistently important effects include minority race/ethnicity, poor social supports, and poor perceived health. In children, risk factors related to parental and child psychologic and behavioral functioning and parental distress and burden are also important. Qualitative systematic reviews highlight the need to tailor interventions to each transplant recipient's unique needs, motivations, and barriers rather than offer a one size fits all approach. To date, relatively few interventions have been studied, and most studies conducted were underpowered to allow definitive conclusions. If the kidney transplant community's goal of "one transplant for life" is to become a reality, then solutions for medication nonadherence must be found and implemented. PMID- 28630232 TI - Long Noncoding RNA H19 Promotes Neuroinflammation in Ischemic Stroke by Driving Histone Deacetylase 1-Dependent M1 Microglial Polarization. AB - BACKGROUND AND PURPOSE: Long noncoding RNA H19 is repressed after birth, but can be induced by hypoxia. We aim to investigate the impact on and underlying mechanism of H19 induction after ischemic stroke. METHODS: Circulating H19 levels in stroke patients and mice subjected to middle cerebral artery occlusion were assessed using real-time polymerase chain reaction. H19 siRNA and histone deacetylase 1 (HDAC1) plasmid were used to knock down H19 and overexpress HDAC1, respectively. Microglial polarization and ischemic outcomes were assessed in middle cerebral artery occlusion mice and BV2 microglial cells subjected to oxygen-glucose deprivation. RESULTS: Circulating H19 levels were significantly higher in stroke patients compared with healthy controls, indicating high diagnostic sensitivity and specificity. Moreover, plasma H19 levels showed a positive correlation with National Institute of Health Stroke Scale score and tumor necrosis factor-alpha levels. After middle cerebral artery occlusion in mice, H19 levels increased in plasma, white blood cells, and brain. Intracerebroventricular injection of H19 siRNA reduced infarct volume and brain edema, decreased tumor necrosis factor-alpha and interleukin-1beta levels in brain tissue and plasma, and increased plasma interleukin-10 concentrations 24 hours poststroke. Additionally, H19 knockdown attenuated brain tissue loss and neurological deficits 14 days poststroke. BV2 cell-based experiments showed that H19 knockdown blocked oxygen-glucose deprivation-driven M1 microglial polarization, decreased production of tumor necrosis factor-alpha and CD11b, and increased the expression of Arg-1 and CD206. Furthermore, H19 knockdown reversed oxygen-glucose deprivation-induced upregulation of HDAC1 and downregulation of acetyl-histone H3 and acetyl-histone H4. In contrast, HDAC1 overexpression negated the effects of H19 knockdown. CONCLUSIONS: Our findings indicate that H19 promotes neuroinflammation by driving HDAC1-dependent M1 microglial polarization, suggesting a novel H19-based diagnosis and therapy for ischemic stroke. PMID- 28630233 TI - Motor Recovery Prediction With Clinical Assessment and Local Diffusion Homogeneity After Acute Subcortical Infarction. AB - BACKGROUND AND PURPOSE: Initial clinical assessment or conventional diffusion tensor imaging parameters alone do not reliably predict poststroke recovery of motor function. Recently, local diffusion homogeneity (LDH) has been proposed to represent the local coherence of water molecule diffusion and can serve as a complementary marker for investigating white matter alterations of the brain. We aimed to determine whether a combination of initial clinical assessment and LDH could predict motor recovery after acute subcortical infarction. METHODS: Standard upper extremity Fugl-Meyer assessment and diffusion tensor imaging were performed 1, 4, and 12 weeks after onset in 50 patients with subcortical infarction. Proportional recovery model residuals were used to assign patients to proportional recovery and poor recovery groups. Tract-based spatial statistics analysis was used to compare diffusion differences between proportional and poor recovery outcomes. Multivariate logistic regression model was used to identify the predictors of motor improvement within 12 weeks after stroke. RESULTS: The poor recovery group had lower LDH than the proportional recovery group, mainly in the ipsilesional corticospinal tract in the superior corona radiate and posterior limb of internal capsule 1 week after stroke (P<0.005; family-wise error corrected). Multivariate logistic regression analysis indicated that both initial Fugl-Meyer assessment and LDH in the ipsilesional corticospinal tract in the superior corona radiate and posterior limb of internal capsule were predictors of motor improvement within 12 weeks after stroke (G=47.22; P<0.001). Leave-one-out cross-validation confirmed a positive predictive value of 0.818, a negative predictive value of 0.833, and an accuracy of 0.824 (P<0.00 001; permutation test). CONCLUSIONS: These results suggest that a combination of clinical assessment and LDH in the ipsilesional corticospinal tract in the acute phase can accurately predict resolution of upper limb impairment within 12 weeks after subcortical infarction. PMID- 28630234 TI - Multiparametric Model for Penumbral Flow Prediction in Acute Stroke. AB - BACKGROUND AND PURPOSE: Identification of salvageable penumbra tissue by dynamic susceptibility contrast magnetic resonance imaging is a valuable tool for acute stroke patient stratification for treatment. However, prior studies have not attempted to combine the different perfusion maps into a predictive model. In this study, we established a multiparametric perfusion imaging model and cross validated it using positron emission tomography perfusion for detection of penumbral flow. METHODS: In a retrospective analysis of 17 subacute stroke patients with consecutive magnetic resonance imaging and H2O15 positron emission tomography scans, perfusion maps of cerebral blood flow, cerebral blood volume, mean transit time, time-to-maximum, and time-to-peak were constructed and combined using a generalized linear model (GLM). Both the GLM maps and the single perfusion maps alone were cross-validated with positron emission tomography cerebral blood flow scans to predict penumbral flow on a voxel-wise level. Performance was tested by receiver-operating characteristics curve analysis, that is, the area under the curve, and the models' fits were compared using the likelihood ratio test. RESULTS: The GLM demonstrated significantly improved model fit compared with each of the single perfusion maps (P<1*e-5) and demonstrated higher performance, with an area under the curve of 0.91. However, the absolute difference between the performance of GLM and the best-performing single perfusion parameter (time-to-maximum) was relatively low (area under the curve difference =0.04). CONCLUSIONS: Our results support a dynamic susceptibility contrast magnetic resonance imaging-based GLM as an improved model for penumbral flow prediction in stroke patients. With given perfusion maps, this model is a straightforward and observer-independent alternative for therapy stratification. PMID- 28630235 TI - Ultrasound Markers of Carotid Atherosclerosis and Cognition: The Northern Manhattan Study. AB - BACKGROUND AND PURPOSE: Ultrasound markers of carotid atherosclerosis may be related to cognitive status. We hypothesized that individuals with greater carotid intima-media thickness (cIMT) and carotid plaque burden would exhibit worse cognition. METHODS: One thousand one hundred sixty-six stroke-free participants from the NOMAS (Northern Manhattan Study) underwent carotid ultrasound and neuropsychological examination. Among them, 826 underwent a second neuropsychological examination an average of 5 years later. cIMT and plaque were assessed by a standardized B-mode ultrasound imaging and reading protocol. We used multivariable linear regression to examine cIMT, carotid plaque presence, and carotid plaque area as correlates of domain-specific neuropsychological Z scores cross-sectionally and over time. We also investigated possible effect modification by APOE epsilon4 allele, age, and race/ethnicity. RESULTS: Participants had a mean (SD) age of 70 (9) years and were 60% women, 66% Hispanic, 15% white, and 18% black. Those with greater cIMT exhibited worse episodic memory after adjustment for demographics and vascular risk factors (beta=-0.60; P=0.04). APOE epsilon4 carriers with greater cIMT exhibited worse episodic memory (beta=-1.31; P=0.04), semantic memory (beta=-1.45; P=0.01), and processing speed (beta=-1.21; P=0.03). Participants with greater cIMT at baseline did not exhibit significantly greater cognitive decline after adjustment. APOE epsilon4noncarriers with greater cIMT exhibited greater declines in executive function (beta=-0.98; P=0.06). Carotid plaque burden was not significantly associated with cognition at baseline or over time. CONCLUSIONS: Subclinical carotid atherosclerosis was associated with worse cognition among those at higher risk for Alzheimer disease. Interventions targeting early stages of atherosclerosis may modify cognitive aging. PMID- 28630236 TI - European evidence-based recommendations for diagnosis and treatment of childhood onset systemic lupus erythematosus: the SHARE initiative. AB - Childhood-onset systemic lupus erythematosus (cSLE) is a rare, multisystem and potentially life-threatening autoimmune disorder with significant associated morbidity. Evidence-based guidelines are sparse and management is often based on clinical expertise. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) was launched to optimise and disseminate management regimens for children and young adults with rheumatic diseases like cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of cSLE. In view of extent and complexity of cSLE and its various manifestations, recommendations for lupus nephritis and antiphospholipid syndrome will be published separately. Recommendations were generated using the EULAR (European League Against Rheumatism) standard operating procedure. An expert committee consisting of paediatric rheumatologists and representation of paediatric nephrology from across Europe discussed evidence-based recommendations during two consensus meetings. Recommendations were accepted if >80% agreement was reached. A total of 25 recommendations regarding key approaches to diagnosis and treatment of cSLE were made. The recommendations include 11 on diagnosis, 9 on disease monitoring and 5 on general treatment. Topics included: appropriate use of SLE classification criteria, disease activity and damage indices; adequate assessment of autoantibody profiles; secondary macrophage activation syndrome; use of hydroxychloroquine and corticosteroid-sparing regimens; and the importance of addressing poor adherence. Ten recommendations were accepted regarding general diagnostic strategies and treatment indications of neuropsychiatric cSLE. The SHARE recommendations for cSLE and neuropsychiatric manifestations of cSLE have been formulated by an evidence-based consensus process to support uniform, high quality standards of care for children with cSLE. PMID- 28630237 TI - Facilitating Prospective Registration of Diagnostic Accuracy Studies: A STARD Initiative. PMID- 28630238 TI - Impact of Sex on Cardiac Troponin Concentrations-A Critical Appraisal. AB - BACKGROUND: The use of sex-specific cutoffs for cardiac troponin (cTn) is currently debated. Although endorsed by scientific working groups, concerns have been raised that sex-specific cutoffs may have only a small clinical effect at the cost of increased complexity in decision-making. METHODS: We reviewed studies investigating the interrelations between high-sensitivity (hs) cTn results and sex, diagnoses, and outcome. Investigated populations included community-dwelling subjects and patients with stable angina, congestive heart failure, or acute chest pain including those with acute coronary syndromes. RESULTS: Men usually have higher hs-cTn concentrations compared with women, regardless of the assessed population or the applied assay. The distribution and prognostic implications of hs-cTn concentrations indicate that women have a broader cardiovascular risk panorama compared with men, particularly at lower hs-cTn concentrations. At higher concentrations, particularly above the 99th percentile, this variation is often attenuated. Sex-specific hs-cTn 99th percentiles have so far shown clinical net benefit in only 1 study assessing patients with chest pain. However, several methodological aspects need to be considered when interpreting study results, e.g., issues related to the determination of the 99th percentiles, the selection bias, and the lack of prospective and sufficiently powered analyses. CONCLUSIONS: Available studies do not show a consistent clinical superiority of sex-specific hs-cTn 99th percentiles. This may reflect methodological aspects. However, from a pathobiological perspective, the use of sex-specific hs-cTn 99th percentiles makes sense for the ruling in of myocardial infarction. We propose a new approach to hs-cTn 99th cutoffs taking into account the analytical properties of the used assays. PMID- 28630239 TI - An unusual case of Escherichia coli O157:H7 infection with pseudomembranous colitis-like lesions associated with haemolytic-uraemic syndrome and neurological sequelae. AB - A 75-year-old man was admitted with abdominal pain and fresh rectal bleeding. Significantly, he had no risk factors for Clostridium difficile infection. An abdominal CT demonstrated colonic thickening, and flexible sigmoidoscopy identified pseudomembranous colitis-like lesions. After initial treatment as C. difficile colitis, a stool sample revealed Escherichia coli O157:H7 infection. Antibiotic therapy was stopped due to the risk of lysis-mediated toxin release, but unfortunately, the patient continued to deteriorate. He developed several of the severe sequelae of E. coli O157:H7 infection, including haemolytic-uraemic syndrome with an acute kidney injury necessitating haemofiltration, plus progressively severe seizures requiring escalating antiepileptic treatment and intubation for airway protection. After a prolonged intensive care admission and subsequent recovery on the ward, our patient was discharged alive. PMID- 28630241 TI - Multipathogenic necrotising supraglottitis in an immunocompetent patient. AB - Supraglottitis is a potentially life-threatening condition. It is now uncommon due to the Haemophilus influenzae type B vaccination and is more recently caused by Streptococcus pneumoniae, S. pyogenes, H. influenzae non-type B, H. parainfluenzae, Staphylococcus aureus and Pasteurella multocida Very rarely, it can cause necrotising supraglottitis/epiglottitis, and this has been reported in immunocompromised individuals. We present a unique case of multipathogenic supraglottitis causing laryngeal fibrinoid necrosis in an immunocompetent patient. During his admission, the patient was critically unwell and required surgical intervention and tracheostomy. However, he made a full recovery with no persisting morbidity. We believe that this was owed to the aggressive antimicrobial therapy, timely surgical management of the disease process and the patienta?TMs immunocompetency. PMID- 28630240 TI - Port site endometrioma: a rare cause of abdominal wall pain following laparoscopic surgery. AB - Endometriomas are a rare cause of abdominal wall pain. We report a case of a port site endometrioma presenting with an umbilical swelling. The patient underwent a laparoscopy for pelvic endometriosis 6 months previously and presented with a swelling around her umbilical port site scar associated with cyclical pain during menses. Ultrasound scan reported a well-defined lesion in the umbilicus and MRI scanning excluded other pathology. As she was symptomatic, she underwent an exploration of the scar and excision of the endometrioma with resolution of her symptoms. Precautions should be taken to reduce the risk of endometrial seeding during laparoscopic surgery. All tissues should be removed in an appropriate retrieval bag and the pneumoperitoneum should be deflated completely before removing ports to reduce the chimney effect of tissue being forced through the port site. The diagnosis should be considered in all women of reproductive age presenting with a painful port site scar. PMID- 28630242 TI - Tumour necrosis factor (TNF) inhibitor-induced isolated pleural granulomas: a rare adverse effect. AB - A 53-year-old man with a history of Crohn's disease on infliximab, presented with several weeks of cough and dyspnoea. He had a right-sided pleural effusion, found to be exudative with lymphocytic predominance. He underwent right-sided video assisted thoracic surgery (VATS) with biopsies and pleurodesis. Histopathology showed pleural-based non-caseating granulomas with unremarkable lung parenchyma. Cultures were only positive for Propionibacterium acnes 8 months later, he was found to have a left-sided exudative, lymphocytic predominant pleural effusion. Left-sided VATS and biopsies again showed pleural-based non-caseating granulomas with normal lung parenchyma. Having ruled out an active infection and malignant lesions, we diagnosed infliximab-induced pleural granulomas. Infliximab was stopped. The patient continues to do well at 6 years of follow-up. We believe this is the first report of tumour necrosis factor (TNF) inhibitor-induced isolated pleural granulomas. P. acnes and cytokine imbalance might be responsible for the pathogenesis of TNF inhibitor-induced granulomas. PMID- 28630243 TI - QUAD fever: beware of non-infectious fever in high spinal cord injuries. AB - A case of cervical spinal cord injury and quadriparesis with prolonged fever is being described. Initially, the patient received treatment for well-documented catheter-related bloodstream infection. High spiking fever returned and persisted with no obvious evidence of infection. The usual non-infectious causes too were carefully excluded. QUAD fever or fever due to spinal cord injury itself was considered. The pathogenetic basis of QUAD fever is unclear but could be attributed to autonomic dysfunction and temperature dysregulation. Awareness of this little known condition could help in avoiding unnecessary antimicrobial therapy and in more accurate prognostication. Unlike several previous reported cases that ended fatally, the present case ran a relatively benign course. The spectrum of presentations may therefore be broader than hitherto appreciated. PMID- 28630244 TI - A case of recurrent, multifocal anastomosing haemangiomas. AB - Anastomosing haemangiomas are relatively rare lesions, with a renal predilection, and which, given their imaging and pathologic appearance, mimic aggressive malignancies such as angiosarcoma. The imaging characteristics of this case are informative when evaluating a vascular lesion of the adrenal gland. PMID- 28630245 TI - Internal carotid artery occlusion and stroke as a complication of cisplatin-based chemotherapy for metastatic testicular germ cell tumour. AB - Testicular tumours are the most common tumours in young men. Germ cell tumours (GCTs) account for 95% of all testicular cancers, and the non-seminomatous type (NSGCT) accounts for 50% of all GCTs. Cisplatin-based chemotherapy is curative in up to 90% of patients, but it is not without its inherent risks. Ischaemic stroke is a very uncommon, but severe complication of cisplatin-based chemotherapy. Strokes in young patients cause a disproportionately large economic impact by leaving victims disabled during their most productive years and strains the healthcare system with expensive hospital stays. We present a case of a young male patient with past medical history of metastatic NSGCT with the sudden onset of dysarthria, left hemiplegia and ipsilateral hemisensory loss 3 days after receiving cisplatin-based chemotherapy. Subsequent studies revealed a stroke involving the right middle cerebral artery territory secondary to an acute right internal carotid occlusion. PMID- 28630246 TI - Ominous triad triggered by high-dose glucocorticosteroid therapy. AB - Glucocorticosteroids (CS) play a key role in the treatment of numerous diseases. Nonetheless, they can be accompanied by several adverse effects. We present the case of a 51-year-old woman who was treated with high-dose CS for a relapse of her multiple sclerosis. After 5 days of treatment, the patient developed severe diabetic ketoacidosis, hypertriglyceridemia and acute pancreatitis-a potentially life-threatening triad which has previously been described, in our case, however, for the first time as a complication of CS therapy. Our patient's condition was further aggravated by a circulatory shock, haemodynamic relevant bleeding from a duodenal ulcer and psychotic symptoms. In the intensive care unit, intravenous insulin infusion, fluid resuscitation, catecholamine support, electrolyte supplementation, endoscopic haemoclipping and antibiotic and antipsychotic treatment were administered, leading to a continuous improvement of the patient's health state. PMID- 28630247 TI - Saksenaea vasiformis infection in an immunocompetent patient in rural Australia. AB - An 81-year-old man from rural Australia presented with right pretibial cellulitis 7 days after minor trauma against furniture. He failed to improve despite antibiotics and surgical debridement. Subsequent cultures grew the rare fungus Saksenaea vasiformis, which was treated with further surgical debridement, amphotericin B and posaconazole. This was successful and the patient made a full recovery. We present the case and discuss lessons learnt. PMID- 28630248 TI - Chest X-ray of a patient with history of pleural effusion. AB - The presented chest X-ray depicts the thoracic duct anatomy of a 50-year-old man who underwent heart transplantation. His postoperative course was complicated by Candida mediastinitis, treated with debridements and closure of the anterior chest wound with myocutaneous flaps. Postoperatively, he had persistent output from a right-sided chest tube. The fluid appeared milky and its triglycerides level was elevated at 254 mg/dL. The drainage persisted despite a low fat diet. The interventional radiologist identified a leak in the upper thoracic duct. It was embolised with coil and onyx. After the procedure, the chylous pleural effusions resolved. The thoracic duct has been visualised on subsequent chest X rays (figures 1 and 2). PMID- 28630249 TI - Bilateral ischaemic optic neuropathy and retinopathy along with cortical infarct in a case of Takayasu disease. PMID- 28630250 TI - Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance. AB - Energy-dense, yet nutritionally poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acids (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFA deficiency lasting from adolescence into adulthood. Starting nutritional deficits in dietary n-3 PUFAs during adolescence decreased n-3 PUFAs in both medial prefrontal cortex (mPFC) and nucleus accumbens, increased anxiety-like behavior, and decreased cognitive function in adulthood. Importantly, we discovered that endocannabinoid/mGlu5-mediated LTD in the mPFC and accumbens was abolished in adult n-3-deficient mice. Additionally, mPFC NMDAR-dependent LTP was also lacking in the n-3-deficient group. Pharmacological enhancement of the mGlu5/eCB signaling complex, by positive allosteric modulation of mGlu5 or inhibition of endocannabinoid 2-arachidonylglycerol degradation, fully restored synaptic plasticity and normalized emotional and cognitive behaviors in malnourished adult mice. Our data support a model where nutrition is a key environmental factor influencing the working synaptic range into adulthood, long after the end of the perinatal period. These findings have important implications for the identification of nutritional risk factors for disease and design of new treatments for the behavioral deficits associated with nutritional n-3 PUFA deficiency.SIGNIFICANCE STATEMENT In a mouse model mimicking n-3 PUFA dietary deficiency during adolescence and adulthood, we found strong increases in anxiety and anhedonia which lead to decreases in specific cognitive functions in adulthood. We found that endocannabinoid/mGlu5-mediated LTD and NMDAR-dependent LTP were lacking in adult n-3-deficient mice. Acute positive allosteric modulation of mGlu5 or inhibition of endocannabinoid degradation normalized behaviors and synaptic functions in n-3 PUFA-deficient adult mice. These findings have important implications for the identification of nutritional risk for disease and the design of new treatments for the behavioral deficits associated with nutritional n-3 PUFAs' imbalance. PMID- 28630251 TI - Valnoctamide Inhibits Cytomegalovirus Infection in Developing Brain and Attenuates Neurobehavioral Dysfunctions and Brain Abnormalities. AB - Cytomegalovirus (CMV) is the most common infectious cause of brain defects and neurological dysfunction in developing human babies. Due to the teratogenicity and toxicity of available CMV antiviral agents, treatment options during early development are markedly limited. Valnoctamide (VCD), a neuroactive mood stabilizer with no known teratogenic activity, was recently demonstrated to have anti-CMV potential. However, it is not known whether this can be translated into an efficacious therapeutic effect to improve CMV-induced adverse neurological outcomes. Using multiple models of CMV infection in the developing mouse brain, we show that subcutaneous low-dose VCD suppresses CMV by reducing the level of virus available for entry into the brain and by acting directly within the brain to block virus replication and dispersal. VCD during the first 3 weeks of life restored timely acquisition of neurological milestones in neonatal male and female mice and rescued long-term motor and behavioral outcomes in juvenile male mice. CMV-mediated brain defects, including decreased brain size, cerebellar hypoplasia, and neuronal loss, were substantially attenuated by VCD. No adverse side effects on neurodevelopment of uninfected control mice receiving VCD were detected. Treatment of CMV-infected human fetal astrocytes with VCD reduced both viral infectivity and replication by blocking viral particle attachment to the cell, a mechanism that differs from available anti-CMV drugs. These data suggest that VCD during critical periods of neurodevelopment can effectively suppress CMV replication in the brain and safely improve both immediate and long-term neurological outcomes.SIGNIFICANCE STATEMENT Cytomegalovirus (CMV) can irreversibly damage the developing brain. No anti-CMV drugs are available for use during fetal development, and treatment during the neonatal period has substantial limitations. We studied the anti-CMV actions of valnoctamide (VCD), a psychiatric sedative that appears to lack teratogenicity and toxicity, in the newborn mouse brain, a developmental period that parallels that of an early second-trimester human fetus. In infected mice, subcutaneous VCD reaches the brain and suppresses viral replication within the CNS, rescuing the animals from CMV-induced brain defects and neurological problems. Treatment of uninfected control animals exerts no detectable adverse effects. VCD also blocks CMV replication in human fetal brain cells. PMID- 28630252 TI - Alpha-Band Brain Oscillations Shape the Processing of Perceptible as well as Imperceptible Somatosensory Stimuli during Selective Attention. AB - Attention filters and weights sensory information according to behavioral demands. Stimulus-related neural responses are increased for the attended stimulus. Does alpha-band activity mediate this effect and is it restricted to conscious sensory events (suprathreshold), or does it also extend to unconscious stimuli (subthreshold)? To address these questions, we recorded EEG in healthy male and female volunteers undergoing subthreshold and suprathreshold somatosensory electrical stimulation to the left or right index finger. The task was to detect stimulation at the randomly alternated cued index finger. Under attention, amplitudes of somatosensory evoked potentials increased 50-60 ms after stimulation (P1) for both suprathreshold and subthreshold events. Prestimulus amplitude of peri-Rolandic alpha, that is mu, showed an inverse relationship to P1 amplitude during attention compared to when the finger was unattended. Interestingly, intermediate and high amplitudes of mu rhythm were associated with the highest P1 amplitudes during attention and smallest P1 during lack of attention, that is, these levels of alpha rhythm seemed to optimally support the behavioral goal ("detect" stimuli at the cued finger while ignoring the other finger). Our results show that attention enhances neural processing for both suprathreshold and subthreshold stimuli and they highlight a rather complex interaction between attention, Rolandic alpha activity, and their effects on stimulus processing.SIGNIFICANCE STATEMENT Attention is crucial in prioritizing processing of relevant perceptible (suprathreshold) stimuli: it filters and weights sensory input. The present study investigates the controversially discussed question whether this attention effect extends to imperceptible (subthreshold) stimuli as well. We found noninvasive EEG signatures for attentional modulation of neural events following perceptible and imperceptible somatosensory stimulation in human participants. Specifically, stimulus processing for both kinds of stimulation, subthreshold and suprathreshold, is enhanced by attention. Interestingly, Rolandic alpha rhythm strength and its influence on stimulus processing are strikingly altered by attention most likely to optimally achieve the behavioral goal. PMID- 28630253 TI - Cold-Induced Thermogenesis and Inflammation-Associated Cold-Seeking Behavior Are Represented by Different Dorsomedial Hypothalamic Sites: A Three-Dimensional Functional Topography Study in Conscious Rats. AB - In the past, we showed that large electrolytic lesions of the dorsomedial hypothalamus (DMH) promoted hypothermia in cold-exposed restrained rats, but attenuated hypothermia in rats challenged with a high dose of bacterial lipopolysaccharide (LPS) in a thermogradient apparatus. The goal of this study was to identify the thermoeffector mechanisms and DMH representation of the two phenomena and thus to understand how the same lesion could produce two opposite effects on body temperature. We found that the permissive effect of large electrolytic DMH lesions on cold-induced hypothermia was due to suppressed thermogenesis. DMH-lesioned rats also could not develop fever autonomically: they did not increase thermogenesis in response to a low, pyrogenic dose of LPS (10 MUg/kg, i.v.). In contrast, changes in thermogenesis were uninvolved in the attenuation of the hypothermic response to a high, shock-inducing dose of LPS (5000 MUg/kg, i.v.); this attenuation was due to a blockade of cold-seeking behavior. To compile DMH maps for the autonomic cold defense and for the cold seeking response to LPS, we studied rats with small thermal lesions in different parts of the DMH. Cold thermogenesis had the highest representation in the dorsal hypothalamic area. Cold seeking was represented by a site at the ventral border of the dorsomedial nucleus. Because LPS causes both fever and hypothermia, we originally thought that the DMH contained a single thermoregulatory site that worked as a fever-hypothermia switch. Instead, we have found two separate sites: one that drives thermogenesis and the other, previously unknown, that drives inflammation-associated cold seeking.SIGNIFICANCE STATEMENT Cold-seeking behavior is a life-saving response that occurs in severe systemic inflammation. We studied this behavior in rats with lesions in the dorsomedial hypothalamus (DMH) challenged with a shock-inducing dose of bacterial endotoxin. We built functional maps of the DMH and found the strongest representation of cold-seeking behavior at the ventral border of the dorsomedial nucleus. We also built maps for cold induced thermogenesis in unanesthetized rats and found the dorsal hypothalamic area to be its main representation site. Our work identifies the neural substrate of cold-seeking behavior in systemic inflammation and expands the functional topography of the DMH, a structure that modulates autonomic, endocrine, and behavioral responses and is a potential therapeutic target in anxiety and panic disorders. PMID- 28630254 TI - Reward Selectively Modulates the Lingering Neural Representation of Recently Attended Objects in Natural Scenes. AB - Theories of reinforcement learning and approach behavior suggest that reward can increase the perceptual salience of environmental stimuli, ensuring that potential predictors of outcome are noticed in the future. However, outcome commonly follows visual processing of the environment, occurring even when potential reward cues have long disappeared. How can reward feedback retroactively cause now-absent stimuli to become attention-drawing in the future? One possibility is that reward and attention interact to prime lingering visual representations of attended stimuli that sustain through the interval separating stimulus and outcome. Here, we test this idea using multivariate pattern analysis of fMRI data collected from male and female humans. While in the scanner, participants searched for examples of target categories in briefly presented pictures of cityscapes and landscapes. Correct task performance was followed by reward feedback that could randomly have either high or low magnitude. Analysis showed that high-magnitude reward feedback boosted the lingering representation of target categories while reducing the representation of nontarget categories. The magnitude of this effect in each participant predicted the behavioral impact of reward on search performance in subsequent trials. Other analyses show that sensitivity to reward-as expressed in a personality questionnaire and in reactivity to reward feedback in the dopaminergic midbrain-predicted reward elicited variance in lingering target and nontarget representations. Credit for rewarding outcome thus appears to be assigned to the target representation, causing the visual system to become sensitized for similar objects in the future.SIGNIFICANCE STATEMENT How do reward-predictive visual stimuli become salient and attention-drawing? In the real world, reward cues precede outcome and reward is commonly received long after potential predictors have disappeared. How can the representation of environmental stimuli be affected by outcome that occurs later in time? Here, we show that reward acts on lingering representations of environmental stimuli that sustain through the interval between stimulus and outcome. Using naturalistic scene stimuli and multivariate pattern analysis of fMRI data, we show that reward boosts the representation of attended objects and reduces the representation of unattended objects. This interaction of attention and reward processing acts to prime vision for stimuli that may serve to predict outcome. PMID- 28630255 TI - Social Context-Dependent Activity in Marmoset Frontal Cortex Populations during Natural Conversations. AB - Communication is an inherently interactive process that weaves together the fabric of both human and nonhuman primate societies. To investigate the properties of the primate brain during active social signaling, we recorded the responses of frontal cortex neurons as freely moving marmosets engaged in conversational exchanges with a visually occluded virtual marmoset. We found that small changes in firing rate (~1 Hz) occurred across a broadly distributed population of frontal cortex neurons when marmosets heard a conspecific vocalization, and that these changes corresponded to subjects' likelihood of producing or withholding a vocal reply. Although the contributions of individual neurons were relatively small, large populations of neurons were able to clearly distinguish between these social contexts. Most significantly, this social context-dependent change in firing rate was evident even before subjects heard the vocalization, indicating that the probability of a conversational exchange was determined by the state of the frontal cortex at the time a vocalization was heard, and not by a decision driven by acoustic characteristics of the vocalization. We found that changes in neural activity scaled with the length of the conversation, with greater changes in firing rate evident for longer conversations. These data reveal specific and important facets of this neural activity that constrain its possible roles in active social signaling, and we hypothesize that the close coupling between frontal cortex activity and this natural, active primate social-signaling behavior facilitates social-monitoring mechanisms critical to conversational exchanges.SIGNIFICANCE STATEMENT We provide evidence for a novel pattern of neural activity in the frontal cortex of freely moving, naturally behaving, marmoset monkeys that may facilitate natural primate conversations. We discovered small (~1 Hz), but reliable, changes in neural activity that occurred before marmosets even heard a conspecific vocalization that, as a population, almost perfectly predicted whether subjects would produce a vocalization in response. The change in the state of the frontal cortex persisted throughout the conversation and its magnitude scaled linearly with the length of the interaction. We hypothesize that this social context-dependent change in frontal cortex activity is supported by several mechanisms, such as social arousal and attention, and facilitates social monitoring critical for vocal coordination characteristic of human and nonhuman primate conversations. PMID- 28630256 TI - The Small GTPase Rac1 Contributes to Extinction of Aversive Memories of Drug Withdrawal by Facilitating GABAA Receptor Endocytosis in the vmPFC. AB - Extinction of aversive memories has been a major concern in neuropsychiatric disorders, such as anxiety disorders and drug addiction. However, the mechanisms underlying extinction of aversive memories are not fully understood. Here, we report that extinction of conditioned place aversion (CPA) to naloxone precipitated opiate withdrawal in male rats activates Rho GTPase Rac1 in the ventromedial prefrontal cortex (vmPFC) in a BDNF-dependent manner, which determines GABAA receptor (GABAAR) endocytosis via triggering synaptic translocation of activity-regulated cytoskeleton-associated protein (Arc) through facilitating actin polymerization. Active Rac1 is essential and sufficient for GABAAR endocytosis and CPA extinction. Knockdown of Rac1 expression within the vmPFC of rats using Rac1-shRNA suppressed GABAAR endocytosis and CPA extinction, whereas expression of a constitutively active form of Rac1 accelerated GABAAR endocytosis and CPA extinction. The crucial role of GABAAR endocytosis in the LTP induction and CPA extinction is evinced by the findings that blockade of GABAAR endocytosis by a dynamin function-blocking peptide (Myr-P4) abolishes LTP induction and CPA extinction. Thus, the present study provides first evidence that Rac1-dependent GABAAR endocytosis plays a crucial role in extinction of aversive memories and reveals the sequence of molecular events that contribute to learning experience modulation of synaptic GABAAR endocytosis.SIGNIFICANCE STATEMENT This study reveals that Rac1-dependent GABAAR endocytosis plays a crucial role in extinction of aversive memories associated with drug withdrawal and identifies Arc as a downstream effector of Rac1 regulations of synaptic plasticity as well as learning and memory, thereby suggesting therapeutic targets to promote extinction of the unwanted memories. PMID- 28630257 TI - Contrasting Effects of Medial and Lateral Orbitofrontal Cortex Lesions on Credit Assignment and Decision-Making in Humans. AB - The orbitofrontal cortex is critical for goal-directed behavior. Recent work in macaques has suggested the lateral orbitofrontal cortex (lOFC) is relatively more concerned with assignment of credit for rewards to particular choices during value-guided learning, whereas the medial orbitofrontal cortex (often referred to as ventromedial prefrontal cortex in humans; vmPFC/mOFC) is involved in constraining the decision to the relevant options. We examined whether people with damage restricted to subregions of prefrontal cortex showed the patterns of impairment observed in prior investigations of the effects of lesions to homologous regions in macaques. Groups of patients with either lOFC (predominantly right hemisphere), mOFC/vmPFC, or dorsomedial prefrontal (DMF), and a comparison group of healthy age- and education-matched controls performed a probabilistic 3-choice decision-making task. We report anatomically specific patterns of impairment. We found that credit assignment, as indexed by the normal influence of contingent relationships between choice and reward, is reduced in lOFC patients compared with Controls and mOFC/vmPFC patients. Moreover, the effects of reward contingency on choice were similar for patients with lesions in DMF or mOFC/vmPFC, compared with Controls. By contrast, mOFC/vmPFC-lesioned patients made more stochastic choices than Controls when the decision was framed by valuable distracting alternatives, suggesting that value comparisons were no longer independent of irrelevant options. Once again, there was evidence of regional specialization: patients with lOFC lesions were unimpaired relative to Controls. As in macaques, human lOFC and mOFC/vmPFC are necessary for contingent learning and value-guided decision-making, respectively.SIGNIFICANCE STATEMENT The lateral and medial regions of the orbitofrontal cortex are cytoarchitectonically distinct and have different anatomical connections. Previous investigations in macaques have shown these anatomical differences are accompanied by functional specialization for learning and decision-making. Here, for the first time, we test the predictions made by macaque studies in an experiment with humans with frontal lobe lesions, asking whether behavioral impairments can be linked to lateral or medial orbitofrontal cortex. Using equivalent tasks and computational analyses, our findings broadly replicate the pattern reported after selective lesions in monkeys. Patients with lateral orbitofrontal damage had impaired credit assignment, whereas damage to medial orbitofrontal cortex meant that patients were more likely to be distracted by irrelevant options. PMID- 28630258 TI - Realization of entry-to-practice milestones by Canadians who studied medicine abroad and other international medical graduates: a retrospective cohort study. AB - BACKGROUND: International medical graduates must realize a series of milestones to obtain full licensure. We examined the realization of milestones by Canadian and non-Canadian graduates of Western or Caribbean medical schools, and Canadian and non-Canadian graduates from other medical schools. METHODS: Using the National IMG Database (data available for 2005-2011), we created 2 cohorts: 1) international medical graduates who had passed the Medical Council of Canada Qualifying Examination Part I between 2005 and 2010 and 2) those who had first entered a family medicine postgraduate program between 2005 and 2009, or had first entered a specialty postgraduate program in 2005 or 2006. We examined 3 entry-to-practice milestones; obtaining a postgraduate position, passing the Medical Council of Canada Qualifying Examination Part II and obtaining a specialty designation. RESULTS: Of the 6925 eligible graduates in cohort 1, 2144 (31.0%) had obtained a postgraduate position. Of the 1214 eligible graduates in cohort 2, 1126 (92.8%) had passed the Qualifying Examination Part II, and 889 (73.2%) had obtained a specialty designation. In multivariate analyses, Canadian graduates of Western or Caribbean medical schools (odds ratio [OR] 4.69, 95% confidence interval [CI] 3.82-5.71) and Canadian graduates of other medical schools (OR 1.49, 95% CI 1.31-1.70) were more likely to obtain a postgraduate position than non-Canadian graduates of other (not Western or Caribbean) medical schools. There was no difference among the groups in passing the Qualifying Examination Part II or obtaining a specialty designation. INTERPRETATION: Canadians who studied abroad were more likely than other international medical graduates to obtain a postgraduate position; there were no differences among the groups in realizing milestones once in a postgraduate program. These findings support policies that do not distinguish postgraduate applicants by citizenship or permanent residency status before medical school. PMID- 28630259 TI - Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy. AB - Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca2+ and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD. PMID- 28630260 TI - Cholesterol auxotrophy and intolerance to ezetimibe in mice with SREBP-2 deficiency in the intestine. AB - SREBP-2 activates transcription of all genes needed for cholesterol biosynthesis. To study SREBP-2 function in the intestine, we generated a mouse model (Vil-BP2-/ ) in which Cre recombinase ablates SREBP-2 in intestinal epithelia. Intestines of Vil-BP2-/- mice had reduced expression of genes required for sterol synthesis, in vivo sterol synthesis rates, and epithelial cholesterol contents. On a cholesterol-free diet, the mice displayed chronic enteropathy with histological abnormalities of both villi and crypts, growth restriction, and reduced survival that was prevented by supplementation of cholesterol in the diet. Likewise, SREBP 2-deficient enteroids required exogenous cholesterol for growth. Blockade of luminal cholesterol uptake into enterocytes with ezetimibe precipitated acutely lethal intestinal damage in Vil-BP2-/- mice, highlighting the critical interplay in the small intestine of sterol absorption via NPC1L1 and sterol synthesis via SREBP-2 in sustaining the intestinal mucosa. These data show that the small intestine requires SREBP-2 to drive cholesterol synthesis that sustains the intestinal epithelia when uptake of cholesterol from the gut lumen is not available, and provide a unique example of cholesterol auxotrophy expressed in an intact, adult mammal. PMID- 28630261 TI - Anti-inflammatory liaisons: T regulatory cells and HDL. PMID- 28630264 TI - It Is Time to End the Dualistic Short Versus Long Duration of Dual Antiplatelet Therapy Debates. PMID- 28630265 TI - Drone-Based Automatic External Defibrillators for Sudden Death? Do We Need More Courage or More Serenity? PMID- 28630263 TI - Determination of the Residues in the Extracellular Domain of the Nicotinic alpha Subunit Required for the Actions of Physostigmine on Neuronal Nicotinic Receptors. AB - Physostigmine can potentiate and inhibit neuronal nicotinic receptors, in addition to inhibiting the activity of acetylcholinesterase. We found that receptors containing three copies of the alpha2 subunit are inhibited by low concentrations of physostigmine in contrast to receptors containing three copies of the alpha4 subunit that are potentiated. We exploited this observation to determine the regions required for the actions of physostigmine. Chimeric constructs of the alpha2 and alpha4 subunits located two regions in the extracellular amino-terminal domain of the subunit: the E loop (a loop of the transmitter-binding domain) and a region closer to the amino-terminus that collectively could completely determine the different effects of physostigmine. Point mutations then identified a single residue, alpha2(I92) versus alpha4(R92), that, when combined with transfer of the E loop, could convert the inhibition seen with alpha2 subunits to potentiation and the potentiation seen with alpha4 subunits to inhibition. In addition, other point mutations could affect the extent of potentiation or inhibition, indicating that a more extensive set of interactions in the amino-terminal domain plays some role in the actions of physostigmine. PMID- 28630266 TI - Defining Ambulatory Blood Pressure Thresholds for Decision Making in Hypertension: The Effect of Race and Methodology. PMID- 28630262 TI - Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation. AB - BACKGROUND: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. METHODS AND RESULTS: IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor alpha, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. CONCLUSIONS: A DPP 4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages. PMID- 28630268 TI - Highlights From the Circulation Family of Journals. PMID- 28630267 TI - A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative. AB - Peripheral artery disease affects >200 million people worldwide and is associated with significant limb and cardiovascular morbidity and mortality. Limb revascularization is recommended to improve function and quality of life for symptomatic patients with peripheral artery disease with intermittent claudication who have not responded to medical treatment. For patients with critical limb ischemia, the goals of revascularization are to relieve pain, help wound healing, and prevent limb loss. The baseline risk of cardiovascular and limb-related events demonstrated among patients with stable peripheral artery disease is elevated after revascularization and related to atherothrombosis and restenosis. Both of these processes involve platelet activation and the coagulation cascade, forming the basis for the use of antiplatelet and anticoagulant therapies to optimize procedural success and reduce postprocedural cardiovascular risk. Unfortunately, few high-quality, randomized data to support use of these therapies after peripheral artery disease revascularization exist, and much of the rationale for the use of antiplatelet agents after endovascular peripheral revascularization is extrapolated from percutaneous coronary intervention literature. Consequently, guideline recommendations for antithrombotic therapy after lower limb revascularization are inconsistent and not always evidence-based. In this context, the purpose of this structured review is to assess the available randomized data for antithrombotic therapy after peripheral arterial revascularization, with a focus on clinical trial design issues that may affect interpretation of study results, and highlight areas that require further investigation. PMID- 28630269 TI - Coverage and Cardioprotective Benefits of PCSK9 Take Center Stage at the American College of Cardiology Meeting. PMID- 28630270 TI - Out-of-Hospital Cardiac Arrest: An Underlying Reversible Cause. PMID- 28630271 TI - Of a Tortuous Nature: An Unusual Cause of Peripartum Congestive Heart Failure. PMID- 28630272 TI - Early Myocardial Strain Changes During Potentially Cardiotoxic Chemotherapy May Occur as a Result of Reductions in Left Ventricular End-Diastolic Volume: The Need to Interpret Left Ventricular Strain With Volumes. PMID- 28630273 TI - Letter by Barakat et al Regarding Article, "Implantable Cardioverter Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis". PMID- 28630274 TI - Letter by Nery et al Regarding Article, "Implantable Cardioverter-Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis". PMID- 28630275 TI - Response by Golwala et al to Letter Regarding Article, "Implantable Cardioverter Defibrillator for Nonischemic Cardiomyopathy: An Updated Meta-Analysis". PMID- 28630276 TI - Letter by Freeman and Freeman Regarding Article, "Sex Differences in Faculty Rank Among Academic Cardiologists in the United States". PMID- 28630277 TI - T-Cell Intracellular Antigens and Hu Antigen R Antagonistically Modulate Mitochondrial Activity and Dynamics by Regulating Optic Atrophy 1 Gene Expression. AB - Mitochondria undergo frequent morphological changes to control their function. We show here that T-cell intracellular antigens (TIA1b/TIARb) and Hu antigen R (HuR) have antagonistic roles in mitochondrial function by modulating the expression of mitochondrial shaping proteins. Expression of TIA1b/TIARb alters the mitochondrial dynamic network by enhancing fission and clustering, which is accompanied by a decrease in respiration. In contrast, HuR expression promotes fusion and cristae remodeling and increases respiratory activity. Mechanistically, TIA proteins downregulate the expression of optic atrophy 1 (OPA1) protein via switching of the splicing patterns of OPA1 to facilitate the production of OPA1 variant 5 (OPA1v5). Conversely, HuR enhances the expression of OPA1 mRNA isoforms through increasing steady-state levels and targeting translational efficiency at the 3' untranslated region. Knockdown of TIA1/TIAR or HuR partially reversed the expression profile of OPA1, whereas knockdown of OPA1 or overexpression of OPA1v5 provoked mitochondrial clustering. Middle-term expression of TIA1b/TIARb triggers reactive oxygen species production and mitochondrial DNA damage, which is accompanied by mitophagy, autophagy, and apoptosis. In contrast, HuR expression promotes mitochondrion-dependent cell proliferation. Collectively, these results provide molecular insights into the antagonistic functions of TIA1b/TIARb and HuR in mitochondrial activity dynamics and suggest that their balance might contribute to mitochondrial physiopathology. PMID- 28630278 TI - Synthetic Deletion of the Interleukin 23 Receptor (IL-23R) Stalk Region Led to Autonomous IL-23R Homodimerization and Activation. AB - Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses and autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R)-IL-12 receptor beta1 (IL-12Rbeta1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellular-membrane-proximal fibronectin type III (FNIII) domains, which are not involved in cytokine binding but are mandatory for signal transduction. In place of FNIII-type domains, IL-23R has a structurally undefined stalk. We hypothesized that the IL-23R stalk acts as a spacer to position the cytokine binding domains at a defined distance from the plasma membrane to enable signal transduction. Minor deletions of the murine, but not of the human, IL-23R stalk resulted in unresponsiveness to IL-23. Complete deletion of the human IL-23R stalk and the extended murine IL-23R stalk, including a 20-amino-acid-long duplication of domain 3, however, induced ligand-independent, autonomous receptor activation, as determined by STAT3 phosphorylation and cell proliferation. Ligand independent, autonomous activity was caused by IL-23R homodimers and was independent of IL-12Rbeta1. Our data show that deletion of the stalk results in biologically active IL-23R homodimers, thereby creating an as-yet-undescribed receptor complex of the IL-6/IL-12 cytokine family. PMID- 28630279 TI - Obesity and p16INK4A Downregulation Activate Breast Adipocytes and Promote Their Protumorigenicity. AB - Obesity is increasingly recognized as a risk factor for breast cancer development. However, the molecular basis of obesity-related breast carcinogenesis remains elusive. In this study, we have shown that obesity reduces the level of the tumor suppressor p16INK4A protein in breast adipocytes, which showed active features and strong procarcinogenic potential both in vitro and in orthotopic tumor xenografts compared to mature adipocytes from lean women. Furthermore, obesity triggered epithelial-to-mesenchymal transition (EMT) in breast ductal epithelial cells. Interestingly, specific downregulation of p16INK4A increased the expression/secretion levels of various adipokines, including leptin, and activated breast adipocytes from lean women. Consequently, like breast adipocytes from obese women, p16-deficient adipocytes induced EMT in normal primary breast luminal cells in a leptin-dependent manner and enhanced tumor growth. Additionally, we have shown that p16INK4A negatively controls leptin at the mRNA level through microRNAs 141 and 146b-5p (miR-141 and miR-146b 5p), which bind the leptin mRNA at a specific sequence in the 3' untranslated region (UTR). These results show that obesity activates breast stromal adipocytes through p16 downregulation, which upregulates leptin and promotes procarcinogenic processes. PMID- 28630280 TI - Ki-67 Contributes to Normal Cell Cycle Progression and Inactive X Heterochromatin in p21 Checkpoint-Proficient Human Cells. AB - The Ki-67 protein is widely used as a tumor proliferation marker. However, whether Ki-67 affects cell cycle progression has been controversial. Here we demonstrate that depletion of Ki-67 in human hTERT-RPE1, WI-38, IMR90, and hTERT BJ cell lines and primary fibroblast cells slowed entry into S phase and coordinately downregulated genes related to DNA replication. Some gene expression changes were partially relieved in Ki-67-depleted hTERT-RPE1 cells by codepletion of the Rb checkpoint protein, but more thorough suppression of the transcriptional and cell cycle defects was observed upon depletion of the cell cycle inhibitor p21. Notably, induction of p21 upon depletion of Ki-67 was a consistent hallmark of cell types in which transcription and cell cycle distribution were sensitive to Ki-67; these responses were absent in cells that did not induce p21. Furthermore, upon Ki-67 depletion, a subset of inactive X (Xi) chromosomes in female hTERT-RPE1 cells displayed several features of compromised heterochromatin maintenance, including decreased H3K27me3 and H4K20me1 labeling. These chromatin alterations were limited to Xi chromosomes localized away from the nuclear lamina and were not observed in checkpoint deficient 293T cells. Altogether, our results indicate that Ki-67 integrates normal S-phase progression and Xi heterochromatin maintenance in p21 checkpoint proficient human cells. PMID- 28630281 TI - Evidence of a prion-like transmission of p53 amyloid in Saccharomyces cerevisiae. AB - Loss of p53 function is largely responsible for the occurrence of cancer in human. Aggregation of mutant p53 has been found in multiple cancer cell types suggesting a role of aggregation for loss of p53 function and cancer development. The p53 protein has recently been hypothesized to possess a prion-like conformation although experimental evidence is lacking. Here, we report that human p53 can be inactivated upon exposure to preformed fibrils containing an aggregation prone sequence specific peptide PILTIITL derived from p53 and the inactive state was found to be stable for many generations. Importantly, we provide evidence of a prion-like transmission of these p53 aggregates. This study has a significant implication in understanding cancer progression due to p53 malfunctioning without any loss of function mutation or occurrence of transcriptional inactivation. Our data might unlock new possibilities for understanding the disease and will lead to rational designing of p53 aggregation inhibitors for drug development against cancer. PMID- 28630283 TI - Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment. AB - Understanding the relationship between the molecular mechanisms underlying neurotoxicity of high-dose methamphetamine (METH) and related clinical manifestations is imperative for providing more effective treatments for human METH users. This article provides an overview of clinical manifestations of METH neurotoxicity to the central nervous system and neurobiology underlying the consequences of administration of neurotoxic METH doses, and discusses implications of METH neurotoxicity for treatment of human abusers of the drug. PMID- 28630282 TI - DeSUMOylation of Gli1 by SENP1 Attenuates Sonic Hedgehog Signaling. AB - The transcriptional output of the Sonic Hedgehog morphogenic pathway is orchestrated by three Kruppel family transcription factors, Gli1 to -3, which undergo extensive posttranslational modifications, including ubiquitination and SUMOylation. Here, we report that the sentrin-specific peptidase SENP1 is the specific deSUMOylation enzyme for Gli1. We show that SUMOylation stabilizes Gli1 by competing with ubiquitination at conserved lysine residues and that SUMOylated Gli1 is enriched in the nucleus, suggesting that SUMOylation is a nuclear localization signal for Gli1. Finally, we show that small interfering RNA (siRNA) mediated knockdown of SENP1 augments the ability of Shh to sustain the proliferation of cerebellar granule cell precursors, demonstrating the physiological significance of the negative regulation of Shh signaling by SENP1. PMID- 28630284 TI - Differential Interaction of Dantrolene, Glafenine, Nalidixic Acid, and Prazosin with Human Organic Anion Transporters 1 and 3. AB - In renal proximal tubule cells, the organic anion transporters 1 and 3 (OAT1 and OAT3) in the basolateral membrane and the multidrug resistance-associated protein 4 (MRP4) in the apical membrane share substrates and co-operate in renal drug secretion. We hypothesized that recently identified MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin also interact with human OAT1 and/or OAT3 stably transfected in human embryonic kidney 293 cells. These four drugs were tested as possible inhibitors of p-[3H]aminohippurate (PAH) and [14C]glutarate uptake by OAT1, and of [3H]estrone-3-sulfate (ES) uptake by OAT3. In addition, we explored whether these drugs decrease the equilibrium distribution of radiolabeled PAH, glutarate, or ES, an approach intended to indirectly suggest drug/substrate exchange through OAT1 and OAT3. With OAT3, a dose-dependent inhibition of [3H]ES uptake and a downward shift in [3H]ES equilibrium were observed, indicating that all four drugs bind to OAT3 and may possibly be translocated. In contrast, the interaction with OAT1 was more complex. With [14C]glutarate as substrate, all four drugs inhibited uptake but only glafenine and nalidixic acid shifted glutarate equilibrium. Using [3H]PAH as a substrate of OAT1, nalidixic acid inhibited but dantrolene, glafenine, and prazosin stimulated uptake. Nalidixic acid decreased equilibrium content of [3H]PAH, suggesting that it may possibly be exchanged by OAT1. Taken together, OAT1 and OAT3 interact with the MRP4 inhibitors dantrolene, glafenine, nalidixic acid, and prazosin, indicating overlapping specificities. At OAT1, more than one binding site must be assumed to explain substrate and drug-dependent stimulation and inhibition of transport activity. PMID- 28630285 TI - Efficient transport of tropospheric aerosol into the stratosphere via the Asian summer monsoon anticyclone. AB - An enhanced aerosol layer near the tropopause over Asia during the June-September period of the Asian summer monsoon (ASM) was recently identified using satellite observations. Its sources and climate impact are presently not well characterized. To improve understanding of this phenomenon, we made in situ aerosol measurements during summer 2015 from Kunming, China, then followed with a modeling study to assess the global significance. The in situ measurements revealed a robust enhancement in aerosol concentration that extended up to 2 km above the tropopause. A climate model simulation demonstrates that the abundant anthropogenic aerosol precursor emissions from Asia coupled with rapid vertical transport associated with monsoon convection leads to significant particle formation in the upper troposphere within the ASM anticyclone. These particles subsequently spread throughout the entire Northern Hemispheric (NH) lower stratosphere and contribute significantly (~15%) to the NH stratospheric column aerosol surface area on an annual basis. This contribution is comparable to that from the sum of small volcanic eruptions in the period between 2000 and 2015. Although the ASM contribution is smaller than that from tropical upwelling (~35%), we find that this region is about three times as efficient per unit area and time in populating the NH stratosphere with aerosol. With a substantial amount of organic and sulfur emissions in Asia, the ASM anticyclone serves as an efficient smokestack venting aerosols to the upper troposphere and lower stratosphere. As economic growth continues in Asia, the relative importance of Asian emissions to stratospheric aerosol is likely to increase. PMID- 28630287 TI - Correction for Mattei et al., Integrated 3D view of postmating responses by the Drosophila melanogaster female reproductive tract, obtained by micro-computed tomography scanning. PMID- 28630286 TI - Efficient switching of mCherry fluorescence using chemical caging. AB - Fluorophores with dynamic or controllable fluorescence emission have become essential tools for advanced imaging, such as superresolution imaging. These applications have driven the continuing development of photoactivatable or photoconvertible labels, including genetically encoded fluorescent proteins. These new probes work well but require the introduction of new labels that may interfere with the proper functioning of existing constructs and therefore require extensive functional characterization. In this work we show that the widely used red fluorescent protein mCherry can be brought to a purely chemically induced blue-fluorescent state by incubation with beta-mercaptoethanol (betaME). The molecules can be recovered to the red fluorescent state by washing out the betaME or through irradiation with violet light, with up to 80% total recovery. We show that this can be used to perform single-molecule localization microscopy (SMLM) on cells expressing mCherry, which renders this approach applicable to a very wide range of existing constructs. We performed a detailed investigation of the mechanism underlying these dynamics, using X-ray crystallography, NMR spectroscopy, and ab initio quantum-mechanical calculations. We find that the betaME-induced fluorescence quenching of mCherry occurs both via the direct addition of betaME to the chromophore and through betaME-mediated reduction of the chromophore. These results not only offer a strategy to expand SMLM imaging to a broad range of available biological models, but also present unique insights into the chemistry and functioning of a highly important class of fluorophores. PMID- 28630288 TI - Intact piRNA pathway prevents L1 mobilization in male meiosis. AB - The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter. Importantly, DNA methylation dynamics of a single-copy transgene were indistinguishable from those of endogenous L1s. Analysis of Mov10l1-/- testes established that de novo methylation of the L1 transgene required the intact piRNA pathway. Consistent with loss of DNA methylation and programmed reduction of H3K9me2 at meiotic onset, the transgene showed 1,400-fold increase in RNA expression and consequently 70-fold increase in retrotransposition in postnatal day 14 Mov10l1-/ germ cells compared with the wild-type. Analysis of adult Mov10l1-/- germ-cell fractions indicated a stage-specific increase of retrotransposition in the early meiotic prophase. However, extrapolation of the transgene data to endogenous L1s suggests that it is unlikely insertional mutagenesis alone accounts for the Mov10l1-/- phenotype. Indeed, pharmacological inhibition of reverse transcription did not rescue the meiotic defect. Cumulatively, these results establish the occurrence of productive L1 mobilization in the absence of an intact piRNA pathway but leave open the possibility of processes preceding L1 integration in triggering meiotic checkpoints and germ-cell death. Additionally, our data suggest that many heritable L1 insertions originate from individuals with partially compromised piRNA defense. PMID- 28630289 TI - Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease. AB - Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein-coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 [Formula: see text]g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs. PMID- 28630290 TI - Childhood social class and cognitive aging in the Swedish Adoption/Twin Study of Aging. AB - In this report we analyzed genetically informative data to investigate within person change and between-person differences in late-life cognitive abilities as a function of childhood social class. We used data from nine testing occasions spanning 28 y in the Swedish Adoption/Twin Study of Aging and parental social class based on the Swedish socioeconomic index. Cognitive ability included a general factor and the four domains of verbal, fluid, memory, and perceptual speed. Latent growth curve models of the longitudinal data tested whether level and change in cognitive performance differed as a function of childhood social class. Between-within twin-pair analyses were performed on twins reared apart to assess familial confounding. Childhood social class was significantly associated with mean-level cognitive performance at age 65 y, but not with rate of cognitive change. The association decreased in magnitude but remained significant after adjustments for level of education and the degree to which the rearing family was supportive toward education. A between-pair effect of childhood social class was significant in all cognitive domains, whereas within-pair estimates were attenuated, indicating genetic confounding. Thus, childhood social class is important for cognitive performance in adulthood on a population level, but the association is largely attributable to genetic influences. PMID- 28630291 TI - Global Sustainable Development priorities 500 y after Luther: Sola schola et sanitate. AB - Martin Luther succinctly summarized his theology in sola statements, such as sola scriptura, viewing the Bible (scriptura) as the only valid source of information about God rather than what he viewed as the extraneous, corrupting church doctrine of the time. As a secular side effect of this focus on individual reading skills, the Protestant territories were the first to acquire high literacy rates, which subsequently fostered health, economic growth, and good governance. Here I argue that a similar priority focus on empowerment of all segments of all populations through education and health (sola schola et sanitate) is needed today for sustainable development. According to decades of research, education and health are essential prerequisites for ending poverty and hunger, for improving institutions and participation in society, for voluntary fertility declines and ending world population growth, for changing behavior and adoption of new and clean technologies, and for enhancing adaptive capacity to already unavoidable climate change. This approach avoids paternalistic imposition of development policies by focusing external aid on enabling people to help themselves, their families, and communities. Prioritizing education and health also helps move more industrialized, aging societies from a focus on material consumption to one on quality of life. Sola schola et sanitate suggests that well being will increasingly be based on health, continued mental stimulation, and consumption of cultural products, rather than fossil fuels and materials. Thus, cognition-or brain power-can be viewed as the zero-emissions energy for sustainable development. PMID- 28630292 TI - Tetrahydrobiopterin regulates monoamine neurotransmitter sulfonation. AB - Monoamine neurotransmitters are among the hundreds of signaling small molecules whose target interactions are switched "on" and "off" via transfer of the sulfuryl-moiety (-SO3) from PAPS (3'-phosphoadenosine 5'-phosphosulfate) to the hydroxyls and amines of their scaffolds. These transfer reactions are catalyzed by a small family of broad-specificity enzymes-the human cytosolic sulfotransferases (SULTs). The first structure of a SULT allosteric-binding site (that of SULT1A1) has recently come to light. The site is conserved among SULT1 family members and is promiscuous-it binds catechins, a naturally occurring family of flavanols. Here, the catechin-binding site of SULT1A3, which sulfonates monoamine neurotransmitters, is modeled on that of 1A1 and used to screen in silico for endogenous metabolite 1A3 allosteres. Screening predicted a single high-affinity allostere, tetrahydrobiopterin (THB), an essential cofactor in monoamine neurotransmitter biosynthesis. THB is shown to bind and inhibit SULT1A3 with high affinity, 23 (+/-2) nM, and to bind weakly, if at all, to the four other major SULTs found in brain and liver. The structure of the THB-bound binding site is determined and confirms that THB binds the catechin site. A structural comparison of SULT1A3 with SULT1A1 (its immediate evolutionary progenitor) reveals how SULT1A3 acquired high affinity for THB and that the majority of residue changes needed to transform 1A1 into 1A3 are clustered at the allosteric and active sites. Finally, sequence records reveal that the coevolution of these sites played an essential role in the evolution of simian neurotransmitter metabolism. PMID- 28630294 TI - Mercury evidence for pulsed volcanism during the end-Triassic mass extinction. AB - The Central Atlantic Magmatic Province (CAMP) has long been proposed as having a causal relationship with the end-Triassic extinction event (~201.5 Ma). In North America and northern Africa, CAMP is preserved as multiple basaltic units interbedded with uppermost Triassic to lowermost Jurassic sediments. However, it has been unclear whether this apparent pulsing was a local feature, or if pulses in the intensity of CAMP volcanism characterized the emplacement of the province as a whole. Here, six geographically widespread Triassic-Jurassic records, representing varied paleoenvironments, are analyzed for mercury (Hg) concentrations and Hg/total organic carbon (Hg/TOC) ratios. Volcanism is a major source of mercury to the modern environment. Clear increases in Hg and Hg/TOC are observed at the end-Triassic extinction horizon, confirming that a volcanically induced global Hg cycle perturbation occurred at that time. The established correlation between the extinction horizon and lowest CAMP basalts allows this sedimentary Hg excursion to be stratigraphically tied to a specific flood basalt unit, strengthening the case for volcanic Hg as the driver of sedimentary Hg/TOC spikes. Additional Hg/TOC peaks are also documented between the extinction horizon and the Triassic-Jurassic boundary (separated by ~200 ky), supporting pulsatory intensity of CAMP volcanism across the entire province and providing direct evidence for episodic volatile release during the initial stages of CAMP emplacement. Pulsatory volcanism, and associated perturbations in the ocean atmosphere system, likely had profound implications for the rate and magnitude of the end-Triassic mass extinction and subsequent biotic recovery. PMID- 28630295 TI - Application of metabolic controls for the maximization of lipid production in semicontinuous fermentation. AB - Acetic acid can be generated through syngas fermentation, lignocellulosic biomass degradation, and organic waste anaerobic digestion. Microbial conversion of acetate into triacylglycerols for biofuel production has many advantages, including low-cost or even negative-cost feedstock and environmental benefits. The main issue stems from the dilute nature of acetate produced in such systems, which is costly to be processed on an industrial scale. To tackle this problem, we established an efficient bioprocess for converting dilute acetate into lipids, using the oleaginous yeast Yarrowia lipolytica in a semicontinuous system. The implemented design used low-strength acetic acid in both salt and acid forms as carbon substrate and a cross-filtration module for cell recycling. Feed controls for acetic acid and nitrogen based on metabolic models and online measurement of the respiratory quotient were used. The optimized process was able to sustain high-density cell culture using acetic acid of only 3% and achieved a lipid titer, yield, and productivity of 115 g/L, 0.16 g/g, and 0.8 g?L-1?h-1, respectively. No carbon substrate was detected in the effluent stream, indicating complete utilization of acetate. These results represent a more than twofold increase in lipid production metrics compared with the current best-performing results using concentrated acetic acid as carbon feed. PMID- 28630293 TI - A null model for microbial diversification. AB - Whether prokaryotes (Bacteria and Archaea) are naturally organized into phenotypically and genetically cohesive units comparable to animal or plant species remains contested, frustrating attempts to estimate how many such units there might be, or to identify the ecological roles they play. Analyses of gene sequences in various closely related prokaryotic groups reveal that sequence diversity is typically organized into distinct clusters, and processes such as periodic selection and extensive recombination are understood to be drivers of cluster formation ("speciation"). However, observed patterns are rarely compared with those obtainable with simple null models of diversification under stochastic lineage birth and death and random genetic drift. Via a combination of simulations and analyses of core and phylogenetic marker genes, we show that patterns of diversity for the genera Escherichia, Neisseria, and Borrelia are generally indistinguishable from patterns arising under a null model. We suggest that caution should thus be taken in interpreting observed clustering as a result of selective evolutionary forces. Unknown forces do, however, appear to play a role in Helicobacter pylori, and some individual genes in all groups fail to conform to the null model. Taken together, we recommend the presented birth-death model as a null hypothesis in prokaryotic speciation studies. It is only when the real data are statistically different from the expectations under the null model that some speciation process should be invoked. PMID- 28630297 TI - Correction for Khan et al., Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease. PMID- 28630296 TI - Subunit-specific role for the amino-terminal domain of AMPA receptors in synaptic targeting. AB - The amino-terminal domain (ATD) of AMPA receptors (AMPARs) accounts for approximately 50% of the protein, yet its functional role, if any, remains a mystery. We have discovered that the translocation of surface GluA1, but not GluA2, AMPAR subunits to the synapse requires the ATD. GluA1A2 heteromers in which the ATD of GluA1 is absent fail to translocate, establishing a critical role of the ATD of GluA1. Inserting GFP into the ATD interferes with the constitutive synaptic trafficking of GluA1, but not GluA2, mimicking the deletion of the ATD. Remarkably, long-term potentiation (LTP) can override the masking effect of the GFP tag. GluA1, but not GluA2, lacking the ATD fails to show LTP. These findings uncover a role for the ATD in subunit-specific synaptic trafficking of AMPARs, both constitutively and during plasticity. How LTP, induced postsynaptically, engages these extracellular trafficking motifs and what specific cleft proteins participate in the process remain to be elucidated. PMID- 28630298 TI - Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need. AB - Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas Hcrtko/ko mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG delta (1.0 to 4.0 Hz) power rebound like WT littermates, spontaneous waking fails to induce a delta power reflecting prior waking duration. This correlates with impaired theta (6.0 to 9.5 Hz) and fast gamma (55 to 80 Hz) activity in prior waking. We algorithmically identify a theta dominated wakefulness (TDW) substate underlying motivated behaviors and typically preceding cataplexy in Hcrtko/ko mice. Hcrtko/ko mice fully implement TDW when waking is enforced, but spontaneous TDW episode duration is greatly reduced. A reformulation of the classic sleep homeostasis model, where homeostatic pressure rises exclusively in TDW rather than all waking, predicts delta power dynamics both in Hcrtko/ko and WT mouse baseline and recovery SWS. The low homeostatic impact of Hcrtko/ko mouse spontaneous waking correlates with decreased cortical expression of neuronal activity-related genes (notably Bdnf, Egr1/Zif268, and Per2). Thus, spontaneous TDW stability relies on Hcrt to sustain theta/fast-gamma network activity and associated plasticity, whereas other arousal circuits sustain TDW during SD. We propose that TDW identifies a discrete global brain activity mode that is regulated by context-dependent neuromodulators and acts as a major driver of sleep homeostasis. Hcrt loss in Hcrtko/ko mice causes impaired TDW maintenance in baseline wake and blunted delta power in SWS, reproducing, respectively, narcolepsy excessive daytime sleepiness and poor sleep quality. PMID- 28630299 TI - Bacteria-mediated hypoxia functions as a signal for mosquito development. AB - Mosquitoes host communities of microbes in their digestive tract that consist primarily of bacteria. We previously reported that several mosquito species, including Aedes aegypti, do not develop beyond the first instar when fed a nutritionally complete diet in the absence of a gut microbiota. In contrast, several species of bacteria, including Escherichia coli, rescue development of axenic larvae into adults. The molecular mechanisms underlying bacteria-dependent growth are unknown. Here, we designed a genetic screen around E. coli that identified high-affinity cytochrome bd oxidase as an essential bacterial gene product for mosquito growth. Bioassays showed that bacteria in nonsterile larvae and gnotobiotic larvae inoculated with wild-type E. coli reduced midgut oxygen levels below 5%, whereas larvae inoculated with E. coli mutants defective for cytochrome bd oxidase did not. Experiments further supported that hypoxia leads to growth and ecdysone-induced molting. Altogether, our results identify aerobic respiration by bacteria as a previously unknown but essential process for mosquito development. PMID- 28630300 TI - G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis. AB - G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome. This inefficiency leads to an increase in H3K9me2 at its target promoters. Blocking the methyltransferase activity of G9a inhibited cellular proliferation and migration in vitro and tumor growth in vivo. Furthermore, an increased level of G9a is a crucial factor in mediating the hypoxic response by down-regulating the expression of specific genes, including ARNTL, CEACAM7, GATA2, HHEX, KLRG1, and OGN This down-regulation can be rescued by a small molecule inhibitor of G9a. Based on the hypothesis that the changes in gene expression would influence patient outcomes, we have developed a prognostic G9a suppressed gene signature that can stratify breast cancer patients. Together, our findings provide an insight into the role G9a plays as an epigenetic mediator of hypoxic response, which can be used as a diagnostic marker, and proposes G9a as a therapeutic target for solid cancers. PMID- 28630301 TI - Potential high-Tc superconducting lanthanum and yttrium hydrides at high pressure. AB - A systematic structure search in the La-H and Y-H systems under pressure reveals some hydrogen-rich structures with intriguing electronic properties. For example, LaH10 is found to adopt a sodalite-like face-centered cubic (fcc) structure, stable above 200 GPa, and LaH8 a C2/m space group structure. Phonon calculations indicate both are dynamically stable; electron phonon calculations coupled to Bardeen-Cooper-Schrieffer (BCS) arguments indicate they might be high-Tc superconductors. In particular, the superconducting transition temperature Tc calculated for LaH10 is 274-286 K at 210 GPa. Similar calculations for the Y-H system predict stability of the sodalite-like fcc YH10 and a Tc above room temperature, reaching 305-326 K at 250 GPa. The study suggests that dense hydrides consisting of these and related hydrogen polyhedral networks may represent new classes of potential very high-temperature superconductors. PMID- 28630302 TI - New perspective on spring vegetation phenology and global climate change based on Tibetan Plateau tree-ring data. AB - Phenological responses of vegetation to climate, in particular to the ongoing warming trend, have received much attention. However, divergent results from the analyses of remote sensing data have been obtained for the Tibetan Plateau (TP), the world's largest high-elevation region. This study provides a perspective on vegetation phenology shifts during 1960-2014, gained using an innovative approach based on a well-validated, process-based, tree-ring growth model that is independent of temporal changes in technical properties and image quality of remote sensing products. Twenty composite site chronologies were analyzed, comprising about 3,000 trees from forested areas across the TP. We found that the start of the growing season (SOS) has advanced, on average, by 0.28 d/y over the period 1960-2014. The end of the growing season (EOS) has been delayed, by an estimated 0.33 d/y during 1982-2014. No significant changes in SOS or EOS were observed during 1960-1981. April-June and August-September minimum temperatures are the main climatic drivers for SOS and EOS, respectively. An increase of 1 degrees C in April-June minimum temperature shifted the dates of xylem phenology by 6 to 7 d, lengthening the period of tree-ring formation. This study extends the chronology of TP phenology farther back in time and reconciles the disparate views on SOS derived from remote sensing data. Scaling up this analysis may improve understanding of climate change effects and related phenological and plant productivity on a global scale. PMID- 28630304 TI - Transitional-turbulent spots and turbulent-turbulent spots in boundary layers. AB - Two observations drawn from a thoroughly validated direct numerical simulation of the canonical spatially developing, zero-pressure gradient, smooth, flat-plate boundary layer are presented here. The first is that, for bypass transition in the narrow sense defined herein, we found that the transitional-turbulent spot inception mechanism is analogous to the secondary instability of boundary-layer natural transition, namely a spanwise vortex filament becomes a [Formula: see text] vortex and then, a hairpin packet. Long streak meandering does occur but usually when a streak is infected by a nearby existing transitional-turbulent spot. Streak waviness and breakdown are, therefore, not the mechanisms for the inception of transitional-turbulent spots found here. Rather, they only facilitate the growth and spreading of existing transitional-turbulent spots. The second observation is the discovery, in the inner layer of the developed turbulent boundary layer, of what we call turbulent-turbulent spots. These turbulent-turbulent spots are dense concentrations of small-scale vortices with high swirling strength originating from hairpin packets. Although structurally quite similar to the transitional-turbulent spots, these turbulent-turbulent spots are generated locally in the fully turbulent environment, and they are persistent with a systematic variation of detection threshold level. They exert indentation, segmentation, and termination on the viscous sublayer streaks, and they coincide with local concentrations of high levels of Reynolds shear stress, enstrophy, and temperature fluctuations. The sublayer streaks seem to be passive and are often simply the rims of the indentation pockets arising from the turbulent-turbulent spots. PMID- 28630303 TI - How members of the human gut microbiota overcome the sulfation problem posed by glycosaminoglycans. AB - The human microbiota, which plays an important role in health and disease, uses complex carbohydrates as a major source of nutrients. Utilization hierarchy indicates that the host glycosaminoglycans heparin (Hep) and heparan sulfate (HS) are high-priority carbohydrates for Bacteroides thetaiotaomicron, a prominent member of the human microbiota. The sulfation patterns of these glycosaminoglycans are highly variable, which presents a significant enzymatic challenge to the polysaccharide lyases and sulfatases that mediate degradation. It is possible that the bacterium recruits lyases with highly plastic specificities and expresses a repertoire of enzymes that target substructures of the glycosaminoglycans with variable sulfation or that the glycans are desulfated before cleavage by the lyases. To distinguish between these mechanisms, the components of the B. thetaiotaomicron Hep/HS degrading apparatus were analyzed. The data showed that the bacterium expressed a single-surface endo-acting lyase that cleaved HS, reflecting its higher molecular weight compared with Hep. Both Hep and HS oligosaccharides imported into the periplasm were degraded by a repertoire of lyases, with each enzyme displaying specificity for substructures within these glycosaminoglycans that display a different degree of sulfation. Furthermore, the crystal structures of a key surface glycan binding protein, which is able to bind both Hep and HS, and periplasmic sulfatases reveal the major specificity determinants for these proteins. The locus described here is highly conserved within the human gut Bacteroides, indicating that the model developed is of generic relevance to this important microbial community. PMID- 28630306 TI - Heat exchange between a bouncing drop and a superhydrophobic substrate. AB - The ability to enhance or limit heat transfer between a surface and impacting drops is important in applications ranging from industrial spray cooling to the thermal regulation of animals in cold rain. When these surfaces are micro/nanotextured and hydrophobic, or superhydrophobic, an impacting drop can spread and recoil over trapped air pockets so quickly that it can completely bounce off the surface. It is expected that this short contact time limits heat transfer; however, the amount of heat exchanged and precise role of various parameters, such as the drop size, are unknown. Here, we demonstrate that the amount of heat exchanged between a millimeter-sized water drop and a superhydrophobic surface will be orders of magnitude less when the drop bounces than when it sticks. Through a combination of experiments and theory, we show that the heat transfer process on superhydrophobic surfaces is independent of the trapped gas. Instead, we find that, for a given spreading factor, the small fraction of heat transferred is controlled by two dimensionless groupings of physical parameters: one that relates the thermal properties of the drop and bulk substrate and the other that characterizes the relative thermal, inertial, and capillary dynamics of the drop. PMID- 28630305 TI - Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines. AB - Mucosa-associated invariant T (MAIT) cells are a large innate-like T-cell subset in humans defined by invariant TCR Valpha7.2 use and expression of CD161. MAIT cells recognize microbial riboflavin metabolites of bacterial or fungal origin presented by the monomorphic MR1 molecule. The extraordinary level of evolutionary conservation of MR1 and the limited known diversity of riboflavin metabolite antigens have suggested that MAIT cells are relatively homogeneous and uniform in responses against diverse microbes carrying the riboflavin biosynthesis pathway. The ability of MAIT cells to exhibit microbe-specific functional specialization has not been thoroughly investigated. Here, we found that MAIT cell responses against Escherichia coli and Candida albicans displayed microbe-specific polyfunctional response profiles, antigen sensitivity, and response magnitudes. MAIT cell effector responses against E. coli and C. albicans displayed differential MR1 dependency and TCR beta-chain bias, consistent with possible divergent antigen subspecificities between these bacterial and fungal organisms. Finally, although the MAIT cell immunoproteome was overall relatively homogenous and consistent with an effector memory-like profile, it still revealed diversity in a set of natural killer cell-associated receptors. Among these, CD56, CD84, and CD94 defined a subset with higher expression of the transcription factors promyelocytic leukemia zinc finger (PLZF), eomesodermin, and T-bet and enhanced capacity to respond to IL-12 and IL-18 stimulation. Thus, the conserved and innate-like MAIT cells harbor multiple layers of functional heterogeneity as they respond to bacterial or fungal organisms or innate cytokines and adapt their antimicrobial response patterns in a stimulus-specific manner. PMID- 28630307 TI - Nanophotonics-enabled solar membrane distillation for off-grid water purification. AB - With more than a billion people lacking accessible drinking water, there is a critical need to convert nonpotable sources such as seawater to water suitable for human use. However, energy requirements of desalination plants account for half their operating costs, so alternative, lower energy approaches are equally critical. Membrane distillation (MD) has shown potential due to its low operating temperature and pressure requirements, but the requirement of heating the input water makes it energy intensive. Here, we demonstrate nanophotonics-enabled solar membrane distillation (NESMD), where highly localized photothermal heating induced by solar illumination alone drives the distillation process, entirely eliminating the requirement of heating the input water. Unlike MD, NESMD can be scaled to larger systems and shows increased efficiencies with decreased input flow velocities. Along with its increased efficiency at higher ambient temperatures, these properties all point to NESMD as a promising solution for household- or community-scale desalination. PMID- 28630308 TI - Measuring shared variants in cohorts of discordant siblings with applications to autism. AB - We develop a method of analysis [affected to discordant sibling pairs (A2DS)] that tests if shared variants contribute to a disorder. Using a standard measure of genetic relation, test individuals are compared with a cohort of discordant sibling pairs (CDS) to derive a comparative similarity score. We ask if a test individual is more similar to an unrelated affected than to the unrelated unaffected sibling from the CDS and then, sum over such individuals and pairs. Statistical significance is judged by randomly permuting the affected status in the CDS. In the analysis of published genotype data from the Simons Simplex Collection (SSC) and the Autism Genetic Resource Exchange (AGRE) cohorts of children with autism spectrum disorder (ASD), we find strong statistical significance that the affected are more similar to the affected than to the unaffected of the CDS (P value ~ 0.00001). Fathers in multiplex families have marginally greater similarity (P value = 0.02) to unrelated affected individuals. These results do not depend on ethnic matching or gender. PMID- 28630309 TI - QnAs with Tony Hunter and James Allison. PMID- 28630310 TI - Group augmentation, collective action, and territorial boundary patrols by male chimpanzees. AB - How can collective action evolve when individuals benefit from cooperation regardless of whether they pay its participation costs? According to one influential perspective, collective action problems are common, especially when groups are large, but may be solved when individuals who have more to gain from the collective good or can produce it at low costs provide it to others as a byproduct. Several results from a 20-y study of one of the most striking examples of collective action in nonhuman animals, territorial boundary patrolling by male chimpanzees, are consistent with these ideas. Individuals were more likely to patrol when (i) they had more to gain because they had many offspring in the group; (ii) they incurred relatively low costs because of their high dominance rank and superior physical condition; and (iii) the group size was relatively small. However, several other findings were better explained by group augmentation theory, which proposes that individuals should bear the short-term costs of collective action even when they have little to gain immediately if such action leads to increases in group size and long-term increases in reproductive success. In support of this theory, (i) individual patrolling effort was higher and less variable than participation in intergroup aggression in other primate species; (ii) males often patrolled when they had no offspring or maternal relatives in the group; and (iii) the aggregate patrolling effort of the group did not decrease with group size. We propose that group augmentation theory deserves more consideration in research on collective action. PMID- 28630311 TI - A prokaryotic viral sequence is expressed and conserved in mammalian brain. AB - A natural and permanent transfer of prokaryotic viral sequences to mammals has not been reported by others. Circular "SPHINX" DNAs <5 kb were previously isolated from nuclease-protected cytoplasmic particles in rodent neuronal cell lines and brain. Two of these DNAs were sequenced after Phi29 polymerase amplification, and they revealed significant but imperfect homology to segments of commensal Acinetobacter phage viruses. These findings were surprising because the brain is isolated from environmental microorganisms. The 1.76-kb DNA sequence (SPHINX 1.8), with an iteron before its ORF, was evaluated here for its expression in neural cells and brain. A rabbit affinity purified antibody generated against a peptide without homology to mammalian sequences labeled a nonglycosylated ~41-kDa protein (spx1) on Western blots, and the signal was efficiently blocked by the competing peptide. Spx1 was resistant to limited proteinase K digestion, but was unrelated to the expression of host prion protein or its pathologic amyloid form. Remarkably, spx1 concentrated in selected brain synapses, such as those on anterior motor horn neurons that integrate many complex neural inputs. SPHINX 1.8 appears to be involved in tissue-specific differentiation, including essential functions that preserve its propagation during mammalian evolution, possibly via maternal inheritance. The data here indicate that mammals can share and exchange a larger world of prokaryotic viruses than previously envisioned. PMID- 28630312 TI - Uncovering BRD4 hyperphosphorylation associated with cellular transformation in NUT midline carcinoma. AB - The epigenetic reader BRD4 plays a vital role in transcriptional regulation, cellular growth control, and cell-cycle progression. Dysregulation of BRD4 function has been implicated in the pathogenesis of a wide range of cancers. However, how BRD4 is regulated to maintain its normal function in healthy cells and how alteration of this process leads to cancer remain poorly understood. In this study, we discovered that BRD4 is hyperphosphorylated in NUT midline carcinoma and identified CDK9 as a potential kinase mediating BRD4 hyperphosphorylation. Disruption of BRD4 hyperphosphorylation using both chemical and molecular inhibitors led to the repression of BRD4 downstream oncogenes and abrogation of cellular transformation. BRD4 hyperphosphorylation is also observed in other cancers displaying enhanced BRD4 oncogenic activity. Our study revealed a mechanism that may regulate BRD4 biological function through phosphorylation, which, when dysregulated, could lead to oncogenesis. Our finding points to strategies to target the aberrant BRD4 signaling specifically for cancer intervention. PMID- 28630314 TI - Robert Treat Paine III (1933-2016). PMID- 28630313 TI - Targeting reactive nitrogen species suppresses hereditary pancreatic cancer. AB - Germline mutation of BRCA2 induces hereditary pancreatic cancer. However, how BRCA2 mutation specifically induces pancreatic tumorigenesis remains elusive. Here, we have examined a mouse model of Brca2-deficiency-induced pancreatic tumors and found that excessive reactive nitrogen species (RNS), such as nitrite, are generated in precancerous pancreases, which induce massive DNA damage, including DNA double-strand breaks. RNS-induced DNA lesions cause genomic instability in the absence of Brca2. Moreover, with the treatment of antioxidant tempol to suppress RNS, not only are DNA lesions significantly reduced, but also the onset of pancreatic cancer is delayed. Thus, this study demonstrates that excess RNS are a nongenetic driving force for Brca2-deficiency-induced pancreatic tumors. Suppression of RNS could be an important strategy for pancreatic cancer prevention. PMID- 28630315 TI - Correction for Koch et al., Genetic rescue models refute nonautonomous rod cell death in retinitis pigmentosa. PMID- 28630317 TI - Correction to Supporting Information for Suzuki et al., Behavioral contagion during learning about another agent's risk-preferences acts on the neural representation of decision-risk. PMID- 28630316 TI - Recombinant silicateins as model biocatalysts in organosiloxane chemistry. AB - The family of silicatein enzymes from marine sponges (phylum Porifera) is unique in nature for catalyzing the formation of inorganic silica structures, which the organisms incorporate into their skeleton. However, the synthesis of organosiloxanes catalyzed by these enzymes has thus far remained largely unexplored. To investigate the reactivity of these enzymes in relation to this important class of compounds, their catalysis of Si-O bond hydrolysis and condensation was investigated with a range of model organosilanols and silyl ethers. The enzymes' kinetic parameters were obtained by a high-throughput colorimetric assay based on the hydrolysis of 4-nitrophenyl silyl ethers. These assays showed unambiguous catalysis with kcat/Km values on the order of 2-50 min 1 MUM-1 Condensation reactions were also demonstrated by the generation of silyl ethers from their corresponding silanols and alcohols. Notably, when presented with a substrate bearing both aliphatic and aromatic hydroxy groups the enzyme preferentially silylates the latter group, in clear contrast to nonenzymatic silylations. Furthermore, the silicateins are able to catalyze transetherifications, where the silyl group from one silyl ether may be transferred to a recipient alcohol. Despite close sequence homology to the protease cathepsin L, the silicateins seem to exhibit no significant protease or esterase activity when tested against analogous substrates. Overall, these results suggest the silicateins are promising candidates for future elaboration into efficient and selective biocatalysts for organosiloxane chemistry. PMID- 28630318 TI - Reducing secondary organic aerosol formation from gasoline vehicle exhaust. AB - On-road gasoline vehicles are a major source of secondary organic aerosol (SOA) in urban areas. We investigated SOA formation by oxidizing dilute, ambient-level exhaust concentrations from a fleet of on-road gasoline vehicles in a smog chamber. We measured less SOA formation from newer vehicles meeting more stringent emissions standards. This suggests that the natural replacement of older vehicles with newer ones that meet more stringent emissions standards should reduce SOA levels in urban environments. However, SOA production depends on both precursor concentrations (emissions) and atmospheric chemistry (SOA yields). We found a strongly nonlinear relationship between SOA formation and the ratio of nonmethane organic gas to oxides of nitrogen (NOx) (NMOG:NOx), which affects the fate of peroxy radicals. For example, changing the NMOG:NOx from 4 to 10 ppbC/ppbNOx increased the SOA yield from dilute gasoline vehicle exhaust by a factor of 8. We investigated the implications of this relationship for the Los Angeles area. Although organic gas emissions from gasoline vehicles in Los Angeles are expected to fall by almost 80% over the next two decades, we predict no reduction in SOA production from these emissions due to the effects of rising NMOG:NOx on SOA yields. This highlights the importance of integrated emission control policies for NOx and organic gases. PMID- 28630319 TI - Chimpanzees return favors at a personal cost. AB - Humans regularly provide others with resources at a personal cost to themselves. Chimpanzees engage in some cooperative behaviors in the wild as well, but their motivational underpinnings are unclear. In three experiments, chimpanzees (Pan troglodytes) always chose between an option delivering food both to themselves and a partner and one delivering food only to themselves. In one condition, a conspecific partner had just previously taken a personal risk to make this choice available. In another condition, no assistance from the partner preceded the subject's decision. Chimpanzees made significantly more prosocial choices after receiving their partner's assistance than when no assistance was given (experiment 1) and, crucially, this was the case even when choosing the prosocial option was materially costly for the subject (experiment 2). Moreover, subjects appeared sensitive to the risk of their partner's assistance and chose prosocially more often when their partner risked losing food by helping (experiment 3). These findings demonstrate experimentally that chimpanzees are willing to incur a material cost to deliver rewards to a conspecific, but only if that conspecific previously assisted them, and particularly when this assistance was risky. Some key motivations involved in human cooperation thus may have deeper phylogenetic roots than previously suspected. PMID- 28630320 TI - Delta20 IFITM2 differentially restricts X4 and R5 HIV-1. AB - CCR5 (R5)-tropic, but not CXCR4 (X4)-tropic, HIV-1 is associated with primary HIV 1 infection and transmission. Recent studies have shown that IFN-induced transmembrane (IFITM) proteins, including IFITM1, IFITM2, and IFITM3, restrict a broad range of viruses. Here, we demonstrate that an IFITM2 isoform (Delta20 IFITM2) lacking 20 amino acids at the N terminus differentially restricts X4 and R5 HIV-1. Delta20 IFITM2 suppresses replication of X4 HIV-1 strains by inhibiting their entry. High levels of Delta20 IFITM2 expression could be detected in CD4+ T cells and in monocytes. Infection of X4 viruses in monocyte-derived macrophages and dendritic cells is enhanced upon depletion of IFITM2 isoforms. Furthermore, we also show that coreceptor use is the determining factor for differential HIV-1 restriction of Delta20 IFITM2. When we replace the C terminus of CCR5 with the C terminus of CXCR4, R5 viruses become more susceptible to Delta20 IFITM2-mediated restriction. In contrast to previous studies, our research reveals that neither X4 nor R5 HIV-1 is suppressed by IFITM2 and IFITM3. The multifactor gatekeeping model has been proposed to explain restriction of X4 viruses in the early stage of HIV-1 diseases. Our findings indicate that Delta20 IFITM2 may serve as a major contributor to this gatekeeping mechanism. PMID- 28630321 TI - How selective severing by katanin promotes order in the plant cortical microtubule array. AB - Plant morphogenesis requires differential and often asymmetric growth. A key role in controlling anisotropic expansion of individual cells is played by the cortical microtubule array. Although highly organized, the array can nevertheless rapidly change in response to internal and external cues. Experiments have identified the microtubule-severing enzyme katanin as a central player in controlling the organizational state of the array. Katanin action is required both for normal alignment and the adaptation of array orientation to mechanical, environmental, and developmental stimuli. How katanin fulfills its controlling role, however, remains poorly understood. On the one hand, from a theoretical perspective, array ordering depends on the "weeding out" of discordant microtubules through frequent catastrophe-inducing collisions among microtubules. Severing would reduce average microtubule length and lifetime, and consequently weaken the driving force for alignment. On the other hand, it has been suggested that selective severing at microtubule crossovers could facilitate the removal of discordant microtubules. Here we show that this apparent conflict can be resolved by systematically dissecting the role of all of the relevant interactions in silico. This procedure allows the identification of the sufficient and necessary conditions for katanin to promote array alignment, stresses the critical importance of the experimentally observed selective severing of the "crossing" microtubule at crossovers, and reveals a hitherto not appreciated role for microtubule bundling. We show how understanding the underlying mechanism can aid with interpreting experimental results and designing future experiments. PMID- 28630322 TI - TCTE1 is a conserved component of the dynein regulatory complex and is required for motility and metabolism in mouse spermatozoa. AB - Flagella and cilia are critical cellular organelles that provide a means for cells to sense and progress through their environment. The central component of flagella and cilia is the axoneme, which comprises the "9+2" microtubule arrangement, dynein arms, radial spokes, and the nexin-dynein regulatory complex (N-DRC). Failure to properly assemble components of the axoneme leads to defective flagella and in humans leads to a collection of diseases referred to as ciliopathies. Ciliopathies can manifest as severe syndromic diseases that affect lung and kidney function, central nervous system development, bone formation, visceral organ organization, and reproduction. T-Complex-Associated-Testis Expressed 1 (TCTE1) is an evolutionarily conserved axonemal protein present from Chlamydomonas (DRC5) to mammals that localizes to the N-DRC. Here, we show that mouse TCTE1 is testis-enriched in its expression, with its mRNA appearing in early round spermatids and protein localized to the flagellum. TCTE1 is 498 aa in length with a leucine rich repeat domain at the C terminus and is present in eukaryotes containing a flagellum. Knockout of Tcte1 results in male sterility because Tcte1-null spermatozoa show aberrant motility. Although the axoneme is structurally normal in Tcte1 mutant spermatozoa, Tcte1-null sperm demonstrate a significant decrease of ATP, which is used by dynein motors to generate the bending force of the flagellum. These data provide a link to defining the molecular intricacies required for axoneme function, sperm motility, and male fertility. PMID- 28630323 TI - Role of the CBP catalytic core in intramolecular SUMOylation and control of histone H3 acetylation. AB - The histone acetyl transferases CREB-binding protein (CBP) and its paralog p300 play a critical role in numerous cellular processes. Dysregulation of their catalytic activity is associated with several human diseases. Previous work has elucidated the regulatory mechanisms of p300 acetyltransferase activity, but it is not known whether CBP activity is controlled similarly. Here, we present the crystal structure of the CBP catalytic core encompassing the bromodomain (BRD), CH2 (comprising PHD and RING), HAT, and ZZ domains at 2.4-A resolution. The BRD, PHD, and HAT domains form an integral structural unit to which the RING and ZZ domains are flexibly attached. The structure of the apo-CBP HAT domain is similar to that of acyl-CoA-bound p300 HAT complexes and shows that the acetyl-CoA binding site is stably formed in the absence of cofactor. The BRD, PHD, and ZZ domains interact with small ubiquitin-like modifier 1 (SUMO-1) and Ubc9, and function as an intramolecular E3 ligase for SUMOylation of the cell cycle regulatory domain 1 (CRD1) of CBP, which is located adjacent to the BRD. In vitro HAT assays suggest that the RING domain, the autoregulatory loop (AL) within the HAT domain, and the ZZ domain do not directly influence catalytic activity, whereas the BRD is essential for histone H3 acetylation in nucleosomal substrates. Several lysine residues in the intrinsically disordered AL are autoacetylated by the HAT domain. Upon autoacetylation, acetyl-K1596 (Ac-K1596) binds intramolecularly to the BRD, competing with histones for binding to the BRD and acting as a negative regulator that inhibits histone H3 acetylation. PMID- 28630324 TI - Trust is heritable, whereas distrust is not. AB - Why do people distrust others in social exchange? To what degree, if at all, is distrust subject to genetic influences, and thus possibly heritable, and to what degree is it nurtured by families and immediate peers who encourage young people to be vigilant and suspicious of others? Answering these questions could provide fundamental clues about the sources of individual differences in the disposition to distrust, including how they may differ from the sources of individual differences in the disposition to trust. In this article, we report the results of a study of monozygotic and dizygotic female twins who were asked to decide either how much of a counterpart player's monetary endowment they wanted to take from their counterpart (i.e., distrust) or how much of their own monetary endowment they wanted to send to their counterpart (i.e., trust). Our results demonstrate that although the disposition to trust is explained to some extent by heritability but not by shared socialization, the disposition to distrust is explained by shared socialization but not by heritability. The sources of distrust are therefore distinct from the sources of trust in many ways. PMID- 28630325 TI - Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization. AB - Transmission of hemorrhagic fever New World arenaviruses from their rodent reservoirs to human populations poses substantial public health and economic dangers. These zoonotic events are enabled by the specific interaction between the New World arenaviral attachment glycoprotein, GP1, and cell surface human transferrin receptor (hTfR1). Here, we present the structural basis for how a mouse-derived neutralizing antibody (nAb), OD01, disrupts this interaction by targeting the receptor-binding surface of the GP1 glycoprotein from Junin virus (JUNV), a hemorrhagic fever arenavirus endemic in central Argentina. Comparison of our structure with that of a previously reported nAb complex (JUNV GP1-GD01) reveals largely overlapping epitopes but highly distinct antibody-binding modes. Despite differences in GP1 recognition, we find that both antibodies present a key tyrosine residue, albeit on different chains, that inserts into a central pocket on JUNV GP1 and effectively mimics the contacts made by the host TfR1. These data provide a molecular-level description of how antibodies derived from different germline origins arrive at equivalent immunological solutions to virus neutralization. PMID- 28630326 TI - Reconstruction and evolutionary history of eutherian chromosomes. AB - Whole-genome assemblies of 19 placental mammals and two outgroup species were used to reconstruct the order and orientation of syntenic fragments in chromosomes of the eutherian ancestor and six other descendant ancestors leading to human. For ancestral chromosome reconstructions, we developed an algorithm (DESCHRAMBLER) that probabilistically determines the adjacencies of syntenic fragments using chromosome-scale and fragmented genome assemblies. The reconstructed chromosomes of the eutherian, boreoeutherian, and euarchontoglires ancestor each included >80% of the entire length of the human genome, whereas reconstructed chromosomes of the most recent common ancestor of simians, catarrhini, great apes, and humans and chimpanzees included >90% of human genome sequence. These high-coverage reconstructions permitted reliable identification of chromosomal rearrangements over ~105 My of eutherian evolution. Orangutan was found to have eight chromosomes that were completely conserved in homologous sequence order and orientation with the eutherian ancestor, the largest number for any species. Ruminant artiodactyls had the highest frequency of intrachromosomal rearrangements, and interchromosomal rearrangements dominated in murid rodents. A total of 162 chromosomal breakpoints in evolution of the eutherian ancestral genome to the human genome were identified; however, the rate of rearrangements was significantly lower (0.80/My) during the first ~60 My of eutherian evolution, then increased to greater than 2.0/My along the five primate lineages studied. Our results significantly expand knowledge of eutherian genome evolution and will facilitate greater understanding of the role of chromosome rearrangements in adaptation, speciation, and the etiology of inherited and spontaneously occurring diseases. PMID- 28630328 TI - Toll-like receptor pathway evolution in deuterostomes. AB - Animals have evolved an array of pattern-recognition receptor families essential for recognizing conserved molecular motifs characteristic of pathogenic microbes. One such family is the Toll-like receptors (TLRs). On pathogen binding, TLRs initiate specialized cytokine signaling catered to the class of invading pathogen. This signaling is pivotal for activating adaptive immunity in vertebrates, suggesting a close evolutionary relationship between innate and adaptive immune systems. Despite significant advances toward understanding TLR facilitated immunity in vertebrates, knowledge of TLR pathway evolution in other deuterostomes is limited. By analyzing genomes and transcriptomes across 37 deuterostome taxa, we shed light on the evolution and diversity of TLR pathway signaling elements. Here, we show that the deuterostome ancestor possessed a molecular toolkit homologous to that which drives canonical MYD88-dependent TLR signaling in contemporary mammalian lineages. We also provide evidence that TLR3 facilitated antiviral signaling predates the origin of its TCAM1 dependence recognized in the vertebrates. SARM1, a negative regulator of TCAM1-dependent pathways in vertebrates, was also found to be present across all major deuterostome lineages despite the apparent absence of TCAM1 in invertebrate deuterostomes. Whether the presence of SARM1 is the result of its role in immunity regulation, neuron physiology, or a function of both is unclear. Additionally, Bayesian phylogenetic analyses corroborate several lineage-specific TLR gene expansions in urchins and cephalochordates. Importantly, our results underscore the need to sample across taxonomic groups to understand evolutionary patterns of the innate immunity foundation on which complex immunological novelties arose. PMID- 28630327 TI - Virus-induced inflammasome activation is suppressed by prostaglandin D2/DP1 signaling. AB - Prostaglandin D2 (PGD2), an eicosanoid with both pro- and anti-inflammatory properties, is the most abundantly expressed prostaglandin in the brain. Here we show that PGD2 signaling through the D-prostanoid receptor 1 (DP1) receptor is necessary for optimal microglia/macrophage activation and IFN expression after infection with a neurotropic coronavirus. Genome-wide expression analyses indicated that PGD2/DP1 signaling is required for up-regulation of a putative inflammasome inhibitor, PYDC3, in CD11b+ cells in the CNS of infected mice. Our results also demonstrated that, in addition to PGD2/DP1 signaling, type 1 IFN (IFN-I) signaling is required for PYDC3 expression. In the absence of Pydc3 up regulation, IL-1beta expression and, subsequently, mortality were increased in infected DP1-/- mice. Notably, survival was enhanced by IL1 receptor blockade, indicating that the effects of the absence of DP1 signaling on clinical outcomes were mediated, at least in part, by inflammasomes. Using bone marrow-derived macrophages in vitro, we confirmed that PYDC3 expression is dependent upon DP1 signaling and that IFN priming is critical for PYDC3 up-regulation. In addition, Pydc3 silencing or overexpression augmented or diminished IL-1beta secretion, respectively. Furthermore, DP1 signaling in human macrophages also resulted in the up-regulation of a putative functional analog, POP3, suggesting that PGD2 similarly modulates inflammasomes in human cells. These findings demonstrate a previously undescribed role for prostaglandin signaling in preventing excessive inflammasome activation and, together with previously published results, suggest that eicosanoids and inflammasomes are reciprocally regulated. PMID- 28630329 TI - The case for defined protein folding pathways. AB - We consider the differences between the many-pathway protein folding model derived from theoretical energy landscape considerations and the defined-pathway model derived from experiment. A basic tenet of the energy landscape model is that proteins fold through many heterogeneous pathways by way of amino acid-level dynamics biased toward selecting native-like interactions. The many pathways imagined in the model are not observed in the structure-formation stage of folding by experiments that would have found them, but they have now been detected and characterized for one protein in the initial prenucleation stage. Analysis presented here shows that these many microscopic trajectories are not distinct in any functionally significant way, and they have neither the structural information nor the biased energetics needed to select native vs. nonnative interactions during folding. The opposed defined-pathway model stems from experimental results that show that proteins are assemblies of small cooperative units called foldons and that a number of proteins fold in a reproducible pathway one foldon unit at a time. Thus, the same foldon interactions that encode the native structure of any given protein also naturally encode its particular foldon-based folding pathway, and they collectively sum to produce the energy bias toward native interactions that is necessary for efficient folding. Available information suggests that quantized native structure and stepwise folding coevolved in ancient repeat proteins and were retained as a functional pair due to their utility for solving the difficult protein folding problem. PMID- 28630331 TI - Distinguishing attosecond electron-electron scattering and screening in transition metals. AB - Electron-electron interactions are the fastest processes in materials, occurring on femtosecond to attosecond timescales, depending on the electronic band structure of the material and the excitation energy. Such interactions can play a dominant role in light-induced processes such as nano-enhanced plasmonics and catalysis, light harvesting, or phase transitions. However, to date it has not been possible to experimentally distinguish fundamental electron interactions such as scattering and screening. Here, we use sequences of attosecond pulses to directly measure electron-electron interactions in different bands of different materials with both simple and complex Fermi surfaces. By extracting the time delays associated with photoemission we show that the lifetime of photoelectrons from the d band of Cu are longer by ~100 as compared with those from the same band of Ni. We attribute this to the enhanced electron-electron scattering in the unfilled d band of Ni. Using theoretical modeling, we can extract the contributions of electron-electron scattering and screening in different bands of different materials with both simple and complex Fermi surfaces. Our results also show that screening influences high-energy photoelectrons (~20 eV) significantly less than low-energy photoelectrons. As a result, high-energy photoelectrons can serve as a direct probe of spin-dependent electron-electron scattering by neglecting screening. This can then be applied to quantifying the contribution of electron interactions and screening to low-energy excitations near the Fermi level. The information derived here provides valuable and unique information for a host of quantum materials. PMID- 28630330 TI - Annual mass drownings of the Serengeti wildebeest migration influence nutrient cycling and storage in the Mara River. AB - The annual migration of ~1.2 million wildebeest (Connochaetes taurinus) through the Serengeti Mara Ecosystem is the largest remaining overland migration in the world. One of the most iconic portions of their migration is crossing of the Mara River, during which thousands drown annually. These mass drownings have been noted, but their frequency, size, and impact on aquatic ecosystems have not been quantified. Here, we estimate the frequency and size of mass drownings in the Mara River and model the fate of carcass nutrients through the river ecosystem. Mass drownings (>100 individuals) occurred in at least 13 of the past 15 y; on average, 6,250 carcasses and 1,100 tons of biomass enter the river each year. Half of a wildebeest carcass dry mass is bone, which takes 7 y to decompose, thus acting as a long-term source of nutrients to the Mara River. Carcass soft tissue decomposes in 2-10 wk, and these nutrients are mineralized by consumers, assimilated by biofilms, transported downstream, or moved back into the terrestrial ecosystem by scavengers. These inputs comprise 34-50% of the assimilated diet of fish when carcasses are present and 7-24% via biofilm on bones after soft tissue decomposition. Our results show a terrestrial animal migration can have large impacts on a river ecosystem, which may influence nutrient cycling and river food webs at decadal time scales. Similar mass drownings may have played an important role in rivers throughout the world when large migratory herds were more common features of the landscape. PMID- 28630332 TI - Evolutionary strata on young mating-type chromosomes despite the lack of sexual antagonism. AB - Sex chromosomes can display successive steps of recombination suppression known as "evolutionary strata," which are thought to result from the successive linkage of sexually antagonistic genes to sex-determining genes. However, there is little evidence to support this explanation. Here we investigate whether evolutionary strata can evolve without sexual antagonism using fungi that display suppressed recombination extending beyond loci determining mating compatibility despite lack of male/female roles associated with their mating types. By comparing full-length chromosome assemblies from five anther-smut fungi with or without recombination suppression in their mating-type chromosomes, we inferred the ancestral gene order and derived chromosomal arrangements in this group. This approach shed light on the chromosomal fusion underlying the linkage of mating-type loci in fungi and provided evidence for multiple clearly resolved evolutionary strata over a range of ages (0.9-2.1 million years) in mating-type chromosomes. Several evolutionary strata did not include genes involved in mating-type determination. The existence of strata devoid of mating-type genes, despite the lack of sexual antagonism, calls for a unified theory of sex-related chromosome evolution, incorporating, for example, the influence of partially linked deleterious mutations and the maintenance of neutral rearrangement polymorphism due to balancing selection on sexes and mating types. PMID- 28630334 TI - Correction for Brumberg et al., Single-crystal Ih ice surfaces unveil connection between macroscopic and molecular structure. PMID- 28630333 TI - Boosting CNS axon regeneration by harnessing antagonistic effects of GSK3 activity. AB - Implications of GSK3 activity for axon regeneration are often inconsistent, if not controversial. Sustained GSK3 activity in GSK3S/A knock-in mice reportedly accelerates peripheral nerve regeneration via increased MAP1B phosphorylation and concomitantly reduces microtubule detyrosination. In contrast, the current study shows that lens injury-stimulated optic nerve regeneration was significantly compromised in these knock-in mice. Phosphorylation of MAP1B and CRMP2 was expectedly increased in retinal ganglion cell (RGC) axons upon enhanced GSK3 activity, but, surprisingly, no GSK3-mediated CRMP2 inhibition was detected in sciatic nerves, thus revealing a fundamental difference between central and peripheral axons. Conversely, genetic or shRNA-mediated conditional KO/knockdown of GSK3beta reduced inhibitory phosphorylation of CRMP2 in RGCs and improved optic nerve regeneration. Accordingly, GSK3beta KO-mediated neurite growth promotion and myelin disinhibition were abrogated by CRMP2 inhibition and largely mimicked in WT neurons upon expression of constitutively active CRMP2 (CRMP2T/A). These results underscore the prevalent requirement of active CRMP2 for optic nerve regeneration. Strikingly, expression of CRMP2T/A in GSK3S/A RGCs further boosted optic nerve regeneration, with axons reaching the optic chiasm within 3 wk. Thus, active GSK3 can also markedly promote axonal growth in central nerves if CRMP2 concurrently remains active. Similar to peripheral nerves, GSK3-mediated MAP1B phosphorylation/activation and the reduction of microtubule detyrosination contributed to this effect. Overall, these findings reconcile conflicting data on GSK3-mediated axon regeneration. In addition, the concept of complementary modulation of normally antagonistically targeted GSK3 substrates offers a therapeutically applicable approach to potentiate the regenerative outcome in the injured CNS. PMID- 28630335 TI - QnAs with Robert Townsend. PMID- 28630336 TI - The Red Queen and King in finite populations. AB - In antagonistic symbioses, such as host-parasite interactions, one population's success is the other's loss. In mutualistic symbioses, such as division of labor, both parties can gain, but they might have different preferences over the possible mutualistic arrangements. The rates of evolution of the two populations in a symbiosis are important determinants of which population will be more successful: Faster evolution is thought to be favored in antagonistic symbioses (the "Red Queen effect"), but disfavored in certain mutualistic symbioses (the "Red King effect"). However, it remains unclear which biological parameters drive these effects. Here, we analyze the effects of the various determinants of evolutionary rate: generation time, mutation rate, population size, and the intensity of natural selection. Our main results hold for the case where mutation is infrequent. Slower evolution causes a long-term advantage in an important class of mutualistic interactions. Surprisingly, less intense selection is the strongest driver of this Red King effect, whereas relative mutation rates and generation times have little effect. In antagonistic interactions, faster evolution by any means is beneficial. Our results provide insight into the demographic evolution of symbionts. PMID- 28630337 TI - Stem caecilian from the Triassic of Colorado sheds light on the origins of Lissamphibia. AB - The origin of the limbless caecilians remains a lasting question in vertebrate evolution. Molecular phylogenies and morphology support that caecilians are the sister taxon of batrachians (frogs and salamanders), from which they diverged no later than the early Permian. Although recent efforts have discovered new, early members of the batrachian lineage, the record of pre-Cretaceous caecilians is limited to a single species, Eocaecilia micropodia The position of Eocaecilia within tetrapod phylogeny is controversial, as it already acquired the specialized morphology that characterizes modern caecilians by the Jurassic. Here, we report on a small amphibian from the Upper Triassic of Colorado, United States, with a melange of caecilian synapomorphies and general lissamphibian plesiomorphies. We evaluated its relationships by designing an inclusive phylogenetic analysis that broadly incorporates definitive members of the modern lissamphibian orders and a diversity of extinct temnospondyl amphibians, including stereospondyls. Our results place the taxon confidently within lissamphibians but demonstrate that the diversity of Permian and Triassic stereospondyls also falls within this group. This hypothesis of caecilian origins closes a substantial morphologic and temporal gap and explains the appeal of morphology-based polyphyly hypotheses for the origins of Lissamphibia while reconciling molecular support for the group's monophyly. Stem caecilian morphology reveals a previously unrecognized stepwise acquisition of typical caecilian cranial apomorphies during the Triassic. A major implication is that many Paleozoic total group lissamphibians (i.e., higher temnospondyls, including the stereospondyl subclade) fall within crown Lissamphibia, which must have originated before 315 million years ago. PMID- 28630338 TI - Self-affirmation facilitates minority middle schoolers' progress along college trajectories. AB - Small but timely experiences can have long-term benefits when their psychological effects interact with institutional processes. In a follow-up of two randomized field experiments, a brief values affirmation intervention designed to buffer minority middle schoolers against the threat of negative stereotypes had long term benefits on college-relevant outcomes. In study 1, conducted in the Mountain West, the intervention increased Latino Americans' probability of entering a college readiness track rather than a remedial one near the transition to high school 2 y later. In study 2, conducted in the Northeast, the intervention increased African Americans' probability of college enrollment 7-9 y later. Among those who enrolled in college, affirmed African Americans attended relatively more selective colleges. Lifting a psychological barrier at a key transition can facilitate students' access to positive institutional channels, giving rise to accumulative benefits. PMID- 28630339 TI - UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction. AB - Brown adipose tissue (BAT) mitochondria exhibit high oxidative capacity and abundant expression of both electron transport chain components and uncoupling protein 1 (UCP1). UCP1 dissipates the mitochondrial proton motive force (Deltap) generated by the respiratory chain and increases thermogenesis. Here we find that in mice genetically lacking UCP1, cold-induced activation of metabolism triggers innate immune signaling and markers of cell death in BAT. Moreover, global proteomic analysis reveals that this cascade induced by UCP1 deletion is associated with a dramatic reduction in electron transport chain abundance. UCP1 deficient BAT mitochondria exhibit reduced mitochondrial calcium buffering capacity and are highly sensitive to mitochondrial permeability transition induced by reactive oxygen species (ROS) and calcium overload. This dysfunction depends on ROS production by reverse electron transport through mitochondrial complex I, and can be rescued by inhibition of electron transfer through complex I or pharmacologic depletion of ROS levels. Our findings indicate that the interscapular BAT of Ucp1 knockout mice exhibits mitochondrial disruptions that extend well beyond the deletion of UCP1 itself. This finding should be carefully considered when using this mouse model to examine the role of UCP1 in physiology. PMID- 28630340 TI - Enhancing T1 magnetic resonance imaging contrast with internalized gadolinium(III) in a multilayer nanoparticle. AB - Multifunctional nanoparticles for biomedical applications have shown extraordinary potential as contrast agents in various bioimaging modalities, near IR photothermal therapy, and for light-triggered therapeutic release processes. Over the past several years, numerous studies have been performed to synthesize and enhance MRI contrast with nanoparticles. However, understanding the MRI enhancement mechanism in a multishell nanoparticle geometry, and controlling its properties, remains a challenge. To systematically examine MRI enhancement in a nanoparticle geometry, we have synthesized MRI-active Au nanomatryoshkas. These are Au core-silica layer-Au shell nanoparticles, where Gd(III) ions are encapsulated within the silica layer between the inner core and outer Au layer of the nanoparticle (Gd-NM). This multifunctional nanoparticle retains its strong near-IR Fano-resonant optical absorption properties essential for photothermal or other near-IR light-triggered therapy, while simultaneously providing increased T1 contrast in MR imaging by concentrating Gd(III) within the nanoparticle. Measurements of Gd-NM revealed a strongly enhanced T1 relaxivity (r1 ~ 24 mM-1?s 1) even at 4.7 T, substantially surpassing conventional Gd(III) chelating agents (r1 ~ 3 mM-1?s-1 at 4.7 T) currently in clinical use. By varying the thickness of the outer gold layer of the nanoparticle, we show that the observed relaxivities are consistent with Solomon-Bloembergen-Morgan (SBM) theory, which takes into account the longer-range interactions between the encapsulated Gd(III) and the protons of the H2O molecules outside the nanoparticle. This nanoparticle complex and its MRI T1-enhancing properties open the door for future studies on quantitative tracking of therapeutic nanoparticles in vivo, an essential step for optimizing light-induced, nanoparticle-based therapies. PMID- 28630343 TI - Correction for Lan et al., Long-read sequencing uncovers the adaptive topography of a carnivorous plant genome. PMID- 28630341 TI - Pig model mimicking chronic hepatitis E virus infection in immunocompromised patients to assess immune correlates during chronicity. AB - Chronic hepatitis E virus (HEV) infection is a significant clinical problem in immunocompromised individuals such as organ transplant recipients, although the mechanism remains unknown because of the lack of an animal model. We successfully developed a pig model of chronic HEV infection and examined immune correlates leading to chronicity. The conditions of immunocompromised patients were mimicked by treating pigs with an immunosuppressive regimen including cyclosporine, azathioprine, and prednisolone. Immunocompromised pigs infected with HEV progressed to chronicity, because 8/10 drug-treated HEV-infected pigs continued fecal virus shedding beyond the acute phase of infection, whereas the majority (7/10) of mock-treated HEV-infected pigs cleared fecal viral shedding at 8 wk postinfection. During chronic infection, serum levels of the liver enzyme gamma glutamyl transferase and fecal virus shedding were significantly higher in immunocompromised HEV-infected pigs. To identify potential immune correlates of chronic infection, we determined serum levels of cytokines and cell-mediated immune responses in pigs. Results showed that HEV infection of immunocompromised pigs reduced the serum levels of Th1 cytokines IL-2 and IL-12, and Th2 cytokines IL-4 and IL-10, particularly during the acute phase of infection. Furthermore IFN gamma-specific CD4+ T-cell responses were reduced in immunocompromised pigs during the acute phase of infection, but TNF-alpha-specific CD8+ T-cell responses increased during the chronic phase of infection. Thus, active suppression of cell mediated immune responses under immunocompromised conditions may facilitate the establishment of chronic HEV infection. This pig model will aid in delineating the mechanisms of chronic HEV infection and in developing effective therapeutics against chronic hepatitis E. PMID- 28630344 TI - Retraction for Zimmerman et al., Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver. PMID- 28630342 TI - Autoantibody profiling on a plasmonic nano-gold chip for the early detection of hypertensive heart disease. AB - The role of autoimmunity in cardiovascular (CV) diseases has been increasingly recognized. Autoimmunity is most commonly examined by the levels of circulating autoantibodies in clinical practices. Measurement of autoantibodies remains, however, challenging because of the deficiency of reproducible, sensitive, and standardized assays. The lack of multiplexed assays also limits the potential to identify a CV-specific autoantibody profile. To overcome these challenges, we developed a nanotechnology-based plasmonic gold chip for autoantibody profiling. This approach allowed simultaneous detection of 10 CV autoantibodies targeting the structural myocardial proteins, the neurohormonal regulatory proteins, the vascular proteins, and the proteins associated with apoptosis and coagulation. Autoantibodies were measured in four groups of participants across the continuum of hypertensive heart diseases. We observed higher levels of all 10 CV autoantibodies in hypertensive subjects (n = 77) compared with healthy participants (n = 30), and the autoantibodies investigated were related to each other, forming a highly linked network. In addition, we established that autoantibodies to troponin I, annexin-A5, and beta 1-adrenegic receptor best discriminated hypertensive subjects with adverse left ventricular (LV) remodeling or dysfunction (n = 49) from hypertensive subjects with normal LV structure and function (n = 28). By further linking these three significant CV autoantibodies to the innate and growth factors, we revealed a positive but weak association between autoantibodies to troponin I and proinflammatory cytokine IL-18. Overall, we demonstrated that this platform can be used to evaluate autoantibody profiles in hypertensive subjects at risk for heart failure. PMID- 28630346 TI - The role of jet and film drops in controlling the mixing state of submicron sea spray aerosol particles. AB - The oceans represent a significant global source of atmospheric aerosols. Sea spray aerosol (SSA) particles comprise sea salts and organic species in varying proportions. In addition to size, the overall composition of SSA particles determines how effectively they can form cloud droplets and ice crystals. Thus, understanding the factors controlling SSA composition is critical to predicting aerosol impacts on clouds and climate. It is often assumed that submicrometer SSAs are mainly formed by film drops produced from bursting bubble-cap films, which become enriched with hydrophobic organic species contained within the sea surface microlayer. In contrast, jet drops formed from the base of bursting bubbles are postulated to mainly produce larger supermicrometer particles from bulk seawater, which comprises largely salts and water-soluble organic species. However, here we demonstrate that jet drops produce up to 43% of total submicrometer SSA number concentrations, and that the fraction of SSA produced by jet drops can be modulated by marine biological activity. We show that the chemical composition, organic volume fraction, and ice nucleating ability of submicrometer particles from jet drops differ from those formed from film drops. Thus, the chemical composition of a substantial fraction of submicrometer particles will not be controlled by the composition of the sea surface microlayer, a major assumption in previous studies. This finding has significant ramifications for understanding the factors controlling the mixing state of submicrometer SSA particles and must be taken into consideration when predicting SSA impacts on clouds and climate. PMID- 28630345 TI - Synthesis of asymmetrical multiantennary human milk oligosaccharides. AB - Despite mammalian glycans typically having highly complex asymmetrical multiantennary architectures, chemical and chemoenzymatic synthesis has almost exclusively focused on the preparation of simpler symmetrical structures. This deficiency hampers investigations into the biology of glycan-binding proteins, which in turn complicates the biomedical use of this class of biomolecules. Herein, we describe an enzymatic strategy, using a limited number of human glycosyltransferases, to access a collection of 60 asymmetric, multiantennary human milk oligosaccharides (HMOs), which were used to develop a glycan microarray. Probing the array with several glycan-binding proteins uncovered that not only terminal glycoepitopes but also complex architectures of glycans can influence binding selectivity in unanticipated manners. N- and O-linked glycans express structural elements of HMOs, and thus, the reported synthetic principles will find broad applicability. PMID- 28630347 TI - QnAs with Wolfgang Lutz. PMID- 28630348 TI - Analysis of a dual domain phosphoglycosyl transferase reveals a ping-pong mechanism with a covalent enzyme intermediate. AB - Phosphoglycosyl transferases (PGTs) are integral membrane proteins with diverse architectures that catalyze the formation of polyprenol diphosphate-linked glycans via phosphosugar transfer from a nucleotide diphosphate-sugar to a polyprenol phosphate. There are two PGT superfamilies that differ significantly in overall structure and topology. The polytopic PGT superfamily, represented by MraY and WecA, has been the subject of many studies because of its roles in peptidoglycan and O-antigen biosynthesis. In contrast, less is known about a second, extensive superfamily of PGTs that reveals a core structure with dual domain architecture featuring a C-terminal soluble globular domain and a predicted N-terminal membrane-associated domain. Representative members of this superfamily are the Campylobacter PglCs, which initiate N-linked glycoprotein biosynthesis and are implicated in virulence and pathogenicity. Despite the prevalence of dual domain PGTs, their mechanism of action is unknown. Here, we present the mechanistic analysis of PglC, a prototypic dual domain PGT from Campylobacter concisus Using a luminescence-based assay, together with substrate labeling and kinetics-based approaches, complementary experiments were carried out that support a ping-pong mechanism involving a covalent phosphosugar intermediate for PglC. Significantly, mass spectrometry-based approaches identified Asp93, which is part of a highly conserved AspGlu dyad found in all dual domain PGTs, as the active-site nucleophile of the enzyme involved in the formation of the covalent adduct. The existence of a covalent phosphosugar intermediate provides strong support for a ping-pong mechanism of PglC, differing fundamentally from the ternary complex mechanisms of representative polytopic PGTs. PMID- 28630349 TI - PI3K-p110alpha mediates the oncogenic activity induced by loss of the novel tumor suppressor PI3K-p85alpha. AB - Mutation or loss of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) is emerging as a transforming factor in cancer, but the mechanism of transformation has been controversial. Here we find that hemizygous deletion of the PIK3R1 gene encoding p85alpha is a frequent event in breast cancer, with PIK3R1 expression significantly reduced in breast tumors. PIK3R1 knockdown transforms human mammary epithelial cells, and genetic ablation of Pik3r1 accelerates a mouse model of HER2/neu-driven breast cancer. We demonstrate that partial loss of p85alpha increases the amount of p110alpha-p85 heterodimers bound to active receptors, augmenting PI3K signaling and oncogenic transformation. Pan PI3K and p110alpha-selective pharmacological inhibition effectively blocks transformation driven by partial p85alpha loss both in vitro and in vivo. Together, our data suggest that p85alpha plays a tumor-suppressive role in transformation, and suggest that p110alpha-selective therapeutics may be effective in the treatment of breast cancer patients with PIK3R1 loss. PMID- 28630350 TI - The United States can keep the grid stable at low cost with 100% clean, renewable energy in all sectors despite inaccurate claims. PMID- 28630351 TI - Evolutionary radiation of lanthipeptides in marine cyanobacteria. AB - Lanthipeptides are ribosomally derived peptide secondary metabolites that undergo extensive posttranslational modification. Prochlorosins are a group of lanthipeptides produced by certain strains of the ubiquitous marine picocyanobacteria Prochlorococcus and Synechococcus Unlike other lanthipeptide producing bacteria, picocyanobacteria use an unprecedented mechanism of substrate promiscuity for the production of numerous and diverse lanthipeptides using a single lanthionine synthetase. Through a cross-scale analysis of prochlorosin biosynthesis genes-from genomes to oceanic populations-we show that marine picocyanobacteria have the collective capacity to encode thousands of different cyclic peptides, few of which would display similar ring topologies. To understand how this extensive structural diversity arises, we used deep sequencing of wild populations to reveal genetic variation patterns in prochlorosin genes. We present evidence that structural variability among prochlorosins is the result of a diversifying selection process that favors large, rather than small, sequence changes in the precursor peptide genes. This mode of molecular evolution disregards any conservation of the ancestral structure and enables the emergence of extensively different cyclic peptides through short mutational paths based on indels. Contrary to its fast-evolving peptide substrates, the prochlorosin lanthionine synthetase evolves under a strong purifying selection, indicating that the diversification of prochlorosins is not constrained by commensurate changes in the biosynthetic enzyme. This evolutionary interplay between the prochlorosin peptide substrates and the lanthionine synthetase suggests that structure diversification, rather than structure refinement, is the driving force behind the creation of new prochlorosin structures and represents an intriguing mechanism by which natural product diversity arises. PMID- 28630352 TI - Structural complexity and molecular heterogeneity of a butterfly ejaculate reflect a complex history of selection. AB - Male ejaculates are often structurally complex, and this complexity is likely to influence key reproductive interactions between males and females. However, despite its potential evolutionary significance, the molecular underpinnings of ejaculate structural complexity have received little empirical attention. To address this knowledge gap, we sought to understand the biochemical and functional properties of the structurally complex ejaculates of Pieris rapae butterflies. Males in this species produce large ejaculates called spermatophores composed of an outer envelope, an inner matrix, and a bolus of sperm. Females are thought to benefit from the nutrition contained in the soluble inner matrix through increases in longevity and fecundity. However, the indigestible outer envelope of the spermatophore delays female remating, allowing males to monopolize paternity for longer. Here, we show that these two nonsperm-containing spermatophore regions, the inner matrix and the outer envelope, differ in their protein composition and functional properties. We also reveal how these divergent protein mixtures are separately stored in the male reproductive tract and sequentially transferred to the female reproductive tract during spermatophore assembly. Intriguingly, we discovered large quantities of female-derived proteases in both spermatophore regions shortly after mating, which may contribute to spermatophore digestion and hence, female control over remating rate. Finally, we report evidence of past selection on these spermatophore proteins and female proteases, indicating a complex evolutionary history. Our findings illustrate how structural complexity of ejaculates may allow functionally and/or spatially associated suites of proteins to respond rapidly to divergent selective pressures, such as sexual conflict or reproductive cooperation. PMID- 28630353 TI - Evaluation of a proposal for reliable low-cost grid power with 100% wind, water, and solar. AB - A number of analyses, meta-analyses, and assessments, including those performed by the Intergovernmental Panel on Climate Change, the National Oceanic and Atmospheric Administration, the National Renewable Energy Laboratory, and the International Energy Agency, have concluded that deployment of a diverse portfolio of clean energy technologies makes a transition to a low-carbon emission energy system both more feasible and less costly than other pathways. In contrast, Jacobson et al. [Jacobson MZ, Delucchi MA, Cameron MA, Frew BA (2015) Proc Natl Acad Sci USA 112(49):15060-15065] argue that it is feasible to provide "low-cost solutions to the grid reliability problem with 100% penetration of WWS [wind, water and solar power] across all energy sectors in the continental United States between 2050 and 2055", with only electricity and hydrogen as energy carriers. In this paper, we evaluate that study and find significant shortcomings in the analysis. In particular, we point out that this work used invalid modeling tools, contained modeling errors, and made implausible and inadequately supported assumptions. Policy makers should treat with caution any visions of a rapid, reliable, and low-cost transition to entire energy systems that relies almost exclusively on wind, solar, and hydroelectric power. PMID- 28630354 TI - Not all cells are equal: effects of temperature and sex on the size of different cell types in the Madagascar ground gecko Paroedura picta. AB - Cell size plays a role in evolutionary and phenotypically plastic changes in body size. To examine this role, we measured the sizes of seven cell types of geckos (Paroedura picta) reared at three constant temperatures (24, 27, and 30 degrees C). Our results show that the cell size varies according to the body size, sex and developmental temperature, but the pattern of this variance depends on the cell type. We identified three groups of cell types, and the cell sizes changed in a coordinated manner within each group. Larger geckos had larger erythrocytes, striated muscle cells and hepatocytes (our first cell group), but their renal proximal tubule cells and duodenal enterocytes (our second cell group), as well as tracheal chondrocytes and epithelial skin cells (our third cell group), were largely unrelated to the body size. For six cell types, we also measured the nuclei and found that larger cells had larger nuclei. The relative sizes of the nuclei were not invariant but varied in a complex manner with temperature and sex. In conclusion, we provide evidence suggesting that changes in cell size might be commonly involved in the origin of thermal and sexual differences in adult size. A recent theory predicts that smaller cells speed up metabolism but demand more energy for their maintenance; consequently, the cell size matches the metabolic demand and supply, which in ectotherms, largely depends on the thermal conditions. The complex thermal dependency of cell size in geckos suggests that further advancements in understanding the adaptive value of cell size requires the consideration of tissue-specific demand/supply conditions. PMID- 28630355 TI - Apical and basal epitheliomuscular F-actin dynamics during Hydra bud evagination. AB - Bending of 2D cell sheets is a fundamental morphogenetic mechanism during animal development and reproduction. A critical player driving cell shape during tissue bending is the actin cytoskeleton. Much of our current knowledge about actin dynamics in whole organisms stems from studies of embryonic development in bilaterian model organisms. Here, we have analyzed actin-based processes during asexual bud evagination in the simple metazoan Hydra We created transgenic Hydra strains stably expressing the actin marker Lifeact-GFP in either ectodermal or endodermal epitheliomuscular cells. We then combined live imaging with conventional phalloidin staining to directly follow actin reorganization. Bending of the Hydra epithelial double layer is initiated by a group of epitheliomuscular cells in the endodermal layer. These cells shorten their apical-basal axis and arrange their basal muscle processes in a circular configuration. We propose that this rearrangement generates the initial forces to bend the endoderm towards the ectoderm. Convergent tissue movement in both epithelial layers towards the centre of evagination then leads to elongation and extension of the bud along its new body axis. Tissue movement into the bud is associated with lateral intercalation of epithelial cells, remodelling of apical septate junctions, and rearrangement of basal muscle processes. The work presented here extends the analysis of morphogenetic mechanisms beyond embryonic tissues of model bilaterians. PMID- 28630356 TI - Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning. AB - The robust axonal growth and regenerative capacities of young neurons decrease substantially with age. This developmental downregulation of axonal growth may facilitate axonal pruning and neural circuit formation but limits functional recovery following nerve damage. While external factors influencing axonal growth have been extensively investigated, relatively little is known about the intrinsic molecular changes underlying the age-dependent reduction in regeneration capacity. We report that developmental downregulation of LIS1 is responsible for the decreased axonal extension capacity of mature dorsal root ganglion (DRG) neurons. In contrast, exogenous LIS1 expression or endogenous LIS1 augmentation by calpain inhibition restored axonal extension capacity in mature DRG neurons and facilitated regeneration of the damaged sciatic nerve. The insulator protein CTCF suppressed LIS1 expression in mature DRG neurons, and this reduction resulted in excessive accumulation of phosphoactivated GSK-3beta at the axon tip, causing failure of the axonal extension. Conversely, sustained LIS1 expression inhibited developmental axon pruning in the mammillary body. Thus, LIS1 regulation may coordinate the balance between axonal growth and pruning during maturation of neuronal circuits. PMID- 28630357 TI - Importation of drugs into the United States from Canada. PMID- 28630360 TI - Superficial dyspareunia. PMID- 28630359 TI - Diagnosis and management of bronchiectasis. AB - KEY POINTSFollowing a diagnosis of bronchiectasis, it is important to investigate for an underlying cause.Goals of management are to suppress airway infection and inflammation, to improve symptoms and health-related quality of life.There are now validated scoring tools to help assess disease severity, which can help to stratify management.Good evidence supports the use of both exercise training and long-term macrolide therapy in long-term disease management. PMID- 28630361 TI - Traumatic pseudoaneurysm of the superficial temporal artery. PMID- 28630358 TI - Assessing the safety and immunogenicity of recombinant vesicular stomatitis virus Ebola vaccine in healthy adults: a randomized clinical trial. AB - BACKGROUND: The 2013-2016 Ebola virus outbreak in West Africa was the most widespread in history. In response, alive attenuated recombinant vesicular stomatitis virus (rVSV) vaccine expressing Zaire Ebolavirus glycoprotein (rVSVDeltaG-ZEBOV-GP) was evaluated in humans. METHODS: In a phase 1, randomized, dose-ranging, observer-blind, placebo-controlled trial, healthy adults aged 18-65 years were randomized into 4 groups of 10 to receive one of 3 vaccine doses or placebo. Follow-up visits spanned 180 days postvaccination for safety monitoring, immunogenicity testing and any rVSV virus shedding. RESULTS: Forty participants were injected with rVSVDeltaG-ZEBOV-GP vaccine (n = 30) or saline placebo (n = 10). No serious adverse events related to the vaccine or participant withdrawals were reported. Solicited adverse events during the 14-day follow-up period were mild to moderate and self-limited, with the exception of injection-site pain and headache. Viremia following vaccination was transient and no longer detectable after study day 3, with no virus shedding in saliva or urine. All vaccinated participants developed serum immunoglobulin G (IgG), as measured by Ebola virus envelope glycoprotein-based enzyme-linked immunosorbent assay (ELISA). Immunogenicity was comparable across all dose groups, and sustained IgG titers were detectable through to the last visit, at study day 180. INTERPRETATION: In this phase 1 study, there were no safety concerns after a single dose of rVSVDeltaG-ZEBOV-GP vaccine. IgG ELISA showed persistent high titers at 180 days postimmunization. There was a period of reactogenicity, but in general, the vaccine was well tolerated. This study provides evidence of the safety and immunogenicity of rVSVDeltaG-ZEBOV-GP vaccine and importance of its further investigation. Trial registration: Clinical-Trials.gov no., NCT02374385. PMID- 28630362 TI - The spaces in between. PMID- 28630363 TI - A comprehensive approach needed to address regional variation. PMID- 28630364 TI - Response to: "A comprehensive approach needed to address regional variation". PMID- 28630365 TI - Hot bodies; Cold War: the forgotten history of breast thermography. PMID- 28630366 TI - A game-changer for hereditary cancer patients. PMID- 28630367 TI - Health Canada wants more funds from pharma. PMID- 28630368 TI - Researchers unite in demand for funding. PMID- 28630370 TI - Evidence for Therapeutic Patient Education Interventions to Promote Cardiovascular Patient Self-Management: A Scientific Statement for Healthcare Professionals From the American Heart Association. AB - BACKGROUND: The burden of cardiovascular disease as a chronic illness increasingly requires patients to assume more responsibility for their self management. Patient education is believed to be an essential component of cardiovascular care; however, there is limited evidence about specific therapeutic patient education approaches used and the impact on patient self management outcomes. METHODS AND RESULTS: An integrative review of the literature was conducted to critically analyze published research studies of therapeutic patient education for self-management in selected cardiovascular conditions. There was variability in methodological approaches across settings and disease conditions. The most effective interventions were tailored to individual patient needs, used multiple components to improve self-management outcomes, and often used multidisciplinary approaches. CONCLUSIONS: This synthesis of evidence expands the base of knowledge related to the development of patient self management skills and provides direction for more rigorous research. Recommendations are provided to guide the implementation of therapeutic patient education in clinical practice and the design of comprehensive self-management interventions to improve outcomes for cardiovascular patients. PMID- 28630369 TI - ALPK3 gene mutation in a patient with congenital cardiomyopathy and dysmorphic features. AB - Primary cardiomyopathy is one of the most common inherited cardiac diseases and harbors significant phenotypic and genetic heterogeneity. Because of this, genetic testing has become standard in treatment of this disease group. Indeed, in recent years, next-generation DNA sequencing has found broad applications in medicine, both as a routine diagnostic tool for genetic disorders and as a high throughput discovery tool for identifying novel disease-causing genes. We describe a male infant with primary dilated cardiomyopathy who was diagnosed using intrauterine echocardiography and found to progress to hypertrophic cardiomyopathy after birth. This proband was born to a nonconsanguineous family with a past history of a male fetus that died because of cardiac abnormalities at 30 wk of gestation. Using whole-exome sequencing, a novel homozygous frameshift mutation (c.2018delC; p.Gln675SerfsX30) in ALPK3 was identified and confirmed with Sanger sequencing. Heterozygous family members were normal with echocardiographic examination. To date, only two studies have reported homozygous pathogenic variants of ALPK3, with a total of seven affected individuals with cardiomyopathy from four unrelated consanguineous families. We include a discussion of the patient's phenotypic features and a review of relevant literature findings. PMID- 28630371 TI - Assessment of Quality Indicators for Acute Myocardial Infarction in the FAST-MI (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) Registries. AB - BACKGROUND: The Acute Cardiovascular Care Association defined quality indicators (QIs) for the management of acute myocardial infarction. The application of these QIs to existing databases is appealing. It remains to be determined what the rates of implementation are, how the QIs are related to long-term survival, and whether quality categorization is possible. METHODS AND RESULTS: The QIs were extracted from the French nationwide registries French Registry of Acute ST Elevation or Non-ST-Elevation Myocardial Infarction (FAST-MI) 2005 (n=3670) and FAST-MI 2010 (n=4169). Implementation rates for each QI are reported for both cohorts. The composite QI was used for benchmarking, and the relationship between QIs and 3-year survival was determined using a Cox model. In FAST-MI 2010, 12 individual and 2 composite QIs could be assessed. Four QIs were not recorded in FAST-MI 2010 and 4 in 2005, either because of treatment nonavailability or because of data not recorded. The degree of implementation ranged from 12% to 89%, with higher rates in 2010 as compared with 2005. Seven individual QIs were associated with survival, and there was a significant and gradual association between survival and categories of the composite QI. Center categorization was possible in 26% to 30% of participating centers; 16 (27%) centers in 2005 and 14 (20%) in 2010 were categorized as low quality. CONCLUSIONS: Twelve of 17 individual QIs could be assessed from FAST-MI 2010. The composite QI was significantly associated with 3-year survival and distinguished centers with high, average, and low quality of care. PMID- 28630372 TI - Multitype Events and the Analysis of Heart Failure Readmissions: Illustration of a New Modeling Approach and Comparison With Familiar Composite End Points. AB - BACKGROUND: Heart failure-related hospital readmissions and mortality are often outcomes in clinical trials. Patients may experience multiple hospital readmissions over time with mortality acting as a dependent terminal event. Univariate composite end points are used for the analysis of readmissions. We may amend these approaches to include emergency department visits as a further outcome. An alternative multivariate modeling approach that categorizes hospital readmissions and emergency department visits as separate event types is proposed. METHODS AND RESULTS: We seek to compare the modeling approach which handles event types as separate, correlated end points against composites that amalgamate them to create a unified end point. Using a heart failure data set for illustration, a model with random effects for event types is estimated. The time-to-first event, unmatched win-ratio, and days-alive-and-out-of-hospital composites are derived for comparison. The model provides supplementary statistics such as the correlation among event types and yields considerably more power than the competing composite end points. CONCLUSIONS: The effect on individual outcomes is lost when they are intermingled to form a univariate composite. Simultaneously modeling different outcomes provides an alternative or supplementary analysis that may yield greater statistical power and additional insights. Improvements in software have made the multitype events model easier to implement and thus a useful, more efficient option when analyzing heart failure hospital readmissions and emergency department visits. PMID- 28630373 TI - Incidence and Time Course for Developing Heart Failure With High-Burden Right Ventricular Pacing. AB - BACKGROUND: Although right ventricular pacing can contribute to cardiomyopathy, the impact of complete atrioventricular block (cAVB) on heart failure (HF) development in pacemaker patients has not been well characterized. We evaluated the incidence and time course for developing HF after pacemaker implantation for cAVB. METHODS AND RESULTS: A MarketScan database identified patients undergoing dual-chamber pacemaker implantation from 2008 to 2014. Patients with cAVB were identified by an atrioventricular node ablation or diagnosis of third-degree AVB. Patients with >=1 year of continuous MarketScan enrollment before and after implant and without a previous diagnosis of HF were dichotomized into those with cAVB and without AVB. The primary end point was new HF assessed over acute (0-6 months) and chronic (6 months to 4 years) phases post-pacemaker implantation. The cohort included 6994 cAVB patients and 14 208 patients without AVB, followed for 2.35 years (interquartile range, 1.62-3.39 years). After adjustment for baseline covariates, patients with cAVB experienced an increased risk of new-onset HF in the acute phase (hazard ratio, 1.62; 95% confidence interval, 1.48-1.79; P<0.001). Although the risk of HF remained elevated among those with cAVB in the chronic phase, the effect was attenuated (hazard ratio, 1.16; 95% confidence interval, 1.08-1.25; P<0.001). After pacemaker implantation, younger patients (<=55 years of age) and those with an antecedent history of atrial fibrillation experienced the highest risk of HF associated with cAVB. CONCLUSIONS: Patients with a diagnosis of cAVB, and thus presumed to have a higher burden of right ventricular pacing, experienced an increased risk of new-onset HF after pacemaker implantation compared with those without AVB. Better tools are needed to identify patients at high risk of developing HF in the setting of right ventricular pacing and to determine whether these patients benefit from upfront biventricular pacing. PMID- 28630374 TI - Classifying the body in Marlene Dumas' The Image as Burden. AB - Medical photography, and in particular dermatological imagery, is often assumed to provide an objective, and functional, representation of disease and that it can act as a diagnostic aid. By contrast, artistic conceptions of the images of the body tend to focus on interpretative heterogeneity and ambiguity, aiming to create or explore meaning rather than enact a particular function. In her 2015 retrospective exhibition at the Tate Modern, South African artist Marlene Dumas questions these disciplinary divides by using medical imagery (among other photographic sources) as the basis for her portraits. Her portrait 'The White Disease' draws on an unidentified photograph taken from a medical journal, but obscures the original image to such a degree that any representation of a particular disease is highly questionable. The title creates a new classification, which reflects on disease and on the racial politics of South Africa during apartheid. Though, on the one hand, these techniques are seemingly disparate from the methods of medical understanding, features such as reliance on classification, and attempts at dispelling ambiguity, bring Dumas' work closer to the history of dermatological portraits than would usually be perceived to be the case. In considering the continuities and disparities between conceptualisations of skin in dermatology and Dumas' art, this paper questions assumptions of photographic objectivity to suggest that there is greater complexity and interpretative scope in medical dermatological images than might initially be assumed. PMID- 28630375 TI - Is pathology-specific diagnosis of the dementia possible in life? PMID- 28630376 TI - Functional connectivity disturbances of the ascending reticular activating system in temporal lobe epilepsy. AB - OBJECTIVE: Seizures in temporal lobe epilepsy (TLE) disturb brain networks and lead to connectivity disturbances. We previously hypothesised that recurrent seizures in TLE may lead to abnormal connections involving subcortical activating structures including the ascending reticular activating system (ARAS), contributing to neocortical dysfunction and neurocognitive impairments. However, no studies of ARAS connectivity have been previously reported in patients with epilepsy. METHODS: We used resting-state functional MRI recordings in 27 patients with TLE (67% right sided) and 27 matched controls to examine functional connectivity (partial correlation) between eight brainstem ARAS structures and 105 cortical/subcortical regions. ARAS nuclei included: cuneiform/subcuneiform, dorsal raphe, locus coeruleus, median raphe, parabrachial complex, pontine oralis, pedunculopontine and ventral tegmental area. Connectivity patterns were related to disease and neuropsychological parameters. RESULTS: In control subjects, regions showing highest connectivity to ARAS structures included limbic structures, thalamus and certain neocortical areas, which is consistent with prior studies of ARAS projections. Overall, ARAS connectivity was significantly lower in patients with TLE than controls (p<0.05, paired t-test), particularly to neocortical regions including insular, lateral frontal, posterior temporal and opercular cortex. Diminished ARAS connectivity to these regions was related to increased frequency of consciousness-impairing seizures (p<0.01, Pearson's correlation) and was associated with impairments in verbal IQ, attention, executive function, language and visuospatial memory on neuropsychological evaluation (p<0.05, Spearman's rho or Kendell's tau-b). CONCLUSIONS: Recurrent seizures in TLE are associated with disturbances in ARAS connectivity, which are part of the widespread network dysfunction that may be related to neurocognitive problems in this devastating disorder. PMID- 28630377 TI - Effects of cognitive reserve depend on executive and semantic demands of the task. AB - BACKGROUND: Cognitive reserve (CR) is one factor that helps to maintain cognitive function in patients with Alzheimer's disease (AD). Whether the effects of CR depend on the semantic/executive components of the task remains unknown. METHODS: 470 patients (138 with AD, 332 with mild cognitive impairment (MCI)) were selected from the Alzheimer's Disease Neuroimaging Initiative database. Linear regression models were used to determine the effects of CR (years of education) on cognitive performance after controlling for demographic factors and regional cortical atrophy. First, we assessed memory tasks with low (Auditory Verbal Learning Test (AVLT) discriminability), moderate (AVLT delayed recall) and high (Logical Memory Test (LMT) delayed recall) executive/semantic components. Next, we assessed tasks with lower (digit span forward, Trails A) or higher (digit span backwards, Trails B) executive demands, and lower (figure copying) or higher (naming, semantic fluency) semantic demands. RESULTS: High CR was significantly associated with performance on the LMT delayed recall, approached significance in the AVLT delayed recall and was not significantly associated with performance on AVLT discriminability. High CR was significantly associated with performance on the Trails B and digit span backwards, mildly associated with Trails A performance and was not associated with performance on digit span forwards. High CR was associated with performance on semantic but not visuospatial tasks. High CR was associated with semantic tasks in patients with both MCI and AD, but was only associated with executive functions in patients with MCI. CONCLUSION: CR may relate to executive functioning and semantic knowledge, leading to preserved cognitive performance in patients with AD pathology. PMID- 28630378 TI - Randomised controlled trial of the efficacy of a blue-enriched light intervention to improve alertness and performance in night shift workers. AB - OBJECTIVES: Night workers often experience high levels of sleepiness due to misalignment of the sleep-wake cycle from the circadian pacemaker, in addition to acute and chronic sleep loss. Exposure to light, in particular short wavelength light, can improve alertness and neurobehavioural performance. This randomised controlled trial examined the efficacy of blue-enriched polychromatic light to improve alertness and neurobehavioural performance in night workers. DESIGN: Participants were 71 night shift workers (42 males; 32.8+/-10.5 years) who worked at least 6 hours between 22:00 and 08:00 hours. Sleep-wake logs and wrist actigraphy were collected for 1-3 weeks, followed by 48-hour urine collection to measure the circadian 6-sulphatoxymelatonin (aMT6s) rhythm. On the night following at least two consecutive night shifts, workers attended a simulated night shift in the laboratory which included subjective and objective assessments of sleepiness and performance. Workers were randomly assigned for exposure to one of two treatment conditions from 23:00 hours to 07:00 hours: blue-enriched white light (17 000 K, 89 lux; n=36) or standard white light (4000 K, 84 lux; n=35). RESULTS: Subjective and objective sleepiness increased during the night shift in both light conditions (p<0.05, etap2=0.06-0.31), but no significant effects of light condition were observed. The 17 000 K light, however, did improve subjective sleepiness relative to the 4000 K condition when light exposure coincided with the time of the aMT6s peak (p<0.05, d=0.41-0.60). CONCLUSION: This study suggests that, while blue-enriched light has potential to improve subjective sleepiness in night shift workers, further research is needed in the selection of light properties to maximise the benefits. TRIAL REGISTRATION NUMBER: The Australian New Zealand Clinical Trials Registry ACTRN12610000097044 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=320845&isReview true). PMID- 28630379 TI - The association between telomere length and mortality in Bangladesh. AB - Telomeres are tandem repeat sequences at the end of chromosomes that bind proteins to protect chromosome ends. Telomeres shorten with age, and shorter leukocyte telomere length (TL) has been associated with overall mortality in numerous studies. However, this association has not been tested in populations outside of Europe and the U.S. We assessed the association between TL and subsequent mortality using data on 744 mortality cases and 761 age-/sex-matched controls sampled from >27,000 participants from three longitudinal Bangladeshi cohorts: Health Effects of Arsenic Longitudinal Study (HEALS), HEALS Expansion (HEALS-E), and Bangladesh Vitamin E and Selenium Trial (BEST). We used conditional logistic regression to estimate odds ratios (ORs) for the association between a standardized TL variable and overall mortality, as well as mortality from chronic diseases, respiratory diseases, circulatory diseases, and cancer. In HEALS and BEST, we observed an association between shorter TL and increased overall mortality (P=0.03 and P=0.03), mortality from chronic disease (P=0.01 and P=0.03) and mortality from circulatory disease (P=0.03 and P=0.04). Results from pooled analyses of all cohorts were consistent with HEALS and BEST. This is the first study demonstrating an association between short TL and increased mortality in a population of non-European ancestry. PMID- 28630380 TI - The Immunological Basis in the Pathogenesis of Gout. AB - Gout is an inflammatory arthritis characterized by red, tender, hot and tumid joints. The development cause and process of gout is very sophisticated; recent studies, notwithstanding, have offered novel perspectives on the mechanism from an immunological viewpoint. The pathological process of gout involves both innate and adaptive immune responses. Other studies have demonstrated that gout development is associated with the presence of monosodium urate (MSU) crystals which serve as a "danger signal" affecting certain immune cells, cytokine production, and effector molecule expression, triggering both types of immune responses. Different cell subsets, cytokines, pattern recognition receptors (PRRs) and the inflammasome have had noticeable effects on the pathogenesis of gout. In the present review, we discuss the contributions of MSU-mediated immune responses in gout, which helps to better understand the mechanism of gout development. PMID- 28630381 TI - Antibody Response to Human Extracellular HER2 Subdomain Proteins in Mice. AB - BACKGROUND: In addition to passive immunotherapy using anti-HER2 monoclonal antibodies, active immunotherapy via HER2 targeting is an interesting approach to inducing specific anti-tumor immune responses. We have recently reported the immunogenicity of HER2 subdomains following DNA immunization and HER2 protein boosting. In the present study, we evaluated the immunogenicity of different HER2 extracellular subdomains for the induction of anti-HER2 antibody response in BALB/c mice. OBJECTIVE: To investigate and characterize antibody responses to human recombinant proteins of HER2 extracellular subdomains in immunized mice. METHODS: Four subdomains of HER2 extracellular domain were expressed in E.coli; subsequently, purified recombinant proteins were intraperitoneally injected in BALB/c mice with Freund's adjuvant. The anti-HER2 antibody response was detected by ELISA, immunoblotting and flow cytometry. RESULTS: All the four HER2 subdomains along with the full extracellular domain (fECD) were able to induce specific anti-HER2 antibodies. Although anti-HER2 subdomains antibodies could not react with eukaryotic recombinant fECD protein by ELISA, they were able to recognize this protein by immunoblotting under both reduced and non-reduced conditions. Furthermore, only the sera of mice immunized with fECD protein could recognize native HER2 on HER2 overexpressing tumor cells (>99%) by flow cytometry. Moreover, fECD immunized mice sera inhibited the proliferation of tumor cells by XTT assay. CONCLUSION: The prokaryotic recombinant proteins of HER2 extracellular subdomains are immunogenic, yet the induced specific antibodies do not react with the native HER2 protein due to the paucity of post translation modifications and /or distortion of the native conformation of isolated HER2 extracellular subdomains which might be potentially effective for induction of cell mediated immune response against HER2. PMID- 28630382 TI - Immunodiagnostic Value of Echinococcus Granulosus Recombinant B8/1 Subunit of Antigen B. AB - BACKGROUND: Cystic echinococcosis (CE), as a chronic parasitic disease, is a major health problem in many countries. The performance of the currently available serodiagnostic tests for the diagnosis of CE is unsatisfactory. OBJECTIVE: The current study aimed at sub-cloning a gene, encoding the B8/1 subunit of antigen B (AgB) from Echinococcus granulosus, using gene optimization for the immunodiagnosis of human CE. METHODS: The coding sequence for AgB8/1 subunit of Echinococcus granulosus was selected from GenBank and was gene optimized. The sequence was synthesized and inserted into pGEX-4T-1 vector. Purification was performed with GST tag affinity column. Diagnostic performance of the produced recombinant antigen, native antigen B and a commercial ELISA kit were further evaluated in an ELISA system, using a panel of sera from CE patients and controls. RESULTS: SDS-PAGE demonstrated that the protein of interest had a high expression level and purity after GST tag affinity purification. Western blotting verified the immunoreactivity of the produced recombinant antigen with the sera of CE patients. In an ELISA system, the sensitivity and specificity (for human CE diagnosis) of the recombinant antigen, native antigen B and commercial kit were respectively 93% and 92%, 87% and 90% and 97% and 95%. CONCLUSION: The produced recombinant antigen showed a high diagnostic value which can be recommended for serodiagnosis of CE in Iran and other CE-endemic areas. Utilizing the combination of other subunits of AgB8 would improve the performance value of the introduced ELISA system. PMID- 28630383 TI - BALB/c Mice Immunity to Hydatidosis Induced by In-vitro Reared Echinococcus granulosus Adult Worm Antigens. AB - BACKGROUND: Echinococcosis is a zoonotic parasitic disease caused by the larval stage of Echinococcus granulosus. Several native and recombinant antigens, derived from different stages of E. granulosus life cycle, have been used for vaccine trials. In vitro reared adult worms are good candidates for vaccination as they do not produce fertile egg/s and do not have any risk of contamination for researchers. OBJECTIVE: To evaluate different antigens derived from in vitro reared E. granulosus adult worms for the immunization of BALB/c mice against secondary hydatidosis. METHODS: Viable protoscoleces (PCSs) of sheep hydatid cyst were cultivated in S.10E.H media. Excretory secretory (E/S) and crude antigens were prepared from reared adult worms. A total of fifty BALB/c mice, each 8-weeks old, were divided into 5 groups of 10 mice. Three groups were subcutaneously immunized with crude, E/S and immunodominant antigens on days 1 and 28. The fourth group received only PBS and the fifth group had no injection. Three weeks following the second immunization, all groups were challenged, intraperitoneal, with viable PSCs. After the autopsy of the mice and opening their abdominal wall, cysts were counted and measured followed by histopathological observations. RESULTS: The highest protective immunity (98.7%) against hydatidosis was induced by crude antigen, followed by E/S and immunodominant antigens. CONCLUSION: Antigens (crude antigens in particular) derived from in vitro reared E. granulosus adult worms, and their different protein components are suitable candidates for the vaccination of intermediate hosts against hydatidosis. PMID- 28630384 TI - Modulation of CD4+ T Cell Subsets by Euphorbia microciadia and Euphorbia osyridea Plant Extracts. AB - BACKGROUND: Euphorbia plants are traditionally used in folk medicine for infections, inflammation, and cancer. OBJECTIVES: To investigate the effects of the butanolic extracts of Euphorbia micorociadia and Euphorbia osyridea on specific transcription factors and cytokines expression of T cell subsets. METHODS: Activated mouse splenocytes were cultured in the presence of non cytotoxic concentrations of the extracts. Cells were evaluated for the gene expressions of T cell transcription factors and cytokines of T helper (Th)1 [T bet and interferon gamma (IFNgamma)], Th17 [retinoic acid receptor related orphan receptor (RORgammat) and interleukin (IL)-17], and T regulatory (Treg) cells [forkhead box P3(Foxp3), IL-10, and Transforming growth factor (TGF)-beta] using real-time PCR. The cytokine secretions were evaluated by ELISA and Foxp3 protein expression by flow cytometry. RESULTS: Both E. osyridea and E. microciadia extracts at 0.1 MUg/ml increased T-bet expression [>1.73 relative fold change (RFC), p<0.05] and IFNgamma production (>1195 pg/ml, p<0.001). Both decreased Foxp3 (<0.41 RFC, p<0.05) expression. At the higher concentration both extracts significantly reduced T-bet mRNA as well as IFNgamma, IL-17, IL-10, and TGF-beta cytokines and Foxp3 at the mRNA and protein levels. CONCLUSION: These data showed the immunomodulatory effects of E. osyridea and E. micorociadia extracts on T cell-mediated responses. The extracts caused upregulation of Th1 and downregulation of Treg cells at a low concentration which suggested their possible therapeutic value in tumor models and infectious diseases. The observed immunosuppressive effects at the higher concentration potentially make these plants candidates for identification of active components and studying their mechanisms of action. PMID- 28630385 TI - Low Dose of Lenalidomide Enhances NK Cell Activity: Possible Implication as an Adjuvant. AB - BACKGROUND: Lenalidomide, a synthetic immunomodulatory drug, has a wide range of features including anti-angiogenic and anti-proliferative properties. To date, researchers have shown that lenalidomide is capable of ameliorating the immune system factors and antitumor responses. Most researchers have reported that lenalidomide enhances the immune response in certain cancer patients through several pathways including the stimulation of Natural Killer cells; notwithstanding, it is still crucial to investigate the effect of lenalidomide on the activity of NK cell cytotoxicity both in vitro and in vivo. OBJECTIVE: To evaluate the in vitro impact of lenalidomide, of different doses, on NK cytotoxicity activity and an in vivo investigation to find the adjuvant behavior of lenalidomide. METHODS: NK cytotoxocity was measured with the lactate dehydrogenase (LDH) release assay via K562 cells. Lenalidomide was prepared at 1 mM, 2 mM, 4 mM and 8 mM for in vitro study. In addition, the adjuvant properties of lenalidomide were assessed in ten mice groups using NS3 HCV DNA vaccine model of antigen pcDNA3.1(+)/NS3. RESULTS: The results showed that, comparisons to other doses, 4 mMol of lenalidomide was able to noticeably increase NK cytotoxicity activity. Furthermore, the animal model indicated that lenalidomide stimulated NK cytotoxicity in vivo, augmenting it from 16.67% +/- 2.07% for the control group to 38.17% +/- 2.87% for the lenalidomide-treated. CONCLUSION: Treatment by lenalidomide and pcDNA3.1(+)/NS3 improves NK cytotoxicity up to 66.80% suggesting that lenalidomide can be used in parallel with such therapeutic vaccines as cancer vaccine or virus vaccines. PMID- 28630386 TI - Low 17beta-estradiol Levels Are Better Inducers of Regulatory Conditioned T Cells In-Vitro. AB - BACKGROUND: 17beta-estradiol (E2) has been known to modulate immune response. Recent studies indicate that E2 at pregnancy level plays a role in regulating T cell response. OBJECTIVE: To investigate the optimum dose of E2 (from 10-9 to 10 7 M) in mediating the generation of regulatory T cells (Tregs), using naive human CD4+ T cells from healthy women. METHODS: Naive peripheral T cells were purified and conditioned with soluble anti-CD28 in anti-CD3-coated plates in the presence or absence of E2. Flow cytometry was employed to assess the expression pattern of forkhead boxP3 (FOXP3) and programmed death-1 (PD-1). Proliferation and cytokine secretions were analyzed, using XTT and ELISA assays. RESULTS: In the presence of different doses of E2, the expression levels of anti-CD3/CD28 antibody-stimulated CD25/ FOXP3 and FOXP3/PD-1 in conditioned T cells (cT) were peaked at 1 ng/ml (early pregnancy level, E2(1)) (47.14% (37.3-74.9) and 32% (27.7-52.5), respectively) and a slight, but not significant, increase after declining at 36 ng/ml (late pregnancy/pharmaceutical, E2(36)) (19.4% (15.2-24.5) and 15.8% (10.6 26.8), respectively). E2(1) cT showed a significantly reduced proliferation capacity (p<0.05) and secretion of IL-10 was enhanced in supernatants of E2(1 and 36) cT (p<0.05). In contrast to decreased TNF-alpha and IFN-gamma secretions in E2(1) cT supernatants, E2(36) stimulated TNF-alpha and IFN-gamma secretions (p<0.05 and p<0.01, respectively). CONCLUSION: Our results indicate that the differential effect of E2 on generation of Tregs is consistent with the possibility that lower levels of pregnancy E2 are most efficient in induction of Tregs. PMID- 28630387 TI - Assessment of T helper 17-associated cytokines in third trimester of pregnancy. AB - BACKGROUND: Preeclampsia is a common pregnancy-specific disorder associated with significant maternal and fetal morbidity and mortality worldwide. It has been proposed that the imbalance between two CD4+ T cell subtypes, regulatory T cells (Treg) and T-helper 17 cells (Th17), is involved in the pathophysiology of preeclampsia. OBJECTIVES: To determine the serum levels of IL-17, IL-21, IL-23 and TGF-beta in patients with preeclampsia. METHODS: Blood samples were collected from 30 preeclampsia patients, 30 normotensive pregnant women and 30 healthy individuals with no history of malignancies or autoimmune disorders based on simple sampling. The serum levels of IL-17, IL-21, IL-23 and TGF-beta were measured by the enzyme linked immunosorbent assay (ELISA). RESULTS: The serum levels of IL-17 and TGF-beta were significantly higher in preeclampsia patients compared to normal pregnant group and healthy individuals (p>0.0001) but interestingly, the opposite was the case for IL-23 (p=0.005). However, there were no significant differences in IL-21 between preeclampsia and normal pregnant group. CONCLUSIONS: Our results conclude that contrary to IL-21, serum levels of IL-17 and TGF-beta significantly increased in preeclampsia compared to normal pregnant women, supporting an imbalance of cytokine profile in preeclamtic patients. PMID- 28630388 TI - Spontaneous liver rupture associated with anticoagulant therapy A case report. AB - : Spontaneous hepatic rupture without underlying liver diseases is uncommon entity. We report a rare case of spontaneous rupture of liver hematoma in patient treated with warfarin end enoxaparin sodium because of pulmonary embolism. Two day after admission the patient complained generalized abdominal pain and hemodynamic instability. The abdominal US and TC scan revealed free fluid and lesion at right liver lobe. The patient, despite intravenous fluid support and blood transfusion, was hemodinamically instable and urgent laparotomy was needed. At laparotomy, it was found that a subcapsular haematoma, involving the diaphragmatic face of the right liver, had ruptured into peritoneum. Hepatic bleeding was stopped using a conservative approach by Pringle manoeuvre, parenchymal suture and fibrin sealant. There was no complication related to hepatic surgery but the patient died because of new massive pulmonary embolism 10 days after surgery. The absence of underlying liver pathology was confirmed by autopsy examination. This case report suggests that the possibility of spontaneous liver rupture should be considered in patients being treated with oral anticoagulants. Early diagnosis are critically important given the high morbidity and mortality. Aggressive resuscitation and immediate exploratory laparotomy is needed when hemodynamic instability occurs. In our case a quick, safe and effective control of bleeding was provided by partial vascular occlusion, parenchymal suture and topical haemostatic agent. KEY WORD: Anticoagulant therapy, Araumatic hemoperitoneum, Liver hematoma. PMID- 28630389 TI - A case report of the first ganglioneuroblastoma of the parotid gland of an the adult. AB - : The ganglioneuroblastoma is a rare form of pediatric tumor, involving innerved tissues of the nervous sympathetic system, whose evolution is very hard to foresee. A 38 year-old patient whose histologic exam unexpectedly showed ganglioneuroblastoma, underwent a parotidectomy. Three years after surgery the patient is in optimal clinical conditions, without any radiological signs or clinical relapses. KEY WORDS: Ganglioneuroblastoma, Parotid gland, Parodidectomy. PMID- 28630392 TI - Nighttime snacking is associated with risk of obesity and hyperglycemia in adults: a cross-sectional survey from Chinese adult teachers. AB - Relationship between nighttime snack and human health conditions remains unclear. In this paper, we analyzed the association of frequency of nighttime snacking with obesity, hyperlipidemia and hyperglycemia using a Chinese teacher cohort. The Chinese teacher study contains 22,176 of the general adult population operated on in 2015. Information of nighttime snacking frequency was acquired by questionnaire. Overweight and obesity outcome were assessed by body mass index (BMI), and hypertension; hyperlipidemia and hyperglycemia were self-reported. Associations between nighttime snacking consumption and outcomes were performed with multivariat regression and further stratification analyses. We found a significant association (OR 2.11, 95% CI 1.24, 3.62;P for trend<0.001) between most frequent nighttime snacking and hyperglycemia. A remarkable association was also observed between most frequent consumption of nighttime snack and obesity (OR 3.10, 95% CI 1.63, 5.89; Pfor trend<0.001). The present results provide epidemiological evidence that consumption of nighttime snack was associated with obesity and hyperglycemia in Chinese adult teachers. However, the underlying mechanisms still need further investigation.. PMID- 28630393 TI - Sample size re-estimation without un-blinding for time-to-event outcomes in oncology clinical trials. AB - Sample size re-estimation is essential in oncology studies. However, the use of blinded sample size reassessment for survival data has been rarely reported. Based on the density function of the exponential distribution, an expectation maximization (EM) algorithm of the hazard ratio was derived, and several simulation studies were used to verify its applications. The method had obvious variation in the hazard ratio estimates and overestimation for the relatively small hazard ratios. Our studies showed that the stability of the EM estimation results directly correlated with the sample size, the convergence of the EM algorithm was impacted by the initial values, and a balanced design produced the best estimates. No reliable blinded sample size re-estimation inference can be made in our studies, but the results provide useful information to steer the practitioners in this field from repeating the same endeavor.. PMID- 28630395 TI - Cerebral Infarction by Paradoxical Gas Embolism During Laparoscopic Liver Resection with Injury of the Hepatic Vessels in a Patient without a Right-to-Left Systemic Shunt. AB - BACKGROUND Carbon dioxide (CO2) is believed to be the safest gas for laparoscopic surgery, which is a standard procedure. We experienced severe cerebral infarction caused by paradoxical CO2 embolism during laparoscopic liver resection with injury of the hepatic vessels despite the absence of a right-to-left systemic shunt. CASE REPORT A 60-year-old man was diagnosed with hepatocellular carcinoma in the right hepatic lobe secondary to alcoholic liver disease. We planned the laparoscopy-assisted liver resection. During the surgery, the root of the right hepatic vein was injured. A 1.5-cm hole was accidentally made in the right hepatic vein, while mobilizing the right hepatic lobe laparoscopically. End-tidal CO2 dropped from 39 to 15.5 mmHg, and systemic blood pressure dropped from 121 to 45 mmHg, returning to normal with the administration of inotropes. The transesophageal echocardiography revealed numerous bubbles in the left atrium and ventricle. The Bispectral Index monitoring system showed low brain activity, suggesting cerebral infarction due to paradoxical gas embolism. The hepatectomy was completed by conversion to open laparotomy. The patient went into a coma and suffered quadriplegia after surgery, despite the cooling of his head and the administration of Thiamylal. Brain MRI revealed cerebral infarction in the broad area of the cerebral cortex right side predominantly, with poor blood flow confirmed by the brain perfusion single-photon emission CT. Rehabilitation was gradually achieved with Botox injections. CONCLUSIONS Cerebral infarction by paradoxical gas embolism is a rare complication in laparoscopic surgery, but it is important to be aware of the risk and to be prepared to treat it. PMID- 28630397 TI - Fetal Hypotrophy Is an Important Marker in Diagnosis of Preeclampsia in Pregnant Patients After Solid Organ Transplantation. AB - BACKGROUND The purpose of this study was to use a multidisciplinary approach to define the importance of fetal growth disturbances in pregnant patients after renal or liver transplantation in diagnosis and treatment of preeclampsia. MATERIAL AND METHODS We assessed 108 pregnancies in patients with renal or liver transplants. Statistical analysis included Pearson's chi-square test and Fisher's exact test. RESULTS In the renal transplant (RTR) group, preeclampsia was diagnosed in 40% according to ISSHP. In the liver transplant (LTR) group, ISSHP guidelines allow this diagnose in 14.6% of patients. Intrauterine fetal hypotrophy occurred in 53.3% of RTR patients with clinical symptoms of preeclampsia and in none of stabile patients. Premature delivery rate was 40% in patients with hypotrophy and only in 15.5% without. For LTR patients, hypotrophy was diagnosed in 16.4% patients with clinical symptoms of preeclampsia and in 12.7% of stabile patients. Premature delivery rate was 14.5% in patients with hypotrophy and in 14.5% without. CONCLUSIONS Fetal hypotrophy is strongly associated with premature delivery and risk of preeclampsia in pregnancies after renal transplantation. There is a need for including ultrasound findings in diagnostic criteria of preeclampsia. Fetal growth monitoring may help in prediction of premature delivery in these group. PMID- 28630396 TI - Comparison of Lavage Techniques for Preventing Incision Infection Following Posterior Lumbar Interbody Fusion. AB - BACKGROUND The main purpose of this study was to compare the effects of various lavage techniques - traditional saline lavage (SL), pulse lavage (PL), closed drainage (CD), and iodine lavage (IL) - on preventing incision-related infection after posterior lumbar interbody fusion. MATERIAL AND METHODS Patients with prolapsed lumbar (intervertebral) discs (PLID) undergoing posterior lumbar interbody fusion surgery (PLIF) over the course of 2 years were included and were randomly allocated into 4 groups: the SL group, the PL group, the CD group, and the IL group. Relevant data were recorded, including preoperative conditions, intraoperative lavage time, lavage fluid volume, incision outlook, pain perception, results of routine blood tests, and postoperative infection rate. RESULTS The PL, CD, and IL groups showed less intraoperative lavage time, lavage volume fluid, effusion, infection rate, and muscle and lower pain perception compared with the SL group (all P<0.05). Significant differences in white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were observed between preoperative and postoperative data in each group (P<0.01). No significant differences in clinical characteristics, postoperative temperature, suture removal time, incision characteristics, WBC, ESR, and CRP were observed among the PL, CD, IL, and SL groups (P>0.05). CONCLUSIONS PL, CD, and IL all showed much better postoperative infection prevention in comparison to SL. PMID- 28630398 TI - HCF-1 encoded by baculovirus AcMNPV is required for productive nucleopolyhedrovirus infection of non-permissive Tn368 cells. AB - Baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) replicates in both Spodoptera frugiperda Sf21 and Trichoplusia ni Tn368 cells, whereas AcMNPV defective in hcf-1 (host cell-factor 1) gene productively infects only Sf21 cells, indicating that HCF-1 is indispensable for the AcMNPV productive infection of Tn368 cells. Here, we demonstrated that HCF-1 protein transiently expressed in Tn368 cells promotes the DNA synthesis of Hyphantria cunea MNPV (HycuMNPV), Orygia pseudotsugata MNPV and Bombyx mori NPV, which are normally unable to replicate in Tn368 cells. We also demonstrated that a recombinant HycuMNPV harboring the hcf-1 gene successfully replicates in Tn368 cells, generating substantial yields of progeny viruses and polyhedra. These results indicate that HCF-1 encoded by AcMNPV is an essential viral factor for productive NPV infection of Tn368 cells. Taken together with the previous findings on HRF-1 (host range factor 1), the present results provide strong evidence that viral genes acquired through horizontal gene transfer play an important role in baculovirus evolution, serving to expand the host range of baculoviruses. PMID- 28630400 TI - In Memorium Dorothy Rice (1922-2017). PMID- 28630399 TI - Dietary mastic oil extracted from Pistacia lentiscus var. chia suppresses tumor growth in experimental colon cancer models. AB - Plant-derived bioactive compounds attract considerable interest as potential chemopreventive anticancer agents. We analyzed the volatile dietary phytochemicals (terpenes) present in mastic oil extracted from the resin of Pistacia lentiscus var. chia and comparatively investigated their effects on colon carcinoma proliferation, a) in vitro against colon cancer cell lines and b) in vivo on tumor growth in mice following oral administration. Mastic oil inhibited - more effectively than its major constituents- proliferation of colon cancer cells in vitro, attenuated migration and downregulated transcriptional expression of survivin (BIRC5a). When administered orally, mastic oil inhibited the growth of colon carcinoma tumors in mice. A reduced expression of Ki-67 and survivin in tumor tissues accompanied the observed effects. Notably, only mastic oil -which is comprised of 67.7% alpha-pinene and 18.8% myrcene- induced a statistically significant anti-tumor effect in mice but not alpha-pinene, myrcene or a combination thereof. Thus, mastic oil, as a combination of terpenes, exerts growth inhibitory effects against colon carcinoma, suggesting a nutraceutical potential in the fight against colon cancer. To our knowledge, this is the first report showing that orally administered mastic oil induces tumor-suppressing effects against experimental colon cancer. PMID- 28630401 TI - Waterpipe product packaging and labelling at the 3rd international Hookah Fair; does it comply with Article 11 of the Framework Convention on Tobacco Control? AB - We assessed compliance of waterpipe product packaging and labelling with the Framework Convention on Tobacco Control's Article 11. We evaluated samples collected at a trade fair against ten domains: health warning location, size, use of pictorials, use of colour, and packaging information on constituents and emissions. We also evaluated waterpipe accessories (e.g., charcoal) for misleading claims. Ten of 15 tobacco products had health warnings on their principal display areas, covering a median of 22.4 per cent (interquartile range 19.4-27.4 per cent) of those areas. Three had pictorial, in-colour health warnings. We judged all packaging information on constituents and emissions to be misleading. Eight of 13 charcoal products displayed environmentally friendly descriptors and/or claims of reduced harm that we judged to be misleading. Increased compliance with waterpipe tobacco regulation is warranted. An improved policy framework for waterpipe tobacco should also consider regulation of accessories such as charcoal products. PMID- 28630402 TI - Exploration of binding and inhibition mechanism of a small molecule inhibitor of influenza virus H1N1 hemagglutinin by molecular dynamics simulation. AB - Influenza viruses are a major public health threat worldwide. The influenza hemagglutinin (HA) plays an essential role in the virus life cycle. Due to the high conservation of the HA stem region, it has become an especially attractive target for inhibitors for therapeutics. In this study, molecular simulation was applied to study the mechanism of a small molecule inhibitor (MBX2329) of influenza HA. Behaviors of the small molecule under neutral and acidic conditions were investigated, and an interesting dynamic binding mechanism was found. The results suggested that the binding of the inhibitor with HA under neutral conditions facilitates only its intake, while it interacts with HA under acidic conditions using a different mechanism at a new binding site. After a series of experiments, we believe that binding of the inhibitor can prevent the release of HA1 from HA2, further maintaining the rigidity of the HA2 loop and stabilizing the distance between the long helix and short helices. The investigated residues in the new binding site show high conservation, implying that the new binding pocket has the potential to be an effective drug target. The results of this study will provide a theoretical basis for the mechanism of new influenza virus inhibitors. PMID- 28630403 TI - New molecular tools in Neospora caninum for studying apicomplexan parasite proteins. AB - The development of molecular genetics has greatly enhanced the study of the biology and pathology associated with parasites of the phylum Apicomplexa. We have established a system specifically designed for Neospora caninum, and used this system as a heterologous platform for the expression of foreign genes. Plasmid constructs containing fluorescent proteins or targeted genes of Toxoplasma gondii, driven by N. caninum promoters, have yielded robust expression and correct trafficking of target gene products as assessed by immunofluorescence assays and Western blot analyses. Using this approach, we here demonstrated that N. caninum expressing T. gondii's GRA15 and ROP16 kinase are biologically active and induced immunological phenotypes consistent with T. gondii strains. N. caninum expressing TgGRA15 differentially disturbed the NF-kappaB pathway, inducing an increased IL-12 production. On the other hand, N. caninum expressing TgROP16 induced host STAT3 phosphorylation and consequent reduction of IL-12 synthesis. These results indicate that heterologous gene expression in N. caninum is a useful tool for the study of specific gene functions and may allow the identification of antigenic targets responsible for the phenotypic differences observed between these two closely related apicomplexan parasites. Additionally, these observations may prove to be useful for the development of vaccine protocols to control toxoplasmosis and/or neosporosis. PMID- 28630404 TI - Activation of D1R/PKA/mTOR signaling cascade in medial prefrontal cortex underlying the antidepressant effects of l-SPD. AB - Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms. Although several antidepressants can influence dopamine system in the medial prefrontal cortex (mPFC), but the role of D1R or D2R subtypes of dopamine receptor during anti-depression process is still vague in PFC region. To address this question, we investigate the antidepressant effect of levo-stepholidine (l-SPD), an antipsychotic medication with unique pharmacological profile of D1R agonism and D2R antagonism, and clarified its molecular mechanisms in the mPFC. Our results showed that l-SPD exerted antidepressant-like effects on the Sprague-Dawley rat CMS model of depression. Mechanism studies revealed that l-SPD worked as a specific D1R agonist, rather than D2 antagonist, to activate downstream signaling of PKA/mTOR pathway, which resulted in increasing synaptogenesis-related proteins, such as PSD 95 and synapsin I. In addition, l-SPD triggered long-term synaptic potentiation (LTP) in the mPFC, which was blocked by the inhibition of D1R, PKA, and mTOR, supporting that selective activation of D1R enhanced excitatory synaptic transduction in PFC. Our findings suggest a critical role of D1R/PKA/mTOR signaling cascade in the mPFC during the l-SPD mediated antidepressant process, which may also provide new insights into the role of mesocortical dopaminergic system in antidepressant effects. PMID- 28630405 TI - Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation. AB - The severity and course of inflammatory processes differ between women and men, but the biochemical mechanisms underlying these sex differences are elusive. Prostaglandins (PG) and leukotrienes (LT) are lipid mediators linked to inflammation. We demonstrated superior LT biosynthesis in human neutrophils and monocytes, and in mouse macrophages from females, and we confirmed these sex differences in vivo where female mice produced more LTs during zymosan-induced peritonitis versus males. Here, we report sex differences in PG production in neutrophils during acute inflammation. In the late phase (4-8 hrs) of mouse zymosan-induced peritonitis and rat carrageenan-induced pleurisy, PG levels in males were higher versus females, seemingly due to higher PG production in infiltrated neutrophils. Accordingly, human neutrophils from males produced more PGE2 than cells from females. Increased PG biosynthesis in males was accompanied by elevated cyclooxygenase (COX)-2 expression connected to increased nuclear factor-kappa B activation, and was abolished when LT synthesis was pharmacologically blocked, suggesting that elevated PG production in males might be caused by increased COX-2 expression and by shunting phenomena due to suppressed LT formation. Conclusively, our data reveal that the biosynthesis of pro-inflammatory PGs and LTs is conversely regulated by sex with consequences for the inflammatory response. PMID- 28630406 TI - Emerging fungal pathogen Ophidiomyces ophiodiicola in wild European snakes. AB - Snake fungal disease (SFD) is an emerging disease of conservation concern in eastern North America. Ophidiomyces ophiodiicola, the causative agent of SFD, has been isolated from over 30 species of wild snakes from six families in North America. Whilst O. ophiodiicola has been isolated from captive snakes outside North America, the pathogen has not been reported from wild snakes elsewhere. We screened 33 carcasses and 303 moulted skins from wild snakes collected from 2010 2016 in Great Britain and the Czech Republic for the presence of macroscopic skin lesions and O. ophiodiicola. The fungus was detected using real-time PCR in 26 (8.6%) specimens across the period of collection. Follow up culture and histopathologic analyses confirmed that both O. ophiodiicola and SFD occur in wild European snakes. Although skin lesions were mild in most cases, in some snakes they were severe and were considered likely to have contributed to mortality. Culture characterisations demonstrated that European isolates grew more slowly than those from the United States, and phylogenetic analyses indicated that isolates from European wild snakes reside in a clade distinct from the North American isolates examined. These genetic and phenotypic differences indicate that the European isolates represent novel strains of O. ophiodiicola. Further work is required to understand the individual and population level impact of this pathogen in Europe. PMID- 28630407 TI - Colony adaptive response to simulated heat waves and consequences at the individual level in honeybees (Apis mellifera). AB - Since climate change is expected to bring more severe and frequent extreme weather events such as heat waves, assessing the physiological and behavioural sensitivity of organisms to temperature becomes a priority. We therefore investigated the responses of honeybees, an important insect pollinator, to simulated heat waves (SHW). Honeybees are known to maintain strict brood thermoregulation, but the consequences at the colony and individual levels remain poorly understood. For the first time, we quantified and modelled colony real time activity and found a 70% increase in foraging activity with SHW, which was likely due to the recruitment of previously inactive bees. Pollen and nectar foraging was not impacted, but an increase in water foragers was observed at the expense of empty bees. Contrary to individual energetic resources, vitellogenin levels increased with SHW, probably to protect bees against oxidative stress. Finally, though immune functions were not altered, we observed a significant decrease in deformed wing virus loads with SHW. In conclusion, we demonstrated that honeybees could remarkably adapt to heat waves without a cost at the individual level and on resource flow. However, the recruitment of backup foraging forces might be costly by lowering the colony buffering capacity against additional environmental pressures. PMID- 28630408 TI - The cellular and circuit basis for evolutionary change in sensory perception in mormyrid fishes. AB - Species differences in perception have been linked to divergence in gross neuroanatomical features of sensory pathways. The anatomical and physiological basis of evolutionary change in sensory processing at cellular and circuit levels, however, is poorly understood. Here, we show how specific changes to a sensory microcircuit are associated with the evolution of a novel perceptual ability. In mormyrid fishes, the ability to detect variation in electric communication signals is correlated with an enlargement of the midbrain exterolateral nucleus (EL), and a differentiation into separate anterior (ELa) and posterior (ELp) regions. We show that the same cell types and connectivity are found in both EL and ELa/ELp. The evolution of ELa/ELp, and the concomitant ability to detect signal variation, is associated with a lengthening of incoming hindbrain axons to form delay lines, allowing for fine temporal analysis of signals. The enlargement of this brain region is also likely due to an overall increase in cell numbers, which would allow for processing of a wider range of timing information. PMID- 28630409 TI - Two-dimensional fluorescence spectroscopy of uranium isotopes in femtosecond laser ablation plumes. AB - We demonstrate measurement of uranium isotopes in femtosecond laser ablation plumes using two-dimensional fluorescence spectroscopy (2DFS). The high resolution, tunable CW-laser spectroscopy technique clearly distinguishes atomic absorption from 235U and 238U in natural and highly enriched uranium metal samples. We present analysis of spectral resolution and analytical performance of 2DFS as a function of ambient pressure. Simultaneous measurement using time resolved absorption spectroscopy provides information on temporal dynamics of the laser ablation plume and saturation behavior of fluorescence signals. The rapid, non-contact measurement is promising for in-field, standoff measurements of uranium enrichment for nuclear safety and security. PMID- 28630410 TI - Investigating the Life Expectancy and Proteolytic Degradation of Engineered Skeletal Muscle Biological Machines. AB - A combination of techniques from 3D printing, tissue engineering and biomaterials has yielded a new class of engineered biological robots that could be reliably controlled via applied signals. These machines are powered by a muscle strip composed of differentiated skeletal myofibers in a matrix of natural proteins, including fibrin, that provide physical support and cues to the cells as an engineered basement membrane. However, maintaining consistent results becomes challenging when sustaining a living system in vitro. Skeletal muscle must be preserved in a differentiated state and the system is subject to degradation by proteolytic enzymes that can break down its mechanical integrity. Here we examine the life expectancy, breakdown, and device failure of engineered skeletal muscle bio-bots as a result of degradation by three classes of proteases: plasmin, cathepsin L, and matrix metalloproteinases (MMP-2 and MMP-9). We also demonstrate the use of gelatin zymography to determine the effects of differentiation and inhibitor concentration on protease expression. With this knowledge, we are poised to design the next generation of complex biological machines with controllable function, specific life expectancy and greater consistency. These results could also prove useful for the study of disease-specific models, treatments of myopathies, and other tissue engineering applications. PMID- 28630411 TI - Single phase 3D phononic band gap material. AB - Phononic band gap materials are capable of prohibiting the propagation of mechanical waves in certain frequency ranges. Band gaps are produced by combining different phases with different properties within one material. In this paper, we present a novel cellular material consisting of only one phase with a phononic band gap. Different phases are modelled by lattice structure design based on eigenmode analysis. Test samples are built from a titanium alloy using selective electron beam melting. For the first time, the predicted phononic band gaps via FEM simulation are experimentally verified. In addition, it is shown how the position and extension of the band gaps can be tuned by utilizing knowledge-based design. PMID- 28630412 TI - The challenges of predicting pesticide exposure of honey bees at landscape level. AB - To evaluate the risks of pesticides for pollinators, we must not only evaluate their toxicity but also understand how pollinators are exposed to these xenobiotics in the field. We focused on this last point and modeled honey bee exposure to pesticides at the landscape level. Pollen pellet samples (n = 60) from 40 Belgian apiaries were collected from late July to October 2011 and underwent palynological and pesticide residue analyses. Areas of various crops around each apiary were measured at 4 spatial scales. The most frequently detected pesticides were the fungicides boscalid (n = 19, 31.7%) and pyrimethanil (n = 10, 16.7%) and the insecticide dimethoate (n = 10, 16.7%). We were able to predict exposure probability for boscalid and dimethoate by using broad indicators of cropping intensity, but it remained difficult to identify the precise source of contamination (e.g. specific crops in which the use of the pesticide is authorized). For pyrimethanil, we were not able to build any convincing landscape model that could explain the contamination. Our results, combined with the late sampling period, strongly suggest that pesticides applied to crops unattractive to pollinators, and therefore considered of no risk for them, may be sources of exposure through weeds, drift to neighboring plants, or succeeding crops. PMID- 28630413 TI - Bayesian inference of physiologically meaningful parameters from body sway measurements. AB - The control of the human body sway by the central nervous system, muscles, and conscious brain is of interest since body sway carries information about the physiological status of a person. Several models have been proposed to describe body sway in an upright standing position, however, due to the statistical intractability of the more realistic models, no formal parameter inference has previously been conducted and the expressive power of such models for real human subjects remains unknown. Using the latest advances in Bayesian statistical inference for intractable models, we fitted a nonlinear control model to posturographic measurements, and we showed that it can accurately predict the sway characteristics of both simulated and real subjects. Our method provides a full statistical characterization of the uncertainty related to all model parameters as quantified by posterior probability density functions, which is useful for comparisons across subjects and test settings. The ability to infer intractable control models from sensor data opens new possibilities for monitoring and predicting body status in health applications. PMID- 28630414 TI - Predicting the Reliability of Drug-target Interaction Predictions with Maximum Coverage of Target Space. AB - Many computational methods to predict the macromolecular targets of small organic molecules have been presented to date. Despite progress, target prediction methods still have important limitations. For example, the most accurate methods implicitly restrict their predictions to a relatively small number of targets, are not systematically validated on drugs (whose targets are harder to predict than those of non-drug molecules) and often lack a reliability score associated with each predicted target. Here we present a systematic validation of ligand centric target prediction methods on a set of clinical drugs. These methods exploit a knowledge-base covering 887,435 known ligand-target associations between 504,755 molecules and 4,167 targets. Based on this dataset, we provide a new estimate of the polypharmacology of drugs, which on average have 11.5 targets below IC50 10 uM. The average performance achieved across clinical drugs is remarkable (0.348 precision and 0.423 recall, with large drug-dependent variability), especially given the unusually large coverage of the target space. Furthermore, we show how a sparse ligand-target bioactivity matrix to retrospectively validate target prediction methods could underestimate prospective performance. Lastly, we present and validate a first-in-kind score capable of accurately predicting the reliability of target predictions. PMID- 28630415 TI - Integrating genome and transcriptome profiling for elucidating the mechanism of muscle growth and lipid deposition in Pekin ducks. AB - Muscle growth and lipid deposition are co-ordinately regulated processes. Cherry Valley Pekin duck is a lean-type duck breed with high growth rate, whereas the native Pekin duck of China has high lipid deposition. Phenotypic analysis showed that native Pekin ducks have smaller fibre diameter and larger density in the breast muscle at 3 weeks of age and higher intramuscular fat content at 6 weeks of age than those in Cherry Valley Pekin ducks. We detected 17 positively selected genes (PSGs) by comparing genes mainly involved with muscle organ development, muscle contraction, peroxisome proliferator activated receptor signalling pathway, and fatty acid metabolism. In all, 52 and 206 differentially expressed genes (DEGs) were identified in transcriptomic comparisons between the two breeds at 3 and 6 weeks of age, respectively, which could potentially affect muscle growth and lipid deposition. Based on the integration of PSGs and DEGs and their functional annotations, we found that 11 and 10 genes were correlated with muscle growth and lipid deposition, respectively. Identification of candidate genes controlling quantitative traits of duck muscle might aid in elucidating the mechanisms of muscle growth and lipid deposition and could help in improving duck breeding. PMID- 28630416 TI - HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death. AB - The local anesthetic lidocaine induces cell death by altering reactive oxygen species (ROS) generation and mitochondrial electron transport chain function. Because hypoxia-inducible factor 1 (HIF-1) is involved in determining oxygen metabolism and mitochondria function, we investigated the involvement of HIF-1 activity in lidocaine-induced cell death. We investigated the role of HIF activation on lidocaine-induced caspase activation and cell death in renal cell derived RCC4 cells lacking functional von Hippel-Lindau (VHL) protein. We demonstrate that HIF-1 suppressed oxygen consumption and facilitated glycolysis in a pyruvate dehydrogenase kinase-1-dependent manner and that activation of HIF 1 conferred resistance to lidocaine-induced cell death. We also demonstrated that exogenous HIF-1 activation, through HIFalpha-hydroxylase inhibition or exposure to hypoxic conditions, alleviates lidocaine toxicity by suppressing mitochondria function and generating ROS, not only in RCC4 cells, but also in the neuronal SH SY5Y cells. In conclusion, we demonstrate that HIF-1 activation due to VHL deletion, treatment with small molecule HIFalpha-hydroxylase inhibitors, and exposure to hypoxic conditions suppresses mitochondrial respiratory chain function and confers resistance to lidocaine toxicity. PMID- 28630417 TI - Ultrarapid Measurement of Diagnostic Antibodies by Magnetic Capture of Immune Complexes. AB - Rapid point-of-care, antibody-based testing is not currently available for the diagnosis of most autoimmune and infectious diseases. Here we report a simple, robust and ultrafast fluid-phase immunocapture method for clinical measurements of antibody levels. This method employs neodymium magnetic sticks that capture protein A/G-coated paramagnetic beads bound to antibody-luciferase-labeled antigen complexes. We demonstrate the ability to effectively measure specific antibody levels in serum samples from patients with varied infectious or autoimmune disorders, and in the case of Sjogren's syndrome directly in saliva, requiring about a minute per assay. We also show the feasibility of coupling this method with a hand-held luminometer for portable testing. Our method offers the potential to quickly diagnose a multitude of autoimmune and infectious diseases in point-of-care settings. PMID- 28630418 TI - Replacing a Century Old Technique - Modern Spectroscopy Can Supplant Gram Staining. AB - Rapid and accurate Gram differentiation is paramount as the first step of pathogen identification and antibiotics administration. However, the current method requires additional reagents, is time-consuming, and is operator dependent. Here we show the principle of tip enhanced Raman spectroscopy (TERS) can differentiate between Gram negative and positive species, by detecting the changes in tip-enhancement in the Raman scattering from the bacteria's lipid bilayer membrane, which specifically enhances Gram negative bacteria. PMID- 28630420 TI - Functional Evaluation of a Bioartificial Liver Support System Using Immobilized Hepatocyte Spheroids in a Porcine Model of Acute Liver Failure. AB - Bioartificial livers (BAL) may offer acute liver failure (ALF) patients an opportunity for cure without liver transplantation. We evaluated the efficacy of a spheroid-based BAL system, containing aggregates of porcine hepatocytes, in a porcine model of ALF. ALF pigs were divided into three groups. The control group consisted of treatment naive pigs (n = 5), blank group consisted of pigs that were attached to the BAL system not containing hepatocytes for 12 hours (n = 5) and BAL group consisted of pigs that were attached to the BAL containing hepatocytes for 12 hours (n = 5). Increase in serum ammonia levels were significantly greater in the blank group (P < 0.01) and control group (P < 0.01), compared to the BAL group during the treatment period. Increase in ICP was significantly greater in the control group compared to the BAL group (P = 0.01). Survival was significantly prolonged in the BAL group compared to the blank group (P = 0.03). A BAL system with a bioreactor containing hepatocyte spheroids showed effective clearance of serum ammonia, preservation of renal function and delayed ICP increase in a porcine model of ALF. PMID- 28630419 TI - Iscador Qu inhibits doxorubicin-induced senescence of MCF7 cells. AB - Chemotherapy in patients with inoperable or advanced breast cancer inevitably results in low-dose exposure of tumor-cell subset and senescence. Metabolically active senescent cells secrete multiple tumor promoting factors making their elimination a therapeutic priority. Viscum album is one of the most widely used alternative anti-cancer medicines facilitating chemotherapy tolerance of breast cancer patients. The aim of this study was to model and investigate how Viscum album extracts execute additive anti-tumor activity with low-dose Dox using ER + MCF7 breast cancer cells. We report that cotreatment of MCF7 with Viscum album and Dox abrogates G2/M cycle arrest replacing senescence with intrinsic apoptotic program. Mechanistically, this switch was associated with down-regulation of p21, p53/p73 as well as Erk1/2 and p38 activation. Our findings, therefore, identify a novel mechanistic axis of additive antitumor activity of Viscum album and low dose-Dox. In conclusion, ER + breast cancer patients may benefit from addition of Viscum album to low-dose Dox chemotherapy due to suppression of cancer cell senescence and induction of apoptosis. PMID- 28630422 TI - Basic surface features of nuclear FKBPs facilitate chromatin binding. AB - The nucleoplasmin family of histone chaperones is identified by a pentamer forming domain and multiple acidic tracts that mediate histone binding and chaperone activity. Within this family, a novel domain organization was recently discovered that consists of an N-terminal nucleoplasmin-like (NPL) domain and a C terminal FKBP peptidyl-proline isomerase domain. Saccharomyces cerevisiae Fpr4 is one such protein. Here we report that in addition to its known histone prolyl isomerase activities, the Fpr4 FKBP domain binds to nucleosomes and nucleosome arrays in vitro. This ability is mediated by a collection of basic patches that enable the enzyme to stably associate with linker DNA. The interaction of the Fpr4 FKBP with recombinant chromatin complexes condenses nucleosome arrays independently of its catalytic activity. Based on phylogenetic comparisons we propose that the chromatin binding ability of 'basic' FKBPs is shared amongst related orthologues present in fungi, plants, and insects. Thus, a subclass of FKBP prolyl isomerase enzymes is recruited to linker regions of chromatin. PMID- 28630421 TI - A genome-wide association study of anorexia nervosa suggests a risk locus implicated in dysregulated leptin signaling. AB - We conducted a genome-wide association study (GWAS) of anorexia nervosa (AN) using a stringently defined phenotype. Analysis of phenotypic variability led to the identification of a specific genetic risk factor that approached genome-wide significance (rs929626 in EBF1 (Early B-Cell Factor 1); P = 2.04 * 10-7; OR = 0.7; 95% confidence interval (CI) = 0.61-0.8) with independent replication (P = 0.04), suggesting a variant-mediated dysregulation of leptin signaling may play a role in AN. Multiple SNPs in LD with the variant support the nominal association. This demonstrates that although the clinical and etiologic heterogeneity of AN is universally recognized, further careful sub-typing of cases may provide more precise genomic signals. In this study, through a refinement of the phenotype spectrum of AN, we present a replicable GWAS signal that is nominally associated with AN, highlighting a potentially important candidate locus for further investigation. PMID- 28630423 TI - Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling. AB - The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2. A TB4 CRISPR also blocked the activation of primary HSCs, with decreased expression of smoothened, GLI2 and ILK compared with cells transfected with nontargeting control CRISPR. Double immunostaining and an immunoprecipitation assay revealed that TB4 interacted with either smoothened at the cytoplasm or GLI2 at the nucleus in LX-2. Smoothened suppression in primary HSCs using a Hh antagonist or adenovirus transduction decreased TB4 expression with the reduced activation of HSCs. Tb4-overexpressing transgenic mice treated with CCl4 were susceptible to the development hepatic fibrosis with higher levels of ILK, pGSK3b, and Hh activity, as compared with wild-type mice. These findings demonstrate that TB4 regulates HSC activation by influencing the activity of Smoothened and GLI2, suggesting TB4 as a novel therapeutic target in liver disease. PMID- 28630424 TI - Characterization of slow cycling corneal limbal epithelial cells identifies putative stem cell markers. AB - In order to identify reliable markers of corneal epithelial stem cells, we employed an inducible transgenic "pulse-chase" murine model (K5Tta * TRE-H2BGFP) to localize, purify, and characterize slow cycling cells in the cornea. The retention of GFP labeling in slowly dividing cells allowed for localization of these cells to the corneal limbus and their subsequent purification by FACS. Transcriptome analysis from slow cycling cells identified differentially expressed genes when comparing to GFP- faster-dividing cells. RNA-Seq data from corneal epithelium were compared to epidermal hair follicle stem cell RNA-Seq to identify genes representing common putative stem cell markers or determinants, which included Sox9, Fzd7, Actn1, Anxa3 and Krt17. Overlapping retention of GFP and immunohistochemical expression of Krt15, DeltaNp63, Sox9, Actn1, Fzd7 and Krt17 were observed in our transgenic model. Our analysis presents an array of novel genes as putative corneal stem cell markers. PMID- 28630426 TI - The down-regulation of SLC7A11 enhances ROS induced P-gp over-expression and drug resistance in MCF-7 breast cancer cells. AB - Adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance in breast cancer cells. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and decreased glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over expression of P-gp. The present study showed that ADR inhibited the influx of cystine (the source material of GSH) and the activity of the SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that the down-regulation/silence of SLC7A11, or cystine deprivation, or enhanced ROS exposure significantly increased P-gp expression in MCF-7 cells. The down regulation of SLC7A11 markedly enhanced ROS induced P-gp over-expression and drug resistance in MCF-7 cells; a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and increased ROS dramatically promoted P-gp expression, which could be reversed by N-acetylcysteine. In contrast, the over-expression of SLC7A11, or supplementation with sufficiently cystine, or treatment with N acetylcysteine significantly decreased P-gp expression and activity. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the expression and function of P-gp, and that SLC7A11 might be a potential target modulating ADR resistance. PMID- 28630425 TI - Reconstructing cell cycle pseudo time-series via single-cell transcriptome data. AB - Single-cell mRNA sequencing, which permits whole transcriptional profiling of individual cells, has been widely applied to study growth and development of tissues and tumors. Resolving cell cycle for such groups of cells is significant, but may not be adequately achieved by commonly used approaches. Here we develop a traveling salesman problem and hidden Markov model-based computational method named reCAT, to recover cell cycle along time for unsynchronized single-cell transcriptome data. We independently test reCAT for accuracy and reliability using several data sets. We find that cell cycle genes cluster into two major waves of expression, which correspond to the two well-known checkpoints, G1 and G2. Moreover, we leverage reCAT to exhibit methylation variation along the recovered cell cycle. Thus, reCAT shows the potential to elucidate diverse profiles of cell cycle, as well as other cyclic or circadian processes (e.g., in liver), on single-cell resolution.In single-cell RNA sequencing data of heterogeneous cell populations, cell cycle stage of individual cells would often be informative. Here, the authors introduce a computational model to reconstruct a pseudo-time series from single cell transcriptome data, identify the cell cycle stages, identify candidate cell cycle-regulated genes and recover the methylome changes during the cell cycle. PMID- 28630427 TI - Insulin use and Excess Fracture Risk in Patients with Type 2 Diabetes: A Propensity-Matched cohort analysis. AB - Despite normal to high bone mineral density, patients with type 2 diabetes (T2DM) have an increased fracture risk. T2DM medications could partially account for this excess risk. The aim of this study was to assess the association between insulin use and bone fracture risk in T2DM patients. A population-based matched cohort study based on a primary care records database validated for research use (Catalonia, Spain) was performed. Propensity score (PS) for insulin use was calculated using logistic regression including predefined predictors of fractures. A total of 2,979 insulin users and 14,895 non-users were observed for a median of 1.42 and 4.58 years respectively. Major fracture rates were 11.2/1,000 person-years for insulin users, compared with 8.3/1,000 among non users. Matched models confirmed a significant association, with an adjusted subhazard ratio (adj SHR) of 1.38 [95% CI 1.06 to 1.80] for major fractures. No differences between types of insulin or different regimens were found. Estimated number needed to harm (fracture) was 82 (95% CI 32 to 416). Insulin use appears to be associated with a 38% excess fracture risk among T2DM patients in the early stages of the disease. Fracture risk should be included among the considerations to initiate insulin treatment. PMID- 28630428 TI - Nuclear accumulation of symplekin promotes cellular proliferation and dedifferentiation in an ERK1/2-dependent manner. AB - Symplekin is a multifunctional protein that localizes to both tight junctions and the nucleus in polarized epithelial cells, with confirmed roles in mRNA maturation, transcriptional modulation and tight-junction assembly. However, the mechanisms governing its subcellular distribution and related functions remain unclear. In this study, we found that symplekin primarily localizes to the nuclei of cultured dedifferentiated colorectal cancer cells, and nuclear symplekin showed higher phosphorylation and binding affinity with YBX3 than its membrane fraction. Moreover, the accumulation of nuclear symplekin promoted cell proliferation and dedifferentiation as well as beta-catenin transactivation in vitro. Nuclear symplekin acts as a transcriptional co-activator for the expression of many cell cycle-related genes. Furthermore, extracellular signal regulated kinase (ERK) phosphorylated symplekin at T1257 to facilitate its nuclear accumulation upon epidermal growth factor (EGF) stimulation. Meanwhile, reduction of total symplekin also induced certain epithelial-mesenchymal transition features in HT-29 cells. Taken together, our results confirm the coordinated roles of symplekin in cell junctions and gene transcription, which are related to its subcellular localization. The significance of nuclear symplekin in tumorigenesis is also highlighted, and ERK-dependent phosphorylation represents a mechanism for its subcellular sorting. PMID- 28630429 TI - Marine diatoms change their gene expression profile when exposed to microscale turbulence under nutrient replete conditions. AB - Diatoms are a fundamental microalgal phylum that thrives in turbulent environments. Despite several experimental and numerical studies, if and how diatoms may profit from turbulence is still an open question. One of the leading arguments is that turbulence favours nutrient uptake. Morphological features, such as the absence of flagella, the presence of a rigid exoskeleton and the micrometre size would support the possible passive but beneficial role of turbulence on diatoms. We demonstrate that in fact diatoms actively respond to turbulence in non-limiting nutrient conditions. TURBOGEN, a prototypic instrument to generate natural levels of microscale turbulence, was used to expose diatoms to the mechanical stimulus. Differential expression analyses, coupled with microscopy inspections, enabled us to study the morphological and transcriptional response of Chaetoceros decipiens to turbulence. Our target species responds to turbulence by activating energy storage pathways like fatty acid biosynthesis and by modifying its cell chain spectrum. Two other ecologically important species were examined and the occurrence of a morphological response was confirmed. These results challenge the view of phytoplankton as unsophisticated passive organisms. PMID- 28630430 TI - A Multinational Analysis of Mutations and Heterogeneity in PZase, RpsA, and PanD Associated with Pyrazinamide Resistance in M/XDR Mycobacterium tuberculosis. AB - Pyrazinamide (PZA) is an important first-line drug in all existing and new tuberculosis (TB) treatment regimens. PZA-resistance in M. tuberculosis is increasing, especially among M/XDR cases. Noted issues with PZA Drug Susceptibility Testing (DST) have driven the search for alternative tests. This study provides a comprehensive assessment of PZA molecular diagnostics in M/XDR TB cases. A set of 296, mostly XDR, clinical M. tuberculosis isolates from four countries were subjected to DST for eight drugs, confirmatory Wayne's assay, and whole-genome sequencing. Three genes implicated in PZA resistance, pncA, rpsA, and panD were investigated. Assuming all non-synonymous mutations cause resistance, we report 90% sensitivity and 65% specificity for a pncA-based molecular test. The addition of rpsA and panD potentially provides 2% increase in sensitivity. Molecular heterogeneity in pncA was associated with resistance and should be evaluated as a diagnostic tool. Mutations near the N-terminus and C terminus of PZase were associated with East-Asian and Euro-American lineages, respectively. Finally, Euro-American isolates are most likely to have a wild-type PZase and escape molecular detection. Overall, the 8-10% resistance without markers may point to alternative mechanisms of resistance. Confirmatory mutagenesis may improve the disconcertingly low specificity but reduce sensitivity since not all mutations may cause resistance. PMID- 28630431 TI - Role of methionine adenosyltransferase 2A in bovine preimplantation development and its associated genomic regions. AB - Methionine adenosyltransferase (MAT) is involved in folate-mediated one-carbon metabolism, which is essential for preimplantation embryos in terms of both short term periconceptional development and long-term phenotypic programming beyond the periconceptional period. Here, our immunofluorescence analysis of bovine oocytes and preimplantation embryos revealed the consistent expression of MAT2A (the catalytic subunit of the ubiquitously expressed-type of MAT isozyme) during this period. Addition of the MAT2A inhibitor FIDAS to the culture media of bovine preimplantation embryos reduced their blastocyst development, revealing the particular importance of MAT2A in successful blastocyst development. Exploration of MAT2A-associated genomic regions in bovine blastocysts using chromatin immunoprecipitation and sequencing (ChIP-seq) identified candidate MAT2A associated genes implicated not only in short-term periconceptional embryo development, but also in long-term phenotypic programming during this period in terms of growth, metabolism, and immune functions. These results suggest the critical involvement of MAT2A in the periconceptional period in life-long programming of health and disease as well as successful preimplantation development. PMID- 28630432 TI - Down-regulation of KCa2.3 channels causes erectile dysfunction in mice. AB - Modulation of endothelial calcium-activated K+ channels has been proposed as an approach to restore arterial endothelial cell function in disease. We hypothesized that small-conductance calcium-activated K+ channels (KCa2.3 or SK3) contributes to erectile function. The research was performed in transgenic mice with overexpression (KCa2.3 T/T(-Dox)) or down-regulation (KCa2.3 T/T(+Dox)) of the KCa2.3 channels and wild-type C57BL/6-mice (WT). QPCR revealed that KCa2.3 and KCa1.1 channels were the most abundant in mouse corpus cavernosum. KCa2.3 channels were found by immunoreactivity and electron microscopy in the apical lateral membrane of endothelial cells in the corpus cavernosum. Norepinephrine contraction was enhanced in the corpus cavernosum of KCa2.3 T/T(+Dox) versus KCa2.3 T/T(-Dox) mice, while acetylcholine relaxation was only reduced at 0.3 uM and relaxations in response to the nitric oxide donor sodium nitroprusside were unaltered. An opener of KCa2 channels, NS309 induced concentration-dependent relaxations of corpus cavernosum. Mean arterial pressure was lower in KCa2.3 T/T( Dox) mice compared with WT and KCa2.3 T/T(+Dox) mice. In anesthetized mice, cavernous nerve stimulation augmented in frequency/voltage dependent manner erectile function being lower in KCa2.3 T/T(+Dox) mice at low frequencies. Our findings suggest that down-regulation of KCa2.3 channels contributes to erectile dysfunction, and that pharmacological activation of KCa2.3 channels may have the potential to restore erectile function. PMID- 28630433 TI - Gut microbiota of liver transplantation recipients. AB - The characteristics of intestinal microbial communities may be affected by changes in the pathophysiology of patients with end-stage liver disease. Here, we focused on the characteristics of intestinal fecal microbial communities in post liver transplantation (LT) patients in comparison with those in the same individuals pre-LT and in healthy individuals. The fecal microbial communities were analyzed via MiSeq-PE250 sequencing of the V4 region of 16S ribosomal RNA and were then compared between groups. We found that the gut microbiota of patients with severe liver disease who were awaiting LT was significantly different from that of healthy controls, as represented by the first principal component (p = 0.0066). Additionally, the second principal component represented a significant difference in the gut microbiota of patients between pre-LT and post-LT surgery (p = 0.03125). After LT, there was a significant decrease in the abundance of certain microbial species, such as Actinobacillus, Escherichia, and Shigella, and a significant increase in the abundance of other microbial species, such as Micromonosporaceae, Desulfobacterales, the Sarcina genus of Eubacteriaceae, and Akkermansia. Based on KEGG profiles, 15 functional modules were enriched and 21 functional modules were less represented in the post-LT samples compared with the pre-LT samples. Our study demonstrates that fecal microbial communities were significantly altered by LT. PMID- 28630434 TI - Metallicity in a Holstein-Hubbard Chain at Half Filling with Gaussian Anharmonicity. AB - The Holstein-Hubbard model with Gaussian phonon anharmonicity is studied in one dimension at half filling using a variational method based on a series of canonical transformations. A fairly accurate phonon state is chosen to average the transformed Holstein-Hubbard Hamiltonian to obtain an effective Hubbard model which is then solved using the exact Bethe - ansatz following Lieb and Wu to obtain the ground state energy, the average lattice displacement and the renormalized parameters. The Mott-Hubbard criterion, local spin moment and the von Neumann entropy (which is a measure of quantum entanglement) are calculated to determine the ground state phase diagram which shows that the width of the metallic phase flanked by the SDW and CDW phases increases with increasing anharmonicity at low and moderate values of anharmonicity but eventually saturates when the anharmonicity becomes substantially large. PMID- 28630435 TI - In situ electrical and thermal monitoring of printed electronics by two-photon mapping. AB - Printed electronics is emerging as a new, large scale and cost effective technology that will be disruptive in fields such as energy harvesting, consumer electronics and medical sensors. The performance of printed electronic devices relies principally on the carrier mobility and molecular packing of the polymer semiconductor material. Unfortunately, the analysis of such materials is generally performed with destructive techniques, which are hard to make compatible with in situ measurements, and pose a great obstacle for the mass production of printed electronics devices. A rapid, in situ, non-destructive and low-cost testing method is needed. In this study, we demonstrate that nonlinear optical microscopy is a promising technique to achieve this goal. Using ultrashort laser pulses we stimulate two-photon absorption in a roll coated polymer semiconductor and map the resulting two-photon induced photoluminescence and second harmonic response. We show that, in our experimental conditions, it is possible to relate the total amount of photoluminescence detected to important material properties such as the charge carrier density and the molecular packing of the printed polymer material, all with a spatial resolution of 400 nm. Importantly, this technique can be extended to the real time mapping of the polymer semiconductor film, even during the printing process, in which the high printing speed poses the need for equally high acquisition rates. PMID- 28630436 TI - A Novel Gd-DTPA-conjugated Poly(L-gamma-glutamyl-glutamine)-paclitaxel Polymeric Delivery System for Tumor Theranostics. AB - The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs. In this study, poly(L-gamma glutamyl-glutamine)-paclitaxel (PGG-PTX), as a model polymer, was chemically conjugated with Gd-DTPA (Gd-diethylenetriaminepentaacetic acid), a T1-contrast agent of MRI, to prepare a Gd-DTPA-conjugated PGG-PTX (PGG-PTX-DTPA-Gd) delivery system used for tumor theranostics. PGG-PTX-DTPA-Gd can be self-assembled to NPs in water with a z-average hydrodynamic diameter about 35.9 nm. The 3 T MRI results confirmed that the relaxivity of PGG-PTX-DTPA-Gd NPs (r1 = 18.98 mM-1S-1) was increased nearly 4.9 times compared with that of free Gd-DTPA (r1 = 3.87 mM 1S-1). The in vivo fluorescence imaging results showed that PGG-PTX-DTPA-Gd NPs could be accumulated in the tumor tissue of NCI-H460 lung cancer animal model by EPR effect, which was similar to PGG-PTX NPs. The MRI results showed that compared with free Gd-DTPA, PGG-PTX-DTPA-Gd NPs showed significantly enhanced and prolonged signal intensity in tumor tissue, which should be attributed to the increased relaxivity and tumor accumulation. PGG-PTX-DTPA-Gd NPs also showed effective antitumor effect in vivo. These results indicated that PGG-PTX-DTPA-Gd NPs are an effective delivery system for tumor theranostics, and should have a potential value in personalized treatment of tumor. PMID- 28630437 TI - Phylogenetic analysis of F-bZIP transcription factors indicates conservation of the zinc deficiency response across land plants. AB - Basic leucine zipper (bZIP) transcription factors control important developmental and physiological processes in plants. In Arabidopsis thaliana, the three gene F bZIP subfamily has been associated with zinc deficiency and salt stress response. Benefiting from the present abundance of plant genomic data, we performed an evolutionary and structural characterization of plant F-bZIPs. We observed divergence during seed plant evolution, into two groups and inferred different selective pressures for each. Group 1 contains AtbZIP19 and AtbZIP23 and appears more conserved, whereas Group 2, containing AtbZIP24, is more prone to gene loss and expansion events. Transcriptomic and experimental data reinforced AtbZIP19/23 as pivotal regulators of the zinc deficiency response, mostly via the activation of genes from the ZIP metal transporter family, and revealed that they are the main regulatory switch of AtZIP4. A survey of AtZIP4 orthologs promoters across different plant taxa revealed an enrichment of the Zinc Deficiency Response Element (ZDRE) to which both AtbZIP19/23 bind. Overall, our results indicate that while the AtbZIP24 function in the regulation of the salt stress response may be the result of neo-functionalization, the AtbZIP19/23 function in the regulation of the zinc deficiency response may be conserved in land plants (Embryophytes). PMID- 28630438 TI - The molecular pathogenesis of the NUP98-HOXA9 fusion protein in acute myeloid leukemia. PMID- 28630439 TI - Recurrent cyclin D2 mutations in myeloid neoplasms. PMID- 28630440 TI - Looking to nature for a new concept in antimicrobial treatments: isoflavonoids from Cytisus striatus as antibiotic adjuvants against MRSA. AB - The spread of multidrug-resistant Staphylococcus aureus strains, including methicillin-resistant S. aureus (MRSA), has shortened the useful life of anti staphylococcal drugs enormously. Two approaches can be followed to address this problem: screening various sources for new leads for antibiotics or finding ways to disable the resistance mechanisms to existing antibiotics. Plants are resistant to most microorganisms, but despite extensive efforts to identify metabolites that are responsible for this resistance, no substantial progress has been made. Plants possibly use multiple strategies to deal with microorganisms that evolved over time. For this reason, we searched for plants that could potentiate the effects of known antibiotics. From 29 plant species tested, Cytisus striatus clearly showed such an activity and an NMR-based metabolomics study allowed the identification of compounds from the plant extracts that could act as antibiotic adjuvants. Isoflavonoids were found to potentiate the effect of ciprofloxacin and erythromycin against MRSA strains. For the structure-activity relationship (SAR), 22 isoflavonoids were assessed as antibiotic adjuvants. This study reveals a clear synergy between isoflavonoids and the tested antibiotics, showing their great potential for applications in the clinical therapy of infections with antibiotic-resistant microorganisms such as MRSA. PMID- 28630441 TI - Overcoming the biological aging of titanium using a wet storage method after ultraviolet treatment. AB - We evaluated whether the biological activity of the surface of titanium, when stored in an aqueous solution after ultraviolet (UV) treatment, is comparable to that of the surface immediately after UV treatment. We subjected Grade IV titanium discs with machined surfaces to UV radiation for 15 min and then tested them immediately and after storage for 28 days, with and without distilled H2O (dH2O). We evaluated the surface characteristics using surface profiling, contact angle analysis, X-ray photoelectron spectroscopy, and in terms of the surface zeta-potential. We determined the level of biological activity by analysing albumin adsorption, MC3T3-E1 and human mesenchymal cell adhesion and cytoskeleton development, as well as the production of intracellular reactive oxygen species between groups. The surface characteristics produced by the UV irradiation were maintained in dH2O for 28 days. We found that titanium stored in dH2O for 28 days after UV treatment exhibited enhanced protein adsorption, cell attachment, and cytoskeleton development. Titanium stored in dH2O for 28 days after UV irradiation exhibited a lower level of oxidative stress, comparable to that of the titanium immediately after UV treatment. UV treatment combined with wet storage can be used as a means of overcoming the biological aging of titanium. PMID- 28630442 TI - IR sensitivity enhancement of CMOS Image Sensor with diffractive light trapping pixels. AB - We report on the IR sensitivity enhancement of back-illuminated CMOS Image Sensor (BI-CIS) with 2-dimensional diffractive inverted pyramid array structure (IPA) on crystalline silicon (c-Si) and deep trench isolation (DTI). FDTD simulations of semi-infinite thick c-Si having 2D IPAs on its surface whose pitches over 400 nm shows more than 30% improvement of light absorption at lambda = 850 nm and the maximum enhancement of 43% with the 540 nm pitch at the wavelength is confirmed. A prototype BI-CIS sample with pixel size of 1.2 MUm square containing 400 nm pitch IPAs shows 80% sensitivity enhancement at lambda = 850 nm compared to the reference sample with flat surface. This is due to diffraction with the IPA and total reflection at the pixel boundary. The NIR images taken by the demo camera equip with a C-mount lens show 75% sensitivity enhancement in the lambda = 700 1200 nm wavelength range with negligible spatial resolution degradation. Light trapping CIS pixel technology promises to improve NIR sensitivity and appears to be applicable to many different image sensor applications including security camera, personal authentication, and range finding Time-of-Flight camera with IR illuminations. PMID- 28630443 TI - Chemical chaperone, TUDCA unlike PBA, mitigates protein aggregation efficiently and resists ER and non-ER stress induced HepG2 cell death. AB - Stress induced BSA (bovine serum albumin) protein aggregation is effectively mitigated in vitro by TUDCA (tauroursodeoxycholic acid) than by PBA (4- phenylbutyric acid), chemical chaperones approved by FDA for the treatment of biliary cirrhosis and urea cycle disorders respectively. TUDCA, unlike PBA, enhances trypsin mediated digestion of BSA. TUDCA activates PERK, an ER-resident kinase that phosphorylates the alpha-subunit of eukaryotic initiation factor2 (eIF2alpha) and promotes the expression of activated transcription factor 4 (ATF4) in HepG2 cells. In contrast, PBA induced eIF2alpha phosphorylation is not mediated by PERK activation and results in low ATF4 expression. Neither chaperones promote expression of BiP, an ER chaperone, and CHOP (C/EBP homologous protein), downstream target of eIF2alpha-ATF4 pathway. Both chaperones mitigate tunicamycin induced PERK-eIF2alpha-ATF4-CHOP arm of UPR and expression of BiP. TUDCA, unlike PBA does not decrease cell viability and it also mitigates tunicamycin, UV-irradiation and PBA induced PARP (poly ADP-ribose polymerase) cleavage and cell death. These findings therefore suggest that TUDCA's antiapoptotic activity to protect HepG2 cells and PBA's activity that limits tumor cell progression may be important while considering their therapeutic potential. PMID- 28630444 TI - Modelling the effects of global climate change on Chikungunya transmission in the 21st century. AB - The arrival and rapid spread of the mosquito-borne viral disease Chikungunya across the Americas is one of the most significant public health developments of recent years, preceding and mirroring the subsequent spread of Zika. Globalization in trade and travel can lead to the importation of these viruses, but climatic conditions strongly affect the efficiency of transmission in local settings. In order to direct preparedness for future outbreaks, it is necessary to anticipate global regions that could become suitable for Chikungunya transmission. Here, we present global correlative niche models for autochthonous Chikungunya transmission. These models were used as the basis for projections under the representative concentration pathway (RCP) 4.5 and 8.5 climate change scenarios. In a further step, hazard maps, which account for population densities, were produced. The baseline models successfully delineate current areas of active Chikungunya transmission. Projections under the RCP 4.5 and 8.5 scenarios suggest the likelihood of expansion of transmission-suitable areas in many parts of the world, including China, sub-Saharan Africa, South America, the United States and continental Europe. The models presented here can be used to inform public health preparedness planning in a highly interconnected world. PMID- 28630445 TI - Myocardial Deformation in Cardiac Amyloid Light-chain Amyloidosis: Assessed with 3T Cardiovascular Magnetic Resonance Feature Tracking. AB - Clinically, assessment of myocardial function is essential in patients with amyloid light-chain cardiac amyloidosis (AL-CA) to predict outcome and determine therapeutic approach. The aim of this study was to investigate the feasibility of cardiovascular magnetic resonance (CMR)-derived feature tracking algorithm for assessing left ventricular (LV) myocardial deformation in AL-CA, and to determine if these abnormal myocardial deformation parameters are correlated to impaired LV myocardial microvascular dysfunction. A total of 42 AL-CA patients, including 26 with preserved systolic function and 16 with impaired LVEF, and 35 healthy controls were enrolled and underwent CMR examination. Our result indicated that AL-CA patients had significantly reduced global peak strain (PS) (longitudinal, circumferential, and radial) (all P < 0.05). AL-CA patients with normal LVEF showed preserved longitudinal PS at apical and significantly reduced longitudinal PS at mid and basal segments. By Spearman's rank correlation analysis, the LV regional radial, circumferential, and longitudinal myocardial deformation values were correlated to myocardial upslope and MaxSI in CA, regardless of LVEF. This study indicated that the abnormal LV myocardial deformation of AL-CA patients can be monitored using feature tracking CMR, even in those with preserved LVEF; and the myocardial deformation was associated with coronary microvascular dysfunction. PMID- 28630446 TI - Strong sub-seasonal wintertime cooling over East Asia and Northern Europe associated with super El Nino events. AB - East Asia experienced a record-breaking cold event during the 2015/16 boreal winter, with pronounced impacts on livelihood in the region. We find that this large-scale cold spell can be attributed to the concurrent super El Nino event in the tropical Pacific. Our analysis reveals that all super El Nino winters (1982/83, 1997/98, and 2015/16) were accompanied by a rapid sub-seasonal North Atlantic Oscillation (NAO)/Arctic Oscillation (AO) phase reversal from a positive to a negative state during early January, which was largely caused by the interaction of these super El Nino events with the subtropical jet annual cycle. The NAO/AO phase transition leads to a rapidly strengthened Siberian High, which favors southward intrusions of cold air to East Asia and thus causes severe local cooling. Similar cold spells can also be detected over Northern Europe associated with the fast sub-seasonal NAO/AO phase reversal. Due to the weaker amplitude of the ENSO forcing, these sub-seasonal atmospheric responses cannot be detected for moderate El Nino events. The super El Nino associated sub-seasonal signal of the East Asian and Northern Europe wintertime temperature responses carries important implications for future predictability of regional extreme events. PMID- 28630447 TI - Evidence for Chemical Vapor Induced 2H to 1T Phase Transition in MoX2 (X = Se, S) Transition Metal Dichalcogenide Films. AB - Electron-donors can impart charge to the surface of transition metal dichalcogenide (TMD) films while interacting with the film via a weak physisorption bond, making them ideal for vapor and gas sensors. We expose monolayer MoS2 and MoSe2 films to strong electron-donor chemical vapor analytes. After analyzing the resultant behavior and taking into consideration doping effects, we conclude that exposure to strong electron-donors could be a method of inducing the semiconductor-metal 2H-1T TMD phase transition. We find that the conductance response to strong electron donors in both monolayer MoS2 and MoSe2 FET devices ceases after moderate exposure, with final value of the conductance being on order of that expected for the 1T phase. Full device relaxation back to a semiconducting state is accomplished by annealing in vacuum at 400 degrees C. We also examine chemically exposed TMD films intermittently interrogated with Raman and photoluminescence spectroscopy. We observe the appearance of weak characteristic 1T phase Raman features for MoS2 and we observed a quenching of the photoluminescence of both TMD films that is recoverable with annealing. Considering all of our data together, the effects cannot be described by doping alone. Additionally, our results suggest a mechanism for a new type of passive chemical vapor sensor. PMID- 28630448 TI - Progesterone prevents epithelial-mesenchymal transition of ovine amniotic epithelial cells and enhances their immunomodulatory properties. AB - The in vitro expansion is detrimental to therapeutic applications of amniotic epithelial cells (AEC), an emerging source of fetal stem cells. This study provides molecular evidences of progesterone (P4) role in preventing epithelial mesenchymal transition (EMT) in ovine AEC (oAEC). oAEC amplified under standard conditions spontaneously acquired mesenchymal properties through the up regulation of EMT-transcription factors. P4 supplementation prevented phenotype shift by inhibiting the EMT-inducing mechanism such as the autocrine production of TGF-beta and the activation of intracellular-related signaling. The effect of P4 still persisted for one passage after steroid removal from culture as well as steroid supplementation promptly reversed mesenchymal phenotype in oAEC which have experienced EMT during amplification. Furthermore, P4 promoted an acute up regulation of pluripotent genes whereas enhanced basal and LPS-induced oAEC anti inflammatory response with an increase in anti-inflammatory and a decrease in pro inflammatory cytokines expression. Altogether, these results indicate that P4 supplementation is crucial to preserve epithelial phenotype and to enhance biological properties in expanded oAEC. Therefore, an innovative cultural approach is proposed in order to improve therapeutic potential of this promising source of epithelial stem cells. PMID- 28630449 TI - Effect of DNA sequence of Fab fragment on yield characteristics and cell growth of E. coli. AB - Codon usage is one of the factors influencing recombinant protein expression. We were interested in the codon usage of an antibody Fab fragment gene exhibiting extreme toxicity in the E. coli host. The toxic synthetic human Fab gene contained domains optimized by the "one amino acid-one codon" method. We redesigned five segments of the Fab gene with a "codon harmonization" method described by Angov et al. and studied the effects of these changes on cell viability, Fab yield and display on filamentous phage using different vectors and bacterial strains. The harmonization considerably reduced toxicity, increased Fab expression from negligible levels to 10 mg/l, and restored the display on phage. Testing the impact of the individual redesigned segments revealed that the most significant effects were conferred by changes in the constant domain of the light chain. For some of the Fab gene variants, we also observed striking differences in protein yields when cloned from a chloramphenicol resistant vector into an identical vector, except with ampicillin resistance. In conclusion, our results show that the expression of a heterodimeric secretory protein can be improved by harmonizing selected DNA segments by synonymous codons and reveal additional complexity involved in heterologous protein expression. PMID- 28630450 TI - Concurrent talking in immersive virtual reality: on the dominance of visual speech cues. AB - Humans are good at selectively listening to specific target conversations, even in the presence of multiple concurrent speakers. In our research, we study how auditory-visual cues modulate this selective listening. We do so by using immersive Virtual Reality technologies with spatialized audio. Exposing 32 participants to an Information Masking Task with concurrent speakers, we find significantly more errors in the decision-making processes triggered by asynchronous audiovisual speech cues. More precisely, the results show that lips on the Target speaker matched to a secondary (Mask) speaker's audio severely increase the participants' comprehension error rates. In a control experiment (n = 20), we further explore the influences of the visual modality over auditory selective attention. The results show a dominance of visual-speech cues, which effectively turn the Mask into the Target and vice-versa. These results reveal a disruption of selective attention that is triggered by bottom-up multisensory integration. The findings are framed in the sensory perception and cognitive neuroscience theories. The VR setup is validated by replicating previous results in this literature in a supplementary experiment. PMID- 28630451 TI - Electronic Band Alignment at Complex Oxide Interfaces Measured by Scanning Photocurrent Microscopy. AB - The band alignment at an Al2O3/SrTiO3 heterointerface forming a two-dimensional electron gas (2DEG) was investigated using scanning photocurrent microscopy (SPCM) in an electrolyte-gated environment. We used a focused UV laser source for above-the-bandgap illumination on the SrTiO3 layer, creating electron-hole pairs that contributed to the photocurrent through migration towards the metal electrodes. The polarity of the SPCM signals of a bare SrTiO3 device shows typical p-type behavior at zero gate bias, in which the photogenerated electrons are collected by the electrodes. In contrast, the SPCM polarity of 2DEG device indicates that the hole carriers were collected by the metal electrodes. Careful transport measurements revealed that the gate-dependent conductance of the 2DEG devices exhibits n-type switching behavior. More importantly, the SPCM signals in 2DEG devices demonstrated very unique gate-responses that cannot be found in conventional semiconducting devices, based on which we were able to perform detailed investigation into the electronic band alignment of the 2DEG devices and obtain the valence band offset at the heterointerface. PMID- 28630452 TI - Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex. AB - The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (<24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC. PMID- 28630453 TI - Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder. AB - In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD. PMID- 28630454 TI - Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo. AB - Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrPSc) that self propagates in the brain of infected individuals by converting the normal prion protein (PrPC) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self replicating, but innocuous PrPSc-like form, termed anti-prion, which can compete with the replication of pathogenic prions. Our results show that a prophylactic inoculation of prion-infected animals with an anti-prion delays the onset of the disease and in some animals completely prevents the development of clinical symptoms and brain damage. The data indicate that a single injection of the anti prion eliminated ~99% of the infectivity associated to pathogenic prions. Furthermore, this treatment caused significant changes in the profile of regional PrPSc deposition in the brains of animals that were treated, but still succumbed to the disease. Our findings provide new insights for a mechanistic understanding of prion replication and support the concept that prion replication can be separated from toxicity, providing a novel target for therapeutic intervention. PMID- 28630455 TI - Autism spectrum disorders and autistic traits share genetics and biology. AB - This corrects the article DOI: 10.1038/mp.2017.98. PMID- 28630456 TI - Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia. AB - Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability. PMID- 28630457 TI - How impaired efficacy happened between Gancao and Yuanhua: Compounds, targets and pathways. AB - As recorded in Traditional Chinese Medicine (TCM) theory, Gancao (Glycyrrhizae Radix et Rhizoma) could weaken the pharmacological effect or increase the toxicity of Yuanhua (Genkwa Flos). However, the theory has been suspected due to lack of evidence. Here, we investigate whether Gancao could weaken Yuanhua's diuretic effect, if so, which chemicals and which targets may be involved. Results showed that Yuanhua exerted diuretic effect through down-regulating renal AQP 2, without electrolyte disturbances such as K+ loss which has been observed as side-effect of most diuretics. Gancao had no diuretic effect, but could impair Yuanhua's diuretic effect through up-regulating renal AQP 2. Glycyrrhetinic acid (GRA) in Gancao could up-regulate AQP 2 and counteract the AQP 2 regulation effect of Yuanhuacine (YHC) and Ginkwanin (GKW) in Yuanhua. Network pharmacology method suggested that YHC, GKW and GRA could bind to MEK1/FGFR1 protein and influence ERK-MAPK pathway, which was verified by Western blotting. This study supports TCM theory and reminds that more attention should be paid to the safety and efficacy problems induced by improper combination between herbs. Moreover, we suggested that promising diuretics with less side effects can be developed from Chinese Medicines such as Yuanhua. PMID- 28630458 TI - The value of instability: an investigation of intrasubject variability in brain activity among obese adolescent girls. AB - BACKGROUND: The present study investigated the value of intrasubject variability (ISV) as a metric for revealing differences in cognition and brain activation associated with an obese versus lean body mass. METHODS: Ninety-six adolescents with a lean body mass (body mass index (BMI) percentile=5-85), and 92 adolescents with an obese body mass (BMI percentile ?95), performed two tasks (Stroop and Go/No-Go) challenging response inhibition skills. The s.d. values and averages of their reaction time and P300 electroencephalographic responses to task stimuli were computed across trials. RESULTS: During the Go/No-Go task, the reaction times of subjects with an obese body mass were more variable than those of their lean body mass peers. Accompanying the greater ISV in reaction times was a group difference in P300 amplitude ISV in the opposite direction across both tasks. The effect sizes associated with these group differences in ISV were marginally greater than the effect sizes for the comparisons of the group means. CONCLUSIONS: ISV may be superior to the mean as a tool for differentiating groups without significant cognitive impairment. The co-occurrence of reduced ISV in P300 amplitude and elevated ISV in reaction time may indicate a constraint among obese adolescent girls in the range of information processing strategies and neural networks that can compete to optimize response output. It remains to be determined whether this decrement in neural plasticity has implications for their problem solving skills as well as their response to weight management interventions. PMID- 28630459 TI - Abdominal subcutaneous adipose tissue cellularity in men and women. AB - BACKGROUND/OBJECTIVE: Differences in subcutaneous abdominal adipose tissue (SAT) fat cell size and number (cellularity) are linked to insulin resistance. Men are generally more insulin resistant than women but it is unknown whether there is a gender dimorphism in SAT cellularity. The objective was to determine SAT cellularity and its relationship to insulin sensitivity in men and women. METHODS: In a cohort study performed at an outpatient academic clinic in Sweden, 798 women and 306 men were included. Estimated SAT mass (ESAT) was derived from measures of dual-energy X-ray absorptiometry and a formula. SAT biopsies were obtained to measure mean fat cell size; SAT adipocyte number was obtained by dividing ESAT with mean fat cell weight. Fat cell size was also compared with level of insulin sensitivity in vivo. RESULTS: Over the entire range of body mass index (BMI) both fat cell size and number correlated positively with ESAT in either sex. On average, fat cell size was larger in men than in women, which was driven by significantly larger fat cells in non-obese men compared with non-obese women; no gender effect on fat cell size was seen in obese subjects. For all subjects fat cell number was larger in women than men, which was driven by a gender effect among non-obese individuals (P<0.0001). The relationship between fat cell size and insulin resistance was significant in both genders (P<0.0001) but steeper in men than in women (F=19, P<0.0001). CONCLUSIONS: Although both fat cell size and number determine SAT mass, adipocyte number contributes more and size less in women than in men and this is most evident in non-obese subjects. Over the entire BMI range, fat cell size contributes stronger to insulin resistance in men. PMID- 28630460 TI - Oxidative and endoplasmic reticulum stress is impaired in leukocytes from metabolically unhealthy vs healthy obese individuals. AB - BACKGROUND: Oxidative stress and inflammation are related to obesity, but the influence of metabolic disturbances on these parameters and their relationship with endoplasmic reticulum (ER) stress is unknown. Therefore, this study was performed to evaluate whether metabolic profile influences ER and oxidative stress in an obese population with/without comorbidities. SUBJECTS AND METHODS: A total of 113 obese patients were enrolled in the study; 29 were metabolically healthy (MHO), 53 were metabolically abnormal (MAO) and 31 had type 2 diabetes (MADO). We assessed metabolic parameters, proinflammatory cytokines (TNFalpha and IL-6), mitochondrial and total reactive oxygen species (ROS) production, glutathione levels, antioxidant enzymes activity, total antioxidant status, mitochondrial membrane potential and ER stress marker expression levels (glucose regulated protein (GRP78), spliced X-box binding protein 1 (XBP1), P-subunit 1 alpha (P-eIF2alpha) and activating transcription factor 6 (ATF6). RESULTS: The MAO and MADO groups showed higher blood pressure, atherogenic dyslipidemia, insulin resistance and inflammatory profile than that of MHO subjects. Total and mitochondrial ROS production was enhanced in MAO and MADO patients, and mitochondrial membrane potential and catalase activity differed significantly between the MADO and MHO groups. In addition, decreases in glutathione levels and superoxide dismutase activity were observed in the MADO vs MAO and MHO groups. GRP78 and CHOP protein and gene expression were higher in the MAO and MADO groups with respect to MHO subjects, and sXBP1 gene expression was associated with the presence of diabetes. Furthermore, MAO patients exhibited higher levels of ATF6 than their MHO counterparts. Waist circumference was positively correlated with ATF6 and GRP78, and A1c was positively correlated with P-Eif2alpha. Interestingly, CHOP was positively correlated with TNFalpha and total ROS production and GRP78 was negatively correlated with glutathione levels. CONCLUSIONS: Our findings support the hypothesis that both inflammation and oxidative stress are involved in the induction of ER stress signaling pathways in the leukocytes of metabolically unhealthy obese vs healthy obese subjects. PMID- 28630461 TI - Antrodia cinnamomea reduces obesity and modulates the gut microbiota in high-fat diet-fed mice. AB - BACKGROUND: Obesity is associated with gut microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Given the high and increasing prevalence of obesity worldwide, anti-obesity treatments that are safe, effective and widely available would be beneficial. We examined whether the medicinal mushroom Antrodia cinnamomea may reduce obesity in mice fed with a high-fat diet (HFD). METHODS: Male C57BL/6J mice were fed a HFD for 8 weeks to induce obesity and chronic inflammation. The mice were treated with a water extract of A. cinnamomea (WEAC), and body weight, fat accumulation, inflammation markers, insulin sensitivity and the gut microbiota were monitored. RESULTS: After 8 weeks, the mean body weight of HFD-fed mice was 39.8+/-1.2 g compared with 35.8+/ 1.3 g for the HFD+1% WEAC group, corresponding to a reduction of 4 g or 10% of body weight (P<0.0001). WEAC supplementation reduced fat accumulation and serum triglycerides in a statistically significant manner in HFD-fed mice. WEAC also reversed the effects of HFD on inflammation markers (interleukin-1beta, interleukin-6, tumor necrosis factor-alpha), insulin resistance and adipokine production (leptin and adiponectin). Notably, WEAC increased the expression of intestinal tight junctions (zonula occludens-1 and occludin) and antimicrobial proteins (Reg3g and lysozyme C) in the small intestine, leading to reduced blood endotoxemia. Finally, WEAC modulated the composition of the gut microbiota, reducing the Firmicutes/Bacteroidetes ratio and increasing the level of Akkermansia muciniphila and other bacterial species associated with anti inflammatory properties. CONCLUSIONS: Supplementation with A. cinnamomea produces anti-obesogenic, anti-inflammatory and antidiabetic effects in HFD-fed mice by maintaining intestinal integrity and modulating the gut microbiota. PMID- 28630462 TI - Identification and molecular characterization of non-polio enteroviruses from children with acute flaccid paralysis in West Africa, 2013-2014. AB - Besides polioviruses, non-polio enteroviruses (NPEVs) may also be associated with acute flaccid paralysis (AFP). Because poliomyelitis is on the verge of eradication, more attention should be paid to study NPEVs from non-polio AFP cases and their epidemic patterns. In West African countries the epidemiology of NPEVs remains largely unexplored. We investigated the genetic diversity, frequency, circulation patterns, and molecular epidemiology of NPEVs in seven West African countries by analyzing retrospectively a panel of 3195 stool samples from children with AFP collected through routine poliomyelitis surveillance activities between 2013 and 2014. VP1 sequencing and typing on 201 isolates revealed 39 NPEV types corresponding to EV-A (6.9%), EV-B (90.5%), EV-C (2%) and EV-D (0.5%) species. Echoviruses were isolated most frequently with 138 cases (68.6%), followed by coxsackievirus group B with 35 cases (17.4%). No single NPEV type was remarkably dominant. Interestingly, several rarely described types with limited detection worldwide were identified (EVA76, EVA119, EVB75, EVB77, EVB97, EVC99, CVA20, CVA21 and EVD94). This study demonstrates the extensive diversity and diverse circulation patterns of NPEVs from AFP surveillance and highlights the need to formulate effective long-term strategies to monitor NPEV circulations in West Africa. PMID- 28630463 TI - The role of Antibody Vkappa Framework 3 region towards Antigen binding: Effects on recombinant production and Protein L binding. AB - Antibody research has traditionally focused on heavy chains, often neglecting the important complementary role of light chains in antibody formation and secretion. In the light chain, the complementarity-determining region 3 (VL-CDR3) is specifically implicated in disease states. By modulating VL-CDR3 exposure on the scaffold through deletions in the framework region 3 (VL-FWR3), we further investigated the effects on secretion in recombinant production and antigen binding kinetics. Our random deletions of two residues in the VL-FWR3 of a Trastuzumab model showed that the single deletions could impact recombinant production without significant effect on Her2 binding. When both the selected residues were deleted, antibody secretion was additively decreased, and so was Her2 binding kinetics. Interestingly, we also found allosteric effects on the Protein L binding site at VL-FWR1 elicited by these deletions in VL- FWR3. Together, these findings demonstrate the importance of light chain FWR3 in antigen binding, recombinant production, and antibody purification using Protein L. PMID- 28630464 TI - Rapid monoisotopic cisplatin based barcoding for multiplexed mass cytometry. AB - Mass cytometry presents an exceptional opportunity to interrogate the biology of highly heterogeneous cell populations, owing to the ability to collect highly parametric proteomic data at a single cell level. However, sample-to-sample variability, due to antibody staining and/or instrument sensitivity, can introduce substantial artifacts into the data, which can in turn lead to erroneous conclusions. This variability can be eliminated by sample barcoding which enables samples to be pooled, stained and run simultaneously. Existing mass cytometry barcoding approaches require time intensive labeling, reduce the number of biologically meaningful parameters and/or rely on expensive reagents. We present an approach utilizing monoisotopic cisplatin to perform cell barcoding that does not require cell permeabilization, can be completed in 10 minutes and can be utilized in combination with existing barcoding techniques to greatly increase the number of samples which can be multiplexed to improve throughput and consistency. PMID- 28630465 TI - Changes in pore structure of coal caused by coal-to-gas bioconversion. AB - ABSTARCT: Microbial enhanced coalbed methane (ME-CBM) recovery is critically examined as a viable technology for natural gas recovery from coalbed methane (CBM) reservoirs. Since the majority of gas-in-place (GIP) is stored as an adsorbed phase in fine pores of coal matrix, the nano-pore structure directly influences gas storage and transport properties. Only limited studies have quantified the alteration of the nano-pore structure due to ME-CBM treatment. This study examines the evolution of the pore structure using a combination of small angle X-ray scattering (SAXS), low-pressure N2 and CO2 adsorption (LPGA) and high-pressure methane adsorption methods. The results show that the surface fractal dimension decreases for the two bioconverted coals compared to the untreated coal. After bio-treatment, the mesopore surface area and pore volume decrease with the average pore diameter increases, while the micropore surface area increases with pore volume decreases. Both inaccessible meso-/micropore size distributions decrease after bioconversion, while the accessible micropore size distribution increases, making a portion of closed micropore network accessible. In addition, the methane adsorption capacities increase after bio-treatment, which is confirmed by the increase of micropore surface area. A conceptual physical model of methanogenesis is proposed based on the evolution of the pore structure. PMID- 28630466 TI - Comparative effectiveness of 9 ovulation-induction therapies in patients with clomiphene citrate-resistant polycystic ovary syndrome: a network meta-analysis. AB - The comparative efficacies of ovulation-induction treatments in patients with clomiphene citrate-resistant (CCR) polycystic ovary syndrome (PCOS) are not well known. Therefore, we conducted a network meta-analysis to rank the reproductive efficacies of these treatments. We ultimately included 26 randomized clinical trials with 2722 participants and 9 types of therapies: clomiphene citrate (CC), metformin, letrozole, follicle stimulating hormone (FSH), human menopausal gonadotropin (hMG), unilateral laparoscopic ovarian drilling (ULOD), bilateral laparoscopic ovarian drilling (BLOD), the combination of metformin with letrozole (metformin+letrozole), and the combination of metformin with CC (metformin+CC). The network meta-analysis demonstrates that hMG therapy result in higher pregnancy rates than BLOD, ULOD and CC therapies. Pregnancy, live birth and ovulation rates are significantly higher in metformin+letrozole and FSH groups than CC group. The abortion rate in the metformin+letrozole group is significantly lower than that in the metformin+CC group. Ranking probabilities show that, apart from gonadotropin (FSH and hMG), metformin+letrozole is also potentially more effective in improving reproductive outcomes than other therapies. In conclusion, owing to the low quality of evidence and the wide confidence intervals, no recommendation could be made for the treatment of ovulation-induction in patients with CCR PCOS. PMID- 28630467 TI - Computational method allowing Hydrogen-Deuterium Exchange Mass Spectrometry at single amide Resolution. AB - Hydrogen-deuterium exchange (HDX) coupled with mass spectrometry (HDXMS) is a rapid and effective method for localizing and determining protein stability and dynamics. Localization is routinely limited to a peptide resolution of 5 to 20 amino acid residues. HDXMS data can contain information beyond that needed for defining protein stability at single amide resolution. Here we present a method for extracting this information from an HDX dataset to generate a HDXMS protein stability fingerprint. High resolution (HR)-HDXMS was applied to the analysis of a model protein of a spectrin tandem repeat that exemplified an intuitive stability profile based on the linkage of two triple helical repeats connected by a helical linker. The fingerprint recapitulated expected stability maximums and minimums with interesting structural features that corroborate proposed mechanisms of spectrin flexibility and elasticity. HR-HDXMS provides the unprecedented ability to accurately assess protein stability at the resolution of a single amino acid. The determination of HDX stability fingerprints may be broadly applicable in many applications for understanding protein structure and function as well as protein ligand interactions. PMID- 28630468 TI - Neurofeedback learning modifies the incidence rate of alpha spindles, but not their duration and amplitude. AB - Although the first experiments on alpha-neurofeedback date back nearly six decades ago, when Joseph Kamiya reported successful operant conditioning of alpha rhythm in humans, the effectiveness of this paradigm in various experimental and clinical settings is still a matter of debate. Here, we investigated the changes in EEG patterns during a continuously administered neurofeedback of P4 alpha activity. Two days of neurofeedback training were sufficient for a significant increase in the alpha power to occur. A detailed analysis of these EEG changes showed that the alpha power rose because of an increase in the incidence rate of alpha episodes, whereas the amplitude and the duration of alpha oscillations remained unchanged. These findings suggest that neurofeedback facilitates volitional control of alpha activity onset, but alpha episodes themselves appear to be maintained automatically with no volitional control - a property overlooked by previous studies that employed continuous alpha-power neurofeedback. We propose that future research on alpha neurofeedback should explore reinforcement schedules based on detection of onsets and offsets of alpha waves, and employ these statistics for exploration and quantification of neurofeedback induced effects. PMID- 28630469 TI - C2238 ANP gene variant promotes increased platelet aggregation through the activation of Nox2 and the reduction of cAMP. AB - Subjects carrying the C2238 variant of the atrial natriuretic peptide (ANP) gene have a higher occurrence of stroke and acute coronary syndrome, suggesting an increased predisposition to acute thrombotic events in these subjects. We evaluated for the first time the direct effects of mutant ANP (C2238/alphaANP) on platelet activation in vitro and in human subjects. In vitro, platelets were incubated with no peptide, with T2238/alphaANP (WT) or with C2238/alphaANP at different concentrations. C2238/alphaANP (10-10 M) induced higher collagen induced platelet aggregation with respect to both control without ANP and T2238/alphaANP. This effect was even stronger at a higher concentration (10-6 M). Mechanistically, C2238/alphaANP significantly lowered platelet cAMP levels, increased ROS production and activated Nox2, with respect to both control and T2238/alphaANP. Forskolin, a cAMP activator, and sNOX2-tat, a Nox2 inhibitor, significantly reduced the pro-aggregant effects of C2238/alphaANP. In vivo, we found that platelet aggregation resulted to be higher in patients with atrial fibrillation carrying the C2238 ANP gene variant with respect to non-carriers. In conclusions, C2238/alphaANP promotes platelet aggregation through the activation of Nox2 and the reduction of cAMP. PMID- 28630470 TI - Overcoming evolved resistance to population-suppressing homing-based gene drives. AB - The recent development of a CRISPR-Cas9-based homing system for the suppression of Anopheles gambiae is encouraging; however, with current designs, the slow emergence of homing-resistant alleles is expected to result in suppressed populations rapidly rebounding, as homing-resistant alleles have a significant fitness advantage over functional, population-suppressing homing alleles. To explore this concern, we develop a mathematical model to estimate tolerable rates of homing-resistant allele generation to suppress a wild population of a given size. Our results suggest that, to achieve meaningful population suppression, tolerable rates of resistance allele generation are orders of magnitude smaller than those observed for current designs for CRISPR-Cas9-based homing systems. To remedy this, we theoretically explore a homing system architecture in which guide RNAs (gRNAs) are multiplexed, increasing the effective homing rate and decreasing the effective resistant allele generation rate. Modeling results suggest that the size of the population that can be suppressed increases exponentially with the number of multiplexed gRNAs and that, with four multiplexed gRNAs, a mosquito species could potentially be suppressed on a continental scale. We also demonstrate successful proof-of-principle use of multiplexed ribozyme flanked gRNAs to induce mutations in vivo in Drosophila melanogaster - a strategy that could readily be adapted to engineer stable, homing-based drives in relevant organisms. PMID- 28630471 TI - Candidatus Mycoplasma girerdii replicates, diversifies, and co-occurs with Trichomonas vaginalis in the oral cavity of a premature infant. AB - Genital mycoplasmas, which can be vertically transmitted, have been implicated in preterm birth, neonatal infections, and chronic lung disease of prematurity. Our prior work uncovered 16S rRNA genes belonging to a novel, as-yet-uncultivated mycoplasma (lineage 'Mnola') in the oral cavity of a premature neonate. Here, we characterize the organism's associated community, growth status, metabolic potential, and population diversity. Sequencing of genomic DNA from the infant's saliva yielded 1.44 Gbp of high-quality, non-human read data, from which we recovered three essentially complete (including 'Mnola') and three partial draft genomes (including Trichomonas vaginalis). The completed 629,409-bp 'Mnola' genome (Candidatus Mycoplasma girerdii str. UC-B3) was distinct at the strain level from its closest relative, vaginally-derived Ca. M. girerdii str. VCU-M1, which is also associated with T. vaginalis. Replication rate measurements indicated growth of str. UC-B3 within the infant. Genes encoding surface associated proteins and restriction-modification systems were especially diverse within and between strains. In UC-B3, the population genetic underpinnings of phase variable expression were evident in vivo. Unique among mycoplasmas, Ca. M. girerdii encodes pyruvate-ferredoxin oxidoreductase and may be sensitive to metronidazole. This study reveals a metabolically unique mycoplasma colonizing a premature neonate, and establishes the value of genome-resolved metagenomics in tracking phase variation. PMID- 28630472 TI - SMYD3 Promotes Homologous Recombination via Regulation of H3K4-mediated Gene Expression. AB - SMYD3 is a methyltransferase highly expressed in many types of cancer. It usually functions as an oncogenic protein to promote cell cycle, cell proliferation, and metastasis. Here, we show that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination. Deficiency of SMYD3 induces DNA-damage hypersensitivity, decreases levels of repair foci, and leads to impairment of homologous recombination. Moreover, the regulation of homologous recombination related genes is via the methylation of H3K4 at the target gene promoters. These data imply that, besides its reported oncogenic abilities, SMYD3 may maintain genome integrity by ensuring expression levels of HR proteins to cope with the high demand of restart of stalled replication forks in cancers. PMID- 28630473 TI - Impact of Antigen Density on the Binding Mechanism of IgG Antibodies. AB - The density and distribution pattern of epitopes at the surface of pathogens have a profound impact on immune responses. Although multiple lines of evidence highlight the significance of antigen surface density for antibody binding, a quantitative description of its effect on recognition mechanisms is missing. Here, we analyzed binding kinetics and thermodynamics of six HIV-1 neutralizing antibodies as a function of the surface density of envelope glycoprotein gp120. Antibodies that recognize gp120 with low to moderate binding affinity displayed the most pronounced sensitivity to variation in antigen density, with qualitative and substantial quantitative changes in the energetics of the binding process as revealed by non-equilibrium and equilibrium thermodynamic analyses. In contrast, the recognition of gp120 by the antibodies with the highest affinity was considerably less influenced by variations in antigen density. These data suggest that a lower affinity of antibodies permits higher dynamics during the antigen recognition process, which may have considerable functional repercussions. These findings contribute to a better understanding of the mechanisms of antigen recognition by antibodies. They are also of importance for apprehending the impact of antigen topology on immune-defense functions of antibodies. PMID- 28630474 TI - Nanoassembly routes stimulate conflicting antibody quantity and quality for transmission-blocking malaria vaccines. AB - Vaccine development efforts have recently focused on enabling strong immune responses to poorly immunogenic antigens, via display on multimerisation scaffolds or virus like particles (VLPs). Typically such studies demonstrate improved antibody titer comparing monomeric and nano-arrayed antigen. There are many such studies and scaffold technologies, but minimal side-by-side evaluation of platforms for both the amount and efficacy of antibodies induced. Here we present direct comparison of three leading platforms displaying the promising malaria transmission-blocking vaccine (TBV) target Pfs25. These platforms encompass the three important routes to antigen-scaffold linkage: genetic fusion, chemical cross-linking and plug-and-display SpyTag/SpyCatcher conjugation. We demonstrate that chemically-conjugated Qbeta VLPs elicited the highest quantity of antibodies, while SpyCatcher-AP205-VLPs elicited the highest quality anti Pfs25 antibodies for transmission blocking upon mosquito feeding. These quantative and qualitative features will guide future nanoassembly optimisation, as well as the development of the new generation of malaria vaccines targeting transmission. PMID- 28630476 TI - First Principles Theory of the hcp-fcc Phase Transition in Cobalt. AB - Identifying the forces that drive a phase transition is always challenging. The hcp-fcc phase transition that occurs in cobalt at ~700 K has not yet been fully understood, although early theoretical studies have suggested that magnetism plays a main role in the stabilization of the fcc phase at high temperatures. Here, we perform a first principles study of the free energies of these two phases, which we break into contributions arising from the vibration of the lattice, electronic and magnetic systems and volume expansion. Our analysis of the energy of the phases shows that magnetic effects alone cannot drive the fcc hcp transition in Co and that the largest contribution to the stabilization of the fcc phase comes from the vibration of the ionic lattice. By including all the contributions to the free energy considered here we obtain a theoretical transition temperature of 825 K. PMID- 28630475 TI - Utilization of a Wheat660K SNP array-derived high-density genetic map for high resolution mapping of a major QTL for kernel number. AB - In crop plants, a high-density genetic linkage map is essential for both genetic and genomic researches. The complexity and the large size of wheat genome have hampered the acquisition of a high-resolution genetic map. In this study, we report a high-density genetic map based on an individual mapping population using the Affymetrix Wheat660K single-nucleotide polymorphism (SNP) array as a probe in hexaploid wheat. The resultant genetic map consisted of 119 566 loci spanning 4424.4 cM, and 119 001 of those loci were SNP markers. This genetic map showed good collinearity with the 90 K and 820 K consensus genetic maps and was also in accordance with the recently released wheat whole genome assembly. The high density wheat genetic map will provide a major resource for future genetic and genomic research in wheat. Moreover, a comparative genomics analysis among gramineous plant genomes was conducted based on the high-density wheat genetic map, providing an overview of the structural relationships among theses gramineous plant genomes. A major stable quantitative trait locus (QTL) for kernel number per spike was characterized, providing a solid foundation for the future high-resolution mapping and map-based cloning of the targeted QTL. PMID- 28630477 TI - The Effect of shape on Cellular Uptake of Gold Nanoparticles in the forms of Stars, Rods, and Triangles. AB - Gold nanomaterials have attracted considerable interest as vehicles for intracellular drug delivery. In our study, we synthesized three different shapes of methylpolyethylene glycol coated-anisotropic gold nanoparticles: stars, rods, and triangles. The cellular internalization of these nanoparticles by RAW264.7 cells was analyzed, providing a parametric evaluation of the effect of shape. The efficiency of cellular uptake of the gold nanoparticles was found to rank in the following order from lowest to highest: stars, rods, and triangles. The possible mechanisms of cellular uptake for the three types of gold nanoparticles were examined, and it was found that different shapes tended to use the various endocytosis pathways in different proportions. Our study, which has demonstrated that shape can modulate the uptake of nanoparticles into RAW264.7 cells and that triangles were the shape with the most efficient cellular uptake, provides useful guidance toward the design of nanomaterials for drug delivery. PMID- 28630478 TI - Assessment of the role of intracranial hypertension and stress on hippocampal cell apoptosis and hypothalamic-pituitary dysfunction after TBI. AB - In recent years, hypopituitarism caused by traumatic brain injury (TBI) has been explored in many clinical studies; however, few studies have focused on intracranial hypertension and stress caused by TBI. In this study, an intracranial hypertension model, with epidural hematoma as the cause, was used to explore the physiopathological and neuroendocrine changes in the hypothalamic pituitary axis and hippocampus. The results demonstrated that intracranial hypertension increased the apoptosis rate, caspase-3 levels and proliferating cell nuclear antigen (PCNA) in the hippocampus, hypothalamus, pituitary gland and showed a consistent rate of apoptosis within each group. The apoptosis rates of hippocampus, hypothalamus and pituitary gland were further increased when intracranial pressure (ICP) at 24 hour (h) were still increased. The change rates of apoptosis in hypothalamus and pituitary gland were significantly higher than hippocampus. Moreover, the stress caused by surgery may be a crucial factor in apoptosis. To confirm stress leads to apoptosis in the hypothalamus and pituitary gland, we used rabbits to establish a standard stress model. The results confirmed that stress leads to apoptosis of neuroendocrine cells in the hypothalamus and pituitary gland, moreover, the higher the stress intensity, the higher the apoptosis rate in the hypothalamus and pituitary gland. PMID- 28630480 TI - Pro-invasive stimuli and the interacting protein Hsp70 favour the route of alpha enolase to the cell surface. AB - Cell surface expression of alpha-enolase, a glycolytic enzyme displaying moonlighting activities, has been shown to contribute to the motility and invasiveness of cancer cells through the protein non-enzymatic function of binding plasminogen and enhancing plasmin formation. Although a few recent records indicate the involvement of protein partners in the localization of alpha enolase to the plasma membrane, the cellular mechanisms underlying surface exposure remain largely elusive. Searching for novel interactors and signalling pathways, we used low-metastatic breast cancer cells, a doxorubicin-resistant counterpart and a non-tumourigenic mammary epithelial cell line. Here, we demonstrate by a combination of experimental approaches that epidermal growth factor (EGF) exposure, like lipopolysaccharide (LPS) exposure, promotes the surface expression of alpha-enolase. We also establish Heat shock protein 70 (Hsp70), a multifunctional chaperone distributed in intracellular, plasma membrane and extracellular compartments, as a novel alpha-enolase interactor and demonstrate a functional involvement of Hsp70 in the surface localization of alpha-enolase. Our results contribute to shedding light on the control of surface expression of alpha-enolase in non-tumourigenic and cancer cells and suggest novel targets to counteract the metastatic potential of tumours. PMID- 28630479 TI - Attention, cognitive control and motivation in ADHD: Linking event-related brain potentials and DNA methylation patterns in boys at early school age. AB - In order to better understand the underpinnings of attention deficit/hyperactivity disorder (ADHD), we targeted the relationship of attentional, cognitive control and motivational processes with DNA methylation patterns of 60 candidate genes in boys at early school age. Participants (6 to 8 years; N = 82) were selected from a German longitudinal cohort (FRANCES). ADHD related behaviour was assessed via maternal ratings. Performance and event related potential measures (inter alia Cue-P3 and Nogo-P3), which were recorded in a motivational go/nogo task, indicated diminished attentional orienting, reduced inhibitory response control and a larger motivational effect on performance in ADHD already at this relatively young age. Methylation patterns were analysed in buccal cell DNA with the Illumina HumanMethylation 450K array. For CpG sites at genes of the dopaminergic (COMT, ANKK1) and the neurotrophic (BDNF, NGFR) system, associations with the Nogo-P3 as well as ADHD symptom severity were found suggesting that these systems are involved in response control deficits in ADHD. Methylation effects related to both functional aspects and ADHD behaviour were also observed for DPP10 and TPH2. Epigenetic mechanisms may play a role in ADHD-associated deficits but findings need to be replicated in larger samples and are limited by the fact that only peripheral methylation could be considered. PMID- 28630481 TI - Near-surface coherent structures explored by large eddy simulation of entire tropical cyclones. AB - Taking advantage of the huge computational power of a massive parallel supercomputer (K-supercomputer), this study conducts large eddy simulations of entire tropical cyclones by employing a numerical weather prediction model, and explores near-surface coherent structures. The maximum of the near-surface wind changes little from that simulated based on coarse-resolution runs. Three kinds of coherent structures appeared inside the boundary layer. The first is a Type-A roll, which is caused by an inflection-point instability of the radial flow and prevails outside the radius of maximum wind. The second is a Type-B roll that also appears to be caused by an inflection-point instability but of both radial and tangential winds. Its roll axis is almost orthogonal to the Type-A roll. The third is a Type-C roll, which occurs inside the radius of maximum wind and only near the surface. It transports horizontal momentum in an up-gradient sense and causes the largest gusts. PMID- 28630482 TI - Circadian and circatidal clocks control the mechanism of semilunar foraging behaviour. AB - How animals precisely time behaviour over the lunar cycle is a decades-old mystery. Experiments on diverse species show this behaviour to be endogenous and under clock control but the mechanism has remained elusive. We present new experimental and analytical techniques to test the hypotheses for the semilunar clock and show that the rhythm of foraging behaviour in the intertidal isopod, Scyphax ornatus, can be precisely shifted by manipulating the lengths of the light/dark and tidal cycles. Using light T-cycles (Tcd) the resultant semilunar beat period undergoes shifts from 14.79 days to 6.47 days under T = 23 hours (h), or to 23.29 days under T = 24.3 h. In tidal T-cycles (Tt) of natural length Tt = 12.42 h, the semilunar rhythm is shifted to 24.5 days under Tt = 12.25 h and to 9.7 days under Tt = 12.65 h. The implications of this finding go beyond our model species and illustrate that longer period rhythms can be generated by shorter period clocks. Our novel analysis, in which periodic spline models are embedded within randomization tests, creates a new methodology for assessing long-period rhythms in chronobiology. Applications are far-reaching and extend to other species and rhythms, potentially including the human-ovarian cycle. PMID- 28630483 TI - Comprehensive analysis of passive generation of parabolic similaritons in tapered hydrogenated amorphous silicon photonic wires. AB - Parabolic pulses have important applications in both basic and applied sciences, such as high power optical amplification, optical communications, all-optical signal processing, etc. The generation of parabolic similaritons in tapered hydrogenated amorphous silicon photonic wires at telecom (lambda ~ 1550 nm) and mid-IR (lambda >= 2100 nm) wavelengths is demonstrated and analyzed. The self similar theory of parabolic pulse generation in passive waveguides with increasing nonlinearity is presented. A generalized nonlinear Schrodinger equation is used to describe the coupled dynamics of optical field in the tapered hydrogenated amorphous silicon photonic wires with either decreasing dispersion or increasing nonlinearity. The impacts of length dependent higher-order effects, linear and nonlinear losses including two-photon absorption, and photon-generated free carriers, on the pulse evolutions are characterized. Numerical simulations show that initial Gaussian pulses will evolve into the parabolic pulses in the waveguide taper designed. PMID- 28630484 TI - Simulated responses of permafrost distribution to climate change on the Qinghai Tibet Plateau. AB - Climate warming causes changes in permafrost distribution, which affects the surface energy balance, hydrologic cycle and carbon flux in cold regions. In this study, the Surface Frost Number model was applied to examine permafrost distribution on the Qinghai-Tibet Plateau (QTP) under the four RCPs (RCP2.6, RCP4.5, RCP6.0, and RCP8.5). The Kappa statistic was used to evaluate model results by comparing simulations of baseline permafrost distribution (1981-2010) with the existing frozen soil maps. The comparison shows that the Surface Frost Number model is suitable for simulating the general characteristics of permafrost distribution on the QTP. Simulated results suggest that areas of permafrost degradation would be the smallest in the near-term (2011-2040) with the rates of 17.17%, 18.07%, 12.95% and 15.66% under RCP2.6, RCP4.5, RCP6.0 and RCP8.5, respectively. The rate of permafrost degradation would be faster in the mid-term (2041-2070), especially under the RCP8.5 scenario (about 41.42%). Areas of permafrost degradation would be the largest in the long-term (2071-2099) relative to baseline conditions, with a modelled 64.31% decrease in permafrost distribution using the RCP8.5 scenario. Our results would help the decision making for engineering construction program on the QTP, and support local units in their efforts to adapt climate change. PMID- 28630486 TI - Integrated optical modulator manipulating the polarization and rotation handedness of Orbital Angular Momentum states. AB - Recent studies demonstrated that the optical channels encoded by Orbital Angular Momentum (OAM) are capable candidates for improving the next generation of communication systems. OAM states can enhance the capacity and security of high dimensional communication channels in both classical and quantum regimes based on optical fibre and free space. Hence, fast and precise control of the beams encoded by OAM can provide their commercial applications in the compatible communication networks. Integrated optical devices are good miniaturized options to perform this issue. This paper proposes a numerically verified integrated high frequency electro-optical modulator for manipulation of the guided modes encoded in both OAM and polarization states. The proposed modulator is designed as an electro-optically active Lithium Niobate (LN) core photonic wire with silica as its cladding in a LN on Insulator (LNOI) configuration. It consists of two successive parts; a phase shifter to reverse the rotation handedness of the input OAM state and a polarization converter to change the horizontally polarized OAM state to the vertically polarized one. It is shown that all four possible output polarization-OAM encoded states can be achieved with only 6 V and 7 V applied voltages to the electrodes in the two parts of the modulator. PMID- 28630485 TI - Acute administration of catalase targeted to ICAM-1 attenuates neuropathology in experimental traumatic brain injury. AB - Traumatic brain injury (TBI) contributes to one third of injury related deaths in the US. Treatment strategies for TBI are supportive, and the pathophysiology is not fully understood. Secondary mechanisms of injury in TBI, such as oxidative stress and inflammation, are points at which intervention may reduce neuropathology. Evidence suggests that reactive oxygen species (ROS) propagate blood-brain barrier (BBB) hyperpermeability and inflammation following TBI. We hypothesized that targeted detoxification of ROS may improve the pathological outcomes of TBI. Following TBI, endothelial activation results in a time dependent increase in vascular expression of ICAM-1. We conjugated catalase to anti-ICAM-1 antibodies and administered the conjugate to 8 wk old C57BL/6J mice 30 min after moderate controlled cortical impact injury. Results indicate that catalase targeted to ICAM-1 reduces markers of oxidative stress, preserves BBB permeability, and attenuates neuropathological indices more effectively than non targeted catalase and anti-ICAM-1 antibody alone. Furthermore, the study of microglia by two-photon microscopy revealed that anti-ICAM-1/catalase prevents the transition of microglia to an activated phenotype. These findings demonstrate the use of a targeted antioxidant enzyme to interfere with oxidative stress mechanisms in TBI and provide a proof-of-concept approach to improve acute TBI management that may also be applicable to other neuroinflammatory conditions. PMID- 28630487 TI - Multicolor two-photon imaging of endogenous fluorophores in living tissues by wavelength mixing. AB - Two-photon imaging of endogenous fluorescence can provide physiological and metabolic information from intact tissues. However, simultaneous imaging of multiple intrinsic fluorophores, such as nicotinamide adenine dinucleotide(phosphate) (NAD(P)H), flavin adenine dinucleotide (FAD) and retinoids in living systems is generally hampered by sequential multi-wavelength excitation resulting in motion artifacts. Here, we report on efficient and simultaneous multicolor two-photon excitation of endogenous fluorophores with absorption spectra spanning the 750-1040 nm range, using wavelength mixing. By using two synchronized pulse trains at 760 and 1041 nm, an additional equivalent two-photon excitation wavelength at 879 nm is generated, and achieves simultaneous excitation of blue, green and red intrinsic fluorophores. This method permits an efficient simultaneous imaging of the metabolic coenzymes NADH and FAD to be implemented with perfect image co-registration, overcoming the difficulties associated with differences in absorption spectra and disparity in concentration. We demonstrate ratiometric redox imaging free of motion artifacts and simultaneous two-photon fluorescence lifetime imaging (FLIM) of NADH and FAD in living tissues. The lifetime gradients of NADH and FAD associated with different cellular metabolic and differentiation states in reconstructed human skin and in the germline of live C. Elegans are thus simultaneously measured. Finally, we present multicolor imaging of endogenous fluorophores and second harmonic generation (SHG) signals during the early stages of Zebrafish embryo development, evidencing fluorescence spectral changes associated with development. PMID- 28630488 TI - Initial pseudo-steady state & asymptotic KPZ universality in semiconductor on polymer deposition. AB - The Kardar-Parisi-Zhang (KPZ) class is a paradigmatic example of universality in nonequilibrium phenomena, but clear experimental evidences of asymptotic 2D-KPZ statistics are still very rare, and far less understanding stems from its short time behavior. We tackle such issues by analyzing surface fluctuations of CdTe films deposited on polymeric substrates, based on a huge spatio-temporal surface sampling acquired through atomic force microscopy. A pseudo-steady state (where average surface roughness and spatial correlations stay constant in time) is observed at initial times, persisting up to deposition of ~104 monolayers. This state results from a fine balance between roughening and smoothening, as supported by a phenomenological growth model. KPZ statistics arises at long times, thoroughly verified by universal exponents, spatial covariance and several distributions. Recent theoretical generalizations of the Family-Vicsek scaling and the emergence of log-normal distributions during interface growth are experimentally confirmed. These results confirm that high vacuum vapor deposition of CdTe constitutes a genuine 2D-KPZ system, and expand our knowledge about possible substrate-induced short-time behaviors. PMID- 28630489 TI - Host-guest assembly for highly sensitive probing of a chiral mono-alcohol with a zinc trisporphyrinate. AB - A zinc trisporphyrinate has been developed as a chirality sensor for chiral mono alcohols. In its structure, there are two "spaces" surrounded by three porphyrin moieties, which allow guests to fill in. It has shown extremely high CD sensitivity for a chiral mono-alcohol with a naphthyl substituent, 1-(1 naphthyl)ethanol, at MUM level, which is at least three orders of magnitude lower concentration than previous reports. A crystallographic study of the host-guest complex reveals the binding of 1-(1-naphthyl)ethanol to the zinc trisporphyrinate is greatly enhanced by multipoint interactions, such as coordination interactions, hydrogen bonding, pi-pi and CH...pi interactions etc. Spectroscopic studies suggest the corresponding binding constant K1 is over 105 M-1, which is two or three orders of magnitude larger than other mono-alcohols. Among porphyrin systems, this trisporphyrin have the strongest binding affinity for 1-(1 naphthyl)ethanol, which leads to the highest CD sensitivity. PMID- 28630490 TI - Pyroptosis, superinfection, and the maintenance of the latent reservoir in HIV-1 infection. AB - A long-lived reservoir of latently infected T cells prevents antiretroviral therapy from eliminating HIV-1 infection. Furthering our understanding of the dynamics of latency generation and maintenance is therefore vital to improve treatment outcome. Using mathematical models and experiments, we suggest that the death of latently infected cells brought about by pyroptosis, or to a lesser extent by superinfection, might be key mechanisms to account for the size and composition of the latent reservoir. Pyroptosis is a form of cell death that occurs in a resting (and thus latently infected) T cell when a productively infected cell attempts cell-to-cell transmission of virus. Superinfection of latently infected cells by productive virus could similarly remove those cells through active virus replication and resulting cytopathicity. The mathematical models presented can explain a number of previously published clinical observations including latent reservoir size and the relationships to viral load in acute HIV infection, measurements of the latent reservoir in chronic infection, and the replacement of wild-type virus by CTL escape mutants within the latent reservoir. Basic virus dynamics models of latency that do not take into account pyroptosis, superinfection, or other potential complexities cannot account for the data. PMID- 28630493 TI - Simultaneous Extraction of Density of States Width, Carrier Mobility and Injection Barriers in Organic Semiconductors. AB - The predictive accuracy of state-of-the-art continuum models for charge transport in organic semiconductors is highly dependent on the accurate tuning of a set of parameters whose values cannot be effectively estimated either by direct measurements or by first principles. Fitting the complete set of model parameters at once to experimental data requires to set up extremely complex multi-objective optimization problems whose solution is, on the one hand, overwhelmingly computationally expensive and, on the other, it provides no guarantee of the physical soundness of the value obtained for each individual parameter. In the present study we present a step-by-step procedure that enables to determine the most relevant model parameters, namely the density of states width, the carrier mobility and the injection barrier height, by fitting experimental data from a sequence of relatively simple and inexpensive measurements to suitably devised numerical simulations. At each step of the proposed procedure only one parameter value is sought for, thus highly simplifying the numerical fitting and enhancing its robustness, reliability and accuracy. As a case study we consider a prototypical n-type organic polymer. A very satisfactory fitting of experimental measurements is obtained, and physically meaningful values for the aforementioned parameters are extracted. PMID- 28630492 TI - Towards affordable biomarkers of frontotemporal dementia: A classification study via network's information sharing. AB - Developing effective and affordable biomarkers for dementias is critical given the difficulty to achieve early diagnosis. In this sense, electroencephalographic (EEG) methods offer promising alternatives due to their low cost, portability, and growing robustness. Here, we relied on EEG signals and a novel information sharing method to study resting-state connectivity in patients with behavioral variant frontotemporal dementia (bvFTD) and controls. To evaluate the specificity of our results, we also tested Alzheimer's disease (AD) patients. The classification power of the ensuing connectivity patterns was evaluated through a supervised classification algorithm (support vector machine). In addition, we compared the classification power yielded by (i) functional connectivity, (ii) relevant neuropsychological tests, and (iii) a combination of both. BvFTD patients exhibited a specific pattern of hypoconnectivity in mid-range frontotemporal links, which showed no alterations in AD patients. These functional connectivity alterations in bvFTD were replicated with a low-density EEG setting (20 electrodes). Moreover, while neuropsychological tests yielded acceptable discrimination between bvFTD and controls, the addition of connectivity results improved classification power. Finally, classification between bvFTD and AD patients was better when based on connectivity than on neuropsychological measures. Taken together, such findings underscore the relevance of EEG measures as potential biomarker signatures for clinical settings. PMID- 28630491 TI - Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation. AB - Under conditions of high fat diet (HFD) consumption, glucose dyshomeostasis develops when beta-cells are unable to adapt to peripheral insulin demands. Few studies have interrogated the molecular mechanisms of beta-cell dysfunction at the level of mRNA translation under such conditions. We sought to address this issue through polyribosome profile analysis of islets from mice fed 16-weeks of 42% HFD. HFD-islet analysis revealed clear trends toward global reductions in mRNA translation with a significant reduction in the polyribosome/monoribosome ratio for Pdx1 mRNA. Transcriptional and translational analyses revealed endoplasmic reticulum stress was not the etiology of our findings. HFD-islets demonstrated evidence of oxidative stress and DNA damage, as well as activation of p53. Experiments in MIN-6 beta-cells revealed that treatment with doxorubicin to directly induce DNA damage mimicked our observed effects in islets. Islets from animals treated with pioglitazone concurrently with HFD demonstrated a reversal of effects observed from HFD alone. Finally, HFD-islets demonstrated reduced expression of multiple ribosome biogenesis genes and the key translation initiation factor eIF4E. We propose a heretofore unappreciated effect of chronic HFD on beta-cells, wherein continued DNA damage owing to persistent oxidative stress results in p53 activation and a resultant inhibition of mRNA translation. PMID- 28630495 TI - The solution plasma process for heteroatom-carbon nanosheets: the role of precursors. AB - The solution plasma process (SPP), known as non-equilibrium cold plasma at atmospheric pressure and room temperature, was used to investigate the synthesis of nitrogen-carbon nasnosheets (NCNs). To verify the effect of elementary composition and structure of N-methyl-2-pyrrolidone (NMP), various precursors were used in the SPP to synthesize NCNs via the bottom-up synthesis method for the first time. The NCNs were analyzed by transmission electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy. Among the various precursors, SPP of 2-pyrrolidone was demonstrated to facilitate the formation of highly ordered NCNs. On the other hand, the SPP with cyclopentanone, cyclohexanone and pyrrole did not lead to the formation of carbon nanosheets. The results of this study would uncover new parameter fields for the growth of heteroatom-carbon nanosheets using this synthesis system. In addition, the study is expected to contribute toward research in improving the large-area growth and quality of two dimensional nanostructures, such as heteroatom-carbon nanosheets or graphene, for various applications in other synthesis methods. PMID- 28630494 TI - Structure-Guided Design of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2 ones as Potent and Mutant-Selective Epidermal Growth Factor Receptor (EGFR) L858R/T790M Inhibitors. AB - Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4 dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFRL858R/T790M (H1975 cell lines) over EGFRWT (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFRL858R/T790M. These results provide a new scaffold for the treatment of dual mutant-driven non-small cell lung cancer. PMID- 28630496 TI - Analytical solutions of the radiative transport equation for turbid and fluorescent layered media. AB - Accurate and efficient solutions of the three dimensional radiative transport equation were derived in all domains for the case of layered scattering media. Index mismatched boundary conditions based on Fresnel's equations were implemented. Arbitrary rotationally symmetric phase functions can be applied to characterize the scattering in the turbid media. Solutions were derived for an obliquely incident beam having arbitrary spatial profiles. The derived solutions were successfully validated with Monte Carlo simulations and partly compared with analytical solutions of the diffusion equation. PMID- 28630498 TI - Minimal control power of controlled dense coding and genuine tripartite entanglement. AB - We investigate minimal control power (MCP) for controlled dense coding defined by the channel capacity. We obtain MCPs for extended three-qubit Greenberger-Horne Zeilinger (GHZ) states and generalized three-qubit W states. Among those GHZ states, the standard GHZ state is found to maximize the MCP and so does the standard W state among the W-type states. We find the lower and upper bounds of the MCP and show for pure states that the lower bound, zero, is achieved if and only if the three-qubit state is biseparable or fully separable. The upper bound is achieved only for the standard GHZ state. Since the MCP is nonzero only when three-qubit entanglement exists, this quantity may be a good candidate to measure the degree of genuine tripartite entanglement. PMID- 28630497 TI - Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer's disease. AB - The present study aimed to assess whether our newly developed redox nanoparticle (RNPN) that has antioxidant potential decreases Abeta levels or prevents Abeta aggregation associated with oxidative stress. The transgenic Tg2576 Alzheimer's disease (AD) mice were used to investigate the effect of chronic ad libitum drinking of RNPN solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNPN-treated mice had significantly attenuated cognitive deficits of both spatial and non-spatial memories, reduced oxidative stress of lipid peroxide, and DNA oxidation. RNPN treatment increased the percent inhibition of superoxide anion and glutathione peroxidase activity, neuronal densities in the cortex and hippocampus, decreased Abeta(1-40), Abeta(1-42) and gamma (gamma)-secretase levels, and reduced Abeta plaque observed using immunohistochemistry analysis and thioflavin S staining. Our results suggest that RNPN may be a promising candidate for AD therapy because of its antioxidant properties and reduction in Abeta aggregation, thereby suppressing its adverse side effect. PMID- 28630499 TI - Spatio-temporal analysis of coding and long noncoding transcripts during maize endosperm development. AB - The maize endosperm consists of three major compartmentalized cell types: the starchy endosperm (SE), the basal endosperm transfer cell layer (BETL), and the aleurone cell layer (AL). Differential genetic programs are activated in each cell type to construct functionally and structurally distinct cells. To compare gene expression patterns involved in maize endosperm cell differentiation, we isolated transcripts from cryo-dissected endosperm specimens enriched with BETL, AL, or SE at 8, 12, and 16 days after pollination (DAP). We performed transcriptome profiling of coding and long noncoding transcripts in the three cell types during differentiation and identified clusters of the transcripts exhibiting spatio-temporal specificities. Our analysis uncovered that the BETL at 12 DAP undergoes the most dynamic transcriptional regulation for both coding and long noncoding transcripts. In addition, our transcriptome analysis revealed spatio-temporal regulatory networks of transcription factors, imprinted genes, and loci marked with histone H3 trimethylated at lysine 27. Our study suggests that various regulatory mechanisms contribute to the genetic networks specific to the functions and structures of the cell types of the endosperm. PMID- 28630500 TI - Hyperuricemia and overexcretion of uric acid increase the risk of simple renal cysts in type 2 diabetes. AB - Previous studies have discussed the relationship between simple renal cysts (SRC) and serum uric acid level in healthy individuals. We performed a cross-sectional study to evaluate the association between serum uric acid level and fractional excretion of uric acid (FEUA) and simple renal cysts in males and postmenopausal females with type 2 diabetes. The overall prevalence of SRC was 18.1% in our population. SRC prevalence was significantly higher in hyperuricemic than normouricemic subjects (27.3% vs. 16.8%, P < 0.001). Subjects who overexcreted uric acid had a higher prevalence of SRC than underexcretors (total population: 21.6% vs. 16.3%; normouricemic subjects: 19.8% vs. 13.7%; hyperuricemic subjects: 50.0% vs. 22.7%, all P-values < 0.05). Hyperuricemia (odds ratio [OR] 1.824, 95% confidence interval [CI] 1.332-2.498, P < 0.001); FEUA (OR 1.046, 95% CI 1.002 1.091, P < 0.05); male gender (OR 1.922, 95% CI 1.489-2.480, P < 0.001); age (OR 1.049, 95% CI 1.035-1.064, P < 0.001); and albuminuria (OR 1.492, 95% CI 1.176 1.892, P < 0.01) were independent risk factors for SRC development. These findings suggested that hyperuricemia and high level of FEUA were both independent risk factors for SRC development in males and postmenopausal females with type 2 diabetes. Half of overproduction hyperuricemic patients had SRC. PMID- 28630502 TI - The Selfie Generation and Pharmacy Education. PMID- 28630501 TI - IFN-lambda4 potently blocks IFN-alpha signalling by ISG15 and USP18 in hepatitis C virus infection. AB - Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-alpha based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-DeltaG genotype, which encodes functional IFN-lambda4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-lambda4 in HCV-infected hepatocytes and their association with responsiveness to IFN-alpha. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-lambda4 expression and IFN-alpha responsiveness. HCV infection induced IFN-lambda4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-lambda4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-alpha signalling. The ISG15/USP18-mediated IFN-alpha unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-lambda4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-lambdas, including IFN-lambda4, and restored IFN-alpha responsiveness. These results demonstrate that virus-induced IFN-lambda4 potently blocks IFN-alpha signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-alpha responsiveness in HCV infected cells. PMID- 28630503 TI - The Pharmacists' Patient Care Process and More. PMID- 28630504 TI - Academic Pharmacy: Where is Our Influence? AB - Objective. To evaluate the talents of fellows from cohorts 1-10 of the Academic Leadership Fellows Program (ALFP). Methods. This was a descriptive analysis of previously collected ALFP cohort data reflecting the talents using the Clifton StrengthsFinder assessment tool. Data consisted of 295 fellows from the first 10 years of the ALFP program. The Clifton StrengthsFinder talents were aggregated and analyzed to determine talents (strengths) distribution and domain. The aggregate of the four domains were compared among ALFP fellows using a chi-square analysis with an a priori alpha of .05. Results. Lowest frequency of talents was found in the influencing domain (11.2%), while the domains with the largest frequency of talents were strategic thinking (34.4%) and executing (31.1%). When looking at the specific talents within the domains among the ALFP fellows, achiever (in the executing domain) and learner (in the strategic thinking domain) were the most frequent talents, while command (in the influencing domain) and adaptability (in the relationship building domain) were the least frequent talents. Conclusions. Since the profession is deficient in the influencing and relationship building domains (command and adaptability talents, respectively), this could help explain our slow progress in moving the profession from a product focused role to a provider-based role. Perhaps the profession should be using a strategy better aligned with our signature leadership domains of executing and strategic thinking and focus on being a member of the health care team by aligning with team-based care rather than obtaining provider status. PMID- 28630505 TI - Analytical Evaluation of the Accuracy and Retention of Compounding Skills Among PharmD Students. AB - Objective. To evaluate the accuracy and retention of compounding skills among students using analytical testing. Methods. Students compounded acetaminophen capsules from the same prescription at three time points (Exercise 1, 2, 3). The compounded products were analyzed (by HPLC) for acetaminophen content and the students' written reports were evaluated for accuracy of calculations and labeling. Results. During Exercise 1, 57.8% of the compounded capsule products were within the acceptable range, 92.2% during Exercise 2 and 75% during Exercise 3. The largest range in acetaminophen content was observed during Exercise 3 (76.08% to 135.2%) mainly due to calculation errors. Conclusion. While most students readily develop compounding skills during regular laboratory coursework, long-term competency depends on constant exposure to compounding activities and the retention of calculation skills. PMID- 28630506 TI - Development of an Instrument to Measure Pharmacy Student Attitudes Toward Social Media Professionalism. AB - Objectives. To develop and validate a scale measuring pharmacy students' attitudes toward social media professionalism, and assess the impact of an educational presentation on social media professionalism. Methods. A social media professionalism scale was used in a pre- and post-survey to determine the effects of a social media professionalism presentation. The 26-item scale was administered to 197 first-year pharmacy (P1) students during orientation. Exploratory factor analysis was applied to determine the number of underlying factors responsible for covariation of the data. Principal components analysis was used as the extraction method. Varimax was selected as the rotation method. Cronbach's alpha was estimated. Wilcoxon signed rank test was used to compare pre and post-scores of each item, subscale, and total scale. Results. There were 187 (95%) students who participated. The final scale had five subscales and 15 items. Subscales were named according to the professionalism tenet they best represented. Scores of items addressing reading/posting to social media during class, an employer's use of social media when making hiring decisions, and a college/university's use of social media as a measure of professional conduct significantly increased from pre-test to post-test. The "honesty and integrity" subscale score also significantly increased. Conclusion. The social media professionalism scale measures five tenets of professionalism and exhibits satisfactory reliability. The presentation improved P1 students' attitudes regarding social media professionalism. PMID- 28630507 TI - Analysis of the Student Experience in an Attending Pharmacist Model General Medicine Advanced Pharmacy Practice Experience. AB - Objective. To characterize and determine the quality of the student experience in an attending pharmacist model (APM). Methods. In-depth interviews were conducted with students completing an advanced pharmacy practice experience (APPE) at two general medicine services using the APM over a 2-year time period. Quantitative information about student learning and interprofessional interactions were extracted from student evaluations of the site. Data from the mixed model were analyzed to identify strengths of the APM and areas needing improvement. Results. Strengths of the APM included positive student interaction with the pharmacy resident and more students reporting full integration in and accountability to the interprofessional team for patient outcomes compared to students in non teaching models. A few students at one site reported a need for greater delineation of expectations, more initial support from preceptors, and initial responsibility for fewer patients. These factors were modified before the second APM year and subsequent reports from students at this site were uniformly positive. Students at the second site did not note areas needing improvement. The APM increased student capacity at both sites. Conclusion. The attending pharmacist model provided a high quality learning experience for students, particularly with regard to integration into and accountability for patient outcomes to the interprofessional team. Qualitative research methods enabled precise detection of areas needing improvement at one site and confirmed that changes made at that site improved the student experience. PMID- 28630508 TI - Relationship Between Grit with Academic Performance and Attainment of Postgraduate Training in Pharmacy Students. AB - Objective. To determine if Grit-S scores correlate with academic success in a doctor of pharmacy (PharmD) program, as well as the pursuit and attainment of pharmacy postgraduate (residency or fellowship) training. Methods. A 28-item survey was administered to third- and fourth-year (P3 and P4) pharmacy students. Variables queried included Grit-S score, demographics, pharmacy experience prior to the PharmD program, and factors that may affect academic performance during didactic coursework. Didactic coursework GPA was used as a surrogate for academic success. Information about pursuit and attainment of a postgraduate training position was also documented and used in the analyses. Results. There was no significant correlation between Grit-S scores and variables related to academic success. However, students were more likely to pursue postgraduate training with higher academic success and higher Grit-S. Lastly, students with higher Grit-S were also more likely to obtain a postgraduate training position. Conclusion. Grit-S scores correlated with the pursuit and successful attainment of postgraduate training, but not with academic success during the didactic years of a PharmD program. PMID- 28630509 TI - Peer Evaluation Instrument Development, Administration, and Assessment in a Team based Learning Curriculum. AB - Objective. To design and implement an instrument capable of providing students with valuable peer feedback on team behaviors and to provide results of the administration of the instrument. Methods. A three-part instrument was designed that requires teammate rankings with justification on attributes aligned with school outcomes and team functioning, reporting of student behaviors, and provision of feedback on the value of peer contributions to their team. Score results after three years of administration were analyzed. Results. Six evaluations per year were completed by members of four different professional classes over a three-year time period. Mean scores increased slightly as students progressed through the program. Students were able to differentially score peers on attributes and behaviors. Conclusion. The peer evaluation instrument presented here provides formative and summative feedback through qualitative and quantitative scores that allow students to acknowledge differential contributions of individual team members. PMID- 28630510 TI - Current Practices of Awarding Graduation Honors within Doctor of Pharmacy Degree Programs. AB - Objective. To survey the practices of awarding honors upon graduation with a doctor of pharmacy degree. Methods. College and school of pharmacy websites were systematically searched to identify if, and then how, graduation honors are awarded. Programs that offer graduation honors were categorized and quantified based upon grade point average (GPA) cutoffs, honors enrollment, research project completion, faculty vote, course failure considerations, and ethics code violations. Results. Of the 132 doctor of pharmacy programs reviewed, 86% (n=114) had accessible online resources and were included in data analysis. Of these 114 programs, 43% (n=49) award honors upon graduation, and 57% (n=65) do not. Among the 49 programs that award honors, 30 award the Latin honors. Of the remaining 19 programs, 18 award alternative graduation honors, and one awards both. Conclusions. Latin honors are the most common form of graduation honors utilized by doctor of pharmacy programs that award honors upon graduation. There is a variety of GPA cutoffs utilized across programs. PMID- 28630511 TI - Comparison of Pharmaceutical Calculations Learning Outcomes Achieved Within a Traditional Lecture or Flipped Classroom Andragogy. AB - Objective. To compare learning outcomes achieved from a pharmaceutical calculations course taught in a traditional lecture (lecture model) and a flipped classroom (flipped model). Methods. Students were randomly assigned to the lecture model and the flipped model. Course instructors, content, assessments, and instructional time for both models were equivalent. Overall group performance and pass rates on a standardized assessment (Pcalc OSCE) were compared at six weeks and at six months post-course completion. Results. Student mean exam scores in the flipped model were higher than those in the lecture model at six weeks and six months later. Significantly more students passed the OSCE the first time in the flipped model at six weeks; however, this effect was not maintained at six months. Conclusion. Within a 6 week course of study, use of a flipped classroom improves student pharmacy calculation skill achievement relative to a traditional lecture andragogy. Further study is needed to determine if the effect is maintained over time. PMID- 28630512 TI - Attitudes and Perceptions of Dual PharmD/MBA Degree Program Students. AB - Objectives. To understand pharmacy students' reasons for pursuing a dual PharmD/MBA degree and their perceptions of the impact a dual degree will have on their careers. Methods. This was a cross-sectional survey of registered students in the University at Buffalo PharmD/MBA program. An electronic survey was developed through collaboration with the UB School of Management and administered in January 2015. Results. A total of 23/24 (96% response rate) students who were enrolled in the PharmD/MBA curriculum responded to the survey. Respondents identified employment opportunities following graduation and career advancement as the most influential determinants in deciding to pursue an MBA degree. All respondents (100%) felt the job marketplace for pharmacy graduates is becoming increasingly difficult, 96% believe they will earn a higher midpoint salary with a PharmD/MBA, and 82% would recommend a PharmD/MBA to first year pharmacy students. Conclusion. Students are increasingly perceptive of the challenges in the current job marketplace and are taking advantage of a dual PharmD/MBA degree. PMID- 28630513 TI - Career Progression of the Pharmacy/MBA Professional: Characterization and Perceptions of the Combined Degree. AB - Objectives. To characterize pharmacy/MBA professionals during their entry-level and current positions and to describe their attitudes and perceptions toward their combined degree. Methods. A cross-sectional survey of University at Buffalo (UB) alumni who obtained both pharmacy and MBA degrees was used. An electronic survey was developed through collaboration with the UB School of Management and administered in winter 2015. Results. A total of 68/115 (59% response rate) pharmacy/MBA professionals responded to the survey. Post-graduate training was completed by 24% of respondents, and most commonly it was a residency program. After adjusting for inflation to 2014 dollars, the median entry-level salary for pharmacy/MBA professionals was $140,123 (mean = $144,327) and this increased to $179,947 (mean = $205,623) for those in their current position. Practice settings for entry-level professionals included pharmaceutical industry (25%) and chain pharmacies (18%). Most respondents believed that a combined degree helped in career advancement (85%) and made them more competitive in the job market (90%). Conclusion. Pharmacy/MBA professionals are well-compensated, work in a wide-range of professional settings, and have a high-level of satisfaction with their combined degree. PMID- 28630514 TI - Editors' Perspectives on Enhancing Manuscript Quality and Editorial Decisions Through Peer Review and Reviewer Development. AB - Objectives. To identify peer reviewer and peer review characteristics that enhance manuscript quality and editorial decisions, and to identify valuable elements of peer reviewer training programs. Methods. A three-school, 15-year review of pharmacy practice and pharmacy administration faculty's publications was conducted to identify high-publication volume journals for inclusion. Editors in-chief identified all editors managing manuscripts for participation. A three round modified Delphi process was used. Rounds advanced from open-ended questions regarding actions and attributes of good reviewers to consensus-seeking and clarifying questions related to quality, importance, value, and priority. Results. Nineteen editors representing eight pharmacy journals participated. Three characteristics of reviews were rated required or helpful in enhancing manuscript quality by all respondents: includes a critical analysis of the manuscript (88% required, 12% helpful), includes feedback that contains both strengths and areas of improvement (53% required, 47% helpful), and speaks to the manuscript's utility in the literature (41% required, 59% helpful). Hands-on experience with review activities (88%) and exposure to good and bad reviews (88%) were identified as very valuable to peer reviewer development. Conclusion. Reviewers, individuals involved in faculty development, and journals should work to assist new reviewers in defining focused areas of expertise, building knowledge in these areas, and developing critical analysis skills. PMID- 28630515 TI - Emotional Intelligence and its Effect on Pharmacists and Pharmacy Students with Autistic-like Traits. AB - Objective. To measure whether Emotional intelligence (EI) would minimize the negative association between autistic-like traits (ALT) and empathic behavior and enhance the positive association between ALT and psychological distress. Methods. Our sample population included 823 hospital pharmacists belonging to a district society, and 378 pharmacy students. Analyses were performed to examine relationships between scores on the Emotional Intelligence Scale (EQS), Autism Spectrum Quotient (AQ), Jefferson Scale of Empathy (JSE), and General Health Questionnaire-12 (GHQ). Results. Complete answers were obtained from 373 pharmacists, and 341 students. EQS partially intervened the associations between AQ and JSE and between AQ and GHQ. Conclusion. EI partially intervened the relationships between ALT and empathy, and between ALT and mental health, both of which are necessary for optimal pharmaceutical practice. PMID- 28630516 TI - Assessment of Burnout and Associated Risk Factors Among Pharmacy Practice Faculty in the United States. AB - Objectives. To measure the level of burnout among pharmacy practice faculty members at US colleges and schools of pharmacy and to identify factors associated with burnout. Methods. Using a cross-sectional, electronic, anonymous survey design, we measured faculty burnout (n=2318) at US colleges and schools of pharmacy using the Maslach Burnout Inventory-Educators Survey (MBI-ES), which measures burnout dimensions: emotional exhaustion, depersonalization, and personal accomplishment. We assessed MBI-ES scores, demographics and possible predictors of burnout. Results. The response rate was 32.7% (n=758). Emotional exhaustion was identified in 41.3% and was higher in women, assistant professors, and those without a hobby. Participants without a mentor had higher scores of depersonalization. Those with children ages 1-12 years had higher emotional exhaustion and depersonalization compared to those with older children. Conclusion. Pharmacy practice faculty members at US colleges and schools of pharmacy are suffering from burnout, exhibited mainly through emotional exhaustion. PMID- 28630517 TI - Enhancing Student Communication Skills Through Arabic Language Competency and Simulated Patient Assessments. AB - Objective. To assess student communication and patient management skill with introduction of Arabic and use of simulated patient assessments to a communication and counseling course. Design. Five, 3-hour tutorials (clinical skill laboratory) were added to the course covering: listening and empathic responding, non-verbal communications, interviewing skills, assertiveness, counseling in special situations: conflict, anger, worry or rushed situations, and professional decision making. Arabic content was introduced to the course to enhance Arabic communications and competence among students. Simulated patient assessment was used to evaluate student skills. Students' feedback about course changes was evaluated. Assessment. The course now covers a wider content and Arabic language. Students' scores were similar in the assessment and other assessments within the course and between Arabic and English groups. Students favorably rated the changes in the course and provided constructive feedback on content usefulness and adequacy. Conclusion. Expanding the course to include Arabic language and content and simulated patient assessments enhanced student communication skills. PMID- 28630518 TI - A Call for an Integrated Program of Assessment. AB - An integrated curriculum that does not incorporate equally integrated assessment strategies is likely to prove ineffective in achieving the desired educational outcomes. We suggest it is time for colleges and schools of pharmacy to re engineer their approach to assessment. To build the case, we first discuss the challenges leading to the need for curricular developments in pharmacy education. We then turn to the literature that informs how assessment can influence learning, introduce an approach to learning assessment that is being used by several medical education programs, and provide some examples of this approach in operation. Finally, we identify some of the challenges faced in adopting such an integrated approach to assessment and suggest that this is an area ripe with research opportunities for pharmacy educators. PMID- 28630519 TI - Strategies for Improving Learner Metacognition in Health Professional Education. AB - Metacognition is an essential skill in critical thinking and self-regulated, lifelong learning. It is important for learners to have skills in metacognition because they are used to monitor and regulate reasoning, comprehension, and problem-solving, which are fundamental components/outcomes of pharmacy curricula. Instructors can help learners develop metacognitive skills within the classroom and experiential setting by carefully designing learning activities within courses and the curriculum. These skills are developed through intentional questioning, modeling techniques, and reflection. This article discusses key background literature on metacognition and identifies specific methods and strategies to develop learners' metacognitive skills in both the classroom and experiential settings. PMID- 28630520 TI - A Plea for Psychometric Rigor. PMID- 28630521 TI - Response to a Plea for Psychometric Rigor. PMID- 28630522 TI - Report of the Journal Editor. PMID- 28630523 TI - On pattern matching with k mismatches and few don't cares. AB - We consider the problem of pattern matching with k mismatches, where there can be don't care or wild card characters in the pattern. Specifically, given a pattern P of length m and a text T of length n, we want to find all occurrences of P in T that have no more than k mismatches. The pattern can have don't care characters, which match any character. Without don't cares, the best known algorithm for pattern matching with k mismatches has a runtime of [Formula: see text]. With don't cares in the pattern, the best deterministic algorithm has a runtime of O(nk polylog m). Therefore, there is an important gap between the versions with and without don't cares. In this paper we give an algorithm whose runtime increases with the number of don't cares. We define an island to be a maximal length substring of P that does not contain don't cares. Let q be the number of islands in P. We present an algorithm that runs in [Formula: see text] time. If the number of islands q is O(k) this runtime becomes [Formula: see text], which essentially matches the best known runtime for pattern matching with k mismatches without don't cares. If the number of islands q is O(k2), this algorithm is asymptotically faster than the previous best algorithm for pattern matching with k mismatches with don't cares in the pattern. PMID- 28630524 TI - A martingale analysis of first passage times of time-dependent Wiener diffusion models. AB - Research in psychology and neuroscience has successfully modeled decision making as a process of noisy evidence accumulation to a decision bound. While there are several variants and implementations of this idea, the majority of these models make use of a noisy accumulation between two absorbing boundaries. A common assumption of these models is that decision parameters, e.g., the rate of accumulation (drift rate), remain fixed over the course of a decision, allowing the derivation of analytic formulas for the probabilities of hitting the upper or lower decision threshold, and the mean decision time. There is reason to believe, however, that many types of behavior would be better described by a model in which the parameters were allowed to vary over the course of the decision process. In this paper, we use martingale theory to derive formulas for the mean decision time, hitting probabilities, and first passage time (FPT) densities of a Wiener process with time-varying drift between two time-varying absorbing boundaries. This model was first studied by Ratcliff (1980) in the two-stage form, and here we consider the same model for an arbitrary number of stages (i.e. intervals of time during which parameters are constant). Our calculations enable direct computation of mean decision times and hitting probabilities for the associated multistage process. We also provide a review of how martingale theory may be used to analyze similar models employing Wiener processes by re-deriving some classical results. In concert with a variety of numerical tools already available, the current derivations should encourage mathematical analysis of more complex models of decision making with time-varying evidence. PMID- 28630525 TI - A Bayesian adaptive design for clinical trials in rare diseases. AB - Development of treatments for rare diseases is challenging due to the limited number of patients available for participation. Learning about treatment effectiveness with a view to treat patients in the larger outside population, as in the traditional fixed randomised design, may not be a plausible goal. An alternative goal is to treat the patients within the trial as effectively as possible. Using the framework of finite-horizon Markov decision processes and dynamic programming (DP), a novel randomised response-adaptive design is proposed which maximises the total number of patient successes in the trial and penalises if a minimum number of patients are not recruited to each treatment arm. Several performance measures of the proposed design are evaluated and compared to alternative designs through extensive simulation studies using a recently published trial as motivation. For simplicity, a two-armed trial with binary endpoints and immediate responses is considered. Simulation results for the proposed design show that: (i) the percentage of patients allocated to the superior arm is much higher than in the traditional fixed randomised design; (ii) relative to the optimal DP design, the power is largely improved upon and (iii) it exhibits only a very small bias and mean squared error of the treatment effect estimator. Furthermore, this design is fully randomised which is an advantage from a practical point of view because it protects the trial against various sources of bias. As such, the proposed design addresses some of the key issues that have been suggested as preventing so-called bandit models from being implemented in clinical practice. PMID- 28630526 TI - Discriminating Value of Calprotectin in Disease Activity and Progression of Nonradiographic Axial Spondyloarthritis and Ankylosing Spondylitis. AB - It has been controversial whether ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA) are separate or different phases of radiographic progression. We determined that serum calprotectin level (ng/ml) was higher in AS (15.30 +/- 6.49) and nr-axSpA (17.76 +/- 8.59) patients than in healthy individuals (7.40 +/- 2.67). No difference was observed in calprotectin level between these two groups. Elevated calprotectin was positively correlated with ESR, CRP, BASDAI, and ASDAS as well as SPARCC scoring and had no correlation with BASFI and mSASSS. No correlation was observed between calprotectin and Wnt/beta-catenin pathway markers. Serum calprotectin can be used as a marker for inflammation in both nr-axSpA and AS, while it does not contribute to the discrimination of AS and nr-axSpA. Calprotectin-mediated inflammation was not correlated with principle effectors of Wnt/beta-catenin pathway, indicating that inflammation and bone fusion might be separate processes of the disease. PMID- 28630528 TI - Description and Evaluation of a Measurement Technique for Assessment of Performing Gender. AB - The influence of masculinity and femininity on behaviors and outcomes has been extensively studied in social science research using various measurement strategies. In the present paper, we describe and evaluate a measurement technique that uses existing survey items to capture the extent to which an individual behaves similarly to their same-gender peers. We use data from the first four waves of The National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative sample of adolescents (age 12-18) in the United States who were re-interviewed at ages 13-19, 18-26, and 24-32. We estimate split-half reliability and provide evidence that supports the validity of this measurement technique. We demonstrate that the resulting measure does not perform as a trait measure and is associated with involvement in violent fights, a pattern consistent with theory and empirical findings. This measurement technique represents a novel approach for gender researchers with the potential for expanding our current knowledge base. PMID- 28630527 TI - A Promising Approach to Integrally Evaluate the Disease Outcome of Cerebral Ischemic Rats Based on Multiple-Biomarker Crosstalk. AB - PURPOSE: The study was designed to evaluate the disease outcome based on multiple biomarkers related to cerebral ischemia. METHODS: Rats were randomly divided into sham, permanent middle cerebral artery occlusion, and edaravone-treated groups. Cerebral ischemia was induced by permanent middle cerebral artery occlusion surgery in rats. To form a simplified crosstalk network, the related multiple biomarkers were chosen as S100beta, HIF-1alpha, IL-1beta, PGI2, TXA2, and GSH-Px. The levels or activities of these biomarkers in plasma were detected before and after ischemia. Concurrently, neurological deficit scores and cerebral infarct volumes were assessed. Based on a mathematic model, network balance maps and three integral disruption parameters (k, phi, and u) of the simplified crosstalk network were achieved. RESULTS: The levels or activities of the related biomarkers and neurological deficit scores were significantly impacted by cerebral ischemia. The balance maps intuitively displayed the network disruption, and the integral disruption parameters quantitatively depicted the disruption state of the simplified network after cerebral ischemia. The integral disruption parameter u values correlated significantly with neurological deficit scores and infarct volumes. CONCLUSION: Our results indicate that the approach based on crosstalk network may provide a new promising way to integrally evaluate the outcome of cerebral ischemia. PMID- 28630529 TI - Effect of cyto/chemokine degradation in effective intercellular communication distances. AB - Many complex biological processes such as cell differentiation, cell proliferation, and cell motility are governed by cell signaling. This mode of intercellular communication is of paramount importance for tissue function and ultimately for entire organism. In intercellular communication cells secrete signaling molecules such as cyto/chemokines which diffuse through the surrounding medium and eventually bind to receptors on other cells whereby the signal transduction is completed. An accurate estimation of the effective communication distances and the time scale on which signaling takes place are important for the interpretation of cell and organ physiology and ultimately in the effective and efficient chemotactically driven tissue engineering. The present study uses a solitary cell model incorporating degradation of secreted molecules to estimate the effective communication distances and the time scale on which signaling takes place. We demonstrate through our model that in presence of degradation the effective communication distances are significantly reduced. PMID- 28630531 TI - Rates of Subthreshold PTSD Among U.S. Military Veterans and Service Members: A Literature Review. PMID- 28630532 TI - First Impressions From Faces. AB - Although cultural wisdom warns 'don't judge a book by its cover,' we seem unable to inhibit this tendency even though it can produce inaccurate impressions of people's psychological traits and has significant social consequences. One explanation for this paradox is that first impressions of faces overgeneralize our adaptive impressions of categories of people that those faces resemble (including babies, familiar or unfamiliar people, unfit people, emotional people). Research testing these 'overgeneralization' hypotheses elucidates why we form first impressions from faces, what impressions we form, and what cues influence these impressions. This article focuses on commonalities in impressions across diverse perceivers. However, brief attention is given to individual differences in impressions and impression accuracy. PMID- 28630530 TI - Gas-phase broadband spectroscopy using active sources: progress, status, and applications. AB - Broadband spectroscopy is an invaluable tool for measuring multiple gas-phase species simultaneously. In this work we review basic techniques, implementations, and current applications for broadband spectroscopy. We discuss components of broad-band spectroscopy including light sources, absorption cells, and detection methods and then discuss specific combinations of these components in commonly used techniques. We finish this review by discussing potential future advances in techniques and applications of broad-band spectroscopy. PMID- 28630533 TI - Smoke screen? The globalization of production, transnational lobbying and the international political economy of plain tobacco packaging. AB - In 2012 Australia became the first country in the world to introduce plain tobacco packaging in an effort to reduce tobacco consumption. This move was vehemently opposed by the tobacco industry, which challenged it on several levels: nationally, bilaterally and multilaterally at the World Trade Organization (WTO). The political behavior of the tobacco companies in this case is puzzling both in terms of scale, operating at multiple levels at the same time and in terms of the countries mobilized in their defence. WTO litigation is typically the result of Multi National Enterprises (MNEs) lobbying their own government, but here third countries were mobilized. Lobbying in third country contexts, with the objective of accessing multilateral dispute settlement systems, has been little studied. We thus know very little about the driving factors behind such activities, how target governments are selected and what lobbying strategies are used. This paper draws on emerging research on transnational lobbying and a case study of the PP case to explore these issues in detail and, by doing so, aims to further our theoretical understanding of the political economy of international trade in the context of increasing regime complexity and globalization of production. PMID- 28630535 TI - Tests for stochastic ordering under biased sampling. AB - In two-sample comparison problems it is often of interest to examine whether one distribution function majorizes the other, i.e., for the presence of stochastic ordering. This paper develops a nonparametric test for stochastic ordering from size-biased data, allowing the pattern of the size bias to differ between the two samples. The test is formulated in terms of a maximally-selected local empirical likelihood statistic. A Gaussian multiplier bootstrap is devised to calibrate the test. Simulation results show that the proposed test outperforms an analogous Wald-type test, and that it provides substantially greater power over ignoring the size bias. The approach is illustrated using data on blood alcohol concentration of drivers involved in car accidents, where the size bias is due to drunker drivers being more likely to be involved in accidents. Further, younger drivers tend to be more affected by alcohol, so in making comparisons with older drivers the analysis is adjusted for differences in the patterns of size bias. PMID- 28630536 TI - Effects of filament size on critical current density in overpressure processed Bi 2212 round wire. AB - Bi2Sr2CaCu2Ox (Bi-2212) conductor is the only high temperature superconductor manufactured as a round wire and is a very promising conductor for very high field applications. One of the key design parameters of Bi-2212 wire is its filament size, which has been previously reported to affect the critical current density (Jc ) and ac losses. Work with 1 bar heat treatment showed that the optimal filament diameter was about 15 MUm but it was not well understood at that time that gas bubbles were the main current limiting mechanism. Here we investigated a recent Bi-2212 wire with a 121*18 filament architecture with varying wire diameter (1.0 to 1.5 mm) using 50 bar overpressure processing. This wire is part of a 1.2 km piece length of 1.0 mm diameter made by Oxford Superconducting Technology. We found that Jc is independent of the filament size in the range from 9 to 14 MUm, although the n value increased with increasing filament size. A new record Jc (4.2 K, 15 T) of 4200 A/mm2 and JE (4.2 K, 15 T) of 830 A/mm2 were achieved. PMID- 28630534 TI - Data Sharing: A New Editorial Initiative of the International Committee of Medical Journal Editors. Implications for the Editors' Network. AB - The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship- emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology. PMID- 28630537 TI - Narratives of Essentialism and Exceptionalism: The Challenges and Possibilities of Using Human Rights to Improve Access to Safe Abortion. PMID- 28630538 TI - Abortion Law and Policy Around the World: In Search of Decriminalization. AB - The aim of this paper is to provide a panoramic view of laws and policies on abortion around the world, giving a range of country-based examples. It shows that the plethora of convoluted laws and restrictions surrounding abortion do not make any legal or public health sense. What makes abortion safe is simple and irrefutable-when it is available on the woman's request and is universally affordable and accessible. From this perspective, few existing laws are fit for purpose. However, the road to law reform is long and difficult. In order to achieve the right to safe abortion, advocates will need to study the political, health system, legal, juridical, and socio-cultural realities surrounding existing law and policy in their countries, and decide what kind of law they want (if any). The biggest challenge is to determine what is possible to achieve, build a critical mass of support, and work together with legal experts, parliamentarians, health professionals, and women themselves to change the law-so that everyone with an unwanted pregnancy who seeks an abortion can have it, as early as possible and as late as necessary. PMID- 28630539 TI - Theorizing Time in Abortion Law and Human Rights. AB - The legal regulation of abortion by gestational age, or length of pregnancy, is a relatively undertheorized dimension of abortion and human rights. Yet struggles over time in abortion law, and its competing representations and meanings, are ultimately struggles over ethical and political values, authority and power, the very stakes that human rights on abortion engage. This article focuses on three struggles over time in abortion and human rights law: those related to morality, health, and justice. With respect to morality, the article concludes that collective faith and trust should be placed in the moral judgment of those most affected by the passage of time in pregnancy and by later abortion-pregnant women. With respect to health, abortion law as health regulation should be evidence-based to counter the stigma of later abortion, which leads to overregulation and access barriers. With respect to justice, in recognizing that there will always be a need for abortion services later in pregnancy, such services should be safe, legal, and accessible without hardship or risk. At the same time, justice must address the structural conditions of women's capacity to make timely decisions about abortion, and to access abortion services early in pregnancy. PMID- 28630540 TI - The Dublin Declaration on Maternal Health Care and Anti-Abortion Activism: Examples from Latin America. AB - The Dublin Declaration on Maternal Healthcare-issued by self-declared pro-life activists in Ireland in 2012-states unequivocally that abortion is never medically necessary, even to save the life of a pregnant woman. This article examines the influence of the Dublin Declaration on abortion politics in Latin America, especially El Salvador and Chile, where it has recently been used in pro life organizing to cast doubt on the notion that legalizing abortion will reduce maternal mortality. Its framers argue that legalizing abortion will not improve maternal mortality rates, but reproductive rights advocates respond that the Dublin Declaration is junk science designed to preserve the world's most restrictive abortion laws. Analyzing the strategy and impact of the Dublin Declaration brings to light one of the tactics used in anti-abortion organizing. PMID- 28630541 TI - Regulation of Conscientious Objection to Abortion: An International Comparative Multiple-Case Study. AB - Since abortion laws were liberalized in Western Europe, conscientious objection (CO) to abortion has become increasingly contentious. We investigated the efficacy and acceptability of laws and policies that permit CO and ensure access to legal abortion services. This is a comparative multiple-case study, which triangulates multiple data sources, including interviews with key stakeholders from all sides of the debate in England, Italy, Norway, and Portugal. While the laws in all four countries have similarities, we found that implementation varied. In this sample, the ingredients that appear necessary for a functional health system that guarantees access to abortion while still permitting CO include clarity about who can object and to which components of care; ready access by mandating referral or establishing direct entry; and assurance of a functioning abortion service through direct provision or by contracting services. Social attitudes toward both objection and abortion, and the prevalence of CO, additionally influence the degree to which CO policies are effectively implemented in these cases. England, Norway, and Portugal illustrate that it is possible to accommodate individuals who object to providing abortion, while still assuring that women have access to legal health care services. PMID- 28630542 TI - The Role of International Human Rights Norms in the Liberalization of Abortion Laws Globally. AB - International and regional human rights norms have evolved significantly to recognize that the denial of abortion care in a range of circumstances violates women's and girls' fundamental human rights. These increasingly progressive standards have played a critical role in transforming national-level abortion laws by both influencing domestic high court decisions on abortion and serving as a critical resource in advancing law and policy reform. Courts in countries such as Argentina, Bolivia, Brazil, Colombia, and Nepal have directly incorporated these standards into groundbreaking cases liberalizing abortion laws and increasing women's access to safe abortion services, demonstrating the influence of these human rights standards in advancing women's reproductive freedom. These norms have also underpinned national-level abortion law and policy reform, including in countries such as Spain, Rwanda, Uruguay, and Peru. As these human rights norms further evolve and increasingly recognize abortion as a human rights imperative, these standards have the potential to bolster transformative jurisprudence and law and policy reform advancing women's and girls' full reproductive autonomy. PMID- 28630543 TI - Pregnancy and the 40-Year Prison Sentence: How "Abortion Is Murder" Became Institutionalized in the Salvadoran Judicial System. AB - Using the case of El Salvador, this article demonstrates how the anti-abortion catchphrase "abortion is murder" can become embedded in the legal practice of state judicial systems. In the 1990s, a powerful anti-abortion movement in El Salvador resulted in a new legal context that outlawed abortion in all circumstances, discouraged mobilization for abortion rights, and encouraged the prosecution of reproduction-related "crimes." Within this context, Salvadoran women initially charged with the crime of abortion were convicted of "aggravated homicide" and sentenced to up to 40 years in prison. Court documents suggest that many of these women had not undergone abortions, but had suffered naturally occurring stillbirths late in their pregnancies. Through analysis of newspaper articles and court cases, this article documents how El Salvador came to prosecute obstetrical emergencies as "murder," and concludes that activism on behalf of abortion rights is central to protecting poor pregnant women from prosecution for reproduction-related "crimes." PMID- 28630544 TI - Pregnancies and Fetal Anomalies Incompatible with Life in Chile: Arguments and Experiences in Advocating for Legal Reform. AB - Chile allows abortion under no circumstances. Whether it's fetal anomaly incompatible with life or congenital malformation resulting in little or no life expectancy, all Chilean women are expected to carry their pregnancies to term. In this context, in January 2015 the Chilean Congress began debating a bill to legalize abortion on three grounds, including fatal congenital malformation. The medical community, including midwives, has presented its views for and against, especially on how the law may affect clinical practices; in addition, women, many of whom have experienced a fatal congenital malformation diagnosis, have weighed in. This qualitative study draws on 22 semi-structured interviews with nine certified nurse-midwives, one neonatologist, nine obstetrician-gynecologists, one psychiatrist, one psychologist, and one sociologist who provide care during gestation, pregnancy, delivery, and post-delivery in the public and private sectors, plus three interviews with two women and the former partner of a woman who underwent the experience. These interviews starkly illustrate the plight facing women carrying nonviable fetuses, including women's shock upon receiving the diagnosis, their feelings of bereavement and loss, and the clinical practices used in an attempt to ease their suffering under the weight of exceedingly difficult legal restrictions. These interviews confirmed that compelling women to carry nonviable fetuses to term violates their human rights. They also show that the chances of legislative change are real and that such change will present new challenges to the Chilean health care system. PMID- 28630545 TI - Legal Knowledge as a Tool for Social Change: La Mesa por la Vida y la Salud de las Mujeres as an Expert on Colombian Abortion Law. AB - In May 2006, Colombia's Constitutional Court liberalized abortion, introducing three circumstances under which the procedure would not be considered a crime: (1) rape or incest; (2) a risk to the woman's health or life; and (3) fetal malformations incompatible with life. Immediately following the court's ruling, known as Sentence C-355, members of La Mesa por la Vida y Salud de las Mujeres (hereinafter La Mesa) began to mobilize to ensure the decision's implementation, bearing in mind the limited impact that the legal framework endorsed by the court has had in other countries in the region. We argue that La Mesa's strategy is an innovative one in the field of legal mobilization insofar as it presumes that law can be shaped not just by public officials and universities but also by social actors engaged in the creation and diffusion of legal knowledge. In this regard, La Mesa has become a legal expert on abortion by accumulating knowledge about the multiple legal rules affecting the practice of abortion and about the situations in which these rules are to be applied. In addition, by becoming a legal expert, La Mesa has been able to persuade health providers that they will not risk criminal prosecution or being fired if they perform abortions. We call this effect of legal mobilization a "pedagogical effect" insofar as it involves the production of expertise and appropriation of knowledge by health professionals. We conclude by discussing La Mesa's choice to become a legal expert on abortion as opposed to recruiting academics to do this work or encouraging women to produce and disseminate this knowledge. PMID- 28630546 TI - The Battle Over Abortion Rights in Brazil's State Arenas, 1995-2006. AB - This article proposes a relational approach to the study of abortion law reform in Brazil. It focuses on the interaction of pro-choice and anti-abortion movements in different state arenas and political contexts. It details the emergence of a strategic action field on abortion during the Brazilian re democratization process and the National Constituent Assembly. We offer analysis on pro-choice and anti-abortion mobilization in state arenas-mainly in the executive and legislative powers-during the two terms of President Fernando Henrique Cardoso (FHC), 1995-1998 and 1999-2002, and the first term of President Luis Inacio Lula da Silva (Lula), 2003-2006. We then map political resources for mobilization, such as legislative bills, public policy norms, and judicial decisions, and track legal continuities and changes. Finally, we analyze anti abortion reaction, which was consolidated through an increased conservative presence in congress after 2006, and discuss how the abortion debate has migrated from congress to the Supreme Court and the public sphere. PMID- 28630547 TI - Abortion Rights Legal Mobilization in the Peruvian Media, 1990-2015. AB - State and non-state actors engaged in disputes to expand and limit abortion rights have engaged in legal mobilization-in other words, strategies using rights and law as a central tool for advancing contested political goals. Peru, like other Latin American countries, has experienced an increase in abortion rights legal mobilization in recent years, including litigation before national and international courts. This paper centers on societal legal mobilization, or the legal mobilization that occurs outside the legislative and judicial branches and that includes strategies promoted by the executive branch, political actors, and non-partisan organizations and individuals. It presents an analysis of op-ed articles published in two national newspapers, El Comercio and La Republica, between 1990 and 2015. The paper argues that the media is also an arena where legal mobilization takes place and is not just a space influenced by legal mobilization. Rather, the media's agenda operates independently of legal mobilization in the legislature and the courts, and it determines whether certain issues receive coverage and the way these issues are framed. PMID- 28630548 TI - The Moderating Influence of International Courts on Social Movements: Evidence from the IVF Case Against Costa Rica. AB - Feminists and religious conservatives across the globe have increasingly turned to courts in their battles over abortion. Yet while a significant literature analyzes legal mobilization on abortion issues, it tends to focus predominantly on domestic scenarios. In this article, we consider the effects of this contentious engagement of pro-choice and anti-abortion movements in international human rights fora, asking what happens to social movement claims when they reach international human rights courts. We answer the question through a detailed description of a single case, Gretel Artavia Murillo et al. v. Costa Rica, decided by the Inter-American Court of Human Rights in 2012 but with ongoing repercussions for abortion rights, given its authoritative interpretation of embryonic right to life. Through our analysis of Artavia Murillo, we show how legal mobilization before international human rights courts moderates social movement claims within the legal arena, as rivals respond to one another and argue within the frame of courts' norms and language. PMID- 28630549 TI - Why is a "Good Abortion Law" Not Enough? The Case of Estonia. AB - There are various ways to critically discuss abortion. Constructing or finding the most suitable analytical framework-whether rooted in legal formalism, socio legal considerations, or comparativism-always depends on the country of subject and whether the analysis is for litigation, advocacy, or more theoretical purposes. This paper offers a model for analyzing abortion in Estonia in order to connect it as a thought-provoking case study to the ongoing transnational abortion discussions. I set out by describing the Estonian Abortion Act as a "good abortion law": a regulation that guarantees in practice women's legal access to safe abortion. Despite this functioning law, I carve a space for criticism by expanding the conversation to the broader power relations and gender dynamics present in Estonian society. Accordingly, I explain the state of the Estonian feminist movement and gender research, the local legal community's minimal engagement with the reproductive rights discourse, and the lingering Soviet-era narratives of reproduction and health, which were not fully extinguished by the combination of human rights commitments and neoliberalism upon restoration of independence in the early 1990s. I consequently show that Estonia's liberal abortion regulation is not grounded in a sufficiently deep understanding of human rights-based approaches to reproductive health, therefore leaving the door open for micro-aggressions toward women and for conservative political winds to gain ground. PMID- 28630550 TI - Macro- and Micro-Political Vernaculizations of Rights: Human Rights and Abortion Discourses in Northern Ireland. AB - How abortion is dealt with in law and policy is shaped through the multiple political and societal discourses on the issue within a particular society. Debate on abortion is constantly in flux, with progressive and regressive movements witnessed globally. This paper examines the translation of human rights norms into discourses on abortion in Northern Ireland, a region where abortion is highly restricted, with extensive contemporary public debate into potential liberalization of abortion law. This paper emanates from research examining political debates on abortion in Northern Ireland and contrasts findings with recent civil society developments, identifying competing narratives of human rights with regard to abortion at the macro- and micro-political level. The paper identifies the complexities of using human rights as a lobbying tool, and questions the utility of rights-based arguments in furthering abortion law reform. The paper concludes that a legalistic rights-based approach may have limited efficacy in creating a more nuanced debate and perspective on abortion in Northern Ireland but that it has particular resonance in arguing for limited reform in extreme cases. PMID- 28630551 TI - Exploring Legal Restrictions, Regulatory Reform, and Geographic Disparities in Abortion Access in Thailand. AB - Despite decades of advocacy among Thai governmental and nongovernmental actors to remove abortion from the country's 1957 Criminal Code, this medically necessary service remains significantly legally restricted. In 2005, in the most recent regulatory reform to date, the Thai Medical Council established regulatory measures to allow a degree of physician interpretation within the confines of the existing law. Drawing on findings from a review of institutional policies and legislative materials, key informant interviews, and informal discussions with health service providers, government representatives, and nonprofit stakeholders, this article explores how legal reforms and health policies have shaped the abortion landscape in Thailand and influenced geographic disparities in availability and accessibility. Notwithstanding a strong medical community and the recent introduction of mifepristone for medication abortion (also known as medical abortion), the narrow interpretation of the regulatory criteria by physicians further entrenches these disparities. This article examines the causes of subnational disparities, focusing on the northern provinces and the western periphery of Thailand, and explores strategies to improve access to abortion in this legally restricted setting. PMID- 28630552 TI - Decriminalization and Women's Access to Abortion in Australia. AB - This article considers the relationship between the decriminalization of abortion and women's access to abortion services. It focuses on the four Australian jurisdictions which are, with Canada, the only jurisdictions in the world where abortion has been removed from the criminal law. This paper draws on documentary evidence and an oral history project to give a "before and after" account of each jurisdiction. The paper assumes that the meaning and impact of decriminalization must be assessed in each local context. Understanding the conditions that shape access must incorporate analysis of the broader social, political and economic environment as well as the law. The article finds that decriminalization does not necessarily deliver any improvement in women's access to abortion, at least in the short term. Further, it is not inconsistent with the neoliberal policy environment that characterizes the provision of abortion care in Australia, where most abortions are provided through the private sector at financial cost to women. If all women are to enjoy their human rights to full reproductive health care, the public health system must take responsibility for the adequate provision of abortion services; ongoing and vigilant activism is central if this is to be achieved. PMID- 28630553 TI - Australia: Abortion and Human Rights. AB - This article adopts a human rights lens to consider Australian law and practice regarding elective abortion. As such, it considers Australian laws within the context of the right to equality, right to privacy, right to health, and right to life. After setting out the human rights framework and noting the connected nature of many of the rights (and their corresponding violations), the article shifts its focus to analyzing Australian law and practice within the framework of these rights. It considers the importance of decriminalizing abortion and regulating it as a standard medical procedure. It discusses the need to remove legal and practical restrictions on access to abortion, including financial obstacles and anti-abortion protestors. Further, it comments on the importance of facilitating access; for example, by keeping accurate health data, securing continuity of health care, increasing the availability of medical abortion, and ensuring appropriate care is provided to the most marginalized and vulnerable women. PMID- 28630554 TI - Abortion Care in Nepal, 15 Years after Legalization: Gaps in Access, Equity, and Quality. PMID- 28630555 TI - The Case for International Guidelines on Human Rights and Drug Control. PMID- 28630558 TI - The Child's Right to Protection from Drugs: Understanding History to Move Forward. PMID- 28630557 TI - International Guidelines on Human Rights and Drug Control: A Tool for Securing Women's Rights in Drug Control Policy. AB - Discrimination and inequality shape women's experiences of drug use and in the drug trade and the impact of drug control efforts on them, with disproportionate burdens faced by poor and otherwise marginalized women. In recent years, UN member states and UN drug control and human rights entities have recognized this issue and made commitments to integrate a 'gender perspective' into drug control policies, with 'gender' limited to those conventionally deemed women. But the concept of gender in international law is broader, rooted in socially constructed and culturally determined norms and expectations around gender roles, sex, and sexuality. Also, drug control policies often fail to meaningfully address the specific needs and circumstances of women (inclusively defined), leaving them at risk of recurrent violations of their rights in the context of drugs. This article explores what it means to 'mainstream' this narrower version of gender into drug control efforts, using as examples various women's experiences as people who use drugs, in the drug trade, and in the criminal justice system. It points to international guidelines on human rights and drug control as an important tool to ensure attention to women's rights in drug control policy design and implementation. PMID- 28630556 TI - How Drug Control Policy and Practice Undermine Access to Controlled Medicines. AB - Drug conventions serve as the cornerstone for domestic drug laws and impose a dual obligation upon states to prevent the misuse of controlled substances while ensuring their adequate availability for medical and scientific purposes. Despite the mandate that these obligations be enforced equally, the dominant paradigm enshrined in the drug conventions is an enforcement-heavy criminal justice response to controlled substances that prohibits and penalizes their misuse. Prioritizing restrictive control is to the detriment of ensuring adequate availability of and access to controlled medicines, thereby violating the rights of people who need them. This paper argues that the drug conventions' prioritization of criminal justice measures-including efforts to prevent non medical use of controlled substances-undermines access to medicines and infringes upon the right to health and the right to enjoy the benefits of scientific progress. While the effects of criminalization under drug policy limit the right to health in multiple ways, we draw on research and documented examples to highlight the impact of drug control and criminalization on access to medicines. The prioritization and protection of human rights-specifically the right to health and the right to enjoy the benefits of scientific progress-are critical to rebalancing drug policy. PMID- 28630559 TI - Drug Policy and Indigenous Peoples. AB - This paper identifies the principal concerns of indigenous peoples with regard to current international treaties on certain psychoactive substances and policies to control and eradicate their production, trafficking, and sale. Indigenous peoples have a specific interest in the issue since their traditional lands have become integrated over time into the large-scale production of coca, opium poppy, and cannabis crops, in response to high demand from the American and European markets, among others. As a consequence, indigenous peoples are persecuted because of their traditional use of these and other plant-based narcotics and hallucinogens. They are also victims of the drug producers who remove them from their lands or forcibly recruit them into the production process. As indigenous peoples are caught in the violent world of illicit drug production, law enforcement often targets them first, resulting in disproportionate rates of criminalization and incarceration. PMID- 28630560 TI - Mechanisms of Accountability for the Realization of the Right to Health in China. AB - China ratified the International Covenant on Economic, Social and Cultural Rights in 2001. It thus bears obligations under Article 12 of the covenant to take appropriate measures at the domestic level to realize the right to health in China. Accountability is an important component of the right to health. This article examines whether the Western concept of accountability, recently imported into China, has the potential to improve the protection of the right to health within China's existing political, legal, and cultural framework. In so doing, it reviews current Chinese institutional mechanisms and considers the use of less formal mechanisms by which duty-bearers might be held accountable in China. More specifically, this article provides an overview of a range of health-related accountability mechanisms, including judicial, political, administrative, professional, and social accountability arrangements. It concludes that although there is the basis of an accountability framework for the right to health in China, the effective operation of accountability mechanisms is hindered by longstanding cultural and political barriers. PMID- 28630561 TI - Human Rights in the World Health Organization: Views of the Director-General Candidates. AB - Before the 2017 election of the Director-General of WHO, and given the importance of human rights to global health governance through WHO, Health and Human Rights asked the three final candidates for their views on human rights, WHO's human rights mandate, and the role of human rights in WHO programming. These questions were developed by the author in collaboration with Audrey Chapman, Lisa Forman, Paul Hunt, Dainius Puras, Javier Vasquez and Carmel Williams. Based on responses to these questions from each of the three candidates, this Perspective was originally published online on April 26, 2017. On May 23, 2017, Dr Tedros Adhanom Ghebreyesus was elected Director-General and will begin his five-year term on July 1, 2017. PMID- 28630562 TI - UNstoppable: How Advocates Persevered in the Fight for Justice for Haitian Cholera Victims. PMID- 28630563 TI - Human Rights, TB, Legislation, and Jurisprudence. PMID- 28630564 TI - CathROB: A Highly Compact and Versatile Remote Catheter Navigation System. AB - Several remote catheter navigation systems have been developed and are now commercially available. However, these systems typically require specialized catheters or equipment, as well as time-consuming operations for the system set up. In this paper, we present CathROB, a highly compact and versatile robotic system for remote navigation of standard tip-steerable electrophysiology (EP) catheters. Key features of CathROB include an extremely compact design that minimizes encumbrance and time for system set-up in a standard cath lab, a force sensing mechanism, an intuitive command interface, and functions for automatic catheter navigation and repositioning. We report in vitro and in vivo animal evaluation of CathROB. In vitro results showed good accuracy in remote catheter navigation and automatic repositioning (1.5 +/- 0.6 mm for the left-side targets, 1.7 +/- 0.4 mm for the right-side targets). Adequate tissue contact was achieved with remote navigation in vivo. There were no adverse events, including absence of cardiac perforation or cardiac damage, indicative of the safety profile of CathROB. Although further preclinical and clinical studies are required, the presented CathROB system seems to be a promising solution for an affordable and easy-to-use remote catheter navigation. PMID- 28630565 TI - Efficacy of Various Scoring Systems for Predicting the 28-Day Survival Rate among Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease Requiring Emergency Intensive Care. AB - We aimed to investigate the efficacy of four severity-of-disease scoring systems in predicting the 28-day survival rate among patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) requiring emergency care. Clinical data of patients with AECOPD who required emergency care were recorded over 2 years. APACHE II, SAPS II, SOFA, and MEDS scores were calculated from severity-of disease indicators recorded at admission and compared between patients who died within 28 days of admission (death group; 46 patients) and those who did not (survival group; 336 patients). Compared to the survival group, the death group had a significantly higher GCS score, frequency of comorbidities including hypertension and heart failure, and age (P < 0.05 for all). With all four systems, scores of age, gender, renal inadequacy, hypertension, coronary heart disease, heart failure, arrhythmia, anemia, fracture leading to bedridden status, tumor, and the GCS were significantly higher in the death group than the survival group. The prediction efficacy of the APACHE II and SAPS II scores was 88.4%. The survival rates did not differ significantly between APACHE II and SAPS II (P = 1.519). Our results may guide triage for early identification of critically ill patients with AECOPD in the emergency department. PMID- 28630566 TI - The Global Lung Function Initiative 2012 Equations Are as Well-Suited as Local Population Derived Equations to a Sample of Healthy Professional Firefighters. AB - BACKGROUND AND OBJECTIVE: We aimed to assess the validity of using the Global Lung Function Initiative's (GLI) 2012 equations to interpret lung function data in a healthy workforce of South Australian Metropolitan Fire Service (SAMFS) personnel. METHODS: Spirometry data from 212 healthy, nonsmoking SAMFS firefighters were collected and predicted normal values were calculated using both the GLI and local population derived (Gore) equations for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC. Two tailed paired sample Student's t-tests, Bland-Altman assessments of agreement, and z-scores were used to compare the two prediction methods. RESULTS: The equations showed good agreement for mean predicted FEV1, FVC, and FEV1/FVC. Mean z-scores were similar for FEV1 and FVC, although not FEV1/FVC, but greater than 0.5. Differences between the calculated lower limits of normal (LLN) were significant (p < 0.01), clinically meaningful, and resulted in an 8% difference in classification of abnormality using the FEV1/FVC ratio. CONCLUSIONS: The GLI equations predicted similar lung function as population-specific equations and resulted in a lower incidence of obstruction in this sample of healthy SAMFS firefighters. Further, interpretation of spirometry data as abnormal should be based on both an FEV1 and FEV1/FVC ratio < LLN. PMID- 28630567 TI - A Clinical Prospective Observational Cohort Study on the Prevalence and Primary Diagnostic Accuracy of Occult Vertebral Fractures in Aged Women with Acute Lower Back Pain Using Magnetic Resonance Imaging. AB - BACKGROUND: Elderly female patients complaints of acute low back pain (LBP) may involve vertebral fracture (VF), among which occult VF (OVF: early-stage VF without any morphological change) is often missed to be detected by primary X-ray examination. The current study aimed to investigate the prevalence of VF and OVF and the diagnostic accuracy of the initial X-ray in detecting OVF. METHOD: Subjects were elderly women (>70 years old) complaining of acute LBP with an accurate onset date. Subjects underwent lumbar X-ray, magnetic resonance imaging (MRI), and bone mineral density (BMD) measurement at their first visit. The distribution of radiological findings from X-ray and magnetic resonance imaging (MRI) as well as the calculation of the prevalence of VF and OVF are investigated. RESULTS: The prevalence of VF among elderly women with LBP was 76.5% and L1 was the most commonly injured level. Among VF cases, the prevalence of OVF was 33.3%. Furthermore, osteoporotic patients tend to show increased prevalence of VF (87.5%). The predictive values in detecting VF on the initial plain X-ray were as follows: sensitivity, 51.3%; specificity, 75.0%; and accuracy rate, 56.7%. CONCLUSIONS: Acute LBP patients may suffer vertebral injury with almost no morphologic change in X-ray, which can be detected using MRI. PMID- 28630568 TI - The Effects of a Self-Efficacy Intervention on Exercise Behavior of Fitness Club Members in 52 Weeks and Long-Term Relationships of Transtheoretical Model Constructs. AB - The transtheoretical model of behavior change (TTM) is often used to understand changes in health-related behavior, like exercise. Exercise behavior in fitness clubs is an understudied topic, but preliminary studies showed low frequencies and large numbers of drop-out. An initial 12-week self-efficacy intervention reported significant effects on exercise behavior. The objective of this follow up study is testing effects on exercise behavior over 52 weeks and the long-term relationships of all TTM constructs. In total 122 participants (Mage 42.02 yr.; SD 12.29; 67% females) were recruited and randomly assigned to group 1 (control), group 2 (self-set activities) and group 3 (self-set goals coaching). All participants were monitored 52-weeks. Measurements at baseline, 4, 8, 12, 26 and 52 weeks, using validated scales for stages of change, self-efficacy, decisional balance and processes of change. Exercise behavior and drop-outs were registered. An ANOVA revealed that group 3 significantly (p < 0.05) differed in exercise sessions from group 1 and 2 during the 12 weeks. A chi-square test indicated significant differences for continuing exercising after the intervention: 7 of group 1; 6 of group 2; 19 of group 3. In total 5 demonstrated regular exercise behavior at 26 weeks, and 3 at 52 weeks. Self-efficacy, decisional balance, and processes of change showed limited long-term changes over the later stages of change. At all measurements, participants reported more pros than cons and used more behavioral than cognitive processes. Exercise behavior of members in fitness clubs demonstrated dramatic developments in 52 weeks. The frequencies of sessions were so low that health effects will be minimal. The integrative character of the TTM appears to be weak; the data indicated limited relationships. More research is needed to understand exercise behavior and define optimal strategies to increase exercise attendance and decrease drop-outs in the long term. PMID- 28630569 TI - Leadership Preferences of Adolescent Players in Sport: Influence of Coach Gender. AB - The authors investigated the coaching behavior preferences and the relationships of these preferences with variables such as gender, type of sport, playing experience, competitive level, and coach gender among young athletes in the national badminton league. Participants were 167 elementary and high school badminton players (91 girls and 76 boys; age range = 9-18 years; M = 13.5 (SD = 2.22) years) competing in the badminton event of a national league. Players' preferences for coaching behavior were measured using athlete preference version of the LSS to evaluate the five dimensions of leadership behavior in a sporting context. Notably, young athletes strongly preferred training and instruction, followed by positive feedback, democratic behavior, social support, and autocratic behavior. An interaction effect of athlete and coach gender on the leadership dimensions of democratic behavior, autocratic behavior, and social support was found. Male athletes with female coaches preferred more democratic behavior, autocratic behavior, and social support behavior than did those with male coaches. Conversely, female players with male coaches favored more democratic behavior, autocratic behavior, and social support than did those with female coaches. This study provides valuable insight into understanding the dynamics of sport leadership environments among young athletes, and how crucial is the role of coach's gender in the athlete-coach dyad interaction. PMID- 28630570 TI - Contralateral Effects After Unilateral Strength Training: A Meta-Analysis Comparing Training Loads. AB - There is solid evidence on the cross-training phenomenon, but the training load required to achieve it has yet to be established. The aim of this meta-analysis was to deduce which unilateral strength training load (duration, frequency, intensity, rest and type) would enable the biggest strength increases to be obtained in the inactive contralateral limb. The examined studies were limited to those written in the English language within the Web of Science, PubMed and SPORTDiscus databases. Ten of the 43 eligible studies were included, covering a total of 409 participants. The studies included in the meta-analysis showed a low risk of bias and had an estimated pooled effect size of 0.56 (95% CI from 0.34 to 0.78). Greater effect sizes were observed in lengthy protocols involving fast eccentric exercises using designs of 3 sets of 10 repetitions and a 2-minute rest time. Effect size did not relate to absolute volume, relative intensity, absolute duration and speed of execution. In conclusion, to optimize contralateral strength improvements, cross-training sessions should involve fast eccentric sets with moderate volumes and rest intervals. PMID- 28630571 TI - Predictive Variables of Half-Marathon Performance for Male Runners. AB - The aims of this study were to establish and validate various predictive equations of half-marathon performance. Seventy-eight half-marathon male runners participated in two different phases. Phase 1 (n = 48) was used to establish the equations for estimating half-marathon performance, and Phase 2 (n = 30) to validate these equations. Apart from half-marathon performance, training-related and anthropometric variables were recorded, and an incremental test on a treadmill was performed, in which physiological (VO2max, speed at the anaerobic threshold, peak speed) and biomechanical variables (contact and flight times, step length and step rate) were registered. In Phase 1, half-marathon performance could be predicted to 90.3% by variables related to training and anthropometry (Equation 1), 94.9% by physiological variables (Equation 2), 93.7% by biomechanical parameters (Equation 3) and 96.2% by a general equation (Equation 4). Using these equations, in Phase 2 the predicted time was significantly correlated with performance (r = 0.78, 0.92, 0.90 and 0.95, respectively). The proposed equations and their validation showed a high prediction of half-marathon performance in long distance male runners, considered from different approaches. Furthermore, they improved the prediction performance of previous studies, which makes them a highly practical application in the field of training and performance. PMID- 28630572 TI - The Role of a Relative Age Effect in the 7th International Children's Winter Games 2016 and the Influence of Biological Maturity Status on Selection. AB - The aim of this study was to analyse the role of a relative age effect (RAE) and to investigate the influence of biological maturity status on the RAE at the 7th International Children's Winter Games. The birth dates of all 572 participants (365 males, 207 females) were analysed, and the biological maturity status of 384 athletes (243 males, 141 females) was assessed by the age at peak height velocity (APHV) method. A RAE was present in the total sample (chi2 = 67.81; p < 0.001), and among both male (chi2 = 49.02; p < 0.001) and female athletes (chi2 = 37.00; p < 0.001) as well as for strength- (chi2 = 56.46; p < 0.001), endurance- (chi2 = 20.48; p = 0.039) and technique-related types of sports (chi2 = 20.48; p = 0.041). No significant differences in biological maturity status were present between the male athletes of single relative age quarters. Among the female athletes a significant difference was present (F = 5.94, p < 0.001); relatively younger female athletes had significantly lower values in the APHV, which indicated that they were maturing earlier. However, when dividing the athletes into normal, early and late maturing athletes, it could be seen that among the relatively younger athletes, hardly any late maturing athletes were present. These findings revealed that relatively younger athletes seemed to only have a chance for selection if they were early maturing, whereas relatively older athletes had an increased likelihood for selection independent of their biological maturity status. In the future, the relative age and the biological maturity status should be considered in the talent development system for various types of winter sport, to contribute to more fairness and to not discriminate against relatively younger and less mature athletes. PMID- 28630573 TI - Effects of Suspended Moxibustion on Delayed Onset Muscle Soreness: A Randomized Controlled Double-Blind Pilot Study. AB - The objective of this study was to investigate the effects of suspended moxibustion upon tender point on delayed onset muscle soreness. The study was a randomized double-blind controlled trial with 50 subjects in each group. Subjects in moxibustion group received suspended moxibustion upon tender point (by palpation) twice. The controls received no treatment. Each subject received treatments twice, 24 hr and 48 hr after the delayed onset muscle soreness induction. The measurements of Pain Visual Analog Scale, maximum isometric muscle strength and circumference were made immediately after delayed onset muscle soreness induction, before and after every treatment session and 72 hr after delayed onset muscle soreness induction. There were no significantly statistical differences between two groups at all measurement time points on maximum isometric muscle strength and circumference. However, the Pain Visual Analog Scale scores after first treatment session and 72 hr after delayed onset muscle soreness induction in moxibustion group was less than the control group, with significant difference (p < 0.05). The suspended moxibustion failed to show the effect on delayed onset muscle soreness. However, results need to be cautiously interpreted because of the pilot character of this study. The suspended moxibustion has a potential effect of pain relief on DOMS from the analysis of the data of this study. A large sample size trial is needed to confirm the effect of the suspended moxibustion on DOMS in the future. PMID- 28630574 TI - Unilateral Rolling of the Foot did not Affect Non-Local Range of Motion or Balance. AB - Non-local or crossover (contralateral and non-stretched muscles) increases in range-of-motion (ROM) and balance have been reported following rolling of quadriceps, hamstrings and plantar flexors. Since there is limited information regarding plantar sole (foot) rolling effects, the objectives of this study were to determine if unilateral foot rolling would affect ipsilateral and contralateral measures of ROM and balance in young healthy adults. A randomized within-subject design was used to examine non-local effects of unilateral foot rolling on ipsilateral and contralateral limb ankle dorsiflexion ROM and a modified sit-and-reach-test (SRT). Static balance was also tested during a 30 s single leg stance test. Twelve participants performed three bouts of 60 s unilateral plantar sole rolling using a roller on the dominant foot with 60 s rest intervals between sets. ROM and balance measures were assessed in separate sessions at pre-intervention, immediately and 10 minutes post-intervention. To evaluate repeated measures effects, two SRT pre-tests were implemented. Results demonstrated that the second pre-test SRT was 6.6% higher than the first pre-test (p = 0.009, d = 1.91). There were no statistically significant effects of foot rolling on any measures immediately or 10 min post-test. To conclude, unilateral foot rolling did not produce statistically significant increases in ipsilateral or contralateral dorsiflexion or SRT ROM nor did it affect postural sway. Our statistically non-significant findings might be attributed to a lower degree of roller-induced afferent stimulation due to the smaller volume of myofascia and muscle compared to prior studies. Furthermore, ROM results from studies utilizing a single pre-test without a sufficient warm-up should be viewed critically. PMID- 28630575 TI - Acute and Post-Exercise Physiological Responses to High-Intensity Interval Training in Endurance and Sprint Athletes. AB - The purpose of the presented study was to compare acute and post-exercise differences in cardiorespiratory, metabolic, cardiac autonomic, inflammatory and muscle damage responses to high-intensity interval exercise (HIIT) between endurance and sprint athletes. The study group consisted of sixteen highly trained males (age 22.1 +/- 2.5 years) participating in endurance (n = 8) or sprint (n = 8) sporting events. All the participants underwent three exercise sessions: short HIIT (work interval duration 30s), long HIIT (3min) and constant load exercise (CE). The exercise interventions were matched for mean power, total time and in case of HIIT interventions also for work-to-relief ratio. The acute cardiorespiratory (HR, VO2, RER) and metabolic (lactate) variables as well as the post-exercise changes (up to 3 h) in the heart rate variability, inflammation (interleukin-6, leucocytes) and muscle damage (creatine kinase, myoglobin) were monitored. Endurance athletes performed exercise interventions with moderately (CE) or largely (both HIIT modes) higher mean VO2. These differences were trivial/small when VO2 was expressed as a percentage of VO2max. Moderately to largely lower RER and lactate values were found in endurance athletes. Markers of cardiac autonomic regulation, inflammation and muscle damage did not reveal any considerable differences between endurance and sprint athletes. In conclusions, endurance athletes were able to perform both HIIT formats with increased reliance on aerobic metabolic pathways although exercise intensity was identical in relative terms for all the participants. However, other markers of the acute and early post-exercise physiological response to these HIIT interventions indicated similarities between endurance and sprint athletes. PMID- 28630576 TI - No Effect of a Whey Growth Factor Extract during Resistance Training on Strength, Body Composition, or Hypertrophic Gene Expression in Resistance-Trained Young Men. AB - Growth factors can be isolated from bovine milk to form a whey growth factor extract (WGFE). This study examined whether WGFE promoted activation of the AKT/mTOR pathway enabling increased lean tissue mass and strength in resistance trained men. Forty six men with >6 months of resistance training (RT) experience performed 12 weeks of RT. Participants consumed 20 g/day of whey protein and were randomised to receive either 1.6 g WGFE/day (WGFE; n = 22) or 1.6 g cellulose/day (control, CONT; n = 24). The primary outcome was leg press one-repetition maximum (LP1-RM) which was assessed at baseline, 6 and 12 weeks. At baseline and 12 weeks body composition was assessed by dual energy x-ray absorptiometry, and muscle protein synthesis and gene expression were assessed (vastus lateralis biopsy) in a sub-sample (WGFE n = 10, CONT n = 10) pre- and 3 hr post-training. RT increased LP1-RM (+34.9%) and lean tissue mass (+2.3%; p < 0.05) with no difference between treatments (p > 0.48, treatment x time). Post-exercise P70s6k phosphorylation increased acutely, FOXO3a phosphorylation was unaltered. There were no differences in kinase signalling or gene expression between treatments. Compared with CONT, WGFE did not result in greater increases in lean tissue mass or strength in experienced resistance trained men. PMID- 28630577 TI - Effects of High Velocity Elastic Band versus Heavy Resistance Training on Hamstring Strength, Activation, and Sprint Running Performance. AB - Hamstring muscle injuries occur during high-speed activities, which suggests that muscular strength at high velocities may be more important than maximal strength. This study examined hamstring adaptations to training for maximal strength and for strength at high velocities. Physically active men (n = 25; age, 23.0 +/- 3.2 years) were randomly divided into: (1) a resistance training (RT, n = 8) group, which performed high-load, low-velocity concentric-eccentric hamstring contractions; (2) a resistance training concentric (RTC; n = 9) group, which performed high-load, low-velocity concentric-only hamstring contractions; and (3) a high-velocity elastic band training (HVT, n = 8) group, which performed low load, high-velocity concentric-eccentric hamstring contractions. Pre- and posttraining tests included hamstring strength on a hamstring-curl apparatus, concentric knee extension-flexion at 60 degrees /s, 240 degrees /s, and 450 degrees /s, eccentric knee flexion at 60 degrees /s and 240 degrees /s, hamstring and quadriceps coactivation, knee flexion and extension frequency in the prone position, and 30-m sprint running speed from a stationary start and with a running start. Knee flexor torque increased significantly by 21.1% +/- 8.1% in the RTC group and 16.2% +/- 4.2% in the RT group (p < 0.05 for both groups). Hamstring coactivation decreased significantly in both groups. In the HVT group, knee flexion and extension frequency increased by 17.8% +/- 8.2%, concentric peak torque of the knee flexors at 450 degrees /s increased by 31.0% +/- 12.0%, hamstring coactivation decreased, and running performance over 30 m improved (p < 0.05 for all parameters). These findings suggest that resistance training at high velocities is superior to traditional heavy resistance training for increasing knee flexor strength at high velocities, movement frequency, and sprint running performance. These findings also indicate that traditional training approaches are effective for increasing knee flexor strength and reducing knee extensor coactivation, but this outcome is limited to low and moderate speeds. PMID- 28630578 TI - Are Change of Direction Speed and Reactive Agility Useful for Determining the Optimal Field Position for Young Soccer Players? AB - Change Of Direction Speed (CODS) and Reactive Agility (RA) are two determining factors in the ability of young soccer players. We aimed to verify if CODS and RA could be useful in order to establish the best young soccer player field position. Ninety-two elite soccer players (15.18 +/- 1.21 years, weight 59.18 +/- 9.93, height 1.72 +/- 0.08, BMI 19.76 +/- 2.22), belonging to two youth categories from the Italian First and Second Divisions, volunteered in this study. The participants included 32 defenders (15.06 +/- 0.80 years), 37 midfielders (15.11 +/- 0.84 years) and 23 forwards (15.48 +/- 1.16 years), and they underwent two tests, each one performed in two different ways: the Y-Agility Test, carried out in a planned and reactive mode (Y-PLAN and Y-REAC), and the Illinois for Change of Direction Test (ICODT) performed with and without the ball. REAC-INDEX, which represents the index of reactivity, was calculated as Y REAC minus Y-PLAN. The difference between the two scores of ICODT (ICODT with the ball minus ICODT without the ball) represents the TECHN-INDEX. Multivariate Analysis of Variances (MANOVA) was used to evaluate significant differences among all position groups, for all the test scores. MANOVA showed no significant differences in test scores or in TECHN-INDEX among the groups, except for the forwards, who were significantly more reactive than the defenders (p < 0.05). The strong and significant Pearson's Correlation between ICODT with and without the ball (p < 0.01) demonstrated that physical and technical preparations have the same relevance in all positions. No significant differences were found among players in different field positions for CODS and RA performances, both with and without the ball. This study does not recommend to use RA and CODS as indicators to assign the players roles in youth soccer. PMID- 28630580 TI - The Effect of Upper Body Anaerobic Pre-Loading on 2000-m Ergometer-Rowing Performance in College Level Male Rowers. AB - Elevated blood lactate has been shown to influence subsequent anaerobic exercise due to an inhibition of glycolysis. The aim of the present study was therefore to investigate the influence of a short and high-intensity anaerobic arm crank pre load exercise (HIE) added to a low-intensity warm-up on cardio-respiratory and metabolic responses on a subsequent all out rowing exercise. Nine well-trained college level male rowers (24.6 +/- 7.1 yrs; 1.87 +/- 0.07 m; 88.9 +/- 9.8 kg; 18.5 +/- 3.7% body fat) volunteered to participate in the study. The subjects performed a maximal 2000-m rowing ergometer performance tests (MPT) twice. One MPT was preceded by a normal low intensity warm-up (MPTlow), while another one was performed with the additional inclusion of the HIE protocol (MPThigh). Overall rowing performance in the MPTlow was significantly faster (p = 0.004) by 3.7 +/- 2.8 sec compared to the MPThigh condition (401.7 +/- 23.0 s v. 405.4 +/- 23.3 s) but the reduction in speed was found only for the first 1000-m (p = 0.017). Net La increase from rest to the end of the MPTlow was 11.9 +/- 2.3 mmol.l-1 which was significantly higher (p = 0.0001) compared to the MPThigh condition (6.3 +/- 1.8 mmol.l-1). Carbon dioxide output was significantly lower in the second (p = 0.041), third (p = 0.009), fourth (p = 0.036) and fifth (p = 0.028) 250-m split in the MPThigh compared to the MPTlow test. In conclusion, HIE upper-body anaerobic pre-load added to a standard low intensity warm-up protocol decreased anaerobic performance only in the early stages of the MPThigh but the latter part was unaffected. The inhibition of glycolysis in the first minute of the workout might allow a different race strategy, which needs to be investigated in further studies. PMID- 28630579 TI - Effects of Exercise in the Fasted and Postprandial State on Interstitial Glucose in Hyperglycemic Individuals. AB - The purpose of the present study was to test if one bout of moderate exercise performed in either the fasted or the postprandial state affects glucose values measured over 22 hours. Twelve participants diagnosed with hyperglycemia not using antidiabetic medications underwent 3 test days in a randomized cross-over design encompassing one test day without exercise, one test day with 60 min of treadmill walking prior to breakfast, and one test day with an identical bout of exercise 30 min after the start of breakfast. Continuous glucose monitoring was performed until the next morning (>22 hours). There was no significant effect of type of test day on the area under the glucose curve for the entire 22 hours period (p = 0.111). None of the exercise interventions had a significant effect on the area under the glucose curve after breakfast, lunch or dinner. However, the postprandial exercise bout tended to decrease the area under the glucose curve after the evening meal compared to the fasted exercise bout (24.2 +/- 6.2 vs. 27.6 +/- 6.0 mmol.hour.L-1, p = 0.031). Furthermore, the postprandial exercise decreased the mean of the 10 highest glucose values measured in each individual (8.6 +/- 1.9 mmol.L-1) over 22 hours compared to both the control day (9.3 +/- 2.1 mmol.L-1) and the day with fasted exercise (9.6 +/- 1.7 mmol.L-1, p = 0.012 and 0.009 respectively). Postprandial exercise also decreased the glycemic variability compared to the control day (1.22 +/- 0.49 vs. 1.58 +/- 0.52 mmol.L-1, p = 0.015). We conclude that performing moderate exercise in the postprandial state after breakfast, but not in the fasted state, decreases glucose excursions during the subsequent 22 hours period in hyperglycemic individuals not using antidiabetic medications. PMID- 28630581 TI - 5000 Meter Run Performance is not Enhanced 24 Hrs After an Intense Exercise Bout and Cold Water Immersion. AB - Cold water immersion (CWI) is used by endurance athletes to speed recovery between exercise bouts, but little evidence is available on the effects of CWI on subsequent endurance performance. The purpose of this study was to investigate the effects of CWI following an acute bout of interval training on 5000 m run performance 24 hrs after interval training, perceived muscle soreness (PMS), range of motion (ROM), thigh circumference (TC), and perceived exertion (RPE). Nine endurance-trained males completed 2 trials, each consisting of an interval training session of 8 repetitions of 1200 m at a running pace equal to 75% of VO2peak, either a control or CWI treatment, and a timed 5000 m run 24 hrs post interval training session. CWI was performed for 12 min at 12 degrees Celsius on the legs. Recovery treatments were performed in a counterbalanced design. Run time for 5000 m was not different between the CWI and control trials (CWI = 1317.33 +/- 128.33 sec, control = 1303.44 +/- 105.53 sec; p = 0.48). PMS increased significantly from baseline to immediately post exercise (BL = 1.17 +/- 0.22, POST = 2.81 +/- 0.52; p = 0.02) and remained elevated from baseline to 24 hrs post exercise (POST24 = 2.19 +/- 0.32; p = 0.02), but no difference was observed between the treatments. No differences were observed for the interaction between time and treatment for TC (lambda = 0.73, p = 0.15) and ROM (lambda = 0.49; p = 0.10). CWI performed immediately following an interval training exercise bout did not enhance subsequent 5000 m run performance or reduce PMS. CWI may not provide a recovery or performance advantage when athletes are accustomed to the demands of the prior exercise bout. PMID- 28630582 TI - Doubly Disadvantaged? The Relative Age Effect in Poland's Basketball Players. AB - The aim of this study was to identify the relative age effect (RAE) in young Polish male (n = 3849) and female (n = 3419) basketball players aged 14 to 22 years competing in the elite games of the Polish Youth Championships. The distribution of birth dates, body height, players' match statistics, and the results of teams participating in championships were identified. The RAE was observed in male and female group, regardless of players age. Nevertheless, the greatest disproportion in the distribution of dates of birth was found in U16 group of boys (V = 0.25, p < 0.0001). Significant differences in body height were identified in U14 and U16 groups of boys (p < 0.0001) and U14 group of girls (p < 0.01). The RAE was the most detrimental in the group of boys from teams ranked 9th or lower (p < 0.0001). The groups of male and female basketball players from the top 3 teams had the highest average body height (p < 0.001). In U14 boys, significantly higher match results and performance index ratings (PIR) were observed for players born in the first half of a calendar year. The research results show the impact of the RAE on the success of youth basketball teams in Poland. The month of birth, body height and sex may determine sporting achievements in youth basketball. Coaches should consider the chronological age and pubertal growth acceleration (APHV-age at peak height velocity) of players to optimize the process of identifying gifted basketball players, especially among boys of 14 years of age. PMID- 28630583 TI - Acute Modification of Cardiac Autonomic Function of High-Intensity Interval Training in Collegiate Male Soccer Players with Different Chronotype: A Cross Over Study. AB - The purpose of this study was to evaluate if the time of the day (8.00 a.m. vs 8.00 p.m.) and chronotype could influence autonomic cardiac control in soccer players in relation to an acute session of high-intensity interval training. The morningness-eveningness questionnaire was administered to recruit Morning-type and Evening-type collegiate male soccer players. Therefore, 24 players (12 Morning-types and 12 Evening-types) were randomly assigned, to either morning (n = 12; age 23 +/- 3 years; height 1.75 +/- 0.07 m; body mass 73 +/- 10 kg; weekly training volume 8 2 hours), or evening (n = 12; age 21 +/- 3 years; height 1.76 +/- 0.05 m; body mass 75 +/- 11 kg; weekly training volume 8 +/- 3 hours) training. Heart Rate Variability vagal and sympatho/vagal indices were calculated in time, frequency and complexity domains at rest, before, after 12 and 24 hours of high-intensity interval training. Before evening training session, a higher resting heart rate was observed which was determined by a marked parasympathetic withdrawal with a sympathetic predominance. Moreover, Evening-type subjects during morning training session, present a significant higher heart rate that corresponded to significant higher vagal indices with a significant lower parasympathetic tone that returned to the rest values after 24 hours of the cessation of high-intensity interval training exercise. On the contrary, Morning type subjects did not reveal any significant differences with Evening-Type subjects during evening high-intensity interval training session. Stress response of high-intensity interval training is influenced by both the time of the day and by the chronotype. Understanding the Heart Rate Variability response to high intensity interval training can be an additional important procedure for evaluating of cardiovascular recovery in soccer players. Moreover, these results suggest that an athlete's chronotype should be taken into account when scheduling a high-intensity interval training exercise. PMID- 28630584 TI - Time-Loss Injuries in Sub-Elite and Emerging Rugby League Players. AB - This study aimed to 1) investigate the incidence and characteristics of injuries in emerging rugby league players; and 2) explore the differences in injury incidence and characteristics between the various sub-elite competitions. An NRL emerging player development squad (n = 34) was observed from the beginning of pre season until the finish of competition. Time-loss injury was defined as any physical pain or impairment sustained that resulted in players missing a match. Injuries were categorised according to circumstance, incidence, characteristics, playing position and competition level. Of a total of 196 injuries that were recorded, 45 were time-loss and 151 were transient. The total injury incidence was 7.9/1,000 playing hours. The most common sites for time-loss injuries were the shoulder, ankle/foot and knee. Ligament injuries accounted for the highest number of injuries by type. Forwards sustained the greatest number of injuries. However, backs suffered the greatest injury cost. The majority of time-loss injuries were sustained during competition matches. Injuries sustained during open age matches resulted in significantly higher injury cost to those received at NYC matches. NRL development and emerging rugby league players are exposed to high risk of injury. Lower limb and shoulder injuries to bone or connective tissue are prevalent as a result of contact during match play. Players at this developmental level feed into several different playing squads where disparities in physical development, maturation, playing intensity and training regimes are evident. This presents a challenge in matching physiological capabilities with playing demands for NRL development squads. PMID- 28630585 TI - Identification of the Plasmodium species in clinical samples from children residing in five epidemiological strata of malaria in Cameroon. AB - BACKGROUND: Malaria in Cameroon was previously known to be caused solely by Plasmodium falciparum but today, evidence points to other Plasmodium species including P. vivax, P. ovale and P. malariae. The purpose of this study was to identify the Plasmodium species in clinical samples from children residing in five epidemiological strata of malaria in Cameroon, so as to advise control policies. METHODS: One thousand six hundred nine febrile children (<=15 years) were recruited from five epidemiological strata of malaria including the Sudano sahelian (SS) strata, the High inland plateau (HIP) strata, the South Cameroonian Equatorial forest (SCEF) strata, the High western plateau (HWP) strata and the Coastal (C) strata. Malaria parasites were detected by Giemsa microscopy (GM) while a multiplex polymerase chain reaction (PCR) was used to identify the Plasmodium species. Statistical analysis performed included the Pearson chi square test, and statistical significance was set at p < 0.05. RESULTS: The PCR adjusted prevalence of malaria was 17.6%. The detection rate of PCR was higher than GM (p = 0.05). However, GM demonstrated a high sensitivity (85.5%) and specificity (100%) and, overall, a perfectly correlated agreement with PCR (97.5%). The prevalence of malaria was significantly higher in children between 60 and 119 months (p < 0.001) and in Limbe (in the Coastal strata) (p < 0.001). Contrariwise, the prevalence of malaria was not associated with gender (p = 0.239). P. falciparum was identified in all (100%) the cases of malaria; P. ovale, P. vivax, P. malariae and P. knowlesi were all absent. No case of mixed infection was identified. CONCLUSIONS: P. falciparum was the only species causing clinical malaria in the target population, which is contrary to studies that have reported P. vivax, P. malariae and P. ovale as causing clinical malaria in Cameroon. PMID- 28630586 TI - Surveillance efforts after mass drug administration to validate elimination of lymphatic filariasis as a public health problem in Vanuatu. AB - BACKGROUND: Vanuatu was formerly highly endemic for lymphatic filariasis (LF), caused by Wuchereria bancrofti and transmitted by Anopheles mosquitoes. After a baseline survey showing 4.8% antigen prevalence in 1998, the country conducted nationwide (in one implementation unit) annual mass drug administration (MDA) with albendazole and diethylcarbamazine citrate from 2000 to 2004 and achieved prevalence of 0.2% by 2006 in a representative nationwide cluster survey among all age groups. METHODS: Post MDA surveillance was conducted from 2006 to 2012. After MDA, the country was divided for surveillance into three evaluation units (EUs) formed by grouping provinces according to baseline prevalence: EU1: Torba, Sanma and Malampa; EU2: Penama; EU3: Shefa and Tafea. The study compiled all past data and information on surveys in Vanuatu from the country programme. This paper reviews the surveillance activities done after stopping MDA to validate the interruption of transmission and elimination of LF as a public health problem. RESULTS: Post-MDA surveillance consisting of at least three transmission assessment surveys (TAS) in each of the three EUs was conducted between 2006 and 2012. Sentinel and spot check surveys identified a few villages with persistent high prevalence; all antigen positive cases in these sites were treated and additional targeted MDA conducted for 3 years in 13 villages in one area of concern. All three EUs passed all TAS in 2007, 2010 and 2012 respectively, with no positives found except in EU2 (Penama province) in 2012 when 2 children tested positive for circulating filariasis antigen. Assessment of the burden of chronic filariasis morbidity found 95 cases in 2003 and 32 remaining cases in 2007, all aged over 60 years. CONCLUSIONS: Vanuatu has achieved validation of elimination of LF as a public health problem. Post-validation surveillance is still recommended especially in formerly highly endemic areas. PMID- 28630587 TI - The most common technologies and tools for functional genome analysis. AB - Since the sequence of the human genome is complete, the main issue is how to understand the information written in the DNA sequence. Despite numerous genome wide studies that have already been performed, the challenge to determine the function of genes, gene products, and also their interaction is still open. As changes in the human genome are highly likely to cause pathological conditions, functional analysis is vitally important for human health. For many years there have been a variety of technologies and tools used in functional genome analysis. However, only in the past decade there has been rapid revolutionizing progress and improvement in high-throughput methods, which are ranging from traditional real-time polymerase chain reaction to more complex systems, such as next generation sequencing or mass spectrometry. Furthermore, not only laboratory investigation, but also accurate bioinformatic analysis is required for reliable scientific results. These methods give an opportunity for accurate and comprehensive functional analysis that involves various fields of studies: genomics, epigenomics, proteomics, and interactomics. This is essential for filling the gaps in the knowledge about dynamic biological processes at both cellular and organismal level. However, each method has both advantages and limitations that should be taken into account before choosing the right method for particular research in order to ensure successful study. For this reason, the present review paper aims to describe the most frequent and widely-used methods for the comprehensive functional analysis. PMID- 28630588 TI - Testicular cancer in two brothers of a quadruplet: a case report and a review of literature. AB - Introduction. Testicular cancer and a multiple birth are both rare events, and the risk of testicular cancer is increased in twins. In Lithuania, only five quadruplets have been recorded since the middle of the 20th century. In this report, we present two rare events in one family: testicular cancer in two brothers of a quadruplet (three brothers and a sister). Case description. Both patients were diagnosed at 21 years of age and died within two years from the diagnosis despite treatment. The third symptomless brother did not have testicular pathology. We also review the risk factors associated with testicular cancer, and the proposed hypotheses how a multiple birth results in an increased risk. The most consistent risk factors for testicular cancer are cryptorchidism, prior history of testicular cancer, and a positive familial history. According to different studies, the risk of testicular cancer in twins is higher from 22% to 30%, compared to the general population. Conclusions. To our knowledge, we have presented the first case of testicular teratoblastoma in brothers of a quadruplet. PMID- 28630589 TI - Laparoscopic colorectal surgery for colorectal polyps: experience of ten years. AB - Background. Laparoscopy or its combination with endoscopy is the next step for "difficult" polyps. The purpose of the paper was to review the outcomes of the laparoscopic approach to the management of "difficult" colorectal polyps. Materials and methods. From 2006 to 2016, 58 patients who underwent laparoscopic treatment for "difficult" polyps that could not be treated by endoscopy at the National Cancer Institute, Lithuania, were included. The demographic data, the type of surgery, length of post-operative stay, complications, and final pathology were reviewed prospectively. Results. The mean patient was 65.9 +/- 8.9 years of age. Laparoscopic mobilization of the colonic segment and colotomy with removal of the polyp was performed in 15 (25.9%) patients, laparoscopic segmental bowel resection in 41 (70.7%) cases: anterior rectal resection with partial total mesorectal excision in 18 (31.0%), sigmoid resection in nine (15.5%), left hemicolectomy in seven (12.1%), right hemicolectomies in two (3.4%), ileocecal resection in two (3.4%), resection of transverse colon in two (3.4%), and sigmoid resection with transanal retrieval of specimen in one (1.7%). Two patients (3.4%) underwent laparoscopic-assisted endoscopic polypectomy. The mean post-operative hospital stay was 5.7 +/- 2.4 days. There were four complications (6.9%). All patients recovered after conservative treatment. The mean polyp size was 3.5 +/- 1.9 cm. Final histopathology revealed hyperplastic polyps (n = 2), tubular adenoma (n = 9), tubulovillous adenoma (n = 31), carcinoma in situ (n = 12), and invasive cancer (n = 4). Conclusions. For the management of endoscopically unresectable polyps, laparoscopic surgery is currently the technique of choice. PMID- 28630590 TI - Analysis of prognostic factors for melanoma patients. AB - Introduction. Melanoma is the most dangerous form of skin cancer. Morbidity from melanoma is increasing every year. Previous studies have revealed that there are some demographic and clinical factors having effect on melanoma survival prognosis. Aim of the study. Purpose of our study was to assess melanoma survival depending on prognostic factors, such as age, sex, stage, depth, histology and anatomical site. Materials and methods. We investigated melanoma-specific survival up to 10 years in 85 primary cases of melanoma from diagnosis at the National Cancer Institute in 2006. Analysis was performed for one-, five-, and ten-year survival. The data were processed with Microsoft Excel, data analysis was conducted using SPSS(r) software. Results. Melanomas diagnosed at stage IV or thicker than 4.00 mm had lower survival (five-year survival: 12.5% and 26.66%, respectively). A significant survival difference was observed among the different stages (p = 0.003) and different depths (p = 0.049) of melanoma. Ten-year survival was 32% for men and 61% for women, but melanoma-specific survival dependent on sex did not have a statistically significant difference (p = 0.121). In persons diagnosed at the age of 65 or older, ten-year survival was lower than in those of 40-64 years of age and in the age group of 15-39 years (44.44% and 26.66%, respectively), but melanoma-specific survival in different age groups did not have a statistically significant difference (p = 0.455). Back/breast skin melanoma had lower ten-year survival (37.03%) than other anatomic sites. Nodular melanoma had the poorest five-year and ten-year melanoma-specific survival among histological subtypes (51.67% and 38.75%). The differences between melanoma localizations (p = 0.457) and histological types (p = 0.364) were not statistically significant. Conclusions. Lower melanoma-specific survival rates were observed among patients diagnosed at a late stage, older age, and when melanomas were thicker than 4.00 mm. Female and younger patients had better melanoma-specific survival than men and older people, and these differences were statistically significant. Melanoma diagnosed at an early stage and of a small depth had higher survival rates. Back/breast skin melanoma had poorer prognosis than other anatomic sites. Nodular melanoma had the lowest melanoma-specific survival, while superficial spreading or lentigo maligna had the best prognosis among histological subtypes. However, differences in melanoma survival in different sex and age groups, localizations and histological types were not statistically significant. PMID- 28630591 TI - ? AB - THE ASSOCIATION BETWEEN THE NOTCH SIGNALING PATHWAY AND GYNAECOLOGICAL MALIGNANCIES: Background. The body's cell behaviour is controlled by various signalling pathways, one of which is NOTCH. It has been found that a partial loss of the NOTCH function or abnormal strengthening of NOTCH signalling are related to various human diseases and developmental disorders. Materials and methods. PubMed was the main source of information for this paper. Results. The paper overviews the association between oncologic diseases and the participants of the NOTCH signalling pathway. In cancerogenesis, the NOTCH signalling pathway can act as a tumour suppressor or an oncogene. The mechanisms of such an effect are yet unknown. The NOTCH signalling pathway is an object of active research because its modulation by pharmacological and genetic approaches could be helpful in discovering new treatment methods of tumours. In this review more attention is paid to gynaecological malignancies, especially to uterine cancer. Conclusions. The findings of recently published studies show that the NOTCH signalling pathway is definitely important for the development of uterine cancer, therefore its components can be potential prognostic biomarkers and molecular therapeutic targets. However, further studies in this field are needed in order to clarify the role of the components of the NOTCH signalling pathway and their interaction with participants of other signalling pathways, which can be important in the development and progression of uterine cancer as well. Keywords: NOTCH signalling pathway, cancer, gynaecological malignancies. PMID- 28630592 TI - The role of different PI-RADS versions in prostate multiparametric magnetic resonance tomography assessment. AB - Background. Standardised Prostate Imaging Reporting and Data System (PI-RADS) guidelines for the assessment of prostate alterations were designed for the assessment of prostate pathology. Published by the ESUR in 2012, PI-RADS v1 was based on the total score of different MRI sequences with subsequent calculation. PI-RADS v2 was published by the American College of Radiology in 2015 and featured different assessment criteria for prostate peripheral and transitory zones. Aim. To assess the correlations of PI-RADS v1 and PI-RADS v2 with Gleason score values and to define their predictive values of the diagnosis of prostate cancer. Materials and methods. A retrospective analysis of 66 patients. Prostate specific antigen (PSA) value and the Gleason score (GS) were assessed. One the most malignant focal lesion was selected in the peripheral zone of each lobe of the prostate (91 in total). Statistical analysis was carried out applying SPSS software, v.23, p < 0.05. Results. Focal lesions assessed by PI-RADS v1 score: 10% - 1, 12% - 2, 41% - 3, 23% - 4, 14% - 5. Assessment applying PI-RADS v.2: 20% - 1, 7.5% - 2, 26%, 29.5%, and 17% were assessed by 3, 4, and 5 scores. Statistically relevant correlation was found only between GS and PI-RADS (p = 0.033). The positive predictive value of both versions of PI-RADS - 75%, negative predictive value of PI-RADS v1 - 46%, PI-RADS v2 - 43%. Conclusions. PI-RADS v1 was more statistically relevant in assessing the grade of tumour. Prediction values were similar in both versions. PMID- 28630593 TI - ? AB - HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS A LITERATURE REVIEW: Hemophagocytic lymphohistiocytosis is an immune dysregulatory syndrome that is associated with alteration in the immune response activation and inhibition balance. There are two basic forms of the syndrome: primary (genetic or familial) determined by genes mutations involved in immune cell interactions, and secondary or sporadic developing as a result of an infectious process. The exact genetic background of the secondary form is still unknown. These forms are characterized by same combination of specific hyperinflammatory reactions and clinical signs and symptoms. Discrimination between primary and secondary forms is often challenging due to the rarity of the pathology, a wide spectrum of clinical signs, and limited availability of specific tests. Etiopathogenetic treatment of the primary form is an urgent allogeneic hematopoietic stem cell transplantation, otherwise a fatal outcome is inevitable. Meanwhile, the approach to the secondary form depends on the clinical manifestation and the type of the infectious trigger. To rescue the patient, a timely diagnosis is crucial for prompt administration of appropriate treatment. Treatment of hemophagocytic lymphohistiocytosis is complicated by the high incidence of treatment-related mortality and the propensity to relapse. Keywords: hemophagocytis lymphohistiocytosis, immunodeficiency, diagnostic criteria. PMID- 28630594 TI - Individual Meaning-Centered Psychotherapy for palliative cancer patients in Lithuania. A case report. AB - Patients with oncological diseases, especially palliative care patients, suffer from physical and psychological difficulties. The quality of life of such patients is bad, they do not have purpose to live and they feel anxiety and distress. In 1959 Victor Frankl wrote the book Man's Search for Meaning in which he stated that the driving force of human life lay in the ability to discern the meaning of faith and spirituality. Inspired by Frankl's ideas, the American psychiatrist William Breitbart with colleagues have developed both an individual and group model of Meaning-Centered Psychotherapy. Studies show that this therapy helps patients to cope with distress, to discover the meaning of life in palliative care patients, and to find the strength to look at life positively; also, it relieves the symptoms of illness. The Meaning-Centered Psychotherapy is integrated in various countries and has recently been initiated for palliative patients in Lithuania. The individual Meaning-Centered Psychotherapy was used in the case reviewed in this paper. PMID- 28630595 TI - QSAR models of human data can enrich or replace LLNA testing for human skin sensitization. AB - Skin sensitization is a major environmental and occupational health hazard. Although many chemicals have been evaluated in humans, there have been no efforts to model these data to date. We have compiled, curated, analyzed, and compared the available human and LLNA data. Using these data, we have developed reliable computational models and applied them for virtual screening of chemical libraries to identify putative skin sensitizers. The overall concordance between murine LLNA and human skin sensitization responses for a set of 135 unique chemicals was low (R = 28-43%), although several chemical classes had high concordance. We have succeeded to develop predictive QSAR models of all available human data with the external correct classification rate of 71%. A consensus model integrating concordant QSAR predictions and LLNA results afforded a higher CCR of 82% but at the expense of the reduced external dataset coverage (52%). We used the developed QSAR models for virtual screening of CosIng database and identified 1061 putative skin sensitizers; for seventeen of these compounds, we found published evidence of their skin sensitization effects. Models reported herein provide more accurate alternative to LLNA testing for human skin sensitization assessment across diverse chemical data. In addition, they can also be used to guide the structural optimization of toxic compounds to reduce their skin sensitization potential. PMID- 28630596 TI - Association between HMGB1 and asthma: a literature review. AB - BACKGROUND: Recently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders. Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated to airway hyper-responsiveness and airway inflammation. OBJECTIVE: This literature review aims to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma. METHODS: We reviewed experimental studies that investigated the pathogenetic role of HMGB in bronchial airway hyper-responsiveness, inflammation and the correlation between HMGB1 level and asthma. RESULTS: A total of 19 studies assessing the association between HMGB1 and asthma were identified. CONCLUSIONS: What emerged from this literature review was the confirmation of HMGB-1 involvement in diseases characterised by chronic inflammation, especially in pulmonary pathologies. Findings reported suggest a potential role of the alarmin in being a stadiation method and a marker of therapeutic efficacy; finally, inhibiting HMGB1 in humans in order to contrast inflammation should be the aim for future further studies. PMID- 28630597 TI - ? AB - [This corrects the article on p. 31 in vol. 28, PMID: 28337070.]. PMID- 28630598 TI - ? AB - [This corrects the article on p. 8 in vol. 28, PMID: 28337071.]. PMID- 28630599 TI - ? AB - [This corrects the article on p. 40 in vol. 28, PMID: 28337072.]. PMID- 28630600 TI - ? AB - [This corrects the article on p. 46 in vol. 28, PMID: 28344519.]. PMID- 28630602 TI - Comparing the Performance of Improved Classify-Analyze Approaches For Distal Outcomes in Latent Profile Analysis. AB - Several approaches are available for estimating the relationship of latent class membership to distal outcomes in latent profile analysis (LPA). A three-step approach is commonly used, but has problems with estimation bias and confidence interval coverage. Proposed improvements include the correction method of Bolck, Croon, and Hagenaars (BCH; 2004), Vermunt's (2010) maximum likelihood (ML) approach, and the inclusive three-step approach of Bray, Lanza, & Tan (2015). These methods have been studied in the related case of latent class analysis (LCA) with categorical indicators, but not as well studied for LPA with continuous indicators. We investigated the performance of these approaches in LPA with normally distributed indicators, under different conditions of distal outcome distribution, class measurement quality, relative latent class size, and strength of association between latent class and the distal outcome. The modified BCH implemented in Latent GOLD had excellent performance. The maximum likelihood and inclusive approaches were not robust to violations of distributional assumptions. These findings broadly agree with and extend the results presented by Bakk and Vermunt (2016) in the context of LCA with categorical indicators. PMID- 28630603 TI - Elevated IL-37 levels in the plasma of patients with severe coronary artery calcification. AB - BACKGROUND: Coronary artery calcification (CAC) is a predictor of cardiovascular events and plaque burden and is closely associated with chronic inflammation. Interleukin (IL)-37 is a newly discovered member of the IL-1 family and is considered an anti-inflammatory cytokine. Our recent study on mice indicated that IL-37 could attenuate atherosclerosis and vascular calcification, which suggests that IL-37 could be associated with the development of atherosclerosis and related diseases. The aim of this study was to investigate if IL-37 plays a role in the progression of CAC in patients. METHODS: Two hundred participants with suspected cardiovascular disease were recruited. The levels of plasma IL-37, osteoprotegerin (OPG), hypersensitive C-reactive protein (hsCRP) together with other biochemical parameters were measured, and a coronary calcium assessment was carried out by multi-detector row CT. A score of < 10 AU (Agatston units) denotes an absence of CAC, a score of 11-100 AU denotes mild CAC, 101-400 denotes moderate CAC, and > 400 AU denotes severe CAC. RESULTS: Our initial data showed that there were no apparent differences in plasma IL-37 levels among patients with or without mild or moderate CAC. However, IL-37 levels were significantly increased in patients with severe CAC (P < 0.001). Similar results were observed for plasma OPG and hsCRP levels. When IL-37 levels in patients with severe calcification were compared with that in all of the other non-severe CAC groups, it became apparent that there was a significant positive correlation between IL 37 level and severe CAC (r = 0.360, P < 0.001; OR = 1.033) using Spearman's correlation and binary logistic regression analysis. CONCLUSIONS: This study demonstrates that the anti-inflammatory cytokine IL-37 is associated with high coronary calcium levels, suggesting that IL-37 expression may be caused by the activation of inflammation and that IL-37 might become a predictor of severe CAC in the future, which requires further investigation. PMID- 28630601 TI - International society of sports nutrition position stand: diets and body composition. AB - Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature regarding the effects of diet types (macronutrient composition; eating styles) and their influence on body composition. The ISSN has concluded the following. 1) There is a multitude of diet types and eating styles, whereby numerous subtypes fall under each major dietary archetype. 2) All body composition assessment methods have strengths and limitations. 3) Diets primarily focused on fat loss are driven by a sustained caloric deficit. The higher the baseline body fat level, the more aggressively the caloric deficit may be imposed. Slower rates of weight loss can better preserve lean mass (LM) in leaner subjects. 4) Diets focused primarily on accruing LM are driven by a sustained caloric surplus to facilitate anabolic processes and support increasing resistance-training demands. The composition and magnitude of the surplus, as well as training status of the subjects can influence the nature of the gains. 5) A wide range of dietary approaches (low-fat to low-carbohydrate/ketogenic, and all points between) can be similarly effective for improving body composition. 6) Increasing dietary protein to levels significantly beyond current recommendations for athletic populations may result in improved body composition. Higher protein intakes (2.3-3.1 g/kg FFM) may be required to maximize muscle retention in lean, resistance-trained subjects under hypocaloric conditions. Emerging research on very high protein intakes (>3 g/kg) has demonstrated that the known thermic, satiating, and LM-preserving effects of dietary protein might be amplified in resistance-training subjects. 7) The collective body of intermittent caloric restriction research demonstrates no significant advantage over daily caloric restriction for improving body composition. 8) The long-term success of a diet depends upon compliance and suppression or circumvention of mitigating factors such as adaptive thermogenesis. 9) There is a paucity of research on women and older populations, as well as a wide range of untapped permutations of feeding frequency and macronutrient distribution at various energetic balances combined with training. Behavioral and lifestyle modification strategies are still poorly researched areas of weight management. PMID- 28630604 TI - Expression of p53 in myocardium following coronary microembolization in rats and its significance. AB - BACKGROUND: Cardiomyocyte apoptosis is a primary cause for coronary microembolization (CME)-induced cardiac dysfunction. p53 induces cell growth retardation and apoptosis through stress pathway. The present study investigated the mechanism of p53-induced myocardial apoptosis and cardiac dysfunction by activating the mitochondrion apoptotic pathway following CME. METHODS: Forty SD rats were equally divided into microembolization (CME), sham operation (sham), CME+siRNA-p53, and CME+control-p53 groups. The CME rat model was established by injecting microembolization spheres via the left ventricle. Cardiac ultrasound, TUNEL, fluorescence quantitative PCR, and Western blot were used to assess the cardiac function indicators, cardiomyocyte apoptosis, and the expressions of mRNA and protein in myocardial tissues, respectively. RESULTS: Echocardiography revealed a significantly reduced cardiac function of the CME group than the sham group while the CME-induced cardiac dysfunction was improved in the CME+siRNA-p53 group. The indicators of myocardial apoptosis in the CME group increased significantly than the sham group; those of the CME+siRNA-p53 group decreased significantly than the CME group. Fluorescence quantitative PCR and Western blot demonstrated that p53, Bbc3 (PUMA), and cleaved caspase-3 expressions were significantly increased, and BCL-2 expression was declined in myocardial tissues of the CME group compared to the sham group. A contrasting result was observed in the CME+siRNA-p53 group as compared to the CME group. CONCLUSIONS: P53 is involved in the CME-induced cardiac dysfunction, which may up-regulate Bbc3 to activate BCL-2/caspase3 mitochondrial apoptotic pathway and induce myocardial apoptosis. Inhibiting the p53 expression can effectively suppress this pathway, thereby reducing myocardial apoptosis and cardiac dysfunction. PMID- 28630605 TI - Xinfuli Granule improves post-myocardial infarction ventricular remodeling and myocardial fibrosis in rats by regulating TGF-beta/Smads signaling pathway. AB - BACKGROUND: Recent clinical and experimental studies have confirmed the effects of Xinfuli Granule (XG), a compound Chinese medicine in the prevention and treatment of heart failure (HF). This study aimed to investigate the effects and the mechanisms of XG on ventricular reconstruction in rats with acute myocardial infarction (AMI). METHODS: Sprague-Dawley rats were subjected to left anterior descending branch ligation. The rats that survived 24 h were randomly assigned to five groups: medium-dose of XG group (MI+XGM), high-dose of XG group (MI+XGH), carvedilol group (MI+C), medium-dose of XG + carvedilol group (MI+C+XGM). Fourteen rats underwent identical surgical procedures without artery ligation, serving as sham controls. At 28 days, left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW) were calculated; left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), left ventricular internal diameter at systole (LVIDS) were measured by ultrasound; HE staining, Masson staining, and Sirius red staining were used to assess the myocardial pathological and physiological changes as well as myocardial fibrosis area and non-infarct zone I/III collagen ratio. Expression of Smad3 were detected and analyzed by Western blot, immunohistochemistry and immunofluorescence. P-Smad3, Smad2 and Smad7 in the TGF-beta/Smads signaling pathway were also analyzed by Western blot. RESULTS: The LVIDS (P < 0.01), HW/BW (P < 0.05), type I/III collagen ratio (P < 0.01) and myocardial collagen (P < 0.01) decreased significantly while the LVW/BW, LVFS (P < 0.05) increased significantly in MI+XGM group as compared with those in other groups. The expression of key signal molecules of the TGF-beta/Smads signaling pathway, including Smad3, P-Smad3 and Smad2 protein were decreased, while the expression of Smad7 increased in both XG and carvedilol treatment groups as compared to those of the MI group (all P < 0.01). Immunohistochemistry and immunofluorescence further confirmed the down-regulated Smad3 expression. CONCLUSION: XG can improve ventricular reconstruction and inhibit myocardial fibrosis in rats with AMI by regulating TGF-beta/Smads signaling pathway. PMID- 28630607 TI - Definition of a plant-based diet and overview of this special issue. PMID- 28630608 TI - Introduction to the "A plant-based diet and cardiovascular disease" special issue. PMID- 28630606 TI - Clinical characteristics, target organ damage and associate risk factors of resistant hypertension determined by ambulatory blood pressure monitoring in patients aged >= 80 years. AB - OBJECTIVES: To investigate clinical characteristics, target organ damage, and the associated risk factors of the patients aged >= 80 years with true resistant hypertension (RH). METHODS: Patients aged >= 80 years with hypertension (n = 1163) were included in this study. The included participants attended a structured clinical examination and an evaluation of RH was carried out. The prevalence, clinical characteristics and target organ damage of patients with RH were assessed. The associated clinical risk factors were analyzed by using logistic regression. RESULTS: The prevalence of RH diagnosis by 24-h ambulatory blood pressure monitoring assessment was 21.15%. End-diastolic left ventricular internal dimension, left ventricular mass index as well as prevalence of left ventricular hypertrophy were significantly greater in patients with RH than in control group. The common carotid artery intimal media thickness, carotid walls thickness, common carotid artery diameter and relative wall thickness were significant greater in RH group than in control. A relatively higher level of creatinine, estimated glomerular filtration rate, microalbuminuria and retinal changes was found in RH group than in control. A multivariate analysis showed that patients with a history of diabetes, higher body mass index (BMI) and lipid profiles were independent risk factors of RH. CONCLUSIONS: The prevalence of RH in patients aged >= 80 years was within the range of reported rates of the general population. Subjects with RH diagnosis showed a higher occurrence of target organ damage than patients with well controlled blood pressure. Patients with diabetes, higher BMI and serum lipid profiles were independent risk factors for RH in patients aged >= 80 years. PMID- 28630609 TI - A plant-based diet and coronary artery disease: a mandate for effective therapy. PMID- 28630610 TI - A plant-based diet and stroke. PMID- 28630611 TI - A plant-based diet and hypertension. PMID- 28630612 TI - A plant-based diet and animal protein: questioning dietary fat and considering animal protein as the main cause of heart disease. PMID- 28630613 TI - Strategies for practitioners to support patients in plant-based eating. PMID- 28630614 TI - A plant-based diet for the prevention and treatment of type 2 diabetes. AB - The prevalence of type 2 diabetes is rising worldwide, especially in older adults. Diet and lifestyle, particularly plant-based diets, are effective tools for type 2 diabetes prevention and management. Plant-based diets are eating patterns that emphasize legumes, whole grains, vegetables, fruits, nuts, and seeds and discourage most or all animal products. Cohort studies strongly support the role of plant-based diets, and food and nutrient components of plant-based diets, in reducing the risk of type 2 diabetes. Evidence from observational and interventional studies demonstrates the benefits of plant-based diets in treating type 2 diabetes and reducing key diabetes-related macrovascular and microvascular complications. Optimal macronutrient ratios for preventing and treating type 2 diabetes are controversial; the focus should instead be on eating patterns and actual foods. However, the evidence does suggest that the type and source of carbohydrate (unrefined versus refined), fats (monounsaturated and polyunsaturated versus saturated and trans), and protein (plant versus animal) play a major role in the prevention and management of type 2 diabetes. Multiple potential mechanisms underlie the benefits of a plant-based diet in ameliorating insulin resistance, including promotion of a healthy body weight, increases in fiber and phytonutrients, food-microbiome interactions, and decreases in saturated fat, advanced glycation endproducts, nitrosamines, and heme iron. PMID- 28630616 TI - A plant-based diet for overweight and obesity prevention and treatment. AB - The goal of this paper is to review the evidence related to the effect of plant based dietary patterns on obesity and weight loss, including both observational and intervention trials. Literature from plant-based diets (PBDs) epidemiological and clinical trial research was used to inform this review. In addition, data on dietary quality, adherence, and acceptability were evaluated and are presented. Both clinical trials and observational research indicate an advantage to adoption of PBDs for preventing overweight and obesity and promoting weight loss. PBDs may also confer higher levels of diet quality than are observed with other therapeutic diet approaches, with similar levels of adherence and acceptability. Future studies should utilize health behavior theory to inform intervention development and delivery of PBDs studies and new technologies to bring interventions to scale for greater public health impact. Research examining PBDs and weight loss is also needed with more diverse populations, including older adults. Based on the available evidence, PBDs should be considered a viable option for the treatment and prevention of overweight and obesity. PMID- 28630615 TI - Plant-based nutrition for healthcare professionals: implementing diet as a primary modality in the prevention and treatment of chronic disease. AB - Cardiovascular disease remains the world's leading cause of death. Yet, we have known for decades that the vast majority of atherosclerosis and its subsequent morbidity and mortality are influenced predominantly by diet. This paper will describe a health-promoting whole food, plant-based diet; delineate macro- and micro-nutrition, emphasizing specific geriatric concerns; and offer guidance to physicians and other healthcare practitioners to support patients in successfully utilizing nutrition to improve their health. PMID- 28630617 TI - A plant-based diet and heart failure: case report and literature review. PMID- 28630618 TI - Perinatal effects of scorpion venoms: maternal and offspring development. AB - Scorpion envenomation is a public health problem, especially in tropical and subtropical countries. Considering the high incidence of scorpionism in some areas, pregnant women and nursing mothers may be possible victims. Scorpion stings alter the release of neurotransmitters and some cytokines. These mediators act as organizers and programmers in the adequate formation of the nerves, and non-physiological concentrations of them during the brain organization originate disorders and diseases that can appear later in the life of the individual. Despite the importance of this subject, there are only a few studies showing the effects of scorpion venom on maternal reproductive development, in the morphology and physical and behavioral development of offspring. The present review article summarizes the major findings on this issue. Biochemical changes in the blood - such as hyperglycemia, increase on the level of sodium and on the creatinine concentration - are observed after scorpion sting in humans and experimental animals. Some studies in the literature demonstrate that the scorpion venom affects the maternal reproductive development in humans and in experimental animals, increasing the frequency and amplitude of uterine contraction and the number of resorptions. The venom can also lead to some alterations in the embryonic or fetal development increasing the total weight of fetuses and of some organs. Moreover, it affects the general activity and locomotion during childhood and adulthood, and the anxiety level in adult females and males. It also alters the number of hippocampal neurons and interferes in the level of some cytokines. Altogether, it is evident that the venom, when administered during the pregnancy or lactation, affects the development of the offspring. Studies are being conducted to determine the actual participation of the venom in the development of the offspring, and to what extent they are detrimental to animal development. PMID- 28630619 TI - A Swarm Optimization Genetic Algorithm Based on Quantum-Behaved Particle Swarm Optimization. AB - Quantum-behaved particle swarm optimization (QPSO) algorithm is a variant of the traditional particle swarm optimization (PSO). The QPSO that was originally developed for continuous search spaces outperforms the traditional PSO in search ability. This paper analyzes the main factors that impact the search ability of QPSO and converts the particle movement formula to the mutation condition by introducing the rejection region, thus proposing a new binary algorithm, named swarm optimization genetic algorithm (SOGA), because it is more like genetic algorithm (GA) than PSO in form. SOGA has crossover and mutation operator as GA but does not need to set the crossover and mutation probability, so it has fewer parameters to control. The proposed algorithm was tested with several nonlinear high-dimension functions in the binary search space, and the results were compared with those from BPSO, BQPSO, and GA. The experimental results show that SOGA is distinctly superior to the other three algorithms in terms of solution accuracy and convergence. PMID- 28630620 TI - Cloud Model-Based Artificial Immune Network for Complex Optimization Problem. AB - This paper proposes an artificial immune network based on cloud model (AINet-CM) for complex function optimization problems. Three key immune operators-cloning, mutation, and suppression-are redesigned with the help of the cloud model. To be specific, an increasing half cloud-based cloning operator is used to adjust the dynamic clone multipliers of antibodies, an asymmetrical cloud-based mutation operator is used to control the adaptive evolution of antibodies, and a normal similarity cloud-based suppressor is used to keep the diversity of the antibody population. To quicken the searching convergence, a dynamic searching step length strategy is adopted. For comparative study, a series of numerical simulations are arranged between AINet-CM and the other three artificial immune systems, that is, opt-aiNet, IA-AIS, and AAIS-2S. Furthermore, two industrial applications-finite impulse response (FIR) filter design and proportional-integral-differential (PID) controller tuning-are investigated and the results demonstrate the potential searching capability and practical value of the proposed AINet-CM algorithm. PMID- 28630621 TI - Development of SNP Genotyping Assays for Seed Composition Traits in Soybean. AB - Seed composition is one of the most important determinants of the economic values in soybean. The quality and quantity of different seed components, such as oil, protein, and carbohydrates, are crucial ingredients in food, feed, and numerous industrial products. Soybean researchers have successfully developed and utilized a diverse set of molecular markers for seed trait improvement in soybean breeding programs. It is imperative to design and develop molecular assays that are accurate, robust, high-throughput, cost-effective, and available on a common genotyping platform. In the present study, we developed and validated KASP (Kompetitive allele-specific polymerase chain reaction) genotyping assays based on previously known functional mutant alleles for the seed composition traits, including fatty acids, oligosaccharides, trypsin inhibitor, and lipoxygenase. These assays were validated on mutant sources as well as mapping populations and precisely distinguish the homozygotes and heterozygotes of the mutant genes. With the obvious advantages, newly developed KASP assays in this study can substitute the genotyping assays that were previously developed for marker-assisted selection (MAS). The functional gene-based assay resource developed using common genotyping platform will be helpful to accelerate efforts to improve soybean seed composition traits. PMID- 28630622 TI - Bowel Ischemia in ICU Patients: Diagnostic Value of I-FABP Depends on the Interval to the Triggering Event. AB - BACKGROUND: Intestinal fatty acid-binding protein (I-FABP) has been shown to be of high diagnostic value in patients with acute mesenteric ischemia. Whether these results can be reproduced in critically ill patients on the ICU was to be investigated. MATERIALS AND METHODS: I-FABP was measured in serum and urine of 43 critically ill patients in ICU when mesenteric ischemia was suspected. Bowel ischemia was confirmed in 21 patients (group 1). 22 patients who survived at least seven days without confirmation of ischemia were assigned to group 2. I FABP levels were compared between the groups, and interval from the event that has triggered ischemia to I-FABP measurement was recorded. RESULTS: For the identification of patients with mesenteric ischemia, sensitivity, specificity, and area under the curve (AUC) for serum and urine I-FABP were 33.3%, 95.5%, and 0.565 and 81.3%, 70.0%, and 0.694, respectively. I-FABP measurements performed within 12 to 48 h after the event that triggered ischemia showed a sensitivity, specificity, and AUC for serum and urine of 75%, 100%, and 0.853 and 100%, 73.3%, and 0.856, respectively. CONCLUSIONS: In ICU patients, one single I-FABP measurement at the time of clinical suspicion failed to reliably detect or exclude mesenteric ischemia. A higher diagnostic value of I-FABP was only confirmed in the early stages of mesenteric ischemia. I-FABP may be used most appropriately in perioperative monitoring. PMID- 28630623 TI - Strategies for Preventing Endoscopic Recurrence of Crohn's Disease 1 Year after Surgery: A Network Meta-Analysis. AB - OBJECTIVE: To assess the benefits of different treatments that aim to prevent the endoscopic recurrence of Crohn's disease (CD) after ileal resection. METHODS: Randomized controlled trials (RCTs) were searched from MEDLINE, Embase, and the Cochrane Central Database. All the included RCTs with an endoscopic recurrence outcome which was defined as Rutgeerts' score >= i2 have a duration of more than 1 year. The quality of the included RCTs was assessed by the Cochrane Risk of Bias Tool. Pairwise treatment effects were estimated through a Bayesian random effects network meta-analysis by using the OpenBUGS 1.4 software and reported as odds ratios (ORs) with a 95% credible interval (CI). RESULTS: Fourteen RCTs (877 participants) were included. Two strategies were superior to placebo for preventing endoscopic recurrence of CD at 1 year after surgery: infliximab (d, 5.475; 95% CI, -10.47 to -1.632) and adalimumab (d, -7.273; 95% CI, -13.84 to 2.585). Nine strategies were not effective: budesnoid, mesalazine (in both high and low dose), azathioprine, Tripterygium wilfordii, mesalazine + infliximab, ornidazole, untreated intervention, and Lactobacillus GG. CONCLUSIONS: Except for infliximab and adalimumab, other strategies included in our analysis were not effective for preventing endoscopic recurrence of CD at 1 year after ileal resection. PMID- 28630624 TI - Evaluation of the Loading, Unloading, and Permanent Deformation of Newly Available Epoxy Resin Coated Ni-Ti Wires Using Self-Ligating Brackets. AB - AIM: The purpose of this study was to evaluate the load and unload deflection and permanent deformation of round 0.016'' and rectangular 0.016'' * 0.022'' regular and coated Ni-Ti wires. MATERIALS AND METHODS: Ni-Ti archwires produced by two manufacturers were evaluated. Both regular and coated round and rectangular Ni-Ti wire segments (n = 15) from each group were submitted to a three-point bending test. Both types of wires were evaluated for permanent deformation at the end of a recovery cycle. RESULTS: The coated round 0.016'' Ni-Ti wires produced a significantly lower force in loading (p < 0.01) and unloading (p < 0.01) than regular wires of the same manufacturer and size. There was no significant difference in permanent deformation between coated and regular round Ni-Ti wires from the same company. For rectangular 0.016 * 0.022'' Ni-Ti wires, there was a significant difference in the loading evaluation, but the unloading test presented no significant differences. The permanent deformation of the rectangular wires revealed no significant difference between them. CONCLUSION: The addition of an esthetic coating to these new Ni-Ti wires produced changes in their mechanical properties, manifested as a reduction in the applied force, which should be considered in clinical management. PMID- 28630625 TI - Quantification of Antioxidant Phenolic Compounds in a New Chrysanthemum Cultivar by High-Performance Liquid Chromatography with Diode Array Detection and Electrospray Ionization Mass Spectrometry. AB - The flowers of Chrysanthemum morifolium Ramat. have been used as an herbal tea and in traditional medicine, and the plant has been developed to produce horticultural cultivars of various colors and shapes. In this study, a new chrysanthemum cultivar with dark purple petals (C. morifolium cv. ARTI-Dark Chocolate; ADC) was developed by radiation-induced mutation breeding of its original cultivar with purple striped white petals (C. morifolium cv. Noble Wine, NW). The phenolic profile and antioxidant property of ADC were investigated and compared with NW and the commercially available medicinal herb, C. morifolium with yellow petals (CM), in order to find a scientific support to produce a new source of natural antioxidant. Flavonoid and phenolic acid profiles of the ethanol extracts of the three flowers were analyzed by high-performance liquid chromatography-diode array detector-electrospray ionization mass spectrometry (HPLC-DAD-ESIMS), while antioxidant properties were evaluated using the 1,1 diphenyl-2-picryl-hydrazyl (DPPH) and 2,2-azino-bis-3-ethylbenzothiazoline-6 sulfonic acid (ABTS) radical scavenging assay. Among the tested flowers, ADC possessed the strongest antioxidant capacity and the highest phenolic contents. Flavonoids (acacetin, apigenin, luteolin, acacetin-7-O-beta-glucoside, apigenin-7 O-beta-glucoside, luteolin-7-O-beta-glucoside, and linarin) and phenolic acids (chlorogenic acid and mixture of 1,4-, 1,5-, and 3,5-dicaffeoylquinic acids) were identified and quantified. PMID- 28630626 TI - Rapid and Selective Determination of Folate Receptor alpha with Sensitive Resonance Rayleigh Scattering Signal. AB - A rapid, simple, and novel method for folate receptor alpha (FRalpha) determination is reported here. A probe of gold nanoparticles (Au NPs) modified with anti-FRalpha antibody was synthesized under the optimized conditions first. The antibody-modified Au NPs would aggregate when FRalpha was added to the probe for the specific interaction between antibody and antigen, resulting in the enhancement of resonance Rayleigh scattering (RRS) intensity. There is a linear relationship between the change of RRS intensity (DeltaIRRS) and the concentration of FRalpha, with the detecting range of 0.50-37.50 ng.mL-1 and the limit of determination of 0.05 ng.mL-1. The determination of FRalpha in serum samples was realized with the advantages of high selectivity, high sensitivity, and easy operation. PMID- 28630627 TI - Changes in Polyphenols Contents and Antioxidant Capacities of Organically and Conventionally Cultivated Tomato (Solanum lycopersicum L.) Fruits during Ripening. AB - Polyphenols of fruits and vegetables form an important part of human dietary compounds. Relatively little is known about accumulation of phenolics during fruits ripening process. The goal of this work was to study the changes in antioxidant activity and in content of 30 polyphenols during ripening of tomato fruits. Five organically and conventionally grown tomato cultivars were investigated at three different ripening stages. Phenolic compounds were extracted with methanol and extracts were analyzed by HPLC-DAD-MS/MS. During ripening, four different changing patterns were observed: (1) high level in green fruits with minimal changes; (2) continuous increase with maximum level in red ripe fruits; (3) decrease; (4) increase and achieving maximum level at half-ripe stage. Similar change patterns were found for organic and conventional fruits. The accumulation patterns of phenolic compounds were similar in standard-type tomatoes but differed in several cases in cherry-type cultivar. Although contents of some polyphenols decreased during ripening, total phenolics and free radical scavenging activity increased in all studied cultivars and in case of both cultivation modes. The changes in content of phenolic compounds during ripening were greatly influenced by cultivars, but cultivation mode had only minor impact on dynamics in polyphenols contents in tomato fruits. PMID- 28630628 TI - Staphylococcus saprophyticus Recovered from Humans, Food, and Recreational Waters in Rio de Janeiro, Brazil. AB - Staphylococcus saprophyticus is an important agent of urinary tract infection (UTI) in young women, but information about this pathogen in human microbiota and in common environment is lacking. The aim of this study was to characterize S. saprophyticus isolates from genitoanal microbiota of 621 pregnant women, 10 minas cheese packs, and five beaches in Rio de Janeiro city and compare PFGE profiles of these isolates with five UTI PFGE clusters described in this city. We investigated 65 S. saprophyticus isolates from microbiota, 13 from minas cheese, and 30 from beaches and 32 UTI isolates. Antimicrobial resistance was determined by disk diffusion, MIC by agar dilution, and PCR. Erythromycin-resistance genes erm(C), msr(A), msr(B), mph(C), and lin(A) were found in 93% of isolates. Trimethoprim-sulfamethoxazole resistance correlated with dfrG or dfrA genes. Three cefoxitin-resistant isolates carried the mecA gene. All isolates obtained from cheese were susceptible to all antimicrobial agents. Six of 10 pregnant women with >1 isolate had monoclonal colonization. Isolates from pregnant women shared 100% similarity with UTI PFGE cluster types A and E obtained almost 10 years previously, suggesting temporal persistence of S. saprophyticus. Antimicrobial resistance of beach isolates reflected the profiles of human isolates. Taken together, results indicate a shared source for human and environmental isolates. PMID- 28630629 TI - The CEDAR Study: A Longitudinal Study of the Clinical Effects of Conventional DMARDs and Biologic DMARDs in Australian Rheumatology Practice. AB - OBJECTIVES: To observe the choices of conventional disease modifying antirheumatic drugs (cDMARDs) and biologic DMARDs (bDMARDs) in the management of rheumatoid arthritis (RA) in Australian routine clinical practice, to assess treatment survival and determine the effect of cDMARDs/bDMARDs on disease activity. METHODS: Routinely collected, deidentified clinical data was sourced from 20 Australian rheumatology practices. RA patients aged >=18 years, who had received cDMARDs/bDMARDs and a recorded subsequent visit, were included. A linear mixed model was used to determine the change over time and the percentage reduction in disease activity was summarized. RESULTS: 12,526 RA patients were included: 72% females, mean age 62 years. cDMARDs and bDMARDs were used in 92% and 30% of patients, respectively. The most commonly prescribed cDMARD was methotrexate (76% patients); median time to stopping treatment was 337 months [95% CI: 279-ND]. Etanercept was the most commonly prescribed bDMARD (12% patients); median time to stopping treatment was 79 months [95% CI: 57-93]. Of 5,341 patients with a first change in medication (cDMARD or bDMARD), 87% had therapy escalation and 13% deescalation. Reduction in DAS28-ESR, 6-month post DMARDs initiation ranged from 3%, adalimumab, to 14%, leflunomide and tocilizumab. CONCLUSIONS: In this large Australian cohort of unselected community RA patients, the choices of cDMARDs/bDMARDs are aligned with current international guidelines. PMID- 28630630 TI - Roles of Mesenchymal Stem Cells in Spinal Cord Injury. AB - Spinal cord injury (SCI) represents one of the most complicated and heterogeneous pathological processes of central nervous system (CNS) impairments, which is still beyond functional regeneration. Transplantation of mesenchymal stem cells (MSCs) has been shown to promote the repair of the injured spinal cord tissues in animal models, and therefore, there is much interest in the clinical use of these cells. However, many questions which are essential to improve the therapy effects remain unanswered. For instance, the functional roles and related molecular regulatory mechanisms of MSCs in vivo are not yet completely determined. It is important for transplanted cells to migrate into the injured tissue, to survive and undergo neural differentiation, or to play neural protection roles by various mechanisms after SCI. In this review, we will focus on some of the recent knowledge about the biological behavior and function of MSCs in SCI. Meanwhile, we highlight the function of biomaterials to direct the behavior of MSCs based on our series of work on silk fibroin biomaterials and attempt to emphasize combinational strategies such as tissue engineering for functional improvement of SCI. PMID- 28630631 TI - Urinalysis and Clinical Correlations in Patients with P. vivax or P. falciparum Malaria from Colombia. AB - BACKGROUND: Urinalysis is a poorly reviewed diagnostic tool in malaria patients; its application can show the presence of severe malaria. METHODS: Urinalysis was performed in a total of 620 patients diagnosed with malaria by thick blood smear; complications were classified according to WHO major criteria for severity and minor criteria according to the Colombian malaria guideline. RESULTS: Severe or moderate clinical complications were diagnosed in 31.1% of patients, hepatic dysfunctions were diagnosed in 25.8%, anemia was diagnosed in 9.8%, thrombocytopenia was diagnosed in 7.7%, renal dysfunction was diagnosed in 4.8%, neurological and pulmonary complications were diagnosed in 2.1% and 2.4%, hypoglycemia was diagnosed in 1.1% of patients with blood glucose analysis, and acidosis was diagnosed in 10 of 25. Bilirubinuria was found in 24.3%, associated with urobilinuria, proteinuria, and increased specific gravity; urobilinuria was found in 30.6% associated with elevated serum bilirubin and alanine aminotransferase; 39.2% had proteinuria, associated with higher blood urea nitrogen, serum bilirubin, aspartate, alanine-transaminase, hematuria, and increased specific gravity. Severe or moderate liver and renal complications were associated with proteinuria and bilirubinuria. Urobilinuria was associated with thrombocytopenia and neurological and hepatic dysfunction. Ketonuria was associated with neurological dysfunctions. CONCLUSIONS: The most frequent alterations in the urinalysis were bilirubinuria, proteinuria, urobilinuria, and increased specific gravity, related to thrombocytopenia and liver, kidney, and neurological alterations. PMID- 28630632 TI - Erchen Decoction and Linguizhugan Decoction Ameliorate Hepatic Insulin Resistance by Inhibiting IRS-1Ser307 Phosphorylation In Vivo and In Vitro. AB - Erchen decoction (ECD) and Linguizhugan decoction (LGZGD), both are Chinese herbal formula, have been used clinically for the treatment of nonalcoholic fatty liver disease (NAFLD). However, their therapeutic mechanisms are still unclear. Because insulin resistance (IR) is a key etiological factor in the pathology of high-fat diet- (HFD-) induced NAFLD, in this study, the protective effects of ECD and LGZGD on HFD-induced insulin resistance in rats were evaluated and their mechanisms were investigated by OGTT and Western blot. The results showed that treatment with ECD and LGZGD significantly improved insulin resistance and liver damage in rats, evidenced by supported serum aminotransferase levels and the histopathological examination. ECD and LGZGD also showed significant protective effects against HFD-induced hyperlipidemia and the inhibition of the hepatocyte proliferation by palmitate. Furthermore, supplementation of ECD and LGZGD decreased TNF-alpha, NF-kappaB, and IRS-1Ser307 phosphorylation expressions in vivo and in vitro. These results indicated that ECD and LGZGD have protective effects against HFD-induced liver IR and their underlying mechanisms involve the TNF-alpha and insulin pathway. These findings would be beneficial for understanding of the therapeutic effects of ECD and LGZGD in treatment of NAFLD. PMID- 28630634 TI - Moxibustion Alleviates Injury in a Rat Focal Segmental Glomerulosclerosis Model. AB - OBJECTIVES: To evaluate the therapeutic effects of moxibustion at Shenshu (BL-23) and Geshu (BL-17) acupoints in a focal segmental glomerulosclerosis (FSGS) model in rats. METHODS: A FSGS rat model was established by single nephrectomy and repeated injection of doxorubicin. The FSGS rats were randomly divided into the model group, losartan (positive control) group, Shenshu moxibustion group, and Geshu moxibustion group. Molecular indicators of kidney function and renal pathological changes were monitored. RESULTS: Urinary protein, serum creatinine, urea nitrogen, and serum uric acid were significantly reduced after 12-week intervention with losartan, Shenshu, or Geshu moxibustion. Renal alpha-SMA, FN, and TGF-beta were also decreased, while podocin and nephrin protein and mRNA were increased. The pathological damage in renal tissue was obviously alleviated by all three treatments, which suggests that moxibustion may have similar efficacy to losartan in the treatment of FSGS. CONCLUSION: Moxibustion alleviates podocyte injury and inhibits renal interstitial fibrosis in the FSGS rat model, thereby minimizing the progression of glomerular sclerosis and improving renal function. PMID- 28630633 TI - DJC Suppresses Advanced Glycation End Products-Induced JAK-STAT Signaling and ROS in Mesangial Cells. AB - The antidiabetic properties and anti-inflammatory effects of Danzhi Jiangtang Capsules (DJC) have been demonstrated in clinical and laboratory experiments. In this study, we explored whether DJC can ameliorate advanced glycation end products- (AGEs-) mediated cell injury and the precise mechanisms of DJC in treating diabetic nephropathy (DN). Western blot analysis was employed to assess the expressions of iNOS, COX2, and SOCS and the phosphorylation of JAK2, STAT1, and STAT3 in glomerular mesangial cells (GMCs) after treatment with DJC. TNF alpha, IL-6, and MCP-1 were determined using double-antibody sandwich ELISA. ROS and NADPH oxidase activity were measured by DCFH-DA assay and lucigenin-enhanced chemiluminescence, respectively. DJC significantly reversed the AGEs-induced expression of COX2 and iNOS. Moreover, DJC inhibited the AGEs-induced JAK2 STAT1/STAT3 activation, resulting in the inhibition of inflammatory cytokines such as IL-6, MCP-1, and TNF-alpha in a concentration-dependent manner. The ability of DJC to suppress STAT activation was also verified by the observation that DJC significantly increased the SOCS3 protein level. DJC reversed the AGEs induced accumulation of ROS and NADPH oxidase activity, thus confirming that DJC possesses antioxidant activity. The results suggest that the anti-inflammatory effects of DJC in GMCs may be due to its ability to suppress the JAK2-STAT1/STAT3 cascades and reduce ROS production. PMID- 28630635 TI - Effect of Abnormal Savda Munziq, a Traditional Uighur Herbal Medicine, on Pulmonary Function and Aquaporins of COPD Rat Model with Abnormal Savda Syndrome. AB - OBJECTIVE: To investigate the effect of abnormal savda munziq (ASM) on the pulmonary function and expression of lung-specific aquaporins in the rat model of chronic obstructive pulmonary disease with abnormal savda syndrome (ASSCOPD). METHODS: Eighty male rats were randomized into ASSCOPD, COPD, and control groups. ASSCOPD was further categorized into ASM and non-ASM groups. COPD model was established by combining fumigation with airway instillation of elastase; ASSCOPD model was developed based on COPD by induction with dry cold diet, cold dry environment, and plantar electric stimulation. ASM was administered twice daily. The pulmonary function was evaluated based on respiration. The mRNA and protein levels of AQPs were estimated by real-time PCR and Western blot, respectively. RESULTS: MV, TV, the mRNA level of AQP5, and the protein expression of AQP1, AQP4, and AQP5 were increased in ASMCOPD compared to ASSCOPD. CONCLUSION: The pulmonary function was impaired in ASSCOPD group; the expression of AQP1, AQP4, and AQP5 was decreased at protein and mRNA levels in ASSCOPD group. ASM can improve the pulmonary function in ASSCOPD for MV and TV. ASM could elevate the protein expression of AQP1, AQP4, and AQP5 and the mRNA level of AQP5 in lung tissue. PMID- 28630636 TI - Targeting Tumor Microenvironment: Effects of Chinese Herbal Formulae on Macrophage-Mediated Lung Cancer in Mice. AB - Our previous studies have shown that Qing-Re-Huo-Xue (QRHX) formulae had significant anti-inflammatory effects in chronic airway diseases such as asthma and chronic obstructive lung disease. Here, we examined the effects of QRHX on lung cancer cell invasion and the potential associated mechanism(s), mainly polarization of macrophages in the tumor microenvironment. In vivo, QRHX both inhibited tumor growth and decreased the number of tumor-associated macrophages (TAMs) in mice with lung cancer. Further study indicated that QRHX inhibited cancer-related inflammation in tumor by decreasing infiltration of TAMs and IL-6 and TNF-alpha production and meanwhile decreased arginase 1 (Arg-1) expression and increased inducible NO synthase (iNOS) expression. QRHX could markedly inhibit CD31 and VEGF protein expression. Additionally, CXCL12/CXCR4 expression and JAK2/STAT3 phosphorylation were reduced in QRHX treatment group. Thus, we draw that QRHX played a more important role in inhibiting tumor growth by regulating TAMs in mice, which was found to be associated with the inhibition of inflammation and the CXCL12/CXCR4/JAK2/STAT3 signaling pathway. PMID- 28630637 TI - Evaluation of circulating sRAGE in osteoporosis according to BMI, adipokines and fracture risk: a pilot observational study. AB - BACKGROUND: Osteoporosis is a systemic metabolic disease based on age-dependent imbalance between the rates of bone formation and bone resorption. Recent studies on the pathogenesis of this disease identified that bone remodelling impairment, at the base of osteoporotic bone fragility, could be related to protein glycation, in association to oxidative stress. The glycation reactions lead to the generation of glycation end products (AGEs) which, in turn, accumulates into bone, where they binds to the receptor for AGE (RAGE). The aim of this study is to investigate the potential role of circulating sRAGE in osteoporosis, in particular evaluating the correlation of sRAGE with the fracture risk, in association with bone mineral density, the fracture risk marker FGF23, and lipid metabolism. RESULTS: Circulating level of soluble RAGE correlate with osteopenia and osteoporosis level. Serum sRAGE resulted clearly associated on the one hand to bone fragility and, on the other hand, with BMI and leptin. sRAGE is particularly informative because serum sRAGE is able to provide, as a single marker, information about both the aspects of osteoporotic disease, represented by bone fragility and lipid metabolism. CONCLUSIONS: The measure serum level of sRAGE could have a potential diagnostic role in the monitoring of osteoporosis progression, in particular in the evaluation of fracture risk, starting from the prevention and screening stage, to the osteopenic level to osteoporosis. PMID- 28630638 TI - Cichorium intybus L. promotes intestinal uric acid excretion by modulating ABCG2 in experimental hyperuricemia. AB - BACKGROUND: Excessive production and/or reduced excretion of uric acid could lead to hyperuricemia, which could be a major cause of disability. Hyperuricemia has received increasing attention in the last few decades due to its global prevalence. Cichorium intybus L., commonly known as chicory, is a perennial herb of the asteraceae family. It was previously shown to exert potent hypouricemic effects linked with decreasing uric acid formation in the liver by down regulating the activity of xanthine oxidase, and increasing uric acid excretion by up-regulating the renal OAT3 mRNA expression. The present study aimed to evaluate its extra-renal excretion and possible molecular mechanism underlying the transporter responsible for intestinal uric acid excretion in vivo. METHODS: Chicory was administered intragastrically to hyperuricemic rats induced by drinking 10% fructose water. The uricosuric effect was evaluated by determining the serum uric acid level as well as the intestinal uric acid excretion by HPLC. The location and expression levels of ATP-binding cassette transporter, sub family G, member 2 (ABCG2) in jejunum and ileum were analyzed. RESULTS: The administration of chicory decreased the serum uric acid level significantly and increased the intestinal uric acid excretion obviously in hyperuricemic rats induced by 10% fructose drinking. Staining showed that ABCG2 was expressed in the apical membrane of the epithelium and glands of the jejunum and ileum in rats. Further examination showed that chicory enhanced the mRNA and protein expressions of ABCG2 markedly in a dose-dependent manner in jejunum and ileum. CONCLUSION: These findings indicate that chicory increases uric acid excretion by intestines, which may be related to the stimulation of intestinal uric acid excretion via down-regulating the mRNA and protein expressions of ABCG2. PMID- 28630639 TI - Erratum to: Evaluation of Lactobacillus coryniformis CECT5711 strain as a coadjuvant in a vaccination process: a randomised clinical trial in healthy adults. AB - [This corrects the article DOI: 10.1186/s12986-017-0187-1.]. PMID- 28630640 TI - Erratum to: Evaluation of Lactobacillus coryniformis CECT5711 strain as a coadjuvant in a vaccination process: a randomised clinical trial in healthy adults. AB - [This corrects the article DOI: 10.1186/s12986-016-0154-2.]. PMID- 28630641 TI - Amisulpride withdrawal dyskinesia: a case report. AB - BACKGROUND: The effects of antipsychotic drug withdrawal have been inadequately studied. Case reports have described dyskinesia occurring in patients with several antipsychotics withdrawn, but studies on amisulpride withdrawal dyskinesia are lacking. CASE PRESENTATION: A 63-year-old man, who was diagnosed with schizophrenia at age 49, received amisulpride treatment since age 62. The dosage of amisulpride was reduced from 200 to 50 mg/day because of occurrence of akathisia during one admission. Severe withdrawal dyskinesia, mixed with dystonia and akathisia, was noted immediately after the dosage reduction. The abnormal involuntary movement showed improvement 2 weeks later when the dosage was increased to 100 mg/day. CONCLUSIONS: Withdrawal dyskinesia and other abnormal involuntary movements could be noted in a patient with reduction of amisulpride dosage or sudden termination. Withdrawal dyskinesia may subsequently lead to persistent tardive dyskinesia. Therefore, withdrawal-emergent dyskinesia should be promptly identified, and appropriate medical interventions should be given early. PMID- 28630642 TI - Infant and young child feeding practice among mothers with 0-24 months old children in Slum areas of Bahir Dar City, Ethiopia. AB - BACKGROUND: Adequate nutrition during infancy and early childhood is essential to ensure the health, growth and development of children. However, infant feeding practice is suboptimal in Bahir Dar City, Ethiopia. The slum area is a heavily populated urban informal settlement characterized by substandard housing, squalor, with a lack of reliable sanitation services, supply of clean water, reliable electricity, law enforcement and other basic services. Residents of the slum area were poor and less educated. This further compromises infant feeding practice. The aim of this study was to assess infant and young child feeding practice among mothers with 0-24 month old children in the study area. METHODS: A community based cross-sectional study was conducted among 423 mothers with 0-24 month old children from June 01-30 / 2016. Simple random sampling technique was used to select the respondents. Infant and young child feeding practice was assessed using the fifteen World Health Organisation (WHO) criteria. RESULTS: The prevalence of exclusive breastfeeding practice was 113 (84%). Sixty (15%) mothers gave prelacteal feeds and, 96 (23%) mothers used a bottle to feed their index child. Appropriate complementary feeding practice was only 20 (7%). Thirty nine out of forty mothers introduced complementary food timely, 131 (47%) of mothers gave the minimum meal frequency, and 20 (7%) children took the minimum food diversity and acceptable diet. Independent predictors for complementary feeding practice were having secondary and above education of the mother, receiving postnatal care, possession of radio and giving birth at hospital. CONCLUSION: In this study infant and young child feeding (IYCF) practice was poor. Therefore, there is a need for strengthening the promotion on IYCF practice during postnatal care and using mass media to giving emphasis for optimal complementary feeding practices, especially for mothers with a lower educational status. PMID- 28630644 TI - Isometric gene tree reconciliation revisited. AB - BACKGROUND: Isometric gene tree reconciliation is a gene tree/species tree reconciliation problem where both the gene tree and the species tree include branch lengths, and these branch lengths must be respected by the reconciliation. The problem was introduced by Ma et al. in 2008 in the context of reconstructing evolutionary histories of genomes in the infinite sites model. RESULTS: In this paper, we show that the original algorithm by Ma et al. is incorrect, and we propose a modified algorithm that addresses the problems that we discovered. We have also improved the running time from [Formula: see text] to [Formula: see text], where N is the total number of nodes in the two input trees. Finally, we examine two new variants of the problem: reconciliation of two unrooted trees and scaling of branch lengths of the gene tree during reconciliation of two rooted trees. CONCLUSIONS: We provide several new algorithms for isometric reconciliation of trees. Some questions in this area remain open; most importantly extensions of the problem allowing for imprecise estimates of branch lengths. PMID- 28630643 TI - Improved classification accuracy of powdery mildew infection levels of wine grapes by spatial-spectral analysis of hyperspectral images. AB - BACKGROUND: Hyperspectral imaging is an emerging means of assessing plant vitality, stress parameters, nutrition status, and diseases. Extraction of target values from the high-dimensional datasets either relies on pixel-wise processing of the full spectral information, appropriate selection of individual bands, or calculation of spectral indices. Limitations of such approaches are reduced classification accuracy, reduced robustness due to spatial variation of the spectral information across the surface of the objects measured as well as a loss of information intrinsic to band selection and use of spectral indices. In this paper we present an improved spatial-spectral segmentation approach for the analysis of hyperspectral imaging data and its application for the prediction of powdery mildew infection levels (disease severity) of intact Chardonnay grape bunches shortly before veraison. RESULTS: Instead of calculating texture features (spatial features) for the huge number of spectral bands independently, dimensionality reduction by means of Linear Discriminant Analysis (LDA) was applied first to derive a few descriptive image bands. Subsequent classification was based on modified Random Forest classifiers and selective extraction of texture parameters from the integral image representation of the image bands generated. Dimensionality reduction, integral images, and the selective feature extraction led to improved classification accuracies of up to [Formula: see text] for detached berries used as a reference sample (training dataset). Our approach was validated by predicting infection levels for a sample of 30 intact bunches. Classification accuracy improved with the number of decision trees of the Random Forest classifier. These results corresponded with qPCR results. An accuracy of 0.87 was achieved in classification of healthy, infected, and severely diseased bunches. However, discrimination between visually healthy and infected bunches proved to be challenging for a few samples, perhaps due to colonized berries or sparse mycelia hidden within the bunch or airborne conidia on the berries that were detected by qPCR. CONCLUSIONS: An advanced approach to hyperspectral image classification based on combined spatial and spectral image features, potentially applicable to many available hyperspectral sensor technologies, has been developed and validated to improve the detection of powdery mildew infection levels of Chardonnay grape bunches. The spatial-spectral approach improved especially the detection of light infection levels compared with pixel-wise spectral data analysis. This approach is expected to improve the speed and accuracy of disease detection once the thresholds for fungal biomass detected by hyperspectral imaging are established; it can also facilitate monitoring in plant phenotyping of grapevine and additional crops. PMID- 28630645 TI - The use of laparoscopy in managing penetrating thoracoabdominal injuries in Africa: 83 cases reviewed. AB - BACKGROUND: The use of laparoscopy in managing haemodynamically stable patients with penetrating thoracoabdominal injuries in developed countries is wildly practiced, but in Africa, the use of laparoscopy is still in its infancy stage. We reviewed a single centre experience in using laparoscopy in Africa for management of patients with both isolated diaphragmatic injuries as well as diaphragmatic injuries associated with intra-abdominal injuries requiring intervention. METHODS: A retrospective analysis of prospectively collected data of patients presenting with penetrating thoracoabdominal injuries was done. All patients offered laparoscopic exploration and repair from January 2012 to December 2015 at Dr. George Mukhari Academic Hospital were analysed. Means (+/ SD) were presented for continuous variables, and frequencies (%) were presented for categorical variables. All analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). RESULTS: A total of 83 stable patients with penetrating thoracoabdominal injuries managed with laparoscopy met the inclusion criteria and were included in the study. The Injury Severity Score ranged from 8 to 24, with a median of 18. The incidence of diaphragmatic injuries was 54%. Majority (46.8%) of patients had Grade 3 (2-10 cm defect) diaphragmatic injury. Associated intra abdominal injuries requiring intervention were encountered in 28 (62%) patients. At least 93.3% of the patients were treated exclusively with laparoscopy. The morbidity was encountered in 7 (16%) patients; the most common cause was a clotted haemothorax Clavien-Dindo III-b, but only 1 patient required a decortication. There was one non-procedure-related mortality. CONCLUSIONS: A success rate of 93% in using laparoscopy exclusively was documented, with an overall 82% uneventful outcome. The positive outcomes found in this study when laparoscopy was used in stable patients with thoracoabdominal injuries support similar work done in other trauma centres. However, in addition, this study seem to suggest that the presence of peritonitis in stable patient is not a contra indication to laparoscopy and thoracoscopy may be useful especially in right side diaphragmatic injury where the liver can preclude adequate visualization of the entire diaphragm and to thoroughly clean the chest cavity and prevent future complication such as residual clotted haemothorax. Clinical relevance: The presence of peritonitis in stable patients with penetrating thoracoabdominal injury is not a contra-indication to laparoscopy provided the operating surgeon has adequate laparoscopic skills. PMID- 28630646 TI - Cognitive behavioral therapy for psychosomatic problems in dental settings. AB - Cognitive behavioral therapy (CBT) has been applied for various problems, including psychiatric diseases such as depression and anxiety, and for physical symptoms such as pain. It has also been applied for dental problems. Although the effect of CBTs on temporomandibular disorders and dental anxiety are well documented, its effectiveness on other types of oral symptoms remain unclear. Little information comparing the different types of CBTs in the dental setting is currently available. Because dental professionals are often expected to conduct CBTs in the dental setting, it is important to develop proper training programs for dental professionals. In this review article, we demonstrate and discuss the application of CBTs for psychosomatic problems, including temporomandibular disorders, dental anxiety, burning mouth syndrome, and other oral complaints in dental settings. PMID- 28630647 TI - Patterns of psychiatric admissions and predictors of patient's outcome in Jimma University Teaching and Referral Hospital: a retrospective study. AB - BACKGROUND: Psychiatric morbidity burden accounts 12.45% of the disease admission burden in Ethiopia; only two referral hospitals are found to manage all cases. The aim of this study is to assess the predictors of patient outcomes. METHOD: A 3 years retrospective patients' cards, charts and medical notes review in psychiatry case admission department of Jimma university teaching and training specialised hospital was conducted. All the admitted cases included in this study. Bivariate and multivariable logistic regression analyses were conducted to identify independent predictors of outcomes. RESULT: Among 402 study participants, the majority of them 301 (74.9%), were improved from their mental illnesses. First to eight grades completed study participants were found to be 1.34 times more likely improved mental illness than not able to read or write [AOR = 1.34, 95% CI (1.18-2.78), P < 0.009)]. The probability of improving from mental illness on married study participants was found 2.81 times more likely than single study participants [AOR = 2.81, CI (1.90-4.50), P < 0.043]. First time admitted cases improved 2.82 times more likely than those having a previous admission history [AOR = 2.82, CI (2.05-3.17), P < 0.05]. Duration of stay from 31 to 44 days showed more likely than from 1 to 20 days on patient improvement, [AOR = 1.88, CI (1.42-2.65), P < 0.034]. However, the hospital stay above 44 days does not show any statistical association with patient's medical improvement. CONCLUSION: Married, better educated, and the hospital stay of one to one-and half month predicts better health outcome. Thus, this study suggests, psychiatric case management needs the collaborative care of the family in concurrence with counselling and guidance with enough time to better-off patients' outcomes. Our findings are useful in designing and improving-patient services for psychiatric patient programs and focused health communication and counselling strategies in relation to psychoactive substances in Ethiopia. PMID- 28630648 TI - Comparative metabolic profiling of the lipid-producing green microalga Chlorella reveals that nitrogen and carbon metabolic pathways contribute to lipid metabolism. AB - Microalgae are a promising feedstock for biofuel production. Microalgal metabolic pathways are heavily influenced by environmental factors. For instance, lipid metabolism can be induced by nitrogen-limiting conditions. However, the underlying mechanisms of lipid biosynthesis are unclear. In this study, we analyzed the global metabolic profiles of three genetically closely related Chlorella strains (C1, C2, and C3) with significant differences in lipid productivity to identify the contributions of key metabolic pathways to lipid metabolism. We found that nitrogen obtained from amino acid catabolism was assimilated via the glutamate-glutamine pathway and then stored as amino acids and intermediate molecules (particularly proline, alanine, arginine, succinate, and gamma-aminobutyrate) via the corresponding metabolic pathways, which led to carbon-nitrogen disequilibrium. Excess carbon obtained from photosynthesis or glycolysis was re-distributed into carbon-containing compounds, such as glucose-6 phosphate, fructose-6-phosphate, phosphoenolpyruvate, lactate, citrate, 3 hydroxybutyrate, and leucine, and then diverted into lipid metabolism for the production of storage lipids via the gamma-aminobutyrate pathway, glycolysis, and the tricarboxylic acid cycle. These results were substantiated in the model green alga Chlamydomonas reinhardtii by analyzing various mutants deficient in glutamate synthase/NADH-dependent, glutamate synthase/Fd-dependent, glutamine synthetase, aspartate aminotransferase, alanine aminotransferase, pyruvate kinase, and citrate synthase. Our study suggests that not only carbon but also nitrogen assimilation and distribution pathways contribute to lipid biosynthesis. Furthermore, these findings may facilitate genetic engineering efforts to enhance microalgal biofuel production. PMID- 28630649 TI - A complete duplication of X chromosome resulting in a tricentric isochromosome originated by centromere repositioning. AB - BACKGROUND: Neocentromeres are rare and considered chromosomal aberrations, because a non-centromeric region evolves in an active centromere by mutation. The literature reported several structural anomalies of X chromosome and they influence the female reproductive capacity or are associated to Turner syndrome in the presence of monosomy X cell line. CASE PRESENTATION: We report a case of chromosome X complex rearrangement found in a prenatal diagnosis. The fetal karyotype showed a mosaicism with a 45,X cell line and a 46 chromosomes second line with a big marker, instead of a sex chromosome. The marker morphology and fluorescence in situ hybridization (FISH) characterization allowed us to identify a tricentric X chromosome constituted by two complete X chromosome fused at the p arms telomere and an active neocentromere in the middle, at the union of the two Xp arms, where usually are the telomeric regions. FISH also showed the presence of a paracentric inversion of both Xp arms. Furthermore, fragility figures were found in 56% of metaphases from peripheral blood lymphocytes culture at birth: a shorter marker chromosome and an apparently acentric fragment frequently lost. CONCLUSIONS: At our knowledge, this is the first isochromosome of an entire non acrocentric chromosome. The neocentromere is constituted by canonical sequences but localized in an unusual position and the original centromeres are inactivated. We speculated that marker chromosome was the result of a double rearrangement: firstly, a paracentric inversion which involved the Xp arm, shifting a part of the centromere at the p end and subsequently a duplication of the entire X chromosome, which gave rise to an isochromosome. It is possible to suppose that the first event could be a result of a non-allelic homologous recombination mediated by inverted low-copy repeats. As expected, our case shows a Turner phenotype with mild facial features and no major skeletal deformity, normal psychomotor development and a spontaneous development of puberty and menarche, although with irregular menses since the last follow-up. PMID- 28630650 TI - A maternally inherited 8.05 Mb Xq21 deletion associated with Choroideremia, deafness, and mental retardation syndrome in a male patient. AB - BACKGROUND: Deletions in Xq21 cause various congenital defects in males including choroideremia, deafness and mental retardation, depending on their size and gene content. Until now only a limited number of patients with Xq21 deletions has been reported. CASE PRESENTATION: Here we describe a 17-year-old male with choroideremia, deafness, and mental retardation syndrome. Using SNP arrays, an 8.05 Mb deletion in Xq21 was identified inherited from the apparently healthy mother. The deleted region harbors 12 OMIM genes, of which POU3F4, CHM, and ZNF711 might have contributed to the patient's phenotype including hearing loss, poor vision, and intellectual disability. Moreover, the patient's mother exhibits a normal phenotype while carrying the same deletion, which is often observed in previous studies on female carriers in families with this syndrome. CONCLUSIONS: Our study confirms the causative effect between the Xq21 deletion in males and choroideremia, deafness and mental retardation. PMID- 28630652 TI - Verification of B-lymphocyte activating factor's involvement in the exacerbation of insulin resistance as well as an autoimmune response in patients with nonalcoholic steatohepatitis and patients with HCV-related chronic liver disease. AB - BACKGROUND: Ten to forty percent of nonalcoholic steatohepatitis (NASH) and HCV related chronic liver disease (CLD-C) patients have antinuclear antibodies (ANAs). However, the relationship between autoimmune response and insulin resistance remains uncertain among those patients. The primary purpose of this study was to investigate whether or not ANA status was associated with the development of insulin resistance and obesity in NASH and CLD-C patients. METHODS: Degrees of hepatic fibrosis and steatosis were evaluated by the classification proposed by Brunt et al. Obesity and insulin resistance were estimated by calculating body mass index and the value of homeostasis model of for assessment of insulin resistance (HOMA-IR), respectively. A revised scoring system was applied to the diagnosis of autoimmune hepatitis (AIH). Serum B lymphocyte activating factor (BAFF) levels were determined, using an ELISA technique. RESULTS: Ten of 25 (40%) NASH patients and 9 of 22 (41%) CLD-C patients had ANAs, though the titers were weak in most patients. Only one NASH patient met the category of "definite" AIH among the enrolled patients. Serum IgG levels were significantly higher in NASH and CLD-C patients with ANAs than in those without ANAs, and NASH and CLD-C patients with ANAs had significantly higher HOMA-IR values than those without ANAs (6.81 +/- 3.36 vs. 4.00 +/- 2.57, p = 0.0305, 3.01 +/- 1.31 vs. 1.28 +/- 0.50, p = 0.0011). CLD-C patients with ANAs had more advanced hepatic fibrosis and steatosis than those without ANAs, while ANA status was not associated with hepatic fibrosis or steatosis in NASH patients. Obesity was independent of ANA status in both subjects. Serum BAFF levels were significantly higher in CLD-C patients with ANAs than those in CLD-C patients without ANAs (1303 +/- 268 vs. 714 +/- 143 pg/ml, p = 0.0036). A close correlation between serum BAFF level and the HOMA-IR value was observed in CLD-C patients (r = 0.467, p = 0.0485). CONCLUSION: Our data suggest that NASH and CLD C patients with ANAs have more severe insulin resistance than those without ANAs. More advanced insulin resistance deriving from excessive BAFF production may result in severe hepatic fibrosis and steatosis in CLD-C patients with ANAs. PMID- 28630653 TI - Outcomes Associated with Pharmacist-Led Diabetes Collaborative Drug Therapy Management in a Medicaid Population. AB - OBJECTIVES: Pharmacist-led diabetes collaborative drug therapy management (CDTM) has been shown to improve outcomes. Whether such programs are effective specifically in Medicaid patients, who face barriers to access and self management, has not been well characterized. This pilot study explores glycemic control, utilization and costs associated with pharmacist-led CDTM in a small population of Medicaid patients with type 2 diabetes mellitus (T2DM). METHODS: A pre-post, historical cohort study was conducted of patients with T2DM and Medicaid coverage who received pharmacist-led CDTM in community-based primary clinics between 2008-2012. Outcomes included change in HbA1c, healthcare costs and utilization. RESULTS: This study included 79 Medicaid patients with T2DM who received pharmacist-led CDTM. A subset of 46 patients with Medicaid coverage through an affiliated Medicaid Plan, Healthy U, was identified for additional analysis. At 6-months follow-up, HbA1c was a mean (SD) of 2.0% (2.0) lower than the baseline of 10.3% (1.7). Primary care clinic encounters increased by a mean (median) of 3.4 (2) visits. Per patient health system charges increased by a mean (median) of $4,392 ($620) and the amount paid by Medicaid in the Healthy U subset was $822 ($68) higher in the follow-up period. CONCLUSION: A pharmacist-led diabetes CDTM intervention was associated with improved glycemic control in Medicaid patients, which corresponded with a higher number of primary care visits and observed costs. These findings are consistent with studies not limited to Medicaid, suggesting that CDTM can be effective in type 2 diabetes patients with Medicaid coverage. PMID- 28630654 TI - Rapid Analysis of Trace Drugs and Metabolites Using a Thermal Desorption DART-MS Configuration. AB - The need to analyze trace narcotic samples rapidly for screening or confirmatory purposes is of increasing interest to the forensic, homeland security, and criminal justice sectors. This work presents a novel method for the detection and quantification of trace drugs and metabolites off of a swipe material using a thermal desorption direct analysis in real time mass spectrometry (TD-DART-MS) configuration. A variation on traditional DART, this configuration allows for desorption of the sample into a confined tube, completely independent of the DART source, allowing for more efficient and thermally precise analysis of material present on a swipe. Over thirty trace samples of narcotics, metabolites, and cutting agents deposited onto swipes were rapidly differentiated using this methodology. The non-optimized method led to sensitivities ranging from single nanograms to hundreds of picograms. Direct comparison to traditional DART with a subset of the samples highlighted an improvement in sensitivity by a factor of twenty to thirty and an increase in reproducibility sample to sample from approximately 45 % RSD to less than 15 % RSD. Rapid extraction-less quantification was also possible. PMID- 28630651 TI - Improving antiretroviral therapy adherence in resource-limited settings at scale: a discussion of interventions and recommendations. AB - Introduction: Successful population-level antiretroviral therapy (ART) adherence will be necessary to realize both the clinical and prevention benefits of antiretroviral scale-up and, ultimately, the end of AIDS. Although many people living with HIV are adhering well, others struggle and most are likely to experience challenges in adherence that may threaten virologic suppression at some point during lifelong therapy. Despite the importance of ART adherence, supportive interventions have generally not been implemented at scale. The objective of this review is to summarize the recommendations of clinical, research, and public health experts for scalable ART adherence interventions in resource-limited settings. Methods: In July 2015, the Bill and Melinda Gates Foundation convened a meeting to discuss the most promising ART adherence interventions for use at scale in resource-limited settings. This article summarizes that discussion with recent updates. It is not a systematic review, but rather provides practical considerations for programme implementation based on evidence from individual studies, systematic reviews, meta-analyses, and the World Health Organization Consolidated Guidelines for HIV, which include evidence from randomized controlled trials in low- and middle-income countries. Interventions are categorized broadly as education and counselling; information and communication technology-enhanced solutions; healthcare delivery restructuring; and economic incentives and social protection interventions. Each category is discussed, including descriptions of interventions, current evidence for effectiveness, and what appears promising for the near future. Approaches to intervention implementation and impact assessment are then described. Results and discussion: The evidence base is promising for currently available, effective, and scalable ART adherence interventions for resource-limited settings. Numerous interventions build on existing health care infrastructure and leverage available resources. Those most widely studied and implemented to date involve peer counselling, adherence clubs, and short message service (SMS). Many additional interventions could have an important impact on ART adherence with further development, including standardized counselling through multi-media technology, electronic dose monitoring, decentralized and differentiated models of care, and livelihood interventions. Optimal targeting and tailoring of interventions will require improved adherence measurement. Conclusions: The opportunity exists today to address and resolve many of the challenges to effective ART adherence, so that they do not limit the potential of ART to help bring about the end of AIDS. PMID- 28630655 TI - Neural patterns elicited by sentence processing uniquely characterize typical development, SLI recovery, and SLI persistence. AB - BACKGROUND: A substantial amount of work has examined language abilities in young children with specific language impairment (SLI); however, our understanding of the developmental trajectory of language impairment is limited. Along with studying the behavioral changes that occur across development, it is important to examine the neural indices of language processing for children with different language trajectories. The current study sought to examine behavioral and neural bases of language processing in adolescents showing three different trajectories: those with normal language development (NL), those exhibiting persistent SLI (SLI Persistent), and those with a history of SLI who appear to have recovered (SLI Recovered). METHODS: Through a sentence judgment task, we examined semantic and syntactic processing. Adolescents judged whether or not each sentence was semantically and syntactically correct. Stimuli consisted of naturally spoken sentences that were either correct, contained a semantic verb error, or contained a syntactic verb agreement error. Verb agreement errors consisted of omission and commission violations of the third-person singular -s. Behavioral button-press responses and electroencephalographic recordings were collected. Behavioral judgments and mean amplitude of the N400 and P600 components were examined. RESULTS: Adolescents in the SLI-Persistent group had lower sentence judgment accuracy overall, relative to the NL and SLI-Recovered groups. Accuracy in judging omission and commission syntactic errors were marginally different, with marginally lower accuracy for commission errors. All groups demonstrated an N400 component elicited by semantic violations. However, adolescents in the SLI Persistent group demonstrated a less robust P600 component for syntactic violations. Furthermore, adolescents in the SLI-Recovered group exhibited a similar neural profile to the NL group for the semantic and syntactic omission violations. However, a unique profile with initial negativity was observed in the SLI-Recovered group in the commission violation condition. CONCLUSIONS: Adolescents with persistent language impairment continue to demonstrate delays in language processing at the behavioral and neural levels. Conversely, the adolescents in the SLI-Recovered group appear to have made gains in language processing skills to overcome their initial impairments. However, our findings suggest that the adolescents in the SLI-Recovered group may have compensatory processing strategies for some aspects of language, as evidenced by a unique event-related potential profile. PMID- 28630657 TI - ARLTS1 polymorphism is associated with an increased risk of familial cancer: evidence from a meta-analysis. AB - Adenosine diphosphate (ADP)-ribosylation factor-like tumour suppressor gene 1(ARLTS1) might be associated with an increased risk of several types of familial cancers. However, previous studies have shown that cancer susceptibility is not completely consistent with ARLTS1 polymorphisms, and the precise mechanism remains unknown. Therefore, we conducted a meta-analysis of case-control studies by searching the PubMed, Embase, OVID, Science Direct and Chinese National Knowledge Infrastructure (CNKI) databases. In total, 12 studies met the inclusion criteria and were included in this meta-analysis. Statistical analyses were performed using STATA 11.0 software. Overall, the Cys148Arg T > C variant significantly increased cancer risk (CC vs. TT: OR = 1.27, 95% CI = 1.15-1.41, P < 0.05). The stratification indicated that the Cys148Arg variant is significantly associated with sporadic cancer (CC vs. TT: OR = 1.36, 95% CI = 1.18-1.55) and familial cancer (CC vs. TT: OR = 1.26, 95% CI = 1.12-1.43). Trp149Stop, Pro131Leu, Ser99Ser and Leu132Leu were not correlated with cancer susceptibility. Based on these results, we demonstrated that the ARLTS1 Cys148Arg polymorphism is associated with an increased risk of sporadic cancer and familial cancer, and there were no associations between the other four SNPs (i.e., Trp149Stop, Pro131Leu, Ser99Ser and Leu132Leu) and cancer risk. PMID- 28630656 TI - Physical activity, black carbon exposure, and DNA methylation in the FOXP3 promoter. AB - BACKGROUND: Physical activity is associated with improvement in lung function; however, pollution exposure during physical activity can lead to a transient reduction in lung function. This paradoxical relationship may be linked to altered T regulatory (Treg) cell activity, which increases with exercise and suppresses airway inflammation, but decreases in association with exposure to air pollution. To clarify these relationships, we investigated buccal cell DNA methylation of the forkhead box p3 (FOXP3) gene promoter, a proposed biomarker of Treg activity. We hypothesized that active urban children would have lower FOXP3 promoter methylation, associated with better lung function compared to non-active children. We also hypothesized that this relationship would be attenuated by high exposure to the air pollutant black carbon (BC). METHODS: We performed a cross sectional study of 135 children ages 9-14 who live in New York City. Activity was measured across 6 days. BC exposure was assessed by personal monitors worn for two 24-h periods, followed by lung function assessment. Buccal swabs were collected for DNA methylation analysis of three regions (six CpG sites) in the FOXP3 promoter. RESULTS: In multivariable regression models, overall, there was no significant relationship between physical activity and FOXP3 promoter methylation (p > 0.05). However, in stratified analyses, among children with higher BC exposure (>=1200 ng/m3), physical activity was associated with 2.37% lower methylation in promoter 2 (CpGs -77, -65, and -58) (betaestimate = -2.37%, p < 0.01) but not among those with lower BC exposure (betaestimate = 0.54%, p > 0.05). Differences across strata were statistically significant (pinteraction = 0.04). Among all children, after controlling for BC concentration, promoter 2 methylation was associated with reduced FEV1/FVC (betaestimate = -0.40%, p < 0.01) and reduced FEF25-75% (betaestimate = -1.46%, p < 0.01). CONCLUSIONS: Physical activity in urban children appeared associated with lower FOXP3 promoter methylation, a possible indicator of greater Treg function, under conditions of high BC exposure. Reduced FOXP3 promoter methylation was associated with higher lung function. These findings suggest that physical activity may induce immunologic benefits, particularly for urban children with greater risk of impaired lung function due to exposure to higher air pollution. FOXP3 promoter buccal cell methylation may function as a useful biomarker of that benefit. PMID- 28630658 TI - Evidence of Mitochondrial Dysfunction in Autism: Biochemical Links, Genetic-Based Associations, and Non-Energy-Related Mechanisms. AB - Autism spectrum disorder (ASD), the fastest growing developmental disability in the United States, represents a group of neurodevelopmental disorders characterized by impaired social interaction and communication as well as restricted and repetitive behavior. The underlying cause of autism is unknown and therapy is currently limited to targeting behavioral abnormalities. Emerging studies suggest a link between mitochondrial dysfunction and ASD. Here, we review the evidence demonstrating this potential connection. We focus specifically on biochemical links, genetic-based associations, non-energy related mechanisms, and novel therapeutic strategies. PMID- 28630659 TI - Homocysteine Induces Apoptosis of Human Umbilical Vein Endothelial Cells via Mitochondrial Dysfunction and Endoplasmic Reticulum Stress. AB - Homocysteine- (Hcy-) induced endothelial cell apoptosis has been suggested as a cause of Hcy-dependent vascular injury, while the proposed molecular pathways underlying this process are unclear. In this study, we investigated the adverse effects of Hcy on human umbilical vein endothelial cells (HUVEC) and the underlying mechanisms. Our results demonstrated that moderate-dose Hcy treatment induced HUVEC apoptosis in a time-dependent manner. Furthermore, prolonged Hcy treatment increased the expression of NOX4 and the production of intracellular ROS but decreased the ratio of Bcl-2/Bax and mitochondrial membrane potential (MMP), resulting in the leakage of cytochrome c and activation of caspase-3. Prolonged Hcy treatment also upregulated glucose-regulated protein 78 (GRP78), activated protein kinase RNA-like ER kinase (PERK), and induced the expression of C/EBP homologous protein (CHOP) and the phosphorylation of NF-kappab. The inhibition of NOX4 decreased the production of ROS and alleviated the Hcy-induced HUVEC apoptosis and ER stress. Blocking the PERK pathway partly alleviated Hcy induced HUVEC apoptosis and the activation of NF-kappab. Taken together, our results suggest that Hcy-induced mitochondrial dysfunction crucially modulated apoptosis and contributed to the activation of ER stress in HUVEC. The excessive activation of the PERK pathway partly contributed to Hcy-induced HUVEC apoptosis and the phosphorylation of NF-kappab. PMID- 28630660 TI - NPC-EXs Alleviate Endothelial Oxidative Stress and Dysfunction through the miR 210 Downstream Nox2 and VEGFR2 Pathways. AB - We have demonstrated that neural progenitor cells (NPCs) protect endothelial cells (ECs) from oxidative stress. Since exosomes (EXs) can convey the benefit of parent cells through their carried microRNAs (miRs) and miR-210 is ubiquitously expressed with versatile functions, we investigated the role of miR-210 in the effects of NPC-EXs on oxidative stress and dysfunction in ECs. NPCs were transfected with control and miR-210 scramble/inhibitor/mimic to generate NPC EXscon, NPC-EXssc, NPC-EXsanti-miR-210, and NPC-EXsmiR-210. The effects of various NPC-EXs on angiotensin II- (Ang II-) induced reactive oxygen species (ROS) overproduction, apoptosis, and dysfunction, as well as dysregulation of Nox2, ephrin A3, VEGF, and p-VEGFR2/VEGFR2 in ECs were evaluated. Results showed (1) Ang II-induced ROS overproduction, increase in apoptosis, and decrease in tube formation ability, accompanied with Nox2 upregulation and reduction of p VEGFR2/VEGFR2 in ECs. (2) Compared to NPC-EXscon or NPC-EXssc, NPC-EXsanti-miR 210 were less whereas NPC-EXsmiR-210 were more effective on attenuating these detrimental effects induced by Ang II in ECs. (3) These effects of NPC-EXsanti miR-210 and NPC-EXsmiR-210 were associated with the changes of miR-210, ephrin A3, VEGF, and p-VEGFR2/VEGFR2 ratio in ECs. Altogether, the protective effects of NPC-EXs on Ang II-induced endothelial injury through miR-210 which controls Nox2/ROS and VEGF/VEGFR2 signals were studied. PMID- 28630663 TI - Presentation of secondary parasitic infection 37 years after primary infection. AB - Echinococcus granulosus (EG) is a neglected pathology that causes cystic echinococcosis and primarily affects the liver and lung. EG infects ~6 million worldwide and mortality is quoted as 2-4% per 100 000 inhabitants. The increase in human traffic from endemic regions demands clinician's awareness. Dogs are the most common definitive host for the EG tapeworm. Human infection requires ingestion of fecal parasitic eggs. Primary infection causes cysts to appear in affected organs, rupture of which leads to secondary infection. Ultrasound remains the mainstay of diagnosis. Treatment can be either; chemotherapeutic, radiological, surgical or a combination depending on the organ affected. PMID- 28630661 TI - Intrainsular connectivity and somatosensory responsiveness in young children with ASD. AB - BACKGROUND: The human somatosensory system comprises dissociable paths for discriminative and affective touch, reflected in separate peripheral afferent populations and distinct cortical targets. Differences in behavioral and neural responses to affective touch may have an important developmental role in early social experiences, which are relevant for autism spectrum disorder (ASD). METHODS: Using probabilistic tractography, we compared the structural integrity of white matter pathways for discriminative and affective touch in young children with ASD and their typically developing (TD) peers. We examined two tracts: (1) a tract linking the thalamus with the primary somatosensory cortex, which carries discriminative tactile information, and (2) a tract linking the posterior insula the cortical projection target of unmyelinated tactile afferents mediating affective touch-with the anterior insula, which integrates sensory and visceral inputs to interpret emotional salience of sensory stimuli. We investigated associations between tract integrity and performance on a standardized observational assessment measuring tactile discrimination and affective responses to touch. RESULTS: Both the thalamocortical and intrainsular tracts showed reduced integrity (higher mean diffusivity) in the ASD group compared to those in the TD group. Consistent with the previous findings, the ASD group exhibited impaired tactile discriminative ability, more tactile defensiveness, and more sensory seeking (e.g., enthusiastic play or repetitive engagement with a specific tactile stimulus). There was a significant relation between intrainsular tract integrity and tactile seeking. The direction of this relation differed between groups: higher intrainsular mean diffusivity (MD) (reflecting decreased tract integrity) was associated with increased tactile seeking in the TD group but with decreased tactile seeking in the ASD group. In the TD group, decreased tactile defensiveness was also associated with higher intrainsular MD, but there was no relation in the ASD group. Discriminative touch was not significantly associated with integrity of either tract in either group. CONCLUSIONS: These results support previous findings suggesting a central role for the insula in affective response to touch. While both discriminative and affective touch and both somatosensory tracts are affected in ASD, the restriction of brain-behavior associations to the intrainsular tract and tactile seeking suggests more complex and perhaps higher-order influence on differences in tactile defensiveness and discrimination. PMID- 28630662 TI - Sex differences in endogenous cortical network activity: spontaneously recurring Up/Down states. AB - BACKGROUND: Several molecular and cellular processes in the vertebrate brain exhibit differences between males and females, leading to sexual dimorphism in the formation of neural circuits and brain organization. While studies on large scale brain networks provide ample evidence for both structural and functional sex differences, smaller-scale local networks have remained largely unexplored. In the current study, we investigate sexual dimorphism in cortical dynamics by means of spontaneous Up/Down states, a type of network activity that is exhibited during slow-wave sleep, quiet wakefulness, and anesthesia and is thought to represent the default activity of the cortex. METHODS: Up state activity was monitored by local field potential recordings in coronal brain slices of male and female mice across three ages with distinct secretion profiles of sex hormones: (i) pre-puberty (17-21 days old), (ii) 3-9 adult (months old), and (iii) old (19 24 months old). RESULTS: Female mice of all ages exhibited longer and more frequent Up states compared to aged-matched male mice. Power spectrum analysis revealed sex differences in the relative power of Up state events, with female mice showing reduced power in the delta range (1-4 Hz) and increased power in the theta range (4-8 Hz) compared to male mice. No sex differences were found in the characteristics of Up state peak voltage and latency. CONCLUSIONS: The present study revealed for the first time sex differences in intracortical network activity, using an ex vivo paradigm of spontaneously occurring Up/Down states. We report significant sex differences in Up state properties that are already present in pre-puberty animals and are maintained through adulthood and old age. PMID- 28630664 TI - Overlapping stent-assisted coil embolization for a ruptured intracranial vertebral artery dissection. AB - Ruptured intracranial vertebral artery dissection is a cause of non-traumatic subarachnoid hemorrhage. Urgent intervention should be considered to prevent fatal rebleeding. Endovascular parent artery occlusion, which is the initial treatment of choice, is not suitable for patients with a hypoplastic or occlusive contralateral vertebral artery. We report a case of ruptured vertebral artery dissection, which was successfully treated with double overlapping stent-assisted coiling. PMID- 28630665 TI - Fronto-orbital mucocele with intracranial extension: a case report. AB - Frontal sinus mucoceles are benign, pseudocystic lesion deriving from the obliteration of the sinus ostium, resulting in a continuous mucous accumulation. The growing process of a mucocele leads to a progressive enlargement of the sinus cavity, thickening and eroding its bony walls up to invading the surrounding tissues. The surgical procedure through an endoscopic endonasal approach is the current treatment option for such conditions, but in cases with an extensive bone erosion and intracranial or intraorbital extension, a transcranial approach should be preferred. We report a case of a frontal sinus mucocele with unusual intraorbital and intracranial extension, causing exophthalmos and ophthalmoplegia, removed through a transcranial frontal approach and the subsequent obliteration of the sinus. PMID- 28630666 TI - Curvature driven motion of a bubble in a toroidal Hele-Shaw cell. AB - We investigate the equilibrium properties of a single area-minimizing bubble trapped between two narrowly separated parallel curved plates. We begin with the case of a bubble trapped between concentric spherical plates. We develop a model which shows that the surface energy of the bubble is lower when confined between spherical plates than between flat plates. We confirm our findings by comparing against Surface Evolver simulations. We then derive a simple model for a bubble between arbitrarily curved parallel plates. The energy is found to be higher when the local Gaussian curvature of the plates is negative and lower when the curvature is positive. To check the validity of the model, we consider a bubble trapped between concentric tori. In the toroidal case, we find that the sensitivity of the bubble's energy to the local curvature acts as a geometric potential capable of driving bubbles from regions with negative to positive curvature. PMID- 28630667 TI - Evaluation of radical scavenging system in amoeba Chaos carolinense during nutrient deprivation. AB - The frequent appearance of non-lamellar membrane arrangements such as cubic membranes (CMs) in cells under stressed or pathological conditions points to an intrinsic cellular response mechanism. CM represents highly curved, three dimensional nano-periodic structures that correspond to mathematically well defined triply periodic minimal surfaces. Specifically, cellular membrane may transform into CM organization in response to pathological, inflammatory and oxidative stress conditions. CM organization, thus, may provide an advantage to cope with various types of stress. The identification of inducible membrane systems, such as in the mitochondrial inner membranes to cubic morphology upon starvation, opens new avenues for understanding the molecular mechanisms of cellular responses to oxidative stress. In this study, we compared the cellular responses of starved and fed amoeba Chaos carolinense to oxidative stress. Food deprivation from C. carolinense induces a significant increase in prooxidants such as superoxide and hydrogen peroxide. Surprisingly, we observed a significant lower rate of biomolecular damage in starved cells (with higher free radicals generation) when compared with fed cells. Specifically, lipid and RNA damages were significantly less in starved cells compared with fed cells. This observation was not due to the upregulation of intracellular antioxidants, as starved amoeba show reduced antioxidant enzymatic activities; however, it could be attributed to CM formation. CM could uptake and retain short segments of nucleic acids (resembles cellular RNA) in vivo and in vitro. Previous results showed that nucleic acids retained within CM sustain a minimal oxidative damage in vitro upon exposure to high level of superoxide. We thus propose that CM may act as a 'protective' shelter to minimize the oxidation of biologically essential macromolecules such as RNA. In summary, we examined enzymatic antioxidant activities as well as oxidative damage biomarkers in starved amoeba C. carolinense in correlation with the potential role of CM as an optimal intracellular membrane organization for the protection of biological macromolecules against oxidative damage. PMID- 28630668 TI - Competition brings out the best: modelling the frustration between curvature energy and chain stretching energy of lyotropic liquid crystals in bicontinuous cubic phases. AB - It is commonly considered that the frustration between the curvature energy and the chain stretching energy plays an important role in the formation of lyotropic liquid crystals in bicontinuous cubic phases. Theoretic and numeric calculations were performed for two extreme cases: parallel surfaces eliminate the variance of the chain length; constant mean curvature surfaces eliminate the variance of the mean curvature. We have implemented a model with Brakke's Surface Evolver which allows a competition between the two variances. The result shows a compromise of the two limiting geometries. With data from real systems, we are able to recover the gyroid-diamond-primitive phase sequence which was observed in experiments. PMID- 28630669 TI - Straight round the twist: frustration and chirality in smectics-A. AB - Frustration is a powerful mechanism in condensed matter systems, driving both order and complexity. In smectics, the frustration between macroscopic chirality and equally spaced layers generates textures characterized by a proliferation of defects. In this article, we study several different ground states of the chiral Landau-de Gennes free energy for a smectic liquid crystal. The standard theory finds the twist grain boundary (TGB) phase to be the ground state for chiral type II smectics. However, for very highly chiral systems, the hierarchical helical nanofilament phase can form and is stable over the TGB. PMID- 28630670 TI - Universal structure motifs in biominerals: a lesson from nature for the efficient design of bioinspired functional materials. AB - Biominerals are typically indispensable structures for their host organism in which they serve varying functions, such as mechanical support and protection, mineral storage, detoxification site, or as a sensor or optical guide. In this perspective article, we highlight the occurrence of both structural diversity and uniformity within these biogenic ceramics. For the first time, we demonstrate that the universality-diversity paradigm, which was initially introduced for proteins by Buehler et al. (Cranford & Buehler 2012 Biomateriomics; Cranford et al. 2013 Adv. Mater.25, 802-824 (doi:10.1002/adma.201202553); Ackbarow & Buehler 2008 J. Comput. Theor. Nanosci.5, 1193-1204 (doi:10.1166/jctn.2008.001); Buehler & Yung 2009 Nat. Mater.8, 175-188 (doi:10.1038/nmat2387)), is also valid in the realm of biomineralization. A nanogranular composite structure is shared by most biominerals which rests on a common, non-classical crystal growth mechanism. The nanogranular composite structure affects various properties of the macroscale biogenic ceramic, a phenomenon we attribute to emergence. Emergence, in turn, is typical for hierarchically organized materials. This is a clear call to renew comparative studies of even distantly related biomineralizing organisms to identify further universal design motifs and their associated emergent properties. Such universal motifs with emergent macro-scale properties may represent an unparalleled toolbox for the efficient design of bioinspired functional materials. PMID- 28630671 TI - BslA-stabilized emulsion droplets with designed microstructure. AB - Emulsions are a central component of many modern formulations in food, pharmaceuticals, agrichemicals and personal care products. The droplets in these formulations are limited to being spherical as a consequence of the interfacial tension between the dispersed phase and continuous phase. The ability to control emulsion droplet morphology and stabilize non-spherical droplets would enable the modification of emulsion properties such as stability, substrate binding, delivery rate and rheology. One way of controlling droplet microstructure is to apply an elastic film around the droplet to prevent it from relaxing into a sphere. We have previously shown that BslA, an interfacial protein produced by the bacterial genus Bacillus, forms an elastic film when exposed to an oil- or air-water interface. Here, we highlight BslA's ability to stabilize anisotropic emulsion droplets. First, we show that BslA is capable of arresting dynamic emulsification processes leading to emulsions with variable morphologies depending on the conditions and emulsification technique applied. We then show that frozen emulsion droplets can be manipulated to induce partial coalescence. The structure of the partially coalesced droplets is retained after melting, but only when there is sufficient free BslA in the continuous phase. That the fidelity of replication can be tuned by adjusting the amount of free BslA in solution suggests that freezing BslA-stabilized droplets disrupts the BslA film. Finally, we use BslA's ability to preserve emulsion droplet structural integrity throughout the melting process to design emulsion droplets with a chosen shape and size. PMID- 28630673 TI - Optimal packings of three-arm star polyphiles: from tricontinuous to quasi uniformly striped bicontinuous forms. AB - Star-shaped molecules with three mutually immiscible arms self-assemble to form a variety of novel structures, with conformations that attempt to minimize interfacial area between the domains composed of the different arms. The geometric frustration caused by the joining of these arms at a common centre limits the size and shape of each domain, encouraging the creation of complex and interesting solutions. Some solutions are tricontinuous, and these solutions (and others) share aspects of bicontinuous structures with amphiphilic assemblies as similar molecular segregation factors are at work. We describe both highly symmetric and balanced structures, as well as unbalanced solutions that take the form of intricately striped amphiphilic membranes. All these patterns can result in chiral assemblies with multiple networks. PMID- 28630672 TI - Circularly polarized reflection from the scarab beetle Chalcothea smaragdina: light scattering by a dual photonic structure. AB - Helicoidal architectures comprising various polysaccharides, such as chitin and cellulose, have been reported in biological systems. In some cases, these architectures exhibit stunning optical properties analogous to ordered cholesteric liquid crystal phases. In this work, we characterize the circularly polarized reflectance and optical scattering from the cuticle of the beetle Chalcothea smaragdina (Coleoptera: Scarabaeidae: Cetoniinae) using optical experiments, simulations and structural analysis. The selective reflection of left-handed circularly polarized light is attributed to a Bouligand-type helicoidal morphology within the beetle's exocuticle. Using electron microscopy to inform electromagnetic simulations of this anisotropic stratified medium, the inextricable connection between the colour appearance of C. smaragdina and the periodicity of its helicoidal rotation is shown. A close agreement between the model and the measured reflectance spectra is obtained. In addition, the elytral surface of C. smaragdina possesses a blazed diffraction grating-like surface structure, which affects the diffuse appearance of the beetle's reflected colour, and therefore potentially enhances crypsis among the dense foliage of its rainforest habitat. PMID- 28630674 TI - Cation effects on haemoglobin aggregation: balance of chemisorption against physisorption of ions. AB - A theoretical model of haemoglobin is presented to explain an anomalous cationic Hofmeister effect observed in protein aggregation. The model quantifies competing proposed mechanisms of non-electrostatic physisorption and chemisorption. Non electrostatic physisorption is stronger for larger, more polarizable ions with a Hofmeister series Li+< K+< Cs+. Chemisorption at carboxylate groups is stronger for smaller kosmotropic ions, with the reverse series Li+ > K+ > Cs+. We assess aggregation using second virial coefficients calculated from theoretical protein protein interaction energies. Taking Cs+ to not chemisorb, comparison with experiment yields mildly repulsive cation-carboxylate binding energies of 0.48 kBT for Li+ and 3.0 kBT for K+. Aggregation behaviour is predominantly controlled by short-range protein interactions. Overall, adsorption of the K+ ion in the middle of the Hofmeister series is stronger than ions at either extreme since it includes contributions from both physisorption and chemisorption. This results in stronger attractive forces and greater aggregation with K+, leading to the non conventional Hofmeister series K+ > Cs+ ~ Li+. PMID- 28630675 TI - How geometric frustration shapes twisted fibres, inside and out: competing morphologies of chiral filament assembly. AB - Chirality frustrates and shapes the assembly of flexible filaments in rope-like, twisted bundles and fibres by introducing gradients of both filament shape (i.e. curvature) and packing throughout the structure. Previous models of chiral filament bundle formation have shown that this frustration gives rise to several distinct morphological responses, including self-limiting bundle widths, anisotropic domain (tape-like) formation and topological defects in the lateral inter-filament order. In this paper, we employ a combination of continuum elasticity theory and discrete filament bundle simulations to explore how these distinct morphological responses compete in the broader phase diagram of chiral filament assembly. We show that the most generic model of bundle formation exhibits at least four classes of equilibrium structure-finite-width, twisted bundles with isotropic and anisotropic shapes, with and without topological defects, as well as bulk phases of untwisted, columnar assembly (i.e. 'frustration escape'). These competing equilibrium morphologies are selected by only a relatively small number of parameters describing filament assembly: bundle surface energy, preferred chiral twist and stiffness of chiral filament interactions, and mechanical stiffness of filaments and their lateral interactions. Discrete filament bundle simulations test and verify continuum theory predictions for dependence of bundle structure (shape, size and packing defects of two-dimensional cross section) on these key parameters. PMID- 28630676 TI - Scaling properties of ageing orientation fluctuations in stripe phases. AB - We investigate the non-equilibrium dynamics of an ordered stripe-forming system free of topological defects. In particular, we study the ageing and the coarsening of orientation fluctuations parallel and perpendicular to the stripes via computer simulations based on a minimal phase-field model (model B with Coulomb interactions). Under the influence of noise, the stripe orientation field develops fluctuations parallel to the stripes, with the dominant modulation length lambda*? increasing with time t as lambda*? ~ t1/4 and the correlation length perpendicular to the stripes xi?theta increasing as xi?theta ~ t1/2. We explain these anisotropic coarsening dynamics with an analytic theory based on the linear elastic model for stripe displacements first introduced by Landau and Peierls. We thus obtain the scaling forms and the scaling exponents characterizing the correlation functions and the structure factor of the stripe orientation field. Our results reveal how the coarsening of orientation fluctuations prevents a periodically modulated phase free of topological defects from reaching equilibrium. PMID- 28630677 TI - Non-lamellar lipid assembly at interfaces: controlling layer structure by responsive nanogel particles. AB - Biological membranes do not only occur as planar bilayer structures, but depending on the lipid composition, can also curve into intriguing three dimensional structures. In order to fully understand the biological implications as well as to reveal the full potential for applications, e.g. for drug delivery and other biomedical devices, of such structures, well-defined model systems are required. Here, we discuss the formation of lipid non-lamellar liquid crystalline (LC) surface layers spin-coated from the constituting lipids followed by hydration of the lipid layer. We demonstrate that hybrid lipid polymer films can be formed with different properties compared with the neat lipid LC layers. The nanostructure and morphologies of the lipid films formed reflect those in the bulk. Most notably, mixed lipid layers, which are composed of glycerol monooleate and diglycerol monooleate with poly(N-isopropylacrylamide) nanogels, can form films of reverse cubic phases that are capable of responding to temperature stimulus. Owing to the presence of the nanogel particles, changing the temperature not only regulates the hydration of the cubic phase lipid films, but also the lateral organization of the lipid domains within the lipid self assembled film. This opens up the possibility for new nanostructured materials based on lipid-polymer responsive layers. PMID- 28630678 TI - On the colour of wing scales in butterflies: iridescence and preferred orientation of single gyroid photonic crystals. AB - Lycaenid butterflies from the genera Callophrys, Cyanophrys and Thecla have evolved remarkable biophotonic gyroid nanostructures within their wing scales that have only recently been replicated by nanoscale additive manufacturing. These nanostructures selectively reflect parts of the visible spectrum to give their characteristic non-iridescent, matte-green appearance, despite a distinct blue-green-yellow iridescence predicted for individual crystals from theory. It has been hypothesized that the organism must achieve its uniform appearance by growing crystals with some restrictions on the possible distribution of orientations, yet preferential orientation observed in Callophrys rubi confirms that this distribution need not be uniform. By analysing scanning electron microscope and optical images of 912 crystals in three wing scales, we find no preference for their rotational alignment in the plane of the scales. However, crystal orientation normal to the scale was highly correlated to their colour at low (conical) angles of view and illumination. This correlation enabled the use of optical images, each containing up to 104-105 crystals, for concluding the preferential alignment seen along the [Formula: see text] at the level of single scales, appears ubiquitous. By contrast, [Formula: see text] orientations were found to occur at no greater rate than that expected by chance. Above a critical cone angle, all crystals reflected bright green light indicating the dominant light scattering is due to the predicted band gap along the [Formula: see text] direction, independent of the domain orientation. Together with the natural variation in scale and wing shapes, we can readily understand the detailed mechanism of uniform colour production and iridescence suppression in these butterflies. It appears that the combination of preferential alignment normal to the wing scale, and uniform distribution within the plane is a near optimal solution for homogenizing the angular distribution of the [Formula: see text] band gap relative to the wings. Finally, the distributions of orientations, shapes, sizes and degree of order of crystals within single scales provide useful insights for understanding the mechanisms at play in the formation of these biophotonic nanostructures. PMID- 28630680 TI - Purely entropic self-assembly of the bicontinuous Ia3d gyroid phase in equilibrium hard-pear systems. AB - We investigate a model of hard pear-shaped particles which forms the bicontinuous Ia[Formula: see text]d structure by entropic self-assembly, extending the previous observations of Barmes et al. (2003 Phys. Rev. E68, 021708. (doi:10.1103/PhysRevE.68.021708)) and Ellison et al. (2006 Phys. Rev. Lett.97, 237801. (doi:10.1103/PhysRevLett.97.237801)). We specifically provide the complete phase diagram of this system, with global density and particle shape as the two variable parameters, incorporating the gyroid phase as well as disordered isotropic, smectic and nematic phases. The phase diagram is obtained by two methods, one being a compression-decompression study and the other being a continuous change of the particle shape parameter at constant density. Additionally, we probe the mechanism by which interdigitating sheets of pears in these systems create surfaces with negative Gauss curvature, which is needed to form the gyroid minimal surface. This is achieved by the use of Voronoi tessellation, whereby both the shape and volume of Voronoi cells can be assessed in regard to the local Gauss curvature of the gyroid minimal surface. Through this, we show that the mechanisms prevalent in this entropy-driven system differ from those found in systems which form gyroid structures in nature (lipid bilayers) and from synthesized materials (di-block copolymers) and where the formation of the gyroid is enthalpically driven. We further argue that the gyroid phase formed in these systems is a realization of a modulated splay-bend phase in which the conventional nematic has been predicted to be destabilized at the mesoscale due to molecular-scale coupling of polar and orientational degrees of freedom. PMID- 28630681 TI - Imaging optical scattering of butterfly wing scales with a microscope. AB - A new optical method is proposed to investigate the reflectance of structurally coloured objects, such as Morpho butterfly wing scales and cholesteric liquid crystals. Using a reflected-light microscope and a digital single-lens reflex (DSLR) camera, we have successfully measured the two-dimensional reflection pattern of individual wing scales of Morpho butterflies. We demonstrate that this method enables us to measure the bidirectional reflectance distribution function (BRDF). The scattering image observed in the back focal plane of the objective is projected onto the camera sensor by inserting a Bertrand lens in the optical path of the microscope. With monochromatic light illumination, we quantify the angle dependent reflectance spectra from the wing scales of Morpho rhetenor by retrieving the raw signal from the digital camera sensor. We also demonstrate that the polarization-dependent reflection of individual wing scales is readily observed using this method, using the individual wing scales of Morpho cypris. In an effort to show the generality of the method, we used a chiral nematic fluid to illustrate the angle-dependent reflectance as seen by this method. PMID- 28630679 TI - Molecular interactions of amyloid nanofibrils with biological aggregation modifiers: implications for cytotoxicity mechanisms and biomaterial design. AB - Amyloid nanofibrils are ubiquitous biological protein fibrous aggregates, with a wide range of either toxic or beneficial activities that are relevant to human disease and normal biology. Protein amyloid fibrillization occurs via nucleated polymerization, through non-covalent interactions. As such, protein nanofibril formation is based on a complex interplay between kinetic and thermodynamic factors. The process entails metastable oligomeric species and a highly thermodynamically favoured end state. The kinetics, and the reaction pathway itself, can be influenced by third party moieties, either molecules or surfaces. Specifically, in the biological context, different classes of biomolecules are known to act as catalysts, inhibitors or modifiers of the generic protein fibrillization process. The biological aggregation modifiers reviewed here include lipid membranes of varying composition, glycosaminoglycans and metal ions, with a final word on xenobiotic compounds. The corresponding molecular interactions are critically analysed and placed in the context of the mechanisms of cytotoxicity of the amyloids involved in diverse pathologies and the non toxicity of functional amyloids (at least towards their biological host). Finally, the utilization of this knowledge towards the design of bio-inspired and biocompatible nanomaterials is explored. PMID- 28630682 TI - Overexpressed PRAME is a potential immunotherapy target in sarcoma subtypes. AB - BACKGROUND: PRAME (preferentially expressed antigen in melanoma), a member of the cancer-testis antigen family, has been shown to have increased expression in solid tumors, including sarcoma, and PRAME-specific therapies are currently in development for other cancers such as melanoma. METHODS: To map the landscape of PRAME expression in sarcoma, we used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) projects and determined which sarcoma subtypes and subsets are associated with increased PRAME expression. We also analyzed how PRAME expression correlates with survival and expression of markers related to antigen presentation and T cell function. Furthermore, tumor and normal tissue expression comparisons were performed using data from the genotype-tissue expression (GTEx) project. RESULTS: We found that uterine carcinosarcoma highly overexpresses the PRAME antigen, and synovial sarcomas and multifocal leiomyosarcomas also show high expressions suggesting that PRAME may be an effective target of immunotherapies of these tumors. However, we also discovered that PRAME expression negatively correlates with genes involved in antigen presentation, and in synovial sarcoma MHC class I antigen presentation deficiencies are also present, potentially limiting the efficacy of immunotherapies of this malignancy. CONCLUSIONS: We determined that uterine carcinosarcoma, synovial sarcoma, and leiomyosarcoma patients would potentially benefit from PRAME-specific immunotherapies. Tumor escape through loss of antigen presentation needs to be further studied. PMID- 28630683 TI - Erratum to: The prevalence, temporal and spatial trends in bulk tank equivalent milk fat depression in Irish milk recorded herds. AB - [This corrects the article DOI: 10.1186/s13620-017-0092-y.]. PMID- 28630684 TI - Two-Step Cycle for Producing Multiple Anodic Aluminum Oxide (AAO) Films with Increasing Long-Range Order. AB - Nanoporous anodic aluminum oxide (AAO) membranes are being used for an increasing number of applications. However, the original two-step anodization method in which the first anodization is sacrificial to pre-pattern the second is still widely used to produce them. This method provides relatively low throughput and material utilization as half of the films are discarded. An alternative scheme that relies on alternating anodization and cathodic delamination is demonstrated that allows for the fabrication of several AAO films with only one sacrificial layer thus greatly improving total aluminum to alumina yield. The thickness for which the cathodic delamination performs best to yield full, unbroken AAO sheets is around 85 MUm. Additionally, an image analysis method is used to quantify the degree of long-range ordering of the unit cells in the AAO films which was found to increase with each successive iteration of the fabrication cycle. PMID- 28630685 TI - Effectiveness of surface coatings containing silver ions in bacterial decontamination in a recovery unit. AB - BACKGROUND: HAIs remain a frequent complication for hospitalised patients and pose a challenge that must be tackled by our health systems. METHODS: Quasi experimental study. In order to determine the antimicrobial effectiveness of surface coating agents containing silver ions (BactiBlock(r)) the degree of contamination of several surfaces in two ICU wards was compared. The association between application of Bactiblock(r) and surface contamination was analysed using a relative risk (RR). Multivariate logistic regressions were performed for each product applied and each sampling location to adjust for the RR of the contamination of surfaces treated with Bactiblock(r) for the independent variables. RESULTS: Surface contamination was observed in 31.5% of treated samples and 27.4 of untreated samples. Contamination was equally prominent on bedside Tables (38.7%), bed rails (38.4%) and sinks (38.3%), while the walls showed minimum contamination (2.6%). For beds under isolation protocols, contamination was higher (32.6%) than when no protocol was followed (26.5%) but the difference was not significant (p = 0.148). After stratification for application method and adjusting the multivariate models for period of the study and presence of isolated patients, the risk of contamination after the intervention increased when the coating agent was applied using a spray (OR = 1.79; 95% CI: 1.08-2.95, particularly in a dry and rugged surface such as that of bedside Tables (OR = 2.59; 95% CI: 1.22-5.52); and decreased when the product was applied using a roller on a smooth and continuously cleaned (or wet) Surface (OR = 0.42; 95% CI: 0.19-0.92). CONCLUSION: Coating of hospital surfaces with substances containing silver ions may reduce bacterial growth. However, the effectiveness of the coating agent is affected by application method and environmental conditions and the type and cleanness of the surface. PMID- 28630686 TI - Fecal carriage of extended-spectrum beta-lactamase- and carbapenemase-producing Enterobacteriaceae in Egyptian patients with community-onset gastrointestinal complaints: a hospital -based cross-sectional study. AB - OBJECTIVES: The aim of this study was to determine the prevalence of extended spectrum beta-lactamase (ESBL) and carbapenemase production among Enterobacteriaceae isolated from ambulatory patients with gastrointestinal complaints admitted to El-Ahrar General Hospital, Zagazig, Egypt in the period between January 2013 and May 2013. METHODS: One hundred and thirteen Enterobacteriaceae isolates were recovered from 100 consecutive Egyptian patients with community-onset gastrointestinal complaints. The fecal samples were plated directly on selective EbSA-ESBL Screening Agar and on MacConkey agar. Isolate identification was performed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Screening for ESBLs and carbapenemases production was done by both the automated VITEK(r)2 system with AST N198 and by disk diffusion method. Real-time PCR and sequencing were used to characterize the resistance genes. Phylogroups of the E. coli isolates were determined by a triplex PCR-based method. RESULTS: Of 100 patients screened for fecal colonization with extended-spectrum beta-lactamase -producing Enterobacteriaceae (ESBL-E) and carbapenemase- producing Enterobacteriaceae (CPE), 68 were colonized with ESBL-E whereas five patients were positive for CPE. One hundred and thirteen Enterobacterceae isolates were recovered from 100 fecal samples, they belonged to E. coli (n = 72), Klebsiella pneumoniae (n = 23), Enterobacter cloacae(n = 3), Salmonella spp. (n = 1) and other Enterobacterceae isolates (n = 14). The blaCTX-M gene was detected in 89.04% (65/73) of the ESBL producing Enterobacteriaceae, whereas blaSHV and blaTEM were detected in 30.14% (22/73) and 19.18% (14/73) respectively. Three out of 5 carbapenem-resistant isolates harbored New Delhi metallo-beta-lactamase (NDM) and 2 produced Verona integron-encoded metallo- beta -lactamase (VIM). Twenty-two (47.83%) of the ESBL positive isolates were multidrug resistant (MDR). Phylogenetic analysis showed that, of the 51 ESBL-EC isolates, 17 belonged to group B2, 13 to group D, 11 to group A and 10 to group B1. CONCLUSIONS: Nearly two-thirds of the Enterobacteriaceae isolates recovered from feces of ambulatory patients with community-onset gastrointestinal complaints admitted to El-Ahrar General Hospital, Zagazig, Egypt were ESBL producers and one in every 20 patients included in our study was colonized by carbapenemase-producing Enterobacteriaceae. These high colonization rates are worrying, therefore prudent antimicrobial use should be adopted in Egyptian community settings. PMID- 28630687 TI - Emerging antimicrobial resistance in early and late-onset neonatal sepsis. AB - BACKGROUND: Compared to developed countries, the use of antimicrobials in Egypt is less regulated and is available over the counter without the need for prescriptions. The impact of such policy on antimicrobial resistance has not been studied. This study aimed to determine the prevalence of early and late onset sepsis, and the frequency of antimicrobial resistance in a major referral neonatal intensive care unit (NICU). METHODS: The study included all neonates admitted to the NICU over a 12-month period. Prospectively collected clinical and laboratory data were retrieved, including blood cultures and endotracheal aspirate cultures if performed. RESULTS: A total of 953 neonates were admitted, of them 314 neonates were diagnosed with sepsis; 123 with early onset sepsis (EOS) and 191 with late onset sepsis (LOS). A total of 388 blood cultures were obtained, with 166 positive results. Total endotracheal aspirate samples were 127; of them 79 were culture-positive. The most frequently isolated organisms in blood were Klebsiella pneumoniae (42%) and Coagulase negative staphylococcus (19%) whereas in endotracheal cultures were Klebsiella pneumoniae (41%) and Pseudomonas aeruginosa (19%). Gram negative organisms were most resistant to ampicillins (100%), cephalosporins (93%-100%) and piperacillin-tazobactam (99%) with less resistance to aminoglycosides (36%-52%). Gram positive isolates were least resistant to vancomycin (18%). Multidrug resistance was detected in 92 (38%) cultures, mainly among gram negative isolates (78/92). CONCLUSIONS: Antibiotic resistance constitutes a challenge to the management of neonatal sepsis in Egypt. Resistance was predominant in both early and late onset sepsis. This study supports the need to implement policies that prohibits the non prescription community use of antibiotics. PMID- 28630688 TI - Prevalence of antimicrobial resistant pathogens from blood cultures: results from a laboratory based nationwide surveillance in Ghana. AB - BACKGROUND: Blood stream infections (BSI) are critical medical conditions with high morbidity and mortality. There is paucity of information on BSI from surveillance studies in Ghana. AIM: This study sought to demonstrate how useful BSI data can be gleaned from population-based surveillance, especially from resource-limited settings. METHODS: Data from a nationwide surveillance of antimicrobial drug resistance (AMR) in Ghana were extracted and analyzed. Secondly, we revived archived Staphylococcus aureus isolates from blood cultures that were cefoxitin resistant (CRSA), and screened these for protein A (spa) and mec A genes. RESULTS: Overall blood culture positivity was 11.2% (714/6351). All together, participating laboratories submitted 100 multidrug resistant blood culture isolates (Gram-negative = 49 and Gram-positive = 51). Prevalence of some Gram-negative isolates was as follows; Escherichia coli (20.4%), Pseudomonas aeruginosa (16.3%), Enterobacter spp. (14.3%), Salmonella serotype Typhi (8.2%) and Non-typhoidal Salmonella [NTS] (8.2%). Gram-positive pathogens included Staphylococcus aureus (66.7%), coagulase negative S. aureus [CoNS] (17.6%) and Streptococcus pneumoniae (11.8%). No methicillin resistance was confirmed in our CRSA isolates. Most blood stream associated infections were from inpatients (75%) and cultured bacteria were resistant to common and cheaper antimicrobials. CONCLUSION: E. coli and S. aureus are common pathogens associated with BSI in Ghana and they are resistant to several antimicrobials. Active and continuous AMR surveillance can serve multiple purposes, including data generation for BSI. PMID- 28630689 TI - Why language matters: a tour through hand hygiene literature. AB - BACKGROUND: Hand hygiene has evolved over the last decades and many terminologies emerged. We aimed to analyse the evolution in the frequency of utilization of key hand hygiene terms in the literature along the years. METHODS: We identified keywords and Medical Subject Headings (MeSH) used in MEDLINE(r) indexation related to hand hygiene by searching international guidelines and the MeSH database. We performed a MEDLINE(r) search combining the selected keywords and MeSH and analysed the number of publications retrieved yearly. RESULTS: The literature search yielded 9019 publications when all hand hygiene related search terms were combined, between 1921 and November 2016. The total number of publications per year increased from a median of 4 (IQR 3, 6) in the 1950's to 554 (IQR 478, 583) between 2011 and 2015. The most frequently used keywords are hand disinfection, hand hygiene, hand washing, handrub, hand sanitizer and alcohol-based hand rub (ABHR). Until the 1990s, hand disinfection and hand washing were the most frequently used terms. Whilst the last decade has seen a remarkable increase in publications mentioning hand disinfection and hand hygiene and for the first time handrub, hand sanitizers and ABHR were introduced in the literature. Hand disinfection, hand hygiene and hand sanitizers are the main MeSH used by MEDLINE(r). Since 2013 hand hygiene is the most frequently used MeSH and keyword. CONCLUSIONS: The change seen in literature in the last two decades, from hand washing and hand disinfection to hand hygiene, most probably reflect the paradigm shift favouring use of ABHR over soap and water promoted by international guidelines in the early 2000s. PMID- 28630690 TI - Incidence and risk factors for surgical site infections in obstetric and gynecological surgeries from a teaching hospital in rural India. AB - BACKGROUND: Surgical site infections (SSI) are one of the most common healthcare associated infections in the low-middle income countries. Data on incidence and risk factors for SSI following surgeries in general and Obstetric and Gynecological surgeries in particular are scare. This study set out to identify risk factors for SSI in patients undergoing Obstetric and Gynecological surgeries in an Indian rural hospital. METHODS: Patients who underwent a surgical procedure between September 2010 to February 2013 in the 60-bedded ward of Obstetric and Gynecology department were included. Surveillance for SSI was based on the Centre for Disease Control (CDC) definition and methodology. Incidence and risk factors for SSI, including those for specific procedure, were calculated from data collected on daily ward rounds. RESULTS: A total of 1173 patients underwent a surgical procedure during the study period. The incidence of SSI in the cohort was 7.84% (95% CI 6.30-9.38). Majority of SSI were superficial. Obstetric surgeries had a lower SSI incidence compared to gynecological surgeries (1.2% versus 10.3% respectively). The risk factors for SSI identified in the multivariate logistic regression model were age (OR 1.03), vaginal examination (OR 1.31); presence of vaginal discharge (OR 4.04); medical disease (OR 5.76); American Society of Anesthesia score greater than 3 (OR 12.8); concurrent surgical procedure (OR 3.26); each increase in hour of surgery, after the first hour, doubled the risk of SSI; inappropriate antibiotic prophylaxis increased the risk of SSI by nearly 5 times. Each day increase in stay in the hospital after the surgery increased the risk of contacting an SSI by 5%. CONCLUSIONS: Incidence and risk factors from prospective SSI surveillance can be reported simultaneously for the Obstetric and Gynecological surgeries and can be part of routine practice in resource-constrained settings. The incidence of SSI was lower for Obstetric surgeries compared to Gynecological surgeries. Multiple risk factors identified in the present study can be helpful for SSI risk stratification in low-middle income countries. PMID- 28630691 TI - Overweight dogs are more likely to display undesirable behaviours: results of a large online survey of dog owners in the UK. AB - Much of the global canine population is now overweight, and this can adversely affect health, lifespan and quality of life. Undesirable behaviours are also common in pet dogs, and these can adversely affect welfare, as well as being stressful to owners. However, links between obesity and behavioural disorders have never previously been explored. An online survey was conducted between June and August in 2014, coinciding with the broadcast of a National UK television programme, exploring dog health, welfare and behaviour. Information gathered included signalment, overweight status and the prevalence of a range of undesirable behaviours. Fisher's exact test and OR were used to determine associations between overweight status and owner-reported behaviours. A total of 17 028 responses were received. After data verification, the final dataset comprised 11 154 dogs, 1801 (16.1 %) of which were reported by owners to be overweight. Owners of overweight dogs were more likely to see them as 'a baby' (P < 0.0001) and allow them to sleep on their bed (P < 0.0001). Overweight dogs were also more likely to guard food (P < 0.0001) and steal food (P < 0.0001). Other undesirable behaviours more commonly reported in overweight dogs included barking, growling or snapping at strangers (P = 0.0011) and other dogs (P = 0.0015), being fearful of outdoors (P < 0.0001), and not always coming back when called (P = 0.0011). Finally, owners were more likely to report that unsociable behaviours adversely affected their dog's health (P < 0.0001). Overweight status is associated with a number of undesirable behaviours in dogs. Further studies are now required to explore the reasons for these associations. PMID- 28630693 TI - Quality of food-frequency questionnaire validation studies in the dietary assessment of children aged 12 to 36 months: a systematic literature review. AB - A child's diet is an important determinant of growth and development. Because of this, the accurate assessment of dietary intake in young children remains a challenge. A systematic search of studies validating FFQ methodologies in children 12 to 36 months of age was completed. English-language articles published until March 2016 were searched using three electronic databases (MEDLINE, EMBASE and CINAHL). Quality assessment of the identified studies was carried out using The Reduced Summary Score and EURopean micronutrient RECommendations Aligned (EURRECA) scoring system. Seventeen studies were included and categorised according to whether they reflected long-term (>=7 d) or short term (<7 d) intake, or used a biomarker. A total score for each micronutrient was calculated from the mean of the correlation coefficients weighted by the study quality score. At least three validation studies per micronutrient were required for inclusion. Fifteen studies (83 %) that considered validity of the FFQ in assessing nutrient intakes had quality scores from 2.5 to 6.0. Of those, ten (67 %) studies found FFQ to have good correlations in assessing dietary intake (>0.4). Of the nutrients with three or more studies available, FFQ validated using a reference method reflecting short-term intake had a good weighted correlation for Ca (0.51), and acceptable weighted correlations for vitamin C (0.31) and Fe (0.33). Semi-quantitative FFQ were shown to be valid and reproducible when estimating dietary intakes at a group level, and are an acceptable instruments for estimating intakes of Ca, vitamin C and Fe in children 12 to 36 months of age. PMID- 28630694 TI - Physical activity level of female and male adult cats before and after running wheel habituation. AB - The objective of the present study was to evaluate whether access to a running wheel increases voluntary physical activity in adult female and male domestic cats. Eight neutered domestic shorthair male cats (mean age 8.6 (sd 0.05) years) and eleven intact domestic shorthair female cats (mean age 3.3 (sd 0.14) years) were group housed for 22 h daily and individually housed during the feeding period. Voluntary physical activity was measured using accelerometers. Experimental design consisted of 1 week of baseline physical activity measurement, followed by 3 weeks of wheel habituation, and 1 week of physical activity measurement post-wheel habituation. Female cat voluntary physical activity levels increased (P < 0.05) post-habituation during the dark period, resulting in an altered (P < 0.05) light:dark activity ratio, whereas male cat voluntary physical activity levels remained unchanged post-habituation. Food anticipatory activity did not differ pre- and post-habituation. However, it corresponded to a numerically greater proportion of daily physical activity for males (17.5 %) v. females (12 %). In general, female cats were more active than male cats. Habituation to a running wheel appears to be an effective method to increase voluntary physical activity of younger female cats. Thus, running wheels might be a potential strategy in the prevention or management of feline obesity. PMID- 28630692 TI - Liver fat: a relevant target for dietary intervention? Summary of a Unilever workshop. AB - Currently it is estimated that about 1 billion people globally have non-alcoholic fatty liver disease (NAFLD), a condition in which liver fat exceeds 5 % of liver weight in the absence of significant alcohol intake. Due to the central role of the liver in metabolism, the prevalence of NAFLD is increasing in parallel with the prevalence of obesity, insulin resistance and other risk factors of metabolic diseases. However, the contribution of liver fat to the risk of type 2 diabetes mellitus and CVD, relative to other ectopic fat depots and to other risk markers, is unclear. Various studies have suggested that the accumulation of liver fat can be reduced or prevented via dietary changes. However, the amount of liver fat reduction that would be physiologically relevant, and the timeframes and dose effect relationships for achieving this through different diet-based approaches, are unclear. Also, it is still uncertain whether the changes in liver fat per se or the associated metabolic changes are relevant. Furthermore, the methods available to measure liver fat, or even individual fatty acids, differ in sensitivity and reliability. The present report summarises key messages of presentations from different experts and related discussions from a workshop intended to capture current views and research gaps relating to the points above. PMID- 28630695 TI - Newly formulated, protein quality-enhanced, extruded sorghum-, cowpea-, corn-, soya-, sugar- and oil-containing fortified-blended foods lead to adequate vitamin A and iron outcomes and improved growth compared with non-extruded CSB+ in rats. AB - Corn and soyabean micronutrient-fortified-blended foods (FBF) are commonly used for food aid. Sorghum and cowpeas have been suggested as alternative commodities because they are drought tolerant, can be grown in many localities, and are not genetically modified. Change in formulation of blends may improve protein quality, vitamin A and Fe availability of FBF. The primary objective of this study was to compare protein efficiency, Fe and vitamin A availability of newly formulated extruded sorghum-, cowpea-, soya- and corn-based FBF, along with a current, non-extruded United States Agency for International Development (USAID) corn and soya blend FBF (CSB+). A second objective was to compare protein efficiency of whey protein concentrate (WPC) and soya protein isolate (SPI) containing FBF to determine whether WPC inclusion improved outcomes. Eight groups of growing rats (n 10) consumed two white and one red sorghum-cowpea (WSC1 + WPC, WSC2 + WPC, RSC + WPC), white sorghum-soya (WSS + WPC) and corn-soya (CSB14 + WPC) extruded WPC-containing FBF, an extruded white sorghum-cowpea with SPI (WSC1 + SPI), non-extruded CSB+, and American Institute of Nutrition (AIN)-93G, a weanling rat diet, for 4 weeks. There were no significant differences in protein efficiency, Fe or vitamin A outcomes between WPC FBF groups. The CSB+ group consumed significantly less food, gained significantly less weight, and had significantly lower energy efficiency, protein efficiency and length, compared with all other groups. Compared with WSC1 + WPC, the WSC1 + SPI FBF group had significantly lower energy efficiency, protein efficiency and weight gain. These results suggest that a variety of commodities can be used in the formulation of FBF, and that newly formulated extruded FBF are of better nutritional quality than non-extruded CSB+. PMID- 28630696 TI - The impact of time of neutering on weight gain and energy intake in female kittens. AB - Neutering is a risk factor for obesity in companion animals. In a study to determine the total energy requirements of kittens (15-52 weeks) the impact of neutering and age when neutered on intake and body weight (BW) was investigated. Females (n 14), neutered when 19 (early neuter; EN) or 31 (conventional neuter; CN) weeks old (n 7/group), were individually fed to maintain an ideal body condition score (BCS). EN kittens gained weight gradually whilst CN kittens' BW gain slowed from week 24, weighing less than EN kittens from week 30 with a reduced energy intake (kcal/kg BW0.67) in weeks 24-32 (P < 0.05). Following neutering, CN cats' BW and energy intake increased rapidly (energy intake CN > EN in weeks 36-40). Although EN required earlier diet restriction, acute hyperphagia and increased rate of BW gain following neutering were not observed. Earlier neutering may aid healthy weight management through growth when regulating intake to maintain an ideal BCS. PMID- 28630697 TI - The effect of position on the precision of dual-energy X-ray absorptiometry and correlation with body condition score in dogs and cats. AB - Dual-energy X-ray absorptiometry (DEXA) has been used to assess body composition in dogs and cats in several studies, but studies are difficult to compare for several reasons. The aim of the present study was to evaluate whether positioning of dogs or cats in either dorsal or ventral recumbency during DEXA scanning influences results. Dogs and cats that were brought to the University Hospital for Companion Animals for euthanasia during the period 15 September-6 November 2015 were consecutively recruited if owners signed a written consent. Following euthanasia and before rigor mortis, the animals were body condition scored (BCS, nine-point scale) and DEXA scanned. DEXA measurements of total body mass (TBM), bone mineral content (BMC), bone mineral density (BMD), lean soft tissue mass (LSTM) and body fat (BF) were performed five times in ventral and two times in dorsal recumbency on each animal. Differences between positioning were analysed using Student's t test or Wilcoxon's test depending on normality of the data. A total of thirteen dogs and seven cats of different breeds, size, sexes and age were included. The CV for DEXA parameters in ventral or dorsal recumbency were, for dogs, TBM <= 0.1 %, BMC <= 1.63 %, BMD <= 1.29 %, LSTM <= 0.89 % and BF <= 1.52 %; and, for cats, TBM <= 0.08 %, BMC <= 0.61 %, BMD <= 0.49 %, LSTM <= 0.45 % and BF <= 0.88 %. In both positions, a good correlation was found for dogs (r 0.84-0.85; P < 0.0003) and cats (r 0.89-0.90; P < 0.0081) between the nine-point BCS system and BF percentage measured by DEXA. Ventral and dorsal recumbency provides comparable results, except that BMD measures were higher in dorsal recumbency (P < 0.0004). PMID- 28630698 TI - Physical activity in the classroom to prevent childhood obesity: a pilot study in Santiago, Chile. AB - This paper describes a 4-month pilot study that tested the suitability of a physical activity intervention for first graders (children aged 6 and 7 years) in a public school in Santiago, Chile. Teachers were trained to deliver the programme in the classroom during the school day. Teachers were surveyed to determine if this intervention fit within their curriculum and classroom routines and they reported in a focus group that it was suitable for them. All children actively participated in the programme and positive changes in their attitudes towards physical activity were observed by their teachers. Anthropometrics, blood pressure and hand grip strength were measured in the students. A significant reduction was observed in children with high waist circumference >= 90th percentile, and in mean systolic blood pressure. However, statistical power values for those comparisons were rather low. Anthropometry and hand grip strength were not modified. The latter calculations and the lack of a control group are showing the weaknesses of this pilot study and that further research with a larger sample size and an experimental design is strongly needed. PMID- 28630699 TI - Nutritional correlates of monetary diet cost in young, middle-aged and older Japanese women. AB - Studies in many Western countries have consistently shown that monetary diet cost is positively associated with diet quality, but this may not necessarily be the case in Japan. This cross-sectional study examined the nutritional correlates of monetary diet cost among 3963 young (all 18 years old), 3800 middle-aged (mean age 48 years) and 2211 older (mean age 74 years) Japanese women. Dietary intakes were assessed using a comprehensive self-administered diet history questionnaire for young and middle-aged women and a brief self-administered diet history questionnaire for older women. Monetary diet cost was estimated using retail food prices. Total vegetables, fish and shellfish, green and black tea, white rice, meat, fruit and alcoholic beverages contributed most (79-89 %) to inter individual variation in monetary diet cost. Multiple regression analyses showed that monetary diet cost was negatively associated with carbohydrate intake, but positively with intakes of all other nutrients examined (including not only dietary fibre and key vitamins and minerals but also saturated fat and Na) in all generations. For food group intakes, irrespective of age, monetary diet cost was associated inversely with white rice and bread but positively with pulses, potatoes, fruit, total vegetables, fruit and vegetable juice, green and black tea, fish and shellfish, and meat. In conclusion, in all three generations of Japanese women and contrary to Western populations, monetary diet cost was positively associated with not only healthy dietary components (including fruits, vegetables, fish and shellfish, dietary fibre, and key vitamins and minerals), but also less healthy components (including saturated fat and Na). PMID- 28630700 TI - Retorting conditions affect palatability and physical characteristics of canned cat food. AB - The effects of different temperature and time conditions during retorting of canned cat food on physicochemical characteristics and palatability were examined. For this purpose, lacquer cans containing an unprocessed loaf-type commercial cat food were heated in a pressurised retorting system at three specified temperature-time profiles (113 degrees C/232 min, 120 degrees C/103 min and 127 degrees C/60 min) to equal a similar lethality (F0 value = 30). Physicochemical properties (viscosity, texture, particle size, pH) were determined, and a 10 d three-bowl palatability test was performed with ten European shorthair cats. Retorting at 113 degrees C/232 min resulted in differences in all the physical parameters examined ( particle size). Significant pH differences were observed (6.53, 6.63 and 6.66 for T113/232, 120 and 127 degrees C, respectively). Preference ratios were 0.38, 0.31 and 0.31 for T113/232, 120 and 127 degrees C, respectively (P = 0.067). It can be concluded that different retorting temperature-time profiles with equal F0 value significantly affect physical characteristics and tended to affect palatability of moist cat food. PMID- 28630701 TI - Evaluation of an in vitro fibre fermentation method using feline faecal inocula: inter-individual variation. AB - The present study aimed to evaluate the inter-individual variability in fermentation of standard fibrous substrates by faecal inocula from ten healthy adult female cats. Substrates were citrus pectin (CP), fructo-oligosaccharides (FOS), guar gum (GG), sugar beet pulp (SBP) and wheat middlings (WM). Each substrate was incubated with faecal inoculum from each cat. Gas production was measured continuously during the 48 h incubation and SCFA and organic matter disappearance (only SBP and WM) after incubation. Out of ten cats, nine produced faeces on the days of inoculum preparation. The substrates contrasted in terms of fermentation parameters measured. The inter-individual variability was in general lower for the more simple and pure substrates (CP, FOS, GG) than for the more complex substrates containing mixtures of fibres (SBP, WM). Furthermore, for total SCFA and gas produced, inter-individual variability was lower than for proportions of butyrate and of branched-chain fatty acids and for the parameters of gas production kinetics. It is concluded that the variability in in vitro fermentation parameters is associated with the complexity of fibrous substrates. The presented data are instrumental for the calculation of number of faecal donors required for precise in vitro characterisation of the fermentability of dietary fibres. In addition, the number of faecal donors should be adjusted to the specific fermentation parameter(s) of interest. PMID- 28630702 TI - Evaluation of an in vitro fibre fermentation method using feline faecal inocula: repeatability and reproducibility. AB - To gain knowledge on the precision of an in vitro method for characterisation of the fermentability of dietary fibres, this study aimed to evaluate the repeatability and reproducibility of such a method. Substrates used were citrus pectin (CP), fructo-oligosaccharides (FOS), guar gum (GG), sugar beet pulp (SBP) and wheat middlings (WM). Each substrate was incubated with faecal inoculum from five cats with three replicates for each substrate-cat combination. Gas production was measured continuously during the 48 h incubation and SCFA and organic matter disappearance (only SBP and WM) were determined after incubation. Four consecutive runs were performed. The within-run variability (repeatability) was generally lower for the more simple and pure substrates (CP, FOS, GG) than for the more complex substrates containing mixtures of fibres (SBP, WM). Replicates showed high variability, in particular for SCFA profiles and parameters of gas production kinetics. The between-run CV (reproducibility) for the measured parameters were, in general, below 10 % for CP, FOS and GG and higher values were obtained for SBP and WM. It is concluded that for precise dietary fibre characterisation, the number of replicates should be multiple and adjusted according to the variability of the parameters of interest and the complexity of fibres. The method yielded reproducible results with some variation in absolute values obtained, which may have an impact on the significance level of the differences among substrates. PMID- 28630703 TI - Energy requirements for growth in the Yorkshire terrier. AB - The 2006 National Research Council (NRC) equation calculating puppy energy requirements does not account for reported breed differences in growth pattern. Energy requirements of toy breed puppies are unknown and it is unclear whether feeding guidelines should differ between breeds. Energy requirements of Yorkshire terrier (YT) puppies were observed over their first year of life and compared with those predicted by the NRC and those previously observed in large (Labrador retriever) and medium (miniature Schnauzer; MS) breed puppies. Twenty-two puppies (from eight litters) were offered complete and balanced diets to maintain ideal body condition score (BCS). Energy intake, body weight and BCS were recorded from 10 to 52 weeks of age. Every 12 weeks, health was monitored by veterinary examination, routine haematology and plasma biochemistry. Puppies remained clinically healthy with normal skeletal development throughout. After analysis by linear mixed models it was observed that the NRC equation overestimates YT energy requirements between 10 and 20 weeks of age by up to 324.3 (95 % CI 390.4, 258.2) kJ/kg0.75. Energy intake was lower (P < 0.05) in YT than Labradors until 29 weeks by up to 376.6 (95 % CI 477.4, 275.3) kJ/kg0.75 and lower than MS between 16 and 25 weeks by up to 216.3 (95 % CI 313.0, 119.7) kJ/kg0.75 (P < 0.05). Data indicate differences in toy, medium and large breed energy requirements for growth. The NRC equation for puppy energy requirements overestimated the requirements of this YT population, suggesting the need for breed-specific feeding guides for growth to avoid overfeeding. PMID- 28630704 TI - The effects of a post-exercise carbohydrate and protein supplement on repeat performance, serum chemistry, insulin and glucagon in competitive weight-pulling dogs. AB - The physiological demands of weight-pulling dogs have yet to be investigated. Two groups of competitive weight-pulling dogs both underwent two identical pull series 3 h apart. The control group (n 8) was compared with a group fed a rapidly digestible carbohydrate and protein supplement after the first pull series (n 9). Blood was drawn before and after each pull series as well as at 15 and 30 min after the first pull series finished. Biochemistry values remained unremarkable throughout the study in both groups regardless of supplementation or exercise over time. Lactic acid showed mild significant increases post-exercise (2.1 (sd 1.2) mmol/l) compared with baseline (1.4 (sd 0.3) mmol/l; P = 0.03) after the initial pull series. When examining the effects of time there was a significant increase in insulin from baseline (median of 10.8 (range 6.8-17.4) MUIU/ml) compared with 30 min after supplementation (17.0 (range 8.1-33.0) MUIU/ml) and at 3 h after supplementation (19.2 (range 9.7-53.4) MUIU/ml). In the treatment group there was also a time effect, with glucagon being elevated from baseline (median of 100 (range 79-115) pg/ml) compared with 30 min after supplementation (114 (range 90-183) pg/ml) and after the second pull series (131 (range 107-152) pg/ml). Evaluation of each dog's ability to pull the same or greater amount of weight on the second pull series revealed no significant differences. In conclusion, weight-pulling dogs have mild elevations in lactate reflecting little anaerobic metabolism compared with other canine sprinting athletes; hormonal changes associated with carbohydrate absorption are reflected within the treatment group, and supplementation had no effect on performance. PMID- 28630705 TI - Physiological effects of stress related to helicopter travel in Federal Emergency Management Agency search-and-rescue canines. AB - Working canines are deployed by the Federal Emergency Management Agency (FEMA), as part of a National Disaster Response Plan. Stress associated with helicopter flight and the resulting physical effects on the dog are unknown. Our objective was to test the hypotheses that (1) helicopter travel affects the physiology and faecal microbiota of working canines, but that (2) physiological consequences of helicopter travel will not negatively affect their work performance. A total of nine FEMA canines were loaded onto helicopters and flown for 30 min in July 2015. Rectal temperature, behavioural stress indicators and saliva swabs (for cortisol) were collected at baseline, loading, mid-flight and post-flight. After flight, canines completed a standardised search exercise to monitor work performance. Faecal samples were collected for microbial DNA extraction and Illumina sequencing. All canines were on a standardised diet (CANIDAE(r) Grain Free PURE Land(r)) for 3 weeks prior to the study. Visible indicators of stress were observed at loading and at mid-flight and corresponded with an increase (P < 0.05) in salivary cortisol from 5.4 ug/l (baseline) to 6.4 ug/l (loading). Additionally, rectal temperature increased (P < 0.05) from 38.61 degrees C (baseline) to 39.33 degrees C (mid-flight) and 39.72 degrees C (post-flight). Helicopter travel did not affect search performance (P > 0.05). We found that alpha- and beta-diversity measures of faecal microbiota were not affected (P > 0.05). Our data suggest that although helicopter travel may cause physiological changes that have been associated with stress in working dogs, it does not make an impact on their search performance or the stability of faecal microbiota. PMID- 28630706 TI - Effects of feeding untreated, pasteurized and acidified waste milk and bunk tank milk on the performance, serum metabolic profiles, immunity, and intestinal development in Holstein calves. AB - BACKGROUND: The present experiment was performed to assess the effects of different sources of milk on the growth performance, serum metabolism, immunity, and intestinal development of calves. Eighty-four Holstein male neonatal calves were assigned to one of the following four treatment groups: those that received bunk tank milk (BTM), untreated waste milk (UWM), pasteurized waste milk (PWM), and acidified waste milk (AWM) for 21 d. RESULTS: Calves in the BTM and AWM groups consumed more starter (P < 0.05) than those in the UWM group. Average daily gain in the UWM group was the highest (P < 0.05). Calves exhibited the highest (P < 0.05) serum total protein, albumin, total cholesterol, high density lipoprotein, triglycerides, growth hormone, immunoglobulin (Ig) A and IgM concentrations in the UWM group, highest malondialdehyde and tumor necrosis factor-alpha in the PWM group (P < 0.05), and highest glutathione peroxidase and IgG in the BTM group (P < 0.05). The jejunum and ileum of the calves in all treatments presented a slight inflammatory response. The jejunal inflammation scores were higher (P < 0.05) in the UWM and AWM groups than the BTM group; the ileal inflammation scores increased more (P < 0.05) in the AWM group than the BTM group. Jejunal immunohistochemical scores (IHS) were higher (P < 0.05) in the PWM and AWM groups than the BTM group. Compared to the other three groups, calves feeding on BTM had lower (P < 0.05) ileal IHS. Jejunal interleukin(IL)-1beta, IL 8, and IL-10 mRNA expression in the UWM group was the highest (P < 0.05). Calves fed AWM increased (P < 0.05) mRNA expression of IL-8 and toll like receptor 4 (TLR-4) in the jejunum and IL-8, IL-1beta, IL-6, IL-8, and IL-10 in the mesenteric lymph nodes. CONCLUSIONS: Overall, bunk tank milk is the best choice for calf raising compared to waste milk. The efficiency of feeding pasteurized and acidified waste milk are comparable, and the acidification of waste milk is an acceptable labor-saving and diarrhea-preventing feed for young calves. PMID- 28630707 TI - Evidence of endometrial amino acid metabolism and transport modulation by peri ovulatory endocrine profiles driving uterine receptivity. AB - BACKGROUND: In beef cattle, changes in the periovulatory endocrine milieu are associated with fertility and conceptus growth. A large preovulatory follicle (POF) and the resulting elevated concentrations of progesterone (P4) during diestrus positively affect pregnancy rates. Amino acids (AA) are important components of maternally derived secretions that are crucial for embryonic survival before implantation. The hypothesis is that the size of the POF and the concentration of P4 in early diestrus modulate the endometrial abundance of SLC transcripts related to AA transport and metabolism and subsequently impact luminal concentrations of AA. The follicle growth of Nelore cows was manipulated to produce two experimental groups: large POF and CL (LF-LCL group) and small POF and CL (SF-SCL group). On Day 4 (D4; Experiment 1) and Day 7 (D7; Experiment 2) after GnRH-induced ovulation (GnRH treatment = D0), the animals were slaughtered and uterine tissues and uterine washings were collected. qRT-PCR was used to evaluate the expression levels of AA transporters in D4 and D7 endometrial tissues. The concentrations of AA were quantified in D4 and D7 uterine washings by HPLC. RESULTS: Transcript results show that, on D4, SLC6A6, SLC7A4, SLC17A5, SLC38A1, SLC38A7 and SCLY and on D7 SLC1A4, SLC6A1, SLC6A14, SLC7A4, SLC7A7, SLC7A8, SLC17A5, SLC38A1, SLC38A7, SLC43A2 and DDO were more abundant in the endometria of cows from the LF-LCL group (P < 0.05). In addition, concentrations of AA in the uterine lumen were influenced by the endocrine profiles of the mother. In this context, D4 uterine washings revealed that greater concentrations of taurine, alanine and alpha-aminobutyric acid were present in SF-SCL (P < 0.05). In contrast, lower concentrations of valine and cystathionine were quantified on D7 uterine washings from SF-SCL cows (P < 0.05). CONCLUSION: The present study revealed an association between the abundance of transcripts related to AA transport and metabolism in the endometrium and specific periovulatory endocrine profiles related to the receptive status of the mother. Such insights suggest that AAs are involved in uterine function to support embryo development. PMID- 28630708 TI - What happens after treatment? A systematic review of relapse, remission, and recovery in anorexia nervosa. AB - BACKGROUND: Relapse after treatment for anorexia nervosa (AN) is a significant clinical problem. Given the level of chronicity, morbidity, and mortality experienced by this population, it is imperative to understand the driving forces behind apparently high relapse rates. However, there is a lack of consensus in the field on an operational definition of relapse, which hinders precise and reliable estimates of the severity of this issue. The primary goal of this paper was to review prior studies of AN addressing definitions of relapse, as well as relapse rates. METHODS: Data sources included PubMed and PsychINFO through March 19th, 2016. A systematic review was performed following the PRISMA guidelines. A total of (N = 27) peer-reviewed English language studies addressing relapse, remission, and recovery in AN were included. RESULTS: Definitions of relapse in AN as well as definitions of remission or recovery, on which relapse is predicated, varied substantially in the literature. Reported relapse rates ranged between 9 and 52%, and tended to increase with increasing duration of follow-up. There was consensus that risk for relapse in persons with AN is especially high within the first year following treatment. DISCUSSION: Standardized definitions of relapse, as well as remission and recovery, are needed in AN to accelerate clinical and research progress. This should improve the ability of future longitudinal studies to identify clinical, demographic, and biological characteristics in AN that predict relapse versus resilience, and to comparatively evaluate relapse prevention strategies. We propose standardized criteria for relapse, remission, and recovery, for further consideration. PMID- 28630709 TI - Mark E Josephson: A Tribute to His Work on Ventricular Arrhythmias. AB - Dr Josephson was passionate about the study of ventricular arrhythmias and bold in his pioneering approach to their evaluation and management. Programmed right ventricular stimulation to test for antiarrhythmic drug efficacy was already pushing the risk limits for the invasive management of cardiac arrhythmias in the 1970s. PMID- 28630710 TI - HDAC Inhibitor Conjugated Polymeric Prodrug Micelles for Doxorubicin Delivery. AB - Amphiphilic diblock copolymers bearing histone deacetylase inhibitors (HDACi) (4 phenyl butyric acid and valproic acid) were synthesized by the ring-opening polymerization of gamma-4-phenylbutyrate-epsilon-caprolactone (PBACL), gamma valproate-epsilon-caprolactone (VPACL), and epsilon-caprolactone (CL) from a poly(ethylene glycol) macroinitiator (PEG). These amphiphilic diblock copolymers self-assembled into stable pro-drug micelles and demonstrated excellent biocompatibility. High loading of doxorubicin (DOX) up to 5.1 wt% was achieved. Optimized micelles enabled sustained drug release in a concentration-dependent manner over time to expand the therapeutic window of cytotoxic small molecule drugs. PMID- 28630711 TI - Matchmaker.com for pandas. PMID- 28630712 TI - Quantifying drivers of wild pig movement across multiple spatial and temporal scales. AB - BACKGROUND: The movement behavior of an animal is determined by extrinsic and intrinsic factors that operate at multiple spatio-temporal scales, yet much of our knowledge of animal movement comes from studies that examine only one or two scales concurrently. Understanding the drivers of animal movement across multiple scales is crucial for understanding the fundamentals of movement ecology, predicting changes in distribution, describing disease dynamics, and identifying efficient methods of wildlife conservation and management. METHODS: We obtained over 400,000 GPS locations of wild pigs from 13 different studies spanning six states in southern U.S.A., and quantified movement rates and home range size within a single analytical framework. We used a generalized additive mixed model framework to quantify the effects of five broad predictor categories on movement: individual-level attributes, geographic factors, landscape attributes, meteorological conditions, and temporal variables. We examined effects of predictors across three temporal scales: daily, monthly, and using all data during the study period. We considered both local environmental factors such as daily weather data and distance to various resources on the landscape, as well as factors acting at a broader spatial scale such as ecoregion and season. RESULTS: We found meteorological variables (temperature and pressure), landscape features (distance to water sources), a broad-scale geographic factor (ecoregion), and individual-level characteristics (sex-age class), drove wild pig movement across all scales, but both the magnitude and shape of covariate relationships to movement differed across temporal scales. CONCLUSIONS: The analytical framework we present can be used to assess movement patterns arising from multiple data sources for a range of species while accounting for spatio-temporal correlations. Our analyses show the magnitude by which reaction norms can change based on the temporal scale of response data, illustrating the importance of appropriately defining temporal scales of both the movement response and covariates depending on the intended implications of research (e.g., predicting effects of movement due to climate change versus planning local-scale management). We argue that consideration of multiple spatial scales within the same framework (rather than comparing across separate studies post-hoc) gives a more accurate quantification of cross-scale spatial effects by appropriately accounting for error correlation. PMID- 28630714 TI - What is this thing they call research? PMID- 28630713 TI - Corneal ulcerative disease in dogs under primary veterinary care in England: epidemiology and clinical management. AB - BACKGROUND: Corneal ulcerative disease (CUD) has the potential to adversely affect animal welfare by interfering with vision and causing pain. The study aimed to investigate for the first time the prevalence, breed-based risk factors and clinical management of CUD in the general population of dogs under primary veterinary care in England. RESULTS: Of 104,233 dogs attending 110 clinics participating within the VetCompass Programme from January 1st to December 31st 2013, there were 834 confirmed CUD cases (prevalence: 0.80%, 95% confidence interval (CI) 0.75-0.86). Breeds with the highest prevalence included Pug (5.42% of the breed affected), Boxer (4.98%), Shih Tzu (3.45%), Cavalier King Charles Spaniel (2.49%) and Bulldog (2.41%). Purebred dogs had 2.23 times the odds (95% CI 1.84-2.87, P < 0.001) of CUD compared with crossbreds. Brachycephalic types had 11.18 (95% CI 8.72-14.32, P < 0.001) and spaniel types had 3.13 (95% CI 2.38 4.12, P < 0.001) times the odds for CUD compared with crossbreds. Pain was recorded in 385 (46.2%) cases and analgesia was used in 455 (54.6%) of dogs. Overall, 62 (7.4%) cases were referred for advanced management and CUD contributed to the euthanasia decision for 10 dogs. CONCLUSIONS: Breeds such as the Pug and Boxer, and conformational types such as brachycephalic and spaniels, demonstrated predisposition to CUD in the general canine population. These results suggest that breeding focus on periocular conformation in predisposed breeds should be considered in order to reduce corneal disease. PMID- 28630715 TI - Can hip arthroscopy in the presence of arthritis delay the need for hip arthroplasty? AB - Hip arthroscopy for joint preservation surgery has grown immensely over the last two decades. There is now an increasing trend to try and expand the role of hip arthroscopy to include patients of an older age or perhaps even with signs of arthritis, instead of the established patient group of young adults with mechanical symptoms or serious athletes. But how much of this growth is really justified? Once arthritis is apparent, the arthroscopic procedures needed to try and limit progression of the disease are likely to be different to those needed in young adult non-arthritic hips. Similarly, the expectation of results following an arthroscopic procedure in an older adult with arthritis must also be different. With an almost 5-fold increase in conversion rate from arthroscopy to arthroplasty in the over 50s population, arthroscopy in arthritis is a different procedure, with a different outcome, to arthroscopy in young adults with no evidence of osteoarthritis. This article takes a closer inspection at outcomes following hip arthroscopy in the older population particularly in those with evidence of early arthritis. This paper does not attempt to make recommendations in other diagnoses such as inflammatory arthritis or other secondary arthritides. It must be considered that hip arthroscopy is not a benign intervention: as well as the surgical risks, the lengthy rehabilitation period should be factored into the equation. Although the nature of surgeons is to find new techniques and push boundaries, we highlight the need for caution in undertaking arthroscopic intervention when arthritis is already apparent at presentation. PMID- 28630716 TI - Femoral neck fractures as a complication of hip arthroscopy: a systematic review. AB - The purpose of this study was to identify the causes and risk factors for hip fractures, a rare but devastating complication, following hip arthroscopy. The electronic databases MEDLINE, EMBASE and PubMed were searched and screened in duplicate for relevant clinical and basic sciences studies and pertinent data was abstracted and analysed in Microsoft Excel. Nineteen studies (12 clinical studies and seven biomechanical studies) with a total of 31 392 patients experiencing 43 hip fractures (0.1% of patients) met the inclusion criteria for this systematic review. Femoral osteochondroplasty was performed in 100% of patients who sustained a hip fracture. Six of the 12 (50%) studies identified early weight bearing (prior to 6 weeks post-operatively) as the cause for the hip fracture. Other causes of this complication included over resection during femoral osteochondroplasty, minor trauma and intensive exercise. The results suggest that early weight bearing is the largest modifiable risk factor for hip fracture after femoral osteochondroplasty. For this reason, an extended period of non-weight bearing or restricted weight bearing should be considered in select patients. Studies report a correlation between risk for post-operative hip fracture and increased age. Increased resection during osteochondroplasty has been correlated with increased risk of fracture in various basic science studies. Resection depth has significantly higher impact on risk of fracture than resection length or width. The reported amounts of resection that depth that can be performed before there is a significantly increased risk of fracture of the femoral neck varies from 10 to 30%. PMID- 28630717 TI - Arthroscopic hip preservation surgery practice patterns: an international survey. AB - To design and conduct a survey analyzing pre-, intra- and post- hip arthroscopy practice patterns among hip arthroscopists worldwide. A 21-question, IRB-exempt, HIPAA-compliant, cross-sectional survey was conducted via email using SurveyMonkey to examine pre-operative evaluation, intra-operative techniques and post-operative management. The survey was administered internationally to 151 hip arthroscopists identified from publicly available sources. Seventy-five respondents completed the survey (151 +/- 116 hip arthroscopy procedures per year; 8.6 +/- 7.1 years hip arthroscopy experience). Standing AP pelvis, false profile and Dunn 45 were the most common radiographs utilized. CT scans were utilized by 54% of surgeons at least some of the time. Only 56% of participants recommended an arthrogram with MRI. Nearly all surgeons either never (40%) or infrequently (58%) performed arthroscopy in Tonnis grade-2 or grade-3 osteoarthritis. Surgeons rarely performed hip arthroscopy on patients with dysplasia (51% never; 44% infrequently). Only 25% of participants perform a routine 'T' capsulotomy and 41% close the capsule if the patient is at risk for post-operative instability. Post-operatively, 52% never use a brace, 39% never use a continuous passive motion, 11% never recommended heterotopic ossification prophylaxis and 30% never recommended formal thromboembolic disease prophylaxis. Among a large number of high-volume experienced hip arthroscopists worldwide, pre , intra- and post- hip arthroscopy practice patterns have been established and reported. Within this cohort of respondents, several areas of patient evaluation and management remain discordant and controversial without universal agreement. Future research should move beyond expert opinion level V evidence towards high quality appropriately designed and conducted investigations. PMID- 28630718 TI - Ability to return to work without restrictions in workers compensation patients undergoing hip arthroscopy. AB - The purpose of this study was to investigate the ability of worker's compensation (WC) patients to return to work without restrictions after hip arthroscopy. Twenty-nine WC patients along with age and gender matched controls who underwent hip arthroscopy were retrospectively reviewed after achieving maximum medical improvement (MMI) status at minimum 1 year postoperatively. Patient demographic factors were evaluated, along with the Hip Outcome Score Activities of Daily Living and Sports-Specific subscales, and the modified Harris Hip Score (mHHS). The majority of WC patients were able to return to work without restrictions after reaching MMI (20/29, 69.0%). WC patients who failed to return to work without restrictions had a prolonged time from injury to surgery (3.01 +/- 2.16 months versus 6.36 +/- 4.16 months; P = 0.0079), more concomitant orthopedic injuries (4/20, 20.0% versus 9/9, 100%; P = 0.0001), and higher body mass index (BMI) (26.61 +/- 3.52 versus 29.54 +/- 3.43; P = 0.047) than those who returned to work without restrictions. WC patients had significant improvement of patient reported outcome scores following hip arthroscopy (P < 0.0001), but WC patients who returned to work without restrictions had higher scores than those who failed to do so (HOD-ADL: P < 0.0001; HOS-SS: P = 0.004; mHHS: P = 0.009). The majority of WC patients are able to return to work without restrictions when they reach MMI status following hip arthroscopy. Factors associated with failure to return to work without restrictions include prolonged time course between injury and surgical treatment, concomitant orthopaedic injuries, and a higher BMI. Level III, retrospective case-control study. PMID- 28630719 TI - Hip arthroscopy results in improved patient reported outcomes compared to non operative management of waitlisted patients. AB - Hip arthroscopy (HA) is an established treatment option to address intra articular pathology of the hip. However, some clinicians encourage non-operative management (NOM). Non-operative management may include active measures such as physiotherapy and intra-articular steroid injections, or NOM may involve so called watchful waiting with no active intervention. These approaches, along with surgery have been detailed recently in the Warwick Agreement, a Consensus Statement regarding diagnosis and treatment of Femoroacetabular Impingement Syndrome The aim of this study is to compare the change in clinical outcome scores of waitlisted patients with intra-articular hip pathology who receive no active treatment with matched controls that have undergone HA. Patients less than 60 years of age were identified from a HA waiting list in a single hospital in the Australian public hospital system. Patient reported outcomes (PRO) were collected whilst patients waited for surgery. During this waiting period no specific treatment was offered. A separate group of patients who had previously undergone HA were matched based on age, sex, body mass index and baseline non arthritic hip scores (NAHS). The groups were compared using the NAHS as the primary outcome measures. Modified Harris Hip Scores were also collected and compared. Thirty-six patients were included in each group, with a mean follow up of 19 months (12-36). There were no significant differences in age, sex, BMI and NAHS between groups at baseline. At final follow up, mean NAHS scores after HA were significantly higher than scores after NOM, 82.1 (36.4-100.0) versus 48.9 (11.3-78.8), respectively (P < 0.001) with a large effect size for mean change in scores between groups (d = 1.77, 95% CI 1.21-2.30). Mean mHHS after HA were significantly higher than scores after NOM, 84.3 (15.4-100.0) versus 48.1 (21.0 66.0) respectively (P < 0.001), with a large effect size for mean change in scores between groups (d = 1.92, 95% CI 1.34-2.46). HA may lead to significant improvements in PRO when compared to non-operative management of waitlisted patients with intra-articular pathology of the hip at 18 months follow-up. PMID- 28630721 TI - Traction-related problems after hip arthroscopy. AB - Traction-related problems are poorly described in the existing literature. The purpose of this prospective study was to describe traction-related problems and how patients perceive these problems. The study was a descriptive cohort study and data were collected from questionnaires and patient files. The questionnaire included questions on patients' perceptions of traction-related problems in the groin area, at the knee and ankle and how patients had coped with these problems. A total of 100 consecutive patients undergoing hip arthroscopy filled out the questionnaire. Primary findings of this study were that 74% of patients reported some sort of traction-related problems after hip arthroscopy. About 32% of the patients had problems in the groin area and 49% of the patients complained of symptoms in the knee joint. A total of 37% of the patients had experienced problems from the traction boot in the ankle area. The complications were found to be temporary and disappeared after 2-4 weeks. Five patients still had complaints after 3 months. All five patients had a pre-existing knee injury prior to undergoing hip arthroscopy. Traction-related problems after hip arthroscopy are a challenge and our study showed that 74% of the patients reported traction related problems. This is significantly higher than previously reported. The present study found a high rate of complaints from the knee and ankle joints that have not previously been reported. The presented data suggest the need for more pre-surgery patient information about possible traction-related problems. PMID- 28630720 TI - Predictors and trajectories of chronic postoperative pain following hip preservation surgery. AB - Factors contributing to chronic postoperative pain (CPOP) are poorly defined in young people and developmental considerations are poorly understood. With over 5 million children undergoing surgery yearly and 25% of adults referred to chronic pain clinics identifying surgery as the antecedent, there is a need to elucidate factors that contribute to CPOP in surgical patients. The present study includes patients undergoing hip preservation surgery at a children's hospital. The HOOS and SF-12 Health Survey were administered to 614 pre-surgical patients with 421 patients completing follow-up (6-months, 1-year and 2-years post-surgery). Pain, quality of life, and functioning across time were examined for each group within the population. A three trajectory model (low pain, pain improvement and high pain) emerged indicating three categories of treatment responders. Pain trajectory groups did not differ significantly on gender, pre-surgical age, BMI, prior hip surgery, surgical type, joint congruence or Tonnis grade. The groups differed significantly from each other on pre-surgical pain, pain chronicity, quality of life and functioning. Those in the high pain and pain improvement groups endorsed having pre-surgical depression at significantly higher rates and lower pre-surgical quality of life compared to those in the low pain group (P < 0.01). Those in the high pain group reported significantly worse pre-surgical functioning compared to those in the pain improvement (P < 0.0001) and low pain groups (P < 0.0001).The results demonstrate the need for preoperative screening prior to hip preservation surgery, as there may be a subset of patients who are predisposed to chronic pain independent of hip health. PMID- 28630722 TI - Hip arthroscopy protocol: expert opinions on post-operative weight bearing and return to sports guidelines. AB - The objectives of this study are to survey the weight-bearing limitation practices and delay for returning to running and impact sports of high volume hip arthroscopy orthopedic surgeons. The study was designed in the form of expert survey questionnaire. Evidence-based data are scares regarding hip arthroscopy post-operative weight-bearing protocols. An international cross-sectional anonymous Internet survey of 26 high-volume hip arthroscopy specialized surgeons was conducted to report their weight-bearing limitations and rehabilitation protocols after various arthroscopic hip procedures. The International Society of Hip Arthroscopy invited this study. The results were examined in the context of supporting literature to inform the studies suggestions. Four surgeons always allow immediate weight bearing and five never offer immediate weight bearing. Seventeen surgeons provide weight bearing depending on the procedures performed: 17 surgeons allowed immediate weight bearing after labral resection, 10 after labral repair and 8 after labral reconstruction. Sixteen surgeons allow immediate weight bearing after psoas tenotomy. Twenty-one respondents restrict weight bearing after microfracture procedures for 3-8 weeks post-operatively. Return to running and impact sports were shorter for labral procedures and bony procedures and longer for cartilaginous and capsular procedures. Marked variability exists in the post-operative weight-bearing practices of hip arthroscopy surgeons. This study suggests that most surgeons allow immediate weight bearing as tolerated after labral resection, acetabular osteoplasty, chondroplasty and psoas tenotomy. For cartilage defect procedures, 6 weeks or more non-weight bearing is suggested depending on the area of the defect and lateral central edge angle. Delayed return to sports activities is suggested after microfracture procedures. The level of evidence was Level V expert opinions. PMID- 28630723 TI - Outcome after arthroscopic labral surgery in patients previously treated with periacetabular osteotomy: a follow-up study of 43 patients. AB - To identify factors predicting failure after hip arthroscopy in patients with previous periacetabular osteotomy (PAO) defined as a conversion to total hip replacement (THR) and to evaluate the patient reported outcome scores. Of 55 hips treated with hip arthroscopy after PAO from Aug 2008 to 2012 at Aarhus University Hospital, 43 hips were included (median age: 36.1 yrs, range 16.3-56.9 yrs). Indications were unacceptable pain, a positive FABER and impingement test and signs of labral damage on MR-arthrography. Outcomes were evaluated with mHHS and HOS. Failure was defined as conversion to a THR. Nine hips were converted to a THR. Kaplan-Meier survival rate was 52.8% (95% CI, 10%-83.8%) at 6.5 years follow up. Statistically significant predictors of failure: joint space width after PAO <3.0 mm and Tonnis grade of 2. Fourteen hips needed revision hip arthroscopy. Labral damage was present in 84% of the hips. In 42% of the hips cartilage lesions of Becks grade >3 were found. Mean mHHS and HOS were 65.7 and 68.8 respectively at follow-up. A NRS pain score of >3 in rest and during activity were present in respectively, 43% and 62% of the patients. Hip arthroscopy after PAO demonstrated limited clinical benefit with no decrease in pain levels and 21% of patients needing reoperation to THR. Radiographic signs of joint degeneration after PAO are predictors of faiElure. Further studies are needed to clarify what role hip arthroscopy should play in this patient group. PMID- 28630725 TI - Endoscopic repair of hip abductor tears: outcomes with two-year follow-up. AB - Abductor lesions are increasingly recognized as a source of recalcitrant laterally based hip pain and dysfunction. There is a growing body of evidence that many of these may be amenable to endoscopic repair. To report the demographic data and outcomes of endoscopic hip abductor repair. Twelve patients underwent endoscopic abductor repair with 2-year follow-up. These patients were prospectively assessed with modified Harris hip and iHOT scores. The indications for surgery were clinical and MRI findings of symptomatic abductor tears that had failed conservative treatment. All patients underwent concomitant or prior arthroscopy of the joint. Repair was performed with suture anchors using an iliotibial band-sparing endoscopic technique; followed by a 4-month structured rehabilitation protocol. Follow-up was obtained on all patients at 24 months. The average age was 56 years (range 39-77 years). These were all females. All demonstrated improved modified Harris hip scores, averaging 43 points (preop 42; postop 85). Eleven of 12 (92%) demonstrated improved iHOT scores, averaging 52 points (preop 21; postop 73). Ten patients had accompanying intra-articular pathology including 10 labral tears, 7 chondral lesions, 6 synovitis and 1 pincer impingement. There were no complications, and none underwent further surgery. Abductor tears of the hip can be clinically relevant and respond well to endoscopic repair. This tends to be a disorder of older females who present with severe disability, reflected by low preoperative modified Harris hip scores, and demonstrate significant, although incomplete, improvement. PMID- 28630724 TI - Labral reconstruction with tendon allograft: histological findings show revascularization at 8 weeks from implantation. AB - This description shows the histological findings of a peroneus brevis tendon allograft used for labral reconstruction, implanted 8 weeks before being retrieved due to a postoperative complication unrelated to the graft. As far as we have knowledge this is the first description about revascularization of an allograft used for hip labral reconstruction. The histological report of the removed peroneus brevis tendon allograft shows evidence of vascular ingrowth represented by small vessels with a thin muscular wall in all layers of the graft and cellular migration mainly represented by mature fibroblasts. PMID- 28630726 TI - The HAPI 'Hip Arthroscopy Pre-habilitation Intervention' study: does pre habilitation affect outcomes in patients undergoing hip arthroscopy for femoro acetabular impingement? AB - The purpose of this randomized prospective comparative controlled pilot study was to determine whether specific patient exercises done pre-hip arthroscopy surgery for femoro-acetabular impingement affected post-operative recovery. Between October 2013 and June 2014, 6 males and twelve females over the age of eighteen, who were listed for hip arthroscopy for femoro-acetabular impingement, were randomized into two groups. A hip-specific, 8-week home exercise programme was given to the experimental group before their surgery. The control group was given no instruction on exercise before surgery. All participants followed the same rehabilitation programme after surgery. Outcome measures were assessed at set time intervals. Hand held dynamometry was used to assess muscle strength, and the EQ-5D-5 L Score and the Non-Arthritic Hip Score were utilized. Sixteen participants completed the study (eight controls: mean age 41.75 years and eight intervention: mean age 37.5 years). A mixed ANCOVA analysis compared the treatment groups taking baseline values into account. A statistically significant difference was found between the treatment groups for knee extension strength on both operative (P = 0.05) and non-operative sides (P = 0.002), hip flexor strength operative side (P = 0.02) and for EQ-5D-5 L health (P = 0.03), in favour of the intervention group. There was no significant difference between the treatment groups for the other measures, although some tended towards significance. This small pilot study has been designed to aid the further research and the differences between the groups found in these results may inform future larger scale studies. PMID- 28630727 TI - Medial synovial fold cyst in the hip leading to pectineofoveal impingement. AB - Pectineofoveal impingement is a relatively rare condition, which can cause hip or groin pain along with mechanical symptoms of clicking in the young adult. We present the case of a 13-year-old girl who was referred to us with left hip pain, which had been affecting her for over six months along with mechanical symptoms of clicking. Following appropriate clinical examination and investigations the patient underwent arthroscopic surgery of her hip. At arthroscopy, a cyst was identified on the medial synovial fold, which was abutting against the zona orbicularis leading to pectineofoveal impingement. The cyst was decompressed and the synovial fold excised arthroscopically. Following arthroscopic intervention, the patient did extremely well and remains asymptomatic at the last follow-up (7 months following the procedure). The case highlights the importance of the medial synovial fold pathology as an important cause for pain and mechanical symptoms in the young adult hip. PMID- 28630728 TI - Parameters for assessment of the inferior acetabulum morphology in 300 adult hips. AB - The inferior acetabulum (IA) has been studied as a stabilizer of the hip in flexed positions with potential implications in femoroacetabular impingement and hip instability. However, there is a paucity of studies considering the normal morphology and parameters for assessment of the IA. The purpose of this study was to define parameters to assess the IA morphology and their normal range. Specifically, the objectives were to assess: (i) the width of the anterior horn (AH) and posterior horn (PH) of the acetabulum; (ii) the inclination of the articular surface of the AH angle (AHA) and PH angle (PHA) in the axial plane; (iii) the anterior opening angle of the IA and differences between genders. One hundred and fifty adult skeletons were utilized in this study. Measurements were taken directly from acetabula in 300 innominate bones utilizing digital calipers. In sequence, the innominate bones were assembled to sacrum and 150 pelvises were digitally photographed in standardized positions. Angular parameters of the acetabulum were then measured utilizing the Adobe Photoshop software. The mean width of the AH was 14.80 +/- 2.35 mm (range 9.44-20.88). The mean width of the PH was 19.72 +/- 2.61 mm (range 13.16-25.86). The AHA was on average 43.58 +/- 7.10 degrees (range 24.70-64) and the PHA was on average 36.07 +/- 7.54 degrees (16.10-53.20). The mean anterior opening angle of the IA was 25.33 +/- 5.40 degrees (10.90-43.10). The IA morphology can be evaluated in all anatomical planes through quantitative parameters. The assessment of the osseous morphology of the IA is the first step to elucidate abnormalities of the IA as potential source of hip pain. PMID- 28630729 TI - Acetabular rim length: an anatomical study to determine reasonable graft sizes for labral reconstruction. AB - The purpose of this article is to determine normative values for the length of the acetabular rim and detect differences between gender, age, ethnicity, height and leg length. Six measurements were taken on the acetabular rim of 143 cadaveric skeleton specimens (286 acetabula) using a coordinate-measuring device: circumferential (excluding acetabular notch), anterior inferior iliac spine (AIIS)-anterior, AIIS-posterior, 12-3 o'clock, 12-9 o'clock and 11-5 o'clock. Museum specimen height data and leg length data from a previous study were recorded for 109 of 143 specimens. Intraclass correlation coefficients were calculated. Student t-tests compared mean values. Multiple regression analysis was used to determine the relationship between acetabular rim length and gender, age, ethnicity, height and leg length. The average acetabular rim length in males for circumferential, AIIS-anterior, AIIS-posterior, 12-3, 12-9 and 11-5 o'clock were 15.8, 4.2, 11.7, 4.9, 4.7 and 9.5 cm, respectively; and for females: 13.7, 3.7, 10.0, 4.3, 4.1 and 8.3 cm, respectively. Intraclass correlation coefficients were 0.953, 0.930, 0.958, 0.857, 0.913 and 0.951, respectively, for each measurement. All six measurements were significantly larger for males (P < 0.001). Multiple regression analysis demonstrated a significant relationship between gender and rim length for all six measurements (P < 0.001) and between height and leg length and acetabular rim length for five of the six measurements exclusive of AIIS-anterior (P < 0.001). No significant trends between age or ethnicity and rim length were found. Average acetabular rim lengths were established. The acetabular rim is significantly longer in males and correlates with height and leg length. Age and ethnicity do not appear to be significant predictors of acetabular rim length. Normative values for acetabular rim lengths may assist in hip preservation surgery. PMID- 28630730 TI - Response to Green et al. PMID- 28630731 TI - What the papers say. PMID- 28630732 TI - Citations-be sure to have a good title. PMID- 28630733 TI - Return to running after arthroscopic hip surgery: literature review and proposal of a physical therapy protocol. AB - The number of hip arthroscopy procedures has significantly increased in the last several years, thereby necessitating individualized rehabilitation protocols for patients following hip arthroscopy. The purpose of this article is to review the literature on rehabilitation protocols for patients following hip arthroscopy and to describe a new protocol specifically designed for patients to return to running following hip arthroscopy. A search of PubMed was performed through October 2016 to locate studies of rehabilitation protocols for patients wishing to return to sport/general activity following hip arthroscopy. Patients at our institution who desired to return to running following hip arthroscopy underwent a set of return to running guidelines which are based on goal achievement within a three-phase system that begins with a walking program and finishes with return to distance running. Rehabilitation protocols for patients following hip arthroscopy frequently use a four-phase system in which Phase I focuses on regaining hip range of motion and protection of surgically repaired tissues, and Phase IV involves a pain-free return to sports. Rehabilitation protocols vary in timing in that some include a timeline with each phase taking a certain number of weeks while others are based on goal achievement. There is an overall lack of published outcomes based on patients adhering to various post-hip arthroscopy rehabilitation protocols. PMID- 28630735 TI - Arthroscopic acetabuloplasty without labral detachment for focal pincer-type impingement: a minimum 2-year follow-up. AB - In order to access and resect the acetabular rim, arthroscopic acetabuloplasty was described with labral detachment. When the chondrolabral junction remains intact, acetabuloplasty and labral refixation can be performed maintaining an unharmed labrum. We aimed to evaluate the outcome of a group of patients treated with arthroscopic acetabuloplasty without labral detachment. During the study period, we retrospectively analysed 44 patients with pincer-type o combined impingement and an intact chondroblabral junction, with an average follow-up of 32 months (range: 27-38). We excluded patients with isolated CAM-type impingement and previous hip pathology. Radiographs were analysed to define impingement and classify grade of osteoarthritis. Clinical evaluation consisted of pre-operative and post-operative modified Harris hip score (mHHS) and WOMAC as well as post operative visual analogue scale (VAS) of pain and satisfaction. Reoperations were considered surgical failures for purposes of survival analysis. Mean mHHS changed from 51.06 (SD 4.81) pre-operatively to 84.97 (SD 12.79) post-operatively. Pre operative WOMAC was 29.18 (SD 8) and post-operative, 13.10 (SD 11). Post operative VAS was 7.5 and 2.27 for satisfaction and pain, respectively. When comparing patients with Tonnis 0 to those with Tonnis 1, the former showed better results regarding post-operative mHHS (89.9 s versus 77.85, P = 0.03), pain VAS (1.5 versus 6.3, P = 0.03) and satisfaction VAS (8.2 versus 6.3, P = 0.01). Survival was 100% at 24 months and 76% at 40 months (95% CI: 35-98%). Arthroscopic acetabuloplasty without labral detachment achieved good clinical outcomes. Slight degenerative changes on radiographs correlated with poorer clinical outcomes. PMID- 28630734 TI - Open treatment of dysplasia-other than PAO: does it have to be a PAO? AB - Hip dysplasia is a developmental disorder that results in anatomic abnormalities in which the acetabular coverage is insufficient. In the absence of severe degenerative changes, younger active patients with these symptomatic structural abnormalities are increasingly managed with joint-preserving operations. Historically there have been numerous reconstructive pelvic osteotomies. In recent years, the Bernese periacetabular osteotomy (PAO) has become the preferred osteotomy by many surgeons. Even so, as our understanding of the hip advances and new diagnostic and treatment techniques are developed, we sought to put a focus on the long-term results of augmental osteotomies and pelvic osteotomies other than the PAO, to see if any of these surgeries still have a place in the current algorithm of treatment for the dysplastic hip. As the longevity of the treatment is the focal point for joint preservation surgeries for the dysplastic hip, these authors have searched databases for articles in the English literature that reported results of long-term follow-up with a minimum of 11-year survivorship after surgical treatment of developmental dysplasia of the hip. Reconstruction osteotomies for the dysplastic hip are intended to restore normal hip anatomy and biomechanics, improve symptoms and prevent degenerative changes, in this manuscript each procedure is independently assessed on the ability to achieve these important characteristics. PMID- 28630736 TI - Abnormal femoral antetorsion-a subtrochanteric deformity. AB - Femoral rotational malalignment is associated with pain and functional disability and may be a contributing factor to hip impingement as well as to instability. In general, the deformity can be addressed surgically by rotational osteotomy. However, the anatomic location of the deformity is debated. The goal of the present study was to narrow down the anatomic site of deformity using the lesser trochanter (LT) as an additional landmark. One hundred and eight patients underwent computer tomography (CT)-based rotational analysis of their lower extremities. Femoral torsion (FT) and LT torsion (LTT) were measured. The combined angle (CoA) between FT and LTT was calculated. Statistical evaluation was done by multiple regression analysis. Ninety-seven extremities were examined for FT and LTT. Average age was 41 years (SD = 16.9) with a range of 18-85 years. Mean values were 20 degrees for FT (SD = 12.2) and -16 degrees for LTT (SD = 11.3). Mean CoA was 37.2 (SD = 8.7). Statistical analysis reveals a strong linear relationship between FT and LTT (y=31+0.74x) and a weaker relationship between FT and CoA (y=31+0.24x). This study identifies the LT as a reliable landmark and shows a strong linear relationship between the orientation of the LT and the overall torsion of the femur below and above the LT with about two-thirds of torsional changes occurring distal to it. These results provide a considerable indication for a subtrochanteric osteotomy to address correction of femoral rotational deformity at its anatomical origin. Level of Evidence: Level III, observational study. PMID- 28630737 TI - Mesenchymal stem cell therapy in the treatment of hip osteoarthritis. AB - This study was performed to investigate the safety and efficacy of the intra articular infusion of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (BM-MSC) to a cohort of patients with articular cartilage defects in the hip. The above rationale is sustained by the notion that MSCs express a chondrocyte differential potential and produce extracellular matrix molecules as well as regulatory signals, that may well contribute to cure the function of the damaged hip joint. A cohort of 10 patients with functional and radiological evidences of hip osteoarthritis, either in one or both legs, was included in the study. BM-MSC (the cell product) were prepared and infused into the damaged articulation(s) of each patient (60 * 106 cells in 3 weekly/doses). Before and after completion of the cell infusion scheme, patients were evaluated (hip scores for pain, stiffness, physical function, range of motion), to assess whether the infusion of the respective cell product was beneficial. The intra-articular injection of three consecutive weekly doses of ex vivo expanded autologous BM-MSC to patients with articular cartilage defects in the hip and proved to be a safe and clinically effective treatment in the restoration of hip function and range of motion. In addition, the statistical significance of the above data is in line with the observation that the radiographic scores (Tonnis Classification of Osteoarthritis) of the damaged leg(s) remained without variation in 9 out of 10 patients, after the administration of the cell product. PMID- 28630738 TI - Outcomes of heterotopic ossification excision following revision hip arthroscopy. AB - This study reviewed pain and outcome scores of patients undergoing revision surgery with heterotopic ossification (HO) excision following previous hip arthroscopy. The aim was to determine if performing the excision arthroscopically improved clinical outcomes. Data were prospectively collected and retrospectively reviewed in patients who had HO removed arthroscopically between February 2008 and 2014. Four patient-reported outcome (PRO) measures were collected: Modified Harris Hip Score (mHHS), Non-Arthritis Hip Score (NAHS), Hip Outcome Score Activity of Daily Living (HOS-ADL) and Sport-Specific (HOS-SS) subscales. Minimum 1.5 year follow-up from index procedure was available for 23 patients (mean age = 38.6 years). Of the 23 patients who had revision surgery and HO removal, 19 (83%) were available for follow-up. Prior to revision, the average mHHS was 53.4, HOS ADL 51.4, HOS-SS 24.5, NAHS 50.3 and VAS 6.7. Following revision with HO excision, each score had improved with an average mHHS of 73.62, HOS-ADL of 68.88, HOS SS of 58.51, NAHS of 70.83 and VAS of 4.33. Overall, mHHS increased by 20.26 points (P < 0.001), HOS-ADL increased by 17.48 points (P = 0.023), HOS-SS increased by 34.03 points (P < 0.001), NAHS increased by 20.55 points (P = 0.001) and VAS decreased by 2.38 points (P < 0.001). Patients undergoing revision hip surgery with HO excision demonstrated improved outcome scores and pain resolution; however, few patients achieved a good or excellent result. Revision hip surgery with HO excision should be approached cautiously because of the modest results in this patient group. PMID- 28630739 TI - Danish Hip Arthroscopy Registry (DHAR): the outcome of patients with femoroacetabular impingement (FAI). AB - The Danish Hip Arthroscopy Registry (DHAR) was initiated in January 2012 as a web based prospective registry. The purpose of this study was to evaluate and report the first registry based outcome data of a national population with radiological and clinical femoroacetabular impingement (FAI) undergoing hip arthroscopic treatment. Our primary hypothesis was that patients undergoing hip arthroscopy would improve significantly in pain, quality of life and sports related outcome measurements in Patient Related Outcome Measures (PROM). Peri-operative data and Patient Reported Outcome Measures (PROM) data from DHAR between January 2012 and November 2015 were extracted. Radiological pincer-type FAI was defined as LCE > 35 degrees and cam FAI as alpha-angle > 55 degrees . These data were combined with FAI surgical data such as osteochondroplasty and labral repair or resection. PROMs consisting of HAGOS, EQ-5 D, HSAS and NRS pain scores were submitted online by the patients pre-operatively and at 1 and 2-years follow-up. 2054 FAI procedures in 1835 patients were included in this study (219 patients had bilateral procedures performed). HAGOS demonstrated significant improvement in all subscales at follow up. EQ-5 D demonstrated improvement after 1 and 2 years from 0.66 pre-op to 0.78 at 2 years. HSAS improved significantly from 2.5 to 3.3. Pain score data demonstrated improvement in NRS-rest 39 to 17 and NRS Walk 49 to 22 at follow-up. We conclude that patients with FAI undergoing hip arthroscopy experience improvement in pain, quality of life and also in function and sports related outcome measures during the first 2 years after surgery. PMID- 28630740 TI - The effects of hip abduction on sciatic nerve biomechanics during terminal hip flexion. AB - Terminal hip flexion contributes to increased strain in peripheral nerves at the level of the hip joint. The effects of hip abduction and femoral version on sciatic nerve biomechanics are not well understood. A decrease in sciatic nerve strain will be observed during terminal hip flexion and hip abduction, independent of femoral version. Six un-embalmed human cadavers were utilized. Three Differential Variable Reluctance Transducers (DVRTs) sensors were placed on the sciatic nerve while the leg was flexed to 70 degrees with a combination of - 10 degrees , 0 degrees , 20 degrees and 40 degrees adduction/abduction. DVRT placement included: (i) under piriformis, (ii) immediately distal to the gemelli/obturator, (iii) four centimeters distal to sensor two. A de-rotational osteotomy to decrease femoral version 10 degrees was performed, and sciatic nerve strain was measured by the same procedure. Data were analyzed with three way analysis of variance and Bonferroni post-hoc analysis to identify differences in the mean values of sciatic nerve strain between native and decreased version state, hip abduction angle and DVRT sensor location. Significant main effects were observed for femoral version (P = 0.04) and DVRT sensor location (P = 0.01). Sciatic nerve strain decreased during terminal hip flexion and abduction in the decreased version state. An 84.23% decrease in sciatic nerve strain was observed during hip abduction from neutral to 40 degrees in the presence of decreased version at terminal hip flexion. The results obtained from this study confirm the role of decreased femoral version and hip abduction at terminal hip flexion to decrease the strain in the sciatic nerve. PMID- 28630742 TI - What the papers say. PMID- 28630741 TI - The reliability of commonly used arthroscopic classifications of ligamentum teres pathology. AB - The importance of the ligamentum teres (LT) in the hip is increasingly being recognized. However, the incidence of LT tears in the literature is extremely variable. Although classification systems exist their reliability in classifying LT pathology arthroscopically has not been well defined. To determine the inter- and intra-observer reliability of two existing classifications systems for the diagnosis of LT pathology at hip arthroscopy. Second, to identify key pathological findings currently not included. Four experienced hip-arthroscopists reviewed 40 standardized arthroscopic videos. Arthroscopic findings of the LT were classified using the Gray and Villar (G&V) and descriptive classification (DC). Reviewers were asked to record other relevant pathology encountered. Inter- and intra-observer reliability was defined using Fleiss-Kappa and Cohen-Kappa statistics. Both classifications demonstrated fair inter-observer reliability. The intra-observer reliability for G&V was moderate-to-substantial and for DC was slight-to-moderate. An absolute agreement rate of 10% (G&V) and 37.5% (DC) was found. Differentiation between normal, and partial or low-grade tears was a common source of disagreement. The prevalence of LT pathology was 90%. Synovitis was the most common diagnostic finding that was not included in either classification system used in this study. Arthroscopic classification of LT pathology using the G&V and the DC demonstrated only fair inter-observer reliability. The major discrepancy in interpretation was between normal, and partial or low-grade tears. The presence of synovitis was not in either classification but was considered an important arthroscopic finding. Thorough arthroscopic scrutiny reveals the prevalence of LT pathology is higher than previously reported. PMID- 28630743 TI - Comparison of five video-assisted intubation devices by novice and expert laryngoscopists for use in the aeromedical evacuation environment. AB - BACKGROUND: The critically ill or injured patient undergoing military medical evacuation may require emergent intubation. Intubation may be life-saving, but it carries risks. The novice or infrequent laryngoscopist has a distinct disadvantage because experience is critical for the rapid and safe establishment of a secured airway. This challenge is compounded by the austere environment of the back of an aircraft under blackout conditions. This study determined which of five different video-assisted intubation devices (VAIDs) was best suited for in flight use by U.S. Air Force Critical Care Air Transport Teams by comparing time to successful intubation between novice and expert laryngoscopists under three conditions, Normal Airway Lights on (NAL), Difficult Airway Lights on (DAL) and Difficult Airway Blackout (DAB), using manikins on a standard military transport stanchion and the floor with a minimal amount of setup time and extraneous light emission. METHODS: A convenience sample size of 40 participants (24 novices and 16 experts) attempted intubation with each of the 5 different video laryngoscopic devices on high-fidelity airway manikins. Time to tracheal intubation and number of optimization maneuvers used were recorded. Kruskal-Wallis testing determined significant differences between the VAIDs in time to intubation for each particular scenario. Devices with significant differences underwent pair-wise comparison testing using rank-sum analysis to further clarify the difference. Device assembly times, startup times and the amount of light emitted were recorded. Perceived ease of use was surveyed. RESULTS: Novices were fastest with the Pentax AWS in all difficult airway scenarios. Experts recorded the shortest median times consistently using 3 of the 5 devices. The AWS was superior overall in 4 of the 6 scenarios tested. Experts and novices subjectively judged the GlideScope Ranger as easiest to use. The light emitted by all the devices was less than the USAF-issued headlamp. CONCLUSIONS: Novices intubated fastest with the Pentax AWS in all difficult airway scenarios. The GlideScope required the shortest setup time, and participants judged this device as the easiest to use. The GlideScope and AWS exhibited the two fastest total setup times. Both devices are suitable for in-flight use by infrequent and seasoned laryngoscopists. PMID- 28630744 TI - Maternal predictors of neonatal outcomes after emergency cesarean section: a retrospective study in three rural district hospitals in Rwanda. AB - BACKGROUND: In sub-Saharan Africa, neonatal mortality post-cesarean delivery is higher than the global average. In this region, most emergency cesarean sections are performed at district hospitals. This study assesses maternal predictors for poor neonatal outcomes post-emergency cesarean delivery in three rural district hospitals in Rwanda. METHODS: This retrospective study includes a random sample of 441 neonates from Butaro, Kirehe and Rwinkwavu District Hospitals, born between 01 January and 31 December 2015. We described the demographic and clinical characteristics of the mothers of these neonates using frequencies and proportions. We assessed the association between maternal characteristics with poor neonatal outcomes, defined as death within 24 h or APGAR < 7 at 5 min after birth, using Fisher's exact test. Factors significant at alpha = 0.20 significance level were considered for the multivariate logistic regression model, built using a backwards stepwise process. We stopped when all the factors were significant at the alpha = 0.05 level. RESULTS: For all 441 neonates included in this study, 40 (9.0%) had poor outcomes. In the final model, three factors were significantly associated with poor neonatal outcomes. Neonates born to mothers who had four or more prior pregnancies were more likely to have poor outcomes (OR = 3.01, 95%CI:1.23,7.35, p = 0.015). Neonates whose mothers came from health centers with ambulance travel times of more than 30 min to the district hospital had greater odds of having poor outcomes (for 30-60 min: OR = 3.80, 95%CI:1.07,13.40, p = 0.012; for 60+ minutes: OR = 5.82, 95%CI:1.47,23.05, p = 0.012). Neonates whose mothers presented with very severe indications for cesarean section had twice odds of having a poor outcome (95% CI: 1.11,4.52, p = 0.023). CONCLUSIONS: Longer travel time to the district hospital was a leading predictor of poor neonatal outcomes post cesarean delivery. Improving referral systems, ambulance availability, number of equipped hospitals per district, and road networks may lessen travel delays for women in labor. Boosting the diagnostic capacity of labor conditions at the health center level through facilities and staff training can improve early identification of very severe indications for cesarean delivery for early referral and intervention. PMID- 28630745 TI - Correlation between Hox code and vertebral morphology in the mouse: towards a universal model for Synapsida. AB - BACKGROUND: The importance of the cervical vertebrae as part of the skull-neck system in facilitating the success and diversity of tetrapods is clear. The reconstruction of its evolution, however, is problematic because of the variation in the number of vertebrae, making it difficult to identify homologous elements. Quantification of the morphological differentiation in the neck of diverse archosaurs established homologous units of vertebrae (i.e. modules) resulting from Hox gene expression patterns within the cervical vertebral column. The present study aims to investigate the modularity of the cervical vertebral column in the mouse and to reveal the genetic patterns and changes underlying the evolution of the neck of modern mammals and their extinct relatives. In contrast to modern mammals, non-mammalian synapsids are characterized by a variable cervical count, the presence of free cervical ribs and the presence of a separate CV1 centrum. How might these evolutionary modifications be associated with changes in the Hox code? RESULTS: In combination with up-to-date information on cervical Hox gene expression including description of the vertebral phenotype of Hox knock-out mutants, the 3D landmark-based geometric morphometric approach demonstrates a correlation between Hox code and vertebral morphology in the mouse. There is evidence that the modularity of the neck of the mouse had already been established in the last common ancestor of mammals, but differed from that of non-mammalian synapsids. The differences that likely occurred during the evolution of synapsids include an anterior shift in HoxA-5 expression in relation to the reduction of cervical ribs and an anterior shift in HoxD-4 expression linked to the development of the highly differentiated atlas-axis complex, whereas the remaining Hox genes may have displayed a pattern similar to that in mammals on the basis of the high level of conservatism in the axial skeleton of this lineage. CONCLUSION: Thus, the mouse Hox code provides a model for understanding the evolutionary mechanisms responsible for the great morphological adaptability of the cervical vertebral column in Synapsida. However, more studies in non-model organisms are required to further elucidate the evolutionary role of Hox genes in axial patterning of the unique mammalian body plan. PMID- 28630746 TI - Delusional parasitosis on the psychiatric consultation service - a longitudinal perspective: case study. AB - BACKGROUND: Delusional parasitosis is infrequently seen in hospital-based consultation-liaison psychiatry. AIMS: Although there are many publications on delusional parasitosis, this report reviews a unique case that was diagnosed during a hospital admission and treated over the next 36 months. METHOD: Case report and literature review. RESULTS: This case report describes a 65-year-old man who was diagnosed with delusional parasitosis during a hospital admission for congestive heart failure and acute kidney injury. A longitudinal description of the patient's condition during the hospital stay and in the 36 months following discharge, during which time he was treated by a consultation psychiatrist, is provided. CONCLUSIONS: In discussing the treatment of a challenging presentation, this case demonstrates the opportunity for consultation psychiatrists to initiate care in patients who might not otherwise seek psychiatric services. Patients with somatic delusions represent one group of patients who are unlikely to independently seek psychiatric treatment. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28630747 TI - Global patterns in coronavirus diversity. AB - Since the emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrom Coronavirus (MERS-CoV) it has become increasingly clear that bats are important reservoirs of CoVs. Despite this, only 6% of all CoV sequences in GenBank are from bats. The remaining 94% largely consist of known pathogens of public health or agricultural significance, indicating that current research effort is heavily biased towards describing known diseases rather than the 'pre-emergent' diversity in bats. Our study addresses this critical gap, and focuses on resource poor countries where the risk of zoonotic emergence is believed to be highest. We surveyed the diversity of CoVs in multiple host taxa from twenty countries to explore the factors driving viral diversity at a global scale. We identified sequences representing 100 discrete phylogenetic clusters, ninety-one of which were found in bats, and used ecological and epidemiologic analyses to show that patterns of CoV diversity correlate with those of bat diversity. This cements bats as the major evolutionary reservoirs and ecological drivers of CoV diversity. Co-phylogenetic reconciliation analysis was also used to show that host switching has contributed to CoV evolution, and a preliminary analysis suggests that regional variation exists in the dynamics of this process. Overall our study represents a model for exploring global viral diversity and advances our fundamental understanding of CoV biodiversity and the potential risk factors associated with zoonotic emergence. PMID- 28630748 TI - Treatment of chronic orthopaedic infection. AB - Chronic infections are one of the major challenges in orthopaedic surgery, both for surgeons and patients. They are characterised by obstinate persistency of the causing microorganisms and resulting long-term disablement of the patients, associated with remarkable costs for the health care system.Difficulties derive from the biofilm-mode of living of pathogens with resistances against immunological defence and antimicrobial substances, and osseous defects resulting from the disease itself and surgical interventions.Established techniques usually require multiple costly operations with extended periods of disablement and impairment of the patients, sometimes making the therapy worse than the disease.Better understanding of the backgrounds of the conditions has led to new surgical techniques and differentiated application of antibiotics, aiming in improved quality of life for our patients. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160063. Originally published online at www.efortopenreviews.org. PMID- 28630749 TI - Imaging in peri-prosthetic assessment: an orthopaedic perspective. AB - As imaging techniques are ever-evolving, this article aims to provide a brief overview of the various modalities including their limitations. The ability of imaging for evaluation of implant osseo-integration will be addressed and also the role of imaging in assessing septic and aseptic loosening, with a particular focus on adverse tissue reactions, will be discussed. Specific features when imaging the big joints such as shoulder, hip, knee and ankle joint will also be outlined.Overall, a lack of standardisation and validity was noted and despite the gross variety of imaging modalities, there is no technique covering all aspects required for evaluation of implant fixation and septic and aseptic loosening. Each imaging modality has a role, depending on the information required and anticipated. The choice of imaging technique should not be primarily based on medical considerations but also on availability, accessibility, expertise and costs. Plain radiographs alone have been recommended in cases of suspected peri-prosthetic joint infections, given the lack of evidence for additional imaging techniques in this context. For aseptic loosening, ultrasound and plain radiographs may serve as initial screening tools. Metal artefact reducing sequences (MARS) MRI are advancing cross-sectional imaging and are likely to promote their role in patient evaluation.We conclude that imaging is one essential part in the work-up of patients with total joint replacements, within a specific clinical context. Close teamwork between experienced radiologists and orthopaedic surgeons is required for optimal patient care. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160058. Originally published online at www.efortopenreviews.org. PMID- 28630750 TI - Tips and tricks for using the internet for professional purposes. AB - Online resources provide access to large amounts of information which is expanding every day. Using search engines for reaching the relevant, updated and complete literature that is indexed in various bibliographical databases has already become part of the medical professionals' everyday life.However, most researchers often fail to conduct a efficient literature search on the internet. The right techniques in literature search save time and improve the quality of the retrieved data.Efficient literature search is not a talent but a learnable skill, which should be a formal part of medical education.This review briefly outlines the commonly used bibliographic databases, namely Pubmed, Cochrane Library, Web of Science, Scopus, EMBASE, CINAHL and Google Scholar. Also the definition of grey literature and its features are summarised. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160066. Originally published online at www.efortopenreviews.org. PMID- 28630751 TI - Correction manoeuvres in the surgical treatment of spinal deformities. AB - Correction manoeuvres are as important as the other issues such as hardware selection, graft options, fusion and osteotomy techniques in the surgical treatment of spinal deformities.The property of materials demonstrating both viscous and elastic characteristics when undergoing deformation is called visco elasticity. Purely elastic materials change in shape with a stress, and go back to their initial form when the stress is removed. However, visco-elastic materials, like the spine, may protect their new formation unless a back stress is applied. Time is a very important parameter during manoeuvre application to the spine because of its visco-elastic behavior.The most common correction manoeuvres that can be used for spinal deformities are rod de-rotation, distraction-compression, in situ rod bending, segmental de-rotation, en bloc de rotation and cantilever.Spontaneous correction of a minor curve is possible after selective fusion of a major curve due to coupling phenomenon. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.170002. Originally published online at www.efortopenreviews.org. PMID- 28630752 TI - Acromion and glenoid shape: Why are they important predictive factors for the future of our shoulders? AB - The shape of the acromion differs between patients with degenerative rotator cuff tears and individuals without rotator cuff pathology.It can be assessed in the sagittal plane (acromion type, acromion slope) and in the coronal plane (lateral acromion angle, acromion index, critical shoulder angle).The inter-observer reliability is better for the measurements in the coronal plane.A large lateral extension (high acromion index or high critical shoulder angle) and a lateral down-sloping of the acromion (low lateral acromion angle) are associated with full-thickness supraspinatus tears.The significance of glenoid inclination for rotator cuff disease is less clear.The postulated patho-mechanism is the compression of the supraspinatus tendon between the humeral head and the acromion. Bursal side tears might be caused by friction and abrasion of the tendon. Articular side tears could be due to impairment of the gliding mechanism between tendon fibrils leading to local stress concentration. Further research is needed to understand the exact pathomechanism of tendon degeneration and tear. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160076. Originally published online at www.efortopenreviews.org. PMID- 28630753 TI - How to deal with a glenoid fracture. AB - The glenoid fossa is involved in approximately 10% of all scapular fractures.Glenoid fossa incongruity is surprisingly well tolerated.Surgery is recommended when 20% or more of the anterior glenoid fossa is involved.Glenoid rim fractures often lead to chronic shoulder instability.Unstable glenoid neck fractures need surgical treatment and stable fractures can be treated conservatively.CT examination with 3D reformations of the glenoid fossa has improved insight into fracture morphology and fracture patterns and is very helpful for clinical decision makers. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160082. Originally published online at www.efortopenreviews.org. PMID- 28630754 TI - Nerve injuries of the upper extremity and hand. AB - A nerve injury has a profound impact on the patient's daily life due to the impaired sensory and motor function, impaired dexterity, sensitivity to cold as well as eventual pain problems.To perform an appropriate treatment of nerve injuries, a correct diagnosis must be made, where the injury is properly classified, leading to an optimal surgical approach and technique, where timing of surgery is also important for the outcome.Knowledge about the nerve regeneration process, where delicate processes occur in neurons, non-neuronal cells (i.e. Schwann cells) and other cells in the peripheral as well as the central nervous systems, is crucial for the treating surgeon.The surgical decision to perform nerve repair and/or reconstruction depends on the type of injury, the condition of the wound as well as the vascularity of the wound.To reconnect injured nerve ends, various techniques can be used, which include both epineurial and fascicular nerve repair, and if a nerve defect is caused by the injury, a nerve reconstruction procedure has to be performed, including bridging the defect using nerve-grafts or nerve transfer techniques.The patients must be evaluated properly and regularly after the surgical procedure and appropriate rehabilitation programmes are useful to improve the final outcome. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160071. Originally published online at www.efortopenreviews.org. PMID- 28630755 TI - Advances in hip arthroplasty surgery: what is justified? AB - Total hip arthroplasty (THA) surgery has shown dramatic changes in terms of increased number of procedures and of technical development in recent years. It has been described as "the operation of the 20th century" for the excellent results, the high satisfaction of the patients and the improvement of the quality of life.A lot of variations have been introduced over the last few decades in THA especially in terms of indications (both in younger and older patients), techniques and devices (approaches, tissue preservation, biomaterials and industrial finishing), per-operative management (blood loss and pain control) and post-operative protocols (the so called "fast track" surgery). Looking at all these advances the emerging question is: have all of them been justified both in terms of improvement of the results for the patients and of the cost/benefit ratio from an economical point of view?The purpose of this paper is to critically analyse the advantages and the disadvantages of the theoretically proposed "advances in hip arthroplasty" and attempt to understand which are justified of such "advances" nowadays, based on the international and the European perspective with a focus on the author's personal clinical experience. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.170008. Originally published online at www.efortopenreviews.org. PMID- 28630756 TI - Fast track in hip arthroplasty. AB - 'Fast-track' surgery was introduced more than 20 years ago and may be defined as a co-ordinated peri-operative approach aimed at reducing surgical stress and facilitating post-operative recovery.The fast-track programmes have now been introduced into total hip arthroplasty (THA) surgery with reduction in post operative length of stay, shorter convalescence and rapid functional recovery without increased morbidity and mortality. This has been achieved by focusing on a multidisciplinary collaboration and establishing 'fast-track' units, with a well-defined organisational set-up tailored to deliver an accelerated peri operative course of fast-track surgical THA procedures.Fast-track THA surgery now works extremely well in the standard THA patient. However, all patients are different and fine-tuning of the multiple areas in fast-track pathways to get patients with special needs or high co-morbidity burden through a safe and effective fast-track THA pathway is important.In this narrative review, the principles of fast-track THA surgery are presented together with the present status of implementation and perspectives for further improvements. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160060. Originally published online at www.efortopenreviews.org. PMID- 28630757 TI - The patellofemoral joint: from dysplasia to dislocation. AB - Patellofemoral dysplasia is a major predisposing factor for instability of the patellofemoral joint. However, there is no consensus as to whether patellofemoral dysplasia is genetic in origin, caused by imbalanced forces producing maltracking and remodelling of the trochlea during infancy and growth, or due to other unknown and unexplored factors.The biomechanical effects of patellofemoral dysplasia on patellar stability and on surgical procedures have not been fully investigated. Also, different anatomical and demographic risk factors have been suggested, in an attempt to identify the recurrent dislocators. Therefore, a comprehensive evaluation of all the radiographic, MRI and CT parameters can help the clinician to assess patients with primary and recurrent patellar dislocation and guide management.Patellofemoral dysplasia still represents an extremely challenging condition to manage. Its controversial aetiology and its complex biomechanical behaviour continue to pose more questions than answers to the research community, which reflects the lack of universally accepted guidelines for the correct treatment. However, due to the complexity of this condition, an extremely personalised approach should be reserved for each patient, in considering and addressing the anatomical abnormalities responsible for the symptoms. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058 5241.2.160081. Originally published online at www.efortopenreviews.org. PMID- 28630758 TI - Optimising position and stability in total knee arthroplasty. AB - Alignment and stability are two key factors for success in total knee arthroplasty (TKA). Several techniques have been advocated, the two best known being measured resection and tensioned gaps.Dogma and fuzzy wording have cast an obscure shadow on the dualistic discussion between proponents of both techniques.This review is an attempt to clarify definitions, analyse the flaws and pitfalls in the different techniques and make some suggestions for improvement. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058 5241.2.170001. Originally published online at www.efortopenreviews.org. PMID- 28630759 TI - The adult cavus foot. AB - Cavovarus deformity can be classified by the severity of malalignment ranging from a subtle and flexible to a severe and fixed cavovarus deformity of the foot.In the mild cavovarus foot, careful clinical assessment is required to identify the deformity.Weight-bearing radiographs are necessary to indicate the apex of the deformity and quantify the correction required.Surgery is performed when conservative measures fail and various surgical procedures have been described, including a combination of soft-tissue releases, tendon transfers and osteotomies, all with the aim of achieving a plantigrade and balanced foot.Joint sparing surgery is the best option in flexible cavovarus foot even in Charcot Marie-Tooth (CMT) disease (peroneal muscular atrophy).Arthrodesis is indicated in severe rigid cavus foot or in degenerative cases. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160077. Originally published online at www.efortopenreviews.org. PMID- 28630760 TI - Treatment of hindfoot and ankle pathologies with posterior arthroscopic techniques. AB - The two-portal hindfoot arthroscopy is an effective procedure enabling direct visualisation of posterior ankle pathology with low invasiveness.An important stage of the hindfoot endoscopy is localisation of the flexor hallucis longus (FHL) tendon to protect the neurovascular bundle which is located just medial to it.Posterior ankle impingement syndrome and FHL tenosynovitis are common causes of posterior ankle pain and frequently occur together.Posteriorly localised talar osteochondral lesions, Achilles tendon disorders, osteoarthritis, talar bone cysts and talar fractures are among the other pathologies that can be treated with hindfoot arthroscopy. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160055. Originally published online at www.efortopenreviews.org. PMID- 28630761 TI - Partial proximal tibia fractures. AB - Partial tibial plateau fractures may occur as a consequence of either valgus or varus trauma combined with a rotational and axial compression component.High energy trauma may result in a more complex and multi-fragmented fracture pattern, which occurs predominantly in young people. Conversely, a low-energy mechanism may lead to a pure depression fracture in the older population with weaker bone density.Pre-operative classification of these fractures, by Muller AO, Schatzker or novel CT-based methods, helps to understand the fracture pattern and choose the surgical approach and treatment strategy in accordance with estimated bone mineral density and the individual history of each patient.Non-operative treatment may be considered for non-displaced intra-articular fractures of the lateral tibial condyle. Intra-articular joint displacement ? 2 mm, open fractures or fractures of the medial condyle should be reduced and fixed operatively. Autologous, allogenic and synthetic bone substitutes can be used to fill bone defects.A variety of minimally invasive approaches, temporary osteotomies and novel techniques (e.g. arthroscopically assisted reduction or 'jail-type' screw osteosynthesis) offer a range of choices for the individual and are potentially less invasive treatments.Rehabilitation protocols should be carefully planned according to the degree of stability achieved by internal fixation, bone mineral density and other patient-specific factors (age, compliance, mobility). To avoid stiffness, early functional mobilisation plays a major role in rehabilitation. In the elderly, low-energy trauma and impression fractures are indicators for the further screening and treatment of osteoporosis. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160067. Originally published online at www.efortopenreviews.org. PMID- 28630762 TI - Articular impaction injuries in the lower limb. AB - The effective management of articular impacted fractures requires the successful elevation of the osteochondral fragment to eliminate joint incongruency and the stable fixation of the fragments providing structural support to the articular surface.The anatomical restoration of the joint can be performed either with elevation through a cortical window, through balloon-guided osteoplasty or direct visualisation of the articular surface.Structural support of the void created in the subchondral area can be achieved through the use of bone graft materials (autologous tricortical bone), or synthetic bone graft substitutes.In the present study, we describe the available techniques and materials that can be used in treating impacted osteochondral fragments with special consideration of their epidemiology and treatment options. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058-5241.2.160072. Originally published online at www.efortopenreviews.org. PMID- 28630763 TI - Malignant tumours of the foot and ankle. AB - Most of tumours of the foot are tumour-like (synovial cyst, foreign body reactions and epidermal inclusion cyst) or benign conditions (tenosynovial giant cells tumours, planta fibromatosis). Malignant tumours of the soft-tissue and skeleton are very rare in the foot and their diagnosis is often delayed with referral to specialised teams after initial inappropriate procedures or unplanned excisions. The adverse effect of these misdiagnosed tumours is the increasing rate of amputation or local recurrences in the involved patients. In every lump, imaging should be discussed before any local treatment. Every lesion which is not an obvious synovial cyst or plantar fibromatosis should have a biopsy performed.After the age of 40 years, chondrosarcoma is the most usual malignant tumour of the foot. In young patients bone tumours such as osteosarcoma or Ewing's sarcoma, are very unusually located in the foot. Synovial sarcoma is the most frequent histological diagnosis in soft tissues. Epithelioid sarcoma or clear cell sarcoma, involve more frequently the foot and ankle than other sites. The classic local treatment of malignant conditions of the foot and ankle was below-knee amputation at different levels. Nowadays, with the development of adjuvant therapies, some patients may benefit from conservative surgery or partial amputation after multidisciplinary team discussions.The prognosis of foot malignancy is not different from that at other locations, except perhaps in chondrosarcoma, which seems to be less aggressive in the foot. The anatomy of the foot is very complex with many bony and soft tissue structures in a relatively small space making large resections and conservative treatments difficult to achieve. Cite this article: EFORT Open Rev 2017;2. DOI: 10.1302/2058 5241.2.160078. Originally published online at www.efortopenreviews.org. PMID- 28630764 TI - Impact of B-Scan Averaging on Spectralis Optical Coherence Tomography Image Quality before and after Cataract Surgery. AB - BACKGROUND AND OBJECTIVE: To determine optimal image averaging settings for Spectralis optical coherence tomography (OCT) in patients with and without cataract. STUDY DESIGN/MATERIAL AND METHODS: In a prospective study, the eyes were imaged before and after cataract surgery using seven different image averaging settings. Image quality was quantitatively evaluated using signal-to noise ratio, distinction between retinal layer image intensity distributions, and retinal layer segmentation performance. Measures were compared pre- and postoperatively across different degrees of averaging. RESULTS: 13 eyes of 13 patients were included and 1092 layer boundaries analyzed. Preoperatively, increasing image averaging led to a logarithmic growth in all image quality measures up to 96 frames. Postoperatively, increasing averaging beyond 16 images resulted in a plateau without further benefits to image quality. Averaging 16 frames postoperatively provided comparable image quality to 96 frames preoperatively. CONCLUSION: In patients with clear media, averaging 16 images provided optimal signal quality. A further increase in averaging was only beneficial in the eyes with senile cataract. However, prolonged acquisition time and possible loss of details have to be taken into account. PMID- 28630765 TI - Enhanced Depth Imaging Optical Coherence Tomography: A New Way Measuring Choroidal Thickness in Pregnant Women. AB - The body changes markedly during pregnancy; each system behaves differently from a nonpregnant state. As the eyes are the only windows to see directly what is going on in the internal environment, more and more researches have been done to explain the association between ocular changes and the physiological and pathological changes during pregnancy. The choroid is one of the critical parts of the eye, providing nutrition. And abnormal choroid may result in ocular dysfunction and visual problems. As the optical coherence tomography develops, a rapid, direct, noninvasive, and nontoxic way is available to obtain the choroid situation of pregnant women, which may explain the mechanism of pregnancy-related eye diseases. This review would summarize relevant original articles published from January 1, 2008 to December 1, 2016 to assess the changes of choroidal thickness (CT) with enhanced depth imaging optical coherence tomography (EDI-OCT) during pregnancy. And the relationship between choroidal thickness changes and pregnancy remains uncertain. To our knowledge, this is the first review of EDI OCT in assessing the choroidal thickness of the pregnant women. PMID- 28630766 TI - Corneal Endothelial Characteristics, Central Corneal Thickness, and Intraocular Pressure in a Population of Chinese Age-Related Cataract Patients. AB - PURPOSE: To describe corneal endothelial characteristics, central corneal thickness, and intraocular pressure in a population of Chinese age-related cataract patients and to determine the effects of age, gender, hypertension, and body mass index (BMI). METHODS: 1551 eyes were examined preoperatively. The parameters measured were endothelial cell density (CD), average cell area (CA), coefficient of variation (CV), cell hexagonality (HEX), central corneal thickness (CCT), intraocular pressure (IOP), and axial length (AL). RESULTS: There were significant differences in CV and BMI between genders. There was a significant decrease in CD, CCT, and IOP and, conversely, an increase in CA and BMI with increasing age. The patients who suffered from hypertension had bigger CA, less CD, and lower HEX than the patients who did not suffer from hypertension. CD has a negative correlation with age and CV and a positive correlation with CCT, CCT has a positive association with CD and IOP, and IOP had a negative relationship with age and a positive relationship with CCT, CA, and HEX. CONCLUSIONS: Normative data for the corneal endothelium, central corneal thickness, and intraocular pressure in the normal age-related cataract patients are reported which will serve as a baseline for comparative studies about cataract. PMID- 28630767 TI - The Learning Preferences among Nursing Students in the King Saud University in Saudi Arabia: A Cross-Sectional Survey. AB - OBJECTIVE: The present study aimed to identify the most common learning preferences among the nursing students in Saudi Arabia and to investigate the associations of certain demographic variables with the learning preferences. METHODS: All the undergraduate nursing students in the nursing college were requested to participate in this descriptive cross-sectional study. An Arabic version of the Felder-Silverman learning style model (FSLSM) questionnaire was used to examine the learning preferences among undergraduate nursing students. RESULTS: A total of 56 (43%) completed questionnaires were included in the final analysis. Results of the present study indicate that the most common learning preferences among the nursing students were visual (67.9%), followed by active (50%) and sequential (37.5%) learning preferences. The verbal style was the least common learning preference (3.6%) among the nursing students. There was no association between gender and learning preferences (p > .05). CONCLUSION: The present study concluded that the visual, active, and sequential styles are the commonest learning preferences among the nursing students. The nursing educators should emphasize the use of this information in their teaching methods to improve learning skills among the nursing students. PMID- 28630768 TI - Plastic Surgery Inclusion in the Undergraduate Medical Curriculum: Perception, Challenges, and Career Choice-A Comparative Study. AB - OBJECTIVE: The undergraduate medical curriculum has been overcrowded with core learning outcomes with no formal exposure to plastic surgery. The aim of this study was to compare medical students from two educational settings for the basic understanding, preferred learning method, and factors influencing a career choice in plastic surgery. DESIGN AND SETTING: A prospective cohort study based on a web based anonymous questionnaire sent to final year medical students at Birmingham University (United Kingdom), McGill University (Canada), and a control group (non medical staff). The questions were about plastic surgery: (1) source of information and basic understanding; (2) undergraduate curriculum inclusion and preferred learning methods; (3) factors influencing a career choice. A similar questionnaire was sent to non-medical staff (control group). The data was analysed based on categorical outcomes (Chi-square chi2) and level of significance p <= 0.05. RESULTS: Questionnaire was analysed for 243 students (Birmingham, n = 171/332, 52%) (McGill n = 72/132, 54%). Birmingham students (14%) considered the word "plastic" synonymous with "cosmetic" more than McGill students (4%, p < 0.025). Teaching was the main source of knowledge for McGill students (39%, p < 0.001) while Birmingham students and control group chose the media (70%, p < 0.001). McGill students (67%) more than Birmingham (49%, p < 0.010) considered curriculum inclusion. The preferred learning method was lectures for McGill students (61%, p < 0.01) but an optional module for Birmingham (61%). A similar proportion (18%) from both student groups considered a career in plastic surgery. CONCLUSIONS: Medical students recognised the need for plastic surgery inclusion in the undergraduate curriculum. There was a difference for plastic surgery source of information, operations, and preferred method of learning for students. The study highlighted the urgent need to reform plastic surgery undergraduate teaching in collaboration with national educational bodies worldwide. PMID- 28630769 TI - Comparing the Expression of Genes Related to Serotonin (5-HT) in C57BL/6J Mice and Humans Based on Data Available at the Allen Mouse Brain Atlas and Allen Human Brain Atlas. AB - Brain atlases are tools based on comprehensive studies used to locate biological characteristics (structures, connections, proteins, and gene expression) in different regions of the brain. These atlases have been disseminated to the point where tools have been created to store, manage, and share the information they contain. This study used the data published by the Allen Mouse Brain Atlas (2004) for mice (C57BL/6J) and Allen Human Brain Atlas (2010) for humans (6 donors) to compare the expression of serotonin-related genes. Genes of interest were searched for manually in each case (in situ hybridization for mice and microarrays for humans), normalized expression data (z-scores) were extracted, and the results were graphed. Despite the differences in methodology, quantification, and subjects used in the process, a high degree of similarity was found between expression data. Here we compare expression in a way that allows the use of translational research methods to infer and validate knowledge. This type of study allows part of the relationship between structures and functions to be identified, by examining expression patterns and comparing levels of expression in different states, anatomical correlations, and phenotypes between different species. The study concludes by discussing the importance of knowing, managing, and disseminating comprehensive, open-access studies in neuroscience. PMID- 28630770 TI - Knowledge on Irradiation, Medical Imaging Prescriptions, and Clinical Imaging Referral Guidelines among Physicians in a Sub-Saharan African Country (Cameroon). AB - BACKGROUND: Clinical imaging guidelines (CIGs) are suitable tools to enhance justification of imaging procedures. OBJECTIVE: To assess physicians' knowledge on irradiation, their self-perception of imaging prescriptions, and the use of CIGs. MATERIALS AND METHODS: A questionnaire of 21 items was self-administered between July and August 2016 to 155 referring physicians working in seven university-affiliated hospitals in Yaounde and Douala (Cameroon). This pretested questionnaire based on imaging referral practices, the use and the need of CIGs, knowledge on radiation doses of 11 specific radiologic procedures, and knowledge of injurious effects of radiation was completed in the presence of the investigator. Scores were allocated for each question. RESULTS: 155 questionnaires were completed out of 180 administered (86.1%). Participants were 90 (58%) females, 63 (40.64%) specialists, 53 (34.20%) residents/interns, and 39 (25.16%) general practitioners. The average professional experience was 7.4 years (1-25 years). The mean knowledge score was 11.5/59 with no influence of sex, years of experience, and professional category. CIGs users' score was better than nonusers (means 14.2 versus 10.6; p < 0.01). 80% of physicians (124/155) underrated radiation doses of routine imaging exams. Seventy-eight (50.3%) participants have knowledge on CIGs and half of them made use of them. "Impact on diagnosis" was the highest justification criteria follow by "impact on treatment decision." Unjustified requests were mainly for "patient expectation or will" or for "research motivations." 96% of interviewees believed that making available national CIGs will improve justification. CONCLUSION: Most physicians did not have appropriate awareness about radiation doses for routine imaging procedures. A small number of physicians have knowledge on CIGs but they believe that making available CIGs will improve justification of imaging procedures. Continuous trainings on radiation protection and implementation of national CIGs are therefore recommended. PMID- 28630771 TI - Polypharmacy among Underserved Older African American Adults. AB - The purpose of the present study was to examine correlates of polypharmacy among underserved community-dwelling older African American adults. Methods. This study recruited 400 underserved older African Americans adults living in South Los Angeles. The structured face-to-face interviews collected data on participants' characteristics and elicited data pertaining to the type, frequency, dosage, and indications of all medications used by participants. Results. Seventy-five and thirty percent of participants take at least five and ten medications per day, respectively. Thirty-eight percent of participants received prescription medications from at least three providers. Inappropriate drug use occurred among seventy percent of the participants. Multivariate analysis showed that number of providers was the strongest correlate of polypharmacy. Moreover, data show that gender, comorbidity, and potentially inappropriate medication use are other major correlates of polypharmacy. Conclusions. This study shows a high rate of polypharmacy and potentially inappropriate medication use among underserved older African American adults. We documented strong associations between polypharmacy and use of potentially inappropriate medications, comorbidities, and having multiple providers. Polypharmacy and potentially inappropriate medications may be attributed to poor coordination and management of medications among providers and pharmacists. There is an urgent need to develop innovative and effective strategies to reduce inappropriate polypharmacy and potentially inappropriate medication in underserved elderly minority populations. PMID- 28630772 TI - Severe Rhabdomyolysis due to Presumed Drug Interactions between Atorvastatin with Amlodipine and Ticagrelor. AB - Atorvastatin and ticagrelor combination is a widely accepted therapy for secondary prevention of ischaemic heart disease. However, rhabdomyolysis is a well-known rare side effect of statins which should be considered when treatments are combined with cytochrome P450 3A4 enzyme inhibitors. We report a case of atorvastatin and ticagrelor associated severe rhabdomyolysis that progressed to multiorgan failure requiring renal replacement therapy, inotropes, intubation, and mechanical ventilation. Despite withdrawal of the precipitating cause and the supportive measures including renal replacement therapy, creatinine kinase increased due to ongoing rhabdomyolysis rapidly progressing to upper and lower limbs weakness. A muscle biopsy was performed to exclude myositis which confirmed extensive myonecrosis, consistent with statin associated rhabdomyolysis. After a prolonged ventilatory course in the intensive care unit, patient's condition improved with recovery from renal and liver dysfunction. The patient slowly regained her upper and lower limb function; she was successfully weaned off the ventilator and was discharged for rehabilitation. To our knowledge, this is a second case of statin associated rhabdomyolysis due to interaction between atorvastatin and ticagrelor. However, our case differed in that the patient was also on amlodipine, which is considered to be a weak cytochrome P450 3A4 inhibitor and may have further potentiated myotoxicity. PMID- 28630773 TI - Functional Treatment of a Child with Extracapsular Mandibular Fracture. AB - Condylar fractures are among the most frequent fractures in the context of traumatic lesions of the face. The management of condylar fractures is still controversial, especially when fractures occur in children: if overlooked or inappropriately treated, these lesions may lead to severe sequelae, both cosmetic and functional. The therapy must be careful because severe long-term complications can occur. In this case report, the authors present a case of mandibular fracture in which the decision between surgical therapy and functional therapeutic regimen may be controversial due to the particular anatomy of the fracture line and the age of the patient. PMID- 28630774 TI - Lead Poisoning Can Be Easily Misdiagnosed as Acute Porphyria and Nonspecific Abdominal Pain. AB - Lead poisoning (LP) is less commonly encountered in emergency departments (ED). However, lead exposure still occurs, and new sources of poisoning have emerged. LP often goes unrecognized due to a low index of suspicion and nonspecific symptoms. We present a case of a 48-year-old man who had recurring abdominal pain with anemia that was misdiagnosed. His condition was initially diagnosed as nonspecific abdominal pain and acute porphyria. Acute porphyria-like symptoms with a positive urine porphyrin test result led to the misdiagnosis; testing for heme precursors in urine is the key to the differential diagnosis between LP and acute porphyria. The final definitive diagnosis of lead toxicity was confirmed based on high blood lead levels after detailed medical history taking. The lead poisoning was caused by traditional Chinese herbal pills. The abdominal pain disappeared after a course of chelating treatment. The triad for the diagnosis of lead poisoning should be a history of medicine intake, anemia with basophilic stippling, and recurrent abdominal pain. PMID- 28630775 TI - A Rare Case of Paraneoplastic Aortitis Associated with Chronic Myelomonocytic Leukemia. AB - Aortitis is a broad term describing inflammation of the aorta. The most common causes of aortitis are the large-vessel vasculitides giant cell arteritis and Takayasu arteritis. Other etiologies include aortitis associated with other autoimmune disorders, infectious causes, and paraneoplastic and idiopathic cases. We describe a rare case of a large-vessel arteritis occurring in association with chronic myelomonocytic leukemia (CMML). A 68-year-old female with recent diagnosis of CMML presented to our office for evaluation of abnormal chest computed tomography (CT) that showed inflammation surrounding the entirety of thoracic and abdominal aorta, consistent with aortitis. In the absence of other evident causes of large-vessel vasculitis, we attributed this finding to a paraneoplastic autoimmune phenomenon and started treatment with systemic glucocorticoids. This rare case emphasizes the need to recognize autoimmune complications in CMML and treat the inflammation along with the primary malignancy promptly. PMID- 28630776 TI - Sudden Onset, Rapidly Expansile, Cervical Cystic Hygroma in an Adult: A Rare Case with Unusual Presentation and Extensive Review of the Literature. AB - Cystic hygroma (CH) is a benign infiltrative malformation of the lymphatic channels. We report a case of a 28-year-old Indian female who presented with rapidly enlarging right sided neck swelling over the posterior triangle since 5 days. Complete resection of CH is sometimes not amenable because of its infiltrative nature and involvement of surrounding vital structures. However, in our patient successful complete surgical resection was undertaken. The MRI findings of our patient were consistent with brachial cleft cyst; this posed a challenge in the diagnosis of CH. The histopathological analysis of the resected mass confirmed CH. CH is rare in adults and such an acute presentation is exceptionally atypical. History of prior trauma and infection are known etiological factors for adult CH; these were conspicuously absent in our patient. CH should be considered in the differentials of rapidly enlarging cystic swelling of posterior region of neck in adults. Optimal and timely management is necessary to achieve a favorable prognosis. Therefore, we report a case of rapidly enlarging cervical CH in an adult along with extensive literature review to have a better understanding regarding epidemiology, etiopathogenesis, clinical presentation, optimal management, and prognosis of such a rare entity in adults. PMID- 28630777 TI - Magnetic Resonance Enterography Findings of Intestinal Behcet Disease in a Child. AB - Behcet's disease (BD) is a multisystem disorder of unknown aetiology, characterized by recurrent oral ulcers, genital ulcers, uveitis, skin lesions, and pathergy. Gastrointestinal disease outside the oral cavity is well recognized and usually takes the form of small intestinal ulcers, with the most significant lesions frequently occurring in the ileocaecal region. Symptoms usually include nausea, vomiting, colicky abdominal pain, and change in bowel habit and it is not unusual that patients may present late, with life-threatening complications requiring surgery. Diagnosis has been hindered for many years by limitations in imaging the small bowel and it is usually achieved by means of endoscopy and CT of the abdomen. Magnetic resonance enterography (MRE) is a relatively new technique, which has a high diagnostic rate in patients with Crohn's disease (CD). Although many similarities between CD and intestinal BD have already been described in literature, the role of MRE in the evaluation of intestinal BD has never been defined up to now. We report a case of a 12-year-old female patient with diagnosis of BD who presented at our institution for recurrent colicky abdominal pain and diarrhoea. The patient underwent MRE that demonstrated the gastrointestinal involvement. PMID- 28630778 TI - Female Urethral Diverticulum Carcinoma: A Case Report and Literature Review. AB - A 48-year-old woman with a history of voiding difficulty visited our hospital. Magnetic resonance imaging revealed a periurethral tumor, which was pathologically diagnosed as an adenocarcinoma via transperineal needle biopsy. Radical cystectomy and urethrectomy were performed, and the urinary tract was reconstructed using an ileal conduit. Pathological examination of a resected specimen confirmed adenocarcinoma of the urethral diverticulum. The patient received adjuvant gemcitabine and cisplatin chemotherapy. She is alive at 5 months since the operation. PMID- 28630779 TI - Impact of Obesity on Serum Levels of Thyroid Hormones among Euthyroid Saudi Adults. AB - AIM OF STUDY: To assess serum thyroid hormones levels among Saudi adults and to correlate participants' serum levels with their grades of body mass index (BMI). METHODOLOGY: A total of 278 adult subjects were recruited. Participants were categorized according to their BMI grades into normal weight (BMI < 25 kg/m2), overweight (BMI 25-29.9 kg/m2), or obese (BMI >= 30 kg/m2). Serum thyroid hormones levels were assessed at the central laboratory of Aseer Central Hospital, Abha City, by chemiluminescence immunoassay. RESULTS: More than three fourths of participants were either overweight (31.3%) or obese (44.6%). Mean TSH serum levels showed a significantly increasing trend with increasing BMI (p < 0.001). A negative trend was observed regarding participants' mean serum levels of fT4 with their BMI, but there were no significant differences in mean serum fT4 levels according to BMI. Moreover, no significant differences were observed in serum fT3 levels according to BMI. CONCLUSIONS: Mean TSH serum levels increase with BMI increase. Further largescale multicentric and longitudinal studies are necessary to prove the association between serum levels of thyroid hormones and BMI of euthyroid adults. PMID- 28630780 TI - A Randomized Controlled Trial of Chinese Medicine on Nonmotor Symptoms in Parkinson's Disease. AB - Nonmotor symptoms (NMS) of Parkinson's disease (PD) have devastating impacts on both patients and their caregivers. Jiawei-Liujunzi Tang (JLT) has been used to treat some NMS of PD based on the Chinese medicine theory since Qing dynasty. Here we report a double-blind, randomized, placebo-controlled, add-on clinical trial aiming at evaluating the efficacy and safety of the JLT in treating NMS in PD patients. We randomly assigned 111 patients with idiopathic PD to receive either JLT or placebo for 32 weeks. Outcome measures were baseline to week 32 changes in Movement Disorder Society-Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Parts I-IV and in NMS assessment scale for PD (NMSS). We observed improvements in the NMSS total score (p = 0.019), mood/cognition (p = 0.005), and reduction in hallucinations (p = 0.024). In addition, post hoc analysis showed a significant reduction in constipation (p < 0.001). However, there was no evidence of improvement in MDS-UPDRS Part I total score (p = 0.216) at week 32. Adverse events (AEs) were mild and comparable between the two groups. In conclusion, long-term administration of JLT is well tolerated and shows significant benefits in improving NMS including mood, cognition, and constipation. PMID- 28630781 TI - Development of Neurological Mouse Model for Toxoplasmosis Using Toxoplasma gondii Isolated from Chicken in Kenya. AB - Animal models for the toxoplasmosis are scarce and have limitations. In this study, a neurological mouse model was developed in BALB/c mice infected intraperitoneally with 15 cysts of a Toxoplasma gondii isolate. The mice were monitored for 42 days and euthanized at different time points. Another group of mice were orally treated with dexamethasone (DXM: 2.66 mg/kg daily, 5.32 mg/kg daily) at 42 days after infection and monitored for a further 42 days. A mortality rate of 15% and 28.6% was observed in mice given 2.66 mg/kg/day and 5.32 mg/kg/day of DXM, respectively. The mean cyst numbers in the brain of DXM treated mice increased up to twofold compared with chronically infected untreated mice. Infections up to 42 days were associated with an increase in both IgM and IgG levels but following dexamethasone treatment, IgM levels declined but IgG levels continued on rising. The brain of toxoplasmosis infected mice showed mononuclear cellular infiltrations, neuronal necrosis, and cuffing. The severity of pathology was higher in mice treated with dexamethasone compared to the positive control groups. The findings of this study demonstrate that DXM-induced reactivation of chronic toxoplasmosis may be a useful development of laboratory animal model in outbred mice used for in vivo studies. PMID- 28630782 TI - Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack. AB - BACKGROUND: The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation. METHODS: Platelet function, assessed by remotely measured surface expression of P selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values. RESULTS: The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2 408.4) (2p < 0.001). Aspirin did not suppress P-selectin levels below 500 units in 23 (4.7%) patients. The clopidogrel test showed that platelet reactivity was lower in 97 patients taking clopidogrel than in 585 patients not: 655 (296) versus 969 (315), difference 314.5 (95% CI 247.3-381.7) (2p < 0.001). Clopidogrel did not suppress P-selectin level below 860 units in 24 (24.7%) patients. CONCLUSIONS: Aspirin and clopidogrel suppress stimulated platelet P-selectin, although one-quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing may be performed remotely in the context of a large multicentre trial. Trial registration ISRCTN47823388. PMID- 28630783 TI - Highly Sensitive Colorimetric Assay for Determining Fe3+ Based on Gold Nanoparticles Conjugated with Glycol Chitosan. AB - A highly sensitive and simple colorimetric assay for the detection of Fe3+ ions was developed using gold nanoparticles (AuNPs) conjugated with glycol chitosan (GC). The Fe3+ ion coordinates with the oxygen atoms of GC in a hexadentate manner (O-Fe3+-O), decreasing the interparticle distance and inducing aggregation. Time-of-flight secondary ion mass spectrometry showed that the bound Fe3+ was coordinated to the oxygen atoms of the ethylene glycol in GC, which resulted in a significant color change from light red to dark midnight blue due to aggregation. Using this GC-AuNP probe, the quantitative determination of Fe3+ in biological, environmental, and pharmaceutical samples could be achieved by the naked eye and spectrophotometric methods. Sensitive response and pronounced color change of the GC-AuNPs in the presence of Fe3+ were optimized at pH 6, 70 degrees C, and 300 mM NaCl concentration. The absorption intensity ratio (A700/A510) linearly correlated to the Fe3+ concentration in the linear range of 0-180 MUM. The limits of detection were 11.3, 29.2, and 46.0 nM for tap water, pond water, and iron supplement tablets, respectively. Owing to its facile and sensitive nature, this assay method for Fe3+ ions can be applied to the analysis of drinking water and pharmaceutical samples. PMID- 28630784 TI - Elemental Characterization of Romanian Crop Medicinal Plants by Neutron Activation Analysis. AB - The metallic elements concentrations of medicinal plants (coriander, dill, Echinacea, lavender, chamomile, mint, and plantain, used for phytopharmaceutical products), cultivated in unpolluted region, were analyzed by neutron activation analysis. The essential nutrients, macro-, micro-, and trace elements (K, Ca, Mg, Na, Fe, Mn, Rb, Sr, and Zn), potentially toxic elements (Al, As, Ba, Co, Sb, Cr, and V), and rare earth elements were monitored and were compared with those presented in the literature. An estimation of their contributions to intake and toxicity for a person was made, which revealed that (a) teas prepared from the examined plants represent useful contribution to the food provided intake of three essential macronutrients (K, Ca, and Mg); (b) the Cu, Mn, Rb, Sr, Zn, and rare earths levels are normal or low; (c) the quantities of As, Ba, Co, Sb, Cr, and V do not represent toxicological concerns; (d) the examination of the estimated Al and Fe quantities recovered in infusions in the conditions of usual daily tea consumption is below the Tolerable Daily Intake values. The strategy of cultivation of medicinal plants in unpolluted areas is efficient and beneficial. However, individual plants ability to concentrate preferentially certain elements suggests controlling the contamination level of raw materials. PMID- 28630785 TI - Assessment of Corneal Densitometry in Rheumatoid Arthritis Patients. AB - OBJECTIVES: To evaluate corneal densitometry and anterior segment parameters of rheumatoid arthritis (RA) patients and compare these results with those of age matched healthy control subjects. MATERIALS AND METHODS: Anterior segment parameters and corneal densitometry of patients with RA and healthy control subjects were assessed by Scheimpflug corneal topography. For densitometry analysis, the 12-mm diameter area of the cornea was subdivided into four concentric radial zones and anterior, central, and posterior layers based on corneal depth. Right eyes of subjects were used for statistical analysis. RESULTS: Twenty-three consecutive patients with RA and 22 healthy control subjects were included in the study. There was no significant difference with regard to age (p=0.487) or gender (p=0.514). When anterior segment parameters of both groups were compared, no significant difference was found (p>0.05). Total corneal densitometry values were statistically higher in the RA group (p=0.030). In addition, when subdivisions of the cornea were evaluated, higher densitometry values were found in the RA group in 0-2 and 2-6 mm radial zones both in the anterior and total depth (p=0.001, p=0.003 for the 0-2 mm zone and p=0.002, p=0.009 for the 2-6 mm zone). Corneal densitometry measurement was not correlated with central corneal thickness or simulated keratometry value in RA patients or healthy control subjects. CONCLUSION: The corneal densitometry values were higher in RA patients when compared to healthy control subjects, even if they had clinically clear corneas. Corneal densitometry as an objective measure of corneal clarity warrants further studies in order to ascertain its clinical relevance in RA patients. PMID- 28630786 TI - Ophthoselfie: Detailed Self-imaging of Cornea and Anterior Segment by Smartphone. AB - OBJECTIVES: To describe the ophthoselfie, a method by which everyone can take detailed self-images of the cornea and anterior segment with a smartphone. MATERIALS AND METHODS: A 90-diopter non-contact double aspheric lens was attached to posterior camera of the smartphone by clear tape. Images of one eye on the screen of the smartphone could be seen with the other eye in the mirror and images were taken. RESULTS: Accurate and detailed images of the cornea and anterior segment of the eye could be taken. CONCLUSION: The ophthoselfie allows everyone to take their own detailed anterior segment images by smartphone. To create a clear and detailed self-image of the cornea and anterior segment on the screen of a smartphone may lead to the development of new applications and facilitate patients' early recognition of certain conditions like keratoconus, refractive errors, corneal rejection, and uveitis. This method may also be useful in some urgent situations by allowing patients to take self-images of the eye and share them with a physician. PMID- 28630787 TI - Evaluation of Aflibercept Treatment Responses in Eyes with Bevacizumab/Ranibizumab-resistant Wet Age-related Macular Degeneration. AB - OBJECTIVES: To evaluate anatomic and functional results after switching from intravitreal bevacizumab or ranibizumab treatment to aflibercept for wet (neovascular) age-related macular degeneration. MATERIALS AND METHODS: This retrospective study included 22 eyes of 22 patients resistant to treatment with at least 6 injections of bevacizumab or ranibizumab. The first three injections had been applied monthly, the others pro re nata (PRN). Outcome measures were follow-up period, injection number, best corrected visual acuity (BCVA), central retinal thickness (CRT) and pigment epithelial detachment (PED) height. Dosing regimen of aflibercept was determined PRN. The patients were examined monthly. In all visits, BCVA and optical coherence tomography results were assessed together and injections were applied according to these findings. Patients with at least three months of follow-up were included in the study. RESULTS: Twenty-two eyes of 22 patients treated with bevacizumab or ranibizumab were switched to aflibercept therapy. Seven patients had serous PED and 4 patients had fibrovascular PED. The mean follow-up periods for these groups were 20.59+/-6.76 months and 8.68+/-3.79 months, respectively. The mean injection numbers were 10.5+/-3.61 vs 4.54+/-1.56. Statistically significant reductions were noted in CRT (533.86+/-164.06 um vs 412.04+/-143.86 um, p<0.05). BCVA levels were almost equal before and after switching (0.18+/-0.17 vs 0.18+/-0.14). Serous and fibrovascular PED heights decreased suboptimally from 460+/-281.51 um to 282.42+/-175.76 um (p>0.05) for serous PEDs and 251.25+/-43.85 um to 225.75+/-73.09 um (p>0.05) for fibrovascular PEDs. CONCLUSION: Switching to aflibercept resulted in significant improvement in CRT, but not in BCVA or PED heights. PMID- 28630788 TI - Evaluation of Ganglion Cell-Inner Plexiform Layer Thickness after Vitreoretinal Surgery with Internal Limiting Membrane Peeling in Cases with Idiopathic Macular Hole. AB - OBJECTIVES: To evaluate macular retinal ganglion cell-inner plexiform layer (GCIPL) thickness after vitrectomy with internal limiting membrane (ILM) peeling for idiopathic macular holes using spectral domain optical coherence tomography (SD-OCT). MATERIALS AND METHODS: Eighteen eyes of 18 patients with unilateral idiopathic macular hole who underwent vitrectomy with ILM peeling were retrospectively analyzed. Healthy fellow eyes of the patients and 18 eyes of 18 age-matched healthy individuals constituted the control group. The patients were evaluated at 1 day, 1 week, 1 month, and 3 months after surgery. The best corrected visual acuity (BCVA) measurements, biomicroscopic examination findings and SD-OCT measurements were recorded. Ganglion cell-inner plexiform layer thickness was evaluated with ganglion cell analysis software of Cirrus HD-OCT before surgery and at 1 month and 3 months after surgery and compared with control groups. Presence of dissociated optic nerve fiber layer (DONFL) was evaluated with C-scan mode. RESULTS: Of the 18 patients, 9 were male and 9 were female with a mean age of 65.6+/-5.6 (55-77) years. Preoperative BCVA was 0.75+/ 0.19 logMAR, while it was 0.44+/-0.17 logMAR and 0.36+/-0.15 logMAR at postoperative 1 and 3 months, respectively (p<0.001). Postoperative mean GCIPL thickness was 66.33+/-17.28 um. There was a correlation between mean GCIPL thickness and BCVA at postoperative 3 months (p<0.01). When compared with the control group, GCIPL thickness was significantly thinner in all quadrants of all patients at postoperative 3 months. Dissociated optic nerve fiber layer appearance was observed on C-scan in 13 of 18 eyes postoperatively. There was no correlation between the presence of DONFL and BCVA (p>0.05). CONCLUSION: Internal limiting membrane peeling during macular hole surgery may cause functional and/or structural changes that may be associated with visual acuity. Significant GCIPL thinning and DONLF appearance may occur postoperatively. PMID- 28630789 TI - Efficacy of Intravitreal Bevacizumab in Treatment of Proliferative Type 2 Idiopathic Juxtafoveal Telangiectasia. AB - OBJECTIVES: To evaluate the effectiveness of intravitreal bevacizumab (IVB) in patients with subretinal neovascularization secondary to type 2 juxtafoveal telangiectasia. MATERIALS AND METHODS: Ten eyes of 10 patients were included in this retrospective study. All cases were treated with IVB (1.25 mg bevacizumab). Visual acuity and slit-lamp anterior and posterior segment examinations were performed at each visit. Central macular thickness (CMT) and intraretinal/subretinal fluid were evaluated via spectral domain optical coherence tomography (OCT). Loss of a line in visual acuity chart and presence of fluid on OCT were defined as criteria for repeated treatment. RESULTS: The mean age of patients was 66.0+/-7.0 years (56-75). The mean follow-up time was 54.7+/ 16.0 month (24-72). The mean BCVA was 0.62+/-0.35 (0.00-1.00) logMAR at baseline and 0.54+/-0.35 (0.00-1.00) logMAR at final exam (p=0.03). The mean CMT was 251+/ 25.4 um at baseline and 239+/-39.3 um at final exam (p=0.01). Patients received an average of 1.7+/-1.0 IVB injections during follow-up. At baseline, all cases had intraretinal/subretinal fluid. There was no fluid at final examination of all cases. CONCLUSION: IVB treatment may be effective in the treatment of subretinal neovascularization secondary to type 2 juxtafoveal telangiectasia. PMID- 28630790 TI - Rehabilitation of Eyelid Malpositions Secondary to Facial Palsy. AB - OBJECTIVES: To evaluate patient satisfaction and outcomes of surgical treatment of eyelid malpositions secondary to facial palsy. MATERIALS AND METHODS: Consecutive patients with facial palsy who underwent surgical treatment by the same surgeon at Izmir Katip Celebi University Ataturk Training and Research Hospital between Jan 2007 and Dec 2012 were included in the study. Ophthalmic examination findings, surgical approaches, and their outcomes were evaluated. A successful result for upper eyelid position was defined as more than 50% reduction in lagophthalmos and induction of less than 2 mm of ptosis. A successful outcome for lower eyelid position was defined as the lower eyelid residing at or within 1 mm above or below the limbus. Linear visual analog scale 1 (VAS-1) (subjective complaints) and VAS-2 (cosmetic outcome), both ranging from 0 to 10, were used to compare preoperative findings with findings at last postoperative visit. RESULTS: The mean age of the 14 female and 21 male patients was 54.5+/-19.9 years. Gold weight implantation (n=31), lateral tarsal strip (n=22), tarsorrhaphy (n=15), suborbicularis oculi fat elevation (n=16), hard palate graft (n=14), and eyebrow ptosis repair (n=6) were performed. Average follow-up time was 17.9+/-16.9 months (range, 2-60). Surgical success rates were 90% for upper lids and 75% for lower lids. Mean lagophthalmos decreased from 7.1+/-2.7 mm to 1.6+/-1.6 mm postoperatively (p=0.000). The use of lubricating drops and gels was reduced from average preoperative daily values of 5.3+/-2.5 drops and 1.3+/-0.6 gel applications to 4.4+/-1.4 and 0.6+/-0.6, respectively (p=0.003, p=0.001). CONCLUSION: An individualized surgical approach tailored according to each patient's severity of facial palsy and associated malpositions resulted in both functional and aesthetic improvements in our patients. PMID- 28630791 TI - Corticosteroid Treatment in Diabetic Macular Edema. AB - Diabetic macular edema is the most common cause of visual impairment in patients with diabetes mellitus. The pathogenesis of macular edema is complex and multifactorial. For many years, laser photocoagulation has been considered the standard therapy for the treatment of diabetic macular edema; however, few patients achieve significant improvements in visual acuity. Today the intravitreal administration of anti-inflammatory or anti-angiogenic agents together with the use of laser photocoagulation represents the standard of care for the treatment of this complication. The intravitreal route of administration minimizes the systemic side effects of corticosteroids. Steroid-related ocular side effects are elevated intraocular pressure and cataract, while injection related complications include endophthalmitis, vitreous hemorrhage, and retinal detachment. In order to reduce the risks and complications, intravitreal implants have been developed recently to provide sustained release of corticosteroids and reduce repeated injections for the management of diabetic macular edema. In this review, the efficacy, safety, and therapeutic potential of intravitreal corticosteroids in diabetic macular edema are discussed with a review of recent literature. PMID- 28630792 TI - Corneal Collagen Crosslinking Treatment in a Case with Pneumococcal Keratitis. AB - Bacterial keratitis is a serious ocular infectious disease that can threaten vision. The disease generally progresses rapidly and can lead to corneal scar, stromal abscess formation, perforation, and dissemination to adjacent tissues if not treated properly. Recent studies showed that corneal collagen crosslinking (CCC) using ultraviolet-A/riboflavin is effective in the treatment of bacterial keratitis refractory to topical antibiotic treatment. In addition to being bactericidal, CCC also decreases risk of perforation by strengthening the corneal collagen structure. Herein, we report a male patient with Streptococcus pneumonia keratitis 6 months after a keratoplasty procedure, which did not respond to fortified topical antibiotic therapy and was treated successfully with riboflavin/ultraviolet-A CCC. His pain decreased remarkably in a few days. The corneal epithelial defect healed and infiltration regressed within 2 weeks after CCC. His vision improved significantly from hand movement to 20/400. CCC might be used as adjuvant treatment in bacterial keratitis refractory to medical treatment. PMID- 28630793 TI - Bilaterally Diffuse Lacrimal Gland Involvement: Initial Presentation of Systemic Sarcoidosis. AB - Orbital involvement in systemic sarcoidosis is a rare condition. We report a case of orbital sarcoidosis with bilaterally huge lacrimal gland involvement as the initial manifestation of systemic sarcoidosis. A 20-year-old woman admitted the ophthalmology department with progressive bilateral upper eyelid swelling for 6 months. The only pathologic finding was the presence of bilateral, symmetrical, solid, lobular masses at the lateral upper eyelids at the location of lacrimal glands. On systemic examination, bilateral parotid and submandibular glands appeared swollen. Magnetic resonance imaging of the orbit revealed bilateral symmetrical diffuse enlargement of the lacrimal glands with maximum and minimum thickness of 11 mm and 7 mm, respectively. The biopsy findings were compatible with sarcoidosis. Although lacrimal gland involvement has been reported in different studies, we for the first time report an unusual case with bilateral diffuse huge lacrimal gland involvement. Normal lacrimal gland thickness is approximately 4-5 mm in magnetic resonance imaging, while our case had bilateral diffuse enlargement of lacrimal glands, which showed maximum and minimum thickness of 11 mm and 7 mm, respectively. Although orbital involvement is uncommon in sarcoidosis, it should be remembered in the differential diagnosis of orbital masses. PMID- 28630794 TI - A Case of Presumed Tuberculosis Uveitis with Occlusive Vasculitis from an Endemic Region. AB - In this report, we present a case with presumed unilateral tuberculosis uveitis from an endemic region. A 23-year-old male presented with decreased vision in his left eye for 15 days. Visual acuities were 1.0 in his right eye and 0.3 in his left eye. Ophthalmologic examination was normal for the right eye. Slit-lamp examination revealed 2+ cells in the vitreous without anterior chamber reaction in his left eye. Fundus examination revealed occlusive vasculitis and granuloma. His history revealed that he had a respiratory infection with fever 3 months ago while visiting his native country, Rwanda, and was treated with non-specific antibiotic therapy. His visual symptom started 2 weeks after his systemic symptoms resolved. Laboratory findings included 15 mm induration in purified protein derivative tuberculin skin test, HIV negativity, and parenchymal lesions in chest X-ray. Bronchoalveolar lavage was negative for acid-fast bacillus. A pulmonary disease consultant reported presumed tuberculosis because of the patient's history. Anti-tuberculosis treatment was initiated. The patient's visual acuity improved rapidly and his signs regressed. A careful history should be taken from patients with uveitis. Travel to tuberculosis-endemic areas may be important for diagnosis and should be asked about directly. PMID- 28630795 TI - Efficacy of Oral Valacyclovir Treatment in a Case with Acute Retinal Necrosis. AB - Acute retinal necrosis (ARN) is a rapidly progressive disease with poor prognosis, leading to visual loss in most cases. Rapid diagnosis and early anti viral treatment significantly affect the course and prognosis of the disease. In this case report, we present a 34-year-old female patient referred to our clinic with symptoms of blurred vision and ocular pain diagnosed as acute glaucoma elsewhere. A clinical diagnosis of ARN was made and anti-viral treatment was started immediately. We herein describe our treatment approach to this particular case and discuss previously reported treatment modalities. PMID- 28630796 TI - Von Hippel-Lindau Disease: The Importance of Retinal Hemangioblastomas in Diagnosis. AB - Von Hippel-Lindau (VHL) disease is a familial cancer syndrome characterized by benign or malignant tumors which may involve more than one system. Retinal hemangioblastomas are usually the initial manifestation of VHL disease and can cause vision loss. A 32-year-old man presented to our clinic with vision loss in the left eye for 2 months. He had a history of cerebral hemangioblastoma operation. Family history showed that his mother had unilateral vision loss and died because of renal cell carcinoma. Ophthalmologic examination revealed multiple retinal hemangioblastomas in both eyes. VHL gene sequencing was performed and heterozygous p.R161X mutation was detected. His sister and daughter were also found to have the same variant. A treatment and follow-up plan was initiated for the patient and affected family members. Considering VHL disease in the differential diagnosis of retinal hemangioblastomas has a very important role in the early detection of life-threatening tumors in these patients. PMID- 28630797 TI - Spontaneous Resolution of Optic Disc Pit Maculopathy. PMID- 28630799 TI - Optimized process for fabrication of free-standing silicon nanophotonic devices. AB - A detailed procedure is presented for fabrication of free-standing silicon photonic devices that accurately reproduces design dimensions while minimizing surface roughness. By reducing charging effects during inductively coupled-plasma reactive ion etching, undercutting in small, high-aspect ratio openings is reduced. Slot structures with a width as small as 40 nm and an aspect ratio of 5.5:1 can be produced with a nearly straight, vertical sidewall profile. Subsequent removal of an underlying sacrificial silicon dioxide layer by wet etching to create free-standing devices is performed under conditions which suppress attack of the silicon. Slotted one-dimensional photonic crystal cavities are used as sensitive test structures to demonstrate that performance specifications can be reached without iteratively adapting design dimensions; optical resonance frequencies are within 1% of the simulated values and quality factors on the order of 105 are routinely attained. PMID- 28630798 TI - The role of cullin4B in human cancers. AB - Cullin 4B (CUL4B) is a scaffold of the Cullin4B-Ring E3 ligase complex (CRL4B) that plays an important role in proteolysis and is implicated in tumorigenesis. Aberrant expression of CUL4B has been reported in various types of human diseases. Recently, studies have shown that CUL4B was overexpressed in a multitude of solid neoplasms and affect the expression of several tumor suppressor genes. In this review, we aim to summarize the biological function of CUL4B in order to better understand its pathogenesis in human cancers. PMID- 28630800 TI - Taxonomic richness and abundance of cryptic peracarid crustaceans in the Puerto Morelos Reef National Park, Mexico. AB - BACKGROUND AND AIMS: Cryptic peracarids are an important component of the coral reef fauna in terms of diversity and abundance, yet they have been poorly studied. The aim of this study was to evaluate the taxonomic richness and abundance of cryptic peracarids in coral rubble in the Puerto Morelos Reef National Park, Mexico (PMRNP), and their relationship with depth. METHODS: Three reef sites were selected: (1) Bonanza, (2) Bocana, and (3) Jardines. At each site six kilograms of coral rubble were collected over four sampling periods at three depths: 3 m (back-reef), 6-8 m (fore-reef), and 10-12 m (fore-reef). RESULTS: A total of 8,887 peracarid crustaceans belonging to 200 taxa distributed over five orders and 63 families was obtained; 70% of the taxa were identified to species and 25% to genus level. Fifty species of those collected represent new records for the Mexican Caribbean Sea. Isopoda was the most speciose order while Tanaidacea was the most abundant. DISCUSSION: Cryptic peracarid taxonomic richness and abundance were related to depth with higher values of both parameters being found in the shallow (3 m) back-reef, possibly due to a higher reef development and a greater accumulation of coral rubble produced during hurricanes. Peracarid data obtained in the present study can be used as a baseline for future monitoring programs in the PMRNP. PMID- 28630801 TI - Characterization of the transcriptome and EST-SSR development in Boea clarkeana, a desiccation-tolerant plant endemic to China. AB - BACKGROUND: Desiccation-tolerant (DT) plants can recover full metabolic competence upon rehydration after losing most of their cellular water (>95%) for extended periods of time. Functional genomic approaches such as transcriptome sequencing can help us understand how DT plants survive and respond to dehydration, which has great significance for plant biology and improving the drought tolerance of crops. Boea clarkeana Hemsl. (Gesneriaceae) is a DT dicotyledonous herb. Its genomic sequences characteristics remain unknown. Based on transcriptomic analyses, polymorphic EST-SSR (simple sequence repeats in expressed sequence tags) molecular primers can be designed, which will greatly facilitate further investigations of the population genetics and demographic histories of DT plants. METHODS: In the present study, we used the platform Illumina HiSeqTM2000 and de novo assembly technology to obtain leaf transcriptomes of B. clarkeana and conducted a BLASTX alignment of the sequencing data and protein databases for sequence classification and annotation. Then, based on the sequence information, the EST-SSR markers were developed, and the functional annotation of ESTs containing polymorphic SSRs were obtained through BLASTX. RESULTS: A total of 91,449 unigenes were generated from the leaf cDNA library of B. clarkeana. Based on a sequence similarity search with a known protein database, 72,087 unigenes were annotated. Among the annotated unigenes, a total of 71,170 unigenes showed significant similarity to the known proteins of 463 popular model species in the Nr database, and 59,962 unigenes and 32,336 unigenes were assigned to Gene Ontology (GO) classifications and Cluster of Orthologous Groups (COG), respectively. In addition, 44,924 unigenes were mapped in 128 KEGG pathways. Furthermore, a total of 7,610 unigenes with 8,563 microsatellites were found. Seventy-four primer pairs were selected from 436 primer pairs designed for polymorphism validation. SSRs with higher polymorphism rates were concentrated on dinucleotides, pentanucleotides and hexanucleotides. Finally, 17 pairs with stable, highly polymorphic loci were selected for polymorphism screening. There was a total of 65 alleles, with 2-6 alleles at each locus. Primarily due to the unique biological characteristics of plants, the HE (0-0.196), HO (0.082-0.14) and PIC (0-0.155) per locus were very low. The functional annotation distribution centered on ESTs containing di- and tri nucleotide SSRs, and the ESTs containing primers BC2, BC4 and BC12 were annotated to vegetative dehydration/desiccation pathways. DISCUSSION: This work is the first genetic study of B. clarkeana as a new plant resource of DT genes. A substantial number of transcriptome sequences were generated in this study. These sequences are valuable resources for gene annotation and discovery as well as molecular marker development. These sequences could also provide a valuable basis for future molecular studies of B. clarkeana. PMID- 28630802 TI - Effects of a wind farm installation on the understory bat community of a highly biodiverse tropical region in Mexico. AB - Wind energy has rapidly become an important alternative among renewable energies, and it is generally considered clean. However, little is known about its impact at the level of ecological communities, especially in biodiversity hotspots. The Isthmus of Tehuantepec is a highly biodiverse region in Mesoamerica, and has the highest potential for generating wind energy in Mexico. To assess the effects of installing a wind farm on the understory bat community in a landscape of fragmented habitat, we assessed its diversity and composition over four stages of installation (site preparation, construction, and two stages of operation). We captured 919 bats belonging to 22 species. Species richness, functional diversity and phylogenetic diversity decreased during construction and the first stage of operation. However, these components of biodiversity increased during the second stage of operation, and species composition began to resemble that of the site preparation stage. No species considered as sensitive to disturbance was recorded at any stage. This is the first study to reveal the diversity of a Neotropical bat community after wind turbines begin to operate. PMID- 28630803 TI - Putative archaeal viruses from the mesopelagic ocean. AB - Oceanic viruses that infect bacteria, or phages, are known to modulate host diversity, metabolisms, and biogeochemical cycling, while the viruses that infect marine Archaea remain understudied despite the critical ecosystem roles played by their hosts. Here we introduce "MArVD", for Metagenomic Archaeal Virus Detector, an annotation tool designed to identify putative archaeal virus contigs in metagenomic datasets. MArVD is made publicly available through the online iVirus analytical platform. Benchmarking analysis of MArVD showed it to be >99% accurate and 100% sensitive in identifying the 127 known archaeal viruses among the 12,499 viruses in the VirSorter curated dataset. Application of MArVD to 10 viral metagenomes from two depth profiles in the Eastern Tropical North Pacific (ETNP) oxygen minimum zone revealed 43 new putative archaeal virus genomes and large genome fragments ranging in size from 10 to 31 kb. Network-based classifications, which were consistent with marker gene phylogenies where available, suggested that these putative archaeal virus contigs represented six novel candidate genera. Ecological analyses, via fragment recruitment and ordination, revealed that the diversity and relative abundances of these putative archaeal viruses were correlated with oxygen concentration and temperature along two OMZ-spanning depth profiles, presumably due to structuring of the host Archaea community. Peak viral diversity and abundances were found in surface waters, where Thermoplasmata 16S rRNA genes are prevalent, suggesting these archaea as hosts in the surface habitats. Together these findings provide a baseline for identifying archaeal viruses in sequence datasets, and an initial picture of the ecology of such viruses in non-extreme environments. PMID- 28630804 TI - Diversity analysis of gut microbiota in osteoporosis and osteopenia patients. AB - Some evidence suggests that bone health can be regulated by gut microbiota. To better understand this, we performed 16S ribosomal RNA sequencing to analyze the intestinal microbial diversity in primary osteoporosis (OP) patients, osteopenia (ON) patients and normal controls (NC). We observed an inverse correlation between the number of bacterial taxa and the value of bone mineral density. The diversity estimators in the OP and ON groups were increased compared with those in the NC group. Beta diversity analyses based on hierarchical clustering and principal coordinate analysis (PCoA) could discriminate the NC samples from OP and ON samples. Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria constituted the four dominant phyla in all samples. Proportion of Firmicutes was significantly higher and Bacteroidetes was significantly lower in OP samples than that in NC samples (p < 0.05), Gemmatimonadetes and Chloroflexi were significantly different between OP and NC group as well as between ON and NC group (p < 0.01). A total of 21 genera with proportions above 1% were detected and Bacteroides accounted for the largest proportion in all samples. The Blautia, Parabacteroides and Ruminococcaceae genera differed significantly between the OP and NC group (p < 0.05). Linear discriminant analysis (LDA) results showed one phylum community and seven phylum communities were enriched in ON and OP, respectively. Thirty-five genus communities, five genus communities and two genus communities were enriched in OP, ON and NC, respectively. The results of this study indicate that gut microbiota may be a critical factor in osteoporosis development, which can further help us search for novel biomarkers of gut microbiota in OP and understand the interaction between gut microbiota and bone health. PMID- 28630805 TI - Dermatitis Herpetiformis as the Initial Presentation of Primary Biliary Cholangitis in a Male with Gluten Sensitivity. AB - Celiac disease is commonly associated with elevated liver enzymes that normalize on a gluten-free diet. Celiac disease is rarely described in patients with primary biliary cholangitis. Dermatitis herpetiformis is the skin manifestation of the celiac disease that is very rarely associated with primary biliary cirrhosis. We present the case of a 62-year-old man who presented with severe chronic pruritus, in whom a diagnosis of primary biliary cholangitis was made initially. However, in the presence of atypical skin lesions, not confirming to chronic cholestasis, an in-depth evaluation including histopathological examination led to the diagnosis of dermatitis herpetiformis associated with gluten sensitivity. Gluten-free diet and medical treatment with dapsone led to beneficial clinical outcomes. PMID- 28630807 TI - An Overview of Food Patterns and Diet Quality in Qatar: Findings from the National Household Income Expenditure Survey. AB - INTRODUCTION: Availability of accurate data pertaining to a population's dietary patterns and associated health outcomes is critical for proper development and implementation of related policies. This article is a first attempt to share the food patterns, amounts and diet quality among households (HH) in Qatar. METHODS: Data from the 2012-2013 Qatar National Household Income and Expenditure Survey (HIES) was used. This cross-sectional survey included 3723 HH (1826 Qatari HH and 1897 non-Qatari HH). Dietary data on monthly amounts food items available at HH according to the nationality was used. The food items were expressed in terms of grams per capita per day and aggregated into groups to examine the food patterns, energy, and adequacy. RESULTS: The overall average amount of purchased food at HH in Qatar was 1885 g/capita/day. Qatari HH purchased more food (2118 g/capita/day) versus non-Qataris (1373 g/capita/day); however, the percentages of the amounts purchased by food types were similar among both nationalities. Average daily energy (kcal) per capita was almost double among Qatari HH (4275 kcal) vs. non Qatari HH (2424 kcal). The food items under subsidy program for Qatari citizens provided 1753 kcal/capita/day and accounted for 41% of total daily energy. Proteins (29.2), fats (39.2), sodium (3.3), and vitamin C (32.5) had higher than recommended levels of nutrient density (grams per 1000 kcal). Calcium (227), vitamin A (302.3), fiber (2.0), and carbohydrates (132.6) had lower than recommended levels of nutrient energy density (g/1000 kcal). CONCLUSIONS: The study predicts unhealthy dietary habits among HH in Qatar and provides useful information for policy makers and healthcare community. PMID- 28630806 TI - Prevalence and Barriers to Lung Cancer Screening in Karachi, Pakistan: A Cross Sectional Survey of Smokers and Physicians. AB - BACKGROUND: Early detection of lung cancer using low-dose computed tomography (LDCT) can potentially reduce morbidity and mortality. However, LDCT for lung cancer screening, especially in low income countries, has been underutilized. The objective of this study was to evaluate the prevalence and the potential personal, social, and economic barriers of lung cancer screening using LDCT. METHODS: A total sample of 156 smokers and 200 general physicians was collected during December 2016-February 2017 from community settings in Karachi, Pakistan. Two separate questionnaires were constructed to characterize participants' knowledge, attitudes, and practices regarding lung cancer screening. Screening eligible smokers and physicians were asked to identify patient barriers to screening and were asked their opinion regarding most effective approach for increasing awareness of screening guidelines. RESULTS: The majority of smokers' (n=91, 58.3%) and physicians' (n=131, 65.7%) beliefs about the US Preventive Services Task Force (USPSTF) eligibility criteria were inconsistent with the actual recommendations. Major barriers to screening included financial cost, lack of patient counseling and health anxiety related to screening. Over two-thirds (n=105, 67.3%) of smokers were receptive to further information about LDCT screening, and half (n=78, 50.0%) favored one-on-one counseling by their physician, compared to other media. Only one-third (n=65, 33.3%) of physicians reported use of LDCT screening, although 54.5% (n=108) felt that screening implementation would be very effective in their practice. CONCLUSION: LDCT screening is currently an uncommon practice in Pakistan. Financial cost, inadequate doctor-patient communication, and lack of awareness of guidelines among both patients and physicians are the major barriers in the utilization of LDCT screening. PMID- 28630808 TI - Management of Acute Uncomplicated Diverticulitis May Exclude Antibiotic Therapy. AB - Diverticulitis is a common ailment that is prevalent in the developed world. As such, the management of diverticulitis places a substantial economic burden on healthcare. Research is ongoing to further elucidate both the pathogenesis of the disease, as well as ways to reduce associated expenditures. One of these emerging areas of research calls into question the use of antibiotics during treatment of acute uncomplicated diverticulitis. Current guidelines are largely based on expert opinion, with little evidence supporting the standard practice of antibiotic therapy. In this literature review, we have compiled and analyzed the latest collection of evidence in managing acute uncomplicated diverticulitis. There have been two randomized controlled trials (RCTs) performed that assessed the possibility of treating acute uncomplicated diverticulitis without antibiotics. Both the Antibiotika Vid Okomplicerad Divertikulit (AVOD) study and Daniels, et al. have found that an observational approach to acute uncomplicated diverticulitis is not inferior to antibiotic treatment and does not result in increased complication or recurrence rates. We also reviewed a single-center cohort study, a prospective observational study, and two retrospective case controlled studies comparing observational management versus antibiotic treatment in patients with acute uncomplicated diverticulitis. We found the results were comparable; there was no difference in complication rates or recurrence in any study. The consensus among the studies reviewed challenges the current practice guidelines issued by the American Gastroenterological Association. However, given the geographical difference in diverticular disease and inherent bias found in these studies, we cannot recommend a modification of the guidelines. Based on this literature review, we feel compelled to suggest, and strongly recommend, further research be conducted in the United States in order to bolster the already significant evidence against antibiotic therapy in acute uncomplicated diverticulitis. PMID- 28630809 TI - Technical Report of the Use of a Novel Eye Tracking System to Measure Impairment Associated with Mild Traumatic Brain Injury. AB - This technical report details the results of an uncontrolled study of EyeGuide Focus, a 10-second concussion management tool which relies on eye tracking to determine the potential impairment of visual attention, an indicator often of mild traumatic brain injury (mTBI). Essentially, people who can visually keep steady and accurate attention on a moving object in their environment likely suffer from no impairment. However, if after a potential mTBI event, subjects cannot keep attention on a moving object in a normal way as demonstrated on their previous healthy baseline tests. This may indicate possible neurological impairment. Now deployed at multiple locations across the United States, Focus (EyeGuide, Lubbock, Texas, United States) to date, has recorded more than 4,000 test scores. Our data analysis of these results shows the promise of Focus as a low-cost, ocular-based impairment test for assessing potential neurological impairment caused by mTBI in subjects ages eight and older. PMID- 28630810 TI - Negative Ion Mode Electrospray Tandem Mass Spectrometry of Hydroxy-Terminated Polydimethylsiloxanes Formed upon in situ Methanolysis. AB - Ethoxy-, methoxy- and hydroxy-terminated polydimethylsiloxanes (PDMS) are formed as the result of the methanolysis of diethoxy-ended PDMS during its infusion in electrospray ionization. The negative ion mode permits only hydroxy-ended products to be detected, and isomeric interference is avoided in single stage and tandem mass spectrometry. The routes for the fragmentation of (ethyl, hydroxy)-, (methyl, hydroxy)- and (hydro, hydroxy)-ended PDMS upon collision activated dissociation (CAD) were explored in the negative ion mode using either formate or acetate anion adduction. Symmetrical (hydro, hydroxy)-ended PDMS decomposed to product ions carrying one of the hydroxy terminations through the abstraction of an acidic hydrogen and depolymerization (expulsion of cyclic neutral species) regardless of the adducted anion. Asymmetric (ethyl, hydroxy)-ended (resp. (methyl, hydroxy)-ended) PDMS yielded both ethoxy-ended (resp. methoxy-ended) fragment ions through the abstraction of the only acidic hydrogens and linear product ions carrying both terminations still interacted with the anion. The production of information-rich ethoxy-ended (resp. methoxy-ended) fragment ions was limited by formate but favored when acetate (higher proton affinity) was used in a CAD fingerprint complementary to the positive ion mode. PMID- 28630811 TI - Development of a Branched Radio-Frequency Ion Trap for Electron Based Dissociation and Related Applications. AB - Collision-induced dissociation (CID) is the most common tool for molecular analysis in mass spectrometry to date. However, there are difficulties associated with many applications because CID does not provide sufficient information to permit details of the molecular structures to be elucidated, including post translational-modifications in proteomics, as well as isomer differentiation in metabolomics and lipidomics. To face these challenges, we are developing fast electron-based dissociation devices using a novel radio-frequency ion trap (i.e., a branched ion trap). These devices have the ability to perform electron capture dissociation (ECD) on multiply protonated peptide/proteins; in addition, the electron impact excitation of ions from organics (EIEIO) can be also performed on singly charged molecules using such a device. In this article, we review the development of this technology, in particular on how reaction speed for EIEIO analyses on singly charged ions can be improved. We also overview some unique, recently reported applications in both lipidomics and glycoproteomics. PMID- 28630812 TI - Molecular properties of a DTD channelrhodopsin from Guillardia theta. AB - Microbial rhodopsins are membrane proteins found widely in archaea, eubacteria and eukaryotes (fungal and algal species). They have various functions, such as light-driven ion pumps, light-gated ion channels, light sensors and light activated enzymes. A light-driven proton pump bacteriorhodopsin (BR) contains a DTD motif at positions 85, 89, and 96, which is unique to archaeal proton pumps. Recently, channelrhodopsins (ChRs) containing the DTD motif, whose sequential identity is ~20% similar to BR and to cation ChRs in Chlamydomonas reinhardtii (CrCCRs), were found. While extensive studies on ChRs have been performed with CrCCR2, the molecular properties of DTD ChRs remain an intrigue. In this paper, we studied a DTD rhodopsin from G. theta (GtCCR4) using electrophysiological measurements, flash photolysis, and low-temperature difference FTIR spectroscopy. Electrophysiological measurements clearly showed that GtCCR4 functions as a light gated cation channel, similar to other G. theta DTD ChRs (GtCCR1-3). Light-driven proton pump activity was also suggested for GtCCR4. Both electrophysiological and flash photolysis experiments showed that channel closing occurs upon reprotonation of the Schiff base, suggesting that the dynamics of retinal and channels are tightly coupled in GtCCR4. From Fourier transform infrared (FTIR) spectroscopy at 77 K, we found that the primary reaction is an all-trans to a 13 cis photoisomerization, like other microbial rhodopsins, although perturbations in the secondary structure were much smaller in GtCCR4 than in CrCCR2. PMID- 28630813 TI - Mutations in the SH1 helix alter the thermal properties of myosin II. AB - The myosin II SH1 helix is a joint that links the converter subdomain to the rest of the myosin motor domain and possibly plays a key role in the arrangement of the converter/lever arm. Several point mutations within the SH1 helix in human myosin IIs have been shown to cause diseases. To reveal whether these SH1 helix mutations affect not only motile activities but also thermal properties of myosin II, here we introduced the E683K or R686C point mutation into the SH1 helix in Dictyostelium myosin II. Thermal inactivation as well as thermal aggregation rates of these mutant proteins demonstrated that these mutations decreased the thermal stability of myosin II. Temperature dependence of sliding velocities of actin filaments showed that these mutations also reduced the activation energy of a rate-limiting process involved in actin movement. Given that these mutations are likely to alter coupling between the subdomains, and thus their thermal fluctuations, we propose that the SH1 helix is a key structural element that determines the flexibility and thermal properties of the myosin motor. These characteristics of the SH1 helix may contribute to the pathogenesis of the human diseases caused by mutations within this structural element. PMID- 28630814 TI - Normative Emotional Responses to Behavior Analysis Jargon or How Not to Use Words to Win Friends and Influence People. AB - It has been suggested that non-experts regard the jargon of behavior analysis as abrasive, harsh, and unpleasant. If this is true, excessive reliance on jargon could interfere with the dissemination of effective services. To address this often discussed but rarely studied issue, we consulted a large, public domain list of English words that have been rated by members of the general public for the emotional reactions they evoke. Selected words that behavior analysts use as technical terms were compared to selected words that are commonly used to discuss general science, general clinical work, and behavioral assessment. There was a tendency for behavior analysis terms to register as more unpleasant than other kinds of professional terms and also as more unpleasant than English words generally. We suggest possible reasons for this finding, discuss its relevance to the challenge of deciding how to communicate with consumers who do not yet understand or value behavior analysis, and advocate for systematic research to guide the marketing of behavior analysis. PMID- 28630815 TI - Acquisition and Generalization of Complex Empathetic Responses Among Children with Autism. AB - Empathy can be defined as a social interaction skill that consists of four components: (1) a statement voiced in the (2) appropriate intonation, accompanied by a (3) facial expression and (4) gesture that correspond to the affect of another individual. A multiple-baseline across response categories experimental design was used to evaluate the effectiveness of a prompt sequence (video modeling, in vivo modeling, manual and verbal prompting) and reinforcement to increase the frequency of complex empathetic responding by four children with autism. The number of complex empathetic responses increased systematically with the successive introduction of the treatment package. Additionally, generalization was demonstrated to untaught stimuli and a novel adult. Responding maintained over time to varying degrees for all participants. The data illustrate that children with autism can be taught using modeling, prompting, and reinforcement to discriminate between categories of affective stimuli and differentially respond with complex empathetic responses. PMID- 28630816 TI - The Effects of an Auditory Matching iPad App on Three Preschoolers' Echoic and Listener Responses. AB - We investigated the effects of an auditory match-to-sample protocol on three preschoolers' accurate echoics to 100 English words and advanced listener responses. The protocol was presented by using an iPad app Sounds the same: an app to target listening and speaking clearly. We used a combination of a multiple probe design (for echoic responses) and a delayed multiple probe design (for advanced listener literacy responses) with a time-lagged baseline across participants to test the effectiveness of the protocol. The three participants ranged from 4 to 5 years old and were all diagnosed as preschoolers with disabilities. They were taught to discriminate between positive and negative exemplars of progressively more difficult sounds, words, and phases by matching the sample stimulus to the matching exemplar. Our data show that the mastery of the intervention resulted in increases in the accuracy of the participants' articulation of their echoics, as well as their advanced listener repertoires as measured by the responses to spoken directions in the presence of visual distractors. PMID- 28630817 TI - An Abbreviated Evaluation of the Efficiency of Listener and Tact Instruction for Children with Autism. AB - We assessed the efficiency of tact and listener training for eight participants with autism spectrum disorder. Tact and listener probes were conducted in baseline for all target sets, and then tact training was initiated with one and listener training with another. Following mastery of one set, tact and listener probes were conducted with only the sets assigned to the same modality of training (i.e., sets 1, 3, and 5 for tact; sets 2, 4, and 6 for listener). Training and probes were repeated for all sets. The measures of efficiency included the number of skills mastered through direct training, the number of skills that emerged without training, the number of trials-to-criterion, and maintenance of skills. Clinical programming based on each participant's results is discussed. For six participants, tact training was more efficient than listener training across multiple measures. For the remaining two participants, tact training and listener training were considered equivalent. PMID- 28630818 TI - Ethical Considerations for Interdisciplinary Collaboration with Prescribing Professionals. AB - Behavior analysts often work as part of an interdisciplinary team, and different team members may prescribe different interventions for a single client. One such intervention that is commonly encountered is a change in medication. Changes in medication regimens have the potential to alter behavior in a number of ways. As such, it is important for all team members to be aware of every intervention and to consider how different interventions may interact with each other. These facts make regular and clear communication among team members vital for treatment success. While working as part of an interdisciplinary team, behavior analysts must abide by their ethics code, which sometimes means advocating for their client with the rest of the team. This article will review some possible implications of medicinal interventions, potential ethical issues that can arise, and a case study from the authors' experience. Finally, the authors propose a decision-making tree that can aid in determining the best course of action when a team member proposes an intervention in addition to, or concurrent with, interventions proposed by the behavior analyst. PMID- 28630819 TI - Concerns About the Registered Behavior TechnicianTM in Relation to Effective Autism Intervention. AB - In 2014, the Behavior Analyst Certification Board (BACB(r)) initiated a program for credentialing behavior technicians. The new credential, Registered Behavior TechnicianTM (RBT(r)), is for providers of behavioral intervention to a wide range of individuals with mental health needs and developmental delays, including individuals diagnosed with autism spectrum disorder (ASD). The RBT(r) would represent the entry-level position within the range of the BACB(r) credentials. Despite the increasing acceptance of this newest level of credential from the behavioral community, the authors of this paper have substantial concerns with the RBT(r) credential as it relates to the delivery of intervention to individuals diagnosed with ASD. The purpose of this paper is to detail these concerns and propose remedies that would ensure that individuals diagnosed with ASD receive effective behavioral intervention. PMID- 28630820 TI - The Registered Behavior TechnicianTM Credential: A Response to Leaf et al. (2017). PMID- 28630821 TI - Evaluation of Practice Trials to Increase Self-Drinking in a Child with a Feeding Disorder. AB - Self-drinking is an important skill for children to acquire as they transition from infancy to early childhood; however, the literature is limited (e.g., Collins, Gast, Wolery, Holcombe, & Leatherby, 1991; Peterson, Volkert, & Zeleny, 2015). We manipulated the consequences associated with self-drinking relative to those associated with being fed along the dimension of response effort. Results demonstrated that self-drinking increased when the child could either choose to self-feed one drink or be fed one drink and 5 practice trials with an empty cup. PMID- 28630822 TI - The Impact of Stimulus Presentation and Size on Preference. AB - The impact of stimulus size and presentation on choice during a preference assessment was investigated using a modified multiple-stimulus without replacement (MSWO) technique. Stimuli were either presented with a uniform magnitude, as determined by mass, or in a manner consistent with caregiver report of reinforcer consumption. While both assessment procedures identified the same top three preferred items in three out of five cases, greater variability in the preference rank of less preferred items was observed between assessments. PMID- 28630823 TI - Teaching On-Task Rollerblading and Ice-Skating to a Child with Autism. AB - The present study used a multi-component intervention package to teach on-task rollerblading and ice-skating to a boy with autism. Intervention consisted of response prompts, stimulus prompts, multiple-exemplar training, and a conditioned reinforcement system. The participant learned to remain on-task while rollerblading in a circular route marked by cones for up to 26 min. Both stimulus and response generalization of skating were demonstrated in a variety of non training settings, including ice-skating at a rink. PMID- 28630824 TI - Effects of Reinforcer Magnitude and Quality on Preference for Response-Reinforcer Arrangements in Young Children with Autism. AB - The present study evaluated the effects of reinforcer magnitude and quality on preference for continuous and discontinuous arrangements. Two preschool children with autism spectrum disorder (ASD) participated in the study. Both participants initially preferred a discontinuous arrangement when choice options included the same quality and magnitude reinforcers; however, magnitude and quality manipulations resulted in a change in preference for continuous arrangements. PMID- 28630825 TI - Video Modeling Training Effects on Types of Attention Delivered by Educational Care-Providers. AB - We evaluated the effects of abbreviated (i.e., one-session) video modeling on delivery of student-preferred attention by educational care-providers. The video depicted a novel care-provider interacting with and delivering attention to the student. Within a concurrent multiple baseline design, video modeling increased delivery of the targeted attention for all participants as well as their delivery of another type of attention that was not trained although these effects were variable within and between care-providers. We discuss the clinical and training implications from these findings. PMID- 28630826 TI - Predicting the Effects of Interventions: A Tutorial on the Disequilibrium Model. AB - The disequilibrium approach to reinforcement and punishment, derived from the probability-differential hypothesis and response deprivation hypothesis, provides a number of potentially useful mathematical models for practitioners. The disequilibrium approach and its accompanying models have proven effective in the prediction and control of behavior, yet they have not been fully espoused and integrated into clinical practice. The purpose of this tutorial is to detail the disequilibrium approach and adapt its mathematical models for use as a tool in applied settings. The disequilibrium models specify how to arrange contingencies and predict the effects of those contingencies. We aggregate these models, and provide them as a single tool, in the form of a Microsoft Excel(r) spreadsheet that calculates the direction and magnitude of behavior change based on baseline measures and a practitioner's choice of intervention parameters. How practitioners take baseline measures and select intervention parameters in accordance with disequilibrium models is explicated. The proposed tool can be accessed and downloaded for use at https://osf.io/knf7x/. PMID- 28630828 TI - Formation of New Reviewers Board - A JOCR initiative. PMID- 28630827 TI - The Role of Experiential Avoidance in the Relation between Anxiety Disorder Diagnoses and Future Physical Health Symptoms in a Community Sample of Young Adult Women. AB - Individuals diagnosed with an anxiety disorder report more physical health problems than those without an anxiety disorder. Few studies have examined the relation of anxiety disorders to later physical health symptoms, or the processes that may explain this relation. One process of interest is experiential avoidance (EA), which is commonly reported in populations characterized by high anxiety and often leads to health-compromising behaviors. The present study examined the relations between anxiety disorder diagnostic status, EA, and physical health symptoms in a community sample of young adult women. Results revealed a significant association between an anxiety disorder diagnosis and physical health problems four months later. Furthermore, levels of EA accounted for this relation. Findings highlight the potential utility of targeting EA as a method for improving health outcomes among individuals with anxiety disorders. PMID- 28630829 TI - Are We Justified Doing Salvage or Amputation Procedure Based on Mangled Extremity Severity Score in Mangled Upper Extremity Injury. AB - INTRODUCTION: Mangled upper limb injuries are at surge because of industrialization, modernization, and severe motor vehicle accidents. The utility of various scoring systems are meant for decision making in mangled lower limb injuries, and the same have been extrapolated for mangled upper limb injuries to make a decision of salvage or amputation for the lack of separate scoring system. MATERIALS AND METHODS: We applied mangled extremity severity score (MESS) and mangled extremity syndrome index (MESI) scoring systems to 10 cases of mangled upper limb injuries during the period of November 2010 to September 2012 presented at our tertiary trauma care center. Average MESS score was 7.7 and MESI score was 18.1. Above elbow, amputation was needed in three patients, and salvage procedure was done in rest of the seven patients. All the patients were subjected to salvage procedure initially unless life threatening because of mangled limb injury. MESS scores over 7, MESI score over 20 is accepted for amputation in lower limbs, but could not be justified in our study for MESS whereas MESI was more reliable. Functional outcome was assessed using visual analog scale score and short form-36 (SF-36) score for all patients, which was satisfactory, elderly and diabetic patients were relatively less satisfied. CONCLUSIONS: (a) Upper limb and lower limb mangled injuries cannot be considered same because of their anatomy. The upper limb has more rich vascularity and efficient collaterals, small muscle mass, so ischemia time is relatively more. Therefore, the different scoring systems are needed for both. (b) In our case series, MESI scoring was more reliable then MESS score, but this needs a large prospective study to validate it. (c) Salvage should be prime realistic aim influenced by several factors. Prosthesis for upper limb is very expensive and not well tolerated, so even a woody limb is well accepted in our patients. PMID- 28630830 TI - Bilateral Humerus and Right Femur Fracture in a Newborn after Cesarean Section for Breech Presentation in a Twin Pregnancy: A Very Rare Case Report. AB - INTRODUCTION: The most common fractures during vaginal delivery occur in the clavicle, humerus, and femur. Cesarean section reduces the chances of a child having a birth injury. However, in some difficult extractions, long bone fractures may occur. Cesarean section further reduces the incidence of birth injuries, especially in a breech delivery. Maneuvers employed during cesarean section, energetic traction, improper uterine incisions, and contracted uterus may cause these injuries. In the medical literature, there are few articles highlighting the occurrence of long bone fractures during cesarean section. There has been no case reported with a combined bilateral humerus and femur fracture in the medical literature. CASE REPORT: A 2-day-old neonate born after cesarean section for breech presentation in a twin pregnancy presented with restricted movements of both his arms and right leg. Infantogram revealed bilateral humerus and right femur fracture. Biochemical tests were normal, and there were no other findings on clinical examination. There was no evidence of child abuse or any positive family history. Child was splinted for 3 weeks. X-rays suggested good callus at the fracture site of the right femur and bilateral humerus fracture were united. CONCLUSION: To conclude, we would like to emphasize that long bone fractures can happen with cesarean section also. To prevent such untoward complications, during delivery of the baby the surgeon should be very careful, avoid energetic traction and should plan his incisions. Appropriate relaxation of the uterus must be achieved. Clavicles and other long bones should be palpated after a difficult delivery. However, it is important to note that long bone fractures in children heal rapidly without the need for any major intervention. PMID- 28630831 TI - Unusual Presentation of Mycetoma of the Foot: A Rare Case Report. AB - INTRODUCTION: Mycetoma is a chronic granulomatous infection. It is caused by actinomycetes or fungi. It is common in tropical countries and males. Predisposing conditions include malnutrition, poor hygiene, history of trauma, wounds on barefeet, and systemic infections. Eumycotic mycetoma commonly involves lower extremities whereas actinomycosis affects the cervicofacial, thoracic, and abdominal regions. Mycetoma presents with a chronic indurated ulcerated plague with swelling and yellowish discharge of sulfur granules. CASE REPORT: We report a rare case of a 40-year-old male with a left foot plantar swelling of 4 months duration with no discharging sinuses, fever, and pain. There was no history of trauma or barefoot walking. Clinical and magnetic resonance imaging (MRI) findings were suggestive of a soft-tissue malignancy. The mass was excised and sent for histopathology. Histopathology reported it as a mycetoma. Complete resolution was seen after 3 months of antifungal treatment and excision of the mass. This was unusual since there were no discharging sinuses, nodules, and even MRI reported as a fibrous or muscular mass. The diagnosis was made only after a histopathological examination. CONCLUSION: Mycetoma is a rare infection caused by fungal or bacterial organisms. In the absence of ulceration and sinuses, diagnosis can be difficult. Diagnosis requires a high degree of suspicion in the absence of such clinical signs. Definitive diagnosis should be made on histopathological examination. Once diagnosis is made, surgical excision with appropriate antifungals can result in complete cure without recurrence. PMID- 28630833 TI - Anti-inflammatory Prophylaxis Prevents Heterotopic Ossification in Contralateral Side Hip Arthroscopy: A Case Report. AB - INTRODUCTION: Heterotopic ossification (HO) after hip surgery is the formation of bone in non-skeletal tissue, usually between the muscle and the joint capsule. HO after hip surgery may be associated with clinical sequelae such as pain, impingement and decreased range of motion, compromising surgical outcomes. CASE REPORT: A 20-year-old basketball player presented with a 2-year duration of the left groin pain after a basketball-related injury. Due to continued disability and failure of conservative management the patient underwent hip arthroscopy. No HO prophylaxis was given. Follow-up radiographs at 3 months after left hip arthroscopy showed Grade 3 HO on the left side. On the 2nd post-operative visit, the patient complained of contralateral (right-sided) hip pain. Due to continued symptoms on the right side and failure to respond to conservative management the patient underwent right hip arthroscopy. HO prophylaxis was initiated with non steroidal anti-inflammatory medications (NSAIDs) treatment (Etodolac) 600 mg/day for 14 days. Follow-up radiographs at 3 months after the right hip arthroscopy showed no HO. CONCLUSION: This case demonstrates the efficacy of HO prophylaxis in a single patient. Routine HO prophylaxis with NSAIDs should be considered for patients undergoing hip arthroscopy with osteoplasty. A minimum of 9 weeks post operative follow-up is recommended to assess the radiographic presence of HO. PMID- 28630832 TI - Total Knee Arthroplasty in a Diagnosed Case of Deep Vein Thrombosis - Our Experience and Review of Literature. AB - INTRODUCTION: Deep vein thrombosis (DVT) following total knee arthroplasty (TKA) and its associated complication, pulmonary thromboembolism (PTE) remains a challenge for orthopedic surgeons. There are wide ranges of predisposing factors which are both patient specific as well as procedure associated, responsible for DVT. PTE is a well-known fatal complication of DVT which may be life-threatening. Medical management and early mobilization are necessary for the management of DVT. Fatal PTE can be prevented by implantation of inferior vena cava (IVC) filter in at risk patients. CASE REPORT: We are presenting a rare case report of 75-year-old female with severe osteoarthritis of the left knee with DVT of the left lower limb in which TKA was done in a prediagnosed case of DVT. IVC filter placement was done before TKA for prevention of fatal PTE, and medical management was done for DVT. CONCLUSION: Prevention of fatal thromboembolism is of prime importance in the management of DVT. This can be achieved by implanting IVC filter. TKA is necessary for early pain free mobilization of the patient, which prevents progression of DVT and early recovery. IVC filter placement prevents fatal thromboembolism. Hence, treatment of both osteoarthritis of knee by TKA and DVT can be done simultaneously. PMID- 28630834 TI - Van Neck-Odelberg Disease: A Rare Case Report. AB - INTRODUCTION: Pain in groin without any history of trauma or positive clinical findings of infection or stress fracture in ischiopubic ramus poses challenges in diagnosis of the condition in prepubertal age. "Osteochondrosis of ischiopubic synchondrosis (IPS)" also called as "Van Neck-Odelberg" disease. Left leg dominant patient presented with pain in groin and limping with left leg dominance. Differential diagnosis - such as stress fractures, osteomyelitis, tuberculosis, post-traumatic osteolysis, or any neoplasia - is need be ruled out to arrive at diagnosis. The literature is reviewed with modern technologies for diagnosis of the same. CASE REPORT: A 12-year-old, left limb dominant boy with tenderness in the right groin as the only clinical finding and sclerotic shadow over ischiopubic region on X-ray posed a challenge for diagnosis. With further studies by computed tomography and magnetic resonance imaging diagnosis was done. Hence, we are presenting a case labeled as Van Neck-Odelberg disease. CONCLUSION: Diagnosis of Van Neck-Odelberg disease is a challenging diagnosis. Other conditions such as post-traumatic osteolysis, osteomyelitis, and stress fractures in prepubertal age need to be ruled out. Clinical symptoms must be present to label it as osteochondritis of IPS on radiographs as unilateral delayed fusion of the same is a physiological process in asymptomatic cases. PMID- 28630835 TI - Intra-articular Fibroma of Tendon Sheath in Knee Joint Associated with Iliotibial Band Friction Syndrome: Rare Occurrence in a Teenage Girl. AB - INTRODUCTION: Iliotibial band (ITB) friction syndrome is a common overuse injury typically seen in active athlete population. A nodular lesion on the inner side of the ITB as an etiology or an accompanying lesion with friction syndrome has rarely been reported. Among such nodular lesions around knee, fibroma of tendon sheath (FTS) is a rare occurrence. All the more intra-articular occurrence is extremely rare. CASE REPORT: A 16-year-old female presented with recurrent pain and movable nodule at the lateral joint area, diagnosed as ITB friction syndrome. The nodule was confirmed as rare intra-articular FTS on the basis of histopathology findings. CONCLUSION: When nodular lesions around knee are detected on magnetic resonance imaging, a FTS could be included in the differential diagnosis. Etiology and pathogenesis of ITB friction syndrome should be revised in view of such rare presentations. PMID- 28630837 TI - Excision of Solitary Osteochondroma on the Ventral Aspect of Left Scapula Presenting as Pseudowinging in a 4-year-old Boy: A Rare Case Report. AB - INTRODUCTION: Osteochondroma is a benign bony lesion with cartilaginous cap occurring usually in long bones, but flat bones may also be involved, either isolated or as a part of a syndrome. Usually, they are asymptomatic, but appearance of symptoms such as mass effect may warrant surgical intervention, which is usually delayed till skeletal maturity. CASE REPORT: A 4-year-old male child presented with swelling on ventral aspect of inferior angle of scapula associated with pain, pseudowinging of scapula, and snapping sound of the left shoulder on movement. Despite young age of the patient, the severity of the symptoms required immediate intervention. After preoperative workup and planning, the mass measuring 4 cm * 3 cm * 2.5 cm was resected completely, following which the patient was relieved of all the symptoms without any recurrence for the next 7-month follow-up. Histopathological examination confirmed the diagnosis of osteochondroma. Normally, as the growth usually stops after skeletal maturity, surgical intervention is delayed till that time. In our case, the symptoms were so debilitating that it required immediate surgical resection, following which the patient was symptom-free for the next 6 months and there were no clinical signs or symptoms of recurrence. CONCLUSION: Excision of osteochondroma can be safely performed in a case, where it is debilitating, progressive, or unmanageable much before skeletal maturity with fair results. PMID- 28630836 TI - Teriparatide Treatment Improved Loosening of Cementless Total Knee Arthroplasty: A Case Report. AB - INTRODUCTION: Along with the increase of osteoporotic patients in an aging society, complications in surgeries associated with osteoporosis are also increasing. In cementless total knee arthroplasty (TKA), poor primary stability and subsequent initial loosening of the implant may be seen. CASE REPORT: The patient, a 75-year-old Asian woman with a history of osteoporosis, underwent cementless TKA. Knee radiography at 5 weeks postoperatively showed radiolucent lines outlined beneath the tibial tray and around the stem. The tibial component was considered unstable due to loosening. A 56.5 ug weekly dose of teriparatide (rh [1-34] parathyroid hormone) was administered. After 2 months of treatment, knee pain and knee swelling had disappeared. Tomosynthesis taken after 6 months of treatment confirmed complete ingrowth of the component to the bone. CONCLUSION: This case showed that a weekly teriparatide administration of 56.5 ug improved initial loosening of the tibial implant in cementless TKA. Administration of teriparatide in cases of the osteoporotic patient who has loosening in cementless TKA may be a useful adjuvant to achieve bone ingrowth again. PMID- 28630838 TI - A Case Report of an Unusual Case of Tuberculous Osteomyelitis Causing Spontaneous Pathological Fracture of Humerus in a Middle Aged Female. AB - INTRODUCTION: Tuberculosis is a major health problem worldwide. Extrapulmonary tuberculosis is often secondary to some primary foci in lungs. There are reports of tuberculous osteomyelitis involving maxilla, ulna, femur, and shoulder joint but none have reported pathological fracture in humeral diaphysis due to tuberculosis osteomyelitis without shoulder joint involvement. We report a case of pathological fracture of humerus diaphysis due to tuberculous osteomyelitis with normal articular space. We noticed favorable outcome following surgery and antitubercular drugs. CASE REPORT: A 62-year-old female diabetic patient presented with complaints of pain in the right shoulder of 2 weeks duration and inability to raise right arm. Initial clinical evaluation revealed local rise of temperature, tenderness over the right shoulder and proximal arm and restricted range of movements in all plane. Neurologically, the patient was normal. Erythrocyte sedimentation rate was raised. Computed tomography chest showed small area of consolidation in the left upper lobe. Plain radiograph of the right shoulder with humerus showed transverse fracture of proximal shaft of the right humerus. J-needle biopsy was done from proximal humerus fracture site. Histopathological examination of biopsy tissue from fracture site confirmed granuloma with epithelioid and Langhan's giant cells. Mantoux test and culture for acid-fast bacilli were non-conclusive. Based on histopathology report, we concluded this to be tuberculous osteomyelitis of humerus and the patient was started on category 1 antitubercular drugs, under Revised National Tuberculosis Control Programme as per revised WHO guidelines. We performed open debridement and fixation of fracture with rush nail. Initial follow-up 4 months, post operative and plain radiograph showed overall improvement in general condition of the patient, weight gain, and good fracture healing. One year following index surgery, rush nails were removed due to pain at insertion site. Fracture healed completely. Shoulder abduction and forward flexion were restricted in terminal 30 degrees , internal and external rotation, and adduction was full compared to opposite shoulder. CONCLUSION: Tuberculosis is very common in India, but its presentation as spontaneous fracture of humerus is unusual. It is highly likely that most orthopedician will encounter and treat tuberculosis and our case highlights the high degree of suspicion one must have in diagnosing pathological fracture of long bones. Error in diagnosis and treatment burdens the medical resources and overall morbidity. PMID- 28630839 TI - Septic Arthritis of the Hip Complicated by Secondary Fungal Superinfection. AB - INTRODUCTION: Fungal joint infection can lead to serious consequences for those affected. It can often be a delayed diagnosis due to initial negative organism growth or lack of clinician awareness. Treatment should be early and aggressive to prevent patient morbidity and mortality. CASE REPORT: We present a case of staphylococcal septic arthritis of the native hip joint with secondary superinfection by Candida albicans in a young patient with no appreciable risk factors. We explain the complexity of a delayed diagnosis and subsequent treatment. CONCLUSION: This case highlights important learning points in terms of considering secondary fungal infection in any septic arthritis patient that does not respond to conventional antimicrobial treatment. PMID- 28630840 TI - Suspension Arthroplasty Combined with Ligament Reconstruction of the Thumb Carpometacarpal Joint to Salvage Two Failed Arthroplasties: A Case Report. AB - INTRODUCTION: Thumb basal joint arthroplasty with removal of the entire trapezium is often followed by proximal subsidence and impingement of the thumb metacarpal to the scaphoid, which is a common cause of post-operative thumb pain. Treatment of this impingement is a challenge among surgeons. We performed suspension arthroplasty combined with intercarpal ligament reconstruction using a strip of the extensor carpi radialis longus (ECRL) tendon on a patient suffering from pain caused by this type of the impingement and obtained a successful outcome. CASE REPORT: We treated a 52-year-old female pianist who complained of pain in her left thumb carpometacarpal (CMC) joint. She had undergone two previous ligament reconstruction and tendon interposition arthroplasty procedures on the joint, for which strips of the flexor carpi radialis tendon and the abductor pollicis longus tendon were used in the first and second operations, respectively. The pre operative X-ray demonstrated proximal subsidence and impingement of the first metacarpal on the scaphoid. We performed suspension arthroplasty combined with intercarpal ligament reconstruction using a strip of the ECRL tendon to create the trapezial space. 3 years after surgery, despite the 3 mm subsidence of the thumb compared with immediately after surgery, her thumb pinch and grip strength had improved, and the thumb basal pain was relieved. CONCLUSION: This case shows that suspension arthroplasty with intermetacarpal ligament reconstruction using an ECRL strip can be applied in revision surgery for impingement of the first metacarpal with the scaphoid following thumb CMC joint arthroplasty after removal of the entire trapezium. This is the first report to describe the treatment of first metacarpal impingement after CMC joint arthroplasty using suspension arthroplasty combined with intercarpal ligament reconstruction. PMID- 28630841 TI - Bipolar Hemiarthroplasty in a Patient with above-knee Amputation: Surgical Technique. AB - INTRODUCTION: Femoral neck fractures are a common occurrence in lower limb amputees. Good post-operative results of hip hemiarthroplasty have been described in below-knee amputees. However, to our knowledge, very few such cases have been reported in above-knee amputees. CASE REPORT: We present a case of a 75-year-old male patient who underwent above-knee amputation of the right lower limb for severe crush injury right leg and a bipolar hemiarthroplasty for an ipsilateral fracture neck of femur sustained in the same road traffic accident. The treatment of neck of femur fracture in above-knee amputee patients is always a challenge for the orthopedic surgeon. We described the surgical technique in an attempt to overcome the challenges encountered in such a setting. CONCLUSION: While performing a hemiarthroplasty in an above-knee amputee, we recommend the use of two perpendicularly placed Schanz pins distally in the subtrochanteric area for control and also as a guide for verifying the version during prosthesis placement. PMID- 28630842 TI - Irreducible Subtalar Dislocation Caused by Sustentaculum Tali Incarceration. AB - INTRODUCTION: Subtalar dislocation is an uncommon lesion in traumatology chiefly when it concerns the lateral form. Surgical treatment is required when a fracture is related or the dislocation is irreducible. Even well treated, these dislocations progress unavoidably to subtalar arthrosis, which stays well tolerated. CASE REPORT: A 46-year-old male with irreducible lateral subtalar dislocation caused sustentaculum tali incarceration confirmed on computed tomography (CT). The patient underwent emergent open reduction and internal fixation; the sustentaculum tali was reduced and fixed with a compression screw. At 3 years, "American Orthopaedic Foot and Ankle Society Ankle-hindfoot" score was 86, and the functional result was considered excellent despite a Grade I subtalar osteoarthritis on the ankle X-ray. CONCLUSION: An irreducible subtalar dislocation is exceptionally due to the incarceration of sustentaculum tali. CT is of great interest for good fracture analysis and management planning. Anatomical reduction of the articular surfaces, stable osteosynthesis, sufficient immobilization, and a well-conducted rehabilitation are the only guarantors of a good functional outcome. PMID- 28630843 TI - Osteosarcoma of Jaw with Varying Histomorphologic Patterns: Case Report. AB - INTRODUCTION: Osteosarcoma is a malignant mesenchymal tumor whose cancerous cells produce osteoid matrix. It is a common primary malignant bone tumor, representing 23% of total head and neck malignancies. Osteosarcomas of the jaws are rare lesions, representing only 4-7% of all osteosarcomas. This presentation discusses the clinical, radiographical, and histopathological features of a case of osteosarcoma of the mandible with unusual histopathological appearance. CASE REPORT: A 21-year-old male patient reported with a diffuse swelling of the right side of mandible with dull ache and increasing difficulties with eating and speech. Incisional biopsy done showed a histopathological picture of osteosarcoma and osteoblastoma. Hemimandibulectomy was done and the histopathology showed varying patterns of the lesion-like osteoblastoma-like osteosarcoma and osteoblastic variant of osteosarcoma. Focal areas in the lesion also showed fibrohistiocytic differentiation which may be mistaken for malignant fibrous histiocytoma. Hemangiopericytomatous appearance was also seen. Hence, it was necessary to differentiate between all the lesions as the treatment plan for all these lesions is different. Rarely, tumor may show a spectrum of histopathology as seen here in a case of osteosarcoma of the mandible. CONCLUSION: The treatment plan and prognosis for each type of these lesions are different. Thus, thorough histopathological evaluation will help in accurate diagnosis, proper treatment planning, and prognosis of these lesions. PMID- 28630844 TI - Multifocal Septic Arthritis Secondary to Infective Endocarditis: A Rare Case Report. AB - INTRODUCTION: Infective endocarditis (IE) is a rare cause of septic arthritis. We report a patient who presented with multifocal septic arthritis as a result of IE, which is an extremely rare condition. CASE REPORT: This 69-year-old gentleman presented to the emergency department (ED) with a 3-day history of acute right knee pain. Initial investigations demonstrated chondrocalcinosis on knee radiographs, acute renal failure with rhabdomyolysis and a CRP of 520. After treatment with intravenous fluid rehydration and analgesia, the knee aspiration grew a Group B Streptococcus, and the patient underwent arthroscopic washout. 48 h after admission the patient developed left wrist and right elbow pain. Further aspirations revealed Group B Streptococcus and the patient underwent further washouts. A multidisciplinary approach was used. Due to ongoing sepsis, an echocardiogram was performed identifying IE. The patient eventually died due to ongoing sepsis and duodenal ulceration. CONCLUSION: This case highlights the importance of considering a systemic cause such as IE for patients presenting with features of multifocal septic arthritis and ensuring all patients undergo a full medical examination as part of the clerking process. Furthermore, it emphasizes the need to adopt a multi-disciplinary approach when presented with complex patients so that the best medical care can be given to prevent morbidity and mortality. PMID- 28630845 TI - Multi-foci Salmonella enteritis Osteomyelitis of Thoracic Spine with Pleural Effusion and Fatal Outcome. A Unique Case Presentation and Review of the Literature. AB - INTRODUCTION: A case of thoracic vertebral osteomyelitis due to Salmonella enteritis (SE) in an immunocompetent patient is reported. This is the third case in the literature of SE thoracic vertebral osteomyelitis, but the first one with this multi-foci presentation and finally fatal outcome due to meningoencephalitis. Further data that makes our case unique are the absence of fever (body temperature: 37.4 degrees C) and gastrointestinal disorders. CASE REPORT: A 57-year-old male patient initially presented with thoracic pain, dyspnea, and knee pain. Examinations revealed a large pleural effusion and septic arthritis. Blood and all these sides (vertebrae, pleural fluid, and joint fluid) cultures revealed SE. The infection was successfully treated with three surgical interventions, plus antibiotic administration. First, a chest tube was inserted and at the same time, we took cultures and specimens from the infected sites. Subsequently, bone debridement and spine fusion were performed, and finally, knee fusion was held with an Illizarov device. Although 8 months later, our patient passed away due to viral meningoencephalitis and severe hydrocephalus, due to immunosuppression after Salmonella infection recurrence. Furthermore, no sign of relapse was found in the last follow-up, just 2 months ago. CONCLUSION: Physicians should be aware for this rare but potentially fatal spinal infection. Osteomyelitis of thoracic spine should be considered in the differential diagnosis of pleural effusion. More suspiciousness is needed due to the possibility of immunosuppression and relapse, even with sufficient antibiotic administration and negative inflammatory markers. Follow-up should be more frequent and accompanied with blood cultures taking. PMID- 28630846 TI - Chronic Recurrent Multifocal Osteomyelitis: A Case Report with Atypical Presentation. AB - INTRODUCTION: Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory condition. The clinical picture consists of sterile osteomyelitis, typically with multiple-site lesions in the metaphysis of long bones and not uncommonly, symmetrical bone involvement. It is a poorly understood entity, whose prognosis, etiology and ideal treatment are still controversial. The authors report a case of unifocal presentation with an atypical location. CASE REPORT: A previously healthy 12-year-old Caucasian girl came to our institution due to progressive pain on her left thigh for the previous 3 months. The initial X-ray showed a permeative, diaphyseal lesion of her left femur, with marked periosteal reaction. The differential initially included Ewing's sarcoma, osteosarcoma, subacute osteomyelitis, and Langerhans cell histiocytosis. Needle and open biopsies demonstrated the presence of chronic inflammatory infiltrate, with fibrosis, but no signs of neoplastic disease. Serologic and microbiological studies failed to demonstrate an infectious etiology. The patient was treated with nonsteroid anti-inflammatories, corticosteroids, and bisphosphonates for 6 months. Although no antibiotics were employed, the patient showed clinical and radiological improvement, at 18-month follow-up. CONCLUSIONS: CRMO is a rare condition, and the absence of specific features constitutes a diagnostic challenge. A high level of suspicion is paramount to avoid unnecessary biopsies and repeated antibiotic regimens. Unifocal presentation of this disease, atypical locations, and absence of recurrence have all been previously reported, with the evidence pointing to a shared etiological process with no distinction being made between these variants. For this reason, the authors believe that the term "nonbacterial osteomyelitis" might be a more all-embracing designation. PMID- 28630847 TI - Hyperplasia of Lamina and Spinous Process of C5 Vertebrae and Associated Hemivertebra at C4 Level. AB - INTRODUCTION: Congenital variants of the cervical spine may mimic traumatic lesions and may cause recurrent episodes of pain. The spectrum of cervical variants includes persistent apophyses of the transverse processes, persistent epiphyses, vertebral platyspondylia, vertebral hypoplasia, and dysplasia of the vertebral arch. Furthermore, abnormalities of the spinous process have been described including doubled spinous processes and hypertrophies. Unilateral hyperplasia of a spinous process is a rare finding that has only been described rarely as case reports. CASE REPORT: We report a 9-year-old male child who was referred to us with swelling in the posterior aspect of the neck. Anteroposterior and lateral radiographs of the cervical spine show an elongated left spinous process in the neck at the level of C5 vertebrae. There was an associated hemivertebra at the C4 level. Computed tomography examination better depicted this congenital variant and clearly showed the associated schisis of the posterior arch as well as unfused spinous process at the same level on the left side. This is a very rare congenital anomaly and probably among the few such cases reported in literature. CONCLUSION: Rare congenital spinal abnormalities including unilateral hyperplasia of a spinous process have to be kept in mind as a differential diagnosis in patients with posterior midline neck swelling and recurrent episodes of cervical neck pain. PMID- 28630848 TI - Pseudotumour Complicated by Implant Loosening One Year After revision Ceramic on Metal Total Hip Arthroplasty: A Case Report. AB - INTRODUCTION: Pseudotumor is not an uncommon complication after total hip arthroplasty (THA). This can occur in relationship to different bearing surfaces of head and liner ranging from soft to hard articulation. There is wide spectrum of presentation from asymptomatic to implant failure. CASE REPORT: We report a case of pseudotumor formation with acetabular cup aseptic loosening after revision ceramic on metal hip arthroplasty. The patient underwent pseudotumor excision and re-revision complex arthroplasty procedure using trabecular metal shell and buttress with ceramic on polyethylene THA. CONCLUSION: The surgeon should aware of this complication during a presentation in revision cases to prevent rapid progression of cup loosening, and to intervene early to avoid complex arthroplasty procedures. PMID- 28630849 TI - A Case of Chronic Inflammation of the Ankle Joint with Subtle Signs of Inflammation: A Rare Presentation of Tuberculosis Ankle. AB - INTRODUCTION: Tuberculosis (TB) of the ankle is an uncommon presentation of extrapulmonary infection. The early diagnosis of TB arthritis of the ankle is difficult because of the uncommon site, the ability of TB to mimic other disorders and, all too common, lack of awareness of about this infection in ankle joint. CASE REPORT: A 30-year-old male presented with a 1-year history of right ankle pain and swelling. He denied any history of recent infection but had had recurrent ankle pain that had been treated accordingly. When he visited our outpatient clinic, he was afebrile. The patient, despite a period of conservative treatment, presented with a localized painful fullness of the ankle. Magnetic resonance imaging helps for the diagnosis with variable specificity, but TB arthritis was diagnosed through a diagnostic arthroscopic procedure, and anti-TB therapy eventually eradicated the infection. CONCLUSION: It is highly recommended that early biopsy and synovial fluid for polymerase chain reaction GeneXpert be performed in suspicious cases to confirm and treat accordingly. PMID- 28630850 TI - Anterior Dislocation of Elbow with Neurovascular Injury: A Rare Case Report. AB - INTRODUCTION: Anterior elbow dislocation is an infrequent lesion, produced by direct trauma to the proximal ulna after a fall on the elbow in flexion and injury to the neurovascular bundle is not infrequent. Authors report a case of acute anterior dislocation of the elbow joint with neurovascular injury. CASE REPORT: A 30-year-old male admitted with a history of accidental fall followed by pain, swelling over his left elbow. Clinical, radiological, Doppler investigations revealed anterior dislocation of the elbow with brachial artery injury with posterior interosseous nerve palsy without any bony injury. Immediate closed reduction, primary vascular repair with fasciotomy was done following which elbow function improved. CONCLUSION: Anterior dislocations of elbow joint are among the rarest of injuries. Because the dislocation is anterior, injury to nerve and vessel can occur frequently. Therefore, a careful assessment for neurovascular injury mandatory. Early proper reduction and management of neurovascular injury if any is necessary for good elbow function. PMID- 28630851 TI - Vacuum-Assisted Closure in Patients with Post-operative Infections after Instrumented Spine Surgery: A Series of 12 Cases. AB - INTRODUCTION: Post-operative wound infections after spinal surgery is a very serious problem, leading to a risk of significant morbidity which may even lead to prolonged hospitalization. Various treatment protocols have been recommended for debridement, antibiotic, and soft-tissue management, but with mixed results. However, the risk of morbidity is still high with these treatment options. Vacuum assisted closure (VAC) system has been gaining popularity recently in the management of subacute, acute, and chronic wounds. This study aims to review the use of the indigenous VAC in the management of deep infections after spinal instrumentation surgery. CASE SERIES: Between 2010 and 2015, 12 out of 514 patients who developed a deep infection after spinal surgery, were selected and reviewed retrospectively at multiple centers (MGM Hospital, Kamothe and Center for Orthopaedic & Spine Surgery, New Panvel, Navi Mumbai, India). Out of 12 patients, one of the patients needed a partial implant exchange although none of the cases needed complete implant removal. All patients had achieved clean closed wounds along with a retention of the instrumentation. There was no need for flap surgery to cover wound defect in any case. However, antibiotic treatment was necessary in all cases. None of the patients showed a new infection after the treatment. CONCLUSION: The study demonstrates the usefulness of VAC therapy as an alternative management for wound conditioning of a back wound with the high complexity in nature after instrumented spine surgeries as it eliminates complex secondary surgeries, prolong use of antibiotics and removal of the implants. PMID- 28630852 TI - Adult Traumatic Inferior Hip Dislocation: Rare Case Ended with Open Reduction. AB - INTRODUCTION: An inferior hip dislocation also called luxatio erecta femoris is a rare type of hip dislocation that is not widely reported in literature. Only 12 cases are reported in British literature. CASE REPORT: This article reports a 17 year-old male involved in a road traffic accident, sustaining inferior hip dislocation. Following resuscitation, computed tomography confirmed the clinical diagnoses. Several attempts to perform a closed reduction of the hip under sedation and general anesthesia failed to reduce the dislocation. The patient underwent open reduction of his hip and capsule repair. Postoperatively no traction was applied, and the patient advised non-weight bearing on that side for 3 months. CONCLUSION: To our knowledge, this is the first reported case of an adult with an inferior hip dislocation not associated with a trochanteric fracture and required open reduction. PMID- 28630853 TI - Mega Tumour (Chondrosarcoma) of Humerus - an Insanely Large Tumor and its Social Implications. AB - INTRODUCTION: Large size bone tumors are rare as patients present quite early. The current article reports a large chondrosarcoma removed from left humerus. The rarity of such large size tumors is focus of the report. CASE REPORT: Forty year old male presented with a huge mass in this left arm. The same patient apparently was admitted three years back for excision of the arm swelling which was relatively small that time. However the patient did not undergo surgery and was takin treatment from local bone setters during the last three years and tumor grew to a larger size during this period. The current dimensions of tumor was 32x28 cms with circumference of 87 cms. X-ray showed complete destruction of the upper humerus with central calcification. Biopsy releveled a chondrosarcoma. Skeletal survey and bone scan did not reveal any other lesion in the body. A forequarter amputation was done and a 16 kg tumor mass was excised. At three years follow up, the patient has no complains with no recurrence of the tumor. CONCLUSION: Large musculoskeletal tumors are rare and probable reason for such late presentation in our case is ignorance and cultural beliefs. Patients should be properly counselled on first presentations regarding management and prognosis. PMID- 28630854 TI - Stacked Flexible Nailing for Radius Ulna Fractures: Revival of a lost Technique. AB - INTRODUCTION: Simultaneous radius and ulna fractures are common in adults and generally osteosynthesis with plating is the treatment of choice. Nailing of such fractures is infrequently advocated. We present our unique technique of radius ulna nailing in adults to achieve closed reduction and early predictable union with minimal or no complications. CASE REPORT: Case 1: 22 year old male with midshaft both bones forearm fracture was treated with stacked nailing. Two 2.5 mm steel elastic nails were used in each radius and ulna. No post-operative splintage was needed and patient was mobilized immediately. Patient was able to go back to work in 2 weeks and at one year follow up he showed excellent functional outcome. Case 2: Fifteen year old boy presented with midshaft both bone fractures secondary to fall from height. He was also treated with stacked flexible nailing. Good stability was achieved and patient was mobilized immediately without any splints. He was able to write his exams which started on 11th day post-surgery and could complete his theory papers. At final follow up both bones united with good callus and no functional limitations. CONCLUSION: Stacked nailing technique is a good option in midshaft transverse or short oblique fractures of radius and ulna. It allows for early mobilization without brace or splint. With proper patient selection, good results can be obtained by this simple and minimally invasive technique. PMID- 28630855 TI - Qualitative correlation between postoperatively increased vertical dimension and mandibular position in skeletal class III using partial-least-square path modeling. AB - BACKGROUND: This study constructed a partial-least-square path-modeling (PLS-PM) model and found the pathway by which the postsurgical vertical dimension (VD) affects the extent of the final mandibular setback on the B point at the posttreatment stage for the skeletal class III surgery-first approach (SFA). METHODS: This study re-analyzed the data from the retrospective study by Lee et al. on 40 patients with skeletal class III bimaxillary SFA. Variables were obtained from cone beam computed tomography (CBCT)-generated cephalograms. Authors investigated all variables at each time point to build a PLS-PM model to verify the effect of the VD on the final setback of the mandible. RESULTS: From PLS-PM, an increase in VD10 was found to decrease the absolute value of the final setback amount of the mandible, which reflects the postsurgical physiological responses to both surgery and orthodontic treatment, which, in turn, can be interpreted as an increase in postoperative mandibular changes. CONCLUSIONS: To resolve the issue of collinear cephalometric data, the present study adopted PLS PM to assess the orthodontic treatment. From PLS-PM, it was able to summarize the effect of increased postsurgery occlusal vertical dimension on the increased changeability of the B point position at the posttreatment stage. PMID- 28630856 TI - Chimeric Genes in Deletions and Duplications Associated with Intellectual Disability. AB - We report on three nonrelated patients with intellectual disability and CNVs that give rise to three new chimeric genes. All the genes forming these fusion transcripts may have an important role in central nervous system development and/or in gene expression regulation, and therefore not only their deletion or duplication but also the resulting chimeric gene may contribute to the phenotype of the patients. Deletions and duplications are usually pathogenic when affecting dose-sensitive genes. Alternatively, a chimeric gene may also be pathogenic by different gain-of-function mechanisms that are not restricted to dose-sensitive genes: the emergence of a new polypeptide that combines functional domains from two different genes, the deregulated expression of any coding sequence by the promoter region of a neighboring gene, and/or a putative dominant-negative effect due to the preservation of functional domains of partially truncated proteins. Fusion oncogenes are well known, but in other pathologies, the search for chimeric genes is disregarded. According to our findings, we hypothesize that the frequency of fusion transcripts may be much higher than suspected, and it should be taken into account in the array-CGH analyses of patients with intellectual disability. PMID- 28630857 TI - Effectiveness of a Commercial Lactic Acid Bacteria Intervention Applied to Inhibit Shiga Toxin-Producing Escherichia coli on Refrigerated Vacuum-Aged Beef. AB - Because of their antagonistic activity towards pathogenic and spoilage bacteria, some members of the lactic acid bacteria (LAB) have been evaluated for use as food biopreservatives. The objectives of this study were to assess the antimicrobial utility of a commercial LAB intervention against O157 and non-O157 Shiga-toxigenic E. coli (STEC) on intact beef strip loins during refrigerated vacuum aging and determine intervention efficacy as a function of mode of intervention application. Prerigor strip loins were inoculated with a cocktail (8.9 +/- 0.1 log10 CFU/ml) of rifampicin-resistant (100.0 MUg/ml; RifR) O157 and non-O157 STEC. Inoculated loins were chilled to <=4 degrees C and treated with 8.7 +/- 0.1 log10 CFU/ml LAB intervention using either a pressurized tank air sprayer (conventional application) or air-assisted electrostatic sprayer (ESS). Surviving STEC were enumerated on tryptic soy agar supplemented with 100.0 MUg/ml rifampicin (TSAR) to determine STEC inhibition as a function of intervention application method (conventional, ESS) and refrigerated aging period (14, 28 days). Intervention application reduced STEC by 0.4 log10 CFU/cm2 (p < 0.05), although application method did not impact STEC reductions (p > 0.05). Data indicate that the LAB biopreservative may assist beef safety protection when utilized within a multi-intervention beef harvest, fabrication, and aging process. PMID- 28630858 TI - Pulsed Vincristine Therapy in Steroid-Resistant Nephrotic Syndrome. AB - Steroid-resistant nephrotic syndrome (SRNS) poses a therapeutic challenge for the paediatric nephrologist. As relentless progression to renal failure occurs with continued proteinuria, such patients will be treated with different cytotoxic medications with variable success rates and side-effects. We present here our findings on administering the anticancer drug vincristine for SRNS patients at a single centre in Sri Lanka. Methods. Between 2002 and 2007, fifty-four children presenting with steroid and cyclophosphamide resistance were treated with vincristine at 1.5 mg/m2 in weekly intravenous pulses for 8 weeks along with a tapering steroid regimen of 6 months. All patients were closely followed up for 5 years. Results. Of the 54 patients 39 were males and 15 were females (age range 3.5-11.6 years, median 6.1 years). At the end of the treatment course, 21 patients achieved complete remission while 7 had partial remission and no response was seen in 26 patients. Sustained remission at 6, 12, 24, and 60 months were 15 (27.78%), 11 (20.37%), 9 (16.67%), and 7 (12.96%), respectively. Most side-effects observed were reversible and no serious side-effects were noted during vincristine therapy. Conclusion. Although its therapeutic mechanisms in nephrotic syndrome are still not elucidated, vincristine appears to be a potent alternative that could be considered for treating SRNS. PMID- 28630859 TI - The Application of Internal Suspension Technique in Retroperitoneal Laparoscopic Partial Nephrectomy for Renal Ventral Tumors. AB - OBJECTIVE: To evaluate the feasibility of an internal suspension technique in retroperitoneal laparoscopic partial nephrectomy for the management of renal ventral tumors. METHODS: Between January 2013 and July 2016, a total of 145 patients underwent retroperitoneal laparoscopic partial nephrectomy with or without internal suspension technique. For patients who underwent internal suspension technique, the surgeons preserved the external fat of the renal tumor as a suspension traction measure when separating the kidney. Propensity score matching (PSM) was performed according to age, gender, body mass index, tumor size, tumor location, and RENAL nephrometry score. Patient characteristics and intraoperative and postoperative outcomes were compared between the groups. RESULTS: After PSM, 32 patients treated with the internal suspension technique were compared with 32 cases treated without such technique. Baseline characteristics were statistically similar for the cohorts. The use of our new technique resulted in shorter warm ischemia time (WIT: 15.0 versus 19.0 minutes, P = .002) and tumor resection time (4.0 versus 7.5 minutes, P < 0.001). The rate of WIT >25 minutes decreased (6.3% versus 25%, P = .04) and the trifecta outcomes were significantly improved (87.5% versus 62.5%, P = .02). CONCLUSION: Internal suspension technique is a feasible and safe procedure in retroperitoneal laparoscopic partial nephrectomy for renal ventral tumors. PMID- 28630860 TI - Regulation of Matrix Metalloproteinase-2 Secretion from Scleral Fibroblasts and Retinal Pigment Epithelial Cells by miR-29a. AB - PURPOSE: To identify an effective method to prevent myopia progression by characterizing the regulation of matrix metalloproteinase- (MMP-) 2 expression and its secretion from scleral fibroblasts and retinal pigment epithelium (RPE) cells by miR-29a. METHODS: The effects of miR-29a on the growth of scleral fibroblasts and RPE cells were assessed using the cell counting kit-8. The changes in MMP-2 mRNA levels in scleral fibroblasts and RPE cells after transfection with miR-29a mimics or inhibitor were measured by quantitative PCR. Enzyme-linked immunosorbent assays were used to determine the changes in MMP-2 secretion from scleral fibroblasts and RPE cells after transfection with miR-29a mimics or inhibitor. RESULTS: The miR-29a mimics or inhibitor did not significantly alter the growth of scleral fibroblasts or RPE cells at 24, 48, or 72 hours after transfection. MMP-2 mRNA levels were significantly decreased in scleral fibroblasts and RPE cells transfected with the miR-29a mimics. The secretion of MMP-2 by scleral fibroblasts and RPE cells was significantly decreased in cells transfected with the miR-29a mimics. CONCLUSIONS: Suppression of scleral fibroblast and RPE cell expression and secretion of MMP-2 by miR-29a can be used as a therapeutic target for the prevention and treatment of myopia. PMID- 28630862 TI - Influence of Deformation and Stress between Bone and Implant from Various Bite Forces by Numerical Simulation Analysis. AB - Endosseous oral implant is applied for orthodontic anchorage in subjects with multiple tooth agenesis. Its effectiveness under orthodontic loading has been demonstrated clinically and experimentally. This study investigates the deformation and stress on the bone and implant for different bite forces by three dimensional (3D) finite element (FE) methods. A numerical simulation of deformation and stress distributions around implants was used to estimate the survival life for implants. The model was applied to determine the pattern and distribution of deformations and stresses within the endosseous implant and on supporting tissues when the endosseous implant is used for orthodontic anchorage. A threaded implant was placed in an edentulous segment of a human mandible with cortical and cancellous bone. Analytical results demonstrate that maximum stresses were always located around the implant neck in marginal bone. The results also reveal that the stress for oblique force has the maximum value followed by the horizontal force; the vertical force causes the stress to have the minimum value between implant and bone. Thus, this area should be preserved clinically to maintain the structure and function of a bone implant. PMID- 28630861 TI - Biophysical Mechanisms Mediating Fibrin Fiber Lysis. AB - The formation and dissolution of blood clots is both a biochemical and a biomechanical process. While much of the chemistry has been worked out for both processes, the influence of biophysical properties is less well understood. This review considers the impact of several structural and mechanical parameters on lytic rates of fibrin fibers. The influences of fiber and network architecture, fiber strain, FXIIIa cross-linking, and particle transport phenomena will be assessed. The importance of the mechanical aspects of fibrinolysis is emphasized, and future research avenues are discussed. PMID- 28630864 TI - Intravoxel Incoherent Motion Diffusion for Identification of Breast Malignant and Benign Tumors Using Chemometrics. AB - The aim of the paper is to identify the breast malignant and benign lesions using the features of apparent diffusion coefficient (ADC), perfusion fraction f, pseudodiffusion coefficient D*, and true diffusion coefficient D from intravoxel incoherent motion (IVIM). There are 69 malignant cases (including 9 early malignant cases) and 35 benign breast cases who underwent diffusion-weighted MRI at 3.0 T with 8 b-values (0~1000 s/mm2). ADC and IVIM parameters were determined in lesions. The early malignant cases are used as advanced malignant and benign tumors, respectively, so as to assess the effectiveness on the result. A predictive model was constructed using Support Vector Machine Binary Classification (SVMBC, also known Support Vector Machine Discriminant Analysis (SVMDA)) and Partial Least Squares Discriminant Analysis (PLSDA) and compared the difference between them both. The D value and ADC provide accurate identification of malignant lesions with b = 300, if early malignant tumor was considered as advanced malignant (cancer). The classification accuracy is 93.5% for cross validation using SVMBC with ADC and tissue diffusivity only. The sensitivity and specificity are 100% and 87.0%, respectively, r2cv = 0.8163, and root mean square error of cross-validation (RMSECV) is 0.043. ADC and IVIM provide quantitative measurement of tissue diffusivity for cellularity and are helpful with the method of SVMBC, getting comprehensive and complementary information for differentiation between benign and malignant breast lesions. PMID- 28630863 TI - The Effects of Melatonin on Elevated Liver Enzymes during Statin Treatment. AB - Taking statins can cause increase in the level of aspartate and alanine aminotransferase. The aim of this study was to assess the usefulness of melatonin in counteracting the adverse hepatic events from statins. Methods. The research program included 60 patients (aged 47-65 years, 41 women and 19 men) with hyperlipidemia taking atorvastatin or rosuvastatin at a dose of 20-40 mg daily. The patients were randomly allocated in two groups. Group I (n = 30) was recommended to take the same statin at a standardized daily dose of 20 mg together with melatonin at a dose of 2 * 5 mg. Group II (n = 30) patients took statin with placebo at the same dose and time of the day. Follow-up laboratory tests (AST, ALT, GGT, and ALP) were evaluated after 2, 4, and 6 months of treatment. Results. In Group I the levels of all enzymes decreased after 6 months, particularly AST, 97,2 +/- 19,1 U/L versus 52,8 +/- 12,3 U/L (p < 0,001); ALT, 87,4 +/- 15,6 U/L versus 49,8 +/- 14,5 U/L (p < 0,001); and GGT, 84,1 +/- 14,8 U/L versus 59,6 U/L (p < 0,001). Conclusion. Melatonin exerts a hepatoprotective effect in patients taking statins. PMID- 28630865 TI - 2D-QSAR and 3D-QSAR Analyses for EGFR Inhibitors. AB - Epidermal growth factor receptor (EGFR) is an important target for cancer therapy. In this study, EGFR inhibitors were investigated to build a two dimensional quantitative structure-activity relationship (2D-QSAR) model and a three-dimensional quantitative structure-activity relationship (3D-QSAR) model. In the 2D-QSAR model, the support vector machine (SVM) classifier combined with the feature selection method was applied to predict whether a compound was an EGFR inhibitor. As a result, the prediction accuracy of the 2D-QSAR model was 98.99% by using tenfold cross-validation test and 97.67% by using independent set test. Then, in the 3D-QSAR model, the model with q2 = 0.565 (cross-validated correlation coefficient) and r2 = 0.888 (non-cross-validated correlation coefficient) was built to predict the activity of EGFR inhibitors. The mean absolute error (MAE) of the training set and test set was 0.308 log units and 0.526 log units, respectively. In addition, molecular docking was also employed to investigate the interaction between EGFR inhibitors and EGFR. PMID- 28630866 TI - CNNdel: Calling Structural Variations on Low Coverage Data Based on Convolutional Neural Networks. AB - Many structural variations (SVs) detection methods have been proposed due to the popularization of next-generation sequencing (NGS). These SV calling methods use different SV-property-dependent features; however, they all suffer from poor accuracy when running on low coverage sequences. The union of results from these tools achieves fairly high sensitivity but still produces low accuracy on low coverage sequence data. That is, these methods contain many false positives. In this paper, we present CNNdel, an approach for calling deletions from paired-end reads. CNNdel gathers SV candidates reported by multiple tools and then extracts features from aligned BAM files at the positions of candidates. With labeled feature-expressed candidates as a training set, CNNdel trains convolutional neural networks (CNNs) to distinguish true unlabeled candidates from false ones. Results show that CNNdel works well with NGS reads from 26 low coverage genomes of the 1000 Genomes Project. The paper demonstrates that convolutional neural networks can automatically assign the priority of SV features and reduce the false positives efficaciously. PMID- 28630868 TI - Serum Dried Samples to Detect Dengue Antibodies: A Field Study. AB - BACKGROUND: Dried blood and serum samples are useful resources for detecting antiviral antibodies. The conditions for elution of the sample need to be optimized for each disease. Dengue is a widespread disease in Mexico which requires continuous surveillance. In this study, we standardized and validated a protocol for the specific detection of dengue antibodies from dried serum spots (DSSs). METHODS: Paired serum and DSS samples from 66 suspected cases of dengue were collected in a clinic in Veracruz, Mexico. Samples were sent to our laboratory, where the conditions for optimal elution of DSSs were established. The presence of anti-dengue antibodies was determined in the paired samples. RESULTS: DSS elution conditions were standardized as follows: 1 h at 4 degrees C in 200 ul of DNase-, RNase-, and protease-free PBS (1x). The optimal volume of DSS eluate to be used in the IgG assay was 40 ul. Sensitivity of 94%, specificity of 93.3%, and kappa concordance of 0.87 were obtained when comparing the antidengue reactivity between DSSs and serum samples. CONCLUSION: DSS samples are useful for detecting anti-dengue IgG antibodies in the field. PMID- 28630867 TI - Potential Challenges of Controlling Leishmaniasis in Sri Lanka at a Disease Outbreak. AB - The present works reviewed the existing information on leishmaniasis in Sri Lanka and in other countries, focusing on challenges of controlling leishmaniasis in the country, in an outbreak. Evidence from recent studies suggests that there is a possibility of a leishmaniasis outbreak in Sri Lanka in the near future. Difficulty of early diagnosis due to lack of awareness and unavailability or inadequacy of sensitive tests are two of the main challenges for effective case management. Furthermore, the absence of a proper drug for treatment and lack of knowledge about vector biology, distribution, taxonomy and bionomics, and reservoir hosts make the problem serious. The evident potential for visceralization in the cutaneous variant of L. donovani in Sri Lanka may also complicate the issue. Lack of knowledge among local communities also reduces the effectiveness of vector and reservoir host control programs. Immediate actions need to be taken in order to increase scientific knowledge about the disease and a higher effectiveness of the patient management and control programs must be achieved through increased awareness about the disease among general public and active participation of local community in control activities. PMID- 28630869 TI - Increase of Soluble RAGE in Cerebrospinal Fluid following Subarachnoid Haemorrhage. AB - Receptors for advanced glycation end-products (RAGE) mediate the inflammatory reaction that follows aneurysmal subarachnoid haemorrhage. Soluble RAGE (sRAGE) may function as a decoy receptor. The significance of this endogenous anti inflammatory mechanism in subarachnoid haemorrhage (SAH) remains unknown. The present study aims to analyse sRAGE levels in the cerebrospinal fluid (CSF) of SAH patients. sRAGE levels were assayed by ELISA kit in 47 CSF samples collected on post-SAH days 0-3, 5-7, and 10-14 from 27 SAH patients with acute hydrocephalus. CSF levels of sRAGE were compared with a control group and correlated with other monitored parameters. In the control group, the CSF contained only a trace amount of sRAGE. By contrast, the CSF of 20 SAH patients collected on post-SAH days 0-3 was found to contain statistically significant higher levels of sRAGE (mean concentration 3.91 pg/mL, p < 0.001). The most pronounced difference in CSF sRAGE levels between good and poor outcome patients was found on days 0-3 post-SAH but did not reach the significance threshold (p = 0.234). CSF sRAGE levels did not change significantly during hospitalisation (p = 0.868) and correlated poorly with treatment outcome, systemic inflammatory markers, and other monitored parameters. Our study revealed an early and constant increase of sRAGE level in the CSF of SAH patients. PMID- 28630870 TI - Placental ABCA1 Expression Is Increased in Spontaneous Preterm Deliveries Compared with Iatrogenic Preterm Deliveries and Term Deliveries. AB - OBJECTIVE: Abnormal expression of ABCA1 and ABCG1 in the placenta can elicit lipid metabolism disorder and adverse pregnancy outcomes. However, whether it is associated with preterm delivery remains unclear. Our present study aimed to evaluate the relationship between abnormal expression of ABCA1 or ABCG1 and preterm delivery. METHODS: Maternal blood and placental tissues from women with spontaneous deliveries (SPD), iatrogenic deliveries (IPD), and term deliveries (TD) were collected. The lipid content and expression of ABCA1 and ABCG1 were subsequently measured. RESULTS: Compared with IPD and TD groups, the HDL, TD, LDL, and TC levels were lower in the maternal blood but higher (except TC) in the cord blood of the SPD group. The extracellular lipid content in the placentas of the SPD group was also notably lower relative to the IPD and TD groups. Moreover, the protein and mRNA expressions of ABCA1 in the placentas of the SPD group were significantly higher compared with the IPD and TD groups; however, there was no obvious difference among the three groups in the protein and mRNA expressions of ABCG1. CONCLUSIONS: Abnormal expression of ABCA1 may be associated with the dysregulation of placental lipid metabolism and the occurrence or development of SPD. PMID- 28630871 TI - A Systematic Review and Meta-Analysis on the Treatment of Cerebral Hemorrhage with NaoXueShu Oral Liquid. AB - NaoXueShu oral liquid invigorates Qi and promotes blood circulation, which is mainly used for treating the acute stage of the meridian of hemorrhagic apoplexy and acute blood stasis syndrome during early convalescence. Its main clinical manifestations include hemiplegia, mouth askew, hemianesthesia, and inarticulateness. It is used mainly in patients with lobar hemorrhage, basal ganglia, and thalamus of the small amount of bleeding without disturbing consciousness of hypertensive cerebral. The purpose of this study was to evaluate the efficacy and adverse effects of NaoXueShu oral liquid on the treatment of cerebral hemorrhage. In this study, literature on randomized controlled trials was collected from seven databases to evaluate the clinical efficiency of the treatment of cerebral hemorrhage alone or combined with Western medicine. The methodologic quality of the included studies was assessed using a standard Cochrane system review and analyzed using RevMan 5.3.0 software. The study included 14 eligible randomized controlled trials. The results showed that the use of NaoXueShu oral liquid alone or combined with other drugs or auxiliary methods can play a significant role in the treatment of cerebral hemorrhage, especially hypertensive intracerebral hemorrhage. PMID- 28630872 TI - Effect of Regular Aerobic Activity in Young Healthy Athletes on Profile of Endothelial Function and Platelet Activity. AB - The aim of the study was to assess the impact of regular professional sports activity on the endothelial and platelet function in young men. The studied group were 79 young men (18-40 y, 25 athletes and 54 without any regular physical activity). The nitric oxide (NO) metabolic pathway intermediates, oxidative stress markers, mediators of inflammation, and platelet aggregation were measured. Flow mediated dilation (FMD) was studied before and after intravenous 16,0 g L-arginine infusion, which was repeated after oral administration of acetylsalicylic acid (ASA-75 mg/day) for 4 days. Both groups had similar demographic characteristics. In the athletes, there was significantly higher hsCRP level, better serum lipid profile, and lower pulse pressure. Greater baseline FMD in athletes and in response to L-arginine disappeared following ASA treatment. There were no differences in the levels of the NO pathway metabolites. The control group was characterized by higher PAI-1 following ASA treatment and sICAM-1 both at baseline and after ASA, but no differences in MDA and 6-keto-PGF 1 alpha and platelet aggregation were noted. Regular professional physical activity modulates endothelial but not platelet function and may thus exert an effect on overall cardiovascular risk. PMID- 28630873 TI - An Integrative Developmental Genomics and Systems Biology Approach to Identify an In Vivo Sox Trio-Mediated Gene Regulatory Network in Murine Embryos. AB - Embryogenesis is an intricate process involving multiple genes and pathways. Some of the key transcription factors controlling specific cell types are the Sox trio, namely, Sox5, Sox6, and Sox9, which play crucial roles in organogenesis working in a concerted manner. Much however still needs to be learned about their combinatorial roles during this process. A developmental genomics and systems biology approach offers to complement the reductionist methodology of current developmental biology and provide a more comprehensive and integrated view of the interrelationships of complex regulatory networks that occur during organogenesis. By combining cell type-specific transcriptome analysis and in vivo ChIP-Seq of the Sox trio using mouse embryos, we provide evidence for the direct control of Sox5 and Sox6 by the transcriptional trio in the murine model and by Morpholino knockdown in zebrafish and demonstrate the novel role of Tgfb2, Fbxl18, and Tle3 in formation of Sox5, Sox6, and Sox9 dependent tissues. Concurrently, a complete embryonic gene regulatory network has been generated, identifying a wide repertoire of genes involved and controlled by the Sox trio in the intricate process of normal embryogenesis. PMID- 28630874 TI - Mental and Reproductive Health Correlates of Academic Performance among Debre Berhan University Female Students, Ethiopia: The Case of Premenstrual Dysphoric Disorder. AB - BACKGROUND: Globally 3 to 8% of reproductive age women are suffering from premenstrual dysphoric disorder (PMDD). Several mental and reproductive health related factors cause low academic achievement during university education. However, limited data exist in Ethiopia. The aim of the study was to investigate mental and reproductive health correlates of academic performance. METHODS: Institution based cross-sectional study was conducted with 667 Debre Berhan University female students from April to June 2015. Academic performance was the outcome variable. Mental and reproductive health characteristics were explanatory variables. Two-way analysis of variance (ANOVA) test of association was applied to examine group difference in academic performance. RESULT: Among 529 students who participated, 49.3% reported mild premenstrual syndrome (PMS), 36.9% reported moderate/severe PMS, and 13.8% fulfilled PMDD diagnostic criteria. The ANOVA test of association revealed that there was no significant difference in academic performance between students with different level of PMS experience (F-statistic = 0.08, p value = 0.93). Nevertheless, there was a significant difference in academic performance between students with different length of menses (F statistic = 5.15, p value = 0.006). CONCLUSION: There was no significant association between PMS experience and academic performance, but on the other hand, the length of menses significantly associated with academic performance. PMID- 28630876 TI - A Dosimetric Comparison of Dose Escalation with Simultaneous Integrated Boost for Locally Advanced Non-Small-Cell Lung Cancer. AB - BACKGROUND: Many studies have demonstrated that a higher radiotherapy dose is associated with improved outcomes in non-small-cell lung cancer (NSCLC). We performed a dosimetric planning study to assess the dosimetric feasibility of intensity-modulated radiation therapy (IMRT) with a simultaneous integrated boost (SIB) in locally advanced NSCLC. METHODS: We enrolled twenty patients. Five different dose plans were generated for each patient. All plans were prescribed a dose of 60 Gy to the planning tumor volume (PTV). In the three SIB groups, the prescribed dose was 69 Gy, 75 Gy, and 81 Gy in 30 fractions to the internal gross tumor volume (iGTV). RESULTS: The SIB-IMRT plans were associated with a significant increase in the iGTV dose (P < 0.05), without increased normal tissue exposure or prolonged overall treatment time. Significant differences were not observed in the dose to the normal lung in terms of the V5 and V20 among the four IMRT plans. The maximum dose (Dmax) in the esophagus moderately increased along with the prescribed dose (P < 0.05). CONCLUSIONS: Our results indicated that escalating the dose by SIB-IMRT is dosimetrically feasible; however, systematic evaluations via clinical trials are still warranted. We have designed a further clinical study (which is registered with ClinicalTrials.gov, number NCT02841228). PMID- 28630877 TI - Male-Partnered Sexual Minority Women: Sexual Identity Disclosure to Health Care Providers During the Perinatal Period. AB - Male-partnered sexual minority women (SMW) have received little research attention, despite the fact that they represent a large proportion of SMW - particularly child-bearing SMW. Male-partnered SMW are less "out" than female partnered SMW and will likely be "read" as heterosexual by perinatal providers. Given this, and evidence that pregnant women have unique mental health care needs, the current study focuses on male-partnered SMW (n = 28) during the perinatal period, recruited from Toronto, Canada and Massachusetts, USA, in an effort to understand disclosure and concealment processes in general and to perinatal heath care providers specifically. Women generally reported that they did not disclose (but made no effort to conceal) their sexual identities and histories in new or unfamiliar relationships, largely because the topic rarely came up, although some women highlighted bisexual invisibility and fear of biphobia as reasons for non-disclosure. Despite overall positive experiences with perinatal providers, less than one-quarter of the sample (n = 6) had disclosed their sexual identities and histories to them. Most women felt that this information was generally not relevant to their health care, and particularly their reproductive/obstetric care, although some believed that disclosure would be appropriate under conditions of sexual health risk (n = 8). Others noted that although they did not feel the need to disclose, they did prefer an LGBQ affirming provider (n = 7). Findings provide insight into male-partnered SMW's views and patterns of disclosure during the perinatal period, and have implications for providers, organizations, and scholars who interface with SMW. Pregnant sexual minority women with male partners are often assumed to be heterosexual, raising questions about whether and when these women disclose their sexual minority status in the perinatal context. This qualitative study of 28 women found that most participants did not share their sexual identity or sexual histories with their perinatal health care providers because this information was perceived as not relevant to their care, although some women nevertheless valued having LGBTQ friendly providers. PMID- 28630878 TI - Prediction of brain tissue temperature using near-infrared spectroscopy. AB - Broadband near-infrared spectroscopy (NIRS) can provide an endogenous indicator of tissue temperature based on the temperature dependence of the water absorption spectrum. We describe a first evaluation of the calibration and prediction of brain tissue temperature obtained during hypothermia in newborn piglets (animal dataset) and rewarming in newborn infants (human dataset) based on measured body (rectal) temperature. The calibration using partial least squares regression proved to be a reliable method to predict brain tissue temperature with respect to core body temperature in the wavelength interval of 720 to 880 nm with a strong mean predictive power of [Formula: see text] (animal dataset) and [Formula: see text] (human dataset). In addition, we applied regression receiver operating characteristic curves for the first time to evaluate the temperature prediction, which provided an overall mean error bias between NIRS predicted brain temperature and body temperature of [Formula: see text] (animal dataset) and [Formula: see text] (human dataset). We discuss main methodological aspects, particularly the well-known aspect of over- versus underestimation between brain and body temperature, which is relevant for potential clinical applications. PMID- 28630875 TI - Contribution of the Microenvironmental Niche to Glioblastoma Heterogeneity. AB - Glioblastoma is the most aggressive cancer of the brain. The dismal prognosis is largely attributed to the heterogeneous nature of the tumor, which in addition to intrinsic molecular and genetic changes is also influenced by the microenvironmental niche in which the glioma cells reside. The cancer stem cells (CSCs) hypothesis suggests that all cancers arise from CSCs that possess the ability to self-renew and initiate tumor formation. CSCs reside in specialized niches where interaction with the microenvironment regulates their stem cell behavior. The reciprocal interaction between glioma stem cells (GSCs) and cells from the microenvironment, such as endothelial cells, immune cells, and other parenchymal cells, may also promote angiogenesis, invasion, proliferation, and stemness of the GSCs and be likely to have an underappreciated role in their responsiveness to therapy. This crosstalk may also promote molecular transition of GSCs. Hence the inherent plasticity of GSCs can be seen as an adaptive response, changing according to the signaling cue from the niche. Given the association of GSCs with tumor recurrence and treatment sensitivity, understanding this bidirectional crosstalk between GSCs and its niche may provide a framework to identify more effective therapeutic targets and improve treatment outcome. PMID- 28630879 TI - Imaging Cajal's neuronal avalanche: how wide-field optical imaging of the point spread advanced the understanding of neocortical structure-function relationship. AB - This review brings together a collection of studies that specifically use wide field high-resolution mesoscopic level imaging techniques (intrinsic signal optical imaging; voltage-sensitive dye optical imaging) to image the cortical point spread (PS): the total spread of cortical activation comprising a large neuronal ensemble evoked by spatially restricted (point) stimulation of the sensory periphery (e.g., whisker, pure tone, point visual stimulation). The collective imaging findings, combined with supporting anatomical and electrophysiological findings, revealed some key aspects about the PS including its very large (radius of several mm) and relatively symmetrical spatial extent capable of crossing cytoarchitectural borders and trespassing into other cortical areas; its relationship with underlying evoked subthreshold activity and underlying anatomical system of long-range horizontal projections within gray matter, both also crossing borders; its contextual modulation and plasticity; the ability of its relative spatiotemporal profile to remain invariant to major changes in stimulation parameters; its potential role as a building block for integrative cortical activity; and its ubiquitous presence across various cortical areas and across mammalian species. Together, these findings advance our understanding about the neocortex at the mesoscopic level by underscoring that the cortical PS constitutes a fundamental motif of neocortical structure-function relationship. PMID- 28630880 TI - Prominent lateral spread of imaged evoked activity beyond cortical columns in barrel cortex provides foundation for coding whisker identity. AB - The posterior medial barrel subfield (PMBSF) of a rat primary somatosensory cortex exquisitely demonstrates topography and columnar organization, defining features of sensory cortices in the mammalian brain. Optical imaging and neuronal recordings in rat PMBSF demonstrate how evoked cortical activity following single whisker stimulation also rapidly spreads laterally into surrounding cortices, disregarding columnar and modality boundaries. The current study quantifies the spatial prominence of such lateral activity spreads by demonstrating that functional connectivity between laterally spaced cortical locations is actually stronger than between vertically spaced cortical locations. Further, the total amount of evoked activity within and beyond single column boundaries was quantified based on intrinsic signal optical imaging, single units and local field potentials recordings, revealing that the vast majority of whisker evoked activity in PMBSF occurs beyond columnar boundaries. Finally, a simple two-layer artificial neural network model of PMBSF demonstrates the capacity of extracolumnar evoked activity spread to provide a foundation for accurate whisker stimulus classification that is robust to random scaling of inputs and local noise. Indeed, classification performance improved when more of the lateral spread was included in the model, providing further evidence for the relevance of the lateral spread. PMID- 28630881 TI - Review of functional and clinical relevance of intrinsic signal optical imaging in human brain mapping. AB - Intrinsic signal optical imaging (ISOI) within the first decade of its use in humans showed its capacity as a precise functional mapping tool. It is a powerful tool that can be used intraoperatively to help a surgeon to directly identify functional areas of the cerebral cortex. Its use is limited to the intraoperative setting as it requires a craniotomy and durotomy for direct visualization of the brain. It has been applied in humans to study language, somatosensory and visual cortices, cortical hemodynamics, epileptiform activity, and lesion delineation. Despite studies showing clear evidence of its usefulness in clinical care, its clinical use in humans has not grown. Impediments imposed by imaging in a human operating room setting have hindered such work. However, recent studies have been aimed at overcoming obstacles in clinical studies establishing the benefits of its use to patients. This review provides a description of ISOI and its use in human studies with an emphasis on the challenges that have hindered its widespread use and the recent studies that aim to overcome these hurdles. Clinical studies establishing the benefits of its use to patients would serve as the impetus for continued development and use in humans. PMID- 28630883 TI - Detection of prostate cancer in multiparametric MRI using random forest with instance weighting. AB - A prostate computer-aided diagnosis (CAD) based on random forest to detect prostate cancer using a combination of spatial, intensity, and texture features extracted from three sequences, T2W, ADC, and B2000 images, is proposed. The random forest training considers instance-level weighting for equal treatment of small and large cancerous lesions as well as small and large prostate backgrounds. Two other approaches, based on an AutoContext pipeline intended to make better use of sequence-specific patterns, were considered. One pipeline uses random forest on individual sequences while the other uses an image filter described to produce probability map-like images. These were compared to a previously published CAD approach based on support vector machine (SVM) evaluated on the same data. The random forest, features, sampling strategy, and instance level weighting improve prostate cancer detection performance [area under the curve (AUC) 0.93] in comparison to SVM (AUC 0.86) on the same test data. Using a simple image filtering technique as a first-stage detector to highlight likely regions of prostate cancer helps with learning stability over using a learning based approach owing to visibility and ambiguity of annotations in each sequence. PMID- 28630882 TI - Review: How do spontaneous and sensory-evoked activities interact? AB - Twenty years ago, the seminal work of Grinvald et al. revolutionized the view cast on spontaneous cortical activity by showing how, instead of being a mere measure of noise, it profoundly impacts cortical responses to a sensory input and therefore could play a role in sensory processing. This paved the way for a number of studies on the interactions between spontaneous and sensory-evoked activities. Spontaneous activity has subsequently been found to be highly structured and to participate in high cognitive functions, such as influencing conscious perception in humans. However, its functional role remains poorly understood, and only a few speculations exist, from the maintenance of the cortical network to the internal representation of an a priori knowledge of the environment. Furthermore, elucidation of this functional role could stem from studying the opposite relationship between spontaneous and sensory-evoked activities, namely, how a sensory input influences subsequent internal activities. Indeed, this question has remained largely unexplored, but a recent study by the Grinvald laboratory shows that a brief sensory input largely dampens spontaneous rhythms, suggesting a more sophisticated view where some spontaneous rhythms might relate to sensory processing and some others not. PMID- 28630884 TI - Evaluation of a high-resolution patient-specific model of the electrically stimulated cochlea. AB - Cochlear implants (CIs) are surgically implanted medical devices used to treat individuals with severe-to-profound sensorineural hearing loss. Although these devices have been remarkably successful at restoring audibility, many patients experience poor outcomes. Our group has developed the first image-guided CI programming technique where the electrode positions are found in CT images and used to estimate neural activation patterns, which is unique information that audiologists can use to define patient-specific processor settings. Currently, neural activation is estimated using only the distance from each electrode to the neural activation sites, which might be less accurate than using high-resolution electro-anatomical models (EAMs) to perform physics-based estimations of neural activation. We propose a patient-customized EAM approach where the EAM is spatially and electrically adapted to a patient-specific configuration. Spatial adaptation is done through nonrigid registration of the model with the patient CT image. Electrical adaptation is done by adjusting tissue resistivity parameters, so the intracochlear voltage distributions predicted by the model best match those directly measured for the patient via their implant. We found that our approach, demonstrated for [Formula: see text] patients, results in mean percent differences between direct and simulated measurements of voltage distributions of 10.9%. PMID- 28630885 TI - Bayesian framework inspired no-reference region-of-interest quality measure for brain MRI images. AB - We describe a postacquisition, attribute-based quality assessment method for brain magnetic resonance imaging (MRI) images. It is based on the application of Bayes theory to the relationship between entropy and image quality attributes. The entropy feature image of a slice is segmented into low- and high-entropy regions. For each entropy region, there are three separate observations of contrast, standard deviation, and sharpness quality attributes. A quality index for a quality attribute is the posterior probability of an entropy region given any corresponding region in a feature image where quality attribute is observed. Prior belief in each entropy region is determined from normalized total clique potential (TCP) energy of the slice. For TCP below the predefined threshold, the prior probability for a region is determined by deviation of its percentage composition in the slice from a standard normal distribution built from 250 MRI volume data provided by Alzheimer's Disease Neuroimaging Initiative. For TCP above the threshold, the prior is computed using a mathematical model that describes the TCP-noise level relationship in brain MRI images. Our proposed method assesses the image quality of each entropy region and the global image. Experimental results demonstrate good correlation with subjective opinions of radiologists for different types and levels of quality distortions. PMID- 28630887 TI - Calculation of the entrance skin dose distribution for fluoroscopically guided interventions using a pencil beam backscatter model. AB - Radiation backscattered from the patient can contribute substantially to skin dose in fluoroscopically guided interventions (FGIs). The distribution of backscatter is not spatially uniform, and use of a single backscatter factor cannot provide an accurate determination of skin dose. This study evaluates a method to determine the backscatter spatial distribution through convolution of a backscatter-to-primary (BP) point spread function (PSFn). The PSFn is derived for a pencil beam using EGSnrc Monte Carlo software and is convolved with primary distributions using a dose-tracking system. The backscatter distribution calculated using the convolution method is validated with Monte Carlo-derived distributions for three different size "uniform" fields and with XR-QA2 Gafchromic film for nonuniform x-ray fields obtained using region-of-interest (ROI) attenuators and compensation filters, both with homogenous poly-methyl methacrylate and nonhomogenous head phantoms. The BP ratios inside uniform fields were calculated within [Formula: see text] of that determined using EGSnrc. For shaped fields, the BP ratio in the unattenuated ROI was calculated within [Formula: see text] of that measured with film; in the beam-attenuated periphery, agreement was within [Formula: see text], due to the larger uncertainty of the dose-response curve of the film in the low-dose region. This backscatter PSFn convolution method is much faster than performing full-field Monte Carlo calculations and provides improved accuracy in skin dose distribution determination for FGI procedures. PMID- 28630886 TI - Review of the current status of radiation protection in diagnostic radiology in Africa. AB - The aim of this paper is to review the available published studies from African countries on patient doses and medical radiation protection and identify strengths, weaknesses, and challenges. Papers on radiation doses to patients published until 2016 pertaining to studies in African countries were reviewed. Radiography, interventional radiology, computed tomography (CT), and mammography modalities were covered. In radiography, the entrance surface air kerma values were below the established diagnostic reference levels (DRLs) provided by the International Atomic Energy Agency, European Commission, and National Council on Radiation Protection and Measurements. Patient and staff doses in interventional procedures were not on the higher side when compared with other published reports from developed countries. The dose length product values in CT in many situations were higher than established DRLs. In mammography, the variations of clinical image quality and dose to standard breast between African countries and other countries were insignificant. In conclusion, like in any continent, not all countries in Africa are active, but some have produced good results. The potential for optimization of radiation protection using simple and inexpensive techniques has been demonstrated. The lack of medical physicists is one of the important challenges. PMID- 28630888 TI - GillesPy: A Python Package for Stochastic Model Building and Simulation. AB - GillesPy is an open-source Python package for model construction and simulation of stochastic biochemical systems. GillesPy consists of a Python framework for model building and an interface to the StochKit2 suite of efficient simulation algorithms based on the Gillespie stochastic simulation algorithms (SSA). To enable intuitive model construction and seamless integration into the scientific Python stack, we present an easy to understand, action-oriented programming interface. Here, we describe the components of this package and provide a detailed example relevant to the computational biology community. PMID- 28630889 TI - Subspace aware recovery of low rank and jointly sparse signals. AB - We consider the recovery of a matrix X, which is simultaneously low rank and joint sparse, from few measurements of its columns using a two-step algorithm. Each column of X is measured using a combination of two measurement matrices; one which is the same for every column, while the the second measurement matrix varies from column to column. The recovery proceeds by first estimating the row subspace vectors from the measurements corresponding to the common matrix. The estimated row subspace vectors are then used to recover X from all the measurements using a convex program of joint sparsity minimization. Our main contribution is to provide sufficient conditions on the measurement matrices that guarantee the recovery of such a matrix using the above two-step algorithm. The results demonstrate quite significant savings in number of measurements when compared to the standard multiple measurement vector (MMV) scheme, which assumes same time invariant measurement pattern for all the time frames. We illustrate the impact of the sampling pattern on reconstruction quality using breath held cardiac cine MRI and cardiac perfusion MRI data, while the utility of the algorithm to accelerate the acquisition is demonstrated on MR parameter mapping. PMID- 28630890 TI - DRD4 Gene Polymorphisms as a Risk Factor for Children with Attention Deficit Hyperactivity Disorder in Iranian Population. AB - BACKGROUND AND OBJECTIVE: Dopamine dysfunction is known to be associated with attention deficit hyperactivity disorder (ADHD). Dopamine D4 receptor gene (DRD4) is one of the important genes in this pathway. This study intended to investigate the variable number of tandem repeats (VNTR) in exon 3 of the DRD4 gene in Iranian children and adolescents. MATERIALS AND METHODS: In this study, 130 children with ADHD, aged 6-14 years, and 130 healthy children, within the same age range, were enrolled. All children were selected from northwest of Iran which have Caucasian ethnic background and are of a Turkic ethnic group. VNTR polymorphisms of the DRD4 gene were evaluated by PCR using exon 3-specific primers followed by agarose gel electrophoresis. FINDINGS: The Hardy-Weinberg principle and Chi-square test showed a significant difference in 4-repetition (4R) alleles between the ADHD (76.2%) and control (53.8%) groups (p = 0.004; X2 = 17.39; df = 5). The least percentage of repetition alleles in both groups was 2R. CONCLUSION: There is a significant correlation between the 4R alleles of DRD4 and ADHD in the northwest of Iran. PMID- 28630891 TI - Frequency of Neurological Disorders in Bullous Pemphigoid Patients: A Cross Sectional Study. AB - BACKGROUND: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering skin disorder which occurs mostly in the elderly. Several studies have reported an association between BP and neurological disorders (ND). OBJECTIVE: The purpose of this study was to evaluate the association between BP and neurological disorders in Iranian patients. METHODS: In this cross-sectional study, 87 patients with BP were enrolled. They were compared to 184 controls. Statistical analysis was done by SPSS statistical software version 19. RESULTS: Out of 87 patients with BP, 17 (19.5%) had at least one neurological disease. Cerebrovascular accident (CVA) was the most common neurological disease that was seen in 7 patients (8.0%) in the case group and 4 (2.1%) in the control group. The incidence of CVA was significantly different between BP patients and the control group (P = 0.022). Dementia was observed in 6 patients in the case group (16.8%) and 2 (1.0%) in the control group. The incidence of dementia was significantly different between BP patients and the control group (P = 0.008). In this study, the incidences of Parkinson's disease (P = 0.830), epilepsy (P = 0.067), and multiple sclerosis (P = 0.326) were not statistically significant between the two groups. CONCLUSION: The incidence of CVA and dementia in patients with BP compared to the control group was significantly higher. PMID- 28630892 TI - Disruption of the Axonal Trafficking of Tyrosine Hydroxylase mRNA Impairs Catecholamine Biosynthesis in the Axons of Sympathetic Neurons. AB - Tyrosine hydroxylase (TH) is the enzyme that catalyzes the rate-limiting step in the biosynthesis of the catecholamine neurotransmitters. In a previous communication, evidence was provided that TH mRNA is trafficked to the axon, where it is locally translated. In addition, a 50-bp sequence element in the 3'untranslated region (3'UTR) of TH mRNA was identified that directs TH mRNA to distal axons (i.e., zip-code). In the present study, the hypothesis was tested that local translation of TH plays an important role in the biosynthesis of the catecholamine neurotransmitters in the axon and/or presynaptic nerve terminal. Toward this end, a targeted deletion of the axonal transport sequence element was developed, using the lentiviral delivery of the CRISPR/Cas9 system, and two guide RNA (gRNA) sequences flanking the 50-bp cis-acting regulatory element in rat superior cervical ganglion (SCG) neurons. Deletion of the axonal transport element reduced TH mRNA levels in the distal axons and reduced the axonal protein levels of TH and TH activity as measured by phosphorylation of SER40 in SCG neurons. Moreover, deletion of the zip-code diminished the axonal levels of dopamine (DA) and norepinephrine (NE). Conversely, the local translation of exogenous TH mRNA in the distal axon enhanced TH levels and activity, and elevated axonal NE levels. Taken together, these results provide direct evidence to support the hypothesis that TH mRNA trafficking and local synthesis of TH play an important role in the synthesis of catecholamines in the axon and presynaptic terminal. PMID- 28630893 TI - A D53 repression motif induces oligomerization of TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex. AB - TOPLESS are tetrameric plant corepressors of the conserved Tup1/Groucho/TLE (transducin-like enhancer of split) family. We show that they interact through their TOPLESS domains (TPDs) with two functionally important ethylene response factor-associated amphiphilic repression (EAR) motifs of the rice strigolactone signaling repressor D53: the universally conserved EAR-3 and the monocot-specific EAR-2. We present the crystal structure of the monocot-specific EAR-2 peptide in complex with the TOPLESS-related protein 2 (TPR2) TPD, in which the EAR-2 motif binds the same TPD groove as jasmonate and auxin signaling repressors but makes additional contacts with a second TPD site to mediate TPD tetramer-tetramer interaction. We validated the functional relevance of the two TPD binding sites in reporter gene assays and in transgenic rice and demonstrate that EAR-2 binding induces TPD oligomerization. Moreover, we demonstrate that the TPD directly binds nucleosomes and the tails of histones H3 and H4. Higher-order assembly of TPD complexes induced by EAR-2 binding markedly stabilizes the nucleosome-TPD interaction. These results establish a new TPD-repressor binding mode that promotes TPD oligomerization and TPD-nucleosome interaction, thus illustrating the initial assembly of a repressor-corepressor-nucleosome complex. PMID- 28630895 TI - Glass eels (Anguilla anguilla) have a magnetic compass linked to the tidal cycle. AB - The European eel (Anguilla anguilla) has one of the longest migrations in the animal kingdom. It crosses the Atlantic Ocean twice during its life history, migrating between the spawning area in the Sargasso Sea and Europe, where it is widely distributed. The leptocephalus larvae drift with the Gulf Stream and other currents for more than a year and metamorphose into glass eels when they arrive on the continental shelf and move toward coastal areas. The mechanisms underlying glass eel orientation toward the coast and into freshwater systems are poorly known. However, anguillid eels, including the glass eel life stage, have a geomagnetic sense, suggesting the possibility that they use Earth's magnetic field to orient toward the coast. To test this hypothesis, we used a unique combination of laboratory tests and in situ behavioral observations conducted in a drifting circular arena. Most (98%) of the glass eels tested in the sea exhibited a preferred orientation that was related to the tidal cycle. Seventy one percent of the same eels showed the same orientation during ebb tide when tested in the laboratory under a manipulated simulated magnetic field in the absence of any other cue. These results demonstrate that glass eels use a magnetic compass for orientation and suggest that this magnetic orientation system is linked to a circatidal rhythm. PMID- 28630897 TI - Flexible and stretchable power sources for wearable electronics. AB - Flexible and stretchable power sources represent a key technology for the realization of wearable electronics. Developing flexible and stretchable batteries with mechanical endurance that is on par with commercial standards and offer compliance while retaining safety remains a significant challenge. We present a unique approach that demonstrates mechanically robust, intrinsically safe silver-zinc batteries. This approach uses current collectors with enhanced mechanical design, such as helical springs and serpentines, as a structural support and backbone for all battery components. We show wire-shaped batteries based on helical band springs that are resilient to fatigue and retain electrochemical performance over 17,000 flexure cycles at a 0.5-cm bending radius. Serpentine-shaped batteries can be stretched with tunable degree and directionality while maintaining their specific capacity. Finally, the batteries are integrated, as a wearable device, with a photovoltaic module that enables recharging of the batteries. PMID- 28630894 TI - Next-generation probes, particles, and proteins for neural interfacing. AB - Bidirectional interfacing with the nervous system enables neuroscience research, diagnosis, and therapy. This two-way communication allows us to monitor the state of the brain and its composite networks and cells as well as to influence them to treat disease or repair/restore sensory or motor function. To provide the most stable and effective interface, the tools of the trade must bridge the soft, ion rich, and evolving nature of neural tissue with the largely rigid, static realm of microelectronics and medical instruments that allow for readout, analysis, and/or control. In this Review, we describe how the understanding of neural signaling and material-tissue interactions has fueled the expansion of the available tool set. New probe architectures and materials, nanoparticles, dyes, and designer genetically encoded proteins push the limits of recording and stimulation lifetime, localization, and specificity, blurring the boundary between living tissue and engineered tools. Understanding these approaches, their modality, and the role of cross-disciplinary development will support new neurotherapies and prostheses and provide neuroscientists and neurologists with unprecedented access to the brain. PMID- 28630896 TI - The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. AB - Although both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) signaling were shown to regulate life span in lower organisms, the role of GH signaling in human longevity remains unclear. Because a GH receptor exon 3 deletion (d3-GHR) appears to modulate GH sensitivity in humans, we hypothesized that this polymorphism could play a role in human longevity. We report a linear increased prevalence of d3-GHR homozygosity with age in four independent cohorts of long-lived individuals: 841 participants [567 of the Longevity Genes Project (LGP) (8% increase; P = 0.01), 152 of the Old Order Amish (16% increase; P = 0.02), 61 of the Cardiovascular Health Study (14.2% increase; P = 0.14), and 61 of the French Long-Lived Study (23.5% increase; P = 0.02)]. In addition, mega analysis of males in all cohorts resulted in a significant positive trend with age (26% increase; P = 0.007), suggesting sexual dimorphism for GH action in longevity. Further, on average, LGP d3/d3 homozygotes were 1 inch taller than the wild-type (WT) allele carriers (P = 0.05) and also showed lower serum IGF-1 levels (P = 0.003). Multivariate regression analysis indicated that the presence of d3/d3 genotype adds approximately 10 years to life span. The LGP d3/d3-GHR transformed lymphocytes exhibited superior growth and extracellular signal regulated kinase activation, to GH treatment relative to WT GHR lymphocytes (P < 0.01), indicating a GH dose response. The d3-GHR variant is a common genetic polymorphism that modulates GH responsiveness throughout the life span and positively affects male longevity. PMID- 28630898 TI - Polymeric lithography editor: Editing lithographic errors with nanoporous polymeric probes. AB - A new lithographic editing system with an ability to erase and rectify errors in microscale with real-time optical feedback is demonstrated. The erasing probe is a conically shaped hydrogel (tip size, ca. 500 nm) template-synthesized from track-etched conical glass wafers. The "nanosponge" hydrogel probe "erases" patterns by hydrating and absorbing molecules into a porous hydrogel matrix via diffusion analogous to a wet sponge. The presence of an interfacial liquid water layer between the hydrogel tip and the substrate during erasing enables frictionless, uninterrupted translation of the eraser on the substrate. The erasing capacity of the hydrogel is extremely high because of the large free volume of the hydrogel matrix. The fast frictionless translocation and interfacial hydration resulted in an extremely high erasing rate (~785 MUm2/s), which is two to three orders of magnitude higher in comparison with the atomic force microscopy-based erasing (~0.1 MUm2/s) experiments. The high precision and accuracy of the polymeric lithography editor (PLE) system stemmed from coupling piezoelectric actuators to an inverted optical microscope. Subsequently after erasing the patterns using agarose erasers, a polydimethylsiloxane probe fabricated from the same conical track-etched template was used to precisely redeposit molecules of interest at the erased spots. PLE also provides a continuous optical feedback throughout the entire molecular editing process writing, erasing, and rewriting. To demonstrate its potential in device fabrication, we used PLE to electrochemically erase metallic copper thin film, forming an interdigitated array of microelectrodes for the fabrication of a functional microphotodetector device. High-throughput dot and line erasing, writing with the conical "wet nanosponge," and continuous optical feedback make PLE complementary to the existing catalog of nanolithographic/microlithographic and three-dimensional printing techniques. This new PLE technique will potentially open up many new and exciting avenues in lithography, which remain unexplored due to the inherent limitations in error rectification capabilities of the existing lithographic techniques. PMID- 28630899 TI - Comment on "Whole-genome sequence analysis shows two endemic species of North American wolf are admixtures of the coyote and gray wolf". AB - Whole-genome data do not support a recent hybrid origin for red and eastern wolves. PMID- 28630900 TI - Reconstructed storm tracks reveal three centuries of changing moisture delivery to North America. AB - Moisture delivery to western North America is closely linked to variability in the westerly storm tracks of midlatitude cyclones, which are, in turn, modified by larger-scale features such as the El Nino-Southern Oscillation system. Instrumental and modeling data suggest that extratropical storm tracks may be intensifying and shifting poleward due to anthropogenic climate change, but it is difficult to separate recent trends from natural variability because of the large amount of decadal and longer variation in storm tracks and their limited instrumental record. We reconstruct cool-season, midlatitude Pacific storm-track position and intensity from 1693 to 1995 CE using existing tree-ring chronologies along with a network of newly developed chronologies from the U.S. Pacific Northwest, where small variations in storm-track position can have a major influence on hydroclimate patterns. Our results show high interannual-to multidecadal variability in storm-track position and intensity over the past 303 years, with spectral signatures characteristic of tropical and northern Pacific influences. Comparison with reconstructions of precipitation and tropical sea surface temperature confirms the relationship between shifting drought patterns in the Pacific Northwest and storm-track variability through time and demonstrates the long-term influence of El Nino. These results allow us to place recent storm-track changes in the context of decadal and multidecadal fluctuations across the long-term record, showing that recent changes in storm track intensity likely represent a warming-related increase amplified by natural decadal variability. PMID- 28630901 TI - Stable anchoring chemistry for room temperature charge transport through graphite molecule contacts. AB - An open challenge for single-molecule electronics is to find stable contacts at room temperature with a well-defined conductance. Common coinage metal electrodes pose fabrication and operational problems due to the high mobility of the surface atoms. We demonstrate how molecules covalently grafted onto mechanically robust graphite/graphene substrates overcome these limitations. To this aim, we explore the effect of the anchoring group chemistry on the charge transport properties of graphite-molecule contacts by means of the scanning tunneling microscopy break junction technique and ab initio simulations. Molecules adsorbed on graphite only via van der Waals interactions have a conductance that decreases exponentially upon stretching the junctions, whereas the molecules bonded covalently to graphite have a single well-defined conductance and yield contacts of unprecedented stability at room temperature. Our results demonstrate a strong bias dependence of the single-molecule conductance, which varies over more than one order of magnitude even at low bias voltages, and show an opposite rectification behavior for covalent and noncovalent contacts. We demonstrate that this bias-dependent conductance and opposite rectification behavior is due to a novel effect caused by the nonconstant, highly dispersive density of states of graphite around the Fermi energy and that the direction of rectification is governed by the detailed nature of the molecule/graphite contact. Combined with the prospect of new functionalities due to a strongly bias-dependent conductance, these covalent contacts are ideal candidates for next-generation molecular electronic devices. PMID- 28630902 TI - Comment (2) on "Formation of the Isthmus of Panama" by O'Dea et al. AB - O'Dea et al. challenged the inference that the Isthmus of Panama has been in place for the last 10 million years or more and from "an exhaustive review and reanalysis of geological, paleontological, and molecular records," they argued for a "formation of the Isthmus of Panama sensu stricto around 2.8 Ma." I review environmental changes since ~5 Ma throughout Earth, and I argue that environmental changes in the Central American-Caribbean region have been part of a concurrent, worldwide phenomenon that requires a global, not local, explanation. Accordingly, evidence of environmental change from the Central American-Caribbean region does not implicate the emergence of the Isthmus of Panama. PMID- 28630903 TI - Comment (1) on "Formation of the Isthmus of Panama" by O'Dea et al. AB - A review and reanalysis of geological, molecular, and paleontological data led O'Dea et al. (1) to propose (i) that reports by Montes et al. (2) and Bacon et al. (3) regarding a middle Miocene closure of the Central American Seaway (CAS) are unsupported, and (ii) a new age of the formation of the Isthmus at 2.8 million years ago (Ma). Here, we reject both of these conclusions. PMID- 28630904 TI - Participatory adaptive management leads to environmental learning outcomes extending beyond the sphere of science. AB - Resolving uncertainties in managed social-ecological systems requires adaptive experimentation at whole-ecosystem levels. However, whether participatory adaptive management fosters ecological understanding among stakeholders beyond the sphere of science is unknown. We experimentally involved members of German angling clubs (n = 181 in workshops, n = 2483 in total) engaged in self governance of freshwater fisheries resources in a large-scale ecological experiment of active adaptive management of fish stocking, which constitutes a controversial management practice for biodiversity and ecosystem functioning when conducted inappropriately. The collaborative ecological experiments spanned several years and manipulated fish densities in 24 lakes with two species. In parallel, we experimentally compared changes in ecological knowledge and antecedents of proenvironmental behavior in stakeholders and managers who were members of a participatory adaptive management treatment group, with those receiving only a standard lecture, relative to placebo controls. Using a within subjects pretest-posttest control design, changes in ecological knowledge, environmental beliefs, attitudes, norms, and behavioral intentions were evaluated. Participants in adaptive management retained more knowledge of ecological topics after a period of 8 months compared to those receiving a standard lecture, both relative to controls. Involvement in adaptive management was also the only treatment that altered personal norms and beliefs related to stocking. Critically, only the stakeholders who participated in adaptive management reduced their behavioral intentions to engage in fish stocking in the future. Adaptive management is essential for robust ecological knowledge, and we show that involving stakeholders in adaptive management experiments is a powerful tool to enhance ecological literacy and build environmental capacity to move toward sustainability. PMID- 28630905 TI - Mechanical deformation induces depolarization of neutrophils. AB - The transition of neutrophils from a resting state to a primed state is an essential requirement for their function as competent immune cells. This transition can be caused not only by chemical signals but also by mechanical perturbation. After cessation of either, these cells gradually revert to a quiescent state over 40 to 120 min. We use two biophysical tools, an optical stretcher and a novel microcirculation mimetic, to effect physiologically relevant mechanical deformations of single nonadherent human neutrophils. We establish quantitative morphological analysis and mechanical phenotyping as label free markers of neutrophil priming. We show that continued mechanical deformation of primed cells can cause active depolarization, which occurs two orders of magnitude faster than by spontaneous depriming. This work provides a cellular level mechanism that potentially explains recent clinical studies demonstrating the potential importance, and physiological role, of neutrophil depriming in vivo and the pathophysiological implications when this deactivation is impaired, especially in disorders such as acute lung injury. PMID- 28630906 TI - Skyrmion lattice structural transition in MnSi. AB - Magnetic skyrmions exhibit particle-like properties owing to the topology of their swirling spin texture, providing opportunities to study crystallization of topological particles. However, they mostly end up with a triangular lattice, and thus, the packing degree of freedom in the skyrmion particles has been overlooked so far. We report a structural transition of the skyrmion lattice in MnSi. By use of small-angle neutron scattering, we explore a metastable skyrmion state spreading over a wide temperature and magnetic field region, after thermal quenching. The quenched skyrmions undergo a triangular-to-square lattice transition with decreasing magnetic field at low temperatures. Our study suggests that various skyrmion lattices can emerge at low temperatures, where the skyrmions exhibit distinct topological nature and high sensitivity to the local magnetic anisotropy arising from the underlying chemical lattice. PMID- 28630907 TI - Wind-invariant saltation heights imply linear scaling of aeolian saltation flux with shear stress. AB - Wind-driven sand transport generates atmospheric dust, forms dunes, and sculpts landscapes. However, it remains unclear how the flux of particles in aeolian saltation-the wind-driven transport of sand in hopping trajectories-scales with wind speed, largely because models do not agree on how particle speeds and trajectories change with wind shear velocity. We present comprehensive measurements, from three new field sites and three published studies, showing that characteristic saltation layer heights remain approximately constant with shear velocity, in agreement with recent wind tunnel studies. These results support the assumption of constant particle speeds in recent models predicting linear scaling of saltation flux with shear stress. In contrast, our results refute widely used older models that assume that particle speed increases with shear velocity, thereby predicting nonlinear 3/2 stress-flux scaling. This conclusion is further supported by direct field measurements of saltation flux versus shear stress. Our results thus argue for adoption of linear saltation flux laws and constant saltation trajectories for modeling saltation-driven aeolian processes on Earth, Mars, and other planetary surfaces. PMID- 28630908 TI - Biofuel by isomerizing metathesis of rapeseed oil esters with (bio)ethylene for use in contemporary diesel engines. AB - Rapeseed oil methyl ester (RME) and (bio)ethylene are converted into biofuel with an evenly rising boiling point curve, which fulfills the strict boiling specifications prescribed by the fuel standard EN 590 for modern (petro)diesel engines. Catalyzed by a Pd/Ru system, RME undergoes isomerizing metathesis in a stream of ethylene gas, leading to a defined olefin, monoester, and diester blend. This innovative refining concept requires negligible energy input (60 degrees C) and no solvents and does not produce waste. It demonstrates that the pressing challenge of increasing the fraction of renewables in engine fuel may be addressed purely chemically rather than by motor engineering. PMID- 28630910 TI - Ferroelastic modulation and the Bloch formalism. AB - The key to the development of advanced materials is to understand their electronic structure-property relationship. Utilization of this understanding to design new electronic materials with desired properties led to modern epitaxial growth approaches for synthesizing artificial lattices, which for almost half a century have become the mainstay of electronic and photonic technologies. In contrast to previous scalar modulation approaches, we now study synthetic crystal lattices that have a tensor artificial modulation and develop a theory for photons and conduction band states in these lattices in a regime with an unusual departure from the familiar consequences of translational symmetry and Bloch's theorem. This study reveals that a nonmagnetic crystal lattice modulated by a purely geometrical orientational superlattice potential can lead to localized states or to spiral states for electrons and photons, as well as weakly or strongly localized states that could be used to markedly slow down the propagation of light and for optical energy storage applications. PMID- 28630909 TI - Dynamic fracture of tantalum under extreme tensile stress. AB - The understanding of fracture phenomena of a material at extremely high strain rates is a key issue for a wide variety of scientific research ranging from applied science and technological developments to fundamental science such as laser-matter interaction and geology. Despite its interest, its study relies on a fine multiscale description, in between the atomic scale and macroscopic processes, so far only achievable by large-scale atomic simulations. Direct ultrafast real-time monitoring of dynamic fracture (spallation) at the atomic lattice scale with picosecond time resolution was beyond the reach of experimental techniques. We show that the coupling between a high-power optical laser pump pulse and a femtosecond x-ray probe pulse generated by an x-ray free electron laser allows detection of the lattice dynamics in a tantalum foil at an ultrahigh strain rate of [Formula: see text] ~2 * 108 to 3.5 * 108 s-1. A maximal density drop of 8 to 10%, associated with the onset of spallation at a spall strength of ~17 GPa, was directly measured using x-ray diffraction. The experimental results of density evolution agree well with large-scale atomistic simulations of shock wave propagation and fracture of the sample. Our experimental technique opens a new pathway to the investigation of ultrahigh strain-rate phenomena in materials at the atomic scale, including high-speed crack dynamics and stress-induced solid-solid phase transitions. PMID- 28630911 TI - The genomic mosaicism of hybrid speciation. AB - Hybridization is widespread in nature and, in some instances, can result in the formation of a new hybrid species. We investigate the genetic foundation of this poorly understood process through whole-genome analysis of the hybrid Italian sparrow and its progenitors. We find overall balanced yet heterogeneous levels of contribution from each parent species throughout the hybrid genome and identify areas of novel divergence in the hybrid species exhibiting signals consistent with balancing selection. High-divergence areas are disproportionately located on the Z chromosome and overrepresented in gene networks relating to key traits separating the focal species, which are likely involved in reproductive barriers and/or species-specific adaptations. Of special interest are genes and functional groups known to affect body patterning, beak morphology, and the immune system, which are important features of diversification and fitness. We show that a combination of mosaic parental inheritance and novel divergence within the hybrid lineage has facilitated the origin and maintenance of an avian hybrid species. PMID- 28630912 TI - A nearly water-saturated mantle transition zone inferred from mineral viscosity. AB - An open question for solid-earth scientists is the amount of water in Earth's interior. The uppermost mantle and lower mantle contain little water because their dominant minerals, olivine and bridgmanite, have limited water storage capacity. In contrast, the mantle transition zone (MTZ) at a depth of 410 to 660 km is considered to be a potential water reservoir because its dominant minerals, wadsleyite and ringwoodite, can contain large amounts of water [up to 3 weight % (wt %)]. However, the actual amount of water in the MTZ is unknown. Given that water incorporated into mantle minerals can lower their viscosity, we evaluate the water content of the MTZ by measuring dislocation mobility, a property that is inversely proportional to viscosity, as a function of temperature and water content in ringwoodite and bridgmanite. We find that dislocation mobility in bridgmanite is faster by two orders of magnitude than in anhydrous ringwoodite but 1.5 orders of magnitude slower than in water-saturated ringwoodite. To fit the observed mantle viscosity profiles, ringwoodite in the MTZ should contain 1 to 2 wt % water. The MTZ should thus be nearly water-saturated globally. PMID- 28630913 TI - An innovative biologic system for photon-powered myocardium in the ischemic heart. AB - Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated. PMID- 28630914 TI - Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin. AB - Obscurins are cytoskeletal proteins with structural and regulatory roles encoded by OBSCN. Mutations in OBSCN are associated with the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Specifically, the R4344Q mutation present in immunoglobulin domain 58 (Ig58) was the first to be linked with the development of HCM. To assess the effects of R4344Q in vivo, we generated the respective knock-in mouse model. Mutant obscurins are expressed and incorporated normally into sarcomeres. The expression patterns of sarcomeric and Ca2+-cycling proteins are unaltered in sedentary 1-year-old knock-in myocardia, with the exception of sarco/endoplasmic reticulum Ca2+ adenosine triphosphatase 2 (SERCA2) and pentameric phospholamban whose levels are significantly increased and decreased, respectively. Isolated cardiomyocytes from 1-year-old knock-in hearts exhibit increased Ca2+-transients and Ca2+-load in the sarcoplasmic reticulum and faster contractility kinetics. Moreover, sedentary 1-year-old knock in animals develop tachycardia accompanied by premature ventricular contractions, whereas 2-month-old knock-in animals subjected to pressure overload develop a DCM like phenotype. Structural analysis revealed that the R4344Q mutation alters the distribution of electrostatic charges over the Ig58 surface, thus interfering with its binding capabilities. Consistent with this, wild-type Ig58 interacts with phospholamban modestly, and this interaction is markedly enhanced in the presence of R4344Q. Together, our studies demonstrate that under sedentary conditions, the R4344Q mutation results in Ca2+ deregulation and spontaneous arrhythmia, whereas in the presence of chronic, pathological stress, it leads to cardiac remodeling and dilation. We postulate that enhanced binding between mutant obscurins and phospholamban leads to SERCA2 disinhibition, which may underlie the observed pathological alterations. PMID- 28630915 TI - Ultralight, scalable, and high-temperature-resilient ceramic nanofiber sponges. AB - Ultralight and resilient porous nanostructures have been fabricated in various material forms, including carbon, polymers, and metals. However, the development of ultralight and high-temperature resilient structures still remains extremely challenging. Ceramics exhibit good mechanical and chemical stability at high temperatures, but their brittleness and sensitivity to flaws significantly complicate the fabrication of resilient porous ceramic nanostructures. We report the manufacturing of large-scale, lightweight, high-temperature resilient, three dimensional sponges based on a variety of oxide ceramic (for example, TiO2, ZrO2, yttria-stabilized ZrO2, and BaTiO3) nanofibers through an efficient solution blow spinning process. The ceramic sponges consist of numerous tangled ceramic nanofibers, with densities varying from 8 to 40 mg/cm3. In situ uniaxial compression in a scanning electron microscope showed that the TiO2 nanofiber sponge exhibits high energy absorption (for example, dissipation of up to 29.6 mJ/cm3 in energy density at 50% strain) and recovers rapidly after compression in excess of 20% strain at both room temperature and 400 degrees C. The sponge exhibits excellent resilience with residual strains of only ~1% at 800 degrees C after 10 cycles of 10% compression strain and maintains good recoverability after compression at ~1300 degrees C. We show that ceramic nanofiber sponges can serve multiple functions, such as elasticity-dependent electrical resistance, photocatalytic activity, and thermal insulation. PMID- 28630917 TI - MnTiO3-driven low-temperature oxidative coupling of methane over TiO2-doped Mn2O3 Na2WO4/SiO2 catalyst. AB - Oxidative coupling of methane (OCM) is a promising method for the direct conversion of methane to ethene and ethane (C2 products). Among the catalysts reported previously, Mn2O3-Na2WO4/SiO2 showed the highest conversion and selectivity, but only at 800 degrees to 900 degrees C, which represents a substantial challenge for commercialization. We report a TiO2-doped Mn2O3 Na2WO4/SiO2 catalyst by using Ti-MWW zeolite as TiO2 dopant as well as SiO2 support, enabling OCM with 26% conversion and 76% C2-C3 selectivity at 720 degrees C because of MnTiO3 formation. MnTiO3 triggers the low-temperature Mn2+< >Mn3+ cycle for O2 activation while working synergistically with Na2WO4 to selectively convert methane to C2-C3. We also prepared a practical Mn2O3-TiO2 Na2WO4/SiO2 catalyst in a ball mill. This catalyst can be transformed in situ into MnTiO3-Na2WO4/SiO2, yielding 22% conversion and 62% selectivity at 650 degrees C. Our results will stimulate attempts to understand more fully the chemistry of MnTiO3-governed low-temperature activity, which might lead to commercial exploitation of a low-temperature OCM process. PMID- 28630916 TI - Surface transport and quantum Hall effect in ambipolar black phosphorus double quantum wells. AB - Quantum wells (QWs) constitute one of the most important classes of devices in the study of two-dimensional (2D) systems. In a double-layer QW, the additional "which-layer" degree of freedom gives rise to celebrated phenomena, such as Coulomb drag, Hall drag, and exciton condensation. We demonstrate facile formation of wide QWs in few-layer black phosphorus devices that host double layers of charge carriers. In contrast to traditional QWs, each 2D layer is ambipolar and can be tuned into n-doped, p-doped, or intrinsic regimes. Fully spin-polarized quantum Hall states are observed on each layer, with an enhanced Lande g factor that is attributed to exchange interactions. Our work opens the door for using 2D semiconductors as ambipolar single, double, or wide QWs with unusual properties, such as high anisotropy. PMID- 28630918 TI - Compressed glassy carbon: An ultrastrong and elastic interpenetrating graphene network. AB - Carbon's unique ability to have both sp2 and sp3 bonding states gives rise to a range of physical attributes, including excellent mechanical and electrical properties. We show that a series of lightweight, ultrastrong, hard, elastic, and conductive carbons are recovered after compressing sp2-hybridized glassy carbon at various temperatures. Compression induces the local buckling of graphene sheets through sp3 nodes to form interpenetrating graphene networks with long range disorder and short-range order on the nanometer scale. The compressed glassy carbons have extraordinary specific compressive strengths-more than two times that of commonly used ceramics-and simultaneously exhibit robust elastic recovery in response to local deformations. This type of carbon is an optimal ultralight, ultrastrong material for a wide range of multifunctional applications, and the synthesis methodology demonstrates potential to access entirely new metastable materials with exceptional properties. PMID- 28630919 TI - Discovery of Lorentz-violating type II Weyl fermions in LaAlGe. AB - In quantum field theory, Weyl fermions are relativistic particles that travel at the speed of light and strictly obey the celebrated Lorentz symmetry. Their low energy condensed matter analogs are Weyl semimetals, which are conductors whose electronic excitations mimic the Weyl fermion equation of motion. Although the traditional (type I) emergent Weyl fermions observed in TaAs still approximately respect Lorentz symmetry, recently, the so-called type II Weyl semimetal has been proposed, where the emergent Weyl quasiparticles break the Lorentz symmetry so strongly that they cannot be smoothly connected to Lorentz symmetric Weyl particles. Despite some evidence of nontrivial surface states, the direct observation of the type II bulk Weyl fermions remains elusive. We present the direct observation of the type II Weyl fermions in crystalline solid lanthanum aluminum germanide (LaAlGe) based on our photoemission data alone, without reliance on band structure calculations. Moreover, our systematic data agree with the theoretical calculations, providing further support on our experimental results. PMID- 28630920 TI - Bioinspired shape-memory graphene film with tunable wettability. AB - Functional materials with specific surface wettability play an important role in a wide variety of areas. Inspired by nature's Nepenthes pitcher plant, we present a novel slippery film with tunable wettability based on a shape-memory graphene sponge. The porous graphene sponge coated with shape-memory polymer was used to lock in inert lubricants and construct slippery surfaces to repel different liquids. The superelasticity and high strength, together with good electrical conductivity, of the graphene sponge imparted the graphene/polymer hybrid films with fast recoverable shape-memory properties. Various droplets could slip on the compressed film with a lubricant-covered surface, but the droplets would be pinned when the shape-memory graphene film rebounded due to electrical stimulation, which caused the penetration of the infused lubricant into the pores and the exposure of rough topography film surfaces. The electrothermally dynamic tuning approach was stable and reversible; thus, the shape-memory graphene film was imparted with controlled slippery properties and functions that would be amenable to a variety of applications, such as liquid handling for microplates. PMID- 28630921 TI - Increasing probability of mortality during Indian heat waves. AB - Rising global temperatures are causing increases in the frequency and severity of extreme climatic events, such as floods, droughts, and heat waves. We analyze changes in summer temperatures, the frequency, severity, and duration of heat waves, and heat-related mortality in India between 1960 and 2009 using data from the India Meteorological Department. Mean temperatures across India have risen by more than 0.5 degrees C over this period, with statistically significant increases in heat waves. Using a novel probabilistic model, we further show that the increase in summer mean temperatures in India over this period corresponds to a 146% increase in the probability of heat-related mortality events of more than 100 people. In turn, our results suggest that future climate warming will lead to substantial increases in heat-related mortality, particularly in developing low latitude countries, such as India, where heat waves will become more frequent and populations are especially vulnerable to these extreme temperatures. Our findings indicate that even moderate increases in mean temperatures may cause great increases in heat-related mortality and support the efforts of governments and international organizations to build up the resilience of these vulnerable regions to more severe heat waves. PMID- 28630922 TI - Flexible ferroelectric element based on van der Waals heteroepitaxy. AB - We present a promising technology for nonvolatile flexible electronic devices: A direct fabrication of epitaxial lead zirconium titanate (PZT) on flexible mica substrate via van der Waals epitaxy. These single-crystalline flexible ferroelectric PZT films not only retain their performance, reliability, and thermal stability comparable to those on rigid counterparts in tests of nonvolatile memory elements but also exhibit remarkable mechanical properties with robust operation in bent states (bending radii down to 2.5 mm) and cycling tests (1000 times). This study marks the technological advancement toward realizing much-awaited flexible yet single-crystalline nonvolatile electronic devices for the design and development of flexible, lightweight, and next generation smart devices with potential applications in electronics, robotics, automotive, health care, industrial, and military systems. PMID- 28630923 TI - Ribosome rearrangements at the onset of translational bypassing. AB - Bypassing is a recoding event that leads to the translation of two distal open reading frames into a single polypeptide chain. We present the structure of a translating ribosome stalled at the bypassing take-off site of gene 60 of bacteriophage T4. The nascent peptide in the exit tunnel anchors the P-site peptidyl-tRNAGly to the ribosome and locks an inactive conformation of the peptidyl transferase center (PTC). The mRNA forms a short dynamic hairpin in the decoding site. The ribosomal subunits adopt a rolling conformation in which the rotation of the small subunit around its long axis causes the opening of the A site region. Together, PTC conformation and mRNA structure safeguard against premature termination and read-through of the stop codon and reconfigure the ribosome to a state poised for take-off and sliding along the noncoding mRNA gap. PMID- 28630924 TI - Capturing the radical ion-pair intermediate in DNA guanine oxidation. AB - Although the radical ion pair has been frequently invoked as a key intermediate in DNA oxidative damage reactions and photoinduced electron transfer processes, the unambiguous detection and characterization of this species remain formidable and unresolved due to its extremely unstable nature and low concentration. We use the strategy that, at cryogenic temperatures, the transient species could be sufficiently stabilized to be detectable spectroscopically. By coupling the two techniques (the cryogenic stabilization and the time-resolved laser flash photolysis spectroscopy) together, we are able to capture the ion-pair transient G+*?Cl- in the chlorine radical-initiated DNA guanine (G) oxidation reaction, and provide direct evidence to ascertain the intricate type of addition/charge separation mechanism underlying guanine oxidation. The unique spectral signature of the radical ion-pair G+*?Cl- is identified, revealing a markedly intense absorption feature peaking at 570 nm that is distinctive from G+* alone. Moreover, the ion-pair spectrum is found to be highly sensitive to the protonation equilibria within guanine-cytosine base pair (G:C), which splits into two resolved bands at 480 and 610 nm as the acidic proton transfers along the central hydrogen bond from G+* to C. We thus use this exquisite sensitivity to track the intrabase-pair proton transfer dynamics in the double-stranded DNA oligonucleotides, which is of critical importance for the description of the proton-coupled charge transfer mechanisms in DNA. PMID- 28630925 TI - Buckyball sandwiches. AB - Two-dimensional (2D) materials have considerably expanded the field of materials science in the past decade. Even more recently, various 2D materials have been assembled into vertical van der Waals heterostacks, and it has been proposed to combine them with other low-dimensional structures to create new materials with hybridized properties. We demonstrate the first direct images of a suspended 0D/2D heterostructure that incorporates C60 molecules between two graphene layers in a buckyball sandwich structure. We find clean and ordered C60 islands with thicknesses down to one molecule, shielded by the graphene layers from the microscope vacuum and partially protected from radiation damage during scanning transmission electron microscopy imaging. The sandwich structure serves as a 2D nanoscale reaction chamber, allowing the analysis of the structure of the molecules and their dynamics at atomic resolution. PMID- 28630927 TI - Welding of 3D-printed carbon nanotube-polymer composites by locally induced microwave heating. AB - Additive manufacturing through material extrusion, often termed three-dimensional (3D) printing, is a burgeoning method for manufacturing thermoplastic components. However, a key obstacle facing 3D-printed plastic parts in engineering applications is the weak weld between successive filament traces, which often leads to delamination and mechanical failure. This is the chief obstacle to the use of thermoplastic additive manufacturing. We report a novel concept for welding 3D-printed thermoplastic interfaces using intense localized heating of carbon nanotubes (CNTs) by microwave irradiation. The microwave heating of the CNT-polymer composites is a function of CNT percolation, as shown through in situ infrared imaging and simulation. We apply CNT-loaded coatings to a 3D printer filament; after printing, microwave irradiation is shown to improve the weld fracture strength by 275%. These remarkable results open up entirely new design spaces for additive manufacturing and also yield new insight into the coupling between dielectric properties and radio frequency field response for nanomaterial networks. PMID- 28630926 TI - Vasculogenic hydrogel enhances islet survival, engraftment, and function in leading extrahepatic sites. AB - Islet transplantation is a promising alternative therapy for insulin-dependent patients, with the potential to eliminate life-threatening hypoglycemic episodes and secondary complications of long-term diabetes. However, widespread application of this therapy has been limited by inadequate graft function and longevity, in part due to the loss of up to 60% of the graft in the hostile intrahepatic transplant site. We report a proteolytically degradable synthetic hydrogel, functionalized with vasculogenic factors for localized delivery, engineered to deliver islet grafts to extrahepatic transplant sites via in situ gelation under physiological conditions. Hydrogels induced differences in vascularization and innate immune responses among subcutaneous, small bowel mesentery, and epididymal fat pad transplant sites with improved vascularization and reduced inflammation at the epididymal fat pad site. This biomaterial-based strategy improved the survival, engraftment, and function of a single pancreatic donor islet mass graft compared to the current clinical intraportal delivery technique. This biomaterial strategy has the potential to improve clinical outcomes in islet autotransplantation after pancreatectomy and reduce the burden on donor organ availability by maximizing graft survival in clinical islet transplantation for type 1 diabetes patients. PMID- 28630928 TI - Novel phase diagram behavior and materials design in heterostructural semiconductor alloys. AB - Structure and composition control the behavior of materials. Isostructural alloying is historically an extremely successful approach for tuning materials properties, but it is often limited by binodal and spinodal decomposition, which correspond to the thermodynamic solubility limit and the stability against composition fluctuations, respectively. We show that heterostructural alloys can exhibit a markedly increased range of metastable alloy compositions between the binodal and spinodal lines, thereby opening up a vast phase space for novel homogeneous single-phase alloys. We distinguish two types of heterostructural alloys, that is, those between commensurate and incommensurate phases. Because of the structural transition around the critical composition, the properties change in a highly nonlinear or even discontinuous fashion, providing a mechanism for materials design that does not exist in conventional isostructural alloys. The novel phase diagram behavior follows from standard alloy models using mixing enthalpies from first-principles calculations. Thin-film deposition demonstrates the viability of the synthesis of these metastable single-phase domains and validates the computationally predicted phase separation mechanism above the upper temperature bound of the nonequilibrium single-phase region. PMID- 28630930 TI - Real-time quantitative analysis of metabolic flux in live cells using a hyperpolarized micromagnetic resonance spectrometer. AB - Metabolic reprogramming is widely considered a hallmark of cancer, and understanding metabolic dynamics described by the conversion rates or "fluxes" of metabolites can shed light onto biological processes of tumorigenesis and response to therapy. For real-time analysis of metabolic flux in intact cells or organisms, magnetic resonance (MR) spectroscopy and imaging methods have been developed in conjunction with hyperpolarization of nuclear spins. These approaches enable noninvasive monitoring of tumor progression and treatment efficacy and are being tested in multiple clinical trials. However, because of their limited sensitivity, these methods require a larger number of cells, on the order of 107, which is impractical for analyzing scant target cells or mass limited samples. We present a new technology platform, a hyperpolarized micromagnetic resonance spectrometer (HMRS), that achieves real-time, 103-fold more sensitive metabolic analysis on live cells. This platform enables quantification of the metabolic flux in a wide range of cell types, including leukemia stem cells, without significant changes in viability, which allows downstream molecular analyses in tandem. It also enables rapid assessment of metabolic changes by a given drug, which may direct therapeutic choices in patients. We further advanced this platform for high-throughput analysis of hyperpolarized molecules by integrating a three-dimensionally printed microfluidic system. The HMRS platform holds promise as a sensitive method for studying metabolic dynamics in mass-limited samples, including primary cancer cells, providing novel therapeutic targets and an enhanced understanding of cellular metabolism. PMID- 28630929 TI - Splitting of the O-O bond at the heme-copper catalytic site of respiratory oxidases. AB - Heme-copper oxidases catalyze the four-electron reduction of O2 to H2O at a catalytic site that is composed of a heme group, a copper ion (CuB), and a tyrosine residue. Results from earlier experimental studies have shown that the O O bond is cleaved simultaneously with electron transfer from a low-spin heme (heme a/b), forming a ferryl state (PR ; Fe4+=O2-, CuB2+-OH-). We show that with the Thermus thermophilus ba3 oxidase, at low temperature (10 degrees C, pH 7), electron transfer from the low-spin heme b to the catalytic site is faster by a factor of ~10 (tau ? 11 MUs) than the formation of the PR ferryl (tau ?110 MUs), which indicates that O2 is reduced before the splitting of the O-O bond. Application of density functional theory indicates that the electron acceptor at the catalytic site is a high-energy peroxy state [Fe3+-O--O-(H+)], which is formed before the PR ferryl. The rates of heme b oxidation and PR ferryl formation were more similar at pH 10, indicating that the formation of the high energy peroxy state involves proton transfer within the catalytic site, consistent with theory. The combined experimental and theoretical data suggest a general mechanism for O2 reduction by heme-copper oxidases. PMID- 28630931 TI - Morphology controls the thermoelectric power factor of a doped semiconducting polymer. AB - The electrical performance of doped semiconducting polymers is strongly governed by processing methods and underlying thin-film microstructure. We report on the influence of different doping methods (solution versus vapor) on the thermoelectric power factor (PF) of PBTTT molecularly p-doped with F n TCNQ (n = 2 or 4). The vapor-doped films have more than two orders of magnitude higher electronic conductivity (sigma) relative to solution-doped films. On the basis of resonant soft x-ray scattering, vapor-doped samples are shown to have a large orientational correlation length (OCL) (that is, length scale of aligned backbones) that correlates to a high apparent charge carrier mobility (MU). The Seebeck coefficient (alpha) is largely independent of OCL. This reveals that, unlike sigma, leveraging strategies to improve MU have a smaller impact on alpha. Our best-performing sample with the largest OCL, vapor-doped PBTTT:F4TCNQ thin film, has a sigma of 670 S/cm and an alpha of 42 MUV/K, which translates to a large PF of 120 MUW m-1 K-2. In addition, despite the unfavorable offset for charge transfer, doping by F2TCNQ also leads to a large PF of 70 MUW m-1 K-2, which reveals the potential utility of weak molecular dopants. Overall, our work introduces important general processing guidelines for the continued development of doped semiconducting polymers for thermoelectrics. PMID- 28630932 TI - Differential intron retention in Jumonji chromatin modifier genes is implicated in reptile temperature-dependent sex determination. AB - In many vertebrates, sex of offspring is determined by external environmental cues rather than by sex chromosomes. In reptiles, for instance, temperature dependent sex determination (TSD) is common. Despite decades of work, the mechanism by which temperature is converted into a sex-determining signal remains mysterious. This is partly because it is difficult to distinguish the primary molecular events of TSD from the confounding downstream signatures of sexual differentiation. We use the Australian central bearded dragon, in which chromosomal sex determination is overridden at high temperatures to produce sex reversed female offspring, as a unique model to identify TSD-specific features of the transcriptome. We show that an intron is retained in mature transcripts from each of two Jumonji family genes, JARID2 and JMJD3, in female dragons that have been sex-reversed by temperature but not in normal chromosomal females or males. JARID2 is a component of the master chromatin modifier Polycomb Repressive Complex 2, and the mammalian sex-determining factor SRY is directly regulated by an independent but closely related Jumonji family member. We propose that the perturbation of JARID2/JMJD3 function by intron retention alters the epigenetic landscape to override chromosomal sex-determining cues, triggering sex reversal at extreme temperatures. Sex reversal may then facilitate a transition from genetic sex determination to TSD, with JARID2/JMJD3 intron retention preserved as the decisive regulatory signal. Significantly, we also observe sex-associated differential retention of the equivalent introns in JARID2/JMJD3 transcripts expressed in embryonic gonads from TSD alligators and turtles, indicative of a reptile-wide mechanism controlling TSD. PMID- 28630933 TI - Statistical thinking for 21st century scientists. AB - Statistical science provides a wide range of concepts and methods for studying situations subject to unexplained variability. Such considerations enter fields ranging from particle physics and astrophysics to genetics, sociology and economics, and beyond; to associated areas of application such as engineering, agriculture, and medicine, in particular in clinical trials. Successful application hinges on absorption of statistical thinking into the subject matter and, hence, depends strongly on the field in question and on the individual investigators. It is the job of theoretical statisticians both to be alive to the challenges of specific applications and, at the same time, to develop methods and concepts that, with good fortune, will be broadly applicable. PMID- 28630934 TI - Ligand binding to a G protein-coupled receptor captured in a mass spectrometer. AB - G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors belong to the largest family of membrane-embedded cell surface proteins and are involved in a diverse array of physiological processes. Despite progress in the mass spectrometry of membrane protein complexes, G protein-coupled receptors have remained intractable because of their low yield and instability after extraction from cell membranes. We established conditions in the mass spectrometer that preserve noncovalent ligand binding to the human purinergic receptor P2Y1. Results established differing affinities for nucleotides and the drug MRS2500 and link antagonist binding with the absence of receptor phosphorylation. Overall, therefore, our results are consistent with drug binding, preventing the conformational changes that facilitate downstream signaling. More generally, we highlight opportunities for mass spectrometry to probe effects of ligand binding on G protein-coupled receptors. PMID- 28630935 TI - Response to Hohenlohe et al. AB - A response to Hohenlohe et al. PMID- 28630936 TI - Pushing the boundaries: Science Advances. PMID- 28630937 TI - High Precision Neural Decoding of Complex Movement Trajectories using Recursive Bayesian Estimation with Dynamic Movement Primitives. AB - Brain-machine interfaces (BMIs) are a rapidly progressing technology with the potential to restore function to victims of severe paralysis via neural control of robotic systems. Great strides have been made in directly mapping a user's cortical activity to control of the individual degrees of freedom of robotic end effectors. While BMIs have yet to achieve the level of reliability desired for widespread clinical use, environmental sensors (e.g. RGB-D cameras for object detection) and prior knowledge of common movement trajectories hold great potential for improving system performance. Here we present a novel sensor fusion paradigm for BMIs that capitalizes on information able to be extracted from the environment to greatly improve the performance of control. This was accomplished by using dynamic movement primitives to model the 3D endpoint trajectories of manipulating various objects. We then used a switching unscented Kalman filter to continuously arbitrate between the 3D endpoint kinematics predicted by the dynamic movement primitives and control derived from neural signals. We experimentally validated our system by decoding 3D endpoint trajectories executed by a non-human primate manipulating four different objects at various locations. Performance using our system showed a dramatic improvement over using neural signals alone, with median distance between actual and decoded trajectories decreasing from 31.1 cm to 9.9 cm, and mean correlation increasing from 0.80 to 0.98. Our results indicate that our sensor fusion framework can dramatically increase the fidelity of neural prosthetic trajectory decoding. PMID- 28630938 TI - Sleep dysfunction and its association to chronic rhinosinusitis: Updated review. AB - BACKGROUND: Poor sleep has significant effects on health contributing to increased morbidity and mortality. The direct and indirect costs of sleep dysfunction total well in to the billions of dollars annually in the US. Chronic rhinosinusitis (CRS) affects up to 16% of the US population and has been linked to poor sleep quality with up to three quarters of patients with CRS reporting poor sleep quality. There is a growing body of literature evaluating the relationship between sleep and CRS. In this review, we organize and present the current knowledge on the associations between sleep and CRS as well as identify areas for further investigation. DATA SOURCES: A structured literature search from 1946 to 2016 was conducted in the English language using OVID MEDLINE database, PubMed and EMBASE. REVIEW METHODS: Abstracts were reviewed for relevance and appropriate studies were included in the narrative review. RESULTS: Studies were analyzed and discussed as they pertained to the following categories of CRS and sleep: (1) subjective measures of sleep dysfunction, (2) objective measures of sleep dysfunction, and (3) outcomes on sleep quality following treatment of CRS. Articles on the pathophysiology of sleep dysfunction in CRS were separately reviewed. CONCLUSIONS: An evolving body of research demonstrates that quality of sleep is compromised in the majority of patients with CRS. Following treatment of CRS, there is significant improvement in subjective sleep quality, but additional research investigating objective measures following treatment is still needed. Additionally, further investigation is required to better elucidate the underlying pathophysiology of the relationship between sleep dysfunction and CRS. PMID- 28630939 TI - Retrospective Surveillance of Wastewater To Examine Seasonal Dynamics of Enterovirus Infections. AB - Enteroviruses are RNA viruses that are responsible for both mild gastroenteritis and mild respiratory illnesses as well as debilitating diseases such as meningitis and myocarditis. The disease burden of enteroviruses in the United States is difficult to assess because most infections are not recorded. Since infected individuals shed enterovirus in feces and urine, surveillance of municipal wastewater can reveal the diversity of enteroviruses circulating in human populations. Therefore, monthly municipal wastewater samples were collected for 1 year and enteroviruses were quantified by reverse transcriptase quantitative PCR and identified by next-generation, high-throughput sequencing. Enterovirus concentrations ranged from 3.8 to 5.9 log10 equivalent copies/liter in monthly samples. From the mean monthly concentration, it can be estimated that 2.8% of the contributing population was shedding enterovirus daily. Sequence analysis showed that Enterovirus A and Enterovirus B alternate in predominance, with Enterovirus B comprising over 80% of the reads during the summer and fall months and Enterovirus A accounting for >45% of the reads in spring. Enterovirus C was observed throughout the year, while Enterovirus D was present intermittently. Principal-component analysis further supported the date corresponding to enterovirus seasonal trends as CVA6 (Enterovirus A) was predominant in the spring months; CVB3, CVB5, and E9 (Enterovirus B) were predominant in the summer and fall months; and CVA1, CVA19, and CVA22 (Enterovirus C) and EV97 (Enterovirus B) were predominant in winter. Rhinoviruses were also observed. Wastewater monitoring of human enterovirus provided improved insight into the seasonal patterns of enteroviruses circulating in communities and can contribute to understanding of enterovirus disease burden. IMPORTANCE Enterovirus infections are often not tracked or reported to health officials. This makes it hard to know how many people in a community are infected with these viruses at any given time. Here, we explored enterovirus in municipal wastewater to look at this issue. We show that enteroviruses are present year-round in municipal wastewater at levels of up to 800,000 genomic copies per liter. We estimate that, on average, 2.8% of the people contributing to the wastewater shed enterovirus daily. Sequence analysis of the viral capsid protein 4 gene shows that 8 enterovirus types are key drivers of seasonal trends. Populations of Enterovirus A members peak in the spring, while Enterovirus B types are most prevalent during the summer and fall months and Enterovirus C members influence the winter months. Enterovirus D was observed sporadically and did not influence seasonal trends. PMID- 28630940 TI - Fluconazole-Induced Ploidy Change in Cryptococcus neoformans Results from the Uncoupling of Cell Growth and Nuclear Division. AB - Cryptococcus neoformans is a pathogenic yeast that causes lethal cryptococcal meningitis in immunocompromised patients. One of the challenges in treating cryptococcosis is the development of resistance to azole antifungals. Previous studies linked azole resistance to elevated numbers of copies of critical resistance genes in aneuploid cells. However, how aneuploidy is formed in the presence of azole drugs remains unclear. This study showed that treatment with inhibitory concentrations of an azole drug, fluconazole (FLC), resulted in a significant population of cells with increased DNA content, through the following defects: inhibition of budding, premature mitosis, and inhibition of cytokinesis followed by replication in the mother cell. Inhibition of and/or a delay in cytokinesis led to the formation of cells with two or more daughter cells attached (multimeric cells). To investigate which part of cytokinesis fails in the presence of FLC, the dynamics of the actomyosin ring (AMR), septins, and Cts1, a protein involved in cell separation, were analyzed with time-lapse microscopy. Following the constriction of the AMR, septins assembled and the septum was formed between the mother and daughter cells. However, final degradation of the septum was affected. Enlarged cells with aberrant morphology, including multimeric cells, exhibited an increased potential to proliferate in the presence of FLC. These findings suggest that pleiotropic effects of FLC on growth and mitotic division lead to an increase in DNA content, resulting in cells less sensitive to the drug. Cells with increased DNA content continue to proliferate and therefore increase the chance of forming resistant populations. IMPORTANCE Azoles are antifungals that are widely utilized due to relatively low toxicity and cost of treatment. One of their drawbacks, however, is that azoles are primarily cytostatic, leaving fungal cells capable of developing drug resistance. The human pathogen Cryptococcus neoformans acquires resistance to the azole drug fluconazole (FLC) through the development of aneuploidy, leading to elevated expression of key resistance genes, a mechanism that is also common for Candida albicans (K. J. Kwon-Chung and Y. C. Chang, PLoS Pathog 8:e1003022, 2012, https://doi.org/10.1371/journal.ppat.1003022; J. Morschhauser, J Microbiol 54:192 201, 2016, https://doi.org/10.1007/s12275-016-5628-4). However, the exact ways in which FLC contributes to increased resistance in either of these important fungal pathogens remain unclear. Here we found that FLC treatment leads to an increase in DNA content in C. neoformans through multiple mechanisms, potentially increasing the size of a pool of cells from which aneuploids with increased resistance are selected. This study demonstrated the importance of FLC's inhibitory effects on growth and cytokinesis in the generation of cell populations with decreased sensitivity to the drug. PMID- 28630941 TI - Furthering the Continental Drift Speciation Hypothesis in the Pathogenic Cryptococcus Species Complexes. PMID- 28630942 TI - Antimalarial drugs and the prevalence of mental and neurological manifestations: A systematic review and meta-analysis. AB - Background: Antimalarial drugs affect the central nervous system, but it is difficult to differentiate the effect of these drugs from that of the malaria illness. We conducted a systematic review to determine the association between anti-malarial drugs and mental and neurological impairment in humans. Methods: We systematically searched online databases, including Medline/PubMed, PsychoInfo, and Embase, for articles published up to 14th July 2016. Pooled prevalence, heterogeneity and factors associated with prevalence of mental and neurological manifestations were determined using meta-analytic techniques. Results: Of the 2,349 records identified in the initial search, 51 human studies met the eligibility criteria. The median pooled prevalence range of mental and neurological manifestations associated with antimalarial drugs ranged from 0.7% (dapsone) to 48.3% (minocycline) across all studies, while it ranged from 0.6% (pyrimethamine) to 42.7% (amodiaquine) during treatment of acute malaria, and 0.7% (primaquine/dapsone) to 55.0% (sulfadoxine) during prophylaxis. Pooled prevalence of mental and neurological manifestations across all studies was associated with an increased number of antimalarial drugs (prevalence ratio= 5.51 (95%CI, 1.05-29.04); P=0.045) in a meta-regression analysis. Headaches (15%) and dizziness (14%) were the most common mental and neurological manifestations across all studies. Of individual antimalarial drugs still on the market, mental and neurological manifestations were most common with the use of sulphadoxine (55%) for prophylaxis studies and amodiaquine (42.7%) for acute malaria studies. Mefloquine affected more domains of mental and neurological manifestations than any other antimalarial drug. Conclusions: Antimalarial drugs, particularly those used for prophylaxis, may be associated with mental and neurological manifestations, and the number of antimalarial drugs taken determines the association. Mental and neurological manifestations should be assessed following the use of antimalarial drugs. PMID- 28630944 TI - ClinVar data parsing. AB - This software repository provides a pipeline for converting raw ClinVar data files into analysis-friendly tab-delimited tables, and also provides these tables for the most recent ClinVar release. Separate tables are generated for genome builds GRCh37 and GRCh38 as well as for mono-allelic variants and complex multi allelic variants. Additionally, the tables are augmented with allele frequencies from the ExAC and gnomAD datasets as these are often consulted when analyzing ClinVar variants. Overall, this work provides ClinVar data in a format that is easier to work with and can be directly loaded into a variety of popular analysis tools such as R, python pandas, and SQL databases. PMID- 28630943 TI - Parasites lacking the micronemal protein MIC2 are deficient in surface attachment and host cell egress, but remain virulent in vivo. AB - Background: Micronemal proteins of the thrombospondin-related anonymous protein (TRAP) family are believed to play essential roles during gliding motility and host cell invasion by apicomplexan parasites, and currently represent major vaccine candidates against Plasmodium falciparum, the causative agent of malaria. However, recent evidence suggests that they play multiple and different roles than previously assumed. Here, we analyse a null mutant for MIC2, the TRAP homolog in Toxoplasma gondii. Methods: We performed a careful analysis of parasite motility in a 3D-environment, attachment under shear stress conditions, host cell invasion and in vivo virulence. Results: We verified the role of MIC2 in efficient surface attachment, but were unable to identify any direct function of MIC2 in sustaining gliding motility or host cell invasion once initiated. Furthermore, we find that deletion of mic2 causes a slightly delayed infection in vivo, leading only to mild attenuation of virulence; like with wildtype parasites, inoculation with even low numbers of mic2 KO parasites causes lethal disease in mice. However, deletion of mic2 causes delayed host cell egress in vitro, possibly via disrupted signal transduction pathways. Conclusions: We confirm a critical role of MIC2 in parasite attachment to the surface, leading to reduced parasite motility and host cell invasion. However, MIC2 appears to not be critical for gliding motility or host cell invasion, since parasite speed during these processes is unaffected. Furthermore, deletion of MIC2 leads only to slight attenuation of the parasite. PMID- 28630945 TI - The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data. AB - Detection of deletions and duplications of whole exons (exon CNVs) is a key requirement of genetic testing. Accurate detection of this variant type has proved very challenging in targeted next-generation sequencing (NGS) data, particularly if only a single exon is involved. Many different NGS exon CNV calling methods have been developed over the last five years. Such methods are usually evaluated using simulated and/or in-house data due to a lack of publicly available datasets with orthogonally generated results. This hinders tool comparisons, transparency and reproducibility. To provide a community resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM or PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs, the most difficult type of exon CNV to detect. The FASTQ files for the ICR96 exon CNV validation series can be accessed through the European-Genome phenome Archive (EGA) under the accession number EGAS00001002428. PMID- 28630947 TI - Evolution of Geographic Atrophy in Participants Treated with Ranibizumab for Neovascular Age-related Macular Degeneration. AB - PURPOSE: To evaluate the risk factors, incidence, and rate of progression of geographic atrophy (GA) in eyes with neovascular age-related macular degeneration (nAMD) treated with ranibizumab. DESIGN: Post-hoc analysis of a prospective clinical study. PARTICIPANTS: 69 participants with nAMD in at least one eye. METHODS: Participants were prospectively treated in the study eye with 0.5 mg intravitreal ranibizumab. Study eyes received 4 monthly injections followed by pro re nata injections until a fluid-free macula was achieved on optical coherence tomography. Risk factors assessed included baseline demographics, treatment, and ocular characteristics on imaging. Eyes were evaluated on fundus autofluorescence (FAF) for GA. The rate of GA area growth in study and fellow eyes was analyzed by linear regression of square-root transformed areas. MAIN OUTCOME MEASURES: Development of new-onset GA and rate of GA area growth measured on ocular imaging, including FAF images of the study eyes. RESULTS: Sixty-nine participants (mean age 78.8+/-7.8 years) with an average of 40.0+/-13.6 months of follow-up were analyzed. Twenty-two of 69 study eyes (32%) were treatment naive. During their first year of the study, participants received an average of 9.2+/ 3.3 injections in the study eye. Of 63 study eyes with quality baseline images, 22 (35%) had pre-existing GA. Of the remaining 41 eyes, 7 (17%) developed new onset GA during study follow-up. Those who developed new GA were older (all >=79 years old) and had received fewer study injections on average (6.9 vs. 10.4 injections at 1 year) compared to those who did not develop new GA. Of the 12 treatment naive study eyes without GA at baseline, 1 (8.3%) developed new GA during the study. In 21 study eyes with quantifiable GA area, eyes with GA present at baseline (16/21) enlarged by 0.34+/-0.26 mm/year, compared to 0.19+/ 0.12 mm/year in eyes developing new-onset GA (5/21). CONCLUSIONS: While 17% of study eyes without GA present at baseline receiving ranibizumab developed new GA, the role of ranibizumab in the development of GA is unclear. Further prospective longitudinal studies are required to determine the eyes most at risk of developing GA in the setting of anti-VEGF treatment. PMID- 28630948 TI - Near Theoretical Gigabit Link Efficiency for Distributed Data Acquisition Systems. AB - Link efficiency, data integrity, and continuity for high-throughput and real-time systems is crucial. Most of these applications require specialized hardware and operating systems as well as extensive tuning in order to achieve high efficiency. Here, we present an implementation of gigabit Ethernet data streaming which can achieve 99.26% link efficiency while maintaining no packet losses. The design and implementation are built on OpenPET, an opensource data acquisition platform for nuclear medical imaging, where (a) a crate hosting multiple OpenPET detector boards uses a User Datagram Protocol over Internet Protocol (UDP/IP) Ethernet soft-core, that is capable of understanding PAUSE frames, to stream data out to a computer workstation; (b) the receiving computer uses Netmap to allow the processing software (i.e., user space), which is written in Python, to directly receive and manage the network card's ring buffers, bypassing the operating system kernel's networking stack; and PMID- 28630946 TI - Differentiation and Inflammation: 'Best Enemies' in Gastrointestinal Carcinogenesis. AB - While recent studies demonstrate that cancer can arise from mutant stem cells, this hypothesis does not explain why tissues without defined stem cell populations are susceptible to inflammation-driven tumorigenesis. We propose that chronic inflammatory diseases, such as colitis and pancreatitis, predispose to gastrointestinal (GI) adenocarcinoma by reprogramming differentiated cells. Focusing on colon and pancreas, we discuss recently discovered connections between inflammation and loss of cell differentiation, and propose that dysregulation of cell fate may be a novel rate-limiting step of tumorigenesis. We review studies identifying differentiation mechanisms that limit tumor initiation and that, upon reactivation, can prevent or revert the cancer cell transformed phenotype. Together, these findings suggest that differentiation-targeted treatments hold promise as a therapeutic strategy in GI cancer. PMID- 28630951 TI - Phenotyping Hypotensive Patients in Critical Care Using Hospital Discharge Summaries. AB - Among critically-ill patients, hypotension represents a failure in compensatory mechanisms and may lead to organ hypoperfusion and failure. In this work, we adopt a data-driven approach for phenotype discovery and visualization of patient similarity and cohort structure in the intensive care unit (ICU). We used Hierarchical Dirichlet Process (HDP) as a nonparametric topic modeling technique to automatically learn a d-dimensional feature representation of patients that captures the latent "topic" structure of diseases, symptoms, medications, and findings documented in hospital discharge summaries. We then used the t Distributed Stochastic Neighbor Embedding (t-SNE) algorithm to convert the d dimensional latent structure learned from HDP into a matrix of pairwise similarities for visualizing patient similarity and cohort structure. Using discharge summaries of a large patient cohort from the MIMIC II database, we evaluated the clinical utility of the discovered topic structure in phenotyping critically-ill patients who experienced hypotensive episodes. Our results indicate that the approach is able to reveal clinically interpretable clustering structure within our cohort and may potentially provide valuable insights to better understand the association between disease phenotypes and outcomes. PMID- 28630949 TI - Multivariate classification of pain-evoked brain activity in temporomandibular disorder. PMID- 28630950 TI - White Matter Hyperintensities in Older Adults and Motoric Cognitive Risk Syndrome. AB - INTRODUCTION: Motoric cognitive risk (MCR) syndrome is a recently described pre dementia syndrome characterized by slow gait and cognitive complaints that has been implicated as a predictor of cognitive decline and dementia in older adults. Previous work suggests that cerebrovascular disease is associated with MCR. White matter hyperintensities (WMH) are postulated to be a product of cerebrovascular disease, and have been associated with impaired mobility and impaired cognition. This study aimed to determine if MCR is associated with regional WMH. METHODS: Two cross-cultural cohorts of non-demented older adults were examined: 174 from a French memory clinic (62.1% male, mean age 70.7 +/- 4.3 years) and 184 from an Indian community-dwelling cohort (55.4% male, mean age 66.2 +/- 5.2 years). Participants were evaluated for slow gait, cognitive complaints, and regional WMH via MRI (fluid attenuated inversion recovery) FLAIR sequence. RESULTS: Overall, 20.7% of participants met criteria for MCR, and 72.9% of participants had WMH on FLAIR. WMH in the frontal, parieto-occipital, temporal, basal ganglia, cerebellum, or brainstem were not associated with MCR in either of the two cohorts. CONCLUSION: WMH was not significantly associated with MCR in this studied sample of participants, suggesting that other cerebrovascular pathophysiological mechanisms, or combination of mechanisms, might underlie MCR. PMID- 28630954 TI - Editorial: Does digital technology lead to better dentistry? PMID- 28630952 TI - Estimating Patient's Health State Using Latent Structure Inferred from Clinical Time Series and Text. AB - Modern intensive care units (ICUs) collect large volumes of data in monitoring critically ill patients. Clinicians in the ICUs face the challenge of interpreting large volumes of high-dimensional data to diagnose and treat patients. In this work, we explore the use of Hierarchical Dirichlet Processes (HDP) as a Bayesian nonparametric framework to infer patients' states of health by combining multiple sources of data. In particular, we employ HDP to combine clinical time series and text from the nursing progress notes in a probabilistic topic modeling framework for patient risk stratification. Given a patient cohort, we use HDP to infer latent "topics" shared across multimodal patient data from the entire cohort. Each topic is modeled as a multinomial distribution over a vocabulary of codewords, defined over heterogeneous data sources. We evaluate the clinical utility of the learned topic structure using the first 24-hour ICU data from over 17,000 adult patients in the MIMIC-II database to estimate patients' risks of in-hospital mortality. Our results demonstrate that our approach provides a viable framework for combining different data modalities to model patient's states of health, and can potentially be used to generate alerts to identify patients at high risk of hospital mortality. PMID- 28630955 TI - Chairside systems: a current review. AB - Since Cerec (Chairside Economical Restoration of Esthetic Ceramics) was introduced as the first dental chairside computer-aided design/computer-aided manufacturing (CAD/CAM) system in the mid-1980s, this technology has enjoyed growing popularity, particularly in the recent past. There has been a considerable increase in the number of available chairside systems in only the last few years. One of the main reasons for this is that intraoral scanners have become increasingly better, smaller, and faster, while the design software has become more and more user-friendly. Many work steps are now automated, and a very large range of materials is now available for dental chairside applications. These advances have driven the rapid increase in the range of indications for chairside dentistry in the areas of prosthodontics, dental implantology, and orthodontics, and have paved the way for more novel treatment and treatment planning strategies. Another reason is that intraoral scanner-based digital impression techniques are already superior to conventional impression techniques in certain respects. Moreover, the quality of fit of digitally designed dental restorations is constantly improving because of advances in milling machine technology. Due to the sheer number of new possibilities, it is only a matter of time before chairside systems become a standard component of dental practice. This article reviews the actual advantages and limitations of the chairside workflow, and provides a summary of all the available chairside systems available today. PMID- 28630956 TI - Accuracy of full-arch scans using intraoral and extraoral scanners: an in vitro study using a new method of evaluation. AB - The aim of this study was to compare the accuracy of six intraoral scanners as regards clinically relevant distances using a new method of evaluation. An additional objective was to compare intraoral scanners with the indirect digitization of model scanners. A resin master model was created by 3D printing and drilled in five places to reflect the following distances: intermolar width (IMW), intercanine width (ICW), and arch length (AL). To determine a gold standard, the distances were measured with a coordinate measuring instrument (Zeiss O-Inspect 422). The master model was scanned 37 times with the following intraoral scanners: Apollo DI (Sirona), CS 3500 (Carestream Dental), iTero (Cadent), PlanScan (Planmeca), Trios (3Shape), and True Definition (3M Espe), and indirectly digitized with the OrthoX Scan (Dentaurum). The digital models were then measured, and deviations from the gold standard calculated. Significant differences were found between the devices. Among the intraoral scanners, Trios and iTero showed the most accurate results, although CS 3500, True Definition, and Apollo DI achieved comparable results. PlanScan demonstrated the highest deviations from the gold standard, and presented a high standard deviation (SD). Direct digitization revealed comparable (and, in fact, slightly higher) accuracy than indirect digitization. Both indirect digitization and most of the intraoral scanners were therefore demonstrated to be suitable for use in the orthodontic office, with the exception of PlanScan, which did not meet the demands of individual orthodontic treatment. PMID- 28630957 TI - Optical profilometry versus intraoral (handheld) scanning. AB - AIM: The aim of this study was to evaluate the difference in maximum height loss values obtained from datasets based on optical profilometry and intraoral scanning. Additionally, two analysis applications were tested with respect to their correspondence. MATERIALS AND METHODS: To obtain baseline data, the occlusal surface of a metal phantom tooth was scanned by optical profilometry [WLP] and an intraoral scanner [IOS]. Then, wear was simulated at two locations of the tooth, three times each ([wear1], [wear2], and [wear3]), and the surface was captured after each status of wear, applying [WLP] and [IOS]. The maximum vertical height loss was evaluated by comparing the 3D datasets of [WLP] and [IOS] at [wear1], [wear2], and [wear3] with the baseline data of [WLP] and [IOS], respectively. For this purpose, two commercially available applications, Geomagic Qualify and Oracheck, were used. RESULTS: Apart from one outlier of 16% difference between the data obtained from [WLP] and [IOS], the maximum difference was 12.6%, which was equal to a metrical value of 15 um. For the corresponding values, which were calculated with Geomagic Qualify and Oracheck at identical wear facets, maximum differences between +7% and -6.7% were obtained. CONCLUSIONS: According to this in vitro study, the wear measurement on the basis of [IOS] seems to be a cost-effective, quick, and easily applicable tool for clinical screening purposes, with an acceptable reliability. With respect to the minor variations between each other, the Geomagic Qualify and Oracheck measurement applications are equivalent. PMID- 28630958 TI - A questionnaire on the use of digital denture impressions in a preclinical setting. AB - Since February 2010, intraoral scanning (Lava COS system, 3M ESPE, Seefeld, Germany) has been integrated into the preclinical curriculum at the Department of Prosthodontics of the Justus Liebig University. All students were given a lecture and were trained using a guided scan exercise. After preparing three teeth (mandibular first premolars and mandibular first molar in the 4th quadrant) for cast crowns, the students were asked to scan the maxillary and mandibular teeth. Their acceptance of the new module, "Scanning," was analyzed with the use of a questionnaire (n = 108). The evaluation showed that 63.9% of the students perceived the digital impression to be informative, and had an overall positive opinion of this new digital technology. Concerning the difficulty of the scanning process, approximately 60.2% considered it to be manageable, while 55.6% reported that the magnified view of their preparations improved their understanding of preparing chamfer finish lines. Altogether, the majority of students appreciated this intraoral scanning device as an enhancement of their education. They indicated that this method contributes to a better understanding of crown preparations. In conclusion, the implementation of intraoral scanning seems promising in preclinical education and will be continued in the curriculum. PMID- 28630959 TI - A completely CAD/CAM individual transmission device for electronic mandible movement registration. AB - The connection of a device for the registration of mandibular movements depends on the coupling of the teeth with a paraocclusal adapter. This is normally done by individualizing a prefabricated metal support, either directly on the patient or in the dental laboratory. The goal was to create an individual paraocclusal adapter by means of additive computer-assisted design/computer-assisted manufacturing (CAD/CAM) procedures, and to test it clinically. Starting from intraoral scans of the maxillary and mandibular teeth, an individual paraocclusal adapter was constructed by combining an adapter piece adapted to the tooth and jaw shape with a prefabricated standard part. This article describes step by step the design using the 3D CAD software, up until production by means of 3D printing. Initial clinical experience is also discussed. PMID- 28630960 TI - A new milling machine for computer-aided, in-office restorations. AB - Chairside computer-aided design/computer-aided manufacturing (CAD/CAM) technology requires an effective technical basis to obtain dental restorations with optimal marginal accuracy, esthetics, and longevity in as short a timeframe as possible. This article describes a compact, 5-axis milling machine based on an innovative milling technology (5XT - five-axis turn-milling technique), which is capable of achieving high-precision milling results within a very short processing time. Furthermore, the device's compact dimensioning and state-of-the-art mode of operation facilitate its use in the dental office. This model is also an option to be considered for use in smaller dental laboratories, especially as the open input format enables it to be quickly and simply integrated into digital processing systems already in use. The possibility of using ceramic and polymer materials with varying properties enables the manufacture of restorations covering all conceivable indications in the field of fixed dental prosthetics. PMID- 28630961 TI - A biocatalytic and thermoreversible hydrogel from a histidine-containing tripeptide. AB - We report the first histidine-containing self-assembling tripeptide devoid of capping groups that forms a thermoreversible hydrogel under physiological conditions and catalyses hydrolysis of an ester, providing a minimalist building block for functional soft materials. PMID- 28630962 TI - Room temperature sintering of polar ZnO nanosheets: I-evidence. AB - Polar ZnO nanosheets of a high specific surface area (~120 m2 g-1) were subjected to storage under different atmospheres at room temperature and analyzed for changes in their textural and crystal properties. During their storage under laboratory conditions (in closed transparent polypropylene vials kept under the light of the laboratory on worktop tables) the nanosheets lost up to 75% of their specific surface area in approximately two months, with most of the loss occurring during the first two weeks. The narrow mesoporosity (~5 nm pore size) became filled with ZnO during the process. No loss or gain in weight was detected. The loss of specific surface area took place under all of the atmospheres assayed, in the following order: moist air (with or without light) > moist CO2-free atmosphere (with or without light and/or oxygen) > dry CO2-free oxygen-containing atmosphere (with or without light) > dry inert atmosphere (with light) > dry inert atmosphere (in the dark). During storage the ZnO crystals grew mainly by the partial merging of their polar surfaces in a process triggered by the action of moisture, oxygen and, in the absence of these two agents, light. The mechanism of this intriguing phenomenon will be analyzed in detail in the second part of this work. PMID- 28630963 TI - A novel borophene featuring heptagonal holes: a common precursor of borospherenes. AB - We propose a novel stable borophene (referred to as H-borophene) by tiling seven membered rings side by side, which is a novel construction pattern never reported in boron sheets or other sheets. It is able to serve as the common precursor of borospherenes (e.g., B39-, B40, B41+, and B422+). Interestingly, a Dirac point appeared at about 0.33 eV below the Fermi level. We found that nanotubes formed by rolling up H-borophene had a great advantage over other boron nanotubes in the case of high curvature, which accounted for the reason why heptagons were preferred in borospherenes. Our study not only proposes a common precursor of borospherenes, but also expands the construction patterns of monolayer sheets. PMID- 28630964 TI - An insertion/self-fusion mechanism for cell membrane immobilization on porous silica beads to fabricate biomimic carriers. AB - Immobilization of membrane proteins on solid supports with high stability, favorable reusability and prevention of contamination is of great interest in nanobiology and medicine. Cell membrane coating technology enables the membrane proteins associated with their surrounding membranes to co-immobilize onto the solid matrix, largely enhancing the loading efficiency and conserving the bioactivity of the membrane proteins. Herein, we systematically illustrate the mechanism of cell membrane immobilization on porous silica beads, facilitating the fabricated biomimic carriers applied for chromatography. Rabbit red blood cell membranes were obtained via a low permeability swelling method. Batch immobilization studies were carried out to investigate the effects of the pore size of porous silica beads and incubation time on cell membrane immobilization. The absorption behavior of cell membranes could be well described by a pseudo second-order kinetic model and the Freundlich model (a multilayer adsorption process) at 298 K, demonstrating an insertion/self-fusion mechanism involved in cell membrane coating onto the surface of porous silica beads. The insertion/self fusion mechanism was further confirmed by confocal imaging and transmission electron microscopy. PMID- 28630965 TI - Correction: Lanthanide separation using size-selective crystallization of Ln MOFs. AB - Correction for 'Lanthanide separation using size-selective crystallization of Ln MOFs' by Heng Ya Gao et al., Chem. Commun., 2017, DOI: 10.1039/c7cc01898c. PMID- 28630966 TI - beta-IminoBODIPY oligomers: facilely accessible pi-conjugated luminescent BODIPY arrays. AB - Imine-linked BODIPY oligomers show fluorescence quantum yields of up to 0.93. The azine linker may mediate pi-conjugation that extends over six BODIPY units with redshifts up to 125 nm. BODIPYs are immobilized on silica gel through heterogeneous imine-bond formation, being fluorescent and robust. PMID- 28630967 TI - Multinuclear zinc bisamidinate catalyzed asymmetric alkylation of alpha ketoesters and its unique chemoselectivity. AB - The multinuclear Zn-bisamidinate catalyzed enantioselective addition of Et2Zn to alpha-ketoesters has been developed. The steric tuning of two amidinate units as well as multiple coordination on the Zn atoms play a key role in achieving high enantioselectivity (up to 98% ee) and unique chemoselectivity. The present catalyst exhibited the preferential alkylation of alpha-ketoesters even in the presence of aldehydes. PMID- 28630968 TI - Designing self-powered materials systems that perform pattern recognition. AB - Inspired by the advances in both materials and computer science, we describe efforts to design "materials that compute" where the material and the computer are the same entity. Using theory and simulation, we devise systems that integrate the behavior of self-oscillating gels and fundamental concepts from oscillator-based computing. We specifically focus on gels that undergo the Belousov-Zhabotinsky (BZ) reaction and thus exhibit self-sustained oscillations. In our models, we couple the BZ gel to an overlaying piezoelectric (PZ) cantilever to create a BZ-PZ unit. By connecting the BZ-PZ units by electrical wires, we design networks that autonomously transduce chemical, mechanical, and electrical energy to propagate a signal across the device and achieve synchronization of the oscillating gels in the network. This synchronization allows the device to perform pattern recognition in a self-organized manner, without the need for external electrical power sources. In particular, we imposed a collection of input patterns onto different BZ-PZ networks, where each network encompassed a distinct stored pattern. The network encompassing the stored pattern closest to the input pattern exhibited the fastest convergence time to the stable synchronization behavior, and could be identified as the "winner". In this way, the networks of coupled BZ-PZ oscillators achieved pattern recognition. We demonstrated that the convergence time to the stable synchronization provides a robust measure of the degree of match between the input and stored patterns. Through these studies, we laid out fundamental and experimentally realizable design rules for creating "materials that compute". PMID- 28630970 TI - Heavy ligand atom induced large magnetic anisotropy in Mn(ii) complexes. AB - In the search for single molecule magnets, metal ions are considered pivotal towards achieving large magnetic anisotropy barriers. In this context, the influence of ligands with heavy elements, showing large spin-orbit coupling, on magnetic anisotropy barriers was investigated using a series of Mn(ii)-based complexes, in which the metal ion did not have any orbital contribution. The mixing of metal and ligand orbitals was achieved by explicitly correlating the metal and ligand valence electrons with CASSCF calculations. The CASSCF wave functions were further used for evaluating spin-orbit coupling and zero-field splitting parameters for these complexes. For Mn(ii) complexes with heavy ligand atoms, such as Br and I, several interesting inter-state mixings occur via the spin-orbit operator, which results in large magnetic anisotropy in these Mn(ii) complexes. PMID- 28630969 TI - Strong circularly polarized luminescence induced from chiral supramolecular assembly of helical nanorods. AB - Chiral supramolecular assemblies (BNS-BPP) can be self-assembled by electrostatic and pi-pi stacking interactions between the chiral binaphthyl sulphonate (BNS) anion and the achiral bipyrene-based pyridinium (BPP) cation chromophore. BNS-BPP can exhibit strong CD and circularly polarized luminescence (CPL) signals, and the dissymmetry factor glum values can be up to 0.079. PMID- 28630971 TI - 2-Thiouracil intersystem crossing photodynamics studied by wavelength-dependent photoelectron and transient absorption spectroscopies. AB - Single-atom substitution within a natural nucleobase-such as replacing oxygen by sulfur in uracil-can result in drastic changes in the relaxation dynamics after UV excitation. While the photodynamics of natural nucleobases like uracil are dominated by pathways along singlet excited states, the photodynamics of thiobases like 2-thiouracil populate the triplet manifold with near unity quantum yield. In the present study, a synergistic approach based on time-resolved photoelectron spectroscopy (TRPES), time-resolved absorption spectroscopy (TRAS), and ab initio computations has been particularly successful at unraveling the underlying photophysical principles and describing the dissimilarities between the natural and substituted nucleobases. Specifically, we find that varying the excitation wavelength leads to differences between gas-phase and condensed-phase experimental results. Systematic trends are observed in the intersystem crossing time constants with varying excitation wavelength, which can be readily interpreted in the context of ab initio calculations performed both in vacuum and including solvent effects. Thus, the combination of TRPES and TRAS experiments with high-level computational techniques allows us to characterize the topology of the potential energy surfaces defining the relaxation dynamics of 2-thiouracil in both gas and condensed phases, as well as investigate the accessibility of conical intersections and crossings, and potential energy barriers along the associated relaxation coordinates. PMID- 28630972 TI - Using the International Classification of Functioning, Disability and Health in Assessment and Intervention of School-Aged Children With Language Impairments. AB - Purpose: The aim of this tutorial is to support speech-language pathologists' (SLPs') application of the International Classification of Functioning, Disability and Health (ICF) in assessment and treatment practices with children with language impairment. Method: This tutorial reviews the framework of the ICF, describes the implications of the ICF for SLPs, distinguishes between students' capacity to perform a skill in a structured context and the actual performance of that skill in naturalistic contexts, and provides a case study of an elementary school child to demonstrate how the principles of the ICF can guide assessment and intervention. Implications: The Scope of Practice and Preferred Practice documents for the American Speech-Language-Hearing Association identify the ICF as the framework for practice in speech-language pathology. This tutorial will facilitate clinicians' ability to identify personal and environmental factors that influence students' skill capacity and skill performance, assess students' capacity and performance, and develop impairment-based and socially based language goals linked to Common Core State Standards that build students' language capacity and their communicative performance in naturalistic contexts. PMID- 28630973 TI - CONSORT Statement for Randomized Trials of Nonpharmacologic Treatments: A 2017 Update and a CONSORT Extension for Nonpharmacologic Trial Abstracts. AB - Incomplete and inadequate reporting is an avoidable waste that reduces the usefulness of research. The CONSORT (Consolidated Standards of Reporting Trials) Statement is an evidence-based reporting guideline that aims to improve research transparency and reduce waste. In 2008, the CONSORT Group developed an extension to the original statement that addressed methodological issues specific to trials of nonpharmacologic treatments (NPTs), such as surgery, rehabilitation, or psychotherapy. This article describes an update of that extension and presents an extension for reporting abstracts of NPT trials. To develop these materials, the authors reviewed pertinent literature published up to July 2016; surveyed authors of NPT trials; and conducted a consensus meeting with editors, trialists, and methodologists. Changes to the CONSORT Statement extension for NPT trials include wording modifications to improve readers' understanding and the addition of 3 new items. These items address whether and how adherence of participants to interventions is assessed or enhanced, description of attempts to limit bias if blinding is not possible, and specification of the delay between randomization and initiation of the intervention. The CONSORT extension for abstracts of NPT trials includes 2 new items that were not specified in the original CONSORT Statement for abstracts. The first addresses reporting of eligibility criteria for centers where the intervention is performed and for care providers. The second addresses reporting of important changes to the intervention versus what was planned. Both the updated CONSORT extension for NPT trials and the CONSORT extension for NPT trial abstracts should help authors, editors, and peer reviewers improve the transparency of NPT trial reports. PMID- 28630974 TI - Guideline: In low back pain, nonpharmacologic treatments are recommended. PMID- 28630975 TI - Guideline: USPSTF makes no recommendation for pelvic exams to screen for gynecologic conditions in asymptomatic women. PMID- 28630976 TI - Review: Compared with systolic BP target of < 160 mm Hg, targeting < 120 is more effective; < 130 balances benefits and harms. PMID- 28630977 TI - In VTE, extending anticoagulation with rivaroxaban vs aspirin reduced recurrence without increasing bleeding. PMID- 28630978 TI - In adults at risk for contrast-induced nephropathy, no prophylactic hydration was noninferior to hydration. PMID- 28630979 TI - An online exercise program plus automated coping skills training improved pain and function in chronic knee pain. PMID- 28630980 TI - In severe aortic stenosis with intermediate surgical risk, TAVR was noninferior to SAVR for death or disabling stroke. PMID- 28630981 TI - Review: Lung ultrasonography had varied sensitivity and specificity for diagnosing pneumonia in adults. PMID- 28630982 TI - Resuming warfarin after intracranial hemorrhage in patients with AF was linked to reduced mortality. PMID- 28630983 TI - Simplified and original Wells rules plus age-adjusted D-dimer test were useful for ruling out suspected PE. PMID- 28630984 TI - Heterogeneity in Treatment Effects. PMID- 28630985 TI - Heterogeneity in Treatment Effects. PMID- 28630986 TI - Brain-Type Natriuretic Peptide and Amino-Terminal Pro-Brain-Type Natriuretic Peptide Discharge Thresholds for Acute Decompensated Heart Failure. PMID- 28630987 TI - Brain-Type Natriuretic Peptide and Amino-Terminal Pro-Brain-Type Natriuretic Peptide Discharge Thresholds for Acute Decompensated Heart Failure. PMID- 28630988 TI - Travel-Associated Zika Virus Disease. PMID- 28630989 TI - Travel-Associated Zika Virus Disease. PMID- 28630991 TI - Correction: In the Clinic: Atrial Fibrillation. PMID- 28630990 TI - Correction: The True Effect of Mass Shootings on Americans. PMID- 28630992 TI - Rock Bottom. PMID- 28630994 TI - Dupuytren's. PMID- 28630993 TI - Moral Dilemma in the ER. PMID- 28630995 TI - Krebs Cycle. PMID- 28630996 TI - Regarding Kindness. PMID- 28630998 TI - Web Exclusives. Annals Consult Guys - Syncope: How Do I Figure This One Out? PMID- 28630997 TI - Web Exclusives. Annals for Hospitalists Inpatient Notes - Research Highlights From Hospital Medicine 2017. PMID- 28631001 TI - The Effect of Emphasizing Patient, Societal, and Institutional Harms of Inappropriate Antibiotic Prescribing on Physician Support of Financial Penalties: A Randomized Trial. PMID- 28631002 TI - Yoga and Low Back Pain: No Fool's Tool. PMID- 28631004 TI - Laser structuring of carbon nanotubes in the albumin matrix for the creation of composite biostructures. AB - This paper presents the composite biostructures created by laser structuring of the single-walled carbon nanotubes (SWCNTs) in an albumin matrix. Under the exposure of femtosecond laser radiation, the heating of the albumin aqueous solution causes liquid water to evaporate. As a result, we obtained a solid-state composite in the bulk or film form. Using the molecular dynamic method, we showed the formation of a framework from SWCNTs by the example of splicing of the open end of one nanotube with the defect region of another nanotube under the action of the laser heating. Laser heating of SWCNTs up to a temperature of 80 degrees C to 100 degrees C causes the C ? C bond formation. Raman spectra measured for the composite biostructures allowed us to describe the binding of oxygen atoms of amino acid residues of the albumin with the carbon atoms of the SWCNTs. It is found that the interaction energy of the nanotube atoms and albumin atoms amounts up to 580 ?? kJ / mol . We used atomic force microscopy to investigate the surface of the composite biostructures. The pore size is in the range of 30 to 120 nm. It is proved that the proliferation of the fibroblasts occurred on the surface of the composite biostructures during 72 h of incubation. PMID- 28631003 TI - Yoga, Physical Therapy, or Education for Chronic Low Back Pain: A Randomized Noninferiority Trial. AB - Background: Yoga is effective for mild to moderate chronic low back pain (cLBP), but its comparative effectiveness with physical therapy (PT) is unknown. Moreover, little is known about yoga's effectiveness in underserved patients with more severe functional disability and pain. Objective: To determine whether yoga is noninferior to PT for cLBP. Design: 12-week, single-blind, 3-group randomized noninferiority trial and subsequent 40-week maintenance phase. (ClinicalTrials.gov: NCT01343927). Setting: Academic safety-net hospital and 7 affiliated community health centers. Participants: 320 predominantly low-income, racially diverse adults with nonspecific cLBP. Intervention: Participants received 12 weekly yoga classes, 15 PT visits, or an educational book and newsletters. The maintenance phase compared yoga drop-in classes versus home practice and PT booster sessions versus home practice. Measurements: Primary outcomes were back-related function, measured by the Roland Morris Disability Questionnaire (RMDQ), and pain, measured by an 11-point scale, at 12 weeks. Prespecified noninferiority margins were 1.5 (RMDQ) and 1.0 (pain). Secondary outcomes included pain medication use, global improvement, satisfaction with intervention, and health-related quality of life. Results: One-sided 95% lower confidence limits were 0.83 (RMDQ) and 0.97 (pain), demonstrating noninferiority of yoga to PT. However, yoga was not superior to education for either outcome. Yoga and PT were similar for most secondary outcomes. Yoga and PT participants were 21 and 22 percentage points less likely, respectively, than education participants to use pain medication at 12 weeks. Improvements in yoga and PT groups were maintained at 1 year with no differences between maintenance strategies. Frequency of adverse events, mostly mild self-limited joint and back pain, did not differ between the yoga and PT groups. Limitations: Participants were not blinded to treatment assignment. The PT group had disproportionate loss to follow-up. Conclusion: A manualized yoga program for nonspecific cLBP was noninferior to PT for function and pain. Primary Funding Source: National Center for Complementary and Integrative Health of the National Institutes of Health. PMID- 28631006 TI - Yoga, Physical Therapy, or Education for Chronic Low Back Pain. PMID- 28631005 TI - Phonological Working Memory for Words and Nonwords in Cerebral Cortex. AB - Purpose: The primary purpose of this study was to identify the brain bases of phonological working memory (the short-term maintenance of speech sounds) using behavioral tasks analogous to clinically sensitive assessments of nonword repetition. The secondary purpose of the study was to identify how individual differences in brain activation were related to participants' nonword repetition abilities. Method: We used functional magnetic resonance imaging to measure neurophysiological response during a nonword discrimination task derived from standard clinical assessments of phonological working memory. Healthy adult control participants (N = 16) discriminated pairs of real words or nonwords under varying phonological working memory load, which we manipulated by parametrically varying the number of syllables in target (non)words. Participants' cognitive and phonological abilities were also measured using standardized assessments. Results: Neurophysiological responses in bilateral superior temporal gyrus, inferior frontal gyrus, and supplementary motor area increased with greater phonological working memory load. Activation in left superior temporal gyrus during nonword discrimination correlated with participants' performance on standard clinical nonword repetition tests. Conclusion: These results suggest that phonological working memory is related to the function of cortical structures that canonically underlie speech perception and production. PMID- 28631007 TI - How Schwann cells facilitate cancer progression in nerves. AB - Recent studies have demonstrated a critical role for nerves in enabling tumor progression. The association of nerves with cancer cells is well established for a variety of malignant tumors, including pancreatic, prostate and the head and neck cancers. This association is often correlated with poor prognosis. A strong partnership between cancer cells and nerve cells leads to both cancer progression and expansion of the nerve network. This relationship is supported by molecular pathways related to nerve growth and repair. Peripheral nerves form complex tumor microenvironments, which are made of several cell types including Schwann cells. Recent studies have revealed that Schwann cells enable cancer progression by adopting a de-differentiated phenotype, similar to the Schwann cell response to nerve trauma. A detailed understanding of the molecular and cellular mechanisms involved in the regulation of cancer progression by the nerves is essential to design strategies to inhibit tumor progression. PMID- 28631010 TI - The metabolic cost of nesting: body condition and blood parameters of Caiman crocodilus and Melanosuchus niger in Central Amazonia. AB - Although nesting ecology is well studied in several crocodilian species, it is not known how nest attendance influences physiology and body condition of nesting females. In this study, we describe body condition and serum biochemical values of nesting female, non-nesting female and male spectacled caiman (Caiman crocodilus) and black caiman (Melanosuchus niger) in two areas of Central Amazonia. We also evaluated the effect of nest age and nest distance to water on body condition and blood parameters of nesting females. Body condition and plasmatic concentrations of glucose, triglycerides, lactate and uric acid of nesting females were significantly different from those of non-nesting females and males in C. crocodilus, but not in M. niger. Our study also demonstrated that nest age and distance to water had a negative effect on female body condition in C. crocodilus, but not in M. niger. Female C. crocodilus attending older nests or nests built further away from permanent water bodies tended to have lower body condition. Our results demonstrate that the nesting strategy of C. crocodilus has a metabolic cost associated with nest attendance for nesting females, which appear to depend on accumulated energetic reserves during nest attendance. In contrast, nest attendance had little effect on the physiology of female M. niger. PMID- 28631008 TI - Regulation of neural circuit formation by protocadherins. AB - The protocadherins (Pcdhs), which make up the most diverse group within the cadherin superfamily, were first discovered in the early 1990s. Data implicating the Pcdhs, including ~60 proteins encoded by the tandem Pcdha, Pcdhb, and Pcdhg gene clusters and another ~10 non-clustered Pcdhs, in the regulation of neural development have continually accumulated, with a significant expansion of the field over the past decade. Here, we review the many roles played by clustered and non-clustered Pcdhs in multiple steps important for the formation and function of neural circuits, including dendrite arborization, axon outgrowth and targeting, synaptogenesis, and synapse elimination. We further discuss studies implicating mutation or epigenetic dysregulation of Pcdh genes in a variety of human neurodevelopmental and neurological disorders. With recent structural modeling of Pcdh proteins, the prospects for uncovering molecular mechanisms of Pcdh extracellular and intracellular interactions, and their role in normal and disrupted neural circuit formation, are bright. PMID- 28631009 TI - Methods of probing the interactions between small molecules and disordered proteins. AB - It is generally recognized that a large fraction of the human proteome is made up of proteins that remain disordered in their native states. Despite the fact that such proteins play key biological roles and are involved in many major human diseases, they still represent challenging targets for drug discovery. A major bottleneck for the identification of compounds capable of interacting with these proteins and modulating their disease-promoting behaviour is the development of effective techniques to probe such interactions. The difficulties in carrying out binding measurements have resulted in a poor understanding of the mechanisms underlying these interactions. In order to facilitate further methodological advances, here we review the most commonly used techniques to probe three types of interactions involving small molecules: (1) those that disrupt functional interactions between disordered proteins; (2) those that inhibit the aberrant aggregation of disordered proteins, and (3) those that lead to binding disordered proteins in their monomeric states. In discussing these techniques, we also point out directions for future developments. PMID- 28631011 TI - Isoprenyl carboxyl methyltransferase inhibitors: a brief review including recent patents. AB - Among the enzymes involved in the post-translational modification of Ras, isoprenyl carboxyl methyltransferase (ICMT) has been explored by a number of researchers as a significant enzyme controlling the activation of Ras. Indeed, inhibition of ICMT exhibited promising anti-cancer activity against various cancer cell lines. This paper reviews patents and research articles published between 2009 and 2016 that reported inhibitors of ICMT as potential chemotherapeutic agents targeting Ras-induced growth factor signaling. Since ICMT inhibitors can modulate Ras signaling pathway, it might be possible to develop a new class of anti-cancer drugs targeting Ras-related cancers. Researchers have discovered indole-based small-molecular ICMT inhibitors through high-throughput screening. Researchers at Duke University identified a prototypical inhibitor, cysmethynil. At Singapore University, Ramanujulu and his colleagues patented more potent compounds by optimizing cysmethynil. In addition, Rodriguez and Stevenson at Universidad Complutense De Madrid and Cancer Therapeutics CRC PTY Ltd., respectively, have developed inhibitors based on formulas other than the indole base. However, further optimization of chemicals targeted to functional groups is needed to improve the characteristics of ICMT inhibitors related to their application as drugs, such as solubility, effectiveness, and safety, to facilitate clinical use. PMID- 28631012 TI - Rapid preparation of bioluminescent tracers for relaxin family peptides using sortase-catalysed ligation. AB - Relaxin family is a group of peptide hormones with a variety of biological functions by activating G protein-coupled receptors RXFP1-4. We recently developed bioluminescent tracers for their receptor-binding assays by chemical conjugation with the ultrasensitive NanoLuc reporter. To simplify preparation of the bioluminescent tracers, in the present study, we established a sortase catalysed ligation approach using the chimeric R3/I5 as a model. Following catalysis by recombinant sortase A, a NanoLuc reporter carrying the LPETG sortase recognition motif at the C-terminus was efficiently ligated to an R3/I5 peptide carrying four successive Gly residues at the A-chain N-terminus, via the formation of a peptide bond between the C-terminal LPET sequence of NanoLuc and the A-chain N-terminal Gly residue of R3/I5. Saturation binding assays demonstrated that the NanoLuc-ligated R3/I5 retained high binding affinity to RXFP3 and RXFP4, with the calculated dissociation constants (K d) of 4.34 +/- 0.33 nM (n = 3) and 5.66 +/- 0.54 nM (n = 3), respectively. Using the NanoLuc ligated R3/I5 as a tracer in competition binding assays, binding potencies of various ligands towards RXFP3 and RXFP4 were conveniently quantified. This work provides a simple method for rapid preparation of bioluminescent tracers for relaxin family peptides and other protein/peptide hormones for ligand-receptor interaction studies. PMID- 28631014 TI - Do Adult Somatic Cells Undergo Reprogramming or Endogenous Pluripotent Stem Cells get Activated to Account for Plasticity, Regeneration and Cancer Initiation? PMID- 28631013 TI - In vivo evaluation of the bone integration of coated poly(vinyl-alcohol) hydrogel fiber implants. AB - Recently, it has been shown that constructs of poly(vinyl alcohol) (PVA) hydrogel fibers reproduce closely the tensile behavior of ligaments. However, the biological response to these systems has not been explored yet. Here, we report the first in vivo evaluation of these implants and focus on the integration in bone, using a rabbit model of bone tunnel healing. Implants consisted in bundles of PVA hydrogel fibers embedded in a PVA hydrogel matrix. Half of the samples were coated with a composite coating of hydroxyapatite (HA) particles embedded in PVA hydrogel. The biological integration was evaluated at 6 weeks using histology and micro-CT imaging. For all implants, a good biological tolerance and growth of new bone tissue are reported. All the implants were surrounded by a fibrous layer comparable to what was previously observed for poly(ethylene terephthalate) (PET) fibers currently used in humans for ligament reconstruction. An image analysis method is proposed to quantify the thickness of this fibrous capsule. Implants coated with HA were not significantly osteoconductive, which can be attributed to the slow dissolution of the selected hydroxyapatite. Overall, these results confirm the relevance of PVA hydrogel fibers for ligament reconstruction and adjustments are proposed to enhance its osseointegration. PMID- 28631015 TI - Ask yeast how to burn your fats: lessons learned from the metabolic adaptation to salt stress. AB - Here, we review and update the recent advances in the metabolic control during the adaptive response of budding yeast to hyperosmotic and salt stress, which is one of the best understood signaling events at the molecular level. This environmental stress can be easily applied and hence has been exploited in the past to generate an impressively detailed and comprehensive model of cellular adaptation. It is clear now that this stress modulates a great number of different physiological functions of the cell, which altogether contribute to cellular survival and adaptation. Primary defense mechanisms are the massive induction of stress tolerance genes in the nucleus, the activation of cation transport at the plasma membrane, or the production and intracellular accumulation of osmolytes. At the same time and in a coordinated manner, the cell shuts down the expression of housekeeping genes, delays the progression of the cell cycle, inhibits genomic replication, and modulates translation efficiency to optimize the response and to avoid cellular damage. To this fascinating interplay of cellular functions directly regulated by the stress, we have to add yet another layer of control, which is physiologically relevant for stress tolerance. Salt stress induces an immediate metabolic readjustment, which includes the up regulation of peroxisomal biomass and activity in a coordinated manner with the reinforcement of mitochondrial respiratory metabolism. Our recent findings are consistent with a model, where salt stress triggers a metabolic shift from fermentation to respiration fueled by the enhanced peroxisomal oxidation of fatty acids. We discuss here the regulatory details of this stress-induced metabolic shift and its possible roles in the context of the previously known adaptive functions. PMID- 28631017 TI - Proton therapy of iris melanoma with 50 CGE : Influence of target volume on clinical outcome. AB - PURPOSE: The aim of this study was to evaluate local tumour control, incidence of radiation-induced glaucoma and associated interventions of sector-based and whole anterior segment proton beam therapy (PBT) for the treatment of iris melanoma. PATIENTS AND METHODS: We retrospectively analysed the data of 77 patients with iris melanoma who underwent PBT applied as 50 CGE in four daily fractions. Of the patients, 47 received PBT with a circular-shaped collimator and 30 with a conformal sector-shaped target volume. Local control, eye preservation and secondary glaucoma were evaluated. RESULTS: Median follow-up time was 54.9 months. Local tumour control was 100% in patients receiving whole anterior segment irradiation. Two patients developed pigment dispersion in the non irradiated area after sector-based PBT and received whole anterior segment salvage PBT. The mean volume of ciliary body irradiated was 89.0% and 34.9% for whole anterior segment and lesion-based irradiation, respectively. At the end of follow-up, secondary glaucoma was found in 74.3% of the patients with whole anterior segment irradiation and in 19.2% with sector-based irradiation. Patients with sector-based PBT had a stable visual acuity of logMAR 0.1, while it declined from logMAR 0.1 to 0.4 after whole anterior segment irradiation. CONCLUSION: We found a significant reduction in radiation-induced secondary glaucoma and glaucoma-associated surgical interventions and stable visual acuity after sector based irradiation compared with whole anterior segment irradiation. Sector-based irradiation revealed a higher risk for local recurrence, but selected patients with well-circumscribed iris melanoma benefit from applying a lesion-based target volume when treated with sector-based PBT. PMID- 28631016 TI - New insights into cohesin loading. AB - Cohesin is a conserved, ring-shaped protein complex that encircles sister chromatids and ensures correct chromosome segregation during mitosis and meiosis. It also plays a crucial role in the regulation of gene expression, DNA condensation, and DNA repair through both non-homologous end joining and homologous recombination. Cohesins are spatiotemporally regulated by the Scc2 Scc4 complex which facilitates cohesin loading onto chromatin at specific chromosomal sites. Over the last few years, much attention has been paid to cohesin and cohesin loader as it became clear that even minor disruptions of these complexes may lead to developmental disorders and cancers. Here we summarize recent developments in the structure of Scc2-Scc4 complex, cohesin loading process, and mediators that determine the Scc2-Scc4 binding patterns to chromatin. PMID- 28631018 TI - Personalized radiotherapy for invasive breast cancer in 2017 : National S3 guidelines and DEGRO and AGO recommendations. PMID- 28631021 TI - Erratum to: Robot-assisted laparoscopic pyeloplasty in the pediatric population: a review of technique, outcomes, complications, and special considerations in infants. PMID- 28631020 TI - Utility of PAS and beta-catenin staining in histological categorisation and prediction of prognosis of hepatoblastomas. AB - AIMS: The aim of this study was to assess the usefulness of PAS, beta-catenin and Ki-67 in categorising hepatoblastomas (HBs) and their significance in predicting prognosis. In addition, we have also documented the various chemotherapy induced histologic changes in HBs. METHOD: In this retrospective observational study of 29 cases of hepatoblastomas, 27 cases were considered for statistical analysis, excluding two cases of diagnostic core biopsies. All clinicopathological parameters and follow up data were collected. All HB cases including the mixed epithelial and mesenchymal HBs were classified into two groups: fetal predominant and embryonal predominant type according to the predominant epithelial component. PAS, beta-catenin and Ki-67 staining were done and their correlation with histologic subtypes was assessed. Kaplan-Meier survival analysis was performed in relation to histology, PAS, beta-catenin and Ki-67 staining characteristics. RESULT: Diffuse nuclear staining of beta-catenin was significantly more common in embryonal predominant type (p = 0.036), whereas strong PAS positivity was significantly associated with fetal predominant type (p = 0.002). But no significant correlation was seen between histologic type and Ki-67 staining (p = 0.42). Survival analysis showed cases with diffuse PAS positivity, focal nuclear beta-catenin staining and low Ki-67 LI had better survival. CONCLUSION: PAS is a simple stain and can be utilised in histological categorisation of HB and also predicting its outcome. Nuclear beta-catenin staining which is significantly common in embryonal elements in HB predicts shorter survival. PMID- 28631022 TI - Risk analysis and outcomes of bronchopulmonary sequestrations. AB - BACKGROUND: Researched and discussed the risks and outcomes of bronchopulmonary sequestrations, especially the intralobar type. METHODS: A retrospective review of our experiences with bronchopulmonary sequestrations from January 2012 to April 2015 is reported. The present study researched and discusses the risks and outcomes of bronchopulmonary sequestrations, especially the intralobar type, compared with other types of bronchopulmonary sequestrations in symptoms, surgery, pathology, and excretion. RESULTS: A total of 126 bronchopulmonary sequestrations were diagnosed. All fetal chest cases (18-30 weeks) of solid or high-echo masses were diagnosed antenatally and then confirmed by ultrasound. Enhanced computed tomography was used to confirm the diagnosis. Eighty-three boys and 43 girls were included. The mean age at surgery was 4.2 +/- 0.5 months. There were 103 cases of left, 22 cases of right, and 1 case of bilateral sequestration. There were 62 extralobar cases, 51 intralobar cases, 13 cases within the diaphragm, and a rare bilateral case. A preoperative history of recurrent respiratory tract infection was present in 39 cases, including 10 extralobar and 29 intralobar cases. Operations were completed successfully, and diagnoses were confirmed pathologically. Thirty-seven cases were associated with congenital bronchopulmonary malformation changes, of which 4 were extralobar, 31 were intralobar, and 2 were within the diaphragm. CONCLUSIONS: The intralobar type was relatively uncommon among bronchopulmonary sequestrations. However, due to communication with normal lung tissue, infection is common in the intralobar type. Computed tomography examinations are very important immediately after birth. It is necessary to resect the mass in early childhood. PMID- 28631023 TI - The influence of perceived parenting styles on socio-emotional development from pre-puberty into puberty. AB - The relative impact of parenting on socio-emotional development of children has rarely been examined in a longitudinal context. This study examined the association between perceived parenting styles and socio-emotional functioning from childhood to adolescence. We hypothesized that optimal parenting associated with improvement in socio-emotional functioning from childhood into early adulthood, especially for those with more behavioral problems in childhood. Children between ages 7 and 9 years were recruited for the Singapore Cohort Study of Risk Factors for Myopia (SCORM). Nine years later, 700 out of 1052 subjects were followed up (67%). During childhood, parents completed the Child Behavior Checklist (CBCL), while young adults completed the Youth Self-Report (YSR) and Parental Bonding Instrument (PBI). Perceived optimal parental care resulted in less internalizing and externalizing problems in early adulthood in comparison to non-optimal parental care styles. Perceived optimal paternal parenting, but not maternal parenting, in interaction with childhood externalizing problems predicted externalizing symptoms in early adulthood. No significant interactions were found between perceived parenting styles and internalizing problems. In conclusion, perceived parental care associates with the quality of socio emotional development, while optimal parenting by the father is especially important for children with more externalizing problems in childhood. PMID- 28631024 TI - The use of tibial tuberosity-trochlear groove indices based on joint size in lower limb evaluation. AB - PURPOSE: The correlation between tibial tuberosity-trochlear groove distance (TT TG) and joint size, taking into account several different parameters of knee joint size as well as lower limb dimensions, is evaluated in order to assess whether TT-TG indices should be used in instead of absolute TT-TG values. METHODS: This study comprised a retrospective analysis of knee CT scans, including 36 cases with patellofemoral instability (PFI) and 30 controls. Besides TT-TG, five measures of knee joint size were evaluated in axial CT slices: medio lateral femur width, antero-posterior lateral condylar height, medio-lateral width of the tibia, width of the patella and the proximal-distal joint size (TT TE). Furthermore, the length of the femur, the tibia and the total leg length were measured in the CT scanogram. Correlation analysis of TT-TG and the other parameters was done by calculating the Spearman correlation coefficient. RESULTS: In the PFI group lateral condylar height (r = 0.370), tibia width (r = 0.406) and patella width (r = 0.366) showed significant moderate correlations (p < 0.03) with TT-TG. Furthermore, we found a significant correlation between TT-TG and tibia length (r = 0.371) and total leg length (r = 381). The control group showed no significant correlation between TT-TG and knee joint size or between TT-TG and measures of lower limb length. CONCLUSIONS: Tibial tuberosity-trochlear groove distance correlates with several parameters of knee joint size and leg length in patients with patellofemoral instability. Application of indices determining TT TG as a ratio of joint size could be helpful in establishing the indication for medial transfer of the tibial tuberosity in patients with PFI. LEVEL OF EVIDENCE: Level III. PMID- 28631025 TI - Diverse Autoantibody Reactivity in Cartilage-Hair Hypoplasia. PMID- 28631026 TI - Erratum to: Prevalence and impact of severe fatigue in adolescent and young adult cancer patients in comparison with population-based controls. PMID- 28631027 TI - Validation of a Liver Index and Its Significance for HCC Aggressiveness. AB - BACKGROUND: We recently constructed a liver index (LI) from four liver parameters, namely: blood total bilirubin, gamma glutamyl transpeptidase (GGTP), albumin, and platelet levels (a cirrhosis surrogate). We found that the scores for the liver index related significantly to a four-parameter HCC aggressiveness index (maximum tumor diameter, multifocality, percent portal vein invasion, and blood AFP levels). AIMS: To validate the relationship of liver parameters to tumor aggressiveness parameters in a larger, different HCC dataset. RESULTS: We now confirm these associations in another large HCC cohort. Furthermore, this liver index showed significant trends with the individual HCC aggressiveness parameters. CONCLUSIONS: These results provide further support for the idea that liver microenvironment, as reflected in liver function tests, may relate to HCC behavior. PMID- 28631028 TI - [Developing a framework for a public health monitoring of the population aged 65 years and older : Results of the IMOA workshop on concepts and indicators]. AB - Main goal of the Improving Health Monitoring in Older Age (IMOA) project is to provide a framework for an indicator-based public health monitoring of the population aged 65 years and older. The workshop served as a forum to discuss and agree upon relevant concepts with gerontologists, nursing care and public health scientists. PMID- 28631029 TI - Syngas Biorefinery and Syngas Utilization. AB - Autotrophic acetogenic bacteria are able to capture carbon (CO or CO2) through gas fermentation, allowing them to grow on a spectrum of waste gases from industry (e.g., steel manufacture and oil refining, coal, and natural gas) and to produce ethanol. They can also consume syn(thesis) gas (CO and H2) made from the gasification of renewable/sustainable resources, such as biomass and domestic/agricultural waste. Acetogenic gas fermentation can, therefore, produce ethanol in any geographic region without competing for food or land. The commercialization of the process is now at an advanced stage. The real potential of acetogens, however, resides in their capacity to produce chemicals and fuels other than ethanol. This requires the redesign and implementation of more efficient metabolic pathways, adapting them to high performing manufacturing processes. Respective species, their bioenergetics, the genetic tools developed for their metabolic engineering, culture techniques and fermenter set-ups, as well as the commercialization, are comprehensively described and discussed in this chapter. PMID- 28631030 TI - The Impact of Impoundment on Mercury Bioaccumulation in Fish Downstream from a Newly Constructed Reservoir, Wujiang River, Southwest China. AB - Mercury concentrations in fish were investigated downstream from a newly impounded subtropical reservoir in August 2008. After 6-7 months of reservoir impoundment, mean mercury concentration in fish from downstream is significantly increased by 1.9 times. Not only carnivorous fish but also benthic fish had significantly higher total mercury concentrations than others. No significant correlation was found between total mercury concentrations and body length or weight of 13 fish species. Compared with the pre-impoundment, total mercury in fish from downstream is significantly increased by reservoir impoundment, but the increased rate is lower than those in subarctic and temperate areas. Fish samples surpassed the Chinese hygienic standard for tolerances of mercury in foods increased by 4.3%. More attention should be given to fish mercury levels from downstream sites to prevent possible adverse effects on the health of local people. PMID- 28631031 TI - Metals in Blood and Eggs of Green Sea Turtles (Chelonia mydas) from Nesting Colonies of the Northern Coast of the Sea of Oman. AB - The green sea turtle (Chelonia mydas) has been a species of global concern for decades. In this study, heavy metals (mercury: Hg; Cadmium: Cd; Lead: Pb; Copper: Cu; and Zinc: Zn) were measured in blood and three egg fraction of green sea turtles nesting on the northern coast of Sea of Oman. Heavy metals concentrations in blood, yolk, albumen, and egg shell ranged between 0.16-36.78, 0.006-33.88, 0.003-4.02, and 0.002-6.85 MUg/g (ww), respectively. According to the results, all heavy metals found in blood samples (n = 12) also were detected in the various parts of the eggs (n = 48). Moreover, there were no significant differences between concentrations of heavy metals in different clutches laid in a nesting season. However, Pb concentrations in blood samples significantly increased in later clutches (p < 0.05), whereas Cu concentrations in blood samples exhibit a declining trend (p < 0.05). These results reveal the existence of maternal transfer phenomenon in green sea turtles on the northern coast of Sea of Oman. Results of this study suggest that heavy metals could be one of the factors influencing reductions in fertilization and hatching success. Results also indicate that green sea turtle on the northern coast of Sea of Oman have high capacity in rapid response and detoxification of heavy metals and/or from the low exposure levels of these turtles to the heavy metals. Further research is required concerning the effects of heavy metals on green sea turtles, especially on their possible influence of fetal development of turtles. PMID- 28631032 TI - Occurrence and Fate of Organic and Organometallic Pollutants in Municipal Wastewater Treatment Plants and Their Impact on Receiving Waters (Adour Estuary, France). AB - To achieve a "Good Environmental Status by 2015," as demanded by the water framework directive, monitoring programs are needed to furnish data on target compounds. In this study, a first evaluation of influents and main emissions of 3 local wastewater treatment plants (WWTP) in the Adour estuary (southwest of France) was performed for 23 pollutants (10 musk fragrances, 5 alkylphenols, and 8 organometallics), as well as receiving estuarine water from the same area. High frequency of occurrence of these compounds was found in influents samples (musks: 22-100%; alkylphenols 11-100%; organometallics 0-100%) and effluents (musks: 0 100%; alkylphenols 0-100%; organometallics 0-100%). The removal efficiencies were calculated and varied from negative values up to 98% with the lowest values for synthetic musk compounds. Temporal variability of the target compounds also was studied, and a few tendencies were observed. Estimation of the daily output of each WWTP into the estuary also showed that galaxolide, nonylphenol, monobuthyltin, and inorganic mercury were the compounds discharged into the environment at the highest concentrations. Finally, the occurrence of these compounds in estuarine waters was evaluated; most of them were present at concentrations below the limits of quantification (musks: 0.53-41.5 ng/L; alkylphenols 3.4-410 ng/L; organometallics 0.02-0.70 ng/L) suggesting a low impact in the resulting receiving waters. PMID- 28631033 TI - [Erratum to: Optimized detection and characterization of liver metastases: The role of current MRI contrast agents]. PMID- 28631034 TI - Cardiac MRI quantitative tissue characterization of right atrial mass using mDixon and parametric mapping. PMID- 28631036 TI - Practical recommendations for radium-223 treatment of metastatic castration resistant prostate cancer. AB - PURPOSE: Radium Ra 223 dichloride (radium-223, Xofigo(r)) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision. METHODS: An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium 223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined. RESULTS: The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway. CONCLUSIONS: These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care. PMID- 28631035 TI - Brief Report: The Negev Hospital-University-Based (HUB) Autism Database. AB - Elucidating the heterogeneous etiologies of autism will require investment in comprehensive longitudinal data acquisition from large community based cohorts. With this in mind, we have established a hospital-university-based (HUB) database of autism which incorporates prospective and retrospective data from a large and ethnically diverse population. The collected data includes social-demographic characteristics, standardized behavioral testing, detailed clinical history from electronic patient records, genetic samples, and various neurological measures. We describe the initial cohort characteristics following the first 18 months of data collection (188 children with autism). We believe that the Negev HUB autism database offers a unique and valuable resource for studying the heterogeneity of autism etiologies across different ethnic populations. PMID- 28631038 TI - The significance of TIMD4 expression in clear cell renal cell carcinoma. AB - T-cell immunoglobulin and mucin domain (TIMD) family genes are related to innate immune responses. TIMD4 is a receptor for phosphatidylserine and is involved in the phagocytosis of apoptotic cells by macrophages. In the present study, we found that TIMD4 is expressed on the cancer cells of patients with clear cell renal cell carcinoma (ccRCC). TIMD4 was immunostained in the resected samples of 89 patients diagnosed as ccRCC. High expression of TIMD4 in cancer cells was closely related to short progression free survival time; however, it was not correlated with other clinicopathological factors. Intracellular expression of TIMD4 was observed in the RCC cell line, 786-O. In vitro studies using 786-O cells and shRNA targeting TIMD4 indicated that TIMD4 expression was associated with resistance to sorafenib but not with cell proliferation. TIMD4 might be useful as a prognostic factor and may also be a new target for therapy of ccRCC. PMID- 28631039 TI - Graft nephrectomy in children. AB - Kidney transplantation is recognised as the gold standard treatment of end-stage renal disease in most children, with excellent graft survival rates. When graft failure occurs, renal transplant recipients (RTRs) have the option of removal of the transplant (graft nephrectomy [GN]), or leaving the failed transplant in situ. The aims of this review are to discuss the indications for GN, surgical techniques, outcomes after GN (including risks of allosensitisation and the impact on subsequent transplants), and the possible role of routine GN in the asymptomatic RTR with a failed renal allograft. Literature in both the pediatric and adult renal transplant fields is reviewed. We also discuss how future research in this area could advance our knowledge of which patients to select for GN, and the most appropriate surgical approach. PMID- 28631037 TI - Inclusion bodies of aggregated hemosiderins in liver macrophages. AB - Hemosiderin formation is a structural indication of iron overload. We investigated further adaptations of the liver to excess iron. Five patients with livers showing iron-rich inclusions larger than 2 um were selected from our database. The clinical features of patients and structures of the inclusions were compared with those of 2 controls with mild iron overload. All patients had severe iron overload with more than 5000 ng/mL of serum ferritin. Etiologies were variable, from hemochromatosis to iatrogenic iron overload. Their histological stages were either portal fibrosis or cirrhosis. Inclusion bodies were ultra structurally visualized as aggregated hemosiderins in the periportal macrophages. X-ray analysis always identified, in addition to a large amount of iron complexes including oxygen and phosphorus, a small amount of copper and sulfur in the mosaic matrixes of inclusions. There were no inclusions in the control livers. Inclusion bodies, when the liver is loaded with excess iron, may appear in the macrophages as isolated organella of aggregated hemosiderins. Trace amounts of copper-sulfur complexes were always identified in the mosaic matrices of the inclusions, suggesting cuproprotein induction against excess iron. In conclusion, inclusion formation in macrophages may be an adaptation of the liver loaded with excess iron. PMID- 28631040 TI - Biomarkers to detect rejection after kidney transplantation. AB - Detecting acute rejection in kidney transplantation has been traditionally done using histological analysis of invasive allograft biopsies, but this method carries a risk and is not perfect. Transplant professionals have been working to develop more accurate or less invasive biomarkers that can predict acute rejection or subsequent worse allograft survival. These biomarkers can use tissue, blood or urine as a source. They can comprise individual molecules or panels, singly or in combination, across different components or pathways of the immune system. This review highlights the most recent evidence for biomarker efficacy, especially from multicenter trials. PMID- 28631041 TI - An adolescent boy progressing insidiously to end-stage renal disease: Answers. AB - Hinman syndrome was a non-neurogenic neurogenic bladder and the most severe form of dysfunctional voiding disorder. The bladder-sphincter discoordination causes damage to the bladder and upper urinary tract if it is not diagnosed early and treated adequately. This case emphasizes the following important message: nighttime wetting is not a benign condition in every child. Parental awareness should be raised about voiding disorders, as it may be possible to prevent important renal diseases such as Hinman syndrome. PMID- 28631042 TI - Dispersal towards food: the singular limit of an Allen-Cahn equation. AB - The effect of dispersal under heterogeneous environment is studied in terms of the singular limit of an Allen-Cahn equation. Since biological organisms often slow down their dispersal if food is abundant, a food metric diffusion is taken to include such a phenomenon. The migration effect of the problem is approximated by a mean curvature flow after taking the singular limit which now includes an advection term produced by the spatial heterogeneity of food distribution. It is shown that the interface moves towards a local maximum of the food distribution. In other words, the dispersal taken in the paper is not a trivialization process anymore, but an aggregation one towards food. PMID- 28631043 TI - Erratum to: Daphnia revisited: local stability and bifurcation theory for physiologically structured population models explained by way of an example. PMID- 28631044 TI - [Personalized treatment of viral hepatitis of the present and the future : Hepatitis B, C, delta, and E]. AB - Precision medicine is also possible for infectious diseases as shown for the treatment of chronic viral hepatitis, especially if different options are available. In hepatitis B virus (HBV) infection, treatment indication as well as the choice of treatment and the decisions to stop treatment are based on viral markers and alanine aminotransferase (ALT) level. Future therapies for HBV infection aiming for functional cure or even virus elimination may be even more personalized and have to take into account the immune status of a given patient. Such treatment modalities might also increase the chance for successful treatment of chronic hepatitis delta where treatment options are still very limited. Some new therapeutic concepts targeting host receptors or host enzymes are promising, but may require individualized approaches. Chronic hepatitis C is a good example for precision medicine based on viral and host factors. However, the main reason for individualized direct-acting antiviral (DAA) treatment is to save costs. As DAAs are effective in more than 95% of patients, elimination of HCV seems to be possible at the level of a given country or even on a global scale. However, owing to high reinfection rates in high-risk groups and limited availability of antiviral therapy in many high endemic countries, it must still be decided whether an HCV vaccine or pre-exposure prophylaxis is required to achieve this goal. Hepatitis E is an emerging topic as this is the most frequent acute hepatitis virus infection. It can result in a chronic infection in immunosuppressed individuals. Treatment options are still limited and individualized management is based on tailoring immunosuppressive therapy and therapy with ribavirin. Thus, personalized therapy of hepatitis E virus infection is still limited. PMID- 28631045 TI - [Headaches]. AB - Headaches can be so severe that patients and doctors often fear life-threatening underlying cerebral pathologies. The spectrum of causes of headache is very heterogeneous and ranges from harmless situations to severe diseases, so that it is very difficult to consider all differential diagnoses simultaneously; however, a few targeted questions and physical examinations are sufficient to be able to make a better classification of the leading symptom headache. The following article serves as a quick guide for identification of patients at risk. It describes basic findings, red flags and specials warning signs that must immediately lead to emergency admission for further diagnostics. PMID- 28631046 TI - Adherence of rheumatoid arthritis patients to biologic disease-modifying antirheumatic drugs: a cross-sectional study. AB - The aims of this study were to evaluate adherence of rheumatoid arthritis (RA) patients to biological disease-modifying antirheumatic drugs (bDMARDs), identify potential risk factors, and analyze the discriminative ability of the Morisky Green test (MGT) to detect bDMARD nonadherence. One hundred and seventy-eight adult RA patients treated with bDMARDs were included. Adherence was measured using the medication possession ratio (MPR) of the previous 6 months. An MPR >80% was considered good adherence. Patient demographics, clinical characteristics, and MGT scores were assessed through a standardized clinical interview at the cross-sectional date. One-hundred and twelve patients (63%) were taking subcutaneous bDMARDs, while 66 (37%) were taking intravenous drugs. One-hundred fifty-eight (88.8%) showed good adherence to bDMARDs, while 79 (61.2%) also correctly took concomitant conventional synthetic DMARDs (csDMARDs). In logistic regression models, nonadherence to bDMARDs was associated with higher disease activity [odds ratio (OR) 1.45; 95% CI, 1.03-2.03; p = 0.032] and subcutaneous route (OR 3.70; 95% CI 1.02-13.48; p = 0.040). MGT accurately identified an MPR >80% of bDMARDs in 76.9% of the patients. A sensitivity of 78%, specificity of 70%, positive predictive value of 95.3%, negative predictive value of 28.5%, positive likelihood ratio (LR) of 2.6, and negative LR of 0.3% were obtained. Adherence may be good for bDMARDs but is low for csDMARDs. Low adherence for bDMARDs is associated with poorer disease control during the past 6 months and use of subcutaneous route. These findings should alert doctors to consider possible low adherence before declaring treatment failure. PMID- 28631047 TI - Periodontal disease in Chinese patients with systemic lupus erythematosus. AB - Disease of systemic lupus erythematosus (SLE) and periodontal disease (PD) shares the common multiple characteristics. The aims of the present study were to evaluate the prevalence and severity of periodontal disease in Chinese SLE patients and to determine the association between SLE features and periodontal parameters. A cross-sectional study of 108 SLE patients together with 108 age- and sex-matched healthy controls was made. Periodontal status was conducted by two dentists independently. Sociodemographic characteristics, lifestyle factors, medication use, and clinical parameters were also assessed. The periodontal status was significantly worse in SLE patients compared to controls. In univariate logistic regression, SLE had a significant 2.78-fold [95% confidence interval (CI) 1.60-4.82] increase in odds of periodontitis compared to healthy controls. Adjusted for potential risk factors, patients with SLE had 13.98-fold (95% CI 5.10-38.33) increased odds against controls. In multiple linear regression model, the independent variable negatively and significantly associated with gingival index was education (P = 0.005); conversely, disease activity (P < 0.001) and plaque index (P = 0.002) were positively associated; Age was the only variable independently associated with periodontitis of SLE in multivariate logistic regression (OR 1.348; 95% CI: 1.183-1.536, P < 0.001). Chinese SLE patients were likely to suffer from higher odds of PD. These findings confirmed the importance of early interventions in combination with medical therapy. It is necessary for a close collaboration between dentists and clinicians when treating those patients. PMID- 28631049 TI - Novel probiotics isolated from a Japanese traditional fermented food, Funazushi, attenuates DSS-induced colitis by increasing the induction of high integrin alphav/beta8-expressing dendritic cells. AB - BACKGROUND: We isolated two novel probiotics strains (s193 and s292) from Funazushi, which is a traditional Japanese fermented food, and evaluated its effects on DSS-induced colitis to determine the possible underlying mechanisms. METHODS: A single colony from homogenized Funazushi was isolated by its ability to suppress TNF-alpha in RAW 264.7. Effect of probiotics on colonic inflammation induced by DSS was evaluated. Effect of probiotics on Treg induction by CD11c+ dendritic cells (DCs) of MLNs were analyzed. RESULTS: Two novel probiotics strains classified into the genus Lactobacillus were isolated (s193 and s292), and those strains showed stronger anti-inflammatory effects on DSS-induced colitis than those of L. gasseri isolated from the gut. mRNA expression beta8 integrin in CD11c+DCs of MLNs and the number of Tregs in the large intestine were significantly increased by s193 and s292 administration compared with L. gasseri administration. Bone marrow DCs treated with s193 and s292 highly increased beta8 integrin, and those cells strongly induced differentiation of CD4+ T cells into Tregs. Differentiation of Tregs was remarkably inhibited by anti-beta8 integrin antibody treatment. CONCLUSIONS: Strains s193 and s292 demonstrate strong anti inflammatory effects on DSS-induced colitis through induction of beta8 integrin expression on DCs. Our results suggested that Japanese traditional fermented foods are valuable sources for probiotics that are effective for IBD therapy and treatment. PMID- 28631048 TI - Celiac disease: from etiological factors to evolving diagnostic approaches. AB - Celiac disease has advanced from a medical rarity to a highly prevalent disorder. Patients with the disease show varying degrees of chronic inflammation within the small intestine due to an aberrant immune response to the digestion of gliadin found in wheat. As a result, cytokines and antibodies are produced in celiac patients that can be used as specific biomarkers for developing diagnostic tests. This review paper describes celiac disease in terms of its etiological cause, pathological effects, current diagnostic tests based on mucosal biopsy, and the genetic basis for the disease. In addition, it discusses the use of gliadin induced cytokines, antibodies and autoantibodies as a diagnostic tool for celiac disease. Despite good initial results in terms of sensitivity and specificity, when these immunological tests were used on a large scale, even in combination with genetic testing, the results showed lower predictive value. This review addresses that issue and ends with an outlook on future work required to develop diagnostic tests with greater accuracy in predicting celiac disease in the general public, thus avoiding the need for endoscopy and mucosal biopsy. PMID- 28631050 TI - Analgesia nociception index (ani) monitoring in patients with thoracic paravertebral block: a randomized controlled study. AB - The goal of the study was to evaluate the effectiveness of analgesia nociception index (ANI) monitoring during intraoperative period for patients with thoracic paravertebral block (TPVB) undergoing breast surgery under general anesthesia. This prospective randomized trial was performed after receiving ethics committee approval in 44 patients who were scheduled to undergo breast surgery under general anesthesia. TPVB was performed in the preoperative period using 20 mL of bupivacaine 0.25% at T4 level. Anesthesia maintenance was provided with sevoflurane in O2: air mixture and remifentanil infusion. Intraoperative concentration of sevoflurane was adjusted according to BIS monitoring keeping the values between 40-60. In a randomized manner patients were divided into two groups. In Group control (n:22) intraoperative remifentanil infusion rate was regulated according to hemodynamic parameters, in Group ANI (n:22) remifentanil infusion rate was titrated to keep ANI monitoring values between 50-70. Total remifentanil consumption was recorded as micrograms. Demographic data, anesthesia and surgery time, intraoperative hemodynamic parameters, post-anesthesia recovery time and requirement of additional analgesic in the recovery drug were recorded. There were no significant difference in demographic data, intraoperative hemodynamic parameters, post-anesthesia recovery time and requirement of additional analgesic drug. There was a statistically significant difference between groups in total remifentanil consumption (Group ANI: 629.6 +/- 422.4 mcg, Group control: 965.2 +/- 543.6 mcg) (p = 0.027). In patients under general anesthesia ANI monitorisation can help optimisation of opioid consumption and provide data about nociception/antinociception intraoperatively but further experimental and clinical trials in a large scale are needed. PMID- 28631052 TI - Anatomic variations of the spleen: current state of terminology, classification, and embryological background. AB - A thorough understanding of the anatomy, physiology, and development of the spleen is essential for determining the pathophysiological mechanisms underpinning splenic diseases and congenital variations. The aim of this review is to briefly summarize current knowledge regarding the normal development of the spleen, and to provide an overview of clinically relevant congenital splenic variations. These include such variations as asplenia, polysplenia, hyposplenia, lobulation of spleen, accessory spleens, accessory splenic nodules, wandering spleen, splenogonadal and splenopancreatic fusion, splenic cysts, and cavernous haemangioma of the spleen. All of these congenital variations are also mentioned in internationally accepted embryological nomenclature, known as the Terminologia Embryologica. Interestingly, most patients who have these diseases are asymptomatic, and are often diagnosed only after an injury or during unrelated medical procedures. Using examples from published case reports, we highlight how an understanding of the embryology of the spleen and the etiology of its disease states would improve clinical practice. PMID- 28631053 TI - Characterization of an orf virus isolate from an outbreak in Heilongjiang province, China. AB - Contagious ecthyma, caused by orf virus (ORFV), is an epitheliotrophic contagious disease with zoonotic implications that mainly affects sheep, goats, wild ruminants, and humans. Recently, a novel ORFV strain, OV/HLJ/04, was successfully isolated from the skin and mucosal lesions of a goat with severe clinical sore mouth symptoms in Heilongjiang province of China. The OV/HLJ/04 isolate was characterized by electron microscopy, serological tests, and experimental reproduction of disease. The purified virions exhibited a typical ovoid shape when observed by electron microscopy. Moreover, experimental reproduction of disease showed that a lamb developed typical clinical signs of contagious ecthyma, such as severe vascular proliferation, when inoculated with the virus. Subsequently, amplification of ORFV011 (B2L) gene fragments of viral DNA by polymerase chain reaction (PCR) and gene sequencing were performed. Phylogenetic analysis of the B2L protein gene revealed that this strain clusters with ORFV strains from epidemic-stricken areas worldwide, including recent mainland China isolates. Analysis using ClustalW MegAlign in DNAStar indicated that OV/HLJ/04 (GenBank: KU523790.1) was genetically closely related to the isolates Gansu (JQ904789), with 99.7% identity; NZ2 (DQ184476), with 97.4% identity; and Xinjiang (KF666560), with 90.6% identity. These results may provide insights into the genotype of the etiological agent responsible for the orf outbreak in Heilongjiang Province. PMID- 28631055 TI - ? PMID- 28631054 TI - Adaptation of tick-borne encephalitis virus from human brain to different cell cultures induces multiple genomic substitutions. AB - The C11-13 strain from the Siberian subtype of tick-borne encephalitis virus (TBEV) was isolated from human brain using pig embryo kidney (PEK), 293, and Neuro-2a cells. Analysis of the complete viral genome of the C11-13 variants during six passages in these cells revealed that the cell-adapted C11-13 variants had multiple amino acid substitutions as compared to TBEV from human brain. Seven out of eight amino acids substitutions in the high-replicating C11-13(PEK) variant mapped to non-structural proteins; 13 out of 14 substitutions in the well replicating C11-13(293) variant, and all four substitutions in the low replicating C11-13(Neuro-2a) variant were also localized in non-structural proteins, predominantly in the NS2a (2), NS3 (6) and NS5 (3) proteins. The substitutions NS2a1067 (Asn -> Asp), NS2a1168(Leu -> Val) in the N-terminus of NS2a and NS31745(His -> Gln) in the helicase domain of NS3 were found in all selected variants. We postulate that multiple substitutions in the NS2a, NS3 and NS5 genes play a key role in adaptation of TBEV to different cells. PMID- 28631056 TI - [Granulomatous diseases of the skin : Always a special challenge]. PMID- 28631057 TI - Diabetes mellitus: a risk factor for seizures in the elderly-a population-based study. AB - AIMS: To evaluate the association between diabetes mellitus (DM) and risk of seizures in a well-defined elderly population. METHODS: The administrative databases of the Lombardy region (a 10 million population area in Northern Italy) were used to identify persons aged 65 years or older with DM (defined by prescription of antidiabetic drugs and/or through ICD-9 CM code and/or exemption code for diabetes) during the year 2002. Seizure-free DM subjects were followed until 2012 in search of individuals with incident seizures (identified through ICD-9 CM codes for epilepsy/seizures or ATC codes for antiepileptic drugs associated with the prescription of an electroencephalogram). To adjust for confounding, comorbidities having epileptogenic potential were also identified through the ICD-9 CM codes. RESULTS: The population at risk included 1,494,071 persons. Of these, 136,941 seizure-free patients had DM. At the end of follow-up, the cumulative time-dependent incidence of seizures was 3.0% in DM patients and 1.9% in No-diabetic individuals (hazard ratio, HR 1.47; 95% confidence interval, 1.41-1.53, adjusted for age classes, sex, comorbidities and number of hospital admission). The HR was unchanged in patients with no history of stroke. The cumulative incidence of seizures after DM increased with the number of hospital admissions. CONCLUSIONS: DM is an independent risk factor for seizures in elderly individuals. In diabetic patients, the risk of seizures increases with the number of comorbidities, supporting the role of vascular disease as a cause of seizures. PMID- 28631058 TI - Expression and Characterization of Glucose Oxidase from Aspergillus niger in Yarrowia lipolytica. AB - Glucose oxidase (GOX) is currently used in clinical, pharmaceutical, food and chemical industries. The aim of this study was expression and characterization of Aspergillus niger glucose oxidase gene in the yeast Yarrowia lipolytica. For the first time, the GOX gene of A. niger was successfully expressed in Y. lipolytica using a mono-integrative vector containing strong hybrid promoter and secretion signal. The highest total glucose oxidase activity was 370 U/L after 7 days of cultivation. An innovative method was used to cell wall disruption in current study, and it could be recommended to use for efficiently cell wall disruption of Y. lipolytica. Optimum pH and temperature for recombinant GOX activity were 5.5 and 37 degrees C, respectively. A single band with a molecular weight of 80 kDa similar to the native and pure form of A. niger GOX was observed for the recombinant GOX in SDS-PAGE analysis. Y. lipolytica is a suitable and efficient eukaryotic expression system to production of recombinant GOX in compered with other yeast expression systems and could be used to production of pure form of GOX for industrial applications. PMID- 28631059 TI - Trends in HIV Risk, Testing, and Treatment among MSM in Chicago 2004-2014: Implications for HIV Elimination Planning. AB - Men who have sex with men (MSM) in the USA continue to have high rates of HIV infection. Increasingly, in addition to behavioral factors, biomedical interventions have been found to play important roles in HIV prevention. In this analysis, we used four waves of cross-sectional data (2004, 2008, 2011, and 2014) from the National HIV Behavioral Surveillance System (NHBS) to examine trends in key behaviors and biomedical interventions among MSM in Chicago (N = 3298). Logistic regression was used to determine changes in behaviors and use of biomedical interventions. Condomless sex increased significantly in waves 3 and 4, compared to wave 1: wave 3 (AOR = 2.07; 95% CI 1.53, 2.78) and wave 4 (AOR = 2.19; 95% CI 1.62, 2.96). Compared to those aged 18-24, older participants were significantly less likely to be routinely tested for HIV: 30-39 (AOR = 0.63; 95% CI 0.48, 0.83), 40-49 (AOR = 0.40; 95% CI 0.29, 0.55), and >50 (AOR = 0.28; 95% CI 0.18, 0.43). Awareness of both post-exposure prophylaxis (PEP)(AOR = 3.13; 95% CI 1.22, 8.03) and pre-exposure prophylaxis (PrEP)(AOR = 10.02; 95% CI 2.95, 34.01) increased significantly in wave 4, compared to wave 3. These results suggest a potential increase in HIV rates among men with main and casual partners and should be monitored closely as PrEP becomes more widespread among MSM of all races and ethnicities in Chicago. This study also suggests that further analyses of the barriers to PEP and PreP uptake among high-risk populations are necessary. PMID- 28631062 TI - JHB as a Collaborative Effort. PMID- 28631060 TI - Estimating the Size of the MSM Population in Metro Vancouver, Canada, Using Multiple Methods and Diverse Data Sources. AB - Men who have sex with men (MSM) are disproportionately affected by HIV globally, regionally in Canada, and locally in Vancouver. Lack of reliable population size estimates of MSM impedes effective implementation of health care services and limits our understanding of the HIV epidemic. We estimated the population size of MSM residing in Metro Vancouver drawing on four data sources: the Canadian Community Health Survey (CCHS), a cross-sectional bio-behavioural MSM survey, HIV testing services data from sexually transmitted infection (STI) clinics serving MSM, and online social networking site Facebook. Estimates were calculated using (1) direct estimates from the CCHS, (2) "Wisdom of the Crowds" (WOTC), and (3) the multiplier method using data from a bio-behavioural MSM survey, clinic-based HIV testing, and online social media network site Facebook. Data sources requiring greater public disclosure of sexual orientation resulted in our mid range population estimates (Facebook 23,760, CCHS 30,605). The WOTC method produced the lowest estimate, 10,000. The multiplier method using STI clinic HIV testing data produced the largest estimate, 41,777. The median of all estimates was 27,183, representing 2.9% of the Metro Vancouver census male adult population, with an interquartile range of 1.1-4.5%. Using multiple data sources, our estimates of the MSM population in Metro Vancouver are similar to population prevalence estimates based on population data from other industrialized nations. These findings will support understanding of the HIV burden among MSM and corresponding public health and health services planning for this key population. PMID- 28631063 TI - Fundamentals of and Critical Issues in Lipid Autacoid Medicine: A Review. AB - The identification of a number of families of lipid signal molecules since the 1990s created new therapeutic possibilities for a great number of disorders characterized by chronic inflammation and pain. These lipid autacoids have been explored in a great variety of animal models related to inflammation, pain, (neuro-)protection, and repair. Based on the data from these models, as well as on a number of proof of principle studies in the clinic in indications such as neuropathic pain, a new chapter in medicine is about to begin. We would like to introduce the term "Autacoid Pain Medicine" for this chapter. There are, however, a number of methodological and strategic issues to overcome in this field. One of the roadblocks is related to patent strategies around families of these molecules. As this is not always recognized we will present a number of examples. PMID- 28631064 TI - Analysis of case-parent trios for imprinting effect using a loglinear model with adjustment for sex-of-parent-specific transmission ratio distortion. AB - Transmission ratio distortion (TRD) is a phenomenon where parental transmission of disease allele to the child does not follow the Mendelian inheritance ratio. TRD occurs in a sex-of-parent-specific or non-sex-of-parent-specific manner. An offset computed from the transmission probability of the minor allele in control trios can be added to the loglinear model to adjust for TRD. Adjusting the model removes the inflation in the genotype relative risk (RR) estimate and Type 1 error introduced by non-sex-of-parent-specific TRD. We now propose to further extend this model to estimate an imprinting parameter. Some evidence suggests that more than 1% of all mammalian genes are imprinted. In the presence of imprinting, for example, the offspring inheriting an over-transmitted disease allele from the parent with a higher expression level in a neighboring gene is over-represented in the sample. TRD mechanisms such as meiotic drive and gametic competition occur in a sex-of-parent-specific manner. Therefore, sex-of-parent specific TRD (ST) leads to over-representation of maternal or paternal alleles in the affected child. As a result, ST may bias the imprinting effect when present in the sample. We propose a sex-of-parent-specific transmission offset in adjusting the loglinear model to account for ST. This extended model restores the correct RR estimates for child and imprinting effects, adjusts for inflation in Type 1 error, and improves performance on sensitivity and specificity compared to the original model without ST offset. We conclude that to correctly interpret the association signal of an imprinting effect, adjustment for ST is necessary to ensure valid conclusions. PMID- 28631065 TI - Framework for Advancing the Reporting of Patient Engagement in Rheumatology Research Projects. AB - PURPOSE OF REVIEW: The term "patient engagement in research" refers to patients and their surrogates undertaking roles in the research process beyond those of study participants. This paper proposes a new framework for describing patient engagement in research, based on analysis of 30 publications related to patient engagement. RECENT FINDINGS: Over the past 15 years, patients' perspectives have been instrumental in broadening the scope of rheumatology research and outcome measurement, such as evaluating fatigue in rheumatoid arthritis. Recent reviews, however, highlight low-quality reporting of patient engagement in research. Until we have more detailed information about patient engagement in rheumatology research, our understanding of how patients' perspectives are being integrated into research projects remains limited. When authors follow our guidance on the important components for describing patients' roles and function as "research partners," researchers and other knowledge users will better understand how patients' perspectives were integrated in their research projects. PMID- 28631066 TI - Rheumatoid Vasculitis: A Diminishing Yet Devastating Menace. AB - PURPOSE OF REVIEW: Rheumatoid vasculitis (RV) is an unusual complication of long standing rheumatoid arthritis, which is characterized by the development of necrotizing or leukocytoclastic vasculitis involving small or medium-sized vessels. In this review, we aim to provide an update on the epidemiology, pathogenesis, clinical presentation, and management of this challenging extra articular manifestation. RECENT FINDINGS: RV is heterogenous in its clinical presentation depending on the organ and size of blood vessels involved. The most common organs involved are the skin and peripheral nerve. Based on recent population studies, the incidence has significantly decreased with early recognition and the advent of immunosuppressive drugs and biologics; however, the mortality rates remain high. RV remains a serious extra-articular manifestation of RA that needs to be promptly recognized and treated. No consensus is available on treatment, given the ongoing debate of whether the biologics can trigger or treat RV. PMID- 28631067 TI - Antibodies Against Complement Components: Relevance for the Antiphospholipid Syndrome-Biomarkers of the Disease and Biopharmaceuticals. AB - PURPOSE OF REVIEW: Laboratory criterion for the diagnosis of antiphospholipid syndrome (APS) is the presence of antiphospholipid antibodies (aPL Abs). Complement system has a role in mediating aPL Abs-induced thrombosis in animal models. The importance of antibodies against complement components (potential biomarkers of APS) and the importance of antibodies with beneficial anti complement effects in APS (as biopharmaceuticals) are reviewed. RECENT FINDINGS: Antibodies against complement components described in APS patients, so far, are anti-C1q and anti-factor H Abs, although anti-factor B Abs and anti-C5a Abs were described in animal models of APS. Clinical studies in APS patients are limited to a small number of case reports. Studies that would confirm potential role of Abs against complement components (as potential biomarkers of APS) are lacking. Lack of randomized clinical trials (that would provide complete data for confirmation of beneficial effects of biopharmaceuticals in complement inhibition) in APS is alarming. PMID- 28631068 TI - Autoinflammatory Diseases with Periodic Fevers. AB - PURPOSE OF REVIEW: One purpose of this review was to raise awareness for the new autoinflammatory syndromes. These diseases are increasingly recognized and are in the differential diagnosis of many disease states. We also aimed to review the latest recommendations for the diagnosis, management, and treatment of these patients. RECENT FINDINGS: Familial Mediterranean fever (FMF), cryopyrin associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), and hyperimmunoglobulinemia D and periodic fever syndrome/mevalonate kinase deficiency (HIDS/MVKD) are the more common autoinflammatory diseases that are characterized by periodic fevers and attacks of inflammation. Recently much collaborative work has been done to understand the characteristics of these patients and to develop recommendations to guide the physicians in the care of these patients. These recent recommendations will be summarized for all four diseases. FMF is the most common periodic fever disease. We need to further understand the pathogenesis and the role of single mutations in the disease. Recently, the management and treatment of the disease have been nicely reviewed. CAPS is another interesting disease associated with severe complications. Anti-interleukin-1 (anti-IL-1) treatment provides cure for these patients. TRAPS is characterized by the longest delay in diagnosis; thus, both pediatricians and internists should be aware of the characteristic features and the follow-up of these patients. HIDS/MVKD is another autoinflammatory diseases characterized with fever attacks. The spectrum of disease manifestation is rather large in this disease, and we need further research on biomarkers for the optimal management of these patients. PMID- 28631069 TI - [S2-Ala-iliac screws for extended pelvic fixation in longer lumbar instrumentations : Description of a freehand technique]. AB - OBJECTIVE: To reduce the rate of implant failures at the lumbosacral junction in polysegmental lumbar fusions. INDICATIONS: Spinal fusion with deformity correction including L5/S1, revision surgery for pseudoarthrosis L5/S1, screw pull-out and pedicle fractures in S1, and S1/S2 fractures after polysegmental fusions. CONTRAINDICATIONS: Osteosynthesis of complex pelvic ring fractures, tumors of the ilium. Relative contraindication: infection, to avoid contamination of the iliosacral joint. SURGICAL TECHNIQUE: Conventional posterior approach to the lumbar spine. Positioning of the lumbar and S1 pedicle screws in common technique. Identification of the correct entrance point for one or two S2-Ala iliac screws for each side and preparation of the drill holes in freehand technique. Connection of the lumbar and S1 pedicle screws and S2-Ala-iliac screws with one stress-free rod on each side without the use of connectors or special plates. POSTOPERATIVE MANAGEMENT: Back-friendly mobilization beginning on day 1 after surgery with support of a physiotherapist. No sports for 12 weeks. RESULTS: In all, 25 patients were treated with an extended pelvic fixation using S2-Ala iliac screws. A primary deformity correction was performed in 11 patients, whereas 14 patients underwent revision surgery. A total of 24 patients were clinically and radiologically followed for a mean of 16 months. Two patients showed a loosening of the S2-Ala-iliac screws on one side, and one patient had broken screw as well only on one side without clinical symptoms. So far, no patient has undergone revision surgery because of S2-Ala-iliac screw-associated complications. PMID- 28631070 TI - Lipids of the Tail Gland, Body and Muzzle Fur of the Red Fox, Vulpes vulpes. AB - The tail gland of the red fox (Vulpes vulpes) secretes lipids containing volatile terpenes used in social communication. We have analysed lipids extracted from fur of the tail gland, body (flanks) and muzzle of foxes. GC-MS showed a novel group of iso-valerate and tiglate monoesters of alkane-1,2-diols (C18:0-22:0). There was also a larger group of Type II diesters in which a second, longer chain, fatty acid (FA) was attached to the free alcohol group. LC-MS showed the full range of diol diesters, mostly C36:0-50:0, with smaller amounts of the corresponding mono-unsaturated tiglate esters. An additional group of diesters with higher MW (C49:0-62:0) containing two long-chain FA was present in the lipids of body and muzzle fur. After saponification and GC-MS, 98 fatty acids were characterized as their methyl esters. Apart from the C5 FA, most were saturated n-, iso-, anteiso- or other methyl-branched FA (C12:0-28:0) whose structures were determined by a combination of their mass spectra and Kovats retention indices. Several FA have not previously been found in nature or in vertebrates. Thirty-four alkane-1,2-diols were found as their TMS derivatives, mostly n-, iso- or anteiso-isomers of C16:0-25:0. The tail gland had the greatest amount of wax esters, from a greater variety of FA and diols, but lacked the esters with two long-chain FA. These findings show that fox skin lipids comprise mono- and di-esters of alkane-1,2-diols, and exhibit enormous complexity due to the diversity of their constituent FA, diols and the many possible isomers of their esters. PMID- 28631071 TI - Oxidation of C18 Hydroxy-Polyunsaturated Fatty Acids to Epoxide or Ketone by Catalase-Related Hemoproteins Activated with Iodosylbenzene. AB - Small catalase-related hemoproteins with a facility to react with fatty acid hydroperoxides were examined for their potential mono-oxygenase activity when activated using iodosylbenzene. The proteins tested were a Fusarium graminearum 41 kD catalase hemoprotein (Fg-cat, gene FGSG_02217), a Pseudomonas fluorescens Pfl01 catalase (37.5 kD, accession number WP_011333788.1), and a Mycobacterium avium ssp. paratuberculosis 33 kD catalase (gene MAP-2744c). 13-Hydroxy octadecenoic acids (which are normally unreactive) were selected as substrates because these enzymes react specifically with the corresponding 13S hydroperoxides (Pakhomova et al. 18:2559-2568, 5; Teder et al. 1862:706-715, 14). In the presence of iodosylbenzene Fg-cat converted 13S-hydroxy-fatty acids to two products: the 15,16-double bond of 13S-hydroxy alpha-linolenic acid was oxidized stereospecifically to the 15S,16R-cis-epoxide or the 13-hydroxyl was oxidized to the 13-ketone. Products were identified by UV, HPLC, LC-MS, NMR and by comparison with authentic standards prepared for this study. The Pfl01-cat displayed similar activity. MAP-2744c oxidized 13S-hydroxy-linoleic acid to the 13-ketone, and epoxidized the double bonds to form the 9,10-epoxy-13-hydroxy, 11,12-epoxy-13 hydroxy, and 9,10-epoxy-13-keto derivatives; equivalent transformations occurred with 9S-hydroxy-linoleic acid as substrate. In parallel incubations in the presence of iodosylbenzene, human catalase displayed no activity towards 13S hydroxy-linoleic acid, as expected from the highly restricted access to its active site. The results indicated that with suitable transformation to Compound I, monooxygenase activity can be demonstrated by these catalase-related hemoproteins with tyrosine as the proximal heme ligand. PMID- 28631072 TI - Down-regulation of soluble fms-like tyrosine kinase 1 expression in invasive placentation. AB - PURPOSE: To confirm reduced expression of soluble fms-like tyrosine kinase 1 (sFlt-1) in accreta/increta. METHODS: Formalin-fixed tissue sections from 11 peripartum hysterectomies with invasive placentation and 5 controls were stained for sFlt-1. Stain intensity was scored in selected 100* microscopic fields. We compared sFlt-1 expression in invasive areas among cases, non-invasive areas among cases and areas from control placentas. RESULTS: Chorionic villi displayed significantly decreased sFlt-1 expression in invasive areas of cases compared to control placentas (p = 0.003), as well as in non-invasive areas of cases compared to control placentas (p = 0.01). There was no difference in sFlt-1 expression between invasive and non-invasive areas among cases. CONCLUSIONS: Expression of sFlt-1 is diminished in villous trophoblasts from patients with placenta increta or percreta. Local depth of invasion was not associated with sFlt-1 expression, suggesting a more global abnormality across the implantation site rather than localized to areas of histologic invasion. PMID- 28631073 TI - Compartment syndrome after gynecologic laparoscopy: systematic review of the literature and establishment of normal values for postoperative serum creatine kinase and myoglobin levels. AB - PURPOSE: To evaluate published evidence in the literature on compartment syndrome (CS) in association with gynecologic surgery and to establish postoperative normal values for serum creatine kinase (CK) and myoglobin. METHODS: The present study consists of a case report of a patient with CS, a systematic review including 37 studies and 86 patients with CS, and a retrospective cohort study of 300 patients undergoing various types of laparoscopy for benign or malignant diseases in order to establish postoperative normal values. RESULTS: We report on a patient with early-stage ovarian cancer, who developed CS after laparoscopic surgery with massively elevated serum CK and myoglobin levels, i.e., 1109 U/L and 18151 ug/L, respectively. In our systematic review, median serum CK and myoglobin levels among women with CS were 19,223 (177-27,412) U/L and 1248 (285-1360) ug/L, respectively. In our cohort study, the median postoperative serum CK and myoglobin levels were 68 (14-1576) U/L and 45 (14-1040) ug/L, respectively. The 95th and 99th percentile of serum CK and myoglobin levels were 158 and 391.5 U/L, and 152.3 and 298.9 ug/L, respectively. CONCLUSION: Markedly elevated postoperative serum levels of CK and myoglobin levels might raise the suspicion for CS and could therefore aid in the rapid diagnosis of CS. PMID- 28631074 TI - No difference in mitochondrial distribution is observed in human oocytes after cryopreservation. AB - PURPOSE: The primary aim of this study was to determine if any difference in mitochondrial distribution can be observed between fresh and cryopreserved (slow frozen/thawed and vitrified/warmed) oocytes when oocytes are stained with Mitotracker Red CMXRos and observed under a conventional fluorescent microscope. Additionally, the influence of cryopreservation procedure on the viable rates of oocytes at different maturation stages was evaluated. METHODS: The germinal vesicle (GV) and MII oocytes were cryopreserved with slow-freezing and vitrification. After thawing/warming, oocytes were stained using Mitotracker Red CMXRos and observed under a conventional fluorescent microscope. RESULTS: Mitotracker staining revealed that in GV oocytes the pattern of mitochondrial distribution appeared as aggregated clusters around the whole oocyte. In mature MII oocytes, three different patterns of mitochondrial distribution were observed; a smooth pattern around the polar body with aggregated clusters at the opposite side of the polar body, a smooth pattern throughout the whole cell, and aggregated clusters as can be seen in GV oocytes. There were no significant differences in the observed patterns between fresh, vitrified/warmed and frozen/thawed oocytes. When comparing the viable rates of oocytes after two different cryopreservation procedures, the results showed no significant differences, although the trend of viable MII oocytes tends to be higher after vitrification/warming and for viable GV oocytes it tends to be higher after slow freezing/thawing. CONCLUSIONS: Mitotracker Red CMXRos staining of mitochondria in oocytes did not reveal differences in mitochondrial distribution between fresh and cryopreserved oocytes at different maturity stages. Additionally, no difference was observed in the viable rates of GV and MII oocytes after slow freezing/thawing and vitrification/warming. PMID- 28631075 TI - Measurement and evaluation of fetal fat layer in the prediction of fetal macrosomia in pregnancies complicated by gestational diabetes. AB - OBJECTIVES: To explore the predictive power of measuring the abdominal fetal fat layer (FFL) as a soft tissue marker at 31, 34, and 37 weeks' gestation to improve the detection of fetal macrosomia in pregnant women with GDM, in addition to the biometric values with close monitoring of maternal blood sugar level and BMI changes. METHODS: We conducted a prospective observational study at the Department of Obstetrics, University Hospitals, Campus Kiel, Germany, in collaboration with diabetic clinic staff. Participants underwent a third trimester scan and extra FFL measurements were performed at 31, 34, and 37 weeks of gestation. The clinical outcomes of pregnancy and birth weight were collected from the obstetric record. All of the enrolled women had an early pregnancy ultrasound scan to confirm gestational age. RESULTS: The FFL at 34 and 37 weeks, with respective cutoff values of >0.48 cm and >0.59 cm, showed a very good sensitivity of 60% for both gestational points, and specificity of 89.3 and 90.6%, respectively. The probability of fetal macrosomia could be more than doubled if the FFL at 34 weeks was more than 0.48 cm. However, the probability of macrosomia dropped to 16% if the FFL was <=0.48 cm. The median FFLs of macrosomic fetuses at 34 and 37 weeks were 0.50 (IQR 0.10) and 0.60 (IQR 0.25) cm, respectively. The mean age of the study population (n = 80) was 32.26 (SD = 5.06) years. In our study population, ten newborns were born with birth weight >4000 g. The body mass index (BMI) for the mothers of later-onset macrosomic newborns showed higher median values of 30 (IQR 8), 32 (IQR 5), and 33 (IQR 9) at 31, 34, and 37 weeks, respectively, in comparison to mothers of non-macrosomic newborn. However, the BMI did not show any statistically significant difference from those with normal-weight newborn and did not show any specific sensitivity for predicting macrosomia. CONCLUSION: Measuring the FFL at 34 and 37 weeks of gestation, in addition to the standard measurement, might be useful for predicting macrosomia and is worth further evaluation. PMID- 28631076 TI - Effects of Glycyrrhizic Acid on the Pharmacokinetics of Pristimerin in Rats and its Potential Mechanism. AB - BACKGROUND AND OBJECTIVES: Pristimerin has been reported to possess a wide range of pharmacological activities. This study investigates the effects of glycyrrhizic acid on the pharmacokinetics of pristimerin in rats. METHODS: The pharmacokinetics of orally administered pristimerin (2 mg/kg) with or without glycyrrhizic acid pretreatment (at a dose of 100 mg/kg/day for 7 days) were investigated. The plasma concentration of pristimerin was determined using a sensitive and reliable LC-MS/MS method, and the pharmacokinetics profiles were calculated and compared. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism. RESULTS: The results showed that when the rats were pretreated with glycyrrhizic acid, the maximum concentration (C max) of pristimerin decreased from 186.43 +/- 14.18 to 124.62 +/- 18.49 ng/mL, and area under the concentration time curve from zero to infinity (AUC0-inf) also decreased from 918.54 +/- 144.72 to 504.72 +/- 115.63 MUg.h/L. The elimination half-life (t 1/2) value of pristimerin decreased from 3.16 +/- 1.18 to 1.88 +/- 0.76 h (P < 0.05). The Caco 2 cell transwell experiments indicated that glycyrrhizic acid could increase the efflux ratio of pristimerin from 2.39 to 3.64, and the rat liver microsome incubation experiments showed that glycyrrhizic acid could significantly increase its intrinsic clearance rate from 51.87 +/- 5.34 to 76.79 +/- 8.52 uL/min/mg protein. CONCLUSIONS: In conclusion, these results indicated that glycyrrhizic acid could affect the pharmacokinetics of pristimerin, and it might work through decreasing the absorption of pristimerin by inducing the activity of P-gp or through increasing the clearance rate in rat liver by inducing the activity of cytochrome P450 enzyme. PMID- 28631077 TI - Noninvasive evaluation of reverse atrial remodeling after catheter ablation of atrial fibrillation by P wave dispersion. AB - Atrial fibrillation (AF) itself creates structural and electrophysiological changes such as atrial enlargement, shortening of refractory period and decrease in conduction velocity, called "atrial remodeling", promoting its persistence. Although the remodeling process is considered to be reversible, it has not been elucidated in detail. The aim of this study was to assess the feasibility of P wave dispersion in the assessment of reverse atrial remodeling following catheter ablation of AF. Consecutive 126 patients (88 males, age 63.0 +/- 10.4 years) who underwent catheter ablation for paroxysmal AF were investigated. P wave dispersion was calculated from the 12 lead ECG before, 1 day, 1 month, 3 months and 6 months after the procedure. Left atrial diameter (LAD), left atrial volume index (LAVI), left ventricular ejection fraction (LVEF), transmitral flow velocity waveform (E/A), and tissue Doppler (E/e') on echocardiography, plasma B type natriuretic peptide (BNP) concentrations, serum creatinine, and estimated glomerular filtration rate (eGFR) were also measured. Of all patients, 103 subjects remained free of AF for 1 year follow-up. In these patients, P wave dispersion was not changed 1 day and 1 month after the procedure. However, it was significantly decreased at 3 and 6 months (50.1 +/- 14.8 to 45.4 +/- 14.4 ms, p < 0.05, 45.2 +/- 9.9 ms, p < 0.05, respectively). Plasma BNP concentrations, LAD and LAVI were decreased (81.1 +/- 103.8 to 44.8 +/- 38.3 pg/mL, p < 0.05, 38.2 +/ 5.7 to 35.9 +/- 5.6 mm, p < 0.05, 33.3 +/- 14.2 to 29.3 +/- 12.3 mL/m2, p < 0.05) at 6 months after the procedure. There were no significant changes in LVEF, E/A, E/e', serum creatinine, and eGFR during the follow up period. P wave dispersion was decreased at 3 and 6 months after catheter ablation in patients without recurrence of AF. P wave dispersion is useful for assessment of reverse remodeling after catheter ablation of AF. PMID- 28631078 TI - Evaluation of the association between sleep apnea and polyunsaturated fatty acids profiles in patients after percutaneous coronary intervention. AB - The long-term outcome is poor in patients with sleep apnea and cardiovascular disease. Polyunsaturated fatty acid (PUFA) is also known as an independent predictor for adverse clinical events. However, the profile of PUFA in sleep apnea patients with coronary artery disease (CAD) is still unclear. This study aimed to clarify the association between sleep apnea and PUFA profiles in patients with CAD. Two hundred seventy-four consecutive patients undergoing percutaneous coronary intervention (PCI) were screened for sleep apnea using nocturnal oximetry. Oxygen desaturation index down to 4% (4%ODI) >=5 was used as an indicator of sleep apnea. Baseline characteristics, including PUFA profiles, were compared between patients with and without sleep apnea. Among 243 enrolled patients, 134 (55%) had sleep apnea. The sleep apnea group included a significantly higher rate of patients with obesity, insulin-requiring diabetes, peripheral artery disease (PAD), and a higher C-reactive protein level than the non-sleep apnea group. The sleep apnea group had a significantly lower eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio than the non-sleep apnea group (0.33 vs. 0.44, respectively, p = 0.024). Additionally, EPA value and EPA/AA ratio were significantly correlated with 4%ODI (r = -0.15, p = 0.028; r = 0.16, p = 0.019, respectively). Results of logistic regression analysis indicated that the comorbidities of obesity, PAD, heart failure and EPA/AA ratio had a significant association with sleep apnea. Our results suggested that patients with sleep apnea who underwent PCI had a lower EPA/AA ratio than those without sleep apnea, and EPA value and EPA/AA ratio were significantly correlated with 4%ODI. PMID- 28631079 TI - Development of pancreatic cancer is predictable well in advance using contrast enhanced CT: a case-cohort study. AB - OBJECTIVES: To investigate the radiological findings prognostic for the development of pancreatic adenocarcinoma in a cohort of patients with hepatocellular carcinoma, using multiphasic computed tomography (CT). METHODS: A case-cohort study performed in a single university hospital. A database of patients who received hepatocellular carcinoma (HCC) treatment and trimonthly follow-up with four-phase dynamic CT was used (n = 1848). The cohort group was randomly extracted from the database (n = 103). The case group comprised nine patients from the database who developed pancreatic adenocarcinoma. The radiological findings were assessed during follow-up (average, 32 months). RESULTS: The incidence of pancreatic mass, inhomogeneous parenchyma, loss of fatty marbling and main pancreatic duct dilatation gradually increased from 4 to 13 months before the diagnosis of pancreatic adenocarcinoma. There was a significantly higher incidence of pancreatic mass, inhomogeneous parenchyma and loss of fatty marbling on CT at baseline (average, 34 months before diagnosis) in the case group compared with the cohort group (P values < 0.01) and those findings at baseline were revealed as prognostic factors for pancreatic carcinogenesis, respectively (log-rank test, P values < 0.001). CONCLUSIONS: Several radiological findings observed on multiphasic CT can assist in predicting pancreatic carcinogenesis well in advance. KEY POINTS: * Pancreatic findings in multiphasic CT help predict development of pancreatic adenocarcinoma. * Key findings are mass, inhomogeneous parenchyma and loss of fatty marbling. * Those findings were observed 34 months before confirmed diagnosis of adenocarcinoma. * Those findings were prognostic factors for pancreatic carcinogenesis. PMID- 28631080 TI - Comparison of volumetric and functional parameters in simultaneous cardiac PET/MR: feasibility of volumetric assessment with residual activity from prior PET/CT. AB - OBJECTIVE: To compare cardiac left ventricular (LV) parameters in simultaneously acquired hybrid fluorine-18-fluorodeoxyglucose ([18F] FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with residual tracer activity of upstream PET/CT. METHODS: Twenty-nine patients (23 men, age 58+/-17 years) underwent cardiac PET/MRI either directly after a non-cardiac PET/CT with homogenous cardiac [18F] FDG uptake (n=20) or for viability assessment (n=9). Gated cardiac [18F] FDG PET and cine MR sequences were acquired simultaneously and evaluated blinded to the cross-imaging results. Image quality (IQ), end diastolic (LVEDV), end-systolic volume (LVESV), ejection fraction (LVEF) and myocardial mass (LVMM) were measured. Pearson correlation and intraclass correlation coefficient (ICC), regression and a Bland-Altman analysis were assessed. RESULTS: Except LVMM, volumetric and functional LV parameters demonstrated high correlations (LVESV: r=0.97, LVEDV: r=0.95, LVEF: r=0.91, LVMM: r=0.87, each p<0.05), but wide limits of agreement (LOA) for LVEDV (-25.3 82.5ml); LVESV (-33.1-72.7ml); LVEF (-18.9-14.8%) and LVMM (-78.2-43.2g). Intra- and interobserver reliability were very high (ICC>=0.95) for all parameters, except for MR-LVEF (ICC=0.87). PET-IQ (0-3) was high (mean: 2.2+/-0.9) with significant influence on LVMM calculations only. CONCLUSION: In simultaneously acquired cardiac PET/MRI data, LVEDV, LVESV and LVEF show good agreement. However, the agreement seems to be limited if cardiac PET/MRI follows PET/CT and only the residual activity is used. KEY POINTS: * [ 18 F] FDG PET-MRI is feasible with residual [ 18 F] FDG activity in patients with homogenous cardiac uptake. * Cardiac volumes and function assessed by PET/MRI show good agreement. * LVEDV and LVESV are underestimated; PET overestimates LVMM and LVEF. * Cardiac PET and MRI data correlate better when acquired simultaneously than sequentially. * PET and MRI should not assess LV parameters interchangeably. PMID- 28631082 TI - Abstracts from the ASENT 19th Annual Meeting. PMID- 28631081 TI - Diffusion-weighted imaging versus contrast-enhanced MR imaging for the differentiation of renal oncocytomas and chromophobe renal cell carcinomas. AB - OBJECTIVES: To compare the performance of diffusion-weighted imaging (DWI) with that of contrast-enhanced MRI in differentiating renal oncocytomas from chromophobe renal cell carcinomas (RCCs). METHODS: We recruited 48 patients with histopathologically confirmed renal oncocytomas (n=16) and chromophobe RCCs (n=32). All patients underwent preoperative DWI and contrast-enhanced MRI. Apparent diffusion coefficient (ADC) and signal intensity were measured in each patient. ADC ratio and percentage of signal intensity change were calculated. RESULTS: Mean ADC values for renal oncoctytomas were significantly higher than those for chromophobe RCCs (1.59+/-0.21 vs. 1.09+/-0.29* 10-3 mm2/s, p < 0.001). Area under the ROC curve, sensitivity and specificity were 0.931, 87.5% and 84.4%, respectively, for ADC measurement of DW imaging; 0.825, 87.5% and 75%, respectively, for enhancement ratio (p > 0.05). Adding ADC values to the enhancement ratios in the ROC, analysis to differentiate renal oncocytoma from chromophobe RCCs increased specificity from 75 to 87.5% at 87.5% sensitivity without significantly increasing the AUC (0.930). CONCLUSIONS: Both DWI and contrast-enhanced MRI may assist in differentiating renal oncocytomas from chromophobe RCCs, with DWI showing higher diagnostic value. The combination of the two parameters could potentially provide better performance in distinguishing these two tumours. KEY POINTS: * ADC values can assist in differentiating renal oncocytomas from chromophobe RCCs. * DW imaging possesses better specificity than does contrast-enhanced MR imaging. * Combining the two parameters provides higher specificity regarding the differential diagnosis. PMID- 28631083 TI - Is there a relationship between serum ox-LDL, oxidative stress, and PON1 in knee osteoarthritis? AB - Previous in vitro studies have shown that oxidized low-density lipoprotein (ox LDL) plays a role in the pathogenesis of osteoarthritis (OA). Paraoxonase-1 (PON1) protects both low-density lipoproteins (LDLs) and high-density lipoprotein (HDLs) against oxidative damage from circulating cells. In addition, PON1 is inactivated by ox-LDL and preserved by antioxidants. However, the relationship between serum ox-LDL, oxidative stress, and PON1 in knee OA remains unclear. Therefore, we investigated ox-LDL association with oxidative stress and PON1 in knee OA, and evaluated their relationships using radiological and clinical parameters. This study included 203 patients and 194 controls. The severity of OA was classified based on the Kellgren-Lawrence scoring system. In addition, each patient was clinically evaluated using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score. Plasma concentrations of ox-LDL, oxidative stress markers, and PON1 were measured. Serum ox-LDL and oxidant parameters were significantly higher in patients compared to controls (p < 0.001 for all), whereas PON1 was significantly lower (p < 0.001). ox-LDL was inversely correlated with PON1, whereas it was positively correlated with radiographic severity, WOMAC score, and oxidant parameters. We found an association between the levels of various serum markers of oxidative injury, especially ox-LDL, and increasing severity of knee OA, as well as indirect evidence for their regulation by PON1. oxLDL seems to play a critical role in OA, both in the beginning, and during progression of, the disease. Therefore, serum oxLDL levels may be a helpful biomarker to evaluate the severity of knee OA. PMID- 28631084 TI - NLRP3 Inflammasome in Inflammatory Bowel Disease: Friend or Foe? PMID- 28631085 TI - Racial Disparities in Clinical Presentation and Survival Times Among Young-Onset Colorectal Adenocarcinoma. AB - BACKGROUND: Recently published data indicate increasing incidence of colorectal adenocarcinoma (CRC) in young-onset (<50 years) patients. AIMS: This study examines racial disparities in presentation and survival times among non-Hispanic Blacks (NHB) and Hispanics compared with non-Hispanic Whites (NHW). METHODS: A retrospective single-center cohort study was conducted from 2004 through 2014 using 96 patient medical charts with a diagnosis of young-onset CRC. Age, gender, primary site, and histological stage at the time of diagnosis were assessed for survival probabilities by racial group over a minimum follow-up period of 5 years. RESULTS: Among subjects with CRC diagnosis before 50 years of age, the majority of subjects were between 40 and 50 years, with CRC presentation occurring among this age group for 51 (79.7%) of NHW, 18 (81.8%) of NHB, and 5 (50.0%) of Hispanics. The majority of all patients presented with advanced stages of CRC (31.3% with stage III and 27.1% with stage IV). NHB exhibited statistically significantly worse survival compared to NHW (adjusted hazard ratio for death = 2.09; 95% confidence interval 1.14-3.84; P = 0.02). A possible trend of worse survival was identified for Hispanics compared to NHW, but this group was low in numbers and results were not statistically significant. CONCLUSION: Disparities between racial groups among young-onset CRC cases were identified in overall survival and reflect growing concern in rising incidence and differentiated care management. PMID- 28631087 TI - Molar incisor hypomineralization: proportion and severity in primary public school children in Graz, Austria. AB - OBJECTIVE: The aim of this study was to determine the proportion and severity of molar incisor hypomineralization (MIH) in primary school children in Graz (southeast of Austria). MATERIALS AND METHODS: In 1111 children aged 6 to 12 years (mean age 9.0 +/- 1.2), a wet examination of all teeth was performed by three trained examiners using a dental chair, optimal illumination, a dental mirror, and a dental explorer. All teeth with MIH lesions were registered so that different definitions of MIH were applicable. According to the European Academy of Pediatric Dentistry criteria that were considered valid at the time of the investigation, MIH was diagnosed when at least one first primary molar (FPM) was affected. RESULTS: MIH was present in 78 children (7.0%). In 64 children (5.8%), at least one molar and one incisor were affected (so-called M + IH). Additionally, in 9 children, only incisors were affected. In 7 affected children, teeth other than FPMs and incisors had MIH lesions. Almost an equal number of males (38) and females (40) were affected. The upper and lower molars were equally affected. The upper incisors were more frequently affected than the lower ones. Demarcated enamel opacities were the predominant types of defects. CONCLUSION: The proportion of MIH was 7.0% in Graz, which is similar to other comparable trials. CLINICAL RELEVANCE: This study has proven that MIH is an existing dental problem in Graz. PMID- 28631086 TI - Nearly a Third of High-Grade Dysplasia and Colorectal Cancer Is Undetected in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: It is unclear whether intensive surveillance protocols have resulted in a decreased incidence of colorectal cancer (CRC) in inflammatory bowel disease (IBD). AIMS: To determine the prevalence and characteristics of IBD associated high-grade dysplasia (HGD) or CRC that was undetected on prior colonoscopy. METHODS: This is a single-center, retrospective study from 1994 to 2013. All participants had a confirmed IBD diagnosis and underwent a colectomy with either HGD or CRC found in the colectomy specimen.The undetected group had no HGD or CRC on prior colonoscopies. The detected group had HGD or CRC identified on previous biopsies. RESULTS: Of 70 participants, with ulcerative colitis (UC) (n = 47), Crohn's disease (CD) (n = 21), and indeterminate colitis (n = 2), 29% (n = 20) had undetected HGD/CRC at colectomy (15 HGD and 5 CRC). In the undetected group, 75% had prior LGD, 15% had indefinite dysplasia, and 10% had no dysplasia (HGD was found in colonic strictures). Patients in the undetected group were more likely to have pancolitis (55 vs. 20%) and multifocal dysplasia (35 vs. 8%). The undetected group was less likely to have CRC at colectomy (25 vs. 62%). There was a trend toward right-sided HGD/CRC at colectomy (40 vs. 20%; p = 0.08). In addition, 84% of the lesions found in the rectum at colectomy were not seen on prior colonoscopy in the undetected group. CONCLUSIONS: The prevalence of previously undetected HGD/CRC in IBD found at colectomy was 29%. The high proportion of undetected rectal and right-sided HGD/CRC suggests that these areas may need greater attention during surveillance. PMID- 28631088 TI - Etiologies, diagnostic work-up and outcomes of acute respiratory distress syndrome with no common risk factor: a prospective multicenter study. AB - BACKGROUND: Patients meeting the Berlin definition for the acute respiratory distress syndrome (ARDS) might lack exposure to one or more "common" risk factors and exhibit different clinical phenotype and outcomes. We aimed to compare the clinical presentation and outcome of ARDS patients with or without risk factors, the impact on hospital mortality, and to assess the diagnostic work-up performed. The current study is an ancillary analysis of an international, multicenter, prospective cohort study (the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure, LUNG SAFE). Patients meeting ARDS criteria within 2 days of acute hypoxemic respiratory failure onset were included in the study and categorized as having risk factors or not. Outcomes were compared using propensity score matching. RESULTS: Among 2813 patients, 234 (8.3% [7.3-9.3]) had no ARDS risk factor identified. These were older, had more frequent chronic diseases and presented with less severe SOFA and non-pulmonary SOFA scores (p < 0.001). Compared to other ARDS, CT scan (32.1 vs 23.9%, p < 0.001) and open lung biopsy (2.6 vs 0.2%, p < 0.001) were slightly more frequent but left heart filling pressures assessment was not (69.4 vs 68.4%, p > 0.99). Among ARDS with no risk factor, 45 patients (19.2%) had a specific diagnosis made. As compared to others, patients having ARDS with no risk factor had a lower ICU but not hospital mortality (34.6 vs 40.0%; p = 0.12). A matched cohort analysis confirmed the lack of significant difference in mortality. CONCLUSION: Eight percent of ARDS patients have no identified risk factor, 80% of whom have no etiological diagnosis made. The outcome of ARDS with no risk factor was comparable to other ARDS but few had a comprehensive diagnostic work-up, potentially leading to missed curable diseases. Trial registration clinicaltrials.gov Identifier: NCT02010073. PMID- 28631090 TI - Subclinical cutaneous inflammation remained after permeability barrier disruption enhances UV sensitivity by altering ER stress responses and topical pseudoceramide prevents them. AB - Stratum corneum forms the UV barrier. The effect of ultraviolet B (UVB) on normal skin was extensively studied; however, its effect on barrier perturbed skin remains undefined. Both barrier perturbation and UVB irradiation induce endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in keratinocytes. Mild ER stress activates homeostatic UPR, while severe ER stress leads to abnormal UPR, promoting apoptosis and inflammation. Here, we investigated UV sensitivity and UVB-induced UPR in barrier-disrupted human skin and the effects of pseudoceramide-dominant emollient on UVB-induced skin responses. Tape-stripped skin of healthy volunteers showed enhanced susceptibility to erythema and augmented proinflammatory cytokines induction following suberythemal UVB irradiation. Suberythemal UVB activated XBP1 in normal skin, while increased CHOP transcription in barrier perturbed skin. After tape stripping, pseudoceramide-dominant emollient was applied for 3 days, and then, the areas were irradiated with suberythemal UVB. Pretreatment with topical pseudoceramide protected against UVB-induced upregulation of IL-1beta, IL-6, and TNF-alpha transcription and reduced susceptibility to erythema following UVB. Topical pseudoceramide also suppressed suberythemal UVB-induced CHOP transcription in barrier-disrupted skin. Taken together, these data indicate that permeability barrier disruption increases UV sensitivity in human skin, partly via switch the UVB-induced UPR, from homeostatic signals to pro-apoptotic and proinflammatory signals. In addition, we conclude that pseudoceramide-dominant emollient suppresses excessive ER stress induction and CHOP activation following UVB in barrier damaged skin, providing evidence that pseudoceramide-dominant emollients can be promising strategies for photoprotection of the barrier damaged skin. PMID- 28631091 TI - The role of microbiota, and probiotics and prebiotics in skin health. AB - During the past decade, scientists have made great strides in understanding the microbiome's role in human health. Today, the microbiome has become key in scientific research, therapeutic development, medical treatment, and as a news feature in the media. Most studies have focused on the microbiome of our gut, but recently researchers have turned their attention to other microbiomes, including that of the skin. These studies of gut and skin microbiomes are yielding very informative results, new treatment strategies, and the development of new prebiotic and probiotic products for the treatment of many skin conditions. PMID- 28631089 TI - Targeted temperature management in the ICU: guidelines from a French expert panel. AB - Over the recent period, the use of induced hypothermia has gained an increasing interest for critically ill patients, in particular in brain-injured patients. The term "targeted temperature management" (TTM) has now emerged as the most appropriate when referring to interventions used to reach and maintain a specific level temperature for each individual. TTM may be used to prevent fever, to maintain normothermia, or to lower core temperature. This treatment is widely used in intensive care units, mostly as a primary neuroprotective method. Indications are, however, associated with variable levels of evidence based on inhomogeneous or even contradictory literature. Our aim was to conduct a systematic analysis of the published data in order to provide guidelines. We present herein recommendations for the use of TTM in adult and paediatric critically ill patients developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. These guidelines were conducted by a group of experts from the French Intensive Care Society (Societe de Reanimation de Langue Francaise [SRLF]) and the French Society of Anesthesia and Intensive Care Medicine (Societe Francaise d'Anesthesie Reanimation [SFAR]) with the participation of the French Emergency Medicine Association (Societe Francaise de Medecine d'Urgence [SFMU]), the French Group for Pediatric Intensive Care and Emergencies (Groupe Francophone de Reanimation et Urgences Pediatriques [GFRUP]), the French National Association of Neuro-Anesthesiology and Critical Care (Association Nationale de Neuro-Anesthesie Reanimation Francaise [ANARLF]), and the French Neurovascular Society (Societe Francaise Neurovasculaire [SFNV]). Fifteen experts and two coordinators agreed to consider questions concerning TTM and its practical implementation in five clinical situations: cardiac arrest, traumatic brain injury, stroke, other brain injuries, and shock. This resulted in 30 recommendations: 3 recommendations were strong (Grade 1), 13 were weak (Grade 2), and 14 were experts' opinions. After two rounds of rating and various amendments, a strong agreement from voting participants was obtained for all 30 (100%) recommendations, which are exposed in the present article. PMID- 28631092 TI - Rituximab treatment in pemphigus vulgaris: effect on circulating Tregs. AB - Rituximab (RTX) has been used successfully to treat refractory pemphigus. We aimed to assess the response of pemphigus vulgaris (PV) cases to RTX therapy and its effect on CD4+CD25+ (T regulatory) cells level. Sixteen PV patients were included in this study, each received one cycle of two RTX infusions (1000 mg on days 1 and 15). Five PV patients served as controls. All cases were on prednisolone +/- adjuvant therapy. Pemphigus disease area index (PDAI), autoimmune bullous skin intensity score (ABSIS), anti-desmoglein antibodies, CD4, CD8, CD20 and CD4+CD25+ levels were assessed at baseline, 3, 6 and 12 months after therapy. Fourteen patients were followed up for a mean duration of 17 while two were lost to follow up 6 months after RTX therapy. A significant decrease in PDAI, ABSIS, Dsg3 (p < 0.0001) was found. The depletion of B cells lasted for 12 months in 11 (69%) patients and for 24 months in 3 (21.4%) patients. There was significant decrease in CD20+ and CD4+CD25+ cells after 12 months of RTX, p values were 0.005 and 0.02, respectively. While no similar change in CD8 and CD4 was found (p = 0.2 for both), no significant change of CD20 and CD4+CD25+ cells were detected in the control group. In conclusion RTX is safe and effective as an adjuvant therapy in refractory cases of PV. In addition to B cell depletion a significant reduction of T regulatory cells occurs in treated cases which may be due to increased skin homing of these cells. PMID- 28631093 TI - Myelin regulatory factor drives remyelination in multiple sclerosis. AB - Remyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) is essential for myelination during development, but its role during remyelination and expression in MS lesions is unknown. To understand the role of MYRF during remyelination, we genetically fate mapped OPCs following lysolecithin induced demyelination of the corpus callosum in mice and determined that MYRF is expressed in new oligodendrocytes. OPC-specific Myrf deletion did not alter recruitment or proliferation of these cells after demyelination, but decreased the density of new glutathione S-transferase pi positive oligodendrocytes. Subsequent remyelination in both the spinal cord and corpus callosum is highly impaired following Myrf deletion from OPCs. Individual OPC-derived oligodendrocytes, produced in response to demyelination, showed little capacity to express myelin proteins following Myrf deletion. Collectively, these data demonstrate a crucial role of MYRF in the transition of oligodendrocytes from a premyelinating to a myelinating phenotype during remyelination. In the human brain, we find that MYRF is expressed in NogoA and CNP-positive oligodendrocytes. In MS, there was both a lower density and proportion of oligodendrocyte lineage cells and NogoA+ oligodendrocytes expressing MYRF in chronically demyelinated lesions compared to remyelinated shadow plaques. The relative scarcity of oligodendrocyte lineage cells expressing MYRF in demyelinated MS lesions demonstrates, for the first time, that chronic lesions lack oligodendrocytes that express this necessary transcription factor for remyelination and supports the notion that a failure to fully differentiate underlies remyelination failure. PMID- 28631094 TI - Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer's disease-like pathologies and cognitive deficits. AB - The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 * Tg-AD, APP +/- /PS1 +/-). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Abeta load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets. PMID- 28631096 TI - A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event. AB - Anti-programmed cell death-1 (PD-1) monoclonal antibodies, such as nivolumab, used for the treatment of several tumors, can trigger effector T-cells against tumor- and self-antigens, leading to the occurrence of different immune-related adverse events. Among them, liver injuries are rare and usually transient. To date, only four cases of immune-related cholangitis in non-small cell lung cancer (NSCLC) patients have been described during nivolumab treatment. Here, we describe laboratory tests, imaging and liver biopsy features that confirm this diagnosis as opposed to other forms of autoimmune liver disease; nevertheless, we also provide evidence of the presence of different clinical-pathological patterns of immune-related cholangitis. PMID- 28631095 TI - Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin 1. AB - The availability of effective medication for the treatment of refractory or recurrent neuroblastoma remains limited. This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained positive for DCN, SPARC and stabilin-1 respectively and correlated to age, stage and N-MYC status in 96 children and adolescents with neuroblastoma. Transfected neuroblastoma cells stably expressed DCN, with in vivo and in vitro studies demonstrating rAAV-DCN sensitized the anticancer effect of nab-paclitaxel. Systemic rAAV-DCN in neuroblastoma-grafted nude mice inhibited stabilin-1, up-regulated SPARC, and increased the intratumoral uptake of paclitaxel. Macrophage depletion or anti-stabilin-1 monoclonal antibody increased the intratumoral uptake of nab-paclitaxel and its anticancer effects to a degree comparable to that achieved by systemic rAAV-DCN. The systemic administration of rAAV-DCN up-regulates DCN in neuroblastoma and accelerates the intratumoral uptake of nab-paclitaxel by inhibiting stabilin-1 mediated SPARC degradation. PMID- 28631097 TI - Phase II study of Amrubicin monotherapy in elderly or poor-risk patients with extensive disease of small cell lung cancer. AB - Background Previous study indicated that an optional anti-cancer drug for the treatment of small-cell lung cancer (SCLC) is amrubicin. However, no prospective studies have evaluated amrubicin in chemo-naive elderly or poor-risk patients with SCLC. Therefore, this study aimed to evaluate the efficacy of amrubicin as first-line chemotherapy for elderly or poor-risk patients with extensive-disease SCLC (ES-SCLC). Methods Patients with chemotherapy-naive ES-SCLC received multiple cycles of 40 mg/m2 amrubicin for 3 consecutive days every 21 days. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results Between March 2011 and August 2015, 36 patients were enrolled in this study. Each patient received a median of four treatment cycles (range, 1-6 cycles). ORR was 52.8% [95% confidence interval (CI), 37-69%]. The median PFS and OS periods were 5.0 months (95% CI, 3.4-6.6 months) and 9.4 months (95% CI, 5.2-13.6 months), respectively. Neutropenia was the most common grade 3 or 4 adverse event (69.4%), with febrile neutropenia developing in 13.9% of patients. No treatment-related death occurred. At the time of starting second-line chemotherapy, 19 of 22 patients (86%) had significantly improved or maintained their performance status (PS) relative to their PS at the time of starting amrubicin monotherapy as first line chemotherapy (P = 0.027). Conclusions The results of the present study suggest that amrubicin could be considered as a viable treatment option for chemotherapy-naive elderly or poor-risk patients with ES-SCLC (Clinical trial registration number: UMIN000011055 www.clinicaltrials.gov ). PMID- 28631098 TI - Urolithins impair cell proliferation, arrest the cell cycle and induce apoptosis in UMUC3 bladder cancer cells. AB - Ellagitannins have been gaining attention as potential anticancer molecules. However, the low bioavailability of ellagitannins and their extensive metabolization in the gastrointestinal tract into ellagic acid and urolithins suggest that the health benefits of consuming ellagitannins rely on the direct effects of their metabolites. Recently, chemopreventive and chemotherapeutic activities were ascribed to urolithins. Nonetheless, there is still a need to screen and evaluate the selectivity of these molecules and to elucidate their cellular mechanisms of action. Therefore, this work focused on the antiproliferative effects of urolithins A, B and C and ellagic acid on different human tumor cell lines. The evaluation of cell viability and the determination of the half-maximal inhibitory concentrations indicated that the sensitivity to the studied urolithins varied markedly between the different cell lines, with the bladder cancer cells (UMUC3) being the most susceptible. In UMUC3 cells, urolithin A was the most active molecule, promoting cell cycle arrest at the G2/M checkpoint, increasing apoptotic cell death and inhibiting PI3K/Akt and MAPK signaling. Overall, the present study emphasizes the chemopreventive/chemotherapeutic potential of urolithins, highlighting the stronger effects of urolithin A and its potential to target transitional bladder cancer cells. PMID- 28631099 TI - Discontinuation of pharmacological treatment of children and adolescents with attention deficit hyperactivity disorder: meta-analysis of 63 studies enrolling 11,788 patients. AB - BACKGROUND: The risk-benefit balance of pharmacological treatment for children and adolescents with ADHD and the factors that moderate this relationship are unclear. METHODS: A systematic review and meta-analysis of randomised, placebo controlled clinical trials (RPCCTs) investigating the efficacy of pharmacological treatment in children or adolescents with ADHD was carried out. Meta-analysis of treatment discontinuation, clinician-, parent- and teacher-rated efficacy and adverse events was performed. The effect of covariates was studied. RESULTS: Sixty-three studies were included. Ten drugs were investigated, with atomoxetine and methylphenidate the most frequently studied. RPCCTs had mostly a short duration (7.9 weeks). All-cause treatment discontinuation was lower with pharmacological treatment than placebo (OR = 0.68). Pharmacological treatment was more efficacious than placebo independently of the rater (clinician, standardised mean difference (SMD) 0.74; parent, SMD = 0.63; or teacher, SMD = 0.75). Evidence of publication bias was found for clinician-rated efficacy, especially in industry-sponsored RPCCT. Psychostimulants showed a higher efficacy and were associated with a better outcome on treatment discontinuation than non-stimulant drugs. Efficacy was smaller in RPCCTs for which a psychiatric comorbid disorder was an inclusion criterion, was larger in studies with a commercial sponsorship and showed a negative association with treatment length. CONCLUSIONS: In the short term, pharmacological treatment provides moderate-high symptom relief, is safe and shows lower treatment discontinuation than placebo, suggesting a suitable risk-benefit balance, particularly with psychostimulants. The efficacy is lower in patients with a comorbid psychiatric disorder and should be assessed periodically, as it appears to reduce over time. Publication bias of clinician rated efficacy in studies with a commercial sponsor is suggested. PMID- 28631100 TI - Co-modulation of an allosteric modulator of nicotinic receptor-cholinesterase inhibitor (galantamine) and a 5-HT4 receptor agonist (RS-67333): effect on scopolamine-induced memory deficit in the mouse. AB - AIM: It is widely assumed that the upcoming therapeutics for Alzheimer's disease will require to act on more than one target to be effective. We investigated here whether a combination of the nicotinic receptor allosteric modulator/cholinesterase inhibitor galantamine can act synergistically with the type 4 serotonin receptor (5-HT4R) partial agonist, RS-67333, to counterbalance deficits in short- and long-term memory. To select sub-efficacious doses of both drugs, dose-response studies were first performed on the scopolamine-induced deficits of spontaneous alternation in the Y-maze task and of acquisition and retrieval processes in a passive avoidance task. RESULT: For spontaneous alternation behavior, combination of 1 mg/kg galantamine and 0.5 mg/kg RS-67333 fully reversed the deficit. In the passive avoidance task, no sub-efficacious doses could be found in the retention paradigm, but a beneficial effect of the association has been demonstrated in the acquisition paradigm. CONCLUSION: Mnesic effects of galantamine can be thus potentiated by activation of 5-HT4R. Such a combination treatment might (1) strengthen symptomatic relief, (2) attenuate adverse effects given the lower doses of each compound required, and (3) afford a disease-modifying effect given the known action of 5-HT4R on amyloidogenesis cascade. PMID- 28631101 TI - Stationary cycling exergame use among inactive children in the family home: a randomized trial. AB - Exergames may be one way to increase child physical activity, but long term adherence has seen little research attention. The primary objective of this study was to evaluate the usage of an exergame bike in comparison to a stationary bike in front of a TV across 3-months within a family home environment among children aged 10-14 years old. Seventy-three inactive children were recruited through advertisements and randomized to either the exergame condition (n = 39) or the standard bike condition (n = 34). Weekly bike use was recorded in a log-book. Both groups declined in bike use over time (t = 3.921, p < .01). Although the exergame group reported higher use (t = 2.0045, p < .05), this was most prominent during the first week. Overall, these results do not support exergames as a standalone physical activity intervention, and suggest that short duration examinations of exergames may be misleading. PMID- 28631102 TI - Experiencing is believing: prior experience moderates the impact of self-based and socially-based cues in the context of blood donation. AB - Two studies explored how self-based cues (i.e., self-efficacy), socially-based cues (i.e., perceived social norms), and prior blood donation experience differentially influence behavioral intentions. In Study 1, undergraduate students (N = 766) completed an online study that evaluated prior experiences, self-efficacy, perceived norms, and behavioral intentions in the context of blood donation. In Study 2, a community sample (N = 199) from a clinic waiting room completed similar measures. Across both studies, having high self-efficacy was a necessary and sufficient antecedent to high intentions, regardless of norm perception for donors. For non-donors, however, high self-efficacy was necessary but not sufficient; non-donors' intentions were higher when giving blood was perceived to be normative, but far lower when it was not. When self-efficacy was low, the effects of experience and norms did not exert meaningful effects and donation intentions were quite low. These results demonstrate that the impact of self-based and socially-based cues on behavioral intentions may differ as a function of experience. The findings can inform public health initiatives and enhance the accuracy of theoretical models by directly examining experience as a moderator. PMID- 28631103 TI - Transesophageal echocardiography in orthotopic liver transplantation: a comprehensive intraoperative monitoring tool. AB - Intraoperative transesophageal echocardiography is a minimally invasive monitoring tool that can provide real-time visual information on ventricular function and hemodynamic volume status in patients undergoing liver transplantation. The American Association for the Study of Liver Diseases states that transesophageal echocardiography should be used in all liver transplant candidates in order to assess chamber sizes, hypertrophy, systolic and diastolic function, valvular function, and left ventricle outflow tract obstruction. However, intraoperative transesophageal echocardiography can be used to "visualize" other organs too; thanks to its proximity and access to multiple acoustic windows: liver, lung, spleen, and kidney. Although only limited scientific evidence exists promoting this comprehensive use, we describe the feasibility of TEE in the setting of liver transplantation: it is a highly valuable tool, not only as a cardiovascular monitoring, but also as a tool to evaluate lungs and pleural spaces, to assess hepatic vein blood flow and inferior vena cava anastomosis and patency, i.e., in cases of modified surgical techniques. The aim of this case series is to add our own experience of TEE as a comprehensive intraoperative monitoring tool in the field of orthotopic liver transplantation (and major liver resection) to the literature. PMID- 28631104 TI - Is there an association between surgeon hat type and 30-day wound events following ventral hernia repair? AB - INTRODUCTION: While several patient and operative variables have been shown to be associated with an increased risk of postoperative wound events, the association between surgical hat type worn by surgeons and postoperative wound events remains controversial. The purpose of this study is to investigate the association between type of surgical hat worn by surgeons and the incidence of postoperative wound events following ventral hernia repair using the Americas Hernia Society Quality Collaborative database. METHODS: All surgeons who input at least ten patients with 30-day follow-up into the AHSQC were identified. These surgeons were sent a survey asking them to identify the type of surgical hat they wear in the operating room. The association of the type of surgical hat worn, patient variables, and operative factors with 30-day wound events was investigated using multivariate logistic regression. RESULTS: A total of 68 surgeons responded to the survey, resulting in 6210 cases available for analysis. The type of surgical hat worn by surgeons was not found to be associated with an increased risk of 30 day surgical site infections or surgical site occurrences requiring procedural intervention. CONCLUSION: Our study is the first study to directly compare the association of surgical hat type with postoperative wound events. There is no association between the type of surgical hat worn and the incidence of postoperative wound events following ventral hernia repair. Our findings suggest that surgical hate type may be chosen at the discretion of operating room personnel without fear of detriment to their patients. PMID- 28631105 TI - Stent fracture is associated with a higher mortality in patients with type-2 diabetes treated by implantation of a second-generation drug-eluting stent. AB - Type 2 diabetes correlates with clinical events after the implantation of a second-generation drug-eluting stent (DES). The rate and prognostic value of stent fracture (SF) in patients with diabetes who underwent DES implantation remain unknown. A total of 1160 patients with- and 2251 without- diabetes, who underwent surveillance angiography at 1 year after DES implantation between June 2004 and August 2014, were prospectively studied. The primary endpoints included the incidence of SF and a composite major adverse cardiac event [MACE, including myocardial infarction (MI), cardiac death, and target-vessel revascularization (TVR)] at 1-year follow-up and at the end of follow-up for overall patients, and target lesion failure [TLF, including cardiac death, target vessel myocardial infarction (TVMI) and target lesion revascularization (TLR)] at the end of study for SF patients. In general, diabetes was associated with a higher rate of MACE at 1-year (18.4 vs. 12.9%) and end of follow-up (24.0 vs. 18.6%, all p < 0.001), compared with those in patients who did not have diabetes. The 1-year SF rate was comparable among patients with diabetes (n = 153, 13.2%) and non-diabetic patients (n = 273, 12.1%, p > 0.05). Diabetic patients with SF had a 2.6-fold increase of SF-related cardiac death at the end of study and threefold increase of re-repeat TLR when compared with non-diabetic patients with SF (5.9 vs. 2.2%, p = 0.040; 6.5 vs. 2.2%, p = 0.032), respectively. Given the fact that diabetes is correlated with increased MACE rate, SF in diabetic patients translates into differences in mortality and re-repeat TLR compared with the non-diabetic group. PMID- 28631106 TI - Transthoracic 3D echocardiographic left heart chamber quantification in patients with bicuspid aortic valve disease. AB - Integration of volumetric heart chamber quantification by 3D echocardiography into clinical practice has been hampered by several factors which a new fully automated algorithm (Left Heart Model, (LHM)) may help overcome. This study therefore aims to evaluate the feasibility and accuracy of the LHM software in quantifying left atrial and left ventricular volumes and left ventricular ejection fraction in a cohort of patients with a bicuspid aortic valve. Patients with a bicuspid aortic valve were prospectively included. All patients underwent 2D and 3D transthoracic echocardiography and computed tomography. Left atrial and ventricular volumes were obtained using the automated program, which did not require manual contour detection. For comparison manual and semi-automated measurements were performed using conventional 2D and 3D datasets. 53 patients were included, in four of those patients no 3D dataset could be acquired. Additionally, 12 patients were excluded based on poor imaging quality. Left ventricular end-diastolic and end-systolic volumes and ejection fraction calculated by the LHM correlated well with manual 2D and 3D measurements (Pearson's r between 0.43 and 0.97, p < 0.05). Left atrial volume (LAV) also correlated significantly although LHM did estimate larger LAV compared to both 2DE and 3DE (Pearson's r between 0.61 and 0.81, p < 0.01). The fully automated software works well in a real-world setting and helps to overcome some of the major hurdles in integrating 3D analysis into daily practice, as it is user independent and highly reproducible in a group of patients with a clearly defined and well-studied valvular abnormality. PMID- 28631107 TI - Non-invasive coronary wave intensity analysis. AB - Wave intensity analysis is calculated from simultaneously acquired measures of pressure and flow. Its mathematical computation produces a profile that provides quantitative information on the energy exchange driving blood flow acceleration and deceleration. Within the coronary circulation it has proven most useful in describing the wave that originates from the myocardium and that is responsible for driving the majority of coronary flow, labelled the backward decompression wave. Whilst this wave has demonstrated valuable insights into the pathogenic processes of a number of disease states, its measurement is hampered by its invasive necessity. However, recent work has used transthoracic echocardiography and an established measures of central aortic pressure to produce coronary flow velocity and pressure waveforms respectively. This has allowed a non-invasive measure of coronary wave intensity analysis, and in particular the backward decompression wave, to be calculated. It is anticipated that this will allow this tool to become more applicable and widespread, ultimately moving it from the research to the clinical domain. PMID- 28631108 TI - Reproduction Number and Asymptotic Stability for the Dynamics of a Honey Bee Colony with Continuous Age Structure. AB - A system of partial differential equations is derived as a model for the dynamics of a honey bee colony with a continuous age distribution, and the system is then extended to include the effects of a simplified infectious disease. In the disease-free case, we analytically derive the equilibrium age distribution within the colony and propose a novel approach for determining the global asymptotic stability of a reduced model. Furthermore, we present a method for determining the basic reproduction number [Formula: see text] of the infection; the method can be applied to other age-structured disease models with interacting susceptible classes. The results of asymptotic stability indicate that a honey bee colony suffering losses will recover naturally so long as the cause of the losses is removed before the colony collapses. Our expression for [Formula: see text] has potential uses in the tracking and control of an infectious disease within a bee colony. PMID- 28631109 TI - Increasing the reach of forensic genetics with massively parallel sequencing. AB - The field of forensic genetics has made great strides in the analysis of biological evidence related to criminal and civil matters. More so, the discipline has set a standard of performance and quality in the forensic sciences. The advent of massively parallel sequencing will allow the field to expand its capabilities substantially. This review describes the salient features of massively parallel sequencing and how it can impact forensic genetics. The features of this technology offer increased number and types of genetic markers that can be analyzed, higher throughput of samples, and the capability of targeting different organisms, all by one unifying methodology. While there are many applications, three are described where massively parallel sequencing will have immediate impact: molecular autopsy, microbial forensics and differentiation of monozygotic twins. The intent of this review is to expose the forensic science community to the potential enhancements that have or are soon to arrive and demonstrate the continued expansion the field of forensic genetics and its service in the investigation of legal matters. PMID- 28631110 TI - Expression of Hsp27 and Hsp70 and vacuolization in the pituitary glands in cases of fatal hypothermia. AB - Hypothermia causes systemic cellular stress. The pituitary gland is an endocrine gland and plays an important role in thermoregulation. When the core body temperature drops, the pituitary gland is activated by stimulation of hypothalamic hormones. In this study, we investigated morphological alterations of the pituitary gland in cases of fatal hypothermia. Several morphological alterations of the anterior lobe of the pituitary gland, such as hemorrhage, vacuolization, and hyperemia, have been previously described in fatal hypothermia. However, the diagnostic value of these findings is controversial. We compared 11 cases of fatal hypothermia with 10 cases lacking antemortem hypothermic influences. In the presence of thermal cellular stress, the expression of heat shock proteins increases to protect cellular structures. Therefore, we immunohistochemically analyzed Hsp27 and Hsp70. Hsp27 expression was detected in 27.3% of the cases of fatal hypothermia and in 10.0% of the control cases, whereas Hsp70 expression was not detected in any case. Additionally, Sudan staining was performed to quantify fatty degeneration. A positive reaction was found in 45.5% of the study group and in 10.0% of the control group. This indicates that fatty degeneration might be a valuable marker when other macroscopic signs of hypothermia are absent. PMID- 28631111 TI - Suffocation caused by plastic wrap covering the face combined with nitrous oxide inhalation. AB - Suicide using a combination of a plastic bag over the head and inhalation of a non-irritating gas, such as helium, argon or nitrogen, has been reported in the literature. Here an unusual suicide method in a 17-year old man by suffocation from covering the face with household plastic wrap, combined with nitrous oxide inhalation, is presented. The case was reviewed based on police, autopsy and hospital reports. A PubMed search for scientific literature related to nitrous oxide abuse and suicide by suffocation was performed and our findings discussed in relation to the scientific literature found. The deceased was a 17-year old man who was found with the nose and mouth closed with a piece of kitchen plastic wrap. The plastic wrap had been removed prior to autopsy. Autopsy findings were suggestive of asphyxia, but were otherwise negative. Nitrous oxide was detected in the brain and lung tissue with headspace-gas chromatography-mass spectrometry (headspace-GCMS). The cause of death was assumed to be suffocation caused by plastic wrap covering the face, combined with nitrous oxide inhalation. Suicide was suspected because of a history of depression for several months. Nitrous oxide, also known as laughing gas, has a euphoric effect and is used as a recreational inhalant drug that can be purchased legally. Deaths caused by recreational nitrous oxide abuse are rare but may occur if used in combination with a plastic bag over the head. This is the first report of suicide by suffocation by external obstruction combined with nitrous oxide inhalation. PMID- 28631112 TI - Risk of Revision Was Not Reduced by a Double-bundle ACL Reconstruction Technique: Results From the Scandinavian Registers. AB - BACKGROUND: Double-bundle anterior cruciate ligament (ACL) reconstruction has demonstrated improved biomechanical properties and moderately better objective outcomes compared with single-bundle reconstructions. This could make an impact on the rerupture rate and reduce the risk of revisions in patients undergoing double-bundle ACL reconstruction compared with patients reconstructed with a traditional single-bundle technique. The National Knee Ligament Registers in Scandinavia provide information that can be used to evaluate the revision outcome after ACL reconstructions. QUESTIONS/PURPOSES: The purposes of the study were (1) to compare the risk of revision between double-bundle and single-bundle reconstructions, reconstructed with autologous hamstring tendon grafts; (2) to compare the risk of revision between double-bundle hamstring tendon and single bundle bone-patellar tendon-bone autografts; and (3) to compare the hazard ratios for the same two research questions after Cox regression analysis was performed. METHODS: Data collection of primary ACL reconstructions from the National Knee Ligament Registers in Denmark, Norway, and Sweden from July 1, 2005, to December 31, 2014, was retrospectively analyzed. A total of 60,775 patients were included in the study; 994 patients were reconstructed with double-bundle hamstring tendon grafts, 51,991 with single-bundle hamstring tendon grafts, and 7790 with single bundle bone-patellar tendon-bone grafts. The double-bundle ACL-reconstructed patients were compared with the two other groups. The risk of revision for each research question was detected by the risk ratio, hazard ratio, and the corresponding 95% confidence intervals. Kaplan-Meier analysis was used to estimate survival at 1, 2, and 5 years for the three different groups. Furthermore, a Cox proportional hazard regression model was applied and the hazard ratios were adjusted for country, age, sex, meniscal or chondral injury, and utilized fixation devices on the femoral and tibial sides. RESULTS: There were no differences in the crude risk of revision between the patients undergoing the double-bundle technique and the two other groups. A total of 3.7% patients were revised in the double-bundle group (37 of 994 patients) versus 3.8% in the single-bundle hamstring tendon group (1952 of 51,991; risk ratio, 1.01; 95% confidence interval (CI), 0.73-1.39; p = 0.96), and 2.8% of the patients were revised in the bone-patellar tendon-bone group (219 of the 7790 bone-patellar tendon-bone patients; risk ratio, 0.76; 95% CI, 0.54-1.06; p = 0.11). Cox regression analysis with adjustment for country, age, sex, menisci or cartilage injury, and utilized fixation device on the femoral and tibial sides, did not reveal any further difference in the risk of revision between the single-bundle hamstring tendon and double-bundle hamstring tendon groups (hazard ratio, 1.18; 95% CI, 0.85-1.62; p = 0.33), but the adjusted hazard ratio showed a lower risk of revision in the single-bundle bone-patellar tendon-bone group compared with the double-bundle group (hazard ratio, 0.62; 95% CI, 0.43-0.90; p = 0.01). Comparisons of the graft revision rates reported separately for each country revealed that double-bundle hamstring tendon reconstructions in Sweden had a lower hazard ratio compared with the single-bundle hamstring tendon reconstructions (hazard ratio, 1.00 versus 1.89; 95% CI, 1.09-3.29; p = 0.02). Survival at 5 years after index surgery was 96.0% for the double-bundle group, 95.4% for the single-bundle hamstring tendon group, and 97.0% for the single bundle bone-patellar tendon-bone group. CONCLUSIONS: Based on the data from all three national registers, the risk of revision was not influenced by the reconstruction technique in terms of using single- or double-bundle hamstring tendons, although national differences in survival existed. Using bone-patellar tendon-bone grafts lowered the risk of revision compared with double-bundle hamstring tendon grafts. These findings should be considered when deciding what reconstruction technique to use in ACL-deficient knees. Future studies identifying the reasons for graft rerupture in single- and double-bundle reconstructions would be of interest to understand the findings of the present study. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28631113 TI - Fast Determination of Ingredients in Solid Pharmaceuticals by Microwave-Enhanced In-Source Decay of Microwave Plasma Torch Mass Spectrometry. AB - Rapid qualitative and quantitative analysis of solid samples (e.g., pharmaceutical preparations) by using a small and low-resolution mass spectrometer without MS/MS function is still a challenge in ambient pressure ionization mass spectrometric analysis. Herein, a practically efficient method termed microwave-enhanced in-source decay (MEISD) using microwave plasma torch desorption ionization coupled with time-of-flight mass spectrometry (MPTDI-TOF MS) was developed for fast analysis of pharmaceutical tablets using a miniature TOF mass spectrometer without tandem mass function. The intensity of ISD fragmentation was evaluated under different microwave power values. Several factors, including desorption distance and time that might affect the signal intensity and fragmentation, were systematically investigated. It was observed that both the protonated molecular ions and major fragment ions from the active ingredients in tablets could be found in the full-scan mass spectra in positive ion mode, which were comparable to those obtained by a commercial LTQ-XL ion trap mass spectrometer. The structures of the ingredients could be elucidated in detail using the MEISD method, which promotes our understanding of the desorption/ionization processes in microwave plasma torch (MPT). Quantitative analysis of 10 tablets was achieved by full-scan MPTDI-TOF MS with low limit of detection (LOD, 0.763 mg/g), acceptable relative standard deviation (RSD < 7.33%, n =10), and 10 s for each tablet, showing promising applications in high throughput screening of counterfeit drugs. Graphical Abstract ?. PMID- 28631114 TI - Derivatization of Dextran for Multiply Charged Ion Formation and Electrospray Ionization Time-of-Flight Mass Spectrometric Analysis. AB - We present the use of a simple, one-pot derivatization to allow the polysaccharide dextran to carry multiple positive charges, shifting its molecular weight distribution to a lower m/z range. We performed this derivatization because molecular weight measurements of polysaccharides by mass spectrometry are challenging because of their lack of readily ionizable groups. The absence of ionizable groups limits proton abstraction and suppresses proton adduction during the ionization process, producing mass spectra with predominantly singly charged metal adduct ions, thereby limiting the detection of large polysaccharides. To address this challenge, we derivatized dextran T1 (approximately 1 kDa) by attaching ethylenediamine, giving dextran readily ionizable, terminal amine functional groups. The attached ethylenediamine groups facilitated proton adduction during the ionization process in positive ion mode. Using the low molecular weight dextran T1, we tracked the number of ethylenediamine attachments by measuring the mass shift from underivatized to derivatized dextran T1. Using electrospray ionization time-of-flight mass spectrometry, we observed derivatized dextran chains ranging from two to nine glucose residues with between one and four attachments/charges. Our success in shifting derivatized dextran T1 toward the low m/z range suggests potential for this derivatization as a viable route for analysis of high molecular weight polysaccharides using electrospray ionization time-of-flight mass spectrometry. Graphical Abstract ?. PMID- 28631115 TI - Gurya cutting and female genital fistulas in Niger: ten cases. AB - INTRODUCTION AND HYPOTHESIS: The objective was to determine the contribution of female genital cutting to genital fistula formation in Niger from the case records of a specialist fistula hospital. METHODS: A retrospective review was undertaken of the records of 360 patients seen at the Danja Fistula Center, Danja, Niger, between March 2014 and September 2016. Pertinent clinical and socio demographic data were abstracted from the cases identified. RESULTS: A total of 10 fistulas resulting from gurya cutting was obtained: 9 cases of urethral loss and 1 rectovaginal fistula. In none of the cases was genital cutting performed for obstructed labor or as part of ritual coming-of-age ceremonies, but all cutting procedures were considered "therapeutic" within the local cultural context as treatment for dyspareunia, lack of interest in or unwillingness to engage in sexual intercourse, or female behavior that was deemed to be culturally inappropriate by the male spouse, parents, or in-laws. Clinical cure (fistula closed and the patient continent) was obtained in all 10 cases, although 3 women required more than one operation. CONCLUSIONS: Gurya cutting is an uncommon, but preventable, cause of genital fistulas in Niger. The socio-cultural context which gives rise to gurya cutting is explored in some detail. PMID- 28631118 TI - [Paediatric pathology in everyday life]. PMID- 28631116 TI - Environmental Factors and Zoonotic Pathogen Ecology in Urban Exploiter Species. AB - Knowledge of pathogen ecology, including the impacts of environmental factors on pathogen and host dynamics, is essential for determining the risk that zoonotic pathogens pose to people. This review synthesizes the scientific literature on environmental factors that influence the ecology and epidemiology of zoonotic microparasites (bacteria, viruses and protozoa) in globally invasive urban exploiter wildlife species (i.e., rock doves [Columba livia domestica], European starlings [Sturnus vulgaris], house sparrows [Passer domesticus], Norway rats [Rattus norvegicus], black rats [R. rattus] and house mice [Mus musculus]). Pathogen ecology, including prevalence and pathogen characteristics, is influenced by geographical location, habitat, season and weather. The prevalence of zoonotic pathogens in mice and rats varies markedly over short geographical distances, but tends to be highest in ports, disadvantaged (e.g., low income) and residential areas. Future research should use epidemiological approaches, including random sampling and robust statistical analyses, to evaluate a range of biotic and abiotic environmental factors at spatial scales suitable for host home range sizes. Moving beyond descriptive studies to uncover the causal factors contributing to uneven pathogen distribution among wildlife hosts in urban environments may lead to targeted surveillance and intervention strategies. Application of this knowledge to urban maintenance and planning may reduce the potential impacts of urban wildlife-associated zoonotic diseases on people. PMID- 28631117 TI - Multi-criteria Decision Analysis to Model Ixodes ricinus Habitat Suitability. AB - Tick-borne diseases present a major threat to both human and livestock health throughout Europe. The risk of infection is directly related to the presence of its vector. Thereby it is important to know their distribution, which is strongly associated with environmental factors: the presence and availability of a suitable habitat, of a suitable climate and of hosts. The present study models the habitat suitability for Ixodes ricinus in Ireland, where data on tick distribution are scarce. Tick habitat suitability was estimated at a coarse scale (10 km) with a multi-criteria decision analysis (MCDA) method according to four different scenarios (depending on the variables used and on the weights granted to each of them). The western part of Ireland and the Wicklow mountains in the East were estimated to be the most suitable areas for I. ricinus in the island. There was a good level of agreement between results from the MCDA and recorded tick presence. The different scenarios did not affect the spatial outputs substantially. The current study suggests that tick habitat suitability can be mapped accurately at a coarse scale in a data-scarce context using knowledge based methods. It can serve as a guideline for future countrywide sampling that would help to determine local risk of tick presence and refining knowledge on tick habitat suitability in Ireland. PMID- 28631120 TI - [Erratum to: Cost effectiveness of GnRH antagonists in patients with prostate cancer and cardiovascular risk. Comparative analysis with leuprolide on the basis of the Number Needed to Treat]. PMID- 28631119 TI - [Expression of cancer testis (CT) antigens in pediatric and adolescent melanomas]. AB - BACKGROUND: One of the main problems in the diagnostics of pediatric melanomas is the differentiation from benign dermal lesions typical for this age group, such as Spitz nevus. The biological behavior of pediatric melanomas differs considerably from that of melanomas in adults. MATERIAL AND METHODS: Cancer testis (CT) antigens are named after their typical expression pattern since they are present in various types of malignant tumors but in normal adult tissues are solely expressed in testicular germ cells. Because of this tumor-associated expression pattern, CT antigens are regarded as potential targets for vaccine based immunotherapy of cancer and might be used as diagnostic tools in surgical pathology. In adults, melanoma is among the tumors showing a high incidence of CT antigen expression; however, while there is ample knowledge about adult melanomas, little is known about the presence of CT antigens in pediatric melanomas. Consequently, the expression of CT antigens MAGE-A1, MAGE-A4, CT7/MAGE C1, NY-ESO-1, and GAGE was analyzed in a series of pediatric melanomas. The study was restricted to cases of metastatic disease and/or fatal outcome. A total of 12 cases were available and immunohistochemically analyzed with monoclonal antibodies (mAb). RESULTS: The expression of CT antigens was generally low and present in only 4 of 12 cases. This is in stark contrast to the expression of these antigens in adult melanomas. Moreover, the extent of expression was very limited with most cases showing only a focal CT antigen expression and only marked in very small tumor areas (<5%). CONCLUSION: Despite the low case numbers this study indicates that CT antigens are most likely not useful as diagnostic markers in pediatric melanomas or as targets for vaccine-based immunotherapy. It supports the notion that pediatric melanomas show a different biological behavior than their adult counterparts. PMID- 28631121 TI - [Prudent use of antimicrobial prophylaxis : Prevention of increasing antibiotic resistance]. AB - BACKGROUND: The use of peri-operative antimicrobial prophylaxis during urological procedures to prevent postoperative complications is very common. OBJECTIVES: What kind of recommendations for reasonable use of peri-operative antimicrobial prophylaxis during urological procedures to prevent increasing antibiotic resistance and postoperative complications exist? METHODS: Review of evidence based recommendations from literature and current Guidelines of the EAU. RESULTS: For urological procedures there are evidenced-based recommendations for using antimicrobial prophylaxis, although the evidence is not always sufficiently high. For endourological procedures it is recommended to use Cephalosporines group 2 (or 3), Aminopenicillin/Beta-lactamase inhibitor or Cotrimoxazole. For transrectal core biopsy of the prostate, depending on the risk, Fluoroquinolones, Cotrimoxazole or targeted prophylaxis are recommended. For laparoscopic or open procedures, partly optional, Cephalosporines group 2 (or 3), Aminopenicillin/Beta lactamase inhibitor or Cotrimoxazole and for a cystectomy with opening of the intestinal tract Cephalosporines group 2 or an Aminopenicillin/Beta-lactamase inhibitor, together with Metronidazole are recommended. CONCLUSIONS: Using prudent peri-operative antimicrobial prophylaxis patient surgical risk factors as well as the expected spectrum of pathogens and the local resistance profile should be considered. Perioperative antibiotic prophylaxis on the one hand aims at preventing postoperative infections, and on the other hand plays an important role in the total antibiotic consumption. It is therefore a pivotal aspect of "Antimicrobial Stewardship" strategies in the health-care system. PMID- 28631122 TI - Predicting massive transfusion in placenta previa. PMID- 28631123 TI - Modeling solubility of CO2/hydrocarbon gas in ionic liquid ([emim][FAP]) using Aspen Plus simulations. AB - The Peng-Robinson equation of state with quadratic van der Waals (vdW) mixing rule model was chosen to perform the thermodynamic calculations in Flash3 column of Aspen Plus to predict the solubility of CO2 or any one of the hydrocarbons (HCs) among methane, ethane, propane, and butane in an ionic liquid 1-ethyl-3 methylimidazolium tris(pentafluoroethyl)trifluorophosphate ([emim][FAP]). Bubble point pressure, solubility, bubble point temperature, fugacity, and partial molar volume at infinite dilution were obtained from the simulations, and enthalpy of absorption, Gibbs free energy of solvation, and entropy change of absorption were estimated by thermodynamic relations. Results show that carbon chain length has a significant effect on the bubble point pressure. Methane has the highest bubble point pressure among all the considered HCs and CO2. The bubble point pressure and fugacity variation with temperature is different for CO2 as compared to HCs for mole fractions above 0.2. Two different profiles are noticed for enthalpy of absorption when plotted as a function of mole fraction of gas soluble in IL. Partial molar volume of CO2 decreases with increase in temperature in [emim][FAP], while it is increased for HCs. Bubble point temperature decreases with increase in the mole fraction of the solute. Entropy of solvation increases with temperature till a particular value followed by a decrease with further increase in temperature. Gibbs free energy change of solvation showed that the process of solubility was spontaneous. PMID- 28631124 TI - Toxicity evaluation of cypermethrin, glyphosate, and malathion, on two indigenous zooplanktonic species. AB - In Aguascalientes, Mexico, there is a special concern about pesticides because of their intensive use on guava production areas, which are located in the vicinity of water reservoirs; thus, non-target organisms could be exposed. Thereafter, the aim of this work was to assess the effect of cypermethrin, Faena(r) (glyphosate), and malathion, which are the most used pesticides in Aguascalientes' guava production, on the indigenous freshwater species Alona guttata (cladoceran) and Lecane papuana (rotifer). Acute 48-h toxicity tests were carried out, and LC50 values were calculated. Then, five sublethal concentrations (1/80, 1/40, 1/20, 1/10, and 1/5 of the respective LC50) were selected for the chronic assays: (a) intrinsic growth rate analysis in the rotifer and (b) partial life table analysis in the cladoceran. The results of the acute toxicity tests showed that A. guttata was more sensitive to malathion (LC50 = 5.26 * 10-3 mg/L) at concentrations found in natural environments with continuous application on guava fields, whereas L. papuana was more sensitive to Faena(r) (LC50 = 19.89 mg/L). The somatic growth of A. guttata was inhibited for the chronic exposure to cypermethrin. In addition, cypermethrin and Faena(r) seemed to exert endocrine disruptive effects on A. guttata. Moreover, malathion chronic exposure significantly decreased the survival of A. guttata. Moreover, L. papuana was affected chronically for the three pesticides. PMID- 28631125 TI - Upgraded modified forms of bituminous coal for the removal of safranin-T dye from aqueous solution. AB - Natural bituminous coal was used as a precursor in the synthesis of different modified products. The modification of coal was performed by treating it with nitric acid (N-coal), coating its surface by zinc oxide nanoparticles (Z-coal), and converting it into porous graphite (PG). The effect of modification processes on the structures, morphologies, and optical properties was followed by X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared spectrum (FT-IR), and UV/VIS spectrophotometer analysis. The surface of N-coal grains becomes smoother than the surface of raw coal grains due to the removal of the associated impurities and the formation of nitrogen function groups. For Z coal, the whole surface of coal grains appears to be completely covered by agglomerated ZnO nanoparticles of massive density and irregular shapes. The average crystallite size of the formed ZnO is ~22.2 nm and density of dislocations is 2.029 * 10-3 dislocation/nm2. Also, the removal of safranin-T dye by natural bituminous coal and its modified forms was investigated as a function of contact time, adsorbent mass, initial dye concentration, and pH value. At pH 8, the PG showed higher efficiency (96%) than Z-coal (93.5%), N-coal (74.5%), and natural coal (62%) after 2 h for 0.1 g on 100 mg/L dye. The obtained results are well fitted by pseudo-second-order kinetic than by intraparticle diffusion and Elovich kinetic models for the adsorption by N-coal, Z-coal, and PG, whereas the adsorption by raw coal is well fitted with both pseudo-second-order and Elovich kinetic models. The Langmuir isotherm model fits well the equilibrium adsorption isotherm of safranin by raw coal and its modified forms. The values of maximum adsorption capacity were calculated for raw coal, N-coal, Z-coal, and PG to be 21.3, 27.4, 32.46, and 33.67 mg/g, respectively. A monolayer model with one energy and a monolayer model with two energies as advanced equilibrium models were investigated for more physical interpretation of the adsorption process. The calculated parameters (number of adsorbed molecules per site and number of receptor sites per unit mass) reflected the role of modification processes in the adsorption behavior of safranin. Graphical abstract High volatile bituminous coal and its modified forms have been used for the removal of Safranin-T dye from aqueous solution. PMID- 28631127 TI - Toxicity of cypermethrin on the embryo and larvae of Gangetic mystus, Mystus cavasius. AB - The objective of the present study was to elucidate the effects of cypermethrin on the embryo and the larvae of Gangetic mystus, Mystus cavasius. Therefore, fertilized eggs (n = 100) and 1-day-old larvae (n = 100) were exposed to six different concentrations of cypermethrin (0, 2, 4, 8, 16 and 32 MUg L-1) in each of the 18 plastic bowls. Each of the treatment and control was maintained in three replicates. The LC10 and LC50 values for Gangetic mystus embryos and larvae were calculated using probit analysis. Results showed the mortality of embryos significantly increased with increasing cypermethrin concentrations. The 24-h LC10 and LC50 (with 95% confidence interval) values of cypermethrin for embryo were 0.42 (0.14-0.81) and 5.60 (4.16-7.19) MUg L-1, respectively. Hatching success decreased and mortality of larvae increased significantly with increasing cypermethrin concentrations. The 24-h LC10 and LC50 values (with 95% confidence limits) of cypermethrin for larvae were 1.72 (1.24-2.20) and 11.57 (10.09-13.42) MUg L-1, respectively; the 48-h LC10 and LC50 for larvae were 1.34 (0.83-1.89) and 8.25 (6.87-9.91) MUg L-1, respectively; the 72-h LC10 and LC50 for larvae were 1.13 (0.63-1.66) and 6.12 (4.91-7.47) MUg L-1, respectively. Furthermore, results showed several malformations in embryos and larvae when exposed to the two highest concentrations of cypermethrin. The findings of the study suggest that 2 MUg L-1 cypermethrin concentration in the aquatic environment may have deleterious effects on the development and the reproduction of Gangetic mystus. PMID- 28631126 TI - A comparative study of hospital admissions for respiratory diseases during normal and dusty days in Iran. AB - During the last century, most of people around the world moved from communicable to non-communicable diseases, mainly due to air pollution. Air pollutants and dust storm increase risk of morbidity, for cardiovascular and respiratory diseases, and increase the number of deaths. The city of Ahvaz is considered as the focal point of air pollution and dust storm in Iran. The aim of this study was to determine the number of Hospital Admission Respiratory Disease (HARD) including asthma attacks, acute bronchitis and chronic obstructive pulmonary disease attributed to PM10 by a descriptive study during normal and dust event days in Ahvaz during the time period 2010-2012. The hourly PM10 data was collected from the Iranian Environmental Protection Agency and Razi hospital. The annual PM10 mean concentrations reached 282, 288 and 278 MUg/m3 in 2010, 2011 and 2012, respectively. The number of HARD attributed to PM10 was 1438, 1945 and 1393 people, respectively, and the highest number of daily admissions was attributed to the highest daily PM10 concentration in Ahvaz. The average number of daily HARD during dusty days was higher than normal days, and a significant positive correlation, between the number of hospital admissions and dusty days, was found. Dust had significant impact on HARD in Ahvaz. PMID- 28631128 TI - The witchcraft of encephalitis in Salem. PMID- 28631129 TI - Optimizing the deep brain stimulation care pathway in patients with Parkinson's disease. AB - Management of Parkinson's disease (PD) using deep brain stimulation (DBS) requires complex care in specialized, multidisciplinary centers. A well organized, efficient patient flow is crucial to ensure that eligible patients can quickly access DBS. Delays or inefficiencies in patient care may impact a center's ability to meet demand, creating a capacity bottleneck. Analysis of the current practices within a center may help identify areas for improvement. After external audit of the DBS workflow of the Lyon Neurological Hospital and comparison with other European centers, manageable steps were suggested to restructure the care pathway. Propositions of the audit comprised, for example: (1) directly admitting referred patients to hospital, without a prior neurological outpatient visit and (2) including the preoperative anesthesia consultation in the hospital stay 1 month before surgery, not separately. This reorganization (between 2013 and 2016) was performed without increases in hospital medical resources or costs. The time from patients' first referral to surgery was reduced (from 22 to 16 months; p = 0.033), as was the number of pre- and postoperative patient visits (11-5; p = 0.025) and the total cumulative length of in-hospital stay (20.5-17.5 nights; p = 0.02). Ultimately, the total number of PD consultations increased (346-498 per year), as did the number of DBS implants per year (32-45 patients). In this single center experience, restructuring the DBS care pathway allowed a higher number of PD patients to benefit from DBS therapy, with a shorter waiting time and without decreasing the quality of care. PMID- 28631131 TI - Endoscopic treatment of adult idiopathic obstruction of the foramen of Monro. AB - BACKGROUND: Adult idiopathic membranous obstruction of the foramen of Monro is an extremely rare condition that can be effectively treated with endoscopic foraminoplasty. A unilateral or bilateral foraminoplasty is performed if one or both of the foramina of Monro are obstructed, respectively. Endoscopic septum pellucidotomy is usually used in combination with the foraminoplasty. METHODS: The operative chart and video of one of our patients undergoing endoscopic treatment for adult idiopathic membranous obstruction of the foramen of Monro were retrieved from our database and reviewed. A description of the surgical technique was then formulated. CONCLUSIONS: The surgical technique of endoscopic foraminoplasty plus septum pellucidotomy for adult idiopathic membranous obstruction of the foramen of Monro is described. PMID- 28631130 TI - New insights into human farnesyl pyrophosphate synthase inhibition by second generation bisphosphonate drugs. AB - Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibition of the human Farnesyl Pyrophosphate Synthase (hFPPS). Available inhibitory activity values show that 2G-BPs act time-dependently, showing big differences in their initial inhibitory activities but similar final IC50 values. However, there is a lack of information explaining this similar final inhibitory potency. Although different residues have been identified in the stabilization of the R2 side chain of 2G-BPs into the active site, similar free binding energies were obtained that highlighted a similar stability of the ternary complexes, which in turns justified the similar IC50 values reported. Free binding energy calculations also demonstrated that the union of 2G-BPs to the active site were 38 to 54 kcal mol-1 energetically more favourable than the union of the natural substrate, which is the basis of the inhibition potency of the hFPPS activity. PMID- 28631132 TI - Adaptive biochemical and physiological responses of Eriobotrya japonica to fluoride air pollution. AB - The biochemical and physiological effects of fluoride were investigated in loquat trees (Eriobotrya japonica) grown in the vicinity of a phosphate fertilizer plant in Tunisia. Photosynthetic rate (Pn), stomatal conductance (Gs), transpiration rate (E), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities were assessed; along with photosynthetic pigments, lipid peroxidation, electrolytic leakage (EL) and total phenolic contents in foliage and roots of trees at different distances from the phosphate fertilizer plant. All assessed parameters showed significant discrepancies in comparison with unpolluted sites. Obtained results showed high oxidative stress indices including H2O2, lipid peroxidation, and EL, SOD, CAT and GPx activities and proline contents in leaves and roots at the polluted sites as compared to control. In contrast, leaf Pn, Gs, E and photosynthetic pigment contents were low as compared to the control. These results indicate that even though antioxidant responses increased near the factory, adverse effects on physiology were pronounced. PMID- 28631133 TI - Bone density in pediatric Crohn's disease: A cross-sectional observation from South India. AB - BACKGROUND: Crohn's disease (CD) frequently manifests in the second and third decades of life. Malnutrition and corticosteroid therapy may affect bone mineralization and delay bone growth. Our aim was to study bone mineral density and factors associated low bone mineral density (BMD) in pediatric CD. METHODS: A cross-sectional observational study in children with CD (aged 5 to <18 years) was done. Demographic and treatment details were noted. Vitamin D levels <20 ng/mL were considered as deficiency. Bone mineral density was evaluated with dual energy X-ray absorptiometry (DEXA) scan and Z score of <-2 SD was considered as low BMD. Data was analyzed descriptively. RESULTS: In 30 cases with CD enrolled over 1 year, mean age of the patients was 13.8+/-3.0 years. Age of onset and diagnosis was 11.4+/-3.2 years and 13.4+/-2.8 years, respectively. 73.3% were in the underweight category. All cases received azathioprine whereas 86.7% were receiving corticosteroids. Vitamin D deficiency was seen in 86.7% cases. A low BMD was evident in 70% children. Overall, low BMI (p=0.005) and vitamin D deficiency (p=0.005) were associated with low BMD. However, no association between severity grade of vitamin D deficiency and low BMD was found. Treatment with corticosteroid was associated with low BMD in 76.9% cases (p=0.069). CONCLUSION: Low BMD was frequent in children with CD and was associated with low BMI and vitamin D deficiency. PMID- 28631134 TI - Budd-Chiari syndrome: outcomes of endovascular intervention-A single-center experience. AB - AIM: Outcomes of endovascular intervention in Budd-Chiari syndrome (BCS) have been reported with varied results. Clinical outcomes of endovascular interventions in BCS and role of various prognostic scores were critically evaluated in this study. METHODS: This study retrospectively analyzed consecutive patients of BCS who underwent endovascular intervention between January 2007 and May 2016 at our center. Technical, clinical successes and complications were documented. The role of the prognostic scores such as Child-Turcotte-Pugh (CTP), model for end-stage liver disease (MELD), Rotterdam index, and original Clichy score in predicting mortality, clinical success, and need for re-interventions were also assessed. RESULTS: A total of 88 patients were analyzed. The median follow up was 12 months (range 1-96 months). Thirteen (14.8%) patients had combined inferior vena cava (IVC) and hepatic vein (HV) obstruction; HV obstruction in 33 (37.5%) and inferior vena cava IVC obstruction in 42 (47.7%) patients. The following interventions were done: IVC angioplasty alone (n = 11), IVC angioplasty with stenting (n = 36), HV angioplasty with stenting (n = 26), combined HV and IVC stent (n = 2), and direct intrahepatic porto-systemic shunt (DIPS) (n = 13). Overall technical success was 87/88 (98.86%), and clinical success was 76/88 (86.36%). Immediate complications were noted in 8 patients (10%). The 1-, 2-, 3-, and 4-year stent patency rates were 90.91%, 81.08%, 74.59%, and 70.45%, respectively. Re-interventions were required in 15 (17%). Overall mortality was 6 (6.8%). Apart from MELD >14, none of the other prognostic score could predict mortality, clinical success, and need for re-interventions. CONCLUSION: Endovascular interventions play an important role in the management of BCS, in properly selected patients, even if prognostic score is unfavorable. PMID- 28631136 TI - The good, the bad and the ugly: rectal cancers in the twenty-first century. PMID- 28631135 TI - Long-term clinical benefit from salvage EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer patients with EGFR wild-type tumors. AB - BACKGROUND: Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond. PATIENTS AND METHODS: Patients with EGFRwt NSCLC who received salvage (>=2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material. RESULTS: Forty four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12-38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6-11.6 months) and 24.1 (95% CI 11.2-37 months), respectively. CONCLUSIONS: Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients. PMID- 28631137 TI - Assessment of Titanium Dioxide Nanoparticles (TiO2-NPs) Induced Hepatotoxicity and Ameliorative Effects of Cinnamomum cassia in Sprague-Dawley Rats. AB - This study assessed the protective effects of Cinnamomum cassia (cinnamon) bark extract in rats exposed to titanium dioxide nanoparticles or titanium dioxide bulk salt. For in vivo evaluation of the ameliorative role of the cinnamon extract, the experimental groups were orally administered with the cinnamon extract at different dose levels (50 or 100 or 150 mg/kg bodyweight) along with the subcutaneous injections of 150 mg/kg bodyweight titanium dioxide nanoparticles or titanium dioxide bulk salt. The extract showed significant ameliorative role on the antioxidant system in response to elevated levels of titanium dioxide nanoparticles or titanium dioxide bulk salt-induced oxidative stress. It aided in the recovery of the antioxidant system as well as protective role in histological damages and some haematological parameters in the rat liver treated with titanium dioxide nanoparticles or titanium dioxide bulk salt. PMID- 28631138 TI - College Student Attitudes Towards "Smart" Guns: Results from a Nationwide Survey. AB - Existing studies focusing on "smart" guns, weapons that can only be fired by an authorized user, have focused largely on overall views towards the topic. Little is known about how views differ within key demographics or why Americans feel positively or negatively towards smart guns. This study used data from a nationwide web survey of 520 college students to address these concerns. Multinomial regression was used to identify patterns of smart gun preference in quantitative data. Respondents' open-ended reasoning for their views was examined through common themes and descriptive statistics. About half of the sample preferred smart guns over traditional firearms, with support more likely among females and liberals. Those with more advanced academic standing were more likely to have a traditional gun preference. The sample did not rank cost as a significant concern. Child protection was a much less prominent theme than concerns over (un)authorized users. PMID- 28631140 TI - Natan Zundel Majerowick, M.D. PMID- 28631139 TI - A Systematic Review of Wearable Patient Monitoring Systems - Current Challenges and Opportunities for Clinical Adoption. AB - The aim of this review is to investigate barriers and challenges of wearable patient monitoring (WPM) solutions adopted by clinicians in acute, as well as in community, care settings. Currently, healthcare providers are coping with ever growing healthcare challenges including an ageing population, chronic diseases, the cost of hospitalization, and the risk of medical errors. WPM systems are a potential solution for addressing some of these challenges by enabling advanced sensors, wearable technology, and secure and effective communication platforms between the clinicians and patients. A total of 791 articles were screened and 20 were selected for this review. The most common publication venue was conference proceedings (13, 54%). This review only considered recent studies published between 2015 and 2017. The identified studies involved chronic conditions (6, 30%), rehabilitation (7, 35%), cardiovascular diseases (4, 20%), falls (2, 10%) and mental health (1, 5%). Most studies focussed on the system aspects of WPM solutions including advanced sensors, wireless data collection, communication platform and clinical usability based on a specific area or disease. The current studies are progressing with localized sensor-software integration to solve a specific use-case/health area using non-scalable and 'silo' solutions. There is further work required regarding interoperability and clinical acceptance challenges. The advancement of wearable technology and possibilities of using machine learning and artificial intelligence in healthcare is a concept that has been investigated by many studies. We believe future patient monitoring and medical treatments will build upon efficient and affordable solutions of wearable technology. PMID- 28631141 TI - Cell Labeling with Magneto-Endosymbionts and the Dissection of the Subcellular Location, Fate, and Host Cell Interactions. AB - PURPOSE: The purposes of this study are to characterize magneto-endosymbiont (ME) labeling of mammalian cells and to discern the subcellular fate of these living contrast agents. MEs are novel magnetic resonance imaging (MRI) contrast agents that are being used for cell tracking studies. Understanding the fate of MEs in host cells is valuable for designing in vivo cell tracking experiments. PROCEDURES: The ME's surface epitopes, contrast-producing paramagnetic magnetosomal iron, and genome were studied using immunocytochemistry (ICC), Fe and MRI contrast measurements, and quantitative polymerase chain reaction (qPCR), respectively. These assays, coupled with other common assays, enabled validation of ME cell labeling and dissection of ME subcellular processing. RESULTS: The assays mentioned above provide qualitative and quantitative assessments of cell labeling, the subcellular localization and the fate of MEs. ICC results, with an ME-specific antibody, qualitatively shows homogenous labeling with MEs. The ferrozine assay shows that MEs have an average of 7 fg Fe/ME, ~30 % of which contributes to MRI contrast and ME-labeled MDA-MB-231 (MDA-231) cells generally have 2.4 pg Fe/cell, implying ~350 MEs/cell. Adjusting the concentration of Fe in the ME growth media reduces the concentration of non-MRI contrast-producing Fe. Results from the qPCR assay, which quantifies ME genomes in labeled cells, shows that processing of MEs begins within 24 h in MDA-231 cells. ICC results suggest this intracellular digestion of MEs occurs by the lysosomal degradation pathway. MEs coated with listeriolysin O (LLO) are able to escape the primary phagosome, but subsequently co-localize with LC3, an autophagy-associated molecule, and are processed for digestion. In embryos, where autophagy is transiently suppressed, MEs show an increased capacity for survival and even replication. Finally, transmission electron microscopy (TEM) of ME-labeled MDA-231 cells confirms that the magnetosomes (the MRI contrast-producing particles) remain intact and enable in vivo cell tracking. CONCLUSIONS: MEs are used to label mammalian cells for the purpose of cell tracking in vivo, with MRI. Various assays described herein (ICC, ferrozine, and qPCR) allow qualitative and quantitative assessments of labeling efficiency and provide a detailed understanding of subcellular processing of MEs. In some cell types, MEs are digested, but the MRI-producing particles remain. Coating with LLO allows MEs to escape the primary phagosome, enhances retention slightly, and confirms that MEs are ultimately processed by autophagy. Numerous intracellular bacteria and all endosymbiotically derived organelles have evolved molecular mechanisms to avoid intracellular clearance, and identification of the specific processes involved in ME clearance provides a framework on which to develop MEs with enhanced retention in mammalian cells. PMID- 28631142 TI - Parametric Imaging of [11C]Flumazenil Binding in the Rat Brain. AB - PURPOSE: This study evaluates the performance of several parametric methods for assessing [11C]flumazenil binding distribution in the rat brain. PROCEDURES: Dynamic (60 min) positron emission tomography data with metabolite-corrected plasma input function were retrospectively analyzed (male Wistar rats, n = 10). Distribution volume (V T) images were generated from basis function method (BFM), Logan graphical analysis (Logan), and spectral analysis (SA). Using the pons as pseudo-reference tissue, binding potential (BP ND and DVR-1) images were obtained from receptor parametric imaging algorithms (RPM and SRTM2) and reference Logan (RLogan). Standardized uptake value images (SUV and SUVR) were also computed for different intervals post-injection. Next, regional averages were extracted from the parametric images, using pre-defined volumes of interest, which were also applied to the regional time-activity curves from the dynamic data. Parametric data were compared to their regional counterparts and to two-tissue compartment model (2TCM)-based values (previously defined as the model of choice for rats). Parameter agreement was assessed by linear regression analysis and Bland-Altman plots. RESULTS: All parametric methods strongly correlated to their regional counterparts (R 2 > 0.97) and to the 2TCM values (R 2 >= 0.95). SA and RLogan underestimated V T and BP ND (slope of 0.93 and 0.86, respectively), while SUVR-1 overestimated BP ND (slope higher than 1.07 for all intervals). While BFM and SRTM2 had the smallest bias to 2TCM values (0.05 for both), ratio Bland-Altman plots showed Logan and RLogan displayed relative errors which were comparable between different regions, in contrast with the other methods. Although SUV consistently underestimated V T, the bias in this method was also constant across regions. CONCLUSIONS: All parametric methods performed well for the analysis of [11C]flumazenil distribution and binding in the rat brain. However, Logan and RLogan slightly outperformed the other methods in terms of precision, providing robust parameter estimation and constant bias. Yet, other methods can be of interest, because they can provide tissue perfusion (i.e., K 1 with BFM and SA), relative flow (i.e., R 1 with RPM and SRTM2), and model order (SA) images. PMID- 28631144 TI - Erratum to: Two doses of low-dose perioperative dexamethasone improve the clinical outcome after total knee arthroplasty: a randomized controlled study. PMID- 28631143 TI - Post-operative 3D CT feedback improves accuracy and precision in the learning curve of anatomic ACL femoral tunnel placement. AB - PURPOSE: To evaluate the feedback from post-operative three-dimensional computed tomography (3D-CT) on femoral tunnel placement in the learning process, to obtain an anatomic anterior cruciate ligament (ACL) reconstruction. METHODS: A series of 60 consecutive patients undergoing primary ACL reconstruction using autologous hamstrings single-bundle outside-in technique were prospectively included in the study. ACL reconstructions were performed by the same trainee-surgeon during his learning phase of anatomic ACL femoral tunnel placement. A CT scan with dedicated tunnel study was performed in all patients within 48 h after surgery. The data obtained from the CT scan were processed into a three-dimensional surface model, and a true medial view of the lateral femoral condyle was used for the femoral tunnel placement analysis. Two independent examiners analysed the tunnel placements. The centre of femoral tunnel was measured using a quadrant method as described by Bernard and Hertel. The coordinates measured were compared with anatomic coordinates values described in the literature [deep-to-shallow distance (X-axis) 28.5%; high-to-low distance (Y-axis) 35.2%]. Tunnel placement was evaluated in terms of accuracy and precision. After each ACL reconstruction, results were shown to the surgeon to receive an instant feedback in order to achieve accurate correction and improve tunnel placement for the next surgery. Complications and arthroscopic time were also recorded. RESULTS: Results were divided into three consecutive series (1, 2, 3) of 20 patients each. A trend to placing femoral tunnel slightly shallow in deep-to-shallow distance and slightly high in high-to-low distance was observed in the first and the second series. A progressive improvement in tunnel position was recorded from the first to second series and from the second to the third series. Both accuracy (+52.4%) and precision (+55.7%) increased from the first to the third series (p < 0.001). Arthroscopic time decreased from a mean of 105 min in the first series to 57 min in the third series (p < 0.001). After 50 ACL reconstructions, a satisfactory anatomic femoral tunnel was reached. CONCLUSION: Feedback from post-operative 3D CT is effective in the learning process to improve accuracy and precision of femoral tunnel placement in order to obtain anatomic ACL reconstruction and helps to reduce also arthroscopic time and learning curve. For clinical relevance, trainee-surgeons should use feedback from post-operative 3DCT to learn anatomic ACL femoral tunnel placement and apply it appropriately. LEVEL OF EVIDENCE: Consecutive case series, Level IV. PMID- 28631145 TI - Biaxial mechanical properties of bovine jugular venous valve leaflet tissues. AB - Venous valve incompetence has been implicated in diseases ranging from chronic venous insufficiency (CVI) to intracranial venous hypertension. However, while the mechanical properties of venous valve leaflet tissues are central to CVI biomechanics and mechanobiology, neither stress-strain curves nor tangent moduli have been reported. Here, equibiaxial tensile mechanical tests were conducted to assess the tangent modulus, strength and anisotropy of venous valve leaflet tissues from bovine jugular veins. Valvular tissues were stretched to 60% strain in both the circumferential and radial directions, and leaflet tissue stress strain curves were generated for proximal and distal valves (i.e., valves closest and furthest from the right heart, respectively). Toward linking mechanical properties to leaflet microstructure and composition, Masson's trichrome and Verhoeff-Van Gieson staining and collagen assays were conducted. Results showed: (1) Proximal bovine jugular vein venous valves tended to be bicuspid (i.e., have two leaflets), while distal valves tended to be tricuspid; (2) leaflet tissues from proximal valves exhibited approximately threefold higher peak tangent moduli in the circumferential direction than in the orthogonal radial direction (i.e., proximal valve leaflet tissues were anisotropic; [Formula: see text]); (3) individual leaflets excised from the same valve apparatus appeared to exhibit different mechanical properties (i.e., intra-valve variability); and (4) leaflets from distal valves exhibited a trend of higher soluble collagen concentrations than proximal ones (i.e., inter-valve variability). To the best of the authors' knowledge, this is the first study reporting biaxial mechanical properties of venous valve leaflet tissues. These results provide a baseline for studying venous valve incompetence at the tissue level and a quantitative basis for prosthetic venous valve design. PMID- 28631146 TI - Motivations for Interest, Disinterest and Uncertainty in Intrauterine Device Use Among Young Women. AB - Objective To elucidate salient contraceptive preferences and priorities as they relate to young women's interest or lack thereof in intrauterine device (IUD) use. Methods Qualitative data were drawn from a 2012 survey on contraceptive preferences and IUD interest. Among 413 young (ages 18-29) women, open-ended responses describing reasons for interest, disinterest or uncertainty in future IUD use were examined using a thematic analysis approach. Results Most participants were unsure about (49.2%) or not interested in (30.0%) future IUD use. Themes regarding IUD interest related to specific facets of IUD use (e.g., risks and side effects, ease of use), as well as broader influences on contraceptive decision-making (e.g., social influences, alignment with pregnancy intentions). For interested participants, a sense of empowerment pervaded the responses, with many references to the ease of use and lack of requisite maintenance. Uninterested participants were concerned about the internal nature of the IUD, with many describing "horror stories" and fears that the IUD would cause injury or infertility. Unsure participants provided more detailed and complex responses, carefully weighing the advantages and disadvantages of IUD use. Uncertainty was often driven by an acknowledged need for specific information, rather than overall lack of knowledge. Conclusions for Practice In this analysis, many women had a clear sense of their contraceptive preferences, which frequently did not align with IUDs. While continuing to remove barriers to IUD access is critical, patient-centered counseling approaches offer the opportunity to support women in best matching with a method that aligns with their preferences. PMID- 28631147 TI - The motor cortical representation of a muscle is not homogeneous in brain connectivity. AB - Functional connectivity patterns of the motor cortical representational area of single muscles have not been extensively mapped in humans, particularly for the axial musculature. Functional connectivity may provide a neural substrate for adaptation of muscle activity in axial muscles that have both voluntary and postural functions. The purpose of this study was to combine brain stimulation and neuroimaging to both map the cortical representation of the external oblique (EO) in primary motor cortex (M1) and supplementary motor area (SMA), and to establish the resting-state functional connectivity associated with this representation. Motor-evoked potentials were elicited from the EO muscle in stimulation locations encompassing M1 and SMA. The coordinates of locations with the largest motor-evoked potentials were confirmed with task-based fMRI imaging during EO activation. The M1 and SMA components of the EO representation demonstrated significantly different resting-state functional connectivity with other brain regions: the SMA representation of the EO muscle was significantly more connected to the putamen and cerebellum, and the M1 representation of the EO muscle was significantly more connected to somatosensory cortex and the superior parietal lobule. This study confirms the representation of a human axial muscle in M1 and SMA, and demonstrates for the first time that different parts of the cortical representation of a human axial muscle have resting-state functional connectivity with distinct brain regions. Future studies can use the brain regions of interest we have identified here to test the association between resting-state functional connectivity and control of the axial muscles. PMID- 28631148 TI - Early postoperative imaging after non-bariatric gastric resection: a primer for radiologists. AB - : Surgical resection represents the mainstay treatment and only potentially curative option for gastric carcinoma, and is increasingly performed laparoscopically. Furthermore, other tumours and selected cases of non-malignant disorders of the stomach may require partial or total gastrectomy. Often performed in elderly patients, gastric resection remains a challenging procedure, with significant morbidity (14-43% complication rate) and non-negligible postoperative mortality (approximately 3%). This paper provides an overview of contemporary surgical techniques for non-bariatric gastric resection, reviews and illustrates the expected postoperative imaging appearances, common and unusual complications after partial and total gastrectomy. Albeit cumbersome or unfeasible in severely ill or uncooperative patients, contrast fluoroscopy remains useful to rapidly check for anastomotic patency and integrity. Currently, emphasis is placed on multidetector CT, which comprehensively visualizes the surgically altered anatomy and consistently detects complications such as anastomotic leaks and fistulas, duodenal stump leakage, afferent loop syndrome, haemorrhages, pancreatic fistulas and porto-mesenteric venous thrombosis. Our aim is to help radiologists become familiar with early postoperative imaging, in order to understand the surgically altered anatomy and to differentiate between expected imaging appearances and abnormal changes heralding iatrogenic complications, thus providing a consistent basis for correct choice between conservative, interventional or surgical treatment. TEACHING POINTS: * Radical gastrectomy is associated with frequent postoperative morbidity and non negligible mortality. * In cooperative patients fluoroscopy allows checking for anastomotic patency and leaks. * Multidetector CT with / without oral contrast comprehensively visualizes the operated abdomen. * Awareness of surgically altered anatomy and expected postoperative appearances is warranted. * Main complications include anastomotic and duodenal leaks, haemorrhages and pancreatic fistulas. PMID- 28631149 TI - Vigor of survival determinism: subtle evolutionary gradualism interspersed with robust phylogenetic leaping. AB - Discussions of the survival determinism concept have previously focused on its primary role in the evolution of early unicellular organisms in the light of findings which have been reported on a number of diseases. The rationale for such parallel was in the view according to which multicellular organisms could be regarded as sophisticated colonies of semi-autonomous, single-celled entities, whereby various diseases were described as conditions arising upon the activation of the respective survival mechanisms in a milieu unsuitable for such robust stress response. The cellular mechanisms that were discussed in these contexts have been known to play various roles in other biological processes. The proposed notion could thereby be further extended to discussion on mechanisms for the implementation of the respective survival pathways in the development of metazoa, considering that they would have been propagated in their evolution for so long. This manuscript first presents a concise overview of the model previously discussed, followed by the discussion on the role of respective mechanism(s) in origins and development of metazoa. Finally, a reflection on the concept in relation to the prominent evolutionary models is put forward to illustrate a broader context of what is being discussed. PMID- 28631150 TI - Low-dose subcutaneous ketamine for postoperative pain management in Rwanda: a dose-finding study. AB - PURPOSE: Good pain control is not a normal part of surgical care in sub-Saharan Africa due to lack of resources. The primary objective of this study was to determine an efficacious dose of subcutaneous ketamine for postoperative pain for use in a future randomized controlled trial. METHODS: Following research ethics board and local hospital approval for this research, we obtained informed consent from 31 patients undergoing major surgery for a random walk dose-finding study. In addition to standard postoperative care, participants received five doses of subcutaneous ketamine at scheduled intervals from arrival in the postanesthesia care unit (PACU) to postoperative day 2. Participants received 50 mg of ketamine (minimum 0.6 to maximum 1.1 mg.kg-1, based on different body weights) for the first and second dose, with subsequent doses adjusted by 10 mg according to pain and side effects. Pain scores were recorded at rest and with movement. RESULTS: The following mean (standard deviation [SD]) pain scores at rest and with movement were recorded on arrival in the PACU and on the afternoon of postoperative days 1 and 2: [at rest: 8.2 (1.5), 3.2 (1.8), and 0.7 (1.0), respectively; with movement: 9.4 (0.8), 5.1 (1.7), and 2.4 (1.1), respectively]. This rate of improvement suggests possible pain relief through use of ketamine. The mean (SD) ketamine dose that appeared efficacious in pain reduction was 0.90 (0.23) mg.kg-1. There were no serious side effects. CONCLUSION: Adding subcutaneous ketamine to standard analgesic measures resulted in decreases in postoperative pain scores without serious side effects. These data can be used to inform a randomized controlled trial to compare subcutaneous ketamine plus standard care with placebo plus standard care for reducing postoperative pain. PMID- 28631151 TI - Epidural blood patch treatment for headache caused by a ruptured Tarlov cyst. PMID- 28631152 TI - Ketamine: We need to continue to advocate against scheduling. PMID- 28631153 TI - Lung Cancer in the Oldest Old: A Nation-Wide Study in The Netherlands. AB - INTRODUCTION: An important step in improving research and care for the oldest patients with lung cancer is analyzing current data regarding diagnostic work-up, treatment choices, and survival. METHODS: We analyzed data on lung cancer from the Netherlands Cancer Registry (NCR-IKNL) regarding diagnostic work-up, treatment, and survival in different age categories; the oldest old (>=85 years of age) versus those aged 71-84 (elderly) and those aged <=70 years (younger patients). RESULTS: 47,951 patients were included in the 2010-2014 NCR database. 2196 (5%) patients were aged >=85 years. Histological diagnosis was obtained significantly less often in the oldest old (38%, p < 0.001), and less standard treatment regimen was given (8%, p < 0.001) compared to elderly and younger patients. 67% of the oldest old received best supportive care only versus 38% of the elderly and 20% of the younger patients (p < 0.001). For the oldest old receiving standard treatment, survival rates were similar in comparison with the elderly patients. In the oldest old, no survival differences were found when comparing standard or adjusted regimens for stage I and IV NSCLC; for stage III, oldest old receiving standard treatment had longer survival. No oldest old patients with stage II received standard treatment. CONCLUSION: Clinicians make limited use of diagnostics and invasive treatment in the oldest old; however, selected oldest old patients experienced similar survival rates as the elderly when receiving some form of anticancer therapy (standard or adjusted). More research is needed to further develop individualized treatment algorithms. PMID- 28631154 TI - Soil-derived organic particles and their effects on the community of culturable microorganisms. AB - Soil microbial community interacts with a range of particulate material in the soil, consisting of both inorganic and organic compounds with different levels of water solubility. Though sparingly water-soluble and insoluble organic compounds in the soil may affect living organisms, they are difficult to introduce into microbiological media. Their biological activity (i.e., their effect on soil microorganisms) thus has been almost neglected in most of the cultivation assays. To fill this gap, we propose the use of fine organic particles prepared from soil organic matter that are introduced into a laboratory medium where microbial community is cultivated. To this purpose, submicrometer particles consisting of sparingly water-soluble or insoluble soil organic matter were obtained from humic horizons of two soils by precipitation of organics dissolved in tetrahydrofuran by addition of water. The particles could then be size fractionated by centrifugation, and coarse fraction obtained from humic horizon formed under spruce forest was tested for effects on complex microbial community developing under laboratory conditions. The results indicate that low concentration (20 mg/L) of the particles is efficient to affect the composition of the bacterial community revealed by terminal restriction fragment length polymorphism. The work contributes to understanding the factors that determine the composition of soil microbial community. PMID- 28631155 TI - A simple and facile synthesis of tricyclic-fused pyrimido[4,5-b]indol-2-amines. AB - In the present investigation, a simple and facile synthetic strategy for the construction of a series of structurally interesting tricyclic-fused N-alkyl-9H pyrimido[4,5-b]indol-2-amines has been successfully achieved. Our synthesis, based on the annulation reaction between readily available 2-chloroindole-3 carbaldehydes or 3-acetyl-2-chloroindoles and guanidine nitrate using KOH as the base in refluxing EtOH medium, has the attractive features such as mild and economical reaction conditions and easy handing with lesser impact on the environment. PMID- 28631156 TI - Diagnosis of secondary pulmonary lymphangiectasia in congenital heart disease: a novel role for chest ultrasound and prognostic implications. AB - BACKGROUND: Secondary pulmonary lymphangiectasia is a complication of congenital heart disease that results from chronic pulmonary venous obstruction. OBJECTIVES: We aimed to evaluate the performance of chest ultrasound (US) in diagnosing secondary pulmonary lymphangiectasia and to review the clinical course of children with secondary pulmonary lymphangiectasia. MATERIALS AND METHODS: Chest US was performed on 26 children with hypoplastic left heart syndrome, total anomalous pulmonary venous connection or cor triatriatum in a prospective observational study. Thirteen children had pulmonary venous obstruction (62% male; median age: 17 days old, range: 1-430 days old) and 13 children did not have obstruction (62% male; median age: 72 days old, range: 4-333 days old). US features of secondary pulmonary lymphangiectasia were documented and diagnostic performance was determined. Clinical course of patients with secondary pulmonary lymphangiectasia was reviewed. RESULTS: Eleven of 13 (84.6%) patients in the obstructed group had a clinical and/or biopsy diagnosis of secondary pulmonary lymphangiectasia. Statistically significant chest US criteria for diagnosis were presence of irregular lung surface (likelihood ratio [LR] 6.8, 95% confidence interval [CI] 1.9-25.1), subpleural cystic appearing structures (LR 3.6, 95% CI 1.2-10.7), and combination of subpleural cystic appearing structures and surface irregularity together (LR 10.9, 95% CI 1.6-75.0). Seven of 11 (63.6%) patients with secondary pulmonary lymphangiectasia died during follow-up, the majority due to cardiopulmonary failure or complications. CONCLUSION: Chest US is an accurate and reproducible bedside method for diagnosing secondary pulmonary lymphangiectasia in patients with pulmonary venous obstruction. These patients may have worse prognoses. PMID- 28631157 TI - Performance characteristics of magnetic resonance imaging without contrast agents or sedation in pediatric appendicitis. AB - BACKGROUND: Magnetic resonance imaging (MRI) has emerged as a promising modality for evaluating pediatric appendicitis. However optimal imaging protocols, including roles of contrast agents and sedation, have not been established and diagnostic criteria have not been fully evaluated. OBJECTIVE: To investigate performance characteristics of rapid MRI without contrast agents or sedation in the diagnosis of pediatric appendicitis. MATERIALS AND METHODS: We included patients ages 4-18 years with suspicion of appendicitis who underwent rapid MRI between October 2013 and March 2015 without contrast agent or sedation. After two radiologist review, we determined performance characteristics of individual diagnostic criteria and aggregate diagnostic criteria by comparing MRI results to clinical outcomes. We used receiver operating characteristic (ROC) curves to determine cut-points for appendiceal diameter and wall thickness for optimization of predictive power, and we calculated area under the curve (AUC) as a measure of test accuracy. RESULTS: Ninety-eight MRI examinations were performed in 97 subjects. Overall, MRI had a 94% sensitivity, 95% specificity, 91% positive predictive value and 97% negative predictive value. Optimal cut-points for appendiceal diameter and wall thickness were >=7 mm and >=2 mm, respectively. Independently, those cut-points produced sensitivities of 91% and 84% and specificities of 84% and 43%. Presence of intraluminal fluid (30/33) or localized periappendiceal fluid (32/33) showed a significant association with acute appendicitis (P<0.01), with sensitivities of 91% and 97% and specificities of 60% and 50%. For examinations in which the appendix was not identified by one or both reviewers (23/98), the clinical outcome was negative. CONCLUSION: Rapid MRI without contrast agents or sedation is accurate for diagnosis of pediatric appendicitis when multiple diagnostic criteria are considered in aggregate. Individual diagnostic criteria including optimized cut-points of >=7 mm for diameter and >=2 mm for wall thickness demonstrate high sensitivities but relatively low specificities. Nonvisualization of the appendix favors a negative diagnosis. PMID- 28631158 TI - Rapid and reliable steroid hormone profiling in Tursiops truncatus blubber using liquid chromatography tandem mass spectrometry (LC-MS/MS). AB - Monitoring of marine mammal steroid hormone status using matrices alternative to blood is desirable due to the ability to remotely collect samples, which minimizes stress to the animal. However, measurement techniques in alternative matrices such as blubber described to date are limited in the number and types of hormones measured. Therefore, a new method using bead homogenization to QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) extraction, C18 post extraction cleanup and analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and applied to the measurement of hormone suites in bottlenose dolphin blubber. Validations were conducted in blubber from fresh dead stranded bottlenose dolphin. The final method consisting of two LC separations and garnet bead homogenization was tested for extraction efficiencies. Steroids were separated using a biphenyl column for reproductive hormones and C18 column for corticosteroids. Three hormones previously noted in blubber, testosterone, progesterone, and cortisol, were quantified in addition to previously unmeasured androstenedione, 17-hydroxyprogesterone, 11-deoxycortisol, 11 deoxycorticosterone, and cortisone in a single sample (0.4 g blubber). Extraction efficiencies of all hormones from blubber ranged from 84% to 112% and all RSDs were comparable to those reported using immunoassay methods (< 15%). The method was successfully applied to remote biopsied blubber samples to measure baseline hormone concentrations. Through this method, increased coverage of steroid hormone pathways from a single remotely collected sample potentially enhances the ability to interpret biological phenomena such as reproduction and stress in wild dolphin populations. Graphical abstract The steroid hormone profile is quantifiable from a single sample of bottlenose dolphin blubber using liquid chromatography tandem mass spectrometry. This profile can be applied to remotely collected dart biopsies and be used to determine reproductive or stress status of a wild-living dolphin. PMID- 28631160 TI - Role of imaging in the follow-up of T2-T3 glottic cancer treated by transoral laser microsurgery. AB - An unblinded retrospective analysis of prospectively collected data was carried out on 138 patients affected by glottic pT2 and selected pT3 squamous cell carcinomas (SCC) treated by transoral laser microsurgery (TLM). The entire cohort was divided into two groups: Group A included 78 "high-risk" patients (pT2 with impaired vocal cord mobility, pT3 for anterior paraglottic and/or pre-epiglottic space invasion, presence of angioembolization, perineural spread, and positive lymph nodes in the neck) who underwent postoperative surveillance by endoscopy and imaging (CT or MR), while Group B included 60 "low-risk" patients (pT2 with absence of the above-mentioned features) who underwent endoscopic follow-up alone. Aim of the present study was to assess the diagnostic gain in performing combined endoscopic and radiologic surveillance in the "high-risk" group compared to endoscopy alone in the "low-risk" one. There was no significant difference in terms of overall and disease-specific survivals between the two follow-up policies in spite of their different risk profiles. The same was true for organ preservation rate, which was 81% in the "high-risk" and 89% in the "low-risk" group. In contrast, the cumulative probability of disease-free survival was 54% for Group A and 65% for Group B (p = 0.0023). Therefore, our combined endoscopy and imaging surveillance protocol allowed increasing the submucosal recurrence detection rate in "high-risk" pT2-pT3 glottic SCC to 43%. An earlier detection of submucosal recurrences made salvage surgery by TLM feasible in at least half of cases, thus closing the gap between oncologic outcomes obtained in "high-"- vs. "low-risk" patients and leading to organ preservation rates that are favorably comparable to those obtained with open-neck partial laryngectomies and non surgical organ preservation protocols. PMID- 28631159 TI - Distinctive pathological and clinical features of lung carcinoids with high proliferation index. AB - Typical (TCs) and atypical carcinoids (ACs) are defined based on morphological criteria, and no grading system is currently accepted to further stratify these entities. The 2015 WHO classification restricts the Ki-67 role to biopsy or cytology samples, rather than for prognostic prediction. We aimed to investigate whether values and patterns of Ki-67 alone would allow for a clinically meaningful stratification of lung carcinoids, regardless of histological typing. Ki-67 proliferation index and pattern (homogeneous versus heterogeneous expression) were assessed in a cohort of 171 TCs and 68 ACs. Cases were subdivided into three Ki-67 ranges (<4/4-9/>=10%). Correlations with clinicopathological data, univariate and multivariate survival analyses were performed. The majority of cases (61.5%) belonged to the <4% Ki-67 range; 25.1 and 13.4% had a proliferation index of 4-9% and >=10%, respectively. The <4% Ki 67 subgroup was significantly enriched for TCs (83%, p < 0.0001); ACs were more frequent in the subgroup showing Ki-67 >= 10% (75%, p < 0.0001). A heterogeneous Ki-67 pattern was preferentially seen in carcinoids with a Ki-67 >=10% (38%, p < 0.02). Mean Ki-67 values >=4 and >=10% identified categories of poor prognosis both in terms of disease-free and overall survival (p = 0.003 and <0.0001). At multivariate analysis, the two thresholds did not retain statistical significance; however, a Ki-67 >= 10% identified a subgroup of dismal prognosis even within ACs (p = 0.03) at univariate analysis. Here, we describe a subgroup of lung carcinoids showing brisk proliferation activity within the necrosis and/or mitotic count-based categories. These patients were associated with specific clinicopathological characteristics, to some extent regardless of histological subtyping. PMID- 28631161 TI - The role of eABR with intracochlear test electrode in decision making between cochlear and brainstem implants: preliminary results. AB - The objective of the study was to discuss the findings of intraoperative electrically evoked auditory brainstem response (eABR) test results with a recently designed intracochlear test electrode (ITE) in terms of their relation to decisions of cochlear or auditory brainstem implantation. This clinical study was conducted in Hacettepe University, Department of Otolaryngology, Head and Neck Surgery and Department of Audiology. Subjects were selected from inner ear malformation (IEM) database. Eleven subjects with profound sensorineural hearing loss were included in the current study with age range from 1 year 3 months to 4 years 3 months for children with prelingual hearing loss. There was only one 42 year-old post-lingual subject. eABR was recorded with an ITE and intraoperatively with an original cochlear implant (CI) electrode in 11 cases with different IEMs. Findings of eABR with ITE and their relation to the decision for CI or auditory brainstem implant (ABI) are discussed. Positive eABR test results were found to be dependent on close to normal cochlear structures and auditory nerve. The probability of positive result decreases with increasing degree of malformation severity. The prediction value of eABR via ITE on decision for hearing restoration was found to be questionable in this study. The results of eABR with ITE have predictive value on what we will get with the actual CI electrode. ITE appears to stimulate the cochlea like an actual CI. If the eABR is positive, the results are reliable. However, if eABR is negative, the results should be evaluated with preoperative audiological testing and MRI findings. PMID- 28631162 TI - Core curriculum case illustration: blunt traumatic thoracic aortic pseudo aneurysm. AB - Core Curriculum Illustration: [blunt thoracic aortic pseudo aneurysm]. This is the [40th] installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.aseronline.org/curriculum/toc.html. PMID- 28631163 TI - Evaluation of Streck BCT and PAXgene Stabilised Blood Collection Tubes for Cell Free Circulating DNA Studies in Plasma. AB - INTRODUCTION: Blood samples for studies of circulating DNA in disease are often collected in clinical settings where prompt processing of samples is not possible. In order to avoid problems associated with leukocyte lysis after prolonged blood storage, stabilised blood tubes have been developed containing preservatives that prevent cell lysis. We evaluated Streck BCT tubes and PAXgene ccfDNA tubes, as well as standard EDTA blood collection tubes, in terms of DNA yield and fragment size. METHODS: Blood was collected in EDTA, Streck BCT or PAXgene ccfDNA tubes and stored for 1 h at 4 degrees C, or 4 days at room temperature. DNA was extracted using the QIAamp Circulating Nucleic Acids kit, and visualised on an agarose gel or quantitated by qPCR. Ratios of a 247-base and a 115-base amplicon of the Alu repetitive element were used to infer size distribution. RESULTS: While plasma DNA in EDTA tube blood samples increased by ~10- to 20-fold after 4 days of storage at room temperature, both Streck BCT tubes and PAXgene ccfDNA tubes maintained stable plasma DNA concentrations. A slight decrease in DNA yield following 1 h of blood storage at 4 degrees C was observed in Streck BCT and PAXgene ccfDNA tubes relative to EDTA tubes. This decrease was reversed by increasing the proteinase digest step of the DNA extraction protocol to 60 min, as recommended by Streck tube product literature. Visualisation of the extracted DNA on an agarose gel showed that after 4 days of room temperature storage, samples collected in EDTA tubes contained abundant high molecular weight DNA, which was partially fragmented in a ladder pattern. A slight increase in high-molecular weight DNA in samples stored for 4 days at room temperature in Streck BCT tubes was also observed, but this was not reflected in a change in large and small Alu fragment ratios as measured by qPCR. CONCLUSIONS: Tubes containing preservative to prevent cell lysis can extend the scope for blood collection in clinical settings; however, slight differences between samples collected in different tube types underscore the requirement for standardised protocols, as well as attention to sample handling. PMID- 28631164 TI - Studies on vertical transmission of Trichinella spiralis in experimentally infected guinea pigs (Cavia porcellus). AB - An experimental study to enhance knowledge on the capability of Trichenella spiralis to pass from guinea pigs to progeny at different periods of pregnancy or lactation was performed. For this purpose, 18 female adult guinea pigs were inoculated with 100 or 1000 T. spiralis muscle larvae (ML) during early, late gestation and during lactation period. The presence of T. spiralis (ML) in mothers and newborns was studied through enzymatic digestion from muscle samples. ML were observed in 9 of 42 newborn guinea pigs and levels of infection were significantly higher when infections of mothers were done during late gestation (p = 0.0046) with the high infective dose (p = 0.0043). T. spiralis ML were not recovered from any of the newborns from mothers infected in the lactation period. Ten out of 18 infected mothers presented larvae 1 in their mammary glands. Muscle samples from the tongue and the masseter showed the highest larval burdens. These observations confirm previous reports on that ML of T. spiralis are capable to pass through placental tissues to reach and encyst in striated muscle groups of newborn guinea pigs. This study may also reinforce the importance of preventive programs to control trichinellosis in those endemic areas where pregnant women would have high risk of infection. PMID- 28631165 TI - Thoracic Aneurysms and Dissections: Towards a Further and Better Knowledge. PMID- 28631166 TI - Morphology and the gradient of a symmetric potential predict gait transitions of dogs. AB - Gaits and gait transitions play a central role in the movement of animals. Symmetry is thought to govern the structure of the nervous system, and constrain the limb motions of quadrupeds. We quantify the symmetry of dog gaits with respect to combinations of bilateral, fore-aft, and spatio-temporal symmetry groups. We tested the ability of symmetries to model motion capture data of dogs walking, trotting and transitioning between those gaits. Fully symmetric models performed comparably to asymmetric with only a [Formula: see text] increase in the residual sum of squares and only one-quarter of the parameters. This required adding a spatio-temporal shift representing a lag between fore and hind limbs. Without this shift, the symmetric model residual sum of squares was [Formula: see text] larger. This shift is related to (linear regression, [Formula: see text], [Formula: see text]) dog morphology. That this symmetry is respected throughout the gaits and transitions indicates that it generalizes outside a single gait. We propose that relative phasing of limb motions can be described by an interaction potential with a symmetric structure. This approach can be extended to the study of interaction of neurodynamic and kinematic variables, providing a system-level model that couples neuronal central pattern generator networks and mechanical models. PMID- 28631167 TI - Copper and ectopic expression of the Arabidopsis transport protein COPT1 alter iron homeostasis in rice (Oryza sativa L.). AB - KEY MESSAGE: Copper deficiency and excess differentially affect iron homeostasis in rice and overexpression of the Arabidopsis high-affinity copper transporter COPT1 slightly increases endogenous iron concentration in rice grains. Higher plants have developed sophisticated mechanisms to efficiently acquire and use micronutrients such as copper and iron. However, the molecular mechanisms underlying the interaction between both metals remain poorly understood. In the present work, we study the effects produced on iron homeostasis by a wide range of copper concentrations in the growth media and by altered copper transport in Oryza sativa plants. Gene expression profiles in rice seedlings grown under copper excess show an altered expression of genes involved in iron homeostasis compared to standard control conditions. Thus, ferritin OsFER2 and ferredoxin OsFd1 mRNAs are down-regulated whereas the transcriptional iron regulator OsIRO2 and the nicotianamine synthase OsNAS2 mRNAs rise under copper excess. As expected, the expression of OsCOPT1, which encodes a high-affinity copper transport protein, as well as other copper-deficiency markers are down-regulated by copper. Furthermore, we show that Arabidopsis COPT1 overexpression (C1 OE ) in rice causes root shortening in high copper conditions and under iron deficiency. C1 OE rice plants modify the expression of the putative iron-sensing factors OsHRZ1 and OsHRZ2 and enhance the expression of OsIRO2 under copper excess, which suggests a role of copper transport in iron signaling. Importantly, the C1 OE rice plants grown on soil contain higher endogenous iron concentration than wild type plants in both brown and white grains. Collectively, these results highlight the effects of rice copper status on iron homeostasis, which should be considered to obtain crops with optimized nutrient concentrations in edible parts. PMID- 28631169 TI - Zika virus infection in Vietnam: current epidemic, strain origin, spreading risk, and perspective. AB - Zika virus infection and its associated microcephaly have being receiving global concern. This infection has spread widely since the first outbreak was recorded in Africa in 1952. Now, it has been reported in over 70 countries on five continents including Africa, North and South America, Asia, and Europe. Vietnam is one of the most recent countries which had cases of Zika virus infection at the end of 2016. This country has also reported the first case of a microcephaly born baby which was probably linked to Zika virus infection. However, information on the Zika virus epidemic in Vietnam is still limited. This brief report intends to update the current Zika virus epidemic, and to discuss challenges and perspectives in controlling this infection in Vietnam. PMID- 28631168 TI - The function of OsbHLH068 is partially redundant with its homolog, AtbHLH112, in the regulation of the salt stress response but has opposite functions to control flowering in Arabidopsis. AB - KEY MESSAGE: The homologous genes OsbHLH068 and AtbHLH112 have partially redundant functions in the regulation of the salt stress response but opposite functions to control flowering in Arabidopsis. The transcription factor (TF) basic/Helix-Loop-Helix (bHLH) is important for plant growth, development, and stress responses. OsbHLH068, which is a homologous gene of AtbHLH112 that is up regulated under drought and salt stresses, as indicated by previous microarray data analysis. However, the intrinsic function of OsbHLH068 remains unknown. In the present study, we characterized the function and compared the role of OsbHLH068 with that of its homolog, AtbHLH112. Histochemical GUS staining indicated that OsbHLH068 and AtbHLH112 share a similar expression pattern in transgenic Arabidopsis during the juvenile-to-adult phase transition. Heterologous overexpression of OsbHLH068 in Arabidopsis delays seed germination, decreases salt-induced H2O2 accumulation, and promotes root elongation, whereas AtbHLH112 knock-out mutant displays an opposite phenotype. Both OsbHLH068 overexpressing transgenic Arabidopsis seedlings and the Atbhlh112 mutant display a late-flowering phenotype. Moreover, the expression of OsbHLH068-GFP driven by an AtbHLH112 promoter can compensate for the germination deficiency in the Atbhlh112 mutant, but the delayed-flowering phenotype tends to be more severe. Further analysis by microarray and qPCR indicated that the expression of FT is down-regulated in both OsbHLH068-overexpressing Arabidopsis plants and Atbhlh112 mutant plants, whereas SOC1 but not FT is highly expressed in AtbHLH112 overexpressing Arabidopsis plants. A comparative transcriptomic analysis also showed that several stress-responsive genes, such as AtERF15 and AtPUB23, were affected in both OsbHLH068- and AtbHLH112-overexpressing transgenic Arabidopsis plants. Thus, we propose that OsbHLH068 and AtbHLH112 share partially redundant functions in the regulation of abiotic stress responses but have opposite functions to control flowering in Arabidopsis, presumably due to the evolutionary functional divergence of homolog-encoded proteins. PMID- 28631170 TI - Development of a peptide ELISA to discriminate vaccine-induced immunity from natural infection of hepatitis A virus in a phase IV study. AB - Hepatitis A virus (HAV) is a highly infectious agent that causes acute liver disease. The infection can trigger the production of antibodies against the structural and non-structural proteins of HAV. Nonetheless, vaccination with an HAV vaccine leads to the production of a primary antibody against the structural proteins. Because the non-structural proteins are only produced during active virus replication, there is no or very little antibody production against the non structural proteins. However, the current commercial immunoassay cannot distinguish between antibodies produced during natural infection and those from vaccination against HAV. In our study, six immune-dominant epitopes from the non structural proteins were designed, synthesized, linked together and cloned into pGEX-5X-1 plasmid. The recombinant protein was expressed in E. coli and purified by Ni2+-coated magnetic agarose beads. Then the purified recombinant protein was used as an ELISA antigen to detect antibodies for HAV non-structural proteins in serum samples. Seventy-seven attenuated and 89 inactivated vaccinated samples collected from our previous phase IV study of HAV vaccines were detected by peptide ELISA developed in this study. The mean OD450 value for the vaccination samples and acute infection samples were 0.529 (0.486 for the attenuated group and 0.567 for the inactivated group) and 1.187, respectively. According to the receiver operating characteristic (ROC) curve, the sensitivity and specificity of the peptide ELISA were 93.80% and 91.00%, respectively. This peptide ELISA was confirmed to discriminate vaccine-induced immunity from natural infection of HAV in a phase IV study with high sensitivity and specificity. PMID- 28631171 TI - Qualitative Assessment of Vaccination Hesitancy Among Members of the Apostolic Church of Zimbabwe: A Case Study. AB - Vaccine hesitancy or lack of confidence in vaccines is considered a threat to the success of vaccination programs. The rise and spread of measles outbreaks in southern Africa in 2009-2010 were linked to objections among Apostolic Church members, estimated at about 3.5 million in Zimbabwe as of 2014. To inform planning of interventions for a measles-rubella vaccination campaign, we conducted an assessment of the factors contributing to vaccine hesitancy using data from various stakeholders. Among nine districts in three regions of Zimbabwe, we collected data on religious attitudes toward, and perceptions of, vaccines through focus group discussions with health workers serving Apostolic communities and members of the National Expanded Programme on Immunization; semi structured interviews with religious leaders; and open-ended questions in structured interviews with Apostolic parents/caregivers. Poor knowledge of vaccines, lack of understanding and appreciation of the effectiveness of vaccinations, religious teachings that emphasize prayers over the use of medicine, lack of privacy in a religiously controlled community, and low levels of education were found to be the main factors contributing to vaccine hesitancy among key community members and leaders. Accepting vaccination in public is a risk of sanctions. Poor knowledge of vaccines is a major factor of hesitancy which is reinforced by religious teachings on the power of prayers as alternatives. Because parents/caregivers perceive vaccines as dangerous for their children and believe they can cause death or disease, members of the Apostolic Church have more confidence in alternative methods such as use of holy water and prayers to treat diseases. Under these circumstances, it is important to debunk the myths about the power of holy water on the one hand and disseminate positive information of the efficacy of vaccines on the other hand in order to reduce hesitancy. Education about vaccines and vaccination in conjunction with government intervention, for example, through the use of social distancing policies can provide a framework for reducing hesitancy and increasing demand for vaccination. PMID- 28631172 TI - Glutamine: a major player in nitrogen catabolite repression in the yeast Dekkera bruxellensis. AB - In the present work we studied the expression of genes from nitrogen central metabolism in the yeast Dekkera bruxellensis and under regulation by the Nitrogen Catabolite Repression mechanism (NCR). These analyses could shed some light on the biological mechanisms involved in the adaptation and survival of this yeast in the sugarcane fermentation process for ethanol production. Nitrogen sources (N sources) in the form of ammonium, nitrate, glutamate or glutamine were investigated with or without the addition of methionine sulfoximine, which inhibits the activity of the enzyme glutamine synthetase and releases cells from NCR. The results showed that glutamine might act as an intracellular sensor for nitrogen availability in D. bruxellensis, by activating NCR. Gene expression analyses indicated the existence of two different GATA-dependent NCR pathways, identified as glutamine-dependent and glutamine-independent mechanisms. Moreover, nitrate is sensed as a non-preferential N-source and releases NCR to its higher level. After grouping genes according to their regulation pattern, we showed that genes for ammonium assimilation represent a regulon with almost constitutive expression, while permease encoding genes are mostly affected by the nitrogen sensor mechanism. On the other hand, nitrate assimilation genes constitute a regulon that is primarily subjected to induction by nitrate and, to a lesser extent, to a repressive mechanism by preferential N-sources. This observation explains our previous reports showing that nitrate is co-consumed with ammonium, a trait that enables D. bruxellensis cells to scavenge limiting N-sources in the industrial substrate and, therefore, to compete with Saccharomyces cerevisiae in this environment. PMID- 28631173 TI - Three New Soil-inhabiting Species of Trichoderma in the Stromaticum Clade with Test of Their Antagonism to Pathogens. AB - Trichoderma is a dominant component of the soil mycoflora. During the field investigations of northern, central, and southwestern China, three new species in the Stromaticum clade were encountered from soil, and named as T. hebeiense, T. sichuanense, and T. verticillatum. Their phylogenetic positions were determined by analyses of the combined two genes: partial sequences of translation elongation factor 1-alpha and the second largest RNA polymerase subunit-encoding genes. Distinctions between the new species and their close relatives were discussed. Trichoderma hebeiense appeared as a separate terminal branch. The species is distinctive by its oblong conidia and aggregated pustules in culture. Trichoderma sichuanense features in concentric colony and produces numerous clean exudates on aerial mycelium in culture. Trichoderma verticillatum is characterized by its verticillium-like synanamorph and production of abundant chlamydospores. In vitro antagonism towards the new species was tested by dual culture technique. PMID- 28631174 TI - Studies of the Interaction of Influenza Virus RNA Polymerase PAN with Endonuclease Inhibitors. AB - Influenza virus is a major causative agent of respiratory viral infections, and RNA polymerase catalyzes its replication and transcription activities in infected cell nuclei. Since it is highly conserved in all virus strains, RNA polymerase becomes a key target of anti-influenza virus agents. Although experimental studies have revealed the good inhibitory activity of endonuclease inhibitors to RNA polymerase, the mechanism is still unclear. In this study, the docking and molecular dynamics simulations have been performed to explore the interaction of three kinds of endonuclease inhibitors with the subunit (PAN) of RNA polymerase. Our calculations indicate that all these endonuclease inhibitors can bind to the binding pocket of PAN, in which the electronegative oxygen atoms of the inhibitors form a chelated structure with the two Mn2+ cations of the active center. The most important interaction between these inhibitors and PAN is electrostatic interaction. The electron density of the chelate oxygen atoms determines the magnitude of the electrostatic energy, and the chelated structure and orientation of inhibitors depend largely on the distance between the chelate oxygen atoms. PMID- 28631176 TI - Familial predisposition of myeloid malignancies: biological and clinical significance of recurrent germ line mutations. PMID- 28631175 TI - Orthodontic force application upregulated pain-associated prostaglandin-I2/PGI2 receptor/TRPV1 pathway-related gene expression in rat molars. AB - This study aimed to analyze the mRNA expression and protein localization of prostaglandin I2 (PGI2) synthase (PGIS), the PGI2 receptor (IP receptor) and transient receptor potential cation channel, subfamily V, member 1 (TRPV1) in force-stimulated rat molars, toward the elucidation of the PGI2-IP receptor-TRPV1 pathway that is in operation in the pulp and possibly associated with orthodontic pain and inflammation. Experimental force was applied to the maxillary first and second molars by inserting an elastic band between them for 6-72 h. PGIS, PTGIR (the IP receptor gene), and TRPV1 mRNA levels in the coronal pulp were analyzed with real-time PCR. PGIS, IP receptor, and TRPV1 proteins were immunostained. The force stimulation induced significant upregulation of PGIS at 6-24 h, and PTGIR and TRPV1 at 6 and 12 h in the pulp. PGIS was immunolocalized in odontoblasts and some fibroblasts in the force-stimulated pulp. The IP receptor and TRPV1 immunoreactivities were detected on odontoblasts and some nerve fibers. It was concluded that PGIS, PTGIR, and TRPV1 in rat molar pulp were significantly upregulated shortly after the force application, and that the IP receptor was co expressed on TRPV1-expressing nerves and odontoblasts. These findings suggest that the PGI2-IP receptor-TRPV1 pathway is associated with the acute phase of force-induced pulp changes involving odontoblasts and nerves. PMID- 28631177 TI - TRAIL in CD8+ T cells from patients with severe aplastic anemia. AB - Severe aplastic anemia (SAA) is an autoimmune disease caused mainly by activated T lymphocytes. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of TNF family, which can induce apoptosis and play a significant role in the pathogenesis of many autoimmune disorders. In this study, we sought to investigate the role of TRAIL in peripheral CD8+ T cells (CTLs) from SAA patients to clarify the autoimmune mechanisms of bone marrow failure in SAA. The expression of TRAIL and TRAIL-R2 in CTLs from SAA patients and normal controls were determined by flow cytometry, real-time PCR, and western blot. Expression of perforin and granzyme B and apoptosis in CTLs were evaluated by flow cytometry. The expression of TRAIL and TRAIL-R2 in SAA patients was significantly decreased compared with controls; however, there was no statistical difference in TRAIL mRNA expression between the two groups. TRAIL expression in CTLs was negatively correlated with the expression of perforin and granzyme B, and negatively correlated with CTLs apoptosis in SAA patients. The TRAIL pathway may be responsible for abnormal CTL activation in SAA patients. Further study of TRAIL and its receptors may elucidate the pathogenesis of SAA. PMID- 28631179 TI - Population Pharmacokinetics of Volasertib Administered in Patients with Acute Myeloid Leukaemia as a Single Agent or in Combination with Cytarabine. AB - BACKGROUND: Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in combination with cytarabine in patients with acute myeloid leukaemia. OBJECTIVES: The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination. METHODS: Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7.3. Covariates evaluated included demographic and disease-related parameters. RESULTS: The pharmacokinetics of volasertib were found to be dose independent from 150 to 550 mg. Body surface area and ethnicity showed significant effects in all the patients. This is reflected as an increase in drug exposure for Japanese patients, although this finding has to be interpreted with caution because only 7% of patients were part of that population group. Volasertib showed low-to-mild inter-individual variability in total clearance. For the case of cytarabine, its pharmacokinetics was affected by body surface area. Finally, volasertib and cytarabine did not influence the pharmacokinetic characteristics of each other. CONCLUSIONS: The pharmacokinetics of volasertib in patients with acute myeloid leukaemia alone or in combination with cytarabine is predictable and associated with low-to-mild patient variability with the exception of the high variability associated with the volume of distribution of the central compartment, having no effect on the area under the plasma concentration-time curve. PMID- 28631178 TI - Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers. AB - Fanconi anemia (FA), the most common form of inherited bone marrow failure, predisposes to leukemia and solid tumors. FA is caused by the genetic disruption of a cellular pathway that repairs DNA interstrand crosslinks. The impaired function of this pathway, and the genetic instability that results, is considered the main pathogenic mechanism behind this disease. The identification of breast cancer susceptibility genes (for example, BRCA1/FANCS and BRCA2/FANCD1) as being major players in the FA pathway has led to a surge in molecular studies, resulting in the concept of the FA-BRCA pathway. In this review, we discuss recent advances in the molecular pathogenesis of FA from three viewpoints: (a) new FA genes, (b) modifier pathways that influence the cellular and clinical phenotypes of FA and (c) non-canonical functions of FA genes that may drive disease progression independently of deficient DNA repair. Potential therapeutic approaches for FA that are relevant to each will also be proposed. PMID- 28631180 TI - Microvascular changes after vitrectomy with internal limiting membrane peeling: an optical coherence tomography angiography study. AB - PURPOSE: To evaluate superficial capillary plexus (SCP) changes occurring after internal limiting membrane (ILM) peeling for the treatment of idiopathic epiretinal membrane (ERM). METHODS: A total of 15 eyes of 15 patients affected by idiopathic ERM (eight males and seven females; mean age 59.8 +/- 9.6 years) were enrolled in the study. Patients were treated with pars plana vitrectomy followed by ERM and ILM peeling. Subjects were evaluated at baseline and at the week-1 and month-1 follow-up visits. At each visit, patients were evaluated with a complete ophthalmologic evaluation, which included imaging with optical coherence tomography angiography. RESULTS: Overall, the SCP vessel density was 43.0 +/- 3.0% at baseline and was stable throughout the follow-up (40.0 +/- 4.0% at week-1 and 41.0 +/- 4.0% at month-1 follow-up visits; p = 0.087 and p = 0.426, respectively). Nevertheless, the SCP vessel density was reduced at week-1 visit in both the superior and inferior sectors. In these sectors, the superficial vessel density was still reduced at the month-1 follow-up visit. CONCLUSIONS: We observed a reduction in the SCP vessel density occurring after pars plana vitrectomy with ILM peeling. The reduction is referred to those areas where other changes (e.g., swelling of the arcuate nerve fiber layer) have been already described. In theory, superficial vessel density modifications may be due to the direct surgical trauma to the inner retina, where the superficial plexus is contained, during the ILM grasping. PMID- 28631181 TI - Glaucoma awareness amongst glaucoma patients seeking a second opinion. AB - PURPOSE: The aim of the study was to assess level of glaucoma awareness amongst glaucoma patients by studying characteristics amongst urban and rural glaucoma populations in North India. METHODS: A questionnaire was designed and administered after appropriate validation amongst patients to identify determinants of glaucoma awareness. Trained personnel delivered the 11 questions to 1506 patients, aged 18 and above through random sampling. The questionnaire evaluated source of awareness, education, gender, location and age on the level of awareness of glaucoma. The outcomes were assessed based on patient's responses. RESULTS: Age and education essay a significant role in glaucoma awareness. Awareness levels increased with the level of education significantly in both rural and urban settings (P value <0.001). Patients from lower educational backgrounds were significantly more likely to share their condition with their spouse compared to those with higher education (P value <0.001). Compared to the middle aged and elderly, young adults were less aware that glaucoma could run in families (P value <0.015). CONCLUSIONS: There is a significant gap in the knowledge about glaucoma and its risks in both urban and rural set-ups in Northern India necessitating active steps to spread awareness regarding glaucoma and its relation with blindness. PMID- 28631182 TI - Association between the 8-oxoguanine DNA glycosylase gene Ser326Cys polymorphism and age-related cataract: a systematic review and meta-analysis. AB - PURPOSE: To investigate the association between the 8-oxoguanine DNA glycosylase (OGG1) gene Ser326Cys (rs1052133) polymorphism and age-related cataract (ARC). METHODS: MEDLINE and EMBASE were searched to identify potential studies published before May 19, 2017, investigating the association between the OGG1 gene Ser326Cys polymorphism and ARC risk. The quality of eligible studies was assessed using the Newcastle-Ottawa Scale tool. The association between the OGG1 gene Ser326Cys polymorphism and ARC was analyzed using meta-analysis. Publication bias and sensitivity analyses were also performed. RESULTS: Six studies were included in this systematic review, and five of these studies with Hardy-Weinberg equilibrium were included in a meta-analysis. The sample size of the meta analysis was 3716, including 1831 patients with cataract and 1885 controls. Odds ratios (ORs) were 0.67 (95% confidence interval (CI) 0.52-0.85), 0.90 (95% CI 0.54-1.51), 0.52 (95% CI 0.32-0.85) and 0.72 (95% CI 0.56-0.92) for recessive, dominant, additive and allele contrast models, respectively. Sensitivity analysis indicated that the results of the meta-analysis were robust. No publication bias was observed. CONCLUSIONS: The OGG1 gene Ser326Cys polymorphism was associated with ARC risk. PMID- 28631183 TI - Comprehension of Idioms in Turkish Aphasic Participants. AB - Brain damaged participants offer an opportunity to evaluate the cognitive and linguistic processes and make assumptions about how the brain works. Cognitive linguists have been investigating the underlying mechanisms of idiom comprehension to unravel the ongoing debate on hemispheric specialization in figurative language comprehension. The aim of this study is to evaluate and compare the comprehension of idiomatic expressions in left brain damaged (LBD) aphasic, right brain damaged (RBD) and healthy control participants. Idiom comprehension in eleven LBD aphasic participants, ten RBD participants and eleven healthy control participants were assessed with three tasks: String to Picture Matching Task, Literal Sentence Comprehension Task and Oral Idiom Definition Task. The results of the tasks showed that in overall idiom comprehension category, the left brain-damaged aphasic participants interpret idioms more literally compared to right brain-damaged participants. What is more, there is a significant difference in opaque idiom comprehension implying that left brain damaged aphasic participants perform worse compared to right brain-damaged participants. On the other hand, there is no statistically significant difference in scores of transparent idiom comprehension between the left brain-damaged aphasic and right brain-damaged participants. This result also contribute to the idea that while figurative processing system is damaged in LBD aphasics, the literal comprehension mechanism is spared to some extent. The results of this study support the view that idiom comprehension sites are mainly left lateralized. Furthermore, the results of this study are in consistence with the Giora's Graded Salience Hypothesis. PMID- 28631184 TI - Willingness to Communicate Orally: The Case of Iranian EFL Learners. AB - This study sets out to develop a questionnaire on willingness to communicate (WTC) orally specific to English as a Foreign Language setting. It also aims to investigate the effect of three independent variables of interlocutor, age and gender on the same construct of WTC orally. Exploratory factor analysis resulted in three dimensions to WTC, namely WTC with teacher, with classmate, and stranger. Also Cronbach's alpha of .86 indicated a high internal consistency. Mixed between-within subjects analysis of variance was used to assess the impact of interlocutors, age and gender on participants' WTC across the three WTC subscale scores. The results showed no interaction effect between any of pairs of variables but the main effect of interlocutor on WTC orally. The results are discussed in the context of language teaching and some pedagogical implications are suggested. PMID- 28631185 TI - The increased expression of follicle-stimulating hormone leads to a decrease of fecundity in transgenic Large White female pigs. AB - Follicle-stimulating hormone (FSH) is a pituitary gonadotropin regulating reproduction in mammals. Overexpression of the exogenous FSHalpha/beta genes from Chinese Erhualian pigs improved female fecundity of transgenic (TG) mice and male spermatogenesis ability of Large White TG boars. Here, we investigated the impact of the exogenous FSHalpha/beta genes on female reproductive performance of Large White TG pigs. First, we identified the integration site of the exogenous FSHalpha/beta genes at 140,646,456 bp on chromosome 9 in these TG pigs using whole-genome sequencing. Then, we showed that TG gilts had higher levels of serum FSH and FSHbeta protein in pituitary while had a potentially lower number of born piglets than their wild-type half sibs. TG gilts grew healthily and normally without significant difference in growth and health parameters as compared to WT gilts. The expression levels of FSHR, LHR, ESR1 and ESR2 were significantly lower in TG gilts than in WT gilts at the age of 300 days. Taken together, we proposed that the overexpressed FSHalpha/beta transgenes could cause deteriorate fecundity via disturbing the normal expression of the endogenous reproduction-related genes in female pigs. Our findings provide insight into the effect of overexpression of FSHalpha/beta on female reproduction performance in pigs. PMID- 28631186 TI - Association between epidermal growth factor receptor amplification and ADP ribosylation factor 1 methylation in human glioblastoma. AB - PURPOSE: Glioblastoma (GB) is the most frequent and most malignant primary brain tumor in adults. Previously, it has been found that both genetic and epigenetic factors may play critical roles in its etiology and prognosis. In addition, it has been found that the epidermal growth factor receptor gene (EGFR) is frequently over-expressed and amplified in primary GBs. Here, we assessed the promoter methylation status of 10 genes relevant to GB and explored associations between these findings and the EGFR gene amplification status. METHODS: Tumor samples were obtained from 36 patients with primary GBs. In addition, 6 control specimens were included from patients who were operated for diseases other than brain tumors. The amplification status of the EGFR gene, and its deletion mutant EGFRvIII, were evaluated using FISH and MLPA, respectively. The IDH1/2 gene mutation status was verified using Sanger sequencing. A commercial DNA methylation kit was used to assess the promoter methylation status of 10 pre selected genes. Metabolic profiles were measured using HR-MAS NMR spectroscopy. The EGFR and ARF1 mRNA expression levels were quantified using qRT-PCR. RESULTS: Of the 10 genes analyzed, we found that only ARF1 promoter hypermethylation was significantly associated with EGFR gene amplification. ARF1 is a GTPase that is involved in vesicle trafficking and the Golgi apparatus. Subsequent tumor metabolism measurements revealed a positive association between EGFR amplification and different membrane precursors and methyl-donor metabolites. Finally, we found that EGFR gene amplifications were associated with distinct tumor infiltration patterns, thus representing a putative novel functional association between EGFR gene amplification and ARF1 gene promoter methylation in GB. CONCLUSIONS: The results reported here provide a basis for a new hypotheses connecting EGFR gene amplification in GB cells with ARF1 gene promoter methylation, vesicle trafficking, membrane turnover and tumor metabolism. The mechanism(s) underlying these connections and their functional consequences remain to be established. PMID- 28631187 TI - Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/beta-catenin axis in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Previously, we reported that cadherin-17 (CDH17) and its related CDH17/beta-catenin axis may be responsible for inducing HCC in a subset of patients exhibiting CDH17 over-expression. Here we aimed at obtaining a better understanding of the CDH17-related HCC biology and to obtain further indications for the design of targeted therapies in CDH17 over-expressing HCC patients. RESULTS: We found that SPINK1 acts as a downstream effector of the CDH17/beta catenin axis in HCC. In addition, we found that SPINK1 expression exhibited a positive correlation with CDH17 expression in human HCCs and was over-expressed in up to 70% of the tumors. We identified SPINK1 as a downstream effector of the CDH17/beta-catenin axis using a spectrum of in vitro assays, including gene expression modulation and inhibitor assays, bioinformatics analyses and luciferase reporter assays. These in vitro results were validated in primary human HCCs, including the observation that alteration in beta-catenin expression (a core component of the CDH17/beta-catenin axis) in tumors affects SPINK1 serum levels in HCC patients. Similar to CDH17, SPINK1 expression in HCC cells was found to be associated with specific tumor-related properties via activating the c-Raf/MEK/ERK pathway. CONCLUSIONS: Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/beta-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients. PMID- 28631188 TI - Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease. AB - Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations. PMID- 28631190 TI - Pedicle screw insertion accuracy in terms of breach and reposition using a new intraoperative cone beam computed tomography imaging technique and evaluation of the factors associated with these parameters of accuracy: a series of 695 screws. AB - PURPOSE: The goals of this study were to assess the accuracy of pedicle screw insertion using an intraoperative cone beam computed tomography (CBCT) system, and to analyze the factors potentially influencing this accuracy. METHODS: Six hundred and ninety-five pedicle screws were inserted in 118 patients between October 2013 and March 2016. Screw insertion was performed using 2D-fluoroscopy or CBCT-based navigation. Accuracy was assessed in terms of breach and reposition. All the intraoperative CBCT scans, done after screw insertion, were reviewed to assess the accuracy of screw placement using two established classification systems: Gertzbein and Heary. Generalized linear mixed models were used to model the odds (95% CI) for a screw to lead to a breach according to the independent variables. RESULTS: The breach rate was 11.7% using the Gertzbein classification and 15.4% using the Heary classification. Seventeen screws (2.4%) were repositioned intraoperatively. The only factor affecting statistically the odds to have a breach was the indication of surgery. The patients with non degenerative disease had a significantly higher risk of breach than those with degenerative disease. CONCLUSION: Use of intraoperative CBCT as 2D-fluoroscopy or coupled with a navigation system for pedicle screw insertion is accurate in terms of breach occurrence and reposition. However, these rates depend on the classification or grading system used. Use of a navigation system does not decrease the risk of breach significantly. And the risk of breach is higher in non-degenerative conditions (trauma, scoliosis, infection, and malignancy disease) than in degenerative diseases. PMID- 28631191 TI - Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab. AB - Given prior studies that suggest the use of angiotensin system inhibitors (ASIs) is associated with prolonged overall survival (OS) in glioblastoma (GBM) patients, we evaluated the effect of ASIs in glioma patients receiving chemotherapy and/or bevacizumab (BEV). Using retrospective IRB-approved electronic chart review of newly diagnosed WHO grade 2-4 glioma patients from the Kaiser Permanente Tumor Registry of Northern California, we evaluated the impact of ASIs on OS by Cox proportional hazard model analysis for subgroups who received cytotoxic therapy, cytotoxic therapy with BEV, or BEV alone, as well as those with recurrent GBM (rGBM). Of the 1186 glioma patients who received chemotherapy ASI exposure improved OS (HR 0.82; 95% CI 0.71, 0.93; p = 0.003). When stratified by BEV exposure, a sub-analysis revealed further OS advantage for the BEV group (HR 0.75, 95% CI 0.62, 0.90; p = 0.002). In a second cohort of 181 rGBM patients who received BEV in varying dosages, ASI exposure conferred an OS advantage (HR 0.649; 95% CI 0.46, 0.92; p = 0.016). Moreover, patients with ASI exposure who received low-dose BEV treatment (AUCBEV < 3.6 mg wk/kg) had a significantly longer OS (median = 99 weeks; 95% CI 44.3, 205) than those without ASI (median OS = 55.6 weeks; 95% CI 37.7-73.7; p = 0.032). ASI use is associated with longer OS in glioma patients. Further survival advantage with ASI use was observed in rGBM patients receiving low-dose bevacizumab. These data warrant prospective evaluation of adding ASI to low-dose BEV treatment in GBM patients to improve the outcome of standard therapies. PMID- 28631192 TI - Leptomeningeal carcinomatosis 9 years after nodule resection for pulmonary carcinoma in situ: MRS and pathological studies. PMID- 28631194 TI - The Use of Cannabinoids in Treating Dementia. AB - PURPOSE OF REVIEW: To review and summarise the current evidence on the safety and efficacy of using cannabinoids to treat behavioural and neuropsychiatric symptoms of dementia. RECENT FINDINGS: Two randomised controlled trials testing a synthetic form of tetrahydrocannabinol have shown that while well tolerated, there was no significant therapeutic effect, based on changes to scores on the neuropsychiatric inventory (NPI). Case reports and open label trials have indicated that there may be some therapeutic benefit of adding synthetic cannabinoids as an adjunctive therapy to reduce agitation, aberrant motor behaviour and nighttime behaviour. More well-controlled clinical trials in older populations with varying severity of dementia are needed to evaluate the effectiveness of cannabinoids in treating behaviour symptoms of dementia. We provide suggestions for designing such trials and evaluating possible adverse effects of cannabinoids on cognitive and neuropsychiatric functioning. PMID- 28631193 TI - Current Concepts of Memory Disorder in Epilepsy: Edging Towards a Network Account. AB - PURPOSE OF REVIEW: A paradigm shift in contemporary epileptology has been the reframing of both epilepsy and its comorbid memory disorders as the product of diseased brain networks. The current review discusses some of the clinical and theoretical implications that stem from this shift. RECENT FINDINGS: Some implications of a network conceptualisation of epilepsy include a need for more widespread cognitive phenotyping in epilepsy; recognition that memory disorders in epilepsy can be multi-determined, including by non-structural factors; deeper consideration given to the neurodevelopmental context in which memory problems emerge; the utility of new methods to characterise memory impairments in epilepsy; and a call for greater recognition of the close interrelationships between memory comorbidities and psychiatric symptoms in epilepsy. Memory disorder significantly worsens the quality of life of people with epilepsy, underscoring the importance to patient wellbeing of giving due consideration to the up-to-date neuropsychological practises outlined in this review. PMID- 28631195 TI - KCNQ2 Epileptic Encephalopathy in Early Infancy. PMID- 28631196 TI - Erratum to: Peroxiredoxins and sports: new insights on the antioxidative defense. PMID- 28631198 TI - Boy with the Glue. PMID- 28631197 TI - Prioritizing Future Research on Allopurinol and Febuxostat for the Management of Gout: Value of Information Analysis. AB - OBJECTIVES: The aim of this study was to quantify the value of conducting additional research and reducing uncertainty regarding the cost effectiveness of allopurinol and febuxostat for the management of gout. METHODS: We used a previously developed Markov model that evaluated the cost effectiveness of nine urate-lowering strategies: no treatment, allopurinol-only fixed dose (300 mg), allopurinol-only dose escalation (up to 800 mg), febuxostat-only fixed dose (80 mg), febuxostat-only dose escalation (up to 120 mg), allopurinol-febuxostat sequential therapy fixed dose, allopurinol-febuxostat sequential therapy dose escalation, febuxostat-allopurinol sequential therapy fixed dose, and febuxostat allopurinol sequential therapy dose escalation. Each strategy was evaluated over the lifetime of a hypothetical gout patient. We calculated population expected value of perfect information (EVPI). We used a linear regression meta-modeling approach to calculate population expected value of partial perfect information (EVPPI), and a Gaussian approximation to calculate the population expected value of sample information for parameters (EVSI) and the expected net benefit of sampling (ENBS) for four potential study designs: (1) an allopurinol efficacy trial; (2) a febuxostat efficacy trial; (3) a prospective observational study evaluating health utilities; and (4) a comprehensive study evaluating the efficacy of allopurinol and febuxostat and health utilities. A 5-year decision time horizon was used in the base-case analysis. RESULTS: EVPI varied by a decision maker's willingness-to-pay (WTP) per quality-adjusted life-year (QALY) and was $US900 million for WTP of $US60,000 per QALY. Population EVPPI was highest across all WTP values for study design #4. For study design #4 and a WTP of $US60,000 per QALY, the optimal sample size was 735 patients per study arm. CONCLUSIONS: Future studies are needed to evaluate the effectiveness of allopurinol and febuxostat dose escalation. PMID- 28631199 TI - Practical Interventions to Enhance Resident Ownership of Patient Care. AB - OBJECTIVE: In the modern training environment, some question whether trainees have the opportunity to develop ownership of patient care, which includes concepts such as advocacy, autonomy, commitment, communication, follow-through, knowledge about the patient, responsibility, and teamwork. Despite descriptions of what ownership is, there is little discussion of how to foster ownership during residency. The objective of this study was to solicit psychiatry resident and faculty perspectives on ways to enhance resident ownership in training. METHODS: Twenty-nine of 74 (39.2%) residents and 31 of 68 (45.6%) faculty members surveyed provided narrative responses to a voluntary, anonymous, electronic survey asking two structured, open-ended questions about what factors make it more or less likely that a resident will take "ownership" of patient care. RESULTS: The coding process produced four overarching categories of themes (attending, resident, educational program, and environment) that reflect domains for possible interventions to increase ownership, with conceptual guidance from the Theory of Planned Behavior. From these factors, the authors propose a number of practical yet theory-based interventions which include setting expectations, modeling, promoting autonomy, countertransference supervision, changing residency culture, and longer rotations. CONCLUSIONS: These interventions address subjective norms, attitudes, perceived ability and control, environment, and actual resident abilities, all of which, according to the Theory of Planned Behavior, would be likely to influence patient care ownership. Future studies could develop curricula and examine the effectiveness of the interventions proposed here in reinforcing or developing ownership in physicians. PMID- 28631200 TI - The R-Rated Comedy Ted: A Teaching Tool for Psychiatric Education. PMID- 28631201 TI - Seven esophageal perforation cases after aortic replacement/stenting for thoracic aortic dissection or aneurysm. AB - BACKGROUND: Esophageal perforation after aortic replacement/stenting for aortic dissection or aneurysm is a rare but severe complication. However, its cause, standard treatment, and prognosis are unclear. We analyzed the treatment and outcome retrospectively from seven cases experienced at our hospital. CASE PRESENTATION: The median age of the patients was 70 years (range, 41-86), and six of the seven cases were male. As the first treatment, aortic replacement techniques were performed in five, and thoracic endovascular aortic repair (TEVAR) procedure was performed in two. We evaluated the treatment of the perforation, the cause of death, and the median survival time after reparative surgery (esophagectomy). Initial treatment of the perforation was esophagectomy without reconstruction in six and esophagogastric bypass (later, esophagectomy was performed) in one. Three of seven cases could be discharged from hospital or moved to another hospital, but two of these three cases died of major bleeding on postoperative days 320 and 645. The other four esophagectomy cases died in hospital because of sepsis on postoperative days 14, 30, and 41 and major bleeding on postoperative day 54. The one surviving case was a 65-year-old man who underwent reconstruction, and was still alive without signs of infection at 424 days postoperatively. CONCLUSION: The prognosis of esophageal perforation cases after aortic replacement/stenting for thoracic aortic dissection or aneurysm is poor, though there were some cases with relatively long survival. Therefore, the indication for invasive esophagectomy should be decided carefully. Control of infection including regional infection is essential for successful treatment. PMID- 28631202 TI - Successful radical resection of pancreatic head carcinoma in a patient with replaced right hepatic artery originating from posterior inferior pancreaticoduodenal artery: a case report. AB - Anatomical variations of hepatic arteries may be problematic in pancreaticoduodenectomy (PD). We experienced pancreatic head cancer in a patient with rare variation of hepatic artery and performed PD successfully with the resection of this artery. A 75-year-old woman showed pancreatic head tumor on CT. Preoperative CT detected rare variation of hepatic artery; posterior segmental branch of right hepatic artery (RHA-PB) originating from posterior inferior pancreaticoduodenal artery. The image also demonstrated that there was a junction between RHA-PB and anterior branch of right hepatic artery (RHA-AB). We performed PD for suspected pancreatic head cancer. We divided RHA-PB for complete resection of cancer because we preoperatively knew that there was the junction between RHA PB and RHA-AB. She was discharged uneventfully, and there was no evidence of local recurrence throughout the whole course. Careful preoperative assessment of hepatic blood supply is the key to perform successful PD even in this troublesome situation. PMID- 28631203 TI - Assessment of MRI contrast agent concentration by quantitative susceptibility mapping (QSM): application to estimation of cerebral blood volume during steady state. AB - OBJECTIVE: One major issue in dynamic susceptibility contrast MRI (DSC-MRI) is to accurately determine contrast agent (CA) concentration, since T2* relaxivity in vivo is generally unknown and varies between blood and tissue. In this study, quantitative susceptibility mapping (QSM) was used for quantification of CA concentration. MATERIALS AND METHODS: A DSC-MRI protocol, including phase data acquisition, was applied to 20 healthy volunteers in a test-retest study. By selecting a CSF reference region of interest (ROI), the values of all QSM images were shifted to show no CA-induced change in CSF. CA concentration and cerebral blood volume (CBV) were estimated using shifted QSM data. CSF reference ROI optimization was evaluated by investigation of CBV repeatability. The CBV age dependence was analysed and tissue T2* relaxivity was estimated. RESULTS: The best repeatability of CBV, using an optimal CSF reference ROI, showed test-versus retest correlations of r = 0.81 and r = 0.91 for white and grey matter, respectively. A slight CBV decrease with age was observed, and the estimated in vivo T2* relaxivity was 85 mM-1s-1. CONCLUSION: Provided that a carefully selected CSF reference ROI is used to shift QSM image values, susceptibility information can be used to estimate concentration of contrast agent and to calculate CBV. PMID- 28631204 TI - Adaptive step size LMS improves ECG detection during MRI at 1.5 and 3 T. AB - OBJECTIVE: We describe a new real-time filter to reduce artefacts on electrocardiogram (ECG) due to magnetic field gradients during MRI. The proposed filter is a least mean square (LMS) filter able to continuously adapt its step size according to the gradient signal of the ongoing MRI acquisition. MATERIALS AND METHODS: We implemented this filter and compared it, within two databases (at 1.5 and 3 T) with over 6000 QRS complexes, to five real-time filtering strategies (no filter, low pass filter, standard LMS, and two other filters optimized within the databases: optimized LMS, and optimized Kalman filter). RESULTS: The energy of the remaining noise was significantly reduced (26 vs. 68%, p < 0.001) with the new filter vs. standard LMS. The detection error of our ventricular complex (QRS) detector was: 11% with our method vs. 25% with raw ECG, 35% with low pass filter, 17% with standard LMS, 12% with optimized Kalman filter, and 11% with optimized LMS filter. CONCLUSION: The adaptive step size LMS improves ECG denoising during MRI. QRS detection has the same F1 score with this filter than with filters optimized within the database. PMID- 28631205 TI - Chemical Tongues and Noses Based upon Conjugated Polymers. AB - We report the uses of conjugated polymers in multisensory applications and in chemical and optoelectronic tongues. We look at the potential of single polymers to discriminate multiple analytes and into small libraries of conjugated polymers that represent sensors. These small libraries combine several barely selective, promiscuous sensor elements and react with the analytes in a fairly non-selective fashion by change of color, emission wavelength, or emission intensity. In such optoelectronic noses and tongues, response of a single element is not specific or particularly useful at all, but the response pattern after the combination of several sensor elements is often specific for an analyte and allows discrimination and identification without any problem. These types of tongues and noses are well suited for quality control of foodstuff, beverages, and biological species such as proteins or cells. The discriminative process is often not well understood but it is powerful, particularly if the obtained data are analyzed by sophisticated statistical methods, i.e., linear discriminant analysis and/or principal component analysis. This added layer of analysis extracts the hidden information/patterns out of the data and allows visualization of the results. PMID- 28631206 TI - Diclofenac Loaded Lipid Nanovesicles Prepared by Double Solvent Displacement for Skin Drug Delivery. AB - PURPOSE: Herein, we detail a promising strategy of nanovesicle preparation based on control of phospholipid self-assembly: the Double Solvent Displacement. A systematic study was conducted and diclofenac as drug model encapsulated. In vitro skin studies were carried out to identify better formulation for dermal/transdermal delivery. METHODS: This method consists in two solvent displacements. The first one, made in a free water environment, has allowed triggering a phospholipid pre-organization. The second one, based on the diffusion into an aqueous phase has led to liposome formation. RESULTS: Homogeneous liposomes were obtained with a size close to 100 nm and a negative zeta potential around -40 mV. After incorporation of acid diclofenac, we obtained nanoliposomes with a size between 101 +/- 45 and 133 +/- 66 nm, a zeta potential between 34 +/- 2 and 49 +/- 3 mV, and the encapsulation efficiency (EE%) was between 58 +/- 3 and 87 +/- 5%. In vitro permeation studies showed that formulation with higher EE% dispayed the higher transdermal passage (18,4% of the applied dose) especially targeting dermis and beyond. CONCLUSIONS: Our results suggest that our diclofenac loaded lipid vesicles have significant potential as transdermal skin drug delivery system. Here, we produced cost effective lipid nanovesicles in a merely manner according to a process easily transposable to industrial scale. Graphical Abstract ?. PMID- 28631207 TI - QRS Width as a Predictor of Right Ventricular Remodeling After Percutaneous Pulmonary Valve Implantation. AB - Recent data showed a right ventricular dyssynchrony in patients with tetralogy of Fallot (TOF). Percutaneous pulmonary valve implantation (PPVI) has become an important procedure to treat a pulmonary stenosis and/or regurgitation of the right ventricular outflow tract in these patients. Despite providing good results, there is still a considerable number of nonresponders to PPVI. The authors speculated that electrical dysfunction of the right ventricle plays an underestimated role in the outcome of patients after PPVI. This study aimed to investigate the influence of right ventricular electrical dysfunction, i.e., right bundle branch block (RBBB) on the RV remodeling after PPVI. The study included consecutive patients after correction of TOF with or without RBBB, who had received a PPVI previously at the Heart Center of the University of Leipzig, Germany during the period from 2012 to 2015. 24 patients were included. Patients without RBBB, i.e., with narrow QRS complexes pre-intervention, had significantly better RV function and had smaller right ventricular volumes. Patients with pre interventionally QRS width below 150 ms showed a post-interventional remodeling of the right ventricle with the decreasing RV volumes (p = 0.001). The parameters of LV function and volume as well as RV ejection fraction remained unaffected by RBBB. The presented data indicate that the QRS width seems to be a valuable parameter in the prediction of right ventricular remodeling after PPVI, as it represents both electrical and mechanical functions of the right ventricle and may serve as an additional parameter for optimal timing of a PPVI. PMID- 28631208 TI - Pulmonary Vein Doppler Patterns in Infants with Single Right Ventricle Anomalies After Initial Staged Palliations. AB - The aim of this study was to describe serial changes in echocardiographic Doppler pulmonary vein flow (PVF) patterns in infants with single right ventricle (RV) anomalies enrolled in the Single Ventricle Reconstruction trial. Measurement of PVF peak systolic (S) and diastolic (D) velocities, velocity time integrals (VTI), S/D peak velocity and VTI ratios, and frequency of atrial reversal (Ar) waves were made at three postoperative time points in 261 infants: early post Norwood, pre-stage II surgery, and 14 months. Indices were compared over time, between initial shunt type [modified Blalock-Taussig shunt (MBTS) and right ventricle-to-pulmonary artery shunt (RVPAS)] and in relation to clinical outcomes. S velocities and VTI increased over time while D wave was stable, resulting in increasing S/D peak velocity and VTI ratios, with a median post Norwood S/D VTI ratio of 1.14 versus 1.38 at pre-stage II and 1.89 at 14 months (P < 0.0001 between intervals). MBTS subjects had significantly higher S/D peak velocity and VTI ratios compared to RVPAS at the post-Norwood and pre-stage II time points (P < 0.0001) but not by 14 months. PVF patterns did not correlate with survival or hospitalization course at 1 year. PVF patterns after Norwood palliation differ from normal infants by having a dominant systolic pattern throughout infancy. PVF differences based upon shunt type resolve by 14 months and did not correlate with clinical outcomes. This study describes normative values and variations in PVF for infants with a single RV from shunt-dependent pulmonary blood flow to cavopulmonary blood flow. PMID- 28631209 TI - Allelopathic effects of exogenous phenylalanine: a comparison of four monocot species. AB - MAIN CONCLUSION: Exogenous phenylalanine stunted annual ryegrass but not switchgrass or winter grain rye, with deuterium incorporation up to 3% from phenyalanine-d 8 . Toxicity to duckweed varied with illumination intensity and glucose uptake. Isotopic labeling of biomolecules through biosynthesis from deuterated precursors has successfully been employed for both structural studies and metabolic analysis. Phenylalanine is the precursor of many products synthesized by plants, including the monolignols used for synthesis of lignin. Possible allelochemical effects of phenylalanine have not been reported, although its deamination product cinnamic acid is known to have deleterious effects on root elongation and growth of several plant species. The effects of phenylalanine and its deuterated analog phenylalanine-d 8 added to growth media were studied for annual ryegrass (Lolium multiflorum), winter grain rye (Secale cereale), and switchgrass (Panicum virgatum) cultivated under hydroponic conditions. Growth of annual ryegrass was inhibited by phenylalanine while switchgrass and rye were not significantly affected. Growth was less affected by deuterated phenylalanine-d 8 than by its protiated counterpart, which may be a typical deuterium kinetic isotope effect resulting in slower enzymatic reaction rates. Deuterium incorporation levels of 2-3% were achieved in biomass of switchgrass and annual ryegrass. Both protiated and deuterated phenylalanine were moderately toxic (IC25 values 0.6 and 0.8 mM, respectively) to duckweed (Lemna minor) grown using a 12 h diurnal cycle under photoautotrophic conditions. A significant increase in toxicity, greater for the deuterated form, was noted when duckweed was grown under higher intensity, full spectrum illumination with a metal halide lamp compared to fluorescent plant growth lamps emitting in the blue and red spectral regions. Supplementation with glucose increased toxicity of phenylalanine consistent with synergy between hexose and amino acid uptake that has been reported for duckweed. PMID- 28631210 TI - Carcinoid heart disease: a guide for screening and timing of surgical intervention. AB - The cardiac manifestations of a neuroendocrine tumour are referred to as carcinoid heart disease (CaHD) and are associated with a poor prognosis. Surgical intervention is the only proven therapeutic option and may prolong survival and quality of life. No consensus has been reached internationally with regard to screening for CaHD and the optimal timing for surgery. Although limited evidence is available on this matter, a trend towards early surgery and subsequent reduced mortality has been observed. In this review we provide an overview of the current understanding and propose a protocol to guide cardiologists in the screening for CaHD and the timing of referral to a specialised surgical centre. PMID- 28631211 TI - Current practice of Dutch cardiologists in detecting and diagnosing atrial fibrillation: results of an online case vignette study. AB - INTRODUCTION: Detection of atrial fibrillation (AF) is important given the risk of complications, such as stroke and heart failure, and the need for preventive measures. Detection is complicated because AF can be silent or paroxysmal. Describing current practice may give clues to improve AF detection. The aim of this study was to describe how cardiologists currently detect AF. METHODS: Between December 2014 and May 2015, we sent Dutch cardiologists an online questionnaire. Firstly, we asked which tools for detection of AF their department has. Secondly, we presented six case vignettes related to AF, in which they could choose a diagnostic tool. Thirdly, we compared the results with current guidelines. RESULTS: We approached 90 cardiology departments and 48 (53%) completed the questionnaire. In asymptomatic patients with risk factors according to CHA2DS2-VASc, 40% of the cardiologists would screen for AF. In patients with signs or symptoms of AF, all but one cardiologist would start a diagnostic process. In both vignettes describing patients with non-frequent symptoms, 46% and 54% of the responders would use short-term (i. e. 24- or 48-hour) electrocardiographic monitoring, 48% and 27% would use long-term (i. e. 7 day, 14 day or one month) monitoring. In both cases describing patients with frequent symptoms, 85% of the responders would use short-term and 15% and 4% long-term monitoring. CONCLUSION: Dutch cardiologists have access to a wide variety of ambulatory arrhythmia monitoring tools. Nearly half of the cardiologists would perform opportunistic screening. In cases with non-frequent symptoms, monitoring duration was shorter than recommended by NICE. PMID- 28631212 TI - Erratum to: Use of three-dimensional computed tomography overlay for real-time cryoballoon ablation in atrial fibrillation reduces radiation dose and contrast dye. PMID- 28631213 TI - The constitutive protease release by primary human acute myeloid leukemia cells. AB - INTRODUCTION: Acute myeloid leukemia (AML) cells show constitutive release of matrix metalloproteases and their inhibitors. We now investigated this constitutive release of protease/protease regulators associated with carcinogenesis (ADAM12, uPA, cystatin B), angiogenesis (serpin E1, uPA, CD147), cancer cell migration (uPA, cystatin C), coagulation (ADAM TS13, serpin C1), inflammation (fetuin A, caspase 1, cystatin C), monocytic differentiation (CFD) or regulation of hematopoiesis (neutrophil elastase). METHODS: AML blasts from 79 consecutive patients were cultured in serum-free medium and mediator levels determined in culture supernatants. RESULTS: Detectable release of serpin C1 and E1, cystatin B and C, CD147 and uPA was seen for most patients. These mediators together with fetuin A, caspase 1, and CFD were included in a hierarchical clustering analysis and three patient subsets were identified (high, intermediate, and low release). High levels were associated with monocytic differentiation. Global gene expression analyses showed increased levels of several zinc finger proteins for low-release patients and high expression of several cell surface molecules, ATPases, and calcium-binding proteins for high release patients. Constitutive release of several mediators was also seen for normal hematopoietic cells and mesenchymal stem cells. In cocultures of the latter and AML blasts, the release level for most mediators was altered to resemble the levels of the mesenchymal cells cultured alone. CONCLUSION: Differences in constitutive release of protease/protease regulators are a part of the disease heterogeneity in AML. PMID- 28631215 TI - Comment on Rosenberg J, et al.: "Deep Neuromuscular Blockade Improves Laparoscopic Surgical Conditions: A Randomized, Controlled Study". PMID- 28631214 TI - Identification of Bufadienolides from the Boreal Toad, Anaxyrus boreas, Active Against a Fungal Pathogen. AB - Amphibian granular glands provide a wide range of compounds on the skin that defend against pathogens and predators. We identified three bufadienolides-the steroid-like compounds arenobufagin, gamabufotalin, and telocinobufagin-from the boreal toad, Anaxyrus boreas, through liquid chromatography mass spectrometry (LC/MS). Compounds were detected both after inducing skin gland secretions and in constitutive mucosal rinses from toads. We described the antimicrobial properties of each bufadienolide against Batrachochytrium dendrobatidis (Bd), an amphibian fungal pathogen linked with boreal toad population declines. All three bufadienolides were found to inhibit Bd growth at similar levels. The maximum Bd inhibition produced by arenobufagin, gamabufotalin, and telocinobufagin were approximately 50%, in contrast to the complete Bd inhibition shown by antimicrobial skin peptides produced by some amphibian species. In addition, skin mucus samples significantly reduced Bd viability, and bufadienolides were detected in 15 of 62 samples. Bufadienolides also appeared to enhance growth of the anti-Bd bacterium Janthinobacterium lividum, and thus may be involved in regulation of the skin microbiome. Here, we localized skin bacteria within the mucus layer and granular glands of toads with fluorescent in situ hybridization. Overall, our results suggest that bufadienolides can function in antifungal defense on amphibian skin and their production is a potentially convergent trait similar to antimicrobial peptide defenses found on the skin of other species. Further studies investigating bufadienolide expression across toad populations, their regulation, and interactions with other components of the skin mucosome will contribute to understanding the complexities of amphibian immune defense. PMID- 28631216 TI - Safety and Tolerability of Empagliflozin in Patients with Type 2 Diabetes: Pooled Analysis of Phase I-III Clinical Trials. AB - INTRODUCTION: We characterized the safety and tolerability of empagliflozin in patients with type 2 diabetes (T2DM) randomized 1:1:1 to placebo, empagliflozin 10 mg, or empagliflozin 25 mg in clinical trials. METHODS: Pooled data were analyzed from patients with T2DM treated with placebo (N = 4203), empagliflozin 10 mg (N = 4221), or empagliflozin 25 mg (N = 4196) in 15 randomized phase I-III trials plus four extension studies. Adverse events (AEs) were assessed descriptively in participants who took at least one dose of study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure between trials. RESULTS: Total exposure was 7369, 7782, and 7754 patient-years in the placebo, empagliflozin 10 mg, and 25 mg groups, respectively. The incidence of any AEs, severe AEs, serious AEs, and AEs leading to discontinuation was no higher in participants treated with empagliflozin vs. placebo. Empagliflozin was not associated with an increased risk of hypoglycemia vs. placebo, except in participants on background sulfonylurea. The incidence of events consistent with urinary tract infection was similar across treatment groups (8.7-9.5/100 patient-years). Events consistent with genital infection occurred more frequently in participants treated with empagliflozin 10 and 25 mg (3.5 and 3.4/100 patient-years, respectively) than placebo (0.9/100 patient years). The incidence of AEs consistent with volume depletion was similar across treatment groups (1.7-1.9/100 patient-years) but was higher with empagliflozin 10 mg and 25 mg vs. placebo in participants aged 75 years or older (3.2 and 3.0 vs. 2.3/100 patient-years, respectively). The rates of bone fractures, cancer events, renal AEs, venous thromboembolic events, hepatic injury, acute pancreatitis, lower limb amputations, and diabetic ketoacidosis were similar across treatment groups. CONCLUSION: This analysis of pooled safety data based on more than 15,000 patient-years' exposure supports a favorable benefit-risk profile of empagliflozin in patients with T2DM. FUNDING: Boehringer Ingelheim Pharma GmbH. PMID- 28631217 TI - 24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk. AB - INTRODUCTION: To clarify the additional efficacy and safety benefits of 24 months' treatment with the once-weekly formulation of teriparatide, which is currently used for 72 weeks. METHODS: This was a multicenter, open-label, single arm study conducted in Japan. Subjects who were 65 years or older with prevalent vertebral fractures received once-weekly subcutaneous injection of 56.5 MUg teriparatide for 24 months. The main outcome measure was percentage change from baseline in lumbar (L2-L4) BMD measured by dual-energy X-ray absorptiometry. RESULTS: A total of 189 subjects received at least one dose of the once-weekly formulation of teriparatide. Lumbar, femoral neck, and total hip BMD increased significantly compared with baseline at Weeks 24, 48, 72, and 104. In addition, significant increases in lumbar (+1.5%) and femoral neck (+0.8%) BMD were noted at Week 104 compared with Week 72. Significant increases from baseline in BMD for radius 1/10 were noted at Weeks 24 and 104. No substantial increases were noted in the cumulative incidences of new vertebral fracture and other types of fracture after Week 72. The safety profile seen in the first 72 weeks remained unchanged until 104 weeks. CONCLUSION: The once-weekly formulation of teriparatide is effective and safe for the treatment of osteoporosis over 24 months. The limitation of this study is that this was an open-label, single-arm study. FUNDING: Asahi Kasei Pharma Corporation. CLINICAL TRIAL REGISTRATION: JapicCTI-132276. PMID- 28631219 TI - Agrobacterium tumefaciens-mediated transformation of oleaginous yeast Lipomyces species. AB - Interest in using renewable sources of carbon, especially lignocellulosic biomass, for the production of hydrocarbon fuels and chemicals has fueled interest in exploring various organisms capable of producing hydrocarbon biofuels and chemicals or their precursors. The oleaginous (oil-producing) yeast Lipomyces starkeyi is the subject of active research regarding the production of triacylglycerides as hydrocarbon fuel precursors using a variety of carbohydrate and nutrient sources. The genome of L. starkeyi has been published, which opens the door to production strain improvements through the development and use of the tools of synthetic biology for this oleaginous species. The first step in establishment of synthetic biology tools for an organism is the development of effective and reliable transformation methods with suitable selectable marker genes and demonstration of the utility of the genetic elements needed for expression of introduced genes or deletion of endogenous genes. Chemical-based methods of transformation have been published but suffer from low efficiency. To address these problems, Agrobacterium-mediated transformation was investigated as an alternative method for L. starkeyi and other Lipomyces species. In this study, Agrobacterium-mediated transformation was demonstrated to be effective in the transformation of both L. starkeyi and other Lipomyces species. The deletion of the peroxisomal biogenesis factor 10 gene was also demonstrated in L. starkeyi. In addition to the bacterial antibiotic selection marker gene hygromycin B phosphotransferase, the bacterial beta-glucuronidase reporter gene under the control of L. starkeyi translation elongation factor 1alpha promoter was also stably expressed in six different Lipomyces species. The results from this study demonstrate that Agrobacterium-mediated transformation is a reliable and effective genetic tool for homologous recombination and expression of heterologous genes in L. starkeyi and other Lipomyces species. PMID- 28631218 TI - An Observational Study of the Effect of Levodopa-Carbidopa Intestinal Gel on Activities of Daily Living and Quality of Life in Advanced Parkinson's Disease Patients. AB - INTRODUCTION: Continuous delivery of levodopa-carbidopa intestinal gel (LCIG) by percutaneous endoscopic gastrojejunostomy (PEG-J) in advanced Parkinson's disease (PD) patients reduces variability in plasma levels, providing better control of motor fluctuations ("on" and "off" states). The MONOTREAT study assessed the effect of LCIG on activities of daily living, motor and non-motor symptoms, and quality of life in advanced PD patients. METHODS: This prospective, observational study included patients with advanced, levodopa-responsive PD with either 2-4 h of "off" time or 2 h of dyskinesia daily. Patients received LCIG via PEG-J for 16 h continuously. Effectiveness was assessed using Unified PD Rating Scale parts II and III, the Non-Motor Symptom Scale, and the PD Questionnaire-8. RESULTS: The mean (SD) treatment duration was 275 (157) days. Patients experienced significant improvement from baseline in activities of daily living at final visit (p < 0.05) as well as at months 3 and 6 (p < 0.0001). Patients also experienced significant improvements from baseline in quality of life and non-motor symptoms at all time points (p < 0.001 for all). Specifically, patients manifested significant improvements in mean change from baseline at every study visit in five of nine non-motor symptom score domains: sleep/fatigue, mood/cognition, gastrointestinal tract, urinary, and miscellaneous. One-third of patients (32.8%) experienced an adverse event; 21.9% experienced a serious adverse event; 11.1% discontinued because of an adverse event. CONCLUSION: This study demonstrated significant and clinically relevant improvements in measures of activities of daily living, quality of life, and a specific subset of non-motor symptoms after treatment with LCIG. FUNDING: AbbVie Inc. PMID- 28631220 TI - Applicability of upflow anaerobic sludge blanket and dynamic membrane-coupled process for the treatment of municipal wastewater. AB - This study investigated the applicability of dynamic membrane filter (DMF) technology in an upflow anaerobic sludge blanket (UASB) and DMF-coupled process for the treatment of municipal wastewater. The overall treatment performance and effects of hydraulic retention time (HRT), operating flux, and mesh pore size on the UASB + DMF were assessed. The UASB + DMF-coupled process demonstrated removal efficiencies of over 64 and 86% for TCOD and TSS, respectively. The effects of filtration flux and support mesh pore size were investigated and it was found that while there was little impact on the treatment performance, a 67% increase in operating flux resulted in a 25% increase in fouling rate. Similarly, with smaller mesh pore size (Mesh 500 with pore size of 28 MUm) the fouling rate increased by fourfold as compared to Mesh 300 (pore size of 46 MUm). In consideration of the operation duration and contaminant removal, the DMF with Mesh 300 support layer and operating at 100 L/m2-h was the most efficient configuration for treating the effluent of the UASB operated with a HRT of 6 h. Microbial analyses of the foulant layer revealed changes in relative abundance as compared to the bulk sludge, particularly with the hydrogenotrophic methanogens completely outcompeting the acetoclastic methanogens. Overall, the coupled process improved the system robustness and reduced variability of the treated effluent. PMID- 28631221 TI - Effects of gas condition on acetic acid fermentation by Clostridium thermocellum and Moorella thermoacetica (C. thermoaceticum). AB - Fermentation with acetogens can be affected by cultivation gas phase, but to date, there is not enough evidence on that matter for Clostridium thermocellum and Moorella thermoacetica. In this work, the effects of sparged CO2 as well as sparged and non-sparged N2 on these microorganisms were studied using glucose and cellobiose as substrates. It was revealed that sparged CO2 and non-sparged N2 supported growth and acetic acid production by C. thermocellum and M. thermoacetica, while sparged N2 inhibited both of the microorganisms. Notably, part of the sparged CO2 was fermented by the co-culture system and contributed to an overestimation of the products from the actual substrate as well as an erring material balance. The best condition for the co-culture was concluded to be N2 without sparging. These results demonstrate the importance of cultivation conditions for efficient fermentation by anaerobic clostridia species. PMID- 28631222 TI - Defining successful treatment of neurogenic orthostatic hypotension with droxidopa in a patient with multiple system atrophy. PMID- 28631223 TI - Adjusting droxidopa for neurogenic orthostatic hypotension in a patient with Parkinson disease. PMID- 28631224 TI - Initiating droxidopa for neurogenic orthostatic hypotension in a patient with Parkinson disease. PMID- 28631225 TI - Definition of the upper reference limit for thyroglobulin antibodies according to the National Academy of Clinical Biochemistry guidelines: comparison of eleven different automated methods. AB - PURPOSE: In the last two decades, thyroglobulin autoantibodies (TgAb) measurement has progressively switched from marker of thyroid autoimmunity to test associated with thyroglobulin (Tg) to verify the presence or absence of TgAb interference in the follow-up of patients with differentiated thyroid cancer. Of note, TgAb measurement is cumbersome: despite standardization against the International Reference Preparation MRC 65/93, several studies demonstrated high inter-method variability and wide variation in limits of detection and in reference intervals. Taking into account the above considerations, the main aim of the present study was the determination of TgAb upper reference limit (URL), according to the National Academy of Clinical Biochemistry guidelines, through the comparison of eleven commercial automated immunoassay platforms. METHODS: The sera of 120 healthy males, selected from a population survey in the province of Verona, Italy, were tested for TgAb concentration using eleven IMA applied on as many automated analyzers: AIA-2000 (AIA) and AIA-CL2400 (CL2), Tosoh Bioscience; Architect (ARC), Abbott Diagnostics; Advia Centaur XP (CEN) and Immulite 2000 XPi (IMM), Siemens Healthineers; Cobas 6000 (COB), Roche Diagnostics; Kryptor (KRY), Thermo Fisher Scientific BRAHMS, Liaison XL (LIA), Diasorin; Lumipulse G (LUM), Fujirebio; Maglumi 2000 Plus (MAG), Snibe and Phadia 250 (PHA), Phadia AB, Thermo Fisher Scientific. All assays were performed according to manufacturers' instructions in six different laboratories in Friuli-Venezia Giulia and Veneto regions of Italy [Lab 1 (AIA), Lab 2 (CL2), Lab 3 (ARC, COB and LUM), Lab 4 (CEN, IMM, KRY and MAG), Lab 5 (LIA) and Lab 6 (PHA)]. Since TgAb values were not normally distributed, the experimental URL (e-URL) was established at 97.5 percentile according to the non-parametric method. RESULTS: TgAb e-URLs showed a significant inter-method variability. Considering the same method, e-URL was much lower than that suggested by manufacturers (m-URL), except for ARC and MAG. Correlation and linear regression were unsatisfactory. Consequently, the agreement between methods was poor, with significant bias in Bland-Altman plot. CONCLUSIONS: Despite the efforts for harmonization, TgAb methods cannot be used interchangeably. Therefore, additional effort is required to improve analytical performance taking into consideration approved protocols and guidelines. Moreover, TgAb URL should be used with caution in the management of differentiated thyroid carcinoma patients since the presence and/or the degree of TgAb interference in Tg measurement has not yet been well defined. PMID- 28631226 TI - Introduction of a Simple Second Tier Screening Test for C5 Isobars in Dried Blood Spots: Reducing the False Positive Rate for Isovaleric Acidaemia in Expanded Newborn Screening. AB - In 2015 the English Newborn Screening programme expanded to include Isovaleric Acidaemia (IVA). Screening is performed by flow injection analysis tandem mass spectrometry of isovalerylcarnitine. Isovalerylcarnitine is isobaric with pivaloylcarnitine which can be present in blood due to the use of pivalic ester pro-drugs or pivalic acid derivatives used as emollients in some nipple creams; the potential for false positives (FP) is well documented. A pilot study in England screened 438,164 babies, 18 had presumptive positive results but only 4 were confirmed as true positives (TP). We developed a simple test to separate the isobaric compounds and investigate these samples further.We studied newborn screening blood spots from 122 randomised controls and 34 infants with an initial raised C5 result. Dried blood spots were eluted with 30% acetonitrile (150 MUL) and injected into a Waters Acquity UPLC coupled to a Waters Premier XE tandem mass spectrometer operating in positive ion mode. Isocratic separation of isovalerylcarnitine, pivaloylcarnitine, valerylcarnitine and 2 methylbutyrylcarnitine was achieved within 8 min. Assay performance characteristics were acceptable and non-parametric reference ranges (n = 122) were determined for each analyte.If this method had been used as a second tier test for the 34 presumptive positive samples, the number of FP's would have reduced from 24 to 8 and the positive predictive value of the screening test would have increased from 29 to 56%. Introduction of this test into the screening protocol has the potential to significantly reduce FP results for IVA and prevent unnecessary anxiety. PMID- 28631228 TI - The Socio-Ecological Model Approach to Understanding Barriers and Facilitators to the Accessing of Health Services by Sex Workers: A Systematic Review. AB - Inequities in accessing health care persist among sex workers. The purpose of the review is to understand the health-seeking behaviours of sex workers and their access to health care services with socio-ecological model. Of 3852 citations screened, 30 met the inclusion criteria for this review. The access that sex workers have to health services is a complex issue. A wide range of barriers and facilitators at multiple levels could influence sex workers' utilization of health care services, such as health or service information, stigma, social support, quality of health care, available, accessible and affordable services, healthcare policy. Health services or future intervention studies should take into account the facilitators and barriers identified in this review to improve the health services utilization and health of sex workers, as part of the effort to protect the right of humans to health. PMID- 28631229 TI - Do terrestrial animals avoid areas close to turbines in functioning wind farms in agricultural landscapes? AB - Most studies on the effects of wind energy on animals have focused on avian and bat activity, habitat use, and mortality, whereas very few have been published on terrestrial, non-volant wildlife. In this paper, we studied the utilization of functioning wind farm areas by four terrestrial animals common to agricultural landscapes: European roe deer, European hare, red fox, and the common pheasant. Firstly, we expected that the studied animals do not avoid areas close to turbines and utilize the whole area of functioning wind farms with a frequency similar to the control areas. Secondly, we expected that there is no relation between the turbine proximity and the number of tracks of these animals. The study was conducted over two winter seasons using the snow-tracking method along 100 m linear transects. In total, 583 transects were recorded. Wind farm operations may affect terrestrial animals both in wind farm interiors and in a 700-m buffer zone around the edge of turbines. The reactions of animals were species specific. Herbivorous mammals (roe deer and European hare) avoided wind farm interiors and proximity to turbines. The common pheasant showed a positive reaction to wind turbine proximity. The red fox had the most neutral response to wind turbines. Although this species visited wind farm interiors less often than the control area, there was no relation between fox track density and turbine proximity. Greater weight should be given to the effects of wind farms on non flying wildlife than at present. Investors and regulatory authorities should always consider the likely impacts of wind farms during environmental impact assessments and try to reduce these negative effects. PMID- 28631227 TI - Frequent Occurrence of Pain and Prescription Opioid Use for Treatment of Pain Among Women with and at Risk for HIV Infection. AB - Pain is frequent and underreported among HIV+ women. We determined occurrence and severity of pain, and types of pain treatments used among HIV+ and HIV- women. Cross-sectional analyses of pain as measured by the Brief Pain Inventory Short Form, and related pain therapies nested in the Women's Interagency HIV Study (WIHS). Multiple variable linear regression models examined differences by HIV status in pain severity and pain interference in general activity, mood, ability to walk, work, relationships with others, sleep, and enjoyment of life. Among 1393 HIV+ and 587 HIV- participants with median age 47-48 years, there was no statistically significant difference in pain reported within the past week by HIV status (HIV+ 50% vs. 49% HIV-, p = 0.70). Ratings of pain severity and interference were similar between HIV+ and HIV- women, as was receipt of pain medication (58% HIV+ vs. 56% HIV-). Pain medications most frequently used were: NSAIDS (90% HIV+, 96% HIV-), opioids (65% HIV+, 67% HIV-), topical anesthetics (46% HIV+, 56% HIV-), muscle relaxants (23% HIV+, 14% HIV-), and anticonvulsants (23% HIV+, 14% HIV-). Nearly half of predominantly low income, minority women reported pain in the past week, and two-thirds reported opioid use for pain management. The occurrence, severity, and treatment of pain did not differ by HIV status, nor did report of pain interference with mood or function. Additional research is needed to better characterize pain etiology among HIV+ women in the era of potent antiretroviral therapy, and determine the extent to which pain severity and type of medication used for pain treatment impact HIV disease outcomes. PMID- 28631230 TI - Sequence analysis of chromosome 1 revealed different selection patterns between Chinese wild mice and laboratory strains. AB - Both natural and artificial selection play a critical role in animals' adaptation to the environment. Detection of the signature of selection in genomic regions can provide insights for understanding the function of specific phenotypes. It is generally assumed that laboratory mice may experience intense artificial selection while wild mice more natural selection. However, the differences of selection signature in the mouse genome and underlying genes between wild and laboratory mice remain unclear. In this study, we used two mouse populations: chromosome 1 (Chr 1) substitution lines (C1SLs) derived from Chinese wild mice and mouse genome project (MGP) sequenced inbred strains and two selection detection statistics: Fst and Tajima's D to identify the signature of selection footprint on Chr 1. For the differentiation between the C1SLs and MGP, 110 candidate selection regions containing 47 protein coding genes were detected. A total of 149 selection regions which encompass 7.215 Mb were identified in the C1SLs by Tajima's D approach. While for the MGP, we identified nearly twice selection regions (243) compared with the C1SLs which accounted for 13.27 Mb Chr 1 sequence. Through functional annotation, we identified several biological processes with significant enrichment including seven genes in the olfactory transduction pathway. In addition, we searched the phenotypes associated with the 47 candidate selection genes identified by Fst. These genes were involved in behavior, growth or body weight, mortality or aging, and immune systems which align well with the phenotypic differences between wild and laboratory mice. Therefore, the findings would be helpful for our understanding of the phenotypic differences between wild and laboratory mice and applications for using this new mouse resource (C1SLs) for further genetics studies. PMID- 28631231 TI - 2',3'-Dideoxycytidine Protects Dopaminergic Neurons in a Mouse Model of Parkinson's Disease. AB - DNA polymerase-beta (DNA pol-beta) plays a crucial role in the pathogenesis of Parkinson's disease (PD). The aim of this study was to investigate the neuroprotective effects of a DNA polymerase-beta inhibitor 2',3'-dideoxycytidine (DDC) in PD models. In the in vitro studies, primary cultured neurons were challenged with 1-methyl-4-phenylpyridinium ion (MPP+). The expression of DNA pol beta was assessed using western blot. The neuroprotective effect of DNA pol-beta knockdown and DNA pol-beta inhibitor DDC was determined using cell viability assay and caspase-3 activity assay. We found that MPP+ induced neuronal death and the activation of caspase-3 in a dose-dependent manner. The expression of DNA pol beta increased after the neurons were exposed to MPP+. DNA pol-beta siRNA or DNA pol-beta inhibitor DDC attenuated neuronal death induced by MPP+. In the 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, MPTP treatment triggered behavioral deficits and nigrostriatal lesions. Pretreatment with DDC attenuated MPTP-induced behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model. These results indicate that DNA pol-beta inhibitors may present a novel promising therapeutic option for the neuroprotective treatment of PD. PMID- 28631232 TI - Activation of Brain Indoleamine-2,3-dioxygenase Contributes to Depressive-Like Behavior Induced by an Intracerebroventricular Injection of Streptozotocin in Mice. AB - There is a lack of information concerning the molecular events underlying the depressive-like effect of an intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. The elevated activity of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) has been proposed to mediate depression in inflammatory disorders. In the present study, we reported that ICV-STZ activates IDO in the hippocampus of mice and culminates in depressive-like behaviors, as measured by the increased duration of immobility in the tail suspension test and decreased sucrose intake in the sucrose preference test. The blockade of IDO activation by the IDO inhibitor 1-methyltryptophan (1-MT) prevents the development of depressive-like behaviors and attenuates STZ-induced up-regulation of proinflammatory cytokines in the hippocampus. 1-MT abrogates kynurenine production and normalizes brain-derived neurotrophic factor (BDNF) and the kynurenine/tryptophan ratio, but does not protect the biomarkers of the serotonin (5-HT) system in the hippocampus of STZ-injected mice. These results implicate IDO as a critical molecular mediator of STZ-induced depressive-like behavior, likely through activation of the kynurenine pathway and subsequent reduction of BDNF levels. Impairment of the 5-HT system may reflect the inflammatory response induced by STZ and also contributes to observed depression symptoms. The present study not only provides evidence that IDO plays a critical role in mediating inflammation-induced depression but also supports the notion that neuroinflammation and the kynurenine pathway are important targets for novel therapeutic drugs for depression. In addition, this study provides new insights on the neurobiological mechanisms underlying ICV-STZ and indicates that this model could be employed in preclinical research of depression. PMID- 28631233 TI - Interval robotic cytoreduction following neoadjuvant chemotherapy in advanced ovarian cancer. AB - The objective of this study is to review our experience with robotic interval cytoreduction following neoadjuvant chemotherapy for advanced ovarian cancer. We retrospectively reviewed patients with advanced ovarian cancer treated with neoadjuvant chemotherapy (NAC) and interval robotic cytoreduction (IRC) between 2011 and 2016 at the University of Rochester Medical Center. Demographic information, chemotherapy treatment, operative results, and follow-up were extracted from medical records. Twenty-nine patients underwent IRC after a mean of 3.9 cycles of NAC. The mean operative time was 165 min with a mean EBL of 107 cc. The mean length of stay was 2.0 days. One case (3.3%) was converted to an open procedure because of extensive tumor not amenable to robotic cytoreduction. Overall, 19 (66%) patients underwent an R0 cytoreduction, 8 (28%) an optimal (<1 cm) cytoreduction, and 2 (7%) a suboptimal cytoreduction. The median overall survival was 39.7 months and median progression-free survival was 21.2 months. Interval robotic cytoreduction following NAC is feasible and may be preferable to open interval cytoreductive surgery, in specific patients, to minimize morbidity and length of hospital stay. PMID- 28631234 TI - Quality Matters: Implementation Moderates Student Outcomes in the PATHS Curriculum. AB - Analyses of the relationship between levels of implementation and outcomes of school-based social and emotional learning (SEL) interventions are relatively infrequent and are typically narrowly focused. Thus, our objective was to assess the relationship between variability in a range of implementation dimensions and intervention outcomes in the Promoting Alternative Thinking Strategies (PATHS) curriculum. Implementation of PATHS was examined in 69 classrooms across 23 schools in the first year of a major randomized controlled trial. Implementation data were generated via classroom-level structured observations. In addition to factual data on dosage and reach, exploratory factor analysis of observer ratings revealed two distinct implementation dimensions, namely, "quality and participant responsiveness" and "procedural fidelity." Student social-emotional skills, pro social behavior, internalizing symptoms, and externalizing problems were captured through child self-report and teacher informant-report surveys (N = 1721). Hierarchical linear modeling of study data revealed that higher implementation quality and participant responsiveness was associated with significantly lower ratings of students' externalizing problems at 12-month follow-up. Conversely, and contrary to expectations, higher dosage was associated with significantly lower pro-social behavior and social-emotional skills at 12-month follow-up. No significant associations were found between variability in either procedural fidelity or reach and any intervention outcomes. The implications of these findings are discussed, and study limitations are noted. PMID- 28631235 TI - Prevention of Aggression, Violence, and Mental Health Problems in Childhood and Adolescence: Innovative and Sustainable Approaches from Around the World: Introduction and Overview. AB - This special issue, Prevention of Aggression, Violence, and Mental Health Problems in Childhood and Adolescence: Innovative and Sustainable Approaches from Around the World, represents a broad set of studies from lower- and middle-income countries. The intent of the special issue was to expand our knowledge of evidence-based programs in less-resourced settings, given that most of the current evidence comes from the USA and other higher-income countries. Many of the articles describe adaptations of evidence-based programs developed in higher income countries, and their findings suggest that this can be an effective approach. Other studies present evidence for context-specific programs that match cultural norms, are efficient and cost-effective to implement, and are aligned with infrastructure and available resources. We also include articles that provide evidence for the preventive effects of everyday activities such as orchestra participation and after-school programs. Our hope is that the studies reported in this special issue will provide useful guidance for policy makers, funders, and key leaders looking for innovative, affordable, and sustainable solutions to preventing violence in childhood and adolescence and promoting mental health and adjustment around the world. PMID- 28631237 TI - Structural characterization of pyoverdines produced by Pseudomonas putida KT2440 and Pseudomonas taiwanensis VLB120. AB - The previously unknown sequences of several pyoverdines (PVD) produced by a biotechnologically-relevant bacterium, namely, Pseudomonas taiwanensis VLB120, were characterized by high performance liquid chromatography (HPLC)-high resolution mass spectrometry (HRMS). The same structural characterization scheme was checked before by analysis of Pseudomonas sp. putida KT2440 samples with known PVDs. A new sample preparation strategy based on solid-phase extraction was developed, requiring significantly reduced sample material as compared to existing methods. Chromatographic separation was performed using hydrophilic interaction liquid chromatography with gradient elution. Interestingly, no signals for apoPVDs were detected in these analyses, only the corresponding aluminum(III) and iron(III) complexes were seen. The chromatographic separation readily enabled separation of PVD complexes according to their individual structures. HPLC-HRMS and complementary fragmentation data from collision-induced dissociation and electron capture dissociation enabled the structural characterization of the investigated pyoverdines. In Pseudomonas sp. putida KT2240 samples, the known pyoverdines G4R and G4R A were readily confirmed. No PVDs have been previously described for Pseudomonas sp. taiwanensis VLB120. In our study, we identified three new PVDs, which only differed in their acyl side chains (succinic acid, succinic amide and malic acid). Peptide sequencing by MS/MS provided the sequence Orn-Asp-OHAsn-Thr-AcOHOrn-Ser-cOHOrn. Of particular interest is the presence of OHAsn, which has not been reported as PVD constituent before. PMID- 28631238 TI - Is it time for personalized cardiac resynchronization therapy. PMID- 28631239 TI - 18F-FDG for imaging microvascular injury. PMID- 28631236 TI - Use of CTX-I and PINP as bone turnover markers: National Bone Health Alliance recommendations to standardize sample handling and patient preparation to reduce pre-analytical variability. AB - : The National Bone Health Alliance (NBHA) recommends standardized sample handling and patient preparation for C-terminal telopeptide of type I collagen (CTX-I) and N-terminal propeptide of type I procollagen (PINP) measurements to reduce pre-analytical variability. Controllable and uncontrollable patient related factors are reviewed to facilitate interpretation and minimize pre analytical variability. INTRODUCTION: The IOF and the International Federation of Clinical Chemistry (IFCC) Bone Marker Standards Working Group have identified PINP and CTX-I in blood to be the reference markers of bone turnover for the fracture risk prediction and monitoring of osteoporosis treatment. Although used in clinical research for many years, bone turnover markers (BTM) have not been widely adopted in clinical practice primarily due to their poor within-subject and between-lab reproducibility. The NBHA Bone Turnover Marker Project team aim to reduce pre-analytical variability of CTX-I and PINP measurements through standardized sample handling and patient preparation. METHODS: Recommendations for sample handling and patient preparations were made based on review of available publications and pragmatic considerations to reduce pre-analytical variability. Controllable and un-controllable patient-related factors were reviewed to facilitate interpretation and sample collection. RESULTS: Samples for CTX-I must be collected consistently in the morning hours in the fasted state. EDTA plasma is preferred for CTX-I for its greater sample stability. Sample collection conditions for PINP are less critical as PINP has minimal circadian variability and is not affected by food intake. Sample stability limits should be observed. The uncontrollable aspects (age, sex, pregnancy, immobility, recent fracture, co-morbidities, anti-osteoporotic drugs, other medications) should be considered in BTM interpretation. CONCLUSION: Adopting standardized sample handling and patient preparation procedures will significantly reduce controllable pre-analytical variability. The successful adoption of such recommendations necessitates the close collaboration of various stakeholders at the global stage, including the laboratories, the medical community, the reagent manufacturers and the regulatory agencies. PMID- 28631240 TI - Myocardial perfusion imaging in extreme obesity: Leveraging modern technologies to meet a modern challenge. PMID- 28631241 TI - Improving Self-Management of Type 2 Diabetes in Overweight and Inactive Patients Through an Educational and Motivational Intervention Addressing Diet and Physical Activity: A Prospective Study in Naples, South Italy. AB - INTRODUCTION: Nutrition and physical activity are key elements in the prevention and management of type 2 diabetes. A community-based, multidisciplinary educational intervention aimed to improve quality of life and disease self management in sedentary, overweight/obese type 2 diabetic patients was implemented in Naples, South Italy. METHODS: The 9-month intervention included a motivational program, a nutrition program, and an exercise program. Satisfaction, worry, and embarrassment regarding their condition, together with disease-related behaviors and propensity towards physical activity, were evaluated through a validated questionnaire before and after the intervention; health status perception was evaluated through the short-form 12 questionnaire. Changes in HbA1c level and weight were also checked. RESULTS: A significant improvement (p < 0.05) was registered in behaviors related to the management of hypoglycemic crisis and food choice; in nearly all the items related to living with the disease (p < 0.01); and in health status perception (p < 0.01). The adoption of healthy behavior was more common among women (OR 2.17, 95% CI 1.09, 3.02) and persons with higher educational levels (OR 1.26, 95% CI 0.83, 2.17; OR 1.54, 95% CI 0.56, 2.27). About 30% of participants did not modify their emotional status after the intervention. Although not significantly (p = 0.18), the trust of patients towards physical activity increased at the end of the study, together with their active lifestyle (p < 0.01) and with the decrease of perceived barriers (p < 0.01). A significant improvement was registered in glycemic control and weight status (p < 0.01). CONCLUSIONS: The intervention was feasible and effective in addressing diet and physical activity among participants, giving consequent improvements in health status. Similar educational interventions including a training program for people with diabetes should be standardized and adopted by the Italian National Health System. PMID- 28631242 TI - Relationship Between Duration of Type 2 Diabetes and Effectiveness of DPP-4 Inhibitor Versus Sulfonylurea as Add-on Therapy: A Post Hoc Analysis. AB - INTRODUCTION: To assess the impact of duration of type 2 diabetes on glucose lowering effectiveness of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin versus sulfonylureas (SUs) in a real-life setting. METHODS: Data were extracted from the large 1-year, observational EDGE study (N = 45,868). Patients receiving either DPP-4 inhibitor or any SU as add-on to monotherapy were selected (N = 36,164). Impact of the disease duration on change in glycated hemoglobin (HbA1c) levels was evaluated by using a linear multiple regression model. Descriptive statistics assessed the proportion of patients achieving the composite endpoint (HbA1c <7.0%; 53.0 mmol/mol without hypoglycemia or weight gain), stratified by diabetes duration. RESULTS: At baseline, the overall mean (+/-SD) type 2 diabetes duration was 5.4 +/- 5.24 years, and HbA1c was 8.2 +/- 1.33% (66.0 +/- 14.5 mmol/mol). HbA1c lowering was directly proportional to the baseline HbA1c (-0.69 per unit; 95% CI -0.696, -0.681; p < 0.0001) and inversely proportional to the disease duration (0.01 per year; 95% CI 0.01, 0.013). There was an increased loss of beta-cell function (less pronounced HbA1c drop with increasing disease duration) in patients treated with SU-based regimens (0.025; 95% CI 0.022, 0.027) compared with vildagliptin-based regimens (0.005; 95% CI 0.003, 0.007), with the mean adjusted difference being 0.10 (95% CI -0.122, 0.092; p < 0.0001). Consistently, a higher proportion of patients achieved the composite endpoint with vildagliptin over the diabetes duration (less than 2 to more than 10 years). CONCLUSION: Vildagliptin demonstrated less dependency on the duration of type 2 diabetes, whereas the effectiveness of SUs diminished faster with increasing duration of the disease in a real-life setting. FUNDING: Novartis Pharma AG. PMID- 28631244 TI - Optical coherence tomography angiography in pre-perimetric open-angle glaucoma. AB - PURPOSE: To evaluate the diagnostic efficacy of optical coherence tomography (OCT) angiography, in patients with pre-perimetric open-angle glaucoma. METHODS: Thirty-eight consecutive eyes of 26 patients with pre-perimetric open-angle glaucoma and 48 normal eyes of 32 controls were included in this prospective study. We evaluated OCT angiography, spectral-domain OCT and visual fields parameters. Differences between controls and patients and between OCT angiography parameters and traditional glaucoma measurements were evaluated. Receiver operating characteristic curves for OCT angiography parameters were assessed. RESULTS: The flow index (p = 0.021) and vessel density (p = 0.001) were significantly lower in pre-perimetric glaucoma eyes versus normal eyes. Ganglion cell complex parameters were significantly correlated to OCT angiography parameters (p < 0.05). Neither retinal nerve fiber layer (RNFL) nor visual field parameters correlated with OCT angiography parameters. CONCLUSIONS: OCT angiography can be considered a reliable, easy-to-perform method with which to evaluate microvascular changes of optic nerve head for the early diagnosis and follow-up of glaucoma. PMID- 28631243 TI - Amyloid plaques beyond Abeta: a survey of the diverse modulators of amyloid aggregation. AB - Aggregation of the amyloid-beta (Abeta) peptide is strongly correlated with Alzheimer's disease (AD). Recent research has improved our understanding of the kinetics of amyloid fibril assembly and revealed new details regarding different stages in plaque formation. Presently, interest is turning toward studying this process in a holistic context, focusing on cellular components which interact with the Abeta peptide at various junctures during aggregation, from monomer to cross-beta amyloid fibrils. However, even in isolation, a multitude of factors including protein purity, pH, salt content, and agitation affect Abeta fibril formation and deposition, often producing complicated and conflicting results. The failure of numerous inhibitors in clinical trials for AD suggests that a detailed examination of the complex interactions that occur during plaque formation, including binding of carbohydrates, lipids, nucleic acids, and metal ions, is important for understanding the diversity of manifestations of the disease. Unraveling how a variety of key macromolecular modulators interact with the Abeta peptide and change its aggregation properties may provide opportunities for developing therapies. Since no protein acts in isolation, the interplay of these diverse molecules may differentiate disease onset, progression, and severity, and thus are worth careful consideration. PMID- 28631245 TI - Hypoxia and inflammation in the release of VEGF and interleukins from human retinal pigment epithelial cells. AB - PURPOSE: Retinal diseases are closely associated with both decreased oxygenation and increased inflammation. It is not known if hypoxia-induced vascular endothelial growth factor (VEGF) expression in the retina itself evokes inflammation, or whether inflammation is a prerequisite for the development of neovascularization. METHODS: Human ARPE-19 cell line and primary human retinal pigment epithelium (RPE) cells were used. ARPE-19 cells were kept either under normoxic (24 h or 48 h) or hypoxic conditions (1% O2, 24 h). Part of the cells were re-oxygenated (24 h). Some ARPE-19 cells were additionally pre-treated with bacterial lipopolysaccharide (LPS). The levels of IL-6, IL-8, IL-1beta, and IL-18 were determined from medium samples by an enzyme-linked immunosorbent assay (ELISA) method. Primary human RPE cells were exposed to hypoxia for 24 h, and the subsequent release of IL-6 and IL-8 was measured with ELISA. VEGF secretion from ARPE-19 cells was determined up to 24 h. RESULTS: Hypoxia induced significant (P < 0.01) increases in the levels of both IL-6 and IL-8 in ARPE-19 cells, and LPS pre-treatment further enhanced these responses. Hypoxia exposure did not affect the IL-1beta or IL-18 release irrespective of LPS pre-treatment. If primary RPE cells were incubated for 4 h in hypoxic conditions, IL-6 and IL-8 concentrations were increased by 7 and 8-fold respectively. Hypoxia increased the VEGF secretion from ARPE-19 cells in a similar manner with or without pre-treatment with LPS. CONCLUSIONS: Hypoxia causes an inflammatory reaction in RPE cells that is potentiated by pre-treatment with the Toll-like receptor-activating agent, LPS. The secretion of VEGF from these cells is regulated directly by hypoxia and is not mediated by inflammation. PMID- 28631246 TI - Smoking as a risk factor for diabetic nephropathy: a meta-analysis. AB - BACKGROUND: Previous studies have investigated the connection between diabetic nephropathy and smoking, and reported widely varying rates. This study aimed to systematically analyze the impact of smoking on diabetic nephropathy. METHODS: We searched the PubMed and EMBASE electronic databases to identify relevant English language studies published up to March 2016. Eligible studies were selected using inclusion and exclusion criteria. Data for each study were extracted independently by two authors. The homogeneity of the effect size across the studies was tested. Odds ratio (OR) was calculated by using the random-effect model. Sensitivity analysis was performed to reduce heterogeneity, and publication biases were examined. RESULTS: A total of 21 eligible studies were selected and pooled analyzed. No significant differences in demographic characteristics were found between patients with diabetic nephropathy and those with non-diabetic nephropathy. Significant heterogeneity across studies was found except those of diabetes mellitus controls. The aggregate OR of smoking in the patients with diabetic nephropathy in comparison with those with non-diabetic nephropathy was 1.70 (95% confidence interval 1.48-1.95). No evidence of publication bias was found. CONCLUSION: Our findings indicate that smoking is a significant risk factor for diabetic nephropathy in diabetic patients. PMID- 28631247 TI - Choice of reserve capacity by hospitals: a problem for prospective payment. AB - This contribution analyzes the impact of prospective payment on hospital decisions with regard to reserve capacity, using Swiss hospital data covering the years 2004-2009. This data set is unique because it permits distinguishing of institutional characteristics (e.g., ownership status) from the mode of payment as determinants of hospital efficiency, due to the fact that some Swiss cantons introduced prospective payment early while others waited for federal legislation to be enacted in 2012. Since a hospital's choice of reserve capacity depends also on the risk preferences of management while affecting the cost function, heterogeneity is predicted even in the presence of identical technology and factor prices. For estimating hospitals' marginal costs, we employ the flexible representation of risk preferences by Pope and Chavas [Am J Agric Econ 76, 196 204 (1994)]. Production uncertainty is measured as the difference between actual admissions and admissions predicted by an autoregressive moving average model. Its effect on hospital cost is analyzed using a multilevel stochastic cost frontier model with random coefficients reflecting unobserved differences in technology. Public hospitals are found to opt for a higher probability of meeting unexpected demand, as predicted. Their operating cost is 1.1% higher than for private hospitals and even 1.9% higher than for teaching hospitals, creating an incentive to turn away patients or to keep them waiting for treatment. PMID- 28631248 TI - Chilean population norms derived from the health-related quality of Life SF-6D. AB - OBJECTIVES: The Health-Related Quality of Life Short Form 6D (HRQoL SF-6D) provides utility values for health status. Utilities generated have a number of potentially valuable applications in economic evaluations and not only to ensure comparability between studies. Reference values can be useful to estimate the effect on patients' HRQoL as a result of interventions in the absence of control groups. Thus, the purpose of this study was to provide normative values in the SF 6D in relation to the Chilean population. METHODS: A cross-sectional study was conducted evaluating 5293 people. SF-6D utilities were derived from the SF-12 questions. RESULTS: Mean SF-6D utility index for the whole sample was 0.74. It was better for men (0.78) than for women (0.71). The ceiling effect was much higher for men (11.16%) than for women (5.31%). Women were more likely to show problems in any dimension than were men. CONCLUSIONS: Chilean population norms for the SF-6D help in the decision-making process around health policies. Men reported higher health status than women in all subcategories analyzed. Likewise, men also reported higher scores than women in overall SF-6D dimensions. PMID- 28631249 TI - Molecular Characterisation of a Novel Isoform of Hepatic Antimicrobial Peptide, Hepcidin (Le-Hepc), from Leiognathus equulus and Analysis of Its Functional Properties In Silico. AB - Hepcidin represents a family of cysteine-rich antimicrobial peptides that are mainly expressed in the liver of living organisms. In this study, we have identified and characterised a novel isoform of hepcidin from the common pony fish, Leiognathus equulus (Le-Hepc). A 261-bp fragment cDNA coding for 86 amino acids was obtained. Homologous analysis showed that Le-Hepc belongs to the hepcidin super family and shares sequence identity with other known fish pre propeptide hepcidin sequences. The ORF encodes for a 24-amino acid (aa) signal peptide coupled to a 36-aa prodomain followed by a 26-aa mature peptide. The mature peptide region has a calculated molecular weight of 2.73 kDa, a net positive charge of +2 and a theoretical pI of 8.23. Phylogenetic analysis of Le Hepc showed a strong relationship with other fish hepcidin sequences and clustered into HAMP2 group hepcidins. Secondary structural analysis indicated that Le-Hepc mature peptide contains two antiparallel beta-sheets strengthened by four disulphide bonds formed by eight conserved cysteine residues. The physicochemical properties of the peptide and its structural parameters are in agreement with characteristic features of an antimicrobial peptide. This is the first report of an antimicrobial peptide from the common pony fish, L. equulus. PMID- 28631250 TI - Lactobacillus salivarius NK02: a Potent Probiotic for Clinical Application in Mouthwash. AB - A specific strain of naturally occurring oral lactobacilli was isolated and identified based on morphological, biochemical, and 16S rRNA gene sequencing. The phylogenetic affiliation of the isolate confirmed that the NK02 strain had close association with the Lactobacillus salivarius. An effective mouthwash was developed for treatment of periodontitis and suppression of the indicator bacterium Aggregatibacter actinomycetemcomitans which is an obvious pathogen of periodontal disease. The mouthwash containing L. salivarius NK02 was tested at a dose level of 108 (colony forming units (CFU) ml-1), monitoring over a period of 4 weeks. The study was a randomized double-blind placebo control trial, and the patients were treated in two groups of control and test by using scaling and root planing (SRP) + placebo and scaling and root planing (SRP) + probiotic, respectively. It appeared that the probiotic mouthwash was able to inhibit the bacterial growth on both saliva and sub-gingival crevice and exhibited antibacterial activity against A. actinomycetemcomitans. The results also showed that SRP+ probiotic treatment led to a significant decrease of gingival index (GI) and bleeding on probing (BOP) compared with that of SRP + placebo for the probiotic group. The rate of decrease in pocket depth was displayed in the group with SRP + probiotic treatment equal to 1/2 mm, and probing pocket depth (PPD) value was decreased in the probiotic bacteria treatment group that can explain the decrease in inflammation in gingiva. Our findings suggest that probiotic mouthwash is healthy for daily use as an alternative for maintaining dental and periodontal health. PMID- 28631252 TI - Synthesis and characterization of novel carboxymethyl Assam Bora rice starch for the controlled release of cationic anticancer drug based on electrostatic interactions. AB - Carboxymethyl Assam Bora rice starch (CM-ABRS) was chemically synthesized in non aqueous medium with the optimum degree of substitution (DS) of 1.23, and physicochemically characterized by FT-IR, DSC, XRD, and SEM analysis. Comparative evaluation of CM-ABRS with native starch (ABRS) for powder flow characteristics, swelling index, apparent solubility, rheological properties, textural properties, and mucoadhesive studies were carried out. The aim of the current work was to investigate the potential of CM-ABRS as a novel carrier for the water-soluble chemotherapeutic, doxorubicin hydrochloride (DOX). Formation of drug/polymer complex (DOX-CM-ABRS) via electrostatic interaction has been evaluated for the controlled release of DOX in three different pH media (phosphate-buffered saline (PBS), pH 7.4, 6.8, and 5.5). In vitro drug release studies illustrated faster release of drug in PBS at pH 5.5 as compared to pH 6.8 and pH 7.4, respectively, indicating the importance of pH-sensitive drug release from the DOX-CM-ABRS complex in malignant tissues. PMID- 28631251 TI - Regulation of cardiac myocyte cell death and differentiation by myocardin. AB - Myocardin is a cardiac- and smooth muscle-enriched transcriptional co-activator that was originally described as an interacting partner of the serum response factor. Shortly after myocardin's discovery, a wealth of published literature described the role of myocardin as a regulator of smooth muscle differentiation and phenotype modulation, while gene-targeting studies confirmed the essential role of myocardin in vascular development. More recently, myocardin has been implicated as an important regulator of cardiac myocyte differentiation in studies demonstrating direct programming of fibroblasts towards the cardiac lineage. This function of myocardin has been attributed to its physical interaction with cardiac-enriched transcription factors such as MEF2C, GATA4, and TBX5. Moreover, conditional knockout models have revealed a critical role for myocardin during cardiac chamber maturation, and a surprising function for myocardin in the regulation of cardiomyocyte proliferation, cell death, and possibly mitochondrial function. This review summarizes the literature surrounding the cardiac-specific roles of myocardin during development and post natal cardiac remodeling. In addition, we take a bioinformatics and computational approach to discuss known and predicted interactions and biological functions of myocardin, which suggests areas for future research. PMID- 28631254 TI - Erratum to: Characterization and Functional Phenotyping of Renal Immune Cells via Flow Cytometry. PMID- 28631253 TI - Portal branch ligation does not counteract the inhibiting effect of temsirolimus on extrahepatic colorectal metastatic growth. AB - The mTor-inhibitor temsirolimus (TEM) has potent anti-tumor activities on extrahepatic colorectal metastases. Treatment of patients with advanced disease may require portal branch ligation (PBL). While PBL can induce intrahepatic tumor growth, the effect of PBL on extrahepatic metastases under TEM treatment is unknown. Therefore, we analyzed the effects of TEM treatment on extrahepatic metastases during PBL-associated liver regeneration. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of BALB/c mice. Mice were randomized to four groups (n = 8). One was treated daily with TEM (1.5 mg/kg), PBS-treated animals served as controls. Another group underwent PBL of the left liver lobe and received daily TEM treatment. Animals with PBL and PBS treatment served as controls. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied over 14 days. In non-PBL animals TEM treatment inhibited tumor cell proliferation as well as vascularization and growth of the extrahepatic metastases. PBL did not influence tumor cell engraftment, vascularization and metastatic growth. Of interest, TEM treatment significantly reduced tumor cell engraftment, neovascularization and metastatic groth also after PBL. PBL does not counteract the inhibiting effect of TEM on extrahepatic colorectal metastatic growth. PMID- 28631255 TI - "Make OSA great again" Report from the 113th American Thoracic Society International Conference (2017) in Washington DC. PMID- 28631257 TI - The Validity and Responsiveness of Isometric Lower Body Multi-Joint Tests of Muscular Strength: a Systematic Review. AB - BACKGROUND: Researchers and practitioners working in sports medicine and science require valid tests to determine the effectiveness of interventions and enhance understanding of mechanisms underpinning adaptation. Such decision making is influenced by the supportive evidence describing the validity of tests within current research. The objective of this study is to review the validity of lower body isometric multi-joint tests ability to assess muscular strength and determine the current level of supporting evidence. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed in a systematic fashion to search, assess and synthesize existing literature on this topic. Electronic databases such as Web of Science, CINAHL and PubMed were searched up to 18 March 2015. Potential inclusions were screened against eligibility criteria relating to types of test, measurement instrument, properties of validity assessed and population group and were required to be published in English. The Consensus-based Standards for the Selection of health Measurement Instruments (COSMIN) checklist was used to assess methodological quality and measurement property rating of included studies. Studies rated as fair or better in methodological quality were included in the best evidence synthesis. RESULTS: Fifty-nine studies met the eligibility criteria for quality appraisal. The ten studies that rated fair or better in methodological quality were included in the best evidence synthesis. The most frequently investigated lower body isometric multi-joint tests for validity were the isometric mid-thigh pull and isometric squat. The validity of each of these tests was strong in terms of reliability and construct validity. The evidence for responsiveness of tests was found to be moderate for the isometric squat test and unknown for the isometric mid-thigh pull. No tests using the isometric leg press met the criteria for inclusion in the best evidence synthesis. CONCLUSIONS: Researchers and practitioners can use the isometric squat and isometric mid-thigh pull with confidence in terms of reliability and construct validity. Further work to investigate other validity components such as criterion validity, smallest detectable change and responsiveness to resistance exercise interventions may be beneficial to the current level of evidence. PMID- 28631256 TI - Vulnerability to a Metabolic Challenge Following Perinatal Asphyxia Evaluated by Organotypic Cultures: Neonatal Nicotinamide Treatment. AB - The hypothesis of enhanced vulnerability following perinatal asphyxia was investigated with a protocol combining in vivo and in vitro experiments. Asphyxia exposed (AS) (by 21 min water immersion of foetuses containing uterine horns) and caesarean-delivered control (CS) rat neonates were used at P2-3 for preparing triple organotypic cultures (substantia nigra, neostriatum and neocortex). At DIV 18, cultures were exposed to different concentrations of H2O2 (0.25-45 mM), added to the culture medium for 18 h. After a 48-h recovery period, the cultures were either assessed for cell viability or for neurochemical phenotype by confocal microscopy. Energy metabolism (ADP/ATP ratio), oxidative stress (GSH/GSSG) and a modified ferric reducing/antioxidant power assay were applied to homogenates of parallel culture series. In CS cultures, the number of dying cells was similar in substantia nigra, neostriatum and neocortex, but it was several times increased in AS cultures evaluated under the same conditions. A H2O2 challenge led to a concentration-dependent increase in cell death (>fourfold after 0.25 mM of H2O2) in CS cultures. In AS cultures, a significant increase in cell death was only observed after 0.5 mM of H2O2. At higher than 1 mM of H2O2 (up to 45 mM), cell death increased several times in all cultures, but the effect was still more prominent in CS than in AS cultures. The cell phenotype of dying/alive cells was investigated in formalin-fixed cultures exposed to 0 or 1 mM of H2O2, co labelling for TUNEL (apoptosis), MAP-2 (neuronal phenotype), GFAP (astroglial phenotype) and TH (tyrosine hydroxylase; for dopamine phenotype), counterstaining for DAPI (nuclear staining), also evaluating the effect of a single dose of nicotinamide (0.8 nmol/kg, i.p. injected in 100 MUL, 60 min after delivery). Perinatal asphyxia produced a significant increase in the number of DAPI/TUNEL cells/mm3, in substantia nigra and neostriatum. One millimolar of H202 increased the number of DAPI/TUNEL cells/mm3 by ~twofold in all regions of CS and AS cultures, an effect that was prevented by neonatal nicotinamide treatment. In substantia nigra, the number of MAP-2/TH-positive cells/mm3 was decreased in AS compared to CS cultures, also by 1 mM of H202, both in CS and AS cultures, prevented by nicotinamide. In agreement, the number of MAP-2/TUNEL-positive cells/mm3 was increased by 1 mM H2O2, both in CS (twofold) and AS (threefold) cultures, prevented by nicotinamide. The number of MAP-2/TH/TUNEL-positive cells/mm3 was only increased in CS (>threefold), but not in AS (1.3-fold) cultures. No TH labelling was observed in neostriatum, but 1 mM of H2O2 produced a strong increase in the number of MAP-2/TUNEL-positive cells/mm3, both in CS (>2.9-fold) and AS (>fourfold), decreased by nicotinamide. In neocortex, H2O2 increased the number of MAP-2/TUNEL-positive cells/mm3, both in CS and AS cultures (~threefold), decreased by nicotinamide. The ADP/ATP ratio was increased in AS culture homogenates (>sixfold), compared to CS homogenates, increased by 1 mM of H202, both in CS and AS homogenates. The GSH/GSSG ratio was significantly decreased in AS, compared to CS cultures. One millimolar of H2O2 decreased that ratio in CS and AS homogenates. The present results demonstrate that perinatal asphyxia induces long-term changes in metabolic pathways related to energy and oxidative stress, priming cell vulnerability with both neuronal and glial phenotype. The observed effects were region dependent, being the substantia nigra particularly prone to cell death. Nicotinamide administration in vivo prevented the deleterious effects observed after perinatal asphyxia in vitro, a suitable pharmacological strategy against the deleterious consequences of perinatal asphyxia. PMID- 28631258 TI - Long-term effects of rotational atherectomy in patients with heavy calcified coronary artery lesions: a single-centre experience. AB - BACKGROUND: Rotational atherectomy (RA) plays a significant role in contemporary percutaneous coronary interventions (PCI), especially in the era of population aging and expansion of PCI indications. AIM: The aim of the current study was to evaluate the rate of periprocedural complications, the long-term effectiveness of RA, and potential factors influencing the incidence of major adverse cardiac events (MACE) and major cardiac as well as cerebrovascular events (MACCE) after RA. METHODS: The study included 60 consecutive patients who underwent effective RA between January 2002 and May 2016. Patients were followed-up for 2,616 days for MACE and MACCE. RESULTS: The mean age of the enrolled patients was 72.1 years, and 78.3% were males. The mean follow-up period lasted 835.3 +/- 611.8 days. Periprocedural complications occurred in 12 (20.0%) patients. In the follow up of up to 2,616 days, 64% of patients were free of MACCE and 68% were free of MACE. Univariate Cox analysis revealed that MACCE occurred more often in patients from the high-risk group based on the EuroSCORE II and those with longer lengths of the implanted stent(s) after the RA procedure. In multivariate Cox regression analysis, both high-risk category and mean stent(s) length were identified as independent predictors of MACCE. EuroSCORE II was confirmed to be the only independent predictor of MACE after RA. CONCLUSIONS: Rotational atherectomy is a safe and sufficient technique for the endovascular treatment of heavily calcified coronary artery lesions. Individuals at a higher risk as assessed by the EuroSCORE II before RA and those with longer stent(s) implanted after RA are predisposed to MACCE in the follow-up. PMID- 28631259 TI - Preventive healthcare and health promotion in local governments based on the example of health policy programmes concerned with cardiovascular diseases implemented in Poland in 2009-2014. AB - BACKGROUND: Cardiovascular diseases (CVD) are the cause of over 4.3 million deaths in the World Health Organisation European Region and around 1.9 million deaths in the European Union member states alone. They are also the number-one cause of death in Poland. In 2010 CVDs accounted for 46% of all deaths, and in 2013 - 45.8%. AIM: The aim of the study was to evaluate the performance of the tasks of local government units in the area of preventive healthcare and health promotion on the basis of health policy programmes concerning CVD. METHODS: The study was based on a desk research. The data included in the annual reports submitted to the Minister of Health concerning completed health policy programmes concerned with CVD, was used. RESULTS: A total of 795 programmes were completed in 2009-2014. The greatest number of programmes were completed by municipalities followed by counties. The costs incurred by voivodeships in connection with the programmes were significantly higher compared to the costs paid by municipalities and counties. Diagnostic programmes accounted for 74% of the overall number of programmes, and preventive programmes made up only 24%. The greatest number of programmes were completed in Mazowieckie and Swietokrzyskie voivodeships. The smallest number of programmes were completed in Lubelskie, Lubuskie, and Podlaskie voivodeships. CONCLUSIONS: Insignificant involvement of local government units can be seen in the fight against CVD. Particular types of local government units demonstrate a varied degree of involvement in the performance of health policy programmes. The small number of preventive programmes points to the fragmentary completion of tasks concerned with preventive healthcare and health promotion. Some of the voivodeships failed to properly address the health needs of local communities in respect of CVD. More programmes need to be completed, and they need to cover more people. Some guidelines should be developed for local government units concerning their involvement in the fight against CVD. PMID- 28631260 TI - Low-Income Ethnically Diverse Children's Engagement as a Predictor of School Readiness Above Preschool Classroom Quality. AB - This study examined whether children's observed individual engagement with teachers, peers, and tasks related to their school readiness after controlling for observed preschool classroom quality and children's baseline skills. The sample included 211 predominately low-income, racially/ethnically diverse 4-year old children in 49 preschool classrooms in one medium-sized U.S. city. Results indicated that children's positive engagement with (a) teachers related to improved literacy skills; (b) peers related to improved language and self regulatory skills; and (c) tasks related to closer relationships with teachers. Children's negative engagement was associated with lower language, literacy, and self-regulatory skills, and more conflict and closeness with teachers. Effect sizes were small to medium in magnitude, and some expected relations between positive engagement and school readiness were not found. PMID- 28631261 TI - Distinct post-translational features of type I collagen are conserved in mouse and human periodontal ligament. AB - BACKGROUND AND OBJECTIVE: Specifics of the biochemical pathways that modulate collagen cross-links in the periodontal ligament (PDL) are not fully defined. Better knowledge of the collagen post-translational modifications that give PDL its distinct tissue properties is needed to understand the pathogenic mechanisms of human PDL destruction in periodontal disease. In this study, the post translational phenotypes of human and mouse PDL type I collagen were surveyed using mass spectrometry. PDL is a highly specialized connective tissue that joins tooth cementum to alveolar bone. The main function of the PDL is to support the tooth within the alveolar bone while under occlusal load after tooth eruption. Almost half of the adult population in the USA has periodontal disease resulting from inflammatory destruction of the PDL, leading to tooth loss. Interestingly, PDL is unique from other ligamentous connective tissues as it has a high rate of turnover. Rapid turnover is believed to be an important characteristic for this specialized ligament to function within the oral-microbial environment. Like other ligaments, PDL is composed predominantly of type I collagen. Collagen synthesis is a complex process with multiple steps and numerous post translational modifications including hydroxylation, glycosylation and cross linking. The chemistry, placement and quantity of intermolecular cross-links are believed to be important regulators of tissue-specific structural and mechanical properties of collagens. MATERIAL AND METHODS: Type I collagen was isolated from several mouse and human tissues, including PDL, and analyzed by mass spectrometry for post-translational variances. RESULTS: The collagen telopeptide cross-linking lysines of PDL were found to be partially hydroxylated in human and mouse, as well as in other types of ligament. However, the degree of hydroxylation and glycosylation at the helical Lys87 cross-linking residue varied across species and between ligaments. These data suggest that different types of ligament collagen, notably PDL, appear to have evolved distinctive lysine/hydroxylysine cross-linking variations. Another distinguishing feature of PDL collagen is that, unlike other ligaments, it lacks any of the known prolyl 3-hydroxylase 2 catalyzed 3-hydroxyproline site modifications that characterize tendon and ligament collagens. This gives PDL a novel modification profile, with hybrid features of both ligament and skin collagens. CONCLUSION: This distinctive post translational phenotype may be relevant for understanding why some individuals are at risk of rapid PDL destruction in periodontal disease and warrants further investigation. In addition, developing a murine model for studying PDL collagen may be useful for exploring potential clinical strategies for promoting PDL regeneration. PMID- 28631263 TI - ISIAQ Academy Awards 2016. PMID- 28631264 TI - Targeted use of LEDs in improvement of production efficiency through phytochemical enrichment. AB - Based on available literature, ecology and economy of light emitting diode (LED) lights in plant foods production were assessed and compared to high pressure sodium (HPS) and compact fluorescent light (CFL) lamps. The assessment summarises that LEDs are superior compared to other lamp types. LEDs are ideal in luminous efficiency, life span and electricity usage. Mercury, carbon dioxide and heat emissions are also lowest in comparison to HPS and CFL lamps. This indicates that LEDs are indeed economic and eco-friendly lighting devices. The present review indicates also that LEDs have many practical benefits compared to other lamp types. In addition, they are applicable in many purposes in plant foods production. The main focus of the review is the targeted use of LEDs in order to enrich phytochemicals in plants. This is an expedient to massive improvement in production efficiency, since it diminishes the number of plants per phytochemical unit. Consequently, any other production costs (e.g. growing space, water, nutrient and transport) may be reduced markedly. Finally, 24 research articles published between 2013 and 2017 were reviewed for targeted use of LEDs in the specific, i.e. blue range (400-500 nm) of spectrum. The articles indicate that blue light is efficient in enhancing the accumulation of health beneficial phytochemicals in various species. The finding is important for global food production. (c) 2017 Society of Chemical Industry. PMID- 28631262 TI - Lifetime Suicidal Behaviors and Career Characteristics Among U.S. Army Soldiers: Results from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). AB - The current report presents data on lifetime prevalence of suicide ideation and nonfatal attempts as reported by the large representative sample of U.S. Army soldiers who participated in the Consolidated All-Army Survey of the Army Study to Assess Risk and Resilience in Servicemembers (N = 29,982). We also examine associations of key Army career characteristics with these outcomes. Prevalence estimates for lifetime suicide ideation are 12.7% among men and 20.1% among women, and for lifetime suicide attempts are 2.5% and 5.1%, respectively. Retrospective age-of-onset reports suggest that 53.4%-70% of these outcomes had preenlistment onsets. Results revealed that, for both men and women, being in the Regular Army, compared with being in the National Guard or Army Reserve, and being in an enlisted rank, compared with being an officer, is associated with increased risk of suicidal behaviors and that this elevated risk is present both before and after joining the Army. PMID- 28631265 TI - Evolution of ventral hernia repair. AB - PURPOSE: The aim of this review was to look at relevant data and research on the evolution of ventral hernia repair. METHODS: Resources including books, research, guidelines, and online articles were reviewed to provide a concise history of and data on the evolution of ventral hernia repair. RESULTS: The evolution of ventral hernia repair has a very long history, from the recognition of ventral hernias to its current management, with significant contributions from different authors. Advances in surgery have led to more cases of ventral hernia formation, and this has required the development of new techniques and new materials for ventral hernia management. The biocompatibility of prosthetic materials has been important in mesh development. The functional anatomy and physiology of the abdominal wall has become important in ventral hernia management. New techniques in abdominal wall closure may prevent or reduce the incidence of ventral hernia in the future. CONCLUSION: The management of ventral hernia is continuously evolving as it responds to new demands and new technology in surgery. PMID- 28631266 TI - For Better or Worse? System-Justifying Beliefs in Sixth-Grade Predict Trajectories of Self-Esteem and Behavior Across Early Adolescence. AB - Scholars call for more attention to how marginalization influences the development of low-income and racial/ethnic minority youth and emphasize the importance of youth's subjective perceptions of contexts. This study examines how beliefs about the fairness of the American system (system justification) in sixth grade influence trajectories of self-esteem and behavior among 257 early adolescents (average age 11.4) from a diverse, low-income, middle school in an urban southwestern city. System justification was associated with higher self esteem, less delinquent behavior, and better classroom behavior in sixth grade but worse trajectories of these outcomes from sixth to eighth grade. These findings provide novel evidence that system-justifying beliefs undermine the well being of marginalized youth and that early adolescence is a critical developmental period for this process. PMID- 28631267 TI - Ethical decision making in aged care. PMID- 28631268 TI - Network for Investigation of Delirium across the U.S.: Advancing the Field of Delirium with a New Interdisciplinary Research Network. PMID- 28631269 TI - Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning. AB - Reduced-toxicity conditioning with fludarabine and treosulfan is a dose-intensive regimen with enhanced anti-leukemia effect and acceptable toxicity in AML/MDS. HLA-C regulates natural-killer (NK) cell function by inhibiting Killer immunoglobulin-like receptors (KIR) and is divided into C1 and C2 epitopes. The missing-ligand theory suggests that missing recipient KIR ligands drives NK alloreactivity after SCT, in the absence of HLA-mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched-siblings (n = 97) or matched-unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m2 ). 34% expressed one HLA C group 1 allele (C1C1), 19% one HLA-C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow-up was 48 months. 5-year relapse, nonrelapse mortality (NRM) and leukemia-free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate-analysis identified chemo-refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA-C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA-C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA-matched SCT with treosulfan conditioning in AML/MDS. PMID- 28631270 TI - Comparison of in vivo toxicity, antioxidant and immunomodulatory activities of coconut, nipah and pineapple juice vinegars. AB - BACKGROUND: Vinegar is widely used as a food additive, in food preparation and as a food supplement. This study compared the phenolic acid profiles and in vivo toxicities, and antioxidant and immunomodulatory effects of coconut, nipah and pineapple juice vinegars, which were respectively prepared via a two-step fermentation using Saccharomyces cerevisiae 7013 INRA and Acetobacter aceti vat Europeans. RESULTS: Pineapple juice vinegar, which had the highest total phenolic acid content, also exhibited the greatest in vitro antioxidant capacity compared to coconut juice and nipah juice vinegars. Following acute and sub-chronic in vivo toxicity evaluation, no toxicity and mortality were evident and there were no significant differences in the serum biochemical profiles between mice administered the vinegars versus the control group. In the sub-chronic toxicity evaluation, the highest liver antioxidant levels were found in mice fed with pineapple juice vinegar, followed by coconut juice and nipah juice vinegars. However, compared to the pineapple juice and nipah juice vinegars, the mice fed with coconut juice vinegar, exhibited a higher population of CD4+ and CD8+ T lymphocytes in the spleen, which was associated with greater levels of serum interleukin-2 and interferon-gamma cytokines. CONCLUSIONS: Overall, the data suggested that not all vinegar samples cause acute and sub-chronic toxicity in vivo. Moreover, the in vivo immunity and organ antioxidant levels were enhanced, to varying extents, by the phenolic acids present in the vinegars. The results obtained in this study provide appropriate guidelines for further in vivo bioactivity studies and pre-clinical assessments of vinegar consumption. (c) 2017 Society of Chemical Industry. PMID- 28631271 TI - Ocular myasthenic syndrome, adverse reaction to omalizumab? A case report. PMID- 28631272 TI - A Unique Fatal Moose Attack Mimicking Homicide. AB - Fatalities caused by animal attacks are rare, but have the potential to mimic homicide. We present a case in which a moose attacked and killed a woman who was walking her dog in a forest. Autopsy showed widespread blunt trauma with a large laceration on one leg in which blades of grass were embedded. Flail chest was the cause of death. The case was initially conceived as homicide by means of a riding lawn mower. A review of the case by moose experts and analyses of biological trace material that proved to originate from moose, established the true source of injury. The dog probably provoked a moose, which, in response, stomped and gored the victim to death. The injuries resembled those previously reported from attacks by cattle and water buffalo. Fatal moose attacks constitute an extremely rare threat in boreal areas, but can be considered in traumatic deaths of unknown cause. PMID- 28631273 TI - Dermoscopic features of ocular and extraocular sebaceous carcinomas. AB - Sebaceous carcinomas are rare but potentially fatal malignant adenocarcinomas with varying degrees of sebaceous differentiation. Several dermoscopic findings of extraocular sebaceous carcinomas have been reported; however, there are no previous reports of ocular sebaceous carcinomas detected using dermoscopy. We present a case of ocular sebaceous carcinomas showing specific findings from dermoscopy, and describe the common dermoscopic characteristics. In our cases and a review of cases in the literature, we noted that polymorphous vessels and yellowish areas were observed in all eight cases. Thus, we consider that dermoscopic findings of polymorphous vessels with yellow backgrounds suggest sebaceous carcinoma. PMID- 28631274 TI - Prenatal Diagnosis of Fetal Goitrous Hypothyroidism in a Euthyroid Mother: A Management Challenge. PMID- 28631275 TI - A Typology of Interprofessional Teamwork in Acute Geriatric Care: A Study in 55 units in Belgium. AB - OBJECTIVES: To explore the quality of interprofessional teamwork in acute geriatric care and to build a model of team types. DESIGN: Cross-sectional multicenter study. SETTING: Acute geriatric units in Belgium. PARTICIPANTS: Team members of different professional backgrounds. MEASUREMENTS: Perceptions of interprofessional teamwork among team members of 55 acute geriatric units in Belgium were measured using a survey covering collaborative practice and experience, managerial coaching and open team culture, shared reflection and decision-making, patient files facilitating teamwork, members' belief in the power of teamwork, and members' comfort in reporting incidents. Cluster analysis was used to determine types of interprofessional teamwork. Professions and clusters were compared using analysis of variance. RESULTS: The overall response rate was 60%. Of the 890 respondents, 71% were nursing professionals, 20% other allied health professionals, 5% physicians, and 4% logistic and administrative staff. More than 70% of respondents scored highly on interprofessional teamwork competencies, consultation, experiences, meetings, management, and results. Fewer than 55% scored highly on items about shared reflection and decision-making, reporting incidents from a colleague, and patient files facilitating interprofessional teamwork. Nurses in this study rated shared reflection and decision-making lower than physicians on the same acute geriatric units (P < .001). Using the mean score on each of the six areas, four clusters that differed significantly in all areas were identified using hierarchical cluster analysis and scree plot analysis (P < .001). CONCLUSION: Interprofessional teamwork in acute geriatric units is satisfactory, but shared reflection and decision-making needs improvement. Four types of interprofessional teamwork are identified and can be used to benchmark the teamwork of individual teams. PMID- 28631276 TI - Comparison of two different analysis approaches for DTI free-water corrected and uncorrected maps in the study of white matter microstructural integrity in individuals with depression. AB - Diffusion tensor imaging (DTI) has often been used to examine white matter (WM) tract abnormalities in depressed subjects, but these studies have yielded inconsistent results, probably, due to gender composition or small sample size. In this study, we applied different analysis pipelines to a relatively large sample of individuals with depression to determine whether previous findings in depression can be replicated with these pipelines. We used a "standard" DTI algorithm and maps computed through a free-water (FW) corrected DTI. This latter algorithm is able to identify and separate the effects of extracellular FW on DTI metrics. Additionally, skeletonized and WM voxel-based analysis (VBA) methods were used. Using the skeletonized method, DTI maps showed lower fractional anisotropy (FA) in depressed subjects in the left brain hemisphere, including the anterior thalamic radiation (ATR L), cortical spinal tract (CST L), inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and superior longitudinal fasciculus (SLF L). Differences in radial diffusivity (RD) were also found. For the VBA using RD, we found different results when we used FW uncorrected and corrected DTI metrics. Relative to the VBA approach, the skeletonized analysis was able to identify more clusters where WM integrity was altered in depressed individuals. Different significant correlations were found between RD and the Patient Health Questionnaire in the CST L, and SLF L. In conclusion, the skeletonized method revealed more clusters than the VBA and individuals with depression showed multiple WM abnormalities, some of which were correlated with disease severity Hum Brain Mapp 38:4690-4702, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631277 TI - Spindle cell oncocytoma of adenohypophysis: Review of literature and report of another recurrent case. AB - Spindle cell oncocytoma (SCO) of adenohypophysis was first described in 2002 by Roncaroli et al. as a new entity in the tumors originating from adenohypophysis. It was subsequently recognized as a distinct entity in the 2007 WHO classification of CNS tumors and retained in the current updated classification. In contrast to that suggested by the original authors, this tumor does have a potential for recurrence as first described by Kloub et al. and later with many such case reports. This tumor can be confused with other sellar tumors like pituicytomas and pituitary adenoma, both radiologically and histopathologically. However, it is imperative to differentiate these tumors from the above-mentioned differential diagnoses as it certainly has a recurrent potential. To date only 34 cases of SCO have been published in the English literature. Herein we present a rare SCO case with unusually aggressive course in a 64-year-old man, which recurred 4 years after the initial diagnosis. PMID- 28631278 TI - Effects of Different Temperatures on the Development of Dermestes Frischii and Dermestes Undulatus (Coleoptera, Dermestidae): Comparison Between Species. AB - Dermestidae could be useful in forensic investigations to assess the PMI as adults and larvae colonize dried remains. We reared two species of Dermestidae (Dermestes frischii and Dermestes undulatus) to understand the effects of different temperatures on the length of their whole life cycle and on their immature stages. Both species were reared at 23 degrees C +/- 0.5, RH 75% and at 26 degrees C +/- 0.5, 75% RH. Our result shows that the temperature is the main factor that influences the development of those species; in fact, increasing temperature leads to a shorter development cycle (59.8 +/- 0.5 and 38.1 +/- 0.2 for D. frischii; 50.6 +/- 0.6 and 36.2 +/- 0.2 for D. undulatus). Furthermore, we found that the number of the molts before the pupa decreases from 5-7 to 5-6 for D. frischii and from 4-6 to 4-5 for D. undulatus, respectively, at 23 degrees C and 26 degrees C. PMID- 28631279 TI - Nurses' attitudes and knowledge regarding organ and tissue donation and transplantation in a provincial hospital: A descriptive and multivariate analysis. AB - The attitudes and knowledge of nursing personnel regarding organ and tissue donation can influence the decision to donate. This study aimed to determine these two factors among nurses at a district hospital in Barcelona, Spain. A survey was carried out using a 35 item questionnaire. Results were subjected to descriptive and comparative statistical analyses using bivariate and multivariate analyses to examine the relation between demographic data and attitudes toward donation. The completion rate was 68.2%, with 98.6% of those responding stating that they were in favor of organ donation. The respondents were unsure as to whether the criteria for inclusion in transplant waiting lists were appropriate (57.5%), whereas 72.2% agreed that brain death is equivalent to death. The bivariate analysis revealed a significant association between a positive attitude toward donation and working on permanent night shift no religious beliefs. Attitudes toward donation among nurses were generally positive; a negative attitude, although attitudes towards donation among the nurses participating in the study were generally positive, it should be pointed out that when a negative attitude does exist this affects significant aspects such as belief in the diagnosis of brain death or the criteria for inclusion on the waiting list, amongst others, which reflects that specific training in donation focused on nurses continues to be needed. PMID- 28631280 TI - Age- and sex-associated morphological variations of metatarsal torsional patterns in humans. AB - It has been demonstrated that the torsional patterns of the metatarsal heads are associated with the presence or absence of the medial longitudinal arch in hominoid feet. The relatively untwisted second metatarsal is unique in humans, but that of the African apes is much more inverted, suggesting that the torsion of the second metatarsal might represent the overall shape and flatness of the foot. Some clinical studies have recently argued that the onset of foot pathologies such as hallux valgus might be related to the torsional pattern of the metatarsals. However, to date, no studies have systematically investigated the morphological variations of the torsional patterns of human metatarsals. In this study, therefore, the aim was to clarify the age- and sex-associated variations in the torsional patterns of human metatarsals using three-dimensional computed tomography. The torsion angles of the five metatarsals were calculated by defining the dorsopalmar vector of the metatarsal base and the vector corresponding to the rotational axis of the metatarsal head. The present result demonstrated that the second metatarsals of females were significantly more inverted with increasing age. Flat foot is known to be most common in elderly women. Whether there is a cause-effect relationship between second metatarsal torsion and flattening of the medial longitudinal arch has yet to be answered, but this study suggested that torsion of the second metatarsal might possibly be used as an indicator for the early diagnosis of flat foot and associated foot pathologies. Clin. Anat. 30:1058-1063, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631281 TI - Detecting large-scale networks in the human brain using high-density electroencephalography. AB - High-density electroencephalography (hdEEG) is an emerging brain imaging technique that can be used to investigate fast dynamics of electrical activity in the healthy and the diseased human brain. Its applications are however currently limited by a number of methodological issues, among which the difficulty in obtaining accurate source localizations. In particular, these issues have so far prevented EEG studies from reporting brain networks similar to those previously detected by functional magnetic resonance imaging (fMRI). Here, we report for the first time a robust detection of brain networks from resting state (256-channel) hdEEG recordings. Specifically, we obtained 14 networks previously described in fMRI studies by means of realistic 12-layer head models and exact low-resolution brain electromagnetic tomography (eLORETA) source localization, together with independent component analysis (ICA) for functional connectivity analysis. Our analyses revealed three important methodological aspects. First, brain network reconstruction can be improved by performing source localization using the gray matter as source space, instead of the whole brain. Second, conducting EEG connectivity analyses in individual space rather than on concatenated datasets may be preferable, as it permits to incorporate realistic information on head modeling and electrode positioning. Third, the use of a wide frequency band leads to an unbiased and generally accurate reconstruction of several network maps, whereas filtering data in a narrow frequency band may enhance the detection of specific networks and penalize that of others. We hope that our methodological work will contribute to rise of hdEEG as a powerful tool for brain research. Hum Brain Mapp 38:4631-4643, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631282 TI - Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines. AB - The okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate-gated chloride channels (GluCls) in invertebrates, not affecting human ligand-gated anion channels. Okaramines B (1) and D (2) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2-dimethyl-3-methyl-azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster (oka) of 1 and 2, then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an alpha-ketoglutarate-dependent non-heme FeII dioxygenase that forged the azetidine ring on the okaramine skeleton. PMID- 28631283 TI - Assessing causal effects of early life-course factors on early childhood caries in 5-year-old Ugandan children using directed acyclic graphs (DAGs): A prospective cohort study. AB - OBJECTIVE: To estimate the effect of distal and proximal early life-course factors on early childhood caries (ECC) in 5-year-old Ugandan children, particularly focusing on the causal effect of exclusive breast feeding (EBF) on ECC using directed acyclic graphs (DAGs) for confounder selection. METHODS: This study had a nested prospective cohort design, focusing on 5 years of follow-ups of caregiver-children pairs from the PROMISE-EBF trial (ClinicalTrials.gov no: NCT00397150) conducted in 2011 in Eastern Uganda. Data were from recruitment interviews, 24-week, 2-year and 5-year follow-ups of a cohort of 417 mother children pairs. Trained research assistants performed interviews with caregivers in the local language and ECC was recorded under field conditions using the World Health Organization's (WHO) decayed missing or filled teeth (dmft) index. Early life-course factors in terms of socio-demographic characteristics, EBF and other feeding habits were assessed at the various follow-ups. The outcome (ECC; dmft>0) was assessed at the 5-year follow-up. Causal diagrams as DAGs were constructed to guide the selection of confounding and collider variables to be included in or excluded from the final multivariable analysis. Negative binomial regression analyses were performed based on two comparative DAGs representing different causal models. RESULTS: Model 1 based on DAG 1, showed EBF to be a protective factor against ECC, with an IRR and 95% CI of 0.62 (0.43-0.91). According to Model 2 based on DAG 2, EBF and having both parents living together had protective effects: the corresponding IRRs and 95% CI were 0.60 (0.41-0.88) and 0.48 (0.25-0.90), respectively. CONCLUSIONS: Both plausible models indicated that being exclusively breastfed for 24 weeks had a protective causal effect against ECC. Further research, examining the unmeasured variables included in the DAGs is necessary to strengthen the present finding and allow stronger causal claims. PMID- 28631284 TI - The role of radiotherapy in bone metastases: A critical review of current literature. AB - Radiotherapy is considered the treatment of choice for painful bone metastases. However, novel modalities of radiotherapy have emerged in the concept of oligometastasic disease. In addition, the increase of overall survival of patients with bone metastatic disease in the last decades due to systemic treatments has issued the silent topic of re-irradiation. The aim of this manuscript was to present a current thorough search of relevant literature. Originally, 6,087 articles revealed from PubMed database related to radiotherapy and bone metastases. The first objective was to identify prospective randomised phase III studies dealing with bone metastases and which treated primary with radiotherapy. Abstracts and non-English citations were excluded. Twenty-three phase III clinical trials, 17 prospective studies and eight meta analysis/systemic reviews matching with these criteria, were identified. Eleven randomised studies were comparing single dose fraction to multi-fraction schedules of radiotherapy. The overall response rates and complete response rates were not significant between the two arms. Re-irradiations rates were significantly higher for the single dose fraction arms. Stereotactic radiotherapy showed excellent tumour control rates more than 80%. All trials showed the equivalence of either single or multi-fractionated radiotherapy for metastatic bone lesions. Stereotactic irradiation is feasible and safe for oligometastatic disease. However, it seems that the single fraction of 8 Gy is superior to 4 Gy, in terms of efficacy. PMID- 28631285 TI - Quality assurance of falls reduction in an orthopaedic ward using a novel bedside trolley table set-up strategy. AB - OBJECTIVE: To assess whether a novel bedside trolley table set-up decreased inpatient falls (IF) postintervention. METHODS: From December 2012 to December 2014, geriatric patients admitted to our orthopaedic ward with extreme falls risk had a bedside trolley placed between them and a floor sensor mat to give responders more time to prevent IF. Pre- and postintervention falls data was reviewed for falls reduction using falls per month as comparison standard. IF were classified as high or low/medium risk using St Thomas's Risk Assessment Tool In Falling Elderly inpatients (STRATIFY) scoring. RESULTS: Sixty-two of 134 falls fulfilled inclusion criteria. The high-risk group had 33 patients preintervention and 22 patients postintervention, with falls per month at 3.4 preintervention and 1 postintervention. IF reduction was 71% in STRATIFY >=17 versus 44% in STRATIFY <17. CONCLUSIONS: The novel set-up with appropriate assessment may decrease falls in the high-risk ortho-geriatric population. Further trials are warranted to confirm its effectiveness. PMID- 28631287 TI - Incidental findings of implant complications on postimplantation CBCTs: A cross sectional study. AB - BACKGROUND: Survival rates of dental implants are reported to be very high and seem to indicate minimal complications related to dental implants. PURPOSE: The aim of this report was to evaluate in a cross-sectional study the prevalence of implant positioning complications as appears in postimplantation Cone-Beam Computerized Tomography (CBCT) in two of the major imaging facilities in Bucharest, Romania. METHODS: Demographic and implant data was collected from two of the three main CBCT facilities in Bucharest, Romania. All postimplantation CBCT imaging were assessed and evaluated for the presence of different implant positioning related complications. Data were entered into Excel spreadsheet and analyzed statistically. RESULTS: Of the 2323 CBCT's that were analyzed, a total of 160 (6.89%) presented with implant positioning related complications. Out of those, 62 cases revealed penetration of the implant to adjacent anatomic structure. More specifically, there were 21 instances of sinus penetration, 19 instances of nasal cavity penetration, 9 instances of inferior alveolar canal penetration, and 13 instances of lingual plate perforations. There were also 15 cases of adjacent tooth injury noted. CONCLUSIONS: Despite the popularity of dental implants, the surgical placement of these implants is not a riskless procedure. Implant mal-positioning might be life-threatening and can lead to serious bleeding, airway obstruction, and unnecessary postoperative surgeries. Complications of dental implants are not obsolete and dental implant associated problems may not be apparent immediately. Surgeons must have proper training and use evidenced-based treatment planning in order to prevent dental implant complications. PMID- 28631288 TI - Higher Intelligence and Later Maternal Age: Which Way Does the Causal Direction Go? PMID- 28631286 TI - Knockdown of mediator subunit Med19 suppresses bladder cancer cell proliferation and migration by downregulating Wnt/beta-catenin signalling pathway. AB - Mediator complex subunit 19 (Med19), a RNA polymerase II-embedded coactivator, is reported to be involved in bladder cancer (BCa) progression, but its functional contribution to this process is poorly understood. Here, we investigate the effects of Med19 on malignant behaviours of BCa, as well as to elucidate the possible mechanisms. Med19 expression in 15 BCa tissues was significantly higher than adjacent paired normal tissues using real-time PCR and Western blot analysis. Immunohistochemical staining of 167 paraffin-embedded BCa tissues was performed, and the results showed that high Med19 protein level was positively correlated with clinical stages and histopathological grade. Med19 was knocked down in BCa cells using short-hairpin RNA. Functional assays showed that knocking down of Med19 can suppress cell proliferation and migration in T24, UM-UC3 cells and 5637 in vitro, and inhibited BCa tumour growth in vivo. TOP/FOPflash reporter assay revealed that Med19 knockdown decreased the activity of Wnt/beta-catenin pathway, and the target genes of Wnt/beta-catenin pathway were down-regulated, including Wnt2, beta-catenin, Cyclin-D1 and MMP-9. However, protein levels of Gsk3beta and E-cadherin were elevated. Our data suggest that Med19 expression correlates with aggressive characteristics of BCa and Med19 knockdown suppresses the proliferation and migration of BCa cells through down-regulating the Wnt/beta catenin pathway, thereby highlighting Med19 as a potential therapeutic target for BCa treatment. PMID- 28631289 TI - Three-dimensional orientation of the acetabulum. AB - This study was designed specifically to determine the normal acetabular orientation and femoral head covering, and whether these are affected by age or sex. Computed tomographic images of normal Japanese hip joints were used (males 60, females 60; mean age 48.3 years, range 15-79 years). Male and female age profiles were matched. The reconstructed 3-D pelvic images were aligned in the anatomical pelvic coordinate system. The acetabular orientation angles and femoral covering angles were measured in the sagittal, coronal, and horizontal planes. In the sagittal plane, the acetabular orientation angle was operative anteversion (O-av), and the femoral covering angles were the anterior and posterior center-edge angles (ACE and PCE). In the coronal plane, they were the Sharp angle (SA) and the lateral center-edge angle (LCE). In the horizontal plane, they were anatomical anteversion (A-av) and the anterior and posterior sector angles (ASA and PSA). The O-av, SA, and A-av were smaller in the male than the female acetabulum (P < 0.01). SA in both males and females was inversely correlated with age (P < 0.01). Both male PCE and PSA were significantly smaller than those of females, while male ASA was larger than female ASA (P < 0.05). The male acetabulum is directed further outward and downward than the female one. However, this does not indicate that the male acetabulum covers the femoral head more, because there is no significant sex difference in the LCE. Femoral coverage is more posteriorly biased in females than in males owing to pelvic inclination. Clin. Anat. 30:753-760, 2017. (c) 2017Wiley Periodicals, Inc. PMID- 28631290 TI - A H2 -oxidizing, 1,2,3-trichlorobenzene-reducing multienzyme complex isolated from the obligately organohalide-respiring bacterium Dehalococcoides mccartyi strain CBDB1. AB - Dehalococcoides mccartyi is a small, slow-growing bacterium of the phylum Chloroflexi that conserves energy using aliphatic and aromatic organohalides as electron acceptors, and hydrogen as sole electron donor. A recent study identified a protein complex in the membrane of strain CBDB1 comprising a Hup hydrogenase, a complex iron-sulphur molybdoprotein and a reductive dehalogenase (RdhA) that catalyses reduction of 1,2,3,4-tetrachlorobenzene. Using a combination of size-exclusion chromatography, in-gel hydrogenase activity staining, immunological analysis and mass spectrometry, we identified here a large molecular mass protein complex solubilized from the cytoplasmic membrane of D. mccartyi strain CBDB1 that catalysed H2 -dependent reduction of 1,2,3 trichlorobenzene (1,2,3-TCB) to 1,3-DCB. In-gel zymographic staining revealed H2 :benzyl viologen oxidoreductase activity associated with the complex and immunological analysis identified co-elution of CdbdA195, the predicted catalytic subunit of the iron-sulphur molybdoenzyme, the chlorobenzene-specific RdhA, CbrA, and traces of HupL, the catalytic subunit of the Hup hydrogenase. Quantitative reverse transcriptase PCR analyses indicated that the expression of the hupL and cbdbA195 genes was induced by 1,2,3-TCB but not by hydrogen. Together, these data identify and describe a protein-based electron-transfer complex catalysing H2 oxidation coupled to chlorobenzene reduction. PMID- 28631291 TI - Folate deficiency disturbs hsa-let-7 g level through methylation regulation in neural tube defects. AB - Folic acid deficiency during pregnancy is believed to be a high-risk factor for neural tube defects (NTDs). Disturbed epigenetic modifications, including miRNA regulation, have been linked to the pathogenesis of NTDs in those with folate deficiency. However, the mechanism by which folic acid-regulated miRNA influences this pathogenesis remains unclear. It is believed that DNA methylation is associated with dysregulated miRNA expression. To clarify this issue, here we measured the methylation changes of 22 miRNAs in 57 human NTD cases to explore whether such changes are involved in miRNA regulation in NTD cases through folate metabolism. In total, eight of the 22 miRNAs tested reduced their methylation modifications in NTD cases, which provide direct evidence of the roles of interactions between DNA methylation and miRNA level in these defects. Among the findings, there was a significant association between folic acid concentration and hsa-let-7 g methylation level in NTD cases. Hypomethylation of hsa-let-7 g increased its own expression level in both NTD cases and cell models, which indicated that hsa-let-7 g methylation directly regulates its own expression. Overexpression of hsa-let-7 g, along with its target genes, disturbed the migration and proliferation of SK-N-SH cells, implying that hsa-let-7 g plays important roles in the prevention of NTDs by folic acid. In summary, our data suggest a relationship between aberrant methylation of hsa-let-7 g and disturbed folate metabolism in NTDs, implying that improvements in nutrition during early pregnancy may prevent such defects, possibly via the donation of methyl groups for miRNAs. PMID- 28631292 TI - Validation of Reduced Reagent Volumes in the Implementation of the Quantifiler(r) Trio Quantification Kit. AB - The Quantifiler(r) Trio Quantification Kit has been developed to quantify the total amount of amplifiable and human male DNA in samples and to estimate the extent of DNA degradation. To minimize the cost of DNA quantification, we evaluated kit performance using a reduced volume of reagents (1/10-volume) using DNA samples of varying types and concentrations. Our results demonstrated concordance between the manufacturer's method and the low-volume method for DNA quantification, DNA degradation index estimation, and human male DNA quantification. We confirmed the practical utility of the low-volume method with 109 casework samples by evaluating short tandem repeat (STR) profiling success with respect to DNA quantity and quality. We also defined a cutoff value for DNA quantity to ensure reliable STR results. Using a reduced volume of reagents, 10 times more reactions per kit are possible; accordingly, this method reduces the cost of DNA quantification, while maintaining performance. PMID- 28631293 TI - Region-dependent patterns of trabecular bone growth in the human proximal femur: A study of 3D bone microarchitecture from early postnatal to late childhood period. AB - OBJECTIVES: Parallel with body growth and development, bone structure in non adults is reorganized to achieve the particular design observed in mature individuals. We traced the changes in three-dimensional trabecular microarchitectural design during the phases of locomotor maturation to clarify how human bone adapts to mechanical demands. MATERIALS AND METHODS: Micro-CT was performed on biomechanically-relevant subregions of the proximal femur (medial, intermediate and lateral neck regions, intertrochanteric region, metaphyseal region) from early postnatal period to late childhood. RESULTS: Developmental patterns of trabecular microarchitecture showed that gestationally overproduced bone present at birth underwent the most dramatic reduction during the first year, followed by a reversing trend in some of the quantitative parameters (e.g., bone volume fraction, trabecular anisotropy). Certain regional anisotropy already present at birth is further accentuated into the childhood suggesting an adaptation to differential loading environments. Trabecular eccentricity in the femoral neck was particularly accentuated during childhood, giving the medial neck-the site mostly loaded in walking-superior microarchitectural design (high bone volume fraction and anisotropy, the earliest appearance and predominance of plate- and honeycomb-shaped trabeculae). DISCUSSION: While providing quantitative data on how bone microarchitecture adapts to increasing mechanical demands occurring during the phases of locomotor maturation, the study reveals how regional anisotropy develops in the proximal femur to ensure a functional and competent bone structure. Decomposing the region-specific patterns of bone mass accrual is important in understanding skeletal adaptations to bipedalism, as well for understanding why fractures often occur location-dependent, both in pediatric and elderly individuals. PMID- 28631294 TI - Practical challenges of I2 as a measure of heterogeneity. PMID- 28631295 TI - An EM algorithm for nonparametric estimation of the cumulative incidence function from repeated imperfect test results. AB - In screening and surveillance studies, event times are interval censored. Besides, screening tests are imperfect so that the interval at which an event takes place may be uncertain. We describe an expectation-maximization algorithm to find the nonparametric maximum likelihood estimator of the cumulative incidence function of an event based on screening test data. Our algorithm has a closed-form solution for the combined expectation and maximization step and is computationally undemanding. A simulation study indicated that the bias of the estimator tends to zero for large sample size, and its mean squared error is in general lower than the mean squared error of the estimator that assumes the screening test is perfect. We apply the algorithm to follow-up data from women treated for cervical precancer. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28631297 TI - An augmented reality tool for learning spatial anatomy on mobile devices. AB - Augmented Realty (AR) offers a novel method of blending virtual and real anatomy for intuitive spatial learning. Our first aim in the study was to create a prototype AR tool for mobile devices. Our second aim was to complete a technical evaluation of our prototype AR tool focused on measuring the system's ability to accurately render digital content in the real world. We imported Computed Tomography (CT) data derived virtual surface models into a 3D Unity engine environment and implemented an AR algorithm to display these on mobile devices. We investigated the accuracy of the virtual renderings by comparing a physical cube with an identical virtual cube for dimensional accuracy. Our comparative study confirms that our AR tool renders 3D virtual objects with a high level of accuracy as evidenced by the degree of similarity between measurements of the dimensions of a virtual object (a cube) and the corresponding physical object. We developed an inexpensive and user-friendly prototype AR tool for mobile devices that creates highly accurate renderings. This prototype demonstrates an intuitive, portable, and integrated interface for spatial interaction with virtual anatomical specimens. Integrating this AR tool with a library of CT derived surface models provides a platform for spatial learning in the anatomy curriculum. The segmentation methodology implemented to optimize human CT data for mobile viewing can be extended to include anatomical variations and pathologies. The ability of this inexpensive educational platform to deliver a library of interactive, 3D models to students worldwide demonstrates its utility as a supplemental teaching tool that could greatly benefit anatomical instruction. Clin. Anat. 30:736-741, 2017. (c) 2017Wiley Periodicals, Inc. PMID- 28631296 TI - Hydrogen sulphide as a signalling molecule regulating physiopathological processes in gastrointestinal motility. AB - The biology of H2 S is a still developing area of research and several biological functions have been recently attributed to this gaseous molecule in many physiological systems, including the cardiovascular, urogenital, respiratory, digestive and central nervous system (CNS). H2 S exerts anti-inflammatory effects and can be considered an endogenous mediator with potential effects on gastrointestinal motility. During the last few years, we have investigated the role of H2 S as a regulator of gastrointestinal motility using both animal and human tissues. The aim of the present work is to review published data regarding the potential role of H2 S as a signalling molecule regulating physiopathological processes in gastrointestinal motor function. H2 S is endogenously produced by defined enzymic pathways in different cell types of the intestinal wall including neurons and smooth muscle. Inhibition of H2 S biosynthesis increases motility and H2 S donors cause smooth muscle relaxation and inhibition of propulsive motor patterns. Impaired H2 S production has been described in animal models with gastrointestinal motor dysfunction. The mechanism(s) of action underlying these effects may include several ion channels, although no specific receptor has been identified. At this time, even though there is much experimental evidence for H2 S as a modulator of gastrointestinal motility, we still do not have conclusive experimental evidence to definitively propose H2 S as an inhibitory neurotransmitter in the gastrointestinal tract, causing nerve-mediated relaxation. PMID- 28631298 TI - High prevalence of osteonecrosis among the hemophagocytic lymphohistiocytosis population: Single institution 10-year retrospective data review. PMID- 28631299 TI - Carbazole-azine based fluorescence 'off-on' sensor for selective detection of Cu2+ and its live cell imaging. AB - A new carbazole-azine based fluorescent sensor was synthesized and characterized. The selectivity of the sensor for Cu2+ over other counter ions in a dimethyl sulfoxide/H2 O mixture was shown through enhancement in fluorescence - an off to on transformation. The specificity of the probe towards Cu2+ was evident in ultraviolet/visible, fluorescence, Fourier transform infrared and mass studies. Application of the probe in the cell imaging and cytotoxicity of living cells is illustrated. PMID- 28631300 TI - A bacterial chloroform reductive dehalogenase: purification and biochemical characterization. AB - We report herein the purification of a chloroform (CF)-reducing enzyme, TmrA, from the membrane fraction of a strict anaerobe Dehalobacter sp. strain UNSWDHB to apparent homogeneity with an approximate 23-fold increase in relative purity compared to crude lysate. The membrane fraction obtained by ultracentrifugation was solubilized in Triton X-100 in the presence of glycerol, followed by purification by anion exchange chromatography. The molecular mass of the purified TmrA was determined to be 44.5 kDa by SDS-PAGE and MALDI-TOF/TOF. The purified dehalogenase reductively dechlorinated CF to dichloromethane in vitro with reduced methyl viologen as the electron donor at a specific activity of (1.27 +/- 0.04) * 103 units mg protein-1 . The optimum temperature and pH for the activity were 45 degrees C and 7.2, respectively. The UV-visible spectrometric analysis indicated the presence of a corrinoid and two [4Fe-4S] clusters, predicted from the amino acid sequence. This is the first report of the production, purification and biochemical characterization of a CF reductive dehalogenase. PMID- 28631301 TI - Prevention of lupus nephritis development in NZB/NZW mice by selective blockade of CD28. AB - Systemic lupus erythematosus (SLE) is a chronic systemic inflammatory disease. Autoantibodies (autoAbs) against double-stranded DNA (ds DNA), the hallmark of lupus, are produced and maintained by the interaction between auto-reactive B cells and CD4+ T cells. This interplay is controlled by the CD28/CD80-86/CTLA-4 axis. Here we investigated whether selective blockade of CD28-CD80/86 co stimulatory interactions abrogates lupus nephritis development in a murine model of SLE. To this aim, NZB/NZW F1 mice were treated for 3 months, either with an anti-CD28 Fab' fragment or a control Fab'-IgG. The effect of CD28 blockade on lupus nephritis onset, survival, production of anti-ds DNA antibodies and costimulatory molecules was evaluated. CD28 blockade prevented the development of lupus nephritis and prolonged survival during the 3-month treatment and 12 weeks after. Furthermore, the production of anti-ds DNA autoAbs was decreased. Lastly, the protective effect of CD28 blockade was associated with increased intrarenal expression of the immunoregulatory molecule, Indoleamine 2, 3-dioxygenase, of the co-inhibitory receptor programmed cell-Death - 1 (PD-1) and of its ligand programmed death ligand - 1 (PDL-1).In conclusion, CD28 blockade prevented the development of lupus nephritis in NZB/NZW F1 mice. This immunomodulatory strategy is a promising candidate for SLE therapy in humans. PMID- 28631302 TI - l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia. AB - BACKGROUND AND PURPOSE: Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l-homocysteine-induced vascular inflammation. EXPERIMENTAL APPROACH: A high methionine diet-induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l-homocysteine and the cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual specificity protein phosphatases (DUSPs) and MAPK pathways. KEY RESULTS: Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l-homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up-regulation of inflammatory cytokines (IL-6, IL-8 and TNF-alpha), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8 and TNF-alpha. CONCLUSIONS AND IMPLICATIONS: This study has identified a novel mechanism, which shows that l-homocysteine-induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK1/2 /STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia-associated vascular diseases. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. PMID- 28631303 TI - Photophobia and Seasonal Variation of Migraine in a Subarctic Population. AB - OBJECTIVE: To investigate associations between photophobia and seasonal variation of migraine. METHODS: In this cross-sectional study, migraineurs consecutively recruited were referred to a specialist center located above the Arctic Circle at 68-71 degrees North during a 2.5-year period. Data were obtained through a structured interview. RESULTS: In total, 302 migraineurs with a mean (+/-SD) age of 35.5 (+/-12.6) years were included. Patients who reported seasonal variation of migraine (n = 90; 29.8%) also reported more often interictal photophobia than the others (61/90, 67.8% vs 92/212, 43.4%, P < .0001). Patients reported sunlight or other bright light to trigger migraine attacks in 74.4% with seasonal migraine (SM) compared with 40.6% in patients with non-seasonal migraine (NSM) (P < .0001), but there were similar frequencies of attacks reported to be triggered by sleep, menstruation, and other precipitating factors. After adjusting for migraine with aura, migraine disability, chronic migraine, interictal photophobia, and insomnia, sunlight or other bright light, photophobia was still associated with SM (OR; 3.47, CI [95%]; 1.83-6.59, P < .0001). CONCLUSIONS: Migraineurs in a subarctic area reporting seasonal variation of attack frequency also report increased interictal photophobia independent of other clinical factors. Chronobiological mechanisms and/or increased activity in the visual system may be responsible for this phenomenon. PMID- 28631304 TI - When and How Do Students Benefit From Ethnic Diversity in Middle School? AB - The effects of school-based ethnic diversity on student well-being and race related views were examined during the first year in middle school. To capture the dynamic nature of ethnic exposure, diversity was assessed both at the school level (n = 26) and based on academic course enrollments of African American, Asian, Latino, and White students (n = 4,302; M = 11.33 years). Across all four pan-ethnic groups, school-level ethnic diversity was associated with lower sense of vulnerability (i.e., feeling safer, less victimized, and less lonely) as well as perceptions of teachers' fair and equal treatment of ethnic groups and lower out-group distance. Underscoring the role of individual experiences, exposure to diversity in academic classes moderated the association between school-level diversity and the two aforementioned race-related views. PMID- 28631305 TI - Two-years results of small-incision lenticule extraction and wavefront-guided laser in situ keratomileusis for Myopia. AB - PURPOSE: To compare the 2-years visual and refractive outcomes between small incision lenticule extraction (SMILE) and wavefront-guided laser in situ keratomileusis (LASIK) in eyes with myopia and myopic astigmatism. METHODS: Our retrospective case-control study examined 30 eyes of 30 patients with the manifest refraction spherical equivalent (MRSE) of -3.71 +/- 1.83 dioptres (D) who underwent SMILE and 30 eyes of 30 patients with MRSE of -3.81 +/- 1.40 D who underwent wavefront-guided LASIK. We assessed the 2-years clinical outcomes. RESULTS: Logarithm of the minimal angle of resolution (LogMAR)-corrected distance visual acuity (CDVA) was -0.23 +/- 0.07 in the SMILE group and -0.24 +/- 0.07 in the wavefront-guided LASIK group 2 years postoperatively (p = 0.82). Logarithm of the minimal angle of resolution-uncorrected distance visual acuity (UDVA) was 0.18 +/- 0.09 and -0.15 +/- 0.11 (p = 0.30, respectively). In the SMILE and wavefront-guided LASIK groups 2 years postoperatively, 100% and 73% of eyes, respectively, were within 0.5 D of the prompted MRSE correction (p = 0.005). Changes in the MRSE of -0.10 +/- 0.30 D and -0.23 +/- 0.51 D occurred from 3 months to 2 years (p = 0.40, respectively). We found a significant correlation between myopic regression and the changes in the keratometric readings from 3 months to 2 years after wavefront-guided LASIK (r = -0.48, p = 0.002), but not after SMILE (r = -0.004, p = 0.90). CONCLUSION: Small-incision lenticule extraction offers better refractive outcomes than wavefront-guided LASIK during a 2-years follow-up for the correction of myopia and myopic astigmatism. PMID- 28631306 TI - Cactus stem (Opuntia ficus-indica Mill): anatomy, physiology and chemical composition with emphasis on its biofunctional properties. AB - Cactus stem (Opuntia ficus-indica Mill) is native to Mesoamerica and marketed in different forms such as fresh, frozen or pre-cooked. Worldwide, this vegetable is recognized for its pharmaceutical actions, including its antioxidant, diuretic, anticarcinogenic, anti-inflammatory, anti-diabetic, and anti-hypercholesterolemic properties, as well as their antiviral and antispermatogenic effects. However, not all of these properties have been associated with its chemical composition; therefore, this review aims to present and integrate information available on the physiology and anatomy of cactus stem and its chemical composition, focusing on some of the many factors that determine its biofunctionality. (c) 2017 Society of Chemical Industry. PMID- 28631307 TI - Interventions for the prevention of recurrent erysipelas and cellulitis. AB - BACKGROUND: Erysipelas and cellulitis (hereafter referred to as 'cellulitis') are common bacterial skin infections usually affecting the lower extremities. Despite their burden of morbidity, the evidence for different prevention strategies is unclear. OBJECTIVES: To assess the beneficial and adverse effects of antibiotic prophylaxis or other prophylactic interventions for the prevention of recurrent episodes of cellulitis in adults aged over 16. SEARCH METHODS: We searched the following databases up to June 2016: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched five trials registry databases, and checked reference lists of included studies and reviews for further references to relevant randomised controlled trials (RCTs). We searched two sets of dermatology conference proceedings, and BIOSIS Previews. SELECTION CRITERIA: Randomised controlled trials evaluating any therapy for the prevention of recurrent cellulitis. DATA COLLECTION AND ANALYSIS: Two authors independently carried out study selection, data extraction, assessment of risks of bias, and analyses. Our primary prespecified outcome was recurrence of cellulitis when on treatment and after treatment. Our secondary outcomes included incidence rate, time to next episode, hospitalisation, quality of life, development of resistance to antibiotics, adverse reactions and mortality. MAIN RESULTS: We included six trials, with a total of 573 evaluable participants, who were aged on average between 50 and 70. There were few previous episodes of cellulitis in those recruited to the trials, ranging between one and four episodes per study.Five of the six included trials assessed prevention with antibiotics in participants with cellulitis of the legs, and one assessed selenium in participants with cellulitis of the arms. Among the studies assessing antibiotics, one study evaluated oral erythromycin (n = 32) and four studies assessed penicillin (n = 481). Treatment duration varied from six to 18 months, and two studies continued to follow up participants after discontinuation of prophylaxis, with a follow-up period of up to one and a half to two years. Four studies were single-centre, and two were multicentre; they were conducted in five countries: the UK, Sweden, Tunisia, Israel, and Austria.Based on five trials, antibiotic prophylaxis (at the end of the treatment phase ('on prophylaxis')) decreased the risk of cellulitis recurrence by 69%, compared to no treatment or placebo (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.13 to 0.72; n = 513; P = 0.007), number needed to treat for an additional beneficial outcome (NNTB) six, (95% CI 5 to 15), and we rated the certainty of evidence for this outcome as moderate.Under prophylactic treatment and compared to no treatment or placebo, antibiotic prophylaxis reduced the incidence rate of cellulitis by 56% (RR 0.44, 95% CI 0.22 to 0.89; four studies; n = 473; P value = 0.02; moderate-certainty evidence) and significantly decreased the rate until the next episode of cellulitis (hazard ratio (HR) 0.51, 95% CI 0.34 to 0.78; three studies; n = 437; P = 0.002; moderate-certainty evidence).The protective effects of antibiotic did not last after prophylaxis had been stopped ('post-prophylaxis') for risk of cellulitis recurrence (RR 0.88, 95% CI 0.59 to 1.31; two studies; n = 287; P = 0.52), incidence rate of cellulitis (RR 0.94, 95% CI 0.65 to 1.36; two studies; n = 287; P = 0.74), and rate until next episode of cellulitis (HR 0.78, 95% CI 0.39 to 1.56; two studies; n = 287). Evidence was of low certainty.Effects are relevant mainly for people after at least two episodes of leg cellulitis occurring within a period up to three years.We found no significant differences in adverse effects or hospitalisation between antibiotic and no treatment or placebo; for adverse effects: RR 0.87, 95% CI 0.58 to 1.30; four studies; n = 469; P = 0.48; for hospitalisation: RR 0.77, 95% CI 0.37 to 1.57; three studies; n = 429; P = 0.47, with certainty of evidence rated low for these outcomes. The existing data did not allow us to fully explore its impact on length of hospital stay.The common adverse reactions were gastrointestinal symptoms, mainly nausea and diarrhoea; rash (severe cutaneous adverse reactions were not reported); and thrush. Three studies reported adverse effects that led to discontinuation of the assigned therapy. In one study (erythromycin), three participants reported abdominal pain and nausea, so their treatment was changed to penicillin. In another study, two participants treated with penicillin withdrew from treatment due to diarrhoea or nausea. In one study, around 10% of participants stopped treatment due to pain at the injection site (the active treatment group was given intramuscular injections of benzathine penicillin).None of the included studies assessed the development of antimicrobial resistance or quality-of-life measures.With regard to the risks of bias, two included studies were at low risk of bias and we judged three others as being at high risk of bias, mainly due to lack of blinding. AUTHORS' CONCLUSIONS: In terms of recurrence, incidence, and time to next episode, antibiotic is probably an effective preventive treatment for recurrent cellulitis of the lower limbs in those under prophylactic treatment, compared with placebo or no treatment (moderate-certainty evidence). However, these preventive effects of antibiotics appear to diminish after they are discontinued (low-certainty evidence). Treatment with antibiotic does not trigger any serious adverse events, and those associated are minor, such as nausea and rash (low-certainty evidence). The evidence is limited to people with at least two past episodes of leg cellulitis within a time frame of up to three years, and none of the studies investigated other common interventions such as lymphoedema reduction methods or proper skin care. Larger, high-quality studies are warranted, including long-term follow-up and other prophylactic measures. PMID- 28631308 TI - Association between inadequate antenatal care utilisation and severe perinatal and maternal morbidity: an analysis in the PreCARE cohort. AB - OBJECTIVE: Because the effectiveness of antenatal care in reducing pregnancy complications is still discussed despite widespread recommendations of its use, we sought to assess the association between utilisation of recommended antenatal care and severe maternal (SMM) and perinatal morbidity (SPM). DESIGN: Prospective cohort study. SETTING: Four maternity units around Paris in 2010-2012. SAMPLE: 9117 women with singleton pregnancies. METHODS: Logistic regression models adjusted for maternal social, demographic and medical characteristics. MAIN OUTCOME MEASURES: Antenatal care utilisation was assessed by: (1) initiation of care after 14 weeks, (2) < 50% of recommended visits made, according to gestational age, (3) absence of the first, second or third trimester ultrasounds, (4) two modified Adequacy of Prenatal Care Utilisation indexes, combining these components. The two main outcomes were composite variables of SMM and SPM. RESULTS: According to the modified Adequacy of Prenatal Care Utilisation index, 34.6% of women had inadequate antenatal care utilisation; the incidence of severe maternal morbidity (SMM) was 2.9% and severe perinatal morbidity (SPM) 5.5%. A percentage of recommended visits below 50% (2.6% of women) was associated with SMM [adjusted odds ratio (OR) 2.40 (1.38-4.17)] and SPM [aOR 2.27 (1.43-3.59)]. Late initiation of care (17.0% of women) was not associated with SMM or SPM. Failure to undergo the recommended ultrasounds (16, 17 and 22% of women) was associated with SPM. Inadequate antenatal care utilisation according to the index was associated with SPM [aOR 1.37 (1.05-1.80)]. CONCLUSION: Inadequate antenatal care utilisation is associated with SMM and SPM, to degrees that vary with the component of care and the outcome considered. TWEETABLE ABSTRACT: Inadequate antenatal care utilisation is associated with severe maternal and perinatal morbidity. PMID- 28631309 TI - Obstructive sleep apnea and silent cerebral infarction in hypertensive individuals. AB - Obstructive sleep apnea syndrome is very prevalent in hypertensive subjects. Moreover, obstructive sleep apnea syndrome activates multiple processes that might be associated with silent cerebral infarct independently of established risk factors. Our aim is to estimate the frequency of obstructive sleep apnea syndrome in hypertensive patients with and without silent cerebral infarct, and to determine whether obstructive sleep apnea syndrome is an independent risk factor of silent cerebral infarct and/or lacunar silent cerebral infarct in patients with hypertension. In this matched cross-sectional study performed in hypertensive subjects, each patient with silent cerebral infarct detected by magnetic resonance imaging was matched with two patients without silent cerebral infarct. Polysomnographic studies were performed, and the apnea-hypopnea index was calculated. Severe obstructive sleep apnea syndrome was considered in those with apnea-hypopnea index >30. One-hundred and eighty-three patients, 61 with silent cerebral infarct and 122 without silent cerebral infarct, were evaluated. The mean age was 64.1 +/- 4.5 years, and 72.1% were men. The frequency of severe obstructive sleep apnea syndrome was 44.3% in patients with silent cerebral infarct and 38.5% in the control group. An adjusted conditional logistic regression model did not show a significant increased risk of silent cerebral infarct in patients with severe obstructive sleep apnea syndrome (odds ratio 1.362; 95% confidence interval: 0.659-2.813; P = 0.404). Forty-three patients (70.5%) of the silent cerebral infarct were lacunar. The presence of severe obstructive sleep apnea syndrome was significantly higher in lacunar silent cerebral infarct when compared with patients without lacunar infarcts (55.8% versus 35.7%, P = 0.019), being independently associated on an adjusted logistic regression model (odds ratio 2.177; 95% confidence interval: 1.058-4.479; P = 0.035). In conclusion, severe obstructive sleep apnea syndrome is highly prevalent among hypertensive subjects, and is independently associated with lacunar silent cerebral infarct. PMID- 28631310 TI - Zinc supplementation for the treatment of measles in children. AB - BACKGROUND: Measles is an important cause of childhood morbidity and mortality globally, despite increasing vaccine coverage. Zinc plays a significant role in the maintenance of normal immunological functions, therefore supplements given to zinc-deficient children will increase the availability of zinc and could reduce measles-related morbidity and mortality. This is an update of a review first published in 2015. OBJECTIVES: To assess the effects of zinc supplementation in reducing morbidity and mortality in children with measles. SEARCH METHODS: We searched CENTRAL (03 February 2017, Issue 2), MEDLINE (1946 to 03 February 2017), Embase (1974 to 03 February 2017), CINAHL (1981 to 03 February 2017), LILACS (1982 to 03 February 2017), Web of Science (1985 to 03 February 2017), and BIOSIS Previews (1985 to 27 June 2014). We also searched ClinicalTrials.gov, the Australian New Zealand Clinical Trials Registry and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 03 February 2017 to identify unpublished and ongoing studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating the effects of zinc in reducing morbidity and mortality in children with measles. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion and extracted data on outcomes, details of the interventions, and other study characteristics using a standardised data extraction form. We used risk ratio (RR) and hazard ratio (HR) as measures of effect with 95% confidence intervals (CI). We included only one study, and did not conduct meta-analysis. MAIN RESULTS: We did not identify any new studies for inclusion in this update. One RCT met our inclusion criteria. The study was conducted in India and included 85 children diagnosed with measles and pneumonia. The trial showed no significant difference in mortality between children with measles and pneumonia who received zinc supplements and those who received placebo (RR 0.34, 95% CI 0.01 to 8.14). There was no significant difference in time to absence of fever between children who received zinc supplements and those who did not (HR 1.08, 95% CI 0.67 to 1.74). No treatment-related side effects were reported in either group. We assessed the overall quality of the evidence as very low. AUTHORS' CONCLUSIONS: We could not draw any definitive conclusions from this review about the effects of zinc supplementation on clinical outcomes of children with measles due to the very low quality of the evidence available. There is insufficient evidence to confirm or refute the effect of zinc supplementation in children with measles. PMID- 28631311 TI - The IL-10/STAT3 axis: Contributions to immune tolerance by thymus and peripherally derived regulatory T-cells. AB - The signal transducer and activator of transcription (STAT) proteins are important mediators for the integration of extrinsic signals provided by cytokines and hormones and thereby adapt cellular processes to their surroundings. In the past decade, the involvement of STAT3 in the regulation of T cell responses has become a topic of increasing interest. STAT3 is activated in response to multiple cytokines, many of which have been shown to influence T-cell responses. Interestingly, many of these factors have been described with apparent opposing roles, such as the highly pro-inflammatory potency of IL-6 and the anti inflammatory properties of IL-10, thus raising the possibility that STAT3 signaling may fulfill diverse roles in CD4+ T-cells. Here, we review the contribution of STAT3 to the induction and function of both peripherally induced as well as thymus-derived regulatory T-cells. Indeed, experimental approaches as well as studies of human patients suffering from e.g. Job's (hyper IgE) syndrome or inflammatory bowel disease (IBD) have now established a clear-cut role for the IL-10/STAT3 axis in immune tolerance; further understanding of these processes could lead to novel therapeutic approaches for autoimmune diseases. PMID- 28631312 TI - The flow and fate of digestive enzymes in the field cricket, Gryllus bimaculatus. AB - The flow of enzymes, the ratio of bound to unbound enzymes, and their inactivation in the cricket Gryllus bimaculatus was studied. The digestive enzymes are forced forward into the crop by caecal contraction and then they are mixed with freshly chewed food and saliva, forming a crop-chyme. This chyme is blended by crop peristalsis, and periodic opening of the preproventricular valve (PPV) allows posterior movement into the proventriculus and further into the midgut. The contraction of the crop is modulated by Grybi-AST and Grybi-SK peptides, which are partially secreted by the caecal endocrine cells. Most of the aminopeptidase and the four disaccharidases examined are membrane bound (62-80%); the remaining (20-38%) as well all trypsin, chymotrypsin, lipase, and amylase are secreted free into the caecal lumen. Cricket trypsin loses only 30% of its activity in 4 h and very little thereafter. The presence of digestive products in the lumen appears to retard further trypsin autolysis. Cricket trypsin digests 42% of the chymotrypsin, 37% of the lipase, and 45% of the amylase in the caecal fluids over 24 h in vitro no significant difference. Without Ca ion amylase was almost completely digested. About 50% of the membrane bound and free aminopeptidase was digested in the caecal lumen, and about 30-38% of the bound and free maltase. This loss of digestive enzyme activity is possible, because enzyme secretion rates are high, the unbound enzymes are effectively recycled, and the time of nutrient passage is short. PMID- 28631313 TI - Salivary, gingival crevicular fluid and serum levels of ghrelin and chemerin in patients with periodontitis and overweight. AB - BACKGROUND AND OBJECTIVE: Nutrition and body weight are modifying factors for periodontitis. The purpose of this study was to quantify two molecules (ghrelin and chemerin), released in association with food intake and obesity, in periodontally healthy and diseased individuals with respect to different body mass categories. MATERIAL AND METHODS: The two main groups (patients with chronic periodontitis and periodontally healthy/gingivitis volunteers) were subdivided into groups of subjects with normal weight [body mass index (BMI) <25] and groups of overweight/obese subjects (BMI >=25). Subgingival bacteria were analysed and the levels of acylated and total ghrelin, chemerin and interleukin-1beta (IL 1beta) were assessed in saliva, gingival crevicular fluid and serum. RESULTS: The amount of Treponema denticola present subgingivally was significantly higher in the groups of patients with chronic periodontitis as well as in periodontally healthy/gingivitis individuals with BMI >=25 than in periodontally healthy/gingivitis individuals with BMI <25. The amount of total ghrelin in gingival crevicular fluid differed significantly between the groups, with the lowest levels found in the group of patients with chronic periodontitis and BMI >=25. The levels of chemerin in gingival crevicular fluid were significantly higher in each chronic periodontitis group than in periodontally healthy/gingivitis individuals with BMI <25. However, the level of IL-1beta in the gingival crevicular fluid was most differentiating between the groups, with the highest levels found in the group of patients with chronic periodontitis and BMI <25 and the lowest levels in periodontally healthy/gingivitis individuals with BMI <25. No significant differences between any groups were seen for chemerin or for acylated ghrelin in the stimulated whole saliva, or for acylated and total ghrelin in peripheral blood serum. The BMI correlated with the serum level of chemerin. CONCLUSION: Low ghrelin and high chemerin levels in the gingival crevicular fluid might be linked to periodontal disease and overweight/obesity. However, unlike IL-1beta, the levels of chemerin and ghrelin in gingival crevicular fluid are not reliable indicators of periodontal destruction. PMID- 28631314 TI - The Covalent Functionalization of Layered Black Phosphorus by Nucleophilic Reagents. AB - Layered black phosphorus has been attracting great attention due to its interesting material properties which lead to a plethora of proposed applications. Several approaches are demonstrated here for covalent chemical modifications of layered black phosphorus in order to form P-C and P-O-C bonds. Nucleophilic reagents are highly effective for chemical modification of black phosphorus. Further derivatization approaches investigated were based on radical reactions. These reagents are not as effective as nucleophilic reagents for the surface covalent modification of black phosphorus. The influence of covalent modification on the electronic structure of black phosphorus was investigated using ab initio calculations. Covalent modification exerts a strong effect on the electronic structure including the change of band-gap width and spin polarization. PMID- 28631315 TI - A Two-Year Study of Delta 9 Tetrahydrocannabinol Concentrations in Drivers; Part 2: Physiological Signs on Drug Recognition Expert (DRE) and non-DRE Examinations,. AB - Whole blood samples were examined for ?9 -Tetrahydrocannabinol (THC) over 2 years in drivers suspected of driving under the influence. Part one of the study examined the link between [THC] and performance on field sobriety tests. This portion examined objective signs, eye examinations and physiological indicators; and their relationship to the presence of THC. Several objective signs were excellent indicators of the presence of THC: red eyes (94%), droopy eyelids (85.6%), affected speech (87.6%), tongue coating (96.2%), and odor of marijuana (82.4%). About 63.6% of THC positive subjects had dialted pupils (room light). THC positive subjects had either rebound dilation or hippus in 88.8% of cases. Pulse and blood pressure (BP) were evaluated to determine any correlation with [THC]. An increased pulse rate correlated well to the presence of THC (88.5%), but not [THC]. BP did not correlate to [THC] and was also a poor indicator of THC in the blood (50% high). PMID- 28631316 TI - Recannulation of the axillary artery in aortic and complex cardiac surgery. AB - OBJECTIVES: Axillary artery cannulation has been used as an alternative site for cardiopulmonary bypass during surgery for aortic dissections and aneurysmal disease of the ascending aorta and arch. This study reports our experience with reusing the axillary artery for cardiopulmonary bypass during complex aortic and cardiac surgical procedures. METHODS: This was a retrospective review of a single surgeon's experience of recannulating the axillary artery for redo operations in complex aortic surgery. Seven patients over a 7-year period have undergone recannulation of their axillary arteries. The old Dacron graft stump was either excised and a new graft was anastamosed to the axillary artery or a new end-to side anastamosis was performed either proximal or distal to the original graft stump. RESULTS: There were no deaths, strokes, or postoperative complications. In one patient, axillary cannulation was aborted intraoperatively due to high-line pressures, suggesting a local dissection. The other patients all had adequate perfusion via the recannulated axillary artery and there were no complications associated with its reuse. CONCLUSIONS: Recannulation of the axillary artery is easily achievable and should be considered in redo aortic and complex cardiac surgery. PMID- 28631317 TI - Platelet counts in women with normal pregnancies: A systematic review. AB - The occurrence of thrombocytopenia in 5% of pregnant women at delivery, described as gestational thrombocytopenia, is well documented. A commonly believed concept is that gestational thrombocytopenia is the result of gradually decreasing platelet counts in all women during pregnancy. The goal of our study was to evaluate the data supporting this concept. To learn what is known about platelet counts throughout normal pregnancies, we systematically reviewed all publications describing platelet counts during pregnancy. We identified 3,039 studies; 46 reporting >=30 women with normal pregnancies were included in our analyses. The combined mean platelet counts from all studies supported the concept that platelet counts decrease during pregnancy and increase postpartum: first trimester, 251,000/uL (95% CI, 238,000-264,000/uL); second trimester, 238,000/uL (95% CI, 222,000-253,000/uL); third trimester, 224,000/uL (95% CI, 213,000 235,000/uL); delivery, 237,000/uL (95% CI, 209,000-264,000/uL); 4-8 weeks postpartum, 247,000/uL (95% CI, 207,000-287,000/uL). However, individual studies were inconsistent. Eleven longitudinal studies compared platelet counts on the same women at different times during gestation: seven reported a decrease; four reported no change. Ten cross-sectional studies compared platelet counts of different women at different times during gestation: five reported a decrease; five reported no change. Five studies compared platelet counts of pregnant to nonpregnant women: three reported that platelet counts were lower in pregnant women; one reported no difference; one reported that platelet counts were higher in pregnant women. These inconsistent data emphasize the need to accurately describe platelet counts throughout normal pregnancies. Accurate data are essential for evaluating the clinical importance of thrombocytopenia during pregnancy. PMID- 28631318 TI - Bupropion Overdose Resulted in a Pharmacobezoar in a Fatal Bupropion (Wellbutrin(r) ) Sustained-release Overdose: Postmortem Distribution of Bupropion and its Major Metabolites. AB - Bupropion (BUP) overdose commonly causes generalized seizures and central nervous system depression. The case of a 28-year-old woman who died from a massive lethal overdose with sustained-release bupropion (Wellbutrin(r) 300 mg) is herein presented. The autopsy revealed the presence of a pharmacobezoar consisting of at least 40 tablets in the stomach. Determination of bupropion and its active metabolites (hydroxybupropion, threobupropion, erythrobupropion) was achieved by a liquid chromatographic mass spectrometry (LC-MS/MS) method. Postmortem concentrations for bupropion, hydroxybupropion, threobupropion, and erythrobupropion were obtained in intracranial blood, urine, bile, liver, kidney, and vitreous humor. In this case, intracranial blood level of the parent drug was 1.9 mg/L. Threobupropion was the most abundant metabolite in both blood and urine, 59.3 and 890.6 mg/L. Tissue distribution showed the highest concentration in the liver, 12.3 mg/kg. The 0.8 bupropion concentration ratio vitreous/blood suggested that vitreous could be a valuable specimen for toxicological analysis should postmortem blood be unavailable. PMID- 28631319 TI - Herbivory-induced jasmonates constrain plant sugar accumulation and growth by antagonizing gibberellin signaling and not by promoting secondary metabolite production. AB - Plants respond to herbivory by reconfiguring hormonal networks, increasing secondary metabolite production and decreasing growth. Furthermore, some plants display a decrease in leaf energy reserves in the form of soluble sugars and starch, leading to the hypothesis that herbivory-induced secondary metabolite production and growth reduction may be linked through a carbohydrate-based resource trade-off. In order to test the above hypothesis, we measured leaf carbohydrates and plant growth in seven genetically engineered Nicotiana attenuata genotypes that are deficient in one or several major herbivore-induced, jasmonate-dependent defensive secondary metabolites and proteins. Furthermore, we manipulated gibberellin and jasmonate signaling, and quantified the impact of these phytohormones on secondary metabolite production, sugar accumulation and growth. Simulated herbivore attack by Manduca sexta specifically reduced leaf sugar concentrations and growth in a jasmonate-dependent manner. These effects were similar or even stronger in defenseless genotypes with intact jasmonate signaling. Gibberellin complementation rescued carbohydrate accumulation and growth in induced plants without impairing the induction of defensive secondary metabolites. These results are consistent with a hormonal antagonism model rather than a resource-cost model to explain the negative relationship between herbivory induced defenses, leaf energy reserves and growth. PMID- 28631321 TI - John A. Raven. PMID- 28631320 TI - Spatial patterns and broad-scale weather cues of beech mast seeding in Europe. AB - Mast seeding is a crucial population process in many tree species, but its spatio temporal patterns and drivers at the continental scale remain unknown . Using a large dataset (8000 masting observations across Europe for years 1950-2014) we analysed the spatial pattern of masting across the entire geographical range of European beech, how it is influenced by precipitation, temperature and drought, and the temporal and spatial stability of masting-weather correlations. Beech masting exhibited a general distance-dependent synchronicity and a pattern structured in three broad geographical groups consistent with continental climate regimes. Spearman's correlations and logistic regression revealed a general pattern of beech masting correlating negatively with temperature in the summer 2 yr before masting, and positively with summer temperature 1 yr before masting (i.e. 2T model). The temperature difference between the two previous summers (DeltaT model) was also a good predictor. Moving correlation analysis applied to the longest eight chronologies (74-114 yr) revealed stable correlations between temperature and masting, confirming consistency in weather cues across space and time. These results confirm widespread dependency of masting on temperature and lend robustness to the attempts to reconstruct and predict mast years using temperature data. PMID- 28631322 TI - Prolonged embryogenesis in Austrobaileya scandens (Austrobaileyaceae): its ecological and evolutionary significance. AB - The embryology of basal angiosperm lineages (Amborella, Nymphaeales and Austrobaileyales) is central to reconstructing the early evolution of flowering plants. Previous studies have shown that mature seeds in Austrobaileyales are albuminous, with a small embryo surrounded by a substantial diploid endosperm. However, little is known of seed ontogeny and seedling germination in Austrobaileya scandens, sister to all other extant Austrobaileyales. Standard histochemical techniques were used to study ovule/seed development and germination of Austrobaileya. Early development of the endosperm in Austrobaileya is ab initio cellular with pronounced cell proliferation. The nucellus transiently accumulates some starch, but is obliterated by expansion of a massive endosperm, where all embryo-nourishing reserves are ultimately stored. Twelve months elapse from fertilization to fruit abscission. Seeds are dispersed with a minute embryo, requiring 12 additional months for seedling establishment. The 2 yr required for seedling establishment is an apomorphic feature of Austrobaileya, probably related to germination in extremely dark understory conditions. Remarkably, although Austrobaileya seeds are nearly 50 times larger (by length) than the smallest seeds of extinct and extant members of early divergent angiosperm lineages, the embryo to seed ratio (E : S) falls squarely within the narrow range that characterizes the albuminous seeds of ancient flowering plant lineages. PMID- 28631323 TI - Interactions of saprotrophic fungi with tree roots: can we observe the emergence of novel ectomycorrhizal fungi? PMID- 28631325 TI - Insights into how the world turned green. PMID- 28631324 TI - Recent origin and rapid speciation of Neotropical orchids in the world's richest plant biodiversity hotspot. AB - The Andean mountains of South America are the most species-rich biodiversity hotspot worldwide with c. 15% of the world's plant species, in only 1% of the world's land surface. Orchids are a key element of the Andean flora, and one of the most prominent components of the Neotropical epiphyte diversity, yet very little is known about their origin and diversification. We address this knowledge gap by inferring the biogeographical history and diversification dynamics of the two largest Neotropical orchid groups (Cymbidieae and Pleurothallidinae), using two unparalleled, densely sampled orchid phylogenies (including more than 400 newly generated DNA sequences), comparative phylogenetic methods, geological and biological datasets. We find that the majority of Andean orchid lineages only originated in the last 20-15 million yr. Andean lineages are derived from lowland Amazonian ancestors, with additional contributions from Central America and the Antilles. Species diversification is correlated with Andean orogeny, and multiple migrations and recolonizations across the Andes indicate that mountains do not constrain orchid dispersal over long timescales. Our study sheds new light on the timing and geography of a major Neotropical diversification, and suggests that mountain uplift promotes species diversification across all elevational zones. PMID- 28631326 TI - Exploring the bark thickness-stem diameter relationship: clues from lianas, successive cambia, monocots and gymnosperms. AB - Bark thickness is ecologically crucial, affecting functions from fire protection to photosynthesis. Bark thickness scales predictably with stem diameter, but there is little consensus on whether this scaling is a passive consequence of growth or an important adaptive phenomenon requiring explanation. With a comparative study across 913 species, we test the expectation that, if bark thickness-stem diameter scaling is adaptive, it should be possible to find ecological situations in which scaling is predictably altered, in this case between species with different types and deployments of phloem. 'Dicots' with successive cambia and monocots, which have phloem-free bark, had predictably thinner inner (mostly living) bark than plants with single cambia. Lianas, which supply large leaf areas with limited stem area, had much thicker inner bark than self-supporting plants. Gymnosperms had thicker outer bark than angiosperms. Inner bark probably scales with plant metabolic demands, for example with leaf area. Outer bark scales with stem diameter less predictably, probably reflecting diverse adaptive factors; for example, it tends to be thicker in fire-prone species and very thin when bark photosynthesis is favored. Predictable bark thickness-stem diameter scaling across plants with different photosynthate translocation demands and modes strongly supports the idea that this relationship is functionally important and adaptively significant. PMID- 28631327 TI - Say hello to my little friends: how microbiota can modulate tree health. PMID- 28631328 TI - Phenotypic characterisation of coagulase-negative staphylococci isolated from blood cultures in newborn infants, with a special focus on Staphylococcus capitis. AB - AIM: This Swedish study determined which species of coagulase-negative staphylococci (CoNS) were found in neonatal blood cultures and whether they included Staphylococcus capitis clones with decreased susceptibility to vancomycin. METHODS: CoNS isolates (n = 332) from neonatal blood cultures collected at Orebro University Hospital during 1987-2014 were identified to species level with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). The antibiotic susceptibility pattern of S. capitis isolates was determined by the disc diffusion test and Etest, and the presence of heterogeneous glycopeptide-intermediate S. capitis (hGISC) was evaluated. RESULTS: Staphylococcus epidermidis (67.4%), Staphylococcus haemolyticus (10.5%) and S. capitis (9.6%) were the most common CoNS species. Of the S. capitis isolates, 75% were methicillin-resistant and 44% were multidrug resistant. No isolate showed decreased susceptibility to vancomycin, but at least 59% displayed the hGISC phenotype. Staphylococcus capitis isolates related to the strain CR01 displaying pulsotype NRCS-A were found. CONCLUSION: Staphylococcus epidermidis, S. haemolyticus and S. capitis were the predominant species detected in neonatal blood cultures by MALDI-TOF MS. The number of episodes caused by S. capitis increased during the study period, but no isolates with decreased susceptibility to vancomycin were identified. However, S. capitis isolates related to the strain CR01 displaying pulsotype NRCS-A were found. PMID- 28631329 TI - Inverting suprastomal granulomas. AB - Although suprastomal granulomas are a common complication of tracheotomy, they usually are an incidental finding and do not always require treatment. However, large granulomas may require removal, either to assist with speech production or to make the airway safer in the event of an accidental decannulation. Very large suprastomal granulomas extending up to or even through the vocal cords have been described. However, inverting suprastomal granulomas extending distally down the length of a tracheotomy tube have not been previously described. We present two cases of large suprastomal granulomas that extended distally down the trachea. Both extended beyond the tip of the tracheotomy tube, causing partial airway obstruction, and therefore required excision. Laryngoscope, 127:2883-2885, 2017. PMID- 28631330 TI - FOXO transcription factors at the interface of metabolism and cancer. AB - Diabetes refers to a group of metabolic diseases characterized by impaired insulin signalling and high blood glucose. A growing body of epidemiological evidence links diabetes to several types of cancer but the underlying molecular mechanisms are poorly understood. The signalling cascade connecting insulin and FOXO proteins provides a compelling example for a conserved pathway at the interface between insulin signalling and cancer. FOXOs are transcription factors that orchestrate programs of gene expression known to control a variety of processes in response to cellular stress. Genes regulated by this family of proteins are involved in the regulation of cellular energy production, oxidative stress resistance and cell viability and proliferation. Accordingly, FOXO factors have been shown to play an important role in the suppression of tumour growth and in the regulation of metabolic homeostasis. There is emerging evidence that deregulation of FOXO factors might account for the association between insulin resistance-related metabolic disorders and cancer. PMID- 28631331 TI - Missing data in clinical trials: control-based mean imputation and sensitivity analysis. AB - In some randomized (drug versus placebo) clinical trials, the estimand of interest is the between-treatment difference in population means of a clinical endpoint that is free from the confounding effects of "rescue" medication (e.g., HbA1c change from baseline at 24 weeks that would be observed without rescue medication regardless of whether or when the assigned treatment was discontinued). In such settings, a missing data problem arises if some patients prematurely discontinue from the trial or initiate rescue medication while in the trial, the latter necessitating the discarding of post-rescue data. We caution that the commonly used mixed-effects model repeated measures analysis with the embedded missing at random assumption can deliver an exaggerated estimate of the aforementioned estimand of interest. This happens, in part, due to implicit imputation of an overly optimistic mean for "dropouts" (i.e., patients with missing endpoint data of interest) in the drug arm. We propose an alternative approach in which the missing mean for the drug arm dropouts is explicitly replaced with either the estimated mean of the entire endpoint distribution under placebo (primary analysis) or a sequence of increasingly more conservative means within a tipping point framework (sensitivity analysis); patient-level imputation is not required. A supplemental "dropout = failure" analysis is considered in which a common poor outcome is imputed for all dropouts followed by a between treatment comparison using quantile regression. All analyses address the same estimand and can adjust for baseline covariates. Three examples and simulation results are used to support our recommendations. PMID- 28631332 TI - Inhibition of microRNA-500 has anti-cancer effect through its conditional downstream target of TFPI in human prostate cancer. AB - PURPOSE: We investigated the prognostic potential and regulatory mechanism of microRNA-500 (miR-500), and human gene of tissue factor pathway inhibitor (TFPI) in prostate cancer. METHODS: MiR-500 expression was assessed by qRT-PCR in prostate cancer cell lines and primary tumors. Cancer patients' clinicopathological factors and overall survival were analyzed according to endogenous miR-500 level. MiR-500 was downregulated in DU145 and VCaP cells. Its effect on prostate cancer proliferation, invasion in vitro, and tumorigenicity in vivo, were probed. Possible downstream target of miR-500, TFPI was assessed by luciferase assay and qRT-PCR in prostate cancer cells. In miR-500-downregulated DU145 and VCaP cells, TFPI was silenced to see whether it was directly involved in the regulation of miR-500 in prostate cancer. TFPI alone was either upregulated or downregulated in DU145 and VCaP cells. Their effect on prostate cancer development was further evaluated. RESULTS: MiR-500 is upregulated in both prostate cancer cells and primary tumors. In prostate cancer patients, high miR 500 expression is associated with poor prognosis and overall survival. In DU145 and VCaP cells, miR-500 downregulation inhibited cancer proliferation, invasion in vitro, and explant growth in vivo. TFPI was verified to be associated with miR 500 in prostate cancer. Downregulation of TFPI reversed anti-cancer effects of miR-500 downregulation in prostate cancer cells. However, neither TFPI upregulation nor downregulation alone had any functional impact on prostate cancer development. CONCLUSION: MiR-500 may be a potential biomarker and molecular target in prostate cancer. TFPI may conditionally regulate prostate cancer in miR-500-downregualted prostate cancer cells. PMID- 28631333 TI - A novel treatment for keratitis sicca (Dry eye): Anatomical feasibility study. AB - Chronic dry eye (keratitis sicca) is a significant problem that in certain populations can result in corneal desiccation and the potential for blindness. Therefore, novel treatments for such disorders might decrease patient morbidity. The present study aimed to investigate a potential treatment for chronic dry eye via a cadaveric feasibility study. On 10 cadaveric sides, the parotid gland branch of the auriculotemporal nerve (ATN) was identified and anastomosed to an anterior superficial temporal branch (STb) of this same nerve. The STb was then transposed anteriorly and sutured to the lacrimal gland. The parotid branch of the ATN was easily identified on all sides. The STb of the ATN was easily identified and mobilized on all sides. This latter nerve had adequate length to be moved to the ipsilateral lacrimal gland on all sides. Rerouting parotid gland secretomotor fibers to the superficial branch of the ATN and then moving this branch to the lacrimal gland is a feasible surgical maneuver based on our cadaveric study. Clinical studies are now necessary to show utility of this procedure in patients with chronic dry eye. Clin. Anat. 30:839-843, 2017. (c) 2017Wiley Periodicals, Inc. PMID- 28631334 TI - Risk factors for developing food-induced bronchospasm during oral food challenge. PMID- 28631335 TI - The mobile dso-gene-sso element in rolling-circle plasmids of staphylococci reflects the evolutionary history of its resistance gene. AB - : The qacC and lnuA genes of Staphylococcus species were recently proposed to comprise a mobile element when residing on rolling-circle plasmids. Here we present other examples of resistance genes on staphylococcal rolling-circle plasmids, including fosB producing resistance to fosfomycin, cat resulting in resistance to chloramphenicol and cadB for resistance to the toxic heavy metal cadmium. For three of these genes (qacC, lnuA and fosB), evidence was obtained that the genes have spread between different plasmid backgrounds. The lack of mutations in qacC suggests that the spread occurred relatively recently, while the build up of mutations in lnuA and fosB suggests their mobilization occurred in the more distant past. These observations can be explained by the use of the respective antibiotics over time. However, the cat and cadB genes sequences analysed had not collected any mutations, an observation that is not completely understood but possible explanations are discussed. SIGNIFICANCE AND IMPACT OF THE STUDY: We have analysed five resistance genes in Staphylococcus aureus that are positioned between the replication elements of rolling-circle plasmids. For three of these genes, evidence was obtained indicative of recent mobilization. The historical use of the antibiotics to which the genes produce resistance could be related to the number of mutations collected in these genes. However, two other resistance genes have not collected any mutations over time, and the reasons for this are discussed. The analyses presented provide insights into the spread and evolution of antibiotic resistance genes. PMID- 28631336 TI - A neuroimaging approach to capture cognitive reserve: Application to Alzheimer's disease. AB - Cognitive reserve (CR) explains interindividual differences in the ability to maintain cognitive function in the presence of neuropathology. We developed a neuroimaging approach including a measure of brain atrophy and cognition to capture this construct. In a group of 511 Alzheimer's disease (AD) biomarker positive subjects in different stages across the disease spectrum, we performed 3T magnetic resonance imaging and predicted gray matter (GM) volume in each voxel based on cognitive performance (i.e. a global cognitive composite score), adjusted for age, sex, disease stage, premorbid brain size (i.e. intracranial volume) and scanner type. We used standardized individual differences between predicted and observed GM volume (i.e. W-scores) as an operational measure of CR. To validate this method, we showed that education correlated with mean W-scores in whole-brain (r = -0.090, P < 0.05) and temporoparietal (r = -0.122, P < 0.01) masks, indicating that higher education was associated with more CR (i.e. greater atrophy than predicted from cognitive performance). In a voxel-wise analysis, this effect was most prominent in the right inferior and middle temporal and right superior lateral occipital cortex (P < 0.05, corrected for multiple comparisons). Furthermore, survival analyses among subjects in the pre-dementia stage revealed that the W-scores predicted conversion to more advanced disease stages (whole-brain: hazard ratio [HR] = 0.464, P < 0.05; temporoparietal: HR = 0.397, P < 0.001). Our neuroimaging approach captures CR with high anatomical detail and at an individual level. This standardized method is applicable to various brain diseases or CR proxies and can flexibly incorporate different neuroimaging modalities and cognitive parameters, making it a promising tool for scientific and clinical purposes. Hum Brain Mapp 38:4703-4715, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631337 TI - A method to assess the loss of a dipole antenna for ultra-high-field MRI. AB - PURPOSE: To describe a new bench measurement based on quality (Q) factors to estimate the coil noise relative to the sample noise of dipole antennas at 7 T. METHODS: Placing a dipole antenna close to a highly conductive sample surrogate (HCSS) greatly reduces radiation loss, and using QHCSS gives a more accurate estimate of coil resistance than Qunloaded . Instead of using the ratio of unloaded and sample-loaded Q factors, the ratio of HCSS-loaded and sample-loaded Q factors should be used at ultra-high fields. A series of simulations were carried out to analyze the power budget of sample-loaded or HCSS-loaded dipole antennas. Two prototype dipole antennas were also constructed for bench measurements to validate the simulations. RESULTS: Simulations showed that radiation loss was suppressed when the dipole antenna was HCSS-loaded, and coil loss was largely the same as when the dipole was loaded by the sample. Bench measurements also showed good alignment with simulations. CONCLUSIONS: Using the ratio QHCSS /Qloaded gives a good estimate of the coil loss for dipole antennas at 7 T, and provides a convenient bench measurement to predict the body noise dominance of dipole antenna designs. The new approach also applies to conventional surface loop coils at ultra-high fields. Magn Reson Med 79:1773 1780, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28631338 TI - Cross-Linkable and Dual Functional Hybrid Polymeric Electron Transporting Layer for High-Performance Inverted Polymer Solar Cells. AB - A cross-linkable dual functional polymer hybrid electron transport layer (ETL) is developed by simply adding an amino-functionalized polymer dopant (PN4N) and a light crosslinker into a commercialized n-type semiconductor (N2200) matrix. It is found that the resulting hybrid ETL not only has a good solvent resistance, facilitating multilayers device fabrication but also exhibits much improved electron transporting/extraction properties due to the doping between PN4N and N2200. As a result, by using PTB7-Th:PC71 BM blend as an active layer, the inverted device based on the hybrid ETL can yield a prominent power conversion efficiency of around 10.07%. More interestingly, photovoltaic property studies of bilayer devices suggest that the absorption of the hybrid ETL contributes to photocurrent and hence the hybrid ETL simultaneously acts as both cathode interlayer material and an electron acceptor. The resulting inverted polymer solar cells function like a novel device architectures with a combination of a bulk heterojunction device and miniature bilayer devices. This work provides new insights on function of ETLs and may be open up a new direction for the design of new ETL materials and novel device architectures to further improve device performance. PMID- 28631339 TI - The length of the large intestine in children determined by computed tomography scan. AB - Little information is available on the length of the normal large intestine and its component parts in children. This information would be useful for procedures such as colonoscopy. The aim of this study was to investigate the length of the large intestine and its component parts in New Zealand children. Archival deidentified pediatric supine abdominopelvic computed tomography (CT) scans were retrospectively analyzed. After exclusion criteria, a total of 112 scans (57 males and 55 females) were included in the study and divided into three age groups: 0-2 years (n = 33), 4-6 years (n = 40), and 9-11 years of age (n = 39). The length of the large bowel increased from a mean of 52 cm in children aged <2 years to 73 cm at 4-6 years and 95 cm at 9-11 years. In all age groups, the transverse colon was the longest segment, contributing ~30% of the total length of the large bowel. In comparison to total large bowel length, the mean proportional length of the rectum (9-12%), sigmoid colon (23-27%), descending colon (19-22%), transverse colon (27-32%), and ascending colon (14-17%) varied little between the three age groups. There were no significant differences between males and females in all age groups. The cecum was located in the right upper quadrant in 27% of children aged 0-2 years but in the right lower quadrant in all 9-11 year olds. These data provide useful information on the length of the large intestine and its component parts in living children, which are particularly relevant to pediatric colonoscopy and surgery. Clin. Anat. 30:887 893, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631340 TI - Insights into the genomic plasticity of Pseudomonas putida KF715, a strain with unique biphenyl-utilizing activity and genome instability properties. AB - Pseudomonas putida KF715 exhibits unique properties in both catabolic activity and genome plasticity. Our previous studies revealed that the DNA region containing biphenyl and salycilate metabolism gene clusters (termed the bph-sal element) was frequently deleted and transferred by conjugation to closely related P. putida strains. In this study, we first determined the complete nucleotide sequence of the KF715 genome. Next, to determine the underlying cause of genome plasticity in KF715, we compared the KF715 genome with the genomes of one KF715 defective mutant, two transconjugants, and several P. putida strains available from public databases. The gapless KF715 genome sequence revealed five replicons: one circular chromosome, and four plasmids. Southern blot analysis indicated that most of the KF715 cell population carries the bph-sal element on the chromosome whereas a small number carry it on a huge plasmid, pKF715A. Moreover, the bph-sal element is present stably on the plasmid and did not integrate into the chromosome of its transconjugants. Comparative genome analysis and experiments showed that a number of diverse putative genetic elements are present in KF715 and are likely involved in genome rearrangement. These data provide insights into the genetic plasticity and adaptability of microorganisms for survival in various ecological niches. PMID- 28631341 TI - Evaluation of flubendiamide-induced mitochondrial dysfunction and metabolic changes in Helicoverpa armigera (Hubner). AB - Phthalic acid diamide insecticides are the most effective insecticides used against most of the lepidopteran pests including Helicoverpa armigera, a polyphagous pest posing threat to several crops worldwide. The present studies were undertaken to understand different target sites and their interaction with insect ryanodine receptors (RyR). Bioassays indicated that flubendiamide inhibited the larval growth in dose-dependent manner with LD50 value of 0.72 MUM, and at 0.8 MUM larval growth decreased by about 88%. Flubendiamide accelerated the Ca2+ -ATPase activity in dose-dependent trend, and at 0.8 MUM, the activity was increased by 77.47%. Flubendiamide impedes mitochondrial function by interfering with complex I and F0 F1 -ATPase activity, and at 0.8 MUM the inhibition was found to be about 92% and 50%, respectively. In vitro incubation of larval mitochondria with flubendiamide induced the efflux of cytochrome c, indicating the mitochondrial toxicity of the insecticide. Flubendiamide inhibited lactate dehydrogenase and the accumulation of H2 O2 , thereby preventing the cells from lipid peroxidation compared to control larvae. At 0.8 MUM the LDH, H2 O2 content and lipid peroxidation was inhibited by 98.44, 70.81, and 70.81%, respectively. Cytochrome P450, general esterases, AChE, and antioxidant enzymes (catalase and superoxide dismutase) exhibited a dose-dependent increasing trend, whereas alkaline phosphatase and the midgut proteases, except amino peptidase, exhibited dose-dependent inhibition in insecticide-fed larvae. The results suggest that flubendiamide induced the harmful effects on the growth and development of H. armigera larvae by inducing mitochondrial dysfunction and inhibition of midgut proteases, along with its interaction with RyR. PMID- 28631342 TI - Efficacy of a high-observation protocol in major head and neck cancer surgery: A prospective study. AB - BACKGROUND: The purpose of this study was to optimize an existing clinical care pathway (CCP) for head and neck cancer with a high-observation protocol (HOP) and to determine the effect on length of intensive care unit (ICU) admission and length of stay in hospital (LOS). METHODS: The HOP mandated initiation of spontaneous breathing trials before the conclusion of the surgery, weaning of sedation, and limiting mechanical ventilation. All patients with head and neck cancer undergoing primary surgery on the HOP were compared to a historical cohort regarding length of ICU admission, ICU readmissions, and LOS. RESULTS: Ninety-six and 52 patients were observed in "historical" and "HOP" cohorts. The length of ICU admission (1.9 vs 1.2 days; p = .021), LOS (20.3 vs 14.1 days; p = .020), and ICU readmissions (10.4% vs 1.9%; p = .013) were significantly decreased in the "HOP" cohort. CONCLUSION: Rapid weaning of sedation and limiting mechanical ventilation may contribute to a shorter length of ICU admission and LOS, as well as decreased ICU readmissions. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1689-1695, 2016. PMID- 28631343 TI - Exploration of difficult conversations among Australian paramedics. AB - Previous studies indicate that healthcare professionals find it challenging to engage in difficult conversations regarding concerning behavior of colleagues. As a result, these conversations are often avoided. The inability to have these difficult conversations is associated with poorer patient outcomes, staff commitment, discretionary effort, and employee satisfaction. This descriptive study used an online questionnaire to examine responses of paramedics employed by Ambulance Victoria (Australia) regarding difficult conversations between colleagues about concerning behavior of co-workers. The results suggest that, like other healthcare professions, many paramedics find it challenging to raise these concerns. To the best knowledge of the authors, this is the first study of its type to be undertaken within the paramedic profession and provides a platform for further research within this and other health professions. PMID- 28631344 TI - Evaluation of the genetic structure of sika deer (Cervus nippon) in Japan's Kanto and Tanzawa mountain areas, based on microsatellite markers. AB - The browsing habits of sika deer (Cervus nippon) in Japan have caused serious ecological problems. Appropriate management of sika deer populations requires understanding the different genetic structures of local populations. In the present study, we used 10 microsatellite polymorphisms to explore the genetic structures of sika deer populations (162 individuals) living in the Kanto region. The expected heterozygosity of the Tanzawa mountain range population (Group I) was lower than that of the populations in the Kanto mountain areas (Group II). Our results suggest that moderate gene flow has occurred between the sika deer populations in the Kanto mountain areas (Group II), but not to or from the Tanzawa mountain range population (Group I). Also, genetic structure analysis showed that the Tanzawa population was separated from the other populations. This is probably attributable to a genetic bottleneck that developed in the Tanzawa sika deer population in the 1950s. However, we found that the Tanzawa population has since recovered from the bottleneck situation and now exhibits good genetic diversity. Our results show that it is essential to periodically evaluate the genetic structures of deer populations to develop conservation strategies appropriate to the specific structures of individual populations at any given time. PMID- 28631346 TI - Historically-informed nursing: A transnational case study in China. AB - The term 'nurse' (hushi-'caring scholar') did not enter the Chinese language until the early 20th century. Modern nursing-a fundamentally Western notion popularized by Nightingale and introduced to China in 1884-profoundly changed the way care of the sick was practiced. For 65 years, until 1949, nursing developed in China as a transnational project, with Western and Chinese influences shaping the profession of nursing in ways that linger today. Co-authored by Chinese, Canadian, and American nurses, this paper examines the early stages of nursing in one province of China as an exemplar of the transnational nature of nursing development. By identifying sociopolitical influences on the early development of nursing in Shandong, the authors aimed not only to contribute to the nascent body of knowledge on China nursing history, but also to heighten readers' sensitivity to the existence of historical echoes, residue, and resonances in their own nursing practices. Tracing current issues, values, or practices back to their roots provides context and helps us to better understand the present. Whether we are aware of the details or not, the gestalt of nursing practice in a particular place has been shaped by its history-including in Shandong province in China. PMID- 28631345 TI - Advantages and disadvantages of using intravenous tissue Plasminogen activator as salvage therapy for inoperable HeartWare thrombosis. AB - Device thrombosis is a devastating complication of left ventricular assist devices. The definitive treatment has been device exchange or explant. Evidence of increasing morbidity and mortality with device exchange has shifted strategies toward conservative management. In this report, we detail the use of thrombolytics as salvage therapy in a patient with an occlusive HeartWare ventricular assist device (HeartWare Inc., Framingham, MA) thrombus, resulting in long-term survival without further intervention. PMID- 28631347 TI - Reducing the maternal dietary intake of indigestible and slowly absorbed short chain carbohydrates is associated with improved infantile colic: a proof-of concept study. AB - BACKGROUND: To investigate if a low fermentable oligo-, di- and mono-saccharides and polyols (FODMAP) diet consumed by breastfeeding mothers may be associated with reduced symptoms of infantile colic. METHODS: Exclusively breastfeeding mothers and their typically-developing healthy infants who met the Wessel Criteria for infantile colic were recruited from the community, to this single blind, open-label, interventional study. After a 3-day qualifying period, mothers were provided a low FODMAP 7-day diet. On days 5, 6 and 7 mothers completed a Baby Day Diary. At baseline and at the end of the 7-day dietary intervention, breast milk was analysed for FODMAP content and infant faecal samples for pH. RESULTS: Eighteen breastfeeding mothers (aged 27-40 years) adhered (100%) to the low FODMAP diet. Infants were of gestational age 37-40.3 weeks and aged 2-17 weeks. At entry, crying durations were a mean [95% CI] of 142 [106-61] min and fell by 52 [178-120] min (P = 0.005; ancova). Combined crying-fussing durations fell by 73 [301-223] min (n = 13; P = 0.007), as did crying episodes (P = 0.01) and fussing durations (P = 0.011). Infant sleeping, feeding, or awake-and-content durations did not change. Infant faecal pH did not change. Breast milk lactose content was stable and other known FODMAPs were not detected. At end of study, mothers reported their baby 'is much more content' and 'can be put down without crying'. CONCLUSIONS: Maternal low FODMAP diet may be associated with a reduction in infant colic symptoms. A randomized controlled study is warranted to determine if a maternal low FODMAP diet is effective in reducing symptoms. PMID- 28631348 TI - Updating of working memory in ecstasy polydrug users: Findings from fNIRS. AB - AIMS/OBJECTIVES: Cognitive deficits are now well documented in ecstasy (MDMA) users with type and relative demand of task emerging as important factors. The updating component of executive processes appears to be particularly affected. The study reported here used functional near infrared spectroscopy imaging to investigate changes in cortical haemodynamics during memory updating. METHOD: Twenty ecstasy users and 20 non-users completed verbal and spatial memory updating tasks and brain blood oxygenation and deoxygenation change was measured using functional near infrared spectroscopy. RESULTS: There was no interaction between group and difficulty on the updating tasks, though there was a significant main effect of difficulty on both tasks. The effects of group approached significance on the verbal updating task. There were significant differences in blood oxygenation and deoxygenation change at optodes centred over the right and left dorsolateral prefrontal cortex, with ecstasy users showing greater blood oxygenation than the other groups. DISCUSSION: The lack of a behavioural difference on both tasks but presence of blood oxygenation and deoxygenation changes in letter updating provides support for the notion that ecstasy-polydrug users are investing more effort to achieve the same behavioural output. Total lifetime dose was high, and recency of use was significantly related to most changes, suggesting that heavy and recent use may be particularly detrimental. PMID- 28631350 TI - Standard errors and confidence intervals for correlations corrected for indirect range restriction: A simulation study comparing analytic and bootstrap methods. AB - A frequent topic of psychological research is the estimation of the correlation between two variables from a sample that underwent a selection process based on a third variable. Due to indirect range restriction, the sample correlation is a biased estimator of the population correlation, and a correction formula is used. In the past, bootstrap standard error and confidence intervals for the corrected correlations were examined with normal data. The present study proposes a large sample estimate (an analytic method) for the standard error, and a corresponding confidence interval for the corrected correlation. Monte Carlo simulation studies involving both normal and non-normal data were conducted to examine the empirical performance of the bootstrap and analytic methods. Results indicated that with both normal and non-normal data, the bootstrap standard error and confidence interval were generally accurate across simulation conditions (restricted sample size, selection ratio, and population correlations) and outperformed estimates of the analytic method. However, with certain combinations of distribution type and model conditions, the analytic method has an advantage, offering reasonable estimates of the standard error and confidence interval without resorting to the bootstrap procedure's computer-intensive approach. We provide SAS code for the simulation studies. PMID- 28631349 TI - Tuning Sulfur Oxidation States on Thioether-Bridged Peptide Macrocycles for Modulation of Protein Interactions. AB - Thioethers, sulfoxides, and sulfonium ions, despite diverse physicochemical properties, all engage in noncovalent interactions with proteins. Thioether containing macrocycles are also attracting attention as protein-protein interaction (PPI) inhibitors. Here, we used a model PPI between alpha-helical mixed lineage leukemia (MLL) protein and kinase-inducible domain interacting (KIX) domain to evaluate oxidation effects on sulfurcontaining macrocycle structure, stability, and protein affinity. Desolvation effects from various polarity states were evaluated computationally and experimentally at the side chain, amino acid, and peptide level. Sulfur-containing side chains spanned polarity ranges between all-hydrocarbon and lactam bridges for modulating solubility, cellular uptake, and affinity. Helical propensity studies showed that, although oxidized sulfur-containing side chains could be tolerated, conformational effects were sequence-dependent. In some cases, proteolytic stability, binding capacity with KIX, and increased helicity were obtained as first steps toward developing PPI inhibitors. PMID- 28631351 TI - Intraoperative acidosis and hypercapnia during thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula. AB - BACKGROUND: Intraoperative hypercapnia and acidosis have been associated with thoracoscopic repair of both congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula. AIM: The aim of the present study was to investigate whether thoracoscopic repair of congenital diaphragmatic hernia or esophageal atresia/tracheoesophageal fistula was associated with acidosis and hypercapnia in a large group of neonates, and to analyze the effects of acidosis and hypercapnia on early postoperative outcomes. METHODS: We reviewed the charts of neonates who underwent open or thoracoscopic congenital diaphragmatic hernia or esophageal atresia/tracheoesophageal fistula repair (2004-2014). Patients with available intraoperative arterial gas values were included. Data (PaCO2 : mm Hg) were compared using paired/unpaired tests and are reported as difference [95% confidence interval]. RESULTS: Congenital diaphragmatic hernia: 187 neonates underwent open (n=153) or thoracoscopic (n=34) repair. Intraoperative arterial gas values were recorded in 96 open and in 23 thoracoscopic operations. Both groups had similar preoperative pH and PaCO2 , and developed intraoperative acidosis (open -0.08 [-0.11, -0.05] P<.001, thoracoscopic -0.14 [-0.24, -0.04] P=.01) and hypercapnia (open: 7.8 [3.2, 12.4], P=.002; thoracoscopic: 20.2 [-2.5, 43, P=.07). Intraoperatively, neonates undergoing thoracoscopic repair developed lower pH than those having open surgery (-0.06 [-0.01, -0.10] P=.018), but maintained similar levels of PaCO2 (-4.0 [-9.0, 4.4] P=.39). Esophageal atresia/tracheoesophageal fistula: 205 neonates underwent open (n=180) or thoracoscopic (n=25) repair. Intraoperative arterial gas values were recorded in 62 open and in 14 thoracoscopic operations. Both groups had similar preoperative pH and PaCO2 , and developed intraoperative acidosis (open: -0.09 [-0.14, -0.04], P<.001; thoracoscopic: 0.21 [-0.28, -0.14], P<.001) and hypercapnia (open: 9.2 [2.6, 15.7] P=.008; thoracoscopic: 15.2 [1.6, 28.7], P=.03). Intraoperatively, neonates undergoing thoracoscopic repair developed lower pH than those having open surgery (difference 0.08 [0.01, 0.15], P=.02) but maintained similar levels of PaCO2 (difference -1 [-9, 3], P=.35). CONCLUSION: Neonates undergoing operative repair of congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula develop intraoperative acidosis and hypercapnia, regardless of the approach used. However, this phenomenon is more severe during thoracoscopic repair. Novel modalities to reduce intraoperative gas derangements, particularly during thoracoscopic repair, need to be established. PMID- 28631353 TI - Microbiome dynamics in early life stages of the scleractinian coral Acropora gemmifera in response to elevated pCO2. AB - Reef-building corals are complex holobionts, harbouring diverse microorganisms that play essential roles in maintaining coral health. However, microbiome development in early life stages of corals remains poorly understood. Here, microbiomes of Acropora gemmifera were analysed during spawning and early developmental stages, and also under different seawater partial pressure of CO2 (pCO2 ) conditions, using amplicon sequencing of 16S rRNA gene for bacteria and archaea and of ITS2 for Symbiodinium. No remarkable microbiome shift was observed in adults before and after spawning. Moreover, microbiomes in eggs were highly similar to those in spawned adults, possibly suggesting a vertical transmission from parents to offspring. However, significant stage-specific changes were found in coral microbiome during development, indicating that host development played a dominant role in shaping coral microbiome. Specifically, Cyanobacteria were particularly abundant in 6-day-old juveniles, but decreased largely in 31-day-old juveniles with a possible subclade shift in Symbiodinium dominance from C2r to D17. Larval microbiome showed changes in elevated pCO2 , while juvenile microbiomes remained rather stable in response to higher pCO2 . This study provides novel insights into the microbiome development during the critical life stages of coral. PMID- 28631352 TI - Overexpressing STAMP2 attenuates adipose tissue angiogenesis and insulin resistance in diabetic ApoE-/- /LDLR-/- mouse via a PPARgamma/CD36 pathway. AB - The aim of this study was to investigate whether overexpression of STAMP2 improves insulin resistance by regulating angiogenesis in adipose tissues. The characteristics of diabetic mice were measured by serial metabolite and pathology tests. Samples were obtained from epididymal, subcutaneous and brown adipose tissues. Histological and morphological analysis demonstrated that STAMP2 gene overexpression reduced adipocyte size, angiogenesis in epididymal and brown adipose tissues. On aortic ring assay, microvessels sprouting from aortas were significantly inhibited after STAMP2 gene overexpression. The cellular effect of STAMP2 on angiogenesis was explored in human umbilical vein endothelial cells (HUVECs) model. Correlation of STAMP2 and angiogenesis was validated by Ad-STAMP2 transfection and STAMP2 siRNA inhibition. In vitro, overexpression of STAMP2 significantly inhibited endothelial cell migration, tube formation. The effects of Ad-STAMP2 transfection on HUVECs were abolished by treatment with PPARgamma antagonist GW9662 (2.5 MUM), and the roles of STAMP2 siRNA on HUVECs were also reversed by treatment with PPARgamma agonist rosiglitazone (RSG) (0.1 mM). RT-PCR indicated that STAMP2 could regulate levels of adhesion molecules, vascular endothelial growth factor A and CD36. The expression of PPARgamma and CD36 was decreased when STAMP2 was inhibited by siRNA, while PPARgamma and CD36 were highly expressed after overexpression of STAMP2. Our results suggested that STAMP2 gene overexpression may improve insulin resistance via attenuating angiogenesis in epididymal and brown adipose tissues through the PPARgamma/CD36 signalling pathway. PMID- 28631354 TI - Cross-population myelination covariance of human cerebral cortex. AB - Cross-population covariance of brain morphometric quantities provides a measure of interareal connectivity, as it is believed to be determined by the coordinated neurodevelopment of connected brain regions. Although useful, structural covariance analysis predominantly employed bulky morphological measures with mixed compartments, whereas studies of the structural covariance of any specific subdivisions such as myelin are rare. Characterizing myelination covariance is of interest, as it will reveal connectivity patterns determined by coordinated development of myeloarchitecture between brain regions. Using myelin content MRI maps from the Human Connectome Project, here we showed that the cortical myelination covariance was highly reproducible, and exhibited a brain organization similar to that previously revealed by other connectivity measures. Additionally, the myelination covariance network shared common topological features of human brain networks such as small-worldness. Furthermore, we found that the correlation between myelination covariance and resting-state functional connectivity (RSFC) was uniform within each resting-state network (RSN), but could considerably vary across RSNs. Interestingly, this myelination covariance RSFC correlation was appreciably stronger in sensory and motor networks than cognitive and polymodal association networks, possibly due to their different circuitry structures. This study has established a new brain connectivity measure specifically related to axons, and this measure can be valuable to investigating coordinated myeloarchitecture development. Hum Brain Mapp 38:4730-4743, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631355 TI - Quantitative risk assessment to guide the treatment of cesarean scar pregnancy. AB - OBJECTIVE: To develop a risk-factor scoring system for the prediction of bleeding during ultrasound-guided dilation and curettage (D&C) for cesarean scar pregnancy (CSP). METHODS: The retrospective study included patients with a CSP of 31-67 days who underwent transabdominal ultrasonography-guided D&C in 2010-2014. Binary logistic regression analysis was used to identify risk factors for the need of Foley catheter hemostasis. The predictive accuracy of a risk-scoring system based on significant factors was evaluated by receiver operating curve analysis. RESULTS: Among 82 included patients, 66 (80%) were successfully treated without any complications, whereas 16 (20%) required Foley catheter compression hemostasis. Four patients who received the Foley catheter needed further treatment. A longer pregnancy duration (odds ratio 1.171, 95% confidence interval 1.050-1.305; P=0.004) and a rich blood supply on ultrasonography (odds ratio 3.282, 95% confidence interval 1.441-4.742; P=0.005) were significant risk factors for the need of compression hemostasis. A scoring system based on these two risk factors would have identified 93.8% of patients requiring compression hemostasis if the optimum cutoff score was used. CONCLUSION: Heavy bleeding during transabdominal ultrasound-guided D&C for CSP is associated with a longer pregnancy duration and a rich blood supply on ultrasonography. The new risk scoring system can be used to predict bleeding during surgery. PMID- 28631356 TI - Immune Tolerance Effect in Mesenteric Lymph Node Lymphocytes of Geniposide on Adjuvant Arthritis Rats. AB - Rheumatoid arthritis (RA) is a systemic, Th1 cytokine-predominant autoimmune disease result in a chronic and inflammatory disorder. Geniposide (GE), an iridoid glycoside compound that is purified from Gardenia jasminoides Ellis, has antiinflammatory and other immunoregulatory effects, but its exact mechanism of actions on RA is unknown. The aim of this study was to elucidate antiinflammation effects of GE on adjuvant arthritis (AA) rats and its possible immune tolerance mechanisms. Male Sprague-Dawley rats were administered with GE (30, 60, and 120 mg/kg) orally from day 17 to 24 after immunization. Lymphocyte proliferation was assessed by MTT. Levels of interleukin-2 (IL-2), IL-4, and transforming growth factor-beta1 were tested by ELISA. The expression of beta2-AR, GRK2, and beta arrestin-1 and beta-arrestin-2 was detected by western blot. Geniposide was found to relieve the secondary hind paw swelling and arthritis scores, along with attenuating histopathologic changes and decreasing IL-2 and increasing IL-4, transforming growth factor-beta1 in mesenteric lymph node (MLN) lymphocytes of AA rats. In addition, GE in vivo increased the expression of beta2-AR and decreased the expression of GRK2, beta-arrestin-1 and beta-arrestin-2, and level of cyclic adenosine monophosphate of MLN lymphocytes in AA rats. From these results, we can infer that GE on immune tolerance effects, beta2-AR desensitization, and beta2-AR AC-cyclic adenosine monophosphate transmembrane signal transduction of MLN lymphocytes plays crucial roles in antiinflammatory and immunoregulatory pathogeneses of RA. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28631357 TI - Revealing the global importance of isoprene metabolism by marine bacteria. PMID- 28631358 TI - Erratum. PMID- 28631359 TI - Management of pediatric hepatocellular carcinoma: A multimodal approach. AB - HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post-transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post-transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC. PMID- 28631361 TI - Optimal right heart filling pressure in acute respiratory distress syndrome determined by strain echocardiography. AB - INTRODUCTION: Right ventricular (RV) systolic dysfunction is common in acute respiratory distress syndrome (ARDS). While preload optimization is crucial in its management, dynamic fluid responsiveness indices lack reliability, and there is no consensus on target central venous pressure (CVP). We analyzed the utility of RV free wall longitudinal strain (RVFWS) in the estimation of optimal RV filling pressure in ARDS. METHODS: A retrospective cross-sectional analysis of clinical data and echocardiograms of patients with ARDS was performed. Tricuspid annular plane systolic excursion (TAPSE), tricuspid peak systolic velocity (S'), RV fractional area change (RVFAC), RVFWS, CVP, systolic pulmonary artery pressure (SPAP), and left ventricular ejection fraction (LVEF) were measured. RESULTS: Fifty-one patients with moderate-severe ARDS were included. There were inverse correlations between CVP and TAPSE, S', RVFAC, RVFWS, and LVEF. The most significant was with RVFWS (r:.74, R2 :.55, P:.00001). Direct correlations with creatinine and lactate were noted. Receiver operating characteristic analysis showed that RVFWS -21% (normal reference value) was associated with CVP: 13 mm Hg (AUC: 0.92, 95% CI: 0.83-1.00). Regression model analysis of CVP, and RVFWS interactions established an RVFWS range from -18% to -24%. RVFWS -24% corresponded to CVP: 11 mm Hg and RVFWS -18% to CVP: 15 mm Hg. Beyond a CVP of 15 mm Hg, biventricular systolic dysfunction rapidly ensues. CONCLUSIONS: Our data are the first to show that an RV filling pressure of 13+/-2 mm Hg-as by CVP correlates with optimal RV mechanics as evaluated by strain echocardiography in patients with moderate-severe ARDS. PMID- 28631360 TI - Reduced cell attachment to poly(2-hydroxyethyl methacrylate)-coated ventricular catheters in vitro. AB - The majority of patients with hydrocephalus are dependent on ventriculoperitoneal shunts for diversion of excess cerebrospinal fluid. Unfortunately, these shunts are failure-prone and over half of all life-threatening pediatric failures are caused by obstruction of the ventricular catheter by the brain's resident immune cells, reactive microglia and astrocytes. Poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels are widely used for biomedical implants. The extreme hydrophilicity of PHEMA confers resistance to protein fouling, making it a strong candidate coating for ventricular catheters. With the advent of initiated chemical vapor deposition (iCVD), a solvent-free coating technology that creates a polymer in thin film form on a substrate surface by introducing gaseous reactant species into a vacuum reactor, it is now possible to apply uniform polymer coatings on complex three-dimensional substrate surfaces. iCVD was utilized to coat commercially available ventricular catheters with PHEMA. The chemical structure was confirmed on catheter surfaces using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. PHEMA coating morphology was characterized by scanning electron microscopy. Testing PHEMA coated catheters against uncoated clinical-grade catheters in an in vitro hydrocephalus catheter bioreactor containing co-cultured astrocytes and microglia revealed significant reductions in cell attachment to PHEMA-coated catheters at both 17-day and 6-week time points. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1268-1279, 2018. PMID- 28631363 TI - Experimental evolution of Bacillus subtilis. AB - The endospore-forming bacteria have persisted on earth perhaps 3Ga, leveraging the flexibility of their distinctive lifestyle to adapt to a remarkably wide range of environments. This process of adaptation can be investigated through the simple but powerful technique of laboratory evolution. Evolved strains can be analyzed by whole genome sequencing and an array of omics technologies. The intensively studied, genetically tractable endospore-former, Bacillus subtilis, is an ideal subject for laboratory evolution experiments. Here, we describe the use of the B. subtilis model system to study the adaptation of these bacteria to reduced and stringent selection for endospore formation, as well as to novel environmental challenges of low atmospheric pressure, high ultraviolet radiation, and unfavourable growth temperatures. In combination with other approaches, including comparative genomics and environmental field work, laboratory evolution may help elucidate how these bacteria have so successfully adapted to life on earth, and perhaps beyond. PMID- 28631365 TI - An intensive occupational therapy discharge planning intervention was not more effective in improving activities of daily living performance and participation than a hospital-based discharge planning consultation for older adults in the acute hospital setting. PMID- 28631366 TI - Author Guidelines of the Australian Occupational Therapy Journal - revised 2017. PMID- 28631367 TI - Parents of children with autism spectrum disorder had lower relationship satisfaction than parents of children without a disability with positive cognitive appraisal and social support found to be protective factors. PMID- 28631369 TI - Inoperable infiltrative basal cell carcinoma successfully treated with vismodegib. AB - Basal cell carcinoma (BCC) is the most common skin cancer but usually has a good prognosis. However, there is a subset of BCC cases with a less favorable prognosis. For patients with locally advanced, recurrent or metastatic BCCs who are not suitable for surgery or radiotherapy, small-molecule drug inhibitors of hedgehog pathway are a new therapeutic opportunity. Here, we present a case of infiltrative BCC with multiple recurrences. Wide excision with reconstructive plastic surgery was performed initially with adjuvant radiotherapy. Due to multiple recurrences afterward, radiotherapy, topical imiquimod and oral itraconazole were used but were not effective. Finally, the patient was treated with vismodegib which led to a complete response. Moreover, the patient's symptoms due to the locally diffused cancer resolved. PMID- 28631368 TI - CRISPR/Cas9-mediated loss of FGF5 function increases wool staple length in sheep. AB - Fibroblast growth factor 5 (FGF5) regulates hair length in humans and a variety of other animals. To investigate whether FGF5 has similar effects in sheep, we used clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated 9 (Cas9) to generate loss-of-function mutations with the FGF5 gene in Chinese Merino sheep. A total of 16 lambs were identified with genetic mutations within the targeting locus: 13 lambs had biallelic modifications and three lambs had monoallelic modifications. Characterization of the modifications revealed that 13 were frameshift mutations that led to premature termination, whereas the other three were in-frame deletions. Thus, CRISPR/Cas9 efficiently generated loss of-function mutations in the sheep FGF5 gene. We then investigated the effect of loss of FGF5 function on wool traits in 12 lambs and found that wool staple length and stretched length of genetically modified (GM) yearling sheep were significantly longer compared with that of wild-type (WT) control animals. The greasy fleece weight of GM yearling sheep was also significantly greater compared with that of WT sheep. Moreover, the mean fiber diameter in GM sheep showed no significant difference compared with WT sheep, suggesting that the increase in greasy fleece weight was likely attributed to the increase in wool length. The results of this study suggest that CRISPR/Cas9-mediated loss of FGF5 activity could promote wool growth and, consequently, increase wool length and yield. PMID- 28631370 TI - Microbial manganese(III) reduction fuelled by anaerobic acetate oxidation. AB - Soluble manganese in the intermediate +III oxidation state (Mn3+ ) is a newly identified oxidant in anoxic environments, whereas acetate is a naturally abundant substrate that fuels microbial activity. Microbial populations coupling anaerobic acetate oxidation to Mn3+ reduction, however, have yet to be identified. We isolated a Shewanella strain capable of oxidizing acetate anaerobically with Mn3+ as the electron acceptor, and confirmed this phenotype in other strains. This metabolic connection between acetate and soluble Mn3+ represents a new biogeochemical link between carbon and manganese cycles. Genomic analyses uncovered four distinct genes that allow for pathway variations in the complete dehydrogenase-driven TCA cycle that could support anaerobic acetate oxidation coupled to metal reduction in Shewanella and other Gammaproteobacteria. An oxygen-tolerant TCA cycle supporting anaerobic manganese reduction is thus a new connection in the manganese-driven carbon cycle, and a new variable for models that use manganese as a proxy to infer oxygenation events on early Earth. PMID- 28631371 TI - Aqueous humour concentrations of TGF-beta, PLGF and FGF-1 and total retinal blood flow in patients with early non-proliferative diabetic retinopathy. PMID- 28631372 TI - Patient and provider characteristics related with prescribing of ADHD medication: Nationwide health insurance claims database study in Korea. AB - BACKGROUND: Little is known about the association between prescribing of attention deficit hyperactivity disorder (ADHD) medication and the patient's age, gender, and type of medical institution in Asia region. INTRODUCTION: This study investigates the prevalence and factors of diagnosis and pharmacological treatment of ADHD in the pediatric population. METHODS: Using the Korea Health Insurance database, study participants were identified as pediatric patients (<=17 years) with at least 1 diagnosis of ADHD (ICD-10, F90) from January 1, 2007 to December 31, 2011. The annual prevalence of ADHD diagnosis and medication was calculated. Annual differences in the prevalence between 2007 and 2011 with 95% confidence intervals (CIs) were estimated. We conducted multiple logistic regression analysis to estimate adjusted odds ratios (aORs) and their 95% CI to investigate predictors associated with prescribing of ADHD medication. RESULTS: The prevalence of ADHD medication prescribing increased by 26.57% (95% CI, 26.27 26.88) from 0.53% in 2007 to 0.72% in 2011. The prevalence increased by 41.56% (95% CI, 40.51-42.65) in females compared with 34.91% (95% CI, 34.47-35.36) in males. Whereas the prevalence decreased in patients younger than 6 years old, it increased by 74.30% (95% CI, 72.84-75.79) in the 13 to 17-year group. Males were more likely than females to be treated with ADHD medication (aOR, 1.12; 95% CI, 1.10-1.13). Physician specialty (psychiatry vs non-psychiatry) (aOR, 1.37; 95% CI, 1.34-1.40) were associated with prescribing of ADHD medication. CONCLUSION: Rapid increases in the diagnosis and pharmacological treatment of ADHD in the pediatric population have been observed. While demographic characteristics were similar to other countries, provider characteristics were different with others reporting that the majority of patients were treated by physicians specializing in psychiatry. PMID- 28631373 TI - The risk of violence associated with novel psychoactive substance misuse in patients presenting to acute mental health services. AB - Novel psychoactive substance (NPS) availability is increasing at a phenomenal rate and so is their associated misuse. Currently, the harms associated with NPS misuse are unclear. This report presents the initial findings of a continuing study looking into the impact of NPS misuse on admissions to an acute mental health facility in London. Violence preadmission and violence during admission have been found to be significant in NPS misusers compared to non-NPS substance misusers. Our findings have important consequences for acute mental health, emergency, and public health services. NPS misusers require specific assessment and risk management to reduce the risk of violence towards others. PMID- 28631374 TI - Multiple papillary fibroelastomas in a patient with severe mitral stenosis. PMID- 28631375 TI - 3D Mimicry of Native-Tissue-Fiber Architecture Guides Tendon-Derived Cells and Adipose Stem Cells into Artificial Tendon Constructs. AB - Tendon and ligament (T/L) function is intrinsically related with their unique hierarchically and anisotropically organized extracellular matrix. Their natural healing capacity is, however, limited. Here, continuous and aligned electrospun nanofiber threads (CANT) based on synthetic/natural polymer blends mechanically reinforced with cellulose nanocrystals are produced to replicate the nanoscale collagen fibrils grouped into microscale collagen fibers that compose the native T/L. CANT are then incrementally assembled into 3D hierarchical scaffolds, resulting in woven constructions, which simultaneously mimic T/L nano-to-macro architecture, nanotopography, and nonlinear biomechanical behavior. Biological performance is assessed using human-tendon-derived cells (hTDCs) and human adipose stem cells (hASCs). Scaffolds nanotopography and microstructure induce a high cytoskeleton elongation and anisotropic organization typical of tendon tissues. Moreover, the expression of tendon-related markers (Collagen types I and III, Tenascin-C, and Scleraxis) by both cell types, and the similarities observed on their expression patterns over time suggest that the developed scaffolds not only prevent the phenotypic drift of hTDCs, but also trigger tenogenic differentiation of hASCs. Overall, these results demonstrate a feasible approach for the scalable production of 3D hierarchical scaffolds that exhibit key structural and biomechanical properties, which can be advantageously explored in acellular and cellular T/L TE strategies. PMID- 28631376 TI - Scale of human mobility in the southern Andes (Argentina and Chile): A new framework based on strontium isotopes. AB - OBJECTIVES: The goal of this article is to assess the scale of human paleomobility and ecological complementarity between the lowlands and highlands in the southern Andes during the last 2,300 years. By providing isotope results for human bone and teeth samples, we assess a hypothesis of "high residential mobility" suggested on the basis of oxygen isotopes from human remains. METHODS: We develop an isotopic assessment of human mobility in a mountain landscape combining strontium and oxygen isotopes. We analyze bone and teeth samples as an approach to life-history changes in spatial residence. Human samples from the main geological units and periods within the last two millennia are selected. RESULTS: We present a framework for the analysis of bioavailable strontium based on the combination of the geological data with isotope results for rodent samples. The 87 Sr/86 Sr values from human samples indicate residential stability within geological regions along life history. When comparing strontium and oxygen values for the same human samples, we record a divergent pattern: while delta18 O values for samples from distant regions overlap widely, there are important differences in 87 Sr/86 Sr values. CONCLUSIONS: Despite the large socio-economic changes recorded, 87 Sr/86 Sr values indicate a persisting scenario of low systematic mobility between the different geological regions. Our results suggest that strontium isotope values provide the most germane means to track patterns of human occupation of distinct regions in complex geological landscapes, offering a much higher spatial resolution than oxygen isotopes in the southern Andes. PMID- 28631377 TI - State of the art technologies to explore long non-coding RNAs in cancer. AB - Long non-coding RNAs (lncRNAs) comprise a vast repertoire of RNAs playing a wide variety of crucial roles in tissue physiology in a cell-specific manner. Despite being engaged in myriads of regulatory mechanisms, many lncRNAs have still remained to be assigned any functions. A constellation of experimental techniques including single-molecule RNA in situ hybridization (sm-RNA FISH), cross-linking and immunoprecipitation (CLIP), RNA interference (RNAi), Clustered regularly interspaced short palindromic repeats (CRISPR) and so forth has been employed to shed light on lncRNA cellular localization, structure, interaction networks and functions. Here, we review these and other experimental approaches in common use for identification and characterization of lncRNAs, particularly those involved in different types of cancer, with focus on merits and demerits of each technique. PMID- 28631378 TI - Runx2-I is an Early Regulator of Epithelial-Mesenchymal Cell Transition in the Chick Embryo. AB - BACKGROUND: Although normally linked to bone and cartilage development, the Runt related transcription factor, RUNX2, was reported in the mouse heart during development of the valves. We examined RUNX2 expression and function in the developing avian heart as it related to the epithelial-mesenchymal transition (EMT) in the atrioventricular canal. EMT can be separated into an activation stage involving hypertrophy and cell separation and an invasion stage where cells invade the extracellular matrix. The localization and activity of RUNX2 was explored in relation to these steps in the heart. As RUNX2 was also reported in cancer tissues, we examined its expression in the progression of esophageal cancer in staged tissues. RESULTS: A specific isoform, RUNX2-I, is present and required for EMT by endothelia of the atrioventricular canal. Knockdown of RUNX2 I inhibits the cell-cell separation that is characteristic of initial activation of EMT. Loss of RUNX2-I altered expression of EMT markers to a greater extent during activation than during subsequent cell invasion. Transforming growth factor beta 2 (TGFbeta2) mediates activation during cardiac endothelial EMT. Consistent with a role in activation, RUNX2-I is regulated by TGFbeta2 and its activity is independent of similarly expressed Snai2 in regulation of EMT. Examination of RUNX2 expression in esophageal cancer showed its upregulation concomitant with the development of dysplasia and continued expression in adenocarcinoma. CONCLUSIONS: These data introduce the RUNX2-I isoform as a critical early transcription factor mediating EMT in the developing heart after induction by TGFbeta2. Its expression in tumor tissue suggests a similar role for RUNX2 in the EMT of metastasis. Developmental Dynamics 247:542-554, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28631379 TI - Early mortality in patients with acute myelogenous leukemia treated in teaching versus non-teaching hospitals: A large database analysis. PMID- 28631380 TI - A Highly Sensitive Enzymatic Catalysis System for Trace Detection of Arsenic in Water. AB - Arsenic (As) is an extremely toxic element that exists in the environment in different chemical forms. The detection of arsenic in potable water remains a challenging task. This study presents a highly sensitive enzymatic catalysis system for trace sensing of inorganic arsenic in water. This is the first enzyme catalyzed fluorescence assay capable of detecting arsenic at concentrations below the allowable level adopted by the World Health Organization (10 ppb in drinking water). The enzyme catalytically produces fluorescent NADH in the presence of arsenate, which enables facile detection of arsenate at concentrations in the 0 200 ppb range. Calibration curves made at a set time interval allow accurate determination of unknown arsenic samples. This method holds potential for interfacing with automated analytical sampling systems to allow arsenic determinations in environmental health applications. PMID- 28631381 TI - Tyrosine Kinase Expressed in Hepatocellular Carcinoma, TEC, Controls Pluripotency and Early Cell Fate Decisions of Human Pluripotent Stem Cells via Regulation of Fibroblast Growth Factor-2 Secretion. AB - Human pluripotent stem cells (hPSC) require signaling provided by fibroblast growth factor (FGF) receptors. This can be initiated by the recombinant FGF2 ligand supplied exogenously, but hPSC further support their niche by secretion of endogenous FGF2. In this study, we describe a role of tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase in this process. We show that TEC mediated FGF2 secretion is essential for hPSC self-renewal, and its lack mediates specific differentiation. Following both short hairpin RNA- and small interfering RNA-mediated TEC knockdown, hPSC secretes less FGF2. This impairs hPSC proliferation that can be rescued by increasing amounts of recombinant FGF2. TEC downregulation further leads to a lower expression of the pluripotency markers, an improved priming towards neuroectodermal lineage, and a failure to develop cardiac mesoderm. Our data thus demonstrate that TEC is yet another regulator of FGF2-mediated hPSC pluripotency and differentiation. Stem Cells 2017;35:2050 2059. PMID- 28631383 TI - Benford's Law for Quality Assurance of Manner of Death Counts in Small and Large Databases. AB - To assess if Benford's law, a mathematical law used for quality assurance in accounting, can be applied as a quality assurance measure for the manner of death determination. We examined a regional forensic pathology service's monthly manner of death counts (N = 2352) from 2011 to 2013, and provincial monthly and weekly death counts from 2009 to 2013 (N = 81,831). We tested whether each dataset's leading digit followed Benford's law via the chi-square test. For each database, we assessed whether number 1 was the most common leading digit. The manner of death counts first digit followed Benford's law in all the three datasets. Two of the three datasets had 1 as the most frequent leading digit. The manner of death data in this study showed qualities consistent with Benford's law. The law has potential as a quality assurance metric in the manner of death determination for both small and large databases. PMID- 28631382 TI - A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy. AB - Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received two courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2-4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5 +/- 10.0% and 83.4 +/- 7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (<5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma. PMID- 28631384 TI - NMR Study of the Reductive Decomposition of [BMIm][NTf2 ] at Gold Electrodes and Indirect Electrochemical Conversion of CO2. AB - Potential controlled electrolyses of [BMIm][NTf2 ] ionic liquid were performed at a gold cathode under nitrogen atmosphere. The structures of the major conversion products of the BMIm+ cation were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) analyses and gas chromatography (GC) analysis of the volatile compounds. Recombination of the imidazol-2-yl radicals, generated at the electrode by single electron transfer, leads to neutral diastereomeric dimers in equal proportions, with a faradaic efficiency of 80 %, while disproportionation of these radicals and/or reaction with hydrogen atoms adsorbed at the electrode generates a neutral monomer with 20 % faradaic efficiency. Both pathways also yield the N-heterocyclic carbene imidazolin-2-ylidene, which is involved in fast proton exchange with the parent BMIm+ cation. The reductive decomposition products of the BMIm+ cation are no longer detected if the pre-electrolysed sample is reacted with CO2 , which undergoes an indirect reduction and generates the carboxylate adduct. PMID- 28631385 TI - Identification of glucose kinase-dependent and -independent pathways for carbon control of primary metabolism, development and antibiotic production in Streptomyces coelicolor by quantitative proteomics. PMID- 28631386 TI - Toward establishing model organisms for marine protists: Successful transfection protocols for Parabodo caudatus (Kinetoplastida: Excavata). AB - We developed protocols for, and demonstrated successful transfection of, the free living kinetoplastid flagellate Parabodo caudatus with three plasmids carrying a fluorescence reporter gene (pEF-GFP with the EF1 alpha promoter, pUB-GFP with Ubiquitin C promoter, and pEYFP-Mitotrap with CMV promoter). We evaluated three electroporation approaches: (1) a square-wave electroporator designed for eukaryotes, (2) a novel microfluidic transfection system employing hydrodynamically-controlled electric field waveforms, and (3) a traditional exponential decay electroporator. We found the microfluidic device provides a simple and efficient platform to quickly test a wide range of electric field parameters to find the optimal set of conditions for electroporation of target species. It also allows for processing large sample volumes (>10 ml) within minutes, increasing throughput 100 times over cuvettes. Fluorescence signal from the reporter gene was detected a few hours after transfection and persisted for 3 days in cells transfected by pEF-GFP and pUB-GFP plasmids and for at least 5 days post-transfection for cells transfected with pEYFP-Mitotrap. Expression of the reporter genes (GFP and YFP) was also confirmed using reverse transcription-PCR (RT-PCR). This work opens the door for further efforts with this taxon and close relatives toward establishing model systems for genome editing. PMID- 28631387 TI - Umeclidinium bromide versus placebo for people with chronic obstructive pulmonary disease (COPD). AB - BACKGROUND: People with chronic obstructive pulmonary disease (COPD) have poor quality of life, reduced survival, and accelerated decline in lung function, especially associated with acute exacerbations, leading to high healthcare costs. Long-acting bronchodilators are the mainstay of treatment for symptomatic improvement, and umeclidinium is one of the new long-acting muscarinic antagonists approved for treatment of patients with stable COPD. OBJECTIVES: To assess the efficacy and safety of umeclidinium bromide versus placebo for people with stable COPD. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, the World Health Organization (WHO) trials portal, and the GlaxoSmithKline (GSK) Clinical Study Register, using prespecified terms, as well as the reference lists of all identified studies. Searches are current to April 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of parallel design comparing umeclidinium bromide versus placebo in people with COPD, for at least 12 weeks. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. If we noted significant heterogeneity in the meta-analyses, we subgrouped studies by umeclidinium dose. MAIN RESULTS: We included four studies of 12 to 52 weeks' duration, involving 3798 participants with COPD. Mean age of participants ranged from 60.1 to 64.6 years; most were males with baseline mean smoking pack-years of 39.2 to 52.3. They had moderate to severe COPD and baseline mean post-bronchodilator forced expiratory volume in one second (FEV1) ranging from 44.5% to 55.1% of predicted normal. As all studies were systematically conducted according to prespecified protocols, we assessed risk of selection, performance, detection, attrition, and reporting biases as low.Compared with those given placebo, participants in the umeclidinium group had a lesser likelihood of developing moderate exacerbations requiring a short course of steroids, antibiotics, or both (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.46 to 0.80; four studies, N = 1922; GRADE: high), but not specifically requiring hospitalisations due to severe exacerbations (OR 0.86, 95% CI 0.25 to 2.92; four studies, N = 1922, GRADE: low). The number needed to treat for an additional beneficial outcome (NNTB) to prevent an acute exacerbation requiring steroids, antibiotics, or both was 18 (95% CI 13 to 37). Quality of life was better in the umeclidinium group (mean difference (MD) -4.79, 95% CI -8.84 to -0.75; three studies, N = 1119), and these participants had a significantly higher chance of achieving a minimal clinically important difference of at least four units in St George's Respiratory Questionnaire (SGRQ) total score compared with those in the placebo group (OR 1.45, 95% CI 1.16 to 1.82; three studies, N = 1397; GRADE: moderate). The NNTB to achieve one person with a clinically meaningful improvement was 11 (95% CI 7 to 29). The likelihood of all-cause mortality, non-fatal serious adverse events (OR 1.33; 95% CI 0.89 to 2.00; four studies, N = 1922, GRADE: moderate), and adverse events (OR 1.06, 95% CI 0.85 to 1.31; four studies, N = 1922; GRADE: moderate) did not differ between umeclidinium and placebo groups. The umeclidinium group demonstrated significantly greater improvement in change from baseline in trough FEV1 compared with the placebo group (MD 0.14, 95% CI 0.12 to 0.17; four studies, N = 1381; GRADE: high). Symptomatic improvement was more likely in the umeclidinium group than in the placebo group, as determined by Transitional Dyspnoea Index (TDI) focal score (MD 0.76, 95% CI 0.43 to 1.09; three studies, N = 1193), and the chance of achieving a minimal clinically important difference of at least one unit improvement was significantly higher with umeclidinium than with placebo (OR 1.71, 95% CI 1.37 to 2.15; three studies, N = 1141; GRADE: high). The NNTB to attain one person with clinically important symptomatic improvement was 8 (95% CI 5 to 14). The likelihood of rescue medication usage (change from baseline in the number of puffs per day) was significantly less for the umeclidinium group than for the placebo group (MD -0.45, 95% CI -0.76 to -0.14; four studies, N = 1531). AUTHORS' CONCLUSIONS: Umeclidinium reduced acute exacerbations requiring steroids, antibiotics, or both, although no evidence suggests that it decreased the risk of hospital admission due to exacerbations. Moreover, umeclidinium demonstrated significant improvement in quality of life, lung function, and symptoms, along with lesser use of rescue medications. Studies reported no differences in adverse events, non-fatal serious adverse events, or mortality between umeclidinium and placebo groups; however, larger studies would yield a more precise estimate for these outcomes. PMID- 28631389 TI - To stand back or step in? Exploring the responses of employees who observe workplace bullying. AB - Bullying remains a pervasive problem in healthcare, and evidence suggests systems in place are not utilised due to perceptions of ineffectiveness and inequity. This study examines bystander responses to bullying and factors that influence decisions to intervene. We explore relationships between bystanders' perceptions of psychological safety across three levels (organisation, supervisor and colleague) and reactions to witnessing bullying. We suggest psychological safety would be positively associated with the decision to intervene. Findings indicate the most pervasive reaction to witnessing incidents of bullying is to discuss with colleagues, a low-involvement reaction. We find perceptions of supervisory and organisational safety/support are positively related to high-involvement decisions such as formal reporting of the incidents, highlighting the importance of support from those in power. However, perceptions of collegial support may lead to low-involvement responses, which risk reinforcing and underpinning dysfunctional organisational dynamics by providing informal social and emotional responses that may substitute more formal organisational responses to this persistent problem. This study highlights the importance of support from individuals in power if bystanders are to feel comfortable making high involvement interventions. PMID- 28631388 TI - The efficacy of commercial tooth storage media for maintaining the viability of human periodontal ligament fibroblasts. AB - AIM: To evaluate Save-A-Tooth (SAT), EMT Toothsaver (EMT) and Hank's Balanced Salt Solution (HBSS) for their influence on the viability and proliferative capacity of human periodontal ligament fibroblasts (HPDLFs). METHODOLOGY: Primary HPDLFs were seeded into 96-well cell culture plates and exposed to SAT, EMT, HBSS and water (negative control) for 0.5, 1, 3, 6, 12 and 24 h at room temperature (22 degrees C). After each exposure time, cell viability was measured through quantifying adenosine triphosphate (ATP) using a luminescent dye. The proliferative capacity was also quantified using the PrestoBlue assay after 12 or 24 h storage in each medium. The data were analysed statistically by two-way anova and post hoc Least Significant Difference (LSD) test (P < 0.05). The morphology of the cells after 12 h storage was also investigated through live/dead viability/cytotoxicity kit together with fluorescence microscopy. RESULTS: There was no significant difference in cell viability amongst HBSS, SAT and EMT groups up to 6 h. SAT was effective in maintaining cell viability only up to 12 h and then became detrimental to HPDLF; after 24 h, the effectiveness of SAT in maintaining cell viability was similar to that of water (P > 0.05). Amongst all the media, only EMT could maintain the proliferative capacity of HPDLFs significantly higher than the negative control, that is water (P < 0.05) after 24 h storage. CONCLUSION: EMT maintained the proliferative capacity of HPDLFs after 24 h storage. PMID- 28631390 TI - Metastatic tonsillar squamous cell carcinoma masquerading as a pancreatic cystic tumor and diagnosed by EUS-guided FNA. AB - Metastatic carcinoma to the pancreas is uncommon and head and neck squamous carcinoma metastatic to the pancreas is extremely rare. Metastatic squamous cell carcinoma to the pancreas presents a unique diagnostic challenge: in addition to mimicking the rare primary squamous cell carcinoma of the pancreas based on cytologic, histologic, and immunohistochemical features, it may be mistaken for a cystic neoplasm of the pancreas because of its high predilection for cystic degeneration in metastatic sites. Herein, we report a case of tonsillar squamous cell carcinoma with a cystic pancreatic metastasis diagnosed by ultrasound-guided fine needle aspiration biopsy (EUS-FNA). This represents a third reported case of metastatic squamous cell carcinoma to the pancreas from the head and neck region. Metastatic squamous cell carcinoma should be considered in the differential diagnosis of EUS-FNA during evaluation of pancreatic cystic lesion. PMID- 28631391 TI - Myosin substitution rate is affected by the amount of cytosolic myosin in cultured muscle cells. AB - In striated muscles, approximately 300 myosin molecules form a single thick filament in myofibrils. Each myosin is continuously displaced by another myosin to maintain the thick filament structure. Our previous study using a fluorescence recovery after photobleaching (FRAP) technique showed that the myosin replacement rate is decreased by inhibition of protein synthesis, but myosin is still exchangeable. This result prompted us to examine whether myosin in the cytoplasm is involved in myosin replacement in myofibrils. To address this, FRAP was measured in green fluorescent protein (GFP)-tagged myosin heavy chain 3 (Myh3) expressing myotubes that were treated with streptolysin-O (SLO), which forms pores specifically in the plasma membrane to induce leakage of cytoplasmic proteins. Our biochemical data demonstrated that the cytoplasmic myosin content was reduced in SLO-permeabilized semi-intact myotubes. Furthermore, FRAP experiments showed a sluggish substitution rate of GFP-Myh3 in SLO-permeabilized myotubes. Taken together, these results demonstrate that the myosin substitution rate is significantly reduced by a decreased amount of myosin in the cytoplasm and that cytoplasmic myosin contributes to myosin replacement in myofibrils. PMID- 28631392 TI - Detection of negative and positive RNA strand of poliovirus Sabin 1 and echovirus E19 by a stem-loop reverse transcription PCR. AB - : In this report a strand specific RT-PCR was established for the detection of the replicative negative RNA strand of poliovirus sabin 1 (Sabin1) and Echovirus 19 (E19) strains. The key for the successful conduction of the assay was the use of a specific reverse transcription primer targeting the 5'-UTR of enteroviruses that consisted of a stem-loop structure at the 5'-end and an enteroviral-specific sequence at the 3'-end. The stem loop RT-PCR was found to be an accurate and sensitive method, detecting even 10-2 CCID50 of poliovirus sabin 1 (Sabin1) and E19 strains 6 h postinfection (p.i.), while CPE appeared 3 days later. This assay was also validated in SiHa and Caski cell lines that are not used for the detection of enteroviruses. The negative RNA strand was detected 6 h and 12 h p.i. in SiHa and Caski cells, when these cell lines were inoculated with 105 and 1 CCID50 respectively, whereas CPE was observed 5 days p.i for SiHa cells and 8 days p.i for Caski cells and that only at 105 CCID50 . The results show that this approach may be used for replacing the time-consuming cell cultures in order to detect the active replication of enteroviruses. SIGNIFICANCE AND IMPACT OF THE STUDY: Enteroviruses are positive stranded RNA viruses that may cause severe diseases. The conventional method for detection of active viral replication involves virus isolation in sensitive cell cultures followed by titration and seroneutralization. In this report, we describe the use of a stem-loop secondary structured oligonucleotide in RT-PCR assay for the detection of the replicative negative strand of the positive-stranded RNA of poliovirus sabin 1 and E19 strains. This approach proved to be a useful tool that may be used for replacing the time-consuming cell culture assays in order to detect the active replication of enteroviruses. PMID- 28631393 TI - Comparison of thiazide-like diuretics versus thiazide-type diuretics: a meta analysis. AB - Thiazide diuretics are widely used for the management of hypertension. In recent years, it has been actively debated that there is interchangeability of thiazide type diuretics hydrochlorothiazide and thiazide-like diuretics including indapamide and chlorthalidone for the treatment of hypertension. With the purpose of seeking out the best thiazide diuretic for clinicians, we summarized the existing evidence on the two types of drugs and conducted a meta-analysis on their efficacy in lowering blood pressure and effects on blood electrolyte, glucose and total cholesterol. Twelve trials were identified: five based on the comparison of indapamide versus hydrochlorothiazide and seven based on the chlorthalidone versus hydrochlorothiazide. In the meta-analysis of blood pressure reduction, thiazide-like diuretics seemed to further reduce systolic BP ([95% CI]; -5.59 [-5.69, -5.49]; P < 0.001) and diastolic BP ([95% CI]; -1.98 [-3.29, 0.66]; P = 0.003). Meanwhile, in the analysis of side effects, the incidence of hypokalemia ([95% CI]; 1.58 [0.80, 3.12]; P = 0.19), hyponatremia ([95% CI]; 0.14 [-0.57, 0.30], P = 0.54), change of blood glucose ([95% CI];0.13 [-0.16, 0.41], P = 0.39) and total cholesterol ([95% CI]; 0.13 [-0.16, 0.41], P = 0.39) showed that there is no statistical significant differences between the two groups of drugs. In conclusion, using thiazide-like diuretics is superior to thiazide-type diuretics in reducing blood pressure without increasing the incidence of hypokalemia, hyponatraemia and any change of blood glucose and serum total cholesterol. PMID- 28631394 TI - Helping Babies Breathe implementation in Zanzibar, Tanzania. AB - AIM: To assess the efficacy and feasibility of implementing Helping Babies Breathe, a neonatal resuscitation programme for resource-limited environments. BACKGROUND: This quality improvement project focused on training midwives on Helping Babies Breathe to address high rates of neonatal mortality secondary to birth asphyxia. METHODS: The convenience sample was 33 midwives in Zanzibar, Tanzania. The train-the-trainer strategy with repeated measures design was used to assess knowledge and skills at 3 time points. Observations were completed during "real-time" deliveries, and a focused interview generated feedback regarding satisfaction and sustainability. RESULTS: Knowledge scores and resuscitation skills significantly improved and were sustained, P < .05. Of the 62 birth observations, 19% needed intervention. All were appropriately resuscitated and survived. CONCLUSION: Results indicate that participants retained knowledge and skills and used them in clinical practice. Observations demonstrated that participants took appropriate actions when presented with a baby who was not breathing. PMID- 28631395 TI - A Univariate Approach to Sex Estimation for the Fragmentary Upper Limb. AB - Although there are numerous reliable multivariate models for sex estimation, many scenarios, both forensic and archaeological, result in the recovery of fragmentary remains, which prevents the collection of various standard measurements. The purpose of this research was to establish metric applications for sex estimation from the distal humerus and distal radius of European/American Whites and American Blacks. Data for this research were retrieved from a sample consisting of a larger database from multiple skeletal collections. Measurements include epicondylar breadth, breadth of the capitulum-trochlea, and distal breadth of the radius. Student's t-test and descriptive statistics were utilized to analyze the data. Classification rates ranged from 75% to 96.4%, with the capitulum-trochlea breadth performing best. Overall, significant metric differences exist between the sexes in the distal humerus and radius and can be utilized to estimate sex. This study offers a reliable alternative sex estimation technique applicable to fragmentary or damaged remains. PMID- 28631396 TI - PTTG3P promotes gastric tumour cell proliferation and invasion and is an indicator of poor prognosis. AB - Pseudogenes play a crucial role in cancer progression. However, the role of pituitary tumour-transforming 3, pseudogene (PTTG3P) in gastric cancer (GC) remains unknown. Here, we showed that PTTG3P expression was abnormally up regulated in GC tissues compared with that in normal tissues both in our 198 cases of clinical samples and the cohort from The Cancer Genome Atlas (TCGA) database. High PTTG3P expression was correlated with increased tumour size and enhanced tumour invasiveness and served as an independent negative prognostic predictor. Moreover, up-regulation of PTTG3P in GC cells stimulated cell proliferation, migration and invasion both in vitro in cell experiments and in vivo in nude mouse models, and the pseudogene functioned independently of its parent genes. Overall, these results reveal that PTTG3P is a novel prognostic biomarker with independent oncogenic functions in GC. PMID- 28631397 TI - The effects and toxicity of cathinones from the users' perspectives: A qualitative study. AB - OBJECTIVE: The objective of this study is to explore the users' perspectives regarding the effects and toxicity of cathinones. METHODS: A systematic search of Internet discussion forums yielded 303 threads relevant to the research objectives. The threads were analysed by conventional content analysis where concepts were developed from codes and themes. RESULTS: The study identified 3 main themes in relation to cathinone use, effects, and toxicity. The first theme considered the modalities of intake of cathinones in relation to the derivative taken (mainly mephedrone, 3-methylmethcathinone, and methylenedioxypyrovalerone), route of administration (eyeballing, insufflation, smoking, intravenous, oral, rectal, and sublingual), multidrug use, and purity of the cathinone derivative. The second theme characterised the main effects of cathinones, that is, increased energy, euphoria, and empathogenic. Toxic effects were reported regarding the nervous system (anxiety, hallucinations, nervousness, and paranoia), cardiovascular system (angina, myocardial infarction, and tachycardia), skin (discolouration, itching, and allergy), and renal system (difficulty in urination). Drug-drug interactions were also reported including multiple drug use between cathinones, stimulants, depressants, and hallucinogens. CONCLUSIONS: The Internet discussion forums provide useful sources of information regarding the effects and toxicity of cathinones, which can be taken into account when assessing the safety of drugs. PMID- 28631398 TI - Transcatheter aortic valve replacement in a patient with Werner syndrome. PMID- 28631399 TI - Into the storm: Chasing the opportunistic pathogen Staphylococcus aureus from skin colonisation to life-threatening infections. AB - Colonisation of the human skin by Staphylococcus aureus is a precursor for a variety of infections ranging from boils to sepsis and pneumonia. The rapid emergence of methicillin-resistant S. aureus following the clinical introduction of this antimicrobial drug and reports of resistance to all currently used anti staphylococcal drugs has added to its formidable reputation. S. aureus survival on the skin and in vivo virulence is underpinned by a remarkable environmental adaptability, made possible by highly orchestrated regulation of gene expression and a capacity to undertake genome remodelling. Depending on the ecological or infection niche, controlled expression of a variety of adhesins can be initiated to facilitate adherence to extracellular matrix proteins, survival against desiccation or biofilm accumulation on implanted medical devices and host tissue. These adherence mechanisms complement toxin and enzyme production, immune evasion strategies, and antibiotic resistance and tolerance to collectively thwart efforts to develop reliable antimicrobial drug regimens and an effective S. aureus vaccine. PMID- 28631400 TI - Effects of uranium concentration on microbial community structure and functional potential. AB - Located in the Northern Territory of Australia, Ranger uranium mine is directly adjacent to the UNESCO World Heritage listed Kakadu National Park, with rehabilitation targets needed to ensure the site can be incorporated into the park following the mine's closure in 2026. This study aimed to understand the impact of uranium concentration on microbial communities, in order to identify and describe potential breakpoints in microbial ecosystem services. This is the first study to report in situ deployment of uranium-spiked sediments along a concentration gradient (0-4000 mg U kg-1 ), with the study design maximising the advantages of both field surveys and laboratory manipulative studies. Changes to microbial communities were characterised through the use of amplicon and shotgun metagenomic next-generation sequencing. Significant changes to taxonomic and functional community assembly occurred at a concentration of 1500 mg U kg-1 sediment and above. At uranium concentrations of >= 1500 mg U kg-1 , genes associated with methanogenic consortia and processes increased in relative abundance, while numerous significant changes were also seen in the relative abundances of genes involved in nitrogen cycling. Such alterations in carbon and nitrogen cycling pathways suggest that taxonomic and functional changes to microbial communities may result in changes in ecosystem processes and resilience. PMID- 28631401 TI - An Intrinsically Stretchable and Compressible Supercapacitor Containing a Polyacrylamide Hydrogel Electrolyte. AB - Stretchability and compressibility of supercapacitors is an essential element of modern electronics, such as flexible, wearable devices. Widely used polyvinyl alcohol-based electrolytes are neither very stretchable nor compressible, which fundamentally limits the realization of supercapacitors with high stretchability and compressibility. A new electrolyte that is intrinsically super-stretchable and compressible is presented. Vinyl hybrid silica nanoparticle cross-linkers were introduced into polyacrylamide hydrogel backbones to promote dynamic cross linking of the polymer networks. These cross-linkers serve as stress buffers to dissipate energy when strain is applied, providing a solution to the intrinsically low stretchability and compressibility shortcomings of conventional supercapacitors. The newly developed supercapacitor and electrolyte can be stretched up to an unprecedented 1000 % strain with enhanced performance, and compressed to 50 % strain with good retention of the initial performance. PMID- 28631402 TI - Authors' response to letter to the editor. PMID- 28631403 TI - Pseudomonas protegens Pf-5 favours self-produced siderophore over free-loading in interspecies competition for iron. AB - Many microorganisms compete for extracellular iron using strain-specific chelators known as siderophores. The ferric-siderophore complex limits local access to iron because import requires a suitable cognate receptor. Interestingly, many species carry receptors that enable 'cross-feeding' on heterologous siderophores made by neighboring organisms, although little is known about how this ubiquitous behaviour is regulated. Here, we investigated the soil bacterium Pseudomonas protegens Pf-5, a strain remarkable for its ability to use dozens of heterologous siderophores. We characterized the expression of six pyoverdine-type (PVD) siderophore receptors in response to their cognate PVD. In general, we found expression is tightly regulated to reflect availability of their cognate PVD. In contrast, Pf-5 continues to secrete its own primary siderophore, PVDPf-5 , despite the capability and opportunity to cross-feed. We demonstrate that this strategy is beneficial in co-culture with a competing PVDPAO1 -producer, P. aeruginosa PAO1. Although Pf-5 can cross-feed on PVDPAO1 , production of PVDPf-5 is required to maintain a competitive advantage. We attribute this to an antagonistic effect of PVDPf-5 on the growth of PAO1, presumably through limiting access to iron. Our results demonstrate the benefits of excluding competitors out-weigh the incentives associated with a free-loader lifestyle for Pf-5. PMID- 28631404 TI - Structural connectivity differences in motor network between tremor-dominant and nontremor Parkinson's disease. AB - Motor phenotypes of Parkinson's disease (PD) are recognized to have different prognosis and therapeutic response, but the neural basis for this clinical heterogeneity remains largely unknown. The main aim of this study was to compare differences in structural connectivity metrics of the main motor network between tremor-dominant and nontremor PD phenotypes (TD-PD and NT-PD, respectively) using probabilistic tractography-based network analysis. A total of 63 PD patients (35 TD-PD patients and 28 NT-PD patients) and 30 healthy controls underwent a 3 T MRI. Next, probabilistic tractography-based network analysis was performed to assess structural connectivity in cerebello-thalamo-basal ganglia-cortical circuits, by measuring the connectivity indices of each tract and the efficiency of each node. Furthermore, dopamine transporter single-photon emission computed tomography (DAT-SPECT) with 123 I-ioflupane was used to assess dopaminergic striatal depletion in all PD patients. Both PD phenotypes showed nodal abnormalities in the substantia nigra, in agreement with DAT-SPECT evaluation. In addition, NT-PD patients displayed connectivity alterations in nigro-pallidal and fronto-striatal pathways, compared with both controls and TD-PD patients, in which the same motor connections seemed to be relatively spared. Of note, in NT PD group, rigidity-bradykinesia score correlated with fronto-striatal connectivity abnormalities. These findings demonstrate that structural connectivity alterations occur in the cortico-basal ganglia circuit of NT-PD patients, but not in TD-PD patients, suggesting that these anatomical differences may underlie different motor phenotypes of PD. Hum Brain Mapp 38:4716-4729, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631405 TI - A Perylene-Based Polycyclic Aromatic Hydrocarbon Electron Donor for a Highly Efficient Solar Cell Dye. AB - The continuing efforts to develop novel polycyclic aromatic hydrocarbons and exploit them as building blocks to create organic donor-acceptor (D-A) dyes with impressive excited-state features should offer an excellent means by which to improve the power conversion efficiency (PCE) of dye-sensitized solar cells (DSSCs). To this end, a nonacyclic aromatic hydrocarbon, N-annulated benzoindenopentaphene (NBIP) was tethered with multiple solubilizing groups, including NBIPs with one 2-hexyldecyl, with one 2-hexyldecyloxy, and with four 4 hexylphenyl substituents. The side- and end-chain-functionalized NBIPs can be conveniently prepared in excellent yield, and further cross-coupled with 4-(7 ethynylbenzo[c][1,2,5]thiadiazol-4-yl)benzoic acid to afford a metal-free D-A dye, which achieves a high power conversion efficiency of 12.6 % under AM1.5G illumination in DSSCs without need for any coadsorbent. PMID- 28631407 TI - ZYGOTE-ARREST 3 that encodes the tRNA ligase is essential for zygote division in Arabidopsis. AB - In sexual organisms, division of the zygote initiates a new life cycle. Although several genes involved in zygote division are known in plants, how the zygote is activated to start embryogenesis has remained elusive. Here, we showed that a mutation in ZYGOTE-ARREST 3 (ZYG3) in Arabidopsis led to a tight zygote-lethal phenotype. Map-based cloning revealed that ZYG3 encodes the transfer RNA (tRNA) ligase AtRNL, which is a single-copy gene in the Arabidopsis genome. Expression analyses showed that AtRNL is expressed throughout zygotic embryogenesis, and in meristematic tissues. Using pAtRNL::cAtRNL-sYFP-complemented zyg3/zyg3 plants, we showed that AtRNL is localized exclusively in the cytoplasm, suggesting that tRNA splicing occurs primarily in the cytoplasm. Analyses using partially rescued embryos showed that mutation in AtRNL compromised splicing of intron-containing tRNA. Mutations of two tRNA endonuclease genes, SEN1 and SEN2, also led to a zygote-lethal phenotype. These results together suggest that tRNA splicing is critical for initiating zygote division in Arabidopsis. PMID- 28631406 TI - A cross-sectional analysis of Kenyan postabortion care services using a nationally representative sample. AB - OBJECTIVE: To assess quality of postabortion care (PAC) offered by Kenyan healthcare facilities. METHODS: A cross-sectional survey was conducted using data from the Incidence and Magnitude of Unsafe Abortions study, conducted among 326 PAC-providing healthcare facilities throughout Kenya from March 13 to June 30, 2012. Descriptive results with weighted proportions and an ordered probit model were used. RESULTS: Overall, 408 (41.8%) first-trimester PAC cases were treated using appropriate technology versus 826 (82.6%) second-trimester cases. Private healthcare facilities lagged behind public healthcare facilities on the use of appropriate technology: 264 (47.5%) public and 144 (33.1%) private facilities used such technology for first-trimester abortion, and 664 (89.6%) public versus 162 (68.8%) private for second-trimester abortions). Most healthcare facilities (251, 70.7%) had at least one provider trained in PAC. A total of 273 (80.7%) healthcare facilities reported offering contraception to all PAC patients, mainly short-acting methods. Delivery of PAC services depended on the availability of separate evacuation room (public level 2-3: odds ratio [OR] 22.93; public level 4 6: OR 77.14), and the number of family planning methods offered within the facility (public level 2-3: OR 1.38; public level 4-6 OR 1.57; private level 2-3: OR 2.27; private level 4-5: 4.89). CONCLUSION: Effective monitoring of PAC services, particularly among private healthcare facilities, might improve overall quality of services. PMID- 28631408 TI - Resonance frequency analysis of dental implants placed at the posterior maxilla varying the surface treatment only: A randomized clinical trial. AB - BACKGROUND: Chemical modifications of the dental implant surface that improve the wettability result in a faster and better osseointegration. PURPOSE: The aim of this randomized clinical trial was to evaluate the implant stability quotient (ISQ) of implants with similar designs, treated with 2 surfaces, sandblasted acid etched (SAE) and hydrophilic SAE, within the initial 16 weeks of healing. MATERIAL AND METHODS: A total of 64 implants (32 SAE-control group and 32 modified SAE-test group) with the same design, length, and diameter (conical and compressive, 4.3 * 10 mm) were inserted into the posterior maxillae of 21 patients partially edentulous. The ISQ values were collected at post-surgery (T0), 1 week (T1), 2 weeks (T2), 3 weeks (T3), 5 weeks (T4), 8 weeks (T5), 12 weeks (T6), and 16 weeks (T7). RESULTS: None of the implants failed. Test group presented ISQ values higher than the control group (ANOVA-P < .01) from T5 to T7. When comparing groups regarding the amount of time required to achieve ISQ >= 70 as a reference, there was a statistically significant difference (cox regression P < .01), and a hazard ratio of 2.24 (CI 1.62-3.11). At the 1-year follow-up, there was a drop out of 1 patient, and 2 implants were no longer evaluated. Survival rate for both groups was 100% at the 1-year follow-up. CONCLUSIONS: The current study suggests that implants with hydrophilic surface (modified SAE) integrate faster than implants with SAE surface. The stability gain of the test group was 2.24 times faster than the control group after 5 weeks of evaluation at the posterior region of the edentulous maxillae. PMID- 28631409 TI - Exploration of a ternary deep eutectic solvent of methyltriphenylphosphonium bromide/chalcone/formic acid for the selective recognition of rutin and quercetin in Herba Artemisiae Scopariae. AB - Methyltriphenylphosphonium bromide/chalcone/formic acid, a green ternary deep eutectic solvent, was applied as a functional monomer and dummy template simultaneously in the synthesis of a new molecularly imprinted polymer. Ternary deep eutectic solvent based molecularly imprinted polymers are used as a solid phase extraction sorbent in the separation and purification of rutin and quercetin from Herba Artemisiae Scopariae combined with high-performance liquid chromatography. Fourier transform infrared spectroscopy and field-emission scanning electron microscopy were applied to characterize the deep eutectic solvent based molecularly imprinted polymers synthesized using different molar ratios of chalcone. The static and competitive adsorption tests were performed to examine the recognition ability of the molecularly imprinted polymers to rutin and quercetin. The ternary deep eutectic solvent consisting of formic acid/chalcone/methyltriphenylphosphonium bromide (1:0.05:0.5) had the best molecular recognition effect. After optimization of the washing solvents (methanol/water, 1:9) and eluting solvents (acetonitrile/acetic acid, 9:1), a reliable analytical method was developed for strong recognition towards rutin and quercetin in Herba Artemisiae Scopariae with satisfactory extraction recoveries (rutin: 92.48%, quercetin: 94.23%). Overall, the chalcone ternary deep eutectic solvent-based molecularly imprinted polymer coupled with solid-phase extraction is an effective method for the selective purification of multiple bioactive compounds in complex samples. PMID- 28631410 TI - Coronary artery bypass grafting to treat coronary arterial occlusion incurred during orthotopic heart transplantation. AB - We report a case of left circumflex coronary artery occlusion sustained during orthotopic heart transplantation. Emergent coronary artery bypass grafting was performed, with recovery of cardiac function. The etiology and management of this complication are reviewed. PMID- 28631411 TI - Function of bacterial community dynamics in the formation of cadaveric semiochemicals during in situ carcass decomposition. AB - The decomposition of dead mammalian tissue involves a complex temporal succession of epinecrotic bacteria. Microbial activity may release different cadaveric volatile organic compounds which in turn attract other key players of carcass decomposition such as scavenger insects. To elucidate the dynamics and potential functions of epinecrotic bacteria on carcasses, we monitored bacterial communities developing on still-born piglets incubated in different forest ecosystems by combining high-throughput Illumina 16S rRNA sequencing with gas chromatography-mass spectrometry of volatiles. Our results show that the community structure of epinecrotic bacteria and the types of cadaveric volatile compounds released over the time course of decomposition are driven by deterministic rather than stochastic processes. Individual cadaveric volatile organic compounds were correlated with specific taxa during the first stages of decomposition which are dominated by bacteria. Through best-fitting multiple linear regression models, the synthesis of acetic acid, indole and phenol could be linked to the activity of Enterobacteriaceae, Tissierellaceae and Xanthomonadaceae, respectively. These conclusions are also commensurate with the metabolism described for the dominant taxa identified for these families. The predictable nature of in situ synthesis of cadaveric volatile organic compounds by epinecrotic bacteria provides a new basis for future chemical ecology and forensic studies. PMID- 28631412 TI - Psychopathology in pediatric bone marrow transplantation survivors and their mothers. AB - BACKGROUND: Bone marrow transplantation (BMT) is used to treat various hematologic, oncologic and metabolic diseases. While the treatment is lifesaving, it is also associated with anxiety, post-traumatic stress disorder, depression and psychosocial problems both in children and parents. METHODS: The aim of this study was to investigate the psychopathology in pediatric BMT survivors and their mothers compared with healthy controls. All children were interviewed using Kiddie Schedule for Affective Disorders and Schizophrenia to assess lifelong psychopathology. For the mothers, the Symptom Checklist-90-Revised (SCL-90-R) was used. RESULTS: In the BMT group, 17 children (63%) had at least one psychiatric disorder, while 15 (53.6%) did in the control group. Although lifelong prevalence of psychopathology in the BMT group did not differ significantly from the control group generally, anxiety disorders were significantly higher in the BMT group. When the SCL-90-R scores of the mothers were compared, Anxiety, Obsessive Compulsive, Interpersonal Sensitivity and Phobic Anxiety were significantly higher in the mothers in the BMT group, indicating more difficulty in these areas. CONCLUSIONS: Bone marrow transplantation is a significant stressor, especially for mothers. Clinicians should address the child and family as a whole in assessments and be aware of psychiatric symptoms in mothers and children who have had such a life-threatening condition. PMID- 28631413 TI - Young children seek out biased information about social groups. AB - Understanding the origins of prejudice necessitates exploring the ways in which children participate in the construction of biased representations of social groups. We investigate whether young children actively seek out information that supports and extends their initial intergroup biases. In Studies 1 and 2, we show that children choose to hear a story that contains positive information about their own group and negative information about another group rather than a story that contains negative information about their own group and positive information about the other group. In a third study, we show that children choose to present biased information to others, thus demonstrating that the effects of information selection can start to propagate through social networks. In Studies 4 and 5, we further investigate the nature of children's selective information seeking and show that children prefer ingroup-favouring information to other types of biased information and even to balanced, unbiased information. Together, this work shows that children are not merely passively recipients of social information; they play an active role in the creation and transmission of intergroup attitudes. PMID- 28631414 TI - Single-nucleotide polymorphisms in cachexia-related genes: Can they optimize the treatment of cancer cachexia? PMID- 28631415 TI - Highlights from the 9th Cachexia Conference. AB - This article highlights updates of pathways as well as pre-clinical and clinical studies into the field of wasting disorders that were presented at the 9th Cachexia Conference held in Berlin, Germany, December 2016. This year, some interesting results from clinical trials and different new therapeutic targets were shown. This article presents the biological and clinical significance of different markers and new diagnostic tools and cut-offs of detecting skeletal muscle wasting. Effective treatments of cachexia and wasting disorders are urgently needed in order to improve the patients' quality of life and their survival. PMID- 28631416 TI - Physical activity for the prevention and treatment of sarcopenic obesity. PMID- 28631417 TI - Response letter: Management of statin-induced myopathies: Much demands and still (almost) empty hands! PMID- 28631418 TI - The effects of Biodentine/polycaprolactone three-dimensional-scaffold with odontogenesis properties on human dental pulp cells. AB - AIM: To determine the feasibility of using three-dimensional printed Biodentine/polycaprolactone composite scaffolds for orthopaedic and dental applications. The physicochemical properties and the odontogenic differentiation of human dental pulp cells (hDPCs) were investigated. METHODOLOGY: Biodentine was well-suspended in ethanol and dropped slowly into molten polycaprolactone with vigorous stirring. The Biodentine/polycaprolactone composite scaffolds were then fabricated into controlled macropore sizes and structures using an extrusion based three-dimensional (3D) printer. The mechanical properties, bioactivity, and the proliferation and odontogenic differentiation of human dental pulp cells (hDPCs) cultured on the scaffolds were evaluated. RESULTS: Biodentine/polycaprolactone scaffolds had uniform macropores 550 MUm in size with established interconnections and a compressive strength of 6.5 MPa. In addition, the composite scaffolds exhibited a good apatite-forming ability and were capable of supporting the proliferation and differentiation of hDPCs. CONCLUSION: The composite scaffolds fabricated by an extrusion-based 3D printing technique had similar characteristics to Biodentine cement, including bioactivity and the ability to promote the differentiation of hDPCs. These results indicate that the composite scaffold would be a candidate for dental and bone regeneration. PMID- 28631419 TI - The CpxR/CpxA system contributes to Salmonella gold-resistance by controlling the GolS-dependent gesABC transcription. AB - Several regulatory systems contribute to bacterial resistance to heavy metals controlling the expression of factors required to eliminate the intoxicant and/or to repair the damage caused by it. In Salmonella, the response to Au ions is mediated by the specific metalloregulator GolS that, among other genes, controls the expression of the RND-efflux pump GesABC. In this work, we demonstrate that CpxR/CpxA, a main cell-envelope stress-responding system, promotes gesABC transcription in the presence of Au ions at neutral pH. Deletion of either cpxA or cpxR, or mutation of the CpxR-binding site identified upstream of the GolS operator in the gesABC promoter region reduces but does not abrogate the GolS- and Au-dependent activation of gesABC. Au also triggers the activation of the CpxR/CpxA system and deletion of the cpxRA operon severely reduces survival in the presence of the toxic metal. Our results indicate that the coordinated action of GolS and CpxR/CpxA contribute to protecting the cell from severe Au damage. PMID- 28631421 TI - Impact of synthetic cannabinoids on the duration of opioid-related withdrawal and craving among patients of addiction clinics in Kazakhstan: A prospective case control study. AB - OBJECTIVE: The aim of the study was to prospectively assess whether regular use of synthetic cannabinoids (SCs) affects the duration of opioid-related withdrawal and craving symptoms in patients undergoing drug detoxification treatments. METHODS: Patients (n = 193) with opioid use disorder, among which 47 patients are regularly using SCs, underwent integrated drug detoxification therapies. The Clinical Opiate Withdrawal Scale and a specific visual analogue scale were used to assess opioid withdrawal and craving symptoms over time. RESULTS: Subjects using SCs had significantly longer duration of withdrawal and craving symptoms (p < .001). Higher intake of SCs in the last 30 days (p = .045), shorter time since the last intake of SCs (p = .033), longer duration of SCs use (p < .001), and higher dosage of SCs (p < .001) were associated with longer duration of symptoms. DISCUSSION: This is the first study to assess the impact of SCs on the course of opioid withdrawal and craving symptoms. The results (a) suggest that patients with opioid use disorder in combination with regular use of SCs exhibit a significantly longer duration of opioid withdrawal and craving symptoms, (b) add to the accumulating evidence showing clinical and molecular cross talks between cannabinoids and opioids, and (c) underline novel harmful effects of SCs. PMID- 28631420 TI - Expression of PTEN-long mediated by CRISPR/Cas9 can repress U87 cell proliferation. AB - PTEN is a tumour suppressor that is frequently mutated in a variety of cancers. Hence, PTEN has significant potential as a therapeutic molecule. PTEN-long is an alternative translation variant, with an additional 173 amino acids added to the N-terminal of the canonical PTEN when CUG of the mRNA is utilized as the start codon. PTEN-long is secreted into serum and can re-enter cells throughout the body. One of the major barriers for gene therapy is to efficiently and specifically deliver DNA or RNA material to target cells. As an alternative approach, if a therapeutic protein can be directly delivered to target cell of interest, it should theoretically function well within the cells, particularly for genes that are deficiently expressed in vivo. Most therapeutic proteins are incapable of efficiently permeating the cell membrane. In this study, we have employed CRISPR/Cas9 gene editing tool combined with single-stranded template to edit CTG of PTEN-long to ATG in the genome. Two guide RNAs close to CTG site were found to have similar efficiency in driving PTEN-long expression. Furthermore, we detected PTEN-long expression in transfected whole-cell lysate and in concentrated culture media in Western blot. Interestingly, the culture media of PTEN-long expression can reduce Akt phosphorylation level and repress U87 cell proliferation compared to wild-type U87 or control media. Taken together, PTEN long driven by CRISPR/Cas9 imports and exports cells and represses nearby cell proliferation, indicating the PTEN-long generated by CRISPR/Cas9 has potential to be an alternative strategy for PTEN gene therapy. PMID- 28631422 TI - Dispersive micro-solid-phase extraction using carbon-based adsorbents for the sensitive determination of verapamil in plasma samples coupled with capillary electrophoresis. AB - A dispersive micro-solid-phase extraction procedure coupled with capillary electrophoresis ultraviolet detection was developed for determination of verapamil in plasma samples. Graphene oxide/polydopamin was synthesized by a one step polymerization method, and graphene oxide/Fe3 O4 (magnetic graphene oxide) nanocomposite was prepared by coprecipitation method. Moreover, they were fully characterized. The use of hazardous and water-immiscible solvents was scaled down, and only 500 MUL of acetone was required as the desorption solvent. The detector response concentration plots were linear in the range of 5-500 ng/mL, and the proposed method was validated according to guidelines. The precision and accuracy were less than 15%. Dispersive micro-solid-phase extraction method provides a rapid, environmentally friendly, and sensitive analysis for the verapamil in patient plasma samples, which is adequate for therapeutic drug monitoring and pharmacokinetic studies. PMID- 28631423 TI - Pet ownership increases human risk of encountering ticks. AB - We examined whether pet ownership increased the risk for tick encounters and tickborne disease among residents of three Lyme disease-endemic states as a nested cohort within a randomized controlled trial. Information about pet ownership, use of tick control for pets, property characteristics, tick encounters and human tickborne disease were captured through surveys, and associations were assessed using univariate and multivariable analyses. Pet owning households had 1.83 times the risk (95% CI = 1.53, 2.20) of finding ticks crawling on and 1.49 times the risk (95% CI = 1.20, 1.84) of finding ticks attached to household members compared to households without pets. This large evaluation of pet ownership, human tick encounters and tickborne diseases shows that pet owners, whether of cats or dogs, are at increased risk of encountering ticks and suggests that pet owners are at an increased risk of developing tickborne disease. Pet owners should be made aware of this risk and be reminded to conduct daily tick checks of all household members, including the pets, and to consult their veterinarian regarding effective tick control products. PMID- 28631424 TI - Unsuccessful treatment of progressive macular hypomelanosis with oral isotretinoin. PMID- 28631425 TI - Retraction Statement: Mitochondrial protein acetylation mediates nutrient sensing of mitochondrial protein synthesis and mitonuclear protein balance. AB - : IUBMB Life (2014) 66:793-802. DOI: 10.1002/iub.1328 The above article, published online on November 15, 2014 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal's Editors-in-Chief, Angelo Azzi and William J. Whelan, Corresponding Author Tina Wenz, the University of Cologne, and Wiley Periodicals, Inc. The article has been retracted on request of the University of Cologne that, after an investigation, established that the data reported in it are not reproducible. Note from the Corresponding Author: "The paper reports on the influence of mitochondrial acetylation on protein synthesis. After publication, several irregularities appeared and have been thoroughly investigated by the lab of the Corresponding Author in cooperation with the commission of Research integrity of the University of Cologne. Both came to the conclusion that data used for the publication are erroneous and that the presented data are not reproducible by the lab of the Corresponding Author and other labs. The Corresponding Author takes responsibility and regrets not having detected these issues before publication. The appropriate corrective action is retraction of the paper. The Corresponding Author apologizes to the scientific community." REFERENCE: Antonella Di Domenico, Annette Hofer, Federica Tundo, Tina Wenz (2014), Mitochondrial protein acetylation mediates nutrient sensing of mitochondrial protein synthesis and mitonuclear protein balance, IUBMB Life. 66: 793-802, 2014. DOI: 10.1002/iub.1328 (c) 2017 IUBMB Life, 69(7):553-553, 2017. PMID- 28631426 TI - Hsp90alpha regulates ATM and NBN functions in sensing and repair of DNA double strand breaks. AB - The molecular chaperone heat shock protein 90 (Hsp90alpha) regulates cell proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90alpha ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90alpha and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. Here, we show that ataxia telangiectasia-mutated kinase (ATM) and nibrin (NBN), but not 53BP1, RAD50, and MRE11, are Hsp90alpha clients as the Hsp90alpha inhibitor 17-(allylamino)-17 demethoxygeldanamycin (17-AAG) induces ATM and NBN polyubiquitination and proteosomal degradation in normal fibroblasts and lymphoblastoid cell lines. Hsp90alpha-ATM and Hsp90alpha-NBN complexes are present in unstressed and irradiated cells, allowing the maintenance of ATM and NBN stability that is required for the MRE11/RAD50/NBN complex-dependent ATM activation and the ATM dependent phosphorylation of both NBN and Hsp90alpha in response to IR-induced DNA double-strand breaks (DSBs). Hsp90alpha forms a complex also with ph-Ser1981 ATM following IR. Upon phosphorylation, NBN dissociates from Hsp90alpha and translocates at the DSBs, while phThr5/7-Hsp90alpha is not recruited at the damaged sites. The inhibition of Hsp90alpha affects nuclear localization of MRE11 and RAD50, impairs DDR signaling (e.g., BRCA1 and CHK2 phosphorylation), and slows down DSBs repair. Hsp90alpha inhibition does not affect DNA-dependent protein kinase (DNA-PK) activity, which possibly phosphorylates Hsp90alpha and H2AX after IR. Notably, Hsp90alpha inhibition causes H2AX phosphorylation in proliferating cells, this possibly indicating replication stress events. Overall, present data shed light on the regulatory role of Hsp90alpha on the DDR, controlling ATM and NBN stability and influencing the DSBs signaling and repair. PMID- 28631429 TI - Journal of the American Geriatrics Society: Evolving Strategies and Processes. PMID- 28631428 TI - An Unremarkable Past History. PMID- 28631430 TI - Internal cyclopexy for complicated traumatic cyclodialysis cleft. AB - PURPOSE: To assess the surgical and functional outcome of internal direct cyclopexy as therapy of complicated traumatic cyclodialysis. METHODS: The single centre interventional case-series study included eyes with traumatic cyclodialysis who had consecutively been treated. Internal cyclopexy was performed using double-armed sutures introduced into the eye through the pars plana opposite to the cyclodialysis cleft and which were laid parallel to limbus. Additional procedures included cataract surgery, and pars plana vitrectomy. The cyclodialysis was documented upon ultrasound biomicroscopy and gonioscopy. RESULTS: The study included 44 patients (44 eyes). The cyclodialysis extended over 4.8 +/- 3.2 clock hours of scleral spur circumference (range 1-12 hr, median 4 hr), involving >180 degrees of the scleral spur circumference in 16 eyes (37%) and 360 degrees in 3 eyes (7%). Besides cyclodialysis, additional trauma-related complications included hyphema, iridodialysis, lens dislocation, cataract, vitreous haemorrhage, retinal detachment, suprachoroidal haemorrhage and endophthalmitis. The surgery performed on average at 64 days after the trauma included a mean number of 4.6 +/- 1.9 sutures (range: 2-9), with 1.2 sutures per 30 degrees width of cyclodialysis. Mean follow-up was 32 +/- 8 weeks (range: 6 51 weeks). Closure of the cyclodialysis was achieved in all 44 eyes, and intraocular pressure (IOP) increased from 8.0 +/- 3.4 mmHg (range: 3 21 mmHg) to 14.4 +/- 4.0 mmHg (range: 11-21 mmHg). Mean visual acuity (VA) improved from 2.3 +/- 1.1 logMAR (range: 0.22-4.0) to 1.2 +/- 0.8 logMAR (range 0.3-4.0 logMAR). CONCLUSION: In conclusion, internal direct cyclopexy is a novel and relatively little invasive surgery technique for the repair of traumatic cyclodialysis. PMID- 28631431 TI - Phaeohyphomycosis breast masquerading as fibroadenoma in a young teenage girl. AB - Phaeohyphomycosis is an unusual granulomatous fungal infection, observed in immunocompromised or diabetic patients; however, it is even rarer in immunocompetent patients. Cytological findings of the same have been infrequently reported. The histopathological diagnosis or fungal culture helps in definitive diagnosis to identify the exact fungal species. Hereby, we report a rare case of invasive fungal infection in a breast lump in a young female, presenting as fibroadenoma breast. Fine needle aspiration cytology from the breast lesion showed the presence of septate acute-angled branching fungal hyphae with focal pigmentation, morphologically suggestive of phaeohyphomycosis which was positive with fungal stains. This was later confirmed on biopsy as histopathology slides showed the presence of prominent pigmented fungal hyphae. The pus culture from needle aspirate also showed phaeohyphomycotic fungal organism delineating the species Exophiala dermatitidis. Aspiration cytology is crucial for the diagnosis of fungal infection in such cases. An appropriate diagnosis will help in early detection and treatment of such infections as these are usually associated with high morbidity and mortality. PMID- 28631432 TI - Profile, effects, and toxicity of novel psychoactive substances: A systematic review of quantitative studies. AB - OBJECTIVE: To investigate the profile, effects, and toxicity of novel psychoactive substances (NPS). METHODS: A systematic literature review was conducted between May 2015 and February 2016 and included 19 databases. Search terms included "novel psychoactive substance(s)," "effect(s)," and "toxicity" and their synonyms. Studies included were those from any country, in any language, and between January 2007 and April 2015. Studies published before 2007 and those regarding the synthesis of NPS were excluded. Data were extracted by evaluating the titles, abstract, and full text, respectively. Consequently, the extraction yielded 20 studies. RESULTS: Forty-three NPS derivatives of 8 main pharmacological classes were identified. NPS were mostly used among young adults and adults within the age range of 16-64 years old. Cathinones and synthetic cannabinoids were the most prevalent among the aforementioned classes. The main desired effects of NPS use were empathy and increased ability to socialise. Reported toxicity associated with the use of NPS included cardiovascular, neurological, and psychoactive adverse reactions. CONCLUSIONS: Despite the unique subjective effects associated with the use of NPS, harmful effects could be severe and/or lethal. Therefore, there is a need to develop research in the area of NPS and promote awareness among healthcare professionals. PMID- 28631433 TI - Forensic Radiology Pitfalls: CT Imaging in Gunshot Wounds of the Head. AB - Computed tomography (CT) imaging is increasingly used in emergency departments and trauma services and is being offered as a supplemental tool with autopsy in coroner's and medical examiner's offices throughout the United States. The availability of CT images in lieu of traditional X-rays for medicolegal autopsies may lead to misinterpretation of images for forensic pathologists who are not familiar with these types of images. Forensic pathologists must become familiar with CT imaging, the basis of CT image formation and how to interpret CT images appropriately. We highlight potential pitfalls of CT image interpretation through two cases of fatal gunshot wounds of the head. Antemortem CT imaging available at the time of autopsy led to discrepancy between the initial image findings and the autopsy due to inexperienced manipulation of the images. With appropriate understanding of CT image interpretation and manipulation, forensic personnel should be able to avoid most sources of misinterpretation. PMID- 28631434 TI - Survival of spray-dried and free-cells of potential probiotic Lactobacillus plantarum 564 in soft goat cheese. AB - A high viability of probiotics in food product, with a living cells threshold of 107 /cfu/g (colony-forming units/g) is a challenge to achieve in food production. Spray drying is an efficient and economic industrial method for probiotic bacterial preservation and its application in food products. In this study, the survival of free and spray-dried cells of potential probiotic strain Lactobacillus plantarum 564 after production and during 8 weeks of storage of soft acid coagulated goat cheese was investigated, as well as compositional and sensory quality of cheese. Total bacterial count of spray-dried Lb. plantarum 564 cells were maintained at the high level of 8.82 log/cfu/g in cheese after 8 weeks of storage, while free-cell number decreased to 6.9 log/cfu/g. However, the chemical composition, pH values and sensory evaluation between control cheese (C1 sample made with commercial starter culture) and treated cheese samples (C2 and C3, made with the same starter, with the addition of free and spray-dried Lb. plantarum 564 cells, respectively) did not significantly differ. High viability of potential probiotic bacteria and acceptable sensory properties indicate that spray-dried Lb. plantarum 564 strain could be successfully used in the production of soft acid coagulated goat cheeses. PMID- 28631435 TI - Polar Intermetallics Pr5 Co2 Ge3 and Pr7 Co2 Ge4 with Planar Hydrocarbon-Like Metal Clusters. AB - Planar hydrocarbon-like metal clusters may foster new insights linking organic molecules with conjugated pi-pi bonding interactions and inorganic structures in terms of their bonding characteristics. However, such clusters are uncommon in polar intermetallics. Herein, we report two polar intermetallic phases, Pr5 Co2 Ge3 and Pr7 Co2 Ge4 , both of which feature such planar metal clusters, namely, ethylene-like [Co2 Ge4 ] clusters plus the concatenated forms and polyacene-like [Co2 Ge2 ]n ribbons in Pr5 Co2 Ge3 , and 1,2,4,5-tetramethylbenzene-like [Co4 Ge6 ] cluster in Pr7 Co2 Ge4 . Just as in the related planar organic structures, these metal-metalloid species are dominated by covalent bonding interactions. Both compounds magnetically order at low temperature with net ferromagnetic components: Pr5 Co2 Ge3 through a series of transitions below 150 K and Pr7 Co2 Ge4 through a single ferromagnetic transition at 19 K. Spin-polarized electronic structure calculations for Pr7 Co2 Ge4 reveal strong spin-orbit coupling within Pr and considerable magnetic contributions from Co atoms. This work suggests that similar structural chemistry can emerge for other rare-earth/late-transition metal/main-group systems. PMID- 28631436 TI - Characterization of a novel p110beta-specific inhibitor BL140 that overcomes MDV3100-resistance in castration-resistant prostate cancer cells. AB - BACKGROUND: Our previous studies demonstrated that the class IA PI3K/p110beta is critical in castration-resistant progression of prostate cancer (CRPC) and that targeting prostate cancer with nanomicelle-loaded p110beta-specific inhibitor TGX221 blocked xenograft tumor growth in nude mice, confirming the feasibility of p110beta-targeted therapy for CRPCs. To improve TGX221's aqueous solubility, in this study, we characterized four recently synthesized TGX221 analogs. METHODS: TGX221 analog efficacy were examined in multiple prostate cancer cell lines with the SRB cell growth assay, Western blot assay for AKT phosphorylation and cell cycle protein levels. Target engagement with PI3K isoforms was evaluated with cellular thermal shift assay. PI3K activity was determined with the Kinase-Glo Plus luminescent kinase assay. Cell cycle distribution was evaluated with flow cytometry after propidium iodide staining. RESULTS: As expected, replacing either one of two major functional groups in TGX221 by more hydrophilic groups dramatically improved the aqueous solubility (about 40-fold) compared to TGX221. In the CETSA assay, all the analogs dramatically shifted the melting curve of p110beta protein while none of them largely affected the melting curves of p110alpha, p110gamma, or Akt proteins, indicating target-specific engagement of these analogs with p110beta protein. However, functional evaluation showed that only one of the analogs BL140 ubiquitously inhibited AKT phosphorylation in all CRPC cell lines tested with diverse genetic abnormalities including AR, PTEN, and p53 status. BL140 was superior than GSK2636771 (IC50 5.74 vs 20.49 nM), the only p110beta-selective inhibitor currently in clinical trials, as revealed in an in vitro Kinase-Glo assay. Furthermore, BL140 exhibited a stronger inhibitory effect than GSK2636771 on multiple CRPC cell lines including a MDV3100-resistant C4-2B cell subline, indicating BL140 elimination of MDV3100 resistance. Mechanistic studies revealed that BL140 blocked G1 phase cell cycle entry by reducing cyclin D1 but increasing p27kip1 protein levels. CONCLUSION: These studies suggested that BL140 is a promising p110beta-specific inhibitor with multiple superb properties than GSK2636771 worthy for further clinical development. PMID- 28631438 TI - Foot health of nurses-A cross-sectional study. AB - AIM: To analyze the level of nurses' foot health and its associations with work well-being. METHODS: A descriptive, cross-sectional study design was applied to a random sample of Finnish nurses (n = 411). The data were collected between May 18 and June 21, 2015 using a self-administered Foot Health Assessment Instrument and analyzed using descriptive statistics and parametric tests. RESULTS: Nurses had a variety of foot problems. Dry skin, foot pain, and corns or calluses were the most prevalent foot problems. Long-term diseases, the need for a physician's appointment due to foot problems, and decreased working ability were all associated with foot health. This finding was also supported by multivariate analysis. CONCLUSIONS: Foot problems are common among nurses and are associated with individual and work-related factors. Prevention of foot problems in nurses should be prioritized to promote their working ability and predisposing factors identified as potential intervention targets. PMID- 28631439 TI - One vowel or two? Diphthongs, digraphs, ligatures, and diaereses, oh my! AB - This is the first in a short series about orthography in anatomical Latin. Although phonology is an important aspect of diphthongs and digraphs, the focus here is on spelling, not the more complicated topic of pronunciation. Recommendations are made for standard spellings of words that contain or may appear to contain diphthongs in Latin anatomical words or their ancient Greek sources. Ligatures and diaereses (typographical symbols that were developed after the classical period) are not recommended for use in anatomical Latin terms. Clin. Anat. 30:1013-1016, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28631440 TI - Recognition cascade and metabolite transfer in a marine bacteria-phytoplankton model system. AB - The trophic linkage between marine bacteria and phytoplankton in the surface ocean is a key step in the global carbon cycle, with almost half of marine primary production transformed by heterotrophic bacterioplankton within hours to weeks of fixation. Early studies conceptualized this link as the passive addition and removal of organic compounds from a shared seawater reservoir. Here, we analysed transcript and intracellular metabolite patterns in a two-member model system and found that the presence of a heterotrophic bacterium induced a potential recognition cascade in a marine phytoplankton species that parallels better-understood vascular plant response systems. Bacterium Ruegeria pomeroyi DSS-3 triggered differential expression of >80 genes in diatom Thalassiosira pseudonana CCMP1335 that are homologs to those used by plants to recognize external stimuli, including proteins putatively involved in leucine-rich repeat recognition activity, second messenger production and protein kinase cascades. Co cultured diatoms also downregulated lipid biosynthesis genes and upregulated chitin metabolism genes. From differential expression of bacterial transporter systems, we hypothesize that nine diatom metabolites supported the majority of bacterial growth, among them sulfonates, sugar derivatives and organic nitrogen compounds. Similar recognition responses and metabolic linkages as observed in this model system may influence carbon transformations by ocean plankton. PMID- 28631441 TI - Genetic landscape and deregulated pathways in B-cell lymphoid malignancies. AB - With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We will detail recurrent alterations affecting important signalling pathways, that is the B-cell receptor/NF-kappaB pathway, NOTCH signalling, JAK-STAT signalling, p53/DNA damage response, apoptosis and cell cycle regulation, as well as other perhaps unexpected cellular processes, such as immune regulation, cell migration, epigenetic regulation and RNA processing. Whilst many of these pathways/processes are commonly altered in different lymphoid tumors, albeit at varying frequencies, others are preferentially targeted in selected B-cell malignancies. Some of these genetic lesions are either involved in disease ontogeny or linked to the evolution of each disease and/or specific clinicobiological features, and some of them have been demonstrated to have prognostic and even predictive impact. Future work is especially needed to understand the therapy-resistant disease, particularly in patients treated with targeted therapy, and to identify novel targets and therapeutic strategies in order to realize true precision medicine in this clinically heterogeneous patient group. PMID- 28631437 TI - Control of virulence gene transcription by indirect readout in Vibrio cholerae and Salmonella enterica serovar Typhimurium. AB - Indirect readout mechanisms of transcription control rely on the recognition of DNA shape by transcription factors (TFs). TFs may also employ a direct readout mechanism that involves the reading of the base sequence in the DNA major groove at the binding site. TFs with winged helix-turn-helix (wHTH) motifs use an alpha helix to read the base sequence in the major groove while inserting a beta sheet 'wing' into the adjacent minor groove. Such wHTH proteins are important regulators of virulence gene transcription in many pathogens; they also control housekeeping genes. This article considers the cases of the non-invasive Gram negative pathogen Vibrio cholerae and the invasive pathogen Salmonella enterica serovar Typhimurium. Both possess clusters of A + T-rich horizontally acquired virulence genes that are silenced by the nucleoid-associated protein H-NS and regulated positively or negatively by wHTH TFs: for example, ToxR and LeuO in V. cholerae; HilA, LeuO, SlyA and OmpR in S. Typhimurium. Because of their relatively relaxed base sequence requirements for target recognition, indirect readout mechanisms have the potential to engage regulatory proteins with many more targets than might be the case using direct readout, making indirect readout an important, yet often ignored, contributor to the expression of pathogenic phenotypes. PMID- 28631443 TI - ? PMID- 28631444 TI - ? PMID- 28631445 TI - ? PMID- 28631442 TI - Osteoblast migration in vertebrate bone. AB - Bone formation, for example during bone remodelling or fracture repair, requires mature osteoblasts to deposit bone with remarkable spatial precision. As osteoblast precursors derive either from circulation or resident stem cell pools, they and their progeny are required to migrate within the three-dimensional bone space and to navigate to their destination, i.e. to the site of bone formation. An understanding of this process is emerging based on in vitro and in vivo studies of several vertebrate species. Receptors on the osteoblast surface mediate cell adhesion and polarization, which induces osteoblast migration. Osteoblast migration is then facilitated along gradients of chemoattractants. The latter are secreted or released proteolytically by several cell types interacting with osteoblasts, including osteoclasts and vascular endothelial cells. The positions of these cellular sources of chemoattractants in relation to the position of the osteoblasts provide the migrating osteoblasts with tracks to their destination, and osteoblasts possess the means to follow a track marked by multiple chemoattractant gradients. In addition to chemotactic cues, osteoblasts sense other classes of signals and utilize them as landmarks for navigation. The composition of the osseous surface guides adhesion and hence migration efficiency and can also provide steering through haptotaxis. Further, it is likely that signals received from surface interactions modulate chemotaxis. Besides the nature of the surface, mechanical signals such as fluid flow may also serve as navigation signals for osteoblasts. Alterations in osteoblast migration and navigation might play a role in metabolic bone diseases such as osteoporosis. PMID- 28631447 TI - ? PMID- 28631446 TI - ? PMID- 28631448 TI - ? PMID- 28631449 TI - ? PMID- 28631450 TI - ? PMID- 28631451 TI - Accuracy of transcutaneous laryngeal ultrasound for detecting vocal cord paralysis in the immediate postoperative period after total thyroidectomy. AB - BACKGROUND: Transcutaneous laryngeal ultrasound (TLUS) has emerged as a promising imaging tool for vocal cord examination in patients undergoing thyroid surgery. The focus of this prospective, double-blind study was to assess the accuracy of TLUS in the diagnosis of vocal cord paralysis in the immediate postoperative period following total thyroidectomy. METHODS: The study included 93 patients undergoing total thyroidectomy and assessed by videostrobolaryngoscopy (VSL) and TLUS. VSL was carried out the day before surgery and was repeated at 4 days postoperatively. TLUS was performed before surgery in the preanesthesia holding area and at completion of the procedure in the postanesthesia care unit. The preoperative and postoperative TLUS results were correlated with those of VSL. The statistical analysis included the sensitivity, specificity, positive predictive value, and negative predictive value (with 95% CI) of TLUS for detecting vocal cord paralysis. RESULTS: The visualization rate associated with TLUS was 93%. The total vocal cord paralysis rate was 16.1%. The performance of TLUS for diagnosing this condition was as follows: sensitivity, 93.3% (95% CI: 77.3-100%); specificity 96.1% (95% CI: 91.2-100%); positive predictive value, 82.3% (95% CI: 61.2-100%); negative predictive value, 98.6% (95% CI, 95.4-100%). CONCLUSIONS: TLUS may be a suitable technique for detecting vocal cord paralysis shortly after total thyroidectomy. PMID- 28631452 TI - The impact of the anesthetic conserving device on occupational exposure to isoflurane among intensive care healthcare professionals. AB - BACKGROUND: Use of anesthetic conserving devices (ACD) for inhalational isoflurane sedation in Intensive Care Units (ICU) has grown in recent years, and healthcare professionals are concerned about isoflurane pollution and exposure related health risks. Real-time measurements to determine isoflurane exposure in ICU personnel during short-term patient care procedures and ACD handling have not yet been performed. METHODS: Isoflurane concentrations in the breathing zones of ICU staff (25 cm around the nose and mouth) were measured, by photoacoustic gas monitoring, during daily practice including tracheal suctioning, oral hygiene, body care, and patient positioning. Isoflurane pollution was further determined during ACD replacement, syringe filling, and after isoflurane spillages. RESULTS: The average mean isoflurane concentration 25 cm above patients' tracheostoma was 0.3 ppm. Mean (cmean) and maximum (cmax) isoflurane exposure in personnel's breathing zones during patient care ranged from 0.4 to 1.9 ppm and 0.7 to 6.6 ppm, respectively. Isoflurane exposure during ACD replacement was cmean 0.5 to 17.4 ppm and cmax 0.8 to 114.3 ppm. Isoflurane concentrations during ACD syringe filling ranged from 2.4 to 9.1 ppm. The maximum isoflurane concentrations after spillage were dose-dependent. CONCLUSIONS: Use of ACDs and patient physical manipulation are accompanied by isoflurane pollution. Baseline concentrations did not exceed long-term exposure limits, but short-term limits were occasionally exceeded during patient care procedures and ACD handling. Spillages should be avoided, especially when air-conditioning and scavenging systems are unavailable. PMID- 28631453 TI - Propofol-dexmedetomidine versus propofol-remifentanil conscious sedation for awake craniotomy during epilepsy surgery. AB - BACKGROUND: Conscious sedation during awake craniotomy requires balanced anesthesia technique to achieve optimum sedation and analgesia. This technique should be done without causing respiratory depression or loss of consciousness. The present study aimed at evaluating the effect of propofol-dexmedetomidine versus propofol-remifentanil conscious sedation during awake craniotomy for epilepsy surgery. METHODS: Sixty patients undergoing awake craniotomy for epilepsy surgery were randomly divided into two groups, PD group and PR group. Thirty patients were included in each group. Patients in PD group received propofol and dexmedetomidine intravenous infusion and patients in PR group received propofol and remifentanil intravenous infusion for conscious sedation. Sedation Score, patients' satisfaction, surgeons' satisfaction, heart rate, mean arterial blood pressure, and oxygen saturation were recorded. Side effects such as respiratory depression, nausea, vomiting, airway obstruction, and oxygen desaturation were also recorded. RESULTS: Sedation Score was higher in PR group compared to PD group (P<0.05). There were no significant differences in patients' satisfaction scores between both groups. The heart rate was lower in the PD group compared to the PR group (P<0.05). The incidences of nausea, vomiting, oxygen desaturation and respiratory depression were statistically higher in PR group compared to PD group (P<0.05). CONCLUSIONS: Propofol-dexmedetomidine combination is as effective as propofol-remifentanil combination but with fewer side effects for conscious sedation during awake craniotomy for epilepsy surgery. PMID- 28631454 TI - Quality of recovery after gastroscopy, colonoscopy, or both endoscopic procedures: an observational pilot study. AB - BACKGROUND: Gastroscopy and colonoscopy are procedures with low complication rates and patients are usually discharged few hours after the procedures. Nevertheless, postoperative cognitive decline is a common condition, is often missed, and can potentially affect patients' ability to drive and undertake other daily living activities. The primary aim was to assess the incidence of failure to recover at Day 1 after either colonoscopy, gastroscopy, or both procedures combined. METHODS: In an observational pilot study, participants of 18 years or above undergoing endoscopy procedures, including colonoscopy (reference group), gastroscopy, or both, were included. Postoperative quality of recovery was measured over a 1-month period using the "Postoperative Quality of Recovery Scale" assessing recovery in five subdomains. RESULTS: In total, 102 participants were enrolled, comprised of 53 colonoscopy participants, 28 gastroscopy participants, and 21 "combined" participants. At Day 1, overall recovery in the colonoscopy group was 57%, compared to 45% in the gastroscopy group with an odds ratio of 1.6 (95% CI 0.5-4.9) and 40% in the "combined" group with an odds ratio of 2.0 (95% CI 0.6-6.9). Failure to recover was mainly due to failure in nociceptive and cognitive recovery at Day 1, which were 76% and 79% for colonoscopy participants, respectively, 61% and 84% for gastroscopy participants, compared with 63% and 60% for the "combined" group, respectively. CONCLUSIONS: This study showed that incomplete recovery is common past discharge after gastroscopy, colonoscopy, or both procedures and the study demonstrated modest but clinically important differences in early quality of recovery between the procedures. PMID- 28631456 TI - Comparison between adenosine and magnesium sulphate as adjuvants for transversus abdominis plane block: a prospective randomized controlled trial. AB - BACKGROUND: Various adjuvants have been employed during different nerve blocks. We aimed to evaluate the effect of adding adenosine versus magnesium sulfate to bupivacaine on the quality and duration of transversus abdominis plane (TAP) block. METHODS: Participants were randomized to TAP block using either 20 mL of bupivacaine hydrochloride 0.375% + 12 mg adenosine in 2 mL of saline 0.9% (adenosine group), 20 mL of bupivacaine hydrochloride 0.375% + 500 mg magnesium sulphate in 2 mL saline 0.9% (magnesium group) or 20 mL of bupivacaine hydrochloride 0.375% + 2 mL saline 0.9% (control group). Primary outcome measure included postoperative pain as assessed by Visual Analog Scale (VAS) for pain scoring on movement and secondary outcomes included analgesia duration, postoperative morphine need and any adverse effects. RESULTS: VAS in adenosine and magnesium groups was significantly less than in control group at 6 and 12 hours postoperatively whereas it was comparable in adenosine and magnesium groups at all time points. Analgesia duration was significantly longer in adenosine and magnesium groups in comparison to the control group and it was relatively longer in the magnesium group when compared to adenosine group (401 vs. 447 vs. 320 minutes in adenosine, magnesium and control groups, respectively; P=0.003). CONCLUSIONS: Both adenosine and magnesium improved the quality and duration of TAP block, but the duration was relatively longer with magnesium. PMID- 28631457 TI - Time to monitor cuff pressures and to start "thinking supraglottic". PMID- 28631458 TI - Pediatric tracheostomy: perhaps good things come to those who do not wait. PMID- 28631459 TI - Could the new ultrasound-guided erector spinae plane block be a valid alternative to paravertebral block in chronic chest pain syndromes? PMID- 28631460 TI - Changing the Italian rules on the legal representative: the Cirinna Act. PMID- 28631461 TI - Extracorporeal CO2 removal in the ICU: an effective treatment awaiting proper indications. PMID- 28631455 TI - The prognostic importance of chronic end-stage diseases in geriatric patients admitted to 163 Italian ICUs. AB - BACKGROUND: The number of elderly patients undergoing major surgical interventions and then needing admission to intensive care unit (ICU) grows steadily. We investigated this issue in a cohort of 232,278 patients admitted in five years (2011-2015) to 163 Italian general ICUs. METHODS: Surgical patients older than 75 registered in the GiViTI MargheritaPROSAFE project were analyzed. The impact on hospital mortality of important chronic conditions (severe COPD, NYHA class IV, dementia, end-stage renal disease, cirrhosis with portal hypertension) was investigated with two prognostic models developed yearly on patients staying in the ICU less or more than 24 hours. RESULTS: 44,551 elderly patients (19.2%) underwent emergency (47.3%) or elective surgery (52.7%). At least one severe comorbidity was present in 14.6% of them, yielding a higher hospital mortality (32.4%, vs. 21.1% without severe comorbidity). In the models for patients staying in the ICU 24 hours or more, cirrhosis, NYHA class IV, and severe COPD were constant independent predictors of death (adjusted odds ratios [ORs] range 1.67-1.97, 1.54-1.91, and 1.34-1.50, respectively), while dementia was statistically significant in four out of five models (adjusted ORs 1.23 1.28). End-stage renal disease, instead, never resulted to be an independent prognostic factor. For patients staying in the ICU less than 24 hours, chronic comorbidities were only occasionally independent predictors of death. CONCLUSIONS: Our study confirms that elderly surgical patients represent a relevant part of all ICUs admissions. About one of seven bear at least one severe chronic comorbidity, that, excluding end-stage renal disease, are all strong independent predictors of hospital death. PMID- 28631462 TI - Thoracic trauma and acute respiratory distress syndrome: mind the link! PMID- 28631463 TI - Anesthesia for endovascular neuroradiology: accepting the challenge. PMID- 28631464 TI - Cognitive resistance towards videolaryngoscopy... and why Macintosh refuses to die. PMID- 28631465 TI - Interfacial Investigation on Printable Carbon-Based Mesoscopic Perovskite Solar Cells with NiOx/C Back Electrode. AB - Solar cells with high efficiency, low cost, and high stability are the target for the new generation of solar cells. A fully printable perovskite (CH3NH3PbI3) solar cell (PSC) with device architecture FTO/TiO2/Al2O3/NiOx/C is fabricated in the current research as a low-cost and relatively stable structure and is investigated to determine how different fabrication factors such as the thickness of the insulating spacer layer (Al2O3) or treatments such as heat and UV-O3 treatments can affect the interfacial properties of this multilayer mesoporous structure. X-ray photoelectron spectra (XPS) show that UV-O3 treatment increases the Ni3+(Ni2O3) phase on the surface of the black nickel oxide layer leading to better charge extraction and increasing open-circuit voltage (VOC) up to 0.945 V. We observe improved CH3NH3PbI3 formation inside the mesoporous layers by the PbI2 penetration at a higher temperature. Impedance spectral together with current voltage measurements show the effect of thickness for the insulator layer in the internal and interfacial resistances and photovoltaic characteristics of the cell. The best performance of the carbon-based PSC attains power conversion efficiency of 12.1% with the thickness of the Al2O3 layer at 450 nm. PMID- 28631466 TI - Enhancing the Performance of Polymer Solar Cells by Using Donor Polymers Carrying Discretely Distributed Side Chains. AB - Conjugated polymers with three components, P1-1 and P1-2, were prepared by one pot Stille polymerization. The two-component polymer P1-0 is only composed of a 5 fluoro-6-alkyloxybenzothiadiazole (AFBT) acceptor unit and a thiophene donor unit, while the three-component polymers P1-1 and P1-2 contain 10% and 20% 5,6 difluorobenzothiadiazole (DFBT), respectively, as the third component. The incorporation of the third component, 5,6-difluorobenzothiadiazole, makes the side chains discretely distributed in the polymer backbones, which can enhance the pi-pi stacking of polymers in film, markedly increase the hole mobility of active layers, and improve the power-conversion efficiency (PCE) of devices. Influence of the third component on the morphology of active layer was also studied by X-ray diffraction (XRD), resonant soft X-ray scattering (R-SoXS), and transmission electron microscopy (TEM) experiments. P1-1/PC71BM-based PSCs gave a high PCE up to 7.25%, whereas similarly fabricated devices for P1-0/PC71BM only showed a PCE of 3.46%. The PCE of P1-1/PC71BM-based device was further enhanced to 8.79% after the use of 1,8-diiodooctane (DIO) as the solvent additive. Most importantly, after the incorporation of 10% 5,6-difluorobenzothiadiazole unit, P1 1 exhibited a marked tolerance to the blend film thickness. Devices with a thickness of 265 nm still showed a PCE above 8%, indicating that P1-1 is promising for future applications. PMID- 28631467 TI - Quantum Dots-Facilitated Printing of ZnO Nanostructure Photodetectors with Improved Performance. AB - A nanocomposite ink composed of zinc oxide precursor (ZnOPr) and crystalline ZnO quantum dots (ZnOPrQDs) has been explored for printing high-performance ultraviolet (UV) photodetectors. The performance of the devices has been compared with their counterparts' printed from ZnOPr ink without ZnO QDs. Remarkably, higher UV photoresponsivity of 383.6 A/W and the on/off ratio of 2470 are observed in the former, which are significantly better than 14.7 A/W and 949 in the latter. The improved performance is attributed to the increased viscosity in the nanocomposite ink to enable a nanoporous structure with improved crystallinity and surface-to-volume ratio. This is key to enhanced surface electron-depletion effect for higher UV responsivity and on/off ratio. In addition, the QD-assisted printing provides a simple and robust method for printing high-performance optoelectronics and sensors. PMID- 28631468 TI - Pyrene-Tagged Ionic Liquids: Separable Organic Catalysts for SN2 Fluorination. AB - We prepared pyrene-substituted imidazolium-based ionic liquids (PILs) as organic catalysts for the SN2 fluorination using alkali metal fluoride (MF). In this system, the PIL significantly enhanced the reactivity of MF due to the phase transfer catalytic effect of the imidazolium moiety as well as the metal cation pi (pyrene) interactions. Furthermore, this homogeneous catalyst PIL was easily separated from the reaction mixture using reduced graphene oxide by pi-pi stacking with the pyrene of PIL. PMID- 28631469 TI - Chemical Composition of Blackberry Press Cake, Polyphenolic Extract, and Defatted Seeds, and Their Effects on Cecal Fermentation, Bacterial Metabolites, and Blood Lipid Profile in Rats. AB - Blackberry fiber (BF), extracted blackberry fiber (EBF), defatted blackberry seeds (DBS), and blackberry polyphenols (BP) were added to the diets of rats. A control diet, fiber diets (BF, EBF, DBS) with 6% addition instead of cellulose, and a polyphenol diet (BP) with 1% addition were administered for 4 weeks. BF and DBS contained polyphenols (3.6%); EBF did not. DBS was free of fat. Ellagitannins were the main phenolics, mostly dimers (sanguiin H-6 with isomers) and monomers (pedunculagin, casuarictin isomer, and sanguiin H-2 isomer). Trimers (lambertianin C with isomers) and tetramers (lambertianin D) were in the minority. EBF increased the production of propionate and butyrate in the cecum and improved the blood lipid profile. Polyphenols beneficially decreased the activity of cecal beta-glucuronidase, but they may have also increased cholesterol levels in blood. Bacterial metabolism of ellagitannins in the colon gave rise to nasutin A and urolithin A. PMID- 28631470 TI - Regioselective Galactofuranosylation for the Synthesis of Disaccharide Patterns Found in Pathogenic Microorganisms. AB - Koenigs-Knorr glycosylation of acceptors with more than one free hydroxyl group by 2,3,5,6-tetrabenzoyl galactofuranosyl bromide was performed using diphenylborinic acid 2-aminoethyl ester (DPBA) as inducer of regioselectivity. High regioselectivity for the glycosylation on the equatorial hydroxyl group of the acceptor was obtained thanks to the transient formation of a borinate adduct of the corresponding 1,2-cis diol. Nevertheless formation of orthoester byproducts hampered the efficiency of the method. Interestingly electron withdrawing groups on O-6 or on C-1 of the acceptor displaced the reaction in favor of the desired galactofuranosyl containing disaccharide. The best yield was obtained for the furanosylation of p-nitrophenyl 6-O-acetyl mannopyranoside. Precursors of other disaccharides, found in the glycocalix of some pathogens, were synthesized according to the same protocol with yields ranging from 45 to 86%. This is a good alternative for the synthesis of biologically relevant glycoconjugates. PMID- 28631471 TI - Great Disparity in Photoluminesence Quantum Yields of Colloidal CsPbBr3 Nanocrystals with Varied Shape: The Effect of Crystal Lattice Strain. AB - Understanding the big discrepancy in the photoluminesence quantum yields (PLQYs) of nanoscale colloidal materials with varied morphologies is of great significance to its property optimization and functional application. Using different shaped CsPbBr3 nanocrystals with the same fabrication processes as model, quantitative synchrotron radiation X-ray diffraction analysis reveals the increasing trend in lattice strain values of the nanocrystals: nanocube, nanoplate, nanowire. Furthermore, transient spectroscopic measurements reveal the same trend in the defect quantities of these nanocrystals. These experimental results unambiguously point out that large lattice strain existing in CsPbBr3 nanoparticles induces more crystal defects and thus decreases the PLQY, implying that lattice strain is a key factor other than the surface defect to dominate the PLQY of colloidal photoluminesence materials. PMID- 28631472 TI - Phosphate Shifted Oxygen Reduction Pathway on Fe@Fe2O3 Core-Shell Nanowires for Enhanced Reactive Oxygen Species Generation and Aerobic 4-Chlorophenol Degradation. AB - Phosphate ions widely exist in the environment. Previous studies revealed that the adsorption of phosphate ions on nanoscale zerovalent iron would generate a passivating oxide shell to block reactive sites and thus decrease the direct pollutant reduction reactivity of zerovalent iron. Given that molecular oxygen activation process is different from direct pollutant reduction with nanoscale zerovalent iron, it is still unclear how phosphate ions will affect molecular oxygen activation and reactive oxygen species generation with nanoscale zerovalent iron. In this study, we systematically studied the effect of phosphate ions on molecular oxygen activation with Fe@Fe2O3 nanowires, a special nanoscale zerovalent iron, taking advantages of rotating ring disk electrochemical analysis. It was interesting to find that the oxygen reduction pathway on Fe@Fe2O3 nanowires was gradually shifted from a four-electron reduction pathway to a sequential one-electron reduction one, along with increasing the phosphate ions concentration from 0 to 10 mmol.L-1. This oxygen reduction pathway change greatly enhanced the molecular oxygen activation and reactive oxygen species generation performances of Fe@Fe2O3 nanowires, and thus increased their aerobic 4 chlorophenol degradation rate by 10 times. These findings shed insight into the possible roles of widely existed phosphate ions in molecular oxygen activation and organic pollutants degradation with nanoscale zerovalent iron. PMID- 28631473 TI - Instrumentation and Method Development for On-Site Analysis of Helium Isotopes. AB - Helium isotope determination may be useful in measuring volcanic activity and issuing earlier warnings of possible eruptions. A method is presented for measuring the 3He/4He ratio in a gas sample using a multiturn time-of-flight mass spectrometer "infiTOF". In contrast to conventional waveform averaging, peaks are determined by counting ion pulses from each time-of-flight trigger. Samples were also measured by conventional magnetic-sector mass spectrometry for comparison. Magnetic sector results were used to designate a standard for infiTOF measurement and to calculate a ratio for each sample measured by infiTOF. Mass assignment error for ultrapure 3He+ standard was 4.30 * 10-5 Da. Mass assignment error of 4He2+ and 3He+ for sample cylinders was 3.00 * 10-8 Da and 2.25 * 10-4 Da, respectively. Abundance ratios determined by infiTOF were found to be within 2% of the abundance ratios determined by magnetic-sector mass spectrometry. Mass drift was <50 * 10-6 Da over 10 h. Sample flow rate was not found to affect the results as long as the reference sample was analyzed under the same conditions. Results indicate that the infiTOF system may be a viable tool for measuring helium isotopes, which may eventually lead to earlier warnings of volcanic activity. PMID- 28631474 TI - Flexible Dual-Mode Tactile Sensor Derived from Three-Dimensional Porous Carbon Architecture. AB - Detecting and monitoring varieties of human activities is one of the most essential functions and design purposes of different kinds of wearable sensors. Apart from excellent sensitivity and durability, limited by the materials, most of the sensors reported in the literature are capable of detecting signals only on the basis of a sole mechanism. In this work, a dual-mode flexible sensor derived from a high-temperature-pyrolysized 3D carbon sponge (C-Sponge) was proposed as a peculiar sensor material that is able to detect human activities based on fundamentally different mechanisms, by either the triboelectric effect or the piezoresistive effect. The sensor generated an average open circuit voltage up to ~2 V and short circuit current up to ~70 nA when being used as self powered triboelectric sensor, which was sufficiently sensitive for detecting finger touching and plantar pressure distribution of human feet. On the other hand, by incorporating MWCNT into the 3D structure, the sensor at piezoresistive mode exhibited a sensitivity improvement of nearly 20-fold, from less than 40% to more than 800%, and a durability improvement of more than 22-fold (240 000 cycles) compared with those of original C-Sponge fabricated at 1000 degrees C (10 800 cycles). All the experimental results indicated that the proposed flexible dual-mode sensor is potentially applicable as wearable sensors for human activity monitoring. PMID- 28631475 TI - Metal-Free Oxidative C-C Bond Functionalization of Methylenecyclopropanes with Ethers Leading to 2-Substituted 3,4-Dihydronaphthalenes. AB - A novel metal-free oxidative ring-opening/cyclization of methylenecyclopropanes with ethers was established for the synthesis of diverse 2-substituted 3,4 dihydronaphthalenes with high selectivity and efficiency. This oxidative cyclization is achieved by C(sp3)-H functionalization, ring-opening, and cyclization, and this method represents a new example of methylenecyclopropane oxidative cyclization with an aromatic carbon and a C(sp3)-H bond by simultaneously forming two new carbon-carbon bonds. PMID- 28631476 TI - Room-Temperature Rutile TiO2 Nanoparticle Formation on Protonated Layered Titanate for High-Performance Heterojunction Creation. AB - We report a methodology for creating protonated layered titanate-rutile heterojunctions on the outer particle surface of protonated layered titanate by treating layered potassium titanate (K0.8Ti1.73Li0.27O4) with dilute HCl and then drying it at room temperature under reduced pressure. After Pt co-catalyst loading, this protonated layered titanate/rutile composite with heterojunctions showed higher photocatalytic H2 evolution activity from water under simulated solar light compared to that of Pt-loaded P25, the standard photocatalyst for this reaction. The high photocatalytic activity was ascribable to enhanced photocatalytic activity of the protonated layered titanate based on an efficient charge separation at the protonated layered titanate-rutile heterojunction in addition to the sensitization effects of rutile, which absorbs light with longer wavelengths compared to those of protonated layered titanate. PMID- 28631477 TI - Influence of the Electrostatic Interaction between a Molecular Catalyst and Semiconductor on Photocatalytic Hydrogen Evolution Activity in Cobaloxime/CdS Hybrid Systems. AB - The influence of the electrostatic interaction on photocatalytic H2 evolution activity in cobaloxime/cadmium sulfide (CdS) hybrid systems was studied by measuring the charges of the cobaloximes and the zeta potentials of CdS under different pH conditions (pHs 4-7). Cobaloxime/CdS hybrid systems may have potential as a valid model for the investigation of the electrostatic interaction between a molecular catalyst and semiconductor because the kinetics of methanol oxidation and the driving force of electron transfer from photoirradiated CdS to cobaloxime have little effect on the pH-dependent photocatalytic H2 evolution activity. Our experimental results suggest that electrostatic repulsion between cobaloxime and CdS disfavors the electron transfer from CdS to cobaloxime and hence lowers the photocatalytic H2 evolution activity. Whereas, electrostatic attraction favors the electron transfer process and enhances the photocatalytic H2 evolution activity. However, an electrostatic attraction interaction that is too strong may accelerate both forward and backward electron transfer processes, which would reduce charge separation efficiency and lower photocatalytic H2 evolution activity. PMID- 28631479 TI - Quantitative Analysis of Ligand Induced Heterodimerization of Two Distinct Receptors. AB - The induced dimerization of two distinct receptors through a heterobifunctional inducer is prevalent among all levels of cellular signaling processes, yet its complexity poses difficulty for systematic quantitative analysis. This paper first shows how to calculate the amount of any possible complex or monomer of heteroligand and two receptors present at equilibrium. The theory is subsequently applied to the determination of three independent equilibrium parameters involved in the rapamycin induced FKBP and FRB dimerization, in which all parameters were simultaneously estimated using one set of fluorescence resonance energy transfer (FRET) experiments. A MATLAB script is provided for parametric fitting. PMID- 28631478 TI - Drying Affects the Fiber Network in Low Molecular Weight Hydrogels. AB - Low molecular weight gels are formed by the self-assembly of a suitable small molecule gelator into a three-dimensional network of fibrous structures. The gel properties are determined by the fiber structures, the number and type of cross links and the distribution of the fibers and cross-links in space. Probing these structures and cross-links is difficult. Many reports rely on microscopy of dried gels (xerogels), where the solvent is removed prior to imaging. The assumption is made that this has little effect on the structures, but it is not clear that this assumption is always (or ever) valid. Here, we use small angle neutron scattering (SANS) to probe low molecular weight hydrogels formed by the self-assembly of dipeptides. We compare scattering data for wet and dried gels, as well as following the drying process. We show that the assumption that drying does not affect the network is not always correct. PMID- 28631480 TI - Fully Transparent Quantum Dot Light-Emitting Diode with a Laminated Top Graphene Anode. AB - A new method to employ graphene as top electrode was introduced, and based on that, fully transparent quantum dot light-emitting diodes (T-QLEDs) were successfully fabricated through a lamination process. We adopted the widely used wet transfer method to transfer bilayer graphene (BG) on polydimethylsiloxane/polyethylene terephthalate (PDMS/PET) substrate. The sheet resistance of graphene reduced to ~540 Omega/? through transferring BG for 3 times on the PDMS/PET. The T-QLED has an inverted device structure of glass/indium tin oxide (ITO)/ZnO nanoparticles/(CdSSe/ZnS quantum dots (QDs))/1,1 bis[(di-4-tolylamino)phenyl] cyclohexane (TAPC)/MoO3/graphene/PDMS/PET. The graphene anode on PDMS/PET substrate can be directly laminated on the MoO3/TAPC/(CdSSe/ZnS QDs)/ZnO nanoparticles/ITO/glass, which relied on the van der Waals interaction between the graphene/PDMS and the MoO3. The transmittance of the T-QLED is 79.4% at its main electroluminescence peak wavelength of 622 nm. PMID- 28631481 TI - 3D Graphene-Ni Foam as an Advanced Electrode for High-Performance Nonaqueous Redox Flow Batteries. AB - Electrodes composed of multilayered graphene grown on a metal foam (GMF) were prepared by directly growing multilayer graphene sheets on a three-dimensional (3D) Ni-foam substrate via a self-catalyzing chemical vapor deposition process. The multilayer graphene sheets are successfully grown on the Ni-foam substrate surface, maintaining the unique 3D macroporous structure of the Ni foam. The potential use of GMF electrodes in nonaqueous redox flow batteries (RFBs) is carefully examined using [Co(bpy)3]+/2+ and [Fe(bpy)3]2+/3+ redox couples. The GMF electrodes display a much improved electrochemical activity and enhanced kinetics toward the [Co(bpy)3]+/2+ (anolyte) and [Fe(bpy)3]2+/3+ (catholyte) redox couples, compared with the bare Ni metal foam electrodes, suggesting that the 2D graphene sheets having lots of interdomain defects provide sufficient reaction sites and secure electric-conduction pathways. Consequently, a nonaqueous RFB cell assembled with GMF electrodes exhibits high Coulombic and voltage efficiencies of 87.2 and 90.9%, respectively, at the first cycle. This performance can be maintained up to the 50th cycle without significant efficiency loss. Moreover, the importance of a rational electrode design for improving electrochemical performance is addressed. PMID- 28631482 TI - Carbohydrate Bis-acetal-Based Substrates as Tunable Fluorescence-Quenched Probes for Monitoring exo-Glycosidase Activity. AB - Tunable Forster resonance energy transfer (FRET)-quenched substrates are useful for monitoring the activity of various enzymes within their relevant physiological environments. Development of FRET-quenched substrates for exo glycosidases, however, has been hindered by their constrained pocket-shaped active sites. Here we report the design of a new class of substrate that overcomes this problem. These Bis-Acetal-Based Substrates (BABS) bear a hemiacetal aglycon leaving group that tethers fluorochromes in close proximity, also positioning them distant from the active site pocket. Following cleavage of the glycosidic bond, the liberated hemiacetal spontaneously breaks down, leading to separation of the fluorophore and quencher. We detail the synthesis and characterization of GlcNAc-BABS, revealing a striking 99.9% quenching efficiency. These substrates are efficiently turned over by the human exo-glycosidase O GlcNAcase (OGA). We find the hemiacetal leaving group rapidly breaks down, enabling quantitative monitoring of OGA activity. We expect this strategy to be broadly useful for the development of substrate probes for monitoring exo glycosidases, as well as a range of other enzymes having constrained pocket shaped active sites. PMID- 28631483 TI - Amyloid Beta Peptide Folding in Reverse Micelles. AB - Previously published experimental studies have suggested that when the 40-residue amyloid beta peptide is encapsulated in a reverse micelle, it folds into a structure that may nucleate amyloid fibril formation (Yeung, P. S.-W.; Axelsen, P. H. J. Am. Chem. Soc. 2012, 134, 6061 ). The factors that induce the formation of this structure have now been identified in a multi-microsecond simulation of the same reverse micelle system that was studied experimentally. Key features of the polypeptide-micelle interaction include the anchoring of a hydrophobic residue cluster into gaps in the reverse micelle surface, the formation of a beta turn at the anchor point that brings N- and C-terminal segments of the polypeptide into proximity, high ionic strength that promotes intramolecular hydrogen bond formation, and deformation of the reverse micelle surface to facilitate interactions with the surface along the entire length of the polypeptide. Together, these features cause the simulation-derived vibrational spectrum to red shift in a manner that reproduces the red-shift previously reported experimentally. On the basis of these findings, a new mechanism is proposed whereby membranes nucleate fibril formation and facilitate the in register alignment of polypeptide strands that is characteristic of amyloid fibrils. PMID- 28631484 TI - Ocular Pharmacokinetics of Therapeutic Antibodies Given by Intravitreal Injection: Estimation of Retinal Permeabilities Using a 3-Compartment Semi Mechanistic Model. AB - Intravitreally (IVT) injected macromolecules for the treatment of age-related macular degeneration must permeate through the inner limiting membrane (ILM) into the retina and through the retinal pigment epithelium (RPE) to enter the choroid. A quantitative understanding of intraocular transport mechanisms, elimination pathways, and the effect of molecular size is currently incomplete. We present a semimechanistic, 3-compartment (retina, vitreous, and aqueous) pharmacokinetic (PK) model, expressed using linear ordinary differential equations (ODEs), to describe the molecular concentrations following a single IVT injection. The model was fit to experimental rabbit data, with Fab, Fc, IgG, and IgG null antibodies and antibody fragments, to estimate key ocular pharmacokinetic parameters. The model predicts an ocular half-life, t1/2, which is the same for all compartments and dependent on the hydrodynamic radius (Rh) of the respective molecules, consistent with observations from the experimental data. Estimates of the permeabilities of the RPE and ILM are derived for Rh values ranging from 2.5 to 4.9 nm, and are found to be in good agreement with ex-vivo measurements from bovine eyes. We show that the ratio of these permeabilities largely determines the ratio of the molecular concentrations in the retina and vitreal compartments and their dependence on Rh. The model further provides estimates for the ratio of fluxes corresponding to the elimination pathways from the eye, i.e., aqueous humor to retina/choroid, which increase from 5:1 to 7:1 as Rh decreases. Our semimechanistic model provides a quantitative framework for interpreting ocular PK and the effects of molecule size on rate-determining parameters. We have shown that intraocular permeabilities can be reasonably estimated from 3-compartment ocular PK data and can determine how these parameters influence the half-life, retinal permeation, and elimination of intravitreally injected molecules from the eye. PMID- 28631485 TI - Suppression of Magnetoresistance in Thin WTe2 Flakes by Surface Oxidation. AB - Recent renewed interest in layered transition metal dichalcogenides stems from the exotic electronic phases predicted and observed in the single- and few-layer limit. Realizing these electronic phases requires preserving the desired transport properties down to a monolayer, which is challenging. Surface oxides are known to impart Fermi level pinning or degrade the mobility on a number of different systems, including transition metal dichalcogenides and black phosphorus. Semimetallic WTe2 exhibits large magnetoresistance due to electron hole compensation; thus, Fermi level pinning in thin WTe2 flakes could break the electron-hole balance and suppress the large magnetoresistance. We show that WTe2 develops an ~2 nm thick amorphous surface oxide, which shifts the Fermi level by ~300 meV at the WTe2 surface. We also observe a dramatic suppression of the magnetoresistance for thin flakes. However, due to the semimetallic nature of WTe2, the effects of Fermi level pinning are well screened and are not the dominant cause for the suppression of magnetoresistance, supported by fitting a two-band model to the transport data, which showed the electron and hole carrier densities are balanced down to ~13 nm. However, the fitting shows a significant decrease of the mobilities of both electrons and holes. We attribute this to the disorder introduced by the amorphous surface oxide layer. Thus, the decrease of mobility is the dominant factor in the suppression of magnetoresistance for thin WTe2 flakes. Our study highlights the critical need to investigate often unanticipated and sometimes unavoidable extrinsic surface effects on the transport properties of layered dichalcogenides and other 2D materials. PMID- 28631486 TI - Melding Caged Compounds with Supramolecular Containers: Photogeneration and Miscreant Behavior of the Coumarylmethyl Carbocation. AB - By merging well-established concepts of supramolecular chemistry, protecting group strategy, and photochemistry, we have solubilized in water hydrophobic organic molecules consisting of a photoactive protecting group and masked carboxylic acids, released the desired acid, and confined a reactive carbocation intermediate within a capsule. Confinement of the photogenerated carbocation brought out the latent radical-like behavior. This observation is consistent with the recent theoretical prediction of the 7-(diethylamino)coumarinyl-4-methyl carbocation having a triplet diradical ground-state electronic contribution. PMID- 28631487 TI - Chemoselective Nitrile Oxide-Alkyne 1,3-Dipolar Cycloaddition Reactions from Nitroalkane-Tethered Peptides. AB - Synthesis and incorporation of a new amino acid with a nitroalkane side chain into peptides, in situ transformation of a nitroalkane side chain into nitrile oxide, and chemoselective 1,3-dipolar cycloaddition reactions between in situ generated nitrile oxide and different alkynes are reported. The nitroalkane mediated nitrile oxide-alkyne cycloaddition was found to be orthogonal to the copper(I)-catalyzed azide-alkyne cycloaddition reaction. The combination of orthogonal nitrile oxide-alkyne and azide-alkyne cycloaddition reactions can be explored to tailor different 1,2,3-triazole and 3,5-isoxazoles, respectively, on the peptide backbone. PMID- 28631488 TI - Synthesis of (-)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition Rearrangement and Cross-electrophile Coupling. AB - An asymmetric synthesis of (-)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the following: (1) highly diastereoselective n alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a beta-hydroxy-alpha-ketoester motif; (2) facilitation of Rh(II)-catalyzed cyclic carbonyl ylide formation-cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalyzed Csp3-Csp2 cross electrophile coupling between tricarboxylate core and unsaturated side chain to complete the natural product. PMID- 28631489 TI - An update on the recognition and treatment of autonomic symptoms in Parkinson's disease. AB - INTRODUCTION: Parkinson's disease (PD) is characterized by motor, autonomic, and neuropsychiatric symptoms. These occur in varying degrees in all stages of the disease. Among the autonomic disorders, cardiovascular, urogenital, gastrointestinal and thermoregulatory disorders are the most relevant. Within cardiovascular disorders drop of blood pressure after orthostasis and non-dipper behavior are very important; but also the influence of cardiovascular medication. Urgency, nocturia, and incontinence are of particular note within the urological problems. Among the gastrointestinal disturbances, swallowing disorders, gastric emptying disorders and constipation are particularly noteworthy. Areas covered: Autonomic symptoms are inherent in PD, in premotor and all other stages of the disease. In this overview, the current status was summarized taking into account original articles and reviews based on relevance to the field and quality of evidence. Expert commentary: The involvement of the autonomic nervous system in Parkinson's disease is still neglected. Because of the significant effects on the quality of life and even the prognosis, appropriate diagnostics and therapy should be performed at all stages of the disease. Despite intensive scientific work the area is still not sufficiently considered and the relevance in pathology is not yet understood. PMID- 28631490 TI - Pregnancy outcomes in women reporting ingestion of levosulpiride in early pregnancy. AB - This study aimed to evaluate pregnancy outcomes of women who were inadvertently exposed to levosulpiride in early pregnancy. All 162 consecutive singleton pregnant women counselled through the Korean Motherisk Program, Cheil General Hospital, between April 2001 and April 2014, on teratogenic risk after inadvertent exposure to levosulpiride in early pregnancy were enrolled in this study. The women were exposed to levosulpiride at median 4.8 gestational weeks. The rate of miscarriage was not significantly different between groups (9.2% in those exposed and 5.5% in the non-exposed; p = .084). The rate of major malformations was not significantly different between exposed (2.7%) and non exposed pregnancies (4.4%) (p = .481). All other pregnancy outcomes between the two groups were comparable (p > .05). Our data suggest that levosulpiride causes no significant adverse effects on pregnancy outcomes and therefore may be not a major teratogen. PMID- 28631491 TI - A longitudinal examination of factors associated with social support satisfaction among HIV-positive young Black men who have sex with men. AB - This study examined the long-term predictors of social support satisfaction among HIV-positive young Black men who have sex with men (YBMSM). Data were collected across three waves between October 2012 and November 2014 as part of the baseline assessment from Project nGage, a preliminary efficacy randomized control study examining the role of social support in improving HIV care among YBMSM. The sample included 92 YBMSM aged 18-29. Major results controlling for age, education and intervention effects indicated that psychological health, social network size, and education at baseline predicted differences in social support satisfaction at Wave 3, with no significant effects based on length of HIV diagnosis. Therefore, interventions that are intended to promote the quality of life for YBMSM and their engagement and retention in HIV care must focus on their psychological health concerns and network size. PMID- 28631492 TI - The efficacy of continuous positive airway pressure therapy in reducing cardiovascular events in obstructive sleep apnea: a systematic review. AB - Prospective studies show an association between obstructive sleep apnea and cardiovascular disease. Continuous positive airway pressure (CPAP) is the treatment of choice and effectively reduces subjective sleepiness and apneic and hypopneic events. However, randomized trials have not shown a reduction in cardiovascular outcomes with CPAP therapy. We review the past 10 years of randomized trial evidence regarding the therapeutic efficacy of CPAP on cardiovascular outcomes and mortality in adults with obstructive sleep apnea. The majority of studies found no significant improvement in cardiovascular outcomes with CPAP, although many noted nonsignificant benefits. Adjusted analysis in several trials showed significant cardiovascular benefit in those patients with higher CPAP compliance. Existing trials may lack sufficient follow-up and CPAP compliance, among other limitations. PMID- 28631493 TI - Awareness and Misperceptions of Hospice and Palliative Care: A Population-Based Survey Study. AB - BACKGROUND: Despite the documented benefits of palliative and hospice care on improving patients' quality of life, these services remain underutilized. Multiple factors limit the utilization of these services, including patients' and caregivers' lack of knowledge and misperceptions. OBJECTIVES: To examine palliative and hospice care awareness, misperceptions, and receptivity among community-dwelling adults. DESIGN: Cross-sectional study. SUBJECTS: New York State residents >=18 years old who participated in the 2016 Empire State Poll. OUTCOMES MEASURED: Palliative and hospice care awareness, misperceptions, and receptivity. RESULTS: Of the 800 participants, 664 (83%) and 216 (27%) provided a definition of hospice care and palliative care, respectively. Of those who defined hospice care, 399 (60%) associated it with end-of-life care, 89 (13.4%) mentioned it was comfort care, and 35 (5.3%) reported hospice care provides care to patients and families. Of those who defined palliative care (n = 216), 57 (26.4%) mentioned it provided symptom management to patients, 47 (21.9%) stated it was comfort care, and 19 (8.8%) reported it was applicable in any course of an illness. Of those who defined hospice or palliative care, 248 (37.3%) had a misperception about hospice care and 115 (53.2%) had a misperception about palliative care. CONCLUSIONS: Most community-dwelling adults did not mention the major components of palliative and hospice care in their definitions, implying a low level of awareness of these services, and misinformation is common among community-dwelling adults. Palliative and hospice care education initiatives are needed to both increase awareness of and reduce misperceptions about these services. PMID- 28631494 TI - A study on preterm births during 2013-2015, Shiraz, Iran. AB - Preterm birth is the leading cause of neonatal and infant mortality and a substantial portion of neonatal morbidities. The perinatal mortality and morbidity statistics in developing countries are inadequate. In this study, we assessed prevalence and health outcomes of preterm deliveries in tertiary care university hospitals. A retrospective study of hospital records of premature babies born in all the five governmental tertiary care settings during the time interval of 2013-2015 in Shiraz was conducted. Result of this study showed that there was an overall 127.6 premature births per 1000 live births in the study duration. 23.8% of premature newborn had RDS and Incidence of prematurity with RDS was 82.4 per thousand live births. 52.6% of premature newborns were hospitalised in NICU and 8.5% had ROP. Five percent suffered from sepsis and 1% suffered from NEC. Overall mortality was nearly 10% of all the premature newborn. In conclusion, this study showed that premature births and its complications for newborn need to be addressed more in Iran. Impact statement Preterm birth is the leading cause of neonatal mortality and morbidities. Mortality and morbidity statistics related to preterm infants are important healthcare indicators implying the quality of the perinatal health care system and are prerequisite for the identification of problems and implementation of preventive measures. However, the perinatal mortality and morbidity statistics in developing countries are inadequate. The aim of this study was to assess prevalence and health outcome of preterm deliveries in tertiary care university hospitals in Shiraz city, Iran. This study showed that prematurity rate was 12.7%. Among preterm cases, 52.6% were admitted to NICU. RDS occurred among 23.8% of the total premature neonates and 8.2% of the total live births. The incidence of NEC was 1/0% of the total premature neonates and 0.4% of the total live births. The incidence of sepsis was 5% of the premature neonates and 1.9% of the total live births and the incidence of ROP was 8.5% among the premature neonate. The overall mortality of premature neonates was 9.9% of the total premature neonates and 1.2% of the total live births. Rigorous measures for prevention of premature births and its complications for newborns are required in Iran. PMID- 28631495 TI - Serum endocannabinoids in assessing pain in patients with chronic pancreatitis and in those with pancreatic ductal adenocarcinoma. AB - BACKGROUND: The endocannabinoid system plays a substantial role in analgesia. AIM: To analyze N-arachidonoylethanolamine (AEA), N-oleoylethanolamine (OEA), linoleoyl ethanolamide (LEA), alpha-linoleoyl ethanolamine (alpha-LNEA), N palmitoylethanolamine (PEA) and N-stearoyl ethanolamine (SEA) in two groups of patients having chronic pancreatic diseases. PATIENTS AND METHODS: Twenty-six patients with chronic pancreatitis, 26 patients with pancreatic ductal adenocarcinoma and 36 healthy subjects were studied. The visual analogic scale (VAS) was used for assessing pain immediately before the venipuncture to obtain blood in all subjects. Six endocannabinoids were measured in serum of the patients enrolled. RESULTS: Only OEA, LEA and PEA serum levels were significantly higher in patients with pain as compared to those without. Using the cutoff values, the sensitivity and specificity of the various endocannabinoids in evaluating pain in patients with chronic pancreatitis and in those with pancreatic ductal adenocarcinoma were: 44.2% and 95.6% for AEA, 83.7% and 73.3% for LEA, 88.4% and 91.1% for LNEA, 81.4% and 82.2% for OEA, 81.4% and 88.9% for PEA, 86.0% and 88.9% for SEA, respectively. CONCLUSION: Endocannabinoids are not useful in assessing pain in patients with chronic pancreatic diseases and they cannot replace a simple method such as VAS for assessing the pain and its intensity. PMID- 28631496 TI - Echocardiographic evaluation of cardiac functions in newborns of mildly preeclamptic pregnant women within postnatal 24-48 hours. AB - The aim of this study is to detect preeclampsia-related cardiac dysfunction within 24-48 hours of delivery in newborns born from preeclamptic mothers. Forty newborns from mildly preeclamptic mothers formed the study group and the control group was formed by 40 healthy newborns. Cardiac function for the groups were evaluated using conventional echocardiography and myocardial performance index (MPI) within the first 24-48 hours of their lifetime and the results of both groups were compared. A significant difference between the groups was observed especially in the PW Doppler MPI measurements (the left ventricle MPI 0.37 +/- 0.09 and 0.26 +/- 0.11, p < .001; the right ventricle MPI 0.29 +/- 0.08 and 0.26 +/- 0.07, p < .035) for the control group and the study group. Elongation in the left and right ventricle MPI was detected to be more significant in terms of comparing systolic and diastolic functions to determine preeclampsia-related cardiac injury in newborns from preeclamptic mothers within the first 24-48 hours of their lifetime. Impact statement Today, the methods which may detect cardiac injury earlier than conventional echocardiographic methods are used for evaluating cardiac functions. Among them, myocardial performance index (MPI) measurement with PW Doppler is the most common ones. While studies are available in the literature evaluating foetal cardiac functions with MPI in foetuses of preeclamptic women, studies evaluating cardiac functions with MPI index within the first 24-48 hours in postnatal period are not available. This is the first study to detect cardiac injury by measuring cardiac functions of the newborns of preeclamptic babies using conventional echocardiography (EF, SF, mitral and tricuspid E/A) and myocardial performance index within the first 24-48 hours of life and compare these values with those of a control group composed of healthy newborns with similar demographic characteristics. According to the results of the study, elongation in right and left ventricle MPI was detected to be more significant compared to systolic and diastolic functions for determining preeclampsia-related cardiac injury in newborns of preeclamptic mothers within 24 48 hours of delivery. Ventricle functions of the newborns of preeclamptic mothers should also be evaluated with MPI measurement besides conventional echocardiographic measurements. PMID- 28631497 TI - Cost-effectiveness of blinatumomab versus salvage chemotherapy in relapsed or refractory Philadelphia-chromosome-negative B-precursor acute lymphoblastic leukemia from a US payer perspective. AB - OBJECTIVE: To evaluate the cost-effectiveness of blinatumomab (Blincyto) vs standard of care (SOC) chemotherapy in adults with relapsed or refractory (R/R) Philadelphia-chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL) based on the results of the phase 3 TOWER study from a US healthcare payer perspective. METHODS: The Blincyto Global Economic Model (B-GEM), a partitioned survival model, was used to estimate the incremental cost-effectiveness ratio (ICER) of blinatumomab vs SOC. Response rates, event-free survival (EFS), overall survival (OS), numbers of cycles of blinatumomab and SOC, and transplant rates were estimated from TOWER. EFS and OS were estimated by fitting parametric survival distributions to failure-time data from TOWER. Utility values were based on EORTC-8D derived from EORTC QLQ-C30 assessments in TOWER. A 50-year lifetime horizon and US payer perspective were employed. Costs and outcomes were discounted at 3% per year. RESULTS: The B-GEM projected blinatumomab to yield 1.92 additional life years and 1.64 additional quality-adjusted life years (QALYs) compared with SOC at an incremental cost of $180,642. The ICER for blinatumomab vs SOC was estimated to be $110,108/QALY gained in the base case. Cost-effectiveness was sensitive to the number and cost of inpatient days for administration of blinatumomab and SOC, and was more favorable in the sub-group of patients who had received no prior salvage therapy. At an ICER threshold of $150,000/QALY gained, the probability that blinatumomab is cost-effective was estimated to be 74%. LIMITATIONS: The study does not explicitly consider the impact of adverse events of the treatment; no adjustments for long-term transplant rates were made. CONCLUSIONS: Compared with SOC, blinatumomab is a cost-effective treatment option for adults with R/R Ph - B-precursor ALL from the US healthcare perspective at an ICER threshold of $150,000 per QALY gained. The value of blinatumomab is derived from its incremental survival and health-related quality-of-life (HRQoL) benefit over SOC. PMID- 28631498 TI - Naturally conceived heterotopic pregnancy treated with abdominal wall-lifting laparoscopic salpingectomy using spinal anaesthesia. PMID- 28631499 TI - The microbial contamination and the presence of beta-lactamase producing Gram negative bacteria in the water and on the surfaces of public recreation water facilities. AB - The microbiological quality of bathing water and the surfaces of the surrounding pool platforms of two pools was estimated. ESBL- and MBL-producing Gram-negative bacteria isolated from water and surface samples were also studied. The water samples were satisfactory in 31 (86.1 %) out of 36 cases. Pseudomonas aeruginosa as well as Escherichia coli were identified in only 2 (5.5 %) cases. There were no correlations between the HPC and number of enterobacteria in the pool water and those found in the surface samples. Isolated strains were resistant to ticarcillin with clavulanic acid in 52.3 % of cases; all of them were susceptible to ciprofloxacin. The sequences for blaCTX-M were found in 21.6 % of strains, mostly from the groups blaCTX-M9 and blaCTX-M25, whilst the genes for chosen carbapenemases were noted in 15 (17.0 %) of strains. It is necessary to implement new approaches to monitoring resistant bacteria, not only clinical ones but also those found in other public environments. PMID- 28631500 TI - Pancreatic-beta-cell survival and proliferation are promoted by protein kinase G type Ialpha and downstream regulation of AKT/FOXO1. AB - Early studies showed nitric oxide as a pro-inflammatory-cytokine-induced toxin involved in pancreatic beta-cell destruction during pathogenesis of type-1 diabetes. However, nitric oxide has both cytotoxic and cytoprotective effects on mammalian cells, depending on concentration and micro-environmental surroundings. Our studies have shown that low/physiological-level nitric oxide selectively activates protein kinase G type Ialpha isoform, promoting cytoprotective/pro-cell survival effects in many cell types. In bone marrow-derived stromal/mesenchymal stem cells, protein kinase G type Ialpha mediates autocrine effects of nitric oxide and atrial natriuretic peptide, promoting DNA-synthesis/proliferation and cell survival. In this study, endothelial nitric oxide synthase/neuronal nitric oxide synthase inhibitor L-NIO (L-N(5)-(1-iminoethyl)ornithine), soluble guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one), atrial natriuretic peptide-receptor inhibitor A71915 and protein kinase G type Ialpha kinase activity inhibitor DT-2 all increased apoptosis and decreased insulin secretion in RINm5F pancreatic beta-cells, suggesting autocrine regulatory role for endogenous nitric oxide- and atrial natriuretic peptide-induced activation of protein kinase G type Ialpha. In four pancreatic beta-cell lines, Beta-TC-6, RINm5F, INS-1 and 1.1B4, protein kinase G type Ialpha small-interfering RNA decreased phospho-serine-239-VASP (indicator of endogenous protein kinase G type Ialpha kinase activity), increased apoptosis and decreased proliferation. In protein kinase G type Ialpha-knockdown beta-cell lines, expressions of phospho protein kinase B (PKB/AKT) (AKT), phospho-Forkhead box protein O1 (FOXO1) (transcriptional repressor of pancreas duodenum homobox-1) and pancreas duodenum homobox-1 were decreased, suppressing proliferation and survival in pancreatic beta-cells. The data suggest autocrine nitric oxide/atrial natriuretic peptide induced activation of protein kinase G type Ialpha/p-AKT/p-FOXO1 promotes survival and proliferation in pancreatic beta-cells, providing therapeutic implications for development of new therapeutic agents for diabetes. PMID- 28631501 TI - Ambivalence in rehabilitation: thematic analysis of the experiences of lower limb amputated veterans. AB - BACKGROUND: Knowledge about the organization and factors of importance to rehabilitation of veterans with lower limb amputation is sparse. The aim of this study was, therefore, to improve understanding of the influences of "military identity" on the organization of rehabilitation services and to investigate those factors influential in achieving successful rehabilitation, including interprofessional collaboration between different sectors involved in the rehabilitation of veterans with lower limb amputations. METHODS: We used a qualitative exploratory design, triangulating interviews and participant observation. Data were generated using in-depth semi-structured interviews (n = 6) exploring in-hospital and post-hospital rehabilitation in Danish veterans after unilateral lower limb amputation due to trauma. We conducted four sessions of participant observation, during weekly post-hospitalization rehabilitation and included field notes in the dataset. RESULTS: Two main themes emerged: "experiencing different identities" and "experiencing discontinuity in rehabilitation." The first theme illustrated how veterans actively shift between the identities of disabled person, wounded veteran and athlete according to the context. The second theme illustrated the frustration of negotiating military versus civilian mindsets during rehabilitation and lack of coordination between the public healthcare system, municipal services and the military. CONCLUSION: Veterans live with shifting identities after returning to civilian life, increasing their awareness of the transition from active service to a new life as a civilian. During rehabilitation, it is important to acknowledge the disparities between the military and civilian mindsets and to integrate the different sets of values, such as structure versus autonomy. IMPLICATIONS FOR REHABILITATION Recommendations for the improvement of rehabilitation of amputated veterans include: Rehabilitation professionals working with veterans should focus on abilities instead of disabilities, in order to support their active identity. Rehabilitation professionals working with veterans should understand and integrate military key components, such as autonomy, structure, clear expectations, goal setting and ongoing testing and adjustment of goals. Rehabilitation professionals working with veterans should facilitate collaboration between civilian and military rehabilitation services, in order to secure both physical and psychosocial reintegration. PMID- 28631502 TI - Impact of acute infarct-related artery patency before percutaneous coronary intervention on 30-day outcomes in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention in the EUROMAX trial. AB - AIMS: Early infarct-related artery patency has been associated with improved outcomes in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. However, it is unknown whether this relationship persists in contemporary practice with pre-hospital initiation of treatment, use of novel P2Y12 inhibitors and frequent use of drug-eluting stents. The purpose of the study was to determine the impact of early infarct-related artery patency on outcomes in the contemporary EUROMAX trial. METHODS AND RESULTS: A total of 2218 patients were enrolled. The current analysis was done on 1863 patients who underwent percutaneous coronary intervention and had infarct related artery patency data. Thirty-day outcomes were compared according to infarct-related artery flow before percutaneous coronary intervention (Thrombolysis in Myocardial Infarction (TIMI) flow 0/1 vs. TIMI flow 2/3), and interaction with antithrombotic strategy was examined. A patent infarct-related artery (TIMI flow 2/3) was present in 707 patients (37.9%) and was associated with a higher rate of final TIMI 3 flow grade (98.9 vs. 92.6%; p<0.001). At 30 days, a patent infarct-related artery was associated with lower rates of cardiac death (1.3% vs. 2.9%; p=0.026) and the composite of death or myocardial infarction (2.7% vs. 4.6%; p=0.039). There were no interactions between antithrombotic treatment and the impact of infarct-related artery patency on cardiac death, myocardial infarction, or the composite of death or myocardial infarction (Breslow-Day interaction p-values of 0.21, 0.33 and 0.46, respectively). CONCLUSION: Despite evolution in primary percutaneous coronary intervention strategies, early infarct-related artery patency is still associated with higher procedural success and improved clinical outcomes. The choice of antithrombotic strategy did not interact with the benefits of a patent infarct related artery at presentation. PMID- 28631503 TI - Exercise-Induced Cardioprotection and the Therapeutic Potential of RIPC. AB - In the search for innovative solutions to treat ischemic heart disease, recent basic science and clinical approaches have focused on remote ischemic preconditioning (RIPC). Remote ischemic preconditioning involves short intervals of limb blood flow occlusion by the application of a blood pressure cuff inflated to a suprasystolic pressure. The promise of RIPC in the development of new cardioprotective therapies is founded on the premise that it is cost-effective, technically simple, and overcomes many logistical and biochemical hurdles associated with other ischemic preconditioning approaches. However, RIPC as a research subarea is still in its infancy and clinical applications for individuals at high risk of cardiovascular disease remain elusive. The thesis of the current review is that observational and mechanistic similarities between exercise-induced preconditioning and RIPC may reveal novel therapeutic links to cardioprotection. While reductionist understanding of the exercised heart is still in the formative stages, available mechanistic knowledge of exercise induced cardioprotection is juxtaposed to RIPC and potential implications discussed. In total, additional research is needed in order to fully appreciate the mechanistic and translative connections between exercise and RIPC. Nonetheless, existing rationale are strong and suggest that RIPC approaches may be helpful in the development and application to pharmacologic interventions in those with ischemic heart disease. PMID- 28631504 TI - Remote Ischemic Conditioning: The Commercial Market: LifeCuff Perspective. AB - Although remote ischemic conditioning promises significant benefit to patients with a variety of acute and chronic illnesses, development of automated, clinically applicable devices has been slow. At least 3 small companies have launched efforts to develop useful tools intended for sale in European and North American markets. The market challenges and opportunities linked to the development of a cost-effective, reliable, and clinically effective device for the application of remote ischemic conditioning are presented in this article. PMID- 28631505 TI - Methylglyoxal-derived hydroimidazolone-1 evokes inflammatory reactions in endothelial cells via an interaction with receptor for advanced glycation end products. AB - OBJECTIVE: Glyceraldehyde-derived advanced glycation end products contribute to vascular inflammation in diabetes. However, what advanced glycation end product structure could evoke inflammatory reactions remains unknown. We examined whether and how methylglyoxal-derived hydroimidazolone 1, one of the advanced glycation end products formed from glyceraldehyde, elicits inflammatory reactions in human umbilical vein endothelial cells. MATERIALS AND METHODS: Glyceraldehyde-advanced glycation end products-aptamer was prepared using a systemic evolution of ligands by exponential enrichment. The binding affinities of methylglyoxal-derived hydroimidazolone 1 to receptor for advanced glycation end products or advanced glycation end product-aptamer were measured with a quartz crystal microbalance. Intracellular reactive oxygen species generation and THP-1 cell adhesion were evaluated using fluorescent probes. Gene expression was analysed by reverse transcription polymerase chain reaction. RESULTS: Methylglyoxal-derived hydroimidazolone 1 bound to receptor for advanced glycation end products and advanced glycation end product-aptamer with a dissociation constant ( Kd) of 56.7 uM and 1.51 mM, respectively. Methylglyoxal-derived hydroimidazolone 1 at 100 ug/mL significantly increased reactive oxygen species generation in human umbilical vein endothelial cells, which were attenuated by anti-receptor for advanced glycation end products antibody or advanced glycation end product aptamer. In all, 100 ug/mL methylglyoxal-derived hydroimidazolone 1 significantly increased receptor for advanced glycation end products and intercellular adhesion molecule-1 messenger RNA levels in, and THP-1 cell adhesion to, human umbilical vein endothelial cells, all of which were blocked by anti-receptor for advanced glycation end products antibody. CONCLUSION: Our present results indicate that methylglyoxal-derived hydroimidazolone 1 evokes inflammatory reactions in human umbilical vein endothelial cells via receptor for advanced glycation end products, although apparently limited to supraphysiological levels of methylglyoxal-derived hydroimidazolone 1. Methylglyoxal-derived hydroimidazolone 1 is a distinct advanced glycation end product structure that could mediate harmful effects of methylglyoxal and glyceraldehyde-mediated glycation processes. PMID- 28631506 TI - The influence of standards and clinical guidelines on prosthetic and orthotic service quality: a scoping review. AB - OBJECTIVES: Standards and guidelines are an integral part of prosthetic and orthotic service delivery in the developed world underpinned by an assumption that they lead to improved services. Implementing them has a cost, however, and that cost needs to be justified, particularly in resource-limited environments. This scoping review thus asks the question, "What is the evidence of the impact of standards and guidelines on service delivery outcomes in prosthetics and orthotics?" MATERIALS AND METHODS: A structured search of three electronic databases (Medline, Scopus and Web of Science) followed by manual searching of title, abstract and full text, yielded 29 articles. RESULTS: Four categories of papers were identified: Descriptions and Commentaries (17 papers), Guideline Development (7), Guideline Testing (2) and Standards implementation (3). No articles were explicitly designed to assess the impact of standards and guidelines on service delivery outcomes in prosthetics and orthotics. DISCUSSION AND CONCLUSION: Studies tended to be commentaries on or descriptions of guideline development, testing or implementation of standards. The literature is not sufficiently well developed to warrant the cost and effort of a systematic review. Future primary research should seek to demonstrate whether and how guidelines and standards improve the outcomes for people that require prostheses, orthoses and other assistive devices. Implications for Rehabilitation International Standards and Clinical Guidelines are now an integral part of clinical service provision in prosthetics and orthotics in the developed world. Complying with standards and guidelines has a cost and, particularly in resource limited environments, it should be possible to justify this in terms of the resulting benefits. This scoping review concludes that there have been no previous studies designed to directly quantify the effects of implementing standards and guidelines on service delivery. PMID- 28631508 TI - Multimodality medical image fusion: applications in congenital cardiology. PMID- 28631507 TI - Placental thickness-to-estimated foetal weight ratios and small-for-gestational age infants at delivery. AB - This study aimed to determine the correlation between the placental thickness-to estimated foetal weight ratio on midterm ultrasonography and small-for gestational-age (SGA) infants. In this retrospective study, the placental thickness at the umbilical cord insertion site was measured and adjusted for foetal body weight at 18-24 weeks gestation. Investigators compared the data of women who delivered SGA infants (birth weight <10th percentile) with those of women who delivered non-SGA infants. Among the 1281 women in this study, those who delivered SGA infants were younger and less likely to be obese. Women with higher placental thickness-to-estimated foetal weight ratios delivered more SGA infants. In logistic regression analysis, a higher placental thickness-to estimated foetal weight ratio remained associated with SGA infants. Since the placental thickness-to-estimated foetal weight ratio in midterm pregnancy was associated with infant body weight at delivery, this ratio could be an effective, adjunctive screening marker for predicting SGA status. PMID- 28631510 TI - Characteristics of the spouse caregiving experience: Comparison between early- and late-onset dementia. AB - OBJECTIVES: To investigate the characteristics of the caregiving experience according to age at onset of dementia to adapt support programs. METHOD: Fifty seven spouse caregivers of persons with early-onset dementia (PEOD) and 93 spouse caregivers of persons with late-onset dementia (PLOD) participated. The characteristics of the caregiving experience were assessed using questionnaires. We compared the two groups according to age at onset of the disease using a multivariate test, Pillai's Trace test. RESULTS: The analysis showed that there were similarities and differences between the two groups of spouse caregivers. All spouse caregivers were confident in their caregiving role and fairly well prepared for future needs and reported mild depressive and anxious symptoms. However, they lacked informal support, had low confidence in requesting respite care and reported effects on their health. Compared to spouse caregivers of PLOD, spouse caregivers of PEOD had more severe perceptions of the cognitive disorders of persons with dementia (PWD) and had a better sense of preparedness and knowledge of services. Spouse caregivers of PLOD were more confident in their ability to control disturbing thoughts. CONCLUSION: The results suggest that programs should provide information on support networks to improve preparedness for spouse caregivers of PLOD as well as emphasizing positive coping strategies for caregivers of PEOD to maintain good-quality relationships with PWD, which influences the perception of the symptoms. For both groups, family relationships should be considered. PMID- 28631509 TI - Comparison of quince with vitamin B6 for treatment of nausea and vomiting in pregnancy: a randomised clinical trial. AB - This trial was performed to compare quince (Cydonia oblonga) fruit with vitamin B6 on 76 pregnant women with a gestational age of 6-14 weeks and mild-to-moderate nausea and vomiting (NVP) (40 in the quince and 36 in the B6 group). The 'Pregnancy-Unique Quantification of Emesis' (PUQE-24) scale was used to examine the severity of NVP. The quince syrup (1 tablespoon/TDS) or vitamin B6 tablets (20 mg/TDS) were used as intervention for 1 week. The mean (+/-SD) age was 27.5 (+/-5.2) years. The score of the PUQE was decreased from 9.5 (+/- 2) at baseline to 5.2 (+/-2.3) on the 7th day and 5.3 (+/-2.6) on the 14th day (p < .001) in the quince group. In the other group, the scores were 8.4 (+/-1.8), 7.3 (+/-2.4) and 7.7 (+/-3.8), respectively (p = .001). The change in symptoms were more marked in the quince group (p < .001). Quince syrup seems to be a suitable treatment for NVP. Impact statement What is already known on this subject: Pregnancy-induced nausea and vomiting (NVP) is one of the most common problems during gestation. Treatment is mainly symptomatic, ranging from dietary changes and oral pharmacological treatment to hospitalization in severe forms. In early pregnancy, the use of chemical drugs is avoided, so there is an increasing tendency to use alternative therapies. According to the literature review in Iranian Traditional Medicine (ITM), the quince fruit (Cydonia oblonga) can be useful in NVP. Quince has a wide range of pharmacological activities including antioxidant, antibacterial, antifungal, anti-inflammatory, hepatoprotective and antidepressant effects. ITM literature suggests some therapeutic effects of the quince fruit on important organs like brain, heart, liver and stomach. What the results of this study add: The results of this study demonstrated the significant efficacy of quince in comparison with vitamin B6. What the implications are of these findings for clinical practice and/or further research: This fruit is also safe to be administered in pregnant women suffering from NVP. PMID- 28631511 TI - Self-collected cervicovaginal sampling for site-of-care primary HPV-based cervical cancer screening: a pilot study in a rural underserved Greek population. AB - In the present pilot study, the feasibility of a site-of-care cervicovaginal self sampling methodology for HPV-based screening was tested in 346 women residing in underserved rural areas of Northern Greece. These women provided self-collected cervicovaginal sample along with a study questionnaire. Following molecular testing, using the cobas(r) HPV Test, Roche(r), HPV positive women, were referred to colposcopy and upon abnormal findings, to biopsy and treatment. Participation rate was 100%. Regular pap-test examination was reported for 17.1%. Among hrHPV testing, 11.9% were positive and colposcopy/biopsy revealed 2 CIN3 cases. Non compliance was the most prevalent reason for no previous attendance. Most women reported non-difficulty and non-discomfort in self-sampling (77.6% and 82.4%, respectively). They would choose self-sampling over clinician-sampling (86.2%), and should self-sampling being available, they would test themselves more regularly (92.3%). In conclusion, self-sampling is feasible and well-accepted for HPV-based screening, and could increase population coverage in underserved areas, helping towards successful prevention. PMID- 28631512 TI - African, male attitudes on female genital mutilation: an Australian survey. AB - Female genital mutilation (FGM) is a traditional practice where female genital organs are altered for non-medical reasons. The custom is outlawed in Australia and associated with an array of medical consequences. Due to the recent influx of migrants from regions endemic to FGM, the practice is becoming a growing concern locally. This federal government funded study aimed to elicit the poorly understood perceptions that young, Sub-Saharan African, migrant males residing in Townsville, Australia have on FGM. Through piloted questionnaires we found that amongst the 67 participants, 23.9% believed that FGM should be allowed under Australian Law. The independent predictors of supportive attitudes in favour of FGM were having resided in Australia for five or less years (p = .016, 95% CI 0.99-8.09) and coming from a basic educational background (high school or TAFE) (p = .003, 95% CI 1.3-12.4). This study also found that participant perceptions on FGM were amenable to change through educational interventional strategies. Impact statement Female genital mutilation (FGM) is a traditional practice where female genital organs are altered for non-medical reasons. The role that males play in the continuation of this outlawed practice remains poorly understood. No research has ever been conducted in Australia looking at the perception that young, migrant males have on FGM. Several European-based studies have examined the perceptions of older, poorly educated, migrant male cohorts. Generally, these studies show that the attitudinal support for FGM and intention to practice remains relatively high amongst these cohorts. This study examined the attitudes of a young, Sub-Saharan African, migrant, male cohort residing in Australia. This adds to the literature base by establishing the perceptions and associated socio demographic variables of this unique and influential subset of the migrant population. This directly facilitates the development of interventional strategies against FGM by highlighting those most likely to have an attitudinal support in favour of FGM. Consequentially, this 'at risk' group can be more effectively focussed on interventional programmes and be further investigated in larger scale studies. PMID- 28631513 TI - The effect of labour pain in caesarean delivery on neonatal and maternal outcomes in a term low-risk obstetric population. AB - Planned caesarean delivery (CD) frequency is increasing in many countries, and elective CD accounts for 50% of preventable causes of neonatal respiratory morbidity. The clearing of fluid in the lungs is important for the establishment of normal gas exchange with inspired air. A defect in this clearance can result in respiratory problems in neonate, but on the other hand patients waiting for the onset of spontaneous labour pain, the increase in emergency CD, together with severe mortality and morbidity are causes of concern and cause anxiety and distrust of obstetricians. In the current study, it was observed that foetal respiratory morbidity was reduced in the group with labour pain. The caesarean applied after the onset of labour pain could be a reason for the significant increase in foetal cord cortisol values in term low-risk neonates. A major advantage of this study was the inclusion of a low-risk patient group, and the increase in foetal cortisol secondary to pain in term neonates was shown objectively. Impact statement What is already known on this subject: The timing of CD is reported to be critical for neonatal morbidity, and elective CD accounts for 50% of preventable causes of neonatal respiratory morbidity. The clearing of fluid in the lungs is important for the establishment of normal gas exchange with inspired air. Cortisol secretion from the foetal adrenal gland is stimulated by stress. What do the results of this study add: Labour pain-related stress in the foetus might be a cause for elevated physiological cortisol, and secondary to that, lower respiratory morbidity. Caesarean delivery commenced after the onset of labour pain could be a reason for the significant increase in foetal cord cortisol values in term neonates. A major advantage of this study was the inclusion of a low-risk patient group, and the increase in foetal cortisol secondary to pain in term neonates was shown objectively. What are the implications of these findings for clinical practice and/or further research: Although it would seem to be rational to perform a caesarean section after the onset of labour pain in cases with a planned caesarean and a history of C-section delivery, with respect to maternal complications, especially in those with a history of more than one caesarean or those who have started active labour; there is a need for further prospective studies. PMID- 28631514 TI - Pharmacokinetics and dosing requirements of digoxin in pregnant women treated for fetal supraventricular tachycardia. AB - BACKGROUND: The objective of this study was to characterize the pharmacokinetics (PK) of digoxin in pregnant women and its potential implications for drug dosing. METHODS: Serum digoxin concentrations (SDCs) obtained in pregnant women treated for fetal supraventricular tachycardia (SVT) was retrospectively collected. PK analysis was comparatively performed using a two-stage approach (PKSTM) and a Population PK approach (NONMEMTM). As clinical outcome the fetal heart rate was recorded. RESULTS: A total of 42 SDCs were obtained from 8 women in the 3rd trimester of pregnancy (mean age 33.0 years). The PK parameters estimated by both two-stage (volume of distribution (Vd) = 682.0 L, CV = 47.5%; serum clearance (CL) = 16.1 L/h, CV = 19%) and population approaches (Vd = 731.3 L, CV = 30.5%; CL = 18.7 L/h, CV = 17.8%) are very similar and show a clear trend of increasing drug disposition in the third trimester of pregnancy. An oral loading dose of 0.5 mg/8 h during 24 h followed by a maintenance regimen of 0.5 mg/12 h been recommended to start treatment. CONCLUSIONS: Despite the small population, these parameters could be used as a guide to calculate the initial dosage requirements in the third trimester of pregnancy for treating fetal SVT. In addition, maternal SDCs should be routinely monitored for dosage adjustment purposes. PMID- 28631515 TI - One pair of new cyclopentaisochromenone enantiomer from Alternaria sp. TNXY-P-1 and their cytotoxic activity. AB - One pair of new cyclopentaisochromenone derivatives, (+)-(S)-6-hydroxy-1,8 dimethoxy-3a-methyl-3,3a-dihydrocyclopenta[c]isochromene-2,5-dione (1a) and (-) (R)-6-hydroxy-1,8-dimethoxy-3a-methyl-3,3a-dihydrocyclopenta[c]isochromene-2,5 dione (1b), together with seven known analog 2-8, were isolated from a rice solid culture of the endophytic fungus Alternaria sp. TNXY-P-1, obtained from fresh leaf of Arisaema heterophyllum. Their structures were elucidated on the basis of detailed 1D, 2D NMR, and HRESIMS analysis. Among them, compounds 1a and 1b were enantiomers separated from 1 by chiral HPLC. The absolute configurations of 1a and 1b were assigned by quantum chemical calculations of the electronic circular dichroic spectra. All isolated compounds were evaluated for cytotoxic activities. Interestingly, enantiomers (+)-1a and (-)-1b showed distinct selective antitumor activities against HL-60 cell lines with IC50 values of >200, 75.3 MUM, respectively. PMID- 28631516 TI - The top cited articles in occupational therapy: a citation analysis study. AB - BACKGROUND: The purpose of this study was to identify and review the most cited articles in the occupational therapy field. METHODS: Using the multi-disciplinary Publish or Perish software to extract data, the top 50 lifetime and annual cited articles were examined. Studies were organized according to the following: year of publication, design, topic, number of authors, country of publication, and number of citations for each cohort. RESULTS: We found that randomized control trials were the dominant design type used in papers with the most lifetime (36.0%) and annual (26.0%) citations. Additionally, in both groups, the most frequently cited articles investigated predictors of functional outcome for patients. CONCLUSIONS: This comprehensive citation analysis will inform future research through its identification of major trends and well-established areas of study. PMID- 28631517 TI - What factors influence emergency department visits by patients with cancer at the end of life? Analysis of a 124,030 patient cohort. AB - BACKGROUND: Emergency department visits towards the end of life by patients with cancer are increasing over time. This is despite evidence of an association with poor patient and caregiver outcomes and most patients preferring home-based care. AIM: To identify socio-demographic and clinical factors associated with end-of life emergency department visits and determine the relationship between patients' prior emergency department use and risk of multiple (?2) visits in the last month of life. DESIGN: Population-based cohort study. SETTING/PARTICIPANTS: All adults who died from cancer, in England, between 1 April 2011 and 31 March 2012. Our primary outcome was the adjusted odds ratio for multiple emergency department visits in the last month of life, derived using multivariable logistic regression. RESULTS: Among 124,030 cancer decedents (52.9% men; mean age: 74.1 years), 30.7% visited the emergency department once in their last month of life and 5.1% visited multiple times. Patients were more likely to visit multiple times if they were men, younger, Asian or Black, of lower socio-economic status, had greater comorbidity, and lung or head and neck cancer. Patients with ?4 emergency department visits in the 11 months prior to their last month of life were also more likely to make multiple visits during their last 30 days; this followed a dose-response pattern ( p for trend <0.001). CONCLUSION: Patients with greater comorbidity, lung or head and neck cancer and a higher number of previous emergency department visits are more likely to visit the emergency department multiple times in the last month of life. Previously reported socio-demographic factors (men, younger age, Black, low socio-economic status) are also confirmed for the first time in a UK population. PMID- 28631518 TI - Parenting Practices and Children's Physical Activity: An Integrative Review. AB - The purpose of this integrative review was to analyze the state of science concerning the influence of parenting practices on children's physical activity (PA) levels. A total of 38 studies met the inclusion criteria after full-text review. The body of research is limited in experimental designs with only three studies measuring the influence of the intervention on parenting practices. Seven of the 30 quantitative studies (23.3%) found significant associations between parental role modeling of PA and children's PA levels. Seven of the eight (87.5%) qualitative studies identified parental role modeling of PA as important in promoting children's PA. Sixteen of the 30 (53.3%) quantitative studies found that parental support of PA was significantly associated with children's PA. Five of the eight (62.5%) qualitative studies identified logistic support as supporting PA in children. The science could be expanded by the development of randomized controlled trials aimed at this area. PMID- 28631519 TI - The Final Fight: An Analysis of Metaphors in Online Obituaries of Professional Athletes. AB - In literature, obituaries from different cultures and languages have been studied on different levels and from different perspectives. One of the popular research topics is the use of metaphors, since metaphors help to cope with death, which in modern society is still a taboo. This article presents a bottom-up, primarily qualitative analysis of the metaphors in 150 obituaries of sportspeople, published in online versions of newspapers/magazines and on the Internet. As expected, the obituaries contain the traditional metaphors of death. Also more original, creative metaphors are introduced to describe death in a euphemistic way. Some of those have a link to sports but not systematically to the sport practiced by the deceased. PMID- 28631520 TI - Striatal changes underlie MPEP-mediated suppression of the acquisition and expression of pramipexole-induced place preference in an alpha-synuclein rat model of Parkinson's disease. AB - Impulsive-compulsive disorders in Parkinson's disease patients have been described as behavioural or substance addictions including pathological gambling or compulsive medication use of dopamine replacement therapy. A substantial gap remains in the understanding of these disorders. We previously demonstrated that the rewarding effect of the D2/D3 agonist pramipexole was enhanced after repeated exposure to L-dopa and alpha-synuclein mediated dopaminergic nigral loss with specific transcriptional signatures suggesting a key involvement of the glutamatergic pathway. Here, we further investigate the therapeutic potential of metabotropic glutamate receptor 5 antagonism in Parkinson's disease/dopamine replacement therapy related bias of reward-mediated associative learning. We identified protein changes underlying the striatal remodelling associated with the pramipexole-induced conditioned place preference. Acquisition and expression of the pramipexole-induced conditioned place preference were abolished by the metabotropic glutamate receptor 5 antagonist 2-methyl-6-phenylethynyl (pyridine) (conditioned place preference scores obtained with pramipexole conditioning were reduced by 12.5% and 125.8% when 2-methyl-6-phenylethynyl (pyridine) was co administrated with pramipexole or after the pramipexole conditioning, respectively). Up-regulation of the metabotropic glutamate receptor 5 was found in the dorsomedial-striatum and nucleus accumbens core. Activation of these two brain sub-regions was also highlighted through FosB immunohistochemistry. Convergent molecular and pharmacological data further suggests metabotropic glutamate receptor 5 as a promising therapeutic target for the management of Parkinson's disease/dopamine replacement therapy related reward bias. PMID- 28631521 TI - On the die compaction of powders used in pharmaceutics. AB - Die compaction is widely used in the compaction of pharmaceutical powders (tableting). It is well known that the powder densification is a result of particle rearrangement and particle deformation. The former is considered to be the governing mechanism of densification in an initial stage of compaction and the latter is regarded as the governing mechanism in the compaction at the higher pressure range. As a more realistic assumption, one can consider that a simultaneous performance of both the rearrangement and deformation mechanisms takes place from the beginning of compaction. To mathematically formulate this assumption, a piston equation is presented where the material relative density is given as a function of the applied pressure on the powder. From the equation, it is possible to obtain the contribution of each mechanism to the material densification at each value of the applied pressure. In the continuation, the piston equation is applied to the tabletting of some pharmaceutical powders. These are the powders of Ascorbic Acid, Avicel(r) PH 101, Avicel(r) PH 301, Emcompress(r), Sodium Chloride, and Tablettose(r) whose tableting results have been previously published in the literature. The results show the piston equation as a suitable approach to describe the tabletting of pharmaceutical powders. PMID- 28631522 TI - Evidence-based management of non-tubal ectopic pregnancies. AB - Recent advances in ultrasonography and the use of other modalities including magnetic resonance imaging scans have led to the early and more accurate diagnosis of non-tubal ectopic pregnancies (NTE). As a result, the management of these pregnancies has evolved. This article addresses the management options currently available for NTE. While surgical management remains the mainstay of treatment for ovarian, abdominal and cornual ectopics, there is growing evidence that some of these can be managed medically. Many authors have utilised a combination of medical and surgical approaches in the management of cervical and caesarean section (CS) scar ectopic pregnancies with good outcome. The availability of dedicated early pregnancy units has further improved diagnosis and more importantly the follow-up care for these patients. The rarity of cases and the difficulty of ethically organising randomised trials for NTE remain a problem in formulating consistent pathways for optimum management of women with NTE. PMID- 28631523 TI - The association among prematurity, cochlear hyperintensity, and hearing loss. AB - Background Prematurity is a major risk factor for neonatal hearing loss. Recent advancements in magnetic resonance imaging (MRI) have made it possible to evaluate structural details of the membranous labyrinths in premature infants that have heretofore been inaccessible. Objective We compared the prevalence of abnormal cochlear signal intensity in premature and term neonates and evaluated for a potential link with hearing loss. Materials and methods We retrospectively reviewed 148 consecutive MR exams performed in premature (< 37 weeks' gestation) and term neonates performed over a 30-month period. Cochlear signal alteration was evaluated on three-dimensional T1-weighted imaging (T1WI) sequences. Each patient's electronic medical record was reviewed to document demographics, symptomatology, physical exam findings, and potential medical variables that could contribute to cochlear signal alteration. Results Cochlear hyperintensity on T1WI was present in 6.8% patients ( n = 10) overall, but was much more common in preterm than term patients (12.2% (9 of 74) vs. 1.4% (1 of 74), respectively; p value < 0.05; Fisher's exact test). Overall, 14.9% ( n = 15) of the patients with hearing test results failed the screening Auditory Brainstem Response exam. However, failure was much more common among patients with cochlear hyperintensity on T1W1 than those with normal findings (56% (5 of 9) vs. 11% (10 of 92), respectively; p value < 0.01; Fisher's exact test). Conclusion Cochlear hyperintensity on T1WI is more common in preterm than term neonates, and potentially associated with hearing loss. Cochleae should be closely scrutinized in all premature infants; signal alterations should prompt further diagnostic inquiry and possible early otolaryngology referral. PMID- 28631524 TI - The Association between Social Jetlag, the Metabolic Syndrome, and Type 2 Diabetes Mellitus in the General Population: The New Hoorn Study. AB - Only a few studies have investigated the metabolic consequences of social jetlag. Therefore, we examined the association of social jetlag with the metabolic syndrome and type 2 diabetes mellitus in a population-based cohort. We used cross sectional data from the New Hoorn Study cohort ( n = 1585, 47% men, age 60.8 +/- 6 years). Social jetlag was calculated as the difference in midpoint sleep (in hours) between weekdays and weekend days. Poisson and linear regression models were used to study the associations, and age was regarded as a possible effect modifier. We adjusted for sex, employment status, education, smoking, physical activity, sleep duration, and body mass index. In the total population, we only observed an association between social jetlag and the metabolic syndrome, with prevalence ratios adjusted for sex, employment status, and educational levels of 1.64 (95% CI 1.1-2.4), for participants with >2 h social jetlag, compared with participants with <1 h social jetlag. However, we observed an interaction effect of median age (<61 years). In older participants (>=61 years), no significant associations were observed between social jetlag status, the metabolic syndrome, and diabetes or prediabetes. In the younger group (<61 years), the adjusted prevalence ratios were 1.29 (95% CI 0.9-1.9) and 2.13 (95% CI 1.3-3.4) for the metabolic syndrome and 1.39 (95% CI 1.1-1.9) and 1.75 (95% CI 1.2-2.5) for diabetes/prediabetes, for participants with 1-2 h and >2 h social jetlag, compared with participants with <1 h social jetlag. In conclusion, in our population-based cohort, social jetlag was associated with a 2-fold increased risk of the metabolic syndrome and diabetes/prediabetes, especially in younger (<61 years) participants. PMID- 28631526 TI - Lifetime experience with (classic) psychedelics predicts pro-environmental behavior through an increase in nature relatedness. AB - In a large-scale ( N = 1487) general population online study, we investigated the relationship between past experience with classic psychedelic substances (e.g. LSD, psilocybin, mescaline), nature relatedness, and ecological behavior (e.g. saving water, recycling). Using structural equation modeling we found that experience with classic psychedelics uniquely predicted self-reported engagement in pro-environmental behaviors, and that this relationship was statistically explained by people's degree of self-identification with nature. Our model controlled for experiences with other classes of psychoactive substances (cannabis, dissociatives, empathogens, popular legal drugs) as well as common personality traits that usually predict drug consumption and/or nature relatedness (openness to experience, conscientiousness, conservatism). Although correlational in nature, results suggest that lifetime experience with psychedelics in particular may indeed contribute to people's pro-environmental behavior by changing their self-construal in terms of an incorporation of the natural world, regardless of core personality traits or general propensity to consume mind-altering substances. Thereby, the present research adds to the contemporary literature on the beneficial effects of psychedelic substance use on mental wellbeing, hinting at a novel area for future research investigating their potentially positive effects on a societal level. Limitations of the present research and future directions are discussed. PMID- 28631525 TI - Polyphenol profile by UHPLC-MS/MS, anti-glycation, antioxidant and cytotoxic activities of several samples of propolis from the northeastern semi-arid region of Brazil. AB - CONTEXT: Propolis has promising biological activities. Propolis samples from the Northeast of Bahia, Brazil - sample A from Ribeira do Pombal and B, from Tucano - were investigated, with new information regarding their biological activities. OBJECTIVE: This paper describes the chemical profile, antioxidant, anti-glycation and cytotoxic activities of these propolis samples. MATERIAL AND METHODS: Ethanol extracts of these propolis samples (EEP) and their fractions were analyzed to determine total phenolic content (TPC); antioxidant capacity through DPPH*, FRAP and lipid peroxidation; anti-glycation activity, by an in vitro glucose (10 mg/mL) bovine serum albumine (1 mg/mL) assay, during 7 d; cytotoxic activity on cancer (SF295, HCT-116, OVCAR-8, MDA-MB435, MX-1, MCF7, HL60, JURKAT, MOLT-4, K562, PC3, DU145) and normal cell lines (V79) at 0.04-25 MUg/mL concentrations, for 72 h. The determination of primary phenols by ultra high-pressure liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) and volatile organic compounds content by gas chromatography-mass spectrometry (GC-MS) were also performed. RESULTS: The EEP polar fractions exhibited up to 90% protection against lipid peroxidation. The IC50 value for anti-glycation activity of EEP was between 16.5 and 19.2 MUg/mL, close to aminoguanidine (IC50 = 7.7 MUg/mL). The use of UHPLC-MS/MS and GC-MS allowed the identification of 12 bioactive phenols in the EEP and 24 volatile compounds, all already reported. CONCLUSIONS: The samples present good antioxidant/anti-glycation/cytotoxic activities and a plethora of biologically active compounds. These results suggest a potential role of propolis in targeting ageing and diseases associated with oxidative and carbonylic stress, aggregating value to them. PMID- 28631527 TI - Buprenorphine/naloxone versus methadone and lofexidine in community stabilisation and detoxification: A randomised controlled trial of low dose short-term opiate dependent individuals. AB - Buprenorphine/naloxone, methadone and lofexidine are medications with utility in the treatment of opiate withdrawal. We report the first randomised controlled trial to compare the effects of these two medications on withdrawal symptoms and outcome during opiate induction/stabilisation and detoxification. A double-blind randomised controlled trial was conducted in an outpatient satellite clinic of a specialist drug service. Eighty opiate dependent individuals meeting DSM-IV criteria for opiate dependence, using ? 1/2 g heroin smoked/chased or 1/4 g heroin injected or ? 30mg methadone, with ? 3 years of opioid dependency, underwent a short-term opiate treatment programme involving induction/stabilisation on methadone 30mg or buprenorphine/naloxone 4mg/1mg, followed by detoxification (where the methadone group was assisted by lofexidine). The main outcome measures were urine drug screens for opiates and withdrawal and craving questionnaires. There were no overall differences in positive urine drug screens and drop-outs during any phase of the study. During induction/stabilisation, withdrawal symptoms subsided more slowly for buprenorphine/naloxone than for methadone, and craving was significantly higher in the buprenorphine/naloxone group ( p<0.05, 95% confidence interval -3.5, 0.38). During detoxification, withdrawal symptoms were significantly greater and the peak of withdrawal was earlier for the methadone/lofexidine group than the buprenorphine/naloxone group ( p<0.01, 95% confidence interval 3.0, 8.3). Methadone/lofexidine and buprenorphine/naloxone had comparable outcomes during rapid outpatient stabilisation and detoxification in low dose opiate users. PMID- 28631528 TI - Determined to stop? Longitudinal analysis of the desire to have no more children in rural Mozambique. AB - Classic demographic theories conceptualize desired family size as a fixed goal that guides fertility intentions over the childbearing years. However, a growing body of research shows that fertility plans, even nominally long-term plans for completed childbearing, change in response to short-term conditions. Because of data limitations, much of this research has focused on low-fertility contexts, but short-term conditions are likely to be even more important in high-fertility contexts. This paper uses three waves of survey data collected in rural Mozambique to study predictors of the desire to stop childbearing in a context of relatively high fertility and high individual and social instability. We use fixed effects models to assess how women's desires to stop childbearing are shaped by demographic factors, household economic conditions, and health status, controlling for constant individual characteristics. Results provide evidence that fertility desires both reflect stable underlying goals and evolve in response to individual and social circumstances. PMID- 28631529 TI - Use of buccal morphine in the management of pain in children with life-limiting conditions: Results of a laboratory study. AB - BACKGROUND: Children and infants with impaired swallow or compromised enteral absorption require alternative routes for administration of analgesia. Recent clinical guidance and practice for paediatric palliative care teams, who often treat such children, supports buccal morphine sulphate as a fast acting, effective and easily administered agent for pain relief. However, a consideration of the physicochemical properties and potency of morphine would suggest that it is not a suitable candidate for delivery via the transmucosal route, raising questions about its use in children and infants. AIM: To explore the permeability of buccal morphine sulphate in an established ex vivo porcine buccal mucosa as a necessary step in examining efficacy for use in children with life-limiting conditions and life-threatening illnesses. DESIGN: A permeation study conducted with morphine sulphate in an ex vivo porcine buccal tissue model. Flux values and pharmacokinetic data were used to calculate the plasma values of morphine that would result following buccal administration in a 20kg child. RESULTS: Results show that the estimated steady state plasma values of morphine sulphate following buccal administration in this model do not achieve minimum therapeutic concentration. CONCLUSION: These data strongly suggest that morphine sulphate is not suitable for buccal administration and that further research is needed to establish its efficacy in relief of pain in children with life-limiting conditions and life-threatening illnesses. PMID- 28631530 TI - Intentional preparation of auditory attention-switches: Explicit cueing and sequential switch-predictability. AB - In an auditory attention-switching paradigm, participants heard two simultaneously spoken number-words, each presented to one ear, and decided whether the target number was smaller or larger than 5 by pressing a left or right key. An instructional cue in each trial indicated which feature had to be used to identify the target number (e.g., female voice). Auditory attention switch costs were found when this feature changed compared to when it repeated in two consecutive trials. Earlier studies employing this paradigm showed mixed results when they examined whether such cued auditory attention-switches can be prepared actively during the cue-stimulus interval. This study systematically assessed which preconditions are necessary for the advance preparation of auditory attention-switches. Three experiments were conducted that controlled for cue-repetition benefits, modality switches between cue and stimuli, as well as for predictability of the switch-sequence. Only in the third experiment, in which predictability for an attention-switch was maximal due to a pre-instructed switch sequence and predictable stimulus onsets, active switch-specific preparation was found. These results suggest that the cognitive system can prepare auditory attention-switches, and this preparation seems to be triggered primarily by the memorised switching-sequence and valid expectations about the time of target onset. PMID- 28631531 TI - Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) causes multiple organ dysfunction frequently leading to intensive care unit (ICU) referral and/or death. We report on a series of critically ill adult patients treated with a non etoposide-based regimen including interleukin 1 antagonist anakinra, intravenous immunoglobulin (IVIG), and/or corticosteroids (CS) for HLH. METHODS: Eight adult (>=18 years) ICU patients having received treatment with anakinra +/- IVIG +/- CS for HLH between March 2014 and March 2016 at a large tertiary care university hospital (Medical University of Vienna, Vienna, Austria) were retrospectively analyzed. RESULTS: Eight patients (median age: 38 years; range: 20-58 years; 4 males and 4 females) received anakinra together with IVIG (n = 7) and/or high dose CS (n = 5) for suspected reactive HLH (median H-score: 214; range: 171-288). Seven (88%) patients required vasopressors and invasive mechanical ventilation and 6 (75%) patients required renal replacement therapy (median Sequential Organ Failure Assessment [SOFA] score at HLH diagnosis: 9.5; range: 6-14). Six patients showed a significant decline in the SOFA score at 1 and 2 weeks following treatment initiation ( P = .03), and the remainder 2 patients experienced early death. Five patients survived to ICU discharge, 4 of them could further be discharged from hospital (hospital survival rate: 50%). No overt treatment related toxicity was noted. CONCLUSION: Anakinra in combination with IVIG and/or CS resulted in a hospital survival rate of 50% in 8 critically ill adult patients with HLH despite a vast degree of organ dysfunction and the need for aggressive ICU treatment. Further research on non-etoposide-based treatment strategies for HLH in critically ill adults is warranted. PMID- 28631532 TI - Measuring Sleep in the Intensive Care Unit: A Critical Appraisal of the Use of Subjective Methods. AB - OBJECTIVES: To collate and appraise the use of subjective measures to assess sleep in the intensive care unit (ICU). DESIGN: A systematic search and critical review of the published literature. DATA SOURCES: Medline, Scopus, and Cumulative Index to Nursing and Allied Health Literature were searched using combinations of the key words "Sleep," "Critical Care," "Intensive Care," and "Sleep Disorders," and this was complemented by hand searching the most recent systematic reviews on related topics. STUDY ELIGIBILITY CRITERIA: Papers were limited to non-gray English-language studies of the adult population, published in the last 10 years. OUTCOME MEASURES: Primary outcomes were the number and categorization of quantitative studies reporting measures of sleep, the number of participants for each data collection method, and a synthesis of related material to appraise the use of survey tools commonly used for sleep measurement in the ICU. RESULTS: Thirty-eight papers reported quantitative empirical data collection on sleep, 17 of which used a primary method of subjective assessment of sleep by the patient or nurse. Thirteen methods of subjective sleep assessment were identified. Many of these tools lacked validity and reliability testing. CONCLUSIONS: Research using questionnaires to assess sleep is commonplace in light of practical barriers to polysomnography or other measures of sleep. A methodologically sound approach to tool development and testing is crucial to gather meaningful data, and this robust approach was lacking in many cases. Further research measuring sleep subjectively in ICU should use the Richards Campbell Sleep Questionnaire, and researchers should maintain a commitment to transparency in describing methods. PMID- 28631534 TI - Measuring Well-Being in Israel and Palestine. AB - This work presents the psychometric properties of the Subjective Well-Being Assessment Scale in a sample of 423 participants composed of Israeli Arabs and Palestinians from the West Bank/Gaza Strip. Psychometric assessment of the instrument was based on confirmatory factor analysis. The convergent and discriminant validity of Subjective Well-Being Assessment Scale were also tested via administration of the General Health Questionnaire and the Positive and Negative Affect Scale. The results suggest that Subjective Well-Being Assessment Scale is valid, reliable, and solid from a psychometric point of view and provides an accurate assessment of respondents' well-being. The questionnaire is therefore recommended for practical use in the psychological and health-care fields, whether locally or in international contexts with migrants and refugees from Arabic-speaking countries. PMID- 28631533 TI - U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden. AB - BACKGROUND: Progress in cancer biomarker discovery is dependent on access to high quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umea Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population. MATERIAL AND METHODS: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin embedded tissue specimens, diagnostic slides and radiology bioimaging data. RESULTS: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort. CONCLUSIONS: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data. PMID- 28631535 TI - High resolution magnetic resonance imaging for exposing facial nerve zonal vulnerability to microbleeds: A rare cause of facial palsy. AB - Background We report a case of hypertensive microbleeds strategically located at the attached segment (AS) and root entry zone (REZ) at the left facial nerve causing facial paralysis. Case Report A 60-year-old woman presented with sudden onset left facial paralysis. Medical history was significant for poorly controlled hypertension secondary to bilateral adrenal hyperplasia (primary hyperaldosteronism). The patient was initially treated for presumptive Bell's palsy. Subsequent magnetic resonance imaging of the brain and internal auditory canal showed two microbleeds at the left cerebellopontine angle. Dedicated coronal T1 magnetization prepared rapid acquisition gradient echo and T2 sampling perfection with application optimized contrasts using different flip angle evolution sequences revealed two acute microbleeds located at the attached AS and REZ of the left facial nerve. The patient experienced only partial recovery from House-Brackmann grade IV facial paralysis at presentation to a House-Brackmann grade III facial paralysis at 1 year of follow up. Conclusions To the best of the authors' knowledge, this is the first reported case of facial paralysis caused by microbleeds directly affecting the vulnerable AS and REZ facial nerve segments. We discuss the zonal microanatomy of the facial nerve and the crucial role of high resolution MRI for diagnosis. PMID- 28631536 TI - Should ovaries be removed or not in early-stage cervical adenocarcinoma: a multicenter retrospective study of 105 patients. AB - The study population consisted of 105 patients with stage IA to IIB cervical adenocarcinoma (AC) who underwent radical hysterectomy and pelvic lymphadenectomy from three institutions between 1994 and 2015, including 86 patients with bilateral salpingo-oophorectomy (BSO) and 19 patients with ovarian preservation operation. Ovarian metastasis were diagnosed in 3 of 86 patients in BSO group with an incidence rate of 3.5% (3/86). Among the 19 patients with ovarian preservation, none developed an ovarian recurrence in the follow-up (2-71 months). The 5-year overall survival rate of the BSO group and ovarian preservation group were 88.6% and 100%, respectively, with no significant difference (p = .266 > .05). FIGO stage was an independent risk factor of ovarian metastasis for cervical AC (p = .000 < .05). So we concluded that ovarian preservation in young women with early-stage cervical AC may be safe and not associated with an increased risk of overall mortality. Impact statement There has been long-running considerable controversy regarding ovarian preservation in women with cervical AC. The incidence of ovarian metastasis in AC varies significantly from 0% to 12.9%. There were few studies regarding the prognosis and risk factors of cervical AC patients with ovarian preservation. No preoperative selection criteria of ovarian preservation in cervical AC have been officially recommended. In our study of 105 patients with stage IA to IIB cervical AC, the overall ovarian metastasis rate was 3.5% (3/86), and the incidence was 1.5% (1/66) with stage IA to IB. The 5-year overall survival rate of 19 cervical adenocarcinoma patients with ovarian preservation was 100%, and no ovarian recurrence was observed during the follow-up. Our univariate analysis with clinicopathologic variables revealed that only FIGO stage was the risk factor associated with ovarian metastasis of cervical AC. Our data implied that ovarian preservation in young women with early-stage cervical AC might be safe and not associated with an increased risk of overall mortality. Considering the deleterious effects of surgical castration on the long-term quality and quantity of life, we hold that ovarian preservation should be seriously considered in the surgical management of premenopausal women with early-stage cervical AC. PMID- 28631537 TI - Sustainability in care through an ethical practice model. AB - BACKGROUND: While sustainability is a key concept in many different domains today, it has not yet been sufficiently emphasized in the healthcare sector. Earlier research shows that ethical values and evidence-based care models create sustainability in care practice. OBJECTIVE: The aim of this study was to gain further understanding of the ethical values central to the realization of sustainability in care and to create an ethical practice model whereby these basic values can be made perceptible and active in care practice. RESEARCH DESIGN: Part of the ongoing "Ethical Sustainable Caring Cultures" research project, a hermeneutical application research design was employed in this study. PARTICIPANTS: Dialogues were used, where scientific researchers and co researchers were given the opportunity to reflect on ethical values in relation to sustainability in care. FINDINGS: An ethical practice model with ethos as its core was created from the results of the dialogues. In the model, ethos is encircled by the ethical values central to sustainability: dignity, responsibility, respect, invitation, and vows. DISCUSSION: The model can be used as a starting point for ethical conversations that support carers' reflections on the ethical issues seen in day-to-day care work and the work community, allowing ethical values to become visible throughout the entire care culture. CONCLUSION: It is intended as a tool whereby carers can more deeply understand an organization's common basic values and what they entail in regard to sustainability in care. PMID- 28631538 TI - Just healthcare and human flourishing: Why resource allocation is not just enough. AB - Over many years, different theories have been developed to guide the social practices and policies of institutions so that they demonstrate equal concern and respect for all, and satisfy the requirements of justice. Although the normative principles described in a theory may support just institutions, whether this results in just outcomes will depend on how the decisions that implement the principles are made and actioned. As a societal institution charged with caring for people, ensuring just outcomes is a distinct concern in healthcare. Relationships within this institution are constitutive of human flourishing and are also important to justice. Yet, it is not possible to create, maintain or evaluate interpersonal relationships in the same manner as institutions because rather than being universal and impartial, they are particular and partial. Consequently, the link between theories of justice that guide decision-making in relation to structures or institutions, and the relationships that influence those with a proximate effect on individuals, is not explicit. To address this gap, this article argues that a focus on human flourishing provides a nexus between the decision-making for just institutions and just outcomes for individuals. PMID- 28631539 TI - Regional Nerve Blocks for Equine Dentistry. AB - Regional nerve blocks are necessary to facilitate equine oral surgery in the standing sedated patient. Step-by-step instruction on how to perform common regional nerve blocks are discussed, including infraorbital, maxillary, middle mental, and inferior alveolar nerve blocks. Regional nerve blocks are critical when performing dental procedures in the standing horse.1 The infraorbital and maxillary nerve blocks provide anesthesia of the infraorbital nerve, which is a branch of the maxillary nerve. Both nerve blocks provide adequate anesthesia for all maxillary dental procedures.1 When the infraorbital nerve block is utilized, care must be taken to advance the needle into the infraorbital foramen in order to appropriately anesthetize the caudal maxillary teeth. Mandibular dental procedures require anesthesia of the inferior alveolar nerve, which is a branch of the mandibular nerve. Local anesthesia at the level of the mental foramen will result in anesthesia of ipsilateral incisors and canines, while anesthesia at the level of the mandibular foramen will anesthetize the entire ipsilateral mandibular dental quadrant. All nerve blocks should have the injection site aseptically prepared prior to the procedure. The 4 most common dental nerve blocks are described step by step. PMID- 28631541 TI - Semilunar Coronally Advanced Periodontal Flap to Increase Soft Tissue Coverage of a Maxillary Fourth Premolar in a Dog. AB - A 7-year-old, 31.3 kg spayed female Golden Retriever dog was presented for the treatment of Miller Class I gingival recession at the right maxillary fourth premolar (108). A semilunar coronally advanced periodontal flap was performed at this tooth and created an increase of approximately 3 mm of soft tissue coverage of the tooth. This method may have benefits over traditional periodontal advancement flaps in that there is no need for suturing, can be done more quickly, maintains lateral blood supply to the flap, and likely has decreased risk of surgical site dehiscence. This case shows that the semilunar coronally advanced periodontal flap demonstrates an appropriate method to treat Miller Class I gingival recession in the maxilla. PMID- 28631543 TI - Scholarship Application. PMID- 28631546 TI - Foundation for Veterinary Dentistry: Veterinary Dental Research Grant. PMID- 28631545 TI - Life Is Short, Take Pictures! PMID- 28631547 TI - Cryptococcal Maxillary Osteomyelitis and Osteonecrosis in a 18-Month-Old Dog. AB - An 18-month-old neutered male labradoodle was treated with surgical debridement for maxillary osteomyelitis and sequestrum formation. Histopathologic findings of the necrotic bone were consistent with Cryptococcus subspecies, confirmed with latex agglutination serum titer testing. The patient responded to a combination of fluconazole and surgical debridement and was titer negative after 8 months of medical therapy. The patient never exhibited signs of systemic illness which is commonly reported with cryptococcosis. Cryptococcus subspecies infection in dogs in the Pacific Northwest is part of an ongoing outbreak in the region, first reported in 2001, and is associated with specific risk factors. This is the first published case of oral cryptococcosis from primary inoculation. PMID- 28631549 TI - Comparison of Histological and Proliferation Features of Canine Oral Squamous Cell Carcinoma Based on Intraoral Location: 36 Cases. AB - Grade and labeling indices for immunohistochemical tumor proliferation markers Ki 67 and proliferating cell nuclear antigen (PCNA) were evaluated in 36 cases of canine oral squamous cell carcinoma (OSCC) based upon intraoral location. Grade was significantly associated with location ( P = .035). Grade II tumors were most frequently diagnosed. Grade I tumors were identified in the gingiva and the buccal mucosa, and grade III tumors were seen in the gingiva and the tonsillar region. Animals with tumors arising from the tonsils and of the tongue tended to be older ( P = .007), and those in the former group were more likely to have metastatic disease at the time of diagnosis ( P = .001). Mean expression of PCNA and Ki-67 proliferation index (PI) for all tumors were 62.54% and 50.70%, respectively, and there was a statistical significant association between the 2 variables ( R = .70; P < .001). Proliferation index was not associated with any of the intraoral locations evaluated, but higher PCNA PI was significantly associated with grade ( P = .031). Ki-67 PI was significantly associated with lymph node metastasis at the time of diagnosis, especially for OSCC of gingival location ( P = .028). The results obtained in this study are preliminary but clinically relevant, since they provide information that can explain differences in biologic behavior among intraoral locations and contribute to more accurate tumor staging to support the choice for different treatment strategies available for OSCC. PMID- 28631551 TI - Apical Microleakage in Root Canals Obturated With 2 Different Endodontic Sealer Systems in Canine Teeth of Dogs. AB - An apical dye leakage test was utilized to compare 2 endodontic sealer systems commonly used in veterinary endodontic treatment. Rotary instrumentation followed by injection of 2 different sealers (GuttaFlow 2 and AH Plus) and a single master cone obturation technique were compared. Following obturation and restoration, specimens were immersed in India ink for 48 hours. A tooth mineral clearing technique was utilized to render the tooth samples transparent. Subsequently, the apices were evaluated for prevalence and magnitude of apical dye penetration under magnification. Statistical analysis of the results revealed no significant differences in the prevalence or magnitude of apical dye penetration between groups. PMID- 28631552 TI - Effect of 2,3',4,4',5-Pentachlorobiphenyl Exposure on Endometrial Receptivity and the Methylation of HOXA10. AB - Polychlorinated biphenyls (PCBs) are one of the most common endocrine-disrupting chemicals and have obvious toxicity on human reproductive development. The aim of our study was to investigate the toxicity of chronic 2,3',4,4',5 pentachlorobiphenyl (PCB 118) exposure on embryo implantation and endometrial receptivity, with the possible mechanism of DNA methylation involved. Virgin CD-1 female mice (3 weeks old) were housed and orally treated with PCB 118 (0, 1, 10, 100 MUg/kg) for a month. After mating with fertile males, the pregnant mice were killed on gestation day 4.5. Compared with the control group, implantation failures were observed in 1 MUg/kg PCB 118- and 100 MUg/kg PCB 118-treated groups. Abnormal endometrial morphology with open uterine lumens and densely compact stromal cells and poorly developed pinopodes were substantially in response to PCB 118 doses above, as well as the significant downregulation of implantation-associated genes (estrogen receptor 1, homeobox A10 [HOXA10], integrin subunit beta 3) and hypermethylation in the promoter region of HOXA10 further. It was confirmed that chronic exposure to PCB 118 produced an increased number of implantation failures in association with a defective uterine morphology during the implantation period. Alterations in methylation of HOXA10 could explain, at least in part, the mechanism of effects of PCB 118 exposure on the implantation process. PMID- 28631553 TI - Administration of Progesterone Throughout Pregnancy Increases Maternal Steroids Without Adverse Effect on Mature Oligodendrocyte Immunostaining in the Guinea Pig. AB - Progesterone is administered to pregnant women at risk of premature labor, despite systematic reviews showing conflicting outcomes regarding its use, highlighting doubt over the effectiveness of the therapy. Progesterone can be rapidly metabolized into a number of steroids, but to date, there has been a lack of investigation into the fetal steroid profiles following administration and whether this impacts fetal neurodevelopment. The objective of this study was to determine the effect of progesterone treatment on allopregnanolone and cortisol levels in the fetus and on a marker of myelination in the fetal brain. We used a guinea pig model where pregnant dams were administered vehicle (beta cyclodextrin) or progesterone orally throughout pregnancy (GA29-61). Maternal and fetal fluids and tissues were collected at both preterm (GA61) and term (GA68) ages. Maternal and fetal progesterone and cortisol were analyzed by enzyme immunoassay and allopregnanolone by radioimmunoassay. Measurement of myelination of fetal brains (hippocampus, cingulum, and subcortical white matter) at preterm and term ages was performed by immunohistochemistry staining for myelin basic protein. We found that dams receiving progesterone had significantly elevated progesterone and cortisol concentrations, but there was no effect on allopregnanolone. Interestingly, the increased cortisol concentrations were not reflected in the fetuses, and there was no effect of progesterone treatment on myelination. Therefore, we conclude that in our guinea pig model, maternal administration of progesterone has no effect on cortisol levels or markers of mature oligodendrocytes in the fetus and suggest this is potentially due to the protective cortisol barrier in the placenta. PMID- 28631554 TI - The Effects of Platelet-Activating Factor on Uterine Contractility, Perfusion, Hypoxia, and Pain in Mice. AB - It is widely hypothesized that menstrual pain is triggered by prostaglandin synthesis that evokes high-pressure uterine contractions and ischemia. However, the effects of molecules implicated in menstrual pain on uterine contractility, perfusion, and oxygenation in vivo have been rarely demonstrated. Studies in women that do not respond to nonsteroidal anti-inflammatory drugs (NSAIDs) have reported elevated levels of platelet-activating factor (PAF). To establish in vivo evidence of PAF's capability to impair uterine homeostasis and to elicit visceral pain, we examined the effects of the PAF receptor agonist (carbamyl PAF [CPAF]) in comparison to other molecules hypothesized to play a role in uterine pain in mice. Uterine pressure was increased by oxytocin, prostaglandin F2alpha (PGF2alpha), and CPAF. Even in the absence of inflammatory molecules, uterine contractions reduced uterine oxygenation by 38%. CPAF reduced uterine perfusion by 40% +/- 8% and elicited further oxygen desaturation approaching hypoxia (9.4 +/- 3.4 mm Hg Pao2). Intraperitoneal injections of CPAF and PGF2alpha evoked visceral pain and pelvic hyperalgesia in awake wild-type mice. However, pain was not observed in identically injected PAF-receptor knockout mice. Thus, our model provides a demonstration that a molecule implicated in NSAID-resistant dysmenorrhea has a detrimental effect on uterine homeostasis and is capable of causing visceral pain. Our results support the general hypothesis that menstrual cramps are caused by uterine contractions, impaired perfusion, and reduced oxygenation. Since this study was limited to mice, confirmation of these results in humans would be valuable for development of novel therapeutics targeted at inflammatory precursors, contractility, perfusion, and tissue oxygenation. PMID- 28631555 TI - GRIK3: A novel oncogenic protein related to tumor TNM stage, lymph node metastasis, and poor prognosis of GC. AB - Glutamate receptor, ionotropic, kainate 3 (GRIK3), as a member of the glutamate kainate receptor family, mainly participated in neuroactive ligand receptor interaction pathway. Other members of GRIK family were previously reported to regulate cellular migration, transformation, and proliferation in tumor. However, the mechanism of GRIK3 in tumor is still unclear. Therefore, the purpose of our study was to reveal the expression and clinical significance of GRIK3 in gastric cancer (GC). First, we performed the expression analysis and survival analysis of GRIK3 using The Cancer Genome Atlas (TCGA) database, and the results showed that the GRIK3 expressed differentially between gastric cancer tissues and the adjacent normal tissues and that higher expression of GRIK3 was associated with poor survival outcomes. And the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that GRIK3 mainly took part in cancer-related process. Subsequently, the validated immunohistochemistry showed that GRIK3 expressed higher in the GC tissues than in the matched normal tissues and the patients with overexpressed GRIK3 had worse survival outcomes. The univariate and multivariate analyses suggested that the expression of GRIK3 was an independent prognostic factor to predict GC prognosis. Furthermore, additional experiment showed that the lymph node metastasis tissues had higher GRIK3 expression than their matched primary GC tissues. These findings suggested that elevated GRIK3 expression could serve as an independent prognostic biomarker and a novel potential treatment target for patients with GC. PMID- 28631556 TI - Kruppel-like factor 4 inhibits non-small cell lung cancer cell growth and aggressiveness by stimulating transforming growth factor-beta1-meidated ERK/JNK/NF-kappaB signaling pathways. AB - Non-small cell lung cancer is one of the most common epithelial tumors that cause the most common cancer-related mortality due to invasive ability. Research has found that Kruppel-like factor 4, a zinc-finger transcription factor, plays a critical role in the tumor evolution and progression. However, the molecular signal pathways mediated by Kruppel-like factor 4 in the progression of non-small cell lung cancer cells have not been well understood yet. In this study, we investigated the possible role and potential mechanism of Kruppel-like factor 4 in growth and aggressiveness of non-small cell lung cancer cells. Results showed that Kruppel-like factor 4 is downregulated in non-small cell lung cancer cells. Here, we found that Kruppel-like factor 4 knockdown promoted growth and aggressiveness of non-small cell lung cancer cells, as well as enhanced apoptotic resistance induced by tunicamycin. We also found that Kruppel-like factor 4 overexpression significantly suppressed growth and aggressiveness of non-small cell lung cancer cells. Apoptosis rate of non-small cell lung cancer cells induced by tunicamycin was promoted by Kruppel-like factor 4 overexpression. Kruppel-like factor 4 overexpression inhibited transforming growth factor-beta1, extracellular signal-regulated protein kinase, C-jun N-terminal kinase, and nuclear factor-kappaB expression levels in non-small cell lung cancer cells. Mechanistically, Kruppel-like factor 4-mediated tumorigenesis involved suppression of a transforming growth factor-beta1-meidated extracellular signal regulated protein kinase/C-jun N-terminal kinase/nuclear factor-kappaB transcriptional program in non-small cell lung cancer cells. Our results revealed that Kruppel-like factor 4 overexpression non-small cell lung cancer cell reduces tumor growth in experimental mice. Overall, these data indicate the inhibitory role of Kruppel-like factor 4 in non-small cell lung cancer cells and elaborate a potential molecular signal pathway involving in growth and aggressiveness. Findings identify Kruppel-like factor 4 can be regarded as a possible new molecular agent for designing novel therapeutic protein drug for lung cancer treatment to control non-small cell lung cancer growth. PMID- 28631557 TI - Bispecific antibody suppresses osteosarcoma aggressiveness through regulation of NF-kappaB signaling pathway. AB - Osteosarcoma is one of the most lethal malignancies, and the prognosis remains dismal due to the paucity of effective therapeutic targets. Bmi-1 and TRIM-14 are associated with the initiation and progression of osteosarcoma, which could promote angiogenesis, invasion, and apoptotic resistance in bone cancer tissue. In this study, we constructed a bispecific antibody of BsAbBmi/TRIM targeting Bmi 1 and TRIM-14 and investigated the therapeutic value in bone carcinoma cells and xenograft mice. Our results showed that Bmi-1 and TRIM-14 expression levels were markedly upregulated correlated with nuclear factor-kappaB nuclear translocation in bone cancer cells and clinical carcinoma tissues. Results have demonstrated that overexpression of Bmi-1 and TRIM-14 promoted growth, proliferation, aggressiveness, and apoptosis resistance of osteosarcoma cells. BsAbBmi/TRIM administration significantly inhibited nuclear factor-kappaB expression derived by matrix metalloproteinase-9 promoter. BsAbBmi/TRIM administration inhibited growth of osteosarcoma cells and downregulated Bmi-1 and TRIM-14 expression levels. Data also demonstrated that migration and invasion of osteosarcoma cells were also inhibited by BsAbBmi/TRIM. In addition, results illustrated that BsAbBmi/TRIM inhibited tumor growth and tumorigenicity by blockaded sensor expression in nuclear factor-kappaB signal pathway. Furthermore, in vivo study showed that BsAbBmi/TRIM treatment markedly inhibited the tumorigenicity and growth of osteosarcoma cells compared to either AbBmi-1 or AbTRIM-14 treatment. Notably, survival of xenograft mice was prolonged by BsAbBmi/TRIM treatment compared to either AbBmi-1 or AbTRIM-14 treatment. In conclusion, these results provided new evidence that BsAbBmi/TRIM inhibited the progression of osteosarcoma, which suggest that BsAbBmi/TRIM may be a novel anti-cancer agent for osteosarcoma therapy. PMID- 28631558 TI - The overexpression and prognostic role of DCAF13 in hepatocellular carcinoma. AB - DDB1 and CUL4 associated factor 13 (DCAF13) is a protein coding gene located on chromosome 8q22.3, which is a hotspot amplified in various cancers. DCAF13 has been reported to be frequently amplified in breast cancer patients. However, the genetic alteration and potential role of DCAF13 in other cancers, including hepatocellular carcinoma, have not been investigated yet. In this study, we found that DCAF13 was amplified in 14.7% of the cases and its expression was upregulated (p < 0.001) in hepatocellular carcinoma samples in The Cancer Genome Atlas dataset. Increased expression of DCAF13 was also noticed in 40 paired hepatocellular carcinoma and adjacent non-tumor tissues both at messenger RNA and protein levels (p = 0.0002 and 0.0016, respectively). A positive relationship was observed between augmented DCAF13 levels and poorer tumor grade (p = 0.005), and we also found that hepatocellular carcinoma patients with increased DCAF13 expression in their tumors had significantly poorer survival compared with those with decreased DCAF13 expression (median survival time: 45.73 and 70.53 months, respectively). Multivariate Cox regression analysis showed that DCAF13 was an independent prognostic predictor of survival in hepatocellular carcinoma patients. Gene ontology and Kyoto Encyclopedia of Genes and genomes analysis indicated the potential role of DCAF13 as a crucial cell cycle regulator. Collectively, our findings revealed that the overexpression of DCAF13 in hepatocellular carcinoma was significantly associated with poor survival and may participate in the regulation of cell cycle progression. PMID- 28631559 TI - PKCzeta in prostate cancer cells represses the recruitment and M2 polarization of macrophages in the prostate cancer microenvironment. AB - Tumor-associated macrophages are key regulators of the complex interplay between tumor and tumor microenvironment. M2 Macrophages, one type of tumor-associated macrophages, are involved in prostate cancer growth and progression. Protein kinase C zeta has been shown to suppress prostate cancer cell growth, invasion, and metastasis as a tumor suppressor; however, its role in chemotaxis and activation of tumor-associated macrophages remains unclear. Here, we investigated the role of protein kinase C zeta of prostate cancer cells in regulation of macrophage chemotaxis and M2 phenotype activation. Immunohistochemistry was performed to analyze the expression of protein kinase C zeta and the number of CD206+ M2 macrophages in human prostate tissue. Macrophage chemotaxis and polarization were examined using Transwell migration assays and a co-culture system. Quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay were used to detect M2 markers, protein kinase C zeta, interleukin-4, and interleukin-10 expression. We found the expression of protein kinase C zeta increased in prostate cancer tissues, especially in the early stage, and was negatively associated with tumor grade and the number of CD206+ macrophages. Inhibition of protein kinase C zeta expression in prostate cancer cells promoted chemotaxis of peripheral macrophages and acquisition of M2 phenotypic features. These results were further supported by the finding that silencing of endogenous protein kinase C zeta promoted the expression of prostate cancer cell-derived interleukin-4 and interleukin-10. These results suggest that protein kinase C zeta plays an important role in reducing infiltration of tumor associated macrophages and activation of a pro-tumor M2 phenotype, which may constitute an important mechanism by which protein kinase C zeta represses cancer progression. PMID- 28631560 TI - Mithramycin inhibits epithelial-to-mesenchymal transition and invasion by downregulating SP1 and SNAI1 in salivary adenoid cystic carcinoma. AB - Mithramycin exhibits certain anticancer effects in glioma, metastatic cerebral carcinoma, malignant lymphoma, chorionic carcinoma and breast cancer. However, its effects on salivary adenoid cystic carcinoma remain unclear. Here, we report that mithramycin significantly inhibited epithelial-to-mesenchymal transition and invasion in human salivary adenoid cystic carcinoma cell lines. The underlying mechanism for this activity was further demonstrated to involve decreasing the expression of the transcription factors specificity protein 1 and SNAI1. Specificity protein 1 is a pro-tumourigenic transcription factor that is overexpressed in SACC-LM and SACC-83 cells, and its expression is inhibited by mithramycin. Moreover, chromatin immunoprecipitation assays showed that specificity protein 1 induced SNAI1 transcription through direct binding to the SNAI1 promoter. In summary, this study uncovered the mechanism through which mithramycin inhibits epithelial-to-mesenchymal transition and invasion in salivary adenoid cystic carcinoma cell lines, namely, via downregulating specificity protein 1 and SNAI1 expression, which suggests mithramycin may be a promising therapeutic option for salivary adenoid cystic carcinoma. PMID- 28631561 TI - Proinflammatory follicular helper T cells promote immunoglobulin G secretion, suppress regulatory B cell development, and correlate with worse clinical outcomes in gastric cancer. AB - Gastric cancer is one of the most common and aggressive malignancies. Both bacterial virulence factors and host chronic inflammation are thought to promote gastric cancer development. In this study, we investigated the potential involvement of follicular helper T cells in gastric cancer. Functions of follicular helper T subsets were examined in Helicobacter pylori-infected gastric cancer patients and H. pylori-infected but asymptomatic individuals. We found that the follicular helper T cells in gastric cancer individuals were skewed toward the Th1 and Th17 subsets compared to those in H. pylori-infected but asymptomatic individuals. In a naive B cell-follicular helper T cell coculture, the Th1-follicular helper T cells by themselves were ineffective at stimulating a robust antibody response, unlike the Th2-follicular helper T and Th17-follicular helper T cells. However, Th1-follicular helper T cells significantly promoted the immunoglobulin G response in collaboration with other follicular helper T subsets, through the secretion of interferon gamma. We also found that Th1 follicular helper T cells suppressed the development of interleukin-10+ regulatory B cells, a cell type previously thought to protect H. pylori-infected individuals from tissue damage. In addition, the frequency of Th1-follicular helper T cells in gastric cancer patients was negatively correlated with the disease-free survival of gastric cancer patients after tumor resection. These results suggested that dysregulation of follicular helper T subsets in gastric cancer patients, characterized by increased Th1-follicular helper T cells, contributed to inflammation and tumor development. PMID- 28631562 TI - Cancer stem cell markers in patterning differentiation and in prognosis of oral squamous cell carcinoma. AB - Differentiation is a major histological parameter determining tumor aggressiveness and prognosis of the patient; cancer stem cells with their slow dividing and undifferentiated nature might be one of the factors determining the same. This study aims to correlate cancer stem cell markers (CD44 and CD147) with tumor differentiation and evaluate their subsequent effect on prognosis. Immunohistochemical analysis in treatment naive oral cancer patients (n = 53) indicated that the expression of CD147 was associated with poorly differentiated squamous cell carcinoma and moderately differentiated squamous cell carcinoma (p < 0.01). Furthermore, co-expression analysis showed that 45% each of moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma patients were CD44high/CD147high as compared to only 10% of patients with well-differentiated squamous cell carcinoma. A three-way analysis indicated that differentiation correlated with recurrence and survival (p < 0.05) in only the patients with CD44high/CD147high cohort. Subsequently, relevance of these cancer stem cell markers in patterning the differentiation characteristics was evaluated in oral squamous cell carcinoma cell lines originating from different grades of oral cancer. Flowcytometry-based analysis indicated an increase in CD44+/CD147+ cells in cell lines of poorly differentiated squamous cell carcinoma (94.35 +/- 1.14%, p < 0.001) and moderately differentiated squamous cell carcinoma origin (93.49 +/- 0.47%, p < 0.001) as compared to cell line of well differentiated squamous cell carcinoma origin (23.12% +/- 0.49%). Expression profiling indicated higher expression of cancer stem cell and epithelial mesenchymal transition markers in SCC029B (poorly differentiated squamous cell carcinoma originated; p <= 0.001), which was further translated into increased spheroid formation, migration, and invasion (p < 0.001) as compared to cell line of well-differentiated squamous cell carcinoma origin. This study suggests that CD44 and CD147 together improve the prognostic efficacy of tumor differentiation; in vitro results further point out that these markers might be determinant of differentiation characteristics, imparting properties of increased self-renewal, migration, and invasion. PMID- 28631563 TI - Prognostic significance of glutathione peroxidase 2 in gastric carcinoma. AB - Increasing evidence suggests that the glutathione peroxidase 2 may actually play important roles in tumorigenesis and progression in various human cancers such as colorectal carcinomas and lung adenocarcinomas. However, the role of glutathione peroxidase 2 in gastric carcinoma remains to be determined. In this study, the expression and prognostic significance of glutathione peroxidase 2 in gastric carcinoma were investigated and the well-known prognostic factor Ki-67 labeling index was also assessed as positive control. Glutathione peroxidase 2 expression levels in the tumor tissue specimens, the matched adjacent normal tissue specimens, and the lymph node metastases of 176 patients with gastric carcinoma were evaluated by quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The associations between glutathione peroxidase 2 expression levels, as determined by immunohistochemical staining, and multiple clinicopathological characteristics were determined by Pearson's chi-square test and Spearman's correlation analysis. The relationships between glutathione peroxidase 2 expression and other clinicopathological variables and patient prognoses were analyzed further by the Kaplan-Meier method, the log-rank test, and Cox multivariate regression. The quantitative polymerase chain reaction, western blotting, and immunohistochemical staining results showed that glutathione peroxidase 2 expression levels were upregulated in both the primary tumor foci and the lymph node metastases of patients with gastric carcinoma (all p values < 0.05). Furthermore, Pearson's chi-square tests, as well as Spearman's correlation analysis, revealed that glutathione peroxidase 2 expression levels were strongly correlated with the Ki-67 labeling index, differentiation, histological patterns, Lauren classifications, lymph node metastasis, vascular invasion, tumor-node-metastasis stages, Helicobacter pylori infection, and overall survival (all p values < 0.05). Kaplan-Meier analysis, as well as the log rank test and multivariate Cox regression analysis, showed that multiple clinicopathological risk factors and glutathione peroxidase 2 expression were novel independent prognostic factors for gastric carcinoma (all p values < 0.05). Glutathione peroxidase 2 expression is a novel independent prognostic biomarker for gastric carcinoma that may be used to devise personalized therapeutic regimens and precision treatments for this disease. PMID- 28631564 TI - Indole-3-carbinol induces apoptosis of chronic myelogenous leukemia cells through suppression of STAT5 and Akt signaling pathways. AB - Signal transducer and activator of transcription 5 and Akt pathways, implicated in signaling transduction downstream of BCR-ABL, play critical roles in the pathogenesis of chronic myeloid leukemia. Therefore, idenication of novel compounds that modulate the activity of such pathways could be a new approach in the treatment of chronic myeloid leukemia. Previous studies have demonstrated that indole-3-carbinol inhibits the proliferation and induces apoptosis of various tumor cells. However, its anticancer activity against chronic myeloid leukemia cells and the underlying mechanism remain unclear. Our data revealed that indole-3-carbinol promoted mitochondrial apoptosis of chronic myeloid leukemia-derived K562 cells, as evidenced by the activation of caspases and poly (ADP-ribose) polymerase cleavage. Treatment with indole-3-carbinol was found to be associated with a decrease in the cellular levels of phospho-Akt and phospho signal transducer and activator of transcription 5. In addition, real-time polymerase chain reaction analysis showed that the downregulation of genes is regulated by Akt and signal transducer and activator of transcription 5. We also found that treatment with indole-3-carbinol resulted in the activation of the p38 mitogen-activated protein kinase and reduced expression of human telomerase and c Myc. Collectively, these results demonstrate that the oncogenic signal transducer and activator of transcription 5/Akt pathway is a cellular target for indole-3 carbinol in chronic myeloid leukemia cells. Thus, this clinically tested natural compound can be a potential candidate in the treatment of chronic myeloid leukemia following confirmation with clinical studies. PMID- 28631565 TI - Genetic and epigenetic alterations affecting PARK-2 expression in cervical neoplasm among North Indian patients. AB - The recent investigation on PARK-2, a putative tumor suppressor gene, has found that it has been altered in multiple human malignancies. However, the clinical impact of PARK-2 alteration in uterine cervix carcinoma has not yet been studied. Therefore, we aimed to examine mutations, promoter hypermethylation, and protein expression of PARK-2 among the North Indian patients and their association with clinical parameters to evaluate the implication of PARK-2 in the genesis of cervical cancer. A total of 168 patient samples were processed for mutational analysis by single-strand conformation polymorphism, sequencing, and further in silico analysis of the identified mutations. Promoter hypermethylation by methylation-specific polymerase chain reaction and expression of PARK-2 were performed using immunohistochemistry. Statistical correlation between molecular findings and the clinicopathological parameters was taken to figure out the meaningful outcome. As per our findings, 3.5% (6/168) tumors showed novel missense mutations in exon 11 of PARK-2. In silico analysis showed high structural deviations manifested by mutations, A398D and Y391N, in both mutant proteins as compared to wild type. Promoter hypermethylation was observed in total of 29% of (48/168) tumor samples. Furthermore, 46.43% tumors (78/168) exhibited loss of PARK-2 expression in cervical carcinoma. The loss of expression of PARK-2 when correlated with clinical parameters resulted in significant association with tumor stage (p = 0.002) and with histological grade (p = 0.025). However, only clinical stage remained significant after Bonferroni correction (p < 0.007). A trend was observed between PARK-2 promoter hypermethylation and its protein expression. Our study provided sufficient information and insight for investigation of PARK-2 and highlighted its role as a tumor suppressor gene in cervical cancer in North Indian population. PMID- 28631566 TI - Role of magnetic resonance spectroscopy to differentiate high-grade gliomas from metastases. AB - This study is to measure the diagnostic examination quality of magnetic resonance spectroscopy in differentiating high-grade gliomas from metastases. PubMed, Embase, and Chinese Biomedical databases were systematically searched for relevant studies published through 10 July 2016. Based on the data from eligible studies, heterogeneity and threshold effect tests were performed; pooled sensitivity, specificity, and areas under summary receiver-operating characteristic curve of magnetic resonance spectroscopy were calculated. Finally, seven studies with a total of 261 patients were included. Quantitative synthesis of studies showed that pooled sensitivity/specificity of Cho/NAA and Cho/Cr ratio in peritumoral region was 0.85 (95% confidence interval: 0.79-0.90)/0.93 (95% confidence interval: 0.80-0.99) and 0.86 (95% confidence interval: 0.76 0.92)/0.86 (95% confidence interval: 0.73-0.94). The area under the curve of the summary receiver-operating characteristic curve was 0.95 and 0.90. Pooled sensitivity, specificity, and area under the curve of magnetic resonance spectroscopy to identify high-grade gliomas from metastases were 0.85 (95% confidence interval: 0.79-0.90), 0.84 (95% confidence interval: 0.75-0.90), and 0.90, respectively. We concluded that magnetic resonance spectroscopy demonstrated moderate diagnostic performance in distinguishing high-grade gliomas from metastases. Furthermore, Cho/NAA ratio showed higher specificity and higher value of area under the curve than Cho/Cr ratio in peritumoral region. We suggest that Cho/NAA ratio of peritumoral region should be used to improve diagnostic accuracy of magnetic resonance spectroscopy for differentiating high-grade gliomas from metastases. PMID- 28631567 TI - MicroRNA-1285-5p influences the proliferation and metastasis of non-small-cell lung carcinoma cells via downregulating CDH1 and Smad4. AB - Abnormal expression of microRNAs has been reported to regulate gene expression and cancer cell growth, invasion, and migration. Recently, upregulation of hsa miR-1285 was demonstrated in bronchoalveolar lavage fluid samples from patients with lung cancer and downregulation in plasma level of stage-I lung cancer patients. However, the function and the underlying mechanism of miR-1285 in non small-cell lung carcinoma have not been elucidated. In this study, we found that miR-1285-5p, the mature form of miR-1285, was significantly upregulated in human non-small-cell lung carcinoma cell lines A549 and SK-MES-1. Additionally, cells transfected with the miR-1285-5p inhibitor LV-anti-miR-1285-5p demonstrated significantly inhibited proliferation and invasion and depressed migration. Further analysis demonstrated that the miR-1285-5p precursor LV-miR-1285-5p attenuated the expression of Smad4 and cadherin-1 (CDH1) but that LV-anti-miR 1285-5p showed opposite results. A luciferase reporter assay confirmed that miR 1285-5p targeted Smad4 and CDH1. Mechanism analyses revealed that silence of Smad4 and CDH1 significantly attenuated the inhibitory effects of LV-anti-miR 1285-5p on non-small-cell lung carcinoma growth and invasion. Taken together, our data suggest that miR-1285-5p functions as a tumor promoter in the development of non-small-cell lung carcinoma by targeting Smad4 and CDH1, indicating a novel therapeutic strategy for non-small-cell lung carcinoma patients. PMID- 28631568 TI - MiR-183 overexpression inhibits tumorigenesis and enhances DDP-induced cytotoxicity by targeting MTA1 in nasopharyngeal carcinoma. AB - MicroRNA 183 (miR-183) was identified to be downregulated in nasopharyngeal carcinoma spheroids and served as a tumor suppressor in nasopharyngeal carcinoma. However, the regulatory mechanism of miR-183 and its role in cisplatin (DDP) resistance in nasopharyngeal carcinoma cells are still unclear. The expression of miR-183 and metastasis-associated protein 1 at messenger RNA and protein levels in nasopharyngeal carcinoma tissues and cells was evaluated using quantitative reverse transcription real-time polymerase chain reaction and western blotting, respectively. CNE1 and CNE2 cells were transfected with miR-183 mimic, miR-183 inhibitor, pcDNA-metastasis-associated protein 1, or respective controls. The effects of miR-183 and metastasis-associated protein 1 overexpression on cell proliferation, invasion, and DDP-induced apoptosis were detected by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Transwell invasion assay, and flow cytometry analysis, respectively. Luciferase reporter assay was performed to explore whether miR-183 directly targeted metastasis-associated protein 1. Xenograft tumor experiment was applied to confirm the biological function of miR-183 in vivo. MiR-183 was downregulated in nasopharyngeal carcinoma tissues and cells and negatively correlated with metastasis-associated protein 1 expression. Ectopic expression of miR-183 markedly suppressed cell proliferation and invasion and strikingly enhanced DDP-induced apoptosis in nasopharyngeal carcinoma cells, whereas metastasis-associated protein 1 overexpression partially reversed these effects. Luciferase reporter assay demonstrated that metastasis-associated protein 1 was a direct target of miR-183. MiR-183 negatively regulated the expression of metastasis-associated protein 1 at both the messenger RNA and protein levels. Xenograft tumor experiment indicated that miR-183 overexpression repressed tumor growth and improved DDP-induced cytotoxicity in nasopharyngeal carcinoma cells in vivo. MiR-183 overexpression inhibited tumorigenesis and enhanced DDP-induced cytotoxicity by targeting metastasis-associated protein 1 in nasopharyngeal carcinoma, contributing to the development of novel therapeutic approaches for the treatment of clinical nasopharyngeal carcinoma patients. PMID- 28631569 TI - Insulin-induced enhancement of MCF-7 breast cancer cell response to 5 fluorouracil and cyclophosphamide. AB - The study was designed to evaluate the potential use of insulin for cancer specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments. PMID- 28631570 TI - The effect of RCAN1 on the biological behaviors of small cell lung cancer. AB - Bone is the third most common site of cancer metastasis. In total, 30%-40% of lung cancer cases can develop skeletal metastasis for which no effective therapy in clinic is available. RCAN1 (regulator of calcineurin 1) is an important regulator in angiogenesis which is vital to tumor growth. In this study, we investigated the changes of biological behaviors in SBC-5 and SBC-3 cells after the RCAN1 expression level was changed. Briefly, overexpression of RCAN1 significantly attenuated their malignancy, including decreased ability of proliferation, colony formation, migration, invasion, and bone adherence. Furthermore, the cell cycle progression was impeded. Although the opposite changes were observed in SBC-3 cells after the RCAN1 expression was suppressed by RNA interference, the apoptosis rate was not affected by the expression level of RCAN1 in these cells. So, our research revealed that RCAN1 was involved in the development of small cell lung cancer, and it might be a cancer-inhibiting gene for the formation of bone metastases in small cell lung cancer. PMID- 28631571 TI - A truncated p53 in human lung cancer cells as a critical determinant of proliferation and invasiveness. AB - As a transcription factor, p53 must accumulate in the nucleus to be effective. Signals related to nuclear localization are distributed mainly in the C-terminal of p53. So these nuclear location domains were reserved and the other part of the C-terminal was removed in this study. We investigated whether the truncated p53 (p53(DEL)) may affect proliferation and invasive potential of human lung cancer cells. H1299 and 801D cells expressing full-length p53 and the p53(DEL) were obtained by screening. Cell proliferation assay, cell apoptotic analysis, cell migration assay, and invasion assay were performed. Protein expression was examined by Western blotting. The data showed H1299-p53(DEL) and 801D-p53(DEL) cells grew more slowly than H1299-p53 and 801D-p53 cells, respectively. The colony formation of H1299-p53(DEL) and 801D-p53(DEL) cells reduced. The truncated p53 induced cell apoptosis. The expression levels of Bax and p53 upregulated modulator of apoptosis were increased in H1299-p53(DEL) and 801D-p53(DEL) cells. H1299-p53(DEL) and 801D-p53(DEL) cells were also characterized by decreased migration and invasion. The expression of the truncated p53 resulted in upregulation of E-cadherin and downregulation of Vimentin, Slug, Twist1, and zinc finger E-box-binding homeobox 1, which suggested the truncated p53 inhibited epithelial-mesenchymal transition occurrence. The above-mentioned characteristics were reverted by treatment of with pifithrin-a, a p53 inhibitor. These findings support the existence of a direct link between the p53(DEL), proliferation, epithelial-mesenchymal transition, and invasiveness in human lung cancer cells. So the p53(DEL) is a promising target for prevention and treatment of lung cancer. PMID- 28631572 TI - Endoplasmic reticulum stress could induce autophagy and apoptosis and enhance chemotherapy sensitivity in human esophageal cancer EC9706 cells by mediating PI3K/Akt/mTOR signaling pathway. AB - The study was designed to explore the mechanism of tunicamycin-induced endoplasmic reticulum stress in human esophageal cancer EC9706 cells and EC109 cells, as well as its effects on cell autophagy, apoptosis, and chemoresistance. Tunicamycin-induced endoplasmic reticulum stress model was established in EC9706 and EC109 cell lines. Western blotting was employed to detect the expression of endoplasmic reticulum stress iconic protein GRP78. 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay was used to evaluate the effect of different cisplatin and tunicamycin concentrations on survival rate of EC9706 cells and EC109 cells. Autophagy was monitored using monodansylcadaverin and apoptosis was detected by flow cytometry. Western blotting was used to detect the expressions of endoplasmic reticulum stress-related proteins (PERK, eIF2alpha, and CHOP), PI3K/Akt/mTOR signaling pathway-related proteins, autophagy-related proteins (LC3-I/LC3-II, Beclin-1, and p62), and apoptosis-related proteins (Bcl 2, Bax, and cleaved caspase-3). Tunicamycin led to increased expression of GRP78. With tunicamycin treatment, phosphorylation of PERK and eIF2alpha and CHOP expression increased. Meanwhile, the increase in cytolysosome was concentration and time dependent. With the increased tunicamycin concentration, there were increased expressions of Bax and cleaved caspase-3, decreased expression of Bcl 2, and lower phosphorylation of PI3K/Akt/mTOR signaling pathway-related proteins. Therefore, it can be concluded that the combination of tunicamycin and cisplatin could improve the sensitivity of EC9706 cells and EC109 cells to cisplatin; PI3K inhibitor BEZ235 could enhance cell autophagy and apoptosis and increase cell sensitivity to cisplatin. PMID- 28631573 TI - Effects of miR-1236-3p and miR-370-5p on activation of p21 in various tumors and its inhibition on the growth of lung cancer cells. AB - The mechanism of dsRNA-induced gene activation (RNAa) is being gradually unveiled. The plentiful evidence that it existed in mammalian species other than human demonstrated that dsRNA-mediated RNAa is a conservative phenomenon. Simultaneously, accumulating evidence suggested that microRNAs could activate gene expression by targeting promoter. Nevertheless, it is ambiguous whether microRNA-induced gene activation in different human cells is a common phenomenon. The study we performed verified that miR-1236-3p (miR-1236) and miR-370-5p can activate p21 expression in bladder cancer (BCa) T24, EJ cells, and non-small-cell lung carcinoma A549 cells, while in hepatocellular HepG2 cells both microRNAs cannot effectively induce the expression of P21WAF1/CIP1 (p21). In pancreatic cancer PANC-1 cells, only miR-370-5p had the potent abilities to induce p21 expression rather than miR-1236-3p. Unlike microRNA-mediated RNA activation, we can observe that dsP21-322 significantly activated p21 in above cells. Besides, we demonstrated that miR-1236 and miR-370 inhibited cyclin D1-CDK4/CDK6 pathway while upregulated E-cadherin expression by upregulation of p21. Overexpression of these two microRNAs in A549 induced cell-cycle arrest and cell senescence, delayed cell proliferation and colony formation, and inhibited migration and invasion. In conclusion, microRNA-mediated RNAa depends on the cell context, and miR-1236 and miR-370 can inhibit non-small-cell lung carcinoma cell growth by upregulating p21 expression in vitro. PMID- 28631574 TI - MicroRNA-125a-5p plays a role as a tumor suppressor in lung carcinoma cells by directly targeting STAT3. AB - Increasing evidence supports that the dysregulation of microRNA expression plays an important role in the process of tumor occurrence and development. Studies have found that mir-125a-5p expression was downregulated in a variety of tumors, but the effects and mechanism of mir-125a-5p in lung cancer are still unclear. The aim of this study is to detect the expression of mir-125a-5p in lung cancer tissues and lung cancer cell lines and to explore the effects of mir-125a-5p on the biological characteristics of lung cancer cells; thus, this study aims to provide new methods and new strategies for the treatment of lung cancer. The result from quantitative reverse transcription polymerase chain reaction showed that the expression of miR-125a-5p was significantly lower in lung cancer tissues and lung cancer cell lines (95-D, A549, HCC827, and NCI-H1299) than that in normal tissue adjacent to lung cancer or normal human bronchial epithelial cells. In order to explore the function and mechanism of mir-125a-5p in lung cancer cells, miR-125a-5p mimic or mir-125a-5p inhibitor was transfected into A549 cells. Mir-125a-5p displayed an obvious upregulation in A549 cells transfected with miR-125a-5p and an obvious downregulation in A549 cells transfected with mir 125a-5p inhibitor compared to that in A549 cells transfected with control miRNA. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, BrdU staining, flow cytometry, and Transwell assay showed that the upregulation of miR-125a-5p could significantly decrease the cell viability, proliferation, and invasion of lung cancer cells and increase apoptosis of lung cancer cells. The downregulation of miR-125a-5p provided very contrasting results. Computational algorithms predicted that the STAT3 is a target of miR-125a-5p. Here, we validated that miR 125a-5p could directly bind to the 3'-untranslated region of STAT3, and miR-125a 5p overexpression could significantly inhibit the protein expression of STAT3. These results suggested that mir-125a-5p can regulate the expression of STAT3 in lung cancer cells. To further verify whether mir-125a-5p can play a biological role through regulating STAT3, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H tetrazolium bromide, flow cytometry, and Transwell analysis demonstrated that overexpression of STAT3 can reverse the cells' biological effects induced by mir 125a-5p overexpression. Mir-125a-5p downregulated in lung cancer tissue and cell lines can negatively regulate STAT3 protein expression. Taken together, mir-125a 5p inhibited the proliferation and invasion of lung cancer cells and facilitated lung cancer cell apoptosis through suppressing STAT3. Enhancing the expression of miR-125a-5p is expected to benefit the therapy for the patients with lung cancer. PMID- 28631575 TI - Long non-coding RNA CCAT1/miR-218/ZFX axis modulates the progression of laryngeal squamous cell cancer. AB - Long non-coding RNAs have been proved to be closely associated with different cancers. This study was designed to elucidate the function and mechanisms of colon cancer-associated transcript-1 in the progression of human laryngeal squamous cell cancer. Expressions of colon cancer-associated transcript-1, microRNA-218, and zinc finger protein, X-linked messenger RNA were measured using quantitative real-time polymerase chain reaction, and the expression level of zinc finger protein, X-linked protein was detected using western blot. Proliferation and invasion of laryngeal squamous cell cancer cell lines were detected by Cell Counting Kit-8 assay and Transwell invasion assay, respectively. Luciferase assay was used to confirm whether microRNA-218 is a target of colon cancer-associated transcript-1 and whether microRNA-218 directly binds to 3' untranslated region of zinc finger protein, X-linked messenger RNA. Effect of colon cancer-associated transcript-1 on tumor growth was observed through xenograft mice models in vivo. The results showed that expressions of colon cancer-associated transcript-1 and zinc finger protein, X-linked were significantly higher while microRNA-218 expression was significantly lower in the laryngeal squamous cell cancer tissues than those in the adjacent normal tissues. MicroRNA-218 overexpression or zinc finger protein, X-linked silencing significantly suppressed proliferation and invasion of laryngeal squamous cell cancer cells. Moreover, knockdown of colon cancer-associated transcript-1 significantly inhibited proliferation and invasion of laryngeal squamous cell cancer cells, which were reversed by microRNA-218 downregulation or zinc finger protein, X-linked upregulation. Finally, colon cancer-associated transcript-1 silencing inhibited xenograft tumor growth of laryngeal squamous cell cancer in vivo. In conclusion, colon cancer-associated transcript-1 knockdown inhibits proliferation and invasion of laryngeal squamous cell cancer cells through enhancing zinc finger protein, X-linked by sponging microRNA-218, elucidating a novel colon cancer-associated transcript-1-microRNA-218-zinc finger protein, X linked regulatory axis in laryngeal squamous cell cancer and providing a promising therapeutic target for laryngeal squamous cell cancer patients. PMID- 28631576 TI - Mid-term results of percutaneous ventricular septal defect closure with Amplatzer Duct Occluder-II in children. AB - : Aim The aim of this study was to share the mid-term results of percutaneous ventricular septal defect closure using Amplatzer Duct Occluder-II in children. BACKGROUND: Nowadays, percutaneous ventricular septal defect closure is accepted as an alternative to surgery, but so far no ideal device has been developed for this procedure. METHODS: In the study centre, between April, 2011 and October, 2016, the ventricular septal defect of 49 patients was closed percutaneously using the Amplatzer Duct Occluder-II device, and seven of them were <1 year old. RESULTS: The mean age of patients was 86.8+/-52.6 months. The mean weight of the patients was 24.3+/-16 kg. The mean diameter of the defect was 3.7+/-1.4 mm. Mean fluoroscopy time and total procedure time were 37+/-19.3 and 74.1+/-27 minutes, respectively. The types of ventricular septal defects were muscular in six patients, and were perimembranous in the rest of them. We did not face any major complications during the procedure, but one patient was admitted with a complete atrioventricular block in the 6th month of follow-up. The total follow-up period was 66 months. CONCLUSION: To our knowledge, our study includes the largest series of paediatric patients whose ventricular septal defect was closed using Amplatzer Duct Occluder-II percutaneously. When the complications during the 66 month follow-up period are taken into consideration, we can state that Amplatzer Duct Occluder-II is a safe and effective device, even in infants aged <1 year. PMID- 28631577 TI - The impact of opioid medications on subsequent fractures in discharged emergency department patients with peripheral vertigo. AB - BACKGROUND: Vertigo is common in the emergency department (ED). Most aetiologies are peripheral and do not require hospitalization, but many patients still fear falling. Some patients may be taking opioid analgesic medications (for other reasons); the risk of falls leading to fractures among patients with vertigo could be potentiated by the simultaneous use of opioids. OBJECTIVES: To examine the risk of fractures in discharged ED patients with peripheral vertigo who were being prescribed opioids during the same time period. METHODS: Linked administrative databases from Ontario were used to compare discharged ED patients aged >=65 with peripheral vertigo to patients with urinary tract infection (UTI) from 2006 to 2011. We used Cox regression analysis with an interaction term to estimate the modifying effect of an opioid prescription on the hazard of fracture within 90 days. RESULTS: There were 13,012 patients with a peripheral vertigo syndrome and 76,885 with a UTI. Thirteen percent of the vertigo cohort and 25% of the UTI cohort had access to a filled opioid prescription. Compared to vertigo patients who did not fill an opioid prescription, the adjusted hazard of fracture among vertigo patients who did fill a prescription was 3.59 (95% CI 1.97-6.13). Among UTI patients who filled an opioid prescription the hazard ratio was 1.68 (95% CI 1.43-1.97) compared to UTI patients who did not. CONCLUSIONS: Patients discharged from the ED with peripheral vertigo who were also being prescribed opioids had a higher hazard of subsequent fracture compared to those who were not, and the effect was much greater than among UTI patients. These results suggest that in the acutely vertiginous older patient, opioid analgesic medications should be modified, where possible. PMID- 28631579 TI - Opening of KATP Channel Regulates Tonic Currents From Pyramidal Neurons in Rat Brain. AB - BACKGROUND: ATP-sensitive K+ (KATP) channels couple metabolic state to cellular excitability. Activation of neuronal and astrocytic mitochondrial KATP (mitoKATP) channels regulates a variety of neuronal functions. However, less is known about the impact of mitoKATP on tonic gamma-aminobutyric acid (GABA) inhibition. Tonic GABA inhibition is mediated by the binding of ambient GABA on extrasynaptic GABA A-type receptors (GABAARs) and is involved in regulating neuronal excitability. METHODS: We determined the impact of activation of KATP channels with diazoxide (DIZ) on tonic inhibition and recorded tonic current from rat cortical layer 5 pyramidal cells by patch-clamp recordings. RESULTS: We found that neonatal tonic current increased with an increase in GABA concentration, which was partially mediated by the GABA A-type receptor (GABAAR) alpha5, and likely the delta subunits. Activation of KATP channels resulted in decreased tonic current in newborns, but there was increased tonic current during the second postnatal week. CONCLUSIONS: These findings suggest that activation of KATP channels with DIZ regulates GABAergic transmission in neocortical pyramidal cells during development. PMID- 28631578 TI - The journey to autism: Insights from neuroimaging studies of infants and toddlers. AB - By definition, autism spectrum disorder (ASD) is a neurodevelopmental disorder that emerges during early childhood. It is during this time that infants and toddlers transition from appearing typical across multiple domains to exhibiting the behavioral phenotype of ASD. Neuroimaging studies focused on this period of development have provided crucial knowledge pertaining to this process, including possible mechanisms underlying pathogenesis of the disorder and offering the possibility of prodromal or presymptomatic prediction of risk. In this paper, we review findings from structural and functional brain imaging studies of ASD focused on the first years of life and discuss implications for next steps in research and clinical applications. PMID- 28631580 TI - Bulletproof heart: Gunshot wound to the ventricular septum without pericardial effusion or hemodynamic collapse. PMID- 28631581 TI - The writer's guide to education scholarship in emergency medicine: Education innovations (part 3). AB - OBJECTIVE: The scholarly dissemination of innovative medical education practices helps broaden the reach of this type of work, allowing scholarship to have an impact beyond a single institution. There is little guidance in the literature for those seeking to publish program evaluation studies and innovation papers. This study aims to derive a set of evidence-based features of high-quality reports on innovations in emergency medicine (EM) education. METHODS: We conducted a scoping review and thematic analysis to determine quality markers for medical education innovation reports, with a focus on EM. A search of MEDLINE, EMBASE, ERIC, and Google Scholar was augmented by a hand search of relevant publication guidelines, guidelines for authors, and website submission portals from medical education and EM journals. Study investigators reviewed the selected articles, and a thematic analysis was conducted. RESULTS: Our search strategy identified 14 relevant articles from which 34 quality markers were extracted. These markers were grouped into seven important themes: goals and need for innovation, preparation, innovation development, innovation implementation, evaluation of innovation, evidence of reflective practice, and reporting and dissemination. In addition, multiple outlets for the publication of EM education innovations were identified and compiled. CONCLUSION: The publication and dissemination of innovations are critical for the EM education community and the training of health professionals. We anticipate that our list of innovation report quality markers will be used by EM education innovators to support the dissemination of novel educational practices. PMID- 28631582 TI - Effect of green tea extract supplementation on glycogen replenishment in exercised human skeletal muscle. AB - The purpose of this study was to investigate the effects of 8-week green tea extract (GTE) supplementation on promoting postexercise muscle glycogen resynthesis and systemic energy substrate utilisation in young college students. A total of eight healthy male participants (age: 22.0 (se 1.0) years, BMI: 24.2 (se 0.7) kg/m2, VO2max: 43.2 (se 2.4) ml/kg per min) participated in this study. GTE (500 mg/d for 8 weeks) was compared with placebo in participants in a double blind/placebo-controlled and crossover study design with an 8-week washout period. Thereafter, all participants performed a 60-min cycling exercise (75 % VO2max) and consumed a carbohydrate-enriched meal immediately after exercise. Vastus lateralis muscle samples were collected immediately (0 h) and 3 h after exercise, and blood and gaseous samples were collected during the 3-h postexercise recovery period. An 8-week oral GTE supplementation had no effects on further promoting muscle glycogen resynthesis in exercised human skeletal muscle, but the exercise-induced muscle GLUT type 4 (GLUT4) protein content was greater in the GTE supplementation trial (P<0.05). We observed that, during the postexercise recovery period, GTE supplementation elicited an increase in energy reliance on fat oxidation compared with the placebo trial (P<0.05), although there were no differences in blood glucose and insulin responses between the two trials. In summary, 8-week oral GTE supplementation increases postexercise systemic fat oxidation and exercise-induced muscle GLUT4 protein content in response to an acute bout of endurance exercise. However, GTE supplementation has no further benefit on promoting muscle glycogen resynthesis during the postexercise period. PMID- 28631584 TI - Clinical characterization of Italian suicide attempters with bipolar disorder. AB - : IntroductionBipolar disorder (BD) is a chronic, highly disabling condition associated with psychiatric/medical comorbidity and substantive morbidity, mortality, and suicide risks. In prior reports, varying parameters have been associated with suicide risk. OBJECTIVES: To evaluate sociodemographic and clinical variables characterizing Italian individuals with BD with versus without prior suicide attempt (PSA). METHODS: A sample of 362 Italian patients categorized as BD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR) was assessed and divided in 2 subgroups: with and without PSA. Sociodemographic and clinical variables were compared between prior attempters and non-attempters using corrected multivariate analysis of variance (MANOVA). RESULTS: More than one-fourth of BD patients (26.2%) had a PSA, with approximately one-third (31%) of these having>1 PSA. Depressive polarity at onset, higher number of psychiatric hospitalizations, comorbid alcohol abuse, comorbid eating disorders, and psychiatric poly comorbidity were significantly more frequent (p<.05) in patients with versus without PSA. Additionally, treatment with lithium, polypharmacotherapy (>=4 current drugs) and previous psychosocial rehabilitation were significantly more often present in patients with versus without PSA. CONCLUSIONS: We found several clinical variables associated with PSA in BD patients. Even though these retrospective findings did not address causality, they could be clinically relevant to better understanding suicidal behavior in BD and adopting proper strategies to prevent suicide in higher risk patients. PMID- 28631585 TI - A case of intracardiac echinococcosis. AB - We describe a case of multisystemic cystic echinococcosis exhibiting intracardiac involvement. A lesion inside the lateral wall of the left ventricle induced negative T waves on leads V5 and V6. PMID- 28631583 TI - Dietary magnesium intake and fracture risk: data from a large prospective study. AB - Research considering the relationship between dietary Mg and osteoporosis as well as fractures are sparse and conflicting. We therefore aimed to investigate Mg intake and the onset of fractures in a large cohort of American men and women involved in the Osteoarthritis Initiative over a follow-up period of 8 years. Dietary Mg intake (including that derived from supplementation) was evaluated through a FFQ at baseline and categorised using sex-specific quintiles (Q); osteoporotic fractures were evaluated through self-reported history. Overall, 3765 participants (1577 men; 2071 women) with a mean age of 60.6 (sd 9.1) years were included. During follow-up, 560 individuals (198 men and 368 women) developed a new fracture. After adjusting for fourteen potential confounders at baseline and taking those with lower Mg intake as reference (Q1), men (hazard ratio (HR) 0.47; 95 % CI 0.21, 1.00, P=0.05) and women (HR 0.38; 95 % CI 0.17, 0.82, P=0.01) in the highest quintile reported a significantly lower risk for fracture. Women meeting the recommended Mg intake were at a 27 % decreased risk for future fractures. In conclusion, higher dietary Mg intake has a protective effect on future osteoporotic fractures, especially in women with a high risk for knee osteoarthritis. Those women meeting the recommended Mg intake appear to be at a lower risk for fractures. PMID- 28631586 TI - Benign positional vertigo and endolymphatic hydrops: what is the connection? AB - BACKGROUND: Although benign paroxysmal positional vertigo and endolymphatic hydrops are considered to be distinct diagnoses, a minority of vertiginous patients exhibit features of both conditions. This coincidence has been reported previously in the literature, and is reviewed here in terms of possible aetiology. RESULTS AND CONCLUSION: A new hypothesis to account for both conditions is offered, implicating free-floating degenerating debris from the otolithic apparatus. It is postulated that the gelatinous/proteinaceous component may account for an osmotically induced hydrops, while the calcified fragments may induce positional vertigo. PMID- 28631587 TI - Dietary supplementation with a nucleotide-rich yeast extract modulates gut immune response and microflora in weaned pigs in response to a sanitary challenge. AB - An experiment was carried out to evaluate the short-term effect of supplementing a nucleotide-rich yeast extract (NRYE) on growth performance, gut structure, immunity and microflora of piglets raised under sanitary and unsanitary conditions. A total of 84, 21-day old piglets were used in this study; 42 piglets were raised in a room designated as the clean room that was washed once per week, whereas the other 42 piglets were raised in a room designated as the unclean room in which 7 kg of manure from the sow herd was spread on each pen floor on day 1 and 7 and the room was not washed throughout the experiment. The pigs were fed a corn-soybean meal-based diet without or with 0.1% NRYE. Each treatment had 7 replicate pens in each room, and each pen housed 3 pigs. Feed disappearance and BW were recorded on day 1 and 14. On day 14, one pig per pen was euthanized to collect ileum, mesenteric lymph nodes and spleen tissues, and cecum and colon digesta. Overall, NRYE supplementation did not affect growth performance in both clean and unclean conditions, improved kidney weight in both clean (P=0.0002) and unclean room (P<0.0001) and tended to improve the villus height/crypt depth ratio in the clean room (P=0.073). Supplementing NRYE was associated with upregulation of Ileal programmed cell death gene-1 (P=0.0003), interleukin (IL)-1beta (P<0.0001), IL-6 (P=0.0003), IL-10 (P<0.0001) and tumor necrosis factor-alpha (TNF-alpha) (P<0.0001) in pigs raised in the unclean room. Supplementing the NRYE in pigs raised in the clean room suppressed growth of cecal Enterobacteriacea (P<0.0001) members and colonic Enterococcus spp. (P<0.019), improved proliferation of cecal Lactobacillus spp. (P<0.002) and colonic Clostridium cluster IV (P<0.011) and XVIa members (P<0.0002). Supplementing the NRYE in the unclean room improved proliferation of cecal Clostridium cluster IV (P<0.026) and suppressed proliferation of colonic Enterococcus spp. (P<0.037). In conclusion, supplementing the NRYE to piglets under unsanitary conditions improved ileal immune response by upregulating inflammatory cytokines, and positively modulated proliferation of beneficial gut bacteria and suppression of harmful ones in both clean and unclean rooms. PMID- 28631588 TI - Spawning performance of Clarias gariepinus (Burchell, 1822) induced with ethanol preserved and fresh catfish pituitary extract. AB - This study was conducted to determine the efficacy of preserved and fresh pituitary extract of Clarias gariepinus (Burchell, 1822) to induced spawning in the same species. Growth performance of fry was also monitored for 15 days to determine the possible effect of natural hormone treatment on the fry. Pituitary glands (PG) were obtained from 12 male broodstocks, six extracted PG were preserved in 96% ethanol 24 h before injection, while the other were extracted and used in their fresh state. The PG solutions (1 g ml-1 of saline water) were injected at 1 ml kg-1 of the female broodstock. Ovaprim(r) (a synthetic hormone) was used as the control and administered at a rate of 0.5 ml kg -1 of fish. After a uniform latency period of 9 h 30 min, fish were striped, fertilized, incubated and the performance evaluated. Results obtained revealed better hatching performance using Ovaprim(r) synthetic hormone (64.52%), however, preserved PG gave better hatchability (59.74%) than fresh PG extract (51.39%). After 15 days of feeding ad libitum with shell-free Artemia cysts, the growth of fry spawn with preserved PG was comparable with that of the control, while least performance was observed using the fresh PG. It was concluded that preservation of PG in ethanol 24 h before injection had a positive effect on breeding performance and could be exploited in the commercial production of C. gariepinus fingerlings. PMID- 28631589 TI - Comparison of protein expression during wild-type, and E1B-55k-deletion, adenovirus infection using quantitative time-course proteomics. AB - Adenovirus has evolved strategies to usurp host-cell factors and machinery to facilitate its life cycle, including cell entry, replication, assembly and egress. Adenovirus continues, therefore, to be an important model system for investigating fundamental cellular processes. The role of adenovirus E1B-55k in targeting host-cell proteins that possess antiviral activity for proteasomal degradation is now well established. To expand our understanding of E1B-55k in regulating the levels of host-cell proteins, we performed comparative proteome analysis of wild-type, and E1B-55k-deletion, adenovirus-infected cancer cells. As such we performed quantitative MS/MS analysis to monitor protein expression changes affected by viral E1B-55k. We identified 5937 proteins, and of these, 69 and 58 proteins were down-regulated during wild-type and E1B-55k (dl1520) adenovirus infection, respectively. This analysis revealed that there are many, previously unidentified, cellular proteins subjected to degradation by adenovirus utilizing pathways independent of E1B-55k expression. Moreover, we found that ALCAM, EPHA2 and PTPRF, three cellular proteins that function in the regulation of cell-cell contacts, appeared to be degraded by E1B-55k/E4orf3 and/or E1B 55k/E4orf6 complexes. These molecules, like integrin alpha3 (a known substrate of E1B-55k/E4orf6), are critical regulators of cell signalling, cell adhesion and cell surface modulation, and their degradation during infection is, potentially, pertinent to adenovirus propagation. The data presented in this study illustrate the broad nature of protein down-regulation mediated by adenovirus. PMID- 28631590 TI - Comparative Evaluation of Veriflow(r) Salmonella Species to USDA and FDA Culture Based Methods for the Detection of Salmonella spp. in Food and Environmental Samples. AB - Veriflow(r) Salmonella species (Veriflow SS) is a molecular-based assay for the presumptive detection of Salmonella spp. from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile), dairy (2% milk), raw meat (20% fat ground beef), chicken carcasses, and ready-to-eat (RTE) food (hot dogs). The assay utilizes a PCR detection method coupled with a rapid, visual, flow based assay that develops in 3 min post-PCR amplification and requires only an 18 h enrichment for maximum sensitivity. The Veriflow SS system eliminates the need for sample purification, gel electrophoresis, or fluorophore-based detection of target amplification and does not require complex data analysis. This Performance Tested MethodSM validation study demonstrated the ability of the Veriflow SS method to detect low levels of artificially inoculated or naturally occurring Salmonella spp. in eight distinct environmental and food matrixes. In each reference comparison study, probability of detection analysis indicated that there was no significant difference between the Veriflow SS method and the U.S. Department of Agriculture Food Safety and Inspection Service Microbiology Laboratory Guidebook Chapter 4.06 and the U.S. Food and Drug Administration Bacteriological Analytical Manual Chapter 5 reference methods. A total of 104 Salmonella strains were detected in the inclusivity study, and 35 nonspecific organisms went undetected in the exclusivity study. The study results show that the Veriflow SS method is a sensitive, selective, and robust assay for the presumptive detection of Salmonella spp. sampled from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile), dairy (2% milk), raw meat (20% fat ground beef), chicken carcasses, and RTE food (hot dogs). PMID- 28631591 TI - Comparative Evaluation of Veriflow(r)Listeria Species to USDA Culture-Based Method for the Detection of Listeria spp. in Food and Environmental Samples. AB - Veriflow(r) Listeria species (Veriflow LS) is a molecular-based assay for the presumptive detection of Listeria spp. from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile) and ready-to-eat (RTE) food matrixes (hot dogs and deli meat). The assay utilizes a PCR detection method coupled with a rapid, visual, flow-based assay that develops in 3 min post-PCR amplification and requires only a 24 h enrichment for maximum sensitivity. The Veriflow LS system eliminates the need for sample purification, gel electrophoresis, or fluorophore-based detection of target amplification and does not require complex data analysis. This Performance Tested MethodSM validation study demonstrated the ability of the Veriflow LS assay to detect low levels of artificially inoculated Listeria spp. in six distinct environmental and food matrixes. In each unpaired reference comparison study, probability of detection analysis indicated that there was no significant difference between the Veriflow LS method and the U.S. Department of Agriculture Food Safety and Inspection Service Microbiology Laboratory Guide Chapter 8.08 reference method. Fifty-one strains of various Listeria spp. were detected in the inclusivity study, and 35 nonspecific organisms went undetected in the exclusivity study. The study results show that the Veriflow LS is a sensitive, selective, and robust assay for the presumptive detection of Listeria spp. sampled from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile) and RTE food matrixes (hot dogs and deli meat). PMID- 28631592 TI - Blastomonas quesadae sp. nov., isolated from a saline soil by dilution-to extinction cultivation. AB - We isolated a Gram-stain-negative, aerobic bacterial strain, 912T, from a soil sample taken from Rambla Salada (Murcia), south-eastern Spain, by using the dilution-to-extinction method. Cells of the strain were motile with a polar flagellum, short rod-shaped, catalase- and oxidase-positive and grew at NaCl concentrations within the range 0-5 % (w/v) (optimum 3 %, w/v), at 4-32 degrees C (optimum 30 degrees C) and at pH 6-9 (optimum pH 7); bacteriochlorophyll a was produced. Analysis of the 16S rRNA gene sequence indicated that this strain belonged to the genus Blastomonas in the class Alphaproteobacteria. Its closest relatives were Blastomonas natatoria EY 4220T, Blastomonas ursincola KR-99T and Blastomonas aquatica PE 4-5T, to which the strain showed 16S rRNA gene sequence similarity values of 95.9, 95.8 and 95.1 %, respectively. The DNA G+C content was 63 mol%. The major fatty acids of strain 912T were C18 : 1omega7c/C18 : 1omega6c, C16 : 1omega7c/C16 : 1omega6c, C16 : 0 and C17 : 1omega6c. The predominant isoprenoid quinone was ubiquinone 10 (Q-10). The polar lipids contained diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, phosphoglycolipid, one unidentified phospholipid and two unidentified polar lipids. Based on the phylogenetic, genotypic, phenotypic and chemotaxonomic data, the strain represents a novel species of the genus Blastomonas, for which the name Blastomonas quesadae sp. nov. is proposed. Strain 912T (=CECT 9186T=LMG 29921T) is the type strain. PMID- 28631593 TI - A DENV-2-type-specific monoclonal antibody binds to the DENV-complex-reactive antigenic site on envelope protein domain 3. AB - The Dengue virus (DENV) envelope (E) protein is the major component of the viral surface and is structurally subdivided into three domains, ED1, ED2 and ED3. ED3 elicits potent neutralizing antibodies and contains two major antigenic sites: the DENV-type-specific and DENV-complex-reactive antigenic sites. Each site is composed of a limited subset of residues that are required for monoclonal antibody (mAb) binding. Here we show that DENV-2-type-specific mAb 9A3D-8 utilizes the functionally critical residues K307, V308, K310, I312, P332, L387, L389 and N390 for ED3 binding. Surprisingly, this DENV-type-specific epitope is predicted to overlap with the ED3 DENV-complex-reactive antigenic site on the viral surface. Further, this unique binding site enables mAb 9A3D-8 to neutralize virus infectivity at relatively low occupancy of virions compared to other ED3 mAbs identified to date. Together, the data in this study indicate that this is a new DENV-2-type-specific antigenic site on ED3. PMID- 28631594 TI - Human picornaviruses associated with neurological diseases and their neutralization by antibodies. AB - Picornaviruses are the most commonly encountered infectious agents in mankind. They typically cause mild infections of the gastrointestinal or respiratory tract, but sometimes also invade the central nervous system. There, they can cause severe diseases with long-term sequelae and even be lethal. The most infamous picornavirus is poliovirus, for which significant epidemics of poliomyelitis were reported from the end of the nineteenth century. A successful vaccination campaign has brought poliovirus close to eradication, but neurological diseases caused by other picornaviruses have increasingly been reported since the late 1990s. In this review we focus on enterovirus 71, coxsackievirus A16, enterovirus 68 and human parechovirus 3, which have recently drawn attention because of their links to severe neurological diseases. We discuss the clinical relevance of these viruses and the primary role of humoral immunity in controlling them, and summarize current knowledge on the neutralization of such viruses by antibodies. PMID- 28631595 TI - A 32 kDa viral attachment protein of lymphocystis disease virus (LCDV) specifically interacts with a 27.8 kDa cellular receptor from flounder (Paralichthys olivaceus). AB - The 27.8 kDa protein in flounder gill (FG) cells was previously proved to be a receptor specific for lymphocystis disease virus (LCDV) entry and infection. In this paper, a 32 kDa viral attachment protein (VAP) of LCDV specifically binding to the 27.8 kDa receptor (27.8R) was found by far-Western blotting coupled with monoclonal antibodies (MAbs) against 27.8R. The 32 kDa protein was confirmed to be encoded by the open reading frame (ORF) 038 gene in LCDV-C, and predicted to contain a putative transmembrane region, multiple N-myristoylation and glycosylation sites and phosphorylation motifs. The expression plasmid of pET-32a ORF038 was constructed and the recombinant VAP (rVAP) was obtained. Rabbit polyclonal antibodies against the rVAP were prepared and could recognize the rVAP and 32 kDa protein in LCDV. Immunogold electron microscopy showed that the 32 kDa protein was located on the surface of LCDV particles. Immunofluorescence assay demonstrated that the rVAP could bind to the 27.8R on the cell membrane of the FG monolayer and the anti-27.8R MAbs could block the rVAP binding. Pre-incubation of the rVAP with FG cells before LCDV infection, or pre-incubation of LCDV with the antibodies against the rVAP, could significantly decrease the LCDV copy numbers (P<0.05) and delay the emergence of cytopathic effects in FG cells in a dose dependent manner. These results indicated for the first time that the 32 kDa protein functioned as an attachment protein for the initial attachment and entry of LCDV, and the interaction of the 32 kDa VAP with the 27.8R-initiated LCDV infection. PMID- 28631596 TI - Cholesterol 25-hydroxylase acts as a host restriction factor on pseudorabies virus replication. AB - Cholesterol 25-hydroxylase (CH25H) catalyses the production of 25 hydroxycholesterol (25HC) from cholesterol by adding a second hydroxyl group at position 25. The aim of this study was to examine the antiviral effect of CH25H on pseudorabies virus (PRV), a swine pathogen that can cause devastating disease and economic losses worldwide. The results showed that porcine ch25h was induced by either interferon or PRV infection. PRV infection of porcine alveolar macrophages (3D4/21 cells) was attenuated by CH25H overexpression and enhanced by silencing of CH25H. Furthermore, treatment of 3D4/21 cells with 25HC inhibited the growth of PRV in vitro, suggesting that CH25H may restrict PRV replication by 25HC production. We further identified that the anti-PRV role of CH25H and 25HC was subject to their inhibitory effect on PRV attachment and entry. Collectively, these findings demonstrate that CH25H is an intrinsic host restriction factor in PRV infection of porcine alveolar macrophages. PMID- 28631597 TI - Colwellia agarivorans sp. nov., an agar-digesting marine bacterium isolated from coastal seawater. AB - A novel Gram-stain-negative, facultatively anaerobic, yellowish and agar digesting marine bacterium, designated strain QM50T, was isolated from coastal seawater in an aquaculture site near Qingdao, China. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate represented a member of the genus Colwellia and exhibited the highest sequence similarity (97.4 %) to Colwellia aestuarii SMK-10T. Average nucleotide identity (ANI) values based on draft genome sequences between strain QM50T and C. aestuarii KCTC 12480T showed a relatedness of 72.0 % (ANIb) and 85.1 % (ANIm). Cells of strain QM50T were approximately 0.3-0.6*0.8-2.5 um in size and motile by means of a polar flagellum. Growth occurred in the presence of 1.0-6.0 % (w/v) NaCl (optimum, 2.0 3.0 %), at pH 6.5-8.5 (optimum, pH 7.0) and at 4-37 degrees C (optimum, 28-30 degrees C). Strain QM50T was found to contain ubiquinone 8 (Q-8) as the predominant ubiquinone and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2 OH), C16 : 0 and C17 : 1omega8c as the main cellular fatty acids. Phosphatidylethanolamine and phosphatidylglycerol were found to be major polar lipids. The DNA G+C content of strain QM50T was determined to be 35.7 mol%. On the basis of phylogenetic and phenotypic data, strain QM50T represents a novel species of the genus Colwellia, for which the name Colwellia agarivorans sp. nov. is proposed. The type strain is QM50T (=KCTC 52273T=MCCC 1H00143T). PMID- 28631598 TI - In vitro and in vivo evidence of a potential A(H1N1)pdm09 antigenic drift mediated by escape mutations in the haemagglutinin Sa antigenic site. AB - Influenza A(H1N1)pdm09 virus continues to circulate worldwide without evidence of significant antigenic drift between 2009 and 2016. By using escape mutants, we previously identified six haemagglutinin (HA) changes (T80R, G143E, G158E, N159D, K166E and A198E) that were located within antigenic sites. Combinations of these mutations were introduced into the A(H1N1)pdm09 HA plasmid by mutagenesis. Reassortant 6 : 2 viruses containing both the HA and NA genes of the A(H1N1)pdm09 and the six internal gene segments of A/PR/8/34 were rescued by reverse genetics. In vitro, HA inhibition and microneutralization assays showed that the HA hexa mutant reassortant virus (RG1) escaped A(H1N1)pdm09 hyper-immune ferret antiserum recognition. C57Black/6 mice that received the vaccine formulated with A/California/07/09 were challenged with 2*104 p.f.u. of either the 6 : 2 wild type (WT) or RG1 viruses. Reductions in body weight loss, mortality rate and lung viral titre were observed in immunized animals challenged with the 6 : 2 WT virus compared to non-immunized mice. However, immunization did not protect mice challenged with RG1 virus. To further characterize the mutations causing this antigenic change, 11 additional RG viruses whose HA gene contained single or combinations of mutations were evaluated in vitro. Although the RG1 virus was still the least reactive against hyper-immune serum by HAI testing, mutations G158E and N159D within the Sa antigenic site appeared to play the major role in the altered antigenicity of the A(H1N1)pdm09 virus. These results show that the Sa antigenic site contains the most prominent epitopes susceptible to cause an antigenic drift, escaping actual vaccine protection. PMID- 28631599 TI - Efficacy and safety of omalizumab in children and adolescents with moderate-to severe asthma: A systematic literature review. AB - BACKGROUND: There are limited pediatric data about the use of omalizumab, especially the effectiveness and safety of omalizumab in the real-world management of allergic asthma. OBJECTIVE: The objective of this study was to summarize the safety and efficacy of omalizumab in both randomized clinical trials (RCT) used for U.S. Food and Drug Administration registration and real world studies (RWS) based on clinical care of children with moderate-to-severe asthma. METHODS: Studies that evaluated omalizumab use in patients <18 years old and with asthma, published between January 2003 and October 2016, were retrieved from medical literature data bases. Assessed outcomes included the following: exacerbation rates, spirometric indices, changes in asthma medication use, asthma control, patient-reported outcomes, and health care resource utilization. RESULTS: A total of five RWS were identified; outcomes reported were compared with three omalizumab RCTs. Overall, the mean rate of annual exacerbations was significantly lower after 6 months to 2 years of treatment with omalizumab in both RCTs and RWS. In two RCTs and three RWS, inhaled corticosteroid use was significantly reduced in patients who used omalizumab. Similar reductions in the use of rescue medication were also observed in the RCTs and RWS on omalizumab. Real-world evidence demonstrated improvement in forced expiratory volume in the first second of expiration (% predicted) in patients treated with omalizumab as well as significant improvement in the level of asthma control observed over 1 year. There also was evidence that omalizumab treatment reduced health care resource utilization, including fewer hospitalizations, emergency department visits, and unscheduled medical visits. Safety outcomes in all five RWS showed no new safety signals and demonstrated that omalizumab was well tolerated. CONCLUSION: Overall, RCT evidence strongly supported omalizumab efficacy and safety as add-on treatment in children 6 to 11 years old with moderate-to-severe persistent allergic asthma. RWS data confirmed these findings in an extended patient population of children and adolescents that is more generalizable to the actual day-to-day management of these patients. PMID- 28631600 TI - Inhibition of Carbonic Anhydrase IX by Ureidosulfonamide Inhibitor U104 Reduces Prostate Cancer Cell Growth, But Does Not Modulate Daunorubicin or Cisplatin Cytotoxicity. AB - Carbonic anhydrase (CA) IX has emerged as a promising target for cancer therapy. It is highly upregulated in hypoxic regions and mediates pH regulation critical for tumor cell survival as well as extracellular acidification of the tumor microenvironment, which promotes tumor aggressiveness via various mechanisms, such as augmenting metastatic potential. Therefore, the aim of this study was to analyze the complex interdependency between CA IX and the tumor microenvironment in prostate tumor cells with regard to potential therapeutic implications. CA IX was upregulated by hypoxia as well as acidosis in prostate cancer cells. This induction did not modulate intracellular pH but led to extracellular acidification. Pharmacological inhibition of CA IX activity by U104 (SLC-0111) resulted in a reduction in tumor cell growth and an increase in apoptotic cell death. Intracellular pH was reduced under normoxic and even more so under hypoxic conditions when CA IX level was high. However, although intracellular pH regulation was disturbed, targeting CA IX in combination with daunorubicin or cisplatin did not intensify apoptotic tumor cell death. Hence, targeting CA IX in prostate cancer cells can lead to intracellular pH dysregulation and, consequently, can reduce cellular growth and elevate apoptotic cell death. Attenuation of extracellular acidification by blocking CA IX might additionally impede tumor progression and metastasis. However, no beneficial effect was seen when targeting CA IX in combination with chemotherapeutic drugs. PMID- 28631601 TI - Viral genes and cellular markers associated with neurological complications during herpesvirus infections. AB - Despite the importance of neurological disorders associated with herpesviruses, the mechanism by which these viruses influence the central nervous system (CNS) has not been definitively established. Owing to the limitations of studying neuropathogenicity of human herpesviruses in their natural host, many aspects of their pathogenicity and immune response are studied in animal models. Here, we present an important model system that enables studying neuropathogenicity of herpesviruses in the natural host. Equine herpesvirus type 1 (EHV-1) is an alphaherpesvirus that causes a devastating neurological disease (EHV-1 myeloencephalopathy; EHM) in horses. Like other alphaherpesviruses, our understanding of virus neuropathogenicity in the natural host beyond the essential role of viraemia is limited. In particular, information on the role of different viral proteins for virus transfer to the spinal cord endothelium in vivo is lacking. In this study, the contribution of two viral proteins, DNA polymerase (ORF30) and glycoprotein D (gD), to the pathogenicity of EHM was addressed. Furthermore, different cellular immune markers, including alpha interferon (IFN-alpha), gamma-interferon (IFN-gamma), interleukin-10 (IL-10) and interleukin-1 beta (IL-1beta), were identified to play a role during the course of the disease. PMID- 28631603 TI - A single point mutation in Tomato spotted wilt virus NSs protein is sufficient to overcome Tsw-gene-mediated resistance in pepper. AB - The nonstructural protein (NSs) of Tomato spotted wilt virus (TSWV) was previously identified as an avirulence determinant for Tsw-based resistance on pepper. The NSs of wild-type (WT) and resistance-breaking (RB) TSWV strains isolated in Hungary had only two amino acid substitutions (104, 461). We have analysed the ability of the NSs and their point mutant variants to trigger Tsw mediated hypersensitive responses and RNA silencing suppressor (RSS) activity in patch assays. We identified a single amino acid change at position 104 (T-A) that was responsible for the necrosis induction or loss, while a significant difference was not detected in the RSS activity of the two parental strains. We have successfully complemented the infection of the WT strain on resistant pepper cultivar with the infectious S RNA transcript of the RB strain and the WT-T104A point mutant. Our work provides direct evidence that a single amino acid change can induce an RB phenotype. PMID- 28631602 TI - Nationwide overview of the distribution of hepatitis B virus genotypes in Brazil: a 1000-sample multicentre study. AB - The influence of hepatitis B virus (HBV) genotypes in the natural history of the disease and its response to antiviral treatment have been addressed in many studies. In Brazil, studies on HBV genotype circulation have been restricted to specific population groups and states. Here, we have conducted a nationwide multicentre study with an unprecedented sample size representing all Brazilian regions in an effort to better understand the viral variants of HBV circulating among chronic carriers. Seven HBV genotypes were found circulating in Brazil. Overall, HBV/A was the most prevalent, identified in 589 (58.7 %) samples, followed by HBV/D (23.4 %) and HBV/F (11.3 %). Genotypes E, G, C and B were found in a minor proportion. The distribution of the genotypes differed markedly from the north to the south of the country. While HBV/A was the most prevalent in the North (71.6 %) and Northeast (65.0 %) regions, HBV/D was found in 78.9 % of the specimens analysed in the South region. HBV/F was the second most prevalent genotype in the Northeast region (23.5 %). It was detected in low proportions (7 to 10 %) in the North, Central-West and Southeast regions, and in only one sample in the South region. HBV/E was detected in all regions except in the South, while monoinfection with HBV/G was found countrywide, with the exception of Central West states. Our sampling covered 24 of the 26 Brazilian states and the Federal District and is the first report of genotype distribution in seven states. This nationwide study provides the most complete overview of HBV genotype distribution in Brazil to date and reflects the origin and plurality of the Brazilian population. PMID- 28631604 TI - Vaccinia virus egress mediated by virus protein A36 is reliant on the F12 protein. AB - Egress of vaccinia virus from its host cell is mediated by the microtubule associated motor kinesin-1, and three viral proteins, A36 and the F12/E2 complex, have been implicated in this process. Deletion of F12 expression causes a more severe reduction in egress than deletion of A36 but whether these proteins are involved in the same or different mechanisms of kinesin-1 recruitment is unknown. Here it is shown that a virus lacking both proteins forms a smaller plaque than mutants lacking either gene alone, indicating non-redundant functions. A36 not only links virions directly to kinesin-1 but also nucleates actin polymerization to propel surface virions away from the host cell. To address the relative importance of these functions for virus spread, a panel of recombinant viruses was constructed in which the ability of A36 to bind kinesin-1 or to nucleate actin polymerization was abrogated individually or together, in the presence or absence of F12 expression. Analysis of these viruses revealed that in the presence of the F12 protein, loss of kinesin-1 interaction made a greater contribution to plaque size than did the formation of actin tails. However in the absence of F12, the ability of A36 to promote egress was abrogated. Therefore, the ability of A36 to promote egress by kinesin-1 is reliant on the F12 protein. PMID- 28631605 TI - Loss of Sendai virus C protein leads to accumulation of RIG-I immunostimulatory defective interfering RNA. AB - Retinoic acid inducible gene (RIG-I)-mediated innate immunity plays a pivotal role in defence against virus infections. Previously we have shown that Sendai virus (SeV) defective interfering (DI) RNA functions as an exclusive and potent RIG-I ligand in DI-RNA-rich SeV-Cantell infected cells. To further understand how RIG-I is activated during SeV infection, we used a different interferon (IFN) inducing SeV strain, recombinant SeVDeltaC, which, in contrast to SeV-Cantell is believed to stimulate IFN production due to the lack of the SeV IFN antagonist protein C. Surprisingly, we found that in SevDeltaC-infected cells, DI RNAs also functioned as an exclusive RIG-I ligand. Infections with wild-type SeV failed to generate any RIG-I-associated immunostimulatory RNA and this correlated with the lack of DI genomes in infected cells, as well as with the absence of cellular innate immune responses. Supplementation of the C protein in the context of SeVDeltaC infection led to a reduction in the number of DI RNAs, further supporting the potential role of the C protein as a negative regulator of DI generation and/or accumulation. Our findings indicate that limiting DI genome production is an important function of viral IFN antagonist proteins. PMID- 28631607 TI - One year in review 2017: ultrasound in crystal arthritis. AB - Musculoskeletal ultrasound (MSUS) has become a relevant part of rheumatology practice and research. This imaging modality substantially allows us to optimise the management of inflammatory, degenerative and crystal-related musculoskeletal diseases. MSUS is a valuable point-of-care tool to accurately assess intra articular and periarticular abnormalities involved in rheumatic diseases. Furthermore, MSUS is a bedside aid for guiding accurate and safe musculoskeletal diagnostic aspirations and therapeutic injections. This review provides an overview of the last year's literature on the role of MSUS in crystal arthritis. PMID- 28631606 TI - Highly pathogenic avian influenza H5N1 clade 2.3.2.1 and clade 2.3.4 viruses do not induce a clade-specific phenotype in mallard ducks. AB - Among the diverse clades of highly pathogenic avian influenza (HPAI) H5N1 viruses of the goose/Guangdong lineage, only a few have been able to spread across continents: clade 2.2 viruses spread from China to Europe and into Africa in 2005 2006, clade 2.3.2.1 viruses spread from China to Eastern Europe in 2009-2010 and clade 2.3.4.4 viruses of the H5Nx subtype spread from China to Europe and North America in 2014/2015. While the poultry trade and wild-bird migration have been implicated in the spread of HPAI H5N1 viruses, it has been proposed that robust virus-shedding by wild ducks in the absence of overt clinical signs may have contributed to the wider dissemination of the clade 2.2, 2.3.2.1 and 2.3.4.4 viruses. Here we determined the phenotype of two divergent viruses from clade 2.3.2.1, a clade that spread widely, and two divergent viruses from clade 2.3.4, a clade that was constrained to Southeast Asia, in young (ducklings) and adult (juvenile) mallard ducks. We found that the virus-shedding magnitude and duration, transmission pattern and pathogenicity of the viruses in young and adult mallard ducks were largely independent of the virus clade. A clade-specific pattern could only be detected in terms of cumulative virus shedding, which was higher with clade 2.3.2.1 than with clade 2.3.4 viruses in juvenile mallards, but not in ducklings. The ability of clade 2.3.2.1c A/common buzzard/Bulgaria/38 WB/2010-like viruses to spread cross-continentally may, therefore, have been strain-specific or independent of phenotype in wild ducks. PMID- 28631608 TI - One year in review 2017: pathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by both genetic and environmental factors. It has been postulated that a high risk genetic background, in combination with epigenetic marks and environmental exposures, leads to a cascade of events inducing synovitis and consequent destructive arthritis. The clinical picture of joint involvement in RA is the result of chronic inflammation of the synovium, characterised by interactions of resident cells such as fibroblast-like synoviocytes (FLS) with cells of the innate (e.g. macrophages, dendritic cells, mast cells and NK cells, neutrophils) and adaptive immune system (e.g. B and T lymphocytes). Currently, our understanding of the role of innate and adaptive immunity in the pathogenesis of RA is expanding. The concept of how immune responses contribute to the disease has dramatically evolved over the last 50 years. Shedding some light on the different aspects of RA pathogenesis will help to identify new targets for the development of disease-modifying therapies. Thus, in this review we report new insights in RA pathogenesis, resulting from a literature research date published in the last year. PMID- 28631609 TI - Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: time ready for a paradigm shift? PMID- 28631611 TI - The gene family that cheats Mendel. AB - Some alleles of the wtf gene family can increase their chances of spreading by using poisons to kill other alleles, and antidotes to save themselves. PMID- 28631610 TI - A large gene family in fission yeast encodes spore killers that subvert Mendel's law. AB - Spore killers in fungi are selfish genetic elements that distort Mendelian segregation in their favor. It remains unclear how many species harbor them and how diverse their mechanisms are. Here, we discover two spore killers from a natural isolate of the fission yeast Schizosaccharomyces pombe. Both killers belong to the previously uncharacterized wtf gene family with 25 members in the reference genome. These two killers act in strain-background-independent and genome-location-independent manners to perturb the maturation of spores not inheriting them. Spores carrying one killer are protected from its killing effect but not that of the other killer. The killing and protecting activities can be uncoupled by mutation. The numbers and sequences of wtf genes vary considerably between S. pombe isolates, indicating rapid divergence. We propose that wtf genes contribute to the extensive intraspecific reproductive isolation in S. pombe, and represent ideal models for understanding how segregation-distorting elements act and evolve. PMID- 28631613 TI - Repairing a bone defect with a three-dimensional cellular construct composed of a multi-layered cell sheet on electrospun mesh. AB - In addition to providing maneuverability, electrospun nanofibrous meshes can make excellent supports for constructing flexible cell sheets to regulate cell behavior by nanofiber features. With the target of bone regeneration, herein composite nanofibers with two different fiber arrangements (nestlike, random) were electrospun from a blend solution containing poly(l-lactide) (PLLA) and gelatin (1:1 in weight ratio). Unlike the non-woven morphology in a random nanofibrous mesh, PLLA/gelatin composite nanofibers in the nestlike nanofibrous mesh displayed both non-woven and parallel morphologies. Both kinds of nanofibrous mesh were ~50 MUm thick as-prepared, and shrank to ~30 MUm after seeding with bone mesenchymal stromal cells (BMSCs). After 7 days of in vitro culture, cell sheets could form on both meshes (CSM) and on the culture plate. It was found that application of nanofibrous mesh promoted the osteogenic differentiation of BMSC sheets compared with the control. The nestlike mesh displayed slight superiority over the random mesh in enhancing osteogenic differentiation, but their different fiber arrangements did not cause much difference in cell proliferation. Three-dimensional multi-layered CSM constructs were built by stacking four mono-layered CSMs together. The CSM constructs (based on a nestlike or random nanofibrous mesh) were incubated in vitro for 3 days before being implanted into rat cranial defects. In comparison with the control group, there was significant formation of new calcified bone in both CSM construct-filled groups at 12 weeks' post-operation. The nestlike group showed slightly better bone healing (based on both qualitative and quantitative analysis) than the random group, while showing insignificant differences. We showed that the concept of using a three-dimensional multi-layered CSM construct in enhancing bone regeneration was feasible. Future studies should take more nanofiber features (e.g. bioactive components) into account to further enhance osteogenesis. PMID- 28631612 TI - wtf genes are prolific dual poison-antidote meiotic drivers. AB - Meiotic drivers are selfish genes that bias their transmission into gametes, defying Mendelian inheritance. Despite the significant impact of these genomic parasites on evolution and infertility, few meiotic drive loci have been identified or mechanistically characterized. Here, we demonstrate a complex landscape of meiotic drive genes on chromosome 3 of the fission yeasts Schizosaccharomyces kambucha and S. pombe. We identify S. kambucha wtf4 as one of these genes that acts to kill gametes (known as spores in yeast) that do not inherit the gene from heterozygotes. wtf4 utilizes dual, overlapping transcripts to encode both a gamete-killing poison and an antidote to the poison. To enact drive, all gametes are poisoned, whereas only those that inherit wtf4 are rescued by the antidote. Our work suggests that the wtf multigene family proliferated due to meiotic drive and highlights the power of selfish genes to shape genomes, even while imposing tremendous costs to fertility. PMID- 28631614 TI - 3D-printed bioceramic scaffolds with antibacterial and osteogenic activity. AB - Bacterial infection poses a significant risk with the wide application of bone graft materials. Designing bone grafts with good antibacterial performance and excellent bone-forming activity is of particular significance for bone tissue engineering. In our study, a 3D printing method was used to prepare beta tricalcium phosphate (beta-TCP) bioceramic scaffolds. Silver (Ag) nanoparticles were uniformly dispersed on graphene oxide (GO) to form a homogeneous nanocomposite (named Ag@GO) with different Ag-to-graphene oxide mass ratios, with this being synthesized via the liquid chemical reduction approach. Ag@GO nanocomposites were successfully modified on the beta-TCP scaffolds by a simple soaking method to achieve bifunctional biomaterials with antibacterial and osteogenic activity. The prepared scaffolds possessed a connected network with triangle pore morphology and the surfaces of the beta-TCP scaffolds were uniformly modified by the Ag@GO nanocomposite layers. The Ag content in the scaffolds was controlled by changing the coating times and concentration of the Ag@GO nanocomposites. The antibacterial activity of the scaffolds was assessed with Gram-negative bacteria (Escherichia coli, E. coli). The results demonstrated that the scaffolds with Ag@GO nanocomposites presented excellent antibacterial activity. In addition, the scaffolds coated with Ag@GO nanocomposites conspicuously accelerated the osteogenic differentiation of rabbit bone marrow stromal cells by improving their alkaline phosphatase activity and bone-related gene expression (osteopontin, runt-related transcription factor 2, osteocalcin and bone sialoprotein). This study demonstrates that bifunctional scaffolds with a combination of antibacterial and osteogenic activity can be achieved for the reconstruction of large-bone defects while preventing or treating infections. PMID- 28631615 TI - Phonon-drag magnetoquantum oscillations in graphene. AB - A theory of low-temperature phonon-drag magnetothermopower [Formula: see text] is presented in graphene in a quantizing magnetic field. [Formula: see text] is found to exhibit quantum oscillations as a function of magnetic field B and electron concentration n e . The amplitude of the oscillations is found to increase (decrease) with increasing B (n e ). The behavior of [Formula: see text] is also investigated as a function of temperature. A large value of [Formula: see text] (~few hundreds of MUV K-1) is predicted. Numerical values of [Formula: see text] are compared with the measured magnetothermopower S xx and the diffusion component [Formula: see text] from the modified Girvin-Jonson theory. PMID- 28631616 TI - On the dynamics of perching manoeuvres with low-aspect-ratio planforms. AB - The dynamics of a simple perching manoeuvre are investigated using circular and aspect-ratio-two elliptical flat plates, as abstractions of low-aspect-ratio planforms observed in highly-manoeuvrable birds. The perching kinematic investigated in this study involves a pitch-up motion from an angle of attack of [Formula: see text] to [Formula: see text], while simultaneously decelerating. This motion is defined by the shape change number, [Formula: see text], which acts as a measure of the relative contributions of added-mass and circulatory effects. This motion has been observed in natural flyers during controlled landings, and has recently been explored through the use of a nominally two dimensional airfoil. The parameter space of low-aspect-ratio plates therefore serves to elucidate how realistic free-end conditions affect the timescales of vortex evolution, and therefore the relative contributions between added mass and circulation. The results presented herein suggest that for the low-aspect-ratio plates, the shedding of vortices occurs more rapidly than for equivalent two dimensional cases, and therefore faster pitching motions are required to compensate for the lower levels of lift and drag. Furthermore, the vortex topology and instantaneous forces that arise during the rapid-area changes show no sensitivity to aspect ratio, and strong collapse is observed between both flat plates. Similar aerodynamic advantages may therefore be exploited during perching manoeuvres by birds of various scale regardless of wing aspect ratio. PMID- 28631617 TI - HfO2 high-k solid-state incandescent devices: performance improvement using a Ti embedded layer and observation of conductive paths as light-emitting sources. AB - Solid-state incandescent light-emission devices (SSI-LEDs) with a metal-oxide semiconductor structure are promising candidates for future broadband light emission devices. In this work, the electrical and light-emission features of SSI LEDs based on HfO2 high-k thin films with or without the Ti-embedded layer on p type silicon wafers have been studied. It turns out that the Ti-embedded layer can effectively reduce the turn-on voltage, thus improving the fluorescence efficiency of SSI-LEDs. The combination of scanning electron microscopy, atomic force microscope (AFM) and conductive AFM results unambiguously clarifies that conductive filaments, which are formed due to local thermal excitation during the forming process, are accompanied by the formation of pits on the HfO2 surface and are responsible for the light emission. This work develops an effective approach to improving the luminescence performance of SSI-LEDs and experimentally explains the light-emitting mechanism of such devices, which is of great importance to eventually realizng broadband light-emitting devices with low power consumption. PMID- 28631618 TI - Exhaled carbon monoxide is correlated with ischemia reperfusion injuries during ex vivo lung perfusion in pigs. AB - Measurement of exhaled carbon monoxide (eCO) might help in the selection of lung grafts during ex vivo lung perfusion (EVLP) since its endogenous production is increased under ischemia reperfusion. The objective of this study was to measure eCO variations depending on the extent of lung ischemia reperfusion injuries. Using a porcine model and a laser spectrometer instrument, eCO was measured during EVLP. eCO was compared after 30 min (D0) or 24 h (D1) of cold ischemia. The ability of eCO to distinguish lungs deemed suitable for transplantation was evaluated. Six lungs were studied at D0 and compared to six lungs studied at D1. eCO was systematically higher on D1 (1.35 +/- 0.26 ppmv versus 0.95 +/- 0.31 ppmv, p = 0.01). The best threshold concentration for eCO to select lungs was 0.86 ppmv (area under the receiver operating characteristic curve: 0.65 [95% confidence interval: 0.34-0.97], p = 0.40). These results show that eCO varies during EVLP. The interpretation of this variation and the role of eCO as a biomarker of ischemia reperfusion injuries during EVLP should be tested in further clinical studies. PMID- 28631619 TI - Modeling trans-spinal direct current stimulation for the modulation of the lumbar spinal motor pathways. AB - OBJECTIVE: Trans-spinal direct current stimulation (tsDCS) is a potential new technique for the treatment of spinal cord injury (SCI). TsDCS aims to facilitate plastic changes in the neural pathways of the spinal cord with a positive effect on SCI recovery. To establish tsDCS as a possible treatment option for SCI, it is essential to gain a better understanding of its cause and effects. We seek to understand the acute effect of tsDCS, including the generated electric field (EF) and its polarization effect on the spinal circuits, to determine a cellular target. We further ask how these findings can be interpreted to explain published experimental results. APPROACH: We use a realistic full body finite element volume conductor model to calculate the EF of a 2.5 mA direct current for three different electrode configurations. We apply the calculated electric field to realistic motoneuron models to investigate static changes in membrane resting potential. The results are combined with existing knowledge about the theoretical effect on a neuronal level and implemented into an existing lumbar spinal network model to simulate the resulting changes on a network level. MAIN RESULTS: Across electrode configurations, the maximum EF inside the spinal cord ranged from 0.47 V m-1 to 0.82 V m-1. Axon terminal polarization was identified to be the dominant cellular target. Also, differences in electrode placement have a large influence on axon terminal polarization. Comparison between the simulated acute effects and the electrophysiological long-term changes observed in human tsDCS studies suggest an inverse relationship between the two. SIGNIFICANCE: We provide methods and knowledge for better understanding the effects of tsDCS and serve as a basis for a more targeted and optimized application of tsDCS. PMID- 28631620 TI - Effectiveness of pelvic lead blanket to reduce the doses to eye lens and hands of interventional cardiologists and assistant nurses. AB - The aim of the present study is to analyse quantitatively the potential reduction of doses to the eye lens and the hands of an operator and a nurse by the use of a pelvic lead blanket during coronary angiography (CA) and percutaneous transluminal coronary angioplasty (PTCA) procedures. Thermoluminescent dosimeters were used to assess dose levels to the left eye lens and fingers on both hands of both physician and nurses during single procedures performed with or without the lead blanket. The measurements were carried out at one medical centre and include dosimetric data from 100 procedures. Additional measurements including physician's and patient's doses were made on phantoms in the laboratory. In order to determine the reduction potential of the lead blanket, the doses normalized to DAP (Dose-Area Product) corresponding to the same position of dosimeter were compared against each other for both procedure categories (with and without protection). There was no statistically significant decrease observed in physicians' and nurses' eye lens doses, nor in doses normalized to DAP due to the use of the lead pelvic shield in clinic. However, some trend in reducing the eye lens doses by this shield can be observed. Regarding finger doses, the differences are statistically significant but only for physicians. The mean DAP normalised doses to the eye lens and left and right finger of physicians, in the presence of a ceiling-suspended transparent lead shield, were 2.24e-5 +/- 1.41e-5 mSv/MUGym2, 2.31e-4 +/- 1.21e-4 mSv/MUGym2, and 2.60e-5 +/- 1.57e-5 mSv/MUGym2 for standard procedures performed without the lead blanket, and 1.77e-5 +/- 1.17e 5 mSv/MUGym2, 1.70e-4 +/- 1.01e-4 mSv/MUGym2, and 1.86e-5 +/- 1.13e-5 mSv/MUGym2 for procedures performed with it. A comparison of the results from the laboratory and the clinic shows that they are consistent regarding the eye lens, while for fingers it suggests that the dose reduction properties of the lead shield are related to the physician's work technique and both patient and lead blanket sizes or its positioning. The highest degree of reduction is observed for cranial and caudal projections together with the use of a patient-adjustable lead blanket; about a 2-fold decrease in finger doses is expected for optimum conditions. However, the laboratory measurements suggest that the use of lead blanket might slightly increase the patient dose, but only when specific projections are constantly used. This limitation should be considered by cardiologists during clinical work if this protection is used. In the light of the presented results, the ceiling-suspended transparent lead shield and the lead glasses seem to be the preferred way to reduce the doses to the eye lens, compared to the lead blanket. PMID- 28631621 TI - Glancing angle deposition of sculptured thin metal films at room temperature. AB - Metallic thin films consisting of separated nanostructures are fabricated by evaporative glancing angle deposition at room temperature. The columnar microstructure of the Ti and Cr columns is investigated by high resolution transmission electron microscopy and selective area electron diffraction. The morphology of the sculptured metallic films is studied by scanning electron microscopy. It is found that tilted Ti and Cr columns grow with a single crystalline morphology, while upright Cr columns are polycrystalline. Further, the influence of continuous substrate rotation on the shaping of Al, Ti, Cr and Mo nanostructures is studied with view to surface diffusion and the shadowing effect. It is observed that sculptured metallic thin films deposited without substrate rotation grow faster compared to those grown with continuous substrate rotation. A theoretical model is provided to describe this effect. PMID- 28631622 TI - Highly-flexible, ultra-thin, and transparent single-layer graphene/silver composite electrodes for organic light emitting diodes. AB - Transparent conductive electrode (TCE) platforms are required in many optoelectronic devices, including organic light emitting diodes (OLEDs). To date, indium tin oxide based electrodes are widely used in TCEs but they still have few limitations in term of achieving flexible OLEDs and display techniques. In this paper, highly-flexible and ultra-thin TCEs were fabricated for use in OLEDs by combining single-layer graphene (SLG) with thin silver layers of only several nanometers in thickness. The as-prepared SLG + Ag (8 nm) composite electrodes showed low sheet resistances of 8.5 Omega/?, high stability over 500 bending cycles, and 74% transmittance at 550 nm wavelength. Furthermore, SLG + Ag composite electrodes employed as anodes in OLEDs delivered turn-on voltages of 2.4 V, with luminance exceeding 1300 cd m-2 at only 5 V, and maximum luminance reaching up 40 000 cd m-2 at 9 V. Also, the devices could work normally under less than the 1 cm bending radius. PMID- 28631623 TI - Morphological self stabilization of locomotion gaits: illustration on a few examples from bio-inspired locomotion. AB - To a large extent, robotics locomotion can be viewed as cyclic motions, named gaits. Due to the high complexity of the locomotion dynamics, to find the control laws that ensure an expected gait and its stability with respect to external perturbations, is a challenging issue for feedback control. To address this issue, a promising way is to take inspiration from animals that intensively exploit the interactions of the passive degrees of freedom of their body with their physical surroundings, to outsource the high-level exteroceptive feedback control to low-level proprioceptive ones. In this case, passive interactions can ensure most of the expected control goals. In this article, we propose a methodological framework to study the role of morphology in the design of locomotion gaits and their stability. This framework ranges from modelling to control aspects, and is illustrated through three examples from bio-inspired locomotion: a three-dimensional micro air vehicle in hovering flight, a pendular planar climber and a bipedal planar walker. In these three cases, we will see how simple considerations based on the morphology of the body can ensure the existence of passive stable gaits without requiring any high-level control. PMID- 28631624 TI - Printing-induced cell injury evaluation during laser printing of 3T3 mouse fibroblasts. AB - Three-dimensional bioprinting has emerged as a promising solution for the freeform fabrication of living cellular constructs, which can be used for tissue/organ transplantation and tissue models. During bioprinting, some living cells are unavoidably injured and may become necrotic or apoptotic cells. This study aims to investigate the printing-induced cell injury and evaluates injury types of post-printing cells using the annexin V/7-aminoactinomycin D and FAM DEVD-FMK/propidium iodide assays during laser printing of NIH 3T3 mouse fibroblasts. As observed, the percentage of post-printing early apoptotic mouse fibroblasts increases with the incubation time, indicating that post-printing apoptotic mouse fibroblasts have different initiation lag times of apoptosis due to different levels of mechanical stress exerted during laser printing. Post printing necrotic mouse fibroblasts can be detected immediately after printing, while post-printing early apoptotic mouse fibroblasts need time to develop into a late apoptotic stage. The minimum time needed for post-printing early apoptotic mouse fibroblasts to complete their apoptosis pathway and transition into late apoptotic mouse fibroblasts is from 4 h to 5 h post-printing. The resulting knowledge of the evolution of different apoptotic post-printing mouse fibroblasts will help better design future experiments to quantitatively determine, model, and mitigate the post-printing cell injury based on molecular signal pathway modeling. PMID- 28631625 TI - High-loading Fe2O3/SWNT composite films for lithium-ion battery applications. AB - Single-walled carbon nanotube (SWNT) films are a potential candidate as porous conductive electrodes for energy conversion and storage; tailoring the loading and distribution of active materials grafted on SWNTs is critical for achieving maximum performance. Here, we show that as-synthesized SWNT samples containing residual Fe catalyst can be directly converted to Fe2O3/SWNT composite films by thermal annealing in air. The mass loading of Fe2O3 nanoparticles is tunable from 63 wt% up to 96 wt%, depending on the annealing temperature (from 450 degrees C to 600 degrees C), while maintaining the porous network structure. Interconnected SWNT networks containing high-loading active oxides lead to synergistic effect as an anode material for lithium ion batteries. The performance is improved consistently with increasing Fe2O3 loading. As a result, our Fe2O3/SWNT composite films exhibit a high reversible capacity (1007.1 mA h g 1 at a current density of 200 mA g-1), excellent rate capability (384.9 mA h g-1 at 5 A g-1) and stable cycling performance with the discharge capacity up to 567.1 mA h g-1 after 600 cycles at 2 A g-1. The high-loading Fe2O3/SWNT composite films have potential applications as nanostructured electrodes for various energy devices such as supercapacitors and Li-ion batteries. PMID- 28631626 TI - From Editor's desk. PMID- 28631627 TI - Ameloblastoma: A 16-year clinicopathological study on Goan population. AB - BACKGROUND: Ameloblastoma is a benign slow growing tumor of odontogenic origin composed of epithelial cells that resemble enamel forming cells namely the ameloblasts however these lesional cells do not differentiate to produce enamel. They are locally aggressive and can cause severe abnormalities of the face and jaw. AIM: This study aimed to correlate the incidence and recurrence rates of ameloblastoma to the different clinical and histopathological parameters. METHODS: A study on ameloblastomas in the Goan population for 16 years (1999 2014) was carried out. Archived documented data of surgically treated cases of ameloblastomas were used in this study. RESULTS: It was revealed that out of 52 cases of ameloblastomas, a male preponderance was seen. Age predisposition was seen to favor the third-fourth decade, the most common site was the posterior aspect of lower jaw for new and recurrent cases. CONCLUSION: The study highlights, the possible etiological role of location influencing the incidence and recurrence rates of ameloblastomas. PMID- 28631628 TI - The absence of CD56 expression can differentiate papillary thyroid carcinoma from other thyroid lesions. AB - CONTEXT: The neural cell adhesion molecule CD56 is an antigen important for the differentiation of the follicular epithelium. Recent studies have reported low or absent expression of CD56 in papillary thyroid carcinoma (PTC) and its presence in normal thyroid tissue, benign thyroid lesions, and most follicular non-PTC tumors. AIM: We wish to estimate the value of CD56 in the differentiation of PTC (including follicular variant-PTC [FV-PTC]) from other nontumoral lesions and follicular thyroid neoplasias. SETTINGS AND DESIGN: This was a retrospective, case-control study. SUBJECTS AND METHODS: We analyzed the expression of CD56 in normal thyroid follicular tissue, 15 nonneoplastic thyroid lesions (nodular hyperplasia, Graves' disease, and chronic lymphocytic thyroiditis/Hashimoto), and 38 thyroid follicular cell neoplasms (25 cases of PTC). The immunohistochemical reactions were performed on sections stained with anti-CD56 antibody. STATISTICAL ANALYSIS USED: We used the Chi-square test, values of P< 0.05 being considered statistically significant. Risk analysis was applied on these studied groups, by calculating the odds ratio (OR) value. RESULTS: Our results indicated that CD56 immunoexpression had differentiated PTC from benign nonneoplastic lesions (P = 0.002), as well as from follicular neoplasias (P = 0.046). There were no significant differences regarding CD56 expression between FV-PTC and classical PTC (P = 0.436). The immunoexpression of CD56 has differentiated PTC from other thyroid non-PTC lesions (P < 0.001), with 26.4 OR value. CONCLUSIONS: CD56 has been proved to be a useful marker in the diagnosis of PTC, including FV-PTC. Its absence can help differentiate FV-PTC from other thyroid nodules with follicular patterns. PMID- 28631629 TI - Poorly differentiated thyroid carcinoma: A hospital-based clinicopathological study and review of literature. AB - INTRODUCTION: Poorly differentiated thyroid carcinoma (PDTC) is a rare aggressive malignancy of thyroid follicular cells and has unique features in morphology and behavior. This study was aimed to describe the experience of a tertiary medical center with PDTC within a 10-year period. MATERIALS AND METHODS: This is a descriptive retrospective study of eight cases of PDTC among 418 various thyroid carcinomas. All cases of PDTC were retrieved along with the clinicopathological information. RESULTS: Only eight cases (1.9%) of PDTC were diagnosed among 418 thyroid carcinomas. Mean age was 48.12 with 3:5 (male:female) and tumor size ranged 3-12 cm. PDTC were diagnosed coexisting with one or more other pathologies; nodular hyperplasia (four cases), papillary carcinoma (one case), follicular carcinoma (three cases), and Hashimoto thyroiditis (two cases); with >=60% PDTC component. Six cases associated with high-grade features died within 3 years after diagnosis. DISCUSSION: Mean age in this study was younger including a 20-year-old girl. Younger age was associated with better prognosis. Most of the cases had underlying benign thyroid lesions and differentiated thyroid carcinoma. Most of the PDTC had poor prognosis associated with PDTC component >=60%, tumor necrosis, high mitotic count, lymph node involvement, vascular invasion and distant metastasis; and these cases died within 3 years after diagnosis. CONCLUSION: Although treatment of PDTC remains surgery followed by radioiodine therapy, correct histopathological diagnosis is important for clinicians and oncologists to predict the prognosis. All thyroid carcinoma should be sampled thoroughly not to miss small foci of PDTC component. PMID- 28631630 TI - Diagnostic value of immunohistochemistry staining of Bcl-2, CD34, CD20 and CD3 for distinction between discoid lupus erythematosus and lichen planus in the skin. AB - BACKGROUND: Cluster of differentiation (CD) markers is a classification system for monoclonal antibodies against cell surface molecules on leukocytes and antigens from other cells. AIMS: The aim of this study is to evaluate immunohistochemical markers in patients with discoid lupus erythematosus (DLE) and lichen planus (LP) and correlation of these markers in two groups and with the normal group in the West of Iran. SETTINGS AND DESIGN: Analytical cross sectional study. MATERIALS AND METHODS: This study was performed on paraffin blocks of DLE and LP patients with normal group (21, 21 and 16 cases, respectively) between 2009 and 2012. Formalin-fixed, paraffin-embedded tissue sections from each DLE, LP, and normal skin biopsy specimen were cut into 4-MU thick sections and mounted on glass slides. Initial sections were stained with hematoxylin and eosin. Primary antihuman antibodies against CD3, CD20, CD34, and Bcl-2 were applied. Positive control samples for CD3, CD20, and Bcl-2 were received from lymph nodes and for CD34 from dermal microvessels. STATISTICAL ANALYSIS USED: SPSS version 19 (SPSS, Inc., Chicago, USA) and Microsoft Excel 2007. RESULTS: The mean staining for four markers was more significant in DLE and LP groups compared to normal group and for CD34 and CD3 was more significant in LP groups versus DLE group. CONCLUSIONS: CD3+, CD34+, Bcl-2+, and CD20+ cells are significantly higher in DLE and LP lesional skins versus normal skin. In addition, there were higher expressions of CD3 and CD34 in LP lesional skin versus DLE lesional skin. PMID- 28631631 TI - Ki-67 evaluation in breast cancer: The daily diagnostic practice. AB - CONTEXT: Breast cancer is the most common malignancy in females. It is routinely classified according to the WHO histological typing. However, there is also a molecular classification of breast cancer which is routinely substituted with surrogate subtypes based on expression of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors and proliferation index (PI). PI is defined as the percentage of Ki-67-positive cells among overall cell population. The method commonly applied by pathologists to determine PI is visual scoring of the sample. Strict recommendations for PI assessment do not exist. Thus, the mode of PI evaluation differs significantly between pathologists. AIMS: The aim of our study was to evaluate the daily approach to defining the PI. SETTINGS AND DESIGN: Four practicing nonscholar pathologists were asked to evaluate PI in cases of invasive breast carcinoma. SUBJECTS AND METHODS: The study was performed on a group of 98 patients diagnosed with invasive breast carcinoma. Immunohistochemical reaction was performed with monoclonal antibody against human Ki-67 antigen using Ventana BenchMark XT. STATISTICAL ANALYSIS USED: Results were compared using Pearson's and Spearman's rank correlation coefficients and Fleiss and Cohen's kappa values. RESULTS: Statistical analysis showed pairwise Pearson's coefficients ranging between 0.77 and 0.84 (P < 0.001) and Spearman's rank correlation coefficients ranging between 0.68 and 0.83 (P < 0.001). The Fleiss kappa value for the 14% cutoff point was 0.58 whereas for the 20% cutoff point was 0.60. The pairwise Cohen's kappa values ranged from 0.45 to 0.69 for the 14% cutoff point and 0.53 to 0.67 for the 20% cutoff point. Friedman's rank ANOVA test showed significant differences among the four pathologists (P < 0.001). CONCLUSIONS: Our study shows a significant difference in results and methods of evaluation of PI between pathologists. PMID- 28631632 TI - Risk of cardiac pacemaker pocket infection in a tertiary care hospital. AB - BACKGROUND: The risk of pacemaker pocket infections (PPIs) is rare with good antisepsis techniques and use of advanced antibiotics. However, injudicious antibiotic usage leads to the rise of multidrug-resistant bacteria, which may cause PPI. Few reports exist about the microbial spectrum of the PPI from our country, prompting us to study the same. METHODS: We conducted this retrospective observational study for 3 years (January 2013-February 2016) from all the patients with PPI. We collected the relevant clinical samples (blood and pus) for the microbial culture using a standard protocol. We included 100 samples collected from the medical staff and the hospital environment as a control sample. The data were analyzed using appropriate statistical methods and a P< 0.05 was considered statistically significant. RESULTS: Our data showed that 17 out of 160 (10.6%) patients had PPI. Coagulase negative Staphylococcus sp. was isolated in 7 (41.2%) patients, followed by Staphylococcus aureus in 4 patients (23.5%). Other isolated bacteria include multidrug-resistant Burkholderia cepacia (n = 3), Mycobacterium abscessus (n = 2) and polymicrobial infection in a single patient. One out of hundred surveillance samples grew B. cepacia. CONCLUSION: Our data revealed a high incidence of Gram-positive cocci causing PPI. Every hospital should formulate their antibiotic policy based on the pattern of the hospital flora and their drug sensitivity. PMID- 28631633 TI - Significance of vascular endothelial growth factor and CD31 and morphometric analysis of microvessel density by CD31 receptor expression as an adjuvant tool in diagnosis of psoriatic lesions of skin. AB - BACKGROUND: Pathogenesis of psoriasis is a debated issue. Several mechanisms have been proposed to identify the etiology and pathogenesis so that specific treatments can be given to patients with psoriasis. AIMS: (1) To compare pattern and distribution of vascular endothelial growth factor (VEGF) and CD31 in patients with psoriasis and other psoriasiform lesions of skin. (2) To study the correlation between VEGF and CD31 expression, clinical severity, and histopathology of psoriasiform lesions of skin. (3) Evaluation of microvessel density (MVD) by using computer-assisted quantitative image analysis in psoriatic skin lesions. MATERIALS AND METHODS: This study was conducted on eighty cases, out of which forty were diagnosed cases of psoriasis and forty cases of clinically suspected psoriasiform lesions, submitted in the Department of Pathology, Pt. B.D. Sharma, University of Health Sciences, Rohtak, for histopathological examination. Histopathological sections were stained by routine hematoxylin and eosin staining, and these biopsies were further subjected to immunohistochemical staining with VEGF and CD31 as per standard technique. RESULTS: Assessment of various histopathological features revealed strong correlation between epidermal hyperplasia, suprapapillary thinning, and elongation of rete ridges. Suprabasilar keratinocytes in psoriatic lesions stained intensely for VEGF. The difference for number of microvessels and MVD in psoriasis and psoriasiform lesions was statistically significant. Correlation between intensity of VEGF staining by suprabasilar keratinocytes and MVD was found to be highly significant in psoriatic lesions. CONCLUSION: The present study concluded that psoriatic lesions exhibit potent angiogenic activity. Early lesions show increased MVD along with other histomorphological parameters such as hypogranulosis, parakeratosis and Munro's microabscesses. Overexpression of VEGF by suprabasilar keratinocytes correlated with increased MVD in papillary dermis. PMID- 28631634 TI - Phenotypic and molecular characterization of cefotaximases, temoniera, and sulfhydryl variable beta-lactamases in Pseudomonas and Acinetobacter isolates in an Indian tertiary health-care center. AB - BACKGROUND: Cefotaximases (CTX-M), temoniera (TEM), and sulfhydryl variable (SHV) constitute a rapidly growing cluster of enzymes that have disseminated geographically. They are spreading to species other than Enterobacteriaceae and might be responsible for the presence of blaCTX-M,blaTEM, and blaSHVgenes in Pseudomonas and Acinetobacter spp. The present study was designed to characterize CTX-M, TEM, and SHV phenotypically and genotypically in Pseudomonas and Acinetobacter spp. MATERIALS AND METHODS: A total of 90 isolates (73 Pseudomonas and 17 Acinetobacter spp.), resistant to any of the third-generation cephalosporins, were randomly selected from clinical samples. RESULTS: Of 90 isolates, 64 (71.11%) were tested positive for extended-spectrum beta-lactamase (ESBL) production. Among phenotypically tested ESBL producers, forty isolates were randomly selected for molecular characterization. The prevalence of CTX-M, TEM, and SHV was found to be 57.5%, 15%, and 75%, respectively. Multiplex polymerase chain reaction assay categorized blaCTX-Mgenes into Groups 1 and 26 where Group 1 was present in only 5 isolates and Group 25 was present in rest of the 18 isolates. CONCLUSION: This is among the premier systemic reports from India documenting phenotypic and molecular characterization of CTX-M, TEM, and SHV beta-lactamases in Pseudomonas and Acinetobacter spp. With judicious use of antibiotics and strict infection control procedures, it may be possible to limit the effects of these newer beta-lactamases. PMID- 28631635 TI - Cytocentrifuged biopsy fixative preparation: A simple cost-effective technique facilitating microscopic diagnosis of lumen-dwelling intestinal parasites. AB - OBJECTIVE: Direct microscopic visualization is the most specific method for detecting intestinal parasites and is commonly achieved by stool examination or mucosal biopsy. However, postfixation, the intestinal biopsy fragment is often curled, and the entire surface of the biopsied mucosa is seldom viewed microscopically. Tissue processing further distorts morphology of the organisms and causes diagnostic difficulties. Examining multiple sections for parasite detection is time-consuming and often requires aid of special stains and/or immunohistochemistry. To overcome these disadvantages, we hypothesized that the fixative in which biopsies are transferred may provide a valid representation of the biopsied mucosal surface and therefore aid in the identification of mucosal surface parasites. MATERIALS AND METHODS: Formalin in which biopsies were transferred was retained, stored at 4 degrees C and processed with a cytocentrifuge. Totally, 120 consequent duodenal biopsy fixatives were processed in this way and the cytocentrifuged smears visualized after May-Grunwald-Giemsa staining. Findings of these smears were correlated with their corresponding formalin fixed paraffin embedded tissue sections. RESULTS: Cytocentrifuged formalin preparations were found to be representative of the mucosal surface contents. Giardia trophozoites were visualized in 10/120 preparations with distinct morphological characteristics which were seldom appreciable in tissue sections, eliminating the need for special stains. Furthermore, two of the corresponding histology sections did not demonstrate the parasites despite step sections, while in one case few parasites could be identified in the step sections. CONCLUSIONS: Cytocentrifuged fixative preparation is a simple and cost effective technique which can be routinely employed for intestinal parasite characterization. PMID- 28631636 TI - Profiling of peripheral T-cell lymphomas in Kerala, South India: A 5-year study. AB - BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are non-Hodgkin's lymphomas (NHLs) with considerable variation in incidence across the world. They show a wide variety of clinicopathological features and generally associated with poor clinical outcome. Lymphoma data from different geographic regions will definitely aid in routine clinical practice and research work. PTCLs are reported with a higher frequency in Asia as compared to Western countries. OBJECTIVE: The objective of this study was to analyze the frequency and distribution of PTCLs diagnosed in a tertiary care cancer center in Kerala. MATERIALS AND METHODS: This was a retrospective study carried out in the Division of Pathology, Regional Cancer Centre, Thiruvananthapuram, for 5 years from January 1, 2011, to December 31, 2015. All PTCLs diagnosed during this period were reviewed and then classified according to the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Statistical significance of the results was evaluated using Chi-square test. RESULTS: Among the total 3108 cases of lymphomas diagnosed at our center, 2404 cases were NHLs (77.35%). PTCLs (n = 333) contributed 13.85% of all NHLs. Among these, PTCL, not otherwise specified, constituted the most common subtype (92 cases, 27.63%), followed by angioimmunoblastic T-cell lymphoma (79 cases, 23.72%), anaplastic large cell lymphoma (75 cases, 22.52%), mycosis fungoides (28 cases, 8.40%), and adult T cell leukemia/lymphoma (ATLL) (28 cases, 8.40%). CONCLUSION: This is the largest study on PTCLs reported from Kerala. We document that the frequency of PTCLs is higher than that reported from Western studies. The frequency of ATLL reported from Kerala is much higher than that reported from other states. PMID- 28631637 TI - An integrated genomic profile that includes copy number alterations is highly predictive of minimal residual disease status in childhood precursor B-lineage acute lymphoblastic leukemia. AB - INTRODUCTION: Copy number alterations (CNA) have been described in childhood precursor B-lineage acute lymphoblastic leukemia (B-ALL) which in conjunction with chromosomal abnormalities drive leukemogenesis. There is no consensus on the clinical incorporation of CNA in B-ALL. An integrated genomic classification (IGC) has been proposed which includes CNA and cytogenetics. METHODS: We correlated this IGC with immunophenotypic minimal residual disease (MRD) as well as other standard criteria for 245 patients of B-ALL such as National Cancer Institute (NCI) risk, D+8 prednisolone response, cytogenetics, and ploidy status. RESULTS: MRD was detectable in 81 patients (33.1%). The most common abnormalities were seen in CDKN2A/B (25.7%) followed by PAX5(20%), ETV6(16.7%), IKZF1(15.5%), Rb1(5.3%), BTG (3.3%), EBF1(2.0%), and PAR1(0.8%). On integrating CNA into the IGC, 170 patients (69.4%) were classified into good genomic risk (GEN-GR) whereas 75 (30.6%) belonged to the poor genomic risk (GEN-PR) category. The IGC showed a significant correlation with MRD and NCI risk. The presence of CNA predicted MRD clearance in intermediate cytogenetics group. CONCLUSION: These data seem to indicate that in addition to cytogenetics, CNA should be incorporated into routine clinical testing and risk algorithms for B-ALL. The IGC is of prognostic relevance and offers an additional avenue for prognostication and risk-adapted therapy. PMID- 28631638 TI - Clinicomicrobiological profile of endophthalmitis: A 10 year experience in a Tertiary Care Center in North India. AB - PURPOSE: To determine the clinicomicrobiological profile of infectious agents and their antibiotic susceptibility in different type of endophthalmitis. METHODS: A retrospective review of clinical and microbiological records from January 2001 to December 2010, was performed in 1110 patients diagnosed with different type of endophthalmitis (postoperative, posttraumatic, endogenous and post keratitis) to record the demographic details, clinical presentations; microbiological agents isolated with their antimicrobial sensitivity pattern. Antimicrobial susceptibility testing for various culture positive isolates (bacterial/fungal) was performed by the disc diffusion technique. RESULTS: Out of the 1110 intra ocular specimens processed, 384 (34.6%) were positive for bacteria. S epidermidis was the most predominant isolate accounting for 42.7% of all bacteria obtained, followed by Pseudomonas aeruginosa (24.5%). Besides Pseudomonas, Acinetobacter spp. were the next common gram negative bacilli detected (8.3%) followed by Klebsiella, E. coli, Enterobacter and Alkaligenes in 2.6%, 0.8%, 0.8% and 0.5% cases respectively. The predominant fungal species were Aspergillus spp., in 36.1%, followed by Fusarium spp. in 26.4% cases. Overall susceptibility pattern in our study showed that gram positive bacteria were most susceptible to glycopeptides like vancomycin (80-100%) and fluoroquinolones (87-91%). The sensitivity pattern of gram negative organisms like Pseudomonas and Klebsiella towards fluoroquinolones ranged between 61% - 82%. CONCLUSION: S epidermidis was the most common bacteria isolated in postoperative and posttraumatic endophthalmitis, Pseudomonas aeruginosa was the most common bacterial isolated in posttraumatic endophthalmitisAmongst fungi Aspergillus was the most common organism. PMID- 28631639 TI - Prevalence of Clostridium difficile infection among the patients attending a tertiary care teaching hospital. AB - BACKGROUND: Clostridium difficile, a most important nosocomial enteric pathogen, is recognized globally as responsible for antibiotic-associated diarrhea and colitis. It is associated with considerable morbidity and mortality due to widespread use of antibiotics. AIMS: The study was done to determine the prevalence of C. difficile infection (CDI) among the patients attending a tertiary care teaching hospital in Puducherry. SETTINGS AND DESIGN: We performed a prospective cohort study in Mahatma Gandhi Medical College and Research Institute. MATERIALS AND METHODS: Around 150 patients were evaluated along with the patient details. C. difficile toxin detection was done as per the standard algorithm using the C. Diff Quik Chek Complete(r) assay (TECHLAB, Blacksburg, VA, USA). STATISTICAL ANALYSIS USED: Analysis was done using statistics software (SPSS 16.0, SPSS Inc., Chicago, IL, USA). RESULTS: The prevalence of CDI was found to be 4%. More toxin-positive cases were between 50 and 60 years of age, and there was no difference in gender. Intensive Care Unit showed more toxin positive cases; however, there was no significant association between the occurrence of CDI and the primary diagnosis of the patients. CONCLUSIONS: The prevalence of CDI in our hospital was found to be 4%, which was relatively lower compared to other Indian studies. However, awareness of the risk factors may assist in identifying patients at higher risk for CDI, guide implementation of appropriate preventive measures, and modulate potential intervention measure during management. PMID- 28631640 TI - Concept map as an adjunct tool to teach pathology. AB - CONTEXT: Concept maps (CMs) were tested for their effectiveness in teaching pathology in a conceptual manner. AIMS: To correlate the quality of CMs drawn by students with their performance on tests involving clinical problem-solving. SUBJECTS AND METHODS: Students were taught "how, why, and so what" about CMs at the start of the course. Each student drew one CM every week and a minimum of ten throughout the course and submitted them for evaluation and corrections. The course which is offered twice a year (approximately 600 students in each class) generates approximately 12,000-13,000 CMs each year. Two thousand nine hundred CMs from 290 students in one class were included in the study. Each CM was scored by three authors independently. The students' scores on the CMs were correlated with their scores on the midterm and final examinations. STATISTICAL ANALYSIS USED: Wilcoxon signed-rank test and Spearman's rank-order correlation. RESULTS: The mean scores for the CMs at the course's midterm and final were 59% and 69.7%, and the mean scores for the examinations were 76% and 84.2% on the midterm and finals, respectively. There was a highly significant correlation between the CM scores and examination scores (P < 0.0001). CONCLUSION: CMs proved to be a great tool to teach pathology effectively. PMID- 28631641 TI - Placental histopathological findings in preterm/term and early/late onset small for gestation age: Are they significant? AB - We undertook a prospective comparison of placental histopathological findings in preterm versus term and early onset versus late onset small for gestation age (SGA) to find more information on the etiological aspects of this disorder. A total of 130 women with nonanomalous SGA were allocated into preterm (n = 60); term (n = 70); early onset (n = 9) and late onset (n = 121) groups. The blinded intergroup placental histopathology comparison was performed both qualitatively (type of lesion) and quantitatively (number of the lesion). All SGA placentae showed varying number of maternal underperfusion (MUP), fetal under perfusion, inflammatory, and others lesions. There was a slight higher percentage of placenta having MUP in preterm and early onset SGA. Perivillous fibrin deposition was peculiar for placenta of preterm SGA (P = 0.043). Both preterm and early onset SGA had a higher number of placental lesions, but there was no statistical difference either in type or number of the placental lesion in any of the examined groups. PMID- 28631643 TI - Multidrug-resistant tuberculosis detection and characterization of mutations in mycobacterium tuberculosis by genotype MTBDRplus. AB - Detection of drug resistance in Mycobacterium tuberculosis by conventional phenotypic drug susceptibility testing methods requires several weeks. Therefore, molecular diagnostic tests for rapid detection of multidrug resistance tuberculosis (MDR-TB) are urgently needed. Early diagnosis helps in initiating optimal treatment which would not only enable cure of an individual patient but also will curb the transmission of drug resistance in the community. Line probe assay (LPA) has shown great promises in the diagnosis of MDR-TB. All MDR suspect patients from ten-linked districts were asked to deposit sputum samples at peripheral designated microscopy centers. The district TB officers facilitated the transport of samples collected during February 2014-December 2014 to our laboratory. The detection of rpoB gene mutations for rifampicin (RIF) and katG and inhA genes for isoniazid (INH), respectively, was performed on 663 samples by LPA. A total of 663 sputum samples from MDR suspects were received of which 321 (50.8%) were found to be MDR. Missing of WT8 along with mutation in codon S531 L was the most common pattern for RIF-resistant isolates (80.8%) and missing WT along with mutation in codon S315T1 of k atG gene was the most common pattern for INH-resistant isolates (91.3%).The MDR-TB in Eastern Uttar Pradesh, India, was found to be 50.8%. The common mutations obtained for RIF and INH in the region was mostly similar to those reported earlier. PMID- 28631642 TI - Sporadic occurrence of cryptococcal meningitis in HIV-seronegative patients: Uncommon etiology? AB - Cryptococcosis in HIV-seronegative patients is rarely reported from India. This prospective study was conducted to look for cryptococcal meningitis in HIV seronegative individuals and compare their laboratory features to cryptococcal meningitis in HIV-seropositive patients. Cerebrospinal fluid was collected from 153 suspected cases of meningitis and subjected to India ink preparation, antigen detection, and culture. Nineteen samples tested positive for Cryptococcus neoformans infection. Seventeen and two patients were HIV reactive and nonreactive, respectively. In vitro susceptibility of C. neoformans isolates to fluconazole and amphotericin B was performed using standard broth microdilution method and E-test. Eighteen strains were susceptible to amphotericin B, while fluconazole was reported susceptible in 15 strains. Hence, index of suspicion of C. neoformans infection as possible cause of meningitis must be maintained even in HIV-negative patients. Use of amphotericin B for treating C. neoformans meningitis should be restricted to prevent any increase in resistance. PMID- 28631644 TI - Evaluation of a new rapid kit, BD MGIT TBc identification test for confirmation of Mycobacterium tuberculosis complex. AB - At present, three rapid kits are available globally for the confirmation of Mycobacterium tuberculosis complex (MTBC) in cultures by MPT64 antigen (MPT64 Ag) detection. These include Capilia TB, SD Bioline, and BD MGIT TBc Identification (TBcID). The third kit is yet to be validated in India. We have tested this kit and compared with SD Bioline using conventional tests as gold standard. Seventy one MTBC (70 M. tuberculosis and one Mycobacterium bovis) and four nontuberculous mycobacteria (NTM) were isolated from 649 clinical specimens in MGIT 960 and/or Lowenstein-Jensen slants (LJ). MPT64 Ag was detected by both TBcID and SD Bioline kits in all the 71 clinical isolates and the reference strain M. tuberculosis H37Rv. All NTM species tested were negative by the two different kits. Thus, TBcID kit showed 100% concordance in terms of sensitivity and specificity. Rapid kits confirm MTBC cultures within 15 min in contrast to several weeks' time required by conventional techniques. PMID- 28631645 TI - Primary leptomeningeal primitive neuroectodermal tumor: A difficult entity to diagnose. AB - A 25-year-old male presented with difficulty in walking, loss of vision, and seizures. A clinical possibility of craniospinal meningeal pathology was considered. On computed tomography (CT) scan and magnetic resonance imaging, there was an enhancement of leptomeninges with few ring-enhancing lesions in both frontal lobes and right frontoparietal region. He was evaluated for low backache and occipital headache 21/2 years earlier and was found to have communicating hydrocephalus on CT scan. He underwent ventriculoperitoneal shunt and was followed up with CT scans. Meningeal biopsy was done in the present admission, and there was a diffusely infiltrating small round cell tumor. Immunohistochemistry was done, and the tumor cells were found to be negative for glial, mesenchymal, melanotic, and lymphoid markers. The cells were positive for neuron-specific enolase, chromogranin, and vimentin. A diagnosis of primitive neuroectodermal tumor involving the meninges was made. A possibility of primary leptomeningeal tumor extending to parenchyma was considered based on the clinical progression. Patient was treated with chemotherapy and radiotherapy. He improved partially and was stable at 3-year follow-up. PMID- 28631646 TI - Primitive neuroectodermal tumor presenting as a presacral mass: A rare case report with review of literature. AB - Primitive neuroectodermal tumors (PNETs) are a group of highly malignant small round cell tumor (SRCT) of neuroectodermal origin. They exhibit a great diversity in their clinical manifestations and pathologic similarities with other SRCTs. PNET commonly occurs in the central nervous system, head and neck region, paravertebral region, pelvis, and lower extremities. PNET presenting as a presacral mass is very rare. We present a case of 65-year-old female patient presented with a mass in the abdomen. Exploratory laparotomy with excision of mass was carried out. Histopathology revealed the diagnosis of PNET. The rarity of PNET at presacral region prompted the description of this case. PMID- 28631648 TI - Leiomyosarcoma of inferior vena cava with intracardiac extension presenting as Budd-Chiari syndrome: Report of a rare case. AB - Primary leiomyosarcoma of vascular origin is a rare malignant smooth muscle tumor. This report describes a case of primary leiomyosarcoma of the inferior vena cava (IVC) in a 52-year-old male who presented with complaints of abdominal pain, chest pain, and bilateral lower limb swelling for 4 months. Imaging of the chest and abdomen revealed a mass in the IVC extending into right atrium, heterogeneous enhancement of liver, hepatosplenomegaly, and ascites. Histopathological examination showed a malignant spindle cell tumor with cells arranged in fascicular and hemangiopericytomatous pattern. Immunohistochemistry for smooth muscle actin and desmin confirmed smooth muscle origin of the tumor. Recognition of this tumor in this rare location and Budd-Chiari syndrome-like presentation is imperative for proper management of the patient. PMID- 28631647 TI - Intrahepatic biliary cystadenoma with ciliary metaplasia: Report of a rare morphological variant. AB - Histological diagnosis of biliary cystadenoma is based on the type of epithelial cells lining the cyst and radiological features. The cyst-lining cells are not usually ciliated. We herein report a very rare example of an intrahepatic biliary cystadenoma with ciliated epithelial lining, which had taken us away from this diagnosis toward an intrahepatic foregut duplication cyst. Radiologically, also the lesion was deceptive, and a possibility of hydatid cyst was considered. However, immunohistochemical workup finally led us to this diagnosis. This report would document this rare morphological variant, which may pose diagnostic difficulty. PMID- 28631649 TI - Chlamydia trachomatis proctitis masquerading as carcinoma rectum: First case report from India. AB - While proctitis is caused both by infectious and noninfectious causes, infectious causes are acquired typically sexually. Chlamydia trachomatis, which is the most frequent bacterial pathogen causing sexually transmitted infections worldwide, is one of the causative agents of proctitis. We report a case history of a bisexual male who presented to us with rectal bleeding. The colonoscopy showed a nodular ulcerated lesion in the rectum suggestive of rectal malignancy, but biopsies from rectal mass did not reveal malignancy. A rectal biopsy was positive for C. trachomatis by polymerase chain reaction assay, and a diagnosis of C. trachomatis proctitis was made. Considering the invasive anorectal disease and patient's sexual history, he was treated with prolonged doxycycline therapy as per Centres for Disease Control and Prevention's treatment recommendation for lymphogranuloma venereum. A high index of clinical suspicion along with appropriate microbiological testing can clinch the diagnosis of C. trachomatis infection. PMID- 28631650 TI - Extraskeletal mesenchymal chondrosarcoma at unusual location involving spleen and kidney with review of literature. AB - Mesenchymal chondrosarcoma (MC) is a rare malignant neoplasm bearing characteristic dimorphic pattern histologically. We describe two rare cases of primary MC involving two different visceral organs (1) a 24-year-old man with solid renal mass and, (2) a 42-year-old man with cystic splenic mass. The histological and immunophenotypical features of both lesions were classical of MC. Although this lesion is uncommon in visceral organs, the possibility of this rare entity must be kept in differential diagnosis with compatible morphology. PMID- 28631651 TI - Follicular variant of peripheral T-cell lymphoma. AB - Globally, peripheral T-cell lymphomas (PTCLs) constitute about 12% of all non Hodgkin lymphomas, of which the unspecified category is the most common subtype (30%). Mostly, the unspecified category shows a diffuse pattern of involvement in the lymph nodes. However, rarely, they may show a follicular/nodular pattern mimicking a follicular lymphoma. We report a case of a follicular variant of PTCL, not otherwise specified. This case displayed a striking nodular/follicular pattern with an admixture of small (centrocyte-like) and large (centroblast-like) cells, thus mimicking a follicular lymphoma. The neoplastic cells were strongly positive for both CD3 and CD20. In addition, they were positive for pan T-cell markers and PD-1. T-cell receptor gene rearrangement studies highlighted a monoclonal T-cell population. Even though this variant of PTCL is very rare, it is important to keep it as a differential for the lymphomas exhibiting nodular pattern. PMID- 28631652 TI - Primary cutaneous large B-cell lymphoma of scalp: Case report of a rare variant. AB - Primary cutaneous large B-cell lymphoma (Bcl) is defined as a lymphoma composed of large cells constituting more than 80% of the infiltrate and absence of extracutaneous involvement after staging investigations. In the new World Health Organization/European Organization for Research and Treatment of Cancer classification, cutaneous Bcls with large cells are of three types - primary cutaneous large Bcl leg type (PCLBCLLT), primary cutaneous follicle center lymphoma diffuse type (PCFCLDT), and primary cutaneous large Bcls other (PCLBCLO). These three different types are distinct in terms of their clinicopathological features and survival. The PCLBCLO has intermediate features between those of PCLBCLLT and PCFCLDT. We present a case of PCLBCLO in a 57-year old male who presented with a scalp swelling. Ultrasonography examination was suggestive of a sebaceous cyst. Computed tomography scan revealed the presence of an ill-defined hyperdense region in the soft tissue of the scalp region extending into the deeper layers of the scalp. Fine-needle aspiration cytology (FNAC) revealed the presence of atypical lymphoid cells. Diagnosis was confirmed by biopsy and immunohistochemistry. Patient received rituximab combined with doxorubicin, vincristine, cyclophosphamide, and prednisolone regimen with complete resolution of the lesion. We present this case for its rarity, the utility of FNAC in early diagnosis, and to discuss the differential diagnosis. PMID- 28631653 TI - Hodgkin's lymphoma with unusual pulmonary presentations: Reporting two cases. AB - Classical Hodgkin's lymphoma (CHL) presenting with exclusively pulmonary symptoms is very unusual. We report two cases of CHL with atypical clinical presentations mimicking pulmonary infections. The first case represents a stage IV CHL with secondary lung involvement, and the second case demonstrates a very rare case of CHL with isolated lung involvement, also known as primary pulmonary Hodgkin's lymphoma. The second patient was initially misdiagnosed and treated with six months of antibiotics before the correct diagnosis was made by a lung biopsy. Both patients received chemotherapy; one patient achieved complete remission and the other achieved near-complete remission. PMID- 28631654 TI - Composite lymphoma with coexistence of diffuse large B-cell lymphoma and anaplastic large cell lymphoma: Diagnostic pitfalls. AB - Composite lymphoma is a rare tumor composed of two or more distinct lymphomas in the same topographic site or tissue. Several combinations of B-cell non-Hodgkin lymphoma (NHL), T-cell NHL, and Hodgkin lymphoma can occur with different prognoses and treatments. The coexistence of a B-cell NHL and a T-cell NHL is unusual. The exact etiology of composite lymphoma is unknown; however, few mechanisms have been proposed to explain its pathogenesis. The chemotherapeutic protocols are heterogeneous but are essentially targeted against the high-grade component. Most of the cases show worse outcome with a median survival of 12 months. In this article, we report a case of composite lymphoma which was initially diagnosed as diffuse large B-cell lymphoma, and the presence of CD3 positive atypical cells in the bone marrow urged us to re-evaluate the lymph node biopsy following which a focus of Alk-1-positive anaplastic large cell lymphoma was identified. PMID- 28631655 TI - Erratum: Squash cytodiagnosis of synchronous papillary serous carcinoma of ovary and endometrium with demonstration of serous tubal intraepithelial carcinoma as a precursor lesion. AB - [This corrects the article DOI: 10.4103/0377-4929.200039]. PMID- 28631656 TI - Brevundimonas diminuta infection in a case of nephrotic syndrome. AB - Brevundimonas has rarely been isolated from clinical specimens. We here report a case of Brevundimonas diminuta infection in an 18-year-old male patient with nephrotic syndrome. B. diminuta was identified by the VITEK 2 Compact system, following isolation from his blood sample. To the best of our knowledge, B. diminuta has not been reported in patients with nephrotic syndrome. PMID- 28631657 TI - Citrobacter freundii as a cause of acute suppurative thyroiditis in an immunocompetent adult female. AB - Acute suppurative thyroiditis (AST) is an uncommon condition, in the patients with preexisting thyroid disease or immunosuppression. The most common cause of AST is bacterial, and the most common bacteria are Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Klebsiella species. Due to various complications such as septicemia, septic thrombophlebitis, necrotizing mediastinitis, or pericarditis, prompt diagnosis and treatment are the keys to reduce mortality and morbidity. Here, we describe a case of a 40-year-old female with AST caused by Citrobacter freundii. This is the first case report of isolation of this bacterium from AST in the world. It is important to differentiate AST from subacute thyroiditis, which is far more frequent and runs a more prolonged course. Various risk factors which predispose to this condition include structural abnormality in the thyroid gland or thyroid disease and immunocompromised state. The route of infection may be either hematogenous or lymphatic seeding. With the increase in number of immunocompromised patients, the cases of AST will increase. PMID- 28631658 TI - A case of Aspergillus tracheobronchitis in a patient with chronic obstructive pulmonary disease. AB - Aspergillus tracheobronchitis (AT) is a unique form of invasive pulmonary aspergillosis, which is commonly found in patients with impaired immunity. Early stage AT presents in a nonspecific way, both clinically and radiographically, thereby delaying diagnosis and resulting in a high mortality. Owing to impaired mucociliary clearance, previous nonfungal infections, and administration of corticosteroids, among other aspects, patients with chronic obstructive pulmonary disease (COPD) are predisposed to AT, although they are mostly immunocompetent. AT in COPD patients has not been well recognized and the condition is often misdiagnosed or missed. We herein report a case of AT diagnosed in a male with past COPD, with the features of pseudomembranous AT upon bronchoscopy. This contradicts the opinion that pseudomembranous AT is found in severely immunocompromised hosts with hematologic malignancies. PMID- 28631659 TI - Subcutaneous cysticercosis presenting as cervical swelling: Amazing and unexpected cytological findings. PMID- 28631660 TI - Crescentic C3 glomerulopathy with acquired partial lipodystrophy: An unusual cause of rapidly progressive renal failure. PMID- 28631661 TI - Primary hydatid cyst of femur masquerading as other bone pathologies. PMID- 28631662 TI - Pediatric nasopharyngeal carcinoma with a spectrum of precursor lesions: Cervical lymph node metastasis initially diagnosed by fine needle aspiration cytology. PMID- 28631663 TI - T helper 17 cells in atopic dermatitis: Study in a tertiary care center. PMID- 28631664 TI - Fine needle aspiration cytology of thyroid metastasis: An unusual presentation of cervical carcinoma; a case report and review of literature. PMID- 28631665 TI - Antineutrophil cytoplasmic antibody-associated vasculitis and chronic lymphocytic leukemia: A rare association. PMID- 28631666 TI - 5q deletion myelodysplastic syndrome. PMID- 28631667 TI - Pediatric plasmablastic lymphoma: Diagnostic and therapeutic dilemma. PMID- 28631668 TI - Poly immunophenotypic expression in a case of diffuse large B-cell lymphoma. PMID- 28631669 TI - Virtual digital pathology: The future is near. PMID- 28631670 TI - [Topographic anatomy of the hook region and its significance for the choice of the surgical technique for the cochlear implantation]. AB - The mode of the introduction of the active electrode of a cochlear implant into the cochlea remains a key issue as far as cochlear implantation is concerned. Especially much attention has recently been given to the relationship between the anatomical features of the basal region of the cochlea (the so-called 'fish hook') and the possibility to approach it. We have undertaken the attempt to optimize the approach to the tympanic canal (scala tympanica) of the cochlea with a view to reducing to a minimum the risk of an injury to the cochlear structures in the course of cochlear implantation. A total of 35 cadaveric temporal bones were examined to measure the fine structures of the hook region and evaluate the risk of their damages associated with various approaches to the tympanic canal. PMID- 28631671 TI - [The anatomical features of the middle ear exerting the influence on the formation of exudative otitis media in the breast-fed infants of different gestational age]. AB - The objective of the present study was to elucidate the anatomical features of the structure of the middle ear and eustachian tube in the breast-fed infants of different gestational age that may be responsible for the formation of exudates (fluids). We have examined 150 temporal bones obtained from the children's cadavers that were allocated to three groups as follows: 50 temporal bones obtained at weeks 26-30 weeks of gestation (group 1), 44 bones 31-36 weeks of gestation (group 2), and 37-40 weeks of gestation (full-term babies, group 3),The analysis of the data obtained on an individual bases revealed either increase or decreases in the selected characteristics of the eustachian tube in comparison with the respective average values as well as the well apparent predominance of a single change or a combination of alteration of several parameters in one case in 26-30 weeks and 31-36 weeks groups. No significant changes were found in group 1. It is concluded that the presence of a single change or a combination of two or three abnormal changes in the parameters of the bone structures of the eustachian tube can affect the development of the secretory process in the middle ear especially in the children born after 36 weeks of pregnancy. PMID- 28631672 TI - [The influence of interleukin gene polymorphism on the serum cytokine level in the patients presenting with chonic suppurative otitis media]. AB - The objective of the present work was to study the influence of allelic variant associations of 1-beta interleukin (C3953T, &511C, T31C), interleukin-6 (C174G), and tumour necrosis factor-alpha (G308A) gene polymorphisms on the serum cytokine level in the patients presenting with chronic suppurative otitis media. A total of 299 patients at the age varying from 16 to 55 years with this condition divided into three groups were examined. Group 1 was comprised of 146 patients suffering from the tubotympanic form of chronic suppurative otitis media (CSOM). Group 2 was composed of 153 patients with epitympanic antral form of this condition. The control group included 183 subjects who have never suffered pathological changes in the middle ear. Human genomic DNA was analyzed with the use of the polymerase chain reaction (PCR). The serum cytokine levels were measured by the solid-state enzyme immunoassay in the beginning and at the end of the treatment period. The study has demonstrated that 56.2% of the healthy residents of the trans-Baikal region had the C/T Il-1b (C3953T) genotype. 79.1% of the patients presenting with the carious carious-destructive form of chronic suppurative otitis media were the heterozygous carriers of the T511C gene of 1 beta interleukin and had the maximally high concentrations of this interleukin in the blood serum. A rise in the production of the pro-inflammatory mediator (IL-6) was found to be related to the severity of the inflammatory process in the middle ear. The TNF-alpha content in the patients with CSOM during the active period of the disease proved to increase by a factor of 6 in comparison with that in the subjects of the control group irrespective of the type of mutation. PMID- 28631673 TI - [The problems associated with the treatment of stenosing laryngotracheitis in the children (the results of the 35 year-long experience)]. AB - Stenosing laryngotracheitis (SLT) affecting the children is considered to be an emergency pediatric condition associated with ENT pathology. Its treatment presents a serious challenge for otolaryngologists, pediatricians, specialists in communicable diseases, allergologists, etc. We have undertaken a retrospective analysis of the available data with a view to summarizing the tendencies in the evolution of SLT morbidity. The results of the 35 year-long experience with the use of the currently available therapeutic strategies for the treatment of the children suffering from stenosing laryngotracheitis are presented. Special emphasis is laid on the advantages of the combined treatment of the patients presenting with this condition based at a specialized infectious department with the participation of an otorhinolaryngologist. PMID- 28631675 TI - [The morphological and clinical aspects of the curvature of the nasal septum]. AB - The curvature of the nasal septum (NS) is one of the most widespread deformations of the facial skeleton. The objective of the present study was to substantiate the principles of and develop the rationale for the surgical correction and conservative treatment of this condition based on the morphological features of various types of deflection of the nasal septum. We have undertaken the morphological analysis of the osseous and cartilaginous structures determining the type and the shape of the curvature of the nasal septum together with the clinical analysis of different morphological variants of the deflection of the nasal septum making use of the R. Mladina classification. Type I-IV vertical deflections are regarded as the acquired deformities whereas type II deviations can just as well be congenital malformations. Types V and VI deflections can be a consequence of the birth injury resulting in the displacement of the nasal structures and leading to the curvature of the nasal septum. The authors describe the defects in the anatomical structures adjoining the nasal cavity associated with various types of the deflection of the nasal septum that the surgeons should take into account when planning and performing septoplasty. PMID- 28631674 TI - [The modern possibilities for the application of multispiral computed tomography in diagnostics of paranasal sinuses mycetomas]. AB - The objective of the present study was the analysis of the health status of 20 patients presenting with histologically verified paranasal sinuses mycetomas (fungus balls) with special reference to CT-semiotics characteristic of the fungal ball as early as during the pre-verification period. The surgical strategy for the management of this condition has been substantiated. It is concluded that the final verification of the pathological process in question is possible only based on the results of the histological studies. PMID- 28631677 TI - [Topographical and anatomical localization of the lacrimal passages in the nasal cavity]. AB - The objective of the present work was to study topographical and anatomical relationships between the lacrimal passages and the walls of the nasal cavity from the standpoint of the rhinosurgeon. The materials for the study were obtained by examining 15 corpses. It was found out that in 91% of the cases, the natural ostium of the maxillary sinus is localized within 11.6 cm from the lacrimal tubercle. In 62% of the cases, the nasolacrimal passage opens in the region of the vault of the inferior nasal passage as an orifice roughly 0.8 mm in size displaced approximately 9.4 mm posteriorly from the edge of the inferior turbinated bone. In 21% of the cases, the ostium of the nasolacrimal passage approximately 2 mm in diameter is situated at the lateral wall of the inferior nasal passage, roughly 6.5 mm above the bottom of the nasal cavity. In 10% of the cases, the nasolacrimal passage opens at the inner surface of the inferior turbinated bone proper at a distance of about 3.4 mm from the site of its attachment. It is concluded that topographical and anatomical localization of the lacrimal passages is of primary importance in terms of endonasal endoscopic interventions on the lateral wall of the nasal cavity including the puncture of the maxillary sinus associated with the potentially high risk of the damage to the nasolacrimal passage and in a lesser extent to the lacrimal sac. PMID- 28631676 TI - [The influence of nasal packing on the quality of life in the early postoperative period following septoplastic surgery]. AB - The objective of the present study was to evaluate the influence of anterior nasal packing on the physical health condition and the quality of life of the patients in the early postoperative period following septoplastic surgery and to propose an alternative to the anterior nasal packing procedure. The study included 90 patients divided into three groups. Those of the first group underwent endoscopic septoplasty, the patients of the second group were managed by standard septoplastic surgery, and the patients of group 3 were given treatment with the use of modified septoplasty including the application of a fibrin sealant as an alternative to nasal tampons. It was shown that anterior nasal packing exerts the undesirable influence on the quality of life during the early postoperative period following septoplastic surgery whereas the use of the modified technique based on the application of a fibrin sealant as an alternative therapeutic modality significantly enhances the effectiveness of the treatment. PMID- 28631678 TI - [The influence of rhinoplasty on the physical and mechanical properties of the skin of the external nose]. AB - This article was designed to report the results of the measurement of the surface acoustic wave velocity in the skin of the external nose following rhinoplastic surgery based on the analysis of the postoperative conditions in 374 patients. The patients were divided into two groups, one comprised of 286 (86.5%) patients who underwent the newly developed rehabilitative treatment and the group of comparison composed of 88 (23.5%) patients who received a different treatment during the postoperative period. The analysis has demonstrated the significant reduction in the velocity of the surface acoustic waves in the skin of the external nose of the patients of the main study group within 1 and 6 months after the surgical intervention. The change was especially well apparent at the sites with the relatively thicker skin underlain by the subcutaneous adipose tissue. This result can be regarded as giving evidence of the effectiveness of the proposed physiotherapeutic treatment that allowed to achieve the rapid decrease of postoperative oedema and prevent the subsequent excessive cicatrization. PMID- 28631679 TI - [The comparative assessment of the vocal function in the professional voice users and non-occupational voice users in the late adulthood]. AB - The objective of the present study was to evaluate the clinical and functional condition of the voice apparatus in the elderly patients and to elaborate recommendations for the prevention of disturbances of the vocal function in the professional voice users. This comprehensive study involved 95 patients including the active professional voice users (n=48) and 45 non-occupational voice users at the age from 61 to 82 years with the employment history varying from 32 to 51 years. The study was designed to obtain the voice characteristics by means of the subjective auditory assessment, microlaryngoscopy, video laryngostroboscopy, determination of maximum phonation time (MPT), and computer-assisted acoustic analysis of the voice with the use of the MDVP Kay Pentaxy system. The level of anxiety of the patients was estimated based on the results of the HADS questionnaire study. It is concluded that the majority of the disturbances of the vocal function in the professional voice users have the functional nature. It is concluded that the method of neuro-muscular electrophonopedic stimulation (NMEPS) of laryngeal muscles is the method of choice for the diagnostics of the vocal function of the voice users in the late adulthood. It is recommended that the professional vocal load for such subjects should not exceed 12-14 hours per week. Rational psychotherapy must constitute an important component of the system of measures intended to support the working capacity of the voice users belonging to this age group. PMID- 28631680 TI - [The influence of retinoids on the regeneration of an open osteal wound]. AB - The objective of the present study was to elucidate the influence of retinoid based pharmaceutical products on the process of regeneration of the tissues surrounding an open osteal wound under the experimental conditions. The experiments were carried out using 20 'Sovetskaya shinshilla' rabbits (12 males and 8 females). The animals with the modelled open osteal wound underwent daily treatment by the placement of the dressings impregnated with a mixture of dioxo methyltetrahydropyrimidine and chloramphenicol ointments supplemented by 0.05% retinoic acid (1:1:1). The rabbits of the control group were treated using the dressings impregnated only with a mixture of dioxo-methyltetrahydropyrimidine and chloramphenicol ointments containing no retinoic acid. The study has demonstrated that the application of the retinoid-based medications for the treatment of the open osteal wound resulted in the well apparent positive dynamics of the wound process in comparison with that in the control animals. It is concluded that the data obtained give evidence that retinoid-based preparations can be used as an adjuvant treatment for the acceleration and promotion of the wound healing process in the trepanation cavity following sanation surgery on the middle ear. PMID- 28631681 TI - [The evaluation of the quality of life in a healthy population with the use of the COMQ-12 questionnaire]. AB - The COMQ-12 questionnaire has been elaborated to evaluate the deterioration in the quality of life of the subjects suffering from chronic suppurative otitis media (CSOM) based on the reports of the patients themselves. This questionnaire is of special interest in that it allows to register the complaints of the patients stated by them in the order of priority beginning from those that are responsible for the most pronounced manifestations of the impairment in the quality of life. It, in turn, helps the medical practitioner to rationally organize the treatment of a concrete patient taking into consideration his or her individual expectations. At the current stage of the development and adaptation of the COMQ-12 questionnaire, the main emphasis is placed on the search for the possible range of the key scores and their normal values allowing to characterize the quality of life in the healthy population. The objective of the present work was to estimate the potential of the COMQ-12 questionnaire for the evaluation of the quality of life among the subjects having no signs of chronic suppurative otitis media. A total of 60 healthy volunteers were recruited for the study and asked to fill up the questionnaire. The following information was selected for the subsequent analysis: sex and age of the respondents, experience with having any ear-related problems other than those related to chronic suppurative otitis media in the course of the lifetime. The patients presenting with chronic suppurative otitis media were excluded from the study. The score values ranged from 0 to 14 among the entire set of the respondents (mean 3.55). The resulting score of the respondents' condition was 5 and less in 75% of the cases; it achieved 10 and less out of the possible maximum of 60 scores in 95% of the participants of the study. It is concluded that the application of the COMQ-12 questionnaire helps to concentrate the attention of the medical specialists on the subjects whose health condition is characterized by score 5 or less and motivates them to carry out the thorough and comprehensive analysis for the interpretation of the data in favour of or against the prescription of the surgical intervention taking into consideration the personal expectations of the patients. PMID- 28631682 TI - [The combined treatment of dysphonia in the subjects engaged in the voice and speech professions]. AB - The objective of the present study was to evaluate the effectiveness of the application of homeovox for the combined treatment of small vocal cord nodules and acute laryngitis in the professional voice users. A total of 40 subjects presenting with dysphonia were examined after they were divided into two study groups and two groups of comparison depending on the nosological form of the pathological condition. The subjects comprising the study groups were given traditional therapy in the combination with the intake of homeovox whereas the patients included in the two groups of comparison received the traditional treatment alone. The outcome of the treatment was evaluated on days 1, 5, and 10 after the initiation of therapy based on the analysis of the changes in the videoendostroboscopic picture of the larynx and the acoustic characteristics obtained by the computer-assisted analysis of the voice. The analysis of the results of the combined treatment has demonstrated the statistically significant differences in some acoustic parameters of the voice between the subjects with small vocal cord nodules and acute laryngitis belonging to the study groups and the groups of comparison. It is concluded that the introduction of homeovox in the combined treatment of the patients presenting with the small nodules in the vocal cords and acute catarrhal laryngitis accelerates the recovery of the acoustic characteristics of the voice within various periods after the onset of the treatment in comparison with the patients treated with the use of traditional therapy alone. PMID- 28631683 TI - [The clinical and bacteriological study of the effectiveness of the application of silver nanoparticle for the treatment of tuberculosis]. AB - The objective of the present study was to evaluate the expediency of the application of nano-scale silver preparations, argovit-C and vitargol, differing in concentration for the treatment of tuberculosis of the upper respiratory tract. The study was carried out based at the Karachaevo-Cherkessian TB dispensary. It has been demonstrated that the 3.3% solution of argovit-C possessed of the 100% bactericidal activity with respect to the medically resistant mycobacteria at both maximum and minimal concentrations of isoniazid. Based on these findings, this preparation was chosen for the clinical study. It was shown to exhibit a higher therapeutic effectiveness in comparison with the standard anti-tuberculosis treatment. The authors conclude that the inhalation of the 3.3% argovit-C solution twice daily for 10 minutes during 2 months can be recommended for the local treatment of laryngeal tuberculosis. PMID- 28631684 TI - [Multiple pneumocele associated with temporal bone hyperpneumatization]. AB - The authors consider in brief epidemiology, diagnostics, and variants of the surgical treatment of the rare clinical condition pneumocele and pneumoencephalocele of the temporal bone. Diagnostic and surgical modalities for the management of multiple pneumocele associated with temporal bone hyperpneumatization are discussed. PMID- 28631685 TI - [The transperygoid approach to the removal of a recurrent juvenile angiofibroma at the base of the skull without preoperative embolization]. AB - The authors report a clinical case of successful elimination of a recurrent juvenile angiofibroma at the base of the skull (JAFBS) with the application of the optical navigation system and a cold plasma scalpel in the absence of preoperative embolization. It has been demonstrated using the proposed transperygoid approach to the extirpation of the tumour that a recurrent juvenile angiofibroma at the base of the skull can be efficiently removed by means of a modern minimally invasive and at the same time radical surgical method. PMID- 28631686 TI - [Laryngeal pleomorphic adenoma]. AB - Pleomorphic adenomas are the most widespread epithelial tumours originating from the salivary glands. In almost 90% of the cases, they are localized in the parotid salivary glands. Pleomorphic adenomas only rarely affect the larynx. To the best of our knowledge, as many as 27 cases of laryngeal pleomorphic adenoma have thus far been described in the special literature. The present article was designed to report a case of pleomorphic adenoma in the larynx of a 76 year-old male patient. The surgical treatment of this condition proved beneficial for the patient whose condition remains uncomplicated by the relapse of the tumour during the 5 year-long postoperative follow-up. PMID- 28631687 TI - [Acquired atresia and stenosis of the external acoustic meatus]. AB - Acquired atresia of the external acoustic meatus is a rare pathological condition characterized by obliteration of the medial part of the external acoustic canal by a soft fibrous plug. The present article presents an overview of a series of cases of acquired atresia and stenosis of the external acoustic meatus with the description of etiology, pathogenesis, and methods for the treatment of this condition. In the majority of the cases, atresia develops at the final stage of granulation external otitis with or without an accompanying dermatological pathology. Another common cause of the acquired atresia of the external acoustic meatus is the fracture of the temporal bone as well as extensive ear surgery, radiation therapy and a neoplasm in the auditory passage. The surgical strategy for the management of the acquired atresia and stenosis of the external acoustic meatus consists, besides the excision of the fibrous plug, of the application of the cutaneous flaps and/or transplants to cover the bare parts of the bone portion of the affected external canal. In spite of such treatment, the state of the external acoustic canal remains unstable, and a relapse of its atresia and stenosis can not be wholly excluded. PMID- 28631688 TI - [Benign paroxysmal positional vertigo: modern concepts of its etiology and pathogenesis]. AB - The objective of the present review of the literature is the analysis of the currently available data concerning etiology and pathogenesis of benign paroxysmal positional vertigo (BPPV). The special emphasis is placed on the modern hypotheses of BPPV formation that collectively account for not more than 15% of all known cases of this condition. The best explored are the following causes of benign paroxysmal positional vertigo: vestibular neuronitis, head injuries, and disorders in the middle ear. During the recent years, much attention has been given to the role of disturbances of calcium metabolism and osteoporosis in etiology of benign paroxysmal positional vertigo. It is supposed that pathogenesis of vertiginous attacks can be explained in terms of the canalolithiasis and cupulolithiasis theories. PMID- 28631689 TI - [Objective tympanophonia caused by myoclonus of the auricular muscles]. AB - The objective of the present literature review was to systematize the available data on the etiology, pathogenesis, clinical features, diagnostics, and treatment of muscular tympanophonia. The commonest source of muscular tympanophonia is the tremor (myoclonus) of the soft palate or the middle ear; sometimes this condition can be a consequence of myoclonus of the external ear muscles or head muscles. Pharmacotherapy of muscular tympanophonia does not invariably result in the favourable outcome. The author describes a rare observation of objective tympanophonia attributable to myoclonus of the auricular muscle. The patient complained of sensation of clicking sounds in the affected right ear in synchrony with involuntary contractions of the muscles above the auricle and in the postaural region. The contractions of these muscular groups were palpable at the moments when the patient felt snaps in the ear. The presence of myoclonus of the auricular muscles was confirmed in the electromyographic studies. Multispiral computed tomography did not reveal pathological changes in the brain stem structures. The patient took the prescribed doses of clonazepam and baclofen during 5 weeks; however, this treatment failed to substantially improve his condition. Tympanophonia was eliminated by means of administration of botulinum toxin into the m. auricularis posterior and m. temporalis region. PMID- 28631690 TI - [Medically-induced rhinitis]. AB - This paper summarizes the currently accepted concepts of the pathogenetic mechanisms underlying the morphological and functional changes in intranasal mucosa of the patients having a long history of the application of the long acting topical vasoconstrictor agents. The author presents the data illustrating the effectiveness of various methods for the pharmacotherapeutic treatment of medically-induced rhinitis. PMID- 28631691 TI - [The all-Russian scientific and practical conference 'Modern problems of otorhinolaryngology' dedicated to the 120th anniversary of the foundation of the Department of Ear, Throat and Nose Diseases at I.M. Sechnov First Moscow State Medical University]. PMID- 28631692 TI - [Multidisciplinary problems of rheumatology and pulmonology]. AB - Damage to the respiratory system worsens prognosis and increases mortality in all systemic immunoinflammatory rheumatic diseases (SIRDs). Leading pulmonary manifestations in each disease are different, so the typical picture of each nosological entity is very peculiar. In all SIRDs, the disease starts with lung involvement in 10-20% of cases, preceding the expanded clinical presentation of a systemic disease. At a certain stage, lung damage may be the only manifestation of the disease or predominate in its clinical picture, determining the severity of a condition. Among the patients referred to consultation with a pulmonologist for interstitial lung disease, about 15% have manifestations of SIRDs that is confirmed by a special survey. The paper discusses the diagnostic features of SIRDs with lung involvement, as well as indications for consultation with a rheumatologist. The key clinical symptoms indicating a possible rheumatic disease in patients with lung involvement are considered. Evidence for the main circulating autoantibodies identifiable in high titers in patients with SIRDs in a serological test is given and its positivity is interpreted. The issues associated with the term 'undifferentiated connective tissue diseases-associated interstitial lung disease' are discussed; the expediency of using the term 'interstitial pneumonia with autoimmune signs (AIS)' is emphasized. The clinical characteristics of and classification criteria for AIS are presented. The prognosis and outcomes of interstitial pneumonias of varying etiologies, as well as the importance of the multidisciplinary approach to managing patients with SIRDs and lung involvement, which improves the quality of diagnosis, adequacy of treatment, and quality of life, are dealt with. PMID- 28631693 TI - [Independent risk factors for severe cardiovascular events in male patients with gout: Results of a 7-year prospective study]. AB - AIM: To determine risk factors for severe cardiovascular (CV) events (CVEs) in male patients with crystal-verified gout. SUBJECTS AND METHODS: 251 male patients with crystal-verified gout were prospectively followed up in 2003 to 2013. The mean follow-up period was 6.9+/-2.0 years. New severe CVE cases and deaths were recorded. Logistic regression was used to analyze the impact of traditional and other risk factors and allopurinol use on the risk for severe CVEs. RESULTS: 32 patients died during the follow-up period. Severe CVEs were recorded in 58 (23.1%) patients; CVE deaths were notified in 22 (8.8%) patients. The risk of all severe CVEs was high for hypertension, increased serum high-sensitivity C reactive protein (hs-CRP) level (>5 mg/l), >= stage III chronic kidney disease (CKD) (glomerular filtration rate, <60 ml/min/1.73 m2), alcohol intake (>20 g/day), coronary heart disease (CHD), and a family history of premature CHD. The risk of fatal CVEs was highest for elevated serum hs-CRP level, >= stage III CKD, a family history of premature CHD, hypercholesterolemia, upper quartile of serum uric acid levels (>552 umol/l), and regular intake of allopurinol. CONCLUSION: In addition to the traditional risk factors of CV catastrophes, the presence of chronic inflammation and the impact of high serum uric acid levels may explain the high frequency of CV catastrophes. PMID- 28631694 TI - [The influence of STAT4 rs7574865 (G/T) polymorphism on the risk of clinical and immunological phenotypes of systemic sclerosis in a Russian patient population: Results of a pilot study]. AB - AIM: To examine the association of signal transducer and activator transcription 4 (STAT4) rs7574865 G/T polymorphism with a predisposition to systemic sclerosis (SSC) and associated clinical and autoimmune phenotypes in a Russian population. SUBJECTS AND METHODS: A total of 102 patients with SSC and 103 healthy individuals as controls were examined. STAT4 rs7574865 polymorphism was investigated by real-time polymerase chain reaction. RESULTS: The carriers of the T allele showed a statistically significant association with SSC, a diffuse form (DF), the presence of interstitial lung disease (ILD), cardiac injury (CI), and seropositivity for anti-topoisomerase I antibodies (ATA). CONCLUSION: The findings results confirm the important role of STAT4 gene in the predisposition to SSC and its phenotypes, such as DF, ILD, CI, and ATA in the Russian population. PMID- 28631695 TI - [Chronic stress and mental disorders in patients with systemic scleroderma: Results of an interdisciplinary study]. AB - AIM: To analyze of the prevalence of stressful factors and mental disorders (MDs), as well as their clinical psychopathological and clinical psychological characteristics to improve the comprehensive diagnosis and treatment of systemic scleroderma (SSD). SUBJECTS AND METHODS: Examinations were performed in 110 patients (predominantly women (n=97 (88.2%); mean age, 49.9+/-2.47 years) with a documented diagnosis of SSD (its mean duration, 7.25+/-0.42 years). 62 (56.4%) patients had limited SSD, 36 (32.7%) had diffuse SSD, and 12 (10.9%) had overlap syndrome. The disease was rapidly and slowly progressive in 33 (30%) and 77 (70%) patients, respectively. Oral glucocorticosteroids were used in 99 (90%) patients included in the study, cytotoxic drugs in 66 (60%), plaquenil in 33 (30%); 8 (7%) patients were treated with the biological agent rituximab. All the patients were examined by a psychologist and a psychiatrist. The psychopathological diagnosis of MD was made during a semistructured interview in accordance with the ICD-10 criteria. The Montgomery-Asberg depression and Hamilton anxiety rating scales were used to evaluate the severity of depression and anxiety, respectively. All patients underwent a clinical and psychological examination, including tests assessing memory, attention, and logical thinking, as well as projective techniques. RESULTS: MDs were detected in 91 (83%) patients with SSD. There was a preponderance of depressive disorders in 74 (67.3%) patients: chronic (dysthymia in 33 (30%) patients)) and recurrent (recurrent depressive disorder in 34 (31%)) depressions. Cognitive impairment (CI) of varying severities was diagnosed in 100% of the patients. Schizotypal personality disorder was stated in 44 (40%) patients. 90% of patients were found to have chronic psychic traumas mainly as parental deprivation in childhood (in children less than 11 years of age). 76.7% of the SSD cases developed recurrent episodes of depression in the presence of long-term MD or had a history of the episodes. There was no relationship of MD to gender, age, duration of SSD and its individual clinical manifestations. The nature of SSD treatment did not affect the frequency and spectrum of MD. CONCLUSION: MDs, predominantly chronic and recurrent depression, and CI are characteristic of most SSD patients. Multiple chronic stressful factors, both previous SSD and those over time, have commonly an impact on the mental health of patients with SSD. PMID- 28631697 TI - [Changes in the serum concentrations of adhesion molecules and vascular endothelial growth factor in active ankylosing spondylitis patients taking amtolmetin guacil: Results of a 56-week prospective oren-label controlled observational study]. AB - AIM: To estimate changes in the concentrations of adhesion molecules and vascular endothelial growth factor A after 30-day additional use of amtolmetin guacil (AMG) in patients with active ankylosing spondylitis (AS) who were unresponsive to previous one-year treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). SUBJECTS AND METHODS: 20 patients with active AS who had not reached a BASDAI score <4.0 at week 52 of NSAID therapy and 10 healthy individuals matched for cardiovascular risk factors were examined. After 52 weeks of NSAID therapy, AMG was administered orally at 1200 mg/day to patients with AS for 30 days. The concentrations of adhesion molecules (sICAM-1 and sVCAM-1) and VEGF-A were measured. BASDAI and ASDAS scores and C-reactive protein (CRP) levels were determined in AS patients. The concentrations of adhesion molecules and VEGF-A were investigated in patients with AS at baseline, at 52 weeks after NSAID treatment start, and at 30 days following AMH initiation (at week 56) and in healthy individuals at baseline and at 30 days. RESULTS: The concentration of sICAM-1 in patients with AS was 987.0+/-217.39, 938.98+/-293.31, and 364.25+/ 363.3 ng/ml at weeks 0, 52, and 56, respectively; that in healthy individuals was 769.25+/-189.32 and 740.05+/-225.76 ng/ml at baseline and at 30 days, respectively. The differences from the baseline concentration were significant in patients with AS (p<0.05) and insignificant in healthy subjects (p>=0.05); the differences between the concentrations in patients with AS and the controls were significant at baseline and at 52 weeks (p<0.05). The concentration of sVCAM-1 in patients with AS was 364.25+/-160.49, 325.34+/-245.1, and 319.1+/-248.73 ng/ml at weeks 0, 52 and 56, respectively; that in healthy individuals was 245.13+/-40.4 and 248.73+/-34.42 ng/ml, respectively (p<0.05 vs baseline values and values in healthy subjects). The level of VEGF-A in AS patients was not different from that in healthy individuals, but decreased during treatment. Correlations were found between the concentration of adhesion molecules and the level of CRP (p<0.01). CONCLUSION: Elevated concentrations of adhesion molecules have been found in AS patients compared with healthy individuals. The study has demonstrated that AMG treatment is efficient in treating patients with AS. NSAID/AMG treatment is associated with lower concentrations of adhesion molecules. Decreased CRP levels serve as predictors for reduced concentration of adhesion molecules. The level of VEGF-A at baseline did not differ from that in healthy subjects, but was decreased during treatment with NSAIDs. PMID- 28631696 TI - [Ankylosing spondylitis and non-radiographic axial spondyloarthritis: Two stages of disease?] AB - AIM: To compare the clinical manifestations of ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nrAxSpA). SUBJECTS AND METHODS: A Moscow early spondyloarthritis cohort has now included 132 patients with axial spondyloarthritis, of whom 69 patients who have been followed up at least 12 months are to be involved in a preliminary analysis. The mean age at the time of inclusion in the study was 28.1+/-5.5 years; the mean disease duration was 24.7+/ 15.8 months; 63 (91.3%) patients were HLA-B27 positive; 41 and 28 included patients were diagnosed with AS and nrAxSpA, respectively. RESULTS: Men were significantly more in the AS group than in the nrAxSpA group (58.5 and 32.1%, respectively; p=0.05). The patients of the two groups did not differ in main clinical parameters (the presence of arthritis and enthesitis), disease activity (BASDAI, ASDAS-CRP) and functional status (BASFI). All indicators of inflammatory activity decreased nearly 2-fold in both groups after 12 months of follow up. In 7 (25%) patients with nrAxSpA, radiologically detectable sacroiliitis (SI) developed over 12 months and the diagnosis of AS was verified. Among them, 2 (28.5%) patients had initially active SI detected by magnetic resonance imaging (MRI); 4 (57.1%) had chronic SI, and 1 (14.4%) had no pathological MRI changes. CONCLUSION: Due to the fact that the clinical manifestations of AS and nrAxSpA are comparable, it can be assumed that the latter is an early stage of AS. PMID- 28631698 TI - [Hepatitis C virus-associated cryoglobulinemic vasculitis: A 20-year experience with treatment]. AB - AIM: To summarize the experience of a multidisciplinary therapy hospital in treating patients with hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis (CV). SUBJECTS AND METHODS: Seventy-two patients (mean age, 49.4+/ 10.3 years) with HCV-associated CV were examined and followed up for an average period of 2.8+/-3.6 years. The efficiency of traditional (corticosteroids +/- cyclophosphamide) and selective (rituximab) immunosuppressive therapy (IST) was estimated in 31 and 15 observations, respectively, and that of antiviral therapy (AVT) in 25. Vasculitis activity was assessed using the Birmingham vasculitis activity score (BVAS). The patients' survival was studied; multivariate logistic regression analysis was carried out. RESULTS: 24 (33.4%) of the 72 patients had a stage of liver cirrhosis (LC). The pretreatment mean BVAS was 11.9+/-7.2 (range 2 to 36). Severe CV (BVAS >=15) was present in 30.6% of the patients. AVT was accompanied by achievement of sustained virologic response in 48% of the patients, clinical remission in 68% and had an advantage over IST in relation to long-term treatment results. Rituximab was significantly more effective than traditional immunosuppressants (remission rates of 73 and 13%, respectively). Combined therapy (rituximab and AVT) was most effective in patients with severe forms of vasculitis. Sixteen patients died from complications of vasculitis (37.5%), infection (37.5%), and LC (25%). The factors adversely affecting prognosis were age >55 years (odds ratio (OR), 4.49), the presence of LC (OR, 3.68), renal failure (OR, 4.66) and the use of glucocorticosteroids (OR, 3.91). CONCLUSION: HCV-associated CV can determine the prognosis of chronic HSV infection. AVT is the treatment of choice in all patients with HSV-associated CV. AVT must be combined with rituximab therapy in patients with severe forms of vasculitis. PMID- 28631699 TI - [Lower extremity venous diseases in primary knee osteoarthritis]. AB - AIM: To establish a possible association between knee osteoarthritis (OA) and lower extremity venous diseases ((LEVDs) on the basis of thorough clinical and instrumental studies. SUBJECTS AND METHODS: A case-control study recruiting 40-60 year-old women was conducted. A study group included 85 women with knee OA; a control group consisted of 50 women without this condition. The patients of both groups underwent assessment of complaints and goal-directed objective examination to identify joint diseases and chronic LEVDs, knee X-ray study, and duplex scanning of the lower extremity veins. RESULTS: The patients with knee OA were more frequently diagnosed with lower extremity varicose vein disease (VVD) (43% vs 22%; p=0.015) and had signs of chronic venous insufficiency (28% vs 12%; p=0.03). Duplex scanning of the lower extremities showed that knee OA was characterized by generalized LEVD (bilateral valve lesions of the great and small saphenous veins and severe valvular incompetence in the veins) that was detected in 53% of the patients in this group versus 20% of the women in the control group (p = 0.0004). After adjustment for body mass index, the differences in the incidence of VVD between the groups remained clinically and statistically significant (odds ratio (OR), 2.7; 95% confidence interval, 1.1-6.7; p=0.036). CONCLUSION: The 40-60-year-old patients with knee OA more commonly develop symptoms of chronic venous insufficiency than their healthy peers. Although obesity is a risk factor for both diseases, there is an independent association between knee OA and lower extremity VVD. PMID- 28631700 TI - [Polymorphism in the regulatory regions -S2578A and +C936T of the vascular endothelial growth factor (VEGF-A) gene in Russian women with rheumatoid arthritis]. AB - AIM: To analyze polymorphism in the regulatory regions of the vascular endothelial growth factor (VEGF) gene in female patients with rheumatoid arthritis (RA). SUBJECTS AND METHODS: The investigation enrolled 257 female patients with RA. A control group consisted of 297 women without chronic diseases. The investigators examined the single-nucleotide polymorphism of VEGF A2578S in the promoter region (rs699947) and that of VEGF+S936T 3 in the retranslated region (rs3025039) of the gene. Genotyping was performed by restriction fragment length polymorphism analysis. RESULTS: There was an increase in the frequency of VEGF+936 CT and a reduction in that of the VEGF+936SS genotypes in the seronegative patients as compared to the healthy women. The VEGF+936SS genotype frequency was higher in the patients with seropositive RA than in the subgroup of seronegative patients. The frequency of the VEGF-2578SS genotype was increased in the patients with RA and rheumatoid nodules, as compared to the healthy women. CONCLUSION: The data presented suggest that the presence of certain VEGF gene variants located in the regulatory regions may reflect the nature of immunopathological mechanisms in RA. PMID- 28631701 TI - [Clinical features of osteoarthritis in patients with metabolic syndrome]. AB - AIM: To estimate clinical and laboratory parameters in patients with osteoarthritis (OA) and in those with OA and metabolic syndrome (MS). SUBJECTS AND METHODS: 164 patients with OA were examined and divided into 2 groups of 82 people: a study group (patients with MS) and a control one (those without MS). OA was defined according to the diagnostic criteria described by R.D. Althmann (1995). MS was identified based on the criteria developed by the International Diabetes Federation (2005). The location of affected and swollen joints was determined according to the Richie index; the intensity of pain syndrome was measured by a visual analogue scale at rest and on movement; the WOMAC and Lequesne indexes were estimated in the patients. Erythrocyte sedimentation rate and C-reactive protein and tumor necrosis factor-alpha levels were determined from laboratory data. RESULTS: In the MS group, the frequency of joint injuries at various sites, the prevalence of synovitis, and the intensity of pain and inflammation were significantly higher than in the non-MS group. CONCLUSION: The negative impact of MS on the clinical picture of OA can be inferred by the findings. PMID- 28631702 TI - [The frequency of ophthalmologic manifestations of granulomatosis with polyangiitis (Wegener's) and their relationship to systemic diseases]. AB - AIM: To estimate the frequency of lesions in the organ of vision in granulomatosis with polyangiitis (GPA) (Wegener's) and to determine their relationship to systemic diseases. SUBJECTS AND METHODS: The retrospective study enrolled 218 patients followed up at the E.M. Tareyev Clinic of Nephrology, Internal and Occupational Diseases, with a diagnosis of GPA. The frequency and association of ophthalmic manifestations with systemic involvement were statistically analyzed using PASW Statistics 18. RESULTS: The organ of vision was impaired in 48.1% of the patients with GPA. The most common manifestations were orbital space-occupying lesion (22.9%), conjunctivitis/episcleritis (14.7%), dacryocystitis (6.0%), and scleritis (4.6%). Orbital space-occupying lesions occurred more frequently in the local type of the disease (p=0.0003), and, on the contrary, the involvement of the conjunctiva and eyeball was seen in patients with the systemic types of GPA (p=0.02). CONCLUSION: The findings may suggest that the orbital lesion is an independent manifestation of GPA, which develops more commonly in its local type. Conjunctivitis/episcleritis is, on the contrary, more frequently seen in the active phase of the disease and generally in the involvement of other organs and systems. PMID- 28631703 TI - [Association of ITGB3, P2RY12, and CYP2C19 gene polymorphisms with platelet functional activity in patients with coronary heart disease during dual antiplatelet therapy]. AB - AIM: To assess the association of CYP2C19 G681A, P2RY12 H1/H2, and ITGB3 T1565C polymorphisms with the extent of platelet aggregation in patients with coronary heart disease (CHD) during antiplatelet therapy. SUBJECTS AND METHODS: 166 male patients with CHD, living in the Western Siberian Region, were examined. All the patients underwent a test for platelet aggregation induced by ADP (2.5 and 5.0 um) and epinephrine (0.2 um). Genotyping was performed using an allele-specific polymerase chain reaction technique. RESULTS: The polymorphic variants of the P2RY12 and ITGB3 genes were ascertained to have no impact on the extent of platelet aggregation in patients receiving clopidogrel and acetylsalicylic acid. An association was found between CYP2C19 681A allele carriage and the increased extent of platelet aggregation induced by ADP. CONCLUSION: The carriage of the cytochrome P450 CYP2C19 681A allele rather than platelet receptor gene polymorphisms determines a risk for clopidogrel resistance in patients with CHD. PMID- 28631705 TI - [Vaccination in rheumatology: Evolution of views on the problem]. AB - The problem of coinfections that are due to both a rheumatic disease (RD) itself and the need to use immunosuppressive drugs deserves apparent attention in modern rheumatology. Coinfections substantially affect morbidity and mortality rates, especially in diffuse connective tissue diseases. The data available in the literature on the above subject matter suggest that vaccination is a powerful method for prevention of infectious diseases that are the most important problem for patients with RD. PMID- 28631704 TI - [Behcet's disease: Intracardiac thrombosis (a description of two cases and a review of literature)]. AB - Behcet's disease (BD) is systemic vasculitis of unknown etiology, which is more common in the countries located along the Great Silk Road. The disease is diagnosed if a patient has 4 key diagnostic signs: aphthous stomatitis, genital sores, and eye and skin lesions. Vascular diseases referred to as minor criteria for BD are characterized by the formation of aneurysms and thrombosis, predominantly in the venous bed. In venous disorders, a blood clot can form in any vessel, including caval, cerebral, pulmonary, and other veins. The paper describes two clinical cases of BD with intracardiac thrombosis. In one case, a 24-year-old male patient with a documented diagnosis of BD, echocardiography revealed a left ventricular spontaneous echo contrast phenomenon that disappeared due to immunosuppressive therapy. The other case was a 34-year-old female patient, in whom the diagnosis was based on the international disease criteria: aphthous stomatitis, skin lesions (pseudopustulosis, erythema nodosum), and genital sores. Computed tomographic angiography showed a 3.7*2.2-cm mass (thrombus) in the right atrium. In addition, blood clots were present in the hepatic and inferior vena cava. No abnormalities in the coagulation system were found in both cases. PMID- 28631706 TI - [Osteoporosis: Current state of the art]. AB - As of now, osteoporosis (OP) is one of the most important sociomedical problems because of its high prevalence and resultant disability, as well as significant mortality attributable to complications. The current strategy for providing care for patients of OP is its early diagnosis, by determining the high risk of fractures, and early pathogenetic treatment. The article gives an update on the epidemiology, risk factors, diagnosis, and treatment of OP. PMID- 28631707 TI - [Chondroprotectors: A range of application in general somatic practice]. AB - Chondroprotectors (CP) are biological agents that contribute to the regeneration of the cartilage surfaces and articular capsule, participating in the metabolic processes of the articular cartilage. Progressive loss of hyaline cartilage and lower levels of chondroitin sulfate were observed in osteoarthritis (OA) at different sites, including dorsopathy. OA therapy is aimed at slowing disease progression, relieving pain symptoms, and reducing functional disorders. For this purpose, oral or injectable CPs (Chondroguard, Sustaguard) are prescribed. The optimal dosing regimen of parenteral CPs is the following: three intramuscular Chondrogard 1 ml (100 mg) jections during the first week; 25-30 intramuscular chondroguard 2 ml (200 mg) injections every other day during the second week, a repeat cycle after 6 months; Sustaguard 400 mg thrice weekly for 4 weeks. PMID- 28631708 TI - [New horizons in the use of biological agents during pregnancy in patients with rheumatic disease]. AB - Pregnancy in the presence of rheumatic diseases (RD) and adequate therapy before planned conception, during gestation, and after delivery during lactation is challenging. Advances in the treatment of RD are largely due to the clinical introduction of a new class of biological agents (BAs). There are less than two decades of experience in using BAs in rheumatology and to date there are no unified standards and accepted rules governing their use during pregnancy. According to the current requirements, information on a medicine should be given in three sections: 1) pregnancy; 2) lactation, and 3) use in men and women who are planning concept (the latter section has appeared for the first time). The present article summarizes data on the possible use of BAs in patients with RD during pregnancy planning, pregnancy, and breastfeeding. PMID- 28631709 TI - [Cancer-testis genes in colon cancer]. AB - The expression of cancer-testis (CT) genes varies with tumor type. There are tumors with high, low, and intermediate gene expressions. Tumor cells of different origin are characterized by ST gene co-expression. The expression of ST genes increases in later stages of tumor development in the presence of metastases. In colon cancer, the tumor samples showed most frequently MAGE-A and SSX mRNA. The peripheral blood samples displayed most commonly XAGE, MAGE-C, and SSX mRNA. In patients with colon cancer, the expression of TSP50, MAGE-A(1-6), and SSX1,2,4 genes was associated with a poor prognosis, that of MAGE-C1 and XAGE1 was related to a favorable prognosis. PMID- 28631710 TI - [Diagnostic problems of histological remission in patients with inflammatory bowel disease]. AB - AIM: to analyze the generally accepted histological criteria for diagnosing the activity of inflammatory bowel disease (IBD) in patients with therapy-induced endoscopic remission. SUBJECTS AND METHODS: Colon biopsy specimens from 57 patients aged from 19 to 52 years (mean age 31+/-2.5 years), including 41 patients with ulcerative colitis (UC) and 16 with Crohn's disease (CD) affecting the colon, were examined. All the patients had no clinical signs of disease activity; endoscopic examination diagnosed remission (none or minimal changes). The biopsy specimens were taken from all colon segments during colonoscopy and processed by conventional methods. RESULTS: Persistence in chronic inflammation with signs of its activity (neutrophils in an infiltrate and cryptitis) and mucosal structural changes (no histological remission) were found in 29.3% of the patients with UC and 37.5% of those with CD (only in 31.6% of the patients). Persistence in chronic inflammation without signs of its activity and/or mucosal structural changes (incomplete histological remission) were detected in 80.5, 81.25, and 80.7% of the patients, respectively. Complete histological remission without mucosal inflammatory and structural changes was observed only in 19.5, 18.75, and 19.3% of the patients, respectively. CONCLUSION: The investigation shows that histological remission is still difficult to achieve to date, despite the use of the present-day treatment protocols for IBD. On the other hand, the conventional morphological criteria for the diagnosis of histological remission in IBD are quite subjective and need further discussion and agreement. Whether there may be a complete structural and functional recovery of the colon mucosa remains open. PMID- 28631711 TI - [Expansion of secretory cells in the fallopian tubal epithelium in the early stages of the pathogenesis of ovarian serous carcinomas]. AB - AIM: to investigate the frequency of the types of fallopian tubal secretory cell expansion (SCE) in diseases of the reproductive organs and to determine the immunophenotype and biological role of the cells in the early stages of the pathogenesis of high-grade ovarian serous carcinomas (HGOSC). SUBJECTS AND METHODS: The investigation enrolled 287 patients with extraovarian diseases and ovarian serous tumors varying in grade, whose fallopian tubes were morphologically and immunohistochemically examined using p53, Ki-67, PAX2, Bcl-2, beta-catenin, and ALDH1 markers. The material was statistically processed applying the Mann-Whitney test and chi2 test. RESULTS: The rate of secretory cell proliferation (SCP) (more than 10 consecutive secretory cells) and that of secretory cell overgrowth (SCO) (more than 30 consecutive secretory cells) increase with age in all investigated reproductive system diseases. The rate of SCP in the corpus fimbriatum of the patients with HGOSC was 5.9 times higher than that in those with extraovarian disease (p<0.01); when comparing the same patient groups, that of SCO was 3.4 times higher (p<0.05). The immunohistochemical characteristics of the investigated lesions (in scores) were as follows: PAX2 was expressed in the intact epithelium (2.8), in SCP (1.3), in SCO (1.2), in serous tubal intraepithelial carcinoma (STIC) (1.0), and in HGOSC (0.9); Bcl-2 was in the intact epithelium (2.2), in SCP (2.1), STIC (0.9), and in HGOSC (0.6), beta catenin was in the intact epithelium (0.5), in SCP (2.85), in SCO (2.95), in STIC (0.6), and in HGOSC (0.5); ALDH1 was in the intact epithelium (0.5), in SCP (2.91), in SCO (2.92), in STIC (1.2), and in HGOSC (0.6). There were statistically significant differences with a 95% confidence interval (p<0.05) for: 1) PAX2 between the intact epithelium and pathology (fallopian tube lesions and HGOSC); 2) Bcl-2 between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 3) beta-catenin between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 4) ALDH1 between the intact epithelium and SCE, between and SCE and STIC, and between STIC and HGOSC. CONCLUSION: SCE was shown to be an independent intraepithelial lesion. The incidence of this abnormality increased with age and significantly differed in the patients with fallopian tubal lesions in extraovarian diseases from that in those with malignant ovarian serous tumors (by 5.3 times), while these groups showed a three fold difference in SCO. Thus, SCP may serve as a more sensitive marker for the early stages of the pathogenesis of ovarian serous carcinoma. The studied types of SCE demonstrated multiple molecular events (loss of PAX2 expression and increased Bcl-2, beta-catenin, and ALDH1 expressions), some of which underwent considerable changes, by increasing the severity of a pathological process (loss of ALDH1, and beta-catenin, and bcl-2 expressions). Thus, therapeutic exposure in the early stages of pathogenesis may have a few points of application and just several molecules can serve as independent markers for early pathological changes in the fallopian tubal epithelium. PMID- 28631712 TI - [The molecular mechanisms and morphological manifestations of leiomyoma reduction induced by selective progesterone receptor modulators]. AB - AIM: to investigate the molecular mechanisms and morphological substrate of reduced uterine leiomyoma in patients receiving the selective progesterone receptor modulator (SPRM) ulipristal acetate for 3 months, by estimating the immunohistochemical expression of the markers steroid receptor coactivator 1 (SRC 1), nuclear receptor corepressor 1 (NCoR-1), ER, PgR, Ki-67, p16, TGF-beta, and VEGF in tumor tissue. SUBJECTS AND METHODS: The investigation enrolled 75 women with uterine leiomyoma, menorrhagias, and anemia. Group 1 included 40 patients who were treated with ulipristal for 3 months, followed by laparoscopic myomectomy. Group 2 consisted of 35 patients who underwent surgery without previous preparation. The intra- and postoperative parameters and molecular and morphological changes in the myomatous nodules were comparatively analyzed in both groups. RESULTS: After 3 months of therapy initiation, menorrhagia completely ceased, myomatous nodules decreased in size (p<0.05), hemoglobin levels were elevated (p<0.01), and total intraoperative blood loss and operative time decreased in all the patients in Group 1. The morphological substrate of partial leiomyoma reduction was leiomyocyte apoptosis and dystrophy, tumor stroma sclerosis and hyalinosis with diminished Ki-67 expression and elevated p16 in the smooth muscle cells, trophic nodular tissue disorders exhibited by vascular wall sclerosis and lower VEGF and TGF-beta expression, and leiomyocyte hormonal reception dysregulation that made itself evident through the reduced expression of SRC-1 with the unchanged expression of PR and ER and the maintained level of NCoR-1. CONCLUSION: The molecular mechanisms of tumor reduction involved the reduced Ki-67 expression and elevated p16, lower VEGF and TGF-beta, diminished SRC-1 expression with the maintained level of PR, ER, and NCoR-1. Overall, this is suggestive of enhanced apoptosis and reduced leiomyoma proliferation and angiogenesis induced by SPRM and indicative of the expediency of using ulipristal acetate as a preoperative agent for organ-sparing surgery in reproductive-aged patients with uterine myoma, menorrhagias, and anemia. PMID- 28631713 TI - [BRAF-positive paucicellular variant of anaplastic carcinoma in the presence of tall cell variant papillary thyroid cancer]. AB - To paper describes a case of paucicellular anaplastic cancer in the presence of tall cell variant papillary thyroid carcinoma. Microscopic examination showed that the differentiated component of the tumor was composed of papillary structures with tall cells, the height of which exceeded 3-4 times the width. Its anaplastic component consisted of fibrous tissue with occasional spindle-shaped cells and focal lymphocytic infiltration to the extent of 70%. The spindle-shaped cells expressed cytokeratins, beta-catenin, p53, and vimentin. The tumor cells and lymphocytes showed an association with Epstein-Barr virus. Molecular genetic study of the tumor revealed the following mutations: BRAF p.Val600Glu (p.V600e was), HRAS p.His27His (p.H27H), PIK3CA p.Glu545Lys (p.E545K), TP53 p.Arg248Gln (p.R248Q). PMID- 28631714 TI - [Extrarenal rhabdoid tumor: A review of literature and a report of cases with atypical morphology]. AB - Extrarenal extracranial rhabdoid tumor (EERT) is a rare malignant pediatric tumor characterized by extremely aggressive behavior, rapid metastatic spread, low survival rates, and no targeted therapy. The morphological diagnosis of classical cases of EERT is not difficult and it is based on its characteristic histologic pattern and immunohistochemical findings in a relatively short time, which allows one to immediately initiate therapy. The paper describes two cases of ERRT in the complete absence of classical rhabdoid morphology, as revealed by light microscopy when the material was primarily assessed. The final diagnostic search could establish a diagnosis of EERT in both cases on the basis of immunohistochemical findings. PMID- 28631715 TI - [Concurrence of acute graft rejection and polyomavirus nephropathy: A clinical case]. AB - The paper describes a case of diagnosing acute renal graft rejection concurrent with polyomavirus nephropathy. Histochemical and electron microscopic methods were used to examine biopsy specimens, which showed morphological changes occurring in the allograft, the ultrastructural characteristics of polyomavirus and the features of its spread in kidney tissue structures. PMID- 28631716 TI - [Anogenital mammary-like glands and related diseases. Part 2. Malignant tumors of the anogenital glands]. AB - Mammary-like glands are a normal anatomical component of the anogenital region and can give rise to many benign and malignant tumors that morphologically mimic the similar diseases of the breast. The literature review is complemented by a description of 199 cases of malignant tumors of mammary-like glands. The paper presents the clinical and morphological characteristics of various malignant tumors of mammary-like glands, including extramammary Paget's disease, ductal, tubulolobular, adenoid cystic adenocarcinoma, low-grade phyllodes tumor, etc. PMID- 28631717 TI - [Work quota setting and man-hour productivity estimation in pathologists]. AB - The paper considers the development and current state of the regulation of work quota setting and remuneration in pathologists. Reasoning from the current staff standards for morbid anatomy departments (units), the authors present a method to calculate the load of pathologists. The essence of the proposed method is demonstrated using a specific example. PMID- 28631718 TI - [Current prerequisites for a molecular genetic classification of endometrial cancer]. AB - The review analyzes current investigators' data on the introduction of an additional endometrial cancer classification based on the results of molecular and genetic studies. This necessity is dictated by clinical observations, according to which the genetic profile of the tumors may not correspond to their morphological structure, which considerably changes patient management tactics. The existing dualistic model of carcinogenesis makes it possible to identify and describe the characteristic molecular features of the tumors in terms of their histological structure. The review also analyzes the concept of 4 new endometrial cancer subgroups: ultramutated, hypermutated, copy-number low, and copy-number high (serous-like). It gives the results of investigations of the molecular and genetic characteristics of each subgroup. Particular attention is paid to the role of POLE gene mutations in the ultramutated subgroup. Different theories justifying a good prognosis in these patients are considered. The molecular characteristics of endometrial cancer versus tumors of other organs are compared. The potential benefits of introducing the new classification, which allow one to change approaches to stratifying the risk for this disease, are presented. PMID- 28631719 TI - Erratum: Changes in initial COPD treatment choice over time and factors influencing prescribing decisions in UK primary care: a real-world study. AB - This corrects the article DOI: 10.1038/npjpcrm.2016.2. PMID- 28631720 TI - Contemporary management of men with high-risk localized prostate cancer in the United States. AB - BACKGROUND: Surgery and radiation-based therapies are standard management options for men with clinically localized high-risk prostate cancer (PCa). Contemporary patterns of care are unknown. We hypothesize the use of surgery has steadily increased in more recent years. METHODS: Using the National Cancer Data Base for 2004-2013, all men diagnosed with high-risk localized PCa were identified using National Comprehensive Cancer Network criteria. Temporal trends in initial management were assessed. Multivariable logistic regression was used to evaluate demographic and clinical factors associated with undergoing radical prostatectomy (RP). RESULTS: In total, 127 391 men were identified. Use of RP increased from 26% in 2004 to 42% in 2013 (adjusted risk ratio (RR) 1.51, 95% CI 1.42-1.60, P<0.001), while external beam radiation therapy (EBRT) decreased from 49% to 42% (P<0.001). African American men had lower odds of undergoing RP (unadjusted rate of 28%, adjusted RR 0.69, 95% CI 0.66-0.72, <0.001) compared to White men (37%). Age was inversely associated with likelihood of receiving RP. Having private insurance was significantly associated with the increased use of RP (vs Medicare, adjusted odds ratio 1.04, 95% CI 1.01-1.08, P=0.015). Biopsy Gleason scores 8-10 with and without any primary Gleason 5 pattern were associated with decreased odds of RP (vs Gleason score ?6, both P<0.001). Academic and comprehensive cancer centers were more likely to perform RP compared to community hospitals (both P<0.001). CONCLUSION: The likelihood of receiving RP for high-risk PCa dramatically increased from 2004 to 2013. By 2013, the use of RP and EBRT were similar. African American men, elderly men and those without private insurance were less likely to receive RP. PMID- 28631722 TI - Intrinsic Excitability of Cocaine-Associated Memories. PMID- 28631721 TI - DISC1 in Astrocytes Influences Adult Neurogenesis and Hippocampus-Dependent Behaviors in Mice. AB - The functional role of genetic variants in glia in the pathogenesis of psychiatric disorders remains poorly studied. Disrupted-In-Schizophrenia 1 (DISC1), a genetic risk factor implicated in major mental disorders, has been implicated in regulation of astrocyte functions. As both astrocytes and DISC1 influence adult neurogenesis in the dentate gyrus (DG) of the hippocampus, we hypothesized that selective expression of dominant-negative C-terminus-truncated human DISC1 (mutant DISC1) in astrocytes would affect adult hippocampal neurogenesis and hippocampus-dependent behaviors. A series of behavioral tests were performed in mice with or without expression of mutant DISC1 in astrocytes during late postnatal development. In conjunction with behavioral tests, we evaluated adult neurogenesis, including neural progenitor proliferation and dendrite development of newborn neurons in the DG. The ameliorative effects of D serine on mutant DISC1-associated behaviors and abnormal adult neurogenesis were also examined. Expression of mutant DISC1 in astrocytes decreased neural progenitor proliferation and dendrite growth of newborn neurons, and produced elevated anxiety, attenuated social behaviors, and impaired hippocampus-dependent learning and memory. Chronic treatment with D-serine ameliorated the behavioral alterations and rescued abnormal adult neurogenesis in mutant DISC1 mice. Our findings suggest that psychiatric genetic risk factors expressed in astrocytes could affect adult hippocampal neurogenesis and contribute to aspects of psychiatric disease through abnormal production of D-serine. PMID- 28631723 TI - Pharmacogenetic biomarkers of response in Crohn's disease. AB - Crohn's disease (CD) is a chronic condition, which affects the immune system. It can also affect any part of the digestive tract and be associated with external manifestations. The causes of the disease remain unknown, although it seems to be the result of a combination of factors, such as genetic predisposition, environment, lifestyle and the composition of the microbiota, among others. The treatment protocol begins with a change in eating and smoking habits, and is continued with different lines of treatment, including corticosteroids, immunomodulators and biologic therapy (infliximab and adalimumab), which have shown differences in response among patients, especially with biologic treatment. Several studies have considered the possibility that these differences in response are caused by the genetic variability of patients. Many genes have been investigated as potential predictors of response to biological drugs, such as ADAM17, ATG16L1, EMSY, CASP9, CCNY, CNTN5, FASLG, FCGR, NOD2, PTGER4, IL13, IL1B, IL27, IL11, IL17F, TNF and TNFR genes. In this review, we will gather the information on influence of gene polymorphisms investigated to date on response to biological drugs in CD patients. PMID- 28631724 TI - Microscopic origins of the large piezoelectricity of leadfree (Ba,Ca)(Zr,Ti)O3. AB - In light of directives around the world to eliminate toxic materials in various technologies, finding lead-free materials with high piezoelectric responses constitutes an important current scientific goal. As such, the recent discovery of a large electromechanical conversion near room temperature in (1 x)Ba(Zr0.2Ti0.8)O3-x(Ba0.7Ca0.3)TiO3 compounds has directed attention to understanding its origin. Here, we report the development of a large-scale atomistic scheme providing a microscopic insight into this technologically promising material. We find that its high piezoelectricity originates from the existence of large fluctuations of polarization in the orthorhombic state arising from the combination of a flat free-energy landscape, a fragmented local structure, and the narrow temperature window around room temperature at which this orthorhombic phase is the equilibrium state. In addition to deepening the current knowledge on piezoelectricity, these findings have the potential to guide the design of other lead-free materials with large electromechanical responses. PMID- 28631725 TI - Erratum: Ruthenium-cobalt nanoalloys encapsulated in nitrogen-doped graphene as active electrocatalysts for producing hydrogen in alkaline media. AB - This corrects the article DOI: 10.1038/ncomms14969. PMID- 28631726 TI - Corrigendum: Ruthenium-cobalt nanoalloys encapsulated in nitrogen-doped graphene as active electrocatalysts for producing hydrogen in alkaline media. AB - This corrects the article DOI: 10.1038/ncomms14969. PMID- 28631727 TI - My Approach to Fecal Incontinence: It's all about Consistency (Stool, that is). PMID- 28631729 TI - Backwash Is Hogwash: The Clinical Significance of Ileitis in Ulcerative Colitis. PMID- 28631730 TI - Finding Freedom from Fecal Incontinence With My Orange Tote. PMID- 28631731 TI - Corrigendum: Treatment of NASH: What Helps Beyond Weight Loss? AB - This corrects the article DOI: 10.1038/ajg.2017.83. PMID- 28631728 TI - ACG and CAG Clinical Guideline: Management of Dyspepsia. AB - We have updated both the American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG) guidelines on dyspepsia in a joint ACG/CAG dyspepsia guideline. We suggest that patients >=60 years of age presenting with dyspepsia are investigated with upper gastrointestinal endoscopy to exclude organic pathology. This is a conditional recommendation and patients at higher risk of malignancy (such as spending their childhood in a high risk gastric cancer country or having a positive family history) could be offered an endoscopy at a younger age. Alarm features should not automatically precipitate endoscopy in younger patients but this should be considered on a case-by-case basis. We recommend patients <60 years of age have a non-invasive test Helicobacter pylori and treatment if positive. Those that are negative or do not respond to this approach should be given a trial of proton pump inhibitor (PPI) therapy. If these are ineffective tricyclic antidepressants (TCA) or prokinetic therapies can be tried. Patients that have an endoscopy where no pathology is found are defined as having functional dyspepsia (FD). H. pylori eradication should be offered in these patients if they are infected. We recommend PPI, TCA and prokinetic therapy (in that order) in those that fail therapy or are H. pylori negative. We do not recommend routine upper gastrointestinal (GI) motility testing but it may be useful in selected patients. PMID- 28631732 TI - Skillful prediction of northern climate provided by the ocean. AB - It is commonly understood that a potential for skillful climate prediction resides in the ocean. It nevertheless remains unresolved to what extent variable ocean heat is imprinted on the atmosphere to realize its predictive potential over land. Here we assess from observations whether anomalous heat in the Gulf Stream's northern extension provides predictability of northwestern European and Arctic climate. We show that variations in ocean temperature in the high latitude North Atlantic and Nordic Seas are reflected in the climate of northwestern Europe and in winter Arctic sea ice extent. Statistical regression models show that a significant part of northern climate variability thus can be skillfully predicted up to a decade in advance based on the state of the ocean. Particularly, we predict that Norwegian air temperature will decrease over the coming years, although staying above the long-term (1981-2010) average. Winter Arctic sea ice extent will remain low but with a general increase towards 2020. PMID- 28631733 TI - Plastid thylakoid architecture optimizes photosynthesis in diatoms. AB - Photosynthesis is a unique process that allows independent colonization of the land by plants and of the oceans by phytoplankton. Although the photosynthesis process is well understood in plants, we are still unlocking the mechanisms evolved by phytoplankton to achieve extremely efficient photosynthesis. Here, we combine biochemical, structural and in vivo physiological studies to unravel the structure of the plastid in diatoms, prominent marine eukaryotes. Biochemical and immunolocalization analyses reveal segregation of photosynthetic complexes in the loosely stacked thylakoid membranes typical of diatoms. Separation of photosystems within subdomains minimizes their physical contacts, as required for improved light utilization. Chloroplast 3D reconstruction and in vivo spectroscopy show that these subdomains are interconnected, ensuring fast equilibration of electron carriers for efficient optimum photosynthesis. Thus, diatoms and plants have converged towards a similar functional distribution of the photosystems although via different thylakoid architectures, which likely evolved independently in the land and the ocean. PMID- 28631735 TI - In the news: From ASCO 2017. PMID- 28631736 TI - Haematological cancer: Staging and restaging patients with lymphoma - a better approach? PMID- 28631737 TI - Haematological cancer: Brentuximab vedotin - a new standard for cutaneous T-cell lymphoma. PMID- 28631734 TI - Learning relative values in the striatum induces violations of normative decision making. AB - To decide optimally between available options, organisms need to learn the values associated with these options. Reinforcement learning models offer a powerful explanation of how these values are learnt from experience. However, human choices often violate normative principles. We suggest that seemingly counterintuitive decisions may arise as a natural consequence of the learning mechanisms deployed by humans. Here, using fMRI and a novel behavioural task, we show that, when suddenly switched to novel choice contexts, participants' choices are incongruent with values learnt by standard learning algorithms. Instead, behaviour is compatible with the decisions of an agent learning how good an option is relative to an option with which it had previously been paired. Striatal activity exhibits the characteristics of a prediction error used to update such relative option values. Our data suggest that choices can be biased by a tendency to learn option values with reference to the available alternatives. PMID- 28631738 TI - Breast cancer: Olaparib improves PFS. PMID- 28631739 TI - Infection: Impeding UPEC gut colonization. PMID- 28631741 TI - Bladder cancer: oligometastases and imaging. AB - The term oligometastases was introduced to describe patients with limited metastatic disease in whom treatment might result in long-term disease-free survival or even cure. Imaging is pivotal for identification of these patients. The definition of oligometastatic bladder cancer and the optimal imaging modalities for diagnosis and response prediction remain to be determined. PMID- 28631740 TI - Radiotherapy for renal cell carcinoma: renaissance of an overlooked approach. AB - Conventional radiotherapy previously had a limited role in the definitive treatment of renal cell carcinoma (RCC), owing to the disappointing outcomes of several trials and the perceived radioresistance of this type of cancer. In this context, radiotherapy has been relegated largely to the palliation of symptoms in patients with metastatic disease, with variable rates of response. Following the availability of newer technologies that enable safe delivery of high-dose radiotherapy, stereotactic ablative radiotherapy (SABR) has become increasingly used in patients with RCC. Preclinical evidence demonstrates that RCC cells are sensitive to ablative doses of radiotherapy (>=8-10 Gy). Trials in the setting of intracranial and extracranial oligometastases, as well as primary RCC, have demonstrated excellent tumour control using this approach. Additionally, an awareness of the capacity of high-dose radiation to stimulate antitumour immunity has resulted in novel combinations of SABR with immunotherapies. Here we describe the historical application of conventional radiotherapy, the current biological understanding of the effects of radiation, and the clinical evidence supporting the use of ablative radiotherapy in RCC. We also explore emerging opportunities to combine systemic targeted agents or immunotherapies with radiation. Radiotherapy, although once an overlooked approach, is moving towards the forefront of RCC treatment. PMID- 28631742 TI - Kidney cancer: Diving into the genome of papillary RCC unearths therapeutic pearls. PMID- 28631743 TI - Kidney cancer: FBV indicates sunitinib response. PMID- 28631744 TI - Traumatic cervical spinal cord injury: a prospective clinical study of laryngeal penetration and aspiration. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: Dysphagia is a relatively common secondary complication in patients with traumatic cervical spinal cord injuries (TCSCI). The purpose of this study was to determine the incidence of aspiration and penetration in patients with acute TCSCI. SETTING: Tampere University Hospital, Tampere, Finland. METHODS: A total of 46 patients with TCSCI were evaluated with a videofluoroscopic swallowing study (VFSS). Rosenbek's penetration-aspiration scale (PAS) was used to classify the degree of penetration or aspiration. The medical records of each patient were systematically reviewed. RESULTS: Of the 46 patients, 85% were male. The mean age at the time of the injury was 62.1 years. Most patients had an incomplete injury (78%), and most of them due to a fall (78%). In the VFSS 19 (41%) patients penetrated and 15 (33%) aspirated. Only 12 (26%) of the patients had a PAS score of 1 indicating that swallowed material did not enter the airway. Of the patients who aspirated, 73% had silent aspiration. CONCLUSION: The incidence of penetration or aspiration according to VFSS is high in this cohort of patients with TCSCI. Therefore, the swallowing function of patients with acute TCSCI should be routinely evaluated before initiating oral feeding. VFSS is highly recommended, particularly to rule out the possibility of silent aspiration and to achieve information on safe nutrition consistency. PMID- 28631745 TI - Achieving assessor accuracy on the International Standards for Neurological Classification of Spinal Cord Injury. AB - STUDY DESIGN: A retrospective audit of assessor accuracy using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) in three multicentre randomised controlled trials (SCIPA: Spinal Cord Injury and Physical Activity) spanning 2010-2014 with standards revised in 2011. OBJECTIVES: To investigate assessor accuracy of neurological classification after spinal cord injury. SETTING: Australia and New Zealand. METHODS: ISNCSCI examinations were undertaken by trained clinicians prior to randomisation. Data were recorded manually and ISNCSCI worksheets circulated to panels, consensus reached and worksheets corrected. An audit team used a 2014 computerised ISNCSCI algorithm to check manual worksheets. A second audit team assessed whether the 2014 computerised algorithm accurately reflected pre- and post-2011 ISNCSCI standards. RESULTS: Of the 208 ISNCSCI worksheets, 24 were excluded. Of the remaining 184 worksheets, 47 (25.5%) were consistent with the 2014 computerised algorithm and 137 (74.5%) contained one or more errors. Errors were in motor (30.1%) or sensory (12.4%) levels, zone of partial preservation (24.0%), motor/sensory scoring (21.5%), ASIA Impairment Scale (AIS, 8.3%) and complete/incomplete classification (0.8%). Other difficulties included classification when anal contraction/sensation was omitted, incorrect neurological levels and violation of the 'motor follows sensory rule in non-testable myotomes' (7.4%). Panel errors comprised corrections that were incorrect or missed or incorrect changes to correct worksheets. CONCLUSION: Given inaccuracies in the manual ISNCSCI worksheets in this long-term clinical trial setting, continued training and a computerised algorithm are essential to ensure accurate scoring, scaling and classification of the ISNCSCI and confidence in clinical trials. PMID- 28631746 TI - Prevalence of androgen deficiency in chronic spinal cord injury patients suffering from erectile dysfunction. AB - STUDY DESIGN: Retrospective cross-sectional study. OBJECTIVES: To estimate the prevalence of biochemical androgen deficiency in Iranian spinal cord injured men suffering from erectile dysfunction (ED) and to determine factors related to this problem. SETTING: An andrology clinic of a teaching hospital in Tehran. METHODS: Men, 18 years of age and older, with chronic (>2 years) spinal cord injury (SCI) suffering from ED were recruited. Demographic data, hormonal and lipid levels, injury variables and drug history were obtained from the medical records. The relationships between biochemical androgen deficiency (unequivocally low serum testosterone levels) and patient characteristics, injury variables and laboratory data were determined. RESULTS: Out of 319 patients, 32.6% had total testosterone deficiency and 29.1% had biochemical androgen deficiency. Of those with biochemical androgen deficiency, 93.5 and 85.7% had luteinizing hormone (LH) and follicle stimulating hormone (FSH) within or below the normal ranges, respectively. Opioid use, triglyceride (TG) and total cholesterol (TC) were associated with biochemical androgen deficiency. Significant correlations between total testosterone level and sex hormone binding globulin (r=0.3, P<0.001), LH (r=0.2, P=0.02), TC (r=-0.1, P=0.04) and TG (r=-0.3, P<0.001) were found. CONCLUSION: A substantial proportion of our patients with chronic SCI and ED had biochemical androgen deficiency. Opioid use, TG and TC levels were associated with biochemical androgen deficiency in our studied population. Standard screening of androgen deficiency and testosterone replacement therapy are recommended in men with chronic SCI suffering from ED. SPONSORSHIP: Tehran University of Medical Sciences. PMID- 28631747 TI - Optimization of the mean arterial pressure and timing of surgical decompression in traumatic spinal cord injury: a retrospective study. AB - STUDY DESIGN: A retrospective comparative study. OBJECTIVES: This study aims to investigate the extent to which early surgical decompression and maintenance of MAP ?85 mm Hg for 5 days postinjury affected neurological recovery utilizing internal controls for comparison of outcomes in patients with traumatic spinal cord injury. SETTING: Acute trauma center, Halifax, Nova Scotia, Canada. METHODS: We identified 94 cases of traumatic SCI. Follow-up data were available at an average of 26.7+/-19.5, 115.0+/-69.3, and 252.0+/-152.8 days postinjury for 61, 48, and 47 patients, respectively. Neurological recovery was assessed using the American Spinal Cord Injury Association (ASIA) Impairment Scale (AIS). RESULTS: Patients with MAP <85 mm Hg for at least 2 consecutive hours during the 5-day period postinjury were 11 times less likely to have an improvement in the AIS grade when compared with patients with MAP ?85 mm Hg (P=0.006). This association was independent of early surgery or the severity of SCI. At a mean of 252.0 days postinjury, a significantly greater proportion of SCI patients treated with early surgical decompression (within 24 h) improved neurologically (P=0.031). CONCLUSIONS: Our data demonstrated that there may be improved neurologic outcomes in patients with SCI who undergo early surgical decompression. Maintenance of MAP ?85 mm Hg for 5 consecutive days post-SCI was also associated with higher rates of AIS grade improvement at mean 26.7 days without a statistically significance difference at prolonged follow-up although a higher rate of neurological recovery persisted in patients with MAP ?85 mm Hg. PMID- 28631750 TI - Atherosclerosis: Trehalose induces macrophage autophagy-lysosomal biogenesis. PMID- 28631748 TI - CCL-2 as a possible early marker for remission after traumatic spinal cord injury. AB - STUDY DESIGN: Prospective observational study. OBJECTIVES: To describe the correlation between CCL-2, CCL-3, CCL-4 and CXCL-5 serum levels and remission after traumatic spinal cord injury (SCI) in a human protocol compared with animal studies. SETTING: Germany, Rhineland-Palatinate (Rheinland-Pfalz). METHODS: We examined the serum levels of CCL-2, CCL-3, CCL-4 and CXCL-5 over a 12-week period; in particular, at admission and 4, 9 and 12 h, 1 and 3 days and 1, 2, 4, 8 and 12 weeks after trauma. According to our study design, we matched 10 patients with TSCI and neurological remission with 10 patients with an initial ASIA A grade and no neurological remission. In all, 10 patients with vertebral fracture without neurological deficits served as control. Our analysis was performed using a Luminex Cytokine Panel. Multivariate logistic regression models were used to examine the predictive value with respect to neurological remission vs no neurological remission. RESULTS: The results of our study showed differences in the serum expression patterns of CCL-2 in association with the neurological remission (CCL-2 at admission P=0.013). Serum levels of CCL-2 and CCL-4 were significantly different in patients with and without neurological remission. The favored predictive model resulted in an area under the curve (AUC) of 93.1% in the receiver operating characteristic (ROC) analysis. CONCLUSIONS: Our results indicate that peripheral serum analysis is a suitable concept for predicting the patient's potential for neurological remission after TSCI. Furthermore, the initial CCL-2 concentration provides an additional predictive value compared with the NLI (neurological level of injury). Therefore, the present study introduces a promising approach for future monitoring concepts and tracking techniques for current therapies. The results indicate that future investigations with an enlarged sample size are needed in order to develop monitoring, prognostic and scoring systems. PMID- 28631749 TI - Causes of death after traumatic spinal cord injury-a 70-year British study. AB - DESIGN: Retrospective and prospective observational. OBJECTIVE: Analyse causes of death after traumatic spinal cord injury (tSCI) in persons surviving the first year post injury, and establish any trend over time. SETTING: Two spinal centres in Great Britain. METHODS: The sample consisted of 5483 patients with tSCI admitted to Stoke Mandeville and Southport spinal centres who were injured between 1943 and 2010, survived first year post injury, had residual neurological deficit on discharge and were British residents. Mortality information, including causes of death, was collected up to 31 December 2014. Age-standardised cause specific mortality rates were calculated for selected causes of death, and included trends over time and comparison with the general population. RESULTS: In total, 2322 persons (42.3% of the sample) died, with 2170 (93.5%) having a reliable cause of death established. The most frequent causes of death were respiratory (29.3% of all certified causes), circulatory, including cardiovascular and cerebrovascular diseases (26.7%), neoplasms (13.9%), urogenital (11.5%), digestive (5.3%) and external causes, including suicides (4.5%). Compared to the general population, age-standardised cause-specific mortality rates were higher for all causes, especially skin, urogenital and respiratory; rates showed improvement over time for suicides, circulatory and urogenital causes, no significant change for neoplasms, and increase for skin and respiratory causes. CONCLUSIONS: Leading causes of death after tSCI in persons surviving the first year post injury were respiratory, circulatory, neoplasms and urogenital. Cause-specific mortality rates showed improvement over time for most causes, but were still higher than the general population rates, especially for skin, urinary and respiratory causes. PMID- 28631751 TI - Thrombosis: Novel target with antithrombotic potential and low bleeding risk. PMID- 28631752 TI - Dyslipidaemia: Statin-associated muscle symptoms - really all in the mind? PMID- 28631753 TI - Dominant and recessive imprinting of exosomes from parent cells. PMID- 28631754 TI - Regenerative medicine: New targets for enhancing cardiac regeneration. PMID- 28631756 TI - Giant capsids from lattice self-assembly of cyclodextrin complexes. AB - Proteins can readily assemble into rigid, crystalline and functional structures such as viral capsids and bacterial compartments. Despite ongoing advances, it is still a fundamental challenge to design and synthesize protein-mimetic molecules to form crystalline structures. Here we report the lattice self-assembly of cyclodextrin complexes into a variety of capsid-like structures such as lamellae, helical tubes and hollow rhombic dodecahedra. The dodecahedral morphology has not hitherto been observed in self-assembly systems. The tubes can spontaneously encapsulate colloidal particles and liposomes. The dodecahedra and tubes are respectively comparable to and much larger than the largest known virus. In particular, the resemblance to protein assemblies is not limited to morphology but extends to structural rigidity and crystallinity-a well-defined, 2D rhombic lattice of molecular arrangement is strikingly universal for all the observed structures. We propose a simple design rule for the current lattice self assembly, potentially opening doors for new protein-mimetic materials. PMID- 28631755 TI - Construction of a synthetic metabolic pathway for biosynthesis of the non-natural methionine precursor 2,4-dihydroxybutyric acid. AB - 2,4-Dihydroxybutyric acid (DHB) is a molecule with considerable potential as a versatile chemical synthon. Notably, it may serve as a precursor for chemical synthesis of the methionine analogue 2-hydroxy-4-(methylthio)butyrate, thus, targeting a considerable market in animal nutrition. However, no natural metabolic pathway exists for the biosynthesis of DHB. Here we have therefore conceived a three-step metabolic pathway for the synthesis of DHB starting from the natural metabolite malate. The pathway employs previously unreported malate kinase, malate semialdehyde dehydrogenase and malate semialdehyde reductase activities. The kinase and semialdehyde dehydrogenase activities were obtained by rational design based on structural and mechanistic knowledge of candidate enzymes acting on sterically cognate substrates. Malate semialdehyde reductase activity was identified from an initial screening of several natural enzymes, and was further improved by rational design. The pathway was expressed in a minimally engineered Escherichia coli strain and produces 1.8 g l-1 DHB with a molar yield of 0.15. PMID- 28631757 TI - Resolving mixed mechanisms of protein subdiffusion at the T cell plasma membrane. AB - The plasma membrane is a complex medium where transmembrane proteins diffuse and interact to facilitate cell function. Membrane protein mobility is affected by multiple mechanisms, including crowding, trapping, medium elasticity and structure, thus limiting our ability to distinguish them in intact cells. Here we characterize the mobility and organization of a short transmembrane protein at the plasma membrane of live T cells, using single particle tracking and photoactivated-localization microscopy. Protein mobility is highly heterogeneous, subdiffusive and ergodic-like. Using mobility characteristics, we segment individual trajectories into subpopulations with distinct Gaussian step-size distributions. Particles of low-to-medium mobility consist of clusters, diffusing in a viscoelastic and fractal-like medium and are enriched at the centre of the cell footprint. Particles of high mobility undergo weak confinement and are more evenly distributed. This study presents a methodological approach to resolve simultaneous mixed subdiffusion mechanisms acting on polydispersed samples and complex media such as cell membranes. PMID- 28631759 TI - ? PMID- 28631760 TI - [Astronauts, asteroids and the universe of antithrombotic therapies in primary percutaneous coronary intervention]. AB - A sensation of self-awareness on the relativity of our certainties comes over looking to the huge amount of data on antithrombotic therapies assessed in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). This sensation can be compared to the so-called "overview effect", a cognitive shift in awareness reported by some astronauts during spaceflight, often while viewing the Earth from orbit. In this review we will mention drugs floated like meteors in the Universe of STEMI treatment and we will discuss the body of evidence on oral and intravenous antithrombotic therapies for patients undergoing pPCI. PMID- 28631758 TI - Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss. AB - Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. Here we show that bioconstructs suffused with genetically-labelled muscle stem cells (MuSCs) and other muscle resident cells (MRCs) are effective to treat VML injuries in mice. Imaging of bioconstructs implanted in damaged muscles indicates MuSCs survival and growth, and ex vivo analyses show force restoration of treated muscles. Histological analysis highlights myofibre formation, neovascularisation, but insufficient innervation. Both innervation and in vivo force production are enhanced when implantation of bioconstructs is followed by an exercise regimen. Significant improvements are also observed when bioconstructs are used to treat chronic VML injury models. Finally, we demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML. PMID- 28631761 TI - [Management of outpatients with cardiac disease: follow-up timing and modalities]. AB - The increasing rate of cardiovascular diseases, the improved survival after the acute phase, the aging of the population and the implementation of primary prevention caused an exponential increase in outpatient cardiac performance, thereby making it difficult to maintain a balance between the citizen-patient request and the economic sustainability of the healthcare system. On the other side, the prescription of many diagnostic tests with a view to defensive medicine and the related growth of patients' expectations, has led several scientific societies to educational campaigns highlighting the concept that "less is more".The present document is aimed at providing the general practitioner with practical information about a prompt diagnosis of signs/symptoms (angina, dyspnea, palpitations, syncope) of the major cardiovascular diseases. It will also provide an overview about appropriate use of diagnostic exams (echocardiogram, stress test), about the appropriate timing of their execution, in order to ensure effectiveness, efficiency, and equity of the health system. PMID- 28631762 TI - [Safety and tolerability of oral hypoglycemic therapies in type 2 diabetes mellitus patients at high cardiovascular risk]. AB - Oral hypoglycemic drugs for type 2 diabetes aim at preventing the metabolic effects of hyperglycemia and cardiovascular (CV) events. The evidence of the possible CV risk related to the prescription of some antidiabetic drugs prompted regulatory agencies to require safety studies. This review provides an updated analysis of CV safety profiles for antidiabetic drugs used for the treatment of patients with high CV risk.The most recent studies analyze different aspects of CV morbidity, such as ischemic events, heart failure and arrhythmia, and their interactions with hyperglycemia. The endpoints include major adverse cardiovascular events (CV mortality, myocardial infarction, stroke) and hospitalization for heart failure. There is extra-and intra-class variability of CV risk among different oral hypoglycemic drugs, including sulfonylureas, metformin, glitazones, glucagon-like peptide-1 analogues, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors. Different treatment settings, selectivity towards pharmacological targets and hypoglycemia-related effects may explain the discrepancies observed.This review may guide cardiologists and diabetologists, in collaboration with general practitioners, to make the most appropriate therapeutic decision fitting the characteristics of the individual diabetic patient. PMID- 28631763 TI - [Noninvasive ventilation: general characteristics, indications, and review of the literature]. AB - Noninvasive ventilation (NIV), including both continuous and bilevel positive airway pressure, plays a pivotal role in the treatment of acute respiratory failure secondary to acute heart failure. For an appropriate use of NIV, it is essential to consider the underlying pathophysiological principles, the differences between the different modes of ventilation, the main indications, contraindications and complications. The aim of this review is also to give practical guidance on how and when to start NIV at the bedside, how to monitor the response and how to choose the most appropriate interface. A review of the literature supports the use of NIV in terms of efficacy (reduction in intubation and mortality) and safety (in particular, the risk of myocardial infarction associated with its use, suggested by a previous study, has been definitely confuted). Nevertheless, NIV is still largely underused in contemporary clinical practice, as reported by data from real-world registries. This may be due to several factors, including lack of knowledge/confidence, reluctance of application in particular settings (acute coronary syndromes) and the risk of adverse effects (hypotension), which need to be reappraised. PMID- 28631764 TI - [Hemodynamic effects of positive end-expiratory pressure]. AB - The application of a positive end-expiratory pressure (PEEP), the cornerstone of noninvasive ventilation (NIV), causes hemodynamic changes in the cardiovascular system. To understand the benefits of NIV it is necessary to resume concepts of cardiovascular physiology and pathophysiology about cardiac function determinants, venous return, ventricular interdependence and heart-lung interaction, and to understand how PEEP interacts with them. The hemodynamic effects of PEEP are mediated by the increase in transpulmonary pressure, which results in increased pulmonary vascular resistance and in an attending small reduction of venous return in conditions of euvolemia, in a substantial reduction of left ventricular afterload and a potential positive effect on left ventricular stroke volume.The aim of this review is to describe how the application of PEEP does not necessarily induce detrimental hemodynamic effects, but may decrease oxygen consumption and improve cardiac performance. These effects can justify the use of NIV in hemodynamically unstable patients. PMID- 28631765 TI - [Noninvasive ventilation and sedation: evidence and practical tools for its utilization]. AB - Noninvasive ventilation (NIV) has gained increased acceptance inside the critical area, since it has been shown to be effective in reducing or avoiding the need for oro-tracheal intubation. NIV efficacy is dependent on the selection of the appropriate patients and on their compliance to therapy. Actually, full collaboration is not easily reached especially in agitated patients.Sedation during NIV is useful to reduce the rate of treatment failure, but robust data to guide the development of best practice are limited and sometimes local customs appear to exert a strong influence on patterns of care. Different sedative drugs are ready for use but none of currently available agents fulfill the criteria for the ideal drug. Knowledge of the pharmacological and hemodynamic characteristics of every single sedative agent is crucial to choose the right drug for every clinical scenario. Close monitoring is mandatory to avoid adverse effects. The aim of this article is to review the currently available literature, to recognize the contraindications for sedation use and to provide practical guidance. PMID- 28631766 TI - [Postural effect in patients with patent foramen ovale: evaluation of right-to left shunt with transcranial Doppler and transthoracic echocardiography and correlation with arterial oxygen saturation]. AB - BACKGROUND: Transcranial Doppler echocardiography and transthoracic echocardiography may detect with high accuracy right-to-left shunt (RLS) due to patent foramen ovale (PFO). However, a standardized diagnostic protocol has never been established. It has been suggested that standing or sitting positions may improve sensitivity of transcranial Doppler due to increased LRS in such positions. We aimed to test efficacy of the sitting position in addition to the supine position in the grading of RLS in patients with PFO. We have also evaluated whether an increase in RLS is associated with a fall in oxygen saturation (SaO2). METHODS: From September 2015 to February 2016, 70 consecutive patients with suspected PFO underwent transcranial Doppler echocardiography and transthoracic echocardiography with microbubble count and evaluation of SaO2. RESULTS: RLS due to PFO was diagnosed in 58 patients (82.9%). An increase in RLS grade in the sitting position was observed in 28 out of 58 patients (48.3%) (group 1), whereas no increase was detected in 30 patients (51.7%) (group 2). Among the clinical and echocardiographic variables considered, group 1 and group 2 differed only in the prevalence of atrial septal aneurysm (35.7 vs 3.3%, p=0.002). Postural changes were not associated with a fall in SaO2. CONCLUSIONS: RLS increases in about half of patients with PFO in the sitting position compared with the supine position, whereas no changes occur in SaO2. PMID- 28631767 TI - [Conservative treatment of a pseudoaneurysm of the mitral-aortic intervalvular fibrosa: 9 years of follow-up]. AB - Pseudoaneurysm of the mitral-aortic intervalvular fibrosa (MAIVF-P) is one of the rare complications of endocarditis or, more rarely, of surgical trauma. This condition is characterized by a pseudoaneurysm in the intra-annular area between the mitral valve and the aortic valve communicating with the outflow tract of the left ventricle, between the coronary or noncoronary left aortic valve and the front flap of the mitral valve. Nowadays, surgery is recommended to avoid further growth and complications. We hereby describe the case of a patient with MAIVF-P as a consequence of a surgical trauma and early appearance of MAIVF-P. During the long echocardiographic and clinical follow-up, the patients showed stable clinical and hemodynamic conditions despite the increase in size of the MAIVF-P. A conservative treatment based on a medical follow-up can represent an alternative in patients refusing surgery, in high-risk surgical patients as well as in patients showing a stable echocardiographic and clinical picture regardless of the MAIVF-P size. PMID- 28631768 TI - [Alternating bundle branch block during bigeminy supraventricular extrasystole triggered by a linking phenomenon]. PMID- 28631771 TI - [Dying in the Three Graces' arms: when ethics dresses up as aesthetics.] AB - The many adjectives usually used to explain the desirable death - painless, decent, human... - do not include the term "graceful". However, this is a way that can be explored, too, if you imagine to die in the Three Graces' arms, namely in a mood that, according to Ugo Foscolo, is "between the exaggerated cheerfulness and the deep pain". The pathway turns out to be much more productive if we allow ourselves to be led by the original names of the Three Graces and by their symbology. Euphrosyne suggests the wisdom through which the mind guides our choices, especially those that show as palliative cures; Aglaea suggests the peace linked to the possibility to keep the death process under control; Talia lets us imagine a death seen as growth, as a pathway that ends at the peak of our own humanity. Therefore, in terms of aesthetics, dying in the Three Graces' arms seems to be a spiritual task and an ethical commitment. PMID- 28631772 TI - [Regional Cancer Registries as observational points for clinical pathways in oncological networks.] AB - Regional Cancer Registries collect population data on incidence and survival for all forms of cancer on a national scale, providing basic elements for National and Regional Health Planning. The availability of the reliable and homogeneous measurement elements about patient outcomes is the key to improving quality and assessing the efficiency of the national healthcare. These measurement elements can be aggregated into predefined indicators for the clinical pathways of the individual regions to calculate their value and assess the phenomenon of health migration. PMID- 28631773 TI - [Cardiovascular complications of cancer chemotherapy. The need for cardio oncology.] AB - Traditional chemotherapic agents as antraciclines and radiumtherapy are known to be the cause of cardiovascular complications from many years. Nevertheless also recent drugs, which were initially considered effective only on cancer cells are now recognized to exert negative effects also on the cardiovascular system. The frequency and the entity of the effects are variable for each drug and depend from the clinical status of the patient. It is therefore necessary the creation of a team of oncologists and cardiologists for the prevention and therapy of cardiovascular complications. PMID- 28631775 TI - [Innovations in the treatment of ovarian cancer. Analysis of the therapeutic development: from platinum to immunotherapy.] AB - Ovarian cancer is the seventh most common cancer in women. The therapeutic approach provides for an appropriate integration between surgery and chemotherapy. Surgery is an important step for diagnosis, staging and therapy, aiming at the complete cytoreduction of all macroscopic visible disease. At the moment, adjuvant and first-line chemotherapy has as a standard the carboplatin paclitaxel combination. Further, the addition of bevacizumab in the advanced stage (IIIB-IV) is strongly recommended. Despite the initial effectiveness, however, 70-80% of patients develop relapsed disease within the first two years and require subsequent treatment lines that have palliative, rather than curative purposes and that seek to reach a chronic state for the disease. Among the causes of recurrences, one of the most studied is related to the stem cells that, due to a quiescent state, are resistant to chemotherapy. The choice of these treatments must consider several factors, including the probability of extending the PFS and OS, the residual toxicity, symptoms control, and the improvement of quality of life, and always remains subject to platinum free interval (PFI). There are not standard therapy. Pegylated liposomal doxorubicin (PLD) as a single agent or in combination with other drugs is one of several treatment modalities that may be considered for relapsed ovaria cancer. In addition, in about 15% to 20% of epithelial tumors, there is a mutation of the BRCA1 and 2 genes. This is fundamental to identify immediately a therapeutic opportunity represented by PARP inhibitors. These drugs, such as olaparib and niraparib, used in maintenance after a previous platinum-response, even partial, have also shown in upfront an activity in BRCA wild type, homologous recombination deficent (HRD) and homologous recombination proficient (HRP). Therefore, after 20 years of chemotherapy alone, new targeted therapies are emerging that will help changing the therapeutic approach, making treatments increasingly personalized. PMID- 28631774 TI - [Il ruolo di niraparib nel trattamento del carcinoma ovarico: attualita e prospettive.] AB - Riassunto. I PARP inibitori interferiscono con la riparazione del danno nella singola elica del DNA determinando una progressione del difetto nella doppia elica. In circa il 50% delle pazienti con carcinoma dell'ovaio sieroso di alto grado sono presenti difetti nei meccanismi di ricombinazione omologa, deputati alla riparazione del danno della doppia elica del DNA. L'incapacita di riparare il danno si traduce nella morte cellulare, un processo definito "letalita sintetica". Nella famiglia dei PARP inibitori il niraparib e stato il primo a essere approvato dalla FDA nel trattamento delle pazienti con carcinoma ovarico ricorrente indipendentemente dalla presenza o assenza di mutazioni BRCA. Questo risultato e stato raggiunto grazie ai dati emersi dal trial di fase III ENGOT OV16/NOVA, favorevoli in termini di prolungamento della sopravvivenza libera da progressione e associati a un buon profilo di tossicita. Ulteriori trial clinici sono in corso per valutare ulteriori indicazioni all'impiego di niraparib nel trattamento del carcinoma ovarico. PMID- 28631776 TI - An overview of pre-clinical studies on the effects of (-)-epigallocatechin-3 gallate, a catechin found in green tea, in treatment of pancreatic cancer AB - Human pancreatic cancer is one of the leading causes of mortality and morbidity worldwide. Despite surgical resection remains the only curative therapeutic treatment for this disease, only the minority of patients can be resected due to late diagnosis. Recently, new chemotherapy schemes with the combination of different drugs have been shown to improve disease-free survival, although best results were obtained mostly as neoadjuvant chemotherapy in the minority of patients with resectable tumor. Consequently, there is stimulated interest in new chemotherapeutic approaches and alternative medicines. Several studies showed that the use of natural compounds, such as phytochemicals, represents a promising strategy for pancreatic cancer treatment. One popular phytochemical with great anticancer properties, is the (-)-epigallocate-chin3-O gallate (EGCG), the most abundant catechin found in green tea. Accumulating evidences demonstrated that EGCG induces apoptosis and inhibits tumor progression by modulating different signaling pathways in pancreatic cancer. For these encouraging results, this catechin is currently used in clinical trials for treatment of various type of cancer and other diseases, although its poor bioavailability and poor stability represent severe limitations. Therefore, many researchers tried to develop a new strategy based of the use of nanotechnology which increases EGCG stability and bioavailability and simultaneously targets cancer cells in order to improve its anti-tumor effects. The aim of this article is to dissect the use of EGCG for management of pancreatic cancer, by reviewing the pre-clinical studies reported in literature. PMID- 28631777 TI - [Continuity of care in oncology. Quantitative analysis of data from patients treated in two different settings in Emilia--Romagna.] AB - INTRODUCTION: In order to ensure high-quality treatment for patients with cancer it is vital to implement organisational models (pathways and networks) and that guarantee continuity of care. Appropriate assessment tools that promote the evaluation and analysis of care pathways from the patients' perspective are available. Hence the aim of this study was to verify whether or not the coordination between the various stages and care providers in a cancer treatment pathway is perceived by our patients. METHODS: Patients being treated for cancer of the lung, breast or colorectal tract by the Ferrara University Hospital (FUH) and the wider Romagna regional health service (RRHS), Italy, were administered the OPTION evaluation questionnaire. Univariate descriptive statistics of patients' sociodemographic features and care pathways were generated, and means and standard deviations were calculated for patient responses to OPTION items 1 19 on continuity of care throughout their treatment pathway. RESULTS: Responses from 341 patients (37.2 % treated by the FUH and 62.8% by the RRHS) were obtained. All mean scores provided for items 1-19 were above 4 on a Likert scale of 1-5, showing that the patients' perception of the continuity of their care was very positive on the whole. The highest mean scores were given for items regarding their emotional experience, while the lowest were given for those regarding information and integration with the GPs. DISCUSSION AND CONCLUSIONS: Organisational efforts to promote patient-centred continuity of oncological care improved the experience of patients in our sample. Our data suggest that integration with the GPs still remains a problem, both from an organisational standpoint and in the perception of the patient being treated for cancer at one of the facilities under investigation. Although our findings are non-controlled and not generalisable to other geographical areas, they do show how such tools can be used to monitor and analyse patient's experience with continuity of care with a view to continual improvement in care provision. PMID- 28631778 TI - ? PMID- 28631779 TI - Recent advances in nanomedicines for the treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a severe systemic inflammatory disease. It is often associated with serious cartilage destruction and massive inflammatory infiltration, which might ultimately cause disability, wide complications and reduced life quality. Current clinical treatments of RA show several drawbacks such as high doses, frequent administration and serious side effects. These limitations have motivated tremendous expansion of the research and application of nanomedicines in RA therapy. In this review, we summarize the cutting edge progress in nanomedicines for the treatment of RA and discuss the application of various targeting strategies. Additionally, we also discuss the pivotal challenges to be addressed, as well as future perspectives. PMID- 28631780 TI - Tuning the photocatalytic activity of bismuth wolframate: towards selective oxidations for the biorefinery driven by solar-light. AB - The sol-gel entrapment of nanostructured Bi2WO6 enhances the activity and the selectivity of the short-gap semiconductor in the sunlight-driven photo-oxidation of trans-ferulic and trans-cinnamic acid dissolved in water with air as the primary oxidant. Valuable products such as vanillin, benzaldehyde, benzoic acid and vanillic acid are obtained. This provides the proof of concept that photocatalysis could be a promising technology in tomorrow's solar biorefineries. PMID- 28631783 TI - Ultrafast charge dynamics in glycine induced by attosecond pulses. AB - The combination of attosecond pump-probe techniques with mass spectrometry methods has recently led to the first experimental demonstration of ultrafast charge dynamics in a biomolecule, the amino acid phenylalanine [Calegari et al., Science, 2014, 346, 336]. Using an extension of the static-exchange density functional theory (DFT) method, the observed dynamics was explained as resulting from the coherent superposition of ionic states produced by the broadband attosecond pulse. Here, we have used the static-exchange DFT method to investigate charge migration induced by attosecond pulses in the glycine molecule. We show that the observed dynamics follows patterns similar to those previously found in phenylalanine, namely that charge fluctuations occur all over the molecule and that they can be explained in terms of a few typical frequencies of the system. We have checked the validity of our approach by explicitly comparing with the photoelectron spectra obtained in synchrotron radiation experiments and with the charge dynamics that follows the removal of an electron from a given molecular orbital, for which fully correlated ab initio results are available in the literature. From this comparison, we conclude that our method provides an accurate description of both the coherent superposition of cationic states generated by the attosecond pulse and its subsequent time evolution. Hence, we expect that the static-exchange DFT method should perform equally well for other medium-size and large molecules, for which the use of fully correlated ab initio methods is not possible. PMID- 28631789 TI - Electrolyte effect in induced charge electroosmosis. AB - This paper reports an interesting phenomenon that the velocity increases with increasing sodium chloride (NaCl) concentration in induced charge electroosmosis (ICEO) around a conducting cylinder measured by microparticle image velocimetry (MUPIV). It is different from the widely reported velocity decay with increasing electrolyte concentration in AC electroosmosis (ACEO) [M. Z. Bazant et al., MicroTAS, 2007, 2875-2878] and induced charge electrophoresis (ICEP) of Janus particles [S. Gangwal et al., Phys. Rev. Lett., 2008, 100, 058302]. In addition, it is found that a reversed vortex flow emerges in deionized water. As the electric field increases or with a slight addition of NaCl, the ICEO vortex flow recovers. Different from the prediction of thin electric double layer (EDL) models, the observed ICEO flow is asymmetric with respect to the cylinder center. The asymmetry presents an electrolyte dependence, and it is intensified as the applied electric field increases. The ICEO flow obtains maximum values at certain electric field frequencies in NaCl and calcium chloride (CaCl2) solutions. But it is surprisingly insensitive to the electric field frequency in sodium dodecyl sulfate (NaDS) solutions. The optimum electric field frequency varies as electrolyte species change. A linear relationship between ICEO velocity and electric field strength squared is observed in all the examined electrolyte solutions, while the slope varies with the changing electrolyte species. PMID- 28631790 TI - Multidentate silyl ligands in transition metal chemistry. AB - Silyl ligands are of great interest in transition metal coordination chemistry since they exhibit a strong trans-influence and create electron rich metals centres, which are in turn eligible to activate reagents. This review presents and discusses the use of multidentate Si-based ligand systems in transition metal coordination chemistry. These include tri- and tetradentate pincer and scorpionate-type ligands, which have been developed in recent years in order to tailor both steric and electronic properties for achieving a defined control over the reactivity of a transition metal complex. A discussion of synthetic and structural aspects of several subgroups of ligand architectures is presented. Some compounds allow for a detailed insight into the activation process of silanes or are capable of activating small molecules. PMID- 28631791 TI - Room temperature sintering of polar ZnO nanosheets: II-mechanism. AB - In a previous work by the authors (A. Fernandez-Perez el al., Room temperature sintering of polar ZnO nanosheets: I-evidence, 2017, DOI: 10.1039/C7CP02306E), polar ZnO nanosheets were stored at room temperature under different atmospheres and the evolution of their textural and crystal properties during storage was followed. It was found that the specific surface area of the nanosheets drastically decreased during storage, with a loss of up to 75%. The ZnO crystals increased in size mainly through the partial merging of their polar surfaces at the expense of narrow mesoporosity, in a process triggered by the action of moisture, oxygen and, in their absence, by light. In the present work, a set of spectroscopic techniques (FTIR, Raman and XPS) has been used in an attempt to unravel the mechanism behind this spontaneous sintering process. The mechanism starts with the molecular adsorption of water, which takes place on Zn atoms close to oxygen vacancies on the (100) surface, where H2O dissociates to form two hydroxyl groups and to heal one oxygen vacancy. This process triggers the room temperature migration of Zn interstitials towards the outer surface of the polar region. What were previously interstitial Zn atoms now gradually occupy the mesopores, with interstitial oxygen being used to build up the O sublattice until total occupancy of the narrow mesoporosity is achieved. PMID- 28631792 TI - Nanoscopic dynamics of bicontinous microemulsions: effect of membrane associated protein. AB - Bicontinous microemulsions (BMUE) generally consist of nanodomains formed by surfactant in a mixture of water and oil at nearly equal proportions and are potential candidates for the solubilization and purification of membrane proteins. Here we present the first time report of nanoscopic dynamics of surfactant monolayers within BMUEs formed by the anionic surfactant sodium dodecyl sulfate (SDS) measured on the nanosecond to picosecond time scale using quasielastic neutron scattering (QENS). BMUEs investigated herein consisted of middle phases isolated from Winsor-III microemulsion systems that were formed by mixing aqueous and oil solutions under optimal conditions. QENS data indicates that surfactants undergo two distinct motions, namely (i) lateral motion along the surface of the oil nanodomains and (ii) localized internal motion. Lateral motion can be described using a continuous diffusion model, from which the lateral diffusion coefficient is obtained. Internal motion of surfactant is described using a model which assumes that a fraction of the surfactants' hydrogens undergoes localized translational diffusion that could be considered confined within a spherical volume. The effect of cytochrome c, an archetypal membrane-associated protein known to strongly partition near the surfactant head groups in BMUEs (a trend supported by small-angle X-ray scattering [SAXS] analysis), on the dynamics of BMUE has also been investigated. QENS results demonstrated that cytochrome c significantly hindered both the lateral and the internal motions of surfactant. The lateral motion was more strongly affected: a reduction of the lateral diffusion coefficient by 33% was measured. This change is mainly attributable to the strong association of cytochrome c with oppositely charged SDS. In contrast, analysis of SAXS data suggested that thermal fluctuations (for a longer length and slower time scale compared to QENS) were increased upon incorporation of cytochrome c. This study demonstrates the utility of QENS for evaluating dynamics of BMUEs in nanoscopic region, and that proteins directly affect the microscopic dynamics, which is of relevance for evaluating release kinetics of encapsulated drugs from BMUE delivery systems and the use of BMUEs as biomembrane mimetic systems for investigating membrane protein biomembrane interactions. PMID- 28631793 TI - Organic-inorganic macroion coacervate complexation. AB - Coacervate complexes that are liquid-liquid separated complex materials are often formed by stoichiometrically mixing oppositely charged polyelectrolytes in salted aqueous solution. Entropy-driven ion pairing, resulting from the release of counterions near polyelectrolytes, has been identified as the primary driving force for coacervate formation between oppositely charged polyelectrolytes, including proteins and DNA, in aqueous solution. In this work we have examined the complexation between net neutral zwitterionic poly(sulfobetaine methacrylate) (PSBMA) and inorganic polyoxometalate (POM) polyanions in LiCl aqueous solutions. Biphasic liquid-like coacervate complexes can be formed over a much broader range of POM-to-PSBMA molar ratio and LiCl concentration than that for conventional polyelectrolyte coacervate complexation. Composition analysis of the dried supernatant and dense coacervate has confirmed that both PSBMA and POM macroions are primarily present in the dense coacervate as the macroion-rich phase in contrast to the presence of LiCl solely in the supernatant as the macroion-poor phase. The increase of net charge negativity of PSBMA and supernatant conductivity suggests stronger binding of PSBMA with POM anions than monovalent Cl-, resulting in the release of bound Cl- anions to the aqueous solution for the formation of PSBMA-POM coacervates in LiCl solution. All experimental evidence has demonstrated the generality of ion-pairing induced coacervate complexation with net neutral zwitterionic polymers and multivalent inorganic nanomaterials. The complexation between organic and inorganic macroions could give insights into many supramolecular assembly processes in nature and also lead to a new paradigm in developing hybrid macroionic materials for emerging applications from green catalysis to nanomedicine. PMID- 28631794 TI - An efficient target-intermediate recycling amplification strategy for ultrasensitive fluorescence assay of intracellular lead ions. AB - An ultrasensitive fluorescence assay for intracellular Pb2+ determination was proposed through target-intermediate recycling amplification based on metal assisted DNAzyme catalysis and strand displacement reactions. Compared with only target recycling-based fluorescence assay with an M amplification ratio, the proposed assay could achieve an M * N amplification ratio to obtain an improved sensitivity by more than 10 times, in which M and N are the amplification ratios of target recycling and intermediate recycling, respectively. Remarkably, this proposed ultrasensitive fluorescence assay could be applied to the determination of various analytes with the well-designed detection probe, especially in intracellular assay, providing a promising tool for clinical diagnosis and biomedical detection. PMID- 28631795 TI - Assembly of dicobalt and cobalt-aluminum oxide clusters on metal-organic framework and nanocast silica supports. AB - NU-1000, a mesoporous metal-organic framework (MOF) featuring hexazirconium oxide nodes and 3 nm wide channels, was infiltrated with a reactive dicobalt complex to install dicobalt active sites onto the MOF nodes. The anchoring of the dicobalt complex onto NU-1000 occurred with a nearly ideal stoichiometry of one bimetallic complex per node and with the cobalt evenly distributed throughout the MOF particle. To access thermally robust multimetallic sites on an all-inorganic support, the modified NU-1000 materials containing either the dicobalt complex, or an analogous cobalt-aluminum species, were nanocast with silica. The resulting materials feature Co2 or Co-Al bimetallated hexazirconium oxide clusters within a silica matrix. The cobalt-containing materials are competent catalysts for the selective oxidation of benzyl alcohol to benzaldehyde. Catalytic activity depends on the number of cobalt ions per node, but does not vary significantly between the NU-1000 and silica supports. Hence, the multimetallic oxide clusters remain site-isolated and substrate-accessible within the nanocast materials. PMID- 28631796 TI - Isomerization versus dissociation of phenylalanylglycyltryptophan radical cations. AB - Four isomers of the radical cation of tripeptide phenylalanylglycyltryptophan, in which the initial location of the radical center is well defined, have been isolated and their collision-induced dissociation (CID) spectra examined. These ions, the pi-centered [FGWpi]+, alpha-carbon- [FGalphaW]+, N-centered [FGWN]+ and zeta-carbon- [FzetaGW]+ radical cations, were generated via collision-induced dissociation (CID) of transition metal-ligand-peptide complexes, side chain fragmentation of a pi-centered radical cation, homolytic cleavage of a labile nitrogen-nitrogen single bond, and laser induced dissociation of an iodinated peptide, respectively. The pi-centered and tryptophan N-centered peptide radical cations produced almost identical CID spectra, despite the different locations of their initial radical sites, which indicated that interconversion between the pi centered and tryptophan N-centered radical cations is facile. By contrast, the alpha-carbon-glycyl radical [FGalphaW]+, and zeta-phenyl radical [FzetaGW]+, featured different dissociation product ions, suggesting that the interconversions among alpha-carbon, pi-centered (or tryptophan N-centered) and zeta-carbon-radical cations have higher barriers than those to dissociation. Density functional theory calculations have been used to perform systematic mechanistic investigations on the interconversions between these isomers and to study selected fragmentation pathways for these isomeric peptide radical cations. The results showed that the energy barrier for interconversion between [FGWpi]+ and [FGWN]+ is only 31.1 kcal mol-1, much lower than the barriers to their dissociation (40.3 kcal mol-1). For the [FGWpi]+, [FGalphaW]+, and [FzetaGW]+, the barriers to interconversion are higher than those to dissociation, suggesting that interconversions among these isomers are not competitive with dissociations. The [z3 - H]+ ions isolated from [FGalphaW]+ and [FzetaGW]+ show distinctly different fragmentation patterns, indicating that the structures of these ions are different and this result is supported by the DFT calculations. PMID- 28631799 TI - Droplet control technologies for microfluidic high throughput screening (MUHTS). AB - The transition from micro well plate and robotics based high throughput screening (HTS) to chip based screening has already started. This transition promises reduced droplet volumes thereby decreasing the amount of fluids used in these studies. Moreover, it significantly boosts throughput allowing screening to keep pace with the overwhelming number of molecular targets being discovered. In this review, we analyse state-of-the-art droplet control technologies that exhibit potential to be used in this new generation of screening devices. Since these systems are enclosed and usually planar, even some of the straightforward methods used in traditional HTS such as pipetting and reading can prove challenging to replicate in microfluidic high throughput screening (MUHTS). We critically review the technologies developed for this purpose in depth, describing the underlying physics and discussing the future outlooks. PMID- 28631800 TI - A hyaluronidase/temperature dual-responsive supramolecular assembly based on the anionic recognition of calixpyridinium. AB - We have successfully constructed a supramolecular assembly based on the anionic recognition of calixpyridinium for the first time employing native biocompatible polysaccharide hyaluronan as the guest, which showed hyaluronidase-responsive disassembly and temperature-responsive morphological conversion from a nanosphere to a nanosquare upon increasing the temperature. PMID- 28631801 TI - Morphology of elastic nematic liquid crystal membranes. AB - Liquid crystalline phases found in many biological materials, such as actin, DNA, cellulose, and collagen can be responsible for the deformation of cell membranes. In this paper, cell membrane deformation is investigated through the coupling between liquid crystal anisotropy and membrane bending elasticity. The generalized shape equation for anisotropic interfaces, which resort to the Cahn Hoffman capillarity vector, the Rapini-Papoular anchoring energy, and the Helfrich elastic energy, is applied to gain insight into the deformation of closed liquid crystal membranes. This study presents a general morphological phase diagram of membrane surface patterns, in which two characteristic regimes of membrane shapes can be classified with respect to the most dominant factor between liquid crystal anisotropy and bending elasticity. To that end, we consider a 2D nematic liquid crystal droplet immersed in a isotropic phase in the presence of an interfacial layer of surfactants, which leads to an additional elastic contribution to the free energy of the system. The presented results indicate that, depending on the bending elasticity of the cell membrane, the liquid crystal might be able to deform the cell, thereby resulting in anisotropic asymmetric shapes. As liquid crystal anisotropy dominates the bending elasticity, spindle-like or tactoid shapes, which are extensively observed in experiments, can be formed. The findings provide a foundational framework to better understand membrane topologies in living soft matters. Furthermore, the coupling between order and curvature of membranes shed new light into the design of novel functional soft materials. PMID- 28631802 TI - Aqueous tantalum polyoxometalate reactivity with peroxide. AB - Peroxide ligation of aqueous metal-oxo clusters provides rich speciation and structural diversity, radiation sensitivity for manipulation with light, and both broadens and shifts pH-range stability. Here we demonstrate peroxide ligation of the polyoxometalate (POM) [Ta6O19]8-. We study in detail solution speciation of the peroxide-substituted cluster, and benchmark it to the peroxide-ligated niobate analogue, [Nb6O10(OH)3(O2)6]5-, whose solid-state structure has been reported. Raman and electrospray ionization mass spectroscopy do not detect any significant differences between the two analogues. However, small and wide-angle and total X-ray scattering strongly indicate that peroxide promotes linking of the hexameric tantalate clusters, rather than terminating and capping the clusters, as observed for the niobate analogue. We used computational studies to identify Raman peak positions, determine the energetics of exchange of oxo ligands for peroxo-ligands, and provide models to help explain the X-ray scattering data. Understanding the solution speciation of peroxide-substituted polyoxotantalates is an important step towards its use in solution processed thin film materials, as well as developing new Ta-POM chemistry. PMID- 28631803 TI - A Gompertz Model Approach to Microbial Inactivation Kinetics by High-Pressure Processing (HPP): Model Selection and Experimental Validation. AB - A recently proposed Gompertz model (GMPZ) approach describing microbial inactivation kinetics by high-pressure processing (HPP) incorporated the initial microbial load (N0 ) and lower microbial quantification limit (Nlim ), and simplified the dynamic effects of come-up time (CUT). The inactivation of Listeria innocua in milk by HPP treatments at 300, 400, 500, and 600 MPa and pressure holding times (thold ) <=10 min was determined experimentally to validate this model approach. Models based on exponential, logistic-exponential, and inverse functions were evaluated to describe the effect of pressure on the lag time (lambda) and maximum inactivation rate (MUmax ), whereas the asymptote difference (A) was fixed as A = log10 (N0 /Nlim ). Model performance was statistically evaluated and further validated with additional data obtained at 450 and 550 MPa. All GMPZ models adequately fitted L. innocua data according to the coefficient of determination (R2 >= 0.95) but those including a logistic exponential function for MUmax (P) were superior (R2 >= 0.97). These GMPZ versions predicted that approximately 597 MPa is the theoretical pressure level (Plambda ) at which microbial inactivation begins during CUT, mathematically defined as lambda (P = Plambda ) = tCUT , and matching the value observed on the microbial survival curve at 600 MPa. As pressure increased, predictions tended to slightly underestimate the HPP lethality in the tail section of the survival curve. This may be overseen in practice since the observed microbial counts were below the predicted log10 N values. Overall, the modeling approach is promising, justifying further validation work for other microorganisms and food systems. PMID- 28631804 TI - Mandarin fruit quality: a review. AB - During the last decade, there has been a continuous rise in consumption and global marketing of fresh, easy-to-peel mandarins, with current annual production of nearly 29 million tons. Nevertheless, most of the existing knowledge on quality traits of citrus fruit comes from research conducted on oranges and grapefruit, which are the main products for the citrus juice manufacturing industry; relatively little is yet known regarding the unique fruit quality traits of mandarins, nor about the great diversity in these traits among the various natural sub-groups and varieties of mandarins. In the present review we discuss the physiological, biochemical, and molecular factors governing key fruit quality attributes of mandarins, including fruit colour, size and shape, ease of peeling, seedlessness, flavour, and nutritional quality. Fruit colour, size, and shape contribute to external appearance; peelability and seedlessness to ease of consumption; and flavour and nutritional quality to internal quality. (c) 2017 Society of Chemical Industry. PMID- 28631805 TI - Drug therapy for chronic idiopathic axonal polyneuropathy. AB - BACKGROUND: Chronic idiopathic axonal polyneuropathy (CIAP) is an insidiously progressive sensory or sensorimotor polyneuropathy that affects elderly people. Although severe disability or handicap does not occur, CIAP reduces quality of life. CIAP is diagnosed in 10% to 25% of people referred for evaluation of polyneuropathy. There is a need to gather and review emerging evidence on treatments, as the number of people affected is likely to increase in ageing populations. This is an update of a review first published in 2004 and previously updated in 2006, 2008, 2011 and 2013. OBJECTIVES: To assess the effects of drug therapy for chronic idiopathic axonal polyneuropathy for reducing disability and ameliorating neurological symptoms and associated impairments, and to assess any adverse effects of treatment. SEARCH METHODS: In July 2016, we searched Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews in the Cochrane Library, MEDLINE, Embase, and the Web of Science. We searched two trials registries for ongoing trials. We also handsearched the reference lists of relevant articles, reviews and textbooks identified electronically, and we would have contacted authors and other experts in the field to identify additional studies if this seemed useful. SELECTION CRITERIA: We sought all randomised or quasi-randomised (alternate or other systematic treatment allocation) trials that examined the effects of any drug therapy in people with CIAP at least one year after the onset of treatment. People with CIAP had to fulfil the following criteria: age 40 years or older, distal sensory or sensorimotor polyneuropathy, absence of systemic or other neurological disease, chronic clinical course not reaching a nadir in less than two months, exclusion of any recognised cause of the polyneuropathy by medical history taking, clinical or laboratory investigations, and electrophysiological studies in agreement with axonal polyneuropathy, without evidence of demyelinating features. The primary outcome was the proportion of participants with a significant improvement in disability. Secondary outcomes were change in the mean disability score, change in the proportion of participants who make use of walking aids, change in the mean Medical Research Council sum score, degree of pain relief and/or reduction of other positive sensory symptoms, change in the proportion of participants with pain or other positive sensory symptoms, and frequency of adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed the results of the literature search and extracted details of trial methodology and outcome data of all potentially relevant trials. MAIN RESULTS: We identified 39 studies and assessed them for possible inclusion in the review, but we excluded all of them because of insufficient quality or lack of relevance. We summarised evidence from non-randomised studies in the Discussion. AUTHORS' CONCLUSIONS: Even though CIAP has been clearly described and delineated, no adequate randomised or quasi randomised controlled clinical treatment trials have been performed. In their absence there is no proven efficacious drug therapy. PMID- 28631806 TI - Increasing Oil Concentration Affects Consumer Perception and Physical Properties of Mayonnaise-type Spreads Containing KCl. AB - Reducing sodium intakes remains a global challenge for the food industry. KCl is a potential salt substitute but imparts bitterness when used at high concentrations. Little is known about how oil concentrations (OC) affect consumers' perception of saltiness and bitterness in emulsion products such as mayonnaise containing KCl. We evaluated consumers' perception and physical properties of mayonnaise-type spreads at various oil and tastant (NaCl or KCl) concentrations. Consumers (N = 306) evaluated saltiness, bitterness, overall taste liking (OTL) and purchase intent (PI). Viscosity, pH, water activity, and consistency/texture were also measured. Oil and tastant (NaCl or KCl) concentrations had significant effects on saltiness, viscosity, and pH. As OC increased, saltiness intensity slightly decreased for spreads. Increasing oil concentration increased viscosity. Generally, spreads containing KCl had higher bitterness and pH than spreads containing NaCl. All spreads containing KCl were penalized for being "too bitter." PI was affected by OTL for all spreads but OC was also a significant factor in the purchase decision of spreads containing NaCl. This study demonstrated that increasing OC affected consumers' taste perception (saltiness and bitterness) and spreads' physical properties including pH and viscosity. PMID- 28631807 TI - Compositional Analyses and Shelf-Life Modeling of Njangsa (Ricinodendron heudelotii) Seed Oil Using the Weibull Hazard Analysis. AB - This study investigated the compositional characteristics and shelf-life of Njangsa seed oil (NSO). Oil from Njangsa had a high polyunsaturated fatty acid (PUFA) content of which alpha eleostearic acid (alpha-ESA), an unusual conjugated linoleic acid was the most prevalent (about 52%). Linoleic acid was also present in appreciable amounts (approximately 34%). Our investigations also indicated that the acid-catalyzed transesterification of NSO resulted in lower yields of alpha-ESA methyl esters, due to isomerization, a phenomenon which was not observed under basic conditions. The triacylglycerol (TAG) profile analysis showed the presence of at least 1 alpha-ESA fatty acid chain in more than 95% of the oil's TAGs. Shelf-life was determined by the Weibull Hazard Sensory Method, where the end of shelf-life was defined as the time at which 50% of panelists found the flavor of NSO to be unacceptable. This was determined as 21 wk. Our findings therefore support the potential commercial viability of NSO as an important source of physiologically beneficial PUFAs. PMID- 28631808 TI - Fabrication of beta-cyclodextrin-mediated single bimolecular inclusion complex: characterization, molecular docking, in-vitro release and bioavailability studies for gefitinib and simvastatin conjugate. AB - OBJECTIVES: Introduction of multiple molecules in a single inclusion complex, albeit cheaper, lacks conclusive attempts in earlier drug delivery reports. This manuscript emphasizes simultaneous incorporation of two anticancer drugs, gefitinib (G) and simvastatin (S), in a single molecule of beta-cyclodextrin for the first time to achieve effective drug delivery. METHODS: The inclusion complex (GSBCD) was prepared by cosolvent evaporation technique using beta-cyclodextrin (BCD) as carrier. Characterization of GSBDC was performed by Fourier transform infrared spectroscopy, COSY, differential scanning calorimetry, X-ray diffraction and dynamic light scattering analyses, which were ascribed to the complex formation inside BCD cavity, micronization of drugs and conversion to amorphous state. KEY FINDINGS: The complex revealed entrapment of G and S in 3 +/- 0.48: 2 +/- 0.19 molar ratio and showed more than 3.5 and 10 fold increase in drug release in in vitro and in vivo, respectively. Docking and COSY studies revealed molecular alignment into BCD central cavity that been achieved via hydrogen bonding between certain groups of the ligands (G and S) and the polar heads of BCD. Partial incorporation of the molecular backbone inside inclusion complex suggests superficial contact with the solvent indicating slow steady release kinetics. CONCLUSIONS: This approach of forming inclusion complex with multiple molecules within a single cavity can be a landmark for further studies in drug delivery. PMID- 28631809 TI - Anabolic steroids for treating pressure ulcers. AB - BACKGROUND: Pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localised injury to the skin or underlying tissue, or both. The ulcers usually arise over a bony prominence, and are recognised as a common medical problem affecting people confined to a bed or wheelchair for long periods of time. Anabolic steroids are used as off-label drugs (drugs which are used without regulatory approval) and have been used as adjuvants to usual treatment with dressings, debridement, nutritional supplements, systemic antibiotics and antiseptics, which are considered to be supportive in healing of pressure ulcers. Anabolic steroids are considered because of their ability to stimulate protein synthesis and build muscle mass. Comprehensive evidence is required to facilitate decision making, regarding the benefits and harms of using anabolic steroids. OBJECTIVES: To assess the effects of anabolic steroids for treating pressure ulcers. SEARCH METHODS: In March 2017 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of anabolic steroids with alternative treatments or different types of anabolic steroids in the treatment of pressure ulcers. DATA COLLECTION AND ANALYSIS: Two review authors independently carried out study selection, data extraction and risk of bias assessment. MAIN RESULTS: The review contains only one trial with a total of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV. The participants were mainly male (98.2%, 106/108) with a mean age of 58.4 (standard deviation 10.4) years in the oxandrolone group and were all male (100%, 104/104) with a mean age of 57.3 (standard deviation 11.6) years in the placebo group. This trial compared oxandrolone (20 mg/day, administered orally) with a dose of placebo (an inactive substance consisting of 98% starch and 2% magnesium stearate) and reported data on complete healing of ulcers and adverse events. There was very low-certainty evidence on the relative effect of oxandrolone on complete ulcer healing at the end of a 24-week treatment period (risk ratio RR) 0.81, 95% confidence interval (CI) 0.52 to 1.26) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, we are uncertain whether oxandrolone improves or reduces the complete healing of pressure ulcers, as we assessed the certainty of the evidence as very low.There was low-certainty evidence on the risk of non-serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 3.85, 95% CI 1.12 to 13.26) (downgraded once for imprecision and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, the treatment with oxandrolone may increase the risk of non-serious adverse events reported in participants.There was very low-certainty evidence on the risk of serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 0.54, 95% CI 0.25 to 1.17) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Of the five serious adverse events reported in the oxandrolone-treated group, none were classed by the trial teams as being related to treatment. We are uncertain whether oxandrolone increases or decreases the risk of serious adverse events as we assessed the certainty of the evidence as very low.Secondary outcomes such as pain, length of hospital stay, change in wound size or wound surface area, incidence of different type of infection, cost of treatment and quality of life were not reported in the included trial.Overall the evidence in this study was of very low quality (downgraded for imprecision and indirectness). This trial stopped early when the futility analysis (interim analysis) in the opinion of the study authors showed that oxandrolone had no benefit over placebo for improving ulcer healing. AUTHORS' CONCLUSIONS: There is no high quality evidence to support the use of anabolic steroids in treating pressure ulcers.Further well-designed, multicenter trials, at low risk of bias, are necessary to assess the effect of anabolic steroids on treating pressure ulcers, but careful consideration of the current trial and its early termination are required when planning future research. PMID- 28631810 TI - Flavonoids of Lotus (Nelumbo nucifera) Seed Embryos and Their Antioxidant Potential. AB - Flavonoids from lotus (Nelumbo nucifera) seed embryos were fractionated over a macroporous resin chromatography into 2 main fractions (I and II), and subsequently identified by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS2 ). Sixteen flavonoids were identified in lotus seed embryos, including 8 flavonoid C-glycosides and 8 flavonoid O-glycosides, in which the flavonoid C-glycosides were the main flavonoids. Among them, 2 flavonoid O-glycosides (luteolin 7-O-neohesperidoside and kaempferol 7-O glucoside) were identified in lotus seed embryos for the 1st time. For further elucidating the effects of flavonoid C-glycosides to the bioactivities of lotus seed embryos, we compared the differences of the flavonoids and their antioxidant activities between leaves and seed embryos of lotus using the same methods. The results showed the antioxidant activity of flavonoids in lotus seed embryos was comparable or higher than that in lotus leaves, whereas the total flavonoid content in seed embryos was lower than lotus leaves which only contained flavonoid O-glycosides. The flavonoid C-glycosides of lotus seed embryos had higher antioxidant properties than the flavonoid O-glycosides presented in lotus leaves. This study suggested that the lotus seed embryos could be promising sources with antioxidant activity and used as dietary supplements for health promotion. PMID- 28631811 TI - The Effects of Fat Structures and Ice Cream Mix Viscosity on Physical and Sensory Properties of Ice Cream. AB - The purpose of this work was to investigate iciness perception and other sensory textural attributes of ice cream due to ice and fat structures and mix viscosity. Two studies were carried out varying processing conditions and mix formulation. In the 1st study, ice creams were collected at -3, -5, and -7.5 degrees C draw temperatures. These ice creams contained 0%, 0.1%, or 0.2% emulsifier, an 80:20 blend of mono- and diglycerides: polysorbate 80. In the 2nd study, ice creams were collected at -3 degrees C draw temperature and contained 0%, 0.2%, or 0.4% stabilizer, a blend of guar gum, locust bean gum, and carrageenan. Multiple linear regressions were used to determine relationships between ice crystal size, destabilized fat, and sensory iciness. In the ice and fat structure study, an inverse correlation was found between fat destabilization and sensory iciness. Ice creams with no difference in ice crystal size were perceived to be less icy with increasing amounts of destabilized fat. Destabilized fat correlated inversely with drip-through rate and sensory greasiness. In the ice cream mix viscosity study, an inverse correlation was found between mix viscosity and sensory iciness. Ice creams with no difference in ice crystal size were perceived to be less icy when formulated with higher mix viscosity. A positive correlation was found between mix viscosity and sensory greasiness. These results indicate that fat structures and mix viscosity have significant effects on ice cream microstructure and sensory texture including the reduction of iciness perception. PMID- 28631812 TI - Identification of allergens by IgE-specific testing improves outcomes in atopic dermatitis. AB - INTRODUCTION: IgE quantitative assaying of allergens (IgEQAA) has long been implemented by allergists in determining patients' reactivities for allergic rhinitis and asthma, two of the three diagnoses in atopic syndrome. This test operates by measuring the patient's IgE response to different allergens and can identify potential triggers for a patient's symptoms. Despite this, IgEQAA has yet to see the same widespread use in the field of dermatology, specifically in the treatment of patients with atopic dermatitis (AD). MATERIALS AND METHODS: The affected body surface area (BSA) at first presentation, IgEQAA classes, and total immunoglobulin E (IgE) concentration were taken retrospectively for 54 patients with AD. RESULTS: Of the 54 patients observed, 41 had an abnormally high total IgE concentration (76%). Additionally, it was observed that nine (17%) of our patients significantly improved after making lifestyle changes. CONCLUSION: Knowledge of the identified specific antigens can guide patients to make lifestyle modifications that may improve disease outcomes. IgEQAA and avoidance of allergens may help some patients with AD. PMID- 28631814 TI - Germination-Assisted Enzymatic Hydrolysis Can Improve the Quality of Soybean Protein. AB - This study aimed to investigate the effects of combined germination and Alcalase hydrolysis on the quality of soybean protein. Protein profiles, water solubility, foaming and emulsifying properties, thixotropic properties, and in vitro protein digestibility (IVPD) were tested, the chemical score (CS), essential amino acid index (EAAI), and protein efficiency ratio (PER) of soybean protein were also defined. The combined treatment of germination and Alcalase hydrolysis remarkably improved the solubility, emulsification activity index, emulsion stability index, and foaming capacity of soybean protein. Notably, a decrease in foaming stability was detected. The electrophoretic profile showed a weak breakdown of soybean protein during germination. However, a strong breakdown of protein was observed after the hydrolysis with Alcalase. The combined treatment also decreased the CS and EAAI of soybean protein, but only by 18%. Meanwhile, the IVPD and PER of soybean protein were significantly improved. Moreover, the protein of the germinated and hydrolyzed soybean flour demonstrated better swallowing properties. These findings indicated that the combined treatment of germination and enzymatic hydrolysis can improve the quality of soybean protein. PMID- 28631813 TI - High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice. AB - There is a growing and alarming prevalence of obesity and the metabolic syndrome in type I diabetic patients (T1DM), particularly in adolescence. In general, low bone mass, higher fracture risk, and increased marrow adipose tissue (MAT) are features of diabetic osteopathy in insulin-deficient subjects. On the other hand, type 2 diabetes (T2DM) is associated with normal or high bone mass, a greater risk of peripheral fractures, and no change in MAT. Therefore, we sought to determine the effect of weight gain on bone turnover in insulin-deficient mice. We evaluated the impact of a 6-week high-fat (HFD) rich in medium chain fatty acids or low-fat diet (LFD) on bone mass and MAT in a streptozotocin (STZ) induced model using male C57BL/6J mice at 8 weeks of age. Dietary intervention was initiated after diabetes confirmation. At the endpoint, lower non-fasting glucose levels were observed in diabetic mice fed with high fat diet compared to diabetic mice fed the low fat diet (STZ-LFD). Compared to euglycemic controls, the STZ-LFD had marked polydipsia and polyphagia, as well as reduced lean mass, fat mass, and bone parameters. Interestingly, STZ-HFD mice had higher bone mass, namely less cortical bone loss and more trabecular bone than STZ-LFD. Thus, we found that a HFD, rich in medium chain fatty acids, protects against bone loss in a T1DM mouse model. Whether this may also translate to T1DM patients who are overweight or obese in respect to maintenance of bone mass remains to be determined through longitudinal studies. PMID- 28631816 TI - Cognitive rehabilitation for adults with traumatic brain injury to improve occupational outcomes. AB - BACKGROUND: Cognitive impairment in people with traumatic brain injury (TBI) could affect multiple facets of their daily functioning. Cognitive rehabilitation brings about clinically significant improvement in certain cognitive skills. However, it is uncertain if these improved cognitive skills lead to betterments in other key aspects of daily living. We evaluated whether cognitive rehabilitation for people with TBI improves return to work, independence in daily activities, community integration and quality of life. OBJECTIVES: To evaluate the effects of cognitive rehabilitation on return to work, independence in daily activities, community integration (occupational outcomes) and quality of life in people with traumatic brain injury, and to determine which cognitive rehabilitation strategy better achieves these outcomes. SEARCH METHODS: We searched CENTRAL (the Cochrane Library; 2017, Issue 3), MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), and clinical trials registries up to 30 March 2017. SELECTION CRITERIA: We identified all available randomized controlled trials of cognitive rehabilitation compared with any other non-pharmacological intervention for people with TBI. We included studies that reported at least one outcome related to : return to work, independence in activities of daily living (ADL), community integration and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials. We used standard methodological procedures expected by Cochrane. We evaluated heterogeneity among the included studies and performed meta-analysis only when we could include more than one study in a comparison. We used the online computer programme GRADEpro to assess the quality of evidence, and generate 'Summary of findings' tables. MAIN RESULTS: We included nine studies with 790 participants. Three trials (160 participants) compared cognitive rehabilitation versus no treatment, four trials (144 participants) compared cognitive rehabilitation versus conventional treatment, one trial (120 participants) compared hospital-based cognitive rehabilitation versus home programme and one trial (366 participants) compared one cognitive strategy versus another. Among the included studies, we judged three to be of low risk of bias.There was no difference between cognitive rehabilitation and no intervention in return to work (risk ratio (RR) 1.80, 95% confidence interval (CI) 0.74 to 4.39, 1 study; very low-quality evidence). There was no difference between biweekly cognitive rehabilitation for eight weeks and no treatment in community integration (Sydney Psychosocial Reintegration Scale): mean difference (MD) -2.90, 95% CI -12.57 to 6.77, 1 study; low-quality evidence). There was no difference in quality of life between cognitive rehabilitation and no intervention immediately following the 12-week intervention(MD 0.30, 95% CI -0.18 to 0.78, 1 study; low-quality evidence). No study reported effects on independence in ADL.There was no difference between cognitive rehabilitation and conventional treatment in return to work status at six months' follow-up in one study (RR 1.43, 95% CI 0.87 to 2.33; low-quality evidence); independence in ADL at three to four weeks' follow-up in two studies (standardized mean difference (SMD) -0.01, 95% CI -0.62 to 0.61; very low-quality evidence); community integration at three weeks' to six months' follow-up in three studies (Community Integration Questionnaire: MD 0.05, 95% CI -1.51 to 1.62; low-quality evidence) and quality of life at six months' follow-up in one study (Perceived Quality of Life scale: MD 6.50, 95% CI -2.57 to 15.57; moderate-quality evidence).For active duty military personnel with moderate-to-severe closed head injury, there was no difference between eight weeks of cognitive rehabilitation administered as a home programme and hospital-based cognitive rehabilitation in achieving return to work at one year' follow-up in one study (RR 0.95, 95% CI 0.85 to 1.05; moderate quality evidence). The study did not report effects on independence in ADL, community integration or quality of life.There was no difference between one cognitive rehabilitation strategy (cognitive didactic) and another (functional experiential) for adult veterans or active duty military service personnel with moderate-to-severe TBI (one study with 366 participants and one year' follow-up) on return to work (RR 1.10, 95% CI 0.83 to 1.46; moderate-quality evidence), or on independence in ADL (RR 0.90, 95% CI 0.75 to 1.08; low-quality evidence). The study did not report effects on community integration or quality of life.None of the studies reported adverse effects of cognitive rehabilitation. AUTHORS' CONCLUSIONS: There is insufficient good-quality evidence to support the role of cognitive rehabilitation when compared to no intervention or conventional rehabilitation in improving return to work, independence in ADL, community integration or quality of life in adults with TBI. There is moderate-quality evidence that cognitive rehabilitation provided as a home programme is similar to hospital-based cognitive rehabilitation in improving return to work status among active duty military personnel with moderate-to-severe TBI. Moderate-quality evidence suggests that one cognitive rehabilitation strategy (cognitive didactic) is no better than another (functional experiential) in achieving return to work in veterans or military personnel with TBI. PMID- 28631815 TI - Expansion of sesquiterpene biosynthetic gene clusters in pepper confers nonhost resistance to the Irish potato famine pathogen. AB - Chemical barriers contribute to nonhost resistance, which is defined as the resistance of an entire plant species to nonadapted pathogen species. However, the molecular basis of metabolic defense in nonhost resistance remains elusive. Here, we report genetic evidence for the essential role of phytoalexin capsidiol in nonhost resistance of pepper (Capsicum spp.) to potato late blight Phytophthora infestans using transcriptome and genome analyses. Two different genes for capsidiol biosynthesis, 5-epi-aristolochene synthase (EAS) and 5-epi aristolochene-1,3-dihydroxylase (EAH), belong to multigene families. However, only a subset of EAS/EAH gene family members were highly induced upon P. infestans infection, which was associated with parallel accumulation of capsidiol in P. infestans-infected pepper. Silencing of EAS homologs in pepper resulted in a significant decrease in capsidiol accumulation and allowed the growth of nonadapted P. infestans that is highly sensitive to capsidiol. Phylogenetic and genomic analyses of EAS/EAH multigene families revealed that the emergence of pathogen-inducible EAS/EAH genes in Capsicum-specific genomic regions rendered pepper a nonhost of P. infestans. This study provides insights into evolutionary aspects of nonhost resistance based on the combination of a species-specific phytoalexin and sensitivity of nonadapted pathogens. PMID- 28631817 TI - Application of high-resolution melting analysis for authenticity testing of valuable Dendrobium commercial products. AB - BACKGROUND: The accurate identification of botanical origin in commercial products is important to ensure food authenticity and safety for consumers. The Dendrobium species have long been commercialised as functional food supplements and herbal medicines in Asia. Three valuable Dendrobium species, namely Dendrobium officinale, D. huoshanense and D. moniliforme, are often mutually adulterated in trade products in pursuit of higher profit. RESULTS: In this paper, a rapid and reliable semi-quantitative method for identifying the botanical origin of Dendrobium products in terminal markets was developed using high-resolution melting (HRM) analysis with specific primer pairs to target the trnL-F region. The HRM analysis method detected amounts of D. moniliforme adulterants as low as 1% in D. huoshanense or D. officinale products. CONCLUSION: The results have demonstrated that HRM analysis is a fast and effective tool for the differentiation of these Dendrobium species both for their authenticity as well as for the semi-quantitative determination of the purity of their processed products. (c) 2017 Society of Chemical Industry. PMID- 28631818 TI - Inactivation of Bacillus cereus Spores on Red Chili Peppers Using a Combined Treatment of Aqueous Chlorine Dioxide and Hot-Air Drying. AB - The effect of a combined treatment using aqueous chlorine dioxide (ClO2 ) and hot air drying to inactivate Bacillus cereus spores on red chili peppers was evaluated. Ten washed and dried pepper samples, each comprising half of a single pepper (Capsicum annuum L.), were inoculated with B. cereus spore suspension. The inoculated samples were washed with sodium hypochlorite (NaOCl; 50, 100, or 200 MUg/mL) or ClO2 (50, 100, or 200 MUg/mL) solution for 1 min and then air-dried (25 +/- 1 degrees C, 47 +/- 1% relative humidity), which was followed by drying with hot air at 55 degrees C for up to 48 h. The spore populations on the samples were enumerated and their aw and chromaticity values were measured. The spore numbers immediately after treatment with NaOCl and ClO2 were not significantly different. A more rapid reduction in spore numbers was observed in the samples treated with ClO2 than those treated with NaOCl during drying. A combined treatment of ClO2 and hot-air drying significantly reduced the spore populations to below the detection limit (1.7 log CFU/sample). B. cereus spores on chili peppers were successfully inactivated by washing with ClO2 solution followed by hot-air drying whereas the pepper color was maintained. PMID- 28631819 TI - Protective effects of tannic acid on pressure overload-induced cardiac hypertrophy and underlying mechanisms in rats. AB - OBJECTIVES: The aim of this study was to examine the cardioprotective effects and latent mechanism of tannic acid (TA) on cardiac hypertrophy. METHODS: Abdominal aortic banding (AAB) was used to induce pressure overload-induced cardiac hypertrophy in male Wistar rats, sham-operated rats served as controls. AAB rats were treated with TA (20 and 40 mg/kg) or captoril. KEY FINDINGS: Abdominal aortic banding rats that received TA showed ameliorated pathological changes in cardiac morphology and coefficients, decreased cardiac hypertrophy and apoptosis, a reduction in over expressions of angiotensin type 1 receptor (AT1 R), angiotensin type 2 receptor (AT2 R), phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2) and transforming growth factor-beta (TGF-beta) mRNA, and modified expression of matrix metal proteinase-9 (MMP-9) mRNA in AAB rat hearts. Furthermore, TA treatment contributed to a decrease in malondialdehyde (MDA) and endothelin-1 (ET-1) activities and content, while it caused an increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), nitric oxide (NO) and endothelial NO synthase (e-NOS). Furthermore, TA downregulated expression of tumour necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), bax, caspase-3 and upregulated expression of bcl-2. CONCLUSIONS: Tannic acid displayed obvious suppression of AAB-induced cardiac hypertrophy in rats. The cardioprotective effects of TA may be attributed to multitargeted inhibition of oxidative stress, inflammation, fibrosis and apoptosis in addition to an increase in NO levels, decrease in ET-1 levels, and downregulation of angiotensin receptors and the phosphorylation of ERK1/2. PMID- 28631820 TI - Dietary Intake of Structured Lipids with Different Contents of Medium-Chain Fatty Acids on Obesity Prevention in C57BL/6J Mice. AB - Three medium- and long-chain triacylglycerols (MLCT) with different contents of medium-chain fatty acids (MCFA) (10% to 30%, w/w) were prepared and evaluated for their anti-obesity potential in C57BL/6J mice. The group fed with a high fat diet of MLCT containing 30% (w/w) MCFA showed significantly decreased body weight and fat mass (P < 0.05) relative to the control mice fed an obesity-inducing high fat rapeseed oil diet. In addition, serum parameters including triacylglycerols, total cholesterol, glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A1 and apolipoprotein B in the treatment group fed with 30% (w/w) MCFA were close to those of mice fed with a low fat rapeseed oil diet, but significantly different (P < 0.05) from those of the obesity control group. Moreover, the intake of MLCT with high content of MCFA reduced the size of adipocytes. In addition, the visceral fat and liver weights, as well as the liver triacylglycerol for 3 treatment groups were lower than those of the obesity control group. These results demonstrate the great potential of MLCT with high content of MCFA in weight loss. PMID- 28631821 TI - A new approach to measuring patience in preschoolers. AB - Patience in children has usually been studied using delay of gratification paradigms. However, another important aspect of patience that has not been well documented is the ability to adjust one's behavior while waiting without an explicit reward as a motivator (e.g., sitting in the doctor's waiting room). To examine this aspect of patience, video-recordings of sixty-one 3- and 4-year olds waiting for two separate 3-min periods were examined and coded for children's spontaneous behaviors. We found that 4-year olds displayed more patient (i.e., staying still) behaviors than 3-year olds during this "waiting paradigm." Interestingly, we also found that children who displayed less patient behaviors during the waiting paradigm were also those who succeeded on a future-thinking task. These findings have important implications for measuring patience in young children and highlight the potential impact of spontaneous behaviors on children's performance in cognitive tasks such as those assessing future-oriented cognition. PMID- 28631822 TI - Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate. AB - OBJECTIVES: Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. KEY FINDINGS: Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 +/- 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 +/- 14.58% as a suspension, compared to 19.92 +/ 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. CONCLUSIONS: The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation. PMID- 28631823 TI - A Comparative Study Between Labeling and Reality: The Case of Phytochemical Composition of Commercial Pomegranate-Based Products. AB - Manufacturers are deeply involved in the development of new pomegranate-based products, which have acquired great prestige due to many studies proving their potential health benefits. Commercial pomegranate products including capsules and supplements and juices and nectars were assayed. The contents of the key phytochemical compounds (punicalagin, ellagic acid, and total polyphenolic content) and the associated antioxidant capacity (DPPH* , ABTS*+ , and FRAP) were analyzed. The experimental ranges of punicalagin and ellagic acid contents were 0.96 to 308 mg/g and 0.09 to 13.1 mg/g, respectively. Punicalagin content was positively correlated (P < 0.001) with DPPH* and total polyphenolic content values. No significant (P > 0.05) correlation was observed among ellagic acid with the antioxidant capacity. The labeling standardization of these products is necessary due to the wide variability among "theoretically" similar pomegranate based products. PMID- 28631824 TI - Incidence of melanoma and keratinocytic carcinomas in patients evaluated by store and-forward teledermatology vs. dermatology clinic. AB - BACKGROUND: It is unclear whether incidence of detected skin cancer in patients evaluated by store-and-forward teledermatology (SAF) vs. face-to-face consultation (F2F) significantly differs, and whether such differences are because of variations in patient demographics, diagnostic accuracy, or both. METHODS: This retrospective cohort study compares patient skin cancer risk profile, pre-post biopsy diagnostic accuracy, and detection rates of any skin cancer, melanoma, and keratinocytic carcinoma between all SAF teledermatology patients and a subset of randomly selected F2F consultations at VA-Boston Healthcare System in 2014. RESULTS: Patients in the teledermatology (n = 434) and F2F visit cohorts (n = 587) had similar baseline demographics except a higher proportion of F2F patients had prior history of skin cancer, 22% (131/587) vs. 10% (45/434), P < 0.001, and received biopsies, 27.2% (160/587) vs. 11.5% (50/434), P < 0.001. When adjusted for age, immunosuppression, and personal and family history of skin cancer, there were no significant differences between the two cohorts in detection rates for any skin cancer (9.5% vs. 5.8%, P = 0.3), melanoma (0.6% vs. 0%, P = N/A), or keratinocytic carcinoma (8.5% vs. 5.5%, P = 0.7). The two cohorts also had similar pre-post biopsy perfect diagnostic concordance, time from initial consult request to biopsy (45.5 d vs. 47.3 d, P = 0.8), and time from biopsy to definitive treatment (67.5 d vs. 65.4 d, P = 0.8). CONCLUSION: F2F patients were more likely to have prior history of skin cancer and receive biopsies. When adjusted for presence of skin cancer risk factors, incidence of detected melanoma, keratinocytic carcinoma, and any skin cancer was similar between SAF teledermatology and F2F patients. PMID- 28631825 TI - Studies on the occurrence of infectious myonecrosis virus in pond-reared Litopenaeus vannamei (Boone, 1931) in India. AB - Whiteleg shrimp, Litopenaeus vannamei, with clinical sign of muscle opaqueness with reddish colour at the distal abdominal segments were observed in farms located in West Bengal State, India. The mortality of shrimp in all disease outbreak ponds ranged from 20% to 50%, and mortality increased gradually. The RT PCR assay of these samples using primer sets specific to infectious myonecrosis virus (IMNV) revealed its presence in the disease outbreak ponds. The IMNV infection was reproduced in healthy shrimp by intramuscular injection to satisfy River's postulates. The virus caused mortality in intramuscularly challenged shrimp, but failed to cause mortality by oral route. Tissue distribution of IMNV in infected shrimp by RT-PCR assay revealed the presence of this virus in haemolymph, gill, hepatopancreas and muscle. This study confirms that the disease outbreak which occurred in the shrimp farms located at Purba Medinipur District, West Bengal, India, was due to IMNV. PMID- 28631826 TI - Effects of dietary supplementation of red pepper (Schinus terebinthifolius Raddi) essential oil on performance, small intestinal morphology and microbial counts of weanling pigs. AB - BACKGROUND: Many strategies, such as the antibiotic growth promoters, have been developed to improve intestinal health and performance of newly weaned piglets. Natural products such as essential oils have been scientifically recognized as growth enhancer feed additives for weanling pigs, replacing the antibiotics. Therefore, it has been hypothesized that Brazilian red pepper could replace performance-enhancing antibiotics also in weanling pig diets. However, one experiment was conducted to determine the effects of dietary Brazilian red pepper essential oil or antimicrobial growth promoter on intestinal health and growth performance of weanling pigs. RESULTS: No effects of treatments were observed on performance and organ weights (P > 0.05). Overall, both additives [red pepper essential oil (RPEO) or antibiotic (ANT)] increased gut Lactobacillus counts compared to negative control, as well as reduced villi density (P < 0.05). Animals fed diets containing 1.5 g kg-1 RPEO presented the lowest incidence of diarrhea (P < 0.05). CONCLUSION: Our findings suggested that essential oil from Brazilian red pepper or chlorohydroxyquinoline added in weanling pig diets affect gut microbiota and histology without affecting performance and organ weights. In addition, there was an indication that high doses of essential oil could reduce the incidence of diarrhea. (c) 2017 Society of Chemical Industry. PMID- 28631827 TI - One-year results of the SCANDIV randomized clinical trial of laparoscopic lavage versus primary resection for acute perforated diverticulitis. AB - BACKGROUND: Recent randomized trials demonstrated that laparoscopic lavage compared with resection for Hinchey III perforated diverticulitis was associated with similar mortality, less stoma formation but a higher rate of early reintervention. The aim of this study was to compare 1-year outcomes in patients who participated in the randomized Scandinavian Diverticulitis (SCANDIV) trial. METHODS: Between February 2010 and June 2014, patients from 21 hospitals in Norway and Sweden presenting with suspected perforated diverticulitis were enrolled in a multicentre RCT comparing laparoscopic lavage and sigmoid resection. All patients with perforated diverticulitis confirmed during surgery were included in a modified intention-to-treat analysis of 1-year results. RESULTS: Of 199 enrolled patients, 101 were assigned randomly to laparoscopic lavage and 98 to colonic resection. Perforated diverticulitis was confirmed at the time of surgery in 89 and 83 patients respectively. Within 1 year after surgery, neither severe complications (34 versus 27 per cent; P = 0.323) nor disease-related mortality (12 versus 11 per cent) differed significantly between the lavage and surgery groups. Among the 144 patients with purulent peritonitis, the rate of severe complications (27 per cent (20 of 74) versus 21 per cent (15 of 70) respectively; P = 0.445) and disease-related mortality (8 versus 9 per cent) were similar. Laparoscopic lavage was associated with more deep surgical site infections (32 versus 13 per cent; P = 0.006) but fewer superficial surgical site infections (1 versus 17 per cent; P = 0.001). More patients in the lavage group underwent unplanned reoperations (27 versus 10 per cent; P = 0.010). Including stoma reversals, a similar proportion of patients required a secondary operation (28 versus 29 per cent). The stoma rate at 1 year was lower in the lavage group (14 versus 42 per cent in the resection group; P < 0.001); however, the Cleveland Global Quality of Life score did not differ between groups. CONCLUSION: The advantages of laparoscopic lavage should be weighed against the risk of secondary intervention (if sepsis is unresolved). Assessment to exclude malignancy (although uncommon) is advised. Registration number: NCT01047462 ( http://www.clinicaltrials.gov). PMID- 28631828 TI - Development of a colloidal gold immunochromatographic assay (GICA) for the rapid detection of Spiroplasma eriocheiris in commercially exploited crustaceans from China. AB - Spiroplasma eriocheiris is an emerging pathogen in freshwater crustaceans. In recent years, Eriocheir sinensis, Procambarus clarkii, Litopenaeus vannamei, Macrobrachium rosenbergii and Macrobrachium nipponense had been infected by this pathogen in China. An immunochromatographic strip test using gold nanoparticles was developed for rapidly detecting this pathogen. The strip test based on the principle of sandwich immunoassay by the specific combination between the pathogen and polyclonal antibody on a nitrocellulose membrane. Positive samples were displayed as red lines at the test and control zones of the nitrocellulose membrane, while negative samples resulted in a red line only at the control zone. The limit of detection was proved to be 106 Color Change Unit/ml. The test strip could be visually detected within 15 min and do not have cross-reaction with other aquatic bacteria. This test strip allows on-site rapid detection of S. eriocheiris in crustacean without the requirement of specialized equipment and professional personnel. The one-step test strips developed in our study had high sensitivity, specificity, reproducibility and stability. In conclusion, this method was proved to be convenient, feasible, rapid and effective for detecting S. eriocheiris. PMID- 28631830 TI - Overactive bladder symptoms after midurethral sling surgery in women: Risk factors and management. AB - INTRODUCTION: Overactive bladder syndrome (OAB) including urgency and urgency urinary incontinence (UUI) occurs frequently after stress urinary incontinence (SUI) surgery. It is important to identify the risk factors for the occurrence of OAB symptoms in order to adequately inform the patient before surgery. Furthermore, when facing OAB after sling surgery it is crucial to know how to manage these symptoms. METHODS: We conducted a literature review in order to assess the risk factors and management of OAB symptoms after SUI surgery. We searched for relevant articles in PubMed that specifically addressed the topic of OAB symptoms after midurethral sling surgery. RESULTS: The incidence of de novo and persistent urgency and UUI is reported around 15% and 30%, respectively. Several studies demonstrated that women with mixed incontinence who have a predominant urge component will have worse outcomes after surgery. Older age was also found to be a predictive factor in three studies. Furthermore, urodynamic signs of overactive bladder (eg, DO, low bladder capacity, elevated detrusor pressure) can predict postoperative urgency or UUI. The management of OAB symptoms after SUI surgery is essentially the same as in idiopathic OAB. However, before commencing therapy it is crucial to rule out other factors than can cause urgency, including bladder outlet obstruction, urinary tract infection, or sling erosion. CONCLUSIONS: OAB symptoms are frequently reported after sling surgery. Women with mixed incontinence and older women are at risk of developing post operative OAB symptoms. We have proposed an algorithm for the treatment of these symptoms which can be useful in clinical practice. PMID- 28631829 TI - Relationship of human herpes virus 6 and multiple sclerosis: A systematic review and meta-analysis. AB - Infection with human herpes viruses has been suggested to contribute to multiple sclerosis (MS), while interaction between human herpes 6 (HHV6) and MS remain unclear yet. Here, we conducted a meta-analysis on the relationship of HHV6 infection and MS. All related studies were collected from major databases. The analyses were performed by STATA 14 and Comprehensive Meta-Analysis V2.0 softwares. Pooled odds ratios (ORs) and 95%CIs were calculated from the raw data of the including studies by the random effects models when I2 > 50% and fix model when I2 < 50%. Thirty nine studies were included in the meta-analysis that 34 studies used molecular assays and 7 studies used serological assays for diagnosis of HHV6 infected cases. The relationship of HHV6 and MS was significant in healthy control group by yielding a summary OR of (2.23 [1.5-3.3], p = 0.06). A significant HHV6 association with MS were in the studies with >6 score that used serum/blood sample with OR of (6.7 [95%CI 4.8-8.6], p < 0.00001) and in serological studies, IgM positive titer in other neurological diseases (OND) control group was significant with OR of (8.3 [95%CI 3-24.07], p < 0.00001). This study has been showed that there were significant relationship between MS and HHV6 infection. PMID- 28631831 TI - Spatial and temporal trends and flow dynamics of glyphosate and other pesticides within an agricultural watershed in Argentina. AB - In the present study, we evaluated the spatial and temporal trends of current-use pesticides in surface water and sediments as well as their relationship with hydrological stream dynamics within the agricultural watershed of El Crespo stream (Buenos Aires Province, Argentina). We sampled 2 contrasting sites: site 1 (upstream), surrounded by agricultural lands, and site 2 (downstream), surrounded by natural grasslands. Most of the applied pesticides (glyphosate, 2,4-D, atrazine, tebuconazole, and imidacloprid) were detected at high frequencies in surface water samples at both sites. However, only glyphosate and aminomethylphosphonic acid (AMPA) were present at high concentrations and had a significant spatial-temporal trend. The highest concentrations were found during spring 2014 at site 1, in association with the intense rains that occurred in that season. The fact that glyphosate and AMPA concentrations were higher than the rest of the studied compounds is closely related to the land use within the watershed, as glyphosate was the most applied herbicide during the fallow period of glyphosate-resistant crops (soybean, maize). The pesticide mixture had a significant spatial-temporal trend, reaching the highest levels during storm flow events in spring 2014. The intensive rains in spring 2014 could be the main factor influencing stream hydrology and pesticide behavior at El Crespo watershed. The estimated annual pesticide losses were 3.11 g/ha at site 1 and 0.72 g/ha at site 2. This result indicates that an attenuation process could be decreasing pesticide loads during downstream transport from site 1 to site 2. Environ Toxicol Chem 2017;36:3206-3216. (c) 2017 SETAC. PMID- 28631832 TI - Synthesis of 2 carbon-14 analogue of thioflavanones. AB - Thioflavanones are prevalent heterocyclic structural units in pharmaceutical and biologically active compound (Scheme ). In this paper, the synthesis of 2 phenylthiochroman-4-ones and 2-phenyl-4H-1-benzothiopyran-4-one labeled with carboxyl-14 is demonstrated. PMID- 28631834 TI - Citizenship, Community Mental Health, and the Common Good. AB - In this article, we address the issue of community mental health and the common good via an applied theory of citizenship to support the social inclusion, empowerment, and inclusion of persons diagnosed with psychiatric disorders. We begin by discussing citizenship, and the concept of the common good, in regard to historical conceptions of citizenship, including the historical exclusion of women, people of color, persons with mental illness, and others. We then review the development of our citizenship framework in response to the limitations of even the most innovative community mental health interventions, specifically the practice of mental health outreach to persons who are homeless. We review findings from three citizenship research studies - a community-level intervention, an individual- and group-level intervention, and development of an individual instrument of citizenship - along with brief comments on current citizenship research. We conclude with a discussion of the challenges of realizing both the individual and collective potential of, and challenges to, the citizenship framework in relation to current and future community mental health systems of care. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28631833 TI - Tools to minimize interlaboratory variability in vitellogenin gene expression monitoring programs. AB - The egg yolk precursor protein vitellogenin is widely used as a biomarker of estrogen exposure in male fish. However, standardized methodology is lacking and little is known regarding the reproducibility of results among laboratories using different equipment, reagents, protocols, and data analysis programs. To address this data gap we tested the reproducibility across laboratories to evaluate vitellogenin gene (vtg) expression and assessed the value of using a freely available software data analysis program. Samples collected from studies of male fathead minnows (Pimephales promelas) exposed to 17alpha-ethinylestradiol (EE2) and minnows exposed to processed wastewater effluent were evaluated for vtg expression in 4 laboratories. Our results indicate reasonable consistency among laboratories if the free software for expression analysis LinRegPCR is used, with 3 of 4 laboratories detecting vtg in fish exposed to 5 ng/L EE2 (n = 5). All 4 laboratories detected significantly increased vtg levels in 15 male fish exposed to wastewater effluent compared with 15 male fish held in a control stream. Finally, we were able to determine that the source of high interlaboratory variability from complementary deoxyribonucleic acid (cDNA) to quantitative polymerase chain reaction (qPCR) analyses was the expression analysis software unique to each real-time qPCR machine. We successfully eliminated the interlaboratory variability by reanalyzing raw fluorescence data with independent freeware, which yielded cycle thresholds and polymerase chain reaction (PCR) efficiencies that calculated results independently of proprietary software. Our results suggest that laboratories engaged in monitoring programs should validate their PCR protocols and analyze their gene expression data following the guidelines established in the present study for all gene expression biomarkers. Environ Toxicol Chem 2017;36:3102-3107. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28631835 TI - Suprameatal urethrolysis with Martius flap for refractory bladder outflow obstruction following stress incontinence surgery in females. AB - AIMS: To present our technique of suprameatal urethrolysis with Martius flap (SMUM) and outcomes of this procedure for refractory female bladder outflow obstruction (BOO). METHODS: A retrospective chart review was performed to identify female patients who underwent SMUM between January 2010 and August 2016 after failed transvaginal urethrolysis (TVU) for BOO due to prior stress urinary incontinence (SUI) surgery. The primary outcome measure was surgical success defined as patient ability to void volitionally without need for catheterization or additional surgery for BOO. Secondary outcomes assessed included perioperative outcomes, intraoperative and 30-day complications, change in post-void residual volume (PVR), resolution of urge urinary incontinence (UUI), incidence of recurrent SUI, and treatment for any urinary incontinence. RESULTS: Eleven patients were identified. After a median follow-up of 10.8 months (range 3.1 20.1), the procedure was successful in nine patients (82%). Postoperative median PVR was 29 cc (range 0-425) and median change in PVR was a 280 cc (range 29-1050) decrease (P < 0.01). Among the seven patients who required catheterization preoperatively, five patients (71%) recovered volitional voiding. Two patients (18%) continued to require indwelling or intermittent catheterization and underwent additional surgery for BOO. SUI recurred in one patient (9%). UUI persisted in all four patients who reported this preoperatively. CONCLUSIONS: SMUM is successful in improving or relieving refractory BOO in this challenging patient population. After TVU, we believe that Martius flap interposition is critical to preventing recurrent fixation of the urethra to the pubic bones and thus achieving improved voiding. PMID- 28631836 TI - Medaka extended one-generation reproduction test evaluating 4-nonylphenol. AB - The medaka extended one-generation test (MEOGRT) was developed as a multigenerational toxicity test for chemicals, particularly endocrine-disrupting chemicals. Briefly, 3 generations of Japanese medaka (Oryzias latipes) are exposed to a chemical over a 20-wk period: 3 wk in the parental generation (F0), 15 wk in the first generation (F1), and 2 wk in the second generation (F2). The present study reports the first MEOGRT results concerning branched isomer mixtures of 4-nonylphenol (NP). Adult F0 medaka exposed to NP at 5 actual concentrations (1.27, 2.95, 9.81, 27.8, 89.4 ug/L) were unaffected in terms of reproduction, although vitellogenin in the male liver was increased dose dependently at concentration of 2.95 ug/L and higher. In F1, in contrast, total egg (fecundity), fertile egg, and fertility decreased as NP increased; lowest observed-effect concentrations (LOECs) for total egg, fertile egg, and fertility were 1.27, 1.27, 27.8 ug/L, respectively. In F1, but not in F0, secondary sex characteristics (i.e., anal fin papillae in males) were suppressed at 27.8 ug/L NP. Vitellogenin induction in adult male fish was slightly weaker in F1 than it was in F0, however. Gonadal sex abnormality and sex reversal occurred at 27.8 and 89.4 ug/L NP in F1 subadults. At 89.4 ug/L NP, all genotypic F1 males in breeding pairs had female phenotype, and some even demonstrated spawning. Concentrations of NP lower than 89.4 ug/L did not affect F2 survival or hatching. The highest detected NP level in environmental freshwater in Japan was approximately a half of the LOEC (1.27 ug/L for F1 fecundity); in other countries, however, environmental concentrations above the LOEC are reported, suggesting that NP may be affecting fish populations. Environ Toxicol Chem 2017;36:3254-3266. (c) 2017 SETAC. PMID- 28631837 TI - Transcriptional and histological alterations in gonad of adult zebrafish after exposure to the synthetic progestin norgestrel. AB - The aim of the present study was to investigate the effects of norgestrel (NGT) on gonadal development in adult zebrafish. Adult zebrafish were exposed to NGT for 14 d at 871 ng L-1 for microarray analysis, and a follow-up experiment was conducted to further study the targeted pathway in adult zebrafish after exposure to NGT at 6.7, 83, and 912 ng L-1 by quantitative polymerase chain reaction (qPCR) and histological analysis. The microarray analysis revealed that 11 545 transcripts were identified. Gene ontology analysis showed organ development, system development, multicellular organismal development, single-organism developmental process, and developmental process were significantly enriched. A Venn diagram displayed 434 target genes involved in organ development, and these genes were common in these 5 development-related processes. Kyoto Encyclopedia of Genes and Genomes analysis showed that the notch signaling pathway was the top toxicity pathway, and it was selected as the target pathway for further qPCR analysis. The qPCR analysis revealed significant and dose-dependent alterations of most target genes involved in the notch signaling pathway in the gonads, even at an environmentally relevant concentration of 6.7 ng L-1 . The transcriptional patterns were consistent with the notch signaling cascade. In addition, NGT significantly increased the frequency of mature sperm and decreased the frequency of immature sperm at all concentrations. Meanwhile, NGT treatment increased the percentage of mature vitellogenic oocytes and atretic follicles at 912 ng L-1 but decreased the percentage of immature vitellogenic oocytes. Thus, the present study demonstrated significant developmental toxicity in the gonad of adult zebrafish even at environmentally relevant NGT concentrations. Environ Toxicol Chem 2017;36:3267-3276. (c) 2017 SETAC. PMID- 28631838 TI - Aging of zinc added to soils with a wide range of different properties: Factors and modeling. AB - The aging of metals added to soil is significant in ecological risk assessment and the derivation of soil environmental quality criteria. Semimechanistic aging models have been developed for some metals, but not for zinc (Zn). In the present study, a published dataset detailing the changes in isotopic exchangeability with time, after water-soluble Zn was added to 23 soils and incubated for 813 d, was used to analyze the effect of soil properties on aging and develop empirical and mechanistic models. Aging was mainly controlled by soil pH, probably because of precipitation, and was linearly correlated with the square root of incubation time, probably as a result of diffusion. Based on precipitation, diffusion, and/or occlusion, semimechanistic aging models were developed using a Zn hydrolysis constant of 6.52 to 6.61, apparent diffusion rate coefficient (D/r2 ) of 1.41 * 10-5 /d, and a root mean square error of less than 15%. The optimized models were accurately validated by 4 independent field-incubated soils, with different doses of Zn under different conditions (the differences between measured and predicted isotopically exchangeable Zn were less than 10%). This enabled an understanding of the long-term behavior of Zn added to soils, and the results can be used for environmental risk assessments and the normalization of ecotoxicity datasets in the derivation of soil environmental quality criteria. Environ Toxicol Chem 2017;36:2925-2933. (c) 2017 SETAC. PMID- 28631839 TI - Natural variability of biochemical biomarkers in the macro-zoobenthos: Dependence on life stage and environmental factors. AB - Biomarkers are widely used in ecotoxicology as indicators of exposure to toxicants. However, their ability to provide ecologically relevant information remains controversial. One of the major problems is understanding whether the measured responses are determined by stress factors or lie within the natural variability range. In a previous work, the natural variability of enzymatic levels in invertebrates sampled in pristine rivers was proven to be relevant across both space and time. In the present study, the experimental design was improved by considering different life stages of the selected taxa and by measuring more environmental parameters. The experimental design considered sampling sites in 2 different rivers, 8 sampling dates covering the whole seasonal cycle, 4 species from 3 different taxonomic groups (Plecoptera, Perla grandis; Ephemeroptera, Baetis alpinus and Epeorus alpicula; Tricoptera, Hydropsyche pellucidula), different life stages for each species, and 4 enzymes (acetylcholinesterase, glutathione S-transferase, alkaline phosphatase, and catalase). Biomarker levels were related to environmental (physicochemical) parameters to verify any kind of dependence. Data were statistically elaborated using hierarchical multilevel Bayesian models. Natural variability was found to be relevant across both space and time. The results of the present study proved that care should be paid when interpreting biomarker results. Further research is needed to better understand the dependence of the natural variability on environmental parameters. Environ Toxicol Chem 2017;36:3158-3167. (c) 2017 SETAC. PMID- 28631840 TI - The effect of infant vocalization in alloparental responsiveness of common marmosets (Callithrix jacchus). AB - Among mammals, alloparental care can be influenced by hormones as well as by previous experience and sensory stimuli from the infants, such as sight and sound, smell, and physical contact with the infant. To determine the responsiveness of common marmoset (Callithrix jacchus) nonreproductive females and males with and without previous experience in caretaking to infant sensory cues, we exposed 12 females and 12 males to vocalization recordings for 10 min under two conditions: (1) exposure to adult conspecific vocalization recordings, and (2) exposure to infant vocalization recordings. We recorded the frequency of approach toward the sound source, the time spent near it and locomotion frequency of males and females in the cage under both conditions. Blood samples were collected after each test for cortisol measuring by EIA method. The infant vocalization affects the behavioral and hormonal responses of males and females of common marmosets. The animals approached and spent more time near the sound source and showed an increase in locomotion during infant vocalization exposure compared to the adult vocalization. However, there was no significant difference in the behavioral response of animals when previous experience and the sex were taken into account. In both sexes, cortisol levels were significantly higher following infant vocalization exposure compared to the adult vocalization. These findings suggest that the infant vocalization appears to be an effective cue that facilitates the approach of the caregiver and maintaining their responsiveness and that the cortisol seems to be important for alertness to sensory stimuli, modulating their motivation to interact with the infant. PMID- 28631841 TI - Introduction to this Special Issue: Community Mental Health and the Common Good. PMID- 28631843 TI - Age-related spontaneous lumbar intervertebral disc degeneration in a mouse model. AB - The pathogenesis of intervertebral disc degeneration is unclear, but it is a major cause of several spinal diseases. Animal models have historically provided an appropriate benchmark for understanding the human spine. However, there is little information about when intervertebral disc degeneration begins in the mouse or regarding the relationship between magnetic resonance imaging and histological findings. The aim for this study was to obtain information about age related spontaneous intervertebral disc degeneration in the mouse lumbar spine using magnetic resonance imaging and a histological score regarding when the intervertebral disc degeneration started and how rapidly it progressed, as well as how our histological score detected the degeneration. The magnetic resonance imaging index yielded a moderate correlation with our Age-related model score. The Pfirrmann grade and magnetic resonance imaging index had moderate correlations with age. However, our Age-related model score had a high correlation with age. Intervertebral disc level was not a significant variable for the severity of disc degeneration. Both Pfirrmann grade and the Age-related model score were higher in the >=14-month-old group than in the 6-month-old group. The present results indicated that mild but significant intervertebral disc degeneration occurred in 14-month-old mice, and the degree of degeneration progressed slowly, reaching a moderate to severe condition for 22-month-old mice. At least a 14-month follow-up is mandatory for evaluating spontaneous age-related mouse intervertebral disc degeneration. The histological classification score can precisely detect the gradual progression of age-related spontaneous intervertebral disc degeneration in the mouse lumbar spine, and is appropriate for evaluating it. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:224-232, 2018. PMID- 28631842 TI - UK consensus statement on the use of plerixafor to facilitate autologous peripheral blood stem cell collection to support high-dose chemoradiotherapy for patients with malignancy. AB - Plerixafor is a CXC chemokine receptor (CXCR4) antagonist that mobilizes stem cells in the peripheral blood. It is indicated (in combination with granulocyte colony stimulating factor [G-CSF]) to enhance the harvest of adequate quantities of cluster differentiation (CD) 34+ cells for autologous transplantation in patients with lymphoma or multiple myeloma whose cells mobilize poorly. Strategies for use include delayed re-mobilization after a failed mobilization attempt with G-CSF, and rescue or pre-emptive mobilization in patients in whom mobilization with G-CSF is likely to fail. Pre-emptive use has the advantage that it avoids the need to re-schedule the transplant procedure, with its attendant inconvenience, quality-of-life issues for the patient and cost of additional admissions to the transplant unit. UK experience from 2 major centers suggests that pre-emptive plerixafor is associated with an incremental drug cost of less than L2000 when averaged over all patients undergoing peripheral blood stem cell (PBSC) transplant. A CD34+ cell count of <15 ul-1 at the time of recovery after chemomobilization or after four days of G-CSF treatment, or an apheresis yield of <1 * 106 CD34+ cells/kg on the first day of apheresis, could be used to predict the need for pre-emptive plerixafor. PMID- 28631844 TI - Sonic hedgehog, Wnt, and brain-derived neurotrophic factor cell signaling pathway crosstalk: potential therapy for depression. AB - There are various theories to explain the pathophysiology of depression and support its diagnosis and treatment. The roles of monoamines, brain-derived neurotrophic factor (BDNF), and Wnt signaling are well researched, but sonic hedgehog (Shh) signaling and its downstream transcription factor Gli1 are not well studied in depression. Shh signaling plays a fundamental role in embryonic development and adult hippocampal neurogenesis and also involved in the growth of cancer. In this article, we summarize the evidence for the Shh signaling pathway in depression and the potential crosstalk of Shh with Wnt and BDNF. Antidepressants are known to upregulate the adult hippocampal neurogenesis to treat depression. Shh plays an important role in adult hippocampal neurogenesis, and its downstream signaling components regulate the synthesis of Wnt proteins. Moreover, the expression of Gli1 and Smo is downregulated in depression. BDNF and Wnt signaling are also regulated by various available antidepressants, so there is the possibility that Shh may be involved in the pathophysiology of depression. Therefore, the crosstalk between the Shh, Wnt, and BDNF signaling pathways is being discussed to identify the potential targets. Specifically, the potential role of the Shh signaling pathway in depression is explored as a new target for better therapies for depression. PMID- 28631846 TI - Visible-Light-Mediated Dual Decarboxylative Coupling of Redox-Active Esters with alpha,beta-Unsaturated Carboxylic Acids. AB - An efficient visible-light-induced decarboxylative coupling between alpha,beta unsaturated carboxylic acids and alkyl N-hydroxyphthalimide esters has been developed. A wide range of redox-active esters derived from aliphatic carboxylic acids (1 degrees , 2 degrees and 3 degrees ) proved viable in this dual decarboxylation process, affording a broad scope of substituted alkenes in moderate to excellent yields with good E/Z selectivities. This redox-neutral procedure was highlighted by its mild conditions, operational simplicity, easy accessibility of carboxylic acids, and excellent functional-group tolerance. PMID- 28631845 TI - Mild metabolic perturbations alter succinylation of mitochondrial proteins. AB - Succinylation of proteins is widespread, modifies both the charge and size of the molecules, and can alter their function. For example, liver mitochondrial proteins have 1,190 unique succinylation sites representing multiple metabolic pathways. Succinylation is sensitive to both increases and decreases of the NAD+ dependent desuccinylase, SIRT5. Although the succinyl group for succinylation is derived from metabolism, the effects of systematic variation of metabolism on mitochondrial succinylation are not known. Changes in succinylation of mitochondrial proteins following variations in metabolism were compared against the mitochondrial redox state as estimated by the mitochondrial NAD+ /NADH ratio using fluorescent probes. The ratio was decreased by reduced glycolysis and/or glutathione depletion (iodoacetic acid; 2-deoxyglucose), depressed tricarboxylic acid cycle activity (carboxyethyl ester of succinyl phosphonate), and impairment of electron transport (antimycin) or ATP synthase (oligomycin), while uncouplers of oxidative phosphorylation (carbonyl cyanide m-chlorophenyl hydrazine or tyrphostin) increased the NAD+ /NADH ratio. All of the conditions decreased succinylation. In contrast, reducing the oxygen from 20% to 2.4% increased succinylation. The results demonstrate that succinylation varies with metabolic states, is not correlated to the mitochondrial NAD+ /NADH ratio, and may help coordinate the response to metabolic challenge. PMID- 28631847 TI - Conjunction of Pyrrole and Amide Moieties: Highly Anion-Responsive pi-Electronic Molecules Forming Ion-Free and Ion-Pairing Assemblies. AB - Dipyrrolyldiketone BF2 complexes with amide units at pyrrole alpha-positions were synthesized in modest yields and showed extremely high anion-binding affinities because of multiple hydrogen-bonding interactions. The phenyl-amide-substituted derivative formed solid-state chiral helical structures, wherein pi planes were oriented parallel to the helical directions. Examination of anion-binding behavior using 1 H NMR spectroscopy combined with theoretical studies suggested fast pyrrole inversions, particularly for the phenyl-amide-substituted derivative. The anion complexes behaved as building units of ion-pairing assemblies in combination with planar and bulky cations. PMID- 28631848 TI - Impact of solar ultraviolet radiation on atopic dermatitis symptoms in young children: A longitudinal study. AB - BACKGROUND: There are controversial data about the effects of sun exposure on atopic dermatitis (AD). We evaluated the association between solar ultraviolet radiation (UVR) exposure and AD symptoms in children. METHODS: Eighty-two children under 6 years (48 boys and 34 girls) with AD living in Seoul, Korea, were enrolled and followed for 12 months between September 2013 and August 2014. Daily symptoms were recorded to describe the degree of itching, sleep disturbance, erythema, dryness, oozing, and edema. We assessed solar UVR by measuring radiation heat flux over the 290-400 nm wavelength range using thermopiles. A generalized linear mixed model and a generalized additive mixed model were used to evaluate the effects of UVR exposure on AD symptoms after adjusting for age, sex, outdoor temperature, outdoor humidity, and ambient air pollution. RESULTS: Symptom records of 12 915 person-days were analyzed. UVR showed a significantly positive relationship with AD symptoms. Over the study period, an increase in UVR by 10 W/cm2 was associated with a 1.46% increase in AD symptoms (95% CI: 0.85-2.07) on the exposure day. An increase in the 6-day average level of UVR of the previous 5 days and the current day by 10 W/cm2 was associated with a 3.58% (95% CI: 2.60-4.56) increase in AD symptoms. UVR exposure significantly increased AD symptoms in autumn, but decreased them in winter. CONCLUSIONS: Atopic dermatitis symptoms in children are likely to be affected by exposure to solar UVR with a cumulative effect, and this effect is different according to season. PMID- 28631850 TI - A parent-infant music therapy intervention to improve neurodevelopment after neonatal intensive care. PMID- 28631849 TI - Experiences of closed-loop insulin delivery among pregnant women with Type 1 diabetes. AB - AIMS: To explore the experiences of pregnant women with Type 1 diabetes, and the relationships between perceptions of glucose control, attitudes to technology and glycaemic responses with regard to closed-loop insulin delivery. METHODS: We recruited 16 pregnant women with Type 1 diabetes [mean +/- sd age 34.1 +/- 4.6 years, duration of diabetes 23.6 +/- 7.2 years, baseline HbA1c 51+/-5 mmol/mol (6.8 +/- 0.6%)] to a randomized crossover trial of sensor-augmented pump therapy vs automated closed-loop therapy. Questionnaires (Diabetes Technology Questionnaire, Hypoglycaemia Fear Survey) were completed before and after each intervention, with qualitative interviews at baseline and follow-up. RESULTS: Women described the benefits and burdens of closed-loop systems during pregnancy. Feelings of improved glucose control, excitement and empowerment were counterbalanced by concerns about device visibility, obsessive data checking and diminished attentiveness to hyper- and hypoglycaemia symptoms. Responding to questionnaires, eight participants felt less worry about overnight hypoglycaemia and that diabetes 'did not run their lives'; however, five reported that closed loop increased time thinking about diabetes, and three felt it made sleep and preventing hyperglycaemia more problematic. Women slightly overestimated their glycaemic response to closed-loop therapy. Most became more positive in their technology attitudes throughout pregnancy. Women with more positive technology attitudes had higher degrees of overestimation, and poorer levels of glycaemic control. CONCLUSIONS: Women displayed complex psychosocial responses to closed loop therapy in pregnancy. Perceptions of glycaemic response may diverge from biomedical data. PMID- 28631851 TI - An association of periostin levels with the severity and chronicity of atopic dermatitis in children. AB - BACKGROUND: Serum periostin might be a biomarker in the pathogenesis of T helper 2-type allergic diseases. The aim of this study was to investigate the relationship between serum periostin levels and the severity and chronicity of atopic dermatitis (AD) in children. METHODS: This population-based study examined 4076 children aged 4 to 13 years between June 2015 and July 2015. Of the 4076 children, 196-137 with a history of AD in the AD group and 59 without allergic diseases history in the healthy control (HC) group-were included for the final analysis. RESULTS: Serum periostin levels were higher in the AD group than in the HC group (P<.001) and were found to be positively associated with SCORAD score (Spearman's rho [r]=.24, P=.001). Children with AD-onset time <2 years had significantly higher periostin levels (P=.030) compared to those with AD-onset time >=2 years. The total eosinophil (P=.189) and IgE levels (P=.140) were comparable between children with AD-onset time <2 years and those with AD-onset time >=2 years. After adjustment for age, gender, and parental allergic history, serum periostin level (OR: 1.03, 95% CI: 1.00-1.06, P=.046) contributed to the development of AD in children with AD-onset time <2 years. CONCLUSION: Serum periostin level may play a role in the severity and chronicity of AD in children. PMID- 28631852 TI - Silver(I) Clusters with Carba-closo-dodecaboranylethynyl Ligands: Synthesis, Structure, and Phosphorescence. AB - Salts of anionic silver(I) clusters with the carba-closo-dodecaboranylethynyl ligand were obtained from {Ag2 (12-C=C-closo-1-CB11 H11 )}n , selected pyridines, and [Et4 N]Cl or [Ph4 P]Br. Salts of octahedral silver(I) clusters [Et4 N]2 [Ag6 (12-C=C-closo-1-CB11 H11 )4 (4-X-C5 H5 N)x ] were formed with pyridine (X=H, x=8), 4-methylpyridine (X=Me, x=8), and 4-cyanopyridine (X=CN, x=10). In contrast, 3,5-lutidine (3,5-Me2 Py) did not result in salts of dianionic clusters, even in the presence of excess of [Et4 N]Cl or [Ph4 P]Br; instead salts of monoanionic AgI7 clusters, [Et4 N][Ag7 (12-C=C-closo-1-CB11 H11 )4 (3,5-Me2 Py)9 ] and [Ph4 P][Ag7 (12-C=C-closo-1-CB11 H11 )4 (3,5-Me2 Py)13 ] were obtained. The AgI7 cluster is pentagonal bipyramidal in the former, but is an edge-capped octahedron in the latter. The 4-methylpyridine and 3,5-lutidine complexes show green phosphorescence at room temperature. Although argentophilic interactions give rise to sufficient spin-orbit coupling for intersystem crossing S1 ->Tn and moderate-to-high radiative rate constants, time-resolved measurements indicate that the quantum yields are greatly influenced by the pyridine ligands, which mainly determine the non-radiative rate constants. In addition, the crystal structures of [Ag16 (12-C=C-closo-1-CB11 H11 )8 (Py)9.25 (CH3 CN)2 (CH2 Cl2 )0.75 ]?CH2 Cl2 , [Ag8 (12-C=C-closo-1-CB11 H11 )4 (Py)12 ], [Ag10 (12-C=C-closo-1-CB11 H11 )4 (4-MePy)10 Br2 ], [Ag7 (12-C=C-closo-1-CB11 H11 )3 (4-tBuPy)11 Cl]?(4 tBuPy), and [Ag9 (12-C=C-closo-1-CB11 H11 )4 (3,5-Me2 Py)11 Cl] were elucidated. PMID- 28631853 TI - High sensitivity MR acoustic radiation force imaging using transition band balanced steady-state free precession. AB - PURPOSE: MR acoustic radiation force imaging (MR-ARFI) provides a method to visualize the focal spot of a focused ultrasound (FUS) beam without introducing a significant temperature rise. With conventional spoiled MR-ARFI pulse sequences, the ARFI phase always equals the motion-encoded phase. In this work, MR-ARFI using transition band balanced steady-state free precession (bSSFP) is presented, which improves the sensitivity of MR-ARFI with high acquisition speed. THEORY AND METHODS: Motion-encoding gradients (MEG) are inserted into bSSFP sequences for MR ARFI. By applying an ultrasound pulse during the MEG, motion-encoded phase is generated, which leads to an amplified change in the image phase when operating in the bSSFP transition band. MR-ARFI was performed on a homemade gel phantom using both the proposed technique and a spoiled gradient echo ARFI sequence with identical MEG and FUS, and ARFI images were compared. RESULTS: The bSSFP-ARFI sequence generated an ARFI image phase that is more than 5 times larger than the motion-encoded phase in a few seconds with 2DFT readout. By keeping FUS pulses as short as 1.45 ms, temperature rise was insignificant during the measurement. CONCLUSION: bSSFP-ARFI has enhanced sensitivity compared with conventional MR ARFI pulse sequences and could provide an efficient way to visualize the focal spot. Magn Reson Med 79:1532-1537, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28631854 TI - Make dopamine neurons great again: An exciting new therapeutic option in parkinson's disease. PMID- 28631855 TI - A Photo-Crosslinkable Biotin Derivative of the Phosphoantigen (E)-4-Hydroxy-3 Methylbut-2-Enyl Diphosphate (HMBPP) Activates Vgamma9Vdelta2 T Cells and Binds to the HMBPP Site of BTN3A1. AB - Vgamma9Vdelta2 T cells play an important role in the cross talk of the innate and adaptive immune system. For their activation by phosphoantigens (PAgs), both cell surface receptors, the eponymous Vgamma9Vdelta2 T cell antigen receptors (Vgamma9Vdelta2 TCRs) on Vgamma9Vdelta2 T cells and butyrophilin 3A1 (BTN3A1) on the phosphoantigen-"presenting" cell, are mandatory. To find yet undetected but further contributing proteins, a biotinylated, photo-crosslinkable benzophenone probe BioBP-HMBPP (2) was synthesized from a known allyl alcohol in nine steps and overall 16 % yield. 2 is based on the picomolar PAg (E)-4-hydroxy-3-methylbut 2-enyl diphosphate (HMBPP, 1). Laser irradiation of 2 at 308 nm initiated the photo-crosslinking reaction with proteins. When the B30.2 domain of BTN3A1, which contains a positively charged PAg-binding pocket, was exposed to increasing amounts of HMBPP (1), labeling by BioBP-HMBPP (2) was reduced significantly. Because BSA labeling was not impaired, 2 clearly binds to the same site as natural ligand 1. Thus, BioBP-HMBPP (2) is a suitable tool to identify co-ligands or receptors involved in PAg-mediated T cell activation. PMID- 28631856 TI - Tetrameric and Dimeric [N???I+ ???N] Halogen-Bonded Supramolecular Cages. AB - Tripodal N-donor ligands are used to form halogen-bonded assemblies via structurally analogous Ag+ -complexes. Selective formation of discrete tetrameric I6 L4 and dimeric I3 L2 halonium cages, wherein multiple [N???I+ ???N] halogen bonds are used in concert, can be achieved by using sterically rigidified cationic tris(1-methyl-1-azonia-4-azabicyclo[2.2.2]octane)-mesitylene ligand, L1(PF6 )3 , and flexible ligand 1,3,5-tris(imidazole-1-ylmethyl)-2,4,6 trimethylbenzene, L2, respectively. The iodonium cages, I6 L14 (PF6 )18 and I3 L22 (PF6 )3 , were obtained through the [N???Ag+ ???N]-> [N???I+ ???N] cation exchange reaction between the corresponding Ag6 L14 (PF6 )18 and Ag3 L22 (PF6 )3 coordination cages, prepared as intermediates, and I2 . The synthesized metallo- and halonium cages were studied in solution by NMR, in gas phase by ESI-MS and in the solid-state by single crystal X-ray diffraction. PMID- 28631857 TI - Pd-Catalyzed Hydroxylation of Aryl Boronic Acids Using In Situ Generated Hydrogen Peroxide. AB - Herein, we describe a benign and efficient palladium-catalyzed hydroxylation of aryl boronic acids under mild conditions, with in situ generated hydrogen peroxide from carbon monoxide, water, and oxygen. This novel procedure combines catalytic production of hydrogen peroxide with an aerobic oxidation process in a sole reaction system. This system shows good functional group tolerance and provides a benign and efficient access to a variety of functionalized phenols. Furthermore, the in situ generated hydroperoxide can be well used for triphenylphosphine oxidation, in which the TON is up to 194. Isotope labelling studies provide important mechanistic insights for this process. PMID- 28631858 TI - Sensory response in host and engrafted astrocytes of adult brain in Vivo. AB - Rapid advances in Ca2+ imaging techniques enable us to simultaneously monitor the activities of hundreds of astrocytes in the intact brain, thus providing a powerful tool for understanding the functions of both host and engrafted astrocytes in sensory processing in vivo. These techniques include both improved Ca2+ indicators and advanced optical recording methods. Astrocytes in multiple cortical and sub-cortical areas are able to respond to the corresponding sensory modalities. These sensory stimuli produce astrocytic Ca2+ responses through different cellular mechanisms. In addition, it has been suggested that astrocytic gene deficiencies in various sensory systems cause impairments in sensory circuits and cognition. Therefore, glial transplantation would be a potentially interesting approach for the cell-based therapy for glia-related disorders. There are multiple cell sources for glial transplantation, including neural stem cells, glial progenitors, and pluripotent stem cells. Both in vitro and in vivo studies have shown that engrafted astrocytes derived from these cell sources are capable of responding to sensory stimulation by elevating the intracellular Ca2+ concentration. These results indicate that engrafted astrocytes not only morphologically but also functionally integrate into the host neural network. Until now, many animal studies have proven that glial transplantation would be a good choice for treating multiple glial disorders. Together, these studies on the sensory responses of host and engrafted astrocytes have provided us a novel perspective in both neuron-glia circuit functions and future treatment strategies for glial disorders. PMID- 28631859 TI - Determining the drivers of population structure in a highly urbanized landscape to inform conservation planning. AB - Understanding the environmental contributors to population structure is of paramount importance for conservation in urbanized environments. We used spatially explicit models to determine genetic population structure under current and future environmental conditions across a highly fragmented, human-dominated environment in Southern California to assess the effects of natural ecological variation and urbanization. We focused on 7 common species with diverse habitat requirements, home-range sizes, and dispersal abilities. We quantified the relative roles of potential barriers, including natural environmental characteristics and an anthropogenic barrier created by a major highway, in shaping genetic variation. The ability to predict genetic variation in our models differed among species: 11-81% of intraspecific genetic variation was explained by environmental variables. Although an anthropogenically induced barrier (a major highway) severely restricted gene flow and movement at broad scales for some species, genetic variation seemed to be primarily driven by natural environmental heterogeneity at a local level. Our results show how assessing environmentally associated variation for multiple species under current and future climate conditions can help identify priority regions for maximizing population persistence under environmental change in urbanized regions. PMID- 28631860 TI - ABi2 (IO3 )2 F5 (A=K, Rb, and Cs): A Combination of Halide and Oxide Anionic Units To Create a Large Second-Harmonic Generation Response with a Wide Bandgap. AB - A family of nonlinear optical materials that contain the halide, oxide, and oxyhalide polar units simultaneously in a single structure, namely ABi2 (IO3 )2 F5 (A=K (1), Rb (2), and Cs (3)), have been designed and synthesized. They crystallize in the same polar space group (P21 ) with a two-dimensional double layered framework constructed by [BiF5 ]2- and [BiO2 F4 ]5- units connected to each other by four F atoms, in which two [IO3 ]- groups are linked to [BiO2 F4 ]5 unit on the same side. A hanging Bi-F bond of [BiF5 ]2- unit is located on the other side via ionic interaction with the layer-inserted alkali metal ions to form three-dimensional structure. The well-ordered alignments of these polar units lead to a very strong second-harmonic generation response of 12 (1), 9.5 (2), and 7.5 (3) times larger than that of potassium dihydrogen phosphate under 1064 nm laser radiation. All of them exhibited a wide energy bandgap over 3.75 eV, suggesting that they will have a high laser damage threshold. PMID- 28631861 TI - Renewable Molecular Flasks with NADH Models: Combination of Light-Driven Proton Reduction and Biomimetic Hydrogenation of Benzoxazinones. AB - Using small molecules with defined pockets to catalyze chemical transformations resulted in attractive catalytic syntheses that echo the remarkable properties of enzymes. By modulating the active site of a nicotinamide adenine dinucleotide (NADH) model in a redox-active molecular flask, we combined biomimetic hydrogenation with in situ regeneration of the active site in a one-pot transformation using light as a clean energy source. This molecular flask facilitates the encapsulation of benzoxazinones for biomimetic hydrogenation of the substrates within the inner space of the flask using the active sites of the NADH models. The redox-active metal centers provide an active hydrogen source by light-driven proton reduction outside the pocket, allowing the in situ regeneration of the NADH models under irradiation. This new synthetic platform, which offers control over the location of the redox events, provides a regenerating system that exhibits high selectivity and efficiency and is extendable to benzoxazinone and quinoxalinone systems. PMID- 28631862 TI - Thalamic deep brain stimulation for orthostatic tremor: A multicenter international registry. AB - BACKGROUND: We report the accumulated experience with ventral intermediate nucleus deep brain stimulation for medically refractory orthostatic tremor. METHODS: Data from 17 patients were reviewed, comparing presurgical, short-term (0-48 months), and long-term (>=48 months) follow-up. The primary end point was the composite activities of daily living/instrumental activities of daily living score. Secondary end points included latency of symptoms on standing and treatment-related complications. RESULTS: There was a 21.6% improvement (P = 0.004) in the composite activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%) in the subgroup of patients with an additional long-term follow-up (8 of 17). The latency of symptoms on standing significantly improved, both in the short-term (P = 0.001) and in the long-term (P = 0.018). Three patients obtained no/minimal benefit from the procedure. CONCLUSIONS: Deep brain stimulation of the ventral intermediate nucleus was, in general, safe and well tolerated, yielding sustained benefit in selected patients with medically refractory orthostatic tremor. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28631863 TI - Endobronchial ultrasound-guided transbronchial needle aspiration: Safe as it sounds. AB - Real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) has earned its place as a standard of care in the evaluation of mediastinal and hilar lymphadenopathy. It is a minimally invasive and a safe procedure with high diagnostic accuracy and efficacy. The increased usage of EBUS-TBNA worldwide has thrown light on its possible complications including death. The complications range from minor to life threatening in few and may occur either early or later in the course after the procedure. The present review summarizes the reported complications from EBUS-TBNA, their outcome and the modalities used for their management. PMID- 28631865 TI - Chemical Communication between Molecules. AB - In this Minireview conceptual approaches towards the communication between (supra)molecular species are illustrated. The reviewed mechanisms include photophysical communication through energy transfer and communication mediated by chemical species that are released from precursors upon application of an external stimulus. The focus is on the stimulation by (reversible) photoreactions. Special attention has been given to supramolecular systems that illustrate the idea of chemical communication and information transfer in a very descriptive manner. PMID- 28631866 TI - Mg2+ -Dependent High Mechanical Anisotropy of Three-Way-Junction pRNA as Revealed by Single-Molecule Force Spectroscopy. AB - Mechanical anisotropy is ubiquitous in biological tissues but is hard to reproduce in synthetic biomaterials. Developing molecular building blocks with anisotropic mechanical response is the key towards engineering anisotropic biomaterials. The three-way-junction (3WJ) pRNA, derived from phi29 DNA packaging motor, shows strong mechanical anisotropy upon Mg2+ binding. In the absence of Mg2+ , 3WJ-pRNA is mechanically weak without noticeable mechanical anisotropy. In the presence of Mg2+ , the unfolding forces can differ by more than 4-fold along different pulling directions, ranging from about 47 pN to about 219 pN. Mechanical anisotropy of 3WJ-pRNA stems from pulling direction dependent cooperativity for the rupture of two Mg2+ binding sites, which is a novel mechanism for the mechanical anisotropy of biomacromolecules. It is anticipated that 3WJ-pRNA can be used as a key element for the construction of biomaterials with controllable mechanical anisotropy. PMID- 28631864 TI - Ceftriaxone reduces L-dopa-induced dyskinesia severity in 6-hydroxydopamine parkinson's disease model. AB - BACKGROUND: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset. Initiation of a ceftriaxone regimen at the time of nigrostriatal lesion can attenuate tyrosine hydroxylase loss in conjunction with increased glutamate uptake and glutamate transporter GLT-1 expression in a rat 6-hydroxydopamine model. In this article, we examined if a ceftriaxone regimen initiated 1 week after nigrostriatal lesion, but prior to l dopa, could reduce l-dopa-induced dyskinesia in an established dyskinesia model. METHODS: Ceftriaxone (200 mg/kg, intraperitoneal, once daily, 7 consecutive days) was initiated 7 days post-6-hydroxydopamine lesion (days 7-13) and continued every other week (days 21-27, 35-39) until the end of the study (day 39 postlesion, 20 days of l-dopa). RESULTS: Ceftriaxone significantly reduced abnormal involuntary movements at 5 time points examined during chronic l-dopa treatment. Partial recovery of motor impairment from nigrostriatal lesion by l dopa was unaffected by ceftriaxone. The ceftriaxone-treated l-dopa group had significantly increased striatal GLT-1 expression and glutamate uptake. Striatal tyrosine hydroxylase loss in this group was not significantly different when compared with the l-dopa alone group. CONCLUSIONS: Initiation of ceftriaxone after nigrostriatal lesion, but prior to and during l-dopa, may reduce dyskinesia severity without affecting l-dopa efficacy or the reduction of striatal tyrosine hydroxylase loss. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28631867 TI - Visible-Light-Irradiated Graphitic Carbon Nitride Photocatalyzed Diels-Alder Reactions with Dioxygen as Sustainable Mediator for Photoinduced Electrons. AB - Photocatalytic Diels-Alder (D-A) reactions with electron rich olefins are realized by graphitic carbon nitride (g-C3 N4 ) under visible-light irradiation and aerobic conditions. This heterogeneous photoredox reaction system is highly efficient, and the apparent quantum yield reaches a remarkable value of 47 % for the model reaction. Dioxygen plays a critical role as electron mediator, which is distinct from the previous reports in the homogeneous RuII complex photoredox system. Moreover, the reaction intermediate vinylcyclobutane is captured and monitored during the reaction, serving as a direct evidence for the proposed reaction mechanism. The cycloaddition process is thereby determined to be the combination of direct [4+2] cycloaddition and [2+2] cycloaddition followed by photocatalytic rearrangement of the vinylcyclobutane intermediate. PMID- 28631868 TI - Manganese(I)-Catalyzed Regio- and Stereoselective 1,2-Diheteroarylation of Allenes: Combination of C-H Activation and Smiles Rearrangement. AB - Heteroarenes are important structural motif in functional molecules. A MnI catalyzed 1,2-diheteroarylation of allenes via a C-H activation/Smiles rearrangement cascade is presented. The reaction occurred under additive-free or even solvent-free conditions, which allowed the creation of two C-C and one C-N bonds in a single operation. A series of structurally diverse bicyclic or tricyclic compounds bearing an exocyclic double bond were constructed in good to excellent efficiency. The decarboxylative ring-opening of the products led to the facile synthesis of vicinal biheteroaryls. Synthetic applications were demonstrated and preliminary mechanistic studies were conducted. PMID- 28631869 TI - Lateralized hippocampal volume increase following high-frequency left prefrontal repetitive transcranial magnetic stimulation in patients with major depression. AB - AIM: Repetitive transcranial magnetic stimulation (rTMS) has been applied as a treatment for patients with treatment-resistant depression in recent years, and a large body of evidence has demonstrated its therapeutic efficacy through stimulating neuronal plasticity. The aim of this study was to investigate structural alterations in the hippocampus (HIPP) and amygdala (AM) following conventional rTMS in patients with depression. METHODS: Twenty-eight patients with depression underwent 10 daily 20-Hz left prefrontal rTMS over 2 weeks. The left dorsolateral prefrontal cortex (DLPFC) was identified using magnetic resonance imaging-guided neuronavigation prior to stimulation. Magnetic resonance imaging scans were obtained at baseline and after the completion of rTMS sessions. The therapeutic effects of rTMS were evaluated with the 17-item Hamilton Depression Rating Scale (HAM-D17 ), and the volumes of the HIPP and AM were measured by a manual tracing method. RESULTS: Statistical analyses revealed a significant volume increase in the left HIPP (+3.4%) after rTMS but no significant volume change in the AM. No correlation was found between the left HIPP volume increase and clinical improvement, as measured by the HAM-D17 . CONCLUSION: The present study demonstrated that conventional left prefrontal rTMS increases the HIPP volume in the stimulated side, indicating a remote neuroplastic effect through the cingulum bundle. PMID- 28631870 TI - Thalamic Deep Brain Stimulation for Neuropathic Pain: Efficacy at Three Years' Follow-Up. AB - OBJECT: Chronic neuropathic pain is estimated to affect 3-4.5% of the worldwide population, posing a serious burden to society. Deep Brain Stimulation (DBS) is already established for movement disorders and also used to treat some "off label" conditions. However, DBS for the treatment of chronic, drug refractory, neuropathic pain, has shown variable outcomes with few studies performed in the last decade. Thus, this procedure has consensus approval in parts of Europe but not the USA. This study prospectively evaluated the efficacy at three years of DBS for neuropathic pain. METHODS: Sixteen consecutive patients received 36 months post-surgical follow-up in a single-center. Six had phantom limb pain after amputation and ten deafferentation pain after brachial plexus injury, all due to traumas. To evaluate the efficacy of DBS, patient-reported outcome measures were collated before and after surgery, using a visual analog scale (VAS) score, University of Washington Neuropathic Pain Score (UWNPS), Brief Pain Inventory (BPI), and 36-Item Short-Form Health Survey (SF-36). RESULTS: Contralateral, ventroposterolateral sensory thalamic DBS was performed in sixteen patients with chronic neuropathic pain over 29 months. A postoperative trial of externalized DBS failed in one patient with brachial plexus injury. Fifteen patients proceeded to implantation but one patient with phantom limb pain after amputation was lost for follow-up after 12 months. No surgical complications or stimulation side effects were noted. After 36 months, mean pain relief was sustained, and the median (and interquartile range) of the improvement of VAS score was 52.8% (45.4%) (p = 0.00021), UWNPS was 30.7% (49.2%) (p = 0.0590), BPI was 55.0% (32.0%) (p = 0.00737), and SF-36 was 16.3% (30.3%) (p = 0.4754). CONCLUSIONS: DBS demonstrated efficacy at three years for chronic neuropathic pain after traumatic amputation and brachial plexus injury, with benefits sustained across all pain outcomes measures and slightly greater improvement in phantom limb pain. PMID- 28631871 TI - Efficacy of percutaneous endoscopic gastro-jejunostomy (PEG-J) decompression therapy for patients with chronic intestinal pseudo-obstruction (CIPO). AB - BACKGROUNDS: Chronic intestinal pseudo-obstruction (CIPO) is an intractable rare digestive disease manifesting persistent small bowel distension without any mechanical cause. Intestinal decompression is a key treatment, but conventional method including a trans-nasal small intestinal tube is invasive and painful. Therefore, a less invasive and tolerable new decompression method is urgently desired. We conducted a pilot study and assessed the efficacy and safety of percutaneous endoscopic gastro-jejunostomy (PEG-J) decompression therapy in CIPO patients. METHODS: Seven definitive CIPO patients (2 males and 5 females) were enrolled. All patients received PEG-J decompression therapy. The number of days with any abdominal symptoms in a month (NODASIM), body mass index (BMI), serum albumin level (Alb), and small intestinal volume before and after PEG-J were compared in all patients. RESULTS: Percutaneous endoscopic gastro-jejunostomy was well tolerated and oral intake improved in all patients. NODASIM has significantly decreased (24.3 vs 9.3 days/months) and BMI/Alb have significantly increased (14.9 vs 17.2 kg/m2 and 2.6 vs 3.8 g/dL, respectively), whereas total volume of the small intestine has not significantly reduced (4.05 vs 2.59 L, P=.18). Reflux esophagitis and chemical dermatitis were observed in one case but was successfully treated conservatively. CONCLUSIONS & INFERENCES: Percutaneous endoscopic gastro-jejunostomy decompression therapy can contribute greatly to improvement of abdominal symptoms and nutritional status in CIPO patients. Although sufficient attention should be paid to acid reflux symptoms, PEG-J has the potential to be a non-invasive novel decompression therapy for CIPO available at home. However, accumulation of more CIPO patients and long-term observation are needed (UMIN000017574). PMID- 28631872 TI - Formation of BiFeO3 from a Binary Oxide Superlattice Grown by Atomic Layer Deposition. AB - We report on the growth of polycrystalline BiFeO3 thin films on SiO2 /Si(001) and Pt(111) substrates by atomic layer deposition using the precursors ferrocene, triphenyl-bismuth, and ozone. By growing alternating layers of Fe2 O3 and Bi2 O3 , we employ a superlattice approach and demonstrate an efficient control of the cation stoichiometry. The superlattice decay and the resulting formation of polycrystalline BiFeO3 films are studied by in situ X-ray diffraction, in situ X ray photoelectron spectroscopy, and transmission electron microscopy. No intermediate ternary phases are formed and BiFeO3 crystallization is initiated in the Bi2 O3 layers at 450 degrees C following the diffusion-driven intermixing of the cations. Our study of the BiFeO3 formation provides an insight into the complex interplay between microstructural evolution, grain growth, and bismuth oxide evaporation, with implications for optimization of ferroelectric properties. PMID- 28631873 TI - Roles of afadin in functional differentiations of hippocampal mossy fiber synapse. AB - A hippocampal mossy fiber synapse has a complex structure and is implicated in learning and memory. In this synapse, the mossy fiber boutons attach to the dendritic shaft by puncta adherentia junctions and wrap around a multiply branched spine, forming synaptic junctions. We have recently shown using transmission electron microscopy, immunoelectron microscopy and serial block face scanning electron microscopy that atypical puncta adherentia junctions are formed in the afadin-deficient mossy fiber synapse and that the complexity of postsynaptic spines and mossy fiber boutons, the number of spine heads, the area of postsynaptic densities and the density of synaptic vesicles docked to active zones are decreased in the afadin-deficient synapse. We investigated here the roles of afadin in the functional differentiations of the mossy fiber synapse using the afadin-deficient mice. The electrophysiological studies showed that both the release probability of glutamate and the postsynaptic responsiveness to glutamate were markedly reduced, but not completely lost, in the afadin-deficient mossy fiber synapse, whereas neither long-term potentiation nor long-term depression was affected. These results indicate that afadin plays roles in the functional differentiations of the presynapse and the postsynapse of the hippocampal mossy fiber synapse. PMID- 28631874 TI - An integrative review of multicomponent weight management interventions for adults with intellectual disabilities. AB - BACKGROUND: Obesity is more prevalent in people with intellectual disabilities and increases the risk of developing serious medical conditions. UK guidance recommends multicomponent weight management interventions (MCIs), tailored for different population groups. METHODS: An integrative review utilizing systematic review methodology was conducted to identify the types of MCIs delivered to adults with intellectual disabilities. FINDINGS: Five studies were identified. All of the studies' MCIs were tailored for adults with intellectual disabilities. Tailoring included measures such as simplified communication tools, individualized sessions, and the presence of carers where appropriate. CONCLUSIONS: Emerging evidence suggests ways in which MCIs can be tailored for adults with intellectual disabilities but, given the few studies identified, it is not possible to recommend how they can be routinely tailored. Further studies are justified for adults with intellectual disabilities at risk of obesity related conditions. PMID- 28631875 TI - Nursing assessment as an effective tool for the identification of delirium risk in older in-patients: A case-control study. AB - AIMS AND OBJECTIVES: To evaluate the usefulness of comprehensive nursing assessment as a strategy for determining the risk of delirium in older in patients from a model of care needs based on variables easily measured by nurses. BACKGROUND: There are many scales of assessment and prediction of risk of delirium, but they are little known and infrequently used by professionals. Recognition of delirium by doctors and nurses continues to be limited. DESIGN AND METHODS: A case-control study. A specific form of data collection was designed to include the risk factors for delirium commonly identified in the literature and the care needs evaluated from the comprehensive nursing assessment based on the Virginia Henderson model of care needs. We studied 454 in-patient units in a basic general hospital. Data were collected from a review of the records of patients' electronic clinical history. RESULTS: The areas of care that were significant in patients with delirium were dyspnoea, problems with nutrition, elimination, mobility, rest and sleep, self-care, physical safety, communication and relationships. The specific risk factors identified as independent predictors were as follows: age, urinary incontinence, urinary catheter, alcohol abuse, previous history of dementia, being able to get out of bed/not being at rest, habitual insomnia and history of social risk. CONCLUSIONS: Comprehensive nursing assessment is a valid and consistent strategy with a multifactorial model of delirium, which enables the personalised risk assessment necessary to define a plan of care with specific interventions for each patient to be made. RELEVANCE TO CLINICAL PRACTICE: The identification of the risk of delirium is particularly important in the context of prevention. In a model of care based on needs, nursing assessment is a useful component in the risk assessment of delirium and one that is necessary for developing an individualised care regime. PMID- 28631876 TI - Incidence of episiotomy in Slovenia: The story behind the numbers. AB - Episiotomy is a surgical cut of the perineum performed in the second stage of labor in order to widen the vaginal opening and thus facilitate the birth of an infant. Despite current recommendations against the routine use of episiotomy, it is one of the most commonly performed surgical interventions during childbirth. This retrospective study explores the number of episiotomies performed in Slovenian maternity hospitals and the differences in episiotomy rates in relation to parity. Data were obtained from the Slovenian National Perinatal Information System and pooled for 2013. A causal and non-experimental method of empirical research was used. The results of the study show that episiotomy rates vary widely across Slovenian maternity hospitals, ranging from 2.5% to 51.7%. Moreover, the majority of Slovenian maternity hospitals exceed the recommended rate, with an overall incidence of episiotomy as high as 31.3%. Further research is recommended to obtain relevant information from women as well as from midwives and to draw new, evidence-based conclusions related to the maternal benefits and adverse effects of episiotomy. PMID- 28631877 TI - Identification of chemical components in Baidianling Capsule based on gas chromatography-mass spectrometry and high-performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry. AB - Baidianling Capsule, which is made from 16 Chinese herbs, has been widely used for treating vitiligo clinically. In this study, the sensitive and rapid method has been developed for the analysis of chemical components in Baidianling Capsule by gas chromatography-mass spectrometry in combination with retention indices and high-performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry. Firstly, a total of 110 potential volatile compounds obtained from different extraction procedures including alkanes, alkenes, alkynes, ketones, ethers, aldehydes, alcohols, phenols, organic acids, esters, furans, pyrrole, acid amides, heterocycles, and oxides were detected from Baidianling Capsule by gas chromatography-mass spectrometry, of which 75 were identified by mass spectrometry in combination with the retention index. Then, a total of 124 components were tentatively identified by high-performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry. Fifteen constituents from Baidianling Capsule were accurately identified by comparing the retention times with those of reference compounds, others were identified by comparing the retention times and mass spectrometry data, as well as retrieving the reference literature. This study provides a practical strategy for rapidly screening and identifying the multiple constituents of a complex traditional Chinese medicine. PMID- 28631878 TI - Gas swallow during meals in patients with excessive belching. AB - BACKGROUND: Swallowed gas is an important source of abdominal gas, and aerophagia is often believed as a putative cause of gas-related abdominal symptoms. However, altered gas-swallow during meals has not been demonstrated. Our aim was to characterize the number of gas swallows during meals in patients complaining of excessive belching and gaseousness and a control group without abdominal symptoms during a 24-h period. METHODS: A 24-h pH-impedance monitoring was performed in 10 patients with excessive belching, and 11 patients without digestive symptoms or reflux in the pH-impedance study. During the study, patients followed their daily routine and customary meals, without any specific limitation. In each patient the number and content of swallows and belches were analyzed. KEY RESULTS: Total meal periods were similar in controls (75+/-26 min) and patients (79+/-21 min; P=.339), but the number of gaseous swallows was greater in patients (114+/-13 swallows) than controls (71+/-8 swallows; P=.007), due to a greater frequency of gaseous swallows during meals (15+/-2 swallows/10 min vs 10+/-1 swallows/10 min, respectively; P=.008). During the 24-h study period, 66+/-13 belches were recorded in patients, but only 13+/-3 belches in controls (P<.001), mainly gastric belches (80+/-4% and 92+/-2% of belches, patients, and controls, respectively) which showed a good correlation with the number of gaseous swallows performed during meals (r=.756; P=.011). CONCLUSION AND INFERENCES: Gas is frequently swallowed during meals. Patients complaining of excessive belching have a different swallow pattern during meals, with an increased ingestion of gas that correlates with increased gastric belching events. PMID- 28631879 TI - Context-dependent effects of cold stress on behavioral, physiological, and life history traits of the red flour beetle. AB - Animals are exposed in nature to a variety of stressors. While stress is generally harmful, mild stress can also be beneficial and contribute to reproduction and survival. We studied the effect of five cold shock events versus a single cold shock and a control group, representing three levels of stress (harsh, mild, and no stress), on behavioral, physiological, and life-history traits of the red flour beetle (Tribolium castaneum, Herbst 1797). Beetles exposed to harsh cold stress were less active than a control group: they moved less and failed more frequently to detect a food patch. Their probability to mate was also lower. Beetle pairs exposed to harsh cold stress frequently failed to reproduce at all, and if reproducing, females laid fewer eggs, which were, as larvae in mid-development, smaller than those in the control group. However, harsh cold stress led to improved female starvation tolerance, probably due to enhanced lipid accumulation. Harsh cold shock also improved tolerance to an additional cold shock compared to the control. Finally, a single cold shock event negatively affected fewer measured response variables than the harsh cold stress, but also enhanced neither starvation tolerance nor tolerance to an additional cold shock. The consequences of a harsher cold stress are thus not solely detrimental but might even enhance survival under stressful conditions. Under benign conditions, nevertheless, harsh stress impedes beetle performance. The harsh stress probably shifted the balance point of the survival-reproduction trade-off, a shift that did not take place following exposure to mild stress. PMID- 28631880 TI - EBUS-TBNA risks and repairs. PMID- 28631881 TI - Advances in equine anti-doping. PMID- 28631882 TI - Tuning the Surface Polarity of Microporous Organic Polymers for CO2 Capture. AB - CO2 capture is very important to reduce the CO2 concentration in atmosphere. Herein, we report the preparation of microporous polymers with tunable surface polarity for CO2 capture. Porous polymers functionalized with -NH2 , -SO3 H, and SO3 Li have been successfully prepared by using a post-synthesis modification of microporous polymers (P-PhPh3 prepared with 1,3,5-triphenylbenzene as the monomer and AlCl3 as the catalyst) by chemical transformations, such as nitration reduction, sulfonation, and cationic exchange. The CO2 adsorption selectivity (CO2 /N2 and CO2 /H2 ) and isosteric heats of the microporous polymers increase markedly after modification, P-PhPh3 -NH2 and P-PhPh3 -SO3 Li afford higher CO2 uptake capacity than P-PhPh3 at pressures of less than 0.15 bar due to the enhanced interaction between CO2 and the -NH2 and -SO3 Li functional groups. Moreover, functionalized porous polymers could be stably used for CO2 capture. Surface modification is an efficient approach to tune the CO2 capture properties of porous polymers. PMID- 28631883 TI - Importance of the patient-physician interaction in assessing acceptability of HIV cure trials. PMID- 28631884 TI - Molecular machines one molecule at a time. PMID- 28631885 TI - Reliability and validity of FluoreCam for white-spot lesion detection: An in vitro study. AB - AIM: In the present study, we tested the reliability and validity of a new light fluorescence device, the FluoreCam. METHODS: Twenty-five human teeth were sectioned mesiodistally into halves. Group 1 (n=30) included specimens with either sound enamel or natural white-spot lesions (WSL). Group 2 (n=20) included specimens with sound enamel used to create artificial WSL. Using the FluoreCam, baseline scans of enamel surfaces were obtained under standardized conditions. Group1 was scanned again the next day. Group 2 specimens were covered with an acid-resistant nail polish, leaving a 2 * 6-mm enamel window exposed, immersed in Queiroz-solution (64 hours, 37 degrees C/pH5 with agitation), and then scanned again. Random error of the repeated measurements (reliability) was determined using method errors and intraclass correlations (ICC). Systematic error and the ability to detect demineralization (validity) were tested using Wilcoxon signed rank test. RESULTS: Method errors for Group 1 replicates were .39 mm2 (area), .72 pixels (intensity), and 5.69 pixels.mm2 (impact). Group 2 method errors were consistently slightly higher than those of group 1. FluoreCam showed highly reliable measurements for group 1 (ICC: 0.93-0.98) and group 2 (ICC: 0.87-0.97). There were no statistically-significant systematic errors for either group (P>.05). In group 2, enamel demineralization was statistically significant in area (P<.001), intensity (P=.001), and impact (P<.001). CONCLUSION: FluoreCam is highly reliable and valid for in vitro assessments of enamel demineralization. PMID- 28631886 TI - NLRP3 expression and urinary HSP72 in relation to biomarkers of inflammation and oxidative stress in diabetic nephropathy patients. AB - Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease. Nod-like receptors nucleotide-binding domain and leucine-rich repeat pyrin-3 domain (NLRP3) inflammasome displays a considerable role in the chronic inflammatory state observed in diabetic patients. Urinary heat shock protein 72 (uHSP72) is a sensitive and specific biomarker for the early detection of acute kidney injury. The aim of this study was to evaluate NLRP3 relative gene expression, its correlation with inflammatory and oxidative stress markers, and to assess the value of uHSP72 in the early detection of DN in type 2 diabetic patients with different degrees of DN. Forty-five type 2 diabetic patients: 15 normoalbuminuric, 15 microalbuminuric, 15 macroalbuminuric, in addition to 15 healthy controls were enrolled in this study. Clinical examination and routine laboratory investigations were performed. NLRP3 mRNA expression was assessed by real time polymerase chain reaction. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), interleukin 1beta (IL-1beta), and uHSP72 levels were estimated by enzyme-linked immunosorbent assay. Serum chitotriosidase (CHIT1) activity was examined. NLRP3 mRNA relative expression, serum levels of 8-OHdG, IL-1beta, and uHSP72, in addition to CHIT 1 activity were significantly increased in the macroalbuminuric patient group as compared to control and the other two diabetic groups. Also, a significant positive correlation was documented between the previously mentioned parameters and urinary albumin/creatinine ratio, serum creatinine, and HbA1c. Multiple linear regression analysis using urinary albumin/creatinine ratio as dependent variable confirmed that uHSP72 and NLRP3 mRNA relative expression were the independent predictors of DN (beta were 0.432 and 0.448 respectively, P < 0.001). Receiver operating characteristic analyses revealed that both NLRP3 mRNA relative expression and uHSP72 levels were useful biomarkers discriminating DN patients from patients with type 2 diabetes mellitus (AUC were 0.957 and 0.983, respectively). uHSP72 may be considered as a novel potential diagnostic biomarker for the early detection of DN. Moreover, these data support the pivotal role of NLRP3 in the development and progression of DN. (c) 2017 IUBMB Life, 69(8):623 630, 2017. PMID- 28631887 TI - Thymic stromal lymphopoietin is expressed in human corneal stromal cells and secreted upon protease-activated receptor 1 activation. AB - Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7) like cytokine that triggers inflammatory responses through activating dendritic cell. It is demonstrated to be involved in a number of disorders, including cancer, gastrointestinal diseases, and autoimmune diseases. In addition, TSLP is also found to be able to induce itch sensation by directly activating the itch sensory neurons. The expression of human TSLP is detected in various tissues such as heart, liver, testis, and prostate. In this study, we report that TSLP was expressed in the human corneal stromal cells, the highly specialized cells that are critical for the function of the cornea. Furthermore, we found that activation of the protease-activated receptor 1 (PAR1) induced secretion of TSLP by the corneal stromal cells. Beside the canonical activator thrombin, PAR1 can also be activated by a few matrix metalloproteases (MMPs) such as MMP1 and MMP13. Since MMPs including MMP1 and MMP13 are upregulated in many corneal diseases as well as the corneal wound healing process, we proposed that TSLP might function as the link between increased protease activity and inflammatory responses or itch sensation in the corneas. (c) 2017 IUBMB Life, 69(8):606-610, 2017. PMID- 28631888 TI - The importance of phase analysis in multiexon copy number variation detected by aCGH in autosomal recessive disorder loci. AB - Cohen Syndrome (CS) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in VPS13B, also known as COH1. Over 100 pathogenic variants in VSP13B, primarily truncations, and copy number variants, have been found in patients with CS. Here, we present an 11-month-old girl with CS caused by two multi-exonic small deletions in VSP13B in trans. Array comparative genomic hybridization has revolutionized the field of genome copy number analysis down to the exonic level, however it has its limitations. It cannot detect balanced structural variation nor determine the phase of copy number variants. Heterozygous multi-exonic copy number variation in autosomal recessive genes should be interpreted in the context of a clinical phenotype, and, if warranted, phase analysis should be performed before sequence analysis for that gene is pursued. This patient emphasizes the need of obtaining clinical information and determining the phase in multi-exonic copy number variants for accurate diagnosis and risk counseling. PMID- 28631889 TI - MicroRNA-containing extracellular vesicles released from endothelial colony forming cells modulate angiogenesis during ischaemic retinopathy. AB - Endothelial colony-forming cells (ECFCs) are a defined subtype of endothelial progenitors that modulate vascular repair and promote perfusion in ischaemic tissues. Their paracrine activity on resident vasculature is ill-defined, but mediated, at least in part, by the transfer of extracellular vesicles (EVs). To evaluate the potential of isolated EVs to provide an alternative to cell-based therapies, we first performed a physical and molecular characterization of those released by ECFCs. Their effects upon endothelial cells in vitro and angiogenesis in vivo in a model of proliferative retinopathy were assessed. The EVs expressed typical markers CD9 and CD63 and formed a heterogeneous population ranging in size from ~60 to 1500 nm by electron microscopy. ECFC EVs were taken up by endothelial cells and increased cell migration. This was reflected by microarray analyses which showed significant changes in expression of genes associated with angiogenesis. Sequencing of small RNAs in ECFCs and their EVs showed that multiple microRNAs are highly expressed and concentrated in EVs. The functional categories significantly enriched for the predicted target genes of these microRNAs included angiogenesis. Intravitreally delivered ECFC EVs were associated with the vasculature and significantly reduced the avascular area in a mouse oxygen-induced retinopathy model. Our findings confirm the potential of isolated EVs to influence endothelial cell function and act as a therapy to modulate angiogenesis. The functions associated with the specific microRNAs detected in ECFC EVs support a role for microRNA transfer in mediating the observed effects. PMID- 28631890 TI - Oxidative stress and psychiatric morbidity in patients with facial acne. AB - BACKGROUND: Acne vulgaris is a common cosmetic problem that is frequently associated with psychosocial disturbances as well as increased oxidative stress. However, oxidative stress and psychological aspects have been studied separately in acne. OBJECTIVE: To evaluate the relationships between oxidative stress, anxiety, depression, and quality of life in acne patients. METHODS: Sixty patients with facial acne and 40 age- and sex-matched healthy individuals were included in the study. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS), and quality of life (QoL) was measured by the Cardiff Acne Disability Index. Disease severity was assessed using the Combined Acne Severity Classification. The serum levels of zinc and malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured in patients and healthy subjects. RESULTS: The mean HADS scores for anxiety and depression were higher in patients than controls (P<.001 for both). Acne patients showed higher serum MDA and lower TAC and serum zinc levels compared with control subjects (P=.019, P<.001, and P=.028, respectively). Anxiety and depression scores did not correlate with oxidative stress parameters. Patients with moderate/severe acne had worse anxiety scores than mild acne (P=.048), and higher anxiety scores were associated with poorer quality of life (r=.436, P=.001). CONCLUSION: Our results indicate that the high levels of anxiety and depression in patients with facial acne were not related to oxidative stress. Anxiety was more common than depression and was directly related to QoL impairment. PMID- 28631891 TI - No detectable human herpesvirus-8 oral shedding in seronegative-healthy, immunocompetent individuals from non-endemic regions for Kaposi's sarcoma: A pilot study. AB - AIM: Saliva can play an important role in human herpesvirus-8 (HHV-8) transmission in endemic regions for Kaposi's sarcoma (KS). Little is known about HHV-8 oral shedding in immunocompetent individuals from non-endemic regions for KS. METHODS: We conducted a prospective study of HHV-8 salivary excretion among 59 healthy, immunocompetent individuals from Sao Paulo, Brazil, followed up weekly for 4 months, resulting in 16 saliva samples from each participant. Antibodies to HHV-8 latency-associated nuclear antigen (LANA) and lytic-phase antigens were investigated with immunofluorescence assays (IFA). HHV-8 DNA detection was performed using real-time polymerase chain reaction (PCR). RESULTS: All 59 individuals were seronegative to LANA and lytic antibodies. HHV-8 DNA was undetectable in saliva samples in 100% of the participants, totaling 944 samples and being consistently negative during the different periods of sampling, which lasted approximately 120 days. No sequences of HHV-8 DNA were detected in the saliva samples of healthy, immunocompetent adults by using real-time PCR, with the resulting data being consistent with IFA-based serological tests. CONCLUSIONS: Unlike other herpesviruses, HHV-8 is not excreted in the saliva of healthy individuals from non-endemic regions for KS. PMID- 28631892 TI - Water-Mediated Structural Transformations of CuII 5-Halonicotinates Coordination Networks with Distinct Mechanisms. AB - Currently, no unequivocal evidence is given for elucidation of "black box" during the structural transformations of dynamic crystalline materials. Here, three types of mechanisms are revealed for such transformations through X-ray diffraction and optical microscopy; namely, single-crystal to single-crystal (SC SC), as well as "core-to-core" and "core-on-shell" processes. As confirmed by time-lapse optical microscopy, the latter two cases can be properly ascribed as partial recrystallization processes, while the former one is a continuous process with two different crystal lattices simultaneously maintained in one single crystal. Interestingly, these three distinct pathways can be exquisitely realized by changing only the halogen substituent (from -F, -Cl, to -Br) of the organic ligands in the coordination supramolecular systems. PMID- 28631893 TI - Expanding the allelic disorders linked to TCTN1 to include Varadi syndrome (Orofaciodigital syndrome type VI). AB - Varadi syndrome is a subtype of orofaciodigital syndrome (OFDS) that combines the typical features of OFDS and the posterior fossa features of Joubert syndrome. The only gene known to be mutated in Varadi syndrome is C5ORF42. In this report, we describe the phenotype of a patient with Varadi syndrome who is homozygous for a previously reported mutation in TCTN1 (NM_001082538.2:c.342-2A>G, p.Gly115Lysfs*8) and suggest that allelic disorders linked to TCTN1 include Varadi syndrome, in addition to Joubert syndrome and Meckel-Gruber syndrome. PMID- 28631894 TI - SERPINI1 pathogenic variants: An emerging cause of childhood-onset progressive myoclonic epilepsy. AB - Progressive myoclonic epilepsies are rare neurodegenerative diseases with a wide spectrum of clinical presentations and genetic heterogeneity that render their diagnosis perplexing. Discovering new imputable genes has been an ongoing process in recent years. We present two pediatric cases of progressive myoclonic epilepsy with SERPINI1 pathogenic variants that lead to a severe presentation; we highlight the importance of including this gene, previously known as causing an adult-onset dementia-epilepsy syndrome, in the genetic work-up of childhood-onset progressive myoclonic epilepsies. PMID- 28631895 TI - Growth hormone excess in children with neurofibromatosis type-1 and optic glioma. AB - In children with neurofibromatosis type 1 (NF1) and optic pathways glioma (OPG), growth hormone (GH) excess has been rarely reported and mainly associated to central precocious puberty. The aim of our study is to evaluate the prevalence of GH excess, the association with central precocious puberty, the relation with tumor site and the evolution over time in a large cohort of children with NF1 and OPG. Sixty-four NF1 children with OPG were evaluated. Patients with stature and/or height velocity >2 SD for age were studied for GH secretion. Seven out of 64 children (10.9%) with NF1 and optic pathways glioma showed GH excess, isolated in 5 cases and associated to central precocious puberty in 2. All the children with GH excess had a tumor involving the chiasma. Children with GH excess underwent medical treatment with lanreotide and a minimum clinical/biochemical follow up of 2 years is reported. The present study demonstrates that GH excess should be considered as a relative frequent endocrine manifestation in NF1 patients, similarly to central precocious puberty. Therefore, these patients should undergo frequent accurate auxologic evaluations. On the other hand, an increase in height velocity in children with NF1, even despite normal ophthalmological exams, can suggest the presence of OPG and therefore represents an indication to perform brain MRI. PMID- 28631896 TI - Boric acid gel as local drug delivery in the treatment of class II furcation defects in chronic periodontitis: a randomized, controlled clinical trial. AB - AIM: Boric acid (BA) exhibits antibacterial, anti-inflammatory, as well as osteoblastic, activity. The aim of the present study was to explore the efficacy of 0.75% BA gel as a local drug-delivery system in adjunct to scaling and root planing (SRP) for the treatment of class II furcation defects in comparison with placebo gel. METHODS: A total of 48 mandibular class II furcation defects were randomized and treated with either 0.75% BA gel or placebo gel. Clinical parameters were recorded at baseline, 3 months, and 6 months, while radiographic parameters were recorded at baseline and 6 months. RESULTS: Greater mean probing depth reduction and mean relative vertical and horizontal clinical attachment level gain were shown to be greater in group 1 than in group 2 at 3 and 6 months. Furthermore, a significantly greater mean percentage of bone fill was found in group 1 (16.98%+/-1.03%) than in the placebo (2.86%+/-0.92%) at 6 months. CONCLUSION: The .75% BA group showed significant improvement in clinical parameters compared to placebo gel as an adjunct to SRP. This implies an alternative for treatment of class II furcation. PMID- 28631897 TI - The Interaction Mode of Groove Binding Between Quercetin and Calf Thymus DNA Based on Spectrometry and Simulation. AB - Quercetin, a ubiquitous flavanoid, has numerous pharmacological effects, such as antioxidant and antitumor. Previous studies showed nucleic acids were the potential biological targets for antitumor medicine. For exploring the mechanism of DNA-target medicine, the interaction between quercetin and calf thymus DNA was studied based on the method of spectrometry and simulation in our study. Firstly, the interaction between quercetin and calf thymus DNA was confirmed by fluorescence spectrometry. Furthermore, circular dichroism, fluorescence polarization, competitive displacement assay, and salt concentration dependence assay were applied to search the interaction mode of quercetin-calf thymus DNA, which proved the existence of groove binding and electrostatic interaction. Meanwhile, quenching constant Ksv , binding constant Ka and the number of binding sites n was calculated, inferring that the fluorescence quenching occurred by static quenching process, and the main acting force was hydrogen bond. Finally, molecular docking was used to simulate and analyze the interaction between quercetin and calf thymus DNA. PMID- 28631898 TI - Mass spectrometry-based protein analysis to unravel the tissue pathophysiology in Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a genetic muscle wasting condition with limited treatment options available and is caused by the lack of dystrophin. However, pathophysiology of different tissues is variable showing different histological and molecular signatures. Recently, a number of studies have employed gel-free proteomic approaches to unveil the molecular pathophysiology in terms of tissue-specific proteome changes in dystrophin deficiency. The authors analyzed studies in models of dystrophin deficiency and patients both from the published literature. The authors created a database containing all of the significantly differentially expressed proteins. By the integration of data from nine studies, the authors have identified 31 proteins which are commonly affected in different tissues by dystrophin deficiency. These proteins represent pathways involved in the maintenance of the actin cytoskeleton and those involved in cellular energy metabolism among others. Also represented is glyceraldehyde-3 phosphate dehydrogenase (GAPDH), often used as a loading control in protein assays, it appears to be highly variable, and should be replaced by other controls. The same intersection of data was performed using studies of the blood and urine of Duchenne muscular dystrophy patients and/or animal models and identified 33 proteins that are commonly differentially expressed. These proteins may themselves be novel therapeutic targets biomarkers that could monitor disease progression. PMID- 28631900 TI - [Experimental development and rationale for a renal decellularization protocol with subsequent comprehensive assessment of the biological scaffold]. AB - : Chronic renal failure (CRF) is one of the most challenging problems of contemporary medicine. Patients with chronic renal failure usually need renal replacement therapy as either hemodialysis, peritoneal dialysis or a kidney transplant. The latter is the most promising option for end-stage kidney disease. However, the shortage of donor organs, the complexity of their delivery, the difficulty in finding an immunologically compatible donor and the need for lifelong immunosuppression triggered advances in modern tissue engineering. In this field, the primary priority is focused on developing bioengineered scaffolds with subsequent recellularization with autologous cells. Using such constructs would allow for solving both ethical and immunological problems of transplantation. The aim of this pilot study was to develop a new method of renal decellularization using small laboratory animals. MATERIALS AND METHODS: The study investigated the morphological structure of the obtained decellularized matrix and quantitatively tested DNA residues in the resulting scaffold. We proposed a new biophysical method for assessing the matrix quality using the EPR spectroscopy and conducted experiments on the matrix recellularization with mesenchymal multipotent stem cells to estimate cytotoxicity, cell viability and metabolic activity. RESULTS: The obtained decellularized renal matrix retained the native tissue architecture after a complete removal of the cell material, had no cytotoxic properties and supported cell adhesion and proliferation. CONCLUSION: All the above suggests that the proposed decellularization protocol is a promising method to produce tissue-engineered kidney constructs with possible clinical application in the foreseeable future. PMID- 28631901 TI - [Female genital prolapse surgery using ultra lightweight polypropylene mesh]. AB - AIM: To compare the results of female genital prolapse (FGP) surgery via vaginal access using lightweight and ultra-lightweight polypropylene mesh. MATERIALS AND METHODS: From 2007 to 2011, 93 women aged from 46 to 71 years with II-IV stage FGP (POP-Q classification) were examined and underwent the vaginal extra peritoneal colpopexy using polypropylene implants in the Department of Urology. Patients were divided into 2 groups. In patients of group 1 (n=50) the surgery was performed according to a newly developed technique using perforated ultra lightweight (surface density 19 g/m2) domestically manufactured polypropylene implant. In group 2, a standard trocar set with light (surface density of 42.7 g/m2) foreign-made polypropylene implants was used. RESULTS AND DISCUSSION: Long term follow-up was from 1 to 5 years. General surgical complications (urinary bladder injury, blood loss over 300 ml, perineal and vaginal hematomas) were detected in 2 (4%) patients of group 1 and in 7 (16.3%) patients of group 2. The most common specific mesh-related complication was the vaginal wall erosion, which was observed in 4 (9.3%) patients of group 2 and in 1 (2%) patient of group 1. FGP recurrence was diagnosed in 5 (10%) patients of group 1 in the non-treated part and in 8 (18.6%) patients of group 2. Three patients (7%) in group 2 developed recurrent cystocele due to the shrinkage of the mesh implant which was not observed in group 1. At 12 month follow-up, the results of FGP surgical treatment were estimated as good (full functional recovery and no FGP recurrence) in 41 (82%) and 32 (74.4%) patients of groups 1 and 2, respectively. CONCLUSION: We have developed a method of vaginal extra-peritoneal colpopexy using a perforated ultra-lightweight polypropylene implant. This technique has resulted in the absence of recurrence in the treated part of FGP, and 4.1, 4.2 and 4.7 fold reductions in the incidence of general surgical complications, vaginal wall erosions and perineal and vaginal hematomas, respectively, compared with FGP patients undergoing the placement of the lightweight polypropylene implant using the standard trocar set. PMID- 28631902 TI - [Comparative estimation of antilithogenic activity of porcine kidney derived biomedical substance and sodium citrate in experimental urolithiasis]. AB - AIM: to compare the anti-lithogenic activity of biomedical substance derived from freeze-dried porcine kidney and sodium citrate. MATERIALS AND METHODS: The experiments were conducted on Wistar rats divided into three groups of 15 animals each: control group (disease control), comparison group (sodium citrate treatment) and experimental group (treatment with biomedical substance from porcine kidneys). Experimental urolithiasis was modeled using the ethylene glycol model. On every 7th day of the 6 week experiment testing was done calcium and oxalate urine concentration and the activity of marker enzymes of renal epithelial damage: lactate dehydrogenase (LDH), -glutamyl transferase (GGT), and N-acetyl--D-glucosaminidase (NAG). At the end of the experiment, a part of the rats were decapitated and the renal tissue was tested for the oxidant status indicators of (renal thiobarbiturate reactive product content, TBRP, and total prooxidant activity, TPA) and antioxidant enzyme activities: glutathione peroxidase (GPO), superoxide dismutase (SOD) and catalase (CAT). To measure the number and size of calcium deposits formed in the renal papillary area, the Koss histochemical method was used. RESULTS: The experimental findings showed developing oxalate nephrolithiasis in the control group, as indicated by urinary supersaturation of oxalate ion, increased activity of marker enzymes, oxidative stress and the formation of numerous calcium deposits in the renal papillary area. In the comparison group, the 3-week use of sodium citrate contributed to a significant decrease in nephrolithiasis: a 3 to 4-fold decrease in the activity of marker enzymes in the urine, a 3.8-fold increase in the concentration of TBRP, normalization of GPO activity; the number and size of urinary calcium deposits decreased by 3.4 and 1.9 times, respectively. In the experimental group, using biomedical substance led to an even greater therapeutic effect. LDH activity and concentration of TPRP showed 1.9 times and by 26.2% greater decrease than in the comparison group, respectively, SOD and CAT activity almost doubled, there were 3.6 times fewer calcium deposits in the field of view and their mean size was 1.7 times smaller than in the comparison group. CONCLUSION: The study findings showed that the porcine kidney derived biomedical substance provide significantly greater antilithogenic effect than sodium citrate. PMID- 28631899 TI - Dual molecular diagnosis contributes to atypical Prader-Willi phenotype in monozygotic twins. AB - We describe monozygotic twin girls with genetic variation at two separate loci resulting in a blended phenotype of Prader-Willi syndrome and Pitt-Hopkins syndrome. These girls were diagnosed in early infancy with Prader-Willi syndrome, but developed an atypical phenotype, with apparent intellectual deficiency and lack of obesity. Array-comparative genomic hybridization confirmed a de novo paternal deletion of the 15q11.2q13 region and exome sequencing identified a second mutational event in both girls, which was a novel variant c.145+1G>A affecting a TCF4 canonical splicing site inherited from the mosaic mother. RNA studies showed that the variant abolished the donor splicing site, which was accompanied by activation of an alternative non-canonical splicing-site which then predicts a premature stop codon in the following exon. Clinical re evaluation of the twins indicated that both variants are likely contributing to the more severe phenotypic presentation. Our data show that atypical clinical presentations may actually be the expression of blended clinical phenotypes arising from independent pathogenic events at two loci. PMID- 28631903 TI - [Solitary stones of the lower renal calyx: how to treat?] AB - INTRODUCTION: The choice of treatment for the stones of the lower renal calyx is one of the challenging issues of modern urology. The aim of this retrospective and prospective study was to investigate the clinical effectiveness and safety of 3 modern minimally invasive techniques for treating renal stones: percutaneous (PNL) and transurethral (TNL) nephrolithotripsy and extracorporeal shock wave lithotripsy (ESWL) in patients with solitary lower calyx stones sized from 10 to 15 mm. MATERIALS AND METHODS: The study included 136 patients with symptomatic stones of the lower calyces, who underwent ESWL, PNL and TNL from November 2010 to the present day. The criteria for inclusion in the study were: the presence of a solitary stone of the lower calyx, the stone size of 10 mm to 15 mm, the performance of the classical (standard) PNL in the prone position (puncture access 28-30 Fr) and the follow-up examination at 3 months after the operation. Forty-six patients underwent ESWL, 49 - PNL, and 41 - TNL. Postoperative follow up was done at 3 months and included a plain radiography, ultrasound and non contrast-enhanced computed tomography. The stone free rate (SFR) was used as a criterion for the effectiveness of the intervention, where the stone size of 3 mm was taken as the upper limit for the possible presence of fragments. Besides, the rate of repeat interventions, complications and subjective assessment of patients treatment satisfaction (0 to 10) by using visual analogue scale (VAS) were investigated. RESULTS: The effectiveness analysis of the three methods for treating the lower calyx stones sized 10-15 mm showed that PNL was no more effective than TNL (SFR 95.9% and 85.4%, respectively), but both methods were significantly more effective than ESWL (SFR 69.5%). 29.3% of patients who underwent TNL required repeat interventions (TNL or ESWL), while among those treated with ESWL, 45.6% required repeat ESWL sessions. PNL resulted in stone clearance in one stage. Postoperative inflammatory complications were most prevalent among patients who underwent TNL (26.8%). Bleeding requiring hemotransfusion was observed only after PNL (14.3%). Obstructive complications were observed in all study groups. For them, internal stenting was most often performed after ESWL (10.9%), puncture nephrostomy - after TNL (7.3%). Statistically significantly higher VAS measured quality of life was found after ESWL (7.9) and PNL (7.0) compared with THL (4.8). CONCLUSION: All three methods (PNL, TNL and ESWL) for treating lower calyceal stones sized from 10 to 15 mm are quite effective. Using them separately or in combination allows most patients to safely achieve a stone-free state. PMID- 28631904 TI - [Analysis of factors affecting the compliance with medical therapy for benign prostatic hyperplasia]. AB - AIM: To investigate factors affecting the compliance of patients with the combination therapy for benign prostatic hyperplasia. MATERIALS AND METHODS: Four hundred BPH outpatients treated with combination therapy were surveyed. RESULTS: The absolute majority of patients (76.16%) expected a quick positive result. 10.47% viewed their disease as too advanced, did not believe in the effectiveness of medical therapy and believed the surgery to be the only treatment option. 24.42% of patients changed the medication dosage on their own, and 11% were ready to discontinue the treatment without consulting their doctors. 76.16% of patients considered the recommended treatment to be effective, 77.33% fully trusted the doctor. In the opinion of 8.7% of patients, the doctor did not sufficiently inform them about the prescribed drug. 22.67% of patients had doubts about a physicians competence, and 5.23% believed the doctor complicated their medical treatment and changed prescriptions too often. CONCLUSIONS: The patients had a high level of trust in doctors and showed psychological adherence to therapy. However, about a quarter of patients changed the treatment regimen on their own. Many patients had exaggerated expectations of the treatment. 8% of patients reported insufficient awareness regarding the nature and appropriateness of drug therapy, and one in five patients had difficulties in perceiving, remembering and following the treatment regimen. CONCLUSION: streamlining therapeutic regimens, prescribing non-titratable or combined drugs will help improve patients therapy compliance. PMID- 28631905 TI - [Rationale of pharmacotherapy duration in patients with benign prostatic hyperplasia (a clinical-morphological study)]. AB - AIM: To investigate the nature of morphological alterations in the urinary bladder wall in BPH patients receiving pharmacotherapy to establish treatment time limits. MATERIALS AND METHODS: The study comprised 120 BPH patients who underwent a transvesical adenomectomy. Prior to the surgery, 110 patients received pharmacotherapy (-blockers and 5-reductase inhibitors) lasting from 1-6 months to 5-10 years. Preoperative evaluation included a standard diagnostic algorithm. During the surgery, the urinary bladder wall specimens were taken for morphological examination. Histologic specimens were stained with hematoxylin eosin and according to van Giesonn, and underwent immunohistochemical examination using desmin, vimentin, CD31, type IV collagen and pancitokeratin monoclonal antibodies. In patients who did not take medications or used them for less than 6 months, the bladder preserved the normal histological structure. Pharmacotherapy lasting 1 to 5 years resulted in microcirculatory alterations characterized by extensive hemorrhages, damage to the endothelium and vessel basal membranes, hypertrophy of the bladder muscle membrane. In patients taking the medications for 6 to 10 years, microcirculatory alterations resulted in the vascular wall sclerosis and thickening, narrowing of the vessel lumen, hypoplasia of the transitional epithelium and muscle layer atrophy. RESULTS: The study findings suggest that prolonged (over 1 year) pharmacotherapy can adversely affect the urinary bladder wall and worsen the results of radical adenomectomy. PMID- 28631906 TI - [Technical features of intestinal ureteroplasty. Part 7: forming ureterointestinal anastomoses]. AB - AIM: To present the results and technical features of forming the ureterointestinal anastomoses in intestinal ureteral substitution. MATERIAL AND METHODS: From 1998 to December 2016, 168 patients (mean age 51 +/- 8.7 years) underwent ureteral substitution using intestinal segments at the Urology Clinic of the I.I. Mechnikov NWSMU. Of them, 76 (45.2%) were males. In 119 (70.8%) patients, intestinal segments were used to replace various parts of the ureters (iliac in 92, colonic in 4, appendix in 23), and in 49 (29.2%) patients ureteroplasty was combined with orthotopic ileocystoplasty. 96 patients underwent isolated ureteral substitution with segments of the small and large bowel. RESULTS: Among the 96 patients, early postoperative complications occurred in 8 (8.3%) patients, whereof 5 (5.2%) required reoperations. Among them, 2 (2.1%) had a proximal anastomotic failure. Late postoperative complications occurred in 7 (7.3%) patients whereof 4 (4.2%) required surgical treatment. These patients developed strictures of the proximal ureter-intestinal anastomoses over 3 or more months after the operation. The urinary flow was restored by antegrade dilation. Vesicoureteral reflux occurred in 2 (2.1%) patients. However, it was not clinically evident and was not accompanied by hydroureteronephrosis and recurrent urinary tract infection. CONCLUSION: A perfect ureterointestinal anastomoses should be easy to create and have a low risk of stenosis and reflux. These requirements are met by direct anastomosis, which is associated with a minimal risk of stricture, and with isoperistaltic positioning and sufficient length (not less than 15 cm) of the graft provides antireflux protection. It should be noted that proximal (ureterointestinal) anastomoses are vulnerable in these operations and prone to the stricture formation. Unlike proximal, the distal anastomosis of the graft with the bladder is always wider, and therefore the risk of its narrowing is minimal. Isoperistaltic positioning of the graft prevents reflux formation. PMID- 28631907 TI - [Cryopresipitate in comprehensive conservative therapy of patients with acute purulent pyelonephritis]. AB - AIM: To investigate the effectiveness of cryoprecipitate in the comprehensive conservative therapy of patients with acute purulent pyelonephritis. MATERIALS AND METHODS: We conducted a retrospective analysis of medical records of patients who were diagnosed with acute non-obstructive pyelonephritis from 2007to 2015. During this period, a total of 3912 patients with acute non-obstructive pyelonephritis were treated at the Department of Urology. Patients were assigned to either receive or not receive cryoprecipitate in the comprehensive conservative therapy. The comprehensive conservative therapy of both groups included antibacterial agents, detoxification, anti-inflammatory therapy. In the study group, patients received additional treatment with cryoprecipitate. By that way we estimated the number of patients who avoided surgery in both groups. RESULTS: There were 3912 patients divided into two groups. The first group included 756 patients (19.3%) who received cryoprecipitate in the comprehensive therapy of pyelonephritis. Of them, 735 patients (97.3%) did not require surgical treatment, and only 21 patients (2.7%) underwent surgery. The second group comprised 3156 patients (80.7%) who did not receive cryoprecipitate. Of them, 2974 patients (94.2%) were treated conservatively without surgical intervention and 182 patients (5.8%) received conservative therapy concurrently with surgical treatment. Therefore, including cryoprecipitate in the comprehensive conservative therapy of acute non-obstructive pyelonephritis results in twice smaller percentage of patients (2.7% vs 5.8%) requiring surgery compared to the comprehensive conservative therapy alone. PMID- 28631908 TI - [Chronobiological approach to managing an exacerbation of chronic recurrent bacterial cystite]. AB - AIM: To investigate the effects of complex therapy with and without phototherapy for an exacerbation of chronic recurrent bacterial cystitis in women at the peaks of chronobiological activity. MATERIALS AND METHODS: The study comprised 60 patients (mean age 30.1+/-5.5 years) with exacerbations of chronic recurrent bacterial cystitis. Patients in the comparison group (n=30) were managed with standard therapy, in the study group (n=30) standard therapy was used concurrently with phototherapy by low-intensity light radiation carried out at the maximum peaks of chronobiological activity. An assessment of the results included estimation of clinical and laboratory outcomes and the chronobiological status of patients in both groups. RESULTS: The study findings showed that phototherapy at the peaks of patients chronobiological activity icombined with standard treatment resulted in a faster reduction of clinical signs of the disease and desynchronosis. PMID- 28631909 TI - [Characterization of microbial flora in patients suspected of having urogenital tuberculosis]. AB - INTRODUCTION: In the structure of tuberculosis morbidity, urogenital tuberculosis (UGT) ranks second or third only to pulmonary tuberculosis. Every fourth patient has the stage of cavern formation at first presentation. Seventy five percent of nephrotuberculosis cases co-occur with nonspecific pyelonephritis, which excludes "sterile pyuria". We aimed to determine the microbial spectrum of urine and gonadal appendages in patients with suspected UGT and to investigate the susceptibility of the isolated microorganisms to the main antibacterial drugs. MATERIAL AND METHODS: The study investigated the spectrum of pathogenic microflora isolated from patients admitted to the urogenital clinic of the TB Research Institute from January 1, 2012 to September 30, 2016 to rule out UGT. Microorganism species were identified by time-of-flight mass spectrometry using the microbiological analyzer Phoenix 100 (Becton Dickinson, USA). Antibiotic resistance was determined using the Phoenix 100 microbiological analyzer (Becton Dickinson, USA). RESULTS: A total of 3004 bacteriological tests for nonspecific microflora were performed during the analyzed period. In the structure of pathogens, E. coli comprised about half of the cases thus confirming its role as the leading uropathogen. Only piperacillin/tazobactam and nitrofurantoin provided relatively plausible antimicrobial resistance rates, for other antibacterial drugs the rates of susceptible strains progressively decreased and by 2016 dropped to 40% and lower. CONCLUSION: Our findings cannot be extrapolated to the entire population since patients presenting for differential diagnosis receive multiple courses of treatment with various antibacterial drugs, which led to the selection of resistant strains. The findings emphasize the need for a strict selection of antibiotics for urogenital infection empirical therapy. In the absence of response, the patient should be immediately examined for tuberculosis using molecular and genetic diagnostic techniques. PMID- 28631910 TI - [Prevalence and risk factors for nephrolithiasis among young rural residents]. AB - AIM: To determine the prevalence of nephrolithiasis, assess the significance of known risk factors, and identify new risk factors for nephrolithiasis among young rural residents. MATERIALS AND METHODS: This cross-sectional study was conducted in 5 settlements of the Irkutsk rural district of the Irkutsk region and involved 408 inhabitants (93 men, 315 women) aged from 18 to 47 years. The selection of candidates for the study was randomized. The response of the population was 81.6%. Diagnostic evaluation included clinical examination, renal ultrasound, urinalysis and questionnaires; drinking water hardness was determined. RESULTS: The prevalence of nephrolithiasis was 10.0% (95% CI 7.1-12.9). The men-to-women ratio for the prevalence of nephrolithiasis in was 0.69. No kidney stones were found in participants younger than 20 years, but after 20 years of age, there was a statistically significant (p=0.04) trend in increasing prevalence of nephrolithiasis. Calculi were detected only in participants with acidic urine and were absent in individuals with alkaline urine (p=0.001). A higher prevalence of nephrolithiasis was found in individuals using hard water (12.5%), compared to those using water of medium hardness (1.6%) (p=0.019). The odds ratio of nephrolithiasis in persons using hard water was 8.9 (95% CI 1.2-66.6). DISCUSSION: and conclusions 1.The incidence of nephrolithiasis in the Irkutsk rural area was 10.0%, which is comparable to that in populations of Europe and North America; 2. The primary risk factors for nephrolithiasis were age, acidic urine and the hardness of drinking water, which is consistent with the data of other authors; 3. Difficulties in measuring, grading and controlling subjective risk factors for nephrolithiasis (fluid intake, diet, heredity, and past diseases) make it difficult to analyze them in cross-sectional studies and prevent direct comparison with other studies. PMID- 28631911 TI - [The study of mineral composition and structure of uroliths in the residents of Tomsk district (Tomsk)]. AB - AIM: To successfully treat and prevent urolithiasis, the composition and structure of uroliths should be examined using modern analytical techniques. For a long time, studies of the biomineral formation in the human body have been conducted exclusively in the field of medicine. The main attention has been paid to the diagnosis and treatment of diseases leading to the occurrence of pathogenic formations. At the same time, it is quite obvious that it is important to have a clear idea about the causes of pathogenic formations, the mechanisms for their further formation, composition and structure. Currently, these issues are widely studied all over the world by mineralogists, biochemists, geo ecologists using methods of mineralogical analysis. The aim of this work was to determine the content of the elements that make up uroliths. This value should be normalized by the clarks of the noosphere. Studies on the mineral composition and structure of uroliths in the Tomsk region allowed to calculate the content of elements. It turned out that each medical district has its own specific geochemical series, which depends, probably, on natural and technogenic factors. MATERIALS AND METHODS: The study included urolith samples obtained from residents of 4 medical sub-districts of Tomsk district. 100 samples of different mineral composition were studied. Analytical techniques including crystal-morphological, spectral, X-ray structural, instrumental neutron-activation, electron microscopic analyses were used to investigate the morphology, mineral composition and structure of uroliths. RESULTS: The average content of elements in the uroliths, and the element concentrations normalized by the clark were established. After calculating the concentration, geochemical associative series of elements were formed. Depending on the morphology, drusiform, microspherolite, porous, coral formations, uroliths with a smoothed surface and stones with combined morphology were identified. Three groups of uroliths were defined according to their structural features: crystalline-granular, spherolithic and combined. CONCLUSION: Studies to determine the mineral composition and structure of the uroliths of the inhabitants of the Tomsk region made it possible to calculate the content of the elements that make up uroliths, normalized by clarks of the noosphere. Each medical sub-district has its own specific geochemical series, which depends on natural and technogenic factors. The increased value of the indicator of the content of elements in uroliths should serve as a warning factor for developing measures to reduce the urolithiasis incidence in the population. PMID- 28631912 TI - [Results of urethral reconstruction in adults after multiple hypospadias repairs]. AB - AIM: To improve treatment results in patients after multiple hypospadias repairs by optimizing the postoperative management. MATERIALS AND METHODS: Eighty-two patients (mean age 48.1+/-15.3 years) with urethral strictures secondary to failed hypospadias repairs underwent staged graft urethroplasty using oral mucosa (cheek, lip, tongue) as a grafting material. In 62 patients, at the end of surgery the bladder was drained with a standard Foley catheter. In twenty patients the bladder was drained with a modified silicone urethral catheter, which had an additional channel for delivering drugs and removing the urethral wound effluent, and a second additional channel for inflating a balloon fixed to the catheter tube at different parts of the catheter. RESULTS: The mean length of the stricture was 5.4+/-1.2 cm (from 1 to 16 cm). Twenty-eight patients had postoperative complications. Using the modified catheter resulted in statistically significantly (p<0.05) smaller percentage of complications (10% vs 41.9%) compared to standard Foley catheter. Urinalysis and sperm test on the follow up examination at 12 months showed that only 9 (10.9%) patients had signs of the inflammatory process. Seventy-five patients (91.5%) rated the appearance of the penis as "good"; only 5 (6.1%) and 2 (2.4%) patients considered the result as "satisfactory" and "unsatisfactory", respectively. Eighty patient (97.6%) regarded the treatment result as "good" for the quality of urination and only two (2.4%) considered it "satisfactory". When assessing the strength of urinary stream, 64 (78.1%), 13 (15.8%) and 5 (6.1%) patients rated it as "good", "satisfactory", and "unsatisfactory", respectively. CONCLUSION: The study findings shows that staged urethroplasty using the oral mucosa restores the urethral patency, reduces the severity of the inflammatory process, thus improving the quality of life of patients after failed hypospadias repair. The proposed modification of the catheter ensures the timely delivery of drugs to the surgical site, evacuation the wound effluent from the urethra and helps prevent strictures by periodically inflating the adjustable balloon-dilator. PMID- 28631913 TI - [Molecular aspects of the impact of the Speroton complex on the male fertility in idiopathic infertility]. AB - AIM: To characterize the effect of the Speroton complex on the free radical homeostasis in the ejaculate of males of infertile couples and the likelihood of pregnancy in partners. MATERIALS AND METHODS: The study group comprised 30 men aged between 26 and 43 years (mean 33 +/- 4.8 years) with idiopathic infertility. All patients received Speroton one sachet once daily during meals for 3 months. The comparison group consisted of 29 men of fertile age having 1 to 3 healthy children. In infertile men, standard semen parameters including the ejaculate volume, sperm concentration, total count and proportion of abnormal forms were within the normal range. Markers of oxidative damage to ejaculate macromolecules were determined using standard diagnostic testing systems. RESULTS: The patients with idiopathic infertility were found to have statistically significant changes in the degree of chemical modification of ejaculate biopolymers. The level of lipid hydroperoxides in infertile men was significantly higher than in fertile participants. Taking Speroton resulted in the decrease of lipid hydroperoxides to the level that did not differ from that in the control group. Using Speroton was also accompanied by a decrease in the level of the oxidative damage DNA biomarker 8-oxodGu and a tendency toward normalization of the carbonyl modification of the ejaculate proteins. Five married couples in the treatment group reported achieving pregnancy. CONCLUSION: Taking Speroton was associated with the normalization of the balance of pro- and antioxidant processes in the ejaculate, as indicated by a decrease in the oxidative destruction of sperm biopolymers. The revealed molecular mechanism of the drug action is the basis for restoring the fertilizing ability and increasing the likelihood of pregnancy. The treatment effectiveness was 16.7%. Speroton is a promising drug that improves the functional sperm characteristics and contributes to achieving pregnancy in couples with a male infertility factor. PMID- 28631914 TI - [Impact of CPAP therapy on erectile function during sleep and testosterone level in men with sleep apnea syndrome]. AB - The article presents the results of a polysomnographic study with simultaneous monitoring spontaneous nocturnal erections - Nocturnal Penile Tumescences (NPT) in 69 men with age-related androgen deficiency (AAD). Of these, 45 patients were diagnosed with obstructive sleep apnea syndrome (OSAS). In 34 of the 45 patients with OSAS, regimens of non-invasive ventilation with positive-positive airway pressure (CPAP) were selected. Titration was carried out using automatic CPAP devices for 2 months. The control group (n=24) comprised men with AAD, matched by the "copy-pair" type without clinical manifestations of respiratory disturbances during sleep. Extreme fragmentation of sleep with a significant predominance of the 1st and 2nd stages of the slow sleep phase, the deficiency of deep sleep stages and the significant shortening of the fast sleep phase was leveled by using a constant positive pressure in the upper respiratory tract. CPAP-therapy produced the phenomenon of a "rebound" of slow-wave sleep and fast-sleep phase. Before treatment, men with OSAS had a disruptive pattern of NPT (quantitative and qualitative characteristics). CPAP-therapy resulted in its recovery and maximum preservation relative to fast sleep phase time boundaries. However, the trend towards increasing testosterone levels was not significant, which requires additional testosterone replacement therapy concurrently with CPAP therapy in patients with OSAS and AAD. PMID- 28631915 TI - [Multispiral computer tomography in differential diagnosis of congenital uretheroidhydronefrosis in children]. AB - AIM: To identify the characteristic MSCT signs of pediatric ureterohydronephrosis allowing to assess the disease severity and differentiate between its various forms. MATERIAL AND METHODS: Sixty five children with III-IV grade ureterohydronephrosis underwent a comprehensive examination including MSCT urography. The study comprised 40 (61.5%) boys and 25 (38.5%) girls aged 3 months to 14 years (mean age 4.15+/-3.21 years). RESULTS: Obstructive disease was detected in 38 (58.5%) children, 27 (41.5%) patients had vesicoureteral reflux (VUR). Bilateral ureterohydronephrosis was found in 31 (47.7%) patients, unilateral - in 34 (52.3%). Twelve (35.3%) and twenty two (64.7%) patients had the right-sided and left-sided disease, respectively. Comparative analysis of MSCT signs of obstructive ureterohydronephrosis and VUR allowed for defining several distinctive symptoms which afford to accurately differentiate between the two pathological conditions. CONCLUSION: Multispiral computed tomography has a high sensitivity and specificity in detecting malformations of the urinary tract, making it possible to accurately differentiate obstructive ureterohydronephrosis from the VUR which plays an important role in assessing the disease severity and selecting a surgical strategy. PMID- 28631916 TI - [Intravesical prostatic protrusion in diagnosing infravesical obstruction in men with benign prostatic hyperplasia]. AB - Infravesical obstruction (IVO) is an important characteristic of the functional state of male lower urinary tract. It is believed that IVO confirmed by pressure flow study findings warrants switching from a medical to surgical management of lower urinary tract symptoms (LUTS). Intravesical prostatic protrusion (IPP) is a new indicator for detecting IVO secondary to benign prostatic hyperplasia (BPH). This indicator has several advantages over other non-invasive methods for evaluating IVO. The initial findings on the relationship between IPP and IVO suggest the feasibility of its clinical use as a screening tool in men with obstructive voiding symptoms. PMID- 28631917 TI - [Contemporary concept of the diagnosis of prostate cancer]. AB - This review summarizes current evidence of the etiology and diagnosis of prostate cancer. As before, a comprehensive urological examination remains the main method of diagnosing the disease. However, the invasive nature of the multicore prostate biopsy, its high cost and the need for specially trained personnel prompts to seek more state-of-the-art and non-invasive methods for diagnosing prostate cancer. The further research in this direction seems promising. PMID- 28631918 TI - [Using of cell biocomposite material in tissue engineering of the urinary bladder]. AB - In a systematic review, to present an overview of the current situation in the field of tissue engineering of urinary bladder related to the use of cell lines pre-cultured on matrices. The selection of eligible publications was conducted according to the method described in the article Glybochko P.V. et al. "Tissue engineering of urinary bladder using acellular matrix." At the final stage, studies investigating the application of matrices with human and animal cell lines were analyzed. Contemporary approaches to using cell-based tissue engineering of the bladder were analyzed, including the formation of 3D structures from several types of cells, cell layers and genetic modification of injected cells. The most commonly used cell lines are urothelial cells, mesenchymal stem cells and fibroblasts. The safety and efficacy of any types of composite cell structures used in the cell-based bladder tissue engineering has not been proven sufficiently to warrant clinical studies of their usefulness. The results of cystoplasty of rat bladder are almost impossible to extrapolate to humans; besides, it is difficult to predict possible side effects. For the transition to clinical trials, additional studies on relevant animal models are needed. PMID- 28631919 TI - [Rehabilitation of patients with complicated forms of urethral obliterations]. AB - The article describes open surgical modalities for managing patients with severe obliterations of the anterior urethra. The mean age of patients was 70 years. The causes of urethral strictures and obliteration included prostatic adenomectomy, scrotal abscess with pelvic bone osteomyelitis, accidental removal of the bulbar and penile urethra during herniotomy and a prolonged use of an indwelling urethral catheter. Two patients underwent perineostomy (median and trapezoidal). In the third patient, scrotal skin was used to form "scrotal hypospadias" (a modified Johansons operation) and the fourth patient underwent Mikhalovskiis operation. All patients regained normal voiding. PMID- 28631921 TI - Direct Electron Beam Writing of Silver-Based Nanostructures. AB - Direct writing utilizing a focused electron beam constitutes an interesting alternative to resist-based techniques, as it allows for precise and flexible growth onto any conductive substrate in a single-step process. One important challenge, however, is the identification of appropriate precursors which allow for deposition of the material of choice, e.g., for envisaged applications in nano-optics. In this regard the coinage metal silver is of particular interest since it shows a relatively high plasma frequency and, thus, excellent plasmonic properties in the visible range. By utilizing the precursor compound AgO2Me2Bu, direct writing of silver-based nanostructures via local electron beam induced deposition could be realized for the first time. Interestingly, the silver deposition was strongly dependent on electron dose; at low doses of 30 nC/MUm2 a dominant formation of pure silver crystals was observed, while at higher electron doses around 104 nC/MUm2 large carbon contents were measured. A scheme for the enhanced silver deposition under low electron fluxes by an electronic activation of precursor dissociation below thermal CVD temperature is proposed and validated using material characterization techniques. Finally, the knowledge gained was employed to fabricate well-defined two-dimensional deposits with maximized silver content approaching 75 at. %, which was achieved by proper adjustment of the deposition parameters. The corresponding deposits consist of plasmonically active silver crystallites and demonstrate a pronounced Raman signal enhancement of the carbonaceous matrix. PMID- 28631920 TI - Microfluidic Mapping of Cancer Cell-Protein Binding Interaction. AB - The interaction between tumor cells and microenvironment during metastasis is mediated by the binding of cell surface receptors, such as integrins and selectins, with protein ligands. Delineation of their binding interaction and identification of key receptors may be particularly important both in understanding extracellular matrix (ECM) remodeling and in developing potential therapeutic targets. Here we present a microfluidic chip that allows qualitative and quantitative mapping of a large population cell-protein interactions. It was found that beta1 integrin showed stronger binding interaction with collagen than with other ECM proteins. The upregulated beta1 integrin in invasive cancer cells enhanced cell-ECM interaction and may promote ECM remodeling. Cancer cells also showed strong interaction with plasma fibrinogen, the elevated level of which may help cancer cells arrest on blood vessels. We also verified that the chip may provide a platform for drug discovery by targeting integrins and cytoskeletons. PMID- 28631922 TI - Dual-Property Supramolecular H-Bonded 15-Crown-5 Ln(III) Chains: Joint Magneto Luminescence and ab Initio Studies. AB - Two complexes comprising 9-coordinate capped square antiprismatic [Ln(NO3)3(OH2)2(MeOH)] units [Ln(III) = Dy 6; Tb 7] are reported in which the metal complexes are hydrogen-bonded to 15C5 (15-crown-5) macrocycles to form supramolecular chains, {[Ln(NO3)3(OH2)2(MeOH)].(15C5)}n. Alternating current magnetic susceptibility measurements supported by ab initio studies show field induced SMM (single-molecule magnet) behavior for 6, but rapid relaxation of the magnetization for 7 because of the presence of dominant quantum tunneling processes as evidenced by the presence of a significant calculated tunnel splitting within the ground-state multiplet. Modeling the high-resolution emission spectra for 6 afforded energies of 37 +/- 5 and 28 +/- 5 cm-1 for the first-excited-state Stark sublevels of the two crystallographically independent Dy1 and Dy2 ions, in excellent agreement with the calculated values of 31 and 21 cm-1 for DeltaE1 derived from ab initio studies. PMID- 28631923 TI - Influence of Ingesting a Flavonoid-Rich Supplement on the Metabolome and Concentration of Urine Phenolics in Overweight/Obese Women. AB - This study evaluated the effect of ingesting a flavonoid-rich supplement (329 mg/d) on total urine phenolics and shifts in plasma metabolites in overweight/obese female adults using untargeted metabolomics procedures. Participants (N = 103, 18-65 y, BMI >= 25 kg/m2) were randomized to flavonoid (F) or placebo (P) groups for 12 weeks with blood and 24 h urine samples collected prestudy and after 4 and 12 weeks in a parallel design. Supplements were prepared as chewable tablets and included vitamin C, wild bilberry fruit extract, green tea leaf extract, quercetin, caffeine, and omega 3 fatty acids. At 4 weeks, urine total phenolics increased 24% in F versus P with similar changes at 12 weeks (interaction effect, P = 0.041). Groups did not differ in markers of inflammation (IL-6, MCP-1, CRP) or oxidative stress (oxLDL, FRAP). Metabolomics data indicated shifts in 63 biochemicals in F versus P with 70% from the lipid and xenobiotics superpathways. The largest fold changes in F were measured for three gut-derived phenolics including 3-methoxycatechol sulfate, 3-(3-hydroxyphenyl)propanoic acid sulfate, and 1,2,3-benzenetriol sulfate (interaction effects, p <= 0.050). This randomized clinical trial of overweight/obese women showed that 12 weeks ingestion of a mixed flavonoid nutrient supplement was associated with a corresponding increase in urine total phenolics and gut-derived phenolic metabolites. PMID- 28631924 TI - Insight into the Bonding Mechanism and the Bonding Covalency in Noble Gas-Noble Metal Halides: An NBO/NRT Investigation. AB - The bonding between noble gas and noble metal halide like hydrogen bonding (H bonding) motivates us to investigate the bonding mechanism and the bonding covalency in NgMX (Ng = He, Ne, Ar, Kr, Xe, Rn; M = Cu, Ag, Au; X = F, Cl, Br, I) complexes using natural bond orbital (NBO) and natural resonance theory (NRT) methods. In this study, we introduce the new resonance bonding model in H-bonding into NgMX bonding. We provide strong evidence for resonance bonding involving two important resonance structures: Ng: M-X <-> Ng+-M :X- in each of NgMX complexes, originating in the nNg -> sigma*MX hyperconjugative interaction. The covalency of the bonding could be understood by the localized nature of Ng-M bonds in these two resonance structures, and the degree of Ng-M covalency can be quantitatively described by calculated NRT bond orders bNgM. Furthermore, we find that the bond order satisfies conservation of bond order, bNgM + bMX = 1, for all of the studied complexes. On the basis of the conservation of bond order and some statistical correlations, we also reveal that the Ng-M bond (except He-Ag and Ne Ag bonds) can be tuned by changing the auxiliary ligand X. Overall, the present studies provide new insight into the bonding mechanism and the covalency of the bonding in noble gas-noble metal halides, and develop one resonance bonding model. PMID- 28631926 TI - Adsorption Geometry and Energy Level Alignment at the PTCDA/TiO2(110) Interface. AB - The adsorption geometry and energy alignment at the PTCDA/TiO2(110) interface are investigated using a combination of experimental and theoretical approaches. The energy alignment is determined experimentally from the occupied and unoccupied states electronic structure measured using X-ray and UV photoemission and inverse photoemission, respectively. Two possible adsorption geometries compatible with previous studies, a flat geometry and a tilted geometry, were explored using DFT techniques, in order to obtain theoretical STM images and energy alignment at the interface. Both STM images simulation and resulting energy alignment point to a tilted geometry for PTCDA on TiO2(110). PMID- 28631925 TI - Anticancer Activity of Polyoxometalate-Bisphosphonate Complexes: Synthesis, Characterization, In Vitro and In Vivo Results. AB - We synthesized a series of polyoxometalate-bisphosphonate complexes containing MoVIO6 octahedra, zoledronate, or an N-alkyl (n-C6 or n-C8) zoledronate analogue, and in two cases, Mn as a heterometal. Mo6L2 (L = Zol, ZolC6, ZolC8) and Mo4L2Mn (L = Zol, ZolC8) were characterized by using single-crystal X-ray crystallography and/or IR spectroscopy, elemental and energy dispersive X-ray analysis and 31P NMR. We found promising activity against human nonsmall cell lung cancer (NCI H460) cells with IC50 values for growth inhibition of ~5 MUM per bisphosphonate ligand. The effects of bisphosphonate complexation on IC50 decreased with increasing bisphosphonate chain length: C0 ~ 6.1*, C6 ~ 3.4*, and C8 ~ 1.1*. We then determined the activity of one of the most potent compounds in the series, Mo4Zol2Mn(III), against SK-ES-1 sarcoma cells in a mouse xenograft system finding a ~5* decrease in tumor volume than found with the parent compound zoledronate at the same compound dosing (5 MUg/mouse). Overall, the results are of interest since we show for the first time that heteropolyoxomolybdate-bisphosphonate hybrids kill tumor cells in vitro and significantly decrease tumor growth, in vivo, opening up new possibilities for targeting both Ras as well as epidermal growth factor receptor driven cancers. PMID- 28631927 TI - Stabilization of a Virus-Like Particle and Its Application as a Nanoreactor at Physiological Conditions. AB - Virus-like particles are very interesting tools for application in bionanotechnology, due to their monodisperse features and biocompatibility. In particular, the cowpea chlorotic mottle virus (CCMV) capsid has been studied extensively as it can be assembled and disassembled reversibly, facilitating cargo encapsulation. CCMV is, however, only stable at physiological conditions when its endogenous nucleic acid cargo is present. To gain more flexibility in the type of cargo encapsulated and to broaden the window of operation, it is interesting to improve the stability of the empty virus-like particles. Here, a method is described to utilize the CCMV capsid at close to physiological conditions as a stable, enzyme-filled nanoreactor. As a proof-of-principle, the encapsulation of T4 lysozyme (T4L) was chosen; this enzyme is a promising antibiotic, but its clinical application is hampered by, for example, its cationic character. It was shown that four T4L molecules can successfully be encapsulated inside CCMV capsids, while remaining catalytically active, which could thus improve the enzyme's application potential. PMID- 28631928 TI - Free Energy of Nanoparticle Binding to Multivalent Polymeric Substrates. AB - Characterization of the interactions between nanosize ligands and polymeric substrates is important for predictive design of nanomaterials and in biophysical applications. The multivalent nature of the polymer-nanoparticle interaction and the dynamics of multiple internal conformations of the polymer chains makes it difficult to infer microscopic interactions from macroscopic binding assays. Using coarse-grained simulations, we estimate the free energy of binding between a nanoparticle and a surface-grafted polymeric substrate as a function of pertinent parameters such as polymer chain length, nanoparticle size, and microscopic polymer-nanoparticle attraction. We also investigate how the presence of the nanoparticle affects the internal configurations of the polymeric substrate, and estimate the entropic cost of binding. The results have important implications for the understanding of complex macromolecular assemblies. PMID- 28631929 TI - 13C Dynamic Nuclear Polarization Using a Trimeric Gd3+ Complex as an Additive. AB - Dissolution dynamic nuclear polarization (DNP) is one of the most successful techniques that resolves the insensitivity problem in liquid-state nuclear magnetic resonance (NMR) spectroscopy and imaging (MRI) by amplifying the signal by several thousand-fold. One way to further improve the DNP signal is the inclusion of trace amounts of lanthanides in DNP samples doped with trityl OX063 free radical as the polarizing agent. In practice, stable monomeric gadolinium complexes such as Gd-DOTA or Gd-HP-DO3A are used as beneficial additives in DNP samples, further boosting the DNP-enhanced solid-state 13C polarization by a factor of 2 or 3. Herein, we report on the use of a trimeric gadolinium complex as a dopant in 13C DNP samples to improve the 13C DNP signals in the solid-state at 3.35 T and 1.2 K and consequently, in the liquid-state at 9.4 T and 298 K after dissolution. Our results have shown that doping the 13C DNP sample with a complex which holds three Gd3+ ions led to an improvement of DNP-enhanced 13C polarization by a factor of 3.4 in the solid-state, on par with those achieved using monomeric Gd3+ complexes but only requires about one-fifth of the concentration. Upon dissolution, liquid-state 13C NMR signal enhancements close to 20 000-fold, approximately 3-fold the enhancement of the control samples, were recorded in the nearby 9.4 T high resolution NMR magnet at room temperature. Comparable reduction of 13C spin-lattice T1 relaxation time was observed in the liquid-state after dissolution for both the monomeric and trimeric Gd3+ complexes. Moreover, W-band electron paramagnetic resonance (EPR) data have revealed that 3-Gd doping significantly reduces the electron T1 of the trityl OX063 free radical, but produces negligible changes in the EPR spectrum, reminiscent of the results with monomeric Gd3+-complex doping. Our data suggest that the trimeric Gd3+ complex is a highly beneficial additive in 13C DNP samples and that its effect on DNP efficiency can be described in the context of the thermal mixing mechanism. PMID- 28631930 TI - Fluorescent and Electrochemical Supramolecular Coordination Polymer Hydrogels Formed from Ion-Tuned Self-Assembly of Small Bis-Terpyridine Monomer. AB - Herein, ditopic ligand DTA comprised of terpyridine and acetylene segments with only one aromatic pi-conjugated building block was designed and synthesized. Driven by metal-ligand coordination interactions, we presented that the use of metal salts can direct the self-assembly of DTA in the generation of fluorescent and electrochemical polymers that entrapped water to form ambidextrous hydrogels. These were characterized by several approaches including fluorescent titrations, UV-vis, circular dichroism, and X-ray diffraction spectra as well as scanning electron microscopy and transmission electron microscopy experiments. DTA can selectively recognize Zn2+ ions and gelate water in the presence of ZnC6H10O6 (zinc lactate), giving Zn2+-specific fluorescent metallogels. Otherwise, DTA/Cu(OAc)2 forms nonfluorescent, electrochemical, and chiral hydrogel that responds to multiple stimuli such as heat, light, shearing, electrolysis, and reducer. The ion-controlled gelation approach, morphology, rheology, as well as fluorescent and chiroptical properties of DTA was studied in detail. Hence, our work demonstrated for the first time the crucial role of metal salts in the supramolecular polymerization and corresponding properties, in which symmetry breaking played an important role for the dynamic assembly difference. PMID- 28631931 TI - Induction of Lactation in the Biological Mother After Gestational Surrogacy of Twins: A Novel Approach and Review of Literature. AB - One of the important challenges in surrogate pregnancies is the early bonding of genetic mother with her infant and the establishment of breastfeeding. A combination of pharmacological and nonpharmacological methods is often used for the induction of lactation. Reports of induced lactation in surrogacy are limited and scattered. In this report, we present a case of induced lactation and initiation of breastfeeding in preterm twins by the genetic mother, through her novel approach after a gestational surrogate pregnancy. Thematic approach of maternal account is summarized with context and rigor. We reviewed the reported literature of induced lactation in similar cases with an aim to address the various methods adopted. PMID- 28631932 TI - Exercise and heart failure: Improve your functional status and your biomarker profile. PMID- 28631933 TI - A salt-reduction smartphone app supports lower-salt food purchases for people with cardiovascular disease: Findings from the SaltSwitch randomised controlled trial. AB - Background SaltSwitch is an innovative smartphone application (app) that enables shoppers to scan the barcode of a packaged food and receive an immediate, interpretive, traffic light nutrition label on the screen, along with suggestions for lower salt alternatives. Our aim was to determine the effectiveness of SaltSwitch to support people with cardiovascular disease to make lower salt food choices. Design Six-week, two-arm, parallel, randomised controlled trial in Auckland, New Zealand (2 weeks baseline and 4 weeks intervention). Methods Sixty six adults with diagnosed cardiovascular disease (mean (SD) age 64 (7) years) were randomly assigned in a 1:1 ratio to either the SaltSwitch smartphone app or control (usual care). The primary outcome was the salt content of household packaged food purchases during the 4-week intervention (g/MJ). Secondary outcomes were the saturated fat content (g/MJ), energy content (kJ/kg) and expenditure (NZ$) of household food purchases; systolic blood pressure (mmHg), urinary sodium (mg) and use and acceptability of the SaltSwitch app. Results Thirty-three participants with cardiovascular disease were allocated to the SaltSwitch intervention, and 33 to the control group. A significant reduction in mean household purchases of salt was observed (mean difference (95% confidence interval), -0.30 (-0.58 to -0.03) g/MJ), equating to a reduction of ~0.7 g of salt per person per day during the 4-week intervention phase. There were no significant between-group differences in any secondary outcomes (all P > 0.05). Conclusions The SaltSwitch smartphone app is effective in supporting people with cardiovascular disease to make lower salt food purchases. A larger trial with longer follow-up is warranted to determine the effects on blood pressure. Trial registration Australian New Zealand Clinical Trials Registry https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365784&isReview= rue ACTRN12614000206628. PMID- 28631934 TI - Breast Milk from Smokers Contains Less Cholesterol and Protein and Smaller Size of Apolipoprotein A-I Resulting in Lower Zebrafish Embryo Survivability. AB - BACKGROUND: To determine the quality of breast milk (BM), we compared the functions of BM from ex-smokers and nonsmokers. SUBJECTS AND METHODS: We analyzed the contents of lipids, glucose, and protein in BM from ex-smokers (10 cigarettes/day for 13 +/- 3 years) as well as infant formula. RESULTS: Nonsmokers' BM showed 2.4- and 1.4-fold higher cholesterol and protein contents, respectively, than BM from smokers. Infant formula contained almost no cholesterol, but did show remarkably higher glucose and triglyceride levels than BM. Microinjection of BM (50 nL) from nonsmokers and smokers into zebrafish embryos resulted in 59% and 44% survival, respectively, whereas formula injection resulted in 31% survival. The higher cholesterol and protein contents of BM were directly correlated with higher embryo survivability, suggesting that cholesterol content is directly and critically associated with growth of neonate infants. Smokers' BM contained smaller-sized apolipoproteinA-I (apoA-I) (24.4 +/- 0.2 kDa) than BM from nonsmokers (26.7 +/- 0.4 kDa), suggesting that putative modification and cleavage occurred in apoA-I. BM containing higher molecular weight apoA-I resulted in higher embryo survivability. CONCLUSIONS: Smoking before pregnancy can affect the composition and quality of BM, resulting in almost complete loss of cholesterol and protein, especially lactoferrin, lactalbumin, and apoA-I, accompanied by proteolytic degradation. These impairment effects of BM are associated with elevation of oxidative stress and lower embryo survivability. PMID- 28631935 TI - Hospital Supplementation Differentially Impacts the Association Between Breastfeeding Intention and Duration Among Women With and Without Gestational Diabetes Mellitus History. AB - BACKGROUND: Little is known about how in-hospital supplementation with water, infant formula, or sugar water affects the relationship between breastfeeding intentions and duration, and whether this differs by gestational diabetes mellitus (GDM) history. Our study objectives were to assess the associations between GDM and exclusive breastfeeding intentions, hospital supplementation, and breastfeeding duration, including whether hospital supplementation mediates the association between exclusive breastfeeding intentions and breastfeeding duration. STUDY DESIGN AND METHODS: Using data from the Infant Feeding Practices Study II (2005-2007), we included women with GDM (n = 160) and women without GDM or prepregnancy diabetes (no diabetes mellitus [NDM]) (n = 2,139). We used multivariable logistic and linear regressions to determine the associations between GDM history and exclusive breastfeeding intentions, and between breastfeeding intentions, hospital supplementation, and breastfeeding duration, by GDM. We used mediation analysis to assess whether hospital supplementation mediated the association between exclusive breastfeeding intention and breastfeeding duration, also by GDM. All analyses were adjusted for prepregnancy body mass index. RESULTS: GDM was associated with lower odds of intending to exclusively breastfeed (adjusted odds ratio [AOR] 0.71; 95% confidence interval [CI, 0.51-0.99]). GDM and NDM women who did not intend to exclusively breastfeed had similarly increased odds of hospital supplementation (GDM: AOR 3.52; 95% CI [1.44-8.57], NDM: AOR 3.66; 95% CI [2.93-4.56]). Breastfeeding duration was similar by exclusive breastfeeding intentions and by hospital supplementation, regardless of GDM. Hospital supplementation partially mediated the association between breastfeeding intentions and duration in NDM women, but it did not mediate the association in women with GDM. CONCLUSIONS: Breastfeeding intentions, rather than hospital supplementation, are particularly important for women with GDM to optimize breastfeeding outcomes. PMID- 28631936 TI - The Recent Developments in Sample Preparation for Mass Spectrometry-Based Metabolomics. AB - Metabolomics is a critical member in systems biology. Although great progress has been achieved in metabolomics, there are still some problems in sample preparation, data processing and data interpretation. In this review, we intend to explore the roles, challenges and trends in sample preparation for mass spectrometry- (MS-) based metabolomics. The newly emerged sample preparation methods were also critically examined, including laser microdissection, in vivo sampling, dried blood spot, microwave, ultrasound and enzyme-assisted extraction, as well as microextraction techniques. Finally, we provide some conclusions and perspectives for sample preparation in MS-based metabolomics. PMID- 28631937 TI - The effect of the sagittal ridge angle on cartilage stress in the equine metacarpo-phalangeal (fetlock) joint. AB - Fatigue failure of bones of the metacarpo-phalangeal (fetlock, MCP) joint is common in thoroughbred racehorses. Stresses within the fetlock joint cartilages are affected by the morphology of the third metacarpal bone (MC3) and proximal phalangeal bone, and the steepness of the median sagittal ridge of MC3 is believed to be associated with fracture. This study investigated the influence of the steepness of the sagittal ridge on cartilage stress distribution using a finite element model of the joint. Changes to the steepness of the sagittal ridge were made by applying a parabolic function to the mesh, creating four different models with sagittal ridge angles ranging from 95 degrees to 105 degrees . In the fetlock joint of Thoroughbred racehorses, sagittal ridge angles of >100 degrees were associated with higher Von Mises stresses in cartilage at the palmar aspect of the condylar groove than such stresses in joints with sagittal ridge angles of <100 degrees . Stresses were high in the specific region where fractures are known to originate in MC3. This aspect of morphology of the fetlock joint thus appears to play an important role in the magnitude and distribution of cartilage stresses, which, when acting on the underlying hard tissues of the articular calcified cartilage and subchondral bone may play a role in the initiation of fatigue fracture in the third metacarpal bone. PMID- 28631938 TI - Aid and authoritarianism in Africa. PMID- 28631939 TI - A High-Throughput Screening Assay for NKCC1 Cotransporter Using Nonradioactive Rubidium Flux Technology. AB - A high-throughput screening (HTS) assay was developed for cotransporter, NKCC1, which is a potential target for the treatment of diverse disorders. This nonradioactive rubidium flux assay coupled with ion channel reader series provides a working screen for this target expressed in human embryonic kidney (HEK) cell line. An eightfold window of detection was achieved with the optimized assay. This new functional assay offered a robust working model for NKCC1 in determining reliable and concordant rank orders of the test compounds supporting its sensitivity and specificity. The robustness of manual assay indicated by Z' of 0.9 qualified its amenability to automation. The Z' of 0.7 was displayed by automated assay employed in high-throughput screening of compound libraries against this target. Being electrically neutral, the NKCC1 screening is difficult to achieve by both manual and automated electrophysiological techniques. These techniques, although considered gold standard, suffer from their inherent problems of being too slow to be in high-throughput format and with high running costs. In addition to being a functional assay for NKCC1, it is nontoxic as compared with thallium flux assay, which is prone to generate high number of false-positive/false-negative rates because of its innate fluorescence issues. PMID- 28631940 TI - Moving Forward with ASSAY. PMID- 28631942 TI - A systematic review of factors affecting driving and public transportation among youth and young adults with acquired brain injury. AB - PURPOSE: Although many people with an acquired brain injury (ABI) encounter difficulties with executive functioning and memory which could negatively affect driving, few people are assessed for fitness to drive after injury. The purpose of this systematic review was to synthesize the literature on factors affecting driving and public transportation among youth and young adults with ABI, post injury. METHOD: Seven databases were systematically searched for articles from 1980 to 2016. Studies were screened independently by two researchers who performed the data extraction. Study quality was appraised using the Standard Quality Assessment Criteria (Kmet) for evaluating primary research from a variety of fields. RESULTS: Of the 6577 studies identified in the search, 25 met the inclusion criteria, which involved 1527 participants with ABI (mean age = 25.1) across eight countries. Six studies focused on driving assessment and fitness to drive, ten on driving performance or risk of accidents and nine studies explored issues related to accessing or navigating public transportation. Quality assessment of the included studies ranged from 0.60 to 0.95. CONCLUSIONS: Our findings highlight several gaps in clinical practice and research along with a critical need for enhanced fitness to drive assessments and transportation related training for young people with ABI. PMID- 28631941 TI - Analytical Characterization of Methyl-beta-Cyclodextrin for Pharmacological Activity to Reduce Lysosomal Cholesterol Accumulation in Niemann-Pick Disease Type C1 Cells. AB - Methyl-beta-cyclodextrin (MbetaCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease type C1 (NPC1) patient fibroblasts. However, the pharmacological activity of MbetaCD reported by different laboratories varies. To determine the potential causes of this variation, we analyzed the mass spectrum characteristics, pharmacological activity of three preparations of MbetaCDs, and the protein expression profiles of NPC1 patient fibroblasts after treatment with different sources of MbetaCDs. Our data revealed varied mass spectrum profiles and pharmacological activities on the reduction of lysosomal cholesterol accumulation in NPC1 fibroblasts for these three preparations of MbetaCDs obtained from different batches and different sources. Furthermore, a proteomic analysis showed the differences of these three MbetaCD preparations on amelioration of dysregulated protein expression levels in NPC1 cells. The results demonstrate the importance of prescreening of different cyclodextrin preparations before use as a therapeutic agent. A combination of mass spectrum analysis, measurement of pharmacological activity, and proteomic profiling provides an effective analytical procedure for characterization of cyclodextrins for therapeutic applications. PMID- 28631943 TI - Evaluation of the genotype MTBDRsl test for detection of second-line drug resistance in drug-resistant Mycobacterium tuberculosis strains in Myanmar. PMID- 28631945 TI - Vildagliptin: any effect on non-alcoholic fatty liver disease and serum uric acid? Re: Shelbaya S, Rakha S. Effectiveness and safety of vildagliptin and vildagliptin add-on to metformin in real-world settings in Egypt - results from the GUARD study. Curr Med Res Opin 2017;33:797-801. PMID- 28631944 TI - Clinical significance of repeat blood cultures during febrile neutropenia in adult acute myeloid leukaemia patients undergoing intensive chemotherapy. AB - BACKGROUND: We evaluated the clinical significance of repeat blood cultures in persistent and recurrent fever during neutropenia in adult acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients undergoing intensive chemotherapy. METHODS: We retrospectively reviewed the chemotherapy cycles at our centre between January 2007 and December 2015. Blood cultures obtained within three days after initial febrile neutropenia (FN) were defined as initial blood cultures and those obtained on or after day 4 were defined as repeat blood cultures. RESULTS: Overall, 321 chemotherapy cycles in 89 patients were subjected to review. FN was identified in 276 (86.0%) chemotherapy cycles. In persistent FN (134 episodes), the causative pathogens were detected by repeat blood cultures in seven episodes (5.2%), including only three episodes (2.2%) of new infection. Shaking chills and high body temperature were identified as significant predictors for bloodstream infection (BSI). In recurrent FN (85 episodes), the causative pathogens were detected in seven episodes (8.2%), and all of these were new organisms. The frequency of detecting new pathogens by repeat blood cultures in recurrent FN (7/85) was higher than that in persistent FN (3/134) (p = .0491). A history of recent BSI was identified as a significant predictor for BSI in recurrent FN. CONCLUSIONS: The diagnostic yield of repeat blood cultures for persistent FN was low in intensive chemotherapy for AML and MDS. The frequency of repeat blood cultures for persistent FN could be reduced based on predictors. On the other hand, blood cultures were considered to be essential in cases with recurrent FN. PMID- 28631946 TI - Stented Versus Stentless Laparoscopic Ureterolithotomy: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: This systematic review and meta-analysis were designed to evaluated the efficacy and safety of stented versus stentless laparoscopic ureterolithotomy (LU). METHODS: We conducted a systematic review and meta-analysis that included six trials that investigated the outcomes, including the rate of prolonged urine leakage, operative time, time to drain removal, and estimated blood loss, between stented versus stentless LU. RESULTS: Four studies with 289 participants were included in the study. There was no significant difference between two groups in rate of prolonged urine leakage (odds ratios [OR] 0.35, 95% confidence intervals [CI] 0.09-1.46, p = 0.15). Significant longer operative time was detected in patients who underwent stented LU compared with stentless group (mean difference 11.36, 95% CI 7.53-15.20, P < .00001). There was no significant difference between two groups in day of drain removal (mean difference -1.09, 95% CI -2.33 0.15, P = .08). No significant difference in blood loss in patients who underwent stented LU compared with stentless group was detected (mean difference 7.67, 95% CI -0.29-15.64, P = .06). CONCLUSION: Our study demonstrated that the rate of prolonged urine leakage, time to drain removal, and estimated blood loss were not significantly different between stented and stentless LU. PMID- 28631947 TI - Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia. AB - Enhanced L-type Ca2+ channel (LTCC) activity in arterial myocytes contributes to vascular dysfunction during diabetes. Modulation of LTCC activity under hyperglycemic conditions could result from membrane potential-dependent and independent mechanisms. We have demonstrated that elevations in extracellular glucose (HG), similar to hyperglycemic conditions during diabetes, stimulate LTCC activity through phosphorylation of CaV1.2 at serine 1928. Prior studies have also shown that HG can suppress the activity of K+ channels in arterial myocytes, which may contribute to vasoconstriction via membrane depolarization. Here, we used a mathematical model of membrane and Ca2+ dynamics in arterial myocytes to predict the relative roles of LTCC and K+ channel activity in modulating global Ca2+ in response to HG. Our data revealed that abolishing LTCC potentiation normalizes [Ca2+]i, despite the concomitant reduction in K+ currents in response to HG. These results suggest that LTCC stimulation may be the primary mechanism underlying vasoconstriction during hyperglycemia. PMID- 28631948 TI - Possible contribution of pannexin-1 to capsaicin-induced ATP release in rat nasal columnar epithelial cells. AB - Current evidence indicates that transient receptor potential (TRP) channel activity involves a relationship between opening of pannexin-1 and release of ATP into the extracellular space. We examined the effects of agonists of thermosensitive TRP channels (TRPM8, TRPA1, TRPV1, and TRPV2) on ATP release from rat nasal mucosa, and measured ciliary beat frequency (CBF) using digital high speed video imaging. Single-cell patch clamping from dissociated rat nasal columnar epithelial cells was performed to confirm the relationship between pannexin-1 and TRP. We demonstrated that ATP release and CBF were significantly potentiated by the heat-sensitive TRPV1 agonist capsaicin (10 MUM), but not by other TRP agonists. Capsaicin-induced ATP release and CBF increase were significantly inhibited by the pannexin-1 blockers carbenoxolone (10 MUM) and probenecid (300 MUM). In addition, the voltage step-evoked currents in the presence of capsaicin were inhibited by the pannexin-1 blockers in single-cell patch clamping. Our results suggest the participation of TRPV1 and pannexin-1 in the physiologic functions of rat nasal mucosa. PMID- 28631949 TI - Diffusion tensor imaging tensor shape analysis for assessment of regional white matter differences. AB - Purpose The purpose of this study was to investigate a novel tensor shape plot analysis technique of diffusion tensor imaging data as a means to assess microstructural differences in brain tissue. We hypothesized that this technique could distinguish white matter regions with different microstructural compositions. Methods Three normal canines were euthanized at seven weeks old. Their brains were imaged using identical diffusion tensor imaging protocols on a 7T small-animal magnetic resonance imaging system. We examined two white matter regions, the internal capsule and the centrum semiovale, each subdivided into an anterior and posterior region. We placed 100 regions of interest in each of the four brain regions. Eigenvalues for each region of interest triangulated onto tensor shape plots as the weighted average of three shape metrics at the plot's vertices: CS, CL, and CP. Results The distribution of data on the plots for the internal capsule differed markedly from the centrum semiovale data, thus confirming our hypothesis. Furthermore, data for the internal capsule were distributed in a relatively tight cluster, possibly reflecting the compact and parallel nature of its fibers, while data for the centrum semiovale were more widely distributed, consistent with the less compact and often crossing pattern of its fibers. This indicates that the tensor shape plot technique can depict data in similar regions as being alike. Conclusion Tensor shape plots successfully depicted differences in tissue microstructure and reflected the microstructure of individual brain regions. This proof of principle study suggests that if our findings are reproduced in larger samples, including abnormal white matter states, the technique may be useful in assessment of white matter diseases. PMID- 28631950 TI - Securing Our Future. PMID- 28631951 TI - Aging-A Call to Arms! PMID- 28631952 TI - The development of visual speech perception in Mandarin Chinese-speaking children. AB - The present study aimed to investigate the development of visual speech perception in Chinese-speaking children. Children aged 7, 13 and 16 were asked to visually identify both consonant and vowel sounds in Chinese as quickly and accurately as possible. Results revealed (1) an increase in accuracy of visual speech perception between ages 7 and 13 after which the accuracy rate either stagnates or drops; and (2) a U-shaped development pattern in speed of perception with peak performance in 13-year olds. Results also showed that across all age groups, the overall levels of accuracy rose, whereas the response times fell for simplex finals, complex finals and initials. These findings suggest that (1) visual speech perception in Chinese is a developmental process that is acquired over time and is still fine-tuned well into late adolescence; (2) factors other than cross-linguistic differences in phonological complexity and degrees of reliance on visual information are involved in development of visual speech perception. PMID- 28631953 TI - A morpho-phonological Past Tense processing as a clinical marker in SLI EFL learners. AB - The clinical marker in specific language impairment (SLI) population is the subject of considerable debate. SLI is the one of the frequently diagnosed atypical language phenomena found among early school-age children (McArthur et al., 2000; Spear-Swerling, 2006). For example, children with SLI have difficulty applying the Past Tense rule to verbs, even though they can accurately repeat phonologically similar forms of the words (Hoeffner & McClelland, 1993). In this study, I discuss the grammatical deficits in the SLI population by studying the generation of both 'regular' and 'irregular' English Past Tense forms and explain how the rates of the correct use of the 'irregular' versus 'regular' form may be considered as a clinical SLI marker. This study defines the differences in the grammatical sensitivity in the EFL learners and provides additional essential insight into SLI, in general, and its identification in the EFL learners, in particular. PMID- 28631954 TI - Parameter setting in the acquisition of consonant clusters by phonologically delayed children. AB - The relationship between the acquisition of initial complex onset clusters, /s/ initial clusters, and non-initial clusters is much studied yet poorly understood. Pan and Snyder (2004), working within the Government Phonology (GP) framework, proposed that the production of the three types of consonant clusters requires the proper setting of three binary parameters [+/- Branching onset (BO), [+/ Branching rhyme (BR)] and [+/-Magic empty nucleus (MEN)]. Specifically, the production of onset clusters require [+BO], /s/-initial clusters require both [+BR] and [+MEN], and non-initial clusters require [+BR]. Two predictions follow: (1) The acquisition of /s/-initial clusters is independent of the acquisition of onset clusters, and (2) /s/-initial clusters should never be acquired prior to non-initial clusters, because the latter only require [+BR]. These predictions were borne out by data from twenty English-speaking children with phonological delay (mean age = 4;10). In support of prediction (1), seven children were able to produce onset clusters, but never produced /s/-initial clusters, and four children had the opposite pattern. Consistent with prediction (2), six children produced non-initial clusters but were unable to produce /s/-initial clusters. We conclude that a parametric approach is applicable to the acquisition of consonant clusters in children with phonological delay. PMID- 28631956 TI - Coping strategies and psychological distress in caregivers of patients with Amyotrophic Lateral Sclerosis (ALS). AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) causes distress in caregivers. The present study aims to examine the association between coping strategies and psychological distress in caregivers of ALS patients. METHODS: Coping strategies were assessed in 96 ALS informal caregivers by means of the Coping Inventory for Stressful Situations. Data about caregivers' demographic characteristics, levels of burden, depression and anxiety (psychological distress) were also gathered by standardised questionnaires. Patients' clinical, cognitive and behavioural disturbances were evaluated by ALS specific assessment tools. RESULTS: Sequential logistic regression analysis showed that emotion-oriented coping strategy was significantly associated with high levels of depressive (p < 0.01) and anxiety (p < 0.05) symptoms and high levels of burden (p < 0.05), after controlling for all other variables. Moreover, a significant relationship of patients' functional dependence levels with burden experienced by caregivers was observed. No relationships were detected between task-oriented and avoidance-oriented coping strategies and caregivers' levels of psychological distress. CONCLUSIONS: The present study supported the mediating effects of coping strategies on intensity of burden, depression and anxiety experienced by ALS caregivers. These findings suggest that interventions aimed at reducing utilisation of maladaptive coping strategies may improve well-being in ALS caregivers, and, possibly, management of symptoms in ALS patients. PMID- 28631955 TI - Cerebrospinal fluid neurofilament light concentration in motor neuron disease and frontotemporal dementia predicts survival. AB - OBJECTIVE: To aid diagnostics, patient stratification and studies seeking to find treatments for the related diseases motor neuron disease (MND) and frontotemporal dementia (FTD), there is a need to establish a way to assess disease severity and the amount of ongoing neurodegeneration. Previous studies have suggested that cerebrospinal fluid (CSF) neurofilament light (NFL) may serve this purpose. METHODS: We cross-referenced the Swedish mortality registry with the laboratory database at Sahlgrenska University Hospital to produce a dataset of CSF NFL concentrations and mortality information for 715 MND patients, 87 FTD patients, and 107 healthy controls. Biomarker concentrations were analysed in relation to recorded cause of death and time of death. RESULTS: MND patients had significantly higher CSF NFL concentrations than FTD patients. Both groups had significantly higher concentrations than the healthy controls (mean 709% increase in MND and 307% increase in FTD). Higher concentrations of CSF NFL were associated with shorter survival in both MND and FTD. CONCLUSIONS: The results of this study strengthen the notion of CSF NFL as a useful tool for determining disease intensity in MND and FTD patients. Further studies in patient cohorts with clinically subtyped and genetically classified diagnoses are needed. PMID- 28631957 TI - Prognostic value of clinical and electrodiagnostic parameters at time of diagnosis in patients with amyotrophic lateral sclerosis. AB - OBJECTIVE: To assess the added prognostic value of the aggregated clinical and electrodiagnostic data, which define a given diagnostic category according to the Awaji or revised El Escorial criteria at time of diagnosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: Clinical signs and electrodiagnostic test results were collected at time of diagnosis in 396 patients with ALS between January 2009 and January 2016. Significant predictors of prognosis were identified using a univariate model, and later combined in a multivariate Cox regression model. RESULTS: Known factors associated with reduced survival included older age at onset, shorter diagnostic delay, higher ALSFRS-R slope and presence of C9orf72 mutation (all p < 0.05). Diagnostic category according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0177) criteria, definite ALS according to Awaji (p < 0.0001) or to revised El Escorial (p = 0.0343) and number of regions with LMN involvement (p < 0.0001) were all associated with shorter survival. DISCUSSION: Clinical and electrodiagnostic data at time of diagnosis provide additional prognostic information compared to other known prognostic factors. Diagnostic category according to Awaji and the extensiveness of LMN involvement contain the most additional value. PMID- 28631958 TI - "Anything that makes life's journey better." Exploring the use of digital technology by people living with motor neurone disease. AB - Our aim was to explore the attitudes of those living with motor neuron disease towards digital technology. Postal and online questionnaires surveyed 83 people with MND (pwMND) and 54 friends and family members (fMND). Five pwMND and five fMND underwent semi-structured interviews. 82% of pwMND and 87% of fMND use technology every day with iPads and laptops being the devices most commonly used. pwMND used technology to help them continue to participate in everyday activities such as socialising, entertainment and accessing the internet. The internet provided peer support and information about MND but information could be distressing or unreliable. Participants preferred information from professionals and official organisations. Participants were generally supportive of using of technology to access medical care. Barriers to technology, such as lack of digital literacy skills and upper limb dysfunction, and potential solutions were identified. More challenging barriers included language and cognitive difficulties, and the fear of becoming dependent on technology. Addressing the barriers identified in this research could help pwMND access technology. However, as healthcare delivery becomes more reliant on digital technology, care should be taken to ensure that those who are unable or unwilling to use technology continue to have their needs met in alternative ways. PMID- 28631960 TI - ALSUntangled 39: Acuscope (micro-Amp electrical muscle stimulation). PMID- 28631959 TI - Advance care planning for patients with amyotrophic lateral sclerosis. AB - PURPOSE: To determine whether an advance care planning (ACP) decision-aid could improve communication about end-of-life treatment wishes between patients with amyotrophic lateral sclerosis (ALS) and their clinicians. METHODS: Forty-four patients with ALS (>21, English-speaking, without dementia) engaged in ACP using an interactive computer based decision-aid. Before participants completed the intervention, and again three months later, their clinicians reviewed three clinical vignettes, and made treatment decisions (n = 18) for patients. After patients indicated their agreement with the team's decisions, concordance was calculated. RESULTS: The mean concordance between patient wishes and the clinical team decisions was significantly higher post-intervention (post = 91.9%, 95% CI = 87.8, 96.1, vs. pre = 52.4%, 95% CI = 41.9, 62.9; p <0.001). Clinical team members reported greater confidence that their decisions accurately represented each patient's wishes post-intervention (mean = 6.5) compared to pre-intervention (mean = 3.3, 1 = low, 10 = high, p <0.001). Patients reported high satisfaction (mean = 26.4, SD = 3.2; 6 = low, 30 = high) and low decisional conflict (mean = 28.8, SD = 8.2; 20 = low, 80 = high) with decisions about end-of-life care, and high satisfaction with the decision-aid (mean = 52.7, SD = 5.7, 20 = low, 60 = high). Patient knowledge regarding ACP increased post-intervention (pre = 47.8% correct responses vs. post = 66.3%; p <0.001) without adversely affecting patient anxiety or self-determination. CONCLUSION: A computer based ACP decision-aid can significantly improve clinicians' understanding of ALS patients' wishes with regard to end-of-life medical care. PMID- 28631961 TI - Intracranial dural chondroma in a child-conventional and advanced neuroimaging characteristics and differential diagnosis. AB - Intracranial chondromas are rare tumors, especially in the pediatric population. We describe the conventional and advanced neuroimaging characteristics of this rare convexity dura-based chondroma in a young adolescent. In particular we demonstrate that diffusion-weighted imaging (DWI) facilitates differentiation between a dura-based chondroma and the more frequent classical meningioma. Chondromas are typically DWI hypointense with high apparent diffusion coefficient (ADC) values while meningiomas are typically DWI hyperintense with low ADC values. We also discuss the relevant additional differential diagnoses of dura based focal lesions for the pediatric population as well as the diagnostic significance of additional imaging modalities, including computed tomography, magnetic resonance imaging and cerebral angiography. PMID- 28631962 TI - Needlestick Injuries in Interventional Radiology Are Common and Underreported. AB - Purpose To determine the prevalence of and risk factors for needlesticks in interventional radiology physicians, as well as the attitudes, behaviors, and conditions that promote or interfere with reporting of these injuries. Materials and Methods A total of 3889 interventional radiologists from academic and private practice in the United States were surveyed by emailing all interventional radiologist members of the Society of Interventional Radiology, including attending-level physicians and trainees (April-August 2016). The institutional review board waived the need for consent. Questions inquired about the nature, frequency, and type of needlestick and sharps injuries and whether and to whom these incidents were reported. Stepwise regression was used to determine variables predicting whether injuries were reported. Results In total, 908 (23%) interventional radiologists completed at least a portion of the survey. Eight hundred fourteen (91%) of 895 respondents reported a prior needlestick injury, 583 (35%) of 895 reported at least one injury while treating an HIV-positive patient, and 626 (71%) of 884 reported prior training regarding needlestick injury. There was, on average, one needlestick for every 5 years of practice. Most needlestick or sharps injuries were self inflicted (711 [87%] of 817) and involved a hollow-bore device (464 [56%] of 824). Only 566 (66%) of 850 injuries were reported. The most common reasons for not reporting included perceived lack of utility of reporting (79 [28%] of 282), perceived low risk for injury (56 [20%] of 282), noncontaminated needle (53 [19%] of 282), too-lengthy reporting process (37 [13%] of 282), and associated stigma (23 [8%] of 282). Only 156 (25%) of 624 respondents informed their significant other. Stepwise regression assessing variables affecting the likelihood of reporting showed that male sex (P = .009), low-risk patient (P < .0001), self injury (P = .010), trainee status (P < .0001), and the total number of prior injuries (P = .019) were independent predictors of not reporting. Conclusion Needlestick injuries are ubiquitous among interventional radiologists and are often not reported. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28631963 TI - Tumor-penetrating Peptide-integrated Thermally Sensitive Liposomal Doxorubicin Enhances Efficacy of Radiofrequency Ablation in Liver Tumors. AB - Purpose To investigate the role of a tumor-penetrating peptide (internalizing CRGDRGPDC [iRGD])-integrated thermally sensitive liposomal (TSL) doxorubicin (DOX) in combination with radiofrequency (RF) ablation of liver tumors in an animal model. Materials and Methods Approval from the institutional animal care and use committee was obtained. Characterization of iRGD-TSL-DOX was performed in vitro. Next, H22 liver adenocarcinomas were implanted in 138 mice in vivo. The DOX accumulation and cell apoptosis of iRGD-TSL-DOX and TSL-DOX with or without RF were evaluated (n = 5) at different time points after treatment with quantitative analysis or pathologic staining. Mice bearing tumors were randomized into the following six groups (each group, eight mice): no treatment, iRGD-TSL DOX, TSL-DOX, RF alone, RF ablation followed by TSL-DOX at 30 minutes (TSL-DOX combined with RF), and RF ablation followed by iRGD-TSL-DOX (iRGD-TSL-DOX combined with RF). Kaplan-Meier method was used to estimate the survival curves and log-rank test was used for comparison with statistical software. Results DOX encapsulation efficiency in iRGD-TSL-DOX was 97.5% +/- 1.3 (standard deviation) with temperature-dependent drug release capability confirmed in vitro. In vivo, the iRGD-TSL-DOX group had overall higher DOX concentration in the tumor and had maximal difference at 24 hours compared with TSL-DOX group (2.7-fold). RF caused more intense cell apoptosis at 24 hours (median, 65% vs 21%, respectively; P < .001). For end-point survival, the iRGD-TSL-DOX combined with RF group had better survival (median, 32 days) than TSL-DOX combined with RF (median, 27 days; P = .035) or RF alone (median, 21 days; P < .001). Conclusion Conjugation to iRGD helped to improve intratumoral DOX accumulation and further enhanced the activity of TSL-DOX in RF ablation of liver tumors. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28631965 TI - Short-term test-retest reliability of the ImPACT in healthy young athletes. AB - The present study examined the short-term test-retest reliability of the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) variables with healthy 11- to 14-year-old athletes. 53 young athletes (Mage = 12.4 years, 9 female) were administered the ImPACT on two separate occasions two weeks apart. Participants were instructed to complete the Post-Concussion Symptom Scale (PCSS) and the baseline computerized neurocognitive test during both the baseline and retest phases. Intraclass correlation (ICC), standard error of measurement (SEM), and reliable change index (RCI) were used as reliability metrics. PCSS Total Symptoms and Visual-Motor Speed were the only scores to reach clinical reliability standards (i.e., R > 0.7). None of the scores exceeded RCI cut-offs. Results indicate that the composite scores of the ImPACT are differentially reliable in a preadolescent sample across a two-week retest period, with only motor processing speed and self-reported symptoms exceeding clinical reliability standards. The findings support the view that neurocognitive testing should not be the sole determining factor in concussion assessment. This study highlights the importance of continuing research with younger athletes to assess the reliability of neurocognitive measures in concussion management programs. Future research should focus on a larger, heterogeneous sample, including children with learning disabilities and ADHD. PMID- 28631964 TI - Evidence-based assessment of ADHD diagnosis in children and adolescents. AB - This study illustrates the accuracy and efficiency of using an evidence-based assessment (EBA) strategy for diagnosis of attention-deficit/hyperactivity disorder (ADHD) by integrating the scale scores obtained on BASC-3 teacher and parent rating scales. The examined process used empirical diagnostic likelihood ratios (DLRs) derived from a sample of children with ADHD (N = 339) matched on demographic characteristics from the normative sample. The results show that behavioral scales of executive functioning and functional communication provided incremental utility in ADHD diagnosis. With a revised probability of .80 or higher as the diagnostic criterion, teachers, and parents positively diagnosed 70% and 94% of the ADHD cases respectively. The EBA approach was efficient, with four scales on average used to reach the proposed posterior probability for final diagnosis. Finally, teachers and parents demonstrated a high agreement with respect to the diagnosis results and scales used for the diagnosis. PMID- 28631966 TI - Executive functioning of Portuguese preschoolers in the Shape School test: A cross cultural study. AB - The Shape School is a neuropsychological test of executive functions (EF) for preschool-aged children. The purposes of this study were: (a) to adapt the use of the Shape School for European Portuguese preschool children and (b) to examine the cultural sensitivity of this test comparing the performance of Portuguese sample and U.S. normative sample. The executive functioning of 233 typically developing children aged 3 to 5 years old (M = 57.52; SD = 10.25; in months) was analyzed and according to our results, the adapted version was appropriate to obtain the discrimination among age-groups. Portuguese and American preschoolers show similar EF profiles. It was possible, in both samples, to note the sensitivity of the measurement to age-related differences, with the older age groups outperforming the younger. Therefore, the Portuguese version of the Shape School was considered suitable for research and clinical purposes. PMID- 28631967 TI - Reasons for referral and findings of clinical neuropsychological assessment in youth with mental illness: A clinical file audit. AB - Study aims were to 1) determine the characteristics and reasons for referral for Clinical Neuropsychological Assessment (CNA) and 2) characterize the findings and recommendations contained in the CNA reports, of clients attending a youth mental health service. File audit of all CNA reports (N = 140) of youth attending a mental health service. Cognitive performances on neuropsychological tests that were administered to >50% of clients were examined. Referral reasons, findings, and recommendations for future treatment were coded and described from neuropsychological files. Age of clients referred for CNA ranged from 13-29, the majority were male (62.5%), referred primarily from the early psychosis clinic (63.2%), and had a mean number of 3.5 presenting problems. Cognitive performances ranged from extremely low to very superior. Mean number of reasons for referral was 2, with treatment recommendation (55%) and diagnostic clarification (50.7%) being the most common. Mean number of findings from CNA was 5.8; most commonly, a diagnosis of clinically meaningful cognitive impairment (85%), followed by a recommendations for additional services/investigations (77.1%). CNA provides diagnostic clarification and treatment recommendations for youth receiving mental health treatment. Future studies should examine the cost-effectiveness, implementation, and objective impact of CNA in clinical practice. PMID- 28631968 TI - Improving kindergarten readiness in children with developmental disabilities: Changes in neural correlates of response monitoring. AB - Among children diagnosed with developmental delays, difficulties in self regulation are prominent and have been linked to school readiness problems. The current study sought to examine the impact of the Kids in Transition to School (KITS) school readiness intervention program on self-regulation, with a specific focus on response monitoring skills, among children with developmental delays. Children (n = 20 in the KITS group and n = 21 in a services as usual group) were administered a flanker task during which event-related potential data were collected to examine group differences in response monitoring. Findings indicated that children in the KITS group showed significant enhancement of a neural index of response monitoring post-intervention. Specifically, the KITS group showed a significant change in the magnitude of their feedback-related negativity in response to negative performance feedback from baseline to post-intervention, whereas children in the services as usual group did not. There were no significant differences between the groups for the error-related negativity or the error-related positivity on incorrect trials nor were there group differences in behavioral performance on the task at the post-intervention assessment. Overall, these findings provide support for the plasticity of response monitoring skills in young children and support the growing literature demonstrating improved self-regulation outcomes via intervention that enhances children's response monitoring. PMID- 28631969 TI - Cognitive functions among predominantly minority urban adolescents with metabolic syndrome. AB - The rise in the rate of adolescent obesity has led to a concurrent rise in the rate of metabolic syndrome (MetS) among young people. In addition to diabetes and cardiovascular disease, MetS has also been linked to cognitive dysfunction. The goal of this study was to assess whether cognitive differences exist between minority urban adolescents carrying excess weight who meet criteria for MetS as compared to their peers without MetS. Two hundred and ninety-six urban adolescents, predominantly Hispanic and carrying excess weight as defined by a BMI above 25 kg/m2, were screened for MetS and divided into MetS and no MetS groups. All participants completed the CNS Vital Signs (CNS-VS) computerized neurocognitive battery that assesses cognitive domains of Memory, Processing Speed, Reaction Time, Executive Function, Complex Attention, and Cognitive Flexibility. The MetS group (29.2%, n = 84) performed significantly lower on 2 of the 7 cognitive domains: Executive Function (EF) and Cognitive Flexibility. Additionally, waist circumference was determined to be a significant predictor of both these domains. These findings suggest EF is negatively impacted in adolescents with MetS, despite there being no statistical differences between MetS groups on most other measured cognitive domains. Due to the interrelated nature of obesity, waist circumference, and MetS, these findings have larger implications for the obesity epidemic as well. PMID- 28631970 TI - Computerized neuropsychological test performance of youth football players at different positions: A comparison of high and low contact players. AB - The aim of this study was to examine the effects of head impact frequency on the neuropsychological test results of football players who participate in different positions on the team. Based on the biomechanical measures of head impact frequency reported in high school football, a High Contact group (n = 480) consisting of offensive and defensive linemen was compared with a Low Contact group (n = 640) comprised of receivers and defensive backs. The results revealed that the High Contact group obtained poorer performances on the Immediate Post Concussion Assessment and Cognitive Testing (ImPACT) on three Composite scores (Verbal Memory, Visual Motor Speed, Impulse Control) and the Total Symptom score compared to the Low Contact group. The present study is the first, to date, to report differences in the neuropsychological test performances of athletes who participate in high and low contact football positions. The findings raise tentative concerns that youth football players exposed to repetitive head trauma, including subconcussive impacts, may be at risk for lowered neuropsychological functioning and increased symptoms. PMID- 28631971 TI - Rapidly progressive dementia: an unusual cause. AB - Brain metastases are known to be present with a history of increased intra cranial pressure headache, seizures or altered sensorium. Corresponding to the clinical brain metastases are the most feared complication of a systemic cancer. Classically, brain metastases are associated with significant morbidity and are known to present with a history of increased intracranial pressure headache, seizures or altered sensorium. Neuroimaging is usually suggestive of massive peri lesional edema and mass effect surrounding the space occupying lesions. This, however it is not a universal rule. We report a 50-year-old gentleman who presented with rapidly progressive forgetfulness. Interestingly, the patient's neuroimaging discretely showed disproportionate involvement with regards to the clinical picture. The lesions were finally recognized as metastases underscoring the importance of an avid search for a primary systemic malignancy if similar findings are noted on radiology. PMID- 28631972 TI - An Analysis of Self: The Development and Assessment of a Measure of Selfobject Needs. AB - Based on the psychoanalysis of adults with borderline and narcissistic personality disorder symptoms, Kohut ( 1971 , 1977, 1980, 1984) formulated a theory of self psychology that emphasized the importance of early developmental experiences; most centrally, the empathic attunement of caregivers as key ingredients for fostering the capacity for healthy self-regulation and interpersonal relations. Kohut elaborated 3 critical selfobject needs (i.e., idealizing, mirroring, and twinship) that were ideally satiated by these early experiences, deeming the fulfillment of these needs as essential for developing a healthy sense of self. The research presented here sought to develop a self report measure, titled the Arble Estimate of Selfobject Pursuits (AESOP), capable of assessing the selfobject needs identified by Kohut. Across 2 studies involving 686 and 672 respondents, participants completed the AESOP. In the first study, an exploratory factor analysis supported the theorized 3-factor structure. In the second study, a confirmatory factor analysis indicated adequate-to-strong model fit and cluster analysis with theoretically related measures supported the AESOP's discriminant and convergent validity. Further research is encouraged to elaborate the implications of these preliminary findings. PMID- 28631973 TI - The Lifespan Self-Esteem Scale: Initial Validation of a New Measure of Global Self-Esteem. AB - This article introduces the Lifespan Self-Esteem Scale (LSE), a short measure of global self-esteem suitable for populations drawn from across the lifespan. Many existing measures of global self-esteem cannot be used across multiple developmental periods due to changes in item content, response formats, and other scale characteristics. This creates a need for a new lifespan scale so that changes in global self-esteem over time can be studied without confounding maturational changes with alterations in the measure. The LSE is a 4-item measure with a 5-point response format using items inspired by established self-esteem scales. The scale is essentially unidimensional and internally consistent, and it converges with existing self-esteem measures across ages 5 to 93 (N = 2,714). Thus, the LSE appears to be a useful measure of global self-esteem suitable for use across the lifespan as well as contexts where a short measure is desirable, such as populations with short attention spans or large projects assessing multiple constructs. Moreover, the LSE is one of the first global self-esteem scales to be validated for children younger than age 8, which provides the opportunity to broaden the field to include research on early formation and development of global self-esteem, an area that has previously been limited. PMID- 28631975 TI - Assessing the Unidimensionality of Trait Reactance Using a Multifaceted Model Assessment Approach. AB - This study employed a multifaceted model assessment approach to investigate the dimensionality and nomological network of a popular measure of trait reactance, the Hong Psychological Reactance Scale (HPRS; Hong & Page, 1989 ). To address confusion regarding the scoring and modeling of the HPRS as well as its limited external validity evidence, we tested competing factor models, diagnosed model data misfit, examined relationships between competing factor models and key personality traits, and cross-validated the results. Confirmatory factor analytic results supported modeling the HPRS via a bifactor model and, when this model was applied, trait reactance was negatively related to agreeableness, conscientiousness, and conformity, and positively related to entitlement, as expected. However, we also demonstrated the consequences of championing a 1 factor model by highlighting differences in relationships with external variables. Specifically, although modeling the HPRS scores with the bifactor model resulted in greater model-data fit than the 1-factor model, relationships with external variables based on the 2 models differed negligibly. Moreover, bifactor statistical indexes indicted that scores were essentially unidimensional, providing some support that HPRS scores can be treated as unidimensional in structure. Implications for using and scoring the HPRS are discussed. PMID- 28631974 TI - Personality Disorders Are Not as We Thought: Hierarchical Factor Structure at the Criterion Level. AB - The use of personality disorder (PD) categories persists, despite the evidence against them. An often overlooked reason for this is the fact that the true structure underlying the Diagnostic and Statistical Manual of Mental Disorders (DSM) taxonomy is still unknown: We cannot be certain which disorders are valid, and which ones are arbitrary mixtures of heterogeneous traits. To address this gap, we factor analyzed the Personality Diagnostic Questionnaire (PDQ-4+; Hyler, 1994 ) at the criterion level in a mixed clinical and nonclinical sample of 2,519 individuals. The resulting structure was more similar to current dimensional taxonomies than to the DSM classification at all hierarchical levels. Whereas paranoid and antisocial PDs-and to a lesser extent avoidant, dependent, depressive, and schizoid PDs-were fairly homogeneous, all other disorders turned out to be combinations of 2 or 3 unrelated dimensions. Our results strongly support the structure of empirically based dimensional taxonomies and relocate DSM criteria within this emerging framework, thus contributing to preserving much of the knowledge accumulated to date. PMID- 28631976 TI - The Thorny Relation Between Measurement Quality and Fit Index Cutoffs in Latent Variable Models. AB - Latent variable modeling is a popular and flexible statistical framework. Concomitant with fitting latent variable models is assessment of how well the theoretical model fits the observed data. Although firm cutoffs for these fit indexes are often cited, recent statistical proofs and simulations have shown that these fit indexes are highly susceptible to measurement quality. For instance, a root mean square error of approximation (RMSEA) value of 0.06 (conventionally thought to indicate good fit) can actually indicate poor fit with poor measurement quality (e.g., standardized factors loadings of around 0.40). Conversely, an RMSEA value of 0.20 (conventionally thought to indicate very poor fit) can indicate acceptable fit with very high measurement quality (standardized factor loadings around 0.90). Despite the wide-ranging effect on applications of latent variable models, the high level of technical detail involved with this phenomenon has curtailed the exposure of these important findings to empirical researchers who are employing these methods. This article briefly reviews these methodological studies in minimal technical detail and provides a demonstration to easily quantify the large influence measurement quality has on fit index values and how greatly the cutoffs would change if they were derived under an alternative level of measurement quality. Recommendations for best practice are also discussed. PMID- 28631977 TI - A Profile-Based Framework for Factorial Similarity and the Congruence Coefficient. AB - We present a novel profile-based framework for understanding factorial similarity in the context of exploratory factor analysis in general, and for understanding the congruence coefficient (a commonly used index of factor similarity) specifically. First, we introduce the profile-based framework articulating factorial similarity in terms of 3 intuitive components: general saturation similarity, differential saturation similarity, and configural similarity. We then articulate the congruence coefficient in terms of these components, along with 2 additional profile-based components, and we explain how these components resolve ambiguities that can be-and are-found when using the congruence coefficient. Finally, we present secondary analyses revealing that profile-based components of factorial are indeed linked to experts' actual evaluations of factorial similarity. Overall, the profile-based approach we present offers new insights into the ways in which researchers can examine factor similarity and holds the potential to enhance researchers' ability to understand the congruence coefficient. PMID- 28631978 TI - Structural and Predictive Properties of the Emotional Quotient Inventory Youth Version-Short Form (EQ-i:YV[S]). AB - Emotional intelligence (EI) is a popular construct with concentrated areas of application in education and health contexts. There is a need for reliable and valid measurement of EI in young people, with brief yet sensitive measures of the construct preferable for use in time-limited settings. However, the proliferation of EI measures has often outpaced rigorous psychometric evaluation (Gignac, 2009 ). Using data from 849 adolescents (407 females, 422 males) aged 11 to 16 years (M age 13.4, SD = 1.2 years), this article systematically examines the structural and predictive properties of a frequently employed measure of adolescent trait EI the Emotional Quotient Inventory Youth Version-Short Form (EQ-i:YV[S]); Bar-On & Parker, 2000 ). Although the intended multidimensional factor structure was recovered through confirmatory factor analysis, the statistical and conceptual coherency of the underlying model was inadequate. Using a multitrait-multimethod approach, the EQ-i:YV(S) was found to converge with other measures of EI; however, evidence for divergent validity (Big Five personality dimensions) was less robust. Predictive utility for adolescent mental health outcomes (depression, disruptive behavior) was also limited. Findings suggest that use of the EQ-i:YV(S) for predictive or evaluative purposes should be avoided until refinements to the scale are made. PMID- 28631979 TI - Comparative study of the production of extracellular beta-glucosidase by four different strains of Aspergillus using submerged fermentation. AB - Four strains of Aspergillus (Aspergillus niger CDBB-H-176, A. niger CDBB-H-175, A. niger ATCC 9642, and Aspergillus terreus CDBB-H-194) were used to produce extracellular beta-glucosidase. Using an orthogonal experimental design (L9), we optimized the parameters of culture medium to maximize the activity of beta glucosidase. The optimal conditions (same for the four strains) were as follows: temperature, 30 degrees C; pH, 6.0; orbital agitation, 200 rpm; concentration of sucrose, 0.5% (w/v). The most productive strain was A. niger CDBB-H-175, with a yield of 701.2 U/mL. In a second stage, we optimized (L18) the concentration of nutrients in the culture medium to determine whether this modification would increase the production of beta-glucosidase. The optimal conditions for A. niger CDBB-H-175 were as follows (%, w/v): NaNO3, 0.3; KCl, 0.3; KH2PO4, 0.15; NH4NO3, 0.1; NH4H2PO4, 0.1; MgSO4 . 7H2O, 0.05; yeast extract, 0.1. The production of beta-glucosidase under these conditions was 1207.9 U/mL. Enzymatic assays were used to characterize the enzyme; the optimum temperature and pH of beta glucosidase produced by the four selected micro-organisms were found to be 65 degrees C and 5.0, respectively. We determined the Michaelis-Menten constants (Km) only for A. niger CDBB-H-175 and CDBB-H-176; the values were 2.7 and 2.2 mM, respectively. PMID- 28631980 TI - Orexin research: patent news from 2016. AB - INTRODUCTION: The orexin system consists of two G-protein-coupled receptors, orexin 1 and orexin 2 and two endogenous ligands, orexin A and orexin B . It is evolutionarily highly conserved. It is involved in the promotion of wakefulness as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists are successfully used to treat primary insomnia. The major open questions are now related to the clinical validation of Ox1 selective antagonists. A strong rationale exists for orexin agonism in the treatment of narcolepsy with cataplexy. Areas covered: The patent applications from Thomson Reuters Integrity Database added in 2016 are summarized and discussed together with the most important findings published in the scientific literature. Expert opinion: The large number of patents shows the continuing interest in the orexin receptors as targets. The structural scope covered is narrow. Questions about novelty and inventiveness are evident. The additional information published on X ray structures on both orexin receptors opens new ways of optimizing antagonists. It might also influence the efforts in the identification of orexin receptor agonists. Being potential treatments for narcolepsy with cataplexy. PMID- 28631981 TI - Patient-centered Radiology: Where Are We, Where Do We Want to Be, and How Do We Get There? AB - Purpose The objectives of the Radiological Society of North America (RSNA) Patient-Centered Radiology Steering Committee survey were to (a) assess RSNA members' general attitudes and experiences concerning patient-centered radiology, with specific attention paid to radiologist-to-patient communication; (b) examine the members' barriers to communicating more directly with patients; and (c) explore their perceptions of how such barriers can be overcome. Materials and Methods A total of 5999 radiologists were invited by e-mail to complete an anonymous electronic survey developed by the Steering Committee and the RSNA Department of Research. Participants were asked to identify aspects of patient centered care important to their practice, report on their interactions with patients, and share their opinions on radiologist-patient communication. Statistical analyses were performed by using the chi2 test and analysis of variance. Results The response rate was 12% (n = 694, 109 invitations were undeliverable). Most respondents (89%, 611 of 684) agreed that promoting awareness of the role of radiology in patients' overall health care is important to how they practice. The majority (73%, 421 of 575) reported that time or workload frequently prevented them from communicating directly with patients. The majority (74%, 423 of 572) reported that a personal sense of satisfaction was likely to motivate them to communicate more directly with patients, but many commented that changes to reimbursement and compensation would help them communicate with patients more directly. Conclusion Many radiologists support the concept of communicating more directly with patients but report they are constrained by time or workload. Changes to reimbursement schemes may help mitigate these barriers to one crucial aspect of patient-centered care. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28631983 TI - 'Worse than HIV': The logics of cancer screening avoidance in Swaziland. AB - This article shows the consequences of competing global health agendas within differential clinical and social worlds. Specifically, it examines how HIV's prominence in local clinical programming in Swaziland influences cervical cancer screening rates. Drawing on 2014 ethnographic research conducted in a semi-urban town in Swaziland, the interview and participant observation data show the relative scarcity of cervical cancer care and the consequences of HIV/AIDS funding and programming dominance. 20 women and 7 health workers were interviewed in homes, clinics and small businesses. Data were analysed using frameworks of medicoscapes and therapeutic citizenship. Results show that women's patterns of screening avoidance were based on lengthy diagnostic procedures, treatment expense, therapeutic travel to neighbouring South Africa, and frequent therapeutic failure. In sum, avoidance of cervical screening in Swaziland has structural components, and is a product of organisational and political choices at local and global levels. This study challenges culturalist assumptions about African women's avoidance of cervical cancer screening. In the future, delivering successful cervical cancer screening in Swaziland will depend on expanding cancer screening and treatment, which should be informed by perceptions of clinical care held by the very women public health practitioners aim to keep healthy. PMID- 28631982 TI - Carotid intraplaque hemorrhage on vessel wall MRI does not correlate with TCD emboli monitoring in patients with recently symptomatic carotid atherosclerosis. AB - Background Carotid intraplaque hemorrhage (IPH) seen on vessel wall MRI is associated with an increased risk of stroke or transient ischemic attack, as are microembolic signals (MES) detected by transcranial Doppler (TCD). We sought to examine the association between IPH and MES in acute stroke patients with symptomatic carotid atherosclerosis. Methods Through a retrospective chart review, we included patients from 2011 to 2013 with acute ischemic stroke due to carotid atherosclerosis of varying stenosis who had both 3D volumetric MRI of the neck and TCD emboli monitoring. Results Twenty-four patients met the inclusion criteria. Mean time from stroke to MRI was 1.4 +/- 1.9 days and to TCD was 2.6 +/ 2.4 days. MES was seen in 10 patients (42%) and IPH was present in seven patients (29%), but we did not find a relationship between MES and IPH ( p = 0.64). Conclusion In patients with recent acute ischemic stroke attributed to carotid atherosclerosis, we did not detect an association between the presence of IPH and MES. While this small study may be underpowered, an alternate explanation is that MES and IPH reflect vulnerable carotid atherosclerosis through different mechanisms. This untested concept warrants prospective study in a larger cohort. PMID- 28631984 TI - Effect of exercise interventions on perceived fatigue in people with multiple sclerosis: synthesis of meta-analytic reviews. AB - Although exercise training has been advocated as a nonpharmacological treatment for multiple sclerosis (MS) related fatigue, no consensus exists regarding its effectiveness. To address this, we collated meta-analytic reviews that explored the effectiveness of exercise training for the treatment of MS-related fatigue. We searched five online databases for relevant reviews, published since 2005, and identified 172 records. Five reviews were retained for systematic extraction of information and evidence quality analysis. Although our review synthesis indicated that exercise training interventions have a moderate effect on fatigue reduction in people with MS, no clear insight was obtained regarding the relative effectiveness of specific types or modes of exercise intervention. Moreover, Grading of Recommendation Assessment, Development and Evaluation revealed that the overall quality of evidence emanating from these five reviews was 'very low'. PMID- 28631985 TI - Effect of a Standardized Protocol of Antibiotic Therapy on Surgical Site Infection after Laparoscopic Surgery for Complicated Appendicitis. AB - BACKGROUND: Although it is accepted that complicated appendicitis requires antibiotic therapy to prevent post-operative surgical infections, consensus protocols on the duration and regimens of treatment are not well established. This study aimed to compare the outcome of post-operative infectious complications in patients receiving old non-standardized and new standard antibiotic protocols, involving either 5 or 10 days of treatment, respectively. METHODS: We enrolled 1,343 patients who underwent laparoscopic surgery for complicated appendicitis between January 2009 and December 2014. At the beginning of the new protocol, the patients were divided into two groups; 10 days of various antibiotic regimens (between January 2009 and June 2012, called the non standardized protocol; n = 730) and five days of cefuroxime and metronidazole regimen (between July 2012 and December 2014; standardized protocol; n = 613). We compared the clinical outcomes, including surgical site infection (SSI) (superficial and deep organ/space infections) in the two groups. RESULTS: The standardized protocol group had a slightly shorter operative time (67 vs. 69 min), a shorter hospital stay (5 vs. 5.4 d), and lower medical cost (US$1,564 vs. US$1,654). Otherwise, there was no difference between the groups. No differences were found in the non-standardized and standard protocol groups with regard to the rate of superficial infection (10.3% vs. 12.7%; p = 0.488) or deep organ/space infection (2.3% vs. 2.1%; p = 0.797). CONCLUSIONS: In patients undergoing laparoscopic surgery for complicated appendicitis, five days of cefuroxime and metronidazole did not lead to more SSIs, and it decreased the medical costs compared with non-standardized antibiotic regimens. PMID- 28631986 TI - Accuracy statistics in predicting Independent Activities of Daily Living (IADL) capacity with comprehensive and brief neuropsychological test batteries. AB - This investigation was designed to determine the predictive accuracy of a comprehensive neuropsychological and brief neuropsychological test battery with regard to the capacity to perform instrumental activities of daily living (IADLs). Accuracy statistics that included measures of sensitivity, specificity, positive and negative predicted power and positive likelihood ratio were calculated for both types of batteries. The sample was drawn from a general neurological group of adults (n = 117) that included a number of older participants (age >55; n = 38). Standardized neuropsychological assessments were administered to all participants and were comprised of the Halstead Reitan Battery and portions of the Wechsler Adult Intelligence Scale-III. A comprehensive test battery yielded a moderate increase over base-rate in predictive accuracy that generalized to older individuals. There was only limited support for using a brief battery, for although sensitivity was high, specificity was low. We found that a comprehensive neuropsychological test battery provided good classification accuracy for predicting IADL capacity. PMID- 28631987 TI - Development of a scale of executive functioning for the RBANS. AB - The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a cognitive battery that contains scales of several cognitive abilities, but no scale in the instrument is exclusively dedicated to executive functioning. Although the subtests allow for observation of executive-type errors, each error is of fairly low base rate, and healthy and clinical normative data are lacking on the frequency of these types of errors, making their significance difficult to interpret in isolation. The aim of this project was to create an RBANS executive errors scale (RBANS EE) with items comprised of qualitatively dysexecutive errors committed throughout the test. Participants included Veterans referred for outpatient neuropsychological testing. Items were initially selected based on theoretical literature and were retained based on item-total correlations. The RBANS EE (a percentage calculated by dividing the number of dysexecutive errors by the total number of responses) was moderately related to each of seven established measures of executive functioning and was strongly predictive of dichotomous classification of executive impairment. Thus, the scale had solid concurrent validity, justifying its use as a supplementary scale. The RBANS EE requires no additional administration time and can provide a quantified measure of otherwise unmeasured aspects of executive functioning. PMID- 28631988 TI - Evidence of practice effect in CANTAB spatial working memory test in a cohort of patients with mild cognitive impairment. AB - The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a system of neuropsychological tests frequently used to track the progression of cognitive deficits in mild cognitive impairment (MCI) and Alzheimer's disease (AD). We investigated test-retest reliability in seven CANTAB tests. Twenty-five MCI patients, with either AD-like or conflicting/normal cerebrospinal fluid profiles underwent three testing sessions at 6-month intervals, including the following tests: Reaction Time and Rapid Visual Information Processing (assessing attention and reaction times); Delayed Matching-to-Sample, Paired Associates Learning, Spatial Recognition Memory and Pattern Recognition Memory (assessing memory); Spatial Working Memory (assessing executive functions). No significant difference was found when comparing the two groups. Many CANTAB measures obtained low or marginal test-retest coefficients. We observed a marked improvement in Spatial Working Memory (SWM) in both groups when comparing the baseline performance with the 6-month follow-up, but no difference in performance between 6- and 12-month follow-ups. A similar trend was documented in Paired Associates Learning (PAL), but the effect size was small. Such improvement may result from a practice effect, likely due to the learning of an effective strategy. Our evidence raised an important issue concerning the need for methodological caution when interpreting the results of longitudinal studies using SWM and PAL. PMID- 28631989 TI - Impact of rapport on neuropsychological test performance. AB - Guides to neuropsychological assessment emphasize the importance of establishing rapport; however, there has been a minimal amount of empirical investigation of the impact of rapport on neuropsychological test performance. In this experiment, participants (N = 98) were randomly assigned to take neuropsychological tests in either a high or low rapport condition. Results showed that we were able to manipulate the level of rapport and that the level of rapport had a significant effect on the Grooved Pegboard Test and the Controlled Oral Word Association Test, with other tests nearing statistical significance. These results suggest that the level of rapport may affect neuropsychological test performance. PMID- 28631990 TI - Corrigendum. PMID- 28631992 TI - Validity of a verbal incidental learning measure from the WAIS-IV in older adults. AB - Incidental memory may reflect a form of learning in everyday life, although it is not consistently evaluated during standard neuropsychological evaluations. Further validation of a recently created measure of verbal Incidental Learning (IL) from the Wechsler Adult Intelligence Scale-IV is necessary to understand the utility of such a measure in clinical settings. Sixty-eight adults aged 50 to 89 were recruited from a Cognitive Disorders Clinic while receiving a standard neuropsychological assessment, along with two additional measures of IL. IL-Total Score was significantly correlated with immediate and delayed memory trials from standard neuropsychological tests (rs = .43 to .73, ps < .001, ds = 0.94-2.14), with worse IL performance being associated with lower memory abilities. Participants with probable Alzheimer's disease performed worse on the IL-Total Score than participants with Mild Cognitive Impairment, t(39.997) = 5.46, p < .001, d = 1.13. Given the strong relationships between this IL task and traditional memory measures in our sample, and the discrimination of IL-Total Score performance among diagnostic groups despite its short administration time, this IL task may play a role as a measure of memory in brief cognitive evaluations. PMID- 28631993 TI - Ovarian ecdysteroid biosynthesis and female germline stem cells. AB - The germline stem cells (GSCs) are critical for gametogenesis throughout the adult life. Stem cell identity is maintained by local signals from a specialized microenvironment called the niche. However, it is unclear how systemic signals regulate stem cell activity in response to environmental cues. In our previous article, we reported that mating stimulates GSC proliferation in female Drosophila. The mating-induced GSC proliferation is mediated by ovarian ecdysteroids, whose biosynthesis is positively controlled by Sex peptide signaling. Here, we characterized the post-eclosion and post-mating expression pattern of the genes encoding the ecdysteroidogenic enzymes in the ovary. We further investigated the biosynthetic functions of the ovarian ecdysteroid in GSC maintenance in the mated females. We also briefly discuss the regulation of the ecdysteroidogenic enzyme-encoding genes and the subsequent ecdysteroid biosynthesis in the ovary of the adult Drosophila. PMID- 28631994 TI - Gene expression and morphogenesis during the deposition of Drosophila wing cuticle. AB - The exoskeleton of insects and other arthropods is a very versatile material that is characterized by a complex multilayer structure. In Sobala and Adler (2016) we analyzed the process of wing cuticle deposition by RNAseq and electron microscopy. In this extra view we discuss the unique aspects of the envelope the first and most outermost layer and the gene expression program seen at the end of cuticle deposition. We discussed the role of undulae in the deposition of cuticle and how the hydrophobicity of wing cuticle arises. PMID- 28631995 TI - Monitoring the effect of pathogenic nematodes on locomotion of Drosophila larvae. AB - One of the key factors that determine the interaction between hosts and their parasites is the frequency of their interactions, which depends on the locomotory behavior of both parts. To address host behavior we used natural infections involving insect pathogenic nematodes and Drosophila melanogaster larvae as hosts. Using a modified version of a recently described method (FIMTrack) to assess several parameters in larger sets of animals, we initially detected specific differences in larval food searching when comparing Drosophila strains. These differences were further influenced by the presence of nematodes. Given a choice, Drosophila larvae clearly avoided nematodes irrespective of their genetic background. Our newly developed methods will be useful to test candidate genes and pathways involved in host/pathogen interactions in general and to assess specific parameters of their interaction. PMID- 28631996 TI - Role of diffusion-weighted imaging in skull base lesions: A pictorial review. AB - Skull base lesions can be related to wide number of pathologies including infections, benign and malignant tumors. Accurate diagnosis and differentiation between these entities is important for prompt and appropriate treatment. However, computed tomography and routine magnetic resonance imaging techniques only provide information on the extent of the lesions, with limited ability to differentiate between benign and malignant lesions. Diffusion-weighted imaging can help in many such situations by providing additional information, including help in differentiating benign from malignant lesions, so that appropriate treatment can be initiated. In this review article, we illustrate the imaging findings of the spectrum of skull base lesions, emphasizing the role of diffusion weighted imaging in this domain. PMID- 28631997 TI - Expression and Purification of a Functional Porcine Soluble Triggering Receptor Expressed on Myeloid Cells 1. AB - Triggering receptor expressed on myeloid cells 1 (TREM-1) plays a vital role in the pathogen-triggered amplification loop required for proinflammatory responses. Blockade of TREM-1 signaling may inhibit expansion of sepsis and prolong survival of animals. In the present study, the gene of porcine soluble TREM-1 was cloned and expressed in E. coli. After purification, the bioactivity of recombinant porcine soluble TREM-1 was tested in vitro on porcine alveolar macrophages. The results showed that supplementation with the recombinant porcine sTREM-1 protein rapidly and dose-dependently attenuated the upregulation of cytokines (IL-1beta, IL-2, IL-4, IL-8, IL-10, IL-12, IL-16, IL-18, and TNF-alpha) caused by LPS stimulation in the cultured porcine alveolar macrophages. These results indicate that the recombinant porcine sTREM-1 protein can prevent TREM-1-mediated hyperinflammatory responses after exposure to LPS. PMID- 28631998 TI - Relevance of anxiety in the perinatal period: prospective study in a Hungarian sample. AB - There is increasing evidence that anxiety occurs frequently during pregnancy and can be one of the most important risk factors and predictors of postpartum depression (PPD). The aim of our study was to investigate whether antenatal anxiety is an independent predictor of PPD. We used the data of 476 women enrolled in a prospective study in a single maternity unit. The first assessment was conducted between 22 and 40 weeks gestation and a second time 8-12 months postpartum. Symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) and the State Trait Anxiety Inventory (STAI). Based on our results, antenatal anxiety measured by a subscale of EPDS has predicted better PPD than the antenatal depressive subscale. However, the most relevant predictor of PPD might be the trait anxiety level of a women measured by STAI Trait Scale, whereas a cutoff value of 38 was identified to indicate higher risk of PPD. PMID- 28631999 TI - Adapting Healthcare Quality Measures to Transgender Individuals. AB - The healthcare system's rapid shift toward value-based payment poses unique quality measurement challenges and new foci for researchers and policy makers. Quality measures that use sex-specific criteria may inappropriately include or exclude transgender individuals. More large-scale studies must be conducted to incorporate transgender individuals into measures that use sex-specific criteria, and "measure stewards" should consider the existing clinical guidelines and recommendations regarding transgender individuals when developing measures. Systems designed only for cisgender individuals will exacerbate existing transgender healthcare disparities unless they are revamped and flexible to transgender individuals' needs. PMID- 28632000 TI - The influence of intrapersonal sensorimotor experiences on the corticospinal responses during action-observation. AB - The coupling of perception and action has been strongly indicated by evidence that the observation of an action primes a response in the observer. It has been proposed that these primed responses may be inhibited when the observer is able to more closely distinguish between self- and other-generated actions - the greater the distinction, then the greater the inhibition of the primed response. This self-other distinction is shown to be enhanced following a period of visual feedback of self-generated action. The present study was designed to examine how sensorimotor experiences pertaining to self-generated action affect primed responses from observed actions. Single-pulse transcranial magnetic stimulation was used to investigate corticospinal activity elicited during the observation of index- and little-finger actions before and after training (self-generated action). For sensorimotor training, participants executed finger movements with or without visual feedback of their own movement. Results showed that the increases in muscle-specific corticospinal activity elicited from action observation persisted after training without visual feedback, but did not emerge following training with visual feedback. This inhibition in corticospinal activity during action-observation following training with vision could have resulted from the refining of internal models of self-generated action, which then led to a greater distinction between "self" and "other" actions. PMID- 28632001 TI - Vasodilator responsiveness in idiopathic pulmonary arterial hypertension: identifying a distinct phenotype with distinct physiology and distinct prognosis. AB - Within the cohort of patients suffering from idiopathic pulmonary arterial hypertension (IPAH) is a group that responds dramatically (VR-PAH) to an acute vasodilator challenge and that has excellent long-term hemodynamic improvement and prognosis on high dose calcium channel blockers compared with vasodilator non responders (VN-PAH). For the purposes of diagnosing VR-PAH, there is to date no test to replace the acute vasodilator challenge. However, recent studies have identified markers that may aid in the identification of VR-PAH, including peripheral blood lymphocyte RNA expression levels of desmogelin-2 and Ras homolog gene family member Q, and plasma levels of provirus integration site for Moloney murine leukemia virus. Genome wide-array studies of peripheral blood DNA have demonstrated differences in disease specific genetic variants between VR-PAH and NR-PAH, with particular convergence on cytoskeletal function pathways and Wnt signaling pathways. These studies offer hope for future non-invasive identification of VR-PAH, and insights into pathogenesis that may lead to novel therapies. Examination of the degree of pulmonary microvascular perfusion in PAH has offered additional insights. During the acute vasodilator challenge, VR-PAH patients demonstrate true vasodilation with recruitment and increased perfusion of the capillary bed, while VN-PAH patients are unable to recruit vasculature. In the very few reports of lung histology, VR-PAH has more medial thickening in the precapillary arterioles, while VN-PAH has the classic histology of PAH, including intimal thickening. VR-PAH is a disorder with a phenotype distinct from VN-PAH and other types of PAH, and should be considered separately in the classification of PAH. PMID- 28632002 TI - Management of prostacyclin side effects in adult patients with pulmonary arterial hypertension. AB - Therapies that target the prostacyclin pathway are considered effective, yet are complex to dose and may cause dose-limiting side effects for patients with pulmonary arterial hypertension (PAH). Careful side effect management and the ability to discern side effects from worsening disease are essential in order for patients to continue, and benefit from, prostacyclin therapy. This manuscript was developed through a collaborative effort of allied health providers with extensive experience in managing patients with PAH who are treated with medications that target the prostacyclin pathway. This article provides an overview of individual prostacyclin pathway therapies approved in the United States, side effects most commonly associated with these therapies, and practical suggestions for side effect management. Most patients will experience significant side effects on prostacyclin therapy. Creating a proactive and careful side effect management program will increase the likelihood that patients are able to stay on therapy and receive the benefits afforded by prostacyclin therapy. PMID- 28632003 TI - Factor Structure of the Urdu Version of the Spence Children's Anxiety Scale in Pakistan. AB - Spence Children's Anxiety Scale (SCAS) is one of the most commonly used self report questionnaires to measure symptoms of anxiety disorders in adolescents. Despite its common use, studies that examine the psychometric properties of SCAS in Pakistan is lacking. Therefore, the purpose of this study was to examine the psychometric properties of the Urdu translated version of the SCAS among adolescents in Pakistan. A total of 1277 students (708 boys and 569 girls), aged 13 to17 years, who had been recruited from 13 schools in Rawalpindi, Pakistan participated in the study. The mean overall anxiety score was significantly higher in girls than males on all the SCAS subscales except for obsessive compulsive disorder. The internal consistency of the Urdu SCAS was good. Confirmatory factor analyses supported six separate factor structures. Results of the study are discussed with reference to the sociocultural milieu of Pakistan and culture sensitive conceptualization of anxiety and its subtypes. PMID- 28632004 TI - Behavioral Interventions to Reduce Infections in Pediatric Long-term Care Facilities: The Keep It Clean for Kids Trial. AB - Children in pediatric long-term care facilities (pLTCF) represent a highly vulnerable population and infectious outbreaks occur frequently, resulting in significant morbidity, mortality, and resource use. The purpose of this quasi experimental trial using time series analysis was to assess the impact of a 4 year theoretically based behavioral intervention on infection prevention practices and clinical outcomes in three pLTCF (288 beds) in New York metropolitan area including 720 residents, ages 1 day to 26 years with mean lengths of stay: 7.9-33.6 months. The 5-pronged behavioral intervention included explicit leadership commitment, active staff participation, work flow assessments, training staff in the World Health Organization "'five moments of hand hygiene (HH)," and electronic monitoring and feedback of HH frequency. Major outcomes were HH frequency, rates of infections, number of hospitalizations associated with infections, and outbreaks. Mean infection rates/1000 patient days ranged from 4.1-10.4 pre-intervention and 2.9-10.0 post-intervention. Mean hospitalizations/1000 patient days ranged from 2.3-9.7 before and 6.4-9.8 after intervention. Number of outbreaks/1000 patient days per study site ranged from 9 24 pre- and 9-18 post-intervention (total = 95); number of cases/outbreak ranged from 97-324 (total cases pre-intervention = 591 and post-intervention = 401). Post-intervention, statistically significant increases in HH trends occurred in one of three sites, reductions in infections in two sites, fewer hospitalizations in all sites, and significant but varied changes in the numbers of outbreaks and cases/outbreak. Modest but inconsistent improvements occurred in clinically relevant outcomes. Sustainable improvements in infection prevention in pLTCF will require culture change; increased staff involvement; explicit administrative support; and meaningful, timely behavioral feedback. PMID- 28632005 TI - Sleep Problems and Life Satisfaction as Predictors of Health in Men with Sex Chromosome Aneuploidies. AB - More knowledge is needed about men with sex chromosome aneuploidies (SCA). We present self-reported data from 53 men with SCA (Mage = 36.8 years, SD = 12.3, range 19-67). The Health Survey-Short Form (SF-36) measured eight health domains (physical functioning, role-physical, role-emotional, vitality, emotional health, social functioning, pain, general health). The Pittsburgh Sleep Quality Index measured sleep problems. The Personal Wellbeing Index measured satisfaction with eight life domains. Compared to norms, SCA reported poorer health (mean d = 0.80) and more sleep problems (mean d = -0.85). Differences between SCA and norms on personal well-being were small, except lower health satisfaction in SCA (d = 1.06). Seven of eight regression models predicting the SF-36 domains from life satisfaction and sleep problems were significant (explained variance 12.2% to 46.2%), except physical functioning (ns). Clinical assessment/intervention for a broad range of health and sleep problems is indicated for men with SCA. PMID- 28632006 TI - Psychosocial Obstacles to Smoking Cessation Attempts Among Young Adult Sexual Minority Women Who Smoke. AB - Sexual minority women (SMW; i.e., women who identify their sexuality as lesbian, bisexual, or something other than heterosexual) report greater smoking behaviors than their heterosexual counterparts across all ages. We conducted a multivariable regression to examine the correlates of prior smoking cessation attempts and smoking cessation intentions in a sample of young SMW who smoke (N = 338; aged 18-24 years). Covariates included sociodemographic characteristics (i.e., race/ethnicity, sexual identity, age, urbanity), general (i.e., perceived stress), and sexuality-specific (i.e., internalized homophobia) stressors, as well as smoking attitudes and subjective norms. Bisexual women (OR = 1.92, 95% CI: 1.11, 3.31) were more likely than lesbian counterparts to report a prior smoking cessation attempt. Prior cessation attempts were associated with less internalized homophobia (OR = 0.44, 95% CI: 0.27, 0.69) and positive attitudes toward smoking (OR = 2.17, 95% CI: 1.27, 3.70). Smoking cessation intentions in the next month were negatively associated with being a daily smoker (beta = 0.14) and attitudes toward smoking (beta = -0.19). Based on these findings, we underscore the need to address the risk correlates associated with SMW's quit attempts and include these in cessation interventions. PMID- 28632007 TI - What Do Medical Students Do for Self-Care? A Student-Centered Approach to Well Being. AB - : Phenomenon: Despite the promotion of medical student health and wellness through recent program and curricular changes, research continues to show that medical education is associated with decreased well-being in medical students. Although many institutions have sought to more effectively assess and improve self-care in medical students, no self-care initiatives have been designed using the explicit perspectives of students themselves. APPROACH: Using concept mapping methodology, the research team created a student-generated taxonomy of self-care behaviors taken from a national sample of medical students in response to a brainstorming prompt. The research team examined how students' conceptualizations of self-care may be organized into a framework suitable for use in programming and curricular change in medical education. FINDINGS: Ten clusters of self-care activities were identified: nourishment, hygiene, intellectual and creative health, physical activity, spiritual care, balance and relaxation, time for loved ones, big picture goals, pleasure and outside activities, and hobbies. Using results of the two-dimensional scaling analysis, students' individual self-care behaviors were organized within two orthogonal dimensions of self-care activities. Insights: This concept map of student-identified self-care activities provides a starting point for better understanding and ultimately improving medical student self-care. Students' brainstormed responses fit within a framework of varying levels of social engagement and physical-psychological health that included a wide range of solitary, social, physical, and mental health behaviors. As students' preferred self-care practices did not often include programmatic activities, medical educators may benefit from consulting this map as they plan new approaches to student self-care and in counseling individual students searching for more effective ways to ease the burdens of medical school. PMID- 28632008 TI - A Cloud With a Silver Lining: Helping Students Learn About Professionalism. AB - PROBLEM: Educators face many challenges in teaching professionalism. Despite attempts to define professionalism, it remains abstract for students and often not fully appreciated until they are in clinic. Without a way to make it personally relevant, students will likely be less motivated to learn. INTERVENTION: We used student-generated word clouds to facilitate reflection and discussions, thereby helping students make their perceptions of professionalism more explicit. Group discussion was followed by a 5-minute written reflection. Word clouds created in Semesters 1 and 7 enabled students to compare perceptions at two points in the curriculum. CONTEXT: The George Washington University Doctor of Physical Therapy Program is a 3-year, 8-semester, 109-credit postgraduate program that includes 34 weeks of clinical practice. Reflection is foundational to the curriculum, and students reflect on their learning and professional growth each semester. Historically, students were introduced to professionalism in Semester 1 using explicit instructional strategies. Despite the wealth of resources, readings, and discussions, engagement remained challenging. OUTCOME: Student-generated word clouds created a personally relevant visual from which uniquely designed prompts were created to facilitate discussion. Having students compare word clouds across semesters enabled them to identify what, when, how, and where they learned about professionalism. Word clouds, categorized words, and 5-minute written reflections provided evidence of individual and collective changes in student perceptions. LESSONS LEARNED: Students will engage in rich discussions on professionalism if it is personally relevant. Anonymity can foster discussion on personal characteristics and biases. Visualization of student generated, narrative data enhanced reflection and discussion. Comparing word clouds from two points in time helped students articulate changes in their perceptions of professionalism. A 5-minute reflection can be a powerful learning tool for students and faculty. Outcomes demonstrated the value of designing interventions grounded in the educational principles. PMID- 28632009 TI - Self-Observation and Peer Feedback as a Faculty Development Approach for Problem Based Learning Tutors: A Program Evaluation. AB - PROBLEM: Good teaching requires spontaneous, immediate, and appropriate action in response to various situations. It is even more crucial in problem-based learning (PBL) tutorials, as the tutors, while directing students toward the identification and attainment of learning objectives, must stimulate them to contribute to the process and provide them with constructive feedback. PBL tutors in medicine lack opportunities to receive feedback from their peers on their teaching strategies. Moreover, as tutorials provide little or no time to stop and think, more could be learned by reflecting on the experience than from the experience itself. We designed and evaluated a faculty development approach to developing PBL tutors that combined self-reflection and peer feedback processes, both powerful techniques for improving performance in education. INTERVENTION: We developed an observation instrument for PBL facilitation to be used both by tutors to self-observe and reflect on own teaching strategies and by peers to observe and provide feedback to tutors. Twenty PBL sessions were video-recorded. Tutors completed the instrument immediately after their PBL session and again while watching their video-recorded session (self-observation). A group of three observers completed the instrument while watching each recorded session and provided feedback to each tutor (peer observation and feedback). We investigated tutors' perceptions of the feasibility and acceptability of the approach and gathered data on its effectiveness in enhancing tutors' facilitation skills. CONTEXT: The preclinical medical curriculum at the University of Geneva is essentially taught by PBL. A new program of faculty development based on self observation and peer feedback was offered to voluntary tutors and evaluated. OUTCOME: Our results suggest that self-observation and peer feedback, supported by an instrument, can be effective in enhancing tutors' facilitation skills. Reflection on self-observation raised teachers' awareness of the effectiveness of the strategies they used to foster student learning. This motivated a need to change their teaching practice. However, for the changes to become operative, peer feedback was required, providing the cues and strategies needed to improve the facilitation skills. LESSONS LEARNED: Peer coaching was considered feasible and useful to improve tutors' facilitation skills. Evaluating the program made it possible to assess tutors' needs and the reasons underlying their difficulties, and this in turn provided the basis for advanced workshops. Nonetheless, aspects related to logistics and the time constraints of such an individualized approach, as well as the cultural appropriation of peer coaching, might be obstacles that need to be addressed. PMID- 28632010 TI - Designing a National Longitudinal Faculty Development Curriculum Focused on Educational Scholarship: Process, Outcomes, and Lessons Learned. AB - PROBLEM: Clinical educators at U.S. academic health centers are frequently disadvantaged in the academic promotion system, lacking needed faculty development, mentoring, and networking support. INTERVENTION: In 2006, we implemented the national Educational Scholars Program to offer faculty development in educational scholarship for early career educators in pediatrics. We aimed to provide them with skills, experience, and initial success in educational scholarship and dissemination. The 3-year curriculum is delivered in interactive sessions at the annual pediatric academic meetings and online intersession modules. Curriculum content progresses from educational scholarship and implementing scholarly projects to dissemination and professional networking. Intersession modules address project planning, building an educator portfolio, reviewing the literature, using technology, authorship, and peer review. Concurrently, all scholars must complete a mentored educational project and demonstrate national dissemination of a peer-reviewed product to obtain a Certificate of Excellence in Educational Scholarship. CONTEXT: The setting of this study was a national, longitudinal, cohort-based faculty development program built within the Academic Pediatric Association, a 2,000-member professional organization. OUTCOME: In 10 years, the Educational Scholars Program has enrolled 172 scholars in 8 cohorts; 94 have graduated so far. We describe how formative evaluation guided curriculum refinement and process improvement. Summative evaluations show that faculty and scholars were satisfied with the program. Participant outcomes from Cohort 1, assessed at Kirkpatrick's four levels of evaluation, demonstrate increases in scholarly productivity, leadership activities, and academic promotions. LESSONS LEARNED: Curriculum building is a dynamic process of ongoing evaluation and modification. Our program benefited from designing an integrated and focused curriculum, developing educational principles to guide program improvements, creating curricular tools to help learners organize and document their efforts, supporting project-based learning with expert mentoring, and facilitating peer and faculty networking and collaboration. A national, longitudinal faculty development program can support growth in academic knowledge and skills, promote professional networking, and thereby enrich educators' career opportunities. PMID- 28632011 TI - Essential Public Health Competencies for Medical Students: Establishing a Consensus in Family Medicine. AB - : Phenomenon: The integration of public health (PH) competency training into medical education, and further integration of PH and primary care, has been urged by the U.S. Institute of Medicine. However, PH competencies are numerous, and no consensus exists over which competencies are most important for adoption by current trainees. Our objective was to conduct a group concept mapping exercise with stakeholders identifying the most important and feasible PH skills to incorporate in medical and residency curricula. APPROACH: We utilized a group concept mapping technique via the Concept System Global Max ( http://www.conceptsystems.com ), where family medicine educators and PH professionals completed the phrase, "A key Public Health competency for physicians-in-training to learn is ..." with 1-10 statements. The statement list was edited for duplication and other issues; stakeholders then sorted the statements and rated them for importance and feasibility of integration. Multidimensional scaling and cluster analysis were used to create a two dimensional point map of domains of PH training, allowing visual comparison of groupings of related ideas and relative importance of these ideas. FINDINGS: There were 116 nonduplicative statements (225 total) suggested by 120 participants. Three metacategories of competencies emerged: Clinic, Community & Culture, Health System Understanding, and Population Health Science & Data. Insights: We identified and organized a set of topics that serve as a foundation for the integration of family medicine and PH education. Incorporating these topics into medical education is viewed as important and feasible by family medicine educators and PH professions. PMID- 28632012 TI - Medical School Outcomes, Primary Care Specialty Choice, and Practice in Medically Underserved Areas by Physician Alumni of MEDPREP, a Postbaccalaureate Premedical Program for Underrepresented and Disadvantaged Students. AB - PROBLEM: Minorities continue to be underrepresented as physicians in medicine, and the United States currently has a number of medically underserved communities. MEDPREP, a postbaccalaureate medical school preparatory program for socioeconomically disadvantaged or underrepresented in medicine students, has a stated mission to increase the numbers of physicians from minority or disadvantaged backgrounds and physicians working with underserved populations. This study aims to determine how MEDPREP enhances U.S. physician diversity and practice within underserved communities. INTERVENTION: MEDPREP recruits disadvantaged and underrepresented in medicine students to complete a 2-year academic enhancement program that includes science coursework, standardized test preparation, study/time management training, and emphasis on professional development. Five hundred twenty-five disadvantaged or underrepresented students over 15 years completed MEDPREP and were tracked through entry into medical practice. CONTEXT: MEDPREP accepts up to 36 students per year, with two thirds coming from the Midwest region and another 20% from nearby states in the South. Students complete science, test preparation, academic enhancement, and professionalism coursework taught predominantly by MEDPREP faculty on the Southern Illinois University Carbondale campus. Students apply broadly to medical schools in the region and nation but are also offered direct entry into our School of Medicine upon meeting articulation program requirements. OUTCOME: Seventy-nine percent of students completing MEDPREP became practicing physicians. Fifty-eight percent attended public medical schools, and 62% attended medical schools in the Midwest. Fifty-three percent of program alumni chose primary care specialties compared to 34% of U.S. physicians, and MEDPREP alumni were 2.7 times more likely to work in medically underserved areas than physicians nationally. LESSONS LEARNED: MEDPREP increases the number of disadvantaged and underrepresented students entering and graduating from medical school, choosing primary care specialties, and working in medically underserved areas. MEDPREP may therefore serve as a model for increasing physician diversity and addressing the needs of medically underserved communities. PMID- 28632013 TI - Task Demands in OSCEs Influence Learning Strategies. AB - THEORY: Models on pre-assessment learning effects confirmed that task demands stand out among the factors assessors can modify in an assessment to influence learning. However, little is known about which tasks in objective structured clinical examinations (OSCEs) improve students' cognitive and metacognitive processes. Research is needed to support OSCE designs that benefit students' metacognitive strategies when they are studying, reinforcing a hypothesis-driven approach. With that intent, hypothesis-driven physical examination (HDPE) assessments ask students to elicit and interpret findings of the physical exam to reach a diagnosis ("Examine this patient with a painful shoulder to reach a diagnosis"). HYPOTHESES: When studying for HDPE, students will dedicate more time to hypothesis-driven discussions and practice than when studying for a part-task OSCE ("Perform the shoulder exam"). It is expected that the whole-task nature of HDPE will lead to a hypothesis-oriented use of the learning resources, a frequent use of adjustment strategies, and persistence with learning. METHOD: In a mixed methods study, 40 medical students were randomly paired and filmed while studying together for two hypothetical OSCE stations. Each 25-min study period began with video cues asking to study for either a part-task OSCE or an HDPE. In a crossover design, sequences were randomized for OSCEs and contents (shoulder or spine). Time-on-task for discussions or practice were categorized as "hypothesis-driven" or "sequence of signs and maneuvers." Content analysis of focus group interviews summarized students' perception of learning resources, adjustment strategies, and persistence with learning. RESULTS: When studying for HDPE, students allocate significantly more time for hypothesis-driven discussions and practice. Students use resources contrasting diagnoses and report persistence with learning. When studying for part-task OSCEs, time-on-task is reversed, spent on rehearsing a sequence of signs and maneuvers. CONCLUSIONS: OSCEs with similar contents but different task demands lead to opposite learning strategies regarding how students manage their study time. Measuring pre-assessment effects from a metacognitive perspective provides empirical evidence to redesign assessments for learning. PMID- 28632014 TI - Coaching the Coach: A Program for Development of Faculty Portfolio Coaches. AB - PROBLEM: Faculty coaching is recognized as an essential element for effective use of portfolios in undergraduate medical education, yet best practices for training these coaches are uncertain. INTERVENTION: New portfolio coaches participated in a multifaceted training program that included orienting modules, a 7.5-hr training workshop featuring analysis of reflective writing, an Observed Structured Teaching Exercise (OSTE), and subsequent longitudinal coaches' meetings for timely task training. Four desired coaching skills were emphasized in the initial training: creating a safe environment, explicitly using performance data, asking questions that elicit reflection, and guiding the student to develop future goals and plans. We collected and analyzed several outcomes: (a) coaches' self-assessment at key intervals, (b) open-ended written responses to three coaching vignettes, (c) video recordings of the OSTE, and (d) subsequent student evaluation of the coach. In an attempt to capture learning from the workshop, both the responses to written vignettes and the video-recorded encounters were coded for presence or absence of the four desired skills. CONTEXT: Our portfolio and coaching program was instituted as part of a major undergraduate medical education reform. A new cohort of 25 coaches is enrolled with each matriculating student class, and each coach is assigned to work individually with 8-10 students, forming a coaching relationship that continues over 4 years. Coaches are compensated at 5% full-time equivalent. OUTCOME: On coach self-assessment, the majority of coaches reported significant improvement in their perceived ability to assess a student's level of reflection, enhance reflection, use performance data, and guide a student to develop goals and plans. After two semesters, coach perception of improved abilities persisted. Students rated coaches as excellent (82%), reporting that coaches created safe environments (99%), promoted insight (92%), and aided in goal setting (97%). Written responses to vignettes before the OSTE found that several coaches omitted desired behaviors; however, posttraining responses showed no discernable pattern of learning. Coding of the OSTE, in contrast, documented that all coaches demonstrated all four of the desired skills. LESSONS LEARNED: Although coaches reported learning related to key skills, learning was not apparent when responses to written vignettes were examined. In contrast, skills were demonstrated in the OSTE, perhaps due to the added structured tasks as well as anticipation of feedback. In conclusion, this portfolio coach training program achieved its desired aim of providing students with portfolio coaches who demonstrated the desired skills, as reported by both coaches and students. PMID- 28632015 TI - The Associations Between Clerkship Objective Structured Clinical Examination (OSCE) Grades and Subsequent Performance. AB - : Construct: We investigated the extent of the associations between medical students' clinical competency measured by performance in Objective Structured Clinical Examinations (OSCE) during Obstetrics/Gynecology and Family Medicine clerkships and later performance in both undergraduate and graduate medical education. BACKGROUND: There is a relative dearth of studies on the correlations between undergraduate OSCE scores and future exam performance within either undergraduate or graduate medical education and almost none on linking these simulated encounters to eventual patient care. Of the research studies that do correlate clerkship OSCE scores with future performance, these often have a small sample size and/or include only 1 clerkship. APPROACH: Students in USU graduating classes of 2007 through 2011 participated in the study. We investigated correlations between clerkship OSCE grades with United States Medical Licensing Examination Step 2 Clinical Knowledge, Clinical Skills, and Step 3 Exams scores as well as Postgraduate Year 1 program director's evaluation scores on Medical Expertise and Professionalism. We also conducted contingency table analysis to examine the associations between poor performance on clerkship OSCEs with failing Step 3 and receiving poor program director ratings. RESULTS: The correlation coefficients were weak between the clerkship OSCE grades and the outcomes. The strongest correlations existed between the clerkship OSCE grades and the Step 2 CS Integrated Clinical Encounter component score, Step 2 Clinical Skills, and Step 3 scores. Contingency table associations between poor performances on both clerkships OSCEs and poor Postgraduate Year 1 Program Director ratings were significant. CONCLUSIONS: The results of this study provide additional but limited validity evidence for the use of OSCEs during clinical clerkships given their associations with subsequent performance measures. PMID- 28632017 TI - Correlation of ISO 16840-2:2007 impact damping and hysteresis measures for a sample of wheelchair seating cushions. AB - Hysteresis and impact damping measures were made on 37 wheelchair seating cushions according to ISO 16840-2:2007 Wheelchair seating-Part 2: Determination of physical and mechanical characteristics of devices intended to manage tissue integrity-seat cushions. These measures were then correlated using Spearman and Pearson correlations to investigate the relationship between them. Correlations were also conducted on the subset of cushions comprising only those with planar foam construction. Correlation between the hysteresis measures (h250 and h500) and the mean number of rebounds greater in amplitude than 10% of the peak acceleration amplitude (R10%) were weak, as were the correlations between the hysteresis measures and the mean peak first rebound acceleration (aa). Correlations between hysteresis and the mean peak second rebound acceleration (a2), and also hysteresis and the ratio of first and second peak (a2:aa) however were moderate. Results demonstrate that the relationship between these two measures is complex. The assertion implicit in ISO 16840-2:2007 is that the two measures are related, but this study shows that these should not be assumed to be equivalent or used interchangeably. PMID- 28632016 TI - The Bacteroides fragilis pathogenicity island links virulence and strain competition. AB - The mature microbiome is a stable ecosystem that resists perturbation despite constant host exposure to exogenous microbes. However, the microbial mechanisms determining microbiome development and composition are poorly understood. We recently demonstrated that a non-toxigenic B. fragilis (NTBF) strain restricts enteric colonization by an enterotoxigenic (ETBF) strain dependent on a type VI secretion system (T6SS). We show here that a second enterotoxigenic strain is competent to colonize, dependent on the Bacteroides fragilis pathogenicity island (BFPAI). Additional data showing complex environmental regulation of the Bacteroides fragilis toxin (BFT) suggest that virulence factors may be adapted to modify the colonic niche to provide a strain-specific colonization advantage. We conclude that more complex models of host-microbe-microbiome interactions are needed to investigate this hypothesis. PMID- 28632018 TI - Exploring the learnability and usability of a near field communication-based application for semantic enrichment in children with language disorders. AB - Recently, a few software applications (apps) have been developed to enhance vocabulary and conceptual networks to address the needs of children with language impairments (LI), but there is no evidence about their impact and their usability in therapy contexts. Here, we try to fill this gap presenting a system aimed at improving the semantic competence and the structural knowledge of children with LI. The goal of the study is to evaluate learnability, usability, user satisfaction and quality of the interaction between the system and the children. The system consists of a tablet, hosting an app with educational and training purposes, equipped with a Near Field Communication (NFC) reader, used to interact with the user by means of objects. Fourteen preschool children with LI played with the device during one 45-minute speech therapy session. Reactions and feedbacks were recorded and rated. The system proved to be easy to understand and learn, as well as engaging and rewarding. The success of the device probably rests on the integration of smart technology and real, tangible objects. The device can be seen as a valuable aid to support and enhance communication abilities in children with LI as well as typically developing individuals. PMID- 28632019 TI - Underappreciated challenges to pediatric powered mobility - Ways to address them as illustrated by a case report. AB - Rehabilitation Engineering and Assistive Technology Society of North America (RESNA) has published a position paper strongly advocating powered mobility (PM) for children with severe physical limitations (Rosen et al., 2009). Many studies have established that there are gains in social skills and functional mobility. While PM can aid independence, there has been more emphasis on the improvements in socialization rather than the positive changes PM can make in a child's daily living. For example, Bottos and colleagues stated the quality of life did not change for the children in their study (2001). This could be an explanation for why insurance companies deny coverage for PM. However, without coverage for PM, these children face major barriers to mobility and accessibility, even if they are able to use PM at physical therapy. If they obtain PM at home through other funding, transportation still remains an issue. These barriers have not been addressed or only briefly mentioned. We present a case of a 2 years 10 months old boy with rachischisis (cervical level spina bifida) who had impressive gains in both functional communication and social skills through achieving PM. PMID- 28632020 TI - Are patients with hemiplegic stroke really walking with a cane fitted at the greater trochanter? AB - The purpose of this study was to determine the cane lengths currently used by patients with hemiplegic stroke for ambulatory assistance. The sample consisted of 116 adults with hemiplegic stroke. Descriptive statistics and Chi-square test for trend were conducted to examine the distributions of cane lengths, which were classified as follows: reaching >2 cm below the greater trochanter (GT), reaching from <2 cm below to <2 cm above the GT, or reaching >2 cm above the GT. Cane lengths reaching >2 cm above the GT were most common (range 62%-88%). No difference in mean cane length was found with respect to gender, age, time elapsed after stroke, nature of pathology (infarction, hemorrhage), paralyzed region (left, right), cane type (mono or four-point), or those responsible for deciding cane lengths (clinicians, patients, family members). These findings mean patients with hemiplegic stroke are actually using canes longer than conventionally proposed cane lengths. PMID- 28632022 TI - The Wounded Brain Healed: The Golden Age of the Montreal Neurological Institute, 1934-1984, by William Feindel and Richard Leblanc. PMID- 28632021 TI - Neuromyelitis optica: Application of computer diagnostics to historical case reports. AB - The retrospective diagnosis of illnesses by medical historians can often be difficult and prone to bias, although knowledge of the medical disorders of historical figures is key to the understanding of their behavior and reactions. The recent application of computer diagnostics to historical figures allows an objective differential diagnosis to be accomplished. Taking an example from clinical neurology, we analyzed the earliest reported cases of Devic's disease (neuromyelitis optica) that commonly affects the optic nerve and spinal cord and was previously often confused with multiple sclerosis. We conclude that in most identified cases the software concurred with the contemporary physicians' interpretation, but some claimed cases either had insufficient data to provide a diagnosis or other possible diagnoses were suggested that had not been considered. Computational methods may, therefore, help historians to diagnose the ailments of historical figures with greater objectivity. PMID- 28632023 TI - On the origin of the term decussatio pyramidum. AB - There is no consensus regarding the origin of the term decussatio pyramidum. Various anatomists of the past are honored by modern scholars, for example, Vieussens, Reil, and Collins. However, contralateral effects of brain lesions were already mentioned in Hippocratic treatises. Aretaeus of Cappadocia assumed that the anatomical reason for this phenomenon is the interchange of the nerves and called it chiasmos. This opinion was discussed in modern times and the anatomists used the term decussatio nervorum. The authorship of the first demonstration of decussatio pyramidum is given to Mistichelli (1709) and Petit (1710), but neither the term decussatio nor any of its vernacular forms are present in their work. A milestone in the history of the term is the Memoire of Gall and Spurzheim presented to the Institut de France in 1808. In the French printed form of the Memoire (1809), the word combination decussation des pyramides was used for the first time in anatomical literature. PMID- 28632024 TI - Performance validity testing in a clinical sample of adults with sickle cell disease. AB - OBJECTIVE: Neuropsychologists utilize performance validity tests (PVTs) as objective means for drawing inferences about performance validity. The Test of Memory Malingering (TOMM) is a well-validated, stand-alone PVT and the Reliable Digit Span (RDS) and Reliable Digit Span-Revised (RDS-R) from the Digit Span subtest of the WAIS-IV are commonly employed, embedded PVTs. While research has demonstrated the utility of these PVTs with various clinical samples, no research has investigated their use in adults with sickle cell disease (SCD), a condition associated with multiple neurological, physical, and psychiatric symptoms. Thus, the purpose of this study was to explore PVT performance in adults with SCD. METHOD: Fifty-four adults with SCD (Mage = 40.61, SD = 12.35) were consecutively referred by their hematologist for a routine clinical outpatient neuropsychological evaluation. During the evaluation, participants were administered the TOMM (Trials 1 and 2), neuropsychological measures including the WAIS-IV Digit Span subtest, and mood and behavioral questionnaires. RESULTS: The average score on the TOMM was 47.70 (SD = 3.47, range = 34-50) for Trial 1 and 49.69 (SD = 1.66, range = 38-50) for Trial 2. Only one participant failed Trial 2 of the TOMM, yielding a 98.1% pass rate for the sample. Pass rates at various RDS and RDS-R values were calculated with TOMM Trial 2 performance as an external criterion. CONCLUSIONS: Results support the use of the TOMM as a measure of performance validity for individuals with SCD, while RDS and RDS-R should be interpreted with caution in this population. PMID- 28632025 TI - Use of Latent Class Analysis to define groups based on validity, cognition, and emotional functioning. AB - OBJECTIVE: Latent Class Analysis (LCA) was used to classify a heterogeneous sample of neuropsychology data. In particular, we used measures of performance validity, symptom validity, cognition, and emotional functioning to assess and describe latent groups of functioning in these areas. METHOD: A data-set of 680 neuropsychological evaluation protocols was analyzed using a LCA. Data were collected from evaluations performed for clinical purposes at an urban medical center. RESULTS: A four-class model emerged as the best fitting model of latent classes. The resulting classes were distinct based on measures of performance validity and symptom validity. Class A performed poorly on both performance and symptom validity measures. Class B had intact performance validity and heightened symptom reporting. The remaining two Classes performed adequately on both performance and symptom validity measures, differing only in cognitive and emotional functioning. In general, performance invalidity was associated with worse cognitive performance, while symptom invalidity was associated with elevated emotional distress. CONCLUSIONS: LCA appears useful in identifying groups within a heterogeneous sample with distinct performance patterns. Further, the orthogonal nature of performance and symptom validities is supported. PMID- 28632026 TI - Keeping High the True Values of Sport. PMID- 28632027 TI - Shc and the mechanotransduction of cellular anchorage and metastasis. AB - Tissue cells continually monitor anchorage conditions by gauging the physical properties of their underlying matrix and surrounding environment. The Rho and Ras GTPases are essential components of these mechanosensory pathways. These molecular switches control both cytoskeletal as well as cell fate responses to anchorage conditions and are thus critical to our understanding of how cells respond to their physical environment and, by extension, how malignant cells gainsay these regulatory pathways. Recent studies indicate that 2 proteins produced by the SHC1 gene, thought for the most part to functionally oppose each other, collaborate in their ability to respond to mechanical force by initiating respective Rho and Ras signals. In this review, we focus on the coupling of Shc and GTPases in the cellular response to mechanical anchorage signals, with emphasis on its relevance for cancer. PMID- 28632028 TI - The Effect of Combined Systemic Erythropoietin and Steroid on Non-arteritic Anterior Ischemic Optic Neuropathy: A Prospective Study. AB - BACKGROUND: To investigate the effect of combined intravenous (IV) erythropoietin (EPO) and corticosteroid as well as systemic steroid alone for the treatment of non-arteritic anterior ischemic optic neuropathy (NAION). METHODS: In this prospective interventional comparative case series, 113 consecutive patients diagnosed with recent onset (less than 14 days) NAION were included. Patients were categorized into three groups. 40 patients received systemic IV corticosteroid combined with recombinant human erythropoietin (rhEPO) (group 1), 43 patients received systemic corticosteroid alone (group 2), and 30 patients were enrolled as the control group (group 3). Functional and structural outcomes were analyzed 3 and 6 months after treatment. Best corrected visual acuity (BCVA) was the main outcome, and mean deviation (MD) and peripaillary retinal nerve fiber layer thickness (PRNFLT) were secondary outcome measures. RESULTS: The mean BCVA at the time of presentation was 0.98 (+/-0.65), 0.96 (+/-0.67), and 1.02 (+/ 0.63) log MAR in groups 1, 2, and 3, respectively (P = 0.95). At month 3, the corresponding values were 0.73 (+/-0.45), 0.76 (+/-0.49), and 0.8 (+/-0.45) log MAR (P = 0.80), and at the 6-month follow-up, they were 0.76 (+/-0.45), 0.71 (+/ 0.4), and 0.71 (+/-0.46) log MAR, respectively (P = 0.87). There was no statistically significant difference in BCVA between months 3 and 6, which implies stabilization of the visual acuity by month 3. Considering the visual field, within 6 months of follow-up after disease onset, the MD index improved in all groups with no statistically significant differences between them (P = 0.82). PRNFLT at presentation was 178 (+/-60), 186 (+/-59), and 166 (+/-57) micrometers in groups 1, 2, and 3, respectively (P= 0.99), which decreased to 77 (+/-16), 83 (+/-22), and 73 (+/-11), respectively, at final visit (P = 0.14) Conclusion: We found no beneficial effect of either systemic steroid alone or combined with EPO in the visual outcome of NAION patients. PMID- 28632029 TI - Longitudinal Evaluation of Wound Healing after Penetrating Corneal Injury: Anterior Segment Optical Coherence Tomography Study. AB - PURPOSE: Ocular imaging can enhance our understanding of wound healing. We report anterior segment optical coherence tomography (ASOCT) findings in penetrating corneal injury. METHODS: Serial ASOCT was performed after repair of penetrating corneal injury. Internal aberrations of wound edges were labeled as "steps" or "gaps" on ASOCT images. The wound type was characterized as: type 1: continuous inner wound edge or step height <= 80 um; type 2: step height > 80 um; type 3: gap between wound edges; and type 4: intraocular tissue adherent to wound. Surgical outcomes of different wound types were compared. RESULTS: 50 consecutive patients were included (6 females, 44 males; mean age 33 +/- 12 years). The average size of wound was 4.2 +/- 2.6 mm (type 1, 8 eyes; type 2, 27 eyes; type 3, 12 eyes; type 4, 3 eyes). At the end of 3 months, 70% (n = 35) of the wounds were type 1. At the end of 6 months, all type 1 wounds had healed completely, whereas about half of type 2 (48.1%) and type 3 (50%) wounds had recovered to type 1 configuration. The wound type at baseline affected the height of step (p = 0.047) and corneal thickness at 6 months (p = 0.035). CONCLUSIONS: ASOCT is a useful tool for monitoring wound healing in cases with penetrating corneal injury. Majority of the wound edges appose between 3 and 6 months after trauma. In our study, baseline wound configuration affected the healing pattern. PMID- 28632030 TI - Ultraviolet B Radiation Stimulates the Interaction between Nuclear Factor of Activated T Cells 5 (NFAT5) and Nuclear Factor-Kappa B (NF-kappaB) in Human Lens Epithelial Cells. AB - PURPOSE: Nuclear factor-kappa B (NF-kappaB) has been proposed as a therapeutic target for the treatment of cataracts. The authors investigated the relationship between nuclear factor of activated T cells 5 (NFAT5) and NF-kappaB in ultraviolet B (UVB)-irradiated human lens epithelial (HLE) cells. METHODS: Human lens epithelial B-3 (HLE-B3) cells were exposed to UVB light at a dose of 10 mJ/cm2 and then incubated for 24 h. Cell viability was assessed by using the Cell Counting Kit-8 (CCK-8) assay. Gene expression level of NFAT5 was determined using real-time quantitative polymerase chain reaction (qPCR). Protein expression levels of NFAT5, NF-kappaB p65, and alpha-smooth muscle actin (alpha-SMA) and the association of NFAT5 with the NF-kappaB p65 subunit were measured by Western blot analysis and a co-immunoprecipitation assay, respectively. The cellular distribution of NFAT5 and NF-kappaB p65 was examined by triple immunofluorescence staining. RESULTS: At 24 h after UVB exposure, cell viability significantly decreased in a dose-dependent manner, and UVB light (15 and 20 mJ/cm2) significantly increased the ROS generation. UVB irradiation increased NFAT5 mRNA and protein levels and increased phosphorylation of NF-kappaB in HLE-B3 cells. alpha-SMA protein levels were increased in the irradiated cells. In addition, NFAT5 and NF-kappaB translocated from the cytoplasm to the nucleus, and binding between the p65 subunit and NFAT5 was increased. CONCLUSIONS: Exposure to UVB radiation induces nuclear translocation and stimulates binding between NFAT5 and NF-kappaB proteins in HLE-B3 cells. These interactions may form part of the biochemical mechanism of cataractogenesis in UVB-irradiated HLECs. PMID- 28632031 TI - MR Imaging of the Anterior Visual Pathway in Primary Open-Angle Glaucoma: Correlation with Octopus 101 Perimetry and Spectralis Optical Coherence Tomography Findings. AB - PURPOSE: To investigate structural changes in the visual pathway measured by magnetic resonance imaging (MRI) and its relationship with the clinical severity of glaucoma in primary open-angle glaucoma (POAG) patients. MATERIALS AND METHODS: The study included 28 patients with POAG and 26 age- and sex-matched healthy volunteers. All the subjects underwent spectral domain optical coherence tomography (OCT) of the peripapillary retina nerve fiber layer (RNFL). The optic nerve diameter (OND), chiasma height (Ch), and lateral geniculate nucleus height (LGNh) were measured bilaterally using a 1.5-Tesla MRI system. RESULTS: The mean values of the OND and LGNh were significantly lower in the POAG group (OND: right p = 0.043 and left p = 0.048; LGNh: right p = 0.008 and left p = 0.025). The OND was not correlated with the clinical stage of glaucoma, but it was correlated with the ipsilateral RNFL thickness. The Ch was correlated with the ipsilateral clinical stage (right r = -0.536, p = 0.004; left r = -0.537, p = 0.004) and average RNFL thickness (RNFLav) (right r = 0.655, p < 0.001; left r = 0.626, p < 0.001). The sum of bilateral clinical stages and left clinical stages showed significant correlations with the right and left LGNh and the sum of both the right and left LGNh. The left RNFLav and the sum of the right-left RNFLav were significantly correlated with all LGNh measurements. CONCLUSIONS: 1.5-Tesla MRI can detect structural changes in the visual pathway early in the course of glaucoma. Thin optic nerve can be a risk factor for glaucoma. The Ch and LGNh seem to be correlated with the clinical stage of glaucoma and RNFL thickness. In particular, LGN can be a target of glaucomatous damage. PMID- 28632032 TI - Plasminogen Activator Inhibitor Type-1 Tag Single-Nucleotide Polymorphisms in Patients with Diabetes Mellitus Type 2 and Diabetic Retinopathy. AB - BACKGROUND: There is accumulating evidence for genetic susceptibility to the development of diabetic retinopathy (DR). The role of plasminogen activator inhibitor-1 (PAI-1) in DR risk remains controversial. OBJECTIVE: The present study was designed to investigate possible influence of PAI-1 gene region polymorphisms on the risk of DR and on the risk of developing DR early vs late in the course of type 2 diabetes mellitus (T2DM). METHODS: A total of 138 patients with DR, 107 patients with T2DM without DR, and 315 healthy controls were recruited. To cover the majority of the genetic variability across the extended region of PAI-1 gene, five tag single-nucleotide polymorphisms (SNPs) from the HapMap using a pairwise approach and an r2 >= 0.8 and a minor allele frequency (MAF) of >0.05 were identified. Using logistic regression analyses, tag SNPs and haplotypes were tested for associations with DR risk and risk of DR development early or late in the course of T2DM. The generalized odds ratio (ORG) was calculated to estimate the mutational load effect on DR development among all participants. Corrections for multiple comparisons were carried out (p-value < 0.01). RESULTS: A significant effect of rs2070682 on the risk of early DR onset was found in the codominant model of inheritance [odds ratio, OR (95% confidence interval, CI): 5.04 (1.47-17.28), p = 0.018]. However, this association marginally did not survive multiple testing corrections. No other significant association between PAI-1 tag-SNPs and haplotypes was revealed. Furthermore, no significant mutational load effect of PAI-1 tag SNPs on the risk of DR development in T2DM course was found. CONCLUSIONS: In conclusion, the present study does not provide any strong evidence that PAI-1 gene variants are implicated in the risk of DR or the development of DR during T2DM course. PMID- 28632033 TI - Overexpression of ALK5 Induces Human Tenon's Capsule Fibroblasts Transdifferentiation and Fibrosis In Vitro. AB - PURPOSE: To investigate the involvement of activin receptor-like kinase 5 (ALK5) in human Tenon's capsule fibroblasts (HTFs) transdifferentiation and fibrosis. METHODS: (1) Cultured HTFs were treated with transforming growth factor beta 1 (TGF-beta1) at different concentrations for different durations, mRNA expression of ALK5 and plasminogen activator inhibitor-1 (PAI-1) was measured by quantitative polymerase chain reaction (PCR) while protein expression of ALK5, alpha-smooth muscle actin (alpha-SMA), and extracellular matrix deposition including fibronectin (FN) and collagen I (Col1) was assessed by western blot. HTFs with or without TGF-beta1 were also treated with an ALK5 activity inhibitor, SB-431542, and fibrosis-related genes were assessed. (2) HTFs were transduced with ALK5 lentivirus (ALK5-OE group) or empty lentivirus (NC-OE) with or without the treatment of SB-431542. Protein expression of ALK5, alpha-SMA, FN, and Col1 was evaluated. (3) HTFs in the ALK5-OE group and NC-OE group were subjected to a scratch-wound assay and their migratory activities assessed. RESULTS: (1) TGF beta1, in a concentration-dependent manner, upregulated ALK5 and PAI-1 expressions in the HTFs, which peaked between 24 and 36 h. These changes were associated with increases in protein levels of FN, Col1, and alpha-SMA. These TGF beta1 effects were blocked by the ALK5 inhibitor SB-431542. (2) Similarly, overexpression of ALK5 by lentiviral vector significantly increased protein expression of alpha-SMA, FN, and Col1. Addition of TGF-beta1 to the ALK5-OE cells did not produce additional expression of any of the marker proteins. The upregulation of extracellular matrix and alpha-SMA can be reduced by SB-431542. (3) In ALK5-OE group, HTFs migration was significantly increased compared with normal control and TGF-beta1 could still promote ALK5-OE cells migration. CONCLUSIONS: Our findings suggest that ALK5 is an important mediator of HTFs fibrosis. ALK5 is a potential therapeutic target to suppress scar formation after filtration surgery. PMID- 28632035 TI - A comprehensive study of worldwide selfie-related accidental mortality: a growing problem of the modern society. AB - Since Oxford dictionary has described 'Selfie', selfie deaths have received a fair amount of coverage but the extent of the problem and the data behind it have not been appropriately explored. The aim of our study is to obtain epidemiological characteristics of selfie-related mortality worldwide with the objective of providing an insight to 'Why selfie', 'Why risky', 'Psychological basis' and 'measures of control.' Despite thousands of web pages, very few scientific articles are available in medical journals. So, we went online via Google search engine compiling every reported instance after confirming it and verifying the information in Wikipedia. Non-fatal injuries and non-selfie type of photography-related deaths were excluded from the study. From 2014 to mid-2016, 75 people have died while attempting selfie in 52 incidents worldwide. Mean age of the victims was 23.3 and 82% were male. India is the most affected country and Russia and US being second. Fall from height, drowning and rail accidents are the top three modes of death. Large-scale use of cell phone worldwide and underlying risk in selfie behaviour seems the culprit. Inability to compare selfie with non selfie photography due to lack of data is definitely a limitation. Worldwide initiatives are being taken like 'NO SELFIE ZONES' but still a multifactorial approach is required before it gets too late. PMID- 28632034 TI - Recombinant Human Nerve Growth Factor Treatment Promotes Photoreceptor Survival in the Retinas of Rats with Retinitis Pigmentosa. AB - PURPOSE: Increasing evidence suggests that nerve growth factor (NGF) exerts protective effects against retinal degeneration in animal models of retinitis pigmentosa (RP). This study aims at investigating the effects of intravitreal injection of recombinant human NGF (rhNGF) on retinal photoreceptors apoptosis in an animal model of RP, the Royal College of Surgeons (RCS) rats. METHODS: Thirty six RCS rats were treated with intravitreal injection of rhNGF or murine NGF (mNGF) or vehicle at 20 postnatal days (pd) and sacrificed at 40 pd. The eyes were enucleated and evaluated by histology, flow cytometric analysis for rhodopsin expression, Western blot for TrkA and activated (phosphorylated) TrkA (pTrkA) levels, and TUNEL assay for apoptosis' detection. RESULTS: RCS rats showed a significant retinal degeneration associated with cell apoptosis at 40 pd when compared to wild-type animals. Histology showed that rhNGF intravitreal treatment significantly increased retinal thickness when compared to untreated eyes. Photoreceptors' number evaluated by flow cytometry was significantly increased in both intravitreal rhNGF- and mNGF-treated groups when compared to untreated eyes. This protective effect was associated with an increase in TrkA and activated pTrkA levels and an inhibition of apoptosis. Intravitreal NGF injection was well tolerated and did not show clinical and histological signs of adverse effects. CONCLUSIONS: Intravitreal rhNGF injection proved safe and effective in favoring retinal cell survival in RCS rats. This is the first report showing that the novel rhNGF already proved safe in a phase I study exerts a biologic effect similar to the well-characterized mNGF-induced retinal protection. These results may trigger further studies to investigate rhNGF administration for the treatment of progressive degenerative retinal disorders such as retinitis pigmentosa. PMID- 28632036 TI - Predictability and interpretability of hybrid link-level crash frequency models for urban arterials compared to cluster-based and general negative binomial regression models. AB - Machine learning (ML) techniques have higher prediction accuracy compared to conventional statistical methods for crash frequency modelling. However, their black-box nature limits the interpretability. The objective of this research is to combine both ML and statistical methods to develop hybrid link-level crash frequency models with high predictability and interpretability. For this purpose, M5' model trees method (M5') is introduced and applied to classify the crash data and then calibrate a model for each homogenous class. The data for 1134 and 345 randomly selected links on urban arterials in the city of Charlotte, North Carolina was used to develop and validate models, respectively. The outputs from the hybrid approach are compared with the outputs from cluster-based negative binomial regression (NBR) and general NBR models. Findings indicate that M5' has high predictability and is very reliable to interpret the role of different attributes on crash frequency compared to other developed models. PMID- 28632037 TI - Construct and concurrent validity of the Cambridge neuropsychological automated tests in Portuguese older adults without neuropsychiatric diagnoses and with Alzheimer's disease dementia. AB - We aimed to analyze the construct and concurrent validity of the Rapid Visual Information Processing (RVP), Paired Associates Learning (PAL), Reaction Time (RTI), and Spatial Working Memory (SWM) tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB(r)). Inclusion criteria were checked in a first session. The CANTAB and additional pencil-and-paper tests were administered within 1 week. The participants (aged 69-96 years) were 137 Portuguese adults without neuropsychiatric diagnoses and 37 adults with mild-to moderate Alzheimer's disease dementia. Comparisons were made between the CANTAB tests and between these tests and the Rey Complex Figure Test (RCFT), Verbal Fluency (VF) test, and some Wechsler Memory Scale-III and Wechsler Adult Intelligence Scale-III subtests. Most intra-test correlations were stronger than the CANTAB inter-test correlations. The RVP correlated more with VF animals (.44), the PAL with RCFT immediate recall (-.52), the RTI with RVP mean latency (.42), and the SWM with Spatial Span backward (-.39). PMID- 28632038 TI - Spatial navigation deficits in amnestic mild cognitive impairment with neuropsychiatric comorbidity. AB - AIMS: To find out whether neuropsychiatric comorbidity (comMCI) influences spatial navigation performance in amnestic mild cognitive impairment (aMCI). METHODS: We recruited aMCI patients with (n = 21) and without (n = 21) neuropsychiatric comorbidity or alcohol abuse, matched for global cognitive impairment and cognitively healthy elderly participants (HE, n = 22). They completed the Mini-Mental State Examination and a virtual Hidden Goal Task in egocentric, allocentric, and delayed recall subtests. RESULTS: In allocentric navigation, aMCI and comMCI performed significantly worse than HE and similarly to each other. Although aMCI performed significantly worse at egocentric navigation than HE, they performed significantly better than patients with comMCI. CONCLUSIONS: Despite the growing burden of dementia and the prevalence of neuropsychiatric symptoms in the elderly population, comMCI remains under studied. Since trials often assess "pure" aMCI, we may underestimate patients' navigation and other deficits. This finding emphasizes the importance of taking account of the cognitive effects of psychiatric disorders in aMCI. PMID- 28632039 TI - Thiocyanate: a review and evaluation of the kinetics and the modes of action for thyroid hormone perturbations. AB - Exposure of the population to thiocyanate is predominantly through the diet and cigarette smoke. Thiocyanate is a potential thyroid disruptor due to its capacity to inhibit the uptake of iodide by the thyroid. Thiocyanate also interacts with the enzymatic reactions associated with iodide organification and thyroid hormone synthesis. Quantification of the dose-response relationships of thiocyanate and alteration in thyroid hormone levels is important for evaluating the risk of exposure to thiocyanate in humans. In this review, we highlight the key whole body and intra-thyroidal aspects of thiocyanate kinetics in rats and its various modes of action for perturbing thyroid function. The inter-play between the various transporter- and enzyme-mediated modes of action contributes to the complexity in the dose-response relationship determinations for thiocyanate. We map the available modes of action in a mechanistic and quantitative manner. Findings summarized in this study can help support the development of a quantitative model to study the interaction effects of thiocyanate on the thyroid function. Additionally, the data gaps identified can help guide future experimental designs to characterize further thiocyanate dose-response. Finally, the strengths and weaknesses in current risk assessment considerations used for thiocyanate as a component of thyroid-active chemical mixtures are discussed. PMID- 28632042 TI - Lesions to the left lateral prefrontal cortex impair decision threshold adjustment for lexical selection. AB - Patients with lesions in the left prefrontal cortex (PFC) have been shown to be impaired in lexical selection, especially when interference between semantically related alternatives is increased. To more deeply investigate which computational mechanisms may be impaired following left PFC damage due to stroke, a psychometric modelling approach is employed in which we assess the cognitive parameters of the patients from an evidence accumulation (sequential information sampling) modelling of their response data. We also compare the results to healthy speakers. Analysis of the cognitive parameters indicates an impairment of the PFC patients to appropriately adjust their decision threshold, in order to handle the increased item difficulty that is introduced by semantic interference. Also, the modelling contributes to other topics in psycholinguistic theory, in which specific effects are observed on the cognitive parameters according to item familiarization, and the opposing effects of priming (lower threshold) and semantic interference (lower drift) which are found to depend on repetition. These results are developed for the blocked-cyclic picture naming paradigm, in which pictures are presented within semantically homogeneous (HOM) or heterogeneous (HET) blocks, and are repeated several times per block. Overall, the results are in agreement with a role of the left PFC in adjusting the decision threshold for lexical selection in language production. PMID- 28632043 TI - Simultanagnosia and object individuation. AB - Simultanagnosic patients have difficulty in perceiving multiple objects when presented simultaneously. In this review article, I discuss how neuropsychological research on simultanagnosia has been inspirational for two interconnected lines of research related to the core mechanisms by which the visual system processes cluttered scenes. First, I review previous studies on enumeration tasks indicating that, despite their inability to identify multiple objects, simultanagnosic patients can enumerate up to 2-3 elements as efficiently as healthy individuals (the so-called "subitizing" phenomenon). This intriguing observation is one of the first results to support the existence of an "object individuation" mechanism that can spatially tag a limited set of objects simultaneously, and resonates with recent research on the brain dynamics of enumeration in healthy individuals. Second, I further develop the implications of the dissociation between object identification and object enumeration in simultanagnosia specifically for the distinction between object identification and individuation. The latter distinction has been the subject of recent neuroimaging research that has provided fine-grained information on the spatial as well as temporal aspects of object individuation and recognition. The lessons learned from neuropsychological research on exact enumeration in simultanagnosia can be generalized to the normal functioning of the human mind, and have provided insightful clues for cognitive neuroscience. PMID- 28632041 TI - Automated volumetry of hippocampus is useful to confirm unilateral mesial temporal sclerosis in patients with radiologically positive findings. AB - Background and purpose We evaluated two methods to identify mesial temporal sclerosis (MTS): visual inspection by experienced epilepsy neuroradiologists based on structural magnetic resonance imaging sequences and automated hippocampal volumetry provided by a processing pipeline based on the FMRIB Software Library. Methods This retrospective study included patients from the epilepsy monitoring unit database of our institution. All patients underwent brain magnetic resonance imaging in 1.5T and 3T scanners with protocols that included thin coronal T2, T1 and fluid-attenuated inversion recovery and isometric T1 acquisitions. Two neuroradiologists with experience in epilepsy and blinded to clinical data evaluated magnetic resonance images for the diagnosis of MTS. The diagnosis of MTS based on an automated method included the calculation of a volumetric asymmetry index between the two hippocampi of each patient and a threshold value to define the presence of MTS obtained through statistical tests (receiver operating characteristics curve). Hippocampi were segmented for volumetric quantification using the FIRST tool and fslstats from the FMRIB Software Library. Results The final cohort included 19 patients with unilateral MTS (14 left side): 14 women and a mean age of 43.4 +/- 10.4 years. Neuroradiologists had a sensitivity of 100% and specificity of 73.3% to detect MTS (gold standard, k = 0.755). Automated hippocampal volumetry had a sensitivity of 84.2% and specificity of 86.7% (k = 0.704). Combined, these methods had a sensitivity of 84.2% and a specificity of 100% (k = 0.825). Conclusions Automated volumetry of the hippocampus could play an important role in temporal lobe epilepsy evaluation, namely on confirmation of unilateral MTS diagnosis in patients with radiological suggestive findings. PMID- 28632045 TI - Comparison of crossover and jab step start techniques for base stealing in baseball. AB - Base stealing is an important tactic for increasing the chance of scoring in baseball. This study aimed to compare the crossover step (CS) and jab step (JS) starts for base stealing start performance and to clarify the differences between CS and JS starts in terms of three-dimensional lower extremity joint kinetics. Twelve male baseball players performed CS and JS starts, during which their motion and the force they applied to the ground were simultaneously recorded using a motion-capture system and two force platforms. The results showed that the normalised average forward external power, the average forward-backward force exerted by the left leg, and the forward velocities of the whole body centre of gravity generated by both legs and the left leg were significantly higher for the JS start than for the CS start. Moreover, the positive work done by hip extension during the left leg push-off was two-times greater for the JS start than the CS start. In conclusion, this study has demonstrated that the jab step start may be the better technique for a base stealing start and that greater positive work produced by left hip extension is probably responsible for producing its larger forward ground reaction force. PMID- 28632046 TI - Targeting associated mechanisms of anterior cruciate ligament injury in female community-level athletes. AB - This study aims to determine if biomechanically informed injury prevention training can reduce associated factors of anterior cruciate ligament injury risk among a general female athletic population. Female community-level team sport athletes, split into intervention (n = 8) and comparison groups (n = 10), completed a sidestepping movement assessment prior to and following a 9-week training period, in which kinetic, kinematic and neuromuscular data were collected. The intervention group completed a biomechanically informed training protocol, consisting of plyometric, resistance and balance exercises, adjunct to normal training, for 15-20 min twice a week. Following the 9-week intervention, total activation of the muscles crossing the knee (n = 7) decreased for both the training (? -15.02%, d = 0.45) and comparison (? -9.68%, d = 0.47) groups. This decrease was accompanied by elevated peak knee valgus (? +27.78%, d = -0.36) and internal rotation moments (? +37.50%, d = -0.56) in the comparison group, suggesting that female community athletes are at an increased risk of injury after a season of play. Peak knee valgus and internal rotation knee moments among athletes who participated in training intervention did not change over the intervention period. Results suggest participation in a biomechanically informed training intervention may mitigate the apparent deleterious effects of community level sport participation. PMID- 28632040 TI - Engineered nanomaterial-induced lysosomal membrane permeabilization and anti cathepsin agents. AB - Engineered nanomaterials (ENMs), or small anthropogenic particles approximately < 100 nm in size and of various shapes and compositions, are increasingly incorporated into commercial products and used for industrial and medical purposes. There is an exposure risk to both the population at large and individuals in the workplace with inhalation exposures to ENMs being a primary concern. Further, there is increasing evidence to suggest that certain ENMs may represent a significant health risk, and many of these ENMs exhibit distinct similarities with other particles and fibers that are known to induce adverse health effects, such as asbestos, silica, and particulate matter (PM). Evidence regarding the importance of lysosomal membrane permeabilization (LMP) and release of cathepsins in ENM toxicity has been accumulating. The aim of this review was to describe our current understanding of the mechanisms leading to ENM-associated pathologies, including LMP and the role of cathepsins with a focus on inflammation. In addition, anti-cathepsin agents, some of which have been tested in clinical trials and may prove useful for ameliorating the harmful effects of ENM exposure, are examined. PMID- 28632047 TI - Reliability and magnitude of mechanical variables assessed from unconstrained and constrained loaded countermovement jumps. AB - This study aimed to (1) assess the reliability of the force, velocity, and power output variables measured by a force plate and a linear velocity transducer (LVT) for both the unconstrained and constrained loaded countermovement jump (CMJ), and (2) examine the effect of both the CMJ type and the measurement method on the magnitudes of the same variables. Twenty-three men were tested on the free CMJ and the CMJ constrained by a Smith machine. Maximum values of force, velocity, and power were recorded by a force plate and by a LVT attached to a bar loaded by 17, 30, 45, 60, and 75 kg. The reliability of all mechanical variables proved to be high (ICC > 0.70; CV < 10%) and similar for two CMJ types. However, force plate-derived measures displayed greater reliability than the LVT. The LVT also markedly overestimated the magnitudes of the mechanical variables, particularly at lower external loads. Therefore, although both jump types and both methods could be acceptable for routine testing, we recommend the force platform due to a higher reliability and more accurate magnitudes of the obtained variables. The unconstrained loaded CMJ could also be recommended due to the simpler equipment needed. PMID- 28632048 TI - Effects of structural components of artificial turf on the transmission of impacts in football players. AB - The third generation of artificial turf systems (ATS) has matched the mechanical behaviour of natural grass, but today a high heterogeneity at structural level and mechanical behaviour in the new ATS also exists. The objective was to analyse the effect of the structural components of ATS football pitches and running speed on the capacity of impact attenuation. A total of 12 athletes were evaluated at three speed conditions (3.33 m/s, 4 m/s and maximum speed) on four different ATS, classifying them by their components (length of fibre, type of in-fill and sub base). Impact attenuation was significantly higher in ATS3, characterised by longer fibre compared to other ATS with less fibre length. The ATS4 with a higher length fibre and built on compacted granular material proportioned significantly lower values in the maximum peaks of tibia acceleration. Finally, as speed increases, the peak tibia impacts were significantly higher. Longer fibre length and the capacity to accommodate a higher quantity of infill facilitate higher impact attenuation. Equally, a compacted granular sub-base is related to lower magnitude of maximum tibia peaks. Finally, the magnitude of the tibia acceleration peaks is dependent of running speed for all ATS analysed, being higher as speed increases. PMID- 28632049 TI - Kinematic comparison of the seoi-nage judo technique between elite and college athletes. AB - This study sought to identify biomechanical factors that determine fast and skilful execution of the seoi-nage (shoulder throw) technique by comparing kinematics between elite and college judo athletes. Three-dimensional motion data were captured using a VICON-MX system with 18 cameras operating at 250 Hz as three male elite and seven male college judo athletes performed seoi-nage. No significant difference was found in motion phase time of the turning phase between the two groups, indicating that motion phase time is not necessarily a factor contributing quickness in seoi-nage. The maximum relative velocity of the whole body centre of mass along the anterior-posterior direction was significantly greater in the elite athletes (2.74 +/- 0.33 m/s) than in the college athletes (1.62 +/- 0.47 m/s) during the turning phase (p = 0.023). The overall angular velocity of the body part lines, particularly the arm line, tended to be greater in the elite athletes (p = 0.068). The results imply that the velocity of the thrower relative to the opponent in the forward drive and turning motion reflects high skill seoi-nage. Coaches should recognise the relative forward velocity as a factor that may contribute to a successful seoi nage when teaching the judo throw technique. PMID- 28632050 TI - Effects of turf and cleat footwear on plantar load distributions in adolescent American football players during resisted pushing. AB - Metatarsal and midfoot injuries are common in American football. Footwear design may influence injury rates by altering plantar foot loading patterns in these regions. The purpose of this study was to determine the effect of cleat design on in-shoe plantar foot loading during a football-specific, resisted pushing task. Twenty competitive football players (age 14.7 +/- 1.8 years, height 1.72 +/- 0.10 m, and mass 71.8 +/- 26.9 kg) completed three trials of pushing a weighted sled at maximal effort in a standard shoe (CLEAT) and artificial turf-specific shoe (TURF), with flexible in-shoe force measuring insoles. Repeated measures ANOVAs identified mean differences in maximum force and relative load under all regions of the foot. Results showed higher forces in the CLEAT under the medial (p < 0.001) and lateral (p = 0.004) midfoot, central (p = 0.007) and lateral (p < 0.001) forefoot, and lesser toes (p = 0.01), but lower forces in the hallux (p = 0.02) compared to the TURF shoe. Additionally, relative loading was higher in the CLEAT under the medial (p < 0.001) and lateral (p = 0.002) midfoot and lateral (p < 0.001) forefoot, but lower in the medial forefoot (p = 0.006) and hallux (p < 0.001) compared to the TURF shoe. The two shoes elicited distinct plantar loading profiles and may influence shoe selection decisions during injury prevention or rehabilitation practices. PMID- 28632051 TI - Quantifying coordination among the rearfoot, midfoot, and forefoot segments during running. AB - Because previous studies have suggested that there is a relationship between injury risk and inter-segment coordination, quantifying coordination between the segments is essential. Even though the midfoot and forefoot segments play important roles in dynamic tasks, previous studies have mostly focused on coordination between the shank and rearfoot segments. This study aimed to quantify coordination among rearfoot, midfoot, and forefoot segments during running. Eleven healthy young men ran on a treadmill. The coupling angle, representing inter-segment coordination, was calculated using a modified vector coding technique. The coupling angle was categorised into four coordination patterns. During the absorption phase, rearfoot-midfoot coordination in the frontal planes was mostly in-phase (rearfoot and midfoot eversion with similar amplitudes). The present study found that the eversion of the midfoot with respect to the rearfoot was comparable in magnitude to the eversion of the rearfoot with respect to the shank. A previous study has suggested that disruption of the coordination between the internal rotation of the shank and eversion of the rearfoot leads to running injuries such as anterior knee pain. Thus, these data might be used in the future to compare to individuals with foot deformities or running injuries. PMID- 28632052 TI - Motor unit firing frequency of lower limb muscles during an incremental slide board skating test. AB - This study investigated how the combination of workload and fatigue affected the frequency components of muscle activation and possible recruitment priority of motor units during skating to exhaustion. Ten male competitive speed skaters performed an incremental maximal test on a slide board. Activation of six muscles from the right leg was recorded throughout the test. A time-frequency analysis was performed to compute overall, high, and low frequency bands from the whole signal at 10, 40, 70, and 90% of total test time. Overall activation increased for all muscles throughout the test (p < 0.05 and ES > 0.80). There was an increase in low frequency (90 vs. 10%, p = 0.035, ES = 1.06) and a decrease in high frequency (90 vs. 10%, p = 0.009, ES = 1.38, and 90 vs. 40%, p = 0.025, ES = 1.12) components of gluteus maximus. Strong correlations were found between the maximal cadence and vastus lateralis, gluteus maximus and gluteus medius activation at the end of the test. In conclusion, the incremental skating test lead to an increase in activation of lower limb muscles, but only gluteus maximus was sensitive to changes in frequency components, probably caused by a pronounced fatigue. PMID- 28632053 TI - The effect of a secondary cognitive task on landing mechanics and jump performance. AB - Anterior cruciate ligament (ACL) injuries commonly occur during jump-landing tasks when individuals' attention is simultaneously allocated to other objects and tasks. The purpose of the current study was to investigate the effect of allocation of attention imposed by a secondary cognitive task on landing mechanics and jump performance. Thirty-eight recreational athletes performed a jump-landing task in three conditions: no counting, counting backward by 1 s from a randomly given number, and counting backward by 7 s from a randomly given number. Three-dimensional kinematics and ground reaction forces were collected and analysed. Participants demonstrated decreased knee flexion angles at initial contact (p = 0.001) for the counting by 1 s condition compared with the no counting condition. Participants also showed increased peak posterior and vertical ground reaction forces during the first 100 ms of landing (p <= 0.023) and decreased jump height (p < 0.001) for the counting by 1 s and counting by 7 s conditions compared with the no counting condition. Imposition of a simultaneous cognitive challenge resulted in landing mechanics associated with increased ACL loading and decreased jump performance. ACL injury risk screening protocols and injury prevention programmes may incorporate cognitive tasks into jump-landing tasks to better simulate sports environments. PMID- 28632054 TI - Middle finger and ball movements around ball release during baseball fastball pitching. AB - The objectives of this study were to investigate middle finger movements and dynamics of ball movements around the instant of ball release during baseball pitching. Baseball pitching from an indoor mound among 14 semi-professional pitchers was captured using a motion capture system with 16 high-speed cameras (1,000 Hz). Kinematics of middle finger joints, ball rotation, and force applied to the ball were calculated. The proximal and distal interphalangeal joints continued to extend until the instant of ball release, then abruptly flexed. The abrupt flexion lasted for only several milliseconds, followed by a short extension phase. The finger made a quick double cycle of extension-flexion movement, suggesting that it attained high stiffness resulting from co contraction. The ball began to roll up to the tip of the finger 8 +/- 1 ms before ball release owing to the start of extension or the increased angular velocity of extension for the proximal interphalangeal joint. A mean force of 195 +/- 27 N was applied in the proximal direction of the hand at the same time as the beginning of ball rolling, and a mean force of 109 +/- 22 N was applied to the throwing direction just before ball release. PMID- 28632055 TI - Muscle activity in sprinting: a review. AB - The use of electromyography (EMG) is widely recognised as a valuable tool for enhancing the understanding of performance drivers and potential injury risk in sprinting. The timings of muscle activations relative to running gait cycle phases and the technology used to obtain muscle activation data during sprinting are of particular interest to scientists and coaches. This review examined the main muscles being analysed by surface EMG (sEMG), their activations and timing, and the technologies used to gather sEMG during sprinting. Electronic databases were searched using 'Electromyography' OR 'EMG' AND 'running' OR 'sprinting'. Based on inclusion criteria, 18 articles were selected for review. While sEMG is widely used in biomechanics, relatively few studies have used sEMG in sprinting due to system constraints. The results demonstrated a focus on the leg muscles, with over 70% of the muscles analysed in the upper leg. This is consistent with the use of tethered and data logging EMG systems and many sprints being performed on treadmills. Through the recent advances in wireless EMG technology, an increase in the studies on high velocity movements such as sprinting is expected and this should allow practitioners to perform the analysis in an ecologically valid environment. PMID- 28632056 TI - Reliability of power and velocity variables collected during the traditional and ballistic bench press exercise. AB - This study aimed to examine the reliability of different power and velocity variables during the Smith machine bench press (BP) and bench press throw (BPT) exercises. Twenty-two healthy men conducted four testing sessions after a preliminary BP one-repetition maximum (1RM) test. In a counterbalanced order, participants performed two sessions of BP in one week and two sessions of BPT in another week. Mean propulsive power, peak power, mean propulsive velocity, and peak velocity at each tenth percentile (20-70% of 1RM) were recorded by a linear transducer. The within-participants coefficient of variation (CV) was higher for the load-power relationship compared to the load-velocity relationship in both the BP (5.3% vs. 4.1%; CV ratio = 1.29) and BPT (4.7% vs. 3.4%; CV ratio = 1.38). Mean propulsive variables showed lower reliability than peak variables in both the BP (5.4% vs. 4.0%, CV ratio = 1.35) and BPT (4.8% vs. 3.3%, CV ratio = 1.45). All variables were deemed reliable, with the peak velocity demonstrating the lowest within-participants CV. Based upon these findings, the peak velocity should be chosen for the accurate assessment of BP and BPT performance. PMID- 28632057 TI - Rotation sequence to report humerothoracic kinematics during 3D motion involving large horizontal component: application to the tennis forehand drive. AB - The aim of this study was to examine the respective aptitudes of three rotation sequences (YtXf'Yh'', ZtXf'Yh'', and XtZf'Yh'') to effectively describe the orientation of the humerus relative to the thorax during a movement involving a large horizontal abduction/adduction component: the tennis forehand drive. An optoelectronic system was used to record the movements of eight elite male players, each performing ten forehand drives. The occurrences of gimbal lock, phase angle discontinuity and incoherency in the time course of the three angles defining humerothoracic rotation were examined for each rotation sequence. Our results demonstrated that no single sequence effectively describes humerothoracic motion without discontinuities throughout the forehand motion. The humerothoracic joint angles can nevertheless be described without singularities when considering the backswing/forward-swing and the follow-through phases separately. Our findings stress that the sequence choice may have implications for the report and interpretation of 3D joint kinematics during large shoulder range of motion. Consequently, the use of Euler/Cardan angles to represent 3D orientation of the humerothoracic joint in sport tasks requires the evaluation of the rotation sequence regarding singularity occurrence before analysing the kinematic data, especially when the task involves a large shoulder range of motion in the horizontal plane. PMID- 28632058 TI - Assessment of model-based image-matching for future reconstruction of unhelmeted sport head impact kinematics. AB - Player-to-player contact inherent in many unhelmeted sports means that head impacts are a frequent occurrence. Model-Based Image-Matching (MBIM) provides a technique for the assessment of three-dimensional linear and rotational motion patterns from multiple camera views of a head impact event, but the accuracy is unknown for this application. The goal of this study is to assess the accuracy of the MBIM method relative to reflective marker-based motion analysis data for estimating six degree of freedom head displacements and velocities in a staged pedestrian impact scenario at 40 km/h. Results showed RMS error was under 20 mm for all linear head displacements and 0.01-0.04 rad for head rotations. For velocities, the MBIM method yielded RMS errors between 0.42 and 1.29 m/s for head linear velocities and 3.53-5.38 rad/s for angular velocities. This method is thus beneficial as a tool to directly measure six degree of freedom head positional data from video of sporting head impacts, but velocity data is less reliable. MBIM data, combined in future with velocity/acceleration data from wearable sensors could be used to provide input conditions and evaluate the outputs of multibody and finite element head models for brain injury assessment of sporting head impacts. PMID- 28632059 TI - Confidence crisis of results in biomechanics research. AB - Many biomechanics studies have small sample sizes and incorrect statistical analyses, so reporting of inaccurate inferences and inflated magnitude of effects are common in the field. This review examines these issues in biomechanics research and summarises potential solutions from research in other fields to increase the confidence in the experimental effects reported in biomechanics. Authors, reviewers and editors of biomechanics research reports are encouraged to improve sample sizes and the resulting statistical power, improve reporting transparency, improve the rigour of statistical analyses used, and increase the acceptance of replication studies to improve the validity of inferences from data in biomechanics research. The application of sports biomechanics research results would also improve if a larger percentage of unbiased effects and their uncertainty were reported in the literature. PMID- 28632060 TI - The collision forces and lower-extremity inter-joint coordination during running. AB - The purpose of this study was to compare the lower extremity inter-joint coordination of different collision forces runners during running braking phase. A dynamical system approach was used to analyse the inter-joint coordination parameters. Data were collected with six infra-red cameras and two force plates. According to the impact peak of the vertical ground reaction force, twenty habitually rearfoot-strike runners were categorised into three groups: high collision forces runners (HF group, n = 8), medium collision forces runners (MF group, n = 5), and low collision forces runners (LF group, n = 7). There were no significant differences among the three groups in the ankle and knee joint angle upon landing and in the running velocity (p > 0.05). The HF group produced significantly smaller deviation phase (DP) of the hip flexion/extension-knee flexion/extension during the braking phase compared with the MF and LF groups (p < 0.05). The DP of the hip flexion/extension-knee flexion/extension during the braking phase correlated negatively with the collision force (p < 0.05). The disparities regarding the flexibility of lower extremity inter-joint coordination were found in high collision forces runners. The efforts of the inter-joint coordination and the risk of running injuries need to be clarified further. PMID- 28632061 TI - The effect of unilateral arm swing motion on lower extremity running mechanics associated with injury risk. AB - Many field sports involve equipment that restricts one or both arms from moving while running. Arm swing during running has been examined from a biomechanical and physiologic perspective but not from an injury perspective. Moreover, only bilateral arm swing suppression has been studied with respect to running. The purpose of this study was to determine the influence of running with one arm restrained on lower extremity mechanics associated with running or sport-related injury. Fifteen healthy participants ran at a self-selected speed with typical arm swing, with one arm restrained and with both arms restrained. Lower extremity kinematics and spatiotemporal measures were analysed for all arm swing conditions. Running with one arm restrained resulted in increased frontal plane knee and hip angles, decreased foot strike angle, and decreased centre of mass vertical displacement compared to typical arm swing or bilateral arm swing restriction. Stride length was decreased and step frequency increased when running with one or both arms restrained. Unilateral arm swing restriction induces changes in lower extremity kinematics that are not similar to running with bilateral arm swing restriction or typical arm swing motion. Running with one arm restrained increases frontal plane mechanics associated with risk of knee injury. PMID- 28632062 TI - Skeleton sled velocity profiles: a novel approach to understand critical aspects of the elite athletes' start phases. AB - The development of velocity across the skeleton start is critical to performance, yet poorly understood. We aimed to understand which components of the sled velocity profile determine performance and how physical abilities influence these components. Thirteen well-trained skeleton athletes (>85% of athletes in the country) performed dry-land push-starts alongside countermovement jump and sprint tests at multiple time-points. A magnet encoder attached to the sled wheel provided velocity profiles, which were characterised using novel performance descriptors. Stepwise regression revealed four variables (pre-load velocity, pre load distance, load effectiveness, velocity drop) to explain 99% variance in performance (beta weights: 1.70, -0.81, 0.25, -0.07, respectively). Sprint times and jump ability were associated (r +/- 90% CI) with pre-load velocity (-0.70 +/- 0.27 and 0.88 +/- 0.14, respectively) and distance (-0.48 +/- 0.39 and 0.67 +/- 0.29, respectively), however, unclear relationships between both physical measures and load effectiveness (0.33 +/- 0.44 and -0.35 +/- 0.48, respectively) were observed. Athletes should develop accelerative ability to attain higher velocity earlier on the track. Additionally, the loading phase should not be overlooked and may be more influenced by technique than physical factors. Future studies should utilise this novel approach when evaluating skeleton starts or interventions to enhance performance. PMID- 28632063 TI - Kinetic analysis of the lower limbs in baseball tee batting. AB - The purpose of this study was to investigate effects of the ground reaction forces on the rotation of the body as a whole and on the joint torques of the lower limbs associated with trunk and pelvic rotation in baseball tee batting. A total of 22 male collegiate baseball players participated in this study. Three dimensional coordinate data were acquired by a motion capture system (250 Hz), and ground reaction forces of both legs were measured with three force platforms (1,000 Hz). Kinetic data were used to calculate the moment about the vertical axis through the body's centre of mass resulting from ground reaction forces, as well as to calculate the torque and mechanical work in the lower limb joints. The lateral/medial ground reaction force generated by both legs resulted in the large whole body moment about its vertical axis. The joint torques of flexion/extension of both hips, adduction of the stride hip and extension of the stride knee produced significantly larger mechanical work than did the other joint torques. To obtain high bat-head speed, the batter should push both legs in the lateral/medial direction by utilising both hips and stride knee torques so as to increase the whole body rotation. PMID- 28632064 TI - The effectiveness of front fork systems at damping accelerations during isolated aspects specific to cross-country mountain biking. AB - Cross-country mountain bike suspension reportedly enhances comfort and performance through reduced vibration and impact exposure. This study analysed the effectiveness of three different front fork systems at damping accelerations during the crossing of three isolated obstacles (stairs, drop, and root). One participant completed three trials on six separate occasions in a randomised order using rigid, air-sprung, and carbon leaf-sprung forks. Performance was determined by time to cross obstacles, while triaxial accelerometers quantified impact exposure and damping response. Results identified significant main effect of fork type for performance time (p < 0.05). The air-sprung and leaf-sprung forks were significantly slower than the rigid forks for the stairs (p < 0.05), while air-sprung suspension was slower than the rigid for the root protocol (p < 0.05). There were no differences for the drop protocol (p < 0.05). Rigid forks reduced overall exposure (p < 0.05), specifically at the handlebars for the stairs and drop trials. More detailed analysis presented smaller vertical accelerations at the handlebar for air-sprung and leaf-sprung forks on the stairs (p < 0.05), and drop (p < 0.05) but not the root. As such, it appears that the suspension systems tested were ineffective at reducing overall impact exposure at the handlebar during isolated aspects of cross-country terrain features which may be influenced to a larger extent by rider technique. PMID- 28632065 TI - Muscle activation sequencing of leg muscles during linear glide shot putting. AB - In the shot put, the athlete's muscles are responsible for generating the impulses to move the athlete and project the shot into the air. Information on phasic muscle activity is lacking for the glide shot put event and therefore important technical information for coaches is not currently available. This study provides an electromyography (EMG) analysis of the muscle activity of the legs during shot put. Fifteen right-handed Irish national level shot putters performed six maximum effort throws using the glide shot put technique. EMG records of eight bilateral lower limb muscles (rectus femoris, biceps femoris, medial- and lateral-gastrocnemius) were obtained during trials. Analysis using smooth EMG linear envelopes revealed patterns of muscle activity across the phases of the throw and compare men and women performers. The results showed that the preferred leg rectus femoris, the preferred leg biceps femoris and the non preferred leg biceps femoris play important roles in the glide technique, with the total duration of high volumes of activity between 34 and 53% of the throw cycle. A comprehensive understanding of movement and muscle activation patterns for coaches could be helpful to facilitate optimal technique throughout each of the key phases of the event. PMID- 28632066 TI - Differences in trunk and thigh muscle strength, endurance and thickness between elite sailors and non-sailors. AB - Dinghy sailors lean their upper body over the windward side of the boat ('hiking') to keep the boat's balance and maximise its speed. Sustaining the hiking position is essential for competitive performance and this study examined sport-specific differences of muscles relevant for hiking in elite sailors. Knee extensor muscle strength as well as trunk muscle strength, muscle endurance and muscle thickness were assessed in elite dinghy sailors (n = 15) and compared to matched, non-sailing controls (n = 15). Isometric extensor strength was significantly higher in sailors at 60 degrees (+14%) but not at 20 degrees knee flexion. Sailors showed significantly higher trunk flexor (but not extensor) strength under isometric (+18%) and eccentric (+11%) conditions, which was associated to greater muscle thickness (rectus abdominis +40%; external oblique +26%) and higher endurance for ventral (+66%) and lateral (+61%) muscle chains compared to non-sailors. Greater muscles thickness and the particular biomechanical requirements to maintain the hiking position may drive the increases in isometric and eccentric muscle strength as well as ventral and lateral trunk endurance. The current findings identified sport-specific muscle function differences and provide performance benchmarks for muscle strength and endurance in elite sailors. PMID- 28632071 TI - Impact of serious mental illness online training for certified nursing assistants in long term care. AB - Certified nurse assistants (CNAs) spend the most staff time with nursing home residents, yet they receive little training in addressing the mental health needs of residents with serious mental illness (SMI). Forty CNAs from four long-term care facilities took the online interactive CARES-(r) Serious Mental IllnessTM training consisting of two modules guided by the Recovery Movement philosophy of care. Responses from pre-post testing, Likert-type items, and open-ended questions indicated that CNAs gained information, changed their perspectives, and had more confidence in dealing with SMI. Although there were minor concerns regarding length, clarity of content, and technical issues, CNAs found the online format acceptable and easy to use, and many said they would recommend the training. CARES Serious Mental Illness online training appears to be a viable way of helping CNAs address the mental health needs of long term care residents. Additional testing on CARES Serious Mental Illness is planned. PMID- 28632072 TI - Maternal obesity, obstetric interventions and post-partum anaemia increase the risk of post-partum sepsis: a population-based cohort study based on Swedish medical health registers. AB - BACKGROUND: The objective was to estimate whether maternal obesity and/or obstetric interventions are associated with diagnosed maternal post-partum sepsis. METHODS: A retrospective observational cohort study including all deliveries in Sweden between 1997 and 2012 (N = 1,558,752). Cases of sepsis (n = 376) were identified by International Classification of Diseases, (ICD-10) codes A40, A41 and O 85 in the Medical Birth Register and the National Patient Register. The reference population was non-infected, and therefore, women with any other infection diagnosis and/or with dispensed antibiotics within eight weeks post-partum were excluded. Information on dispensed drugs was available in the prescribed drug Register. Women with sepsis were compared with non-infected women concerning maternal characteristics and obstetric interventions. Adjusted odds ratios (aOR) were determined using the Mantel-Haenszel technique. Adjustments were made for maternal age, parity and smoking. RESULTS: Obese women (body mass index >=30) had a doubled risk of sepsis (3.6/10,000) compared with normal weight women (2.0/10,000) (aOR 1.85 (95%CI: 1.37-2.48)). Induction of labour (aOR 1.44 (95%CI: 1.09-1.91)), caesarean section overall (aOR 3.06 (95%CI: 2.49-3.77)) and elective caesarean section (aOR 2.41 (95%CI: 1.68-3.45)) increased the risk of sepsis compared with normal vaginal delivery. Post-partum anaemia due to acute blood loss was associated with maternal sepsis (aOR 3.40 (95%CI: 2.59-4.47)). CONCLUSIONS: Maternal obesity, obstetric interventions and post-partum anaemia due to acute blood loss increased the risk of diagnosed post partum sepsis indicating that interventions in obstetric care should be considered carefully and anaemia should be treated if resources are available. PMID- 28632073 TI - Clinical Characteristics and Laparoscopic Treatment of Supravesical Hernia. AB - AIM: Inguinal hernias may be direct or indirect, and supravesical hernias, a subtype of inguinal hernias, are often mistaken as direct hernias as their symptoms are similar. The purpose of this study was to describe the characteristics of supravesical hernias and to introduce a minimally invasive surgical method as a treatment for supravesical hernias. MATERIALS AND METHODS: Thirty-seven patients with supravesical hernias were treated using laparoscopic herniorrhaphy and wall defect suture with a mesh implant from September 2012 to December 2016 at Damsoyu hospital, Seoul, Korea. Patient characteristics and surgical outcomes were retrospectively evaluated. RESULTS: All 37 patients were men with external supravesical hernias. The mean age was 55.3 (range 32-79) years; 23 patients had right-sided, 12 had left-sided, and 2 had bilateral hernias. Comorbidities included lipoma (7/37), contralateral indirect hernia (1/37), and contralateral direct hernia (14/37). No recurrences were reported at the end of the study period. CONCLUSIONS: Laparoscopic transabdominal defect closure with a mesh implant herniorrhaphy seems to be an effective, minimally invasive treatment option for supravesical hernia. PMID- 28632074 TI - Isopropyl Alcohol Swabs as a Preferred Substance of Abuse. AB - The authors describe the treatment of a 36-year-old woman who presented with excessive consumption of antiseptic alcohol swabs. Her behavior was diagnosed as a severe substance use disorder with isopropyl alcohol as the primary drug of choice. Diagnostic and treatment challenges involved in the case are discussed in detail, with particular focus on the differential diagnosis for this unusual presentation, including obsessive compulsive disorder, pica, and intentional self injurious behavior. A brief review of the literature on non-ethanol ingestion for the purposes of intoxication is included, as well as clinical information about the potential dangers posed by isopropyl alcohol consumption. PMID- 28632075 TI - "Is Marijuana Even a Drug?" A Qualitative Study of How Teens View Marijuana Use and Why They Use It. AB - This qualitative study examines how youth in the San Francisco Bay Area perceive marijuana and their motives for using or not using marijuana. Current regular users were more likely to perceive marijuana smoking as an enjoyable activity, comparable to a hobby or sport. Current occasional users commonly reported smoking marijuana when it was offered to them, on special occasions, and sometimes as a result of not wanting to be left out. Most former regular users reported quitting marijuana use due to getting into trouble, being ordered into drug treatment and/or being drug tested. Former occasional users mostly reported that they did not like the somatic effects of marijuana and did not feel it enhanced their social interactions or activities. Teens who reported never having used marijuana did so out of concerns for their health. Except for never-users, marijuana was seen as safe to use. Teens mentioned the widespread use of marijuana by people they know and legalization for medical and recreational use as evidence that marijuana is not harmful. The findings suggest that normalization of marijuana use is taking place. Differences in motives for and against marijuana use should be taken into consideration when designing interventions and prevention messages. PMID- 28632076 TI - Association of OPRD1 Gene Variants with Opioid Dependence in Addicted Male Individuals Undergoing Methadone Treatment in the North of Iran. AB - Genetic association of rs678849 along with neuroimaging and biomarker phenotypes, parallel with the known involvements of the OPRD1 in drug abuse, provided additional support for targeting these receptors as potential therapeutic targets in both neurodegenerative diseases and neuropsychiactric disorders such as Alzheimer's disease. Samples were selected among 202 opium-addicted participants undergoing methadone treatment and 202 healthy controls. Genomic DNA of all subjects was extracted from whole blood samples through a Salting Out procedure. Four variants (rs678849, 2236857, 2236855, and 760589) were genotyped in the studied subjects using ARMS-PCR. The analysis was performed using SNPalyze and SPSS ver.20 software. According to single locus analysis, rs678849 under dominant model (p < 0.001), rs2236857 under recessive model (p = 0.006), and the two variants, rs2236855 and rs760589 under co-dominant model, showed significant contributions between groups (p = 0.001 and p = 0.009, respectively). rs2236855 was associated with the development of libido dysfunction in opium-addicted patients undergoing methadone treatment (p = 0.011). Through haplotype analyses, five haplotypes with frequency of more than 5% displayed significant association with opioid dependence in study participants. In conclusion, the four studied OPRD1 gene variants and their haplotypes can play important roles in susceptibility to opioid dependence. PMID- 28632077 TI - Medical Cannabis in Serbia: The Survey of Knowledge and Attitudes in an Urban Adult Population. AB - There are some indices in which legalization of medical cannabis in the Republic of Serbia might be considered. The purpose of this research was to assess knowledge and attitudes towards medical cannabis in an urban adult population. This cross-sectional study was conducted in December 2015 and January 2016. A convenience sample of study participants comprised users of the Community Health Center. A total of 360 adults were invited to participate. Data were collected through an anonymous questionnaire. Most participants (77.1%) answered correctly that cancer was indicative of medical cannabis treatment, while the remaining conditions were less frequently recognized. A total of 42% answered correctly that adverse effects of cannabis were hallucinations and dizziness. Persons who previously used cannabis were more knowledgeable on conditions for medical cannabis treatment (rho = 0.155; p = 0.006). Study respondents expressed positive attitude towards legalization of medical cannabis (median 5 out of 5) and negative towards legalization of recreational cannabis (median 2 out of 5). In conclusion, the adult population in Belgrade had some knowledge of medical cannabis. The overall attitude of our population regarding legalization of medical cannabis was positive, while the attitude towards legalization of cannabis for recreational purposes was negative. PMID- 28632078 TI - "Less than a Vapor": Positioning Black lesbian women in history teacher education. AB - In this article, I discuss the possibilities and implications of centering Black lesbian identities and relationships in history teacher education through a case study with one straight Black woman preservice history teacher named Danitra. Danitra's understanding and navigation of historical research on Black lesbians are discussed in relation to core themes of lesbian historiography and emancipatory historiography. Though the literature on this group is limited, I argue that critical considerations of Black lesbians' interests and experiences help educators to conceive of and teach about history, citizenship, justice, and sexuality in more liberatory ways. I conclude by offering recommendations to history teachers and teacher educators who hope to draw on lesbian and emancipatory historiographies to challenge discourses of invisibility in history teacher education classrooms. PMID- 28632079 TI - "No there is nothing wrong with your eyes, my letterhead is indeed crooked": An introduction to the study of Black and Brown lesbian educators. AB - To date, there is a noticeable lack of studies that focus exclusively on the pedagogical practices, teaching experiences, identity, and gender performances of Black and Brown lesbian educators (BBLE). This special issue of the Journal of Lesbian Studies aims to make the hyperinvisibility of BBLE visible and proposes to fill this scholarly gap by exploring this topic from a variety of cultural and disciplinary perspectives. PMID- 28632080 TI - Lesbian disclosure and health care seeking in the United States: A replication study. AB - The current study explored factors associated with lesbian disclosure to health care providers (HCPs) and engagement in preventative health behaviors by replicating and extending a Canadian path analysis study with a sample of U.S. lesbians. Both patient (education, feminism, global outness, and internalized homophobia) and HCP-related (lesbian-friendly HCPs and patient comfort) factors were either directly or indirectly associated with disclosure and engagement in preventative health behaviors, including avoidance of health-compromising behaviors (e.g., smoking) and health care seeking. Importantly, findings suggest that HCPs-particularly those who are inclusive of lesbian patients-may play a role in assuaging their patients' experiences of minority stress. Overall, the findings were similar to those originally reported in the Canadian study, with the exception of internalized homophobia playing a more visible role in the current study. PMID- 28632081 TI - Meeting other moms: Lesbian adoptive mothers' relationships with other parents at school and beyond. AB - Little research has examined the friendships of lesbian parents, especially within the context of children's schools. This study of 40 lesbian adoptive parents (20 couples) focused on their relationships with other parents in the school community and how sexual orientation, race, and class dynamics impacted these relationships. Half of the participants described friendships with parents at the school, sometimes in spite of demographic differences, whereas others felt disconnected due to these differences. Outside of school, most participants reported friendships with other lesbian/gay parents. Parents who felt less connected to other parents at school tended to describe more lesbian/gay parent connections. Findings highlight the impact of life stage and context in shaping friendship patterns among lesbian parents. PMID- 28632082 TI - The alpha-helix alignment of proteins in water solution toward a high-frequency electromagnetic field: A FTIR spectroscopy study. AB - The aim of this article was to study the effects of mobile phone electromagnetic waves at 1750 MHz on the Amide I and Amide II vibration bands of some proteins in bidistilled water solution by means of Fourier transform infrared (FTIR) spectroscopy and Fourier self-deconvolution (FSD) analysis. The proteins that were used for the experiment were hemoglobin, myoglobin, bovine serum albumin and lysozyme. The exposure system consisted of microwaves emitted by an operational mobile phone at the frequency at 1750 MHz at the average power density of 1 W/m2. Exposed and control samples were analyzed using FTIR spectroscopy and FSD analysis. The main result was that Amide I band of the proteins that were used increased significantly (p < 0.05) after 4 h of exposure to MWs, whereas Amide II band did not change significantly. This result can be explained assuming that the alpha-helix structure of the proteins aligned itself with the direction of the electromagnetic field due to the alignment of C = O stretching and N - H bending ligands that are oriented along with the alpha-helix axis that give rise to the Amide I mode. PMID- 28632087 TI - Psychopathology and expressed emotion in parents of patients with eating disorders: Relation to patient symptom severity. AB - The purpose of the current study was to examine the relation between parental psychopathology, parental expressed emotion, and patient symptom severity. One hundred twenty-six parents of 79 patients receiving treatment for an eating disorder completed measures of expressed emotion and general psychopathology, and patients completed a measure of eating disorder psychopathology. Mothers reported higher expressed emotion scores than fathers. Both mothers and fathers scored higher on general psychopathology compared to nonpatient population means. Maternal psychopathology was found to be associated with symptom severity. Parental psychopathology and expressed emotion were found to be related, and MANCOVAs revealed that maternal criticism and maternal psychopathology were associated with patient symptom severity, but fathers' scores on the same measures were not. It is recommended that parental expressed emotion and parental psychopathology are assessed at the beginning of treatment so that appropriate clinical interventions can be utilized. PMID- 28632083 TI - Patient Reported Outcome Measure of Spiritual Care as Delivered by Chaplains. AB - Chaplains are employed by health organizations around the world to support patients in recognizing and addressing their spiritual needs. There is currently no generalizable measure of the impact of these interventions and so the clinical and strategic worth of chaplaincy is difficult to articulate. This article introduces the Scottish PROM, an original five-item patient reported outcome measure constructed specifically to address this gap. It describes the validation process from its conceptual grounding in the spiritual care literature through face and content validity cycles. It shows that the Scottish PROM is internally consistent and unidimensional. Responses to the Scottish PROM show strong convergent validity with responses to the Warwick and Edinburgh Mental Well-Being Scale, a generic well-being scale often used as a proxy for spiritual well-being. In summary, the Scottish PROM is fit for purpose. It measures the outcomes of spiritual care as delivered by chaplains in this study. This novel project introduces an essential and original breakthrough; the possibility of generalizable international chaplaincy research. PMID- 28632088 TI - The Association of Daytime Maternal Napping and Exercise With Nighttime Sleep in First-Time Mothers Between 3 and 6 Months Postpartum. AB - OBJECTIVE: This study investigated the relationship of daytime maternal napping, exercise, caffeine, and alcohol intake to objective and subjective sleep indices. PARTICIPANTS: Sixty healthy, nondepressed, first-time mothers between 3 and 6 months postpartum. METHODS: Seven consecutive days of online behavior diaries, sleep diaries, and wrist actigraphy, collecting Total Sleep Time (TST), Sleep Onset Latency (SOL), and Wake After Sleep Onset (WASO). RESULTS: After controlling for infant age, employment status, infant feeding method, and infant sleeping location, mixed linear models showed that longer average exercise durations were associated with longer average TST, and longer average nap durations were associated with longer average WASO durations. Significant within person differences in TST and SOL were also observed, such that, on days when participants exercised and napped longer than average, their respective TST and SOL durations that night were longer. CONCLUSION: Shorter nap durations and longer exercise durations were associated with longer TST, shorter SOL, and reduced WASO. Even small changes in daily exercise and napping behaviors could lead to reliable improvements in postpartum maternal sleep. PMID- 28632089 TI - Older lesbians receiving home care: formal and informal dimensions of caregiving. AB - Older lesbians face the triple jeopardy of ageism, sexism, and heterosexism, and their experiences are largely invisible. This qualitative, exploratory study examines the formal and informal caregiving experiences of 20 lesbians, 65 and older, who had utilized home care services due to acute illness or chronic disabilities. Half of those not partnered reported some level of isolation from support networks. Nearly all study participants eventually found home care workers with whom they were satisfied and even quite connected. Practice implications are discussed in context of study participants' views of how being lesbian affects their aging process and day-to-day lives. PMID- 28632090 TI - From the Editor. PMID- 28632091 TI - A phenomenological study of romantic love for women in late life. AB - Romantic love in late life is often beneficial, though not without challenges. Financial concerns and objections of adult children can interfere with a late life individual's decision to commit to a romantic relationship. In this study, the experience of romantic love for women who enter committed relationships in later life was examined. Fourteen women between the ages of 65 and 84 who had lived the experience of romantic love in late life were interviewed. By using Moustakas's qualitative Transcendental Phenomenological method, several themes emerged to provide a description of the phenomena. These themes included openness to experience, attraction, commitment, adjournment, and generativity. According to the findings of this study, women in late life who form committed romantic love relationships negate the physical and emotional effects of loneliness brought about by bereavement or single status in late-life women. In addition, this study found these women were attracted to partners to fulfill their needs for love, esteem, spiritual connection, and self-actualization. PMID- 28632092 TI - Unscripted: Exploring representations of older unpartnered women's sexuality. AB - Images of sexually active women beyond the age of 50 are lacking in popular culture and in particular on television. Dominant sexual scripts depict older women as generally asexual. The television program Hot in Cleveland features unpartnered midlife and older women as main characters. In this article, based on analysis of four seasons of Hot in Cleveland, we look closely at portrayals of sexual activity to see whether they underscore dominant sexual scripts mocking older women's sexual interest, position aging as sexual decline, or reinforce the narrative of "successful" aging/aging as progress. We find that women are depicted as desirable and desiring, counter to the narrative of aging as sexual decline. Hot in Cleveland thus provides sexual scripts for older women and reinforces the idea of lifelong sexual desire. PMID- 28632093 TI - Allergic contact dermatitis from ophthalmics. AB - In this article we summarize the recently described allergens responsible for allergic contact dermatitis due to ophthalmic drugs and contact lens solutions, and emphaage the need on how to perform diagnostic testing in this special clinical entity. PMID- 28632094 TI - The interactive effects of social support and physical functioning on HIV medical outcomes among African Americans whom inject drugs. AB - Research suggests a syndemic of substance use, mental illness, and familial conflict is associated with poor HIV medical outcomes among African American persons living with HIV (PLHIV). Social support may facilitate positive health outcomes. This study explores psychosocial correlates of HIV medical outcomes, defined as undetectable viral load (UVL) and acute care minimization. Data were from baseline of the BEACON study (N = 351). UVL was <=40 copies/mL. Acute care minimization was defined as no ER visits and/or hospitalizations in 6 months. Descriptive statistics and Poisson regression were implemented (N = 351). Moderate syndemic burden was associated with viral suppression. Individuals with main partner caregivers had 35% higher likelihood of viral suppression than individuals whose main supporters were neither kin nor main partners (adjusted point-prevalence rate ratio [APR] = 1.35; 95% CI [1.05, 1.74]). Surprisingly, individuals with more health-related support were more likely to use acute care than individuals with less health-related support (p<.05). Interaction analyses showed that physical function modified the relationship between main supporter type and acute care minimization. Results suggest that social support receipt was not consistently associated with HIV medical outcomes. Conversely, higher syndemic burden may have facilitated positive outcomes through necessitating increased rates of health care engagement. Health care professionals should elicit discussion of social support to strengthen PLHIVs' and their supporters' relationships to improve their health. Results highlight the need for culturally tailored interventions to improve HIV medical outcomes among African American PLHIV substance users. PMID- 28632095 TI - Transgressing gender norms in addiction treatment: Transgender rights to access within gender-segregated facilities. AB - Despite having disproportionately high rates of substance use disorder and co occurring health and mental health issues compared to the general population, transgender individuals experience significant barriers to accessing and engaging in addiction treatment programs. Inpatient addiction treatment centers were originally designed to treat substance-dependent heterosexual cisgender populations and, as such, feature gender-segregated housing, bathrooms, and treatment sessions. The heteronormative structural and programmatic barriers, combined with exposures to stigmatic and prejudicial attitudes, may dissuade transgender populations from benefiting from the addiction treatment they so direly need. The purpose of this article is to examine the current policy debate surrounding the rights of transgender individuals in public accommodations in the context of inpatient addiction treatment centers. PMID- 28632096 TI - Racial/ethnic differences in life-course heavy drinking from adolescence to midlife. AB - Information on heavy drinking over the life course might help to explain racial/ethnic disparities in alcohol-related problems, morbidity, and mortality. Using data from the 2009-2010 U.S. National Alcohol Survey (n = 3,026), we analyzed retrospective decades-based measures of heavy drinking during respondents' teens, 20s, 30s, and 40s. Results indicate that Latino men and African American women have greater risk for persistent-high (vs. declining) heavy-drinking trajectories than Caucasian men and women, and that socioeconomic disadvantage partly accounts for this disparity in women. Prospective longitudinal studies are needed to confirm these results and to elucidate the relationship of life-course heavy-drinking patterns with health-related outcomes, and disparities in these. PMID- 28632097 TI - The moderating effect of neighborhood sense of community on predictors of substance use among Hispanic urban youth. AB - Hispanic adolescents represent a disproportionate number of youth living in urban communities. These youth confront significant social problems that increase their likelihood for substance use. However, youth that have a greater neighborhood sense of community are postulated, through empowerment theory, to be less influenced by negative environmental experiences and less inclined to engage in drug and alcohol use. We examine the moderating effect neighborhood SOC has on predictors of substance use among Hispanic (N = 538) urban youth in low- (n = 246) and high-conflict homes (n = 292). Using logistic regression analysis and a plotting technique to examine interaction effects, we explore these relationships and provide recommendations for practice and prevention. PMID- 28632098 TI - Utility and accuracy of perceptual voice and speech distinctions in the diagnosis of Parkinson's disease, PSP and MSA-P. AB - AIM: To determine if perceptual speech measures distinguish people with Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P) and progressive supranuclear palsy (PSP). METHODS: Speech-language therapists blind to patient characteristics employed clinical rating scales to evaluate speech/voice in 24 people with clinically diagnosed PD, 17 with PSP and 9 with MSA-P, matched for disease duration (mean 4.9 years, standard deviation 2.2). RESULTS: No consistent intergroup differences appeared on specific speech/voice variables. People with PD were significantly less impaired on overall speech/voice severity. Analyses by severity suggested further investigation around laryngeal, resonance and fluency changes may characterize individual groups. CONCLUSION: MSA-P and PSP compared with PD were distinguished by severity of speech/voice deterioration, but individual speech/voice parameters failed to consistently differentiate groups. PMID- 28632099 TI - How Working With a Helpful Versus Less Helpful Confederate Influences Joint Action in a Pegboard Task. AB - Actors change their movement strategies to complement a coactor's movements when performing cooperative tasks. To further investigate this topic, the authors designed a pegboard task whereby a participant-confederate pair worked together to move a peg from one side of the board to the other. The authors examined how the experience of working with a helpful confederate versus less helpful confederate influenced the participant's movement behavior. Results provide evidence that participants change their movement behaviors in response to the actions of the confederate. Here the human capacity to act in such a manner exemplifies an individual's ability to utilize his or her own action system to understand others and interact to complete joint action tasks. Individuals appear to adapt their behavior to their experiences, and thus may be helpful in some contexts and less helpful in others. PMID- 28632100 TI - When an Object Appears Unexpectedly: Object Circumvention in Adults. AB - Obstacles often appear unexpectedly in our pathway and these require us to make immediate adjustments. Despite how regularly we encounter such situations only few studies have considered how we adjust to unexpected obstacles in the pathway that require us to walk around them. The authors considered how adults adjust to the possibility of an obstacle appearing and then also how foot placement is adjusted to circumvent an obstacle. Fifteen healthy adults walked down an 11-m walkway, initially they were told this was a clear pathway and nothing in the environment would change (no gate), they then performed a series of trials in which a gate may (gate close) or may not (gate open) partially obstruct their pathway. The authors found that mediolateral trunk velocity and acceleration was significantly increased when there was the possibility of an obstacle but before the obstacle appeared. This demonstrates an adaptive walking strategy that seems to enable healthy young adults to successfully circumvent obstacles. The authors also categorized foot placement adjustments and found that adults favored making shorter and wider steps away from the obstacle. They suggest this combination of adjustments allows participants to maintain stability while successfully circumventing the obstacle. PMID- 28632102 TI - Effect of Transient Perturbations of Short-Term Memory on Target-Directed Blind Locomotion. AB - It is difficult to walk without vision to a nearby destination if there is a time delay between watching the destination and walking toward it. Indeed, path deviation occurred when delays were introduced before initiating straight ahead blindfolded walking (R. A. Tyrrell, K. K., Rudolph, B. G., Eggers, & H. W. Leibowitz, 1993 ). The questions are whether the location of a 60-s delay in the walking path and whether performing a cognitive task during the delay influence the accuracy in reaching a previously seen target while walking without vision. Thirty young adults walked blindfolded and stopped when they believed they had reached a target at 8 m. Delays were 60 s in duration, were located at 0, 4, and 7 m, and involved waiting or backward counting. Significant differences were found between 0-m and 4-m delay locations for distance to target, distance travelled and path deviation (p < .05). Significant effect of backward counting during the 60-s delay was found at the 0-m delay for distance travelled (p < .05). The interaction between retaining visual guidance information during 60 s and performing a cognitive task likely influenced target-directed blind navigation. PMID- 28632101 TI - Decline of Hip Joint Movement Relates to Overestimation of Maximum Forward Reach in Elderly Persons. AB - The authors aimed to characterize age-related changes in the performance of maximum reach and identify kinematic parameters that explain the age-related discrepancy between perceived and actual maximum reach distance. Maximum reach was evaluated in 22 younger women (21.3 years old) and 20 older women (81.2 years old). Both the perceived and actual maximum forward reach and forward excursion of the center of pressure was shorter in older women. Older women also overestimated their maximum reach distance to a greater extent. Decline of movement at the hip joint specifically correlated with both the maximum distance and the overestimation. Based on these results, decline of hip control may be a primary factor for the age-related retardation of perceived and actual maximum reach. PMID- 28632103 TI - Developmental Characteristics of Disparate Bimanual Movement Skills in Typically Developing Children. AB - Mastery of many tasks in daily life requires role differentiated bimanual hand use with high spatiotemporal cooperation and minimal interference. The authors investigated developmental changes in the performance of a disparate bimanual movement task requiring sequenced movements. Age groups were attributed to changes in CNS structures critical for bimanual control such as the corpus callosum (CC) and the prefrontal cortex; young children (5-6 years old), older children (7-9 years old), and adolescents (10-16 years old). Results show qualitative changes in spatiotemporal sequencing between the young and older children which typically marks a phase of distinct reduction of growth and myelination of the CC. Results show qualitative changes in spatiotemporal sequencing between the young and older children, which coincides with distinct changes in the growth rate and myelination of the CC. The results further support the hypothesis that CC maturation plays an important role in the development of bimanual skills. PMID- 28632104 TI - Bimanual Lifting: Do Fingertip Forces Work Independently or Interactively? AB - Bimanual coordination is a commonplace activity, but the consequences of using both hands simultaneously are not well understood. The authors examined fingertip forces across 4 experiments in which participants undertook a range of bimanual tasks. They first measured fingertip forces during simultaneous lifts of 2 identical objects, noting that individuals held the objects with more force bimanually than unimanually. They then varied the mass of the objects held by each hand, noting that when both hands lifted together performance was equivalent to unimanual lifts. The authors next measured one hand's static grip force while the other hand lifted an object. They found a gradual reduction of grip force throughout the trial, but once again no evidence of one hand influencing the other. In the final experiment the authors tested whether tapping with one hand could influence the static grip force of its counterpart. Although the authors found no changes in static grip force as a direct consequence of the other hand's actions, they found clear differences from one task to the other, suggesting an effect of task instruction. Overall, these results suggest that fingertip forces are largely independent between hands in a bimanual lifting context, but are sensitive to different task requirements. PMID- 28632105 TI - Obstacle Avoidance Increases Asymmetry of Crossing Step in Individuals With Parkinson's Disease and Neurologically Healthy Individuals. AB - The authors' aim was to investigate gait asymmetry of crossing step during obstacle avoidance while walking in people with Parkinson's disease (PD) under and without the effects of dopaminergic medication. Thirteen individuals with PD and 13 neurologically healthy individuals performed 5 trials of unobstructed gait and 10 trials of obstacle crossing during gait (5 trials with each leg) and spatiotemporal parameters were analyzed. Obstacle crossing increased step duration of the crossing step for the most-affected or nondominant limb compared to the crossing step with the least-affected or dominant limb. Individuals with PD without the effects of medication increased step duration for the step with the least-affected limb compared to the step with the most-affected limb during obstacle crossing. PMID- 28632106 TI - Speed-Interactive Treadmill Training Using Smartphone-Based Motion Tracking Technology Improves Gait in Stroke Patients. AB - This study was conducted to investigate the effects of speed-interactive treadmill training (SITT) using smartphone-based motion tracking technology on gait in stroke patients. Thirty-four chronic stroke patients were randomly divided into a SITT group (n = 18) and a standard treadmill training (control) group (n = 16). The SITT group underwent smartphone-based SSIT while the control group underwent standard treadmill training. Both groups performed the training for 35 min per session, 3 times per week, for 6 weeks. Both groups used nonmotorized treadmills so that patients could control the speed. Evaluation was conducted during the week before and after the training. The OptoGait system measured gait spatiotemporal parameters. Both groups showed significant improvement in the temporal and spatial gait parameters (p < .05). In the SITT group, compared to the control group, the two-way analysis of variance with repeated measures showed an improvement in the temporal and spatial gait parameters after the intervention period (p < .05). This study confirmed that SITT improved the gait function of stroke patients. Based on this result, the authors propose that SITT, by improving gait, can be used as an effective training method to improve patients' functional activities in the clinic. PMID- 28632107 TI - Linking attentional control and PTSD symptom severity: the role of rumination. AB - Although deficits in attentional control have been linked to posttraumatic stress disorder (PTSD), the mechanism that may account for this association has not been fully elucidated. The present study examined rumination as a mediator of the relationship between attentional control and PTSD symptoms. Veterans with PTSD and trauma-exposed veterans without PTSD completed measures of attentional control, rumination, and PTSD symptom severity. As predicted, the findings showed that veterans with PTSD reported significantly lower levels of attentional control than veterans without PTSD. Veterans with PTSD also reported significantly higher levels of rumination than veterans without PTSD. Subsequent analysis of the total sample revealed that the relationship between attentional control and PTSD symptom severity was accounted for by excessive rumination. Attentional control may contribute to PTSD symptoms through excessive rumination. Attentional control and rumination may be important targets for PTSD interventions. PMID- 28632108 TI - Swallowing in Parkinson's disease: clinical issues and management. AB - Changes to swallowing affect most people with Parkinson's disease (PD). Changes may not initially exercise a decisive impact, but can later pose significant threats to nutritional, hydration and respiratory health and psychosocial quality of life. This review, from a largely clinical viewpoint, outlines the nature of changes in PD and considers the issue of how many people are affected and in what ways. It outlines main approaches to assessment and management, with an emphasis on aspects relevant to PD. Dysphagia contributes to drooling in PD. The review therefore also touches on the nature and management of this condition that has its own set of health and psychosocial quality-of-life issues. PMID- 28632110 TI - Erratum. PMID- 28632109 TI - Successful treatment of sexually acquired acute HCV reinfection with ledipasvir/sofosbuvir in a HIV-infected patient. AB - Here we describe the case of a HIV-positive patient with acute hepatitis C virus reinfection, who was successfully treated with an interferon-free regimen of ledipasvir/sofosbuvir. PMID- 28632111 TI - Herpes neolabialis: herpes simplex virus type 1 infection of the neolabia in a transgender woman. AB - A 24-year-old transgender woman consulted our outpatient clinic with a painful, itchy and red left labia. She underwent a penile inversion vaginoplasty 18 months before presentation. At physical examination of the left labia, erythema, edema and herpetic vesicles with ulceration were observed. A vesicle fluid swab was obtained and the presence of herpes simplex virus type 1 (HSV-1) was detected by PCR assay. Treatment consisted of oral valaciclovir (500 mg twice daily) for a total of five days.Topically-applied lidocaine cream (3%) was used for pain management. Treatment gave symptom relief in five days. At physical examination 14 days after symptom onset, there were no signs of active infection. To our knowledge, this is the first case report of HSV-1 infection of the neolabia in a transgender woman. PMID- 28632112 TI - The 2016 European guideline on the management of epididymo-orchitis. AB - Epididymo-orchitis is a commonly encountered condition with a reported incidence of 2.45 cases per 1000 men in the United Kingdom. This 2016 International Union against Sexually Transmitted Infections guideline provides up-to-date advice on the management of this condition. It describes the aetiology, clinical features and potential complications, as well as presenting diagnostic considerations and clear recommendations for management and follow-up. Early diagnosis and management are essential, as serious complications can include abscess formation, testicular infarction and infertility. Recent epidemiological evidence suggests that selection of fluoroquinolone antibiotics with anti-Chlamydial activity is more appropriate in the management of sexually active men in the over 35 years age group. PMID- 28632113 TI - Paracandidimonas soli gen. nov., sp. nov., isolated from soil. AB - A slightly yellow-pigmented, Gram-stain-negative, rod-shaped bacterium, strain IMT-305T, was isolated from soil in Alabama, USA. Phylogenetic analysis based on the nearly full-length 16S rRNA gene sequence placed the strain in between the genera Pusillimonas, Parapusillimonas and Candidimonas with highest 16S rRNA gene sequence similarity to the type strain of Parapusillimonas granuli (97.5 %) and Candidimonas nitroreducens (97.4 %). The genomic G+C content of strain IMT-305T was 63.9 mol%. The main cellular fatty acids were C18:1omega7c, C17:0 cyclo, C16:0 and C16:1omega7c/iso-C15:0 2-OH (detected as summed feature 3). The polyamine pattern of strain IMT-305T contained the major compound putrescine and the betaproteobacterial diagnostic 2-hydroxyputrescine and the major respiratory quinone was ubiquinone Q-8. Predominant polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, an unidentified aminolipid, an unidentified aminophospholipid and an unidentified lipid lacking any functional group. Based on phylogenetic, chemotaxonomic and phenotypic analyses a novel species within a new genus, Paracandidimonas soli gen. nov., sp. nov., is proposed. The type strain of Paracandidimonas soli is IMT 305T (=DSM 100048T=CIP 110902T=LMG 28740T=CCM 8599T). PMID- 28632114 TI - Enterococcus crotali sp. nov., isolated from faecal material of a timber rattlesnake. AB - A facultatively anaerobic, Gram-stain-positive bacterium, designated ETRF1T, was found in faecal material of a timber rattlesnake (Crotalus horridus). Based on a comparative 16S rRNA gene sequence analysis, the isolate was assigned to the genus Enterococcus. The 16S rRNA gene sequence of strain ETRF1T showed >97 % similarity to that of the type strains of Enterococcus rotai, E. caccae, E. silesiacus, E haemoperoxidus, E. ureasiticus, E. moraviensis, E. plantarum, E. quebecensis, E. ureilyticus, E. termitis, E. rivorum and E. faecalis. The organism could be distinguished from these 12 phylogenetically related enterococci using conventional biochemical testing, the Rapid ID32 Strep system, comparative pheS and rpoA gene sequence analysis, and comparative whole genome sequence analysis. The estimated in silico DNA-DNA hybridization values were <70 %, and average nucleotide identity values were <96 %, when compared to these 12 species, further validating that ETRF1T represents a unique species within the genus Enterococcus. On the basis of these analyses, strain ETRF1T (=CCUG 65857T=LMG 28312T) is proposed as the type strain of a novel species, Enterococcus crotali sp. nov. PMID- 28632115 TI - Flaviaesturariibacter luteus sp. nov., isolated from an agricultural floodplain soil, and emended description of the genus Flaviaesturariibacter. AB - A novel slow-growing bacterial strain designated as AW305T was isolated from an agricultural floodplain soil located in Mashare, Kavango region, Namibia. Cells stained Gram-negative, were non-motile, non-spore-forming, coccoid to rod-shaped and did not form a capsule. Colonies were yellow-pigmented, but flexirubin-type pigments were not detected. AW305T had an aerobic chemo-organoheterotrophic metabolism, using a narrow spectrum of carbon sources for growth, with preference for complex protein substrates, organic acids and amino acids. AW305T was able to grow at 15-40 degrees C, pH 5.3-8.3 and in the presence of up to 0.25 % (w/v) NaCl. 16S rRNA gene sequence comparison showed that AW305T belonged to the genus Flaviaesturariibacter (family Chitinophagaceae). Its closest relatives were Flaviaesturariibacter amylovorans GCR0105T (97.0 %), Flavisolibacter ginsengiterrae Gsoil 492T (93.6 %) and Flavisolibacter ginsengisoli Gsoil 643T (93.2 %). DNA-DNA hybridization experiments corroborated that AW305T represents an independent genomospecies. The genomic DNA G+C content was 57.6 mol%. Major fatty acids were iso-C15 : 1 G, iso-C15 : 0, C16 : 1omega5c, iso-C17 : 0 3-OH and summed feature 3 (C16 : 1omega7c and/or iso-C15 : 0 2-OH). The predominant respiratory quinone was MK-7, albeit minor amounts of MK-6 were also detected. The polar lipids comprised major amounts of phosphatidylethanolamine and minor amounts of two unidentified lipids, an unidentified phospholipid, an unidentified glycolipid and an unidentified aminoglycophospholipid. On the basis of the polyphasic characterization, strain AW305T represents a novel species of the genus Flaviaesturariibacter for which the name Flaviaesturariibacter luteus sp. nov. is proposed, with the type strain AW305T (=DSM 100282T=LMG 29416T). PMID- 28632116 TI - Reyranella terrae sp. nov., isolated from an agricultural soil, and emended description of the genus Reyranella. AB - A novel strain designated 11G32T was isolated from an agricultural soil cultivated with Chinese cabbage in Korea. The cells were Gram-stain-negative, aerobic, non-motile and rod-shaped. The strain grew at 15-28 degrees C (optimum, 20 degrees C), pH 5.0-7.0 (optimum, pH 5.0-6.0) and without NaCl. Phylogenetically, the strain was found to be closely related to members of the genus Reyranella and showed 16S rRNA gene sequence similarities of 97.18, 96.76 and 95.99 % with Reyranella graminifolii Wo-34T, Reyranella massiliensis 521T and Reyranella soli KIS14-15T, respectively. The major fatty acids were C19 : 0 cyclo omega8c, C16 : 0, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and 11 methyl C18 : 1omega7c. The predominant ubiquinone was Q-10. The polar lipids profile revealed the presence of phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, unidentified aminolipids, unidentified phospholipids and unidentified lipids. On the basis of data presented, strain 11G32T is considered to represent a novel species of the genus Reyranella, for which the name Reyranella terrae sp. nov. is proposed. The type strain is 11G32T (=KACC 18486T=NBRC 111476T). PMID- 28632117 TI - Saccharopolyspora spongiae sp. nov., a novel actinomycete isolated from the marine sponge Scopalina ruetzleri (Wiedenmayer, 1977). AB - A novel marine actinomycete, designated strain CMAA 1452T, was isolated from the sponge Scopalina ruetzleri collected from Saint Peter and Saint Paul Archipelago, in Brazil, and subjected to a polyphasic taxonomic investigation. The organism formed a distinct phyletic line in the Saccharopolyspora 16S rRNA gene tree and had chemotaxonomic and morphological properties consistent with its classification in this genus. It was found to be closely related to Saccharopolyspora dendranthemae KLBMP 1305T (99.5% 16S rRNA gene sequence similarity) and shared similarities of 99.3, 99.2 and 99.0 % with 'Saccharopolyspora endophytica' YIM 61095, Saccharopolyspora tripterygii YIM 65359T and 'Saccharopolyspora pathumthaniensis' S582, respectively. DNA-DNA relatedness values between the isolate and its closest phylogenetic neighbours, namely S. dendranthemae KLBMP 1305T, 'S. endophytica' YIM 61095 and S. tripterygii YIM 65359T, were 53.5, 25.8 and 53.2 %, respectively. Strain CMAA 1452T was also distinguished from the type strains of these species using a range of phenotypic features. On the basis of these results, it is proposed that strain CMAA 1452T (=DSM 103218T=NRRL B-65384T) merits recognition as the type strain of a novel Saccharopolyspora species, Saccharopolyspora spongiae sp. nov. PMID- 28632118 TI - Tessaracoccus arenae sp. nov., isolated from sea sand. AB - A Gram-stain positive, non-spore-forming, non-motile, facultatively anaerobic bacterial strain, designated CAU 1319T, was isolated from sea sand and the strain's taxonomic position was investigated using a polyphasic approach. Strain CAU 1319T grew optimally at 30 degrees C and at pH 7.5 in the presence of 2 % (w/v) NaCl. Phylogenetic analysis, based on the 16S rRNA gene sequence, revealed that strain CAU 1319T belongs to the genus Tessaracoccus, and is closely related to Tessaracoccus lapidicaptus IPBSL-7T (similarity 97.69 %), Tessaracoccus bendigoensis Ben 106T (similarity 95.64 %) and Tessaracoccus flavescens SST-39T (similarity 95.84 %). Strain CAU 1319T had ll-diaminopimelic acid as the diagnostic diamino acid in the cell-wall peptidoglycan, MK-9 (H4) as the predominant menaquinone, and anteiso-C15 : 0 as the major fatty acid. The polar lipids consisted of phosphatidylglycerol, phosphatidylinositol, two unidentified aminolipids, three unidentified phospholipids and one unidentified glycolipid. Predominant polyamines were spermine and spermidine. The DNA-DNA hybridization value between strain CAU 1319T and T. lapidicaptus IPBSL-7T was 24 %+/-0.2. The DNA G+C content of the novel strain was 69.5 mol%. On the basis of phenotypic and chemotaxonomic properties, as well as phylogenetic relatedness, strain CAU 1319Tshould be classified as a novel species of the genus Tessaracoccus, for which the name Tessaracoccus arenae sp. nov. is proposed. The type strain is CAU 1319T(=KCTC 39760T=NBRC 111973T). PMID- 28632119 TI - Alkaliphilus namsaraevii sp. nov., an alkaliphilic iron- and sulfur-reducing bacterium isolated from a steppe soda lake. AB - A novel alkaliphilic spore-forming bacterium was isolated from the benthic sediments of the highly mineralized steppe Lake Khilganta (Transbaikal Region, Russia). Cells of the strain, designated X-07-2T, were straight to slightly curved rods, Gram-stain-positive and motile. Strain X-07-2T grew in the pH range from 7.0 to 10.7 (optimum pH 9.6-10.3). Growth was observed at 25-47 degrees C (optimum 30 degrees C) and at an NaCl concentration from 5 to 150 g l-1 with an optimum at 40 g l-1. Strain X-07-2T was a chemo-organoheterotroph able to reduce amorphous ferric hydroxide, Fe(III) citrate and elemental sulfur in the presence of yeast extract as the electron donor. It used tryptone, peptone and trypticase with Fe(III) citrate as the electron acceptor. The predominant fatty acids in cell walls were C16:1omega8, iso-C15:0, C14 : 0 3-OH and C16 : 0. The DNA G+C content was 32.6 mol%. 16S rRNA gene sequence analysis revealed that strain X-07 2T was related most closely to members of the genus Alkaliphilus within the family Clostridiaceae. The closest relative was Alkaliphilus peptidifermentans Z 7036T (96.4 % similarity). On the basis of the genotypic, chemotaxonomic and phenotypic data, strain X-07-2T represents a novel species in the genus Alkaliphilus, for which the name Alkaliphilus namsaraevii sp. nov. is proposed. The type strain is X-07-2T (=VKM V-2746T=DSM 26418T). PMID- 28632120 TI - Basolateral amygdala-ventromedial prefrontal cortex connectivity predicts cognitive behavioural therapy outcome in adults with obsessive-compulsive disorder. AB - BACKGROUND: Cognitive behavioural therapy (CBT), including exposure and ritual prevention, is a first-line treatment for obsessive-compulsive disorder (OCD), but few reliable predictors of CBT outcome have been identified. Based on research in animal models, we hypothesized that individual differences in basolateral amygdala-ventromedial prefrontal cortex (BLA-vmPFC) communication would predict CBT outcome in patients with OCD. METHODS: We investigated whether BLA-vmPFC resting-state functional connectivity (rs-fc) predicts CBT outcome in patients with OCD. We assessed BLA-vmPFC rs-fc in patients with OCD on a stable dose of a selective serotonin reuptake inhibitor who then received CBT and in healthy control participants. RESULTS: We included 73 patients with OCD and 84 healthy controls in our study. Decreased BLA-vmPFC rs-fc predicted a better CBT outcome in patients with OCD and was also detected in those with OCD compared with healthy participants. Additional analyses revealed that decreased BLA-vmPFC rs-fc uniquely characterized the patients with OCD who responded to CBT. LIMITATIONS: We used a sample of convenience, and all patients were receiving pharmacological treatment for OCD. CONCLUSION: In this large sample of patients with OCD, BLA-vmPFC functional connectivity predicted CBT outcome. These results suggest that future research should investigate the potential of BLA-vmPFC pathways to inform treatment selection for CBT across patients with OCD and anxiety disorders. PMID- 28632121 TI - Anti-inflammatory treatment and risk for depression after first-time stroke in a cohort of 147 487 Danish patients. AB - BACKGROUND: Depression is a common complication after stroke, and inflammation may be a pathophysiological mechanism. This study examines whether anti inflammatory treatment with acetylsalicylic acid (ASA), nonsteroid anti inflammatory drugs (NSAIDs) or statins influence the risk of depression after stroke. METHODS: A register-based cohort including all patients admitted to hospital with a first-time stroke from Jan. 1, 2001, through Dec. 31, 2011, and a nonstroke population with a similar age and sex distribution was followed for depression until Dec. 31, 2014. Depression was defined as having a hospital contact with depression or having filled prescriptions for antidepressant medication. The associations between redeemed prescriptions of ASA, NSAIDs or statins with early- (<= 1 year after stroke or study entry) and late-onset (> 1 year after stroke or study entry) depression were analyzed using Cox proportional hazard regression. RESULTS: We identified 147 487 patients with first-time stroke and 160 235 individuals without stroke for inclusion in our study. Redeemed prescriptions of ASA, NSAIDs or statins after stroke decreased the risk for early onset depression, especially in patients with ischemic or severe stroke. Patients who received a combination of anti-inflammatory treatments had the lowest risk for early-onset depression. On the other hand, use of ASA or NSAIDs 1 year after stroke increased the risk for late-onset depression, whereas statin use was associated with a tendency toward a decreased risk. LIMITATIONS: The study used prescription of antidepressant medication as a proxy measure for depression and did not include anti-inflammatory drugs bought over the counter. CONCLUSION: Anti inflammatory treatment is associated with a lower risk for depression shortly after stroke but a higher risk for late depression. This suggests that inflammation contributes differently to the development of depression after stroke depending on the time of onset. PMID- 28632131 TI - Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration. AB - Zebrafish display a distinct ability to regenerate their heart following injury. However, this ability is not shared by another teleost, the medaka. In order to identify cellular and molecular bases for this difference, we performed comparative transcriptomic analyses following cardiac cryoinjury. This comparison points to major differences in immune cell dynamics between these models. Upon closer examination, we observed delayed and reduced macrophage recruitment in medaka, along with delayed neutrophil clearance. To investigate the role of immune responses in cardiac regeneration, we delayed macrophage recruitment in zebrafish and observed compromised neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. In contrast, stimulating Toll like receptor signaling in medaka enhanced immune cell dynamics and promoted neovascularization, neutrophil clearance, cardiomyocyte proliferation and scar resolution. Altogether, these data provide further insight into the complex role of the immune response during regeneration, and serve as a platform to identify and test additional regulators of cardiac repair. PMID- 28632130 TI - The laminar organization of the Drosophila ellipsoid body is semaphorin-dependent and prevents the formation of ectopic synaptic connections. AB - The ellipsoid body (EB) in the Drosophila brain is a central complex (CX) substructure that harbors circumferentially laminated ring (R) neuron axons and mediates multifaceted sensory integration and motor coordination functions. However, what regulates R axon lamination and how lamination affects R neuron function remain unknown. We show here that the EB is sequentially innervated by small-field and large-field neurons and that early developing EB neurons play an important regulatory role in EB laminae formation. The transmembrane proteins semaphorin-1a (Sema-1a) and plexin A function together to regulate R axon lamination. R neurons recruit both GABA and GABA-A receptors to their axon terminals in the EB, and optogenetic stimulation coupled with electrophysiological recordings show that Sema-1a-dependent R axon lamination is required for preventing the spread of synaptic inhibition between adjacent EB lamina. These results provide direct evidence that EB lamination is critical for local pre-synaptic inhibitory circuit organization. PMID- 28632133 TI - Correction: Functionally diverse human T cells recognize non-microbial antigens presented by MR1. PMID- 28632136 TI - Perinatal mortality after the Fukushima accident. PMID- 28632132 TI - Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenalin. AB - In the arcuate nucleus of the hypothalamus (ARH) satiety signaling (anorexigenic) pro-opiomelanocortin (POMC)-expressing and hunger signaling (orexigenic) agouti related peptide (AgRP)-expressing neurons are key components of the neuronal circuits that control food intake and energy homeostasis. Here, we assessed whether the catecholamine noradrenalin directly modulates the activity of these neurons in mice. Perforated patch clamp recordings showed that noradrenalin changes the activity of these functionally antagonistic neurons in opposite ways, increasing the activity of the orexigenic NPY/AgRP neurons and decreasing the activity of the anorexigenic POMC neurons. Cell type-specific transcriptomics and pharmacological experiments revealed that the opposing effect on these neurons is mediated by the activation of excitatory alpha1A - and beta- adrenergic receptors in NPY/AgRP neurons, while POMC neurons are inhibited via alpha2A - adrenergic receptors. Thus, the coordinated differential modulation of the key hypothalamic neurons in control of energy homeostasis assigns noradrenalin an important role to promote feeding. PMID- 28632137 TI - Electrospun silk-polyaniline conduits for functional nerve regeneration in rat sciatic nerve injury model. AB - The present study describes the fabrication of polyaniline-silk fibroin (PASF) nanocomposite-based nerve conduits and their subsequent implantation in a rat sciatic nerve injury model for peripheral nerve regeneration. This is the first in vivo study of polyaniline-based nerve conduits describing the safety and efficacy of the conduits in treating peripheral nerve injuries. The nanocomposite was synthesized by electrospinning a mixture of silk fibroin protein and polyaniline wherein the silk nanofibers were observed to be uniformly coated with polyaniline nanoparticles. Tubular shaped nerve conduits were subsequently formed by multiple rolling of the electrospun sheet over a stainless steel mandrel. The conduits were characterized in vitro for their physico-chemical properties as well as their compatibility with rat Schwann cells. Upon implantation in a 10 mm sciatic nerve injury model, the conduits were evaluated for their neuro regenerative potential through extensive electrophysiological studies and monitoring of gait pattern over a course of 12 months. Gross examination, histological and ultra-structure analyses of the conduits and the regenerated nerve were also performed to evaluate morphological regeneration of transected nerve. PASF nanocomposite conduits seeded with Schwann cell (cell seeded PASF) exhibited excellent nerve conduction velocity (NCV) (50 m s-1), compound muscle action potential (CMAP) (12.8 mV), motor unit potential (MUP) (124 MUV), growth of healthy tissue along the nerve gap and thick myelination of axons 12 months after implantation indicating enhanced neuro-regeneration. The excellent functional recovery achieved by animals implanted with cell seeded PASF conduits (86.2% NCV; 80.00% CMAP; 76.07% MUP) are superior to outcomes achieved previously with similar electrically conductive conduits. We believe that the present study would encourage further research in developing electrically active neural implants using synthetic conducting polymers and the in vivo applications of the same. PMID- 28632138 TI - Monitoring lung contusion in a porcine polytrauma model using EIT: an application study. AB - : Lung contusion is the most common lung injury following blunt chest trauma which, in turn, is associated with high mortality rates (Gavelli et al 2002 Eur. Radiol. 12 1273-94). Lung contusion is characterized by hemorrhage and edema with consecutively reduced compliance. Objective and Approach: In this study, unilateral lung contusion and other traumata were induced in 12 pigs by using a bolt gun machine. To investigate the pathophysiological consequences of lung contusion, information on clinical parameters was collected and monitored regularly while animals were additionally monitored with electrical impedance tomography (EIT) before trauma, and at 4, 24, 48 and 72 h after polytrauma. MAIN RESULTS: Statistical analyses showed significant differences between the measurement time points in terms of lung compliance ([Formula: see text]) and in global EIT parameters, such as absolute global impedance (aGlobImp) ([Formula: see text]), tidal impedance variation (TIV) ([Formula: see text]) and the center of ventilation (CoV) ([Formula: see text]). Additionally, distinct analyses for the left (non-injured) and right (injured) lung were also performed. In this context, during the progress of lung contusion, significant changes were found for the injured lung in TIV ([Formula: see text]), global inhomogeneity ([Formula: see text]), regional ventilation delay ([Formula: see text]), CoV ([Formula: see text]) and in regions of non-ventilation (rNoVent) ([Formula: see text]). Furthermore, TIV and rNoVent were capable to differentiate the injured and the contralateral healthy lung at 4 and 24 h after injury (TIV: [Formula: see text] and [Formula: see text]; rNoVent: [Formula: see text] and [Formula: see text]). TIV reached a sensitivity of 82% (specificity of 100%) at 4 h and sensitivity of 82% (specificity of 82%) at 24 h after injury, in detecting lung contusion specific consequences. SIGNIFICANCE: The results indicate that EIT might be a valuable tool to detect and to monitor lung injuries including lung contusion. Most probably, EIT-derived indices could also be used to adapt ventilator settings to optimize individual lung protection. PMID- 28632139 TI - Peptide functionalized gold nanoparticles: the influence of pH on binding efficiency. AB - We report herein on the synthesis of mixed monolayer gold nanoparticles (AuNPs) capped with both polyethylene glycol (PEG) and one of three peptides. Either a receptor-mediated endocytosis peptide, an endosomal escape pathway (H5WYG) peptide or the Nrp-1 targeting RGD peptide (CRGDK) labeled with FITC. All three peptides have a thiol containing cysteine residue which can be used to bind the peptides to the AuNPs. In order to investigate the influence of pH on peptide attachment, PEGylated AuNPs were centrifuged, the supernatant removed, and the nanoparticles were then re-suspended in a range of pH buffer solutions above, below and at the respective isoelectric points of the peptides before co functionalization. Peptide attachment was investigated using dynamic light scattering, Ultra-violet visible spectroscopy (UV/Vis), FTIR and photo luminescence spectroscopy. UV/Vis analysis coupled with protein assay results and photoluminescence of the FITC tagged RGD peptide concluded that a pH of ~8 optimized the cysteine binding and stability, irrespective of the peptide used. PMID- 28632140 TI - Thermal stability and rheological properties of the 'non-stick' Caf1 biomaterial. AB - The ability to culture cells in three-dimensions has many applications, from drug discovery to wound healing. 3D cell culture methods often require appropriate scaffolds that mimic the cellular environments of different tissue types. The choice of material from which these scaffolds are made is of paramount importance, as its properties will define the manner in which cells interact with the scaffold. Caf1 is a protein polymer that is secreted from its host organism, Yersinia pestis, to enable escape from phagocytosis. In vitro, cells adhere poorly to the protein unless adhesion motifs are specifically introduced. Caf1 is a good candidate biomaterial due to its definable bioactivity, economical production and its ability to form hydrogels, through the use of cross-linkers. In this study, the thermostability of Caf1 was tested over a range of chemical conditions, and an initial characterisation of its rheological properties conducted in order to assess the suitability of Caf1 as a biomedical material. The results show that Caf1 retains its high thermostability even in harsh conditions such as extremes of pH, high salt concentrations and the presence of detergents. In solution, the concentrated polymer behaves as a complex viscous liquid. Due to these properties, Caf1 polymers are compatible with 3D bioprinting technologies and could be made to form a stimuli-responsive biomaterial that can alter its macrorheological properties in response to external factors. Caf1 biomaterials could therefore prove useful as 3D cell scaffolds for use in cell culture and wound repair. PMID- 28632141 TI - Phase transitions of the dimerized Kane-Mele model with/without strong interaction. AB - The dimerized Kane-Mele model with/without strong interaction is studied using analytical methods. The boundary of the topological phase transition of the model without strong interaction is obtained. Our results show that the occurrence of the transition only depends on dimerized parameter [Formula: see text]. From the one-particle spectrum, we obtain the completed phase diagram including the quantum spin Hall state and the topologically trivial insulator. Then, using different mean field methods, we investigate the Mott transition and the magnetic transition of the strongly correlated dimerized Kane-Mele model. In the region between the two transitions, the topological Mott insulator with characteristics of Mott insulators and topological phases may be the most interesting phase. In this work, the effects of hopping anisotropy and Hubbard interaction U on the boundaries of the two transitions are observed in detail. The completed phase diagram of the dimerized Kane-Mele-Hubbard model is also obtained in this work. Quantum fluctuations have extremely important influences on a quantum system. However, investigations are under the framework of mean field treatment in this work and the effects of fluctuations in this model will be discussed in the future. PMID- 28632142 TI - Flat bands and Dirac cones in breathing lattices. AB - In breathing pyrochlores and kagomes, couplings between neighbouring tetrahedra and triangles are free to differ. Breathing lattices thus offer the possibility to explore a different facet of the rich physics of these systems. Here we consider nearest-neighbour classical Heisenberg interactions, both ferromagnetic and antiferromagnetic, and study how the anisotropy of breathing lattices modifies the mode spectrum of pyrochlore and kagome systems. The nature and degeneracy of the flat bands are shown to be preserved for any value of the anisotropy. These flat bands can coexist with Dirac nodes at the [Formula: see text] point when the model becomes particle-hole symmetric. We also derive the nature of the ground state for the breathing kagome lattice, which bears a spontaneous chirality when neighbouring triangles are alternatively ferromagnetic and antiferromagnetic. PMID- 28632143 TI - The thermal expansion of (Fe1-y Ni y )Si. AB - We have measured the thermal expansion of (Fe1-y Ni y )Si for y = 0, 0.1 and 0.2, between 40 and 1273 K. Above ~700 K the unit-cell volumes of the samples decrease approximately linearly with increasing Ni content. Below ~200 K the unit cell volume of FeSi falls to a value between that of (Fe0.9Ni0.1)Si and (Fe0.8Ni0.2)Si. We attribute this extra contraction of the FeSi, which is a narrow band-gap semiconductor, to the depopulation of the conduction band at low temperatures; in the two alloys the additional electrons introduced by the substitution of Ni lead to the conduction band always being populated. We have fit the unit-cell volume data with a Debye internal energy model of thermal expansion and an additional volume term, above 800 K, to take account of the volumetric changes associated with changes in the composition of the sample. Using the thermophysical parameters of the fit we have estimated the band gap in FeSi to be 21(1) meV and the unit-cell volume change in FeSi associated with the depopulation of the conduction band to be 0.066(35) A3/unit-cell. PMID- 28632144 TI - Optimal pitching axis location of flapping wings for efficient hovering flight. AB - Flapping wings can pitch passively about their pitching axes due to their flexibility, inertia, and aerodynamic loads. A shift in the pitching axis location can dynamically alter the aerodynamic loads, which in turn changes the passive pitching motion and the flight efficiency. Therefore, it is of great interest to investigate the optimal pitching axis for flapping wings to maximize the power efficiency during hovering flight. In this study, flapping wings are modeled as rigid plates with non-uniform mass distribution. The wing flexibility is represented by a linearly torsional spring at the wing root. A predictive quasi-steady aerodynamic model is used to evaluate the lift generated by such wings. Two extreme power consumption scenarios are modeled for hovering flight, i.e. the power consumed by a drive system with and without the capacity of kinetic energy recovery. For wings with different shapes, the optimal pitching axis location is found such that the cycle-averaged power consumption during hovering flight is minimized. Optimization results show that the optimal pitching axis is located between the leading edge and the mid-chord line, which shows close resemblance to insect wings. An optimal pitching axis can save up to 33% of power during hovering flight when compared to traditional wings used by most of flapping wing micro air vehicles (FWMAVs). Traditional wings typically use the straight leading edge as the pitching axis. With the optimized pitching axis, flapping wings show higher pitching amplitudes and start the pitching reversals in advance of the sweeping reversals. These phenomena lead to higher lift-to-drag ratios and, thus, explain the lower power consumption. In addition, the optimized pitching axis provides the drive system higher potential to recycle energy during the deceleration phases as compared to their counterparts. This observation underlines the particular importance of the wing pitching axis location for energy-efficient FWMAVs when using kinetic energy recovery drive systems. PMID- 28632145 TI - What really is an indeterminate FNA thyroid nodule? AB - BACKGROUND: Thyroid nodules are usually benign; however, 5 to 15% prove to be malignant. Fine-needle aspiration (FNA) has become the gold standard in the evaluation of thyroid nodules, especially in single nodule more than a centimeter and / or in smaller nodule with ultrasound characters of malignancy. METHODS: We evaluated retrospectively 179 patients with "undetermined" thyroid fine needle aspiration, undergoing surgery. We compared cytology and histology and we evaluated sex, age, the presence of thyroiditis and dimension of the indeterminate nodule as predictors of malignancy. RESULTS: In 48 patients (26.8%) histological examination confirmed the indeterminate cytological diagnosis and this means that the nodule underwent FNA was diagnosed in effects such as cancer. In 29 patients, on histological examination, the nodule underwent FNA was not diagnosed as cancer, but one or more carcinomas were diagnosed in the same lobe of indeterminate nodule, but in different location and / or in the contralateral lobe. In 102 patients, the definitive histological examination did not confirm the suspected diagnosis and we found a significant positive association only between male sex and histological malignancy. CONCLUSIONS: The indeterminate FNA still remains a challenge for the surgeon because it is not yet possible to discriminate patients who really need surgery from those that can be followed in follow-up. The potential of molecular diagnostics for thyroid nodules with indeterminate cytology is promising, but many of these markers are too complex or expensive for routine clinical use or are still poorly standardized. KEY WORDS: Indeterminate FNA, Thyroid, Thyroid fine needle aspiration. PMID- 28632146 TI - Physiological interrelationships between the venous shunts of penile corpus spongiosum and cavernous compartments during erection used in the pharmacotherapy of erectile dysfunction. AB - AIM OF THE STUDY: Alprostadil (A) induces smooth-muscle relaxation by stimulating the increasing of intracellular cAMP. Intra-urethral administration is an alternative to its intra-cavernose injection in inducing erection. In order to understand the functional and anatomical basis for drug transfer, the possible communications of the corpus spongiosum with the corpora cavernosa were studied. MATERIAL OF STUDY: A "Spongiogram" (SP) was performed in 44patients (pt.) by injection of radiological contrast into the glans. The SP visualized drainage of the glans into the deep dorsal vein, as well as that of the spongiosum into the circumflex veins, which in turn drained into the deep dorsal vein. RESULTS: In 34pt. (77,2%) filling of the corpora was also visualized; in 10pt.(22.8%), with ectasia of the deep dorsal vein, such a filling was not visualized. DISCUSSION: Filling of the corpora cavernosa, in 34 pt. demonstrated the presence of "spongiosal-cavernosal" shunts. CONCLUSIONS: The presence of "spongiosal cavernosal" shunts justified the efficacy of A in term of complete penile erection, regarding also corpora cavernosa; in the other cases an increased speed of venous discharge justified the drug's lack of local efficacy, with poor results in terms of erection. KEY WORDS: Alprostadil, Erectile Dysfunction, Spongiosography. PMID- 28632147 TI - Crossover iliofemoral bypass graft through tension-free abdominal wall-repair mesh. AB - INTRODUCTION: In vascular surgery the crossover iliofemoral bypass grafting is a well-known surgical technique. In general surgery the repair of an abdominal defect using a Polypropylene mesh is also a standard procedure. A particular technique is defined by the performance of these 2 separate procedures inside a single operation in which the crossover arterial graft is directed from the retroperitoneal space toward the contra-lateral femoral bifurcation through a Polypropylene mesh which closes the musculoaponeurotic layers of the abdominal wall. We present our experience with the use of this particular surgical technique in patients with critical limb ischemia and with indication for extra anatomic crossover bypass (high-risk patients with contra-indication for the transperitoneal approach, extensive calcified aortic or iliac wall which contraindicated the direct arterial reconstruction or secondary arterial reconstruction after the occlusion of an aorto- femoral graft). METHODS: In principle, the hernioplasty was performed by using the Lichtenstein tension-free hernia repair technique, followed by the crossover iliofemoral bypass. The main feature of this technique is to pass the vascular graft from the retroperitoneal space above the mesh through a calibrated hole in the mesh RESULTS: The 7 patients with inguinal hernia and l limb-threatening ischemia had favorable evolution, without hernia recurrence, limb-threatening ischemia or any graft complication at 3 years. DISCUSSION: Using this particular surgical technique we treated 2 surgical diseases using a single intervention for highrisk patients who had both inguinal hernia and contra-lateral critical limb ischemia. Being encouraged by the initial satisfactory results, we extended this technique even for the patients with indication of crossover iliofemoral bypass but without inguinal hernia. CONCLUSIONS: The particular surgical technique of the crossover bypass in which the vascular graft crosses a tension-free Polypropylene mesh from the retroperitoneal space toward the Retzius space represents an efficient and short procedure which treats simultaneously 2 different surgical diseases (inguinal hernia and contra-lateral critical limb ischemia) in high-risk patients. The results were satisfactory: we had no hernia recurrence and the limb threatening ischemia was successfully treated. The preferred vascular graft for this particular technique is the reversed autogenous vein because its resistance to infections and the vein long-term patency is better than of a vascular prosthesis. When a prosthetic graft is required, we prefer to use the classic technique in which the crossover graft is placed in an under-aponeurosis site, in order to diminish the prosthesis infection risk. KEY WORDS: Abdominal wall, Iliofemoral bypass, Vascular surgery. PMID- 28632148 TI - Claw foot A case report. AB - : A cutaneous horn could be defined as a conical projection on the surface of skin made of cornified material and resembling an animal horn. These lesions most commonly affect light-skinned men aged between 50 to 89 years and usually appear in sun exposed areas. Radiation, chronic irritation and even human papilloma virus-2 infection may be precipitating factors. More than half of the cases originate from either malignant or premalignant lesions, therefore the base of the lesion must be carefully examined histologically. Long standing presence of the lesion, conspicuous protrusion of the horn and pain are positive predictive factors for malignancy and invasivity. In these cases an invasive surgical approach is needed. KEY WORDS: Basal cell carcinoma, Cancer, Clow foot, Non melanoma skin cancer, Skin cancer. PMID- 28632149 TI - Association between Air Pollution and Emergency Room Visits for Atrial Fibrillation. AB - Despite the large prevalence in the population, possible factors responsible for the induction of atrial fibrillation (AF) events in susceptible individuals remain incompletely understood. We investigated the association between air pollution levels and emergency department admissions for AF in Rome. We conducted a 14 years' time-series study to evaluate the association between the daily levels of air pollution (particulate matter, PM10 and PM2.5, and nitrogen dioxide, NO2) and the daily count of emergency accesses for AF (ICD-9 code: 427.31). We applied an over-dispersed conditional Poisson model to analyze the associations at different lags after controlling for time, influenza epidemics, holiday periods, temperature, and relative humidity. Additionally, we evaluated bi-pollutant models by including the other pollutant and the influence of several effect modifiers such as personal characteristics and pre-existing medical conditions. In the period of study, 79,892 individuals were admitted to the emergency departments of Rome hospitals because of AF (on average, 15.6 patients per day: min = 1, max = 36). Air pollution levels were associated with increased AF emergency visits within 24 h of exposure. Effect estimates ranged between 1.4% (0.7-2.3) for a 10 ug/m3 increase of PM10 to 3% (1.4-4.7) for a 10 ug/m3 increase of PM2.5 at lag 0-1 day. Those effects were higher in patients >=75 years for all pollutants, male patients for PM10, and female patients for NO2. The presence of previous cardiovascular conditions, but not other effect modifiers, increase the pollution effects by 5-8% depending on the lag. This study found evidence that air pollution is associated with AF emergency visits in the short term. PMID- 28632151 TI - Micro-Viscometer for Measuring Shear-Varying Blood Viscosity over a Wide-Ranging Shear Rate. AB - In this study, a micro-viscometer is developed for measuring shear-varying blood viscosity over a wide-ranging shear rate. The micro-viscometer consists of 10 microfluidic channel arrays, each of which has a different micro-channel width. The proposed design enables the retrieval of 10 different shear rates from a single flow rate, thereby enabling the measurement of shear-varying blood viscosity with a fixed flow rate condition. For this purpose, an optimal design that guarantees accurate viscosity measurement is selected from a parametric study. The functionality of the micro-viscometer is verified by both numerical and experimental studies. The proposed micro-viscometer shows 6.8% (numerical) and 5.3% (experimental) in relative error when compared to the result from a standard rotational viscometer. Moreover, a reliability test is performed by repeated measurement (N = 7), and the result shows 2.69 +/- 2.19% for the mean relative error. Accurate viscosity measurements are performed on blood samples with variations in the hematocrit (35%, 45%, and 55%), which significantly influences blood viscosity. Since the blood viscosity correlated with various physical parameters of the blood, the micro-viscometer is anticipated to be a significant advancement for realization of blood on a chip. PMID- 28632150 TI - Centrosomal Protein 70 Is a Mediator of Paclitaxel Sensitivity. AB - Centrosome aberrations have been implicated in the development and progression of breast cancer. Our previous worked show that centrosomal protein 70 (Cep70) regulates breast cancer growth and metastasis. However, it remains elusive whether Cep70 is implicated in the sensitivity of the anti-microtubule drug paclitaxel in breast cancer. Here we provide evidence that Cep70 is a mediator of paclitaxel sensitivity in breast cancer. Cell proliferation assays show that Cep70 expression correlates with paclitaxel sensitivity in breast cancer cell lines. In addition, paclitaxel sensitivity varies when altering Cep70 expression level. Mechanistic studies reveal that Cep70 interacts with tubulin, and promotes the ability of paclitaxel to stimulate microtubule assembly. These data demonstrate that Cep70 mediates paclitaxel sensitivity in breast cancer. PMID- 28632152 TI - Isolation and Characterization of Microsatellite Loci for Cotesia plutellae (Hymenoptera: Braconidae). AB - Fourteen polymorphic microsatellite loci were isolated in this transcriptome based data analysis for Cotesia plutellae, which is an important larval parasitoid of the worldwide pest Plutella xylostella. A subsequent test was performed for a wild C. plutellae population (N = 32) from Fuzhou, Fujian, southeastern China, to verify the effectiveness of the 14 microsatellite loci in future studies on C. plutellae genetic diversity. The observed number of alleles ranged from two to six. The expected and observed heterozygosity ranged from 0.123 to 0.316 and from 0.141 to 0.281, respectively. The polymorphism information content (PIC) value ranged from 0.272 to 0.622. Potentially due to the substructure of the sampled population, three of the 14 microsatellite loci deviated from Hardy-Weinberg equilibrium (HWE). Further, loci C6, C22, and C31 could be amplified in Cocobius fulvus and Encarsia japonica, suggesting the transferability of these three polymorphic loci to other species of Hymenoptera. PMID- 28632153 TI - Fabrication and Characterization of Plasmonic Nanopores with Cavities in the Solid Support. AB - Plasmonic nanostructures are widely used for various sensing applications by monitoring changes in refractive index through optical spectroscopy or as substrates for surface enhanced Raman spectroscopy. However, in most practical situations conventional surface plasmon resonance is preferred for biomolecular interaction analysis because of its high resolution in surface coverage and the simple single-material planar interface. Still, plasmonic nanostructures may find unique sensing applications, for instance when the nanoscale geometry itself is of interest. This calls for new methods to prepare nanoscale particles and cavities with controllable dimensions and curvature. In this work, we present two types of plasmonic nanopores where the solid support underneath a nanohole array has been etched, thereby creating cavities denoted as 'nanowells' or 'nanocaves' depending on the degree of anisotropy (dry or wet etch). The refractometric sensitivity is shown to be enhanced upon removing the solid support because of an increased probing volume and a shift of the asymmetric plasmonic field towards the liquid side of the finite gold film. Furthermore, the structures exhibit different spectral changes upon binding inside the cavities compared to the gold surface, which means that the structures can be used for location-specific detection. Other sensing applications are also suggested. PMID- 28632154 TI - Synthesis and Biodegradation of Poly(l-lactide-co-beta-propiolactone). AB - Although the copolymerizations of l-lactide (LA) with seven- or six-membered ring lactones have been extensively studied, the copolymerizations of LA with four membered ring lactones have scarcely been reported. In this work, we studied the copolymerization of LA with beta-propiolactone (PL) and the properties of the obtained copolymers. The copolymerization of LA with PL was carried out using trifluoromethanesulfonic acid as a catalyst and methanol as an initiator to produce poly(LA-co-PL) with Mn of ~50,000 and PL-content of 6-67 mol %. The Tg values of the copolymers were rapidly lowered with increasing PL-contents. The Tm and DeltaHm of the copolymers gradually decreased with increasing PL-contents, indicating their decreased crystallinity. Biodegradation test of the copolymers in compost demonstrated their improved biodegradability in comparison with the homopolymer of LA. PMID- 28632156 TI - Image Mosaicking Approach for a Double-Camera System in the GaoFen2 Optical Remote Sensing Satellite Based on the Big Virtual Camera. AB - The linear array push broom imaging mode is widely used for high resolution optical satellites (HROS). Using double-cameras attached by a high-rigidity support along with push broom imaging is one method to enlarge the field of view while ensuring high resolution. High accuracy image mosaicking is the key factor of the geometrical quality of complete stitched satellite imagery. This paper proposes a high accuracy image mosaicking approach based on the big virtual camera (BVC) in the double-camera system on the GaoFen2 optical remote sensing satellite (GF2). A big virtual camera can be built according to the rigorous imaging model of a single camera; then, each single image strip obtained by each TDI-CCD detector can be re-projected to the virtual detector of the big virtual camera coordinate system using forward-projection and backward-projection to obtain the corresponding single virtual image. After an on-orbit calibration and relative orientation, the complete final virtual image can be obtained by stitching the single virtual images together based on their coordinate information on the big virtual detector image plane. The paper subtly uses the concept of the big virtual camera to obtain a stitched image and the corresponding high accuracy rational function model (RFM) for concurrent post processing. Experiments verified that the proposed method can achieve seamless mosaicking while maintaining the geometric accuracy. PMID- 28632157 TI - Development of a Novel Transparent Flexible Capacitive Micromachined Ultrasonic Transducer. AB - This paper presents the world's first transparent flexible capacitive micromachined ultrasonic transducer (CMUT) that was fabricated through a roll lamination technique. This polymer-based CMUT has advantages of transparency, flexibility, and non-contacting detection which provide unique functions in display panel applications. Comprising an indium tin oxide-polyethylene terephthalate (ITO-PET) substrate, SU-8 sidewall and vibrating membranes, and silver nanowire transparent electrode, the transducer has visible-light transmittance exceeding 80% and can operate on curved surfaces with a 40 mm radius of curvature. Unlike the traditional silicon-based high temperature process, the CMUT can be fabricated on a flexible substrate at a temperature below 100 degrees C to reduce residual stress introduced at high temperature. The CMUT on the curved surfaces can detect a flat target and finger at distances up to 50 mm and 40 mm, respectively. The transparent flexible CMUT provides a better human-machine interface than existing touch panels because it can be integrated with a display panel for non-contacting control in a health conscious environment and the flexible feature is critical for curved display and wearable electronics. PMID- 28632158 TI - On the Application of Image Processing Methods for Bubble Recognition to the Study of Subcooled Flow Boiling of Water in Rectangular Channels. AB - This work introduces the use of machine vision in the massive bubble recognition process, which supports the validation of boiling models involving bubble dynamics, as well as nucleation frequency, active site density and size of the bubbles. The two algorithms presented are meant to be run employing quite standard images of the bubbling process, recorded in general-purpose boiling facilities. The recognition routines are easily adaptable to other facilities if a minimum number of precautions are taken in the setup and in the treatment of the information. Both the side and front projections of subcooled flow-boiling phenomenon over a plain plate are covered. Once all of the intended bubbles have been located in space and time, the proper post-process of the recorded data become capable of tracking each of the recognized bubbles, sketching their trajectories and size evolution, locating the nucleation sites, computing their diameters, and so on. After validating the algorithm's output against the human eye and data from other researchers, machine vision systems have been demonstrated to be a very valuable option to successfully perform the recognition process, even though the optical analysis of bubbles has not been set as the main goal of the experimental facility. PMID- 28632155 TI - Microbiota, Inflammation and Colorectal Cancer. AB - Colorectal cancer, the fourth leading cause of cancer-related death worldwide, is a multifactorial disease involving genetic, environmental and lifestyle risk factors. In addition, increased evidence has established a role for the intestinal microbiota in the development of colorectal cancer. Indeed, changes in the intestinal microbiota composition in colorectal cancer patients compared to control subjects have been reported. Several bacterial species have been shown to exhibit the pro-inflammatory and pro-carcinogenic properties, which could consequently have an impact on colorectal carcinogenesis. This review will summarize the current knowledge about the potential links between the intestinal microbiota and colorectal cancer, with a focus on the pro-carcinogenic properties of bacterial microbiota such as induction of inflammation, the biosynthesis of genotoxins that interfere with cell cycle regulation and the production of toxic metabolites. Finally, we will describe the potential therapeutic strategies based on intestinal microbiota manipulation for colorectal cancer treatment. PMID- 28632159 TI - Better than Membranes at the Origin of Life? AB - Organelles without membranes are found in all types of cells and typically contain RNA and protein. RNA and protein are the constituents of ribosomes, one of the most ancient cellular structures. It is reasonable to propose that organelles without membranes preceded protocells and other membrane-bound structures at the origins of life. Such membraneless organelles would be well sheltered in the spaces between mica sheets, which have many advantages as a site for the origins of life. PMID- 28632160 TI - The Protease Inhibitor CI2c Gene Induced by Bird Cherry-Oat Aphid in Barley Inhibits Green Peach Aphid Fecundity in Transgenic Arabidopsis. AB - Aphids are phloem feeders that cause large damage globally as pest insects. They induce a variety of responses in the host plant, but not much is known about which responses are promoting or inhibiting aphid performance. Here, we investigated whether one of the responses induced in barley by the cereal aphid, bird cherry-oat aphid (Rhopalosiphum padi L.) affects aphid performance in the model plant Arabidopsis thaliana L. A barley cDNA encoding the protease inhibitor CI2c was expressed in A. thaliana and aphid performance was studied using the generalist green peach aphid (Myzus persicae Sulzer). There were no consistent effects on aphid settling or preference or on parameters of life span and long term fecundity. However, short-term tests with apterous adult aphids showed lower fecundity on three of the transgenic lines, as compared to on control plants. This effect was transient, observed on days 5 to 7, but not later. The results suggest that the protease inhibitor is taken up from the tissue during probing and weakly inhibits fecundity by an unknown mechanism. The study shows that a protease inhibitor induced in barley by an essentially monocot specialist aphid can inhibit a generalist aphid in transgenic Arabidopsis. PMID- 28632161 TI - Endogenous Retroviral Insertions Indicate a Secondary Introduction of Domestic Sheep Lineages to the Caucasus and Central Asia between the Bronze and Iron Age. AB - Sheep were one of the first livestock species domesticated by humans. After initial domestication in the Middle East they were spread across Eurasia. The modern distribution of endogenous Jaagsiekte sheep retrovirus insertions in domestic sheep breeds suggests that over the course of millennia, successive introductions of improved lineages and selection for wool quality occurred in the Mediterranean region and most of Asia. Here we present a novel ancient DNA approach using data of endogenous retroviral insertions in Bronze and Iron Age domestic sheep from the Caucasus and Pamir mountain areas. Our findings support a secondary introduction of wool sheep from the Middle East between the Late Bronze Age and Iron Age into most areas of Eurasia. PMID- 28632162 TI - Beyond Food Access: The Impact of Parent-, Home-, and Neighborhood-Level Factors on Children's Diets. AB - Despite the growth in empirical research on neighborhood environmental characteristics and their influence on children's diets, physical activity, and obesity, much remains to be learned, as few have examined the relationship between neighborhood food availability on dietary behavior in children, specifically. This analysis utilized data from a community-based, cross-sectional sample of children (n = 199) that was collected in New Orleans, Louisiana, in 2010. This dataset was linked to food environment data to assess the impact of neighborhood food access as well as household and parent factors on children's diets. We observed a negligible impact of the neighborhood food environment on children's diets, except with respect to fast food, with children who had access to fast food within 500 m around their home significantly less likely (OR = 0.35, 95% CI: 0.1, 0.8) to consume vegetables. Key parental and household factors did play a role in diet, including receipt of public assistance and cooking meals at home. Children receiving public assistance were 2.5 times (95% CI: 1.1, 5.4) more likely to consume fruit more than twice per day compared with children not receiving public assistance. Children whose family cooked dinner at home more than 5 times per week had significantly more consumption of fruit (64% vs. 58%) and vegetables (55% vs. 39%), but less soda (27% vs. 43%). Findings highlight the need for future research that focuses on the dynamic and complex relationships between built and social factors in the communities and homes of children that impact their diet in order to develop multilevel prevention approaches that address childhood obesity. PMID- 28632163 TI - Melatonin as a Novel Interventional Candidate for Fragile X Syndrome with Autism Spectrum Disorder in Humans. AB - Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation (fmr) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety of physiological and behavioral abnormalities. This disorder is also correlated with clock components underlying behavioral circadian rhythms and, thus, a mutation of the fmr gene can result in disturbed sleep patterns and altered circadian rhythms. As a result, FXS with ASD individuals may experience dysregulation of melatonin synthesis and alterations in melatonin-dependent signaling pathways that can impair vigilance, learning, and memory abilities, and may be linked to autistic behaviors such as abnormal anxiety responses. Although a wide variety of possible causes, symptoms, and clinical features of ASD have been studied, the correlation between altered circadian rhythms and FXS with ASD has yet to be extensively investigated. Recent studies have highlighted the impact of melatonin on the nervous, immune, and metabolic systems and, even though the utilization of melatonin for sleep dysfunctions in ASD has been considered in clinical research, future studies should investigate its neuroprotective role during the developmental period in individuals with ASD. Thus, the present review focuses on the regulatory circuits involved in the dysregulation of melatonin and disruptions in the circadian system in individuals with FXS with ASD. Additionally, the neuroprotective effects of melatonin intervention therapies, including improvements in neuroplasticity and physical capabilities, are discussed and the molecular mechanisms underlying this disorder are reviewed. The authors suggest that melatonin may be a useful treatment for FXS with ASD in terms of alleviating the adverse effects of variations in the circadian rhythm. PMID- 28632164 TI - The Role of Hemoproteins: Hemoglobin, Myoglobin and Neuroglobin in Endogenous Thiosulfate Production Processes. AB - Thiosulfate formation and biodegradation processes link aerobic and anaerobic metabolism of cysteine. In these reactions, sulfite formed from thiosulfate is oxidized to sulfate while hydrogen sulfide is transformed into thiosulfate. These processes occurring mostly in mitochondria are described as a canonical hydrogen sulfide oxidation pathway. In this review, we discuss the current state of knowledge on the interactions between hydrogen sulfide and hemoglobin, myoglobin and neuroglobin and postulate that thiosulfate is a metabolically important product of this processes. Hydrogen sulfide oxidation by ferric hemoglobin, myoglobin and neuroglobin has been defined as a non-canonical hydrogen sulfide oxidation pathway. Until recently, it appeared that the goal of thiosulfate production was to delay irreversible oxidation of hydrogen sulfide to sulfate excreted in urine; while thiosulfate itself was only an intermediate, transient metabolite on the hydrogen sulfide oxidation pathway. In the light of data presented in this paper, it seems that thiosulfate is a molecule that plays a prominent role in the human body. Thus, we hope that all these findings will encourage further studies on the role of hemoproteins in the formation of this undoubtedly fascinating molecule and on the mechanisms responsible for its biological activity in the human body. PMID- 28632165 TI - Fano Effect and Quantum Entanglement in Hybrid Semiconductor Quantum Dot-Metal Nanoparticle System. AB - In this paper, we review the investigation for the light-matter interaction between surface plasmon field in metal nanoparticle (MNP) and the excitons in semiconductor quantum dots (SQDs) in hybrid SQD-MNP system under the full quantum description. The exciton-plasmon interaction gives rise to the modified decay rate and the exciton energy shift which are related to the exciton energy by using a quantum transformation method. We illustrate the responses of the hybrid SQD-MNP system to external field, and reveal Fano effect shown in the absorption spectrum. We demonstrate quantum entanglement between two SQD mediated by surface plasmon field. In the absence of a laser field, concurrence of quantum entanglement will disappear after a few ns. If the laser field is present, the steady states appear, so that quantum entanglement produced will reach a steady state entanglement. Because one of all optical pathways to induce Fano effect refers to the generation of quantum entangled states, It is shown that the concurrence of quantum entanglement can be obtained by observation for Fano effect. In a hybrid system including two MNP and a SQD, because the two Fano quantum interference processes share a segment of all optical pathways, there is correlation between the Fano effects of the two MNP. The investigations for the light-matter interaction in hybrid SQD-MNP system can pave the way for the development of the optical processing devices and quantum information based on the exciton-plasmon interaction. PMID- 28632166 TI - Dual-Channel Cosine Function Based ITD Estimation for Robust Speech Separation. AB - In speech separation tasks, many separation methods have the limitation that the microphones are closely spaced, which means that these methods are unprevailing for phase wrap-around. In this paper, we present a novel speech separation scheme by using two microphones that does not have this restriction. The technique utilizes the estimation of interaural time difference (ITD) statistics and binary time-frequency mask for the separation of mixed speech sources. The novelties of the paper consist in: (1) the extended application of delay-and-sum beamforming (DSB) and cosine function for ITD calculation; and (2) the clarification of the connection between ideal binary mask and DSB amplitude ratio. Our objective quality evaluation experiments demonstrate the effectiveness of the proposed method. PMID- 28632167 TI - Preparation of Ce- and La-Doped Li4Ti5O12 Nanosheets and Their Electrochemical Performance in Li Half Cell and Li4Ti5O12/LiFePO4 Full Cell Batteries. AB - This work reports on the synthesis of rare earth-doped Li4Ti5O12 nanosheets with high electrochemical performance as anode material both in Li half and Li4Ti5O12/LiFePO4 full cell batteries. Through the combination of decreasing the particle size and doping by rare earth atoms (Ce and La), Ce and La doped Li4Ti5O12 nanosheets show the excellent electrochemical performance in terms of high specific capacity, good cycling stability and excellent rate performance in half cells. Notably, the Ce-doped Li4Ti5O12 shows good electrochemical performance as anode in a full cell which LiFePO4 was used as cathode. The superior electrochemical performance can be attributed to doping as well as the nanosized particle, which facilitates transportation of the lithium ion and electron transportation. This research shows that the rare earth doped Li4Ti5O12 nanosheets can be suitable as a high rate performance anode material in lithium ion batteries. PMID- 28632168 TI - A Comparative Study of the Structural Dynamics of Four Terminal Uridylyl Transferases. AB - African trypanosomiasis occurs in 36 countries in sub-Saharan Africa with 10,000 reported cases annually. No definitive remedy is currently available and if left untreated, the disease becomes fatal. Structural and biochemical studies of trypanosomal terminal uridylyl transferases (TUTases) demonstrated their functional role in extensive uridylate insertion/deletion of RNA. Trypanosoma brucei RNA Editing TUTase 1 (TbRET1) is involved in guide RNA 3' end uridylation and maturation, while TbRET2 is responsible for U-insertion at RNA editing sites. Two additional TUTases called TbMEAT1 and TbTUT4 have also been reported to share similar function. TbRET1 and TbRET2 are essential enzymes for the parasite viability making them potential drug targets. For this study, we clustered molecular dynamics (MD) trajectories of four TUTases based on active site shape measured by Pocket Volume Measurer (POVME) program. Among the four TUTases, TbRET1 exhibited the largest average pocket volume, while TbMEAT1's and TbTUT4's active sites displayed the most flexibility. A side pocket was also identified within the active site in all TUTases with TbRET1 having the most pronounced. Our results indicate that TbRET1's larger side pocket can be exploited to achieve selective inhibitor design as FTMap identifies it as a druggable pocket. PMID- 28632169 TI - The Novel Mechanisms Concerning the Inhibitions of Palmitate-Induced Proinflammatory Factor Releases and Endogenous Cellular Stress with Astaxanthin on MIN6 beta-Cells. AB - Astaxanthin, an antioxidant agent, can protect pancreatic beta-cells of db/db mice from glucotoxicity and resolve chronic inflammation in adipose tissue. Nonetheless, the effects of astaxanthin on free-fatty-acid-induced inflammation and cellular stress in beta-cells remain to be demonstrated. Meanwhile, palmitate enhances the secretion of pro-inflammatory adipokines monocyte chemoattractant protein-1 (MCP-1) and VEGF120 (vascular endothelial growth factor). We therefore investigated the influence of astaxanthin on palmitate-stimulated MCP-1 and VEGF120 secretion in mouse insulinoma (MIN6) pancreatic beta-cells. Furthermore, whether astaxanthin prevents cellular stress in MIN6 cells was also assessed. Pre treatment with astaxanthin or with N-acetyl-cysteine (NAC) which is an antioxidant drug, significantly attenuated the palmitate-induced MCP-1 release through downregulation of phosphorylated c-Jun NH2-terminal protein kinase (JNK) pathways, and suppressed VEGF120 through the PI3K/Akt pathways relative to the cells stimulated with palmitate alone. In addition, palmitate significantly upregulated homologous protein (CHOP) and anti-glucose-regulated protein (GRP78), which are endoplasmic reticulum (ER) stress markers, in MIN6 cells. On the other hand, astaxanthin attenuated the increased CHOP content, but further up-regulated palmitate-stimulated GRP78 protein expression. By contrast, NAC had no effects on either CHOP or GRP78 enhancement induced by palmitate in MIN6 cells. In conclusion, astaxanthin diminishes the palmitate-stimulated increase in MCP-1 secretion via the downregulation of JNK pathways in MIN6 cells, and affects VEGF120 secretion through PI3K/Akt pathways. Moreover, astaxanthin can prevent not only oxidative stress caused endogenously by palmitate but also ER stress, which NAC fails to attenuate, via upregulation of GRP78, an ER chaperon. PMID- 28632170 TI - Current Research in Lidar Technology Used for the Remote Sensing of Atmospheric Aerosols. AB - Lidars are active optical remote sensing instruments with unique capabilities for atmospheric sounding. A manifold of atmospheric variables can be profiled using different types of lidar: concentration of species, wind speed, temperature, etc. Among them, measurement of the properties of aerosol particles, whose influence in many atmospheric processes is important but is still poorly stated, stands as one of the main fields of application of current lidar systems. This paper presents a review on fundamentals, technology, methodologies and state-of-the art of the lidar systems used to obtain aerosol information. Retrieval of structural (aerosol layers profiling), optical (backscatter and extinction coefficients) and microphysical (size, shape and type) properties requires however different levels of instrumental complexity; this general outlook is structured following a classification that attends these criteria. Thus, elastic systems (detection only of emitted frequencies), Raman systems (detection also of Raman frequency-shifted spectral lines), high spectral resolution lidars, systems with depolarization measurement capabilities and multi-wavelength instruments are described, and the fundamentals in which the retrieval of aerosol parameters is based is in each case detailed. PMID- 28632171 TI - A New Privacy-Preserving Handover Authentication Scheme for Wireless Networks. AB - Handover authentication is a critical issue in wireless networks, which is being used to ensure mobile nodes wander over multiple access points securely and seamlessly. A variety of handover authentication schemes for wireless networks have been proposed in the literature. Unfortunately, existing handover authentication schemes are vulnerable to a few security attacks, or incur high communication and computation costs. Recently, He et al. proposed a handover authentication scheme PairHand and claimed it can resist various attacks without rigorous security proofs. In this paper, we show that PairHand does not meet forward secrecy and strong anonymity. More seriously, it is vulnerable to key compromise attack, where an adversary can recover the private key of any mobile node. Then, we propose a new efficient and provably secure handover authentication scheme for wireless networks based on elliptic curve cryptography. Compared with existing schemes, our proposed scheme can resist key compromise attack, and achieves forward secrecy and strong anonymity. Moreover, it is more efficient in terms of computation and communication. PMID- 28632172 TI - Fiber Optic Thermo-Hygrometers for Soil Moisture Monitoring. AB - This work deals with the fabrication, prototyping, and experimental validation of a fiber optic thermo-hygrometer-based soil moisture sensor, useful for rainfall induced landslide prevention applications. In particular, we recently proposed a new generation of fiber Bragg grating (FBGs)-based soil moisture sensors for irrigation purposes. This device was realized by integrating, inside a customized aluminum protection package, a FBG thermo-hygrometer with a polymer micro-porous membrane. Here, we first verify the limitations, in terms of the volumetric water content (VWC) measuring range, of this first version of the soil moisture sensor for its exploitation in landslide prevention applications. Successively, we present the development, prototyping, and experimental validation of a novel, optimized version of a soil VWC sensor, still based on a FBG thermo-hygrometer, but able to reliably monitor, continuously and in real-time, VWC values up to 37% when buried in the soil. PMID- 28632173 TI - Gene Expression Profiling Reveals Potential Players of Left-Right Asymmetry in Female Chicken Gonads. AB - Most female birds develop only a left ovary, whereas males develop bilateral testes. The mechanism underlying this process is still not completely understood. Here, we provide a comprehensive transcriptional analysis of female chicken gonads and identify novel candidate side-biased genes. RNA-Seq analysis was carried out on total RNA harvested from the left and right gonads on embryonic day 6 (E6), E12, and post-hatching day 1 (D1). By comparing the gene expression profiles between the left and right gonads, 347 differentially expressed genes (DEGs) were obtained on E6, 3730 were obtained on E12, and 2787 were obtained on D1. Side-specific genes were primarily derived from the autosome rather than the sex chromosome. Gene ontology and pathway analysis showed that the DEGs were most enriched in the Piwi-interactiing RNA (piRNA) metabolic process, germ plasm, chromatoid body, P granule, neuroactive ligand-receptor interaction, microbial metabolism in diverse environments, and methane metabolism. A total of 111 DEGs, five gene ontology (GO) terms, and three pathways were significantly different between the left and right gonads among all the development stages. We also present the gene number and the percentage within eight development-dependent expression patterns of DEGs in the left and right gonads of female chicken. PMID- 28632174 TI - Fluorescence Analysis of Vitamin D Receptor Status of Circulating Tumor Cells (CTCS) in Breast Cancer: From Cell Models to Metastatic Patients. AB - The Vitamin D receptor (VDR) expressed in normal breast tissue and breast tumors has been suggested as a new prognostic biomarker in breast cancer (BC). Besides, increasing evidence supports the view that the detection of circulating tumor cells (CTCs) predicts outcome in early and metastatic BC. Consequently, an evaluation of VDR expression in the CTCs of BC patients may allow optimization of their treatment. As an attempt to profile and subtype the CTCs of metastatic patients, we established an innovative fluorescence technique using nine BC cell lines to visualize, define, and compare their individual VDR status. Afterwards, we tested the CTC presence and VDR expression in blood samples (cytospins) collected from 23 metastatic BC patients. The results demonstrated major differences in the VDR levels among the nine cell lines, and VDR positive CTCs were detected in 46% of CTC-positive patients, with a total of 42 CTCs individually analyzed. Due to the limited number of patients in this study, no correlation between VDR expression and BC subtype classification (according to estrogen receptor (ER), progesterone receptor (PR) and HER2) could be determined, but our data support the view that VDR evaluation is a potential new prognostic biomarker to help in the optimization of therapy management for BC patients. PMID- 28632175 TI - Physical Fitness, Physical Activity, Sedentary Behavior, or Diet-What Are the Correlates of Obesity in Polish School Children? AB - There is substantial evidence of rising prevalence of overweight and obesity and its co-morbidities among children in western-high income developed countries. In the European Union, the prevalence of overweight and obesity is increasing fastest among Polish children. Yet, there is paucity of evidence on the relationship of behavioral factors with body weight status of children in Poland. This study examined the association of obesity with physical fitness, physical activity, sedentary behavior and diet among Polish children. A total of 641 children (10-15 years) recruited from the Lower Silesia region of Poland participated in this cross-sectional study. Participants' anthropometrics, physical fitness, physical activity, sedentary behavior and dietary intake were assessed. Outcome variables were weight categories (according to body mass index [BMI], waist-to-hip ratio [WHR], and percentage body fat [% BF]). The strongest negative correlation was found between VO2max and %BF (r = -0.39, p <0.05). Significant negative correlation was also found between VO2max and weight categories (r = -0.15). Results of the multinomial logit analysis showed that VO2max increased in groups of overweight, normal weight and underweight children by 13%, 26% and 19%, respectively as compared to the group of obese children. VO2max and weight and obesity indices were strongly correlated in both gender and age groups. Education and intervention programs to increase physical fitness (VO2max) through aerobic training are recommended for Physical Education teachers, parents and children in order to reduce the rate of overweight and obesity among children in the Lower Silesia region of Poland. PMID- 28632176 TI - The Ship Movement Trajectory Prediction Algorithm Using Navigational Data Fusion. AB - It is essential for the marine navigator conducting maneuvers of his ship at sea to know future positions of himself and target ships in a specific time span to effectively solve collision situations. This article presents an algorithm of ship movement trajectory prediction, which, through data fusion, takes into account measurements of the ship's current position from a number of doubled autonomous devices. This increases the reliability and accuracy of prediction. The algorithm has been implemented in NAVDEC, a navigation decision support system and practically used on board ships. PMID- 28632178 TI - An Increased Dietary Supply of Medium-Chain Fatty Acids during Early Weaning in Rodents Prevents Excessive Fat Accumulation in Adulthood. AB - Medium-chain fatty acids (MCFA) are a directly and readily absorbed source of energy. Exposure early-in-life to increased MCFA levels might affect development and impact (lipid) metabolism later in life. We tested whether an increased MCFA intake early-in-life positively affects adult body composition and metabolic status when challenged by a western-style diet (WSD). Male offspring of C57Bl/6j mice and Wistar rats were fed a control diet (CTRL; 10 w% fat, 14% MCFA) or a medium-chain triglycerides (MCT) diet with 20% MCFA until postnatal (PN) day 42, whereupon animals were fed a WSD (10 w% fat) until PN day 98. Body composition was monitored by Dual Energy X-ray Absorptiometry (DEXA). In rats, glucose homeostasis was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT); in mice, the HOmeostasis Model Assessment of Insulin Resistance (HOMA IR) was calculated. At autopsy on PN day 98, plasma lipid profiles, glucose, insulin, and adipokines were measured; organs and fat pads were collected and the adipocyte size distribution was analysed. Milk analysis in mice showed that the maternal MCT diet was not translated into milk, and pups were thus only exposed to high MCT levels from early weaning onward: PN day 16 until 42. Mice exposed to MCT showed 28% less fat accumulation vs. CTRL during WSD. The average adipocyte cell size, fasting plasma triglycerides (TG), and leptin levels were reduced in MCT mice. In rats, no effects were found on the adult body composition, but the adipocyte cell size distribution shifted towards smaller adipocytes. Particularly mice showed positive effects on glucose homeostasis and insulin sensitivity. Increased MCFA intake early-in-life protected against the detrimental effects of an obesogenic diet in adulthood. PMID- 28632179 TI - The Antiproliferative Effect of Cyclodipeptides from Pseudomonas aeruginosa PAO1 on HeLa Cells Involves Inhibition of Phosphorylation of Akt and S6k Kinases. AB - Pseudomonas aeruginosa PAO1, a potential pathogen of plants and animals, produces the cyclodipeptides cyclo(l-Pro-l-Tyr), cyclo(l-Pro-l-Phe), and cyclo(l-Pro-l Val) (PAO1-CDPs), whose effects have been implicated in inhibition of human tumor cell line proliferation. Our purpose was to investigate in depth in the mechanisms of HeLa cell proliferation inhibition by the PAO1-CDPs. The results indicate that PAO1-CDPs, both purified individually and in mixtures, inhibited HeLa cell proliferation by arresting the cell cycle at the G0-G1 transition. The crude PAO1-CDPs mixture promoted cell death in HeLa cells in a dose-dependent manner, showing efficacy similar to that of isolated PAO1-CDPs (LD50 of 60-250 uM) and inducing apoptosis with EC50 between 0.6 and 3.0 uM. Moreover, PAO1-CDPs showed a higher proapoptotic activity (~103-105 fold) than their synthetic analogs did. Subsequently, the PAO1-CDPs affected mitochondrial membrane potential and induced apoptosis by caspase-9-dependent pathway. The mechanism of inhibition of cells proliferation in HeLa cells involves inhibition of phosphorylation of both Akt-S473 and S6k-T389 protein kinases, showing a cyclic behavior of their expression and phosphorylation in a time and concentration dependent fashion. Taken together our findings indicate that PI3K-Akt-mTOR-S6k signaling pathway blockage is involved in the antiproliferative effect of the PAO1-CDPs. PMID- 28632177 TI - The Intersection of NGF/TrkA Signaling and Amyloid Precursor Protein Processing in Alzheimer's Disease Neuropathology. AB - Dysfunction of nerve growth factor (NGF) and its high-affinity Tropomyosin receptor kinase A (TrkA) receptor has been suggested to contribute to the selective degeneration of basal forebrain cholinergic neurons (BFCN) associated with the progressive cognitive decline in Alzheimer's disease (AD). The aim of this review is to describe our progress in elucidating the molecular mechanisms underlying the dynamic interplay between NGF/TrkA signaling and amyloid precursor protein (APP) metabolism within the context of AD neuropathology. This is mainly based on the finding that TrkA receptor binding to APP depends on a minimal stretch of ~20 amino acids located in the juxtamembrane/extracellular domain of APP that carries the alpha- and beta-secretase cleavage sites. Here, we provide evidence that: (i) NGF could be one of the "routing" proteins responsible for modulating the metabolism of APP from amyloidogenic towards non-amyloidogenic processing via binding to the TrkA receptor; (ii) the loss of NGF/TrkA signaling could be linked to sporadic AD contributing to the classical hallmarks of the neuropathology, such as synaptic loss, beta-amyloid peptide (Abeta) deposition and tau abnormalities. These findings will hopefully help to design therapeutic strategies for AD treatment aimed at preserving cholinergic function and anti amyloidogenic activity of the physiological NGF/TrkA pathway in the septo hippocampal system. PMID- 28632180 TI - PREVIEW: Prevention of Diabetes through Lifestyle Intervention and Population Studies in Europe and around the World. Design, Methods, and Baseline Participant Description of an Adult Cohort Enrolled into a Three-Year Randomised Clinical Trial. AB - Type-2 diabetes (T2D) is one of the fastest growing chronic diseases worldwide. The PREVIEW project has been initiated to find the most effective lifestyle (diet and physical activity) for the prevention of T2D, in overweight and obese participants with increased risk for T2D. The study is a three-year multi-centre, 2 * 2 factorial, randomised controlled trial. The impact of a high-protein, low glycaemic index (GI) vs. moderate protein, moderate-GI diet in combination with moderate or high-intensity physical activity on the incidence of T2D and the related clinical end-points are investigated. The intervention started with a two month weight reduction using a low-calorie diet, followed by a randomised 34 month weight maintenance phase comprising four treatment arms. Eight intervention centres are participating (Denmark, Finland, United Kingdom, The Netherlands, Spain, Bulgaria, Australia, and New Zealand). Data from blood specimens, urine, faeces, questionnaires, diaries, body composition assessments, and accelerometers are collected at months 0, 2, 6, 12, 18, 24, and 36. In total, 2326 adults were recruited. The mean age was 51.6 (SD 11.6) years, 67% were women. PREVIEW is, to date, the largest multinational trial to address the prevention of T2D in pre diabetic adults through diet and exercise intervention. Participants will complete the final intervention in March, 2018. PMID- 28632182 TI - MinT: Middleware for Cooperative Interaction of Things. AB - This paper proposes an Internet of Things (IoT) middleware called Middleware for Cooperative Interaction of Things (MinT). MinT supports a fully distributed IoT environment in which IoT devices directly connect to peripheral devices easily construct a local or global network, and share their data in an energy efficient manner. MinT provides a sensor abstract layer, a system layer and an interaction layer. These enable integrated sensing device operations, efficient resource management, and active interconnection between peripheral IoT devices. In addition, MinT provides a high-level API to develop IoT devices easily for IoT device developers. We aim to enhance the energy efficiency and performance of IoT devices through the performance improvements offered by MinT resource management and request processing. The experimental results show that the average request rate increased by 25% compared to Californium, which is a middleware for efficient interaction in IoT environments with powerful performance, an average response time decrease of 90% when resource management was used, and power consumption decreased by up to 68%. Finally, the proposed platform can reduce the latency and power consumption of IoT devices. PMID- 28632181 TI - Spirulina Protects against Hepatic Inflammation in Aging: An Effect Related to the Modulation of the Gut Microbiota? AB - Aging predisposes to hepatic dysfunction and inflammation that can contribute to the development of non-alcoholic fatty liver disease. Spirulina, a cyanobacterium used as a food additive or food supplement, has been shown to impact immune function. We have tested the potential hepatoprotective effect of a Spirulina in aged mice and to determine whether these effects can be related to a modulation of the gut microbiota. Old mice have been fed a standard diet supplemented with or without 5% Spirulina for six weeks. Among several changes of gut microbiota composition, an increase in Roseburia and Lactobacillus proportions occurs upon Spirulina treatment. Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice. Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice. We conclude that the oral administration of a Spirulina is able to modulate the gut microbiota and to activate the immune system in the gut, a mechanism that may be involved in the improvement of the hepatic inflammation in aged mice. Those data open the way to new therapeutic tools in the management of immune alterations in aging, based on gut microbe-host interactions. PMID- 28632183 TI - Measurement of Rayleigh Wave Beams Using Angle Beam Wedge Transducers as the Transmitter and Receiver with Consideration of Beam Spreading. AB - A theoretical model, along with experimental verification, is developed to describe the generation, propagation and reception of a Rayleigh wave using angle beam wedge transducers. The Rayleigh wave generation process using an angle beam wedge transducer is analyzed, and the actual Rayleigh wave sound source distributions are evaluated numerically. Based on the reciprocity theorem and considering the actual sound source, the Rayleigh wave beams are modeled using an area integral method. The leaky Rayleigh wave theory is introduced to investigate the reception of the Rayleigh wave using the angle beam wedge transducers, and the effects of the wave spreading in the wedge and transducer size are considered in the reception process. The effects of attenuations of the Rayleigh wave and leaky Rayleigh wave are discussed, and the received wave results with different sizes of receivers are compared. The experiments are conducted using two angle beam wedge transducers to measure the Rayleigh wave, and the measurement results are compared with the predictions using different theoretical models. It is shown that the proposed model which considers the wave spreading in both the sample and wedges can be used to interpret the measurements reasonably. PMID- 28632185 TI - The Effects of Selected Sesquiterpenes from Myrica rubra Essential Oil on the Efficacy of Doxorubicin in Sensitive and Resistant Cancer Cell Lines. AB - beta-caryophyllene oxide (CAO), alpha-humulene (HUM), trans-nerolidol (NER) and valencene (VAL) are constituents of the essential oil of Myrica rubra (MEO), which has significant antiproliferative effect in various cancer cell lines. In the present study, we compared the antiproliferative effect of these sesquiterpenes alone and in combination with the cytostatic drug doxorubicin (DOX) in cancer cell lines with different sensitivity to DOX. Two ovarian cancer cell lines (sensitive A2780 and partly resistant SKOV3) and two lymphoblast cancer cell lines (sensitive CCRF/CEM and completely resistant CEM/ADR) were used. The observed effects varied among sesquiterpenes and also differed in individual cell lines, with only VAL being effective in all the cell lines. A strong synergism of DOX with NER was found in the A2780 cells, while DOX acted synergistically with HUM and CAO in the SKOV3 cells. In the CCRF/CEM cells, a synergism of DOX with CAO and NER was observed. In resistant CEM/ADR cells, sesquiterpenes did not increase DOX efficacy, although they significantly increased accumulation of DOX (up to 10-times) and rhodamine-123 (substrate of efflux transporter ABCB1) within cancer cells. In conclusion, the tested sesquiterpenes were able to improve DOX efficacy in the sensitive and partly resistant cancer cells, but not in cells completely resistant to DOX. PMID- 28632184 TI - Crude Fucoidan Extracts Impair Angiogenesis in Models Relevant for Bone Regeneration and Osteosarcoma via Reduction of VEGF and SDF-1. AB - The marine origin polysaccharide fucoidan combines multiple biological activities. As demonstrated by various studies in vitro and in vivo, fucoidans show anti-viral, anti-tumor, anti-oxidant, anti-inflammatory and anti-coagulant properties, although the detailed molecular action remains to be elucidated. The aim of the present study is to assess the impact of crude fucoidan extracts, on the formation of vascular structures in co-culture models relevant for bone vascularization during bone repair and for vascularization processes in osteosarcoma. The co-cultures consisted of bone marrow derived mesenchymal stem cells, respectively the osteosarcoma cell line MG63, and human blood derived outgrowth endothelial cells (OEC). The concentration dependent effects on the metabolic activity on endothelial cells and osteoblast cells were first assessed using monocultures of OEC, MSC and MG63 suggesting a concentration of 100 ug/mL as a suitable concentration for further experiments. In co-cultures fucoidan significantly reduced angiogenesis in MSC/OEC but also in MG63/OEC co-cultures suggesting a potential application of fucoidan to lower the vascularization in bone tumors such as osteosarcoma. This was associated with a decrease in VEGF (vascular endothelial growth factor) and SDF-1 (stromal derived factor-1) on the protein level, both related to the control of angiogenesis and furthermore discussed as crucial factors in osteosarcoma progression and metastasis. In terms of bone formation, fucoidan slightly lowered on the calcification process in MSC monocultures and MSC/OEC co-cultures. In summary, these data suggest the suitability of lower fucoidan doses to limit angiogenesis for instance in osteosarcoma. PMID- 28632186 TI - Insights into Penicillium brasilianum Secondary Metabolism and Its Biotechnological Potential. AB - Over the past few years Penicillium brasilianum has been isolated from many different environmental sources as soil isolates, plant endophytes and onion pathogen. All investigated strains share a great ability to produce bioactive secondary metabolites. Different authors have investigated this great capability and here we summarize the metabolic potential and the biological activities related to P. brasilianum's metabolites with diverse structures. They include secondary metabolites of an alkaloid nature, i.e., 2,5-diketopiperazines, cyclodepsipeptides, meroterpenoids and polyketides. Penicillium brasilianum is also described as a great source of enzymes with biotechnological application potential, which is also highlighted in this review. Additionally, this review will focus on several aspects of Penicillium brasilianum and interesting genomic insights. PMID- 28632187 TI - Complex Coacervation of Soy Proteins, Isoflavones and Chitosan. AB - In this study, the chitosan-induced coacervation of soy protein-isoflavone complexes in soymilk was investigated. Most of the soymilk proteins, including beta-conglycinin (7S), glycinin (11S), and isoflavones, were found to coacervate into the soymilk pellet fraction (SPF) following the addition of 0.5% chitosan. The total protein in the soymilk supernatant fraction (SSF) decreased from 18.1 +/- 0.3 mg/mL to 1.6 +/- 0.1 mg/mL, and the pH values decreased slightly, from 6.6 +/- 0.0 to 6.0 +/- 0.0. The results of SDS-PAGE revealed that the 7S alpha', 7S alpha, 7S beta, 11S A3, and 11S acidic subunits, as well as the 11S basic proteins in the SSF, decreased to 0.7 +/- 0.5%, 0.2 +/- 0.1%, 0.1 +/- 0.0%, 0.2 +/- 0.2%, 0.2 +/- 0.2% and 0.3 +/- 0.2%, respectively. We also found that isoflavones in the SSF, including daidzein, glycitein, and genistein, decreased to 9.6 +/- 2.3%, 5.7 +/- 0.9% and 5.9 +/- 1.5%, respectively. HPLC analysis indicated that isoflavones mixed with soy proteins formed soy protein-isoflavone complexes and were precipitated into the SPF by 0.5% chitosan. PMID- 28632188 TI - Smartphone-Based Food Diagnostic Technologies: A Review. AB - A new generation of mobile sensing approaches offers significant advantages over traditional platforms in terms of test speed, control, low cost, ease-of operation, and data management, and requires minimal equipment and user involvement. The marriage of novel sensing technologies with cellphones enables the development of powerful lab-on-smartphone platforms for many important applications including medical diagnosis, environmental monitoring, and food safety analysis. This paper reviews the recent advancements and developments in the field of smartphone-based food diagnostic technologies, with an emphasis on custom modules to enhance smartphone sensing capabilities. These devices typically comprise multiple components such as detectors, sample processors, disposable chips, batteries and software, which are integrated with a commercial smartphone. One of the most important aspects of developing these systems is the integration of these components onto a compact and lightweight platform that requires minimal power. To date, researchers have demonstrated several promising approaches employing various sensing techniques and device configurations. We aim to provide a systematic classification according to the detection strategy, providing a critical discussion of strengths and weaknesses. We have also extended the analysis to the food scanning devices that are increasingly populating the Internet of Things (IoT) market, demonstrating how this field is indeed promising, as the research outputs are quickly capitalized on new start-up companies. PMID- 28632189 TI - Phenolic Glycosides from Capsella bursa-pastoris (L.) Medik and Their Anti Inflammatory Activity. AB - A new sesquilignan glycoside 1, together with seven known phenolic glycosides 2-8 were isolated from the aerial parts of Capsella bursa-pastoris. The chemical structure of the new compound 1 was elucidated by extensive nuclear magnetic resonance (NMR) data (1H- and 13C-NMR, 1H-1H correlation spectroscopy (1H-1H COSY), heteronuclear single-quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), and nuclear overhauser effect spectroscopy (NOESY)) and HR-FABMS analysis. The anti-inflammatory effects of 1-8 were evaluated in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells. Compounds 4 and 7 exhibited moderate inhibitory effects on nitric oxide production in LPS activated BV-2 cells, with IC50 values of 17.80 and 27.91 uM, respectively. PMID- 28632190 TI - Soluble (Pro)renin Receptor and Obstructive Sleep Apnea Syndrome: Oxidative Stress in Brain? AB - (Pro)renin receptor ((P)RR) is a multi-functional molecule that is related to both the renin-angiotensin system (RAS) and vacuolar H+-ATPase (v-ATPase), an ATP dependent multi-subunit proton pump. Soluble (P)RR (s(P)RR), which consists of the extracellular domain of (P)RR, is present in blood and urine. Elevated plasma s(P)RR concentrations are reported in patients with chronic kidney disease and pregnant women with hypertension or diabetes mellitus. In addition, we have shown that plasma s(P)RR concentrations are elevated in patients with obstructive sleep apnea syndrome (OSAS). Interestingly, the levels are elevated in parallel with the severity of OSAS, but are not related to the presence of hypertension or the status of the circulating RAS in OSAS. It is known that v-ATPase activity protects cells from endogenous oxidative stress, and loss of v-ATPase activity results in chronic oxidative stress. We hypothesize that hypoxia and subsequent oxidative stress, perhaps in the brain, may be one of the factors that elevate plasma s(P)RR levels in OSAS. PMID- 28632191 TI - Sexually Transmitted Infections: A Novel Screening Strategy for Improving Women's Health in Vulnerable Populations. AB - BACKGROUND: Migrant women are one of the most vulnerable population to health problems and well-being. This study aimed at implementing a counseling and preventive strategy for sexually transmitted infections (STIs) in undocumented migrant women in Milan, Italy. METHODS: Women (ages 18-65) were enrolled at the NAGA Centre (2012-2013) and asked for a urine sample in order to carry out molecular detection of Human papillomavirus (HPV), Chlamydia trachomatis (Ct), Trichomonas vaginalis (Tv), Neisseria gonorrhoeae (Ng)-DNA. Socio-demographic and sexual behavior information were collected. All HPV/Ct+ women were offered Pap tests and/or were prescribed antibiotic treatment. RESULTS: 537/757 women participated in the study (acceptability rate: 70.9%). Most of the women were from Latin America (45.6%) and Eastern Europe (30.7%); >60% of them had stable partners, did not use contraception and had had at least one pregnancy. The prevalence rates of HPV, Ct, Tv and Ng infections were 24.2%, 7.8%, 4.8% and 0%, respectively. In all, 43.2% of the positive women agreed to undergo a gynecological examination and accepted suitable treatment. CONCLUSIONS: This study shows an overall high prevalence of STIs in undocumented migrant women in Milan. The screening strategy based on counseling and urine testing contributed to the successfully high acceptability rate. More appropriate health services that adequately address all aspects of women's health are required. PMID- 28632192 TI - Coverage and Influencing Determinants of Influenza Vaccination in Elderly Patients in a Country with a Poor Vaccination Implementation. AB - : The seasonal influenza vaccination uptake of the elderly in Poland is one of the lowest in Europe. Objective: to assess the vaccination coverage and influencing determinants in patients >=65 years of age. METHODS: A cross sectional study was conducted (November 2015-April 2016) among consecutive patients admitted to a municipal hospital located in the city of Szczecin, North west Poland. Patients completed researcher-administered, anonymous questionnaires on socio- demographic data/factors related to the vaccination. Results: The response rate: 92.0%. Among 230 patients (79.6% women, median of age 69 years, range 65-89) who agreed to participate, 34.8% (95% Confidence Interval: 28.6 41.0%) were vaccinated. About 15.7% of respondents had not previously heard about the vaccination; 41.3% of those who stated they were vaccinated or planned on being vaccinated the following year, compared to 19.3% of respondents who stated they were not currently vaccinated (p < 0.001). A multivariable regression analysis revealed that patient factors, such as younger age (Odds Ratio, OR = 7.69), living in the urban area (OR = 7.69), having comorbidities (OR = 2.70), having a vaccinated family member (OR = 3.57), and being informed about vaccination (OR = 5.00) were each associated with greater odds of being immunized. Willingness for vaccination the next year was strongly associated (OR = 8.59) with vaccination status. Conclusions: The influenza vaccination uptake in the elderly population in Poland is disturbingly low. Improved education strategies are needed to increase the uptake. Vaccinated respondents are more likely to plan on being vaccinated the following year. Future interventions related to maximizing vaccination coverage should be more tailored, focusing especially on older patients living in rural areas. PMID- 28632193 TI - Adolescents' Knowledge of Breastfeeding and Their Intention to Breastfeed in the Future. AB - The aim of this paper is to analyze third-year secondary school students' knowledge of breastfeeding and intention to breastfeed their children, based on the results of a questionnaire. The respondents were 154 students (101 female/43 male) of two secondary schools in Bjelovar. The students completed a questionnaire which consisted of 23 questions regarding knowledge and intention to breastfeed. The answers were analyzed statistically and different results were compared by nonparametric tests. About half of the respondents think that both partners should decide on breastfeeding and recognize the role that fathers have in initiating and maintaining breastfeeding. Only 13.64% of the respondents know that breastfeeding is to be done only on demand. Exclusive breastfeeding for 6 months, as recommended by the medical profession, is recognized by 70.13% of the students. The question on how justified is the initiation of formula together with the mother's milk was answered correctly by 29.22% of the students. Secondary school students' knowledge of breastfeeding is insufficient, and schools, families, social communities and other sources of information should share the responsibility for improving this. We consider it necessary to pay more attention to improving students' knowledge of breastfeeding through school curricula. PMID- 28632194 TI - A Mind-Body Approach to Pediatric Pain Management. AB - Pain is a significant public health problem that affects all populations and has significant financial, physical and psychological impact. Opioid medications, once the mainstay of pain therapy across the spectrum, can be associated with significant morbidity and mortality. Centers for Disease and Control (CDC) guidelines recommend that non-opioid pain medications are preferred for chronic pain outside of certain indications (cancer, palliative and end of life care). Mindfulness, hypnosis, acupuncture and yoga are four examples of mind-body techniques that are often used in the adult population for pain and symptom management. In addition to providing significant pain relief, several studies have reported reduced use of opioid medications when mind-body therapies are implemented. Mind-body medicine is another approach that can be used in children with both acute and chronic pain to improve pain management and quality of life. PMID- 28632195 TI - Towards a Long-Term Strategy for Voluntary-Based Internal Radiation Contamination Monitoring: Representativeness of the Monitoring Results in Fukushima, Japan. AB - Following Japan's 2011 Fukushima nuclear incident, voluntary participation, rather than mandatory, was adopted as the default scenario for individual radiation monitoring. We evaluated the representativeness of the internal monitoring results from voluntary participants in Minamisoma City, which is located 10-40 km from the Fukushima nuclear plant. Of approximately 70,000 individuals who were residing in Minamisoma City before the incident, a total of 19,263 residents (aged >=21 years) participated in the monitoring from 1 October 2011 to 31 March 2015. Based on regression projection techniques with the available data obtained from the voluntary participants, the modeled probabilities of radiocesium (Cs) detection in October 2011 for Cs-137 and Cs-134 were 66.9% and 52.9%, respectively, which declined dramatically within a year following the incident. The rate of decline had stagnated since mid-2012, and the probability was close to zero after mid-2014. Sufficient agreement between the modeled probabilities of Cs detection (for the whole population) versus the measured Cs levels (for voluntary participants) was observed, except for Cs-134 in October 2011, indicating that the voluntary monitoring participant group was a good representative sample. Our findings affirmed the clinical importance of voluntary-based monitoring as a screening and dose-assessment tool in a post nuclear incident. Our study informs societal decision-making regarding the long term maintenance of the monitoring program under the current low exposure levels. PMID- 28632196 TI - Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches. AB - Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcepsilonRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a "bench to bedside" approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications. PMID- 28632198 TI - Community Response to Multiple Sound Sources: Integrating Acoustic and Contextual Approaches in the Analysis. AB - Sufficient data refer to the relevant prevalence of sound exposure by mixed traffic sources in many nations. Furthermore, consideration of the potential effects of combined sound exposure is required in legal procedures such as environmental health impact assessments. Nevertheless, current practice still uses single exposure response functions. It is silently assumed that those standard exposure-response curves accommodate also for mixed exposures-although some evidence from experimental and field studies casts doubt on this practice. The ALPNAP-study population (N = 1641) shows sufficient subgroups with combinations of rail-highway, highway-main road and rail-highway-main road sound exposure. In this paper we apply a few suggested approaches of the literature to investigate exposure-response curves and its major determinants in the case of exposure to multiple traffic sources. Highly/moderate annoyance and full scale mean annoyance served as outcome. The results show several limitations of the current approaches. Even facing the inherent methodological limitations (energy equivalent summation of sound, rating of overall annoyance) the consideration of main contextual factors jointly occurring with the sources (such as vibration, air pollution) or coping activities and judgments of the wider area soundscape increases the variance explanation from up to 8% (bivariate), up to 15% (base adjustments) up to 55% (full contextual model). The added predictors vary significantly, depending on the source combination. (e.g., significant vibration effects with main road/railway, not highway). Although no significant interactions were found, the observed additive effects are of public health importance. Especially in the case of a three source exposure situation the overall annoyance is already high at lower levels and the contribution of the acoustic indicators is small compared with the non-acoustic and contextual predictors. Noise mapping needs to go down to levels of 40 dBA,Lden to ensure the protection of quiet areas and prohibit the silent "filling up" of these areas with new sound sources. Eventually, to better predict the annoyance in the exposure range between 40 and 60 dBA and support the protection of quiet areas in city and rural areas in planning sound indicators need to be oriented at the noticeability of sound and consider other traffic related by-products (air quality, vibration, coping strain) in future studies and environmental impact assessments. PMID- 28632199 TI - Modulatory Effects of Guarana (Paullinia cupana) on Adipogenesis. AB - Guarana (Paullinia cupana) is a plant originated in Brazil that presents a beneficial effect on body weight control and metabolic alterations. The aim of this study was to evaluate the effects of guarana on genes and miRNAs related to adipogenesis in 3T3L1 cells. The anti-adipogenic effect of guarana was evaluated by Oil Red-O staining. Gene and miRNA expression levels were determined by real time PCR. The Cebpalpha and beta-catenin nuclear translocation were evaluated using immunocytochemistry. Our data indicated that the triglyceride-reducing effect of guarana was dose-dependent from 100 to 300 ug/mL (-12%, -20%, -24% and 40%, respectively, p < 0.0001). An up-regulation of the anti-adipogenic genes Wnt10b, Wnt3a, Wnt1, Gata3 and Dlk1 and a down-regulation of pro-adipogenic genes Cebpalpha, Ppargamma and Creb1 were also observed. Furthermore, guarana repressed mmu-miR-27b-3p, mmu-miR-34b-5p and mmu-miR-760-5p, that contributed for up regulation of their molecular targets Wnt3a, Wnt1 and Wnt10b. Additionally, cells treated with guarana presented an increase on beta-catenin nuclear translocation (p < 0.0018). In summary, our data indicate that guarana has an anti-adipogenic potential due to its ability to modulate miRNAs and genes related to this process. Together our data demonstrate the important role of guarana as a putative therapeutic agent. PMID- 28632197 TI - Toxic AGE (TAGE) Theory for the Pathophysiology of the Onset/Progression of NAFLD and ALD. AB - Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are among the most common causes of chronic liver diseases in the westernized world. NAFLD and ALD are frequently accompanied by extrahepatic complications, including hepatocellular carcinoma and cardiovascular diseases, which have a negative impact on patient survival. The chronic ingestion of an excessive daily diet containing sugar/high-fructose corn syrup increases the level of the fructose/glucose metabolite, glyceraldehyde (GA), while the chronic consumption of an excessive number of alcoholic beverages increases the level of the alcohol metabolite, acetaldehyde (AA) in the liver. GA and AA are known to react non enzymatically with the epsilon- or alpha-amino groups of proteins, thereby generating advanced glycation end-products (AGEs, GA-AGEs, and AA-AGEs, respectively) in vivo. The interaction between GA-AGEs and the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro inflammatory molecules and also elicits the production of reactive oxygen species by human hepatocytes and hepatic stellate cells, all of which may contribute to the pathological changes associated with chronic liver diseases. We herein discuss the pathophysiological roles of GA-AGEs and AA-AGEs (toxic AGEs, TAGE) and a related novel theory for preventing the onset/progression of NAFLD and ALD. PMID- 28632200 TI - The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair 86Y and 90Y. AB - In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the "best one" for that individual patient. Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair 86Y/90Y, which allowed a combination of PET and internal radiotherapy. Whereas the beta-emitting therapeutic radionuclide 90Y (t1/2 = 2.7 d) had been available for a long time via the 90Sr/90Y generator system, the beta+ emitter 86Y (t1/2 = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of 86Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue 90Y-labelled compound in terms of mGy or mSv per MBq 90Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed. PMID- 28632201 TI - Advantageous developmental outcomes of advancing paternal age. AB - Advanced paternal age (APA) at conception has been associated with negative outcomes in offspring, raising concerns about increasing age at fatherhood. Evidence from evolutionary and psychological research, however, suggests possible link between APA and a phenotypic advantage. We defined such advantage as educational success, which is positively associated with future socioeconomic status. We hypothesised that high IQ, strong focus on the subject of interest and little concern about 'fitting in' will be associated with such success. Although these traits are continuously distributed in the population, they cluster together in so-called 'geeks'. We used these measures to compute a 'geek index' (GI), and showed it to be strongly predictive of future academic attainment, beyond the independent contribution of the individual traits. GI was associated with paternal age in male offspring only, and mediated the positive effects of APA on education outcomes, in a similar sexually dimorphic manner. The association between paternal age and GI was partly mediated by genetic factors not correlated with age at fatherhood, suggesting contribution of de novo factors to the 'geeky' phenotype. Our study sheds new light on the multifaceted nature of the APA effects and explores the intricate links between APA, autism and talent. PMID- 28632203 TI - Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease. AB - Early identification of Alzheimer's disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls. Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. These results associate a decreased level of DYRK1A with AD and challenge the use of DYRK1A inhibitors in peripheral tissues as treatment. These measures will be useful for diagnosis purposes. PMID- 28632206 TI - Letters. PMID- 28632207 TI - Hot Rockets. PMID- 28632204 TI - Successful pharmacotherapy for the treatment of severe feeding aversion with mechanistic insights from cross-species neuronal remodeling. AB - Pediatric feeding disorders affect up to 5% of children, causing severe food intake problems that can result in serious medical and developmental outcomes. Behavioral intervention (BI) is effective in extinguishing feeding aversions, and also expert-dependent, time/labor-intensive and not well understood at a neurobiological level. Here we first conducted a double-blind, placebo-controlled trial comparing BI with BI plus d-cycloserine (DCS). DCS is a partial N-methyl-d aspartate (NMDA) receptor agonist shown to augment extinction therapies in multiple anxiety disorders. We examined whether DCS enhanced extinction of feeding aversion in 15 children with avoidant/restrictive food intake disorder (ages 20-58 months). After five treatment days, BI improved feeding by 37%. By contrast, BI+DCS improved feeding by 76%. To gain insight into possible mechanisms of successful intervention, we next tested the neurobiological consequences of DCS in a murine model of feeding aversion and avoidance. In mice with conditioned food aversion, DCS enhanced avoidance extinction across a broad dose range. Confocal fluorescence microscopy and three-dimensional neuronal reconstruction indicated that DCS enlarged dendritic spine heads-the primary sites of excitatory plasticity in the brain-within the orbitofrontal prefrontal cortex, a sensory-cognition integration hub. DCS also increased phosphorylation of the plasticity-associated extracellular signal-regulated kinase 1/2. In summary, DCS successfully augments the extinction of food aversion in children and mice, an effect that may involve plasticity in the orbitofrontal cortex. These results warrant a larger-scale efficacy study of DCS for the treatment of pediatric feeding disorders and further investigations of neural mechanisms. PMID- 28632209 TI - Uncharted Territory. PMID- 28632208 TI - Letters. PMID- 28632205 TI - Speckle-modulating optical coherence tomography in living mice and humans. AB - Optical coherence tomography (OCT) is a powerful biomedical imaging technology that relies on the coherent detection of backscattered light to image tissue morphology in vivo. As a consequence, OCT is susceptible to coherent noise (speckle noise), which imposes significant limitations on its diagnostic capabilities. Here we show speckle-modulating OCT (SM-OCT), a method based purely on light manipulation that virtually eliminates speckle noise originating from a sample. SM-OCT accomplishes this by creating and averaging an unlimited number of scans with uncorrelated speckle patterns without compromising spatial resolution. Using SM-OCT, we reveal small structures in the tissues of living animals, such as the inner stromal structure of a live mouse cornea, the fine structures inside the mouse pinna, and sweat ducts and Meissner's corpuscle in the human fingertip skin-features that are otherwise obscured by speckle noise when using conventional OCT or OCT with current state of the art speckle reduction methods. PMID- 28632211 TI - Amazon Atlantis. PMID- 28632210 TI - We Can't Avoid Future Disease Outbreaks. PMID- 28632202 TI - Genome-wide association study of borderline personality disorder reveals genetic overlap with bipolar disorder, major depression and schizophrenia. AB - Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 * 10-7) and PKP4 (P=8.67 * 10-7); and gene set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 * 10-3]), SCZ (rg=0.34 [P=4.37 * 10-5]) and MDD (rg=0.57 [P=1.04 * 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies. PMID- 28632212 TI - Designing the City of Tomorrow Today. PMID- 28632214 TI - Quick Hits. PMID- 28632215 TI - Operation: Diabetes. PMID- 28632213 TI - Can Plants Hear? PMID- 28632217 TI - Boogie Bears. PMID- 28632216 TI - The Evolution of Dance. PMID- 28632218 TI - The Stuff of Dreams. PMID- 28632219 TI - Raise Alcohol Taxes, Reduce Violence. PMID- 28632220 TI - The Mouse Parent Trap. PMID- 28632221 TI - Probiotics Are No Panacea. PMID- 28632222 TI - 50, 100 &150 Years Ago. PMID- 28632223 TI - Black Holes from the Beginning of Time. PMID- 28632224 TI - Secrets and Lies. PMID- 28632226 TI - The Baby Spike. PMID- 28632225 TI - Waning Woods. PMID- 28632227 TI - Who Are You? PMID- 28632228 TI - From Parking Lot to Paradise. PMID- 28632229 TI - Grandma's Robot Helper. PMID- 28632230 TI - Recommended. PMID- 28632231 TI - Computer-Aided Creativity. PMID- 28632233 TI - Drilling for Fossil Gold. PMID- 28632232 TI - Memory's Intricate Web. PMID- 28632234 TI - How Cities Could Save Us. PMID- 28632235 TI - Tapping the Trash. PMID- 28632236 TI - MERRAclim, a high-resolution global dataset of remotely sensed bioclimatic variables for ecological modelling. AB - Species Distribution Models (SDMs) combine information on the geographic occurrence of species with environmental layers to estimate distributional ranges and have been extensively implemented to answer a wide array of applied ecological questions. Unfortunately, most global datasets available to parameterize SDMs consist of spatially interpolated climate surfaces obtained from ground weather station data and have omitted the Antarctic continent, a landmass covering c. 20% of the Southern Hemisphere and increasingly showing biological effects of global change. Here we introduce MERRAclim, a global set of satellite-based bioclimatic variables including Antarctica for the first time. MERRAclim consists of three datasets of 19 bioclimatic variables that have been built for each of the last three decades (1980s, 1990s and 2000s) using hourly data of 2 m temperature and specific humidity. We provide MERRAclim at three spatial resolutions (10 arc-minutes, 5 arc-minutes and 2.5 arc-minutes). These reanalysed data are comparable to widely used datasets based on ground station interpolations, but allow extending their geographical reach and SDM building in previously uncovered regions of the globe. PMID- 28632237 TI - Auricular Point Acupressure to Manage Aromatase Inhibitor-Induced Arthralgia in Postmenopausal Breast Cancer Survivors: A Pilot Study. AB - PURPOSE/OBJECTIVES: To assess the feasibility of auricular point acupressure to manage aromatase inhibitor-induced arthralgia.?. DESIGN: Wait list control design.?. SETTING: Outpatient clinics and oncology center.?. SAMPLE: 20 women with aromatase inhibitor-induced arthralgia.?. METHODS: After baseline data were collected, participants waited one month before they received acupressure once per week for four weeks at a convenient time. The baseline data served as the control comparison. Self-reported measures and blood samples were obtained at baseline, at preintervention, weekly during the intervention, and at post intervention.?. MAIN RESEARCH VARIABLES: The primary outcomes included pain intensity, pain interference, stiffness, and physical function. Inflammatory cytokines and chemokines were tested.?. FINDINGS: After the four-week intervention, participants reported decreases in worst pain and pain interference, and improvements in physical function, cancer-related symptom severity, and interference. The proinflammatory cytokines and chemokines displayed a trend of a mean percentage reduction. The anti-inflammatory cytokine interleukin-13 increased from pre- to postintervention.?. CONCLUSIONS: Auricular point acupressure is feasible and may be effective in managing arthralgia in breast cancer survivors.?. IMPLICATIONS FOR NURSING: Nurses can administer acupressure in clinical settings, which could enhance the management of aromatase inhibitor-induced arthralgia and contribute to a shift from traditional disease based biomedical models to a broader, integrative, medical paradigm for managing aromatase inhibitor-induced arthralgia. PMID- 28632238 TI - Attitudes Among Nurses Toward the Integration of Complementary Medicine Into Supportive Cancer Care. AB - PURPOSE/OBJECTIVES: To explore the attitudes of nurses treating patients with cancer regarding the use of complementary and integrative medicine (CIM) therapies to reduce symptoms and improve quality of life (QOL). ?. DESIGN: Prospective and descriptive.? ?. SETTING: 12 hospital and community care settings in Israel. ?. SAMPLE: 973 nurses working in oncology and non-oncology departments.?. METHODS: A 26-item questionnaire was administered to a convenience sample of nurses treating patients with cancer. ?. MAIN RESEARCH VARIABLES: Interest in CIM integration and training in supportive cancer care.?. FINDINGS: Of the 973 nurses who completed the questionnaire, 934 expressed interest in integrating CIM into supportive cancer care. A logistic regression model indicated that nurses with a greater interest in integration tended to be older, believed that CIM improved patients' QOL, and had no structured postgraduate oncology training. Nurses who believed CIM to be beneficial for QOL-related outcomes were more likely to express interest in related training. The goals of such training include improving QOL-related outcomes, such as anxiety, insomnia, gastrointestinal symptoms, and pain. ?. CONCLUSIONS: Most nurses working with patients with cancer are interested in the integration of CIM into supportive cancer care. ?. IMPLICATIONS FOR NURSING: Most nurses would like to undergo training in CIM to supplement conventional care. CIM-trained integrative nurses can help promote the integration of patient-centered CIM therapies in supportive cancer care settings. PMID- 28632239 TI - Feasibility of Mind-Body Movement Programs for Cancer Survivors. AB - PURPOSE/OBJECTIVES: To evaluate mind-body movement exercise (MBME) classes (yoga, tai chi, and Qigong) for cancer survivors. ?. DESIGN: A single-group, repeated measures design.?. SETTING: The Ohio State University Wexner Medical Center Arthur G. James Cancer Hospital in Columbus.?. SAMPLE: 33 adult cancer survivors, with any cancer diagnosis, participating in MBME classes.?. METHODS: The researchers sought to examine feasibility of multiple data collection time points and data collection measures; acceptability; and changes to physical, emotional, and biometric measures over time, as a result of participation in MBME classes.?. MAIN RESEARCH VARIABLES: Quality of life, sleep, depressive symptomatology, fatigue, stress, upper body strength, gait and balance, body mass index, heart rate, and blood pressure.?. FINDINGS: The current study was feasible because survivors were willing to participate and completed most of the questionnaires. Participants found these classes to be beneficial not only for exercise, but also for social support and social connectedness. Poor sleep quality was consistently reported by participants. MBME classes should be recommended to survivors and are beneficial for oncology practices to offer.?. CONCLUSIONS: Conducting MBME research with cancer survivors is feasible, and participants find the MBME acceptable and a way of addressing health and managing cancer-related symptoms.?. IMPLICATIONS FOR NURSING: Nurses should help patients and caregivers identify locations and times when MBME class participation is possible, assess MBME class participation during each clinic visit to promote continued involvement and to understand if positive effects are occurring, and continue to provide support for MBME classes throughout the survivorship experience. PMID- 28632240 TI - Body-Related Shame and Guilt Predict Physical Activity in Breast Cancer Survivors Over Time. AB - PURPOSE/OBJECTIVES: To test body-related shame and guilt as predictors of breast cancer survivors' (BCS') moderate to vigorous intensity physical activity (MVPA) during six months and to examine motivational regulations as mediators of this association.?. DESIGN: Prospective study.?. SETTING: Survivors were recruited through advertisements and oncologist referrals from medical clinics and hospitals in Montreal, Quebec, Canada.?. SAMPLE: 149 female BCS.?. METHODS: Self reports of body-related shame and guilt, motivational regulations, and MVPA were measured among BCS at baseline. MVPA was assessed a second time six months later. Residual change scores were used.?. MAIN RESEARCH VARIABLES: Body-related shame and guilt; external, introjected, and autonomous (identified and intrinsic) motivational regulations; MVPA.?. FINDINGS: In the multiple mediation models, body-related shame was associated with low levels of MVPA, as well as external, introjected, and autonomous motivational regulations. Guilt was related to high levels of MVPA and introjected and autonomous motivational regulations. Indirect effects linked shame, guilt, and MVPA via autonomous motivation. Only body related shame was a significant predictor of six-month changes in MVPA.?. CONCLUSIONS: Based on these results, the specific emotions of shame and guilt contextualized to the body differentially predict BCS' health motivations and behavior over time.?. IMPLICATIONS FOR NURSING: Survivorship programs may benefit from integrating intervention strategies aimed at reducing body-related shame and helping women manage feelings of guilt to improve physical activity. PMID- 28632241 TI - Nursing Support of Home Hospice Caregivers on the Day of Patient Death. AB - PURPOSE/OBJECTIVES: To describe nurse-caregiver communication on the day of patient death.?. DESIGN: A descriptive secondary analysis of 44 audio-recorded home hospice nursing visits on day of death.?. SETTING: Nine hospices in Utah, Oregon, and Massachusetts.?. SAMPLE: 42 caregiver-patient dyads, 27 hospice nurses.?. METHODS: Transcripts of audio recordings were coded for supportive nursing communication and relative time spent in physical, psychosocial, and spiritual discussion.?. MAIN RESEARCH VARIABLES: Tangible, emotional, informational, esteem, and networking supportive communication; nurses' self reported communication effectiveness; caregiver religious affiliation.?. FINDINGS: Nurses reported that their communication skills were less effective when discussing difficult topics as compared to their overall communication effectiveness. Eleven patients died before the nursing visit, 3 died during the visit, and 30 died post-visit. Nurses primarily engaged in discussions facilitating caregiver emotional, tangible, and informational support. More informational support was observed when patient death occurred during the nursing visit. Time spent in general conversation showed that physical care conversations predominated (80% of the average overall amount of conversation time), compared to lifestyle/psychosocial discussions (14%) and spiritual discussions (6%). Spiritual discussions were observed in only 7 of 44 hospice visits. Spiritual discussions, although short and infrequent, were significantly longer, on average, for caregivers without a religious affiliation.?. CONCLUSIONS: Nurses support caregivers on the day of patient death using multiple supportive communication strategies. Spiritual discussions are minimal.?. IMPLICATIONS FOR NURSING: Communication skills programs can potentially increase self-reported communication effectiveness. Emerging acute spiritual concerns, particularly for caregivers without a previous religious affiliation, should be anticipated. Spiritual support is included in the hospice model of holistic care. PMID- 28632243 TI - Team Science and Big Brains. AB - Recently, I was honored with the task of moderating a session at the Oncology Nursing Society's 42nd Annual Congress in Denver, Colorado. The panel discussion, "Team Science: A Discussion With the Experts," was described as an opportunity to learn about team science implementation in the conduct of cancer research. The panel members were leaders in oncology research. As the session was about to begin, I looked over at the panelists and decided that this session should have been called "The Big Brains Session" because the panelists are giants in the field. And yes, I was just a little intimidated to be posing questions to the panel, not to mention moderating their discussion.?. PMID- 28632242 TI - Exploring Gender Differences in Self-Reported Physical Activity and Health Among Older Caregivers. AB - PURPOSE/OBJECTIVES: To document self-reported physical health and activity levels of older caregivers. Gender differences in physical health, physical activity levels, and predictors of physical activity were also examined.?. DESIGN: A cross sectional study.?. SETTING: Tom Baker Cancer Centre in Calgary, Alberta, Canada.?. SAMPLE: 130 caregivers aged 60 years or older caring for individuals with breast, prostate, or colorectal cancer.?. METHODS: Self-report survey including validated questionnaires on physical and mental health and physical activity levels. Convenience sampling was used. Data were analyzed using descriptive statistics, correlations, and multiple regression.?. MAIN RESEARCH VARIABLES: The physical component score of the SF-36v2(r) was the main research variable. Other variables included the mental component score of the SF-36v2, sleep quality, depression, social support, physical activity levels, and anxiety.?. FINDINGS: The mean age of caregivers was 70 years. Physical health and physical activity levels were higher than population norms. A significant difference in physical health (p = 0.015) existed between men and women but not in physical activity levels (p = 0.079). Predictors of physical activity levels were age (beta = -0.291), physical health (beta = 0.307), and caregiving hours per week (beta = -0.221).?. CONCLUSIONS: The findings suggest that gender had a minimal effect on physical health and no effect on physical activity levels in older caregivers. Depression and poor sleep quality were high in some caregivers but did not predict physical activity levels. ?. IMPLICATIONS FOR NURSING: The negative effects of caregiving on physical health and physical activity levels in older caregivers are not universal. Nurses should be aware of the caregiving situation and promote health based on the individual. PMID- 28632244 TI - Pain Management in the Middle East: Building Capacity With Global Partners. AB - The Middle East (ME) is an economically diverse region that includes countries in Central Asia and Northern Africa. Regardless, cancer is a major health concern in the ME, and pain management is an essential component of cancer care across the disease trajectory. This column will provide background on opioid use for pain management in the ME and highlight the collaborative work of the Middle Eastern Cancer Consortium, Omani Cancer Association, and the Oncology Nursing Society to increase pain assessment and management capacity in the ME. PMID- 28632245 TI - Development of an Instrument to Examine Nursing Attitudes Toward Fertility Preservation in Oncology. AB - PURPOSE/OBJECTIVES: To develop an instrument to measure staff nurse perceptions of the barriers to and benefits of addressing fertility preservation (FP) with patients newly diagnosed with cancer. ?. DESIGN: A prospective, nonrandomized instrument development approach. ?. SETTING: Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center in Dallas. ?. SAMPLE: 224 RNs who care for patients with cancer. ?. METHODS: The instrument was developed with content experts and field-tested with oncology staff nurses. Responses to a web-based survey were used in exploratory factor analysis. After refining the instrument, the authors conducted a confirmatory factor analysis with 230 web-based survey responses. ?. MAIN RESEARCH VARIABLES: Self-perceived barriers to providing FP options to patients newly diagnosed with cancer.?. FINDINGS: The results supported a 15-item instrument with five domains. CONCLUSIONS: This instrument can be used to explore oncology nurses' attitudes toward FP in newly diagnosed people with cancer in their reproductive years. ?. IMPLICATIONS FOR NURSING: A more comprehensive understanding of attitudes and barriers related to FP will guide the building of optimal systems that support effective FP options, resources, and programs for individuals with cancer. PMID- 28632246 TI - Declines Noted in Cognitive Processes and Association With Achievement Among Children With Leukemia. AB - PURPOSE/OBJECTIVES: To assess change in specific cognitive processes during treatment with chemotherapy only among children with acute lymphoblastic leukemia (ALL). ?. DESIGN: A prospective, repeated measures design.?. SETTING: Pediatric oncology treatment centers at Banner-University Medical Center Tucson/Banner Children's-Diamond Medical Center (University of Arizona) and Texas Children's Cancer and Hematology centers (Baylor College of Medicine) in Houston. ?. SAMPLE: 71 children with ALL, with a mean age of 6.18 years at the time of diagnosis. ?. METHODS: Using mixed-effects latent growth curve modeling with time since diagnosis as a fixed effect, age-adjusted standardized measures of working memory, processing speed, executive function, and attention were obtained and repeated about one and two years later. A subsample was tested for academic achievement at the end of treatment.?. MAIN RESEARCH VARIABLES: Verbal working memory, visual spatial memory, processing speed, academic achievement, age, and gender. ?. FINDINGS: A significant main effect was observed for age at diagnosis on decline in verbal working memory during treatment. Planned contrasts revealed greater decline among children who were diagnosed when aged younger than five years compared to those diagnosed when aged five years or older. Decline in verbal working memory and achievement in letter-word identification and calculation skills were associated, and decline in spatial memory was associated with calculation. A main effect of gender was observed on processing speed, with female patients showing greater decline than male patients. ?. CONCLUSIONS: Findings from this study may guide the timing of interventions that could improve school achievement among survivors. ?. IMPLICATIONS FOR NURSING: Children undergoing treatment for ALL may experience issues with verbal working memory and increased difficulty in school. Nurses are in a position to refer parents and children to school resources for additional academic support. PMID- 28632247 TI - Antecedents and Outcomes of Uncertainty in Older Adults With Cancer: A Scoping Review of the Literature. AB - PROBLEM IDENTIFICATION: Uncertainty is a major source of distress for cancer survivors. Because cancer is primarily a disease of older adults, a comprehensive understanding of the antecedents and outcomes of uncertainty in older adults with cancer is essential. ?. LITERATURE SEARCH: MEDLINE(r), PsycINFO(r), Scopus, and CINAHL(r) were searched from inception to December 2015. Medical Subject Headings (MeSH) terms and free text words were used for the search concepts, including neoplasms, uncertainty, and aging. ?. DATA EVALUATION: Extracted data included research aims; research design or analysis approach; sample size; mean age; type, stage, and duration of cancer; type and duration of treatment; uncertainty scale; and major results. ?. SYNTHESIS: Of 2,584 articles initially identified, 44 studies (30 qualitative, 12 quantitative, and 2 mixed-methods) were included. Evidence tables were developed to organize quantitative and qualitative data. Descriptive numeric and thematic analyses were used to analyze quantitative results and qualitative findings, respectively. Outcomes were reported under four main categories. CONCLUSIONS: Uncertainty is an enduring and common experience in cancer survivorship. Uncertainty is affected by a number of demographic and clinical factors and affects quality of life (QOL) and psychological well-being. ?. IMPLICATIONS FOR PRACTICE: Uncertainty should be considered a contributing factor to psychological well-being and QOL in older adults with cancer. Nurses are in a unique position to assess negative effects of uncertainty and manage these consequences by providing patients with information and emotional support. PMID- 28632248 TI - Perceived Benefits and Barriers to Exercise for Recently Treated Adults With Acute Leukemia. AB - PURPOSE/OBJECTIVES: To explore perceived exercise benefits and barriers in adults with acute leukemia who recently completed an inpatient exercise intervention during induction therapy.?. RESEARCH APPROACH: Descriptive, exploratory design using semistructured interviews.?. SETTING: Inpatient hematology/oncology unit at North Carolina Cancer Hospital in Chapel Hill.?. PARTICIPANTS: 6 adults with acute leukemia aged 35-67 years.?. METHODOLOGIC APPROACH: Content analyses of semistructured interviews that were conducted with each participant prior to hospital discharge.?. FINDINGS: Most participants were not meeting the recommended physical activity levels of 150 minutes of moderate-intensity exercise per week before their diagnosis. Patients were highly pleased with the exercise intervention and the overall program. Common barriers to exercise were anxiety and aches and pains.?. INTERPRETATION: Overall, participants experienced physical and psychological benefits with the exercise intervention with no adverse events from exercising regularly during induction chemotherapy. Referrals for cancer rehabilitation management will lead to prolonged recovery benefits.?. IMPLICATIONS FOR NURSING: Findings inform the nurses' role in encouraging and supporting adults with acute leukemia to exercise and be physically active during their hospitalization. Nurses should also be responsible for assisting patients with physical function activities to increase mobility and enhance overall health related quality of life. PMID- 28632249 TI - Ethical Considerations When Using Social Media for Research. AB - Because of its adaptation across age groups and populations, social media is being used as a venue for the conduction of research studies. The implications for use of social media to streamline data collection and analyses to understand epidemiologic effects of disease are intriguing. Public access to personalized Internet-based searches and conversations for patients with or at risk for cancer can potentially allow providers to target individuals for earlier interventions and improved outcomes. Although publicly posted, the use of personal information to solicit research participants, implement interventions, or abstract information for research studies raises questions regarding maintaining the ethical conduct of research. PMID- 28632250 TI - Measurement of Hyperglycemia and Impact on Health Outcomes in People With Cancer: Challenges and Opportunities. AB - PROBLEM IDENTIFICATION: Poor health outcomes have been associated with hyperglycemia in patients with and without diabetes. However, the impact of hyperglycemia on the health-related outcomes of patients with cancer has shown conflicting results. The purpose of this review was to explore definitions and measurement issues related to the assessment of hyperglycemia and the subsequent impact on the findings of health-related outcomes in adults with cancer.?. LITERATURE SEARCH: Four electronic databases were searched. DATA EVALUATION: A total of 30 articles were reviewed. Quantitative articles were synthesized using integrative review strategies. ?. SYNTHESIS: Three key gaps were identified in the literature. CONCLUSIONS: This review highlights the inconsistencies in measuring or assessing hyperglycemia and the lack of standardized guidelines in treating hyperglycemia. Failure to have a standard approach to the measurement and management of hyperglycemia impedes the ability of healthcare providers to determine the significance of its impact on health outcomes. Further research is needed to establish appropriate measurement guidelines to address hyperglycemia in people with cancer.?. IMPLICATIONS FOR PRACTICE: Evidence-based measurement and treatment guidelines are needed to inform and assist healthcare providers with clinical decision making for people with cancer who experience hyperglycemia. PMID- 28632251 TI - Effects of Nurse-Led Telephone-Based Supportive Interventions for Patients With Cancer: A Meta-Analysis. AB - PROBLEM IDENTIFICATION: To evaluate the effects of nurse-led telephone-based supportive interventions (NTSIs) for patients with cancer.?. LITERATURE SEARCH: Electronic databases, including EMBASE(r), MEDLINE, Google Scholar, ?Cochrane Library CENTRAL, ProQuest Medical Library, and CINAHL(r), were searched through February 2016.?. DATA EVALUATION: 239 studies were identified; 16 were suitable for meta-analysis. Cochrane's risk of bias tool and the Comprehensive Meta Analysis software were used.?. SYNTHESIS: The authors performed a meta-analysis of 16 trials that met eligibility criteria. Thirteen randomized, controlled trials (RCTs) and three non-RCTs examined a total of 2,912 patients with cancer. Patients who received NTSIs were compared with those who received attentional control or usual care (no intervention).?. CONCLUSIONS: Telephone interventions delivered by a nurse in an oncology care setting reduced cancer symptoms with a moderate effect size (ES) (-0.33) and emotional distress with a small ES (-0.12), and improved self-care with a large ES (0.64) and health-related quality of life (HRQOL) with a small ES (0.3). Subgroup analyses indicated that the significant effects of NTSIs on cancer symptoms, emotional distress, and HRQOL were larger for studies that combined an application of a theoretical framework, had a control group given usual care, and used an RTC design.?. IMPLICATIONS FOR RESEARCH: The findings suggest that an additional tiered evaluation that has a theoretical underpinning and high-quality methodology is required to confirm the efficacy of NTSI for adoption of specific care models. PMID- 28632252 TI - Improving Oncology Nurses' Knowledge About Nutrition and Physical Activity for Cancer Survivors. AB - PURPOSE/OBJECTIVES: To assess what percentage of oncology nurses perceived themselves as having insufficient knowledge to provide advice on nutrition and/or physical activity (PA), which characteristics were associated with nurses' perception, and whether the content and information sources differed among those nurses.?. DESIGN: A cross-sectional study.?. SETTING: A web-based survey among oncology nurses in the Netherlands.?. SAMPLE: 355 oncology nurses provided advice on nutrition; of these, 327 provided advice on PA.?. METHODS: From May to July 2013, oncology nurses were invited to complete an online questionnaire. Pearson's chi-squared tests and uni- and multivariate logistic regression analyses were conducted.?. MAIN RESEARCH VARIABLES: Oncology nurses' perception of having sufficient or insufficient knowledge to be able to provide advice on nutrition and PA, the content of the advice, and the information sources on which the advice was based.?. FINDINGS: 43% of oncology nurses perceived themselves as having insufficient knowledge to provide advice on nutrition, and 46% perceived insufficient knowledge to provide advice on PA. Factors associated with perceiving insufficient knowledge on nutrition were being aged younger, having lower education, and providing counseling during treatment only. Those nurses were more likely to suggest taking oral nutritional supplements or visiting a dietitian and were less likely to provide information on fluid intake. Nurses perceiving insufficient knowledge about PA used oncology guidelines less often.?. CONCLUSIONS: Almost half of the oncology nurses providing advice on nutrition and PA perceived themselves as having insufficient knowledge to be able to provide such advice. In particular, younger oncology nurses and oncology nurses with an intermediate vocational education may benefit most from education about these topics. ?. IMPLICATIONS FOR NURSING: Educational training for oncology nurses should include nutrition and PA. Oncology nurses should collaborate with dietitians to discuss what information should be provided to patients by whom, and specific PA advice should be provided by a physical therapist. PMID- 28632253 TI - Accuracy of Implant Placement with Computer-Guided Surgery: A Systematic Review and Meta-Analysis Comparing Cadaver, Clinical, and In Vitro Studies. AB - PURPOSE: The aim of this systematic review was to analyze the accuracy of implant placement using computer-guided surgery and to compare virtual treatment planning and outcome in relation to study type (in vitro, clinical, or cadaver). A further objective was to compare the accuracy of half-guided implant surgery with that of full-guided implant surgery. MATERIALS AND METHODS: A PubMed search was performed to identify studies published between January 2005 and February 2015, searching the keywords "reliability AND dental implant planning" and "accuracy dental implant planning." Inclusion criteria were established a priori. Horizontal coronal deviation, horizontal apical deviation, angular deviation, and vertical deviation were analyzed. RESULTS: A total of 186 articles were reviewed, and 34 fulfilled the inclusion criteria. Information about 3,033 implants was analyzed in 8 in vitro studies (543 implants), 4 cadaver studies (246 implants), and 22 clinical studies (2,244 implants). Significantly less horizontal apical deviation and angular deviation were observed in in vitro studies compared to clinical and cadaver studies, but there were no statistically significant differences in apical coronal deviation or vertical deviation between the groups. Compared to half-guided surgery, full-guided implant surgery showed significantly less horizontal coronal deviation for cadaver studies, significantly less horizontal apical deviation for clinical studies, and significantly less angular deviation for both clinical and cadaver studies. CONCLUSION: Implant placement accuracy was lower in clinical and cadaver studies compared with in vitro studies, especially in terms of horizontal apical deviation and angular deviation. Full-guided implant surgery achieved greater accuracy than half-guided surgery. PMID- 28632254 TI - Osteogenic Potential of Gingival Mesenchymal Stem Cells Over Titanium Machined Surfaces. AB - PURPOSE: To evaluate the biochemical composition of bone nodules deposited by gingival mesenchymal stem cells (GMSCs) over titanium machined surfaces in vitro. MATERIALS AND METHODS: GMSCs were isolated from healthy gingival tissues of patients undergoing crown-lengthening surgical procedures. GMSCs were characterized following the International Society for Cellular Therapy guidelines. After incubation of the GMSCs with titanium discs, osteogenic differentiation was induced for 28 days. Osteogenic lineage was confirmed by means of Alizarin Red S staining. Bone nodule morphology and deposition by GMSCs were characterized by scanning electron microscopy (SEM). An elemental analysis of the bone nodules was done using energy-dispersive x-ray spectroscopy (EDS). The biochemical composition of these nodules was further characterized via Raman spectroscopy, with native alveolar bone used as a control. RESULTS: GMSCs adhered and proliferated on the titanium discs and exhibited a spindle-shaped fibroblast like morphology under standard culture conditions. Their phenotype was confirmed by the expression of CD105, CD90, CD73, and CD146, observed using flow cytometry. Deposits of calcium bone nodules were evident in the cultures after staining with Alizarin Red S, but were absent in the controls. Calcium and phosphate, the major components of hydroxyapatite, were present in the bone nodules, as shown by means of the EDS analysis. The results obtained from Raman spectra of these nodules showed the phosphate ions (nu[PO43-], ~960 cm1), amide III (delta[NH], ~1,245 cm 1), CH2 scissors (~1,451 cm-1), amide I (nu[C = O], ~1,667 cm-1), and nu(CH) (2,800-3,100 cm-1) bands were similar to those observed in native bone. CONCLUSION: GMSCs can deposit a bone-like mineral highly similar to native bone (HA) over titanium surfaces. Ongoing studies are aimed at determining whether GMSCs can deposit a similar bone matrix/tissue over removed failed dental implants. If HA can be placed over removed failed dental implants, it may be possible to re-osseointegrate dental implants that are failing as a result of peri-implantitis in vivo. PMID- 28632255 TI - Intake of Proton Pump Inhibitors Is Associated with an Increased Risk of Dental Implant Failure. AB - PURPOSE: To investigate the association between the intake of proton pump inhibitors (PPIs) and the risk of dental implant failure. MATERIALS AND METHODS: The present retrospective cohort study is based on patients consecutively treated between 1980 and 2014 with implant-supported/retained prostheses at one specialist clinic. Modern endosseous dental implants with cylindrical or conical design were included, and only complete cases were considered; ie, only those implants with information available for all variables measured were included in the regression model analysis. Zygomatic implants and implants detected in radiographies but without basic information about them in the patients' files were excluded from the study. Implant- and patient-related data were collected. Multilevel mixed-effects parametric survival analysis was used to test the association between PPI exposure (predictor variable) and risk of implant failure (outcome variable), adjusting for several potential confounders. RESULTS: A total of 3,559 implants were placed in 999 patients, with 178 implants reported as failures. The implant failure rates were 12.0% (30/250) for PPI users and 4.5% (148/3,309) for nonusers. A total of 45 out of 178 (25.3%) failed implants were lost up to abutment connection (6 in PPI users, 39 in nonusers), with an early-to late failure ratio of 0.34:1. The intake of PPIs was shown to have a statistically significant negative effect for implant survival rate (HR 2.811; 95% CI: 1.139 to 6.937; P = .025). Bruxism, smoking, implant length, prophylactic antibiotic regimen, and implant location were also identified as factors with a statistically significant effect on the implant survival rate. CONCLUSION: This study suggests that the intake of PPIs may be associated with an increased risk of dental implant failure. PMID- 28632256 TI - Scanning Electron Microscopy Analysis of the Adaptation of Single-Unit Screw Retained Computer-Aided Design/Computer-Aided Manufacture Abutments After Mechanical Cycling. AB - PURPOSE: To measure the microgap between dental implants and custom abutments fabricated using different computer-aided design/computer-aided manufacture (CAD/CAM) methods before and after mechanical cycling. MATERIALS AND METHODS: CAD software (Dental System, 3Shape) was used to design a custom abutment for a single-unit, screw-retained crown compatible with a 4.1-mm external hexagon dental implant. The resulting stereolithography file was sent for manufacturing using four CAD/CAM methods (n = 40): milling and sintering of zirconium dioxide (ZO group), cobalt-chromium (Co-Cr) sintered via selective laser melting (SLM group), fully sintered machined Co-Cr alloy (MM group), and machined and sintered agglutinated Co-Cr alloy powder (AM group). Prefabricated titanium abutments (TI group) were used as controls. Each abutment was placed on a dental implant measuring 4.1* 11 mm (SA411, SIN) inserted into an aluminum block. Measurements were taken using scanning electron microscopy (SEM) (*4,000) on four regions of the implant-abutment interface (IAI) and at a relative distance of 90 degrees from each other. The specimens were mechanically aged (1 million cycles, 2 Hz, 100 N, 37 degrees C) and the IAI width was measured again using the same approach. Data were analyzed using two-way analysis of variance, followed by the Tukey test. RESULTS: After mechanical cycling, the best adaptation results were obtained from the TI (2.29 +/- 1.13 MUm), AM (3.58 +/- 1.80 MUm), and MM (1.89 +/ 0.98 MUm) groups. A significantly worse adaptation outcome was observed for the SLM (18.40 +/- 20.78 MUm) and ZO (10.42 +/- 0.80 MUm) groups. Mechanical cycling had a marked effect only on the AM specimens, which significantly increased the microgap at the IAI. CONCLUSION: Custom abutments fabricated using fully sintered machined Co-Cr alloy and machined and sintered agglutinated Co-Cr alloy powder demonstrated the best adaptation results at the IAI, similar to those obtained with commercial prefabricated titanium abutments after mechanical cycling. The adaptation of custom abutments made by means of SLM or milling and sintering of zirconium dioxide were worse both before and after mechanical cycling. PMID- 28632257 TI - Modeling of Crestal Bone After Submerged vs Transmucosal Implant Placement: A Systematic Review with Meta-Analysis. AB - PURPOSE: To determine differences in marginal bone changes when using submerged or transmucosal dental implants through a systematic review of the literature. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Library were electronically searched for trials comparing marginal bone loss between submerged and transmucosal dental implants with a minimum follow-up of 12 months published between January 1980 and January 2016. Manual searches of the bibliographies of the included studies were also carried out. Screening of titles and abstracts, data extraction from the included studies, and quality assessment following the PRISMA statement were conducted in duplicate. Outcome measures were radiographic marginal bone level changes, implant survival, prosthesis failure, prosthetic complications, and esthetics. RESULTS: The search strategy identified a total of 4,991 studies. Two of the authors independently screened 855 abstracts, resulting in a total of 12 studies; however, the total included in the systematic review was 11, as 2 studies were based on data from the same patients and were therefore counted as 1. A total of 998 implants (413 submerged and 585 transmucosal) were observed in 542 patients. Seven of the studies had a randomized study design and a follow-up of 12 months; therefore, they were included in the meta-analysis of bone loss and implant survival. The overall estimate of the bone loss difference was -0.01 mm (95% confidence interval [95% CI] -0.11 to 0.09 mm), and there was less bone loss in the transmucosal implants than in the submerged implants (P = .811, I2 = 63.7%). The estimated relative risk for implant loss at 12 months was 0.31 (0.09 to 1.09, P = .068, I2 = 0%) in favor of the submerged healing protocol. Augmentation procedures seemed to be successful irrespective of the implant placement modality, but owing to few clinical data no evidence could be found. Because of the lack of clinical data, esthetic outcomes could be reported only in a descriptive way. CONCLUSION: In the present meta-analysis, no evidence was found of differences between submerged and transmucosal implant placement protocols with regard to changes in marginal crestal bone levels or implant survival at 12 months follow-up. Therefore, it can be concluded that in many clinical situations it seems questionable whether a closed healing protocol offers an advantage over a transmucosal protocol. PMID- 28632259 TI - Sterically controlled diastereoselectivity in thio-Staudinger cycloadditions of alkyl/alkenyl/aryl-substituted thioketenes. AB - The [2 + 2] cycloadditions of thioketenes and imines are named as thio-Staudinger cycloadditions. The diastereoselectivity in thio-Staudinger cycloaddtions of alkyl/alkenyl/aryl-substituted thioketenes is rationalized. The steric effects of the thioketenes play an extremely important role in deciding the diastereoselectivity (cis/trans selectivity) through controlling exo- and endo attack and subsequent ring closure. The conclusion is further supported by our additional experimental and calculational results. The isomerization of the iminium moiety in zwitterionic intermediates generated from the thioketenes and linear imines also affects the diastereoselectivity. The electronic effect of imine substituents slightly impacts the diastereoselectivity, while epimerization of cis-beta-thiolactams to trans-diastereomers is a significant factor in the thio-Staudinger cycloadditions of mono-substituted thioketenes under basic conditions. PMID- 28632260 TI - Visualization of the protein corona: towards a biomolecular understanding of nanoparticle-cell-interactions. AB - The use of nanocarriers in biology and medicine is complicated by the current need to understand how nanoparticles interact in complex biological surroundings. When nanocarriers come into contact with serum, proteins immediately adsorb onto their surface, forming a protein corona which defines their biological identity. Although the composition of the protein corona has been widely determined by proteomics, its morphology still remains unclear. In this study we show for the first time the morphology of the protein corona using transmission electron microscopy. We are able to demonstrate that the protein corona is not, as commonly supposed, a dense, layered shell coating the nanoparticle, but an undefined, loose network of proteins. Additionally, we are now able to visualize and discriminate between the soft and hard corona using centrifugation-based separation techniques together with proteomic characterization. The protein composition of the ~15 nm hard corona strongly depends on the surface chemistry of the respective nanomaterial, thus further affecting cellular uptake and intracellular trafficking. Large diameter protein corona resulting from pre incubation with soft corona or Apo-A1 inhibits cellular uptake, confirming the stealth-effect mechanism. In summary, the knowledge on protein corona formation, composition and morphology is essential to design therapeutic effective nanoparticle systems. PMID- 28632261 TI - Syntheses and post-functionalization of tri-substituted polyalkoxohexavanadates containing tris(alkoxo) ligands. AB - A new synthetic approach to tri-substituted trisalkoxy-hexavanadate clusters containing different organic groups was developed in this work. Four mixed valence or fully reduced POV hybrids were synthesized and structurally characterized, including an amino-containing derivative of hexavanadate, Na2[VVO10{NH2C(CH2O)3}3] (1). Furthermore, a novel mixed-valence POV hybrid was prepared via the amidation of 1, indicating that 1 can be used as an excellent building block for the design and synthesis of mixed-valence POV functional materials. PMID- 28632262 TI - Copper(ii)-promoted oxidative C-H/C-H cross-coupling for rapid access to aza BODIPY-indole derivatives with broad optical absorption. AB - The direct C-H activation of electron-deficient aza-BODIPYs has been effectively achieved via a concise and inexpensive Cu(ii)-promoted oxidative C-H/C-H coupling approach. The resulting indole-aza-BODIPY 6b covers a broad spectrum of 429-900 nm with a FWHM of 294 nm in solution and covers a UV-vis-NIR region up to 1100 nm in film. PMID- 28632263 TI - Fabrication of a graphene/C60 nanohybrid via gamma-cyclodextrin host-guest chemistry for photodynamic and photothermal therapy. AB - The wonderful chemical structures and characteristics of low-dimensional carbon materials have exciting applications in life sciences. In the present study, we developed a facile strategy to conjugate C60 with graphene via host-guest chemistry for targeted phototherapy. A versatile carrier based on folic acid functionalized graphene (GO-FA) and comprising gamma-cyclodextrin (gamma-CD) at its surface was assembled via pi-pi interaction, creating hybrid structures with drug storage and tumor targeting properties. This gamma-CD-modified graphene (GO FA/Py-gamma-CD) is capable of hosting pristine C60 molecules for the fabrication of a GO-FA/Py-gamma-CD/C60 nanohybrid. The hybridization of GO-FA, gamma-CD, and C60 hinders the aggregation of C60, promotes cellular uptake, enhances light absorption, and finally demonstrates enhanced phototherapy effects of GO-FA/Py gamma-CD/C60. Under Xe lamp irradiation (2 W cm-2) for 4 min, GO-FA/Py-gamma CD/C60 simultaneously causes heating and intracellular ROS production, which further significantly reduces the cell viability to 16.2% at low content of loading (30 MUg mL-1). Moreover, it represents an excellent tumor killing efficiency, better than that of the other reported graphene/C60 nanohybrids; thus, this material is suitable for applications in phototherapy of cancer. PMID- 28632264 TI - A modular synthesis approach to multinuclear heterometallic oxo clusters in polyoxometalates. AB - We report a "modular synthesis approach" to multinuclear heterometallic oxo clusters in lacunary polyoxometalates (POMs). This approach allowed the synthesis of a POM containing a nonanuclear {CrMn4}Lu2Ag2 cluster with the widest variety of metals among the discrete metal oxo clusters prepared to date. PMID- 28632265 TI - 3D printed conformal microfluidics for isolation and profiling of biomarkers from whole organs. AB - The ability to interface microfluidic devices with native complex biological architectures, such as whole organs, has the potential to shift the paradigm for the study and analysis of biological tissue. Here, we show 3D printing can be used to fabricate bio-inspired conformal microfluidic devices that directly interface with the surface of whole organs. Structured-light scanning techniques enabled the 3D topographical matching of microfluidic device geometry to porcine kidney anatomy. Our studies show molecular species are spontaneously transferred from the organ cortex to the conformal microfluidic device in the presence of fluid flow through the organ-conforming microchannel. Large animal studies using porcine kidneys (n = 32 organs) revealed the profile of molecular species in the organ-conforming microfluidic stream was dependent on the organ preservation conditions. Enzyme-linked immunosorbent assay (ELISA) studies revealed conformal microfluidic devices isolate clinically relevant metabolic and pathophysiological biomarkers from whole organs, including heat shock protein 70 (HSP-70) and kidney injury molecule-1 (KIM-1), which were detected in the microfluidic device as high as 409 and 12 pg mL-1, respectively. Overall, these results show conformal microfluidic devices enable a novel minimally invasive 'microfluidic biopsy' technique for isolation and profiling of biomarkers from whole organs within a clinically relevant interval. This achievement could shift the paradigm for whole organ preservation and assessment, thereby helping to relieve the organ shortage crisis through increased availability and quality of donor organs. Ultimately, this work provides a major advance in microfluidics through the design and manufacturing of organ-conforming microfluidic devices and a novel technique for microfluidic-based analysis of whole organs. PMID- 28632258 TI - Materials and microfluidics: enabling the efficient isolation and analysis of circulating tumour cells. AB - We present a critical review of microfluidic technologies and material effects on the analyses of circulating tumour cells (CTCs) selected from the peripheral blood of cancer patients. CTCs are a minimally invasive source of clinical information that can be used to prognose patient outcome, monitor minimal residual disease, assess tumour resistance to therapeutic agents, and potentially screen individuals for the early diagnosis of cancer. The performance of CTC isolation technologies depends on microfluidic architectures, the underlying principles of isolation, and the choice of materials. We present a critical review of the fundamental principles used in these technologies and discuss their performance. We also give context to how CTC isolation technologies enable downstream analysis of selected CTCs in terms of detecting genetic mutations and gene expression that could be used to gain information that may affect patient outcome. PMID- 28632266 TI - Proteomic analysis reveals Xuesaitong injection attenuates myocardial ischemia/reperfusion injury by elevating pyruvate dehydrogenase-mediated aerobic metabolism. AB - Xuesaitong injection (XST), which mainly consists of Panax notoginseng saponins, has been widely used for treating cardio-cerebral vascular diseases. However, the underlying mechanisms of XST associated with its cardioprotective effects are still unclear. To identify the potential target proteins of XST, two-dimensional gel electrophoresis (2-DE)-based proteomics was utilized to analyze the protein profile of myocardium in rats with myocardial ischemia/reperfusion (I/R) injury. The differentially expressed proteins were identified by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. It is interesting that XST can alter the expression of 7 proteins, including pyruvate dehydrogenase E1 alpha (PDHA1), hydroxyacyl-coenzyme A dehydrogenase (HADHA), peroxiredoxin 3 (PRX3), gamma-enolase, acetyl-coenzyme A acyltransferase 2 (ACAA2), etc. Functional analysis revealed that those proteins were chiefly related to cardiac energy metabolism and oxidative stress. The cardioprotective effects of XST were further validated in H9c2 cardiac muscle cells with hypoxia/reoxygenation injury. We found that XST can promote the activity of PDH, an important enzyme related to the TCA cycle, as well as increase the intracellular content of acetyl-CoA and ATP. Moreover, XST also attenuated intracellular MDA release in H2O2-injured cardiac cells. This is the first study on the proteomic expression of XST-treated myocardium with I/R injury to reveal that the cardioprotective effects of XST may be attributed to the PDH-mediated restoration of aerobic glucose oxidation. PMID- 28632267 TI - Ultrahigh broadband photoresponse of SnO2 nanoparticle thin film/SiO2/p-Si heterojunction. AB - The SnO2/Si heterojunction possesses a large band offset and it is easy to control the transportation of carriers in the SnO2/Si heterojunction to realize high-response broadband detection. Therefore, we investigated the potential of the SnO2 nanoparticle thin film/SiO2/p-Si heterojunction for photodetectors. It is demonstrated that this heterojunction shows a stable, repeatable and broadband photoresponse from 365 nm to 980 nm. Meanwhile, the responsivity of the device approaches a high value in the range of 0.285-0.355 A W-1 with the outstanding detectivity of ~2.66 * 1012 cm H1/2 W-1 and excellent sensitivity of ~1.8 * 106 cm2 W-1, and its response and recovery times are extremely short (<0.1 s). This performance makes the device stand out among previously reported oxide or oxide/Si based photodetectors. In fact, the photosensitivity and detectivity of this heterojunction are an order of magnitude higher than that of 2D material based heterojunctions such as (Bi2Te3)/Si and MoS2/graphene (photosensitivity of 7.5 * 105 cm2 W-1 and detectivity of ~2.5 * 1011 cm H1/2 W-1). The excellent device performance is attributed to the large Fermi energy difference between the SnO2 nanoparticle thin film and Si, SnO2 nanostructure, oxygen vacancy defects and thin SiO2 layer. Consequently, practical highly-responsive broadband PDs may be actualized in the future. PMID- 28632268 TI - Ball-in-ball ZrO2 nanostructure for simultaneous CT imaging and highly efficient synergic microwave ablation and tri-stimuli-responsive chemotherapy of tumors. AB - Combined thermo-chemotherapy displays outstanding synergically therapeutic efficiency when compared with standalone thermotherapy and chemotherapy. Herein, we developed a smart tri-stimuli-responsive drug delivery system involving X@BB ZrO2 NPs (X represents loaded IL, DOX, keratin and tetradecanol) based on novel ball-in-ball-structured ZrO2 nanoparticles (BB-ZrO2 NPs). The microwave energy conversion efficiency of BB-ZrO2 NPs was 41.2% higher than that of traditional single-layer NPs due to the cooperative action of self-reflection and spatial confinement effect of the special two-layer hollow nanostructure. The tri-stimuli responsive controlled release strategy indicate that integrated pH, redox and microwaves in single NPs based on keratin and tetradecanol could effectively enhance the specific controlled release of DOX. The release of DOX was only 8.1% in PBS with pH = 7.2 and GSH = 20 MUM. However, the release could reach about 50% at the tumor site (pH = 5.5, GSH = 13 mM) under microwave ablation. The as-made X@BB-ZrO2 NPs exhibited perfect synergic therapy effect of chemotherapy and microwave ablation both in subcutaneous tumors (H22 tumor-bearing mice) and deep tumors (liver transplantation VX2 tumor-bearing rabbit model). There was no recurrence and death in the X@BB-ZrO2 + MW group during the therapy of subcutaneous tumors even on the 42nd day. The growth rates in the deep tumor of the control, MW and X@BB-ZrO2 + MW groups were 290.1%, 14.1% and -42% 6 days after ablation, respectively. Dual-source CT was used to monitor the metabolism behavior of the as-made BB-ZrO2 NPs and traditional CT was utilized to monitor the tumor growth in rabbits. Frozen section examination and ICP results indicated the precise control of drug delivery and enhanced cytotoxicity by the tri-stimuli responsive controlled release strategy. The ball-in-ball ZrO2 NPs with high microwave energy conversion efficiency were first developed for synergic microwave ablation and tri-stimuli-responsive chemotherapy, which may have potential applications in clinic. PMID- 28632269 TI - Late-stage divergent synthesis and antifouling activity of geraniol-butenolide hybrid molecules. AB - Hybrid molecules consisting of geraniol and butenolide were designed and synthesized by the late-stage divergent strategy. In the synthetic route, ring closing metathesis was utilized for the construction of a butenolide moiety. A biological evaluation of the eight synthetic hybrid compounds revealed that these molecules exhibit antifouling activity against the cypris larvae of the barnacle Balanus (Amphibalanus) amphitrite with EC50 values of 0.30-1.31 MUg mL-1. These results show that hybridization of the geraniol and butenolide structural motifs resulted in the enhancement of the antifouling activity. PMID- 28632270 TI - Silicon anodes protected by a nitrogen-doped porous carbon shell for high performance lithium-ion batteries. AB - Silicon (Si) anodes, which are among the most promising candidates for high energy lithium-ion batteries (LIBs), have attracted considerable attention from both academic and industrial communities. However, Si anodes usually suffer from an inherently low conductivity and extremely large volume change during the lithiation and delithiation processes, and consequently exhibit an inferior rate capability and poor cycle life. In this paper, we report new porous polymer derived carbon coated Si nanoparticles (NPs) as the next generation anodes for LIBs to overcome these serious problems. Specifically, a porous covalent triazine framework (CTF) polymer shell was synthesized by in situ trimerization of p benzenedinitrile in molten ZnCl2. Then, core-shell structured Si/nitrogen-doped porous carbon (Si@NPC) spheres were easily produced after high-temperature annealing. As an anode for LIBs, Si@NPC delivers a high capacity of 1390 mA h g-1 at 0.5 A g-1, stable cycle performance (107% capacity retention at 1 A g-1 for 200 cycles), and excellent rate capability of up to approximately 420 mA h g-1 at 16 A g-1. Such an exciting performance can be attributed to the ultra-stable, highly conductive, N-doped, and porous carbon shell. This work not only offers a new solution to the large volume change of Si-based anodes, but also enables the synthesis of porous polymer-based core-shell structures for energy storage and conversion. PMID- 28632271 TI - Copper-promoted direct C-H alkoxylation of S,S-functionalized internal olefins with alcohols. AB - Copper-promoted direct C-H alkoxylation of S,S-functionalized internal olefins, that is, alpha-oxo ketene dithioacetals, was efficiently achieved with alcohols as the alkoxylating agents, (diacetoxyiodo)benzene (PhI(OAc)2) as the oxidant, and benzoquinone (BQ) as the co-oxidant. The alkoxylated olefins were thus constructed and applied for the synthesis of alkoxylated N-heterocycles. The polarization of the olefinic carbon-carbon double bond by the electron-donating dialkylthio and electron-withdrawing alpha-oxo functionalities plays a crucial role in making such C-H alkoxylation reactions to occur under mild conditions. Mechanistic studies implicate a single-electron-transfer (SET) reaction pathway involved in the overall catalytic cycle. PMID- 28632272 TI - Interfacial synthesis of a three-dimensional hierarchical MoS2-NS@Ag-NP nanocomposite as a SERS nanosensor for ultrasensitive thiram detection. AB - Interfacial self-assembly of ordered nanostructures at oil-water interfaces towards the fabrication of nanofilms has attracted the interest of plenty of scientists, since its discovery in 2004. Herein, further developments have been achieved, and we report a new strategy for the synthesis of a three-dimensional (3D) hierarchical nanostructure, through an interfacial synthesis driven microemulsion process. Thus, the synthesis route has been simplified, with the rigorous experimental conditions of traditional compositing technology. Combined with a two-step seed-mediated growth method for preparing uniform Ag-NPs, a plasmonic 3D MoS2-NS@Ag-NP nanostructure was successfully developed as a Surface Enhanced Raman Scattering (SERS) active substrate, with plenty of surface hot spots, leading to an enhancement factor (EF) of 1.2 * 108 derived from both electromagnetic mechanism (EM) and chemical mechanism (CM) effects. The 3D MoS2 NS@Ag-NP nanostructure can be applied to detect trace thiram in apple juice and local lake water, with a detection limit as low as 10 ppb (42 nM), which is much lower than the maximal residue limit (MRL) of 7 ppm in fruit prescribed by the U.S. Environmental Protection Agency (EPA). Furthermore, quantitative analysis was achieved in the range of 10 ppb-1 ppm with good homogeneity and selectivity. PMID- 28632273 TI - A model for C-F activation by electrophilic phosphonium cations. AB - The synthesis of the electrophilic phosphonium cation (EPC) salt [C10H6(CF3)PF(C6F5)2][B(C6F5)4] 4 was achieved via oxidation of phosphine [C10H6(CF3)P(C6F5)2] 2 with XeF2 to form phosphorane [C10H6(CF3)PF2(C6F5)2] 3 and subsequent fluoride ion abstraction. Structural and spectroscopic characterization of 4 provides evidence of an interaction between the CF3 functionality and the phosphonium centre. AIM and NBO analyses also support donation from a lone pair on a fluorine atom of the CF3 group to the P-F sigma* orbital of the fluorophosphonium unit, consistent with previously proposed mechanisms for main group C-F bond activations. PMID- 28632274 TI - t-BuOK-mediated reductive addition of P(O)-H compounds to terminal alkynes forming beta-arylphosphine oxides. AB - A novel and efficient t-BuOK-mediated reductive addition of P(O)-H compounds to terminal alkynes was developed. A variety of beta-arylphosphine oxides including the valuable beta-heteroarylphosphine oxides were produced in moderate to high yields under mild reaction conditions. This reaction may proceed via a tandem process involving regio-selective double addition and subsequent transfer hydrogenation. PMID- 28632275 TI - Architectures of soft robotic locomotion enabled by simple mechanical principles. AB - In nature, a variety of limbless locomotion patterns flourish, from the small or basic life forms (Escherichia coli, amoebae, etc.) to the large or intelligent creatures (e.g., slugs, starfishes, earthworms, octopuses, jellyfishes, and snakes). Many bioinspired soft robots based on locomotion have been developed in the past few decades. In this work, based on the kinematics and dynamics of two representative locomotion modes (i.e., worm-like crawling and snake-like slithering), we propose a broad set of innovative designs for soft mobile robots through simple mechanical principles. Inspired by and going beyond the existing biological systems, these designs include 1-D (dimensional), 2-D, and 3-D robotic locomotion patterns enabled by the simple actuation of continuous beams. We report herein over 20 locomotion modes achieving various locomotion functions, including crawling, rising, running, creeping, squirming, slithering, swimming, jumping, turning, turning over, helix rolling, wheeling, etc. Some are able to reach high speed, high efficiency, and overcome obstacles. All these locomotion strategies and functions can be integrated into a simple beam model. The proposed simple and robust models are adaptive for severe and complex environments. These elegant designs for diverse robotic locomotion patterns are expected to underpin future deployments of soft robots and to inspire a series of advanced designs. PMID- 28632276 TI - Optimising the relaxivities of Mn2+ complexes by targeting human serum albumin (HSA). AB - We report two novel macrocyclic ligands based on the 1,4-DO2AM platform (1,4 DO2AM = 2,2'-(1,4,7,10-tetraazacyclododecane-1,4-diyl)diacetamide) and containing two benzyl groups attached either to the nitrogen atoms of the macrocyclic unit (1,4-BzDO2AM) or to the amide pendant arms (1,4-DO2AMBz). The protonation constants of the ligands and the stability constants of their Mn2+ complexes were determined using pH potentiometry. The introduction of benzyl groups results in a slight decrease of the stability constants of the Mn2+ complexes and a slight increase of their acid-catalysed dissociation reactions. A detailed relaxometric characterisation of the complexes using nuclear magnetic dispersion relaxation (NMRD) and 17O NMR studies indicated that the increase in molecular weight associated with the presence of benzyl groups results in a remarkable increase of proton relaxivities r1p, which take values of 3.8, 3.5 and 2.5 mM-1 s-1 for [Mn(1,4-BzDO2AM)]2+, [Mn(1,4-DO2AMBz)]2+ and [Mn(1,4-DO2AM)]2+ (at 25 degrees C and 20 MHz). The [Mn(1,4-BzDO2AM)]2+ and [Mn(1,4-DO2AMBz)]2+ complexes form relatively strong adducts with Human Serum Albumin (HSA) with association constants of (3.9 +/- 0.6) * 103 and (2.0 +/- 0.3) * 103 M-1, respectively. The interaction with the protein slows down the rotational tumbling of the complex in solution, which results in adducts endowed with remarkably high proton relaxivities (r1pb = 18.5 +/- 0.7 and 27.4 +/- 1.4 mM-1 s-1 for [Mn(1,4 BzDO2AM)]2+ and [Mn(1,4-DO2AMBz)]2+, respectively). PMID- 28632277 TI - Variable temperature and high-pressure crystal chemistry of perovskite formamidinium lead iodide: a single crystal X-ray diffraction and computational study. AB - We investigate the variable temperature (100-450 K) and high-pressure (p = ambient - 0.74 GPa) crystal chemistry of the black perovskite formamidinium lead iodide, [(NH2)2CH]PbI3, using single crystal X-ray diffraction. In both cases we find a phase transition to a tetragonal phase. Our experimental results are combined with first principles calculations, providing information about the electronic properties of [(NH2)2CH]PbI3 as well as the most probable orientation of the [(NH2)2CH]+ cations. PMID- 28632278 TI - Paper microfluidics for nucleic acid amplification testing (NAAT) of infectious diseases. AB - The diagnosis of infectious diseases is entering a new and interesting phase. Technologies based on paper microfluidics, coupled to developments in isothermal amplification of Nucleic Acids (NAs) raise opportunities for bringing the methods of molecular biology in the field, in a low setting environment. A lot of work has been performed in the domain over the last few years and the landscape of contributions is rich and diverse. Most often, the level of sample preparation differs, along with the sample nature, the amplification and detection methods, and the design of the device, among other features. In this review, we attempt to offer a structured description of the state of the art. The domain is not mature and there exist bottlenecks that hamper the realization of Nucleic Acid Amplification Tests (NAATs) complying with the constraints of the field in low and middle income countries. In this domain however, the pace of progress is impressively fast. This review is written for a broad Lab on a Chip audience. PMID- 28632279 TI - epsilon-Polylysine-based thermo-responsive adsorbents for immunoglobulin adsorption-desorption under mild conditions. AB - Thermo-responsive adsorbents for immunoglobulin G (IgG) employing epsilon polylysine (EPL) as a polymer backbone were developed. The introduction of mercaptoethylpyridine (MEP) as an IgG-binding ligand and hydrophobization of side chains afforded thermo-responsive IgG adsorbents, whose thermo-responsive IgG desorption ratio was up to 88% (EPL/MEP derivative 3m). The changes in surface densities of active MEP groups, which are caused by thermal conformational changes of the adsorbents, play key roles for IgG desorption. Although a trade off of IgG adsorption capacity and IgG desorption ratio was observed, the present study offers a novel molecular design for thermo-responsive adsorbents with high synthetic accessibility and potentially low toxicity. PMID- 28632280 TI - Implantable Cardioverter-Defibrillators for Primary Prevention in Patients With Ischemic or Nonischemic Cardiomyopathy: A Systematic Review and Meta-analysis. AB - Background: Implantable cardioverter-defibrillators (ICDs) have a role in preventing cardiac arrest in patients at risk for life-threatening ventricular arrhythmias. Purpose: To compare ICD therapy with conventional care for the primary prevention of death of various causes in adults with ischemic or nonischemic cardiomyopathy. Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, Google Scholar, and EMBASE databases, as well as several Web sites, from 1 April 1976 through 31 March 2017. Study Selection: Randomized controlled trials, published in any language, comparing ICD therapy with conventional care and reporting mortality outcomes (all-cause, sudden, any cardiac, or noncardiac) in the primary prevention setting. Data Extraction: 2 independent investigators extracted study data and assessed risk of bias. Data Synthesis: Included were 11 trials involving 8716 patients: 4 (1781 patients) addressed nonischemic cardiomyopathy, 6 (4414 patients) ischemic cardiomyopathy, and 1 (2521 patients) both types of cardiomyopathy. Mean follow-up was 3.2 years. An overall reduction in all-cause mortality, from 28.26% with conventional care to 21.37% with ICD therapy (hazard ratio [HR], 0.81 [95% CI, 0.70 to 0.94]; P = 0.043), was found. The magnitude of reduction was similar in the cohorts with nonischemic (HR, 0.81 [CI, 0.72 to 0.91]) and ischemic (HR, 0.82 [CI, 0.63 to 1.06]) disease, although the latter estimate did not reach statistical significance. The rate of sudden death fell from 12.15% with conventional care to 4.39% with ICD therapy (HR, 0.41 [CI, 0.30 to 0.56]), with a similar magnitude of reduction in patients with ischemic (HR, 0.39 [CI, 0.23 to 0.68]) and those with nonischemic disease (HR, 0.44 [CI, 0.17 to 1.12]). Noncardiac and any cardiac deaths did not differ significantly by treatment. Limitation: Heterogeneous timing of ICD placement; heterogeneous pharmacologic and resynchronization co interventions; trials conducted in different eras; adverse events and complications not reviewed. Conclusion: Overall, primary prevention with ICD therapy versus conventional care reduced the incidence of sudden and all-cause death. Primary Funding Source: None. PMID- 28632285 TI - Whole-Genome Sequencing in Primary Care. PMID- 28632284 TI - Benefits and Risks of Antithrombotic Therapy in Essential Thrombocythemia: A Systematic Review. AB - Background: Patients with essential thrombocythemia (ET) are at high risk for both thrombosis and hemorrhage. Purpose: To evaluate the risks and benefits of antithrombotic therapy in adults with ET. Data Sources: Multiple databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, through 4 March 2017. Study Selection: Randomized and observational studies of antiplatelet or anticoagulant therapy, published in any language and reporting thrombotic or hemorrhagic events. Data Extraction: Two reviewers independently extracted data, assessed risk of bias, and graded certainty of evidence. Data Synthesis: No relevant randomized trials were identified. Twenty four observational studies (18 comparative and 6 single-group) involving 6153 patients followed for 31 711 patient-years were reviewed; most were deemed to have high risk of bias. Most patients receiving antiplatelet therapy (3613 of 4527 [80%]) received low-dose aspirin (50 to 150 mg/d); 914 (20%) received high dose aspirin (300 to 600 mg/d), dipyridamole, or other agents. Overall, findings were inconsistent and imprecise. The reported incidence rates of thrombosis, any bleeding, and major bleeding without antiplatelet therapy ranged from 5 to 110 (median, 20), from 3 to 39 (median, 8), and from 2 to 53 (median, 6) cases per 1000 patient-years, respectively. The reported relative risks for thrombosis, any bleeding, and major bleeding with antiplatelet therapy compared with none ranged from 0.26 to 3.48 (median, 0.74), from 0.48 to 11.04 (median, 1.95), and from 0.48 to 5.17 (median, 1.30), respectively. Certainty of evidence was rated low or very low for all outcomes. Limitation: No randomized trials, no extractable data on anticoagulants, lack of uniform bleeding definitions, and systematic reporting of outcomes. Conclusion: Available evidence about the risk-benefit ratio of antiplatelet therapy in adults with ET is highly uncertain. Primary Funding Source: Regional Medical Associates. (PROSPERO: CRD42015027051). PMID- 28632288 TI - All-Arthroscopic Superior Shoulder Capsule Reconstruction With Partial Rotator Cuff Repair. AB - Massive irreparable rotator cuff tears are difficult to treat. Although several treatment options exist, none provides superior long-term results. There is no consensus on optimal surgical technique. Superior capsular reconstruction is an operative treatment option aimed at restoring native biomechanics of the glenohumeral joint by providing a restraint to superior subluxation. Partial rotator cuff repair for massive tears has also been shown to improve shoulder kinematics and can be performed in conjunction with superior capsule reconstruction. The authors describe a technique for arthroscopic superior capsular reconstruction with a dermal allograft with concomitant partial rotator cuff repair. [Orthopedics. 2017; 40(4):e735-e738.]. PMID- 28632289 TI - Novel Anterior Plating Technique for Patella Fracture Fixation. AB - Patella fracture fixation remains a significant challenge for orthopedic surgeons. Although tension band fixation allows for reliable osseous union, especially in simple fracture patterns, it still presents several problems. Plate fixation of patella fractures is a method that allows for more rigid stabilization and earlier mobilization. At the authors' level 1 trauma center, one fellowship-trained trauma surgeon has transitioned to using a novel anterior, low-profile mesh plate construct for all types of patella fractures. This construct allows for stable fixation, osseous union, and neutralization of the inferior pole for even the most comminuted of patella fractures. [Orthopedics. 2017; 40(4):e739-e743.]. PMID- 28632291 TI - ? PMID- 28632290 TI - A Single-Incision Technique for Distal Biceps Repair Using a Flexible Reamer. AB - Distal biceps tendon ruptures are rare injuries that usually occur in middle-aged men. Most of these injuries are repaired acutely to restore preinjury function and strength. There is concern regarding the higher prevalence of certain complications with the double-incision technique. As such, the single-incision technique has also been studied to determine if it may produce superior safety and efficacy. In addition, the point of fixation may be created with either a rigid or a flexible reamer. The authors describe a technique that uses a single incision cortical fixation achieved with a flexible reamer. [Orthopedics. 2017; 40(4):e744-e748.]. PMID- 28632292 TI - ? PMID- 28632293 TI - ? PMID- 28632295 TI - ? PMID- 28632294 TI - [Pneumonia is an uncertain diagnosis even during medical visits]. PMID- 28632296 TI - ? PMID- 28632297 TI - ? AB - Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research Core needle biopsies (CNBs) are widely used in clinical diagnostic labs to aid in the diagnosis of malignant lymphomas and in latter years their use is increasing. CNBs provide a rapid method for obtaining tumour material and may be beneficial when the affected lymph nodes are located deep in the abdominal cavity or mediastinum and surgical excisional biopsies may be difficult to perform. However, according to the Swedish Haematopathology Quality and Standardization Committee, CNBs are insufficient for lymphoma diagnostic purposes and the guidelines state that material from surgical excisional biopsies are mandatory in order to obtain a robust histopathological evaluation of the lymph node architecture, cellular composition and growth pattern. Surgical excision biopsies also ensure that adequate material is available if additional molecular analyses should be required and also to facilitate future research. PMID- 28632298 TI - ? AB - Rapid improvement of tick-borne encephalitis after treatment with corticosteroids Tick-borne encephalitis (TBE) is a viral disease transmitted by ticks. The virus is divided into three subtypes named Western, Siberian and Far Eastern TBE virus (TBEV). Western TBEV is endemic in parts of Europe and Sweden and typically causes a biphasic illness with influenza-like symptoms followed by neurological symptoms ranging from mild meningitis to severe meningoencephalitis and death. Despite an effective vaccine, TBE is increasing in Sweden and Europe. The pathogenesis of TBE is poorly understood; direct infection of neurons as well as immunological reactions mediated by T-cells have been implicated. In some endemic areas, such as Lithuania, patients with TBE are given corticosteroids based on the clinical experience that it results in rapid improvement. However, existing retrospective studies have failed to show beneficial effects of corticosteroids compared to symptomatic treatment in patients with TBE. This case report describes how an elderly man with meningoencephalitis and cranial nerve palsy due to TBE rapidly improved after administration of high dose corticosteroids. PMID- 28632299 TI - ? AB - Swimming-induced pulmonary edema (SIPE) has been described in sports and military medicine during strenuous swimming in open water. Symptoms include dyspnea, cough, frothy mucus and hemoptysis. Hypertension, a tight wetsuit, overhydration and previous episodes of SIPE are suggested risk factors. Immediate interruption of swimming prevents more serious symptoms. In the open water race at Vansbro 2016, 69 swimmers (of 13,878 in total) were treated for symptoms suspected for SIPE. Continuous positive airway pressure (CPAP) was successfully used to treat suspected SIPE in 46 patients in the on-site emergency care center. Open water swimming races are increasingly popular and also attract many unexperienced swimmers. There is a need of validated guidelines for organizers of open water races, swimmers and health professionals. PMID- 28632300 TI - Chemobacterial Synthesis of a Sialyl-Tn Cyclopeptide Vaccine Candidate. AB - A conjugatable form of the tumour-associated carbohydrate antigen sialyl-Tn (Neu5Ac-alpha-2,6-GalNAc) was efficiently produced in Escherichia coli. Metabolically engineered E. coli strains overexpressing the 6-sialyltransferase gene of Photobacterium sp. and CMP-Neu5Ac synthetase genes of Neisseria meningitidis were cultivated at high density in the presence of GalNAc-alpha propargyl as the exogenous acceptor. The target disaccharides, which were produced on the scale of several hundreds of milligrams, were then conjugated by using copper(I)-catalysed azide-alkyne cycloaddition click chemistry to a fully synthetic and immunogenic scaffold with the aim to create a candidate anticancer vaccine. Four sialyl-Tn epitopes were introduced on the upper face of an azido functionalised multivalent cyclopeptide scaffold, the lower face of which was previously modified by an immunogenic polypeptide, PADRE. The ability of the resulting glycoconjugate to interact with oncofoetal sialyl-Tn monoclonal antibodies was confirmed in ELISA assays. PMID- 28632301 TI - Regulation of kindling epileptogenesis by hippocampal Toll-like receptors 2. AB - This study examined whether Toll-like receptors 2 (TLR2) contribute to rapid kindling epileptogenesis. A TLR2 agonist, lipoteichoic acid (LTA), LTA antibody (LTA-A), or normal saline (control) was administered daily over 3 consecutive days, unilaterally into ventral hippocampus of adult male Wistar rats. Thirty minutes after the last injection, the animals were subjected to a rapid kindling procedure. The ictogenesis was gauged by comparing afterdischarge threshold (ADT) and afterdischarge duration (ADD) before the treatments, after the treatments prior to kindling, and 24 h after kindling. Kindling progression and retention were analyzed using video recording. The results showed that before kindling, LTA produced an ADT reduction. Neither LTA nor LTA-A affected baseline ADD. On kindling progression, LTA accelerated occurrence of generalized seizures, whereas LTA-A delayed this effect. Treatment with LTA-A reduced the number of secondary generalized complex partial seizures. Twenty-four hours after kindling, the rats of both the saline and LTA groups showed increased hippocampal excitability as compared with prekindling parameters. Administration of LTA-A prevented kindling induced increase of hippocampal excitability. Immunostaining revealed that LTA-A attenuated the inflammatory response produced by seizures. These findings suggest that the activation of TLR2 in the hippocampus may facilitate limbic epileptogenesis. PMID- 28632302 TI - Sequentially Responsive Shell-Stacked Nanoparticles for Deep Penetration into Solid Tumors. AB - Nanomedicine to overcome both systemic and tumor tissue barriers ideally should have a transformable size and surface, maintaining a certain size and negative surface charge for prolonged circulation, while reducing to a smaller size and switching to a positive surface charge for efficient penetration to and retention in the interstitial space throughout the tumor tissue. However, the design of such size and charge dual-transformable nanomedicine is rarely reported. Here, the design of a shell-stacked nanoparticle (SNP) is reported, which can undergo remarkable size reduction from about 145 to 40 nm, and surface charge reversal from -7.4 to 8.2 mV at acidic tumor tissue, for enhanced tumor penetration and uptake by cells in deep tumor tissue. The disulfide-cross-linked core maintains the stability of the particle and prevents undesired premature drug release until the shedding of the shell, which accelerates the cleavage of more exposed disulfide bond sand intracellular drug release. SNP penetrates about 1 mm into xenografted A549 lung carcinoma, which is about four times penetration depth of the nontransformable one. The doxorubicin (DOX)-loaded SNP (SNP/DOX) shows significant antitumor efficacy and nearly eradicates the tumor, substantiating the importance of the design of size and charge dual-transformable nanomedicine. PMID- 28632303 TI - Audition-specific temporal processing deficits associated with language function in children with autism spectrum disorder. AB - : Sensory processing alterations are highly prevalent in autism spectrum disorder (ASD). Neurobiologically-based theories of ASD propose that abnormalities in the processing of temporal aspects of sensory input could underlie core symptoms of ASD. For example, rapid auditory temporal processing is critical for speech perception, and language difficulties are central to the social communication deficits defining the disorder. This study assessed visual and auditory temporal processing abilities and tested their relation to core ASD symptoms. 53 children (26 ASD, 27 TD) completed visual and auditory psychophysical gap detection tasks to measure gap detection thresholds (i.e., the minimum interval between sequential stimuli needed for individuals to perceive an interruption between the stimuli) in each domain. Children were also administered standardized language assessments such that the relation between individual differences in auditory gap detection thresholds and degree of language and communication difficulties among children with ASD could be assessed. Children with ASD had substantially higher auditory gap detection thresholds compared to children with TD, and auditory gap detection thresholds were correlated significantly with several measures of language processing in this population. No group differences were observed in the visual temporal processing. Results indicate a domain-specific impairment in rapid auditory temporal processing in ASD that is associated with greater difficulties in language processing. Findings provide qualified support for temporal processing theories of ASD and highlight the need for future research testing the nature, extent, and universality of auditory temporal processing deficits in this population. Autism Res 2017, 10: 1845-1856. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Sensory symptoms are common in ASD. Temporal processing alterations are often implicated, but understudied. The ability to process rapid sensory information, particularly auditory input, is critical for language functioning. This study tested auditory and visual temporal processing in ASD and controls. Findings suggest that rapid auditory (but not visual) processing is impaired in ASD and related to language functioning. These results could provide mechanistic clues to understanding core symptoms and lead to novel intervention targets. PMID- 28632305 TI - Vanadium Hydroxide Cluster Ions in the Gas Phase: Bond-Forming Reactions of Doubly-Charged Negative Ions by SO2 -Promoted V-O Activation. AB - The gas-phase reactivity of doubly-charged vanadium hydroxides anions with SO2 has been studied by experimental and computational methods. The obtained results highlight the role of sulfur dioxide in promoting unprecedented bond-forming reactions, which produce singly-charged products by breaking the Vx Oy skeleton or a terminal V-O bond. PMID- 28632304 TI - Are visceral adiposity index and lipid accumulation product reliable indices for metabolic disturbances in patients with type 2 diabetes mellitus? AB - BACKGROUND: Visceral adiposity index (VAI) and Lipid accumulation product (LAP) are novel visceral adiposity indexes, proposed for the evaluation of cardiometabolic risk in adult population. Considering contradictory results obtained from many studies so far, we aimed to examine the potential benefit of applicability of VAI and LAP, over simple anthropometric indices and traditional lipid parameters in individuals with type 2 diabetes mellitus (DM2). METHODS: A total of 180 DM2 (of them 50% females) and 119 controls who volunteered to participate in this cross-sectional study were enrolled. Anthropometric and biochemical parameters, as well as blood pressure were obtained. VAI and LAP were calculated. RESULTS: Multivariate logistic regression analysis showed that high density lipoprotein cholesterol (HDL-c), (P<.001), waist circumference (WC), (P=.027), age (P=.001), hypolipemic therapy (P=.024), and LAP (P=.005) were independent predictors of DM2 in adjusted models. In Receiver Operating Characteristic curve analysis, used to discriminate subjects with DM2 from those who did not have it, good accuracy of the applied procedures was only achieved with models which were consisted of parameters used in VAI (Body mass index, WC, HDL-c, triglycerides) and LAP (WC, triglycerides) indexes equations, respectively [Area under the curve (AUC)=0.819 and AUC=0.800, respectively], but not with VAI (AUC=0.781) and LAP (AUC=0.784) indexes themselves. CONCLUSION: Visceral adiposity index and Lipid accumulation product may not be better than parameters that enter its equation in type 2 diabetes prediction. PMID- 28632306 TI - Analytical modeling provides new insight into complex mutual coupling between surface loops at ultrahigh fields. AB - Ultrahigh-field (UHF) (>=7 T) transmit (Tx) human head surface loop phased arrays improve both the Tx efficiency (B1+ /?P) and homogeneity in comparison with single-channel quadrature Tx volume coils. For multi-channel arrays, decoupling becomes one of the major problems during the design process. Further insight into the coupling between array elements and its dependence on various factors can facilitate array development. The evaluation of the entire impedance matrix Z for an array loaded with a realistic voxel model or phantom is a time-consuming procedure when performed using electromagnetic (EM) solvers. This motivates the development of an analytical model, which could provide a quick assessment of the Z-matrix. In this work, an analytical model based on dyadic Green's functions was developed and validated using an EM solver and bench measurements. The model evaluates the complex coupling, including both the electric (mutual resistance) and magnetic (mutual inductance) coupling. Validation demonstrated that the model does well to describe the coupling at lower fields (<=3 T). At UHFs, the model also performs well for a practical case of low magnetic coupling. Based on the modeling, the geometry of a 400-MHz, two-loop transceiver array was optimized, such that, by simply overlapping the loops, both the mutual inductance and the mutual resistance were compensated at the same time. As a result, excellent decoupling (below -40 dB) was obtained without any additional decoupling circuits. An overlapped array prototype was compared (signal-to-noise ratio, Tx efficiency) favorably to a gapped array, a geometry which has been utilized previously in designs of UHF Tx arrays. PMID- 28632307 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Multidisciplinary Management. PMID- 28632308 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Anal Cancer. PMID- 28632310 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Pathology Standards and Datasets. PMID- 28632309 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Surgical Management. PMID- 28632311 TI - Preface. PMID- 28632312 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Diagnosis, Investigations and Screening. PMID- 28632313 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Audit and Outcome Reporting. PMID- 28632314 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Introduction. PMID- 28632315 TI - Association of Coloproctology of Great Britain & Ireland (ACPGBI): Guidelines for the Management of Cancer of the Colon, Rectum and Anus (2017) - Follow Up, Lifestyle and Survivorship. PMID- 28632316 TI - Does umbilical cord milking result in higher measures of systemic blood flow in preterm infants? PMID- 28632317 TI - Quantum Mechanics/Molecular Mechanics Study on the Photoreactions of Dark- and Light-Adapted States of a Blue-Light YtvA LOV Photoreceptor. AB - The dark- and light-adapted states of YtvA LOV domains exhibit distinct excited state behavior. We have employed high-level QM(MS-CASPT2)/MM calculations to study the photochemical reactions of the dark- and light-adapted states. The photoreaction from the dark-adapted state starts with an S1 ->T1 intersystem crossing followed by a triplet-state hydrogen transfer from the thiol to the flavin moiety that produces a diradical intermediate, and a subsequent internal conversion that triggers a barrierless C-S bond formation in the S0 state. The energy profiles for these transformations are different for the four conformers of the dark-adapted state considered. The photochemistry of the light-adapted state does not involve the triplet state: photoexcitation to the S1 state triggers C-S bond cleavage followed by recombination in the S0 state; both these processes are essentially barrierless and thus ultrafast. The present work offers new mechanistic insights into the photoresponse of flavin-containing blue-light photoreceptors. PMID- 28632319 TI - Child shyness and peer likeability: The moderating role of pragmatics and vocabulary. AB - The association between shyness and children's likeability by peers was examined, with pragmatic difficulty and receptive and expressive vocabularies as moderators. Participants were 164 preschoolers (72 boys, 92 girls) between 52 and 79 months old in Singapore. A cross-informant methodology was used, with peers and teachers contributing to separate peer likeability ratings. The findings highlighted a conceptual distinction between peer- and teacher-rated likeability by peers. For the latter only, a 3-way interaction involving shyness, vocabulary, and pragmatic difficulty was found, indicating that for shy children with low vocabulary scores, those who experienced less pragmatic difficulty tended to be seen by teachers as more well-liked by peers than those with more pragmatic difficulty. This suggests that pragmatic skills may serve a protective function especially for shy children with poor vocabulary skills. Statement of contribution What is already known on this subject? Child shyness is related to poorer peer acceptance and social competence Expressive vocabulary and pragmatic competence each has a buffering effect for shy children What the present study adds? Shyness is related to poorer peer likeability as assessed by teachers Shyness is unrelated to peer likeability as assessed by same- or different-sex peers Pragmatic skills buffer the effects of teacher-rated shyness only for children with poor receptive and expressive vocabularies The buffering effect of language ability is shown in a multilingual educational context. PMID- 28632318 TI - "The Easier the Better" Preparation of Efficient Photocatalysts-Metastable Poly(heptazine imide) Salts. AB - Cost-efficient, visible-light-driven hydrogen production from water is an attractive potential source of clean, sustainable fuel. Here, it is shown that thermal solid state reactions of traditional carbon nitride precursors (cyanamide, melamine) with NaCl, KCl, or CsCl are a cheap and straightforward way to prepare poly(heptazine imide) alkali metal salts, whose thermodynamic stability decreases upon the increase of the metal atom size. The chemical structure of the prepared salts is confirmed by the results of X-ray photoelectron and infrared spectroscopies, powder X-ray diffraction and electron microscopy studies, and, in the case of sodium poly(heptazine imide), additionally by atomic pair distribution function analysis and 2D powder X-ray diffraction pattern simulations. In contrast, reactions with LiCl yield thermodynamically stable poly(triazine imides). Owing to the metastability and high structural order, the obtained heptazine imide salts are found to be highly active photocatalysts in Rhodamine B and 4-chlorophenol degradation, and Pt assisted sacrificial water reduction reactions under visible light irradiation. The measured hydrogen evolution rates are up to four times higher than those provided by a benchmark photocatalyst, mesoporous graphitic carbon nitride. Moreover, the products are able to photocatalytically reduce water with considerable reaction rates, even when glycerol is used as a sacrificial hole scavenger. PMID- 28632320 TI - Synthesis, Optoelectronic and Self-Assembly Properties of Diazadioxaacene Derivatives. AB - Two novel diazadioxaacene derivatives (ADOP and ADOQ) have been successfully synthesized and characterized. Their single crystal analyses disclose that molecule ADOP forms a twisted topology configuration, whereas ADOQ adopts reclining-chair architecture. Both of them emit strong blue fluorescence in organic solvents. Moreover, they can self-assemble to form regular nanobelts and nanowires, respectively, via a simple surfactant-assisted method. PMID- 28632321 TI - Is Aggregatibacter actinomycetemcomitans the missing link between periodontitis and rheumatoid arthritis? PMID- 28632322 TI - Reduced-intensity conditioning allogeneic transplantation after salvage treatment with DT-PACE in myeloma patients relapsing early after autologous transplant. AB - OBJECTIVE: In this retrospective single-centre study, we have looked into the transplant outcomes(overall survival OS, progression-free survival PFS, GvHD) and the role of chimerism, DLI and pretransplant characteristics in patients who had a suboptimal response (<12 months) to an autologous stem cell transplant for myeloma and underwent an alemtuzumab T-cell depleted reduced-intensity allograft(RIC). METHODS: Twenty-four patients were salvaged with two cycles of DT PACE and received a RIC transplant with fludarabine, melphalan and alemtuzumab. All the patients received PBSC grafts, eight patients had a sibling donor, and 16 had a graft from a fully matched unrelated donor. The median follow-up was 65.3 months (6-132 months). RESULTS: The median overall survival was 55.4 months. DLI administration was associated with a trend towards better overall survival (P=.05). Disease status at allo-HCT, PR or VGPR, ISS score and CMV serostatus was not significant predictors of OS and PFS. Full donor whole blood chimerism (>=98%) at 3 months post-transplant was associated with PFS (P=.04) but did not have a significant impact on OS(P=.45). CONCLUSION: Reduced-intensity alemtuzumab conditioned allograft for myeloma after DT-PACE salvage chemotherapy is an efficient and low toxicity treatment for those who had a suboptimal response postautologous stem cell transplant for myeloma. PMID- 28632323 TI - Clinical outcomes of HLA-DPB1 mismatches in 10/10 HLA-matched unrelated donor recipient pairs undergoing allogeneic stem cell transplant. AB - OBJECTIVE: HLA-DPB1 matching may impact allogeneic hematopoietic stem cell transplantation (ASCT) outcomes; however, this locus is not in linkage disequilibrium with the remainder of the HLA genes. After classifying HLA-DPB1 mismatches based on T-cell epitope, avoiding non-permissive mismatches may impact survival. We tested this hypothesis at a single academic institution. METHODS: Retrospective HLA-DPB1 genotyping was performed on 153 adult patients who underwent ASCT and unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 loci (10/10). Using the ImMunoGeneTics/HLA T-cell epitope matching algorithm, mismatch status was classified as permissive or non-permissive. RESULTS: Of 153 donor recipient pairs, 22 (14.4%) were HLA-DPB1 matches, 64 (42.8%) permissive mismatches, and 67 (43.8%) non-permissive mismatches. DPB1 mismatch increased risk of chronic graft-versus-host disease (cGVHD; RR 2.89 [1.19-9.53], P=.016) compared with DPB1-matched transplants, but there were no differences in overall mortality, risk of relapse, or acute GVHD (aGVHD). Combining matches and permissive mismatches and comparing to non-permissive mismatches, there was no significant difference in overall survival or relapse; however, patients receiving non-permissive mismatched transplants experienced greater risk of aGVHD overall and severe aGVHD (RR 1.66 [1.13-2.44], P=.010 and RR 1.97 [1.10-3.59], P=.024, respectively). CONCLUSION: In this single-center study, HLA-DPB1 matching influenced outcomes of patients undergoing ASCT for hematologic malignancy. PMID- 28632324 TI - Why the donor risk index and Eurotransplant donor risk index can also be applied in France; reply to Winter et al. and statistical perspective. PMID- 28632326 TI - Abstracts of the 13th Congress of the European Association of Dermato-Oncology (EADO), Athens, Greece, 3-6 May 2017. PMID- 28632325 TI - Nickelocene-Precursor-Facilitated Fast Growth of Graphene/h-BN Vertical Heterostructures and Its Applications in OLEDs. AB - The direct growth of high-quality, large-area, uniform, vertically stacked Gr/h BN heterostructures is of vital importance for applications in electronics and optoelectronics. However, the main challenge lies in the catalytically inert nature of the hexagonal boron nitride (h-BN) substrates, which usually afford a rather low decomposition rate of carbon precursors, and thus relatively low growth rate of graphene. Herein, a nickelocene-precursor-facilitated route is developed for the fast growth of Gr/h-BN vertical heterostructures on Cu foils, which shows much improved synthesis efficiency (8-10 times faster) and crystalline quality of graphene (large single-crystalline domain up to ~20 um). The key advantage of our synthetic route is the utilization of nickel atoms that are decomposed from nickelocene molecules as the gaseous catalyst, which can decrease the energy barrier for graphene growth and facilitate the decomposition of carbon sources, according to our density functional theory calculations. The high-quality Gr/h-BN stacks are proved to be perfect anode/protecting layers for high-performance organic light-emitting diode devices. In this regard, this work offers a brand-new route for the fast growth of Gr/h-BN heterostructures with practical scalability and high crystalline quality, thus should propel its wide applications in transparent electrodes, high-performance electronic devices, and energy harvesting/transition directions. PMID- 28632327 TI - Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease. AB - OBJECTIVE: This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes. METHODS: Retrospective clinical chart review of a series of patients diagnosed with CLN2 disease from 2005 to 2015 at a single center in Italy. Clinical, MRI, and EEG findings were reviewed. RESULTS: A total of 14 patients were included. For the whole group, median (range) age at disease onset was 3.0 (2.0-3.8) years. Epilepsy was the most commonly reported presenting symptom (in 50% [seven of 14] of patients), occurring at the age of 3.2 (2.6-3.8) years. First seizure was myoclonic in 36% (five of 14) of patients, followed by generalized tonic-clonic in 29% (4 of 14), atonic in 22% (three of 14), and focal with motor signs in 14% (two of 14). All patients walked independently at the age of 12.0 (11.0-18.0) months, but delayed speech or regression of acquired verbal skills was present in 100% of patients at 3 years. EEGs revealed a photoparoxysmal response (PPR) on intermittent photic stimulation in 93% (13 of 14) of patients. PPR was present from the first EEG, which was performed at 3.6 (3.1-4.0) years, in 43% (six of 14) of patients; it was documented at low (1-3 Hz) stimulation frequencies in 69% (nine of 13) and took the form of a flash-per-flash response in 69% (nine of 13). First brain MRI at the age of 3.8 (3.0-5.1) years revealed cerebellar atrophy in 100% (14 of 14) of patients and alteration of the periventricular white matter signal in the posterior hemispheric region in 79% (11 of 14). SIGNIFICANCE: Early photosensitivity (typically PPR at low stimulation frequencies of 1-3 Hz) is a hallmark of CLN2 disease. This diagnosis should be considered in a child presenting with any type of seizure, and particularly if it is accompanied by delayed speech and/or ataxia or MRI abnormalities (posterior white matter signal alteration or cerebellar atrophy). PMID- 28632328 TI - Traveling with food allergy: What to expect from the airlines? PMID- 28632329 TI - Postictal hypoperfusion/hypoxia provides the foundation for a unified theory of seizure-induced brain abnormalities and behavioral dysfunction. AB - A recent article by Farrell et al. characterizes the phenomenon, mechanisms, and treatment of a local and severe hypoperfusion/hypoxia event that occurs in brain regions following a focal seizure. Given the well-established role of cerebral ischemia/hypoxia in brain damage and behavioral dysfunction in other clinical settings (e.g., stroke, cerebral vasospasm), we put forward a new theory: postictal hypoperfusion/hypoxia is responsible for the negative consequences associated with seizures. Fortunately, inhibition of two separate molecular targets, cyclooxygenase-2 (COX-2) and l-type calcium channels, can prevent the expression of postictal hypoperfusion/hypoxia. These inhibitors are important experimental tools used to separate the seizure from the resulting hypoperfusion/hypoxia and can allow researchers to address the contribution of this phenomenon to negative outcomes associated with seizures. Herein we address the implications of this postictal stroke-like event in acute behavioral dysfunction (e.g., Todd's paresis) and sudden unexpected death in epilepsy (SUDEP). Moreover, anatomic alterations such as increased blood-brain barrier permeability, glial activation, central inflammation, and neuronal loss could also be a consequence of repeated hypoperfusion/hypoxic events and, in turn, underlie chronic interictal cognitive and behavioral comorbidities (e.g., memory deficits, anxiety, depression, and psychosis) and exacerbate epileptogenesis. Thus these seemingly disparate and clinically important observations may share a common point of origin: postictal hypoperfusion/hypoxia. PMID- 28632330 TI - From Peptides to Peptidomimetics: A Strategy Based on the Structural Features of Cyclopropane. AB - Peptidomimetics, non-natural mimicries of bioactive peptides, comprise an important class of drug molecules. The essence of the peptidomimetic design is to mimic the key conformation assumed by the bioactive peptides upon binding to their targets. Regulation of the conformation of peptidomimetics is important not only to enhance target binding affinity and selectivity, but also to confer cell membrane permeability for targeting protein-protein interactions in cells. The rational design of peptidomimetics with suitable three-dimensional structures is challenging, however, due to the inherent flexibility of peptides and their dynamic conformational changes upon binding to the target biomolecules. In this Minireview, a three-dimensional structural diversity-oriented strategy based on the characteristic structural features of cyclopropane to address this challenging issue in peptidomimetic chemistry is described. PMID- 28632331 TI - The validity of register data to identify children with atopic dermatitis, asthma or allergic rhinoconjunctivitis. AB - BACKGROUND: The incidence of atopic dermatitis, wheezing, asthma and allergic rhinoconjunctivitis has been increasing. Register-based studies are essential for research in subpopulations with specific diseases and facilitate epidemiological studies to identify causes and evaluate interventions. Algorithms have been developed to identify children with atopic dermatitis, asthma or allergic rhinoconjunctivitis using register information on disease-specific dispensed prescribed medication and hospital contacts, but the validity of the algorithms has not been evaluated. This study validated the algorithms vs gold standard deep telephone interviews with the caretaker about physician-diagnosed atopic dermatitis, wheezing, asthma or allergic rhinoconjunctivitis in the child. METHODS: The algorithms defined each of the three atopic diseases using register based information on disease-specific hospital contacts and/or filled prescriptions of disease-specific medication. Confirmative answers to questions about physician-diagnosed atopic disease were used as the gold standard for the comparison with the algorithms, resulting in sensitivities and specificities and 95% confidence intervals. The interviews with the caretaker of the included 454 Danish children born 1997-2003 were carried out May-September 2015; the mean age of the children at the time of the interview being 15.2 years (standard deviation 1.3 years). RESULTS: For the algorithm capturing children with atopic dermatitis, the sensitivity was 74.1% (95% confidence interval: 66.9%-80.2%) and the specificity 73.0% (67.3%-78.0%). For the algorithm capturing children with asthma, both the sensitivity of 84.1% (78.0%-88.8%) and the specificity of 81.6% (76.5%-85.8%) were high compared with physician-diagnosed asthmatic bronchitis (recurrent wheezing). The sensitivity remained high when capturing physician diagnosed asthma: 83.3% (74.3%-89.6%); however, the specificity declined to 66.0% (60.9%-70.8%). For allergic rhinoconjunctivitis, the sensitivity was 84.4% (78.0 89.2) and the specificity 81.6% (75.0-84.4). CONCLUSION: The algorithms are valid and valuable tools to identify children with atopic dermatitis, wheezing, asthma or allergic rhinoconjunctivitis on a population level using register data. PMID- 28632332 TI - Microscale disruption of microorganisms for parallelized process development. AB - Escherichia coli, Saccharomyces cerevisiae, and Pichia pastoris are the standard platforms for biopharmaceutical production with 40% of all between 2010 to 2014 approved protein drugs produced in those microbial hosts. Typically, products overexpressed E. coli and S. cerevisiae remain in the cytosol or are secreted into the periplasm. Consequently, efficient cell disruption is essential for high product recovery during microbial production. Process development platforms at microscale are essential to shorten time to market. While high-pressure homogenization is the industry standard for cell disruption at large scale this method is not practicable for experiments in microscale. This review describes microscale methods for cell disruption at scales as low as 200 uL. Strategies for automation, parallelization and miniaturization, as well as comparability of the results at this scale to high pressure homogenization are considered as those criteria decide which methods are most suited for scale down. Those aspects are discussed in detail for protein overexpression in E. coli and yeast but also the relevance for alternative products and host such as microalgae are taken into account. The authors conclude that bead milling is the best comparable microscale method to large scale high-pressure homogenization and therefore the most suitable technique for automated process development of microbial hosts with the exception of pDNA production. PMID- 28632333 TI - From Chemical Topology to Molecular Machines (Nobel Lecture). AB - To a large extent, the field of "molecular machines" started after several groups were able to prepare, reasonably easily, interlocking ring compounds (named catenanes for compounds consisting of interlocking rings and rotaxanes for rings threaded by molecular filaments or axes). Important families of molecular machines not belonging to the interlocking world were also designed, prepared, and studied but, for most of them, their elaboration was more recent than that of catenanes or rotaxanes. Since the creation of interlocking ring molecules is so important in relation to the molecular machinery area, we will start with this aspect of our work. The second part will naturally be devoted to the dynamic properties of such systems and to the compounds for which motions can be directed in a controlled manner from the outside, that is, molecular machines. We will restrict our discussion to a very limited number of examples which we consider as particularly representative of the field. PMID- 28632335 TI - To Brexit or not to Brexit: The roles of Islamophobia, conspiracist beliefs, and integrated threat in voting intentions for the United Kingdom European Union membership referendum. AB - We used an identities approach to examine voting intentions in the June 2016 UK referendum on membership of the European Union (EU). In April 2016, 303 British adults (58.7% women, age M = 34.73) indicated their voting intentions for the referendum and completed measures of identification with the national in-group, perceived threat from Muslim immigrants, belief in Islamophobic conspiracy narratives, Islamophobia, general conspiracist beliefs, ambiguity tolerance, and belief in a clash of civilizations. Path and mediation analyses indicated that greater belief in Islamophobic conspiracy theories mediated the link between Islamophobia and intention to vote to leave. Islamophobia and Islamophobic conspiracist beliefs also mediated the effects of perceived threat from Muslims on voting intentions. Other variables acted as antecedents of perceived threat or Islamophobic conspiracy narratives. These findings highlight the role that identity-based cognitions may have played in shaping voting intentions for the UK EU referendum. PMID- 28632334 TI - Functional analysis of female-biased odorant binding protein 6 for volatile and nonvolatile host compounds in Adelphocoris lineolatus (Goeze). AB - The polyphagous mirid bug Adelphocoris lineolatus relies heavily on olfactory cues to track suitable host plants. Thus, a better understanding of the molecular basis of its olfactory detection could contribute to the development of effective pest management strategies. In the present study, we report the expression profile of the odorant binding protein gene A. lineolatus odorant binding protein 6 (AlinOBP6). Quantitative real-time PCR experiments suggest that AlinOBP6 is female adult antennae-biased. Cellular immunolocalization analyses show that AlinOBP6 is highly expressed in the lymph of both multiporous sensilla basiconica and uniporous sensilla chaetica. A ligand binding analysis showed that recombinant AlinOBP6 not only bound tightly to host plant volatile compounds but also to nonvolatile compounds. Homology modelling and molecular docking analyses confirmed these unusual ligand binding profiles and revealed that the amino acid residues involved in the recognition of volatile and nonvolatile compounds are distinct. The results of our study are the first to suggest that an antenna- and female-biased OBP in an hemipteran insect is expressed in both olfactory and gustatory sensilla as a mechanism to respond to volatile and nonvolatile host compounds. These findings warrant further research into the molecular mechanisms of chemosensation for mirid bugs in responsive to host plant location. PMID- 28632336 TI - Serious life events and the risk of latent autoimmune diabetes in adults (LADA) and Type 2 diabetes. AB - AIM: It has been suggested that experiencing serious life events may promote Type 1 diabetes in children. Studies in adults are lacking, as are studies on the interaction of life events with genetic factors. We aimed to investigate life events and the risk of latent autoimmune diabetes in adults (LADA) and Type 2 diabetes while taking into account HLA genotype. METHODS: Analysis was based on 425 incident cases of LADA, 1417 incident cases of Type 2 diabetes and 1702 population-based controls recruited in Sweden between 2010 and 2016. Self reported information on life events including conflicts, divorce, illness/accidents, death and financial problems experienced during the 5 years preceding diagnosis/index year was used. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated by logistic regression and adjusted for age, sex, BMI, family history of diabetes, smoking, physical activity and education. RESULTS: Overall there was no association between experience of any life event and either LADA (OR 0.86, 95% CI 0.68-1.08) or Type 2 diabetes (OR 1.00, 95% CI 0.83-1.21). The results were similar for individual events as well as in separate analysis of men and women. Similar results were seen in more autoimmune LADA (glutamic acid decarboxylase antibodies > median) [OR (any life event) 0.88, 95% CI 0.64-1.21] and in LADA carriers of the high-risk HLADR4-DQ8 genotype (OR 0.89, 95% CI 0.61-1.29). CONCLUSIONS: Our findings indicate that experience of a serious life event, including the death of a family member, divorce or financial problems, is not associated with an increased risk of LADA, overall or in genetically susceptible individuals. PMID- 28632337 TI - Non-Equilibrium Assembly of Light-Activated Colloidal Mixtures. AB - The collective phenomena exhibited by artificial active matter systems present novel routes to fabricating out-of-equilibrium microscale assemblies. Here, the crystallization of passive silica colloids into well-controlled 2D assemblies is shown, which is directed by a small number of self-propelled active colloids. The active colloids are titania-silica Janus particles that are propelled when illuminated by UV light. The strength of the attractive interaction and thus the extent of the assembled clusters can be regulated by the light intensity. A remarkably small number of the active colloids is sufficient to induce the assembly of the dynamic crystals. The approach produces rationally designed colloidal clusters and crystals with controllable sizes, shapes, and symmetries. This multicomponent active matter system offers the possibility of obtaining structures and assemblies that cannot be found in equilibrium systems. PMID- 28632338 TI - Difluoromethylation Reactions of Organic Compounds. AB - The relevance of the -CF2 H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, the CF2 H moiety can establish hydrogen-bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF2 H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals. Consequently, the late-stage introduction of CF2 H is a sought-after strategy in designing bioactive compounds. Secondly, but nonetheless relevant and meaningful, is the study of synthetic pathways to introduce a CF2 -Y moiety (Y?H, F) into organic substrates because compounds that contain a CF2 -Y functionality have also found vast applications in medicinal chemistry and in other areas, such as that of fungicides, insecticides, etc., and thus, this functionality deserves special attention. Although emphasis is made on difluoromethylation strategies to functionalize different families of organic compounds, three main methodological protocols will be presented in this review article for the late-stage introduction of a CF2 H or CF2 Y moieties into organic substrates: i) a metal photoredox catalysis; ii) through transition metal-catalyzed thermal protocols; and iii) from transition-metal-free strategies. PMID- 28632339 TI - Polymorphisms of human leukocyte antigen B*27 on clinical phenotype of spondyloarthritis in Chinese. AB - BACKGROUND: In recent years, an ever-increasing number of alleles of human leukocyte antigen B*27 (HLA-B*27) have been identified. This study aimed to establish an updated method for HLA-B*27 subtyping, and to investigate the impact of HLA-B*27 polymorphisms on the clinical phenotype of spondyloarthritis (SpA). METHODS: Overall, 184 SpA patients were recruited for analyzing diversity of HLA B*27 via an updated high-resolution polymerase chain reaction amplification with sequence specific primers (PCR-SSP). RESULTS: The prevalence of HLA-B*27 was 94.0%, and four subtypes were identified including HLA-B*2704 (77.5%), B*2705 (20.2%), B*2707 (1.7%), and B*2724 (0.6%). There was an obvious male predominance (P=.05) and markedly elevated C-reaction protein (CRP) in B*27 positive SpA (P<.01). In multivariate linear regression analysis, the elevated CRP was positively associated with HLA-B*27 positivity (regression coefficient B=46.1, P=.0003), grade of sacroiliitis (B=47.5, P=.0032), and male gender (B=20.4, P=.0041). Notably, a male predilection was also found in B*2705 positive SpA while B*2707 was associated with older age, higher positive family history, and higher prevalence of extra-articular features (all P<.05). CONCLUSIONS: In this study, an updated PCR-SSP technique to identify increasing alleles of HLA-B*27 was developed and their different effects on clinical manifestations of SpA were demonstrated. Genotyping of HLA-B*27 would shed light on our understanding of the pathogenesis of SpA. PMID- 28632341 TI - Corrigendum. PMID- 28632340 TI - Prescribing in the oldest old inpatients: a retrospective analysis of patients referred for specialist geriatric consultation. AB - BACKGROUND: While medications may prolong life and prevent morbidity in older people, adverse effects of polypharmacy are increasingly recognised. As patients age and become frail, prescribing may be expected to focus more on symptom control and minimise potentially harmful preventive medication use that confer little benefit within a short lifespan. Whether prescribing practice shifts to one of symptom controls among the oldest old admitted to hospital remains unclear. AIM: To determine, in the oldest old inpatients, whether preventive versus symptom control medication prescribing was associated with age or level of frailty. METHODS: Retrospective analysis of all patients aged >=85 years referred for comprehensive geriatric assessment at a tertiary care hospital between May 2006 and December 2014 for whom all prescribed medications were documented. Medication use was assessed according to age group (85-89, 90-94, >=95) and categories of frailty index calculated for patients based on 52 deficits (fitter, moderately frail, frail and severely frail). RESULTS: Seven hundred and eighty three inpatients were assessed of mean (SD) age 89.0 (3.4) and mean frailty index 0.45 (SD 0.14) with a median of eight co-morbidities (IQR 6-10) and who were prescribed a mean of 8.3 (SD 3.8) regular medications per day. Polypharmacy (5-9 medications per day) was observed in 406 patients (51.9%) and hyper-polypharmacy (>=10 medications per day) in 268 patients (34.2%). While there was a significant decrease in number of prescribed medications as age increased, there were no differences across age groups or frailty categories in proportions of medications used for prevention versus symptom control. CONCLUSION: Polypharmacy is prevalent in oldest old inpatients and prescribing patterns according to prevention versus symptom control appear unaffected by age and frailty status. PMID- 28632342 TI - Variation in gene regulation underlying annual and perennial flowering in Arabideae species. AB - The diversity of life history strategies within the angiosperms illustrates the evolutionary flexibility of reproductive characteristics. The number of times an individual reproduces is a key life history trait, and transitions from iteroparous perennials to semelparous annuals have occurred frequently in the flowering plants. Despite the frequency of this evolutionary transition, and the importance of annuality versus perenniality to both agriculture and ecology, understanding the molecular and genetic mechanisms involved in perennial flowering is in their infancy. In this issue of Molecular Ecology, Kiefer et al. () make significant progress towards understanding divergence in seasonal flowering between annual and perennial species in the Arabideae tribe of Brassicaceae. By combining a comparative approach with gene expression and sequence comparisons, they show that transcriptional differences in FLC orthologs, a floral inhibitor in Arabidopsis thaliana, have occurred repeatedly and underlie differences in flowering between annuals and perennials. PMID- 28632343 TI - Dispersal, isolation and diversification with continued gene flow in an Andean tropical dry forest. AB - The Andes are the world's longest mountain chain, and the tropical Andes are the world's richest biodiversity hot spot. The origin of the tropical Andean cordillera is relatively recent because the elevation of the mountains was relatively low (400-2500 m palaeoelevations) only 10 MYA with final uplift being rapid. These final phases of the Andean orogeny are thought to have had a fundamental role in shaping processes of biotic diversification and biogeography, with these effects reaching far from the mountains themselves by changing the course of rivers and deposition of mineral-rich Andean sediments across the massive Amazon basin. In a recent issue of Molecular Ecology, Oswald, Overcast, Mauck, Andersen, and Smith (2017) investigate the biogeography and diversification of bird species in the Andes of Peru and Ecuador. Their study is novel in its focus on tropical dry forests (Figure 1) rather than more mesic biomes such as rain forests, cloud forests and paramos, which tend to be the focus of science and conservation in the Andean hot spot. It is also able to draw powerful conclusions via the first deployment of genomic approaches to a biogeographic question in the threatened dry forests of the New World. PMID- 28632344 TI - A life-cycle approach to species barriers. AB - What maintains reproductive barriers between closely related species is, of course, of fundamental interest to a closer understanding of the mechanisms that generate new biodiversity. One important dichotomy is to separate barriers evolved from divergent selection over environmental gradients (extrinsic barriers) from barriers caused by incompatibilities between different genetic arrangements that may have evolved in isolation (intrinsic barriers). This dichotomy also reflects an important applied consequence. As the extrinsic barriers are associated with specific environmental contexts, they may be partly or completely erased if the environment changes. In contrast, intrinsic barriers are inert to the environmental context and resistant to environmental changes. From a conservation biology perspective, it may thus be important to be able to separate extrinsic and intrinsic species barriers, but this may in many organisms be a complex matter. In this issue of Molecular Ecology, Montecinos et al. () found a tractable approach that works for species with life cycles that include two reproductive but ecologically similar generations, one haploid and the other diploid. What they demonstrate is that using a life-cycle approach offers a unique possibility to separate between prezygotic and postzygotic barriers. Indeed, in the case of an isomorphic life cycle, there is even a possibility to suggest whether postzygotic barriers are more likely to be intrinsic or extrinsic. In this way, their approach may be useful both to increase our understanding of the basic mechanisms of speciation and to single out when species barriers will better resist environmental changes. PMID- 28632345 TI - Multiple traumatic experiences, post-traumatic stress disorder and offending behaviour in female prisoners. AB - BACKGROUND: Although it is well established that prisoners commonly have histories of childhood trauma, little is known about mediators between exposure to trauma and criminal behaviour. HYPOTHESES: We hypothesised that the experience of trauma in adulthood, post-traumatic stress disorder (PTSD) and emotional dysregulation would mediate the relationship between childhood traumatic events and later criminal behaviour. METHODS: Eighty-nine female prisoners were interviewed using standardised scales, in a cross-sectional study design. History of traumatic events, DSM-5 PTSD and emotional regulation were assessed, along with offending and demographic information. A series of regression and mediation analyses were undertaken on the data. RESULTS: Almost all (91%) of the 89 women reported both childhood and adulthood trauma. Over half (58%) met the criteria for DSM-5 PTSD. Multiple traumas were significantly associated with seriousness of offence, as indicated by sentence length. Adult experience of trauma was the only significant mediator between childhood trauma and subsequent offending. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Women who have experienced multiple traumatic events may be more likely to commit serious offences, so it is very important to assess and meet their trauma-related needs. While prisons should never be used as substitutes for healthcare facilities, when women or girls are sent to prison, the opportunity for constructive interventions must be seized. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28632346 TI - Transvaginal, rather than traditional, laparoscopy should be used for the assessment of infertility: FOR: Transvaginal laparoscopy:a first-line diagnostic procedure in infertility investigation. PMID- 28632347 TI - Re: Antidepressant use in late gestation and risk of postpartum haemorrhage: a retrospective cohort study: Antidepressants in pregnancy and postpartum haemorrhage. PMID- 28632348 TI - Re: Never Events-the ongoing problem of the retained vaginal sponge/swab: Retained vaginal sponge/swab: improve the NPSA seven-point action plan to be less overzealous yet crucially more inclusive. PMID- 28632349 TI - Re: Insights gained from a negative trial of steroid blocks for perineal pain. PMID- 28632352 TI - Corrigendum. PMID- 28632351 TI - Transvaginal, rather than traditional, laparoscopy should be used for the assessment of infertility: AGAINST: Practising specialists prefer traditional laparoscopy. PMID- 28632354 TI - Author's reply re: Never Events-the ongoing problem of the retained vaginal sponge/swab. PMID- 28632353 TI - Authors' reply re: Antidepressant use in late gestation and risk of postpartum haemorrhage: a retrospective cohort study. PMID- 28632355 TI - Changes in the abortion legislation in Ireland: The Protection of Life During Pregnancy Act 2013. PMID- 28632356 TI - Obstetric consent and the cost of severe obstetric adverse events. PMID- 28632357 TI - Self-control depletion impairs goal maintenance: A meta-analysis. AB - Initial exertion of self-control has been suggested to impair subsequent self regulatory performance. The specific cognitive processes that underlie this ego depletion effect have rarely been examined. Drawing on the dual-process theory of executive control (Engle & Kane, ; Kane & Engle, ), the current meta-analysis revealed that initial self-control exertion impairs participants' capacities of maintaining the task goal but its effect on capacities of resolving response competition is in need of further investigation. Our results are more consistent with recent theoretical views that consider ego depletion as a switch cost and a result arising from reduced motivation to engage in further self-control. PMID- 28632358 TI - Increased beta power in the bereaved families of the Sewol ferry disaster: A paradoxical compensatory phenomenon? A two-channel electroencephalography study. AB - AIM: The Sewol ferry capsizing accident on South Korea's southern coast resulted in the death of 304 people, and serious bereavement problems for their families. Electroencephalography (EEG) beta frequency is associated with psychiatric symptoms, such as insomnia. The aim of this study was to investigate the relation between frontal beta power, psychological symptoms, and insomnia in the bereaved families. METHODS: Eighty-four family members of the Sewol ferry victims (32 men and 52 women) were recruited and their EEG was compared with that of 25 (13 men and 12 women) healthy controls. A two-channel EEG device was used to measure cortical activity in the frontal lobe. Symptom severity of insomnia, post traumatic stress disorder, complicated grief, and anxiety were evaluated. RESULTS: The bereaved families showed a higher frontal beta power than healthy controls. Subgroup analysis showed that frontal beta power was lower in the individuals with severe insomnia than in those with normal sleep. There was a significant inverse correlation between frontal beta power and insomnia symptom in the bereaved families. CONCLUSION: This study suggests that increased beta power, reflecting the psychopathology in the bereaved families of the Sewol ferry disaster, may be a compensatory mechanism that follows complex trauma. Frontal beta power could be a potential marker indicating the severity of sleep disturbances. Our results suggest that sleep disturbance is an important symptom in family members of the Sewol ferry disaster's victims, which may be screened by EEG beta power. PMID- 28632360 TI - [Is autism a different kind of intelligence? New insights from cognitive neurosciences]. AB - After being considered a mental disorder for years, then a neurodevelopmental handicap, autism is increasingly being considered a human variant that sometimes involves extreme adaptive advantages and disadvantages. This point of view partly emerges from the fact that autistics perform certain human tasks at the same level, and in some cases even better than neurotypical persons. Furthermore, they perform these tasks using cognitive strategies and cerebral allocations that are different from the majority of humans. We will present some empirical and theoretical cognitive neuroscience studies from our group that support this school of thought. PMID- 28632379 TI - Intracellular Delivery Platform for "Recalcitrant" Cells: When Polymeric Carrier Marries Photoporation. AB - The intracellular delivery of exogenous macromolecules is of great interest for both fundamental biological research and clinical applications. Although traditional delivery systems based on either carrier mediation or membrane disruption have some advantages; however, they are generally limited with respect to delivery efficiency and cytotoxicity. Herein, a collaborative intracellular delivery platform with excellent comprehensive performance is developed using polyethylenimine of low molecular weight (LPEI) as a gene carrier in conjunction with a gold nanoparticle layer (GNPL) acting as a photoporation agent. In this system, the LPEI protects the plasmid DNA (pDNA) to avoid possible nuclease degradation, and the GNPL improves the delivery efficiency of the LPEI/pDNA complex to the cells. The collaboration of LPEI and GNPL is shown to give significantly higher transfection efficiencies for hard-to-transfect cells (88.5 +/- 9.2% for mouse embryonic fibroblasts, 94.0 +/- 6.3% for human umbilical vein endothelial cells) compared to existing techniques without compromising cell viability. PMID- 28632380 TI - Recent Progress in Nanomaterial-Based Optical Aptamer Assay for the Detection of Food Chemical Contaminants. AB - Food chemical contaminants are a major factor in the cause of foodborne diseases and can do harm to human health. Hence, it is highly desirable to develop robust, easy, and sensitive methods for rapid evaluation of food chemical contaminants. Nanomaterial-based optical aptasensors combined with the advantages of the high selectivity of optical detection techniques, excellent stability of aptamer, and the unique properties of nanomaterials have been recognized as useful tools for routine biosensing applications. The recent progress in nanomaterial-based optical aptamer assays to determine food chemical contaminants including heavy metals, toxins, pesticides, and antibiotics are presented in this paper. Furthermore, the major challenges and future prospects in this field are discussed to provide ideas for further research. PMID- 28632381 TI - Molecular Modeling of the Interactions between Carborane-Containing Analogs of Indomethacin and Cyclooxygenase-2. AB - Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase-2 (COX-2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource-intensive quantum chemical calculations, and the interpretation of the theoretical results would not have been straightforward without the supporting experimental data. The inclusion of full receptor and ligand flexibility into the molecular modeling of carborane containing drug molecules may yield more definitive results, but is currently hindered by the lack of appropriate carborane force field parameters. PMID- 28632382 TI - Manipulation of Chain Conformation for Optimum Charge-Transport Pathways in Conjugated Polymers. AB - A pair of different diketopyrrolopyrrole-based conjugated polymers (CPs) were designed and synthesized to investigate the effect of chain conformation on their molecular assembly. Conformation management was achieved by the incorporation of different linkers during polymerization. Through the use of computational calculations and UV-vis absorption measurements, the resulting CPs (PDPP-T and PDPP-BT) were found to exhibit partly modulated chain geometry. Grazing incident X-ray diffraction experiments with a two-dimensional detector revealed that PDPP T having a planar chain conformation exhibited an edge-on type molecular arrangement, which evolved to a face-on type chain assembly when the planar geometry was altered to a slightly twisted one as in PDPP-BT. In addition, it was verified that the directional electric carrier mobility of CPs was critically distinguished by the distinctive chain arrangement in spite of their similar chemical structure. Concentration-dependent absorption measurements could provide an improved understanding of the assembly mechanism of CP chains: the planar conformation of PDPP-T facilitates the formation of preassembled chains in a concentrated solution and further directs the edge-on stacking, while the twisted dihedral angle along the benzothiophene in PDPP-BT prevents chain assembly, resulting in the face-on stacking. Because CP chain conformation is inevitably connected with the generation of preassembled chains, manipulating CP geometry could be an efficient tool for extracting an optimum chain assembly that is connected with the principal charge-transport pathway in CPs. PMID- 28632384 TI - Finite Field Method for Nonlinear Optical Property Prediction Using Rational Function Approximants. AB - The finite field (FF) method is a quick, easy-to-implement tool for the prediction of nonlinear optical properties. Here, we present and explore a novel variant of the FF method, which uses a rational function to fit a molecule's energy with respect to an electric field. Similarly to previous FF methods, factors crucial for the method's accuracy were tuned. These factors include the number of terms in the function, the distribution of fields used to construct the approximation, and the initial field in the approximation. It was found that the approximant form that best fits the energy has four numerator terms and three denominator terms. To determine a reasonable field distribution, the common ratio of a geometric progression was optimized to ?2. Finally, an algorithm for determining a good initial field guess was devised. The optimized FF method was used to compute the polarizability and second hyperpolarizability for a set of 121 molecules and the first hyperpolarizability for a set of 91 molecules. The results from this were compared to a previous polynomial-based FF method. It was found that using a rational function gives higher errors compared to the polynomial model. However, unlike the polynomial model, no subsequent refinement steps were needed to obtain usable results. An overall comparison of the behavior of the two methods also shows that the rational function is less sensitive to the chosen initial field, making it a good choice for new quantum chemistry codes. PMID- 28632383 TI - Taking Advantage of Disorder: Small-Molecule Organic Glasses for Radiation Detection and Particle Discrimination. AB - A series of fluorescent silyl-fluorene molecules were synthesized and studied with respect to their photophysical properties and response toward ionizing neutron and gamma-ray radiation. Optically transparent and stable organic glasses were prepared from these materials using a bulk melt-casting procedure. The prepared organic glass monoliths provided fluorescence quantum yields and radiation detection properties exceeding the highest-performing benchmark materials such as solution-grown trans-stilbene crystals. Co-melts based on blends of two different glass-forming compounds were prepared with the goal of enhancing the stability of the amorphous state. Accelerated aging experiments on co-melt mixtures ranging from 0% to 100% of each component indicated improved resistance to recrystallization in the glass blends, able to remain fully amorphous for >1 month at 60 degrees C. Secondary dopants comprising singlet fluorophores or iridium organometallic compounds provided further improved detection efficiency, as evaluated by light yield and neutron/gamma particle discrimination measurements. Optimized singlet and triplet doping levels were determined to be 0.05 wt % 1,4-bis(2-methylstyryl)benzene singlet fluorophore and 0.28 wt % Ir3+, respectively. PMID- 28632385 TI - Fatigue Resistant Bioinspired Composite from Synergistic Two-Dimensional Nanocomponents. AB - Portable and wearable electronics require much more flexible graphene-based electrode with high fatigue life, which could repeatedly bend, fold, or stretch without sacrificing its mechanical properties and electrical conductivity. Herein, a kind of ultrahigh fatigue resistant graphene-based nanocomposite via tungsten disulfide (WS2) nanosheets is synthesized by introducing a synergistic effect with covalently cross-linking inspired by the orderly layered structure and abundant interfacial interactions of nacre. The fatigue life of resultant graphene-based nanocomposites is more than one million times at the stress level of 270 MPa, and the electrical conductivity can be kept as high as 197.1 S/cm after 1.0 * 105 tensile testing cycles. These outstanding properties are attributed to the synergistic effect from lubrication of WS2 nanosheets for deflecting crack propagation, and covalent bonding between adjacent GO nanosheets for bridging crack, which is verified by the molecular dynamics (MD) simulations. The WS2 induced synergistic effect with covalent bonding offers a guidance for constructing graphene-based nanocomposites with high fatigue life, which have great potential for applications in flexible and wearable electronic devices, etc. PMID- 28632387 TI - Poly(trehalose) Nanoparticles Prevent Amyloid Aggregation and Suppress Polyglutamine Aggregation in a Huntington's Disease Model Mouse. AB - Prevention and therapeutic strategies for various neurodegenerative diseases focus on inhibiting protein fibrillation, clearing aggregated protein plaques from the brain, and lowering protein-aggregate-induced toxicity. We have designed poly(trehalose) nanoparticles that can inhibit amyloid/polyglutamine aggregation under extra-/intracellular conditions, reduce such aggregation-derived cytotoxicity, and prevent polyglutamine aggregation in a Huntington's disease (HD) model mouse brain. The nanoparticles have a hydrodynamic size of 20-30 nm and are composed of a 6 nm iron oxide core and a zwitterionic polymer shell containing ~5-12 wt % covalently linked trehalose. The designed poly(trehalose) nanoparticles are 1000-10000 times more efficient than molecular trehalose in inhibiting protein fibrillation in extra-cellular space, in blocking aggregation of polyglutamine-containing mutant huntingtin protein in model neuronal cells, and in suppressing mutant huntingtin aggregates in HD mouse brain. We show that the nanoparticle form of trehalose with zwitterionic surface charge and a trehalose multivalency (i.e., number of trehalose molecules per nanoparticle) of ~80-200 are crucial for efficient brain targeting, entry into neuronal cells, and suppression of mutant huntingtin aggregation. The present work shows that nanoscale trehalose can offer highly efficient antiamyloidogenic performance at micromolar concentration, compared with millimollar to molar concentrations for molecular trehalose. This approach can be extended to in vivo application to combat protein-aggregation-derived neurodegenerative diseases. PMID- 28632386 TI - Synthesis of Hierarchically Structured Hybrid Materials by Controlled Self Assembly of Metal-Organic Framework with Mesoporous Silica for CO2 Adsorption. AB - The HKUST-1@SBA-15 composites with hierarchical pore structure were constructed by in situ self-assembly of metal-organic framework (MOF) with mesoporous silica. The structure directing role of SBA-15 had an obvious impact on the growth of MOF crystals, which in turn affected the morphologies and structural properties of the composites. The pristine HKUST-1 and the composites with different content of SBA-15 were characterized by XRD, N2 adsorption-desorption, SEM, TEM, FT-IR, TG, XPS, and CO2-TPD techniques. It was found that the composites were assembled by oriented growth of MOF nanocrystals on the surfaces of SBA-15 matrix. The interactions between surface silanol groups and metal centers induced structural changes and resulted in the increases in surface areas as well as micropore volumes of hybrid materials. Besides, the additional constraints from SBA-15 also restrained the expansion of HKUST-1, contributing to their smaller crystal sizes in the composites. The adsorption isotherms of CO2 on the materials were measured and applied to calculate the isosteric heats of adsorption. The HS-1 composite exhibited an increase of 15.9% in CO2 uptake capacity compared with that of HKUST 1. Moreover, its higher isosteric heats of CO2 adsorption indicated the stronger interactions between the surfaces and CO2 molecules. The adsorption rate of the composite was also improved due to the introduction of mesopores. Ten cycles of CO2 adsorption-desorption experiments implied that the HS-1 had excellent reversibility of CO2 adsorption. This study was intended to provide the possibility of assembling new composites with tailored properties based on MOF and mesoporous silica to satisfy the requirements of various applications. PMID- 28632388 TI - Accelerating Dynamics of H on Graphene by Coadsorbates. AB - There are several factors that affect the dynamics of adsorbed hydrogen atoms on a carbon surface. Using density functional calculations we show that coadsorption can be a highly influential factor. The diffusion of hydrogen adsorbed on graphene is explored in the presence of H-containing molecules. Without coadsorbates the diffusion barrier of H on graphene is 0.94 eV, while with water/ammonia it is 0.85/0.12 eV. The low barrier in the case of ammonia is attributed to the formation of a stable intermediate state NH4, while such a stable state is not found in the case of water. In addition, hydrogen fluoride, hydrogen sulfide, arsine, and phosphine were also considered. We found that stronger hydrogen-hydride bonds lead to lower diffusion barriers of H on graphene. PMID- 28632389 TI - Chiral Selenide-Catalyzed Enantioselective Construction of Saturated Trifluoromethylthiolated Azaheterocycles. AB - An indane-based, bifunctional, chiral selenide catalyst has been developed. The new catalyst is efficient for the enantioselective synthesis of saturated azaheterocycles possessing a trifluoromethylthio group. The desired products were obtained in good yields with high diastereo- and enantioselectivities. PMID- 28632390 TI - Atomistic Simulation Derived Insight on the Irreversible Structural Changes of Si Electrode during Fast and Slow Delithiation. AB - Quantifying the irreversible chemical and structural changes of Si during cycling remains challenging. In this study, a continuous reactive molecular dynamics delithiation algorithm, with well-controlled potential gradient and delithiation rate, was developed and used to investigate the "natural" delithiation responses of an aluminum-oxide coated silicon thin-film. Fast delithiation led to the formation of dense Si network near the surface and nanoporosity inside the a LixSi, resulting in 141% volume dilation and significant amount of Li trapped inside (a-Li1.2Si) at the end of delithiation process. In contrast, slow delithiation allowed the a-LixSi to shrink by near-equilibrium condition, demonstrating no permanent inner pore with nearly Li-free structure (a-Li0.2Si) and minimal volume dilation (44%). However, even without trapped Li, the delithiated a-LixSi still exhibited higher volume (lower density) than the equilibrium structure with the same Li concentration, despite delithiation rate. The origin of this excess volume is the loss of directly bonded Si-Si pairs, which made the subsequent relithiation faster. On the basis of the atomistic modeling and the quantified degradation mechanism, battery operating guidelines, including the delithiation rate and the depth of charge to avoid trapped Li and coating delamination, were suggested to improve the durability Si electrodes. PMID- 28632391 TI - Transfer Hydrogenation of Carbonyl Derivatives Catalyzed by an Inexpensive Phosphine-Free Manganese Precatalyst. AB - A very simple and inexpensive catalytic system based on abundant manganese as transition metal and on an inexpensive phosphine-free bidendate ligand, 2 (aminomethyl)pyridine, has been developed for the reduction of a large variety of carbonyl derivatives with 2-propanol as hydrogen donor. Remarkably, the reaction proceeds at room temperature with low catalyst loading (down to 0.1 mol %) and exhibits a good tolerance toward functional groups. High TON (2000) and TOF (3600 h-1) were obtained. PMID- 28632392 TI - Lewis Acid Promoted Hydrogenation of CO2 and HCOO- by Amine Boranes: Mechanistic Insight from a Computational Approach. AB - We employ quantum chemical calculations to study the hydrogenation of carbon dioxide by amine boranes, NMe3BH3 (Me3AB) and NH3BH3 (AB) weakly bonded to a bulkier Lewis acid, Al(C6F5)3 (LA). Additionally, computations have also been conducted to elucidate the mechanism of hydrogenation of carbon dioxide by Me3AB while captured between one Lewis base (P(o-tol3), LB) and two Lewis acids, Al(C6F5)3. In agreement with the experiments, our computational study predicts that hydride transfer to conjugated HCO2-, generated in the reaction of Me3AB-LA with CO2, is not feasible. This is in contrast to the potential hydrogenation of bound HCO2H, developed in the reduction of CO2 with AB-LA, to further reduced species like H2C(OH)2. However, the FLP-trapped CO2 effortlessly undergoes three hydride (H-) transfers from Me3AB to produce a CH3O- derivative. DFT calculations reveal that the preference for a H- abstraction by an intrinsically anionic formate moiety is specifically dependent on the electrophilicity of the 2 e- reduced carbon center, which in particular is controlled by the electron withdrawing capability of the associated substituents on the oxygen. These theoretical predictions are justified by frontier molecular orbitals and molecular electrostatic potential plots. The global electrophicility index, which is a balance of electron affinity and hardness, reveals that the electrophilicity of the formate species undergoing hydrogenation is twice the electrophilicity of the ones where hydrogenation is not feasible. The computed activation energies at M06-2X/6-31++G(d,p) closely predict the observed reactivity. In addition, the possibility of a dissociative channel of the frustrated Lewis pair trapped CO2 system has been ruled out on the basis of predominantly high endergonicity. Knowledge of the underlying principle of these reactions would be helpful in recruiting appropriate Lewis acids/amine boranes for effective reduction of CO2 and its hydrogenated forms in a catalytic fashion. PMID- 28632394 TI - Changes in Eating Behaviors of Children with Obesity in Response to Carbohydrate Modified and Portion-Controlled Diets. AB - OBJECTIVE: This study's objective was to determine whether two distinct carbohydrate (CHO)-modified diets and a standard portion-controlled (PC) diet differentially impacted children's eating behaviors and whether eating behavior scores predicted lower BMI among children with obesity. METHODS: Children (n = 102) aged 7-12 years with obesity were randomly assigned to a 12-month intervention of a low-carbohydrate (LC), reduced glycemic load (RGL), or standard PC diet. The Three-Factor Eating Questionnaire (TFEQ) was completed at baseline, 3, 6, and 12 months by parents to characterize their child's hunger (H), disinhibition (D), and cognitive restraint (CR). Baseline and follow-up TFEQ scores by diet were evaluated relative to BMI status over time. RESULTS: All diet groups showed increased CR and decreased H and D from baseline to 3 months, with differences from baseline remaining at 12 months for CR and H. Lower BMI status during study follow-up was associated with different TFEQ scores by diet group (LC and RGL: higher CR; PC: lower H), adjusting for sex, age, and race. Higher CR at follow-up was predicted by race and higher baseline CR; only lower H at baseline predicted lower H at follow-up. CONCLUSION: Eating behaviors improved significantly with all diets during the initial 3 months; higher CR and lower H were sustained at treatment's end. BMI outcomes were associated with different eating behaviors in CHO-modified diet groups compared with PC diets. Targeting diets of children with obesity with specific baseline characteristics may lead to improved outcomes. PMID- 28632393 TI - The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites. AB - Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an alpha-truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at 2.2 and 1.9 A resolution, respectively. We found that only (S)-SBFI-26 was present in the crystal structures. The inhibitor largely mimics the fatty acid binding pattern, but it also has several unique interactions. Notably, the FABP7 complex corroborates key aspects of the ligand binding pose at the canonical site previously predicted by virtual screening. In FABP5, SBFI-26 was unexpectedly found to bind at the substrate entry portal region in addition to binding at the canonical ligand-binding pocket. Our structural and binding energy analyses indicate that both R and S forms appear to bind the transporter equally well. We suggest that the S enantiomer observed in the crystal structures may be a result of the crystallization process selectively incorporating the (S)-SBFI-26-FABP complexes into the growing lattice, or that the S enantiomer may bind to the portal site more rapidly than to the canonical site, leading to an increased local concentration of the S enantiomer for binding to the canonical site. Our work reveals two binding poses of SBFI-26 in its target transporters. This knowledge will guide the development of more potent FABP inhibitors based upon the SBFI-26 scaffold. PMID- 28632395 TI - Design, synthesis and multitarget biological profiling of second-generation anti Alzheimer rhein-huprine hybrids. AB - AIM: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. MATERIALS & METHODS: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Abeta42 and tau aggregation, of antioxidant activity, and of brain permeation. RESULTS: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2 e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Abeta42 and tau antiaggregating and antioxidant activities. CONCLUSION: Second-generation naphthyridine- and thienopyridine-based rhein huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD. PMID- 28632396 TI - Probabilistic Analysis of the (1+1)-Evolutionary Algorithm. AB - We give a detailed analysis of the optimization time of the [Formula: see text] Evolutionary Algorithm under two simple fitness functions (OneMax and LeadingOnes). The problem has been approached in the evolutionary algorithm literature in various ways and with different degrees of rigor. Our asymptotic approximations for the mean and the variance represent the strongest of their kind. The approach we develop is based on an asymptotic resolution of the underlying recurrences and can also be extended to characterize the corresponding limiting distributions. While most of our approximations can be derived by simple heuristic calculations based on the idea of matched asymptotics, the rigorous justifications are challenging and require a delicate error analysis. PMID- 28632397 TI - Decomposition Algorithms for a Multi-Hard Problem. AB - Real-world optimization problems have been studied in the past, but the work resulted in approaches tailored to individual problems that could not be easily generalized. The reason for this limitation was the lack of appropriate models for the systematic study of salient aspects of real-world problems. The aim of this article is to study one of such aspects: multi-hardness. We propose a variety of decomposition-based algorithms for an abstract multi-hard problem and compare them against the most promising heuristics. PMID- 28632398 TI - The Mitochondrial Protein Atlas: A Database of Experimentally Verified Information on the Human Mitochondrial Proteome. AB - Given its central role in various biological systems, as well as its involvement in numerous pathologies, the mitochondrion is one of the best-studied organelles. However, although the mitochondrial genome has been extensively investigated, protein-level information remains partial, and in many cases, hypothetical. The Mitochondrial Protein Atlas (MPA; URL: lifeserv.bgu.ac.il/wb/jeichler/MPA ) is a database that provides a complete, manually curated inventory of only experimentally validated human mitochondrial proteins. The MPA presently contains 911 unique protein entries, each of which is associated with at least one experimentally validated and referenced mitochondrial localization. The MPA also contains experimentally validated and referenced information defining function, structure, involvement in pathologies, interactions with other MPA proteins, as well as the method(s) of analysis used in each instance. Connections to relevant external data sources are offered for each entry, including links to NCBI Gene, PubMed, and Protein Data Bank. The MPA offers a prototype for other information sources that allow for a distinction between what has been confirmed and what remains to be verified experimentally. PMID- 28632399 TI - Prokaryotic Contig Annotation Pipeline Server: Web Application for a Prokaryotic Genome Annotation Pipeline Based on the Shiny App Package. AB - Genome annotation is a primary step in genomic research. To establish a light and portable prokaryotic genome annotation pipeline for use in individual laboratories, we developed a Shiny app package designated as "P-CAPS" (Prokaryotic Contig Annotation Pipeline Server). The package is composed of R and Python scripts that integrate publicly available annotation programs into a server application. P-CAPS is not only a browser-based interactive application but also a distributable Shiny app package that can be installed on any personal computer. The final annotation is provided in various standard formats and is summarized in an R markdown document. Annotation can be visualized and examined with a public genome browser. A benchmark test showed that the annotation quality and completeness of P-CAPS were reliable and compatible with those of currently available public pipelines. PMID- 28632400 TI - Evidence of Noncompetent HIV after Ex Vivo Purging Among ART-Suppressed Individuals. PMID- 28632401 TI - MOTIFSIM 2.1: An Enhanced Software Platform for Detecting Similarity in Multiple DNA Motif Data Sets. AB - Finding binding site motifs plays an important role in bioinformatics as it reveals the transcription factors that control the gene expression. The development for motif finders has flourished in the past years with many tools have been introduced to the research community. Although these tools possess exceptional features for detecting motifs, they report different results for an identical data set. Hence, using multiple tools is recommended because motifs reported by several tools are likely biologically significant. However, the results from multiple tools need to be compared for obtaining common significant motifs. MOTIFSIM web tool and command-line tool were developed for this purpose. In this work, we present several technical improvements as well as additional features to further support the motif analysis in our new release MOTIFSIM 2.1. PMID- 28632402 TI - 3-(Benzyloxy)-1-(5-[18F]fluoropentyl)-5-nitro-1H-indazole: a PET radiotracer to measure acetylcholinesterase in brain. AB - AIM: Noninvasive studies of the acetylcholinesterase (AChE) level in Alzheimer's disease (AD) patients can contribute to a better understanding of the disease and its therapeutic. We propose 3-(benzyloxy)-1-(5-[18F]fluoropentyl)-5-nitro-1H indazole, [18F]-IND1, structurally related to the AChE-inhibitor CP126,998, as a new positron emission tomography-radiotracer. EXPERIMENTAL: Radiosynthesis, with 18F, stability, lipophilicity and protein binding of [18F]-IND1 were studied. In vivo behavior, in normal mice and on AD mice models, were also analyzed. RESULTS: [18F]-IND1 was obtained in good radiochemical yield, was stable for at least 2 h in different conditions, and had adequate lipophilicity for blood-brain barrier penetration. Biodistribution studies, in normal mice, showed that [18F]-IND1 was retained in the brain after 1 h. In vivo tacrine-blocking experiments indicated this uptake could be specifically due to AChE interaction. Studies in transgenic AD mice showed differential, compared with normal mice, binding in many brain regions. CONCLUSION: [18F]-IND1 can be used to detect AChE changes in AD patients. PMID- 28632403 TI - Effect of Amblyopia Treatment on Choroidal Thickness in Children with Hyperopic Anisometropic Amblyopia. AB - PURPOSE: To evaluate choroidal thickness (CT) in the eyes of children with hyperopic anisometropic amblyopia and to assess changes in CT during amblyopia treatment using spectral-domain optical coherence tomography (SD-OCT). METHODS: This longitudinal study, initially enrolled 40 patients, aged 3-9 years with hyperopic anisometropic amblyopia. Patients underwent treatment with refractive correction alone for 16 weeks and if needed, with refractive correction and patching treatment thereafter (6 months). CT was measured perpendicularly (from the outer edge of the hyper-reflective retinal pigment epithelium to the inner sclera) at the fovea, and 1.5-mm temporal, 3.0-mm temporal, 1.5-mm nasal, and 3.0 mm nasal to the fovea using SD-OCT in amblyopic eyes and fellow eyes during treatment and in the control subjects (n = 22). RESULTS: The baseline subfoveal CT measurement was mean 367.9 +/- 54 in the amblyopic eyes, 283.9 +/- 39.6 in the fellow eyes, and 267.3 +/- 41.3 um in the control eyes. Before amblyopia treatment, the subfoveal CT and CT at 1.5-mm nasal and temporal to the fovea and 3.0-mm nasal to fovea in the amblyopic eyes were significantly thicker than those of the control subjects after adjustment for refraction and axial length by multivariate ANCOVA. CT at all locations decreased significantly after treatment in the amblyopic eyes. The final measurement of subfoveal choroid and CT at 1.5 mm nasal to the fovea of the amblyopic eyes was significantly thicker than those of the control subjects after adjusting for axial length and refraction. CONCLUSIONS: The findings of this study indicate that children with hyperopic anisometropic amblyopia have significant CT alterations, and these changes partially regress after amblyopia treatment. PMID- 28632404 TI - Medial and Lateral Rectus Muscle Insertion Distance and Width in Esotropia and Exotropia Patients. AB - PURPOSE: The hypothesis that the extraocular muscle insertion distance and muscle width may be associated with the type and size of deviation was tested. METHODS: This was a prospective study of 129 patients who had surgery for horizontal strabismus or retinal detachment. The insertion distances and widths of the medial rectus (MR) and lateral rectus (LR) muscles were measured intraoperatively in esotropia, exotropia, and buckling surgery (control group) patients. Statistical analysis was performed to compare measured factors between the groups. RESULTS: Median medial and lateral muscle insertions were 5.7 and 6.9 mm in esotropia (ET), 6.0 and 7.1 mm in exotropia (XT), and 5.5 and 6.7 mm in the control groups (p > 0.05). The widths of the medial and lateral muscles ranged from 7.0 to 13.0 mm in ET and XT groups and from 9.5 to 11.0 mm in the control group (p > 0.05). Muscle insertion distance and LR muscle width were not correlated with deviation size. Only the MR muscle width was positively correlated with the deviation size. CONCLUSIONS: Insertion distances of the medial and LR muscles are not statistically different in ET, XT, and control patients. Only MR muscle width was affected by the size of the deviation in ET patients. PMID- 28632405 TI - Reading Performance Improvements in Patients with Central Vision Loss without Age Related Macular Degeneration after Undergoing Personalized Rehabilitation Training. AB - PURPOSE: To evaluate the efficacy of a reading rehabilitation program (RRP) in patients with central visual loss (CVL) and assess the impact of the RRP on the quality of life (QoL). METHODS: The RRP included four in-office and 39 in-home training sessions over 6 weeks. Reading speed, duration, and font size were evaluated during each in-office session. The subjective perception of the QoL was assessed before and after the RRP using the short version of a questionnaire (World Health Organization Quality of Life). A control group who received advice about ocular conditions and low-vision aids also was included. RESULTS: Seventeen patients with Stargardt's disease (STGD), 11 with adult-onset foveomacular vitelliform dystrophy (AFVD), and eight with myopic macular degeneration (MMD) were included. The control group included five patients each with STGD, AFVD, and MMD. The respective mean corrected distance visual acuities (VAs) in patients with STGD, AFVD, MMD, and the control group were 0.57 +/- 0.38, 0.51 +/- 0.38, 0.49 +/- 0.24, and 0.55 +/- 0.25 logarithm of the minimum angle of resolution; the mean corrected near VAs were 0.89 +/- 0.20, 1.08 +/- 0.17, 0.99 +/- 0.34, and 1.18 +/- 0.37 (M notation) using low-vision aids. The reading speed, duration, and font size improved in all groups. The RRP groups obtained (p <= 0.01) greater improvements than the control group in each reading performance variable assessed. Patients with STGD obtained greater improvements in the subjective evaluation; the control group did not obtain noteworthy improvement in any domain. CONCLUSIONS: The RRP improved reading performance in patients with CVL and positively impacted the subjective perception of the QoL. PMID- 28632406 TI - Tailored-pharmacophore model to enhance virtual screening and drug discovery: a case study on the identification of potential inhibitors against drug-resistant Mycobacterium tuberculosis (3R)-hydroxyacyl-ACP dehydratases. AB - AIM: Virtual screening (VS) is powerful tool in discovering molecular inhibitors that are most likely to bind to drug targets of interest. Herein, we introduce a novel VS approach, so-called 'tailored-pharmacophore', in order to explore inhibitors that overcome drug resistance. Methodology & results: The emergence and spread of drug resistance strains of tuberculosis is one of the most critical issues in healthcare. A tailored-pharmacophore approach was found promising to identify in silico predicted hit with better binding affinities in case of the resistance mutations in MtbHadAB as compared with thiacetazone, a prodrug used in the clinical treatment of tuberculosis. CONCLUSION: This approach can potentially be enforced for the discovery and design of drugs against a wide range of resistance targets. PMID- 28632407 TI - Prediction of the structural response of the femoral shaft under dynamic loading using subject-specific finite element models. AB - The goal of this study was to predict the structural response of the femoral shaft under dynamic loading conditions using subject-specific finite element (SS FE) models and to evaluate the prediction accuracy of the models in relation to the model complexity. In total, SS-FE models of 31 femur specimens were developed. Using those models, dynamic three-point bending and combined loading tests (bending with four different levels of axial compression) of bare femurs were simulated, and the prediction capabilities of five different levels of model complexity were evaluated based on the impact force time histories: baseline, mass-based scaled, structure-based scaled, geometric SS-FE, and heterogenized SS FE models. Among the five levels of model complexity, the geometric SS-FE and the heterogenized SS-FE models showed statistically significant improvement on response prediction capability compared to the other model formulations whereas the difference between two SS-FE models was negligible. This result indicated the geometric SS-FE models, containing detailed geometric information from CT images with homogeneous linear isotropic elastic material properties, would be an optimal model complexity for prediction of structural response of the femoral shafts under the dynamic loading conditions. The average and the standard deviation of the RMS errors of the geometric SS-FE models for all the 31 cases was 0.46 kN and 0.66 kN, respectively. This study highlights the contribution of geometric variability on the structural response variation of the femoral shafts subjected to dynamic loading condition and the potential of geometric SS-FE models to capture the structural response variation of the femoral shafts. PMID- 28632408 TI - The Burden of Sexual Problems: Perceived Effects on Men's and Women's Sexual Partners. AB - Sexual dysfunction sometimes negatively affects the individual, his or her partner, and the relationship. We investigated the relationship between the distress experienced by men and women with orgasmic phase difficulties and the perceived distress of their partner(s). We also identified predictors of perceived partner distress, and related self and partner distress to severity of the problem and relationship quality. Data were drawn from 374 men with premature ejaculation (PE) and 377 women with anorgasmia who responded to a survey regarding their sexual functioning, including their distress about their condition and the perceived distress of their partners. Results yielded an overall distress score consisting of combined self and perceived partners distress, with women showing a higher overall score and higher perceived partner distress than men. For men, significant predictors of perceived partner distress included self-distress, relationship quality, interest in sex, and arousal difficulty; for women, only the level of self-distress significantly predicted perceived partner distress. These findings indicate the burden of experiencing sexual difficulty, identify factors related to perceived partner distress, and demonstrate differences in self versus partner distress across men and women. Overall, such findings reiterate the strong need for the inclusion of the partner in any attempted remediation of a sexual problem. PMID- 28632409 TI - L-Satropane Prevents Retinal Neuron Damage by Attenuating Cell Apoptosis and Abeta Production via Activation of M1 Muscarinic Acetylcholine Receptor. AB - : Muscarinic acetylcholine receptor (mAChR) agonists have been used to treat glaucoma due to their intraocular pressure-lowering effects. Recently, it has been reported that retinal mAChRs activation can also stimulate neuroprotective pathways. PURPOSE: In our study, we evaluated the potential neuroprotective effect of L-satropane, a novel mAChR agonist, on retinal neuronal injury induced by cobalt chloride (CoCl2) and ischemia/reperfusion (I/R). METHODS: CoCl2-induced hypoxia injury in cultured cell models and I/R-induced retinal neuronal damage in rats in vivo were used to evaluate the abilities of L-satropane. In detail, we measured the occurrence of retinal pathological changes including molecular markers of neuronal apoptosis and Abeta expression. RESULTS: Pretreatment with L satropane protects against CoCl2-induced neurotoxicity in PC12 and primary retinal neuron (PRN) cells in a dose-dependent manner by increasing retinal neuron survival. CoCl2 or I/R-induced cell apoptosis by upregulating Bax expression and downregulating Bcl-2 expression, which resulted in an increased Bax/Bcl-2 ratio, and upregulating caspase-3 expression/activity was significantly reversed by L-satropane treatment. In addition, L-satropane significantly inhibited the upregulation of Abeta production in both retinal neurons and tissue. We also found that I/R-induced histopathological retinal changes including cell loss in the retinal ganglion cell layer (GCL) and increased TUNEL positive retinal ganglion cells in GCL and thinning of the inner plexiform layer (IPL) and inner nuclear layer (INL) were markedly improved by L-satropane. The effects of L-satropane were largely abolished by the nonselective mAChRs antagonist atropine and M1-selective mAChR antagonist pirenzepine. CONCLUSION: These results demonstrated that L-satropane might be effective in preventing retinal neuron damage caused by CoCl2 or I/R. The neuroprotective effects of L satropane may be attributed to decreasing cell apoptosis and Abeta production through activation of M1 mAChR. PMID- 28632410 TI - Correlation between Interleukin-6 and Thrombin-Antithrombin III Complex Levels in Retinal Diseases. AB - PURPOSE: This study aims to evaluate and correlate the levels of interleukin-6 (IL-6) and thrombin-antithrombin III complex (TAT) in the vitreous of patients with different vitreoretinal pathologies. METHODS: Vitreous samples were collected from 78 patients scheduled for pars plana vitrectomy at a tertiary medical center. Patients were divided by the underlying vitreoretinal pathophysiology, as follows: macular hole (MH)/epiretinal membrane (ERM) (n = 26); rhegmatogenous retinal detachment (RRD) (n = 32); and proliferative diabetic retinopathy (PDR) (n = 20). Levels of IL-6 and TAT were measured by enzyme-linked immunosorbent assay and compared among the groups. RESULTS: A significant difference was found in the vitreal IL-6 and TAT levels between the MH/ERM group and both the PDR and RRD groups (P < 0.001 for all). Diabetes was associated with higher IL-6 levels in the RRD group. Different relationships between the IL-6 and TAT levels were revealed in patients with different ocular pathologies. CONCLUSION: Our results imply that variations in vitreal TAT level may be attributable not only to an inflammatory reaction or blood-retinal barrier breakdown, but also to intraocular tissue-dependent regulation of thrombin. PMID- 28632411 TI - The Effect of Dexamethasone Intravitreal Implant on Retinal Nerve Fiber Layer in Patients Diagnosed with Branch Retinal Vein Occlusion. AB - PURPOSE: To evaluate the effect of a single dose of intravitreal dexamethasone (DEX) implant on retinal nerve fiber layer (RNFL) thickness in patients with branch retinal vein occlusion (BRVO) in a 6-month period. MATERIALS AND METHODS: This retrospective observational study included the patients with BRVO who received intravitreal DEX implant and whose assessment included the baseline RNFL thickness measurements. The data of 26 eyes of 24 patients were retrospectively analyzed. Spectral domain optic coherence tomography was used to measure peripapillary RNFL thickness in six regional subfields. Intraocular pressure (IOP) values at each visit were recorded. The data of single dose DEX implant during 6 months were assessed. RESULTS: The mean preoperative and postoperative 6th month nasal RNFL values were 85.4 +/- 23.0 MUm and 82.1 +/- 17.6 MUm, respectively, and the difference between the measurements was not statistically significant (p = 0.372). There was a slight decrease in the mean RNFL values postoperatively compared to the baseline values in all quadrants except supero temporal quadrant; however, none of them reached statistically significant level (p > 0.05). The mean IOP values before and 6 months after implantation were 15.7 +/- 2.9 mmHg and 16.5 +/- 4.2 mmHg, respectively. The difference between the 6th month IOP values and baseline IOP values was not statistically significant (p = 0.236). CONCLUSION: Intravitreal DEX implant seems to have no adverse effect on RNFL thickness in BRVO patients in a 6-month period. PMID- 28632412 TI - Not Practicing What You Preach: Religion and Incongruence Between Pornography Beliefs and Usage. AB - Religious Americans, and conservative Protestants in particular, have historically been the most ardent opponents of pornography's production, dissemination, and use. Yet while religiously committed and theologically conservative Americans are generally less likely to view pornography than others, the difference is often not as great or consistent as one might suppose given their strong moral stance. Drawing on insights from religious incongruence theory, this study considered whether religious commitment and theological conservatism predicted a greater incongruence between what Americans say they believe about pornography morally and whether they actually watch it. Data are taken from the nationally representative 2006 Portraits of American Life Study (N = 2,279). Analyses show that greater religious service attendance and prayer frequency are predictive of American men (not women) affirming that viewing pornography is "always morally wrong" while still viewing it in the previous year. Evangelicalism and other sectarian Protestantism are also the religious traditions most likely to believe pornography is always morally wrong while also viewing it. Findings ultimately suggest that religious commitment and affiliation with theological conservatism may influence Americans (primarily men) to oppose pornography more strongly in principle than reflected in actual practice. Data limitations and implications for future research are discussed. PMID- 28632413 TI - alpha-Synuclein aggregation modulation: an emerging approach for the treatment of Parkinson's disease. AB - Parkinson's disease (PD) is a multifactorial progressive neurological disorder. Pathological hallmarks of PD are characterized by the presence of alpha-synuclein (alphaSyn) aggregates known as Lewy bodies. alphaSyn aggregation is one of the leading causes for the neuronal dysfunction and death in PD. It is also associated with neurotransmitter and calcium release. Current therapies of PD are limited to only symptomatic relief without addressing the underlying pathogenic factors of the disease process such as aggregation of alphaSyn. Consequently, the progression of the disease continues with the current therapies. Therefore, the modulation of alphaSyn aggregation is an emerging approach as a novel therapeutic target to treat PD. There are two major aspects that might be targeted therapeutically: first, protein is prone to aggregation, therefore, anti aggregative or compounds that can break the pre-existing aggregates should be helpful. Second, there are number of molecular events that may be targeted to combat the disease. PMID- 28632414 TI - Changing US Population Demographics: What Does This Mean for Listeriosis Incidence and Exposure? AB - Listeria monocytogenes is an important cause of foodborne illness hospitalization, fetal loss, and death in the United States. Listeriosis incidence rate varies significantly among population subgroups with pregnant women, older persons, and the Hispanic population having increased relative risks compared with the other subpopulations. Using estimated rates of listeriosis per subpopulation based on FoodNet data from 2004 to 2009, we evaluate the expected number of cases and incidence rates of listeriosis in the US population and the pregnant women subpopulation as the demographic composition changes over time with respect to ethnicity, pregnancy status, and age distribution. If the incidence rate per subpopulation is held constant, the overall US population listeriosis incidence rate would increase from 0.25 per 100,000 (95% confidence interval [CI]: 0.19-0.34) in 2010 to 0.28 (95% CI: 0.22-0.38) in 2020 and 0.32 (95% CI: 0.25-0.43) in 2030, because of the changes in the population structure. Similarly, the pregnancy-associated incidence rate is expected to increase from 4.0 per 100,000 pregnant women (95% CI: 2.5-6.5) in 2010 to 4.1 (95% CI: 2.6-6.7) in 2020 and 4.4 (95% CI: 2.7-7.2) in 2030 as the proportion of Hispanic pregnant women increases. We further estimate that a reduction of 12% in the exposure of the US population to L. monocytogenes would be needed to maintain a constant incidence rate from 2010 to 2020 (current trend), assuming infectivity (strain virulence distribution and individual susceptibility) is unchanged. To reduce the overall US population incidence rate by one-third (Healthy People 2020 goal) would require a reduction in exposure (or infectivity) to L. monocytogenes of 48% over the same time period. Reduction/elimination in exposure of pregnant and Hispanic subpopulations alone could not meet this target. This information may be useful in setting public health targets, developing risk management options, and in interpreting trends in the public health burden of foodborne listeriosis in the United States. PMID- 28632415 TI - Synthesis and biological evaluation of tanshinone IIA derivatives as novel endothelial protective agents. AB - AIM: Oxidative stress-induced endothelial injury is a main risk factor in the pathogenesis of cardiovascular diseases. Tanshinone IIA (Tan IIA) exerts protective functions on endothelial cells in response to oxidative stress. To exploit new bioactive compounds from this natural product, 12 derivatives were first synthesized and evaluated for endothelial protective activities. MATERIALS & METHODS: Title compounds were prepared according to high-yielded synthetic routes, and their protective effects on human endothelial EA.hy926 cells were evaluated. To explore the mechanism, their inhibition on apoptosis of endothelial cells and Nrf2 activating activities were investigated. Furthermore, computational ADME prediction and water solubility assay were carried out for active compounds. RESULTS: Most of them exhibited potent endothelial protective effects on EA.hy926 cells injured by H2O2. In particular, compounds I-2 and II showed increased activity and water solubility compared with Tan IIA. Moreover, they reduced H2O2-induced apoptosis of EA.hy926 cells. A further exploration on the two compounds suggested that their actions were mediated by upregulation of antioxidant genes through activating Nrf2 pathway. CONCLUSION: These Tan IIA derivatives clearly showed related activities for the development of a new type of endothelial protective agents. [Formula: see text]. PMID- 28632416 TI - Survival of Escherichia coli on Lettuce under Field Conditions Encountered in the Northeastern United States. AB - Although wildlife intrusion and untreated manure have been associated with microbial contamination of produce, relatively few studies have examined the survival of Escherichia coli on produce under field conditions following contamination (e.g., via splash from wildlife feces). This experimental study was performed to estimate the die-off rate of E. coli on preharvest lettuce following contamination with a fecal slurry. During August 2015, field-grown lettuce was inoculated via pipette with a fecal slurry that was spiked with a three-strain cocktail of rifampin-resistant nonpathogenic E. coli. Ten lettuce heads were harvested at each of 13 time points following inoculation (0, 2.5, 5, and 24 h after inoculation and every 24 h thereafter until day 10). The most probable number (MPN) of E. coli on each lettuce head was determined, and die-off rates were estimated. The relationship between sample time and the log MPN of E. coli per head was modeled using a segmented linear model. This model had a breakpoint at 106 h (95% confidence interval = 69, 142 h) after inoculation, with a daily decrease of 0.70 and 0.19 log MPN for 0 to 106 h and 106 to 240 h following inoculation, respectively. These findings are consistent with die-off rates obtained in similar studies that assessed E. coli survival on produce following irrigation. Overall, these findings provide die-off rates for E. coli on lettuce that can be used in future quantitative risk assessments. PMID- 28632417 TI - Detection and Antigenic Profiling of Undeclared Peanut in Imported Garlic Using an xMAP Multiplex Immunoassay for Food Allergens. AB - A shipment of imported garlic powder was suspected of containing peanut. Samples (subs) collected from the shipment displayed considerable variability in peanut antigenicity when analyzed by enzyme-linked immunosorbent assay (ELISA). This raised questions regarding whether peanut was actually present, the amount present, and the basis for the variability in antigenic content. Analyses that used an xMAP multiplex assay for the detection of peanut and additional food allergens generated responses that were characteristic of peanut. Specifically, the relative intensities of two different peanut-specific antibodies coupled to beads (peanut-37 and -38) and the antigen profiles were identical to garlic controls spiked with peanut. In addition, the xMAP data did not indicate the presence of other allergens. Quantitative analyses indicated an approximately fivefold variation in peanut concentration among different subs. In contrast, within a sub, the apparent peanut concentration appeared constant. Particle size analyses of the garlic powder subs indicated a single distribution profile, with a peak at 380 MUm. ELISA analysis of sieve-fractionated garlic powder from one of the subs indicated that slightly less than half of the detectable peanut was smaller than 212 MUm, with the remainder almost evenly split between 212 and 300 MUm and >300 MUm. Modeling to predict possible oral exposure levels of peanut other than those directly measured requires additional research on the physicochemical properties of peanut and garlic, along with information on the production of the garlic powder. PMID- 28632418 TI - Therapeutic monitoring of unfractionated heparin - trials and tribulations. AB - INTRODUCTION: Heparin is one of the oldest biological medicines with an established role in prevention and treatment of arterial and venous thromboembolism. Published therapeutic ranges for unfractionated heparin (UFH) mostly precede the large increase in the number of activated partial thromboplastin time (APTT) reagent/instrument combinations that now show wide variability. Areas covered: This paper explores the use of UFH, the development of heparin therapeutic ranges (HTRs), and the strengths and limitations of the methods used to monitor heparin's anticoagulant effect. Expert commentary: Despite longstanding use of UFH for management of thromboembolic conditions, the optimal test for monitoring UFH remains undetermined. Although used extensively for monitoring UFH, routine APTT-derived HTRs are based on limited science that may have little relevance to current laboratory practice. Anti-FXa levels may provide better and more reliable HTRs; however, even these levels show considerable inter-laboratory variation, and there are insufficient clinical studies proving improved clinical efficacy. Alternative tests for monitoring UFH reported over time have not been proven effective nor feasible, secondary to technical or cost issues, or lack of general adoption. Thus, despite limited evidence of clinical utility, an uncomfortable marriage of convenience represented by heparin laboratory monitoring is unlikely to be terminated in the immediate future. PMID- 28632419 TI - In vitro co-expression of human amyloidogenic immunoglobulin light and heavy chain proteins: a relevant cell-based model of AL amyloidosis. AB - Immunoglobulin (Ig) light chain (LC) amyloidosis (AL) is characterized by the overproduction and tissue deposition of monoclonal LC in various organs and tissues. The plasma circulating monoclonal LC is believed to be the precursor of the deposited protein and in vitro studies aimed at understanding AL pathobiology have mainly focused on LC and its variable domain. While 33% of patients have free circulating monoclonal LC, ~40% feature LC complexed to heavy chain (HC) forming a monoclonal intact Ig; the significance of free vs. bound LC in the amyloid forming pathway is unknown. To address this issue, we developed a cell based model using stable mouse plasmacytoma Sp2/0 cells that co-express patient derived amyloidogenic LC and HC proteins. The system was designed using amyloidogenic kappa and lambda LC, and gamma HC sequences; stable production and secretion of either free LC and/or intact Ig were accomplished by varying the LC to HC ratios. This novel cell-based system provides a relevant tool to systematically investigate LC and HC interactions, and the molecular events leading to the development of AL amyloidosis. PMID- 28632420 TI - Medicinal chemistry advances in neurodegenerative disease therapy: part 2. PMID- 28632421 TI - Novel urushiol derivatives as HDAC8 inhibitors: rational design, virtual screening, molecular docking and molecular dynamics studies. AB - Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The compounds' binding affinity toward HDAC8 was screened by Glide docking. The highest-scoring compounds were processed further with molecular docking, MD simulations, and binding free energy studies to analyze the binding modes and mechanisms. Ten compounds had Glide scores of -8.2 to -10.2, which revealed that introducing hydroxy, carbonyl, amino, or methyl ether groups into the alkyl side chain or addition of -F, -Cl, sulfonamide, benzamido, amino, or hydroxy substituents on the benzene ring could significantly increase binding affinity. Molecular docking studies revealed that zinc ion coordination, hydrogen bonding, and hydrophobic interactions contributed to the high calculated binding affinities of these compounds toward HDAC8. MD simulations and binding free energy studies showed that all complexes possessed good stability, as characterized by low RMSDs, low RMSFs of residues, moderate hydrogen bonding and zinc ion coordination and low values of binding free energies. Hie147, Tyr121, Phe175, Hip110, Phe119, Tyr273, Lys21, Gly118, Gln230, Leu122, Gly269, and Gly107 contributed favorably to the binding; and Van der Waals and electrostatic interactions provided major contributions to the stability of these complexes. These results show the potential of urushiol derivatives as HDAC8 binding lead compounds, which have great therapeutic potential in the treatment of various malignancies, neurological disorders, and human parasitic diseases. PMID- 28632422 TI - Risk of diabetes and dyslipidemia during clozapine and other antipsychotic drug treatment of schizophrenia in Iceland. AB - BACKGROUND: Type 2 diabetes (T2D) and raised blood lipids are associated with the use of antipsychotics, not least clozapine. AIMS: To describe the prevalence of high blood glucose levels, T2D, and dyslipidemia, in association with the use of clozapine or other antipsychotics in patients with schizophrenia in Iceland. METHOD: This study identified 188 patients treated with clozapine and 395 patients never treated with clozapine by searching the electronic health records of Landspitali, the National University Hospital. The comparison group consisted of Icelandic population controls. Data were obtained on blood glucose, HbA1c, and blood lipid levels from these health records. RESULTS: The prevalence of T2D was 14.3% in the clozapine group, where the mean age was 51.2 years, and 13.7% in the never-on-clozapine group, where the mean age was 58.6 years. Males on clozapine were 2.3-times more likely and females 4.4-times more likely to have developed T2D than controls from an age-adjusted Icelandic cohort, while males on other antipsychotics were 1.5-times more likely and females 2.3-times as likely to have T2D than controls. Only one case of ketoacidosis was identified. Triglyceride levels were significantly higher in both treatment groups compared to controls in the age-adjusted Icelandic cohort. CONCLUSIONS: Clinicians must take active steps to reduce the risk of T2D and raised triglycerides in patients with schizophrenia. Antipsychotics were associated with a greater risk of T2D developing in females compared to males. PMID- 28632423 TI - Making Kin, Making Trouble: Donna Haraway's Critical Ongoingness. PMID- 28632424 TI - The progress in the research of antiplatelet agents (1995-2017). AB - Antiplatelet therapy displays a critical role in the treatment and prevention of antithrombotic disorders. Many new antiplatelet agents have been developed following the emergence of various clinical limitations of classical antiplatelet drugs. This review covers mainly the recent advances in the development of P2Y12 antagonists and GPIIb/IIIa antagonists. Meanwhile, it summarizes promising approaches to new platelet surface receptors such as prostanoid EP3 receptor, thromboxane A2 prostanoid receptor, protease-activated receptors, GPIb-IX-V receptor and P-selectin. In addition, PI3Kbeta, a critical protein at the inside signaling pathway of platelet activation is also mentioned as an important antiplatelet target. Moreover, the development of respective drug candidates is discussed in detail. PMID- 28632425 TI - Factors Influencing Occupational Therapists' Decision to Supervise Fieldwork Students. AB - The purpose of this study was to identify factors that influence the decision to supervise a Level II occupational therapy fieldwork student. A survey was sent to occupational therapists identified from licensure boards and alumni rosters, including those who have and have not supervised students (n = 548). The results identified both positive and negative influences along with predictive factors of supervising a student. While positive factors included continuing education units, education on fieldwork expectations, their own fieldwork experiences, shared supervision, and access to educational resources, negative influences consisted of: job responsibilities, caseload, productivity standards, working part-time, and fear of failing a student. The discussion focuses on how to address the needs of the clinician and facilitate fieldwork placement. PMID- 28632426 TI - What is behind the epidemiological difference between community-acquired and health-care associated methicillin-resistant Staphylococcus aureus? PMID- 28632427 TI - Speed of processing and executive functions in adults with phenylketonuria: Quick in finding the word, but not the ladybird. AB - A reduction in processing speed is widely reported in phenylketonuria (PKU), possibly due to white matter pathology. We investigated possible deficits and their relationships with executive functions in a sample of 37 early-treated adults with PKU (AwPKUs). AwPKUs were not characterized by a generalized speed deficit, but instead their performance could be explained by two more specific impairments: (a) a deficit in the allocation of visuo-spatial attention that reduced speed in visual search tasks, in some reading conditions and visuo-motor coordination tasks; and (b) a more conservative decision mechanism that slowed down returning an answer across domains. These results suggest that the impairments in executive functions seen in AwPKUs are not the consequence of a generalized speed deficit. They also suggest that processing speed is linked to the efficiency of a particular cognitive component and cannot be considered a general function spanning domains. Similarities with patterns in ageing are discussed. PMID- 28632428 TI - Clinical and socio-demographic correlates of anxious distress in Asian outpatients with major depressive disorder. AB - BACKGROUND: Anxious distress in major depressive disorder (MDD) is common and associated with poor outcomes and management difficulties. AIMS: This post hoc analysis aimed to examine the socio-demographic and clinical correlates of anxiety distress in Asian outpatients with MDD. METHODS: Instead of two out of five specifiers defined by the Diagnostic and Statistical Manual Version-5, anxious distress defined in this study was operationalized as the presence of at least two out of four proxy items drawn from the 90-item Symptom Checklist, Revised (SCL-90-R). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), the Fatigue Severity Scale, the Sheehan Disability Scale and the Multidimensional Scale of Perceived Social Support. RESULTS: The data of 496 patients with MDD were included. Anxious distress was found in 371 participants (74.8%). The binary logistic regression analysis found that anxious distress was independently and significantly correlated with working status, higher MADRS scores, severe insomnia and functional impairment. CONCLUSIONS: Three-fourths of Asian patients with MDD in tertiary care settings may have DSM-5 anxious distress of at least moderate distress. Its prevalence may vary among working groups. The specifier was associated with greater depressive symptom severity, severe insomnia and functional impairment. PMID- 28632429 TI - On Stable States in a Topologically Driven Protein Folding Model. AB - Theoretical models of protein folding often make simplifying assumptions that allow analysis, yielding interesting theoretical results. In this article, we study models where folding dynamics is primarily driven by local topological features in an iterative manner. We illustrate the merit of the proposed approach through its ability to simulate realistic protein folding processes even when the sequence content information is reduced to just hydrophobic and polar. We then analyze our models and show that under our simple assumptions, certain structures are inherently unstable, and that determining whether structures can be stable is an [Formula: see text]-hard problem. Interestingly, we find that when our model has only two amino acids, the problem becomes solvable in polynomial time. PMID- 28632430 TI - Hematopoietic Developmental Potential of Human Pluripotent Stem Cell Lines Is Accompanied by the Morphology of Embryoid Bodies and the Expression of Endodermal and Hematopoietic Markers. AB - The potential clinical applications of hematopoietic stem cells (HSCs) derived from human pluripotent stem cells (hPSCs) are limited by the difficulty of recapitulating embryoid hematopoiesis and by the unknown differentiation potential of hPSC lines. To evaluate their hematopoietic developmental potential, available hPSC lines were differentiated by an embryoid body (EB) suspension culture in serum-free medium supplemented with three different cytokine mixes (CMs). The hPSC differentiation status was investigated by the flow cytometry expression profiles of cell surface molecules, and the gene expression of pluripotency and differentiation markers over time was evaluated by real-time reverse transcription polymerase chain reaction (qRT-PCR). hPSC lines differed in several aspects of the differentiation process, including the absolute yield of hematopoietic progenitors, the proportion of hematopoietic progenitor populations, and the effect of various CMs. The ability to generate hematopoietic progenitors was then associated with the morphology of the developing EBs, the expression of the endodermal markers AFP and SOX17, and the hematopoietic transcription factor RUNX1. These findings deepen the knowledge about the hematopoietic propensity of hPSCs and identify its variability as an aspect that must be taken into account before the usage of hPSC-derived HSCs in downstream applications. PMID- 28632431 TI - Psychometric testing of a Swedish version of the Apathy Evaluation Scale. AB - BACKGROUND: Apathy, a prevalent and clinically relevant symptom in neurodegenerative disease, is often evaluated by the instrument Apathy Evaluation Scale (AES). However, this instrument has not been translated into Swedish, halting clinical and research efforts. Furthermore, previous studies lack analyses of some basic properties, such as the legitimacy of a total score, or have analysed dimensionality by questionable methods. AIM: To translate and psychometrically evaluate a Swedish version of the AES. METHOD: The AES was translated, and its psychometric properties were tested in the Swedish BioFINDER study, including cognitively well elderly, and subjects with mild cognitive or parkinsonian symptoms. Psychometric analyses were conducted according to classical test theory (CTT) and aimed to resemble those performed in the English original study by Marin et al. in 1991. Dimensionality was additionally analysed on a matrix of polychoric correlations and parallel analyses. RESULTS: Data indicate that the Swedish AES performs satisfactorily regarding data completeness, scaling assumptions, targeting, and reliability. Principal component analyses (with parallel analysis) of polychoric correlation matrices identified a single component. Convergent and discriminative validity correlations accorded with a priori expectations. CONCLUSIONS: The study provides initial support that this Swedish AES performs similarly to the English original, and exhibits acceptable psychometric properties according to CTT, including supported unidimensionality, and may be adopted for use in clinical and research settings. PMID- 28632432 TI - Serum microRNAs as Early Indicators for Estimation of Exposure Degree in Response to Ionizing Irradiation. AB - Exposure to ionizing radiation from nuclear devices, spaceflights or terrorist attacks represents a major threat to human health and public security. After a radiological incident, noninvasive biomarkers that can facilitate rapid assessment of exposure risk in the early stages are urgently needed for optimal medical treatment. Serum microRNAs (miRNAs) are ideal biomarkers because they are stable in response to environmental changes, they are common among different species and are easily collected. Here, we performed miRNA PCR arrays to analyze miRNA expression profiles at 24 h postirradiation. Blood samples were collected from animals that received 0.5-2 Gy total-body carbon-ion irradiation. A specific signature with 12 radiosensitive miRNAs was selected for further validation. After exposure to 0.1-2 Gy of carbon-ion, iron-ion or X-ray radiations, five miRNAs that showed a significant response to these radiation types were selected for further observation of dose- and time-dependent changes: miR-183-5p, miR-9 3p, miR-200b-5p, miR-342-3p and miR-574-5p. We developed a universal model using these five miRNAs to predict the degree of exposure to different radiation types with high sensitivity and specificity. In conclusion, we have identified a set of miRNAs that are quite sensitive to different radiation types in the early stages after exposure, demonstrating their potential use as effective indicators to predict the degree of exposure. PMID- 28632433 TI - Comments on "Solid Cancer Incidence among the Life Span Study of Atomic Bomb Survivors: 1958-2009" (Radiat Res 2017; 187:513-537) PMID- 28632434 TI - Screening for celiac disease, by endomysial antibodies, in patients with unexplained hypertransaminasaemia. AB - OBJECTIVE: To do a serological screening for celiac disease in patients with unexplained liver cytolysis. MATERIALS AND METHODS: Fifty-six patients with liver cytolysis without known aetiology were studied. Endomysial antibodies were determined by indirect immunofluorescence on human umbilical cord. Two thousand and five hundred blood donors served as control group. For statistical analysis, we used Chi-square or Fisher's exact test. RESULTS: The frequency of IgA endomysial antibodies in our patients was significantly higher than in the control group (8.92% vs. 0.28%, p < .001). In female, endomysial antibodies were significantly more frequent in patients than in healthy subjects (12.12% vs. 0.4%; p < .001). In male, endomysial antibodies were significantly more frequent in patients than in healthy subjects (4.34% vs. 0.22%; p = .006). The frequency of positive EMA in female patients was higher than in male, but the difference was not statistically significant (12.12% vs. 4.43%; p = .6). Two patients were non-compliant with the gluten-free diet. One patient was out of touch. For the two other patients, transaminase levels reverted to normal level within six months of strict gluten withdrawal. CONCLUSIONS: A screening for celiac disease should be included within the diagnosis protocol of liver cytolysis. PMID- 28632435 TI - Relative effects of plasma, fibrinogen concentrate, and factor XIII on ROTEM coagulation profiles in an in vitro model of massive transfusion in trauma. AB - Massive traumatic haemorrhage is aggravated through the development of trauma induced coagulopathy, which is managed by plasma transfusion and/or fibrinogen concentrate administration. It is yet unclear whether these treatments are equally potent in ensuring adequate haemostasis, and whether additional factor XIII (FXIII) administration provides further benefits. In this study, we compared ROTEM whole blood coagulation profiles after experimental massive transfusion with different transfusion regimens in an in vitro model of dilution- and transfusion-related coagulopathy. Healthy donor blood was mixed 1 + 1 with six different transfusion regimens. Each regimen contained RBC, platelet concentrate, and either fresh frozen plasma (FFP) or Ringer's acetate (RA). The regimens were further augmented through addition of a low- or medium-dose fibrinogen concentrate and FXIII. Transfusion with FFP alone was insufficient to maintain tissue-factor activated clot strength, coincidental with a deficiency in fibrin based clot strength. Fibrinogen concentrate conserved, but did not improve coagulation kinetics and overall clot strength. Only combination therapy with FFP and low-dose fibrinogen concentrate improved both coagulation kinetics and fibrin based clot strength. Administration of FXIII did not result in an improvement of clot strength. In conclusion, combination therapy with both FFP and low-dose fibrinogen concentrate improved clotting time and produced firm clots, representing a possible preferred first-line regimen to manage trauma-induced coagulopathy when RBC and platelets are also transfused. Further research is required to identify optimal first-line transfusion fluids for massive traumatic haemorrhage. PMID- 28632436 TI - Development of Computer Algorithm for Editing of Next Generation Sequencing Metagenome Data. AB - The successful implementation of the advanced sequencing technology, the next generation sequencing (NGS) motivates scientists from diverse fields of biological research especially from genomics and transcriptomics in generating large genomic data set to make their analysis more robust and come up with strong inference. However, exploiting this huge genomic data set becomes a challenge for the molecular biologists. To corroborate this problem, computational software and hardware are being developed in parallel and become an integral part of life science. While executing the "Genomics project of Indian Drosophila species," we found strings of Ns in the whole genome sequences generated on Illumina platform. The present article aims at developing a computer algorithm (MATLAB and Python based) for editing raw sequences mainly eliminating bad residues before submitting to the publicly accessible sequence repository. These algorithms will be helpful to life scientists for analyzing large amount of biological data in short span of time. PMID- 28632437 TI - Conscientious Classification: A Data Scientist's Guide to Discrimination-Aware Classification. AB - Recent research has helped to cultivate growing awareness that machine-learning systems fueled by big data can create or exacerbate troubling disparities in society. Much of this research comes from outside of the practicing data science community, leaving its members with little concrete guidance to proactively address these concerns. This article introduces issues of discrimination to the data science community on its own terms. In it, we tour the familiar data-mining process while providing a taxonomy of common practices that have the potential to produce unintended discrimination. We also survey how discrimination is commonly measured, and suggest how familiar development processes can be augmented to mitigate systems' discriminatory potential. We advocate that data scientists should be intentional about modeling and reducing discriminatory outcomes. Without doing so, their efforts will result in perpetuating any systemic discrimination that may exist, but under a misleading veil of data-driven objectivity. PMID- 28632439 TI - Call for Papers: Special Issue on Computational Propaganda and Political Big Data. PMID- 28632438 TI - Fair Prediction with Disparate Impact: A Study of Bias in Recidivism Prediction Instruments. AB - Recidivism prediction instruments (RPIs) provide decision-makers with an assessment of the likelihood that a criminal defendant will reoffend at a future point in time. Although such instruments are gaining increasing popularity across the country, their use is attracting tremendous controversy. Much of the controversy concerns potential discriminatory bias in the risk assessments that are produced. This article discusses several fairness criteria that have recently been applied to assess the fairness of RPIs. We demonstrate that the criteria cannot all be simultaneously satisfied when recidivism prevalence differs across groups. We then show how disparate impact can arise when an RPI fails to satisfy the criterion of error rate balance. PMID- 28632440 TI - Call for Papers: Special Issue on Profit-Driven Analytics. PMID- 28632441 TI - Research Dilemmas with Behavioral Big Data. AB - Behavioral big data (BBD) refers to very large and rich multidimensional data sets on human and social behaviors, actions, and interactions, which have become available to companies, governments, and researchers. A growing number of researchers in social science and management fields acquire and analyze BBD for the purpose of extracting knowledge and scientific discoveries. However, the relationships between the researcher, data, subjects, and research questions differ in the BBD context compared to traditional behavioral data. Behavioral researchers using BBD face not only methodological and technical challenges but also ethical and moral dilemmas. In this article, we discuss several dilemmas, challenges, and trade-offs related to acquiring and analyzing BBD for causal behavioral research. PMID- 28632442 TI - Social and Technical Trade-Offs in Data Science. PMID- 28632443 TI - Diversity in Big Data: A Review. AB - Big data technology offers unprecedented opportunities to society as a whole and also to its individual members. At the same time, this technology poses significant risks to those it overlooks. In this article, we give an overview of recent technical work on diversity, particularly in selection tasks, discuss connections between diversity and fairness, and identify promising directions for future work that will position diversity as an important component of a data responsible society. We argue that diversity should come to the forefront of our discourse, for reasons that are both ethical-to mitigate the risks of exclusion and utilitarian, to enable more powerful, accurate, and engaging data analysis and use. PMID- 28632444 TI - The Structural Consequences of Big Data-Driven Education. AB - Educators and commenters who evaluate big data-driven learning environments focus on specific questions: whether automated education platforms improve learning outcomes, invade student privacy, and promote equality. This article puts aside separate unresolved-and perhaps unresolvable-issues regarding the concrete effects of specific technologies. It instead examines how big data-driven tools alter the structure of schools' pedagogical decision-making, and, in doing so, change fundamental aspects of America's education enterprise. Technological mediation and data-driven decision-making have a particularly significant impact in learning environments because the education process primarily consists of dynamic information exchange. In this overview, I highlight three significant structural shifts that accompany school reliance on data-driven instructional platforms that perform core school functions: teaching, assessment, and credentialing. First, virtual learning environments create information technology infrastructures featuring constant data collection, continuous algorithmic assessment, and possibly infinite record retention. This undermines the traditional intellectual privacy and safety of classrooms. Second, these systems displace pedagogical decision-making from educators serving public interests to private, often for-profit, technology providers. They constrain teachers' academic autonomy, obscure student evaluation, and reduce parents' and students' ability to participate or challenge education decision-making. Third, big data driven tools define what "counts" as education by mapping the concepts, creating the content, determining the metrics, and setting desired learning outcomes of instruction. These shifts cede important decision-making to private entities without public scrutiny or pedagogical examination. In contrast to the public and heated debates that accompany textbook choices, schools often adopt education technologies ad hoc. Given education's crucial impact on individual and collective success, educators and policymakers must consider the implications of data-driven education proactively and explicitly. PMID- 28632445 TI - Critique and Contribute: A Practice-Based Framework for Improving Critical Data Studies and Data Science. AB - What would data science look like if its key critics were engaged to help improve it, and how might critiques of data science improve with an approach that considers the day-to-day practices of data science? This article argues for scholars to bridge the conversations that seek to critique data science and those that seek to advance data science practice to identify and create the social and organizational arrangements necessary for a more ethical data science. We summarize four critiques that are commonly made in critical data studies: data are inherently interpretive, data are inextricable from context, data are mediated through the sociomaterial arrangements that produce them, and data serve as a medium for the negotiation and communication of values. We present qualitative research with academic data scientists, "data for good" projects, and specialized cross-disciplinary engineering teams to show evidence of these critiques in the day-to-day experience of data scientists as they acknowledge and grapple with the complexities of their work. Using ethnographic vignettes from two large multiresearcher field sites, we develop a set of concepts for analyzing and advancing the practice of data science and improving critical data studies, including (1) communication is central to the data science endeavor; (2) making sense of data is a collective process; (3) data are starting, not end points, and (4) data are sets of stories. We conclude with two calls to action for researchers and practitioners in data science and critical data studies alike. First, creating opportunities for bringing social scientific and humanistic expertise into data science practice simultaneously will advance both data science and critical data studies. Second, practitioners should leverage the insights from critical data studies to build new kinds of organizational arrangements, which we argue will help advance a more ethical data science. Engaging the insights of critical data studies will improve data science. Careful attention to the practices of data science will improve scholarly critiques. Genuine collaborative conversations between these different communities will help push for more ethical, and better, ways of knowing in increasingly datum saturated societies. PMID- 28632446 TI - Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-beta aggregation. AB - AIM: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug design strategy has emerged as a chance to face the disease network. METHODS: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways. RESULTS: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-beta aggregation. CONCLUSION: The compounds emerged as a suitable starting point for a further optimization process. PMID- 28632447 TI - In-Hospital Breastfeeding Experiences Among Women with Gestational Diabetes. AB - BACKGROUND: In-hospital experiences among women with gestational diabetes mellitus (GDM) could impact breastfeeding success. We sought (1) to determine changes in the prevalence of hospital breastfeeding experiences between 2004-2008 and 2009-2011 among women with GDM and women without diabetes; (2) to determine whether GDM is associated with higher occurrence of experiencing Baby-Friendly hospital practices because of their known higher rates of breastfeeding difficulties. MATERIALS AND METHODS: Data from the 2004 to 2011 Pregnancy Risk Assessment Monitoring System, a survey of women with a recent live birth from 16 states and New York City, were used based on inclusion of an optional survey question about hospital breastfeeding experiences. We examined the association of in-hospital experiences with GDM within each survey phase using chi-square tests. Weighted multivariable logistic regression was used to determine the association between GDM and hospital breastfeeding experiences. RESULTS: Among 157,187 (8.8% GDM), there were crude differences by GDM status for at least 60% of hospital experiences despite increases in positive hospital experiences between time periods. Women with GDM were less likely to report breastfeeding in the first hour (adjusted odds ratio: 0.83, confidence interval [95% CI] 0.73-0.94), feeding only breast milk in the hospital (0.73, 0.65-0.82), and feeding on demand (0.86, 0.74-0.99) compared with women without diabetes. Women with GDM were significantly more likely to report receiving a pump (1.28, 1.07-1.53) and a formula gift pack (1.17, 1.03-1.34) compared with women without diabetes. CONCLUSIONS: Although women with GDM experienced improvements in-hospital breastfeeding experiences over time, disparities in breastfeeding practices remained for five in-patient (hospital) practices that included four negative practices (breastfeeding in the first hour, feeding only breast milk in the hospital, told to feed per mother's preference, receiving a formula gift pack) and one positive practice (receiving a pump). PMID- 28632448 TI - Neuroregeneration versus neurodegeneration: toward a paradigm shift in Alzheimer's disease drug discovery. AB - Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches. To circumvent specific liabilities, nanomedicines emerge as a feasible alternative. However, this review is not intended to be comprehensive. Its purpose is to focus on recent examples that could accelerate development of neuroregenerative drugs against Alzheimer's disease. PMID- 28632449 TI - Prevalence of Essential Hypertension and Its Complications Among Chinese Population at High Altitude. AB - : Yue Le, Zhiqing Fan, Lin Sun, Wei Feng, and Jingjie Li. Prevalence of essential hypertension and its complications among Chinese population at high altitude. High Alt Med Biol. 18:140-144, 2017. OBJECTIVES: This study examined the prevalence of essential hypertension (EH) and its complications among Chinese population at different altitude regions in Qinghai province. METHODS: This cross sectional analysis used data from 2000 residents living in the area with two different latitudes for more than 20 years, using 1:1 pairing mode. The EH patients above were, respectively, found in these two groups by blood osmotic pressure and electrocardiogram (ECG). Then, the plasma renin activity (PRA), urinary albumin, urine protein in 24 hours, urine and blood osmotic pressure, coronary angiography, and cardinal enzyme were measured. RESULTS: The prevalence of hypertension in the highlander (36.3%) was significantly higher than that in the lowlander (19.6%) [OR = 1.85; 95% CI 1.29-2.41; p = 0.015], in which the EH patients in the highlander (20.8%) was also much higher than that in the lowlander (8.4%) (OR = 2.48; 95% CI 1.64-3.32; p = 0.002). Considering the age and gender, the prevalence of EH was higher in the subjects who were men and older than 50 years in both the highlander and lowlander (p < 0.05). The concentration of urinary microalbumin, PRA, cardinal enzyme, and the abnormal occurrence rate of ECG and coronary angiography among EH patients in the highlander was higher than those in the lowlander (p < 0.05), while the urine/blood osmotic pressure ratio in the highlander was lower than that in the lowlander (p < 0.001). Positive correlations were also shown between the blood pressure and renal injury (r = 0.462, p < 0.05) or coronary heart disease (r = 0.353, p < 0.05). CONCLUSION: The prevalence of EH and its complications such as renal injury and coronary heart disease were all higher in the highlander. PMID- 28632451 TI - Prolyl oligopeptidase and its role in the organism: attention to the most promising and clinically relevant inhibitors. AB - Prolyl oligopeptidase (POP), also called prolyl endopeptidase, is a cytosolic enzyme investigated by several research groups. It has been proposed to play an important role in physiological processes such as modulation of the levels of several neuronal peptides and hormones containing a proline residue. Due to its proteolytic activity and physiological role in cell signaling pathways, inhibition of POP offers an emerging approach for the treatment of Alzheimer's and Parkinson's diseases as well as other diseases related to cognitive impairment. Furthermore, it may also represent an interesting target for treatment of neuropsychiatric disorders, and as an antiangiogenesis or antineoplastic agent. In this review paper, we summarized naturally occurring POP inhibitors together with peptide-like inhibitors and their biological effects. Some of them have shown promising results and interesting pharmacological profiles. However, to date, there is no POP inhibitor available on the market although several clinical trials have been undertaken. PMID- 28632450 TI - Combinations of Activin A or Nicotinamide with the Pancreatic Transcription Factor PDX1 Support Differentiation of Human Amnion Epithelial Cells Toward a Pancreatic Lineage. AB - The differentiation of multipotent stem cells toward a pancreatic lineage provides us with an alternative cell-based therapeutic approach to type 1 diabetes and enables us to study pancreas development. The current study aims to study the effect of growth factors such as activin A or nicotinamide, alone and in combinations with the transcription factor, PDX1 (pancreatic and duodenal homeobox-1), on human amnion epithelial cells (hAECs) toward a pancreatic lineage. Ectopic expression of Pdx1 followed by treatment of hAECs with nicotinamide for 4 days resulted in strong induction of pancreatic endoderm and pancreatic progenitor genes, including NKX6.1 and NEUROD1. Pancreatic lineage cells expressing PDX1, SOX17, and RFX6 are derived from Pdx1-transduced hAECs treated with activin A or nicotinamide, but not cells treated with activin A or nicotinamide alone. Our study provides a novel culture protocol for generating pancreas-committed cells from hAECs and reveals an interplay between Pdx1 and activin A/nicotinamide signaling in early pancreatic fate determination. PMID- 28632452 TI - The effect of G-CSF on infertile women undergoing IVF treatment: A meta-analysis. AB - Evidence for the effect of granulocyte colony stimulating factor (G-CSF) on infertile women undergoing in vitro fertilization (IVF) remains inconsistent. This study aimed to evaluate the effectiveness of G-CSF on infertile women undergoing IVF. PubMed and EMBASE databases were searched before August 2016. Comparing the transvaginal perfusion of G-CSF and placebo or no treatment, the available studies were considered. The pooled risk ratio (RR) with 95% confidence intervals (CIs) was used in the analysis and six studies were included. Transvaginal perfusion of G-CSF was significantly associated with a higher clinical pregnancy rate versus the placebo (RR=1.563, 95%CI: 1.122, 2.176), especially for the Asian population. Among patients with a thin endometrium or repeated IVF failure, the implantation and biochemical pregnancy rates were also significantly increased in patients with the use of G-CSF (implantation rate: RR = 1.887, 95% CI: 1.256, 2.833; biochemical pregnancy rate: RR = 2.385, 95% CI: 1.414, 4.023). However, no statistical significance in increasing endometrial thickness was detected. Transvaginal perfusion of G-CSF for infertile women may play a critical role in assisting human reproduction, especially for patients with a thin endometrium or repeated IVF failure in the Asian population. PMID- 28632454 TI - Localized amyloidogenic immunoglobulin light chain-derived amyloidosis in a young boy and an adolescent girl. PMID- 28632453 TI - Survey of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and non-ortho-polychlorinated biphenyls in US meat and poultry, 2012-13: toxic equivalency levels, patterns, temporal trends and implications. AB - The US Department of Agriculture (USDA) conducts a statistically based survey of the domestic meat supply (beef, pork, chicken and turkey) to determine current levels of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and non-ortho-polychlorinated biphenyls (no-PCBs) every 5 years. Fat samples for each slaughter class were collected from US federally licensed slaughter facilities. The samples were processed and analysed for 17 PCDD/Fs and three no-PCBs. The sum of PCDD, PCDF and no-PCB toxic equivalencies (sum-TEQ) calculated using 2005 toxic-equivalency factors for all slaughter classes ranged from non-detect (n.d.) to 6.47 pg TEQ g-1 lipid. The median sum TEQs, when n.d. = 0.5 LOD, for beef, pork, chicken and turkey were 0.66, 0.12, 0.13 and 0.34 pg TEQ g-1 lipid respectively. A comparison of the current survey with the previous three surveys shows a declining trend, with decreasing differences between medians; differences between the median sum-TEQs from 2007-08 and 2012-13 were -10%, -29%, -33% and -25% for beef, pork, chicken and turkey respectively. Several beef samples underwent further characterisation and congener patterns from these beef samples suggested pentachlorophenol treated wood as the likely exposure source. US consumer exposure to these compounds is relatively low and no slaughter class contributed more than 26% to the US Environmental Protection Agency (USEPA) chronic oral reference dose of 0.7 pg TEQ kg-1 bw day-1. PMID- 28632456 TI - Effect of Carbon Dioxide Laser on Increasing Vestibular Depth in Cleft Lip and Palate Patients. AB - BACKGROUND: Shallow upper buccal sulcus deformity in cleft lip and palate patients is one of the common secondary deformities after primary cleft lip and palate repair; this deformity may prevent or complicate orthodontic and prosthodontic procedures causing aesthetic and functional problems. A number of methods are described to increase the anterior maxillary sulcus in these patients. PURPOSE: This study assessed the use of a carbon dioxide laser (CO2) to increase the sulcus depth. METHOD: Fifteen patients with cleft lip and palate (eight unilateral and seven bilateral) were studied. The surgical procedure was performed using CO2 laser. The vestibular depth and lip length were measured at three time points namely before surgery (T0), 1 week following surgery (T1), and 4 months following surgery (T2). After data collection, statistical analyses were done using PASW(r) version 18 SPSS. RESULTS: The mean values of vestibular depth were 9.46 +/- 1.92, 13.83 +/- 1.88, and 13.23 +/- 1.76 mm for T0, T1, and T2, respectively. The vestibular depth significantly increased after 4 months of follow-up (p = 0.001). The mean amount of vestibular depth gain was not significantly different in unilateral and bilateral cleft groups (p = 0.908). The mean value of upper lip length increased by a mean of 1.23 mm and was statistically significant (p = 0.001). CONCLUSIONS: Upper buccal sulcus reconstruction with CO2 laser provides successful and stable results. CO2 laser application is suggested as an alternative to conventional vestibuloplasty. PMID- 28632455 TI - Joint Preservation Techniques in Orthopaedic Surgery. AB - CONTEXT: With increasing life expectancy, there is growing demand for preservation of native articular cartilage to delay joint arthroplasties, especially in younger, active patients. Damage to the hyaline cartilage of a joint has a limited intrinsic capacity to heal. This can lead to accelerated degeneration of the joint and early-onset osteoarthritis. Treatment in the past was limited, however, and surgical treatment options continue to evolve that may allow restoration of the natural biology of the articular cartilage. This article reviews the most current literature with regard to indications, techniques, and outcomes of these restorative procedures. EVIDENCE ACQUISITION: MEDLINE and PubMed searches relevant to the topic were performed for articles published between 1995 and 2016. Older articles were used for historical reference. This paper places emphasis on evidence published within the past 5 years. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Autologous chondrocyte implantation and osteochondral allografts (OCAs) for the treatment of articular cartilage injury allow restoration of hyaline cartilage to the joint surface, which is advantageous over options such as microfracture, which heal with less favorable fibrocartilage. Studies show that these techniques are useful for larger chondral defects where there is no alternative. Additionally, meniscal transplantation can be a valuable isolated or adjunctive procedure to prolong the health of the articular surface. CONCLUSION: Newer techniques such as autologous chondrocyte implantation and OCAs may safely produce encouraging outcomes in joint preservation. PMID- 28632457 TI - The BEVPS: A new test battery to assess visual perceptual and spatial processing abilities in 5-14 year-old children. AB - This study aims to examine the different levels of visual perceptual object recognition (early, intermediate, and late) defined in Humphreys and Riddoch's model as well as basic visual spatial processing in children using a new test battery (BEVPS). It focuses on the age sensitivity, internal coherence, theoretical validity, and convergent validity of this battery. French-speaking, typically developing children (n = 179; 5 to 14 years) were assessed using 15 new computerized subtests. After selecting the most age-sensitive tasks though ceiling effect and correlation analyses, an exploratory factorial analysis was run with the 12 remaining subtests to examine the BEVPS' theoretical validity. Three separate factors were identified for the assessment of the stimuli's basic features (F1, four subtests), view-dependent and -independent object representations (F2, six subtests), and basic visual spatial processing (F3, two subtests). Convergent validity analyses revealed positive correlations between F1 and F2 and the Beery-VMI visual perception subtest, while no such correlations were found for F3. Children's performances progressed until the age of 9-10 years in F1 and in view-independent representations (F2), and until 11-12 years in view dependent representations (F2). However, no progression with age was observed in F3. Moreover, the selected subtests, present good-to-excellent internal consistency, which indicates that they provide reliable measures for the assessment of visual perceptual processing abilities in children. PMID- 28632458 TI - Aquaporins: Novel Targets for Age-Related Ocular Disorders. AB - Aquaporins (AQPs), a large family of membrane protein channels that facilitate transport of water and other small solutes, play important roles in physiological functions and human diseases. Up till now, 13 types of AQPs, numbered 0 through 12, have been identified in various mammalian tissues. Homologous genes for AQPs in amphibians, insects, and bacteria highlight the evolutionary conservation and, thus, the importance of these membrane channels. Many members of the AQP family are expressed in the eye. AQP1, which is a water-selective channel, is expressed in the anterior chamber (cornea, ciliary body, trabecular meshwork) and posterior chamber (retina and microvessels in choroid), controlling the fluid homeostasis in the eye. Mice knockout studies have indicated that AQP1 plays an important function in the eye by suggesting its role in aqueous humor dynamics and retina angiogenesis. This review will focus on the role of AQP1 as a novel target for ocular disorders such as glaucoma and age-related macular degeneration, and it will discuss challenges and advances in identifying modulators of AQP1 function that could be useful in clinical applications. PMID- 28632460 TI - From the Editor. PMID- 28632459 TI - The web of microRNA in B lymphoblastic leukemia. PMID- 28632461 TI - Consuming Ecstasy: Representations of Male and Female Orgasm in Mainstream Pornography. AB - Social representations, which appear in a variety of media, can influence the way sexual experiences are perceived and understood. While pornography is not the only medium in which orgasm is portrayed, it is the most explicit, and it is widespread and easily accessible. As such, pornography is an ideal medium for examining representations of male and female orgasm. PornHub's 50 most viewed videos of all time were viewed and coded for the frequency of male and female orgasm, orgasm-inducing sex acts (and whether activity inducing female orgasms included some form of clitoral stimulation), and auditory (verbal, vocal) and visual (bodily) indicators of orgasm. Content analysis was used to code and analyze the data. Results were analyzed in light of sexual script theory and previous orgasm research. Only 18.3% of women, compared to 78.0% of men, were shown reaching orgasm. Sex differences in depictions of orgasm, beyond the appearance of semen, were documented. Results support the male performance script as evident in pornographic depictions of orgasm, as well as coital and orgasm imperatives. As a result, representations of male and female orgasm in mainstream pornography may serve to perpetuate unrealistic beliefs and expectations in relation to female orgasm and male sexual performance. PMID- 28632462 TI - Examining changes in negative mood regulation expectancies, posttraumatic stress disorder, depression, and substance use following integrated cognitive-behavioral therapy. AB - BACKGROUND: The comorbidity of depression, posttraumatic stress disorder (PTSD), and substance use disorder (SUD) is common among veterans. Some research indicates that poor expectancies for negative mood regulation (NMR) may be associated with depression, trauma symptoms, and substance abuse. However, little is known about whether NMR expectancies can be changed through psychotherapy and if so, whether changes in NMR expectancies are related to changes in depression, PTSD, and SUD. METHODS: Therefore, this study examined (1) whether NMR expectancies correlate with depression, PTSD, and SUD symptoms; (2) whether NMR expectancies improve after group integrated cognitive-behavioral therapy (ICBT); and (3) whether these changes were associated with improvements in depression, PTSD, and SUD symptoms in a sample of 123 veterans (89% male, 64% non-Hispanic Caucasian) recruited from a Department of Veteran Affairs (VA) Healthcare System. RESULTS: Findings indicated that (1) NMR expectancies were significantly associated with depression and PTSD symptoms but not substance use at baseline; (2) NMR expectancies significantly improved following group ICBT treatment; (3) following treatment, improvements in NMR expectancies were associated with decreases in depression and PTSD symptoms but were unrelated to changes in substance use outcomes; and (4) baseline NMR expectancies did not predict treatment outcomes. Similarly, pre-post NMR expectancies change scores were significantly associated with changes in depression and PTSD symptoms, but not percentage days using or percentage days heavy drinking. CONCLUSIONS: In conclusion, this study suggests that group ICBT is associated with improvements in NMR expectancies among veterans with depression, PTSD, and SUD, which are associated with improvements in depression and PTSD symptoms. PMID- 28632463 TI - The effects of dosage time and frequency on motor outcomes in children with cerebral palsy: A systematic review. AB - PURPOSE: Provide an updated review regarding treatment dosage for children with cerebral palsy (CP) by examining the variables of type, time, frequency, and intensity. METHODS: A systematic review was performed with 30 articles meeting the inclusion criteria. Two authors independently extracted data including information about risk of bias. Ten articles were included in the review. RESULTS: Eight studies manipulated time, two studies manipulated frequency, and three studies manipulated both variables. No studies investigated intensity. Findings suggest that manipulating time and/or frequency may result in better motor function for higher total dosing; however, benefits were not consistent across studies and few showed clinically significant improvements. CONCLUSION: This most current evidence regarding the effect of dosage on motor function for children with CP suggests that there is insufficient evidence to support implementing high-dosage therapy. Further research is needed to clarify the relationship between dosage variables on motor function for children with CP. PMID- 28632464 TI - Effects of video modeling with video feedback on vocational skills of adults with autism spectrum disorder. AB - OBJECTIVE: To examine the effectiveness of a video modeling (VM) with video feedback (VFB) intervention to teach vocational gardening skills to three adults with autism spectrum disorder (ASD). METHOD: A multiple probe design across skills was used to assess the effects of the intervention on the three participants' ability to perform skills accurately. RESULTS: The use of VM with VFB led to improvements across skills for two of the participants. The third participant required video prompting (VP) for successful skill acquisition. Skill performance generalized across personnel and settings for two of the participants, but it was not assessed for the third. Skill performance maintained at follow-up for all three participants. Social validity data gathered from participants, parents, and co-workers were positive. CONCLUSION: These findings suggest that VM with VFB and VP with VFB were effective and socially acceptable interventions for teaching vocational gardening skills to young adults with ASD. PMID- 28632465 TI - Psychosocial outcome and quality of life following childhood stroke - A systematic review. AB - OBJECTIVES: The aim of this paper was to critically review the recent literature on psychosocial and behavioral outcome following childhood stroke, to assess whether quality of life is affected and to investigate the factors related to psychosocial outcome. METHODS: Literature searches were conducted and identified 36 relevant papers from the period 1908-2016. RESULTS: The systematic review found that many children experience difficulties in a wide range of psychosocial domains. Quality of life can also be significantly reduced. Inconsistent findings regarding the correlates of outcome are likely due to methodological limitations. These issues include small and heterogeneous samples, lack of control groups, and measurement difficulties. CONCLUSIONS: This systematic review strongly indicates that childhood stroke can affect a myriad of psychosocial domains and a child's quality of life. Methodological issues, particularly around heterogeneous samples and measures, limit the conclusions that can be drawn regarding the predictors of outcome. PMID- 28632466 TI - Neuropsychological profiles of children with cerebral palsy. AB - PURPOSE: To explore factors contributing to variability in cognitive functioning in children with cerebral palsy (CP). METHOD: A geographical cohort of 70 children with CP was assessed with tests of language comprehension, visual spatial reasoning, attention, working memory, memory, and executive functioning. Mean age was 9;9 years (range 5;1-17;7), 54.3% were girls, and 50.0% had hemiplegic, 25.7% diplegic, 12.9% quadriplegic, and 11.4% dyskinetic CP. For the participants with severe motor impairments, assessments were adapted for gaze pointing. A cognitive quotient (CQ) was computed. RESULTS: Mean CQ was 78.5 (range 19-123). Gross motor functioning, epilepsy, and type of brain injury explained 35.5% of the variance in CQ (F = 10.643, p = .000). CONCLUSION: Twenty four percent had an intellectual disability, most of them were children with quadriplegic CP. Verbal comprehension and perceptual reasoning scores did only differ for the 21% with an uneven profile, of whom two-thirds had challenges with perceptual reasoning. PMID- 28632467 TI - Effects of a single session of transcranial direct current stimulation on upper limb movements in children with cerebral palsy: A randomized, sham-controlled study. AB - INTRODUCTION: Motor impairment in children with spastic hemiparetic cerebral palsy (CP) is generally more prominent in the affected upper limb, leading to limitations in hand function stemming from deficiencies in motor coordination and selective motor control as well as muscle weakness, slower execution of movements and deficient integration of sensory-motor information. OBJECTIVE: Determine the effect of a single session of anodal transcranial direct current stimulation (tDCS) combined with functional training on the spatiotemporal variables of upper arm movements in children with spastic hemiparesis. METHOD: A randomized, sham controlled trial with a blinded evaluator was conducted involving 20 children with CP between 6 and 12 years of age. The spatiotemporal variables of the upper limbs were analyzed by comparing the results of Evaluation 1 (before stimulation) and Evaluation 2 (immediately after stimulation). The protocol consisted of a 20 minute session of functional training of the paretic upper limb combined with tDCS administered over the primary motor cortex of the hemisphere contralateral to the motor impairment at an intensity of 1 mA. The participants were randomly allocated to two groups: experimental group (anodal tDCS) and control group (sham tDCS). RESULTS: Statistically significant (p < 0.05) reductions in total movement duration and returning movement duration were found in both the paretic and non paretic limbs in the group submitted to active tDCS. No significant differences were found in the control group for any of the variables analyzed. CONCLUSION: A single session of anodal tDCS over the primary motor cortex of the hemisphere ipsilateral to the brain lesion led to momentary motor improvements in both upper limbs of the children with spastic hemiparetic CP analyzed in the present study. PMID- 28632468 TI - Willingness to use pre-exposure prophylaxis among Black and White men who have sex with men in Atlanta, Georgia. AB - PrEP willingness may be different among black and white men who have sex with men (MSM) given known disparities in HIV incidence, sociodemographic factors, and healthcare access between these groups. We surveyed 482 black and white HIV negative MSM in Atlanta, GA about their willingness to use pre-exposure prophylaxis (PrEP) and facilitators and barriers to PrEP willingness. Overall, 45% (215/482) of men indicated interest in using PrEP. Engaging in recent unprotected anal intercourse (UAI) was the only factor significantly associated with PrEP willingness in multivariate analyses (OR 1.73, 95% CI 1.13, 2.65). Willing men identified "extra protection" against HIV as the most common reason for interest in using PrEP, whereas unwilling men most commonly cited not wanting to take medication daily, and this reason was more common among white MSM (42.3% of white MSM vs. 28.9% of black MSM, p = 0.04). Most men indicated willingness to use PrEP if cost was <50 dollars/month; however, more black MSM indicated willingness to use PrEP only if cost were free (17.9% of white MSM vs. 25.9% of black MSM, p = 0.03). Overall, these data are useful to scale up PrEP interventions targeting at-risk MSM in Atlanta and highlight the need for implementation of low cost-programs, which will be especially important for black MSM. PMID- 28632469 TI - Stressful point-of-care rapid testing for human immunodeficiency virus, hepatitis C virus, and syphilis. AB - Even with technological advances in point-of-care rapid testing for HIV, hepatitis, and syphilis, individuals may still find the experience of submitting to testing, and receiving results, to be stressful. Participants completed the rapid test experience questionnaires to assess stress both prior to and after the specimen collection. Participants completed the risk behavior assessment, the coping strategies indicator, and the Barratt impulsivity scale. Participants chose which rapid tests they wanted using a list administered via computer. Logistic regression analysis was used to model self-reported stress prior to testing and after testing. A total of 1097 individuals completed testing. Individuals who scored high on avoidance reported a stressful experience at pretest (OR = 1.15, CI = 1.04, 1.26) while higher educational attainment was associated with no stress at both time points. Injection drug users, avoidant, and impulsive individuals experience stress either before or after rapid testing. Education appears to be protective against stressful testing. PMID- 28632470 TI - Self-collected glans/meatal 'dry' swab specimen and NAAT technology detects Chlamydia trachomatis and Neisseria gonorrhoeae - implications for public policy changes. AB - Increasing Chlamydia trachomatis (CT) rates and ever-present Neisseria gonorrhoeae (NG) infections in women have given rise in the past to consideration of male screening programs in order to address the silent male reservoir. Non medical venues (e.g. home collection, restrooms or other private locations) may be viable venues to reach certain populations that in the past have not been accessed. Effortlessly collected, non-invasive, self-collected male specimens that are stable and easy to transport would enhance the success of male screening programs. We designed a head-to-head study to consider the effectiveness of non invasive self-collected glans/meatal dry swab (SCS) specimens to detect CT and NG nucleic acid when compared to traditional clinician-collected swab (CCS) specimens and first-catch urine (FCU) specimens. A total of 284 male patients were included in the study. Specimens were processed using the Becton Dickinson ProbeTec ET system. The overall sensitivity of SCS was 91.1% with a specificity of 99.2%. There was an overall SCS agreement of 97.7% with CCS specimens and 90.4% with FCU specimens. Dry swab specimens are easy to collect, transport and test. Non-invasive dry self-collected glans/meatal swab specimens are a viable specimen choice. PMID- 28632472 TI - Recalcitrant giant condyloma acuminatum treated successfully with a novel combination of Mycobacterium indicus pranii immunotherapy and acitretin. AB - Giant condyloma acuminatum occurs infrequently in children and adolescents. It is a challenging condition which is difficult to treat with both surgical and medical modalities. We present a case of a 15-year-old boy with giant condyloma acuminatum of the glans penis refractory to several therapeutic modalities. The lesions were treated successfully with a novel combination of Mycobacterium indicus pranii immunotherapy and acitretin. There was no recurrence of lesions after two years of follow-up. PMID- 28632471 TI - Lenalidomide as a treatment for relapsed AL amyloidosis in an HIV-positive patient. AB - We present a case of an HIV-positive man with systemic immunoglobulin light chain (AL) amyloid with cardiac involvement. At relapse, he was treated with lenalidomide and dexamethasone having previously developed autonomic neuropathy with bortezomib-based chemotherapy. The patient achieved a serological complete response with symptomatic improvement. After 11 cycles, lenalidomide was discontinued due to extensive ischaemia of the gastrointestinal tract. The patient remains symptomatically stable with normal levels of serum-free light chains 11 months after the treatment was discontinued. Lenalidomide can be a good treatment option for AL amyloidosis in HIV-infected patients on antiretroviral therapy. PMID- 28632473 TI - A rare occurrence of epidermolysis bullosa acquisita in a patient with retroviral disease. AB - Epidermolysis bullosa acquisita is a chronic subepidermal blistering disease associated with autoimmunity to type-VII collagen within anchoring fibrils located at the dermo-epidermal junction. This entity is rarely reported from India. It can have a variety of presentations. Its occurrence with retroviral disease has rarely been reported. Here, we present a case of epidermolysis bullosa acquisita in a patient with HIV infection. PMID- 28632474 TI - Evaluation of the concurrent use of dolutegravir and metformin in human immunodeficiency virus-infected patients. AB - An analysis of the interaction between dolutegravir and metformin was conducted in the HIV ambulatory clinic setting. This was a multicenter, retrospective case series evaluating adult, HIV-infected patients concurrently prescribed dolutegravir and metformin. Historical electronic medical records were utilized to collect case-specific data. Laboratory parameters including serum creatinine (SCr), hemoglobin A1c (HgbA1c), plasma HIV RNA, CD4 cell count, and lactate were reviewed. Adverse drug reactions were assessed using patient-reported gastrointestinal intolerance and hypoglycemic symptoms. Metformin dose reduction or discontinuation was also recorded. Nineteen patients identified as concurrently taking metformin and dolutegravir were included. Eighteen patients were on metformin prior to dolutegravir initiation, with 13 having received metformin for at least six months prior to dolutegravir. At the time of dolutegravir initiation, one patient had a preemptive metformin dose reduction. Seven patients were initiated on dolutegravir with a metformin dose greater than 1000 mg daily. Eleven patients had baseline and three- to six-month follow-up HgbA1c. Of those 11 patients, eight had stable or decreased values. Thirteen of the 19 patients had an increase in SCr, with a median increase of 0.3 mg/dl (0.03 0.43). Gastrointestinal distress (N = 3) and hypoglycemic symptoms (N = 3) were reported in a total of five patients. Adverse drug reactions resulted in metformin dose reduction (N = 2) and/or discontinuation (N = 2). There were no reported cases of lactic acidosis. Providers concurrently prescribing dolutegravir and metformin should be aware of potential consequences with this combination and may consider an empiric metformin dose reduction to prevent intolerable adverse drug reactions. PMID- 28632475 TI - Generic substitution of antiretrovirals: patients' and health care providers' opinions. AB - There is interest in introducing generic antiretroviral drugs (ARVs) into high income countries in order to maximise efficiency in health care budgets. Studies examining patients' and providers' knowledge and attitudes to generic substitution in HIV are few. This was a cross-sectional, observational study with a convenience sample of adult HIV-infected patients and health care providers (HCPs). Data on demographics, knowledge of generic medicine and facilitators of generic substitution were collected. Descriptive and univariate analysis was performed using SPSS V.23TM. Questionnaires were completed by 66 patients. Seventy-one per cent would have no concerns with the introduction of generic ARVs. An increase in frequency of administration (61%) or pill burden (53%) would make patients less likely to accept generic ARVs. There were 30 respondents to the HCP survey. Concerns included the supply chain of generics, loss of fixed dose combinations, adherence and use of older medications. An increase in dosing frequency (76%) or an increase in pill burden (50%) would make HCPs less likely to prescribe a generic ARV. The main perceived advantage was financial. Generic substitution of ARVs would be acceptable to the majority of patients and HCPs. Reinvesting savings back into HIV services would facilitate the success of such a programme. PMID- 28632476 TI - Extensive brain masses and cavitary lung lesions associated with toxoplasmosis and acquired immunodeficiency syndrome. AB - Toxoplasmosis is an important cause of enhancing brain lesions in patients with acquired immunodeficiency syndrome (AIDS), and it is typically associated with low CD4-lymphocyte counts. Extensive toxoplasma encephalitis when the CD4 lymphocyte count is above 100 cells/ul is unusual. Cavitary lung lesions are also not typically associated with toxoplasmosis. Here, we present a case of toxoplasmosis associated with extensive brain masses and cavitary lung lesions, both of which improved with directed toxoplasmosis therapy, in an AIDS patient with a CD4 cell count of 120 cells/ul. PMID- 28632477 TI - Antiretroviral therapy adherence and self-efficacy among people living with HIV and a history of drug use in Vietnam. AB - People living with HIV with a history of drug use face additional psychosocial challenges that could compromise their adherence to antiretroviral therapy (ART). This study examined ART treatment adherence and adherence self-efficacy among people living with HIV with a history of drug use in Vietnam. We used cross sectional baseline data collected between October 2014 and February 2015 from a randomized controlled trial in Vietnam. Of the 900 persons with a history of drug use in the trial, a sample of 109 people living with HIV currently on ART were included in the study. The vast majority (92%) of the participants reported not missing any medications in the past 30 days. Multiple regression results indicated that social support was positively associated with adherence self efficacy (beta = 0.420, P < 0.001) and general adherence to ART (beta = 0.201, P = 0.0368). General adherence to ART was negatively associated with depressive symptoms (beta = -0.188, P = 0.046) and current heroin use (beta = -0.196, P = 0.042). These findings underscore the importance of addressing mental health and social challenges facing people living with HIV with a history of drug use to promote ART treatment adherence. Clinical management of HIV should identify and address concurrent substance use behaviors to maximize adherence and treatment outcomes. PMID- 28632478 TI - Sexual risk behaviors and predictors of inconsistent condom use among crack cocaine users in the French overseas territories in the Americas. AB - The French overseas territories in the Americas are the French territories most affected by HIV. Crack cocaine users are particularly impacted. The objective of this study was to describe sexual risk behaviors and inconsistent condom use among crack cocaine users. A total of 640 crack cocaine users were interviewed. The sampling method was non-probabilistic. An anonymous standardized questionnaire of 110 questions was used. Over a third of persons did not use condoms systematically with casual sex partners (36.2%) or commercial sex partners (32.3%), and 64% did not use condoms systematically with regular sex partners. In a context of multiple sexual partnerships, frequent forced sex, and insufficient HIV testing, the lack of systematic condom use may favor the spread of HIV. Different predictive factors of inconsistent condom use were identified, depending on the type of partner, with a log binomial regression. However, among the predictor variables identified, two predictive factors frequently occur among the different type of sex partners: high perceived risk of HIV and self-perceived capacity to persuade a sex partner to use condom. These results pointed towards interventions improving access to rights and raising perceived self-efficacy. PMID- 28632479 TI - Use and acceptability of salivary hepatitis C virus testing in an English Young Offender Institution. AB - People held in prison are at a high risk of having hepatitis C virus (HCV) and there is a public health drive in the UK to increase HCV testing in prisons and Young Offender Institutions (YOIs), with opt-out testing. There is an oral antibody test for HCV; this project aims to determine its acceptability in an English YOI setting. This project offered HCV oral point-of-care testing (POCT) using the OraQuick(r) test to 107 male young offenders attending a sexual health service at an English YOI, monitoring HCV positivity and evaluating acceptability. It also investigated young offenders' histories of sexually transmitted infections (STIs) and drug use. Mean age was 19.1 years. A total of 80.4% reported lifetime drug use and 0.9% reported lifetime drug injection. A total of 19.6% reported previous STIs. One patient (0.9%) was positive for HCV on OraQuick(r) testing. All patients found the POCT acceptable and one stated he would have refused a fingerprick test had it been the only test available for HCV testing. Salivary rapid HCV testing is acceptable among English YOI inmates. It is not as sensitive or specific as standard HCV tests and is more expensive. In our cohort, HCV positivity was low. PMID- 28632480 TI - Healthcare contacts among patients lost to follow-up in HIV care: review of a large regional cohort utilizing electronic health records. AB - In the United States 40% of HIV patients are lost to follow-up (LTFU) following linkage to HIV care and an estimated 30-61% of new HIV transmissions are attributed to this group. To characterize those LTFU and healthcare contacts they make, we retrospectively analyzed a large regional HIV cohort in Calgary, Canada, utilizing a province-wide electronic health record. Adults engaged in HIV care between January 2010 and August 2014 who had >12 months without HIV clinic contact were identified as LTFU. Of 1928 individuals engaged in care, 176 became LTFU with 64% having no healthcare contacts, 20% receiving HIV care elsewhere, and 16% making non-HIV healthcare contacts. Those LTFU making non-HIV healthcare contacts did so a median of six times (interquartile range 2-8), 76% attending emergency departments (ED). Compared to those retained in care, LTFU patients were younger (median age 43 versus 47 years), had lower CD4+ cell counts (median 420 versus 500 * 106/l) and more commonly resided outside of the centralized HIV clinic's city (odds ratio 4.58) (all p < 0.01). Our finding that a majority of those LTFU did not make healthcare contacts suggests that community and HIV clinic-based relinkage programs are needed. For those LTFU who make healthcare contacts enhanced ED-based relinkage programs could engage a majority. PMID- 28632481 TI - Trends in CD4 cell count response to first-line antiretroviral treatment in HIV positive patients from Asia, 2003-2013: TREAT Asia HIV Observational Database Low Intensity Transfer. AB - Antiretroviral treatment (ART) guidelines have changed over the past decade, recommending earlier initiation and more tolerable regimens. The study objective was to examine the CD4 response to ART, depending on the year of ART initiation, in HIV-positive patients in the Asia-Pacific. We included HIV-positive adult patients who initiated ART between 2003 and 2013 in our regional cohort from eight urban referral centres in seven countries within Asia. We used mixed effects linear regression models to evaluate differences in CD4 response by year of ART initiation during 36 months of follow-up, adjusted a priori for other covariates. Overall, 16,962 patients were included. Patients initiating in 2006-9 and 2010-13 had an estimated mean CD4 cell count increase of 8 and 15 cells/ul, respectively, at any given time during the 36-month follow-up, compared to those in 2003-5. The median CD4 cell count at ART initiation also increased from 96 cells/ul in 2003-5 to 173 cells/ul in 2010-13. Our results suggest that the CD4 response to ART is modestly higher for those initiating ART in more recent years. Moreover, fewer patients are presenting with lower absolute CD4 cell counts over time. This is likely to reduce their risk of opportunistic infections and future non-AIDS defining cancers. PMID- 28632482 TI - Staff, associate specialist and specialty doctors' national audit on the management of gonorrhoea in the United Kingdom, 2015. AB - The British Association for Sexual Health and HIV (BASHH) revised United Kingdom national guideline for the management of gonorrhoea in adults, 2011, identified five auditable outcome measures, namely, that all patients should receive first line treatment, be screened or treated for chlamydial infection, have a test of cure (TOC), be offered written information and have partner notification carried out. The UK National Guideline for Gonorrhoea Testing, Clinical Effectiveness Group, BASHH, 2012, recommended in addition that all reactive nucleic acid amplification tests (NAATs) from pharynx and rectum should be confirmed by supplementary testing, using a second NAAT which detects a different nucleic acid target, all those with a positive NAAT for gonorrhoea should have culture and antimicrobial susceptibility testing and that TOC should be done by two weeks. Staff, associate specialist and specialty doctors performed a national audit against these standards. Data from 3233 cases were submitted; 8% of cases of gonorrhoea diagnosed in England, Scotland and Wales over this period. We found that 83% patients received first-line treatment with a reason for not doing so provided for 11%. TOC was documented for 62% and written information was offered to 41%. Results about supplementary testing were inconsistent. The results for the other outcomes were satisfactory. PMID- 28632483 TI - Cardiovascular disease risk profile of NCAA Division III intercollegiate football athletes: a pilot study. AB - OBJECTIVES: Concerns about the long-term cardiovascular health implications of American football participation have been investigated at the professional and Division I levels, but limited research is available at the less resourced Division III level. Therefore, the objective was to assess the cardiovascular disease risk profile of NCAA Division III intercollegiate football athletes. METHODS: Eighty-nine varsity football athletes (age = 19.6 +/- 1.7 years, height = 1.81 +/- 0.07m, weight = 92.7 +/- 16.2kg; n = 21 linemen, n = 68 non-linemen) at a private Division III university volunteered to participate. During a preseason pre-participation physical examination, all participants completed a health history screening form (to assess personal and family history of cardiac related pathologies), and were assessed for height, weight, body mass index (BMI), and blood pressure (BP). Linemen only additionally gave a blood sample for fasting blood glucose and cholesterol analysis, and were assessed for waist and hip circumference, metabolic syndrome, and percent body fat (%BF). These measures were reported as averages and frequencies of elevated cardiovascular. Independent t-tests compared linemen to non-linemen, all other data was presented descriptively. RESULTS: On average, linemen were significantly taller, heavier, had a higher BMI and higher systolic BP than non-linemen (all P < 0.05); there was no difference in diastolic BP between the groups (P = 0.331). The average anthropometric and cardiac risk characteristics for linemen were largely within normal ranges, however analyzed individually, a substantial number of participants were at elevated risk (BMI >=30 = 85.7%, %BF >=25 = 71.4%, waist circumference >=1 = 42.9%, hypertension = 9.5%, high density lipoproteins <40mg/dL = 42.9%, and triglycerides >=150mg/dL = 6.7%; metabolic syndrome prevalence = 19%). CONCLUSIONS: Similar to research in elite athletics, linemen at a single Division III university have elevated cardiovascular disease risk. Physicians and other healthcare providers should consider this elevated risk during pre-participation physical examinations and in planning educational or dietary programming targeted to promoting cardiovascular health. PMID- 28632485 TI - Will strict limits on opioid prescription duration prevent addiction? Advocating for evidence-based policymaking. PMID- 28632484 TI - Rab GTPases and their interacting protein partners: Structural insights into Rab functional diversity. AB - Rab molecular switches are key players in defining membrane identity and regulating intracellular trafficking events in eukaryotic cells. In spite of their global structural similarity, Rab-family members acquired particular features that allow them to perform specific cellular functions. The overall fold and local sequence conservations enable them to utilize a common machinery for prenylation and recycling; while individual Rab structural differences determine interactions with specific partners such as GEFs, GAPs and effector proteins. These interactions orchestrate the spatiotemporal regulation of Rab localization and their turning ON and OFF, leading to tightly controlled Rab-specific functionalities such as membrane composition modifications, recruitment of molecular motors for intracellular trafficking, or recruitment of scaffold proteins that mediate interactions with downstream partners, as well as actin cytoskeleton regulation. In this review we summarize structural information on Rab GTPases and their complexes with protein partners in the context of partner binding specificity and functional outcomes of their interactions in the cell. PMID- 28632486 TI - Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naive, Metastatic, Castration-Resistant Prostate Cancer. AB - Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naive, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve >= 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed >= 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor-targeted therapy. Overall, 35 patients (55.6%) had confirmed >= 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had >= 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve >= 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved >= 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of >= 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes. PMID- 28632488 TI - Vector-Borne Pathogens in Stray Dogs in Northeastern Turkey. AB - This experiment was carried out to attain prevalence and molecular characterization of pathogens causing canine vector-borne diseases (CVBDs) including babesiosis, hepatozoonosis, leishmaniasis, filariosis (Dirofilaria immitis, Dirofilaria repens, and Acanthocheilonema reconditum), ehrlichiosis (Ehrlichia canis), and anaplasmosis (Anaplasma platys) in stray dogs. The study material consisted of 133 asymptomatic female (n = 96) and male (n = 37) stray dogs (<=1 year old, n = 16 and 1-6 years old, n = 117) housed in the Animal Care and Rehabilitation Center, Erzurum, Northeastern Turkey. Conventional and nested PCR were performed on blood samples to detect Babesia spp., Leishmania spp., Hepatozoon spp., D. immitis, D. repens, A. reconditum, E. canis, and A. platys. Sex and age association with the pathogen prevalence was determined using X2 statistics. The positivity rate for at least one CVBD pathogen was 48.9% (65/133). DNA of B. canis, Hepatozoon spp., H. canis, D. immitis, and E. canis were detected in 5.3% (7/133), 27.1% (36/133), 5.3% (7/133), 1.5% (2/133), and 9.8% (13/133) of the dogs, respectively. Leishmania spp., D. repens, A. reconditum, and A. platys DNA were not detected. Mixed pathogens were determined in seven (10.8%) of the infected dogs, with predominant involvement of Hepatozoon spp. or H. canis. The pathogen prevalence did not vary by sex or age. Nucleotide blast analysis of Erzurum isolates showed 99.8-100% identities with the corresponding reference isolates. This study indicates presence of five CVB pathogens, including the first report of E. canis, in stray dogs in Erzurum, Turkey. PMID- 28632487 TI - Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in Induction Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia. AB - Purpose We compared two induction regimens, idarubicin (12 mg/m2/d for 3 days) versus high-dose daunorubicin (90 mg/m2/d for 3 days), in young adults with newly diagnosed acute myeloid leukemia (AML). Patients and Methods A total of 299 patients (149 randomly assigned to cytarabine plus idarubicin [AI] and 150 assigned to cytarabine plus high-dose daunorubicin [AD]) were analyzed. All patients received cytarabine (200 mg/m2/d for 7 days). Results Complete remission (CR) was induced in 232 patients (77.6%), with no difference in CR rates between the AI and AD arms (80.5% v 74.7%, respectively; P = .224). At a median follow-up time of 34.9 months, survival and relapse rates did not differ between the AI and AD arms (4-year overall survival, 51.1% v 54.7%, respectively; P = .756; cumulative incidence of relapse, 35.2% v 25.1%, respectively; P = .194; event free survival, 45.5% v 50.8%, respectively; P = .772). Toxicity profiles were also similar in the two arms. Interestingly, overall and event-free survival times of patients with FLT3 internal tandem duplication (ITD) mutation were significantly different (AI v AD: median overall survival, 15.5 months v not reached, respectively; P = .030; event-free survival, 11.9 months v not reached, respectively; P = .028). Conclusion This phase III trial comparing idarubicin with high-dose daunorubicin did not find significant differences in CR rates, relapse, and survival. Significant interaction between the treatment arm and the FLT3-ITD mutation was found, and high-dose daunorubicin was more effective than idarubicin in patients with FLT3-ITD mutation. PMID- 28632489 TI - The effects of platelet gel on cultured human retinal pigment epithelial (hRPE) cells. AB - The positive role of platelet gel (PG) in tissue regeneration is well known, however, other characteristics of PG still remain to be determined. We investigated cellular and molecular changes in cultured human retinal pigment epithelial (hRPE) cells when treated with different concentrations of PG named PG1, PG2, and PG3. hRPE cells were isolated from donor eyes of two newborn children, within 24 hours after their death. The cells were treated with three concentrations of PG for 7 days: 3 * 104/ml (PG1), 6 * 104/ml (PG2), and 9 * 104/ml (PG3). Fetal bovine serum was used as a control. Immunocytochemistry was performed with anti-RPE65 (H-85), anti-Cytokeratin 8/18 (NCL-5D3), and anti-PAX6 antibody. We used MTT assay to determine cell viability. Gene expressions of PAX6, MMP2, RPE65, ACTA2, MKI67, MMP9, and KDR were analyzed using real-time PCR. A significant increase in viability was observed for PG3-treated cells compared to control (p = 0.044) and compared to PG1 group (p = 0.027), on day 7. Cellular elongation together with dendritiform extensions were observed in PG-treated cells on days 1 and 3, while epithelioid morphology was observed on day 7. All cells were immunoreactive for RPE65, cytokeratin 8/18, and PAX6. No significant change was observed in the expression of MKI67 and PAX6, but the expressions of MMP2, MMP9, ACTA2, and KDR were significantly higher in PG2-treated cells compared to controls (p < 0.05). Our results indicate that increased concentration of PG and extended exposure time have positive effects on viability of hRPE cells. PG may be useful for hRPE cell encapsulation in retinal cell replacement therapy. PMID- 28632492 TI - Is the location of the signal intensity weighted centroid a reliable measurement of fluid displacement within the disc? AB - Degenerated discs have shorter T2-relaxation time and lower MR signal. The location of the signal-intensity-weighted-centroid reflects the water distribution within a region-of-interest (ROI). This study compared the reliability of the location of the signal-intensity-weighted-centroid to mean signal intensity and area measurements. L4-L5 and L5-S1 discs were measured on 43 mid-sagittal T2-weighted 3T MRI images in adults with back pain. One rater analysed images twice and another once, blinded to measurements. Discs were semi automatically segmented into a whole disc, nucleus, anterior and posterior annulus. The coordinates of the signal-intensity-weighted-centroid for all regions demonstrated excellent intraclass-correlation-coefficients for intra- (0.99-1.00) and inter-rater reliability (0.97-1.00). The standard error of measurement for the Y-coordinates of the signal-intensity-weighted-centroid for all ROIs were 0 at both levels and 0 to 2.7 mm for X-coordinates. The mean signal intensity and area for the whole disc and nucleus presented excellent intra-rater reliability with intraclass-correlation-coefficients from 0.93 to 1.00, and 0.92 to 1.00 for inter-rater reliability. The mean signal intensity and area had lower reliability for annulus ROIs, with intra-rater intraclass-correlation-coefficient from 0.5 to 0.76 and inter-rater from 0.33 to 0.58. The location of the signal intensity-weighted-centroid is a reliable biomarker for investigating the effects of disc interventions. PMID- 28632491 TI - Lessons Learned on Health Adaptation to Climate Variability and Change: Experiences Across Low- and Middle-Income Countries. AB - BACKGROUND: There is limited published evidence of the effectiveness of adaptation in managing the health risks of climate variability and change in low- and middle-income countries. OBJECTIVES: To document lessons learned and good practice examples from health adaptation pilot projects in low- and middle-income countries to facilitate assessing and overcoming barriers to implementation and to scaling up. METHODS: We evaluated project reports and related materials from the first five years of implementation (2008-2013) of multinational health adaptation projects in Albania, Barbados, Bhutan, China, Fiji, Jordan, Kazakhstan, Kenya, Kyrgyzstan, Philippines, Russian Federation, Tajikistan, and Uzbekistan. We also collected qualitative data through a focus group consultation and 19 key informant interviews. RESULTS: Our recommendations include that national health plans, policies, and budget processes need to explicitly incorporate the risks of current and projected climate variability and change. Increasing resilience is likely to be achieved through longer-term, multifaceted, and collaborative approaches, with supporting activities (and funding) for capacity building, communication, and institutionalized monitoring and evaluation. Projects should be encouraged to focus not just on shorter-term outputs to address climate variability, but also on establishing processes to address longer-term climate change challenges. Opportunities for capacity development should be created, identified, and reinforced. CONCLUSIONS: Our analyses highlight that, irrespective of resource constraints, ministries of health and other institutions working on climate-related health issues in low- and middle-income countries need to continue to prepare themselves to prevent additional health burdens in the context of a changing climate and socioeconomic development patterns. https://doi.org/10.1289/EHP405. PMID- 28632493 TI - Interplay between PAPP-A, inflammation and adiposity in patients with angiographically proven acute coronary syndrome (ACS). AB - Introduction Studies conducted in the recent past have demonstrated the role of inflammation, obesity and dysfunctional insulin signaling as contributing factors in the pathogenesis of acute coronary syndrome (ACS). However, pharmacological interventions targeting a single pathway have not proven useful in the long run. This indicates that a synergism occurs between the various risk factors and hence calls for a combinatorial approach. This study was planned to study the interplay, if any, between pregnancy associated plasma protein-A (PAPP-A), inflammation and adiposity in patients with ACS. Materials and methods The study was conducted in a tertiary care hospital in Delhi. The study population consisted of 128 subjects, divided into two groups. The control group consisted of 64 healthy subjects without ACS. Cases consisted of 64 subjects with angiographically proven ACS cases. PAPP-A and high sensitivity C-reactive protein (hs-CRP) were estimated by enzyme-linked immunosorbent assay (ELIZA) kits. Results The mean level of PAPP-A and hs-CRP were significantly higher in cases as compared to the controls. A positive correlation of PAPP-A was observed with hs CRP, insulin, ApoB and Lp(a). The relative risk for ACS was 14.2 with a p value of <0.001 when all the three parameters - hs-CRP, PAPP-A and body mass index (BMI) were considered together. This was significantly higher when each risk factor was assessed standalone. Conclusions Our study results suggest a possible interplay between chronic inflammation, obesity and plaque instability among patients with ACS. This interaction can accelerate the process of plaque rupture in patients with increased BMI as compare to those patients with low/normal BMI. PMID- 28632490 TI - The Florence Statement on Triclosan and Triclocarban. AB - The Florence Statement on Triclosan and Triclocarban documents a consensus of more than 200 scientists and medical professionals on the hazards of and lack of demonstrated benefit from common uses of triclosan and triclocarban. These chemicals may be used in thousands of personal care and consumer products as well as in building materials. Based on extensive peer-reviewed research, this statement concludes that triclosan and triclocarban are environmentally persistent endocrine disruptors that bioaccumulate in and are toxic to aquatic and other organisms. Evidence of other hazards to humans and ecosystems from triclosan and triclocarban is presented along with recommendations intended to prevent future harm from triclosan, triclocarban, and antimicrobial substances with similar properties and effects. Because antimicrobials can have unintended adverse health and environmental impacts, they should only be used when they provide an evidence-based health benefit. Greater transparency is needed in product formulations, and before an antimicrobial is incorporated into a product, the long-term health and ecological impacts should be evaluated. https://doi.org/10.1289/EHP1788. PMID- 28632494 TI - Long-term dutasteride therapy in men with benign prostatic hyperplasia alters glucose and lipid profiles and increases severity of erectile dysfunction. AB - Background Dutasteride has been successfully used in treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). However, dutasteride inhibits 5alpha-reductase type 1 and type 2 enzymes and may compromises glucocorticoids and androgen metabolism and alters metabolic function resulting in undesirable metabolic and sexual adverse side effects. Aim The aim of this study was to investigate the long-term adverse effects of dutasteride therapy in men with BPH on: i) blood glucose, ii) glycated hemoglobin (HbA1c), iii) low density lipoprotein-cholesterol (LDL-C); high density lipoprotein cholesterol (HDL-C) and total cholesterol (TC), iv) testosterone (T), v) liver alanine and aspartate aminotransferases (ALT and AST) and vi) erectile dysfunction (ED). Methods A retrospective registry study, with a cohort of 230 men aged between 47 and 68 years (mean 57.78 +/- 4.81) were treated with dutasteride (0.5 mg/day) for LUTS, secondary to BPH. A second cohort of 230 men aged between 52 and 72 years (mean 62.62 +/- 4.65) were treated with tamsulosin (0.4 mg). All men were followed up for 36-42 months. At intervals of 3-6 months, and at each visit, plasma glucose, HbA1c, TC, LDL-cholesterol, T levels and liver alanine amino transferase (ALT) and aspartate aminotransferase (AST) were determined. Further patient assessment was made by the International Index of Erectile Function (IIEF-EF) questionnaire, the Aging Male Symptom (AMS) and International Prostate Symptom Scores (IPSS). Results Long-term treatment with dutasteride therapy is associated with significant improvements in LUTS, as assessed by reduction in prostate volume, IPSS and prostate specific antigen (PSA). Long-term dutasteride therapy, however, resulted in increased blood glucose, HbA1c, TC and LDL levels, ALT and AST activities, AMS Score and reduced T levels and worsened ED as assessed by the IIEF-EF scores. No worsening of ED, glucose, HbA1c, ALT, AST, AMS were observed in men treated with tamsulosin. Most importantly, long-term dutasteride therapy resulted in reduction in total T levels, contributing to a state of hypogonadism. Conclusion Our findings suggest that long-term dutasteride therapy produces worsening of ED, reduced T levels and increased glucose, HbA1c and alters lipid profiles, suggesting induced imbalance in metabolic function. We strongly recommend that physicians discuss with their patients these potential serious adverse effects of long-term dutasteride therapy prior to instituting this form of treatment. PMID- 28632495 TI - Sad and lonely: body dissatisfaction among adolescent girls. AB - Purpose To further understand the association between body dissatisfaction and sadness/loneliness among adolescent girls, we examine how this association, as reported by pre-teen and adolescent girls, is mediated or moderated by the quality of peer and family relationships. Methods Our data are from the Health Behavior of School-Aged Children 2009-2010, a nationally representative survey of school-aged children in the US. We analyze a sample of 5658 girls in Grades 5 through 10. We utilize ordinary least squares (OLS) regression techniques and adjust for the complex sampling design. We explore how the link between body dissatisfaction and sadness/loneliness is mediated or moderated by family and peer relationships and also include controls for age, race, media exposure, and physical health. Results We find that body dissatisfaction is predictive of sadness/loneliness for girls at all grade levels and that the quality of peer and family relationships mediates 27%-38% of this association, particularly among early adolescent girls. Positive peer relationships also moderate or help mitigate the association between body dissatisfaction and sadness/loneliness among pre-teens. Conclusion Our findings underscore the association between body dissatisfaction and sadness/loneliness among early adolescent girls. In addition, our results highlight the importance of quality peer and family relationships in terms of how girls think about their bodies and respond emotionally to them. To evaluate feelings of sadness and loneliness among early adolescent girls, health care professionals need to consider not only body dissatisfaction but also the context of peer and family relationships. PMID- 28632496 TI - Clustering of chronic diseases risk factors among adolescents: a quasi experimental study in Sousse, Tunisia. AB - Background The objective of the study was to evaluate the effectiveness of a school-based physical activity and nutritional behavior intervention, on the reduction of clustering of chronic diseases risk factors among school children. Materials and methods A quasi-experimental school-based intervention was conducted with an intervention group and a control group in the region of Sousse in Tunisia. The intervention was implemented between 2010 and 2013, with data collected at pre and at post intervention. Studied risk factors were: smoking, sedentary behavior, low fruit and vegetable intake and obesity. Odds ratios (ORs) were used to calculate the clustering of two risk factors. We calculated ORs in each group before and after the intervention. Results In the intervention group, the prevalence of adolescents that had no risk factors has significantly increased (p = 0.004). In the control group the prevalence of adolescents carrying two or more risk factors has increased (p = 0.06). The results showed that all risk factors tended to cluster together in both groups. In the intervention group, the calculated OR for smoking and sedentary behavior decreased after assessment (OR = 5.93) as well as the OR for smoking and low fruit and vegetable intake (OR = 3.26). In the control group, all ORs increased, showing an enhancement of the association. Conclusion This study showed the effectiveness of a school-based intervention in reducing the clustering of chronic diseases risk factors. PMID- 28632498 TI - Can early ultrasonography explain the lower miscarriage rates in twin as compared to singleton pregnancies following assisted reproduction? PMID- 28632499 TI - Model-based sphere localization (MBSL) in x-ray projections. AB - The detection of spherical markers in x-ray projections is an important task in a variety of applications, e.g. geometric calibration and detector distortion correction. Therein, the projection of the sphere center on the detector is of particular interest as the used spherical beads are no ideal point-like objects. Only few methods have been proposed to estimate this respective position on the detector with sufficient accuracy and surrogate positions, e.g. the center of gravity, are used, impairing the results of subsequent algorithms. We propose to estimate the projection of the sphere center on the detector using a simulation based method matching an artificial projection to the actual measurement. The proposed algorithm intrinsically corrects for all polychromatic effects included in the measurement and absent in the simulation by a polynomial which is estimated simultaneously. Furthermore, neither the acquisition geometry nor any object properties besides the fact that the object is of spherical shape need to be known to find the center of the bead. It is shown by simulations that the algorithm estimates the center projection with an error of less than [Formula: see text] of the detector pixel size in case of realistic noise levels and that the method is robust to the sphere material, sphere size, and acquisition parameters. A comparison to three reference methods using simulations and measurements indicates that the proposed method is an order of magnitude more accurate compared to these algorithms. The proposed method is an accurate algorithm to estimate the center of spherical markers in CT projections in the presence of polychromatic effects and noise. PMID- 28632497 TI - DHA reduces oxidative stress following hypoxia-ischemia in newborn piglets: a study of lipid peroxidation products in urine and plasma. AB - BACKGROUND: Lipid peroxidation mediated by reactive oxygen species is a major contributor to oxidative stress. Docosahexaenoic acid (DHA) has anti-oxidant and neuroprotective properties. Our objective was to assess how oxidative stress measured by lipid peroxidation was modified by DHA in a newborn piglet model of hypoxia-ischemia (HI). METHODS: Fifty-five piglets were randomized to (i) hypoxia, (ii) DHA, (iii) hypothermia, (iv) hypothermia+DHA or (v) sham. All groups but sham were subjected to hypoxia by breathing 8% O2. DHA was administered 210 min after end of hypoxia and the piglets were euthanized 9.5 h after end of hypoxia. Urine and blood were harvested at these two time points and analyzed for F4-neuroprostanes, F2-isoprostanes, neurofuranes and isofuranes using UPLC-MS/MS. RESULTS: F4-neuroprostanes in urine were significantly reduced (P=0.006) in groups receiving DHA. Hypoxia (median, IQR 1652 nM, 610-4557) vs. DHA (440 nM, 367-738, P=0.016) and hypothermia (median, IQR 1338 nM, 744-3085) vs. hypothermia+DHA (356 nM, 264-1180, P=0.006). The isoprostane compound 8-iso PGF2alpha was significantly lower (P=0.011) in the DHA group compared to the hypoxia group. No significant differences were found between the groups in blood. CONCLUSION: DHA significantly reduces oxidative stress by measures of lipid peroxidation following HI in both normothermic and hypothermic piglets. PMID- 28632500 TI - Photon detection efficiency of laboratory-based x-ray phase contrast imaging techniques for mammography: a Monte Carlo study. AB - An important challenge in real-world biomedical applications of x-ray phase contrast imaging (XPCI) techniques is the efficient use of the photon flux generated by an incoherent and polychromatic x-ray source. This efficiency can directly influence dose and exposure time and ideally should not affect the superior contrast and sensitivity of XPCI. In this paper, we present a quantitative evaluation of the photon detection efficiency of two laboratory based XPCI methods, grating interferometry (GI) and coded-aperture (CA). We adopt a Monte Carlo approach to simulate existing prototypes of those systems, tailored for mammography applications. Our simulations were validated by means of a simple experiment performed on a CA XPCI system. Our results show that the fraction of detected photons in the standard energy range of mammography are about 1.4% and 10% for the GI and CA techniques, respectively. The simulations indicate that the design of the optical components plays an important role in the higher efficiency of CA compared to the GI method. It is shown that the use of lower absorbing materials as the substrates for GI gratings can improve its flux efficiency by up to four times. Along similar lines, we also show that an optimized and compact configuration of GI could lead to a 3.5 times higher fraction of detected counts compared to a standard and non-optimised GI implementation. PMID- 28632501 TI - Evaluation of automatic dose rate control for flat panel imaging using a spatial frequency domain figure of merit. AB - Current automatic dose rate controls (ADRCs) of dynamic x-ray imaging systems adjust their acquisition parameters in response to changes in patient thickness in order to achieve a constant signal level in the image receptor. This work compares a 3 parameter (3P) ADRC control to a more flexible 5-parameter (5P) method to meet this goal. A phantom composed of 15 composite poly(methyl) methacrylate (PMMA)/aluminium (Al) plates was imaged on a Siemens Artis Q dynamic system using standard 3P and 5P ADRC techniques. Phantom thickness covered a water equivalent thickness (WET) range of 2.5 cm to 37.5 cm. Acquisition parameter settings (tube potential, tube current, pulse length, copper filtration and focus size) and phantom entrance air kerma rate (EAKR) were recorded as the thickness changed. Signal difference to noise ratio (SDNR) was measured using a 0.3 mm iron insert centred in the PMMA stack, positioned at the system isocentre. SDNR was then multiplied by modulation transfer function (MTF) based correction factors for focal spot penumbral blurring and motion blurring, to give a spatial frequency dependent parameter, SDNR(u). These MTF correction factors were evaluated for an object motion of 25 mm s-1 and at a spatial frequency of 1.4 mm 1 in the object plane, typical for cardiac imaging. The figure of merit (FOM) was calculated as SDNR(u)2/EAKR for the two ADRC regimes. Using 5P versus 3P technique showed clear improvements over all thicknesses. Averaged over clinically relevant adult WET values (20 cm-37.5 cm), EAKR was reduced by 13% and 27% for fluoroscopy and acquisition modes, respectively, while the SDNR(u) based FOM increased by 16% and 34% for fluoroscopy and acquisition. In conclusion, the generalized FOM, taking into account the influence of focus size and object motion, showed benefit in terms of image quality and patient dose for the 5 parameter control over 3-parameter method for the ADRC programming of dynamic x ray imaging systems. PMID- 28632503 TI - The catastrophic antiphospholipid syndrome in children. AB - PURPOSE OF REVIEW: To review the difficult syndrome of catastrophic antiphospholipid syndrome, emphasizing new developments in the diagnosis, pathogenesis and treatment. RECENT FINDINGS: Few recent publications directly address pediatric catastrophic antiphospholipid syndrome (CAPS). Most articles are case reports or are data from adult and pediatric registries. The major factors contributing to most pediatric catastrophic antiphospholipid syndrome include infection and the presence of antiphospholipid antibodies, but complement activation also is important in creating diffuse thrombosis in the microcirculation. Treatment of the acute emergency requires anticoagulation, suppression of the hyperinflammatory state and elimination of the triggering infection. Inhibition of complement activation appears to improve outcome in limited studies, and suppression of antiphospholipid antibody formation may be important in long-term management. SUMMARY: CAPS, an antibody-mediated diffuse thrombotic disease of microvasculature, is rare in childhood but has high mortality (33-50%). It requires prompt recognition and aggressive multimodality treatment, including anticoagulation, anti-inflammatory therapy and elimination of inciting infection and pathogenic autoantibodies. PMID- 28632502 TI - Targeting activated protein C to treat hemophilia. AB - PURPOSE OF REVIEW: Hemophilia is a debilitating disease, marked by frequent, painful bleeding events, joint deterioration and early death. All current treatments consist of i.v. infusions of replacement factor or other procoagulant factors, and are incompletely effective, due in part to the short half-lives of the proteins. An alternative approach is to rebalance hemostasis by inhibiting natural anticoagulant mechanisms. In this article, we explain why activated protein C (APC) is an appropriate and safe target for the treatment of hemophilia. RECENT FINDINGS: A serpin (serine protease inhibitor) was engineered to specifically inhibit APC and was found to rescue hemostasis in a hemophilia mouse model, even after a severe tail clip injury. However, APC is also anti inflammatory and has cytoprotective activities, raising safety concerns over the use of an APC inhibitor to treat hemophilia. We summarize the molecular basis of the anticoagulant and signaling activities of APC to assess the potential impact of targeting APC. SUMMARY: We conclude that the signaling and anticoagulant functions of APC are in spatially and kinetically distinct compartments, and that it is possible to specifically inhibit the anticoagulant activity of APC. Targeting APC with a serpin is remarkably effective and may be safe for long-term prophylactic use in the treatment of hemophilia. PMID- 28632505 TI - Obesity and prostate cancer. AB - PURPOSE OF REVIEW: To investigate the association between obesity and prostate cancer (PCa). RECENT FINDINGS: Obesity has been proposed to be involved in the pathogenesis of PCa through different biological mechanisms that include deregulation of the insulin axis, sex hormone secretion, adipokines signaling, and oxidative stress. Hypertrophic peritumoral adipocytes may also facilitate the local spread of PCa through the chemo-attraction of tumor cells. Clinical studies demonstrate that obesity might have clinical implications also in disease detection and management. Obese men have been shown to be less likely to be diagnosed with early-stage disease. Moreover, they are at increased risk of experiencing upgrading and upstaging when managed with active surveillance. However, the association between obesity and the risk of PCa recurrence and mortality after radical treatment is still debated. SUMMARY: Obesity may facilitate the development and progression of PCa trough different biologic mechanisms that may pose obese men at higher risk of advanced and high-grade disease. However, the association between obesity and long-term oncologic outcome after radical treatments appears unclear. PMID- 28632504 TI - What is New in Gastrointestinal Stromal Tumor? AB - The classification "gastrointestinal stromal tumor" (GIST) became commonplace in the 1990s and since that time various advances have characterized the GIST lineage of origin, tyrosine kinase mutations, and mechanisms of response and resistance to targeted therapies. In addition to tyrosine kinase mutations and their constitutive activation of downstream signaling pathways, GISTs acquire a sequence of chromosomal aberrations. These include deletions of chromosomes 14q, 22q, 1p, and 15q, which harbor putative tumor suppressor genes required for stepwise progression from microscopic, preclinical forms of GIST (microGIST) to clinically relevant tumors with malignant potential. Recent advances extend our understanding of GIST biology beyond that of the oncogenic KIT/PDGFRA tyrosine kinases and beyond mechanisms of KIT/PDGFRA-inhibitor treatment response and resistance. These advances have characterized ETV1 as an essential interstitial cell of Cajal-GIST transcription factor in oncogenic KIT signaling pathways, and have characterized the biologically distinct subgroup of succinate dehydrogenase deficient GIST, which are particularly common in young adults. Also, recent discoveries of MAX and dystrophin genomic inactivation have expanded our understanding of GIST development and progression, showing that MAX inactivation is an early event fostering cell cycle activity, whereas dystrophin inactivation promotes invasion and metastasis. PMID- 28632506 TI - Adenotonsillectomy for the Management of Pulmonary Hypertension in a Patient With Complex Congenital Heart Disease: A Case Report. AB - Pulmonary hypertension is a feared complication in congenital heart disease patients. Patients with pulmonary hypertension are at risk for major perioperative cardiopulmonary complications when undergoing any surgical procedure, especially airway and laparoscopic procedures. We present the anesthetic management for a 2-year old with Down syndrome and complex cyanotic congenital heart disease undergoing tonsillectomy and adenoidectomy for severe obstructive sleep apnea. PMID- 28632507 TI - Tibialis Posterior Tenosynovitis: A Unique Musculoskeletal Manifestation of Gout. AB - Extra-articular manifestations of gout can present in several ways, including tenosynovitis. We present a rare case of acute tibialis posterior gouty tenosynovitis. An 82-year-old man with a history of well-controlled gout presented with acute onset of left ankle pain, occurring without inciting event. The medial ankle was slightly erythematous with moderate dorsal-medial swelling and mild dorsal-lateral swelling, with severe tenderness to palpation over the medial retro-malleolar region. Range of motion and manual muscle testing were pain limited throughout. Ultrasound examination revealed a left posterior tibialis tendon sheath tenosynovitis with effusion and overlying soft tissue edema. Tendon sheath aspirate revealed sodium urate crystals and a white blood cell count of 6400/MUL. Tendon sheath injection with a mixture of 1% lidocaine and dexamethasone 4 mg resulted in symptom resolution. Repeat ultrasound examination demonstrated no evidence of tibialis posterior tendon sheath effusion. This case is unique not only because acute gouty posterior tibialis tenosynovitis is very rare, particularly in a normouricemic individual, but also because the sonographic evidence of gouty infiltration into the posterior tibialis tendon and overlying subcutaneous tissue considerably aided in arriving at the correct diagnosis in a timely manner. PMID- 28632508 TI - Combined Dextroamphetamine and Transcranial Direct Current Stimulation in Poststroke Aphasia. AB - There is a growing need for various effective adjunctive treatment options for speech recovery after stroke. A pharmacological agent combined with noninvasive brain stimulation has not been previously reported for poststroke aphasia recovery. In this "proof of concept" study, we aimed to test the safety of a combined intervention consisting of dextroamphetamine, transcranial direct current stimulation, and speech and language therapy in subjects with nonfluent aphasia. Ten subjects with chronic nonfluent aphasia underwent two experiments where they received dextroamphetamine or placebo along with transcranial direct current stimulation and speech and language therapy on two separate days. The Western Aphasia Battery-Revised was used to monitor changes in speech performance. No serious adverse events were observed. There was no significant increase in blood pressure with amphetamine or deterioration in speech and language performance. Western Aphasia Battery-Revised aphasia quotient and language quotient showed a statistically significant increase in the active experiment. Comparison of proportional changes of aphasia quotient and language quotient in active experiment with those in placebo experiment showed significant difference. We showed that the triple combination therapy is safe and implementable and seems to induce positive changes in speech and language performance in the patients with chronic nonfluent aphasia due to stroke. PMID- 28632509 TI - Evaluation and Management of Axillary Artery Injury: The Orthopaedic and Vascular Surgeon's Perspective. PMID- 28632510 TI - Itraq-Based Quantitative Proteomic Analysis of Lungs in Murine Polymicrobial Sepsis with Hydrogen Gas Treatment. AB - Sepsis-associated acute lung injury (ALI), which carries a high morbidity and mortality in patients, has no effective therapeutic strategies to date. Our group has already reported that hydrogen gas (H2) exerts a protective effect against sepsis in mice. However, the molecular mechanisms underlying H2 treatment are not fully understood. This study investigated the effects of H2 on lung injuries in septic mice through the isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic analysis. Male ICR mice used in this study were subjected to cecal ligation and puncture (CLP) or sham operation. And 2% H2 was inhaled for 1 h beginning at 1 and 6 h after sham or CLP operation. The iTRAQ based liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was preformed to investigate lung proteomics. Sepsis-challenged animals had decreased survival rate, as well as had increased bacterial burden in blood, peritoneal lavage, and lung sample, which were significantly ameliorated by H2 treatment. Moreover, a total of 4,472 proteins were quantified, and 192 differentially expressed proteins were related to the protective mechanism of H2 against sepsis. Functional enrichment analysis showed that H2-related differential proteins could be related to muscle contraction, oxygen transport, protein synthesis, collagen barrier membranes, cell adhesion, and coagulation function. These proteins were significantly enriched in four signaling pathways, and two of which are associated with coagulation. In addition, H2 alleviates ALI in septic mice through downregulating the expression of Sema 7A, OTULIN, and MAP3K1 as well as upregulating the expression of Transferrin. Thus, our findings provide an insight into the mechanism of H2 treatment in sepsis by proteomic approach, which may be helpful to the clinic application of H2 in patients with sepsis. PMID- 28632511 TI - Zika virus: a cause of concern in transplantation? AB - PURPOSE OF REVIEW: Worldwide, the number of countries reporting Zika virus (ZKV) infection continues to increase. Although 80% of cases are asymptomatic, ZKV has been identified as a neurotropic virus associated with congenital microcephaly, Guillain-Barre' syndrome, and meningoencephalitis. Until recently, infection in transplant recipients has not been identified. This study will review the existing literature on ZKV infection, laboratory testing, and management in transplant recipients. RECENT FINDINGS: Donor-derived transfusion of contaminated blood products and naturally occurring ZKV infections have been recently reported in solid organ and stem cell transplant recipients, ranging from asymptomatic infections to meningoencephalitis. Interpretation of diagnostic testing of ZKV is evolving, with prolonged viral shedding identified in blood, semen, and urine of unclear significance. Serologic testing may be associated with cross-reactivity with other flaviviridae, requiring plaque reduction neutralization testing for confirmation. Thus far, donor screening guidelines for transplantation have not been established. SUMMARY: The study reviews the limited existing literature in transplant recipients infected with ZKV, available laboratory testing and management. Ultimately, guidelines are needed for donor screening from high-risk areas, interpretation of studies and management of infected patients to ensure safe transplantation. PMID- 28632512 TI - Why current drug adherence programs fail: addressing psychological risk factors of nonadherence. AB - PURPOSE OF REVIEW: To provide an overview of a selection of largely neglected psychological risk factors for nonadherence, and to offer new approaches to improve medication adherence. RECENT FINDINGS: Current adherence research and intervention programs focus on a few risk factors for nonadherence, such as complexity of the drug regimen. In addition, other important risk factors of nonadherence are neglected or insufficiently addressed. There is good evidence for the significant role of the quality of the patient-healthcare provider relationship. Other risk factors like the individual history of nonadherence, the lack of acceptance of having a treatable disorder, fear of side-effects, comorbid depression, and cognitive impairment have been broadly neglected in adherence programs, although they offer a powerful key to improve adherence-oriented interventions. SUMMARY: Current research on determinants of nonadherence has focused on a few risk factors, while neglecting crucial psychological predictors of nonadherence. The personalized consideration of a multiplicity of risk factors offers a new basis for the development and evaluation of interventions to better promote adherence. PMID- 28632513 TI - Prevalence and Predictors of Posttraumatic Stress and Depression Symptoms Among Syrian Refugees in a Refugee Camp. AB - Turkey is hosting the majority of Syrian refugees. The current study investigates the prevalence of probable posttraumatic stress disorder (PTSD) and depression among adult Syrians residing in a camp (N = 781) and potential predictors. The Impact of Event Scale-Revised was used to measure PTSD and the Beck Depression Inventory depression. Probable PTSD prevalence was 83.4%, with predictors being female sex (odds ratio [OR], 4.1), previous mental health problems (OR, 4.5), life threat (OR, 3.0), and injury of a loved one (OR, 1.8). Probable depression prevalence was 37.4%, with predictors being female sex (OR, 5.1), previous mental health problems (OR, 2.9), having a loved one who was tortured (OR, 1.7), and not being satisfied at the camp (OR, 1.7). The current study reveals high rates of probable PTSD and depression among Syrian refugees and highlights vulnerabilities such as great risk for women of having psychopathology. PMID- 28632514 TI - Childhood Precursors of the Narcissistic Personality. AB - This research identifies the childhood personality characteristics that predict the presence of narcissism in adulthood. Using data from the longitudinal study of Block and Block (The California Child Q-set. Palo Alto, CA: Consulting Psychologists Press, 1980), childhood personality characteristics were assessed at age 11 (N = 100) using the California Child Q-set. A number of these were shown to differentially predict the presence of grandiose or vulnerable narcissism at age 23. Factor analyses of the Child Q-set items showed that the presence of Grandiose Narcissism was positively related to childhood factors representing social presence and negatively related to planfulness. In contrast, vulnerable narcissism was positively related to childhood impulsivity and negatively related to stable self-esteem. Both types of narcissism were positively related to childhood factors representing need for control. PMID- 28632516 TI - Is Robotic Surgery the Future for Abdominal Wall Hernia Repair? Not So Fast. PMID- 28632515 TI - P4 Stump Approach for Intraoperative Portal Vein Stenting in Pediatric Living Donor Liver Transplantation: An Innovative Technique for a Challenging Problem. AB - OBJECTIVE: The aim of this study was to evaluate the utility of the P4 stump stenting approach for treating portal vein (PV) complications in pediatric living donor liver transplantation (LDLT). BACKGROUND: PV complications cause significant morbidity and mortality in pediatric LDLT. Biliary atresia in the backdrop of pathological PV hypoplasia and sclerosis heightens the complexity of PV reconstruction. The authors developed a novel approach for intraoperative PV stenting via the graft segment 4 PV stump (P4 stump) to address this challenge. METHODS: From April 2009 to December 2016, 15 pediatric LDLT recipients (mean age 10.3 +/- 5.0 months, mean graft-recipient weight ratio 3.70%) underwent intraoperative stenting for suboptimal PV flow (<10 cm/s) or PV occlusion after collateral ligation and graft repositioning. Under portography, metallic stents were deployed via the reopened P4 stump of the left lateral segment grafts. RESULTS: PV diameter and peak flow increased significantly after stent placement (2.93 +/- 1.74 to 7.01 +/- 0.91 mm and 2.0 +/- 9.2 to 17.3 +/- 3.5 cm/s, respectively, P = 0.001 for both), and there were no technical failures. Stents in all surviving patients remained patent up to 8 years (mean 27.7 months), with no vascular or biliary complications. After implementation of the P4 approach, the incidence of variceal bleeding as a late complication decreased from 7% to zero. CONCLUSION: The P4 stump stenting approach affords procedural convenience, ease of manipulation, and consistent results with the potential for excellent long-term patency in children despite continued growth. This technique obviates the need for more demanding post-transplant stenting, and may become a substitute for complicated revision surgery, portosystemic shunting, or retransplantation. PMID- 28632517 TI - The Changing Face of Surgery Today: It is Not a Women's Issue, It's a Work Force Issue. PMID- 28632518 TI - #VisualAbstract: A Revolution in Communicating Science? PMID- 28632519 TI - Age is the Most Significantly Associated Risk Factor With the Development of Delirium in Patients Hospitalized for More Than Five Days in Surgical Wards: Retrospective Cohort Study. AB - OBJECTIVE: The primary purpose of this study was to assess risk factors for delirium in patients staying in a surgical ward for more than 5 days. The secondary purpose was to assess outcomes in patients with delirium. BACKGROUND: Delirium is a syndrome characterized by acute fluctuations in mental status. Patients with delirium are at increased risk of adverse inpatient events, higher mortality and morbidity rates, prolonged hospital stays, and increased health care costs. METHODS: Participants in this study were 2168 patients who had been admitted to the surgical ward of St. Luke's International Hospital for 5 days or more between January 2011 and December 2014. Data on these patients were collected retrospectively from hospital medical records. Firstly, univariate and multivariate analyses were conducted to identify risk factors for delirium. Secondly, morbidity and mortality associated with delirium were analyzed. RESULTS: Delirium occurred in 205 of 2168 patients (9.5%). Age, physical restraint, past history of a cerebrovascular disorder, malignancy, intensive care unit stay, pain, and high blood urea nitrogen value were significant risk factors for delirium in the multivariate analysis. Among these, age was the strongest factor, with an odds ratio for delirium of 12.953 in patients 75 years of age or older. The length of hospital stays and the mortality rates were higher in patients with delirium. CONCLUSIONS: Results showed that age, and also physical restraint, past history of cerebrovascular disorder, malignancy, intensive care unit stay, pain, and high serum blood urea nitrogen were important factors associated with delirium in patients hospitalized for more than 5 days in a surgical ward. PMID- 28632520 TI - Are Sex-Related Category-Specific Differences in Semantic Tasks Innate or Influenced by Social Roles? A Viewpoint. AB - In semantic tasks, sex-related categorical differences, in the form of better processing of fruits and vegetables by women and of artifacts (human-made objects) and animals by men, have been reported both in healthy participants and in brain-damaged patients. Researchers' interpretation of these sex-related categorical asymmetries has, however, been controversial, being connected with the more general (innatist versus experience-dependent) interpretations that had been given of the mechanisms subsuming the categorical organization of the brain. I begin this review with a brief reminder of the debate between supporters of the innatist and the experience-related accounts of categorical brain organization. Then I summarize results that have documented a preference by women for fruits and vegetables and a preference by men for artifacts and animals, and I discuss the innatist and social role-related interpretations that have been given of these results. I conclude that sex-related categorical effects disappear in generations in which the traditional social roles have almost completely disappeared, and these differences are not seen in young individuals raised in societies that emphasize sex equality. PMID- 28632521 TI - Verbal and Figural Fluency in Temporal Lobe Epilepsy: Does Hippocampal Sclerosis Affect Performance? AB - BACKGROUND AND OBJECTIVES: Clinicians commonly use verbal and nonverbal measures to test fluency in patients with epilepsy, either during routine cognitive assessment or as part of pre- and postsurgical evaluation. We hypothesized that patients with mesial temporal lobe epilepsy (TLE) with hippocampal sclerosis would perform worse than patients with lateral TLE in both verbal and design fluency. METHODS: We assessed semantic, phonemic, and nonverbal fluency in 49 patients with TLE: 31 with lateral TLE and 18 with mesial TLE plus hippocampal sclerosis. We also gave non-fluency cognitive measures: psychomotor speed, attentional set shifting, selective attention, abstract reasoning, verbal and visual episodic memory, and incidental memory. RESULTS: Patients with mesial TLE performed significantly worse on figural fluency than patients with lateral TLE. Even though group differences on verbal fluency measures were not significant, the patients with mesial TLE had a pattern of poorer performance. The patients with mesial TLE scored significantly worse on measures of selective attention, verbal episodic memory, and incidental memory. CONCLUSIONS: Our study underlines differences in cognitive function between patients with mesial and lateral TLE, particularly in figural fluency. Although we cannot directly assess the role of the hippocampus in cognitive aspects of creative and divergent thinking related to figural fluency, the cognitive discrepancies between these two TLE groups could be ascribed to the mesial TLE hippocampal pathology shown in our study and addressed in the literature on hippocampal involvement in divergent thinking. Our findings could benefit cognitive rehabilitation programs tailored to the needs of patients with TLE. PMID- 28632522 TI - Relationship of Reaction Time to Perception of a Stimulus and Volitionally Delayed Response. AB - BACKGROUND AND OBJECTIVE: Initiation of response in a simple reaction time (RT) task may precede conscious perception of the stimulus. Since volitionally delayed responses may require conscious perception of the stimulus before response initiation, it has been hypothesized that volitionally delayed responses will markedly delay RT. METHODS: We conducted two experiments with separate groups of healthy volunteers (n=16; n=13) who performed computerized simple and choice RT tasks. In the standard condition, we instructed the participants to respond to a visual stimulus by pushing a button as quickly as possible. In the second condition, we instructed the participants to respond after a slight volitional delay. The second experiment had an additional volitional delay condition in which we asked participants to delay their responses by an estimated 50% above their usual standard response. RESULTS: We found marked delays and increased variability when participants volitionally delayed their responses, averaging 322 ms for standard and 861 ms for delayed simple RTs (267% increase), and 650 ms for standard and 1018 ms for delayed choice RTs (157% increase). Effects did not differ across age, sex, or handedness. However, a minority of participants did not meaningfully delay their RT during the volitional delay conditions. CONCLUSIONS: On average, participants had marked delays when they tried to delay their responses slightly, but a subset of participants exhibited essentially no delay despite trying to delay. We suggest some potential mechanisms that future investigations might delineate. PMID- 28632524 TI - Callosal Motor Impersistence: A Novel Disconnection Syndrome. AB - Motor impersistence, an inability to sustain a certain position or movement, is a motor-intentional disorder, caused more often by right than left hemisphere lesions. Since the right hemisphere is dominant for mediating motor persistence, callosal lesions that disconnect the left hemisphere from the right may induce impersistence of the right upper and lower limbs. After an undiagnosed left callosal infarction, a 65-year-old right-handed man suddenly developed a transient loss of volitional movement of his left leg. Five days after onset, he was admitted to our hospital with signs of callosal disconnection: left-hand agraphia and apraxia, left-hand tactile anomia, failures on cross-replication of hand postures, and intermanual conflict. He had neither weakness nor ataxia of his upper or lower extremities, but when asked to keep his arms or legs extended he could not maintain his right arm and leg in the extended position, suggesting motor impersistence in his dominant limbs. When we examined him 3 months after onset, the motor impersistence had disappeared. In conclusion, motor impersistence of dominant limbs can result from isolated callosal injury that disconnects the left hemisphere from the right hemisphere's frontal-subcortical networks. PMID- 28632523 TI - Frontotemporal Dementia Presenting as Gambling Disorder: When a Psychiatric Condition Is the Clue to a Neurodegenerative Disease. AB - Behavioral variant frontotemporal dementia, the most common form of frontotemporal dementia, is characterized by executive dysfunction and changes in personality and behavior, sometimes with associated psychiatric disorders. We report a man who suddenly developed a gambling disorder when he was 55 years old. A year later he developed personality changes of agitation, euphoria, and disinhibition, along with binge eating and dysthymia. He did not improve on paroxetine 40 mg/day. Two years after the onset of his symptoms, he came to our clinic for evaluation. Neuropsychological testing showed deficits in cognitive control, planning, and attention. Brain magnetic resonance imaging and 18F fluorodeoxyglucose positron emission tomography scans showed predominant frontal and temporal alterations, worse in the right hemisphere than the left. Cerebrospinal fluid analysis was not compatible with Alzheimer disease. On the basis of current criteria, we gave him a diagnosis of probable behavioral variant frontotemporal dementia presenting with a psychiatric symptom. Our findings in this unusual patient confirm the importance of close clinical monitoring in people who have a psychiatric disorder with atypical features, because the condition may mask an underlying neurodegenerative disease. PMID- 28632525 TI - Clozapine Safety and Efficacy for Interictal Psychotic Disorder in Pharmacoresistant Epilepsy. AB - Since the middle of the 19th century, both neurologists and psychiatrists have linked psychosis and epilepsy. Clozapine, the most effective antipsychotic drug, alters electroencephalographic activity and carries a significant risk of causing seizures. Unfortunately, this risk limits the drug's potential use in treating pharmacoresistant psychosis in patients with epilepsy. We present a unique case in which we used clozapine successfully as a last resort treatment for chronic interictal psychosis in a 43-year-old woman with severe pharmacoresistant epilepsy and recurrent status epilepticus. Her psychotic symptoms improved markedly without an increase in the frequency of seizures despite gradual titration of the clozapine dose up to 300 mg daily. Her response demonstrates that, properly monitored, clozapine can be an effective treatment for psychosis even in patients with daily seizures. PMID- 28632527 TI - Assessment of Postoperative Analgesic Drug Efficacy: Method of Data Analysis Is Critical. AB - BACKGROUND: Pain intensity ratings and opioid consumption (OC) are ubiquitous indicators of pain in postoperative trials of the efficacy of interventional procedures. Unfortunately, consensus on the appropriate statistical handling of these outcomes has not been reached. The aim of this article was, therefore, to reexamine original data obtained from a postoperative analgesic drug trial, applying a collection of standard statistical methods in analgesic outcome assessments. Furthermore, a modified integrated assessment method of these outcomes was evaluated. METHODS: Data from a randomized, double-blind, placebo controlled study investigating the analgesic efficacy of a regional anesthetic block following a major elective surgical procedure were analyzed. The original data included measurements of pain intensity (visual analog scale [VAS]) at rest and during coughing (VAS0/2/4/6/12/18/24 h) and OC0-6/0-24 h administered by patient-controlled analgesia. The statistical analyses included comparisons of discrete pain intensity scores (VAS0/2/4/6/12/18/24 h), summary measures of pain intensity ratings (area under the curve [AUC]-VAS0-6/0-24 h; mean VAS0-6/0-24 h), and OC0-6/0-24 h. Finally, the analyses also included an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC0-6/0-24 h). Also, estimation of effect size, generalized odds ratio of the individual analgesic outcome variables was performed. RESULTS: Sixty-one patients were included in the final data analysis. Discrete pain intensity ratings differed significantly between the treatment groups at specific postoperative time points, but appropriate correction for multiple comparisons eliminated some of these differences. AUC-VAS0-6 h differed significantly at rest and during coughing, while no difference was found for AUC-VAS0-24 h. In contrast, mean VAS0-6 h and VAS0-24 h differed significantly between treatment groups at rest and during coughing. OC0-6/0-24 h differed significantly between the treatment groups. Finally, also PIOC0-6/0-24 h differed significantly at rest and during coughing. CONCLUSIONS: Our analyses demonstrate that the applied statistical method may alter the statistical significance and estimates of effect size of analgesic outcome variables in postoperative pain trials. Our findings underline the importance of defining valid statistical methods for future analgesic drug trials. We propose an integrated assessment of longitudinally measured pain intensity and opioid consumption (PIOC). The method combines two interdependent analgesic outcomes, lowers the risk of mass significance, and provides more accurate representation of the dynamic nature of postoperative pain and analgesic drug efficacy. PMID- 28632528 TI - False Low ETCO2 Measurements From Carbon Dioxide Sampling Nasal Cannula and How to Correct the Situation. PMID- 28632526 TI - Persistent hypothyroid symptoms in a patient with a normal thyroid stimulating hormone level. AB - PURPOSE OF REVIEW: A subset of patients being treated for hypothyroidism do not feel well while taking levothyroxine (LT4) replacement therapy, despite having a normal serum thyroid stimulating hormone level. Pursuing a relative triiodothyronine deficiency as a potential explanation for patient dissatisfaction, has led to trials of combination therapy with liothyronine (LT3), with largely negative outcomes. This review attempts to reconcile these diverse findings, consider potential explanations, and identify areas for future research. RECENT FINDINGS: Patients being treated with LT4 often have lower triiodothyronine levels than patients with endogenous thyroid function. Linking patient dissatisfaction with low triiodothyronine levels has fueled multiple combination therapy trials that have generally not shown improvement in patient quality of life, mood, or cognitive performance. Some trials, however, suggest patient preference for combination therapy. There continues, moreover, to be anecdotal evidence that patients have fewer unresolved symptoms while taking combination therapy. SUMMARY: The 14 trials completed to date have suffered from employing doses of LT3 that do not result in steady triiodothyronine levels, and having insufficient power to analyze results based on baseline dissatisfaction with therapy and patient genotype. Future trials that are able to incorporate such features may provide insight into what thyroid hormone preparations will most improve patient satisfaction with therapy. PMID- 28632530 TI - In Response. PMID- 28632529 TI - Respiratory System Mechanics During Low Versus High Positive End-Expiratory Pressure in Open Abdominal Surgery: A Substudy of PROVHILO Randomized Controlled Trial. AB - BACKGROUND: In the 2014 PROtective Ventilation using HIgh versus LOw positive end expiratory pressure (PROVHILO) trial, intraoperative low tidal volume ventilation with high positive end-expiratory pressure (PEEP = 12 cm H2O) and lung recruitment maneuvers did not decrease postoperative pulmonary complications when compared to low PEEP (0-2 cm H2O) approach without recruitment breaths. However, effects of intraoperative PEEP on lung compliance remain poorly understood. We hypothesized that higher PEEP leads to a dominance of intratidal overdistension, whereas lower PEEP results in intratidal recruitment/derecruitment (R/D). To test our hypothesis, we used the volume-dependent elastance index %E2, a respiratory parameter that allows for noninvasive and radiation-free assessment of dominant overdistension and intratidal R/D. We compared the incidence of intratidal R/D, linear expansion, and overdistension by means of %E2 in a subset of the PROVHILO cohort. METHODS: In 36 patients from 2 participating centers of the PROVHILO trial, we calculated respiratory system elastance (E), resistance (R), and %E2, a surrogate parameter for intratidal overdistension (%E2 > 30%) and R/D (%E2 < 0%). To test the main hypothesis, we compared the incidence of intratidal overdistension (primary end point) and R/D in higher and lower PEEP groups, as measured by %E2. RESULTS: E was increased in the lower compared to higher PEEP group (18.6 [16...22] vs 13.4 [11.0...17.0] cm H2O.L; P < .01). %E2 was reduced in the lower PEEP group compared to higher PEEP (-15.4 [-28.0...6.5] vs 6.2 [ 0.8...14.0] %; P < .05). Intratidal R/D was increased in the lower PEEP group (61% vs 22%; P = .037). The incidence of intratidal overdistension did not differ significantly between groups (6%). CONCLUSIONS: During mechanical ventilation with protective tidal volumes in patients undergoing open abdominal surgery, lung recruitment followed by PEEP of 12 cm H2O decreased the incidence of intratidal R/D and did not worsen overdistension, when compared to PEEP <=2 cm H2O. PMID- 28632531 TI - A Descriptive Survey of Anesthesiology Residency Simulation Programs: How Are Programs Preparing Residents for the New American Board of Anesthesiology APPLIED Certification Examination? AB - BACKGROUND: Anesthesiology residency programs may need new simulation-based programs to prepare residents for the new Objective Structured Clinical Examination (OSCE) component of the American Board of Anesthesiology (ABA) Primary Certification process. The design of such programs may require significant resources, including faculty time, expertise, and funding, as are currently needed for structured oral examination (SOE) preparation. This survey analyzed the current state of US-based anesthesiology residency programs regarding simulation-based educational programming for SOE and OSCE preparation. METHODS: An online survey was distributed to every anesthesiology residency program director in the United States. The survey included 15 to 46 questions, depending on each respondent's answers. The survey queried current practices and future plans regarding resident preparation specifically for the ABA APPLIED examination, with emphasis on the OSCE. Descriptive statistics were summarized. chi and Fisher exact tests were used to test the differences in proportions across groups. Spearman rank correlation was used to examine the association between ordinal variables. RESULTS: The responding 66 programs (49%) were a representative sample of all anesthesiology residencies (N = 136) in terms of geographical location (chi P = .58). There was a low response rate from small programs that have 12 or fewer clinical anesthesia residents. Ninety-one percent (95% confidence interval [CI], 84%-95%) of responders agreed that it is the responsibility of the program to specifically prepare residents for primary certification, and most agreed that it is important to practice SOEs (94%; 95% CI, 88%-97%) and OSCEs (89%; 95% CI, 83%-94%). While 100% of respondents reported providing mock SOEs, only 31% (95% CI, 24%-40%) of respondents provided mock OSCE experiences. Of those without an OSCE program, 75% (95% CI, 64%-83%) reported plans to start one. The most common reasons for not having an OSCE program already in place, and the perceived challenges for implementing an OSCE program, were the same: lack of time (faculty and residents), expertise in OSCE development and assessment, and funding. CONCLUSIONS: The results provide data from residency programs for benchmarking their simulation curriculum and ABA APPLIED Examination preparation offerings. Despite agreement that residency programs should prepare residents for the ABA APPLIED Examination, many programs have yet to implement an OSCE preparation program, in part due to lack of financial resources, faculty expertise, and time. Additionally, in contrast to the SOE, the OSCE is a new format for ABA primary certification. As a result, the lack of consensus concerning preparation needs could be related to the amount information that is available regarding the examination content and assessment process. PMID- 28632532 TI - Postpartum Tubal Sterilization: Making the Case for Urgency. AB - The parturient who requests postpartum sterilization has given consideration to and has made decisions regarding this aspect of her medical care long before her delivery. She arrives at parturition expecting the postpartum procedure to be performed as intended. The American Congress of Obstetricians and Gynecologists has reaffirmed its opinion that postpartum sterilization is an urgent procedure, owing to the safety and superior effectiveness of tubal sterilization via minilaparotomy in the immediate postpartum period, and the adverse consequences for mothers, babies, and society when the procedure is not actualized as desired and intended. In contrast, recent practice guidelines for obstetric anesthesia address anesthetic procedural aspects and short-term safety but overlook the long term complications and considerations associated with failure to perform postpartum sterilization as planned. In practice, procedure completion rates are strikingly low, reportedly ranging from 31% to 52%. Reasons for failure to complete abound and include inadequate resources or inavailability of necessary personnel; obstetrician reluctance due to concerns for patient regret in younger women or medical comorbidities; barriers related to provision of obstetric care in a religiously affiliated hospital, or incomplete, improperly completed, or unavailable original federal consent forms among Medicaid-insured women. The federal requirement to wait 30 days after signing informed consent, and to retain the original signed document to be physically verified at time of the procedure, serves as a significant source of health care disparity for Medicaid-dependent mothers. This article reviews these larger issues of maternal health and comprehensive maternal care to broaden the anesthesiologist's appreciation of major benefits and potential risks of postpartum sterilization, including long term effects, to promote an evidence-based, informed, and proactive role in delivering equitable, safe, and optimal care for these patients. PMID- 28632533 TI - Investigation of Two Prototypes of Novel Noncontact Technologies for Automated Real-Time Capture of Incremental Drug Administration Data From Syringes. AB - BACKGROUND: An ideal electronic anesthesia recording system would be capable of not only recording physiological data but also injectable drug doses given, including those given incrementally from one syringe, without recourse to manual data entry. We compared 2 prototype devices which wirelessly recognized individual syringes and measured changes in their plunger positions via 2 different optical noncontact means, allowing calculation of incremental drug doses given. METHODS: Both devices incorporated a radio-frequency identification reader, which wirelessly read a unique code from a radio-frequency identification tag within syringe drug labels. A custom-designed cradle oriented any inserted 1 mL to 20-mL syringe in a repeatable position. The "laser" device had a moving laser beam broken by the end of the syringe plunger. The infrared (IR) device measured time of travel of IR light from a sender to a syringe plunger and back to a receiver. Both devices could therefore determine the drug and volume administered since the previous occasion when any syringe had been used. For each syringe size of 1, 2, 5, 10, and 20 mL, 121 plunger-length measurements were made over their full range, with each machine against a reference method of water filling and weighing using a randomized de Bruijn sequence. RESULTS: For every syringe size, the laser device showed greater accuracy and precision, lower bias, and narrower limits of agreement (95% confidence intervals = bias +/- 1.96 SD) than the IR device when compared to the reference method. For all syringe sizes, the range of bias was -0.05 to 0.32 mL for the laser and -2.42 to 1.38 mL for the IR. Lin concordance correlation coefficient values for the IR versus reference methods ranged from 0.6259 to 0.9255, with the lowest coefficients seen in syringes with the shortest distance of plunger travel (2 and 5 mL), while in laser versus reference comparisons, these coefficients were similar (0.9641 0.9981) over all syringe lengths. CONCLUSIONS: Both devices measured syringe volume changes, demonstrating potential for measuring incremental drug doses, recording these, and also the time of each measurement. The IR device had no moving parts, which would be advantageous in a clinical situation. However, the current embodiment was not deemed accurate enough for clinical use, potentially remediable through improvements in hardware and software design. The laser device showed high accuracy and precision over all syringe sizes and contained volumes, and was considered potentially accurate enough for clinical use with suitable development. PMID- 28632534 TI - Administration of Tetrahydrobiopterin (BH4) Protects the Renal Microcirculation From Ischemia and Reperfusion Injury. AB - BACKGROUND: Abdominal aortic aneurysm surgery with suprarenal cross-clamping is often associated with renal injury. Although the mechanism underlying such injury is unclear, tissue ischemia and reperfusion, which induces endothelial dysfunction and decreases the availability of tetrahydrobiopterin (BH4), may play a role. We evaluated whether BH4 administration prevents renal ischemia/reperfusion injury in an animal model of aortic cross-clamping. METHODS: Nineteen anesthetized, mechanically ventilated, and invasively monitored adult sheep were randomized into 3 groups: sham animals (n = 5) that underwent surgical preparation but no aortic clamping; an ischemia/reperfusion group (n = 7), where the aorta was clamped above the renal arteries for 1 hour, and a BH4 group (n = 7), in which animals received 20 mg/kg of BH4 followed by aortic cross-clamp for 1 hour. Animals were followed for a maximum of 6 hours after reperfusion. The renal microcirculation was evaluated at baseline (before clamping), and 1, 4, and 6 hours after reperfusion using side-stream dark field videomicroscopy. The renal lactate-to-pyruvate ratio was evaluated using microdialysis. The primary outcome was the change in proportion of small perfused vessels before and after injury. Secondary outcomes were renal tissue redox state and renal function. RESULTS: Ischemia/reperfusion injury was associated with increases in heart rate and mean arterial pressure, which were blunted by BH4 administration. From the first to the sixth hour after reperfusion, the small vessel density (estimated mean difference [EMD], 1.03; 95% confidence interval [CI], 0.41-1.64; P = .003), perfused small vessel density (EMD, 0.84; 95% CI, 0.29-1.39; P = .005), and proportion of perfused small vessels (EMD, 8.60; 95% CI, 0.85-16.30; P = .031) were altered less in the BH4 than in the ischemia/reperfusion group. The renal lactate-to-pyruvate ratios were lower in the cortex in the BH4 than in the ischemia/reperfusion group from the first to the sixth hour after reperfusion (EMD, -19.16; 95% CI, -11.06 to 33.16; P = .002) and in the medulla from the first to the fourth hour (EMD, -26.62; 95% CI, -18.32 to 38.30; P = .020; and EMD, -8.68; 95% CI, -5.96 to 12.65; P = .019). At the sixth hour, serum creatinine was lower in the BH4 than in the ischemia/reperfusion group (EMD, 3.36; 95% CI, -0.29 to 1.39; P = .026). CONCLUSIONS: In this sheep model of renal ischemia/reperfusion, BH4 pretreatment reduced renal microvascular injury and improved renal metabolism and function. Further work is needed to clarify the potential role of BH4 in ischemia/reperfusion injury. PMID- 28632535 TI - Perioperative Surgical Home: Evaluation of a New Protocol Focused on a Multidisciplinary Approach to Manage Children Undergoing Posterior Spinal Fusion Operation. AB - BACKGROUND: The concept of Perioperative Surgical Home has been gaining significant attention in surgical centers. This model is delivering and improving coordinated care in a cost-effective manner to patients undergoing surgical procedures. It starts with the decision for surgical intervention, continues to the intraoperative and postoperative periods, and follows into long-term recovery. Constant re-evaluation of outcomes and modifications of delivery provides a feedback loop for improvement. Children's Hospital Los Angeles initiated a new protocol in June 2014 to manage children undergoing Posterior Spinal Fusion (PSF) with the goal to improve patient experience and lower the hospital length of stay and cost. METHODS: A retrospective chart review identified patients who underwent a PSF for idiopathic scoliosis before and after initiation of a new treatment protocol designed by a team of anesthesiologists, surgeons, nurses, and physical therapists. The new protocol included preoperative teaching of parents and patients, intraoperative anesthetic and surgical management, and immediate to long-term postoperative medical management. In addition to demographics, we examined length of stay, cost of hospitalization, pain scores on discharge, length of patient-controlled analgesia use, time to first solid food intake, and time to ambulation. RESULTS: Thirty-six patients were identified preinitiation and postinitiation of the protocol (total n = 72). There was no statistically significant difference in age, sex, use of intrathecal morphine, or estimated blood loss. Patients enrolled in the new protocol had higher American Society of Anesthesiologists classification (P = .003), significantly lower duration of patient-controlled analgesia use, time to first solid food intake, and time to ambulation (P= .001). The pain scores were higher at the time of discharge, although the difference was not statistically significant. Length of stay was significantly shorter in the new protocol group (P = .001), accounting for $292,560 in cost savings for the hospital. CONCLUSIONS: These data show that the cooperation of different teams in designing new management guidelines for patients requiring a PSF can significantly decrease the total length of stay and cost of hospitalization without altering quality of care. PMID- 28632536 TI - Pupillary Unrest: Is It a Generalizable Finding? PMID- 28632538 TI - In Response. PMID- 28632537 TI - Platelet Counts and Postoperative Stroke After Coronary Artery Bypass Grafting Surgery. AB - BACKGROUND: Declining platelet counts may reveal platelet activation and aggregation in a postoperative prothrombotic state. Therefore, we hypothesized that nadir platelet counts after on-pump coronary artery bypass grafting (CABG) surgery are associated with stroke. METHODS: We evaluated 6130 adult CABG surgery patients. Postoperative platelet counts were evaluated as continuous and categorical (mild versus moderate to severe) predictors of stroke. Extended Cox proportional hazard regression analysis with a time-varying covariate for daily minimum postoperative platelet count assessed the association of day-to-day variations in postoperative platelet count with time to stroke. Competing risks proportional hazard regression models examined associations between day-to-day variations in postoperative platelet counts with timing of stroke (early: 0-1 days; delayed: >=2 days). RESULTS: Median (interquartile range) postoperative nadir platelet counts were 123.0 (98.0-155.0) * 10/L. The incidences of postoperative stroke were 1.09%, 1.50%, and 3.02% for platelet counts >150 * 10/L, 100 to 150 * 10/L, and <100 * 10/L, respectively. The risk for stroke increased by 12% on a given postoperative day for every 30 * 10/L decrease in platelet counts (adjusted hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.01-1.24; P= .0255). On a given day, patients with moderate to severe thrombocytopenia were almost twice as likely to develop stroke (adjusted HR, 1.89; 95% CI, 1.13-3.16; P= .0155) as patients with nadir platelet counts >150 * 10/L. Importantly, such thrombocytopenia, defined as a time-varying covariate, was significantly associated with delayed (>=2 days after surgery; adjusted HR, 2.83; 95% CI, 1.48-5.41; P= .0017) but not early postoperative stroke. CONCLUSIONS: Our findings suggest an independent association between moderate to severe postoperative thrombocytopenia and postoperative stroke, and timing of stroke after CABG surgery. PMID- 28632540 TI - A Shared Opportunity for Improving Electronic Medical Record Data. AB - With the recent rapid adoption of electronic medical records (EMRs), studies reporting results based on EMR data have become increasingly common. While analyzing data extracted from our EMR for a retrospective study, we identified various types of erroneous data entries. This report investigates the root causes of the incompleteness, inconsistency, and inaccuracy of the medical records analyzed in our study. While experienced health information management professionals are well aware of the many shortcomings with EMR data, the aims of this case study are to highlight the significance of the negative impact of erroneous EMR data, to provide fundamental principles for managing EMRs, and to provide recommendations to help facilitate the successful use of electronic health data, whether to inform clinical decisions or for clinical research. PMID- 28632539 TI - Epidemiologic Analysis of Elective Operative Procedures in Infants Less Than 6 Months of Age in the United States. AB - BACKGROUND: This study uses publicly available data to analyze the total number of elective, potentially deferrable operative procedures involving infants <6 months of age in the United States. We investigated the factors associated with the performance of these procedures in this population. METHODS: The State Ambulatory Surgery Database was used to identify patients in California, North Carolina, New York, and Utah during the years of 2007-2010 who were younger than 6 months of age at the time that they underwent outpatient (ambulatory) surgery. Operations that could reasonably be postponed until 6 months of age were classified as potentially deferrable procedures. Hernia repairs were analyzed separately from other deferrable procedures. Primary outcomes included the total number of elective procedures and the number and rates of potentially deferrable procedures per state per year in this population. RESULTS: Over the study period, a total of 27,540 procedures were identified as meeting inclusion criteria; of those, 7832 (28%) were classified as potentially deferrable, 4315 of which were hernia repairs. The average rates of potentially deferrable nonhernia procedures in California, North Carolina, New York, and Utah were 8.3, 43.8, 30.0, and 11.7 per 10,000 person-years, respectively. In multivariable analysis, private insurance (odds ratio [OR] = 1.36), self-pay status (OR = 1.50), and treatment in a different state (OR = 0.48-3.16) were independent predictors of a potentially deferrable procedure being performed on an infant younger than 6 months. CONCLUSIONS: Potentially deferrable procedures are still performed in infants <6 months of age. There appears to be significant variation in timing of these procedures among states. Insurance status and geography may be independent predictors of a procedure being potentially deferrable. PMID- 28632541 TI - Hospital-Based Acute Care Within 7 Days of Discharge After Outpatient Arthroscopic Shoulder Surgery. AB - BACKGROUND: The rate of hospital-based acute care (defined as hospital transfer at discharge, emergency department [ED] visit, or subsequent inpatient hospital [IP] admission) after outpatient procedure is gaining momentum as a quality metric for ambulatory surgery. However, the incidence and reasons for hospital based acute care after arthroscopic shoulder surgery are poorly understood. METHODS: We studied adult patients who underwent outpatient arthroscopic shoulder procedures in New York State between 2011 and 2013 using the Healthcare Cost and Utilization Project database. ER visits and IP admissions within 7 days of surgery were identified by cross-matching 2 independent Healthcare Cost and Utilization Project databases. RESULTS: The final cohort included 103,476 subjects. We identified 1867 (1.80%, 95% confidence interval [CI], 1.72%-1.89%) events, and the majority of these encounters were ER visits (1643, or 1.59%, 95% CI, 1.51%-1.66%). Direct IP admission after discharged was uncommon (224, or 0.22%, 95% CI, 0.19%-0.24%). The most common reasons for seeking acute care were musculoskeletal pain (23.78% of all events). Nearly half of all events (43.49%) occurred on the day of surgery or on postoperative day 1. Operative time exceeding 2 hours was associated with higher odds of requiring acute care (odds ratio [OR], 1.28; 99% CI, 1.08-1.51). High-volume surgical centers (OR, 0.67; 99% CI, 0.58-0.78) and regional anesthesia (OR, 0.72; 99% CI, 0.56-0.92) were associated with lower odds of requiring acute care. CONCLUSIONS: The rate of hospital-based acute care after outpatient shoulder arthroscopy was low (1.80%). Complications driving acute care visits often occurred within 1 day of surgery. Many of the events were likely related to surgery and anesthesia (eg, inadequate analgesia), suggesting that anesthesiologists may play a central role in preventing acute care visits after surgery. PMID- 28632542 TI - Creation and Execution of a Novel Anesthesia Perioperative Care Service at a Veterans Affairs Hospital. AB - Physician-led perioperative surgical home models are developing as a method for improving the American health care system. These models are novel, team-based approaches that help to provide continuity of care throughout the perioperative period. Another avenue for improving care for surgical patients is the use of enhanced recovery after surgery pathways. These are well-described methods that have shown to improve perioperative outcomes. An established perioperative surgical home model can help implementation, efficiency, and adherence to enhanced recovery after surgery pathways. For these reasons, the Tennessee Valley Healthcare System, Nashville Veterans Affairs Medical Center created an Anesthesiology Perioperative Care Service that provides comprehensive care to surgical patients from their preoperative period through the continuum of their hospital course and postdischarge follow-up. In this brief report, we describe the development, implementation, and preliminary outcomes of the service. PMID- 28632543 TI - Stroke Volume Variation-Guided Versus Central Venous Pressure-Guided Low Central Venous Pressure With Milrinone During Living Donor Hepatectomy: A Randomized Double-Blinded Clinical Trial. AB - BACKGROUND: We previously demonstrated the usefulness of milrinone for living donor hepatectomy. However, a less-invasive alternative to central venous catheterization and perioperative contributors to good surgical outcomes remain undetermined. The current study evaluated whether the stroke volume variation (SVV)-guided method can substitute central venous catheterization during milrinone-induced profound vasodilation. METHODS: We randomly assigned 42 living liver donors to receive either SVV guidance or central venous pressure (CVP) guidance to obtain milrinone-induced low CVP. Target SVV of 9% was used as a substitute for CVP of 5 mm Hg. The surgical field grade evaluated by 2 attending surgeons on a 4-point scale was compared between the CVP- and SVV-guided groups (n = 19, total number of scores = 38 per group) as a primary outcome variable. Multivariable analysis was performed to identify independent factors associated with the best surgical field as a post hoc analysis. RESULTS: Surgical field grades, which were either 1 or 2, were not found to be different between the 2 groups via Mann-Whitney U test (P = .358). There was a very weak correlation between SVV and CVP during profound vasodilation such as CVP <= 5 mm Hg (R = 0.06; 95% confidence interval, -0.09 to -0.04; P < .001). Additional post hoc analysis suggested that younger age, lower baseline CVP, and longer duration of milrinone infusion might be helpful in providing the best surgical field. CONCLUSIONS: Milrinone-induced vasodilation resulted in favorable surgical environment regardless of guidance methods of low CVP during living donor hepatectomy. However, SVV was not a useful indicator of low CVP because of very weak correlation between SVV and CVP during profound vasodilation. In addition, factors contributing to the best surgical field such as donor age, proactive fasting, and proper dosing of milrinone need to be investigated further, ideally through prospective studies. PMID- 28632544 TI - Improving Outcomes in Emergency General Surgery Patients: What Evidence Is Out There? PMID- 28632545 TI - Computer-assisted Minimally Invasive Transforaminal Lumbar Interbody Fusion May Be Better Than Open Surgery for Treating Degenerative Lumbar Disease. AB - STUDY DESIGN: This study was a retrospective review of prospectively collected clinical data. OBJECTIVE: To evaluate the clinical and radiologic outcomes of computer-assisted minimally invasive spine surgery transforaminal lumbar interbody fusion (CAMISS-TLIF) and open TLIF for the treatment of 1-level degenerative lumbar disease. SUMMARY OF BACKGROUND DATA: Minimally invasive TLIF is becoming increasingly popular; however, the limited space and high rate of hardware complications associated with this method are challenging to surgeons. Computer-assisted navigation has the potential to dynamically show the fine anatomic structures, which could theoretically facilitate minimally invasive spine procedures. METHODS: Sixty-one patients underwent 1-level TLIF procedures (30, CAMISS-TLIF; 31, open TLIF). The computer-assisted navigation system was used for CAMISS-TLIF, whereas conventional fluoroscopy was used for open TLIF. Demographic, operative, visual analog scale, and Oswestry disability index data were collected. Screw insertion was assessed by computed tomography, and radiologic fusion based on Bridwell grading was evaluated 2 years after surgery by independent investigators. RESULTS: The CAMISS-TLIF group had significantly less blood loss, postoperative drain, need for transfusion, and initial postoperative back pain; earlier rehabilitation; and shorter postoperative hospitalization than the open TLIF group, whereas CAMISS-TLIF took longer surgical time than open TLIF. However, no significant differences between the 2 groups in visual analog scale scores and Oswestry disability index were observed at 3 months, 1 year, and 2 years postoperatively. A total of 93.33% and 73.39% of screws in the CAMISS and open groups, respectively, had no pedicle perforation (P=0.016), and the fusion rate was similar in both groups (P=0.787). CONCLUSIONS: Computer-assisted navigation facilitated minimally invasive spine surgery-TLIF. CAMISS-TLIF was superior to open TLIF for treating 1-level degenerative lumbar disease, although it required longer operation time in the initial stage. CAMISS TLIF showed several benefits compared with open TLIF, including less intraoperative blood loss, postoperative drainage, and pain; earlier rehabilitation; and shorter postoperative hospitalization. PMID- 28632546 TI - Clinical Outcome and Postoperative CT Measurements of Microendoscopic Decompression for Lumbar Spinal Stenosis. AB - STUDY DESIGN: This was a retrospective case series. OBJECTIVE: To retrospectively evaluate the clinical outcome of microendoscopic decompression for lumbar spinal stenosis (LSS) including an evaluation of the extent of decompression using computed tomography. SUMMARY OF BACKGROUND DATA: Microendoscopic decompression has been a widely applied procedure to treat LSS with satisfactory outcomes and comparatively fewer complications and revision. However, few reports showed computed tomography (CT) measurements of the lumbar spine to assess the postoperative decompression. METHODS: This study included 103 patients (55 males and 48 females; mean age, 69 y) who underwent microendoscopic decompression for treatment of LSS between January 2009 and January 2011. All patients underwent preoperative CT and postoperative CT at 6 months and 2 years of follow-up to measure the vertebral canal area and the sagittal diameter of the lateral recess at the outer rim. The Japanese Orthopedic Association (JOA) scale, Oswestry Disability Index, and Visual Analogue Scale were used to evaluate clinical efficacy. RESULTS: The mean vertebral canal area and sagittal diameter of the lateral recess were significantly larger at 6 months and 2 years after surgery compared with 1 day before surgery (P<0.001). The mean JOA scale scores were significantly higher at 6 and 24 months following surgery compared with before surgery (P<0.001). The mean Oswestry Disability Index scores and Visual Analogue Scale scores at 6 months and 2 years after surgery were significantly lower compared with before surgery (both P<0.001). The mean JOA recovery rates at 6 months and 2 years of follow-up were 61% and 64.3%, respectively. CONCLUSIONS: The results confirm that microendoscopic decompression for LSS is safe and effective. This study is one of the first to obtain CT measurements of the lumbar spine to assess the postoperative decompression of this procedure. PMID- 28632547 TI - A Less-Invasive Retroperitoneal Lumbar Approach: Animal Feasibility Study and Primary Clinical Study. AB - STUDY DESIGN: Surgical approach development in an animal model, and a prospective study comparing clinical outcomes between novel and conventional approaches in thoracolumbar burst fracture fixation. OBJECTIVE: To investigate the feasibility of a less-invasive retroperitoneal approach to the lumbar spine in a sheep model and to compare the clinical outcomes of anterior reconstruction in the treatment of thoracolumbar burst fractures using novel and conventional approaches. SUMMARY OF BACKGROUND DATA: The anterior retroperitoneal lumbar approach is well established for anterior lumbar surgical procedures in both humans and animal models. However, potential concerns include the increased risk of complications such as soft-tissue trauma, and extended periods of rehabilitation postoperatively. MATERIALS AND METHODS: A less-invasive retroperitoneal approach was designed in a sheep model with minimal soft-tissue dissection to keep the abdominal and paravertebral muscles intact. Eight sheep underwent anterior lumbar interbody fusion using this approach. In the clinical study, 48 patients with thoracolumbar burst fractures underwent anterior decompression and reconstruction. The less-invasive approach and conventional approach were applied in 12 and 36 cases, respectively. The clinical outcomes during the minimum 12 month follow-up of the 2 groups were compared. RESULTS: With the less-invasive approach, anterior lumbar interbody fusion was accomplished in all sheep, and no surgical complications were observed. In the clinical study, operation time, blood loss, and duration of hospitalization were comparable between 2 groups. Using the less-invasive approach decreased the length of incision, 3-day postoperative visual analogue scale score, postoperative independent standing, and narcotic-dependent duration. No surgical complications were observed in either group. CONCLUSIONS: Our results and early experience suggests that the less-invasive retroperitoneal approach is safe and effective for anterior lumbar surgery. Compared with the conventional approach, significantly better postoperative rehabilitation and abdominal muscle preservation were seen with this novel approach. PMID- 28632548 TI - Are Modic Changes Able to Help Us in Our Clinical Practice? A Study of the Modic Changes in Young Adults During Working Age. AB - STUDY DESIGN: Modic changes [vertebral endplate spinal changes (VESC)] have been related to degenerative disk disease, and in past decades it was thought that their presence justified the surgical treatment, in particular spinal fusion. OBJECTIVE: The aim of the present study is to investigate its prevalence and features in a population of young workers suffering from low back pain, and explore the eventual relationship with the treatment applied in each case. BACKGROUND DATA: We conducted a retrospectively review of 450 magnetic resonance images from our hospital, in patients with low back pain or sciatica and age below 40. MATERIALS AND METHODS: Age, sex, symptoms predominance, concurrence with other spine disease, VESC type, evolution, level/s of involvement and placement, affected disk location and extent of the disease, disk height, and status of the endplate were recorded. The applied treatment was divided in groups according to the degree of invasiveness of the procedure. RESULTS: Prevalence of VESC was 13.05% predominant in patients over 30 years, and 100% associated to disk degenerative changes. Most frequent features were: type I (54%), lower lumbar region (98%), along with a decreased disk height (68%), and distortion of the disk endplates (98%, P<0.01). The patients with VESC presented a favorable outcome with conservative treatment, but were more frequently associated with invasive treatment, compared with non-VESC patients (P<0.024). CONCLUSIONS: VESC prevalence increases with age, underlying the degenerative causative etiology. Surgical indication should not be stated on the basis of the VESC findings alone, the main factor for indicating surgery depends more on other associated degenerative spinal changes. PMID- 28632549 TI - Biomechanical Investigation of a Novel Revision Device in an Osteoporotic Model: Pullout Strength of Pedicle Screw Anchor Versus Larger Screw Diameter. AB - STUDY DESIGN: In vitro cadaveric biomechanical study. OBJECTIVE: To assess revision pullout strength of novel anchored screws (AS) versus conventional larger diameter traditional pedicle screws (TPS) in an osteoporotic model. SUMMARY OF BACKGROUND DATA: Pedicle screws are the most ubiquitous method of treating spinal pathologies requiring lumbar fusion. Although these screws are effective in providing 3-column stabilization of the spine, revision surgeries are occasionally necessary, particularly for geriatric and osteoporotic populations. Innovative technologies should be tested to ensure continued improvement in revision techniques. METHODS: For 4 specimens at L2-L5 (T-score= 3.6+/-0.54), 6.5-mm-diameter TPS were inserted into left and right pedicles and were pulled out; revision screws were then inserted. Polyether-ether-ketone anchors, designed to expand around a 6.5-mm screw, were inserted into all left pedicles. On the contralateral side, 7.5-mm-diameter TPS were inserted at L2-L3, and 8.5-mm-diameter TPS at L4-L5. Pullout testing was performed at 10 mm/min. The maximum pullout strength and insertion forces were recorded. RESULTS: The initial average pullout force (6.5-mm screw) was 837 N (+/-329 N) and 642 N (+/-318 N) in L2-L3 and L4-L5 left pedicles, and 705 N (+/-451 N) and 779 N (+/-378 N) in L2-L3 and L4-L5 right pedicles, respectively. Comparison of revision pullout forces versus initial pullout forces revealed the following: 87% and 63% for AS in L2-L3 and L4-L5 left pedicles, respectively; 56% for 7.5-mm and 93% for 8.5-mm TPS in L2-L3 and L4-L5 right pedicles, respectively. CONCLUSIONS: Anchor sleeves with 6.5-mm-diameter pedicle screws provided markedly higher resistance to screw pullout than 7.5-mm-diameter revision screws and fixation statistically equivalent to 8.5-mm-diameter screws, possibly because of medial-lateral expansion within the vertebral space and/or convex filling of the pedicle. AS results had the lowest SD, indicating minimal variability in bone-screw purchase. PMID- 28632550 TI - Suture Choice in Lumbar Dural Closure Contributes to Variation in Leak Pressures: Experimental Model. AB - STUDY DESIGN: Open-label laboratory investigational study; non-animal surgical simulation. OBJECTIVE: The authors perform a comparison of dural closure strength in a durotomy simulator across 2 different suture materials. SUMMARY OF BACKGROUND DATA: Incidental durotomy leading to persistent cerebrospinal fluid leak adds considerable morbidity to spinal procedures, often complicating routine elective lumbar spinal procedures. Using an experimental durotomy simulation, the authors compare the strength of closure using Gore-Tex with other suture types and sizes, using various closure techniques. METHODS: A comparison of dural closures was performed through an analysis of the peak pressure at which leakage occurred from a standardized durotomy closure in an established cerebrospinal fluid repair model with a premade L3 laminectomy. Nurolon was compared with Gore Tex sutures sizes (for Gore-Tex, CV-6/5-0 and CV-5/4-0 was compared with Nurolon 4-0, 5-0, and 6-0). RESULTS: Thirty-six trials were performed with Nurolon 4-0, 5 0, and 6-0, whereas 21 trials were performed for 4-0 and 5-0 Gore-Tex. The mean peak pressure at which fluid leakage was observed was 21 cm H2O for Nurolon and 34 cm H2O for Gore-Tex. Irrespective of suture choice, all trials were grouped by closure technique: running suture, locked continuous, and interrupted suture. No significant difference was noted between the groups. For each of the 3 trials groups by closure technique, running, locked continuous, and interrupted, Gore Tex closures had a significantly higher peak pressure to failure. Interrupted Gore-Tex was significantly higher than Interrupted Nurolon (P=0.007), running Gore-Tex was significantly higher than running Nurolon (P=0.034), and locked Gore Tex was significantly higher than locked Nurolon (P=0.014). CONCLUSIONS: Durotomy closure in the lumbar spine with Gore-Tex suture may be a reasonable option for providing a watertight closure. In this laboratory study, Gore-Tex suture provided watertight dural closures that withstood higher peak pressures. PMID- 28632551 TI - Comparative Study of C-arms for Intraoperative 3-dimensional Imaging and Navigation in Minimally Invasive Spine Surgery Part I: Applicability and Image Quality. AB - STUDY DESIGN: This was a retrospective analysis. OBJECTIVE: This study compares 2 different 3-dimensional (3D) C-arm devices for intraoperative imaging and navigation with regard to clinical applicability and image quality. SUMMARY OF BACKGROUND DATA: Minimally invasive spine surgery requires intraoperative imaging techniques to adequately visualize the unexposed spine. For this purpose, mobile 3D C-arms became available along with the evolution of intraoperative navigation techniques. METHODS: The C-arm devices Siremobil Iso-C 3D (Siemens) and Vision FD Vario 3D (Ziehm) perform an automated orbital rotation around the patient acquiring a 3D image set out of multiple successive fluoroscopic images. We report on technical specifications of the C-arms and our daily experience regarding clinical applicability. Furthermore, 5 spine surgeons evaluated blinded triplanar planes of 40 cervical, thoracic, and lumbar 3D scans that were obtained during routine surgery regarding usability for navigation. We assessed the delineation of cortical bone, artifacts, and overall image quality using a 0-10 numeric rating scale. RESULTS: The Siremobil Iso-C 3D requires 128 seconds for its 190-degree scanning arc with equidistant isocenter. The Vision FD Vario 3D performs an elliptical scanning arc and completes its 135-degree scan in 64 seconds; furthermore, it features a flat panel detector and fully digital imaging. The smaller dimensions of the Vision FD Vario 3D made it easier to maneuver in the operating room compared with the more bulky Siremobil Iso-C 3D. With respect to image quality in cervical 3D scans, the Siremobil Iso-C 3D reached significantly higher scores in all categories. The Vision FD Vario 3D revealed less artifacts in lumbar 3D scans. CONCLUSIONS: The Siremobil Iso-C 3D provides high-quality 3D scans in slender spine regions (eg, cervical spine), whereas the Vision FD Vario 3D appears to have advantages in the lumbar spine. Further evolution and novel devices are needed to optimize image quality and handling. PMID- 28632552 TI - Comparative Study of C-Arms for Intraoperative 3-dimensional Imaging and Navigation in Minimally Invasive Spine Surgery Part II: Radiation Exposure. AB - STUDY DESIGN: A radiation exposure study in vitro. OBJECTIVE: This study aimed to compare the radiation exposure of 2 different 3-dimensional (3D) C-arm devices on an anthropomorphic phantom. SUMMARY OF BACKGROUND DATA: Minimally invasive pedicle screw placement requires intraoperative imaging techniques for visualization of the unexposed spine. Mobile 3D C-arms compose a 3D image data set out of multiple successive fluoroscopic images. METHODS: We compared the 3D C arm devices Siremobil Iso-C 3D (Siemens Sector Healthcare, Erlangen, Germany) and Vision FD Vario 3D (Ziehm Imaging, Nuremberg, Germany) regarding their radiation exposure. For this purpose, dosimeters were attached on an anthropomorphic phantom at various sites (eye lenses, thyroid gland, female, and male gonads). With each C-arm, 10 automated 3D scans as well as 400 fluoroscopic images were performed on the cervical and lumbar spine, respectively. RESULTS: The Vision FD Vario 3D generally causes higher radiation exposures than the Siremobil Iso-C 3D. Significantly higher radiation exposures were assessed at the eye lenses performing cervical (294.1 vs. 84.6 MUSv) and lumbar 3D scans (22.5 vs. 11.2 MUSv) as well as at the thyroid gland performing cervical 3D scans (4405.2 vs. 2761.9 MUSv). Moreover, the Vision FD Vario 3D caused significantly higher radiation exposure at the eye lenses for standard cervical fluoroscopic images (3.2 vs. 0.4 MUSv). CONCLUSIONS: 3D C-arms facilitate minimally invasive and accurate pedicle screw placement by providing 3D image datasets for intraoperative 3D imaging and navigation. However, the hereby potentially increased radiation exposure has to be considered. In particular, the Vision FD Vario 3D appears to generally evoke higher radiation exposures than the Siremobil Iso-C 3D. Well-indicated application of ionizing radiation and compliance with radiation protection principles remain mandatory to keep radiation exposure to patient and staff as low as reasonably achievable. PMID- 28632553 TI - Lumbar Retrolisthesis in Aging Spine: What are the Associated Factors? AB - STUDY DESIGN: A retrospective radiographic study. OBJECTIVE: The aim of this study is to demonstrate that lumbar retrolisthesis serves as an important compensatory mechanism and to identify the possible factor related to lumbar retrolisthesis. SUMMARY OF BACKGROUND DATA: Lumbar instability is one of the common degenerative changes, which presents as 2 radiologic features: anterolisthesis and retrolisthesis. Compared with the extensive studies on anterolisthesis, limit data are available on the characteristics and clinical relevance of lumbar retrolisthesis. MATERIALS AND METHODS: In this study, 105 adult patients with low back pain were prospectively recruited, of which 60 patients had retrolisthesis (group 1) and 45 patients had anterolisthesis (group 2). Another 40 healthy age-matched adults (group 3) were also included to serve as the control group. Sagittal spinopelvic parameters were measured from the standing lateral radiograph, including thoracic kyphosis (TK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL), pelvic incidence (PI), sacrum slope (SS), pelvic tilt (PT), sagittal vertical axis (SVA), spinosacral angle (SSA), and C7 tilt (C7T). In addition, disk degeneration was quantitatively evaluated by Pfirrmann score on T2-weighted magnetic resonance images in patients with retrolisthesis. RESULTS: For all the sagittal parameters, SVA, PI, SS, and LL in retrolisthesis group were found to be significantly lower than those in the anterolisthesis group and in the control group, respectively (P<0.05), whereas TLK in retrolisthesis group was significantly larger than other 2 groups (P<0.01). In addition, the average Pfirrmann disk score was 2.11 at levels with retrolisthesis indicating that the disks were not severely degenerated. CONCLUSIONS: Lumbar retrolisthesis, together with thoracolumbar kyphosis, appears to be associated with mechanisms associated with regulation of sagittal balance. Low PI and disk instability due to degeneration may contribute to the development and progression of retrolisthesis. PMID- 28632554 TI - The Correlation Between Cage Subsidence, Bone Mineral Density, and Clinical Results in Posterior Lumbar Interbody Fusion. AB - STUDY DESIGN: A retrospective review of prospectively collected radiographic and clinical data. OBJECTIVE: This study aims to investigate the relationship between cage subsidence and bone mineral density (BMD), and to reveal the clinical implications of cage subsidence. SUMMARY OF BACKGROUND DATA: Posterior lumbar interbody fusion (PLIF) has become one of the standard treatment modality for lumbar degenerative disease. However, cage subsidence might result in recurrent foraminal stenosis and deteriorate the clinical results. Furthermore, numbers of osteoporosis patients who underwent PLIF are increasing. Therefore, the information on the correlations between cage subsidence, BMD, and clinical results will be of great significance. MATERIALS AND METHODS: A total 139 segments was included in this retrospective study. We examined functional rating index (Visual Analogue Scale for pain, Oswestry Disability Index, Short Form-36 score) preoperatively, and investigated their changes after postoperative 1 year. Correlation between cage subsidence and clinical scores was investigated. Plain anteroposterior and lateral radiograph were taken preoperatively and postoperatively and during follow-up. Preoperative BMD and subsidence measured by postoperative 1 year 3-dimensional computed tomography were achieved and their correlation was assessed. RESULTS: All postoperative clinical scores improved significantly compared with preoperative ones (pain Visual Analogue Scale: 7.34 2.89, Oswestry Disability Index: 25.34-15.86, Short Form-36: 26.45-16.46, all P<0.001). BMD showed significant weak correlation with subsidence (r=-0.285, P<0.001). Severe osteoporotic segments (T score <-3.0) had more risk to develop severe subsidence (>3 mm) compared with the segments in which T score were higher than -3.0 (P=0.012), and its odds ratio was 8.44. Subsidence had no significant correlation with all clinical scores. CONCLUSIONS: This study revealed that cage subsidence is relevant to BMD. However, it was demonstrated that subsidence is not related to the clinical deterioration. Therefore, PLIF procedure which is conducted carefully can be a good surgical option to treat lumbar degenerative disease for osteoporotic patients. PMID- 28632555 TI - Changes in Cytokines, Sensory Tests, and Self-reported Pain Levels After Manual Treatment of Low Back Pain. AB - STUDY DESIGN: Unbalanced 3-factor design with repeated measures on 1 factor. OBJECTIVE: To determine the effect of manual treatment (MT) on cytokine and pain sensations in those with and without low back pain (LBP). SUMMARY OF BACKGROUND DATA: Evidence suggests that MT reduces LBP but by unknown mechanisms. Certain cytokines have been elevated in patients with LBP and may be affected by MT. METHODS: Participants aged 20-60 years with chronic LBP or without LBP were recruited and randomly assigned to MT, sham ultrasound treatment, or no treatment groups. Venous blood samples were collected and pain levels assessed at baseline, 1 hour later, and 24 hours later. Blood was analyzed for interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and C-reactive protein. Pain levels were measured by pressure pain threshold (PPT), mechanical detection threshold (MDT), dynamic mechanical allodynia, and self-report. RESULTS: Forty (30 women, age 36+/ 11 y) participants completed the study, 33 with LBP (13 MT, 13 sham ultrasound treatment, and 7 no treatment) and 7 without LBP. Participants with or without LBP could not be differentiated on the basis of serum cytokine levels, PPT, or MDT (P>=0.08). There were no significant differences between the groups at 1 hour or 24 hours on serum cytokines, PPT, or MDT (P>=0.07). There was a significant decrease from baseline in IL-6 for the no treatment (LBP) group (P=0.04), in C reactive protein for the sham ultrasound treatment group (P=0.03), in MDT for all 3 LBP groups (P<=0.02), and in self-reported pain for the MT and sham ultrasound treatment groups (P=0.03 and 0.01). CONCLUSIONS: Self-reported pain was reduced with MT and sham ultrasound treatment 24 hours after treatment, but inflammatory markers within venous circulation and quantitative sensory tests were unable to differentiate between study groups. Therefore, we were unable to characterize mechanisms underlying chronic LBP. PMID- 28632556 TI - Watertight Sealing Without Lumbar Drainage for Incidental Ventral Dural Defect in Transthoracic Spine Surgery: A Retrospective Review of 53 Cases. AB - STUDY DESIGN: A retrospective review. OBJECTIVES: To evaluate the therapeutic efficacy of the triple layer closure technique to establish watertight sealing without diversion of lumbar drainage, in preventing persistent incidental subarachnoid-pleural fistula and other neurological complications related to excessive drainage of cerebrospinal fluid (CSF) after dural defect in transthoracic ossified posterior longitudinal ligament (OPLL) surgery. SUMMARY OF BACKGROUND DATA: CSF leakage into the pleural cavity leads to unfavorable conditions for natural healing of incidental durotomy due to the negative pressure environment of the pleural space and lack of wound healing around the bony cavity near the decompressed spinal cord. This often leads to a persistent incidental subarachnoid-pleural fistula. In addition, diversion of lumbar drainage may lead to excessive CSF drainage resulting in intracranial hypotension. To avoid this, we studied the efficacy of a modified sealing method to establish a more watertight covering at the ventral dural defect without lumbar CSF drainage. METHODS: Fifty-three patients who had CSF leakage from the ventral aspect of the spinal cord during transthoracic spine surgery for thoracic OPLL between 2004 and 2013 were retrospectively reviewed. Patients were divided into 2 groups: a conventional group (group A) and a triple layer closure group (group B). In group A (n=33 patients), the dural defect was covered with fibrin glue (Beriplast P) mixed with gelfoam (Spongostan Standard) with subsequent subarachnoid lumbar drainage. In group B (n=20 patients), the dural defect was sealed using the triple layer technique with 2 layers of fibrin glue and gelatin sponge plus a third layer of synthetic hydrogel (Duraseal, Dural Sealant System) without subsequent subarachnoid lumbar drainage. Both groups had chest tubes that drained through an underwater seal. Clinical data including duration and total amount of drainage (chest tube and lumbar drainage), related complications, and duration of hospital stay were compared between the 2 groups. RESULTS: Compared with the patients in group A, group B had a significantly smaller total volume of drainage and shorter chest tube drainage time (P<0.05) during their hospital stay. In group A, complications occurred in 6 cases (18.2%), including 3 cases of intracranial hypotension combined with transient mental status alteration, postural headache, and dizziness, 1 case of regional atelectasis with pneumonia, and 2 cases of revision thoracotomy. Revision thoracotomy was performed to treat persistent subarachnoid-pleural fistula due to significant and prolonged CSF leakage. In group B, there were no complications and no revision thoracotomy was needed. The mean duration of hospital stay was shorter in group B (15.6 d) compared with group A (22.4 d). CONCLUSIONS: The established watertight closure of the dural defect using the triple layer sealing method without lumbar drainage was more effective and safe. PMID- 28632557 TI - Vertebral End-Plate Perforation for Intervertebral Disc Height Preservation After Single-level Lumbar Discectomy: A Randomized-controlled Trial. AB - STUDY DESIGN: Pilot single-centre, stratified, prospective, randomized, double blinded, parallel-group, controlled study. OBJECTIVE: To determine whether vertebral end-plate perforation after lumbar discectomy causes annulus reparation and intervertebral disc volume restoration. To determine that after 6 months there would be no clinical differences between the control and study group. SUMMARY OF BACKGROUND DATA: Low back pain is the most common long-term complication after lumbar discectomy. It is mainly caused by intervertebral disc space loss, which promotes progressive degeneration. This is the first study to test the efficiency of a previously described method (vertebral end-plate perforation) that should advocate for annulus fibrosus reparation and disc space restoration. METHODS: We selected 30 eligible patients according to inclusion and exclusion criteria and randomly assigned them to the control (no end-plate perforation) or study (end-plate perforation) group. Each patient was evaluated in 5 different periods, where data were collected [preoperative and 6-mo follow up magnetic resonance imaging and functional outcome data: visual analogue scale (VAS) back, VAS legs, Oswestry disability index (ODI)]. Intervertebral space volume (ISV) and height (ISH) were measured form the magnetic resonance images. Statistical analysis was performed using paired t test and linear regression. P<0.05 was considered statistically significant. RESULTS: We found no statistically significant difference between the control group and the study group concerning ISV (P=0.6808) and ISH (P=0.8981) 6 months after surgery. No statistically significant differences were found between ODI, VAS back, and VAS legs after 6 months between the 2 groups, however, there were statistically significant differences between these parameters in different time periods. Correlation between the volume of disc tissue removed and preoperative versus postoperative difference in ISV was statistically significant (P=0.0020). CONCLUSIONS: The present study showed positive correlation between the volume of removed disc tissue and decrease in postoperative ISV and ISH. There were no statistically significant differences in ISV and ISH between the group with end plate perforation and the control group 6 months after lumbar discectomy. Clinical outcome and disability were significantly improved in both groups 3 and 6 months after surgery. PMID- 28632558 TI - The Long-term Clinical Effect of Minimal-Invasive TLIF Technique in 1-Segment Lumbar Disease. AB - STUDY DESIGN: A prospective cohort double-center study. OBJECTIVE: To assess the clinical effect of minimally invasive transforaminal lumbar interbody fusion (miTLIF) using the tunnel technique. SUMMARY OF BACKGROUND DATA: A series of short-term studies have indicated that miTLIF could reduce blood loss and improve clinical results. However, long-term clinical study and magnetic resonance imaging research are still scare. METHODS: From January 2008 to January 2009, 187 patients with 1-segment lumbar disease requiring intervertebral fusion were enrolled in this study. Patients were divided into 2 groups according to the operative methods. Postoperative low back pain (LBP), postoperative lumbar function, the fusion rate, lower extremity pain relief, variation of lumbar lordosis, and implant failure were assessed. At 48 months postoperation, the cross-sectional area of the paraspinal muscle was measured using magnetic resonance imaging. RESULTS: The mean duration of follow-up was 54.4+/-5.9 months. The intermuscular pressure generated by the tunnel in the miTLIF group was lower than that generated in the oTLIF group. Patients in the miTLIF group reported a lower degree of LBP at all timepoints. The ODI scores were similar to the VAS scores. No significant differences were found in fusion rate, lower extremity pain relief, lumbar lordosis, or implant failure rate. A significant difference was found between the 2 groups in postoperative cross-sectional area. CONCLUSIONS: This study confirmed the advantages of miTLIF in reducing postoperative LBP, improving postoperative quality of life and preventing paraspinal muscle atrophy compared with oTLIF, while achieving a similar therapeutic outcome. The lower intermuscular pressure generated by minimally invasive tunnel and subsequent moderate muscle atrophy were presumed to be possible reasons for its superiority. PMID- 28632559 TI - Counting the Cost of Failed Spinal Fusion for Relief of Low Back Pain: Does Primary Fusion With Bone Morphogenetic Protein Make Economic Sense From a Primary Payer Perspective? AB - STUDY DESIGN: A retrospective cohort study. OBJECTIVES: To investigate the unknown direct costs of failed instrumented lumbar fusion using iliac crest bone graft (ICBG) and subsequent reoperation utilizing recombinant human bone morphogenetic protein-2 (rhBMP-2) from a primary payer perspective. SUMMARY OF BACKGROUND DATA: Recent evidence has demonstrated increased rates of instrumented lumbar fusion and utilization of rhBMP-2 to treat a range of conditions causing lower back pain. For health care providers with finite financial resources, there is an increasing demand to evaluate economic costs of available treatment modalities. The high cost of rhBMP-2 has often been cited as a leading reason for delaying its universal acceptance as a preferred substitute to ICBG. It has been hypothesized that rhBMP-2 may demonstrate cost-effectiveness if pseudarthrosis and reoperation rates are decreased, thus avoiding subsequent expenditure. METHODS: This was a retrospective cohort study of patients who underwent instrumented lumbar fusions utilizing rhBMP-2. Hospital finance records were used to calculate direct total expenditure incurred by the primary payer for the procedure using rhBMP-2. For patients who received rhBMP-2 in a secondary lumbar fusion, additional total expenditure related to the patients' failed primary instrumented fusion with ICBG was also sought. RESULTS: The mean total costs associated with failed instrumented lumbar fusion using ICBG and reoperation using rhBMP-2 totaled L47,734 per patient. The total direct costs of a policy of primary instrumented lumbar fusion with rhBMP-2 were less at L26,923 per patient; however, this was not significant. CONCLUSIONS: To date, this is the first study to report the costs of failed primary instrumented lumbar fusions using ICBG and subsequent secondary fusions using rhBMP-2 from a primary payer perspective. On the basis of this evidence, a policy of using rhBMP-2 in all patients undergoing a primary instrumented lumbar fusion cannot be recommended. PMID- 28632560 TI - Preoperative Depression, Smoking, and Employment Status are Significant Factors in Patient Satisfaction After Lumbar Spine Surgery. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To determine whether comorbidities and demographics, identified preoperatively, can impact patient outcomes and satisfaction after lumbar spine surgery. SUMMARY OF BACKGROUND DATA: The surgical treatment of lower back pain does not always eliminate a patient's pain and symptoms. Revision surgeries are costly and expose the patient to additional risk. We aim to identify patient characteristics that may suggest a greater or lesser likelihood of postsurgical success by examining patient reported measures and outcomes after surgery. METHODS: Preoperative smoking status, self-reported depression, prevalence of diabetes, obesity, level of education, and employment status were assessed in the context of patient outcome and satisfaction after lumbar spine surgery. Patients were contacted before surgery, and at 3 and 12 months postoperatively, and responded to Oswestry Disability Index (ODI) and EuroQol-5 Dimensions (EQ-5D) self-assessment examinations, as well as a satisfaction measure. RESULTS: A total of 166 patients who underwent lumbar spine surgeries at Iowa Spine and Brain Institute, a department of Covenant Medical Center, and were included in the National Neurosurgery Quality and Outcomes Database were assessed preoperatively, and at 3 and 12 months postoperatively using self-assessment tools. Depression, smoking, and employment status were found to be significant factors in patient satisfaction. Depressed patients, smokers, and patients on disability at the time of surgery have worse ODI and EQ-5D scores at all of the timepoints (baseline, 3 months, and 12 months postsurgery). CONCLUSIONS: Depression, smoking, and employment status, specifically whether a patient is on disability at the time of surgery, are all significant factors in patient satisfaction after lumbar spine surgery. These factors are also shown in impact ODI and EQ-5D scores. Surgeons should consider these particular characteristics when developing a lower back pain treatment plan involving surgery. PMID- 28632561 TI - Early Postoperative Magnetic Resonance Imaging in Detecting Radicular Pain After Lumbar Decompression Surgery: Retrospective Study of the Relationship Between Dural Sac Cross-sectional Area and Postoperative Radicular Pain. AB - STUDY DESIGN: A retrospective analysis. OBJECTIVE: To evaluate the association between early postoperative dural sac cross-sectional area (DCSA) and radicular pain. SUMMARY OF BACKGROUND DATA: The correlation between postoperative magnetic resonance imaging (MRI) findings and postoperative neurological symptoms after lumbar decompression surgery is controversial. METHODS: This study included 115 patients who underwent lumbar decompression surgery followed by MRI within 7 days postoperatively. There were 46 patients with early postoperative radicular pain, regardless of whether the pain was mild or similar to that before surgery. The intervertebral level with the smallest DCSA was identified on MRI and compared preoperatively and postoperatively. Risk factors for postoperative radicular pain were determined using univariate and multivariate analyses. Subanalysis according to absence/presence of a residual suction drain also was performed. RESULTS: Multivariate regression analysis showed that smaller postoperative DCSA was significantly associated with early postoperative radicular pain (per -10 mm; odds ratio, 1.26). The best cutoff value for radicular pain was early postoperative DCSA of 67.7 mm. Even with a cutoff value of <70 mm, sensitivity and specificity are 74.3% and 75.0%, respectively. Early postoperative DCSA was significantly larger before suction drain removal than after (119.7+/-10.1 vs. 93.9+/-5.4 mm). CONCLUSIONS: Smaller DCSA in the early postoperative period was associated with radicular pain after lumbar decompression surgery. The best cutoff value for postoperative radicular pain was 67.7 mm. Absence of a suction drain at the time of early postoperative MRI was related to smaller DCSA. PMID- 28632562 TI - Degenerative Changes of the Facet Joints in Adults With Lumbar Spondylolysis. AB - STUDY DESIGN: Radiologic analysis using computed tomography. OBJECTIVES: To analyze the degenerative changes of the facet joints in patients with spondylolysis in comparison with control subjects. SUMMARY OF BACKGROUND DATA: Defects of the pars interarticularis are thought to result in a reduction of biomechanical stress on adjacent facet joints. Therefore, degenerative changes of the facet joints in patients with spondylolysis are expected to be less than those in patients without spondylolysis. METHODS: Abdominal and pelvic multidetector computed tomography scans of 2000 subjects, performed for conditions unrelated to low back pain, were reviewed. A total of 107 patients (37 women and 70 men) with L5 spondylolysis were identified [spondylolysis (+) group]. Sex-matched and age-matched controls without spondylolysis were chosen randomly [spondylolysis (-) group]. Subjects in the spondylolysis group were subdivided into either bilateral spondylolysis or unilateral spondylolysis groups for comparison with the control group. Four radiologic findings (narrowing, sclerosis, osteophyte, and bone cyst) indicative of degenerative change of the facet joints adjacent to the L5 pars defects were evaluated and the degree of degenerative change was graded by summing the number of degenerative changes (score range, 0-4). The chi test and Mann-Whitney U test were used for statistical analysis. RESULTS: Significantly more degenerative changes in both L4/L5 and L5/S facet joints were found in the spondylolysis (+) group than in the spondylolysis (-) group (chi test, P <0.05). Degenerative changes of the facet joints at both L4/L5 and L5/S were more severe in the bilateral spondylolysis (+) group than in the spondylolysis (-) group. Degenerative changes of the facet joints at both L4/L5 and L5/S were more severe in the unilateral spondylolysis (+) group than in the spondylolysis (-) group. CONCLUSIONS: Degenerative changes of the facet joints in patients with lumbar spondylolysis were more severe than those without spondylolysis. PMID- 28632563 TI - Why Lumbar Artificial Disk Replacements (LADRs) Fail. AB - STUDY DESIGN: A retrospective review of prospectively collected data. OBJECTIVE: To determine why artificial disk replacements (ADRs) fail by examining results of 91 patients in FDA studies performed at a single investigational device exemption (IDE) site with minimum 2-year follow-up. SUMMARY OF BACKGROUND DATA: Patients following lumbar ADR generally achieve their 24-month follow-up results at 3 months postoperatively. MATERIALS AND METHODS: Every patient undergoing ADR at 1 IDE site by 2 surgeons was evaluated for clinical success. Failure was defined as <50% improvement in ODI and VAS or any additional surgery at index or adjacent spine motion segment. Three ADRs were evaluated: Maverick, 25 patients; Charite, 31 patients; and Kineflex, 35 patients. All procedures were 1-level operations performed at L4-L5 or L5-S1. Demographics and inclusion/exclusion criteria were similar and will be discussed. RESULTS: Overall clinical failure occurred in 26% (24 of 91 patients) at 2-year follow-up. Clinical failure occurred in: 28% (Maverick) (7 of 25 patients), 39% (Charite) (12 of 31 patients), and 14% (Kineflex) (5 of 35 patients). Causes of failure included facet pathology, 50% of failure patients (12 of 24). Implant complications occurred in 5% of total patients and 21% of failure patients (5 of 24). Only 5 patients went from a success to failure after 3 months. Only 1 patient went from a failure to success after a facet rhizotomy 1 year after ADR. CONCLUSIONS: Seventy-four percent of patients after ADR met strict clinical success after 2-year follow-up. The clinical success versus failure rate did not change from their 3-month follow-up in 85 of the 91 patients (93%). Overall clinical success may be improved most by patient selection and implant type. PMID- 28632564 TI - Accuracy of Percutaneous Pedicle Screw Placement: Does Training Level Matter? AB - STUDY DESIGN: In vitro human cadaveric surgical technique study. OBJECTIVE: To assess the accuracy of percutaneous pedicle screw placement in a human cadaveric model using standard fluoroscopic guidance technique, compared across varying levels of experience. SUMMARY OF BACKGROUND DATA: The current literature varies widely in the reported frequency of facet violation during placement of percutaneous pedicle screws. However, as of yet there are no studies examining the effect that training level has on accuracy of placement. MATERIALS AND METHODS: Four surgeons with differing levels of training (PGY-2, PGY-4, fellow, attending) were evaluated on their accuracy of percutaneous placement of screws in a uniform manner. Each of the 10 cadavers was instrumented from L1 to S1 bilaterally, for a total of 120 screws. Specimens were dissected to evaluate for facet and pedicle wall violations. These were then recorded and analyzed to evaluate for correlation among participating surgeons, laterality, spinal level, and cadaver body mass index. RESULTS: Of 120 screws placed, there were 35 total violations [26 superior articular facet violations (21.7%), 5 intra-articular facet joint violations (4.2%), and 4 pedicle breaches (3.3%)]. Among the trainees there was no difference in the likelihood of causing a violation (P=0.8863) but there was a difference when compared with the attending surgeon (P=0.0175). Laterality (P=0.1598), spinal level (P=0.3536), and body mass index (P=0.8547) did not correlate with the likelihood of a violation. CONCLUSIONS: Surgeons of differing training levels are able to safely and accurately place lumbar pedicle screws in a percutaneous manner, with a low likelihood of facet and pedicle wall violations. PMID- 28632565 TI - Neuroforaminal Bone Growth Following Minimally Invasive Transforaminal Lumbar Interbody Fusion With BMP: A Computed Tomographic Analysis. AB - STUDY DESIGN: Computed tomographic analysis. OBJECTIVE: To identify radiographic patterns of symptomatic neuroforaminal bone growth (NFB) in patients who have undergone a single-level minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) augmented with bone morphogenetic proteins (BMP) utilizing computed tomography (CT). SUMMARY OF BACKGROUND DATA: BMP induces osteoblast differentiation leading to new bone formation. The association of BMP utilization and heterotopic bone formation after an MIS-TLIF has been described. However, studies have been limited in their patient population and details regarding diagnosis and treatment of NFB. MATERIALS AND METHODS: Postoperative CT scans of the symptomatic and asymptomatic patients were analyzed to identify patterns of heterotopic bone growth on axial and sagittal views. The area of bone growth at the disk level, lateral recess, adjacent foramen, and retrovertebral area were measured. Mann-Whitney U test was used to compare the areas of bone growth between cohorts. RESULTS: Postoperative CT images between 18 symptomatic and 13 asymptomatic patients were compared. On axial views, the symptomatic patients demonstrated greater areas of bone growth at the disk level (164.0+/-92.4 vs. 77.0+/-104.9 mm), and lateral recess (69.6+/-70.5 and 5.9+/-12.5 mm) as well as in the total cross-sectional area (290.3+/-162.1 vs. 119.4+/-115.6 mm). On sagittal imaging, the mean bone growth at the subarticular level (148.7+/-185.1 vs. 35.8+/-37.4 mm) and the total cross-sectional area (298.4+/-324.4 vs. 85.8+/ 76.3 mm) were greater in symptomatic patients (P<0.01). Amount of BMP utilized and operative levels were no different between cohorts. CONCLUSIONS: The findings of the present study suggest that an anatomic association exists between recalcitrant postoperative radiculopathy and NFB following an MIS-TLIF with BMP. Increased total bone growth as measured on serial axial and sagittal sections was associated with postoperative radiculopathy. The association between radiculopathy and the extension of BMP-induced bone growth toward the traversing nerve root appeared the most significant. PMID- 28632566 TI - Gottron Papules Show Histopathologic Features of Localized Lymphedema. AB - Although Gottron papules are a relevant feature of dermatomyositis, they are reported in very few papers in the literature, and the largest series on the subject includes 11 cases. We intend to study the main histopathologic features of Gottron papules in a series of 12 biopsies. We evaluated hematoxylin-eosin stains on all cases. We also performed histochemical stains to evaluate the dermal deposition of mucin. Finally, we studied the CD123 cell population in the inflammatory infiltrate by immunohistochemistry. We found that the epidermis was either acanthotic or hyperplastic in all cases. We found a dermal inflammatory infiltrate in all cases but one. Mucin deposition in the reticular dermis was an inconstant feature. Vacuolization of the basal layer was also a frequent finding. There was thickening of the base membrane on periodic acid-Schiff stains in all our cases. We identified CD123 cells in all cases but 2. Intraepidermal CD123 cells were also found in 8 cases. All cases but one showed lymphangiectasia in the upper part of the dermis, including the papillary and reticular dermis. In addition, collapsed lymphatics were evident underlying the dermal sclerosis. We conclude that Gottron papules show typical features of localized lymphedema. PMID- 28632567 TI - Transducing-Like Enhancer of Split 1: A Potential Immunohistochemical Marker for Glomus Tumor. AB - Glomus tumors (GTs) are rare, perivascular soft tissue tumors. Although GTs are usually found in the subcutaneous tissue, they may be detected in extracutaneous sites and mucosal areas. Transducing-like enhancer of split 1 (TLE1) is a highly useful immunohistochemical marker, which basically helps in differential diagnosis of synovial sarcoma. Based on a coincidental detection of TLE1 in one GT case, we studied 26 additional GT cases to establish the importance and distribution of TLE1 in GTs. Of 24 subcutaneous GTs, 22 (91.6%) were positive for TLE1 antibody and the remaining 2 mucosal GTs were negative. Of the 22 positive cases, 10 showed strong nuclear positivity. There was no difference between the subtypes of the GTs. Although TLE1 expression is significantly correlated to SS18 (SYT) rearrangements in synovial sarcomas, the fluorescence in situ hybridization analyses of the GTs showed no evidence of translocation involving this locus. TLE1 is a potential immunohistochemical marker for GTs, but further studies are required to confirm this finding. PMID- 28632568 TI - Gluteal Papular Eruption. PMID- 28632569 TI - Multiple Follicular Keratotic Papules in a Patient With a Distal Limb Polyneuropathy: Challenge. PMID- 28632570 TI - Annular Plaque on the Inner Thigh. PMID- 28632571 TI - Elastic Fibers in Scars and Alopecia. PMID- 28632572 TI - Gluteal Papular Eruption. PMID- 28632573 TI - Multiple Follicular Keratotic Papules in a Patient With a Distal Limb Polyneuropathy. PMID- 28632574 TI - An Annular Plaque on the Inner Thigh. PMID- 28632575 TI - Clinical Profile, Etiology, and Outcome of Infantile Ocular Trauma: A Developing Country Perspective. AB - OBJECTIVE: The aim of this article was to study the clinical profile, etiology, and outcome of infantile ocular trauma in a developing country setting. METHODS: A retrospective study on corneal trauma in infants (<=12 months old) was undertaken in a tertiary care hospital during a 2-year period. An analysis of clinical profile, etiology, microbiological profile, clinical course, and outcome was studied. RESULTS: Seventy-six infants were included. Approximately 69% presented within 24 hours of injury. The common presentations were inability to open the eyelids, redness of eyes, and watering. Self-infliction by child's hand (49%) was found to be the main cause of corneal trauma. Corneal abrasion was seen in 34 cases (45%), isolated epithelial defects were seen in 30%, and infective keratitis was seen in 25%. Infection was found in 14 cases (fungal filaments in 7 and gram-positive cocci in 7). Only 36 infants followed up regularly in the hospital. All the infants following up in the hospital recovered in due course. CONCLUSIONS: Infantile ocular trauma is a common morbidity that is underreported. Self-infliction by child's hand was found to be the main cause of corneal trauma. Cases presenting early and following up regularly till recovery have a favorable clinical course with good outcome. A high loss to follow-up indicates that awareness needs to be created among the caregivers. PMID- 28632576 TI - Understanding the Constipation Conundrum: Predictors of Obtaining an Abdominal Radiograph During the Emergency Department Evaluation of Pediatric Constipation. AB - OBJECTIVES: Many children with constipation who are evaluated in emergency departments (EDs) receive an abdominal radiograph (AR) despite evidence-based guidelines discouraging imaging. The objectives of this study were to identify predictors associated with obtaining an AR and to determine if ARs were associated with a longer length of stay (LOS) among children with constipation evaluated in the ED. METHODS: A review of billing and electronic health records was conducted in an academic pediatric ED for children ages 0 to 17 years who had a primary discharge diagnosis of constipation from July 2013 to June 2014. Logistic regression was used to identify predictors for obtaining an AR. Differences in mean LOS were analyzed using linear regression. RESULTS: In total, 326 children met inclusion criteria, and 60% of the children received an AR. In logistic regression, significant predictors included age (odds ratio [OR] = 1.1/year of age, P = 0.004), presenting with abdominal pain as chief complaint compared with constipation (OR = 4.4, P < 0.0001), and history of emesis (OR = 2.8, P = 0.001) after controlling for provider type and previous constipation medication use. In linear regression, the adjusted mean LOS for those with an AR was 163 minutes compared with 117 minutes for those without after controlling for age, provider type, and history of constipation medication use (P < 0.0001). CONCLUSIONS: Abdominal radiographs were used frequently in the ED diagnosis and management of constipation, particularly in older children and those with abdominal pain and emesis. Abdominal radiographs were associated with increased LOS. PMID- 28632577 TI - Outcome of Pediatric Forearm Fracture Reductions Performed by Pediatric Emergency Medicine Providers Compared With Reductions Performed by Orthopedic Surgeons: A Retrospective Cohort Study. AB - OBJECTIVE: The aim of this study was to describe the outcome differences between board-certified orthopedists and pediatric emergency medicine (PEM) physicians conducting forearm fracture reductions. METHODS: We performed an analysis of patients between 1 and 14 years of age who presented to the emergency department (ED) with a forearm fracture requiring reduction. Data collected included reducing provider (PEM or orthopedist) and prereduction, postreduction, and follow-up fracture angles and displacements of both radius and ulna. We collected costs of care, both in the ED and at follow-up, as well as length-of-stay data. chi Tests and Fisher exact test compared associations between categorical variables; 2-sample t tests compared the PEM and orthopedic groups. Regression models were used to control for injury severity confounders. RESULTS: Of the 222 fractures, orthopedists reduced 135, and PEM doctors reduced 87. Based on fracture angle and displacement, the orthopedic group tended to have slightly more complicated cases. After adjusting for age and time to follow-up, fractures reduced by orthopedists were less likely to require remanipulation (adjusted odds ratio, 0.30; P = 0.020). The PEM group had a significantly lower length of stay (59.4 minutes shorter; P < 0.001) and a small overall saving in charges ($273.90; P = 0.47). CONCLUSIONS: Orthopedists performed better in maintaining fracture reductions compared with PEM physicians but lengthened the ED stay for our patients. There was no significant difference in cost. PMID- 28632578 TI - Acute Abdominal Pain: Recognition and Management of Constipation in the Emergency Department. AB - OBJECTIVE: The main aim of the study was to investigate the incidence and the clinically relevant features of functional constipation in patients evaluated for acute abdominal pain in a tertiary care pediatric emergency department. METHODS: This is a retrospective study. We analyzed 4394 medical records and recorded the information (demographics, triage code, symptoms, medical history, physical evaluation, laboratory tests, radiological studies, procedures, and treatments) of all patients admitted for acute abdominal pain to the emergency department of the IRCCS Burlo Garofolo, Trieste, during 2010 to 2013. RESULTS: In this study, a quarter of patients (1020) presenting in the emergency department with acute abdominal pain were affected by functional constipation. Acute pain associated with functional constipation is generally rated from moderate to severe, and the location of the pain on physical evaluation was not a sufficient criterion to guide diagnosis. Isolated vomiting may be present in a minority of cases. Digital rectal exploration was never performed; the majority of patients were treated by means of an enema with prompt relief. Six percent of patients with constipation underwent radiological studies. CONCLUSIONS: This study confirms that the medical history provides a pivotal role in the diagnosis of functional constipation. Digital rectal exploration and x-rays should be avoided in this setting, whereas an enema plays a useful diagnostic and therapeutic role in our study patients. PMID- 28632579 TI - Correspondence. PMID- 28632580 TI - Reply. PMID- 28632581 TI - Multicenter retrospective study of noncompressible torso hemorrhage: Anatomic locations of bleeding and comparison of endovascular versus open approach. AB - BACKGROUND: Rational development of technology for rapid control of noncompressible torso hemorrhage (NCTH) requires detailed understanding of what is bleeding. Our objectives were to describe the anatomic location of truncal bleeding in patients presenting with NCTH and compare endovascular (ENDO) management versus open (OPEN) management. METHODS: This is a retrospective study of adult trauma patients with NCTH admitted to four urban Level I trauma centers in the Houston and San Antonio metropolitan areas in 2008 to 2012. Inclusion criteria include named axial torso vessel disruption, Abbreviated Injury Scale chest or abdomen score of 3 or higher with shock (base excess, <-4) or truncal operation in 90 minutes or less, or pelvic fracture with ring disruption. Exclusion criteria include isolated hip fractures, falls from standing, or prehospital cardiopulmonary resuscitation. After dichotomizing into OPEN, ENDO, and resuscitative thoracotomy (RT) groups based on the initial approach to control NCTH, a mixed-effects Poisson regression with robust error variance (controlling for age, mechanism, Injury Severity Score, shock, hypotension, and severe head injury as fixed effects and site as a random effect) was used to test the hypothesis that ENDO was associated with reduced in-hospital mortality in NCTH patients. RESULTS: Five hundred forty-three patients with NCTH underwent ENDO (n = 166, 31%), OPEN (n = 309, 57%), or RT (n = 68, 12%). Anatomic bleeding locations were 25% chest, 41% abdomen, and 31% pelvis. ENDO was used to treat relatively few types of vascular injuries, whereas OPEN and RT injuries were more diverse. ENDO patients had more blunt trauma (95% vs. 34% vs. 32%); severe injuries (median Injury Severity Score, 34 vs. 27 vs. 21), and increased time to intervention (median, 298 vs. 92 vs. 51 minutes) compared with OPEN and RT. Mortality was 15% versus 20% versus 79%. ENDO was associated with decreased mortality compared to OPEN (relative risk, 0.58; 95% confidence interval, 0.46 0.73). CONCLUSION: Although ENDO may reduce mortality in NCTH patients, significant group differences limit the generalizability of this finding. LEVEL OF EVIDENCE: Therapeutic, level V. PMID- 28632582 TI - The effect of resuscitative endovascular balloon occlusion of the aorta, partial aortic occlusion and aggressive blood transfusion on traumatic brain injury in a swine multiple injuries model. AB - BACKGROUND: Despite clinical reports of poor outcomes, the degree to which resuscitative endovascular balloon occlusion of the aorta (REBOA) exacerbates traumatic brain injury (TBI) is not known. We hypothesized that combined effects of increased proximal mean arterial pressure (pMAP), carotid blood flow (Qcarotid), and intracranial pressure (ICP) from REBOA would lead to TBI progression compared with partial aortic occlusion (PAO) or no intervention. METHODS: Twenty-one swine underwent a standardized TBI via computer Controlled cortical impact followed by 25% total blood volume rapid hemorrhage. After 30 minutes of hypotension, animals were randomized to 60 minutes of continued hypotension (Control), REBOA, or PAO. REBOA and PAO animals were then weaned from occlusion. All animals were resuscitated with shed blood via a rapid blood infuser. Physiologic parameters were recorded continuously and brain computed tomography obtained at specified intervals. RESULTS: There were no differences in baseline physiology or during the initial 30 minutes of hypotension. During the 60-minute intervention period, REBOA resulted in higher maximal pMAP (REBOA, 105.3 +/- 8.8; PAO, 92.7 +/- 9.2; Control, 48.9 +/- 7.7; p = 0.02) and higher Qcarotid (REBOA, 673.1 +/- 57.9; PAO, 464.2 +/- 53.0; Control, 170.3 +/- 29.4; p < 0.01). Increases in ICP were greatest during blood resuscitation, with Control animals demonstrating the largest peak ICP (Control, 12.8 +/- 1.2; REBOA, 5.1 +/- 0.6; PAO, 9.4 +/- 1.1; p < 0.01). There were no differences in the percentage of animals with hemorrhage progression on CT (Control, 14.3%; 95% confidence interval [CI], 3.6-57.9; REBOA, 28.6%; 95% CI, 3.7-71.0; and PAO, 28.6%; 95% CI, 3.7-71.0). CONCLUSION: In an animal model of TBI and shock, REBOA increased Qcarotid and pMAP, but did not exacerbate TBI progression. PAO resulted in physiology closer to baseline with smaller increases in ICP and pMAP. Rapid blood resuscitation, not REBOA, resulted in the largest increase in ICP after intervention, which occurred in Control animals. Continued studies of the cerebral hemodynamics of aortic occlusion and blood transfusion are required to determine optimal resuscitation strategies for multi-injured patients. PMID- 28632583 TI - Incremental balloon deflation following complete resuscitative endovascular balloon occlusion of the aorta results in steep inflection of flow and rapid reperfusion in a large animal model of hemorrhagic shock. AB - INTRODUCTION: To avoid potential cardiovascular collapse after resuscitative endovascular balloon occlusion of the aorta (REBOA), current guidelines recommend methodically deflating the balloon for 5 minutes to gradually reperfuse distal tissue beds. However, anecdotal evidence suggests that this approach may still result in unpredictable aortic flow rates and hemodynamic instability. We sought to characterize aortic flow dynamics following REBOA as the balloon is deflated in accordance with current practice guidelines. METHODS: Eight Yorkshire-cross swine were splenectomized, instrumented, and subjected to rapid 25% total blood volume hemorrhage. After 30 minutes of shock, animals received 60 minutes of Zone 1 REBOA with a low-profile REBOA catheter. During subsequent resuscitation with shed blood, the aortic occlusion balloon was gradually deflated in stepwise fashion at the rate of 0.5 mL every 30 seconds until completely deflated. Aortic flow rate and proximal mean arterial pressure (MAP) were measured continuously over the period of balloon deflation. RESULTS: Graded balloon deflation resulted in variable initial return of aortic flow (median, 78 seconds; interquartile range [IQR], 68-105 seconds). A rapid increase in aortic flow during a single balloon deflation step was observed in all animals (median, 819 mL/min; IQR, 664 1241 mL/min) and corresponded with an immediate decrease in proximal MAP (median, 30 mm Hg; IQR, 14.5-37 mm Hg). Total balloon volume and time to return of flow demonstrated no correlation (r = 0.016). CONCLUSION: This study is the first to characterize aortic flow during balloon deflation following REBOA. A steep inflection point occurs during balloon deflation that results in an abrupt increase in aortic flow and a concomitant decrease in MAP. Furthermore, the onset of distal aortic flow was inconsistent across study animals and did not correlate with initial balloon volume or relative deflation volume. Future studies to define the factors that affect aortic flow during balloon deflation are needed to facilitate controlled reperfusion following REBOA. PMID- 28632584 TI - Featured Articles for CME Credit July 2017. PMID- 28632586 TI - Interrater and Intrarater Reliability of Arthroscopic Measurements of Articular Cartilage Defects in the Knee. AB - BACKGROUND: Cartilage lesions of the knee are difficult to treat. Lesion size is a critical factor in treatment algorithms, and the accurate, reproducible sizing of lesions is important. In this study, we evaluated the interrater and intrarater reliability of, and correlations in relation to, various arthroscopic sizing techniques. METHODS: Five lesions were created in each of 10 cadaveric knees (International Cartilage Repair Society grade 3C). Three orthopaedic surgeons used 4 techniques (visualization and use of a 3-mm probe, a simple metal ruler, and a sliding metallic ruler tool) to estimate lesion size. Repeated measures data were analyzed using a mixed-effect linear model. The differences between observed and gold-standard (plastic mold) values were used as the response. Intraclass and interclass correlation coefficient (ICC) values for intrarater and interrater reliability were computed, as were overall correlation coefficients between measurements and gold standards. RESULTS: The mean lesion size was 2.37 cm (range, 0.36 to 6.02 cm). Rater, lesion location and size, and measurement method all affected the cartilage defect measurements. Surgeons underestimated lesion size, and measurements of larger lesions had a higher percentage of error compared with those of smaller lesions. When compared with plastic molds of lesions, 60.5% of surgeon measurements underestimated lesion size. Overall, the correlation between measurements and gold standards was strongest for the simple metal ruler method and weakest for the visualization method. CONCLUSIONS: Several factors may influence arthroscopic estimation of cartilage lesion size: the lesion location, measurement tool, surgeon, and defect size itself. The intrarater and interrater reliability was moderate to good using a 3-mm probe, sliding metallic ruler tool, or simple metal ruler and was fair to moderate using visualization only. CLINICAL RELEVANCE: There is a need for more accurate methods of determining the size of articular cartilage lesions. PMID- 28632587 TI - The Clinical Outcome of Computer-Navigated Compared with Conventional Knee Arthroplasty in the Same Patients: A Prospective, Randomized, Double-Blind, Long Term Study. AB - BACKGROUND: The available comparative studies of computer navigation-assisted and conventional knee arthroplasties have short-term follow-up periods. Therefore, the clinical benefits after long-term follow-up are not clear. The purposes of the current long-term study were to compare clinical outcomes, alignment of the knee components, prevalence of aseptic loosening of the components, implant survival, and complications of total knee arthroplasties performed with and without computer navigation. METHODS: We prospectively compared the results of 162 consecutive patients (324 knees) with osteoarthritis. These patients had computer-navigated knee arthroplasty in 1 knee and knee arthroplasty without computer navigation in the other. Nine men and 153 women were enrolled in the study. At the time of the index arthroplasty, the mean age of these patients was 68.1 years (range, 49 to 81 years). The mean duration of follow-up was 12.3 years (range, 12 to 13 years). Clinical and radiographic follow-up examinations of the patients were performed at 3 months, 1 year after the operation, and every 2 or 3 years thereafter. RESULTS: The Knee Society knee score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and range of knee motion were not significantly different between the groups preoperatively or at 12.3 years of follow-up. Patient satisfaction at the final follow-up was not significantly different between the groups. There were no significant differences between the groups with respect to the position and loosening of the components at 12.3 years of follow-up. The Kaplan-Meier survivorship, with revision or loosening as the end point, was 100% (95% confidence interval [CI], 94% to 100%) at 12.3 years in both groups. The prevalence of anterior femoral notching was higher in the computer-navigated knee arthroplasty group (5%) than in the conventional knee arthroplasty group (0.6%). CONCLUSIONS: Clinical function, position, and survivorship of the components were similar between the groups. The only effect of navigation was a negative one, anterior femoral notching. However, comparison of bilateral total knee arthroplasties may dampen the differentiation regarding pain outcomes. Further, the findings of this study are specific to a single navigation and total knee system. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632588 TI - Survivorship and Outcomes 10 Years Following Hip Arthroscopy for Femoroacetabular Impingement: Labral Debridement Compared with Labral Repair. AB - BACKGROUND: Studies have demonstrated hip arthroscopy to be an effective treatment for femoroacetabular impingement (FAI) with associated labral tears. The purposes of this study were to report 10-year outcomes and hip survival following hip arthroscopy for FAI and to compare labral debridement with labral repair. METHODS: Prospectively collected data on patients followed for a minimum of 10 years after hip arthroscopy for FAI with either labral debridement or labral repair performed by a single surgeon were retrospectively analyzed. The primary patient-reported outcome measure was the Hip Outcome Score (HOS) Activities of Daily Living (ADL) subscale. Mann-Whitney U tests were used to compare outcomes between groups, and Wilcoxon signed-rank tests were used to compare preoperative with postoperative scores. Survival analysis was performed using a multivariate Cox proportional hazards model. RESULTS: Seventy-nine patients who underwent labral repair and 75 who underwent debridement were included in the study, and 94% (145) were followed for >=10 years. Fifty patients (34%) underwent total hip arthroplasty (THA) within 10 years following the arthroscopy. Older patients, hips with >2 mm of joint space preoperatively, and patients requiring acetabular microfracture had significantly higher prevalences of THA. The multivariate Cox proportional hazards model showed that increased age (hazard ratio [HR] for 31 years to 51 years = 3.06, 95% confidence interval [CI] = 1.69 to 5.56, p < 0.001), a joint space of <=2 mm (HR = 4.26, 95% CI = 1.98 to 9.21, p < 0.001), and acetabular microfracture (HR = 2.86, 95% CI = 1.07 to 7.62, p = 0.036) were independently associated with an increased hazard rate for THA. When the analysis was adjusted for these factors, there was no significant difference in the HR between treatment groups (HR = 1.10, 95% CI = 0.59 to 2.05, p = 0.762). There was also no significant difference in postoperative outcome scores between groups. The debridement group demonstrated a significant increase, between the preoperative and postoperative evaluations, in the HOS-ADL score (from 71 to 96; p < 0.001), HOS-Sport score (from 42 to 89; p < 0.001), modified Harris hip score (mHHS) (from 62 to 90; p < 0.001), and Short Form-12 physical component summary (SF-12 PCS) score (from 43 to 56; p < 0.001). The repair group also demonstrated a significant increase in the HOS-ADL score (from 71 to 96; p < 0.001), HOS-Sport score (from 47 to 87; p < 0.001), mHHS score (from 65 to 85; p < 0.001), and SF-12 PCS score (from 41 to 56; p < 0.001). The median patient satisfaction score was 10 (very satisfied) in both groups. CONCLUSIONS: Hip arthroscopy for FAI with labral debridement or repair resulted in significant improvements in the patient-reported outcomes and satisfaction of patients who did not eventually require THA. Higher rates of conversion to THA were seen in older patients, patients treated with acetabular microfracture, and hips with <=2 mm of joint space preoperatively, regardless of labral treatment. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632589 TI - Emergency Department Visits Following Elective Total Hip and Knee Replacement Surgery: Identifying Gaps in Continuity of Care. AB - BACKGROUND: Major joint replacement surgical procedures are common, elective procedures with a care episode that includes both inpatient readmissions and postoperative emergency department (ED) visits. Inpatient readmissions are well studied; however, to our knowledge, little is known about ED visits following these procedures. We sought to characterize 30-day ED visits following a major joint replacement surgical procedure. METHODS: We used administrative records from California, Florida, and New York, from 2010 through 2012, to identify adults undergoing total knee and hip arthroplasty. Factors associated with increased risk of an ED visit were estimated using hierarchical regression models controlling for patient variables with a fixed hospital effect. The main outcome was an ED visit within 30 days of discharge. RESULTS: Among the 152,783 patients who underwent major joint replacement, 5,229 (3.42%) returned to the inpatient setting and 8,883 (5.81%) presented to the ED for care within 30 days. Among ED visits, 17.94% had a primary diagnosis of pain and 25.75% had both a primary and/or a secondary diagnosis of pain. Patients presenting to the ED for subsequent care had more comorbidities and were more frequently non-white with public insurance relative to those not returning to the ED (p < 0.001). There was a significantly increased risk (p < 0.05) of isolated ED visits with regard to type of insurance when patients with Medicaid (odds ratio [OR], 2.28 [95% confidence interval (CI), 2.04 to 2.55]) and those with Medicare (OR, 1.38 [95% CI, 1.29 to 1.47]) were compared with patients with private insurance and with regard to race when black patients (OR, 1.38 [95% CI, 1.25 to 1.53]) and Hispanic patients (OR, 1.12 [95% CI, 1.03 to 1.22]) were compared with white patients. These increases in risk were stronger for isolated ED visits for patients with a pain diagnosis. CONCLUSIONS: ED visits following an elective major joint replacement surgical procedure were numerous and most commonly for pain-related diagnoses. Medicaid patients had almost double the risk of an ED or pain-related ED visit following a surgical procedure. The future of U.S. health-care insurance coverage expansions are uncertain; however, there are ongoing attempts to improve quality across the continuum of care. It is therefore essential to ensure that all patients, particularly vulnerable populations, receive appropriate postoperative care, including pain management. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632590 TI - Comparison of Anterior and Posterior Surgery for Degenerative Cervical Myelopathy: An MRI-Based Propensity-Score-Matched Analysis Using Data from the Prospective Multicenter AOSpine CSM North America and International Studies. AB - BACKGROUND: Surgeons often choose between 2 different approaches (anterior and posterior) for surgical treatment of degenerative cervical myelopathy on the basis of imaging features of spinal cord compression, the number of levels affected, and the spinal alignment. However, there is a lack of consensus on which approach is preferable. The objective of the present study was to use magnetic resonance imaging (MRI)-based propensity-score-matched analysis to compare postoperative outcomes between the anterior and posterior surgical approaches for degenerative cervical myelopathy. METHODS: A total of 757 patients were enrolled in 2 prospective multicenter AOSpine studies, which involved 26 international sites. Preoperative MRIs were reviewed to characterize the causes of the cord compression, including single-level disc disease, multilevel disc disease, ossification of the posterior longitudinal ligament, enlargement of the ligamentum flavum, vertebral subluxation/spondylolisthesis, congenital fusion, number of compressed levels, or kyphosis. The propensity to choose anterior decompression was calculated using demographic data, preoperative MRI findings, and the modified Japanese Orthopaedic Association (mJOA) scores in a logistic regression model. We then performed 1-to-1 matching of patients who had received anterior decompression with those who had the same propensity score but had received posterior decompression to compare 2-year postoperative outcomes and 30 day perioperative complication rates between the 2 groups after adjustment for background characteristics. RESULTS: A total of 435 cases were included in the propensity score calculation, and 1-to-1 matching resulted in 80 pairs of anterior and posterior surgical cases; 99% of these matched patients had multilevel compression. The anterior and posterior groups did not differ significantly in terms of the postoperative mJOA score (15.1 versus 15.3, p = 0.53), Neck Disability Index (20.5 versus 24.1, p = 0.44), or Short Form-36 (SF 36) Physical Component Summary (PCS) score (41.9 versus 40.9, p = 0.30). The overall rates of perioperative complications were similar between the 2 groups (16% versus 11%, p = 0.48); however, dysphagia/dysphonia was reported only in the anterior group whereas surgical site infection and C5 radiculopathy were reported only in the posterior group. CONCLUSIONS: Anterior and posterior decompression for degenerative cervical myelopathy resulted in similar postoperative outcomes and rates of complications. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632591 TI - Acetabular Retroversion, but Not Increased Acetabular Depth or Coverage, in Slipped Capital Femoral Epiphysis: A Matched-Cohort Study. AB - BACKGROUND: Femoral head overcoverage by a deep and retroverted acetabulum has been postulated as a mechanical factor in slipped capital femoral epiphysis (SCFE). We assessed acetabular depth, coverage, and version in the hips of patients with unilateral SCFE; in the contralateral, uninvolved hips; and in healthy control hips. METHODS: Thirty-six patients affected by unilateral SCFE were matched to 36 controls on the basis of sex and age. The acetabular depth width ratio (ADR), the lateral center-edge angle (LCEA), the anterior and posterior acetabular sector angle (ASA), and version (10 mm distal to the highest point of the acetabular dome and at the level of the femoral head center) were assessed on computed tomography (CT). A repeated-measures analysis of variance was used to assess differences among the SCFE, contralateral, and matched-control hips. Pairwise comparisons were conducted using Bonferroni correction for multiple comparisons. RESULTS: The mean coronal ADR was significantly lower in the hips affected by SCFE (311.6) compared with the contralateral hips (336.1) (p = 0.001) but did not differ from that of controls (331.9) (p = 0.08). The mean LCEA was significantly lower in the SCFE hips (29.8 degrees ) compared with the contralateral hips (33.7 degrees ) (p < 0.001) but did not differ from that of controls (32.2 degrees ) (p = 0.25). The mean anterior ASA did not differ between the SCFE hips (65.0 degrees ) and the contralateral hips (66.0 degrees ) (p = 0.68) or the control hips (64.5 degrees ) (p = 1.00). The mean posterior ASA in the SCFE hips (92.5 degrees ) was significantly lower than that in the contralateral hips (96.5 degrees ) (p = 0.002), but no difference was observed between the SCFE hips and controls (96.0 degrees ) (p = 0.83). The acetabulum was retroverted cranially in the SCFE hips compared with the contralateral hips (2.7 degrees versus 6.6 degrees ; p = 0.01) and compared with controls (2.7 degrees versus 9.6 degrees ; p = 0.005). A lower mean value for acetabular version at the level of the femoral head center was also observed in the SCFE hips compared with the contralateral hips (13.9 degrees versus 15.5 degrees ; p = 0.04) and compared with controls (13.9 degrees versus 16.0 degrees ; p = 0.045). No significant difference (p > 0.05) in acetabular measurements was observed between the contralateral and control hips. CONCLUSIONS: In SCFE, the acetabulum has reduced version but is not deeper, nor is there acetabular overcoverage. Additional longitudinal studies will clarify whether acetabular retroversion is a primary abnormality influencing the mechanics of SCFE development or an adaptive response to the slip. Our data suggest that the contralateral, uninvolved hip in patients with unilateral SCFE has normal acetabular morphology. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632592 TI - Changes in Psychological Status and Health-Related Quality of Life Following Total Shoulder Arthroplasty. AB - BACKGROUND: There has been little documentation of the effects of total shoulder arthroplasty (TSA) on psychological status and health-related quality of life (HRQoL). We investigated changes in psychological status (depression and anxiety) and HRQoL following TSA and assessed the effect of preoperative psychological status on postoperative clinical and functional outcome. We hypothesized that TSA would improve both psychological status and HRQoL. METHODS: We prospectively enrolled 46 patients undergoing TSA for osteoarthritis. Preoperatively and at 3, 6, and 12 months postoperatively, all of the subjects completed the visual analog scale (VAS) for pain, the American Shoulder and Elbow Surgeons Scale (ASES), the Subjective Shoulder Value (SSV) measure, the Hospital Anxiety and Depression Scale (HADS), and the World Health Organization Quality of Life Scale Abbreviated Version (WHOQOL-BREF). RESULTS: From 3 months after surgery, significant improvement in HADS-depression, HADS-anxiety, and WHOQOL-BREF scores as well as in the other outcome measures of VAS pain score, ASES score, and SSV were observed. The prevalence of depression and anxiety decreased from a rate of 15.2% and 19.5%, respectively, preoperatively to a rate of 6.5% for each at 12 months postoperatively. Preoperative HADS-depression and HADS-anxiety scores did not correlate with any of the clinical and functional outcome measures at 12 months after surgery. CONCLUSIONS: This study showed significant improvement in psychological status and HRQoL as well as in pain and functional ability from 3 months after TSA in patients with osteoarthritis. Preoperative depression and anxiety did not predict poor postoperative outcome. Our findings suggest that TSA offers an excellent chance of improving psychological status and HRQoL. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632593 TI - Functional and Radiographic Outcomes Following Growth-Sparing Management of Early Onset Scoliosis. AB - BACKGROUND: In this study, we sought to evaluate radiographic, functional, and quality-of-life outcomes of patients who have completed growth-sparing management of early-onset scoliosis. METHODS: This prospective study involved patients with early-onset scoliosis who underwent growth-sparing treatment and either "final" fusion or observation for >=2 years since the last lengthening procedure. Demographics, radiographic parameters, pulmonary function test (PFT) values, and scores of patient-reported assessments (Early-Onset Scoliosis Questionnaire [EOSQ] and Scoliosis Research Society [SRS]-30) were obtained. At the most recent follow-up, patients performed 2 additional functional outcome tests: step activity monitoring and a treadmill exercise-tolerance test. RESULTS: Twelve patients were evaluated as "graduates" of growth-sparing management of early onset scoliosis (mean of 37 months since the most recent surgery). The major scoliosis curve measurement averaged 88 degrees before treatment and 47 degrees at the most recent follow-up. T1-S1 height increased from a mean of 22.3 cm to 34.7 cm and T1-T12 height, from 13.3 to 22.3 cm. At the most recent follow-up, the mean forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) as a percentage of the predicted volume were 52.1% and 55.3%, respectively, and were essentially unchanged from the earliest PFT that patients could perform (FEV1 = 53.8% of predicted and FVC = 53.5% of predicted). There was no difference between graduates and controls with respect to activity time or total steps in step-activity monitoring, and in the exercise-tolerance test, graduates walked at the same speed but at a higher heart rate and at a significantly higher (p <0.001) VO2 cost (rate of oxygen consumed per distance traveled). The EOSQ mean score was 102.2 of a possible 120 points, and the SRS mean score was 4.1 of a possible 5 points. CONCLUSIONS: A realistic long-term goal for the management of early-onset scoliosis appears to be spine elongation and maintenance of pulmonary function at a level that is no less than the percentage of normal at initial presentation. Functional testing and patient-reported outcomes at a mean of 3 years from the last surgery suggest that activity levels were generally equal to those of controls but required greater physiologic demand. General health and physical function outcomes revealed continued impairment in these domains. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632594 TI - Outcome of Early and Late Diagnosed Essex-Lopresti Injury. AB - BACKGROUND: The aim of this study was to investigate the outcomes in a large series of Essex-Lopresti injuries (ELIs) and to compare patients with early and late diagnoses. METHODS: Thirty-one patients with an ELI (average age and standard deviation [SD], 46 +/- 10 years) who were followed for a minimum of 2 years were included in the study. Patients were grouped according to whether the ELI had been diagnosed early (on the day of the injury) or late (>4 weeks after the radial head injury). Acute treatment of early-diagnosed ELI included temporary stabilization of the distal radioulnar joint (DRUJ) by Kirschner wires with the forearm in supination for 6 weeks. Clinical outcomes were assessed on the basis of the range of motion, Mayo Elbow Performance Score (MEPS), Mayo Wrist Score (MWS), visual analog scale (VAS) score for wrist and elbow pain, and Disabilities of the Arm, Shoulder and Hand (DASH) score. RESULTS: The ELI was diagnosed on the day of the injury in 16 patients (52%; the early group) and late (at a mean of 7 +/- 7 months; range, 1 to 24 months) in 15 (48%; the late group). After a mean duration of follow-up of 5.3 +/- 3.0 years (range, 2.0 to 13.1 years), patients with an early diagnosed ELI had significantly better clinical outcomes, compared with those with a late diagnosis, with regard to the MEPS (91.3 +/- 8.7 versus 74.7 +/- 15.3, p = 0.003), MWS (81.3 +/- 16.5 versus 66.3 +/ 17.6, p = 0.019), DASH score (12.5 +/- 8.7 versus 45.3 +/- 23.5, p = 0.001), VAS elbow pain score (0.7 +/- 1.1 versus 3.3 +/- 2.1, p = 0.001), and VAS wrist pain score (0.9 +/- 1.2 versus 3.9 +/- 1.7, p < 0.001). The ranges of motion of the elbow and wrist did not differ significantly between the early and late groups (p > 0.05). A significantly higher percentage of patients had complications or subsequent surgical procedures in the early than in the late group (38% [6 of 16] versus 93% [14 of 15], p < 0.001). CONCLUSIONS: Early diagnosis of an ELI with temporary stabilization of the DRUJ leads to satisfactory clinical mid-term results, whereas late diagnosis of an ELI is associated with a deteriorated outcome. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632595 TI - Plate Fixation Versus Nonoperative Treatment for Displaced Midshaft Clavicular Fractures: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: The aim was to analyze whether patients with a displaced midshaft clavicular fracture are best managed with plate fixation or nonoperative treatment with respect to nonunion, secondary operations, and functional outcome, by evaluating all available randomized controlled trials (RCTs) on this subject. METHODS: A systematic search of electronic databases (PubMed, MEDLINE, Embase, and Web of Science) was performed to identify RCTs comparing nonoperative treatment with plate fixation for displaced midshaft clavicular fractures. Risk of bias of the studies was assessed. Outcomes evaluated were nonunion, shoulder function (Constant score and Disabilities of the Arm, Shoulder and Hand [DASH] score), and secondary operations. RESULTS: Six RCTs (614 patients) were included. The risk of nonunion was lower in the operatively treated patients (relative risk [RR] = 0.14, 95% confidence interval [CI] = 0.06 to 0.32). One-third of the patients with a nonunion did not receive further treatment. Secondary operations for adverse events were performed less often in the operatively treated patients (RR = 0.42, 95% CI = 0.25 to 0.71). When plate removal operations were also included, a secondary operation was performed in 17.6% in the operative group and 16.6% in the nonoperative group (RR = 1.01, 95% CI = 0.64 to 1.59). Constant and DASH scores after 1 year were somewhat better after plate fixation, with mean differences of 4.4 points (95% CI, 0.9 to 7.9 points) and 5.1 points (95% CI, 0.1 to 10.1 points), respectively. CONCLUSIONS: Plate fixation significantly reduces the risk of nonunion, but does not have a clinically relevant advantage regarding final functional outcome. Secondary operations are common after both treatments. Overall, there is not enough evidence to support routine operative treatment for all patients with a displaced midshaft clavicular fracture. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632596 TI - What's New in Spine Surgery. PMID- 28632597 TI - Leadership, Communication, and Negotiation Across a Diverse Workforce*: An AOA Critical Issues Symposium. AB - The current workforce in the United States is rapidly changing and is increasingly inclusive of individuals from a broad range of ages, ethnicities, and cultural backgrounds. Engaging and leading a diverse workforce creates great opportunities for innovation and adaptation in our evolving medical economic and clinical care delivery environment. For optimal engagement of employees and partners, orthopaedic surgeons must develop the necessary skills for executing change inside complex organizations and across teams composed of a variety of providers and skilled workers. Important skills include leadership, effective communication, and negotiation within an ever-changing employee milieu. Understanding generalizable differences between age-based generations can increase the effectiveness of one's strategies to execute change and increase organizational performance. One of the greatest impediments to effective communication and negotiations that all leaders face is unconscious bias. For leaders, even the tiniest unconscious biases have an outsized impact. Common domains that harbor unconscious bias include sex, race, and ethnicity. Addressing unconscious bias begins with developing awareness and then deploying various tactics that might include equity in compensation, promotion, and "being heard." Effective negotiation skills also are essential to lead a diverse workforce and develop a successful organization. The most basic goal in any negotiation should be to establish a relationship (or deepen an existing relationship) while seeking an agreement that provides win-win opportunities for all parties. To effectively achieve a win-win scenario, leaders must recognize and address their tendency to interpret others' behaviors, values, and beliefs through the lens of their own beliefs and experiences. Finally, and fortunately, there is a set of leader attributes that transcends the generational differences and diversity that is encountered in the workplace. These attributes include integrity, credibility, effective listening, having a vision of your destination, fairness, humility, and caring. PMID- 28632598 TI - The 2015 Austrian-Swiss-German Fellowship Report. PMID- 28632599 TI - Publication Productivity of Orthopaedic Surgery Chairs. AB - BACKGROUND: As academic leaders, orthopaedic chairs represent role models for scholarly activities. Despite the importance of journal publications as a measure of scholarly activity, data on the publication productivity of orthopaedic chairs remain limited. The goals of this study were to record the publication productivity of orthopaedic chairs and evaluate the extent to which they maintained their scholarly activity while serving as chairs. METHODS: The chairs of all orthopaedic residency programs in the United States were identified through the Accreditation Council for Graduate Medical Education (ACGME) web site, and were confirmed by information found on the web site of each orthopaedic program that was included in the study. University and non-university chairs were defined based on affiliation of the program with a medical school. The publication records of the program chairs were retrieved through the Scopus database. RESULTS: During the 7 years prior to their appointment to chair, the mean number of total publications was significantly higher for university chairs (n = 58.6, range 0 to 217) than for non-university chairs (n = 29.1, range 0 to 13) (p = 0.003). The mean number of publications per year during the 7 years leading up to the chair position was 4.66 (range, 0 to 25) for the university chairs, and 2.29 (range, 0 to 10.9) for the non-university group (p = 0.02). While serving as chair, the mean number of publications per year significantly decreased among the university chairs to 3.75 (range, 0 to 32.8; p = 0.015), whereas no significant change was observed among non-university chairs. The mean percentage of first authorships was not significantly different between university and non-university chairs. Both groups showed significant declines in first authorships while serving as chair. CONCLUSIONS: At the time of becoming chair, the average university chair had published approximately 60 manuscripts, whereas the average non-university chair had published approximately 30 manuscripts. While serving as chair, the number of publications per year significantly decreased for university chairs. Among all chairs, the percentage of first authorships significantly decreased while serving as chair. PMID- 28632600 TI - Does Size Really Matter?: Commentary on an article by David C. Flanigan, MD, et al.: "Interrater and Intrarater Reliability of Arthroscopic Measurements of Articular Cartilage Defects in the Knee". PMID- 28632601 TI - Navigation in Total Knee Arthroplasty: A Procedure Whose Time Has Not Come: Commentary on an article by Young-Hoo Kim, MD, et al.: "The Clinical Outcome of Computer-Navigated Compared with Conventional Knee Arthroplasty in the Same Patients. A Prospective, Randomized, Double-Blind, Long-Term Study". PMID- 28632602 TI - Visits to the Emergency Department After Joint Replacement: Commentary on an article by Micaela A. Finnegan, BA, et al.: "Emergency Department Visits Following Elective Total Hip and Knee Replacement Surgery: Identifying Gaps in Continuity of Care". PMID- 28632603 TI - Which Way Do We Go?: Commentary on an article by So Kato, MD, et al.: "Comparison of Anterior and Posterior Surgery for Degenerative Cervical Myelopathy. An MRI Based Propensity-Score-Matched Analysis Using Data from the Prospective Multicenter AOSpine CSM North America and International Studies". PMID- 28632604 TI - Reassessing the Anatomic Origin of the Juvenile Nasopharyngeal Angiofibroma. AB - OBJECTIVE: A modern imaging review is necessary to further define the anatomic origin of the juvenile nasopharyngeal angiofibroma. METHODS: After institutional review board approval, a search from January 1998 to January 2013 yielded 33 male patients (aged 10-23 years) with pathologically proven juvenile nasopharyngeal angiofibroma lesions, as well as pretreatment computed tomography/magnetic resonance imaging. Juvenile nasopharyngeal angiofibroma involvement was assessed in the following regions: sphenopalatine foramen, pterygopalatine fossa, vidian canal, nasopharynx, nasal cavity, sphenoid sinus, choana, pterygomaxillary fissure/masticator space, orbit, and sphenoid bone. RESULTS: The choana and nasopharynx were involved in all 33 patients. In contrast, only 22 lesions involved the pterygopalatine fossa, 24 lesions involved the sphenopalatine foramen, and 28 lesions involved the vidian canal. CONCLUSIONS: Our results suggest that the juvenile nasopharyngeal angiofibroma origin is in the region of the choana and nasopharynx rather than the sphenopalatine foramen or pterygopalatine fossa. PMID- 28632614 TI - Images in Anesthesiology: Torus Palatinus and Airway Management. PMID- 28632616 TI - Should Neuromuscular Blocking Agents Always Be Reversed? PMID- 28632617 TI - Neuromuscular Blockade and Risk of Postoperative Pneumonia. PMID- 28632618 TI - Accounting for Planned Postoperative Intubation. PMID- 28632619 TI - Risk of Postoperative Pneumonia with Neuromuscular Blockade: Keep It Simple! PMID- 28632620 TI - Science or Fiction? Risk of Postoperative Pneumonia with Neuromuscular Blockade. PMID- 28632621 TI - In Reply. PMID- 28632622 TI - In Reply. PMID- 28632623 TI - Assessing Success of Rescue Intubation Techniques after Failed Direct Laryngoscopy. PMID- 28632624 TI - Is Airway Management Better? PMID- 28632625 TI - Apneic Intubation: Video Laryngoscopy Lacks the Continuous Ventilation Offered by Other Airway Management Techniques. PMID- 28632626 TI - In Reply. PMID- 28632627 TI - Calculating Ideal Body Weight: Keep It Simple. PMID- 28632628 TI - In Reply. PMID- 28632629 TI - Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia II (ENIGMA II) Revisited: Patients Still Vomiting. PMID- 28632630 TI - In Reply. PMID- 28632631 TI - Promoting Sustainable Practices via Art. PMID- 28632633 TI - Reply: Role of Rhinoplasty in Transsexual Patients. PMID- 28632634 TI - Role of Rhinoplasty in Transsexual Patients. PMID- 28632635 TI - Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. PMID- 28632636 TI - Reply: Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. PMID- 28632637 TI - Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. PMID- 28632639 TI - Reply: Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. PMID- 28632640 TI - Reply: Facial Contouring by Targeted Restoration of Facial Fat Compartment Volume: The Midface. PMID- 28632641 TI - Reply: Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. PMID- 28632642 TI - Comparing Round and Anatomically Shaped Implants in Augmentation Mammaplasty: The Experts' Ability to Differentiate the Type of Implant. PMID- 28632643 TI - Early Impact of Postoperative Bracing on Pain and Quality of Life After Posterior Instrumented Fusion for Lumbar Degenerative Conditions: A Randomized Trial. AB - STUDY DESIGN: A randomized controlled trial. OBJECTIVE: To investigate whether bracing after posterior spinal instrumented fusion (PSIF) can improve pain relief and quality of life (QoL) 6 weeks and 3 months postoperatively. SUMMARY OF BACKGROUND DATA: Braces are commonly prescribed after PSIF in patients with lumbar degenerative conditions with the aim of improving pain relief and QoL. However, there is a lack of evidence on the indication for postoperative bracing, as surgeons use braces mainly based on their experience and training. METHODS: A randomized blinded and controlled trial of 43 patients with PSIF for lumbar degenerative conditions were recruited. The caregivers were blinded but not the orthotist in the present study. There were 25 patients in the brace group and 18 patients in the control group with similar baseline characteristics. All patients completed the Oswestry Disability Index (ODI), the short form (SF)-12v2 General Health Survey and Visual Analog Scale (VAS) for back pain preoperatively, at 6 weeks and 3 months follow-up. Wilcoxon-Mann-Whitney test and a level of significance of 0.05 were used for statistical analyses. RESULTS: Both groups had comparable demographic characteristics, and preoperative SF-12v2, ODI, and VAS scores. The ODI, SF-12v2, and VAS for back pain were improved in comparison to preoperative scores. The improvement was significant at 3 months follow-up regarding ODI and VAS for both groups and significant only for the control group regarding SF-12v2 scores. The improvement in ODI, SF-12v2, and VAS was significantly greater for control group at 3 months postoperatively. Moreover, larger proportion of patients in the control group reached minimum clinically important difference as compared to brace group at 6 weeks and 3 months. CONCLUSION: Postoperative bracing did not result in better improvement in QoL or pain relief up to 3 months after PSIF in patients with lumbar degenerative conditions. LEVEL OF EVIDENCE: 1. PMID- 28632644 TI - Do Former Smokers Exhibit a Distinct Profile Before and After Lumbar Spine Surgery? AB - STUDY DESIGN: Retrospective longitudinal cohort. OBJECTIVES: To determine if former smokers undergoing lumbar spine surgery have distinct baseline and postoperative patient-reported outcomes (PROs) compared with never smokers and current smokers. SUMMARY OF BACKGROUND DATA: Smoking has known deleterious effects on patients undergoing lumbar spine surgery. However, former smokers have not been extensively evaluated. There are few studies regarding the relationship between pack-years or duration of smoking cessation, and subsequent clinical outcome. METHODS: Patients undergoing lumbar spine surgery at three Quality Outcomes Database participating sites were identified. Demographic, surgical and PRO data including pre-op and 12-month post-op back and leg pain scores, Oswestry Disability Index (ODI) and EuroQOL-5D were collected. Smoking status was assessed from individual medical records. Three cohorts, never smokers, former smokers and current smokers, were compared. Association between PROs and quantitative smoking history and duration of pre-op smoking cessation were evaluated in the former smokers. RESULTS: Of 1187 eligible cases, 843 (71%) had complete data, with 477 never, 250 former, and 116 current smokers. Among patients who had a fusion, baseline and 12-month post-op PROs were significantly different between cohorts, with former smokers having intermediate scores between current and never smokers. In the decompression only group, 12-month ODI was worse in the Current smokers, but overall the effects were much less pronounced. There was a significant negative correlation between smoke-free days before surgery and baseline back pain, ODI, 12-month leg pain and ODI and improvement in ODI. However, the correlation coefficients were small. CONCLUSION: Former smokers have distinct baseline and 12-month post-op PROs that are intermediate between those of never smokers and current smokers. Smoking cessation does not entirely mitigate the negative effects of smoking on baseline and postoperative PROs for patients undergoing lumbar fusion surgery. This effect is less pronounced in patients undergoing decompression alone. LEVEL OF EVIDENCE: 2. PMID- 28632645 TI - Management of Symptomatic Lumbar Disk Herniation: An International Perspective. AB - : : The diversity among the current international practice patterns and the discrepancy between the eminence-based medicine and the evidence-based medicine in the treatment of lumbar disk herniation is presented. Minimally invasive techniques were expected to give the lowest postoperative low back pain, however, also to give the highest risk of recurrent disk herniation. STUDY DESIGN: A questionnaire survey. OBJECTIVE: To evaluate the current practice patterns of surgeons regarding both the surgical and nonsurgical management of lumbar disk herniation (LDH) worldwide and to compare this with the current literature. SUMMARY OF BACKGROUND DATA: Sciatica is a common diagnosis in the general population. Sciatica is most frequently caused by LDH. Multiple surgical techniques and treatment modalities are available to treat LDH, albeit some with small effect sizes or without compelling evidence. METHODS: A survey including questions on the application of physical examination, expectations regarding different surgical and nonsurgical techniques, factors influencing the outcome of surgery were distributed among members of AOSpine International and the European Association of Neurosurgical Societies. RESULTS: Eight hundred and seventeen surgeons from 89 countries completed the questionnaire. These surgeons perform a total of 62.477 discectomies yearly. Pain medication and steroid injections were expected to be the most effective nonsurgical treatments. The severity of pain and/ or disability and failure of conservative therapy were the most important indications for surgery. A period of 1 to 2 months of radiculopathy was regarded as a minimum for indicating surgery. Unilateral transflaval discectomy was the procedure of choice among the majority and was expected to be the most effective technique with the lowest complication risk. Surgeons performing more lumbar discectomies, with more clinical experience and those located in Asia, were more likely to offer minimally invasive surgical techniques. CONCLUSION: This study shows that current international practice patterns for LDH surgery are diverse. There seems to be a discrepancy between preferred surgical techniques and the attitudes of surgeons worldwide and the evidence. Further research should focus on developing international guidelines to reduce practice variety and offer patients the optimal treatment for LDH. LEVEL OF EVIDENCE: N/A. PMID- 28632646 TI - Utility of Adding Magnetic Resonance Imaging to Computed Tomography Alone in the Evaluation of Cervical Spine Injury: A Propensity-Matched Analysis. AB - STUDY DESIGN: Adult patients who received computed tomography (CT) alone or CT magnetic resonance imaging (MRI) for the evaluation of cervical spine injury. OBJECTIVE: To evaluate the utility of CT-MRI in the diagnosis of cervical spine injury using propensity-matched techniques. SUMMARY OF BACKGROUND DATA: The optimal evaluation (CT alone vs. CT and MRI) for patients with suspected cervical spine injury in the setting of blunt trauma remains controversial. METHODS: The primary outcome was the identification of a cervical spine injury, with decision for surgery and change in management considered secondarily. A propensity score was developed based on the likelihood of receiving evaluation with CT-MRI, and this score was used to balance the cohorts and develop two groups of patients around whom there was a degree of clinical equipoise in terms of the imaging protocol. Logistic regression was used to evaluate for significant differences in injury detection in patients evaluated with CT alone as compared to those receiving CT-MRI. RESULTS: Between 2007 and 2014, 8060 patients were evaluated using CT and 693 with CT-MRI. Following propensity-score matching, each cohort contained 668 patients. There were no significant differences between the two groups in baseline characteristics. The odds of identifying a cervical spine injury were significantly higher in the CT-MRI group, even after adjusting for prior injury recognition on CT (odds ratios 2.6; 95% confidence interval 1.7-4.0; P < 0.001). However, only 53/668 patients (8%) in the CT-MRI group had injuries identified on MRI not previously recognized by CT. Only a minority of these patients (n = 5/668, 1%) necessitated surgical intervention. CONCLUSION: In this propensity-matched cohort, the addition of MRI to CT alone identified missed injuries at a rate of 8%. Only a minority of these were serious enough to warrant surgery. This speaks against the standard addition of MRI to CT-alone protocols in cervical spine evaluation after trauma. LEVEL OF EVIDENCE: 3. PMID- 28632648 TI - The Amount of Fluid Given During Surgery That Leaks Into the Interstitium Correlates With Infused Fluid Volume and Varies Widely Between Patients: Erratum. PMID- 28632649 TI - In the Beginning-There Is the Introduction-and Your Study Hypothesis: Erratum. PMID- 28632647 TI - High Osteogenic Potential of Adipose- and Muscle-derived Mesenchymal Stem Cells in Spinal-Ossification Model Mice. AB - STUDY DESIGN: Basic experiments in a mouse model of ossification of the posterior longitudinal ligament (OPLL). OBJECTIVE: To assess the osteogenic potential of mesenchymal stem cells (MSCs) obtained from muscle and adipose tissue in Tiptoe walking (ttw) mice, in which cervical OPLL compresses the spinal cord and causes motor and sensory dysfunction. SUMMARY OF BACKGROUND DATA: In humans, MSCs have been implicated in the pathogenesis of cervical OPLL. Cervical OPLL in ttw mice causes chronic compression of the spinal cord. Few studies have compared the MSC osteogenic potential with behavioral changes in an OPLL animal model. METHODS: We compared the osteogenic potential and behavioral characteristics of MSCs from ttw mice (4 to 20 weeks old) with those from control wild-type mice (without hyperostosis). Ligament ossification was monitored by micro-computed tomography and pathology; tissues were double stained with fluorescent antibodies against markers for MSCs (CD45 and CD105), at 8 weeks. The Basso Mouse Scale was used to assess motor function, and heat and mechanical tests to assess sensory function. The osteogenic potential of adipose and muscle MSCs was assessed by Alizarin Red S absorbance, staining for osteogenic mineralization, and real-time quantitative polymerase chain reaction for osteogenesis-related genes. RESULTS: Spinal ligament ossification began in ttw mice at 8 weeks of age, and the ossified area increased with age. Immunofluorescence staining identified MSCs in the ossification area. The ttw mice became hyposensitive at 8 weeks of age, and Basso Mouse Scale scores showed motor-function deficits starting at 12 weeks of age. Alizarin Red S staining for mineralization showed a higher osteogenic potential in the adipose- and muscle-derived MSCs from ttw mice than from wild-type mice at 4, 8, and 20 weeks of age. Real-time quantitative polymerase chain reaction showed that ttw MSCs strongly expressed osteogenesis-related genes. CONCLUSION: MSCs derived from muscle and adipose tissue in ttw mice had a high osteogenic potential. LEVEL OF EVIDENCE: N/A. PMID- 28632650 TI - Advanced Cardiac Imaging in Adults With Congenital Heart Disease: The Great Wave. PMID- 28632651 TI - Imaging in Adult Congenital Heart Disease. AB - There has been tremendous growth in the population of adults with congenital heart disease (CHD) over the last few decades because of advances in medical care. Whereas some cases are cured during childhood, most patients instead undergo palliation, which leaves them at risk for late complications. Lifelong clinical follow-up involving serial multimodality imaging is helpful to monitor and guide the treatment of late complications. Imaging of these individuals is challenging because of their unique anatomy and therefore requires careful consideration on a case-by-case basis. Knowledge of late complications associated with various diseases and surgical palliations provides a basis for selection and interpretation of an appropriate imaging study. This review highlights the most common conditions in adult CHD and the clinical questions that imaging hopes to answer, as well as the advantages and disadvantages of available imaging modalities. We illustrate clinical scenarios and the use of noninvasive imaging modalities including echocardiography, computed tomography, and magnetic resonance imaging, as well as applications in the following CHDs: tetralogy of Fallot, transposition of the great arteries, coarctation of the aorta, shunts, functional single ventricle, and coronary anomalies. PMID- 28632652 TI - Utility of Cardiac Magnetic Resonance Imaging in the Management of Adult Congenital Heart Disease. AB - The increasing number of patients with adult congenital heart disease (ACHD) calls for the development of noninvasive imaging techniques that allow a long term evaluation of native and postsurgical anatomy and function. Echocardiography remains the imaging modality of choice for congenital heart disease, but it is affected by limited acoustic windows and poor tissue characterization. Cardiac computed tomography and cardiac catheter angiography are 2 valid alternatives for the anatomic and functional assessment of ACHD; however, both use ionizing radiation, and cardiac catheter angiography requires an invasive approach. Cardiac magnetic resonance (CMR), noninvasively and in the absence of ionizing radiation, has the ability to evaluate the biventricular function, quantify flows, characterize tissue, and provide information on cardiac anatomy. Despite the long acquisition time and lower spatial resolution compared with cardiac computed tomography, CMR represents the ideal technique for long-term follow-up of ACHD. CMR is now widely utilized and is well described in the literature with regard to diagnosis, identification of complications, timing of surgery, and postoperative prognosis in ACHD. CMR represents a fundamental technique for the evaluation of patients with ACHD. PMID- 28632653 TI - Imaging Adults With Congenital Heart Disease Part II: Advanced CMR Techniques. AB - Because of great strides in medical care, survival into adulthood has become a common expectation in patients suffering from nearly all forms of congenital heart disease. As this aging population expands, the utilization of cardiac magnetic resonance imaging in their care continues to grow. Magnetic resonance technology has developed exponentially over the last 2 decades, and several advanced techniques for imaging adults with congenital heart disease have moved from the purely research arena into routine clinical care. In particular, 4 dimensional phase-contrast imaging allows comprehensive hemodynamic assessment, myocardial characterization quantifies fibrosis, stress magnetic resonance imaging detects vulnerable myocardium and hemodynamic reserve, and 3-dimensional modeling enables preinterventional planning, all of which are now widespread in their applications. PMID- 28632654 TI - An Overview of Cardiac Computed Tomography in Adults With Congenital Heart Disease. AB - Familiarity with congenital heart disease (CHD) and its manifestations in adults is becoming increasingly important for the practicing cardiothoracic imager. The use of computed tomographic angiography is becoming commonplace not only in adults with a history and subsequent interventions for CHD as a child but also in de novo detection of-typically-milder, survivable forms of CHD, which are clinically suspected because of declining cardiac performance, cardiac events, or murmurs. Occasionally, adult CHD (ACHD) is found incidentally on scans performed for other indications (eg, trauma or neoplasm staging) because of improvements in computed tomographic technology and advanced visualization. A growing number of patients with CHD survive into adulthood and lead essentially normal lives all over the world and may present in community hospitals and emergency rooms to receive care. Advancements in computed tomographic angiography technology have further allowed us to individually tailor cardiovascular scans according to the patient's anatomy and specifically for the clinical question raised, aiming at reduced exposure to iodinated contrast and radiation dose, while obtaining diagnostic-quality images. This task, however, is not simple. There is no one size-fits-all cardiac scan that serves as a one-stop shop for ACHD patients. Careful planning and patient preparation, close supervision of the scan, sophisticated postprocessing, and interdisciplinary interpretation of the findings are all required ingredients for managing patients with ACHD. In this review we highlight the technical principles that should be observed to optimize imaging in ACHD. We also provide practical insight into how specific clinical questions can be answered utilizing this technology in the most frequently encountered forms of ACHD. PMID- 28632655 TI - Scientific Abstracts: 4th World Congress of Thoracic Imaging. PMID- 28632656 TI - Intramedullary Nail Fixation of Atypical Femur Fractures With Bone Marrow Aspirate Concentrate Leads to Faster Union: A Case-Control Study. AB - OBJECTIVES: To evaluate bone marrow aspirate concentrate (BMAC) use in the treatment of AFF. DESIGN: Retrospective case control. SETTING: Level 1 trauma center. PATIENTS: Complete AFF, defined according to American Society of Bone and Mineral Research (ASBMR) criteria, from September 2009 to April 2015 with minimum 1-year follow-up. INTERVENTION: Operative treatment with antegrade intramedullary nails. Beginning June 2014, BMAC from the ipsilateral iliac crest was added to all AFFs. MAIN OUTCOME MEASUREMENTS: Time to union as determined by a blinded panel of 3 attending orthopaedic surgeons, union rates, complications. RESULTS: Thirty-five patients with 36 AFFs were reviewed, of which 33 AFFs were included and 11 received BMAC. Alendronate was the most commonly prescribed bisphosphonate, with a similar mean duration of use in controls and BMAC cases (5.6 versus 6 years, P = 0.79). BMAC use significantly decreased time to union (3.5 versus 6.8 months, P = 0.004). Varus malreduction was associated with a significant delay in union (9.7 versus 4.7 months, P = 0.04). Overall, 1 year union rate was 86.2% and nonsignificantly higher in BMAC compared with controls (100.0% versus 77.3%, P = 0.11). Multivariate analysis revealed BMAC and varus malreduction as independent predictors of time to union. There were no complications related to BMAC use. CONCLUSION: Our findings support intramedullary nailing of AFFs as an effective treatment option with a low surgical complication rate and highlight the importance of avoiding varus malreduction. BMAC use significantly reduced time to fracture union without an increase in surgical complication rates. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28632657 TI - Role of Computed Tomography in the Classification of Pediatric Pelvic Fractures Revisited. AB - OBJECTIVES: To determine the need for computerized tomography (CT) scans in the assessment of pediatric pelvic fractures. DESIGN: Retrospective Chart Review. SETTING: Level-1 Pediatric Trauma Center. PATIENTS/PARTICIPANTS: Thirty pediatric trauma patients with pelvic fractures who have obtained both a radiograph and CT scan. MAIN OUTCOME MEASUREMENTS: Fleiss Kappa coefficient to compare interreliability. RESULTS: The average age of the patients was 7 years (range 1 13 years). Seventeen were males and 13 were females. The Torode and Zieg classification included 3 type I, 6 type II, 13 type III, and 8 type IV. The Kappa value for interobserver agreement comparing radiographs was 0.453, and for CT was 0.42. Three patients (10%) were treated with a spica cast, and none required surgery for their pelvic fracture. Four patients (11%) demonstrated liver, spleen, or kidney injuries on CT. Out of those 4, 1 had indications for laparotomy and drain placement, 1 died secondary to shock, and 2 were treated conservatively. CONCLUSIONS: The results of this study demonstrated that plain radiographs alone can be used to classify and manage most pediatric fractures, confirming Silber previous findings. Furthermore, we recommend the specific instances of Schreck and Haasz et al in which CT scans should be used, sparing the general pediatric population unnecessary radiation. Such cases include patients with an abnormal abdominal or pelvic examination, complex fracture patterns, displacement greater than 1 cm, femur deformities, hematuria, Glasgow Coma Scale <13, hemodynamic instability, an aspartate aminotransferase > 200 U/L, an Hct < 30%, or an abnormal chest x-ray. PMID- 28632658 TI - The Retrograde-Antegrade-Retrograde Technique for Successful Placement of a Retrograde Superior Ramus Screw. AB - Stabilization of pelvic ring injuries and certain acetabular fractures using percutaneous techniques is becoming increasingly more common. Intramedullary superior ramus screw fixation is beneficial in both injury types. While implants can be placed in an antegrade or retrograde direction, parasymphyseal ramus fractures benefit from retrograde implant insertion. In some patients, the parabolic osseous anatomy or obstructing soft tissues of the anterior pelvis or thigh can prevent appropriate hand and instrumentation positioning for appropriate retrograde ramus screw insertion through the entire osseous fixation pathway. Instead of abandoning medullary fixation, we propose a technique utilizing cannulated screws to successfully place retrograde screws in this distinct clinical scenario. PMID- 28632659 TI - The 20th Annual Meeting of the Japanese Research Society of Ultrasound Stimulation for Fracture Repair. PMID- 28632660 TI - Clinical Experience With the Use of Low-Intensity Pulsed Ultrasound (LIPUS) in the Treatment of Atypical Femoral Fractures. AB - OBJECTIVE: The aim of this study was to report the clinical results of atypical femoral fractures (AFFs) treated with low-intensity pulsed ultrasound (LIPUS). MATERIALS AND METHODS: The data on AFFs that were surgically treated in our hospital from 2010 to 2016 was retrospectively analyzed. AFF was diagnosed based on the criteria defined by the second report of an ASBMR task force. RESULTS: Seven fractures in 6 cases were included in this study. Two fractures were referred to us as being nonunion. Five fractures were subtrochanteric fractures and 2 fractures were shaft fractures. Five fresh AFFs were fixed with an intramedullary nail and 2 nonunion fractures were fixed with plates. LIPUS was used in 6 fractures. Bone union was achieved in 5 fractures with the average time to union being 17 months (5-29). In 4 out of the 6 fractures treated with LIPUS, bone union was achieved after 14 months on average. In the other 2 LIPUS-treated fractures, bone union was not achieved even at 1 year after surgery. DISCUSSION: It is known that AFF healing tends to be very slow. Some case reports indicate that AFF healing might be accelerated by LIPUS. In the current series, the subtrochanteric fracture that was not treated with LIPUS healed at 29 months after surgery, which was much longer than the average time to union in the 5 fractures that were treated with LIPUS. Although our number of cases is small, LIPUS may be a potentially useful tool for accelerating AFF repair. PMID- 28632661 TI - Efficacy and Limitations of Conservative Treatment for Painful Patella Partita: Positioning of an Ultrasound-Accelerated Fracture Healing Apparatus. AB - OBJECTIVE: Generally, painful patella partita is conservatively treated, but the usefulness of a low-intensity pulsed ultrasound (LIPUS) healing apparatus is unclear. The objective of this study was to investigate the usefulness of LIPUS for conservative treatment of painful patella partita. SUBJECTS AND METHODS: The subjects included 17 patients diagnosed with painful patella partita. The subjects were divided into 2 groups: those without pain at 6 months (responsive group) and those with pain that persisted for 6 months or longer (non-responsive group). The reasons for the different responses between the 2 groups were investigated. We evaluated various factors, including age, gender, presence or absence of epiphyseal closure on plain xp at the first examination, Saupe classification, presence or absence of bone union, and type of conservative treatment. The grade of limitation of movement, the presence or absence of instruction on quadriceps femoris muscle stretch, and use of an orthosis and LIPUS were also investigated. RESULTS: The responsive and non-responsive groups consisted of 12 and 5 patients, respectively, and included only male patients. The average age was 13 and 16 years old in the responsive and non-responsive groups, respectively. Epiphyseal closure was present in 1 of the 12 patients in the responsive group and 3 of the 5 patients in the non-responsive group. The Saupe classifications in the responsive and in the non-responsive groups, respectively, were type I in 1 and 2 patients (3 total), type II in 6 and 1 patients (7 total), and type III in 4 and 3 patients (7 total). Bone union was achieved in 10 patients in the responsive group, whereas no patient achieved bone union and 3 patients underwent excision in the non-responsive group. Conservative treatment in the responsive and non-responsive groups, respectively, included prohibition of exercise for 7 and 2 patients (9 total) and instruction on quadriceps femoris muscle stretch for 5 and 2 patients (7 total). In addition, all of the 8 patients wearing an orthosis and 2 patients treated with LIPUS were in the responsive group. DISCUSSION: The findings suggest that painful Saupe type II patella partita can be improved by appropriate conservative treatment before epiphyseal closure. LIPUS may be advantageous for bone union and pain relief. PMID- 28632662 TI - Treatment of Incomplete Jones Fractures With Low-Intensity Pulsed Ultrasound (LIPUS). AB - OBJECTIVE: Stress fractures of the proximal epiphysis of the fifth metatarsal bone (termed Jones fracture) frequently occur in both senior high-school-age and older contestant-level soccer players, and its incidence in Japanese soccer players is higher than that in European players. Surgery is most commonly indicated for a complete fracture, and about 3 months are required before the patient is able to return to the sport. We have performed a "Jones fracture screening" to reduce the incidence of these fractures. While surveying its frequency and promoting education on its prevalence and symptoms, we tried to discover incomplete fractures early and treat them using LIPUS without limiting their soccer practice. SUBJECTS AND METHODS: The subjects were 341 students (682 feet) from 3 senior high schools and university soccer clubs. Primary screening for tenderness and by diagnostic ultrasound imaging was performed as a Jones fracture screening. Fifty subjects (50 feet) were positive on the ultrasonic diagnosis, and secondary screening was recommended. Forty subjects underwent radiography (secondary screening rate: 80%), and 5 subjects (5 feet) were diagnosed with incomplete Jones fractures. Conservative treatment centering on LIPUS was performed in these 5 players who still continued to participate in all soccer practices. RESULTS: Bone union was achieved in 2 subjects (2 feet) after about 6 months without taking a break from soccer practice. The other 3 subjects (3 feet) are at 2 months after the diagnosis and are being followed without taking a break from soccer practice. DISCUSSION: Incomplete Jones fractures that are discovered early by an ultrasonic check-up for bone expansion with subsequent early treatment with LIPUS may heal without taking a break from practice. No preventive method has been established for Jones fractures. This check-up may serve as a useful preventative approach, and we will make an effort to suggest it as a common practice. PMID- 28632663 TI - An Examination of the Factors Related to a Reduction in the Use of Low-Intensity Pulsed Ultrasound (LIPUS). AB - OBJECTIVE: We examined the factors related to a reduction in the use of low intensity pulsed ultrasound (LIPUS) for patients at both our hospital and other affiliated institutions. MATERIALS AND METHODS: Of 350 patients who used LIPUS at our and other affiliated institutions from May 2010 to April 2015, 279 (168 males, 111 females) were evaluated, after excluding mortalities and those with unexplained bone adhesion. Those patients with LIPUS compliance [calculated as: (number of days LIPUS was used/number of days LIPUS was available) * 100] below 80% were defined as the non-compliant group (170 patients), and those patients with a compliance rate of 80% or above were defined as the compliant group (109 patients). Factors related to a reduction in compliance were examined and included duration of use, age, sex, fracture side (right or left), and fracture site. RESULTS: The duration of use was longer in the non-compliant group compared with that in the compliant group (mean +/- SD: 160 +/- 118 days vs. 126 +/- 81 days; P = 0.01), and the mean age was younger in the non-compliant group (42 +/- 20 years vs. 50 +/- 21 years; P = 0.002). Additionally, there was a higher ratio of females/males in the compliant group (60/49 vs. 120/50; P = 0.008). However, the side of the fracture was not significantly different between the groups (P = 0.449). Fractures of the forearm were more frequent in the non-compliant group than that in the compliant group (25/170 vs. 7/109; P = 0.003). DISCUSSION: The results suggest that the factors predictive of a reduction in the use of LIPUS are a long period of use, younger age, male gender, and use on fractures of the forearm. PMID- 28632664 TI - Outcome of Low-Intensity Pulsed Ultrasound (LIPUS) for Opening Wedge High Tibial Osteotomy. AB - OBJECTIVE: Opening Wedge High Tibial Osteotomy (OWHTO) for knee osteoarthritis and for osteonecrosis has reported good results. Use of low intensity pulsed ultrasound (LIPUS) after OWHTO had become an option for the treatment of OWHTO since April 2016. The purpose of this study was to examine whether LIPUS has an accelerating effect on synostosis after OWHTO. MATERIALS AND METHODS: The control subjects were 24 patients with a total of 26 knees (9 male with knees and 15 female with 17 knees treated) treated with OWHTO only. OWHTO was performed from April 2015 to March 2016 (non-LIPUS control group). The average age of the patients was 61 years. The test subjects were 25 patients with a total of 27 knees (8 male with 9 knees and 17 female with 18 knees treated) treated with OWHTO and LIPUS. OWHTO was performed from April 2016 until the present. LIPUS was started after the surgery (LIPUS + group). The average age was 64.6 years. FTA, ROM, intraoperative open angle, and the time to bone union were examined. RESULTS: There was no difference between the 2 groups in FTA, ROM, and open angle. Synostosis was obtained in 18 knees in the control group (no LIPUS) with an average duration of 8.4 months. The LIPUS + group had a short observation period with none of the patients experiencing bone union. DISCUSSION: The synostosis promoting effect of LIPUS is expected. In this study, there were no bone union cases because of the short observation period. It is necessary to extend the follow-up period, and clarify the utility of LIPUS. PMID- 28632665 TI - Effect of Low-Intensity Pulsed Ultrasound on Bone Healing at Osteotomy Sites After Open Wedge High Tibial Osteotomy. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of low-intensity pulsed ultrasound (LIPUS) on bone healing at osteotomy sites after open wedge high tibial osteotomy (OWHTO). MATERIALS AND METHODS: Twenty-six patients underwent OWHTO without bone grafting. Thirty cases treated with LIPUS (group L) after surgery were compared with 13 cases without LIPUS treatment (group C). We divided the osteotomy gap into the lateral hinge and 4 zones on anteroposterior radiography, and the progression of gap filling was evaluated at 1, 3, and 6 months post-operatively in both groups. RESULTS: In group L, the lateral hinge formed a union at 3 months postoperatively in 11 knees (84.6%). At 6 months, gap filling in 10 knees (76.9%) reached to zone 2. In group C, while the lateral hinge formed a union at 3 months postoperatively in all cases. At 6 months, gap filling in 6 knees (46.1%) reached to zone 2. The progression of gap filling were 8.5%, 18.9%, and 32.9% (at 1, 3, and 6 months after surgery, respectively) in group L, while the progress levels at the same time points were 7.7%, 16.6%, and 24.4% in group C. There were significant differences at 6 months after surgery between the 2 groups. DISCUSSION: LIPUS accelerated bone healing at 6 months after OWHTO. It is important that the accuracy of LIPUS methods be further studied and improved. PMID- 28632666 TI - Change in Calcaneal Bone Strength in Long-Term Care Residents Treated With Low Intensity Pulsed Ultrasound. AB - OBJECTIVE: We examined the effect of low-intensity pulsed ultrasound (LIPUS) on bone strength in osteoporotic elderly residents. MATERIALS AND METHODS: This was a randomized controlled trial. Elderly residents with osteoporosis in a long-term care facility were treated with LIPUS (oscillation frequency 100 KHz) that involved treatment of the heel bone for 2 minutes a day. The selection of the treated heel was decided randomly with a personal computer. The heel bone mineral density before and after treatment was measured by calcaneal quantitative ultrasound (GE-1000 Express). RESULTS: The study included 23 residents but 3 patients developed fractures and 1 withdrew from the study. Nineteen elder residents (average age 86.9 years) completed the study with ultrasonic quantitation before and after treatment. The average speed of sound (following SOS) of the treated and non-treated side was 1438.3 and 1437.4 m/s, respectively at baseline. After 3 months, the SOS was increased to 1450.8 and 1450.5 m/s, respectively, and after 8 months it increased to, 1452.8 and 1451.6 m/s. There were no significant changes between the treated and the non-treated side of the heel bone. DISCUSSION: LIPUS had no effect on increasing bone density in the elderly residents when treatment duration was 2 minutes per day. We suggest that therapy for osteoporosis with LIPUS for the elderly should be studied in the future to reduce the number of prescribed oral agents. PMID- 28632667 TI - Study on Ultrasound Irradiation Induction of Electrical Potentials in Bone. AB - OBJECTIVE: It is well known that applied stress induces electrical potentials in bone. We have experimentally studied whether induced potentials could be found in bone using an ultrasound irradiation system similar to low-intensity pulsed ultrasound (LIPUS). MATERIALS AND METHODS: Circular plate specimens (diameter 10 mm, thickness 1 mm) were obtained from bovine femora in order to determine if bone behaved as a piezoelectric material. Using these specimens, ultrasound receivers were fabricated. The irradiation of an ultrasound pulsed wave (amplitude 5 kPa, around 1 MHz) induced weak electrical potentials that were almost 0.1% of that observed with conventional ultrasonic transducers using piezoelectric polymer films. RESULTS AND DISCUSSION: The induced potentials clearly depended on the angle between the direction of the irradiation and the direction of the bone axis and showed a maximum when the angle was 45 degrees. It is known that the ultrasonic wave velocity changes due to the propagation direction and shows anisotropy. The behavior of induced potentials, however, was different from the anisotropy of wave velocities. These results tell us that the amount of induced electrical potentials possibly changes depending on the direction of the ultrasound wave produced by the LIPUS system. PMID- 28632668 TI - Low-Intensity Pulsed Ultrasound (LIPUS) Promotes BMP9-Induced Osteogenesis and Suppresses Inflammatory Responses in Human Periodontal Ligament-Derived Stem Cells. AB - OBJECTIVE: We previously reported that low intensity pulsed ultrasound (LIPUS) promotes marrow stromal cell (MSC) osteogenesis and suppresses the LPS-induced inflammatory response in osteoblasts. Here, we examined the effects of LIPUS on human periodontal ligament-derived stem cells (hPDLSCs) in chronic inflammatory bone disease, such as periodontitis. MATERIALS AND METHODS: hPDLSCs were collected from 3 healthy third molars. hPDLSCs were induced to differentiate by either recombinant BMP2 or BMP9 with or without daily LIPUS treatment (20 min/d). hPDLSCs were also stimulated by Porphyromonas gingivalis-derived LPS (LPS-PG), IL 1beta, and TNF-alpha with or without LIPUS. Matrix mineralization was evaluated by alizarin red S staining. The expression of genes for osteogenic makers and for inflammatory cytokines were analyzed by real time RT-PCR. RESULTS: LIPUS promoted BMP9-induced osteogenesis of hPDLSCs based on increases in both cell calcification and osteogenic marker expression. In contrast, LIPUS did not affect BMP2-induced osteogenic differentiation. LIPUS-induced Noggin expression was potentially involved in the differential response of the cells. Either LPS-PG, IL 1beta, or TNF-alpha-induced ERK phosphorylation and IL-8, CCL2, and RANKL expression were decreased in LIPUS-treated hPDLSCs. Moreover, the inhibitory effects of LPS-PG and IL-1beta on osteogenesis of hPDLSCs were significantly blocked by LIPUS. DISCUSSION: LIPUS is an effective tool to promote osteogenic differentiation under inflammatory conditions. PMID- 28632669 TI - Effect of Low-Intensity Pulsed Ultrasound (LIPUS) on Endochondral Ossification via the Wnt Signaling Pathway. AB - OBJECTIVE: We have previously demonstrated that LIPUS stimulates endochondral ossification with decreased expression of sclerostin. The Wnt signaling pathway was examined in vitro to further address the effect of LIPUS on endochondral ossification. MATERIALS AND METHODS: ATDC5 cells were plated at an initial density of 6 * 10 cells/well in a 6-multiwell plate and cultured in the presence of 5% FBS plus ITS. The bottom of the culture plate was treated every day with LIPUS for 20 minutes. The level of calcification and the expression of Wnt signaling were investigated. RESULTS: The area of calcified nodules in the LIPUS treated group was significantly greater than in the control group. The expression of Wnt was significantly elevated by LIPUS exposure. Markers associated with endochondral ossification were increased in the LIPUS-treated group. When sclerostin was added to the culture media, calcified nodule formation and the expression of Wnt were inhibited in both the LIPUS-treated group and the control group. DISCUSSION: This study suggests that endochondral ossification was stimulated by LIPUS via the Wnt signaling pathway. PMID- 28632670 TI - Competency Assessment in Regional Anesthesia: Quantity Today, Quality Tomorrow. PMID- 28632671 TI - Recognizing the Hourglass/Bow-Tie Pattern. PMID- 28632672 TI - Transversus Thoracic Muscle Plane Block on a Cadaver With History of Coronary Artery Bypass Grafting. PMID- 28632673 TI - The Ultrasound-Guided Continuous Erector Spinae Plane Block for Postoperative Analgesia in Video-Assisted Thoracoscopic Lobectomy. PMID- 28632674 TI - Something Is Growing Inside: An Unusual Adverse Effect of Paravertebral Block. PMID- 28632675 TI - Intermittent Bolus Injection Via Peripheral Nerve Catheters May Exceed Occlusion Pressure Limit of an Ambulatory Infusion Pump: An In Vitro Study. PMID- 28632676 TI - Is Central Neuraxial Block Advisable in a Patient With Preexisting Ocular Motor Palsy? PMID- 28632677 TI - Preexisting Ocular Motor Palsy and Central Neuroaxial Block: A Reply to Dr Nair. PMID- 28632678 TI - Transversus Abdominis Plane Block as Analgesic Technique for Postoperative Pain Management After Cesarean Section: No More? PMID- 28632679 TI - Reply to Dr Fusco et al. PMID- 28632680 TI - Single-Injection Technique for Medial Parapatellar Arthrotomy. PMID- 28632681 TI - Reply to Drs Johnston and Sondekoppam. PMID- 28632682 TI - Diaphragm-Sparing Nerve Blocks for Shoulder Surgery: An Alternative Approach. PMID- 28632683 TI - Reply to Dr Bansal et al. PMID- 28632684 TI - If Wishes Were Horses, Beggars Would Ride. PMID- 28632685 TI - "Don't Throw the Baby Out With the Bath Water: " A Reply to Dr. Onwochei et al. PMID- 28632686 TI - Quadratus Lumborum 1 and Transversalis Fascia Blocks: Different Names for the Same Posterior Pararenal Space Block. PMID- 28632687 TI - Reply to Dr Choquet et al. PMID- 28632688 TI - High-Quality 3-Dimensional 1H Magnetic Resonance Spectroscopic Imaging of the Prostate Without Endorectal Receive Coil Using A Semi-LASER Sequence. AB - OBJECTIVES: Inclusion of 3-dimensional H magnetic resonance spectroscopic imaging (3D-H-MRSI) in routine multiparametric MRI of the prostate requires good quality spectra and easy interpretable metabolite maps of the whole organ obtained without endorectal coil in clinically feasible acquisition times. We evaluated if a semi-LASER pulse sequence with gradient offset independent adiabaticity refocusing pulses (GOIA-sLASER) for volume selection can meet these requirements. MATERIALS AND METHODS: Thirteen patients with suspicion of prostate cancer and 1 patient known to have prostate cancer were examined at 3 T with a multichannel body-receive coil. A 3D-H-MRSI sequence with GOIA-sLASER volume selection (echo time, 88 milliseconds) was added to a routine clinical multiparametric MRI examination of these patients. Repetition times from 630 to 1000 milliseconds and effective voxel sizes of approximately 0.9 and 0.6 cm were tested. Spectral components were quantified by LCModel software for quality assessment and to construct choline and citrate maps. RESULTS: Three-dimensional MRSI of the prostate was successfully performed in all patients in measurement times of 5 to 10 minutes. Analysis of the multiparametric MRI examination or of biopsies did not reveal malignant tissue in the prostate of the 13 patients. In 1404 evaluated voxels acquired from 13 patients, the citrate resonance could be fitted with a high reliability (Cramer-Rao lower bound <30%), 100% for 7 * 7 * 7-mm voxels and 96 +/- 7 in 6 * 6 * 6-mm voxels. The percentage of 7 * 7 * 7-mm voxels in which the choline signal was fitted with Cramer-Rao lower bound of less than 30% was approximately 50% at a TR of 630 milliseconds and increased to more than 80% for TRs of 800 milliseconds and above. In the patient with prostate cancer, choline was detectable throughout the prostate in spectra recorded at a TR of 700 milliseconds. The homogeneous B1 field over the prostate of the receive coil enabled the generation of whole organ metabolite maps, revealing choline and citrate variations between areas with normal prostate tissue, seminal vesicles, proliferative benign prostatic hyperplasia, and tumor. CONCLUSIONS: The good signal-to-noise ratio and low chemical shift artifacts of GOIA-sLASER at an echo time of 88 milliseconds enable acquisition of high-quality 3D-H-MRSI of the prostate without endorectal coil in less than 10 minutes. This facilitates reconstruction of easy interpretable, quantitative metabolite maps for routine clinical applications of prostate MRSI. PMID- 28632689 TI - 18F-FDG Uptake in Ischemic Colitis During Follow-up of a Patient With Lung Cancer. AB - A 61-year-old man with previous history of lung adenocarcinoma underwent 2 F-FDG PET/CT investigations. The first for assessment of enlarged mediastinal lymph nodes revealed an area of increased FDG uptake in the sigmoid colon (located at the right pelvis). Colonoscopy showed a segmental area of ischemic sigmoid colitis, confirmed on histology postbiopsy. The asymptomatic man had no risk factors, and no specific treatment was administered, apart from supportive measures. One year later, there was no significantly abnormal uptake on PET/CT. Incidental ischemic colitis may be demonstrated with FDG and PET/CT needing no specific therapeutic measures for resolution. PMID- 28632690 TI - Noninvasive Nuclear SPECT Myocardial Blood Flow Quantitation to Guide Management for Coronary Artery Disease. AB - Recently, myocardial blood flow quantitation with dynamic SPECT has been validated to enhance the detection of multivessel coronary artery disease (CAD) and conclude equivocal SPECT myocardial perfusion study. This advance opened an important clinical application to utilize the tool in guiding CAD management for area where myocardial perfusion tracers for PET are unavailable or unaffordable. We present a clinical patient with ongoing recursive angina who underwent multiple nuclear stress tests for a sequence of CAD evaluation in 26 months and demonstrated that SPECT myocardial blood flow quantitation properly guided CAD management to warrant patient outcome. PMID- 28632691 TI - 18F-FDG Uptake in Benign Fibrous Histiocytoma of Adrenal Gland: A Potential Pitfall. AB - A 47-year-old man with newly diagnosed nasopharyngeal carcinoma underwent staging F-FDG PET/CT. Apart from showing increased FDG uptake in the primary site and locoregional nodal and liver metastases, an unusual site of intense FDG focus was demonstrated in the left adrenal gland. He underwent CT-guided biopsy, and the histopathologic diagnosis was benign fibrous histiocytoma. PMID- 28632692 TI - Improved 123I-Ioflupane Binding After Immunotherapy in Anti-NAE Antibody-Positive Hashimoto Encephalopathy That Clinically Mimicked Multiple System Atrophy. AB - We describe an 84-year-old man with anti-NH2-terminal of alpha-enolase antibody positive Hashimoto encephalopathy that clinically mimicked multiple system atrophy who underwent investigation by dopamine transporter SPECT before and after immunotherapy. Before treatment, dopamine transporter SPECT showed reduced striatal I-ioflupane binding, with a mean specific binding ratio of 2.42, even though he had no apparent parkinsonism. After immunotherapy, mean specific binding ratio was improved to 3.22. Dopamine transporter SPECT was useful in this case to detect subclinical striatal dysfunction, and evaluation both before and after immunotherapy helped to distinguish between neurodegenerative disease and neuroimmunological disorder. PMID- 28632693 TI - Extraosseous Extension of Aggressive Vertebral Hemangioma as a Potential Pitfall on 68Ga-PSMA PET/CT. AB - A 74-year-old man with newly diagnosed prostate cancer underwent Ga-PSMA PET/CT, which demonstrated intense uptake in and adjacent the L2 vertebral body. Subsequent MRI of the lumbar spine showed an aggressive L2 hemangioma with adjacent soft tissue extension. There was congruence of the intraosseous and extraosseous components of the hemangioma and the PSMA PET uptake. This is a rare but important potential pitfall in Ga-PSMA PET/CT-a soft tissue lesion with intense tracer uptake related not to a nodal metastasis of prostate cancer but to extraosseous extension of an aggressive vertebral body hemangioma. PMID- 28632694 TI - Multiorgan Involvement of Chemotherapy-Induced Sarcoidosis Mimicking Progression of Lymphoma on FDG PET/CT. AB - A 35-year-old woman with biopsy-proven recurrent Hodgkin lymphoma in the neck lymph nodes received salvage chemotherapy of brentuximab/insulin growth factor methotrexate. Although the patient continued doing well clinically with no constitutional symptoms or significant laboratory abnormalities following the second recurrence, subsequent FDG PET CT examinations over the next 2 years revealed multiple new FDG-avid foci including lymph nodes above/below the diaphragm, liver, spleen, lungs, and bone. An alternate diagnosis of chemotherapy induced sarcoidosis was suggested and confirmed on both bone marrow and right inguinal node biopsy. PMID- 28632695 TI - Serum Ceruloplasmin and Striatal Dopamine Transporter Density in Parkinson Disease: Comparison With 123I-FP-CIT SPECT. AB - PURPOSE: In patients with Parkinson disease (PD), decreased serum ceruloplasmin levels have been observed. This study investigated a correlation between serum ceruloplasmin-along with its related serum markers- and striatal presynaptic dopaminergic denervation measured with I-FP-CIT SPECT. METHODS: We analyzed a total of 141 de novo patients divided into 2 groups: the PD group (107 patients with PD) and the disease control group (34 patients with vascular pseudoparkinsonism, essential tremor, or drug-induced parkinsonism). Serum ceruloplasmin and related serum markers, such as copper, iron, total iron-binding capacity, and ferritin, were measured. Specific binding ratios of the striatum, caudate nucleus, putamen, and posterior putamen were obtained by I-FP-CIT SPECT. RESULTS: There was no difference in the serum markers, except for ceruloplasmin, between the 2 groups. Ceruloplasmin level was significantly lower in PD patients with longer symptom duration (>2 years) than in the disease control group (21.4 +/- 3.4 vs 24.0 +/- 3.8, P = 0.03). Serum ceruloplasmin had a significant correlation with specific binding ratios of the striatum, caudate nucleus, and putamen in a subgroup with longer symptom duration (P = 0.01, P = 0.02, P = 0.02, respectively, for the subgroup with symptom duration >1 year, and P < 0.01, P < 0.01, P = 0.04, respectively, for the subgroup with symptom duration >2 years). CONCLUSIONS: Decrease in serum ceruloplasmin had a positive correlation with a decrease in dopamine transporter density in PD patients with symptom duration of more than 1 year. PMID- 28632696 TI - Infection of Ventricular Assist Device Detected and Monitored by 18F-FDG PET/CT. AB - We report a case of a 59-year-old man who presented with fever, sepsis, and left cervicothoracic cutaneous inflammation 13 months after implantation of Jarvik 2000 device. Device infection was suspected and F-FDG PET/CT showed an intense and homogeneous uptake along driveline cable. Bacteriological local sample showed Staphylococcus aureus. After adapted antibiotherapy, control F-FDG PET/CT displays treatment efficacy with no residual uptake in driveline. F-FDG PET/CT could be an important tool for early noninvasive detection of left ventricular assist device infection and monitoring antibiotherapy response. PMID- 28632697 TI - Increased Activity in the Lung Field on Gastroesophageal Scintigraphy Is Not Always Due to Aspiration. AB - Elevated activity in the lung field on gastroesophageal scintigraphy (milk scan) generally indicates aspiration of the gastric content that has refluxed to the pharynx. An 18-year-old man underwent to gastroesophageal scintigraphy to assess the rate of gastric emptying. Increased activity was noted in the left lower lung field during the image acquisition. Careful analysis of the images showed that this activity was caused by hiatal herniation. PMID- 28632698 TI - Primary Cutaneous Angiosarcoma Mimicking Metastasis on 18F-FDG PET/CT in Woman With Cervix Cancer. AB - Primary cutaneous angiosarcoma is a rare vascular tumor usually affecting the whole body, and its hypermetabolic features on F-FDG PET/CT may be confused with those of infection, metastasis, or primary malignancy. This is a case report of a cutaneous angiosarcoma of the lower anterior abdomen showing increased FDG uptake on F-FDG PET/CT mimicking a cutaneous metastasis in an 84-year-old woman with cervical cancer. PMID- 28632699 TI - Inadvertent Arterial Injection of 123I-MIBG Does Not Necessarily Cause Any Symptoms. AB - An 123I-MIBG scan was obtained to evaluate a right adrenal mass in a 10-year-old boy, which showed no elevated activity in the lesion. However, diffuse increased activity was noted in the right forearm with typical manifestation of an "arterial injection." Different from a prior case report, no symptoms or signs related to arterial injection were observed in our patient. PMID- 28632700 TI - Editorial on histocompatibility section 2017. PMID- 28632701 TI - Effects of Active, Student-Centered Teaching Strategies on Nursing Students' Knowledge, Skills, Attitudes, and Comfort Related to Patient Safety. PMID- 28632702 TI - Benchmarking of Prelicensure Nursing Students' Evidence-Based Practice Knowledge. AB - Evidence-based practice (EBP) knowledge among prelicensure nursing students was measured before, immediately following, and 1 year after completion of an EBP course using a relatively new instrument. There was a significant increase in EBP knowledge immediately following the course, and knowledge was sustained 1 year later. Results enabled faculty to gauge the effectiveness of the EBP course within the curriculum to prepare students with the knowledge needed to enact EBP in practice. PMID- 28632704 TI - Metal homeostasis: Pumping iron. PMID- 28632703 TI - Motivating Reading Compliance: Adaptation of Monte Carlo Quizzes for Online Delivery. AB - Getting students to complete reading assignments is often a source of frustration for nurse educators. Monte Carlo Quizzes (MCQs) were adapted for online delivery in a hybrid nursing course to encourage timely completion and deep processing of readings. Students indicated that MCQs motivated them to complete the assigned readings and to read more carefully. However, there were no significant differences on scores for other course assignments between those who completed readings and those who did not. PMID- 28632706 TI - Synthetic biology: Playing favorites. PMID- 28632707 TI - Peptidoglycan: Another brick in the wall. PMID- 28632705 TI - Targeting the N terminus for site-selective protein modification. AB - The formation of well-defined protein bioconjugates is critical for many studies and technologies in chemical biology. Tried-and-true methods for accomplishing this typically involve the targeting of cysteine residues, but the rapid growth of contemporary bioconjugate applications has required an expanded repertoire of modification techniques. One very powerful set of strategies involves the modification of proteins at their N termini, as these positions are typically solvent exposed and provide chemically distinct sites for many protein targets. Several chemical techniques can be used to modify N-terminal amino acids directly or convert them into unique functional groups for further ligations. A growing number of N-terminus-specific enzymatic ligation strategies have provided additional possibilities. This Perspective provides an overview of N-terminal modification techniques and the chemical rationale governing each. Examples of specific N-terminal protein conjugates are provided, along with their uses in a number of diverse biological applications. PMID- 28632708 TI - Antimicrobials: Targeting fungal chromatin. PMID- 28632709 TI - Circadian regulation: Switching periods. PMID- 28632710 TI - Tissue-specific amplifiers. PMID- 28632711 TI - Atypical matters in myeloid differentiation. PMID- 28632712 TI - Regulating hair growth. PMID- 28632713 TI - Systems immunology: just getting started. AB - Systems-biology approaches in immunology take various forms, but here we review strategies for measuring a broad swath of immunological functions as a means of discovering previously unknown relationships and phenomena and as a powerful way of understanding the immune system as a whole. This approach has rejuvenated the field of vaccine development and has fostered hope that new ways will be found to combat infectious diseases that have proven refractory to classical approaches. Systems immunology also presents an important new strategy for understanding human immunity directly, taking advantage of the many ways the immune system of humans can be manipulated. PMID- 28632716 TI - Julius Youngner 1920-2017. PMID- 28632715 TI - A Hippo in the Fox(p3) house. PMID- 28632718 TI - Epigenetic changes in TILs. PMID- 28632717 TI - Polymorphisms in IFIH1: the good and the bad. PMID- 28632714 TI - The multiple pathways to autoimmunity. AB - Efforts to understand autoimmunity have been pursued relentlessly for several decades. It has become apparent that the immune system evolved multiple mechanisms for controlling self-reactivity, and defects in one or more of these mechanisms can lead to a breakdown of tolerance. Among the multitude of lesions associated with disease, the most common seem to affect peripheral tolerance rather than central tolerance. The initial trigger for both systemic autoimmune disorders and organ-specific autoimmune disorders probably involves the recognition of self or foreign molecules, especially nucleic acids, by innate sensors. Such recognition, in turn, triggers inflammatory responses and the engagement of previously quiescent autoreactive T cells and B cells. Here we summarize the most prominent autoimmune pathways and identify key issues that require resolution for full understanding of pathogenic autoimmunity. PMID- 28632719 TI - A rheostat tuning thymic selection. PMID- 28632720 TI - Highly localized memory. PMID- 28632721 TI - IL-22 in Peyer's patches. PMID- 28632722 TI - Learning during inflammation. PMID- 28632723 TI - MiR-646 inhibited cell proliferation and EMT-induced metastasis by targeting FOXK1 in gastric cancer. AB - BACKGROUND: MiR-646 has been reported to be aberrantly expressed in human cancers. However, the underlying molecular mechanisms of action of miR-646 in gastric cancer (GC) have not yet been investigated. METHODS: In vitro function of miR-646 in GC was evaluated using EdU assay, plate colony formation assay, and matrigel invasion assay. Real-time PCR or western blotting was performed to detect miR-646 and FOXK1 expressions. In vivo tumour growth and metastasis were conducted in nude mice. RESULTS: MiR-646 expression was downregulated in GC tissues compared with adjacent normal tissues. Low miR-646 expression is associated with malignant progression. Transient transfection of GC cells with miR-646 inhibited their growth and migration. Moreover, miR-646 influenced the expression of epithelial-mesenchymal transition (EMT)-associated proteins. TGF beta1 treatment significantly suppressed the expression of miR-646 and overexpression of this microRNA counteracted the influence of the TGF-beta1 induced EMT phenotype. In terms of the underlying mechanism, miR-646 directly targeted FOXK1. In vivo, it inhibited the FOXK1-mediated proliferation and EMT induced metastasis. Consistently, inverse correlations were also observed between the expression of miR-646 and FOXK1 in human GC tissue samples. Furthermore, miR 646 regulated Akt/mTOR signalling after FOXK1. CONCLUSIONS: miR-646 inhibited GC cell proliferation and the EMT progression in GC cells by targeting FOXK1. PMID- 28632724 TI - Oral squamous cell carcinoma patients can be differentiated from healthy individuals with label-free serum proteomics. AB - BACKGROUND: No blood biomarkers to detect early oral cavity squamous cell carcinoma (OSCC) without clinical signs exist - diagnosis is solely based on histology of a visible tumour. Most OSCC patients are diagnosed at advanced stage, which leads to significant morbidity and poor survival. Our aim was to find the serum screening or detection biomarkers in OSCC. METHODS: Serum samples from patients with OSCC treated at the Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital (Finland) were collected. Age- and gender-matched healthy individuals served as controls. Quantitative label-free proteomics in high definition MSE mode(HDMSE) was performed on 13 patients and 12 healthy samples. Various statistical analyses were performed on quantitative proteomics data to obtain the most influential proteins, which classify the patients vs healthy samples. RESULTS: In quantitative proteomic analysis (HDMSE), 388 proteins were quantified in our pilot study. A complete separation between cases and controls was seen in supervised and unsupervised classification techniques such as orthogonal projections on latent structure-discriminant analysis (OPLS-DA) and self-organising maps. Using OPLS-DA S-plot, we identified a set of eight proteins that completely separated OSCC patients from healthy individuals. CONCLUSIONS: Although the tumour stages varied from I to IVa, these potential biomarkers were able to identify all OSCCs demonstrating their sensitivity to detect tumours of all stages. We are the first to suggest a set of serum biomarkers in our pilot study to be evaluated further as a diagnostic panel to detect preclinical OSCC in risk patients. PMID- 28632725 TI - The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab. AB - BACKGROUND: The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting. METHODS: We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months. RESULTS: Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN?2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN?2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001). CONCLUSIONS: In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies. PMID- 28632726 TI - Infradiaphragmatic irradiation and high procarbazine doses increase colorectal cancer risk in Hodgkin lymphoma survivors. AB - BACKGROUND: Hodgkin lymphoma (HL) survivors are at increased risk of second malignancies, but few studies have assessed colorectal cancer (CRC) risk after HL treatment. We assessed long-term, subsite-specific CRC risk associated with specific radiation fields and chemotherapy regimens. METHODS: In a Dutch cohort of 3121 5-year HL survivors treated between 1965 and 1995, subsite-specific CRC incidence was compared with general population rates. Treatment effects were quantified by Cox regression analyses. RESULTS: After a median follow-up of 22.9 years, 55 patients developed CRC. The standardized incidence ratios (SIR) was 2.4 fold increased (95% confidence interval (95%CI) 1.8-3.2), leading to 5.7 excess cases per 10 000 patient-years. Risk was still increased 30 years after HL treatment (SIR: 2.8; 95%CI: 1.6-4.6). The highest (SIR: 6.5, 95%CI: 3.3-11.3) was seen for transverse colon cancer (15.0 (95%CI: 4.3-40.8) after inverted-Y irradiation). A prescribed cumulative procarbazine dose >4.2 g m-2 was associated with a 3.3-fold higher CRC risk (95%CI: 1.8-6.1) compared to treatment without procarbazine. Patients receiving >4.2 g m-2 procarbazine and infradiaphragmatic radiotherapy had a hazard ratio of 6.8 (95%CI: 3.0-15.6) compared with patients receiving neither treatment, which is significantly higher than an additive joint effect (Padditivity=0.004). CONCLUSIONS: Colorectal cancer surveillance should be considered for HL survivors who received Infradiaphragmatic radiotherapy and a high cumulative procarbazine dose. PMID- 28632727 TI - Post-translational regulation contributes to the loss of LKB1 expression through SIRT1 deacetylase in osteosarcomas. AB - BACKGROUND: The most prevalent form of bone cancer is osteosarcoma (OS), which is associated with poor prognosis in case of metastases formation. Mice harbouring liver kinase B1 (LKB1+/-) develop osteoblastoma-like tumours. Therefore, we asked whether loss of LKB1 gene has a role in the pathogenesis of human OS. METHODS: Osteosarcomas (n=259) were screened for LKB1 and sirtuin 1 (SIRT1) protein expression using immunohistochemistry and western blot. Those cases were also screened for LKB1 genetic alterations by next-generation sequencing, Sanger sequencing, restriction fragment length polymorphism and fluorescence in situ hybridisation approaches. We studied LKB1 protein degradation through SIRT1 expression. MicroRNA expression investigations were also conducted to identify the microRNAs involved in the SIRT1/LKB1 pathway. RESULTS: Forty-one per cent (106 out of 259) OS had lost LKB1 protein expression with no evident genetic anomalies. We obtained evidence that SIRT1 impairs LKB1 protein stability, and that SIRT1 depletion leads to accumulation of LKB1 in OS cell lines resulting in growth arrest. Further investigations revealed the role of miR-204 in the regulation of SIRT1 expression, which impairs LKB1 stability. CONCLUSIONS: We demonstrated the involvement of sequential regulation of miR-204/SIRT1/LKB1 in OS cases and showed a mechanism for the loss of expression of LKB1 tumour suppressor in this malignancy. PMID- 28632728 TI - Downregulation of serum metabolite GTA-446 as a novel potential marker for early detection of colorectal cancer. AB - BACKGROUND: We previously reported that GTA-446 may be a useful biomarker for early detection of colorectal cancer. In the present study, we confirmed the clinical feasibility of GTA-446 as a screening tool for colorectal cancer with a novel measurement system developed for clinical use. We also improved sensitivity by analysing GTA-446 levels according to gender. METHODS: Serum samples were collected from 225 colorectal cancer patients and 916 healthy volunteers to measure GTA-446 levels by flow injection analysis-mass spectrometry. RESULTS: GTA 446 levels were downregulated in colorectal cancer patients compared with the healthy volunteers, and in females compared with the males in both groups. Receiver operating characteristic curve analysis revealed an optimal cut-off of 2.72 MUmol l-1 in males and 1.87 MUmol l-1 in females, with a large area under the curve of 0.89-0.93. The sensitivity and specificity were 90.4% and 84.9% for males, 85.2% and 80.5% for females, and 83.3% and 84.8% for all subjects, respectively. CONCLUSIONS: GTA-446 is a clinically relevant biomarker for colorectal cancer with high sensitivity when analysed by gender. Thus, GTA-446 is a promising tool for primary colorectal cancer screening to identify populations at a higher risk of colorectal cancer, with an emphasis on early detection. PMID- 28632729 TI - Radiation-associated breast cancer and gonadal hormone exposure: a report from the Childhood Cancer Survivor Study. AB - BACKGROUND: The relationship between hormone exposure and breast cancer risk in women treated with chest radiotherapy for childhood cancer is uncertain. METHODS: Participants included 1108 females from the Childhood Cancer Survivor Study who were diagnosed with childhood cancer 1970-1986, treated with chest radiotherapy, and survived to ages ?20 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox models adjusted for chest radiation field, delivered dose, anthracycline exposure, and age at childhood cancer estimated risk. RESULTS: Among 195 women diagnosed with breast cancer, 102 tumours were oestrogen-receptor positive (ER+). Breast cancer risk increased with ?10 years of ovarian function after chest radiotherapy vs <10 years (HR=2.89, CI 1.56-5.53) and for radiotherapy given within 1 year of menarche vs >1 year from menarche (HR=1.80, CI 1.19-2.72). Risk decreased with decreasing age at menopause (Ptrend=0.014). Risk factors did not differ for ER+ breast cancer. Survivors with an age at menopause <20 years treated with hormone therapy had a lower breast cancer risk than premenopausal survivors (HR=0.47, CI 0.23-0.94). CONCLUSIONS: Endogenous hormones are key contributors to breast cancer observed among childhood cancer survivors. Hormone therapy given for premature ovarian insufficiency does not fully replace the function that endogenous hormones have in breast cancer development. PMID- 28632730 TI - Phase 2 study of combination SPI-1620 with docetaxel as second-line advanced biliary tract cancer treatment. AB - BACKGROUND: This multicentre, open-label study evaluated the efficacy and safety of SPI-1620, an analogue of endothelin-1, administered in combination with docetaxel as second-line treatment for patients with advanced biliary tract cancer (ABTC). METHODS: Eligible patients received continuous cycles of combination therapy with SPI-1620 (11 MUg m-2) and docetaxel (75 mg m-2) intravenously every 3 weeks until disease progression (PD) or intolerable toxicity. Tumour response was evaluated using computed tomography or magnetic resonance imaging every 2 cycles (6 weeks). The primary efficacy end point was progression-free survival (PFS); secondary end points included overall response rate (ORR), duration of response, and overall survival (OS) that were estimated using the Kaplan-Meier method. RESULTS: Of the 30 enrolled patients, 25 patients had qualifying events (PD or death), 1 patient was nonevaluable, and 4 patients were censored at the time of their last tumour assessment. Our primary end point of PFS ?5 months was not reached. Median PFS was 2.6 months (95% confidence interval (CI): 1.4-2.8), ranging from 0.7 to 8.4 months. The ORR was 10.3% (95% CI: 0.02-0.27). Eleven additional patients achieved stable disease. The OS was 4.87 months. The most common grade 3-4 toxicities were febrile neutropenia and neutropenia. CONCLUSIONS: The addition of docetaxel to SPI-1620 in second-line ABTC did not meet the pre-specified primary end point of PFS ?5 months in unselected patient population. PMID- 28632731 TI - CD47 overexpression is associated with decreased neutrophil apoptosis/phagocytosis and poor prognosis in non-small-cell lung cancer patients. AB - BACKGROUND: Non-small-cell lung cancer (NSCLC) patients often exhibit neutrophilia, which has been associated with poor clinical outcomes. However, the mechanisms that lead to neutrophilia have not been fully established. CD47 is an antiphagocytic molecule that promotes neutrophil recruitment. METHODS: Blood was collected from 50 treatment-naive patients with advanced NSCLC and from 25 healthy subjects. The frequency of CD66b+ cells and the expression of CD47 were determined by flow cytometry. Neutrophil apoptosis was determined by 7-amino actinomycin D/Annexin V-APC staining. Phagocytosis was assessed by flow cytometry. Reactive oxygen species production after phorbol 12-myristate 13 acetate treatment was quantified by 2',7'-dichlorofluorescein fluorescence. Pro inflammatory plasma cytokines were quantified using a cytometric bead array assay. RESULTS: The percentage of circulating neutrophils was significantly higher in patients than in controls (P<0.001). Patient-derived neutrophils had a higher oxidative potential than those of controls (P=0.0286). The number of neutrophils in late apoptosis/necrosis was lower in patients than in controls (P=0.0317). Caspase 3/7 activation was also lower in patients than in controls (P=0.0079). CD47 expression in whole-blood samples and in the neutrophil fraction was higher in NSCLC patients than in controls (P=0.0408 and P<0.001). Patient derived neutrophils were phagocytosed at a lower rate than those of controls (P=0.0445). CD47 expression in neutrophils negatively correlated with their ingestion by macrophages (P=0.0039). High CD47 expression was associated with a lower overall survival. CONCLUSIONS: Increased CD47 expression on the surface of neutrophils was associated with a delay in neutrophil apoptosis and with an impairment in their phagocytic clearance by macrophages, suggesting that CD47 overexpression may be one of the underlying mechanisms leading to neutrophilia in NSCLC patients. PMID- 28632732 TI - Fructo-oligosaccharides and intestinal barrier function in a methionine-choline deficient mouse model of nonalcoholic steatohepatitis. AB - Impairments in intestinal barrier function, epithelial mucins, and tight junction proteins have been reported to be associated with nonalcoholic steatohepatitis. Prebiotic fructo-oligosaccharides restore balance in the gastrointestinal microbiome. This study was conducted to determine the effects of dietary fructo oligosaccharides on intestinal barrier function and steatohepatitis in methionine choline-deficient mice. Three groups of 12-week-old male C57BL/6J mice were studied for 3 weeks; specifically, mice were fed a methionine-choline-deficient diet, a methionine-choline-deficient diet plus 5% fructo-oligosaccharides in water, or a normal control diet. Fecal bacteria, short-chain fatty acids, and immunoglobulin A (IgA) levels were investigated. Histological and immunohistochemical examinations were performed using mice livers for CD14 and Toll-like receptor-4 (TLR4) expression and intestinal tissue samples for IgA and zonula occludens-1 expression in epithelial tight junctions. The methionine choline-deficient mice administered 5% fructo-oligosaccharides maintained a normal gastrointestinal microbiome, whereas methionine-choline-deficient mice without prebiotic supplementation displayed increases in Clostridium cluster XI and subcluster XIVa populations and a reduction in Lactobacillales spp. counts. Methionine-choline-deficient mice given 5% fructo-oligosaccharides exhibited significantly decreased hepatic steatosis (p = 0.003), decreased liver inflammation (p = 0.005), a decreased proportion of CD14-positive Kupffer cells (p = 0.01), decreased expression of TLR4 (p = 0.04), and increases in fecal short chain fatty acid and IgA concentrations (p < 0.04) compared with the findings in methionine-choline-deficient mice that were not administered this prebiotic. This study illustrated that in the methionine-choline-deficient mouse model, dietary fructo-oligosaccharides can restore normal gastrointestinal microflora and normal intestinal epithelial barrier function, and decrease steatohepatitis. The findings support the role of prebiotics, such as fructo-oligosaccharides, in maintaining a normal gastrointestinal microbiome; they also support the need for further studies on preventing or treating nonalcoholic steatohepatitis using dietary fructo-oligosaccharides. PMID- 28632733 TI - Ponseti method in the management of clubfoot under 2 years of age: A systematic review. AB - BACKGROUND: Congenital talipes equinovarus (CTEV), also known as clubfoot, is common congenital orthopedic foot deformity in children characterized by four components of foot deformities: hindfoot equinus, hindfoot varus, midfoot cavus, and forefoot adduction. Although a number of conservative and surgical methods have been proposed to correct the clubfoot deformity, the relapses of the clubfoot are not uncommon. Several previous literatures discussed about the technical details of Ponseti method, adherence of Ponseti protocol among walking age or older children. However there is a necessity to investigate the relapse pattern, compliance of bracing, number of casts used in treatment and the percentages of surgical referral under two years of age for clear understanding and better practice to achieve successful outcome without or reduce relapse. Therefore this study aims to review the current evidence of Ponseti method (manipulation, casting, percutaneous Achilles tenotomy, and bracing) in the management of clubfoot under two years of age. MATERIALS AND METHODS: Articles were searched from 2000 to 2015, in the following databases to identify the effectiveness of Ponseti method treatment for clubfoot: Medline, Cumulative Index to Nursing and Allied Health Literature (CINHAL), PubMed, and Scopus. The database searches were limited to articles published in English, and articles were focused on the effectiveness of Ponseti method on children with less than 2 years of age. RESULTS: Of the outcome of 1095 articles from four electronic databases, twelve articles were included in the review. Pirani scoring system, Dimeglio scoring system, measuring the range of motion and rate of relapses were used as outcome measures. CONCLUSIONS: In conclusion, all reviewed, 12 articles reported that Ponseti method is a very effective method to correct the clubfoot deformities. However, we noticed that relapses occur in nine studies, which is due to the non-adherence of bracing regime and other factors such as low income and social economic status. PMID- 28632734 TI - Choroidal thickness in patients with coronary artery disease. AB - PURPOSE: To evaluate choroidal thickness (CTh) in patients with coronary artery disease (CAD) compared to healthy controls. DESIGN: Cross-sectional. METHODS: Setting: Ambulatory clinic of a large city hospital. Patient population: Thirty four patients had documented CAD, defined as history of >50% obstruction in at least one coronary artery on cardiac catheterization, positive stress test, ST elevation myocardial infarction, or revascularization procedure. Twenty-eight age matched controls had no self-reported history of CAD or diabetes. Patients with high myopia, dense cataracts, and retinal disease were excluded. Observation procedures: Enhanced depth imaging optical coherence tomography and questionnaire regarding medical and ocular history. Main outcome measures: Subfoveal CTh and CTh 2000 MUm superior, inferior, nasal, and temporal to the fovea in the left eye, measured by 2 readers. RESULTS: CTh was significantly lower in patients with CAD compared to controls at the subfoveal location (252 vs. 303 MUm, P = 0.002) and at all 4 cardinal macular locations. The mean difference in CTh between the 2 groups ranged from 46 to 75 MUm and was greatest in the inferior location. Within the CAD group, CTh was significantly lower temporally (P = 0.007) and nasally (P<0.001) than subfoveally, consistent with the pattern observed in controls. On multivariate analysis, CAD was negatively associated with subfoveal CTh (P = 0.006) after controlling for diabetes, hypertension, and hypercholesterolemia. CONCLUSIONS AND RELEVANCE: Patients with CAD have a thinner macular choroid than controls, with preservation of the normal spatial CTh pattern. Decreased CTh might predispose patients with CAD to high-risk phenotypes of age-related macular degeneration such as reticular pseudodrusen and could serve as a potential biomarker of disease in CAD. PMID- 28632735 TI - Validity of a minimally invasive autopsy for cause of death determination in stillborn babies and neonates in Mozambique: An observational study. AB - BACKGROUND: Over 5 million stillbirths and neonatal deaths occur annually. Limited and imprecise information on the cause of these deaths hampers progress in achieving global health targets. Complete diagnostic autopsies (CDAs)-the gold standard for cause of death determination-are difficult to perform in most high burden settings. Therefore, validation of simpler and more feasible methods is needed. METHODS AND FINDINGS: In this observational study, the validity of a minimally invasive autopsy (MIA) method in determining the cause of death was assessed in 18 stillbirths and 41 neonatal deaths by comparing the results of the MIA with those of the CDA. Concordance between the categories of diseases obtained by the 2 methods was assessed by the Kappa statistic, and the sensitivity, specificity, positive, and negative predictive values of the MIA diagnoses were calculated. A cause of death was identified in 16/18 (89%) and 15/18 (83%) stillborn babies in the CDA and the MIA, respectively. Fetal growth restriction accounted for 39%, infectious diseases for 22%, intrapartum hypoxia for 17%, and intrauterine hypoxia for 11% of stillborn babies. Overall, the MIA showed in this group a substantial concordance with the CDA (Kappa = 0.78, 95% CI [0.56-0.99]). A cause of death was identified in all (100%) and 35/41 (85%) neonatal deaths in the CDA and the MIA, respectively. In this group, the majority of deaths were due to infectious diseases (66%). The overall concordance of the MIA with the CDA in neonates was moderate (Kappa = 0.40, 95% CI [0.18-0.63]). A high percentage of accuracy was observed for the MIA in all the diagnostic categories in both stillbirths and neonates (>75%). The main limitation of this study is that some degree of subjective interpretation is inherent to cause-of death attribution in both the MIA and the CDA; this is especially so in stillbirths and in relation to fetal growth restriction. CONCLUSIONS: The MIA could be a useful tool for cause-of-death determination in stillbirths and neonatal deaths. These findings may help to accelerate progress towards meeting global health targets by obtaining more accurate information on the causes of death in these age groups, which is essential in guiding the design of new interventions and increasing the effectiveness of those already implemented. PMID- 28632736 TI - From the motor cortex to the movement and back again. AB - The motor cortex controls motor behaviors by generating movement-specific signals and transmitting them through spinal cord circuits and motoneurons to the muscles. Precise and well-coordinated muscle activation patterns are necessary for accurate movement execution. Therefore, the activity of cortical neurons should correlate with movement parameters. To investigate the specifics of such correlations among activities of the motor cortex, spinal cord network and muscles, we developed a model for neural control of goal-directed reaching movements that simulates the entire pathway from the motor cortex through spinal cord circuits to the muscles controlling arm movements. In this model, the arm consists of two joints (shoulder and elbow), whose movements are actuated by six muscles (4 single-joint and 2 double-joint flexors and extensors). The muscles provide afferent feedback to the spinal cord circuits. Cortical neurons are defined as cortical "controllers" that solve an inverse problem based on a proposed straight-line trajectory to a target position and a predefined bell shaped velocity profile. Thus, the controller generates a motor program that produces a task-specific activation of low-level spinal circuits that in turn induce the muscle activation realizing the intended reaching movement. Using the model, we describe the mechanisms of correlation between cortical and motoneuronal activities and movement direction and other movement parameters. We show that the directional modulation of neuronal activity in the motor cortex and the spinal cord may result from direction-specific dynamics of muscle lengths. Our model suggests that directional modulation first emerges at the level of muscle forces, augments at the motoneuron level, and further increases at the level of the motor cortex due to the dependence of frictional forces in the joints, contractility of the muscles and afferent feedback on muscle lengths and/or velocities. PMID- 28632737 TI - Supervised filters for EEG signal in naturally occurring epilepsy forecasting. AB - Nearly 1% of the global population has Epilepsy. Forecasting epileptic seizures with an acceptable confidence level, could improve the disease treatment and thus the lifestyle of the people who suffer it. To do that the electroencephalogram (EEG) signal is usually studied through spectral power band filtering, but this paper proposes an alternative novel method of preprocessing the EEG signal based on supervised filters. Such filters have been employed in a machine learning algorithm, such as the K-Nearest Neighbor (KNN), to improve the prediction of seizures. The proposed solution extends with this novel approach an algorithm that was submitted to win the third prize of an international Data Science challenge promoted by Kaggle contest platform and the American Epilepsy Society, the Epilepsy Foundation, National Institutes of Health (NIH) and Mayo Clinic. A formal description of these preprocessing methods is presented and a detailed analysis in terms of Receiver Operating Characteristics (ROC) curve and Area Under ROC curve is performed. The obtained results show statistical significant improvements when compared with the spectral power band filtering (PBF) typical baseline. A trend between performance and the dataset size is observed, suggesting that the supervised filters bring better information, compared to the conventional PBF filters, as the dataset grows in terms of monitored variables (sensors) and time length. The paper demonstrates a better accuracy in forecasting when new filters are employed and its main contribution is in the field of machine learning algorithms to develop more accurate predictive systems. PMID- 28632738 TI - Correction: Phenotypic heterogeneity promotes adaptive evolution. AB - [This corrects the article DOI: 10.1371/journal.pbio.2000644.]. PMID- 28632740 TI - Soft bilateral filtering volumetric shadows using cube shadow maps. AB - Volumetric shadows often increase the realism of rendered scenes in computer graphics. Typical volumetric shadows techniques do not provide a smooth transition effect in real-time with conservation on crispness of boundaries. This research presents a new technique for generating high quality volumetric shadows by sampling and interpolation. Contrary to conventional ray marching method, which requires extensive time, this proposed technique adopts downsampling in calculating ray marching. Furthermore, light scattering is computed in High Dynamic Range buffer to generate tone mapping. The bilateral interpolation is used along a view rays to smooth transition of volumetric shadows with respect to preserving-edges. In addition, this technique applied a cube shadow map to create multiple shadows. The contribution of this technique isreducing the number of sample points in evaluating light scattering and then introducing bilateral interpolation to improve volumetric shadows. This contribution is done by removing the inherent deficiencies significantly in shadow maps. This technique allows obtaining soft marvelous volumetric shadows, having a good performance and high quality, which show its potential for interactive applications. PMID- 28632739 TI - Validity of a minimally invasive autopsy tool for cause of death determination in pediatric deaths in Mozambique: An observational study. AB - BACKGROUND: In recent decades, the world has witnessed unprecedented progress in child survival. However, our knowledge of what is killing nearly 6 million children annually in low- and middle-income countries remains poor, partly because of the inadequacy and reduced precision of the methods currently utilized in these settings to investigate causes of death (CoDs). The study objective was to validate the use of a minimally invasive autopsy (MIA) approach as an adequate and more acceptable substitute for the complete diagnostic autopsy (CDA) for pediatric CoD investigation in a poor setting. METHODS AND FINDINGS: In this observational study, the validity of the MIA approach in determining the CoD was assessed in 54 post-neonatal pediatric deaths (age range: >=1 mo to 15 y) in a referral hospital of Mozambique by comparing the results of the MIA with those of the CDA. Concordance in the category of disease obtained by the two methods was evaluated by the Kappa statistic, and the sensitivity, specificity, and positive and negative predictive values of the MIA diagnoses were calculated. A CoD was identified in all cases in the CDA and in 52/54 (96%) of the cases in the MIA, with infections and malignant tumors accounting for the majority of diagnoses. The MIA categorization of disease showed a substantial concordance with the CDA categorization (Kappa = 0.70, 95% CI 0.49-0.92), and sensitivity, specificity, and overall accuracy were high. The ICD-10 diagnoses were coincident in up to 75% (36/48) of the cases. The MIA allowed the identification of the specific pathogen deemed responsible for the death in two-thirds (21/32; 66%) of all deaths of infectious origin. Discrepancies between the MIA and the CDA in individual diagnoses could be minimized with the addition of some basic clinical information such as those ascertainable through a verbal autopsy or clinical record. The main limitation of the analysis is that both the MIA and the CDA include some degree of expert subjective interpretation. CONCLUSIONS: The MIA showed substantial concordance with CDA for CoD identification in this series of pediatric deaths in Mozambique. This minimally invasive approach, simpler and more readily acceptable than the more invasive CDA, could provide robust data for CoD surveillance, especially in resource-limited settings, which could be helpful for guiding child survival strategies in the future. PMID- 28632741 TI - Aging, mortality, and the fast growth trade-off of Schizosaccharomyces pombe. AB - Replicative aging has been demonstrated in asymmetrically dividing unicellular organisms, seemingly caused by unequal damage partitioning. Although asymmetric segregation and inheritance of potential aging factors also occur in symmetrically dividing species, it nevertheless remains controversial whether this results in aging. Based on large-scale single-cell lineage data obtained by time-lapse microscopy with a microfluidic device, in this report, we demonstrate the absence of replicative aging in old-pole cell lineages of Schizosaccharomyces pombe cultured under constant favorable conditions. By monitoring more than 1,500 cell lineages in 7 different culture conditions, we showed that both cell division and death rates are remarkably constant for at least 50-80 generations. Our measurements revealed that the death rate per cellular generation increases with the division rate, pointing to a physiological trade-off with fast growth under balanced growth conditions. We also observed the formation and inheritance of Hsp104-associated protein aggregates, which are a potential aging factor in old-pole cell lineages, and found that these aggregates exhibited a tendency to preferentially remain at the old poles for several generations. However, the aggregates were eventually segregated from old-pole cells upon cell division and probabilistically allocated to new-pole cells. We found that cell deaths were typically preceded by sudden acceleration of protein aggregation; thus, a relatively large amount of protein aggregates existed at the very ends of the dead cell lineages. Our lineage tracking analyses, however, revealed that the quantity and inheritance of protein aggregates increased neither cellular generation time nor cell death initiation rates. Furthermore, our results demonstrated that unusually large amounts of protein aggregates induced by oxidative stress exposure did not result in aging; old-pole cells resumed normal growth upon stress removal, despite the fact that most of them inherited significant quantities of aggregates. These results collectively indicate that protein aggregates are not a major determinant of triggering cell death in S. pombe and thus cannot be an appropriate molecular marker or index for replicative aging under both favorable and stressful environmental conditions. PMID- 28632742 TI - The association between serum uric acid and the incidence of prediabetes and type 2 diabetes mellitus: The Rotterdam Study. AB - BACKGROUND: Limited evidence is available about the association between serum uric acid and sub-stages of the spectrum from normoglycaemia to type 2 diabetes mellitus. We aimed to investigate the association between serum uric acid and risk of prediabetes and type 2 diabetes mellitus. METHODS: Eligible participants of the Rotterdam Study (n = 8,367) were classified into mutually exclusive subgroups of normoglycaemia (n = 7,030) and prediabetes (n = 1,337) at baseline. These subgroups were followed up for incident prediabetes (n = 1,071) and incident type 2 diabetes mellitus (n = 407), respectively. We used Cox proportional hazard models to determine hazard ratios (HRs) for incident prediabetes among individuals with normoglycaemia and incident type 2 diabetes mellitus among individuals with prediabetes. RESULTS: The mean duration of follow up was 7.5 years for incident prediabetes and 7.2 years for incident type 2 diabetes mellitus. A standard deviation increment in serum uric acid was significantly associated with incident prediabetes among individuals with normoglycaemia (HR 1.10, 95% confidence interval (CI) 1.01; 1.18), but not with incident type 2 diabetes mellitus among individuals with prediabetes (HR 1.07, 95% CI 0.94; 1.21). Exclusion of individuals who used diuretics or individuals with hypertension did not change our results. Serum uric acid was significantly associated with incident prediabetes among normoglycaemic women (HR 1.13, 95% CI 1.02; 1.25) but not among normoglycaemic men (HR 1.08, 95% CI 0.96; 1.21). In contrast, serum uric acid was significantly associated with incident type 2 diabetes mellitus among prediabetic men (HR 1.23, 95% CI 1.01; 1.48) but not among prediabetic women (HR 1.00, 95% CI 0.84; 1.19). CONCLUSIONS: Our findings agree with the notion that serum uric acid is more closely related to early-phase mechanisms in the development of type 2 diabetes mellitus than late-phase mechanisms. PMID- 28632743 TI - In silico assessment of the effects of quinidine, disopyramide and E-4031 on short QT syndrome variant 1 in the human ventricles. AB - AIMS: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology. METHODS: The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue. RESULTS: At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (deltaV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide. CONCLUSIONS: The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients. PMID- 28632744 TI - Comparison between gastrostomy feeding and self-expandable metal stent insertion for patients with esophageal cancer and dysphagia. AB - BACKGROUND: Self-expandable metal stent (SEMS) insertion and percutaneous gastrostomy (PG) feeding are commonly used for patients with esophageal cancer and dysphagia. This study aimed to compare outcomes between SEMS insertion and PG feeding for them. METHODS: We retrospectively analyzed 308 patients with esophageal cancer who underwent fully covered SEMS insertion (stent group) or PG (gastrostomy group) for dysphagia due to tumor. Patients with other causes of dysphagia, such as radiation-induced or postoperative stricture, were excluded from the study. Clinical outcomes were compared between the two groups, including overall survival and need for additional intervention and postprocedural nutritional status. RESULTS: At baseline, the stent group (n = 169) had more stage IV patients, less cervical cancers, and received radiotherapy and esophagectomy less often than the gastrostomy group (n = 64). The Kaplan-Meier curves showed higher overall survival in the gastrostomy group than in the stent group. Multivariate analysis revealed that PG was associated with better survival compared with SEMS insertion (hazard ratio 0.541, 95% confidence interval 0.346 0.848, p = 0.007). In addition, the gastrostomy group needed additional intervention less often (3.1% vs. 21.9%, p < 0.001) and experienced less decrease in serum albumin levels (-0.15 +/- 0.56 g/dL vs. -0.39 +/- 0.58 g/dL, p = 0.011) than the stent group after procedure. CONCLUSIONS: Our data suggested that, compared with SEMS insertion, PG is associated with better overall survival in patients with esophageal cancer and dysphagia. Stabilized nutritional status by PG may play a role in improving patient survival. PMID- 28632745 TI - Evaluating patterns and drivers of spatial change in the recreational guided fishing sector in Alaska. AB - Understanding the impacts of recreational fishing on habitats and species, as well as the social and ecological importance of place to anglers, requires information on the spatial distribution of fishing activities. This study documented long-term changes in core fishing areas of a major recreational fishery in Alaska and identified biological, regulatory, social, and economic drivers of spatial fishing patterns by charter operators. Using participatory mapping and in-person interviews, we characterized the spatial footprint of 46 charter operators in the communities of Sitka and Homer since the 1990s. The spatial footprint differed between Homer and Sitka respondents, with Homer operators consistently using larger areas for Pacific halibut than Sitka operators. Homer and Sitka showed opposite trends in core fishing location area over time, with an overall decrease in Homer and an overall increase in Sitka. For both Sitka and Homer respondents, the range of areas fished was greater for Pacific halibut than for rockfish/lingcod or Pacific salmon. Spatial patterns were qualitatively different between businesses specializing in single species trips and those that operated multispecies trips and between businesses with one vessel and those with multiple vessels. In Homer, the most frequently cited reasons for changes in the location and/or extent of fishing were changes in trip type and the price of fuel, while in Sitka, the most frequently cited reasons for spatial shifts were changes to Pacific halibut regulations and gaining experience or exploring new locations. The diversity of charter fishing strategies in Alaska may allow individual charter operators to respond differently to perturbations and thus maintain resilience of the industry as a whole to social, environmental, and regulatory change. This research also highlights the importance of understanding fishers' diverse portfolio of activities to effective ecosystem based management. PMID- 28632746 TI - Body-part compatibility effects are modulated by the tendency for women to experience negative social comparative emotions and the body-type of the model. AB - Although exposure to physique-salient media images of women's bodies has been consistently linked with negative psychological consequences, little is known about the cognitive processes that lead to these negative effects. The present study employed a novel adaptation of a computerized response time (RT) task to (i) assess implicit cognitive processing when exposed to the body of another individual, and (ii) examine individual differences in social comparative emotions that may influence the cognitive processing of human bodies. Adult females with low (n = 44) or high (n = 23) tendencies for comparative emotions completed a task in which they executed responses to coloured targets presented on the hands or feet of images of ultra-thin, average-size, and above average size female models. Although the colour of the target is the only relevant target feature, it is typically found that the to-be-ignored location of the target on the body of the model influences RTs such that RTs are shorter when the target is on a body-part that is compatible with the responding limb (e.g., hand response when target was on hand) than on a body-part that is incompatible with the responding limb (e.g., hand response when target was on foot). Findings from the present study revealed that the magnitude of the body-part compatibility effect (i.e., the index of the cognitive processing of the model) was modulated by tendencies for affective body-related comparisons. Specifically, women who were prone to experiencing social comparative emotions demonstrated stronger and more consistent body-part compatibility effects across models. Therefore, women with higher social comparison tendencies have heightened processing of bodies at a neurocognitive level and may be at higher risk of the negative outcomes linked with physique-salient media exposure. PMID- 28632747 TI - Selective cyclooxygenase inhibition by SC-560 improves hepatopulmonary syndrome in cirrhotic rats. AB - OBJECTIVE: Hepatopulmonary syndrome (HPS) is characterized by hypoxia in patients with chronic liver disease. The mechanism of HPS includes pulmonary vasodilatation, inflammation, and angiogenesis. Prostaglandins synthesized by cyclooxygenases (COX) participate in vascular responsiveness, inflammation and angiogenesis, which can be modulated by COX inhibitors. We therefore evaluated the impact of COX inhibition in rats with common bile duct ligation (CBDL) induced liver cirrhosis and HPS. METHODS: Cirrhotic rats were randomly allocated to receive non-selective COX inhibitor (indomethacin), selective COX-1 inhibitor (SC-560), or COX-2 inhibitor (celecoxib) for 14 days. After that, hemodynamic parameters, severity of hypoxia and intrapulmonary shunts, liver and renal biochemistry parameters, histological finding and protein expressions were evaluated. RESULTS: Non-selective COX inhibition by indomethacin improved hepatic fibrosis and pulmonary inflammation in cirrhotic rats with HPS. It also decreased mean arterial blood pressure, portal pressure, and alleviated hypoxia and intrapulmonary shunts. However, indomethacin increased mortality rate. In contrast, selective COX inhibitors neither affected hemodynamics nor increased mortality rate. Hypoxia was improved by SC-560 and celecoxib. In addition, SC-560 decreased intrapulmonary shunts, attenuated pulmonary inflammation and angiogenesis through down-regulating COX-, NFkappaB- and VEGF-mediated pathways. CONCLUSION: Selective COX-1 inhibitor ameliorated HPS by mitigating hypoxia and intrapulmonary shunts, which are related to anti-inflammation and anti angiogenesis. PMID- 28632748 TI - Trimetazidine therapy for diabetic mouse hearts subjected to ex vivo acute heart failure. AB - Acute heart failure (AHF) is the most common primary diagnosis for hospitalized heart diseases in Africa. As increased fatty acid beta-oxidation (FAO) during heart failure triggers detrimental effects on the myocardium, we hypothesized that trimetazidine (TMZ) (partial FAO inhibitor) offers cardioprotection under normal and obese-related diabetic conditions. Hearts were isolated from 12-14 week-old obese male and female diabetic (db/db) mice versus lean non-diabetic littermates (db/+) controls. The Langendorff retrograde isolated heart perfusion system was employed to establish an ex vivo AHF model: a) Stabilization phase Krebs Henseleit buffer (10 mM glucose) at 100 mmHg (25 min); b) Critical Acute Heart Failure (CAHF) phase-(1.2 mM palmitic acid, 2.5 mM glucose) at 20 mmHg (25 min); and c) Recovery Acute Heart Failure phase (RAHF)-(1.2 mM palmitic acid, 10 mM glucose) at 100 mmHg (25 min). Treated groups received 5 MUM TMZ in the perfusate during either the CAHF or RAHF stage for the full duration of each respective phase. Both lean and obese males benefited from TMZ treatment administered during the RAHF phase. Sex differences were observed only in lean groups where the phases of the estrous cycle influenced therapy; only the lean follicular female group responded to TMZ treatment during the CAHF phase. Lean luteal females rather displayed an inherent cardioprotection (without treatments) that was lost with obesity. However, TMZ treatment initiated during RAHF was beneficial for obese luteal females. TMZ treatment triggered significant recovery for male and obese female hearts when administered during RAHF. There were no differences between lean and obese male hearts, while lean females displayed a functional recovery advantage over lean males. Thus TMZ emerges as a worthy therapeutic target to consider for AHF treatment in normal and obese-diabetic individuals (for both sexes), but only when administered during the recovery phase and not during the very acute stages. PMID- 28632751 TI - OWL2 benchmarking for the evaluation of knowledge based systems. AB - OWL2 semantics are becoming increasingly popular for the real domain applications like Gene engineering and health MIS. The present work identifies the research gap that negligible attention has been paid to the performance evaluation of Knowledge Base Systems (KBS) using OWL2 semantics. To fulfil this identified research gap, an OWL2 benchmark for the evaluation of KBS is proposed. The proposed benchmark addresses the foundational blocks of an ontology benchmark i.e. data schema, workload and performance metrics. The proposed benchmark is tested on memory based, file based, relational database and graph based KBS for performance and scalability measures. The results show that the proposed benchmark is able to evaluate the behaviour of different state of the art KBS on OWL2 semantics. On the basis of the results, the end users (i.e. domain expert) would be able to select a suitable KBS appropriate for his domain. PMID- 28632750 TI - Renal sodium handling and blood pressure changes in gestational protein restricted offspring: Role of renal nerves and ganglia neurokinin expression. AB - BACKGROUND: Considering long-term changes in renal sodium handling and blood pressure in maternal protein-restricted (LP) offspring, we assumed that the development of LP hypertension results from abnormal dorsal root ganglia (DRG) neurokinin expression associated with impaired responsiveness of renal sensory receptors, promoting a reduced urinary excretion of sodium. The present study investigates whether increased blood pressure in protein-restricted offspring would be associated with changes in the DRG cells and in renal pelvic wall expression of NK1R, SP and CGRP when compared to NP offspring. In addition, we assessed the tubular sodium handling, estimated by creatinine and lithium clearances before and after bilateral renal denervation in conscious LP offspring relative to age-matched NP counterparts. METHODS: Dams received a normal (NP) or low-protein diet (LP) during their entire pregnancy period. Male NP or LP offspring underwent bilateral surgical renal denervation before the 8-week renal functional test and blood pressure measurements. Immunofluorescence staining in DRG cells was assessed in optical sections by confocal laser scanning microscope. RESULTS: The current data demonstrated a sustained rise in blood pressure associated with a decrease in fractional excretion of sodium (FENa) by reducing post-proximal tubule sodium rejection in 16-wk old LP rats relative to age matched NP counterparts. According to this study, bilateral renal denervation attenuated blood pressure and increased FENa in LP offspring. Furthermore, an immunohistochemical analysis showed a reduced expression of SP and CGRP in DRGs of LP when compared with NP rats. Renal pelvis of LP rats did not show a strong CGRP expression related to NP rats, whereas there was no change in SP immunostaining. CONCLUSIONS: These observations raise the possibility that impaired DRG and pelvic neurokinin expression associated with responsiveness of renal sensory receptors in 16-wk old LP offspring are conducive to excess renal reabsorption of sodium and development of hypertension in this programmed model. PMID- 28632749 TI - Using a health-rating system to evaluate the usefulness of Caenorhabditis elegans as a model for anthelmintic study. AB - Soil-transmitted helminths (STHs) are intestinal parasitic nematodes that infect humans, and are transmitted through contaminated soil. These nematodes include the large roundworm (Ascaris lumbricoides), whipworm (Trichuris trichiura), and hookworm (Ancylostoma ceylanicum, Ancylostoma duodenale, and Necator americanus). Nearly 1.5 billion people (~24% of the population) worldwide are infected with at least one species of these parasites, burdening the poor, in particular, children and pregnant women. To combat these diseases, the WHO only recognizes four anthelmintic drugs, including the preferred drug, albendazole, for mass drug administration (MDA). These four drugs have a total of two different mechanisms of action, and, as expected, resistance has been observed. This problem calls for new drugs with different mechanisms of action. Although there is precedence for the use of Caenorhabditis elegans (C. elegans), a free-living nematode, as a model for drug screening and anthelmintic testing, their usefulness for such anthelmintic study is not clear as past research has shown that C. elegans did not show a strong response to albendazole, the MDA drug of choice, in comparison with various STHs under similar treatment. To further examine if C. elegans has the potential to be a good model organism for anthelmintic drug study, we employed a health rating scale in order to tease out potential effects of albendazole, and other anthelmintics, that may have been missed using a binary, dead/alive scale. Using the health-rating scale we found that although the worms may have not been dying, they were sick, showing dose responses to anthelmintic drugs, including albendazole, reinforcing C. elegans as a useful model for anthelmintic study. PMID- 28632752 TI - Learning to exploit a hidden predictor in skill acquisition: Tight linkage to conscious awareness. AB - It is often assumed that implicit learning of skills based on predictive relationships proceeds independently of awareness. To test this idea, four groups of subjects played a game in which a fast-moving "demon" made a brief appearance at the bottom of the computer screen, then disappeared behind a V-shaped occluder, and finally re-appeared briefly on either the upper-left or upper-right quadrant of the screen. Points were scored by clicking on the demon during the final reappearance phase. Demons differed in several visible characteristics including color, horn height and eye size. For some subjects, horn height perfectly predicted which side the demon would reappear on. For subjects not told the rule, the subset who demonstrated at the end of the experiment that they had spontaneously discovered the rule showed strong evidence of exploiting it by anticipating the demon's arrival and laying in wait for it. Those who could not verbalize the rule performed no better than a control group for whom the demons moved unpredictably. The implications of this tight linkage between conscious awareness and implicit skill learning are discussed. PMID- 28632754 TI - Permissive hypercapnia for severe acute respiratory distress syndrome in immunocompromised children: A single center experience. AB - BACKGROUND: Controlled hypoventilation while accepting hypercapnia has been advocated to reduce ventilator-induced lung injury. The aim of the study was to analyze outcomes of a cohort of immunocompromised children with acute respiratory distress syndrome (ARDS) ventilated with a strategy of stepwise increasing PCO2 targets up to 140 mm Hg. METHODS: Retrospective analysis of outcomes of a cohort of children with oncologic disease or after stem cell transplantation and severe respiratory failure in comparison with a historical control cohort. RESULTS: Out of 150 episodes of admission to the PICU 88 children underwent invasive mechanical ventilation for >24h (overall survival 75%). In a subgroup of 38 children with high ventilator requirements the PCO2 target ranges were increased stepwise. Fifteen children survived and were discharged from the PICU. Severe pulmonary hypertension was seen in two patients and no case of cerebral edema was observed. Long term outcome was available in 15 patients and 10 of these patients survived without adverse neurological sequelae. With introduction of this strategy survival of immunocompromised children undergoing mechanical ventilation for >24h increased to 48% compared to 32% prior to introduction (historical cohort). CONCLUSIONS: A ventilation strategy incorporating very high carbon dioxide levels to allow for low tidal volumes and limited inspiratory pressures is feasible in children. Even severe hypercapnia may be well tolerated. No severe side effects associated with hypercapnia were observed. This strategy could potentially increase survival in immunocompromised children with severe ARDS. PMID- 28632753 TI - MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen induced immunopathology and immunosuppression. AB - Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa associated invariant T (MAIT) cells, as the most powerful source of pro inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD scid IL-2Rgammanull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or gammadelta T cells, and is characterized by production of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vbeta-specific manner but are largely contributed by IL-12 and IL 18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses. PMID- 28632755 TI - Potassium is a key signal in host-microbiome dysbiosis in periodontitis. AB - Dysbiosis, or the imbalance in the structural and/or functional properties of the microbiome, is at the origin of important infectious inflammatory diseases such as inflammatory bowel disease (IBD) and periodontal disease. Periodontitis is a polymicrobial inflammatory disease that affects a large proportion of the world's population and has been associated with a wide variety of systemic health conditions, such as diabetes, cardiovascular and respiratory diseases. Dysbiosis has been identified as a key element in the development of the disease. However, the precise mechanisms and environmental signals that lead to the initiation of dysbiosis in the human microbiome are largely unknown. In a series of previous in vivo studies using metatranscriptomic analysis of periodontitis and its progression we identified several functional signatures that were highly associated with the disease. Among them, potassium ion transport appeared to be key in the process of pathogenesis. To confirm its importance we performed a series of in vitro experiments, in which we demonstrated that potassium levels a increased the virulence of the oral community as a whole and at the same time altering the immune response of gingival epithelium, increasing the production of TNF-alpha and reducing the expression of IL-6 and the antimicrobial peptide human beta-defensin 3 (hBD-3). These results indicate that levels of potassium in the periodontal pocket could be an important element in of dysbiosis in the oral microbiome. They are a starting point for the identification of key environmental signals that modify the behavior of the oral microbiome from a symbiotic community to a dysbiotic one. PMID- 28632756 TI - Identification of ATF-7 and the insulin signaling pathway in the regulation of metallothionein in C. elegans suggests roles in aging and reactive oxygen species. AB - It has been proposed that aging results from the lifelong accumulation of intracellular damage via reactions with reactive oxygen species (ROS). Metallothioneins are conserved cysteine-rich proteins that function as efficient ROS scavengers and may affect longevity. To better understand mechanisms controlling metallothionein expression, the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified. The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens. PMK-1 and members of the insulin signaling pathway, PDK-1 and AKT-1/2, were also identified as mtl-1 regulators. Genetic and previous results support a model for the regulation of cadmium-inducible mtl-1 transcription based on the derepression of the constitutively active transcription factor ELT-2. In addition, knockdown of the mammalian homologs of PDK1 and ATF7 in HEK293 cells resulted in changes in metallothionein expression, suggesting that this pathway was evolutionarily conserved. The insulin signaling pathway is known to influence the aging process; however, various factors responsible for affecting the aging phenotype are unknown. Identification of portions of the insulin signaling pathway as regulators of metallothionein expression supports the hypothesis that longevity is affected by the expression of this efficient ROS scavenger. PMID- 28632757 TI - Molecular mechanism of DRP1 assembly studied in vitro by cryo-electron microscopy. AB - Mitochondria are dynamic organelles that continually adapt their morphology by fusion and fission events. An imbalance between fusion and fission has been linked to major neurodegenerative diseases, including Huntington's, Alzheimer's, and Parkinson's diseases. A member of the Dynamin superfamily, dynamin-related protein 1 (DRP1), a dynamin-related GTPase, is required for mitochondrial membrane fission. Self-assembly of DRP1 into oligomers in a GTP-dependent manner likely drives the division process. We show here that DRP1 self-assembles in two ways: i) in the presence of the non-hydrolysable GTP analog GMP-PNP into spiral like structures of ~36 nm diameter; and ii) in the presence of GTP into rings composed of 13-18 monomers. The most abundant rings were composed of 16 monomers and had an outer and inner ring diameter of ~30 nm and ~20 nm, respectively. Three-dimensional analysis was performed with rings containing 16 monomers. The single-particle cryo-electron microscopy map of the 16 monomer DRP1 rings suggests a side-by-side assembly of the monomer with the membrane in a parallel fashion. The inner ring diameter of 20 nm is insufficient to allow four membranes to exist as separate entities. Furthermore, we observed that mitochondria were tubulated upon incubation with DRP1 protein in vitro. The tubes had a diameter of ~ 30nm and were decorated with protein densities. These findings suggest DRP1 tubulates mitochondria, and that additional steps may be required for final mitochondrial fission. PMID- 28632758 TI - Safety and tolerability of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil fumarate in a real life setting: Data from surveillance cohort long term toxicity antiretrovirals/antivirals (SCOLTA) project. AB - OBJECTIVES: The study aim was to evaluate the impact on Liver and Kidney toxicity of the single tablet regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate (EVG/COBI/FTC/TDF) on Antiretroviral Therapy (ART) experienced or naive patients. METHODS: Patients initiating EVG/COBI/FTC/TDF were enrolled in the SCOLTA project, a multicenter observational study reporting grade 3-4 Adverse Events in subjects beginning new antiretroviral drug regimens. In this analysis, patients were evaluated at T0 (baseline), T1 (six months) and at T2 (twelve months). RESULTS: A total of 329 patients were enrolled, and 280 (85.1%) of these had at least one follow-up visit. Median observation time was 11 months (IQR 7.0-15.5). Two hundred and two patients (72.1%) were ART experienced and 78 (27.9%) ART naive. Prevalence of HCV-co-infection was 21.4%. At T1, we observed a significant decline in estimated glomerular filtration rate (eGFR), both in experienced and naive patients (mean change from T0-7.5 +/- 12.8 ml/min, 15.5 +/- 17.8 ml/min, respectively, p = 0.0005), which was confirmed at T2 (mean change from T0-8.2 +/- 15.8 ml/min, -17.6 +/- 19.4 ml/min, respectively, p = 0.001). Regarding aspartate aminotransferase (AST) and alanine transaminase (ALT) grade 1-2 modifications, no significant differences were observed between experienced and naive subjects, but an increased prevalence of abnormal liver function test was observed in patients with chronic HCV infection (p<0.001). CONCLUSIONS: A significant decline in eGFR was observed in patients initiating EVG/COBI/FTC/TDF in the first 6 months, with no significant worsening occurring at 12 months vs. 6 months of therapy. Patients with chronic HCV infection were at higher risk to develop abnormal liver tests. PMID- 28632759 TI - Analysis of intra-host genetic diversity of Prunus necrotic ringspot virus (PNRSV) using amplicon next generation sequencing. AB - PCR amplicon next generation sequencing (NGS) analysis offers a broadly applicable and targeted approach to detect populations of both high- or low frequency virus variants in one or more plant samples. In this study, amplicon NGS was used to explore the diversity of the tripartite genome virus, Prunus necrotic ringspot virus (PNRSV) from 53 PNRSV-infected trees using amplicons from conserved gene regions of each of PNRSV RNA1, RNA2 and RNA3. Sequencing of the amplicons from 53 PNRSV-infected trees revealed differing levels of polymorphism across the three different components of the PNRSV genome with a total number of 5040, 2083 and 5486 sequence variants observed for RNA1, RNA2 and RNA3 respectively. The RNA2 had the lowest diversity of sequences compared to RNA1 and RNA3, reflecting the lack of flexibility tolerated by the replicase gene that is encoded by this RNA component. Distinct PNRSV phylo-groups, consisting of closely related clusters of sequence variants, were observed in each of PNRSV RNA1, RNA2 and RNA3. Most plant samples had a single phylo-group for each RNA component. Haplotype network analysis showed that smaller clusters of PNRSV sequence variants were genetically connected to the largest sequence variant cluster within a phylo-group of each RNA component. Some plant samples had sequence variants occurring in multiple PNRSV phylo-groups in at least one of each RNA and these phylo-groups formed distinct clades that represent PNRSV genetic strains. Variants within the same phylo-group of each Prunus plant sample had >=97% similarity and phylo-groups within a Prunus plant sample and between samples had less <=97% similarity. Based on the analysis of diversity, a definition of a PNRSV genetic strain was proposed. The proposed definition was applied to determine the number of PNRSV genetic strains in each of the plant samples and the complexity in defining genetic strains in multipartite genome viruses was explored. PMID- 28632760 TI - The development of acquired equivalence from childhood to adulthood-A cross sectional study of 265 subjects. AB - Acquired equivalence (AE) is a form of feedback-based associative learning where the subject learns that two or more stimuli are equivalent in terms of being mapped onto the same outcomes or responses. While several studies dealt with how various neurological and psychiatric conditions affect performance on AE tasks (typically with small populations), studies dealing with AE in healthy subjects are rare, and no study has ever made an attempt to plot the development of this form of learning from the childhood through adulthood. In a cross-sectional study, we assessed the AE performance of 265 healthy subjects aged 3 to 52 years with the computer-based Rutgers Equivalence Test (Fish-Face Test, FFT). The test assesses three main aspects of AE: the efficiency of pair learning, the efficiency of the retrieval of acquired pairs, and the ability to generalise previous knowledge to a new stimulus that partially overlaps with the previous ones. It has been demonstrated in imaging studies that the initial, pair learning phase of this specific test is dependent on the basal ganglia, while its generalization phase requires the hippocampi. We found that both pair learning and retrieval exhibited development well into adulthood, but generalisation did not, after having reached its adult-like level by the age of 6. We propose that these findings might be explained by the integrative encoding theory that focuses on the parallel dopaminergic midbrain-striatum/midbrain-hippocampus connections. PMID- 28632761 TI - Experience improves the performance of endobronchial ultrasound-guided transbronchial biopsy for peripheral pulmonary lesions: A learning curve at a medical centre. AB - BACKGROUND: Endobronchial ultrasound(EBUS)-guided transbronchial biopsy(TBB) is the preferred diagnostic tool for peripheral pulmonary lesions(PPLs) and mastering this procedure is an important task in the training of chest physicians. Little has been published about the learning experience of physicians with this technique, particularly at an institutional level. We aimed to establish a learning curve for EBUS-guided TBB for PPLs at a medical center. METHODS: Between 2008 and 2015, consecutive patients with PPLs referred for EBUS guided TBB at National Taiwan University Hospital were enrolled. To build the learning curve, the diagnostic yield of TBB (plus brushings and washings) was calculated and compared. Meanwhile, lesion characteristics, and procedure-related features and complications were obtained to analyze associations with TBB yield and safety profile. RESULTS: A total of 2144 patients were included and EBUS guided TBB was diagnostic for 1547(72%). The TBB yield was 64% in 2008 and reached a plateau of 72% after 2010. It took approximately 400 EBUS-guided procedures to achieve stable proficiency. Further analysis showed that improvement in diagnostic yield over time was mainly observed in PPLs, in cases in which the diameter was <=2 cm or the EBUS probe could not be positioned within. Complication rates were low, with 1.8% and 0.5% for pneumothorax and hemorrhage, respectively. CONCLUSIONS: Even though EBUS-guided TBB is an easy-to learn technique, it takes 3 years or around 400 procedures for a medical center to achieve a better and stable performance. In particular, the diagnostic yield for lesions without the probe within or those sized <=2 cm could improve with time. PMID- 28632762 TI - DOT1L inhibitor improves early development of porcine somatic cell nuclear transfer embryos. AB - Incomplete epigenetic reprogramming of the genome of donor cells causes poor early and full-term developmental efficiency of somatic cell nuclear transfer (SCNT) embryos. Previous research indicate that inhibition of the histone H3 K79 methyltransferase DOT1L, using a selective pharmacological inhibitor EPZ004777 (EPZ), significantly improved reprogramming efficiency during the generation of mouse induced pluripotent stem cells. However, the roles of DOT1L in porcine nuclear transfer-mediated cellular reprogramming are not yet known. Here we showed that DOT1L inhibition via 0.5 nM EPZ treatment for 12 or 24 h significantly enhanced the blastocyst rate of SCNT embryos and dramatically reduced the level of H3K79me2 during SCNT 1-cell embryonic development. Additionally, H3K79me2 level in the EPZ-treated SCNT embryos was similar to that in in vitro fertilized embryos, suggesting that DOT1L-mediated H3K79me2 is a reprogramming barrier to early development of porcine SCNT embryos. qRT-PCR analysis further demonstrated that DOT1L inactivation did not change the expression levels of DOT1L itself but increased the expression levels of POU5F1, LIN28, SOX2, CDX2 and GATA4 associated with pluripotency and early cell differentiation. In conclusion, DOT1L inhibitor improved early developmental efficiency of porcine SCNT embryos probably via inducing the increased expression of genes important for pluripotency and lineage specification. PMID- 28632763 TI - Efficacy of ibuprofen on prevention of high altitude headache: A systematic review and meta-analysis. AB - OBJECTIVE: Ibuprofen is used to prevent high altitude headache (HAH) but its efficacy remains controversial. We conducted a systematic review and meta analysis of randomized, placebo-controlled trials (RCTs) of ibuprofen for the prevention of HAH. METHODS: Studies reporting efficacy of ibuprofen for prevention of HAH were identified by searching electronic databases (until December 2016). The primary outcome was the difference in incidence of HAH between ibuprofen and placebo groups. Risk ratios (RR) were aggregated using a Mantel-Haenszel random effect model. Heterogeneity of included trials was assessed using the I2 statistics. RESULTS: In three randomized-controlled clinical trials involving 407 subjects, HAH occurred in 101 of 239 subjects (42%) who received ibuprofen and 96 of 168 (57%) who received placebo (RR = 0.79, 95% CI 0.66 to 0.96, Z = 2.43, P = 0.02, I2 = 0%). The absolute risk reduction (ARR) was 15%. Number needed to treat (NNT) to prevent HAH was 7. Similarly, The incidence of severe HAH was significant in the two groups (RR = 0.40, 95% CI 0.17 to 0.93, Z = 2.14, P = 0.03, I2 = 0%). Severe HAH occurred in 3% treated with ibuprofen and 10% with placebo. The ARR was 8%. NNT to prevent severe HAH was 13. Headache severity using a visual analogue scale was not different between ibuprofen and placebo. Similarly, the difference between the two groups in the change in SpO2 from baseline to altitude was not different. One included RCT reported one participant with black stools and three participants with stomach pain in the ibuprofen group, while seven participants reported stomach pain in the placebo group. CONCLUSIONS: Based on a limited number of studies ibuprofen seems efficacious for the prevention of HAH and may therefore represent an alternative for preventing HAH with acetazolamide or dexamethasone. PMID- 28632764 TI - Accuracy and reliability of retinal photo grading for diabetic retinopathy: Remote graders from a developing country and standard retinal photo grader in Australia. AB - BACKGROUND: To evaluate the accuracy and reliability of fundus retinal photos graded by local graders in Bangladesh with those graded by an expert at the Centre for Eye Research Australia (CERA) in the context of mass scale diabetic retinopathy (DR) screening in Bangladesh. METHODS: A population-based cross sectional study of 3,104 adults identified 213 (7.2%) eligible patients with diabetes of age >= 40 years in 2012-2013. Retinal photographs were collected using a non-mydriatic digital fundus retinal camera and a two-field imaging protocol. The photos were graded by two remote graders (G1 and G2) who were trained by a retinal specialist (RS) in Bangladesh, by the RS himself, and by a Centre for Eye Research Australia (CERA) grader. The local graders up skilled their grading ability by comparing 30% of the photos graded by the CERA grader with their own grades. Learning from that exercise was applied to the remaining 70% of photos, which were re-graded. Reliability and accuracy of grading amongst the graders were reported using cross tabulation, inter- and intra-grader reliability, and with sensitivity and specificity. RESULTS: Of 122 eyes from 61 patients, the mild (R1) DR was estimated to be 14 to 25%, pre-proliferative (R2) DR 4-8%, and proliferative (R3) DR 0.8 to 1.6%, whereas 25%, 8%, 18%, and 15% were found to be ungradable by CERA, RS, G1, and G2, respectively. Of 8 (6.6%) eyes identified as R2 by the CERA grader, 5 (63%), 3 (38%) and 3 (38%) were correctly classified as R2, whereas the rest were classified either as R1 or R3 but none were classified as no DR (R0) or ungradable by the RS, G1 and G2, respectively. After getting experience reviewing the 30% test set graded by the CERA grader, the local graders graded moderate and severe DR with 100% accuracy. After excluding ungradable photos, the sensitivity (specificity) relative to the CERA grader was 82% (88%) before and 80% (93%) after training for G1 and 56% (87%) before and 77% (90%) after training for G2. In case of maculopathy, the CERA grader reported 11.2% eyes with maculopathy, which included 100% of the 4.9% by RS, 6.6% by G1, and 7.4% by G2. CONCLUSIONS: Local graders in Bangladesh are able to grade retinal photos with high accuracy if the DR is at least of a moderate level. With appropriate training and experience, local graders have the ability to contribute significantly to the grading of millions of retinal photos, which required grading in resource- poor countries. PMID- 28632765 TI - CTRP3 is a novel biomarker for diabetic retinopathy and inhibits HGHL-induced VCAM-1 expression in an AMPK-dependent manner. AB - OBJECTIVES: Diabetic retinopathy (DR) is a severe complication of chronic diabetes. The C1q/TNF-related protein family (CTRPs) has been demonstrated to exert protective effects against obesity and atherosclerosis in animal studies. Heretofore, the association between circulating CTRPs and DR patients has been unexplored. In the current study, we attempt to define this association, as well as the effect of CTRPs upon DR pathophysiology. DESIGN: The present investigation is a case control study that enrolled control subjects and type 2 diabetes mellitus (T2DM) patients diagnosed with DR. Serum CTRPs and sVACM-1 were determined by ELISA. RESULTS: Serum CTRP3 and CTRP5 levels were markedly decreased in patients with T2DM compared to controls (p<0.05) and inversely associated with T2DM. Furthermore, mutivariate regression and ROC analysis revealed CTRP3 deficiency, not CTRP5, was associated with proliferative diabetic retinopathy (PDR). Spearman's rank correlation assay demonstrated an inverse association between CTRP3 and sVCAM-1. Finally, exogenous CTRP3 administration attenuated high glucose high lipid (HGHL)-induced VCAM-1 production in an AMPK dependent manner in cultured human retinal microvascular endothelial cells (HRMECs). CONCLUSION: CTRP3 may serve as a novel biomarker for DR severity. CTRP3 may represent a future novel therapeutic against DR, a common ocular complication of diabetes. PMID- 28632766 TI - Associations between anthropometric parameters and lipid profiles in Chinese individuals with age >=40 years and BMI <28kg/m2. AB - BACKGROUND: Lipid abnormalities are associated with overweight and obesity. Some simple anthropometric measurements such as body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR), may link to increased risk of dyslipidemia. However, diverse results were found in different population studies. We focused on the associations between these measurements and dyslipidemia in non-obese (BMI <28kg/m2) population aged more than 40 years. METHODS AND FINDINGS: Cross-sectional study of 4185 non-obese adults aged more than 40 years was conducted in Nanchang, Jiangxi province, China. Questionnaire, anthropometric and laboratory tests were conducted. The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) criteria were used to define high total cholesterol (TC), high low density lipoprotein cholesterol (LDL-C), low high-density lipoprotein cholesterol (HDL-C), hypertriglyceridemia and dyslipidemia. The overall prevalence of high TC, high LDL-C, low HDL-C, hypercholesterolemia, hypertriglyceridemia and dyslipidemia were 15.68%, 27.98%, 20.12%, 44.01%, 21.98% and 49.06% respectively. Multiple logistic regressions showed only BMI (per quartile increment) increased risks for prevalent high LDL-C, low HDL-C, hypercholesterolemia, hypertriglyceridemia, and dyslipidemia. Regardless of sex, age and prevalent metabolic syndrome, increasing BMI was persistently independent risk factor for having low HDL-C, hypercholesterolemia and dyslipidemia, however was not associated with high TC. CONCLUSIONS: In non-obese Chinese population aged more than 40 years, increasing BMI may better identify the prevalent dyslipidemia than other anthropometric measurements. However, due to the different meanings, both BMI and WC should be measured and monitored for metabolic risk assessment. PMID- 28632768 TI - The cost of demand creation activities and voluntary medical male circumcision targeting school-going adolescents in KwaZulu-Natal, South Africa. AB - BACKGROUND: Voluntary medical male circumcision is an integral part of the South African government's response to the HIV and AIDS epidemic. However, there remains a limited body of economic analysis on the cost of VMMC programming, and the demand creation activities used to mobilize males, especially among adolescent boys in school. This study addresses this gap by presenting the costs of a VMMC program which adopted two demand creation strategies targeting school going males in South Africa. METHODS: Cost data was collected from a VMMC program in the KwaZulu-Natal province of South Africa. A retrospective, micro-costing ingredient approach was applied to identify, measure and value resources of two demand creation strategies targeting young males. RESULTS: The program circumcised 4987 young males between May 2011 and February 2013, at a cost of $127.68 per circumcision. Demand creation activities accounted for 32% of the total cost, HCT contributing 10% with the medical circumcision procedure accounting for 58% of the total cost. Using the first demand creation strategy, 2168 circumcisions were performed at a cost of $149.57 per circumcision. Following this first strategy, a second demand creation strategy was adopted which saw the cost fall to $110.85 per circumcision. More young males were recruited following the second strategy with clinic services more efficiently utilized. Whilst the cost per circumcision of demand activities rose slightly between the first ($39.94) and second ($41.65) strategy, there was a substantial reduction in the cost of the circumcision procedure; $90.01 under the first strategy falling to $60.60 following the adoption of the second demand creation strategy. CONCLUSION: Ensuring the optimal use of clinic facilities was the primary driver in reducing the cost per circumcision. This VMMC program has illustrated the value of evaluating progress and instituting changes to attain better cost efficiencies. This adjustment resulted in a substantial reduction in the cost per circumcision. PMID- 28632767 TI - How is Indonesia coping with its epidemic of chronic noncommunicable diseases? A systematic review with meta-analysis. AB - BACKGROUND: Chronic noncommunicable diseases (NCDs) have emerged as a huge global health problem in low- and middle-income countries. The magnitude of the rise of NCDs is particularly visible in Southeast Asia where limited resources have been used to address this rising epidemic, as in the case of Indonesia. Robust evidence to measure growing NCD-related burdens at national and local levels and to aid national discussion on social determinants of health and intra-country inequalities is needed. The aim of this review is (i) to illustrate the burden of risk factors, morbidity, disability, and mortality related to NCDs; (ii) to identify existing policy and community interventions, including disease prevention and management strategies; and (iii) to investigate how and why an inequitable distribution of this burden can be explained in terms of the social determinants of health. METHODS: Our review followed the PRISMA guidelines for identifying, screening, and checking the eligibility and quality of relevant literature. We systematically searched electronic databases and gray literature for English- and Indonesian-language studies published between Jan 1, 2000 and October 1, 2015. We synthesized included studies in the form of a narrative synthesis and where possible meta-analyzed their data. RESULTS: On the basis of deductive qualitative content analysis, 130 included citations were grouped into seven topic areas: risk factors; morbidity; disability; mortality; disease management; interventions and prevention; and social determinants of health. A quantitative synthesis meta-analyzed a subset of studies related to the risk factors smoking, obesity, and hypertension. CONCLUSIONS: Our findings echo the urgent need to expand routine risk factor surveillance and outcome monitoring and to integrate these into one national health information system. There is a stringent necessity to reorient and enhance health system responses to offer effective, realistic, and affordable ways to prevent and control NCDs through cost-effective interventions and a more structured approach to the delivery of high-quality primary care and equitable prevention and treatment strategies. Research on social determinants of health and policy-relevant research need to be expanded and strengthened to the extent that a reduction of the total NCD burden and inequalities therein should be treated as related and mutually reinforcing priorities. PMID- 28632769 TI - Combining 'omics and microscopy to visualize interactions between the Asian citrus psyllid vector and the Huanglongbing pathogen Candidatus Liberibacter asiaticus in the insect gut. AB - Huanglongbing, or citrus greening disease, is an economically devastating bacterial disease of citrus. It is associated with infection by the gram-negative bacterium Candidatus Liberibacter asiaticus (CLas). CLas is transmitted by Diaphorina citri, the Asian citrus psyllid (ACP). For insect transmission to occur, CLas must be ingested during feeding on infected phloem sap and cross the gut barrier to gain entry into the insect vector. To investigate the effects of CLas exposure at the gut-pathogen interface, we performed RNAseq and mass spectrometry-based proteomics to analyze the transcriptome and proteome, respectively, of ACP gut tissue. CLas exposure resulted in changes in pathways involving the TCA cycle, iron metabolism, insecticide resistance and the insect's immune system. We identified 83 long non-coding RNAs that are responsive to CLas, two of which appear to be specific to the ACP. Proteomics analysis also enabled us to determine that Wolbachia, a symbiont of the ACP, undergoes proteome regulation when CLas is present. Fluorescent in situ hybridization (FISH) confirmed that Wolbachia and CLas inhabit the same ACP gut cells, but do not co localize within those cells. Wolbachia cells are prevalent throughout the gut epithelial cell cytoplasm, and Wolbachia titer is more variable in the guts of CLas exposed insects. CLas is detected on the luminal membrane, in puncta within the gut epithelial cell cytoplasm, along actin filaments in the gut visceral muscles, and rarely, in association with gut cell nuclei. Our study provides a snapshot of how the psyllid gut copes with CLas exposure and provides information on pathways and proteins for targeted disruption of CLas-vector interactions at the gut interface. PMID- 28632771 TI - Avian influenza in Latin America: A systematic review of serological and molecular studies from 2000-2015. AB - Avian influenza or bird flu is a highly contagious acute viral disease that can occur in epidemics and cross-border forms in poultry and wild birds. The characteristics of avian influenza viruses (AIVs) allow the emergence of new viral variants, some with zoonotic and pandemic potential. AIVs have been identified in Latin America; however, there is a lack of understanding of these viruses at the regional level. We performed a systematic literature review on serological or molecular evidence of AIVs circulation in Latin America. Methods were designed based on the PRISMA and STROME guidelines. Only peer-reviewed studies published between 2000 to 2015 and data was analysed based on country, viral subtype, avian species, and phylogenetic origins. From 271 studies initially found only twenty-six met our inclusion criteria. Evidence of AIVs infection was found in most Latin American countries, with Mexico as the country with the largest number of conducted studies and reported cases during the period analysed, followed by Chile and Argentina. Most of the AIVs were early reported through surveillance systems and at least 14 different subtypes of influenza viruses were reported in birds, and the presence of both low (92.9%) and high (7.1%) pathogenic AIVs was shown in Latin America. Of the reported AIVs in Latin America, 43.7% belong to migratory birds, 28.1% to local wild birds, and 28.1% to poultry. The migratory bird population mainly comprises families belonging to the orders Anseriformes and Charadriformes. We highlight the importance of epidemiological surveillance systems and the possible role of different migratory birds in the transmission of AIVs within the Americas. Our findings demonstrate the limited information on AIVs in Latin America and highlight the need of more studies on AIVs at the regional level, particularly those focused on identifying the endemic subtypes in regional wild birds. PMID- 28632770 TI - Men, women...who cares? A population-based study on sex differences and gender roles in empathy and moral cognition. AB - Research on sex differences in empathy has revealed mixed findings. Whereas experimental and neuropsychological measures show no consistent sex effect, self report data consistently indicates greater empathy in women. However, available results mainly come from separate populations with relatively small samples, which may inflate effect sizes and hinder comparability between both empirical corpora. To elucidate the issue, we conducted two large-scale studies. First, we examined whether sex differences emerge in a large population-based sample (n = 10,802) when empathy is measured with an experimental empathy-for-pain paradigm. Moreover, we investigated the relationship between empathy and moral judgment. In the second study, a subsample (n = 334) completed a self-report empathy questionnaire. Results showed some sex differences in the experimental paradigm, but with minuscule effect sizes. Conversely, women did portray themselves as more empathic through self-reports. In addition, utilitarian responses to moral dilemmas were less frequent in women, although these differences also had small effect sizes. These findings suggest that sex differences in empathy are highly driven by the assessment measure. In particular, self-reports may induce biases leading individuals to assume gender-role stereotypes. Awareness of the role of measurement instruments in this field may hone our understanding of the links between empathy, sex differences, and gender roles. PMID- 28632772 TI - Characterization of slow-cycling cells in the mouse cochlear lateral wall. AB - Cochlear spiral ligament fibrocytes (SLFs) play essential roles in the physiology of hearing including ion recycling and the generation of endocochlear potential. In adult animals, SLFs can repopulate after damages, yet little is known about the characteristics of proliferating cells that support SLFs' self-renewal. Here we report in detail about the characteristics of cycling cells in the spiral ligament (SL). Fifteen P6 mice and six noise-exposed P28 mice were injected with 5-bromo-2'-deoxyuridine (BrdU) for 7 days and we chased BrdU retaining cells for as long as 60 days. Immunohistochemistry revealed that the BrdU positive IB4 (an endotherial marker) negative cells expressed an early SLF marker Pou3f4 but negative for cleaved-Caspase 3. Marker studies revealed that type 3 SLFs displayed significantly higher percentage of BrdU+ cells compared to other subtypes. Notably, the cells retained BrdU until P72, demonstrating they were dividing slowly. In the noise-damaged mice, in contrast to the loss of the other types, the number of type 3 SLFs did not altered and the BrdU incorporating- phosphorylated Histone H3 positive type 3 cells were increased from day 1 to 14 after noise exposure. Furthermore, the cells repopulating type 1 area, where the cells diminished profoundly after damage, were positive for the type 3 SLF markers. Collectively, in the latral wall of the cochlea, type 3 SLFs have the stem cell capacity and may contribute to the endogenous regeneration of lateral wall spiral ligament. Manipulating type 3 cells may be employed for potential regenerative therapies. PMID- 28632773 TI - Simulation of oak early life history and interactions with disturbance via an individual-based model, SOEL. AB - Early tree life history and demography are driven by interactions with the environment such as seed predation, herbivory, light availability, and drought. For oak (Quercus) in the eastern United States, these interactions may contribute to oak regeneration failure. Numerous studies have examined the impact of individual factors (like seed predation) on the oak regeneration process, but less information is available on the relative and combined impacts of multiple intrinsic and extrinsic factors on early oak life history. We developed an individual-based, spatially explicit model to Simulate Oak Early Life history (SOEL). The model connects acorn survival, acorn dispersal, germination, seedling growth, and seedling survival submodels based on empirical data with an existing gap model (JABOWA). Using SOEL, we assessed the sensitivity of several metrics of oak regeneration to different parameters associated with early oak life history. We also applied the model in three individual case studies to assess: (1) how variable acorn production interacts with timing of timber harvest; (2) the effect of shelterwood harvest-induced differences on seed predation; and (3) the consequences of interactions between drought, seedling growth and survival, and timber harvest. We found that oak regeneration metrics including percent emergence, seedling density, and sapling density were most sensitive to the amount of acorn production, acorn caching probability by scatterhoarders, and seedling growth rates. In the case studies, we found that timing harvest to follow large acorn crops can increase the density of oak regeneration in the short term following harvest, at least under some conditions. Following midstory removal, lower weevil infestation probability and lower post-dispersal acorn survival resulted in a modest decline in seedling density, but the decline did not persist to the sapling life stage class. Drought frequency had a powerful negative impact on both growth and survival for individual seedlings, which resulted in large reductions in both seedling and sapling density. The case studies presented here represent only a few examples of what could be accomplished within the SOEL modeling framework. Further studies could focus on different early life history parameters, or connect the parameter values to different predictor variables based on field data. PMID- 28632774 TI - Short-term EEG dynamics and neural generators evoked by navigational images. AB - The ecological environment offered by virtual reality is primarily supported by visual information. The different image contents and their rhythmic presentation imply specific bottom-up and top-down processing. Because these processes already occur during passive observation we studied the brain responses evoked by the presentation of specific 3D virtual tunnels with respect to 2D checkerboard. For this, we characterized electroencephalograhy dynamics (EEG), the evoked potentials and related neural generators involved in various visual paradigms. Time-frequency analysis showed modulation of alpha-beta oscillations indicating the presence of stronger prediction and after-effects of the 3D-tunnel with respect to the checkerboard. Whatever the presented image, the generators of the P100 were situated bilaterally in the occipital cortex (BA18, BA19) and in the right inferior temporal cortex (BA20). In checkerboard but not 3D-tunnel presentation, the left fusiform gyrus (BA37) was additionally recruited. P200 generators were situated in the temporal cortex (BA21) and the cerebellum (lobule VI/Crus I) specifically for the checkerboard while the right parahippocampal gyrus (BA36) and the cerebellum (lobule IV/V and IX/X) were involved only during the 3D-tunnel presentation. For both type of image, P300 generators were localized in BA37 but also in BA19, the right BA21 and the cerebellar lobule VI for only the checkerboard and the left BA20-BA21 for only the 3D-tunnel. Stronger P300 delta-theta oscillations recorded in this later situation point to a prevalence of the effect of changing direction over the proper visual content of the 3D-tunnel. The parahippocampal gyrus (BA36) implicated in navigation was also identified when the 3D-tunnel was compared to their scrambled versions, highlighting an action-oriented effect linked to navigational content. PMID- 28632776 TI - Dynamic knee valgus alignment influences impact attenuation in the lower extremity during the deceleration phase of a single-leg landing. AB - Dynamic knee valgus during landings is associated with an increased risk of non contact anterior cruciate ligament (ACL) injury. In addition, the impact on the body during landings must be attenuated in the lower extremity joints. The purpose of this study was to investigate landing biomechanics during landing with dynamic knee valgus by measuring the vertical ground reaction force (vGRF) and angular impulses in the lower extremity during a single-leg landing. The study included 34 female college students, who performed the single-leg drop vertical jump. Lower extremity kinetic and kinematic data were obtained from a 3D motion analysis system. Participants were divided into valgus (N = 19) and varus (N = 15) groups according to the knee angular displacement during landings. The vGRF and angular impulses of the hip, knee, and ankle were calculated by integrating the vGRF-time curve and each joint's moment-time curve. vGRF impulses did not differ between two groups. Hip angular impulse in the valgus group was significantly smaller than that in the varus group (0.019 +/- 0.033 vs. 0.067 +/- 0.029 Nms/kgm, p<0.01), whereas knee angular impulse was significantly greater (0.093 +/- 0.032 vs. 0.045 +/- 0.040 Nms/kgm, p<0.01). There was no difference in ankle angular impulse between the groups. Our results indicate that dynamic knee valgus increases the impact the knee joint needs to attenuate during landing; conversely, the knee varus participants were able to absorb more of the landing impact with the hip joint. PMID- 28632775 TI - Unique cellular interactions between pancreatic cancer cells and the omentum. AB - Pancreatic cancer is a common cause of cancer-related mortality. Omental spread is frequent and usually represents an ominous event, leading to patient death. Omental metastasis has been studied in ovarian cancer, but data on its role in pancreatic cancer are relatively scarce and the molecular biology of this process has yet to be explored. We prepared tissue explants from human omental fat, and used conditioned medium from the explants for various in vitro and in vivo experiments designed to evaluate pancreatic cancer development, growth, and survival. Mass spectrometry identified the fat secretome, and mRNA array identified specific fat-induced molecular alternations in tumor cells. Omental fat increased pancreatic cancer cellular growth, migration, invasion, and chemoresistance. We identified diverse potential molecules secreted by the omentum, which are associated with various pro-tumorigenic biological processes. Our mRNA array identified specific omental-induced molecular alternations that are associated with cancer progression and metastasis. Omental fat increased the expression of transcription factors, mRNA of extracellular matrix proteins, and adhesion molecules. In support with our in vitro data, in vivo experiments demonstrated an increased pancreatic cancer tumor growth rate of PANC-1 cells co cultured for 24 hours with human omental fat conditioned medium. Our results provide novel data on the role of omental tissue in omental metastases of pancreatic cancer. They imply that omental fat secreted factors induce cellular reprogramming of pancreatic cancer cells, resulting in increased tumor aggressiveness. Understanding the mechanisms of omental metastases may enable us to discover new potential targets for therapy. PMID- 28632778 TI - Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice. AB - Non-alcoholic steatohepatitis (NASH) is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6) has been implicated in the pathogenesis of NASH, with the so-called IL-6 'trans-signaling' cascade being responsible for the pro-inflammatory actions of this cytokine. We aimed to block IL-6 'trans-signaling', using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice) fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet) and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL 6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH. PMID- 28632777 TI - Immunohistochemiocal subtyping using CK20 and CK5 can identify urothelial carcinomas of the upper urinary tract with a poor prognosis. AB - PURPOSE: Genome-wide analyses revealed basal and luminal subtypes of urothelial carcinomas of the bladder. It is unknown if this subtyping can also be applied to upper tract urothelial carcinomas. MATERIALS AND METHODS: Tumor samples from 222 patients with upper tract urothelial carcinomas who were treated with radical nephroureterectomy were analyzed for the expression of seven basal/luminal immunohistochemical markers (CK5, EGFR, CD44, CK20, p63, GATA3, FOXA1). RESULTS: Hierarchical clustering revealed a basal-like subtype (enrichment of CK5, EGFR and CD44) in 23.9% and a luminal-like subtype (enrichment of CK20, GATA3, p63 and FOXA1) in 13.1% of the patients. In 60.8%, little to no markers were expressed, whereas markers of both subtypes were expressed in 2.2%. By using CK5 and CK20 as surrogate markers for the basal and luminal subtypes, we defined four subtypes of upper tract urothelial carcinomas: (i) exclusively CK20 positive and CK5 negative (CK20+/CK5-), (ii) exclusively CK5 positive and CK20 negative (CK20-/ CK5+), (iii) both markers positive (CK20+/CK5+) and (iv) both markers negative (CK20 /CK5-). A receiver-operator analysis provided the optimal cut-off values for this discrimination. An immunoreactive score >1 for CK5 and >6 for CK20 were defined as positive. In multivariate Cox's regression analysis, the CK20+/CK5- subtype was an independent negative prognostic marker with a 3.83-fold increased risk of cancer-specific death (p = 0.02) compared to the other three subtypes. CONCLUSIONS: Immunohistochemical subgrouping of upper tract urothelial carcinomas by analyzing CK5 and CK20 expression can be performed in a routine setting and can identify tumors with a significantly worse cancer-specific survival prognosis. PMID- 28632779 TI - Base-rate sensitivity through implicit learning. AB - Two experiments assessed the contributions of implicit and explicit learning to base-rate sensitivity. Using a factorial design that included both implicit and explicit learning disruptions, we tested the hypothesis that implicit learning underlies base-rate sensitivity from experience (and that explicit learning contributes comparatively little). Participants learned to classify two categories of simple stimuli (bar graph heights) presented in a 3:1 base-rate ratio. Participants learned either from "observational" training to disrupt implicit learning or "response" training which supports implicit learning. Category label feedback on each trial was followed either immediately or after a 2.5 second delay by onset of a working memory task intended to disrupt explicit reasoning about category membership feedback. Decision criterion values were significantly larger following response training, suggesting that implicit learning underlies base-rate sensitivity. Disrupting explicit processing had no effect on base-rate learning as long as implicit learning was supported. These results suggest base-rate sensitivity develops from experience primarily through implicit learning, consistent with separate learning systems accounts of categorization. PMID- 28632780 TI - Metformin intake associates with better cognitive function in patients with Huntington's disease. AB - Huntington's disease (HD) is an inherited, dominant neurodegenerative disorder caused by an abnormal expansion of CAG triplets in the huntingtin gene (htt). Despite extensive efforts to modify the progression of HD thus far only symptomatic treatment is available. Recent work suggests that treating invertebrate and mice HD models with metformin, a well-known AMPK activator which is used worldwide to treat type 2-diabetes, reduces mutant huntingtin from cells and alleviates many of the phenotypes associated to HD. Herein we report statistical analyses of a sample population of participants in the Enroll-HD database, a world-wide observational study on HD, to assess the effect of metformin intake in HD patients respect to cognitive status using linear models. This cross-sectional study shows for the first time that the use of metformin associates with better cognitive function in HD patients. PMID- 28632781 TI - Climate change and marine fisheries: Least developed countries top global index of vulnerability. AB - Future impacts of climate change on marine fisheries have the potential to negatively influence a wide range of socio-economic factors, including food security, livelihoods and public health, and even to reshape development trajectories and spark transboundary conflict. Yet there is considerable variability in the vulnerability of countries around the world to these effects. We calculate a vulnerability index of 147 countries by drawing on the most recent data related to the impacts of climate change on marine fisheries. Building on the Intergovernmental Panel on Climate Change framework for vulnerability, we first construct aggregate indices for exposure, sensitivity and adaptive capacity using 12 primary variables. Seven out of the ten most vulnerable countries on the resulting index are Small Island Developing States, and the top quartile of the index includes countries located in Africa (17), Asia (7), North America and the Caribbean (4) and Oceania (8). More than 87% of least developed countries are found within the top half of the vulnerability index, while the bottom half includes all but one of the Organization for Economic Co-operation and Development member states. This is primarily due to the tremendous variation in countries' adaptive capacity, as no such trends are evident from the exposure or sensitivity indices. A negative correlation exists between vulnerability and per capita carbon emissions, and the clustering of states at different levels of development across the vulnerability index suggests growing barriers to meeting global commitments to reducing inequality, promoting human well-being and ensuring sustainable cities and communities. The index provides a useful tool for prioritizing the allocation of climate finance, as well as activities aimed at capacity building and the transfer of marine technology. PMID- 28632782 TI - Microbial inhibitors of the fungus Pseudogymnoascus destructans, the causal agent of white-nose syndrome in bats. AB - Pseudogymnoascus destructans, the fungus that causes white-nose syndrome in hibernating bats, has spread across eastern North America over the past decade and decimated bat populations. The saprotrophic growth of P. destructans may help to perpetuate the white-nose syndrome epidemic, and recent model predictions suggest that sufficiently reducing the environmental growth of P. destructans could help mitigate or prevent white-nose syndrome-associated bat colony collapse. In this study, we screened 301 microbes from diverse environmental samples for their ability to inhibit the growth of P. destructans. We identified 145 antagonistic isolates, 53 of which completely or nearly completely inhibited the growth of P. destructans in co-culture. Further analysis of our best antagonists indicated that these microbes have different modes of action and may have some specificity in inhibiting P. destructans. The results suggest that naturally-occurring microbes and/or their metabolites may be considered further as candidates to ameliorate bat colony collapse due to P. destructans. PMID- 28632783 TI - Transient effects of transfusion and feeding advances (volumetric and caloric) on necrotizing enterocolitis development: A case-crossover study. AB - OBJECTIVE: To evaluate the short-term effects of feed fortification, feed volume increase, and PRBC transfusion on the odds of developing NEC. STUDY DESIGN: Case crossover study of neonatal intensive care infants born at <= 32 weeks' gestation who were admitted to 5 central Ohio intensive care units from January 2012-July 2016 and developed NEC Bell Stage >=2. Each patient served as their own control, with exposure during the 48-hour period just prior to NEC onset (hazard period) being compared to a preceding 48-hour control period, thus eliminating confounding by patient factors fixed between both intervals. NEC onset was determined by chart review as the earliest occurrence of one of the following within 24 hours of confirmatory x-ray: (1) antibiotic initiation, (2) enteral feeding cessation, (3) physician first notified of abdominal concerns, or (4) abdominal x-ray ordered. Conditional logistic regression compared exposures to feed volume increase, fortification, and PRBC transfusion during the 48-hour period prior to NEC onset to those during a preceding 48-hour control period. Analyses were stratified by gestational age and anemia (defined: hemoglobin <= 9.3 g/dL within 7 days of NEC onset). RESULTS: We included 63 infants with confirmed NEC. Acute exposure to fortification (odds ratio [OR]: 1.67, 95% confidence interval [CI]: 0.61, 4.59), feed volume increase (OR: 0.63, 95% CI: 0.28, 1.38), and PRBC transfusion (OR: 1.80, 95% CI: 0.60, 5.37) was not associated with the onset of NEC. Gestational age and anemia did not significantly modify the associations. Sensitivity testing substituting 24- and 72-hour hazard and control periods produced similar results. CONCLUSION: Using a case-crossover design, we did not detect an association between NEC development and feed fortification, feed volume increase, or PRBC transfusion within 48-hours prior to NEC-onset. Replication in a larger set of cases is needed. PMID- 28632784 TI - Contemporary use of P2Y12-inhibitors in patients with acute coronary syndrome undergoing percutaneous coronary intervention in Austria: A prospective, multi centre registry. AB - BACKGROUND: To this day, there is no data concerning guideline adherence on P2Y12 inhibitors in Austria. Prasugrel and ticagrelor have been shown to be superior to clopidogrel in the treatment of acute coronary syndromes (ACS). However, recent data from European registries showed a reluctant prescription policy with rates of clopidogrel at discharge ranging from 35 to 55%. METHODS: In this prospective, multi-centre registry we assessed prescription rates of P2Y12-inhibitors in patients with ACS in four Austrian PCI centres. Parameters associated with the use of clopidogrel have been evaluated in multivariate logistic regression. RESULTS: Between January and June 2015, 808 patients with ACS undergoing PCI were considered for further analysis. 416 (51.5%) presented with STEMI and 392 (48.5%) with NSTE-ACS. Mean age was 65.7 +/- 12.4 and 240 (30.9%) were female. Twenty eight (3.5%) died during the hospital stay. At discharge, 212 (27.2% of all patients) received clopidogrel, 260 (32.2%) prasugrel and 297 (36.8%) ticagrelor, while 11 (1.4%) did not receive any P2Y12-inhibitor. Of those patients, who were discharged with clopidogrel, 117 (55.2%) had no absolute contraindication against a more potent P2Y12-inhibitor. Diagnosis of NSTE-ACS (p<0.001), COPD (p = 0.049), and age (p<0.001) next to factors contributing to absolute contraindication were positively associated with the use of clopidogrel. CONCLUSIONS: Despite a high level of care, a considerable number of patients were not treated with the more potent P2Y12-inhibitors. Parameters associated with a presumably higher risk of bleeding and side-effects against the more effective P2Y12 inhibitors were the most prominent factors for the prescription of clopidogrel. PMID- 28632785 TI - The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product accumulation. AB - BACKGROUND: Skin autofluorescence, a biomarker for advanced glycation end products (AGEs) accumulation, has been shown to predict diabetes-related cardiovascular complications and is associated with several environmental and lifestyle factors. In the present study, we examined the association between various smoking behaviors and skin autofluorescence, as well as the association between several cotinine biomarkers and skin autofluorescence, using both epidemiological and metabolomics data. METHODS: In a cross-sectional study, we evaluated participants from the LifeLines Cohort Study and the Qatar Metabolomics Study on Diabetes (QMDiab). In the LifeLines Cohort Study smoking behavior and secondhand smoking were assessed in 8,905 individuals including 309 individuals (3.5%) with type 2 diabetes. In QMDiab, cotinine biomarkers were measured in saliva, plasma and urine in 364 individuals of whom 188 (51%) had type 2 diabetes. Skin autofluorescence was measured non-invasively in all participants using the AGE Reader. RESULTS: Skin autofluorescence levels increased with a higher number of hours being exposed to secondhand smoking. Skin autofluorescence levels of former smokers approached levels of never smokers after around 15 years of smoking cessation. Urinary cotinine N-oxide, a biomarker of nicotine exposure, was found to be positively associated with skin autofluorescence in the QMDiab study (p = 0.03). CONCLUSIONS: In the present study, we have demonstrated that secondhand smoking is associated with higher skin autofluorescence levels whereas smoking cessation has a beneficial effect on skin autofluorescence. Finally, urinary cotinine N-oxide might be used as an alternative way for questionnaires to examine the effect of (environmental) tobacco smoking on skin autofluorescence. PMID- 28632786 TI - Diagnostic accuracy of magnetic resonance, computed tomography and contrast enhanced ultrasound in radiological multimodality assessment of peribiliary liver metastases. AB - PURPOSE: We compared diagnostic performance of Magnetic Resonance (MR), Computed Tomography (CT) and Ultrasound (US) with (CEUS) and without contrast medium to identify peribiliary metastasis. METHODS: We identified 35 subjects with histological proven peribiliary metastases who underwent CEUS, CT and MR study. Four radiologists evaluated the presence of peribiliary lesions, using a 4-point confidence scale. Echogenicity, density and T1-Weigthed (T1-W), T2-W and Diffusion Weighted Imaging (DWI) signal intensity as well as the enhancement pattern during contrast studies on CEUS, CT and MR so as hepatobiliary-phase on MRI was assessed. RESULTS: All lesions were detected by MR. CT detected 8 lesions, while US/CEUS detected one lesion. According to the site of the lesion, respect to the bile duct and hepatic parenchyma: 19 (54.3%) were periductal, 15 (42.8%) were intra-periductal and 1 (2.8%) was periductal-intrahepatic. According to the confidence scale MRI had the best diagnostic performance to assess the lesion. CT obtained lower diagnostic performance. There was no significant difference in MR signal intensity and contrast enhancement among all metastases (p>0.05). There was no significant difference in CT density and contrast enhancement among all metastases (p>0.05). CONCLUSIONS: MRI is the method of choice for biliary tract tumors but it does not allow a correct differential diagnosis among different histological types of metastasis. The presence of biliary tree dilatation without hepatic lesions on CT and US/CEUS study may be an indirect sign of peribiliary metastases and for this reason the patient should be evaluated by MRI. PMID- 28632787 TI - Risk of Alzheimer's disease or dementia following a cancer diagnosis. AB - OBJECTIVE: We evaluated dementia and Alzheimer's disease (AD) risks after a cancer diagnosis in a population-based prospective cohort, the Adult Changes in Thought (ACT) study. METHODS: We followed community-dwelling people aged >=65 years without dementia at study entry for incident dementia and AD from 1994 2015. We linked study data with cancer registry data and categorized cancer diagnoses as prevalent (diagnosed before ACT study enrollment) or incident (diagnosed during follow-up). We used Cox regression to estimate cause-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for dementia or AD risk comparing people with a cancer diagnosis to people without cancer. We conducted sensitivity analyses restricted to people surviving beyond age 80, and stratified by cancer stage, type, and whether the cancer was smoking-related. RESULTS: Among 4,357 people, 756 (17.4%) had prevalent cancer; 583 (13.4%) developed incident cancer, 1,091 (25.0%) developed dementia, and 877 (20.1%) developed AD over a median 6.4 years (34,482 total person-years) of follow-up. Among complete cases (no missing covariates) with at least one follow-up assessment, adjusted HRs for dementia following prevalent and incident cancer diagnoses were 0.92 (95%CI: 0.76, 1.11) and 0.87 (95%CI: 0.64, 1.04), compared to no cancer history. HRs for AD were 0.95 (95%CI: 0.77, 1.17) for prevalent cancer and 0.73 (95%CI: 0.55, 0.96) for incident cancer. In sensitivity analyses, prevalent late-stage cancers were associated with reduced risks of dementia (HR = 0.51, 95%CI: 0.30, 0.89) and AD (HR = 0.50, 95%CI: 0.27, 0.94). When limited to people who survived beyond age 80, incident cancers were still associated with reduced AD risk (HR = 0.69, 95%CI: 0.51, 0.92). CONCLUSIONS: Our results do not support an inverse association between prevalent cancer diagnoses, which were primarily early-stage, less aggressive cancers, and risk of dementia or AD. A reduced risk of AD following an incident cancer diagnosis is biologically plausible but may reflect selective mortality. PMID- 28632788 TI - High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance. AB - Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that bypass drug resistance. Trimethoprim and sulfamethizole are both folate biosynthesis inhibitors. We find that this activity disrupts nucleotide homeostasis, which blocks DNA replication in the presence of AZT. Building on these data, we show that other small molecules that disrupt nucleotide homeostasis through other mechanisms (hydroxyurea and floxuridine) also act synergistically with AZT. These novel combinations inhibit the growth and virulence of trimethoprim-resistant clinical Escherichia coli and Klebsiella pneumoniae isolates, suggesting that they may be able to be rapidly advanced into clinical use. In sum, we present a generalizable method to screen for novel synergistic combinations, to identify particular mechanisms resulting in synergy, and to use the mechanistic knowledge to rationally design new combinations that bypass drug resistance. PMID- 28632790 TI - Diversity structure of culturable bacteria isolated from the Fildes Peninsula (King George Island, Antarctica): A phylogenetic analysis perspective. AB - It has been proposed that Antarctic environments select microorganisms with unique biochemical adaptations, based on the tenet 'Everything is everywhere, but, the environment selects' by Baas-Becking. However, this is a hypothesis that has not been extensively evaluated. This study evaluated the fundamental prediction contained in this hypothesis-in the sense that species are structured in the landscape according to their local habitats-, using as study model the phylogenetic diversity of the culturable bacteria of Fildes Peninsula (King George Island, Antarctica). Eighty bacterial strains isolated from 10 different locations in the area, were recovered. Based on phylogenetic analysis of 16S rRNA gene sequences, the isolates were grouped into twenty-six phylotypes distributed in three main clades, of which only six are exclusive to Antarctica. Results showed that phylotypes do not group significantly by habitat type; however, local habitat types had phylogenetic signal, which support the phylogenetic niche conservatism hypothesis and not a selective role of the environment like the Baas Becking hypothesis suggests. We propose that, more than habitat selection resulting in new local adaptations and diversity, local historical colonization and species sorting (i.e. differences in speciation and extinction rates that arise by interaction of species level traits with the environment) play a fundamental role on the culturable bacterial diversity in Antarctica. PMID- 28632789 TI - Movement and contact patterns of long-distance free-grazing ducks and avian influenza persistence in Vietnam. AB - Presence of ducks, and in particular of free-grazing ducks, has consistently been shown to be one of the most important risk factors for highly pathogenic avian influenza outbreaks which has compromised poultry production in South-East Asia since the early 2000s and continues to threaten public health, farmers' livelihood and food security. Although free-grazing duck production has been practised for decades in South-East Asia, there are few published studies describing this production system, which is suspected to play an important role in the maintenance of avian influenza viruses. This study aimed at describing quantitatively the long-distance free-grazing duck production system in South Vietnam, characterising the movement and contact patterns of the duck flocks, and identifying potential associations between farming practices, movement and contact patterns and the circulation of avian influenza viruses. We conducted interviews among stakeholders involved in the free-grazing duck production system (duck farmers, transporters and rice paddy owners) in combination with a virological cross-sectional survey in South Vietnam. Results show that both direct and indirect contacts between free-grazing duck flocks were frequent and diverse. The flocks were transported extensively across district and province boundaries, mainly by boat but also by truck or on foot. A third of the investigated flocks had a positive influenza A virology test, indicating current circulation of avian influenza viruses, but none were positive for H5 subtypes. The age and size of the flock as well as its location at the time of sampling were associated with the risk of influenza A circulation in the flocks. These findings should be considered when developing risk assessment models of influenza virus spread aimed at informing the development of improved biosecurity practices leading to enhanced animal health, sustainable animal production and reliable income for farmers. PMID- 28632791 TI - Long term oncological outcome of thymoma and thymic carcinoma - an analysis of 235 cases from a single institution. AB - BACKGROUND AND OBJECTIVES: Thymoma has a variable long-term oncological outcome after surgical resection. Survival and tumor recurrence were analyzed to determine the predisposing factors for tumor recurrence. METHODS: A total of 235 patients who underwent surgery for thymoma or thymic carcinoma from December 1997 to March 2013 were analyzed using Masaoka staging system and World Health Organization (WHO) histological classification. Surgical intervention included extended thymothymectomy via median sternotomy and thymomectomy via thoracotomy/ video-assisted thoracoscopic surgery (VATS). RESULTS: The median duration of follow-up was 105 months (12-198 months). Among these 235 patients, recurrence was observed in 25 patients (10.7%). according to Masaoka stage I, IIA, IIB, III, IVA, IVB, recurrence rates were 1/65(1.5%), 8/106(7.5%), 1/32(3.1%), 6/20(30.0%), 8/10(80.0%), 1/1(100.0%), respectively. Disease or treatment-related mortality was observed in 13 patients. Overall survival rate was 94.4%. After univariate analysis, predisposing factors for tumor recurrence included Masaoka stage, WHO histologic type, tumor size, adjuvant therapy and margin status. CONCLUSIONS: Due to the indolent behavior of thymoma, tumor recurrence appears to be a better assessment of oncological outcome rather than survival. Factors associated with tumor recurrence include Masaoka stage, WHO histologic type, tumor size, adjuvant therapy and margin status. PMID- 28632792 TI - Identification of cell proliferation, immune response and cell migration as critical pathways in a prognostic signature for HER2+:ERalpha- breast cancer. AB - BACKGROUND: Multi-gene prognostic signatures derived from primary tumor biopsies can guide clinicians in designing an appropriate course of treatment. Identifying genes and pathways most essential to a signature performance may facilitate clinical application, provide insights into cancer progression, and uncover potentially new therapeutic targets. We previously developed a 17-gene prognostic signature (HTICS) for HER2+:ERalpha- breast cancer patients, using genes that are differentially expressed in tumor initiating cells (TICs) versus non-TICs from MMTV-Her2/neu mammary tumors. Here we probed the pathways and genes that underlie the prognostic power of HTICS. METHODS: We used Leave-One Out, Data Combination Test, Gene Set Enrichment Analysis (GSEA), Correlation and Substitution analyses together with Receiver Operating Characteristic (ROC) and Kaplan-Meier survival analysis to identify critical biological pathways within HTICS. Publically available cohorts with gene expression and clinical outcome were used to assess prognosis. NanoString technology was used to detect gene expression in formalin fixed paraffin embedded (FFPE) tissues. RESULTS: We show that three major biological pathways: cell proliferation, immune response, and cell migration, drive the prognostic power of HTICS, which is further tuned by Homeostatic and Glycan metabolic signalling. A 6-gene minimal Core that retained a significant prognostic power, albeit less than HTICS, also comprised the proliferation/immune/migration pathways. Finally, we developed NanoString probes that could detect expression of HTICS genes and their substitutions in FFPE samples. CONCLUSION: Our results demonstrate that the prognostic power of a signature is driven by the biological processes it monitors, identify cell proliferation, immune response and cell migration as critical pathways for HER2+:ERalpha- cancer progression, and defines substitutes and Core genes that should facilitate clinical application of HTICS. PMID- 28632794 TI - Migrants, healthy worker effect, and mortality trends in the Gulf Cooperation Council countries. AB - The Gulf Cooperation Council (GCC) countries namely, Bahrain, Kuwait, Oman, Qatar, United Arab Emirates (UAE), and Saudi Arabia, have experienced unique demographic changes. The major population growth contributor in these countries is young migrants, which has led to a shift in the population age pyramid. Migrants constitute the vast proportion of GCC countries' population reaching >80% in Qatar and UAE. Using Global Burden of Disease Study 2015 (GBD 2015) and United Nations data, for the GCC countries, we assessed the association between age-standardized mortality and population size trends with linear and polynomial regressions. In 1990-2015, all-cause age-standardized mortality was inversely proportional to national population size (p-values: 0.0001-0.0457). In Bahrain, Qatar, Oman, and Saudi Arabia, the highest annual decrease in mortality was observed when the annual population growth was the highest. In Qatar, all-cause age-specific mortality was inversely proportional to age-specific population size. This association was statistically significant among the 5-14 and 15-49 age groups, which have the largest population size. Cause-specific age-standardized mortality was also inversely proportional to population size. This association was statistically significant for half of the GBD 2015-defined causes of death such as "cirrhosis and other chronic liver diseases" and "HIV/AIDS and tuberculosis". Remarkably, incoming migrants to Qatar have to be negative for HIV, hepatitis B and C, and tuberculosis. These results show that decline in mortality can be partly attributed to the increase in GCC countries' population suggesting a healthy migrant effect that influences mortality rates. Consequently, benefits of health interventions and healthcare improvement are likely to be exaggerated in such countries hosting a substantial proportion of migrants compared with countries where migration is low. Researchers and policymakers should be cautious to not exclusively attribute decline in mortality within the GCC countries as a result of the positive effects of health interventions or healthcare improvement. PMID- 28632793 TI - The prevalence and correlates of low sexual functioning in women on hemodialysis: A multinational, cross-sectional study. AB - Sexual dysfunction may affect 80% of women in hemodialysis. However the specific patterns and clinical correlates of sexual functioning remain poorly described. The aim of this study was to assess prevalence and correlates of the individual domains of sexual functioning in women treated with hemodialysis. We recruited, into this multinational cross-sectional study, women treated with long-term hemodialysis (Collaborative Working Group on Depression and Sexual dysfunction in Hemodialysis study). Self-reported domains of sexual functioning were assessed by the Female Sexual Function Index, which is routinely administered within the network of dialysis patients followed by the working group. Lower scores represented lower sexual functioning. Socio-demographic and clinical correlates of each domain of sexual functioning were identified by stepwise multivariable linear regression. Sensitivity analyses were restricted to women who reported being sexually active. We found that of 1309 enrolled women, 659 (50.3%) provided complete responses to FSFI survey questions and 232 (35%) reported being sexually active. Overall, most respondents reported either no sexual activity or low sexual functioning in all measured domains (orgasm 75.1%; arousal 64.0%; lubrication 63.3%; pain 60.7%; satisfaction 60.1%; sexual desire 58.0%). Respondents who were waitlisted for a kidney transplant reported scores with higher sexual functioning, while older respondents reported scores with lower functioning. The presence of depression was associated with worse lubrication and pain scores [mean difference for depressed versus non-depressed women (95% CI) 0.42 (-0.73 to -0.11), -0.53 (-0.89 to -0.16), respectively] while women who had experienced a previous cardiovascular event reported higher pain scores [-0.77 ( 1.40- to -0.13)]. In conclusion, women in hemodialysis reported scores consistent with marked low sexual functioning across a range of domains; the low functioning appeared to be associated with comorbidity. PMID- 28632795 TI - Sun protection for infants: parent behaviors and beliefs in Miami, Florida. AB - Children who are not adequately protected from the sun have an increased risk for developing skin cancers later in life. The primary objective of this study was to determine the sun protection behaviors that black and Hispanic parents in Miami, Florida, employ in infants younger than 6 months. Secondary objectives included determining if this patient population is at risk for infant sunburns and tanning, beliefs among parents regarding sunscreen's efficacy in the prevention of skin cancers, and limitations of sunscreen use. An institutional review board approved survey was administered to parents presenting to the University of Miami general pediatrics clinic. The main outcome measure was the self-reported consistency with which parents employed each of 6 sun protection strategies in infants. The results of this study highlight some potential shortcomings in current practices in sun protection for black and Hispanic infants. PMID- 28632796 TI - Handheld reflectance confocal microscopy to aid in the management of complex facial lentigo maligna. AB - Diagnosis and management of lentigo maligna (LM) and LM melanoma (LMM) is challenging. Novel noninvasive imaging technologies such as reflectance confocal microscopy (RCM) have advanced the ability to better diagnose and monitor challenging lesions. In addition, the new handheld RCM (HRCM) together with the use of videomosaics has allowed an accurate evaluation of large lesions in concave/convex areas of the body (eg, the face). Herein, we review the impact of HRCM in the detection, treatment decision-making, and monitoring of 5 cases of complex facial LM/LMM. In the cases presented, HRCM enabled the detection of subclinical margins, presence of invasion, detection of persistence/recurrence, and monitoring of surgical and nonsurgical therapies. In this preliminary report, our results suggest that HRCM is a versatile ancillary tool in pretreatment decision-making, intraoperative surgical mapping, and posttreatment monitoring of complex facial LM/LMM. PMID- 28632797 TI - Approach to management of giant basal cell carcinomas. AB - Basal cell carcinoma (BCC) is a common nonmelanoma skin cancer with increasing incidence in the United States and worldwide. It is strongly linked to UV radiation exposure and typically is slow growing. Malignancy in BCCs is due to local growth and invasion rather than metastasis, and the prognosis is generally favorable. We report the case of a 60-year-old man with a large, locally destructive giant BCC on the right side of the upper back that was successfully treated via complete surgical excision (SE) and did not recur in the subsequent 36 months. We review the indications, evidence, advantages, and disadvantages associated with multiple surgical and nonsurgical treatment modalities available for the management of giant BCCs. PMID- 28632798 TI - Skin cancer mortality in patients with skin of color. PMID- 28632799 TI - Recalcitrant solitary erythematous scaly patch on the foot. PMID- 28632800 TI - Total-body photography in skin cancer screening: the clinical utility of standardized imaging. AB - Early detection of skin cancer is essential to reducing morbidity and mortality from both melanoma and nonmelanoma skin cancers. Total-body skin examinations (TBSEs) may improve early detection of malignant melanomas (MMs) but are controversial due to the poor quality of data available to establish a mortality benefit from skin cancer screening. Total-body photography (TBP) promises to provide a way forward by lowering the costs of dermatologic screening while simultaneously leveraging technology to increase patient access to dermatologic care. Standardized TBP also offers the ability for dermatologists to work synergistically with modern computer technology involving algorithms capable of analyzing high-quality images to flag concerning lesions that may require closer evaluation. On a population level, inexpensive TBP has the potential to increase access to skin cancer screening and it has several specific applications in a military population. The utility of standardized TBP is reviewed in the context of skin cancer screening and teledermatology. PMID- 28632802 TI - Diversity in dermatology: a society devoted to skin of color. AB - The US Census Bureau predicts that more than half of the country's population will identify as a race other than non-Hispanic white by the year 2044. Racial disparities also exist in the physician population where black individuals and Latinos are underrepresented. The Skin of Color Society (SOCS) was established to address the need for parity among dermatology patients with skin of color. The society provides educational support on dermatologic health related to skin of color and functions through committees that represent the multifaceted aspects of the organization. This column highlights the ongoing efforts of SOCS and its impact since its inception. We also chronicle the society's approach to broadening the scope of the specialty of dermatology. PMID- 28632801 TI - Enlarging mass on the lateral neck. PMID- 28632803 TI - What's eating you? Cheyletiella mites. AB - Cheyletiella are nonburrowing mites commonly found on rabbits, dogs, and cats. The mites have been known to cause disease in humans, ranging from mild dermatitis to more severe illness with systemic symptoms. Because these mites do not complete any part of their life cycle in humans, diagnosis can be challenging. Herein, we review various clinical presentations associated with Cheyletiella mites as well as diagnostic techniques and treatment options for both humans and animals. PMID- 28632804 TI - Black linear streaks on the face with pruritic plaques on the trunk and arms. PMID- 28632805 TI - Perifollicular papules on the trunk. PMID- 28632806 TI - Granulomatous cheilitis mimicking angioedema. PMID- 28632807 TI - Transverse melanonychia and palmar hyperpigmentation secondary to hydroxyurea therapy. PMID- 28632808 TI - Unilateral verrucous porokeratosis of the gluteal cleft. PMID- 28632809 TI - Acquired epidermodysplasia verruciformis occurring in a renal transplant recipient. AB - Acquired epidermodysplasia verruciformis (EDV) is a rare condition occurring in patients with depressed cellular immunity, particularly individuals with human immunodeficiency virus (HIV). Acquired EDV is less commonly reported in recipients of stem cell or solid organ transplantation. This condition typically manifests within 5 years of initial immunosuppression and can present as multiple hypopigmented to red, tinea versicolor-like macules or as multiple verrucous, flat-topped papules distributed over the trunk, arms, and legs. Human papillomavirus (HPV) types 5 and 8 are the most commonly isolated EDV-HPV subtypes as well as the most oncogenic subtypes, carrying the greatest risk for malignant transformation into squamous cell carcinoma (SCC). We present the case of a 44-year-old renal transplant recipient who developed multiple hypopigmented papules on the chest and neck with histopathology showing characteristic changes of EDV. PMID- 28632810 TI - Hydralazine-associated cutaneous casculitis presenting with aerodigestive tract involvement. AB - Hydralazine-induced small vessel vasculitis is a rare entity with a limited number of cases reported in the dermatologic literature. A characteristic pattern of acral pseudoembolic vesiculopustules with necrosis and ulceration has been suggested along with involvement of the aerodigestive tract, indicating mucosal involvement is an important feature of this disease. We report the case of a patient with hydralazine-induced vasculitis who exemplified this characteristic presentation associated with severe involvement of the aerodigestive tract and gastrointestinal tract bleeding. In addition to the distinctive clinical presentation, the patient's workup revealed the characteristic antineutrophil cytoplasmic antibody (ANCA)-positive serologic profile. Increased recognition of the clinical and serological features of hydralazine-induced small vessel vasculitis may lead to earlier recognition of this disease and decreased time to discontinuation of hydralazine when appropriate. Drug withdrawal is the cornerstone of therapy, and depending on the severity of symptoms, additional immunosuppressive treatment such as corticosteroids may be necessary. PMID- 28632811 TI - Management of poorly controlled indolent systemic mastocytosis using narrowband UVB phototherapy. AB - The mastocytoses comprise a group of proliferative stem cell disorders defined by the abnormal accumulation of mast cells (MCs) in the skin or other body tissues including the bone marrow, gastrointestinal tract, and liver. Systemic mastocytosis is defined by the presence of one major and one minor criterion or 3 minor criteria delineated by the World Health Organization (WHO). We present the case of a 57-year-old woman with a 10-year history of red-brown pruritic maculopapular lesions on the upper and lower extremities and trunk who was originally diagnosed with cutaneous mastocytosis. Symptoms had been adequately controlled with a combination of topical corticosteroids and antihistamines. After 9 years of controlled disease, the patient presented with increasingly severe breakthrough pruritus and new skin lesions on the head and neck. Further workup included bone marrow biopsy, which demonstrated dense mastocyte infiltrates without evidence of functional impairment, and elevated serum tryptase levels. Narrowband UVB (NB-UVB) phototherapy was initiated, and after 20 treatments the patient reported a marked decrease in symptoms. This case provides evidence of the efficacy of NB-UVB phototherapy in managing patients with long standing indolent systemic mastocytosis (ISM) who have stopped responding adequately to topical corticosteroids and antihistamines. PMID- 28632812 TI - Systemic interferon alfa injections for the treatment of a giant orf. AB - Orf is a zoonotic infection caused by a parapoxvirus and is endemic in sheep and goats. It may be transmitted to humans by direct contact with infected animals. We report a case of a giant orf in a patient with chronic lymphocytic leukemia (CLL), which proliferated dramatically after surgical excision and resolved after systemic interferon alfa-2a injections. PMID- 28632813 TI - Cutaneous metastasis of a pulmonary carcinoid tumor. AB - Carcinoid tumors are uncommon neoplasms of neuroendocrine origin that generally arise in the gastrointestinal or bronchopulmonary tracts and typically are characterized by an indolent clinical course. Metastases from these primary neoplasms more commonly affect the viscera, with rare reports of cutaneous metastases to the skin. We report the case of a patient with a cutaneous carcinoid metastasis that was incidentally brought to our attention because of the exquisite tenderness of the lesion. A brief review of the literature also is provided. PMID- 28632818 TI - Benefits of Islet Transplantation as an Alternative to Pancreas Transplantation: Retrospective Study of More Than 10 Ten Years of Experience in a Single Center. AB - BACKGROUND: Pancreas transplantation (PTx) represents the method of choice in type 1 diabetic patients with conservatively intractable hypoglycemia unawareness syndrome. In 2005, the Institute for Clinical and Experimental Medicine (IKEM) launched a program to investigate the safety potential of islet transplantation (ITx) in comparison to PTx. AIM: This study aims to compare the results of PTx and ITx regarding severe hypoglycemia elimination, metabolic control, and complication rate. METHODS: We analyzed the results of 30 patients undergoing ITx and 49 patients treated with PTx. All patients were C-peptide-negative and suffered from hypoglycemia unawareness syndrome. Patients in the ITx group received a mean number of 12,349 (6,387-15,331) IEQ/kg/person administered percutaneously into the portal vein under local anesthesia and radiological control. The islet number was reached by 1-3 applications, as needed. In both groups, we evaluated glycated hemoglobin, insulin dose, fasting and stimulated C peptide, frequency of severe hypoglycemia, and complications. We used the Mann Whitney test, Wilcoxon signed-rank test, and paired t-test for analysis. We also individually assessed the ITx outcomes for each patient according to recently suggested criteria established at the EPITA meeting in Igls. RESULTS: Most of the recipients showed a significant improvement in metabolic control one and two years after ITx, with a significant decrease in HbA1c, significant elevation of fasting and stimulated C-peptide, and a markedly significant reduction in insulin dose and the frequency of severe hypoglycemia. Seventeen percent of ITx recipients were temporarily insulin-independent. The results in the PTx group were comparable to those in the ITx group, with 73% graft survival and insulin independence in year 1, 68% 2 years and 55% 5 years after transplantation. There was a higher rate of complications related to the procedure in the PTx group. Severe hypoglycemia was eliminated in the majority of both ITx and PTx recipients. CONCLUSION: This report proves the successful initiation of pancreatic islet transplantation in a center with a well-established PTx program. ITx has been shown to be the method of choice for hypoglycemia unawareness syndrome, and may be considered for application in clinical practice if conservative options are exhausted. PMID- 28632820 TI - The Nexus of Stem Cell-Derived Beta-Cells and Genome Engineering. AB - Diabetes, type 1 and type 2 (T1D and T2D), are diseases of epidemic proportions, which are complicated and defined by genetics, epigenetics, environment, and lifestyle choices. Current therapies consist of whole pancreas or islet transplantation. However, these approaches require life-time immunosuppression, and are compounded by the paucity of available donors. Pluripotent stem cells have advanced research in the fields of stem cell biology, drug development, disease modeling, and regenerative medicine, and importantly allows for the interrogation of therapeutic interventions. Recent developments in beta-cell differentiation and genomic modifications are now propelling investigations into the mechanisms behind beta-cell failure and autoimmunity, and offer new strategies for reducing the propensity for immunogenicity. This review discusses the derivation of endocrine lineage cells from human pluripotent stem cells for the treatment of diabetes, and how the editing or manipulation of their genomes can transcend many of the remaining challenges of stem cell technologies, leading to superior transplantation and diabetes drug discovery platforms. PMID- 28632822 TI - [Strategies to reduce infections and antibiotic use and its effects in a neonatal care unit]. AB - INTRODUCTION: Late onset sepsis (LOS) remains an important cause of morbidity and mortality in neonatal intensive care units (NICU). The empirical use of vancomycin and other broad spectrum antibiotics is very frequent and is associated with the emergence of resistant agents, infection by gram-negative bacilli (GNB), fungal infections and increased morbidity and mortality. OBJECTIVE: To evaluate the impact of 5 intervention protocols designed to reduce infections and promote the rational use of antibiotics (AB) in a single NICU. PATIENTS AND METHOD: Retrospective analysis included all hospitalized patients before (year 2012) and after interventions (August 2013 through July 2014). All episodes of positive cultures (blood, urine, tracheal and spinal fluid) were considered as late onset infections. RESULTS: After intervention, a significant decrease of late onset infections was observed from 14.3 to 8.5 per 1,000 live births (p < 0.01); with a decrease in LOS from 5.7 to 2.9 per 1,000 live births, although no significant. There was a decrease in vancomycin and 3rd generation cephalosporin use without Candida spp infections in the intervention period. Mortality rates and length of hospital stay were similar in both study periods. CONCLUSION: After interventions, there was an important reduction in overall late onset infections and AB related costs. PMID- 28632819 TI - Enzyme Development for Human Islet Isolation: Five Decades of Progress or Stagnation? AB - In comparison to procedures used for the separation of individual cell types from other organs, the process of human pancreatic islet isolation aims to digest the pancreatic exocrine matrix completely without dispersing the individual cells within the endocrine cell cluster. This objective is unique within the field of tissue separation, and outlines the challenge of islet isolation to balance two opposing priorities. Although significant progress has been made in the characterization and production of enzyme blends for islet isolation, there are still numerous areas which require improvement. The ultimate goal of enzyme production, namely the routine production of a consistent and standardized enzyme blend, has still not been realized. This seems to be mainly the result of a lack of detailed knowledge regarding the structure of the pancreatic extracellular matrix and the synergistic interplay between collagenase and different supplementary proteases during the degradation of the extracellular matrix. Furthermore, the activation of intrinsic proteolytic enzymes produced by the pancreatic acinar cells, also impacts on the chance of a successful outcome of human islet isolation. This overview discusses the challenges of pancreatic enzymatic digestion during human islet isolation, and outlines the developments in this field over the past 5 decades. PMID- 28632824 TI - [Adolescents find it easy to collect their own samples to study sexually transmitted infections]. AB - BACKGROUND: As alternative for patients that fear genital examination, we assessed adolescent's comfort and ease with self-collected samples for nucleic acid amplification testing for sexually transmitted infections. PATIENTS AND METHODS: Sexually active Chilean adolescents and youth under 25 years (174 males and 117 females) were enrolled. Females used self-collected vaginal swabs and males collected first-stream urine. A satisfaction survey evaluating self sampling system was applied. RESULTS: Self-collection was considered easy in 99.3% of the interviewees (CI 95% 0.88-0.98). In women, 79.3% preferred vaginal self-collected samples than pelvic exam (CI 95% 0.73-0.85). In men, 80.3% preferred self-collected first-stream urine to urethral swabs (CI 95% 0.73-0.87). Assuming that self-collected sampling were available, 89.6% of women (CI 95% 0.85 0.94) and 93.2% of men (CI 95% 0.89-0.98) would be prone to be tested more often. Ease of self-collected sampling is not associated with age, gender, educational level or poverty. CONCLUSIONS: Chile currently does not have sexually transmitted infections surveillance or screening programs for youth and adolescents. Given self-collected sampling's good acceptability, it could be successfully used when these programs are implemented. PMID- 28632823 TI - [Features of Bordetella pertussis, Bordetella spp. infection and whopping cough in Cordoba province, Argentina]. AB - INTRODUCTION: Whooping cough is a re-emerging infection in the world and Latin America. OBJECTIVE: It was considered relevant to investigate the clinical and epidemiological profile of Bordetella spp. and Bordetella pertussis infection in Cordoba province, Argentina; evaluating, at the same time, the co-infection with virus producing respiratory infections that may be confused with whooping cough. MATERIAL AND METHODS: All whooping cough suspected cases were studied by Polimerase Chain Reaction, amplifying the repeated insertion sequence (IS) 481 and the promoter gene encoding pertussis toxin, between 2011 and 2013. The data were obtained from the clinical and epidemiological records. RESULTS: From 2,588 whooping cough suspected cases, 11.59% was infected by Bordetella spp. and 9.16% was confirmed as Bordetella pertussis infection. The rate of infection was 7.22 and 1.84 per 100,000 for 2011 and 2012, respectively. The infection presented a seasonal tendency and it was mainly found on the group of children between 13 and 24 months old. The co-infection with virus producing respiratory infections, were uncommon. Paroxysmal cough, cyanosis and/or vomiting were predictors of the infection for Bordetella pertussis. DISCUSSION AND CONCLUSIONS: To deal with the re-emergence of whooping cough is important the knowledge of the regional epidemiological situation. This paper shows the situation of these infections in the regional clinical and epidemiological context, and makes the information available for health decision-making. PMID- 28632821 TI - Encapsulated Islet Transplantation: Where Do We Stand? AB - Transplantation of pancreatic islets encapsulated within immuno-protective microcapsules is a strategy that has the potential to overcome graft rejection without the need for toxic immunosuppressive medication. However, despite promising preclinical studies, clinical trials using encapsulated islets have lacked long-term efficacy, and although generally considered clinically safe, have not been encouraging overall. One of the major factors limiting the long term function of encapsulated islets is the host's immunological reaction to the transplanted graft which is often manifested as pericapsular fibrotic overgrowth (PFO). PFO forms a barrier on the capsule surface that prevents the ingress of oxygen and nutrients leading to islet cell starvation, hypoxia and death. The mechanism of PFO formation is still not elucidated fully and studies using a pig model have tried to understand the host immune response to empty alginate microcapsules. In this review, the varied strategies to overcome or reduce PFO are discussed, including alginate purification, altering microcapsule geometry, modifying alginate chemical composition, co-encapsulation with immunomodulatory cells, administration of pharmacological agents, and alternative transplantation sites. Nanoencapsulation technologies, such as conformal and layer-by-layer coating technologies, as well as nanofiber, thin-film nanoporous devices, and silicone based NanoGland devices are also addressed. Finally, this review outlines recent progress in imaging technologies to track encapsulated cells, as well as promising perspectives concerning the production of insulin-producing cells from stem cells for encapsulation. PMID- 28632826 TI - [Pyogenic liver abscess in children: clinical experience in a pediatric reference center]. AB - INTRODUCTION: Liver abscess is a serious and an uncommon pediatric disease. OBJECTIVE AND METHOD: Description of 20 pediatric patients with liver abscess admitted in "Ricardo Gutierrez" Children's Hospital, a Tertiary Reference Center of Buenos Aires, between 2009 and 2015. RESULTS: The hospitalization rate was 35/100.000 admissions. Median age was 5 years old, male/female ratio 4/1. Five patients (25%) had predisposing factors. Median days at diagnosis were 12. FEATURES: Fever 100%, prolonged fever 60%, abdominal pain 50%. The majority had leukocytosis and elevated CRP (median 160 mg/L). Liver enzymes were elevated in only 40% of patients. Ultrasonography detected 90%. A single abscess was observed in 60%; localized at right hepatic lobe, 65%. Purulent material was positive in 12/17 (70%) and bacteremia was present in 3/20 (15%). Wide empirical antibiotic therapy was used. Treatment shift was needed in four patients. The median days of intravenous antibiotics were 30 and the median of total treatment were 53. Surgical procedures were performed in 13/20 (65%). CONCLUSION: Community-acquired methicillin resistant Staphylococcus aureus (CA-MRSA) was the most frequent pathogen, especially in healthy children that associated skin or respiratory illness. Appropriate antibiotic treatment and eventual drainage allows good outcome without sequela or deaths. PMID- 28632825 TI - [What do the numbers tell us about the temporal evolution of Chagas' disease?] AB - Chagas disease remains highly prevalent in Chile, especially between the regions of Arica and Parinacota, and Coquimbo. Since 1999 it is considered that in Chile the vector transmission was interrupted. Under this premise, the epidemiological dynamics should be changing. We analyzed the evolution of the prevalence of Chagas' disease analyzing 64,995 xenodiagnosis performed in the laboratory of Parasitology of the Faculty of Medicine of the University of Chile between 1949 and 2014. The evolution of the mortalities and incidences from the databases of the Ministry of Health in the periods in which it was analyzed. The rates of domiciliary infestation and the number of vector insects sent to the Public Health Institute and its trypano-triatomine indices were also analyzed. The prevalence of Chagas' disease in inhabitants of risk areas remained stable in this period as well as mortality. The incidence rate shows a progressive increase with a tendency towards stabilization. A significant decrease in sampling effort was found, declining by two orders of magnitude, especially since 2000. The progressive increase in morbidity had no clear relation to the interruption of the vector chain nor to the greater diagnostic effort occurred in 2009, since it was evident from before. While home infestation declines, reports of intrusion of solitary individuals and wild foci of T. infestans have increased. Trypano triatomine indices were maintained with high values in all vector species. This study shows a worrying situation, for while on the one hand the interruption of the vector transmission and improvement in the research systems is emphasized, the concern for this disease seems to be decreasing with less diagnostic efforts and lower education at the higher level, and by the other hand the numbers show that the problem if it is not increasing, at least maintains its careless historical magnitude. PMID- 28632827 TI - [Occult bacteremia in Sotero del Rio Hospital: Experience after pneumococcal conjugated vaccine]. AB - BACKGROUND: Occult bacteremia (OB) is one of the possible diagnoses of children younger than 3 years with fever without source in the emergency room. OBJECTIVE: describe OB in the era after introduction of pneumococcal vaccine in Chile. PATIENTS AND METHODS: Prospective descriptive review of data of children with possible OB diagnosis, referred from the emergency department between 2010-2013. RESULTS: Possible OB was diagnosed on 391 patients. 233 had focus, mainly respiratory virus and urinary tract infection. On 158 patients, probable BO was diagnosed, 20 had proven OB from which 15 had positive blood culture for Streptococcus pneumoniae. From these, 7 were fully or partially vaccinated. The serotype was identified on 14 cases: 6 were PCV10 vaccine serotypes (none of them vaccinated), 2 were serotype related (both partially vaccinated) and 6 were non vaccine serotypes (partially or totally vaccinated). DISCUSSION: It is necessary to improve diagnostic methods for respiratory viruses and urinary tract infections and try to expand coverage of pneumococcal conjugated vaccines in the pediatric population in order to reduce the risk of invasive pneumococcal disease in Chile. PMID- 28632828 TI - [Phialocephala sp]. PMID- 28632829 TI - [Advances in dengue virus research in Colombia: the role of cellular microRNAs as an anti-dengue virus response]. AB - Dengue is one of the most important mosquito-borne diseases, and its incidence has increased at an alarming rate in recent years, becoming a real public health problem. Currently, there is no vaccine or medication or proper treatment for dengue control. Considering this situation, it is necessary to prioritize the search for new alternatives and strategies for dengue prevention and control, in order to reduce not only the economic burden of endemic countries, but also to improve the quality of life of patients. In this regard, a brief reflection on some aspects related to the search for new alternatives in Colombia is presented. This is focused on the use of microRNAs, which could be a new strategy with great therapeutic potential. PMID- 28632830 TI - [Declaration of the Chilean Academy of Medicine of Law 20.850 "On clinical trials of pharmaceutical products and medical devices" and of the bylaw that will regulate its application]. AB - In Chile, high cost treatments required by selected medical conditions are financed by the State, according to Law 20.850. A bylaw under discussion by the Senate regulates clinical trials, posing complex issues that will endanger local interest in front-line research: 1) The exclusive and mandatory control bestowed to the Institute of Public Health during all stages of the trials and also the surveillance of institutions performing clinical trials, overriding their Clinical Research Review Boards; 2) The 10 year period during which any adverse event is assumed to have been caused by the medication or devise evaluated by the trial, unless the contrary is proven in a judicial process; 3) Individuals submitted to the trials are entitled to free post trial access to the treatment received during the study, financed by the trial supporting entities and as long as the drug or devise is considered to be useful. While agreeing with the need to have a National Registry of Clinical Trials, we predict that the mentioned critical issues in the bylaw will lead to difficulties and unnecessary judicial processes, thus limiting clinicians' interest in performing research. We propose to modify the bylaw, excluding responsibilities on events associated with the natural evolution of the medical condition, with patients' ageing or with comorbidities and clinical events considered unpredictable when the protocol was accepted. We recommend that the free post trial access should be a joint decision involving the patient and the attending physician, taking in consideration that the volunteer has been exposed to risks and burdens, or when discontinuation of treatment entails a vital risk until the treatment under study has been approved and becomes available in the national market. PMID- 28632831 TI - [Antiseptics and disinfectants: aiming at rational use. Recommendations of the Advisory Committee on Healthcare Associated Infections. Sociedad Chilena de Infectologia]. AB - Proper use of antiseptics and disinfectants, is an essential tool to prevent the spread of infectious agents and to control of healthcare-associated infections (HAI). Given the increasing importance of environmental aspects, as well as several advances and updates in the field of its proper use at local and intemational level, the SOCHINF HAI Advisory Committee considers that it is necessary to develop a guide for the rational use of antiseptics and disinfectants, which it will provide consistent scientific basis with that purpose. PMID- 28632832 TI - [A hundred years since the beginning of the Great War: trichinosis outbreak in Dresden marine in Chile: Chronicle of an announced infection]. AB - In commemoration of one hundred years of the beginning of World War I, the occurrence of an outbreak of trichinosis in the crew of the SMS Dresden, a German ship that participated in that world conflagration, is re-viewed. In September 1915, while the sailors of SMS Dresden were forcibly detained on Isla Quiriquina, Bio Bio Region, Chile, 60 individuals became ill. The cause of the outbreak was the consumption of sausages made from pork infected with the parasite Trichinella spiralis. There was a fatal case. The review of the epidemiological aspects that facilitated the presentation and spread of human trichinosis at that time allows to conclude that, pork breeded in poor hygienic conditions, meat and its by products clandestinely sold without sanitary inspection and the language barrier were determinant in the occurrence of the epidemic outbreak. PMID- 28632833 TI - [Tetanus after cat scratch and bites in a previously immunized patient]. AB - : Tetanus is declining due to vaccination, professional labor management and appropriate wound care. Tetanus cases have been reported despite immunization. We report the case of a previously healthy 21 years old female patient that presented a mild generalized tetanus requiring admission after mild and recurrent cat scratch and bites. She had received six vaccine shots during childhood, and a booster dose five years earlier after a rabbit bite. Symptoms appeared seven weeks after the last contact, and included headache, muscle spasms and mild opisthotonus. Laboratory evaluation, including CSF analysis and microbiological investigation, as well as imaging studies were all normal. The patient received 6,000 IU of human antitoxin immunoglobulin. No autonomic manifestations or respiratory compromise were registered. Symptoms resolved rapidly and she was discharge after seven days with an order to complete a tetanus toxoid immunization schedule with three doses. CONCLUSIONS: Tetanus is possible in urban settings with a declining epidemiologic curve of disease in previously immunized patients. Severity of disease is modulated by previous vaccination. PMID- 28632834 TI - [Bladder fungus ball by Candida tropicalis: a pediatric case report]. AB - Vesical fungus ball is a mobile, oval and echogenic mass as a result of accumulation of long and wide numerous hyphae. Fungal urinary tract infection incidence has increased notoriously and there are isolated yeast in 7 to 8% of urine cultures. Different species of Candida are cause of urinary tract infection. Epidemiologically, the first isolated pathogen is Candida albicans, followed by Candida tropicalis. Bladder poll has been documented as the most important risk factor for candiduria in critical patients into intensive care. PMID- 28632835 TI - [Evaluation of antimicrobial susceptibility testing directly from positive blood cultures using the Vitek 2 system: comparison of two rapid protocols]. AB - Antimicrobial susceptibility testing using Vitek(r) 2 (bioMerieux) cards inoculated directly from positive blood cultures was compared with the standard method for gramnegative rods. Two different protocols for the inoculum preparation were evaluated. Protocol 2 was faster and easier to perform. Rapid susceptibility testing was accurate and reduced time to results in 24 h. PMID- 28632836 TI - [Multidrug-resistant Candida auris: "new kid on the block" in hospital-associated infections?] PMID- 28632837 TI - [Conventional versus prolonged infusion of meropenem in neonates with Gram negative late-onset sepsis: a randomized controlled trial]. PMID- 28632839 TI - ? PMID- 28632838 TI - [Infeccion por el virus Zika en el embarazo y su impacto]. PMID- 28632840 TI - The Effect of Stimulus Valence on Lexical Retrieval in Younger and Older Adults. AB - Purpose: Although there is evidence that emotional valence of stimuli impacts lexical processes, there is limited work investigating its specific impact on lexical retrieval. The current study aimed to determine the degree to which emotional valence of pictured stimuli impacts naming latencies in healthy younger and older adults. Method: Eighteen healthy younger adults and 18 healthy older adults named positive, negative, and neutral images, and reaction time was measured. Results: Reaction times for positive and negative images were significantly longer than reaction times for neutral images. Reaction times for positive and negative images were not significantly different. Whereas older adults demonstrated significantly longer naming latencies overall than younger adults, the discrepancy in latency with age was far greater when naming emotional pictures. Conclusions: Emotional arousal of pictures appears to impact naming latency in younger and older adults. We hypothesize that the increase in naming latency for emotional stimuli is the result of a necessary disengagement of attentional resources from the emotional images prior to completion of the naming task. We propose that this process may affect older adults disproportionately due to a decline in attentional resources as part of normal aging, combined with a greater attentional preference for emotional stimuli. PMID- 28632841 TI - Green-Light Autofluorescence Versus Combined Blue-Light Autofluorescence and Near Infrared Reflectance Imaging in Geographic Atrophy Secondary to Age-Related Macular Degeneration. AB - Purpose: To compare the intermodality and interreader agreement for geographic atrophy (GA) lesion size quantification in green-light fundus autofluorescence (GAF; excitation = 518 nm) versus combined blue-light fundus autofluorescence (BAF; excitation = 488 nm) and near-infrared reflectance (NIR; 820 nm) -based grading. Methods: Confocal scanning laser ophthalmoscopy (cSLO) GAF, BAF, and NIR images of 40 eyes from 29 patients (mean age 79.7 years) with GA secondary to AMD were recorded according to a standardized protocol. GA areas were analyzed in GAF, BAF combined with NIR (BAF+NIR), or BAF alone, by four independent readers using semiautomated software (RegionFinder; Heidelberg Engineering, Heidelberg, Germany). A mixed-effects model was used to assess the effect of image modality on the measured square-root lesion area. The coefficient of repeatability (CR) and intraclass correlation coefficient (ICC) were assessed for the square-root lesion area, lesion perimeter, and circularity. Results: GAF-based measurements were on average 0.062 mm (95% confidence interval [CI] 0.04-0.08 mm) larger than BAF+NIR-based measurements and 0.077 mm (95% CI 0.06 - 0.10 mm) larger than BAF based measurements. Interreader agreement was highest for GAF-based analysis ([CR, ICC] 0.196 mm, 0.995) followed by BAF+NIR (0.232 mm, 0.992) and BAF alone (0.263 mm, 0.991). The same was noted for the lesion perimeter and circularity. Post hoc review revealed that interreader differences were associated with media opacification interfering with lesion boundary demarcation to a larger extent in BAF than in GAF. Conclusions: cSLO-based GAF and combined BAF+NIR imaging with semiautomated lesion delineation allow for an accurate and reproducible quantification of GA. The slightly better interreader agreement using cSLO GAF suggests that its use may be preferable in clinical trials examining the change in lesion size as a clinical endpoint. PMID- 28632842 TI - Practical Considerations for the US Preventive Services Task Force Recommendations on Obesity in Children and Adolescents. PMID- 28632843 TI - The Promise and Opportunities for Screening and Treating Childhood Obesity: USPSTF Recommendation Statement. PMID- 28632844 TI - Complement-Mediated Regulation of Apolipoprotein E in Cultured Human RPE Cells. AB - PURPOSE: Complement activation is implicated in the pathogenesis of age-related macular degeneration (AMD). Apolipoprotein E (ApoE) and complement activation products such as membrane attack complex (MAC) are present in eyes of individuals with AMD. Herein, we investigated the effect of complement activation on induction of ApoE accumulation in human retinal pigment epithelial (RPE) cells. METHODS: Cultured human RPE cells were primed with a complement-fixing antibody followed by treatment with C1q-depleted (C1q-Dep) human serum to elicit alternative pathway complement activation. Controls included anti-C5 antibody treated serum and heat-inactivated C1q-Dep. Total protein was determined on RPE cell extracts, conditioned media, and extracellular matrix (ECM) by Western blot. ApoE and MAC colocalization was assessed on cultured RPE cells and human eyes by immunofluorescent stain. ApoE mRNA expression was evaluated by quantitative PCR (qPCR). RESULTS: Complement challenge upregulated cell-associated ApoE, but not apolipoprotein A1. ApoE accumulation was blocked by anti-C5 antibody and enhanced by repetitive complement challenge. ApoE mRNA levels were not affected by complement challenge. ApoE was frequently colocalized with MAC in complement treated cells and drusen from human eyes. ApoE was released into complement treated conditioned media after a single complement challenge and accumulated on ECM after repetitive complement challenge. CONCLUSIONS: Complement challenge induces time-dependent ApoE accumulation in RPE cells. An understanding of the mechanisms by which complement affects RPE ApoE accumulation may help to better explain drusen composition, and provide insights into potential therapeutic targets. PMID- 28632845 TI - Iris Malformation and Anterior Segment Dysgenesis in Mice and Humans With a Mutation in PI 3-Kinase. AB - Purpose: To determine the ocular consequences of a dominant-negative mutation in the p85alpha subunit of phosphatidylinositol 3-kinase (PIK3R1) using a knock-in mouse model of SHORT syndrome, a syndrome associated with short stature, lipodystrophy, diabetes, and Rieger anomaly in humans. Methods: We investigated knock-in mice heterozygous for the SHORT syndrome mutation changing arginine 649 to tryptophan in p85alpha (PIK3R1) using physical examination, optical coherence tomography (OCT), tonometry, and histopathologic sections from paraffin-embedded eyes, and compared the findings to similar investigations in two human subjects with SHORT syndrome heterozygous for the same mutation. Results: While overall eye development was normal with clear cornea and lens, normal anterior chamber volume, normal intraocular pressure, and no changes in the retinal structure, OCT images of the knock-in mouse eyes revealed a significant decrease in thickness and width of the iris resulting in increased pupil area and irregularity of shape. Both human subjects had Rieger anomaly with similar defects including thin irides and irregular pupils, as well as a prominent ring of Schwalbe, goniosynechiae, early cataract formation, and glaucoma. Although the two subjects had had diabetes for more than 30 years, there were no signs of diabetic retinopathy. Conclusions: A dominant-negative mutation in the p85alpha regulatory subunit of PI3K affects development of the iris, and contributes to changes consistent with anterior segment dysgenesis in both humans and mice. PMID- 28632846 TI - Suppression of HSP27 Restores Retinal Function and Protects Photoreceptors From Apoptosis in a Light-Induced Retinal Degeneration Animal Model. AB - Purpose: We used a light-induced retinal degeneration animal model to investigate possible roles of heat shock protein 27 (HSP27) in retinal/photoreceptor protection. Methods: Sprague-Dawley rats were used for the light-induced retinal degeneration animal model. The histology of eye sections was observed for morphologic changes in the retina. Cell apoptosis was examined in each group using the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electroretinography was used to evaluate retinal function. Protein and mRNA expression levels of different retinal cell markers were also detected through immunofluorescence staining, Western blotting, and real-time PCR. Results: The thickness of the outer nuclear layer significantly decreased after 7-day light exposure. Moreover, we injected a viral vector for silencing HSP27 expression into the eyes and observed that photoreceptors were better preserved in the HSP27 suppressed (sHSP27) retina 2 weeks after injection. HSP27 suppression also reduced retinal cell apoptosis caused by light exposure. In addition, the loss of retinal function caused by light exposure was reversed on suppressing HSP27 expression. We subsequently found that the expression of the Rho gene and immunofluorescence staining of rhodopsin and arrestin (cell markers for photoreceptors) increased in sHSP27-treated retinas. HSP27 suppression did not affect the survival of ganglion and amacrine cells. Conclusions: Retinal cell apoptosis and functional loss were observed after 7-day light exposure. However, in the following 2 weeks after light exposure, HSP27 suppression may initiate a protective effect for retinal cells, particularly photoreceptors, from light induced retinal degeneration. PMID- 28632848 TI - Effect of Gabapentin/Memantine on the Infantile Nystagmus Syndrome in the Zebrafish Model: Implications for the Therapy of Ocular Motor Diseases. AB - Purpose: Infantile nystagmus syndrome (INS) is a disorder characterized by typical horizontal eye oscillations. Due to the uncertain etiology of INS, developing specific treatments remains difficult. Single reports demonstrated, on limited measures, alleviating effects of gabapentin and memantine. In the current study, we employed the zebrafish INS model belladonna (bel) to conduct an in depth study of how gabapentin and memantine interventions alleviate INS signs, which may further restore visual conditions in affected subjects. Moreover, we described the influence of both medications on ocular motor functions in healthy zebrafish, evaluating possible iatrogenic effects. Methods: Ocular motor function and INS characteristics were assessed by eliciting optokinetic response, spontaneous nystagmus, and spontaneous saccades in light and in dark, in 5- to 6 day postfertilization bel larvae and heterozygous siblings. Single larvae were recorded before and after a 1-hour drug treatment (200 mM gabapentin/0.2 mM memantine). Results: Both interventions significantly reduced nystagmus intensity (gabapentin: 59.98%, memantine: 39.59%). However, while the application of gabapentin affected all tested ocular motor functions, memantine specifically reduced nystagmus amplitude and intensity, and thus left controls completely unaffected. Finally, both drug treatments resulted in specific changes in nystagmus waveform and velocity. Conclusions: Our study provides deeper insight into gabapentin and memantine treatment effect in the zebrafish INS model. Moreover, this study should establish zebrafish as a pharmacologic animal model for treating nystagmus and ocular motor disease, serving as a basis for future large-scale drug screenings. PMID- 28632847 TI - Pattern Recognition Analysis of Age-Related Retinal Ganglion Cell Signatures in the Human Eye. AB - Purpose: To characterize macular ganglion cell layer (GCL) changes with age and provide a framework to assess changes in ocular disease. This study used data clustering to analyze macular GCL patterns from optical coherence tomography (OCT) in a large cohort of subjects without ocular disease. Methods: Single eyes of 201 patients evaluated at the Centre for Eye Health (Sydney, Australia) were retrospectively enrolled (age range, 20-85); 8 * 8 grid locations obtained from Spectralis OCT macular scans were analyzed with unsupervised classification into statistically separable classes sharing common GCL thickness and change with age. The resulting classes and gridwise data were fitted with linear and segmented linear regression curves. Additionally, normalized data were analyzed to determine regression as a percentage. Accuracy of each model was examined through comparison of predicted 50-year-old equivalent macular GCL thickness for the entire cohort to a true 50-year-old reference cohort. Results: Pattern recognition clustered GCL thickness across the macula into five to eight spatially concentric classes. F-test demonstrated segmented linear regression to be the most appropriate model for macular GCL change. The pattern recognition derived and normalized model revealed less difference between the predicted macular GCL thickness and the reference cohort (average +/- SD 0.19 +/- 0.92 and 0.30 +/- 0.61 MUm) than a gridwise model (average +/- SD 0.62 +/- 1.43 MUm). Conclusions: Pattern recognition successfully identified statistically separable macular areas that undergo a segmented linear reduction with age. This regression model better predicted macular GCL thickness. The various unique spatial patterns revealed by pattern recognition combined with core GCL thickness data provide a framework to analyze GCL loss in ocular disease. PMID- 28632849 TI - Putting the US Preventive Services Task Force Recommendation for Childhood Obesity Screening in Context. PMID- 28632850 TI - Cetuximab or Bevacizumab With First-Line Chemotherapy in Advanced KRAS Wild-Type Colorectal Cancer: No Difference, but Not the Same. PMID- 28632852 TI - Antioxidant Drug Approved for ALS. PMID- 28632851 TI - Losing Weight During the Postpartum Period. PMID- 28632853 TI - Immunotherapy for Bladder Cancer. PMID- 28632854 TI - Warnings for Anesthetic Drugs. PMID- 28632856 TI - The Patent Laws and Patent Office Practice. PMID- 28632858 TI - Nonreproducibility of Preclinical Research. PMID- 28632857 TI - Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014. PMID- 28632860 TI - Temporal Changes in Subsequent Malignancies Among Childhood Cancer Survivors. PMID- 28632859 TI - Changes in Coronary Artery Plaque With Testosterone Therapy. PMID- 28632861 TI - Nonreproducibility of Preclinical Research-Reply. PMID- 28632862 TI - Changes in Coronary Artery Plaque With Testosterone Therapy-Reply. PMID- 28632863 TI - Temporal Changes in Subsequent Malignancies Among Childhood Cancer Survivors Reply. PMID- 28632864 TI - Junk Food Ads Reach Children Despite Food Industry Self-regulation. PMID- 28632865 TI - Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. AB - Importance: Combining biologic monoclonal antibodies with chemotherapeutic cytotoxic drugs provides clinical benefit to patients with advanced or metastatic colorectal cancer, but the optimal choice of the initial biologic therapy in previously untreated patients is unknown. Objective: To determine if the addition of cetuximab vs bevacizumab to the combination of leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) regimen or the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen is superior as first-line therapy in advanced or metastatic KRAS wild-type (wt) colorectal cancer. Design, Setting, and Participants: Patients (>=18 years) enrolled at community and academic centers throughout the National Clinical Trials Network in the United States and Canada (November 2005-March 2012) with previously untreated advanced or metastatic colorectal cancer whose tumors were KRAS wt chose to take either the mFOLFOX6 regimen or the FOLFIRI regimen as chemotherapy and were randomized to receive either cetuximab (n = 578) or bevacizumab (n = 559). The last date of follow-up was December 15, 2015. Interventions: Cetuximab vs bevacizumab combined with either mFOLFOX6 or FOLFIRI chemotherapy regimen chosen by the treating physician and patient. Main Outcomes and Measures: The primary end point was overall survival. Secondary objectives included progression-free survival and overall response rate, site-reported confirmed or unconfirmed complete or partial response. Results: Among 1137 patients (median age, 59 years; 440 [39%] women), 1074 (94%) of patients met eligibility criteria. As of December 15, 2015, median follow-up for 263 surviving patients was 47.4 months (range, 0-110.7 months), and 82% of patients (938 of 1137) experienced disease progression. The median overall survival was 30.0 months in the cetuximab-chemotherapy group and 29.0 months in the bevacizumab-chemotherapy group with a stratified hazard ratio (HR) of 0.88 (95% CI, 0.77-1.01; P = .08). The median progression-free survival was 10.5 months in the cetuximab-chemotherapy group and 10.6 months in the bevacizumab chemotherapy group with a stratified HR of 0.95 (95% CI, 0.84-1.08; P = .45). Response rates were not significantly different, 59.6% vs 55.2% for cetuximab and bevacizumab, respectively (difference, 4.4%, 95% CI, 1.0%-9.0%, P = .13). Conclusions and Relevance: Among patients with KRAS wt untreated advanced or metastatic colorectal cancer, there was no significant difference in overall survival between the addition of cetuximab vs bevacizumab to chemotherapy as initial biologic treatment. Trial Registration: clinicaltrials.gov identifier: NCT00265850. PMID- 28632868 TI - Screening for Obesity in Children and Adolescents. PMID- 28632867 TI - Effect of an Internet-Based Program on Weight Loss for Low-Income Postpartum Women: A Randomized Clinical Trial. AB - Importance: Postpartum weight retention increases lifetime risk of obesity and related morbidity. Few effective interventions exist for multicultural, low income women. Objective: To test whether an internet-based weight loss program in addition to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC program) for low-income postpartum women could produce greater weight loss than the WIC program alone over 12 months. Design, Setting, and Participants: A 12-month, cluster randomized, assessor-blind, clinical trial enrolling 371 adult postpartum women at 12 clinics in WIC programs from the California central coast between July 2011 and May 2015 with data collection completed in May 2016. Interventions: Clinics were randomized to the WIC program (standard care group) or the WIC program plus a 12-month primarily internet-based weight loss program (intervention group), including a website with weekly lessons, web diary, instructional videos, computerized feedback, text messages, and monthly face-to-face groups at the WIC clinics. Main Outcomes and Measures: The primary outcome was weight change over 12 months, based on measurements at baseline, 6 months, and 12 months. Secondary outcomes included proportion returning to preconception weight and changes in physical activity and diet. Results: Participants included 371 women (mean age, 28.1 years; Hispanic, 81.6%; mean weight above prepregnancy weight, 7.8 kg; mean months post partum, 5.2 months) randomized to the intervention group (n = 174) or standard care group (n = 197); 89.2% of participants completed the study. The intervention group produced greater mean 12-month weight loss compared with the standard care group (3.2 kg in the intervention group vs 0.9 kg in standard care group, P < .001; difference, 2.3 kg (95% CI, 1.1 to 3.5). More participants in the intervention group than the standard care group returned to preconception weight by 12 months (32.8% in the intervention group vs 18.6% in the standard care group, P < .001; difference, 14.2 percentage points [95% CI, 4.7 to 23.5]). The intervention group and standard care group did not significantly differ in 12-month changes in physical activity (mean [95% CI]: -7.8 min/d [-16.1 to 0.4] in the intervention group vs -7.2 min/d [-14.6 to 0.3] in the standard care group; difference, -0.7 min/d [95% CI, -42.0 to 10.6], P = .76), calorie intake (mean [95% CI]: -298 kcal/d [-423 to -174] in the intervention group vs -144 kcal/d [-257 to -32] in the standard care group; difference, -154 kcal/d [-325 to 17], P = .06), or incidences of injury (16 in the intervention group vs 16 in the standard care group) or low breastmilk supply from baseline to month 6 (21 of 61 participants in the intervention group vs 23 of 72 participants in the standard care group) and from month 6 to 12 (13 of 32 participants in the intervention group vs 14 of 37 participants in the standard care group). Conclusions and Relevance: Among low income postpartum women, an internet-based weight loss program in addition to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC program) compared with the WIC program alone resulted in a statistically significant greater weight loss over 12 months. Further research is needed to determine program and cost-effectiveness as part of the WIC program. Trial Registration: clinicaltrials.gov Identifier: NCT01408147. PMID- 28632869 TI - Phenytoin Toxicity. PMID- 28632866 TI - Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. AB - Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for >=2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831 c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment. PMID- 28632871 TI - Speak Up. PMID- 28632875 TI - Podoconiosis Is the Diagnosis. PMID- 28632873 TI - Screening for Obesity and Intervention for Weight Management in Children and Adolescents: Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Obesity is common in children and adolescents in the United States, is associated with negative health effects, and increases the likelihood of obesity in adulthood. Objective: To systematically review the benefits and harms of screening and treatment for obesity and overweight in children and adolescents to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, PsycINFO, Cochrane Collaboration Registry of Controlled Trials, and the Education Resources Information Center through January 22, 2016; references of relevant publications; government websites. Surveillance continued through December 5, 2016. Study Selection: English-language trials of benefits or harms of screening or treatment (behavior-based, orlistat, metformin) for overweight or obesity in children aged 2 through 18 years, conducted in or recruited from health care settings. Data Extraction and Synthesis: Two investigators independently reviewed abstracts and full-text articles, then extracted data from fair- and good-quality trials. Random-effects meta-analysis was used to estimate the benefits of lifestyle-based programs and metformin. Main Outcomes and Measures: Weight or excess weight (eg, body mass index [BMI]; BMI z score, measuring the number of standard deviations from the median BMI for age and sex), cardiometabolic outcomes, quality of life, other health outcomes, harms. Results: There was no direct evidence on the benefits or harms of screening children and adolescents for excess weight. Among 42 trials of lifestyle-based interventions to reduce excess weight (N = 6956), those with an estimated 26 hours or more of contact consistently demonstrated mean reductions in excess weight compared with usual care or other control groups after 6 to 12 months, with no evidence of causing harm. Generally, intervention groups showed absolute reductions in BMI z score of 0.20 or more and maintained their baseline weight within a mean of approximately 5 lb, while control groups showed small increases or no change in BMI z score, typically gaining a mean of 5 to 17 lb. Only 3 of 26 interventions with fewer contact hours showed a benefit in weight reduction. Use of metformin (8 studies, n = 616) and orlistat (3 studies, n = 779) were associated with greater BMI reductions compared with placebo: -0.86 (95% CI, -1.44 to -0.29; 6 studies; I2 = 0%) for metformin and -0.50 to -0.94 for orlistat. Groups receiving lifestyle based interventions offering 52 or more hours of contact showed greater improvements in blood pressure than control groups: -6.4 mm Hg (95% CI, -8.6 to 4.2; 6 studies; I2 = 51%) for systolic blood pressure and -4.0 mm Hg (95% CI, 5.6 to -2.5; 6 studies; I2 = 17%) for diastolic blood pressure. There were mixed findings for insulin or glucose measures and no benefit for lipids. Medications showed small or no benefit for cardiometabolic outcomes, including fasting glucose level. Nonserious harms were common with medication use, although discontinuation due to adverse effects was usually less than 5%. Conclusions and Relevance: Lifestyle-based weight loss interventions with 26 or more hours of intervention contact are likely to help reduce excess weight in children and adolescents. The clinical significance of the small benefit of medication use is unclear. PMID- 28632876 TI - Cholera Vaccine Safe During Pregnancy. PMID- 28632874 TI - Screening for Obesity in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. AB - Importance: Based on year 2000 Centers for Disease Control and Prevention growth charts, approximately 17% of children and adolescents aged 2 to 19 years in the United States have obesity, and almost 32% of children and adolescents are overweight or have obesity. Obesity in children and adolescents is associated with morbidity such as mental health and psychological issues, asthma, obstructive sleep apnea, orthopedic problems, and adverse cardiovascular and metabolic outcomes (eg, high blood pressure, abnormal lipid levels, and insulin resistance). Children and adolescents may also experience teasing and bullying behaviors based on their weight. Obesity in childhood and adolescence may continue into adulthood and lead to adverse cardiovascular outcomes or other obesity-related morbidity, such as type 2 diabetes. Subpopulation Considerations: Although the overall rate of child and adolescent obesity has stabilized over the last decade after increasing steadily for 3 decades, obesity rates continue to increase in certain populations, such as African American girls and Hispanic boys. These racial/ethnic differences in obesity prevalence are likely a result of both genetic and nongenetic factors (eg, socioeconomic status, intake of sugar sweetened beverages and fast food, and having a television in the bedroom). Objective: To update the 2010 US Preventive Services Task Force (USPSTF) recommendation on screening for obesity in children 6 years and older. Evidence Review: The USPSTF reviewed the evidence on screening for obesity in children and adolescents and the benefits and harms of weight management interventions. Findings: Comprehensive, intensive behavioral interventions (>=26 contact hours) in children and adolescents 6 years and older who have obesity can result in improvements in weight status for up to 12 months; there is inadequate evidence regarding the effectiveness of less intensive interventions. The harms of behavioral interventions can be bounded as small to none, and the harms of screening are minimal. Therefore, the USPSTF concluded with moderate certainty that screening for obesity in children and adolescents 6 years and older is of moderate net benefit. Conclusions and Recommendation: The USPSTF recommends that clinicians screen for obesity in children and adolescents 6 years and older and offer or refer them to comprehensive, intensive behavioral interventions to promote improvements in weight status. (B recommendation). PMID- 28632877 TI - Blood-Clotting Drug Saves Lives During Childbirth. PMID- 28632879 TI - Reliability and Agreement Between Metrics of Cone Spacing in Adaptive Optics Images of the Human Retinal Photoreceptor Mosaic. AB - Purpose: To assess reliability and agreement among three metrics used to evaluate the distribution of cell distances in adaptive optics (AO) images of the cone mosaic. Methods: Using an AO flood illumination retinal camera, we acquired images of the cone mosaic in 20 healthy subjects and 12 patients with retinal diseases. The three spacing metrics studied were the center-to-center spacing (Scc), the local cone spacing (LCS), and the density recovery profile distance (DRPD). Each metric was calculated in sampling areas of different sizes (64 * 64 MUm and 204 * 204 MUm) across the parafovea. Results: Both Scc and LCS were able to discriminate between healthy subjects and patients with retinal diseases; DRPD did not reliably detect any abnormality in the distribution of cell distances in patients with retinal diseases. The agreement between Scc and LCS was high in healthy subjects (intraclass correlation coefficient [ICC] >= 0.79) and moderate in patients with retinal diseases (ICC <= 0.51). The DRPD had poor agreement with Scc (ICC <= 0.47) and LCS (ICC <= 0.37). The correlation between the spacing metrics of the two sampling areas was greater in healthy subjects than in patients with retinal diseases. Conclusions: The Scc and LCS provided interchangeable estimates of cone distance in AO retinal images of healthy subjects but could not be used interchangeably when investigating retinal diseases with significant cell reflectivity loss (>=30%). The DRPD was unreliable for describing cell distance in a human retinal cone mosaic and did not correlate with Scc and LCS. Caution is needed when comparing spacing metrics evaluated in sampling areas of different sizes. PMID- 28632881 TI - Clinically Available Assessment Measures for Lingual and Labial Somatosensation in Healthy Adults: Normative Data and Test Reliability. AB - Purpose: High-quality orofacial somatosensory inputs are essential for achieving rapid and accurate motor outputs. Little somatosensory testing is currently being completed in clinical settings. The purpose of this study is to assess the feasibility and test-retest reliability of clinical assessment tools for orofacial somatosensory testing in healthy young adults. Method: A total of 45 healthy young adults (ages 20-41 years) was recruited. Participants reported basic health information, completed pure-tone hearing thresholds, and were assessed using two-point discrimination discs and Von Frey hair detection and discrimination thresholds for bilateral lip and tongue. A subsample of participants (n = 18; 40%) returned to complete reliability testing. Results: Descriptive results are presented for the normative group as well as the reliability group. Difference scores between Tests 1 and 2 for each testing measure and location show high agreement. Conclusion: Two-point discrimination and Von Frey hair monofilament assessment for both detection- and discrimination threshold estimates have high test-retest reliability in a healthy young population. These testing measures could be a way to easily complete objective somatosensory testing of the orofacial region in a clinical context. PMID- 28632880 TI - The Urokinase Receptor-Derived Peptide UPARANT Recovers Dysfunctional Electroretinogram and Blood-Retinal Barrier Leakage in a Rat Model of Diabetes. AB - Purpose: The activation of the urokinase-type plasminogen activator and its receptor system is associated with retinal diseases. Among peptide inhibitors of this system, UPARANT acts by preventing the onset of pathologic signs of neovascular ocular diseases. We investigated whether systemic UPARANT may act in a therapeutic regimen by suppressing the retinal damage that characterizes diabetic retinopathy using a rat model of streptozotocin-induced diabetes. Methods: In healthy rats, plasma, eye, and retina concentrations of UPARANT were evaluated by mass spectrometry. In rat models of streptozotocin-induced diabetes, the appearance of diabetic retinopathy was assessed by electroretinogram (ERG). UPARANT was then administered at different dosages and daily regimens. ERG recording, Evans blue perfusion, and real-time PCR were used to evaluate UPARANT efficacy. UPARANT safety was also determined. Results: UPARANT was found in plasma, eye, and retina soon after its administration and remained detectable after 24 hours. Between the 4th and the 5th week after diabetes onset, UPARANT at 8 mg/kg (daily for 5 days) was effective in recovering dysfunctional ERG. Three day treatments at 8 mg/kg or a half dose for 5 days were ineffective. ERG recovery lasted approximately 2 weeks. ERG recovery was accompanied by restored blood-retinal barrier integrity and inhibition of inflammatory and angiogenic responses. UPARANT showed a safety profile. Conclusions: These data suggest that targeting the urokinase-type plasminogen activator and its receptor system by systemic UPARANT is a potential therapeutic approach for the treatment of early diabetic retinopathy, thus providing a potential alternative approach to delay disease progression in humans. PMID- 28632878 TI - Identification of Novel G Protein-Coupled Receptor 143 Ligands as Pharmacologic Tools for Investigating X-Linked Ocular Albinism. AB - Purpose: GPR143 regulates melanosome biogenesis and organelle size in pigment cells. The mechanisms underlying receptor function remain unclear. G protein coupled receptors (GPCRs) are excellent pharmacologic targets; thus, we developed and applied a screening approach to identify potential GPR143 ligands and chemical modulators. Methods: GPR143 interacts with beta-arrestin; we therefore established a beta-arrestin recruitment assay to screen for compounds that modulate activity. Because GPR143 is localized intracellularly, screening with the wild-type receptor would be restricted to agents absorbed by the cell. For the screen we used a mutant receptor, which shows similar basal activity as the wild type but traffics to the plasma membrane. We tested two compound libraries and investigated validated hits for their effects on melanocyte pigmentation. Results: GPR143, which showed high constitutive activity in the beta-arrestin assay, was inhibited by several compounds. The three validated inhibitors (pimozide, niclosamide, and ethacridine lactate) were assessed for impact on melanocytes. Pigmentation and expression of tyrosinase, a key melanogenic enzyme, were reduced by all compounds. Because GPR143 appears to be constitutively active, these compounds may turn off its activity. Conclusions: X-linked ocular albinism type I, characterized by developmental eye defects, results from GPR143 mutations. Identifying pharmacologic agents that modulate GPR143 activity will contribute significantly to our understanding of its function and provide novel tools with which to study GPCRs in melanocytes and retinal pigment epithelium. Pimozide, one of three GPR143 inhibitors identified in this study, maybe be a good lead structure for development of more potent compounds and provide a platform for design of novel therapeutic agents. PMID- 28632882 TI - Tattooing and psoriasis: demographics, motivations and attitudes, complications, and impact on body image in a series of 90 Finnish patients. AB - INTRODUCTION: Koebner phenomenon (KP) affects up to a third of patients with psoriasis and can occur on tattoos. Little is known about the extent of tattooing and its consequences among psoriatic patients. A survey was conducted to determine the demographics, motivations and attitudes towards tattoos, and complications among tattooed patients with psoriasis, and the impact on their body image. METHODS: Ninety Finnish patients completed an internet self-reported questionnaire in June 2016. RESULTS: Fifty-two percent (48/90) had one tattoo or more (mean number of three tattoos, range 1-20). They were younger than non tattooed patients (p = 0.001). Of these, 27.6% experienced a KP on their tattoos from 1 week to 15 to 20 years after tattooing. Among those, 30% reported an acute flare-up of psoriasis within the first weeks after tattooing. They were more likely to have a history of KP. Less than 7% reported a psoriasis flare-up on another part of the body after tattooing. Eighty-two percent stated that their tattoo(s) had a positive effect on their body image. CONCLUSION: KP on tattoos is not particularly frequent in patients with psoriasis. Tattooing has a bolstering effect on body image and should not be a contraindication. However, patients need proper counseling before receiving tattoos. PMID- 28632883 TI - Importance of immunogenicity testing for cost-effective management of psoriasis patients treated with adalimumab. AB - INTRODUCTION: Up to 30% of patients treated with anti-tumor necrosis factor drugs do not respond adequately, and up to 50% lose response over time. Immunogenicity is now known to be one of the main causes of this loss of response. METHODS: Serum levels of adalimumab and anti-drug antibodies (ADAs) were measured in 19 patients with psoriasis. RESULTS: Eighty-nine percent of the patients were responders (Psoriasis Area Severity Index (PASI) > 75) and 11% were partial responders (PASI 50-75). The serum levels of adalimumab were lower than the cutoff in both of the partial responders and the ADAs were high, whereas the other 17 patients had adalimumab levels above the cutoff and low ADA levels. Both partial responders were obese and none of them were taking methotrexate. Both patients switched to ustekinumab, and a PASI 90 response was observed after 16 weeks. CONCLUSION: Immunogenicity is a risk of biological drugs. In this work, the detection of low levels of adalimumab and high levels of ADAs using a sandwich ELISA correlated with loss of clinical response. Testing immunogenicity and the drug pharmacokinetics of biological drugs in psoriasis patients will probably be part of the daily management of these patients in the future. PMID- 28632884 TI - Components of the alternative complement pathway in patients with psoriasis. AB - INTRODUCTION: Psoriasis is a chronic inflammatory skin disease. Adipose tissue plays important roles in the events that regulate body metabolism. This study determined the levels of complement 3 ( C3), acylation-stimulating protein (ASP), and adipsin, which take part in the alternate complement pathway, and are synthesized in and secreted by adipose tissue. METHODS: Thirty-two patients with psoriasis were matched with 22 controls in terms of age, sex, body mass index, and lipid profiles. Serum C3, ASP, and adipsin levels were measured in both groups. RESULTS: The serum C3 level was higher and ASP and adipsin levels were lower in the patient group, but these differences were not significant (p = 0.708, p = 0.628, and p = 0.218, respectively). ASP and adipsin levels were correlated positively in patients with psoriasis (p = 0.029). CONCLUSION: To our knowledge, this study is the first to evaluate ASP and adipsin levels in patients with psoriasis. The roles of ASP and adipsin in the etiopathogenesis of psoriasis are unclear. Although not statistically significant, the lower ASP and adipsin levels in the patient group suggest a potential anti-inflammatory role of these proteins in psoriasis. Further studies should examine the relationships between ASP/adipsin and psoriasis. PMID- 28632886 TI - Dermatobia hominis misdiagnosed as abscesses in a traveler returning from Brazil to Denmark. AB - We present the case of a 62-year-old woman that consulted us for two boil-like lesions on her thighs after returning from a trip to Sao Paulo, Brazil, where she had swum in a freshwater lake. After consulting three specialist doctors and undergoing two antibiotic treatments, she was diagnosed with furuncular myiasis caused by Dermatobia hominis. The parasites were excised with no complications. PMID- 28632885 TI - Restoring facial symmetry through non-surgical cosmetic procedures after permanent facial paralysis: a case report. AB - Facial nerve paralysis can occur due to infection, inflammation, trauma, surgery, and tumors. It leads to facial asymmetry, impaired oral competence, articulation deficits, and psychological problems. Treatment options include physical therapy, static slings, nerve and muscle transfers, blepharoplasty, brow lift, and chemodenervation with botulinum toxin. We report the case of a 66-year-old Caucasian female with permanent facial paralysis following middle ear surgery. The facial asymmetry was treated successfully with botulinum toxin A injection, hyaluronic acid dermal filler injection, and a thread-lift procedure. PMID- 28632887 TI - Pushing the edge of dermoscopy in new directions: entomodermoscopy of Trombicula autumnalis. AB - Dermatologists are often faced with the challenge of patients presenting with non specific symptoms such as itching and or erythema. These symptoms may be attributed to a number of diseases, many of which are trivial, and others even life-threatening. In order to establish the correct diagnosis, dermatologists must rely on good diagnostic tools and knowledge. Dermoscopy was introduced mainly for inspection of pigmented lesions, but its use has now also spread to non-melanoma skin cancer, inflammatory diseases, and almost any skin disease. This diagnostic technique also applies to skin infestation today, often offering the opportunity to rapidly identify new hidden features of parasites. This case report describes an unusual but representative case in which entomodermoscopy enabled a rapid diagnosis in a patient with a non specific erythematous patch. Whereas differential diagnosis of such skin manifestations could have been too laborious and misleading, dermoscopy easily allowed us to find a small parasite, later identified as Trombicula autumnalis. PMID- 28632888 TI - Excellent response to tofacitinib treatment in a patient with alopecia universalis. AB - Alopecia universalis (AU) is generally considered a variant of alopecia areata (AA), in which the treatment options seldom provide satisfactory results. However, successful treatment of several cases of AA and its variants with oral Janus kinase (JAK) inhibitors have been reported recently. Here we report a 23 year-old female patient with AU successfully treated with tofacitinib, a selective JAK-3 inhibitor. The initial tofacitinib dose was 5 mg twice daily. After 2 months of treatment, partial hair regrowth was seen on the scalp and eyebrows. Thereafter, the dose was increased to 10 mg in the morning and 5 mg at night. By 6 months of the treatment, there was complete hair regrowth throughout the entire body. Our patient tolerated tofacitinib well, without any significant side effects. Tofacitinib emerges as a promising novel therapy in alopecia universalis. We believe further study is required to establish the safety and confirm the efficacy of tofacitinib treatment for alopecia universalis. PMID- 28632889 TI - Onychodystrophy due to porokeratosis of Mibelli: a rare association. AB - Porokeratosis is a specific keratinization disorder that manifests clinically as well-demarcated annular or linear keratotic plaques of various sizes and forms and with distinguished histology showing cornoid lamella, which is a column of closely packed parakeratotic cells extending through the stratum corneum. Nail changes secondary to porokeratotic lesions involving digits are quite uncommon and rarely reported in the porokeratosis of Mibelli (PM) subtype. Here we report the case of a young girl with a PM lesion over the hand along with nail dystrophy of the involved digit. PMID- 28632890 TI - Minimally invasive surgery and its impact on 30-day postoperative complications, unplanned readmissions and mortality. AB - BACKGROUND: A critical appraisal of the benefits of minimally invasive surgery (MIS) is needed, but is lacking. This study examined the associations between MIS and 30-day postoperative outcomes including complications graded according to the Clavien-Dindo classification, unplanned readmissions, hospital stay and mortality for five common surgical procedures. METHODS: Patients undergoing appendicectomy, colectomy, inguinal hernia repair, hysterectomy and prostatectomy were identified in the American College of Surgeons National Surgical Quality Improvement Program database. Non-parsimonious propensity score methods were used to construct procedure-specific matched-pair cohorts that reduced baseline differences between patients who underwent MIS and those who did not. Bonferroni correction for multiple comparisons was applied and P < 0.006 was considered significant. RESULTS: Of the 532 287 patients identified, 53.8 per cent underwent MIS. Propensity score matching yielded an overall sample of 327 736 patients (appendicectomy 46 688, colectomy 152 114, inguinal hernia repair 59 066, hysterectomy 59 066, prostatectomy 10 802). Within the procedure-specific matched pairs, MIS was associated with significantly lower odds of Clavien-Dindo grade I II, III and IV complications (P <= 0.004), unplanned readmissions (P < 0.001) and reduced hospital stay (P < 0.001) in four of the five procedures studied, with the exception of inguinal hernia repair. The odds of death were lower in patients undergoing MIS colectomy (P < 0.001), hysterectomy (P = 0.002) and appendicectomy (P = 0.002). CONCLUSION: MIS was associated with significantly fewer 30-day postoperative complications, unplanned readmissions and deaths, as well as shorter hospital stay, in patients undergoing colectomy, prostatectomy, hysterectomy or appendicectomy. No benefits were noted for inguinal hernia repair. PMID- 28632891 TI - Estimating the size of an open population using sparse capture-recapture data. AB - Sparse capture-recapture data from open populations are difficult to analyze using currently available frequentist statistical methods. However, in closed capture-recapture experiments, the Chao sparse estimator (Chao, 1989, Biometrics 45, 427-438) may be used to estimate population sizes when there are few recaptures. Here, we extend the Chao (1989) closed population size estimator to the open population setting by using linear regression and extrapolation techniques. We conduct a small simulation study and apply the models to several sparse capture-recapture data sets. PMID- 28632892 TI - Maternal Overweight and Obesity and Genital Anomalies in Male Offspring: A Population-Based Swedish Cohort Study. AB - BACKGROUND: Overweight and obese pregnant women face higher risk of several critical birth outcomes, including an overall increased risk of congenital abnormalities. Only few studies have focused on associations between maternal overweight and the genital anomalies in boys, cryptorchidism and hypospadias, and results are inconclusive. METHODS: We performed a population-based cohort study and assessed the associations between maternal body mass index (BMI) in early pregnancy and occurrence of cryptorchidism and hypospadias. All live-born singleton boys born in Sweden from 1992 to 2012 were included. From the Swedish Patient Register, information on cryptorchidism and hypospadias was available. Data were analysed using Cox proportional hazards regression adjusted for potential confounders. Mediation analyses were performed to estimate how much of the association between BMI and genital anomalies were mediated through obesity related diseases. RESULTS: Of the 1 055 705 live-born singleton boys born from 1992 to 2012, 6807 (6.4 per 1000) were diagnosed with hypospadias and 16 469 (15.6 per 1000) were diagnosed with cryptorchidism, of which 9768 (9.3 per 1000) underwent corrective surgery for cryptorchidism. We observed dose-response associations between maternal BMI and hypospadias and cryptorchidism. Boys of mothers with BMI >=40.0 kg/m2 had the highest adjusted hazard ratios for hypospadias (HR 1.35, 95% confidence interval [CI] 1.04, 1.76) and cryptorchidism (HR 1.25, 95% CI 1.00, 1.58). A substantial proportion of the associations between BMI and the genital anomalies were mediated through preeclampsia. CONCLUSION: This large register-based study adds to the current literature and indicates that the occurrence of hypospadias and cryptorchidism increase with maternal overweight and obesity severity. PMID- 28632893 TI - Atopic dermatitis is associated with anxiety, depression, and suicidal ideation, but not with psychiatric hospitalization or suicide. AB - BACKGROUND: Atopic dermatitis (AD) has been linked with psychiatric disease in adults. However, the exact relationship and its consequences have been insufficiently studied. Our aim of this study was to assess the association between depression, anxiety, and AD in adults and examine the risk of hospitalization and suicide. METHODS: We utilized questionnaire data from a large general population study with data on social habits and psychiatric symptoms to compare prevalences of depression, anxiety, suicidal ideation, and anxiety attacks, in adults with and without a history of AD. Additionally, we used nationwide hospital/clinic registry and prescription data to examine the risk of anxiety and depression in Danish adults with mild and moderate-severe AD, as well as the risk of hospitalization and suicide. RESULTS: In the general population study, those with AD reported clinician-diagnosed depression and anxiety more often than non-AD subjects, and had an increased prevalence of suicidal ideation and depressive symptoms. In the health registry study, moderate-severe AD patients had increased risk of antidepressant and anxiolytic medication use, while patients with mild AD only had increased risk of anxiolytic medication use. There was no increased risk of hospitalization or outpatient contacts due to depression or anxiety, or risk of suicide in AD patients. CONCLUSIONS: Depression, anxiety, and suicidal ideation are more common among AD individuals, but do not lead to psychiatric consultations, hospitalization, or suicide. PMID- 28632896 TI - Reliability of a novel approach for quadriceps motor point assessment. AB - INTRODUCTION: We studied the ability of clinicians to identify quadriceps motor points using a transcutaneous electrical stimulation unit (TENS). METHODS: Twenty two certified athletic trainers and 1 expert-rater identified the 7 motor points of the quadriceps at 2 time-points separated by 1 week. The difference was calculated between where each participant and the expert-rater identified each motor point using an x-y coordinate system. Bland-Altman plots were used to compare differences between 2 testing sessions. RESULTS: No differences were observed between participants and the expert-rater for motor point location. The smallest variability in the limits of agreements were observed in the distal vastus medialis oblique (-1.89 to 1.86 cm) and proximal vastus lateralis (-1.61 to 2.35 cm). DISCUSSION: Our results suggest the utilization of a TENS unit may be 1 way to identify quadriceps motor points to improve electrical stimulation applications. The smallest limits of agreement were over the most common quadriceps electrical stimulation electrode positions. Muscle Nerve 57: E1-E7, 2018. PMID- 28632894 TI - Flavonoids as modulators of metabolic enzymes and drug transporters. AB - Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR. PMID- 28632895 TI - Genome mining reveals high incidence of putative lipopeptide biosynthesis NRPS/PKS clusters containing fatty acyl-AMP ligase genes in biofilm-forming cyanobacteria. AB - Cyanobacterial lipopeptides have antimicrobial and antifungal bioactivities with potential for use in pharmaceutical research. However, due to their hemolytic activity and cytotoxic effects on human cells, they may pose a health issue if produced in substantial amounts in the environment. In bacteria, lipopeptides can be synthesized via several well-evidenced mechanisms. In one of them, fatty acyl AMP ligase (FAAL) initiates biosynthesis by activation of a fatty acyl residue. We have performed a bioinformatic survey of the cyanobacterial genomic information available in the public databases for the presence of FAAL-containing non-ribosomal peptide synthetase/polyketide synthetase (NRPS/PKS) biosynthetic clusters, as a genetic basis for lipopeptide biosynthesis. We have identified 79 FAAL genes associated with various NRPS/PKS clusters in 16% of 376 cyanobacterial genomic assemblies available, suggesting that FAAL is frequently incorporated in NRPS/PKS biosynthetases. FAAL was present either as a stand-alone protein or fused either to NRPS or PKS. Such clusters were more frequent in derived phylogenetic lineages with larger genome sizes, which is consistent with the general pattern of NRPS/PKS pathways distribution. The putative lipopeptide clusters were more frequently found in genomes of cyanobacteria that live attached to surfaces and are capable of forming microbial biofilms. While lipopeptides are known in other bacterial groups to play a role in biofilm formation, motility, and colony expansion, their functions in cyanobacterial biofilms need to be tested experimentally. According to our data, benthic and terrestrial cyanobacteria should be the focus of a search for novel candidates for lipopeptide drug synthesis and the monitoring of toxic lipopeptide production. PMID- 28632897 TI - Delving within: the new science of the unconscious. AB - What exactly is the relationship between conscious awareness and the unconscious mind? How, for example, does the brain classify and sort its different functions into conscious or unconscious processes? How has the history of human conceptualizations about the unconscious influenced current theories? Steve Paulson, executive producer of To the Best of Our Knowledge, moderated a discussion among neuroscientist Heather Berlin, psychologist Efrat Ginot, and psychiatrist George Makari to shed light on the history of the mind and the latest insights into the still emerging science of the unconscious. PMID- 28632898 TI - HBsAg loss after peginterferon-nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow-up. AB - Combining peginterferon-alfa-2a (pegIFN) with a nucleotide analogue can result in higher rates of HBsAg loss than either therapy given alone. Here, we investigated the durability of the response to combination therapy in chronic hepatitis B (CHB) patients after 5 years of follow-up. In the initial study, 92 CHB patients (44 HBeAg-positive, 48 HBeAg-negative) with HBV DNA >100 000 c/mL (~20 000 IU/mL) and active hepatitis were treated for 48 weeks with pegIFN 180 MUg/week and 10 mg adefovir dipivoxil daily. For the long-term follow-up (LTFU) study, patients were followed up for 5 years after the end of treatment. At year 5, 70 (32 HBeAg positive, 38 HBeAg-negative) patients remained in the study. At year 5, 19% (6/32) of HBeAg-positive patients and 16% (6/38) of HBeAg-negative patients lost HBsAg, and no HBsAg seroreversion was observed. The 5-year cumulative Kaplan Meier estimate for HBsAg loss was 17.2% for HBeAg-positive patients and 19.3% for HBeAg-negative patients. Fourteen of sixteen patients who lost HBsAg at any time point during follow-up developed anti-HBs antibodies (>10 IU/L). At year 5, in total 63% (20/32) of HBeAg-positive and 71% (27/38) of HBeAg-negative patients were retreated with nucleos(t)ide analogues during follow-up. The cumulative Kaplan-Meier estimate for retreatment was 60% of patients at year 5. At year 5 of follow-up, 18% of CHB patients treated with pegIFN/nucleotide analogue combination therapy had durable HBsAg loss and 88% of these had developed anti HBs antibodies. PMID- 28632899 TI - Novel intracytoplasmic inclusions immunoreactive for phosphorylated-TDP43 and cystatin C in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis. AB - Novel intracytoplasmic inclusions immunoreactive for phosphorylated transactivation response DNA-binding protein 43 (p-TDP43), cystatin C, and transferrin were found in anterior horn cells in a case of sporadic amyotrophic lateral sclerosis (ALS). The patient was a 59-year-old woman, who died of ALS after a clinical course of 8 years. She had been receiving mechanical support for respiration for 6 years and in a "totally locked-in" state for 4 years prior to death. The spinal cord showed severe degeneration involving the anterior and lateral funiculi, whereas the posterior funiculus was preserved. Neurons in the anterior horn and Clarke's column were markedly lost, and many Bunina bodies and a few skein-like inclusions were found. Some remaining anterior horn cells had round and densely eosinophilic or amphophilic intracytoplasmic inclusions. They were immunoreactive for ubiquitin, p-TDP43, cystatin C and transferrin. On confocal laser microscopy, cystatin C was found to consistently surround p-TDP43 within the inclusions. The inclusions ultrastructurally consisted of granule associated fibrils and, in the central portion, dense aggregates of fibrils were associated with masses of electron-dense, coarsely granular or amorphous material. Although their pathogenesis remains unknown, these unique inclusions may have been formed under a specific condition whereby p-TDP43 and cystatin C interacted with each other. PMID- 28632900 TI - Native-predator-invasive-prey trophic interactions in Tierra del Fuego: the beginning of biological resistance? PMID- 28632901 TI - Biexponential T1rho relaxation mapping of human knee cartilage in vivo at 3 T. AB - The purpose of this study was to demonstrate the feasibility of biexponential T1rho relaxation mapping of human knee cartilage in vivo. A three-dimensional, customized, turbo-flash sequence was used to acquire T1rho -weighted images from healthy volunteers employing a standard 3-T MRI clinical scanner. A series of T1rho -weighted images was fitted using monoexponential and biexponential models with two- and four-parametric non-linear approaches, respectively. Non-parametric Kruskal-Wallis and Mann-Whitney U-statistical tests were used to evaluate the regional relaxation and gender differences, respectively, with a level of significance of P = 0.05. Biexponential relaxations were detected in the cartilage of all volunteers. The short and long relaxation components of T1rho were estimated to be 6.9 and 51.0 ms, respectively. Similarly, the fractions of short and long T1rho were 37.6% and 62.4%, respectively. The monoexponential relaxation of T1rho was 32.6 ms. The experiments showed good repeatability with a coefficient of variation (CV) of less than 20%. A biexponential relaxation model showed a better fit than a monoexponential model to the T1rho relaxation decay in knee cartilage. Biexponential T1rho components could potentially be used to increase the specificity to detect early osteoarthritis by the measurement of different water compartments and their fractions. PMID- 28632902 TI - Impaired hippocampal glucose metabolism during and after flurothyl-induced seizures in mice: Reduced phosphorylation coincides with reduced activity of pyruvate dehydrogenase. AB - OBJECTIVE: To determine changes in glucose metabolism and the enzymes involved in the hippocampus ictally and postictally in the acute mouse flurothyl seizure model. METHODS: [U-13 C]-Glucose was injected (i.p.) prior to, or following a 5 min flurothyl-induced seizure. Fifteen minutes later, mice were killed and the total metabolite levels and % 13 C enrichment were analyzed in the hippocampal formation using gas chromatography-mass spectrometry. Activities of key metabolic and antioxidant enzymes and the phosphorylation status of pyruvate dehydrogenase were measured, along with lipid peroxidation. RESULTS: During seizures, total lactate levels increased 1.7-fold; however, [M + 3] enrichment of both lactate and alanine were reduced by 30% and 43%, respectively, along with a 28% decrease in phosphofructokinase activity. Postictally the % 13 C enrichments of all measured tricarboxylic acid (TCA) cycle intermediates and the amino acids were reduced by 46-93%. At this time, pyruvate dehydrogenase (PDH) activity was 56% of that measured in controls, and there was a 1.9-fold increase in the phosphorylation of PDH at ser232. Phosphorylation of PDH is known to decrease its activity. SIGNIFICANCE: Here, we show that the increase of lactate levels during flurothyl seizures is from a source other than [U-13 C]-glucose, such as glycogen. Surprisingly, although we saw a reduction in phosphofructokinase activity during the seizure, metabolism of [U-13 C]-glucose into the TCA cycle seemed unaffected. Similar to our recent findings in the chronic phase of the pilocarpine model, postictally the metabolism of glucose by glycolysis and the TCA cycle was impaired along with reduced PDH activity. Although this decrease in activity may be a protective mechanism to reduce oxidative stress, which is observed in the flurothyl model, ATP is critical to the recovery of ion and neurotransmitter balance and return to normal brain function. Thus we identified promising novel strategies to enhance energy metabolism and recovery from seizures. PMID- 28632904 TI - Nerve growth factor and basic fibroblast growth factor promote reinnervation by nerve-muscle-endplate grafting. AB - INTRODUCTION: This study was designed to test whether exogenous application of nerve growth factor (NGF) and basic fibroblast growth factor (FGF-2) to muscles reinnervated with nerve-muscle-endplate band grafting (NMEG) could promote specific outcomes. METHODS: The right sternomastoid muscle in adult rats was experimentally denervated and immediately reinnervated by implanting an NMEG pedicle from the ipsilateral sternohyoid muscle. A fibrin sealant containing NGF and FGF-2 was focally applied to the implantation site. Maximal tetanic force, muscle weight, regenerated axons, and motor endplates were analyzed 3 months after treatment. RESULTS: Mean tetanic force, wet muscle weight, and number of regenerated axons in the treated muscles were 91%, 92%, and 84% of the contralateral controls, respectively. The majority of endplates (86%) in the treated muscles were reinnervated by regenerated axons. DISCUSSION: Focal administration of NGF and FGF-2 promotes efficacy of the NMEG technique. Muscle Nerve 57: 449-459, 2018. PMID- 28632903 TI - Immunohistochemical dissection of cystic panfolliculoma focusing on the expression of multiple hair follicle lineage markers with an insight into the pathogenesis. AB - Panfolliculoma (PF) is a rare benign tumor with signs of differentiation toward all components of the hair follicle (HF). Cystic panfolliculoma (CPF) is a subset of PF with histological similarity to trichofolliculoma making the differential diagnosis difficult in some cases. Immunohistopathological investigations of PF have been reported; however, previous studies focused mostly on the expression profile of the outer root sheath markers. Herein, we report a case of CPF. A panel of antibodies was developed and used for the detection of the expression of cytokeratin (CK) 10, CK13, CK14, CK15, hair-hard keratin (AE13) and EpCAM within the lesion, supporting the differentiation of all epithelial lineages of the HF and the diagnosis of CPF. Immunohistopathological examinations clearly showed the spatial distribution pattern of each subset of tumor cells with distinct HF differentiation marker expression. Intriguingly, fibroblastic dermal cells were distributed preferentially near CK15-negative epithelium or CK13-positive HF-like structures, suggesting a role for epithelial-mesenchymal interactions (EMIs) in CPF pathogenesis. Further characterization of EMIs between the tumor and surrounding mesenchymal cells in CPF may provide an explanation for immature HF differentiation. These findings suggest that the more intense and coordinated EMI in the analogous tumorigenesis gives rise to mature HF structures, resulting in trichofolliculoma, which may explain their histological resemblance. PMID- 28632905 TI - The malleable brain: plasticity of neural circuits and behavior - a review from students to students. AB - One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on doi: 10.1111/jnc.14102. PMID- 28632907 TI - Preferential aerosolization of bacteria in bioaerosols generated in vitro. AB - AIMS: Little is known about how bacteria are aerosolized in terms of whether some bacteria will be found in the air more readily than others that are present in the source. This report describes in vitro experiments to compare aerosolization rates (also known as preferential aerosolization) of Gram-positive and Gram negative bacteria as well as rod- and coccus-shaped bacteria, using two nebulization conditions. METHODS AND RESULTS: A consortium of five bacterial species was aerosolized in a homemade chamber. Aerosols generated with a commercial nebulizer and a homemade bubble-burst aerosol generator were compared. Data suggest that Pseudomonas aeruginosa was preferentially aerosolized in comparison to Moraxella catarrhalis, Lactobacillus paracasei, Staphylococcus aureus and Streptococcus suis, independently of the method of aerosolization. Bacterial integrity of Strep. suis was more preserved compared to other bacteria studied as revealed with PMA-qPCR. CONCLUSION: We reported the design of an aerosol chamber and bubble-burst generator for the in vitro study of preferential aerosolization. In our setting, preferential aerosolization was influenced by bacterial properties instead of aerosolization mechanism. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings could have important implications for predicting the composition of bioaerosols in various locations such as wastewater treatment plants, agricultural settings and health care settings. PMID- 28632906 TI - Improving the histologic characterization of burn depth. AB - BACKGROUND: Visual assessment of burn wound appearance is the standard of care to determine the depth of thermal injury but often incorrectly predicts wound healing potential. Histologic evaluation of hematoxylin and eosin (H&E) stained burn tissue is prone to subjectivity and is challenging for the novice. Lactate dehydrogenase (LDH) staining may offer a simplified and consistent technique to identify burn tissue viability. METHODS: Thirty tissue samples were obtained from 6 patients undergoing surgical excision for clinically determined deep partial thickness or full thickness burns. Tissues were stained with H&E or LDH. Each specimen was scored by 3 individuals with varying levels of skill in histologic interpretation using a standardized checklist at 2 distinct time points. RESULTS: Agreement within raters was highest for the expert rater and lowest for the novice; however, the LDH stained tissue method had improved agreement for an experienced burn surgeon and novice. Agreement between raters was greater for the LDH stained samples which were determined to have greater viability than the corresponding H&E section in 100% of samples scored by the expert and in 80% for the novice clinician. CONCLUSION: LDH staining offers a more consistent measure of tissue viability that can be used by experienced and novice clinicians. PMID- 28632908 TI - Prediction of Groundwater Quality Trends Resulting from Anthropogenic Changes in Southeast Florida. AB - The effects of surface water flow system changes caused by constructing water conservation areas and canals in southeast Florida on groundwater quality under the Atlantic Coastal Ridge was investigated with numerical modeling. Water quality data were used to delineate a zone of groundwater with low total dissolved solids (TDS) within the Biscayne aquifer under the ridge. The delineated zone has the following characteristics. Its location generally coincides with an area where the Biscayne aquifer has high transmissivities, corresponds to a high recharge area of the ridge, and underlies a part of the groundwater mound formed under the ridge prior to completion of the canals. This low TDS groundwater appears to be the result of pre-development conditions rather than seepage from the canals constructed after the 1950s. Numerical simulation results indicate that the time for low TDS groundwater under the ridge to reach equilibrium with high TDS surface water in the water-conservation areas and Everglades National Park are approximately 70 and 60 years, respectively. The high TDS groundwater would be restricted to the water-conservation areas and the park due to its slow eastward movement caused by small hydraulic gradients in Rocky Glades and its mixing with the low TDS groundwater under the high-recharge area of the ridge. The flow or physical boundary conditions such as high recharge rates or low hydraulic conductivity layers may affect how the spatial distribution of groundwater quality in an aquifer will change when a groundwater flow system reaches equilibrium with an associated surface water flow system. PMID- 28632909 TI - Catalyst-Controlled, Enantioselective, and Diastereodivergent Conjugate Addition of Aldehydes to Electron-Deficient Olefins. AB - A chiral-amine-catalyzed enantioselective and diastereodivergent method for aldehyde addition to electron-deficient olefins is presented. Hydrogen bonding was used as a control element to achieve unusual anti selectivity, which was further elucidated through mechanistic and computational studies. PMID- 28632910 TI - WITHDRAWN: Hypnosis for children undergoing dental treatment. AB - BACKGROUND: Managing children is a challenge that many dentists face. Many non pharmacological techniques have been developed to manage anxiety and behavioural problems in children, such us: 'tell, show & do', positive reinforcement, modelling and hypnosis. The use of hypnosis is generally an overlooked area, hence the need for this review. OBJECTIVES: This systematic review attempted to answer the question: What is the effectiveness of hypnosis (with or without sedation) for behaviour management of children who are receiving dental care in order to allow successful completion of treatment?Null hypothesis: Hypnosis has no effect on the outcome of dental treatment of children. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE (OVID), EMBASE (OVID), and PsycINFO. Electronic and manual searches were performed using controlled vocabulary and free text terms with no language restrictions. Date of last search: 11th June 2010. SELECTION CRITERIA: All children and adolescents aged up to 16 years of age. Children having any dental treatment, such as: simple restorative treatment with or without local anaesthetic, simple extractions or management of dental trauma. DATA COLLECTION AND ANALYSIS: Information regarding methods, participants, interventions, outcome measures and results were independently extracted, in duplicate, by two review authors. Authors of trials were contacted for details of randomisation and withdrawals and a quality assessment was carried out. The methodological quality of randomised controlled trials (RCTs) was assessed using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions 5.0.2. MAIN RESULTS: Only three RCTs (with 69 participants) fulfilled the inclusion criteria. Statistical analysis and meta-analysis were not possible due to insufficient number of studies. AUTHORS' CONCLUSIONS: Although there are a considerable number of anecdotal accounts indicating the benefits of using hypnosis in paediatric dentistry, on the basis of the three studies meeting the inclusion criteria for this review there is not yet enough evidence to suggest its beneficial effects. PMID- 28632911 TI - Polymer functionalized gold nanoparticles as nonviral gene delivery reagents. AB - BACKGROUND: In the present study, we investigated the ability of polyethylene glycol (PEG) functionalized gold nanoparticles to function as nonviral vectors in the transfection of different cell lines, comparing them with commercial lipoplexes. METHODS: Positively-charged gold nanoparticles were synthesized using polyethylenimine (PEI) as a reducing and stabilizer agent and its cytotoxicity was reduced by its functionalization with PEG. We bound the nanoparticles to three plasmids with different sizes (4-40 kpb). Vector internalization was evaluated by confocal and electronic microscopy. Its transfection efficacy was studied by fluorescence microscopy and flow cytometry. The application of the resulting vector in gene therapy was evaluated indirectly using ganciclovir in HeLa cells transfected to express the herpes virus thymidine kinase. RESULTS: An appropriate ratio between the nitrogen from the PEI and the phosphorous from the phosphate groups of the DNA, together with a reduced size and an elevated electrokinetic potential, are responsible for an increased nanoparticle internalization and enhanced protein expression when carrying plasmids of up to 40 kbp (plasmid size close to the limit of the DNA-carrying capacity of viral vectors). Compared to a commercial transfection reagent, an equal or even higher expression of reporter genes (on HeLa and Hek293t) and a suicide effect on HeLa cells transfected with the herpes virus thymidine kinase gene were observed when using this novel nanoparticulated vector. CONCLUSIONS: Nonviral vectors based on gold nanoparticles covalently coupled with PEG and PEI can be used as efficient transfection reagents showing expression levels that are the same or greater than those obtained with commercially available lipoplexes. PMID- 28632912 TI - Surveillance and early warning systems of infectious disease in China: From 2012 to 2014. AB - Appropriate surveillance and early warning of infectious diseases have very useful roles in disease control and prevention. In 2004, China established the National Notifiable Infectious Disease Surveillance System and the Public Health Emergency Event Surveillance System to report disease surveillance and events on the basis of data sources from the National Notifiable Infectious Disease Surveillance System, China Infectious Disease Automated-alert and Response System in this country. This study provided a descriptive summary and a data analysis, from 2012 to 2014, of these 3 key surveillance and early warning systems of infectious disease in China with the intent to provide suggestions for system improvement and perfection. PMID- 28632913 TI - A Carbene Catalysis Strategy for the Synthesis of Protoilludane Natural Products. AB - The Armillaria and Lactarius genera of fungi produce the antimicrobial and cytotoxic mellolide, protoilludane, and marasmane sesquiterpenoids. We report a unified synthetic strategy to access the protoilludane, mellolide, and marasmane families of natural products. The key features of these syntheses are 1) the organocatalytic, enantioselective construction of key chiral intermediates from a simple achiral precursor, 2) the utility of a key 1,2-cyclobutanediol intermediate to serve as a precursor to each natural product class, and 3) a direct chemical conversion of a protoilludane to a marasmane through serendipitous ring contraction, which provides experimental support for their proposed biosynthetic relationships. PMID- 28632916 TI - Diastasis of the pubic symphysis following vaginal delivery. PMID- 28632915 TI - Increasing awareness and knowledge of lifestyle recommendations for cancer prevention in Lynch syndrome carriers: Randomized controlled trial. AB - Lynch syndrome (LS) mutation carriers may reduce their cancer risk by adhering to lifestyle recommendations for cancer prevention. This study tested the effect of providing LS mutation carriers with World Cancer Research Fund-the Netherlands (WCRF-NL) health promotion materials on awareness and knowledge of and adherence to these recommendations. In this randomized controlled trial (n = 226), the intervention group (n = 114) received WCRF-NL health promotion materials. All LS mutation carriers were asked to fill out questionnaires at 2 weeks before (baseline, T0) and at 2 weeks (T1) and 6 months (T2) after the intervention. Linear mixed models were performed on awareness (0-7) and knowledge (0-7) of the recommendations, and on the secondary outcomes, that is adherence, distress, cancer worry, and risk perception. Compared with the control group, the intervention group became significantly more aware (overall mean difference = 1.24; 95%CI = 0.82-1.67) and obtained significantly improved knowledge of the recommendations (overall mean difference = 1.65; 95%CI = 1.27-2.03). Differences were significantly larger for T1 (Pinteraction = .003 and <=.001, respectively) but remained significant for T2. No effect on secondary outcomes was found. In conclusion, provision of WCRF-NL health promotion materials increases awareness and knowledge of lifestyle recommendations for cancer prevention among LS mutation carriers without causing additional distress, but does not affect adherence. PMID- 28632914 TI - Contrast-enhanced harmonic endoscopic ultrasonography for differential diagnosis of localized gallbladder lesions. AB - BACKGROUND AND AIM: Differential diagnosis of localized gallbladder lesions is challenging. The aim of the present study was to evaluate the utility of contrast enhanced harmonic endoscopic ultrasonography (CH-EUS) for diagnosis of localized gallbladder lesions. METHODS: One hundred and twenty-five patients with localized gallbladder lesions were evaluated by CH-EUS between March 2007 and February 2014. This was a single-center retrospective study. Utilities of fundamental B mode EUS (FB-EUS) and CH-EUS in the differentiation of gallbladder lesions and sludge plug were initially compared. Thereafter, these two examinations were compared with respect to their accuracy in the diagnosis of malignant lesions. Five reviewers blinded to the clinicopathological results evaluated microcirculation patterns in the vascular and perfusion images. RESULTS: In the differentiation between gallbladder lesions and sludge plug, FB-EUS had a sensitivity, specificity, and accuracy of 82%, 100%, and 95%, respectively, whereas CH-EUS had a sensitivity, specificity, and accuracy of 100%, 99%, and 99%, respectively. FB-EUS-based diagnosis of carcinomas based on tumor size and/or shape had a sensitivity, specificity, and accuracy of 61-87%, 71-88%, and 74-86%, respectively. Additional information regarding irregular vessel patterns in the vascular image and/or heterogeneous enhancement in the perfusion image on CH-EUS increased the sensitivity, specificity, and accuracy for the diagnosis of carcinomas to 90%, 98%, and 96%, respectively. There was a significant difference between FB-EUS and CH-EUS in terms of carcinoma diagnosis. CONCLUSION: CH-EUS was useful for the evaluation of localized gallbladder lesions. PMID- 28632917 TI - Miniaturization of sebaceous glands: A novel histopathological finding in pemphigus vulgaris and pemphigus foliaceus of the scalp. AB - BACKGROUND: Intraepidermal acantholysis is a characteristic histopathological feature of pemphigus. The histopathology of scalp biopsies in pemphigus has not been widely discussed in the literature, although the scalp is commonly involved in pemphigus. METHODS: A total of 32 consecutive patients with scalp involvement (17 with pemphigus vulgaris [PV] and 15 with pemphigus foliaceus [PF]) were enrolled into the study. The histopathological examination of scalp biopsies was performed in all patients. Tissue specimens were stained with hematoxylin and eosin. RESULTS: Acantholysis extended down the entire length of the outer root sheath of the hair follicle in 12 of 17 (70.6%) patients with PV. Follicular acantholysis in PF was restricted to the infundibulum and occurred in 12 of 15 (80.0%) patients. Acantholysis in the vellus hair follicles was observed in 12 of 17 (70.6%) and 9 of 15 (60.0%) cases, respectively. The miniaturization of sebaceous glands was seen in 14 of 17 (82.4%) and 12 of 15 (80.0%) patients, respectively. CONCLUSIONS: Follicular acantholysis is a common histopathological feature of pemphigus. It may serve as a clue to the diagnosis of pemphigus subtypes, as PV and PF differ in the depth of follicular acantholysis. The miniaturization of sebaceous glands is a common histopathological feature observed in scalp specimens of patients with pemphigus. PMID- 28632919 TI - Isolated facial palsy from perineural spread of cutaneous squamous cell carcinoma. PMID- 28632918 TI - Predicting inpatient hypoglycaemia in hospitalized patients with diabetes: a retrospective analysis of 9584 admissions with diabetes. AB - AIMS: To explore whether a quantitative approach to identifying hospitalized patients with diabetes at risk of hypoglycaemia would be feasible through incorporation of routine biochemical, haematological and prescription data. METHODS: A retrospective cross-sectional analysis of all diabetic admissions (n=9584) from 1 January 2014 to 31 December 2014 was performed. Hypoglycaemia was defined as a blood glucose level of <4 mmol/l. The prediction model was constructed using multivariable logistic regression, populated by clinically important variables and routine laboratory data. RESULTS: Using a prespecified variable selection strategy, it was shown that the occurrence of inpatient hypoglycaemia could be predicted by a combined model taking into account background medication (type of insulin, use of sulfonylureas), ethnicity (black and Asian), age (>=75 years), type of admission (emergency) and laboratory measurements (estimated GFR, C-reactive protein, sodium and albumin). Receiver operating curve analysis showed that the area under the curve was 0.733 (95% CI 0.719 to 0.747). The threshold chosen to maximize both sensitivity and specificity was 0.15. The area under the curve obtained from internal validation did not differ from the primary model [0.731 (95% CI 0.717 to 0.746)]. CONCLUSIONS: The inclusion of routine biochemical data, available at the time of admission, can add prognostic value to demographic and medication history. The predictive performance of the constructed model indicates potential clinical utility for the identification of patients at risk of hypoglycaemia during their inpatient stay. PMID- 28632920 TI - Rural health: Better together. PMID- 28632921 TI - Conference recommendations set bold agenda. PMID- 28632922 TI - Comparison of Manual and Automated Measurements of Tracheobronchial Airway Geometry in Three Balb/c Mice. AB - Mammalian lungs are comprised of large numbers of tracheobronchial airways that transition from the trachea to alveoli. Studies as wide ranging as pollutant deposition and lung development rely on accurate characterization of these airways. Advancements in CT imaging and the value of computational approaches in eliminating the burden of manual measurement are providing increased efficiency in obtaining this geometric data. In this study, we compare an automated method to a manual one for the first six generations of three Balb/c mouse lungs. We find good agreement between manual and automated methods and that much of the disagreement can be attributed to method precision. Using the automated method, we then provide anatomical data for the entire tracheobronchial airway tree from three Balb/C mice. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:2046-2057, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28632928 TI - N-acylsulfonamides: Synthetic routes and biological potential in medicinal chemistry. AB - Sulfonamide is a common structural motif in naturally occurring and synthetic medicinal compounds. The rising interest in sulfonamides and N-acyl derivatives is attested by the large number of drugs and lead compounds identified in last years, explored in different fields of medicinal chemistry and showing biological activity. Many acylsulfonamide derivatives were designed and synthesized as isosteres of carboxylic acids, being the characteristics of these functional groups very close. Starting from chemical routes to N-acylsulfonamides, this review explores compounds of pharmaceutical interest, developed as enzymatic inhibitors or targeting receptors. PMID- 28632926 TI - Meta-analysis of health-related quality of life after minimally invasive versus open oesophagectomy for oesophageal cancer. AB - BACKGROUND: The aim of this systematic review and meta-analysis was to compare health-related quality of life (HRQoL) outcomes between minimally invasive and open oesophagectomy for cancer at different postoperative time points. METHODS: A search of PubMed (MEDLINE), Web of Science, Embase, Scopus, CINAHL and the Cochrane Library was performed for studies that compared open with minimally invasive oesophagectomy. A random-effects meta-analysis was conducted for studies that measured HRQoL scores using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-OES18 questionnaires. Mean differences (MDs) greater than 10 in scores were considered clinically relevant. Pooled effects of MDs with 95 per cent confidence intervals were estimated to assess statistical significance. RESULTS: Nine studies were included in the qualitative analysis, involving 1157 patients who had minimally invasive surgery and 907 patients who underwent open surgery. Minimally invasive surgery resulted in better scores for global quality of life (MD 11.61, 95 per cent c.i. 3.84 to 19.39), physical function (MD 11.88, 3.92 to 19.84), fatigue (MD -13.18, -17.59 to -8.76) and pain (MD -15.85, -20.45 to -11.24) compared with open surgery at 3 months after surgery. At 6 and 12 months, no significant differences remained. CONCLUSION: Patients report better global quality of life, physical function, fatigue and pain 3 months after minimally invasive surgery compared with open surgery. No such differences remain at longer follow-up of 6 and 12 months. PMID- 28632929 TI - Persistent neuropsychiatric impairment in HCV patients-or educational mismatch? PMID- 28632927 TI - Prospective associations between environmental heavy metal exposure and renal outcomes in adults with chronic kidney disease. AB - AIM: In Taiwan, Changhua County residents were exposed to high heavy metal pollution and exhibited high heavy metal levels in blood and urine. We examined associations between heavy metals in residential soil and renal outcomes of residents with chronic kidney disease (CKD). METHOD: From 1 January 2003 to 30 June 2015, we retrospectively identified CKD patients with an estimated glomerular filtration rate of <60 mL/min per 1.73 m2 at one tertiary care centre. We linked data displaying heavy metal concentrations from farm soil adjacent to the patients' residences to clinical outcomes. We included 2343 CKD patients (533 with progression to end-stage renal disease [ESRD] and 1810 without]. We followed these patients for 3.49 +/- 2.27 years, until death or initiation of maintenance dialysis. RESULTS: There were high correlations among the concentrations of the eight metals: arsenic, cadmium, chromium, mercury, copper, lead, nickel, and zinc. After factor analysis, chromium, copper, nickel, and zinc were grouped and labelled Factor 1. High Factor 1 concentration near the patients' residences was associated with diagnoses of hypertension, diabetes mellitus, and cerebral vascular accident. Patients living in areas with high Factor 1 concentrations were at higher risk of ESRD. After multivariate adjustment [adjusted hazard ratio: 1.08, 95% Confidence interval: 1.01-1.14, P = 0.02], only zinc and nickel were risk factors for progression to ESRD. CONCLUSION: Patients with CKD, with long-term exposure to soil-based heavy metals, had rapid progression to ESRD. Groups of minerals from the same source of contamination may accumulate and lead to additional harm. PMID- 28632924 TI - Metabolomics as a Driver in Advancing Precision Medicine in Sepsis. AB - The objective of this review is to explain the science of metabolomics-a science of systems biology that measures and studies endogenous small molecules (metabolites) that are present in a single biological sample-and its application to the diagnosis and treatment of sepsis. In addition, we discuss how discovery through metabolomics can contribute to the development of precision medicine targets for this complex disease state and the potential avenues for those new discoveries to be applied in the clinical environment. A nonsystematic literature review was performed focusing on metabolomics, pharmacometabolomics, and sepsis. Human (adult and pediatric) and animal studies were included. Metabolomics has been investigated in the diagnosis, prognosis, and risk stratification of sepsis, as well as for the identification of drug target opportunities. Metabolomics elucidates a new level of detail when compared with other systems biology sciences, with regard to the metabolites that are most relevant in the pathophysiology of sepsis, as well as highlighting specific biochemical pathways at work in sepsis. Metabolomics also highlights biochemical differences between sepsis survivors and nonsurvivors at a level of detail greater than that demonstrated by genomics, transcriptomics, or proteomics, potentially leading to actionable targets for new therapies. The application of pharmacometabolomics and its integration with other systems pharmacology to sepsis therapeutics could be particularly helpful in differentiating drug responders and nonresponders and furthering knowledge of mechanisms of drug action and response. The accumulated literature on metabolomics suggests it is a viable tool for continued discovery around the pathophysiology, diagnosis and prognosis, and treatment of sepsis in both adults and children, and it provides a greater level of biochemical detail and insight than other systems biology approaches. However, the clinical application of metabolomics in sepsis has not yet been fully realized. Prospective validation studies are needed to translate metabolites from the discovery phase into the clinical utility phase. PMID- 28632931 TI - Iowa Model of Evidence-Based Practice: Revisions and Validation. AB - BACKGROUND: The Iowa Model is a widely used framework for the implementation of evidence-based practice (EBP). Changes in health care (e.g., emergence of implementation science, emphasis on patient engagement) prompted the re evaluation, revision, and validation of the model. METHODS: A systematic multi step process was used capturing information from the literature and user feedback via an electronic survey and live work groups. The Iowa Model Collaborative critically assessed and synthesized information and recommendations before revising the model. RESULTS: Survey participants (n = 431) had requested access to the Model between years 2001 and 2013. Eighty-eight percent (n = 379) of participants reported using the Iowa Model and identified the most problematic steps as: topic priority, critique, pilot, and institute change. Users provided 587 comments with rich contextual rationale and insightful suggestions. The revised model was then evaluated by participants (n = 299) of the 22nd National EBP Conference in 2015. They validated the model as a practical tool for the EBP process across diverse settings. Specific changes in the model are discussed. CONCLUSION: This user driven revision differs from other frameworks in that it links practice changes within the system. Major model changes are expansion of piloting, implementation, patient engagement, and sustaining change. LINKING EVIDENCE TO ACTION: The Iowa Model-Revised remains an application-oriented guide for the EBP process. Intended users are point of care clinicians who ask questions and seek a systematic, EBP approach to promote excellence in health care. PMID- 28632923 TI - Comparing the risk of hepatitis B virus reactivation between direct-acting antiviral therapies and interferon-based therapies for hepatitis C. AB - Hepatitis B virus (HBV) reactivation has been reported during antihepatitis C treatment in patients with hepatitis C virus (HCV) and HBV co-infection. We aimed to evaluate the frequency and risk factors of HBV reactivation during anti-HCV therapy and compared those between interferon (IFN)-free direct-acting antiviral (DAA) therapies and IFN-based therapies. Three hundred and twenty-two patients with HCV infection receiving anti-HCV therapy were retrospectively screened. The baseline HBV infection statuses of all eligible patients and the HBV-DNA level of all patients with current or previous HBV infection were examined at the end of treatment. In patients with baseline anti-HBs positivity, changes in anti-HBs titre were evaluated. Of 287 patients who met the inclusion criteria, 157 had current (n=4) or previous (n=153) HBV infection; 85 were treated with IFN-free DAA therapies and 72 were treated with IFN-based therapies. Six patients experienced HBV reactivation (n=2) or HBV reappearance (n=4) after IFN-free DAA therapies, while no patient developed HBV reactivation after IFN-based therapies. The risk factors of HBV reactivation or reappearance were DAA therapies and a reduction in anti-HBs titre to <12 mIU mL-1 by the end of treatment. The decline changes of anti-HBs titre were significantly higher in patients treated with DAA therapies. Although HBV reactivation hepatitis was not observed, three of four patients with HBV reactivation or reappearance after achieving HCV eradication had viremia 8 weeks after completion of therapy. A significant proportion of patients develop HBV reactivation or reappearance without hepatitis after IFN free DAA therapies. Low levels of anti-HBs and their decrease to <12 mIU mL-1 after treatment are significant risk factors for HBV reactivation or reappearance. PMID- 28632930 TI - Long-term follow-up of intra-cytoplasmic sperm injection-conceived offspring compared with in vitro fertilization-conceived offspring: a systematic review of health outcomes beyond the neonatal period. AB - The use of intra-cytoplasmic sperm injection (ICSI) has increased significantly worldwide, often chosen instead of in vitro fertilization (IVF), yet long-term health outcomes are unknown and health differences between ICSI and IVF conceptions have not been comprehensively assessed. A systematic review of health outcomes of ICSI-conceived offspring beyond the neonatal period compared to IVF conceived offspring was carried out. PubMed, OVID Medline/Embase, Informit, Web of Science and Proquest databases were searched on 9 November 2016 for studies reporting on health outcomes in ICSI-conceived offspring beyond 28 days after birth. Physical and psychosocial health were the main outcome measures. The search strategy yielded 2781 articles; 2539 were not relevant or did not meet inclusion criteria and 137 were duplicates. One hundred and five full-text papers were evaluated further and 34 satisfied the inclusion criteria. Studies comparing ICSI- and IVF-conceived children suggest their neurodevelopment is comparable. Growth and aspects of physical health are also similar; however, studies are few and limited to childhood. ICSI-conceived children may be at increased risk of autism and intellectual impairment. No difference in risk of childhood cancer was reported in one study. Whilst the neurodevelopment of ICSI-conceived children appears comparable to those of IVF conception, data relating to neurodevelopmental disorders, growth, physical health and childhood cancer are inconclusive. Further research into health outcomes in adolescence and adulthood is required before conclusions can be drawn about the long-term safety of ICSI compared to IVF. Until then, ICSI might be better reserved for its original intended use, male-factor infertility. PMID- 28632933 TI - Patient Characteristics Associated With a Successful Response to Nurse-Led Care Programs Targeting the Oldest-Old: A Comparison of Two RCTs. AB - BACKGROUND: To improve the effectiveness of community-based care programs, especially those targeting the oldest-old population (80+), data are needed that elucidate those factors associated with a successful response to the intervention. Two comparable nurse-led care programs have been evaluated in two large randomized controlled trials (RCTs), one in Switzerland and one in the Netherlands. AIMS: To identify common patient characteristics that are related to a successful response to proactive nurse-led care, we explored if and to what extent, identical factors were present in both study populations. METHODS: A secondary data analysis using trial data from the intervention group of both RCTs was conducted. The study sample consisted 461 older adults, 230 from the U-PROFIT trial (the Netherlands) and 231 from the HPC trial (Switzerland). The mean age of the total sample was 85.1 years (SD 3.7). The UPROFIT intervention, delivered by registered nurses, included a frailty assessment and a comprehensive geriatric assessment (CGA) at home followed by an individualized evidence-based care plan, care coordination, and follow-up. The HCP intervention was delivered by advanced practice nurses consisting of four home visits and three phone calls, and was guided by the principles of health promotion, empowerment, partnership, and family-centeredness. A successful response was defined as "stable" or "no decline" in daily functioning at follow-up. Daily functioning was measured with 13 items of activities of daily living and instrumental activities of daily living. Multivariate logistic regression models were applied to calculate the association between individual characteristics and a successful response. RESULTS: Almost half of the participants in the U-PROFIT trial (50.9%), and two thirds (65.7%) of the participants in the HCP trial had a successful response at follow-up. Fewer comorbidities and a better self-rated health had the strongest predictive value for benefiting from the intervention (OR = 0.83 [95% CI 0.66 1.03], and OR = 1.5 [95% CI 0.92-2.45]), respectively. LINKING EVIDENCE TO ACTION: Two large RCTs demonstrated that a preventive nurse-led care program can preserve daily functioning in the oldest-old population. Older people with few comorbidities and higher self-rated health had a higher likelihood of a positive outcome. Unraveling the characteristics associated with a successful response provides important information for further refining and targeting an intervention to obtain maximum effectiveness. More effort is needed to modify interventions for the oldest-old with multiple morbidities and low levels of education. PMID- 28632932 TI - Compliance Versus Innovation in Evidence-Based Nursing. PMID- 28632925 TI - A kallikrein-targeting RNA aptamer inhibits the intrinsic pathway of coagulation and reduces bradykinin release. AB - : Essentials Kallikrein amplifies contact activation and is a potential target for preventing thrombosis. We developed and characterized a kallikrein aptamer using convergent evolution and kinetic assays. Kall1-T4 prolongs intrinsic clotting time by inhibiting factor XIIa-mediated prekallikrein activation. Kall1 T4 decreases high-molecular-weight kininogen cleavage and bradykinin release. SUMMARY: Background Plasma kallikrein is a serine protease that plays an integral role in many biological processes, including coagulation, inflammation, and fibrinolysis. The main function of kallikrein in coagulation is the amplification of activated factor XII (FXIIa) production, which ultimately leads to thrombin generation and fibrin clot formation. Kallikrein is generated by FXIIa-mediated cleavage of the zymogen prekallikrein, which is usually complexed with the non enzymatic cofactor high molecular weight kininogen (HK). HK also serves as a substrate for kallikrein to generate the proinflammatory peptide bradykinin (BK). Interestingly, prekallikrein-deficient mice are protected from thrombotic events while retaining normal hemostatic capacity. Therefore, therapeutic targeting of kallikrein may provide a safer alternative to traditional anticoagulants with anti-inflammatory benefits. Objectives To isolate and characterize an RNA aptamer that binds to and inhibits plasma kallikrein, and to elucidate its mechanism of action. Methods and Results Using convergent Systematic Evolution of Ligands by Exponential Enrichment (SELEX), we isolated an RNA aptamer that targets kallikrein. This aptamer, Kall1-T4, specifically binds to both prekallikrein and kallikrein with similar subnanomolar binding affinities, and dose-dependently prolongs fibrin clot formation in an activated partial thromboplastin time (APTT) coagulation assay. In a purified in vitro system, Kall1-T4 inhibits the reciprocal activation of prekallikrein and FXII primarily by reducing the rate of FXIIa-mediated prekallikrein activation. Additionally, Kall1-T4 significantly reduces kallikrein-mediated HK cleavage and subsequent BK release. Conclusions We have isolated a specific and potent inhibitor of prekallikrein/kallikrein activity that serves as a powerful tool for further elucidating the role of kallikrein in thrombosis and inflammation. PMID- 28632936 TI - Peritumoral cuffing by T-cell tumor-infiltrating lymphocytes distinguishes HPV related oropharyngeal squamous cell carcinoma from oral cavity squamous cell carcinoma. AB - BACKGROUND: It is unclear why human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has improved clinical behavior compared to HPV negative HNSCC. We sought to better characterize the immune microenvironment of tongue cancers by examining the CD3 and CD8 TIL pattern in HPV-positive and HPV negative tumors. METHODS: Histologic sections from 40 oral tongue and oropharyngeal cases were analyzed (n=21 HPV DNA-positive, n=19 HPV DNA-negative). CD3 and CD8 T-cell immunostaining were performed on whole-slide sections to quantify tumor-infiltrating lymphocyte (TIL) density and assess its morphology. RESULTS: A subset of cases (HPV-positive) displayed a unique TIL pattern consisting of circumferential peritumoral population T cells, which was absent in the HPV-negative cases. The presence of peritumoral cuffing was strongly predictive of improved recurrence-free survival compared to cases that lacked this morphologic pattern of immune infiltrate. Four HPV-positive cases lacked the pattern, including two cases with disease recurrence. CONCLUSIONS: For the first time, we show an architectural pattern of immune infiltrate in HNSCC is seen exclusively in HPV-positive patients with improved recurrence-free survival and suggests an organized host immunological response contributes to disease control. PMID- 28632935 TI - Impact of preoperative calculation of nephron volume loss on future of partial nephrectomy techniques; planning a strategic roadmap for improving functional preservation and securing oncological safety. AB - OBJECTIVES: To assess the correlation of the resected and ischaemic volume (RAIV), which is a preoperatively calculated volume of nephron loss, with the amount of postoperative renal function (PRF) decline after minimally invasive partial nephrectomy (PN) in a multi-institutional dataset. PATIENTS AND METHODS: We identified 348 patients from March 2005 to December 2013 at six institutions. Data on all cases of laparoscopic (n = 85) and robot-assisted PN (n = 263) performed were retrospectively gathered. Univariable and multivariable linear regression analyses were used to identify the associations between various time points of PRF and the RAIV, as a continuous variable. RESULTS: The mean (sd) RAIV was 24.2 (29.2) cm3 . The mean preoperative estimated glomerular filtration rate (eGFR) and the eGFRs at postoperative day 1, 6 and 36 months after PN were 91.0 and 76.8, 80.2 and 87.7 mL/min/1.73 m2 , respectively. In multivariable linear regression analysis, the amount of decline in PRF at follow-up was significantly correlated with the RAIV (beta 0.261, 0.165, 0.260 at postoperative day 1, 6 and 36 months after PN, respectively). This study has the limitation of its retrospective nature. CONCLUSION: Preoperatively calculated RAIV significantly correlates with the amount of decline in PRF during long-term follow-up. The RAIV could lead our research to the level of prediction of the amount of PRF decline after PN and thus would be appropriate for assessing the technical advantages of emerging techniques. PMID- 28632937 TI - Synthesis, biological evaluation and docking studies of trans-stilbene methylthio derivatives as cytochromes P450 family 1 inhibitors. AB - Cytochromes P450 family 1 (CYP1) are responsible for the metabolism of procarcinogens, for example polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines. The inhibition of CYP1 activity is examined in terms of chemoprevention and cancer chemotherapy. We designed and synthesized a series of trans-stilbene derivatives possessing a combination of methoxy and methylthio functional groups attached in different positions to the trans-stilbene skeleton. We determined the effects of synthesized compounds on the activities of human recombinant CYP1A1, CYP1A2 and CYP1B1 and, to explain the variation of inhibitory potency of methoxystilbene derivatives and their methylthio analogues, we employed computational analysis. The compounds were docked to CYP1A1, CYP1A2 and CYP1B1 binding sites with the use of Accelrys Discovery Studio 4.0 by the CDOCKER procedure. For CYP1A2 and CYP1B1, values of scoring functions correlated well with inhibitory potency of stilbene derivatives. All compounds were relatively poor inhibitors of CYP1A2 that possess the most narrow and flat enzyme cavity among CYP1s. For the most active CYP1A1 inhibitor, 2-methoxy-4'-methylthio-trans stilbene, a high number of molecular interactions was observed, although the interaction energies were not distinctive. PMID- 28632934 TI - A prospective microbiome-wide association study of food sensitization and food allergy in early childhood. AB - BACKGROUND: Alterations in the intestinal microbiome are prospectively associated with the development of asthma; less is known regarding the role of microbiome alterations in food allergy development. METHODS: Intestinal microbiome samples were collected at age 3-6 months in children participating in the follow-up phase of an interventional trial of high-dose vitamin D given during pregnancy. At age 3, sensitization to foods (milk, egg, peanut, soy, wheat, walnut) was assessed. Food allergy was defined as caretaker report of healthcare provider-diagnosed allergy to the above foods prior to age 3 with evidence of IgE sensitization. Analysis was performed using Phyloseq and DESeq2; P-values were adjusted for multiple comparisons. RESULTS: Complete data were available for 225 children; there were 87 cases of food sensitization and 14 cases of food allergy. Microbial diversity measures did not differ between food sensitization and food allergy cases and controls. The genera Haemophilus (log2 fold change -2.15, P=.003), Dialister (log2 fold change -2.22, P=.009), Dorea (log2 fold change -1.65, P=.02), and Clostridium (log2 fold change -1.47, P=.002) were underrepresented among subjects with food sensitization. The genera Citrobacter (log2 fold change 3.41, P=.03), Oscillospira (log2 fold change -2.80, P=.03), Lactococcus (log2 fold change -3.19, P=.05), and Dorea (log2 fold change -3.00, P=.05) were underrepresented among subjects with food allergy. CONCLUSIONS: The temporal association between bacterial colonization and food sensitization and allergy suggests that the microbiome may have a causal role in the development of food allergy. Our findings have therapeutic implications for the prevention and treatment of food allergy. PMID- 28632939 TI - Acute skin trauma induces hyperemia, but superficial papillary nutritive perfusion remains unchanged. AB - OBJECTIVES: Superficial skin papillary capillaries with blood supply from a superficial vascular plexus and regulated by local metabolic needs supply oxygen and nutrients for epithelial cell proliferation. A deep vascular plexus regulated by autonomous nerves serves body thermoregulation. In healthy volunteers, we assessed circulatory effects of a standardized skin trauma by CAVM, DRS, and LDPM to assess the measuring depth of the three techniques and to describe the acute trauma effects on nutritive and thermoregulatory perfusion. METHODS: Volunteers (n=12) were examined at baseline and after induction of a 5.0 mm*1.0 mm incision on the forearm; 30 minutes after the trauma induction, data were collected at 0 1, 2-3 and 30 mm distances. RESULTS: LDPM showed hyperemia at 2-3 mm distance (35.8+/-15.2 a.u.), but not at 30 mm distance (7.4+/-2.5 a.u.) compared to baseline (8.8+/-1.8 a.u.). The DRS saturation increased at 2-3 mm (71.2+/-4.8%), but not at 30 mm (49.8+/-7.9%) compared to baseline (45.8+/-7.4%). Capillary density and flow velocities were unaffected at all distances. CONCLUSIONS: The results indicate that skin nutritive papillary capillary function can be assessed by CAVM and DRS, but not with LDPM because of its dependence of the deep plexus perfusion. PMID- 28632938 TI - MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK-mediated HER2 phosphorylation at Thr701. AB - Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2-positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase-dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin-dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK-mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor-induced Akt activation. PMID- 28632942 TI - The glycan-mediated mechanism on the interactions of gp120 with CD4 and antibody: Insights from molecular dynamics simulation. AB - N-linked glycans such as 234 and 276 gp120 glycans are vital components of HIV evasion from humoral immunity and important for HIV-1 neutralization of many broadly neutralizing antibodies (bNAbs). However, it is unknown the action mechanism of two glycans. To investigate the roles of the glycans on the interactions of gp120 with CD4 and antibody, molecular dynamic simulations based on gp120-CD4-8ANC195 complex with 234 and 276 gp120 glycans, 234 gp120 glycan, 276 gp120 glycan, and without glycan were performed. Our results reveal that 276 gp120 glycan can enhance gp120-CD4 and gp120-antibody interactions through the formation of hydrogen bonds of the glycan with CD4 and antibody and make the binding interface of gp120, CD4 and antibody stable; 234 gp120 glycan primarily reinforces gp120-antibody interactions and weakly affects gp120-CD4 interactions as it mainly lies between gp120 and antibody. The co-operating of two glycans can enhance gp120-CD4 and gp120-antibody associations. Through the structural analysis, it can be seen that 234 gp120 glycan leads to moving upward of two glycans and the variable region of heavy chain, which is favorable for the interactions of gp120 with CD4 and antibody. The information obtained in this study can provide the guidance for design vaccines and small molecule inhibitors. PMID- 28632944 TI - Deconstructing the landscape of fear in stable multi-species societies. AB - Animal distributions are influenced by variation in predation risk in space, which has been described as the "landscape of fear." Many studies suggest animals also reduce predation risk by eavesdropping on heterospecific alarm calls, allowing them to occupy otherwise risky habitats. One unexplored area of study is understanding how different species' alarms vary in quality, and how this variation is distributed in the landscape. We tested this phenomenon in a unique system of avian mixed species flocks in Amazonian rainforests: flock mates (eavesdropping species) strongly associate with alarm-calling antshrikes (genus Thamnomanes), which act as sentinel species. Up to 70 species join these flocks, presumably following antshrike behavioral cues. Since flocks in this region of the Amazon are exclusively led by a single antshrike species, this provides a unique natural system to compare differences in sentinel quality between flocks. We simulated predation threat by flying three species of live trained raptors (predators) towards flocks to compare sentinel probability to (1) produce alarm calls, and (2) encode information about magnitude and type of threat within such alarm calls. Our field experiments show significant differences in the probability of different sentinel species to produce alarm calls and distinguish predators. This variation may have important fitness consequences and shape the "landscape of fear" for eavesdropping species. PMID- 28632943 TI - Habitat coupling writ large: pelagic-derived materials fuel benthivorous macroalgal reef fishes in an upwelling zone. AB - Coastal marine upwelling famously supports elevated levels of pelagic biological production, but can also subsidize production in inshore habitats via pelagic benthic coupling. Consumers inhabiting macroalgae-dominated rocky reef habitats are often considered to be members of a food web fuelled by energy derived from benthic primary production; conversely, they may also be subsidized by materials transported from pelagic habitats. Here, we used stable isotopes (delta13 C, delta15 N) to examine the relative contribution of pelagic and benthic materials to an ecologically and economically important benthivorous fish assemblage inhabiting subtidal macroalgae-dominated reefs along ~1,000 km of the northern Chilean coast where coastal upwelling is active. Fish were isotopically most similar to the pelagic pathway and Bayesian mixing models indicated that production of benthivorous fish was dominated (median 98%, range 69-99%) by pelagic-derived C and N. Although the mechanism by which these materials enter the benthic food web remains unknown, our results clearly highlight the importance of pelagic-benthic coupling in the region. The scale of this subsidy has substantial implications for our basic understanding of ecosystem functioning and the management of nearshore habitats in northern Chile and other upwelling zones worldwide. PMID- 28632941 TI - Systematic review of carotid artery procedures and the volume-outcome relationship in Europe. AB - BACKGROUND: Hospitals that conduct more procedures on the carotid arteries may achieve better outcomes. In the context of ongoing reconfiguration of UK vascular services, this systematic review was conducted to evaluate the relationship between the volume of carotid procedures and outcomes, including mortality and stroke. METHODS: Searches of electronic databases identified studies that reported the effect of hospital or clinician volume on outcomes. Reference and citation searches were also performed. Inclusion was restricted to European populations on the basis that the model of healthcare delivery is similar across Europe, but differs from that in the USA and elsewhere. Analyses of hospital and clinician volume, and carotid endarterectomy (CEA) and carotid artery stenting (CAS) were conducted separately. RESULTS: Eleven eligible studies were identified (233 411 participants), five from the UK, two from Sweden, one each from Germany, Finland and Italy, and a combined German, Austrian and Swiss population. All studies were observational. Two large studies (179 736 patients) suggested an inverse relationship between hospital volume and mortality (number needed to treat (NNT) as low as 165), and combined mortality and stroke (NNT as low as 93), following CEA. The evidence was less clear for CAS; multiple analyses in three studies did not identify convincing evidence of an association. Limited data are available on the relationship between clinician volume and outcome in CAS; in CEA, an inverse relationship was identified by two of three small studies. CONCLUSION: The evidence from the largest and highest-quality studies included in this review support the centralization of CEA. PMID- 28632940 TI - Characterization of the I4399M variant of apolipoprotein(a): implications for altered prothrombotic properties of lipoprotein(a). AB - : Essentials Elevated lipoproteinp(a) is an independent and causal risk factor for atherothrombotic diseases. rs3798220 (Ile/Met substitution in apo(a) protease like domain) is associated with disease risk. Recombinant I4399M apo(a) altered clot structure to accelerate coagulation/delay fibrinolysis. Evidence was found for increased solvent exposure and oxidation of Met residue. SUMMARY: Background Lipoprotein(a) (Lp[a]) is a causal risk factor for a variety of cardiovascular diseases. Apolipoprotein(a) (apo[a]), the distinguishing component of Lp(a), is homologous with plasminogen, suggesting that Lp(a) can interfere with the normal fibrinolytic functions of plasminogen. This has implications for the persistence of fibrin clots in the vasculature and hence for atherothrombotic diseases. A single-nucleotide polymorphism (SNP) (rs3798220) in the gene encoding apo(a) has been reported that results in an Ile->Met substitution in the protease-like domain (I4399M variant). In population studies, the I4399M variant has been correlated with elevated plasma Lp(a) levels and higher coronary heart disease risk, and carriers of the SNP had increased cardiovascular benefit from aspirin therapy. In vitro studies suggested an antifibrinolytic role for Lp(a) containing this variant. Objectives We performed a series of experiments to assess the effect of the Ile->Met substitution on fibrin clot formation and lysis, and on the architecture of the clots. Results We found that the Met variant decreased coagulation time and increased fibrin clot lysis time as compared with wild-type apo(a). Furthermore, we observed that the presence of the Met variant significantly increased fibrin fiber width in plasma clots formed ex vivo, while having no effect on fiber density. Mass spectrometry analysis of a recombinant apo(a) species containing the Met variant revealed sulfoxide modification of the Met residue. Conclusions Our data suggest that the I4399M variant differs structurally from wild-type apo(a), which may underlie key differences related to its effects on fibrin clot architecture and fibrinolysis. PMID- 28632948 TI - Nodular cutaneous amyloidoma of the extremity secondary to chronic granulomatous inflammation in setting of sarcoidosis. AB - Soft tissue amyloidoma is a rare condition that presents primarily in the abdomen and/or mediastinum and more uncommonly on the extremities. Soft tissue amyloidomas on the extremities have been associated with chronic inflammation, particularly when accompanied by AA-type amyloid deposition as seen in local trauma, surgery, hypertension and diabetes. To our knowledge, this is the first reported case of nodular cutaneous amyloidoma in the setting of systemic and cutaneous sarcoidosis. A 65-year-old woman presented with an asymptomatic subcutaneous nodule above her left lateral malleolus. Histopathology of the lesion showed an inconspicuous epidermis with amorphous eosinophilic material deposited in masses within the entire dermis. Congo red and crystal violet stains were positive. Based on the clinical and pathologic findings she was diagnosed with nodular cutaneous amyloidoma. We hypothesize that this process developed secondary to the chronic granulomatous inflammation of sarcoidosis. PMID- 28632945 TI - Developing multidisciplinary clinics for neuromuscular care and research. AB - Multidisciplinary care is considered the standard of care for both adult and pediatric neuromuscular disorders and has been associated with improved quality of life, resource utilization, and health outcomes. Multidisciplinary care is delivered in multidisciplinary clinics that coordinate care across multiple specialties by reducing travel burden and streamlining care. In addition, the multidisciplinary care setting facilitates the integration of clinical research, patient advocacy, and care innovation (e.g., telehealth). Yet, multidisciplinary care requires substantial commitment of staff time and resources. We calculated personnel costs in our ALS clinic in 2015 and found an average cost per patient visit of $580, of which only 45% was covered by insurance reimbursement. In this review, we will describe classic and emerging concepts in multidisciplinary care models for adult and pediatric neuromuscular disease. We will then explore the financial impact of multidisciplinary care with emphasis on sustainability and metrics to demonstrate quality and value. Muscle Nerve 56: 848-858, 2017. PMID- 28632946 TI - Emerging Biomarkers of Illness Severity: Urinary Metabolites Associated with Sepsis and Necrotizing Methicillin-Resistant Staphylococcus aureus Pneumonia. AB - Our objective was to illustrate the potential of metabolomics to identify novel biomarkers of illness severity in a child with fatal necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA). We present a case report with two control groups and a metabolomics analysis: an infant with fatal MRSA pneumonia, four children with influenza pneumonia (pneumonia control group), and seven healthy children with no known infections (healthy control group). Urine samples were collected from all children. Metabolites were identified and quantified using 1 H-nuclear magnetic resonance spectrometry. Normalized metabolite concentration data from children with influenza pneumonia and healthy controls were compared by using an unpaired Student t test. To identify differentiating metabolites of MRSA pneumonia, the fold change of each metabolite was calculated by dividing each urine metabolite concentration of the patient with fatal MRSA pneumonia by the median urine concentration values of the same metabolite of the patients with influenza pneumonia and healthy controls, respectively. MetScape (http://metscape.ncibi.org/), a bioinformatics tool, was used for data visualization and interpretation. Urine metabolite concentrations previously identified as associated with sepsis in children (e.g., 3 hydroxybutyrate, carnitine, and creatinine) were higher in the patient with fatal MRSA pneumonia compared with those of patients with influenza pneumonia and healthy controls. The concentrations of additional metabolites-acetone, acetoacetate, choline, fumarate, glucose, and 3-aminoisobutyrate-were more than 25-fold higher in the patient with MRSA pneumonia than those of patients with influenza pneumonia and healthy controls. These metabolic changes in the urine preceded the clinical severe sepsis phenotype, suggesting that detection of the extent of metabolic disruption can aid in the early identification of a sepsis phenotype in advance of the clinical diagnosis. These data also support the utility of metabolomics for the development of clinical assays to identify patients with pediatric pneumonia at high risk for deterioration. PMID- 28632954 TI - Pharmacology (2017/028). PMID- 28632950 TI - Fibroblastic connective tissue nevus: Clinicopathological and immunohistochemical study of 14 cases. AB - BACKGROUND: We present herein a series of 14 lesions showing overlapping features with the newly defined benign cutaneous mesenchymal neoplasm labeled as fibroblastic connective tissue nevus (FCTN). METHODS AND RESULTS: Total of 8 patients were male and 5 were female, ranging in age from 1 to 56 years. Lesions appeared as isolated nodules or plaques on the trunk (7 cases), the limbs (4 cases) and the neck (2 cases). Histologically, all cases were composed of bundles of bland spindle cells of fibroblastic/myofibroblastic lineage irregularly branching within the reticular dermis and along fibrous septa in the subcutis. Adnexal structures and dermal adipocytes were entrapped by the fascicles, the epidermis was often papillomatous and elastic fibers were decreased and fragmented. Expression of CD34 and ASMA was found in 8 and 7 cases, respectively. Follow-up was available for 7 patients (mean follow-up, 5 years; range, 1-10 years). None of the cases metastasized or recurred, even when incompletely excised. CONCLUSION: The differential diagnosis of FCTN is broad and includes hypertrophic scar, dermatofibroma, dermatomyofibroma, pilar leiomyoma, plaque stage DFSP, CD34-positive plaque-like dermal fibroma, fibroblastic-predominant plexiform fibrohistiocytic tumor, lipofibromatosis, superficial desmoid fibromatosis and fibrous hamartoma of infancy, of which it represents probably the monophasic variant. PMID- 28632955 TI - The Hallmarks of Midwifery Connect This Diverse Pharmacology Continuing Education Theme Issue. PMID- 28632957 TI - Iridium(I)-Catalyzed Intramolecular Hydrocarbonation of Alkenes: Efficient Access to Cyclic Systems Bearing Quaternary Stereocenters. AB - A catalytic, versatile and atom-economical C-H functionalization process that provides a wide variety of cyclic systems featuring methyl-substituted quaternary stereocenters is described. The method relies on the use of a cationic IrI bisphosphine catalyst, which promotes a carboxamide-assisted activation of an olefinic C(sp2 )-H bond followed by exo-cyclization to a tethered 1,1 disubstituted alkene. The extension of the method to aromatic and heteroaromatic C-H bonds, as well as developments on an enantioselective variant, are also described. PMID- 28632947 TI - Pimozide reduces toxic forms of tau in TauC3 mice via 5' adenosine monophosphate activated protein kinase-mediated autophagy. AB - In neurodegenerative diseases like Alzheimer's disease (AD), tau is hyperphosphorylated and forms aggregates and neurofibrillary tangles in affected neurons. Autophagy is critical to clear the aggregates of disease-associated proteins and is often altered in patients and animal models of AD. Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD. However, pharmacological strategies to increase autophagy by targeting mTOR inhibition cause various side effects. Therefore, autophagy activation mediated by non-mTOR pathways is a new option for autophagy-based AD therapy. Here, we report that pimozide activates autophagy to rescue tau pathology in an AD model. Pimozide increased autophagic flux through the activation of the AMPK-Unc-51 like autophagy activating kinase 1 (ULK1) axis, but not of mTOR, in neuronal cells, and this function was independent of dopamine D2 receptor inhibition. Pimozide reduced levels of abnormally phosphorylated tau aggregates in neuronal cells. Further, daily intraperitoneal (i.p.) treatment of pimozide led to a recovery from memory deficits of TauC3 mice expressing a caspase-cleaved form of tau. In the brains of these mice, we found increased phosphorylation of AMPK1 and ULK1, and reduced levels of the soluble oligomers and NP40-insoluble aggregates of abnormally phosphorylated tau. Together, these results suggest that pimozide rescues memory impairments in TauC3 mice and reduces tau aggregates by increasing autophagic flux through the mTOR-independent AMPK-ULK1 axis. PMID- 28632952 TI - Injecting drug use in low and middle-income countries: Opportunities to improve care and prevent harm. AB - Inadequate response to injecting drug use (IDU) is a significant problem the world over. Low levels of funding, political inaction, poor levels of health service coverage, high prevalence and incidence of IDU-related blood-borne viruses (BBVs) and ongoing stigmatization/marginalization affect people who inject drugs (PWID) regardless of the income status of the country they reside in. These barriers and system failings are, however, exacerbated in low and middle-income countries (LMICs), meaning that the potential consequences of inaction are more pressing. In this narrative review, we describe the levels of IDU and IDU-specific BBV prevalence in LMICs; levels of harm reduction implementation; the consequences of late or insufficient response, the shortcomings of data collection and dissemination; and the barriers to effective LMIC harm reduction implementation. We also exemplify cases where IDU-related harms and BBV epidemics have been successfully curtailed in LMICs, showing that effective response, despite the barriers, is possible. In conclusion, we suggest four key priorities on the basis of the review: confirming the presence or absence of IDU in LMICs, improving the collection and dissemination of national IDU-specific data, increasing the level of harm reduction programme implementation in LMICs, and increasing both national and international advocacy for PWID and attendant public health interventions. PMID- 28632953 TI - Updates to the US Food and Drug Administration Regulations for Mifepristone: Implications for Clinical Practice and Access to Abortion. AB - This article provides information on recent changes in the US Food and Drug Administration (FDA) labeling and safety regulations for mifepristone (Mifeprex). The revised label now permits midwives, advanced practice nurses, and physician assistants to order and prescribe mifepristone, eliminating the requirement for physician supervision. The updated label also extends eligibility for use from 49 to 70 days' gestation and decreases the number of required visits from 3 to 2. The recommended dose of mifepristone has been reduced, and the dosage, timing, and route of administration for misoprostol have also been changed to reflect current research. These changes have implications for clinical practice and may lead to expanded access for women in the United States. PMID- 28632949 TI - Potential impact of nonavalent HPV vaccine in the prevention of high-grade cervical lesions and cervical cancer in Portugal. AB - OBJECTIVE: To estimate the potential impact of the nonavalent HPV vaccine for high-grade cervical lesions and invasive cervical cancer (ICC) in Portugal. METHODS: The present secondary analysis used data collected in the CLEOPATRE II study on the prevalence of HPV 6/11/16/18/31/33/45/52/58 among female patients aged 20-88 years. The prevalence of HPV types in patients with cervical intraepithelial neoplasia (CIN) grades 2/3 and ICC was examined. RESULTS: Data were included from 582 patients. There were 177, 341, and 64 patients with CIN2, CIN3, and ICC, respectively, and 169 (95.5%), 339 (99.4%), and 62 (96.9) of them had HPV infections. Of patients with HPV infections, HPV 16, 18, 31, 33, 45, 52, and 58 infections were identified in 150 (88.8%), 329 (97.1%), and 60 (96.8%) patients with CIN2, CIN3, and ICC, respectively. HPV genotypes 6, 11, 16, 18, 31, 33, 45, 52, and 58 were identified in 540 (94.7%) of the patients with HPV infections. CONCLUSION: The addition of the five HPV genotypes included in the nonavalent HPV vaccine (HPV 31/33/45/52/58) could result in the new HPV vaccine preventing 94.7% of CIN2/3 and ICC occurrences. PMID- 28632951 TI - Improving the quality of maternity services in Uganda through accelerated implementation of essential interventions by healthcare professional associations. AB - OBJECTIVE: To assess whether the implementation of a package of activities through the joint action of the three international healthcare professionals associations (HCPAs) increased the use of intrapartum and postnatal essential interventions (EIs) in two hospitals in Uganda. METHODS: A non-controlled before and-after study was undertaken to evaluate the effect of a package of activities designed to change practice relating to nine EIs among providers. Coverage of the EIs was measured in a 3-month pre-implementation period and a 3-month post implementation period in 2014. Data were obtained for women older than 18 years who delivered vaginally or by cesarean. RESULTS: Overall, 4816 women were included. Level of use remained high for EIs used widely at baseline. Some EIs that had low use at baseline did not show improvement after the implementation. Promotion of breastfeeding showed a significant improvement in the Kampala hospital, from 8.5% (8/94) to 25.6% (30/117; P=0.001), whereas promotion of hygiene in cord care improved at the Mbarara hospital, from 0.1% (2/1592) to 46.0% (622/1351; P<0.001). CONCLUSION: These exploratory results show that a package delivered through the joint work of the three HCPAs was feasible to implement along with rigorous data collection. Although the data show disparities, trends suggest that improvement could be achieved. PMID- 28632956 TI - Anti-inflammatory potential of a heat-killed Lactobacillus strain isolated from Kimchi on house dust mite-induced atopic dermatitis in NC/Nga mice. AB - AIMS: Atopic dermatitis (AD) is an allergic skin disease driven by the Th2-prone immune response. Therefore, a fundamental approach to restoring the Th1/Th2 balance is needed to treat AD. METHODS AND RESULTS: Eighteen different Lactobacillus strains isolated from Kimchi were screened to identify those that stimulated immune cells to secret Th1-type or Th2-type cytokines. Lactobacillus brevis NS1401 induced the greatest IFN-gamma and IL-12 secretion and the least IL 4 production among the tested Lactobacillus strains. Furthermore, oral administration of heat-killed NS1401 ameliorated the symptoms of dust mite induced AD in NC/Nga mice by decreasing the serum IgE level and reducing the number of mast cells and eosinophils in lesions. Also, the size and number of cells in the draining lymph nodes of NS1401-administered mice were significantly reduced. In agreement with these results, secretion of a Th1-type cytokine (IFN gamma) and allergen-specific IgG2a were increased, whereas secretion of Th2-type cytokines (IL-4, IL-5, and IL-10) and allergen-specific IgG1 were decreased upon administration of NS1401 in mice. CONCLUSIONS: Lactobacillus brevis NS1401 alleviates the symptoms of AD by restoring the Th1/Th2 balance through enhancing Th1-prone immunity. SIGNIFICANCE AND IMPACT OF THE STUDY: The immunomodulatory function of L. brevis NS1401 may provide effective new therapeutics against AD. PMID- 28632958 TI - Decreased portal vein velocity is predictive of the development of portal vein thrombosis: A matched case-control study. AB - BACKGROUND & AIMS: Portal vein thrombosis (PVT) in cirrhosis may lead to hepatic decompensation and increased mortality. We aimed to investigate if decreased portal vein (PV) velocity is associated with future PVT. METHODS: Data on adult patients with cirrhosis and PVT between January 1, 2005 and July 30, 2015 were obtained. Cases with PVT were matched by age, gender and Model for End-stage Liver Disease (MELD) score to corresponding controls without PVT. Cox proportional hazards models, receiver operator curves and Kaplan Meier curves were constructed. RESULTS: One hundred subjects (50 matched pairs) with mean age 53.8+/-13.1 y and MELD score 14.9+/-5.5 were included in our analysis. Sixty-four percent were male and 76% were Child-Turcotte-Pugh Class A or B. Baseline characteristics (prior to development of PVT) were similar, except for baseline PV velocity (16.9 cm/s, 95% CI 13.9-20.0 PVT vs 25.0, 95% CI 21.8-28.8 no PVT, P<.001). 30 PVT subjects had PV velocity <15 cm/s compared to five without PVT (P<.001). On adjusted multivariable analysis, PV velocity was the strongest independent risk factor predicting PVT development (HR 0.86, 95% CI 0.80-0.93). The predictive value for PVT development was greatest for flow <15 cm/s (c statistic 0.77). PV velocity <15 cm/s had a highly significant association with future PVT (HR 6.00, 95% CI 2.20-16.40, P=<.001). CONCLUSIONS: Decreased PV velocity is associated with increased risk of future PVT. Patients with cirrhosis and decreased PV velocity are a high-risk subgroup that warrants further investigation with prospective study. PMID- 28632959 TI - Defect-Based Modulation of Optoelectronic Properties for Biofunctionalized Hexagonal Boron Nitride Nanosheets. AB - Defect engineering potentially allows for dramatic tuning of the optoelectronic properties of two-dimensional materials. With the help of DFT calculations, a systematic study of DNA nucleobases adsorbed on hexagonal boron-nitride nanoflakes (h-BNNFs) with boron (VB ) and nitrogen (VN ) monovacancies is presented. The presence of VN and VB defects increases the binding strength of nucleobases by 9 and 34 kcal mol-1 , respectively (h-BNNF-VB >h-BNNF-VN >h-BNNF). A more negative electrostatic potential at the VB site makes the h-BNNF-VB surface more reactive than that of h-BNNF-VN , enabling H-bonding interactions with nucleobases. This binding energy difference affects the recovery time-a significant factor for developing DNA biosensors-of the surfaces in the order h BNNF-VB >h-BNNF-VN >h-BNNF. The presence of VB and VN defect sites increases the electrical conductivity of the h-BNNF surface, VN defects being more favorable than VB sites. The blueshift of absorption peaks of the h-BNNF-VB -nucleobase complexes, in contrast to the redshift observed for h-BNNF-VN -nucleobase complexes, is attributed to their observed differences in binding energies, the HOMO-LUMO energy gap and other optoelectronic properties. Time-dependent DFT calculations reveal that the monovacant boron-nitride-sheet-nucleobase composites absorb visible light in the range 300-800 nm, thus making them suitable for light emitting devices and sensing nucleobases in the visible region. PMID- 28632960 TI - SNAP-Tag-Based Subcellular Protein Labeling and Fluorescent Imaging with Naphthalimides. AB - Genetically encoded technologies provide methods for the specific labeling and imaging of proteins, which is essential to understand the subcellular localization of these proteins and their function. Herein, we employed naphthalimide, an efficient two-photon fluorophore, to develop O6 -benzylguanine (BG) derivatives for specific labeling of subcellular proteins and fluorescent imaging through the SNAP-tag. Three naphthalimide-BG derivatives, TNI-BG, QNI-BG, and ONI-BG, were conveniently synthesized through modular "click chemistry" in high yields. All of them showed high labeling efficiency with SNAP-tag in solution (~1-2*103 s-1 m-1 ) and in bacteria. Among them, ONI-BG showed high specificity to diffused, histone H2B and mitochondria COX8A targeted SNAP-tag in mammalian cells. The protein-labeled naphthalimides exhibited high two-photon absorption cross-sections, which indicated their potential application in protein specific two-photon fluorescent imaging, such as two-photon fluorescent lifetime imaging and two-photon multicolor imaging. Therefore, ONI-BG is a versatile tool that can be used to track subcellular proteins through multiple fluorescent techniques. PMID- 28632961 TI - Increased neural response to social rejection in major depression. AB - BACKGROUND: Being a part of community is critical for survival and individuals with major depressive disorder (MDD) have a greater sensitivity to interpersonal stress that makes them vulnerable to future episodes. Social rejection is a critical risk factor for depression and it is said to increase interpersonal stress and thereby impairing social functioning. It is therefore critical to understand the neural correlates of social rejection in MDD. METHODS: To this end, we scanned 15 medicated MDD and 17 healthy individuals during a modified cyberball passing game, where participants were exposed to increasing levels of social exclusion. Neural responses to increasing social exclusion were investigated and compared between groups. RESULTS: We showed that compared to controls, MDD individuals exhibited greater amygdala, insula, and ventrolateral prefrontal cortex activation to increasing social exclusion and this correlated negatively with hedonic tone and self-esteem scores across all participants. CONCLUSIONS: These preliminary results support the hypothesis that depression is associated with hyperactive response to social rejection. These findings highlight the importance of studying social interactions in depression, as they often lead to social withdrawal and isolation. PMID- 28632962 TI - A Novel Minimally Invasive Wireless Technology for Neuromodulation via Percutaneous Intercostal Nerve Stimulation for Post-Herpetic Neuralgia: A Case Report with Short-Term Follow-up. AB - BACKGROUND: Peripheral nerve stimulation of primary afferent neurons provides control of localized chronic pain. This technique applies permanent electrical stimulation at the target area via a minimally invasive, subcutaneous placement of an electrode. OBJECTIVE: To assess the analgesic effects of minimally invasive wireless neuromodulation in the treatment of chronic intractable pain secondary to post-herpetic neuralgia. CASE SUMMARY: A 78-year-old man presented with severe intractable post-herpetic neuralgic pain. He was known to have non-Hodgkin's lymphoma under remission following treatment with chemotherapy and stem cell transplantation, twice. He also developed steroid-induced diabetes mellitus during this treatment. In view of his compromised immune status, he was deemed a suitable candidate for our minimally invasive neuromodulation technology. Two subcutaneous electrodes were placed on the right-hand side of the trunk, 10 cm medial and parallel to the spinous process at the level of T7-T8 under fluoroscopic guidance along the T7 intercostal nerve. The external transmitter was worn with a belt over a single layer of clothing and used to transmit power to the stimulator. The entire procedure required only a small incision for the introduction of the electrode placement. RESULTS: After an uneventful procedure, the pain score decreased from 8 to 3, with a reduction in pain medication. The EuroQol Five Dimensions Questionnaire scores were 0.102 before the trial, 0.630 at 1 month, and 0.576 at 3 months. CONCLUSIONS: Subcutaneous placement of electrodes with our minimally invasive technique and wireless neuromodulation technology was safe and effective. Significant improvements in pain relief ensued, and no further adverse events had been reported at the end of 3 months' follow-up. PMID- 28632963 TI - Metal-Ion Induced In Situ Ligand Oxidation for Self-Assembled Clusters: from Bis(5-(2-pyridine-2-yl)-1,2,4-triazole-3-yl)methane to Alcohol or Ketone. AB - Hydrothermal reactions of metal nitrates and ligand bis(5-(pyridine-2-yl)-1,2,4 triazol-3-yl)methane (H2 L1 ) gave three cluster compounds, {Cr2 }, {Zn12 } and {Fe8 }. Notably, methylene group of H2 L1 was in situ oxidized either to hydroxymethylated (L2 -O)3- in the metallo-ring {Zn12 } or to a rigid carbonylated (L3 =O)2- in the screw-type {Fe8 }. In light of comparative experimental results, NO3- was deduced to be of a catalytic role in the ligand oxidation. Metal ion could be regarded as an "induced" tool for clusters generation in self-assembly process. PMID- 28632964 TI - Long-term follow-up of patients triply infected with HIV and hepatitis B and C viruses in a comprehensive hospital in central China. PMID- 28632966 TI - Characterizing Alzheimer's disease through metabolomics and investigating anti Alzheimer's disease effects of natural products. AB - Alzheimer's disease (AD) is the most common cause of dementia in elderly people and is among the greatest healthcare challenges of the 21st century. However, the etiology and pathogenesis of AD remain poorly understood, and no curative treatments are available to slow down or stop the degenerative effects of AD. As a high-throughput approach, metabolomics is gaining significant attention in AD research, because it has a powerful potential to discover novel biomarkers, unravel new therapeutic targets for AD, and identify perturbed metabolic pathways involved in AD progression. Here, we systematically review metabolomics with regard to its recent advances and applications in the identification of potential biomarkers for early AD diagnosis and pathogenesis research. In addition, we illustrate the developments in metabolomics as an effective tool for understanding the anti-AD mechanisms of natural products. We believe that the insights from these advances can narrow the gap between metabolomics research and clinical applications of laboratory findings. Moreover, we discuss some limitations and perspectives of biomarker identification in metabolomics. PMID- 28632965 TI - Frequent COL4 mutations in familial microhematuria accompanied by later-onset Alport nephropathy due to focal segmental glomerulosclerosis. AB - Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen IV glomerulopathies, frequently averting the need for invasive renal biopsies. PMID- 28632967 TI - Prevalence and orthopedic management of foot and ankle deformities in Charcot Marie-Tooth disease. AB - INTRODUCTION: Foot deformities are frequent complications in Charcot-Marie-Tooth disease (CMT) patients, often requiring orthopedic surgery. However, there are no prospective, randomized studies on surgical management, and there is variation in the approaches among centers both within and between countries. METHODS: In this study we assessed the frequency of foot deformities and surgery among patients recruited into the Inherited Neuropathies Consortium (INC). We also designed a survey addressed to orthopedic surgeons at INC centers to determine whether surgical approaches to orthopedic complications in CMT are variable. RESULTS: Foot deformities were reported in 71% of CMT patients; 30% of the patients had surgery. Survey questions were answered by 16 surgeons working in different specialized centers. Most of the respondents were foot and ankle surgeons. There was marked variation in surgical management. DISCUSSION: Our findings confirm that the approaches to orthopedic management of CMT are varied. We identify areas that require further research. Muscle Nerve 57: 255-259, 2018. PMID- 28632968 TI - Perspective on Precision Medicine in Oncology. AB - The topic of precision medicine is increasingly more prevalent in the general medical literature, with oncology research leading the way. Many factors, such as availability of targeted drugs, advances in laboratory science, and improved information systems, converged to make precision medicine research possible on a large scale at the National Cancer Institute. The resultant big data will spur new kinds of research in the decades to come, but until then, all clinicians are challenged to make sense of an overabundance of information when managing individual patients. PMID- 28632969 TI - Vascular endothelial growth factor is neuroprotective against ischemic brain injury by inhibiting scavenger receptor A expression on microglia. AB - Vascular endothelial growth factor (VEGF) is a secreted mitogen associated with angiogenesis. VEGF has long been thought to be a potent neurotrophic factor for the survival of spinal cord neurons. However, the role of VEGF in the regulation of ischemic brain injury remains unclear. In this study, rats were subjected to MCAO (middle cerebral artery occlusion) followed by intraperitoneal injection of VEGF165 (10 mg/kg) immediately after surgery and once daily until the day 10. The expression of target genes was assayed using qPCR, western blot and immunofluorescence to investigate the role of VEGF165 in regulating ischemic brain injury. We found that VEGF165 significantly inhibited MCAO-induced up regulation of Scavenger receptor class A (SR-A) on microglia in a VEGFR1 dependent manner. VEGF165 inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines IL-1beta, tumor necrosis factor alpha (TNF-alpha) and iNOS in microglia. More importantly, the role of VEGF165 in inhibiting neuroinflammation is partially abolished by SR-A over-expression. SR-A further reduced the protective effect of VEGF165 in ischemic brain injury. These data suggest that VEGF165 suppresses neuroinflammation and ischemic brain injury by inhibiting SR-A expression, thus offering a new target for prevention of ischemic brain injury. PMID- 28632970 TI - Hexaazatriphenylene-Based Hydrogen-Bonded Organic Framework with Permanent Porosity and Single-Crystallinity. AB - Hydrogen-bonded organic frameworks (HOFs) have drawn unprecedented interest because of their high crystallinity as well as facile process for construction, deconstruction, and reassembly arising from reversible bond formation dissociation. However, structural fragility and low stability frequently prevent formation of robust HOFs with permanent porosity. Here, we report that hexakis(4 carboxyphenyl)-hexaazatriphenylene (CPHAT) forms three dimensionally networked H bonded framework CPHAT-1. Interestingly, the activated framework CPHAT-1 a retains not only permanent porosity but single-crystallinity, enabling precise structural characterization and property evaluation on a single crystal. Moreover, CPHAT-1 a retains its framework up to 339 degrees C or in hot water and in acidic aqueous solution. These results clearly show that even a simple H bonding motif can be applied for the construction of robust HOFs, which creates a pathway to establish a new class of porous organic frameworks. We also characterize its uptake of gases and I2 , in addition to a detailed photophysical study (spectroscopy and dynamics of proton and charge transfers) of its unit in solution, and of its single crystal under fluorescence microscopy, in which we observed a marked strong anistropy and narrow distribution. The results bring new findings to the area of HOFs and their possible applications in science and technology. PMID- 28632971 TI - Maternal depression and bullying victimization among adolescents: Results from the 2004 Pelotas cohort study. AB - BACKGROUND: Maternal depression impacts on several detrimental outcomes during a child's life course, and could increase their risk of victimization. This longitudinal study examined the association between antenatal maternal depression, postnatal trajectories, and current maternal depression and offspring bullying victimization at 11 years. METHODS: We included 3,441 11-year-old adolescents from the 2004 Pelotas Cohort Study. Antenatal maternal depression, postnatal trajectories, and current maternal depression data were assessed during the follow-up waves. Bullying victimization was self-reported by the adolescents. We used ordinal logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (CIs), for the association between maternal depression and offspring bullying victimization. RESULTS: The most prevalent type of bullying was verbal victimization (37.9%). We observed a positive association between antenatal maternal depression, postnatal trajectories, and current maternal depression and physical bullying victimization. Maternal mood symptoms during pregnancy were associated with physical (OR = 1.30, 95%CI = 1.11-1.53), verbal (OR = 1.29, 95%CI = 1.12-1.49), and any victimization (OR = 1.22, 95%CI = 1.05 1.41). Severe current maternal depression was associated with physical (OR = 1.34, 95%CI = 1.10-1.62), social manipulation (OR = 1.29, 95%CI = 1.08-1.53), attacks on property (OR = 1.30, 95%CI = 1.08-1.57) and any victimization (OR = 1.32, 95%CI = 1.12-1.56). Regarding maternal depression trajectories, the "chronic-high" group was associated with higher risk of social manipulation, attacks on property and any victimization, than the "low" group. CONCLUSIONS: Our results strengthen the evidence of association between maternal depression and offspring bullying victimization, and physical victimization appears to be the main component. Further studies are warranted to confirm our findings and to elucidate the theoretical pathways for this longitudinal association. PMID- 28632972 TI - Nonrandomised interventional study showed that early aggressive nutrition was effective in reducing postnatal growth restriction in preterm infants. AB - AIM: This study evaluated whether an early aggressive nutrition (EAN) strategy could limit extrauterine growth restriction (EUGR) in a cohort of preterm infants. METHODS: This prospective nonrandomised interventional study was carried out in the neonatal intensive care unit of an Italian hospital from January 2013 to December 2015. The prevalence of EUGR was assessed in 100 infants with a gestational age of <=34 weeks, 50 after the introduction of an EAN regimen in October 2014 and 50 before. RESULTS: The prevalence of EUGR at discharge was significantly lower after the introduction of EAN than before for weight (34% vs. 66%), head circumference (22% vs. 42%) and length at discharge (20% vs. 48%). The Z-scores for all measurements were significantly higher after the introduction of EAN. In the EAN group, weight velocity was significantly higher and maximum weight loss and negative changes in the Z-scores from birth to discharge for weight were lower than in the pre-intervention controls. In extremely low birthweight subjects, the weight Z-score and weight velocity were significantly higher in the EAN group than the control group. CONCLUSION: The use of EAN at a very early age reduced EUGR and improved auxological outcomes in preterm infants. PMID- 28632974 TI - HCV-Positive Donor Organs in Solid Organ Transplantation: "Mind the Gap!" PMID- 28632973 TI - Molecular modeling study on the tubulin-binding modes of epothilone derivatives: Insight into the structural basis for epothilones activity. AB - Molecular dynamics (MD) simulations were employed to study the tubulin-binding modes of 20 epothilone derivatives spanning a wide range of antitumor activity. Trajectory analysis revealed that active ligands shared a common region of association and similar binding poses compared to the high-resolution crystal structure of the tubulin complex with epothilone A, the stathmin-like protein RB3, and tubulin tyrosine ligase (PDB code 4I50). Conformational analysis of epothilones in aqueous solution and tubulin-bound states indicated that the bound conformations of active species can be found to a significant extent within the ensemble of conformers available in aqueous solution. On the other hand, inactive derivatives were unable to adopt bound-like conformations in aqueous solution, thus requiring an extensive conformational pre-organization to accomplish an effective interaction with the tubulin receptor. Additionally, MD results revealed that epothilone binding-induced structuring of the M-loop and local flexibility changes in protein regions involved in interdimeric contacts that are relevant for microtubule stabilization. These results provide novel, valuable structural information to increase understanding about the underlying molecular aspects of epothilones activity and support further work on the search for new active tubulin-binding agents. PMID- 28632977 TI - 32nd Annual BACCN Conference. PMID- 28632975 TI - Effects of Messages Delivered by Mobile Phone on Increasing Compliance With Shoulder Exercises Among Patients With a Frozen Shoulder. AB - PURPOSE: The aim of this study was to examine the effects of reminders, encouragement, and educational messages delivered by mobile phone on shoulder exercise compliance and improvements in shoulder function among patients with a frozen shoulder. DESIGN AND METHODS: A randomized controlled trial design was used. A convenience sample of patients with a frozen shoulder in an orthopedic outpatient clinic was recruited. All participants were instructed on how to do shoulder exercises and were provided with a printed pamphlet about shoulder exercises. Then, the intervention group received reminders, encouragement, and educational messages by mobile phone daily for the next 2 weeks, while the comparison group did not. FINDINGS: The intervention group had higher compliance with shoulder exercises than did the comparison group (t = 2.263, p = .03) and had significant improvements in shoulder forward flexion (F = 12.067, p = .001), external rotation (F = 13.61, p = .001), and internal rotation (F = 5.903, p = .018) compared to those in the comparison group after the 2-week intervention. CONCLUSIONS: The text messages significantly increased patient compliance with shoulder exercises and thus improved patients' shoulder range of motion. CLINICAL RELEVANCE: Hospital or clinics can send appropriate messages to patients via text message platforms in order to remind and encourage them to do shoulder exercises. PMID- 28632976 TI - Succession planning: a case for revisiting the process in critical care. PMID- 28632978 TI - What's in this issue? PMID- 28632980 TI - Are you interested in joining the BACCN national board? PMID- 28632979 TI - BACCN clinically commissioned papers. PMID- 28632981 TI - BACCN Twitter chats. PMID- 28632982 TI - Regional news and events. PMID- 28632983 TI - A descriptive Study of a Community-Based Home-Visiting Program with Preschool Children Prenatally Exposed to Alcohol. AB - BACKGROUND: Research suggests that prenatal alcohol exposure (PAE) and Fetal Alcohol Spectrum Disorder (FASD) increases the risk of insecure caregiver-child attachment and related negative child emotional-behavioural outcomes. Research also shows positive effects of attachment-focused interventions in preventing disrupted caregiver-child attachment relationships; however, such interventions have not been specifically adapted for children with FASD. OBJECTIVES: This paper describes the implementation, challenges, and results of a community home-based attachment intervention, Circle of Security(r) (COS), with preschool children affected by PAE/FASD in Manitoba, Canada. METHODS: Twelve caregiver-child dyads completed the FASD adapted COS intervention. Children's ages ranged from 2-5 years. RESULTS: Results support a positive influence of this individualized intervention on child behaviour and parent efficacy. There was a significant reduction in parent stress that was maintained at 3-month follow-up, and a clinically significant reduction in child behavioural issues was noted. Children showed increased ability to communicate their needs more effectively to their parent. Parents also showed an improvement in their ability to attend to their child's cues. CONCLUSIONS: This study supports the use of community home-based attachment intervention for caregivers of children with PAE/FASD. PMID- 28632984 TI - Aging Induced Changes in Biochar's Functionality and Adsorption Behavior for Phosphate and Ammonium. AB - Biochar, a form of pyrogenic carbon, can contribute to agricultural and environmental sustainability by increasing soil reactivity. In soils, biochar could change its role over time through alterations in its surface chemistry. However, a mechanistic understanding of the aging process and its role in ionic nutrient adsorption and supply remain unclear. Here, we aged a wood biochar (550 degrees C) by chemical oxidation with 5-15% H2O2 and investigated the changes in surface chemistry and the adsorption behavior of ammonium and phosphate. Oxidation changed the functionality of biochar with the introduction of carboxylic and phenolic groups, a reduction of oxonium groups and the transformation of pyridine to pyridone. After oxidation, the adsorption of ammonium increased while phosphate adsorption decreased. Ammonium adsorption capacity was nonlinearly related to the biochar's surface charge density (r2 = 0.94) while electrostatic repulsion and loss of positive charge due to destruction of oxonium and pyridine, possibly caused the reduced phosphate adsorption. However, the oxidized biochar substantially adsorbed both ammonium and phosphate when biochar derived organic matter (BDOM) was included. Our results suggest that aging of biochar could reverse its capacity for the adsorption of cationic and anionic species but the inclusion of BDOM could increase ionic nutrient and contaminant retention. PMID- 28632985 TI - Healable, Reconfigurable, Reprocessable Thermoset Shape Memory Polymer with Highly Tunable Topological Rearrangement Kinetics. AB - The unique capability of topological rearrangement for dynamic covalent polymer networks has enabled various unusual properties (self-healing, solid-state plasticity, and reprocessability) that are not found in conventional thermosets. Achieving these properties in one network in a synergetic fashion can open up new opportunities for shape memory polymer. To accomplish such a goal, the freedom to tune topological rearrangement kinetics is critical. This is, however, challenging to achieve. In this work, two sets of dynamic bonds (urethane and hindered urea) are incorporated into a hybrid network for synthesizing shape memory poly(urea-urethane). By changing the bond ratio, networks with highly tunable topological rearrangement kinetics are obtained. Combining self-healing, solid-state plasticity, and reprocessability in one such shape memory network leads to unusual versatility in its shape-shifting performance. PMID- 28632986 TI - Atom Probe Tomography Unveils Formation Mechanisms of Wear-Protective Tribofilms by ZDDP, Ionic Liquid, and Their Combination. AB - The development of advanced lubricant additives has been a critical component in paving the way for increasing energy efficiency and durability for numerous industry applications. However, the formation mechanisms of additive-induced protective tribofilms are not yet fully understood because of the complex chemomechanical interactions at the contact interface and the limited spatial resolution of many characterizing techniques currently used. Here, the tribofilms on a gray cast iron surface formed by three antiwear additives are systematically studied; a phosphonium-phosphate ionic liquid (IL), a zinc dialkyldithiophosphate (ZDDP), and an IL+ZDDP combination. All three additives provide excellent wear protection, with the IL+ZDDP combination exhibiting a synergetic effect, resulting in further reduced friction and wear. Atom probe tomography (APT) and scanning transmission electron microscopy (STEM) imaging and electron energy loss spectroscopy (EELS) were used to interrogate the subnm chemistry and bonding states for each of the tribofilms of interest. The IL tribofilm appeared amorphous and was Fe, P, and O rich. Wear debris particles having an Fe-rich core and an oxide shell were present in this tribofilm and a transitional oxide (Fe2O3)-containing layer was identified at the interface between the tribofilm and the cast iron substrate. The ZDDP+IL tribofilm shared some of the characteristics found in the IL and ZDDP tribofilms. Tribofilm formation mechanisms are proposed on the basis of the observations made at the atomic level. PMID- 28632987 TI - The Usher Syndrome Type IIIB Histidyl-tRNA Synthetase Mutation Confers Temperature Sensitivity. AB - Histidyl-tRNA synthetase (HARS) is a highly conserved translation factor that plays an essential role in protein synthesis. HARS has been implicated in the human syndromes Charcot-Marie-Tooth (CMT) Type 2W and Type IIIB Usher (USH3B). The USH3B mutation, which encodes a Y454S substitution in HARS, is inherited in an autosomal recessive fashion and associated with childhood deafness, blindness, and episodic hallucinations during acute illness. The biochemical basis of the pathophysiologies linked to USH3B is currently unknown. Here, we present a detailed functional comparison of wild-type (WT) and Y454S HARS enzymes. Kinetic parameters for enzymes and canonical substrates were determined using both steady state and rapid kinetics. Enzyme stability was examined using differential scanning fluorimetry. Finally, enzyme functionality in a primary cell culture was assessed. Our results demonstrate that the Y454S substitution leaves HARS amino acid activation, aminoacylation, and tRNAHis binding functions largely intact compared with those of WT HARS, and the mutant enzyme dimerizes like the wild type does. Interestingly, during our investigation, it was revealed that the kinetics of amino acid activation differs from that of the previously characterized bacterial HisRS. Despite the similar kinetics, differential scanning fluorimetry revealed that Y454S is less thermally stable than WT HARS, and cells from Y454S patients grown at elevated temperatures demonstrate diminished levels of protein synthesis compared to those of WT cells. The thermal sensitivity associated with the Y454S mutation represents a biochemical basis for understanding USH3B. PMID- 28632988 TI - Solid Sampling with a Diode Laser for Portable Ambient Mass Spectrometry. AB - A hand-held diode laser is implemented for solid sampling in portable ambient mass spectrometry (MS). Specifically, a pseudocontinuous wave battery-powered surgical laser diode is employed for portable laser diode thermal desorption (LDTD) at 940 nm and compared with nanosecond pulsed laser ablation at 2940 nm. Postionization is achieved in both cases using atmospheric pressure photoionization (APPI). The laser ablation atmospheric pressure photoionization (LAAPPI) and LDTD-APPI mass spectra of sage leaves (Salvia officinalis) using a field-deployable quadrupole ion trap MS display many similar ion peaks, as do the mass spectra of membrane grown biofilms of Pseudomonas aeruginosa. These results indicate that LDTD-APPI method should be useful for in-field sampling of plant and microbial communities, for example, by portable ambient MS. The feasibility of many portable MS applications is facilitated by the availability of relatively low cost, portable, battery-powered diode lasers. LDTD could also be coupled with plasma- or electrospray-based ionization for the analysis of a variety of solid samples. PMID- 28632989 TI - Impact of Interface Mixing on the Performance of Solution Processed Organic Light Emitting Diodes-Impedance and Ultraviolet Photoelectron Spectroscopy Study. AB - We investigated interfacial mixing of solution-processed organic light-emitting devices (OLEDs) using impedance spectroscopy (IS) and ultraviolet photoelectron spectroscopy (UPS) and its impact on device performance. We focused on interfacial mixing between a solution-processed cross-linkable hole transport layer (XM) and an emitting layer (EML), formed either by solution processing or vacuum evaporation. The results of IS and UPS clearly indicated that extensive interfacial mixing was unavoidable, even after the XM was cross-linked to make it insoluble and rinsed to remove residual soluble species, if the subsequent EML was solution processed. In addition, we also demonstrated that interfacial mixing indeed increased hole current density in corresponding hole only device (HOD). In fact, the hole injection efficiency could be an order of magnitude better when the EML was solution processed rather than vacuum evaporated. We investigated such behavior to find the desirable process condition of solution-processed OLEDs. PMID- 28632990 TI - Shortening gametes co-incubation time improves live birth rate for couples with a history of fragmented embryos. AB - : Short gamete co-incubation (SGCO) consists in decreasing the duration of contact between oocytes and sperm from the standard overnight insemination (SOI) toward 2 hours. However, the effectiveness of this technique to improve in vitro fertilization and embryo transfer (IVF-ET) outcomes remains controversial. Our study was designed to evaluate the efficiency of SGCO in a poor prognosis population with a history of fragmented embryos defined by the presence of at least 50% of the embryos with more than 25% of cytoplasmic fragments. From January 2010 to January 2014, 97 couples were included in a SGCO protocol. We separated women into 2 subgroups: younger and older than 35 years. Compared to SOI, after SGCO, 2-cell stage embryos were higher in all women (p<0.001) and less fragmented in women over 35 years (p<0.05). On day 2, top quality embryos obtained and transferred were higher with SCGO than with SOI, independently of the age of the women (p<0.001). Moreover, the number of embryos with less than 25% of fragmentation was higher after SGCO than SOI (p<0.001) whereas the number of multinucleated embryos was lower (p<0.001). We observed that after fresh ET, independently of the age of the women, the clinical pregnancy rate was 3 times higher after SGCO than after SOI. However, the live-birth rate was 4 times higher with SGCO than with SOI in women above 35 years but 3 times higher with SGCO than with SOI in women younger than 35 years. The present results indicate that for a particular indication, reducing the time of oocytes and sperm co-incubation may improve IVF-ET outcomes in terms of live-birth rate. ABBREVIATIONS: AMH: anti mullerian hormone; COC: cumulus-oocytes complex; E2: estradiol; ET: embryo transfer; FET: frozen embryo transfer; FSH: follicle stimulating hormone; GnRH: gonadotrophin releasing hormone; hCG: human chorionic gonadotropin hormone; hMG: human menopausal gonadotropin hormone; IRB: institutional review board; IVF: in vitro fertilization; IVF-ET: in vitro fertilization and embryo transfer; MNB: multinucleated blastomere; mRNA: messanger ribonucleic acid; OC: oocyte retrieval; O2: oxygen; ROS: reactive oxygen species; SGCO: short gamete co incubation; SOI: standard overnight insemination. PMID- 28632991 TI - Uncovering the repertoire of fungal secondary metabolites: From Fleming's laboratory to the International Space Station. AB - Fungi produce a variety of secondary metabolites (SMs), low-molecular weight compounds associated with many potentially useful biologic activities. The examples of biotechnologically relevant fungal metabolites include penicillin, a beta-lactam antibiotic, and lovastatin, a cholesterol-lowering drug. The discovery of pharmaceutical lead compounds within the microbial metabolic pools relies on the selection and biochemical characterization of promising strains. Not all SMs are produced under standard cultivation conditions, hence the uncovering of chemical potential of investigated strains often requires the use of induction strategies to awake the associated biosynthetic genes. Triggering the secondary metabolic pathways can be achieved through the variation of cultivation conditions and growth media composition. The alternative strategy is to use genetic engineering to activate the respective genomic segments, e.g. by the manipulation of regulators or chromatin-modifying enzymes. Recently, whole genome sequencing of several fungi isolated from the Chernobyl accident area was reported by Singh et al. (Genome Announc 2017; 5:e01602-16). These strains were selected for exposure to microgravity at the International Space Station. Biochemical characterization of fungi cultivated under extreme conditions is likely to provide valuable insights into the adaptation mechanism associated with metabolism and, possibly, a catalog of novel molecules of potential pharmaceutical importance. PMID- 28632992 TI - Targeting the RhoGTPase/ROCK pathway for the treatment of VHL/HIF pathway-driven cancers. AB - The loss of the von Hippel-Lindau (VHL) tumor-suppressor is a major driver of Clear Cell Renal Cell Carcinoma (CC-RCC) resulting in the stabilization and overactivation of hypoxia inducible factors (HIFs). ROCK1 is a well-known protein serine/threonine kinase which is recognized as having a role in cancer including alterations in cell motility, metastasis and angiogenesis. We recently investigated and identified a synthetic lethal interaction between VHL loss and ROCK1 inhibition in CC-RCC that is dependent on HIF overactivation. Increased expression and activity of both HIFs and ROCK1 occurs in many types of cancer supporting the potential therapeutic role of ROCK inhibitors beyond CC-RCC. We also discuss future research required to establish prognostic markers to predict tumor response to ROCK inhibitors. PMID- 28632994 TI - Role of the small GTPase Rap1 in signal transduction, cell dynamics and bacterial infection. AB - Rap1 belongs to the Ras family of small GTPases, which are involved in a multitude of cellular signal transduction pathways and have extensively been linked to cancer biogenesis and metastasis. The small GTPase is activated in response to various extracellular and intracellular cues. Rap1 has conserved functions in Dictyostelium discoideum amoeba and mammalian cells, which are important for cell polarity, substrate and cell-cell adhesion and other processes that involve the regulation of cytoskeletal dynamics. Moreover, our recent study has shown that Rap1 is required for the formation of the replication-permissive vacuole of an intracellular bacterial pathogen. Here we review the function and regulation of Rap1 in these distinct processes, and we discuss the underlying signal transduction pathways. PMID- 28632995 TI - Microenvironment and tumors-a nurturing relationship. AB - When exposed to adverse environmental conditions, cells degrade their own content to recycle cellular building blocks through a process called autophagy. A large body of literature has connected autophagy to cancer, but most studies up until now focused on its function in transformed cells. In her thesis, Nadja Katheder dissected the role of autophagy in a well-characterized neoplastic in vivo tumor model in Drosophila and demonstrates a novel non-cell-autonomous requirement of this process for tumor growth. Neighboring epithelial cells and distal tissues increase autophagy in the presence of a malignant tumor. Pharmacological autophagy inhibition reduces tumor growth and genetic ablation of autophagy in the microenvironment reveals a tumor-supportive role of this process in this specific cell population. Tumor cells are metabolically stressed and induce autophagy in their neighbors through a TNFalpha-JNK-IL-6 signaling cascade. Moreover, they are dependent on amino acid import to sustain their proliferation, which indicates a coupling of metabolism between these two cell populations. Finally, allografted growth-impaired tumors from autophagy-deficient donor animals resume growth in an autophagy-competent host. Together, the results described in this thesis highlight the tumor-promoting role of autophagy the microenvironment and show that cancer cells engage their epithelial neighbors as essential contributors aiding their own growth. PMID- 28632993 TI - The role of small GTPases and EPAC-Rap signaling in the regulation of the blood brain and blood-retinal barriers. AB - Maintenance and regulation of the vascular endothelial cell junctional complex is critical for proper barrier function of the blood-brain barrier (BBB) and the highly related blood-retinal barrier (BRB) that help maintain proper neuronal environment. Recent research has demonstrated that the junctional complex is actively maintained and can be dynamically regulated. Studies focusing on the mechanisms of barrier formation, maintenance, and barrier disruption have been of interest to understanding development of the BBB and BRB and identifying a means for therapeutic intervention for diseases ranging from brain tumors and dementia to blinding eye diseases. Research has increasingly revealed that small GTPases play a critical role in both barrier formation and disruption mechanisms. This review will summarize the current data on small GTPases in barrier regulation with an emphasis on the EPAC-Rap1 signaling pathway to Rho in endothelial barriers, as well as explore its potential involvement in paracellular flux and transcytosis regulation. PMID- 28632997 TI - Epidemiology of Obesity and Pharmacologic Treatment Options. AB - Prevalence of obesity and its related morbidity have increased to alarming levels in adults and children in the United States and globally. Weight loss results in improvement of much of the obesity-related morbidity. Lifestyle changes such as dietary modifications, increased physical activity, and behavioral therapy form the crux of weight management. However, many individuals need additional assistance (pharmacologic or surgical) to initiate or sustain weight loss. Pharmacologic therapy consists of a number of agents that work by decreasing appetite, gastric emptying, or nutrient absorption or by increasing satiety. Five classes of drug are currently approved for adults, including sympathomimetics (with and without an antiepileptic agent topiramate), gastrointestinal lipase inhibitors, serotonin agonists, glucagon-like peptide 1 agonists, and antidepressant/opioid antagonist combination. Pharmacologic options for children with obesity are minimal (lipase inhibitor orlistat is the only approved medication for children aged >12 years); however, all adult medications are approved by the Food and Drug Administration for children aged >16 years old. While side effect profiles of these medications are far superior to older medications, their use is limited by lack of long-term cardiovascular safety data, costs of medications and variable insurance coverages, and the need for continued usage for sustainable benefits. Weight loss medications may induce complacence, on part of both the patient and the provider, regarding lifestyle modifications, without which the drug therapy is almost certain to be of minimal benefit. Several novel drugs are in the pipeline targeting brown fat, energy expenditure, appetite suppression, and satiety. PMID- 28632996 TI - Taking control: Hijacking of Rab GTPases by intracellular bacterial pathogens. AB - Intracellular bacterial pathogens survive and replicate within specialized eukaryotic cell organelles. To establish their intracellular niches these pathogens have adopted sophisticated strategies to control intracellular membrane trafficking. Since Rab-family GTPases are critical regulators of endocytic and secretory membrane trafficking events, many intracellular pathogens have evolved specific mechanisms to modulate or hijack Rab GTPases dynamics and trafficking functions. One such strategy is the delivery of bacterial effectors through specialized machines to specifically target Rab GTPases. Some of these effectors functionally mimic host proteins that regulate the Rab GTP cycle, while others regulate Rabs proteins through their post-translation modifications or proteolysis. In this review, we examine how the localization and function of Rab family GTPases are altered during infection with 3 well-studied intracellular bacterial pathogens, Mycobacterium tuberculosis, Salmonella enterica and Legionella pneumophila. We also discuss recent findings about specific mechanisms by which these intracellular pathogens target this protein family. PMID- 28632998 TI - tRNA structure and evolution and standardization to the three nucleotide genetic code. AB - Cloverleaf tRNA with a 75 nucleotide (nt) core is posited to have evolved from ligation of three 31 nt minihelices followed by symmetric internal deletions of 9 nt within ligated acceptor stems. Statistical tests strongly support the model. Although the tRNA anticodon loop and T loop are homologs, their U-turns have been treated as distinct motifs. An appropriate comparison, however, shows that intercalation of D loop G19 between T loop bases 4 and 5 causes elevation of T loop base 5 and flipping of T loop bases 6 and 7 out of the 7 nt loop. In the anticodon loop, by contrast, loop bases 3-7 stack tightly to form a stiff connection to mRNA. Furthermore, we identify ancient repeat sequences of 3 (GCG), 5 (UAGCC) and 17 nt (~CCGGGUUCAAAACCCGG) that comprise 75 out of 75 nts of the tRNA cloverleaf core. To present a sufficiently stiff 3-nt anticodon, a 7-nt anticodon loop was necessary with a U-turn between loop positions 2 and 3. Cloverleaf tRNA, therefore, was a radical evolutionary innovation essential for the 3-nt code. Conservation of GCG and UAGCC repeat sequences indicates that cloverleaf tRNA is at the interface between a strange RNA repeat world and the first evolution of molecules that fold to assume biologic functions. We posit that cloverleaf tRNA was the molecular archetype around which translation systems evolved. PMID- 28632999 TI - Long noncoding RNA lnc-sox5 modulates CRC tumorigenesis by unbalancing tumor microenvironment. AB - Long non-coding RNAs (LncRNAs) have been recently regarded as systemic regulators in multiple biologic processes including tumorigenesis. In this study, we observed the expression of lncRNA lnc-sox5 was significantly increased in colorectal cancer (CRC). Despite the CRC cell growth, cell cycle and cell apoptosis was not affected by lnc-sox5 knock-down, lnc-sox5 knock-down suppressed CRC cell migration and invasion. In addition, xenograft animal model suggested that lnc-sox5 knock-down significantly suppressed the CRC tumorigenesis. Our results also showed that the expression of indoleamine 2,3-dioxygenase 1 (IDO1) was significantly reduced by lnc-sox5 knock-down and therefore modulated the infiltration and cytotoxicity of CD3+CD8+T cells. Taken together, these results suggested that lnc-sox5 unbalances tumor microenvironment to regulate colorectal cancer progression. PMID- 28633000 TI - Nutrition Support for Critically Ill Patients With Cancer. AB - Oncology patients often experience the classic signs of malnutrition-weight loss as well as fat and muscle wasting, which have been associated with poor tolerance to treatment and increased morbidity and mortality. Nutrition status may be an important factor in determining tolerance to treatment and outcomes associated with it. Thus, identification of those with preexisting malnutrition or who are at risk for developing malnutrition is crucial not only at time of cancer diagnosis but also throughout the treatment course so that nutrition interventions may be implemented to prevent development or worsening of malnutrition in this high-risk population. These patients often have extremely complicated hospital courses due to the aggressive nature of the disease and treatment, leading to intensive care unit admission and periods of critical illness. Critical illness is associated with catabolism, extreme stress on the body, and a state of systemic inflammation. During critical illness, it is important to provide adequate nutrition to prevent further break down of lean muscle mass and oxidative cellular injury and to regulate favorable immune responses. The purpose of this review is to discuss the importance of nutrition screening and assessment for the critically ill patient with cancer; to appropriately identify those at risk for, or who have developed, malnutrition; and to provide appropriate interventions to optimize nutrition status. This review also discusses the complications and difficulties associated with feeding this patient population and offers nutrition support recommendations. PMID- 28633001 TI - Impact of 4 weeks of interval training on resting metabolic rate, fitness, and health-related outcomes. AB - Resting metabolic rate (RMR) and substrate oxidation (respiratory exchange ratio; RER) are important indicators of health. The effects of interval training on RMR have not been thoroughly investigated, which was the purpose of the present study. Thirty men and women (mean +/- SD age and maximal oxygen uptake: 28.8 +/- 7.6 years and 33.0 +/- 8.3 mL.kg-1.min-1) completed 4 weeks of Wingate-based sprint interval training (SIT), repeated 1-min high-intensity intervals (HIIT), or served as controls. Before and after training, RMR, resting RER, maximal oxygen uptake, body composition, physical activity, and energy intake were recorded. Data were analyzed using a repeated-measures ANOVA. RMR increased in response to 4 weeks of SIT training (1789 +/- 293 to 1855 +/- 320 kcal.day-1; p = 0.003) but did not increase after HIIT (1670 +/- 324 to 1704 +/- 329 kcal.day-1; p = 0.06). While SIT increased RMR by ~2* the magnitude of HIIT, the difference was not significant (p = 0.5). Fasting substrate oxidation and RER did not change (p > 0.05). Maximal oxygen uptake increased, and small changes were also observed in percent body fat and fat mass (p < 0.05 for all). In conclusion, SIT provided a time-efficient stimulus to increase RMR after 4 weeks in healthy adults. However, the clinical relevance of the changes observed in this study remains to be determined. Further studies should be conducted in obese individuals and those with diabetes or insulin resistance to examine if interval training (>=4 weeks) influences resting metabolic rate in magnitudes similar to that reported here. PMID- 28633003 TI - Assessment of Selected Overdose Poisoning Indicators in Health Care Administrative Data in 4 States, 2012. AB - OBJECTIVES: In 2012, a consensus document was developed on drug overdose poisoning definitions. We took the opportunity to apply these new definitions to health care administrative data in 4 states. Our objective was to calculate and compare drug (particularly opioid) poisoning rates in these 4 states for 4 selected Injury Surveillance Workgroup 7 (ISW7) drug poisoning indicators, using 2 ISW7 surveillance definitions, Option A and Option B. We also identified factors related to the health care administrative data used by each state that might contribute to poisoning rate variations. METHODS: We used state-level hospital and emergency department (ED) discharge data to calculate age-adjusted rates for 4 drug poisoning indicators (acute drug poisonings, acute opioid poisonings, acute opioid analgesic poisonings, and acute or chronic opioid poisonings) using just the principal diagnosis or first-listed external cause-of injury fields (Option A) or using all diagnosis or external cause-of-injury fields (Option B). We also calculated the high-to-low poisoning rate ratios to measure rate variations. RESULTS: The average poisoning rates per 100 000 population for the 4 ISW7 poisoning indicators ranged from 11.2 to 216.4 (ED) and from 14.2 to 212.8 (hospital). For each indicator, ED rates were usually higher than were hospital rates. High-to-low rate ratios between states were lowest for the acute drug poisoning indicator (range, 1.5-1.6). Factors potentially contributing to rate variations included administrative data structure, accessibility, and submission regulations. CONCLUSIONS: The ISW7 Option B surveillance definition is needed to fully capture the state burden of opioid poisonings. Efforts to control for factors related to administrative data, standardize data sources on a national level, and improve data source accessibility for state health departments would improve the accuracy of drug poisoning surveillance. PMID- 28633004 TI - Field evaluations of newly available "interference-free" monitors for nitrogen dioxide and ozone at near-road and conventional National Ambient Air Quality Standards compliance sites. AB - : Long-standing measurement techniques for determining ground-level ozone (O3) and nitrogen dioxide (NO2) are known to be biased by interfering compounds that result in overestimates of high O3 and NO2 ambient concentrations under conducive conditions. An increasing near-ground O3 gradient (NGOG) with increasing height above ground level is also known to exist. Both the interference bias and NGOG were investigated by comparing data from a conventional Federal Equivalent Method (FEM) O3 photometer and an identical monitor upgraded with an "interference-free" nitric oxide O3 scrubber that alternatively sampled at 2 m and 6.2 m inlet heights above ground level (AGL). Intercomparison was also made between a conventional nitrogen oxide (NOx) chemiluminescence Federal Reference Method (FRM) monitor and a new "direct-measure" NO2 NOx 405 nm photometer at a near-road air quality measurement site. Results indicate that the O3 monitor with the upgraded scrubber recorded lower regulatory-oriented concentrations than the deployed conventional metal oxide-scrubbed monitor and that O3 concentrations 6.2 m AGL were higher than concentrations 2.0 m AGL, the nominal nose height of outdoor populations. Also, a new direct-measure NO2 photometer recorded generally lower NO2 regulatory-oriented concentrations than the conventional FRM chemiluminescence monitor, reporting lower daily maximum hourly average concentrations than the conventional monitor about 3 of every 5 days. IMPLICATIONS: Employing bias-prone instruments for measurement of ambient ozone or nitrogen dioxide from inlets at inappropriate heights above ground level may result in collection of positively biased data. This paper discusses tests of new regulatory instruments, recent developments in bias-free ozone and nitrogen dioxide measurement technology, and the presence/extent of a near-ground O3 gradient (NGOG). Collection of unbiased monitor inlet height-appropriate data is crucial for determining accurate design values and meeting National Ambient Air Quality Standards. PMID- 28633002 TI - The TRPM2 channel: A thermo-sensitive metabolic sensor. AB - Living organisms continually experience changes in ambient temperature. To detect such temperature changes for adaptive behavioral responses, we evolved the ability to sense temperature. Thermosensitive transient receptor potential (TRP) channels, so-called thermo-TRPs, are involved in many physiologic functions in diverse organisms and constitute important temperature sensors. One of the important roles of thermo-TRPs is detecting ambient temperature in sensory neurons. Importantly, the functional expression of thermo-TRPs is observed not only in sensory neurons but also in tissues and cells that are not exposed to drastic temperature changes, indicating that thermo-TRPs are involved in many physiologic functions within the body's normal temperature range. Among such thermo-TRPs, this review focuses on one thermo-sensitive metabolic sensor in particular, TRPM2, and summarizes recent progress to clarify the regulatory mechanisms and physiologic functions of TRPM2 at body temperature under various metabolic states. PMID- 28633006 TI - Corrigendum. PMID- 28633007 TI - Human Vaccines & Immunotherapeutics: News. PMID- 28633008 TI - Letter from the Editor. PMID- 28633005 TI - Autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia. AB - The majority of diabetic patients develop neuropathy and there is an increasing prevalence of neurodegeneration in the central nervous system (CNS). However, the mechanism behind this is poorly understood. Here we first observed that macroautophagy/autophagy was suppressed in the hippocampus of diabetic GK rats with hyperglycemia, whereas it was unchanged in ob/ob mice without hyperglycemia. Autophagy could be directly inhibited by high glucose in mouse primary hippocampal neurons. Moreover, autophagy was protective in high-glucose-induced neurotoxicity. Further studies revealed that autophagic flux was suppressed by high glucose due to impaired autophagosome synthesis illustrated by mRFP-GFP-LC3 puncta analysis. We showed that decreased autophagy was dependent on NO produced under high glucose conditions. Therefore, (LC-MS/MS)-based quantitative proteomic analysis of protein S-nitrosation was performed and a core autophagy protein, ATG4B was found to be S-nitrosated in the hippocampus of GK rats. ATG4B was also verified to be S-nitrosated in neuronal cells cultured with high glucose. The activities of ATG4B in the processing of unmodified, precursor Atg8-family proteins and in the deconjugation of PE from lipidated Atg8-family proteins, which are essential for efficient autophagosome biogenesis were both compromised by S-nitrosation at Cys189 and Cys292 sites. In addition, ATG4B processing of the GABARAPL1 precursor was affected the least by S-nitrosation compared with other substrates. Finally, ATG4B S-nitrosation was verified to be responsible for decreased autophagy and neurotoxicity in response to high glucose. In conclusion, autophagy impairment mediated by S-nitrosation of ATG4B leads to neurotoxicity in response to hyperglycemia. Our research reveals a novel mechanism linking hyperglycemia with CNS neurotoxicity and shows that S-nitrosation is a novel post transcriptional modification of the core autophagy machinery. PMID- 28633009 TI - RNA Interference Reveals the Coregulatory Effects of Cylindromatosis on Apoptosis and Necroptosis of Photoreceptor Cells in Experimental Retinal Detachment. AB - Inhibiting only cell apoptosis or necroptosis in photoreceptor cells does not protect them against death after traumatic retinal detachment. This study was designed to evaluate the coregulatory effects of the deubiquitinating enzyme cylindromatosis on the apoptosis and necroptosis of photoreceptor cells in experimental retinal detachment. Lentivirus Cyld shRNA was generated and used to suppress cylindromatosis expression in Sprague-Dawley rats. Three weeks after injection of lentivirus Cyld shRNA, retinal detachment surgery was performed. Transmission electron microscopy, propidium iodide staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, electroretinography, and determination of ubiquitination and phosphorylation of receptor-interacting protein 1 were performed to detect the apoptosis and necroptosis of photoreceptor cells. Knockdown of cylindromatosis expression led to inhibition of caspase 8 activity, a decrease in the number of apoptotic photoreceptor cells, and an increase in the ubiquitination level of receptor interacting protein 1. In addition, the number of necroptotic cells decreased and the phosphorylation level of receptor-interacting protein 1 decreased dramatically; significant protective effects of RNA interference-mediated suppression of cylindromatosis expression on electroretinogram wave were observed. Cylindromatosis coregulates the apoptosis and necroptosis of photoreceptor cells by regulating the ubiquitination of receptor-interacting protein 1 after retinal detachment. PMID- 28633010 TI - Tensing Up for Lipid Droplet Formation. AB - Lipid droplets are fat storage organelles in cells that physically resemble stable oil-water emulsion droplets. In this issue of Developmental Cell, Ben M'barek et al. (2017) show that the resemblance is more than superficial: physical principles governing emulsion stability also control lipid droplet nucleation and growth. PMID- 28633011 TI - Partners in Crime. AB - Caspases have apoptotic and non-apoptotic functions, both of which depend on their abilities to cleave proteins at specific sites. What distinguishes apoptotic from non-apoptotic substrates has so far been unclear. In this issue of Developmental Cell, Weaver et al. (2017) now provide an answer to this crucial question. PMID- 28633012 TI - Morph or Move? How Distinct Endothelial Cell Responses to Blood Flow Shape Vascular Networks. AB - Blood vessel shape is malleable and dynamically regulated. In two recent papers in Nature Cell Biology, Jin et al. (2017) and Sugden et al. (2017) show that endoglin alters endothelial cell shape or behavior in response to blood flow, thus regulating vessel structure. PMID- 28633013 TI - Sphingosine-1-Phosphate as the Lymphocyte's Ticket to Ride and Survive. AB - An established role of sphingosine 1-phosphate receptor-1 in T cells is to guide their exit from lymph nodes. Reporting in Nature, Mendoza et al. (2017) now show that lymphatic endothelial sphingosine 1-phosphate signals through sphingosine 1 phosphate receptor-1 to prevent mitochondria degradation and thereby support survival of naive T cells. PMID- 28633014 TI - A KRABsody for Embryo-Placental Development. AB - Many of the hundreds of KRAB zinc finger proteins encoded by human and mouse are involved in taming the transcriptional regulatory potential of transposable elements. Reporting recently in Science, Yang et al. (2017) reveal that one murine family member, ZFP568, controls Igf2 expression for proper embryonic and placental development. PMID- 28633015 TI - Haploidy in Humans: An Evolutionary and Developmental Perspective. AB - Although haploidy has not been observed in vertebrates, its natural occurrence in various eukaryotic species that had diverged from diploid ancestors suggests that there is an innate capacity for an organism to regain haploidy and that haploidy may confer evolutionary benefits. Haploid embryonic stem cells have been experimentally generated from mouse, rat, monkey, and humans. Haploidy results in major differences in cell size and gene expression levels while also affecting parental imprinting, X chromosome inactivation, and mitochondrial metabolism genes. We discuss here haploidy in evolution and the barriers to haploidy, in particular in the human context. PMID- 28633016 TI - MLL/WDR5 Complex Regulates Kif2A Localization to Ensure Chromosome Congression and Proper Spindle Assembly during Mitosis. AB - Mixed-lineage leukemia (MLL), along with multisubunit (WDR5, RbBP5, ASH2L, and DPY30) complex catalyzes the trimethylation of H3K4, leading to gene activation. Here, we characterize a chromatin-independent role for MLL during mitosis. MLL and WDR5 localize to the mitotic spindle apparatus, and loss of function of MLL complex by RNAi results in defects in chromosome congression and compromised spindle formation. We report interaction of MLL complex with several kinesin and dynein motors. We further show that the MLL complex associates with Kif2A, a member of the Kinesin-13 family of microtubule depolymerase, and regulates the spindle localization of Kif2A during mitosis. We have identified a conserved WDR5 interaction (Win) motif, so far unique to the MLL family, in Kif2A. The Win motif of Kif2A engages in direct interactions with WDR5 for its spindle localization. Our findings highlight a non-canonical mitotic function of MLL complex, which may have a direct impact on chromosomal stability, frequently compromised in cancer. PMID- 28633017 TI - Distinct Roles of RNA Helicases MVH and TDRD9 in PIWI Slicing-Triggered Mammalian piRNA Biogenesis and Function. AB - Small RNAs called PIWI-interacting RNAs (piRNAs) act as an immune system to suppress transposable elements in the animal gonads. A poorly understood adaptive pathway links cytoplasmic slicing of target RNA by the PIWI protein MILI to loading of target-derived piRNAs into nuclear MIWI2. Here we demonstrate that MILI slicing generates a 16-nt by-product that is discarded and a pre-piRNA intermediate that is used for phased piRNA production. The ATPase activity of Mouse Vasa Homolog (MVH) is essential for processing the intermediate into piRNAs, ensuring transposon silencing and male fertility. The ATPase activity controls dissociation of an MVH complex containing PIWI proteins, piRNAs, and slicer products, allowing safe handover of the intermediate. In contrast, ATPase activity of TDRD9 is dispensable for piRNA biogenesis but is essential for transposon silencing and male fertility. Our work implicates distinct RNA helicases in specific steps along the nuclear piRNA pathway. PMID- 28633018 TI - Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes that Are Eliminated by the Immune System. AB - Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways that limit the prevalence of such cells exist? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell-cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance. PMID- 28633019 TI - EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related Physiological Decline in Drosophila. AB - The unfolded protein response (UPR), which protects cells against accumulation of misfolded proteins in the ER, is induced in several age-associated degenerative diseases. However, sustained UPR activation has negative effects on cellular functions and may worsen disease symptoms. It remains unknown whether and how UPR components can be utilized to counteract chronic ER proteinopathies. We found that promotion of ER-associated degradation (ERAD) through upregulation of ERAD enhancing alpha-mannosidase-like proteins (EDEMs) protected against chronic ER proteinopathy without inducing toxicity in a Drosophila model. ERAD activity in the brain decreased with aging, and upregulation of EDEMs suppressed age dependent behavioral decline and extended the lifespan without affecting the UPR gene expression network. Intriguingly, EDEM mannosidase activity was dispensable for these protective effects. Therefore, upregulation of EDEM function in the ERAD protects against ER proteinopathy in vivo and thus represents a potential therapeutic target for chronic diseases. PMID- 28633021 TI - Sex Differences: Satellite DNA Directs Male-Specific Gene Expression. PMID- 28633022 TI - Phoresy. AB - White et al. introduce the phenomenon of phoresy - animals hitching a ride on other animals. PMID- 28633020 TI - Apoptosis and Compensatory Proliferation Signaling Are Coupled by CrkI-Containing Microvesicles. AB - Apoptosis has been implicated in compensatory proliferation signaling (CPS), whereby dying cells induce proliferation in neighboring cells as a means to restore homeostasis. The nature of signaling between apoptotic cells and their neighboring cells remains largely unknown. Here we show that a fraction of apoptotic cells produce and release CrkI-containing microvesicles (distinct from exosomes and apoptotic bodies), which induce proliferation in neighboring cells upon contact. We provide visual evidence of CPS by videomicroscopy. We show that purified vesicles in vitro and in vivo are sufficient to stimulate proliferation in other cells. Our data demonstrate that CrkI inactivation by ExoT bacterial toxin or by mutagenesis blocks vesicle formation in apoptotic cells and inhibits CPS, thus uncoupling apoptosis from CPS. We further show that c-Jun amino terminal kinase (JNK) plays a pivotal role in mediating vesicle-induced CPS in recipient cells. CPS could have important ramifications in diseases that involve apoptotic cell death. PMID- 28633023 TI - The insular cortex. AB - Whether you see the person you are in love with, try to listen to your own heartbeat, suffer from a headache, or crave for a chocolate cookie, one part of your brain is sure to increase its activity strongly: the insular cortex. The insular cortex, or 'insula' for short, is part of the cerebral cortex. J.C. Reil, a German neurologist, first named this brain structure in the early 19th century. Subsequent research findings have implicated the insula in an overwhelming variety of functions ranging from sensory processing to representing feelings and emotions, autonomical and motor control, risk prediction and decision-making, bodily- and self-awareness, and complex social functions like empathy. How is one single brain area involved in so many different tasks? Is the insula comprised of several functional regions? How are these related? And, are there any common themes underlying the apparently so heterogeneous roles of the insula? PMID- 28633024 TI - Seeing lightness in the dark. AB - From intense sunlight in bright snow down to a moonless night in a dark forest, we can use light to recognize objects and guide our actions. This remarkable range mainly rests on having two different types of photoreceptors, the rods and the cones. The cones are active under daylight conditions, allowing high acuity and color vision. Rods are mainly active under very dim illumination conditions and have an exquisite sensitivity to light [1]. There are obvious detriments to visual perception in near darkness, such as a central scotoma, reduced motion perception [2], and most of all a lack of color [3]. There is only one type of rod, and thus intensity and wavelength differences cannot be disentangled when only the rods are active. This is captured well by the old saying "at night all cats are gray", meaning that different colors inevitably get mapped onto different shades of gray. Here we show that the perception of lightness is also different for night vision: our results indicate that surfaces that appear to be white under daylight conditions, at best, appear medium gray under night vision, suggesting that activation of the cones is necessary for the perception of white. PMID- 28633025 TI - Chimpanzee culture extends beyond matrilineal family units. AB - The 'grooming handclasp' is one of the most well-established cultural traditions in chimpanzees. A recent study by Wrangham et al.[1] reduced the cultural scope of grooming-handclasp behavior by showing that grooming-handclasp style convergence is "explained by matrilineal relationship rather than conformity" [1]. Given that we previously reported cultural differences in grooming-handclasp style preferences in captive chimpanzees [2], we tested the alternative view posed by Wrangham et al.[1] in the chimpanzee populations that our original results were based on. Using the same outcome variable as Wrangham et al.[1] - the proportion of high-arm grooming featuring palm-to-palm clasping - we found that matrilineal relationships explained neither within-group homogeneity nor between-group heterogeneity, thereby corroborating our original conclusion that grooming-handclasp behavior can represent a group-level cultural tradition in chimpanzees. PMID- 28633026 TI - Response to: Chimpanzee culture extends beyond matrilineal family units. AB - We thank van Leeuwen et al.[1] for their response to our finding that matrilineal relationships strongly influence the style of high-arm grooming in wild chimpanzees of the Kanyawara community. We agree with them that grooming styles could be transmitted by different mechanisms in different contexts, and we appreciate their effort to assess whether the transmission of grooming styles within two captive groups in Chimfunshi accords with our result. PMID- 28633027 TI - Cell Size: Fat Makes Cells Fat. AB - Nutrients are required for the multiple biosynthetic pathways that result in cell growth, and faster growth due to increased nutrient supply results in larger cell volume. A new study demonstrates that fatty-acid availability limits growth rate and cell envelope capacity, revealing that fatty-acid synthesis is the primary determinant of cell size in bacteria and in budding yeast. PMID- 28633028 TI - Visual Perception: Neural Networks for Stereopsis. AB - How does our brain use differences between the images in our two eyes, binocular disparities, to generate depth perception? New work shows that a type of neural network trained on natural binocular images can learn parameters that match key properties of visual cortex. Most information is conveyed by cells which sense differences between the two eyes' images. PMID- 28633029 TI - Evolution: Hearing and Feeding in Fossil Whales. AB - The evolution of whales marks one of the major transitions in the history of mammals. Two new studies provide key insights into the evolution of hearing specializations and feeding strategies in early whales. PMID- 28633030 TI - Human Navigation: Occipital Place Area Detects Potential Paths in a Scene. AB - Navigation - determining how to get from where you are to somewhere else - has obvious importance for the survival of motile animals. A new neuroimaging study has revealed that, in the human brain, the occipital place area detects the number of possible paths in a vista. PMID- 28633031 TI - Cell Division: Centrosomes Have Separation Anxiety. AB - Prior to mitosis, duplicated centrosomes are tethered together, which is thought to prevent mitotic defects. A new study establishes the role of tetrameric Kif25, a microtubule minus-end-directed kinesin-14 motor, in preventing premature centrosome separation through a microtubule-dependent pathway. PMID- 28633032 TI - Animal Navigation: The Eel's Magnetic Guide to the Gulf Stream. AB - The geographic distribution of migratory species can span thousands of kilometers. Yet, traits that enable large-scale migrations are poorly understood. A recent study demonstrates that juvenile eels use the Earth's magnetism for their dispersal, with possible implications for their evolution. PMID- 28633033 TI - Centrosome Assembly: Reconstructing the Core Cartwheel Structure In Vitro. AB - Centrioles are microtubule-based cylinders essential for the formation of centrosomes and cilia. A recent study provides a new cell-free assay that reconstitutes the initial structure formed during centriole assembly - the cartwheel - and proposes a new model for its formation and growth. PMID- 28633034 TI - Evolution: Complex Multicellular Life with 5,500 Genes. AB - The origin of complex multicellularity was a major transition in evolution and is generally associated with higher genomic complexity. However, some complex multicellular fungi defy this principle, having small genomes that resemble those of unicellular yeasts rather than those of other complex multicellular organisms. PMID- 28633035 TI - Economy and Endurance in Human Evolution. AB - The evolutionary pressures shaping humans' unique bipedal locomotion have been a focus of research since Darwin, but the origins of humans' economical walking gait and endurance running capabilities remain unclear. Here, I review the anatomical and physiological determinants of locomotor economy (e.g., limb length and posture) and endurance (e.g., muscle volume and fiber type) and investigate their development in the hominin fossil record. The earliest hominins were bipedal but retained ape-like features in the hind limb that would have limited their walking economy compared to living humans. Moreover, the evolution of bipedalism and the loss of the forelimbs in weight support and propulsion would have reduced locomotor endurance in the earliest hominins and likely restricted ranging. Australopithecus evinced longer hind limbs, extended limb posture, and a stiff midfoot, suggesting improved, human-like economy, but were likely still limited in their endurance compared to modern humans. The appearance of skeletal traits related to endurance (e.g., larger limb joints, spring-like plantar arch) in Homo was somewhat mosaic, with the full endurance suite apparent only ~1 million years ago. The development of endurance capabilities in Homo appears to parallel the evolutionary increase in brain size, cognitive sophistication, and metabolic rate. PMID- 28633036 TI - Recent advances in understanding multiple myeloma. AB - There have been major recent advancements in the understanding and management of multiple myeloma which in turn has led to unprecedented survival outcomes for patients. Diagnostic and response criteria have been recently revised. Our understanding of clonal progression, evolution, and clonal tides will inform therapeutic choices and appropriate treatment for patients. Response rates to initial induction with modern triplet therapies containing proteasome inhibitors and immunomodulators have made this approach the global standard for initial treatment. Although the relevance of autologous transplantation has been questioned in the setting of modern induction therapy, we have new data suggesting its continued relevance. Recent studies performed in the context of novel agent induction suggest that autologous transplantation continues to improve response rates and progression-free survival, thus underscoring its role in transplant-eligible patients. Emerging paradigms in the treatment of multiple myeloma include immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations, all of which seem to synergize with a transplant platform. Allogeneic transplantation is limited in scope by the concern of prohibitive toxicity and is applicable mainly to younger patients with high-risk disease. However, the allogeneic approach offers even more options of immunotherapy at relapse, including donor lymphocyte infusions, immunomodulatory drug maintenance, and withdrawal of immune suppression. PMID- 28633037 TI - Treatment with methotrexate, rituximab, and cytosine arabinoside followed by autologous stem cell transplantation in primary central nervous system lymphoma: A single-center experience. AB - OBJECTIVE/BACKGROUND: Primary central nervous system lymphoma (PCNSL) is associated with worst prognosis compared with other aggressive non-Hodgkin's lymphomas. However, recent trials have demonstrated that long-term progression free survival can be achieved by immunochemotherapy. Our goal is to present our experience in aggressive PCNSL in this study. METHODS: We retrospectively evaluated the clinical features and management of 13 PCNSL patients who were diagnosed and treated between 2006 and 2015. RESULTS: Nine patients received rituximab (R) 375mg/m2/day on Day 1, methotrexate (MTX) 3.5g/m2/day and cytosine arabinoside (ARA-C) 4.4g/m2/day on Day 2, as well as ARA-C 4.4g/m2/day on Day 3 every 28days, and underwent autologous stem cell transplantation. Two patients received procarbazine instead of ARA-C. One patient relapsed, and allogeneic hematopoietic stem cell transplantation was performed. All nine patients are followed in complete remission. Two of 13 patients received one course of MTX and 36-45Gy radiotherapy and died. One patient with renal transplantation had progressive disease and died. Grade 3-4 hematological toxicity was detected in 11 (85%), Grade 3-4 mucositis in 11 (85%), and febrile neutropenia in 12 (92%) patients. The median overall survival in the R-MTX-ARA-C/procarbazine group was 28+/-16months. CONCLUSION: R-MTX-ARA-C followed by autologous stem cell transplantation seems a promising strategy with high response rates in PCNSL. PMID- 28633038 TI - Hematopoietic cell transplantation for diffuse large B-cell and follicular lymphoma: Current controversies and advances. AB - Non-Hodgkin's lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with diverse biologic, histologic, and clinical features. With a better understanding of the molecular pathogenesis, recently there have been major advances in the treatment of NHLs including addition of novel monoclonal antibodies, targeted therapies, and immune activators to the therapy armamentarium. Despite these remarkable developments, autologous hematopoietic cell transplantation (auto-HCT) remains not only a standard-of-care curative option for aggressive NHL but also an important therapeutic option for indolent NHL. In NHL, for patients with high-risk features, including those heavily pretreated or with refractory disease or those experiencing failure after an auto HCT, allogeneic HCT (allo-HCT) remains the only curative option. In this review, we briefly discuss the role of transplantation in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). In DLBCL patients, we discuss the role of HCT in clinically and biologically defined ultra-high-risk disease. In FL patients, auto-HCT is best reserved for relapsed chemosensitive patients after two to three lines of prior chemoimmunotherapies, who are not candidates for allo HCT, either because of donor unavailability, associated comorbidities, or patient preference. Reduced-intensity conditioning allo-HCT offers the curative option for patients with relapsed/refractory FL. Although the emergence of targeted, biologic, and immunological therapies is welcoming, it is currently unclear how these new therapies might enhance or replace allo-HCT. Until we have further definitive data, allo-HCT remains the only curative option. PMID- 28633039 TI - Giant-cell tumor of bone with pathological evidence of blood vessel invasion. AB - Giant cell tumor of bone is a rare but aggressive benign tumor that arises at the end of long tubular bones. The tumor rarely metastasizes; however, we report a case in which a giant cell tumor of bone presented with progressive pulmonary metastases. There has been no clear pathologic evidence of the definitive cause or route of metastasis. In our case, the primary tumor site was located in the left femur with pathological evidence of blood vessel invasion. The histological and pathological features of this entity are discussed in this letter to the editor. PMID- 28633040 TI - Hematopoietic cell transplantation: Training challenges and potential opportunities through networking and integration of modern technologies to the practice setting. AB - Hematopoietic cell transplantation (HCT), particularly allogeneic HCT, is a complex and a high-risk procedure requiring expertise to manage potential treatment complications. Published data supports the value of quality management systems in improving post-transplant outcomes; however, there are no universally established, or agreed upon, criteria to assess adequacy of training of physicians, transplant or nontransplant, and supporting staff, among others. It is of paramount importance for transplant centers to identify the needed area(s) of expertise in order to seek appropriate training for their staff. Moreover, transplant physicians need to keep up-to-date with the rapidly occurring advances in the field. Outcomes of patients undergoing HCT are affected by various factors related to patient, disease, procedure, preventative, and supportive strategies, among others. Accordingly, availability of databases is necessary to collect information on these variables and use to benchmark future prospective clinical trials aiming at further improving clinical outcomes. Twinning with leading centers worldwide is helping to not only bridge the survival gap of patients diagnosed with cancer in the developing vis-a-vis the developed world, but eventually closing it. The advent of the World Wide Web and revolution in telecommunication has made access to information more readily available to various sectors including healthcare. Telemedicine is enabling healthcare delivery to remote and underserved geographic areas. In the setting of HCT, ensuring compliance to prescribed therapies and post-transplant surveillance are some areas where implementing telemedicine programs could fulfill an unmet need. PMID- 28633041 TI - Study of platelet activation, hypercoagulable state, and the association with pulmonary hypertension in children with beta-thalassemia. AB - BACKGROUND: The increased survival rate of thalassemic patients has led to unmasking of management related complications which were infrequently encountered. OBJECTIVE: Study the increased coagulation and platelet activation in children with beta-thalassemia, to analyze the factors that lead to such hypercoagulable state and to study pulmonary hypertension (PH) in conjunction with platelet activation and hypercoagulable state in children with beta thalassemia. METHODS: 36 Egyptian children with beta-thalassemia with a mean age of 9.9years (+/-4.7 SD). In addition, 20 healthy Egyptian children matched for age and sex were enrolled as a control group. Both were subjected to clinical and laboratory assessments. Echocardiography was done to the patient group and PH was diagnosed based on calculated mean pulmonary artery pressure [MPAP] >25mmHg. RESULTS: We found that, mean+/-SD serum P-selectin level (platelet activator marker) was significantly higher in thalassemic patients (2337+/-566pg/ml) in comparison to controls (1467+/-247pg/ml) (P<0.001). Mean serum protein-C and antithrombin-III levels were significantly lower in thalassemic patients (1.2+/ 1.3ug/ml, 27.3+/-7.5mg/dl) in comparison to controls (2.3+/-1.3ug/ml, 35.1+/ 4.1mg/dl) (P=0.003 and <0.001) respectively. PH was detected in 17 (47.2%) patients and it was significantly associated with splenectomy (P=0.01) and non transfusion dependent thalassemia (NTDT) (P=0.04). PH was positively correlated with serum levels of P-selectin (r=0.38, P=0.02), fibrinogen (r=0.41, P=0.01) and negatively correlated with serum protein-C level (r=-0.48, P=0.003). CONCLUSION: A chronic hypercoagulable state and platelet activation is present in children with beta-thalassemia. Splenectomy and transfusion infrequency are the main risk factors noted to be associated with such hypercoagulable state and platelet activation and consequently the PH among our thalassemic patients. PMID- 28633042 TI - Feasibility study of a family-focused intervention to improve outcomes for children with FASD. AB - BACKGROUND: Growing evidence shows that children with fetal alcohol spectrum disorder (FASD) can benefit from interventions, and specifically interventions focused on improving self-regulation. However, novel ways of improving outcomes for children with FASD need further investigation so that programs target not only the individual child but also the family context, which includes the parent child relationship. AIMS: The current study aimed to evaluate the feasibility of an adapted version of the Parents under Pressure (PuP) program that addresses self-regulatory processes, through improving the parent-child relationship and the use of mindfulness-based strategies for both children and parents. METHODS: This was a mixed methods study. Feasibility was examined by evaluating recruitment, data collection/outcome measures, and intervention procedures. The study used a phenomenological approach to obtain qualitative information from caregivers and a single-case experimental design to evaluate the preliminary participant responses to the intervention. RESULTS: Two out of three families completed treatment. The recruitment and intervention procedures were found to be suitable for and acceptable to the families involved. Some concerns were identified regarding the outcome measures that would need to be addressed in future research. Quantitative and qualitative outcomes were positive. CONCLUSIONS AND IMPLICATIONS: The results provide preliminary support for the feasibility of an adapted version of the PuP program. Thus, offering a potential multi-component option, that aims to improve self-regulatory skills for children with FASD, through focusing on improving the parent-child relationship and incorporating mindfulness-based techniques for both parents and children. PMID- 28633043 TI - De novo 12q22.q23.3 duplication associated with temporal lobe epilepsy. AB - PURPOSE: Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and may be associated with acquired central nervous system lesions or could be genetic. Various susceptibility genes and environmental factors are believed to be involved in the aetiology of TLE, which is considered to be a heterogeneous, polygenic, and complex disorder. Rare point mutations in LGI1, DEPDC5, and RELN as well as some copy number variations (CNVs) have been reported in families with TLE patients. METHODS: We perform a genetic analysis by Array-CGH in a patient with dysmorphic features and temporal lobe epilepsy. RESULTS: We report a de novo duplication of the long arm of chromosome 12. CONCLUSION: We confirm that 12q22 q23.3 is a candidate locus for familial temporal lobe epilepsy with febrile seizures and highlight the role of chromosomal rearrangements in patients with epilepsy and intellectual disability. PMID- 28633044 TI - Written accounts of living with psychogenic nonepileptic seizures: A thematic analysis. AB - PURPOSE: Qualitative studies examining lived experiences of psychogenic nonepileptic seizures (PNES) have predominantly relied on datasets collected using clinical or research interviews. This study pursued a different approach by investigating individuals' written accounts of their condition. METHODS: Participants (n=19) were recruited from membership-led organisations for individuals living with seizures and from a United Kingdom hospital. Participants were instructed to produce four pieces of writing: 1) about their thoughts and feelings about their condition; 2) a letter to their condition; 3) a letter to their younger self; and 4) about a personal value. All writings were analysed using thematic analysis. RESULTS: Six main-themes emerged from the data. Theme 1: 'living with PNES' demonstrated that all participants presented the condition as having a debilitating effect. Theme 2: 'Emotions' revealed that individuals were struggling with anxiety, low mood and self-worth. Theme 3: 'Seizure symptoms' showed variability was a prominent feature in the description of ictal events. Theme 4: 'Treatment and outcomes' demonstrated that individual's perception of diagnosis and therapy differed greatly. Theme 5: 'Causation and development' revealed that the majority of participants spontaneously reported experiencing a traumatic event in the past. Theme 6: 'Lack of understanding' by themselves, the public and healthcare professionals appeared to pose considerable challenges to participants. CONCLUSIONS: Qualitative research has an important role to play for improving our understanding of PNES. The findings contribute to the literature by highlighting the nature of stigma that people with PNES experience, and also their proneness to demonstrate problems with self-worth. PMID- 28633045 TI - mRNA transport & local translation in neurons. AB - Neurons are amongst the most structurally complex cells and exhibit a high degree of spatial compartmentalization. Also, neurons exhibit rapid and dynamic signaling by processing information in a precise and, sometimes, spatially restricted manner. The signaling that occurs in axons and dendrites necessitates the maintenance and modification of their local proteomes. Local translation of mRNAs into protein is one solution that neurons use to meet synaptic demand and activity. Here we review some of the key findings and recent discoveries that have shaped our understanding of local translation in neuronal function and highlight important new techniques that might pave the way for new insights. PMID- 28633047 TI - The impacts of the global financial crisis on hospitalizations due to depressive illnesses in Taiwan: A prospective nationwide population-based study. AB - BACKGROUND: In the third quarter of 2008, a major financial crisis hit many developed countries. Taiwan suffered its own share: a rise in unemployment and a severe decline in gross domestic product. This study is to address the health consequences of this crisis on different socioeconomic populations in Taiwan. METHODS: A sample of 6,225,766 men and 5,417,651 women, was obtained and their admissions data over 2007-2012 were retrieved. Stratified into three income levels, the sample was examined on the 147,921 episodes of hospitalization due to depressive illnesses (DIs) over that period by an interrupted time series analysis for monthly incidence rates of DI hospitalizations RESULTS: The adjusted incidence rates of hospitalization (AIRH) for DIs among the low income were 10 times that of the high income group. The AIRHs were generally higher in all of three female income groups than they were in the three male income groups. The low income men and women showed increases (of 18.0% and 14.2%, respectively) beginning in April 2008 that sustained for two years. The high income women exhibited a 5.0% monthly rise in the rate of DI hospitalizations. LIMITATIONS: Our time series models can control some confounding factors, but the ecological fallacy remained. CONCLUSIONS: This study provides evidence that the economic recession resulted in increased rates of DI hospitalization in Taiwan, especially among the low income population. Women of higher incomes may have suffered a more enduring impact. PMID- 28633046 TI - Macrophages with cellular backpacks for targeted drug delivery to the brain. AB - Most potent therapeutics are unable to cross the blood-brain barrier following systemic administration, which necessitates the development of unconventional, clinically applicable drug delivery systems. With the given challenges, biologically active vehicles are crucial to accomplishing this task. We now report a new method for drug delivery that utilizes living cells as vehicles for drug carriage across the blood brain barrier. Cellular backpacks, 7-10 MUm diameter polymer patches of a few hundred nanometers in thickness, are a potentially interesting approach, because they can act as drug depots that travel with the cell-carrier, without being phagocytized. Backpacks loaded with a potent antioxidant, catalase, were attached to autologous macrophages and systemically administered into mice with brain inflammation. Using inflammatory response cells enabled targeted drug transport to the inflamed brain. Furthermore, catalase loaded backpacks demonstrated potent therapeutic effects deactivating free radicals released by activated microglia in vitro. This approach for drug carriage and release can accelerate the development of new drug formulations for all the neurodegenerative disorders. PMID- 28633048 TI - Affective traits and history of depression are related to ventral striatum connectivity. AB - INTRODUCTION: Studying remitted Major Depressive Disorder (rMDD) facilitates a better understanding of neural mechanisms for risk, given that confounding effects of active symptoms are removed. Disrupted functional connectivity has been reported in multiple networks in MDD. However, no study to date of rMDD has specifically examined connectivity of the ventral striatum (VS), a region highly implicated in reward and motivation. We investigated functional connectivity of the VS in individuals with and without a history of MDD, and in relation to affective personality traits. METHODS: Forty-two individuals with rMDD and 28 healthy controls across two sites completed resting-state fMRI and the Behavioral Inhibition System/Behavioral Activation System Scale. Voxel-wise, whole-brain comparisons were conducted across and between groups for four seeds: left and right inferior VS (VSi), left and right superior VS (VSs). RESULTS: VSs connectivity to temporal and subcortical regions including the putamen and amygdala was positive and greater in HCs compared to rMDD individuals. Across groups, VSi connectivity was positively correlated with trait reward responsiveness in somatomotor regions. Across groups, VSs connectivity was positively correlated with trait drive, particularly in the putamen, parahippocampal, and inferior temporal gyrus, and was negatively associated with trait behavioral inhibition in the anterior cingulate, frontal gyri, and insula. LIMITATIONS: Limitations include scanning at two sites and using multiple comparisons. DISCUSSION: Group connectivity differences emerged from the VSs rather than VSi. VSs showed associations with trait drive and behavioral inhibition, whereas VSi corrrelated with reward-responsiveness. Depression history and affective traits contribute meaningful and specific information about VS connectivity in understanding risk for MDD. PMID- 28633049 TI - Physical activity correlates among 24,230 people with depression across 46 low- and middle-income countries. AB - BACKGROUND: There is a paucity of nationally representative data available on the correlates of physical activity (PA) among people with depression, especially in low- and middle-income countries (LMICs). Thus, we investigated PA correlates among community-dwelling adults with depression in this setting. METHODS: World Health Survey data included 24,230 adults (43.1 +/- 16.1 years; 36.1% male) with ICD-10 diagnoses of depression including brief depressive episode and subsyndromal depression aged >= 18 years from 46 LMICs. PA was assessed by the International Physical Activity Questionnaire. Participants were dichotomised into low and moderate-to-high physically active groups. Associations between PA and a range of sociodemographic, health behaviour and mental and physical health variables were examined using multivariable logistic regressions. RESULTS: 34.8% of participants with depression were physically inactive. In the multivariate analyses, inactivity was associated with male sex, older age, not being married/cohabiting, high socio-economic status, unemployment, living in an urban setting, less vegetable consumption, and poor sleep/ low energy. In addition, mobility difficulties and some somatic co-morbidity were associated with not complying with the 150min per week moderate-to-vigorous PA recommendations. CONCLUSIONS: The current data provide guidance for future population level interventions across LMICs to help people with depression engage in regular PA. PMID- 28633050 TI - The adenosine-mediated, neuronal-glial, homeostatic sleep response. AB - Slow wave activity (SWA) during slow wave sleep (SWS) is the best indicator of the sleep homeostasis. The intensity of the SWA observed during SWS that follows prolonged waking is directly correlated with the duration of prior waking and its intensity decays during SWS suggesting a buildup and a resolution of sleep need. This sleep-homeostasis related SWA results from a buildup and decay of extracellular adenosine that acts at neuronal adenosine A1 receptors to facilitate SWA and is metabolized by adenosine kinase found in glia. This local neuronal-glial circuit for homeostatic SWA is primarily under the requisite control of two genes, the Adora1 and Adk, encoding the responsible adenosine receptor and adenosine's highest affinity metabolizing enzyme. PMID- 28633051 TI - Influence of lactic acid and post-treatment recovery time on the heat resistance of Listeria monocytogenes. AB - The aim of this study was to evaluate the effect of lactic acid (LA) with and without organic material at various post-treatment recovery times on the heat resistance of Listeria monocytogenes (Lm). LA decreased Lm numbers; however, the effect was remarkably attenuated by the presence of organic matter. Five strains of Lm were treated with LA and the listericidal effects were compared. The effect of LA varied depending on the strain, with >=3.0% (w/w) LA required to kill the Lm strains in a short time. The heat resistance of Lm treated with LA was examined with respect to the time interval between the acid treatment and the subsequent manufacturing step. The heat resistance of Lm was shown to significantly increase during the post-treatment period. Heat tolerance (D value) increased up to 3.4-fold compared with the non-treated control bacteria. RNA sequencing and RT-PCR analyses suggested that several stress chaperones, proteins controlled by RecA and associated with high-temperature survival, were involved in the mechanism of enhanced heat resistance. These results are applicable to manufacturers when LA and heat treatment methods are utilized for the effective control of Lm in foods. PMID- 28633052 TI - Disinfection efficiencies of sage and spearmint essential oils against planktonic and biofilm Staphylococcus aureus cells in comparison with sodium hypochlorite. AB - Staphylococcus aureus causes human infections and foodborne intoxications. This study explored the potential antibacterial actions of sage and spearmint essential oils (EOs) against both its planktonic and biofilm cells, in comparison with sodium hypochlorite (NaOCl), a commonly applied chemical sanitizer. Initially, the minimum inhibitory and bactericidal concentrations (MICs, MBCs) of each plant mixture were determined against planktonic cultures, following growth at 30 degrees C for 24h. Stationary phase planktonic bacteria were then individually exposed for 6min to either each EO (applied at 1-2*MBC; 2.5-5%), or NaOCl (250-450ppm). These were also left to form biofilms on 96-well polystyrene microplates, at 30 degrees C for 96h, with medium renewal at 48h, in the presence of 10 different concentrations of each EO, expanding from sub- to super inhibitory for planktonic growth, and the minimum biofilm inhibitory concentrations (MBICs; >90% inhibition) of each plant mixture were calculated. Formed biofilms were finally exposed for 6min to either each EO (applied at 2 6*MBC; 5-15%), or NaOCl (7500-25,000ppm; applied either alone or in combination with each EO at 5%). Results showed that both EOs presented MIC and MBC equal to 1.25 and 2.5%, respectively. As expected, their application at their MIC and above significantly inhibited biofilm formation, while spearmint EO was still able to cause this at 1/2 of its MIC, with MBICs equal to 1.25 and 0.63% for sage and spearmint EOs, respectively. Alarmingly, the application of both EOs at 1/8 to 1/16 of their MIC further increased biofilm formation. Regarding biofilm disinfection experiments, the individual application of each EO against the pre established sessile communities resulted in log decrease ranges of 0.8 3logCFU/cm2, while in the case of NaOCl application (either alone or combined with each EO), the observed reductions never exceeded 1.7logCFU/cm2. These last results highlight the great antimicrobial recalcitrance of biofilm communities, found here to be ca. 100 times more resistant to NaOCl compared to planktonic ones, and stress the urgent need for further research on alternative, adequate and safe disinfection strategies to control them in food processing and other environments. PMID- 28633053 TI - The major Alternaria alternata allergen, Alt a 1: A reliable and specific marker of fungal contamination in citrus fruits. AB - The ubiquitously present spores of Alternaria alternata can spoil a wide variety of foodstuffs, including a variety of fruits belonging to the Citrus genus. The major allergenic protein of A. alternata, Alt a 1, is a species-specific molecular marker that has been strongly associated with allergenicity and phytopathogenicity of this fungal species. This study aimed to evaluate the potential of the detection of Alt a 1 as a reliable indicator of A. alternata contamination in citrus fruits. To accomplish this aim, sixty oranges were artificially infected with a spore suspension of A. alternata. Internal fruit material was collected at different incubation times (one, two and three weeks after the fungal inoculation) and used for both total RNA extraction and protein extraction. Alt a 1 detection was then performed by polymerase chain reaction (PCR) amplification using Alt a 1 specific primers and by enzyme-linked immunosorbent assay (ELISA). The experimental model presented in this work was effective to simulate the typical Alternaria black rot phenotype and its progression. Although both PCR and ELISA techniques have been successfully carried out for detecting Alt a 1 allergen in A. alternata infected oranges, the PCR method was found to be more sensitive than ELISA. Nevertheless, ELISA results were highly valuable to demonstrate that considerable amounts of Alt a 1 are produced during A. alternata fruit infection process, corroborating the recently proposed hypothesis that this protein plays a role in the pathogenicity and virulence of Alternaria species. Such evidence suggests that the detection of Alt a 1 by PCR-based assay may be used as a specific indicator of the presence of pathogenic and allergenic fungal species, A. alternata, in fruits. This knowledge can be employed to control the fungal infection and mitigate agricultural losses as well as human exposure to A. alternata allergens and toxins. PMID- 28633054 TI - Men and women with psychosis and the impact of illness-duration on sex differences: The second Australian national survey of psychosis. AB - We aimed to examine and compare sex-differences in people receiving treatment for psychotic illnesses in community settings, based on long or short duration of illness; expecting association between longer illness-duration and worse outcomes in women and men. Clinical, demographic and service-use data from the Survey of High Impact Psychosis were analysed by sex and duration of illness (<=5 years; >=6 years), using independent t-tests, chi-square tests, one-way ANOVA, and Cramer's V. Of the 1825 participants, 47% had schizophrenia, 17.5% bipolar and 16.1% schizo-affective disorders. More women than men had undertaken post-school education, maintained relationships, and been living in their own homes. Women with a shorter-illness-duration showed social functioning equivalent to non-ill women in the general population. Men tended to have an early illness onset, show premorbid dysfunction, be single, show severe disability, and to use illicit substances. Men with a longer-illness-duration were very socially disadvantaged and isolated, often experiencing homelessness and substance use. Men with a short illness-duration were most likely to be in paid employment, but two-thirds earned less than $AUD500 per fortnight. Men with longer-illness-duration showed most disability, socially and globally. Interventions should be guided by diagnosis, but also by a person's sex and duration of illness. PMID- 28633055 TI - Face-related visual search deficits in first-episode schizophrenia. AB - Schizophrenia is considered a complex illness with multiple cognitive dysfunctions, including a deficit in visual processing. However, whether the deficiency of visual processing in schizophrenia is general across stimuli or stimulus-specific remains the subject of debate. In the current study, eighteen first-episode schizophrenic patients and eighteen healthy controls participated in three visual search tasks in which they were asked to search a specific target of a triangle, face identity or facial affect. The results showed that, compared to healthy controls, the accuracies for face identity and facial affect searches were significantly lower in schizophrenic patients, while the performance of the triangle search was the same. Furthermore, the accuracy of the facial affect search was negatively correlated to negative symptoms in schizophrenia. These results revealed a face-related deficit in schizophrenia and suggest that visual processing deficits in schizophrenia were stimuli-specific. PMID- 28633057 TI - Predicting falls in community dwelling older adults using the Activities-specific Balance Confidence Scale. AB - OBJECTIVES: Falls are a significant problem associated with aging, and can lead to serious consequences including injury and death. The purpose of this study was to determine whether balance confidence differed between future fallers and non fallers, and whether the construct prospectively predicted falls. METHODS: Forty five community dwelling older adults aged 65 or older completed the Activities specific Balance Confidence scale (ABC) and reported falls experienced during the next 6 months. RESULTS: Eleven (24.4%) subjects were fallers, and had significantly poorer ABC scores (x=50.6%) than their non-faller counterparts (x=76.3%). The regression model was significant, where the ABC score predicted falls at 6 months. DISCUSSION: Our findings suggest that balance confidence differs between fallers and non-fallers, and that ABC scores can predict future falls in community dwelling older adults. CONCLUSION: Balance confidence is a fall risk predictor, and thus a critical component of fall risk assessment. Balance confidence should be measured regularly in community dwelling older adults using the ABC. PMID- 28633058 TI - Prenatal and early postnatal depression and child maltreatment among Japanese fathers. AB - We investigated the association of paternal depression in the prenatal and early postnatal period with child maltreatment tendency at two months postpartum among Japanese fathers. This population-based longitudinal study recruited Japanese perinatal women and their partners living in Nishio City, Aichi, Japan. Of the 270 fathers who participated, 196 were included in the analysis. All data were collected via self-administrated questionnaires at four time points: 20 weeks' gestation and in the first few days, one month, and two months postpartum. Paternal depression was assessed using the Edinburgh Postnatal Depression Scale. Three definitions of paternal depression were coded based on participants' scores on this measure: prenatal, prior, and current. Child maltreatment tendency was evaluated using the Child Maltreatment Scale at two months postpartum. The associations of the three definitions of paternal depression and child maltreatment tendency were separately analyzed using logistic regression analysis. The prevalence of prenatal, prior, and current paternal depression was 9.7%, 10.2%, and 8.8%, respectively. According to the multivariate analysis, current paternal depression was significantly associated with child maltreatment tendency at two months postpartum (adjusted odds ratio: 7.77, 95% CI: 1.83 33.02). The other two types of depression, however, were not related to child maltreatment tendency. Thus, current paternal depression increased the risk of child maltreatment tendency in the postnatal period, suggesting that early detection and treatment of paternal depression might be useful for the prevention of child maltreatment. PMID- 28633056 TI - Exploratory analysis of normative performance on the UCSD Performance-Based Skills Assessment-Brief. AB - The UCSD Performance-Based Skills Assessment (UPSA) is a performance-based measure of functional capacity. The brief, two-domain (finance and communication ability) version of the assessment (UPSA-B) is now widely used in both clinical research and treatment trials. To date, research has not examined possible demographic-UPSA-B relationships within a non-psychiatric population. We aimed to produce and describe preliminary normative scores for the UPSA-B over a full range of ages and educational attainment. The finance and communication subscales of the UPSA were administered to 190 healthy participants in the context of three separate studies. These data were combined to examine the effects of age, sex, and educational attainment on the UPSA-B domain and total scores. Fractional polynomial regression was used to compute demographically-corrected T-scores for the UPSA-B total score, and percentile rank conversion was used for the two subscales. Age and education both had significant non-linear effects on the UPSA B total score. The finance subscale was significantly related to both gender and years of education, whereas the communication subscale was not significantly related to any of the demographic characteristics. Demographically corrected T scores and percentile ranks for UPSA-B scores are now available for use in clinical research. PMID- 28633059 TI - Adverse family experiences and flourishing amongst children ages 6-17 years: 2011/12 National Survey of Children's Health. AB - Adverse Childhood Experiences (ACEs) are prevalent in the population and linked to various negative long-term health and social consequences. However, due to the retrospective nature of most studies on the topic, little is currently known regarding ACEs' immediate health impact. This study aims to provide insight into this area by examining the association between a new measurement, Adverse Family Experiences (AFEs), and flourishing amongst children ages 6-17 years in the United States. Data from the 2011/12 National Survey of Children's Health were analyzed. Adjusted prevalence ratios assessed flourishing by the number of AFEs (0 events versus 1, 2, 3/3+) controlling for individual/household characteristics. A sub-analysis examined characteristics of flourishing children ages 12-17 years with 3/3+ AFEs. The results showed children with 1 AFE (APR=0.87; 95% CI=0.83-0.91), 2 AFEs (0.74; 0.69-0.79), and 3/3+ AFEs (0.68; 0.62 0.72) were less likely to flourish compared to those without any AFEs. Sub analysis of children ages 12-17 years with 3/3+ AFEs revealed a higher proportion of flourishing children volunteering, participating in extracurricular activities, and working for pay compared to those who did not flourish. Findings show significant differences in flourishing by number of AFEs and suggest that social connectedness may play a role in determining flourishing amongst children with 3/3+ AFEs. Furthermore, the results highlight the potential importance of identifying children with high AFE counts and helping them build resilience outside of the home. PMID- 28633061 TI - 1,4-Anthraquinone: A new useful pre-column reagent for the determination of N acetylcysteine and captopril in pharmaceuticals by high performance liquid chromatography. AB - 1,4-Anthraquinone (ANQ) is proposed as a novel pre-column reagent for high performance liquid chromatography (HPLC) determination of N-acetylcysteine (NAC) and captopril (CAP) in pharmaceutical formulations. The derivatization reactions were carried out at room temperature: NAC at pH 8 for 1min, while CAP at pH 7.5 for 20min. Both reactions reached completeness at a reagent to thiol molar ratio of about 2.5. The synthesised derivatives were characterized by 1H NMR and IR. The chromatographic separations were performed on a C18 Phenomenex Synergi Fusion 4MUm (250mm*4.6mm I.D.) stainless steel column with detection at lambda=300nm. The mobile phase consisted of methanol/triethylammonium (TEA) phosphate buffer (pH 3; 0.05mol/L) 75:25 (v/v) at a flow-rate of 0.4mL/min for NAC and 88:12 (v/v), at a flow-rate of 0.6mL/min for CAP. The validation parameters (linearity, sensitivity, accuracy, precision, specificity and stability) were highly satisfactory. Linear response was observed (determination coefficient >=0.9996). Detection limits were about 8 and 18ng/mL for NAC and CAP, respectively. Intra day precision (relative standard deviation, R.S.D.) was <=1.58%, for thiol to internal standard (IS) peak area ratio and <=0.33%, for thiol and IS retention times (tR), without significant differences between intra- and inter-day data. Thiol recovery studies were satisfactory (99.50%) with R.S.D. <=0.56%. The results highlight the high sensitivity of the method and the remarkable reactivity and selectivity of the reagent towards the thiol function. The developed method is suitable for the quality control of both thiols in commercial products. The method can be applied in any analytical laboratory not requiring a sophisticated instrumentation. PMID- 28633060 TI - Childhood adversity and cognitive functioning in patients with major depression. AB - OBJECTIVE: Major depression is often accompanied by deficits in cognitive functioning and lowered executive functions. However, not all depressed patients show impairments in these domains. The aim of this study was to examine whether different kinds of childhood adversity might account for cognitive deficits in patients with major depression. METHODS: Ninety-one patients with major depression (DSM-IV) and 40 healthy controls completed a neuropsychological test battery assessing memory, processing speed and executive functions. The Childhood Trauma Questionnaire (CTQ) was used to measure the severity and number of incidences of sexual, physical and emotional abuse and physical and emotional neglect. RESULTS: Patients with major depression had a significantly higher number of traumas and reported more severe emotional abuse, emotional neglect and physical neglect than healthy controls. Patients performed less well in memory tasks, general knowledge and processing speed than healthy controls. Hierarchical regression analyses indicated that the overall number of traumas was significantly associated with poorer general knowledge, lower processing speed and impaired executive functions in patients with major depression. A second model including all CTQ-subscales simultaneously demonstrated an association between physical neglect and poorer verbal learning, and physical abuse and diminished executive functions. CONCLUSION: A higher number of childhood adversities may influence general knowledge, processing speed and executive functions in patients with major depression. In addition, physical abuse and neglect seemed to be associated with verbal learning deficits and poorer executive functions. PMID- 28633062 TI - Blue light induced reactive oxygen species from flavin mononucleotide and flavin adenine dinucleotide on lethality of HeLa cells. AB - Photodynamic therapy (PDT) is a safe and non-invasive treatment for cancers and microbial infections. Various photosensitizers and light sources have been developed for clinical cancer therapies. Flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) are the cofactor of enzymes and are used as photosensitizers in this study. Targeting hypoxia and light-triggering reactive oxygen species (ROS) are experimental strategies for poisoning tumor cells in vitro. HeLa cells are committed to apoptosis when treated with FMN or FAD and exposed to visible blue light (the maximum emitted wavelength of blue light is 462nm). Under blue light irradiation at 3.744J/cm2 (=0.52mW/cm2 irradiated for 2h), the minimal lethal dose is 3.125MUM and the median lethal doses (LD50) for FMN and FAD are 6.5MUM and 7.2MUM, respectively. Individual exposure to visible blue light irradiation or riboflavin photosensitizers does not produce cytotoxicity and no side effects are observed in this study. The western blotting results also show that an intrinsic apoptosis pathway is activated by the ROS during photolysis of riboflavin analogues. Blue light triggers the cytotoxicity of riboflavins on HeLa cells in vitro. Based on these results, this is a feasible and efficient of PDT with an intrinsic photosensitizer for cancer research. PMID- 28633063 TI - Serum perfluoroalkyl acids (PFAAs) and associations with behavioral attributes. AB - The ubiquitous use of poly- and perfluoroalkyl substances (PFASs) in a variety of industrial and consumer products has resulted in chronic exposure in most industrialized nations, and led to measurable concentrations in blood and other tissues in humans across all life stages; however, behavioral attributes that relate to exposure are not well studied. To further investigate how behavior may relate to PFAS exposure, 37 adults were recruited from central North Carolina. Participants provided blood samples and behavioral questionnaires were administered, asking questions about a variety of household, dietary, and behavioral outcomes. Six PFAAs, including PFHxA (geometric mean: 0.14 ng/mL), PFOA (1.57 ng/mL), PFNA (0.67 ng/mL), PFDA (0.28 ng/mL), PFHxS (3.17 ng/mL) and PFOS (4.96 ng/mL) were detected in >50% of the samples. Generally, males had higher serum levels than females across all chemicals, and levels were very similar to NHANES levels; however, PFHxS and PFDA levels were higher in our study population. Several personal characteristics and behaviors were associated with serum PFAS levels. Reported use of filtration devices was associated with lower levels of PFOA (28% lower, p = 0.03), but higher levels of PFHxA (122% higher, p = 0.04). Serum PFHxS levels were also elevated in individuals that vacuumed less often, and in individuals that reported consuming more microwavable foods. These results suggest that personal behaviors may be important determinants of PFAS exposures. PMID- 28633064 TI - An innovative approach to bioremediation of mercury contaminated soils from industrial mining operations. AB - Soils contaminated with mercury (Hg) have proved expensive and logistically difficult to remediate. Research continues into finding suitable environmentally friendly and efficient ways of achieving this end. Bioremediation is an option, which employs the strategies microorganisms have evolved to deal with Hg. One microbial strategy involves uptake and intracellular volatilisation of mercuric ions, which passively diffuse from the cell and back into the atmosphere. In this work, Pseudomonas veronii cells grown to stationary phase were immobilised in a xanthan gum-based biopolymer via encapsulation. The P. veronii-biopolymer mix was then coated onto natural zeolite granules. Zeolite immobilised cells remained viable for at least 16 weeks stored under ambient room temperature. Furthermore, the immobilised cells were shown to retain both viability and Hg volatilisation functionality after transportation from Australia to the USA, where they were applied to Hg contaminated soil. Maximum flux rates exceeded 10 MUg Hg m2 h-1 from mine tailings (~7 mg kg-1 Hg with 50% v/v water). This was 4 orders of magnitude above background flux levels. It is envisioned that emitted gaseous elemental mercury (GEM) can be readily captured, and transformed back into metallic Hg, which can then be stored appropriately or recycled. This breaks the Hg cycle, as GEM is no longer translocated back to the atmospheric compartment. The immobilising excipients used in this research overcome many logistical issues with delivery of suitable microbial loads to locations of mercury contamination and presents a facile and inexpensive method of augmenting contaminated sites with selected microbial consortia for bioremediation. PMID- 28633066 TI - An EMG-assisted modeling approach to assess passive lumbar tissue loading in vivo during trunk bending. AB - Lower back pain (LBP) is a condition with high prevalence and high cost both in the United States and around the world. The magnitude of mechanical loading on spine is strongly associated with the occurrence of LBP. Previously, to assess spinal loading, biologically assisted biomechanical models were developed to estimate trunk muscle contraction forces. Loadings on lumbar passive tissues are estimated using anatomical models. However, despite the substantial individual variability in lumbar ligament geometry and viscoelastic properties, the existing anatomical models do not account for these differences. As such, the accuracy of model prediction is compromised especially when mid to full range of trunk motions are involved. This paper describes a new modeling approach to assess lumbar passive tissue loading with the consideration of individual differences in lumbar passive tissue properties. A data set that has trunk bending data from 13 human participants was analyzed; on average, lumbar passive tissue contributes to ~89% of the total spinal compression force at fully flexed trunk postures; the estimated spinal tissue loadings were in feasible ranges as reported from previous cadaver studies; the estimated spinal loadings were also mostly in agreement with results from previous in vivo studies. PMID- 28633065 TI - Differential accumulation of PAHs, elements, and Pb isotopes by five lichen species from the Athabasca Oil Sands Region in Alberta, Canada. AB - A 2014 case study investigated the relative accumulation efficiency of polycyclic aromatic hydrocarbons (PAHs), total sulfur (S), total nitrogen (N), major and minor elements and Pb isotopes in five common lichen species at three boreal forest sites in the Athabasca Oil Sands Region (AOSR) in northeastern Alberta, Canada to identify the optimum lichen species for future biomonitoring. Differences in concentrations of PAHs, multiple elements, and Pb isotopes in fruticose (Bryoria furcellata, Cladina mitis, Evernia mesomorpha) and foliose (Hypogymnia physodes and Tuckermannopsis americana) lichens were found along a 100 km distance gradient from the primary oil sands operations. Integration of insights from emission source samples and oil sands mineralogy in consort with aerosol collection indicates incorporation of more fine particulate matter (PM) into foliose than fruticose lichen biomass. Contrasting PAH with element concentrations allowed lichen species specific accumulation patterns to be identified. The ability of lichen species to incorporate different amounts of gas phase (S and N), petrogenic (V, Ni, Mo), clay (low Si/Al and more rare earth elements), and sand (higher Si/Al and Ti) components from the oil sand operations reflects aerosol particle size and lichen physiology differences that translate into differences in PM transport distances and lichen accumulation efficiencies. Based on these findings Hypogymnia physodes is recommended for future PAH biomonitoring and source attribution studies. PMID- 28633067 TI - Microbial electrosynthesis of butyrate from carbon dioxide: Production and extraction. AB - To date acetate is the main product of microbial electrosynthesis (MES) from carbon dioxide (CO2). In this work a tubular bioelectrochemical system was used to carry out MES and enhance butyrate production over the other organic products. Batch tests were performed at a fixed cathode potential of -0.8V vs SHE. The reproducibility of the results according to previous experiments was validated in a preliminary test. According to the literature butyrate production could take place by chain elongation reactions at low pH and high hydrogen partial pressure (pH2). During the experiment, CO2 supply was limited to build up pH2 and trigger the production of compounds with a higher degree of reduction. In test 1 butyrate became the predominant end-product, with a concentration of 59.7mMC versus 20.3mMC of acetate, but limitation on CO2 supply resulted in low product titers. CO2 limitation was relaxed in test 2 to increase the bioelectrochemical activity but increase pH2 and promote the production of butyrate, what resulted in the production of 87.5mMC of butyrate and 34.7mMC of acetate. The consumption of ethanol, and the presence of other products in the biocathode (i.e. caproate) suggested that butyrate production took place through chain elongation reactions, likely driven by Megasphaera sueciensis (>39% relative abundance). Extraction and concentration of butyrate was performed by liquid membrane extraction. A concentration phase with 252.4mMC of butyrate was obtained, increasing also butyrate/acetate ratio to 16.4. The results are promising for further research on expanding the product portfolio of MES. PMID- 28633069 TI - Mitogenomic diversity in Russians and Poles. AB - Complete mtDNA genome sequencing improves molecular resolution for distinguishing variation between individuals and populations, but there is still deficiency of mitogenomic population data. To overcome this limitation, we used Sanger-based protocol to generate complete mtDNA sequences of 376 Russian individuals from six populations of European part of Russia and 100 Polish individuals from northern Poland. Nearly complete resolution of mtDNA haplotypes was achieved - about 97% of haplotypes were unique both in Russians and Poles, and no haplotypes overlapped between them when indels were considered. While European populations showed a low, but statistically significant level of between-population differentiation (Fst=0.66%, p=0), Russians demonstrate lack of between-population differences (Fst=0.22%, p=0.15). Results of the Bayesian skyline analysis of Russian mitogenomes demonstrate not only post-Last Glacial Maximum expansion, but also rapid population growth starting from about 4.3kya (95% CI: 2.9-5.8kya), i.e. in the Bronze Age. This expansion strongly correlates with the Kurgan model established by archaeologists and confirmed by paleogeneticists. PMID- 28633068 TI - Multi-electrode system for measurement of transmembrane ion-fluxes through living epithelial cells. AB - Cystic Fibrosis (CF) is the most common fatal human genetic disease. It is caused by the defect in a single anion channel protein which affects ion and water transport across the epithelial tissue. A flat multi-electrode platform of diameter 12mm, allowing for measurement of four ions: sodium, potassium, hydrogen and chloride by exchangeable/replaceable ion-selective electrodes is described. The measurement is possible owing to the architecture of the platform which accommodates all the electrodes and inlets/outlets. The platform fits to the cup and operates in a small volume of the solution bathing the living epithelial cell layer (membrane) deposited on a porous support of the cup, which allows for effective monitoring of ion concentration changes. By applying two multi electrode platforms, it is possible to measure the ion transmembrane fluxes. The inlet and outlet tubes in the platforms allow for on-fly change of the calibrants, ion-concentration changes and ion channel blockers. Using different ion-concentration gradients and blockers of ion-transporting molecules we show for the first time that sodium ions flow from the basolateral to apical face of the cell monolayer via a paracellular route and return also via a transcellular one, while chloride anions are transported back and forth exclusively via a transcellular route. PMID- 28633070 TI - Length and repeat-sequence variation in 58 STRs and 94 SNPs in two Spanish populations. AB - We have genotyped the 58 STRs (27 autosomal, 24 Y-STRs and 7 X-STRs) and 94 autosomal SNPs in Illumina ForenSeqTM Primer Mix A in 88 Spanish Roma (Gypsy) samples and 143 Catalans. Since this platform is based in massive parallel sequencing, we have used simple R scripts to uncover the sequence variation in the repeat region. Thus, we have found, across 58 STRs, 541 length-based alleles, which, after considering repeat-sequence variation, became 804 different alleles. All loci in both populations were in Hardy-Weinberg equilibrium. FST between both populations was 0.0178 for autosomal SNPs, 0.0146 for autosomal STRs, 0.0101 for X-STRs and 0.1866 for Y-STRs. Combined a priori statistics showed quite large; for instance, pooling all the autosomal loci, the a priori probabilities of discriminating a suspect become 1-(2.3*10-70) and 1-(5.9*10-73), for Roma and Catalans respectively, and the chances of excluding a false father in a trio are 1-(2.6*10-20) and 1-(2.0*10-21). PMID- 28633071 TI - Structural characterization of the immunostimulatory exopolysaccharide produced by Leuconostoc mesenteroides strain NTM048. AB - The exopolysaccharide (EPS) produced by probiotic Leuconostoc mesenteroides subsp. mesenteroides strain NTM048 has been reported to be an immunostimulant that enhances mucosal IgA production. In this study, we found that intranasal administration of mice with the EPS and an antigen (ovalbumin) resulted in secretion of antigen-specific IgA and IgG in the airway mucosa and the serum, suggesting that the EPS has the adjuvant activity for use with mucosal vaccination. Methylation analysis coupled to GC-MS, and 1D and 2D NMR spectroscopy revealed that 94% of the EPS consists of an alpha-(1 -> 6) glucan containing 4% of 1->3-linked alpha-glucose branches. To determine structures of minor components, we enzymatically digested the glucan with dextranase and used 2D NMR spectroscopy to identify the remaining polymer as a fructan (or fructans), containing both beta-(2 -> 6)- and beta-(2 -> 1)-linked fructofuranose residues. These residues may either enter into separate polymers of each linkage type or form a mixed fructan containing both linkage types. PMID- 28633073 TI - Aggregation of N,N'-diallylurea and N,N'-diallylthiourea in solutions. AB - Joint studies by IR spectroscopy, dipole moments, average molecular weight measurements and DFT calculations on the self-aggregation of N,N'-diallylureas and N,N'-diallylthioureas in solvents of different polarities were performed. Simultaneous uses of all these methods are required for better understanding the mechanism of aggregation and the effects of different polarity of solvents. In this study also the measurements of IR spectra in polarized light were additionally performed, which gives information on arrangement of aggregates in liquid crystal matrix-built of 4-CN biphenyl derivative. It was demonstrated that in such conditions two forms of dimers the linear and cyclic ones are in equilibrium with different arrangements according the axis of CN group. PMID- 28633074 TI - Programming cells for cardiac repair. AB - Because the heart is a poorly regenerative organ, there has been considerable interest in developing novel cell-based approaches to restore lost contractile function after myocardial infarction (MI). While a wide variety of candidate cell types have been tested in animal MI models, the vast majority of clinical trials have used adult stem cell types, usually derived from bone marrow. These studies have generally yielded disappointing results, an outcome that may reflect in part the limited cardiogenic potential of the adult stem cell sources employed. Post MI heart failure is ultimately a disease of cardiomyocyte deficiency, so better outcomes may be possible with more cardiogenic approaches that may 'remuscularize' the infarct scar with new, electrically-integrated myocardium. In this review, we summarize work in the field to 'program' exogenous or endogenous cells into such a cardiogenic state, as well as efforts to test their capacity to mediate true heart regeneration. PMID- 28633072 TI - Roles of serum in innate immune responses of human leukocytes to synthetic lipopeptide. AB - Tripalmitoyl-S-glyceryl-l-Cys-Ser-(Lys)4 (Pam3CSK4) is a highly conserved molecular motif found in various classes of lipoproteins. The requirement for leukocyte to respond to synthetic Pam3CSK4 were studied. Pam3CSK4 primed neutrophils for a respiratory burst in a serum-dependent manner. Pam3CSK4 upregulated CD11b, CD14, and cytochrome b558, and downregulated Leu-8. Treatment of neutrophils with anti-CD14 antibodies and treatment of serum with anti-LPS binding protein (LBP) antibodies resulted in the inhibition of priming for respiratory burst by Pam3CSK4. It should be noted that LBP could not replicate the effects of serum in priming of neutrophils for respiratory burst by Pam3CSK4. Serum LBP bound to immobilized Pam3CSK4. Pam3CSK4 induced the interleukin-8 (IL 8) production by leukocytes in a serum-dependent manner. Further, Pam3CSK4 induced priming of neutrophils for respiratory burst was not inhibited by the LPS antagonists LA-14-PP, Rhodobacter sphaeroides LPS, or E5531, and Pam3CSK4-induced IL-8 production by leukocytes was not affected by LPS antagonist, E5531, indicating that Pam3CSK4 was recognized by a different receptor than LPS. Thus, Pam3CSK4 and LPS had similar biological activities and similar requirement to act on leukocytes, but were recognized by different receptors. Serum in the action of Pam3CSK4 on leukocytes was not replicated by LBP, suggesting that Pam3CSK4 might be disaggregated by serum to result in the activation of leukocytes. PMID- 28633075 TI - Elective unilateral nodal irradiation in head and neck squamous cell carcinoma: A paradigm shift. AB - There is a long-standing convention to irradiate the great majority of head and neck squamous cell carcinoma (HNSCC) electively to both sides of the neck, to reduce the theoretically increased risk of contralateral regional failure (cRF). With the currently available diagnostic imaging techniques this treatment paradigm means, in our opinion, an overtreatment in considerable proportion of these patients. From all the published studies (n = 11, with 1116 patients treated in total), the incidence of cRF in patients with oropharyngeal cancer treated to one side of the neck is 2.4%. The incidence was higher in patients with tumours involving the midline (12.1%). The low incidence of cRF was also seen in patients with HNSCC treated by local excision combined with unilateral neck dissection or sentinel node procedure. It seems clear from the aggregated data of these studies that a less conservative approach with regard to the selection of patients for unilateral elective nodal irradiation is justified. The fear of leaving the contralateral neck untreated in well-selected groups of patients with HNSCC needs nowadays to be mitigated since the incidence of cRF in lateralised tumours extending to but not crossing the midline is low. Furthermore, the obviously improved diagnostic imaging nowadays could help us to guide the selection of considerable proportion of patients with lateralised HNSCC for unilateral elective nodal irradiation with significant reduction of radiation related toxicity and improved quality of life. PMID- 28633077 TI - Simplified empirical model for phosphorous removal in a facultative wastewater lagoon. AB - Nutrient removal in a facultative lagoon in Manitoba, Canada, was monitored from May 2015 to April 2016. According to the 12-month data, phosphorous concentration in the effluent did not meet the regulatory requirement. Various models have been developed to predict nitrogen removal from lagoon through the years; however, not much effort has been deployed to model phosphorous removal from lagoons. Therefore, this research aims to relate the lagoon phosphate removal to the volatile suspended solids (VSS), metal concentration, and detention time. A simple empirical equation was derived by observing the one-year data, which considers assimilation into biomass as a major mechanism of phosphorous removal. The metals' concentration was found to be very low in the facultative lagoon studied. Hence, phosphorous precipitation by metals was neglected. The model relates assimilation directly to VSS which is simple to evaluate practically unlike other models that require individual algae and bacteria concentration. The correlation coefficient (R2) between the observed and the predicted effluent VSS was 0.92, which indicates excellent fit. The R2 between observed and predicted effluent orthophosphate was 0.83, which indicates moderate fit. The trend of modeled effluent phosphate is similar to the observed effluent phosphate concentration, which approves the validity of this model. The model developed in this research can be used to predict the average effluent VSS and phosphorous concentration in similar facultative lagoons. PMID- 28633076 TI - Resting-state functional connectivity of anterior and posterior hippocampus in posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) has been associated with altered resting state functional connectivity (rs-FC) of several brain regions within the salience (SN) and default-mode (DMN) networks, including the hippocampus. However, most rs-FC studies have not focused primarily on the hippocampus, nor have they appreciated its structural heterogeneity, despite clear evidence for a dissociation between posterior and anterior hippocampal connectivity. Here, we examine rs-FC of anterior and posterior hippocampus with key regions in the SN (amygdala, insula, and dorsal anterior cingulate cortex/pre-supplementary motor area) and DMN (ventromedial prefrontal cortex, posterior cingulate cortex, and precuneus) previously implicated in PTSD, using a seed-based approach. Resting state magnetic resonance images were obtained from 48 PTSD patients and 34 trauma exposed healthy participants (TEHC). Results indicated no group differences when examining the hippocampus as a whole. However, examining the anterior and posterior hippocampus revealed a loss of anterior to posterior connectivity differentiation in PTSD patients. The PTSD group also demonstrated lower negative connectivity of the posterior hippocampus-precuneus pathway compared with the TEHC group. Finally, as differences in anterior and posterior hippocampus connectivity have been also related to age, we performed a secondary analysis exploring the association between age and posterior- and anterior-hippocampus connectivity in both groups. Results showed that among PTSD patients, increased age had the effect of normalizing posterior hippocampus-precuneus and hippocampus posterior cingulate cortex connectivity, whereas no such effect was noted for the control group. These findings highlight the need for PTSD connectivity research to consider sub-parts of the hippocampus and to account for age-related connectivity differences. PMID- 28633078 TI - Utilization of phosphogypsum and phosphate tailings for cemented paste backfill. AB - This research is an investigation of the feasibility of utilizing phosphogypsum (PG) and phosphate tailings (PTS) for cemented paste backfill. Some experiments were conducted with various combinations of PTS and PG as aggregates, along with slags and/or Portland cement as binders and CaO as an additive. The influence of the PG's ageing time on the consolidation of backfill was also explored. The unconfined compressive strength (UCS), the generated gases and the scanning electron microscope (SEM) were all tested and used in the analysis of backfill characteristics. The results show that (i) the highest UCS of backfill prepared by PG and PTS after curing for either 7 days or 28 days is still less than 1.0 MPa, with a large amount of CO2 and SO2 generated; (ii) the slags can improve the UCS by a factor of three, but not without a vast generation of CO2, SO2, and H2S. However, the gases were not produced when CaO was added, but the UCS decreases suddenly to 0.2 or 0.4 MPa after curing for 7 days or 28 days, respectively; (iii) the UCS of backfill increases linearly with increasing cement content. When the CaO was added at 2%, the UCS reached 3.36 MPa after curing for 7 days and 4.44 MPa after curing for 28 days, and no gases were generated; (iv) the influence of the PG's ageing time on the UCS is negligible after 4 days of aging. Based on these results, it was concluded that PG and PTS can be utilized as backfill materials when Portland cement is used as a binder and CaO is used as an additive. PMID- 28633080 TI - Disruptive non-disruptive applications of CRISPR/Cas9. AB - The bacterial type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR Associated (Cas) systems, and in particular Streptococcus pyogenes CRISPR-Cas9, have been broadly applied to edit the genome of bacterial and eukaryotic cells. Cas9, which is an RNA-guided programmable nuclease, is a powerful tool for disrupting protein-coding genes. Cas9 cleaves target sites to generate a double-strand break (DSB) that is repaired via an error-prone repair process, leading to insertion/deletion mutations and gene knockouts. However, Cas9 can also be used to modulate genome function without gene disruption, enabling base editing, transcriptional and epigenetic reprogramming, genome imaging, cellular barcoding, genetic recording, and genetic computation. PMID- 28633079 TI - Assessment of stormwater runoff management practices and BMPs under soil sealing: A study case in a peri-urban watershed of the metropolitan area of Rome (Italy). AB - By 2006, almost 100,000 km2 of EU soil (2.3% of the whole territory) had been sealed, with a per capita quota of 200 m2 of sealed surface for each EU citizen. Italy, in 2016, recorded a soil sealing rate of 2.8% of the entire territory. In this context, the urban expansion which occurred in past decades is considered one of the main causes of the increase in flood frequency and intensity in small catchments, causing both social and financial damage. In the present paper, the positive impact of introducing Best Management Practices (BMPs) at urban scale is assessed, with particular regard to the decreasing of flood prone areas. A suburban watershed of the metropolitan area of Rome has been selected for a study case, as its soil sealing rate can be considered paradigmatic at this scale. Starting from the analysis of rainfall events occurring between 2008 and 2011 which caused millions of euros worth of damage, and using a high resolution data set in a GIS environment, two scenarios, with and without BMP introduction, are evaluated applying a rainfall-runoff model and a bidimensional hydraulic model. From a comparison of the flood maps with and without the introduction of BMPs, it was determined that in 90% of the circumstances the employment of the BMPs would completely remove the hydraulic risk, while in the remaining 10% the BMP would at least reduce the areas subjected to flooding. PMID- 28633081 TI - Deflagration to detonation transition in JP-10 mist/air mixtures in a large-scale tube. AB - Deflagration to detonation transitions (DDTs) in JP-10 mist/air mixtures have been studied in a horizontal multiphase combustion and explosion tube with inner diameter of 199mm and length of 32.8m. The mist/air mixtures were generated by injecting liquid samples into the experimental tube. Experiments were performed at 298k and 101kPa with equivalence ratio ranged from 0.51 to 2.09. The coupling process of deflagration wave with leading shock wave and low-velocity self sustained detonation were observed in JP-10 mist/air mixture with a concentration of 142.86g/m3, and the average velocity of the self-sustained detonation wave is 510m/s, which is as low as 26% of C-J value. The low-velocity detonation in JP-10 mist/air mixture can be explained by the low-volatile property of JP-10 liquid and boundary condition. The leanest and richest critical detonable concentrations were studied. The detonation structure was studied by using pressure sensors array mounted in the wave structure test section. A single-head spin detonation wave front was observed and the cellular structure resulting from the spinning movement of the triple point was analyzed. PMID- 28633082 TI - Role of indigenous microbiota from heavily contaminated sediments in the bioprecipitation of arsenic. AB - High arsenic concentrations have been detected in alluvial aquifers of arid and semi-arid zones in Mexico. This work describes the potential of microbial arsenate reduction of the indigenous community present in sediments from an arsenic contaminated aquifer. Microcosms assays were conducted to evaluate arsenate and sulfate-reducing activities of the native microbiota. Two different sediments were used as inoculum in the assays amended with lactate (10mM) as electron donor and with sulfate and arsenate (10mM each) as electron acceptors. Sediments were distinguished by their concentration of total arsenic 238.3+/ 4.1mg/kg or 2263.1+/-167.7mg/kg, which may be considered as highly contaminated sediments with arsenic. Microbial communities present in both sediments were able to carry out arsenate reduction, accomplished within 4days, with the corresponding formation of arsenite; sulfate reduction took place as well. Both reducing activities occurred without previous acclimation period or enrichment, even at potential inhibitory concentrations of arsenate as high as 750mg/L (10mM). The formation of a yellowish colloidal precipitate was evident when both reducing processes occurred in the microcosm, which contributed to remove between 52 and 90.9% of As(III) from the liquid phase by bioprecipitation of arsenic as arsenic sulfide. PMID- 28633083 TI - Adsorption of Cu (II), Pb (II) and Cr (VI) from aqueous solutions using black wattle tannin-immobilized nanocellulose. AB - A novel nanocomposite based on black wattle (BW) tannin and nanocellulose was prepared and applied in heavy metal ions adsorptive removal from aqueous solutions. Firstly, nanocrystalline cellulose was oxidized by sodium periodate to get dialdehyde nanocellulose (DANC). BW tannin was then covalently immobilized onto DANC, which was used as both the matrix and crosslinker, to obtain tannin nanocellulose (TNCC) composite. The resulting nanocomposite was characterized using FTIR, AFM, and TG. The successful immobilization was confirmed by the chromogenic reaction between FeCl3 and TNCC and FT-IR analysis. AFM images revealed that TNCC was ellipsoidal particles with lengths ranging from 100-400nm. Zeta potential measurement showed that TNCC was negative charged at a pH range from 1-12. Compared to the original tannin, the thermal stability of TNCC was slightly increased by the addition of nanocellulose. TNCC demonstrated the maximum adsorption efficiency at pH2 for Cr(VI) and pH 6 for Cu(II) and Pb(II), respectively. The adsorption for these three metal ions followed pseudo second order kinetics, indicating the chemisorption nature. The adsorption isotherms all fitted well with the Sips model, and the calculated maximum adsorption capacities were 51.846mgg-1, 53.371mgg-1 and 104.592mgg-1 for Cu(II), Pb(II) and Cr (VI), respectively. PMID- 28633084 TI - Public health costs accounting of inorganic PM2.5 pollution in metropolitan areas of the United States using a risk-based source-receptor model. AB - In order to design effective strategies to reduce the public health burden of ambient fine particulate matter (PM2.5) imposed in an area, it is necessary to identify the emissions sources affecting that location and quantify their contributions. However, it is challenging because PM2.5 travels long distances and most constituents are the result of complex chemical processes. We developed a reduced-form source-receptor model for estimating locations and magnitudes of downwind health costs from a source or, conversely, the upwind sources that contribute to health costs at a receptor location. Built upon outputs from a state-of-the-art air quality model, our model produces comprehensive risk-based source apportionment results with trivial computational costs. Using the model, we analyzed all the sources contributing to the inorganic PM2.5 health burden in 14 metropolitan statistical areas (MSAs) in the United States. Our analysis for 12 source categories shows that 80-90% of the burden borne by these areas originates from emissions sources outside of the area and that emissions sources up to 800 km away need to be included to account for 80% of the burden. Conversely, 60-80% of the impacts of an MSA's emissions occurs outside of that MSA. The results demonstrate the importance of regionally coordinated measures to improve air quality in metropolitan areas. PMID- 28633085 TI - Biotechnological production of recombinant tissue plasminogen activator protein (reteplase) from transplastomic tobacco cell cultures. AB - Transplastomic plants are a system of choice for the mass production of biopharmaceuticals due to the polyploidy of the plastid genome and the low risk of pollen-mediated outcrossing because of maternal inheritance. However, as field grown plants, they can suffer contamination by agrochemicals and fertilizers, as well as fluctuations in yield due to climatic changes and infections. Tissue-type plasminogen activator (tPA), a protein used to treat heart attacks, converts plasminogen into plasmine, which digests fibrin and induces the dissolution of fibrin clots. Recently, we obtained transplastomic tobacco plants carrying the K2S gene encoding truncated human tPA (reteplase) with improved biological activity, and confirmed the presence of the target protein in the transgenic plant leaves. Considering the advantages of plant cell cultures for biopharmaceutical production, we established a cell line derived from the K2S tobacco plants. The active form of reteplase was quantified in cultures grown in light or darkness, with production 3-fold higher in light. PMID- 28633086 TI - Beneficial effects of melatonin in overcoming drought stress in wheat seedlings. AB - Melatonin plays an important role in abiotic stress in plant, but its role in wheat drought tolerance is less known. To verify its role, wheat seedlings (Triticum aestivum L. 'Yan 995') at 60% and 40% of field capacity were treated with 500 MUM melatonin in this study. Melatonin treatment significantly enhanced the drought tolerance of wheat seedlings, as demonstrated by decreased membrane damage, more intact grana lamella of chloroplast, higher photosynthetic rate, and maximum efficiency of photosystem II, as well as higher cell turgor and water holding capacity in melatonin-treated seedlings. Besides, melatonin markedly decreased the content of hydrogen peroxide and superoxide anion in melatonin treated seedlings, which is attributed to the increased total antioxidant capacity, GSH and AsA contents, as well as enzyme activity including ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), glutathione peroxidase (GPX), and glutathione transferase (GST). The GSH-AsA related genes including APX, MDHAR, and DHAR were commonly upregulated by melatonin and correlated to the antioxidant enzyme activity as well as the content of GSH and AsA, indicating that the increase of GSH and AsA was attributed to the expression of these genes. Our result confirmed the mitigation potential of melatonin in drought stress and certain mechanisms of melatonin-induced GSH and AsA accumulation, which could deepen our understanding of melatonin-induced drought tolerance in wheat. PMID- 28633087 TI - In-field study on traditional Italian tomato landraces: The constitutive activation of the ROS scavenging machinery reduces effects of drought stress. AB - The involvement and the efficiency of the antioxidants scavenging system upon drought were examined by comparing traditional tomato landraces with respect to an industrial commercial genotype (Red Setter); for the first time, comprehensive analyses of physiological, biochemical and molecular parameters were investigated directly under real field conditions, in a typical agricultural environment of Southern Italy. The characterization of the responses upon drought evidenced peculiar changes in stomatal conductance, ascorbate peroxidase and catalase activities and expression in drought tolerant tomato landraces, with respect to the industrial genotype. An in silico analysis (promoter and co-expression study) coupled to a phylogenetic investigation of selected enzymes was performed, reinforcing the hypothesis of a basal activation of ROS scavenging machinery in the Mediterranean landraces. Thus our data suggest a constitutive increase in the expression and activities of specific enzymes involved in ROS detoxification that can play a pivotal role in the drought response shown by tomato landraces. Therefore, traditional landraces could represent an important source of useful genetic variability for the improvement of commercial varieties; their ROS detoxifying capabilities denote peculiar aspects worth being explored to better describe their specific stress tolerance. PMID- 28633088 TI - Second line with oxaliplatin- or irinotecan-based chemotherapy for gemcitabine pretreated pancreatic cancer: A systematic review. AB - BACKGROUND: oxaliplatin (OXA)- and irinotecan (IRI)-based chemotherapies are the most frequently used salvage regimens in patients with metastatic pancreatic cancer (PC) after first-line gemcitabine-based therapy. There are no prospective comparisons of these regimens in this setting. We conducted a systematic review of published trials to compare the efficacy of these treatments. METHODS: studies that enrolled patients with stage IV disease receiving chemotherapy with OXA or IRI plus fluoropyrimidines were identified using electronic databases (Pubmed, Embase, SCOPUS, CINAHL, Web of Science and Cochrane Library). Clinical outcomes were compared using weighted values of median overall survival (OS), progression free survival (PFS), response rates (RRs), and clinical benefit rates (CBRs). A 2 tailed t-test with a significance level of 0.05 for comparisons of continuous variables and a Chi-squared test for comparisons of proportions were used. RESULTS: overall, 24 studies were included. The pooled overall response rate (ORR), disease control rate (DCR), PFS and OS were 11%, 37.9%, 2.87 and 5.48 months respectively. There was no significant difference in response rates between OXA-based and IRI-based chemotherapies (11.9% versus 8.7%; Chi-squared P = 0.1), respectively. Also there was no significant difference in median PFS (2.9 months versus 2.7 months; t-test P = 0.72), OS (5.3 months versus 5.5 months; t test P = 0.72), but a greater DCR with OXA-based chemotherapy (41.1% versus 29.4%; Chi-squared P = 0.0008). CONCLUSION: OXA- and IRI-containing regimens were associated with similar efficacy when used after gemcitabine-based chemotherapy in patients with advanced pancreatic cancer. PMID- 28633090 TI - Pulmonary and cardiac pathology in sudden unexpected death in epilepsy (SUDEP). AB - OBJECTIVE: To review studies on structural pulmonary and cardiac changes in SUDEP cases as well as studies showing pulmonary or cardiac structural changes in living epilepsy patients. METHODS: We conducted electronic literature searches using the PubMed database for articles published in English, regardless of publication year, that included data on cardiac and/or pulmonary structural abnormalities in SUDEP cases or in living epilepsy patients during the postictal period. RESULTS: Fourteen postmortem studies reported pulmonary findings in SUDEP cases. Two focused mainly on assessing lung weights in SUDEP cases versus controls; no group difference was found. The other 12 reported descriptive autopsy findings. Among all SUDEP cases with available descriptive postmortem pulmonary examination, 72% had pulmonary changes, most often pulmonary edema/congestion, and, less frequently, intraalveolar hemorrhage. Eleven studies reported on cardiac pathology in SUDEP. Cardiac abnormalities were found in approximately one-fourth of cases. The most common findings were myocyte hypertrophy and myocardial fibrosis of various degrees. Among living epilepsy patients, postictal pulmonary pathology was the most commonly reported pulmonary abnormality and the most common postictal cardiac abnormality was transient left ventricular dysfunction - Takotsubo or neurogenic stunned myocardium. SIGNIFICANCE: Cardiac and pulmonary pathological abnormalities are frequent among SUDEP cases, most commonly pulmonary edema/congestion and focal interstitial myocardial fibrosis. Most findings are not quantified, with subjective elements and undefined interobserver reliability, and lack of controls such as matched epilepsy patients who died from other causes. Further, studies have not systematically evaluated potential confounding factors, including postmortem interval to autopsy, paramedic resuscitation and IV fluids administration, underlying heart/lung disease, and risk factors for cardiac or pulmonary disease. Prospective studies with controls are needed to define the heart and lung changes in SUDEP and understand their potential relationship to mechanisms of death in SUDEP. PMID- 28633089 TI - First-line panitumumab plus FOLFOX4 or FOLFIRI in colorectal cancer with multiple or unresectable liver metastases: A randomised, phase II trial (PLANET-TTD). AB - BACKGROUND: In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations. METHODS: Multicentre, open-label study in untreated patients >= 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients. RESULTS: Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6-1.5]; WT-RAS:13/15; HR: 0.7 [0.4-1.3]). Median OS was 37/41 months (HR:1.0 [0.6-1.8]; WT-RAS: 39/49; HR:0.9 [0.4-1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS >= 30%/ >= 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm. CONCLUSIONS: In patients with WT KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov:NCT00885885). PMID- 28633091 TI - Cyclic alternating pattern and interictal epileptiform discharges during morning sleep after sleep deprivation in temporal lobe epilepsy. AB - PURPOSE: Sleep deprivation (SD) increases the occurrence of interictal epileptiform discharges (IED) compared to basal EEG in temporal lobe epilepsy (TLE). In adults, EEG after SD is usually performed in the morning after SD. We aimed to evaluate whether morning sleep after SD bears additional IED-inducing effects compared with nocturnal physiological sleep, and whether changes in sleep stability (described by the cyclic alternating pattern-CAP) play a significant role. METHODS: Adult patients with TLE underwent in-lab night polysomnography (n PSG) and, within 7days from n-PSG, they underwent also a morning EEG after night SD (SD-EEG). We included only TLE patients in which both recordings showed IED. SD-EEG consisted of waking up patients at 2:00 AM and performing video EEG at 8:00 AM. For both recordings, we obtained the following markers for the first sleep cycle: IED/h (Spike Index, SI), sleep macrostructure, microstructure (NREM CAP rate; A1, A2 and A3 Indices), and SI association with CAP variables. RESULTS: The macrostructure of the first sleep cycle was similar in n-PSG and morning SD EEG, whereas CAP rate and SI were significantly higher in SD-EEG. SI increase was selectively associated with CAP phases. CONCLUSIONS: SD increases the instability of morning recovery sleep compared with n-PSG, and particularly enhances CAP A1 phases, which are associated with the majority of IED. Thus, higher instability of morning recovery sleep may account at least in part for the increased IED yield in SD-EEG in TLE patients. PMID- 28633092 TI - Epilepsy in neurofibromatosis type 1. AB - OBJECTIVES: To describe the characteristics of epilepsy in patients with Neurofibromatosis type 1 (NF1). METHODS: Analysis of a cohort of consecutive NF1 patients seen in our NF1 clinic during a three-year period. RESULTS: Of the 184 NF1 patients seen during that period, 26 had epilepsy and three had febrile seizures. Of the 26, 17 (65%) had localization-related epilepsy, seven of whom (41%) were drug resistant. Six (23%) had apparently primary generalized epilepsy (0/6 drug resistant), two (8%) Lennox-Gastaut syndrome, and one (4%) West syndrome (all three were drug-resistant). As compared to the patients with no epilepsy, those with epilepsy were more likely to have MRI findings of mesial temporal sclerosis (MTS) (23% vs. 5%, p=0.0064), and cerebral hemisphere tumors (31% vs. 10%, p=0.0079), but not of the other MRI findings including neurofibromatosis bright objects, or optic gliomas. Three of the six patients with MTS underwent temporal lobectomy with subsequent control of their seizures with confirmation of MTS on pathology in 3/3 and presence of coexisting focal cortical dysplasia (FCD) in 2/3. We also have observed three additional patients outside the above study with the association of NF1, MTS, and intractable epilepsy. SIGNIFICANCE: Epilepsy is relatively common in NF1, often occurs in patients with brain tumors or with MTS which can coexist with FCD, can be associated with multiple types of epilepsy syndromes, and when localization related is often drug-resistant. Patients with NF1 and MTS can respond to medial temporal lobectomy and may have coexisting medial temporal lobe cortical dysplasia. PMID- 28633093 TI - Fracture resistance of ceramic and polymer-based occlusal veneer restorations. AB - OBJECTIVES: The purpose of this in vitro study was to evaluate the influence of thermodynamic loading on the durability and fracture resistance behavior of occlusal veneers fabricated from different biomedical dental CAD/CAM materials. METHODS: The occlusal surfaces of 64 extracted premolars were prepared in the enamel layer and restored with occlusal veneers with a fissure/cusp thickness of 0.5/0.8mm made from four different dental CAD/CAM materials: group LD lithium disilicate (e.max CAD), group LS zirconia-reinforced lithium silicate (Vita Suprinity), group PI polymer-infiltrated ceramic (Vita Enamic), and group PM polymethylmethacrylate PMMA (Telio CAD). The prepared teeth were etched with phosphoric acid. The occlusal veneers were then bonded using an adhesive luting system (Multilink Primer A/B and Multilink Automix luting resin). Half of the specimens were subjected to thermodynamic loading in a chewing simulator (1.2 million cycles at 98N). All specimens were quasi-statically loaded until fracture. The statistical analysis was made using the t-test and one-way ANOVA followed by the Tukey HSD test (alpha = 0.05). RESULTS: All aged specimens survived the thermodynamic loading. Thermodynamic loading significantly raised the fracture resistance in groups LS, PI, and PM (P < 0.03). Occlusal veneers made from lithium disilicate and zirconia-reinforced lithium silicate recorded higher fracture resistance than those made from polymer-infiltrated ceramic and PMMA resin. CONCLUSIONS: All tested dental CAD/CAM biomaterials exhibited a fracture resistance considerably exceeding the average occlusal force in the posterior dentition. Therefore, they might present a viable long-term treatment for restoring the occlusal surfaces of posterior teeth. PMID- 28633094 TI - Impact of management on mortality in patients with invasive cervical cancer in Reunion Island. AB - OBJECTIVE: In Reunion Island, the standardized mortality rate for cervical cancer is 4.8/100,000 women, twice higher than in Metropolitan France. For locally advanced disease, the standard of care includes a treatment by brachytherapy. Nevertheless, brachytherapy was not available on the Island before 2016. The objective of this study was to assess the impact of the management of patients with invasive cervical cancer on mortality in Reunion. METHODS: We have identified all the women hospitalized in one of the health care centers of the Island diagnosed with invasive cervical cancer between 01/01/2010 and 31/12/2015. The guidelines of the French Society of Gynecological Oncology (FSGO) were considered as the reference to evaluate professional practices. The characteristics that had an influence on global survival after log-rank test were included in a multivariate analysis according to the Cox Model. RESULTS: Retrospective analysis identified 303 women meeting inclusion criteria. The assessment of professional practices showed that the decisions on 11.6% of the patients discussed during multidisciplinary meetings, were not applied, consequentially leading to a decrease in survival (p=0.001). A total of 156 patients (51.5%) were administered a treatment in accordance with the guidelines of the FSGO and had a better survival, even after multivariate analysis (HR 2.53 [CI 95% 1.55-4.14], p<10-3). Nonconformity was associated with the lack of access to brachytherapy on the Island. Women on the Island presented low rates of screening tests (cover rates 53.2%). CONCLUSION: The absence of treatment in accordance with the guidelines and decisions taken during multidisciplinary meetings and the absence of brachytherapy were associated to a higher mortality among patients with invasive cervical cancer in Reunion Island. We hope that the implementation of brachytherapy in Reunion will address these deficiencies. PMID- 28633095 TI - Development and validation of the Polish version of the Urogenital Distress Inventory short form and the Incontinence Impact Questionnaire short form. AB - OBJECTIVE: The Incontinence Impact Questionnaire (IIQ) measures the impact of urinary incontinence on activities, roles, and emotional states of women, whereas the Urogenital Distress Inventory (UDI) measures how troubling the symptoms are. The aim of this study was to develop and assess the effectiveness of a Polish version of the IIQ and UDI. STUDY DESIGN: The translation into Polish followed standardized procedures. 206 women aged between 31 and 83 years were included into the study. All patients were recruited from women attending the Outpatient Clinic of the 2nd Gynecology Department of the Medical University in Lublin. SUI was observed in 116 cases; OAB in 16 patients and 24 had MUI (confirmed by medical history, bladder diary and urodynamic investigation). 50 healthy women served as control. All patients completed the Polish version of the ICIQ - 'the gold standard' in UI diagnosis - as well as the newly translated Polish versions of the UDI-6 and IIQ-7 questionnaires at baseline. Moreover, 116 women repeated the UDI-6 and IIQ-7 self-assessment again 7days later. RESULTS: The internal consistency was tested by calculating Cronbach's alpha, using baseline scores. The high reliability of the scale indicates a value greater than 0.7. The reliability was calculated by way of the Intraclass Correlation (ICC) and was considered acceptable when ICC was>=0.7. In fact, ICC in all investigated groups was >0.95. The Cronbach's alpha values were as follows: for SUI patients - 0.74; for OAB - 0.78; and for MUI - 0.28 (the UDI-6 total score for the whole study group was 0.72). Cronbach's alpha total score for IIQ-7-0.89 (SUI group - 0.89; OAB group - 0.93; and MUI group - 0.77). Finally, the Cronbach's alpha total score for the ICIQ Questionnaire was 0.73 (SUI group - 0.71; OAB group - 0.65 and MUI group - 0.81). CONCLUSIONS: The Polish versions of the UDI-6 and IIQ-7 Questionnaires are reliable, valid, and responsive instruments for assessing the severity of symptoms and quality of life in females suffering from urinary incontinence. PMID- 28633096 TI - Hysterectomy is not associated with de-novo urinary incontinence: A ten-year cohort study. AB - OBJECTIVE: To determine prevalence, incidence proportion, and changes of urinary incontinence (UI) 10-13 years after hysterectomy compared to two control groups. STUDY DESIGN: A longitudinal cohort study of 661 women with follow-up for ten years. Originally, 866 women answered a questionnaire on continence status preoperatively. Ten years postoperatively the queries were repeated in 371 with a hysterectomy, 89 with laparoscopic cholecystectomy (LC), and 201 with transcervical endometrial resection (TCRE). Significant incontinence was UI at least once a week. The main outcome measures were prevalence and incidence proportions of UI. RESULTS: The overall prevalence of stress UI ten years after surgery was 23% compared to 12% preoperatively. Urge UI was prevalent in 12% compared to 5% preoperatively. Incidence proportions of stress UI were in hysterectomies 21%, in LC 15%, and in TCRE 18%. Similarly, incidence proportions of urge UI were in hysterectomies 11%, in LC 11%, and in TCRE 8%. No significant differences between surgical procedures were found; however, we found substantial amount of changes in continence status from continent to incontinent and vice versa in all three groups. CONCLUSIONS: No significant difference was found after hysterectomy compared to controls in the prevalence or incidence proportions of UI after 10 years follow-up. Hysterectomy is not a risk factor of UI. PMID- 28633097 TI - Results of the first international HIV-1 coreceptor proficiency panel test. AB - BACKGROUND: Quality Assurance (QA) programs are essential to evaluate performance in diagnostics laboratories. OBJECTIVES: We present the results from the first QA for HIV-1 genotypic tropism testing, organized and coordinated by the Institute of Virology at the University of Cologne. STUDY DESIGN: 12 cell culture-derived viral strains of different HIV-1 clades from the NIH AIDS Reagent Program were sent to the participants to be processed with their standard diagnostic methods Fasta files containing the V3 region sequence were centrally analyzed at the Institute of Virology, Cologne. All samples were sent in parallel for phenotypic testing. RESULTS: 36 laboratories from 16 countries reported genotypic results. The sequence-generation efficacy was 95.1%, while the phenotypic assays ESTA(r) and PhenXR only achieved results for 58.3% of the samples. All four X4 samples were identified by 31/36 laboratories, two laboratories amplified 3/4*4 samples, and three detected 2/4*4 samples. There was high concordance among the genotypic and phenotypic results, although differences in FPR values were detected. Most deficiencies in sequence editing did not result in wrong classification of X4 viruses as R5, with the exception of sample NRZ05 by laboratory 38, but in an overestimation of CXCR4 use. CONCLUSIONS: This demonstrates that genotypic tropism prediction is a safe procedure for clinical purposes. As we used homogeneous cell culture samples and all sequence fasta files were centrally analyzed, variations in FPR values can only be attributed to sample preparation, RT-PCR or sequence editing protocols. PMID- 28633098 TI - High prevalence of cytomegalovirus infection in surgical intestinal specimens from infants with necrotizing enterocolitis and spontaneous intestinal perforation: A retrospective observational study. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a severe, often fatal gastrointestinal emergency that predominantly affects preterm infants, and there is evidence that neonatal cytomegalovirus (CMV) infection may in some cases contribute to its pathogenesis. OBJECTIVES: This study aimed to evaluate the prevalence of CMV in infants with NEC. STUDY DESIGN: Seventy intestinal specimens from 61 infants with NEC, spontaneous intestinal perforation (SIP), or related surgical complications were collected at Karolinska University Hospital and Uppsala University Hospital, Sweden. Ten specimens from autopsied infants without bowel disease served as controls. Samples were analyzed for CMV immediate-early antigen (IEA), CMV late antigen (LA), 5-lipoxigenase (5LO) and CMV-DNA by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. In 10 index samples, CMV DNA was analyzed with Taqman PCR after laser capture microdissection (LCM) of cells positive for CMV IEA by IHC. RESULTS: CMV IEA was detected by IHC in 57 (81%) and CMV LA in 45 (64%) of 70 intestinal specimens from index cases; 2 (20%) of 10 control specimens were positive for both antigens. 5LO was detected in intestinal tissue section obtained from all examined index and controls. CMV DNA was detected in 4 of 10 samples (40%) after LCM. By ISH, all 13 IHC-IEA-positive samples were positive for CMV DNA; however, 3 of 5 IHC-IEA-negative samples (60%) were also positive. CONCLUSIONS: CMV specific antigens and CMV DNA were highly prevalent in intestinal specimens from infants with NEC, SIP, and related surgical complications. Our findings provide further evidence that neonatal CMV infection contributes to the pathogenesis of these diseases and may affect patient outcome. PMID- 28633099 TI - Simultaneous and specific enrichment of several amphenicol antibiotics residues in food based on novel aptamer functionalized magnetic adsorbents using HPLC-DAD. AB - In this work, a novel aptamer functionalized magnetic adsorbent was developed and combined with magnetic dispersive solid phase extraction (MDSPE) for selective enrichment of several amphenicol antibiotics residues (chloramphenicol(CAP), thiamphenicol(TAP) and florphenicol(FF)) in foodstuff then determined by High Performance Liquid Chromatography (HPLC)-Diode array detector(DAD). Firstly, a magnetic silica-coated Fe3O4 microsphere(Fe3O4@SiO2) was synthetized by sol-gel method, then it was functionalized by amino groups through 3 Aminopropyltriethoxysilane (APTES) reagent to form Fe3O4@SiO2-NH2; Thirdly, the amino group on Fe3O4@SiO2-NH2 was transferred to carboxylic group via the succinic anhydride to form Fe3O4@SiO2-COOH. Finally a kind of DNA aptamer with amino group which can simultaneously recognize CAP, TAP, FF, was functionalized on Fe3O4@SiO2-COOH through adding the EDC/sulfo-NHS coupling reagent (Fe3O4@SiO2@Apt). Therefore, a very stable and useful adsorbent was synthesized for the detection of chloramphenicol series antibiotics. This adsorbent can specifically and simultaneously recognize and enrich CAP, TAP, and FF with high adsorption amount from some complicated food matrix, e.g. milk based on the high affinity of aptamer towards the analytes. The saturated extraction capacities for CAP, TAP and FF by the adsorbent were 2.82, 2.56, 2.72MUg/g (mass of target/adsorbent)respectively and the enrichment folds were more than 100 times. Afterwards, the target analytes were washed away by pH 8.5 0.1M Tris-HCl buffer solution and detected by HPLC-DAD. The parameters including extraction temperature, extraction capacity, extraction & desorption pH, extraction & desorption time were investigated. With the optimized conditions, the limits of detection (LOD) and limits of quantitation (LOQ) were 0.12-0.17ng/ml and 0.40 0.55ng/ml for the amphenicols in milk. The adsorbent also has good reproducibility for extraction which can be reused at least for 60 cycles with the recovery over 80% (Fig. S2). The MDSPE combined with HPLC-DAD detection possessed the advantages of high selectivity, extraction capacity and very convenient for magnetic separation. In addition, this method is environment friendly and employed no organic solution in the period of pretreatment and extracting. It is a universal platform which can be extended to selective enrichment other organic pollutants residues if changing the modified aptamers. PMID- 28633100 TI - Improving the accuracy of hyaluronic acid molecular weight estimation by conventional size exclusion chromatography. AB - There is an unreasonably high variation in the literature reports on molecular weight of hyaluronic acid (HA) estimated using conventional size exclusion chromatography (SEC). This variation is most likely due to errors in estimation. Working with commercially available HA molecular weight standards, this work examines the extent of error in molecular weight estimation due to two factors: use of non-HA based calibration and concentration of sample injected into the SEC column. We develop a multivariate regression correlation to correct for concentration effect. Our analysis showed that, SEC calibration based on non-HA standards like polyethylene oxide and pullulan led to approximately 2 and 10 times overestimation, respectively, when compared to HA-based calibration. Further, we found that injected sample concentration has an effect on molecular weight estimation. Even at 1g/l injected sample concentration, HA molecular weight standards of 0.7 and 1.64MDa showed appreciable underestimation of 11-24%. The multivariate correlation developed was found to reduce error in estimations at 1g/l to <4%. The correlation was also successfully applied to accurately estimate the molecular weight of HA produced by a recombinant Lactococcus lactis fermentation. PMID- 28633102 TI - An integrated assessment of ceftazidime and photoproducts on the feeding behavior of rotifers: From exposure to post-exposure. AB - Compared to traditional toxicological studies, which depict the dose-effect of contaminants themselves on organisms at the given time, the exposure and post exposure impacts of antibiotic ceftazidime and its photoproducts are carried out to systematically evaluate the environmental risk fate of ceftazidime in aquatic environments. For the exposure process, the promotion effect of ceftazidime on the feeding behavior of the rotifers decreased when the target compound was irradiated by sunlight, and the promotion effect was converted into inhibition effect, which indicated that the highest toxicity of ceftazidime on the feeding behavior of the rotifers was found after UV-B irradiation. The overcompensation occurred in the post-exposure, indicating a short - term effect of the corresponding photoproducts on the rotifer. In order to better understand the mechanism of this change, the photodegradation pathways of the target compound was analyzed and compared. The degradation degree under the UV-B irradiation had intensified greatly than that under the nature light irradiation. The reactive oxygen species (ROS) of the rotifer in exposure and post-exposure was also detected. Ceftazidime and photoproducts induced generation of ROS, indicating that oxidative damage occurred, and the decreasing of ROS levels could be viewed as the recovery of the rotifers in the post-exposure. PMID- 28633101 TI - Assessment of environmental and health risks in former polymetallic ore mining and smelting area, Slovakia: Spatial distribution and accumulation of mercury in four different ecosystems. AB - Former long-term mining and smelting of pollymetallic ores in the Middle Spis area caused a serious contamination problem of the environment with heavy metals and metalloids, especially mercury (Hg). Several studies have reported concentration of Hg in the area but this paper provides first detailed characterization of Hg contamination of different environmental components in agricultural, forest, grassland and urban ecosystems. The ecosystems are in different distances from emission sources - former mercury and copper smelting plants in NE Slovakia. Total Hg content was studied in soil/substrate samples (n = 234) and characteristic biological samples (Athyrium filix-femina (L.) Roth, Macrolepiota procera (Scop.) Singer, Boletus edulis Bull., Cyanoboletus pulverulentus (Opat.) Gelardi, Vizzini & Simonini, Triticum aestivum (L.), Poa pratensis (L.)) (n = 234) collected in the above-mentioned ecosystems. The level of contamination and environmental risks were assessed by contamination factor (Cf), index of geoaccumulation (Igeo) and potential environmental risk index (PER). To determine the level of transition of Hg from abiotic to biotic environment, bioconcentration factor (BCF) was used. To determine a health risk resulting from regular and long-term consumption of the locally available species, the results of the Hg content were compared with the Provisional Tolerable Weekly Intake (PTWI) for Hg defined by World Health Organization. The results suggest that almost 63% of the area belong to the very high risk category and 80% of the sampling sites shown very high contamination factor. Geoaccumulation index showed that almost 30% of the area is very strongly contaminated and only 8% is not contaminated with Hg. Spearman's correlation relationship confirmed that the values of PER, BCF, Cf and Igeo decreased with an increasing distance from the pollution source. The percentage of contribution to PTWI ranged between 5.76-69.0% for adults and 11.5-138% for children. Mushroom M. procera showed the highest %PTWI among the tested biological samples. Studied ecotoxicological parameters showed high level of health risk for population living in the area. Consumption of the crops grown in the area and mainly edible wild mushrooms might negatively affect the health of the consumers in the long term. PMID- 28633103 TI - Dietary risk ranking for residual antibiotics in cultured aquatic products around Tai Lake, China. AB - Antibiotics are widely used in aquaculture and therefore may be present as a dietary risk in cultured aquatic products. Using the Tai Lake Basin as a study area, we assessed the presence of 15 antibiotics in 5 widely cultured aquatic species using a newly developed dietary risk ranking approach. By assigning scores to each factor involved in the ranking matrices, the scores of dietary risks per antibiotic and per aquatic species were calculated. The results indicated that fluoroquinolone antibiotics posed the highest dietary risk in all aquatic species. Then, the total scores per aquatic species were summed by all 15 antibiotic scores of antibiotics, it was found that Crab (Eriocheir sinensis) had the highest dietary risks. Finally, the most concerned antibiotic category and aquatic species were selected. This study highlighted the importance of dietary risk ranking in the production and consumption of cultured aquatic products around Tai Lake. PMID- 28633104 TI - Transcriptional and cellular effects of paracetamol in the oyster Crassostrea gigas. AB - Acetaminophen (paracetamol) (PAR) is one of the most popular non-steroidal anti inflammatory drugs (NSAIDs) with analgesic and antipyretic properties consumed worldwide and often detected in the aquatic environment. Due to the fact that PAR induces oxidative stress in mammals, the aim of this study was to evaluate if similar effects were observed in oysters Crassostrea gigas, given their economic and ecological importance and worldwide distribution. Oysters were exposed for 1, 4 and 7 days to two different sublethal PAR concentrations (0, 1 and 100MUgL-1). Cell viability, DNA damage in hemocytes and enzymatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), glutathione reductase (GR), glucose 6-phosphate dehydrogenase (G6PDH) and glutathione S transferases (GST) were evaluated in oyster gills. In addition, changes at transcriptional level of Cu/Zn superoxide dismutase (SOD), catalase-like (CAT like), cytochrome P450 genes (CYP30C1, CYP2AU2, CYP3071A1, CYP356A1), glutathione S-transferase isoforms (GST-omega and GST-pi-like), cyclooxygenase (COX), fatty acid binding proteins-like (FABP-like), and caspase genes were evaluated in oyster gills and digestive gland. No changes in cell viability and DNA damage were observed in oysters exposed to both PAR concentrations. Similarly, no significant changes were detected in the major antioxidant enzymes (except for auxiliary enzyme GR) in oyster gills, suggesting that changes in GR activity are enough to counteract a potential oxidative stress in C. gigas gills under these experimental conditions. Furthermore, changes at transcriptional level are concentration and tissue dependent. PAR elicited an inhibition of CYP30C1, CYP3071A1 and FABP-like transcripts highlighting their role in drug metabolism, transport and detoxification of PAR in the gills. GST transcript levels were type, tissue and concentration-dependent. GST-pi-like was down-regulated in oyster gills exposed to the lowest PAR concentration and up-regulated in the digestive gland of oysters exposed to the highest PAR concentration. However, GST omega transcript levels were lower only in oysters digestive gland exposed to the lowest PAR concentration. Therefore, changes at transcriptional level were more sensitive to assess the exposure to PAR at environmental relevant concentrations. PMID- 28633105 TI - Effects of triacontanol on ascorbate-glutathione cycle in Brassica napus L. exposed to cadmium-induced oxidative stress. AB - The ability of exogenous triacontanol (TRIA), a plant growth regulator, to reduce Cd toxicity was studied in canola (Brassica napus L.) plants. The following biological parameters were examined in canola seedlings to investigate TRIA induced tolerance to Cd toxicity: seedling growth, chlorophyll damage and antioxidant response. In particular, TRIA application reduced Cd-induced oxidative damage, as shown by reduction of ROS content, lipoxygenase (LOX) activity and lipid peroxidation level. TRIA pretreatment increased non-enzymatic antioxidant contents (ascorbate, AsA, glutathione and GSH), phytochelatin content (PCs) and activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), guaiacol peroxidase (GPX), monodehydroascorbate reductase (MDHAR), dehydro ascorbate reductase (DHAR), and glutathione reductase (GR), so reducing the oxidative stress. These results clearly indicate the protective ability of TRIA to modulate the redox status through the antioxidant pathway AGC and GSH, so reducing Cd-induced oxidative stress. PMID- 28633106 TI - Selective photocytotoxicity of anthrols on cancer stem-like cells: The effect of quinone methides or reactive oxygen species. AB - Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal and show increased resistance to chemo- and radiotherapy. Targeting CSC, rather than cancer cells in general, is a novel and promising strategy for cancer treatment. Novel therapeutic approaches, such as photodynamic therapy (PDT) have been investigated. A promising group of phototherapeutic agents are reactive intermediates - quinone methides (QMs). This study describes preparation of QM precursor, 2-hydroxy-3-hydroxymethylanthracene (2) and a detailed photochemical and photobiological investigation on similar anthracene derivatives 3 and 4. Upon photoexcitation with near visible light at lambda > 400 nm 1 and 2 give QMs, that were detected by laser flash photolysis and their reactivity with nucleophiles has been demonstrated in the preparative irradiation experiments where the corresponding adducts were isolated and characterized. 3 and 4 cannot undergo photodehydration and deliver QM, but lead to the formation of phenoxyl radical and singlet oxygen, respectively. The activity of 1-4 was tested on a panel of human tumor cell lines, while special attention was devoted to demonstrate their potential selectivity towards the cells with CSC-like properties (HMLEshEcad). Upon the irradiation of cell lines treated with 1-4, an enhancement of antiproliferative activity was demonstrated, but the DNA was not the target molecule. Confocal microscopy revealed that these compounds entered the cell and, upon irradiation, reacted with cellular membranes. Our experiments demonstrated moderate selectivity of 2 and 4 towards CSC-like cells, while necrosis was shown to be a dominant cell death mechanism. Especially interesting was the selectivity of 4 that produced higher levels of ROS in CSC-like cells, which forms the basis for further research on cancer phototherapy, as well as for the elucidation of the underlying mechanism of the observed CSC selectivity based on oxidative stress activation. PMID- 28633107 TI - Effects of chemical and physical enhancement techniques on transdermal delivery of 3-fluoroamphetamine hydrochloride. AB - The present study investigated the passive transdermal delivery of 3 fluoroamphetamine hydrochloride (PAL-353) and evaluated the effects of chemical and physical enhancement techniques on its permeation through human skin. In vitro drug permeation studies through dermatomed human skin were performed using Franz diffusion cells. Passive permeation of PAL-353 from propylene glycol and phosphate buffered saline as vehicles was studied. Effect of oleic acid, maltose microneedles, ablative laser, and anodal iontophoresis on its transdermal permeation was investigated. Infrared spectroscopy, scanning electron microscopy, calcein imaging, confocal laser microscopy, and histology studies were used to characterize the effects of chemical and physical treatments on skin integrity. Passive permeation of PAL-353 (propylene glycol) after 24h was found to be 1.03+/ 0.17MUg/cm2. Microneedles, oleic acid, and laser significantly increased the permeation to 7.35+/-4.87MUg/cm2, 38.26+/-5.56MUg/cm2, and 523.24+/-86.79MUg/cm2 (p<0.05), respectively. A 548-fold increase in drug permeation was observed using iontophoresis as compared to its passive permeation from phosphate buffered saline (p<0.05). The characterization studies depicted disruption of the stratum corneum by microneedles and laser treatment. Overall, transdermal permeation of PAL-353 was significantly enhanced by the use of chemical and physical enhancement techniques. PMID- 28633108 TI - Bioactivity and quantitative analysis of isohexenylnaphthazarins in root periderm of two Echium spp.: E. plantagineum and E. gaditanum. AB - Isohexenylnaphthazarins are commonly found in the root periderm of several Boraginaceous plants and are known for their broad range of biological activities. The work described herein concerns the biological activity of compounds from the roots of Echium plantagineum L. and Echium gaditanum Boiss (Boraginaceae) collected from field sites in southern Spain and Australia. Bioactivity was assessed using etiolated wheat coleoptile bioassay and in vitro growth inhibitory activity in HeLa and IGROV-1 cells. The quantification of four isohexenylnaphthazarins (shikonin/alkannin, deoxyshikonin/deoxyalkannin, acetylshikonin/acetylalkannin and dimethylacrylshikonin/dimethylacrylalkannin) was performed by LC-MS/MS using juglone as internal standard. Correlation coefficient values for the activities and concentrations of these four analytes were in the linear range and were greater than 0.99. Acetylshikonin/acetylalkannin and dimethylacrylshikonin/dimethylacrylalkannin were present in the highest concentrations in extracts of both species. The results reveal that greatest overall inhibition was observed in both bioassays with E. gaditanum extracts. Strong correlations between time of collection, sampling location and bioactivity were identified. PMID- 28633110 TI - Emerging contaminants related to the occurrence of forest fires in the Spanish Mediterranean. AB - Forest fires can be a source of contamination because, among others, of the use of chemicals to their extinction (flame retardants, FRs), or by the production of Polycyclic Aromatic Hydrocarbons (PAHs) derived from high temperature alteration of organic matter. Up to our knowledge, this study is the first to assess the direct (PAHs 16 on the USA EPA's priority list), and indirect [tri- to hepta- brominated diphenyl ethers (PBDEs), organophosphorus flame retardants (PFRs) and perfluoroalkyl substances (PFASs)] contamination related to forest fires. The abundance and distribution of these contaminants were monitored on two Mediterranean hillslopes, one burned and one unburned, near Azuebar (SE Spain). Samples were taken in the foot, middle, and top of the slope, at two depths, and in two environments (under canopy and bare soil). Sediments were collected from sediment fences after erosive rainfall events. Most of the screened compounds were found in both, burned and control hillslopes, though significant differences were found between both. In burned soil, low concentrations of PBDEs (maximum SigmaPBDEs: 7.3ngg-1), PFRs (664.4ngg-1) and PFASs (56.4ngg-1) were detected in relation to PAHs (Sigma16 PAHs=1255.3ngg-1). No significant influence of the hillslope position was observed for any of the contaminants but differences based on depth and vegetation presence tended to be significant, particularly for the PAHs. After the first erosive event, concentrations of PBDEs and PAHs were higher in sediment than in soil (SigmaPBDEs: 17.8ngg-1 and Sigma16 PAHs=3154.2ngg-1) pointing out the importance of connectivity processes, especially shortly after fire. PMID- 28633111 TI - Drought-avoiding plants with low water use can achieve high rainfall retention without jeopardising survival on green roofs. AB - Green roofs are increasingly being used among the suite of tools designed to reduce the volume of surface water runoff generated by cities. Plants provide the primary mechanism for restoring the rainfall retention capacity of green roofs, but selecting plants with high water use is likely to increase drought stress. Using empirically-derived plant physiological parameters, we used a water balance model to assess the trade-off between rainfall retention and plant drought stress under a 30-year climate scenario. We compared high and low water users with either drought avoidance or drought tolerance strategies. Green roofs with low water-using, drought-avoiding species achieved high rainfall retention (66-81%) without experiencing significant drought stress. Roofs planted with other strategies showed high retention (72-90%), but they also experienced >50days of drought stress per year. However, not all species with the same strategy behaved similarly, therefore selecting plants based on water use and drought strategy alone does not guarantee survival in shallow substrates where drought stress can develop quickly. Despite this, it is more likely that green roofs will achieve high rainfall retention with minimal supplementary irrigation if planted with low water users with drought avoidance strategies. PMID- 28633109 TI - Endothelial NLRP3 inflammasome activation and arterial neointima formation associated with acid sphingomyelinase during hypercholesterolemia. AB - The NLRP3 inflammasome has been reported to be activated by atherogenic factors, whereby endothelial injury and consequent atherosclerotic lesions are triggered in the arterial wall. However, the mechanisms activating and regulating NLRP3 inflammasomes remain poorly understood. The present study tested whether acid sphingomyelinase (ASM) and ceramide associated membrane raft (MR) signaling platforms contribute to the activation of NLRP3 inflammasomes and atherosclerotic lesions during hypercholesterolemia. We found that 7-ketocholesterol (7-Keto) or cholesterol crystal (ChC) markedly increased the formation and activation of NLRP3 inflammasomes in mouse carotid arterial endothelial cells (CAECs), as shown by increased colocalization of NLRP3 with ASC or caspase-1, enhanced caspase-1 activity and elevated IL-1beta levels, which were markedly attenuated by mouse Asm siRNA, ASM inhibitor- amitriptyline, and deletion of mouse Asm gene. In CAECs with NLRP3 inflammasome formation, membrane raft (MR) clustering with NADPH oxidase subunits was found remarkably increased as shown by CTXB (MR marker) and gp91phox aggregation indicating the formation of MR redox signaling platforms. This MR clustering was blocked by MR disruptor (MCD), ROS scavenger (Tempol) and TXNIP inhibitor (verapamil), accompanied by attenuation of 7-Keto or ChC-induced increase in caspase-1 activity. In animal experiments, Western diet fed mice with partially ligated left carotid artery (PLCA) were found to have significantly increased neointimal formation, which was associated with increased NLRP3 inflammasome formation and IL-1beta production in the intima of Asm+/+ mice but not in Asm-/- mice. These results suggest that Asm gene and ceramide associated MR clustering are essential to endothelial inflammasome activation and dysfunction in the carotid arteries, ultimately determining the extent of atherosclerotic lesions. PMID- 28633113 TI - Transformation and toxicity assessment of two UV filters using UV/H2O2 process. AB - The treatment of two typical UV filters benzophenone-4 (BP4) and benzophenone-9 (BP9) was evaluated in aqueous solutions by UV/H2O2 process. High-resolution accurate mass spectrometry (HRMS) was used to identify the degradation intermediates. A total of 12 BP4 degradation products and 17 BP9 degradation products were identified. A series of OH-initiated reactions, including hydroxylation, dihydroxylation, decarboxylation, demethylation, and ring breaking, lead to the final mineralization of BP4 and BP9. The degradation mechanisms of BP4 and BP9 are also proposed, separately. Toxicity prediction and assessment indicate that the bio-toxicity of the intermediates is higher, even if the parent compounds are completely transformed. It is necessary to further assess the environmental risk of BP4, BP9 and their intermediates in engineered systems and ambient aquatic environments. PMID- 28633112 TI - Perfluorinated alkyl substances in Spanish adults: Geographical distribution and determinants of exposure. AB - Per- and polyfluoroalkyl substances (PFAS) are widely found in humans and the environment. Their persistence, bioaccumulation and toxicity make them a source of increasing public health concern. In this study, we analyzed the concentrations and geographical distribution of six PFAS in the serum of 755 Spanish adults aged 18-65. The geometric mean concentrations (and P95 values) for PFOS (perfluoroctane sulfonate), PFOA (perfluorooctanoic acid), PFHxS (perfluorohexane sulfonate), PFNA (perfluorononanoic acid) and PFDA (perfluorodecanoic acid) were 7.67 (19.3), 1.99 (5.48), 0.91 (2.84), 0.96 (2.44) and 0.42 (0.99) MUg/L, respectively. N-Methylperfluorooctane sulfonamide (N MeFOSAA) was detected in only 3.3% of samples. Residents in northeast (Catalonia) and northwest of Spain (Galicia) were found to have the highest serum values, whereas residents in the Canary Islands had the lowest values for almost all PFAS. Men presented higher levels than women, and we confirm that lactation (breastfeeding) contributes to a reduced body burden for all PFAS in women. Our data provide new information on exposure to PFAS in a national cross section sample of Spanish adults, thus providing a proxy for reference values for the Spanish population and forming the base for following temporal trends in the future. PMID- 28633114 TI - Do glucosinolate hydrolysis products reduce nitrous oxide emissions from urine affected soil? AB - New Zealand agriculture is predominantly comprised of pastoral grazing systems and deposition of animal excreta during grazing has been identified as a major source of nitrous oxide (N2O) emissions. Nitrification inhibitors have been shown to significantly reduce nitrous oxide emissions from grazing pastoral systems, and some plants have been identified as having nitrification inhibiting properties. Brassica crops are one such example as they contain the secondary metabolite glucosinolate (GLS) whose hydrolysis products are thought to slow soil nitrogen cycling. Forage brassicas have been increasingly used to supplement the diet of grazing animals. The aim of this study was to determine if GLS hydrolysis products (phenylethyl isothiocyanate, 4-pent-1-yl isothiocyanate, 2-propenyl nitrile, 2 propenyl isothiocyanate, 4-pentene nitrile) produced in brassica crops reduced N2O emissions from soil amended with urea or animal urine. In the laboratory, some GLS hydrolysis products added with urea to soil were found to decrease N2O emissions and the most effective product (phenylethyl isothiocyante) reduced N2O emissions by 51% during the study. There was some evidence that the reduction in N2O emissions found in the lab could be attributed to inhibition of nitrification. Results suggest that the inhibition by GLS hydrolysis products was short-lived and, if considered for use, multiple applications may be necessary to achieve effective inhibition of N2O emissions. This reduction, however, was not observed under field conditions. Further investigation is required to test more GLS hydrolysis products to fully understand their impact on N2O emissions from urine affected soil. PMID- 28633115 TI - Occurrence of commonly used pesticides in personal air samples and their associated health risk among paddy farmers. AB - Tanjung Karang, Selangor, is widely known for its paddy cultivation activity and hosts the third largest paddy field in Malaysia. Pesticides contamination in agriculture fields has become an unavoidable problem, as pesticides are used to increase paddy productivity and reduce plant disease. Human exposure to agrichemicals is common and could results in both acute and chronic health effects, such as acute and chronic neurotoxicity. This study aims to determine the concentrations of commonly used pesticides (azoxystrobin, buprofezin, chlorantraniliprole, difenoconazole, fipronil, imidacloprid, isoprothiolane, pretilachlor, propiconazole, pymetrozine, tebuconazole, tricyclazole, and trifloxystrobin) in personal air samples and their associated health risks among paddy farmers. Eighty-three farmers from Tangjung Karang, Selangor were involved in this study. A solid sorbent tube was attached to the farmer's breathing zone with a clip, and an air pump was fastened to the belt to collect personal air samples. Pesticides collected in the XAD-2 resin were extracted with acetone, centrifuged, concentrated via nitrogen blowdown and reconstituted with 1mL of 3:1 ultrapure water/HPLC-grade methanol solution. The extract was analyzed using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC MS/MS). The target compounds were detected with a maximum concentration reaching up to 462.5ngm-3 (fipronil). The hazard quotient (HQ) was less than 1 and the hazard index (HI) value was 3.86*10-3, indicating that the risk of pesticides related diseases was not significant. The lifetime cancer risk (LCR) for pymetrozine was at an acceptable level (LCR<10-6) with 4.10*10-8. The results reported in this study can be beneficial in terms of risk management within the agricultural community. PMID- 28633116 TI - Spatial and temporal variation in autochthonous and allochthonous contributors to increased organic carbon and nitrogen burial in a plateau lake. AB - Increased organic carbon and nitrogen accumulation rates (OCAR and ONAR) in lake sediment significantly regulate the global carbon cycle. However, the reasons for and contributors to the increased OCAR and ONAR are unclear. Seven sediment cores, collected in July 2014 from Dianchi Lake, China, were used to evaluate the effects of autochthonous and allochthonous sources on OCAR and ONAR. The results indicate that OCAR and ONAR increased by factors of 4.33 and 7.34 over the past hundred years (1900-2000), particularly after algal blooms began to occur frequently (beginning in the 1980s). Dianchi stored 0.467+/-0.0055Tg (mean value+/-standard deviation) organic carbon (OC) and 0.033+/-0.0004Tg organic nitrogen (ON) after 1986, which is almost equal to the total storage of OC and ON from 1900 to 1985 (OC, 0.468+/-0.0022Tg; ON, 0.032+/-0.0002Tg). OCAR and ONAR increases were due to increasing autochthonous production and allochthonous loading. Examination of the increased OCAR, which was estimated from a newly developed multi-source mixing model, suggests that >90% of increased OCAR was caused by allochthonous sources (such as intensified cultivation, land-use cover change, etc.) in southern and eastern Dianchi and that >70% of the increased OCAR was due to autochthonous sources in western and northern Dianchi Lake. The significant spatial and temporal variation in the contributors to increased OCAR indicates complicated migration and transformation of OC in inland lakes. Land use cover change around Dianchi and the occurrence of algal blooms regulate the contributions of allochthonous and autochthonous sources to the increased OC and ON. PMID- 28633117 TI - Breakup characteristics of aqueous droplet with surfactant in oil under direct current electric field. AB - The breakup process of aqueous droplet with surfactant suspended in oil under direct current (DC) electric field is investigated in this paper. The characteristics of the breakup process, stretching, necking and breakup, are discussed quantitatively with the electric capillary number Ca and the dimensionless surfactant concentration C* which is the ratio of surfactant concentration to the critical micelle concentration. The results show that the presence of surfactant reduces the steady deformation of droplet and significantly decelerates the stretching process, resulting from the redistribution of surfactant molecules within the oil/water interface. The law of droplet stretching process when C*>=1 indicates that the exchange of surfactant molecules between the bulk phase and the interface could not catch up with the increase of oil/water interfacial area. Ca and C* count a great deal to the necking position and the daughter droplet size. The daughter droplet size decreases with the increase of surfactant concentration. These results provide a mechanistic framework to promote the electrocoalescence efficiency of oil/water emulsion and to the application of electric emulsification. PMID- 28633118 TI - Surface enhanced Raman scattering properties of dynamically tunable nanogaps between Au nanoparticles self-assembled on hydrogel microspheres controlled by pH. AB - We developed an interesting route for preparing a poly (acrylamide-co-acrylic acid) (P(AAm-co-AA)) hydrogel microsphere with a coating of Au nanospheres (hydrogel microsphere @ Au nanospheres) through self-assembly based on electrostatic interaction. The fabricated composites could be used as highly sensitive enhanced Raman scattering substrates. The nanogaps between adjacent Au nanospheres were dynamically tuned by volume changes in the hydrogel microspheres in the semiwet state under different pH conditions. At pH 6, the hydrogel microsphere @ Au nanospheres demonstrated highly sensitive SERS with an enhancement factor of 109. The product could detect very low concentrations of analytes up to 10-12M 4-aminothiophenol (4-ATP) molecules. This paper proposes a new method for detecting trace amounts of environmental organic pollutants by dynamically tuning the SERS enhancement in the semiwet testing state. PMID- 28633119 TI - Polymer grafted-magnetic halloysite nanotube for controlled and sustained release of cationic drug. AB - In this research, novel polymer grafted-magnetic halloysite nanotubes with norfloxacin loaded (NOR-MHNTs) and controlled-release, was achieved by surface initiated precipitation polymerization. The magnetic halloysite nanotubes exhibited better adsorption of NOR (72.10mgg-1) compared with the pristine HNTs (30.80mgg-1). Various parameters influencing the drug adsorption of the MHNTs for NOR were studied. Polymer grafted NOR-MHNTs has been designed using flexible docking in computer simulation to choose optimal monomers. NOR-MHNTs/poly (methacrylic acid or acrylamide-co-ethylene glycol dimethacrylate) nanocomposite were synthesized using NOR-MHNTs, methacrylic acid (MAA) or acrylamide (AM), ethylene glycol dimethacrylate (EGDMA) and AIBN as nanotemplate, monomers, cross linker and initiator, respectively. The magnetic nanocomposites were characterized by FTIR, TEM, XRD and VSM. The magnetic nanocomposites show superparamagnetic property and fast magnetic response (12.09emug-1). The copolymerization of monomers and cross linker led to a better sustained release of norfloxacin (>60h) due to the strong interaction formed between monomers and this cationic drug. The cumulative release rate of NOR is closely related to the cross linker amount. In conclusion, combining the advantages of the high adsorption capacity and magnetic proprieties of this biocompatible clay nanotube and the advantages of polymer shell in the enhancement of controlled-sustained release of cationic drug, a novel formulation for the sustained-controlled release of bioactive agents is developed and may have considerable potential application in targeting drug delivery system. PMID- 28633120 TI - Heatwave and infants' hospital admissions under different heatwave definitions. AB - OBJECTIVES: Data on the health impacts of heatwaves in infants are limited, and this study aimed to examine how heatwaves affect hospital admissions in infants. METHODS: A quasi-Poisson generalized additive model was used to assess the effects of heatwaves on hospital admissions in infants from 1st January 2005 to 31st December 2015 in Brisbane, Australia, using a series of heatwave definitions after controlling for possible confounders. A case-only analysis was conducted to examine the possible modification effects of personal and community characteristics on the heatwaves effects on infants' hospital admissions. RESULTS: There was no significant increase in infants' hospital admissions when heatwave intensity was defined as mean temperature >=90th percentile or >=95th percentile of the mean temperature across the study period. When heatwave intensity increased to >=97th percentile, infants' hospital admissions increased significantly (RR: 1.05, 95% CI: 1.01, 1.10), and this increase raised with the increase of heatwave duration. No modification effect of gender, indigenous status, or Socio-Economic Indexes for Areas (SEIFA) level on heatwave effect was observed. CONCLUSIONS: Infants in Brisbane were sensitive to intense heatwaves, and future heat early warning system based on a local evidence-based heatwave definition is needed to protect infants from heatwave impacts. Community-based heatwave adaptation programs aiming at raising the awareness of the adverse health impacts of intense heatwaves among infants' caregivers may relieve the postnatal health care demand in infants. PMID- 28633121 TI - Biomaterials based strategies for rotator cuff repair. AB - Tearing of the rotator cuff commonly occurs as among one of the most frequently experienced tendon disorders. While treatment typically involves surgical repair, failure rates to achieve or sustain healing range from 20 to 90%. The insufficient capacity to recover damaged tendon to heal to the bone, especially at the enthesis, is primarily responsible for the failure rates reported. Various types of biomaterials with special structures have been developed to improve tendon-bone healing and tendon regeneration, and have received considerable attention for replacement, reconstruction, or reinforcement of tendon defects. In this review, we first give a brief introduction of the anatomy of the rotator cuff and then discuss various design strategies to augment rotator cuff repair. Furthermore, we highlight current biomaterials used for repair and their clinical applications as well as the limitations in the literature. We conclude this article with challenges and future directions in designing more advanced biomaterials for augmentation of rotator cuff repair. PMID- 28633122 TI - Plasma treatment switches the regime of wetting and floating of pepper seeds. AB - Cold radiofrequency plasma treatment modified wetting and floating regimes of pepper seeds. The wetting regime of plasma-treated seeds was switched from the Wenzel-like partial wetting to the complete wetting. No hydrophobic recovery following the plasma treatment was registered. Environmental scanning electron microscopy of the fine structure of the (three-phase) triple line observed with virgin and plasma-treated seeds is reported. Plasma treatment promoted rapid sinking of pepper seeds placed on the water/air interface. Plasma treatment did not influence the surface topography of pepper seeds, while charged them electrically. Electrostatic repulsion of floating plasma-treated seeds was observed. The surface charge density was estimated from the data extracted from floating of charged seeds and independently with the electrostatic pendulum as sigma~1-2MUC/m2. PMID- 28633123 TI - Severe but reversible neuropathy and encephalopathy due to vitamin E deficiency. PMID- 28633124 TI - Mesothelial cyst in the liver round ligament: A case report and review of the literature. AB - INTRODUCTION: Cysts of the liver round ligament are rare and they are benign in the majority of cases. Current literature has been reviewed on this subject. PRESENTATION OF CASE: A 22-year-old woman with a history of epigastric pain was admitted at our institution. Computed tomography (CT) of the abdomen showed a 14 mm cystic lesion in the epigastrium. A large cyst of the liver round ligament was successfully removed during exploratory laparoscopy and histopathology revealed a benign mesothelial cyst. DISCUSSION: Mesothelial cysts of the liver round ligament are rare entities and we found a total of 5 cases from the literature. Diameter varies from 5 to 14cm. Most patients were asymptomatic or may complain abdominal pain in the upper quadrants. Ultrasonography and CT scan are the most useful diagnostic tools, however differential diagnosis between various abdominal cystic lesions can be difficult. Treatment is usually surgical excision. CONCLUSION: Mesothelial cysts of the liver round ligament are extremely rare but should be taken in consideration in the differential diagnosis of intra-abdominal cystic lesions. We stress the importance of exploratory laparoscopy that can allow both diagnosis and radical surgical excision. PMID- 28633126 TI - Emergency incarcerated obturator hernia repair with biologic mesh in a male patient after ipsilateral hip disarticulation: A case report. AB - INTRODUCTION: An obturator hernia is an uncommon form of abdominal hernia that is difficult to diagnose due to its non-distinct presentation. This case investigates an emergency treatment of an obturator hernia presenting in a patient with an ipsilateral hip disarticulation in a 266-bed community hospital. PRESENTATION OF CASE: A 53-year old man with a history of a left hip disarticulation 3-weeks prior presented to the emergency department with fever, nausea, vomiting, and diarrhea for the past 5-days. An elevated WBC and presence of gas within the hip stump on CT led to an emergency operation to rule out necrotizing fasciitis within the stump. Opening of the stump incision revealed two herniated loops of small bowel corresponding to the left obturator foramen, revealing the diagnosis of an incarcerated obturator hernia. The bowel was reduced and secured within the hip stump and the defect was covered with Strattice biologic mesh. DISCUSSION: Obturator hernias are rare and can involve vague symptoms, but it is essential to make an accurate diagnosis and repair the defect on an emergency basis. Obturator hernias may appear in the setting of a hip disarticulation, being caused by iatrogenic anatomic alteration, and can be treated in a community acute care hospital. CONCLUSION: Being aware of the possibility of obturator foramen herniation and bowel incarceration as part of the differential diagnosis for patients with abdominal pain after a prior hip disarticulation can facilitate prompt diagnosis and reduce morbidity and mortality. PMID- 28633125 TI - Primary squamous cell carcinoma of the thyroid: Case report and systematic review of the literature. AB - BACKGROUND: Primary squamous cell cancer (PSCC) of thyroid is a rare malignancy with poor prognosis. It is mandatory to exclude secondary involvement of the thyroid by panendoscopy, CT-scan and immunohistochemical analysis. As treatment surgery, radiation and rarely chemotherapy is employed. METHODS: A systematic review of the literature was conducted searching medline and embase database using the medical subject headings "primary squamous cell carcinoma of thyroid" and "primary squamous cell cancer of thyroid", for articles published until April 2016 (n=1733). Of interest were the used treatment modalities and survival outcomes. RESULTS: A total of 35 publications reporting on 50 cases including ours were finally analyzed. A curative treatment approach was described in 24 patients (48%). Additional radiotherapy, chemotherapy or radiochemotherapy was applied in 17, 7 and 7 patients respectively. Median overall survival was 6 months [range 0-48] for 47 patients. Disease free survival was only achieved in 8 patients with disease limited to the thyroid gland, complete surgical resection and additional radiotherapy or radiochemotherapy [reported median 20 months; range 12-48]. CONCLUSION: Reported disease free survival of PSCC of the thyroid was only achieved in patients with complete surgical resection in combination with adjuvant radio- and/or chemotherapy. However long term survival has not been reported in the literature yet. PMID- 28633127 TI - Successful endoscopic treatment of gastric phytobezoar: A case report. AB - INTRODUCTION: Gastric bezoars are a rare condition associated with situations of gastric dysmotility and prior gastric surgery, though sometimes they can present without any risk factor. We describe the first successful treatment in medical literature of a large gastric bezoar in the outpatient setting through endoscopic fragmentation. CASE PRESENTATION: A 76-year-old man was referred to our outpatient endoscopy clinic because of dyspepsia and epigastric pain. Upper GI endoscopy with a standard endoscope revealed a 10-cm-diameter gastric phytobezoar with necrotic pressure ulcer of the angulus. We fragmentized the bezoar into smaller pieces, with complete dissolution and without any complication. The patient was then promptly discharged home with a medical therapy. Follow-up endoscopy at 6 months showed the total disappearance of any residual fibers. DISCUSSION: Different types of bezoars are described in literature, of which phyto- and trychobezoars are the most frequent. They can be absolutely asymptomatic or can arise with epigastric pain, pressure ulcer bleeding, gastrointestinal perforation or small bowel obstruction. The treatment is debated though endoscopic removal or fragmentation with the help of Coca-Cola lavages has showed the best success rate. The main experiences in literature concern hospitalized patients or describe treatment techniques which require overnight stays. An effective and rapid treatment in the outpatient setting is described in our experience, without short- or long-term complications. CONCLUSION: The endoscopic fragmentation of large gastric bezoars in the outpatient setting is safe with a good clinical course. PMID- 28633128 TI - Involvement of UDP-glucuronosyltransferases in higenamine glucuronidation and the gender and species differences in liver. AB - OBJECTIVES: Higenamine (HG), an active ingredient of Aconite root in Chinese herbal medicine, is mainly metabolized by UDP-glucuronosyltransferases (UGT). However, the systematic glucuronidation of HG in humans remains unclear. The purpose of this study was to investigate the glucuronidation of HG. METHODS: 12 recombinant human UGT (rUGT) isozymes were used to characterize the HG glucuronidation. Liver microsomes from male and female mice, rats, guinea pigs, dogs, and humans were used to determine the species and gender differences using liquid chromatography-mass spectrometry. KEY FINDINGS: One monoglucuronide was detected in reactions catalyzed by rUGT1A6, rUGT1A8, rUGT1A9, also human and dog liver microsomes. UGT1A9 is the most important glucuronosyltransferase that metabolizes HG. Because carvacrol, a specific inhibitor of UGT1A9, can significantly decrease the glucuronidation of HG in Human liver microsomes and UGT1A9. HG metabolism by UGT1A9 described in Michaelis-Menten kinetics (Km=15.4 mM,Vmax=2.2 nmol/mg/min) and glucuronidation in liver microsomes were species dependent. Gender did not affect the kinetic parameters among species except in rats. CONCLUSIONS: UGT1A9 is a major isoenzyme responsible for the glucuronidation of HG in Human liver microsomes (HLMs). Dog may be an appropriate animal model to evaluate HG metabolism. PMID- 28633129 TI - Inhibition effect of tacrolimus and platelet-derived growth factor-BB on restenosis after vascular intimal injury. AB - Excessive proliferation and migration of vascular smooth muscle cells(VSMCs) and delayed proliferation and migration of endothelial cells(ECs) were the main cause of restenosis after endovascular interventional therapy. Since tacrolimus has proved to be more sensitive to inhibiting VSMCs' proliferation,and platelet derived growth factor-BB(PDGF-BB) benefitted ECs' and VSMCs' proliferation, this study was aimed to identify combined effect of tacrolimus and PDGF-BB, investigate any mechanisms underneath and demonstrate combined effect of two drugs in vivo. As the results showed we confirmed differential effect of PDGF-BB and tacrolimus on ECs and VSMCs. On the concentration level of 2-5MUg/ml tacrolimus plus 10ng/ml PDGF-BB, combination of drugs could effectively promote ECs proliferation and migration, and meanwhile inhibit VSMCs proliferation and migration, and the inhibition of p-mTOR's expression within VSMCs played an important role in this differentiated effect. Raising concentration level of PDGF BB would weaken inhibitory effect of tacrolimus on both kinds of cell. For injured intima, the mix solution of two drugs could promote intima healing and suppress excessive intimal hyperplasia. PMID- 28633130 TI - Synthesis, screening and pro-apoptotic activity of novel acyl spermidine derivatives on human cancer cell lines. AB - The polyamines putrescine, spermidine, and spermine are polycationic, alkyl polyamines which play a significant role in eukaryotic cell proliferation. The polyamine metabolism and function are dysregulated in tumor cells making them an attractive therapeutic target by employing polyamine analogs. These analogs have a high degree of similarity with the structure of polyamines but not with their function. Multidrug resistance is a major factor in the failure of many chemotherapeutic drugs which necessitates further research and exploration of better novel alternatives. In the present study, Twenty-six novel acylspermidine derivatives were synthesized and evaluated for their anti-proliferative and pro apoptotic activities on human breast cancer cells and T-lymphoblastic leukemia cells. The cell proliferation and apoptosis assays using WST-1 and annexin-V/7AAD staining respectively suggest that Compound 1 (C19H41N3O2), Compound 7(C25H51N3O2) and Compound 8 (C29H59N3O) significantly reduced cancer cell viability in a dose- and time-dependent manner. Interestingly, compounds 7, 8 and 9 had slight or no effect on cell proliferation of non-cancerous cells. These studies speculate that these novel acylspermidine derivatives could be promising candidates in designing an anti-proliferative drug, targeting both solid and blood cancer cells. PMID- 28633131 TI - Dose calculation using Haar wavelets with buildup correction. AB - In this work, we focus on the buildup correction of dose calculation using Haar wavelets in the Tunisian gamma irradiation facility. The buildup effect of gamma rays was used to adjust absorbed dose calculation for different depth in the irradiated products. A buildup study with different product densities was carried out to generalize the dose adjustment approach to any product at any depth. PMID- 28633132 TI - Radon emanation from fresh, altered and disturbed granitic rock characterized by 14C-PMMA impregnation and autoradiography. AB - Radon emanation from intact samples of fresh ("BG"), altered ("Fract") and disturbed ("EDZ") Finnish granitic rock from Kuru (Finland) and its dependence on humidity and rock structural factors was studied. The pore network of the rock was characterized by microscopy and impregnation with 14C-PMMA (polymethylmethacrylate) resin and autoradiography. The radon emanation factor was increasing linearly with the relative humidity. 14C-PMMA autoradiography of the altered zones and the EDZ indicated significant, mineral-specific increase of porosity and porosity gradients towards the fracture surfaces (Fract) and microcracks within the EDZ. For small samples in the cm-scale emanation was not diffusion, but source term controlled. PMID- 28633133 TI - Optically stimulated luminescence study in rare earth doped SrBPO5. AB - Optically stimulated luminescence (OSL) was studied in rare earth doped SrBPO5 for the possible applications in radiation dosimetry using optically stimulated luminescence. The study shows that the sensitivity of the Eu doped SrBPO5 shows good OSL and the sensitivity is comparable to that of Al2O3:C. It is observed that annealing has a profound effect on the OSL sensitivity. Slowly cooled Eu doped sample shows highest sensitivity and is 77% compared to that Al2O3:C whereas lowest sensitivity is observed in the quenched sample. Other properties like good linearity and low fading will make this phosphor suitable for the applications in radiation dosimetry using OSL. PMID- 28633135 TI - Children with a Higher Activity of Carbonic Anhydrase VI in Saliva Are More Likely to Develop Dental Caries. AB - OBJECTIVE: This study aimed to analyze the concentration and activity of carbonic anhydrase (CA) VI in the saliva of school children. We investigated the relationship among caries, CA VI concentration/activity, flow rate, pH, and buffering capacity. MATERIALS AND METHODS: Seventy-four school children were divided into a caries-free group and a caries group. Clinical examinations were conducted by one examiner according to World Health Organization criteria + early caries lesions. Salivary flow rate, pH, and buffering capacity were analyzed. Salivary CA VI concentration and activity were evaluated by ELISA and zymography, respectively. The data were analyzed using Student's t test and the Mann-Whitney test, and Pearson and Spearman correlation analyses were also done. In multivariate modeling, associations between variables were expressed as odds ratios. RESULTS: The results showed that salivary flow rate, salivary pH, and BC were significantly higher in the saliva of caries-free children. Also, the salivary CA VI concentration was significantly higher in the saliva of caries free children. The salivary CA VI activity was higher in children with caries. We found a negative correlation between BC and dental caries. Also, in the caries group we found a positive correlation between the concentration and the activity of CA VI and a negative correlation between BC and CA VI activity. A negative correlation between salivary pH and CA VI concentration was observed in the caries-free group. A high activity of CA and a low salivary flow rate were associated with dental caries. CONCLUSION: These results support the conclusion that dental caries is highly affected by the activity of CA VI in saliva as well as by the salivary flow rate. PMID- 28633134 TI - Peritoneal Water Transport Characteristics of Diabetic Patients Undergoing Peritoneal Dialysis: A Longitudinal Study. AB - BACKGROUND: Volume overload is frequent in diabetics undergoing peritoneal dialysis (PD), and may play a significant role in the excess mortality observed in these patients. The characteristics of peritoneal water transport in this population have not been studied sufficiently. METHOD: Following a prospective, single-center design we made cross-sectional and longitudinal comparisons of peritoneal water transport in 2 relatively large samples of diabetic and nondiabetic PD patients. We used 3.86/4.25% glucose-based peritoneal equilibration tests (PET) with complete drainage at 60 min, for these purposes. MAIN RESULTS: We scrutinized 59 diabetic and 120 nondiabetic PD patients. Both samples showed relatively similar characteristics, although diabetics were significantly more overhydrated than nondiabetics. The baseline PET disclosed lower ultrafiltration (mean 439 mL diabetics vs. 532 mL nondiabetics, p = 0.033) and sodium removal (41 vs. 53 mM, p = 0.014) rates in diabetics. One hundred and nine patients (36 diabetics) underwent a second PET after 12 months, and 45 (14 diabetics) underwent a third one after 24 months. Longitudinal analyses disclosed an essential stability of water transport in both groups, although nondiabetic patients showed a trend where an increase in free water transport (p = 0.033) was observed, which was not the case in diabetics. CONCLUSIONS: Diabetic patients undergoing PD present lower capacities of ultrafiltration and sodium removal than their nondiabetic counterparts. Longitudinal analyses disclose an essential stability of water transport capacities, both in diabetics and nondiabetics. The clinical significance of these differences deserves further analysis. PMID- 28633136 TI - Malaria Fever Therapy for General Paralysis of the Insane: A Historical Cohort Study. AB - BACKGROUND/AIMS: This year marks the 100th anniversary of the first malaria fever treatment (MFT) given to patients with general paralysis of the insane (GPI) by the Austrian psychiatrist and later Nobel laureate, Julius Wagner-Jauregg. In 1921 Wagner-Jauregg reported an impressive therapeutic success of MFT and it became the standard treatment for GPI worldwide. In this study, MFT practice in the Dutch Vincent van Gogh psychiatric hospital in GPI patients who had been admitted in the period 1924-1954 is explored. METHODS: To identify patients with GPI, cause-of-death statistics was used. Data on MFT were retrieved from annual hospital reports and individual patient records. RESULTS: Data on MFT were mentioned in the records of 43 out of 105 GPI patients. MFT was practiced in a wide range of patients with GPI, including those with disease duration of more than 1 year, up to 70 years of age, and those with a broad array of symptoms and comorbidities, such as (syphilitic) cardiac disease. Inoculation with malaria was done by patient-to-patient transmission of infected blood. CONCLUSIONS: MFT practice and mortality rates in MFT-treated patients correspond to similar findings worldwide. MFT was well tolerated and MFT-treated patients had a significantly longer survival. PMID- 28633137 TI - Incidence and Characteristics of Congenital Cataract Surgery in France from 2010 to 2012: The EPISAFE Program. AB - INTRODUCTION: Prevention of visual impairment due to congenital cataract is an international priority as part of VISION 2020 - The Right to Sight, the joint initiative of the World Health Organization and the International Agency for the Prevention of Blindness. The present study is part of the Epidemiology and Safety (EPISAFE) collaborative program aiming at assessing the epidemiology and safety of interventions in ophthalmology. METHODS: All children who underwent cataract surgery before the age of 1 year in France between January 2010 and December 2012 were identified by using the Programme de Medicalisation des Systemes d'Information. RESULTS: In 3 years, 532 children (699 eyes; 46.6% girls) had cataract surgery before the age of 1 year; 31.4% had bilateral surgery. During the first year of life, the incidence of cataract surgery was 2.15/10,000 births. The median (interquartile range) age at surgery was 3.5 (2.2-4.8) months for children with unilateral cataract and 4.0 (2.2-7.2) months for children with bilateral cataract. Of the 699 operated eyes, 76.49% received intraocular lens implantation during the cataract surgery. CONCLUSIONS: The incidence of congenital cataract surgery observed in France is close to that in the literature in the industrialized world, which is estimated at 1-3/10,000 births. The timing of surgery is critical for visual development. Surgery was performed younger in children with monocular cataracts than in those with bilateral cataracts. PMID- 28633138 TI - Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells. AB - The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN) gamma production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF) alpha, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-gamma and TNF alpha production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation. PMID- 28633139 TI - Mitochondrial Metabolism in a Large-Animal Model of Huntington Disease: The Hunt for Biomarkers in the Spermatozoa of Presymptomatic Minipigs. AB - BACKGROUND: Huntington disease (HD) is a fatal neurodegenerative disorder involving reduced muscle coordination, mental and behavioral changes, and testicular degeneration. In order to further clarify the decreased fertility and penetration ability of the spermatozoa of transgenic HD minipig boars (TgHD), we applied a set of mitochondrial metabolism (MM) parameter measurements to this promising biological material, which can be collected noninvasively in longitudinal studies. OBJECTIVE: We aimed to optimize methods for MM measurements in spermatozoa and to establish possible biomarkers of HD in TgHD spermatozoa expressing the N-terminal part of mutated human huntingtin. METHODS: Semen samples from 12 TgHD and wild-type animals, aged 12-65 months, were obtained repeatedly during the study. Respiration was measured by polarography, MM was assessed by the detection of oxidation of radiolabeled substrates (mitochondrial energy-generating system; MEGS), and the content of the oxidative phosphorylation system subunits was detected by Western blot. Three possibly interfering factors were statistically analyzed: the effect of HD, generation and aging. RESULTS: We found 5 MM parameters which were significantly diminished in TgHD spermatozoa and propose 3 specific MEGS incubations and complex I-dependent respiration as potential biomarkers of HD in TgHD spermatozoa. CONCLUSIONS: Our results suggest a link between the gain of toxic function of mutated huntingtin in TgHD spermatozoa and the observed MM and/or glycolytic impairment. We determined 4 biomarkers useful for HD phenotyping and experimental therapy monitoring studies in TgHD minipigs. PMID- 28633140 TI - Early Intrauterine Transfusion in Fetuses with Severe Anemia Caused by Parvovirus B19 Infection. AB - OBJECTIVE: To describe procedure-related complications and perinatal survival after intrauterine transfusion (IUT) before 20 weeks of gestation in fetuses with severe anemia due to human parvovirus B19 infection. MATERIALS AND METHODS: A retrospective study was conducted of all fetuses requiring IUT before 20 weeks of gestation in two tertiary referral centers between January 2002 and July 2015. Gestational age (GA) at first IUT, fetal blood sampling results, and presence of hydrops were related to procedure-related complications, fetal death (FD), and perinatal outcome. RESULTS: A total of 93 IUTs was performed on 55 fetuses. The mean GA at first IUT was 16+6 (13+0-19+6) weeks. FD occurred in 11 (20.0%) of the 55 fetuses. Overall survival was 80.0% (44/55). Hydrops was present in 38.2% (21/55) and was strongly associated with FD (p = 0.001). There was no difference with regard to FD, hydrops, or hemoglobin concentration at first IUT in fetuses with transfusion before or after 16+0 weeks. CONCLUSION: Severe anemia due to parvovirus B19 infection in the early second trimester can be treated successfully by IUT before 20 weeks of gestation in specialized centers with sufficient expertise. PMID- 28633141 TI - Interaction of Soluble CXC Ligand 16 and Cardiac Injury Markers in Hemodialysis Patients. AB - BACKGROUND: Recent data suggest that there is a pathogenic role for CXC ligand 16 (CXCL16) in cardiovascular diseases. Little is known about circulating CXCL16 in patients with kidney dysfunction. We explored the relationships of plasma CXCL16 with cardiac injury markers in a group of dialysis patients. METHODS: Plasma CXCL16 and C-reactive protein (CRP) were measured in 366 patients who were on maintenance hemodialysis. Cardiac injury was evaluated via measurements of the circulating B-type natriuretic peptide (BNP), N-terminal prohormone of brain natriuretic peptide (NT proBNP), Troponin I (TnI), and Troponin T (TnT). Sixty healthy subjects who were frequency matched with the patients on the basis of age and gender were recruited as healthy controls. RESULTS: The mean age of the patients was 52.5 +/- 12.1 years and 56.3% were male. Circulating CXCL16 was significantly higher in the patients than in the controls (patients vs. CONTROLS: 477.3 (367.0-647.1) pg/mL vs. 229.5 (203.8-254.5) pg/mL; p < 0.001). The log transformed (log-) CXCL16 level was correlated with all 4 cardiac markers (log BNP, log-NTproBNP, log-TnI, and log-TnT) with high levels of significance (all p < 0.001), even after extensive controls for the covariates. In contrast, CRP was correlated only with BNP (marginally) and NT proBNP and was not correlated with troponins. CONCLUSION: We showed, for the first time, highly significant relationships of circulating CXCL16 level with cardiac injury markers in dialysis patients. Our data suggest that circulating CXCL16 is possibly involved in the pathological process of cardiovascular damage in dialysis patients and may serve as a therapeutic target for cardiac protection in these patients. PMID- 28633142 TI - Multifactorial Analysis of a Biomarker Pool for Alzheimer Disease Risk in a North Indian Population. AB - BACKGROUND: Alzheimer disease (AD) is a progressive neurodegenerative disease with a complex multifactorial etiology. Here, we aim to identify a biomarker pool comprised of genetic variants and blood biomarkers as predictor of AD risk. METHODS: We performed a case-control study involving 108 cases and 159 non demented healthy controls to examine the association of multiple biomarkers with AD risk. RESULTS: The APOE genotyping revealed that epsilon4 allele frequency was significantly high (p value = 0.0001, OR = 2.66, 95% CI 1.58-4.46) in AD as compared to controls, whereas epsilon2 (p = 0.0430, OR = 0.29, CI 0.07-1.10) was overrepresented in controls. In biochemical assays, significant differences in levels of total copper, free copper, zinc, copper/zinc ratio, iron, epidermal growth factor receptor (EGFR), leptin, and albumin were also observed. The AD risk score (ADRS) as a linear combination of 6 candidate markers involving age, education status, APOE epsilon4 allele, levels of iron, Cu/Zn ratio, and EGFR was created using stepwise linear discriminant analysis. The area under the ROC curve of the ADRS panel for predicting AD risk was significantly high (AUC = 0.84, p < 0.0001, 95% CI 0.78-0.89, sensitivity = 70.0%, specificity = 83.8%) compared to individual parameters. CONCLUSION: These findings support the multifactorial etiology of AD and demonstrate the ability of a panel involving 6 biomarkers to discriminate AD cases from non-demented healthy controls. PMID- 28633143 TI - Tumor-Associated Macrophages in the Development of 4-Nitroquinoline-1-Oxide Induced Tongue Squamous Cell Carcinoma in a Mouse Model. AB - OBJECTIVE: We aimed to determine the distribution of tumor-associated macrophages (TAMs) in the development of tongue squamous cell carcinoma (SCC) and to elucidate the role of TAMs in the progression of tongue SCC. METHODS: The expression of the macrophage markers nitric oxide synthase, Retnla, and mannose receptor 1 in the development of tongue SCC was longitudinally observed using real-time quantitative polymerase chain reaction. Additionally, an immunohistochemical study using an anti-mannose receptor (MR) antibody was performed. RESULTS: The numbers of both of M1 and M2 macrophages in the tongues of mice treated with 4-nitroquinoline-1-oxide (4NQO) were significantly lower compared with those of normal tongues. The cyclooxygenase-2 (COX-2) inhibitor did not prevent cancer progression and did not affect the total number of macrophages in the tongues of 4NQO-treated mice. In the immunohistochemical studies, MR staining was observed in lymphangioendothelium in the subepithelial area of the tongues. The staining intensity of the MR was significantly stronger in the 4NQO treated mice compared with that in control mice and 4NQO-treated mice treated with the COX-2 inhibitor. CONCLUSION: TAMs may not contribute to the development of 4NQO-induced tongue SCC. MR expression is associated with the progression of 4NQO-induced tongue SCC. PMID- 28633144 TI - Standardized Renal Endpoints for Perioperative Clinical Trials: The Standardized Endpoints in Perioperative Medicine Initiative. AB - Perioperative acute kidney injury is a common problem. While clinical trials seek to evaluate the impact of interventions on a variety of primary and secondary endpoints with the aim of implementing this knowledge to improve perioperative outcomes, the use of valid and relevant endpoints within clinical trials is of critical importance to achieving this goal. Suitable endpoints must be validated for the study population and in light of the clinical context under investigation while also considering regulatory requirements that govern the licensing of new therapeutic agents as well as the values of patients whose outcomes we seek to improve. Heterogeneity in perioperative clinical trial endpoints and their definitions limits the ability to compare and interpret differences in outcomes across studies or to pool outcomes from different studies in meta-analysis. The Standardized Endpoints in Perioperative Medicine (StEP) initiative is an international collaboration whose goal is to identify and recommend a suite of clearly and precisely defined endpoints across multiple domains, specifically suited for use in perioperative clinical trials. The current review describes the rationale, goals and the planned pathway of the StEP renal subgroup. Development of a set of standardized and core renal endpoints, valid and relevant for use in the perioperative context, precisely defined and yet with sufficient flexibility to encourage broad uptake and application should facilitate high-quality and practice-changing perioperative research into the future. PMID- 28633145 TI - Urinary Volatile Organic Compounds as Potential Biomarkers in Idiopathic Membranous Nephropathy. AB - OBJECTIVE: To detect urinary volatile organic compounds (VOCs) in patients with idiopathic membranous nephropathy (iMN) and normal controls, and to examine whether or not urinary VOCs can act as biomarkers for the diagnosis of iMN independent of renal biopsy. MATERIALS AND METHODS: Gas chromatography/mass spectrometry (GC/MS) was used to assess the urine collected from 63 iMN patients and 15 normal controls. The statistical methods of principal component analysis and partial least squares discriminant analysis were performed to process the final data in Common Data Format which were converted from GC/MS data. RESULTS: Six VOCs in the urine samples of iMN patients exhibited significant differences from those of normal controls: carbamic acid monoammonium salt, 2-pentanone, 2,4 dimethyl-pentanal, hydrogen azide, thiourea, and 4-heptanone were significantly higher than in controls (p < 0.05). CONCLUSIONS: Six urinary VOCs were isolated from patients with iMN using GC/MS. The analysis of urinary VOCs using GC/MS could be developed into a non-invasive method for the detection of iMN. PMID- 28633147 TI - Tranexamic Acid Safely Reduced Blood Loss in Hemi- and Total Hip Arthroplasty for Acute Femoral Neck Fracture: A Randomized Clinical Trial. AB - OBJECTIVES: We aimed to determine whether (1) tranexamic acid (TXA) reduces the incidence of transfusion (2) TXA reduces the calculated blood loss, and (3) there are any observable differences in 30- and 90-day complications with TXA administration during arthroplasty for femoral neck fracture (FNF). DESIGN: Prospective, double-blinded, randomized controlled trial. SETTING: Level 1 Academic Trauma Center. PATIENTS/PARTICIPANTS: One hundred thirty-eight patients who presented with a low-energy, isolated, FNF (AO 31B) treated with either hemi- or total hip arthroplasty within 72 hours of injury were randomized to either the TXA group (69 patients) or placebo group (69 patients). INTERVENTION: In the TXA group, patients received 2 doses of 15 mg/kg intravenous TXA dissolved in 100 mL of saline, each administered over 10 minutes; 1 dose just before incision, and the second at wound closure. In the placebo group, 100 mL of saline solution was administered in a similar fashion. Perioperative care was otherwise standardized including conservative transfusion criteria. MAIN OUTCOME MEASUREMENTS: Our primary outcome was to determine the proportion of patients who underwent blood transfusion during hospitalization. Secondary outcomes were calculated blood loss, number of units transfused during hospitalization, and incidence of adverse events at 30 and 90 days including thromboembolic event, wound complications, reoperation, hospital readmission, and all-cause mortality. RESULTS: TXA reduced mean incidence of transfusion by 305 mL (P = 0.0005). There was a trend toward decreased transfusion rate in the TXA group (17% vs. 26%, P = 0.22). TXA was safe with no differences in adverse events at 30 and 90 days. CONCLUSIONS: This randomized clinical trial found that TXA administration safely reduced blood loss with a tendency for decreased transfusion rate and total blood product consumption for patients undergoing hip arthroplasty for acute FNF. More studies are needed to further ascertain the role of TXA in the management of patients with FNF. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28633148 TI - Clinical and Functional Results of 119 Patients With Knee Dislocations. AB - OBJECTIVES: To describe clinical results and functional outcomes of knee dislocations treated with a consistent strategy within our institution. DESIGN: Retrospective case series. SETTING: Level 1 trauma center. PATIENTS: One hundred nineteen patients were treated at one institution between 2000 and 2014 for knee dislocation. MAIN OUTCOME MEASUREMENTS: Knee range of motion, functional instability, and complications were recorded. Musculoskeletal Function Assessment (MFA) and Lysholm scores were obtained after minimum of 1 year. RESULTS: Sixty three early complications were noted in 36 patients (32%), with an overall amputation rate of 9.2% (8 early and 3 late amputations). Of the patients who retained their limb, 4.5% reported instability. Open knee dislocations were associated with amputation (26% vs. 1.3%, P < 0.001). Popliteal arterial injuries were associated with more amputation (31% vs. 3.2%, P = 0 < 0.001), infection (37% vs. 8%, P = 0.002), and deep venous thrombosis (32% vs. 8.8%, P = 0.014). Patients with wound infection were more likely to develop heterotopic ossification (36% vs. 9.4%, P = 0.017) and less knee motion (77.5 vs. 117 degrees P = 0.049). Knee motion improved over time for all patients with a mean arc of 86 degrees at 3 months, 109 degrees at 6 months, and 115 degrees at 12 months. An Injury Severity Score of >=20 was associated with less knee motion (97 vs. 121 degrees P = 0.029). Mean Lysholm score was 86.7, and mean MFA score was 35.7 after mean follow-up of 90 months and 82 months, respectively. CONCLUSIONS: Few patients (4.5%) experienced functional instability. However, early complications occurred frequently (32%) as expected, particularly in patients with open injuries and/or arterial injury. Limitations in knee motion were associated with high Injury Severity Score, infection, and heterotopic ossification. Mean knee scores were good, consistent with reasonable knee function, although MFA scores suggest a lower level of generalized function. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28633149 TI - Tibial Eminence Involvement With Tibial Plateau Fracture Predicts Slower Recovery and Worse Postoperative Range of Knee Motion. AB - OBJECTIVES: To examine 1-year functional and clinical outcomes in patients with tibial plateau fractures with tibial eminence involvement. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Academic Medical Center. PATIENTS/PARTICIPANTS: All patients who presented with a tibial plateau fracture (Orthopaedic Trauma Association (OTA) 41-B and 41-C). INTERVENTION: Patients were divided into fractures with a tibial eminence component (+TE) and those without ( TE) cohorts. All patients underwent similar surgical approaches and fixation techniques for fractures. No tibial eminence fractures received fixation specifically. MAIN OUTCOME MEASUREMENTS: Short musculoskeletal functional assessment (SMFA), pain (Visual Analogue Scale), and knee range-of-motion (ROM) were evaluated at 3, 6, and 12 months postoperatively and compared between cohorts. RESULTS: Two hundred ninety-three patients were included for review. Patients with OTA 41-C fractures were more likely to have an associated TE compared with 41-B fractures (63% vs. 28%, P < 0.01). At 3 months postoperatively, the +TE cohort was noted to have worse knee ROM (75.16 +/- 51 vs. 86.82 +/- 53 degree, P = 0.06). At 6 months, total SMFA and knee ROM was significantly worse in the +TE cohort (29 +/- 17 vs. 21 +/- 18, P <= 0.01; 115.6 +/- 20 vs. 124.1 +/- 15, P = 0.01). By 12 months postoperatively, only knee ROM remained significantly worse in the +TE cohort (118.7 +/- 15 vs. 126.9 +/- 13, P < 0.01). Multivariate analysis revealed that tibial eminence involvement was a significant predictor of ROM at 6 and 12 months and SFMA at 6 months. Body mass index was found to be a significant predictor of ROM and age was a significant predictor of total SMFA at all time points. CONCLUSION: Knee ROM remains worse throughout the postoperative period in the +TE cohort. Functional outcome improves less rapidly in the +TE cohort but achieves similar results by 1 year. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28633150 TI - Hexapod Frame Stacked Transport for Tibial Infected Nonunions With Bone Loss: Analysis of Use of Adjunctive Stability. AB - OBJECTIVES: The stacked hexapod bone transport technique is an effective treatment for infected tibial nonunions with bone loss. The purpose of this study was to evaluate the patients' risk factors and timing for requiring adjunctive stabilization. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Seventy-five patients with infected posttraumatic nonunions of the tibia. INTERVENTION: Resection of nonunion with application of stacked hexapod frame for bone transport. MAIN OUTCOME MEASUREMENTS: Parameters measured included age, sex, diabetes, smoking, use of a free flap, bone defect size, length in frame, external fixation index, and direction of lengthening. Outcomes recorded: removal of frame, below knee amputation, or adjunctive stability. Further analysis evaluated location of nonunion, timing of adjunctive stabilization, and type of fixation. RESULTS: The average patient age was 45.7 +/ 12.5 years, 76% patients were men, 11% were diabetic, and 44% were smokers. Forty two percent had soft tissue defects that required a free flap. Thirty-eight patients had removal of frame, whereas 36 patients required adjunctive stability of the hexapod frame. Patient receiving adjunctive stabilization had a longer length of time in the hexapod frame (P = 0.026) and were more likely to require a free flap (P = 0.053). Ninety-three percent docking site nonunions occurred after the removal of the frame (P = 0.032); whereas 79% regenerate nonunions occurred before the hexapod frame was removed (P = 0.029). CONCLUSIONS: The use of a hexapod frame for the infected tibial nonunions with bone loss is an effective method for achieving union and eradicating infection in a difficult orthopaedic patient population. Use of adjunctive stabilization is a reasonable technique to address delayed regenerate and docking site nonunions. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28633151 TI - Age-Based Normative Measurements of the Pediatric Pelvis. AB - OBJECTIVES: Pediatric pelvic trauma is associated with high rates of morbidity and mortality. Current classifications do not take into account age-dependent quantitative differences of the pediatric pelvis making accurate diagnosis of pathologic diastasis of the pubic symphysis, sacroiliac (SI) joints, and triradiate cartilage difficult. The purpose of this study was to establish age based normative values for the width of the pubic symphysis, SI joints, and the triradiate cartilage of the pediatric pelvis. METHODS: All computed tomographic (CT) scans of the abdomen and pelvis from patients between the ages 2 and 16 years over a 3-year period at a single institution were evaluated. Patients were excluded if the CT was performed as part of a trauma evaluation or for a history of neuromuscular disease or spinopelvic instrumentation. A total of 821 CT were included. The width of pubic symphysis, right and left SI joints, and each limb of the triradiate cartilages was measured using the PACS digital measurement tool. Left and right measurements of the SI joints and triradiate cartilage were combined and reported together. RESULTS: From age 2 to 16 years, the average widths of the SI joint and pubic symphysis decreased from 3.11 to 1.80 mm and 5.55 to 3.69 mm, respectively. The average widths of the 3 limbs of the triradiate cartilage also slightly decreased from age 2 until closure: ilioischial, iliopubic, and ischiopubic cartilages decreasing from 3.72 to 2.74 mm, 4.42 to 3.52 mm, and 3.08 to 2.97 mm, respectively. CONCLUSIONS: This study demonstrates an age-dependent decrease in width of the pubic symphysis and left and right SI joints. By contrast, the widths of the triradiate cartilage remain relatively stable until closure. We believe that these age-based normative values will aid in future diagnosis of pathologic diastasis of these areas of the pediatric pelvis. PMID- 28633152 TI - State of Pelvic and Acetabular Surgery in the Developing World: A Global Survey of Orthopaedic Surgeons at Surgical Implant Generation Network (SIGN) Hospitals. AB - OBJECTIVES: To document the current state of pelvic and acetabular surgery in the developing world and to identify critical areas for improvement in the treatment of these complex injuries. DESIGN: A 50-question online survey. SETTING: International, multicenter. PATIENTS/PARTICIPANTS: One hundred eighty-one orthopaedic surgeons at Surgical Implant Generation Network (SIGN) hospitals, which represent a cross-section of institutions in low- and middle-income countries that treat high-energy musculoskeletal trauma. INTERVENTIONS: Administration and analysis of 50-question survey. MAIN OUTCOME MEASURES: Surgeon training and experience; hospital resources; volume and patterns of pelvic/acetabular fracture management; postoperative protocols and resources for rehabilitation; financial responsibilities for patients with pelvic/acetabular fractures. RESULTS: Complete surveys were returned by 75 institutions, representing 61.8% of the global SIGN nail volume. Although 96% of respondents were trained in orthopaedic surgery, 53.3% have no formal training in pelvic or acetabular surgery. Emergency access to the operating room is available at all responding sites, but computed tomography scanners are available at only 60% of sites, and a mere 21% of sites have access to angiography for pelvic embolization. Cannulated screws (53.3%) and pelvic reconstruction plates (56%) are available at just over half of the sites, and 68% of sites do not have pelvic reduction clamps and retractors. 21.3% of sites do not have access to intraoperative fluoroscopy. Responding hospitals see an average of 38.8 pelvic ring injuries annually, with 24% of sites treating them all nonoperatively. Sites treated an average of 22.5 acetabular fractures annually, with 34.7% of institutions treating them all nonoperatively. Patients travel up to 1000 km or 20 hours for pelvic/acetabular treatment at some sites. Although 78.7% of sites have inpatient physical or occupational therapy services, only 17% report access to home physical therapy, and only 9% report availability of nursing or rehabilitation facilities postdischarge. At over 80% of hospitals, patients and their families are at least partially responsible for payment of surgical, implant, hospital, and outpatient fees. Government aid is available for inpatient fees at over 40% of sites, but outpatient services are subsidized at only 28% of sites. CONCLUSIONS: We report the current state of pelvic and acetabular surgery in low- and middle-income countries. Our results identify significant needs in surgeon training, hospital resources, availability of instruments and implants, and access to appropriate postoperative rehabilitation services for pelvic and acetabular surgery in the developing world. Targeted programs designed to overcome these barriers are required to advance the care of pelvic and acetabular fractures in the developing world. PMID- 28633153 TI - ASSOCIATION BETWEEN VISUAL FUNCTION AND SUBRETINAL DRUSENOID DEPOSITS IN NORMAL AND EARLY AGE-RELATED MACULAR DEGENERATION EYES. AB - PURPOSE: To examine the association between subretinal drusenoid deposits (SDDs) identified by multimodal retinal imaging and visual function in older eyes with normal macular health or in the earliest phases of age-related macular degeneration (AMD). METHODS: Age-related macular degeneration status for each eye was defined according to the Age-Related Eye Disease Study (AREDS) 9-step classification system (normal = Step 1, early AMD = Steps 2-4) based on color fundus photographs. Visual functions measured were best-corrected photopic visual acuity, contrast and light sensitivity, mesopic visual acuity, low-luminance deficit, and rod-mediated dark adaptation. Subretinal drusenoid deposits were identified through multimodal imaging (color fundus photographs, infrared reflectance and fundus autofluorescence images, and spectral domain optical coherence tomography). RESULTS: The sample included 1,202 eyes (958 eyes with normal health and 244 eyes with early AMD). In normal eyes, SDDs were not associated with any visual function evaluated. In eyes with early AMD, dark adaptation was markedly delayed in eyes with SDDs versus no SDD (a 4-minute delay on average), P = 0.0213. However, this association diminished after age adjustment, P = 0.2645. Other visual functions in early AMD eyes were not associated with SDDs. CONCLUSION: In a study specifically focused on eyes in normal macular health and in the earliest phases of AMD, early AMD eyes with SDDs have slower dark adaptation, largely attributable to the older ages of eyes with SDD; they did not exhibit deficits in other visual functions. Subretinal drusenoid deposits in older eyes in normal macular health are not associated with any visual functions evaluated. PMID- 28633154 TI - Localized Bilateral Juxtafoveal Photoreceptor Loss in POEMS: A New Association. PMID- 28633155 TI - Regional Anesthesia and Pain Medicine: US Anesthesiology Resident Training-The Year 2015. AB - BACKGROUND AND OBJECTIVES: The Anesthesiology Review Committee of the Accreditation Council for Graduate Medical Education sets core requirements for residency program accreditation. We periodically report and analyze the US anesthesiology residents' training experience in regional anesthesia and pain medicine. METHODS: Resident caseload, procedure, and pain medicine evaluation data were aggregated for the resident cohort who graduated in 2015. These data were analyzed for present-day experience and compared with previous reports from years 1980, 1990, and 2000 graduates. RESULTS: Data were available for 1631 residents who graduated from 129 training programs. Regional anesthesia as a portion of the overall anesthesiology residents' training experience remains unchanged since 1990. The distribution of regional anesthesia training has shifted from neuraxial to peripheral blocks. All residents at the 10th percentile and above achieved the benchmark for spinal, epidural, and peripheral nerve block anesthetics and for new pain evaluations. CONCLUSIONS: The focus of US anesthesiology resident training in regional anesthesia and pain medicine has changed over the past 15 years by shifting from neuraxial to peripheral nerve block techniques. Previous training deficits have resolved for spinal anesthesia and peripheral nerve block. Procedural experience in pain medicine overwhelmingly involves epidural and facet injections. PMID- 28633156 TI - Generalized Indeterminate Cell Histiocytosis Presenting as Eroded Papules and Crusts. AB - Indeterminate cell histiocytosis (ICH) is a very rare histiocytic disease. We reported a case of generalized ICH presenting as eroded papules and crusts, accompanied with intermittent fever, pulmonary disorder, lymphadenectasis in the mediastinum, and the retroperitoneum. The histopathology indicated a neoplasm that was composed of small nests of large cells with ample pale cytoplasm. Immunohistochemistry results and the absence of Birbeck granules led us to the diagnosis of ICH. Four months later, the patient died of anemia, ascites, and swelling of the limbs. PMID- 28633158 TI - [Humoral response markers in GCK MODY]. AB - BACKGROUND: The prevalence of antibodies to pancreatic islets in monogenic diabetes remains unknown and the incidence estimation is difficult as the occurrence of autoantibodies in patient is one of the well-known exclusion criteria for further genetic diagnostics. They has been found not only among patients with type 1 diabetes, but also in other types of diabetes: Type 2 diabetes, Latent Autoimmune Diabetes in Adults (LADA) (16) and monogenic diabetes (MD). AIM: Immunological characteristic of GCK MODY patients. METHODS: The study group included families of 27 adolescent patients with GCK MODY (39 parents and 19 siblings) monitored in the Department of Pediatrics, Endocrinology and Diabetes and in the Diabetes Clinic of John Paul II Upper Silesian Child Health Centre in Katowice in the years 2007-2012. All patients and family members with GCK MODY underwent a blood sample drawing for immunological (classic humoral response markers: ICA, GAD, IA-2, IAA) and biochemical diagnostics. Pediatric, diabetes and family medical history was collected from the subjects and parents. RESULTS: Immunological diagnostics was performed in all patients except 1 (96.3%). Immunological diagnostics included 17 (89.5%) parents and 7 (87.5%) siblings with diagnosed GCK MODY. 8 (30.8%) adolescent patients with GCK MODY, 3 subjects (17.64%) among parents (with GCK MODY), as well as 2 subjects (28.57%) among siblings (with GCK MODY) showed a positive antibodies screen. CONCLUSION: The results of our study in children with GCK MODY and their family members suggest that the occurrence of classic antibodies directed against pancreatic islets antigens is fairly common in patients with GCK MODY. Despite various observations and many legitimate discussions, it is difficult to clarify the pathogenesis of the occurrence of autoantibodies in monogenic diabetes. PMID- 28633159 TI - [Carotid artery intima-media thickness (cIMT) in young type 1 diabetic patients in relation to comorbid additional autoimmune diseases and microvascular complications]. AB - INTRODUCTION: Atherosclerosis, which is the cause of diseases of the cardiovascular system, and frequent and serious complications of type 1 diabetes (T1DM), has an autoimmune origin. Some diseases of this type, as rheumatoid arthritis, but also Hashimoto thyroiditis or celiac disease are associated with a higher incidence of heart disease. So far no studies evaluated the preclinical phase of development of atherosclerosis (cIMT) in young patients with T1DM and the comorbid additional autoimmune diseases. AIM OF THE STUDY: was evaluation of cIMT (carotid intima media thickness) carotid arteries and the risk factors of atherosclerosis in young patients with type 1 diabetes according to the comorbid autoimmune diseases and a comparison group of patients with known vascular complications and a group of healthy people. PATIENTS AND METHODS: The study involved a group of 90 adolescents and young adults with T1DM in middle age 17,1+/-3years, with an average disease duration of 10,5+/-3,3 years. Diabetes patients were divided into 4 groups - diabetes without complications - C, diabetes with celiac disease - CC, diabetes with Hashimoto's thyroiditis - CH, diabetes with vascular complications - CN. The control group (K) consisted of 22 healthy age-matched volunteers. In statistical analysis rated: average A1C of all the years of illness, BMI, blood pressure, lipid values, duration of illness, presence of diabetes complications, daily insulin dose and cIMT thickness of the common carotid artery. RESULTS: cIMT of T1DM patients was significantly higher: 0,470 mm than in healthy: 0,409 mm. In the group with vascular complications of diabetes was found the highest rate of cIMT: 0,501 mm in comparison to the group of diabetes without complications: 0,462 mm, diabetes with celiac disease: 0,462 mm, and diabetes with Hashimoto's thyroiditis: 0,453 mm. HbA1c was highest in the group CN: 9,84+/-1,5%, compared to CH: 9,04+/- 1,2%, CC: 8,84+/-1,8% and C without complications: 8,55+/-1,2%. BMI was highest in the group CN: 23,3+/- 4,4kg/m2and CH: 22,6 +/- 2,4 kg/m2. It was the same with waist circumference: CN: 79,33+/- 9,39and CH: 79,2 +/- 9,56 cm. Patients with vascular complications were characterized by the higher value of blood pressure and lipids compared to patients with additional autoimmune disease. Coexistence of celiac disease was not associated with a greater value of cIMT and cardiovascular risk factors in young patients with type 1 diabetes. CONCLUSIONS: 1. Increased value of cIMT, and thus increased risk of early disease of the cardiovascular system depends primarily on metabolic compensation and classic risk factors for atherosclerosis. 2. The coexistence of additional autoimmune disease does not significantly affect the value of cIMT in the study population. 3. Young patients with diabetes type 1 and coexisting Hashimoto disease have greater BMI and waist circumference, what can lead to earlier macroangiopathy in the future. PMID- 28633160 TI - [Proposals for therapeutic decisions according to glucose trends in patients with type 1 diabetes]. AB - Nowadays, self-management of diabetes is more and more often based on continuous and flash glucose monitoring systems. In addition to measuring current glucose levels, both systems provide blood glucose levels from the past few hours in the form of a graph, as well as an indication of glucose trends via arrows. This information adds a new dimension to the self-management of diabetes, and should result in the modification of diabetes therapy. The paper presents proposals for modifications of treatment decisions based on glucose trends in patients with type 1 diabetes. By considering glucose trends, it is hoped that glycemic variability and numbers of hypoglycemia and hyperglycemia episodes will be reduced. PMID- 28633161 TI - [Insulin secretion in the early phase of type 1 diabetes mellitus (T1DM) and new hopes for maintaining it through therapy]. AB - Type 1 diabetes mellitus (T1DM) is an autoimmune disease with a progressive loss of pancreatic beta cell functional mass and subsequent impairment of insulin secretion. At present, the most important factors that help sustain insulin secretion at the early stage of the disease and have the potential to reduce the risk or even prevent long-term diabetic complications include early diagnosis, early initiation of the insulin therapy, an appropriate education of patients and immunotherapeutic interventions. In this paper, the issue of insulin secretion at the early stage of T1DM and some of the most recent research on novel therapies supporting traditional treatments are discussed. PMID- 28633162 TI - [Neurotrophins, VEGF and matrix metalloproteinases: new markers or causative factors of metabolic syndrome components?] AB - Currently the number of obese people in the world is still growing, as well as people suffering from other metabolic disorders included in the metabolic syndrome. The factors responsible for this are anincorrect diet, low physical activity, as well as a tendency of the population to aging. Therefore, more research aimed at seeking potential factors that could in the future be useful in the prevention or treatment of obesity and related diseases is carried out. In this article we present a few selected biochemical markers, affecting the metabolism of carbohydrates and lipids in a way that is not always clear and obvious. PMID- 28633163 TI - [Permanent neonatal diabetes mellitus in a young Ukrainian child]. AB - Diabetes mellitus is a chronic metabolic disease with the manifestation possible in any period of life. The incidence of diabetes is rising around the world, and studies show that children are at an increasing risk of developing the disease. Type 1 diabetes accounts for over 90% of childhood and adolescent diabetes, although less than 10% of children suffer from type 2 diabetes. Over the last few decades, inherited monogenic forms of DM were discovered and studied. An extremely rare form of diabetes (less than 1-2% of all diabetes in young people), with neonatal diabetes as a subset, and is usually suspected if a child is diagnosed with diabetes at less than 6 months of age. We present the first case reported in Ukraine of a child diagnosed with permanent neonatal diabetes resulting from a EIF2AK3 gene missense mutation of exon 15 (WolcottRallison Syndrome). Despite low incidence of the permanent neonatal diabetes, this diagnosis should be considered in infants with persistent hyperglycaemia requiring insulin therapy. PMID- 28633164 TI - Neural Network Optimization of Ligament Stiffnesses for the Enhanced Predictive Ability of a Patient-Specific, Computational Foot/Ankle Model. AB - Computational models of diarthrodial joints serve to inform the biomechanical function of these structures, and as such, must be supplied appropriate inputs for performance that is representative of actual joint function. Inputs for these models are sourced from both imaging modalities as well as literature. The latter is often the source of mechanical properties for soft tissues, like ligament stiffnesses; however, such data are not always available for all the soft tissues nor is it known for patient-specific work. In the current research, a method to improve the ligament stiffness definition for a computational foot/ankle model was sought with the greater goal of improving the predictive ability of the computational model. Specifically, the stiffness values were optimized using artificial neural networks (ANNs); both feedforward and radial basis function networks (RBFNs) were considered. Optimal networks of each type were determined and subsequently used to predict stiffnesses for the foot/ankle model. Ultimately, the predicted stiffnesses were considered reasonable and resulted in enhanced performance of the computational model, suggesting that artificial neural networks can be used to optimize stiffness inputs. PMID- 28633166 TI - A Heavy Burden. PMID- 28633165 TI - Investigation of Biotransport in a Tumor With Uncertain Material Properties Using a Nonintrusive Spectral Uncertainty Quantification Method. AB - In this study, statistical models are developed for modeling uncertain heterogeneous permeability and porosity in tumors, and the resulting uncertainties in pressure and velocity fields during an intratumoral injection are quantified using a nonintrusive spectral uncertainty quantification (UQ) method. Specifically, the uncertain permeability is modeled as a log-Gaussian random field, represented using a truncated Karhunen-Loeve (KL) expansion, and the uncertain porosity is modeled as a log-normal random variable. The efficacy of the developed statistical models is validated by simulating the concentration fields with permeability and porosity of different uncertainty levels. The irregularity in the concentration field bears reasonable visual agreement with that in MicroCT images from experiments. The pressure and velocity fields are represented using polynomial chaos (PC) expansions to enable efficient computation of their statistical properties. The coefficients in the PC expansion are computed using a nonintrusive spectral projection method with the Smolyak sparse quadrature. The developed UQ approach is then used to quantify the uncertainties in the random pressure and velocity fields. A global sensitivity analysis is also performed to assess the contribution of individual KL modes of the log-permeability field to the total variance of the pressure field. It is demonstrated that the developed UQ approach can effectively quantify the flow uncertainties induced by uncertain material properties of the tumor. PMID- 28633167 TI - Medical Student Perceptions of Their Education About Suffering. AB - BACKGROUND AND OBJECTIVES: To explore student perceptions of their medical school teaching and learning about human suffering and to elicit student recommendations for better approaches to teaching about suffering. METHODS: Qualitative study involving focus groups of students from each class at two US medical schools. RESULTS: Students reported that teaching about human suffering was variable, rarely explicit, and occurred primarily in the pre-clinical curriculum. In the clinical curriculum, addressing patient suffering was neither overtly valued nor evaluated by attending physicians. Students perceived little or no explicit educational attention to the suffering of patients and their families, with the exceptions of specific rotations and attendings. They described little or no teaching of clinical skills to identify and manage suffering and desired such training. Students learned about the clinical management of suffering primarily by ad hoc observation of role models. Some also noted that exposure to patient suffering and the demands of medical education contributed to their own suffering. Students recommended intentional, integrated and longitudinal teaching about suffering, with regular reinforcement and evaluation, across the medical school curriculum. CONCLUSIONS: Students perceived teaching about human suffering as insufficient at the institutions studied and desired to learn clinical skills to identify and help patients manage suffering. Medical educators should explicitly address patient suffering and create longitudinal curricula with improved clinical teaching, faculty role modeling, and student evaluation. PMID- 28633168 TI - Integration of Clinical Pharmacists in Family Medicine Residency Programs. AB - BACKGROUND AND OBJECTIVES: Clinical pharmacists are valued educators and practitioners within family medicine residency programs (FMRPs). Since the last survey of clinical pharmacists within FMRPs, there have been significant advancements to pharmacy education and training as well as growth of interprofessional education and collaborative practice within family medicine. The objective of this study is to describe the integration of clinical pharmacists within FMRPs. METHODS: All 480 Accreditation Council for Graduate Medical Education (ACGME)-approved FMRPs were contacted to identify clinical pharmacists involved with their programs. An electronic survey was distributed to these 253 pharmacists. Questions addressed educational, clinical, scholarly, and administrative activities. RESULTS: Of 396 FMRPs reached, 208 (52.5%) reported 253 clinical pharmacists within their programs. Survey responses were received from 142 (56.1%) pharmacists. Academic appointments in colleges/schools of pharmacy and medicine were held by 105 (75.5%) and 69 (50.0%) respondents, respectively. Eighty-nine (64.0%) pharmacists reported a single source of salary, 19.1% of which received full support from the FMRP. Clinical pharmacists dedicated an average of 50.4% of their overall time to the FMRP, and 14.5% of pharmacists dedicated all of their time to the FMRP. Time within the FMRP was spent on patient care (52.9%), teaching (31.6%), research/scholarship (7.5%), administrative activities (5.9%), and drug dispensing (0.7%). DISCUSSION: Prevalence of clinical pharmacists within FMRPs has increased since 2000, from 27.9% to 52.5%. However, the amount of time dedicated to the FMRPs has decreased. This shift from teaching to a more clinical role may reflect both a growth of patient-centered, interprofessional care and a needed mechanism to assist funding these positions. PMID- 28633169 TI - Untapped Potential: Performance of Procedural Skills in the Family Medicine Clerkship. AB - BACKGROUND AND OBJECTIVES: While family medicine residency directors have expressed concern about low procedural skills proficiency among incoming residents, curricular recommendations do not provide widely accepted guidance. This study was designed to describe requirements and experiences in procedural skill training during the family medicine clerkship and test the hypothesis that more rural placements may support this training. METHODS: The survey was conducted as part of the CAFM Educational Research Alliance (CERA) Family Medicine Clerkship Director (CD) 2013 survey. All Liaison Committee on Medical Education (LCME)-accredited medical schools in the US and Canada with a family medicine educator as family medicine or primary care CD were surveyed. CDs answered questions about clerkship structure and procedure experience and requirements for students. Choosing from a list of procedures, respondents detailed how often students perform specific skills during a rotation. RESULTS: The response rate was 73% (94 out of 129). Thirty-six procedures were performed during the family medicine clerkship. Of the procedures performed at least once, the most common were Pap test (57.1%), vaginal swab (42.9%), ECG recording (41.9%), urinalysis (40.0%), and throat swab (39.0%). Of the procedures performed more than three times, the most common were Pap test (21.0%) and sterile technique (20.0%). Learners in rural rotations were more likely to perform a range of procedures. CONCLUSIONS: Though exposed to a wide range of procedures during the family medicine clerkship, students did not often repeat procedures. Creation of a core list of procedures and taking better advantage of rural placements may improve procedural skill training in the family medicine clerkship. PMID- 28633170 TI - Teaching Primary Care Genetics: A Randomized Controlled Trial Comparison. AB - BACKGROUND AND OBJECTIVE: Given the increasing discussions of the impact of genetic medicine within family medicine, it is important to determine the most effective way of teaching this material to family medicine residents (FMRs). The objective of this study was to evaluate and compare the impact of three methods of delivering primary care genetic content to FMRs. METHODS: Curriculum materials and assessment tools were created to teach and evaluate knowledge, skills, and attitudes around four core competencies in primary care genetics, with a focus on hereditary colorectal cancer (CRC). Participants were randomly allocated to four learning conditions: (1) no intervention (control), (2) web-based module outlining genetic concepts applied to CRC, (3) live presentation of the web-based material, (4) live presentation and subsequent standardized patient (SP) encounter. Three months later, all participants completed a written knowledge test, attitude survey, and a standardized patient-based performance assessment. RESULTS: Sixty FMRs completed the study. All three educational interventions resulted in significantly improved outcome measures in knowledge and skills but not attitudes, compared to control. There was no significant difference in outcomes between intervention groups. CONCLUSION: FMRs acquired knowledge and improved skills in genetic medicine with three educational methods. Resources such as faculty expertise in genetic medicine and cost should guide decisions on curricular development for this rapidly expanding field. This may be especially relevant for programs with distributed teaching sites. PMID- 28633157 TI - Epidemiology, practice of ventilation and outcome for patients at increased risk of postoperative pulmonary complications: LAS VEGAS - an observational study in 29 countries. AB - BACKGROUND: Limited information exists about the epidemiology and outcome of surgical patients at increased risk of postoperative pulmonary complications (PPCs), and how intraoperative ventilation was managed in these patients. OBJECTIVES: To determine the incidence of surgical patients at increased risk of PPCs, and to compare the intraoperative ventilation management and postoperative outcomes with patients at low risk of PPCs. DESIGN: This was a prospective international 1-week observational study using the 'Assess Respiratory Risk in Surgical Patients in Catalonia risk score' (ARISCAT score) for PPC for risk stratification. PATIENTS AND SETTING: Adult patients requiring intraoperative ventilation during general anaesthesia for surgery in 146 hospitals across 29 countries. MAIN OUTCOME MEASURES: The primary outcome was the incidence of patients at increased risk of PPCs based on the ARISCAT score. Secondary outcomes included intraoperative ventilatory management and clinical outcomes. RESULTS: A total of 9864 patients fulfilled the inclusion criteria. The incidence of patients at increased risk was 28.4%. The most frequently chosen tidal volume (VT) size was 500 ml, or 7 to 9 ml kg predicted body weight, slightly lower in patients at increased risk of PPCs. Levels of positive end-expiratory pressure (PEEP) were slightly higher in patients at increased risk of PPCs, with 14.3% receiving more than 5 cmH2O PEEP compared with 7.6% in patients at low risk of PPCs (P < 0.001). Patients with a predicted preoperative increased risk of PPCs developed PPCs more frequently: 19 versus 7%, relative risk (RR) 3.16 (95% confidence interval 2.76 to 3.61), P < 0.001) and had longer hospital stays. The only ventilatory factor associated with the occurrence of PPCs was the peak pressure. CONCLUSION: The incidence of patients with a predicted increased risk of PPCs is high. A large proportion of patients receive high VT and low PEEP levels. PPCs occur frequently in patients at increased risk, with worse clinical outcome. TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, number NCT01601223. PMID- 28633171 TI - Examining Accuracy of Self-Assessment of In-Training Examination Performance in a Context of Guided Self-Assessment. AB - BACKGROUND AND OBJECTIVES: In our family medicine residency program, we have established a culture of guided self-assessment through a systematic approach of direct observation of residents and documentation of formative feedback. We have observed that our residents have become more accurate in self-assessing their clinical performance. The objective of this study was to examine whether this improved accuracy extended to residents' self-assessment of their medical knowledge and clinical reasoning on the In-Training Examination (ITE). METHODS: In November each year, residents in their first (PGY1) and second (PGY2) years of residency take the ITE (240 multiple-choice questions). Immediately before and right after taking the ITE, residents complete a questionnaire, self-assessing their knowledge and predicting their performances, overall and in eight high level domains. Consented data from residents who took the ITE in 2009-2015 (n=380, 60% participation rate) were used in the Generalized Estimating Equations analyses. RESULTS: PGY2 residents outperformed PGY1 residents; Canadian medical graduates consistently outperformed international medical graduates; urban and rural residents performed similarly overall. Residents' pre-post self-assessments were in line with residents' actual performance on the overall examination and in the domains of Adult Medicine and Care of Surgical Patients. The underperforming residents in this study accurately predicted both pre- and post-ITE that they would perform poorly. CONCLUSION: Our findings suggest that the ITE operates well in our program. There was a tendency among residents in this study to appropriately adjust their self-assessment of their overall performance after completing the ITE. Irrespective of the residency year, resident self-assessment was less accurate on individual domains. PMID- 28633173 TI - Exploring Residents' Skills in Diagnosing Dementia: The Unexpected Dissonance Between Ability and Confidence. AB - BACKGROUND AND OBJECTIVES: The diagnosis of dementia is a challenge for physicians due to numerous interrelated barriers. Research shows that this difficulty may be rooted in an incomplete knowledge about dementia. To address this gap, we developed an assessment scale of resident confidence in the diagnosis of dementia and used it to compare resident confidence to their practical ability to diagnose dementia. METHODS: The study used a piloted confidence assessment tool for diagnosing dementia correlated with family medicine residents (n=45) performance during an objective structured clinical examination (OSCE). Residents were evaluated during the OSCE for thoroughness of evaluation and patient-centeredness. Following the OSCE, they completed knowledge and diagnostic questionnaires and the confidence assessment tool. RESULTS: Residents with more years of training performed a more thorough exam and were more confident in their ability to diagnose dementia. However, residents who missed the diagnosis were no less confident in their ability than residents who correctly diagnosed dementia. CONCLUSIONS: Using confidence as a self-assessment may be an inaccurate representation of resident knowledge and ability to diagnose dementia. PMID- 28633172 TI - Burnout and Depression in MS1 and MS3 Years: A Comparison of Cohorts at One Medical School. AB - BACKGROUND: Losses of idealism, empathy, and professionalism over the course of medical education have been described previously in the literature. A 2012 national survey of medical students estimated 37%-44% with burnout, 58% screen positive for depression, and 9.4% with suicidal ideation in the past 12 months. Given changes in related traits, we sought to explore whether burnout and symptoms of depression change over time. The objectives of this study were to assess the differences in medical student burnout and symptoms of depression between first year (MS1) and third-year (MS3) medical students at one medical college. METHODS: Students were administered the modified Maslach Burnout Inventory (MBI) and the Patient Health Questionnaire-2 (PHQ-2) depression screening instrument as an optional part of a mandatory annual survey administered by the medical college near the end of the academic year (March-May, 2015). Anonymous responses from MS1s and MS3s were analyzed to estimate trends in burnout and possible depression over time and to examine the relationship between the two measures. RESULTS: Possible depression (Total PHQ2 equal or greater than 3) was present in 28.5% of all respondents. MS3s had significantly higher levels of Emotional Exhaustion (EE) and Depersonalization (DP), and lower levels of Personal Accomplishment (PA), than MS1s. When PHQ2, gender, and campus/program effects were controlled via regression, MS3s tended to record EE and DP scores over 2 points higher than MS1s and PA scores over 2 points lower. Regrets about entering medicine were also higher in MS3s in the controlled models. PHQ2 scores were also positively associated with all subscales except for PA. CONCLUSIONS: Students appear to be at slightly greater risk for burnout as they temporally progress through medical school. These findings are consistent with similar measurements of decreasing empathy and idealism when comparing cohorts of early versus late medical students. PMID- 28633174 TI - Do US Medical Licensing Applications Treat Mental and Physical Illness Equivalently? AB - BACKGROUND AND OBJECTIVES: State medical licensing boards are responsible for evaluating physician impairment. Given the stigma generated by mental health issues among physicians and in the medical training culture, we were interested in whether states asked about mental and physical health conditions differently and whether questions focused on current impairment. METHODS: Two authors reviewed physician medical licensing applications for US physicians seeking first time licensing in 2013 in the 50 states and the District of Columbia. Questions about physical and mental health, as well as substance abuse, were identified and coded as to whether or not they asked about diagnosis and/or treatment or limited the questions to conditions causing physician impairment. RESULTS: Forty-three (84%) states asked questions about mental health conditions, 43 (84%) about physical health conditions, and 47 (92%) about substance use. States were more likely to ask for history of treatment and prior hospitalization for mental health and substance use, compared with physical health disorders. Among states asking about mental health, just 23 (53%) limited all questions to disorders causing functional impairment and just 6 (14%) limited to current problems. CONCLUSIONS: While most state medical licensing boards ask about mental health conditions or treatment, only half limited queries to disorders causing impairment. Differences in how state licensing boards assess mental health raise important ethical and legal questions about assessing physician ability to practice and may discourage treatment for physicians who might otherwise benefit from appropriate care. PMID- 28633175 TI - The Marshall Family Medicine Residency twINTERN Schedule: The Impact of an Innovative Hospital Coverage Scheme on Resident Fatigue. AB - BACKGROUND AND OBJECTIVES: Work hour restriction has strained the balance between resident service and education. Night Float (NF) rotations are a popular answer to managing this balance but weakens continuity, an essential tenant of family medicine. An innovative short call system for Marshall University's Family Medicine Hospital Service (FMHS), the twINTERN call model, was created in response. We studied the impact of this approach on resident fatigue. METHODS: Anonymous surveys assessed fatigue of the Marshall University's 2013-2014 Family Medicine intern resident class while on NF rotations (ICU, Pediatrics and Surgery) and the twINTERN call. Stanford Sleepiness Score (SSS) and Epworth Sleepiness Score (ESS) were administered trimonthly. RESULTS were categorized 'Alert' or 'Fatigued' and evaluated by Chi Square analysis. Also, outpatient office frequency was evaluated. RESULTS: 146 surveys were completed by eight residents. More even distribution of resident office experience was seen. The twINTERN call model didn't show worsening fatigue compared to NF systems in any parameter measured. It was superior mitigating fatigue by ESS for night shifts (P value 0.047). While fatigue was statistically worse for night float rotations by both parameters (ESS P value = 0.009; SSS P value = 0.008), the twINTERN call model only showed worsening fatigue in the SSS (P value = 0.038). CONCLUSIONS: Our study demonstrated that the twINTERN Call Model, which allows for improved continuity on the inpatient service, was at least as effective, and by some parameters superior to NF systems for mitigating resident fatigue. PMID- 28633177 TI - Give Me What's in Your Heart. PMID- 28633176 TI - Determinants of the 5-Year Retention and Rural Location of Family Physicians: Results from the Iowa Family Medicine Training Network. AB - BACKGROUND AND OBJECTIVES: States are seeking ways to retain primary care physicians trained within their borders. We analyzed the 5-year retention and rural Iowa location decisions for 1,645 graduates of the Iowa Family Medicine Training Network (IFMTN)-eight residency programs (in seven different cities) that are affiliated with the Carver College of Medicine (University of Iowa). METHODS: Data from 1977-2014 includes 98.5% of active graduates. Location in Iowa 5 years after graduation was the dependent variable in a binary logistic regression. A second model used rural location in Iowa as the dependent variable. Independent variables included graduation year cohort, IMG status, sex, undergraduate medical training in Iowa, medical degree, and residency location. RESULTS: Undergraduate medical training in Iowa was strongly related to retention. Compared to graduates of the AMC residency, graduates of six of the seven community-based programs were significantly more likely to be practicing in Iowa. While the overall proportion of graduates practicing in rural Iowa was high (47.3%), women and IMGs were significantly less likely to practice in rural areas. Graduates of the Mason City program were significantly more likely to practice in a rural area after graduation. CONCLUSIONS: The experience of the IFMTN suggests that educating family physicians in community-based programs contributes significantly to in-state retention even 5 years after graduation. While all programs contribute to the rural FM workforce in Iowa, the residency program located in a rural community (Mason City) has a disproportionately positive impact. PMID- 28633178 TI - I Don't Want to Know. PMID- 28633179 TI - Rethinking the "Black Cloud" of Medical Training. PMID- 28633182 TI - Agreement Between Family Medicine Residency Program Directors and Clerkship Directors Is Crucial to the Formation of the Next Generation of Physicians. PMID- 28633183 TI - Shared Goals, Togetherness, Accountability, and Embracing Love. PMID- 28633184 TI - Peritoneal Dialysis Catheter Position Evaluated by Ultrasound: Can it Replace Abdomen X-Ray in Patients Presenting Catheter Misplacement? AB - Background Malfunction of the peritoneal dialysis catheter is frequently caused by dislocation. The diagnostic approach is classically based on abdomen X-ray together with detailed case history and physical examination. Despite being rarely applied in clinical practice to evaluate catheter misplacement, ultrasound is a noninvasive, radiation-free technique that is potentially useful also to explore reasons for catheter malfunction. Consequently, we aimed to evaluate the diagnostic accuracy of ultrasound to identify peritoneal catheter misplacement. Methods In a multicenter observational blinded study, we compared ultrasound to abdomen X-ray for catheter localization in 93 consecutive peritoneal dialysis patients with dialysate outflow problems enrolled in two nephrology and dialysis units. The position of the catheter was annotated on a standard scheme of nine abdominopelvic regions. The sensitivity, specificity, positive and negative predictive value and Kappa coefficient were calculated. Results Dislocation out of the inferior abdominopelvic regions was present in 19 patients (20 %) at X-ray and 23 patients (25 %) at ultrasound. Correct determination of the position of the catheter in the lower abdomen by ultrasound had a sensitivity of 93 % (95 % CI 84 - 97 %), specificity of 95 % (95 % CI 72 - 100 %), positive predictive value of 99 % (95 % CI 91 - 100 %), negative predictive value of 78 % (95 %CI 56 92 %) and Kappa coefficient of 0.82 (95 % CI 0.67 - 0.96). In 10 out of 93 patients (11 %), there was a position mismatch between X-ray and ultrasound in an adjacent abdominopelvic region. Conclusion Our results suggest that abdomen X-ray for the evaluation of peritoneal catheter position can be replaced by ultrasound in experienced hands. This bedside diagnostic procedure might reduce costs, the time necessary for diagnosis and lifetime radiation exposure. PMID- 28633185 TI - Erratum: The Prevalence of Cruciate Ligament and Meniscus Knee Injury in Young Adults and Associations with Gender, Body Mass Index, and Height a Large Cross Sectional Study. PMID- 28633186 TI - Erratum: Early Removal of Drainage Tube after Fast-Track Primary Total Knee Arthroplasty. PMID- 28633187 TI - [Development and Validation of a Fully Automated, Experimental Set-Up for Ex-Vivo Burst Pressure Testing after Surgical Vessel Closure]. AB - Background A growing number of operations are performed using minimally invasive techniques. Therefore, a lot of new requirements must be met by the staplers currently available. At the present time, the most widely used methods of minimally invasive vascular occlusion involve high-frequency energy, clips, and staplers. The most important quality parameter is burst pressure, which is measured with a variety of experimental set-ups, all of which are subject to criticism. With this study, we want to introduce a fully automated vascular burst pressure measuring system that largely mimics physiological conditions. An important feature of this set-up is the detection of very early leakage from the staple line (FAIR Leakage = First Appearance of Leakage requiring Intervention). Material and Methods Burst pressure was measured in vessel segments of porcine common carotid arteries. For vascular occlusion, we used the stapler device Micro Cutter XCHANGE(r) by DexteraSurgical. Prior to closure, the vessel was filled to a pressure of 80 mmHg. The pressure was increased at a defined flow rate. Burst pressure was defined as staple line leakage requiring intervention. Results and Validation 30 staple lines were examined. The average burst pressure visually determined by two independent investigators was 515.8 mmHg +/- 236.3 mmHg. Maximal burst pressure was 911 mmHg, and minimal burst pressure 80 mmHg. The average burst pressure detected electronically was 511.8 mmHg +/- 239.1 mmHg. Statistically, there was a highly significant correlation of visually and electronically detected burst pressures. Conclusion This is the first experimental set-up for a systematic burst pressure test that is fully automated and therefore eliminates any bias related to the investigator. The experimental set-up with a defined intravascular pressure prior to closure and the use of a liquid with blood-like viscosity enabled us to largely mimic intraoperative conditions. Since burst pressure is not defined as a complete rupture of the staple line, but as the moment of first occurrence of leakage requiring intervention, the results can be transferred into daily surgical practice. PMID- 28633188 TI - Clarification to article Meier R., Panzica M. First Results with a Resorbable MgYREZr Compression Screw in Unstable Scaphoid Fractures Show Extensive Bone Cysts. PMID- 28633189 TI - ? PMID- 28633190 TI - [Intravesical salpingiosis: case report and review of the literature]. AB - Endosalpingiosis of the urinary bladder is a rare benign condition characterised by the presence of ectopic endosalpingeal tissue in the bladder. If histology shows two or more Mullerian-derived components, this condition is referred to as Mullerianosis.To our knowledge less than 20 cases of Mullerianosis and 5 cases of endosalpingiosis have been documented in the literature.Although the pathogenesis remains unclear, two theories exist. The implantation theory assumes that Mullerian-derived tissue gets implanted in the wall of the urinary bladder during pelvic surgery. The second theory proposes a metaplastic origin of the disease.Patients suffering from endosalpingiosis or Mullerianosis may present with symptoms such as suprapubic pain, frequent urination, dysuria or gross haematuria, possibly with a cyclical appearance.We present the case of a 40-year old female patient, who primarily presented with painful haematuria and was diagnosed with endosalpingiosis and treated by transurethral resection. Also we review the current literature. PMID- 28633191 TI - [Urothelial cancer: update on systemic treatment options]. AB - Perioperative chemotherapy is likely to improve survival in both the neoadjuvant and the adjuvant setting. Therefore, it is an integral part of the modern treatment of patients with muscle-invasive urothelial bladder cancer. All patients who are suitable for cisplatin-based chemotherapy should be involved in a corresponding concept.Cisplatin-based combinations are standard regimens in the perioperative and palliative systemic treatment of urothelial cancer. Carboplatin is only an inferior substitute for "unfit" patients in the palliative treatment situation. Vinflunine may be used as a second-line agent in case of recurrence after palliative first-line treatment or in patients presenting with rapid progression after perioperative treatment. Alternatively, taxane or taxane-based combinations can be used in these situations.New therapeutic options may include the use of immune checkpoint inhibitors, which have shown promising results in early studies. Two substances have already been approved by the FDA for the treatment of advanced/metastatic urothelial cancer following platin-based upfront treatment. Other future options may be "tailored" treatment concepts based on the molecular pathogenesis of the individual patient. However, extensive pre-clinical work is still required for this approach. PMID- 28633192 TI - Position-tunable diazirine tags for peptide-peptide ion cross-linking in the gas phase. PMID- 28633193 TI - Trictide, a tricellulin-derived peptide to overcome cellular barriers. AB - The majority of tight junction (TJ) proteins restrict the paracellular permeation of solutes via their extracellular loops (ECLs). Tricellulin tightens tricellular TJs (tTJs) and regulates bicellular TJ (bTJ) proteins. We demonstrate that the addition of recombinantly produced extracellular loop 2 (ECL2) of tricellulin opens cellular barriers. The peptidomimetic trictide, a synthetic peptide derived from tricellulin ECL2, increases the passage of ions, as well as of small and larger molecules up to 10 kDa, between 16 and 30 h after application to human epithelial colorectal adenocarcinoma cell line 2. Tricellulin and lipolysis stimulated lipoprotein receptor relocate from tTJs toward bTJs, while the TJ proteins claudin-1 and occludin redistribute from bTJs to the cytosol. Analyzing the opening of the tricellular sealing tube by the peptidomimetic using super resolution stimulated-emission depletion microscopy revealed a tricellulin-free area at the tricellular region. Cis-interactions (as measured by fluorescence resonance energy transfer) of tricellulin-tricellulin (tTJs), tricellulin-claudin 1, tricellulin-marvelD3, and occludin-occludin (bTJs) were strongly affected by trictide treatment. Circular dichroism spectroscopy and molecular modeling suggest that trictide adopts a beta-sheet structure, resulting in a peculiar interaction surface for its binding to tricellulin. In conclusion, trictide is a novel and promising tool for overcoming cellular barriers at bTJs and tTJs with the potential to transiently improve drug delivery. PMID- 28633194 TI - Moving forward in circles: challenges and opportunities in modelling population cycles. AB - Population cycling is a widespread phenomenon, observed across a multitude of taxa in both laboratory and natural conditions. Historically, the theory associated with population cycles was tightly linked to pairwise consumer resource interactions and studied via deterministic models, but current empirical and theoretical research reveals a much richer basis for ecological cycles. Stochasticity and seasonality can modulate or create cyclic behaviour in non intuitive ways, the high-dimensionality in ecological systems can profoundly influence cycling, and so can demographic structure and eco-evolutionary dynamics. An inclusive theory for population cycles, ranging from ecosystem-level to demographic modelling, grounded in observational or experimental data, is therefore necessary to better understand observed cyclical patterns. In turn, by gaining better insight into the drivers of population cycles, we can begin to understand the causes of cycle gain and loss, how biodiversity interacts with population cycling, and how to effectively manage wildly fluctuating populations, all of which are growing domains of ecological research. PMID- 28633195 TI - Survival of patients with cancer starting chronic dialysis: Data from kidney and cancer registries in lower Normandy. AB - AIM: Cancer and chronic kidney disease are known to be associated. The way in which a history of cancer can influence outcome in dialysis is not well described. This work aimed to evaluate survival of cancer patients starting chronic dialysis after their diagnosis of cancer. METHODS: We merged data from cancer registries and a dialysis registry, and explored patients' charts. RESULTS: Between January 2001 and December 2008, 74 patients with incident cancer in the two-counties-study-area (Calvados and Manche) started chronic dialysis after their diagnosis of cancer. Survival of these incident dialysis patients with a previous diagnosis of cancer was respectively 80.9% (confidence interval 69.9; 88.2) and 68.3% (confidence interval 56.3%; 77.7%) at 1 and 2 years. Only 29 of the 74 patients (39.2%) were still alive at the end of the observation period; median participation time was 2.8 years (1st and 3rd quartiles: 1.3-4.4). Survival of patients with cancer was not different to that of non-cancer dialysis patients matched for age and sex, except in patients with haematological malignancies who had a poorer outcome. In a multivariate stratified Cox model, the history of cancer before dialysis start was not associated with death, after adjustment on diabetes. CONCLUSION: In our study, survival in dialysis was not different among patients with a history of cancer compared to matched patients without malignancy. We can hypothesize that only some selected patients with cancer have access to dialysis. Studies in ESRD patients with cancer should be performed to evaluate access to dialysis in that population. PMID- 28633197 TI - Influence of electron beam irradiation doses on bone regeneration by octacalcium phosphate collagen composites. AB - An octacalcium phosphate and collagen composite (OCP/Col) achieved efficient bone regeneration with excellent resorbability. After the confirmation of its safety and efficacy in preclinical animal studies, the present study investigated the influence of electron beam irradiation doses on bone regeneration by OCP/Col in order to secure its commercialization. OCP/Col was prepared as previously described and the packed OCP/Col was sterilized using different doses of electron beam irradiation. A standardized defect, 9 mm in diameter, was made in the rat calvarium. A disk of OCP/Col (diameter 9 mm, thickness 1.5 mm) sterilized using different doses of electron beam irradiation was then implanted into the defect. Five defects in each group were treated and fixed 4, 12 and 24 weeks after implantation. Specimens were decalcified and stained with haematoxylin and eosin. In a histomorphometrical analysis, the percentage of newly formed bone in the defect (n-Bone%) was calculated. In OCP/Col 15 kGy, newly formed bone was enhanced and present throughout the defect with the resorption of OCP/Col. Furthermore, vigorous bone remodelling and bone maturation were observed. In OCP/Col 40 kGy, newly formed bone was not as prominent as that with OCP/Col 15 kGy. A histomorphometrical analysis using Student's t-test at 24 weeks revealed that the n-Bone% of OCP/Col 15 kGy (65.9 +/- 7.14%) was significantly higher than that of OCP/Col 40 kGy (38.0 +/- 10.2%). These results suggest that different electron beam irradiation doses influence bone regeneration by OCP/Col. PMID- 28633196 TI - Tight junction strand formation by claudin-10 isoforms and claudin-10a/-10b chimeras. AB - Claudins are integral components of tight junctions (TJs) in epithelia and endothelia. When expressed in cell lines devoid of TJs, claudins are able to form TJ-like strands at contacts between adjacent cells. According to a current model of TJ strand formation, claudin protomers assemble in an antiparallel double row within the plasma membrane of each cell (cis-interaction) while binding to corresponding double rows from the neighboring cells (trans-interaction). Cis interaction was proposed to involve two interfaces of the protomers' first extracellular segment (extracellular loop (ECL)1). In the current study, three naturally occurring claudin-10 isoforms and two claudin-10 chimeras were used to investigate strand formation. All constructs were able to interact in cis (Forster/fluorescence resonance energy transfer (FRET)), to integrate into TJs of MDCK-C7 cells (confocal laser scanning microscopy), and to form TJ-like strands in HEK293 cells (freeze-fracture electron microscopy). Strand formation occurred despite the fact that isoform claudin-10a_i1 lacks both structural ECL1 elements reported to be crucial for cis-interaction. Furthermore, results from FRET experiments on claudin-10 chimeras indicated that identity of the first transmembrane region rather than ECL1 is decisive for claudin-10 cis-interaction. Therefore, in addition to the interaction interfaces suggested in the current model for TJ strand assembly, alternative interfaces must exist. PMID- 28633198 TI - Factors related to the efficacy of radiofrequency ablation for benign thyroid nodules. PMID- 28633199 TI - Diffuse-Type Caroli Disease with Characteristic Central Dot Sign Complicated by Multiple Intrahepatic and Common Bile Duct Stones. AB - Caroli disease (CD) is a rare congenital malformation of the liver characterized by non-obstructive, segmental, cystic dilatation of the intrahepatic bile ducts (IHDs). The clinical course is usually asymptomatic for the first 5-20 years, and symptoms may seldom occur throughout the patient's life. Bile stagnation leads to recurrent episodes of cholangitis, stone formation, or liver abscesses, and biliary cirrhosis usually occurs years later. Here we report on a 42-year-old man diagnosed with diffuse-type CD with a characteristic central dot sign, who had multiple intrahepatic and common bile duct (CBD) stones. CBD stones were treated successfully with endoscopic retrograde cholangiopancreatography (ERCP). PMID- 28633200 TI - Complete response of advanced hepatocellular carcinoma to sorafenib: another case and a comprehensive review. AB - Since sorafenib was introduced in 2007 for treating advanced hepatocellular carcinoma (HCC), 15 patients have achieved a complete response (CR) in advanced HCC. However, only four of these reports can be regarded as real CRs involving adequate assessments including imaging, serum tumor markers, and histologic examinations of completely resected specimens. A 54-year-old man with hepatitis C virus (HCV)-related liver cirrhosis (LC) presented to our unit. A CT scan demonstrated a 3.8-cm arterial hypervascular/portal-washout mass in the right lobe and invasion in the right portal vein. Twelve weeks after beginning sorafenib therapy, the AFP level was normalized and a CT scan showed a prominent decrease in the hepatic mass and a significant decrease in the volume of portal vein thrombosis (PVT). The patient received a right liver hemihepatectomy after 12 months. No viable tumor cells were found in the resected specimen, and there was no thrombotic obstruction of the portal vein. Twelve months later the patient showed no clinical evidence of HCC recurrence. This is the first case of CR in HCC treatment following sorafenib with histologically confirmed HCV-related HCC without LC evidence, HCC with PVT, and a follow-up of longer than 12 months. This case seems to be an extremely unusual clinical outcome in advanced HCC. PMID- 28633202 TI - Time to take notice: The impact of previous transradial catheterization on radial artery graft performance in coronary artery bypass grafting. PMID- 28633203 TI - Out of sight, out of mind. PMID- 28633201 TI - Rapid start-up of denitrifying granular sludge by dosing with semi-starvation fluctuation C/N ratio strategy. AB - This study cultivated denitrifying granular sludge in three UASB reactors by the semi-starvation fluctuation C/N ratio strategy (reactor 1 (R1): constant C/N ratio; R2: regular fluctuation C/N ratio; and R3: semi-starvation fluctuation C/N ratio (SSF)). Microbial aggregates appeared in R1, R2 and R3 on days 28, 14 and 6, respectively. Compared with the results in R1 and R2, the guanosine tetraphosphate (ppGpp) concentration was highest, the acyl homoserine lactones (AHLs) concentration quickly reached a certain threshold, and more protein (PN) of extracellular polymeric substances (EPS) secretion resulted in the rapid formation of denitrifying granular sludge in R3. The SSF strategy enhances microbial diversity, and denitrifying granular sludge has a better nitrogen removal performance. The result demonstrates that ppGpp, AHLs, EPS and the denitrifying sludge granulation process are associated. A mechanism for denitrifying sludge granulation with SSF strategy was proposed from the aspect of quorum sensing (QS). PMID- 28633204 TI - Hands off, the radial artery is mine! PMID- 28633205 TI - Advancing the science of myocardial recovery with mechanical circulatory support: A Working Group of the National, Heart, Lung, and Blood Institute. AB - The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts from June 2 to 3, 2016, in Bethesda, Maryland, to develop NHLBI recommendations aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MCS devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling. Research in this field could be innovative in many ways, and the Working Group specifically discussed opportunities associated with genome phenome systems biology approaches; genetic epidemiology; bioinformatics and precision medicine at the population level; advanced imaging modalities, including molecular and metabolic imaging; and the development of minimally invasive surgical and percutaneous bioengineering approaches. These new avenues of investigations could lead to new treatments that target phylogenetically conserved pathways involved in cardiac reparative mechanisms. A central point that emerged from the NHLBI Working Group meeting was that the lessons learned from the MCS investigational setting can be extrapolated to the broader HF population. With the precedents set by the significant effect of studies of other well-controlled and tractable subsets on larger populations, such as the genetic work in both cancer and cardiovascular disease, the work to improve our understanding of cardiac recovery and resilience in MCS patients could be transformational for the greater HF population. PMID- 28633206 TI - When and how should surgeons treat subsolid nodule? PMID- 28633207 TI - Ground-glass opacities: A curable disease but a big challenge for surgeons. PMID- 28633208 TI - Effect of transcatheter aortic valve size and position on valve-in-valve hemodynamics: An in vitro study. PMID- 28633209 TI - Response to mr bapat: does size matter? it does in texas. PMID- 28633210 TI - Value of surgery for infective endocarditis in dialysis patients. AB - OBJECTIVES: To determine the value of surgery for infective endocarditis (IE) in patients on hemodialysis by comparing the nature and invasiveness of endocarditis in hemodialysis and nonhemodialysis patients and their hospital and long-term outcomes, and identifying risk factors for time-related mortality after surgery. METHODS: From January 1997 to January 2013, 144 patients on chronic hemodialysis and 1233 nonhemodialysis patients underwent valve surgery for IE at our institution. Propensity matching identified 99 well-matched hemodialysis and nonhemodialysis patient pairs for comparison of outcomes. RESULTS: Staphylococcus aureus infection was more common in hemodialysis patients than in nonhemodialysis patients (42% vs 21%; P < .0001), but invasive disease was similar in the 2 groups (47%; P = .3). Hospital mortality was 13% and 5-year survival was 20% for hemodialysis patients, 20% below that expected in a general hemodialysis population but 15% above that of hemodialysis patients treated nonsurgically for IE. For matched patients, hospital mortality was 13% for hemodialysis patients versus 5.1% for nonhemodialysis patients (P = .05), and survival at 1 and 5 years was 56% versus 83% and 24% versus 59%, respectively (P < .004). Use of an arteriovenous graft for dialysis access (P = .01) and preoperative placement of a pacemaker (P < .0001) were risk factors for late mortality in hemodialysis patients. For matched patients, freedom from reoperation was similar in the hemodialysis and nonhemodialysis groups (P > .9). CONCLUSIONS: Intermediate-term survival after surgery for IE in hemodialysis patients is substantially worse than that in nonhemodialysis patients, but only slightly worse than that in the general hemodialysis population and substantially better than that in hemodialysis patients with IE treated nonsurgically, supporting continued surgical intervention for IE. PMID- 28633211 TI - Discussion. PMID- 28633212 TI - Transatlantic editorial on transcatheter aortic valve replacement. PMID- 28633213 TI - Plowing with unicorns. PMID- 28633214 TI - Plan, scan, model, print, manufacture, and implant personalized external aortic root support (PEARS). PMID- 28633215 TI - No free lunch: Even with a diet heavy on PEARS. PMID- 28633217 TI - Invited Commentary. PMID- 28633216 TI - Transatlantic Editorial on Transcatheter Aortic Valve Replacement. PMID- 28633218 TI - Invited Commentary. PMID- 28633219 TI - Optimizing Public Reporting of Congenital Heart Surgery Outcomes. PMID- 28633220 TI - Invited Commentary. PMID- 28633221 TI - Invited Commentary. PMID- 28633222 TI - Endosonographic Mediastinal Lymph Node Staging in Non-Small Cell Lung Cancer: How I Teach It. PMID- 28633224 TI - Invited Commentary. PMID- 28633223 TI - Primary Pulmonary Vein Stenosis: Outcomes, Risk Factors, and Severity Score in a Multicentric Study. AB - BACKGROUND: Primary pulmonary vein stenosis (PPVS) still carries a poor prognosis, and prognostic factors remain controversial. The aim of this study was to determine outcomes and prognostic factors after PPVS repair in the current era. METHODS: Thirty patients with PPVS and a normal pulmonary vein (PV) connection operated on in 10 European/North American centers (2000-2012) were included retrospectively. A specific PVS severity score was developed based on the assessment of each PV. Studied end points were death, PV reoperation, and restenosis. A univariate and multivariate risk analysis was performed. RESULTS: The mean number of affected PVs per patient was 2.7 +/- 1.1. Sutureless repair was used in 21 patients (70%), endovenectomy was used in 5 patients, and patch venoplasty was used in 4 patients. Overall PV restenosis, reoperation, and mortality occurred in 50%, 40%, and 30% of patients respectively. Freedom from mortality, reoperation, and restenosis at 8 years of follow-up was 70% +/- 8%, 62% +/- 8%, and 47% +/- 9%, respectively. Restenosis and mortality rates after sutureless repair versus nonsutureless repair were 57% (n = 12 of 21) versus 33% (n = 3 of 9) (p = 0.42) for restenosis and 38% (n = 8 of 21) versus 11% (n = 1 of 9) (p = 0.21) for mortality. Patients selected for a sutureless technique were younger and smaller and had more severe disease before operation. A postoperative high PVS score and pulmonary hypertension 1 month after the operation were independent risk factors for restenosis (hazard ratio [HR], 1.34; p = 0.002 and HR, 6.81; p = 0.02, respectively), reoperation (HR, 1.24; p = 0.01 and HR, 7.60; p = 0.02), and mortality (HR, 1.39; p = 0.01 and HR, 39.5; p = 0.008). CONCLUSIONS: Primary PVS still has a guarded prognosis in the current era despite adoption of the sutureless technique. Postoperative pulmonary hypertension and severity of disease evaluated by a new severity score are independent prognostic factors regardless of surgical technique. PMID- 28633225 TI - Patient-Specific Simulation of Endovascular Thoracic Aortic Repair: Initial Experience. AB - PURPOSE: Endovascular thoracic aortic repair (TEVAR) has become the treatment modality of diverse aortic pathology. We report the use of patient-specific simulation using a dedicated PROcedure Rehearsal Studio (PRS) platform (Simbionix USA Corp, Cleveland, OH) before TEVAR and evaluate the feasibility and realism of this technology. DESCRIPTION: Virtual three-dimensional models of the patient's relevant anatomy were reconstructed from computed tomography data. PRS was used in 2 patients before TEVAR. In a multicenter retrospective study, we evaluated how PRS compares with real TEVAR. EVALUATION: PRS before TEVAR was feasible and demonstrated good correlation with the actual procedure. In the retrospective study, 16 patients were reconstructed (median duration, 26 minutes; interquartile range, 21 to 36 minutes). The realism of the simulated angiographies was rated highly (median, 4; interquartile range, 3 to 4). Final angiography revealed type I endoleak in 2 simulated cases and 1 real case. CONCLUSION: Patient-specific rehearsal before TEVAR is feasible and permits the creation of realistic case studies; however, software updates are required to improve face validity and to foster implementation in clinical practice. PMID- 28633226 TI - The Early Days of Cardiac Surgery in South Asia: The History and Heritage. AB - The 1.79 billion people of South Asia share common history and heritage. The fascinating stories of introducing cardiac surgery in this region would inspire the surgeons today. Information was collected for more than a decade from these countries through personal visits, interviews, and searching journals and the Internet. India was first to establish cardiac surgery chronologically, followed by Sri Lanka, Pakistan, Bangladesh, Nepal, and Afghanistan. South Asia did not lag far behind the Western world in commencing cardiac surgery. The pioneering surgeons deserve respect for their dedication and innovation overcoming the economic hardship and bureaucratic barriers ensuring service for one-quarter of the world's population today. PMID- 28633227 TI - Reply. PMID- 28633229 TI - A Hand is a Terrible Thing to Waste. PMID- 28633228 TI - Catamenial Pneumothorax: A Matter of Anamnesis. PMID- 28633230 TI - Reply. PMID- 28633231 TI - Use of Unfolded Gauze in Video-Assisted Thoracoscopic Surgery. PMID- 28633232 TI - Reply. PMID- 28633233 TI - Reply. PMID- 28633234 TI - Aortic Cannulation: First Option in Aortic Dissection? PMID- 28633235 TI - Effects of Blood Transfusion on Long-Term Survival of Cardiac Surgery Patients. PMID- 28633236 TI - Mild to Moderate Ischemic Mitral Regurgitation: Should a Mitral Surgical Procedure be Added to Revascularization? PMID- 28633237 TI - Reply. PMID- 28633238 TI - Reply. PMID- 28633239 TI - Cardiothoracic Surgery in Developing Countries. PMID- 28633240 TI - Reply. PMID- 28633241 TI - Extent of Lymphadenectomy in Operable Esophageal Cancer. PMID- 28633242 TI - Reply. PMID- 28633244 TI - Corrigendum. PMID- 28633243 TI - Tracheal Resection and Pregnancy. PMID- 28633245 TI - Invited Commentary. PMID- 28633246 TI - Invited Commentary. PMID- 28633247 TI - Invited Commentary. PMID- 28633248 TI - Endobronchial-Guided Vascularized Tissue Flaps for a Bronchopleural Fistula. AB - The management of bronchopleural fistulas can be challenging. The initial treatment is usually conservative, but operative intervention with transposition of vascularized pedicled flaps may be required in refractory cases. We present the case of a 67-year-old man with stage IIIa squamous cell carcinoma of the lung who underwent a lower and middle bilobectomy after receiving neoadjuvant chemoradiation. His postoperative course was complicated by empyema and a bronchopleural fistula. Because of difficulty accessing the fistula, endobronchial-guided vascularized tissue flaps were successfully used to close the fistula. PMID- 28633249 TI - Augmentation of Bridging Leaflets in Repair of Atrioventricular Canal Defects. AB - Left atrioventricular (AV) valve regurgitation is the most common complication after a atrioventricular canal defect (AVCD) repair. Despite what appears to be a less complex repair, patients with partial and transitional AV canal have higher reoperation rates for left AV valve regurgitation and left ventricular outflow tract (LVOT) obstruction. Retraction of bridging leaflets with secondary attachments to the septal crest commonly produces increased tension and flattening of the medial left AV valve leaflet and LVOT obstruction after cleft closure. We describe a novel technique of detachment and patch augmentation of bridging leaflets to avoid these complications. PMID- 28633250 TI - Permeable Nonabsorbable Mesh for Total Diaphragmatic Replacement in Extended Pneumonectomy. AB - After complex thoracic exenterations, total diaphragmatic resection and reconstruction is challenging. We describe our novel technique for total diaphragmatic replacement with permeable nonabsorbable mesh after extended pneumonectomy. PMID- 28633251 TI - Successful Lung Transplantation for Pulmonary Disease Associated With Erdheim Chester Disease. AB - A 53-year-old man with pulmonary fibrosis associated with Erdheim-Chester disease achieved long-term survival after lung transplantation. Major clinical manifestations included lung and bone injuries, and other vital organs were functionally unaffected by the disease. After a careful observation for the disease progression, he underwent bilateral deceased-donor lung transplantation. He has returned to his normal social life and is doing well without recurrence of Erdheim-Chester disease in the lung allograft or progression in other organs 5 years after transplant. Lung transplantation is a potentially reasonable treatment option for Erdheim-Chester disease involving the lungs if the functions of other vital organs remain stable. PMID- 28633252 TI - Delayed Management of Partial Aortic Valve Avulsion After Transcatheter Aortic Valve Replacement. AB - We report a case of delayed treatment of a partial aortic valve leaflet avulsion during transcatheter aortic valve replacement (TAVR) and its successful management by a percutaneous snare retrieval technique. Post-TAVR transesophogeal echocardiography showed an avulsed native valve leaflet. We deferred retrieval of the mass with anticoagulant agents. One month later, a 30-mm EN-Snare was used to snare the mass. This case report demonstrates that the management of an avulsed aortic valve leaflet can be safely deferred with the use of an anticoagulant agent. Snare retrieval of the avulsed valve can be achieved under local anesthesia with close neurological monitoring. PMID- 28633253 TI - Transforming Growth Factor Beta-2 Mutations in Barlow's Disease and Aortic Dilatation. AB - We report on a patient operated on for degenerative myxomatous mitral and tricuspid valve disease (Barlow's disease) and aortic root dilatation. A valve repair operation and the postoperative course were uneventful. Multigenerational genetic analyses revealed two different mutations in the transforming growth factor beta-2 gene in the same patient. The two mutations in different exons were inherited from both parents each. None of the parents presented with either valve dysfunction or aortic root dilatation. This rare case illustrates potentially common genetic and signaling pathways of concomitant myxomatous valve disease and aortic root dilatation. PMID- 28633254 TI - Successful Surgical Treatment of an Aggressive Pelvic Angiomyxoma With Intracardiac Extension. AB - We present a case of an intravenous tumor with extension into the right atrium and right ventricle of the heart. Pelvic angiomyxoma is a rare benign tumor, which in this case carried a significant operative risk due to its extension. The patient initially presented with suspected caval and intracardiac thrombus, but unsuccessful treatment led to further investigations. The tumor was extensively dissected from the right atrium, suprarenal vena cava, and left iliac vein on cardiopulmonary bypass and deep hypothermic circulatory arrest. Affected gynecological organs were removed. The patient recovered uneventfully and received hormonal therapy postoperatively. PMID- 28633255 TI - Surgical Management of Giant Left Sinus of Valsalva Aneurysm Causing Left Anterior Descending Coronary Artery Occlusion. AB - Sinus of Valsalva aneurysm (SVA) is a rare cardiac anomaly, which mostly occurs in the right or noncoronary sinus of Valsalva. Left sinus of Valsava is infrequent. Unruptured SVAs are usually asymptomatic, and the diagnosis of unruptured SVA is usually accidental. A giant unruptured SVA may compress the coronary artery and cause myocardial infarction. Here, we report a rare case of a 50-year-old patient with unruptured giant left SVA causing occlusion of the left anterior descending coronary artery, which was successfully managed with our apparently unique surgical procedure. PMID- 28633256 TI - Successful Delivery in a Patient With Left Ventricular Assist Device and Unplanned Pregnancy. AB - We report the case of a woman supported by a left ventricular assist device (LVAD) who presented at 20 weeks of gestation and decided against recommendations to continue with her pregnancy. This was managed with well-developed plan for a multidisciplinary team approach. With close and regular follow-up and regular adjustment of the patient's medications and LVAD parameters, successful delivery and outcome for both the mother and the newborn were achieved. PMID- 28633257 TI - Takayasu Arteritis Mimicking Type A Intramural Hematoma. AB - Takayasu arteritis is a panarteritis of unknown etiology involving the aorta and its main branches, with higher prevalence in women and peak of incidence in the second and third decades of life. Up to 30% of patients have coronary lesions and aortic valve involvement. Presentation mimicking aortic dissection is quite rare. Here described is the case of a young patient, presenting with an acute coronary syndrome associated with severe aortic regurgitation, who underwent emergent surgery with the suspicion of acute aortic dissection. The diagnostic and therapeutic implications are discussed. PMID- 28633258 TI - Stepwise Total Aortic Repairs With Fenestrated Endografts in a Patient With Loeys Dietz Syndrome. AB - Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder (CTD) caused by mutations in the gene encoding transforming growth factor-beta receptors I and II. Patients with LDS manifest spontaneous aneurysms and dissections of the aorta and peripheral artery. We report a successful treatment with a hybrid endovascular repair for a rapidly expanding thoracoabdominal aneurysm in a 41 year-old woman affected by LDS. To overcome the difficulties of anatomical and surgical repair, we applied an original strategy using surgeon-modified fenestrated endografts. PMID- 28633259 TI - Mycobacterium chimaera Infection After Cardiac Surgery: First Canadian Outbreak. AB - Recently reported in Europe and United States, disseminated Mycobacterium chimaera infection is a novel clinical entity linked to point contamination of Stockert 3T heater-cooler units used for cardiopulmonary bypass. We present here the first two cases in Canada. Both patients presented with nonspecific extracardiac symptoms 1 year after undergoing minimally invasive mitral surgical repair. Before the right diagnosis was established, the patients were initially treated with prednisone for suspected sarcoidosis. One patient is currently improving, and the other needed mitral valve repair despite aggressive treatment. Because of the nonspecific mode and timing of presentation, a high index of suspicion is necessary for the diagnosis of M. chimaera infection. PMID- 28633260 TI - Total Chordal Sparing Mitral Valve Replacement in Rheumatic Disease: A Word of Caution. AB - Total chordal preservation is the standard for mitral valve replacement to maintain long-term left ventricular geometry. Whereas it is appropriate for functional and degenerative mitral regurgitation, the role of chordal sparing in rheumatic valve disease is less well understood, with limited evidence supporting total chordal sparing. Inasmuch as this autoimmune disease affects the subvalvular apparatus in addition to the leaflets, it can be expected to continue after surgical repair. Here we present 2 patients who experienced adverse events associated with total chordal sparing mitral replacement as a result of disease progression with rapid fibrous growth causing inflow obstruction and early prosthetic valve failure. PMID- 28633261 TI - Mediastinal Abscess Caused by an Expanded Polytetrafluoroethylene Membrane. AB - A 76-year-old man who had undergone tricuspid annuloplasty 13 years earlier was admitted to our hospital because of a high fever. Although he was treated with antibiotics for pneumonia, a mild fever persisted. Computed tomography and gallium scintigraphy revealed a mediastinal abscess with an expanded polytetrafluoroethylene (ePTFE) membrane. There were no positive cultures or sternal changes indicating poststernotomy mediastinitis. The membrane was removed by a left parasternal approach without resternotomy, and its total removal was essential for the patient's recovery. This is the first reported case of sterile mediastinal abscess caused by an ePTFE membrane after a cardiac operation. PMID- 28633262 TI - Intratracheal Thyroid: A Different Approach. AB - During embryonic development, the abnormal migration of thyroid tissue may cause ectopic localization of the gland in the intralaryngotracheal space. This case report describes the management of a young patient with a recent diagnosis of asthma. During bronchoscopy, a large mass occupying the tracheal lumen was discovered. After tracheotomy to protect the airway, an incisional biopsy was performed and revealed an intratracheal ectopic thyroid. The deep incisions through the tracheotomy to the base of the lesion allowed colloidal content to leak out of the mass until complete resolution of airway obstruction. Fifteen days later the patient was released totally rehabilitated. PMID- 28633263 TI - Structural Valve Deterioration of a Subcoronary Implanted Stentless Bioprosthesis: How to Treat? AB - We present a case of transcatheter valve-in-valve replacement performed because of structural valve deterioration of a subcoronary implanted stentless aortic bioprosthesis. A 23-mm self-expandable transcatheter heart valve (THV) with supraannular seating was chosen. The procedure was performed with the patient under conscious sedation. After anchoring and partial valve deployment, the patient experienced an acute onset of angina. The angiogram showed left main coronary artery obstruction. Prompt resheathing and retrieval of the THV was performed, and the procedure was aborted. Subsequently, an open-heart redo operation was performed by the use of a sutureless aortic bioprosthesis, with satisfactory hemodynamic and clinical results. PMID- 28633264 TI - Rapidly Progressive Bioprosthetic Aortic Valve Stenosis Due to Bartonella Species Endocarditis. AB - Rapid progression of valvular stenosis in the setting of infective endocarditis is extremely rare. Here we describe a patient with Bartonella endocarditis on a bioprosthetic aortic valve that caused rapidly progressive aortic stenosis without regurgitation. At operation the bioprosthetic valve was severely fibrotic and calcified, with markedly thickened and distorted leaflets and circular partial detachment from the aortic ring. The patient underwent aortic root replacement with aortic bioprosthesis and aortic grafting with reimplantation of the coronary ostia. PMID- 28633265 TI - Again, Two Melodies in Concert: Transcatheter Double Valve Replacement in Hedinger Syndrome. AB - Transcatheter pulmonary valve implantation is established as a valuable option to reconstruct failing right ventricular outflow tract function. Percutaneous tricuspid valve-in-valve or valve-in-ring reconstruction is even applied with increasing acceptance. A 46-year-old woman with a diagnosis of carcinoid dependent right heart failure underwent surgical bioprosthetic tricuspid and pulmonary valve replacement. Almost 1 year later, she presented again with markedly dilatated and reduced right heart function caused by degeneration of both biologic valves. We report a successful two-stage percutaneous transcatheter double-valve replacement with the use of a Melody valve in pulmonary and tricuspid positions. PMID- 28633266 TI - Complete Neurological Recovery After Acute Total Occlusion of the Superior Vena Cava. AB - Superior vena cava (SVC) syndrome, characterized by swelling of the upper torso, can result from a wide range of causes. The presence and severity of clinical symptoms depends on the degree of stenosis, the location of stenosis, the speed of development of stenosis, and existing collateral flow. Acute complete occlusion of the SVC frequently leads to poor neurologic outcomes such as coma or death. We report a case of a patient who had complete neurologic recovery after 26 minutes of acute total occlusion of the SVC. This report highlights the importance of meticulous management during acute SVC occlusion to improve patient outcome. PMID- 28633268 TI - Surgical-Interventional Hybrid Concept in a Newborn With Borderline Left Heart. AB - Through a series of complex surgical and interventional procedures including downsizing of an unrestricted atrial septal defect, aortic arch reconstruction, pulmonary artery banding, reversed Potts shunt, and Melody valve in a mitral position, biventricular conversion was successfully achieved in a patient with a distinct borderline left ventricle. By use of these interventional steps, flow mediated and load-mediated growth of a small left ventricle was observed, highlighting the plasticity of hearts in growing children. Surgical and catheter interventional teamwork may lead to fascinating results, provoking us to quote Aristotle's wisdom: "The whole is more than the sum of its parts." PMID- 28633267 TI - Perventricular Implantation of Melody Valve in Child With Pulmonary Hypertension After a Potts Shunt. AB - The Potts operation is a surgical option for the treatment of children with suprasystemic pulmonary arterial hypertension (PAH). Its positive hemodynamic effect may be obliterated by pulmonary valvar insufficiency. We describe a case in which the Potts shunt was followed by perventricular Melody valve implantation in the pulmonary position in a 12-kg child with a previously repaired truncus arteriosus communis (TAC) in whom PAH developed. The combined approach using both procedures significantly improved functional capacity and led to spectacular reverse remodeling of the right ventricle seen at 2-year follow-up. Elimination of significant pulmonary insufficiency is crucial in achieving the hemodynamic benefits of a Potts shunt in patients with pulmonary hypertension. PMID- 28633269 TI - Stenting and Reimplanting Disconnected Pulmonary Artery in Tetralogy of Fallot. AB - Tetralogy of Fallot with absent pulmonary valve syndrome (TOF/APV) is a rare congenital malformation. Although pulmonary artery (PA) anomalies have been observed in TOF, its association with disconnected PA is extremely rare. We report successful stenting of the disconnected left PA in a 3-year-old boy with TOF/APV followed by surgical reimplantation. The significance of this transcatheter intervention for guidance during surgery and the importance of visualizing a ductal stump on angiography as an indicator of disconnected PA are discussed. PMID- 28633270 TI - Surgical Correction for a Neonate With Ebstein's Anomaly Associated With Tetralogy of Fallot. AB - Ebstein's anomaly in combination with tetralogy of Fallot (TOF) is rare. We report a male infant with these combined anomalies who presented with severe cyanosis, heart failure, and respiratory distress after birth. Biventricular repair was successfully performed with 1-stage correction of his ventricular septal defect (VSD), right ventricular outflow tract (RVOT) obstruction, and tricuspid regurgitation. The downward displaced tricuspid valve was also restored to the normal annulus position. The infant recovered well. The surgical technique for this rare and severe anomaly is reported here. PMID- 28633271 TI - Rupture of a Metastatic Uterine Leiomyosarcoma Invading the Right Atrium Causing Cardiac Tamponade. PMID- 28633272 TI - Mechanical Failure of Extracorporeal Membrane Oxygenation Induced by Hypertriglyceridemia. PMID- 28633273 TI - Percutaneous Intervention of a Rare Complication Post Cardiac Surgery. PMID- 28633274 TI - Intraventricular Septal Echinococcosis. PMID- 28633275 TI - Phrenic Nerve Reconstruction and Bilateral Diaphragm Plication After Lobectomy. AB - A 49-year-old man with left phrenic nerve paralysis caused by mediastinal tumor resection 28 years earlier was found to have a nodule in the right upper lobe. The right phrenic nerve was severed during right upper lobectomy but was reconstructed along with bilateral plication of the diaphragm. The patient was weaned from the ventilator during the daytime on postoperative day 13 and was discharged home on postoperative day 48. Three months postoperatively, chest fluoroscopic imaging showed recovery of movement of the right diaphragm. Nerve conduction studies showed improvement of function of the reconstructed right phrenic nerve. PMID- 28633277 TI - Giant Transdiaphragmatic Intercostal Hernia. PMID- 28633276 TI - Heart Failure Caused by Misdiagnosed Subaortic Stenosis in Adulthood: Lesson for Daily Practice. PMID- 28633278 TI - Radiopaque Marker Addition During Aortic Root Replacement With the Use of a Freestyle Porcine Bioprosthesis. AB - Aortic root replacement is indicated for aortic root aneurysm, small aortic root, and most root abscesses. This report describes the placement of a radiopaque marker during aortic root replacement using a Freestyle porcine bioprosthesis. This marker is a useful landmark during fluoroscopy for transcatheter valve-in valve aortic valve replacement in the event of bioprosthesis degeneration. PMID- 28633279 TI - Off-Pump Semicircular Annuloplasty: Effective Treatment of Concurrent Moderate Aortic Regurgitation. AB - The treatment of aortic regurgitation (AR) in patients undergoing off-pump coronary artery bypass grafting (CABG) is a difficult problem. Aortic valve repair has become a promising therapy for AR. Various annuloplasty approaches have been used and have gained satisfactory results. Thus we adopted off-pump semicircular annuloplasty to treat concurrent moderate AR in 12 high-risk patients. Early follow-up results showed that this way is simple, safe, and effective. PMID- 28633280 TI - MotifHyades: expectation maximization for de novo DNA motif pair discovery on paired sequences. AB - Motivation: In higher eukaryotes, protein-DNA binding interactions are the central activities in gene regulation. In particular, DNA motifs such as transcription factor binding sites are the key components in gene transcription. Harnessing the recently available chromatin interaction data, computational methods are desired for identifying the coupling DNA motif pairs enriched on long range chromatin-interacting sequence pairs (e.g. promoter-enhancer pairs) systematically. Results: To fill the void, a novel probabilistic model (namely, MotifHyades) is proposed and developed for de novo DNA motif pair discovery on paired sequences. In particular, two expectation maximization algorithms are derived for efficient model training with linear computational complexity. Under diverse scenarios, MotifHyades is demonstrated faster and more accurate than the existing ad hoc computational pipeline. In addition, MotifHyades is applied to discover thousands of DNA motif pairs with higher gold standard motif matching ratio, higher DNase accessibility and higher evolutionary conservation than the previous ones in the human K562 cell line. Lastly, it has been run on five other human cell lines (i.e. GM12878, HeLa-S3, HUVEC, IMR90, and NHEK), revealing another thousands of novel DNA motif pairs which are characterized across a broad spectrum of genomic features on long-range promoter-enhancer pairs. Availability and implementation: The matrix-algebra-optimized versions of MotifHyades and the discovered DNA motif pairs can be found in http://bioinfo.cs.cityu.edu.hk/MotifHyades. Contact: kc.w@cityu.edu.hk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633282 TI - Editorial: Host Attractiveness and Malaria Transmission to Mosquitoes. PMID- 28633283 TI - Janus kinase inhibitors clear to land: Janus kinase inhibitors in RA. PMID- 28633281 TI - The sweet side of the pathogenic Neisseria: the role of glycan interactions in colonisation and disease. AB - Glycomics is a rapidly growing field that focuses on the structure and function of carbohydrates (glycans) in biological systems. Glycan interactions play a major role in infectious disease, at all stages of colonisation and disease progression. Neisseria meningitidis, the cause of meningococcal sepsis and meningitis, and Neisseria gonorrhoeae, which causes the sexually transmitted infection gonorrhoea, are responsible for significant morbidity and mortality worldwide. Neisseria meningitidis displays a range of surface glycosylations including capsule polysaccharide, lipooligosaccharide and O-linked glycoproteins. While N. gonorrhoeae does not have a capsule, it does express both lipooligosaccharide and O-linked glycoproteins. Neisseria gonorrhoeae also has the ability to scavenge host sialic acids, while several N. meningitidis serogroups can synthesise sialic acid. Surface expressed sialic acid is key in serum resistance and survival in the host. On the host side, the pathogenic Neisseria protein adhesins such as Opc and NHBA bind to host glycans for adherence and colonisation of host cells. Essentially, from both the bacterial and host perspective, glycan interactions are fundamental in colonisation and disease of pathogenic Neisseria. The key aspects of glycobiology of the pathogenic Neisseria are reviewed herein. PMID- 28633284 TI - Determination of Some beta-Blockers and beta2-Agonists in Plasma and Urine Using Liquid Chromatography-tandem Mass Spectrometry and Solid Phase Extraction. AB - A highly sensitive method for the determinations of acebutolol, clenbuterol, nadolol, oxprenolol, propranolol, terbutaline and timolol beta-blockers and beta2 agonists in plasma and urine was developed. The method was optimized using electrospray ionization liquid chromatography-tandem mass spectrometry (LC-ESI-MS MS) and clean screen solid phase extraction cartridges. Matrix effect was reduced by removing co-extractives from the SPE cartridges using methanol prior to drugs' elution. Using blood and serum matrices for calibration and applying the internal standard method has also contributed to the reduction of matrix effect. Method's validation yielded linear dynamic ranges of 5.0-50.0 and 50.0-1000.0 ng/ml for drugs spiked in plasma and urine respectively. It also gave correlation coefficients of 0.94-0.99, detection limits ranged in 0.06-5.04 pg/ml and quantification limits ranged in 0.14-22.88 pg/ml for the target drugs. Developed method was successfully applied to the analysis of beta-blockers and beta2 agonists in plasma and urine samples. Plasma samples fortified with drugs at 7.5, 40.0 and 75.0 ng/ml gave percentage recoveries ranged in 78.66-118.10, 67.02 83.97 and 74.77-93.80, respectively. Urine samples fortified with drugs at 80.0, 400.0 and 800.0 ng/ml gave percentage recoveries ranged in 104.68-130.18, 110.23 125.16 and 109.46-116.89, respectively. Variance coefficients ranged in 0.05-0.35 and 0.04-0.12 were, respectively, obtained for the analyses of drugs in plasma and urine samples. Results suggest that developed method is well suited for the analysis of investigated drugs in biological fluids. PMID- 28633285 TI - Chronic Kidney Disease in the Aging Human Immunodeficiency Virus-Infected Population. PMID- 28633286 TI - Do Treatment Attitudes and Decisions of Psychotherapists-in-Training Depend on a Patient's Age? AB - Objective: The objective of this study was to analyze how psychotherapists' treatment attitudes and decisions depend on a patient's age. Methods: A sample of psychotherapists-in-training (N = 97) responded to questions concerning a naturalistic case vignette of a female patient with symptoms of depression and anxiety. The patient was described as being either 79 or 47 years old. Results: Results revealed no evidence that psychotherapists-in-training had more negative treatment attitudes towards an older relative to a younger patient. However, the patient's age had an influence on participants' therapeutic approach. Specifically, psychotherapists-in-training recommended short- as opposed to long term therapy, considered motivational clarification less important, and viewed clarifying techniques as less appropriate for an older patient. Conclusions: The stereotype of the rigid and resigned old person appears to be an important and potentially problematic factor in psychotherapy. Interventions to help therapists to reflect on their individual representations of aging may increase the likelihood of successful psychotherapy. PMID- 28633287 TI - Genetic diseases and aneuploidies can be detected with a single blastocyst biopsy: a successful clinical approach. AB - STUDY QUESTION: Can simultaneous detection of aneuploidies and genetic diseases or chromosomal aberrations in blastocysts reduce the chance of transferring embryos with low implantation potential, guaranteeing good clinical outcomes? SUMMARY ANSWER: The screening for chromosomal aneuploidies revealed that 50.6% of blastocysts diagnosed free of genetic disease or balanced, were aneuploid, therefore avoiding the transfer of blastocysts potentially resulting in implantation failures, miscarriages, or in some cases, in health affected live births. WHAT IS KNOWN ALREADY: PGD is applied in patients at risk of transmitting genetically inheritable diseases to their offspring. It has been demonstrated that aneuploidies can involve chromosomes other than those investigated with PGD, affecting embryo implantation competence. Performing the biopsy at blastocyst level produces higher clinical outcomes allowing a more accurate diagnosis, compared to blastomere biopsy. STUDY DESIGN, SIZE, DURATION: This consecutive case series study was performed from October 2011 to May 2016. Clinical and biological outcomes from 1122 blastocysts obtained in 304 PGD cycles for monogenic diseases (N = 163) or chromosomal rearrangements (N = 141) were analyzed. When the blastocyst resulted transferable after the PGD analysis or chromosomal rearrangement analysis, its ploidy status by mean of preimplantation genetic screening (PGS) was also detected using the same biopsy sample. Mean female age was 35.4 +/- 4.2 years old. All biopsies were performed at blastocyst stage and analyzed by Whole Genome Amplification (WGA) followed by PCR for monogenic diseases, and by array-comparative genotype hybridization (array-CGH) for all cycles. PARTICIPANTS/MATERIALS, SETTING, METHOD: All mature oocytes retrieved were injected and cultured individually until the blastocyst stage at 37 degrees C, 6% CO2, 5% O2. When the blastocyst was formed, it was biopsied and vitrified, awaiting the genetic results. The frozen-thawed embryo transfer was performed in a subsequent cycle. In some cases, when the blastocyst was obtained within the morning of Day 5 of culture, it had been maintained in culture and transferred on Day 6, after receiving the genetic report. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 2809 (2718 fresh and 91 frozen-thawed) mature oocytes were injected with a fertilization rate of 75.5% (N = 2120), leading to the development of 2102 embryos. A further 24 frozen embryos, previously vitrified without any genetic testing, were successfully warmed for genetic screening. A total of 2126 embryos were cultured with a blastocyst formation rate of 52.8% (N = 1122); all of them were biopsied from Day 4 to Day 7 of culture. After the genetic analysis, 309 (27.5%) blastocysts resulted transferable, both for monogenic disease or translocation and for their ploidy status, 42 were diploid/aneuploid mosaic, 55 were no result and 716 were not transferable, due to genetic disease or chromosomal rearrangement and/or for their ploidy status. Of note, 316 (50.6% of transferable blastocysts after PGD and 28.2% of total number of biopsied blastocysts) of the blastocysts resulted healthy for the genetic disease or chromosomal rearrangement were aneuploid. Out of 304 PGD/PGS cycles performed, 28.6% (N = 87) resulted in no-transferable blastocysts after only PGD analysis; this percentage increased to 39.8% (N = 121) when also PGS was carried out (Mc Nemar test P < 0.001). A total of 202 embryo-transfers were performed, 53 fresh and 149 cryopreserved, in which 218 healthy or carrier euploid blastocysts were transferred. Clinical pregnancy, implantation and miscarriage rates were 49.0, 47.7 and 9.9%, respectively. To date, 66 deliveries occurred with 70 healthy babies born and 13 pregnancies are still ongoing. Finally, 91 euploid healthy blastocysts are still cryopreserved waiting to be transferred. LIMITATIONS, REASONS FOR CAUTION: A higher than expected cycle cancellation rate could be found due to the double genetic analysis performed. For this reason, particular care should be taken in drafting and explaining informed consent, in order to avoid patient drop out. WIDER IMPLICATIONS OF THE FINDINGS: When the biopsy has to be performed in order to prevent the transmission of an inheritable disease, it should be mandatory to analyze also the genetic status of the blastocyst, avoiding useless embryo-transfers in this particular category of patients. In our study, 316 aneuploid healthy blastocysts could have been transferred without performing PGS, leading to implantation failures, miscarriages, or in some cases, to live births affected by different syndromes. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 28633288 TI - Invited Commentary: Quantifying the Added Value of Repeated Measurements. AB - Meaningful inference in epidemiology relies on accurate exposure measurement. In longitudinal observational studies, having more exposure data in the form of repeated measurements in the same individuals adds useful information. But exactly how much do repeated measurements add, incremental to the information provided by baseline measurements? In this issue of the Journal, Paige et al. (Am J Epidemiol. 2017;186(8):899-907 have quantified the value of adding repeated cholesterol and blood pressure measurements to baseline measurements in a meta analysis of individual participant data from 38 longitudinal cohort studies. Repeated measurements improve prediction significantly, but the magnitude of this gain in information may be less than expected. In research studies and clinical practice, quality of measurement is more important than quantity. PMID- 28633289 TI - Discussion: Is the FDA in need of a major change in the way it regulates? PMID- 28633290 TI - Planning, evaluating and vetting receptor signaling studies to assess hyaluronan size-dependence and specificity. AB - Exciting discoveries in many diverse fields of hyaluronan (HA) biology over the last 40 years have centered around the ability of HA to bind cell surface HA receptors (e.g., CD44, Layilin, LYVE-1, HARE/Stab2 and RHAMM) and sometimes also to activate intracellular signal transduction pathways, frequently involving ERK1/2. Although perplexing, a major characteristic of HA-mediated signal pathway activation for some receptors has been a dependence on the size of the bound HA. Receptors that directly interact with HA, which may not include TLR2/4, bind very well to any HA molecule >8-20 sugars, depending on the receptor. Despite their ability to bind virtually any size HA, only HA chains of a particular mass range can activate receptor-mediated cell signaling. Many studies have demonstrated parts of this emerging story by utilizing different: HA receptors, cell types, animal models, HA sources, HA sizes, assays to assess HA mass and varying controls to verify HA specificity or HA size-dependence. Recent reports have highlighted issues with potential endotoxin contamination of HA fragments, especially those generated by hyaluronidase digestion. Also, researchers unfamiliar with HA polydispersity must adjust to working with, and interpreting data for, preparations without a unique molecular mass (molecular weight). The confusion, uncertainty and skepticism generated by these and other factors has hindered the development of a general consensus about HA-specific and HA-size dependent receptor activation. An overview of issues, suggested strategies and validating controls is presented to aid those planning an HA-mediated receptor signaling study or those trying to evaluate the literature. PMID- 28633291 TI - P2X7 Receptors Drive Spine Synapse Plasticity in the Learned Helplessness Model of Depression. AB - Background: Major depressive disorder is characterized by structural and functional abnormalities of cortical and limbic brain areas, including a decrease in spine synapse number in the dentate gyrus of the hippocampus. Recent studies highlighted that both genetic and pharmacological invalidation of the purinergic P2X7 receptor (P2rx7) leads to antidepressant-like phenotype in animal experiments; however, the impact of P2rx7 on depression-related structural changes in the hippocampus is not clarified yet. Methods: Effects of genetic deletion of P2rx7s on depressive-like behavior and spine synapse density in the dentate gyrus were investigated using the learned helplessness mouse model of depression. Results: We demonstrate that in wild-type animals, inescapable footshocks lead to learned helplessness behavior reflected in increased latency and number of escape failures to subsequent escapable footshocks. This behavior is accompanied with downregulation of mRNA encoding P2rx7 and decrease of spine synapse density in the dentate gyrus as determined by electron microscopic stereology. In addition, a decrease in synaptopodin but not in PSD95 and NR2B/GluN2B protein level was also observed under these conditions. Whereas the absence of P2rx7 was characterized by escape deficit, no learned helpless behavior is observed in these animals. Likewise, no decrease in spine synapse number and synaptopodin protein levels was detected in response to inescapable footshocks in P2rx7-deficient animals. Conclusion: Our findings suggest the endogenous activation of P2rx7s in the learned helplessness model of depression and decreased plasticity of spine synapses in P2rx7-deficient mice might explain the resistance of these animals to repeated stressful stimuli. PMID- 28633292 TI - AHP2, AHP3, and AHP5 act downstream of CKI1 in Arabidopsis female gametophyte development. AB - Histidine phosphotransfer proteins (HPs) are key elements of the two-component signaling system, which act as a shuttle to transfer phosphorylation signals from histidine kinases (HKs) to response regulators (RRs). CYTOKININ INDEPENDENT 1 (CKI1), a key regulator of central cell specification in the Arabidopsis female gametophyte, activates the cytokinin signaling pathway through the Arabidopsis histidine phosphotransfer proteins (AHPs). There are five HP genes in Arabidopsis, AHP1-AHP5, but it remains unknown which AHP genes act downstream of CKI1 in Arabidopsis female gametophyte development. Promoter activity analysis of AHP1-AHP5 in embryo sacs revealed AHP1, AHP2, AHP3, and AHP5 expression in the central cell. Phenotypic studies of various combinations of ahp mutants showed that triple mutations in AHP2, AHP3, and AHP5 resulted in defective embryo sac development. Using cell-specific single and double markers in the female gametophyte, the ahp2-2 ahp3 ahp5-2/+ triple mutant ovules showed loss of central cell and antipodal cell fates and gain of egg cell or synergid cell attributes, resembling the cki1 mutant phenotypes. These data suggest that AHP2, AHP3, and AHP5 are the major factors acting downstream of CKI1 in the two-component cytokinin signaling pathway to promote Arabidopsis female gametophyte development. PMID- 28633294 TI - Response to Pre-Pregnancy Blood Pressure and Offspring Sex in the HUNT Study, Norway. PMID- 28633293 TI - The Tonoplast-Localized Transporter MTP8.2 Contributes to Manganese Detoxification in the Shoots and Roots of Oryza sativa L. AB - Manganese (Mn) cation diffusion facilitators (Mn-CDFs) play important roles in the Mn homeostasis of plants. In rice, the tonoplast-localized Mn-CDF metal tolerance protein 8.1 (MTP8.1) is involved in Mn detoxification in the shoots. This study functionally characterized the Mn-CDF MTP8.2 and determined its contribution to Mn tolerance. MTP8.2 was found to share 68% identity with MTP8.1 and was expressed in both the shoots and roots, but its transcription level was lower than that of MTP8.1. Transient expression of the MTP8.2:green fluorescent protein (GFP) fusion protein and immunoblotting studies indicated that MTP8.2 was also localized to the tonoplast. MTP8.2 expression in yeast conferred tolerance to Mn but not to Fe, Zn, Co, Ni or Cd. MTP8.2 knockdown caused further growth reduction of shoots and roots in the mtp8.1 mutant, which already exhibits stunted growth under conditions of excess Mn. In the presence of high Mn, the MTP8.2 knockdown lines of the mtp8.1 mutant showed lower root Mn concentrations, as well as lower root:total Mn ratios, than those of wild-type rice and the mtp8.1 mutant. These findings indicate that MTP8.2 mediates Mn tolerance along with MTP8.1 through the sequestration of Mn into the shoot and root vacuoles. PMID- 28633295 TI - Long cold exposure induces transcriptional and biochemical remodelling of xylem secondary cell wall in Eucalyptus. AB - Although eucalypts are the most planted hardwood trees worldwide, the majority of them are frost sensitive. The recent creation of frost-tolerant hybrids such as Eucalyptus gundal plants (E. gunnii * E. dalrympleana hybrids), now enables the development of industrial plantations in northern countries. Our objective was to evaluate the impact of cold on the wood structure and composition of these hybrids, and on the biosynthetic and regulatory processes controlling their secondary cell-wall (SCW) formation. We used an integrated approach combining histology, biochemical characterization and transcriptomic profiling as well as gene co-expression analyses to investigate xylem tissues from Eucalyptus hybrids exposed to cold conditions. Chilling temperatures triggered the deposition of thicker and more lignified xylem cell walls as well as regulation at the transcriptional level of SCW genes. Most genes involved in lignin biosynthesis, except those specifically dedicated to syringyl unit biosynthesis, were up regulated. The construction of a co-expression network enabled the identification of both known and potential new SCW transcription factors, induced by cold stress. These regulators at the crossroads between cold signalling and SCW formation are promising candidates for functional studies since they may contribute to the tolerance of E. gunnii * E. dalrympleana hybrids to cold. PMID- 28633297 TI - Sauna Bathing and Incident Hypertension: A Prospective Cohort Study. AB - BACKGROUND: Sauna bathing is associated with reduced cardiovascular risk, but the mechanisms underlying this beneficial effect are not entirely understood. We aimed to assess the relationship between sauna bathing and risk of incident hypertension. METHODS: Frequency of sauna bathing was ascertained using questionnaires in the Kuopio Ischemic Heart Disease Study, a prospective cohort study conducted in Eastern Finland that comprised a population-based sample of 1,621 men aged 42 to 60 years without hypertension at baseline. The incidence of hypertension was defined as a physician diagnosis of hypertension, systolic blood pressure (SBP) >140 mm Hg, diastolic blood pressure >90 mm Hg, or use of antihypertensive medication. RESULTS: During a median follow-up of 24.7 years, 251 incident cases (15.5%) were recorded. In Cox regression analysis adjusted for baseline age, smoking, body mass index, and SBP; compared to participants reporting 1 sauna session per week, the hazard ratio for incident hypertension in participants reporting 2 to 3 sessions and 4 to 7 sessions was 0.76 (95% confidence interval: 0.57-1.02) and 0.54 (0.32-0.91), respectively. The corresponding hazard ratios were similar after further adjustment for glucose, creatinine, alcohol consumption, heart rate, family history of hypertension, socioeconomic status, and cardiorespiratory fitness: 0.83 (95% confidence interval: 0.59-1.18) and 0.53 (0.28-0.98), respectively. CONCLUSIONS: Regular sauna bathing is associated with reduced risk of hypertension, which may be a mechanism underlying the decreased cardiovascular risk associated with sauna use. Further epidemiological and experimental studies could help elucidate the effects of sauna bathing on cardiovascular function. PMID- 28633296 TI - Similar Ratios of Introns to Intergenic Sequence across Animal Genomes. AB - One central goal of genome biology is to understand how the usage of the genome differs between organisms. Our knowledge of genome composition, needed for downstream inferences, is critically dependent on gene annotations, yet problems associated with gene annotation and assembly errors are usually ignored in comparative genomics. Here, we analyze the genomes of 68 species across 12 animal phyla and some single-cell eukaryotes for general trends in genome composition and transcription, taking into account problems of gene annotation. We show that, regardless of genome size, the ratio of introns to intergenic sequence is comparable across essentially all animals, with nearly all deviations dominated by increased intergenic sequence. Genomes of model organisms have ratios much closer to 1:1, suggesting that the majority of published genomes of nonmodel organisms are underannotated and consequently omit substantial numbers of genes, with likely negative impact on evolutionary interpretations. Finally, our results also indicate that most animals transcribe half or more of their genomes arguing against differences in genome usage between animal groups, and also suggesting that the transcribed portion is more dependent on genome size than previously thought. PMID- 28633298 TI - Protein expression in tension wood formation monitored at high tissue resolution in Populus. AB - Tension wood (TW) is a specialized tissue with contractile properties that is formed by the vascular cambium in response to gravitational stimuli. We quantitatively analysed the proteomes of Populus tremula cambium and its xylem cell derivatives in stems forming normal wood (NW) and TW to reveal the mechanisms underlying TW formation. Phloem-, cambium-, and wood-forming tissues were sampled by tangential cryosectioning and pooled into nine independent samples. The proteomes of TW and NW samples were similar in the phloem and cambium samples, but diverged early during xylogenesis, demonstrating that reprogramming is an integral part of TW formation. For example, 14-3-3, reactive oxygen species, ribosomal and ATPase complex proteins were found to be up regulated at early stages of xylem differentiation during TW formation. At later stages of xylem differentiation, proteins involved in the biosynthesis of cellulose and enzymes involved in the biosynthesis of rhamnogalacturonan-I, rhamnogalacturonan-II, arabinogalactan-II and fasciclin-like arabinogalactan proteins were up-regulated in TW. Surprisingly, two isoforms of exostosin family proteins with putative xylan xylosyl transferase function and several lignin biosynthesis proteins were also up-regulated, even though xylan and lignin are known to be less abundant in TW than in NW. These data provided new insight into the processes behind TW formation. PMID- 28633300 TI - Pre-pregnancy Blood Pressure and Offspring Sex in the HUNT Study, Norway. PMID- 28633299 TI - Structural Covariance Networks in Children with Autism or ADHD. AB - Background: While autism and attention-deficit/hyperactivity disorder (ADHD) are considered distinct conditions from a diagnostic perspective, clinically they share some phenotypic features and have high comorbidity. Regardless, most studies have focused on only one condition, with considerable heterogeneity in their results. Taking a dual-condition approach might help elucidate shared and distinct neural characteristics. Method: Graph theory was used to analyse topological properties of structural covariance networks across both conditions and relative to a neurotypical (NT; n = 87) group using data from the ABIDE (autism; n = 62) and ADHD-200 datasets (ADHD; n = 69). Regional cortical thickness was used to construct the structural covariance networks. This was analysed in a theoretical framework examining potential differences in long and short-range connectivity, with a specific focus on relation between central graph measures and cortical thickness. Results: We found convergence between autism and ADHD, where both conditions show an overall decrease in CT covariance with increased Euclidean distance between centroids compared with a NT population. The 2 conditions also show divergence. Namely, there is less modular overlap between the 2 conditions than there is between each condition and the NT group. The ADHD group also showed reduced cortical thickness and lower degree in hub regions than the autism group. Lastly, the ADHD group also showed reduced wiring costs compared with the autism groups. Conclusions: Our results indicate a need for taking an integrated approach when considering highly comorbid conditions such as autism and ADHD. Furthermore, autism and ADHD both showed alterations in the relation between inter-regional covariance and centroid distance, where both groups show a steeper decline in covariance as a function of distance. The 2 groups also diverge on modular organization, cortical thickness of hub regions and wiring cost of the covariance network. Thus, on some network features the groups are distinct, yet on others there is convergence. PMID- 28633301 TI - Reply to Chung et al. PMID- 28633302 TI - Mumps clinical diagnostic uncertainty. AB - Background: During recent years, various mumps outbreaks have occurred among populations vaccinated for mumps worldwide. In Italy, improving routine coverage with two doses of measles, mumps and rubella (MMR) vaccine is one of the key strategies to eliminate measles and rubella. To monitor the effect of the vaccination programme on the population, the surveillance of these vaccine preventable diseases has been implemented. This provided the opportunity to evaluate the accuracy of the clinical diagnosis of those diseases, including mumps. In fact, vaccinated children may develop a variety of diseases caused by a series of different viruses [Epstein-Barr virus (EBV), parainfluenza virus types 1-3, adenoviruses, herpes virus and parvovirus B19] whose symptoms (i.e. swelling of parotid glands) may mimic mumps. For this reason, laboratory diagnosis is essential to confirm clinical suspicion. Methods: The accuracy of clinical diagnosis of mumps was evaluated by differential diagnosis on EBV in Italy, a country at low incidence of mumps. This retrospective study investigated whether the etiology of 131 suspected mumps cases with a negative molecular/serological result for mumps virus, obtained from 2007 to 2016, were due to EBV, in order to establish a diagnosis. Results: Differential diagnosis revealed a EBV positivity rate of 19.8% and all cases were caused by EBV type 1. Conclusions: This study confirms the importance of a lab based differential diagnosis that can discriminate between different infectious diseases presenting with symptoms suggestive of mumps and, in particular, emphasize the importance to discriminate between mumps and EBV-related mononucleosis. PMID- 28633303 TI - Cognitive Trajectories of Older Adults With Prediabetes and Diabetes: A Population-Based Cohort Study. AB - Background: Diabetes has been linked to dementia risk; however, the cognitive trajectories in older adults with diabetes remain unclear. We aimed to investigate the effect of prediabetes and diabetes on cognitive trajectories among cognitively intact older adults in a long-term follow-up study. Methods: Within the Swedish Adoption/Twin Study of Aging, 793 cognitively intact older adults aged >=50 were identified at baseline and followed for up to 23 years. Based on standardized scores from 11 cognitive tests, administered at baseline and up to seven follow-ups, four cognitive domains (verbal abilities, spatial/fluid, memory, perceptual speed) were identified by principal-component analysis. Prediabetes was defined according to blood glucose levels in diabetes free participants. Diabetes was ascertained based on self-report, hypoglycemic medication use and blood glucose levels. Data were analyzed with linear mixed effect models adjusting for potential confounders. Results: At baseline, 68 participants (8.6%) had prediabetes and 45 (5.7%) had diabetes. Compared to diabetes-free individuals, people with diabetes had a steeper decline over time in perceptual speed and verbal abilities. The annual declines in these domains were greater than the annual decline in memory. Prediabetes was associated with lower performance in memory in middle-age, but also associated with a less steep memory decline over the follow-up. Conclusions: Diabetes is associated with a faster decline in perceptual speed and verbal abilities, while prediabetes is associated with lower memory performance in middle-age. However, the detrimental effects of hyperglycemia seem to not affect memory over time. PMID- 28633304 TI - Molecular aspects of the biophysical CO2-concentrating mechanism and its regulation in marine diatoms. AB - Diatoms operate a CO2-concentrating mechanism (CCM) that drives upwards of 20% of annual global primary production. Recent progress in CCM research in the marine pennate diatom Phaeodactylum tricornutum revealed that this diatom directly takes up HCO3- from seawater through low-CO2-inducible plasma membrane HCO3- transporters, which belong to the solute carrier (SLC) 4 family. Apart from this, studies of carbonic anhydrases (CAs) in diatoms have revealed considerable diversity in classes and localization among species. This strongly suggests that the CA systems, which control permeability and flux of dissolved inorganic carbon (DIC) by catalysing reversible CO2 hydration, have evolved from diverse origins. Of particular interest is the occurrence of low-CO2-inducible external CAs in the centric marine diatom Thalassiosira pseudonana, offering a strategy of CA catalysed initial CO2 entry via passive diffusion, contrasting with active DIC transport in P. tricornutum. Molecular mechanisms to transport DIC across chloroplast envelopes are likely also through specific HCO3- transporters, although details have yet to be elucidated. Furthermore, recent discovery of a luminal theta-CA in the diatom thylakoid implied a common strategy in the mechanism to supply CO2 to RubisCO in the pyrenoid, which is conserved among green algae and some heterokontophytes. These results strongly suggest an occurrence of convergent coevolution between the pyrenoid and thylakoid membrane in aquatic photosynthesis. PMID- 28633305 TI - Circulating microRNAs as potential biomarkers for the identification of vascular dementia due to cerebral small vessel disease. AB - Background: the diagnosis of cerebral small vessel disease, a leading cause of vascular dementia (VaD), relies solely on neuroimaging studies. Circulating microRNAs (miRNAs) have been proposed as diagnostic biomarkers in various disorders. Our aim was to identify differentially expressed, circulating miRNAs in small vessel VaD which could serve as diagnostic biomarkers for this disease. Method: we performed plasma miRNA profiling by quantitative polymerase chain reaction (qPCR) array in small vessel VaD patients and age- and gender-matched, cognitively normal and healthy controls. Selected, differentially expressed miRNAs were validated by qPCR. Sensitivity, specificity and area under the curve (AUC) were calculated for each individual miRNA. Results: profiling results showed that 44 miRNAs were differentially expressed in small vessel VaD cases (P < 0.05 with a fold change of <2 or >2). A set of seven, highly differentially expressed miRNAs (fold change of <3.6 or >3.6), were estimated in a cohort of 204 small vessel VaD patients and 200 healthy, age and gender-matched controls. Validation study revealed that four miRNAs (miR-409-3p, miR-502-3p, miR-486-5p and miR-451a) could be used as valuable biomarkers for identifying the disease. Sensitivity, specificity and AUC for these miRNAs were 76, 75, 75 and 70%; 89, 89, 83 and 75% and 0.94, 0.92, 0.90 and 0.86, respectively. However, combined receiver operating characteristic curve analysis of seven miRNAs revealed an AUC of 0.64 with sensitivity of 55.5% and specificity of 65.7%. Conclusion: plasma miR-409-3p, miR-502-3p, miR-486-5p and miR-451a could be used to differentiate small vessel VaD patients from healthy controls. Large-scale studies of their biomarker potential are warranted. PMID- 28633306 TI - Multivariate Phylogenetic Comparative Methods: Evaluations, Comparisons, and Recommendations. AB - Recent years have seen increased interest in phylogenetic comparative analyses of multivariate data sets, but to date the varied proposed approaches have not been extensively examined. Here we review the mathematical properties required of any multivariate method, and specifically evaluate existing multivariate phylogenetic comparative methods in this context. Phylogenetic comparative methods based on the full multivariate likelihood are robust to levels of covariation among trait dimensions and are insensitive to the orientation of the data set, but display increasing model misspecification as the number of trait dimensions increases. This is because the expected evolutionary covariance matrix (V) used in the likelihood calculations becomes more ill-conditioned as trait dimensionality increases, and as evolutionary models become more complex. Thus, these approaches are only appropriate for data sets with few traits and many species. Methods that summarize patterns across trait dimensions treated separately (e.g., SURFACE) incorrectly assume independence among trait dimensions, resulting in nearly a 100% model misspecification rate. Methods using pairwise composite likelihood are highly sensitive to levels of trait covariation, the orientation of the data set, and the number of trait dimensions. The consequences of these debilitating deficiencies are that a user can arrive at differing statistical conclusions, and therefore biological inferences, simply from a dataspace rotation, like principal component analysis. By contrast, algebraic generalizations of the standard phylogenetic comparative toolkit that use the trace of covariance matrices are insensitive to levels of trait covariation, the number of trait dimensions, and the orientation of the data set. Further, when appropriate permutation tests are used, these approaches display acceptable Type I error and statistical power. We conclude that methods summarizing information across trait dimensions, as well as pairwise composite likelihood methods should be avoided, whereas algebraic generalizations of the phylogenetic comparative toolkit provide a useful means of assessing macroevolutionary patterns in multivariate data. Finally, we discuss areas in which multivariate phylogenetic comparative methods are still in need of future development; namely highly multivariate Ornstein-Uhlenbeck models and approaches for multivariate evolutionary model comparisons. PMID- 28633307 TI - Discussion: The role, position, and function of the FDA-The past, present, and future. PMID- 28633308 TI - Prior-Season Vaccination and Risk of Influenza During the 2014-2015 Season in the United States. PMID- 28633310 TI - Macromolecular creatine kinase type 1 in immune-mediated necrotizing myopathy. PMID- 28633313 TI - Discussion: New directions for the FDA in the 21st century. PMID- 28633311 TI - Cofactor specificity switch in Shikimate dehydrogenase by rational design and consensus engineering. AB - Consensus engineering has been used to design more stable variants using the most frequent amino acid at each site of a multiple sequence alignment; sometimes consensus engineering modifies function, but efforts have mainly been focused on studying stability. Here we constructed a consensus Rossmann domain for the Shikimate dehydrogenase enzyme; separately we decided to switch the cofactor specificity through rational design in the Escherichia coli Shikimate dehydrogenase enzyme and then analyzed the effect of consensus mutations on top of our design. We found that consensus mutations closest to the 2' adenine moiety increased the activity in our design. Consensus engineering has been shown to result in more stable proteins and our findings suggest it could also be used as a complementary tool for increasing or modifying enzyme activity during design. PMID- 28633312 TI - The influence of Dekkera bruxellensis on the transcriptome of Saccharomyces cerevisiae and on the aromatic profile of synthetic wine must. AB - A double compartment membrane system was constructed in order to systematically study possible microbial interactions between yeasts Saccharomyces cerevisiae and Dekkera bruxellensis and their impact on wine aroma. The presence of D. bruxellensis induced 77 transcripts of S. cerevisiae. These were mostly of unknown function; however, some were involved in thiamine biosynthesis and in amino acid and polyamine transport, suggesting a competitive relationship between the two yeast species. Among the transcripts with no biological function, 14 of them were found to be the members of the PAU gene family that is associated with response to anaerobiosis stress. In separated cultures, S. cerevisiae produced glycerol which was subsequently consumed by D. bruxellensis. The concentration of ethylphenols was reduced and we assume that they were absorbed onto the surfaces of S. cerevisiae yeast walls. Also in separated cultures, D. bruxellensis formed a typical profile of aromatic esters with decreased levels of acetate esters and increased level of ethyl esters. PMID- 28633309 TI - TMPRSS2:ERG Gene Fusions in Prostate Cancer of West African Men and a Meta Analysis of Racial Differences. AB - The prevalence of fusions of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2:ERG, in prostate cancer varies by race. However, such somatic aberration and its association with prognostic factors have neither been studied in a West African population nor been systematically reviewed in the context of racial differences. We used immunohistochemistry to assess oncoprotein encoded by the ERG gene as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study (2004-2006). Poisson regression with robust variance estimation provided prevalence ratios and 95% confidence intervals of ERG expression in relation to patient characteristics. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Meta analysis showed the prevalence of TMPRSS2:ERG fusions in prostate cancer to be highest in men of European descent (49%), followed by men of Asian (27%) and then African (25%) descent. The lower prevalence of TMPRSS2:ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations. PMID- 28633315 TI - Estimating Demand and Cross-Price Elasticity for Very Low Nicotine Content (VLNC) Cigarettes Using a Simulated Demand Task. PMID- 28633316 TI - Discussion: Is the FDA in need of a major change in the way it regulates? PMID- 28633314 TI - Qualitative Identification of Fentanyl Analogs and Other Opioids in Postmortem Cases by UHPLC-Ion Trap-MSn. AB - Since 2013, the Miami-Dade County Medical Examiner Department has experienced an increase in the number of opioid-related deaths. The majority of cases coincided with the introduction of fentanyl into the local heroin supply. From 2014 to 2015, Miami-Dade County experienced a near 600% increase in fentanyl-related deaths, followed by an additional 200% increase in 2016. In 2015, two novel fentanyl analogs were identified in medical examiner cases: beta hydroxythiofentanyl and acetyl fentanyl. In 2016, four additional fentanyl analogs emerged: para-fluoroisobutyryl fentanyl, butyryl fentanyl, furanyl fentanyl and carfentanil, as well as the synthetic opioid U-47700. In order to address this epidemic, a method was developed and validated to identify 44 opioid related and analgesic compounds in postmortem samples using ultra high performance liquid chromatography ion trap mass spectrometry with MSn capabilities. The limit of detection for all compounds ranged from 0.1 to 5 ng/mL, with a majority having MS3 spectral fragmentation. Blood, urine, liver or brain specimens from ~500 postmortem cases were submitted for analysis based on case history and/or initial screening results. Of those cases, 375 were positive for illicit fentanyl and/or one or more fentanyl analogs. Due to the potency of these compounds, they were almost always included in the cause of death. Worth emphasizing and extremely alarming is the detection of carfentanil in 134 cases, 104 of which were initially missed by gas chromatography mass spectrometry. By incorporating this sensitive, highly specific, and evolving screening procedure into the workflow, the toxicology laboratory continues to effectively assist the medical examiners in determining the cause and manner of death of decedents in Miami-Dade County. PMID- 28633317 TI - Discussion: The FDA is Unprepared for Personalized Medicine. PMID- 28633318 TI - Evaluation of Oral Fluid as a Specimen for DUID. AB - Drugged driving has become more prevalent than drunk driving and is quickly gaining national attention due to increased prescription drug abuse and recent cannabis legalization. Unlike alcohol, police officers do not generally have access to approved devices to screen for drugs at the roadside. Onsite drug screening devices do exist and are used in other countries, but have not garnered widespread approval for use in the United States in driving under the influence of drugs (DUID) cases. One reason for this is that the devices are designed to test oral fluid, which is not a commonly accepted specimen for DUID. A study was conducted to test the effectiveness of using oral fluid during routine traffic stops in DUID cases in conjunction with drug recognition expert (DRE) officers from the Tulsa Police Department (TPD). Samples were screened at the roadside using an Alere DDS(r)2 Mobile Test System and QuantisalTM collection devices were used for laboratory based screening by enzyme-linked immunosorbent assay and confirmation by liquid chromatography-tandem mass spectrometry. The results of the DRE observations, alternate specimens like blood and urine, onsite oral fluid screening and laboratory based oral fluid screening and confirmations were used to assess the usefulness of oral fluid as a DUID specimen. Due to the small sample size (N = 9), no significant differences in the measured performance of onsite and laboratory based tests was seen. The results of this study indicate that oral fluid testing is a viable option both at the roadside and in a laboratory setting. PMID- 28633320 TI - Discussion: Is FDA in need of a major change in the way it regulates? PMID- 28633319 TI - Immunotherapy Targeting Adenosine Synthase A Decreases Severity of Staphylococcus aureus Infection in Mouse Model. AB - Staphylococcusaureus is a severe pathogen found in the community and in hospitals. Most notably, methicillin-resistant S. aureus (MRSA) is resistant to almost all antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments such as immunotherapeutic approaches. Previous research showed that S. aureus exploit the immunomodulatory attributes of adenosine to escape host immunity. In this study, we investigated adenosine synthase A (AdsA), an S. aureus cell wall anchored enzyme as possible targets for immunotherapy. Mice vaccinated with aluminum hydroxide-formulated recombinant AdsA (rAdsA) induced high-titer anti AdsA antibodies, thereby providing consistent protection in 3 mouse infection models when challenged with 2 S. aureus strains. The importance of anti-AdsA antibody in protection was demonstrated by passive transfer experiments. Moreover, AdsA-specific antisera promote killing S. aureus by immune cells. Altogether, our data demonstrate that the AdsA is a promising target for vaccines and therapeutics development to alleviate severe S. aureus diseases. PMID- 28633321 TI - Places in the Brain: Bridging Layout and Object Geometry in Scene-Selective Cortex. AB - Diverse animal species primarily rely on sense (left-right) and egocentric distance (proximal-distal) when navigating the environment. Recent neuroimaging studies with human adults show that this information is represented in 2 scene selective cortical regions-the occipital place area (OPA) and retrosplenial complex (RSC)-but not in a third scene-selective region-the parahippocampal place area (PPA). What geometric properties, then, does the PPA represent, and what is its role in scene processing? Here we hypothesize that the PPA represents relative length and angle, the geometric properties classically associated with object recognition, but only in the context of large extended surfaces that compose the layout of a scene. Using functional magnetic resonance imaging adaptation, we found that the PPA is indeed sensitive to relative length and angle changes in pictures of scenes, but not pictures of objects that reliably elicited responses to the same geometric changes in object-selective cortical regions. Moreover, we found that the OPA is also sensitive to such changes, while the RSC is tolerant to such changes. Thus, the geometric information typically associated with object recognition is also used during some aspects of scene processing. These findings provide evidence that scene-selective cortex differentially represents the geometric properties guiding navigation versus scene categorization. PMID- 28633322 TI - The Detrimental Consequences of Overestimating Future Health in Late Life. AB - Objectives: Although forecasting a positive future can be adaptive, it may not be when expectations are unmet. Our study examined whether such inaccurate expectations about future health status (overestimation) were maladaptive for older adults who commonly experience late life declines in physical functioning. Method: We analyzed data from the nationally representative German Aging Survey (DEAS; 1996-2011; n = 2,539; age range 60-85 years) using multilevel growth models that assessed the influence of inaccurate health expectations on older adults' physical functioning over a 9-year period. Results: Overestimating future health status predicted reduced day-to-day physical functioning when age, gender, and self-rated health were controlled. A Time * Overestimation interaction indicated that the negative effects of overestimation on physical functioning became more pronounced over the 9-year period. Discussion: Results suggest that repeatedly unmet health expectations may undermine motivational resources and accelerate late life declines in physical functioning. PMID- 28633323 TI - E-Cigarette Susceptibility as a Predictor of Youth Initiation of E-Cigarettes. PMID- 28633324 TI - Mammographic Density Reduction as a Prognostic Marker for Postmenopausal Breast Cancer: Results Using a Joint Longitudinal-Survival Modeling Approach. AB - Previous studies have linked reductions in mammographic density after a breast cancer diagnosis to an improved prognosis. These studies focused on short-term change, using a 2-stage process, treating estimated change as a fixed covariate in a survival model. We propose the use of a joint longitudinal-survival model. This enables us to model long-term trends in density while accounting for dropout as well as for measurement error. We studied the change in mammographic density after a breast cancer diagnosis and its association with prognosis (measured by cause-specific mortality), overall and with respect to hormone replacement therapy and tamoxifen treatment. We included 1,740 women aged 50-74 years, diagnosed with breast cancer in Sweden during 1993-1995, with follow-up until 2008. They had a total of 6,317 mammographic density measures available from the first 5 years of follow-up, including baseline measures. We found that the impact of the withdrawal of hormone replacement therapy on density reduction was larger than that of tamoxifen treatment. Unlike previous studies, we found that there was an association between density reduction and survival, both for tamoxifen treated women and women who were not treated with tamoxifen. PMID- 28633325 TI - Malus hupehensis miR168 Targets to ARGONAUTE1 and Contributes to the Resistance against Botryosphaeria dothidea Infection by Altering Defense Responses. AB - MicroRNA (miRNA)-mediated post-transcriptional regulation plays a fundamental role in various plant physiological processes, including responses to pathogens. MicroRNA168 has been implicated as an essential factor of miRNA pathways by targeting ARGONAUTE1 (AGO1), the core component of the RNA-induced silencing complex (RISC). A fluctuation in AGO1 expression influences various plant pathogen interactions, and the homeostasis of AGO1 and miR168 accumulation is maintained by a complicated feedback regulatory loop. In this study, the connection between miR168 and the resistance of Malus hupehensis to Botryosphaeria dothidea is revealed. The induction of both the mature miR168 and its precursor in plants subjected to B. dothidea infection indicate the transcriptional activation of MIR168a. MIR168a promoter analysis demonstrates that the promoter can be activated by B. dothidea and salicylic acid (SA). However, the direct target of miR168, M. hupehensis ARGONAUTE1 (MhAGO1), is shown to be induced under the infection. Expression and transcription activity analysis demonstrate the transcriptional activation and the post-transcriptional suppression of MhAGO1 in response to B. dothidea infection. By inhibiting reactive oxygen species (ROS) production and enhancing SA-mediated defense responses, miR168a delays the symptom development of leaves inoculated with B. dothidea and impedes the pathogen growth, while MhAGO1 is found to have the opposite effects. Collectively, these findings suggest that the expression of miR168 and MhAGO1 in M. hupehensis in response to B. dothidea infection is regulated by a complicated mechanism. Targeting to MhAGO1, a negative regulator, miR168 plays a positive role in the resistance by alterations in diverse defense responses. PMID- 28633326 TI - The Association between Subjective Memory Complaints and Sleep within Older African American Adults. AB - Objective: The purpose of the current study is to examine the association between subjective memory complaints and sleep (quantity and quality) in African American older adults. Method: Participants from the Baltimore Study of Black Aging (BSBA; n = 351; mean age = 71.99) completed a self-report sleep scale, subjective memory complaint scale, global cognitive status measure, and demographic questionnaire. Results: Worse overall sleep quality was significantly associated with subjective reports of difficulty recalling the placement of objects, recalling specific facts from reading materials, and worse memory currently compared to the past. Specific sleep parameters (e.g., longer sleep latency and shorter sleep duration) were associated with negative appraisals of participants' ability to do specific tasks involving memory (e.g., difficulty recalling placement of objects). Participants classified as poor sleepers (Pittsburgh Sleep Quality Index [PSQI] total score > 5) were more likely to report worse memory now compared to the past than participants classified as good sleepers (PSQI total score <= 5). Conclusions: Evaluation of sleep may be warranted when older adults, particularly African Americans, communicate concerns regarding their memory. Insufficient sleep may be a useful marker of acute daytime dysfunction and, perhaps, cognitive decline. Given memory problems are the hallmark of dementia, our findings support further evaluation of whether poor sleep can aid in the diagnosis of cognitive impairment. PMID- 28633327 TI - A prognosis-based approach to infertility: understanding the role of time. AB - The current definition of infertility acknowledges the importance of duration of pregnancy seeking but fails to recognize the prevalent negative impact of female age. In fact, the diagnosis of unexplained infertility increases with women's age because of our incapacity to discern between age-related infertility and real unexplained infertility. Physicians' response to the pressures of increased female age has been to take prompt refuge in assisted reproduction despite the lack of robust evidence and the inherent risks and costs of these procedures. Moreover, the prioritization of immediate health gains over those in the future, preference for accessing active treatment rapidly and reluctance to wait for spontaneous pregnancy expose patients to additional risks of overtreatment. Solutions are not simple to find but an alternative and innovative vision of infertility based on prognosis may be a valid solution. The availability of validated dynamic models based on real-life data that could predict both natural and ART-mediated conceptions may be of benefit. They could facilitate patients' counselling and could optimize the chances of success without exposing patients to unnecessary, expensive and demanding treatments. PMID- 28633329 TI - Mid-Term Blood Pressure Variability Is Associated With Clinical Outcome After Ischemic Stroke. AB - BACKGROUND: The aim of this study was to investigate the relation between mid term blood pressure (BP) variability (BPV) within 7 days of onset and the prognosis in acute stroke patients. METHODS: Total 873 acute ischemic stroke patients were included in this study. Mid-term BPV was evaluated through the calculations of coefficient of variation (CV) of the systolic BP (SBP) and diastolic BP (DBP) within 7 days of onset. Clinical outcomes were assessed using the recovery situations of neurological function at 3 months, the primary outcome (symptomatic recurrent stroke) and the secondary outcomes (recurrent stroke, all cause mortality, and the composite of cardiovascular events) within 12 months. RESULTS: Among 873 patients with ischemic stroke, 83 died, 125 developed recurrent stroke, and 212 developed cardiovascular events during 12 months' follow-up. At 3 months, systolic or diastolic BPV (within 7 days of onset) was associated with the recovery situations of neurological function in three models (all P < 0.05). Both higher CV of SBP and CV of DBP were significantly correlated with the increased risk of recurrent stroke (hazard ratio [HR] = 2.32, 95% confidence interval [CI]: 1.29-4.18, P = 0.005 for CV of SBP; HR = 2.33, 95% CI: 1.29-4.19, P = 0.005 for CV of DBP) and composite cardiovascular events (HR = 2.22, 95% CI: 1.41-3.48, P = 0.001 for CV of SBP; HR = 2.21, 95% CI: 1.41-3.47, P = 0.001 for CV of DBP) during 12 months' follow-up. CONCLUSIONS: After acute ischemic stroke, high systolic or diastolic BPV within 7 days of onset was associated with the recovery situations of neurological function at 3 months, and recurrent stroke and composite cardiovascular events within 12 months. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org.cn. Unique identifier: ChiCTR-TRC 14004804. PMID- 28633328 TI - Identification and characterization of a solute carrier, CIA8, involved in inorganic carbon acclimation in Chlamydomonas reinhardtii. AB - The supply of inorganic carbon (Ci) at the site of fixation by Rubisco is a key parameter for efficient CO2 fixation in aquatic organisms including the green alga, Chlamydomonas reinhardtii. Chlamydomonas reinhardtii cells, when grown on limiting CO2, have a CO2-concentrating mechanism (CCM) that functions to concentrate CO2 at the site of Rubisco. Proteins thought to be involved in inorganic carbon uptake have been identified and localized to the plasma membrane or chloroplast envelope. However, current CCM models suggest that additional molecular components are involved in Ci uptake. In this study, the gene Cia8 was identified in an insertional mutagenesis screen and characterized. The protein encoded by Cia8 belongs to the sodium bile acid symporter subfamily. Transcript levels for this gene were significantly up-regulated when the cells were grown on low CO2. The cia8 mutant exhibited reduced growth and reduced affinity for Ci when grown in limiting CO2 conditions. Prediction programs localize this protein to the chloroplast. Ci uptake and the photosynthetic rate, particularly at high external pH, were reduced in the mutant. The results are consistent with the model that CIA8 is involved in Ci uptake in C. reinhardtii. PMID- 28633330 TI - The asparagine-rich protein NRP interacts with the Verticillium effector PevD1 and regulates the subcellular localization of cryptochrome 2. AB - The soil-borne fungal pathogen Verticillium dahliae infects a wide range of dicotyledonous plants including cotton, tobacco, and Arabidopsis. Among the effector proteins secreted by V. dahliae, the 16 kDa PevD1 induces a hypersensitive response in tobacco. Here we report the high-resolution structure of PevD1 with folds resembling a C2 domain-like structure with a calcium ion bound to the C-terminal acidic pocket. A yeast two-hybrid screen, designed to probe for molecular functions of PevD1, identified Arabidopsis asparagine-rich protein (NRP) as the interacting partner of PevD1. Extending the pathway of V. dahliae effects, which include induction of early flowering in cotton and Arabidopsis, NRP was found to interact with cryptochrome 2 (CRY2), leading to increased cytoplasmic accumulation of CRY2 in a blue light-independent manner. Further physiological and genetic evidence suggests that PevD1 indirectly activates CRY2 by antagonizing NRP functions. The promotion of CRY2-mediated flowering by a fungal effector outlines a novel pathway by which an external stimulus is recognized and transferred in changing a developmental program. PMID- 28633331 TI - Does timing of antiretroviral treatment influence treatment outcomes of visceral leishmaniasis in Northwest Ethiopia? AB - Background: Visceral leishmaniasis (VL) patients with HIV co-infection should receive antiretroviral treatment (ART). However, the best timing for initiation of ART is not known. Among such individuals, we assessed the influence of ART timing on VL outcomes. Methods: A retrospective cohort study was conducted in Northwest Ethiopia among VL patients starting ART between 2008 and 2015. VL outcomes were assessed by the twelfth month of starting ART, within 4 weeks of VL diagnosis or thereafter. Results: Of 213 VL-HIV co-infected patients with ART initiation, 96 (45.1%) had moderate to severe malnutrition, 53 (24.9%) had active TB and 128 (60.1%) had hemoglobin levels under 9 g/dL. Eighty-nine (41.8%) were already on ART before VL diagnosis, 46 (21.6%) started ART within 4 weeks, and 78 (36.6%) thereafter. Definitive cure in those starting ART within 4 weeks 59% (95% CI 43-75%) and those starting thereafter 56% (95% CI 44-68%) was not significantly different. Those starting ART before primary VL had higher 12 months mortality compared to those starting later (RR 0.6; 95% CI 0.4-0.9; p=0.012). Conclusions: VL-HIV patients are severely ill and with serious additional comorbidities. Outcomes of HIV-VL management are unsatisfactory and early ART initiation was associated with higher mortality. Further research on the optimal timing of ART initiation, and ensuring earlier diagnosis of VL patients, with improved management of comorbidities are needed. PMID- 28633332 TI - Anti-Fas2 IgM antibodies in Fasciola hepatica infected patients with positive IgG serology. AB - Background: Fascioliasis is an infectious disease caused by parasites Fasciola hepatica and F. gigantica. Humans are infected by the consumption of vegetables and water contaminated with the infective form of the parasite. Materials and Methods: In this study, an IgM-ELISA with the cysteine proteinase Fas2 antigen was evaluated with sera from 76 patients infected with F. hepatica, 24 patients with other parasite infections and 84 healthy volunteers. Results: IgM-ELISA resulted in 43% positives in F. hepatica patients with positive serology to Fas2 ELISA, but no positives resulted from testing healthy volunteers and individuals infected with other parasites. The IgM-ELISA diagnostic parameters showed a sensitivity of 43.4% (95% CI 0.321-0.553), specificity of 100% (95% CI 0.957-1), and no cross-reactivity with other parasitic infection. Interference by rheumatoid factor in the IgM immunoassay was controlled by treating sera with rheumatoid factor absorbent before testing. Conclusions: Fas2 antigen is detected by circulating IgM in patients infected with F. hepatica and IgM-ELISA using Fas2 appears as a specific immunoassay to detect the acute phase of the acute phase of F. hepatica infection in humans. PMID- 28633333 TI - Anti-natural octyl disaccharide-leprosy IDRI diagnostic (NDO-LID) antibodies as indicators of leprosy reactions and neuritis. AB - Background: Leprosy is a complex infectious and neurological disease caused by Mycobacterium leprae. Nerve damage is related to immunological hypersensitivity responses known as leprosy reactions (LRs). Diagnostic tools to predict LRs are not available. We hypothesized that natural octyl disaccharide-leprosy IDRI diagnostic (NDO-LID) would be helpful as an indicator of LRs and neuritis. Methods: To assess the utility of NDO-LID in indicating reactions, ELISA were used to detect specific antibodies in serum samples from 80 Colombian leprosy patients (40 with and 40 without history of LRs). Responses were detected using a range of detection reagents detecting IgG, IgM or both isotypes. Results: Patients with a history of LRs had an increased seropositivity rate for anti-NDO LID antibodies compared to patients without (anti-NDO-LID protein A [p=0.02], IgG anti-NDO-LID [p=0.01] and IgM anti-NDO-LID [p=0.01]). Further analyses of patients with a history of LRs indicated that both seropositivity rate and magnitude of responses were elevated among patients with neuritis versus those without neuritis (anti-NDO-LID protein A [p=0.03], IgG anti-NDO-LID [p=0.001] and IgM anti-NDO-LID [p=0.06]). Conclusions: Our data indicate that testing for serum anti-NDO-LID antibodies can be a useful screen to identify patients at risk of developing LRs and neuritis. PMID- 28633334 TI - Knowledge, attitude and practice of Gambian health practitioners towards antibiotic prescribing and microbiological testing: a cross-sectional survey. AB - Background: Inappropriate antibiotic use is the leading cause of antibiotic resistance worldwide. At the same time, the practice of antibiotic prescribing in Africa is less well documented when compared to developed countries. The objective of the study was to assess the knowledge, attitude, and practice (KAP) of health practitioners towards antibiotic prescribing and microbiological testing in The Gambia. Methods: A KAP survey was conducted in The Gambia from March to May 2016. Self-administered paper-based questionnaires were distributed to health practitioners working in 12 health facilities. Results: Out of 241 questionnaires distributed, 216 (89.6%) were returned. One third of respondents reported making a request for microbiological tests or using results as a guide in less than 25% of patients with possible infectious disease. Thirty-two percent of the participants reported that '25-50%' of antibiotic prescriptions in their departments were inappropriate. Only 16.1% of the participants had some training on antibiotic prescribing in the last 12 months. Respondents agreed with the options 'inadequate supervision' (82.6%) and 'insufficient laboratory support' (82.5%) as the main causes of inappropriate antibiotic use in their settings. Conclusions: There are deficits related to antibiotic prescriptions in The Gambia. Availability and use of microbiological services and training should be emphasized. PMID- 28633335 TI - Pulmonary TB: varying radiological presentations in individuals with HIV in Soweto, South Africa. AB - Background: HIV-uninfected individuals with pulmonary TB (PTB) commonly present with radiological features of upper lobe cavitatory disease. In contrast, individuals with HIV and PTB may present differently. This study compared radiological features of individuals with laboratory-confirmed PTB by HIV status from the largest study in South Africa. Methods: We conducted a cross-sectional analysis of adults recruited between 2012 and 2015 with laboratory-confirmed PTB in Soweto, South Africa. Baseline characteristics and chest radiograph (CXR) findings were compared by chi2 test stratified by HIV status. Results: Of the 474 individuals with PTB, 348 (73.4%) had HIV. Individuals with HIV had a higher proportion of infiltrates (58.9% vs 46.8%, p=0.02) and a lower proportion of cavitations (40.8% vs 68.3%; p<0.0001) compared to HIV-uninfected individuals. Additionally, individuals with HIV had a lower proportion of cavitations sized >=4 cm (16.7% vs 36.5%, p<0.001) and a lower proportion of disease extent involving half or more of the total lung area radiologically (25.9% vs 45.3%, p<0.0001). Conclusions: Individuals with HIV co-infected with PTB have a higher proportion of infiltrates and a lower proportion of cavitations relative to the HIV-uninfected PTB individuals. The absence of classical upper lobe cavitatory disease on CXR does not exclude PTB in individuals with HIV. PMID- 28633336 TI - A278C mutation of dihydropteridine reductase decreases autophagy via mTOR signaling. AB - Dihydropteridine reductase (QDPR) plays an important role in the recycling of BH4 and is closely related to oxidative stress. We have previously reported that the overexpression of QDPR in human kidney HEK293T cells significantly protected against oxidative stress, and these beneficial effects were abolished by A278C mutation. To evaluate the effect of wild-type and mutant QDPR on autophagy and its mechanism in HEK293T cells, we constructed the wild-type and mutant QDPR expression plasmids and transfected them into HEK293T cells. Three days later, cells were collected to observe the expression of fusion protein and the intracellular production of reactive oxygen species (ROS). Western blot analysis was employed to evaluate the change of mTOR and ribosomal protein S6 kinase B1 (S6K1) signaling and the expression of LC-I, LC-II, Bcl-1, Bcl-2, p62, and p53. The results showed that the exogenous wild-type QDPR significantly decreased the expression of mTOR and phosphorylation of the mTOR and S6K1. Mutation of QDPR inhibited the regulation of mTOR, suggesting that QDPR is a positive regulator of autophagy via suppressing mTOR signaling. The expressions of p62, LC3-II and Beclin 1 were dramatically enhanced in wild-type QDPR group, which were reversed after QDPR mutation. Additionally, mutation of QDPR altered the upregulation of QDPR on Beclin 2. It is therefore concluded that QDPR appears to play an important role in enhancing autophagy, and its mutation contributes to dysregulation of autophagy. PMID- 28633337 TI - Differences in below-ground bud bank density and composition along a climatic gradient in the temperate steppe of northern China. AB - Background and Aims: Understanding the changes in below-ground bud bank density and composition along a climatic gradient is essential for the exploration of species distribution pattern and vegetation composition in response to climatic changes. Nevertheless, investigations on bud banks along climatic gradients are still scarce. The below-ground bud bank is expected to be reduced in size in arid conditions, and costly, bud-bearing organs with long spacers would be replaced by more compact forms with buds that are better protected than those found in moist conditions. Methods: How total bud density and composition (different bud bank types) change with aridity (calculated value 0.43-0.91), mean annual precipitation (MAP; 93-420 mm) and mean annual temperature (MAT; -1.51 to 6.93 degrees C) was tested at 21 sites along a 2500-km climatic gradient in the temperate steppe of northern China. Conclusions: Belowground bud bank density decreases towards the dry, hot end of the climatic gradient. Based on the distribution of bud types along the climatic gradient, bulb buds and tiller buds of tussock grasses seem to be more resistant to environmental stress than rhizome buds. The dominance of annual species and smaller bud banks in arid region implies that plant reproductive strategies and vegetation composition will be shifted in scenarios of increased drought under future climate change. PMID- 28633338 TI - Corrigendum. PMID- 28633339 TI - Will electronic health record data become the standard resource for clinical research? PMID- 28633340 TI - Citrus CitNAC62 cooperates with CitWRKY1 to participate in citric acid degradation via up-regulation of CitAco3. AB - Citric acid is the predominant organic acid of citrus fruit. Degradation of citric acid occurs during fruit development, influencing fruit acidity. Associations of CitAco3 transcripts and citric acid degradation have been reported for citrus fruit. Here, transient overexpression of CitAco3 significantly reduced the citric acid content of citrus leaves and fruits. Using dual luciferase assays, it was shown that CitNAC62 and CitWRKY1 could transactivate the promoter of CitAco3. Subcellular localization results showed that CitWRKY1 was located in the nucleus and CitNAC62 was not. Yeast two-hybrid analysis and bimolecular fluorescence complementation (BiFC) assays indicated that the two differently located transcription factors could interact with each other. Furthermore, BiFC showed that the protein-protein interaction occurred only in the nucleus, indicating the potential mobility of CitNAC62 in plant cells. A synergistic effect on citrate content was observed between CitNAC62 and CitWRKY1. Transient overexpression of CitNAC62 or CitWRKY1 led to significantly lower citrate content in citrus fruit. The combined expression of CitNAC62 and CitWRKY1 resulted in lower citrate content compared with the expression of CitNAC62 or CitWRKY1 alone. The transcript abundance of CitAco3 was consistent with the citrate content. Thus, we propose that a complex of CitWRKY1 and CitNAC62 contributes to citric acid degradation in citrus fruit, potentially via modulation of CitAco3. PMID- 28633341 TI - SWALLOWING COMPUTED TOMOGRAPHY: DOSE ESTIMATION IN A PHANTOM STUDY CONDUCTED AT VARIOUS PATIENT RECLINING ANGLES. AB - Swallowing computed tomography (SCT) is a relatively new technique for the morphological and kinematic analyses of swallowing. However, no optimal scan protocols are available till date. We conducted the present SCT study to estimate the patient dose at various patient reclining positions. A RANDO phantom with a thermoluminescent dosemeter was placed on a hard Table board in a semi-reclining position at the centre and off-centre. According to predetermined scan protocols, irradiation was performed to acquire scanograms at reclining angles of 55 degrees and 65 degrees . The effective dose was the lowest at the centre 45 degrees (3.8 mSv) reclining angle. Comparison between the off-centre (4.6 mSv at 55 degrees , 6.8 mSv at 65 degrees ) and centre (4.5 mSv, 5.8 mSv) values suggested that the off-centre position is undesirable with regard to the patient dose. Accordingly, we believe that SCT methods must be revised on the basis of these factors. PMID- 28633343 TI - An unknown reaction to pembrolizumab: giant cell arteritis. PMID- 28633342 TI - Associations of Biomarker-Calibrated Sodium and Potassium Intakes With Cardiovascular Disease Risk Among Postmenopausal Women. AB - Studies of the associations of sodium and potassium intakes with cardiovascular disease incidence often rely on self-reported dietary data. In the present study, self-reported intakes from postmenopausal women at 40 participating US clinical centers are calibrated using 24-hour urinary excretion measures in cohorts from the Women's Health Initiative, with follow-up from 1993 to 2010. The incidence of hypertension was positively related to (calibrated) sodium intake and to the ratio of sodium to potassium. The sodium-to-potassium ratio was associated with cardiovascular disease incidence during an average follow-up period of 12 years. The estimated hazard ratio for a 20% increase in the sodium-to-potassium ratio was 1.13 (95% confidence interval (CI): 1.04, 1.22) for coronary heart disease, 1.20 (95% CI: 1.01, 1.42) for heart failure, and 1.11 (95% CI: 1.04, 1.19) for a composite cardiovascular disease outcome. The association with total stroke was not significant, but it was positive for ischemic stroke and inverse for hemorrhagic stroke. Aside from hemorrhagic stroke, corresponding associations of cardiovascular disease with sodium and potassium jointly were positive for sodium and inverse for potassium, although some were not statistically significant. Specifically, for coronary heart disease, the hazard ratios for 20% increases were 1.11 (95% CI: 0.95, 1.30) for sodium and 0.85 (95% CI: 0.73, 0.99) for potassium; and corresponding values for heart failure were 1.36 (95% CI: 1.02, 1.82) for sodium and 0.90 (95% CI: 0.69, 1.18) for potassium. PMID- 28633344 TI - Pheno4J: a gene to phenotype graph database. AB - Summary: Efficient storage and querying of large amounts of genetic and phenotypic data is crucial to contemporary clinical genetic research. This introduces computational challenges for classical relational databases, due to the sparsity and sheer volume of the data. Our Java based solution loads annotated genetic variants and well phenotyped patients into a graph database to allow fast efficient storage and querying of large volumes of structured genetic and phenotypic data. This abstracts technical problems away and lets researchers focus on the science rather than the implementation. We have also developed an accompanying webserver with end-points to facilitate querying of the database. Availability and implementation: The Java and Python code are available at https://github.com/phenopolis/pheno4j. Contact: n.pontikos@ucl.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633345 TI - Reply to Marx et al. PMID- 28633346 TI - Tetramethylpyrazine reverses intracerebroventricular streptozotocin-induced memory deficits by inhibiting GSK-3beta. AB - Brain dysfunction, especially cognitive impairment, is one of the main complications in Alzheimer's disease (AD), which threatens the health of 46.8 million people worldwide. At present, the pathogenesis of cognitive dysfunction is only partially understood, and effective therapies for memory loss in AD remain elusive. Tetramethylpyrazine (TMP) is one of the major bioactive compounds purified from Chuanxiong, a Chinese herb used for the treatment of neurovascular and cardiovascular diseases. The neuroprotective properties of TMP are evident in some neurodegenerative diseases, including Parkinson's disease. However, whether TMP plays a neuroprotective role in AD is still unknown. Here, we report that 2 week treatment with TMP rescued both short-term and long-term fear memory impairment induced by intracerebroventricular injection of streptozotocin in a well-known AD rat model. Administration of TMP also restored spatial learning and memory retention abilities in streptozotocin-injected rats. Furthermore, TMP inhibited the activity of GSK-3beta, an important kinase that mediates hippocampal synaptic and memory disorders in diabetes mellitus. Finally, we found that TMP treatment restored the function of cholinergic neurons. Our data suggest that dietary uptake of TMP can provide protection against memory loss in AD, and the inhibition of GSK-3beta may play an important role in this protective effect. PMID- 28633347 TI - Uniportal video-assisted thoracoscopic surgery in tracheal tumour under spontaneous ventilation anaesthesia. AB - We present an innovative method using uniportal video-assisted thoracoscopic surgery under spontaneous ventilation anaesthesia (SVA) to perform tracheal surgery in a 46-year-old man with distal tracheal squamous cell carcinoma. SVA offered better exposure of the surgical field and facilitated anastomosis following a single incision. Such simplification of the ventilation strategy and uniportal incision accelerated the postoperative recovery and reduced the side effects of conventional anaesthesia. PMID- 28633348 TI - Lifelong arrhythmic risk stratification in arrhythmogenic right ventricular cardiomyopathy: distribution of events and impact of periodical reassessment. AB - Aims: The arrhythmic risk stratification of arrhythmogenic right ventricular cardiomyopathy (ARVC) remains controversial. We evaluated the long-term distribution of life-threatening arrhythmic events assessing the impact of periodical risk reassessment. Methods and results: Ninety-eight ARVC patients with no previous major ventricular arrhythmias were retrospectively analysed. Patients were assessed at baseline, at 22 [inter-quartile range (IQR) 16-26], 49 (IQR 41-55) and 97 months (IQR 90-108). The primary endpoint was a composite of sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia or appropriate implanted cardioverter-defibrillator intervention. During a median follow-up of 91 months (IQR 34-222) 28 patients (29%) experienced the composite endpoint. The median time for the primary event was 35 months (IQR 18-86 months), and 39% of events occurred beyond 49 months of follow-up. History of syncope (HR 4.034; 95% CI, 1.488 to 10.932; P-value = 0.006), non-sustained ventricular tachycardia (NSVT; HR 3.534; 95% CI 1.265-9.877; P-value = 0.016), premature ventricular contractions (PVC) >1000/24h (HR 2.761; 95% CI 1.120-6.807; P-value = 0.027), and right ventricular fractional area change (RVFAC; HR 0.945; 95% CI 0.906-0.985; P-value = 0.008) were found as independent predictors at baseline multivariate analysis. Nevertheless, when the prognostic impact of each variable was reassessed overtime only NSVT (HR 3.282; 95% CI, 1.122 to 9.598, P-value = 0.023) and RVFAC (HR 0.351, 95% CI, 0.157 to 0.780; P-value = 0.010) remained independent predictors throughout the whole follow-up. Conclusion: In our cohort of ARVC patients only NSVT and RVFAC maintained their independent prognostic impact in predicting arrhythmic events during the long-term follow-up. Periodical re-assessment of risk in these patients is strongly recommended. PMID- 28633349 TI - Colchicine application significantly affects plant performance in the second generation of synthetic polyploids and its effects vary between populations. AB - Background and Aims: Understanding the direct consequences of polyploidization is necessary for assessing the evolutionary significance of this mode of speciation. Previous studies have not studied the degree of between-population variation that occurs due to these effects. Although it is assumed that the effects of the substances that create synthetic polyploids disappear in second-generation synthetic polyploids, this has not been tested. Methods: The direct consequences of polyploidization were assessed and separated from the effects of subsequent evolution in Vicia cracca , a naturally occurring species with diploid and autotetraploid cytotypes. Synthetic tetraploids were created from diploids of four mixed-ploidy populations. Performance of natural diploids and tetraploids was compared with that of synthetic tetraploids. Diploid offspring of the synthetic tetraploid mothers were also included in the comparison. In this way, the effects of colchicine application in the maternal generation on offspring performance could be compared independently of the effects of polyploidization. Key Results: The sizes of seeds and stomata were primarily affected by cytotype, while plant performance differed between natural and synthetic polyploids. Most performance traits were also determined by colchicine application to the mothers, and most of these results were largely population specific. Conclusions: Because the consequences of colchicine application are still apparent in the second generation of the plants, at least the third-generation polyploids should be considered in future comparisons. The specificities of the colchicine-treated plants may also be caused by strong selection pressures during the creation of synthetic polyploids. This could be tested by comparing the initial sizes of plants that survived the colchicine treatments with those of plants that did not. High variation between populations also suggests that different polyploids follow different evolutionary trajectories, and this should be considered when studying the effects of polyploidization. PMID- 28633350 TI - Accuracy of on-line self-reported weights and heights by young adults. AB - Background: e-epidemiology, a convenient and low-cost research method, is becoming increasingly popular. This study seeks to validate on-line self-reported heights and weights against objectively measured data in young adults. Methods: Young adults self-reported heights and weights in an on-line lifestyle survey. These were validated using two methods: (i) measurements by staff at the primary care clinic and (ii) measurements by a researcher within two weeks of distribution of the survey. Analyses were conducted to determine differences between the self-reported and measured heights and weights and to identify characteristics associated with under- or over-reporting of these. Results: From a total of 23 010 young adults invited to the survey, 24% provided on-line data, mean age = 19.2 (SD 3.2) years, 43% male, 91% EU citizens. Both self-reported and measured data were available for 1446 individuals (547 men, 896 women and mean age 19.2 (SD2.6) years); 1278 validated using medical records, 168 by researcher measurements. Intra-class correlations between self-reported and measured parameters were weight (r = 0.99), height (r = 0.98), with acceptable levels of agreement between measured and self-reported weight, height and BMI using Bland & Altman analyses. Self-reported weight was underestimated uniformly across BMI categories, gender and ethnicity, by a mean -0.4 (SD 0.4) kg (P < 0.001). Height was accurately reported overall across BMI and gender: both self-reported and measured heights =1.72 (SD 0.01) m, P = 0.783. Discrepancies between methods caused misclassification of BMI category for 17 (1.8%) of participants. Conclusions: Engagement of young adults with on-line research is encouraging. On line self-reporting provides acceptably reliable anthropometric data for young adults, with under-reporting of weight by just 0.4 kg. PMID- 28633351 TI - Data compression can discriminate broilers by selection line, detect haplotypes, and estimate genetic potential for complex phenotypes. AB - Accurately establishing the relationships among individuals lays the foundation for genetic analyses such as genome-wide association studies and identification of selection signatures. Of particular interest to the poultry industry are estimates of genetic merit based on molecular data. These estimates can be commercially exploited in marker-assisted breeding programs to accelerate genetic improvement. Here, we test the utility of a new method we have recently developed to estimate animal relatedness and applied it to genetic parameter estimation in commercial broilers. Our approach is based on the concept of data compression from information theory. Using the real-world compressor gzip to estimate normalized compression distance (NCD) we have built compression-based relationship matrices (CRM) for 988 chickens from 4 commercial broiler lines-2 male and 2 female lines. For all pairs of individuals, we found a strong negative relationship between the commonly used genomic relationship matrix (GRM) and NCD. This reflects the fact that "similarity" is the inverse of "distance." The CRM explained more genetic variation than the corresponding GRM in 2 of 3 phenotypes, with corresponding improvements in accuracy of genomic-enabled predictions of breeding value. A sliding-window version of the analysis highlighted haplotype regions of the genome apparently under selection in a line-specific manner. In the male lines, we retrieved high population-specific scores for IGF-1 and a cognate receptor, INSR. For the female lines, we detected an extreme score for a region containing a reproductive hormone receptor (GNRHR). We conclude that our compression-based method is a valid approach to established relationships and identify regions under selective pressure in commercial lines of broiler chickens. PMID- 28633352 TI - Aortopulmonary window: results of repair beyond infancy. AB - OBJECTIVES: To study the anatomic and haemodynamic data and results of surgery in patients undergoing surgical repair of aortopulmonary window beyond infancy. METHODS: Between July 2005 and December 2015, 23 patients, older than 1 year undergoing surgery for aortopulmonary window were analysed retrospectively. Postoperative clinical and echocardiography follow-up were performed. RESULTS: Median age and weight at repair was 4 years (range 14 months-12 years) and 12 kg (range 3.5-22 kg), respectively. Fifteen patients had Richardson's Type I, 6 patients had Type II and 2 patients had Type III aortopulmonary window. Six patients had associated defects. Baseline mean systolic pulmonary artery pressure was 101 +/- 14.9 mmHg (range 80-130, median 100 mmHg) and pulmonary vascular resistance index was 9.6 +/- 5.9 (median 7.7 Wood units/m2, range 3.7-23.5 Wood units/m2). Patch repair of aortopulmonary window was performed using the sandwich method (transwindow) (n = 15), transaortic (n = 3) and transpulmonary artery (n = 2) approaches; 2 patients underwent double ligation and 1 underwent division and suturing. Two patients underwent valved patch closure of aortopulmonary window and 1 patient underwent valved patch closure of associated ventricular septal defect. There were 2 in-hospital deaths: one due to intractable pulmonary hypertension and the other due to low cardiac output. Mean follow-up was 36 months (range 2-119 months). Eighteen patients were in NYHA Class I at last follow-up. There were no late deaths or reoperation. CONCLUSIONS: Surgery can be safely undertaken beyond infancy in carefully selected patients of aortopulmonary window with acceptable early and mid-term outcomes. PMID- 28633353 TI - Modulating role of ROS in re-establishing desiccation tolerance in germinating seeds of Caragana korshinskii Kom. AB - In close agreement with visible germination, orthodox seeds lose desiccation tolerance (DT). This trait can be regained under osmotic stress, but the mechanisms are poorly understood. In this study, germinating seeds of Caragana korshinskii Kom. were investigated, focusing on the potential modulating roles of reactive oxygen species (ROS) in the re-establishment of DT. Germinating seeds with 2 mm long radicles can be rendered tolerant to desiccation by incubation in a polyethylene glycol (PEG) solution (-1.7 MPa). Upon PEG incubation, ROS accumulation was detected in the radicles tip by nitroblue tetrazolium chloride staining and further confirmed by confocal microscopy. The PEG-induced re establishment of DT was repressed when ROS scavengers were added to the PEG solution. Moreover, ROS act downstream of abscisic acid (ABA) to modulate PEG mediated re-establishment of DT and serve as a new inducer to re-establish DT. Transcriptomic analysis revealed that re-establishment of DT by ROS involves the up-regulation of key genes in the phenylpropanoid-flavonoid pathway, and total flavonoid content and key enzyme activity increased after ROS treatment. Furthermore, DT was repressed by an inhibitor of phenylalanine ammonia lyase. Our data suggest that ROS play a key role in the re-establishment of DT by regulating stress-related genes and the phenylpropanoid-flavonoid pathway. PMID- 28633354 TI - Multicentric reticulohistiocytosis associated with thymic carcinoma. PMID- 28633355 TI - How proteins bind to DNA: target discrimination and dynamic sequence search by the telomeric protein TRF1. AB - Target search as performed by DNA-binding proteins is a complex process, in which multiple factors contribute to both thermodynamic discrimination of the target sequence from overwhelmingly abundant off-target sites and kinetic acceleration of dynamic sequence interrogation. TRF1, the protein that binds to telomeric tandem repeats, faces an intriguing variant of the search problem where target sites are clustered within short fragments of chromosomal DNA. In this study, we use extensive (>0.5 ms in total) MD simulations to study the dynamical aspects of sequence-specific binding of TRF1 at both telomeric and non-cognate DNA. For the first time, we describe the spontaneous formation of a sequence-specific native protein-DNA complex in atomistic detail, and study the mechanism by which proteins avoid off-target binding while retaining high affinity for target sites. Our calculated free energy landscapes reproduce the thermodynamics of sequence specific binding, while statistical approaches allow for a comprehensive description of intermediate stages of complex formation. PMID- 28633356 TI - Ridesharing and Motor Vehicle Crashes in 4 US Cities: An Interrupted Time-Series Analysis. AB - Uber, the world's largest ridesharing company, has reportedly provided over 2 billion journeys globally since operations began in 2010; however, the impact on motor vehicle crashes is unclear. Theoretically, ridesharing could reduce alcohol involved crashes in locations where other modes of transportation are less attractive than driving one's own vehicle while under the influence of alcohol. We conducted interrupted time-series analyses using weekly counts of injury crashes and the proportion that were alcohol-involved in 4 US cities (Las Vegas, Nevada; Reno, Nevada; Portland, Oregon; and San Antonio, Texas). We considered that a resumption of Uber operations after a temporary break would produce a more substantial change in ridership than an initial launch, so we selected cities where Uber launched, ceased, and then resumed operations (2013-2016). We hypothesized that Uber's resumption would be associated with fewer alcohol involved crashes. Results partially supported this hypothesis. For example, in Portland, Uber's resumption was associated with a 61.8% reduction (95% confidence interval: 38.7, 86.4) in the alcohol-involved crash rate (an absolute decrease of 3.1 (95% confidence interval: 1.7, 4.4) alcohol-involved crashes per week); however, there was no concomitant change in all injury crashes. Relationships between ridesharing and motor vehicle crashes differ between cities over time and may depend on specific local characteristics. PMID- 28633357 TI - matter: an R package for rapid prototyping with larger-than-memory datasets on disk. AB - Summary: We introduce matter , an R package for direct interactions with larger than-memory datasets, stored in an arbitrary number of files of any size. matter is primarily designed for datasets in new and rapidly evolving file formats, which may lack extensive software support. matter enables a wide variety of data exploration and manipulation steps, and is extensible to many bioinformatics applications. It supports reproducible research by minimizing the need of converting and storing data in multiple formats. We illustrate the performance of matter in conjunction with the Bioconductor package Cardinal for analysis of high resolution, high-throughput mass spectrometry imaging experiments. Availability: The package, vignettes, and examples of applications in several areas of bioinformatics are available open-source at www.bioconductor.org under the Artistic-2.0 license. Contact: o.vitek@neu.edu. PMID- 28633359 TI - Does long-term intraoral service affect the mechanical properties and elemental composition of multistranded wires of lingual fixed retainers? AB - Purpose: The aim of this study was to evaluate the elemental and mechanical alterations of stainless steel (SS) multistranded orthodontic wires used in fixed retention after intraoral ageing. Materials and Methods: Two types of 0.022-inch, seven-stranded wires, Lingual Retainer Wire (LRW) and Tru-Chrome (TCH), from the same manufacturer (Rocky Mountain Orthodontics, Denver, Colo, USA) were tested. Thirty-three samples from LRW group and thirty-seven from TCH were collected, whereas three unused wires from each package were used as controls. The median ageing time for LRW was 7.4 years and 8.4 for TCH. All samples were subjected to scanning electron microscope/X-ray energy dispersive spectroscopy analysis. Three spectra were taken from the surface of each wire and then all samples were used for the assessment of Martens hardness, indentation modulus (EIT), and elastic index (etaIT) with the instrumented indentation testing method (IIT). The intraoral ageing time was statistically compared between the two groups by Mann Whitney rank sum test and the compositional and mechanical properties were compared by unpaired t-test. The Spearman correlation between elemental content and ageing time was carried out for all elements (a = 0.05). Results: No significant differences were found for both the elemental content and for the mechanical properties between the wires tested. Spearman analysis revealed no correlation between elemental content and intraoral time while two groups share statistically equal intraoral ageing times (P > 0.05). Conclusions: Both wires seemed to maintain their mechanical and elemental integrity within a period of 14 year intraoral exposure, whereas no measurable ionic release could be identified. PMID- 28633358 TI - Phylogeography of herbarium specimens of asexually propagated paper mulberry [Broussonetia papyrifera (L.) L'Her. ex Vent. (Moraceae)] reveals genetic diversity across the Pacific. AB - Background and Aims: Paper mulberry or Broussonetia papyrifera (L.) L'Her. ex Vent. (Moraceae) is a dioecious species native to continental South-east Asia and East Asia, including Taiwan, that was introduced to the Pacific by pre-historic voyagers and transported intentionally and propagated asexually across the full range of Austronesian expansion from Taiwan to East Polynesia. The aim of this study was to gain insight into the dispersal of paper mulberry into Oceania through the genetic analysis of herbaria samples which represent a more complete coverage of the historical geographical range of the species in the Pacific before later introductions and local extinctions occurred. Methods: DNA from 47 herbarium specimens of B. papyrifera collected from 1882 to 2006 from different islands of the Pacific was obtained under ancient DNA protocols. Genetic characterization was based on the ribosomal internal transcribed spacer ITS-1 sequence, a sex marker, the chloroplast ndhF-rpl32 intergenic spacer and a set of ten microsatellites developed for B. papyrifera. Key Results: Microsatellites allowed detection of 15 genotypes in Near and Remote Oceanian samples, in spite of the vegetative propagation of B. papyrifera in the Pacific. These genotypes are structured in two groups separating West and East Polynesia, and place Pitcairn in a pivotal position. We also detected the presence of male plants that carry the Polynesian chloroplast DNA (cpDNA) haplotype, in contrast to findings in contemporary B. papyrifera populations where only female plants bear the Polynesian cpDNA haplotype. Conclusions: For the first time, genetic diversity was detected among paper mulberry accessions from Remote Oceania. A clear separation between West and East Polynesia was found that may be indicative of pulses during its dispersal history. The pattern linking the genotypes within Remote Oceania reflects the importance of central Polynesia as a dispersal hub, in agreement with archaeological evidence. PMID- 28633360 TI - Expression properties exhibit correlated patterns with the fate of duplicated genes, their divergence, and transcriptional plasticity in Saccharomycotina. AB - Gene duplication is an important source of novelties and genome complexity. What genes are preserved as duplicated through long evolutionary times can shape the evolution of innovations. Identifying factors that influence gene duplicability is therefore an important aim in evolutionary biology. Here, we show that in the yeast Saccharomyces cerevisiae the levels of gene expression correlate with gene duplicability, its divergence, and transcriptional plasticity. Genes that were highly expressed before duplication are more likely to be preserved as duplicates for longer evolutionary times and wider phylogenetic ranges than genes that were lowly expressed. Duplicates with higher expression levels exhibit greater divergence between their gene copies. Duplicates that exhibit higher expression divergence are those enriched for TATA-containing promoters. These duplicates also show transcriptional plasticity, which seems to be involved in the origin of adaptations to environmental stresses in yeast. While the expression properties of genes strongly affect their duplicability, divergence and transcriptional plasticity are enhanced after gene duplication. We conclude that highly expressed genes are more likely to be preserved as duplicates due to their promoter architectures, their greater tolerance to expression noise, and their ability to reduce the noise-plasticity conflict. PMID- 28633362 TI - Human papillomavirus-related oropharyngeal cancer. AB - High-risk human papillomavirus (HPV) is now recognised as the principal cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in some parts of the world. The primary risk factor for developing HPV-related OPSCC is oral HPV-infection and the majority of oral HPV-infections are acquired by oral sex. Progression into an OPSCC includes persistent infection with evasion of immune response in the microenvironment, the activation of viral early genes (E6, E7) in basal epithelial cells, the deregulation of cell cycle and the accumulation of chromosomal instability. Patients affected by HPV-related OPSCC tend to be younger and have better outcomes. This observation has lead current research to evaluate treatment de-escalation options to reduce long-term associated morbidity. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new options for targeted therapy and immunotherapy approaches. This paper comprehensively reviews our accumulated knowledge regarding the role of HPV in OPSCC spanning from infection to cancer development, including its clinical diagnosis, management and preventive strategies. PMID- 28633361 TI - Evolution of miRNA Tailing by 3' Terminal Uridylyl Transferases in Metazoa. AB - In bilaterian animals the 3' ends of microRNAs (miRNAs) are frequently modified by tailing and trimming. These modifications affect miRNA-mediated gene regulation by modulating miRNA stability. Here, we analyzed data from three nonbilaterian animals: two cnidarians (Nematostella vectensis and Hydra magnipapillata) and one poriferan (Amphimedon queenslandica). Our analysis revealed that nonbilaterian miRNAs frequently undergo modifications like the bilaterian counterparts: the majority are expressed as different length isoforms and frequent modifications of the 3' end by mono U or mono A tailing are observed. Moreover, as the factors regulating miRNA modifications are largely uncharacterized in nonbilaterian animal phyla, in present study, we investigated the evolution of 3' terminal uridylyl transferases (TUTases) that are known to involved in miRNA 3' nontemplated modifications in Bilateria. Phylogenetic analysis on TUTases showed that TUTase1 and TUTase6 are a result of duplication in bilaterians and that TUTase7 and TUTase4 are the result of a vertebrate specific duplication. We also find an unexpected number of Drosophila-specific gene duplications and domain losses in most of the investigated gene families. Overall, our findings shed new light on the evolutionary history of TUTases in Metazoa, as they reveal that this core set of enzymes already existed in the last common ancestor of all animals and was probably involved in modifying small RNAs in a similar fashion to its present activity in bilaterians. PMID- 28633363 TI - Development, Initial Testing and Challenges of an Ecologically Valid Reward Prediction Error FMRI Task for Alcoholism. AB - Aims: To advance translational studies of the role of reward prediction error (PE) in alcohol use disorder, the present study sought to develop and conduct an initial test of an alcohol-specific PE task paradigm using functional magnetic resonance imaging in humans. Methods: Alcohol dependent or social drinkers received small tastes of their preferred alcohol beverage or control beverage, with preceding visual cues indicating whether alcohol (or water) would be delivered. To assess both positive and negative PE signals, expectancies were systematically violated in both positive (i.e. expecting water and receiving alcohol) and negative (i.e. expecting alcohol and receiving water) directions. Exploratory trial-by-trial analyses were conducted to explore temporal fluctuations of activation within a priori-defined regions of interest that have been implicated in cue reactivity and PE processing. Results: Across the entire sample of participants, positive PE-related brain activation was found in a large cluster comprised of frontal lobe regions, as well as insular cortex, and motor/sensory cortices. Compared to social drinking subjects, alcohol dependent subjects had greater positive PE-related brain activity in left superior parietal lobule, lateral occipital cortex and postcentral gyrus. Exploratory trial-by trial analyses indicated differences in activation specific to type of taste, mostly at earlier trials. Conclusions: This task-development oriented pilot study found that PE signaling may not be detected in expected brain regions when image analyses average across all PE trials of the task. Rather, a trial-by-trial analysis approach may help detect sparse, temporally distinct PE signaling in expected reward processing regions. Short Summary: This fMRI study of reward prediction error found greater positive prediction error-related activity (i.e. expecting water taste, receiving alcohol taste) in alcohol dependent individuals relative to social drinkers in parietal and occipital cortices. Trial-by-trial analyses may be able to better detect sparse prediction error signaling in expected reward processing regions. PMID- 28633364 TI - Restricted health care entitlements for child migrants in Europe and Australia. AB - Background: More than 300 000 asylum seeking children were registered in Europe alone during 2015. In this study, we examined entitlements for health care for these and other migrant children in Europe and Australia in a framework based on United Nations Convention of the Rights of the Child (UNCRC). Methods: Survey to child health professionals, NGO's and European Ombudspersons for Children in 30 EU/EEA countries and Australia, supplemented by desktop research of official documents. Migrant children were categorised as asylum seekers and irregular/undocumented migrants. Results: Five countries (France, Italy, Norway, Portugal and Spain) explicitly entitle all migrant children, irrespective of legal status, to receive equal health care to that of its nationals. Sweden and Belgium entitle equal care to asylum seekers and irregular non-EU migrants, while entitlements for EU migrants are unclear. Twelve European countries have limited entitlements to health care for asylum seeking children, including Germany that stands out as the country with the most restrictive health care policy for migrant children. In Australia entitlements for health care are restricted for asylum seeking children in detention and for irregular migrants. The needs of irregular migrants from other EU countries are often overlooked in European health care policy. Conclusion: Putting pressure on governments to honour the obligations of the UNCRC and explicitly entitle all children equal rights to health care can be an important way of advocating for better access to primary and preventive care for asylum seeking and undocumented children in Australia and the EU. PMID- 28633366 TI - Magnesium-deficiency-induced alterations of gas exchange, major metabolites and key enzymes differ among roots, and lower and upper leaves of Citrus sinensis seedlings. AB - Magnesium (Mg)-deficiency is a widespread problem adversely affecting the quality and yield of crops, including citrus. 'Xuegan' [Citrus sinensis (L.) Osbeck] seedlings were irrigated every other day with nutrient solution at an Mg concentration of 0 mM (Mg-deficiency) or 1 mM (Mg-sufficiency) for 16 weeks. Thereafter, biomass, leaf mass per area, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), pigments in the upper and lower leaves, Mg, gas exchange, organic acids, nonstructural carbohydrates, total soluble proteins, amino acids, phenolics and anthocyanins, and key enzymes related to organic acid, amino acid and phenolic metabolisms in the roots, and upper and lower leaves were assayed in order to test the hypothesis that Mg-deficiency-induced alterations of gas exchange, major metabolites and key enzymes may differ among the roots, and upper and lower leaves. Magnesium-deficiency affected the most measured parameters more in the lower than in the upper leaves except for the nonstructural carbohydrates, but the variation trends were similar between the two. Despite increased accumulation of nonstructural carbohydrates, the lower CO2 assimilation in the Mg-deficient leaves was not caused by the feedback inhibition mechanism via sugar accumulation. Both dark respiration and organic acid metabolism were elevated in the Mg-deficient lower leaves to 'consume' the excess carbohydrates, and inhibited in the Mg-deficient roots with less accumulation of nonstructural carbohydrates to keep the balance of net carbon. More total phenolics and fewer anthocyanins were accumulated in the Mg-deficient lower leaves, whereas the accumulation of both total phenolics and anthocyanins was reduced in the Mg-deficient roots. Interestingly, amino acid biosynthesis was repressed in the Mg-deficient roots and lower leaves, thus lowering the level of total free amino acids in these roots and leaves. To conclude, great differences existed in the Mg-deficiency-induced alterations of gas exchange, major metabolites and key enzymes among the roots, and upper and lower leaves. PMID- 28633365 TI - Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. AB - Background: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the alpha- and delta-isoforms. Patients and methods: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. Results: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively; median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%; grade >=3, 23.8%), hypertension (54.8%; grade >=3, 40.5%), and diarrhea (40.5%; grade >=3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. Conclusion: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A). PMID- 28633367 TI - Cortical glutamate in migraine. AB - Cortical hyperexcitability due to enhanced glutamatergic activity has been implicated in migraine pathophysiology but direct evidence is lacking. Here we assessed glutamate levels and intracellular mobility of glutamate in the visual cortex of migraineurs in-between attacks. We included 50 migraineurs (23 with aura and 27 without aura) and 24 age- and gender-matched non-headache controls. We used proton magnetic resonance spectroscopy (1H-MRS) and diffusion weighted spectroscopy at 7 T with a single volume of interest (2 * 2 * 3 cm) located in the primary and secondary visual cortex. For 1H-MRS we used a semi-LASER sequence with water referencing for absolute quantification. For diffusion weighted spectroscopy we used an adapted PRESS sequence with gradients applied in three directions and two different gradient amplitudes. Between-group differences were evaluated using analysis of covariance with the grey matter fraction in the volume of interest as covariate and post hoc comparisons with Bonferroni correction. Glutamate concentrations differed between groups (P = 0.047) and were higher in migraineurs without aura (mean +/- standard deviation: 7.02 +/- 0.50 mM) compared to controls (mean +/- standard deviation: 6.40 +/- 0.78 mM, P = 0.042). The apparent diffusion coefficient of glutamate was similar among groups (P = 0.129) suggesting similar inter- and intracellular mobility of glutamate in all three study groups. No differences were observed for concentrations and diffusion constants of other metabolites. The present study suggests that interictal glutamate levels are increased in the visual cortex of migraineurs without aura, supporting the hypothesis of cortical hyperexcitability in migraine. PMID- 28633369 TI - Fine Subdivisions of the Semantic Network Supporting Social and Sensory-Motor Semantic Processing. AB - Neuroimaging studies have consistently indicated that semantic processing involves a brain network consisting of multimodal cortical regions distributed in the frontal, parietal, and temporal lobes. However, little is known about how semantic information is organized and processed within the network. Some recent studies have indicated that sensory-motor semantic information modulates the activation of this network. Other studies have indicated that this network responds more to social semantic information than to other information. Using fMRI, we collectively investigated the brain activations evoked by social and sensory-motor semantic information by manipulating the sociality and imageability of verbs in a word comprehension task. We detected 2 subgroups of brain regions within the network showing sociality and imageability effects, respectively. The 2 subgroups of regions are distinct but overlap in bilateral angular gyri and adjacent middle temporal gyri. A follow-up analysis of resting-state functional connectivity showed that dissociation of the 2 subgroups of regions is partially associated with their intrinsic functional connectivity differences. Additionally, an interaction effect of sociality and imageability was observed in the left anterior temporal lobe. Our findings indicate that the multimodal cortical semantic network has fine subdivisions that process and integrate social and sensory-motor semantic information. PMID- 28633368 TI - Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life. AB - Objectives: Data quantifying outcomes of recurrent Clostridium difficile infection (rCDI) are lacking. We sought to determine the UK hospital resource use and health-related quality of life (HRQoL) associated with rCDI hospitalizations. Patients and methods: A non-interventional study in six UK acute hospitals collected retrospective clinical and resource use data from medical records of 64 adults hospitalized for rCDI and 64 matched inpatient controls with a first episode only (f)CDI. Patients were observed from the index event (date rCDI/fCDI confirmed) for 28 days (or death, if sooner); UK-specific reference costs were applied. HRQoL was assessed prospectively in a separate cohort of 30 patients hospitalized with CDI, who completed the EQ-5D-3L questionnaire during their illness. Results: The median total management cost (post-index) was L7539 and L6294 for rCDI and fCDI, respectively (cost difference, P = 0.075); median length of stay was 21 days and 15.5 days, respectively (P = 0.269). The median cost difference between matched rCDI and fCDI cases was L689 (IQR=L1873-L3954). Subgroup analysis demonstrated the highest median costs (L8542/patient) in severe rCDI cases. CDI management costs were driven primarily by hospital length of stay, which accounted for >85% of costs in both groups. Mean EQ-5D index values were 46% lower in CDI patients compared with UK population values (0.42 and 0.78, respectively); EQ visual analogue scale scores were 38% lower (47.82 and 77.3, respectively). Conclusions: CDI has considerable impact on patients and healthcare resources. This multicentre study provides a contemporaneous estimate of the real-world UK costs associated with rCDI management, which are substantial and comparable to fCDI costs. PMID- 28633370 TI - Therapeutic catheterization in congenital heart disease: reflections on the value of risk scores. PMID- 28633371 TI - Does atrial fibrillation lead to cognitive decline and dementia? PMID- 28633372 TI - Farmer suicides: a qualitative study from Australia. AB - Background: Farmers in Australia, in general, have poorer health outcomes, including higher rates of suicide. Aims: To investigate risk and protective factors and attitudes towards suicide and help-seeking among farmers living and working in New South Wales and Queensland in Australia. Methods: A qualitative study in which three farming sites were selected in each state to represent an area with a suicide rate equal to, below and above the state average. Focus groups were conducted with men and women separately. Results: Focus groups involved 30 men and 33 women. Inductive thematic analysis showed three broad themes characterized responses: environment and society; community and relationships; and individual factors. There was considerable overlap and dynamic interaction between themes. A combination of individual factors, as well as social and environmental stressors, was described as most likely to increase risk of suicide death and reduce help-seeking. The vast majority of known farmer suicides described involved men and many of the issues discussed pertained specifically to male farmers. Participants found suicide as an act complex, intertwined with many factors, and hard to fathom. A common belief was that an individual must feel a complete lack of hope and perceive their situation vastly differently from others to contemplate suicide. Conclusions: Future suicide prevention efforts for farmers should take a biopsycho-ecological approach. Physical, psychological and cultural isolation could be addressed with education and training programmes and public campaigns. These could also improve people's ability to recognize possible suicidality. PMID- 28633373 TI - Auxin transport and response requirements for root hydrotropism differ between plant species. AB - The direction of auxin transport changes in gravistimulated roots, causing auxin accumulation in the lower side of horizontally reoriented roots. This study found that auxin was similarly involved in hydrotropism and gravitropism in rice and pea roots, but hydrotropism in Lotus japonicus roots was independent of both auxin transport and response. Application of either auxin transport inhibitors or an auxin response inhibitor decreased both hydrotropism and gravitropism in rice roots, and reduced hydrotropism in pea roots. However, Lotus roots treated with these inhibitors showed reduced gravitropism but an unaltered or an enhanced hydrotropic response. Inhibiting auxin biosynthesis substantially reduced both tropisms in rice and Lotus roots. Removing the final 0.2 mm (including the root cap) from the root tip inhibited gravitropism but not hydrotropism in rice seedling roots. These results suggested that modes of auxin involvement in hydrotropism differed between plant species. In rice roots, although auxin transport and responses were required for both gravitropism and hydrotropism, the root cap was involved in the auxin regulation of gravitropism but not hydrotropism. Hydrotropism in Lotus roots, however, may be regulated by a novel mechanism that is independent of both auxin transport and the TIR1/AFBs auxin response pathway. PMID- 28633374 TI - Cohort study of preoperative blood pressure and risk of 30-day mortality after elective non-cardiac surgery. AB - Background: Preoperative blood pressure (BP) thresholds associated with increased postoperative mortality remain unclear. We investigated the relationship between preoperative BP and 30-day mortality after elective non-cardiac surgery. Methods: We performed a cohort study of primary care data from the UK Clinical Practice Research Datalink (2004-13). Parsimonious and fully adjusted multivariable logistic regression models, including restricted cubic splines for numerical systolic and diastolic BP, for 30-day mortality were constructed. The full model included 29 perioperative risk factors, including age, sex, comorbidities, medications, and surgical risk scale. Sensitivity analyses were conducted for age (>65 vs <65 years old) and the timing of BP measurement. Results: A total of 251 567 adults were included, with 589 (0.23%) deaths within 30 days of surgery. After adjustment for all risk factors, preoperative low BP was consistently associated with statistically significant increases in the odds ratio (OR) of postoperative mortality. Statistically significant risk thresholds started at a preoperative systolic pressure of 119 mm Hg (adjusted OR 1.02 [95% confidence interval (CI) 1.01-1.02]) compared with the reference (120 mm Hg) and diastolic pressure of 63 mm Hg [OR 1.24 (95% CI 1.03-1.49)] compared with the reference (80 mm Hg). As BP decreased, the OR of mortality risk increased. Subgroup analysis demonstrated that the risk associated with low BP was confined to the elderly. Adjusted analyses identified that diastolic hypertension was associated with increased postoperative mortality in the whole cohort. Conclusions: In this large observational study we identified a significant dose-dependent association between low preoperative BP values and increased postoperative mortality in the elderly. In the whole population, elevated diastolic, not systolic, BP was associated with increased mortality. PMID- 28633375 TI - Final 5-year clinical and echocardiographic results for treatment of severe aortic stenosis with a self-expanding bioprosthesis from the ADVANCE Study. AB - Aims: The ADVANCE study was designed to evaluate the safety and effectiveness of transcatheter aortic valve implantation (TAVI) with a self-expanding bioprosthesis in real-world patients with symptomatic, severe aortic stenosis at high surgical risk for valve replacement. Methods and results: Study participants were enrolled from 44 experienced centres in 12 countries. Patient eligibility, treatment approach, and choice of anaesthesia were determined by the local Heart Team. The study was 100% monitored, and adverse events were adjudicated by an independent clinical events committee using Valve Academic Research Consortium (VARC-1) criteria. There were 1015 patients enrolled with 996 attempted TAVI procedures. Mean age was 81 years, and mean logistic EuroSCORE was 19.3 +/- 12.3%. Five-year follow-up was available on 465 (46.7%) patients. At 5 years, the rate of all-cause mortality was 50.7% (95% confidence interval: 46.7%, 54.5%), and the rate of major stroke was 5.4%. Haemodynamic measures remained consistent for paired patients with a mean aortic valve gradient of 8.8 +/- 4.4 mmHg (n = 198) and an effective orifice area of 1.7 +/- 0.4 cm2 (n = 123). Aortic regurgitation (AR) decreased over time and among paired patients dropped from 12.8% to 8.0% moderate AR at 5 years (n = 125). Of the 860 patients with echocardiographic data or a reintervention after 30 days, there were 22 (2.6%) patients meeting the VARC-2 criteria for valve dysfunction and 10 (1.2%) patients with a reintervention >30 days. Conclusion: Five-year results in real-world, elderly, high-risk patients undergoing TAVI with a self-expanding bioprosthesis provided evidence for continued valve durability with low rates of reinterventions and haemodynamic valve dysfunction. Trial registration: ClinicalTrials.gov, NCT01074658. PMID- 28633376 TI - Keeping Things in Balance: Family Experiences of Living With Alzheimer's Disease. AB - Background and Objectives: Historically, research, practice, and policy on Alzheimer's family care has been largely focused on dyadic relationships and the experience of burden and stress, often failing to capture the complex caring dynamics as they unfold over time. This study sought to develop a more nuanced understanding of how people with Alzheimer's disease (AD) and their families are affected by the disease and how they respond to the challenges AD poses. Research Design and Methods: Using constructivist grounded theory, the study explored the experiences of living with AD for native Spanish families residing in Navarra. Data were collected from a series of 26 interviews with seven family units living with early stage AD and further validated with three focus groups with 14 caregivers of people with mid/advanced AD. Data were analyzed to capture the main processes involved and charted how these evolved over time. Results: Keeping things in balance describes the way family works to preserve a balance between caring and their lives before the onset of AD. Three main temporal stages to the experience of early AD, along with their associated processes, were identified: (a) what's going on here and the processes of noticing, suspecting, and confirming; (b) our life is changing underpinned by the processes of watching and redefining; and (c) keeping things together and its associated balancing process. These reinforced the dynamic nature of living with AD over time. Discussion and Implications: This study was novel in its design as it included the person with AD as part of the functioning family unit. The temporal stages and the key social processes identified have the potential to inform the development of "stage specific" interventions for the support of the whole family at various points in time. PMID- 28633379 TI - Making sense of remote monitoring studies in heart failure. PMID- 28633378 TI - The cost of avoiding freezing in stems: trade-off between xylem resistance to cavitation and supercooling capacity in woody plants. AB - Stems and leaves of Olea europaea L. (olive) avoid freezing damage by substantial supercooling during the winter season. Physiological changes during acclimation to low temperatures were studied in five olive cultivars. Water relations and hydraulic traits, ice nucleation temperature (INT) and temperatures resulting in 50% damage (LT50) were determined. All cultivars showed a gradual decrease in INT and LT50 from the dry and warm summer to the wet and cold winter in Patagonia, Argentina. During acclimation to low temperatures there was an increase in leaf cell wall rigidity and stomatal conductance (gs), as well as a decrease in leaf apoplastic water content, leaf water potential (Psi), sap flow and stem hydraulic conductivity (ks). More negative Psi as a consequence of high gs and detrimental effects of low temperatures on root activity resulted in a substantial loss of ks due to embolism formation. Seasonal stem INT decrease from summer to winter was directly related to the xylem resistance to cavitation, determined by the loss of ks across cultivars. Thus the loss of freezable water in xylem vessels by embolisms increased stem supercooling capacity and delayed ice propagation from stems to the leaves. For the first time, a trade-off between xylem resistance to cavitation and stem and leaf supercooling capacity was observed in plants that avoid extracellular freezing by permanent supercooling. The substantial loss of hydraulic function in olive cultivar stems by embolism formation with their high repair costs are compensated by avoiding plant damage at very low subzero temperatures. PMID- 28633377 TI - Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease. AB - Aminoacyl-tRNA synthetases (ARSs) are responsible for charging amino acids to cognate tRNA molecules, which is the essential first step of protein translation. Interestingly, mutations in genes encoding ARS enzymes have been implicated in a broad spectrum of human inherited diseases. Bi-allelic mutations in ARSs typically cause severe, early-onset, recessive diseases that affect a wide range of tissues. The vast majority of these mutations show loss-of-function effects and impair protein translation. However, it is not clear how a subset cause tissue-specific phenotypes. In contrast, dominant ARS-mediated diseases specifically affect the peripheral nervous system-most commonly causing axonal peripheral neuropathy-and usually manifest later in life. These neuropathies are linked to heterozygosity for missense mutations in five ARS genes, which points to a shared mechanism of disease. However, it is not clear if a loss-of-function mechanism or a toxic gain-of-function mechanism is responsible for ARS-mediated neuropathy, or if a combination of these mechanisms operate on a mutation specific basis. Here, we review our current understanding of recessive and dominant ARS-mediated disease. We also propose future directions for defining the molecular mechanisms of ARS mutations toward designing therapies for affected patient populations. PMID- 28633380 TI - Epigallocatechin-3-gallate and related phenol compounds redirect the amyloidogenic aggregation pathway of ataxin-3 towards non-toxic aggregates and prevent toxicity in neural cells and Caenorhabditis elegans animal model. AB - The protein ataxin-3 (ATX3) triggers an amyloid-related neurodegenerative disease when its polyglutamine stretch is expanded beyond a critical threshold. We formerly demonstrated that the polyphenol epigallocatechin-3-gallate (EGCG) could redirect amyloid aggregation of a full-length, expanded ATX3 (ATX3-Q55) towards non-toxic, soluble, SDS-resistant aggregates. Here, we have characterized other related phenol compounds, although smaller in size, i.e. (-)-epigallocatechin gallate (EGC), and gallic acid (GA). We analysed the aggregation pattern of ATX3 Q55 and of the N-terminal globular Josephin domain (JD) by assessing the time course of the soluble protein, as well its structural features by FTIR and AFM, in the presence and the absence of the mentioned compounds. All of them redirected the aggregation pattern towards soluble, SDS-resistant aggregates. They also prevented the appearance of ordered side-chain hydrogen bonding in ATX3 Q55, which is the hallmark of polyQ-related amyloids. Molecular docking analyses on the JD highlighted three interacting regions, including the central, aggregation-prone one. All three compounds bound to each of them, although with different patterns. This might account for their capability to prevent amyloidogenesis. Saturation transfer difference NMR experiments also confirmed EGCG and EGC binding to monomeric JD. ATX3-Q55 pre-incubation with any of the three compounds prevented its calcium-influx-mediated cytotoxicity towards neural cells. Finally, all the phenols significantly reduced toxicity in a transgenic Caenorhabditis elegans strain expressing an expanded ATX3. Overall, our results show that the three polyphenols act in a substantially similar manner. GA, however, might be more suitable for antiamyloid treatments due to its simpler structure and higher chemical stability. PMID- 28633383 TI - Commentary: Utilization of Quantitative Susceptibility Mapping for Direct Targeting of the Subthalamic Nucleus During Deep Brain Stimulation Surgery. PMID- 28633382 TI - Detecting Predeath Grief in Family Caregivers of Persons With Dementia: Validity and Utility of the Marwit-Meuser Caregiver Grief Inventory in a Multiethnic Asian Population. AB - Background and Objectives: Coping with predeath grief (PDG) is an unmet need in caregivers of persons with dementia (PWD). The Marwit-Meuser Caregiver Grief Inventory (MM-CGI) and its abbreviated MM-CGI-Short-Form (MM-CGI-SF) are among the few empirically developed scales that detect PDG, yet they have not been substantially validated outside United States. We evaluated the reliability and validity of the PDG scales in a multiethnic Asian population distinct from that of United States. Research Design and Methods: Family caregivers of community dwelling PWD (n = 300) completed self-administered questionnaires containing MM CGI and other scales of related construct. Sixty percent of the participants repeated the questionnaires 1 week later for test-retest reliability. Internal consistency reliability was assessed by Cronbach's alpha, test-retest reliability by intraclass-correlation-coefficient, construct validity by Spearman's correlation-coefficient, and factorial validity by confirmatory factor analysis (CFA). Cohen's kappa was used to compare the agreement between MM-CGI and a commonly-used caregiver burden scale (Zarit Burden Interview). Results: MM-CGI and MM-CGI-SF demonstrated internal-consistency reliability, test-retest reliability, construct validity, and known-group validity. In CFA, MM-CGI showed modest model-fit (comparative-fit-index, CFI = .80; Tucker-Lewis-index, TLI = .79), whereas MM-CGI-SF showed better model-fit (CFI = .91; TLI = .90). Eighty six percent of the caregivers reported average or high levels of PDG, with 18% reporting high PDG. High scores in the caregiver burden scale only showed modest agreement with high scores in MM-CGI (kappa = .47). Discussion and Implications: MM-CGI and MM-CGI-SF demonstrated adequate psychometric properties and utility, beyond that of a caregiver burden scale, in detecting high PDG in a multiethnic Asian population. They open the way for PDG intervention in clinical care, as well as further exploration in caregiver research. PMID- 28633381 TI - Robust Tests for Additive Gene-Environment Interaction in Case-Control Studies Using Gene-Environment Independence. AB - There have been recent proposals advocating the use of additive gene-environment interaction instead of the widely used multiplicative scale, as a more relevant public health measure. Using gene-environment independence enhances statistical power for testing multiplicative interaction in case-control studies. However, under departure from this assumption, substantial bias in the estimates and inflated type I error in the corresponding tests can occur. In this paper, we extend the empirical Bayes (EB) approach previously developed for multiplicative interaction, which trades off between bias and efficiency in a data-adaptive way, to the additive scale. An EB estimator of the relative excess risk due to interaction is derived, and the corresponding Wald test is proposed with a general regression setting under a retrospective likelihood framework. We study the impact of gene-environment association on the resultant test with case control data. Our simulation studies suggest that the EB approach uses the gene environment independence assumption in a data-adaptive way and provides a gain in power compared with the standard logistic regression analysis and better control of type I error when compared with the analysis assuming gene-environment independence. We illustrate the methods with data from the Ovarian Cancer Association Consortium. PMID- 28633384 TI - Correlates of dyspnoea and its association with adverse outcomes in a cohort of adults aged 80 and over. AB - Background: adults aged 80 and over, a fast growing age-group, with increased co morbidity and frailty have not been the focus of previous research on dyspnoea. We investigate the correlates of dyspnoea and its association with adverse outcomes in a cohort of adults aged 80 and over. Methods: about 565 community dwelling adults aged 80 and over of the BELFRAIL prospective cohort had assessment of Medical Research Council dyspnoea scale (MRC), forced expiratory volume in 1 s (FEV1), N-terminal pro-brain natriuretic peptide (NT-proBNP), physical performance tests, grip strength, 15 items geriatric depression scale, activities of daily living (ADL), body mass index (BMI) and demographics data. Kaplan-Meier survival curves, Cox and logistic multivariable regression, classification and regression tree (CART) analysis assessed association of dyspnoea (MRC 3-5) with time-to-cardiovascular and all-cause death (5 years), time to first hospitalisation (3 years), new/worsened ADL disability (2 years), and its correlates. Results: participants with dyspnoea MRC 3-5 (29.9%) had increased hazard ratios for cardiovascular mortality 2.85 (95% confidence interval 1.93-4.20), all-cause mortality 2.04 (1.58-2.64), first hospitalisation 1.72 (1.35-2.19); and increased odds ratio for new/worsened disability 2.49 (1.54 4.04), independent of age, sex and smoking status. Only FEV1, physical performance, BMI and NT-proBNP (in order of importance) were selected in the tree based classification model for dyspnoea. Conclusions: in a cohort of adults aged 80 and over, dyspnoea was common and an independent predictor of adverse outcomes, with cardio-respiratory and physical performance impairments as key independent correlates. Its routine and comprehensive evaluation in primary care could be very valuable in caring for this age-group. PMID- 28633385 TI - TIminer: NGS data mining pipeline for cancer immunology and immunotherapy. AB - Summary: Recently, a number of powerful computational tools for dissecting tumor immune cell interactions from next-generation sequencing data have been developed. However, the assembly of analytical pipelines and execution of multi step workflows are laborious and involve a large number of intermediate steps with many dependencies and parameter settings. Here we present TIminer, an easy to-use computational pipeline for mining tumor-immune cell interactions from next generation sequencing data. TIminer enables integrative immunogenomic analyses, including: human leukocyte antigens typing, neoantigen prediction, characterization of immune infiltrates and quantification of tumor immunogenicity. Availability and implementation: TIminer is freely available at http://icbi.i-med.ac.at/software/timiner/timiner.shtml. Contact: zlatko.trajanoski@i-med.ac.at. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633386 TI - Oral administration of tea saponins to relive oxidative stress and immune suppression in chickens. AB - The present study was designed to evaluate the effects of tea saponins on oxidative stress induced by cyclophosphamide in chickens. One hundred twenty chickens were randomly divided into 5 groups. Groups 3 to 4 received intramuscular injection of cyclophosphamide to induce oxidative stress and immunosuppression. After that, groups 2 and 4 were orally administered tea saponins in drinking water for 7 d. Then, groups 1 to 4 were immunized with a live, bivalent vaccine of Newcastle disease virus and infectious bronchitis virus. Blood samples were collected for analysis of oxidative parameters and specific antibody titers, and splenocytes were prepared for lymphocyte proliferative assay. The results showed that administration of tea saponins significantly increased total antioxidant capacity, total superoxide dismutase, catalase, glutathione peroxidase, glutathione, ascorbic acid, and alpha tocopherol, and decreased malondialdehyde and protein carbonyl. Enhanced immune responses, such as lymphocyte proliferation induced by concanavalin A and lipopolysaccharides, and serum Newcastle disease virus- and infectious bronchitis virus-specific antibodies were also observed in chickens injected with or without cyclophosphamide. In addition, no side effects were found in chickens throughout the study. Therefore, tea saponins may be a potential agent to improve imunosuppression induced by oxidative stress in chickens. PMID- 28633387 TI - Anal Intercourse Among Female Sex Workers in Cote d'Ivoire: Prevalence, Determinants, and Model-Based Estimates of the Population-Level Impact on HIV Transmission. AB - Current evidence suggests that anal intercourse (AI) during sex work is common in sub-Saharan Africa, but there have been few studies in which the contribution of heterosexual AI to human immunodeficiency virus (HIV) epidemics has been investigated. Using a respondent-driven sampling survey of female sex workers (FSWs; n = 466) in Abidjan, Cote d'Ivoire, in 2014, we estimated AI prevalence and frequency. Poisson regressions were used to identify AI determinants. Approximately 20% of FSWs engaged in AI during a normal week (95% confidence interval: 15, 26). Women who performed AI were generally younger, had been selling sex for longer, were born in Cote d'Ivoire, and reported higher sex-work income, more frequent sex in public places, and violence from clients than women not reporting AI. Condom use was lower, condom breakage/slippage more frequent, and use of water-based lubricants was less frequently reported for AI than for vaginal intercourse. Using a dynamic transmission model, we estimated that 22% (95% credible interval: 11, 37% of new HIV infections could have been averted among FSWs during 2000-2015 if AI had been substituted for vaginal intercourse. Despite representing a small fraction of all sex acts, AI is an underestimated source of HIV transmission. Increasing availability and uptake of condoms, lubricants, and pre-exposure prophylaxis for women engaging in AI could help mitigate HIV risk. PMID- 28633388 TI - Sex, Obesity, and Blood Pressure Among African American Adolescents: The Jackson Heart KIDS Pilot Study. AB - BACKGROUND: This study examined the degree to which sex, weight status, and the presence of hypertension and obesity in parents/grandparents were associated with systolic (SBP) and diastolic (DBP) blood pressure (BP) among African American youth in a pilot offspring study examining obesity-related cardiovascular disease (CVD) risks among adolescents. RESULTS: Fully adjusted linear regression models of the total sample produced results indicating that obesity was associated with BP (SBP: beta = 7.08, P < 0.01; DBP: beta = 8.14, P < 0.001). Sex-stratified analyses indicated that overweight and obesity were associated with SBP (overweight: beta = 6.77, P < 0.01; obese: beta = 11.65, P < 0.001) and obesity was correlated with DBP (beta = 9.86, P < 0.001) among males. For females, overweight was correlated with SBP (beta = 4.11, P < 0.05) while obesity was associated with DBP (beta = 6.98, P < 0.01). Attempting to lose weight was inversely related to SBP (beta = -4.01, P < 0.05) in the full sample and among males (beta = -11.94, P < 0.001). Familial presence of hypertension and/or obesity was significantly associated with SBP among adolescent females but not males. CONCLUSIONS: The relationship between weight status, familial hypertension and obesity status, and BP among adolescents vary by sex. This study underscores the need for additional research investigating the relationship between individual sex, weight status, BP and familial BP, and obesity status on risk among African American adolescents. PMID- 28633390 TI - Investigating microRNA-mediated regulation of the nascent nuclear transcripts in plants: a bioinformatics workflow. AB - Most of the microRNAs (miRNAs) play their regulatory roles through posttranscriptional target decay or translational inhibition. For both plants and animals, these regulatory events were previously considered to take place in cytoplasm, as mature miRNAs were observed to be exported to the cytoplasm for Argonaute (AGO) loading and subsequent target binding. Recently, this notion was challenged by increasing pieces of evidence in the animal cells that uncovered the nuclear importation and action of the AGO-associated miRNAs. The nuclear localized regulatory mode was also reported for the plant miRNAs. However, evidence is still lacking to show the universality and conservation of the miRNA mediated regulation in the plant nuclei. Here, we introduced a bioinformatics workflow for genome-wide investigation of miRNA-guided, cleavage-based regulation of the nascent nuclear transcripts. Facilitated by the tool package PmiRNTSA (Plant microRNA-mediated nascent transcript slicing analyzer), plant biologists could perform a comprehensive search for the miRNA slicing sites located within the introns or the exon-intron/intron-exon junctions of the target transcripts, which are supported by degradome sequencing data. The results enable the researchers to examine the co-transcriptional regulatory model of the miRNAs for a specific plant species. Moreover, a case study was performed to search for the slicing sites located within the exon-intron/intron-exon junctions in two model plants. A case study was performed to show the feasibility and reliability of our workflow. Together, we hope that this work could inspire much more innovative research efforts to expand the current understanding of the miRNA action modes in plants. PMID- 28633389 TI - Multiple Soluble TGF-beta Receptors in Addition to Soluble Endoglin Are Elevated in Preeclamptic Serum and They Synergistically Inhibit TGF-beta Signaling. AB - Context: Preeclampsia (PE) can be classified into early-onset (<34 weeks of gestation) and late-onset (>34 weeks of gestation) subtypes. Soluble endoglin, an auxiliary receptor for transforming growth factor (TGF)-beta ligands, is increased in PE circulation and believed to inhibit TGF-beta action by sequestering the ligands. However, soluble endoglin, with a low affinity to TGF beta ligands, has been demonstrated to have little effect by itself on TGF-beta action. Objectives: We examined whether multiple soluble TGF-beta receptors are elevated in PE circulation and whether they synergistically block TGF-beta signaling. Design: TGF-beta receptors were measured using enzyme-linked immunosorbent assay in sera collected from preeclamptic pregnancies and gestation age-matched controls. TGF-beta signaling was assessed using an in vitro bioassay and a tube formation assay. Results: TGF-beta type I, II, and III receptors were all identified in pregnant serum; all were substantially elevated in early-onset but not late-onset PE. Endoglin was increased in both subtypes. At the greatest concentrations detected in PE, none of these soluble TGF-beta receptors alone, including endoglin, inhibited TGF-beta signaling. However, when all four soluble receptors were present, signaling of both TGF-beta1 and TGF-beta2 was substantially reduced. Removal of any one of these soluble receptors alleviated TGF-beta1 inhibition; however, removal of soluble TGFbetaRIII was necessary to relieve TGF-beta2 inhibition. Conclusions: Multiple soluble TGF-beta receptors are present in pregnant circulation and elevated in early-onset PE; they synergistically inhibit TGF-beta signaling, which might be more likely to occur in early-onset than late-onset PE. Reducing soluble TGFbetaRIII, rather than endoglin, would be more effective in alleviating the inhibition of both TGF-beta1 and TGF-beta2 signaling in PE. PMID- 28633391 TI - kmerPyramid: an interactive visualization tool for nucleobase and k-mer frequencies. AB - Summary: Bioinformatics methods often incorporate the frequency distribution of nulecobases or k-mers in DNA or RNA sequences, for example as part of metagenomic or phylogenetic analysis. Because the frequency matrix with sequences in the rows and nucleobases in the columns is multi-dimensional it is hard to visualize. We present the R-package 'kmerPyramid' that allows to display each sequence, based on its nucleobase or k-mer distribution projected to the space of principal components, as a point within a 3-dimensional, interactive pyramid. Using the computer mouse, the user can turn the pyramid's axes, zoom in and out and identify individual points. Additionally, the package provides the k-mer frequency matrices of about 2000 bacteria and 5000 virus reference sequences calculated from the NCBI RefSeq genbank. The 'kmerPyramid' can particularly be used for visualization of intra- and inter species differences. Availability and implementation: The R-package 'kmerPyramid' is available from the GitHub website at https://github.com/jkruppa/kmerPyramid. Contact: klaus.jung@tiho-hannover.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633392 TI - Invited Commentary: Can Estimation of Sodium Intake Be Improved by Borrowing Information From Other Variables? AB - Estimation of dietary sodium intake is problematic. The most accurate measure is average sodium excretion from multiple 24-hour urine collections, but such an approach is impractical. Using data from the Women's Health Initiative, Prentice et al. (Am J Epidemiol. 2017;186(9):1035-1043) assessed the relationship of calibrated estimates of sodium and potassium excretion with cardiovascular outcomes. The calibrated estimates were a function of self-reported sodium-to potassium ratio from a food frequency questionnaire, age, body mass index, race, supplement use, smoking status, educational level, income, and aspirin use. In general, associations with outcomes using the calibrated estimates were in the expected direction: direct for the sodium-to-potassium ratio and sodium intake and indirect for potassium. The unexpected associations were an increased risk of hemorrhagic stroke with lower sodium-to-potassium ratio and sodium intake and increased risk with higher potassium intake, along with a null relationship of sodium intake with ischemic stroke. Overall, our assessment is that the authors have improved the estimation of mean dietary sodium and potassium intakes. However, more work is needed to show that calibrated estimates actually improve estimation of future clinical events. If this methodological issue can be successfully addressed, their approach has the potential to improve estimation of dietary sodium and potassium intakes in observational studies. PMID- 28633393 TI - Outcomes of palliative right ventricle to pulmonary artery connection for pulmonary atresia with ventricular septal defect. AB - OBJECTIVES: To determine the early, intermediate and long-term outcomes of pulmonary atresia with ventricular septal defect (PA/VSD) Types I, II and III initially palliated by a right ventricle to pulmonary artery (RVPA) connection. METHODS: We performed a retrospective study from 2000 to 2014 that included 109 patients with PA/VSD who had undergone an RVPA connection (tetralogy of Fallot and PA/VSD Type IV excluded). The end-points of this strategy were adequate pulmonary artery tree post-palliation, second palliation, biventricular repair, right ventricular pressure post-biventricular repair and late reoperation. Mean follow-up was 5.4 years (1 day to 14-78 years). RESULTS: Early mortality after an RVPA connection was 2.7% (3 of 109). The interstage mortality rate was 6.6% (7 of 106). Eighty-four (77%) patients had a biventricular repair and 8 patients (7%) are awaiting repair. Overall survival was 90% at 1 year and 81% at 10 years. The RVPA connection allowed significant growth of the native pulmonary artery with a Nakata index of 101 mm2/m2 before the RVPA connection and 274 mm2/m2 after (P = 0.001). Twenty-nine reinterventions for restrictive pulmonary blood flow have been done (9 before 2 months and 20 after 2 months). Of the 84 patients who had a repair, 22 patients (26%) initially had a right ventricular pressure greater than 40 mmHg. Twenty-eight patients (33%) required late reoperation. CONCLUSIONS: Hospital deaths after the RVPA connection were low. The procedure allowed good growth of the native pulmonary artery. Biventricular repair was possible in a large number of cases. The late morbidity rate remains significant. Early reinterventions could be avoided by appropriate calibration. This technique appears to be suitable for any type of PA/VSD with central pulmonary arteries. PMID- 28633394 TI - Diagnostic Accuracy of Somatosensory Evoked Potential Monitoring in Evaluating Neurological Complications During Endovascular Aneurysm Treatment. AB - BACKGROUND: Somatosensory evoked potential (SSEP) monitoring is used extensively for early detection and prevention of neurological complications in patients undergoing many different neurosurgical procedures. However, the predictive ability of SSEP monitoring during endovascular treatment of cerebral aneurysms is not well detailed. OBJECTIVE: To evaluate the performance of intraoperative SSEP in the prediction postprocedural neurological deficits (PPNDs) after coil embolization of intracranial aneurysms. METHODS: This population-based cohort study included patients >=18 years of age undergoing intracranial aneurysm embolization with concurrent SSEP monitoring between January 2006 and August 2012. The ability of SSEP to predict PPNDs was analyzed by multiple regression analyses and assessed by the area under the receiver operating characteristic curve. RESULTS: In a population of 888 patients, SSEP changes occurred in 8.6% (n = 77). Twenty-eight patients (3.1%) suffered PPNDs. A 50% to 99% loss in SSEP waveform was associated with a 20-fold increase in risk of PPND; a total loss of SSEP waveform, regardless of permanence, was associated with a greater than 200 fold risk of PPND. SSEPs displayed very good predictive ability for PPND, with an area under the receiver operating characteristic curve of 0.84 (95% CI 0.76 0.92). CONCLUSION: This study supports the predictive ability of SSEPs for the detection of PPNDs. The magnitude and persistence of SSEP changes is clearly associated with the development of PPNDs. The utility of SSEP monitoring in detecting ischemia may provide an opportunity for neurointerventionalists to respond to changes intraoperatively to mitigate the potential for PPNDs. PMID- 28633395 TI - Is sarcopenia associated with depression? A systematic review and meta-analysis of observational studies. AB - Objectives: to explore whether sarcopenia is associated with depression. Design: electronic literature databases from PubMed, Scopus, Embase and Google Scholar were searched. A systematic review and meta-analysis of observational studies was conducted. Setting: community and outpatient clinic. Participants: people with and without diagnoses of sarcopenia. Measurements: outcome measures of depression. Results: about 15 articles were included, 5 of which were retrieved for narrative review. The crude odds ratios (ORs) between sarcopenia and depression were extracted from the remaining 10 studies, 6 of which also included adjusted ORs. Sarcopenia was associated with depression without adjusting covariates (crude OR, 1.640; 95% confidence interval (CI), 1.247-2.155). After adjusting for potential confounders such as age, gender, cognitive performance and physical activity, sarcopenia still demonstrated a significant positive association with depression (adjusted OR, 1.821; 95% CI, 1.160-2.859). A stratified analysis showed that the studies that used bioelectrical impedance analysis for measurement of body composition tended to have an elevated association between sarcopenia and depression compared with those that used dual energy X-ray absorptiometry or equation estimation. Conclusion: sarcopenia was independently associated with depression. The causal relationship between the two clinical conditions requires future validation with cohort studies. PMID- 28633396 TI - Response to "Motor Output Variability Impairs Driving Ability in Older Adults". PMID- 28633397 TI - Impact of a refined advanced design for left atrial appendage exclusion. AB - OBJECTIVES: Exclusion of the left atrial appendage has been proposed to reduce the risk of stroke in patients with atrial fibrillation. The aim of this study was to evaluate the feasibility and efficacy of the AtriClip PRO.V device (AOD2), now in development, for left atrial appendage exclusion in a canine model. METHODS: The newest AtriClip design comprises a dual-spring mechanism that allows the clip to open into a 'V' shape while still providing equivalent force along the length of the beam. The AOD2's hallmark is a distal tip closure to help retain the appendage during clip closure. Six dogs were implanted via thoracotomy with the clinically available AtriClip device (AOD1) on the right atrial appendage and the AOD2 on the left. At 90 days after implantation, all devices were evaluated by epicardial echocardiography, computed tomography, gross pathology and histology. System performance at the initial surgery was evaluated as well. RESULTS: The ease of use of the clinically available AtriClip device (AOD1) and AOD2 was deemed comparable in all cases. All animals survived for the planned 90-day duration without complications. The atrial appendages were fully occluded in all cases without device migration. On histology, all AtriClip devices demonstrated an acceptable biocompatibility response. CONCLUSIONS: The AOD2 achieved easy, reliable and safe exclusion of the left atrial appendage, with favourable histologic findings. Once approved for clinical application, the AOD2 could provide a new therapeutic option to lower the risks of stroke in patients with atrial fibrillation. PMID- 28633398 TI - A novel system for the treatment of aortic annular dilation: an ex vivo investigation. AB - OBJECTIVES: The main reason for aortic repair failures is recurrent annular dilatation. The fibrous portion of left ventricular outflow tract dilates. A novel device was designed to tackle this problem. METHODS: The device consists of an internal ring applied at the aortic annulus plus an external flexible band at the level of the aortic root. The internal ring has a semi-rigid portion (40%, placed at ventriculo-arterial junction) and a flexible portion to allow it to conform along the curves of the non-coronary/right coronary leaflet and right coronary/left coronary leaflet commissures. The external band acts as a reinforcement to the internal ring. A pulsatile mock loop capable of housing porcine aortic valve was used. Working conditions were 60 bpm of heart rate, 75 of stroke volumes and 120-80 mmHg of simulated pressure. Mean gradient, effective orifice area, annular diameter, coaptation height and length were recorded on 11 aortic root units (ARUs). High-speed video and standard echocardiographic images were also recorded. All data were acquired in the following conditions: (i) basal (untreated ARU); (ii) pathological condition (left coronary/non-coronary triangle was dilated by suturing an aortic patch); and (iii) ARU treated with the device. RESULTS: Gradients and effective orifice area were respectively 0.9 +/- 0.64 mmHg and 3.1 +/- 0.7cm2 (pathological) and 3.7 +/- 1.1 mmHg and 1.5 +/- 0.2cm2 (treated, P < 0.05). Left coronary/non-coronary diameter decreased from 2.4 +/- 0.2 cm (pathological) to 2.0 +/- 0.2 (treated, P < 0.05). Coaptation length and height were fully restored to basal values following treatment. Visual inspection showed proper dynamics of the leaflet, confirmed by high-speed video and echocardiography. CONCLUSIONS: The device allowed for restoring physiologic-like coaptation in the experimental model, without inducing clinically relevant worsening of the haemodynamics of the treated ARU. PMID- 28633399 TI - The interfacial character of antibody paratopes: analysis of antibody-antigen structures. AB - Summary: In this study, computational methods are applied to investigate the general properties of antigen engaging residues of a paratope from a non redundant dataset of 403 antibody-antigen complexes to dissect the contribution of hydrogen bonds, hydrophobic, van der Waals contacts and ionic interactions, as well as role of water molecules in the antigen-antibody interface. Consistent with previous reports using smaller datasets, we found that Tyr, Trp, Ser, Asn, Asp, Thr, Arg, Gly, His contribute substantially to the interactions between antibody and antigen. Furthermore, antibody-antigen interactions can be mediated by interfacial waters. However, there is no reported comprehensive analysis for a large number of structured waters that engage in higher ordered structures at the antibody-antigen interface. From our dataset, we have found the presence of interfacial waters in 242 complexes. We present evidence that suggests a compelling role of these interfacial waters in interactions of antibodies with a range of antigens differing in shape complementarity. Finally, we carry out 296 835 pairwise 3D structure comparisons of 771 structures of contact residues of antibodies with their interfacial water molecules from our dataset using CLICK method. A heuristic clustering algorithm is used to obtain unique structural similarities, and found to separate into 368 different clusters. These clusters are used to identify structural motifs of contact residues of antibodies for epitope binding. Availability and implementation: This clustering database of contact residues is freely accessible at http://mspc.bii.a star.edu.sg/minhn/pclick.html. Contact: minhn@bii.a-star.edu.sg, chandra@bii.a star.edu.sg or zhong_pingyu@immunol.a-star.edu.sg. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633400 TI - Herpes zoster encephalitis: a rare complication in a nonagenarian. PMID- 28633402 TI - Pitcher perfect: arrhythmia monitoring at the Munich Oktoberfest. PMID- 28633401 TI - Biomedical text mining for research rigor and integrity: tasks, challenges, directions. AB - An estimated quarter of a trillion US dollars is invested in the biomedical research enterprise annually. There is growing alarm that a significant portion of this investment is wasted because of problems in reproducibility of research findings and in the rigor and integrity of research conduct and reporting. Recent years have seen a flurry of activities focusing on standardization and guideline development to enhance the reproducibility and rigor of biomedical research. Research activity is primarily communicated via textual artifacts, ranging from grant applications to journal publications. These artifacts can be both the source and the manifestation of practices leading to research waste. For example, an article may describe a poorly designed experiment, or the authors may reach conclusions not supported by the evidence presented. In this article, we pose the question of whether biomedical text mining techniques can assist the stakeholders in the biomedical research enterprise in doing their part toward enhancing research integrity and rigor. In particular, we identify four key areas in which text mining techniques can make a significant contribution: plagiarism/fraud detection, ensuring adherence to reporting guidelines, managing information overload and accurate citation/enhanced bibliometrics. We review the existing methods and tools for specific tasks, if they exist, or discuss relevant research that can provide guidance for future work. With the exponential increase in biomedical research output and the ability of text mining approaches to perform automatic tasks at large scale, we propose that such approaches can support tools that promote responsible research practices, providing significant benefits for the biomedical research enterprise. PMID- 28633403 TI - Structured Populations of Sulfolobus acidocaldarius with Susceptibility to Mobile Genetic Elements. AB - The impact of a structured environment on genome evolution can be determined through comparative population genomics of species that live in the same habitat. Recent work comparing three genome sequences of Sulfolobus acidocaldarius suggested that highly structured, extreme, hot spring environments do not limit dispersal of this thermoacidophile, in contrast to other co-occurring Sulfolobus species. Instead, a high level of conservation among these three S. acidocaldarius genomes was hypothesized to result from rapid, global-scale dispersal promoted by low susceptibility to viruses that sets S. acidocaldarius apart from its sister Sulfolobus species. To test this hypothesis, we conducted a comparative analysis of 47 genomes of S. acidocaldarius from spatial and temporal sampling of two hot springs in Yellowstone National Park. While we confirm the low diversity in the core genome, we observe differentiation among S. acidocaldarius populations, likely resulting from low migration among hot spring "islands" in Yellowstone National Park. Patterns of genomic variation indicate that differing geological contexts result in the elimination or preservation of diversity among differentiated populations. We observe multiple deletions associated with a large genomic island rich in glycosyltransferases, differential integrations of the Sulfolobus turreted icosahedral virus, as well as two different plasmid elements. These data demonstrate that neither rapid dispersal nor lack of mobile genetic elements result in low diversity in the S. acidocaldarius genomes. We suggest instead that significant differences in the recent evolutionary history, or the intrinsic evolutionary rates, of sister Sulfolobus species result in the relatively low diversity of the S. acidocaldarius genome. PMID- 28633404 TI - Agreement Between 35 Published Frailty Scores in the General Population. AB - In elderly populations, frailty is associated with higher mortality risk. Although many frailty scores (FS) have been proposed, no single score is considered the gold standard. We aimed to evaluate the agreement between a wide range of FS in the English Longitudinal Study of Ageing (ELSA). Through a literature search, we identified 35 FS that could be calculated in ELSA wave 2 (2004-2005). We examined agreement between each frailty score and the mean of 35 FS, using a modified Bland-Altman model and Cohen's kappa (kappa). Missing data were imputed. Data from 5,377 participants (ages >=60 years) were analyzed (44.7% men, 55.3% women). FS showed widely differing degrees of agreement with the mean of all scores and between each pair of scores. Frailty classification also showed a very wide range of agreement (Cohen's kappa = 0.10-0.83). Agreement was highest among "accumulation of deficits"-type FS, while accuracy was highest for multidimensional FS. There is marked heterogeneity in the degree to which various FS estimate frailty and in the identification of particular individuals as frail. Different FS are based on different concepts of frailty, and most pairs cannot be assumed to be interchangeable. Research results based on different FS cannot be compared or pooled. PMID- 28633405 TI - Addressing the key communication barriers between microbiology laboratories and clinical units: a qualitative study. AB - Background: Many countries are on the brink of establishing antibiotic stewardship programmes in hospitals nationwide. In a previous study we found that communication between microbiology laboratories and clinical units is a barrier to implementing efficient antibiotic stewardship programmes in Norway. We have now addressed the key communication barriers between microbiology laboratories and clinical units from a laboratory point of view. Methods: Qualitative semi structured interviews were conducted with 18 employees (managers, doctors and technicians) from six diverse Norwegian microbiological laboratories, representing all four regional health authorities. Interviews were recorded and transcribed verbatim. Thematic analysis was applied, identifying emergent themes, subthemes and corresponding descriptions. Results: The main barrier to communication is disruption involving specimen logistics, information on request forms, verbal reporting of test results and information transfer between poorly integrated IT systems. Furthermore, communication is challenged by lack of insight into each other's area of expertise and limited provision of laboratory services, leading to prolonged turnaround time, limited advisory services and restricted opening hours. Conclusions: Communication between microbiology laboratories and clinical units can be improved by a review of testing processes, educational programmes to increase insights into the other's area of expertise, an evaluation of work tasks and expansion of rapid and point-of-care test services. Antibiotic stewardship programmes may serve as a valuable framework to establish these measures. PMID- 28633406 TI - In Saccharomyces cerevisiae gene targeting fidelity depends on a transformation method and proportion of the overall length of the transforming and targeted DNA. AB - Gene replacement is one of the most essential approaches in construction of the genetically modified yeast strains. However, the fidelity of gene targeting and the effort needed for construction of a particular strain can vary significantly. We investigated the influence of two important factors-the choice of the transformation method and the design of the transforming DNA fragment, which can vary in overall length (including flanking regions and selectable marker) compared to the length of the targeted region in the genome. Gene replacement fidelity was determined in several assays using electroporation and spheroplast transformation, and compared with our previous results obtained by lithium acetate. We have demonstrated clearly that gene targeting fidelity depends on the transformation protocol, being highest for lithium acetate method. In contrast, lower fidelity was observed with electroporation and spheroplast transformation. Additionally, the fidelity also depends on a design of the transformation assay, since a higher overall length ratio of the transforming DNA and targeted region results in higher fidelity. Moreover, the karyotype analysis of the aberrant transformants by qPCR demonstrates that gene targeting can result in diploidisation of haploid strains, most likely via targeted chromosome duplication followed by subsequent duplication of other chromosomes. PMID- 28633408 TI - Risk Factors for Readmission with Cerebrospinal Fluid Leakage Within 30 Days of Vestibular Schwannoma Surgery. AB - BACKGROUND: Cerebrospinal fluid (CSF) leak is a well-recognized complication after surgical resection of vestibular schwannomas and is associated with a number of secondary complications, including readmission and meningitis. OBJECTIVE: To identify risk factors for and timing of 30-d readmission with CSF leak. METHODS: Patients who had undergone surgical resection of a vestibular schwannoma from 1995 to 2010 were identified in the California Office of Statewide Health Planning and Development database. The most common admission diagnoses were identified by International Classification of Disease, ninth Revision, diagnosis codes, and predictors of readmission with CSF leak were determined using logistic regression. RESULTS: A total of 6820 patients were identified. CSF leak, though a relatively uncommon cause of admission after discharge (3.52% of all patients), was implicated in nearly half of 490 readmissions (48.98%). Significant independent predictors of readmission with CSF leak were male sex (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.32 2.25), first admission at a teaching hospital (OR 3.32, 95% CI 1.06-10.39), CSF leak during first admission (OR 1.84, 95% CI 1.33-2.55), obesity during first admission (OR 2.10, 95% CI 1.20-3.66), and case volume of first admission hospital (OR of log case volume 0.82, 95% CI 0.70-0.95). Median time to readmission was 6 d from hospital discharge. CONCLUSION: This study has quantified CSF leak as an important contributor to nearly half of all readmissions following vestibular schwannoma surgery. We propose that surgeons should focus on technical factors that may reduce CSF leakage and take advantage of potential screening strategies for the detection of CSF leakage prior to first admission discharge. PMID- 28633407 TI - Exploring fungus-plant N transfer in a tripartite ant-plant-fungus mutualism. AB - Background and Aims: The plant Hirtella physophora, the ant Allomerus decemarticulatus and a fungus, Trimmatostroma sp., form a tripartite association. The ants manipulate both the plant trichomes and the fungus to build galleries under the stems of their host plant used to capture prey. In addition to its structural role, the fungus also improves nutrient uptake by the host plant. But it still remains unclear whether the fungus plays an indirect or a direct role in transferring nutrients to the plant. This study aimed to trace the transfer of N from the fungus to the plant's stem tissue. Methods: Optical microscopy and transmission electron microscopy (TEM) were used to investigate the presence of fungal hyphae in the stem tissues. Then, a 15N-labelling experiment was combined with a nanoscale secondary-ion mass spectrometry (NanoSIMS 50) isotopic imaging approach to trace the movement of added 15N from the fungus to plant tissues. Key Results: The TEM images clearly showed hyphae inside the stem tissue in the cellular compartment. Also, fungal hyphae were seen perforating the wall of the parenchyma cell. The 15N provisioning of the fungus in the galleries resulted in significant enrichment of the 15N signature of the plant's leaves 1 d after the 15N-labelling solution was deposited on the fungus-bearing trap. Finally, NanoSIMS imaging proved that nitrogen was transferred biotrophically from the fungus to the stem tissue. Conclusions: This study provides evidence that the fungi are connected endophytically to an ant-plant system and actively transfer nitrogen from 15N-labelling solution to the plant's stem tissues. Overall, this study underlines how complex the trophic structure of ant-plant interactions is due to the presence of the fungus and provides insight into the possibly important nutritional aspects and tradeoffs involved in myrmecophyte-ant mutualisms. PMID- 28633409 TI - The effect of PD-L1 testing on the cost-effectiveness and economic impact of immune checkpoint inhibitors for the second-line treatment of NSCLC. AB - Background: Immune checkpoint inhibitors improve outcomes compared with chemotherapy in lung cancer. Tumor PD-L1 receptor expression is being studied as a predictive biomarker. The objective of this study was to assess the cost effectiveness and economic impact of second-line treatment with nivolumab, pembrolizumab, and atezolizumab with and without the use of PD-L1 testing for patient selection. Design: We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and second-line immunotherapy versus docetaxel. The model used outcomes data from randomized clinical trials (RCTs) and drug acquisition costs from the United States. Thereafter, we used epidemiologic data to estimate the economic impact of the treatment. Results: We included four RCTs (2 with nivolumab, 1 with pembrolizumab, and 1 with atezolizumab). The incremental quality-adjusted life year (QALY) for nivolumab was 0.417 among squamous tumors and 0.287 among non-squamous tumors and the incremental cost-effectiveness ratio (ICER) were $155 605 and $187 685, respectively. The QALY gain in the base case for atezolizumab was 0.354 and the ICER was $215 802. Compared with treating all patients, the selection of patients by PD-L1 expression improved incremental QALY by up to 183% and decreased the ICER by up to 65%. Pembrolizumab was studied only in patients whose tumors expressed PD-L1. The QALY gain was 0.346 and the ICER was $98 421. Patient selection also reduced the budget impact of immunotherapy. Conclusion: The use of PD-L1 expression as a biomarker increases cost-effectiveness of immunotherapy but also diminishes the number of potential life-years saved. PMID- 28633410 TI - Cryptococcus neoformans and gattii promote DNA damage in human peripheral blood mononuclear cells. AB - Cryptococcosis, a systemic mycosis capable of disseminating to the central nervous system with frequent lethal effects, is caused by the species Cryptococus neoformans and Cryptococcus gattii. Several infectious agents such as virus, bacteria, and parasites may be associated to DNA damage and carcinogenesis in humans. Products of the oxidative metabolism, such as NO, produced as a host defense mechanism to destroy these pathogens, have been implicated in this damage process, due to excessive production related to an established chronic inflammatory response. Here, we investigated whether C. neoformans and /or C. gattii can cause DNA damage in human peripheral blood mononuclear cells (PBMCs) and whether this process is related to NO levels produced by PBMCs. We found that both species are equally able to induce genotoxicity in PBMCs. However, an association between DNA damage and high NO levels was only detected in relation to C. gattii. The results point to the possibility that patients with cryptococcosis are more susceptible to the development of other diseases. PMID- 28633411 TI - Surgeon-Level Variability in Outcomes, Cost, and Comorbidity Adjusted-Cost for Elective Lumbar Decompression and Fusion. AB - BACKGROUND: The costs and outcomes following degenerative spine surgery may vary from surgeon to surgeon. Patient factors such as comorbidities may increase the health care cost. These variations are not well studied. OBJECTIVE: To understand the variation in outcomes, costs, and comorbidity-adjusted cost for surgeons performing lumbar laminectomy and fusions surgery. METHODS: A total of 752 patients undergoing laminectomy and fusion, performed by 7 surgeons, were analyzed. Patient-reported outcomes and 90-d cost were analyzed. Multivariate regression model was built for high-cost surgery. A separate linear regression model was built to derive comorbidity-adjusted 90-d costs. RESULTS: No significant differences in improvement were found across all the patient-reported outcomes, complications, and readmission among the surgeons. In multivariable model, surgeons #4 (P < .0001) and #6 (P = .002) had higher odds of performing high-cost fusion surgery. The comorbidity-adjusted costs were higher than the actual 90-d costs for surgeons #1 (P = .08), #3 (P = .002), #5 (P < .0001), and #7 (P < .0001), whereas they were lower than the actual costs for surgeons #2 (P = .128), #4 (P < .0001), and #6 (P = .44). CONCLUSION: Our study provides valuable insight into variations in 90-d costs among the surgeons performing elective lumbar laminectomy and fusion at a single institution. Specific surgeons were found to have greater odds of performing high-cost surgeries. Adjusting for preoperative comorbidities, however, led to costs that were higher than the actual costs for certain surgeons and lower than the actual costs for others. Patients' preoperative comorbidities must be accounted for when crafting value based payment models. Furthermore, designing intervention targeting "modifiable" factors tied to the way the surgeons practice may increase the overall value of spine care. PMID- 28633412 TI - Are leaves only involved in flowering? Bridging the gap between structural botany and functional morphology. PMID- 28633413 TI - 4-Bromodiphenyl Ether Induces Germ Cell Apoptosis by Induction of ROS and DNA Damage in Caenorhabditis elegans. PMID- 28633414 TI - An extended model of heartwood secondary metabolism informed by functional genomics. AB - The development of heartwood (HW) and the associated accumulation of secondary metabolites, which are also known as 'specialized metabolites' or 'extractives', is an important feature of tree biology. Heartwood development can affect tree health with broader implications for forest health. Heartwood development also defines a variety of wood quality traits that are important in the forest industry such as durability and colour of wood products. In the bioproducts industry, HW provides a source of high-value small molecules such as fragrances and antimicrobials. The HW properties of decay resistance in living trees, durability and colour of wood products, and small molecule bioproducts are largely defined by secondary metabolites, the biosynthesis of which appears to be activated during the onset of HW formation. Traditionally, it is thought that HW formation involves a spike in the activity of secondary metabolism in parenchyma cells in a transition zone between sapwood and HW, followed by programmed cell death. The resulting HW tissue is thought to consist entirely of dead cells. Here, we discuss a variation of existing models of HW formation, based on the recent discovery of HW-specific transcriptome signatures of terpenoid biosynthesis in sandalwood (Santalum album L.) that invokes the activity of living cells in HW. PMID- 28633416 TI - Corrigendum. PMID- 28633415 TI - Prentice et al. Respond to "Improving Estimation of Sodium Intake". PMID- 28633418 TI - Detecting and removing multiplicative spatial bias in high-throughput screening technologies. AB - Motivation: Considerable attention has been paid recently to improve data quality in high-throughput screening (HTS) and high-content screening (HCS) technologies widely used in drug development and chemical toxicity research. However, several environmentally- and procedurally-induced spatial biases in experimental HTS and HCS screens decrease measurement accuracy, leading to increased numbers of false positives and false negatives in hit selection. Although effective bias correction methods and software have been developed over the past decades, almost all of these tools have been designed to reduce the effect of additive bias only. Here, we address the case of multiplicative spatial bias. Results: We introduce three new statistical methods meant to reduce multiplicative spatial bias in screening technologies. We assess the performance of the methods with synthetic and real data affected by multiplicative spatial bias, including comparisons with current bias correction methods. We also describe a wider data correction protocol that integrates methods for removing both assay and plate-specific spatial biases, which can be either additive or multiplicative. Conclusions: The methods for removing multiplicative spatial bias and the data correction protocol are effective in detecting and cleaning experimental data generated by screening technologies. As our protocol is of a general nature, it can be used by researchers analyzing current or next-generation high-throughput screens. Availability and implementation: The AssayCorrector program, implemented in R, is available on CRAN. Contact: makarenkov.vladimir@uqam.ca. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633417 TI - Polypyrimidine tract-binding protein (PTB) and PTB-associated splicing factor in CVB3 infection: an ITAF for an ITAF. AB - The 5' UTR of Coxsackievirus B3 (CVB3) contains internal ribosome entry site (IRES), which allows cap-independent translation of the viral RNA and a 5' terminal cloverleaf structure that regulates viral replication, translation and stability. Here, we demonstrate that host protein PSF (PTB associated splicing factor) interacts with the cloverleaf RNA as well as the IRES element. PSF was found to be an important IRES trans acting factor (ITAF) for efficient translation of CVB3 RNA. Interestingly, cytoplasmic abundance of PSF protein increased during CVB3 infection and this is regulated by phosphorylation status at two different amino acid positions. Further, PSF protein was up-regulated in CVB3 infection. The expression of CVB3-2A protease alone could also induce increased PSF protein levels. Furthermore, we observed the presence of an IRES element in the 5'UTR of PSF mRNA, which is activated during CVB3 infection and might contribute to the elevated levels of PSF. It appears that PSF IRES is also positively regulated by PTB, which is known to regulate CVB3 IRES. Taken together, the results suggest for the first time a novel mechanism of regulations of ITAFs during viral infection, where an ITAF undergoes IRES mediated translation, sustaining its protein levels under condition of translation shut off. PMID- 28633419 TI - Is a Health Interview Survey an appropriate tool to assess domestic violence? AB - Background: The aim of this study is to assess if a Health Interview Survey (HIS) targeting the general population is an appropriate tool to collect valid data on domestic violence. Studying item non-response on the question on domestic violence and its association with socio-demographic and health characteristics compared with victims of domestic violence can contribute to this. Methods: Cross sectional data from the Belgian HIS 2013 were analysed. A question whether the perpetrator of a violent event was a member of the respondents' household was embedded in a general topic on violence in the self-administered questionnaire. This study is limited to people aged 15+ that at least completed the first question of this topic. Socio-demographic characteristics of item non-respondents and of victims of domestic violence were explored and the association with health status was assessed through ORs calculated via logistic regression. Results: The year prevalence of domestic violence is 1.1%. Although the question on domestic violence yields a high level of non-response (62%), this does not hinder the further completion of the questionnaire. When compared with victims of domestic violence, those not responding on the question on the perpetrator have better (mental) health. When compared with those not being victim of domestic violence, victims report poorer physical and mental health. Conclusion: An HIS can be an appropriate tool to assess domestic violence in the general population and its association with health. However, a solution should be found for the high item non-response on the question on the perpetrator of the violent event. PMID- 28633420 TI - Pancreas Fat and beta Cell Mass in Humans With and Without Diabetes: An Analysis in the Japanese Population. AB - Context: The mechanisms by which beta cell mass is reduced in patients with type 2 diabetes remain unclear. It has been postulated that ectopic fat deposits in the pancreas induce beta cell apoptosis, leading to the development of diabetes. Objective: The aim of this study was to clarify the effects of intrapancreatic fat on beta and alpha cell mass in humans with and without diabetes. Design and Subjects: Using our tissue database, pancreas sections of 72 Japanese nondiabetic (NDM) autopsy cases and 50 diabetic and 49 age- and body mass index (BMI)-matched NDM patients who underwent pancreatic surgery were analyzed. In addition to histological grading, intrapancreatic fat area (IPFA) was quantified as fractional intralobular, but not interlobular, fat area to the whole pancreas area. Results: Although IPFA was positively correlated with age and BMI, there was no significant difference in IPFA between cases with and without diabetes. Moreover, no association was found between IPFA and either beta or alpha cell area, or glycated hemoglobin. Conclusion: These findings suggest that pancreatic fat deposits have little effect on beta cell mass and the development of diabetes in humans. PMID- 28633421 TI - Linking noise to cardiovascular disease pathogenesis. PMID- 28633422 TI - "Research on Infertility: Definition Makes a Difference" Revisited. AB - In a 1989 paper, Marchbanks et al. (Am J Epidemiol. 1989;130(2):259-267) noted inconsistent definitions of infertility across research and clinical practice and examined differences in prevalence estimates across definitions. Since their study, there have been substantial changes in society, technology, and clinical practice related to female reproductive health. In response, we revisited the original paper using data from a recent study among reproductive-aged women. Internal comparisons across various definitions of infertility were made by assessing how many and which women were classified as infertile, their age at infertility, and the probability of spontaneous pregnancy after infertility. Results were also compared with Marchbanks et al. Black women were more likely to be classified as infertile than white women based on the definition "12 months of unprotected intercourse" (40.1% vs. 33.7%) but less likely by "12 months of attempting pregnancy" (14.3% vs. 21.8%) and "visiting a doctor for help getting pregnant" (8.4% vs. 19.7%). After unprotected intercourse for 12 months, 36.1% of women who were attempting pregnancy spontaneously conceived by 6 months compared with 13.5% of women who were not attempting pregnancy. While our results for most infertility definitions were similar to those of Marchbanks et al., prevalence estimates continued to differ across demographic groups by definition. PMID- 28633423 TI - rqt: an R package for gene-level meta-analysis. AB - Motivation: Despite recent advances of modern GWAS methods, it is still remains an important problem of addressing calculation an effect size and corresponding p value for the whole gene rather than for single variant. Results: We developed an R package rqt, which offers gene-level GWAS meta-analysis. The package can be easily included into bioinformatics pipeline or used stand-alone. We applied this tool to the analysis of Alzheimer's disease data from three datasets CHS, FHS and LOADFS. Test results from meta-analysis of three Alzheimer studies show its applicability for association testing. Availability and implementation: The package rqt is freely available under the following link: https://github.com/izhbannikov/rqt. Contact: ilya.zhbannikov@duke.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633424 TI - From the Cover: Three-Dimensional (3D) HepaRG Spheroid Model With Physiologically Relevant Xenobiotic Metabolism Competence and Hepatocyte Functionality for Liver Toxicity Screening. AB - Effective prediction of human responses to chemical and drug exposure is of critical importance in environmental toxicology research and drug development. While significant progress has been made to address this challenge using invitro liver models, these approaches often fail due to inadequate tissue model functionality. Herein, we describe the development, optimization, and characterization of a novel three-dimensional (3D) spheroid model using differentiated HepaRG cells that achieve and maintain physiologically relevant levels of xenobiotic metabolism (CYP1A2, CYP2B6, and CYP3A4/5). This invitro model maintains a stable phenotype over multiple weeks in both 96- and 384-well formats, supports highly reproducible tissue-like architectures and models pharmacologically- and environmentally important hepatic receptor pathways (ie AhR, CAR, and PXR) analogous to primary human hepatocyte cultures. HepaRG spheroid cultures use 50-100* fewer cells than conventional two dimensional cultures, and enable the identification of metabolically activated toxicants. Spheroid size, time in culture and culture media composition were important factors affecting basal levels of xenobiotic metabolism and liver enzyme inducibility with activators of hepatic receptors AhR, CAR and PXR. Repeated exposure studies showed higher sensitivity than traditional 2D cultures in identifying compounds that cause liver injury and metabolism-dependent toxicity. This platform combines the well-documented impact of 3D culture configuration for improved tissue functionality and longevity with the requisite throughput and repeatability needed for year-over-year toxicology screening. PMID- 28633426 TI - Atypical Histiocytoid Cells in Metastatic Papillary Thyroid Carcinoma: An Underrecognized Cytologic Pattern. AB - Objectives: Fine-needle aspiration (FNA) of head and neck lymph nodes (LNs) is useful in diagnosing metastatic papillary thyroid carcinoma (PTC) and most commonly shows classic cytologic features of PTC. Metastatic PTC, however, may occasionally present with a pattern unfamiliar to most pathologists: atypical histiocytoid cells (AHCs). Methods: All PTC thyroidectomy specimens with associated FNA of LNs were retrieved from our files for 2007 to 2013. We aimed to assess cytologic features of metastatic PTC, as well as the presence of AHCs and their morphology. Results: Fifty-six FNAs from LNs with metastatic PTC were reviewed. AHCs were identified in 38 (68%) cases, while only PTC with classic cytologic features was seen in 18 (32%) cases. AHCs did not show diagnostic nuclear features of PTC and presented as large cells with abundant cytoplasm either vacuolated or dense. Nuclei varied from vesicular with prominent nucleoli to dark and smudgy. Thirty-one cases showed mixed AHCs and classic PTC, but seven cases (13% of all metastatic PTCs in LNs) consisted only of AHCs. Conclusions: AHCs are an often unrecognized metastatic morphologic pattern of cystic PTC, as it does not show diagnostic classic nuclear features of PTC. AHCs are the predominant cytologic finding in approximately 13% of metastatic PTCs to neck LNs. PMID- 28633425 TI - Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. AB - Background: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide treated CRPC patients. Patients and methods: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (>=6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). Results: Of the 97 total patients, 51 had nmCRPC, 25 had AAP naive mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naive and 1 post AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. Conclusions: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. ClinicalTrials.gov identifier: NCT01171898. PMID- 28633428 TI - Integrated Multimaneuver Dissection Technique of the Sylvian Fissure: Operative Nuances. PMID- 28633427 TI - Genotypic variation in tolerance to drought stress is highly coordinated with hydraulic conductivity-photosynthesis interplay and aquaporin expression in field grown mulberry (Morus spp.). AB - Hydraulic conductivity quantifies the efficiency of a plant to transport water from root to shoot and is a major constriction on leaf gas exchange physiology. Mulberry (Morus spp.) is the most economically important crop for sericulture industry. In this study, we demonstrate a finely coordinated control of hydraulic dynamics on leaf gas exchange characteristics in 1-year-old field-grown mulberry genotypes (Selection-13 (S13); Kollegal Local (KL) and Kanva-2 (K2)) subjected to water stress by withholding water for 20 days and subsequent recovery for 7 days. Significant variations among three mulberry genotypes have been recorded in net photosynthetic rates (Pn), stomatal conductance and sap flow rate, as well as hydraulic conductivity in stem (KS) and leaf (KL). Among three genotypes, S13 showed significantly high rates of Pn, KS and KL both in control as well as during drought stress (DS) and recovery, providing evidence for superior drought adaptive strategies. The plant water hydraulics-photosynthesis interplay was finely coordinated with the expression of certain key aquaporins (AQPs) in roots and leaves. Our data clearly demonstrate that expression of certain AQPs play a crucial role in hydraulic dynamics and photosynthetic carbon assimilation during DS and recovery, which could be effectively targeted towards mulberry improvement programs for drought adaptation. PMID- 28633429 TI - Corrigendum. PMID- 28633430 TI - Giant steps forward. PMID- 28633431 TI - Differential Effects of Alcohol on Memory Performance in Adolescent Men and Women with a Binge Drinking History. AB - Aims: Binge drinking (BD) is characterized by intermittent consumption of large quantities of alcohol in short periods. This pattern of drinking is prevalent among adolescents, and has been associated with undermined learning and memory ability. This study investigates the relationships between a history of BD and the effects of acute exposure to alcohol on learning and memory performance in adolescent men and women. Methods: A high, acute dose of alcohol or control refreshment was administered to a sample of 172 adolescent undergraduate students, some of which had a history of BD and others of which had refrained from alcohol consumption. Subsequently, immediate visual memory (IVM) and working memory (WM) was measured according to the Wechsler Memory Scale in females and males with different BAC (Experiment 1) and similar BAC (Experiment 2). Results: In both experiments, IVM was reduced after acute alcohol consumption and there was no significant main effect of Drinking Pattern. Furthermore, an effect of cognitive alcohol tolerance on IVM was observed in women but not in men. WM was not affected by alcohol, but a gender difference was evident in that performance was superior in men than in women. Conclusions: In adolescents, IVM is more sensitive than WM to impairment by alcohol, and women are more vulnerable to the neurotoxic effects of alcohol than men, since the cognitive tolerance effect of alcohol on IVM develops in BD women but not in BD men. These findings emphasize the need to investigate the neurotoxic effects of alcohol in adolescent women. Short summary: In adolescents, immediate visual memory (IVM) is more sensitive than working memory to impairment by alcohol, and women are more vulnerable to the neurotoxic effects of alcohol than men, because the cognitive tolerance effect of alcohol on IVM develops in binge drinking (BD) women but not in BD men. PMID- 28633432 TI - Factors Associated With Home Blood Pressure Monitoring Among US Adults: National Health and Nutrition Examination Survey, 2011-2014. AB - BACKGROUND: Home blood pressure monitoring (HBPM) has a substantial role in hypertension management and control. METHODS: Cross-sectional data for noninstitutionalized US adults 18 years and older (10,958) from the National Health and Nutrition Examination Survey (NHANES), years 2011-2014, were used to examine factors related to HBPM. RESULTS: In 2011-2014, estimated 9.5% of US adults engaged in weekly HBPM, 7.2% engaged in monthly HBPM, 8.0% engaged in HBPM less than once a month, and 75.3% didn't engage any HBPM. The frequency of HBPM increased with age, body mass index, and the number of health care visits (all, P < 0.05). Also, race/ethnicity (Non-Hispanic Blacks and non-Hispanic Asians), health insurance, diagnosed with diabetes, told by a health care provider to engage in HBPM, and diagnosed as hypertensive, were all associated with more frequent HBPM (P < 0.05). Adjusting for covariates, hypertensives who were aware of, treated for, and controlled engaged in more frequent HBPM compared to their respective references: unaware (odds ratio [OR] = 2.00, 95% confidence interval [CI] = 1.53-2.63), untreated (OR = 1.99, 95% CI = 1.52-2.60), and uncontrolled (OR = 1.42, 95% CI = 1.13-1.82). Hypertensive adults (aware/unaware, treated/untreated, or controlled/uncontrolled), who received providers' recommendations to perform HBPM, were more likely to do so compared to those who did not receive recommendations (OR = 8.04, 95% CI = 6.56-9.86; OR = 7.98, 95% CI = 6.54-9.72; OR = 8.75, 95% CI = 7.18-10.67, respectively). CONCLUSIONS: Seventeen percent of US adults engaged in monthly or more frequent HBPM and health care providers' recommendations to engage in HBPM have a significant impact on the frequency of HBPM. PMID- 28633433 TI - The International Society for Computational Biology and WikiProject Computational Biology: celebrating 10 years of collaboration towards open access. PMID- 28633434 TI - PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes. AB - Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in BC initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in BC progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses revealed that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis. PMID- 28633435 TI - MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability. AB - Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability. PMID- 28633436 TI - Membrane Androgen Receptor ZIP9 Induces Croaker Ovarian Cell Apoptosis via Stimulatory G Protein Alpha Subunit and MAP Kinase Signaling. AB - Recent studies show that androgen-induced apoptosis in Atlantic croaker primary granulosa and theca (G/T) cells and in human breast and prostate cancer cell lines is mediated by the membrane androgen receptor ZIP9, which belongs to the SLC39A zinc transporter family. However, the apoptotic signaling pathways remain unclear because ZIP9 activates an inhibitory G protein in human cancer cells, whereas recombinant croaker ZIP9 activates a stimulatory G protein (Gs) in transfected cancer cells. We investigated androgen-dependent apoptotic pathways to identify the signaling pathways regulated through wild-type croaker ZIP9 in ovarian follicle cells. We show that the ZIP9-mediated apoptotic signaling pathway in croaker G/T cells shares several proapoptotic members with those in human cancer cells, but is activated through a Gsalpha subunit-dependent pathway. Testosterone treatment of croaker G/T cells increased intracellular zinc levels, mitogen-activated protein (MAP) kinase activity, caspase 3 activity, messenger RNA levels of proapoptotic members Bax, p53, and c-Jun N-terminal kinase, and the incidence of apoptosis, similar to findings in mammalian cancer cells, but also increased cyclic adenosine monophosphate concentrations. Transfection with small interfering RNA targeting croaker ZIP9 blocked testosterone-induced increase in bax, p53, and jnk expression. Testosterone-induced apoptosis and caspase 3 activation depended on the presence of extracellular zinc and were effectively blocked with cotreatment of inhibitors of the Gsalpha subunit, adenylyl cyclase, protein kinase A, and MAP kinase (Erk1/2) activation. These results indicate that ZIP9-mediated testosterone signaling in croaker G/T cells involves multiple pathways, some of which differ from those activated through ZIP9 in human cancer cells even though a similar apoptotic response is observed. PMID- 28633437 TI - Corrigendum: Barriers to Alcohol Screening Among Hypertensive Patients and the Role of Stigma: Lessons for the Implementation of Screening and Brief Interventions in European Primary Care Settings. PMID- 28633439 TI - Mobility Difficulties, Physical Activity, and All-cause Mortality Risk in a Nationally representative Sample of Older Adults. AB - Background: This study sought to determine the association between levels of physical activity and mobility difficulties and time to death while accounting for the effect of several confounders. We also examined the possible interaction between them and how various daily-life mobility difficulties could predict all cause mortality. Methods: A nationally representative sample of 2,074 noninstitutionalized adults aged 60 years and older was analyzed. Vital status over a 3-year follow-up period was ascertained through national registers or by asking participants' relatives. Kaplan-Meier survival curves were stratified by levels of physical activity and mobility difficulties. Unadjusted and adjusted Cox proportional hazards regression models (by age, gender, marital status, years of education, multimorbidity, tobacco and alcohol consumption, depression, and memory function) were calculated, and interactions between the predictors and the covariates were explored. Results: There was a dose-gradient effect of physical activity on time to death, with high levels associated with a 51% lower risk of dying, compared with moderate physical activity. Each unit increase in mobility functioning was associated with a 2% drop in mortality. Difficulties in standing for long periods, getting where one wants to go or extending arms to reach objects, were also found to be strong predictors of all-cause mortality. Conclusions: Our results confirm the importance of older adults practicing moderate-to-vigorous physical activity. The assessment of self-reported difficulties in daily-life mobility activities, such as standing for long periods or not being able to move around, could be used in health settings as a screening for mortality risk. PMID- 28633438 TI - SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across Actinobacteria. AB - Summary: Nonribosomally synthesized peptides (NRPs) are natural products with widespread applications in medicine and biotechnology. Many algorithms have been developed to predict the substrate specificities of nonribosomal peptide synthetase adenylation (A) domains from DNA sequences, which enables prioritization and dereplication, and integration with other data types in discovery efforts. However, insufficient training data and a lack of clarity regarding prediction quality have impeded optimal use. Here, we introduce prediCAT, a new phylogenetics-inspired algorithm, which quantitatively estimates the degree of predictability of each A-domain. We then systematically benchmarked all algorithms on a newly gathered, independent test set of 434 A-domain sequences, showing that active-site-motif-based algorithms outperform whole domain-based methods. Subsequently, we developed SANDPUMA, a powerful ensemble algorithm, based on newly trained versions of all high-performing algorithms, which significantly outperforms individual methods. Finally, we deployed SANDPUMA in a systematic investigation of 7635 Actinobacteria genomes, suggesting that NRP chemical diversity is much higher than previously estimated. SANDPUMA has been integrated into the widely used antiSMASH biosynthetic gene cluster analysis pipeline and is also available as an open-source, standalone tool. Availability and implementation: SANDPUMA is freely available at https://bitbucket.org/chevrm/sandpuma and as a docker image at https://hub.docker.com/r/chevrm/sandpuma/ under the GNU Public License 3 (GPL3). Contact: chevrette@wisc.edu or marnix.medema@wur.nl. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633440 TI - Low Alanine Aminotransferase Levels in the Elderly Population: Frailty, Disability, Sarcopenia, and Reduced Survival. AB - Background: Although low alanine aminotransferase (ALT) levels have been associated with poor outcomes in the elderly population, the determinants subtending this association have been poorly explored. To gain insight into this topic, we analyzed data from a prospective population-based database (InCHIANTI study) in which frailty, disability, sarcopenia, and pyridoxine levels were systematically assessed. Methods: Data are from 765 participants aged more than 65 years (mean age 75.3 years, women 61.8%), without chronic liver disease, malignancies, or alcohol abuse. Frailty was defined according to Fried criteria, sarcopenia through peripheral Quantitative-Computed-Tomography (lowest gender specific tertile of the residuals of a linear regression of muscle mass from height and fat mass), and disability as self-reported need for help in at least one basic daily living activity. Associations of ALT with overall and cardiovascular mortality were assessed by Cox-models with time-dependent covariates. Results: ALT activity was inversely associated with frailty, sarcopenia, disability, and pyridoxine deficiency; however, higher ALT was confirmed to be protective with respect of overall and cardiovascular mortality even in multiple-adjusted models including all these covariates (overall: hazard ratio [HR] 0.98 [0.96-1], p = .02; cardiovascular: 0.94 [0.9-0.98], p < .01). The association between ALT activity and mortality was nonlinear (J-shaped), and subjects in the lower quintiles of ALT levels showed a sharply increased overall and cardiovascular mortality. Conclusions: These results suggest that reduced ALT levels in older individuals can be considered as a marker of frailty, disability, and sarcopenia, and as an independent predictor of adverse outcomes. The possible relationship between reduced ALT and impaired hepatic metabolic functions should be explored. PMID- 28633441 TI - BioQueue: a novel pipeline framework to accelerate bioinformatics analysis. AB - Motivation: With the rapid development of Next-Generation Sequencing, a large amount of data is now available for bioinformatics research. Meanwhile, the presence of many pipeline frameworks makes it possible to analyse these data. However, these tools concentrate mainly on their syntax and design paradigms, and dispatch jobs based on users' experience about the resources needed by the execution of a certain step in a protocol. As a result, it is difficult for these tools to maximize the potential of computing resources, and avoid errors caused by overload, such as memory overflow. Results: Here, we have developed BioQueue, a web-based framework that contains a checkpoint before each step to automatically estimate the system resources (CPU, memory and disk) needed by the step and then dispatch jobs accordingly. BioQueue possesses a shell command-like syntax instead of implementing a new script language, which means most biologists without computer programming background can access the efficient queue system with ease. Availability and implementation: BioQueue is freely available at https://github.com/liyao001/BioQueue. The extensive documentation can be found at http://bioqueue.readthedocs.io. Contact: li_yao@outlook.com or gcsui@nefu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633442 TI - Continuous Glucose Monitoring in Female NOD Mice Reveals Daily Rhythms and a Negative Correlation With Body Temperature. AB - Previous studies with continuous glucose monitoring in mice have been limited to several days or weeks, with the mouse's physical attachment to the equipment affecting behavior and measurements. In the current study, we measured blood glucose and body temperature at 10-second intervals for 12 weeks in a cohort of NOD/ShiLtJ female mice using wireless telemetry. This allowed us to obtain a high resolution profile of the circadian rhythm of these two parameters and the onset of hyperglycemic development in real time. The most striking observations were the elevated nocturnal concentrations of glucose into the diabetic range days before elevations in diurnal glucose (when glucose concentrations are historically measured) and the strong, negative correlation between elevated blood glucose concentrations and body temperature with a steady decline of the body temperature with diabetes development. Taken together, this technological advancement provides improved resolution in the study of the disease trajectory of diabetes in mouse models, including relevant translatability to the current technologies of continuous glucose monitoring now regularly used in patients. PMID- 28633443 TI - NOD2 Genetic Variants Predispose One of Two Familial Adenomatous Polyposis Siblings to Pouchitis Through Microbiome Dysbiosis. AB - Background and Aims: Individuals with familial adenomatous polyposis (FAP) may undergo a total proctocolectomy with ileal pouch-anal anastomosis (IPAA) to surgically treat their disease. Inflammation of the ileal pouch, termed pouchitis, is uncommon in FAP patients but prevalent in patients who received IPAA for ulcerative colitis, a type of inflammatory bowel disease (IBD). Methods and Results: We report on two FAP siblings, living in the same household, who underwent IPAA surgery within one week of each other. Their mother also had an IPAA for FAP. One sibling developed pouchitis while his brother and mother have remained pouchitis-free. We investigated the genetic and microbial factors that might explain the development of pouchitis in the one sibling. We surveyed DNA isolated from the two brothers and their parents for NOD2 IBD risk variants by Sanger sequencing. The composition of mucosa-associated bacteria was analyzed by 16S rRNA gene sequencing on terminal ileum and rectal tissue collected at the time of surgical resection from the two brothers. The sibling with pouchitis inherited the IBD-associated risk alleles for NOD2 (rs17221417 and rs2076756) from his healthy father. Both the mother and unaffected brother lacked these variants. Microbiome sequencing of the terminal ileum and rectum found reduced levels of potentially 'beneficial' bacteria (Faecalibacterium prausnitzii, Bacteroides, and Ruminococcaceae) in the sibling with pouchitis relative to his brother. Conclusion: These findings suggest that the NOD2 signaling pathway may contribute to intrinsic bacterial dysbiosis which is pre-existing and which may then predispose individuals to pouchitis after IPAA surgery. PMID- 28633445 TI - BPP: a sequence-based algorithm for branch point prediction. AB - Motivation: Although high-throughput sequencing methods have been proposed to identify splicing branch points in the human genome, these methods can only detect a small fraction of the branch points subject to the sequencing depth, experimental cost and the expression level of the mRNA. An accurate computational model for branch point prediction is therefore an ongoing objective in human genome research. Results: We here propose a novel branch point prediction algorithm that utilizes information on the branch point sequence and the polypyrimidine tract. Using experimentally validated data, we demonstrate that our proposed method outperforms existing methods. Availability and implementation: https://github.com/zhqingit/BPP. Contact: djguo@cuhk.edu.hk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28633447 TI - A rare pathological entity of right ventricular diverticulum. PMID- 28633448 TI - The Origin of Novelty Through the Evolution of Scaling Relationships. AB - Morphological novelty is often thought of as the evolution of an entirely new body plan or the addition of new structures to existing body plans. However, novel morphologies may also arise through modification of organ systems within an existing body plan. The evolution of novel scaling relationships between body size and organ size constitutes such a novel morphological feature. Experimental studies have demonstrated that there is genetic variation for allometries and that scaling relationships can evolve under artificial selection. We show that an allometry equation derived from Gompertz growth kinetics can accurately reconstruct complex non-linear allometries, and can be used to deduce the growth kinetics of the parts being compared. The equation also shows the relationship between ontogenetic and static allometries. We discuss how changes in the non linear kinetics of growth can give rise to novel allometric relationships. Using parameters for wing and body growth of Manduca sexta, and a population simulation of the allometry equation, we show that selection on wing-body scaling can dramatically alter wing size without changing body size. PMID- 28633446 TI - Genetic Indicators of Drug Resistance in the Highly Repetitive Genome of Trichomonas vaginalis. AB - Trichomonas vaginalis, the most common nonviral sexually transmitted parasite, causes ~283 million trichomoniasis infections annually and is associated with pregnancy complications and increased risk of HIV-1 acquisition. The antimicrobial drug metronidazole is used for treatment, but in a fraction of clinical cases, the parasites can become resistant to this drug. We undertook sequencing of multiple clinical isolates and lab derived lines to identify genetic markers and mechanisms of metronidazole resistance. Reduced representation genome sequencing of ~100 T. vaginalis clinical isolates identified 3,923 SNP markers and presence of a bipartite population structure. Linkage disequilibrium was found to decay rapidly, suggesting genome-wide recombination and the feasibility of genetic association studies in the parasite. We identified 72 SNPs associated with metronidazole resistance, and a comparison of SNPs within several lab-derived resistant lines revealed an overlap with the clinically resistant isolates. We identified SNPs in genes for which no function has yet been assigned, as well as in functionally-characterized genes relevant to drug resistance (e.g., pyruvate:ferredoxin oxidoreductase). Transcription profiles of resistant strains showed common changes in genes involved in drug activation (e.g., flavin reductase), accumulation (e.g., multidrug resistance pump), and detoxification (e.g., nitroreductase). Finally, we identified convergent genetic changes in lab-derived resistant lines of Tritrichomonas foetus, a distantly related species that causes venereal disease in cattle. Shared genetic changes within and between T. vaginalis and Tr. foetus parasites suggest conservation of the pathways through which adaptation has occurred. These findings extend our knowledge of drug resistance in the parasite, providing a panel of markers that can be used as a diagnostic tool. PMID- 28633444 TI - Controversies in the Management of Low-Risk Differentiated Thyroid Cancer. AB - Controversy exists over optimal management of low-risk differentiated thyroid cancer. This controversy occurs in all aspects of management, including surgery, use of radioactive iodine for remnant ablation, thyroid hormone supplementation, and long-term surveillance. Limited and conflicting data, treatment paradigm shifts, and differences in physician perceptions contribute to the controversy. This lack of physician consensus results in wide variation in patient care, with some patients at risk for over- or undertreatment. To reduce patient harm and unnecessary worry, there is a need to design and implement studies to address current knowledge gaps. PMID- 28633449 TI - Night work as a risk factor of future disability pension due to musculoskeletal diagnoses: a prospective cohort study of Swedish twins. AB - Background: This study investigated the associations between night work, sleep and disability pension (DP) due to musculoskeletal disorders (MSD), while controlling for several confounding factors including both genetic factors and shared family background. Methods: The study sample consisted of 27 165 Swedish twin individuals born in 1935-58 with comprehensive survey data on sociodemographic, health and lifestyle factors. Night work was assessed as years of working hours at night at least every now and then, and categorized into 'not at all, 1-10 years and over 10 years'. Data on DP with MSD (ICD-diagnoses M00 M99) were obtained from the National Social Insurance Agency. Follow-up was from the time of the interview in 1998-2003 until 2013. Information on the length and quality of sleep was available for a sub-sample of twins (n = 1684). Cox proportional hazards models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). Results: During the follow-up, 1338 (5%) participants were granted DP due to MSD. Both 1-10 years (HR 1.33, 95% CI 1.17-1.53) and over 10 years of night work (HR 1.39 95% CI 1.18-1.64) increased the risk of future DP. The associations were not affected by health, lifestyle or sleep factors. In the discordant twin pair analysis, the associations between night work and DP due to MSD attenuated. Conclusions: Night work was associated with increased risk of DP due to MSD independently from health and lifestyle factors. Familial confounding could not be ruled out. PMID- 28633451 TI - CHA2DS2-VASc score and blood biomarkers to identify patients with atrial high rate episodes and paroxysmal atrial fibrillation: the role of TIMP-4 regulation. PMID- 28633450 TI - Comparative Genomics of All Three Campylobacter sputorum Biovars and a Novel Cattle-Associated C. sputorum Clade. AB - Campylobacter sputorum is a nonthermotolerant campylobacter that is primarily isolated from food animals such as cattle and sheep. C. sputorum is also infrequently associated with human illness. Based on catalase and urease activity, three biovars are currently recognized within C. sputorum: bv. sputorum (catalase negative, urease negative), bv. fecalis (catalase positive, urease negative), and bv. paraureolyticus (catalase negative, urease positive). A multi locus sequence typing (MLST) method was recently constructed for C. sputorum. MLST typing of several cattle-associated C. sputorum isolates suggested that they are members of a divergent C. sputorum clade. Although catalase positive, and thus technically bv. fecalis, the taxonomic position of these strains could not be determined solely by MLST. To further characterize C. sputorum, the genomes of four strains, representing all three biovars and the divergent clade, were sequenced to completion. Here we present a comparative genomic analysis of the four C. sputorum genomes. This analysis indicates that the three biovars and the cattle-associated strains are highly related at the genome level with similarities in gene content. Furthermore, the four genomes are strongly syntenic with one or two minor inversions. However, substantial differences in gene content were observed among the three biovars. Finally, although the strain representing the cattle-associated isolates was shown to be C. sputorum, it is possible that this strain is a member of a novel C. sputorum subspecies; thus, these cattle-associated strains may form a second taxon within C. sputorum. PMID- 28633453 TI - A multifaceted quality improvement strategy reduces the risk of catheter associated urinary tract infection. AB - Objective: Catheter-associated urinary tract infections (CAUTIs) are common and preventable hospital-acquired infections, yet their rate continues to rise nationwide. We describe the implementation of a multifaceted program to reduce catheter use and CAUTI rates while simultaneously addressing barriers to long term success. Design/Setting/Participants: Pre-post study of medical inpatient veterans between December 2012 and February 2015. Intervention: Five component intervention: (i) a bedside catheter reminder; (ii) multidisciplinary educational campaign; (iii) structured catheter order set with clinical decision support; (iv) automated catheter discontinuation orders; and (v) protocol for post catheter removal care. Main Outcome Measure(s): Catheter utilization rates and CAUTI rates on the study ward were followed during the 14-week baseline period, the 27-week transition/intervention period and the 70-week period of full implementation/sustainability. Rates of patient falls per bed days and catheter reinsertions were collected during the same time periods as balancing measures. Results: Catheter use declined by 35% from the baseline period to the full implementation/sustainability period. This improvement was not realized until deployment of the structured electronic orders with automated catheter discontinuation and protocolized post-catheter care. The average number of days between CAUTIs on the study ward increased from 101 days in the baseline period to over 400 days in the full implementation/sustainability period. There was no significant change in the rates of falls or catheter reinsertions during the study period. Conclusions: A multicomponent intervention aimed specifically at targeting local barriers was successful in reducing catheter utilization as well as CAUTIs in a veteran population without compensatory increase in patient falls or catheter replacement. PMID- 28633454 TI - Long-Term Efficacy of Ultrasound-Guided Injection of IncobotulinumtoxinA in Piriformis Syndrome. PMID- 28633452 TI - Threshold Effects of Circulating Angiopoietin-Like 3 Levels on Plasma Lipoproteins. AB - Context: Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of function gene mutations results in familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low-density lipoprotein (LDL) phenotype in carriers of ANGPTL3 mutations is unexplained. Objective: To determine whether reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to determine whether proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in determining low LDL levels in this condition. Design: We studied subjects from 19 families with ANGPTL3 mutations and subjects with familial combined hypobetalipoproteinemia type 1 (FHBL1) due to truncated apolipoprotein B (apoB) species. Results: First, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels but only when the latter was <25% of normal (<60 ng/dL). Second, the very low-density lipoprotein particle concentration correlated strongly with plasma ANGPTL3 when the latter was <58% of normal. Third, both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9 and higher levels of its furin-cleaved form. Finally, LDL-bound PCSK9 is protected from cleavage by furin and binds to the LDL receptor more strongly than apoB-free PCSK9. Conclusions: Our results suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on a threshold of plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues. PMID- 28633456 TI - Feeding during dialysis-risks and uncertainties. AB - Allowing dialysis patients to eat during the treatment is controversial. It is, therefore, no surprise that practices and policies with respect to intradialytic food consumption vary considerably from unit to unit and from country to country. Those who defend the position of feeding during dialysis reason that intradialytic meals offer a supervised and effective therapy for protein-energy wasting. Those who take the opposite view argue that intradialytic food intake should be avoided for the following three reasons. First, interventional studies show that eating during dialysis causes a clinically significant reduction in systemic blood pressure during the postprandial period and elevates the risk of symptomatic intradialytic hypotension; the latter is associated with increased mortality risk. Second, clinical studies have shown that eating during dialysis interferes with the adequacy of the delivered dialysis, whereas eating 2-3 h before the dialysis session has no impact on the efficiency of the subsequent dialysis treatment. And third, randomized studies show that eating during dialysis focus on the positive outcomes but do not adequately balance this potential benefit against the risk of intradialytic hemodynamic instability and poor quality of delivered dialysis. Even after half a century of providing long term dialysis, definitive randomized trials that balance risks and benefits of eating during dialysis are missing. These knowledge gaps require randomized trials. Since there is a real possibility of harm with eating during dialysis, we caution that instead of encouraging the widespread use of intradialytic meals, practices and policies should focus on adequate nutrient intake during the interdialytic interval. PMID- 28633455 TI - Fetal Metabolic Stress Disrupts Immune Homeostasis and Induces Proinflammatory Responses in Human Immunodeficiency Virus Type 1- and Combination Antiretroviral Therapy-Exposed Infants. AB - Increased morbidity and fetal growth restriction are reported in uninfected children born to human immunodeficiency virus type 1 (HIV-1)-infected women treated with antiretroviral (ARV) therapy. Viruses and/or pharmacological interventions such as ARVs can induce metabolic stress, skewing the cell's immune response and restricting (cell) growth. Novel metabolomic techniques provided the opportunity to investigate the impact of fetal HIV-1 and combination ARV therapy (cART) exposure on the infants' immune metabolome. Peroxidized lipids, generated by reactive oxygen species, were increased in cART/HIV-1-exposed infants, indicating altered mitochondrial functioning. The lipid metabolism was further dysregulated with increased triglyceride species and a subsequent decrease in phospholipids in cART/HIV-1-exposed infants compared to control infants. Proinflammatory immune mediators, lysophospholipids as well as cytokines such as CXCL10 and CCL3, were increased whereas anti-inflammatory metabolites from the cytochrome P450 pathway were reduced in cART/HIV-1-exposed infants. Taken together, these data demonstrate that the fetal metabolism is impacted by maternal factors (cART and HIV-1) and skews physiological immune responses toward inflammation in the newborn infant. PMID- 28633458 TI - Causes of death and mortality trends of all individuals reported with HIV/AIDS in Israel, 1985-2010. AB - Background: Highly active antiretroviral therapy (HAART) has changed life expectancy and mortality trends among people living with HIV/AIDS (PLWHA) since 1996. This retrospective cohort study aimed to assess the mortality epidemiology of PLWHA in Israel and analyze the causes of death. Methods: This cohort study included all adult Israeli-citizens PLWHA between 1985 and 2010 and crossed matched with the Civil Registry to identify those who died. Death certificates were classified into AIDS or non-AIDS deaths related-causes. Standardized mortality-ratio (SMR) represented mortality excess. Results: Of all 5140 PLWHA who were followed-up for 36 955 person-years, 1066 (20.7%) died. The ratio of AIDS-related deaths to non-AIDS related deaths reduced from 1.2:1 before 1996 to 0.6:1 after 1997, and case-fatality rates reduced from 12.0 to 0.9%, respectively (P < 0.001). SMR were 3.0 (95% CI: 2.3-3.5) for males and 3.9 (95% CI: 3.3-4.5) for females. Fatality cases were more likely older Israeli-born males, co infected with tuberculosis, reported before 1996 and acquired HIV by drug injection or infected-blood products. Deaths of AIDS-related causes were common among Israeli-born gay men, while non-AIDS deaths were common among those reported after 1997 and drug users. Conclusions: Death rates declined since HAART introduction. Yet, SMR remained high, and PLWHA infected by drug-use or blood products have not enjoyed relative longevity. PMID- 28633457 TI - The Hemagglutinin A Stem Antibody MEDI8852 Prevents and Controls Disease and Limits Transmission of Pandemic Influenza Viruses. AB - Background: MEDI8852 is a novel monoclonal antibody (mAb) that neutralizes both group I and group II influenza A viruses (IAVs) in vitro. We evaluated whether MEDI8852 was effective for prophylaxis and therapy against representative group I (H5N1) and group II (H7N9) pandemic IAVs in mice and ferrets and could be used to block transmission of influenza H1N1pdm09 in ferrets, compared to an irrelevant control mAb R347 and oseltamivir. Methods: MEDI8852 was administered to mice and ferrets by intraperitoneal injection at varying doses, 24 hours prior to intranasal infection with H5N1 and H7N9 viruses for prophylaxis, and 24, 48, and 72 hours post-infection for treatment. A comparison with oseltamivir alone and combination of MEDI8852 and oseltamivir was included in some studies. Survival, weight loss, and viral titers were assessed over a 14-day study period. For the transmission study, naive respiratory contact ferrets received MEDI8852 or R347 prior to exposure to ferrets infected with an H1N1pdm09 virus. Results: MEDI8852 was effective for prophylaxis and treatment of H7N9 and H5N1 infection in mice, with a clear dose-dependent response and treatment with MEDI8852 24, 48, or 72 hours postinfection was superior to oseltamivir for H5N1. MEDI8852 alone was effective treatment for lethal H5N1 infection in ferrets compared to oseltamivir and R347, and MEDI8852 plus oseltamivir was better than oseltamivir alone. MEDI8852 or oseltamivir alone early in infection was equally effective for H7N9 infection in ferrets while the combination yielded similar protection when treatment was delayed. MEDI8852 was able to protect naive ferrets from airborne transmission of H1N1pdm09. Conclusions: MEDI8852, alone or with oseltamivir, shows promise for prophylaxis or therapy of group I and II IAVs with pandemic potential. Additionally, MEDI8852 blocked influenza transmission in ferrets, a unique finding among influenza-specific mAbs. PMID- 28633459 TI - Electron microscopy of voids in Si formed by permeable pulse laser irradiation. AB - Voids formed in Si by permeable laser irradiation were investigated by comprehensive electron microscopy. Two types of voids were identified: Type (1): This type was formed mostly closer to the entrance surface of a laser, and a considerable volume of a non-diamond Si (DS) phase was formed in the surrounding matrix. Type (2): This type was formed at the focus of an incident laser, and none of dislocations, cracks and non-DS phase was observed in the surrounding matrix. Type (1) voids are considered to be formed to accommodate volume change resulting from transformation from DS to the non-DS. However, it is difficult to explain formation of Type (2) voids by this mechanism. PMID- 28633460 TI - Guidelines for Composing and Assessing a Paper on Treatment of Pain. AB - Authors, readers, and editors share a common focus. Authors want to publish their work. Readers want to see high-quality, new information. Referees and editors serve to ensure that authors provide valid conclusions based on the quality of information that readers want.Common to each of these roles are instructions to authors. However, these are typically written in an uninspiring, legalistic style, as if they are a set of rules that authors must obey if they expect to get published. This renders the instructions boring and oppressive, if not forbidding. Yet they need not be so, if they are set in context.Instructions to authors can be cast in a way as to reflect common purpose. They can remind authors what perceptive readers want to see in a paper and, thereby, prompt authors to include all necessary information. If cast in this way, instructions to authors are not a set of rules by which to satisfy publishers; they become guidelines for the etiquette of communication between authors and their readers.Against this background, the present article has been composed to serve several purposes. Foremost, it amplifies instructions to authors beyond the conventional technicalities such as headings, layout, font size, and line spacing. It prescribes the type of information that should be communicated and explains the reasons for those recommendations. Doing so not only informs authors about what to write, but also informs readers and referees about what to look for in a good paper. Secondarily, the article publicizes examples of errors and deficiencies of manuscripts submitted to the Journal in the past that have delayed their acceptance and publication, which could have been avoided had the forthcoming recommendations been followed. The recommendations also reprise the elements taught in courses conducted by the Spine Intervention Society in their extended program on evidence-based medicine. Doing so underscores that instructions for authors are not a procedural technicality but a way to ensure that what authors write, what readers read, and what the Journal publishes comply with contemporary precepts of good evidence.Some 20 years ago, the Journal of the American Medical Association published a comprehensive series of articles with a common title: "Users' Guides to the Medical Literature" [1,2]. These articles focused on the science of statistical tests and critical appraisal, and their importance for properly understanding the literature. The present article differs in that it does not presume to teach technicalities. Instead, it describes and explains, step by step, the critical components of an article, what authors should include, and what readers should look for, so that the Journal can ensure that consistent, high-quality information is shared between its authors and readers.The present article focuses on articles concerning treatment of pain, largely because this type of article is more commonly submitted than articles on reliability or validity of diagnostic procedures. Although the present article principally focuses on papers for the Spine Section of the Journal, the same principles, appropriately adapted, serve for other sections. PMID- 28633461 TI - TRAC(ERx)-ing lung cancer evolution. PMID- 28633462 TI - In Reply: Genealogy of Training in Vascular Neurosurgery. PMID- 28633463 TI - The Body Odor Disgust Scale (BODS): Development and Validation of a Novel Olfactory Disgust Assessment. AB - Disgust plays a crucial role in the avoidance of pathogen threats. In many species, body odors provide important information related to health and disease, and body odors are potent elicitors of disgust in humans. With this background, valid assessments of body odor disgust sensitivity are warranted. In the present article, we report the development and psychometric validation of the Body Odor Disgust Scale (BODS), a measure suited to assess individual differences in disgust reaction to a variety of body odors. Collected data from 3 studies (total n = 528) show that the scale can be used either as a unidimensional scale or as a scale that reflects two hypothesized factors: sensitivity to one's own body odors versus those of others. Guided by our results, we reduced the scale to 12 items that capture the essence of these 2 factors. The final version of the BODS shows an excellent internal consistency (Cronbach's alphas > 0.9). The BODS subscales show convergent validity with other general disgust scales, as well as with other olfactory functions measures and with aspects of personality that are related to pathogen avoidance. A fourth study confirmed the construct validity of the BODS and its measurement invariance to gender. Moreover, we found that, compared with other general disgust scales, the BODS is more strongly related to perceived vulnerability to disease. The BODS is a brief and valid assessment of trait body odor disgust sensitivity. PMID- 28633464 TI - Hyposmia and Disgust: Gender-Specific Effects. AB - Reduced olfactory function is associated with altered trait disgust in men. This study sought to determine whether hyposmic women show similar changes in disgust responsiveness. We compared patients with hyposmia (25 men, 23 women) and 50 normosmic individuals (25 men, 25 women) with regard to their tendency to experience disgust across different disgust domains (disgust proneness), their self-disgust and their tendency to perceive their own disgust feelings as difficult to control and embarrassing (disgust sensitivity). We replicated the finding that male patients reported elevated self-disgust and disgust proneness toward a specific disgust domain (poor hygiene), whereas female patients obtained comparable disgust scores as the female control group. Both men and women of the patient group indicated disgust regulation difficulties in social contexts. In conclusion, we found greater changes in trait disgust in men with hyposmia. This gender-specific effect, which might be a result of more efficient compensatory behaviors in women, needs further investigation. PMID- 28633465 TI - Erratum. PMID- 28633467 TI - Erratum. PMID- 28633466 TI - Is complete response the answer? PMID- 28633468 TI - Skin Sensitization: Challenging the Conventional Thinking-A Case Against 2 Out of 3 as Integrated Testing Strategy. PMID- 28633469 TI - A Framework Illustrating Care-Seeking Among Older Adults in a Hospital Emergency Department. AB - Background and Objectives: Older adults seeking emergency department (ED) care often have multiple, complex chronic conditions. We sought to understand factors that influence ED care-seeking by older adults and present a theoretical framework illustrating this process. Research Design and Methods: In this grounded theory study, we interviewed 40 older adults with chronic illness within 90 days of an ED visit to explore their decision-making about seeking ED care. We also interviewed 10 primary care and ED physicians to explore conditions that influence ED referrals. Interview transcripts were analyzed using constant comparison and dimensional analysis. Results: ED care-seeking among older adults is complex and influenced by multiple internal and external conditions including symptom type, severity, and onset; previous experience with and meaning of similar symptoms; limited access to prompt primary care; social and financial concerns; and deciding if symptoms warranted immediate attention. When contacting their primary care providers (PCPs), patients were often referred to the ED. Discussion and Implications: Older adults seeking ED care make rational and appropriate choices which are often predicated by referrals from their PCPs. Expecting patients to have the requisite knowledge to determine if symptoms require emergency care is unrealistic. ED visits are often the best strategy for patients to receive appropriate care. A healthcare system that provides better continuity between PCPs and the ED, better access to PCPs for urgent care, and timely follow-up care that takes into account the multiple and complex medical and social needs of older community-living adults is needed. PMID- 28633470 TI - Longitudinal Trajectories of Quality of Life and Depression by Housing Tenure Status. PMID- 28633471 TI - Development of a chicken ileal explant culture model for measurement of gut inflammation induced by lipopolysaccharide. AB - Gut mucosa holds a single layer of epithelial cells and the largest mass of lymphoid tissue in the body. Although the epithelial cell culture model is widely used to assess intestinal barrier function, it has limitations for studying cellular interactions, in particular those of the immune system. In this study, a chicken ileal explant culture model was developed for investigating short-term gut inflammatory and secretory responses in an ex vivo environment. Initially, ileal explants from broilers at 21 d of age were cultured ex vivo up to 6 h. Explants cultured for a maximum of 2 h remained over 90% viable, based on lactate dehydrogenase (LDH) release assay. Morphologically, explants cultured for 2 h displayed normal morphology compared to those cultured longer, further confirming that short-term culture for up to 2 h duration is an acceptable model for studying ex vivo regulation of inflammation. Subsequently, lipopolysaccharide (LPS) dose-related responses were determined for explants cultured for 2 h. Results from LDH activity assay showed that the viability of explants was decreased (P <= 0.05) at an LPS dose higher than 50 MUg/mL. A significant (P <= 0.05) nitric oxide release was observed at LPS concentrations of 10 and 20 MUg/mL. In addition, the highest inflammatory and secretory responses were detected at 20 MUg/mL LPS based on gene expression of TLR-4, IL-1beta, IL-8, MUC2, IgA, and pIgR (P <= 0.05). However, the gene expression of claudin-1 and claudin-4 were not increased at the determined LPS concentrations (P > 0.05). These results demonstrated the potential usefulness of this intestinal explant culture model for short-term study of biological factors in gut inflammatory and secretory responses, but not a sufficient duration for evaluation of tight junction responsiveness. PMID- 28633472 TI - Association Between Subjective Sleep Quality and Future Risk of Falls in Older People: Results From LOHAS. AB - Background: Inadequate sleep is correlated with morbidity and mortality among older adults. However, the longitudinal relationship between subjective sleep quality and risk of falls in the elderly population remains to be clarified. Methods: Study participants were from Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS) sites (1,071 community-dwelling people ?65 years of age, mean: 71 years). Subjective sleep quality was measured by the Pittsburgh Sleep Quality Index (PSQI). Occurrence of falls (defined as experiencing at least one fall) during the subsequent year was ascertained by a self-reported questionnaire. Results: Mean global PSQI score was 4.3 (SD 3.2), with 28.9% of participants rating their sleep quality as poor (PSQI > 5). A total of 210 participants (19.6%) fell at least once in the year following sleep examination. Multivariable analysis revealed that participants reporting worse subjective sleep quality had significantly higher odds of experiencing falls during the 1 year follow-up period (adjusted odds ratio [AOR] = 1.50 for each three-point increase in global PSQI score; 95% confidence interval [CI] = 1.20, 1.89). Participants in the highest global PSQI score (PSQI > 5) quartile had significantly increased odds of experiencing falls compared to those in the lowest global score quartile (PSQI < 2; AOR = 2.14; 95% CI = 1.09, 4.22). This association was similarly significant in subgroup analyses for older men and women, nonusers of sleep medication, and those without a history of falls at baseline. Conclusion: Subjective poor sleep quality, as measured by the PSQI, is longitudinally associated with greater risk of experiencing falls in community dwelling older adults. PMID- 28633473 TI - Experimental evolution and the adjustment of metabolic strategies in lactic acid bacteria. AB - Experimental evolution of microbes has gained lots of interest in recent years, mainly due to the ease of strain characterisation through next-generation sequencing. While evolutionary and systems biologists use experimental evolution to address fundamental questions in their respective fields, studies with lactic acid bacteria are often more directed by applied questions. Insight into population and genome dynamics are valuable for experimental design and data interpretation, and it is becoming increasingly apparent how different constraints limit and govern the outcome of microbial adaptation to a selective environment. Examples for such constraints are the finite membrane and cellular space which can lead to trade-offs between cellular strategies. A powerful perspective is that of resource allocation, which allows cells to maximise fitness. This impacts on metabolic strategies that have different protein/resource demands. This review focuses on parameters and forces that shape cellular optimisation processes and that are determining for the outcome of laboratory evolution experiments. Phenotypic changes of experimentally evolved lactic acid bacteria will be discussed in the light of the selection conditions and the prevailing constraints. PMID- 28633474 TI - Interleukin-1 blockade for the treatment of pericarditis. AB - Pericarditis is a debilitating condition that results from profound inflammation of the pericardial tissue. Between 10 and 15% of first episodes of acute pericarditis will be followed by several episodes refractory to conventional treatment. Current standard of care for pericarditis treatment includes high-dose non-steroidal anti-inflammatory drugs, colchicine, and systemic corticosteroids, each associated with potentially severe toxicities and nominal efficacy. Interleukin-1 (IL-1), an apical pro-inflammatory cytokine, plays an important role as an autocrine magnifier of systemic inflammation in pericarditis. Interruption of the IL-1 circuit has been shown to have a favourable risk profile in several disease states. In this review, we discuss the growing body of evidence which supports the use of IL-1 blockade in the treatment of recurrent pericarditis as well as provide practical considerations for the use of IL-1 blockade in clinical practice. PMID- 28633475 TI - Cloning and Characterization of Cheilanthifoline and Stylopine Synthase Genes from Chelidonium majus. AB - The most prominent alkaloid of Chelidonium majus is dihydrocoptisine, revealing the characteristic benzophenanthridine skeleton. To date, any informationon on the enzymes responsible for its biosynthesis and the related genes in C. majus is lacking. Based on sequence similarities to the corresponding methylenedioxy bridge-forming Cyt P450 enzymes involved in isoquinoline alkaloid biosynthesis in Eschscholzia californica, genes for a cheilanthifoline synthase and a stylopine synthase from C. majus were isolated, sequenced and heterologously expressed in yeast. The activity of the heterologously expressed Cyt P450 enzymes was determined in situ as well as on the basis of microsomal fractions. It was shown that cheilanthifoline synthase (c8931) converts scoulerine into cheilanthifoline, the latter subsequently being converted to stylopine by the action of a stylopine synthase (c1128). Based on the well-known instability of stylopine, it can be assumed that in vivo-under the acidic conditions in the vacuole-this alkaloid is converted to dihydrocoptisine, which accumulates in C. majus leaves. Both methylenedioxy bridge-forming Cyt P450 enzymes from C. majus are characterized by their high substrate specificity. Apart from their genuine substrates, i.e. scoulerine and cheilanthifoline, cheilanthifoline synthase and stylopine synthase do not accept other substrates tested; the only alternative substrate identified was scoulerine, which is converted by stylopine synthase to yield minor amounts of nandinine. Quantitative real-time PCR revealed that the expression of cheilanthifoline synthase and stylopine synthase genes is very similar in both roots and leaves from C. majus, although the alkaloid accumulation patterns in these organs are quite different. PMID- 28633476 TI - Corrigendum. PMID- 28633477 TI - Loop diuretics for chronic heart failure: a foe in disguise of a friend? AB - Loop diuretics are recommended for relieving symptoms and signs of congestion in patients with chronic heart failure and are administered to more than 80% of them. However, several of their effects have not systematically been studied. Numerous cohort and four interventional studies have addressed the effect of diuretics on renal function; apart from one prospective study, which showed that diuretics withdrawal is accompanied by increase in some markers of early-detected renal injury, all others converge to the conclusion that diuretics receipt, especially in high doses is associated with increased rates of renal dysfunction. Although a long standing perception has attributed a beneficial effect to diuretics in the setting of chronic heart failure, many cohort studies support that their use, especially in high doses is associated with adverse outcome. Several studies have used propensity scores in order to match diuretic and non diuretic receiving patients; their results reinforce the notion that diuretics use and high diuretics dose are true risk factors and not disease severity markers, as some have suggested. One small, randomized study has demonstrated that diuretics decrease is feasible and safe and accompanied by a better prognosis. In conclusion, until elegantly designed, randomized trials, powered for clinical endpoints answer the unsettled issues in the field, the use of diuretics in chronic heart failure will remain subject to physicians' preferences and biases and not evidence based. PMID- 28633478 TI - Efficacy of 3D transoesophageal echocardiography for transcatheter device closure of atrial septal defect without balloon sizing. AB - Aims: Using balloon sizing to determine device size may cause complications and increase procedure time in performing transcatheter closure of atrial septal defect (ASD). We aimed to validate the clinical utility of a formula using measurements from 3D transoesophageal echocardiography (TOE) images in performing the procedure without balloon sizing. Methods and results: We enrolled 248 consecutive patients with ASD in a prospective registry. In the first tier (n = 53), we determined the device size before the procedure using our formula and performed balloon sizing during the procedure to verify our decision. In the second tier (n = 195), the procedure was performed without balloon sizing. In the first tier, the estimated device size correlated well with the device size finally implanted (R = 0.961, P < 0.001; bias, 0.38 +/- 1.5 mm, P < 0.001) and with the stretched balloon diameter (R = 0.929, P < 0.001; bias, 0.13 +/- 2.0 mm, P < 0.001). In the second tier, the device size derived from the formula was used in all patients, with the exception of one patient who showed a deficient rim on the aorta and superior sides and ASD that was not on a single plane. Two patients with unfavourable morphologies for device implantation experienced embolization of the device. Of the 193 patients with procedural success (99.0%), 2 suffered from haemopericardium caused by atrial wall erosion by the device. There were no procedure-related deaths. Conclusion: The transcatheter closure of ASD using the 3D TOE-derived formula without balloon sizing is clinically feasible and safe. However, caution should be taken to exclude unfavourable features of ASD (ClinicalTrials.gov number NCT 02097758). PMID- 28633479 TI - Geographical inequalities in uptake of NHS funded eye examinations: Poisson modelling of small-area data for Essex, UK. AB - Background: Small-area analysis of National Health Service (NHS)-funded sight test uptake in Leeds showed significant inequalities in access among people aged <16 or >=60. Methods: Data were extracted from 604 126 valid General Ophthalmic Services (GOS)1 claim forms for eye examinations for Essex residents between October 2013 and July 2015. Expected GOS1 uptake for each lower super output area was based on England annual uptake. Poisson regression modelling explored associations in GOS1 uptake ratio with deprivation. Results: People aged >=60 or <16 living in the least deprived quintile were 15% and 26%, respectively, more likely to have an NHS funded eye examination than the most deprived quintile, although all are equally entitled. GOS1 uptake is higher in the more deprived quintiles among 16-59-year old, as means tested social benefits are the main eligibility criteria in this age-group. Inequalities were also observed at local authority level. Conclusions: Inequalities in access among people >=60 years were not as large as those reported in Leeds, although inequalities in <16-year old were similar. However, demonstrable inequalities in this data set over a longer time period and a larger and more diverse area than Leeds, reinforce the argument that interventions are needed to address eye examination uptake inequalities. PMID- 28633480 TI - A prospective examination of circulating tumor cell profiles in non-small-cell lung cancer molecular subgroups. AB - Background: We report the first study examining the clinical, numerical and biological properties of circulating tumor cells according to molecular subtypes of non-small-cell lung cancer. Patients and methods: 125 patients with treatment naive stage IIIb-IV NSCLC were prospectively recruited for CellSearch analysis. Anti-vimentin antibody was included for examination of CTCs to assess their mesenchymal character. Associations of total CTCs and vimentin-positive (vim +) CTCs with clinical characteristics, tumor genotype, and survival were assessed. Results: 51/125 patients (40.8%) were total CTC+ and 26/125 (20.8%) were vim CTC+ at baseline. Multivariate analysis showed patients with >=5 total CTCs had significantly reduced OS (HR 0.55, 95% CI 0.33-0.92, P = 0.022) but not PFS (HR 0.68, 95% CI 0.42-1.1, P = 0.118) compared to patients with <5 total CTCs. No OS difference was evident between vim+ CTC and vim-negative CTC patients overall (HR 1.24, 95% CI 0.67-2.28, P = 0.494), but after subdivision according to NSCLC driver mutation, we found an increase of vim+ CTCs in the EGFR-mutated subgroup (N = 21/94 patients; mean 1.24 vs 1.22 vim+ CTCs, P = 0.013), a reduction of total CTCs in the ALK-rearranged subgroup (N = 13/90 patients; mean 1.69 vs 5.82 total CTCs, P = 0.029), and a total absence of vim+ CTCs in KRAS-mutated adenocarcinomas (N = 19/78 patients; mean 0 vs 1.4 vim+ CTCs, P = 0.006). Conclusions: We validate that the baseline presence of >=5 total CTCs in advanced NSCLC confers a poor prognosis. CTCs from EGFR-mutant NSCLC express epithelial mesenchymal transition characteristics, not seen in CTCs from patients with KRAS mutant adenocarcinoma. PMID- 28633481 TI - Adherence to oral chemotherapy medications among gastroenterological cancer patients visiting an outpatient clinic. AB - Objective: The purpose of this study was to investigate medication adherence to oral chemotherapy medications and determinants of medication non-adherence to them among gastroenterological cancer patients. Methods: A cross-sectional study was conducted on 117 consecutive, consenting, eligible patients visiting an outpatient clinic of university hospital in Japan. Good medication adherence was defined as taking 100% of the prescribed dose. Medication adherence was measured via self-report. We hypothesized that there was a significant relationship between medication non-adherence and the five factors defined by the World Health Organization: patient-related, socioeconomic-related, condition-related, treatment-related, and healthcare-system/provider-related factors. Multiple logistic regression models were used to identify factors associated with oral chemotherapy medication non-adherence. Results: The proportion of patients showing good medication adherence was 56.4%. The multiple logistic regression analysis revealed that the determinants of medication non-adherence to oral chemotherapy medications included having a history of patient-caused treatment interruptions due to worsening of symptoms (adjusted odds ratio [AOR] = 9.59, 95% confidence interval [CI] = 1.38-66.47), having diarrhea (AOR = 3.25, 95% CI = 1.13-9.34), experiencing pain (AOR = 0.17, 95% CI = 0.05-0.55), taking oral chemotherapy medication every 8 h (AOR = 5.52, 95% CI = 1.71-17.81), and diminished sense of priority for medication (AOR = 1.40, 95% CI = 1.21-1.63). Conclusions: This study suggests that many patients with gastroenterological cancer were non-adherent to oral chemotherapy medications. It might be necessary to conduct periodic screening and connect patients at a high risk of medication non-adherence to appropriate support. PMID- 28633483 TI - An informatics research agenda to support patient and family empowerment and engagement in care and recovery during and after hospitalization. AB - As part of an interdisciplinary acute care patient portal task force with members from 10 academic medical centers and professional organizations, we held a national workshop with 71 attendees representing over 30 health systems, professional organizations, and technology companies. Our consensus approach identified 7 key sociotechnical and evaluation research focus areas related to the consumption and capture of information from patients, care partners (eg, family, friends), and clinicians through portals in the acute and post-acute care settings. The 7 research areas were: (1) standards, (2) privacy and security, (3) user-centered design, (4) implementation, (5) data and content, (6) clinical decision support, and (7) measurement. Patient portals are not yet in routine use in the acute and post-acute setting, and research focused on the identified domains should increase the likelihood that they will deliver benefit, especially as there are differences between needs in acute and post-acute care compared to the ambulatory setting. PMID- 28633482 TI - Markers of Adipogenesis, but Not Inflammation, in Adipose Tissue Are Independently Related to Insulin Sensitivity. AB - Context: In obesity, adipose tissue (AT) undergoes dynamic remodeling, including an alternation in adipogenesis, AT-resident cell content, angiogenesis, and turnover of extracellular matrix (ECM) components. Studies of AT in humans have been carried out mostly in people with severe metabolic abnormalities, like type 2 diabetes or morbid obesity. Objective: The purpose of this study was to investigate subcutaneous AT gene expression of markers of adipogenesis, ECM remodeling, and inflammation in young, healthy, overweight or obese subjects. Design: The study group comprised 83 normal-weight, 48 overweight, and 19 obese subjects. Euglycemic hyperinsulinemic clamp, biopsy of subcutaneous AT, and isolation of peripheral blood mononuclear cells (PBMCs) were performed. Gene expression was measured with real-time polymerase chain reaction. Results: Overweight/obese subjects had lower AT expression of markers of adipogenesis, insulin signaling, and angiogenesis; higher expression of markers of ECM remodeling; altered expression of genes of the nuclear factor-kappa-B (NFkappaB), but not c-Jun NH2-terminal kinase, pathway; and higher expression of macrophage markers but not markers of other immune cells. In multiple regression analysis, the expression of CEBPA, ADIPOQ, IRS1, IRS2, SLC2A4, and MMP9 was associated with insulin sensitivity independently of body mass index. No differences were found in inflammatory-gene PBMC expression. Conclusion: Overweight/obesity is associated with altered expression of genes of adipogenesis, insulin signaling, ECM remodeling, and inflammation. NFkappaB seems to be the earliest inflammatory pathway altered at the transcriptional level in AT. Macrophages seem to be the first immune cells to infiltrate AT. Adipogenesis and ECM remodeling are the initial processes in AT that are independently associated with insulin sensitivity. PMID- 28633484 TI - Disparities in cigarette smoking and use of other tobacco products in Minnesota, 2003-14. AB - Background: Despite efforts to reduce disadvantages across society, widening health disparities have been observed in Minnesota. This research examined whether observed declines in state-wide smoking prevalence were experienced equally by all adults with varying educational attainment. Methods: Serial cross sectional data from the 2003, 2007, 2010 and 2014 Minnesota Adult Tobacco Survey (MATS) were analyzed. Weighted regression analyses for smoking status, time to first cigarette, cigarettes per day and non-cigarette other tobacco products (OTP) were conducted across education levels. Results: Controlling for age and gender, a decreased rate of smoking among high and middle education groups was offset by an increase in the low education group. Dependence (time to first cigarette) was twice as high in the lowest education group compared to highest, yet dependence did not decline over time for any group. There was a decline in cigarettes per day in all education groups, but an increase in OTP use in the lowest and middle education groups. Conclusions: Given existing smoking disparities, novel efforts are urgently needed. Complementing known population level strategies with community and individual-level approaches will be necessary to eliminate the widening gap in smoking disparities and to end the burden of tobacco-related disease. PMID- 28633485 TI - Whole-genome sequencing identifies nosocomial transmission of extra-pulmonary Mycobacterium tuberculosis. PMID- 28633486 TI - Electron microscopy gain a glimpse into the pathogenesis of cardiac sarcoidosis. PMID- 28633487 TI - High Intensity Interval Training Improves Physical Performance and Frailty in Aged Mice. AB - Sarcopenia and frailty are highly prevalent in older individuals, increasing the risk of disability and loss of independence. High intensity interval training (HIIT) may provide a robust intervention for both sarcopenia and frailty by achieving both strength and endurance benefits with lower time commitments than other exercise regimens. To better understand the impacts of HIIT during aging, we compared 24-month-old C57BL/6J sedentary mice with those that were administered 10-minute uphill treadmill HIIT sessions three times per week over 16 weeks. Baseline and end point assessments included body composition, physical performance, and frailty based on criteria from the Fried physical frailty scale. HIIT-trained mice demonstrated dramatic improvement in grip strength (HIIT 10.9% vs -3.9% in sedentary mice), treadmill endurance (32.6% vs -2.0%), and gait speed (107.0% vs 39.0%). Muscles from HIIT mice also exhibited greater mass, larger fiber size, and an increase in mitochondrial biomass. Furthermore, HIIT exercise led to a dramatic reduction in frailty scores in five of six mice that were frail or prefrail at baseline, with four ultimately becoming nonfrail. The uphill treadmill HIIT exercise sessions were well tolerated by aged mice and led to performance gains, improvement in underlying muscle physiology, and reduction in frailty. PMID- 28633488 TI - Viral Diagnostics: Only Half the Battle. PMID- 28633489 TI - Effects of early pregnancy on uterine lymphocytes and endometrial expression of immune-regulatory molecules in dairy heifers. AB - Natural killer (NK) cells are essential for establishment of human and rodent pregnancies. The function of these and other cytotoxic T cells (CTL) is controlled by stimulatory and inhibitory signaling. A role for cytotoxic cells during early pregnancy in cattle has not been described, but regulation of their function at the fetal-maternal interface is thought to be critical for conceptus survival. The hypothesis that the relative abundance of CTL and expression of inhibitory signaling molecules is increased by the conceptus during early pregnancy was tested. The proportions of lymphoid lineage cells and expression of inhibitory signaling molecules in the endometrium during early pregnancy in dairy heifers were determined using flow cytometry, immunofluorescence, and real-time PCR on days 17 and 20 of pregnancy and day 17 of the estrous cycle. Results revealed an increased percentage of NKp46+ and CD8+ cells in the uterus of pregnant heifers. Furthermore, a large percentage of uterine immune cells coexpressed these proteins. Compared to cyclic heifers, CD45+ uterine cells from pregnant heifers exhibited greater degranulation. Endometrium from pregnant heifers had greater mRNA abundance for the inhibitory molecules, CD274 and lymphocyte activating gene 3 (LAG3), and greater cytotoxic T lymphocyte associated protein 4 (CTLA4), molecules that can interact with receptors on antigen-presenting cells and induce lymphocyte tolerance. This study demonstrates a dynamic regulation of both cytotoxic immune cells and tolerogenic molecules during the peri-implantation period that may be required to support establishment of pregnancy and placentation. PMID- 28633490 TI - Isolated Fourth Ventricle: To Shunt or Stent. AB - BACKGROUND: Of the various management options for isolated fourth ventricle (IFV), fourth ventriculoperitoneal shunts (FVPS) and aqueductal stents (AST) have been the most favored. Though effective, FVPS are often difficult to place and have higher complication rates than conventional ventricular shunts. OBJECTIVE: To assess the efficacy of AST in IFV and compare the outcome with FVPS. METHODS: Twenty-five patients surgically treated for IFV were analyzed. In all, a preoperative magnetic resonance imaging assessed the extent of aqueductal obstruction. Patients with an identified short-segment aqueductal stenosis were considered for AST placement; those with long-segment aqueductal obstruction underwent FVPS. RESULTS: Of the 25, 12 were symptomatic, while 13 were asymptomatic (progressive dilation of IFV in 9, persistent dilation with distortion of the brain stem in 4). In 3 with normal ventricles, the ventricles had to be dilated by externalizing the shunt before placing the stent. Nineteen underwent AST placement, whereas in 6 FVPS was performed. Sixteen patients underwent a simultaneous cerebrospinal fluid diversion procedure and fourth ventricular decompression. At follow-up (mean: 45 mo), stent migration was observed in 2 patients. In the FVPS group, 1 had 2 shunt revisions while another developed reversible cranial nerve paresis. Though a reduction of the IFV was observed with both procedures, the extent of reduction was more with FVPS. CONCLUSION: Both FVPS and AST are effective in managing IFV. The extent of aqueductal obstruction and degree of ventriculomegaly are often the deciding factors in choosing the management option. PMID- 28633491 TI - Optimization of inactivated H5N9 highly pathogenic avian influenza vaccine and inactivated Salmonella enterica serovar Typhimurium vaccine with antigen dose and prime-boost regimen in domestic ducks. AB - Owing to the increase in the number of diseases affecting ducks and the demand for food safety by consumers, vaccination has become one of the factors that influence duck meat productivity. The highly pathogenic avian influenza (HPAI) virus is one of the most prevalent and causes one of the most lethal diseases in domestic ducks, and Salmonella enterica serovar Typhimurium is a food-borne pathogen persistent in the domestic duck population. To better understand the optimal usage of HPAI and S. enterica serovar Typhimurium vaccines, we aimed to determine antigen dose, oil and gel adjuvant usage with prime-boost regimen, and vaccination age, inducing the best immune response in ducks, without an effect on body weight gain. In the case of the inactivated H5N9 vaccine, a single dose of vaccine was inadequate to induce proper antibody titer when administered to day old ducks, which necessitates boost vaccination. Administration of the oil adjuvanted H5N9 vaccine administration in day-old and 2-week-old ducks resulted in a lower body weight at the time of slaughtering, compared to that of gel adjuvanted H5N9 vaccine. However, gel-adjuvanted H5N9 vaccine failed to induce proper immune response to an extent recommend by OIE-World Organization for Animal Health. In the case of the Salmonella enterica serovar Typhimurium vaccine, a moderate or low dose of vaccine was appropriate for day-old ducks receiving the gel prime-oil boost vaccination. Single vaccination with oil adjuvants affects the mean body weight of 7-week-old ducks, suggesting that the gel adjuvant is more suitable for meat production. We expect that the use of adjuvants in a prime-boost regimen and at antigen doses set in this study will be helpful to maximize body weight in the case of domestic duck production at the actual farm site. PMID- 28633492 TI - Letter: Stereotactic Radiosurgery for Cystic Vestibular Schwannomas. PMID- 28633493 TI - Corrigendum. PMID- 28633494 TI - Silencing Effect of Hominoid Highly Conserved Noncoding Sequences on Embryonic Brain Development. AB - Superfamily Hominoidea, which consists of Hominidae (humans and great apes) and Hylobatidae (gibbons), is well-known for sharing human-like characteristics, however, the genomic origins of these shared unique phenotypes have mainly remained elusive. To decipher the underlying genomic basis of Hominoidea restricted phenotypes, we identified and characterized Hominoidea-restricted highly conserved noncoding sequences (HCNSs) that are a class of potential regulatory elements which may be involved in evolution of lineage-specific phenotypes. We discovered 679 such HCNSs from human, chimpanzee, gorilla, orangutan and gibbon genomes. These HCNSs were demonstrated to be under purifying selection but with lineage-restricted characteristics different from old CNSs. A significant proportion of their ancestral sequences had accelerated rates of nucleotide substitutions, insertions and deletions during the evolution of common ancestor of Hominoidea, suggesting the intervention of positive Darwinian selection for creating those HCNSs. In contrary to enhancer elements and similar to silencer sequences, these Hominoidea-restricted HCNSs are located in close proximity of transcription start sites. Their target genes are enriched in the nervous system, development and transcription, and they tend to be remotely located from the nearest coding gene. Chip-seq signals and gene expression patterns suggest that Hominoidea-restricted HCNSs are likely to be functional regulatory elements by imposing silencing effects on their target genes in a tissue-restricted manner during fetal brain development. These HCNSs, emerged through adaptive evolution and conserved through purifying selection, represent a set of promising targets for future functional studies of the evolution of Hominoidea-restricted phenotypes. PMID- 28633495 TI - Estradiol Protects Against Cardiorespiratory Dysfunctions and Oxidative Stress in Intermittent Hypoxia. AB - Study Objectives: We tested the hypothesis that estradiol (E2) protects against cardiorespiratory disorders and oxidative stress induced by chronic intermittent hypoxia (CIH) in adult female rats. Methods: Sprague-Dawley female rats (230-250 g) were ovariectomized and implanted with osmotic pumps delivering vehicle or E2 (0.5 mg/kg/d). After 14 days of recovery, the rats were exposed to CIH (21%-10% O2: 8 h/d, 10 cycles per hour) or room air (RA). After 7 days of CIH or RA exposure, we measured arterial pressures (tail cuff), metabolic rate (indirect calorimetry), minute ventilation, the frequency of sighs and apneas at rest, and ventilatory responses to hypoxia and hypercapnia (whole body plethysmography). We collected the cerebral cortex, brainstem, and adrenal glands to measure the activity of NADPH and xanthine oxidase (pro-oxidant enzymes), glutathione peroxidase, and the mitochondrial and cytosolic superoxide dismutase (antioxidant enzymes) and measured lipid peroxidation and advanced oxidation protein products (markers of oxidative stress). Results: CIH increased arterial pressure, the frequency of apnea at rest, and the hypoxic and hypercapnic ventilatory responses and reduced metabolic rate. CIH also increased oxidant enzyme activities and decreased antioxidant activity in the cortex. E2 treatment reduced body weight and prevented the effects of CIH. Conclusions: E2 prevents cardiorespiratory disorders and oxidative stress induced by CIH. These observations may help to better understand the underlying mechanisms linking menopause and occurrence of sleep apnea in women and highlight a potential advantage of hormone therapy. PMID- 28633497 TI - Genome-Wide Identification and Functional Characterization of UDP Glucosyltransferase Genes Involved in Flavonoid Biosynthesis in Glycine max. AB - Flavonoids, natural products abundant in the model legume Glycine max, confer benefits to plants and to animal health. Flavonoids are present in soybean mainly as glycoconjugates. However, the mechanisms of biosynthesis of flavonoid glycosides are largely unknown in G. max. In the present study, 212 putative UDP glycosyltransferase (UGT) genes were identified in G. max by genome-wide searching. The GmUGT genes were distributed differentially among the 20 chromosomes, and they were expressed in various tissues with distinct expression profiles. We further analyzed the enzymatic activities of 11 GmUGTs that are potentially involved in flavonoid glycosylation, and found that six of them (UGT72X4, UGT72Z3, UGT73C20, UGT88A13, UGT88E19 and UGT92G4) exhibited activity toward flavonol, isoflavone, flavone and flavanol aglycones with different kinetic properties. Among them, UGT72X4, UGT72Z3 and UGT92G4 are flavonol specific UGTs, and UGT73C20 and UGT88E19 exhibited activity toward both flavonol and isoflavone aglycones. In particular, UGT88A13 exhibited activity toward epicatechin, but not for the flavonol aglycones kaempferol and quercetin. Overexpression of these six GmUGT genes significantly increased the contents of isoflavone and flavonol glucosides in soybean hairy roots. In addition, overexpression of these six GmUGT genes also affected flavonol glycoside contents differently in seedlings and seeds of transgenic Arabidopsis thaliana. We provide valuable information on the identification of all UGT genes in soybean, and candidate GmUGT genes for potential metabolic engineering of flavonoid compounds in both Escherichia coli and plants. PMID- 28633496 TI - Clinical sensitivity and specificity of the Check-Points Check-Direct ESBL Screen for BD MAX, a real-time PCR for direct ESBL detection from rectal swabs. AB - Objectives: To determine the diagnostic accuracy of the Check-Direct ESBL Screen for BD MAX (ESBL qPCR) and an ESBL culture method to identify ESBLs directly from rectal swabs. Methods: Rectal swabs were obtained from clinical patients by performing cross-sectional (point)prevalence measurements in three regional hospitals. Rectal swabs were analysed by direct culture (ChromID ESBL agar) and with the ESBL qPCR. Suspected ESBL-producing isolates were confirmed with the combination disc method and analysed by WGS. Results: Out of 354 rectal swabs and 351 patients, 21 rectal swabs and 20 patients were positive for ESBL-producing isolates, resulting in a regional ESBL colonization prevalence of 5.7%. One rectal swab was false negative with the ESBL qPCR (blaTEM-12) and not covered by the ESBL qPCR. Eight ESBL qPCR-positive rectal swabs could not be confirmed by culture and were classified as false ESBL qPCR positive. The sensitivity and specificity of the ESBL qPCR were 95.2% (n = 20) and 97.6% (n = 323), respectively. When an optimal cycle threshold cut-off value of 37 was used, the ESBL qPCR displayed a sensitivity and specificity of 95.2% (n = 20) and 98.8% (n = 327), respectively (AUC = 0.975, 95% CI = 0.922-1). Conclusions: This ESBL qPCR offers rapid direct detection of the most prevalent ESBL types (blaCTX-M group and blaSHV group) from rectal swabs. The relatively high false-positive rate renders this test the most suitable as a screening test in high-prevalence regions or in an outbreak setting where a fast result is essential. PMID- 28633498 TI - Thymol as natural antioxidant additive for poultry feed: oxidative stability improvement. AB - Antioxidant are regularly included in poultry feed as protection from deterioration during storage. Recently the interest for the use of natural phytochemicals in animal diets has been increased. Thymol (THY) has been proven to be an effective antioxidant for extending broiler meat quality during storage with similar action to the widely used butylated hydroxytoluene (BHT). This study evaluates whether THY can also have a protective effect on the feed mash by assessing its antioxidant potential and related changes in fatty acid (FA) balance. Feed mash was assigned to 1 of 4 treatments, control (CON, no additive), vehicle (VEH, ethanol 96%), BHT (400 mg BHT /kg feed) and THY (400 mg THY /kg feed). Three replicates of each treatment were taken after 0, 30, and 60 d of storage at room temperature (23 +/- 3 degrees C) and relative humidity (40 +/- 5%). Peroxide value (PV), titratable acidity (TA) and FA relative composition were determined. As expected, there were no treatment effects on those variables at 0 d of storage. However, higher PV values were detected in the CON and VEH groups after 30 and 60 d of storage in comparison to the THY and BHT treated samples (CON = VEH > THY = BHT). While a slight increase was also observed in TA through storage time, no particular treatment effects were detected. Relative FA composition changed with storage time only in the CON and VEH group which had a decrease in polyunsaturated fatty acids and an increase in saturated FA. No changes were detected in the Thy and BHT treated feeds. The results suggest a similar THY and BHT protective effect on feed mash lipid oxidation. Thus, THY could be considered as a useful natural alternative to help sustain quality of poultry feed. PMID- 28633500 TI - Examining the health status of homeless adults entering permanent supportive housing. AB - Background: Permanent supportive housing (PSH) has been recognized as an effective intervention and the national policy for addressing chronic homelessness in the United States. Due to an aging cohort of homeless adults and prioritizing those who are most vulnerable for housing, the health status of those entering PSH is likely worse than those previously reported in the literature. Methods: This report examined the self-reported health and health conditions of a sample of 421 homeless adults entering PSH between 2014 and 2016. The average age of our sample was 54 years old. Results: Overall, 90% reported two or more chronic conditions (either physical or mental), 68% reported at least two chronic physical health conditions and 56% indicated at least two chronic mental health conditions. Describing their health status, 57% reported fair, poor or very poor health. Conclusions: These findings suggest that access to housing will not easily remedy the well-documented premature mortality among chronically homeless adults. PMID- 28633499 TI - Lateralized Basal Ganglia Vulnerability to Pesticide Exposure in Asymptomatic Agricultural Workers. AB - Pesticide exposure is linked to Parkinson's disease, a neurodegenerative disorder marked by dopamine cell loss in the substantia nigra of the basal ganglia (BG) that often presents asymmetrically. We previously reported that pesticide-exposed agricultural workers (AW) have nigral diffusion tensor imaging (DTI) changes. The current study sought to confirm this finding, and explore its hemisphere and regional specificity within BG structures using an independent sample population. Pesticide exposure history, standard neurological exam, high-resolution magnetic resonance imaging (T1/T2-weighted and DTI), and [123I]ioflupane SPECT images (to quantify striatal dopamine transporters) were obtained from 20 AW with chronic pesticide exposure and 11 controls. Based on median cumulative days of pesticide exposure, AW were subdivided into high (AWHi, n = 10) and low (AWLo, n = 10) exposure groups. BG (nigra, putamen, caudate, and globus pallidus [GP]) fractional anisotropy (FA), mean diffusivity (MD), and striatal [123I]ioflupane binding in each hemisphere were quantified, and compared across exposure groups using analysis of variance. Left, but not right, nigral and GP FA were significantly lower in AW compared with controls (p's < .029). None of the striatal (putamen and caudate) DTI or [123I]ioflupane binding measurements differed between AW and controls. Subgroup analyses indicated that significant left nigral and GP DTI changes were present only in the AWHi (p <= .037) but not the AWLo subgroup. AW, especially those with higher pesticide exposure history, demonstrate lateralized microstructural changes in the nigra and GP, whereas striatal areas appear relatively unaffected. Future studies should elucidate how environmental toxicants cause differential lateralized- and regionally specific brain vulnerability. PMID- 28633501 TI - Epidemiology of Pediatric Multidrug-Resistant Tuberculosis in the United States, 1993-2014. AB - Background: Multidrug-resistant tuberculosis (MDR-TB) is an important global public health threat, but accurate estimates of MDR-TB burden among children are lacking. Methods: We analyzed demographic, clinical, and laboratory data for newly diagnosed pediatric (age <15 years) TB cases reported to the US National TB Surveillance System during 1993-2014. MDR-TB was defined as culture-confirmed TB disease with resistance to at least isoniazid and rifampicin. To ascertain potential underestimation of pediatric MDR-TB, we surveyed high-burden states for clinically diagnosed cases treated for MDR-TB. Results: Of 20789 pediatric TB cases, 5162 (24.8%) had bacteriologically confirmed TB. Among 4826 (93.5%) with drug susceptibility testing, 82 (1.7%) had MDR-TB. Most pediatric MDR-TB cases were female (n = 51 [62%]), median age was 5 years (interquartile range, 1-12 years), one-third were Hispanic (n = 28 [34%]), and two-thirds (n = 55 [67%]) were born in the United States. Most cases had additional resistance to >=1 other first-line drug (n = 66 [81%]) and one-third had resistance to >=1 second-line drug (24/73 tested). Of 77 who started treatment prior to 2013, 66 (86%) completed treatment and 4 (5%) died. Among the 4 high-TB-burden states/jurisdictions surveyed, there was 42%-55% underestimation of pediatric MDR TB cases when using only culture-confirmed case definitions. Conclusions: Only one-quarter of pediatric TB cases had culture-confirmed TB, likely resulting in underestimation of true pediatric MDR-TB burden in the United States using strictly bacteriologic criteria. Better estimates of pediatric MDR-TB burden in the United States are needed and should include clinical diagnoses based on epidemiologic criteria. PMID- 28633502 TI - Promoting Seniors' Health With Home Care Aides: A Pilot. AB - Purpose: Regular physical activity (PA) benefits older adults. However, frail older adults lack opportunities to be physically active. This pilot study aimed to test and enhance the feasibility of a PA program delivered by home care aides (HCAs) for community-dwelling older adults in a Medicaid-funded home care setting and to generate preliminary efficacy and cost data. Design and Methods: HCAs were trained to deliver a brief motivational enhancement and three chair-bound movements to motivate their older clients to do PA daily and to help maintain their independence in the community. Mixed methods were used to evaluate clients' function and health before and after the 4-month intervention. Results: Clients' daily activity function and health outcomes (physical fitness, self-rated health, pain interference, and fear of falling) improved significantly. The program was well-received by clients (N = 54) and their HCAs (N = 46) as indicated by high retention rates among client participants (93%) and remarks provided by clients. Implications: Building PA into the everyday care of older adults and the routine work of HCAs is feasible. The intervention has the potential for further implementation and dissemination. PMID- 28633503 TI - Range Expansion and Increasing Borrelia burgdorferi Infection of the Tick Ixodes scapularis (Acari: Ixodidae) in Iowa, 1990-2013. AB - A passive surveillance program monitored ticks submitted by the public in Iowa from 1990-2013. Submitted ticks were identified to species and life stage, and Ixodes scapularis Say nymphs and adults were tested for the presence of Borrelia burgdorferi. An average of 2.6 of Iowa's 99 counties submitted first reports of I. scapularis per year over the surveillance period, indicating expansion of this tick species across the state. The proportion of vector ticks infected by B. burgdorferi increased over time between 1998 and 2013. In 2013, 23.5% of nymphal and adult I. scapularis were infected with B. burgdorferi, the highest proportion of any year. Active surveillance was performed at selected sites from 2007-2009. Ixodes scapularis nymphs collected at these sites were tested for the presence of B. burgdorferi, Anaplasma phagocytophilum, and spotted fever group Rickettsia spp. (likely representing Rickettsia buchneri). Nymphs tested were 17.3% positive for B. burgdorferi, 28.9% for A. phagocytophilum, and 67.3% for Rickettsia spp. The results of these surveillance programs indicate an increasing risk of disease transmission by I. scapularis in Iowa. PMID- 28633505 TI - Aging Parents' Daily Support Exchanges With Adult Children Suffering Problems. AB - Objectives: When adult children incur life problems (e.g., divorce, job loss, health problems), aging parents generally report providing more frequent support and experiencing poorer well-being. Yet, it is unclear how adult children's problems may influence aging parents' daily support exchanges with these children or the parents' daily mood. Methods: Aging parents from the Family Exchanges Study Wave 2 (N = 207, Mage = 79.86) reported providing and receiving emotional support, practical support, and advice from each adult child each day for 7 days. Parents also rated daily positive and negative mood. Results: Multilevel models showed that aging parents were more likely to provide emotional and practical support to adult children incurring life problems than children not suffering problems. Parents were also more likely to receive emotional support and advice from these children with problems. Further, parents reported less negative mood on days when providing practical support to children with problems. Discussion: Examining daily support exchanges adds to our understanding of how children's problems influence parent-child ties in late life. Prior research suggests that children's problems upset parents. In this study, however, it appears that supporting adult children who suffer problems may alleviate aging parents' distress regarding such children. PMID- 28633506 TI - Role of Glucagon-Like Peptide-1 and Gastric Inhibitory Peptide in Anorexia Induction Following Oral Exposure to the Trichothecene Mycotoxin Deoxynivalenol (Vomitoxin). AB - Deoxynivalenol (DON), which is a Type B trichothecene mycotoxin produced by Fusarium, frequently contaminates cereal staples, such as wheat, barley and corn. DON threatens animal and human health by suppressing food intake and impairing growth. While anorexia induction in mice exposed to DON has been linked to the elevation of the satiety hormones cholecystokinin and peptide YY3-36 in plasma, the effects of DON on the release of other satiety hormones, such as glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), have not been established. The purpose of this study was to determine the roles of GLP-1 and GIP in DON-induced anorexia. In a nocturnal mouse food consumption model, the elevation of plasma GLP-1 and GIP concentrations markedly corresponded to anorexia induction by DON. Pretreatment with the GLP-1 receptor antagonist Exendin9-39 induced a dose-dependent attenuation of both GLP-1- and DON-induced anorexia. In contrast, the GIP receptor antagonist Pro3GIP induced a dose dependent attenuation of both GIP- and DON-induced anorexia. Taken together, these results suggest that GLP-1 and GIP play instrumental roles in anorexia induction following oral exposure to DON, and the effect of GLP-1 is more potent and long-acting than that of GIP. PMID- 28633504 TI - A Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy. AB - Background: The three-drug combination of a 5-hydroxytryptamine type 3 receptor antagonist, a neurokinin 1 receptor antagonist and dexamethasone is recommended for patients receiving highly emetogenic chemotherapy. However, standard antiemetic therapy is not completely effective in all patients. Methods: We conducted an open-label, single-center, single-arm Phase II study to evaluate the efficacy of olanzapine in combination with standard antiemetic therapy in preventing chemotherapy-induced nausea and vomiting in patients with thoracic malignancy receiving their first cycle of cisplatin-based chemotherapy. Patients received 5 mg oral olanzapine on Days 1-5 in combination with standard antiemetic therapy. The primary endpoint was complete response (no vomiting and no use of rescue therapy) during the overall Phase (0-120 h post-chemotherapy). Results: Twenty-three men and seven women were enrolled between May and October 2015. The median age was 64 years (range: 36-75 years). The most common chemotherapy regimen was 75 mg/m2 cisplatin and 500 mg/m2 pemetrexed, which was administered to 14 patients. Complete response rates in acute (0-24 h post-chemotherapy), delayed (24-120 h post-chemotherapy) and overall phases were 100%, 83% and 83% (90% confidence interval: 70-92%; 95% confidence interval: 66-93%), respectively. There were no Grade 3 or Grade 4 adverse events. Although four patients (13%) experienced Grade 1 somnolence, no patients discontinued olanzapine. Conclusions: The addition of 5 mg oral olanzapine to standard antiemetic therapy demonstrates promising efficacy in preventing cisplatin-based chemotherapy-induced nausea and vomiting and an acceptable safety profile in patients with thoracic malignancy. PMID- 28633507 TI - Digenic DUOX1 and DUOX2 Mutations in Cases With Congenital Hypothyroidism. AB - Context: The DUOX2 enzyme generates hydrogen peroxide (H2O2), a crucial electron acceptor for the thyroid peroxidase-catalyzed iodination and coupling reactions mediating thyroid hormone biosynthesis. DUOX2 mutations result in dyshormonogenetic congenital hypothyroidism (CH) that may be phenotypically heterogeneous, leading to the hypothesis that CH severity may be influenced by environmental factors (e.g., dietary iodine) and oligogenic modifiers (e.g., variants in the homologous reduced form of NAD phosphate-oxidase DUOX1). However, loss-of-function mutations in DUOX1 have not hitherto been described, and its role in thyroid biology remains undefined. Case Description: We previously described a Proband and her brother (P1, P2) with unusually severe CH associated with a DUOX2 homozygous nonsense mutation (p.R434*); P1, P2: thyrotropin >100 uU/mL [reference range (RR) 0.5 to 6.3]; and P1: free T4 (FT4) <0.09 ng/dL (RR 0.9 to 2.3). Subsequent studies have revealed a homozygous DUOX1 mutation (c.1823 1G>C) resulting in aberrant splicing and a protein truncation (p.Val607Aspfs*43), which segregates with CH in this kindred. Conclusion: This is a report of digenic mutations in DUOX1 and DUOX2 in association with CH, and we hypothesize that the inability of DUOX1 to compensate for DUOX2 deficiency in this kindred may underlie the severe CH phenotype. Our studies provide evidence for a digenic basis for CH and support the notion that oligogenicity as well as environmental modulators may underlie phenotypic variability in genetically ascertained CH. PMID- 28633509 TI - A qualitative study exploring awareness and attitudes towards tuberculosis in migrant populations in a Metropolitan District Council in the North of England. AB - Background: The majority of tuberculosis (TB) cases in the UK occur among people born in high-burden countries (73%), and are concentrated in large urban centres. This study explores migrants' attitudes and beliefs towards TB in an English District where the incidence is higher than the UK average. Methods: Community engagement workers ran 26 focus groups using a standardized questionnaire. Purposeful sampling was used to obtain a cross-section of migrant communities. The summary reports were analysed using thematic analysis. Results: Most groups did not see TB as a current issue in their community and associated it either with the past or with their country of birth. It appeared to be rarely discussed in their communities and generally not noted as being associated with stigma. Conclusions: This study revealed a change in social attitudes to TB in migrant groups to those reported in previous literature. Stigma had considerably less effect than expected. However, the evidence revealed that these high-risk groups made the erroneous assumption that, by moving to a low incidence country, they were no longer at risk of the disease. TB services need to respond by revising the information that they provide to take into account the risk perception of these populations. PMID- 28633508 TI - Rescue of peripheral vestibular function in Usher syndrome mice using a splice switching antisense oligonucleotide. AB - Usher syndrome type 1C (USH1C/harmonin) is associated with profound retinal, auditory and vestibular dysfunction. We have previously reported on an antisense oligonucleotide (ASO-29) that dramatically improves auditory function and balance behavior in mice homozygous for the harmonin mutation Ush1c c.216G > A following a single systemic administration. The findings were suggestive of improved vestibular function; however, no direct vestibular assessment was made. Here, we measured vestibular sensory evoked potentials (VsEPs) to directly assess vestibular function in Usher mice. We report that VsEPs are absent or abnormal in Usher mice, indicating profound loss of vestibular function. Strikingly, Usher mice receiving ASO-29 treatment have normal or elevated vestibular response thresholds when treated during a critical period between postnatal day 1 and 5, respectively. In contrast, treatment of mice with ASO-29 treatment at P15 was minimally effective at rescuing vestibular function. Interestingly, ASO-29 treatment at P1, P5 or P15 resulted in sufficient vestibular recovery to support normal balance behaviors, suggesting a therapeutic benefit to balance with ASO-29 treatment at P15 despite the profound vestibular functional deficits that persist with treatment at this later time. These findings provide the first direct evidence of an effective treatment of peripheral vestibular function in a mouse model of USH1C and reveal the potential for using antisense technology to treat vestibular dysfunction. PMID- 28633510 TI - In Reply: Stereotactic Radiosurgery for Cystic Vestibular Schwannomas. PMID- 28633511 TI - Cardiovascular risk at health checks performed opportunistically or following an invitation letter. Cohort study. AB - Background: A population-based programme of health checks has been established in England. Participants receive postal invitations through a population-based call recall system but health check providers may also offer health checks opportunistically. We compared cardiovascular risk scores for 'invited' and 'opportunistic' health checks. Methods: Cohort study of all health checks completed at 18 general practices from July 2013 to June 2015. For each general practice, cardiovascular (CVD) risk scores were compared by source of check and pooled using meta-analysis. Effect estimates were compared by gender, age-group, ethnicity and fifths of deprivation. Results: There were 6184 health checks recorded (2280 invited and 3904 opportunistic) with CVD risk scores recorded for 5359 (87%) participants. There were 17.0% of invited checks and 22.2% of opportunistic health checks with CVD risk score >=10%; a relative increment of 28% (95% confidence interval: 14-44%, P < 0.001). In the most deprived quintile, 15.3% of invited checks and 22.4% of opportunistic checks were associated with elevated CVD risk (adjusted odds ratio: 1.94, 1.37-2.74, P < 0.001). Conclusions: Respondents at health checks performed opportunistically are at higher risk of cardiovascular disease than those participating in response to a standard invitation letter, potentially reducing the effect of uptake inequalities. PMID- 28633512 TI - Media optimization for economic succinic acid production by Enterobacter sp. LU1. AB - Enterobacter sp. LU1 could efficiently convert glycerol to succinic acid under anaerobic conditions after the addition of lactose. In this study, media constituents affecting both Enterobacter sp. LU1 biomass and succinic acid production were investigated employing response surface methodology (RSM) with central composite design. Statistical methods led to the development of an efficient and inexpensive microbiological media based on crude glycerol, whey permeate as carbon sources and urea as a nitrogen source. The optimized production of bacterial biomass in aerobic conditions was predicted and the interactive effects between crude glycerol, urea and magnesium sulfate were investigated. As a result, a model for predicting the concentration of bacterial biocatalyst biomass was developed with crude glycerol as a sole carbon source. In addition, it was observed that the interactive effect between crude glycerol and urea was statistically significant. Response surface methodology was also employed to develop the model for predicting the concentration of succinic acid produced. Validity of the model was confirmed during verification experiments wherein actual results differed from predicted values by 0.77%. The applied statistical methods proved the feasibility for anaerobic succinic acid production on crude glycerol without expensive yeast extract addition. In conclusion, the RSM method can provide valuable information for succinic acid scale-up fermentation using Enterobacter sp. LU1. PMID- 28633513 TI - Gram-Scale Production of Ginsenoside F1 Using a Recombinant Bacterial beta Glucosidase. AB - Naturally occurring ginsenoside F1 (20-O-beta-D-glucopyranosyl-20(S) protopanaxatriol) is rare. Here, we produced gram-scale quantities of ginsenoside F1 from a crude protopanaxatriol saponin mixture comprised mainly of Re and Rg1 through enzyme-mediated biotransformation using recombinant beta-glucosidase (BgpA) cloned from a soil bacterium, Terrabacter ginsenosidimutans Gsoil 3082T. In a systematic step-by-step process, the concentrations of substrate, enzyme, and NaCl were determined for maximal production of F1. At an optimized NaCl concentration of 200 mM, the protopanaxatriol saponin mixture (25 mg/ml) was incubated with recombinant BgpA (20 mg/ml) for 3 days in a 2.4 L reaction. Following octadecylsilyl silica gel column chromatography, 9.6 g of F1 was obtained from 60 g of substrate mixture at 95% purity, as assessed by chromatography. These results represent the first report of gramscale F1 production via recombinant enzyme-mediated biotransformation. PMID- 28633514 TI - Metagenomic SMRT Sequencing-Based Exploration of Novel Lignocellulose-Degrading Capability in Wood Detritus from Torreya nucifera in Bija Forest on Jeju Island. AB - Lignocellulose, composed mostly of cellulose, hemicellulose, and lignin generated through secondary growth of woody plant, is considered as promising resources for biofuel. In order to use lignocellulose as a biofuel, biodegradation besides high cost chemical treatments were applied, but knowledge on the decomposition of lignocellulose occurring in a natural environment is insufficient. We analyzed the 16S rRNA gene and metagenome to understand how the lignocellulose is decomposed naturally in decayed Torreya nucifera (L) of Bija forest (Bijarim) in Gotjawal, an ecologically distinct environment. A total of 464,360 reads were obtained from 16S rRNA gene sequencing, representing diverse phyla; Proteobacteria (51%), Bacteroidetes (11%) and Actinobacteria (10%). The metagenome analysis using single molecules real-time sequencing revealed that the assembled contigs determined originated from Proteobacteria (58%) and Actinobacteria (10.3%). Carbohydrate Active enZYmes (CAZy)- and Protein families (Pfam)-based analysis showed that Proteobacteria was involved in degrading whole lignocellulose, and Actinobacteria played a role only in a part of hemicellulose degradation. Combining these results, it suggested that Proteobacteria and Actinobacteria had selective biodegradation potential for different lignocellulose substrates. Thus, it is considered that understanding of the systemic microbial degradation pathways may be a useful strategy for recycle of lignocellulosic biomass, and the microbial enzymes in Bija forest can be useful natural resources in industrial processes. PMID- 28633515 TI - Crystal Structure and Functional Characterization of a Cytochrome P450 (BaCYP106A2) from Bacillus sp. PAMC 23377. AB - Bacterial cytochrome P450 (CYP) steroid hydroxylases are effectively useful in the pharmaceutical industry for introducing hydroxyl groups to a wide range of steroids. We found a putative CYP steroid hydroxylase (BaCYP106A2) from the bacterium Bacillus sp. PAMC 23377 isolated from Kara Sea of the Arctic Ocean, showing 94% sequence similarity with BmCYP106A2 (Bacillus megaterium ATCC 13368). In this study, soluble BaCYP106A2 was overexpressed to evaluate its substrate binding activity. The substrate affinity (Kd value) to 4-androstenedione was 387 +/- 37 uM. Moreover, the crystal structure of BaCYP106A2 was determined at 2.7 A resolution. Structural analysis suggested that the alpha8-alpha9 loop region of BaCYP106A2 is intrinsically mobile and might be important for initial ligand binding. The hydroxyl activity of BaCYP106A2 was identified using in vitro enzyme assays. Its activity was confirmed with two kinds of steroid substrates, 4 androstenedione and nandrolone, using chromatography and mass spectrometry methods. The main products were monohydroxylated compounds with high conversion yields. This is the second study on the structure of CYP106A steroid hydroxylases, and should contribute new insight into the interactions of bacterial CYP106A with steroid substrates, providing baseline data for studying the CYP106A steroid hydroxylase from the structural and enzymatic perspectives. PMID- 28633516 TI - Synthesis of Curcumin Glycosides with Enhanced Anticancer Properties Using One Pot Multienzyme Glycosylation Technique. AB - Curcumin is a natural polyphenolic compound, widely acclaimed for its antioxidant, antiinflammatory, antibacterial, and anticancerous properties. However, its use has been limited due to its low-aqueous solubility and poor bioavailability, rapid clearance, and low cellular uptake. In order to assess the effect of glycosylation on the pharmacological properties of curcumin, one-pot multienzyme (OPME) chemoenzymatic glycosylation reactions with UDP- alpha-D glucose or UDP-alpha-D-2-deoxyglucose as donor substrate were employed. The result indicated significant conversion of curcumin to its glycosylated derivatives: curcumin 4'-O-beta- glucoside, curcumin 4',4''-di-O-beta-glucoside, curcumin 4'-O-beta-2-deoxyglucoside, and curcumin 4',4''-di-O-beta-2 deoxyglucoside. The products were characterized by ultra-fast performance liquid chromatography, high-resolution quadruple-time-of-flight electrospray ionization mass spectrometry, and NMR analyses. All the products showed improved water solubility and comparable antibacterial activities. Additionally, the curcumin 4' O-beta-glucoside and curcumin 4'-O-beta-2-deoxyglucoside showed enhanced anticancer activities compared with the parent aglycone and diglycoside derivatives. This result indicates that glycosylation can be an effective approach for enhancing the pharmaceutical properties of different natural products, such as curcumin. PMID- 28633517 TI - Biomethanation of Sewage Sludge with Food Waste Leachate Via Co-Digestion. AB - Anaerobic mono- and co-digestion of sewage sludge and food waste leachate (FWL) were performed by assessing methane production and characterizing microbial communities. Anaerobic digestion (AD) of waste activated sludge (WAS) alone produced the lowest methane (281 ml CH4), but an approximately 80% increase in methane production was achieved via co-digestion of WAS and FWL (506 ml CH4). There were less differences in the diversity of bacterial communities in anaerobic digesters, while archaeal (ARC) and bacterial (BAC) amounts reflected AD performance. Compared with the total ARC and BAC amounts in the mono-digestion of WAS, the ARC and BAC amounts increased two and three times, respectively, during co-digestion of FWL and WAS. In characterized archaeal communities, the dominant ratio of hydrogenotrophic methanogens in the mono-digestion of WAS approached nearly a 1:1 ratio of the two acetoclastic and hydrogenotrophic methanogens in the co-digestion of FWL and WAS. The ARC/BAC ratio in the digesters varied in the range of 5.9% to 9.1%, indicating a positive correlation with the methane production of AD. PMID- 28633518 TI - Optimization of Siderophore Production by Bacillus sp. PZ-1 and Its Potential Enhancement of Phytoextration of Pb from Soil. AB - In this study, the siderophore-producing characteristics and conditions of Bacillus sp. PZ-1 were investigated and the enhancement of siderophores on Pb uptake and translocation in Brassica juncea were determined. Results of single factor experiment showed that glucose, pH, and Pb(NO3)2 could stimulate PZ-1 growth and siderophore production. The maximum siderophore production of 90.52% siderophore units was obtained by response surface methodology optimization at the glucose concentration of 21.84 g/l, pH 6.18, and Pb(NO3)2 concentration of 245.04 MUmol/l. The type of siderophore was hydroxamate and its concentration in the fermentation broth amounted to 32.24 MUg/ml. Results of pot experiments indicated that the siderophores enhanced B. juncea to assimilate more Pb from soil with the uptake ratio from 1.04 to 2.74, and to translocate more Pb from underground to overground with the TF values from 1.21 to 1.48. The results revealed that Bacillus sp. PZ-1 could produce abundant siderophores and might be potentially used to augment the phytoextraction of Pb from soil. PMID- 28633519 TI - Changes in abdominal aortic aneurysm epidemiology. AB - The epidemiology and treatment of abdominal aortic aneurysms (AAA) has changed over the past 30 years. This review aims to give the reader an overview of these changes and current trends in AAA epidemiology, management and outcome. In the past decades there have been three changes in AAA management and epidemiology: 1) introduction of endovascular aortic repair (EVAR); 2) population screening; and 3) a markedly reduced prevalence of the disease. These developments have resulted in an increased incidence of intact AAA-repair and reduced incidence of ruptured AAA-repair. Overall, survival after both intact and ruptured AAA repair has improved, much thanks to the broad introduction of EVAR. Additionally, both elective and rupture repair in the elderly population has increased, with octogenarians constituting >20% of intact AAA repairs performed in several countries. International analyses of vascular registries indicate that important variations remain in AAA management and results. The changes in AAA epidemiology and management have led to a situation where most AAAs today are treated with EVAR electively. The incidence of ruptured AAA-repair continues to decrease. These changes are accompanied by improvements in both short- and long-term survival. PMID- 28633520 TI - Ion-Selective Nanosensor for Photoacoustic and Fluorescence Imaging of Potassium. AB - Ion-selective optodes (ISOs), the optical analog of ion-selective electrodes, have played an increasingly important role in chemical and biochemical analysis. Here we extend this technique to ion-selective photoacoustic optodes (ISPAOs) that serve at the same time as fluorescence-based ISOs, and apply it specifically to potassium (K+). Notably, the potassium ion is one of the most abundant cations in biological systems, involved in numerous physiological and pathological processes. Furthermore, it has been recently reported that the presence of abnormal extracellular potassium concentrations in tumors suppresses the immune responses and thus suppresses immunotherapy. However, unfortunately, sensors capable of providing potassium images in vivo are still a future proposition. Here, we prepared an ion-selective potassium nanosensor (NS) aimed at in vivo photoacoustic (PA) chemical imaging of the extracellular environment, while being also capable of fluorescence based intracellular ion-selective imaging. This potassium nanosensor (K+ NS) modulates its optical properties (absorbance and fluorescence) according to the potassium concentration. The K+ NS is capable of measuring potassium, in the range of 1 mM to 100 mM, with high sensitivity and selectivity, by ISPAO based measurements. Also, a near infrared dye surface modified K+ NS allows fluorescence-based potassium sensing in the range of 20 mM to 1 M. The K+ NS serves thus as both PA and fluorescence based nanosensor, with response across the biologically relevant K+ concentrations, from the extracellular 5 mM typical values (through PA imaging) to the intracellular 150 mM typical values (through fluorescence imaging). PMID- 28633521 TI - Consideration of Natural Sources in a Bacteria TMDL-Lines of Evidence, Including Beach Microbial Source Tracking. AB - Total Maximum Daily Load (TMDL) stipulations remained unmet at a southern California beach despite a suite of management actions carried out since 2001, prompting exploration of a Natural Sources Exclusion (NSE) provision within the TMDL. Quantitative Microbial Source Tracking (MST) was employed from 2012 to 2015 to inventory sources of natural and anthropogenic fecal indicator bacteria (FIB). Data suggested FIB exceedances could be traced to gulls based on gull marker prevalence and correlations with FIB concentrations in seawater, sand, and eelgrass. In contrast, human marker concentrations and a tracer dye test did not indicate prevalent human sources. Exponential decay of gull marker in sand amended with live Catellicoccus marimammalium suggested that measured marker reflected fecal inputs versus growth outside the host. Improved water quality was coincident with a 2013 bird exclusion structure, consistent with NSE. However, load allocation needed for TMDL reconsideration was hampered by variable ratios of FIB, MST markers, and pathogens measured in seawater and in gull, cat, and raccoon feces. Quantitative Microbial Risk Assessment is a suggested path forward because such models can incorporate distributions from a combination of FIB sources and communicate criteria in terms of human health risk. PMID- 28633522 TI - Molecular Dynamics Information Improves cis-Peptide-Based Function Annotation of Proteins. AB - cis-Peptide bonds, whose occurrence in proteins is rare but evolutionarily conserved, are implicated to play an important role in protein function. This has led to their previous use in a homology-independent, fragment-match-based protein function annotation method. However, proteins are not static molecules; dynamics is integral to their activity. This is nicely epitomized by the geometric isomerization of cis-peptide to trans form for molecular activity. Hence we have incorporated both static (cis-peptide) and dynamics information to improve the prediction of protein molecular function. Our results show that cis-peptide information alone cannot detect functional matches in cases where cis-trans isomerization exists but 3D coordinates have been obtained for only the trans isomer or when the cis-peptide bond is incorrectly assigned as trans. On the contrary, use of dynamics information alone includes false-positive matches for cases where fragments with similar secondary structure show similar dynamics, but the proteins do not share a common function. Combining the two methods reduces errors while detecting the true matches, thereby enhancing the utility of our method in function annotation. A combined approach, therefore, opens up new avenues of improving existing automated function annotation methodologies. PMID- 28633523 TI - Effect of Pseudomonas fluorescens on Buried Steel Pipeline Corrosion. AB - Buried steel infrastructure can be a source of iron ions for bacterial species, leading to microbiologically influenced corrosion (MIC). Localized corrosion of pipelines due to MIC is one of the key failure mechanisms of buried steel pipelines. In order to better understand the mechanisms of localized corrosion in soil, semisolid agar has been developed as an analogue for soil. Here, Pseudomonas fluorescens has been introduced to the system to understand how bacteria interact with steel. Through electrochemical testing including open circuit potentials, potentiodynamic scans, anodic potential holds, and electrochemical impedance spectroscopy it has been shown that P. fluorescens increases the rate of corrosion. Time for oxide and biofilms to develop was shown to not impact on the rate of corrosion but did alter the consistency of biofilm present and the viability of P. fluorescens following electrochemical testing. The proposed mechanism for increased corrosion rates of carbon steel involves the interactions of pyoverdine with the steel, preventing the formation of a cohesive passive layer, after initial cell attachment, followed by the formation of a metal concentration gradient on the steel surface. PMID- 28633524 TI - Charge Migration in Eyring, Walter and Kimball's 1944 Model of the Electronically Excited Hydrogen-Molecule Ion. AB - In an elementary variational treatment of the electronic structure of H2+, Eyring, Walter, and Kimball (EWK) serendipitously discovered charge migration (CM) in 1944. Using an analytic expression for the electronic probability density (EPD), they found that if the electron is initially localized on one of the protons (by taking the initial state to be a superposition of the ground and first excited electronic energy eigenstates), then it oscillates adiabatically between fixed protons with a period T inversely proportional to the energy gap between the eigenstates. At the equilibrium internuclear separation, T = 550.9 as. As shown here, the EWK model also yields an analytic formula for the electronic flux density (EFD). While the EPD indicates where the electron is at any instant, the EFD reveals the pathways the electron follows during its migration. Thus, the EFD complements the EPD, providing valuable new insight into the mechanism of CM. The formula for the EFD is a simple product of a time factor and a spatial factor. This factoring exposes a plethora of spatial-temporal symmetry relations which imply novel and surprising properties. An especially significant finding is that, in contrast to multielectron systems, where electron correlation may play a role in CM, in the EWK model of H2+, CM is due strictly to quantum interference between the ground and first excited electronic states. PMID- 28633525 TI - Use of Dimethyl Pimelimidate with Microfluidic System for Nucleic Acids Extraction without Electricity. AB - The isolation of nucleic acids in the lab on a chip is crucial to achieve the maximal effectiveness of point-of-care testing for detection in clinical applications. Here, we report on the use of a simple and versatile single-channel microfluidic platform that combines dimethyl pimelimidate (DMP) for nucleic acids (both RNA and DNA) extraction without electricity using a thin-film system. The system is based on the adaption of DMP into nonchaotropic-based nucleic acids and the capture of reagents into a low-cost thin-film platform for use as a microfluidic total analysis system, which can be utilized for sample processing in clinical diagnostics. Moreover, we assessed the use of the DMP system for the extraction of nucleic acids from various samples, including mammalian cells, bacterial cells, and viruses from human disease, and we also confirmed that the quality and quantity of the nucleic acids extracted were sufficient to allow for the robust detection of biomarkers and/or pathogens in downstream analysis. Furthermore, this DMP system does not require any instruments and electricity, and has improved time efficiency, portability, and affordability. Thus, we believe that the DMP system may change the paradigm of sample processing in clinical diagnostics. PMID- 28633526 TI - Reduced-Graphene Oxide/Poly(acrylic acid) Aerogels as a Three-Dimensional Replacement for Metal-Foil Current Collectors in Lithium-Ion Batteries. AB - We report the synthesis and properties of a low-density (~5 mg/cm3) and highly porous (99.6% void space) three-dimensional reduced graphene oxide (rGO)/poly(acrylic acid) (PAA) nanocomposite aerogel as the scaffold for cathode materials in lithium-ion batteries (LIBs). The rGO-PAA is both simple and starts from readily available graphite and PAA, thereby providing a scalable fabrication procedure. The scaffold can support as much as a 75 mg/cm2 loading of LiFePO4 (LFP) in a ~430 MUm thick layer, and the porosity of the aerogel is tunable by compression; the flexible aerogel can be compressed 30-fold (i.e., to as little as 3.3% of its initial volume) while retaining its mechanical integrity. Replacement of the Al foil by the rGO-PAA current collector of the slurry-cast LFP (1.45 +/- 0.2 g/cm3 tap density) provides for exemplary mass loadings of 9 mgLFP/cm2 at 70 MUm thickness and 1.4 g/cm3 density or 16 mgLFP/cm2 at 100 MUm thickness and ~1.6 g/cm3 density. When compared to Al foil, the distribution of LFP throughout the three-dimensional rGO-PAA framework doubles the effective LFP solution-contacted area at 9 mg/cm2 loading and increases it 2.5-fold at 16 mg/cm2 loading. Overall, the rGO-PAA current collector increases the volumetric capacity by increasing the effective electrode area without compromising the electrode density, which was compromised in past research where the effective electrode area has been increased by reducing the particle size. PMID- 28633527 TI - Molecular Beam Epitaxy of Highly Crystalline Monolayer Molybdenum Disulfide on Hexagonal Boron Nitride. AB - Atomically thin molybdenum disulfide (MoS2), a direct-band-gap semiconductor, is promising for applications in electronics and optoelectronics, but the scalable synthesis of highly crystalline film remains challenging. Here we report the successful epitaxial growth of a continuous, uniform, highly crystalline monolayer MoS2 film on hexagonal boron nitride (h-BN) by molecular beam epitaxy. Atomic force microscopy and electron microscopy studies reveal that MoS2 grown on h-BN primarily consists of two types of nucleation grains (0 degrees aligned and 60 degrees antialigned domains). By adopting a high growth temperature and ultralow precursor flux, the formation of 60 degrees antialigned grains is largely suppressed. The resulting perfectly aligned grains merge seamlessly into a highly crystalline film. Large-scale monolayer MoS2 film can be grown on a 2 in. h-BN/sapphire wafer, for which surface morphology and Raman mapping confirm good spatial uniformity. Our study represents a significant step in the scalable synthesis of highly crystalline MoS2 films on atomically flat surfaces and paves the way to large-scale applications. PMID- 28633528 TI - Binding Space Concept: A New Approach To Enhance the Reliability of Docking Scores and Its Application to Predicting Butyrylcholinesterase Hydrolytic Activity. AB - Docking simulations are very popular approaches able to assess the capacity of a given ligand to interact with a target. Docking simulations are usually focused on a single best complex even though many studies showed that ligands retain a significant mobility within a binding pocket by assuming different binding modes all of which may contribute to the monitored ligand affinity. The present study describes an innovative concept, the binding space, which allows an exploration of the ligand mobility within the binding pocket by simultaneously considering several ligand poses as generated by docking simulations. The multiple poses and the relative docking scores can then be analyzed by taking advantage of the same concepts already used in the property space analysis; hence the binding space can be parametrized by (a) mean scores, (b) score ranges, and (c) score sensitivity values. The first parameter represents a very simple procedure to account for the contribution of the often neglected alternative binding modes, while the last two descriptors encode the degree of mobility which a given ligand retains within the binding cavity (score range) as well as the ease with which a ligand explores such a mobility (score sensitivity). Here, the binding space concept is applied to the prediction of the hydrolytic activity of BChE by synergistically considering multiple poses and multiple protein structures. The obtained results shed light on the remarkable potential of the binding space concept, whose parameters allow a significant increase of the predictive power of the docking results as revealed by extended correlative analyses. Mean scores are the parameters affording the largest statistical improvement, and all the here proposed docking-based descriptors show enhancing effects in developing predictive models. Finally, the study describes a new score function (Contacts score) simply based on the number of surrounding residues which appears to be particularly productive in the framework of the binding space. PMID- 28633529 TI - The Weekday Wheezer. PMID- 28633530 TI - Essential oil composition of Rydingia michauxii (Briq.) Scheen & V.A. Albert endemic of Iran. AB - The chemical composition of the essential oil (EO) obtained from the aerial parts of Rydingia michauxii (Briq.) Scheen & V.A. Albert was analysed by gas chromatography and gas chromatography/mass spectrometry (GC/MS). Eighty components were identified in the oil with caryophyllene oxide (20.1%), trans verbenol (10.2%), linalool (5.3%) and humulene epoxide II (4.6%) as main constituents. We reported here the chemical compositions of R. michauxii EOs from southern Zagros of Iran with a distinct chemical profile for the first time. PMID- 28633532 TI - Complementary therapies - conflicting complications? PMID- 28633531 TI - The effectiveness of aided augmented input techniques for persons with developmental disabilities: a systematic review. AB - When working with individuals with little or no functional speech, clinicians often recommend that communication partners use the client's augmentative and alternative communication (AAC) device when speaking to the client. This is broadly known as "augmented input" and is thought to enhance the client's learning of language form and content. The purpose of this systematic review was to determine the effects of augmented input on communication outcomes in persons with developmental disabilities and persons with childhood apraxia of speech who use aided AAC. Nineteen studies met the inclusion criteria. Each included study was reviewed in terms of participant characteristics, terminology used, symbol format, augmented input characteristics, outcomes measured, effectiveness, and study quality. Results indicate that augmented input can improve single-word vocabulary skills and expression of multi-symbol utterances; however, comprehension beyond the single word level has not been explored. Additionally, it is difficult to form conclusions about the effect of augmented input on specific diagnostic populations. Directions for future research are posited. PMID- 28633533 TI - In the modern era of percutaneous coronary intervention: Is cardiac rehabilitation engagement purely a patient or a service level decision? AB - Aims Despite the proven benefits of cardiac rehabilitation (CR), utilization rates remain below recommendation in the percutaneous coronary intervention cohort in most European countries. Although extensive research has been carried out on CR uptake, no previous study has investigated the factors that lead patients to attend the initial CR baseline assessment (CR engagement). This paper attempts to provide new insights into CR engagement in the growing percutaneous coronary intervention population. Methods and results In total, we analysed data on 59,807 patients who underwent percutaneous coronary intervention during 2013 to 2016 (mean age 65 years; 25% female). Twenty factors were hypothesized to have a direct impact on CR engagement and they were grouped into four main categories; namely socio-demographic factors, cardiac risk factors, medical status and service-level factors. A binary logistic regression model was constructed to examine the association between CR engagement and tested factors. All but one of the proposed factors had a statistically significant impact on CR engagement. Results showed that CR engagement decreases by 1.2% per year of age (odds ratio 0.98) and is approximately 7% lower (odds ratio 0.93) in female patients, while patients are 4.4 times more likely to engage if they receive a confirmed joining date (odds ratio 4.4). The final model achieved 86.6% sensitivity and 49.0% specificity with an area under the receiver operating characteristic curve of 0.755. Conclusion The present results highlight the important factors of the likelihood of CR engagement. This implies that future strategies should focus on factors that are associated with CR engagement. PMID- 28633534 TI - Neuromuscular electrical stimulation improves exercise tolerance in patients with advanced heart failure on continuous intravenous inotropic support use-randomized controlled trial. AB - OBJECTIVE: To evaluate the impact of a short-term neuromuscular electrical stimulation program on exercise tolerance in hospitalized patients with advanced heart failure who have suffered an acute decompensation and are under continuous intravenous inotropic support. DESIGN: A randomized controlled study. SUBJECTS: Initially, 195 patients hospitalized for decompensated heart failure were recruited, but 70 were randomized. INTERVENTION: Patients were randomized into two groups: control group subject to the usual care ( n = 35); neuromuscular electrical stimulation group ( n = 35) received daily training sessions to both lower extremities for around two weeks. MAIN MEASURES: The baseline 6-minute walk test to determine functional capacity was performed 24 hours after hospital admission, and intravenous inotropic support dose was daily checked in all patients. The outcomes were measured in two weeks or at the discharge if the patients were sent back home earlier than two weeks. RESULTS: After losses of follow-up, a total of 49 patients were included and considered for final analysis (control group, n = 25 and neuromuscular electrical stimulation group, n = 24). The neuromuscular electrical stimulation group presented with a higher 6-minute walk test distance compared to the control group after the study protocol (293 +/ 34.78 m vs. 265.8 +/- 48.53 m, P < 0.001, respectively). Neuromuscular electrical stimulation group also demonstrated a significantly higher dose reduction of dobutamine compared to control group after the study protocol (2.72 +/- 1.72 ug/kg/min vs. 3.86 +/- 1.61 ug/kg/min, P = 0.001, respectively). CONCLUSION: A short-term inpatient neuromuscular electrical stimulation rehabilitation protocol improved exercise tolerance and reduced intravenous inotropic support necessity in patients with advanced heart failure suffering a decompensation episode. PMID- 28633535 TI - Changes in the level of cardiac troponine and disorders in pulmonary gas exchange as predictors of short- and long-term outcomes of patients with aneurysm subarachnoid haemorrhage. AB - SUBJECT: Cardiopulmonary abnormalities are common after aneurysmal subarachnoid haemorrhage (aSAH). However, the relationship between short- and long-term outcome is poorly understood. In this paper, we present how cardiac troponine elevations (cTnI) and pulmonary disorders are associated with short- and long term outcomes assessed by the Glasgow Outcome Scale (GOS) and Extended Glasgow Outcome Scale (GOSE). METHODS: A total of 104 patients diagnosed with aSAH were analysed in the study. The non-parametric U Mann-Whitney test was used to evaluate the difference between good (GOS IV-V, GOSE V-VIII) and poor (GOS I-III, GOSE I-IV) outcomes in relation to cTnI elevation and pulmonary disorders. Outcome was assessed at discharge from the hospital, and then followed up 6 and 12 months later. Pulmonary disorders were determined by the PaO2/FiO2 ratio and radiography. The areas under the ROC curves (AUCs) were used to determine the predictive power of these factors. RESULTS: In the group with good short-term outcomes cTnI elevation on the second day after aSAH was significantly lower (p = .00007) than in patients with poor short-term outcomes. The same trend was observed after 6 months, although there were different results 12 months from the onset (p = .024 and n.s., respectively). A higher peak of cTnI was observed in the group with a pathological X-ray (p = .008) and pathological PaO2/FiO2 ratio (p ? .001). cTnI was an accurate predictor of short-term outcomes (AUC = 0.741, p ? .001) and the outcome after 6 months (AUC = 0.688, p = .015). CONCLUSION: The results showed that cardiopulmonary abnormalities perform well as predictive factors for short- and long-term outcomes after aSAH. PMID- 28633536 TI - A new bisabolane sesquiterpenoid and a new abietane diterpenoid from Cephalotaxus sinensis. AB - Phytochemical investigation of Cephalotaxus sinensis has led to the isolation of a new bisabolane sesquiterpenoid (1), a new abietane diterpenoid (2), and 13 known compounds (3-15). Their structures were elucidated by extensive spectroscopic analysis (MS, UV, IR, and NMR). PMID- 28633537 TI - Extensive Assessment of Blood Glucose Monitoring During Postprandial Period and Its Impact on Closed-Loop Performance. AB - BACKGROUND: Closed-loop (CL) systems aims to outperform usual treatments in blood glucose control and continuous glucose monitors (CGM) are a key component in such systems. Meals represents one of the main disturbances in blood glucose control, and postprandial period (PP) is a challenging situation for both CL system and CGM accuracy. METHODS: We performed an extensive analysis of sensor's performance by numerical accuracy and precision during PP, as well as its influence in blood glucose control under CL therapy. RESULTS: During PP the mean absolute relative difference (MARD) for both sensors presented lower accuracy in the hypoglycemic range (19.4 +/- 12.8%) than in other ranges (12.2 +/- 8.6% in euglycemic range and 9.3 +/- 9.3% in hyperglycemic range). The overall MARD was 12.1 +/- 8.2%. We have also observed lower MARD for rates of change between 0 and 2 mg/dl. In CL therapy, the 10 trials with the best sensor spent less time in hypoglycemia (PG < 70 mg/dl) than the 10 trials with the worst sensors (2 +/- 7 minutes vs 32 +/- 38 minutes, respectively). CONCLUSIONS: In terms of accuracy, our results resemble to previously reported. Furthermore, our results showed that sensors with the lowest MARD spent less time in hypoglycemic range, indicating that the performance of CL algorithm to control PP was related to sensor accuracy. PMID- 28633538 TI - Relationship between emergency care utilization, ambient temperature, and the pollution standard index in Taiwan. AB - This study applied a vector error correction model to investigate the effects of ambient temperature (AT) and air quality index values on emergency care utilization (ECU). The Pollution Standards Index (PSI) and total suspended particulates (TSP) were used for analysis. Data were obtained from the National Health Insurance Research Database of the Ministry of Transportation and Communications and Ministry Environmental of Protection Administration of Taiwan. Data from January of 1998 to December of 2012 (180 months) were analyzed. Study results showed that, regardless of long-term equilibrium or short-term dynamics, a 1 degrees C increase in AT will decrease ECU, showing that AT strongly affects ECU. There were no significant corrections of long-term equilibrium of PSI and TSP on ECU. Only short-term TSP dynamics caused negative effects in the first ECU phase. Emergency care requires special monitoring of AT and TSP to respond to the increased number of high-risk patients consulting emergency departments. PMID- 28633539 TI - A Survey on Chemical Constituents and Indications of Aromatic Waters Soft Drinks (Hydrosols) Used in Persian Nutrition Culture and Folk Medicine for Neurological Disorders and Mental Health. AB - In Persian nutrition culture, drinking aromatic waters (hydrosols, distillate) has a long history as functional beverages or therapeutic remedies. The co distilled water with essential oils, which contains partial amounts of more water soluble volatile compounds are diluted and used as beverages. Since the solubility of volatile components is different in water, the overall composition, and thus the biological activities of aromatic waters seem to be different from the essential oils they were co-distilled with. Despite the essential oils, chemical constituents of many aromatic waters have not been evaluated scientifically. This research investigated hydrosols used for mental and neurological health maintenance in Persian nutrition culture and their chemical constituents. Constitutions of these hydrosols were extracted by liquid/liquid extraction method and identified by gas chromatography-mass spectrometry. Furthermore, cluster analysis was used to evaluate the relevance of these hydrosols chemical constituents. About 93 compounds were identified from 20 aromatic waters. the major or second major constituents were thymol (azarol howthorn, frankincense, lemon balm, valerian, shadab), phenethyl alcohol (damask rose, dog-rose, starflower), carvacrol (basil, creeping buttercup, lemon balm); eugenol (shadab, dog-rose, starflower, basil), camphor (yarrow and wormwood), carvone (oriental plane), caryophyllene (cuminum), cinnamaldehyde (Chinese cinnamon), p-cymen-7-ol (musk willow), limonene (lemon verbena), linalool and alpha-terpineol (bitter orange), menthol (date palm) and methyl 5-vinylnicotinate (olive). Although, these hydrosols prepared from plants belong to different genus and families, but cluster analysis showed obvious similarities between their chemical constituents. Results of this investigation showed in many cases that the constituents of aromatic waters are different from the pure essential oil. PMID- 28633540 TI - Benign ependymoma with extensive intracranial and spinal cerebrospinal fluid dissemination: case report and literature review. AB - Myxopapillary ependymoma (MPE) is a rare variant of ependymoma that is most commonly located in the cauda equina and filum terminale. We present a case of 23 year-old man diagnosed with MPE in the fourth ventricle and sacral canal area with extensive disseminated lesions along the cerebrospinal ventricular system. Additionally, a molecular pathological diagnosis was performed. The patient underwent a craniotomy and a lumbar laminectomy. In the course of 18 months of follow-up, the patient have recovered very well. PMID- 28633541 TI - The Development of a Glucose Dehydrogenase 3D-Printed Glucose Sensor: A Proof-of Concept Study. AB - This work represents a preliminary proof-of-concept design and verification of a 3D-printed glucose biosensor. The proof of concept presented is the first example of glucose dehydrogenase sensor fabricated by a 3D-printer while maintaining similar features to current lab-industry standards. The sensor was verified to detect physiological glucose concentrations between 0 and 400 mg/dL with a linear coefficient as high as .97. This study showed that it was possible to use 3D printed technology to create a biosensor sensitive to glucose detection. As availability and functionality of 3D-printers expands, this technology has the potential to be an option for diabetes management. This preliminary study shows that the 3D-printed sensor platform holds promise for sensitive glucose detection. PMID- 28633542 TI - Deciphering participation: an interpretive synthesis of its meaning and application in rehabilitation. AB - PURPOSE: Participation is widely recognized as an important outcome for rehabilitation. However, it lacks a universally accepted definition. The purpose of this review is to synthesize the literature about participation in rehabilitation in order to clarify the term and increase its usefulness for rehabilitation providers and researchers. METHODS: We undertook an interpretive synthesis of the literature, drawing from a broad and varied selection of the vast number of publications on the subject of participation. The search and analysis was iterative and continued until saturation of themes was achieved. RESULTS AND CONCLUSIONS: Seventy-six articles were included in our analysis. We argue that three essential dimensions - performance, subjective experience, and interpersonal connection - constitute participation. We further divide participation into community-based and interventional contexts. Interventional participation is circumscribed by the treatment setting, whereas community-based encompasses all other areas. Participation in either interventional or community based contexts is largely determined by the available opportunities from which a person can choose, with such opportunities affected by conditions that are either internal or external to the individual. As defined in this framework, participation is not inherently good or bad; rather, its effect is determined by a person's unique life circumstances and the impact may not always be apparent. We posit this model as a resource for future research as well as clinical reasoning. Implications for Rehabilitation The often tacit assumption that increasing participation is a desirable outcome needs to be challenged and considered in each patient's life situation. Treatment settings constitute a unique context in which patients participate. Intervention goals should be clearly connected with patients' personal goals for community-based participation. PMID- 28633543 TI - Staffs' documentation of participation for adults with profound intellectual disability or profound intellectual and multiple disabilities. AB - PURPOSE: This study investigated what areas of International Classification of Functioning, Disability and Health were documented in implementation plans for adults with profound intellectual disability or profound intellectual and multiple disabilities with focus on participation. METHODS: A document analysis of 17 implementation plans was performed and International Classification of Functioning, Disability and Health was used as an analytic tool. RESULTS: One hundred and sixty-three different codes were identified, especially in the components Activities and participation and Environmental factors. Participation was most frequently coded in the chapters Community, social and civic life and Self-care. Overall, the results showed that focus in the implementation plans concerned Self-care and Community, social and civic life. The other life areas in Activities and participation were seldom, or not at all, documented. CONCLUSIONS: A deeper focus on participation in the implementation plans and all life areas in the component Activities and participation is needed. It is important that the documentation clearly shows what the adult wants, wishes, and likes in everyday life. It is also important to ensure that the job description for staff contains both life areas and individual preferences so that staff have the possibility to work to fulfill social and individual participation for the target group. Implications for rehabilitation There is a need for functioning working models to increase participation significantly for adults with profound intellectual disability or profound intellectual and multiple disabilities. For these adults, participation is achieved through the assistance of others and support and services carried out must be documented in an implementation plan. The International Classification of Functioning, Disability and Health can be used to support staff and ensure that information about the most important factors in an individual's functioning in their environment is not omitted in documentation. PMID- 28633544 TI - Medical versus surgical management of penetrating Crohn's disease: the current situation and future perspectives. AB - INTRODUCTION: The development of penetrating Crohn's disease (CD) occurs in up to 50% of patients over the course of their lifetime. While the presentation of these complications, including free perforation, intra-abdominal abscess, and enteric fistula, are usually obvious, the management can require a nuanced approach, with distinct short and long-term approaches. Areas covered: This review discusses medical and surgical methods of treating these complications, including the role of percutaneous drainage of abscesses, the implications of a stricture associated with a fistula, and the efficacy of postoperative anti-TNF therapy in preventing recurrence after surgical treatment. Expert commentary: An approach to the management of these complications that begins with control of sepsis, including broad-spectrum antibiotics, bowel rest, and nutritional support is proposed. The next appropriate step is a diagnostic evaluation to determine the utility of medical versus surgical therapy, considering the presence of a stricture and prior immunosuppressive therapy. Postoperative anti-TNF therapy, a highly effective method to prevent recurrence, should be considered in many cases. PMID- 28633545 TI - Late recovery of awareness in prolonged disorders of consciousness -a cross sectional cohort study. AB - PURPOSE: To detect any improvement of awareness in prolonged disorders of consciousness in the long term. METHODS: A total of 34 patients with prolonged disorders of consciousness (27 vegetative state and seven minimally conscious state; 16 males; aged 21-73) were included in the study. All patients were initially diagnosed with vegetative/minimally conscious state on admission to our specialist neurological rehabilitation unit. Re-assessment was performed 2-16 years later using Coma Recovery Scale-Revised. RESULTS: Although remaining severely disabled, 32% of the patients showed late improvement of awareness evidenced with development of non-reflexive responses such as reproducible command following and localization behaviors. Most of the late recoveries occurred in patients with subarachnoid hemorrhage (5/11, 45.5%). The ages of patients within the late recovery group (Mean = 45, SD = 11.4) and non-recovery group (Mean = 43, SD = 15.5) were not statistically different (p = 0.76). CONCLUSIONS: This study shows that late improvements in awareness are not exceptional in non-traumatic prolonged disorders of consciousness cases. It highlights the importance of long-term follow up of patients with prolonged disorders of consciousness, regardless of the etiology, age, and time passed since the brain injury. Long-term follow up will help clinicians to identify patients who may benefit from further assessment and rehabilitation. Although only one patient achieved recovery of function, recovery of awareness may have important ethical implications especially where withdrawal of artificial nutrition and hydration is considered. Implications for rehabilitation Long-term regular follow-up of people with prolonged disorders of consciousness is important. Albeit with poor functional outcomes late recovery of awareness is possible in both traumatic and non-traumatic prolonged disorders of consciousness cases. Recovery of awareness has significant clinical and ethical implications especially where withdrawal of artificial nutrition and hydration is considered. PMID- 28633546 TI - Identification of specific antibodies against the Ag85C-MPT51-HspX fusion protein (CMX) for serological screening of tuberculosis in endemic area. AB - OBJECTIVES: Development of new tools for rapid and accurate diagnosis of tuberculosis (TB) is considered a strategy for controlling the disease. The recombinant CMX fusion protein is composed of immunodominant epitopes of the Ag85C (Rv0129c), MPT51 (Rv3803c) and the entire HspX (Rv2031c) proteins from Mycobacterium tuberculosis H37Rv (Mtb). The aim of this study was to evaluate the applicability of a test using the CMX protein in individuals suspected of TB. METHODS: Indirect ELISA was used to measure serum anti-CMX IgM and IgG in individuals with pulmonary TB. RESULTS: Patients with pulmonary TB had higher titers of IgM (OD = 0.502 +/- 0.281) than healthy controls (OD = 0.200 +/- 0.125). The cutoff for IgM-ELISA was determined using ROC curve analyzes (AUC = 0.868) with a sensitivity of 80.1% and a specificity of 78.2%. Patients with pulmonary TB also had higher titers of IgG (OD = 0.525 +/- 0.391) than healthy controls (OD = 0.215 +/- 0.077). The cutoff for IgG-ELISA was determined using ROC curve analyzes (AUC = 0.864) with a sensitivity of 81.7% and a specificity of 74.7%. CONCLUSION: The results suggest that the recombinant protein CMX can be used in a serological test to complement the screening of individuals suspected of having active pulmonary TB. PMID- 28633547 TI - Lipid-based nanosystem of edaravone: development, optimization, characterization and in vitro/in vivo evaluation. AB - Edaravone (EDR) is a well-recognized lipophilic free radical scavenger for diseases including neurodegenerative disease, cardiovascular disease, and cancer. However, its oral use is restricted due to poor oral bioavailability (BA). The aim of present research was to enable its oral use by developing a lipid-based nanosystem (LNS). The components of LNS including oil, surfactants, and co surfactants were selected based on their potential to maximize the solubilization in gastrointestinal (GI) fluids, reduce its glucuronidation and improve transmembrane permeability. The liquid LNS (L-LNS) with CapryolTM PGMC (Oil), Cremophor(r) RH 40:Labrasol(r):TPGS 1000 (1:0.8:0.2) (Surfactant) and Transcutol P(r) (Co-surfactant) were optimized to form microemulsion having droplet size (16.25 nm), polydispersity index (0.039), % Transmittance (99.85%), and self emulsification time (32 s). It significantly improved the EDR loading as well as its metabolism and permeability profile during transport across the GI tract. To overcome the possible drawbacks of L-LNS, Aerosil(r) 200 was used to formulate solid LNS (S-LNS), and its concentration was optimized based on flow properties. S-LNS possessed all quality attributes of L-LNS confirmed by solid-state characterization, reconstitution ability, and stability study. The dissolution rate of EDR was significantly enhanced with L-LNS and S-LNS in simulated gastric, and intestinal fluids. The pharmacokinetic study revealed significant improvement in relative BA, Cmax, and t1/2 with L-LNS and S-LNS against EDR suspension. Moreover, S-LNS showed superior cellular uptake and neuroprotective effect compared to EDR in SH-SY5Y695 cell line. An appropriate selection of the components of LNS could enable effective oral delivery of challenging therapeutics that are conventionally used by the parenteral administration. PMID- 28633548 TI - Polyquaternium-mediated delivery of morpholino oligonucleotides for exon-skipping in vitro and in mdx mice. AB - Antisense oligonucleotide therapy for Duchenne muscular dystrophy has shown great potential in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few polyquaterniums (PQs) with different size and composition for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that LuviquatTM series, especially PQ-1 and PQ-3, promoted the exon-skipping efficiency comparable to Endoporter-mediated PMO delivery in vitro. Significant enhancement in skipping dystrophin exon 23 has also been achieved with PQ-3 up to seven-fold when compared to PMO alone in mdx mice. Cytotoxicity of the PQs was lower than Endoporter and PEI 25 K in vitro and muscle damage not clearly detected in vivo under the tested concentrations. These results together demonstrate that the optimization of PQ in molecular size, composition and distribution of positive charges is the key factor to achieve enhanced PMO exon-skipping efficiency. The higher efficiency and lower toxicity endow polyquaternium series as AO delivery enhancing agents for treating muscular dystrophy and other diseases. PMID- 28633549 TI - An update on Zika vaccine developments. AB - INTRODUCTION: The devastating consequences of congenital Zika virus (ZIKV) infection led to a global response directed toward a better understanding of the epidemiology and pathogenesis of ZIKV and to efforts at vaccine development. As a result, there are currently 45 ZIKV vaccine candidates in development. Areas covered: Both traditional (purified inactivated, live attenuated, viral-vectored, recombinant sub-unit) and novel (DNA, self-replicating RNA, mRNA) vaccine platforms are being utilized. For emergency use, vaccines that are appropriate for women of child-bearing age (including pregnant women) are being developed. Live vaccines that may be contraindicated in pregnancy are also in development for potential inclusion in national immunization programmes in childhood or pre teenage age groups. WHO developed a target product profile for Zika vaccines for use in an emergency. Expert commentary: Although ZIKV vaccine development had a quick head start, further development may be hampered because of the inability to conduct large efficacy trials with the decline in cases globally and unpredictability of new outbreaks. Furthermore, there are complex ethical issues involved in conducting efficacy trials in pregnant women. PMID- 28633550 TI - Right Fronto-Temporal EEG can Differentiate the Affective Responses to Award Winning Advertisements. AB - Affective engineering aims to improve service/product design by translating the customer's psychological feelings. Award-winning advertisements (AAs) were selected on the basis of the professional standards that consider creativity as a prerequisite. However, it is unknown if AA is related to satisfactory advertising performance among customers or only to the experts' viewpoints towards the advertisements. This issue in the field of affective engineering and design merits in-depth evaluation. We recruited 30 subjects and performed an electroencephalography (EEG) experiment while watching AAs and non-AAs (NAAs). The event-related potential (ERP) data showed that AAs evoked larger positive potentials 250-1400 [Formula: see text]ms after stimulus onset, particularly in the right fronto-temporal regions. The behavioral results were consistent with the professional recognition given to AAs by experts. The perceived levels of creativity and "product-like" quality were higher for the AAs than for the NAAs. Event-related spectral perturbation (ERSP) analysis further revealed statistically significant differences in the theta, alpha, beta, and gamma band activity in the right fronto-temporal regions between the AAs and NAAs. Our results confirm that EEG features from the time/frequency domains can differentiate affective responses to AAs at a neural circuit level, and provide scientific evidence to support the identification of AAs. PMID- 28633551 TI - A Pareto-based Ensemble with Feature and Instance Selection for Learning from Multi-Class Imbalanced Datasets. AB - Imbalanced classification is related to those problems that have an uneven distribution among classes. In addition to the former, when instances are located into the overlapped areas, the correct modeling of the problem becomes harder. Current solutions for both issues are often focused on the binary case study, as multi-class datasets require an additional effort to be addressed. In this research, we overcome these problems by carrying out a combination between feature and instance selections. Feature selection will allow simplifying the overlapping areas easing the generation of rules to distinguish among the classes. Selection of instances from all classes will address the imbalance itself by finding the most appropriate class distribution for the learning task, as well as possibly removing noise and difficult borderline examples. For the sake of obtaining an optimal joint set of features and instances, we embedded the searching for both parameters in a Multi-Objective Evolutionary Algorithm, using the C4.5 decision tree as baseline classifier in this wrapper approach. The multi objective scheme allows taking a double advantage: the search space becomes broader, and we may provide a set of different solutions in order to build an ensemble of classifiers. This proposal has been contrasted versus several state of-the-art solutions on imbalanced classification showing excellent results in both binary and multi-class problems. PMID- 28633553 TI - Giant Bullous Emphysema With Placental Transmogrification: A Case Report of a 14 Year-Old With Right Middle- and Lower-Lobe Involvement. AB - Giant bullous emphysema with placental transmogrification is an extremely rare entity, with 30 previously reported cases. Of these reported cases, it is typically identified with varied clinical and radiological impressions, presents in young adulthood to elderly, is always unilateral, and usually involves just one lobe. Despite the unknown pathogenesis, this diagnosis carries an excellent prognosis and is curative with complete resection. The pulmonary placental transmogrification is histologically indistinguishable from placental origin. Although not necessary to utilize because of the male predominance and no reported association, immunohistochemical stains can be used to prove lung origin. We report an extremely rare case of 2-lobe involvement of giant bullous emphysema with placental transmogrification in a boy 14 years of age, who is the youngest diagnosed patient with this lung abnormality. PMID- 28633552 TI - Cabozantinib for the treatment of kidney cancer. AB - INTRODUCTION: Cabozantinib is a small molecule tyrosine kinase inhibitor that initially showed activity in medullary thyroid cancer and was recently approved by the Food and Drug Administration for the treatment of metastatic renal cell carcinoma after progression on first line therapy. Areas covered: In the METEOR trial, cabozantinib demonstrated significantly improved efficacy in all three endpoints; response rates, progression free survival and overall survival in a randomized trial with everolimus as an active comparator. Cabozantinib also showed activity in the front line setting in RCC within the CABOSUN trial. The study randomized untreated metastatic RCC patients to either cabozantinib or sunitinib and the former showed improved progression free survival which was the primary endpoint. The future holds promise for indications in other malignancies, given the preliminary efficacy and unique mechanism of action of cabozantinib. In this review we address the mechanism of action, pharmacodynamics and pharmacokinetics of cabozantinib, and also review the development pathway of this agent in the treatment of advanced renal cell carcinoma. The potential benefit in specific patient populations, such as poor risk patients and bone metastases subgroups is also discussed. Expert commentary: The clinical applications of cabozantinib will be addressed within the context of the current competitive therapeutic landscape of RCC. PMID- 28633554 TI - Belief in Life After Death and Attitudes Toward Voluntary Euthanasia. AB - Research has documented associations among religious affiliation, religious practice, and attitudes toward voluntary euthanasia, yet very few studies have investigated how particular religious beliefs influence these attitudes. I use data from the General Social Survey (GSS; N = 19,967) to evaluate the association between the belief in life after death and attitudes toward voluntary euthanasia. I find that those who believe in life after death are significantly less likely than those who do not believe in life after death or those who doubt the existence of life after death to have positive attitudes toward voluntary euthanasia. These associations hold even after controlling for religious affiliation, religious attendance, views of the Bible, and sociodemographic factors. The findings indicate that to understand individuals' views about voluntary euthanasia, one must pay attention to individuals' particular religious beliefs. PMID- 28633555 TI - Glutamine Administration in Early or Late Septic Phase Downregulates Lymphocyte PD-1/PD-L1 Expression and the Inflammatory Response in Mice With Polymicrobial Sepsis. AB - BACKGROUND: Sepsis is a severe inflammatory response to infection. Excessive compensation to inflammation leads to dysregulated immune response that ultimately results in organ damage and lethality of sepsis. This study administered glutamine (GLN) in the early or late phase of sepsis to investigate its effects on regulating leukocyte programmed cell death 1 (PD-1) and its ligand (programmed cell death ligand 1 [PD-L1]) expression, macrophage function, inflammation, and acute kidney injury in sepsis. METHODS: Mice were randomly assigned to cecal ligation and puncture (CLP) or sham-operated groups. Septic mice were respectively injected once with saline or 0.75 g GLN/kg body weight at 3 or 10 hours post-CLP via tail vein. All mice were sacrificed 24 hours after CLP. RESULTS: Sepsis enhanced the percentage of interferon-gamma-expressing and interleukin (IL)-17A-expressing CD4+ T cells, expression of PD-1 on T cells, and PD-L1 on B cells and monocytes. Inflammatory mediator messenger RNA (mRNA) expression in kidney tissues and proapoptotic caspase-3 mRNA expression in mesenteric lymph nodes were also upregulated. GLN administration decreased plasma IL-6 level, downregulated the percentage of IL-17A-expressing CD4+ T cells, attenuated macrophage dysfunction, decreased caspase-3 mRNA expression, and reduced PD-1/PD-L1 expression by T and B cells. Histological findings also showed that kidney damage was attenuated. GLN administered at 3 and 10 hours after CLP offered nearly equal effects on PD-1/PD-L1 and inflammatory mediator expression after CLP. CONCLUSIONS: These findings suggest that a single dose of GLN administration in either the early or late phase during sepsis promotes a more balanced immune regulation and reduced systemic and kidney inflammatory responses in mice. PMID- 28633556 TI - Oxidative stress and DNA damage in newborns born to mothers with hyperglycemia - a prospective cohort study. AB - BACKGROUND: Hyperglycemic mothers have increased oxidative stress during pregnancy, which can adversely affect the outcome in their neonates. OBJECTIVES: To measure the oxidative stress and DNA damage in newborns born to mothers with hyperglycemia and correlate their immediate outcome with the amount of oxidative stress and DNA damage. METHODS: This prospective cohort study conducted in a tertiary care teaching hospital, South India included three groups - newborns born to pregestational diabetic mothers, gestational diabetic mothers, and euglycemic mothers with 24 newborns in each. Oxidative stress parameters - malondialdehyde (MDA), total antioxidant capacity (TAC), and DNA damage (comet assay) were assessed in umbilical cord blood. Association between these parameters and immediate neonatal outcome among three groups were studied. RESULTS: Newborns born to diabetic mothers had more MDA levels and DNA damage compared to euglycemic mothers. There was a positive correlation between comet parameters and MDA levels. There was an inverse correlation between comet parameters and TAC. Newborns born to diabetic mothers were at high risk to develop respiratory distress syndrome, hypoglycemia, and sepsis. CONCLUSIONS: Newborns born to diabetic mothers had increased oxidative stress and DNA damage compared to those born to mothers with euglycemia. PMID- 28633558 TI - An introduction to Bayesian statistics in health psychology. AB - The aim of the current article is to provide a brief introduction to Bayesian statistics within the field of health psychology. Bayesian methods are increasing in prevalence in applied fields, and they have been shown in simulation research to improve the estimation accuracy of structural equation models, latent growth curve (and mixture) models, and hierarchical linear models. Likewise, Bayesian methods can be used with small sample sizes since they do not rely on large sample theory. In this article, we discuss several important components of Bayesian statistics as they relate to health-based inquiries. We discuss the incorporation and impact of prior knowledge into the estimation process and the different components of the analysis that should be reported in an article. We present an example implementing Bayesian estimation in the context of blood pressure changes after participants experienced an acute stressor. We conclude with final thoughts on the implementation of Bayesian statistics in health psychology, including suggestions for reviewing Bayesian manuscripts and grant proposals. We have also included an extensive amount of online supplementary material to complement the content presented here, including Bayesian examples using many different software programmes and an extensive sensitivity analysis examining the impact of priors. PMID- 28633557 TI - CXCL12/CXCR4 signaling mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats. AB - Background: It has been demonstrated that upregulation of CXCL12 and CXCR4 in spinal cord involves in the pathogenesis of neuropathic, inflammatory, and cancer pain. However, whether CXCL12/CXCR4 signaling contributes to postsurgical pain remains unknown. The aim of the present study is to investigate the role of CXCL12/CXCR4 signaling in the genesis of postsurgical pain and the underlying mechanism. Results: Plantar incision in rat hind paw resulted in increased expressions of CXCL12 and CXCR4 in spinal dorsal horn. Double immunofluorescence staining revealed that CXCL12 expressed in neurons and astrocytes, and CXCR4 exclusively co-localized with neuronal cells. Prior administration of AMD3100, a specific antagonist of CXCR4, or CXCL12 neutralizing antibody, intrathecally attenuated plantar incision-induced mechanical allodynia and thermal hyperalgesia. Plantar incision also augmented the phosphorylation of NF-kappaB p65 in spinal cord. Pre intrathecal (i.t.) injection of PDTC, a specific NF kappaB activation inhibitor, alleviated plantar incision-induced postsurgical pain and reduced the expression of CXCL12 in spinal cord. Correlated with the upregulation of CXCL12 and CXCR4, plantar incision also resulted in an increased phosphorylation of extracellular signal-regulated kinase 1/2 and Akt in spinal cord. Prior i.t. administration of AMD3100 prevented extracellular signal regulated kinase, but not Akt, activation in spinal cord. Rats when given a repetitive i.t. PD98059, a specific extracellular signal-regulated kinase inhibitor, started 30 min before surgery also ameliorate plantar incision-induced mechanical and thermal pain hypersensitivity. Conclusion: Our results suggests that plantar incision-induced activation of NF-kappaB signaling may mediate upregulation of CXCL12 in spinal cord, and CXCL12/CXCR4 signaling via extracellular signal-regulated kinase activation contributes to the genesis of postsurgical pain. PMID- 28633559 TI - Dating persons with physical disabilities: the perceptions of South Africans without disabilities. AB - There is good reason to believe that the attitudes of persons without disability towards dating a person with a physical disability might be unfavourable. However, in general, and in the Global South in particular, there is a dearth of research in this area. This study sought to take the first step in addressing this lack of enquiry, by surveying the attitudes of a general population sample in South Africa towards dating people with physical disabilities, using a vignette. Data from 1723 survey respondents were analysed thematically. Findings reveal largely negative attitudes towards people with physical disabilities. Respondents without disability perceived numerous barriers to dating a person with a physical disability, including social stigma, anxiety and concerns about the burden of care they believed such a relationship would place upon them. However, there was some evidence to suggest that some positive attitudes do exist, and a few respondents were open to dating a person with physical disabilities. Findings contribute to a nuancing and expanding of the 'myth of asexuality' among physically disabled people by showing that people with physical disabilities are actively desexualised by persons without disability. Future research is needed to explore how the inclusive attitudes, of which we did find evidence here, can be further cultivated. PMID- 28633561 TI - Regulation of Energy Homeostasis After Gastric Bypass Surgery. AB - The obesity epidemic continues to escalate each year in the United States more than anywhere else in the world. The existing pharmaceutical and other nonsurgical treatments for morbid obesity produce suboptimal physiologic outcomes compared with those of Roux-en-Y gastric bypass (RYGB) surgery. RYGB has been the gold standard of bariatric surgery because the beneficial long-term outcomes, which include sustainable weight loss and type 2 diabetes mellitus (T2DM) resolution, are far superior to those obtained with other bariatric surgeries. However, the current understanding of RYGB's mechanisms of actions remains limited and incomplete. There is an urgent need to understand these mechanisms as gaining this knowledge may lead to the development of innovative and less invasive procedures and/or medical devices, which can mirror the favorable outcomes of RYGB surgery. In this review, we highlight current observations of the metabolic and physiologic events following RYGB, with a particular focus on the role of the anatomical reconfiguration of the gastrointestinal tract after RYGB. PMID- 28633562 TI - Advances in Imaging Brain Metabolism. AB - Metabolism is central to neuroimaging because it can reveal pathways by which neuronal and glial cells use nutrients to fuel their growth and function. We focus on advanced magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) methods used in brain metabolic studies. 17O-MRS and 31P-MRS, respectively, provide rates of oxygen use and ATP synthesis inside mitochondria, whereas 19F-MRS enables measurement of cytosolic glucose metabolism. Calibrated functional MRI (fMRI), an advanced form of fMRI that uses contrast generated by deoxyhemoglobin, provides maps of oxygen use that track neuronal firing across brain regions. 13C-MRS is the only noninvasive method of measuring both glutamatergic neurotransmission and cell-specific energetics with signaling and nonsignaling purposes. Novel MRI contrasts, arising from endogenous diamagnetic agents and exogenous paramagnetic agents, permit pH imaging of glioma. Overall, these magnetic resonance methods for imaging brain metabolism demonstrate translational potential to better understand brain disorders and guide diagnosis and treatment. PMID- 28633563 TI - Mammalian Synthetic Biology: Engineering Biological Systems. AB - The programming of new functions into mammalian cells has tremendous application in research and medicine. Continued improvements in the capacity to sequence and synthesize DNA have rapidly increased our understanding of mechanisms of gene function and regulation on a genome-wide scale and have expanded the set of genetic components available for programming cell biology. The invention of new research tools, including targetable DNA-binding systems such as CRISPR/Cas9 and sensor-actuator devices that can recognize and respond to diverse chemical, mechanical, and optical inputs, has enabled precise control of complex cellular behaviors at unprecedented spatial and temporal resolution. These tools have been critical for the expansion of synthetic biology techniques from prokaryotic and lower eukaryotic hosts to mammalian systems. Recent progress in the development of genome and epigenome editing tools and in the engineering of designer cells with programmable genetic circuits is expanding approaches to prevent, diagnose, and treat disease and to establish personalized theranostic strategies for next generation medicines. This review summarizes the development of these enabling technologies and their application to transforming mammalian synthetic biology into a distinct field in research and medicine. PMID- 28633560 TI - Bioinspired Hydrogels to Engineer Cancer Microenvironments. AB - Recent research has demonstrated that tumor microenvironments play pivotal roles in tumor development and metastasis through various physical, chemical, and biological factors, including extracellular matrix (ECM) composition, matrix remodeling, oxygen tension, pH, cytokines, and matrix stiffness. An emerging trend in cancer research involves the creation of engineered three-dimensional tumor models using bioinspired hydrogels that accurately recapitulate the native tumor microenvironment. With recent advances in materials engineering, many researchers are developing engineered tumor models, which are promising platforms for the study of cancer biology and for screening of therapeutic agents for better clinical outcomes. In this review, we discuss the development and use of polymeric hydrogel materials to engineer native tumor ECMs for cancer research, focusing on emerging technologies in cancer engineering that aim to accelerate clinical outcomes. PMID- 28633564 TI - Energy Harvesting from the Animal/Human Body for Self-Powered Electronics. AB - Living subjects (i.e., humans and animals) have abundant sources of energy in chemical, thermal, and mechanical forms. The use of these energies presents a viable way to overcome the battery capacity limitation that constrains the long term operation of wearable/implantable devices. The intersection of novel materials and fabrication techniques offers boundless possibilities for the benefit of human health and well-being via various types of energy harvesters. This review summarizes the existing approaches that have been demonstrated to harvest energy from the bodies of living subjects for self-powered electronics. We present material choices, device layouts, and operation principles of these energy harvesters with a focus on in vivo applications. We discuss a broad range of energy harvesters placed in or on various body parts of human and animal models. We conclude with an outlook of future research in which the integration of various energy harvesters with advanced electronics can provide a new platform for the development of novel technologies for disease diagnostics, treatment, and prevention. PMID- 28633566 TI - Microsphere-Based Scaffolds in Regenerative Engineering. AB - Microspheres have long been used in drug delivery applications because of their controlled release capabilities. They have increasingly served as the fundamental building block for fabricating scaffolds for regenerative engineering because of their ability to provide a porous network, offer high-resolution control over spatial organization, and deliver growth factors/drugs and/or nanophase materials. Because they provide physicochemical gradients via spatiotemporal release of bioactive factors and nanophase ceramics, microspheres are a desirable tool for engineering complex tissues and biological interfaces. In this review we describe various methods for microsphere fabrication and sintering, and elucidate how these methods influence both micro- and macroscopic scaffold properties, with a special focus on the nature of sintering. Furthermore, we review key applications of microsphere-based scaffolds in regenerating various tissues. We hope to inspire researchers to join a growing community of investigators using microspheres as tissue engineering scaffolds so that their full potential in regenerative engineering may be realized. PMID- 28633565 TI - FEBio: History and Advances. AB - The principal goal of the FEBio project is to provide an advanced finite element tool for the biomechanics and biophysics communities that allows researchers to model mechanics, transport, and electrokinetic phenomena for biological systems accurately and efficiently. In addition, because FEBio is geared toward the research community, the code is designed such that new features can be added easily, thus making it an ideal tool for testing novel computational methods. Finally, because the success of a code is determined by its user base, integral goals of the FEBio project have been to offer support and outreach to our community; to provide mechanisms for dissemination of results, models, and data; and to encourage interaction between users. This review presents the history of the FEBio project, from its initial developments through its current funding period. We also present a glimpse into the future of FEBio. PMID- 28633568 TI - The potential inhibitory effect of beta-casein on the aggregation and deposition of Abeta1-42 fibrils in Alzheimer's disease: insight from in-vitro and in-silico studies. AB - Abeta1-40 and Abeta1-42 have been shown to be the main components of the amyloid plaques found in the extracellular environment of neurons in Alzheimer's disease. beta-Casein, a milk protein, has been shown to display a remarkable chaperone ability in preventing the aggregation of proteins. In this study, the ability of beta-casein to suppress the amyloid fibril formation of Abeta1-42 has been examined through in vitro studies and molecular docking simulation. The results demonstrate the inhibitory effect of beta-casein on fibril formation in Abeta1 42, in a concentration dependent manner, suggesting that the chaperone binds to the Abeta1-42 and prevents amyloid fibril formation. Molecular docking results show that the inhibitory effect of the beta-casein may be due to binding of the chaperone with the aggregation-prone region of the Abeta1-42 mainly via hydrophobic interactions. beta-Casein probably binds to the CHC and C-terminal domain of the Abeta1-42, and stabilizes proteins by inhibiting the conversion of monomeric Abeta1-42 into fibrils. Thus our data suggests that the hydrophobic interactions between beta-casein and Abeta1-42 play an important role in the burial of the hydrophobic part of the Abeta1-42. This means that beta-casein maybe considered for use in preventing amyloid fibril formation in degenerative diseases such as Alzheimer. PMID- 28633567 TI - Endogenous Bioelectric Signaling Networks: Exploiting Voltage Gradients for Control of Growth and Form. AB - Living systems exhibit remarkable abilities to self-assemble, regenerate, and remodel complex shapes. How cellular networks construct and repair specific anatomical outcomes is an open question at the heart of the next-generation science of bioengineering. Developmental bioelectricity is an exciting emerging discipline that exploits endogenous bioelectric signaling among many cell types to regulate pattern formation. We provide a brief overview of this field, review recent data in which bioelectricity is used to control patterning in a range of model systems, and describe the molecular tools being used to probe the role of bioelectrics in the dynamic control of complex anatomy. We suggest that quantitative strategies recently developed to infer semantic content and information processing from ionic activity in the brain might provide important clues to cracking the bioelectric code. Gaining control of the mechanisms by which large-scale shape is regulated in vivo will drive transformative advances in bioengineering, regenerative medicine, and synthetic morphology, and could be used to therapeutically address birth defects, traumatic injury, and cancer. PMID- 28633569 TI - Thermal and chemical denaturation of Colocasia esculenta tuber agglutinin from alpha2beta2 to unfolded state. AB - The major tuber storage protein of Colocasia esculenta, is a monocot mannose binding, widely used dietary lectin, containing two polypeptides of 12.0 and 12.4 kDa. By both gel filtration and dynamic light scattering at pH 7.2, the lectin has a alpha2beta2 form of apparent molecular mass of 48.2 kDa and a hydrodynamic radius of 6.1 +/- .2 nm; however, at pH 3, it migrates as alphabeta and has a reduced hydrodynamic radius of 4.6 +/- .3 nm. Our circular dichroism spectroscopy studies show that the lectin retains approximately 100% of its secondary structure between pH 2-8, going down to ~90% for extreme acidic/alkaline conditions. The fluorescence emission maxima of 346 to 350 nm for pH 4 to 10 show that the tryptophan residues are relatively exposed. The unfolding is a simple two-state process, N4 <-> 4U, as seen in our denaturation scan profiles. These denaturation profiles, monitored separately by fluorescence, far-UV CD, and near UV CD, are completely super imposable. Analyses of these profiles provide an estimate of several thermodynamic parameters at each guanidinium chloride concentration, including the melting temperature Tg, which is 346.9 K in 0 M, but lowers to 321.8 K in 3.6 M. Dimeric and tetrameric interfaces observed in the crystal structure for the same protein are used to rationalize solution data in some detail. PMID- 28633570 TI - Enantioselective light switch effect of Delta- and Lambda-[Ru(phenanthroline)2 dipyrido[3,2-a:2', 3'-c]phenazine]2+ bound to G-quadruplex DNA. AB - The interaction of Delta- and Lambda-[Ru(phen)2DPPZ]2+ (DPPZ = dipyrido[3,2-a:2', 3'-c]phenazine, phen = phenanthroline) with a G-quadruplex formed from 5' G2T2G2TGTG2T2G2-3'(15-mer) was investigated. The well-known enhancement of luminescence intensity (the 'light-switch' effect) was observed for the [Ru(phen)2DPPZ]2+ complexes upon formation of an adduct with the G-quadruplex. The emission intensity of the G-quadruplex-bound Lambda-isomer was 3-fold larger than that of the Delta-isomer when bound to the G-quadruplex, which is opposite of the result observed in the case of double stranded DNA (dsDNA); the light switch effect is larger for the dsDNA-bound Delta-isomer. In the job plot of the G-quadruplex with Delta- and Lambda-[Ru(phen)2DPPZ]2+, a major inflection point for the two isomers was observed at x ~ .65, which suggests a binding stoichiometry of 2:1 for both enantiomers. When the G base at the 8th position was replaced with 6-methyl isoxanthopterin (6MI), a fluorescent guanine analog, the excited energy of 6-MI transferred to bound Delta- or Lambda [Ru(phen)2DPPZ]2+, which suggests that at least a part of both Ru(II) enantiomers is close to or in contact with the diagonal loop of the G-quadruplex. A luminescence quenching experiment using [Fe(CN)6]4- for the G-quadruplex-bound Ru(II) complex revealed downward bending curves for both enantiomers in the Stern Volmer plot, which suggests the presence of Ru(II) complexes that are both accessible and inaccessible to the quencher and may be related to the 2:1 binding stoichiometry. PMID- 28633572 TI - Not having verbal repetitiveness might increase confidence that cognitive concerns in ageing are not due to Alzheimer's disease. PMID- 28633571 TI - The role of peri-traumatic stress and disruption distress in predicting symptoms of major depression following exposure to a natural disaster. AB - OBJECTIVE: Few studies have examined the contribution of specific disaster related experiences to symptoms of depression. The aims of this study were to do this by examining the roles of peri-traumatic stress and distress due to lingering disaster-related disruption in explaining linkages between disaster exposure and major depressive disorder symptoms among a cohort exposed to the 2010-2011 Canterbury (New Zealand) earthquakes. METHODS: Structural equation models were fitted to data obtained from the Christchurch Health and Development Study at age 35 ( n = 495), 20-24 months following the onset of the disaster. Measures included earthquake exposure, peri-traumatic stress, disruption distress and symptoms of major depressive disorder. RESULTS: The associations between earthquake exposure and major depression were explained largely by the experience of peri-traumatic stress during the earthquakes (beta = 0.180, p < 0.01) and not by disruption distress following the earthquakes (beta = 0.048, p = 0.47). CONCLUSION: The results suggest that peri-traumatic stress has been under recognised as a predictor of major depressive disorder. PMID- 28633573 TI - Should we encourage smokers with severe mental illness to switch to electronic cigarettes? PMID- 28633574 TI - An Erudite Encounter with: Robert Post. PMID- 28633575 TI - Personality disorders: A Retrospective. PMID- 28633576 TI - Trauma, treatment and temperament: From troubling times to troubled thinking. PMID- 28633577 TI - Psychotropic pharmacogenetics - Distraction or destiny? PMID- 28633578 TI - The imperative to screen for obstructive sleep apnoea in people with schizophrenia. PMID- 28633579 TI - 'Hey, how's it going?' The practical value of assessing quality of life in mental illness. PMID- 28633580 TI - Platinum agents and mitomycin C-specific complications in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been found to prolong survival in patients with peritoneal disease but is associated with significant morbidity. We evaluate the perioperative complications and the association with the chemotherapy agent used for HIPEC. METHODS: Retrospective analysis of a prospectively collected database of CRS-HIPEC cases between April 2001 and February 2016 was performed. Patients were stratified by the chemotherapy used, and perioperative complications were compared. RESULTS: Out of 214 CRS-HIPEC cases, 113 procedures used Mitomycin C(MMC), 92 used cisplatin, 8 used oxaliplatin and the HIPEC regimen for one procedure was not recorded and excluded. 94 patients (44%) suffered low-grade complications (grade I-II), and 49 patients (23%) suffered high-grade complications (grade III-V). The frequency of low-grade complications for the cisplain, oxaliplatin and MMC groups were 49%, 50% and 40%, respectively, whereas that of high-grade complications were 24%, 50% and 20%, respectively. HIPEC with platinum agents was associated with a higher rate of acute renal impairment (ARI) compared to MMC (32% and 62% for cisplatin and oxaliplatin vs. 5.6% for MMC), whereas grade IV ARI requiring dialysis occurred only in the cisplatin group (5.6%). HIPEC with oxaliplatin was associated with higher rates of post-operative bleeding (25% vs. 1.1% and 0.88%). Rates of other complications did not differ significantly between the groups receiving different HIPEC regimens. CONCLUSIONS: The overall complication rates do not significantly differ after HIPEC with MMC and platinum based agents. Renal impairment tends to be more common and of greater severity when a platinum agent is used, whereas oxaliplatin is associated with significant post-operative bleeding. PMID- 28633581 TI - Prediction and management of drug reaction with eosinophilia and systemic symptoms (DRESS). PMID- 28633582 TI - Dopamine and light: effects on facial emotion recognition. AB - Bright light can affect mood states and social behaviours. Here, we tested potential interacting effects of light and dopamine on facial emotion recognition. Participants were 32 women with subsyndromal seasonal affective disorder tested in either a bright (3000 lux) or dim light (10 lux) environment. Each participant completed two test days, one following the ingestion of a phenylalanine/tyrosine-deficient mixture and one with a nutritionally balanced control mixture, both administered double blind in a randomised order. Approximately four hours post-ingestion participants completed a self-report measure of mood followed by a facial emotion recognition task. All testing took place between November and March when seasonal symptoms would be present. Following acute phenylalanine/tyrosine depletion (APTD), compared to the nutritionally balanced control mixture, participants in the dim light condition were more accurate at recognising sad faces, less likely to misclassify them, and faster at responding to them, effects that were independent of changes in mood. Effects of APTD on responses to sad faces in the bright light group were less consistent. There were no APTD effects on responses to other emotions, with one exception: a significant light * mixture interaction was seen for the reaction time to fear, but the pattern of effect was not predicted a priori or seen on other measures. Together, the results suggest that the processing of sad emotional stimuli might be greater when dopamine transmission is low. Bright light exposure, used for the treatment of both seasonal and non-seasonal mood disorders, might produce some of its benefits by preventing this effect. PMID- 28633583 TI - Severe viral pneumonia in adults: what is important for the ICU physician? PMID- 28633584 TI - Variation of alkaloid contents and antimicrobial activities of Papaver rhoeas L. growing in Turkey and northern Cyprus. AB - CONTEXT: Papaver rhoeas L. (Papaveraceae) corn poppy, widely distributed in Turkey, is used to make a cough syrup for children, as a tea for disturbed sleep, for pain relief and as a sedative in folk medicine. OBJECTIVE: Samples of P. rhoeas collected from eight different locations in Turkey and three from northern Cyprus were investigated for their alkaloid content and screened for their antimicrobial activities. MATERIALS AND METHODS: From the aerial parts of P. rhoeas samples, alkaloids were isolated by column and preparative thin-layer chromatography. The alkaloids were identified by comparing their spectral data (UV, IR and 1H-NMR) and TLC Rf values with those of authentic samples. The antimicrobial study was carried out by microbroth dilution technique against six strains of bacteria and three strains of fungi. RESULTS: Twelve different alkaloids belonging to proaporphine (mecambrine), aporphine (roemerine), promorphinan (salutaridine), protopine (coulteropine and protopine) and rhoeadine (epiglaucamine, glaucamine, glaudine, isorhoeadine, isorhoeagenine, rhoeadine and rhoeagenine) groups were isolated. The most significant activity was observed with the alkaloid extract of P8 against Staphylococcus aureus with a MIC value of 1.22 MUg/mL and against Candida albicans with a MIC value of 2.4 MUg/mL. DISCUSSION: The results indicate that P. rhoeas samples (P8 and P9), which contain roemerine as their major alkaloid, were the most active extracts. PMID- 28633585 TI - Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes. AB - OBJECTIVES: Some evidence suggests that serum lipoprotein[Lp](a) may be inversely linked to type-2 diabetes. We aimed to determine in nondiabetic people the relationship of serum [Lp](a) with insulin resistance and new-onset diabetes (NOD). MATERIALS AND METHODS: Population-based middle-aged adults (n = 1685) were categorized by fasting glucose and stratified to gender, having excluded prevalent diabetic subjects. NOD (n = 90) occurred over a median 5 years' follow up. RESULTS: Subjects that subsequently developed NOD, derived both from the normoglycemia and impaired fasting glucose (IFG) groups,were distinguished, among others, primarily by significantly elevated serum gamma glutamyltransferase, reduced Lp(a) (by 31%) and, compared to IFG, by low total cholesterol levels. Partial correlation of Lp(a) with homeostatic model assessment (HOMA) was inverse in normoglycemic men; such correlation, neutral in normoglycemic women, proved inverse in IFG (r = -0.17). Circulating Lp(a) in individuals with paired measures increased significantly (1.55-fold) in the period from baseline up to NOD. Multivariable-adjusted logistic regression analysis for NOD in combined sexes indicated independent and additive prediction by serum Lp(a), albeit inverse in direction (RR 0.84, [95%CI 0.72; 0.97]). CONCLUSION: Lp(a) is significantly reduced in the period preceding NOD and is inversely associated with HOMA index, observations consistent with underlying autoimmune activation. PMID- 28633586 TI - Porphyromonas gingivalis and its LPS differentially regulate the expression of peptidyl arginine deiminases in human chondrocytes. AB - Periodontitis, an inflammatory disease initiated by Gram-negative bacteria such as Porphyromonas gingivalis ( Pg), is considered as a risk factor for rheumatoid arthritis (RA). Our study aimed to determine the effect of Pg and its LPS on the expression of peptidyl arginine deiminase isotypes (PADs) in human primary chondrocytes (HC). HCs were infected with Pg and activated by its LPS (LPS- Pg). The mRNA expression levels of human PADs (1, 2, 3, 4 and 6) and bacterial enzyme (PADPg) were quantified by RT-qPCR. Cellular extracts served to measure the enzymatic activities of PADs and PADPg and to visualize the profiles of citrullinated proteins/peptides by Western blotting. Our data showed significant inhibitions of mRNA expressions of human PAD-2, PAD-3 and PAD-4 during infection of HC with live Pg. Activation of HC by LPS- Pg increased mRNA expressions of human PAD-2 and PAD-3. The PADPg enzymatic activity was significantly increased in only infected HC. Analysis of citrullinated proteins/peptides profiles revealed the occurrence of low molecular bands only in cellular extracts from HC infected with Pg. Our data showed that Pg and its LPS differentially regulate the expression of PADs in human chondrocytes and that Pg favors the apparition of new citrullinated proteins/peptides. PMID- 28633587 TI - Sarcomatoid Carcinoma Manifesting as Recurrent Rectal Cancer and Mimicking Radiation-Induced Extraskeletal Osteosarcoma: A Case Report. AB - Here, we report an unusual case of sarcomatoid carcinoma mimicking extraskeletal osteosarcoma that manifested as recurrent rectal cancer. Five years earlier, a 76 year-old male patient had undergone neoadjuvant chemoradiotherapy followed by a laparoscopic low anterior resection due to adenocarcinoma of the rectum. He was admitted because of pain in the anus and left hip. He underwent abdominal computed tomography that revealed a newly developed left perirectal mass with gluteus maximus invasion measuring up to 8 cm, and therefore, an abdominoperineal resection was performed. Histologically, the tumor revealed sheets of spindled or epithelioid cells, an absence of gland formation, mucicarmine and periodic acid Schiff stain negativity, and prominent intercellular deposits of osteoid-like calcified tissue. Tumor cells were diffusely immunoreactive for vimentin and cytokeratins. Ultrastructural examination demonstrated microvilli on the surface or within intercellular spaces. In this report, we also discuss the possible pathogenesis as well as the differential diagnosis. PMID- 28633588 TI - New strategies for cancer management: how can temozolomide carrier modifications improve its delivery? PMID- 28633589 TI - Laser-induced thermal ablation of cancerous cell organelles. AB - AIM: By exploiting the physical changes experienced by cancerous organelles, we investigate the feasibility of destroying cancerous cells by single and multipulse modes of laser heating. MATERIALS & METHODS: Our procedure consists of two primary steps: determining the normal and cancerous organelles optical properties and simulating the heating of all of the major organelles in the cell to find the treatment modes for the laser ablation of cancerous organelles without harming healthy cells. RESULTS & CONCLUSION: Our simulations show that the cancerous nucleus can be selectively heated to damaging temperatures, making this nucleus a feasible therapeutic particle and removing the need for nanoparticle injection. Because of the removal of this extra step, the procedure we propose is simpler and safer for the patient. PMID- 28633590 TI - Polymeric therapeutic delivery systems for the treatment of infectious diseases. AB - Infectious diseases caused by germs, parasites, fungi, virus and bacteria are one of the leading causes of death worldwide. Polymeric therapeutics are nanomedicines that offer several advantages making them useful for the treatment of infectious diseases such as targeted drug release mechanism, ability to maintain the drug concentration within a therapeutic window for a desired duration, biocompatibility with low immunogenicity and reduced drug toxicity resulting in enhanced therapeutic efficacy of the incorporated drug. Although polymeric therapeutics have been evaluated for the treatment of infectious diseases in vitro and in vivo with improved therapeutic efficacy, most treatments for infectious disease have not been evaluated using polymeric therapeutics. This review will focus on the applications of polymeric therapeutics for the treatment of infectious diseases (preclinical studies and clinical trials), with particular focus on parasitic and viral infections. PMID- 28633591 TI - Approaches in topical ocular drug delivery and developments in the use of contact lenses as drug-delivery devices. AB - Drug-delivery approaches have diversified over the last two decades with the emergence of nanotechnologies, smart polymeric systems and multimodal functionalities. The intended target for specific treatment of disease is the key defining developing parameter. One such area which has undergone significant advancements relates to ocular delivery. This has been expedited by the development of material advancement, mechanistic concepts and through the deployment of advanced process technologies. This review will focus on the developments within lens-based drug delivery while touching on conventional and current methods of topical ocular drug delivery. A summary table will provide quick reference to note the key findings in this area. In addition, the review also elucidates current theranostic and diagnostic approaches based on ocular lenses. PMID- 28633592 TI - Recent advances in therapeutic delivery systems of bacteriophage and bacteriophage-encoded endolysins. AB - Antibiotics have been the cornerstone of clinical management of bacterial infection since their discovery in the early 20th century. However, their widespread and often indiscriminate use has now led to reports of multidrug resistance becoming globally commonplace. Bacteriophage therapy has undergone a recent revival in battle against pathogenic bacteria, as the self-replicating and co-evolutionary features of these predatory virions offer several advantages over conventional therapeutic agents. In particular, the use of targeted bacteriophage therapy from specialized delivery platforms has shown particular promise owing to the control of delivery location, administration conditions and dosage of the therapeutic cargo. This review presents an overview of the recent formulations and applications of such delivery vehicles as an innovative and elegant tool for bacterial control. PMID- 28633594 TI - Targeting and delivery of therapeutic enzymes. AB - Biotechnology has revolutionized therapeutics for the treatment of a wide range of diseases. Recent advances in protein engineering and material science have made the targeted delivery of enzyme therapeutics using nanocarriers (NCs) a new model of treatment. Several NCs have been approved for clinical use in drug delivery. Despite their advantages, few NCs have been approved to deliver enzyme cargo in a targeted manner. This review details the current arsenal of platforms developed to deliver enzyme therapeutics as well as the advantages and challenges of using enzymes as drugs, with examples from the literature, and discusses the benefits and liabilities of a given approach. We conclude by providing a perspective on how this field may evolve over the near and long-term. PMID- 28633595 TI - Central venous catheter insertion into the false lumen of a complicated aortic dissection. AB - Thoracic endovascular repair is considered the first-line treatment in complicated acute type B dissection. Central venous catheters provide valuable vascular access during endovascular treatments. However, central venous catheters are not without complications. Herein, we report a case of central venous catheter insertion into the false lumen of a complicated acute type B aortic dissection by direct aortic puncture. The tip of the central venous catheter was in the false lumen. The central venous catheter was left in place initially and was removed after graft stent deployment. This case illustrates the importance of image guidance during central venous catheter insertion, which may further complicate an already complicated aortic dissection case. PMID- 28633596 TI - Laparotomy site implantation metastasis of carcinoma of the papilla of Vater. AB - Introduction Carcinomas of the papilla of Vater make up a heterogeneous group of tumours arising from different types of epithelium. Regional lymph nodes, liver and lungs are the primary sites of metastatic progression of these tumours. Case presentation We present a patient with an abdominal incision site metastasis of low-grade (mixed type) adenocarcinoma of the papilla of Vater one year after pylorus-preserving pancreaticoduodenectomy. Implantation metastasis of low-grade ampullary carcinoma in the laparotomy wound after open Whipple's procedure is unusual. Conclusion Adjuvant chemoradiation might be considered for patients with low-grade localised disease as a potentially preventative measure vs. metastatic progression. PMID- 28633597 TI - Effect of T-2 toxin-injected shrimp muscle extracts on mouse macrophage cells (RAW264.7). AB - Following intramuscular injections of 0.1 mL, 3 mg kg-1 BW-1(1/10 LD50) T-2 toxin (T-2), the tissue concentration of T-2 in shrimp was quantitatively detected using LC-MS/MS. The biological half-time (t1/2) of T-2 in blood was 40.47 +/- 0.24 min. The highest number of intramuscular T-2 shrimp could tolerate when given at blood t1/2 intervals was 4. The shrimps which were injected 5 T-2 died. The T-2 toxin highest accumulation was 0.471 +/- 0.012 ng g-1 BW-1. The effect of toxic shrimp muscle subjected to different processing conditions (high pressure, trifluoroacetic acid, acid and alkali digestions, artificial digestive juice [to simulate exposure to gastric and intestinal juices]) on mouse macrophage cells (RAW267.4) were evaluated by the MTT assay. The inhibition ratio of 2% muscle extract on RAW267.4 was 85.70 +/- 2.63%. The immunocytotoxicity of muscle extracts to RAW264.7 was highest in muscle extracts subjected to physical and chemical digestion (high pressure > NaOH > trifluoroacetic acid > 0.02 M HCl > 0.2 M HCl > controls), and also artificial digestion (artificial intestinal juice > artificial gastric juice > N type intestinal juice > N type gastric liquid > controls). Results showed that high-pressure and artificial intestinal juice were most effective in the release of modified T-2 to free T-2 thus enhancing toxicity. These results can be interpreted as measurement of T-2 in food being of little value because of enhanced toxicity of T-2-contaminated food as they pass through the gastrointestinal tract. PMID- 28633598 TI - Metabolism of inhaled methylethylketone in rats. AB - Methylethylketone (MEK) is widely used in industry, often in combination with other compounds. Although nontoxic, it can make other chemicals harmful. This study investigates the fate of MEK in rat blood, brain and urine as well as its hepatic metabolism following inhalation over 1 month (at 20, 200 or 1400 ppm). MEK did not significantly accumulate in the organism: blood concentrations were similar after six-hour or 1-month inhalation periods, and brain concentrations only increased slightly after 1 month's exposure. Urinary excretion, based on the major metabolites, 2,3-butanediols (+/- and meso forms), accounted for less than 2.4% of the amount inhaled. 2-Butanol, 3-hydroxy-2-butanone and MEK itself were only detectable in urine in the highest concentration conditions investigated, when metabolic saturation occurred. Although MEK exposure did not alter the total cytochrome P450 concentration, it induced activation of both CYP1A2 and CYP2E1 enzymes. In addition, the liver glutathione concentration (reduced and oxidized forms) decreased, as did glutathione S-transferase (GST) activity (at exposure levels over 200 ppm). These metabolic data could be useful for pharmacokinetic model development and/or verification and suggest the ability of MEK to influence the metabolism (and potentiate the toxicity) of other substances. PMID- 28633599 TI - Mechanism of deltamethrin induced thymic and splenic toxicity in mice and its protection by piperine and curcumin: in vivo study. AB - Deltamethrin (DLM) is a well-known pyrethroid insecticide which is widely used in the agriculture and home pest control due to restriction on the sale of organophosphate. DLM induced apoptosis is well known but its mechanism is still unclear. This study has been designed to find out its mechanism of apoptosis with the help of computational methods along with in vivo methods. The QikProp and ProTox results have shown that DLM has good oral absorption. The docking results reveal that DLM has a strong binding affinity toward the CD4, CD8, CD28 and CD45 receptors. Further, to understand the toxicity of DLM on lymphoid cells, a single dose of DLM (5 mg/kg, oral for seven days) has been administered to male Balb/c mice and cytotoxicity (MTT assay), oxidative stress indicators (glutathione, reactive oxygen species) and apoptotic markers (caspase-3 activity, DNA fragmentation) have been assessed in thymic and splenic single cell suspensions. Lowering of body weight, cellularity and loss in cell viability have been observed in DLM treated mice. The significant increase in ROS and GSH depletion in spleen and thymus, indicate the possible involvement of oxidative stress. The spleen cells appear more susceptible to the adverse effects of DLM than thymus cells. Further, for the amelioration of its effect, two structurally different bioactive herbal extracts, piperine and curcumin have been evaluated and have shown the cytoprotective effect by inhibiting the apoptogenic signaling pathways induced by DLM. PMID- 28633600 TI - Direct comparison of tricyclic and serotonin-reuptake inhibitor antidepressants in randomized head-to-head trials in acute major depression: Systematic review and meta-analysis. AB - BACKGROUND: A comparison across trials conducted over several decades suggested superior efficacy of tricyclic antidepressants (TCAs) over selective serotonin reuptake inhibitors (SSRIs). However, this outcome may reflect a selective secular decline of responses after randomization to placebo. Remaining uncertainty encouraged direct comparison of the drug-types in trials involving randomized, head-to-head comparisons. METHODS: We systematically identified reports of randomized trials of TCAs versus SSRIs for major depression in several digital databases, and applied standard meta-analytic and multiple-factor regression methods to analyze and pool the findings. RESULTS: In 89 head-to-head trials, there was no detectable overall difference in responder rates or percent improvement between TCAs and SSRIs. In addition to non-difference between drug types, outcomes were unrelated to reporting-year, trial-size or nominal duration, proportion of women participants, initial depression ratings, rating scales, subjects/arm, imipramine-equivalent mg/day drug dose, or dropout rate. Trial size and duration increased significantly over the years 1980-2016. CONCLUSIONS: Previous evidence suggesting superior benefits of TCAs over SSRIs for the treatment of acute major depression is probably an artifact of a selective secular decline in responses to placebo, as no difference was found in a large series of direct comparisons of these antidepressant-types. PMID- 28633601 TI - Lectin microarray analysis of isolated polysaccharides from Sasa veitchii. AB - We report lectin microarray profile of the polysaccharide fraction derived from Sasa veitchii leaf that exhibits anti-influenza activity. This fraction showed higher reactivities with lectins known as binders to oligo-mannose, fucose, or galactose. Our findings along with previously reported monosaccharide components suggest that the polysaccharide can be cross-reactive with cell surface receptors involved in immune system, thereby exerting anti-influenza activity. PMID- 28633602 TI - Functional principal component analysis of glomerular filtration rate curves after kidney transplant. AB - This article is motivated by some longitudinal clinical data of kidney transplant recipients, where kidney function progression is recorded as the estimated glomerular filtration rates at multiple time points post kidney transplantation. We propose to use the functional principal component analysis method to explore the major source of variations of glomerular filtration rate curves. We find that the estimated functional principal component scores can be used to cluster glomerular filtration rate curves. Ordering functional principal component scores can detect abnormal glomerular filtration rate curves. Finally, functional principal component analysis can effectively estimate missing glomerular filtration rate values and predict future glomerular filtration rate values. PMID- 28633603 TI - Standardized and weighted time-dependent receiver operating characteristic curves to evaluate the intrinsic prognostic capacities of a marker by taking into account confounding factors. AB - Time-dependent receiver operating characteristic curves allow to evaluate the capacity of a marker to discriminate between subjects who experience the event up to a given prognostic time from those who are free of this event. In this article, we propose an inverse probability weighting estimator of a standardized and weighted time-dependent receiver operating characteristic curve. This estimator provides a measure of the prognostic capacities by taking into account potential confounding factors. We illustrate the robustness of the estimator by a simulation-based study and its usefulness by two applications in kidney transplantation. PMID- 28633604 TI - A two-stage approach to the joint analysis of longitudinal and survival data utilising the Coxian phase-type distribution. AB - The Coxian phase-type distribution is a special type of Markov model which can be utilised both to uncover underlying stages of a survival process and to make inferences regarding the rates of flow of individuals through these latent stages before an event of interest occurs. Such models can be utilised, for example, to identify individuals who are likely to deteriorate faster through a series of disease states and thus require more aggressive medical intervention. Within this paper, a two-stage approach to the analysis of longitudinal and survival data is presented. In Stage 1, a linear mixed effects model is first used to represent how some longitudinal response of interest changes through time. Within this linear mixed effects model, the individuals' random effects can be considered as a proxy measure for the effect of the individuals' genetic profiles on the response of interest. In Stage 2, the Coxian phase-type distribution is employed to represent the survival process. The individuals' random effects, estimated in Stage 1, are incorporated as covariates within the Coxian phase-type distribution so as to evaluate their effect on the individuals' rates of flow through the system represented by the Coxian. The approach is illustrated using data collected on individuals suffering from chronic kidney disease, where focus is given to an emerging longitudinal biomarker of interest - an individual's haemoglobin level. PMID- 28633605 TI - Controlling response dependence in the measurement of change using the Rasch model. AB - The advantages of using person location estimates from the Rasch model over raw scores for the measurement of change using a common test include the linearization of scores and the automatic handling of statistical properties of repeated measurements. However, the application of the model requires that the responses to the items are statistically independent in the sense that the specific responses to the items on the first time of testing do not affect the responses at a second time. This requirement implies that the responses to the items at both times of assessment are governed only by the invariant location parameters of the items at the two times of testing and the location parameters of each person each time. A specific form of dependence that is pertinent when the same items are used is when the observed response to an item at the second time of testing is affected by the response to the same item at the first time, a form of dependence which has been referred to as response dependence. This paper presents the logic of applying the Rasch model to quantify, control and remove the effect of response dependence in the measurement of change when the same items are used on two occasions. The logic is illustrated with four sets of simulation studies with dichotomous items and with a small example of real data. It is shown that the presence of response dependence can reduce the evidence of change, a reduction which may impact interpretations at the individual, research, and policy levels. PMID- 28633606 TI - Exact Bayesian p-values for a test of independence in a 2 * 2 contingency table with missing data. AB - Altham (Altham PME. Exact Bayesian analysis of a 2 * 2 contingency table, and Fisher's "exact" significance test. J R Stat Soc B 1969; 31: 261-269) showed that a one-sided p-value from Fisher's exact test of independence in a 2 * 2 contingency table is equal to the posterior probability of negative association in the 2 * 2 contingency table under a Bayesian analysis using an improper prior. We derive an extension of Fisher's exact test p-value in the presence of missing data, assuming the missing data mechanism is ignorable (i.e., missing at random or completely at random). Further, we propose Bayesian p-values for a test of independence in a 2 * 2 contingency table with missing data using alternative priors; we also present results from a simulation study exploring the Type I error rate and power of the proposed exact test p-values. An example, using data on the association between blood pressure and a cardiac enzyme, is presented to illustrate the methods. PMID- 28633607 TI - Corrigendum. PMID- 28633608 TI - Biomechanics of increased spin velocity of flying discs during forehand throws by skilled and unskilled throwers. AB - We aimed to assess the relationship between throwing distance and kinematic release parameters of the flying disc in unskilled throwers, and to assess the relationship between kinetic variables acting on flying discs and the change in spin velocity during long forehand throws by skilled and unskilled throwers. Ten skilled and eleven unskilled throwers performed throws at maximum effort. Reflective marker positions on the disc and body were recorded with a 3D motion capture system during the throws to derive kinematic variables of a disc and kinetic variables acting on the disc. The analysis interval was from maximum external shoulder rotation to disc release. Significant correlations were observed between the throwing distance and spin velocity in skilled (r = 0.722, P < 0.05) and unskilled throwers (r = 0.794, P < 0.01), between the change in spin velocity and the angular impulse of moments of force, in unskilled throwers (r = 0.703, P < 0.05), and between the change in spin velocity and the angular impulse of torque among skilled throwers (r = 0.680, P < 0.01). Therefore, a strategy for increasing spin velocity in unskilled throwers could be used to generate a larger torque, similar to that observed in skilled throwers. PMID- 28633609 TI - Modelling and sample size reestimation for longitudinal count data with incomplete follow up. AB - We consider modelling and inference as well as sample size estimation and reestimation for clinical trials with longitudinal count data as outcomes. Our approach is general but is rooted in design and analysis of multiple sclerosis trials where lesion counts obtained by magnetic resonance imaging are important endpoints. We adopt a binomial thinning model that allows for correlated counts with marginal Poisson or negative binomial distributions. Methods for sample size planning and blinded sample size reestimation for randomised controlled clinical trials with such outcomes are developed. The models and approaches are applicable to data with incomplete observations. A simulation study is conducted to assess the effectiveness of sample size estimation and blinded sample size reestimation methods. Sample sizes attained through these procedures are shown to maintain the desired study power without inflating the type I error. Data from a recent trial in patients with secondary progressive multiple sclerosis illustrate the modelling approach. PMID- 28633610 TI - Popliteal artery entrapment syndrome presenting as Raynaud phenomenon. PMID- 28633611 TI - Rawification and the careful generation of open government data. AB - Drawing on a two-year ethnographic study within several French administrations involved in open data programs, this article aims to investigate the conditions of the release of government data - the rawness of which open data policies require. This article describes two sets of phenomena. First, far from being taken for granted, open data emerge in administrations through a progressive process that entails uncertain collective inquiries and extraction work. Second, the opening process draws on a series of transformations, as data are modified to satisfy an important criterion of open data policies: the need for both human and technical intelligibility. There are organizational consequences of these two points, which can notably lead to the visibilization or the invisibilization of data labour. Finally, the article invites us to reconsider the apparent contradiction between the process of data release and the existence of raw data. Echoing the vocabulary of one of the interviewees, the multiple operations can be seen as a 'rawification' process by which open government data are carefully generated. Such a notion notably helps to build a relational model of what counts as data and what counts as work. PMID- 28633613 TI - Thermal effects on cognition: a new quantitative synthesis. AB - There is little doubt that increases in thermal load beyond the thermo-neutral state prove progressively stressful to all living organisms. Increasing temperatures across the globe represent in some locales, and especially for outdoors workers, a significant source of such chronic load increase. However, increases in thermal load affect cognition as well as physical work activities. Such human cognition has perennially been viewed as the primary conduit through which to solve many of the iatrogenic challenges we now face. Yet, thermal stress degrades the power to think. Here, we advance and refine the isothermal description of such cognitive decrements, founded upon a synthesis of extant empirical evidence. We report a series of mathematical functions which describe task-specific patterns of performance deterioration, linking such degrees of decrement to the time/temperature conditions in which they occur. Further, we provide a simple, free software tool to support such calculations so that adverse thermal loads can be monitored, assessed and (where possible) mitigated to preserve healthy cognitive functioning. PMID- 28633612 TI - Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL). AB - Large granular lymphocytic leukemia (LGLL) represents a clonal/oligoclonal lymphoproliferation of cytotoxic T and natural killer cells often associated with STAT3 mutations. When symptomatic, due to mostly anemia and neutropenia, therapy choices are often empirically-based, because only few clinical trials and systematic studies have been performed. Incorporating new molecular and flow cytometry parameters, we identified 204 patients fulfilling uniform criteria for LGLL diagnoses and analyzed clinical course with median follow-up of 36 months, including responses to treatments. While selection of initial treatment was dictated by clinical features, the initial responses, as well as overall responses to methotrexate (MTX), cyclosporine (CsA), and cyclophosphamide (CTX), were similar at 40-50% across drugs. Sequential use of these drugs resulted in responses in most cases: only 10-20% required salvage therapies such as ATG, Campath, tofacitinib, splenectomy or abatacept. MTX yielded the most durable responses. STAT3-mutated patients required therapy more frequently and had better overall survival. PMID- 28633614 TI - Detection of prognostically relevant mutations and translocations in myeloid sarcoma by next generation sequencing. PMID- 28633615 TI - Experts' opinion on manual wheelchair adjustments for adults with diabetes. AB - : Diabetes is a global health concern that can lead to mobility limitations necessitating a wheelchair. However, there are currently no guidelines for wheelchair adjustments tailored to the diabetic population. PURPOSE: To describe relevant manual wheelchair adjustments for adults with diabetes, and to explore how these adjustments apply to populations living in less-resourced countries. METHODS: Semi-structured interviews were conducted with 13 wheelchair experts from five different countries working with adult with diabetes. Interviews were analyzed using the constant comparison method. RESULTS: The most frequently mentioned wheelchair adjustments were related to neuropathies, skin integrity, decreased strength and amputations. Air cushions were preferred for managing seat sores. Lightweight wheelchairs could be advantageous for people with decreased strength and endurance. In less-resourced settings, wheelchair adjustment decisions prioritized durability and low maintenance. DISCUSSION: The recommendation of lightweight wheelchairs for adults with diabetes may be limited by the lack of adjustment possibilities compared to regular weight wheelchairs. In less-resourced settings, prioritizing durability and low maintenance may limit prevention and management of conditions associated to diabetes. CONCLUSION: This study represents a first step towards the development of guidelines for manual wheelchair adjustments specifically tailored to adults with diabetes, in a global health context. Implications of rehabilitation When prescribing manual wheelchairs to persons with diabetes, expert clinicians agree that skin integrity, neuropathies and decreased strength are their primary concerns. Compromises are often necessary when adjusting a wheelchair for a person with diabetes, due to the complexity of their symptoms: same modification can be indicated for one symptom but contraindicated for another. Diabetes prevalence is high in less-resourced settings. There is a need for increased availability of affordable wheelchair equipment that is durable, reliable and adapted to persons with diabetes. PMID- 28633616 TI - Sclerosing Stromal Tumor Mimicking a Pregnancy Luteoma: Case Report of a Diagnostically Challenging Entity Further Complicated by the Presence of Metastatic Signet Ring Cell Carcinoma From the Stomach. AB - Sclerosing stromal tumors of the ovary are very rare. We report the case of a 29 year-old pregnant woman who presented with a history of preterm labor and gestational hypertension. A huge mass measuring 30 cm in greatest dimension was recognized on the right ovary during cesarean section. Signet ring cell infiltration was seen during intraoperative frozen section consultation. She underwent a right salpingo-oophorectomy, and the permanent diagnosis was sclerosing stromal tumor infiltrated by signet ring cells. Pregnancy-related changes were seen in tumor morphology. Signet ring cells were immunoreactive with antibodies MUC5ac, MUC2, and EMA. Thus, stromal cells were immunoreactive with antibodies inhibin and calretinin. Endoscopic biopsy of the stomach showed a signet ring cell carcinoma, from which the metastasis had originated. This is the first reported case in the literature, and is notable for its challenging differential diagnosis, which included a pregnancy luteoma and primary signet ring stromal tumor of the ovary. PMID- 28633617 TI - Simultaneous determination of primary and secondary d- and l-amino acids by reversed-phase high-performance liquid chromatography using pre-column derivatization with two-step labelling method. AB - This work describes a method for the simultaneous determination of primary d- and l-amino acids and secondary amino acids such as d- and l-proline. In order to remove interferences in the simultaneous determination of primary and secondary amines, the primary amines were derivatized with o-phthalaldehyde/N-acetyl-l cysteine (OPA/NAC) and subsequently with 1-(9-fluorenyl)ethyl chloroformate (FLEC) for secondary amines, in a pre-column separation derivatization technique. These fluorescent diastereomers of the amino acids were obtained within 3 min at room temperature and determined simultaneously by changing wavelengths during analysis in a single eluting run in the high-performance liquid chromatography column. This method, referred to as the "two-step labelling method," is effective for the simultaneous determination of d- and l-amino acids. PMID- 28633618 TI - Specialized consultations in a hospital-based referral center for patients suspected of having limb lymphedema: Impact on diagnosis. AB - Lymphedema, a chronic debilitating disease, is not always easily diagnosed. A total of 254 new patients ((217 women, 37 men), median (Q1-Q3) age 61 (46-72) years) were referred for suspected limb lymphedema to an exclusively lymphedema dedicated department for a first consultation (January - March 2015) were included; among 118 with upper limb involvement, 100 (84.7%) were diagnosed with post-breast cancer therapy and four with primary lymphedemas; among 136 with lower limb involvement, 31 (22.8%) were diagnosed with primary lymphedemas and 35 (25.7%) with post-cancer lymphedemas. The main alternative diagnoses were: 32 (45.7%) lipedemas/lipo-lymphedemas and 21 (30%) chronic venous insufficiencies. Age at symptom onset, body mass index, referral origins and first-symptom-to specialized-consultation intervals differed between primary, post-cancer lymphedema and alternative diagnosis patients. Among the entire cohort, 57 (22.4%) had cellulitis. For all 135 (53.1%) upper or lower limb post-cancer lymphedemas and the 119 (46.9%) others, the median (Q1-Q3) first-symptom-to specialized-consultation intervals were 1.4 (0.7-3.8) and 4 (1.1-18.8) years, respectively ( p < 0.0001). Specialized consultations confirmed primary and post cancer lymphedema diagnoses and identified others, especially for patients with suspected lower limb lymphedema. PMID- 28633619 TI - The Affect Misattribution Procedure. AB - The Affect Misattribution Procedure (AMP) has been forwarded as one of the most promising alternatives to the Implicit Association Test and the evaluative priming task for measuring attitudes such as prejudice indirectly. We investigated whether the AMP is indeed able to detect an evaluative out-group bias. In contrast to recent conclusions about the robustness of AMP effects, six out of seven pilot studies indicated that participants did not show any prejudice effects in the AMP. Yet, these pilot studies were not fully conclusive with regard to our research question because they investigated different domains of prejudice, used small sample sizes, and employed a modified AMP version. In a preregistered, high-powered AMP study, we therefore examined whether the standard AMP does reveal prejudice against Turks, the biggest minority in Germany, and found a significant, albeit very small prejudice effect. We discuss possible reasons for the AMP's weak sensitivity to evaluations in socially sensitive domains. PMID- 28633620 TI - Reversing the Manual Digit Bias in Two-Digit Number Comparison. AB - Though recent work in numerical cognition has supported a strong tie between numerical and spatial representations (e.g., a mental number line), less is known about such ties in multi-digit number representations. Along this line, Bloechle, Huber, and Moeller (2015) found that pointing positions in two-digit number comparison were biased leftward toward the decade digit. Moreover, this bias was reduced in unit-decade incompatible pairs. In the present study, we tracked computer mouse movements as participants compared two-digit numbers to a fixed standard (55). Similar to Bloechle et al. (2015) , we found that trajectories exhibited a leftward bias that was reduced for unit-decade incompatible comparisons. However, when positions of response labels were reversed, the biases reversed. That is, we found a rightward bias for compatible pairs that was reduced for incompatible pairs. This result calls into question a purely embodied representation of place value structure and instead supports a competition model of two-digit number representation. PMID- 28633621 TI - Heads Up! AB - Possibilities for behavior (i.e., affordances) can be perceived with units spanning anatomical components and external objects. For example, affordances for standing on an inclined surface can be perceived with an object held in the hand or attached to the head. We investigated whether these two person-plus-object perceptual systems exhibit the same pattern of nonlinear phase transitions in perception of this affordance. Blindfolded participants explored an inclined surface with a rod held in the hand or attached to the head and reported whether they could stand on that surface. Inclinations were presented in ascending or descending sequences. In both conditions, responses exhibited negative hysteresis - perceptual boundaries occurred at steeper angles for descending than for ascending sequences. The generalization of this pattern across components that differ in physiology, sensitivity, and experience is consistent with both the soft assembly of perceptual devices and with a dynamical systems perspective on perception of affordances. PMID- 28633622 TI - Search for Capacity-Limited and Super-Capacity Search. AB - The present study investigated capacity limitations of visual search. In a series of experiments, participants searched for a singleton target among homogenous distractors, a conjunction target defined by combination of two features, or a feature target among heterogeneous distractors. Using the simultaneous-sequential paradigm, I found that singleton search proceeded in a capacity-unlimited manner. By contrast, the performance of the conjunction search was found to depend on a capacity-limited process. For feature searches, the performance of searching for a specific color was not affected by how the stimuli were presented, while the orientation search performance was enhanced as the number of distractors simultaneously presented with the target increased. These results imply that distinct colors are individually coded, whereas multiple orientations are encoded as an ensemble in a structured way. Taken together, the present study clarifies which type of search process are capacity-limited and reveals how this limit can be overcome. PMID- 28633623 TI - Numerical Congruency Effect in the Sentence-Picture Verification Task. AB - In two experiments, we showed that irrelevant numerical information influenced the speed of sentence-picture verification. Participants were asked to verify whether the concept mentioned in a sentence matched the object presented in a subsequent picture. Concurrently, the number word attached to the concept in the sentence and the quantity of objects presented in the picture were manipulated (numerical congruency). The number of objects varied from one to four. In Experiment 1, participants read statements such as three dogs. In Experiment 2, they read sentences such as three dogs were wandering in the street. In both experiments, the verification speed revealed the interaction between response and numerical congruency. The verification times for concept-object match were faster when there was also numerical congruence (compared with incongruence) between the number word and quantity. On the other hand, there was no difference between numerical congruence and incongruence when the concept and object mismatched. The results are interpreted as evidence for the symbol grounding of number words in perceptual representation of small quantities, that is, quantities falling in the subitization range. PMID- 28633624 TI - The Automatic Mapping of Magnitude to Temporal Order Is Space-Dependent. AB - Past research has shown that performance in ordinal magnitude tasks is enhanced when stimuli are presented in ascending order, suggesting that magnitude is mapped to temporal order, with small magnitude associated with early and large with late presentation. The present study addresses the automaticity of this effect and its limitations. We used the "same/different" task for numbers (Experiment 1) and physical sizes of shapes (Experiment 2) as well as identity of shapes (Experiment 3). The advantage for stimuli in ascending order was found for both numbers and physical sizes of shapes. However, it was limited to specific conditions - when magnitude processing was required for the task and when a "different" response was mapped to the right hand side. Thus, it seems that the automatic mapping of magnitude to temporal order is dependent on the mapping of magnitude to space. PMID- 28633625 TI - On the Inability to Ignore Useless Advice. AB - Research in the judge-advisor-paradigm suggests that advice is generally utilized less than it should be according to its quality. In a series of four experiments, we challenge this widely held assumption. We hypothesize that when advice quality is low, the opposite phenomenon, namely overutilization of advice, occurs. We further assume that this overutilization effect is the result of anchoring: advice serves as an anchor, thus causing an adjustment toward even useless advice. The data of our four experiments support these hypotheses. Judges systematically adjusted their estimates toward advice that we introduced to them as being useless, and this effect was stable after controlling for intentional utilization of this advice. Furthermore, we demonstrate that anchoring-based adjustment toward advice is independent of advice quality. Our findings enhance our understanding of the processes involved in advice taking and identify a potential threat to judgment accuracy arising from an inability to discount useless advice. PMID- 28633626 TI - Age-related differences in management and outcomes in hospitalized healthy and well-functioning bacteremic pneumococcal pneumonia patients: a cohort study. AB - BACKGROUND: Limited data are available regarding fit and healthy patients with pneumonia at different ages. We evaluated the association of age with clinical presentation, serotype and outcomes among healthy and well-functioning patients hospitalized for bacteremic pneumococcal community-acquired pneumonia. METHODS: We performed a prospective cohort study of consecutive healthy and well functioning patients hospitalized for this type of pneumonia. Patients were stratified into younger (18 to 64 years) and older (>=65 years) groups. RESULTS: During the study period, 399 consecutive patients were hospitalized with bacteremic pneumococcal pneumonia. We included 203 (50.8%) patients who were healthy and well-functioning patients, of whom 71 (35%) were classified as older. No differences were found in antibiotic treatment, treatment failure rate, antibiotic resistance, or serotype, except for serotype 7F that was less common in older patients. In the adjusted multivariate analysis, the older patients had higher 30-day mortality (OR 6.83; 95% CI 1.22-38.22; P = 0.028), but were less likely to be admitted to the ICU (OR 0.14; 95% CI 0.05-0.39; P < 0.001) and had shorter hospital stays (OR 0.71; 95% CI 0.54-0.94; P = 0.017). CONCLUSIONS: Healthy and well-functioning older patients have higher mortality than younger patients, but nevertheless, ICU admission was less likely and hospital stays were shorter. These results suggest that the aging process is a determinant of mortality, beyond the functional status of patients with bacteremic pneumococcal pneumonia. PMID- 28633627 TI - Effectiveness of a motivational intervention on overweight/obese patients in the primary healthcare: a cluster randomized trial. AB - BACKGROUND: Overweight and obesity are common health problems which increase the risk of developing several serious health conditions. The main difficulty in the management of weight-loss lies in its maintenance, once it is achieved. The aim of this study was to investigate whether a motivational intervention, together with current clinical practice, was more efficient than a traditional intervention, in the treatment of overweight and obesity and whether this intervention reduces cardiovascular risk factors associated with overweight and obesity. METHODS: Multi-centre cluster randomized trial with a 24-month follow-up included 864 overweight/obese patients randomly assigned. Motivational intervention group (400 patients), delivered by a nurse trained by an expert psychologist, in 32 sessions, 1 to 12 fortnightly, and 13 to 32, monthly, on top of their standard programmed diet and exercise. The control group (446 patients), received the usual follow-up. RESULTS: Weight reduction was statistically significant in the second year with a mean reduction of 1.0 Kg in the control group and 2.5 Kg in the intervention group (p = 0. 02). While 18.1% of patients in the control group reduced their weight by more than 5%, this percentage rose to 26.9% in the intervention group, which is statistically significant (p = 0.04). Patients in the motivational intervention group had significantly greater improvements in triglycerides and APOB/APOA1ratio. CONCLUSIONS: The results highlight the importance of the group motivational interview in the treatment of overweight /obese patients in primary care, and in the improvement of their associated cardiovascular risks factors. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01006213 October 30, 2009. PMID- 28633628 TI - Olfactory testing in consecutive patients referred with suspected dementia. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia and early and accurate diagnosis is important. Olfactory dysfunction is an early sign of AD. The contribution by test of olfactory function has been surveyed in AD vs a line of conditions but remains to be settled in the workup of unselected patients referred with suspected dementia. METHODS: We performed a two-step investigation: first, a comparative study of healthy controls and probable AD patients to test the applicability of the chosen scents (cuisine study); second, a study of consecutive patients referred to our geriatric outpatient clinic for suspected dementia with the investigating personnel blinded to the results of the Olfactory Test (blinded study). RESULTS: The sum of scents detected discriminated patients with probable AD from controls in the cuisine study (n = 40; p < 0.001; area under ROC curve 0.94). In the blinded study (n = 50) the diagnosis was probable AD in 48%, minimal cognitive impairment in 24%, vascular dementia in 8%, alcohol induced impairment in 12%, depression in 4%, and Parkinson's disease and Lewy body dementia in 2%. Area under the ROC-curve was 0.67. The odds ratio for probable AD with 2+ smell errors was 12 (95%-CI: 1.3-101; p = 0.026 (reference 0 1 smell errors)) age adjusted. None in the AD group had zero smell errors (Negative Predictive Value 100%). CONCLUSION: Olfactory testing may support to dismiss the diagnosis of probable AD in the workup of a mixed group of patients referred with cognitive impairment. Still, it had a low sensitivity for probable AD. PMID- 28633630 TI - Clinical characteristics of acute hepatitis A outbreak in Taiwan, 2015-2016: observations from a tertiary medical center. AB - BACKGROUND: Acute hepatitis A is a fecal-oral transmitted disease related to inadequate sanitary conditions. In addition to its traditional classification, several outbreaks in the men who have sex with men (MSM) population have resulted in acute hepatitis A being recognized as a sexually transmitted disease. However, few studies have clarified the clinical manifestations in these outbreaks involving the MSM population. METHODS: Beginning in June 2015, there was an outbreak of acute hepatitis A involving the MSM population in Northern Taiwan. We conducted a 15-year retrospective study by recruiting 207 patients with the diagnosis of acute hepatitis A that included the pre-outbreak (January 2001 to May 2015) and outbreak (June 2015 to August 2016) periods in a tertiary medical center in Northern Taiwan. Using risk factors, comorbidities, presenting symptoms, laboratory test results and imaging data, we aimed to evaluate the clinical significance of acute hepatitis A in the MSM population, where human immunodeficiency virus (HIV) coinfection is common. RESULTS: There was a higher prevalence of reported MSM (p < 0.001), HIV (p < 0.001) and recent syphilis (p < 0.05) coinfection with acute hepatitis A during the outbreak period. The outbreak population had more prominent systemic symptoms, was more icteric with a higher total bilirubin level (p < 0.05) and had a 7-times higher tendency (p < 0.05) to have a hepatitis A relapse. CONCLUSIONS: The clinical course of acute hepatitis A during an outbreak involving the MSM and HIV-positive population is more symptomatic and protracted than in the general population. PMID- 28633629 TI - Prevalence of and risk factors for severe cognitive and sleep symptoms in ME/CFS and MS. AB - BACKGROUND: There are considerable phenotypic and neuroimmune overlaps between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS). While the precise aetiologies of both MS and ME/CFS are unclear, evidence suggests that deterioration in cognitive function is widely prevalent in patients with either condition. Little is known about differing risk factors or exposures, which may lead to severe cognitive or sleep symptoms. This study aims to gauge the extent of cognitive and sleep symptoms in ME/CFS and MS patients participating in the UK ME/CFS Biobank and identify the characteristics of those experiencing severe symptoms. METHODS: This was a cross-sectional study of 395 UK ME/CFS Biobank participants, recruited from primary care and the community, using similar standardised protocols, and matched by age, sex and geographical area. Data were collected from participants using a standardized written questionnaire at clinical visits. Cognitive symptoms included problems with short-term memory, attention, and executive function. Sleep symptoms included unrefreshing sleep and poor quality or inadequate duration of sleep. All participants reported symptoms based on an ordinal severity scale. Multivariable logistic regression was carried out in the ME/CFS group to investigate socio-demographic factors associated with severe symptoms. RESULTS: All cognitive and sleep symptoms were more prevalent in the ME/CFS group, with 'trouble concentrating' (98.3%) the most commonly reported symptom. Severe symptoms were also more commonly reported in the ME/CFS group, with 55% reporting 'severe, unrefreshing sleep'. Similarly, in the MS group, the most commonly reported severe symptoms were sleep-related. Logistic regression analysis revealed that ME/CFS patients aged over 50 years were more than three times as likely to experience severe symptoms than those younger than 30 (OR 3.23, p = 0.031). Current smoking was associated with severe symptoms, increasing the risk by approximately three times (OR 2.93, p = 0.003) and those with household incomes of more than L15,000 per year were less likely to experience severe symptoms compared to those earning less than this (OR 0.31, p = 0.017). CONCLUSIONS: Cognitive and sleep symptoms are more common in ME/CFS patients than in MS patients and healthy controls, providing further support for existing evidence of central nervous system abnormalities in ME/CFS. Our findings suggest that people with ME/CFS who are smokers, or have a low income, are more likely to report severe cognitive and sleep symptoms. Future research should aim to develop strategies to prevent the progression of severe cognitive and sleep symptoms through early interventions that prioritise patients identified as being at highest risk. PMID- 28633631 TI - Knowledge of antibiotic resistance and antibiotic prescription practices among prescribers in the Brong Ahafo Region of Ghana; a cross-sectional study. AB - BACKGROUND: Antibiotic resistance (ABR) has become a major public health challenge in most parts of the world including Ghana and is a major threat to gain in bacterial disease control. The role of prescribers in the control of antibiotics is identified as crucial in developing interventions to control ABR. To guide policy recommendations on ABR, a study was carried out among prescribers to identify gaps in their knowledge of ABR and to document their prescription practices. METHOD: A cross-sectional survey was conducted among prescribers from both public and private facilities in the Brong Ahafo Region of Ghana using both quantitative and qualitative methods in 2014. RESULTS: Three hundred and seventy nine prescribers participated in the quantitative study and a subset of 33 participated in in-depth interviews. Majority (50.0%) of the prescribers interviewed were nurses. Most (51.0%) of the prescribers were located in hospitals. Knowledge of ABR was high among all the prescribers. About 80.0% percent of all prescribers agreed that the antibiotics that are currently used could lose its efficacy in future. There is no singular formal source of information on antibiotic resistance. The prescribers held a strong perception that antibiotic resistance is imminent though their knowledge on various resistant bacterial strains was limited. Prescribers attributed ABR burden to factors such as poor prescription practices and limited ABR control measures. The prescription practices of the prescribers vary but were mostly inappropriate among the lower cadre. CONCLUSION: The knowledge of ABR is high among prescribers. There is however a gap in the knowledge and perception of optimal antibiotic prescription practices among prescribers. There is the need for a formal source of information on ABR to support prescriber's antibiotic prescription practices. PMID- 28633633 TI - Utilization and farmers' knowledge on pigeonpea diversity in Benin, West Africa. AB - BACKGROUND: Understanding factors driving farmers' uses of crop genetic resources is a key component not only to design appropriate conservation strategies but also to promote sustainable production. However, in Benin, limited information is available on farmers' knowledge related to pigeonpea uses and conservation. This study aimed at i) identifying and investigating the different uses of pigeonpea in relation with socio-cultural factors, namely age, gender, ethnic group and respondents' residence, ii) assessing pigeonpea varieties richness at household level and iii) evaluating the extent and distribution of pigeonpea varieties. METHODS: Three hundred and two farmers were surveyed using structured questionnaire. Direct observation, field visit and focus group discussion were carried out. Association between number of varieties maintained at household level and socio-cultural variables was tested. Mann-Whitney test was used to assess whether the number of varieties held by households headed by men and women were different. Distribution and extent of diversity was assessed through four cells analysis. RESULTS: Farmers in Benin mainly grow pigeonpea for its grains for home consumption. Pigeonpea's stem and leaves are used for medicinal purposes to treat malaria, dizziness, measles, and eye infection. The ethnic group and the locality of residence of farmers influenced on the use of pigeonpea for medicinal purposes (P < 0.01). There was no significant association (P > 0.05) between the number of varieties held by household and the age of the respondent, number of years of experience in pigeonpea cultivation, the size of household, number of family members engaged in agricultural activities and gender. Farmers used criteria including seed colors, seed size, plant height, maturity groups and cooking time to classify their varieties. Varieties with white seed coat color were the most grown while varieties with black, red or mottled seed coat color are being abandoned and deserve to be conserved. CONCLUSION: Knowledge on medicinal uses of pigeonpea is vertically transmitted within community and pigeonpea varieties maintenance at household level does not depend on socio cultural factors. This study will contribute to raise awareness on the various utilization of pigeonpea. In addition, it provides the basis for designing conservation strategies of pigeonpea genetic resources. PMID- 28633632 TI - Antagonizing miR-455-3p inhibits chemoresistance and aggressiveness in esophageal squamous cell carcinoma. AB - BACKGROUND: The plasticity of cancer stem cells (CSCs)/tumor-initiating cells (T ICs) suggests that multiple CSC/T-IC subpopulations exist within a tumor and that multiple oncogenic pathways collaborate to maintain the CSC/T-IC state. Here, we aimed to identify potential therapeutic targets that concomitantly regulate multiple T-IC subpopulations and CSC/T-IC-associated pathways. METHODS: A chemoresistant patient-derived xenograft (PDX) model of human esophageal squamous cell carcinoma (ESCC) was employed to identify microRNAs that contribute to ESCC aggressiveness. The oncogenic effects of microRNA-455-3p (miR-455-3p) on ESCC chemoresistance and tumorigenesis were examined by in vivo and in vitro chemoresistance, tumorsphere formation, side-population, and in vivo limiting dilution assays. The roles of miR-455-3p in activation of the Wnt/beta-catenin and transforming growth factor-beta (TGF-beta)/Smad pathways were determined by luciferase and RNA immunoprecipitation assays. RESULTS: We found that miR-455-3p played essential roles in ESCC chemoresistance and tumorigenesis. Treatment with a miR-455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90+ and CD271+ T-ICs via deactivation of multiple stemness associated pathways, including Wnt/beta-catenin and TGF-beta signaling. Importantly, miR-455-3p exhibited aberrant upregulation in various human cancer types, and was significantly associated with decreased overall survival of cancer patients. CONCLUSIONS: Our results demonstrate that miR-455-3p functions as an oncomiR in ESCC progression and may provide a potential therapeutic target to achieve better clinical outcomes in cancer patients. PMID- 28633634 TI - The development and appraisal of a tool designed to find patients harmed by falsely labelled, falsified (counterfeit) medicines. AB - BACKGROUND: Falsely labelled, falsified (counterfeit) medicines (FFCm's) are produced or distributed illegally and can harm patients. Although the occurrence of FFCm's is increasing in Europe, harm is rarely reported. The European Directorate for the Quality of Medicines & Health-Care (EDQM) has therefore coordinated the development and validation of a screening tool. METHODS: The tool consists of a questionnaire referring to a watch-list of FFCm's identified in Europe, including symptoms of their use and individual risk factors, and a scoring form. To refine the questionnaire and reference method, a pilot-study was performed in 105 self-reported users of watch-list medicines. Subsequently, the tool was validated under "real-life conditions" in 371 patients in 5 ambulatory and in-patient care sites ("sub-studies"). The physicians participating in the study scored the patients and classified their risk of harm as "unlikely" or "probable" (cut-off level: presence of >=2 of 5 risk factors). They assessed all medical records retrospectively (independent reference method) to validate the risk classification and documented their perception of the tool's value. RESULTS: In 3 ambulatory care sites (180 patients), the tool correctly classified 5 patients as harmed by FFCm's. The positive and negative likelihood ratios (LR+/LR ) and the discrimination power were calculated for two cut-off levels: a) 1 site (50 patients): presence of two risk factors (at 10% estimated health care system contamination with FFCm's): LR + 4.9/LR-0, post-test probability: 35%; b) 2 sites (130 patients): presence of three risk factors (at 5% estimated prevalence of use of non-prescribed medicines (FFCm's) by certain risk groups): LR + 9.7/LR-0, post test probability: 33%. In 2 in-patient care sites (191 patients), no patient was confirmed as harmed by FFCm's. The physicians perceived the tool as valuable for finding harm, and as an information source regarding risk factors. CONCLUSIONS: This "decision aid" is a systematic tool which helps find in medical practice patients harmed by FFCm's. This study supports its value in ambulatory care in regions with health care system contamination and in certain risk groups. The establishment of systematic communication between authorities and the medical community concerning FFCm's, current patterns of use and case reports may sustain positive public health impacts. PMID- 28633635 TI - Maternal use of selective serotonin reuptake inhibitors during pregnancy is associated with Hirschsprung's disease in newborns - a nationwide cohort study. AB - BACKGROUND: Hirschsprung's disease is a rare condition caused by congenital malformation of the gastrointestinal tract affecting 1:5000 children. Not much is known about risk factors for development of Hirschsprung's disease. Two clinical cases of hirschsprung's disease led to an investigation of the association between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and development of Hirschsprung's Disease in the newborn child. The study examined a nationwide, unselected cohort of children born in Denmark from 1 January 1996 until 12 March 2016 (n = 1,256,317). We applied multivariate models to register-based data to estimate the odds ratio of Hirschsprung's disease, adjusting for possible confounders. The studied exposure period for SSRIs were 30 days prior to conception to the end of the first trimester. RESULTS: In the main exposed cohort the prevalence of Hirschsprung's disease was 16/19.807 (0.08%) compared to 584/1.236.510 (0.05%) in the unexposed cohort. In women who redeemed a minimum of one prescription of selective serotonin reuptake inhibitors, the adjusted odds ratio for development of Hirschsprung's disease was 1.76 (95%CI: 1.07-2.92). In women who redeemed a minimum of two prescriptions, the adjusted odds ratio for Hirschsprung's disease was 2.34 (95% CI: 1.21-4.55). CONCLUSIONS: Our data suggest that early maternal use of selective serotonin reuptake inhibitors is significantly associated with the development of Hirschsprung's disease in the newborn child. Treatment of depression during pregnancy always has to be weighed against the risks posed by untreated maternal depression. Our results have to be confirmed in other studies. PMID- 28633636 TI - Typology of birth centres in the Netherlands using the Rainbow model of integrated care: results of the Dutch Birth Centre Study. AB - BACKGROUND: The goal of integrated care is to offer a continuum of care that crosses the boundaries of public health, primary, secondary, and tertiary care. Integrated care is increasingly promoted for people with complex needs and has also recently been promoted in maternity care systems to improve the quality of care. Especially when located near an obstetric unit, birth centres are considered to be ideal settings for the realization of integrated care. At present, however, we know very little about the degree of integration in these centres and we do not know if increased levels of integration improve the quality of the care delivered. The Dutch Birth Centre Study is designed to evaluate birth centres and their contribution to the Dutch maternity care system. The aim of this particular sub-study is to classify birth centres in clusters with similar characteristics based on integration profiles, to support the evaluation of birth centre care. METHODS: This study is based on the Rainbow Model of Integrated Care. We used a survey followed by qualitative interviews in 23 birth centres in the Netherlands to determine which integration profiles can be distinguished and to describe their discriminating characteristics. Cluster analysis was used to classify the birth centres. RESULTS: Birth centres were classified into three clusters: 1)"Mono-disciplinary-oriented birth centres" (n = 10): which are mainly owned by primary care organizations and established as physical facilities to provide an alternative birthplace for low risk births; 2) "Multi-disciplinary oriented birth centres" (n = 6): which are mainly multi-disciplinary oriented and can be regarded as facilities to give birth, with a focus on integrated birth care; 3) "Mixed Cluster of birth centres" (n = 7): which have a range of organizational forms that differentiate them from centres in the other clusters. CONCLUSION: We identified a recognizable classification, with similar characteristics between birth centres in the clusters. The results of this study can be used to relate integration profiles of birth centres to quality of care, costs, and perinatal outcomes. This assessment makes it possible to develop recommendations with regard to the type and degree of integration of Dutch birth centres in the future. PMID- 28633638 TI - Evaluating the impact of prescription drug monitoring program implementation: a scoping review. AB - BACKGROUND: Prescription drug monitoring programs (PDMPs) have been implemented in 49 out of 50 states in an effort to reduce opioid-related misuse, abuse, and mortality, yet the literature evaluating the impact of PDMP implementation remains limited. We conducted a scoping review to: (1) describe available evidence regarding impact of PDMPs in the U.S.; and (2) propose a conceptual model to inform future PDMP implementation and evaluation efforts. METHODS: Scoping systematic review following Arksey and O'Malley's (2005) methodology. We identified 11 relevant studies based on inclusion criteria using a PubMed database search of English-language studies published 1/1/2000-5/31/16. Data were extracted and thematic analysis conducted to synthesize results. RESULTS: Extant evidence for the impact of PDMPs as an opioid risk mitigation tool remains mixed. Thematic analysis revealed four domains of opioid-related outcomes frequently examined in original studies evaluating PDMP implementation: (1) opioid prescribing; (2) opioid diversion and supply; (3) opioid misuse; and (4) opioid related morbidity and mortality. An evaluation framework incorporating these domains is presented that highlights significant gaps in empirical research across each of these domains. CONCLUSIONS: Evidence for the impact of state-level PDMPs remains mixed. We propose a conceptual model for evaluating PDMP implementation toward the goals of clarifying PDMP mechanisms of impact, identifying characteristics of PDMPs associated with best outcomes, and maximizing the utility of PDMP policy and implementation to reduce opioid-related public health burden. PMID- 28633637 TI - Seroma change during magnetic resonance imaging-guided partial breast irradiation and its clinical implications. AB - BACKGROUND: To investigate the patterns of post-lumpectomy seroma volume (SV) change and related clinical factors to determine the benefits of adaptive planning in magnetic resonance imaging (MRI)-guided partial breast irradiation (PBI). METHODS: MRI data obtained from 37 women with early breast cancer acquired at simulation and at the 1st, 6th, and 10th fractions were analyzed. The planning target volume (PTV) was defined as unequal margins of 10-15 mm added according to the directional surgical margin status of each seroma. Treatment was performed using a 0.35 T MRI-guided radiotherapy system. Univariate analysis was performed to assess the correlations between SV change rate and clinical factors. Seroma and PTV for adaptive planning were based on the images obtained at the 6th fraction. RESULTS: The average time intervals between surgery-simulation, simulation-1st, 1st-6th, and 6th-10th fractions were 23.1, 8.5, 7.2, and 5.9 days, respectively. Of the 37 patients, 33 exhibited decreased SV over the treatment period. The mean SV of these 33 patients decreased from 100% at simulation to 60, 48, and 40% at each MRI scan. In most cases (26/33), the logarithm of SV was inversely proportional to the elapsed time from surgery (R 2 > 0.90, Pearson's correlation test). The volume of spared normal tissue from adaptive radiotherapy was proportional to the absolute change in SV (R 2 = 0.89, Pearson's correlation test). CONCLUSION: Seromas exhibit exponential shrinkage over the course of PBI. In patients receiving PBI, frequent monitoring of SV could be helpful in decision-making regarding adaptive planning, especially those with a large seroma. PMID- 28633639 TI - Fusobacterial liver abscess: a case report and review of the literature. AB - BACKGROUND: Fusobacteriae are facultative anaerobic gram-negative bacilli which cause a range of invasive infections, amongst which pyogenic liver abscesses are rare. We describe a case of Fusobacterium nucleatum liver abscess and review the relevant literature. CASE PRESENTATION: A 51-year-old lady presented with a 4-day history of abdominal pain, diarrhoea, fever, rigors, and lethargy. Imaging revealed an abscess which was drained. Cultures of the blood and abscess aspirate grew Fusobacterium nucleatum and Prevotella pleuritidis respectively. She achieved full recovery following treatment. A MEDLINE search was undertaken using free-text and Medical Subject Headings (MeSH), keywords "Fusobacterium" and "Liver abscess". Non-English language reports and cases without confirmed growth of Fusobacterium species were excluded. Additional cases were identified by surveying the references of each report and by using the same keywords in a web based search. Forty-eight cases were identified, 41 in men. The median age was 42.5, with an interquartile range of 33. F. nucleatum and F. necrophorum were in involved in 22 cases each, and 4 cases were not further speciated. Among cases of F. nucleatum liver abscess, nine were attributed to periodontal disease, four to lower gastrointestinal tract disease, one to Lemierre's Syndrome, and eight were considered cryptogenic. All patients treated made a full recovery. Antimicrobial treatment duration ranged from 2 weeks to 6 months with a median of 6 weeks. CONCLUSION: Fusobacterium nucleatum is an uncommon cause of liver abscess generally associated with good clinical outcomes with contemporary medical and surgical care. PMID- 28633640 TI - Biological mechanisms discriminating growth rate and adult body weight phenotypes in two Chinese indigenous chicken breeds. AB - BACKGROUND: Intensive selection has resulted in increased growth rates and muscularity in broiler chickens, in addition to adverse effects, including delayed organ development, sudden death syndrome, and altered metabolic rates. The biological mechanisms underlying selection responses remain largely unknown. Non-artificially-selected indigenous Chinese chicken breeds display a wide variety of phenotypes, including differential growth rate, body weight, and muscularity. The Wuding chicken breed is a fast growing large chicken breed, and the Daweishan mini chicken breed is a slow growing small chicken breed. Together they form an ideal model system to study the biological mechanisms underlying broiler chicken selection responses in a natural system. The objective of this study was to study the biological mechanisms underlying differential phenotypes between the two breeds in muscle and liver tissues, and relate these to the growth rate and body development phenotypes of the two breeds. RESULTS: The muscle tissue in the Wuding breed showed higher expression of muscle development genes than muscle tissue in the Daweishan chicken breed. This expression was accompanied by higher expression of acute inflammatory response genes in Wuding chicken than in Daweishan chicken. The muscle tissue of the Daweishan mini chicken breed showed higher expression of genes involved in several metabolic mechanisms including endoplasmic reticulum, protein and lipid metabolism, energy metabolism, as well as specific immune traits than in the Wuding chicken. The liver tissue showed fewer differences between the two breeds. Genes displaying higher expression in the Wuding breed than in the Daweishan breed were not associated with a specific gene network or biological mechanism. Genes highly expressed in the Daweishan mini chicken breed compared to the Wuding breed were enriched for protein metabolism, ABC receptors, signal transduction, and IL6 related mechanisms. CONCLUSIONS: We conclude that faster growth rates and larger body size are related to increased expression of genes involved in muscle development and immune response in muscle, while slower growth rates and smaller body size are related to increased general cellular metabolism. The liver of the Daweishan breed displayed increased expression of metabolic genes. PMID- 28633641 TI - Expression levels of atherosclerosis-associated miR-143 and miR-145 in the plasma of patients with hyperhomocysteinaemia. AB - BACKGROUND: An elevated level of homocysteine (Hcy) in the blood is designated hyperhomocysteinaemia (Hhcy) and is regarded as a strong risk factor for the development of atherosclerosis (ATH), although the association remains controversial. Considered to be essential gene expression regulators, micro-RNAs (miRNAs) modulate cardiovascular disease development and thus can be regarded as potential biomarkers and therapeutic targets in atherosclerosis. The aim of the current study is to investigate the expression levels of atherosclerosis associated miR-143 and miR-145 in Hhcy patients and predict the progress of atherosclerosis in Hhcy patients. METHODS: A total of 100 participants were enrolled and included normal control subjects (NC = 20), hyperhomocysteinaemia alone subjects (Hhcy = 25), hyperhomocysteinaemia and carotid artery atherosclerosis combined subjects (Hhcy + ATH = 30) and patients with standalone carotid artery atherosclerosis (ATH = 25). Plasma Hcy, supplementary biochemical parameters and carotid artery ultrasonography (USG) were measured in all participants. MicroRNA expression levels in the peripheral blood were calculated by real-time reverse transcription-polymerase chain reaction (qRT-PCR). The correlations of miR-143 and miR-145 with Hcy, blood lipid parameters and carotid artery atherosclerotic plaques were evaluated using Pearson's correlation coefficients. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the capacities of miR-143 and miR-145 for the detection of Hhcy and atherosclerosis patients. RESULTS: MiR-143 and miR-145 exhibited trends towards significance with stepwise decreases from the NC to Hhcy groups and then to the Hhcy + ATH and ATH groups. Similar results were observed in the carotid artery plaque group (Hhcy + ATH and ATH grups) compared with the no-plaque group (NC and Hhcy groups). The miR-143 expression level exhibited significant negative correlations with Hcy, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c). The miR-145 expression level exhibited significant negative correlations with Hcy, TC, triglyceride (TG) and LDL-c. MiR-143 and miR-145 exhibited the greatest area under the curves (AUCs) (0.775 and 0.681, respectively) for the detection of every Hhcy patient, including those in the Hhcy and Hhcy + ATH groups, from among all subjects. CONCLUSION: The results indicated that the levels of atherosclerosis-associated circulating miR-143 and miR-145 are linked to Hhcy. MiR-143 may be used as a potential non-invasive biomarkers of Hhcy and thus may be helpful in predicting the progress of atherosclerosis in Hhcy patients. PMID- 28633642 TI - Prediction and analysis of three gene families related to leaf rust (Puccinia triticina) resistance in wheat (Triticum aestivum L.). AB - BACKGROUND: The resistance to leaf rust (Lr) caused by Puccinia triticina in wheat (Triticum aestivum L.) has been well studied over the past decades with over 70 Lr genes being mapped on different chromosomes and numerous QTLs (quantitative trait loci) being detected or mapped using DNA markers. Such resistance is often divided into race-specific and race-nonspecific resistance. The race-nonspecific resistance can be further divided into resistance to most or all races of the same pathogen and resistance to multiple pathogens. At the molecular level, these three types of resistance may cover across the whole spectrum of pathogen specificities that are controlled by genes encoding different protein families in wheat. The objective of this study is to predict and analyze genes in three such families: NBS-LRR (nucleotide-binding sites and leucine-rich repeats or NLR), START (Steroidogenic Acute Regulatory protein [STaR] related lipid-transfer) and ABC (ATP-Binding Cassette) transporter. The focus of the analysis is on the patterns of relationships between these protein coding genes within the gene families and QTLs detected for leaf rust resistance. RESULTS: We predicted 526 ABC, 1117 NLR and 144 START genes in the hexaploid wheat genome through a domain analysis of wheat proteome. Of the 1809 SNPs from leaf rust resistance QTLs in seedling and adult stages of wheat, 126 SNPs were found within coding regions of these genes or their neighborhood (5 Kb upstream from transcription start site [TSS] or downstream from transcription termination site [TTS] of the genes). Forty-three of these SNPs for adult resistance and 18 SNPs for seedling resistance reside within coding or neighboring regions of the ABC genes whereas 14 SNPs for adult resistance and 29 SNPs for seedling resistance reside within coding or neighboring regions of the NLR gene. Moreover, we found 17 nonsynonymous SNPs for adult resistance and five SNPs for seedling resistance in the ABC genes, and five nonsynonymous SNPs for adult resistance and six SNPs for seedling resistance in the NLR genes. Most of these coding SNPs were predicted to alter encoded amino acids and such information may serve as a starting point towards more thorough molecular and functional characterization of the designated Lr genes. Using the primer sequences of 99 known non-SNP markers from leaf rust resistance QTLs, we found candidate genes closely linked to these markers, including Lr34 with distances to its two gene-specific markers being 1212 bases (to cssfr1) and 2189 bases (to cssfr2). CONCLUSION: This study represents a comprehensive analysis of ABC, NLR and START genes in the hexaploid wheat genome and their physical relationships with QTLs for leaf rust resistance at seedling and adult stages. Our analysis suggests that the ABC (and START) genes are more likely to be co-located with QTLs for race-nonspecific, adult resistance whereas the NLR genes are more likely to be co-located with QTLs for race-specific resistance that would be often expressed at the seedling stage. Though our analysis was hampered by inaccurate or unknown physical positions of numerous QTLs due to the incomplete assembly of the complex hexaploid wheat genome that is currently available, the observed associations between (i) QTLs for race-specific resistance and NLR genes and (ii) QTLs for nonspecific resistance and ABC genes will help discover SNP variants for leaf rust resistance at seedling and adult stages. The genes containing nonsynonymous SNPs are promising candidates that can be investigated in future studies as potential new sources of leaf rust resistance in wheat breeding. PMID- 28633643 TI - Enhancement of thermoalkaliphilic xylanase production by Pichia pastoris through novel fed-batch strategy in high cell-density fermentation. AB - BACKGROUND: Xylanase degrades xylan into monomers of various sizes by catalyzing the endohydrolysis of the 1,4-beta-D-xylosidic linkage randomly, possessing potential in wide industrial applications. Most of xylanases are susceptible to be inactive when suffering high temperature and high alkaline process. Therefore, it is necessary to develop a high amount of effective thermoalkaliphilic xylanases. This study aims to enhance thermoalkaliphilic xylanase production in Pichia pastoris through fermentation parameters optimization and novel efficient fed-batch strategy in high cell-density fermentation. RESULTS: Recombinant xylanase activity increased 12.2%, 7.4%, 12.0% and 9.9% by supplementing the Pichia pastoris culture with 20 g/L wheat bran, 5 mg/L L-histidine, 10 mg/L L tryptophan and 10 mg/L L-methionine in shake flasks, respectively. Investigation of nutritional fermentation parameters, non-nutritional fermentation parameters and feeding strategies in 1 L bioreactor and 1 L shake flask revealed that glycerol and methanol feeding strategies were the critical factors for high cell density and xylanase activity. In 50 L bioreactor, a novel glycerol feeding strategy and a four-stage methanol feeding strategy with a stepwise increase in feeding rate were developed to enhance recombinant xylanase production. In the initial 72 h of methanol induction, the linear dependence of xylanase activity on methanol intake was observed (R2 = 0.9726). The maximum xylanase activity was predicted to be 591.2 U/mL, while the actual maximum xylanase activity was 560.7 U/mL, which was 7.05 times of that in shake flask. Recombinant xylanase retained 82.5% of its initial activity after pre-incubation at 80 degrees C for 50 min (pH 8.0), and it exhibited excellent stability in the broad temperature (60-80 degrees C) and pH (pH 8.0-11.0) ranges. CONCLUSIONS: Efficient glycerol and methanol fed-batch strategies resulting in desired cell density and xylanase activity should be applied in other P. pastoris fermentation for other recombinant proteins production. Recombinant xylanases with high pH- and thermal stability showed potential in various industrial applications. PMID- 28633644 TI - Risk factors for pulmonary complications after hepatic resection: role of intraoperative hemodynamic instability and hepatic ischemia. AB - BACKGROUND: Postoperative operative pulmonary complications (PPCs) after hepatic surgery are associated with increased length of hospital stays. Intraoperative blood transfusion, extensive resection and different comorbidities have been identified. Other parameters, like time of hepatic ischemia, have neither been clinically studied, though experimental studies show that hepatic ischemia can provide lung injury. The objective of this study was to determinate the risk factors of postoperative pulmonary complications (PPCs) after hepatic resection within 7 postoperative days. METHOD: Ninety-four patients consecutively who underwent elective hepatectomy between January and December 2013. Demographic data, pathological variables, and preoperative, intraoperative, and postoperative variables had been prospectively collected in a data base. The dependant variables studied were the occurrence of PPCs, defined before analysis of the data. RESULTS: PPCs occurred in 32 (34%) patients. A multivariate analysis allowed identifying the risk factors for PPCs. On multivariate analysis, preoperative gamma-glutamyltransferase (GGT) elevation OR =5,12 [1,85-15,69] p = 0,002, liver ischemia duration OR = 1,03 [1,01-1,06] p = 0,01 and the intraoperative use of vasopressor OR = 4,40 [1,58-13,36] p = 0,006 were independently associated with PPCs. For every 10 min added in ischemia duration, the OR of the risk of PPCs was estimated to be 1.37 (CI95% = [1.08-1.81], p = 0.01). CONCLUSION: Three risk factors for PPCs have been identified in a population undergoing liver resection: preoperative GGT elevation, ischemia duration and the intraoperative use of vasopressor. PPCs after liver surgery could be related to lung injury induced by liver ischemia reperfusion and not solely by direct infectious process. That could explain why factors influencing directly or indirectly liver ischemia were independently associated with PPCs. PMID- 28633646 TI - Role of serotonin on the intestinal mucosal immune response to stress-induced diarrhea in weaning mice. AB - BACKGROUND: During weaning, babies and young animal often experience diarrhea from food intolerance and/or decreasing levels of maternal antibodies, and diarrhea tends to be particularly severe during the early-weaned period, which often exhibits an underdeveloped immune system, a disturbed gut environment and results in nutrient malabsorption and dehydration. It was deduced that neuroendocrine might have close relation with diarrhea, especially 5-HT. METHODS: To explore the role of serotonin (5-HT) in weaning mice subjected to stress induced diarrhea, 21-day-old weaned mice were divided into the following groups: control group, stress-induced diarrhea group (restrained by binding the hind limbs and intragastric administration of folium sennae with 0.4 g/mL, 15 mL/kg body weight) and para-chlorophenylalanine (PCPA) + stress-induced diarrhea group (30 mg/mL, 300 mg/kg body weight PCPA intraperitoneal injection before stress induced diarrhea treatment). RESULTS: Based on results from enzyme-linked immunosorbent assays, histological staining, lymphocyte proliferation assays and flow cytometry analysis, we found that the mice experienced increases in several stress markers, which coincided with severe diarrhea and an increase in 5-HT levels. However, pre-treatment with PCPA resulted in a decrease in the stress indicators and the severity of diarrhea, which correlated with decreased 5-HT levels. Interestingly, stress-induced diarrhea caused changes in various aspects of the immune system, including the amount of intraepithelium lymphocytes, CD4+/CD8+ T lymphocyte populations, B and T lymphocyte proliferation, and the secretion of sIgA and cytokines in the small intestine and ileum. However, these immune system changes could be reversed upon treatment with PCPA. CONCLUSIONS: We observed a distinct correlation between 5-HT levels and the occurrence of stress induced diarrhea in weaning mice, which may result in the deregulation of the mucosal immune system. PMID- 28633645 TI - Generation of populations of antigen-specific cytotoxic T cells using DCs transfected with DNA construct encoding HER2/neu tumor antigen epitopes. AB - BACKGROUND: Recent fundamental and clinical studies have confirmed the effectiveness of utilizing the potential of the immune system to remove tumor cells disseminated in a patient's body. Cytotoxic T lymphocytes (CTLs) are considered the main effectors in cell-mediated antitumor immunity. Approaches based on antigen presentation to CTLs by dendritic cells (DCs) are currently being intensively studied, because DCs are more efficient in tumor antigen presentation to T cells through their initiation of strong specific antitumor immune responses than other types of antigen-presenting cells. Today, it has become possible to isolate CTLs specific for certain antigenic determinants from heterogeneous populations of mononuclear cells. This enables direct and specific cell-mediated immune responses against cells carrying certain antigens. The aim of the present study was to develop an optimized protocol for generating CTL populations specific for epitopes of tumor-associated antigen HER2/neu, and to assess their cytotoxic effects against the HER2/neu-expressing MCF-7 tumor cell line. METHODS: The developed protocol included sequential stages of obtaining mature DCs from PBMCs from HLA A*02-positive healthy donors, magnet-assisted transfection of mature DCs with the pMax plasmid encoding immunogenic peptides HER2 p369-377 (E75 peptide) and HER2 p689-697 (E88 peptide), coculture of antigen activated DCs with autologous lymphocytes, magnetic-activated sorting of CTLs specific to HER2 epitopes, and stimulation of isolated CTLs with cytokines (IL-2, IL-7, and IL-15). RESULTS: The resulting CTL populations were characterized by high contents of CD8+ cells (71.5% in cultures of E88-specific T cells and 90.2% in cultures of E75-specific T cells) and displayed strong cytotoxic effects against the MCF-7 cell line (percentages of damaged tumor cells in samples under investigation were 60.2 and 65.7% for E88- and E75-specific T cells, respectively; level of spontaneous death of target cells was 17.9%). CONCLUSIONS: The developed protocol improves the efficiency of obtaining HER2/neu-specific CTLs and can be further used to obtain cell-based vaccines for eradicating targeted tumor cells to prevent tumor recurrence after the major tumor burden has been eliminated and preventing metastasis in patients with HER2-overexpressing tumors. PMID- 28633647 TI - Meeting the oral health needs of 12-year-olds in China: human resources for oral health. AB - BACKGROUND: An appropriate level of human resources for oral health [HROH] is required to meet the oral health needs of population, and enable maximum improvement in health outcomes. The aim of this study was to estimate the required HROH to meet the oral health needs of the World Health Organization [WHO] reference group of 12-year-olds in China and consider the implications for education, practice, policy and HROH nationally. METHODS: We estimated the need of HROH to meet the needs of 12-year-olds based on secondary analysis of the epidemiological and questionnaire data from the 3rd Chinese National Oral Health Survey, including caries experience and periodontal factors (calculus), dentally related behaviour (frequency of toothbrushing and sugar intake), and social factors (parental education). Children's risk for dental caries was classified in four levels from low (level 1) to high (level 4). We built maximum and minimum intervention models of dental care for each risk level, informed by contemporary evidence-based practice. The needs-led HROH model we used in the present study incorporated need for treatment and risk-based prevention using timings verified by experts in China. These findings were used to estimate HROH for the survey sample, extrapolated to 12-year-olds nationally and the total population, taking account of urban and rural coverage, based on different levels of clinical commitment (60-90%). RESULTS: We found that between 40,139 and 51,906 dental professionals were required to deliver care for 12-year-olds nationally based on 80% clinical commitment. We demonstrated that the majority of need for HROH was in the rural population (72.5%). Over 93% of HROH time was dedicated to prevention within the model. Extrapolating the results to the total population, the estimate for HROH nationally was 3.16-4.09 million to achieve national coverage; however, current HROH are only able to serve an estimated 5% of the population with minimum intervention based on a HROH spending 90% of their time in providing clinical care. CONCLUSIONS: The findings highlight the gap between dental workforce needs and workforce capacity in China. Significant implications for health policy and human resources for oral health in this country with a developing health system are discussed including the need for public health action. PMID- 28633648 TI - Radiologic comparison of posterior release, internal distraction, final PSO and spinal fusion with one-stage posterior vertebral column resection for multi-level severe congenital scoliosis. AB - BACKGROUND: To compare radiologic results of posterior release, internal distraction, and final pedicle subtraction osteotomy (PSO) and spinal fusionwith one-stage posterior vertebral column resection (PVCR) in treating multi-level severe congenital scoliosis. METHODS: Forty-onesevere congenital scoliosis patients were used in the study. Group A comprised 24 patients who underwent one stage PVCR. Group B comprised 17 patients who underwent posterior release with internal distraction, followed by final posterior fusion and instrumentation. The average preoperative main curve was 110.4 degrees (95-130 degrees ) in group A and 109.4 degrees (range 90 degrees -126 degrees ) in group B. Postoperative follow-up time was >=2 years (2.0-4.5 years) to analyze the radiographic and clinical outcomes. RESULTS: A comparison of posterior release, internal distraction, and final spinal fusion with PVCR showed no significant differences in postoperative main curve and compensatory caudal curve correction, coronal and sagittal imbalance. However, significant differences were found between the 2 groups in compensatory cranial curve correction. CONCLUSIONS: Posterior release, internal distraction, and final spinal fusion produce better corrective results in compensatory cranial curve correction than PVCR in treating severe multi-level congenital scoliosis. PMID- 28633649 TI - Erratum to: Pesticide exposures and chronic kidney disease of unknown etiology: an epidemiologic review. PMID- 28633650 TI - Effects of Tolvaptan in patients with acute heart failure: a systematic review and meta-analysis. AB - BACKGROUND: Acute heart failure, which requires urgent evaluation and treatment, is a leading cause for admission to the emergency department. The aim of this meta-analysis was to evaluate the effects of tolvaptan on acute heart failure and compare them with the effects of conventional therapy or placebo. METHODS: The electronic databases PubMed, EMBASE, and the Cochrane Controlled Trial registry were searched from their starting dates to October 24, 2016. Two authors independently read the trials and extracted related information from the included studies. We used fixed-effects or random-effects models to assess the overall combined risk estimates according to I2 statistics. Analysis to determine sensitivity and publication bias was conducted. RESULTS: Six randomised controlled trials from eight articles, with a total of 746 patients, were included for analysis. Compared with the control, tolvaptan reduced body weight in two days (WMD 1.35; 95% CI 0.75 to 1.96), elevated sodium level in two days (WMD 2.33; 95% CI 1.08 to 3.57) and five days (WMD 1.57; 95% CI 0.04 to 3.09), and ameliorated symptoms of dyspnoea (RR 0.82; 95% CI 0.71-0.95). However, tolvaptan did not improve long-term (RR 1.04; 95% CI 0.66-1.62) or short-term all cause mortality (RR 0.89; 95% CI 0.45-1.76), incidence of clinical events (worsening heart failure, RR 0.75; 95% CI 0.50-1.12 and worsening renal function, RR 0.97; 95% CI 0.75-1.27), and length of hospital stay in patients (WMD 0.14; 95% CI -0.29 to 2.38) with acute heart failure. CONCLUSION: Tolvaptan can decrease body weight, increase serum sodium level, and ameliorate some of the congestion symptoms in patients with acute heart failure, which may help avoid the overdose of loop diuretics, especially in patients with renal dysfunction. PMID- 28633651 TI - Epidemiology of intestinal helminthiasis among school children with emphasis on Schistosoma mansoni infection in Wolaita zone, Southern Ethiopia. AB - BACKGROUND: Intestinal helminth infections are major parasitic diseases causing public health problems in Ethiopia. Although the epidemiology of these infections are well documented in Ethiopia, new transmission foci for schistosomiasis are being reported in different parts of the country. The objective of this study was to assess the prevalence of Schistosoma mansoni and other intestinal helminth infections among school children and determine the endemicity of schistosomiasis in Wolaita Zone, southern Ethiopia. METHODS: Cross-sectional parasitological and malacological surveys were conducted by collecting stool samples for microscopic examination and snails for intermediate host identification. Stool samples were collected from 503 children and processed for microscopic examination using Kato Katz and formalin-ether concentration methods. Snails collected from aquatic environments in the study area were identified to species level and Biomphalaria pfeifferi snails, the intermediate host of S. mansoni,, were individually exposed to artificial light in order to induce cercariae shedding. Cercariae shed from snails were used to infect laboratory-bred Swiss albino mice in order to identify the schistosome to species level. RESULTS: The overall prevalence of intestinal helminth infections was 72.2% among school children. S. mansoni infection prevalence was 58.6%. The prevalence and intensity of S. mansoni infections varied among schools and sex of children. Swimming was the only factor reported to be significantly associated with S. mansoni infection (AOR = 2.954, 95% CI:1.962-4.449). Other intestinal helminth species identified were hookworms (27.6%), Ascaris lumbricoides (8.7%), E. vermicularis (2.8%), Taenia species (2.6%), T. trichiura (1.2%) and H. nana (0.6%). Only B. pfeifferi snails collected from streams shed schistosome cercariae and 792 adult S. mansoni worms were harvested from mice exposed to cercariae shed from B. pfeifferi on the 6th week post-exposure. CONCLUSION: The present study found high level of intestinal helminth infections in the study area. The study also confirmed autochthonous transmission and endemicity of S. mansoni as evidenced by both parasitological and malacological findings as well as by further establishing infections in lab bred mice. Therefore, there is a need to include the area in the control programs with anti-helminth drugs and also consider other complementary measures including sanitation, provision of clean water supply, and snail control. PMID- 28633652 TI - Spontaneous rupture of the common hepatic duct associated with acute pancreatitis: a case report. AB - BACKGROUND: Rupture of the common bile duct is a life-threatening condition, usually observed after a trauma or in association with choledocholithiasis or an obstructive tumor of the bile duct. However, a spontaneous rupture of the common bile duct is a rare entity. CASE PRESENTATION: We report a new observation of a spontaneous rupture of the common bile duct, associated with biliary peritonitis and pancreatitis, in a 15-year-old North African girl. Etiological aspects, specificities of clinical presentation, means of diagnosis, as well as surgical and perioperative management are discussed. CONCLUSIONS: The diagnosis of spontaneous rupture of the common bile duct is a challenge for both radiologist and surgeon. Beyond the difficulty of diagnosis, which requires radiological exploration, management of the subsequent biliary peritonitis involves urgent surgery, life-supporting measures, and close monitoring. PMID- 28633653 TI - Household cereal crop harvest and children's nutritional status in rural Burkina Faso. AB - BACKGROUND: Reduction of child undernutrition is one of the Sustainable Development Goals for 2030. Achievement of this goal may be made more difficult in some settings by climate change through adverse impact on agricultural productivity. However, there is only limited quantitative evidence on the link between household crop harvests and child nutrition. We examined this link in a largely subsistence farming population in rural Burkina Faso. METHODS: Data on the middle-upper arm circumference (MUAC) of 975 children <=5 years of age, household crop yields, and other parameters were obtained from the Nouna Health and Demographic Surveillance System. Multilevel modelling was used to assess the relationship between MUAC and the household crop harvest in the year 2009 estimated in terms of kilocalories per adult equivalent per day (kcal/ae/d). RESULTS: Fourteen percent of children had a MUAC <125 mm (a value indicative of acute undernutrition). The relationship between MUAC and annual household food energy production adjusted for age, sex, month of MUAC measurement, household wealth, whether a household member had a non-agricultural occupation, garden produce, village infrastructure and market presence, suggested a decline in MUAC below around 3000 kcal/ae/d. The mean MUAC was 2.49 (95% CI 0.45, 4.52) mm less at 1000 than at 3000 kcal/ae/d. CONCLUSIONS: Low per capita household crop production is associated with poorer nutritional status of children in a rural farming population in Burkina Faso. This and similar populations may thus be vulnerable to the adverse effects of weather on agricultural harvest, especially in the context of climate change. PMID- 28633654 TI - Physical activity and associated factors from a cross-sectional survey among adults in northern Tanzania. AB - BACKGROUND: Insufficient physical activity (PA) is a major contributing factor in the growing problem of non-communicable diseases (NCDs) in urban and rural Sub Saharan Africa. This study aimed to determine PA and associated factors among adults in Northern Tanzania. METHODS: We analyzed secondary data from a cross sectional serological survey nested within the Magu health and demographic sentinel surveillance population in Magu District Northwestern Tanzania. All resident adults aged 15 years and older were invited to participate in the study, and physical activity data were analyzed for 5663 participants. Data were analyzed using Stata version 13.0. We used logistic regression to obtain odds ratios and 95% confidence intervals (CI) for risk factors associated with differences in PA. RESULTS: In this mainly rural population, 96% reported sufficient PA, with a higher proportion in males (97.3%) compared to females (94.8%). In males the odds of sufficient PA were lower in rural areas compared to urban areas (OR = 0.19; P < 0.001; 95% CI = 0.08-0.42), while in females the odds of sufficient PA were higher in rural areas compared to urban areas (OR = 2.27; P < 0.001; 95%CI = 1.59-3.24). Leisure-related activity was low compared to work related and transport-related activity. Farmers had a higher odds of sufficient PA than those in professional jobs in both males (OR = 9.75; P < 0.001; 95% CI = 3.68-5.82) and females (OR = 2.83; P = 0.021; 95% CI = 1.17-6.86). CONCLUSION: The prevalence of PA in this population was high. However, there is need for PA programs to maintain the high level of compliance during and following the transition to a more urban-based culture. PMID- 28633655 TI - Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. AB - BACKGROUND: Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, -9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, -9 in Rb metastasis. METHODS: We compare MMP-2, -9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay. RESULTS: Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L 66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-beta1 in both Rb models. CONCLUSIONS: Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti metastatic therapy for Rb. PMID- 28633656 TI - Children's physical activity during a segmented school week: results from a quasi experimental education outside the classroom intervention. AB - BACKGROUND: Movement integration (MI) into traditional classroom teaching is a promising opportunity for children to increase physical activity (PA). Education outside the classroom (EOtC) can be regarded as MI, and has increased children's PA in case studies. The aim of this study is to investigate the effects of EOtC on children's PA by segmenting weekly activity-related behavior into a range of day types and domains. METHODS: In a quasi-experimental design, 33 classes were recruited and participants' PA was objectively measured using accelerometers taped to the lower back. In total, 361 (10.89 +/- 1.03 years) participants with 7 days of 24 h wear time per day were included in a day type PA analysis, and 194 of these participants (10.46 +/- 0.99 years) provided information on time spent in specific domains (e.g. EOtC or recess) and were included in a domain-specific PA analysis. Differences in proportion of time spent in PA intensities were tested using mixed-effects regression models. RESULTS: More moderate-to-vigorous physical activity (MVPA) occurred on days with physical education (PE) than days with EOtC (girls 0.79%, p = .001, CI = .26% to 1.31%; boys 1.35%, p = .003, CI = .32% to 2.38%), while no difference was found between EOtC days and school days without EOtC and PE. Light physical activity (LPA) was higher on EOtC days than school days without EOtC and PE (girls 2.43% p < .001, CI = 1.21% to 3.65%; boys 2.08%, p < .001, CI = .69% to 3.47%) and PE days (girls 2.18%, p < .001, CI = .80% to 3.56%; boys 2.40%, p < .001, CI = .83% to 3.96%). Comparing EOtC and classroom domains, boys proportionally spent 7.95% (p < .001, CI = 3.00% to 12.90%) more time in MVPA while no difference (p = 1.000) was measured for LPA, and girls had no difference (p = .176) in MVPA, but spent 9.76% (p < .001, CI = 7.12% to 12.41%) more time in LPA. CONCLUSIONS: EOtC was implemented without the provision of additional resources and with positive effects on PA. Findings suggest EOtC as a way to provide children with an additional opportunity to accumulate PA within the existing school setting. PMID- 28633657 TI - Patient safety culture in Norwegian nursing homes. AB - BACKGROUND: Patient safety culture concerns leader and staff interaction, attitudes, routines, awareness and practices that impinge on the risk of patient adverse events. Due to their complex multiple diseases, nursing home patients are at particularly high risk of adverse events. Studies have found an association between patient safety culture and the risk of adverse events. This study aimed to investigate safety attitudes among healthcare providers in Norwegian nursing homes, using the Safety Attitudes Questionnaire - Ambulatory Version (SAQ-AV). We studied whether variations in safety attitudes were related to professional background, age, work experience and mother tongue. METHODS: In February 2016, 463 healthcare providers working in five nursing homes in Tonsberg, Norway, were invited to answer the SAQ-AV, translated and adapted to the Norwegian nursing home setting. Previous validation of the Norwegian SAQ-AV for nursing homes identified five patient safety factors: teamwork climate, safety climate, job satisfaction, working conditions and stress recognition. SPSS v.22 was used for statistical analysis, which included estimations of mean values, standard deviations and multiple linear regressions. P-values <0.05 were considered to be significant. RESULTS: Out of the 463 employees invited, 288 (62.2%) answered the questionnaire. Response rates varied between 56.9% and 72.2% across the five nursing homes. In multiple linear regression analysis, we found that increasing age and job position among the healthcare providers were associated with significantly increased mean scores for the patient safety factors teamwork climate, safety climate, job satisfaction and working conditions. Not being a Norwegian native speaker was associated with a significantly higher mean score for job satisfaction and a significantly lower mean score for stress recognition. Neither professional background nor work experience were significantly associated with mean scores for any patient safety factor. CONCLUSIONS: Patient safety factor scores in nursing homes were poorer than previously found in Norwegian general practices, but similar to findings in out-of-hours primary care clinics. Patient safety culture assessment may help nursing home leaders to initiate targeted quality improvement interventions. Further research should investigate associations between patient safety culture and the occurrence of adverse events in nursing homes. PMID- 28633658 TI - Nucleated red blood cells, critical illness survivors and postdischarge outcomes: a cohort study. AB - BACKGROUND: Little is known about risk factors associated with out-of-hospital outcomes in survivors of critical illness. We hypothesized that the presence of nucleated red blood cells in patients who survived critical care would be associated with adverse outcomes following hospital discharge. METHODS: We performed a two-center observational cohort study of patients treated in medical and surgical intensive care units in Boston, Massachusetts. All data were obtained from the Research Patient Data Registry at Partners HealthCare. We studied 2878 patients, age >= 18 years, who received critical care between 2011 and 2015 and survived hospitalization. The exposure of interest was nucleated red blood cells occurring from 2 days prior to 7 days after critical care initiation. The primary outcome was mortality in the 90 days following hospital discharge. Secondary outcome was unplanned 30-day hospital readmission. Adjusted odds ratios were estimated by multivariable logistic regression models with inclusion of covariate terms thought to plausibly interact with both nucleated red blood cells and outcome. Adjustment included age, race (white versus nonwhite), gender, Deyo Charlson Index, patient type (medical versus surgical), sepsis and acute organ failure. RESULTS: In patients who received critical care and survived hospitalization, the absolute risk of 90-day postdischarge mortality was 5.9%, 11.7%, 15.8% and 21.9% in patients with 0/MUl, 1-100/MUl, 101-200/MUl and more than 200/MUl nucleated red blood cells respectively. Nucleated red blood cells were a robust predictor of postdischarge mortality and remained so following multivariable adjustment. The fully adjusted odds of 90-day postdischarge mortality in patients with 1-100/MUl, 101-200/MUl and more than 200/MUl nucleated red blood cells were 1.77 (95% CI, 1.23-2.54), 2.51 (95% CI, 1.36-4.62) and 3.72 (95% CI, 2.16-6.39) respectively, relative to patients without nucleated red blood cells. Further, the presence of nucleated red blood cells is a significant predictor of the odds of unplanned 30-day hospital readmission. CONCLUSION: In critically ill patients who survive hospitalization, the presence of nucleated red blood cells is a robust predictor of postdischarge mortality and unplanned hospital readmission. PMID- 28633659 TI - Computing patient data in the cloud: practical and legal considerations for genetics and genomics research in Europe and internationally. AB - Biomedical research is becoming increasingly large-scale and international. Cloud computing enables the comprehensive integration of genomic and clinical data, and the global sharing and collaborative processing of these data within a flexibly scalable infrastructure. Clouds offer novel research opportunities in genomics, as they facilitate cohort studies to be carried out at unprecedented scale, and they enable computer processing with superior pace and throughput, allowing researchers to address questions that could not be addressed by studies using limited cohorts. A well-developed example of such research is the Pan-Cancer Analysis of Whole Genomes project, which involves the analysis of petabyte-scale genomic datasets from research centers in different locations or countries and different jurisdictions. Aside from the tremendous opportunities, there are also concerns regarding the utilization of clouds; these concerns pertain to perceived limitations in data security and protection, and the need for due consideration of the rights of patient donors and research participants. Furthermore, the increased outsourcing of information technology impedes the ability of researchers to act within the realm of existing local regulations owing to fundamental differences in the understanding of the right to data protection in various legal systems. In this Opinion article, we address the current opportunities and limitations of cloud computing and highlight the responsible use of federated and hybrid clouds that are set up between public and private partners as an adequate solution for genetics and genomics research in Europe, and under certain conditions between Europe and international partners. This approach could represent a sensible middle ground between fragmented individual solutions and a "one-size-fits-all" approach. PMID- 28633660 TI - A re-assessment of the safety of silver in household water treatment: rapid systematic review of mammalian in vivo genotoxicity studies. AB - BACKGROUND: Despite poor evidence of their effectiveness, colloidal silver and silver nanoparticles are increasingly being promoted for treating potentially contaminated drinking water in low income countries. Recently, however, concerns have been raised about the possible genotoxicity of particulate silver. OBJECTIVES: The goal of this paper was to review the published mammalian in vivo genotoxicity studies using silver micro and nanoparticles. METHODS: SCOPUS and Medline were searched using the following search string: ("DNA damage" OR genotox* OR Cytotox* OR Embryotox*) AND (silver OR AgNP). Included papers were any mammalian in vivo experimental studies investigating genotoxicity of silver particles. Studies were quality assessed using the ToxRTool. RESULTS: 16 relevant papers were identified. There were substantial variations in study design including the size of silver particles, animal species, target organs, silver dose, route of administration and the method used to detect genotoxicity. Thus, it was not possible to produce a definitive pooled result. Nevertheless, most studies showed evidence of genotoxicity unless using very low doses. We also identified one human study reporting evidence of "severe DNA damage" in silver jewellery workers occupationally exposed to silver particles. CONCLUSIONS: With the available evidence it is not possible to be definitive about risks to human health from oral exposure to silver particulates. However, the balance of evidence suggests that there should be concerns especially when considering the evidence from jewellery workers. There is an urgent need to determine whether people exposed to particulate silver as part of drinking water treatment have evidence of DNA damage. PMID- 28633661 TI - Prevalence of arthritis according to age, sex and socioeconomic status in six low and middle income countries: analysis of data from the World Health Organization study on global AGEing and adult health (SAGE) Wave 1. AB - BACKGROUND: In higher income countries, social disadvantage is associated with higher arthritis prevalence; however, less is known about arthritis prevalence or determinants in low to middle income countries (LMICs). We assessed arthritis prevalence by age and sex, and marital status and occupation, as two key parameters of socioeconomic position (SEP), using data from the World Health Organization Study on global AGEing and adult health (SAGE). METHODS: SAGE Wave 1 (2007-10) includes nationally-representative samples of older adults (>=50 yrs), plus smaller samples of adults aged 18-49 yrs., from China, Ghana, India, Mexico, Russia and South Africa (n = 44,747). Arthritis was defined by self-reported healthcare professional diagnosis, and a symptom-based algorithm. Marital status and education were self-reported. Arthritis prevalence data were extracted for each country by 10-year age strata, sex and SEP. Country-specific survey weightings were applied and weighted prevalences calculated. RESULTS: Self reported (lifetime) diagnosed arthritis was reported by 5003 women and 2664 men (19.9% and 14.1%, respectively), whilst 1220 women and 594 men had current symptom-based arthritis (4.8% and 3.1%, respectively). For men, standardised arthritis rates were approximately two- to three-fold greater than for women. The highest rates were observed in Russia: 38% (95% CI 36%-39%) for men, and 17% (95% CI 14%-20%) for women. For both sexes and in all LMICs, arthritis was more prevalent among those with least education, and in separated/divorced/widowed women. CONCLUSIONS: High arthritis prevalence in LMICs is concerning and may worsen poverty by impacting the ability to work and fulfil community roles. These findings have implications for national efforts to prioritise arthritis prevention and management, and improve healthcare access in LMICs. PMID- 28633662 TI - OrthoReD: a rapid and accurate orthology prediction tool with low computational requirement. AB - BACKGROUND: Identifying orthologous genes is an initial step required for phylogenetics, and it is also a common strategy employed in functional genetics to find candidates for functionally equivalent genes across multiple species. At the same time, in silico orthology prediction tools often require large computational resources only available on computing clusters. Here we present OrthoReD, an open-source orthology prediction tool with accuracy comparable to published tools that requires only a desktop computer. The low computational resource requirement of OrthoReD is achieved by repeating orthology searches on one gene of interest at a time, thereby generating a reduced dataset to limit the scope of orthology search for each gene of interest. RESULTS: The output of OrthoReD was highly similar to the outputs of two other published orthology prediction tools, OrthologID and/or OrthoDB, for the three dataset tested, which represented three phyla with different ranges of species diversity and different number of genomes included. Median CPU time for ortholog prediction per gene by OrthoReD executed on a desktop computer was <15 min even for the largest dataset tested, which included all coding sequences of 100 bacterial species. CONCLUSIONS: With high-throughput sequencing, unprecedented numbers of genes from non-model organisms are available with increasing need for clear information about their orthologies and/or functional equivalents in model organisms. OrthoReD is not only fast and accurate as an orthology prediction tool, but also gives researchers flexibility in the number of genes analyzed at a time, without requiring a high-performance computing cluster. PMID- 28633663 TI - Targeting psychologic stress signaling pathways in Alzheimer's disease. AB - Alzheimer's Disease (AD) is the most prevalent progressive neurodegenerative disease; to date, no AD therapy has proven effective in delaying or preventing the disease course. In the search for novel therapeutic targets in AD, it has been shown that increased chronic psychologic stress is associated with AD risk. Subsequently, biologic pathways underlying psychologic stress have been identified and shown to be able to exacerbate AD relevant pathologies. In this review, we summarize the literature relevant to the association between psychologic stress and AD, focusing on studies investigating the effects of stress paradigms on transgenic mouse models of Amyloid-beta (Abeta) and tau pathologies. In recent years, a substantial amount of research has been done investigating a key stress-response mediator, corticotropin-releasing hormone (CRH), and its interactions with AD relevant processes. We highlight attempts to target the CRH signaling pathway as a therapeutic intervention in these transgenic mouse models and discuss how targeting this pathway is a promising avenue for further investigation. PMID- 28633665 TI - Optimizing bronchodilation in the prevention of COPD exacerbations. AB - The natural disease course of chronic obstructive pulmonary disease (COPD) is often punctuated by exacerbations: acute events of symptom worsening associated with significant morbidity and healthcare resource utilization; reduced quality of life; and increased risk of hospitalization and death. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that patients at risk of exacerbations (GOLD Groups C and D) receive a long-acting muscarinic antagonist (LAMA) or a long-acting beta2-agonist (LABA)/LAMA combination, respectively, as preferred initial treatments. The latter recommendation is based on recent trial evidence demonstrating the superior efficacy of a fixed-dose LABA/LAMA over an inhaled corticosteroid (ICS)/LABA in exacerbation prevention. ICS in combination with a LABA is also indicated for prevention of exacerbations, but the use of ICS is associated with an increased risk of adverse events such as pneumonia, and offers limited benefits beyond those provided by LABA or LAMA monotherapy. In this review, we examine evidence from a number of pivotal studies of LABAs and LAMAs, administered as monotherapy or as part of dual or triple combination therapy, with a specific focus on their effect on exacerbations. We also discuss a new proposed treatment paradigm for the management of COPD that takes into account this recent evidence and adopts a more cautious approach to the use of ICS. In alignment with GOLD 2017, we suggest that ICS should be reserved for patients with concomitant asthma or in whom exacerbations persist despite treatment with LABA/LAMA. PMID- 28633666 TI - Molecular detection of vector-borne pathogens in dogs and cats from Qatar. AB - BACKGROUND: Vector-borne diseases (VBDs) have been increasingly reported in dogs and cats worldwide. However, no data are currently available regarding canine and feline VBDs in Qatar and limited information is available from other Persian Gulf countries. METHODS: Blood samples from 98 client-owned animals (i.e. 64 dogs and 34 cats) living in Doha (Qatar) were collected and the presence of genomic DNA of Anaplasma spp., Babesia spp., Dirofilaria spp., Ehrlichia spp., Hepatozoon spp., Mycoplasma spp. and Rickettsia spp. was assessed by polymerase chain reaction (PCR), real time-PCR (rt-PCR) and sequence analysis. RESULTS: Of the 64 dogs, 12 (18.8%) were infected with at least one pathogen (i.e. 7.8% with Mycoplasma spp., 4.7% with Babesia vogeli, 3.1% with Ehrlichia canis, and 1.6% with Anaplasma platys, Babesia gibsoni and Hepatozoon canis, each). One of the 12 dogs was co infected with B. vogeli and E. canis. Of the 34 cats, seven (20.6%) animals were infected with at least one pathogen (i.e. 5.9% were positive for Mycoplasma spp., and 2.9% for Babesia felis, B. vogeli, E. canis, "Candidatus Mycoplasma haemominutum" and Mycoplasma haemofelis, each). No dogs or cats were positive for Dirofilaria spp. or Rickettsia spp. CONCLUSIONS: Although the sample sizes of dogs and cats herein analysed was moderately small, data from this study report the occurrence of A. platys, B. vogeli, B. gibsoni, E. canis, H. canis and Mycoplasma spp. in domestic dogs and of B. felis, B. vogeli, "Candidatus M. haemominutum", E. canis and M. haemofelis in domestic cats from Qatar. Further investigations along with prophylactic measures are strongly recommended in order to reduce the risk of dogs and cats acquiring VBDs in Qatar. PMID- 28633664 TI - A review of Sarcoptes scabiei: past, present and future. AB - The disease scabies is one of the earliest diseases of humans for which the cause was known. It is caused by the mite, Sarcoptes scabiei, that burrows in the epidermis of the skin of humans and many other mammals. This mite was previously known as Acarus scabiei DeGeer, 1778 before the genus Sarcoptes was established (Latreille 1802) and it became S. scabiei. Research during the last 40 years has tremendously increased insight into the mite's biology, parasite-host interactions, and the mechanisms it uses to evade the host's defenses. This review highlights some of the major advancements of our knowledge of the mite's biology, genome, proteome, and immunomodulating abilities all of which provide a basis for control of the disease. Advances toward the development of a diagnostic blood test to detect a scabies infection and a vaccine to protect susceptible populations from becoming infected, or at least limiting the transmission of the disease, are also presented. PMID- 28633667 TI - HPV and cofactors for invasive cervical cancer in Morocco: a multicentre case control study. AB - BACKGROUND: Limited national information is available in Morocco on the prevalence and distribution of HPV-sub-types of cervical cancer and the role of other risk factors. The aim was to determine the frequency of HPV-sub-types of cervical cancer in Morocco and investigate risk factors for this disease. METHODS: Between November 2009 and April 2012 a multicentre case-control study was carried out. A total of 144 cases of cervical cancer and 288 age-matched controls were included. Odds-ratios and corresponding confidence-intervals were computed by conditional logistic regression models. RESULTS: Current HPV infection was detected in 92.5% of cases and 13.9% of controls. HPV16 was the most common type for both cases and controls. Very strong associations between HPV-sub-types and cervical cancer were observed: total-HPV (OR = 39), HPV16 (OR = 49), HPV18 (OR = 31), and multiple infections (OR = 13). Education, high parity, sexual intercourse during menstruation, history of sexually transmitted infections, and husband's multiple sexual partners were also significantly associated with cervical cancer in the multivariate analysis. CONCLUSIONS: Our results could be used to establish a primary prevention program and to prioritize limited screening to women who have specific characteristics that may put them at an increased risk of cervical cancer. PMID- 28633668 TI - Use of social adaptability index to explain self-care and diabetes outcomes. AB - BACKGROUND: To examine whether the social adaptability index (SAI) alone or components of the index provide a better explanatory model for self-care and diabetes outcomes. METHODS: Six hundred fifteen patients were recruited from two primary care settings. A series of multiple linear regression models were run to assess (1) associations between the SAI and diabetes self-care/outcomes, and (2) associations between individual SAI indicator variables and diabetes self care/outcomes. Separate models were run for each self-care behavior and outcome. Two models were run for each dependent variable to compare associations with the SAI and components of the index. RESULTS: The SAI has a significant association with the mental component of quality of life (0.23, p < 0.01). In adjusted analyses, the SAI score did not have a significant association with any of the self-care behaviors. Individual components from the index had significant associations between self-care and multiple SAI indicator variables. Significant associations also exist between outcomes and the individual SAI indicators for education and employment. CONCLUSIONS: In this population, the SAI has low explanatory power and few significant associations with diabetes self care/outcomes. While the use of a composite index to predict outcomes within a diabetes population would have high utility, particularly for clinical settings, this SAI lacks statistical and clinical significance in a representative diabetes population. Based on these results, the index does not provide a good model fit and masks the relationship of individual components to diabetes self-care and outcomes. These findings suggest that five items alone are not adequate to explain or predict outcomes for patients with type 2 diabetes. PMID- 28633669 TI - Impact of exercise programs among helicopter pilots with transient LBP. AB - BACKGROUND: Flight related low back pain (LBP) among helicopter pilots is frequent and may influence flight performance. Prolonged confined sitting during flights seems to weaken lumbar trunk (LT) muscles with associated secondary transient pain. Aim of the study was to investigate if structured training could improve muscular function and thus improve LBP related to flying. METHODS: 39 helicopter pilots (35 men and 4 women), who reported flying related LBP on at least 1 of 3 missions last month, were allocated to two training programs over a 3-month period. Program A consisted of 10 exercises recommended for general LBP. Program B consisted of 4 exercises designed specifically to improve LT muscular endurance. The pilots were examined before and after the training using questionnaires for pain, function, quality of health and tests of LT muscular endurance as well as ultrasound measurements of the contractility of the lumbar multifidus muscle (LMM). RESULTS: Approximately half of the participants performed the training per-protocol. Participants in this subset group had comparable baseline characteristics as the total study sample. Pre and post analysis of all pilots included, showed participants had marked improvement in endurance and contractility of the LMM following training. Similarly, participants had improvement in function and quality of health. Participants in program B had significant improvement in pain, function and quality of health. CONCLUSIONS: This study indicates that participants who performed a three months exercise program had improved muscle endurance at the end of the program. The helicopter pilots also experienced improved function and quality of health. TRIAL REGISTRATION: Identifier: NCT01788111 Registration date; February 5th, 2013, verified April 2016. PMID- 28633670 TI - Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair. AB - BACKGROUND: Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. METHODS: The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. RESULTS: EDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6 4.8 MUM) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk*MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by alpha-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in gammaH2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as gammaH2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. CONCLUSION: These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors. PMID- 28633671 TI - Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study. AB - BACKGROUND: Prokinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT4) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT4 receptor affinity. Prucalopride is a high-affinity 5-HT4 receptor agonist with no major cardiac issues, for which the efficacy in SSc has not yet been assessed. METHODS: Forty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 * 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods. RESULTS: There were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations (p < 0.001), improvement of UCLA GIT constipation (-0.672 +/- 0.112 vs 0.086 +/- 0.115; p < 0.001), reflux (-0.409 +/- 0.094 vs 0.01 +/- 0.096; p < 0.005) and bloating ( 0.418 +/- 0.088 vs -0.084 +/- 0.09; p = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 +/- 20.1 vs no treatment: 45.8 +/- 21.3 minutes; treatment effect = -65.9 minutes; p = 0.035). CONCLUSIONS: The safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating. TRIAL REGISTRATION: EU Clinical Trial Registry, EudraCT2012-005348-92 . Registered on 19 February 2013. PMID- 28633672 TI - Influence of the number and timing of malaria episodes during pregnancy on prematurity and small-for-gestational-age in an area of low transmission. AB - BACKGROUND: Most evidence on the association between malaria in pregnancy and adverse pregnancy outcomes focuses on falciparum malaria detected at birth. We assessed the association between the number and timing of falciparum and vivax malaria episodes during pregnancy on small-for-gestational-age (SGA) and preterm birth. METHODS: We analysed observational data collected from antenatal clinics on the Thailand-Myanmar border (1986-2015). We assessed the effects of the total number of malaria episodes in pregnancy on SGA and the effects of malaria in pregnancy on SGA, very preterm birth, and late preterm birth, by the gestational age at malaria detection and treatment using logistic regression models with time dependent malaria variables (monthly intervals). World Health Organisation definitions of very preterm birth (>=28 and <32 weeks) and late preterm birth (>=32 and <37 weeks) and international SGA standards were used. RESULTS: Of 50,060 pregnant women followed, 8221 (16%) had malaria during their pregnancy. Of the 50,060 newborns, 10,005 (21%) were SGA, 540 (1%) were very preterm, and 4331 (9%) were late preterm. The rates of falciparum and vivax malaria were highest at 6 and 5 weeks' gestation, respectively. The odds of SGA increased linearly by 1.13-fold (95% confidence interval: 1.09, 1.17) and 1.27-fold (1.21, 1.33) per episode of falciparum and vivax malaria, respectively. Falciparum malaria at any gestation period after 12-16 weeks and vivax malaria after 20-24 weeks were associated with SGA (falciparum odds ratio, OR range: 1.15-1.63 [p range: <0.001 0.094]; vivax OR range: 1.12-1.54 [p range: <0.001-0.138]). Falciparum malaria at any gestation period after 24-28 weeks was associated with either very or late preterm birth (OR range: 1.44-2.53; p range: <0.001-0.001). Vivax malaria at 24 28 weeks was associated with very preterm birth (OR: 1.79 [1.11, 2.90]), and vivax malaria at 28-32 weeks was associated with late preterm birth (OR: 1.23 [1.01, 1.50]). Many of these associations held for asymptomatic malaria. CONCLUSIONS: Protection against malaria should be started as early as possible in pregnancy. Malaria control and elimination efforts in the general population can avert the adverse consequences associated with treated asymptomatic malaria in pregnancy. PMID- 28633673 TI - The influence of total hysterectomy in a cervical cancer screening population: a register-based cross-sectional study. AB - BACKGROUND: High coverage of a screening program is essential to program success. Many European screening programs cover only 10-80% of their target population. A possible explanation for the low coverage may be that some women in the screening population have had a total hysterectomy, thus they are not at risk of cervical cancer. The aim of this study was to identify the prevalence of hysterectomy in the target population of the Danish National Cervical Cancer Screening Program (NCCSP) and to recalculate coverage after excluding women with total hysterectomy. Furthermore, to analyze the association between hysterectomy and sociodemographic factors within the screening population. METHODS: A population based cross-sectional study using register data on all women in the target population of the NCCSP on January 12, 2012 (women born January 12, 1947, to January 12, 1986). The total coverage included women with hysterectomy in the target population whereas the recalculated coverage was calculated excluding women with total hysterectomy. To test the differences between the total coverage and the recalculated coverage, a two-sample z-test between the proportion of covered hysterectomized women and the proportion of covered non-hysterectomised women were used. A logistic regression model adjusted for age and sociodemographic characteristics was used to analyze the association between sociodemographic factors and total hysterectomy. RESULTS: The coverage among women aged 26-49 years and 55-64 years were 77.4% and 72.7%, respectively. The recalculated coverage was 78.2% (26-49 years) and 79.4% (55-64 years). Recalculating the coverage did not result in coverage higher than 82.7% at any age. The effect of excluding women with total hysterectomy increased with age, reaching its maximum of 8 % points for the oldest women. Women with higher socioeconomic status (higher education and higher disposable income) had lower odds of being hysterectomized compared to other women. Also, immigrants and descendants had lower odds of being hysterectomized compared to ethnic Danes. CONCLUSIONS: Excluding women with total hysterectomy only partly explained the low coverage of the NCCSP. Thus, initiatives must be made to improve acceptability of and accessibility to the NCCSP, especially in the youngest and the oldest women. PMID- 28633674 TI - Primary tumor volume delineation in head and neck cancer: missing the tip of the iceberg? AB - BACKGROUND: The aim was to evaluate the geometric and corresponding dosimetric differences between two delineation strategies for head and neck tumors neighboring air cavities. METHODS: Primary gross and clinical tumor volumes (GTV and CTV) of 14 patients with oropharynx or larynx tumors were contoured using a soft tissue window (S). In a second strategy, the same volumes were contoured with an extension to include the parts which became visible on lung window (L). For the calculation of Hausdorff-distances (HD) between contoured volumes of the two strategies, triangular meshes were exported. Two radiotherapy plans with identical goals and optimization parameters were generated for each case. Plan_S were optimized on CTV_S, and Plan_L on CTV_L. The dose coverages of CTV_L and CTV_Delta (CTV_L minus CTV_S) were evaluated in Plan_S. OAR doses were compared among Plan_S and Plan_L. RESULTS: Median three-dimensional HD for GTVs and CTVs were 5.7 (+/-2.6) and 9.3 (+/-2.8) mm, respectively. The median volume differences between structures contoured using L and S windows were 9% (+/-5%) and 9% (+/-4%) for GTV and CTV, respectively. In 13 out of 14 cases, Plan_S met the plan acceptance criteria for CTV_L. In 8 cases CTV_Delta was covered insufficiently in Plan_S. Mean and median differences in OAR dose-volume histogram parameters between Plan_S and Plan_L were within 3%. CONCLUSION: For the current practice in radiotherapy planning for head and neck cancer, the delineation of L-based volumes seems unnecessary. However, in special settings, where smaller or no PTV margins are used, this approach may play an important role for local control. PMID- 28633675 TI - Acupuncture treatment on the motor area of the scalp for motor dysfunction in patients with ischemic stroke: study protocol for a randomized controlled trial. AB - BACKGROUND: Scalp acupuncture has shown a remarkable treatment efficacy on motor dysfunction in patients with stroke in China, especially the motor area of Jiao's scalp acupuncture, which is the most widely used treatment. However, previous studies have summarized that the clinical curative effect of acupuncture treatment for stroke remains uncertain. Meanwhile, no randomized controlled trials on Jiao's scalp acupuncture have been performed. The aim of this study is to evaluate the efficacy and safety of Jiao's scalp acupuncture for motor dysfunction in ischemic stroke. METHODS/DESIGN: This is an assessor- and analyst blinded, randomized controlled trial. One hundred and eight stroke patients with motor dysfunction meeting the inclusion criteria will be allocated by a 1:1 ratio into either an acupuncture treatment group or a control group. Stroke patients in the control group will receive conventional rehabilitation treatment, whereas a combination of Jiao's scalp acupuncture and conventional rehabilitation treatment will be applied to the acupuncture group. Forty treatment sessions will be performed over an 8-week period. The Fugl-Meyer Assessment scale will be assessed as the primary outcome measure. The Modified Barthel Index, the Stroke-Specific Quality of Life, and the Stroke Syndrome of Traditional Chinese Medicine scales will be selected as secondary outcome measurements. All assessments will be conducted at baseline, week 4 (treatment 20), week 8 (treatment 40), week 12 (follow-up), and week 16 (follow-up). DISCUSSION: This is the first trial evaluating the efficacy and safety of Jiao's scalp acupuncture for motor dysfunction in ischemic stroke. The results of this trial are expected to provide relevant evidence demonstrating that Jiao's scalp acupuncture can be used as an effective rehabilitation treatment method for improving motor dysfunction in ischemic stroke. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02871453 . Registered on 17 July 2016. PMID- 28633676 TI - Evaluation of P16 expression in canine appendicular osteosarcoma. AB - BACKGROUND: Osteosarcoma (OSA) is a common malignant bone tumor of large breed dogs that occurs at predictable anatomic sites. At the time of initial diagnosis, most affected dogs have occult pulmonary metastases. Even with aggressive surgical treatment combined with chemotherapy, the majority of dogs diagnosed with OSA live less than 1 year from the time of diagnosis. The ability to identify canine OSA cases most responsive to treatment is needed. In humans, OSA is also an aggressive tumor that is histologically and molecularly similar to canine OSA. The expression of the tumor suppressor gene product P16 by human OSA tissue has been linked to a favorable response to chemotherapy. RESULTS: We identified an antibody that binds canine P16 and developed a canine OSA tissue microarray in order to test the hypothesis that P16 expression by canine OSA tissue is predictive of clinical outcome following amputation and chemotherapy. Although statistical significance was not reached, a trend was identified between the lack of canine OSA P16 expression and a shorter disease free interval. CONCLUSIONS: The identification of a molecular marker for canine OSA is an important goal and the results reported here justify a larger study. PMID- 28633677 TI - Surveillance of Endoscopes: Comparison of Different Sampling Techniques. AB - OBJECTIVE To compare different techniques of endoscope sampling to assess residual bacterial contamination. DESIGN Diagnostic study. SETTING The endoscopy unit of an 1,100-bed university hospital performing ~13,000 endoscopic procedures annually. METHODS In total, 4 sampling techniques, combining flushing fluid with or without a commercial endoscope brush, were compared in an endoscope model. Based on these results, sterile physiological saline flushing with or without PULL THRU brush was selected for evaluation on 40 flexible endoscopes by adenosine triphosphate (ATP) measurement and bacterial culture. Acceptance criteria from the French National guideline (<25 colony-forming units [CFU] per endoscope and absence of indicator microorganisms) were used as part of the evaluation. RESULTS On biofilm-coated PTFE tubes, physiological saline in combination with a PULL THRU brush generated higher mean ATP values (2,579 relative light units [RLU]) compared with saline alone (1,436 RLU; P=.047). In the endoscope samples, culture yield using saline plus the PULL THRU (mean, 43 CFU; range, 1-400 CFU) was significantly higher than that of saline alone (mean, 17 CFU; range, 0-500 CFU; P<.001). In samples obtained using the saline+PULL THRU brush method, ATP values of samples classified as unacceptable were significantly higher than those of samples classified as acceptable (P=.001). CONCLUSION Physiological saline flushing combined with PULL THRU brush to sample endoscopes generated higher ATP values and increased the yield of microbial surveillance culture. Consequently, the acceptance rate of endoscopes based on a defined CFU limit was significantly lower when the saline+PULL THRU method was used instead of saline alone. Infect Control Hosp Epidemiol 2017;38:1062-1069. PMID- 28633678 TI - Variation in Empiric Coverage Versus Detection of Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa in Hospitalizations for Community-Onset Pneumonia Across 128 US Veterans Affairs Medical Centers. AB - OBJECTIVE To examine variation in antibiotic coverage and detection of resistant pathogens in community-onset pneumonia. DESIGN Cross-sectional study. SETTING A total of 128 hospitals in the Veterans Affairs health system. PARTICIPANTS Hospitalizations with a principal diagnosis of pneumonia from 2009 through 2010. METHODS We examined proportions of hospitalizations with empiric antibiotic coverage for methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (PAER) and with initial detection in blood or respiratory cultures. We compared lowest- versus highest-decile hospitals, and we estimated adjusted probabilities (AP) for patient- and hospital-level factors predicting coverage and detection using hierarchical regression modeling. RESULTS Among 38,473 hospitalizations, empiric coverage varied widely across hospitals (MRSA lowest vs highest, 8.2% vs 42.0%; PAER lowest vs highest, 13.9% vs 44.4%). Detection rates also varied (MRSA lowest vs highest, 0.5% vs 3.6%; PAER lowest vs highest, 0.6% vs 3.7%). Whereas coverage was greatest among patients with recent hospitalizations (AP for anti-MRSA, 54%; AP for anti-PAER, 59%) and long-term care (AP for anti-MRSA, 60%; AP for anti-PAER, 66%), detection was greatest in patients with a previous history of a positive culture (AP for MRSA, 7.9%; AP for PAER, 11.9%) and in hospitals with a high prevalence of the organism in pneumonia (AP for MRSA, 3.9%; AP for PAER, 3.2%). Low hospital complexity and rural setting were strong negative predictors of coverage but not of detection. CONCLUSIONS Hospitals demonstrated widespread variation in both coverage and detection of MRSA and PAER, but probability of coverage correlated poorly with probability of detection. Factors associated with empiric coverage (eg, healthcare exposure) were different from those associated with detection (eg, microbiology history). Providing microbiology data during empiric antibiotic decision making could better align coverage to risk for resistant pathogens and could promote more judicious use of broad-spectrum antibiotics. Infect Control Hosp Epidemiol 2017;38:937-944. PMID- 28633679 TI - Multistate Modeling to Analyze Nosocomial Infection Data: An Introduction and Demonstration. AB - OBJECTIVE Multistate and competing risks models have become an established and adequate tool with which to quantify determinants and consequences of nosocomial infections. In this tutorial article, we explain and demonstrate the basics of these models to a broader audience of professionals in health care, infection control, and hospital epidemiology. METHODS Using a publicly available data set from a cohort study of intensive care unit patients, we show how hospital infection data can be displayed and explored graphically and how simple formulas are derived under some simplified assumptions for illustrating the basic ideas behind multistate models. Only a few simply accessible values (event counts and patient days) and a pocket calculator are needed to reveal basic insights into cumulative risk and clinical outcomes of nosocomial infection in terms of mortality and length of stay. RESULTS We show how to use these values to perform basic multistate analyses in own data or to correct biased estimates in published data, as these values are often reported. We also show relationships between multistate-based hazard ratios and odds ratios, which are derived from the popular logistic regression model. CONCLUSIONS No sophisticated statistical software is required to apply a basic multistate model and to avoid typical pitfalls such as time-dependent or competing-risks bias. Infect Control Hosp Epidemiol 2017;38:953-959. PMID- 28633680 TI - Impact of Organism Identification Method on Central Line-Associated Bloodstream Infection Designation. PMID- 28633681 TI - COPEWELL: A Conceptual Framework and System Dynamics Model for Predicting Community Functioning and Resilience After Disasters. AB - OBJECTIVE: Policy-makers and practitioners have a need to assess community resilience in disasters. Prior efforts conflated resilience with community functioning, combined resistance and recovery (the components of resilience), and relied on a static model for what is inherently a dynamic process. We sought to develop linked conceptual and computational models of community functioning and resilience after a disaster. METHODS: We developed a system dynamics computational model that predicts community functioning after a disaster. The computational model outputted the time course of community functioning before, during, and after a disaster, which was used to calculate resistance, recovery, and resilience for all US counties. RESULTS: The conceptual model explicitly separated resilience from community functioning and identified all key components for each, which were translated into a system dynamics computational model with connections and feedbacks. The components were represented by publicly available measures at the county level. Baseline community functioning, resistance, recovery, and resilience evidenced a range of values and geographic clustering, consistent with hypotheses based on the disaster literature. CONCLUSIONS: The work is transparent, motivates ongoing refinements, and identifies areas for improved measurements. After validation, such a model can be used to identify effective investments to enhance community resilience. (Disaster Med Public Health Preparedness. 2018;12:127-137). PMID- 28633682 TI - Effect of space allowance and floor type on performance, welfare and physiological measurements of finishing beef heifers. AB - Accommodating cattle indoors during the winter is widely practiced throughout Europe. There is currently no legislation surrounding the space allowance and floor type that should be provided to cattle during this time, however, concerns have been raised regarding the type of housing systems currently in use. The objective of the study was to investigate the effect of space allowance and floor type on performance and welfare of finishing beef heifers. Continental crossbred heifers (n=240: mean initial live; weight, 504 (SD 35.8) kg) were blocked by breed, weight and age and randomly assigned to one of four treatments; (i) 3.0 m2, (ii) 4.5 m2 and (iii) 6.0 m2 space allowance per animal on a fully slatted concrete floor and (iv) 6.0 m2 space allowance per animal on a straw-bedded floor, for 105 days. Heifers were offered a total mixed ration ad libitum. Dry matter intake was recorded on a pen basis and refusals were weighed back twice weekly. Heifers were weighed, dirt scored and blood sampled every 3 weeks. Whole blood was analysed for complete cell counts and serum samples were assayed for metabolite concentrations. Behaviour was recorded continuously using IR cameras from days 70 to 87. Heifers' hooves were inspected for lesions at the start of the study and again after slaughter. Post-slaughter, carcass weight, conformation and fat scores and hide weight were recorded. Heifers housed at 4.5 m2 had a greater average daily live weight gain (ADG) than those on both of the other concrete slat treatments; however, space allowance had no effect on carcass weight. Heifers accommodated on straw had a greater ADG (0.15 kg) (P<0.05), hide weight (P<0.01) better feed conversion ratio (P<0.05) and had greater dirt scores (P<0.05) at slaughter than heifers accommodated on concrete slats at 6.0 m2. The number of heifers lying at any one time was greater (P<0.001) on straw than on concrete slats. Space allowance and floor type had no effect on the number of hoof lesions gained or on any of the haematological or metabolic variables measured. It was concluded that increasing space allowance above 3.0 m2/animal on concrete slats was of no benefit to animal performance but it did improve animal cleanliness. Housing heifers on straw instead of concrete slats improved ADG and increased lying time; however carcass weight was not affected. PMID- 28633683 TI - Plasminogen Activator Inhibitor-1 is Regulated Through Dietary Fat Intake and Heritability: Studies in Twins. AB - In different pathophysiological conditions plasminogen activator inhibitor-1 (PAI 1) plasma concentrations are elevated. As dietary patterns are considered to influence PAI-1 concentration, we aimed to determine active PAI-1 plasma concentrations and mRNA expression in adipose tissue before and after consumption of a high-fat diet (HFD) and the impact of additive genetic effects herein in humans. For 6 weeks, 46 healthy, non-obese pairs of twins (aged 18-70) received a normal nutritionally balanced diet (ND) followed by an isocaloric HFD for 6 weeks. Active PAI-1 plasma levels and PAI-1 mRNA expression in subcutaneous adipose tissue were assessed after the ND and after 1 and 6 weeks of HFD. Active PAI-1 plasma concentrations and PAI-1 mRNA expression in adipose tissue were significantly increased after both 1 and 6 weeks of HFD when compared to concentrations determined after ND (p < .05), with increases of active PAI-1 being independent of gender, age, or changes of BMI and intrahepatic fat content, respectively. However, analysis of covariance suggests that serum insulin concentration significantly affected the increase of active PAI-1 plasma concentrations. Furthermore, the increase of active PAI-1 plasma concentrations after 6 weeks of HFD was highly heritable (47%). In contrast, changes in PAI-1 mRNA expression in fatty tissue in response to HFD showed no heritability and were independent of all tested covariates. In summary, our data suggest that even an isocaloric exchange of macronutrients - for example, a switch to a fat-rich diet - affects PAI-1 concentrations in humans and that this is highly heritable. PMID- 28633684 TI - Double burden of underweight and overweight among Bangladeshi adults differs between men and women: evidence from a nationally representative survey. AB - OBJECTIVE: To estimate the prevalence of underweight and overweight among Bangladeshi adults and to determine if the double burden of underweight and overweight differs by gender and other socio-economic characteristics of individuals. DESIGN: We used data from the Bangladesh Demographic and Health Survey 2011. Multinominal logistic regression was used to examine associations between the different nutritional statuses of individuals and related determinants. Interaction effect was checked between gender and various socio economic factors. SETTING: Nationwide, covering the whole of Bangladesh. SUBJECTS: Individuals aged >18 years (women, n 16 052; men, n 5090). RESULTS: Underweight was observed among 28.3 % of men and 24.4 % of women, whereas overweight was observed among 8.4 % of men and 16.9 % of women. The odds of being overweight were significantly lower among urban men (OR=0.46; 95 % CI 0.37, 0.57) compared with urban women, whereas the odds of being underweight were significantly higher among urban men (OR=1.33; 95 % CI 1.07, 1.64) compared with urban women. The odds of being overweight were lower among higher educated men (OR=0.48; 95 % CI 0.39, 0.58) and men of rich households (OR=0.45; 95 % CI 0.37, 0.54) compared with higher educated women and women of rich households, respectively. CONCLUSIONS: There are important gender differences in the prevalence of underweight and overweight among the adult population in Bangladesh. Women with higher education, in rich and urban households have higher chances of being overweight and lower chances of being underweight compared with their male counterparts. PMID- 28633685 TI - Cross-validation analysis for genetic evaluation models for ranking in endurance horses. AB - Ranking trait was used as a selection criterion for competition horses to estimate racing performance. In the literature the most common approaches to estimate breeding values are the linear or threshold statistical models. However, recent studies have shown that a Thurstonian approach was able to fix the race effect (competitive level of the horses that participate in the same race), thus suggesting a better prediction accuracy of breeding values for ranking trait. The aim of this study was to compare the predictability of linear, threshold and Thurstonian approaches for genetic evaluation of ranking in endurance horses. For this purpose, eight genetic models were used for each approach with different combinations of random effects: rider, rider-horse interaction and environmental permanent effect. All genetic models included gender, age and race as systematic effects. The database that was used contained 4065 ranking records from 966 horses and that for the pedigree contained 8733 animals (47% Arabian horses), with an estimated heritability around 0.10 for the ranking trait. The prediction ability of the models for racing performance was evaluated using a cross validation approach. The average correlation between real and predicted performances across genetic models was around 0.25 for threshold, 0.58 for linear and 0.60 for Thurstonian approaches. Although no significant differences were found between models within approaches, the best genetic model included: the rider and rider-horse random effects for threshold, only rider and environmental permanent effects for linear approach and all random effects for Thurstonian approach. The absolute correlations of predicted breeding values among models were higher between threshold and Thurstonian: 0.90, 0.91 and 0.88 for all animals, top 20% and top 5% best animals. For rank correlations these figures were 0.85, 0.84 and 0.86. The lower values were those between linear and threshold approaches (0.65, 0.62 and 0.51). In conclusion, the Thurstonian approach is recommended for the routine genetic evaluations for ranking in endurance horses. PMID- 28633686 TI - Polymorphisms of the TNF-alpha gene interact with plasma fatty acids on inflammatory biomarker profile: a population-based, cross-sectional study in Sao Paulo, Brazil. AB - The aim of the present study was to investigate the relationship of four TNF alpha SNP with inflammatory biomarkers and plasma fatty acids (FA), and the interaction among them in a population-based, cross-sectional study in Sao Paulo, Brazil. A total of 281 subjects, aged >19 and <60 years, participated in a cross sectional, population-based study performed in Brazil. The following SNP spanning the TNF-alpha gene were genotyped: -238G/A (rs361525), -308G/A (rs1800629), 857C/T (rs1799724) and -1031T/C (rs1799964). In all, eleven plasma inflammatory biomarkers and plasma FA profile were determined. To analyse the interaction between TNF-alpha SNP and plasma FA, a cluster analysis was performed to stratify individuals based on eleven inflammatory biomarkers into two groups used as outcome: inflammatory (INF) and non-inflammatory clusters. The -238A allele carriers had higher TNF-alpha (P=0.033), IL-6 (P=0.013), IL-1beta (P=0.037), IL 12 (0.048) and IL-10 (P=0.010) than the GG genotype. The -308A allele carriers also had lower levels of plasma palmitoleic acid (P=0.009), oleic acid (P=0.039), total MUFA (P=0.014), stearoyl-CoA desaturase (SCD) activity index-16 (P=0.007), SCD-18 (P=0.020) and higher levels of PUFA (P=0.046) and DHA (P=0.044). Significant interactions modifying the risk of belonging to the INF cluster were observed with inflammatory cluster as outcome between -857C/T and plasma alpha linolenic acid (P=0.026), and also between -308G/A and plasma stearic acid (P=0.044) and total SFA (P=0.040). Our study contributes to knowledge on TNF alpha SNP and their association with inflammatory biomarker levels, plasma FA and the interaction among them, of particular interest for the Brazilian population. PMID- 28633687 TI - Facilitators and barriers experienced by federal cross-sector partners during the implementation of a healthy eating campaign. AB - OBJECTIVE: To identify facilitators and barriers that Health Canada's (HC) cross sector partners experienced while implementing the Eat Well Campaign: Food Skills (EWC; 2013-2014) and describe how these experiences might differ according to distinct partner types. DESIGN: A qualitative study using hour-long semi structured telephone interviews conducted with HC partners that were transcribed verbatim. Facilitators and barriers were identified inductively and analysed according partner types. SETTING: Implementation of a national mass-media health education campaign. SUBJECTS: Twenty-one of HC's cross-sector partners (food retailers, media and health organizations) engaged in the EWC. RESULTS: Facilitators and barriers were grouped into seven major themes: operational elements, intervention factors, resources, collaborator traits, developer traits, partnership factors and target population factors. Four of these themes had dual roles as both facilitators and barriers (intervention factors, resources, collaborator traits and developer traits). Sub-themes identified as both facilitators and barriers illustrate the extent to which a facilitator can easily become a barrier. Partnership factors were unique facilitators, while operational and target population factors were unique barriers. Time was a barrier that was common to almost all partners regardless of partnership type. There appeared to be a greater degree of uniformity among facilitators, whereas barriers were more diverse and unique to the realities of specific types of partner. CONCLUSIONS: Collaborative planning will help public health organizations anticipate barriers unique to the realities of specific types of organizations. It will also prevent facilitators from becoming barriers. Advanced planning will help organizations manage time constraints and integrate activities, facilitating implementation. PMID- 28633689 TI - The relationship between community nutritionists' use of policy, systems and environmental strategies to prevent obesity and its determinants depends on networking. AB - OBJECTIVE: To apply the Theory of Planned Behaviour to examine the relationship between the constructs of background factors and beliefs towards using policy, systems and environmental (PSE) strategies and reported use of PSE strategies to prevent obesity by a group of professional nutrition educators. DESIGN: Cross sectional study using self-reported survey. SETTING: Cooperative Extension in New York, USA. SUBJECTS: Nutrition educators (n 58); survey response rate 100 %. RESULTS: Nutrition educators' reported use of PSE strategies to prevent obesity were positively associated with background factors of their community networking and number of staff they managed, their belief of other people's expectations of them to make PSE changes and the belief that their communities were ready to use PSE strategies; and negatively associated with their belief that individual-level factors contributed to obesity. The relationships among these variables were complicated and their use of PSE strategies occurred only when they utilized their professional networks at a moderately high level (above mean of 5.3 on a scale of 1-7), given that their community was also ready to use PSE strategies. CONCLUSIONS: Nutrition educators' use of PSE strategies depends on several internal and external factors. Community networking needs to be emphasized as one of the most significant factors contributing to nutrition educators' work in this area. Organizational and community support should be in place in order to facilitate nutrition educators' effective use of PSE strategies. PMID- 28633688 TI - Normative development of the Child Behavior Checklist Dysregulation Profile from early childhood to adolescence: Associations with personality pathology. AB - The Dysregulation Profile (DP) is a broad indicator of concurrent affective, behavioral, and cognitive dysregulation, often measured with the anxious/depressed, aggressive behavior, and attention problems syndrome scales of the Child Behavior Checklist. Despite an expanding body of research on the DP, knowledge of the normative developmental course of the DP from early childhood to adolescence is lacking. Furthermore, although we know that the DP longitudinally predicts personality pathology, no research yet has examined whether next to the DP in early childhood, the rate of change of the DP across development predicts personality pathology. Therefore, using cohort-sequential latent growth modeling in a population-based sample (N = 668), we examined the normative developmental course of mother-reported DP from ages 4 to 17 years and its associations with a wide range of adolescent-reported personality pathology dimensions 3 years later. The results showed that the DP follows a nonlinear developmental course with a peak in early adolescence. The initial level of the DP at age 4 and, to a lesser extent, the rate of change in the DP predicted a range of personality pathology dimensions in late adolescence. The findings suggest that the DP is a broad developmental precursor of personality pathology in late adolescence. PMID- 28633690 TI - Early solid additional feeding of suckling rabbits from 3 to 15 days of age. AB - Studies have shown that nutrient requirement of suckling kits is not satisfied, but they can be fed a double quantity of milk (double nursing) resulting in improved BW and weight gain. The aim of our trials was to give additional solid feed during the early suckling period (3 to 15 days of age) when rabbit kits drink exclusively milk. Two experiments were conducted with animals from Pannon Rabbit Breeding Program. In experiment 1 (n=77 does, 734 kits) the does received commercial feed (C) or C pellet supplemented with 0.2 g powdered thyme/kg (CT). Within both dietary groups of the does three groups of litters were formed: no additional solid creep feeding (N); soya bean-based pellet (S); S pellet with 1% added powdered thyme (ST). In group S and ST, cylinder-shaped solid pellets were made. At the beginning (3 days of age) two pieces of pellets were placed daily into the nestbox after nursing. Later on it was increased to six pellets till 15 days of age. The kits consumed the additional solid feed (S and ST), however, it did not affect the BW, weight gain or survival. In experiment 2 (n=30 does, 240 kits) all does consumed commercial feed. The additional feed for kits was based on commercial piglet feed. Three groups were formed: the litters in control group were fed no additional solid feed (K), kits were fed additionally with pellets (8 mm of diameter) based on piglet feed powder, pellet adhesive and water (PI), and extra glycerin powder was added to the mixture of piglet feed powder and water (PG). The experiment lasted from the age of 3 days till 21 days. At the beginning six pellets were placed on the nest material. Later on the amount was gradually increased to 24 pellets till age of 15 days. The kits consumed the pellets. The BW of PI group differed from group PG at age of 5, 9, 12 and 21 days by +7.3%, +6.5%, +5.9%, +4.8%, respectively (P<0.05) and from group K at age of 12 days by +5.9% (P< 0.05). The differences were more expressed at age of 16 and 19 days in favour of group PI (from K by +7.1%, +6.9% and from PG by +5.9%, +5 8%, respectively, P<0.01) and at 21 days of age (from K by +6.2%, P<0.01). To find appropriate composition of creep feed for kits further studies are needed. PMID- 28633691 TI - Dietary gap assessment: an approach for evaluating whether a country's food supply can support healthy diets at the population level. AB - OBJECTIVE: Dietary diversity, and in particular consumption of nutrient-rich foods including fruits, vegetables, nuts, beans and animal-source foods, is linked to greater nutrient adequacy. We developed a 'dietary gap assessment' to evaluate the degree to which a nation's food supply could support healthy diets at the population level. Design/Setting In the absence of global food-based dietary guidelines, we selected the Dietary Approaches to Stop Hypertension (DASH) diet as an example because there is evidence it prevents diet-related chronic disease and supports adequate micronutrient intakes. We used the DASH guidelines to shape a hypothetical 'healthy' diet for the test country of Cameroon. Food availability was estimated using FAO Food Balance Sheet data on country-level food supply. For each of the seven food groups in the 'healthy' diet, we calculated the difference between the estimated national supply (in kcal, edible portion only) and the target amounts. RESULTS: In Cameroon, dairy and other animal-source foods were not adequately available to meet healthy diet recommendations: the deficit was -365 kcal (-1527 kJ)/capita per d for dairy products and -185 kcal (-774 kJ)/capita per d for meat, poultry, fish and eggs. Adequacy of fruits and vegetables depended on food group categorization. When tubers and plantains were categorized as vegetables and fruits, respectively, supply nearly met recommendations. Categorizing tubers and plantains as starchy staples resulted in pronounced supply shortfalls: -109 kcal (-457 kJ)/capita per d for fruits and -94 kcal (-393 kJ)/capita per d for vegetables. CONCLUSIONS: The dietary gap assessment illustrates an approach for better understanding how food supply patterns need to change to achieve healthier dietary patterns. PMID- 28633692 TI - Cross-border collaboration in tuberculosis prevention and care in Europe: can we do better? PMID- 28633693 TI - The role of pre-migration medical screening in high TB burden countries. PMID- 28633694 TI - Is it time to rethink the role of AFB smears? PMID- 28633695 TI - How should discordance between molecular and growth-based assays for rifampicin resistance be investigated? AB - Molecular tests to detect the presence of Mycobacterium tuberculosis and genetic polymorphisms in the rpoB gene conferring resistance to rifampicin (RMP) have become integral parts of tuberculosis diagnostics worldwide. These assays are often performed sequentially or in parallel to phenotypic drug susceptibility testing. Discordances between molecular and phenotypic tests invariably occur. Root causes range from pre-, post- and analytic errors to co-existence of non tuberculous mycobacteria, silent mutations, mutations outside the 81 base-pair RMP resistance-determining region, non-canonical mutations conferring increased minimal inhibitory concentrations below the critical concentration in some phenotypic drug susceptibility tests, and heteroresistance. Resolving discordant results is challenging. This guide aims to assist both clinicians and microbiologists in interpreting discordances by providing a structured approach to manage further investigations. Case scenarios are discussed, including the likelihood of occurrence. PMID- 28633696 TI - Cross-border collaboration for improved tuberculosis prevention and care: policies, tools and experiences. AB - As tuberculosis (TB) spreads beyond borders with people movements, several interventions ensuring the continuity of care are essential, although difficult to put in place in the absence of well-defined agreements allowing data sharing and easy referral of patients to appropriate health facilities. This article first sets out general principles for cross-border collaboration and continuity of care. It then presents a series of case studies. Policies and practices on cross-border collaboration in selected low-incidence countries (Australia, Italy, Norway, The Netherlands, the United Kingdom and the United States) are described and critically appraised. Details of the World Health Organization's (WHO's) European Respiratory Society TB Consilium for transborder migration and those of the Health Network's TBNet activities are described. With increasing population movement, including migrants and travellers, it is time to build on good practices and existing tools and to remove legal, financial and social barriers to ensure early diagnosis, full treatment and continuity of care across our world. Data sharing between the sending and the receiving countries is of utmost importance and must be conducted in line with privacy protection rules. Successful implementation of these interventions is key to being on track with the WHO's End TB strategy targets for 2030. PMID- 28633697 TI - Capacity strengthening through pre-migration tuberculosis screening programmes: IRHWG experiences. AB - Effective tuberculosis (TB) prevention and care for migrants requires population health-based approaches that treat the relationship between migration and health as a progressive, interactive process influenced by many variables and addressed as far upstream in the process as possible. By including capacity building in source countries, pre-migration medical screening has the potential to become an integral component of public health promotion, as well as infection and disease prevention, in migrant-receiving nations, while simultaneously increasing capabilities in countries of origin. This article describes the collaborative experiences of five countries (Australia, Canada, New Zealand, United Kingdom and the United States of America, members of the Immigration and Refugee Health Working Group [IRHWG]), with similar pre-migration screening programmes for TB that are mandated. Qualitative examples of capacity building through IRHWG programmes are provided. Combined, the IRHWG member countries screen approximately 2 million persons overseas every year. Large-scale pre-entry screening programmes undertaken by IRHWG countries require building additional capacity for health care providers, radiology facilities and laboratories. This has resulted in significant improvements in laboratory and treatment capacity, providing availability of these facilities for national public health programmes. As long as global health disparities and disease prevalence differentials exist, national public health programmes and policies in migrant-receiving nations will continue to be challenged to manage the diseases prevalent in these migrating populations. National TB programmes and regulatory systems alone will not be able to achieve TB elimination. The management of health issues resulting from population mobility will require integration of national and global health initiatives which, as demonstrated here, can be supported through the capacity building endeavours of pre-migration screening programmes. PMID- 28633698 TI - Feasibility of a streamlined tuberculosis diagnosis and treatment initiation strategy. AB - OBJECTIVE: To assess the feasibility of a streamlined strategy for improving tuberculosis (TB) diagnostic evaluation and treatment initiation among patients with presumed TB. DESIGN: Single-arm interventional pilot study at five primary care health centers of a streamlined, SIngle-saMPLE (SIMPLE) TB diagnostic evaluation strategy: 1) examination of two smear results from a single spot sputum specimen using light-emitting diode fluorescence microscopy, and 2) daily transportation of smear-negative sputum samples to Xpert(r) MTB/RIF testing sites. RESULTS: Of 1212 adults who underwent sputum testing for TB, 99.6% had two smears examined from the spot sputum specimen. Sputum was transported for Xpert testing within 1 clinic day for 83% (907/1091) of the smear-negative patients. Of 157 (13%) patients with bacteriologically positive TB, 116 (74%) were identified using sputum smear microscopy and 41 (26%) using Xpert testing of smear-negative samples. Anti-tuberculosis treatment was initiated in 142 (90%) patients with bacteriologically positive TB, with a median time to treatment of 1 day for smear positive patients and 6 days for smear-negative, Xpert-positive patients. CONCLUSION: The SIMPLE TB strategy led to successful incorporation of Xpert testing and rapid treatment initiation in the majority of patients with bacteriologically confirmed TB in a resource-limited setting. PMID- 28633699 TI - Migration histories of multidrug-resistant tuberculosis patients from the Thailand-Myanmar border, 2012-2014. AB - SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing public health threat in South-East Asia. TB is typically a disease of poverty and can be spread by infectious humans who migrate from one region to another. DESIGN: We interviewed 20 MDR-TB patients on the Thailand-Myanmar border with regard to their migration histories. Migration origins and destinations were mapped. RESULTS: All but one participant had a history of migration, and maps of migration ranges revealed wide geographic dispersal. Most described living and work conditions that could contribute to the spread of drug-resistant TB, including numerous contacts and crowded living quarters. CONCLUSION: Our results show that at least some migrant workers in the region carry MDR-TB, and indicate that this subgroup of the population is important with regard to the transmission of MDR-TB throughout the region. Migrants in this region come into contact with high numbers of people and may be able to spread the disease across wide geographic ranges. Access to diagnosis and treatment and socio-economic development are at least as important as any TB control measures, meaning that innovative and bold approaches that extend across international borders are needed to address these problems. PMID- 28633700 TI - Trends in drug-resistant tuberculosis after the implementation of the DOTS strategy in Shenzhen, China, 2000-2013. AB - SETTING: The DOTS strategy has been regarded as the most cost-effective way to stop the spread of tuberculosis (TB) since its launch by the World Health Organization. OBJECTIVE: To estimate the effects of DOTS by tracking long-term trends in multidrug-resistant TB (MDR-TB). DESIGN: A retrospective cohort study was conducted from 2000 to 2013 to analyse trends in resistance to anti tuberculosis drugs and the effect of DOTS-based treatment in Shenzhen, China, using the chi2 test. RESULTS: An overall MDR-TB rate of 4.2% was observed between 2000 and 2013, with an annual reduction of 0.16%. From 2000 to 2013, trends in resistance to isoniazid (INH), rifampicin (RMP) and MDR-TB declined significantly in new TB patients (P < 0.01), but not in retreatment cases. Sputum smear conversion rates after 2 months of treatment decreased significantly, in particular after 2007, in new and retreatment cases. CONCLUSION: INH and RMP resistance and MDR-TB rates declined significantly, suggesting that DOTS-based programmes were successful in reducing drug resistance in new cases but not in retreatment cases. The decreasing sputum smear conversion rates may have been due to an increase in the number of migrants. These two findings suggest that TB is unlikely to be completely eliminated by 2050 in Shenzhen. PMID- 28633701 TI - Management of child MDR-TB contacts across countries in the WHO European Region: a survey of current practice. AB - The World Health Organization European Region has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) in the world, resulting in many vulnerable children being exposed each year. Evidence for preventive therapy following MDR-TB exposure is limited and current guidance is conflicting. An internet-based survey was performed to determine clinical practice in this region. Seventy-two clinicians from 25 countries participated. Practices related to screening and decision-making were highly variable. Just over half provided preventive therapy for children exposed to MDR-TB; the only characteristic associated with provision was practice within the European Union (adjusted OR 4.07, 95%CI 1.33-12.5). PMID- 28633702 TI - Impact of isoniazid preventive therapy on the evaluation of long-term effectiveness of infant MVA85A vaccination. AB - SETTING: South Africa. OBJECTIVE: To evaluate the long-term effectiveness of infant modified vaccinia Ankara virus-expressing antigen 85A (MVA85A) vaccination against tuberculosis (TB). DESIGN: We analysed data from a double-blind randomised placebo-controlled Phase 2b MVA85A infant TB vaccine trial (2009 2012), with extended post-trial follow-up (2012-2014). Isoniazid preventive therapy (IPT) was provided by public health services according to national guidelines. The primary outcome was curative treatment for TB disease. Survival analysis and Poisson regression were used for study analysis. RESULTS: Total follow-up was 10 351 person-years of observation (pyo). Median follow-up age was 4.8 years (interquartile range 4.4-5.2). There were 328 (12%) TB cases. TB disease incidence was 3.2/100 pyo (95%CI 2.8-3.5) overall, and respectively 3.3 (95%CI 2.9-3.9) and 3.0 (95%CI 2.6-3.5)/100 pyo in the MVA85A vaccine and placebo arms. A total of 304 children (11%) received IPT, with respectively 880 and 9471 pyo among IPT and non-IPT recipients. There were 23 (7.6%) TB cases among 304 IPT recipients vs. 305 (12.9%) among 2374 non-IPT recipients (P = 0.008). IPT effectiveness was 85% (95%CI 76-91). CONCLUSION: Extended follow-up confirms no long-term effectiveness of infant MVA85A vaccination, but a six-fold reduction in TB risk can be attributed to IPT. National TB programmes in high TB burden countries should ensure optimal implementation of IPT for eligible children. PMID- 28633703 TI - Tuberculosis inequalities and socio-economic deprivation in Portugal. AB - OBJECTIVE: To analyse the geographical distribution of tuberculosis (TB) in Portugal and estimate the association between TB and socio-economic deprivation. METHODS: An ecological study at the municipality level using TB notifications for 2010-2014 was conducted. Spatial Bayesian models were used to calculate smoothed standardised notification rates, identify high- and low-risk areas and estimate the association between TB notification and the European Deprivation Index (EDI) for Portugal and its component variables. RESULTS: Standardised notification rates ranged from 4.41 to 76.44 notifications per 100 000 population. Forty-one high-risk and 156 low-risk municipalities were identified. There was no statistically significant association between TB notification rate and the EDI, but some of its variables, such as the proportion of manual workers and the percentage unemployed, were significantly and directly associated with TB notification, whereas the variable 'proportion of residents with low education level' showed an inverse relationship. CONCLUSION: Wide inequalities in TB notification rates were observed, and some areas continued to exhibit high TB notification rates. We found significant associations between TB and some socio economic factors of the EDI. PMID- 28633704 TI - Effect of Brazil's conditional cash transfer programme on tuberculosis incidence. AB - OBJECTIVE: To evaluate the impact of the Brazilian cash transfer programme (Bolsa Familia Programme, BFP) on tuberculosis (TB) incidence in Brazil from 2004 to 2012. DESIGN: We studied tuberculosis surveillance data using a combination of an ecological multiple-group and time-trend design covering 2458 Brazilian municipalities. The main independent variable was BFP coverage and the outcome was the TB incidence rate. All study variables were obtained from national databases. We used fixed-effects negative binomial models for panel data adjusted for selected covariates and a variable representing time. RESULTS: After controlling for covariates, TB incidence rates were significantly reduced in municipalities with high BFP coverage compared with those with low and intermediate coverage (in a model with a time variable incidence rate ratio = 0.96, 95%CI 0.93-0.99). CONCLUSION: This was the first evidence of a statistically significant association between the increase in cash transfer programme coverage and a reduction in TB incidence rate. Our findings provide support for social protection interventions for tackling TB worldwide. PMID- 28633705 TI - Household food insecurity is associated with low interferon-gamma levels in pregnant Indian women. AB - SETTING: Over 20% of tuberculosis (TB) cases during pregnancy occur in India. OBJECTIVE: To determine the association between household food insecurity and interferon-gamma (IFN-gamma) levels in pregnancy. DESIGN: Pregnant women in India were administered the Household Food Insecurity Access Scale (HFIAS) questionnaire and underwent an IFN-gamma release assay. Logistic regression was used to identify factors associated with food insecurity. RESULTS: Of 538 women, 60 (11%) had household food insecurity, 47 (78%) of which were moderate or severe food insecure. After mitogen stimulation, moderate or severe food insecure women had a median IFN-gamma concentration of 4.2 IU/ml (IQR 2.2-9.8) vs. 8.4 IU/ml (IQR 3.0-10) in women with no or mild food insecurity (P = 0.03). In multivariate analysis, higher IFN-gamma concentrations were associated with human immunodeficiency virus infection (OR 1.3, 95%CI 0.51-2.1, P = 0.001), and inversely associated with moderate or severe food insecurity (OR -1.6, 95%CI -2.9 to -0.27, P = 0.02) and the number of adults in the household (OR -0.08, 95%CI 0.16 to -0.01, P = 0.03). There was no association between food insecurity and IFN-gamma response to Mycobacterium tuberculosis antigen. CONCLUSION: Food insecurity in pregnancy is associated with low IFN-gamma levels. There was no association between food insecurity and IFN-gamma response to M. tuberculosis antigen, but our study was underpowered to detect this outcome. PMID- 28633706 TI - Depression and risk of tuberculosis: a nationwide population-based cohort study. AB - BACKGROUND: Studies on the association between depression and risk of tuberculosis (TB) are lacking. OBJECTIVE: To determine the association between depression and risk of TB. METHODS: From a nationwide database, patients with depression were identified to form the exposure cohort between 2003 and 2013. The control cohort comprised an equivalent number of subjects without any mood disorders, with each subject age- and sex-matched to a patient in the exposure cohort. The incidence of TB was identified in the exposure cohort and control cohort between 2003 and 2013. A multivariable Cox proportional hazards model was used to estimate the association between depression and the subsequent risk of TB. RESULTS: A total of 32 372 patients with depression and the same number of controls were identified. The risk of TB in the depression cohort was 2.63-fold (95%CI 1.74-3.96) higher than in the control cohort. When the depression was classified as 'mild' and 'severe', the risk of TB was proportional to depression severity. CONCLUSIONS: Patients with depression are at a higher risk for TB, and a dose-response relationship exists between depression and the subsequent risk of TB. PMID- 28633707 TI - Qualitative analysis of biological tuberculosis samples by an electronic nose based artificial neural network. AB - OBJECTIVE: To apply an e-nose system for monitoring headspace volatiles in biological samples from Egyptian patients with active pulmonary tuberculosis (TB) and healthy controls (HCs) and compare them with standard sputum analysis. DESIGN: The study population comprised 260 (140 males, 120 females) newly diagnosed TB patients and 240 (120 males, 120 females) HCs matched by age and socio-economic level admitted to hospitals specialising in chest diseases in Alexandria, Behera, Giza and Damietta Governorates, Egypt. Participants provided a history of TB and underwent clinical examinations, chest X-ray, and microbiological and e-nose analyses. Biological samples (blood, breath, sputum and urine) were collected. RESULTS AND CONCLUSION: Being a confirmed TB patient was directly proportional to e-nose 10-sensor responses. Principal component analysis clusters showed a clear distinction between TB and HC groups, with variances of 93%, 85%, 75% and 95% for blood, breath, sputum and urine samples, respectively. Overall accuracy, sensitivity and specificity of the artificial neural network (ANN) analysis for classifying samples were >99%. The e-nose successfully distinguished TB patients from HC participants for all measured biological samples with great precision. With urine samples gaining broader acceptance for clinical diagnosis, an e-nose-based ANN can be a very useful tool for low-cost mass screening and early detection of TB patients in developing countries. PMID- 28633708 TI - Once-daily dosing of amikacin for treatment of Mycobacterium abscessus lung disease. AB - SETTING: Tertiary referral centre, Samsung Medical Center, South Korea. OBJECTIVE: To evaluate the pharmacokinetic parameters and toxicities of once daily amikacin (AMK) dosing for lung disease due to Mycobacterium abscessus. DESIGN: A retrospective review of 48 patients with M. abscessus lung disease who received once-daily AMK for 4 weeks between January 2012 and June 2015. RESULTS: With a starting dose of 15 mg/kg/day and adjustment of AMK dose according to the peak serum level (Cmax), the Cmax target of 55-65 MUg/ml was achieved in 31.3% (15/48) of patients in the first week, 68.8% (33/48) in week 2, 91.7% (44/48) in week 3 and 95.8% (46/48) in week 4. Transient nephrotoxicity developed in 6.3% (3/48) of patients and ototoxicity in 25.0% (6/24), which was determined by audiogram as hearing loss, asymptomatic in five patients and tinnitus in one. Multivariate analysis revealed that the highest drug concentration 12 h after administration was significantly associated with the development of toxicities (adjusted odds ratio 1.862, P = 0.047). CONCLUSION: Our results suggest that once daily AMK for 4 weeks with a target Cmax of 55-65 MUg/ml can be used in patients with M. abscessus lung disease, with careful monitoring of toxicity. PMID- 28633709 TI - Primary pulmonary actinomycosis: a retrospective analysis of 145 cases in mainland China. AB - OBJECTIVE: To improve our understanding of pulmonary actinomycosis. METHODS: A retrospective analysis of 145 cases in mainland China was conducted. RESULTS: The male:female ratio was 2.7:1. Mean age at diagnosis was 48 years (+/- 12). Main symptoms were cough (87.6%), expectoration (40%), blood-stained sputum (37.2%), fever (26.9%), chest pain (24.8%) and haemoptysis (16.6%). Eighty-eight (60.7%) patients had no underlying disease. Only five patients received a correct initial diagnosis; 60 patients were misdiagnosed with lung cancer, followed by pulmonary tuberculosis (TB) and lung abscess. Most patients were diagnosed using surgical resection, transthoracic needle aspiration or flexible bronchoscopy. Sixty-seven patients received penicillin G, and one patient did not receive any antibiotics after surgery. The mean duration of treatment with antibiotics was 4.5 months (+/ 3.7). Overall, 110 (75.9%) patients were fully cured, 4 died, 1 was lost to follow-up, and a record of the prognosis was not available for 30 patients. Mean duration of follow-up was 26 months (+/- 32). CONCLUSION: Pulmonary actinomycosis is a rare bacterial infection and is often misdiagnosed as lung cancer or pulmonary TB. The definitive diagnosis depends on pathology; sulfur granules are suggestive, but not specific. Penicillin G is the standard treatment. The optimal duration of antibiotic treatment merits further investigation. PMID- 28633710 TI - Symptom-based screening of child TB contacts: defining 'symptomatic'. PMID- 28633711 TI - In reply. PMID- 28633712 TI - Use of inhaled corticosteroids for obstructive lung disease following anti tuberculosis treatment. PMID- 28633713 TI - ERRATUM. PMID- 28633714 TI - Three-Generation Family With Congenital Central Hypoventilation Syndrome and Novel PHOX2B Gene Non-Polyalanine Repeat Mutation. AB - ABSTRACT: PHOX2B non-polyalanine repeat mutation (NPARM) in patients with congenital central hypoventilation syndrome (CCHS) is generally considered to be associated with full-time ventilator dependence and severe autonomic nervous system dysfunction. We report a three-generation family with four individuals possessing a novel PHOX2B NPARM (c.245C > T) with variable phenotypes. This mutation was inherited in an autosomal dominant pattern with variable penetrance. The affected family members with CCHS have a milder phenotype than is typically expected with a NPARM. Two family members are ventilator dependent only during sleep and do not have Hirschsprung disease or neural crest tumors. One family member was asymptomatic until systemic hypertension developed during adulthood and another family member remains asymptomatic as an adult. Our findings emphasize the importance of monitoring adults with a PHOX2B NPARM who are considered asymptomatic in childhood. PMID- 28633716 TI - Sense and Sensitivity: Obstructive Sleep Apnea, Morning Blood Pressure, and Occult Hypertension. PMID- 28633717 TI - Aerophagia During CPAP for OSA: The Case for Auto-CPAP and Nasal Mask. PMID- 28633715 TI - Restless Legs Syndrome and Sleep-Wake Disturbances in Pregnancy. AB - STUDY OBJECTIVES: To estimate the association of restless legs syndrome (RLS) and its frequency with sleep-wake disturbances in pregnancy. METHODS: A cohort of 1,563 women in their third trimester of pregnancy were recruited from prenatal clinics between March 2007 and December 2010. Demographic, pregnancy, and delivery data were extracted from medical records and sleep information was collected with questionnaires. To diagnose RLS, we used standardized criteria of RLS symptoms and frequency that were developed by the International Restless Legs Study Group. Logistic regression models were constructed to investigate the association of RLS and its frequency with sleep-wake disturbances (poor sleep quality, daytime sleepiness, poor daytime function) and delivery outcomes. RESULTS: Overall 36% of the pregnant women had RLS, and half had moderate to severe symptoms. Compared to women without RLS, those with RLS were more likely to have poor sleep quality (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.7 2.9), poor daytime function (OR 1.9, 95% CI 1.4-2.4), and excessive daytime sleepiness (OR 1.6, 95% CI 1.3-2.0). A dose-response relationship also was evident between RLS frequency and each of the sleep-wake disturbances. There was no evidence for any association between RLS and delivery outcomes. CONCLUSIONS: RLS is a significant contributor to poor sleep quality, daytime sleepiness, and poor daytime function, all common and often debilitating conditions in pregnancy. Obstetric health care providers should be aware of these associations and screen women for RLS. COMMENTARY: A commentary on this article appears in this issue on page 857. PMID- 28633718 TI - Shaking Up Perspectives of Restless Legs Syndrome in Pregnancy. PMID- 28633719 TI - A Case of Recurrent Hypersomnia With Autonomic Dysfunction. AB - ABSTRACT: We report the case of a 50-year-old man with disabling recurrent hypersomnia with autonomic instability due to catatonia in the setting of atypical bipolar disorder. Treatment with valproic acid for bipolar disorder resulted in complete resolution of symptoms. PMID- 28633720 TI - Evaluation of Continuous Negative External Pressure (cNEP) for the Treatment of Obstructive Sleep Apnea: A Pilot Study. AB - STUDY OBJECTIVES: To determine if the application of continuous negative external pressure (cNEP) is effective and safe in individuals with obstructive sleep apnea (OSA) during an overnight in-laboratory sleep study. METHODS: A prospective, open label pilot study in subjects with documented OSA recruited from the patient population at one sleep clinic. The intervention was application and titration of cNEP during overnight polysomnography. RESULTS: Of the 15 subjects studied (mean apnea-hypopnea index [AHI] at baseline, 43.9 events/h), 13 (87%) were responders to cNEP: 9 had an excellent response (AHI < 5 events/h) and 4 had a partial response (AHI < 50% baseline and < 15 events/h). Three minor, self-limited adverse events occurred, which appeared related to contact pressure of the cNEP device on the skin. CONCLUSIONS: In this pilot study, cNEP appears to be safe and effective during short-term use in subjects with OSA. Further studies are warranted. PMID- 28633722 TI - Characterization of Patients Who Present With Insomnia: Is There Room for a Symptom Cluster-Based Approach? AB - STUDY OBJECTIVES: This study examined empirically derived symptom cluster profiles among patients who present with insomnia using clinical data and polysomnography. METHODS: Latent profile analysis was used to identify symptom cluster profiles of 175 individuals (63% female) with insomnia disorder based on total scores on validated self-report instruments of daytime and nighttime symptoms (Insomnia Severity Index, Glasgow Sleep Effort Scale, Fatigue Severity Scale, Beliefs and Attitudes about Sleep, Epworth Sleepiness Scale, Pre-Sleep Arousal Scale), mean values from a 7-day sleep diary (sleep onset latency, wake after sleep onset, and sleep efficiency), and total sleep time derived from an in laboratory PSG. RESULTS: The best-fitting model had three symptom cluster profiles: "High Subjective Wakefulness" (HSW), "Mild Insomnia" (MI) and "Insomnia Related Distress" (IRD). The HSW symptom cluster profile (26.3% of the sample) reported high wake after sleep onset, high sleep onset latency, and low sleep efficiency. Despite relatively comparable PSG-derived total sleep time, they reported greater levels of daytime sleepiness. The MI symptom cluster profile (45.1%) reported the least disturbance in the sleep diary and questionnaires and had the highest sleep efficiency. The IRD symptom cluster profile (28.6%) reported the highest mean scores on the insomnia-related distress measures (eg, sleep effort and arousal) and waking correlates (fatigue). Covariates associated with symptom cluster membership were older age for the HSW profile, greater obstructive sleep apnea severity for the MI profile, and, when adjusting for obstructive sleep apnea severity, being overweight/obese for the IRD profile. CONCLUSIONS: The heterogeneous nature of insomnia disorder is captured by this data-driven approach to identify symptom cluster profiles. The adaptation of a symptom cluster-based approach could guide tailored patient-centered management of patients presenting with insomnia, and enhance patient care. PMID- 28633721 TI - Allergic and Non-Allergic Rhinitis Are Common in Obstructive Sleep Apnea but Not Associated With Disease Severity. AB - STUDY OBJECTIVES: Several studies have suggested that rhinitis contributes to the pathogenesis of obstructive sleep apnea (OSA). We aimed to investigate the prevalence and influence of allergic rhinitis (AR) and non-allergic rhinitis (NAR) on severity of OSA. METHODS: Two hundred forty patients with OSA confirmed by standardized polysomnography were assessed for presence of AR and NAR, using validated questionnaires and skin prick tests. Data comparison was carried out by using chi-square test, analysis of variance, and least significant difference test. Associations between severity of OSA and rhinitis, age, sex, and body mass index were assessed with ordinal logistic regression analysis. RESULTS: The prevalence of AR and NAR among patients with OSA was 27.1% and 28.7%, respectively, with no significant differences in the severity of rhinitis. Ordinal logistic regression analysis showed AR and NAR were not the risk factors for severity of OSA. There were significant differences of polysomnography parameters in sleep efficiency (79.7 +/- 2.0 versus 85.2 +/- 1.4 between AR and NAR; 79.7 +/- 2.0 versus 87.2 +/- 1.4 between AR and no-rhinitis) and arousal index (36.8 +/- 4.1 versus 24.7 +/- 3.5 between AR and no-rhinitis). Patients with NAR had lower average arterial oxygen saturation (91.9 +/- 0.6 versus 94.0 +/- 0.6) and minimal arterial oxygen saturation (70.6 +/- 1.7 versus 77.3 +/- 1.8), compared with subjects categorized as no-rhinitis. CONCLUSIONS: This study suggests that despite a comparatively high prevalence in patients with OSA, the presence or severity of AR or NAR does not influence the severity of OSA; however, rhinitis may significantly disturb sleep in patients with OSA. PMID- 28633723 TI - Validated Measures of Insomnia, Function, Sleepiness, and Nasal Obstruction in a CPAP Alternatives Clinic Population. AB - STUDY OBJECTIVES: Although efficacious in the treatment of obstructive sleep apnea (OSA), continuous positive airway pressure (CPAP) can be difficult to tolerate, with long-term adherence rates approaching 50%. CPAP alternatives clinics specialize in the evaluation and treatment of CPAP-intolerant patients; yet this population has not been studied in the literature. To better understand these patients, we sought to assess insomnia, sleep-related functional status, sleepiness, and nasal obstruction, utilizing data from validated instruments. METHODS: After approval from the Emory University Institutional Review Board, a retrospective chart review was performed from September 2015 to September 2016 of new patient visits at the Emory CPAP alternatives clinic. Patient demographics and responses were recorded from the Insomnia Severity Index, Functional Outcomes of Sleep Questionnaire-10 (FOSQ-10), Epworth Sleepiness Scale, and Nasal Obstruction Symptom Evaluation questionnaires. RESULTS: A total of 172 patients were included, with 81% having moderate-severe OSA. Most of the patients demonstrated moderate-severe clinical insomnia and at least moderate nasal obstruction. FOSQ-10 scores indicated sleep-related functional impairment in 88%. However, most patients did not demonstrate excessive daytime sleepiness. CONCLUSION: This patient population demonstrates significant symptomatology and functional impairment. Because of the severity of their OSA, they are at increased risk of complications. In order to mitigate the detrimental effects of OSA, these significantly impacted patients should be identified and encouraged to seek CPAP alternatives clinics that specialize in the treatment of this population. PMID- 28633724 TI - Change in End-Expiratory Lung Volume During Sleep in Patients at Risk for Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: As lung volume decreases radial traction on the upper airway is reduced, making it more collapsible. The purpose of this study was to measure change in end-expiratory lung volume (EELV) following sleep onset and to evaluate the relationship between change in EELV and sleep-disordered breathing. METHODS: Twenty subjects underwent overnight polysomnography, of whom 14 (70%) had obstructive sleep apnea (OSA). Change in EELV was measured throughout the night using magnetometry. Sleep was staged and respiratory events scored using American Academy of Sleep Medicine criteria. An additional 10 subjects had change in EELV measured simultaneously by magnetometer and spirometer while awake. RESULTS: In the subjects studied while awake, change in EELV calculated from magnetometer data correlated very strongly (r = 0.89, P < .001) with that obtained by spirometry. In the 20 subjects who underwent polysomnography, there was a decline in EELV for sleep stages N1, N2, N3, and R (REM sleep); 17.9 +/- 121.0 mL (mean +/- standard deviation), 228.5 +/- 151.8 mL, 198.1 +/- 122.1 mL, and 316.7 +/- 131.9 mL, respectively. Mean EELV reduction during stage R sleep doubled that noted during non-stage R sleep (316.7 +/- 131.9 mL versus 150.9 +/- 89.7 mL, respectively) (P < .001). The difference in EELV between non-stage R and stage R sleep inversely correlated with mean oxygen saturation (r = -0.56, P = .06). EELV reduction in individuals with moderate and severe OSA was greater than in those with mild SDB but did not reach statistical significance. CONCLUSIONS: Magnetometry provides a precise, unobtrusive, and continuous means to study lung volume changes during sleep. EELV declines from sleep onset, reaching its nadir during stage R sleep. The reduction in EELV in stage R sleep was associated with lower mean oxygen saturation but was not associated with greater sleep-disordered breathing. PMID- 28633725 TI - Well-Differentiated Neuroendocrine Tumor-A Low b-Grade Tumor's Aggressive Course and Dismal Outcome: A Case Report. AB - INTRODUCTION: Incidence of well-differentiated neuroendocrine tumors (NETs) of the colon and rectum is increasing and is now approximately 1 per 100,000 in the US. NETs are either well-differentiated (indolent) or poorly differentiated (aggressive). The majority of these tumors are found incidentally during screening colonoscopies and rarely are associated with symptoms of hormonal syndrome, even during the advanced stage. Metastatic well-differentiated NETs of the colon and rectum are incurable, hard to treat, and associated with a poor prognosis and survival rates similar to colorectal adenocarcinoma survival. CASE PRESENTATION: A 56-year-old man presented to our clinic with right-sided weakness and a 40-pound weight loss during the previous 2 months. A neurologic examination was remarkable for atrophy of the right trapezius muscle and decreased strength in the right upper extremity. Imaging revealed extensive blastic and lytic lesions involving the axial skeleton, a large rectal mass, a large necrotic nodal mass extending from the left iliac region to the level of the left renal veins, and multiple necrotic liver metastasis. Liver lesion fine-needle aspiration findings were consistent with metastatic well-differentiated neuroendocrine carcinoma. DISCUSSION: This case illustrates how a low-grade tumor can have an aggressive course with poor outcomes. Metastatic well-differentiated NETs of the colon and rectum remain difficult to treat because evidence is scarce. More research is needed on this topic. PMID- 28633726 TI - Small-Bowel Intussusception in a Pregnant Woman: A Case Report. AB - INTRODUCTION: Intussusception usually is associated with children, rarely with adults. CASE PRESENTATION: A 42-year-old pregnant woman (29 weeks' gestation) reported mild pain in the upper aspect of the abdomen after an intense physical effort. Ultrasound examination found a normally evolving pregnancy and a bowel obstacle, without bowel distention. Because it was not a surgical emergency at the time of evaluation, she was sent to the hospital's Obstetrics Department. The patient's symptoms worsened the next day. Ultrasound examination revealed dilated bowel loops and free fluid. Strangulated epigastric hernia was suspected. Computed tomography was not performed. Exploratory laparotomy revealed a small bowel intussusception, which was successfully manually reduced, and no leading point was found. Four days later, she delivered a premature baby boy. Two days later the necrotized reduced ileal loop had to be surgically removed because of the patient's altered status. After this procedure, the patient's recovery was uneventful. DISCUSSION: To our knowledge, this is the first case of small-bowel intussusception in a pregnant woman reported in the literature. PMID- 28633728 TI - Bilateral Large Pneumothoraxes Following Implantable Cardioverter-Defibrillator Generator Change: A Case Report of an Uncommon Event Complicating a Common Procedure. AB - INTRODUCTION: A bilateral large spontaneous pneumothorax to our knowledge has never been reported after a device implantation. We report an unusual case of a patient developing spontaneous bilateral large pneumothoraxes after an implantable cardioverter-defibrillator generator and lead revision without evidence of any obvious traumatic cardiac injury. CASE PRESENTATION: A 79-year old white man was scheduled for implantable cardioverter-defibrillator generator change and addition of an atrial lead. Approximately one hour after the procedure, he suddenly went into respiratory distress with profuse sweating, and pallor with falling oxygen saturation and blood pressure. Chest x-ray showed bilateral large pneumothoraxes. DISCUSSION: In our literature search, we found no reports of large bilateral pneumothorax in the absence of any traumatic cardiac or lung injury. Rupture of bilateral pleura during subclavian access or presence of pleuropleural communication or a right atrial microperforation could be possible causes. PMID- 28633729 TI - Image Diagnosis: Bronchial Anthracofibrosis-A Bronchoscopic Diagnosis. PMID- 28633730 TI - Lessons Learned in War. PMID- 28633731 TI - Image Diagnosis: Multivessel Percutaneous Coronary Intervention in Dextrocardia: Success with Usual Techniques in a Case of Mirror-Image Heart. PMID- 28633732 TI - To Err is Human: Can American Medicine Learn from Past Mistakes? AB - The history of medicine includes many errors. Some persisted for decades and caused great harm. Several are highlighted in this article, including the mythical thymic diseases: thymic asthma and status thymicolymphaticus. Some medical mistakes, such as the diet-heart hypothesis of Ancel Keys, continue to cause harm. To avoid future errors and their associated harm, I suggest a cultural shift encouraging professional humility and greater questioning of medical dogma. Medical education focused on teaching students this history may help with this cultural shift. PMID- 28633733 TI - Rituximab in the management of juvenile pemphigus foliaceus. AB - BackgroundPemphigus foliaceus (PF) is a blistering disorder most commonly presenting in middle age. As PF is restricted to the superficial epidermis, it is considered more benign than other pemphigus diseases. However, progression to severe disease is not uncommon. Although rituximab's efficacy has been well documented in adults with refractory PF, little data is available on its role in adolescents.PurposeWe describe a patient with juvenile PF treated with rituximab and review the literature for similar cases.MethodsPubMed was searched for the terms: antibody, B cells, blistering, CD20, foliaceus, juvenile, pemphigus, rituximab, immunosuppression. As the first reported case of rituximab treated pemphigus was in 2001, only cases from 2001 and after were included. Juvenile PF was defined as disease diagnosis between ages 12-17.ResultsFive cases have been reported. The indication for rituximab in most cases was refractory PF unresponsive to systemic glucocorticoids and non-steroidal adjuvant therapies. All cases demonstrated significant improvement or complete remission and most experienced no adverse events.ConclusionsRituximab appears to be both well tolerated and efficacious for refractory juvenile PF. Therefore, it may be considered for severe cases of PF to avoid side effects associated with conventional glucocorticoid therapy. PMID- 28633734 TI - Cutaneous HIV-associated Kaposi sarcoma: a potential setting for management by clinical observation. AB - Kaposi sarcoma (KS) is a malignancy of viral etiology whose course ranges from cutaneous limited lesions to fulminant disease with multi-organ involvement. Four clinical variants of the disease exist: classic, endemic, iatrogenic, and epidemic. Iatrogenic and epidemic variants of Kaposi sarcoma develop in the setting of immune suppression. Transplant recipients who develop iatrogenic KS typically demonstrate improvement of lesions following de-escalation of immunosuppressive therapy. Similarly, HIV-infected patients who begin highly active antiretroviral therapy (HAART) experience immune reconstitution, which can induce KS regression. We describe two patients with varying clinical outcomes of cutaneous-limited HIV-associated KS after immune reconstitution with HAART. We propose that immune reconstitution with HAART, followed by clinical and radiographic surveillance for disease progression, may be an appropriate initial management strategy for limited cutaneous HIV-associated KS. In patients with more extensive disease at presentation or failure of HAART alone, antineoplastic therapy should be instituted. PMID- 28633735 TI - Angiolymphoid hyperplasia with eosinophilia of the nail unit. AB - Angiolymphoid hyperplasia with eosinophilia (ALHE) is a distinctive lymphocyte rich vasoformative proliferation comprising epithelioid-appearing endothelial cells with partially canalized capillary vessels in a lymphohistiocytic and eosinophil rich environment. ALHE presents clinically as single or multiple pink brown dome-shaped papules or nodules, most commonly on the ear and peri-auricular area, followed by the face, and scalp. ALHE involving the subungual unit is rare with only 5 previously reported cases and all involved the underlying bone. The authors describe a case of a painful subungual nodule of the left 1st fingernail in a 48-year-old woman. An excisional biopsy was performed confirming a diagnosis of ALHE. There was no bone involvement and immediately following excision of the tumor, there was complete resolution of her symptoms. Our patient's presentation expands upon the clinical and histopathological spectrum of subungual ALHE. PMID- 28633736 TI - Klippel-Trenauney syndrome with axillary hyperhidrosis. AB - Klippel-Trenaunay syndrome (KTS) is a rare, clinically variable congenital disorder involving capillary malformations, soft tissue or bone hypertrophy, and venous malformations or varicose veins. We report a 28-year-old man who presented with a hypertrophic right arm as well as markedly increased ipsilateral axillary hyperhidrosis and erythematous patches on the back, chest, and arm. This case of KTS is unusual because our patient presented with a markedly increased unilateral axillary hyperhidrosis ipsilateral to the hypertrophic limb. PMID- 28633737 TI - Linear verrucous hemangioma of the upper limb: a rare case. AB - Verrucous hemangioma is a rare, congenital vascular malformation of the cutaneous and subcutaneous tissue. It is usually present at birth and gradually increases in size and number with age; occasionally it presents in later adulthood. It has a predilection for the lower extremity and usually presents as warty or hyperkeratotic, bluish and partly confluent papules and plaques. Verrucous hemangioma occurring in a linear pattern is an even more uncommon presentation and very few cases have been reported. We report a boy with verrucous hemangioma localized to the left upper extremity in a linear pattern. We also discuss management. PMID- 28633738 TI - Sebaceous carcinoma on the arm of a 10-year-old girl. AB - We report a case of a 10 year-old girl diagnosed with sebaceous carcinoma of the posterior left arm. The presented case reviews the histopathological and immunohistochemical characteristics of this malignancy, including a review of the literature in pediatric patients regarding prognosis and treatment. Sebaceous carcinoma is a malignant neoplasm with sebaceous differentiation, typically occurring in the sixth-to-seventh decades of life. It most commonly arises in the periocular region. It is extremely rare in the pediatric population. PMID- 28633740 TI - Parvovirus B19 infection in an adult presenting with connective tissue disease like symptoms: a report of the clinical and histological findings. AB - Parvovirus B19 infections in adults are usually associated with nonspecific and mild symptoms. However, cases presenting with a lupus-like syndrome have been described, leading to the hypothesis that parvovirus infection can induce connective tissue disease. Various histopathologic features of cutaneous manifestations of parvovirus have been reported, including features which overlap with those of connective tissue disease. Herein, we discuss an unusual case of Parvovirus B19 infection in a middle-aged woman. The biopsy results showed granulomatous vasculitis and were consistent with the previously described superantigen id reaction. This case demonstrates that infectious causes should be considered in the differential diagnosis for granulomatous vasculitis and clinicopathologic correlation is required for accurate diagnosis. We also provide a review of the literature highlighting the possible role of parvovirus in induction of a connective tissue disease-like presentation. PMID- 28633739 TI - Autoimmune progesterone dermatitis presenting as fixed drug eruption: a case report. AB - Autoimmune progesterone dermatitis (APD) is a rare disorder characterized by periodic skin lesions that erupt during the luteal phase of the menstrual cycle. Clinical manifestations of APD is caused by an unusual allergy to progesterone and has a wide range of clinical manifestations from eczema and urticaria to angioedema and erythema multiforme. A 46-year-old woman described recurrent, round erythematous plaques on the lower lip, both forearms and buttocks. These skin eruptions waxed and waned for 10 months, reoccurring 3-4 days before menstruation. Based on her medical history and physical examination, APD was suspected and the progesterone challenge test showed positive results. After treatment with oral prednisolone (30 mg/day) before menstruation, the severity of eruptions decreased dramatically but recurrence did not cease completely. PMID- 28633741 TI - High-frequency ultrasound features in a case of gouty panniculitis. AB - Gouty panniculitis is caused by the deposition of urate crystals in the subcutaneous tissue, accompanied by a lobular panniculitis. It presents as subcutaneous nodules, most commonly located on the lower extremities. Being an unusual clinical presentation of gout, the sonographic findings of gouty panniculitis have been scarcely described in the literature. Our report describes the ultrasound features we found in a case of gouty panniculitis and the usefulness of this technique for diagnosis and monitoring of this disease. PMID- 28633742 TI - Cutaneous varicella zoster virus infection following zoster vaccination: report of post-vaccination herpes zoster skin infection and literature review of zoster vaccination efficacy and guidelines. AB - : BackgroundHerpes zoster vaccine is currently recommended in the United States for immune competent individuals >=60 years. The efficacy of the herpes zoster vaccine decreases with age and with time following vaccination.PurposeAn elderly man with herpes zoster following vaccination is described. The guidelines for vaccination and issues regarding re-vaccination are reviewed. METHODS: PubMed was used to search the following terms: efficacy, elderly, herpes zoster, herpes zoster incidence, herpes zoster recurrence, and vaccination. The papers and relevant citations were reviewed. The clinical features of a patient with post vaccination herpes zoster skin infection are presented; in addition, vaccine efficacy and guidelines are reviewed.ResultsA 91-year-old man, vaccinated for herpes zoster 10 years earlier, presented with crusted erosions on his face corresponding to the area innervated by the ophthalmic division of the left trigeminal nerve. Evaluation using polymerase chain reaction confirmed the diagnosis of herpes zoster.ConclusionsHerpes zoster vaccine decreases in efficacy with both age and number of years following vaccination. Therefore, booster shots or revaccination in the older population may be of benefit. PMID- 28633743 TI - Lichen sclerosus et atrophicus: atypical case simulating lichen planus. AB - Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory dermatosis, characterized by shiny, atrophic, hypochromic papules with a predilection for the genital and perineal skin. Extragenital involvement may occur, but is rare in the isolated form. LSA more commonly affects prepubertal and postmenopausal women. We describe an unusual case of isolated extragenital LSA, restricted to the wrists and mimicking lichen planus. PMID- 28633744 TI - Examining the race-specific prevalence of hidradenitis suppurativa at a large academic center; results from a retrospective chart review. AB - Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating disease of unknown etiology. HS can occur in people of all ethnicities and ages, and affects approximately 3-4% of the United States. To date, few studies have specifically examined the race prevalence of HS; further epidemiological research is needed to identify specific trends among HS and its racial predilections. At our center, 1.3% of African-American patients were seen for HS, compared to 18% of Caucasian patients (p<0.05), and the percent ratio of African-American versus Caucasian patients with HS was 7.22:1. Our number ratio of African-American patients versus Caucasian patients with HS was 1.19:1. Studies performed at Henry Ford Medical Center and University of Pittsburgh report ratios of 1.64:1 and 1.98:1 respectively. These data support study trends suggesting HS is more common among patients of African-American descent. A large, population-based study across the United States is needed to better assess the associations between ethnicity and HS. Examining this patient population has the potential to improve our understanding of HS pathophysiology, and will enable clinicians to better manage patients with this disease. PMID- 28633745 TI - Carcinoma hemorrhagiectoides: case report of an uncommon presentation of cutaneous metastatic breast carcinoma. AB - In most cases, cutaneous metastases develop after the diagnosis of the primary internal malignancy has been established, but sometimes they can be discovered earlier or simultaneously. We describe a case of a 90-year-old woman who presented to the emergency room in poor general condition, with cutaneous lesions characterized by hot, infiltrated, violaceous and erythematous plaques involving the left chest wall. The clinical and histopathological findings were consistent with the recently described variant of inflammatory cutaneous metastatic carcinoma named carcinoma hemorrhagiectoides. Microscopic examination demonstrated extensive infiltration of the dermis by tumor cells as well as intralymphatic involvement by neoplastic cells. This is a very rare presentation of cutaneous metastasis from breast cancer. PMID- 28633746 TI - Extragenital bullous lichen sclerosus on the anterior lower extremities: report of a case and literature review. AB - Lichen sclerosus (LS) is a benign, chronic, inflammatory skin disease with a predilection for the anogenital region in women. Although males can also be affected, the ratio of female to male incidence has been reported to be as high as 6-10:1 and possesses a bimodal age distribution of pre-pubertal girls and postmenopausal women [1, 2]. Affected skin usually demonstrates polygonal papules that coalesce into porcelain white plaques and can be associated with edema, telangiectasias, and comedo-like plug formation [3]. Lichen sclerosus can be debilitating for some patients causing significant pruritus, pain, dysuria, and dyspareunia [4]. Rarely, lichen sclerosus appears in various extragenital areas, although most cases are relatively asymptomatic [3]. Even more uncommonly, as displayed in this case report of a 69-year-old woman, LS can present extragenitally with a bullous or hemorrhagic appearance [5]. PMID- 28633747 TI - Trichomycosis axillaris dermoscopy. AB - Trichomycosis axillaris is a common but underdiagnosed condition of the skin. The dermoscopic image of this disease is not previously described in the scientific literature. We believe that dermoscopy is a convenient and interesting diagnostic method that may aid in the diagnosis. PMID- 28633748 TI - Multiple papulonodular lesions on central area of the face: what is your diagnosis? AB - A healthy 31-year-old woman presented with a 20-year history of asymptomatic skin colored papules and nodules on the central area of the face. Her maternal grandmother, aunts, mother, and sister also had similar lesions. Clinical, histopathological, and genetic features allowed the diagnosis of multiple familial trichoepithelioma. The patient and family were referred to the genetic department for genetic counselling. Close follow-up for the possibility of secondary basal cell carcinoma is warranted. PMID- 28633749 TI - Lichen planus pigmentosus in a blaschkoid distribution. AB - Lichen planus pigmentosus is a pigmentary disorder of unknown etiology, with diffuse hyperpigmentation of sun-exposed areas, more commonly seen in some ethnic and racial groups. We report an unusual case of lichen planus pigmentosus in a 40 year-old man with Fizpatrick type III skin that was present in a blaschkoid distribution on the trunk, a distribution that has been rarely reported. This unique presentation of lichen planus pigmentosus may contribute to better understanding of the etiology, as the blaschkoid distribution may reflect underlying cutaneous mosaicism that renders those cells more susceptible to an insult that results in lichen planus pigmentosus. This disorder should be considered in the differential diagnosis of macular hyperpigmentation, especially in those from more commonly affected ethnic and racial groups, even when the distribution is atypical and in the absence of history of sun exposure. PMID- 28633750 TI - Evaluating cultural competency and patient satisfaction in an urban dermatology clinic. AB - Cultural competency continues to gain increased attention in medicine. Not only does it play a significant role in the delivery of health care and patient outcomes, but it also remains a major determinant of patient satisfaction. This study investigated how patients in an urban dermatology clinic rated their satisfaction with cultural competency. Compared to White patients, satisfaction scores were greater for Hispanic or Latino patients and less for Asian patients, while there was no significant difference for Black or African American patients. There were clear differences in patient satisfaction rates of various dimensions of cultural competency. A follow-up study with a larger sample size is needed for closer examination into the conclusions. PMID- 28633751 TI - Use of a punch tool for paring plantar warts in an "awl-like" manner. AB - Paring is useful for both diagnosis and treatment of plantar warts. Paring techniques generally involve scalpel blades, abrasive tools, or curettes. However, these tools do not permit the use of an "awl-like" carving technique of the wart afforded by using a punch biopsy tool. We have found this technique to be associated with greater precision and safety, as well as potentially increased efficacy compared to traditional methods. PMID- 28633752 TI - Rituximab administration in a patient with pemphigus vulgaris following reactivation of occult hepatitis B virus infection. AB - Immunosuppressive drugs are the milestone of treatment of autoimmune diseases, but they can lead to serious complications, including hepatitis B virus reactivation in HBV carriers as well as in patients with occult HBV infection (OBI). A 36-year-old man with OBI was diagnosed with pemphigus vulgaris. He was prescribed prednisolone and his hepatitis B surface antigen turned positive. Viral replication was successfully controlled by lamivudine and adefovir. Mycophenolate mofetil and intravenous immunoglobulin were not effective in controlling the pemphigus vulgaris. The patient received rituximab 500 mg weekly for four weeks and went into remission without any adverse effect. He safely received another course of rituximab after a relapse one year later. In conclusion, testing for hepatitis B core antibody should be considered mandatory, in addition to HBsAg, for the screening of pemphigus patients to detect rare cases of OBI before starting therapy. Furthermore, rituximab may in some cases be safely used in HBV carriers using antivirals concomitantly. PMID- 28633753 TI - Tumor necrosis factor-induced alopecia: alternative pathology and therapy. AB - Tumor necrosis factor (TNF) inhibitors are used to treat Crohn disease and psoriasis. Although they are typically well tolerated, adverse effects include the development of alopecia, and paradoxically, psoriatic lesions. We recently described a woman with Crohn disease who developed alopecia and scalp psoriasis during infliximab therapy. After discontinuing infliximab and beginning oral and topical therapies, her alopecia completely resolved. We compared our experience with that of the Craddock et al. who described a woman with Crohn disease and alopecia secondary to adalimumab therapy. Although the authors described typical histopathologic features of TNF inhibitor-induced alopecia, including decreased sebaceous glands, psoriasiform changes, superficial and deep perifollicular infiltrate of peribulbar lymphocytes, prominent plasma cells, and variable eosinophils, we observed atypical findings that included chronic folliculitis and perifolliculitis with dermal scarring and naked hair shafts in the dermis - reminiscent of folliculitis decalvans. Both patients experienced a complete recovery; however, Craddock et al. described continuing adalimumab therapy and using intralesional triamcinolone acetonide whereas our patient discontinued infliximab therapy, used a combination of topical scalp therapies including betamethasone lotion and mineral oil overnight under occlusion, and began oral minocycline. In conclusion, various histopathologies are observed with TNF inhibitor induced alopecia and multiple, effective, therapeutic avenues exist for this affliction. PMID- 28633754 TI - Total body skin examination adherence among young adults with an increased risk for skin cancer. AB - Although ultraviolent radiation exposure and skin cancer rates are rising in the US, there is not a consistent national message calling for routine total body skin examinations (TBSE) by a healthcare provider. This pilot study examined TBSE rates among adults at an increased risk for skin cancer (history of sunburn, indoor tanning use, excessive UV exposure, poor sunscreen use). Overall skin cancer prevention behaviors were insufficient among respondents (n=953) and only a quarter of respondents considered at an increased risk for skin cancer reported a TBSE. White, older students with light skin who regularly use sunscreen were significantly more likely to report a TBSE. These findings highlight the need for a national study examining TBSE across the lifespan among high-risk individuals. PMID- 28633756 TI - Immunotherapy: The Wave of the Future in Bladder Cancer? AB - Urothelial cell carcinoma (UC) is one of the most common cancers and one of the most deadly. Metastatic UC is particularly hard to treat, because it is typically diagnosed when patients are elderly and have medical comorbidities. Many patients with metastatic UC are unable to receive cisplatin-based chemotherapy, due to older age at diagnosis and comorbidities, and even when platinum chemotherapy can be administered, it has limited success in prolonging survival. Recently, improved understanding of molecular targets and immunologic characteristics of urothelial tumor cells has resulted in new therapeutic approaches that may help optimize first- and second-line therapy. The most exciting of these approaches is inhibition of cytotoxic T-lymphocyte-associated antigen 4 or programmed cell death protein 1. These so-called "immune checkpoint" proteins are negative regulators of T-cell immune function, and inhibiting these proteins results in increased activation of the immune response to tumors. Two checkpoint inhibitors, atezolizumab and nivolumab, are now approved by the Food and Drug Administration as second-line therapy for advanced UC, and a wealth of clinical trials of these and other agents are ongoing. This review shows how oncology clinicians can incorporate checkpoint inhibitors into the management of patients with locally advanced or metastatic UC. It also introduces other forms of immunotherapy that are being investigated in bladder cancer: antibody-drug conjugates, vaccines, adoptive immunotherapy, and recombinant Bacillus Calmette-Guerin. PMID- 28633757 TI - The relationship between circulating mitochondrial DNA and inflammatory cytokines in patients with major depression. AB - BACKGROUND: Although inflammatory cytokines are established biomarkers of mood disorders, their molecular mechanism is not known. We hypothesized that circulating mitochondrial DNA (mtDNA) contributes to inflammation and could be used as biomarkers. We investigated if circulating mtDNA level is associated with inflammatory cytokines and can be used as a biomarker of mood disorders. METHODS: Plasma mtDNA concentration was measured with real-time quantitative PCR targeting two regions of the mtDNA and plasma levels of four cytokines (GM-CSF, IL-2, IL-4, and IL-6) were measured with a multiplex immunoassay method in 109 patients with major depressive disorder (MDD). The most significantly correlated cytokine was verified with an enzyme-linked immunosorbent assay (ELISA). The data from 28 patients with bipolar disorder (BD), 17 patients with schizophrenia (SZ), and 29 healthy controls were compared. RESULTS: MtDNA levels showed a nominal positive correlation with GM-CSF, IL-2 and IL-4 in patients with MDD. The most significant correlation with IL-4 (rho = 0.38, P < 0.00005) was verified with an ELISA (rho = 0.19, P = 0.049). Unexpectedly, patients with MDD and BD showed significantly lower plasma mtDNA levels than controls. MtDNA levels were lower in the depressive state than in the euthymic state in patients with MDD. Patients with depression, bipolar disorder, and schizophrenia did not show significantly higher levels of these four cytokines than controls. LIMITATIONS: There is a possibility that the patients in this study are different from previous studies in which increased cytokine levels were reported. MtDNA levels should be measured in patients showing elevated plasma cytokine levels. A larger sample is required to generalize the results. CONCLUSIONS: The present findings coincide with our hypothesis that circulating mtDNA contributes to the inflammation in MDD. Further studies are needed to conclude whether plasma mtDNA would be a biomarker of mood disorders. PMID- 28633758 TI - Listen: When words don't come easy. AB - OBJECTIVE: Listening is at the very heart of communication in healthcare, but largely ignored in research and teaching. This paper presents different perspectives on listening within the context of healthcare and its implications for goal-directed communication. METHODS: The assets of listening are examined from several angles (the listening patient, the listening health professional, and the listening self) and illustrated by the results of relevant research. RESULTS: Listening is a multidimensional concept and serves different purposes in healthcare. To benefit fully from it's potentials, the listening attitude and skills of patients and health professionals need to be enhanced through interventions at the level of policy, practice and research. Results from research evaluating creative and innovative ways of strenghtening persons' listening skills are encouraging. CONCLUSION: Listening has underused potential which can be boosted by interventions directed at the level of healthcare policy, practice and research. PRACTICE IMPLICATIONS: For healthcare practice, it is helpful to keep in mind that listening involves more than hearing what the other person says; one also needs eyes, a heart, and undivided attention. PMID- 28633760 TI - The future is now: A 2020 view of alcoholism research. PMID- 28633761 TI - The opinion of health professionals regarding the presence of relatives during cardiopulmonary resucitation. AB - BACKGROUND: The latest recommendations from the American Heart Association and the European Resuscitation Council invite allowance for the presence of relatives (PR) during cardiopulmonary resuscitation (CPR) as an extra measure of family care. OBJECTIVE: To discover the opinion of health professionals on the PR during CPR. METHOD: Cross-sectional observational study through an online survey in Spain, based on a non-probability sample (n=315). RESULTS: 45% consider that the PR during CPR is not demanded by users. 64% value the implementation of this practice in a negative or a very negative way. 45% believe that the practice would avoid the feeling of abandonment that is instilled in the relatives, this being the most widely perceived potential benefit. 30% do not believe that it can help reduce the anxiety of relatives. The majority remarked that PR would cause situations of violence, psychological harm in witnesses, and more mistakes during care. 48% feel prepared to perform the role of companion. CONCLUSIONS: Most professionals perceive more risks than benefits, and are not in favour of allowing PR due to a paternalistic attitude, and fear of the reactions that could be presented to the team. Extra-hospital emergency personnel seems to be the group most open to allowing this practice. Most professionals do not feel fully prepared to perform the role of companion. PMID- 28633759 TI - Martini Coarse-Grained Force Field: Extension to RNA. AB - RNA has an important role not only as the messenger of genetic information but also as a regulator of gene expression. Given its central role in cell biology, there is significant interest in studying the structural and dynamic behavior of RNA in relation to other biomolecules. Coarse-grain molecular dynamics simulations are a key tool to that end. Here, we have extended the coarse-grain Martini force field to include RNA after our recent extension to DNA. In the same way DNA was modeled, the tertiary structure of RNA is constrained using an elastic network. This model, therefore, is not designed for applications involving RNA folding but rather offers a stable RNA structure for studying RNA interactions with other (bio)molecules. The RNA model is compatible with all other Martini models and opens the way to large-scale explicit-solvent molecular dynamics simulations of complex systems involving RNA. PMID- 28633762 TI - Usefulness of Mean Platelet Volume-to-Lymphocyte Ratio for Predicting Angiographic No-Reflow and Short-Term Prognosis After Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction. AB - Primary percutaneous coronary intervention (pPCI) is associated with improved prognosis in patients with ST-segment elevation myocardial infarction (STEMI). However, no-reflow phenomenon limits the benefit of revascularization and predicts adverse outcomes. The specific mechanism for its occurrence is still not entirely clear, and it is believed at present that platelet activation and inflammation play a pivotal role in developing no-reflow. Both increased mean platelet volume (MPV), which is a platelet activation marker, and lymphopenia, which is an inflammation marker, have been linked to adverse events and poor prognosis after STEMI. Recently, MPV-to-lymphocyte ratio (MPVLR) has emerged as a novel marker of poor short- and long-term prognosis in diabetic patients with STEMI who underwent pPCI. In this study, we aimed to investigate whether MPVLR predicts angiographic no-reflow and in-hospital mortality in all STEMI patients. From January 2014 to January 2017, a total of 1,206 patients who underwent pPCI, admitted within 12 hours from symptom onset, were enrolled and divided into 2 groups based on the final thrombolysis in myocardial infarction (TIMI) flow grading. No-reflow was defined as post-pPCI TIMI grade 0, 1, and 2 flows and normal-reflow was defined as TIMI 3 flow. The incidence of no-reflow was 16.1% (n = 198). The MPVLR values were higher in no-reflow group than in normal-reflow group (p <0.001). In multivariate analysis, MPVLR was an independent predictor of angiographic no-reflow. Furthermore, in multivariable Cox regression models adjusted for potential confounders, MPVLR was independently and positively associated with the hazard of 30-day all-cause mortality. In conclusion, the MPVLR was a strong independent predictor for angiographic no-reflow and short term mortality in patients with STEMI who underwent pPCI. PMID- 28633764 TI - beta-blocker treatment of vascular disease in cocaine addiction. PMID- 28633763 TI - Bioinformatics analysis in type 1 diabetes increases retention of low-density lipoprotein in the atherosclerosis-prone area of the murine aorta. PMID- 28633766 TI - Health Services Research and the Health Insurance Experiment? PMID- 28633765 TI - Neck dissection for unknown cancer of the head and neck in the era of chemoradiation. AB - PURPOSE: To report outcomes for patients with cervical lymph node metastases from an unknown primary site of the head and neck treated with either non-operative therapy or neck dissection followed by adjuvant therapy. MATERIALS AND METHODS: All patients with squamous cell carcinoma of an unknown primary site of the head or neck seen between 2003 and 2013 were reviewed. The Kaplan-Meier method was used to estimate overall survival, local recurrence free survival, loco-regional recurrence free survival, and progression free survival. The log-rank test and proportional hazards regression were used to analyze factors influencing outcomes. RESULTS: Of 2258 patients with a new diagnosis of head and neck cancer, no primary site was identified in 66 patients. Twenty-nine patients were treated with definitive non-operative therapy (15 with chemoradiation and 14 with radiation alone). Thirty-seven patients received an upfront neck dissection followed by adjuvant radiation or chemoradiation. Three-year loco-regional recurrence free survival, progression free survival, and overall survival were 55.9%, 55.4%, and 69.4% respectively. Patients treated with preoperative neck dissection had improved local recurrence free survival (96.7% vs 54.1%, p=0.003) and loco-regional recurrence free survival (82.2% vs 46.4%, p=0.068) compared to patients treated with definitive chemoradiation with no difference in overall survival (p=0.641). CONCLUSIONS: Neck dissection improved local and regional control but not overall survival in patients with unknown primary squamous cell carcinoma of the head and neck over non-operative therapy alone. PMID- 28633767 TI - Temporal Variation in Ankle Fractures and Orthopedic Resident Program Planning in an Urban Level 1 Trauma Center. AB - Previous studies have described the mechanism of ankle fractures, their seasonal variation, and fracture patterns but never in conjunction. In addition, the cohorts previously studied were either not from trauma centers or were often dominated by low-energy mechanisms. The present study aimed to describe the epidemiology of ankle fractures presenting to an urban level 1 trauma center. The records from an urban level 1 trauma center located in the Midwestern United States were retrospectively reviewed, and the injury mechanism and energy, time of injury, day of week, month, and patient characteristics (age, gender, comorbidities, smoking status) were collected. The fractures were classified using the AO (Arbeitsgemeinschaft fur Osteosynthesefragen), Lauge-Hansen, and Danis-Weber systems. Of these systems, the Lauge-Hansen classification system resulted in the greatest number of "unclassifiable" cases. Most ankle fractures were due to high-energy mechanisms, with motor vehicle collisions the most common high-energy mechanism. The review found that most ankle fractures were malleolar fractures, regardless of the mechanism of injury. The ankle fracture patients had greater rates of obesity, diabetes, and smoking than present in the region where the hospital is located. The fractures were most likely to occur in the afternoon, with more fractures presenting on the weekend than earlier in the week and more fractures in the fall and winter than in the spring and summer. The temporal variation of these fractures should be considered for health services planning, in particular, in regard to resident physician staffing at urban level 1 trauma centers. PMID- 28633768 TI - Comparing Different Surgical Techniques for Addressing the Posterior Malleolus in Supination External Rotation Ankle Fractures and the Need for Syndesmotic Screw Fixation. AB - Trimalleolar ankle fractures are unstable injuries with possible syndesmotic disruption. Recent data have described inherent morbidity associated with screw fixation of the syndesmosis, including the potential for malreduction, hardware irritation, and post-traumatic arthritis. The posterior malleolus is an important soft tissue attachment for the posterior inferior syndesmosis ligament. We hypothesized that fixation of a sizable posterior malleolar (PM) fracture in supination external rotation type IV (SER IV) ankle fractures would act to stabilize the syndesmosis and minimize or eliminate the need for trans syndesmotic fixation. A retrospective review of trimalleolar ankle fractures surgically treated from October 2006 to April of 2011 was performed. A total of 143 trimalleolar ankle fractures were identified, and 97 were classified as SER IV. Of the 97 patients, 74 (76.3%) had a sizable PM fragment. Syndesmotic fixation was required in 7 of 34 (20%) and 27 of 40 (68%), respectively, when the PM was fixed versus not fixed (p = .0002). When the PM was indirectly reduced using an anterior to posterior screw, 7 of 15 patients (46.7%) required syndesmotic fixation compared with none of 19 patients when the PM fragment was fixated with direct posterior lateral plate fixation (p = .0012). Fixation of the PM fracture in SER IV ankle fractures can restore syndesmotic stability and, thus, lower the rate of syndesmotic fixation. We found that fixation of a sizable PM fragment in SER IV or equivalent injuries through posterolateral plating can eliminate the need for syndesmotic screw fixation. PMID- 28633769 TI - Blisters in Ankle Fractures: A Retrospective Cohort Study. AB - The most frequent postoperative complications after an ankle fracture are usually skin related. We present the results of a retrospective study of 112 patients with ankle fracture who had undergone open reduction and internal fixation from January 2014 to December 2014. The following features were analyzed: patient comorbidities, fracture type, the presence of an open fracture or fracture dislocation, timing and duration of surgery, preoperative glucose level, and short-term complications (i.e., blisters, wound dehiscence, deep and superficial infections, and reintervention). The mean age of the patients was 50.38 years. Fracture blisters were present in 20.5% of the cases. The operative time was 75.74 +/- 25.09 minutes for patients with blisters and 64.48 +/- 19.73 minutes for patients without blisters (p = .023). The preoperative blood glucose levels were 122.96 +/- 28.46 g/dL in the patients with blisters and 106.70 +/- 21.32 g/dL in the patients without blisters (p = .003). No statistically significant differences were observed between the patients who had undergone surgery <24 hours after injury and those who had done so >24 hours after injury. In conclusion, the presence of postoperative blisters in patients with ankle fractures was associated with prolonged surgical procedures and high serum glucose levels. PMID- 28633770 TI - A 24-Month Follow-Up of a Custom-Made Suture-Button Assembly for Syndesmotic Injuries of the Ankle. AB - In the present retrospective analysis, we introduce a custom suture-button fixation device for acute ankle syndesmotic injuries that allows for early weightbearing without another planned operation for hardware removal. We evaluated 87 consecutive ankles in 87 patients (49 males [56.32%] and 38 females [43.68%]). Of the 87 patients, 15 (17.24%) withdrew or were lost to follow-up, leaving 72 patients (82.76%) in the present study. Their mean age was 35.2 (range 17 to 67) years. Nineteen patients (26.39%) presented with a pure syndesmotic disruption, and 53 (73.61%) had associated malleolar fractures. The American Orthopaedic Foot and Ankle Society scale score improved significantly from 31.2 +/- 4.2 preoperatively to 88.5 +/- 5.3 at an average of 24 months postoperatively (p < .0043). Revision was undertaken because of implant failure in 4 ankles (5.56%). Two revisions (2.78%) were performed in 2 ankles because of early weightbearing in the first 2 weeks after surgery. The third patient (1.39%) underwent revision at 5 weeks postoperatively. This syndesmotic reduction failure was attributed to failure of the threads, which was noted at the second surgery. The fourth patient (1.39%), a 66-year-old male, underwent revision at 5 months postoperatively because of persistent infection. An 18-month postoperative radiograph was available for all patients. The medial clear space had significantly decreased, from 8.2 +/- 3.1 mm preoperatively to 3.5 +/- 2.2 mm at 18 months postoperatively (p < .0344). Likewise, the tibiofibular clear space had decreased significantly, from a mean of 8.8 +/- 3.7 mm preoperatively to a mean of 3.7 +/- 2.2 mm at 18 months postoperatively (p < .0322). In conclusion, suture button fixation described in the present report delivered satisfactory functional outcomes and anatomic reduction at minimum of 18 months after surgery. PMID- 28633771 TI - Relationship of Cuboid Height to Plantar Ulceration and Other Radiographic Parameters in Midfoot Charcot Neuroarthropathy. AB - The objective of the present investigation was to examine the effect of cuboid height on the presence of plantar midfoot ulceration and the relationship of cuboid height to other commonly performed radiographic parameters during evaluation of midfoot Charcot neuroarthropathy. A retrospective analysis was performed of 68 feet in 60 subjects who met the inclusion criteria. We did not observe statistically significant differences in the presence of a plantar midfoot ulceration when considering a cuboid height threshold of 0.0 mm, 2.0 mm, 2.0 mm, or -5.0 mm nor was the cuboid height a robust predictor for the presence of plantar midfoot ulceration when considering the positive predictive value, negative predictive value, sensitivity, or specificity. We observed a significant negative association between a negative cuboid height and the presence of Sanders Type 2 deformities (76.2% of those with negative height versus 50.0% of those with positive height had type 2 deformities; p = .0036), the absence of radiographic visualization of the lateral tarsometatarsal joint (71.4% of those with negative height versus 26.9% of those with positive height had an absence of radiographic visualization; p = .005), and lower calcaneal inclination angles (6.06 degrees versus 15.08 degrees ; p < .001). We further observed significant positive correlations between the cuboid height and the calcaneal-fifth metatarsal angle (0.655; p < .000), calcaneal inclination angle (0.591; p < .001), calcaneal-cuboid angle (0.254; p = .038), medial column height (0.264; p = .029), and first metatarsal inclination angle (0.245; p = .047). We also observed negative correlations with Meary's angle (-0.475; p < .001) and the talar declination angle (-0.387; p < .001). These findings showed a general trend toward a decreasing cuboid height and increasing sagittal plane deformity involving both the medial and the lateral columns. The results of the present investigation provide evidence against a single radiographic parameter being associated with the presence of plantar midfoot ulceration. PMID- 28633772 TI - Omnidirectional Internal Fixation by Double Approaches for Treating Ruedi Allgower Type III Pilon Fractures. AB - In the present study, we explored the effectiveness and complications of omnidirectional internal fixation using a double approach for treating Ruedi Allgower type III pilon fractures. A retrospective analysis was performed of 19 cases of Ruedi-Allgower type III unilateral closed pilon fracture. With preoperative preparation and correct surgical timing, the reduction was performed using anteromedial and posterolateral approaches, and the fracture fragments were fixed by omnidirectional internal fixation. Imaging evaluation was performed using the Burwell-Charnley scoring system. The Johner-Wruhs scoring system was used to assess the functional status of the patients. A comprehensive evaluation of efficacy was performed using a 5-point Likert score. The complications were also recorded and analyzed. All patients were followed up for an average of 16.2 months. The operative incisions of 15 cases healed by primary intent and with delayed healing in 4. All patients had achieved bony union at an average of 16 weeks postoperatively. No deep infection, broken nail or withdrawn nail, exposed plate, or skin flap necrosis occurred. The Burwell-Charnley imaging evaluation showed that 14 patients had anatomic reduction of the articular surface and 5 had acceptable reduction. Using the Johner-Wruhs scoring system, the results were excellent for 8, good for 7, fair for 2, and poor for 2 patients; the combined rate of excellent and good results was 78.9%. The Likert score of efficacy self reported by the patients was 3 to 4 points for 12 patients, 2 points for 4 patients, and 0 to 1 point for 3 patients. The Likert score of therapeutic efficacy reported by the physicians was 3 to 4 points for 10 patients, 2 points for 5 patients, and 0 to 1 point for 4 patients. Omnidirectional internal fixation using double approaches was an effective method to treat Ruedi-Allgower type III pilon fractures with satisfactory reduction and rigid fixation, good joint function recovery, and few complications. PMID- 28633773 TI - Magnetic Resonance Imaging and Clinical Outcomes of Laser Therapy, Ultrasound Therapy, and Extracorporeal Shock Wave Therapy for Treatment of Plantar Fasciitis: A Randomized Controlled Trial. AB - We determined and compared the effectiveness of low-level laser therapy (LLLT), therapeutic ultrasound (US) therapy, and extracorporeal shock wave therapy (ESWT) using magnetic resonance imaging (MRI). We performed a randomized, prospective, comparative clinical study. A total of 60 patients with a diagnosis of chronic plantar fasciitis were divided randomly into 3 treatment groups: group 1 underwent 15 sessions of LLLT (8 J/cm2; 830 nm); group 2 underwent 15 sessions of continuous US (1 mHz; 2 W/cm2); and group 3 underwent 3 sessions of ESWT (2000 shocks). All patients were assessed using the visual analog scale (VAS), heel tenderness index (HTI), American Orthopaedic Foot and Ankle Society (AOFAS) ankle hindfoot scale, Roles-Maudsley score, and MRI before and 1 month after treatment. The primary efficacy success criterion was the percentage of decrease in heel pain of >60% from baseline at 1 month after treatment for >=2 of the 3 heel pain (VAS) measurements. Significant improvement was measured using the mean VAS, AOFAS scale, and HTI scores for all 3 groups. The thickness of the plantar fascia had decreased significantly on MRI in all 3 groups. The treatment success rate was 70.6% in the LLLT group, 65% in the ESWT group, and 23.5% in the US group. LLLT and ESWT proved significantly superior to US therapy using the primary efficacy criterion (p = .006 and p = .012, respectively), with no significant difference between the LLLT and ESWT groups (p > .05). The treatment of chronic plantar fasciitis with LLLT and ESWT resulted in similar outcomes and both were more successful than US therapy in pain improvement and functional outcomes. PMID- 28633774 TI - Treatment of Chronic Plantar Fasciitis with Noninvasive Interactive Neurostimulation: A Prospective Randomized Controlled Study. AB - The initial treatment of plantar fasciitis should be conservative, with most cases responding to standard physiotherapy, nonsteroidal anti-inflammatory drugs (NSAIDs), heel pads, and stretching. In cases of chronic refractory symptoms, more invasive treatment could be necessary. Noninvasive interactive neurostimulation (NIN) is a form of electric therapy that works by locating areas of lower skin impedance. The objective of the present prospective randomized controlled study was to evaluate whether the use of NIN for chronic plantar fasciitis could result in greater improvement in a foot functional score, lower levels of reported pain, reduced patient consumption of NSAIDs, and greater patient satisfaction compared with electric shockwave therapy in patients without a response to standard conservative treatment. The patients were randomized using random blocks to the NIN program (group 1) or electric shockwave therapy (group 2). The outcome measurements were the pain subscale of the validated Foot Function Index (PS-FFI), patient-reported subjective assessment of the level of pain using a standard visual analog scale, and daily intake of NSAID tablets (etoricoxib 60 mg). The study group was evaluated at baseline (time 0), week 4 (time 1), and week 12 (final follow-up point). Group 1 (55 patients) experienced significantly better results compared with group 2 (49 patients) in term of the PS-FFI score, visual analog scale score, and daily intake of etoricoxib 60 mg. NIN was an effective treatment of chronic resistant plantar fasciitis, with full patient satisfaction in >90% of cases. The present prospective randomized controlled study showed superior results for noninvasive neurostimulation compared with electric shockwave therapy, in terms of the functional score, pain improvement, and use of NSAIDs. PMID- 28633775 TI - Ball and Socket Ankle: Mechanism and Computational Evidence of Concept. AB - The ball and socket ankle joint is a morphologically abnormal joint characterized by rounding of the articular surface of the talus. Other than anecdotal observation, little evidence has been presented to describe the development of this deformity. The purpose of the present study was to review ankle and subtalar joint mechanics and to kinematically examine the functional combination of these joints as a mechanism of the ball and socket ankle deformity. We reviewed functional representations of the ankle joint, subtalar joint, and ball and socket ankle deformity. A computational study of joint kinematics was then performed using a 3-dimensional model derived from a computed tomography scan of a ball and socket deformity. The joint kinematics were captured by creating a "virtual map" of the combined kinematics of the ankle and subtalar joints in the respective models. The ball and socket ankle deformity produces functionally similar kinematics to a combination of the ankle and subtalar joints. The findings of the present study support the notion that a possible cause of the ball and socket deformity is bony adaptation that compensates for a functional deficit of the ankle and subtalar joints. PMID- 28633776 TI - Bioabsorbable Calcaneo-Stop Implant for the Treatment of Flexible Flatfoot: A Retrospective Cohort Study at a Minimum Follow-Up of 4 Years. AB - Arthroereisis of the subtalar joint is a common surgical technique in Europe for the management of flexible flatfoot in the pediatric population. In most cases, it is performed using a calcaneo-stop metallic screw. Despite the good clinical results, screw removal is always advised after 2 to 3 years. The use of a bioabsorbable screw might overcome the need for a second operation to remove a nonabsorbable device. We report the results of a biodegradable calcaneo-stop screw at a minimum of 4 years of follow-up. Eighty-eight procedures were performed on 44 children. All patients were clinically and radiologically evaluated preoperatively and at a minimum 4-year follow-up period. Patient satisfaction and plantar collapse using Viladot's classification were recorded. Meary's talus-first metatarsal angle and talocalcaneal angle were measured on radiographs preoperatively and at the last follow-up visit. The presence of the device at the last follow-up examination was assessed by magnetic resonance imaging. The mean follow-up duration was 56 months. Of the 44 patients, 33 (75%) reported excellent clinical outcomes, 9 (20.5%) good outcomes, and 2 (4.5%) poor. Foot print improvement was registered for all patients. The mean Meary's talus first metatarsal angle had improved from 160.6 degrees +/- 7.7 degrees preoperatively to 170.6 degrees +/- 6.5 degrees at the last follow-up visit (p < .001). The talocalcaneal angle had decreased from 39.9 degrees +/- 5.2 degrees preoperatively to 29.4 degrees +/- 4 degrees at the last follow-up examination (p < .001). At the 4-year follow-up point, the implant could be seen to have almost completely biodegraded on magnetic resonance imaging. Two screw breakages occurred. The bioabsorbable calcaneo-stop screw seems to be an effective solution for flexible flatfoot in pediatric patients. Also, owing to its biodegradable composition, the need of a second operation for implant removal will not always be necessary. PMID- 28633777 TI - Shall We Inject Superficial or Deep to the Plantar Fascia? An Ultrasound Study of the Treatment of Chronic Plantar Fasciitis. AB - We compared the effectiveness of ultrasound (US)-guided corticosteroid, injected superficial or deep to the fascia, in patients with plantar fasciitis. Thirty patients (24 females [75%] and 6 males [25%]) with unilateral chronic plantar fasciitis were divided into 2 groups according to the corticosteroid injection site: superficial (n = 15) or deep (n = 15) to the plantar fascia. Patient heel pain was measured using a Likert pain scale and the Foot Ankle Outcome Scale (FAOS) for foot disability, evaluated at baseline and repeated in the first and sixth weeks. The plantar fascia and heel pad thicknesses were assessed on US scans at baseline and the sixth week. The groups were similar in age, gender, and body mass index (p > .05 for all). Compared with the baseline values, the Likert pain scale (p < .001 for all) and FAOS subscale (p < .01 for all) scores had improved at the first and sixth week follow-up visits in both groups. Although the plantar fascia thickness had decreased significantly in both groups at the sixth week (p < .001 for both), the heel pad thickness remained unchanged (p > .05 for both). The difference in the FAOS subscales (pain, p = .002; activities of daily living, p = .003; sports/recreational activities, p = .008; quality of life, p = .009) and plantar fascia thickness (p = .049) showed better improvement in the deep than in the superficial injection group. US-guided corticosteroid injections are safe and effective in the short-term therapeutic outcome of chronic plantar fasciitis. Additionally, injection of corticosteroid deep to the fascia might result in greater reduction in plantar fascia thickness, pain, and disability and improved foot-related quality of life. PMID- 28633778 TI - Results of HemiCAP(r) Implantation as a Salvage Procedure for Osteochondral Lesions of the Talus. AB - Osteochondral defects (OCDs) of the talus remain a surgical challenge, especially after failed primary treatment. The aim of the present study was to examine the clinical outcomes after HemiCAP(r) implantation for OCDs of the medial talar dome after failed previous surgery. Our retrospective study included 11 patients, who had undergone surgery from June 2009 to September 2012 for an OCD of the medial talar dome and received a HemiCAP(r) on the talus after failed previous surgery for OCD. The data were acquired using patients' medical records and standardized questionnaires, including the Foot and Ankle Outcome Score (FAOS), University of California at Los Angeles (UCLA) activity score, EQ-5D, numerical rating scale (NRS), and Short-Form 36-item Health Survey (SF-36). Using these scores, the possibility of returning to work and sports was determined. Any complications and the need for revision surgery were recorded. One patient refused to participate in the study, leaving 10 patients for evaluation. The mean age was 47.64 +/- 10.97 years. The mean follow-up period was 43.5 +/- 35.51 months. The FAOS and SF 36 subscale scores and the EQ-5D and UCLA activity scores did not improve significantly (p < .05). The mean postoperative pain score on the NRS improved significantly from 6.6 +/- 1.77 preoperatively to 5.1 +/- 2.02 postoperatively (p < .05). A greater body mass index led to worse postoperative outcomes with higher scores on the pain-NRS and less satisfaction (p < .05). Ten revisions for ongoing pain were performed in 7 patients (70.0%) within a mean of 28.4 +/- 13.35 months of the initial procedure, and 6 patients (60%) indicated they would undergo surgery again. The results of the present study have shown that implantation of the HemiCAP(r) as a salvage procedure for OCDs of the talus is challenging and does not consistently lead to good clinical results. Also, overweight patients appear to have an increased risk of postoperative dissatisfaction and persistent ankle pain. PMID- 28633779 TI - Differences in Classification Between Mono- and Polytrauma and Low- and High Energy Trauma Patients With an Ankle Fracture: A Retrospective Cohort Study. AB - Although fracture type and treatment options for ankle fractures are well defined, the differences between mono- and polytrauma patients and low- and high energy trauma have not been addressed. The aim of the present study was to compare the fracture type and trauma mechanism between mono- and polytrauma and low- and high-energy trauma patients with an ankle fracture. We performed a single-center retrospective cohort study. Fractures were classified according to the Lauge-Hansen classification and a descriptive classification. High-energy trauma (HET) was defined using triage criteria. All other patients were classified as having experienced low-energy trauma (LET). The patients were divided into 2 groups according to the injury severity score (ISS). Monotrauma patients were defined as patients with an ISS of 4 to 11 with an isolated ankle fracture or an ankle fracture with a minor contusion or laceration. Polytrauma patients were defined as patients with an ISS of >=16 with >=2 body regions involved. Patients with an ISS from 12 to 15 were excluded. A total of 96 patients were eligible for analysis. Of the 96 patients, 62 had experienced monotrauma and 34 had experienced polytrauma. A significant difference was found between the mono- and polytrauma patients in the Lauge-Hansen classification (p < .001). Monotrauma patients had a high incidence of an isolated supination external rotation injury. Supination adduction and pronation abduction injuries were more often observed in polytrauma patients. The same pattern was observed for ankle fractures after HET compared with LET (p < .001), because all pronation abduction and supination adduction injuries were observed after a HET mechanism. The results of the present study indicate that polytrauma patients sustain different types of ankle fractures than patients with an isolated ankle fracture. This difference likely results from the high-energy transfer associated with polytrauma, because pronation abduction and supination adduction injuries were only observed after HET. PMID- 28633780 TI - Subtalar Coalitions: Does the Morphology of the Subtalar Joint Involvement Influence Outcomes After Coalition Excision? AB - Posteromedial subtalar (PMST) coalitions are a recently described anatomic subtype of tarsal coalitions. We compared with clinical patient-based outcomes of patients with PMST and standard middle facet (MF) coalitions who had undergone surgical excision of their coalition. The included patients had undergone surgical excision of a subtalar tarsal coalition, preoperative computed tomography (CT), and patient-based outcomes measures after surgery (including the American Orthopaedic Foot and Ankle Society [AOFAS] scale and University of California, Los Angeles [UCLA], activity score). Blinded analysis of the preoperative CT scan findings determined the presence of a standard MF versus a PMST coalition. The perioperative factors and postoperative outcomes between the MF and PMST coalitions were compared. A total of 51 feet (36 patients) were included. The mean follow-up duration was 2.6 years after surgery. Of the 51 feet, 15 (29.4%) had a PMST coalition and 36 (70.6%) had an MF coalition. No difference was found in the UCLA activity score; however, the mean AOFAS scale score was higher for patients with PMST (95.7) than for those with MF (86.5; p = .018). Of the patients with a PMST, none had foot pain limiting their activities at the final clinical follow-up visit. However, in the group with an MF subtalar coalition, 10 (27.8%) had ongoing foot pain limiting activity at the final follow up visit (p = .024). Compared with MF subtalar tarsal coalitions, patients with PMST coalitions showed significantly improved clinical outcomes after excision. Preoperative identification of the facet morphology can improve patient counseling and expectations after surgery. PMID- 28633781 TI - Beaming in Charcot Arthropathy-Intramedullary Fixation for Complicated Reconstructions: A Cadaveric Study. AB - In the modern treatment of Charcot neuroarthropathy, beam screw fixation is an alternative to plate and screw fixation. Exposure is minimized for implantation, and this technique supports the longitudinal columns of the foot as a rigid load sharing construct. A published data review identified a paucity of data regarding metatarsal intramedullary canal morphology relevant to beam screw fixation. The purpose of the present study was to describe metatarsal diaphyseal morphology qualitatively and quantitatively in an effort to provide data that can be used by surgeons when selecting axially based intramedullary fixation. Twenty fresh frozen cadaveric below-the-knee specimens were obtained. The metatarsals were exposed, cleaned of soft tissue, and axially transected at the point of the narrowest external diameter. Next, a digital caliper was used to measure the size and shape of the diaphysis of the first through fourth metatarsals. The diaphyseal canal shape was categorized as round, oval, triangular, or pear. The widest distance between the endosteal cortical surfaces was measured. Triangular endosteal canals were only found in the first metatarsal, and the remainder of the metatarsal canals were largely round or oval. These data help to approximate the size of fixation needed to achieve maximal screw-endosteal purchase. PMID- 28633782 TI - Factors Predicting Length of Hospital Stay and Extended Care Facility Admission After Hindfoot Arthrodesis Procedures. AB - Delayed identification of patients requiring admission to extended care facilities (ECFs) can lead to greater healthcare costs through an increased length of hospital stay (LOHS). Previous studies of hip and knee arthroplasty identified factors associated with a likely discharge to an ECF. These issues have not been extensively studied for major hindfoot procedures. We conducted a retrospective review of 198 cases treated during a 3-year period to identify the risk factors for an extended LOHS and ECF admission after ankle arthrodesis, triple arthrodesis, pantalar arthrodesis, and subtalar arthrodesis. The primary outcomes were LOHS and ECF admission. The independent predictors included age, sex, body mass index, housing status, American Society of Anesthesiologists class, diabetes and/or diabetic neuropathy, health insurance, fixation type, and perioperative infection. Stepwise multiple regression analysis was used to determine which variables were related to a longer LOHS. Nonparametric discriminant function analysis was used to identify the preoperative factors that best predicted ECF admission. A longer LOHS was significantly related to postoperative ECF admission, Centers for Medicare and Medicaid Services (CMS) insurance, diabetic neuropathy, external fixation, and infection. ECF admission was required for 34 of 198 patients (17.2%). Discriminant analysis found that older age, living alone, external fixation, and CMS insurance predicted a greater probability of ECF admission. The function accurately classified 94% of ECF admissions and 80% of non-ECF admission patients. ECF admission and CMS insurance extended the LOHS, likely owing to the administrative process of arranging an ECF discharge. If externally validated, the function we have derived could provide preoperative identification of likely ECF discharge candidates and reduce costs by shortening the LOHS. PMID- 28633783 TI - A Biomechanical Analysis of Interference Screw Versus Bone Tunnel Fixation of Flexor Hallucis Longus Tendon Transfers to the Calcaneus. AB - The flexor hallucis longus tendon transfer is commonly used to restore function in chronic Achilles tendon ruptures and chronic Achilles tendinopathy. The tendon is often secured to the calcaneus either through a bone tunnel or by an interference screw. We hypothesized that tenodesis using the bone tunnel method would be mechanically superior to interference screw fixation for flexor hallucis longus transfers. Eight matched pairs of cadaveric specimens were assigned randomly to the bone tunnel or interference screw technique and were loaded to failure. Biomechanical analysis was performed to evaluate the ultimate strength, peak stress, Young's modulus, failure strain, and strain energy. Unpaired comparison, paired comparison, and linear regression analyses were used to determine statistical significance. A slight 22% +/- 9% decrease in Young's modulus and a 52% +/- 18% increase of strain energy were found in the interference screw group. However, no differences in ultimate strength, peak stress, or failure strain were seen between the 2 groups on paired comparison. Our findings suggest that interference screw fixation provides similar spontaneous biomechanical properties to the use of a bone tunnel for flexor hallucis longus transfer to the calcaneus. The interference screw is a practical option for fixation of the flexor hallucis longus tendon to the calcaneus and can be performed through a single incision approach. PMID- 28633784 TI - Complications of Talar Neck Fractures by Hawkins Classification: A Systematic Review. AB - The goal of the present study was to perform a systematic review of the published data on talar neck fractures for a better understanding of the postoperative clinical outcomes using open reduction and internal fixation stratified by Hawkins type. A PubMed search was performed using the keywords "talar," "neck," and "fracture." This search identified 209 potential studies, which were reviewed to yield 16 studies that met the criteria. The surgical outcomes of talar neck fractures stratified by the Hawkins classification analyzed in the present study were as follows: American Orthopaedic Foot and Ankle Society scale score was 77.00 for type I, 86.10 for type II, 68.30 for type III, 68.30 for type IV, and 76.50 for all talar neck fractures. Avascular necrosis presented in 0.00% of type I fractures, 15.91% of type II fractures, 38.89% of type III fractures, 55.00% of type IV fractures, and 26.47% of all fractures. Osteoarthritis presented in 25.00% of type I fractures, 41.33% of type II fractures, 54.23% of type III fractures, 72.73% of type IV fractures, and 51.69% of all fractures. Subtalar arthritis presented in 0.00% of type I fractures, 54.29% of type II fractures, 46.43% of type III fractures, 45.45% of type IV fractures, and 44.97% of all fractures. The malunion prevalence was 13.29% and the nonunion prevalence was 3.97% for all fractures. Type II fractures were the most common (50.88%) fracture type reported in the reports reviewed in the present study. PMID- 28633785 TI - The Lisfranc Amputation: A More Reliable Level of Amputation With Proper Intraoperative Tendon Balancing. AB - Traditional transmetatarsal amputations are a reliable level of amputation. However, amputations at the Lisfranc level have met with limited success owing to improper biomechanics resulting from tendon imbalance, ultimately leading to foot deformity positions and an unstable soft tissue envelope with ensuing skin breakdown, infection, and below-the-knee amputation. We describe proper tendon rebalancing that results in improved biomechanics and a more reliable and stable amputation at the more proximal Lisfranc level. PMID- 28633786 TI - Metastatic Pulmonary Adenocarcinoma of the Talus: A Case Report. AB - Tumors rarely metastasize to the foot bones; however, a misdiagnosis can lead to a poor outcome. These metastatic tumors can cause foot pain and other symptoms in patients who are asymptomatic for the primary tumor. To accurately diagnose acrometastases, the attending physician must have a high index of suspicion and conduct a thorough examination and appropriate diagnostic testing. We present a rare case of metastatic pulmonary adenocarcinoma of the talus, which was initially misdiagnosed as a benign bone cyst. After pulmonary adenocarcinoma was diagnosed, the patient received multidrug treatment for the primary and metastatic lesions and was still responding well at the 12-month follow-up visit. PMID- 28633787 TI - The Disappearing Phalanx: A Case Report of a Vascular Tumor of the Toe. AB - We report a unique case of an epithelioid hemangioma of the third middle phalanx in which the lesion replaced the phalanx, became symptomatic, and then required resection, bone grafting, and joint arthroplasty. To the best of our knowledge, this is the first report of an epithelioid hemangioma in the toe that was treated using this approach. PMID- 28633788 TI - Fluoroscopic and Gait Analyses for the Functional Performance of a Custom-Made Total Talonavicular Replacement. AB - The present study evaluated the restoration of joint function in a special clinical case: a professional rock climber who underwent an original total talonavicular replacement with a custom-made prosthesis after a complex articular fracture. Full body gait analysis and 3-dimensional joint kinematics using single plane fluoroscopy were performed on the same day at the 30-month follow-up examination. Gait analysis was performed using stereophotogrammetric, dynamometric, electromyographic, and baropodometric systems. Gait analysis showed good restoration of rotation, as well as moment patterns in the main lower limb and foot joints in the operated leg. At the artificial tibiotalar joint, videofluoroscopic analysis revealed a flexion capability of about 20 degrees , together with a few degrees of motion in the frontal and transverse planes. The neighboring joints of the foot did not present with severe kinematic abnormalities. A full talonavicular replacement can be a viable and effective solution for complex ankle injury sequelae, even in patients with highly demanding functionality. PMID- 28633789 TI - Displaced Salter-Harris Type I Distal Fibula Fractures: Two Case Reports and a Review of the Literature. AB - Salter-Harris type I (SH-I) fractures of the distal fibula are commonly encountered in pediatric orthopedics. We describe 2 unique cases of adolescents with completely displaced SH-I distal fibula fractures that were treated operatively. In the first case, a closed reduction attempt failed and the patient required open reduction and internal fixation of the distal fibula and syndesmosis. The syndesmotic ligaments were avulsed from the distal fibular metaphysis. In the second case, closed reduction of the distal fibula fracture was partially successful, but anatomic reduction could not be achieved without open reduction. The distal fibula fracture was fixed with an intramedullary screw. We believe this pattern of injury represents a variant of the adolescent transitional ankle fracture. Because the distal tibial physes were nearing complete closure in these patients, the energy propagated through the distal fibular physis. To the best of our knowledge, this combination of injuries has not been previously reported. This type of physeal fracture raises concern for premature physeal closure, fibular growth disturbance, syndesmotic instability, and medial (deltoid ligament) injury. Both patients had excellent outcomes after anatomic reduction and fixation of the displaced SH-I distal fibula fractures at 1 and 6 years of follow up, respectively. PMID- 28633790 TI - Ochrobactrum anthropi-Caused Osteomyelitis in the Foot Mimicking a Bone Tumor: Case Report and Review of the Literature. AB - Osteomyelitis due to Ochrobactrum anthropi, a new genus Ochrobacterum widely distributed in the environment and occasionally associated with human infection, has been described in only a few case reports. We present a report of an unusual case of osteomyelitis caused by O. anthropi that was identified 9 years after a nail puncture to the lateral cuneiform bone. The patient was an 18-year-old male with a painful foot lesion that had originally been misdiagnosed as an osteolytic tumor. He underwent surgery and 2 firm pieces of rubber measuring 7 and 10 mm were removed from the lower portion of the lateral cuneiform bone, which appeared to be affected by an infection. After surgical debridement, O. anthropi was isolated from the bone cultures. The patient was successfully treated with a 6 week course of oral ciprofloxacin and clindamycin. At 1 year after the corrected diagnosis and appropriate treatment, he was symptom free and had resumed regular activities and an athletic lifestyle. PMID- 28633791 TI - Peroneus Tertius Tendon Tear Causing Lateral Ankle Pain in a Child. AB - The peroneus tertius muscle arises in the anterior compartment of the leg and demonstrates significant morphologic variation. Its function is not yet clearly delineated. We present the case of a 12-year-old patient with an isolated tear of the peroneus tertius tendon that resulted in lateral based ankle pain. After surgical reconstruction, the patient's pain resolved, and he was able to return to his normal activities. PMID- 28633792 TI - Nonoperative Treatment of a Lesser Toe Plantar Plate Tear with Serial MRI Follow up: A Case Report. AB - With the current data concentrating on different operative treatment options for plantar plate tears, few data can be found on possible nonoperative treatment strategies for this entity and the specifics of such treatment. In the present case report, the successful nonoperative treatment of a patient with a rupture of the plantar plate in a lesser toe metatarsophalangeal joint is presented. The patient was followed up using repeat clinical examinations and high-resolution magnetic resonance imaging scans for 1 year after the imitation of therapy to provide information on the different stages of the healing process. PMID- 28633793 TI - Treatment of a Focal Articular Cartilage Defect of the Talus with Polymer-Based Autologous Chondrocyte Implantation: A 12-Year Follow-Up Period. AB - Autologous chondrocyte implantation (ACI) is a first-line treatment option for large articular cartilage defects. Although well-established for cartilage defects in the knee, studies of the long-term outcomes of matrix-assisted ACI to treat cartilage defects in the ankle are rare. In the present report, we describe for the first time the long-term clinical and radiologic results 12 years after polymer-based matrix-assisted ACI treat a full-thickness talar cartilage defect in a 25-year-old male patient. The clinical outcome was assessed using the visual analog scale and Freiburg ankle score, magnetic resonance imaging evaluation using the Henderson-Kreuz scoring system and T2 mapping. Clinical assessment revealed improved visual analog scale and Freiburg ankle scores. The radiologic analysis and T2 relaxation time values indicated the formation of hyaline-like repair tissue. Polymer-based autologous chondrocytes has been shown to be a safe and clinically effective long-term treatment of articular cartilage defects in the talus. PMID- 28633794 TI - Glomus Tumor in the Tarsal Tunnel: A Case Report. AB - Glomus tumors are painful benign neoplasms. They commonly present in the hand and are mostly solitary lesions. We report a rare case of multiple glomus tumors in the lower leg. Moreover, 1 of the tumors was in the tarsal tunnel. Resection of the tumors resulted in the early diagnosis of glomus tumors and complete symptom relief. Because of its rarity, diagnosing an extradigital glomus tumor is difficult. Recognition of glomus tumors allows for an early diagnosis and resection, and preoperative magnetic resonance imaging helps in the detection of multiple lesions. Before resection, we considered tarsal tunnel syndrome in the differential diagnosis because of the symptoms and location of the tumor. Tarsal tunnel syndrome is a comparatively well-known disease in the foot. When tarsal tunnel syndrome is suspected, a glomus tumor should also be considered in the differential diagnosis. PMID- 28633795 TI - Valgus Ankle Degenerative Arthritis with an Isolated Deltoid Insufficiency and Tibial Varus: A Case Report. AB - We report a case of valgus ankle degenerative arthritis due to chronic isolated deltoid insufficiency combined with tibial varus that was treated successfully with ankle joint preserving surgery. A 63-year-old male complained of right lateral ankle pain with 10 minutes of maximal pain-free walking time. The assessed American Orthopaedic Foot and Ankle ankle-hindfoot scale score was 33 points. The ankle joint showed 18 degrees of valgus deformity with 6 degrees of tibia varus. Medial displacement calcaneal osteotomy, supramalleolar open wedge osteotomy, and deltoid ligament imbrication were performed. At the 2-year follow up examination, the ankle joint showed 10 degrees of valgus and the tibial plafond showed flattening. The hindfoot showed 7 degrees of valgus. He could run for 2 hours on the treadmill without pain. The American Orthopaedic Foot and Ankle ankle-hindfoot scale score was 90 points. In conclusion, valgus ankle degenerative arthritis with isolated deltoid insufficiency and tibial varus could be treated successfully with realignment using a double osteotomy and additional deltoid imbrication. PMID- 28633796 TI - Cotton Osteotomy in Flatfoot Reconstruction: A Case Report Highlighting Surgical Technique and Modified Incision to Protect the Medial Dorsal Cutaneous Nerve. AB - The Cotton osteotomy or opening wedge medial cuneiform osteotomy is a useful adjunctive flatfoot reconstructive procedure that is rarely performed in isolation. The Cotton procedure is relatively quick to perform and effectively corrects forefoot varus deformity after rearfoot fusion or osteotomy to achieve a rectus forefoot to rearfoot relationship. Proper patient selection is critical, because preoperative findings of medial column joint instability, concomitant hallux valgus deformity, or degenerative joint disease of the medial column might be better treated with arthrodesis of the naviculocuneiform or first tarsometatarsal joints. Procedure indications also include elevatus of the first ray, which can be a primary deformity in hallux limitus, or iatrogenic deformity after base wedge osteotomy in hallux valgus. We present the case of an adolescent patient who underwent flatfoot reconstruction, including Cotton osteotomy for correction of forefoot varus that was accentuated after double heel osteotomy. This case highlights our preferred procedure technique, including the use of a nerve-centric incision design. The use of an oblique dorsal medial incision is primarily intended to minimize the risk of trauma to the medial dorsal cutaneous nerve. At 20 months postoperatively for the right extremity and 12 months postoperatively for the left extremity, sensation remained intact, and the patient had not experienced any postoperative nerve symptoms. The patient had returned to playing sports without pain or restrictions. PMID- 28633797 TI - Sponge Rubber Revealed Two Years After Penetrating Injury: A Case Report. AB - The present report illustrates a very rare case report of a foreign body granuloma of the foot associated with a 2-year period of a retained spongeous rubber foreign body after a penetrating injury. Because it appeared almost 2 years after the injury, the history of trauma was minimized, the foreign body had migrated from the plantar to the dorsal side of the foot, and the radiographic appearance resembled a malignant process, it was difficult to rule out the possibility of a malignant tumor. This case shows the weakness of magnetic resonance imaging in detecting spongeous rubber in the body. Also, a bone osteoblastic reaction to the foreign body has very rarely been noted. To the best of our knowledge, just 5 cases have been previously reported. Provided suspicion exists of previous trauma with an embedded foreign body, the differential diagnosis of a bone neoplasm should consider the possibility of a foreign body reaction. Biopsy proved to be the best diagnostic tool. PMID- 28633798 TI - Case Report: Irreducible Ankle Fracture With Posterior Tibialis Tendon and Retinaculum, Deltoid Ligament, and Anteromedial Joint Capsule Entrapment. AB - Irreducible ankle fractures are a relatively rare phenomenon. We present a case of a pronation abduction-type ankle fracture that was irreducible in the emergency room despite sedation. The patient was taken to the operating room, where the posterior tibialis tendon and retinaculum, deltoid ligament, and anteromedial capsule were found to be trapped within the joint. After removal of the tissue, alignment was restored. The patient did well clinically and was advanced to full weightbearing at 6 weeks. This is, to the best of our knowledge, the first report of entrapment of all 4 anatomic structures, preventing closed reduction. PMID- 28633799 TI - Interposition Ankle Arthroplasty Using Acellular Dermal Matrix: A Small Series. AB - Although ankle arthrodesis is the reference standard for end-stage ankle arthritis, loss of mobility and adjacent joint arthritis are consequences that alternatives to arthrodesis attempt to avoid. The purpose of the present study was to report the clinical results of interpositional arthroplasty using acellular dermal matrix in 4 patients (age 32 to 42 years) for the treatment of advanced ankle osteoarthritis. The primary findings included relief of pain, with improvement in tibiotalar joint range of motion from a mean of 16.5 degrees (range 0 degrees to 24 degrees ) preoperatively to a mean of 31 degrees (range 25 degrees to 40 degrees ) postoperatively. All 4 patients underwent open arthrotomy of the anterior and posterior tibiotalar capsule with plafond exostectomy and debridement of all deleterious tissue within the ankle capsule. The articular surface of the talar dome was denuded down to smooth subchondral bone, and microfracture was performed. Autologous calcaneal bone marrow aspirate was applied, and talar resurfacing was achieved using an acellular dermal matrix. Knotless anchors placed medially and laterally within the anterior and posterior dome were used to affix the dermal matrix. The follow-up period ranged from 12 to 18 (mean 14) months. The mean pre- and 12-month postoperative Association of Orthopaedic Foot and Ankle Society hindfoot-ankle scale scores were 35 and 88.5, respectively. These outcomes suggest that interpositional tibiotalar arthroplasty using an acellular dermal matrix is successful in improving function and range of motion and decreasing pain. As an alternative to tibiotalar arthrodesis, interpositional tibiotalar arthroplasty might be the procedure of choice for young patients with end-stage ankle arthritis. Longer follow-up periods, histologic testing, and arthroscopic evaluations would be advantageous to further assess the durability of this procedure. PMID- 28633800 TI - Two-View Gravity Stress Imaging Protocol for Nondisplaced Type II Supination External Rotation Ankle Fractures: Introducing the Gravity Stress Cross-Table Lateral View. AB - Assessing ankle stability in nondisplaced Lauge-Hansen supination external rotation type II injuries requires stress imaging. Gravity stress mortise imaging is routinely used as an alternative to manual stress imaging to assess deltoid integrity with the goal of differentiating type II from type IV injuries in cases without a posterior or medial fracture. A type II injury with a nondisplaced fibula fracture is typically treated with cast immobilization, and a type IV injury is considered unstable and often requires operative repair. The present case series (two patients) highlights a standardized 2-view gravity stress imaging protocol and introduces the gravity stress cross-table lateral view. The gravity stress cross-table lateral view provides a more thorough evaluation of the posterior malleolus owing to the slight external rotation and posteriorly directed stress. External rotation also creates less bony overlap between the tibia and fibula, allowing for better visualization of the fibula fracture. Gravity stress imaging confirmed medial-sided injury in both cases, confirming the presence of supination external rotation type IV or bimalleolar equivalent fractures. Open reduction and internal fixation was performed, and both patients achieved radiographic union. No further treatment was required at 21 and 33 months postoperatively. PMID- 28633801 TI - Total Talar Prosthesis Replacement after Talar Extrusion. AB - Dislocation of the talus is a serious and extremely rare injury, with 86 cases reported in the published data in 20 years. The reference standard for case management involves replacement of the dislocated talus to restore the height and function of the tibiotalar joint. The risk of avascular necrosis remains very high, and the standard treatment in such cases is tibiotalar arthrodesis. We report the case of total dislocation of the talus, which was treated with the insertion of a custom total talar prosthesis affixed directly to the tibial cartilage at 6 months after injury. At the 2-year follow-up point, the preliminary results were rather encouraging, with well-functioning activity and an improved American Orthopaedic Foot and Ankle Society foot function scale score increasing from 11 to 77 of 100 and a Short-Form 36-item Health Survey score increasing from 17 to 82. Much longer follow-up periods are necessary to evaluate longer term trends. PMID- 28633802 TI - Assumptions of Statistical Tests: What Lies Beneath. AB - We have discussed many statistical tests and tools in this series of commentaries, and while we have mentioned the underlying assumptions of the tests, we have not explored them in detail. We stop to look at some of the assumptions of the t-test and linear regression, justify and explain them, mention what can go wrong when the assumptions are not met, and suggest some solutions in this case. PMID- 28633803 TI - Why don't we mention "impact on intimacy" when we ask patients to give consent for treatment of oral cancer? PMID- 28633804 TI - Protective effect of N-acetylcysteine on progression to end-stage renal disease: Necessity for prospective clinical trial. AB - BACKGROUND: We aimed to evaluate the potential benefits of N-acetylcysteine (NAC) on the risk of chronic kidney disease (CKD) progression to dialysis-requiring end stage renal disease (ESRDd). METHODS: In a population-based cohort study of 145,062 individuals, 123,608 CKD patients who were followed up for 10years were included, and CKD patients treated with NAC (ICD-9-CM) were compared with those who were not treated. Using propensity score matching, we analyzed the predictors of CKD progression to ESRDd by Cox proportional hazards regression with adjustments for sex, age, and comorbidities, and evaluated the effect of NAC using cumulative defined daily dose (cDDD). RESULTS: NAC use was associated with a reduced risk for progression to ESRDd [hazard ratio (HR), 0.819; 95% confidence interval (CI), 0.781-0.965; P=0.017]. Risk reduction was proportional to cDDD in NAC users compared with that in NAC non users (HR, 0.835, 0.811, and 0.799 for cDDD 91-180, 181-360, and >360, respectively; P for trend=0.018). Risk reduction was apparent in women (P=0.001) and in younger-aged patients of 18-29years (P=0.021) and 30-39years (P=0.033), in the presence of hypertension (P=0.003), and in the absence of diabetes mellitus (P=0.042) and congestive heart failure (P=0.036). CONCLUSION: NAC use was associated with a reduced risk for progression to ESRDd. These results, obtained from retrospective data, indicate that a prospective study is warranted. PMID- 28633805 TI - Somatic support following cardiac arrest for 90 days leading to a healthy baby boy: A case report. AB - Due to a lack of published case reports regarding the somatic support of brain dead pregnant patients, each one adds to the limited knowledge that directs care for this patient population. A young woman experienced a cardiac arrest and was subsequently determined to be approximately 20 weeks pregnant following cardio pulmonary resuscitation. Soon after, she was diagnosed as brain dead, but her family chose to keep her supported in hopes of the delivery of a healthy child. She was transferred to our facility, where she was supported after being diagnosed as brain dead for a total of 90 days and delivered a healthy baby boy at almost 32 weeks gestational age. Following delivery, the pregnant patient expired per brain death protocol. The following case report outlines the details of her care and the outcome of our somatic support to share and collaborate with other healthcare professionals caring for this rare patient population. PMID- 28633806 TI - IL-17 for therapy. AB - The cytokine IL-17 is now a target for an array of therapeutic monoclonal antibodies supposed to treat a variety of inflammatory diseases. The forerunner Secukinumab, an IL-17A neutralizing antibody, is meanwhile approved as first-line treatments for moderate-to-severe plaque psoriasis, and as second-line treatment for psoriatic arthritis and ankylosing spondylitis. Ixekizumab and Brodalumab, both also targeting the IL-17 pathway, were also recently approved by the FDA for plaque psoriasis. Using mice overexpressing IL-17A in a tissue of choice, we showed that the ectopic expression of this cytokine in keratinocytes resulted in a spontaneous and very strong form of psoriasis-like dermatitis. Interestingly, this model showed some typical comorbidities found in humans with psoriasis. In this review, we will discuss why IL-17 is a good target especially in psoriasis and what we learned from mouse models about its functions in pathological situations. PMID- 28633807 TI - Differential induction of ATF3 and HO-1 in myeloid cells and keratinocytes via Dimethylfumarate or Cyclosporine A. AB - BACKGROUND: Chronic inflammatory skin diseases are characterized by controlled proliferation of keratinocytes. Here, activating transcription factor 3 (ATF3) might play a fundamental role. In these inflammatory diseases, proliferation is controlled and only rarely leads to cancer development which can be supported by an inflammatory microenvironment. ATF3 is a dual function protein as it suppresses pro-inflammatory IL-6 and IL-8, but also acts as a pro-oncogenic factor by the suppression of p53. We therefore analyzed ATF3 expression comparing myeloid cells with keratinocytes. OBJECTIVE: To dissect the bi-modal role of ATF3 we pharmacologically induced ATF3 and analyzed its influence on cytokine expression and secretion in a cell type specific manner. METHODS: Since inflammatory skin diseases can be treated systemically with Cyclosporin A or Dimethylfumarate we stimulated myeloid cells and primary human keratinocytes with these drugs and analyzed gene expression by quantitative real-time PCR. Cytokine secretion was measured by ELISA. RESULTS: In the present study, we could show that ATF3 is induced in PBMCs by DMF and weakly by Ebselen, while CsA is the most prominent inducer of ATF3 in keratinocytes without enhancing HO-1 transcription. Further we could show that induction of stress by LPS treatment elevates IL-1beta and IL-6 and weakly ATF3 transcription in PBMCs. While transcription of both cytokines is elevated, LPS treatment mediates IL-6 secretion with only little IL 1beta secretion. Treatment with DMF dampens LPS-induced transcription. CONCLUSIONS: Taken together, our results shed light into the different carcinogenic potential of CsA and DMF, which both target ATF3. Collectively our data demonstrate that CsA strongly induces pro-carcinogenic ATF3 in keratinocytes, whereas ATF3 induction by DMF in myeloid cells acts anti inflammatory. PMID- 28633808 TI - Impact of MR-guided boiling histotripsy in distinct murine tumor models. AB - Interest in mechanical high intensity focused ultrasound (HIFU) ablation is rapidly growing. Boiling histotripsy (BH) is applied for mechanical fragmentation of soft tissue into submicron fragments with limited temperature increase using the shock wave and cavitation effects of HIFU. Research on BH has been largely limited to ex vivo experiments. As a consequence, the in vivo pathology after BH treatment and the relation to preexistent tissue characteristics are not well understood. This study reports on in vivo MR guided BH treatment, either with 100 or 200 pulses per focal spot, in three different subcutaneous mouse tumor models: a soft-tissue melanoma (B16OVA), a compact growing thymoma (EL4), and a highly vascularized neuroblastoma (9464D). Extensive treatment evaluation was performed using MR imaging followed by histopathology 2h after treatment. T2 weighted MRI allowed direct in vivo visualization of the BH lesions in all tumor models. The 100-pulse treated area in the B16OVA tumors was larger than the predicted treatment volume (500+/-10%). For the more compact growing EL4 and 9464D tumors this was 95+/-13% and 55+/-33%, respectively. Histopathology after the 100-pulse treatment revealed completely disintegrated lesions in the treated area with sharp borders in the compact EL4 and 9464D tumors, while for B16OVA tumors the lesion contained a mixture of discohesive (partly viable) clusters of cells, micro-vessel remainings, and tumor cell debris. The treatment of B16OVA with 200 pulses increased the fragmentation of tumor tissue. In all tumor types only micro hemorrhages were detected after ablation (slightly higher after 200-pulse treatment for the highly vascularized 9464D tumors). Collagen staining revealed that the collagen fibers were to a greater or lesser extent still intact and partly clotted together near the lesion border in all tumor models. In conclusion, this study reveals effective mechanical fragmentation of different tumor types using BH without major hemorrhages. However, treatment settings may need to be adjusted to the tissue characteristics for optimal tissue fragmentation. PMID- 28633809 TI - Extraction of olive oil assisted by high-frequency ultrasound standing waves. AB - High-frequency ultrasound standing waves (megasonics) have been demonstrated to enhance oil separation in the palm oil process at an industrial level. This work investigated the application of megasonics in the olive oil process on laboratory and pilot scale levels. Sound pressure level and cavitational yield distribution were characterised with hydrophones and luminol to determine associated physical and sonochemical effects inside the reactor. The effect of water addition (0%, 15%, and 30%), megasonic power levels (0%, 50%, and 100%), and malaxation time (10min, 30min, and 50min) was evaluated using response surface methodology (RSM) in a 700g batch extraction process. The RSM showed that the effect of the megasonic treatment (585kHz) in the presence of a reflector is more prominent at longer malaxation time (50min) and at higher water addition (30%) levels post malaxation. Longer megasonic treatment of the malaxed paste (up to 15min; 220kJ/kg) increased oil extractability by up to 3.2%. When treating the malaxed paste with the same specific energy, higher oil extractability was obtained with longer treatments and low megasonic power levels in comparison to higher power levels and shorter times. Megasonic treatment of the paste before malaxation (585kHz, 10min, 146kJ/kg) and no water addition provided an increase in oil extractability of up to 3.8% with respect to the non-sonicated control. A double sonication intervention, before and after malaxation, using low (40kHz) and high (585kHz) frequency, respectively, provided up to 2.4% increase in oil extractability. A megasonic intervention post-malaxation (400 and 600kHz, 57 67min, 18-21kJ/kg) on a pilot scale using early-harvest olive fruits resulted in up to 1.7% extra oil extractability. Oil extracted under a high sonication frequency (free radical production regime) did not impact on olive oil quality parameters at reactor characterisation levels. Megasonic standing wave forces can enhance olive oil separation at various stages of the olive oil extraction process. PMID- 28633810 TI - Sonochemical rate enhanced by a new nanomagnetic embedded core/shell nanoparticles and catalytic performance in the multicomponent synthesis of pyridoimidazoisoquinolines. AB - A sonochemical approach for the one-pot three-component synthesis of pyridoimidazoisoquinolines via by using phthalaldehyde, trimethylsilylcyanide and aminopyridines the presence of a catalytic amount of a new nanomagnetic catalyst Fe3O4@SiO2-CO-C6H4-NH2 is described. The characterization of the nanocatalyst and the product was done by various methods, such as FT-IR, SEM, EDX, TGA/DTA, NMR, MS and CHN analyses. This is the first design, preparation, characterization and application of the present core/shell nanomaterial and also the first ultrasound irradiated synthesis of the biologically and pharmaceutically important fused polycyclic compounds in ethanol as a green solvent. This novel protocol offers several advantages such as high yields, short reaction times, environmentally friendly reaction media, easily isolation of the products, simple preparation and recoverability of the nanocatalyst by an external magnet and reusing several times without significant decrease in catalytic activity. PMID- 28633811 TI - Effects and mechanism of ultrasonic irradiation on solidification microstructure and mechanical properties of binary TiAl alloys. AB - In spite of their high temperature and reactivity, the binary TiAl alloys are successfully imposed by the ultrasonic irradiation and the microstructure evolution, solidification behaviors and mechanical properties are elaborately investigated. After ultrasonic irradiation, a high quality ingot without shrinkage defects and element segregation is obtained and the coarse dendrite structure is well modified into fine non-dendrite globular grains. The coarse lamellar colony and lamellar space of Ti44Al alloy is refined from 685MUm to 52MUm and 1185nm to 312nm, respectively (similarly, 819MUm to 102MUm and 2085nm to 565nm for Ti48Al alloy). For Ti48Al alloy, the alpha peritectic phase is simultaneously precipitated from the melt as well as the beta primary phase before the peritectic reaction and the solidification is transformed into the mixed alpha-solidifying and beta-solidifying. Ultrasonic irradiation promotes the peritectic reaction and phase transformation completely and the phase constituent becomes more close to the equilibrium level. The compressive strength of Ti44Al and Ti48Al alloys are increased from 623MPa to 1250MPa and 980MPa to 1295MPa, respectively. The grain refinement and dendrite transformation enhance the grain boundary sliding improving the plastic deformation ability. Ultrasonic irradiation significantly accelerates the melt flow and solute redistribution and the main grain refinement mechanism is the cavitation-enhanced nucleation by inclusion activation and heightened supercooling. PMID- 28633812 TI - Sonochemical synthesis of a new cobalt(II) complex: Crystal structure, thermal behavior, Hirshfeld surface analysis and its usage as precursor for preparation of CoO/Co3O4 nanoparticles. AB - A bidentate Schiff base ligand and its nano-structured cobalt(II) complex were synthesized under ultrasound irradiation and then their structures were identified by physical and spectral techniques SEM and XRD techniques were used to confirm the nanostructure character of the complex. Single crystal X-ray diffraction analysis showed that the complex crystallizes in the triclinic system with space group of P1- and two crystallographically independent molecules participate in its asymmetric unit. In the structure of complex, cobalt center is four-coordinated by two iminic nitrogens of bidentate Schiff base ligand and two bromide anions in a distorted tetrahedral geometry. Crystal packing analysis well indicates that C-H?Br, C-H?pi and pi?pi are the most intermolecular interactions. Moreover Hirshfeld surface analysis and 2D Fingerprint plots were applied for more investigation of intermolecular interactions. In addition, sonochemically prepared cobalt(II) bromide complex was subjected to calcination process under air atmosphere for preparation of cobalt oxide nanoparticles. The XRD pattern confirmed the simultaneous formation of CoO and Co3O4 nanoparticles. PMID- 28633813 TI - Multi-stimuli responsive smart chitosan-based microcapsules for targeted drug delivery and triggered drug release. AB - In the present study, we designed a novel, multi-stimuli responsive, biocompatible and non-immunogenic smart carrier for targeted delivery and triggered release of hydrophobic drugs. The designed multi-stimuli responsive smart chitosan-based microcapsules (MSRS-CS-MCs) have been fabricated successfully from folic acid (FA) functionalized thiolated chitosan via a facile sonochemical method. Targeting moiety FA and red fluorescent dye (Rhodamine B isothiocyanate, RITC) were immobilized onto the shells of microcapsules. Meanwhile, oleic acid (OA) modified Fe3O4 magnetic nanoparticles (OA-Fe3O4MNPs) and a model hydrophobic drug, green fluorescent dye (Coumarin 6, C6), were encapsulated into the microcapsules. As drug carriers, the obtained spherical MSRS-CS-MCs with the average size of 500nm showed excellent magnetic responsive ability, favorable selectively folate-receptor-mediated targeting functionality to the HeLa cells, and attractive reduction-responsive release ability for hydrophobic drugs. The integration of magnetic and reduction dual-responsiveness, folate-receptor-mediated targeting functionality and fluorescence visualization into the versatile microcapsules make MSRS-CS-MCs promising nanocarriers for future biomedical applications. PMID- 28633814 TI - Na emission and bubble instability in single-bubble sonoluminescence. AB - Na emission in single-bubble sonoluminescence (SBSL) was observed from 0.1mM sodium dodecyl sulfate (SDS) solution containing a dissolved noble gas at a low acoustic pressure, at which a continuous spectral component was negligible. High speed shadowgraph movies were captured at a frame rate of 30,000fps, which indicated that bubble dancing is responsible for the Na emission. The measured bubble path length was well correlated with the Na intensity. The disintegration of a daughter bubble followed by immediate coalescence was frequently observed, which may have been the cause of the bubble dancing. A comparison of the Na spectra obtained in SBSL and multibubble SL showed that the conditions under which Na emission is generated are twofold. A narrow component was observed in the Na spectrum in SBSL, while narrow and broad components were observed in MBSL. PMID- 28633815 TI - Ultrasound assisted selective catalytic transfer hydrogenation of soybean oil using 5% Pd/C as catalyst under ambient conditions in water. AB - Catalytic transfer hydrogenation (CTH) is an alternative approach that does not require the use of potentially dangerous hydrogen gas. Pd/C is the most favoured catalyst for the selective hydrogenation of soybean oil yielding lower extent of formation of stearic acid and trans-isomer, which have adverse health effects. The present work deals with intensification of catalytic transfer hydrogenation of soybean oil in the presence of 5wt.% Pd/C using ultrasound under ambient reaction conditions. The effect of important operating parameters such as ultrasound power, temperature, type of hydrogen donor, catalyst loading and donor concentration on the progress of reaction has been investigated. It was established that the maximum extent of hydrogenation as indicated by reduction in iodine value from 135 to 95 was observed under optimized conditions of irradiation power as 100W, 22kHz frequency, 90% duty cycle, ammonium formate concentration of 0.32mol/50ml water and 2% (w/w) Pd/C loading at ambient temperature and pressure in the presence of water as solvent. The approach also offered excellent selectivity with much lower trans-isomer formation as compared to the conventional approach of high pressure hydrogenation. Overall, the work has successfully demonstrated process intensification benefits due to the use of ultrasound for the Pd/C catalyzed transfer hydrogenation of soybean oil. PMID- 28633816 TI - A derivation of the stable cavitation threshold accounting for bubble-bubble interactions. AB - The subharmonic emission of sound coming from the nonlinear response of a bubble population is the most used indicator for stable cavitation. When driven at twice their resonance frequency, bubbles can exhibit subharmonic spherical oscillations if the acoustic pressure amplitude exceeds a threshold value. Although various theoretical derivations exist for the subharmonic emission by free or coated bubbles, they all rest on the single bubble model. In this paper, we propose an analytical expression of the subharmonic threshold for interacting bubbles in a homogeneous, monodisperse cloud. This theory predicts a shift of the subharmonic resonance frequency and a decrease of the corresponding pressure threshold due to the interactions. For a given sonication frequency, these results show that an optimal value of the interaction strength (i.e. the number density of bubbles) can be found for which the subharmonic threshold is minimum, which is consistent with recently published experiments conducted on ultrasound contrast agents. PMID- 28633817 TI - Computational study of state equation effect on single acoustic cavitation bubble's phenomenon. AB - Many models have been established to study the evolution of the bubble dynamics and chemical kinetics within a single acoustic cavitation bubble during its oscillation. The content of the bubble is a gas medium that generates the evolution of a chemical mechanism governed by the internal bubble conditions. These gases are described by a state equation, linking the pressure to the volume, temperature and species amounts, and influencing simultaneously the dynamical, the thermal and the mass variation in the cavitation bubble. The choice of the state equation to apply has then a non-neglected effect on the obtained results. In this paper, a comparative study was conducted through two numerical models based on the same assumptions and the same scheme of chemical reactions, except that the first one uses the ideal gas equation to describe the state of the species, while the second one uses the Van der Waals equation. It was found that though the dynamic of the bubble is not widely affected, the pressure and temperature range are significantly increased when passing from an ideal gas model to a real one. The amounts of chemical products are consequently raised to approximately the double. This observation was more significant for temperature and pressure at low frequency and high acoustic amplitude, while it is noticed that passing from ideal gas based approach to the Van der Waals one increases the free radicals amount mainly under high frequencies. When taking the results of the second model as reference, the relative difference between both results reaches about 60% for maximum attained temperature and 100% for both pressure and free radicals production. PMID- 28633818 TI - Insight into the synthesis procedure of Fe3+/TiO2-based photocatalyst applied in the selective photo-oxidation of benzyl alcohol under sun-imitating lamp. AB - Fe3+/TiO2/zeolite Y photocatalyst synthesized by using sonophotodeposition method was compared with photocatalysts prepared by simple photodeposition and sonodeposition methods in order to clarify the role of light irradiation and ultrasounds while they are used simultaneously. To gain an insight into the mechanism of this method a detailed characterization of the photocatalysts was carried out by means of the following techniques: UV-vis diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, transmission electron microscopy, Mossbauer measurements and photocatalytic test reaction. Basing on the results from these techniques the chemical role of light and mainly mechanical role of ultrasound were observed. The selective photocatalytic oxidation of benzyl alcohol into benzaldehyde in liquid phase was a test reaction verifying the utility of the prepared materials. The best photocatalytic efficiency in this reaction was performed by photocatalyst synthesized using compilation of ultrasound energy with photoexcitation. PMID- 28633819 TI - Effects of ultrasound pretreatment with different frequencies and working modes on the enzymolysis and the structure characterization of rice protein. AB - The effects of ultrasound pretreatment with different frequencies and working modes, including mono-frequency ultrasound (MFU), dual-frequency ultrasound (DFU) and tri-frequency ultrasound (TFU), on the degree of hydrolysis (DH) of rice protein (RP) and angiotensin-I-converting enzyme (ACE) inhibitory activity of RP hydrolysate were investigated. Ultraviolet-visible (UV) spectroscopy, fourier transform infrared (FTIR) spectroscopy, surface hydrophobicity and scanning electron microscopy (SEM) of RP pretreated with ultrasound were measured. The results showed that ultrasound pretreatment did not increase DH of RP significantly (p>0.05). However, all the ultrasound pretreatment increased the ACE inhibitory activity of RP hydrolysate significantly (p<0.05). The MFU of 20kHz showed higher ACE inhibitory activity compared to that of other MFU. The ACE inhibitory activity of sequential DFU was higher than that of simultaneous with the same frequency combination. Sequential TFU of 20/35/50kHz produced the highest increase in ACE inhibitory activity in contrast with other ultrasound frequencies and working modes. All the results under ultrasound pretreatment showed that ultrasound frequencies and working modes were of great effect on the ACE inhibitory activity of RP. The changes in UV-Vis spectra and surface hydrophobicity indicated the unfolding of protein and exposure of hydrophobic groups by ultrasound. The FTIR analysis showed that all the ultrasound pretreatment with different frequencies and working modes decreased alpha-helix, beta-turn content and increased beta-sheet, random coil content of RP. The SEM results indicated that ultrasound pretreatment resulted in the deformation of RP. In conclusion, the frequency selection of ultrasound pretreatment of RP is essential for the preparation of ACE inhibitory peptide. PMID- 28633820 TI - Green synthesis of Ag-Cr-AC nanocomposites by Azadirachta indica and its application for the simultaneous removal of binary mixture of dyes by ultrasonicated assisted adsorption process using Response Surface Methodology. AB - In the present studies the Ag-Cr-AC nanocomposites were synthesized by Azadirachta indica leaves extract. They were inoculated on the amorphous surface of activated carbon. The surface morphology and structural identification was determined by SEM, FTIR and XRD techniques. The simultaneous removal of binary dye system of Reactive Red and Crystal Violet were performed by ultrasonicated assisted adsorption process utilizing Ag-Cr-AC nanocomposites. Central Composite Design (CCD) having 5 factors of time, pH, amount of Ag-Cr-AC (adsorbent), concentrations of Reactive Red (RR) and Crystal Violet (CV) was employed. Response Surface Methodology was applied to study the Optimum Operating Parameters (OOP) for the adsorption process. The current studies showed that they can be efficiently employed to remove the coloured effluent from aqueous media as the simultaneous removal of dyes was observed to be 64.92% and 82.47% for RR and CV dyes respectively. Adsorption equilibrium was studied by Freundlich, Langmuir, Dubinin-Radushkevich, Temkin and Harkins-Jura Isotherm Models. The Langmuir isotherm was observed to be followed by the RR-Ag-Cr-AC system while CV-Ag-Cr-AC followed Harkins-Jura Isotherm model. For the binary system, the removal of CV and RR dyes by the nanocomposites obeyed Harkins-Jura model at temperature of 40 degrees C. Thermodynamics studies affirmed the spontaneous nature of adsorption process. pHpzc was evaluated to be 6.29. The purification cost per cubic meter of the effluent was evaluated to be US$ 85.08. The proposed method might prove to be an efficient and cost effective way to eradicate color from the binary mixture of RR and CV dyes. PMID- 28633821 TI - Enhanced production of hypocrellin A by ultrasound stimulation in submerged cultures of Shiraia bambusicola. AB - Hypocrellin A (HA), a naturally occurring fungal perylenequinone, is widely used in clinic to treat skin diseases and developed as a photodynamic therapy (PDT) agent against cancers. In this study, a low intensity ultrasound (US, 0.28W/cm2 at 40kHz) was conducted thrice of repeated US exposure (5-min) with an interval of 12h to stimulate HA production of Shiraia bambusicola after 72h of the initial submerged cultures. US not only increased the content of HA by 177.2% in mycelia, but stimulated the release of HA into the medium with the highest total production of HA (247.67mg/L) on day 8. US could result in the decreased pellet diameter, the enhanced membrane permeability, the alternation of membrane compounds and reactive oxygen species (ROS) generation. Furthermore, the ultrasonic treatment up-regulated the expression of some HA biosynthetic genes including polyketide synthase gene (PKS), O-methyltransferase gene (Omef), O methyltransferase/FAD-dependent monooxygenase (Mono) and FAD/FMN-dependent oxidoreductase gene (FAD), and activated major facilitator superfamily transporter gene (MFS) for HA exudation. The enhancement of HA production was mainly due to both the stimulated cellular biosynthesis and the enhanced fungal exudation of HA. These results provide a basis for understanding the US elicitation and a valuable strategy for enhancing HA production in submerged Shiraia cultures. PMID- 28633822 TI - Effects of pulsed ultrasound on rheological and structural properties of chicken myofibrillar protein. AB - The effects of pulsed ultrasound (PUS) (power: 240w) with varying time (0, 3, 6, 9, 12 and 15min) on rheological and structural properties of chicken myofibrillar protein (CMP) were examined. PUS treatment significantly caused a decrease in the viscosity coefficients (k) but an increase in the flow index (n) value of CMP solutions within short time (0-6min), while had no significant effect for longer time (9-15min). Besides, at 6min, the solubility and microstructure of CMP samples were optimum. The primary structure of CMP was not altered by PUS treatment. However, Raman spectroscopy revealed a decrease in the alpha-helix and beta-sheets proportion and an increase in the beta-turn of CMP following PUS treatment. Random coil reached a maximum at 6min. The changes in tertiary and quaternary structure of CMP by PUS treatment also occurred. As PUS time extended, S0-ANS for CMP increased measured by ANS fluorescence probe method. However, the normalized intensity of 760cm-1 increased from 0min to 6min, and then decreased to 15min by Raman test. Moreover, the reactive sulphur (SH) contents and disulfide bonds (S-S) of samples increased while the total SH contents decreased within 0-6min. At 9min and above, the contents of reactive SH groups were almost equal to the contents of total SH groups. Differential scanning calorimetry (DSC) of CMP showed that peak temperature (Td2) for myosin and peak temperature (Td3) for actin were both reduced in the first 6min, while Td3 was not observed from 9min following PUS treatment. Therefore, 6min was the optimum PUS time to obtain better CMP rheological and structural properties. PMID- 28633823 TI - Sono-synthesis of solar light responsive S-N-C-tri doped TiO2 photo-catalyst under optimized conditions for degradation and mineralization of Diclofenac. AB - C-N-S-tri doped TiO2 anatase phase was synthesized using a facile, effective and novel sonochemical method at low frequency (20kHz) and at room temperature. Titanium butoxide as the titanium precursor and thiourea as the dopant source were used in the synthesis of the photo-catalyst. The effects of important parameters such as thiourea/Ti molar ratio, ultrasound intensity, sonication time and temperature were studied on the synthesis of tri-doped TiO2. The XPS results confirmed the presence of N, S, and C in the photo-catalyst. The photo-catalytic efficiency of the synthesized catalyst was studied toward the removal of Diclofenac as a model pharmaceutical organic pollutant. The results confirmed that the photo-catalyst synthesized with narrower band gap energy, shorter sonication time and higher ultrasound intensity leads to a rapid removal of Diclofenac. The effect of operational variables on the photo-catalytic activity of C-N-S tri doped TiO2 nanoparticles was studied and optimized using the Taguchi method as a statistical technique. Additionally, the degradation process followed the pseudo-first-order kinetics model and the highest apparent rate constant of 0.0632min-1 achieved in 90min. Chemical oxygen demand (COD) analysis confirmed that the mineralization took place completely (100%) under the optimized conditions in 180min. Different scavengers were applied during the degradation process and active species such as OH and O2- had key roles in the photo catalytic process. PMID- 28633824 TI - Ultrasound-assisted extraction of polysaccharides from Rhododendron aganniphum: Antioxidant activity and rheological properties. AB - In this study, we aimed to optimize the extraction of polysaccharides from the leaves of Rhododendron aganniphum and investigate its rheological properties and antioxidant activity. After optimizing the operating parameters using a Box Behnken design (BBD), the results showed that the optimal ultrasound-assisted extraction conditions were as follows: extraction temperature, 55 degrees C; liquid-solid ratio, 25:1; extraction time, 2.2h; and ultrasound treatment power, 200W. The optimized experimental yield of polysaccharides by ultrasound-assisted extraction (PUAE) was 9.428%, higher than that obtained by hot water extraction (PHWE) for 12h at the same liquid-solid ratio and extraction temperature. In the in vitro antioxidant activity tests, PUAE had higher positive radical scavenging activity for hydroxyl, superoxide and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals than PHWE. However, PUAE and PHWE solutions had similar intermolecular interactions in the steady-shear flow and dynamic viscoelasticity tests, resulting in similar macroscopic behaviour. With respect to the apparent viscosity, storage modulus (G') and loss modulus (G") of PUAE were lower at the same shear rate or angular frequency. All PUAE solutions exhibited non-Newtonian shear-thinning pseudoplastic behaviour that was accurately described by the Carreau model but was better fit by the power-law model at high shear rates (>=1/s), which demonstrated that the variation in the apparent viscosity dependence was greater at higher concentrations and shear rates. The G' and G" of the solutions increased as the experimental frequency increased from 0.05 to 500rad/s under all experimental concentrations, and the modulus crossover point decreased gradually with increasing PUAE concentration. The above results demonstrated that the ultrasound-assisted extraction methods gave a higher yield of polysaccharides from the leaves of R. aganniphum with a shorter extraction time than the hot water extraction method, which could affect the apparent viscosity and dynamic viscoelasticity. PUAE presented good radical scavenging activity for DPPH, superoxide and hydroxyl radicals in vitro and could be used as a natural antioxidant in the food and medical industries. PMID- 28633826 TI - Optimization and characterization of ultrasound assisted preparation of curcumin loaded solid lipid nanoparticles: Application of central composite design, thermal analysis and X-ray diffraction techniques. AB - This study is devoted to preparation of novel solid lipid nanoparticles (SLNs) for the encapsulation of curcumin which is produced by micro-emulsion and ultrasonication using stearic acid and tripalmitin as solid lipids, tween80 and span80 as surfactants. The relation between particle size and entrapment efficiency of the produced SLNs was operated by central composite design (CCD) under response likes surface method (RSM). The variables including the ratio of lipids (X1), the ratio of surfactants (X2), drug/lipid ratio (X3), time of sonication (X4) and time of homogenization (X5). Particle size and entrapment efficiency of the loaded curcumin was justified according to the minimum particle size and maximum entrapment efficiency. The curcumin loaded SLNs presented fairly spherical shape with the mean diameter and entrapment efficiency of 112.0+/-2.6nm and 98.7+/-0.3%, respectively. The optimized SLNs were characterized by X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC), photon correlation spectroscopy (PCS) and field emission scanning electron microscopy (FESEM). The drug release profile of the optimal formulated material was examined in aqueous media and almost 30% of the curcumin loaded in SLNs was gradually released during 48h, which reveals efficient prolonged release of the drug. PMID- 28633825 TI - Structural evolution, growth mechanism and photoluminescence properties of CuWO4 nanocrystals. AB - Copper tungstate (CuWO4) crystals were synthesized by the sonochemistry (SC) method, and then, heat treated in a conventional furnace at different temperatures for 1h. The structural evolution, growth mechanism and photoluminescence (PL) properties of these crystals were thoroughly investigated. X-ray diffraction patterns, micro-Raman spectra and Fourier transformed infrared spectra indicated that crystals heat treated and 100 degrees C and 200 degrees C have water molecules in their lattice (copper tungstate dihydrate (CuWO4.2H2O) with monoclinic structure), when the crystals are calcinated at 300 degrees C have the presence of two phase (CuWO4.2H2O and CuWO4), while the others heat treated at 400 degrees C and 500 degrees C have a single CuWO4 triclinic structure. Field emission scanning electron microscopy revealed a change in the morphological features of these crystals with the increase of the heat treatment temperature. Transmission electron microscopy (TEM), high resolution-TEM images and selected area electron diffraction were employed to examine the shape, size and structure of these crystals. Ultraviolet-Visible spectra evidenced a decrease of band gap values with the increase of the temperature, which were correlated with the reduction of intermediary energy levels within the band gap. The intense photoluminescence (PL) emission was detected for the sample heat treat at 300 degrees C for 1h, which have a mixture of CuWO4.2H2O and CuWO4 phases. Therefore, there is a synergic effect between the intermediary energy levels arising from these two phases during the electronic transitions responsible for PL emissions. PMID- 28633827 TI - Effect of ultrasonic vibration treatment on solid-state reactions between Fe2O3 and CaO. AB - In the present study, ultrasonic vibration was applied to the solid-state reaction between Fe2O3 and CaO. The effect of the ultrasonic vibration treatment on the formation of CaFe2O4 (CF) from the solid-state reaction was investigated by X-ray diffraction (XRD) and the Rietveld structure refinement method. The results indicated that the solid-state reaction between Fe2O3 and CaO was accelerated by ultrasonic treatment (UT), which efficiently lowered the formation temperature of the solid-state CF and increased the quantity formed by enhancing the mass transfer process of the reactions. Without the UT, CF and Ca2Fe2O5 (C2F) were produced at 750 degrees C and the mass fractions of CF and C2F increased with the experiment temperature, with approximately 47.76% CF and 40.66% C2F produced at 850 degrees C. With the UT, mass fractions of 5.67% CF and 18.20% C2F were formed at 700 degrees C, and increasing the experiment temperature enhanced the formation of CF and C2F. Moreover, a significantly greater amount of CF than C2F was formed when the temperature exceeded 700 degrees C. A CF mass fraction of approximately 98.73% was obtained by UT at 850 degrees C, much higher than the 47.76% obtained without UT. In addition, increasing the ultrasonic power influenced the formation of the CF phase. The CF content increased from 19% to 77.34% with increasing ultrasonic power from 0 to 89%*2kW. Furthermore, a prolonged UT time also promoted the formation of solid phase CF. The mass fraction of CF ranged from 19% to 77.34% when the UT time was varied from 0 to 150min. PMID- 28633828 TI - Bi25VO40 microcube with step surface for visible light photocatalytic reduction of Cr(VI): Enhanced activity and ultrasound assisted regeneration. AB - In this study, a kind of bismuth vanadium (Bi25VO40) microcube with step surface was successfully synthesized by a fast and mild hydrothermal method. The reaction time and hydrothermal temperature are the key factors which are accounted for the formation of this unique structure. The as-prepared Bi25VO40 microcube exhibited considerably higher visible light photocatalytic activity compared with the smooth one, revealing that fabrication of Bi25VO40 with step surface was an effective method to improve the photocatalytic activity. The enhanced photocatalytic activity over this Bi25VO40 could be attributed to its enhanced separation efficiency of photo-generated holes and electrons. In addition, the XPS analysis of the Bi25VO40 after photo-reduction showed that most of highly toxic Cr(VI) were reduced into less dangerous Cr(III). The XRD results indicated the reduced Cr(III) existed in the form of Cr2O3 and Cr3O8 on the catalyst surface and occupied the active site, counting for the decreased activity after multiple use. A facile ultrasound treatment facilitated the regeneration of deactivated photocatalyst by removing the adsorbed Cr2O3 and Cr3O8, improving the removal ratio of Cr(VI) over the photocatalyst from 74.0% to 85.6% after four recycling use, which make it applicable for the photocatalytic removal of a typical Cr(VI) pollutant continuously. PMID- 28633829 TI - Different valence Sn doping - A simple way to detect oxygen concentration variation of ZnO quantum dots synthesized under ultrasonic irradiation. AB - An ultrasonic method is employed to synthesize the Sn doped Zn0.95Sn0.05O quantum dots with green light emission. Sn2+ and Sn4+ ions are used to create different optical defects inside Zn0.95Sn0.05O quantum dots and the changing trend of oxygen concentration under different ultrasonic irradiation power are investigated. The photoluminescence spectra are employed to characterize the optical defects of Zn0.95Sn0.05O quantum dots. The UV-vis spectra are used to study the band gap of Zn0.95Sn0.05O quantum dots, which is influenced by their sizes. The results indicate that ultrasonic power would influence the size of Zn0.95Sn0.05O quantum dots as well as the type and quantity of defects in ZnO quantum dots. Changing trends in size of Sn2+ and Sn4+ doped Zn0.95Sn0.05O quantum dots are quite similar with each other, while the changing trends in optical defects types and concentration of Sn2+ and Sn4+ doped Zn0.95Sn0.05O quantum dots are different. The difference of the optical defects concentration changing between Sn2+ doped Zn0.95Sn0.05O quantum dots (VO defects) and Sn4+ doped Zn0.95Sn0.05O quantum dots (OZn and Oi defects) shows that the formation process of ZnO under ultrasonic irradiation wiped oxygen out. PMID- 28633830 TI - Accompanying the frequency shift of the nonlinear resonance of a gas bubble using a dual-frequency excitation. AB - An asymptotic method is applied to analyze the nonlinear oscillations of a gas bubble driven by a dual-frequency excitation. More specifically, the latter is considered as a combination of two neighboring, incommensurate frequencies and is treated as a nonstationary excitation. This implies that both amplitude and phase of the bubble response are slowly oscillating at the time scale of the frequency difference, thus leading to a regime of aperiodic oscillations. The approximate solution is successfully compared with numerical simulations and reveals the possibility of achieving larger bubble response amplitude compared to the monofrequency excitation for sufficiently high driving pressure and specific values of the frequency difference. The asymptotic theory captures the generation of additional spectral components coming from the nonlinear mixing of both driving frequencies. This mechanism is responsible for a global enhancement of the dual-frequency bubble response as it enables an energy transfer towards more efficient components which are successively tuned with the nonlinearly shifted resonance frequency of the bubble, thus limiting the saturation due to softening. PMID- 28633831 TI - The effects of organoclay on the morphology and mechanical properties of PAI/clay nanocomposites coatings prepared by the ultrasonication assisted process. AB - In this research, solvent based polyamide - imide (PAI)/clay nanocomposites were prepared successfully using the solution dispersion technique. With the assistance of the ultrasonic wave, the effect of the ultrasonic wave time on the microstructure of 3wt% PAI/C20A nanocomposite (NC) was investigated. Then, the best ultrasonic parameters were selected and the effects of the concentration of Cloisite 20A (C20A) (1, 3 and 5wt% C20A) on the microstructure and mechanical properties (adhesion, hardness, flexibility, wear and impact) of NCs were investigated. The PAI, C20A and nanocomposites (NC)s were characterized by Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray analysis (EDX), and Wide-angle X-ray diffraction (WAXD). The results showed that the sample with 1 and 3wt% C20A had better mechanical properties, as compared to the pure PAI and the 5wt% NC. PMID- 28633832 TI - Effects of ultrasound on the beef structure and water distribution during curing through protein degradation and modification. AB - The objective of this study was to explore the mechanisms of power ultrasound (PUS, 150 and 300W) and treatment time (30 and 120min) on the water-holding capacity (WHC) and tenderness of beef during curing. Beef muscle at 48h post mortem was subjected to PUS treatment at a frequency of 20kHz. Analysis of compression loss and shear force showed that PUS-assisted curing significantly increased the WHC and the tenderness of beef compared to static brining (p<0.05). According to the analysis of LF-NMR, PUS treatment could increase the P21 values which indicated an improvement in water-binding ability of beef muscle. SDS-PAGE and LC-ESI-MS/MS analysis suggested that PUS induced moderate oxidation of myosin causing polymerization, which may contribute to increased water retention. On the other hand, an increased tenderness of beef is suggested by the increased MFI values and proteolysis of desmin and troponin-T. Transmission electron microscopy (TEM) further supported the effects of PUS on WHC and tenderness changes due to the swelling and disruption of myofibrils. Thus, these results provide knowledge about the mechanism for improving WHC and tenderness of beef by PUS curing, which could be employed as an emerging technology for various meat curing processes. PMID- 28633833 TI - Recent advances in ultrasonic treatment: Challenges and field applications for controlling harmful algal blooms (HABs). AB - Algal blooms are a naturally occurring phenomenon which can occur in both freshwater and saltwater. However, due to excess nutrient loading in water bodies (e.g. agricultural runoff and industrial activities), harmful algal blooms (HABs) have become an increasing issue globally, and can even cause health effects in humans due to the release of cyanotoxins. Among currently available treatment methods, sonication has received increasing attention for algal control because of its low impact on ecosystems and the environment. The effects of ultrasound on algal cells are well understood and operating parameter such as frequency, intensity, and duration of exposure has been well studied. However, most studies have been limited to laboratory data interpretation due to complicated environmental conditions in the field. Only a few field and pilot tests in small reservoirs were reported and the applicability of ultrasound for HABs prevention and control is still under question. There is a lack of information on the upscaling of ultrasonication devices for HAB control on larger water bodies, considering field influencing factors such as rainfall, light intensity/duration, temperature, water flow, nutrients loading, and turbidity. In this review article, we address the challenges and field considerations of ultrasonic applications for controlling algal blooms. An extensive literature survey, from the fundamentals of ultrasound techniques to recent ultrasound laboratory and field studies, has been thoroughly conducted and summarized to identify future technical expectations for field applications. Case studies investigating spatial distribution of frequency and pressure during sonication are highlighted with future implications. PMID- 28633834 TI - Preparation of a novel sonocatalyst, Au/NiGa2O4-Au-Bi2O3 nanocomposite, and application in sonocatalytic degradation of organic pollutants. AB - A novel nanocomposite, Au/NiGa2O4-Au-Bi2O3, as an effective sonocatalyst was prepared through hydrothermal process and high-temperature calcination methods, and then characterized by X-ray diffractometer (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). The sonocatalytic activity of Au/NiGa2O4-Au-Bi2O3 nanocomposite was detected through the degradation of some organic pollutants under ultrasonic irradiation. Furthermore, the influences of mass ratio of NiGa2O4 and Bi2O3, ultrasonic irradiation time and used times on the sonocatalytic degradation efficiency were investigated by using Total Organic Carbon (TOC) and UV-vis spectroscopy. The experimental results showed that, because of the existence of Au nanoparticles (AuNPs) served as both conductive passageway and co-catalyst, the nanocomposite sonocatalyst (Au/NiGa2O4-Au-Bi2O3) displayed an excellent sonocatalytic activity in degradation of some organic pollutants under ultrasonic irradiation. PMID- 28633835 TI - Influence of increase in static pressure on bulk nanobubbles. AB - The concentration and size distribution of bulk nanobubbles (ultrafine bubbles) of air in liquid was measured before and after increasing the static pressure. It was found that, after pressurization, the number concentration decreased and the size increased. The effect of pressurization is to compress the bubbles and decrease the distance between solids on the bubble surface, which act as nucleation sites for bubble growth and coalescence when the static pressure is returned to atmospheric pressure. PMID- 28633836 TI - A parametric review of sonochemistry: Control and augmentation of sonochemical activity in aqueous solutions. AB - In this review the phenomenon of ultrasonic cavitation and associated sonochemistry is presented through system parameters. Primary parameters are defined and considered, namely; pressure amplitude, frequency and reactor design; including transducer type, signal type, vessel-transducer ratio, liquid flow, liquid height, liquid temperature and the presence of a reflective plate. Secondary parameters are similarly characterised and involve the use of gas and liquid additives to influence the chemical and physical environments. Each of the parameters are considered in terms of their effect on bubble characteristics and subsequent impact on sonochemical activity. Evidence suggests that via parametric variation, the reaction products and efficiency may be controlled. This is hypothesised to occur through manipulation of the structural stability of the bubble. PMID- 28633837 TI - Synthesis and characterization of ZnS:Ni-NPs loaded on AC derived from apple tree wood and their applicability for the ultrasound assisted comparative adsorption of cationic dyes based on the experimental design. AB - The applicability of ZnS:Ni nanoparticles loaded on activated carbon derived from apple tree wood (ZnS:Ni-NPs-ACATW) for the adsorption of Methylene Blue (MB) and Janus Green B (JGB) dyes in single system from water solution has been described. The synthesized adsorbent characterized and identified by UV-Vis, FE-SEM, EDX, TEM, FTIR and XRD. The influences of operation parameters including initial MB or JGB concentration (9.0-33.0mgL-1), pH (4.0-10.0), extent of adsorbent (0.08 0.12g) and sonication time (4.0-8.0min) investigated and subsequently best operational condition optimized by central composite design (CCD) combined with response surface methodology (RSM) and desirability function (DF) using STATISTICA 10.0 software. At optimum conditions, maximum MB and JSB adsorption onto ZnS:Ni-NPs-ACATW, i.e. 99.57%+/-1.34 and 98.70%+/-2.01, respectively was achieved pH of 7.0, 0.11g adsorbent, 14 and 28mgL-1 of MB and JSB concentration respectively and 8min sonication time. Experimental data were modelled by Langmuir, Freundlich, Temkin and Dubinin-Radushkevich (D-R) isotherms. Langmuir isotherm and monolayer adsorption capacity of MB and JSB was found to be 21.79 and 28.01mgg-1 respectively. The regression results strongly support more contribution of pseudo-second-order model for more accurate and repeatable representation of kinetic data. These results reveal that ZnS:Ni-NPs-ACATW could be useful as agents to efficiently remove dyes (JGB and MB) from contaminated water and can be very well recommended for wastewater remediation and control of environmental pollution. PMID- 28633838 TI - Sonochemically preparation and characterization of bimetallic Ni-Co/Al2O3-ZrO2 nanocatalyst: Effects of ultrasound irradiation time and power on catalytic properties and activity in dry reforming of CH4. AB - The catalytic performance of nanostructured Ni-Co/Al2O3-ZrO2 catalysts, prepared by ultrasound-assisted impregnation method was examined in the dry reforming of methane. The effect of irradiation power and irradiation time have been studied by changing time (0, 20, 80min) and power of the sonication (30, 60, 90W) during the synthesis which resulted in different physiochemical properties of the nanocatalyst. The nanocatalysts were characterized by XRD, FESEM, PSD, EDX, TEM, TPR-H2, BET, FTIR and TG analyses. Based on the characterization results, ultrasound treatment endowed the sample with more uniform and smaller nanoparticles; higher surface area, stronger metal-support interaction and more homogenous dispersion. Moreover, the analyses exhibited smaller particles with higher surface area and less population of particle aggregates at longer and highly irradiated nanocatalysts. The nanocatalyst irradiated at 90W for 80min (the longest irradiation time and the most intense power) showed a uniform morphology and a very narrow particles size distribution. More than 65% of particles of this nanocatalyst were in the range of 10-30nm. Activity tests demonstrated that employing ultrasound irradiation during impregnation improves feed conversion and products yield, reaching values close to equilibrium. Among sonicated nanocatalysts, with increasing power and time of irradiation, the nanocatalyst represents higher activity. The superior performance amongst the various bimetallic catalysts tested was observed over the catalyst with 90W and 80min ultrasonic irradiation which is stable in 24h time on stream test. The excellent anti-coking performance of this bimetallic catalyst, confirmed by TG and FESEM analyses of spent catalyst, is closely related to the promoting effect of sonication on the metal-support interaction, Ni dispersion and particle size; and probably, the synergy between metallic species. PMID- 28633839 TI - Permeability recovery of damaged water sensitive core using ultrasonic waves. AB - It is imperative to recover the well productivity lose due to formation damage nearby wellbore during variant well operations. Some indispensable issues in conventional techniques make ultrasonic technology more attractive due to simple, reliable, favorable, cost-effective, and environment friendly nature. This study proposes the independent and combined use of ultrasonic waves and chemical agents for the treatment of already damaged core samples caused by exposure to distilled water. Results elucidate that ultrasonic waves with optimum (20kHz, 1000W) instead of maximum frequency and power worked well in the recovery owing to peristaltic transport caused by matching of natural frequency with acoustic waves frequency. In addition, hundred minutes was investigated as optimum irradiation time which provided ample time span to detach fine loosely suspended particles. However, further irradiation adversely affected the damaged permeability recovery. Moreover, permeability improvement attributes to cavitation due to ultrasonic waves propagation through fluid contained in porous medium and thermal energy generated by three different ways. Eventually, experimental outcomes indicated that maximum (25.3%) damaged permeability recovery was witnessed by applying ultrasonic waves with transducer #2 (20kHz and 1000W) and optimum irradiation timeframe (100min). This recovery was further increased to 45.8% by applying chemical agent and optimum ultrasonic waves simultaneously. PMID- 28633840 TI - Changes in pore size distribution inside sludge under various ultrasonic conditions. AB - The pore size distribution is quite significant for determining the transport capacity of heat and moisture in sludge during the drying process. It is crucial to investigate the transformation of the pore size in sludge under sonication. In this paper, the microstructures of pores inside sludge before and after ultrasonic treatment with various ultrasonic conditions were observed using a microscope. Fractal geometry and image analysis were combined to quantitatively identify the evolution of pore size in sludge undergoing various acoustic energy densities and treatment times. The surface fractal dimension (df) was applied to characterize the pore size distribution of sludge. The results confirmed that sonication has a positive influence on the characteristics of pore structure inside the sludge and that the average pore size increases with increasing ultrasonic energy level, as determined by both acoustic energy density and treatment time. The df appropriately characterizes and quantifies the evolution of the pore size distribution of sludge under various ultrasonic conditions. This work is quite valuable for further investigating and evaluating moisture removal in the sludge drying process assisted by ultrasonic treatment. PMID- 28633841 TI - Novel approaches based on ultrasound for treatment of wastewater containing potassium ferrocyanide. AB - Industrial wastewaters containing biorefractory compounds like cyanide offer significant environmental problems attributed to the fact that the conventional methods have limited effectiveness and hence developing efficient treatment approaches is an important requirement. The present work investigates the use of novel treatment approach of ultrasound (US) combined with advanced oxidation techniques for the degradation of potassium ferrocyanide (KFC) for the first time. An ultrasonic bath equipped with longitudinal horn (1kW rated power and 25kHz frequency) has been used. The effect of initial pH (2-9) on the progress of degradation has been investigated initially and subsequently using the optimized pH, effect of addition of hydrogen peroxide (ratio of KFC:H2O2 varied over the range of 1:0.5-1:5) and TiO2 in the presence of H2O2 (1:1 ratio by weight of TiO2) as process intensifying approach has been studied. Combination of ultrasonic irradiation with ozone (O3) (100-400mg/h) and ultraviolet irradiation (UV) has also been investigated. Use of combination of US with H2O2, H2O2+TiO2 and ozone resulted in extent of KFC degradation as 54.2%, 74.82% and 82.41% respectively. Combination of US with both UV and ozone was established to be the best approach yielding 92.47% degradation. The study also focused on establishing kinetic rate constants for all the treatment approaches which revealed that all the approaches followed first order kinetic mechanism with higher rate constants for the combination approaches. Overall, it has been conclusively established that ultrasound based combined treatment schemes are very effective for the treatment of KFC containing wastewaters. PMID- 28633842 TI - Effects of multi-frequency ultrasound pretreatment under low power density on the enzymolysis and the structure characterization of defatted wheat germ protein. AB - The effects of ultrasonic frequency mode, power density, pretreatment time and other parameters under low power density on the degree of hydrolysis (DH) of defatted wheat germ protein (DWGP) and angiotensin-I-converting enzyme (ACE) inhibitory activity of DWGP hydrolysate were studied in this research. Ultraviolet-visible (UV-Vis) spectra, free sulfhydryl (SH), disulfide bond (SS), surface hydrophobicity and hydrophobic protein content of ultrasound-pretreated protein and hydrophobic amino acid (HAA) content of alcalase-hydrolysate of DWGP were measured under optimized ultrasonic condition. The ultrasonic frequency mode with dual-fixed frequency combination of 28/40kHz showed higher ACE inhibitory activity of DWGP hydrolysate compared with that of other ultrasound frequency modes and all the ultrasonic frequency combinations involving in 28kHz showed higher ACE inhibitory activity. Under the dual-fixed frequency ultrasound mode of 28/40kHz, ultrasonic power density of 60W/L, pretreatment time of 70min, temperature of 60 degrees C and substrate concentration of 60g/L, the ACE inhibitory activity of DWGP hydrolysate was the highest with its value of 74.75% (increased by 62.30% compared to control). However, all the ultrasonic pretreatment did not increase the DH of DWGP significantly (p>0.05). The changes in UV-Vis spectra, SH and SS groups, surface hydrophobicity and hydrophobic protein content indicated that the structure of DWGP unfolded after ultrasound pretreatment. The HAA content of hydrolysate from the pretreated DWGP increased significantly (p<0.05). The results proved that ultrasound pretreatment loosed the protein structure and exposed more HAA residues of protein to be attacked easily by alcalase. This resulted in the increase in the HAA content which related to the ACE inhibitory activity. PMID- 28633843 TI - Ultrasound-assisted dispersive magnetic solid phase extraction for preconcentration and determination of trace amount of Hg (II) ions from food samples and aqueous solution by magnetic graphene oxide (Fe3O4@GO/2-PTSC): Central composite design optimization. AB - In this work, the synthesis of the magnetic graphene oxide modified by 2 pyridinecarboxaldehyde thiosemicarbazone groups (Fe3O4@GO/2-PTSC) was utilized for preconcentration and determination of mercuric ions in a trace amount by inductively coupled plasma-optical emission spectrometry (ICP-OES). Characterization of the adsorbent was performed using various techniques, such as FT-IR, VSM, SEM and XRD analysis. Central composite design (CCD) under response surface methodology (RSM) was used for obtaining the most important parameters and probable interactions in variables. The variables such as adsorbent dosage, pH, desorption time, and eluent volume was optimized. These values were 8mg, 5.4min, 0.5mL (HCl, 0.1M), respectively. Sonication had an important role in shortening the adsorption time of Hg (II) ions by enhancing the dispersion of adsorbent in solution. Under the optimal conditions, the proposed method presented high enrichment factor of 193, an extraction percentage of 96.5, a detection limit of 0.0079ugL-1 and a relative standard deviation (RSD %) of 1.63%. Finally, the application of the synthesized material was evaluated for preconcentration and determination of mercuric ions from foods and environmental waters samples. PMID- 28633844 TI - Effect of ultrasound pretreatment on the hydrothermal synthesis of SSZ-13 zeolite. AB - SSZ-13 zeolite has been identified as effective material for catalysts and membranes for years because of its structure, but the long crystallization time is the main obstacle for the industry application. The sonochemical-assisted method was identified as one of the potential pre-treatment methods which could reduce the formation duration of zeolites as well as other microporous and mesoporous materials. In this work, zeolite SSZ-13 was prepared by ultrasound pretreatment prior to hydrothermal crystallization. For comparison, samples by the conventional pretreatment and hydrothermal method were also prepared. The synthesized powders were characterized by XRD, SEM, BET, FTIR, NMR and TGA. The results showed that the complete crystallization of SSZ-13 synthesized by the ultrasound-assisted hydrothermal method was achieved within 72h, and much faster than conventional hydrothermal synthesis (120h). Furthermore, the ultrasound pretreatment showed very little effect on the structure properties of the final product compared with the conventional aging method. PMID- 28633845 TI - Intensification of extraction of curcumin from Curcuma amada using ultrasound assisted approach: Effect of different operating parameters. AB - Curcumin, a dietary phytochemical, has been extracted from rhizomes of Curcuma amada using ultrasound assisted extraction (UAE) and the results compared with the conventional extraction approach to establish the process intensification benefits. The effect of operating parameters such as type of solvent, extraction time, extraction temperature, solid to solvent ratio, particle size and ultrasonic power on the extraction yield have been investigated in details for the approach UAE. The maximum extraction yield as 72% was obtained in 1h under optimized conditions of 35 degrees C temperature, solid to solvent ratio of 1:25, particle size of 0.09mm, ultrasonic power of 250W and ultrasound frequency of 22kHz with ethanol as the solvent. The obtained yield was significantly higher as compared to the batch extraction where only about 62% yield was achieved in 8h of treatment. Peleg's model was used to describe the kinetics of UAE and the model showed a good agreement with the experimental results. Overall, ultrasound has been established to be a green process for extraction of curcumin with benefits of reduction in time as compared to batch extraction and the operating temperature as compared to Soxhlet extraction. PMID- 28633846 TI - Aqueous norfloxacin sonocatalytic degradation with multilayer flower-like ZnO in the presence of peroxydisulfate. AB - Multilayer ZnO nanoflowers were synthesized through a simple precipitation method and characterized by field-emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), X-ray photoelectron spectra (XPS) and nitrogen absorption desorption techniques. The FE-SEM images show the integrated morphology of an individual flower-like ZnO nanostructure, which is made of nano-platelets with uniform thickness (20-30nm). The average pore size and Brunauer-Emmet-Teller (BET) surface area of the as-synthesized ZnO were 27.25nm and 13.53m2/g. The sonocatalytic ability of the prepared samples was evaluated through norfloxacin (NF) degradation in an aqueous system using ultrasound (US) irradiation. To improve degradation efficiency, peroxydisulfate (Na2S2O8) was introduced to develop a US/ZnO/peroxydisulfate system, which exhibited an excellent synergistic effect. The effects of ZnO dosage, Na2S2O8 concentration, pH, and initial NF concentration were studied to determine the performances of the US/ZnO/peroxydisulfate process. Corresponding results showed that NF degradation rate increased with the increase of ZnO dosage but decreased with the increase of initial NF concentration. Under the optimal Na2S2O8 concentration of 0.1gL-1 at pH 9, the best degradation efficiency can be achieved. Moreover, based on the scavenging experiment results and literatures, NF degradation through US/ZnO/peroxydisulfate system is majorly induced by OH and SO4- radicals. PMID- 28633847 TI - The role of ultrasound in hydrogen removal and microstructure refinement by ultrasonic argon degassing process. AB - In this work, the role of ultrasound in hydrogen removal and microstructure refinement by the ultrasonic argon degassing has been fully investigated by the experimental work in water and AZ91-0.4Ca magnesium melt, respectively. Ultrasound is able to break up argon gas into numbers of small bubbles and drive them diving deeply to the bottom of water, which are responsible for the efficient degassing regime of ultrasonic argon process. The argon flowrate plays a dominant role in promoting hydrogen removal effect. Meanwhile, the increasing argon flowrate can suppress the microstructure refinement, due to the subdued ultrasonic cavitation under a large argon flowrate. Mechanical properties of AZ91 0.4Ca alloy can be much promoted by the ultrasonic argon degassing process. Ultrasound is the key to achieve not only efficient degassing regime, but also microstructure refinement as well as mechanical properties promotion. PMID- 28633848 TI - Novel synthesis of nanocomposite for the extraction of Sildenafil Citrate (Viagra) from water and urine samples: Process screening and optimization. AB - A sensitive analytical method is investigated to concentrate and determine trace level of Sildenafil Citrate (SLC) present in water and urine samples. The method is based on a sample treatment using dispersive solid-phase micro-extraction (DSPME) with laboratory-made Mn@ CuS/ZnS nanocomposite loaded on activated carbon (Mn@ CuS/ZnS-NCs-AC) as a sorbent for the target analyte. The efficiency was enhanced by ultrasound-assisted (UA) with dispersive nanocomposite solid-phase micro-extraction (UA-DNSPME). Four significant variables affecting SLC recovery like; pH, eluent volume, sonication time and adsorbent mass were selected by the Plackett-Burman design (PBD) experiments. These selected factors were optimized by the central composite design (CCD) to maximize extraction of SLC. The results exhibited that the optimum conditions for maximizing extraction of SLC were 6.0 pH, 300MUL eluent (acetonitrile) volume, 10mg of adsorbent and 6min sonication time. Under optimized conditions, virtuous linearity of SLC was ranged from 30 to 4000ngmL-1 with R2 of 0.99. The limit of detection (LOD) was 2.50ngmL-1 and the recoveries at two spiked levels were ranged from 97.37 to 103.21% with the relative standard deviation (RSD) less than 4.50% (n=15). The enhancement factor (EF) was 81.91. The results show that the combination UAE with DNSPME is a suitable method for the determination of SLC in water and urine samples. PMID- 28633849 TI - Effects of bovine serum albumin on a single cavitation bubble. AB - The dynamics and sonoluminescence (SL) of a single cavitation bubble in bovine serum albumin (BSA) aqueous solutions have been experimentally and theoretically investigated. A phase-locked integral imaging has been used to record the bubble pulsation evolutions. The results show that, under the optimum driving condition, the endurable driving pressure, maximum radius, radius compression ratio and SL intensity of the cavitation bubble increase correspondingly with the increase of BSA concentrations within the critical micelle concentration, which indicates that the addition of BSA increases the power capability of the cavitation bubble. In addition, BSA molecules dampen the interfacial motion, and especially the rebounds of the bubble after its collapse. BSA molecules modify the dilatational viscosity and elasticity of the bubble wall. A viscoelastic interfacial rheological model that mainly emphasizes on the description of the bubble wall has been introduced and modified to theoretically explain the measured bubble dynamics. A good consensus between the experimental observation and model calculation has been achieved. PMID- 28633851 TI - Nano-Fe3O4/PEG/succinic anhydride: A novel and efficient catalyst for the synthesis of benzoxanthenes under ultrasonic irradiation. AB - In this paper, we reported the successful synthesis of Fe3O4/polyethyleneglycol (PEG)/succinic anhydride nanocatalyst. The catalyst was fully characterized by scanning electronic microscopy (SEM), vibrating sample magnetometer (VSM), X-ray diffraction (XRD), thermal gravimetric analysis (TGA), dynamic laser scattering (DLS) and FT-IR spectroscopy. Fe3O4/PEG/succinic anhydride nanocatalyst as an efficient and green catalyst has been used for the synthesis of benzoxanthenes by the three-component condensation reaction of aldehydes, 2-hydroxynaphthalene-1,4 dione and 2-naphthol or dimedone under ultrasonic irradiation. This method offers several advantages such as easy work-up, excellent yields, short reaction times, using of ultrasonic as a green method, recoverability of the catalyst and little catalyst loading. PMID- 28633850 TI - Stabilization of nano-structured ZnO particles onto the surface of cotton fibers using different surfactants and their antimicrobial activity. AB - ZnO NPs were prepared and deposited onto cotton fibers via ultrasound irradiation successfully. Different surfactants (SDS, HY, CTAB, TX-100) have been used to stabilize, homogenize the coated ZnO NPs and control their shape and size as encapsulated species. The use of surfactants has improved the durability of ZnO NPs and decreased its leaching in particular SDS. The small mean crystallite size for ZnO particles due to the use of surfactants is the main reason for decreasing the leached of ZnO particles from cotton substrate. SEM and XRD analysis revealed information about the shape and size of the coated ZnO nanoparticles. The use of SDS and HY surfactants in the synthesis of ZnO NPs coated fabrics showed the highest antibacterial and antifungal activities against different pathogenic bacterial and fungal species with high reduction reached over 90%. PMID- 28633852 TI - Lipase-ultrasound assisted synthesis of polyesters. AB - Poly (ethylene glutarate), poly (ethylene malonate) and poly (ethylene phthalate), were enzymatically synthesized by immobilized Candida antarctica lipase B in solvent free conditions. The synthesis of these polyesters was based on the ester-ester exchange reaction between ethylene glycol diacetate and di ethyl glutarate, di-benzyl malonate, di-n-octyl phthalate to produce poly (ethylene glutarate), poly (ethylene malonate) and poly (ethylene phthalate), respectively. The effect of ultrasound and PET polymeric beads was evaluated and showed to improve the synthesis of all polyesters. Ultrasound, as a green solvent free technology, showed high potentiality for the polyester synthesis intensification. PMID- 28633853 TI - Multi-objective optimization of oxidative desulfurization in a sono-photochemical airlift reactor. AB - Response surface methodology (RSM) was employed to optimize ultrasound/ultraviolet-assisted oxidative desulfurization in an airlift reactor. Ultrasonic waves were incorporated in a novel-geometry reactor to investigate the synergistic effects of sono-chemistry and enhanced gas-liquid mass transfer. Non hydrotreated kerosene containing sulfur and aromatic compounds was chosen as a case study. Experimental runs were conducted based on a face-centered central composite design and analyzed using RSM. The effects of two categorical factors, i.e., ultrasound and ultraviolet irradiation and two numerical factors, i.e., superficial gas velocity and oxidation time were investigated on two responses, i.e., desulfurization and de-aromatization yields. Two-factor interaction (2FI) polynomial model was developed for the responses and the desirability function associate with overlay graphs was applied to find optimum conditions. The results showed enhancement in desulfurization ability corresponds to more reduction in aromatic content of kerosene in each combination. Based on desirability approach and certain criteria considered for desulfurization/de-aromatization, the optimal desulfurization and de-aromatization yields of 91.7% and 48% were obtained in US/UV/O3/H2O2 combination, respectively. PMID- 28633854 TI - An investigation of lipase catalysed sonochemical synthesis: A review. AB - Ultrasonic irradiation has recently gained attention of researchers for its process intensification in numerous reactions. Earlier ultrasound was known for its application either to deactivate enzyme activity or to disrupt the cell. However, in recent years, practice of ultrasonic irradiation began to emerge as a tool for the activation of the enzymes under mild frequency conditions. The incorporation of ultrasound in any of enzymatic reactions not only increases yield but also accelerates the rate of reaction in the presence of mild conditions with better yield and less side-products. To attain maximum yield, it is crucial to understand the mechanism and effect of sonication on reaction especially for the lipase enzyme. Thus, the influence of ultrasound irradiation on reaction yield for different parameters including temperature, enzyme concentration, mole ratio of substrates, solvents ultrasonic frequency and power was reviewed and discussed. The physical effect of cavitation determined by bubble dynamics and rate of reaction through kinetic modelling also needs to be assessed for complete investigation and scale up of synthesis. Thus, prudish utilisation of ultrasound for enzymatic synthesis can serve better future for sustainable and green chemistry. PMID- 28633855 TI - Nanocomposites: Synthesis, characterization and its application to removal azo dyes using ultrasonic assisted method: Modeling and optimization. AB - S-doped and Cu- and Co-doped TiO2 was synthesized by a sol-gel method and characterized by FE-SEM, XRD, EDX and FTIR. The Co/Cu/S-TiO2 nanocomposite loaded on the activated carbon as new nanoadsorbent was used for simultaneous removal of methylene blue (MB) and sunset yellow (SY) from aqueous solution by ultrasonic assisted adsorption method. In this work, central composite design (CCD) and adaptive neuro-fuzzy inference system (ANFIS) as a support tool for examining data and making prediction are used to recognize and predict the removal percentage in MB and SY dye solution of different concentrations. The predictive capabilities of CCD and ANFIS are compared in terms of square correlation coefficient (R2), root mean square error (RMSE), mean absolute error (MAE) and absolute average deviation (AAD) against the empirical data. It is found that the ANFIS model shows the better prediction accuracy than the CCD model. In addition to, the optimization of ultrasound-assisted simultaneous removal of methylene blue (MB) and sunset yellow (SY) on the Co/Cu/S-TiO2/AC nanocomposite by response surface methodology (RSM) for the optimization of the process variables, such as MB and SY concentrations, Co/Cu/S-TiO2/AC nanocomposite dose and sonication time, was investigated. Various isotherm and kinetic models were used in the experimental data. The results revealed that the langmuir isotherm and pseudo second-order model had a better correlation than the other models. PMID- 28633856 TI - Using of sonochemically prepared SbSI for electrospun nanofibers. AB - A novel polymeric, polyacrylonitrile (PAN) nanofibers containing ferroelectric and semiconducting antimony sulfoiodide (SbSI) have been made by electrospinning. SbSI nanowires, used as the filler, have been prepared sonochemically from antimony sulphide (Sb2S3) and antimony tri-iodide (SbI3) for the first time. Nanocrystalline SbSI has been fabricated in ethanol under ultrasonic irradiation (20kHz, 565W/cm2) at 323K within 2h. The products have been characterized by using techniques such as powder X-ray diffraction, scanning electron microscopy, energy dispersive X-ray analysis, high-resolution transmission electron microscopy, selected area electron diffraction and optical diffuse reflection as well as transmission spectroscopy. The good quality of the nanocrystals and their dispersion in the nanofiber's volume is important because this material is attractive for nanogenerators due to its ferroelectric and piezoelectric properties. The amplitude of the voltage pulse, generated under shock pressure of 3.0MPa, has reached 180V in the prototype PAN/SbSI piezoelectric nanogenerator. The peak output voltage of about 0.2V was measured in bending/releasing conditions with the deformation frequency of 1Hz. PMID- 28633857 TI - State-of-the-art on ultrasonic oil production technique for EOR in China. AB - Ultrasonic oil production technique for enhanced oil recovery (EOR) attracts more attention due to its high adaptability, simple operation, low cost and zero pollution to the oil reservoir. In this paper, recent new downhole tools used for enhanced oil recovery developed in China are summarized. Furthermore, research advance on some key problems that affect the widespread application of ultrasonic oil production technique in China are also summarized in view of what are the primary factors that influence crude oil paraffin inhibition and viscosity reduction, whether ultrasonic excitation is better than chemical agent for any plugs removal and whether ultrasound-chemical combination plug removal technology has the best plugs removal effect. The purpose of this paper is to provide reference for the broad application of ultrasonic oil production for enhance oil recovery. PMID- 28633858 TI - Effects of processing parameters in the sonic assisted water extraction (SAWE) of 6-gingerol. AB - The use of water in subcritical conditions for extraction has several drawbacks. These include the safety features, higher production costs and possible degradation of the bioactive compounds. To overcome these problems, sonic energy and an entrainer were used as external interventions to decrease the polarity of water at milder operating conditions. The effect of low (28kHz) and high (800kHz) frequencies of sonication in the extraction of the main ginger bioactive compound (6-gingerol) were compared. Six parameters were studied: mean particle size (MPS, mm), time of extraction, applied power, sample to solvent ratio (w/v), temperature of extraction, and the percentage of entrainer. The optimum conditions for high frequency SAWE prototype were MPS 0.89-1.77mm, 45min, 40W applied power, 1:30 (w/v), 45 degrees C, and 15% of ethanol as entrainer. Two-way analysis of variance (ANOVA) gave the most significant parameter, which was power with F (1, 45.07), p<2.50*10-9. Although the effect of low frequency was stronger than high frequency, at the optimum conditions of the sample to solvent ratio 1:30 (w/v) with 700mL solvent and temperature 45 degrees C, the concentration and recovery of 6-gingerol from high frequency of SAWE prototype was 2.69 times higher than at low frequency of SAWE. It was found that although the effects of high frequency (800kHz) were negligible in other studies, it could extract suitable compounds, such as 6-gingerol, at lower temperature. Therefore, the effects of sonication, which cause an enlargement in the cell wall of the ginger plant matrix, were observed using a Scanning Electron Microscope (SEM). It was found that the applied power of sonication was the most significant parameter compared to the other parameters. PMID- 28633859 TI - Stability of cavitation structures in a thin liquid layer. AB - The inception and evolution of acoustic cavitation structures in thin liquid layers under different conditions and perturbations are investigated experimentally with high speed photography. The stability and characterization of cavitation structures are quantified by image analysis methods. It is found that cavitation structures (shape of bubble cloud and number of bubbles) are stable under unaltered experimental conditions, and the cavitation bubble cloud will return to the original structure and remain stable even in the face of large perturbations. When the experimental conditions are altered (for example, acoustic intensity, cavitation nuclei, boundary), the cavitation structures will vary correspondingly. Further analysis implies that the stability of cavitation structures is closely related to the number of bubbles in the cavitation bubble cloud. There are two mechanisms acting simultaneously in the cavitation bubble cloud evolution, one "bubble production" and the other "bubble disappearance". We propose that the two mechanisms acting together constitute the most likely explanation for the stability of cavitation structures and their transformation. PMID- 28633861 TI - Optimization of magnetic field-assisted ultrasonication for the disintegration of waste activated sludge using Box-Behnken design with response surface methodology. AB - This study investigated for the first time the feasibility of using a magnetic field for sludge disintegration. Approximately 41.01% disintegration degree (DD) was reached after 30min at 180mT magnetic field intensity upon separate magnetic field treatment. Protein and polysaccharide contents significantly increased. This test was optimized using a Box-Behnken design (BBD) with response surface methodology (RSM) to fit the multiple equation of the DD. The maximum DD was 43.75% and the protein and polysaccharide contents increased to 56.71 and 119.44mg/L, respectively, when the magnetic field strength was 119.69mT, reaction time was 30.49min, and pH was 9.82 in the optimization experiment. We then analyzed the effects of ultrasound alone. We are the first to combine magnetic field with ultrasound to disintegrate waste-activated sludge (WAS). The optimum effect was obtained with the application of ultrasound alone at 45kHz frequency, with a DD of about 58.09%. By contrast, 62.62% DD was reached in combined magnetic field and ultrasound treatment. This combined test was also optimized using BBD with RSM to fit the multiple equation of DD. The maximum DD of 64.59% was achieved when the magnetic field intensity was 197.87mT, ultrasonic frequency was 42.28kHz, reaction time was 33.96min, and pH was 8.90. These results were consistent with those of particle size and electron microscopy analyses. This research proved that a magnetic field can effectively disintegrate WAS and can be combined with other physical techniques such as ultrasound for optimal results. PMID- 28633860 TI - Influencing factors and kinetics analysis on the leaching of iron from boron carbide waste-scrap with ultrasound-assisted method. AB - In this paper, the ultrasound-assisted leaching of iron from boron carbide waste scrap was investigated and the optimization of different influencing factors had also been performed. The factors investigated were acid concentration, liquid solid ratio, leaching temperature, ultrasonic power and frequency. The leaching of iron with conventional method at various temperatures was also performed. The results show the maximum iron leaching ratios are 87.4%, 94.5% for 80min-leaching with conventional method and 50min-leaching with ultrasound assistance, respectively. The leaching of waste-scrap with conventional method fits the chemical reaction-controlled model. The leaching with ultrasound assistance fits chemical reaction-controlled model, diffusion-controlled model for the first stage and second stage, respectively. The assistance of ultrasound can greatly improve the iron leaching ratio, accelerate the leaching rate, shorten leaching time and lower the residual iron, comparing with conventional method. The advantages of ultrasound-assisted leaching were also confirmed by the SEM-EDS analysis and elemental analysis of the raw material and leached solid samples. PMID- 28633862 TI - Ultrasound assisted methods for enhanced extraction of phycobiliproteins from marine macro-algae, Gelidium pusillum (Rhodophyta). AB - Extraction of phycobiliproteins (R-phycoerythrin, R-PE and R-phycocyanin, R-PC) from macro-algae is difficult due to the presence of large polysaccharides (agar, cellulose etc.) present in the cell wall which offer major hindrance for cell disruption. The present study is aimed at developing most suitable methodology for the primary extraction of R-PE and R-PC from marine macro-algae, Gelidium pusillum(Stackhouse) Le Jolis. Such extraction of phycobiliproteins by using ultrasonication and other conventional methods such as maceration, maceration in presence of liquid nitrogen, homogenization, and freezing and thawing (alone and in combinations) is reported for the first time. Standardization of ultrasonication for different parameters such as ultrasonication amplitude (60, 90 and 120um) and ultrasonication time (1, 2, 4, 6, 8 and 10mins) at different temperatures (30, 35 and 40 degrees C) was carried out. Kinetic parameters were estimated for extraction of phycobiliproteins by ultrasonication based on second order mass transfer kinetics. Based on calorimetric measurements, power, ultrasound intensity and acoustic power density were estimated to be 41.97W, 14.81W/cm2 and 0.419W/cm3, respectively. Synergistic effect of ultrasonication was observed when employed in combination with other conventional primary extraction methods. Homogenization in combination with ultrasonication resulted in an enhancement in efficiency by 9.3% over homogenization alone. Similarly, maceration in combination with ultrasonication resulted in an enhancement in efficiency by 31% over maceration alone. Among all the methods employed, maceration in combination with ultrasonication resulted in the highest extraction efficiency of 77 and 93% for R-PE and R-PC, respectively followed by homogenization in combination with ultrasonication (69.6% for R-PE and 74.1% for R-PC). HPLC analysis was carried out in order to ensure that R-PE was present in the extract and remained intact even after processing. Microscopic studies indicated a clear relation between the extraction efficiency of phycobiliproteins and degree of cell disruption in a given primary extraction method. These combination methods were found to be effective for extraction of phycobiliproteins from rigid biomass of Gelidium pusillum macro-algae and can be employed for downstream processing of biomolecules also from other macro-algae. PMID- 28633863 TI - Targeted Deletion of an Entire Chromosome Using CRISPR/Cas9. AB - CRISPR/Cas9 genome editing can facilitate efficient deletion of genomic region, but it has not been used to delete an entire chromosome. Here, Adikusuma et al. show proof-of-concept for efficient CRISPR-mediated selective chromosome deletion by removing the centromere or shredding the chromosome arm in mouse embryonic stem cells and zygotes. PMID- 28633865 TI - Corrigendum to "Neural correlates of reduced awareness in instrumental activities of daily living in frontotemporal dementia" [Exp. Gerontol. 83 (2016) 158-164]. PMID- 28633866 TI - Tea consumption may decrease the risk of osteoporosis: an updated meta-analysis of observational studies. AB - Several epidemiological investigations have evaluated the correlation between tea consumption and risk of osteoporosis, but the results are inconsistent. Therefore, we conducted an updated meta-analysis of observational studies to assess this association. We searched for all relevant studies including cohort, cross-sectional, and case-control studies published from database inception to July 15, 2016, using MEDLINE EMBASE, and Cochrane Library. Polled odds ratios (ORs) were calculated using the random-effect model. Fourteen articles (16 studies) that examined 138523 patients were included in this meta-analysis. Seven studies concerning bone mineral density (BMD) showed an increase in BMD with tea consumption, including 4 cross-sectional studies (OR, 0.04, 95% confidence interval [CI], 0.01-0.08) and 3 cohort studies (OR, 0.01; 95% CI, 0.01-0.01). The remaining 9 studies concerning fracture, including 6 case-control studies and 3 cohort studies, showed no association between tea consumption and osteoporotic fracture (OR, 0.86; 95% CI, 0.74-1.01). This updated meta-analysis demonstrates that tea consumption could increase BMD, but the association with osteoporotic fracture requires further investigation. Together, the results highlight the need for future, high-quality-designed clinical trials on tea consumption and osteoporosis. PMID- 28633864 TI - Perinatal Group B Streptococcal Infections: Virulence Factors, Immunity, and Prevention Strategies. AB - Group B streptococcus (GBS) or Streptococcus agalactiae is a beta-hemolytic, Gram positive bacterium that is a leading cause of neonatal infections. GBS commonly colonizes the lower gastrointestinal and genital tracts and, during pregnancy, neonates are at risk of infection. Although intrapartum antibiotic prophylaxis during labor and delivery has decreased the incidence of early-onset neonatal infection, these measures do not prevent ascending infection that can occur earlier in pregnancy leading to preterm births, stillbirths, or late-onset neonatal infections. Prevention of GBS infection in pregnancy is complex and is likely influenced by multiple factors, including pathogenicity, host factors, vaginal microbiome, false-negative screening, and/or changes in antibiotic resistance. A deeper understanding of the mechanisms of GBS infections during pregnancy will facilitate the development of novel therapeutics and vaccines. Here, we summarize and discuss important advancements in our understanding of GBS vaginal colonization, ascending infection, and preterm birth. PMID- 28633867 TI - Review of a causal role of fructose-containing sugars in myocardial susceptibility to ischemia/reperfusion injury. AB - In 2012, the World Health Organization Global Status Report on noncommunicable diseases showed that 7.4 million deaths were due to ischemic heart disease. Consequently, cardiovascular disease is a significant health burden, especially when partnered with comorbidities such as obesity, metabolic syndrome, and type 2 diabetes mellitus. Of note, these diseases can all be induced or exacerbated by diet. Carbohydrates, in particular, fructose and glucose, generally form the largest part of the human diet. Accumulating evidence from animal studies suggests that if large amounts of fructose are consumed either in isolation or in combination with glucose (fructose-containing sugars), myocardial susceptibility to ischemia/reperfusion (I/R) injury increases. However, the underlying mechanisms that predisposes the myocardium to I/R injury in the fructose model are not elucidated, and no single mechanistic pathway has been described. Based on all available data on this topic, this review describes previously investigated mechanisms and highlights 3 main mechanistic pathways whereby fructose has shown to increase myocardial susceptibility to I/R injury. These pathways include (1) increased reactive oxygen species, resulting in reduced nitric oxide synthase and coronary flow; (2) elevated plasma fatty acids and insulin, leading to increased cardiac triglyceride content and lipotoxicity; and (3) disrupted myocardial calcium handling/homeostasis. Moreover, we highlight various factors that should be taken into account when the fructose animal model is used, such as rat strain, treatment periods, and doses. We argue that failure to do so would result in erratic inferences drawn from the existing body of evidence on fructose animal models. PMID- 28633868 TI - Daidzein stimulates osteogenesis facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via estrogen receptor dependent MEK/ERK and PI3K/Akt activation. AB - Daidzein, a natural soy isoflavone, has a structure similar to estradiol and exhibiting bone-sparing effects against osteoporosis. However, the molecular mechanisms of osteogenesis remain unclear. We hypothesized that daidzein stimulates osteogenesis through estrogen receptor (ER)-dependent signal pathways. To test this hypothesis, we investigated the effects of daidzein compared with 17beta-estradiol on proliferation, differentiation, and cisplatin-induced apoptosis in human osteoblast-like MG-63 cells containing 2 ER isoforms. The results showed that daidzein stimulated cell proliferation by altering cell cycle distribution, promoted cell differentiation by increasing the alkaline phosphatase activity and collagen content, and reduced cell apoptosis associated by up-regulating the expression of Bcl-xL. The above actions of daidzein were prevented by cotreatment with the ER antagonist ICI 182780. Using small interfering RNA technology, we further demonstrated that the effects of daidzein on alkaline phosphatase activity, collagen content, and cell apoptosis are mediated by both ERalpha and ERbeta, whereas the effects on cell proliferation are primarily mediated by ERalpha. However, the effects of 17beta-estradiol on osteoblastic proliferation and survival are mediated by both ER isotypes, and the effects on osteoblastic differentiation are primarily mediated by ERalpha. The use of specific inhibitors indicated that activation of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) and phosphoinositide 3-kinase/protein kinase B or PKB (PI3K/Akt) signaling pathway at least partially accounts for these effects of daidzein. Taken together, the results indicate that daidzein stimulates osteogenesis through facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via activation of MEK/ERK and PI3K/Akt in an ER-dependent manner. PMID- 28633869 TI - Baccaurea angulata fruit juice ameliorates altered hematological and biochemical biomarkers in diet-induced hypercholesterolemic rabbits. AB - Hypercholesterolemia is an important risk factor linked to the alteration of blood hematology and clinical chemistry associated with the development and progression of atherosclerosis. Previous studies have demonstrated the safety and potential health benefits of Baccaurea angulata (BA) fruit. We hypothesized that the oral administration of BA fruit juice could ameliorate the alteration in the hematological and biochemical biomarkers of diet-induced hypercholesterolemic rabbits. The aim of this study was to investigate the effects of different doses of BA juice on the hematological and biochemical biomarkers in normo- and hypercholesterolemic rabbits. Thirty-five healthy adult New Zealand White rabbits were assigned to seven different groups for 90days of diet intervention. Four atherogenic groups were fed a 1% cholesterol diet and 0, 0.5, 1.0, and 1.5mL of BA juice per kg of rabbit daily. The other three normal groups were fed a commercial rabbit pellet diet and 0, 0.5, and 1.0mL of BA juice per kg of rabbit daily. Baseline and final blood samples after 90days of repeated administration BA juice were analyzed for hematological parameters while serum, aortic and hepatic lysates were analyzed for lipid profiles and other biochemical biomarkers. The alteration of the hemopoietic system, physiological changes in serum and tissues lipid profiles and other biochemicals resulting from the consumption of a high-cholesterol diet were significantly (P<.05) ameliorated by the administration of BA juice. Improvements of the biomarkers in rabbits were dose-dependent, markedly enhanced at the highest dose of juice (1.5mL/kg/day). The results suggest potential health benefits of the antioxidant-rich BA fruit juice against hypercholesterolemia-associated hematological and biochemical alterations in the rabbit. PMID- 28633870 TI - Omega-3 free fatty acids attenuate insulin-promoted breast cancer cell proliferation. AB - High insulin levels in obese people are considered as a risk factor to induce breast carcinogenesis. And consumption of fish oils which mainly contain omega-3 fatty acids is associated with a reduced risk of breast cancer. However, whether omega-3 free fatty acids (FFAs) modulate insulin signaling pathway to prevent breast cancer is poorly understood. The current study tested the hypothesis that omega-3 FFAs attenuate insulin-induced breast cancer cell proliferation and regulate insulin signaling pathway. We show here that omega-3 FFAs attenuate MCF 7 cell proliferation and Akt and Erk1/2 phosphorylation levels stimulated by insulin. Knockdown Shp2 by siRNA resulted in significantly elevated omega-3 FFAs activated Akt phosphorylation but failed to change insulin-stimulated Akt and Erk1/2 phosphorylation. And viable cell number was not affected by either downregulation of Shp2 expression or Erk1/2 inhibitor U0126 treatment. These observations indicated that omega-3 FFAs attenuate insulin-promoted breast cancer cell proliferation and insulin-activated Akt phosphorylation. PMID- 28633871 TI - High-fat diet-induced plasma protein and liver changes in obese rats can be attenuated by melatonin supplementation. AB - Obesity triggers changes in protein expression in various organs that might participate in the pathogenesis of obesity. Melatonin has been reported to prevent or attenuate such pathological protein changes in several chronic diseases. However, such melatonin effects on plasma proteins have not yet been studied in an obesity model. Using a proteomic approach, we investigated the effect of melatonin on plasma protein profiles after rats were fed a high-fat diet (HFD) to induce obesity. We hypothesized that melatonin would attenuate abnormal protein expression in obese rats. After 10weeks of the HFD, animals displayed increased body weight and fat accumulation as well as increased glucose levels, indicating an obesity-induced prediabetes mellitus-like state. Two dimensional gel electrophoresis and liquid chromatography-mass spectrometry/mass spectrometry revealed 12 proteins whose expression was altered in response to the HFD and the melatonin treatment. The altered proteins are related to the development of liver pathology, such as cirrhosis (alpha1-antiproteinase), thrombosis (fibrinogen, plasminogen), and inflammation (mannose-binding protein A, complement C4, complement factor B), contributing to liver steatosis or hepatic cell death. Melatonin treatment most probably reduced the severity of the HFD-induced obesity by reducing the amplitude of HFD-induced plasma protein changes. In conclusion, we identified several potential biomarkers associated with the progression of obesity and its complications, such as liver damage. Furthermore, our findings reveal melatonin's beneficial effect of attenuating plasma protein changes and liver pathogenesis in obese rats. PMID- 28633872 TI - Frozen yogurt and ice cream were less healthy than yogurt, and adding toppings reduced their nutrition value: evidence from 1999-2014 National Health and Nutrition Examination Survey. AB - It was hypothesized that frozen yogurt and ice cream would be less healthy than yogurt. We examined daily energy and nutrient intake from yogurt, frozen yogurt, and ice cream among US adults. In-person 24-hour dietary recall data (n=6453) came from the 1999-2014 National Health and Nutrition Examination Survey. Regression analyses were performed to examine the differences in energy/nutrient intake from frozen yogurt and ice cream (with/without toppings) in comparison to yogurt. Approximately 5.3%, 0.9%, and 14.3% of US adults consumed yogurt, frozen yogurt, and ice cream on any given day, respectively. Among frozen yogurt and ice cream consumers, 29.7% and 14.8% added toppings to their consumption, respectively. Compared with yogurt, frozen yogurt consumption with and without toppings was associated with increased daily energy intake by 214.6 and 97.9kj, respectively; whereas ice cream consumption with and without toppings was associated with increased daily energy intake by 427.2 and 343.5kj, respectively. Compared with yogurt, frozen yogurt consumption was associated with a decreased intake of most vitamins/minerals under examination, but increased intake of sugar, total/saturated fat, cholesterol, fiber, and iron. Adding toppings to frozen yogurt further increased total and saturated fat intake. Compared with yogurt, ice cream consumption was associated with a decreased intake of multiple micronutrients, but increased intake of sugar, total/saturated fat, cholesterol, fiber, vitamins A and E, and iron. Adding toppings to ice cream further increased sugar intake. In conclusion, frozen yogurt and ice cream were less healthy than yogurt, and adding toppings made them even less desirable. PMID- 28633873 TI - Elental(r) amino acid component has protective effects on primary cultured hepatocytes and a rat model of acute liver injury. AB - Amino acids can exert protective effects on the liver either when administered as a medication or following an operation. In this study, we examined the protective effects of amino acids on the liver using in vitro and in vivo models by studying their influence on the induction of inducible nitric oxide synthase (iNOS) and nitric oxide production as a liver injury marker in cultured hepatocytes and liver-protective effects in d-galactosamine and lipopolysaccharide (GalN/LPS) treated rats, respectively. Primary cultured rat hepatocytes were treated with interleukin (IL)-1beta in the presence or absence of Elental(r) amino acid component (EleAA; 17 amino acids). Rats were pretreated with either EleAA or a diet containing selected amino acids followed by GalN/LPS injection. Survival rate and mRNA expression were analyzed. EleAA inhibited iNOS induction through reduction of mRNA synthesis and stability in cultured hepatocytes, indicating prevention of liver injury, but did not show a liver-protective effect in GalN/LPS rats. Among EleAA, Lys, Trp, His, and Arg (4AA) markedly decreased nitric oxide production and inhibited nuclear factor-kappaB (NF-kappaB) activation. In GalN/LPS rats, 4AA (3% of each amino acid in diet) increased survival rate by 50% and decreased mRNA expression of iNOS, tumor necrosis factor alpha, and cytokine-induced neutrophil chemoattractant-1 in the liver. 4AA reduced NF-kappaB activation induced by GalN/LPS. 4AA inhibited the expression of inflammatory mediators, in part through inhibition of NF-kappaB activation in cultured hepatocytes and GalN/LPS-treated rats. The results suggest that EleAA has therapeutic potential for organ injuries including liver. PMID- 28633874 TI - Proportional bias between dual-energy x-ray absorptiometry and bioelectrical impedance analysis varies based on sex in active adults consuming high- and low carbohydrate diets. AB - Dual-energy x-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) are common methods of body composition assessment, but the agreement between these methods varies. Bias between DXA and single-frequency BIA was evaluated at 6 different time points in 48 active male and female adults consuming standardized high- and low-carbohydrate diets. It was hypothesized that fixed and proportional biases exist between DXA and BIA but that the extent of bias does not differ based on sex. Substantial fixed bias was present for estimates obtained by DXA and BIA, and both men and women exhibited proportional bias for fat mass (FM) and fat-free mass (FFM). The magnitude of bias was greater in women, and only women exhibited proportional bias for body fat percentage. In individuals with less FM, the mean difference between DXA and BIA was high, indicating that BIA underestimated FM relative to DXA. However, in individuals with greater FM, better agreement was seen. Correspondingly, the mean difference in FFM estimates was greater in individuals with less FFM. In some individuals with high quantities of FM or FFM relative to the sample, the relationship between devices was reversed such that BIA overestimated FM and underestimated FFM. The degree of disagreement between DXA and BIA varies substantially based on body size and sex such that all-encompassing statements regarding the comparability of these technologies cannot presently be made. PMID- 28633875 TI - Rational drug loading of liposomes revisited. PMID- 28633877 TI - Epithelial proteome profiling suggests the essential role of interferon-inducible proteins in patients with allergic rhinitis. AB - BACKGROUND: Seasonal allergic rhinitis (SAR) caused by intermittent exposure to seasonal pollen causes itching, nasal congestion, and repeated sneezing, with profound effects on quality of life, work productivity, and school performance. Although both the genotype and environmental factors can contribute to the immunologic basis of allergic reactions, the molecular underpinnings associated with the pathogenesis of allergic rhinitis are not entirely clear. METHODS: To address these questions, nasal epithelial brushings were collected from 29 patients with SAR and 31 control subjects during and after the pollen season. We then implemented an orbitrap-based, bottom-up, label-free quantitative proteomics approach, followed by multivariate analyses to identify differentially abundant (DA) proteins among the 4 sample groups. RESULTS: We identified a total of 133 DA proteins for which the most significantly overrepresented functional category was found to be interferon 1 signaling. Two proteins, cystatin 1 and myeloblastin, the former of which protects against protease activity of allergens and the latter with a role in epithelial barrier function, were DA in patients with SAR and control subjects, irrespective of season. Moreover, interferon-inducible protein with tetratricopeptide repeats 1, cystatin 1, and interferon-inducible protein with tetratricopeptide repeats 3 were found to be differentially regulated between patients with SAR and control subjects, with inverse abundance dynamics during the transition from fall to spring. CONCLUSION: We identified type 1 interferon-regulated proteins as biomarkers in patients with SAR, potentially playing an important role in its pathogenesis. Moreover, when compared with patients with SAR, healthy subjects exhibit an antagonistic proteomic response across seasons, which might prove to be a therapeutic target for disease prevention. PMID- 28633876 TI - Hemophagocytic lymphohistiocytosis as presenting manifestation of profound combined immunodeficiency due to an ORAI1 mutation. PMID- 28633878 TI - Reply to Basu et al. PMID- 28633879 TI - Intensive preoperative rehabilitation improves functional capacity and postoperative hospital length of stay in elderly patients with lung cancer [commentary]. PMID- 28633880 TI - Beliefs about Medicine Questionnaire. PMID- 28633881 TI - Placebo pills provided without deception may help to reduce pain and disability in people with chronic low back pain [commentary]. PMID- 28633882 TI - Knee osteoarthritis. PMID- 28633883 TI - The Gross Motor Function Measure (GMFM). PMID- 28633884 TI - Differences in Practice Characteristics Between Male and Female Chiropractors in Switzerland. AB - OBJECTIVES: A total of 75% of the chiropractic medicine students in the new program at the University of Zurich are women, which is in stark contrast to the traditional ratio of chiropractors in Switzerland, where 75% have been men. Therefore, the purpose of this study was to compare work behaviors between female and male chiropractors relating to workload, patient variety, and chiropractic treatment techniques. METHODS: This is a secondary analysis of data from the Swiss Job Analysis 2009 study. The design was an online survey to all practicing chiropractors in Switzerland that had a 70% response rate of 183 returned surveys. Differences between male and female chiropractors in the various categorical responses involving practice workload, characteristics and patient types were compared using the chi2 test. RESULTS: Male chiropractors had significantly more years in practice (P = .0001), worked more hours per week (P = .0001), and saw more patients (P = .0001) and more new patients (P = .004) per week compared with female chiropractors. Female chiropractors spent significantly more time with patients during follow-up visits (P = .017). There were no significant differences in treatment techniques used or the types of patients seen between the sexes. CONCLUSION: Because female chiropractors work fewer hours and see fewer patients per week, this may lead to a shortage of chiropractors in the future as the sex ratio within the profession slowly changes in Switzerland. PMID- 28633885 TI - Characteristics of Paraspinal Muscle Spindle Response to Mechanically Assisted Spinal Manipulation: A Preliminary Report. AB - OBJECTIVES: The purpose of this preliminary study is to determine muscle spindle response characteristics related to the use of 2 solenoid powered clinical mechanically assisted manipulation (MAM) devices. METHODS: L6 muscle spindle afferents with receptive fields in paraspinal muscles were isolated in 6 cats. Neural recordings were made during L7 MAM thrusts using the Activator V (Activator Methods Int. Ltd., Phoenix, AZ) and/or Pulstar (Sense Technology Inc., Pittsburgh, PA) devices at their 3 lowest force settings. Mechanically assisted manipulation response measures included (a) the time required post-thrust until the first action potential, (b) differences in mean frequency (MF) and mean instantaneous frequency (MIF) 2 seconds before and after MAM, and (c) the time required for muscle spindle discharge (MF and MIF) to return to 95% of baseline after MAM. RESULTS: Depending on device setting, between 44% to 80% (Pulstar) and 11% to 63% (Activator V) of spindle afferents required >6 seconds to return to within 95% of baseline MF values; whereas 66% to 89% (Pulstar) and 75% to 100% (Activator V) of spindle responses returned to within 95% of baseline MIF in <6 seconds after MAM. Nonparametric comparisons between the 22 N and 44 N settings of the Pulstar yielded significant differences for the time required to return to baseline MF and MIF. CONCLUSION: Short duration (<10 ms) MAM thrusts decrease muscle spindle discharge with a majority of afferents requiring prolonged periods (>6 seconds) to return to baseline MF activity. Physiological consequences and clinical relevance of described MAM mechanoreceptor responses will require additional investigation. PMID- 28633887 TI - Visual integration of fear and anger emotional cues by children on the autism spectrum and neurotypical peers: An EEG study. AB - Communication deficits in children with autism spectrum disorders (ASD) are often related to inefficient interpretation of emotional cues, which are conveyed visually through both facial expressions and body language. The present study examined ASD behavioral and ERP responses to emotional expressions of anger and fear, as conveyed by the face and body. Behavioral results showed significantly faster response times for the ASD than for the typically developing (TD) group when processing fear, but not anger, in isolated face expressions, isolated body expressions, and in the integration of the two. In addition, EEG data for the N170 and P1 indicated processing differences between fear and anger stimuli only in TD group, suggesting that individuals with ASD may not be distinguishing between emotional expressions. These results suggest that ASD children may employ a different neural mechanism for visual emotion recognition than their TD peers, possibly relying on inferential processing. PMID- 28633886 TI - Remembering and imagining alternative versions of the personal past. AB - Although autobiographical memory and episodic simulations recruit similar core brain regions, episodic simulations engage additional neural recruitment in the frontoparietal control network due to greater demands on constructive processes. However, previous functional neuroimaging studies showing differences in remembering and episodic simulation have focused on veridical retrieval of past experiences, and thus have not fully considered how retrieving the past in different ways from how it was originally experienced may also place similar demands on constructive processes. Here we examined how alternative versions of the past are constructed when adopting different egocentric perspectives during autobiographical memory retrieval compared to simulating hypothetical events from the personal past that could have occurred, or episodic counterfactual thinking. Participants were asked to generate titles for specific autobiographical memories from the last five years, and then, during functional magnetic resonance (fMRI) scanning, were asked to repeatedly retrieve autobiographical memories or imagine counterfactual events cued by the titles. We used an fMRI adaptation paradigm in order to isolate neural regions that were sensitive to adopting alternative egocentric perspectives and counterfactual simulations of the personal past. The fMRI results revealed that voxels within left posterior inferior parietal and ventrolateral frontal cortices were sensitive to novel visual perspectives and counterfactual simulations. Our findings suggest that the neural regions supporting remembering become more similar to those underlying episodic simulation when we adopt alternative egocentric perspectives of the veridical past. PMID- 28633888 TI - Burden of acute gastroenteritis caused by norovirus in China: A systematic review. AB - BACKGROUND: To understand the epidemiology and disease burden of norovirus (NoVs) gastroenteritis in China, a systematic review was conducted. METHODS: Studies on acute gastroenteritis (AGE) caused by NoVs from mainland China, published before 2017 were searched. All retrieved articles were screened and reviewed by a standardized algorithm. NoVs detection rates as well as strain variations by ages, seasonal variations and geographic locations were analyzed using random effects model. RESULTS: A total of 225 articles were included in the final analysis. Similar detection rates at 21.0% and 19.8% were obtained from the North and the South, respectively. NoVs infection occurred year round, with a peak between October and January in the North and between August and November in the South. High detection rates (~29%) of NoVs were found in adults and the elderly and in children aged 6-35 months (~22%). The predominant strains were GII.4 (70.4%), followed by GII.3 (13.5%). CONCLUSION: NoVs cause significant disease burden in China which warrants development of vaccines against NoVs, particularly for children and the elderly who are vulnerable to gastroenteritis diseases. To achieve a broad protection, continual monitoring NoV epidemics and strain variations for selection of proper vaccine strains is critical. PMID- 28633889 TI - Serious pneumococcal disease outbreak in men exposed to metal fume - detection, response and future prevention through pneumococcal vaccination. AB - Welders and those exposed to metal fume are known to be at increased risk of pneumococcal pneumonia and invasive pneumococcal disease. Current UK guidance recommends that vaccination against pneumococcus be considered in those at risk of frequent or continuous occupational exposure to metal fume, taking into account the exposure control measures in place. We report an outbreak of serious pneumococcal disease that occurred between April and June 2015 among a multinational workforce exposed to metal fumes while working on the refurbishment of an oil rig in a Belfast shipyard. Four confirmed and five probable cases were identified, which occurred despite the use of environmental control measures and the availability of respiratory protective equipment. To provide direct protection to those at risk of pneumococcal disease and to eradicate carriage of pneumococcus and interrupt transmission, pneumococcal polysaccharide vaccine (PPV23) and antibiotic prophylaxis were offered to 680 individuals identified as potentially exposed to metal fume. Low levels of prior pneumococcal vaccination were reported among this target group (<1%). Genomic sequencing indicated a common strain of serotype 4 pneumococcus in two of the confirmed cases and a distinct serotype 4 in one case. The fourth confirmed case was identified as likely serotype 3 using a serotype-specific immunoassay on a urine specimen. Both serotypes 3 and 4 are vaccine-preventable strains covered by the conjugate and polysaccharide pneumococcal vaccines currently available. We propose that consideration should be given to strengthening implementation around pneumococcal vaccination for those exposed to metal fume through their work, even when other control measures are in place, to reduce the risk of future cases and outbreaks of serious pneumococcal disease. PMID- 28633890 TI - Universal measles-mumps-rubella vaccination to new recruits and the incidence of mumps in the military. AB - In response to the resurgence of mumps, the Korean Armed Forces started the measles-mumps-rubella (MMR) vaccination to all new recruits regardless of prior vaccination history. We evaluated the effectiveness of the vaccination by comparing the incidence between the military and civilian populations before and after implementation of the new policy. The standardized incidence ratio of mumps in the military was 7.06 in the prevaccine period, which declined to 0.96 in the postvaccine period. Vaccine effectiveness was estimated at 86.4%. Incidence rate ratio was lower in the 1996-1998 birth cohort (BC) compared with 1989-1995 BC (0.10 vs. 0.55), suggesting higher effectiveness of vaccination in the 1996-1998 BC. Our data provide evidence for the use of the MMR vaccination in the prevention of mumps in high-risk adults. PMID- 28633891 TI - AIDS, Avian flu, SARS, MERS, Ebola, Zika... what next? AB - Emerging infections have threatened humanity since times immemorial. The dramatic anthropogenic, behavioral and social changes that have affected humanity and the environment in the past century have accelerated the intrusion of novel pathogens into the global human population, sometimes with devastating consequences. The AIDS and influenza pandemics have claimed and will continue to claim millions of lives. The recent SARS and Ebola epidemics have threatened populations across borders. The emergence of MERS may well be warning signals of a nascent pandemic threat, while the potential for geographical spread of vector-borne diseases, such as Zika, but also Dengue and Chikungunya is unprecedented. Novel technologies and innovative approaches have multiplied to address and improve response preparedness towards the increasing yet unpredictable threat posed by emerging pathogens. PMID- 28633892 TI - Seropositivity to non-vaccine incorporated genotypes induced by the bivalent and quadrivalent HPV vaccines: A systematic review and meta-analysis. AB - BACKGROUND: Human papillomavirus vaccines have demonstrated remarkable efficacy against persistent infection and disease associated with vaccine-incorporated genotypes and a degree of efficacy against some genetically related, non-vaccine incorporated genotypes. The vaccines differ in the extent of cross-protection against these non-vaccine genotypes. Data supporting the role for neutralizing antibodies as a correlate or surrogate of cross-protection are lacking, as is a robust assessment of the seroconversion rates against these non-vaccine genotypes. METHODS: We performed a systematic review and meta-analysis of available data on vaccine-induced neutralizing antibody seropositivity to non vaccine incorporated HPV genotypes. RESULTS: Of 304 articles screened, 9 were included in the analysis representing ca. 700 individuals. The pooled estimate for seropositivity against HPV31 for the bivalent vaccine (86%; 95%CI 78-91%) was higher than that for the quadrivalent vaccine (61%; 39-79%; p=0.011). The pooled estimate for seropositivity against HPV45 for the bivalent vaccine (50%; 37-64%) was also higher than that for the quadrivalent vaccine (16%; 6-36%; p=0.007). Seropositivity against HPV33, HPV52 and HPV58 were similar between the vaccines. Mean seropositivity rates across non-vaccine genotypes were positively associated with the corresponding vaccine efficacy data reported from vaccine trials. CONCLUSIONS: These data improve our understanding of vaccine-induced functional antibody specificity against non-vaccine incorporated genotypes and may help to parameterize vaccine-impact models and improve patient management in a post vaccine setting. PMID- 28633893 TI - Genes encoding cuticular proteins are components of the Nimrod gene cluster in Drosophila. AB - The Nimrod gene cluster, located on the second chromosome of Drosophila melanogaster, is the largest synthenic unit of the Drosophila genome. Nimrod genes show blood cell specific expression and code for phagocytosis receptors that play a major role in fruit fly innate immune functions. We previously identified three homologous genes (vajk-1, vajk-2 and vajk-3) located within the Nimrod cluster, which are unrelated to the Nimrod genes, but are homologous to a fourth gene (vajk-4) located outside the cluster. Here we show that, unlike the Nimrod candidates, the Vajk proteins are expressed in cuticular structures of the late embryo and the late pupa, indicating that they contribute to cuticular barrier functions. PMID- 28633894 TI - Synthesis and antibacterial activity of 5-methylphenanthridium derivatives as FtsZ inhibitors. AB - 5-Methylphenanthridium derivatives were designed, synthesized and evaluated for their in vitro antibacterial activity and cell division inhibitory activity against various Gram-positive and -negative bacteria. Among them, compounds 5A2, 5B1, 5B2, 5B3, 5C1 and 5C2 displayed the best on-target antibacterial activity with an MIC value of 4ug/mL against B. subtilis ATCC9372 and S. pyogenes PS, showing over 2-fold better activity than sanguinarine. The SARs showed that the 5 methylphenanthridium derivatives with the alkyl side chains at the 2-postion, especially the straight alkyl side chains exerted better on-target antibacterial activity. PMID- 28633895 TI - Synthesis of MeON-neoglycosides of digoxigenin with 6-deoxy- and 2,6-dideoxy-d glucose derivatives and their anticancer activity. AB - Cardiac glycosides show anticancer activities and their deoxy-sugar chains are vital for their anticancer effects. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and get more potent anticancer agents, a series of MeON-neoglycosides of digoxigenin was synthesized and evaluated. First, ten 6-deoxy- and 2,6-dideoxy-d-glucopyranosyl donors were synthesized starting from methyl alpha-d-glucopyranoside and 2-deoxy-d-glucose. Meanwhile, the digoxigenin was obtained by acidic hydrolysis of commercially available digoxin as glycosyl acceptor. Then, a 22-member MeON-neoglycoside library of digoxigenin was successfully synthesized by neoglycosylation method. Finally, the induction of Nur77 expression and its translocation from the nucleus to cytoplasm together with cytotoxicity of these MeON-neoglycosides were evaluated. The SAR analysis revealed that C3 glycosylation is required for their induction of Nur77 expression. Moreover, some MeON-neoglycosides (2b and 8b) could significant induce the expression of Nur77 and its translocation from the nucleus to cytoplasm. However, these compounds showed no inhibitory effects on the proliferation of cancer cells, suggesting that they may not induce apoptosis of NIH-H460 cancer cells and their underlying potential and application toward cancer cells deserves future study. PMID- 28633896 TI - Design, synthesis and biological evaluation of novel 3H-imidazole [4,5-b] pyridine derivatives as selective mTOR inhibitors. AB - A series of 3H-imidazo [4,5-b] pyridines derivatives were designed and synthesized as selective mTOR inhibitors. The systematic optimization of the molecules resulted in the identification of two compounds 10d and 10n with nanomolar mTOR inhibitory activity and selectivity over PI3Kalpha. Besides, compounds 10d and 10n demonstrated attractive potency against human breast cancer cells (MCF-7) and human ovarian cancer cell (A2780). PMID- 28633897 TI - Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6 (piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists. AB - This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4 aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp=2.1, Kp,uu=1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists. PMID- 28633898 TI - 2-Chlorophenyl-substituted benzofuro[3,2-b]pyridines with enhanced topoisomerase inhibitory activity: The role of the chlorine substituent. AB - A new series of 2-chloropheny-substituted benzofuro[3,2-b]pyridines were designed, synthesized, and evaluated for topoisomerase I and II inhibition and antiproliferative activity. Compounds 17-19, 23, 24, 26, and 27 exhibited excellent topo II inhibitory activity. A systematic structure-activity relationship study revealed the important role of chlorine substitution in the strong topoisomerase inhibitory activity. PMID- 28633899 TI - Discovery of BMS-961955, an allosteric inhibitor of the hepatitis C virus NS5B polymerase. AB - The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS 961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as XimencyTM. PMID- 28633901 TI - Patient ethnicity and causative species determine the manifestations of anti interferon-gamma autoantibody-associated nontuberculous mycobacterial disease: a review. AB - Nontuberculous mycobacteria (NTM) infections involving anti-interferon-gamma (IFN gamma)-neutralizing autoantibodies have been described in previously immunocompetent adults. To investigate the factors underlying various disease manifestations, we reviewed 35 articles published between January 2004 and November 2016 and identified 111 NTM patients with anti-IFN-gamma autoantibodies. Rapidly growing mycobacteria (RGM) accounted for 53% of the isolated species. RGM were predominant among the NTM species isolated from Thai (73%), Chinese (58%) and Filipino (56%) patients, whereas M. avium complex (MAC) was predominant among Japanese (58%) and non-Asian (80%) patients. The commonly involved organs included the lymph nodes (79%), bones/joints (34%) and lungs (32%). Compared with the patients with MAC, the patients with RGM had a higher incidence of lymph node lesions (P<0.05) and a lower incidence of bone/joint (P<0.01), lung (P<0.01), soft tissue (P<0.01), bronchus (P<0.01) and muscle (P<0.05) lesions. Clinical manifestations of NTM disease with anti-IFN-gamma-neutralizing autoantibodies differ across ethnicities and NTM species. PMID- 28633900 TI - Analytical and clinical performance of a Chikungunya qRT-PCR for Central and South America. AB - Chikungunya was introduced into the Americas in 2015 causing a pandemic across the continent. Testing during the acute phase of infection relies on qRT-PCR, but available assays have a number of limitations. A qRT-PCR assay specific to the chikungunya E1 gene was designed using sequence data from contemporary strains. A probit analysis established the 95% limit of detection as 19.6 copies per reaction. We compared the assay with a US Centers for Disease Control (CDC) chikungunya qRT-PCR as the reference standard. The assay had a sensitivity and specificity of 98.4% and 100% in 90 samples retrospectively collected in Guatemala. In a further 74 febrile samples prospectively collected in Ecuador and Guatemala the test had a sensitivity and specificity of 100% and 98.4%, respectively. Sequencing the nsp4 gene of the discordant positive sample indicated the presence of chikungunya RNA, and mismatches to the primer binding sites of the CDC assay. PMID- 28633902 TI - Calcium sensing receptor initiating cystathionine-gamma-lyase/hydrogen sulfide pathway to inhibit platelet activation in hyperhomocysteinemia rat. AB - Hyperhomocysteinemia (HHcy, high homocysteine) induces the injury of endothelial cells (ECs). Hydrogen sulfide (H2S) protects ECs and inhibits the activation of platelets. Calcium-sensing receptor (CaSR) regulates the production of endogenous H2S. However, whether CaSR inhibits the injury of ECs and the activation of platelets by regulating the endogenous cystathionine-gamma-lyase (CSE, a major enzyme that produces H2S)/H2S pathway in hyperhomocysteinemia has not been previously investigated. Here, we tested the ultrastructure alterations of ECs and platelets, the changes in the concentration of serum homocysteine and the parameters of blood of hyperhomocysteinemia rats were measured. The aggregation rate and expression of P-selectin of platelets were assessed. Additionally, the expression levels of CaSR and CSE in the aorta of rats were examined by western blotting. The mitochondrial membrane potential and the production of reactive oxygen species (ROS) were measured; the expression of phospho-calmodulin kinases II (p-CaMK II) and Von Willebrand Factor (vWF) of cultured ECs from rat thoracic aortas were measured. We found that the aggregation rate and the expression of P selectin of platelets increased, and the expression of CaSR and CSE decreased in HHcy rats. In the ECs of HHcy group, the ROS production increased and the mitochondrial membrane potential decreased markedly, the expression of CSE and the p-CaMK II increased after treatment with CaSR agonist while decreased upon administration of U73122 (PLC-specific inhibitor) and 2-APB (IP3 Receptor inhibitor). CaSR agonist or NaHS significantly reversed the ECs injured and platelet aggregation caused by hyperhomocysteinemia. Our results demonstrate that CaSR regulates the endogenous CSE/H2S pathway to inhibit the activation of platelets which concerts the protection of ECs in hyperhomocysteinemia. PMID- 28633903 TI - Internal validation of a scoring system to evaluate the probability of ureteral stones: The CHOKAI score. AB - OBJECTIVE: The CHOKAI and STONE scores are prediction models for ureteral stones. The aims of the present study were to evaluate the diagnostic performance, to examine the optimal cut-off value, and to compare the diagnostic performance of each model. METHODS: Patients who presented to our emergency department with renal colic were considered for this prospective study. We analyzed the predictive performance of both STONE and CHOKAI scores at their optimal cut-off values, using receiver operating characteristic (ROC) curve and area under the curve (AUC), as well as sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) at the optimal cut-off value. RESULTS: Of the 96 patients who met the inclusion criteria, 79 were definitively diagnosed with ureteral stones. All patients were of Japanese descent. The AUC of the CHOKAI score was 0.971 at an optimal cut-off value of 6, showing a sensitivity of 0.911, specificity of 0.941, LR+ of 15.49, and LR- of 0.094. The AUC of the STONE score was 0.873 at an optimal cut-off value of 8, showing a sensitivity of 0.823, specificity of 0.824, LR+ of 4.662, and LR- of 0.215. The AUC of the CHOKAI score was significantly higher than that of the STONE score (p=0.010). Of the 73 patients with a CHOKAI score of >=6, 98.6% had ureteral stones, and of the 68 patients with a STONE score of >=8, 95.6% had ureteral stones. CONCLUSIONS: The simplified CHOKAI score is a useful tool to screen for ureteral stones in patients with renal colic. PMID- 28633904 TI - Clinical characteristics of type A acute aortic dissection with CNS symptom. AB - BACKGROUND AND PURPOSE: Accurate diagnosis of acute aortic dissection (AAD) is sometimes difficult because of accompanying central nervous system (CNS) symptoms. The purpose of this study was to investigate the clinical characteristics of Type A AAD (TAAAD) with CNS symptoms. METHODS: We retrospectively reviewed the medical records of 8403 patients ambulanced to our emergency and critical care center between April 2009 and May 2014. RESULTS: We identified 59 TAAAD patients for the analysis (mean age, 67.3+/-10.5years; 37 (62.0%) male). Eleven patients (18.6%) presented CNS symptoms at the onset of TAAAD, and these patients complained less frequently of typical chest and back pain than those without CNS symptoms (p<0.0001). Initial systolic and diastolic blood pressure were lower (p=0.003, and p=0.049, respectively) and involvement of the supra-aortic artery was more frequent in patients with CNS symptoms (p<0.0001). CONCLUSION: Because CNS symptom can mask chest and back pain caused by TAAAD, physicians should always consider the possibility of TAAAD in patients with CNS symptoms in emergency medicine settings. PMID- 28633905 TI - Short and long-term mortality of patients presenting with bleeding events to the Emergency Department. AB - BACKGROUND: Death of patients presenting with bleeding events to the Emergency Department still represent a major problem. We sought to analyze clinical characteristics associated with worse outcomes including short- and long-term death, beyond antithombotic treatment strategy. METHODS: Patients presenting with any bleeding events during 2016-2017years were enrolled. Clinical parameters, site of bleeding, major bleeding, ongoing anti-thrombotic treatment strategy and death were collected. Hard 5:1 propensity score matching was performed to adjust dead patients in baseline characteristics. Endpoints were one-month and one-year death. RESULTS: Out of 166,000 visits to the Emergency Department, 3.050 patients (1.8%) were enrolled and eventually 429 were analyzed after propensity. Overall, anticoagulants or antiplatelets were given to 234(54%). Major bleeding account for 111(26%) patients, without differences between those taking anticoagulants or antiplatelets versus others. Death at one-month and one-year was 26(6%) and 72(17%), respectively. Independent predictors of one-month death were major bleeding (Odds Ratio, OR 26, p<0.001), female gender (OR 7, p<0.001) and white blood cells (OR 1.2, p=0.01); of one-year were major bleeding (OR 7, p<0.001), age (OR 1.1, p<0.001) and female gender (OR 2.3, p=0.043). Of note, death rate of gastrointestinal and intracranial bleeding where higher than others (p<0.001). Overall mortality was approximately 40% on one-month; 60% in older patients and 80% in female gender with CHA2D2VASC-score>=2. Receiver operator characteristics analysis showed larger areas for major bleeding and age (0.75 and 0.72, respectively) over others; p<0.05 on C-statistic. CONCLUSIONS: In patients with bleeding events, death rate was driven by major bleeding on short-term and older age on long-term. Among dead patients mortality was approximately 40% on one month; 60% in older patients, and 80% in female gender. PMID- 28633906 TI - RSV in adult ED patients: Do emergency providers consider RSV as an admission diagnosis? AB - BACKGROUND: Respiratory Syncytial Virus (RSV) has been recognized for over half a century as a cause of morbidity in infants and children. Over the past 20years, data has emerged linking RSV as a cause of illness in adults resulting in 177,000 annual hospitalizations and up to 14,000 deaths among older adults. OBJECTIVE: Characterize clinical variables in a cohort of adult RSV patients. We hypothesize that emergency physicians do not routinely consider RSV in the differential diagnosis (DDx) of influenza like illness. METHODS: Observational study of all adult inpatients, age>=19, with a positive RSV swab ordered within 48h of their hospital visit, including their emergency department (ED) visit, and who initially presented to a university affiliated urban 100,000 annual visit emergency department from 2007 to 2014. A data collection form was created, and a single trained clinical research assistant abstracted demographic, clinical variables. ED providers were given credit for RSV DDx if an RSV swab was ordered as part of the diagnostic ED workup. RESULTS: 295 consecutive inpatients (mean age=66.5years, range, 19-97, 53% male) were RSV positive during the 7-year study period. 207 cases (70%) were age>=60. 76 (26%) had fever, 86 (29%) had O2sat <92% and 145 (49%) had wheezing. 279 patients required admission, 30 needed ICU stay and overall mortality was 12 patients (4%). Age>=60 was associated with overall mortality (p=0.09). There were 106 (36%) immunocompromised patients (23% transplant, 40% cancer, 33% steroid use) in the cohort. A diagnosis of RSV was considered in the ED in 105 (36%) of patients. Being immunocompromised, having COPD/asthma, O2sat <92, or wheezing did not alert the ED provider to order an RSV test. CONCLUSION: Adults can harbor RSV as this can lead to significant mobility and mortality, especially in individuals who are over the age of 60. RSV is not being considered in the DDx diagnosis, and this was especially surprising in the transplant/immunocompromised subgroups. Given antiviral treatment options, educational efforts should be undertaken to raise awareness of RSV in adults. PMID- 28633907 TI - An increase in per-patient naloxone requirements in an opioid epidemic. PMID- 28633908 TI - Dynamics of the cell division orientation of granule cell precursors during cerebellar development. AB - The cerebellar granule cell (GC) system provides a good model for studying neuronal development. In the external granule layer (EGL), granule cell precursors (GCPs) rapidly and continuously divide to produce numerous GCs as well as GCPs. In some brain regions, the orientation of cell division affects daughter cell fate, thus the direction of GCP division is related to whether it produces a GCP or a GC. Therefore, we tried to characterize the orientation of GCP division from embryonic to postnatal stages and to identify an environmental cue that regulates the orientation. By visualizing chromatin in EGL GCPs at M-phase, we found that the directions of cell divisions were not random but dynamically regulated during development. While horizontal and vertical divisions were equivalently observed in embryos, horizontal division was more frequently observed at early postnatal stages. Vertical division became dominant at late cerebellar developmental stages. Administration of a SHH inhibitor to cultured cerebellar slices resulted in randomized orientation of cell division, suggesting that SHH signaling regulates the direction of cell division. These results provide fundamental data towards understanding the development of GCs. PMID- 28633910 TI - Gentle antibody-mimetic affinity chromatography with polyol-responsive nanoCLAMPs. PMID- 28633909 TI - Resolving in vivo gene expression during collective cell migration using an integrated RNAscope, immunohistochemistry and tissue clearing method. AB - During collective cell migration individual cells display diverse behaviors that complicate our understanding of group cell decisions of direction and cohesion. In vivo gene and protein expression analyses would shed light on the underlying molecular choreography. However, this information has been limited due to difficulties to integrate single cell detection methods and the simultaneous readout of multiple signals deep within the embryo. Here, we optimize and integrate multiplex fluorescence in situ hybridization by RNAscope, immunohistochemistry, and tissue clearing to visualize transcript and protein localization within single cells deep within intact chick embryos. Using standard confocal microscopy, we visualize the mRNA expression of up to 3 genes simultaneously within protein labeled HNK1-positive migrating cranial neural crest cells within 2day old cleared chick embryos. Gene expression differences measured between adjacent cells or within subregions are quantified using spot counting and polyline kymograph methods, respectively. This optimization and integration of methods provide an improved 3D in vivo molecular interrogation of collective cell migration and foundation to broaden into a wider range of embryo and adult model systems. PMID- 28633911 TI - Fate of metals and emissions of organic pollutants from torrefaction of waste wood, MSW, and RDF. AB - Torrefaction of municipal solid waste (MSW), refuse-derived fuel (RDF), and demolition and construction wood (DC) was performed at 220 degrees C and a residence time of 90min in a bench-scale reactor. The levels of toxic polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDF) contained in emission from the torrefaction process were evaluated. In addition, main ash forming elements and trace metals in the raw feedstock and char were determined. The use of MSW in fuel blends with DC resulted in lower PCDD and PCDF emissions after torrefaction, compared with the RDF blends. The migration of chlorine from the feedstock to the gas phase reduces the chlorine content of the char which may reduce the risk of alkali chloride-corrosion in char combustion. However, trace metals catalytically active in the formation of PCDD and PCDF remain in the char, thereby may promote PCDD and PCDF formation during subsequent char combustion for energy recovery; this formation is less extensive than when the feedstock is used. PMID- 28633912 TI - Life cycle assessment and life cycle costs for pre-disaster waste management systems. AB - This study develops a method of environmental and economic evaluation of an integrated disaster waste management system that considers the spatial scale of removal, transport, and treatment of disaster waste. A case study was conducted on combustibles, which is a type of disaster waste derived from dwellings, in Mie Prefecture, Japan. First, we calculated the quantity and the spatial distribution of disaster waste derived from dwellings and tsunami debris produced as a result of a large-scale earthquake. The quantity of disaster waste was estimated as 7,178,000t with functioning flood-preventing facilities and 11,956,000t without functioning flood prevention facilities. Ensuring resilience in the face of earthquakes and tsunamis by renovating flood-preventing facilities is extremely important in decreasing the production of wastes, especially in coastal regions. Next, the transportation network for transporting combustibles in disaster waste to temporary storage sites, incineration plants, and landfill was constructed using an optimization model. The results showed that if flood-preventing facilities do not function properly, the installation of temporary incineration facilities becomes essential. Life-cycle emissions of CO2, SOx, NOx, and PM and the costs of removal, storage, and treatment of combustibles were calculated as 258,000t, 618t, 1705t, 7.9t, and 246millionUSD, respectively, in the case of functioning flood-preventing facilities. If flood-preventing facilities do not function, the quantity of environmentally unfriendly emissions and the costs increase. This result suggested the significance of renovation in order to maintain the conditions of flood-preventing facilities to decrease the environmental burden and costs as well as keep the production of disaster waste at a minimum. PMID- 28633913 TI - Commentary on "The New Opt-Out Dutch National Breast Implant Registry: Lessons learnt from the road to implementation". PMID- 28633914 TI - Breast reconstruction by exclusive fat grafting: What about the breast projection? PMID- 28633916 TI - Novel variant of OCT4B4 is differentially expressed in human embryonic stem and embryonic carcinoma cells. AB - POU domain proteins are an important family of transcription factors that regulates cell type-specific gene expression. One of the most crucial members of this family that maintains pluripotency and self-renewal of embryonic stem cells is POU5F1/OCT4. The OCT4 gene can generate several variants under different situations/cell types includes OCT4A that is the major factor sustains pluripotency in embryonic stem and embryonic carcinoma cells, and also OCT4B and OCT4B1, which are transcribed from a different potential promoter located in intron1 and are expressed in various tissues and cell types. In present study, during expression check of OCT4B1 in embryonic carcinoma cells (NT2), we discovered a novel OCT4 transcript for the first time and designated it as OCT4B4. This variant is expressed in various human pluripotent cells and its expression is down-regulated upon induction of differentiation. Moreover, knocking down of OCT4B4 by shRNA resulted in increased accumulation of transfected cells in G0/G1 phase compared to the mock-transfected control cells. PMID- 28633915 TI - Patient-centered care in obstructive sleep apnea: A vision for the future. AB - Obstructive sleep apnea is a common condition, with multiple potential neurocognitive, cardiovascular, and metabolic consequences. Efficacious treatment is available, but patient engagement is typically required for treatment to be effective. Patients with sleep apnea are phenotypically diverse and have individual needs, preferences, and values that impact treatment decisions. There has been a shift in obstructive sleep apnea management from diagnosis to chronic care management. Making treatment decisions that incorporate an individual patient's values and preferences and are personalized for that patient's biology has the potential to improve patient outcomes. A patient-centered care approach in obstructive sleep apnea is reviewed including 1) determining patient-specific needs to guide treatment decisions, 2) understanding patient values, preferences, and other factors impacting treatment decisions and using shared decision-making, 3) enhancing patient education and support to improve treatment adherence, 4) promoting patient engagement, 5) optimizing care coordination, continuity of care, and access to care, and 6) determining and assessing patient-centered outcomes. PMID- 28633917 TI - Polymorphic variants of Caspase genes (8 & 3) in the risk prediction of Coronary Artery Disease. AB - Apoptosis has been involved in a number of pathological conditions including coronary artery disease (CAD). Caspases (CASP) are important regulators and executioners in both extrinsic and intrinsic apoptotic pathways. The aim of the present study is to examine the role of Caspase 8 and 3 polymorphisms in the pathogenesis of CAD. CAD patients (n=300) and healthy controls (n=300) were genotyped for polymorphisms in CASP8 (-652 6N del/ins, IVS12-19G>A), CASP3 (rs4647601;G>T) by PCR-RFLP. Splicing defects were determined by HSF. Gene interactions, Linkage disequilibrium and haplotype analysis were carried out by MDR analysis and Haploview software respectively. Molecular analysis revealed that insertion genotype (II) of CASP8 -652 6N del/ins and TT genotype of CASP3 rs4647601;G>T polymorphism conferred risk for the development of CAD. HSF analysis showed that intronic cryptic donor site for CASP8 -652 6N del/ins and a new ESE site for CASP3 rs4647601;G>T polymorphisms. SNP combinations of Caspase 8 and 3 were in perfect LD (D'=1) in controls. D-A, I-G haplotypes of Caspase 8 polymorphisms (-652 6N del/ins & IVS12-19G>A) were found to be significantly predominant in the disease group. The present study suggests that CASP8 & 3 polymorphic variants might be used as markers for susceptibility to CAD. PMID- 28633918 TI - Traction force and its regulation during cytokinesis in Dictyostelium cells. AB - Cytokinesis is the final stage of cell division. Dictyostelium cells have multiple modes of cytokinesis, including cytokinesis A, B and C. Cytokinesis A is a conventional mode, which depends on myosin II in the contractile ring. Myosin II null cells divide depending on substratum-attachment (cytokinesis B) or in a multi-polar fashion independent of the cell cycle (cytokinesis C). We investigated the traction stress exerted by dividing cells in the three different modes using traction force microscopy. In all cases, the traction forces were directed inward from both poles. Interestingly, the traction stress of cytokinesis A was the smallest of the three modes. Latrunculin B, an inhibitor of actin polymerization, completely diminished the traction stress of dividing cells, but blebbistatin, an inhibitor of myosin II ATPase, increased the traction stress. Myosin II is proposed to contribute to the detachment of cell body from the substratum. When the cell-substratum attachment was artificially strengthened by a poly-lysine coating, wild type cells increased their traction stress in contrast to myosin II null and other cytokinesis-deficient mutant cells, which suggests that wild type cells may increase their own power to conduct their cytokinesis. The cytokinesis-deficient mutants frequently divided unequally, whereas wild type cells divided equally. A traction stress imbalance between two daughter halves was correlated with cytokinesis failure. We discuss the regulation of cell shape changes during cell division through mechanosensing. PMID- 28633919 TI - Guiding Stars Influences Perception of Healthy Food Choices at a 4-Year University. PMID- 28633920 TI - Identifying Underlying Beliefs About Fruit and Vegetable Consumption Among Low Income Older Adults: An Elicitation Study Based on the Theory of Planned Behavior. AB - OBJECTIVE: Identify underlying salient behavioral, normative, and control beliefs about fruit and vegetable (F&V) consumption among limited-income older adults. DESIGN: The Theory of Planned Behavior (TPB) was used as the framework for conducting semistructured individual interviews in 2016. SETTING: Two congregate meal sites in the city of Tuscaloosa, AL. PARTICIPANTS: A total of 25 low-income older adults aged >=60 years. MAIN OUTCOME MEASURES: Behavioral, normative, and control beliefs about F&V intake. ANALYSIS: All interviews were audiotaped and transcribed verbatim. Data were analyzed using a hybrid inductive and deductive content analysis approach. RESULTS: The elicitation interviews identified salient behavioral, normative, and control beliefs about F&V intake among low-income older adults. CONCLUSIONS: These results can be used to develop nutrition education programs aimed at improving economically vulnerable older adults' F&V intake. PMID- 28633921 TI - Applying the National Committee for Quality Assurance Patient-Centered Specialty Practice Framework to Radiology. PMID- 28633923 TI - "Quality in Practice": An Introduction to a New Bimonthly Column Focused on Radiology Quality and Safety. PMID- 28633922 TI - Quantifying Language Before and After Instituting Structured CT Reports. AB - AIM: Our aim was to quantify the language in abdominopelvic CT reports before and after implementing structured reporting templates, specifically evaluating the terms normal and unremarkable. METHODS: We performed a search of our database for all CT abdomen and pelvis examinations before and after full template implementation. There were 1,753 studies included-878 "pretemplate" reports, 875 "posttemplate" reports. Pre- and posttemplate reports were analyzed for word count in preliminary report, word count in final report, number of changed words between preliminary and final report, and frequency of normal and unremarkable. The averages of each data point for both pre- and posttemplate reports were calculated and compared. RESULTS: Between all pre- and posttemplate reports, the total number of words and number of changes between preliminary and final reports was not significantly changed. The frequency of the word normal increased from an average of 5.29 (pretemplate) to 8.92 (posttemplate) per report (P < .0001). The frequency of the word unremarkable increased from an average of 0.11 (pretemplate) to 0.22 (posttemplate) per report (P < .0001). CONCLUSIONS: When comparing language before and after implementing structured reports, we found an increase in the frequency of normal, without any significant change in number of words per report. The increase in normal in posttemplate reports reflects a trend toward more definitive reporting, which may increase clarity and satisfaction among referring physicians. The increased use of the less definitive term unremarkable identifies an area in need of further training and improvement in our department. PMID- 28633924 TI - The Just Culture Framework. PMID- 28633925 TI - The discovery of plasma cells: An historical note. AB - The name plasma cell was introduced by the anatomist Heinrich H. von Hartz Waldeyer in 1875. Plasma cells derive from small B lymphocytes after their activation. A fully mature plasma cell lacks surface immunoglobulin expression. Its form is round or oval, with characteristic basophilic cytoplasm and an eccentric nucleus that contains coarse heterochromatin. Antigen activation of mature B cells leads initially to germinal center development, the transient generation of plasmablasts that secrete antibody while still dividing, and short lived extrafollicular plasma cells that secrete antigen-specific germ line encoded antibodies. Plasma cells are characterized by the co-expression of CD138 and CD38, which allows their identification in flow cytometry in bone marrow, peripheral blood, or cell suspensions from tissues. The identification of plasma cells as antibody producers was a key discovery that paved the way for the development of monoclonal antibodies. PMID- 28633926 TI - Synergic stimulation of serotonin 5-HT1A receptor and alpha2-adrenoceptors for neuropathic pain relief: Preclinical effects of 2-substituted imidazoline derivatives. AB - Neuropathic pain affects millions of people causing disability and impairing quality of life. Commonly used analgesics are generally characterized by limited therapeutic outcomes. The serotonin 5-HT1A receptor and the alpha2 adrenergic receptors are involved in central nociceptive mechanisms with a pivotal role in the inhibitory descending pain pathway. Since their stimulation may modulate the nervous signaling altered by neuropathies, the purpose of the present research is the study of the combined activation of 5-HT1A and alpha2 receptors by rationally designed imidazoline ligands ((S)-(-)-1 and 2-5) in a rat model of neuropathic pain (chronic constriction injury - CCI). On day 14 after nerve damage, the acute administration per os (p.o.) of low doses of (S)-(-)-1 (0.1-1mg/kg) was able to significantly increase the pain threshold to mechanical noxious stimuli for more than 1h. (S)-(-)-1 efficacy was confirmed by the decrease of spontaneous pain evaluated as hind limb weight bearing alterations. The clinically-used compound gabapentin (100mg/kg p.o.) induced a pain relieving effect similar to (S)-(-)-1 administered at 100 fold lower dose. In the same model, the selected analogues, compounds 2-5 (1mg/kg p.o.) were effective 30min after administration. In particular, 5 fully reverted the CCI-induced hypersensitivity. The pain relieving activity of 5 was significantly prevented by the selective 5-HT1A receptor antagonist WAY 100635 (1mg/kg intraperitoneally, i.p.) and, at a lesser extent, by the alpha2 antagonist yohimbine (3mg/kg i.p.). A novel pharmacodynamic approach to the treatment of neuropathic pain is presented. PMID- 28633927 TI - Dencichine ameliorates kidney injury in induced type II diabetic nephropathy via the TGF-beta/Smad signalling pathway. AB - Diabetic nephropathy (DN), a common complication associated with both type I and type II diabetes mellitus (DM), is a major cause of chronic nephropathy and a common cause of end-stage renal diseases (ESRD) throughout the world. This study is aimed to determine whether dencichine (De) can ameliorate renal damage in high glucose-and-fat diet combined STZ (streptozocin) induced DN in type II DM rats and to investigate the potential underlying mechanisms. Markers of metabolism, diabetes, and renal function, and levels of extracellular matrix (ECM) collagen I (Col I), collagen IV (Col IV), fibronectin (FN) and laminin (LN), and of proteins in the TGF-beta/Smad pathway were analysed through RT-PCR, western blot, immunofluorescence and immunohistochemistry. The results show that De significantly alleviates metabolism disorder, improved renal function, relieved pathological alterations in the glomerulus of DN rats, decreased ECM deposition and increased the ratio of matrix metalloproteinase (MMP)-9 to tissue inhibitor of metalloproteinase (TIMP)-1 both in vivo and in vitro. Moreover, De negatively regulated TGF-beta/Smad signalling pathway and increased the expression of Smad7, an endogenic inhibitory Smad located downstream of the signalling pathway. In conclusion, we provide experimental evidence indicating that the renoprotective effect of De could significantly prevent the progression of DN possibly attribute to down-regulation of the TGF-beta/Smad pathway and rebalance the deposition and degradation of ECM proteins. PMID- 28633928 TI - Clinical immunophenotype of nasopharyngeal neuroendocrine carcinoma with metastatic liver cancer. AB - BACKGROUND: Nasopharyngeal neuroendocrine carcinoma (NNC) refers to a rare and lethal cancer, characterized with high risk of metastases. Here, we report a case of nasopharyngeal neuroendocrine carcinoma with subsequent liver metastases to discuss its clinical immunophenotype and challenges. METHODS: In clinical biochemical assays, hematological determination, immunohistochemical examination, imaging medicine investigations, and therapeutical analysis were subjected to the hospitalized patient, respectively. RESULTS: A group of clinical detectable data highlighted that clinical immunophenotype of nasopharyngeal neuroendocrine carcinoma was identified in immunohistochemical inspection, followed by validation of liver metastases via imaging observations. Subsequent chemotherapy schedule showed disease remission in certain aspect before patient' death. CONCLUSION: Our current clinical data disclose that it is vital to identify nasopharyngeal neuroendocrine carcinoma for main cause of liver metastases with potential risk. Further, early diagnosis and effective pharmacotherapy may improve the survival rate of NNC patient with liver metastases. PMID- 28633929 TI - Biomechanical evaluation of different osteosynthesis methods after mandibular sagittal split osteotomy in major advancements. AB - The aim of this study was to assess the biomechanical stability of six different osteosynthesis methods after sagittal split osteotomy. Sixty polyurethane hemimandibles were divided into two groups, with six subgroups in each. After 10 mm advancement of the distal segment (group 1) and 10-mm advancement combined with 20 degrees counterclockwise rotation (group 2), the bone segments were fixed using 2.0-mm plates/screws as follows: subgroup A, one conventional straight plate; subgroup B, two conventional straight plates; subgroup C, one conventional sagittal plate; subgroup D, one locking straight plate; subgroup E, two locking straight plates; subgroup F, one locking sagittal plate. The hemimandibles were tested for compressive strength by three-point biomechanical test, until there was 3mm of displacement between the segments. The fixations showed better performance in group 1 than in group 2 in all cases, with statistical significance for subgroups A, C, and D. In both groups, the use of two straight miniplates showed the most resistance, followed by the sagittal miniplates. However, in counterclockwise rotations, no statistically significant difference was found between two conventional straight plates and the sagittal locking plate. This study shows that the use of two plates is the form of fixation with the minimum displacement. If the clinician opts to use one plate, a sagittal plate is the best alternative. PMID- 28633930 TI - Phospholipase A2 in the venom of three cottonmouth snakes. AB - Two phospholipase A2s (PLA2s), Asp49 (D49) and Lys49 (K49), were purified by one step reverse-phase high performance liquid chromatography (RP-HPLC) from the venom of each of the three subspecies of cottonmouth snake, Western cottonmouth (Agkistrodon piscivorus leucostoma; Apl), Eastern cottonmouth (Agkistrodon piscivorus piscivorus; App) and Florida cottonmouth (Agkistrodon piscivorus conanti; Apc). Venom protein profiles and PLA2s elution pattern of the three cottonmouth snakes were remarkably similar displaying four similar sharp and two wide peaks; in all cases K49 PLA2 eluted first followed by D49 PLA2. The yields of K49 and D49 PLA2s were, respectively, 13.2 and 17.5 mg/g venom from the Western cottonmouth, 16.8 and 19.2 mg/g from the Eastern cottonmouth, and 17.3 and 22.7 mg/g from the Florida cottonmouth. Biochemical and enzymatic techniques were used to characterize the purified PLA2. The amino acid sequences of all three K49PLA2s were identical; App-D49 and Apc-D49 were also identical but displayed a single amino acid difference with Apl-D49. To our knowledge, this is the first report on the amino acid sequence and molecular mass of Apc-D49 and Apc K49 PLA2s from Florida cottonmouth venom. As expected, PLA2 enzymatic analysis revealed that D49 PLA2s from all three venoms hydrolyze phospholipids to a similar extent, whereas no phospholipid hydrolysis was detectable by any of the K49 PLA2s purified. Cottonmouth snake venoms contain abundant PLA2 isoforms, thus the identification of PLA2s in these venoms is of interest to facilitate the purification of specific PLA2 from rich sources of subspecies venom for future biological and biomedical research. Results of this study also contribute towards the understanding of venom protein profiles, variation, and evolution in subspecies of venomous snakes. PMID- 28633931 TI - Dyspigmentation of Skin as a Clue to the Diagnosis of Dystonia. PMID- 28633932 TI - beta2-adrenoreceptor stimulation dampens the LPS-induced M1 polarization in pig macrophages. AB - The cross-talk between sympatho-adreno-medullar axis and innate immunity players was mainly studied in rodents. In intensive husbandry, pigs are exposed to multiple stressors inducing repeated releases of catecholamines that bind to adrenoreceptors (AR) on target cells. Among adrenoreceptors, the beta2-AR is largely expressed by immune cells including macrophages. We report herein on the effects of catecholamines, through beta2-AR stimulation, on pig macrophage functions activated by LPS. beta2-AR stimulation of porcine macrophages prevented the LPS-induced increase in TNFalpha and IL-8 secretion while increasing IL-10 secretion. In contrast, treatment with a beta2-agonist had no effect on anti microbial functions. Lastly, beta2-AR stimulation of macrophages reduced the expression of genes up-regulated by LPS. Altogether, we demonstrated that beta2 AR stimulation of porcine macrophages prevented polarization towards a pro inflammatory phenotype. Since porcine macrophages are a suitable model for human macrophages, our results might be relevant to appreciate catecholamine effects on human macrophages. PMID- 28633933 TI - Trajectories of self-evaluation bias in primary and secondary school: Parental antecedents and academic consequences. AB - Using a longitudinal approach spanning nine years of children's formal education, this study investigated the developmental trajectories of self-evaluation bias of academic competence. The study also examined how parenting styles were associated with the trajectories of bias in mid-primary school, and how those trajectories predicted academic outcomes at the end of secondary school and the beginning of college. A total of 711 children in 4th and 5th grades (mean age=10.71years old; 358 girls) participated in this study. Using a latent class growth modeling framework, results indicated that children can be classified in three latent growth trajectories of self-evaluation bias: the optimistic, realistic and pessimistic trajectories. These trajectories differed in their initial status of bias and also in their development over time. Children's adherence to a specific trajectory was associated with parenting variables in childhood. Finally, the optimistic, realistic, or pessimistic trajectories distinctively predicted achievement and persistence. PMID- 28633934 TI - The impact of ordinate scaling on the visual analysis of single-case data. AB - Visual analysis is the primary method for detecting the presence of treatment effects in graphically displayed single-case data and it is often referred to as the "gold standard." Although researchers have developed standards for the application of visual analysis (e.g., Horner et al., 2005), over- and underestimation of effect size magnitude is not uncommon among analysts. Several characteristics have been identified as potential contributors to these errors; however, researchers have largely focused on characteristics of the data itself (e.g., autocorrelation), paying less attention to characteristics of the graphic display which are largely in control of the analyst (e.g., ordinate scaling). The current study investigated the impact that differences in ordinate scaling, a graphic display characteristic, had on experts' accuracy in judgments regarding the magnitude of effect present in single-case percentage data. 32 participants were asked to evaluate eight ABAB data sets (2 each presenting null, small, moderate, and large effects) along with three iterations of each (32 graphs in total) in which only the ordinate scale was manipulated. Results suggest that raters are less accurate in their detection of treatment effects as the ordinate scale is constricted. Additionally, raters were more likely to overestimate the size of a treatment effect when the ordinate scale was constricted. PMID- 28633935 TI - Teacher-student relationship quality and academic achievement in elementary school: A longitudinal examination of gender differences. AB - Multiple group longitudinal cross-lagged panel models were implemented to understand the directional influences between teacher-student closeness and conflict and measured math and reading achievement across elementary grades and gender groups using the National Institute of Child Health and Human Development longitudinal sample (N=1133). Specifically, after testing multiple group longitudinal measurement invariance to ensure consistent measurement across genders and time, and tests of equivalence of the latent parameters, we were interested in whether longitudinal changes in teacher-rated closeness and conflict explained longitudinal changes in achievement, and vice versa, and whether those longitudinal influences varied by gender. Latent teacher-student closeness decreased for both genders over time (Cohen's d=-0.15 to -0.32), but latent conflict increased for males (Cohen's d=0.16). There was also increased heterogeneity in teacher-student relationship quality for males relative to females. Math and reading achievement had medium reciprocal effects (beta=0.12 to 0.23), and previous math achievement had small to medium effects on subsequent teacher-student closeness (beta=0.08 to 0.11) and conflict (beta=-0.07 to -0.09). Teacher-student conflict and closeness did not influence subsequent levels of math or reading achievement once previous levels were controlled. Further, these influences were consistent across gender groups despite latent differences in teacher-student closeness and conflict with teachers reporting closer relationships with female students and more conflictual relationships with male students. PMID- 28633936 TI - Additional comparisons of randomization-test procedures for single-case multiple baseline designs: Alternative effect types. AB - A number of randomization statistical procedures have been developed to analyze the results from single-case multiple-baseline intervention investigations. In a previous simulation study, comparisons of the various procedures revealed distinct differences among them in their ability to detect immediate abrupt intervention effects of moderate size, with some procedures (typically those with randomized intervention start points) exhibiting power that was both respectable and superior to other procedures (typically those with single fixed intervention start points). In Investigation 1 of the present follow-up simulation study, we found that when the same randomization-test procedures were applied to either delayed abrupt or immediate gradual intervention effects: (1) the powers of all of the procedures were severely diminished; and (2) in contrast to the previous study's results, the single fixed intervention start-point procedures generally outperformed those with randomized intervention start points. In Investigation 2 we additionally demonstrated that if researchers are able to successfully anticipate the specific alternative effect types, it is possible for them to formulate adjusted versions of the original randomization-test procedures that can recapture substantial proportions of the lost powers. PMID- 28633937 TI - Our teacher likes you, so I like you: A social network approach to social referencing. AB - A teacher is a social referent for peer liking and disliking when students adjust their evaluations of a peer based on their perceptions of teacher liking and disliking for this peer. The present study investigated social referencing as an intra-individual process that occurs over time, using stochastic actor-oriented modeling with RSiena. The co-evolution of peer-perceived teacher liking and disliking networks with peer liking and disliking networks was analyzed in 52 fifth-grade classes in the Netherlands, with 1370 students (Mage=10.60). Results showed that when a student viewed the teacher to like a peer, this student would also like this peer. Regarding disliking, there was a stronger effect in the opposite direction, indicating that students' disliking a peer increased the likelihood that they would view the peer as disliked by the teacher as well. In sum, partial evidence for social referencing as an intra-individual process was found. For teachers this implies that the cues they provide regarding their liking of a student, and not necessarily their disliking, may affect individual peers' liking of this student. PMID- 28633938 TI - Classroom relationship qualities and social-cognitive correlates of defending and passive bystanding in school bullying in Sweden: A multilevel analysis. AB - Using the social-ecological and social cognitive theories as integrated guiding frameworks, the present study examined whether moral disengagement and defender self-efficacy at the individual level, and moral disengagement, quality of teacher-student relationships and quality of student-student relationships at the classroom level were associated with passive bystanding and defending in bullying situations. Participants were 900 Swedish students from 43 classrooms, ranging in age from 9 to 13years. Multilevel regression analyses revealed that passive reactions by bystanders were associated with greater moral disengagement and less defender self-efficacy. Defending, in turn, was associated with less moral disengagement and greater defender self-efficacy and classroom student-student relationship quality. Furthermore, students who scored high in moral disengagement were even less prone to defend victims when the classroom student student relationship quality was low, but more prone to act as defenders when the classroom student-student relationship quality was high. In addition, the negative association between defender self-efficacy and passive bystanding was stronger both in classrooms with higher student-student relationship quality and in those with lower class moral disengagement. Implications for prevention are discussed. PMID- 28633939 TI - A comparison of problem identification interviews conducted face-to-face and via videoconferencing using the consultation analysis record. AB - School psychologists who experience challenges delivering face-to-face consultation may utilize videoconferencing to facilitate their consultation activities. Videoconferencing has been found to be an effective method of service delivery in related fields and emerging research suggests that it may be effective for providing teacher training and support in school settings. In this exploratory investigation, we used the Consultation Analysis Record (Bergan & Tombari, 1975) and its four indices to assess the effectiveness of conducting problem identification interviews via videoconferencing versus face-to-face. Overall, findings indicated significant differences across these two conditions, with videoconference interviews coded as having higher indices of content relevance, process effectiveness, and message control, but lower content focus, compared to face-to-face interviews. As these indices have been positively associated with favorable consultation outcomes, the results provide initial support for the effectiveness of consultation delivered via videoconferencing. PMID- 28633940 TI - Mindfulness-based interventions with youth: A comprehensive meta-analysis of group-design studies. AB - The treatment effects of Mindfulness-Based Interventions (MBIs) with youth were synthesized from 76 studies involving 6121 participants. A total of 885 effect sizes were aggregated using meta-regression with robust variance estimation. Overall, MBIs were associated with small treatment effects in studies using pre post (g=0.305, SE=0.039) and controlled designs (g=0.322, SE=0.040). Treatment effects were measured after a follow-up period in 24 studies (n=1963). Results demonstrated that treatment effects were larger at follow-up than post-treatment in pre-post (g=0.462, SE=0.118) and controlled designs (g=0.402, SE=0.081). Moderator analyses indicated that intervention setting and intervention dosage were not meaningfully related to outcomes after controlling for study design quality. With that said, the between-study heterogeneity in the intercept-only models was consistently small, thus limiting the amount of variance for the moderators to explain. A series of exploratory analyses were used to investigate the differential effectiveness of MBIs across four therapeutic process domains and seven therapeutic outcome domains. Small, positive results were generally observed across the process and outcome domains. Notably, MBIs were associated with moderate effects on the process variable of mindfulness in controlled studies (n=1108, g=0.510). Limitations and directions for future research and practice are discussed. PMID- 28633941 TI - Pancreatic Cyst Fluid Vascular Endothelial Growth Factor A and Carcinoembryonic Antigen: A Highly Accurate Test for the Diagnosis of Serous Cystic Neoplasm. AB - BACKGROUND: Accurate differentiation of pancreatic cystic lesions is important for pancreatic cancer early detection and prevention as well as avoidance of unnecessary surgical intervention. Serous cystic neoplasms (SCN) have no malignant potential, but may mimic premalignant mucinous cystic lesions: mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm (IPMN). We recently identified vascular endothelial growth factor (VEGF)-A as a novel pancreatic fluid biomarker for SCN. We hypothesize that combining cyst fluid carcinoembryonic antigen (CEA) with VEGF-A will improve the diagnostic accuracy of VEGF-A. METHODS: Pancreatic cyst/duct fluid was collected from consenting patients undergoing surgical cyst resection with corresponding pathologic diagnoses. Pancreatic fluid VEGF-A and CEA levels were detected by ELISA. RESULTS: One hundred forty-nine patients with pancreatic cystic lesions met inclusion criteria. Pathologic diagnoses included pseudocyst (n=14), SCN (n=26), MCN (n=40), low/moderate grade IPMN (n=34), high grade IPMN (n=20), invasive IPMN (n=10) and solid pseudopapillary neoplasm (n=5). VEGF-A was significantly elevated in SCN cyst fluid compared to all other diagnoses (p<0.001). With a threshold of >5,000 pg/ml, VEGF-A alone has 100% sensitivity and 83.7% specificity to distinguish SCN from other cystic lesions. With a threshold of <=10ng/ml, CEA alone identifies SCN with 95.5% sensitivity and 81.5% specificity. Sensitivity and specificity of the VEGF-A/CEA combination are 95.5% and 100% respectively. The c-statistic increased from 0.98 to 0.99 when CEA was added to VEGF-A alone in the ROC analysis. CONCLUSIONS: Although VEGF-A alone is a highly accurate test for SCN, the combination of VEGF-A with CEA approaches the gold standard of pathologic diagnosis, thus importantly avoiding false positives. Patients with a positive test indicating benign SCN can be spared a high risk surgical pancreatic resection. PMID- 28633942 TI - Outbreak of immediate-type hydrolyzed wheat protein allergy due to a facial soap in Japan. PMID- 28633943 TI - Diet-borne systemic inflammation is associated with prevalent tooth loss. AB - BACKGROUND & AIMS: The deleterious effect of cariogenic dietary patterns on tooth loss is well characterized, but the contribution of diet-borne systemic inflammation to loss of teeth remains uncharted. Recent efforts have unveiled a protective role of single nutrients to periodontal health. However, the assessment of overall diet as a modifiable risk factor for oral health remains elusive. Thus, the aim of this study was to assess the association between diet borne systemic inflammation and tooth loss in a representative sample of the US adult non-institutionalized population. METHODS: A cross-sectional analysis of a sample of participants of the 2009-2010 and 2011-2012 continuous NHANES receiving an oral exam and providing dietary recall data was performed. Dietary inflammatory potential was assessed by the Dietary Inflammatory Index (DII), a composite measure computed based on the association between nutrients and systemic pro-inflammatory cytokine levels. The outcome measure was prevalent tooth loss. Numbers of missing teeth were regressed across quartiles of the DII using multivariable linear regression models. RESULTS: 6887 eligible NHANES participants were included in the analysis; participants in the highest quartile of the DII index (pro-inflammatory diet) had an average [95% CI] of 0.84 [0.24, 1.45] additional more teeth lost as compared to those in the lowest quartile of DII (anti-inflammatory diet) (p = 0.015), after adjusting for known confounders. This significant association remained in subgroup analyses, including the lowest tertiles of energy-adjusted carbohydrate intake, and in persons aged >=50 years. CONCLUSIONS: Adherence to an anti-inflammatory diet is associated with fewer missing teeth. These results suggest protective dietary patterns as a modifiable protective factor for tooth loss in the US adult population and support the incorporation of tooth loss prevention in the agenda of dietary public health interventions to prevent chronic inflammatory diseases. PMID- 28633944 TI - Gene expression analysis identify a metabolic and cell function alterations as a hallmark of obesity without metabolic syndrome in peripheral blood, a pilot study. AB - BACKGROUND: Understanding molecular basis involved in overweight is an important first step in developing therapeutic pathways against excess in body weight gain. OBJECTIVE: The purpose of our pilot study was to evaluate the gene expression profiles in the peripheral blood of obese patients without other metabolic complications. DESIGN: A sample of 17 obese patients without metabolic syndrome and 15 non obese control subjects was evaluated in a prospective way. Following 'One-Color Microarray-Based Gene Expression Analysis' protocol Version 5.7 (Agilent p/n 4140-90040), cRNA was hybridized with Whole Human Genome Oligo Microarray Kit (Agilent p/n G2519F-014850) containing 41,000+ unique human genes and transcripts. RESULTS: The average age of the study group was 43.6 +/- 19.7 years with a sex distribution of 64.7% females and 35.3% males. No statistical differences were detected with healthy controls 41.9 +/- 12.3 years with a sex distribution of 70% females and 30% males. Obese patients showed 1436 genes that were differentially expressed compared to control group. Ingenuity Pathway Analysis showed that these genes participated in 13 different categories related to metabolism and cellular functions. In the gene set of cellular function, the most important genes were C-terminal region of Nel-like molecule 1 protein (NELL1) and Pigment epithelium-derived factor (SPEDF), both genes were over expressed. In the gene set of metabolism, insulin growth factor type 1 (IGF1), ApoA5 (apolipoprotein subtype 5), Foxo4 (Forkhead transcription factor 4), ADIPOR1 (receptor of adiponectin type 1) and AQP7 (aquaporin channel proteins7) were over expressed. Moreover, PIKFYVE (PtdIns(3) P 5-kinase), and ROCK-2 (rho kinase II) were under expressed. CONCLUSION: We showed that PBMCs from obese subjects presented significant changes in gene expression, exhibiting 1436 differentially expressed genes compared to PBMCs from non-obese subjects. Furthermore, our data showed a number of genes involved in relevant processes implicated in metabolism, with genes presenting high fold-change values (up regulation and down regulation) associated with lipid, carbohydrate and protein metabolism. PMID- 28633945 TI - Assessment of Heavy Metal Contamination in Marine Sediments of East Coast of Tamil Nadu Affected by Different Pollution Sources. AB - The aim of this study was to determine the concentration of heavy metals in the sediments of Periyakalapet to Parangipettai coast, east coast of Tamil Nadu, by using energy-dispersive X-ray fluorescence (EDXRF) technique. The average heavy metal concentrations in the sediment samples were found in the order Al>Fe>Ca>Ti>K>Mg>Mn>Ba>V>Cr>Zn>La>Ni>Pb>Co>Cd>Cu. The average heavy metal concentrations were below the world crustal average. The degree of contamination by heavy metals was evaluated using pollution indices. The results of pollution indices revealed that titanium (Ti) and cadmium (Cd) were significantly enriched in sediments. Pearson correlation analysis was performed among heavy metal concentrations to know the existing relationship between them. Multivariate statistical technique was employed to identify the heavy metal pollution sources. PMID- 28633946 TI - Microplastics in gut contents of coastal freshwater fish from Rio de la Plata estuary. AB - The presence of microplastics (MPs) in gut contents of coastal freshwater fish of the Rio de la Plata estuary was studied. Samples were taken in six sites where 87 fish belonging to 11 species and four feeding habits were captured. Presence of MPs was verified in the 100% of fish. The fibres represented the 96% of MPs found. The number of MPs in gut contents was significantly higher close to sewage discharge. There was not found relationship between number of MPs and fish length, weight or feeding habit. The spatial differences in mean number of MPs in fish observed in this study, suggest that environmental availability of MPs could be of great importance to explain the differences found among sampling sites analysed. This work represents the first study about the interaction between MPs and aquatic organisms in this important estuarine ecosystem of South America. PMID- 28633947 TI - Occurrence and spatial distribution of organophosphorus flame retardants and plasticizers in the Bohai and Yellow Seas, China. AB - Seawater samples from 50 sites in the BS and YS were collected to investigate the spatial distribution of 7 OPs. Concentrations of the total OPs (?OPs) in the BS and YS ranged from 8.12ngL-1 to 98.04ngL-1 with a geometric mean (GM) of 23.70ngL 1. Tris(1-chloro-2-propyl) phosphate (TCPP) was the dominant compound, followed by tris(2-chloroethyl) phosphate (TCEP) and triphenylphosphine oxide (TPPO). The ?OPs together with the most commonly detected individual OPs (TCPP, TCEP, tris(1,3-dichloro-2-propyl) phosphate (TDCPP), tri-iso-butyl phosphate (TiBP), triphenyl phosphate (TPhP), and TPPO) tended to decrease from nearshore to offshore and from the surface to the bottom seawaters, indicating major land based sources. Furthermore, the Yellow Sea Cold Water Mass (YSCWM), Changjiang Diluted Water (CDW), Taiwan Warm Current (TaWC), and Subei Coastal Water (SCW) influenced the horizontal and vertical distributions of the OPs in the study area. PMID- 28633948 TI - Effect of nutrient pollution on dinoflagellate cyst assemblages across estuaries of the NW Atlantic. AB - We analyzed surface sediments from 23 northeast USA estuaries, from Maine to Delaware, and nine estuaries from Prince Edward Island (PEI, Canada), to determine how dinoflagellate cyst assemblages varied with nutrient loading. Overall the abundance of cysts of heterotrophic dinoflagellates correlates with modeled nitrogen loading, but there were also regional signals. On PEI cysts of Gymnodinium microreticulatum characterized estuaries with high nitrogen loading while the sediments of eutrophic Boston Harbor were characterized by high abundances of Spiniferites spp. In Delaware Bay and the Delaware Inland Bays Polysphaeridium zoharyi correlated with higher temperatures and nutrient loading. This is the first study to document the dinoflagellate cyst eutrophication signal at such a large geographic scale in estuaries, thus confirming their value as indicators of water quality change and anthropogenic impact. PMID- 28633949 TI - Habitat suitability index model of the sea cucumber Apostichopus japonicus (Selenka): A case study of Shandong Peninsula, China. AB - A habitat suitability index (HSI) model for the sea cucumber Apostichopus japonicus (Selenka) was established in the present study. Based on geographic information systems, the HSI model was used to identify potential sites around the Shandong Peninsula suitable for restoration of immature (<25g) and mature (>25g) A. japonicus. Six habitat factors were used as input variables for the HSI model: sediment classification, water temperature, salinity, water depth, pH and dissolved oxygen. The weighting of each habitat factor was defined through the Delphi method. Sediment classification was the most important condition affecting the HSI of A. japonicus in the different study areas, while water temperature was the most important condition in different seasons. The HSI of Western Laizhou Bay was relatively low, meaning the site was not suitable for aquaculture-based restoration of A. japonicus. In contrast, Xiaoheishan Island, Rongcheng Bay and Qingdao were preferable sites, suitable as habitats for restoration efforts. PMID- 28633950 TI - A multi-scale integrated modeling framework to measure comprehensive impact of coastal reclamation activities in Yellow River estuary, China. AB - In this paper, an improved multi-scale integrated modeling framework has been established to evaluate coastal reclamation intensity (CRI). About 7 indicators are considered, including ecological degradation intensity (EDI), hydrodynamic disturbance (IHD), engineering types, water quality, economic investment, population growth, and reclaimed land area. Meanwhile, an integrated framework enhanced methods in terms of (a) measuring intensity of ecological degradation process under multi-scale impact, (b) developing the indicator system of CRI, and discussing the driving forces and trends of coastal reclamation, (c) determining fuzzy preference relations of weight and calculating the specific value of CRI with the case study areas of Yellow River estuary from 2000 to 2015. As the result, the CRI has been expanded unceasingly in recent years. The total growth rate from 2000 to 2015 is about 37.97%. It is concluded that CRI has climbed to a higher intensity level in resent 15years. PMID- 28633951 TI - Beach litter sourcing: A trawl along the Northern Ireland coastline. AB - Fourteen non-recreational coastal locations in Northern Ireland were investigated as to whether beach litter deposition was related to seasonal or site specific factors. Litter items were counted in 100m width transects and 1km strand-line surveys over a five-season period (autumn to autumn). Survey sites comprised fishing ports; estuarine areas, north (high energy) and east coast (low energy) beaches. Fishing ports accumulated the most litter. In the 100m beach surveys, plastics, string and cord, bottle caps, food items, rope, and drink containers dominated. In strand-line surveys, large plastic pieces were dominant, followed by rope, string and cord, strapping bands (absent on beach surveys), cloth, wood (mainly pallets, fish boxes) and metal items. Multivariate analyses revealed major litter category differences between the ports and all other sites, with a lesser distinction between exposed and estuarine sites. There was no simple coastline trend and no apparent effect of seasonality between samples. PMID- 28633952 TI - Chronic methylphenidate regulates genes and proteins mediating neuroplasticity in the juvenile rat brain. AB - Methylphenidate (MPH) is the front-line psychostimulant medication prescribed for alleviating the symptoms associated with attention deficit hyperactivity disorder (ADHD) in children. Here, we investigated the effects of chronic MPH (2.0mg/kg, twice daily for 15days) exposure to young rats (20-25days old at start of treatment) on the expression of genes and proteins associated with neuroplasticity, such as activity regulated cytoskeleton-associated protein (Arc), insulin receptor substrate protein 53 (IRSp53), cell division control protein 42 (Cdc42), and actin-related protein 2 (Arp2). Chronic MPH increased Arc expression in areas of the cerebrum including, the striatum, nucleus accumbens and hippocampus. In addition, chronic MPH also increased the expression of IRSp53 in the striatum, while Cdc42 and Arp2 were specifically increased in the nucleus accumbens. Conversely, chronic MPH decreased Arc and IRSp53 protein expression in the cerebellum, indicating differential effects of the drug in cerebral areas relative to the cerebellum. Overall, our results indicate that chronic MPH treatment increases expression of genes and proteins associated with dendritic spine formation and neuronal plasticity in target areas of the cerebrum while it decreases the expression in the cerebellum. PMID- 28633953 TI - Reversal learning and resurgence of operant behavior in zebrafish (Danio rerio). AB - Zebrafish are used extensively as vertebrate animal models in biomedical research for having such features as a fully sequenced genome and transparent embryo. Yet, operant-conditioning studies with this species are scarce. The present study investigated reversal learning and resurgence of operant behavior in zebrafish. A target response (approaching a sensor) was reinforced in Phase 1. In Phase 2, the target response was extinguished while reinforcing an alternative response (approaching a different sensor). In Phase 3, extinction was in effect for the target and alternative responses. Reversal learning was demonstrated when responding tracked contingency changes between Phases 1 and 2. Moreover, resurgence occurred in 10 of 13 fish in Phase 3: Target response rates increased transiently and exceeded rates of an unreinforced control response. The present study provides the first evidence with zebrafish supporting reversal learning between discrete operant responses and a laboratory model of relapse. These findings open the possibility to assessing genetic influences of operant behavior generally and in models of relapse (e.g., resurgence, renewal, reinstatement). PMID- 28633954 TI - Resident challenges with daily life in Chinese long-term care facilities: A qualitative pilot study. AB - As traditional family-based care in China declines, the demand for residential care increases. Knowledge of residents' experiences with long-term care (LTC) facilities is essential to improving quality of care. This pilot study aimed to describe residents' experiences in LTC facilities, particularly as it related to physical function. Semi-structured open-ended interviews were conducted in two facilities with residents stratified by three functional levels (n = 5). Directed content analysis was guided by the Adaptive Leadership Framework. A two-cycle coding approach was used with a first-cycle descriptive coding and second-cycle dramaturgical coding. Interviews provided examples of challenges faced by residents in meeting their daily care needs. Five themes emerged: staff care, care from family members, physical environment, other residents in the facility, and personal strategies. Findings demonstrate the significance of organizational context for care quality and reveal foci for future research. PMID- 28633955 TI - The microbiome and transfusion in cancer patients. AB - Our microbiota is determined by many variables including ABO blood groups. The microbiota is not only confined to the gut and skin but is also recoverable from blood of healthy donors. The microbiota shape our immune system through cross reactivity with antigens, the expression of direct molecular patterns, the release of cytokines, the effects on nutrients and micronutrients and even through an interplay with epigenetics. It is likely, therefore, that a donor's microbiota could alter the antigenicity of blood and its components and potentially contribute to transfusion-related immune modulation [TRIM]. It could also potentially transmit infections. The recipient's microbiome contributes, on the other hand, to the tolerance to transfused blood, or to the development of transfusion reactions. Cancer patients are a particularly vulnerable population, often immunosuppressed with a significantly altered microbiota. They are more at risk for transmission of "dormant" bacteria via blood transfusion. Furthermore, chemotherapy and radiation induce mucositis that likely results in significant translocation of gut microbiota and abnormal immune reactions to transfused blood. It is therefore relevant to revisit transfusion thresholds and consider transfusion-saving strategies in cancer patients. PMID- 28633956 TI - A time-adjustable pulsatile release system for ketoprofen: In vitro and in vivo investigation in a pharmacokinetic study and an IVIVC evaluation. AB - A time-adjustable pulsatile release system (TAPS) containing ketoprofen (KF) as an active pharmaceutical agent was developed having been designed for bedtime dosing and releasing drug in the early morning to control the symptoms of rheumatoid arthritis (RA). The formulation involved a tablet core (KF) and a control-release layer, and the coating membrane was composed of EC and Eudragit L100. A single-factor study, a central composite design and a response surface method were selected to optimize the formula and the optimum prescription was as follows: tablet core (KF 50mg, MCC 70mg, lactose 40mg, L-HPC 38mg), and film (EC 7.8g, Eudragit L100 4.2g, PEG 6000 1.8g in 95% alcohol each 200ml). The in vivo release behavior of the tablets was evaluated in Beagle dogs after a parallel oral administration of KF TAPS tablets and commercial KF capsules, when it was found that the KF TAPS tablets released the drug after a lag-time of 3.458h and the Tmax was 5.833h. The relative bioavailability was 85.01%, and the two formulations were bioequivalent in terms of Cmax and AUC0-t and the in vitro- in vivo correlations indicated that test formulation had a good in vivo-in vitro correlation (r=0.9703). These results show that the novel drug delivery system (TAPS) has the potential to be used as a KF preparation with chronophamacokinetics characteristics. PMID- 28633957 TI - Displacement patterns of stranded I-125 seeds after permanent brachytherapy of the prostate: Dosimetry in the operating room put into perspective. AB - BACKGROUND AND PURPOSE: The reliability of post-implant dosimetry in the OR depends on the geometrical variability of implant and anatomy after the procedure. The purpose was to gain detailed information on seed displacement patterns in different sectors of the prostate. MATERIALS AND METHODS: Of 33 patients with stranded seed implants the seed geometry and the dose distribution were compared between the situation in the OR just after the procedure, based on ultrasound images, and the situation after 1month, based on registered CT and MR images. RESULTS: There was a substantial displacement of ventral seeds of 3.8+/ 2.5mm in caudal direction (p<0.001). Of these ventral seeds cranially located seeds moved more than caudally located seeds, 4.5+/-2.7mm and 2.9+/-2.6mm, respectively (p<0.001). The D90 in the dorsal-caudal and ventral-caudal sectors increased with respectively 44+/-20Gy and 29+/-28Gy (p<0.001) and decreased with 17+/-31Gy in the ventral-cranial sector (p=0.008). CONCLUSIONS: There were substantial changes in dose distribution 1month after the procedure, mainly due to implant and prostate shrinkage and displacement of ventral seed strands in caudal direction. When performing dynamic dosimetry or dosimetry at the end of the procedure the effect of these phenomena has to be taken into account when using stranded seeds. PMID- 28633958 TI - Small Talk: Identifying communication problems in maltreated children. AB - Development of speech and language is rapid in early years, yet if developmental problems in speech and language are not addressed they are likely to continue and impact negatively on a child's overall development and their life trajectory. Children who have experienced abuse and or neglect are particularly vulnerable. The aim of this study was to develop a tool to assist in identifying a child's need for assessment by a speech pathologist so that there could be early identification of problems. A culturally sensitive tool was developed to be completed by the child's carer included questions on language, speech and hearing, voice, fluency, understanding sentences, vocabulary and expression. Sixty-five children aged between 4 and 8 years, who had experienced abuse and/or neglect participated in the study. Fourteen percent were Aboriginal. A speech pathologist undertook an assessment for each child and the results were compared with the information on the Small Talk tool. The Tool was found to be high in sensitivity but low in specificity, requiring further refinement. However, it has the potential to assist non speech pathologists to identify a child's need for speech and language assessment with the findings identifying the Tool as promising practice. PMID- 28633959 TI - Characterization of the superior olivary complex of Canis lupus domesticus. AB - The superior olivary complex (SOC) is a collection of brainstem auditory nuclei which play essential roles in the localization of sound sources, temporal coding of vocalizations and descending modulation of the cochlea. Notwithstanding, the SOC nuclei vary considerably between species in accordance with the auditory needs of the animal. The canine SOC was subjected to anatomical and physiological examination nearly 50 years ago and was then virtually forgotten. Herein, we aimed to characterize the nuclei of the canine SOC using quantitative morphometrics, estimation of neuronal number, histochemistry for perineuronal nets and immunofluorescence for the calcium binding proteins calbindin and calretinin. We found the principal nuclei to be extremely well developed: the lateral superior olive (LSO) contained over 20,000 neurons and the medial superior olive (MSO) contained over 15,000 neurons. In nearly all non chiropterian terrestrial mammals, the MSO exists as a thin, vertical column of neurons. The canine MSO was folded into a U-shaped contour and had associated with the ventromedial tip a small, round collection of neurons we termed the tail nucleus of the MSO. Further, we found evidence within the LSO, MSO and medial nucleus of the trapezoid body (MNTB) for significant morphological variations along the mediolateral or rostrocaudal axes. Finally, the majority of MNTB neurons were calbindin-immunopositive and associated with calretinin immunopositive calyceal terminals. Together, these observations suggest the canine SOC complies with the basic plan of the mammalian SOC but possesses a number of unique anatomical features. PMID- 28633961 TI - Full-genome amplification and sequencing of Zika viruses using a targeted amplification approach. AB - We have developed methods for full-genome sequencing of Zika viruses (ZIKVs) based on a targeted amplification approach. We used alignments of publicly available complete genome data to design a primer set that selectively amplifies ZIKVs. The approach includes amplification strategies for templates present at both high- and low-copy number, and PCR cycling conditions that have been normalized across genome fragments in order to streamline laboratory handling. Abundant templates can be amplified using a strategy that uses 6 overlapping amplicons to cover the complete viral genome, whereas scarce templates can be amplified using a strategy that uses 11 overlapping amplicons of smaller size. The workflow is sequencing platform agnostic, and thus, can be used in low resource settings where access to traditional Sanger sequencing is the only option available. Given the scarcity of tools for ZIKV, this approach should facilitate epidemiological surveillance and other studies that require the generation of complete viral genomic information quickly and cost-effectively. PMID- 28633962 TI - Evaluation of three commercial multiplex assays for the detection of respiratory viral infections. AB - BACKGROUND: Timely identification of respiratory virus infection is essential to mitigate inappropriate antibiotic use and to implement appropriate treatment and/or infection control procedures. As such, multiplexed PCR assays have become standard in many virology laboratories. OBJECTIVES: To compare the Seeplex RV15 (test of record) with two newer generation multiplex assays, the Anyplex II RV16 and the xTAG respiratory virus panels. STUDY DESIGN: Two hundred and three retrospective and 36 prospective respiratory samples were tested by all three assays. Samples were deemed to be positive if they tested positive for a virus by at least two of the three respective assays. Negative samples also had to test negative by at least two of the three assays. Inconclusive samples were those that showed band signal intensity between 0 and 100 on the RV15, but had not been previously tested on the RV16 or xTAG. RESULTS AND CONCLUSIONS: Overall sensitivity and specificity of all three assays were similar (~85% and 100%, respectively). Given each assay can identify multiple different viruses, the targets reported by one assay did not always agree with each target from another assay. Partial discordant rates were 47% and 21% for positive and negative samples, respectively. These higher than expected partial discordant rates may be due to primer or chemistry differences amongst the three multiplex assays. PMID- 28633960 TI - Effect of stimulus level on the temporal response properties of the auditory nerve in cochlear implants. AB - Electrically evoked compound action potentials (ECAPs) have been used to examine temporal response patterns of the auditory nerve in cochlear implant (CI) recipients. ECAP responses to individual pulses in a pulse train vary across stimulation rates for individual CI users. For very slow rates, auditory neurons have ample time to discharge, recover, and respond to each pulse in the train. As the pulse rate increases, an alternating ECAP-amplitude pattern occurs. As the stimulation rate increases further, the alternating pattern eventually ceases and the overall ECAP amplitudes are diminished, yielding a relatively stochastic state that presumably reflects a combination of adaptation, desynchronization, and facilitation across fibers. Because CIs operate over a range of current levels in everyday use, it is important to understand auditory-nerve responses to pulse trains over a range of levels. The effect of stimulus level on ECAP temporal response patterns in human CI users has not been well studied. The first goal of this study was to examine the effect of stimulus level on various aspects of ECAP temporal responses to pulse-train stimuli. Because higher stimulus levels yield more synchronous responses and faster recovery, it was hypothesized that: (1) the maximum alternation would occur at slower rates for lower levels and faster rates at higher levels, (2) the alternation depth at its maximum would be smaller for lower levels, (3) the rate that produces a stochastic state ('stochastic rate') would decrease with level, (4) adaptation would be greater for lower levels as a result of slower recovery, and (5) refractory-recovery time constants would be longer (slower) for lower levels, consistent with earlier studies. The second goal of this study was to examine how refractory-recovery time constants relate specifically to maximum alternation and stochastic rate. Data were collected for 12 ears in 10 CI recipients. ECAPs were recorded in response to each of 13 pulses in an equal-amplitude pulse train ranging in rate from 900-3500 pps for three levels (low, medium, high). The results generally supported hypotheses 1-4; there were no significant effects of level on the refractory-recovery time constants (hypothesis 5). When data were pooled across level, there was a significant negative correlation between alternation depth and refractory recovery time. Understanding the effects of stimulus level on auditory nerve responses may provide further insight into improving the use of objective measures for potentially optimizing speech-processing strategies. PMID- 28633963 TI - Comparison of gargle samples and throat swab samples for the detection of respiratory pathogens. AB - Respiratory illness causes significant morbidity especially in children, the elderly and the immunocompromised. The sample type taken and the quality of that sample are of great significance in providing an accurate diagnosis. Gargle samples are easy to take and sample the same area as a throat swab (THS). In this study, we assessed the utility of gargle samples for the molecular detection of common respiratory infections. Paired gargle and THS samples collected on the same day from the same patient were compared. We also included in our analysis paired THS and gargle samples that were collected within three days of each other as these samples are likely to have been taken during the same illness. Overall the data suggests that gargle samples are a more sensitive sample type than THS samples as overall the diagnostic yield was higher in the gargle samples and the Ct value of the gargle samples was stronger for the majority of samples in comparison to THS samples. Similar data was seen in the paired samples collected within one to three days of each other, as although the diagnostic yield between the sample types was similar (similar discrepant results), the majority of gargles had stronger Ct values than THS samples. This paper highlights the usefulness of gargle samples as non-invasive sensitive respiratory sample in comparison to THS samples. We recommend that other testing sites should consider using gargle samples for respiratory diagnosis as it will bring benefits in terms of sensitivity and sampling ease of use. PMID- 28633964 TI - Sampling methods for recovery of human enteric viruses from environmental surfaces. AB - Acute gastroenteritis causes the second highest infectious disease burden worldwide. Human enteric viruses have been identified as leading causative agents of acute gastroenteritis as well as foodborne illnesses in the U.S. and are generally transmitted by fecal-oral contamination. There is growing evidence of transmission occurring via contaminated fomite including food contact surfaces. Additionally, human enteric viruses have been shown to remain infectious on fomites over prolonged periods of time. To better understand viral persistence, there is a need for more studies to investigate this phenomenon. Therefore, optimization of surface sampling methods is essential to aid in understanding environmental contamination to ensure proper preventative measures are being applied. In general, surface sampling studies are limited and highly variable among recovery efficiencies and research parameters used (e.g., virus type/density, surface type, elution buffers, tools). This review aims to discuss the various factors impacting surface sampling of viruses from fomites and to explore how researchers could move towards a more sensitive and standard sampling method. PMID- 28633965 TI - Phosphoproteome analysis reveals a critical role for hedgehog signalling in osteoblast morphological transitions. AB - The reciprocal and adaptive interactions between cells and substrates governing morphological transitions in the osteoblast compartment remain largely obscure. Here we show that osteoblast cultured in basement membrane matrix (MatrigelTM) exhibits significant morphological changes after ten days of culture, and we decided to exploit this situation to investigate the molecular mechanisms responsible for guiding osteoblast morphological transitions. As almost all aspects of cellular physiology are under control of kinases, we generated more or less comprehensive cellular kinome profiles employing PepChip peptide arrays that contain over 1000 consensus substrates of kinase peptide. The results obtained were used to construct interactomes, and these revealed an important role for FoxO in mediating morphological changes of osteoblast, which was validated by Western blot technology when FoxO was significantly up-expressed in response to MatrigelTM. As FoxO is a critical protein in canonical hedgehog signalling, we decided to explore the possible involvement of hedgehog signalling during osteoblast morphological changes. It appeared that osteoblast culture in MatrigelTM stimulates release of a substantial amounts Shh while concomitantly inducing upregulation of the expression of the bona fide hedgehog target genes Gli-1 and Patched. Functional confirmation of the relevance of these results for osteoblast morphological transitions came from experiments in which Shh hedgehog signalling was inhibited using the well-established pathway inhibitor cyclopamine (Cyc). In the presence of Cyc, culture of osteoblasts in MatrigelTM is not capable of inducing morphological changes but appears to provoke a proliferative response as evident from the upregulation of Cyclin D3 and cdk4. The most straightforward interpretation of our results is that hedgehog signalling is both necessary and sufficient for membrane matrix-based morphological transitions. PMID- 28633966 TI - The effect of feed composition on anaerobic co-digestion of animal-processing by products. AB - Four streams and their mixtures have been considered for anaerobic co-digestion, all of them generated during pig carcasses processing or in related industrial activities: meat flour (MF), process water (PW), pig manure (PM) and glycerin (GL). Biochemical methane potential assays were conducted at 37 degrees C to evaluate the effects of the substrate mix ratio on methane generation and process behavior. The results show that the co-digestion of these products favors the anaerobic fermentation process when limiting the amount of meat flour in the mixture to co-digest, which should not exceed 10%. The ratio of other tested substrates is less critical, because different mixtures reach similar values of methane generation. The presence in the mixture of process water contributes to a quick start of the digester, something very interesting when operating an industrial reactor. The analysis of the fraction digested reveals that the four analyzed streams can be, a priori, suitable for agronomic valorization once digested. PMID- 28633968 TI - Editorial: ICRM-LLRMT'16 7th International Conference on Radionuclide Metrology Low Level Radioactivity Measurement Techniques. PMID- 28633969 TI - Single-fraction Radiotherapy Should be the Standard of Care for Palliation of Cancer Symptoms in Patients with Limited Life Expectancy. PMID- 28633967 TI - The effects of chronic FAAH inhibition on myocardial lipid metabolism in normotensive and DOCA-salt hypertensive rats. AB - AIMS: There is significant evidence that the endocannabinoid system (ECS) takes part in the regulation of the cardiovascular system in hypertension. It is quite well established that hypertension causes several changes in the heart metabolism, but it is still unknown whether the ECS affects this process. Therefore, we investigated the influence of prolonged ECS activation on myocardial lipid metabolism in deoxycorticosterone acetate (DOCA)-salt hypertensive rats by chronic fatty acid amide hydrolase (FAAH) inhibition. MATERIALS AND METHODS: We examined the uptake and oxidation of palmitic acid during the heart perfusion as well as intramyocardial and plasma lipid contents using gas liquid chromatography. Total, plasmalemmal and intracellular expressions of selected proteins were estimated by the Western blot technique. Moreover, the left ventricle's morphology, including myocardial vessels density, was measured using immunohistochemistry. KEY FINDINGS: We demonstrated that hypertension induced cardiomyocytes and myocardial blood vessels hypertrophy, followed by a reduction in myocardial palmitate oxidation. Interestingly, prolonged activation of the ECS in the normotensive rats induced cardiomyocyte enlargement and intensified fatty acids metabolism. We have also shown that FAAH inhibition improved morphology of coronary blood vessels and only partially maintained its effect on lipid metabolism in the DOCA-salt hearts (i.e. elevated plasma and intramyocardial TAG contents as well as plasmalemmal FAT/CD36 and total FATP1 expressions). SIGNIFICANCE: This study revealed that chronic FAAH inhibition has no protective effects on the heart lipid metabolism in hypertension. PMID- 28633970 TI - Unified neural field theory of brain dynamics underlying oscillations in Parkinson's disease and generalized epilepsies. AB - The mechanisms underlying pathologically synchronized neural oscillations in Parkinson's disease (PD) and generalized epilepsies are explored in parallel via a physiologically-based neural field model of the corticothalamic-basal ganglia (CTBG) system. The basal ganglia (BG) are approximated as a single effective population and their roles in the modulation of oscillatory dynamics of the corticothalamic (CT) system and vice versa are analyzed. In addition to normal EEG rhythms, enhanced activity around 4 Hz and 20 Hz exists in the model, consistent with the characteristic frequencies observed in PD. These rhythms result from resonances in loops formed between the BG and CT populations, analogous to those that underlie epileptic oscillations in a previous CT model, and which are still present in the combined CTBG system. Dopamine depletion is argued to weaken the dampening of these loop resonances in PD, and network connections then explain the significant coherence observed between BG, thalamic, and cortical population activity around 4-8 Hz and 20 Hz. Parallels between the afferent and efferent connection sites of the thalamic reticular nucleus (TRN) and BG predict low dopamine to correspond to a reduced likelihood of tonic-clonic (grand mal) seizures, which agrees with experimental findings. Furthermore, the model predicts an increased likelihood of absence (petit mal) seizure resulting from pathologically low dopamine levels in accordance with experimental observations. Suppression of absence seizure activity is demonstrated when afferent and efferent BG connections to the CT system are strengthened, which is consistent with other CTBG modeling studies. The BG are demonstrated to have a suppressive effect on activity of the CTBG system near tonic-clonic seizure states, which provides insight into the reported efficacy of current treatments in BG circuits. Sleep states of the TRN are also found to suppress pathological PD activity in accordance with observations. Overall, the findings demonstrate strong parallels between coherent oscillations in generalized epilepsies and PD, and provide insights into possible comorbidities. PMID- 28633972 TI - The neural basis of form and form-motion integration from static and dynamic translational Glass patterns: A rTMS investigation. AB - A long-held view of the visual system is that form and motion are independently analysed. However, there is physiological and psychophysical evidence of early interaction in the processing of form and motion. In this study, we used a combination of Glass patterns (GPs) and repetitive Transcranial Magnetic Stimulation (rTMS) to investigate in human observers the neural mechanisms underlying form-motion integration. GPs consist of randomly distributed dot pairs (dipoles) that induce the percept of an oriented stimulus. GPs can be either static or dynamic. Dynamic GPs have both a form component (i.e., orientation) and a non-directional motion component along the orientation axis. GPs were presented in two temporal intervals and observers were asked to discriminate the temporal interval containing the most coherent GP. rTMS was delivered over early visual area (V1/V2) and over area V5/MT shortly after the presentation of the GP in each interval. The results showed that rTMS applied over early visual areas affected the perception of static GPs, but the stimulation of area V5/MT did not affect observers' performance. On the other hand, rTMS was delivered over either V1/V2 or V5/MT strongly impaired the perception of dynamic GPs. These results suggest that early visual areas seem to be involved in the processing of the spatial structure of GPs, and interfering with the extraction of the global spatial structure also affects the extraction of the motion component, possibly interfering with early form-motion integration. However, visual area V5/MT is likely to be involved only in the processing of the motion component of dynamic GPs. These results suggest that motion and form cues may interact as early as V1/V2. PMID- 28633971 TI - Manganese-enhanced magnetic resonance imaging depicts brain activity in models of acute and chronic pain: A new window to study experimental spontaneous pain? AB - Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10ug/50ul; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50ul; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 +/- 5.2%, MIA: 15 +/- 3%), and a reduction in PWT in the MIA model (8.3 +/- 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats. PMID- 28633973 TI - Patellofemoral Osteoarthritis Progression and Alignment Changes after Open-Wedge High Tibial Osteotomy Do Not Affect Clinical Outcomes at Mid-term Follow-up. AB - PURPOSE: To evaluate the clinical and radiological outcomes of open-wedge high tibial osteotomy (OWHTO) with respect to the patellofemoral joint and to assess whether patellofemoral osteoarthritis (OA) progression and alignment changes after OWHTO affect clinical outcomes. METHODS: Inclusion criteria were consecutive patients who underwent OWHTO from March 2005 to September 2013. Exclusion criteria were loss to follow-up within 2 years and absence of second look arthroscopy findings at the time of plate removal. The clinical parameters, including anterior knee pain while climbing stairs, Japanese Orthopedic Association score, and Oxford Knee Score, were evaluated. Radiological outcomes, including weight-bearing line ratio, modified Blackburne-Peel ratio, posterior tibial slope, tilting angle, lateral shift ratio, and patellofemoral OA (Kellgren Lawrence grade), were evaluated preoperatively and at the final follow-up. Cartilage status (International Cartilage Repair Society grade) was evaluated at the initial HTO and at plate removal. RESULTS: Fifty-three patients (60 knees) were included in this study. The mean follow-up was 58.2 +/- 22.4 months. Two knees (3%) presented with mild anterior knee pain after OWHTO. The mean Japanese Orthopedic Association score (66.9 +/- 11.2 to 91.2 +/- 9.7) significantly improved (P < .001), and the mean Oxford Knee Score at the final follow-up was 42.0 +/- 5.3. The mean modified Blackburne-Peel ratio (0.9 +/- 0.1 to 0.7 +/- 0.1, P < .001) and tilting angle (6.8 +/- 3.7 to 5.6 +/- 3.4, P = .033) significantly decreased after OWHTO, whereas no significant changes in posterior tibial slope (P = .511) and lateral shift ratio (P = .522) were observed. Radiologically, patellofemoral OA had progressed in 15 knees (27%), and arthroscopically patellofemoral cartilage degeneration had progressed in 27 knees (45%). However, there was no significant correlation between changes in patellofemoral alignment and clinical outcomes. CONCLUSIONS: Changes in patellofemoral alignment and patellofemoral OA progression did not affect the clinical outcomes of OWHTO at mid-term follow-up. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 28633974 TI - Ribosomes Dance to a Daily Rhythm. AB - Sinturel et al. demonstrate that feeding-fasting rhythms and light-dark cycles direct daily changes in liver mass and cell size. These feeding-fasting- and light-dark-driven diurnal fluctuations are controlled by an unconventional mechanism that affects ribosome assembly and protein levels during the active phase. PMID- 28633975 TI - Efficacy of inactivation of viral contaminants in hyperimmune horse plasma against botulinum toxin by low pH alone and combined with pepsin digestion. AB - Assuring viral safety of horse plasma-derived products is fundamental for ethical and regulatory reasons. We previously demonstrated the ability of pepsin digestion at low pH to inactivate West Nile and Sindbis viruses in horse plasma. The present study further examined the efficiency of pepsin digestion to inactivate four additional viruses: HSV-1 and BVDV (lipid-enveloped), BPV and Reo 3 (nonenveloped). These viruses were spiked into hyperimmunized horse plasma against botulinum toxin and subjected to low pH (3.2) alone or combined with pepsin digestion (1200 units/ml). Peptic digestion inactivated the lipid enveloped viruses, whereas the nonenveloped viruses were unaffected. Interestingly, HSV-1 was rapidly inactivated by acidic pH alone (>=4.9 +/- 0.6 log10), whereas a non-robust but meaningful BVDV inactivation (2.9 +/- 0.7 log10) was achieved by combined low pH and pepsin. The current study demonstrated the ability of low pH alone and in combination with pepsin digestion to inactivate enveloped viral contaminants in anti-toxin horse plasma. PMID- 28633976 TI - Transnasal endoscopic removal of bilateral postoperative maxillary cysts after aesthetic orthognathic ssurgery: Differences from that of Caldwell-Luc operations. AB - Postoperative maxillary cysts (PMCs) after orthognathic surgery are a rare disease condition. In this study, we reported first case of bilateral PMCs after cosmetic orthognathic surgery which was treated via the intranasal endoscopic approach. In addition, we compared the characteristics of PMCs after aesthetic orthognathic surgery with those of PMCs after Caldwell-Luc operation. We expect that this case will be helpful to surgeons who encounter similar cases. PMID- 28633977 TI - Vascular endothelial cell mechanosensing: New insights gained from biomimetic microfluidic models. AB - In vivo, cells of the vascular system are subjected to various mechanical stimuli and have demonstrated the ability to adapt their behavior via mechanotransduction. Recent advances in microfluidic and "on-chip" techniques have provided the technology to study these alterations in cell behavior. Contrary to traditional in vitro assays such as transwell plates and parallel plate flow chambers, these microfluidic devices (MFDs) provide the opportunity to integrate multiple mechanical cues (e.g. shear stress, confinement, substrate stiffness, vessel geometry and topography) with in situ quantification capabilities. As such, MFDs can be used to recapitulate the in vivo mechanical setting and systematically vary microenvironmental conditions for improved mechanobiological studies of the endothelium. Additionally, adequate modelling provides for enhanced understanding of disease progression, design of cell separation and drug delivery systems, and the development of biomaterials for tissue engineering applications. Here, we will discuss the advances in knowledge about endothelial cell mechanosensing resulting from the design and application of biomimetic on-chip and microfluidic platforms. PMID- 28633978 TI - Airborne nitro-PAHs induce Nrf2/ARE defense system against oxidative stress and promote inflammatory process by activating PI3K/Akt pathway in A549 cells. AB - Ambient particulate matter (PM) is a worldwide health issue of concern. However, limited information is available regarding the toxic contributions of the nitro derivatives of polycyclic aromatic hydrocarbons (nitro-PAHs). This study intend to examine whether 1-nitropyrene (1-NP) and 3-nitrofluoranthene (3-NF) could activate the nuclear factor-erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) antioxidant defense system, and whether the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway participates in regulating pro-inflammatory responses in A549 cells. Firstly, 1-NP and 3-NF concentration-dependently induced cellular apoptosis, reactive oxygen species (ROS) generation, DNA damage, S phase cell cycle arrest and differential expression of related cytokine genes. Secondly, 1-NP and 3-NF activated the Nrf2/ARE defense system, as evidenced by increased protein expression levels and nuclear translocation of transcription factor Nrf2, elevated Nrf2/ARE binding activity, up-regulated expression of the target gene heme oxygenase-1 (HO-1). Significantly increased protein expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and phosphorylation level of Akt indicated that the PI3K/Akt pathway was activated during pro-inflammatory process. Further, both PI3K inhibitor (LY294002) and Akt inhibitor (MK-2206) reversed the elevated TNF alpha expression to control level. Our results suggested that Nrf2/ARE pathway activation might cause an initiation step in cellular protection against oxidative stress caused by nitro-PAHs, and the PI3K/Akt pathway participated in regulating inflammatory responses. PMID- 28633979 TI - Zerumbone modulates CD1d expression and lipid antigen presentation pathway in breast cancer cells. AB - Natural Killer T (NKT) cells based cancer immunotherapy is an evolving area of cancer therapy, but tumors escape from this treatment modality by altering CD1d expression and its antigen presentation pathway. Here, we have studied the relation of CD1d expression in various breast cancer cell lines to their viability and progression. We observed a novel phenomenon that CD1d expression level increases with the progressive stage of the cancer. A small molecule, zerumbone (ZER) caused down-regulation of CD1d that was accompanied by breast cancer cell growth in vitro. The growth inhibitory effect of ZER against breast cancer cells was augmented by treatment with anti-CD1d mAb. This effect was mediated by G1-phase cell cycle arrest and apoptosis induction coupled with an increase in mitochondrial membrane depolarization. CD1d expression and cell proliferation were inhibited by both CD1d siRNA and ZER. The alpha galactosylceramide, a ligand for CD1d, showed increased CD1d expression as well as cell proliferation which was opposite to the effects of ZER. This study shows that, CD1d overexpression is associated with the progressive stages of breast cancer and ZER could be an adjuvant to potentiate cancer immunotherapy. PMID- 28633980 TI - The Genes That Make a Good Parent. AB - What is the genetic basis of differences in parental care between promiscuous and monogamous mammal species? A team led by Hopi Hoekstra studied an intercross between deer mice and old-field mice that differ in their mating systems and parental behaviours. The authors discovered 12 genomic regions contributing to those differences and identified vasopressin as a regulator of nestbuilding behaviour. PMID- 28633981 TI - Development of a propidium monoazide-polymerase chain reaction assay for detection of viable Lactobacillus brevis in beer. AB - The spoilage of beer by bacteria is of great concern to the brewer as this can lead to turbidity and abnormal flavors. The polymerase chain reaction (PCR) method for detection of beer-spoilage bacteria is highly specific and provides results much faster than traditional microbiology techniques. However, one of the drawbacks is the inability to differentiate between live and dead cells. In this paper, the combination of propidium monoazide (PMA) pretreatment and conventional PCR had been described. The established PMA-PCR identified beer spoilage Lactobacillus brevis based not on their identity, but on the presence of horA gene which we show to be highly correlated with the ability of beer spoilage LAB to grow in beer. The results suggested that the use of 30MUg/mL or less of PMA did not inhibit the PCR amplification of DNA derived from viable L. brevis cells. The minimum amount of PMA to completely inhibit the PCR amplification of DNA derived from dead L. brevis cells was 2.0MUg/mL. The detection limit of PMA-PCR assay described here was found to be 10 colony forming units (CFU)/reaction for the horA gene. Moreover, the horA-specific PMA-PCR assays were subjected to 18 reference isolates, representing 100% specificity with no false positive amplification observed. Overall the use of horA-specific PMA-PCR allows for a substantial reduction in the time required for detection of potential beer spoilage L. brevis and efficiently differentiates between viable and nonviable cells. PMID- 28633982 TI - Corrigendum to 'Does Size and Site Matter in Therapeutic Decompressive Craniectomy? A Laboratory-Based Experimental Study' [World Neurosurgery 95 (2016) 441-446]. PMID- 28633983 TI - Corrigendum to 'Cost-Utility of Video-Electroencephalography Monitoring Followed by Surgery in Adults with Drug-Resistant Focal Epilepsy in Thailand' [World Neurosurgery 98 (2017) 750-760]. PMID- 28633984 TI - Herbal medicinal products in pregnancy - which data are available? AB - This review aims to highlight recent approaches concerning usage of (traditional) herbal medicinal products in pregnancy and to discuss appropriate strategies to handle limited information. Therefore, published monographs of the Committee on Herbal Medicinal products (HMPC) and selected publicly funded webpages, medicinal handbooks, publications and industry and health care organisations webpages were evaluated. While within the monographs of the HMPC a rather conservative approach could be found (mainly because of lacking nonclinical and/or clinical studies), all other sources display a wide variety of information or assessments, thereby often giving contradictory recommendations. However, some experience with the usage of herbal substances/preparations exists in daily clinical practise without clinical trials or observational studies and some herbal substances/preparations are also used as food/food supplements/cosmetics/medical devices. Discussions should be started how to use that knowledge and experience to adjust regulatory decisions on a case-by-case basis, if possible. PMID- 28633985 TI - Autophagy: A Double-Edged Sword to Fight Plant Viruses. AB - In metazoans, autophagy is an essential component of host defense against viruses, orchestrating their degradation. Such antiviral functions for autophagy have also been long suspected in the green lineage. Two recent reports provide molecular insights on how plants selectively send viral proteins and even particles to the vacuole. PMID- 28633987 TI - A paradigm shift for bone quality in dentistry: A literature review. AB - PURPOSE: The aim of this study was to present the current concept of bone quality based on the proposal by the National Institutes of Health (NIH) and some of the cellular and molecular factors that affect bone quality. STUDY SELECTION: This is a literature review which focuses on collagen, biological apatite (BAp), and bone cells such as osteoblasts and osteocytes. RESULTS: In dentistry, the term "bone quality" has long been considered to be synonymous with bone mineral density (BMD) based on radiographic and sensible evaluations. In 2000, the NIH proposed the concept of bone quality as "the sum of all characteristics of bone that influence the bone's resistance to fracture," which is completely independent of BMD. The NIH defines bone quality as comprising bone architecture, bone turnover, bone mineralization, and micro-damage accumulation. Moreover, our investigations have demonstrated that BAp, collagen, and bone cells such as osteoblasts and osteocytes play essential roles in controlling the current concept of bone quality in bone around hip and dental implants. CONCLUSION: The current concept of bone quality is crucial for understanding bone mechanical functions. BAp, collagen and osteocytes are the main factors affecting bone quality. Moreover, mechanical loading dynamically adapts bone quality. Understanding the current concept of bone quality is required in dentistry. PMID- 28633986 TI - Gray Matter Abnormalities in Non-comorbid Medication-naive Patients with Major Depressive Disorder or Social Anxiety Disorder. AB - BACKGROUND: An overlap of clinical symptoms between major depressive disorder (MDD) and social anxiety disorder (SAD) suggests that the two disorders exhibit similar brain mechanisms. However, few studies have directly compared the brain structures of the two disorders. The aim of this study was to assess the gray matter volume (GMV) and cortical thickness alterations between non-comorbid medication-naive MDD patients and SAD patients. METHODS: High-resolution T1 weighted images were acquired from 37 non-comorbid MDD patients, 24 non-comorbid SAD patients and 41 healthy controls (HCs). Voxel-based morphometry analysis of the GMV (corrected with a false discovery rate of p<0.001) and vertex-based analysis of cortical thickness (corrected with a clusterwise probability of p<0.001) were performed, and group differences were compared by ANOVA followed by post hoc tests. OUTCOMES: Relative to the HCs, both the MDD patients and SAD patients showed the following results: GMV reductions in the bilateral orbital frontal cortex (OFC), putamen, and thalamus; cortical thickening in the bilateral medial prefrontal cortex, posterior dorsolateral prefrontal cortex, insular cortex, left temporal pole, and right superior parietal cortex; and cortical thinning in the left lateral OFC and bilateral rostral middle frontal cortex. In addition, MDD patients specifically showed a greater thickness in the left fusiform gyrus and right lateral occipital cortex and a thinner thickness in the bilateral lingual and left cuneus. SAD patients specifically showed a thinner cortical thickness in the right precentral cortex. INTERPRETATION: Our results indicate that MDD and SAD share common patterns of gray matter abnormalities in the orbitofrontal-striatal-thalamic circuit, salience network and dorsal attention network. These consistent structural differences in the two patient groups may contribute to the broad spectrum of emotional, cognitive and behavioral disturbances observed in MDD patients and SAD patients. In addition, we found disorder-specific involvement of the visual processing regions in MDD and the precentral cortex in SAD. These findings provide new evidence regarding the shared and specific neuropathological mechanisms that underlie MDD and SAD. PMID- 28633988 TI - A cross-clade H5N1 influenza A virus neutralizing monoclonal antibody binds to a novel epitope within the vestigial esterase domain of hemagglutinin. AB - The sporadic outbreaks of highly pathogenic H5N1 avian influenza virus have raised public health concerns. Monoclonal antibodies (MAbs) against hemagglutinin (HA) have been increasingly used successfully for therapeutic purposes. Previously, MAb 9F4, generated against clade 1 H5N1 HA, was observed to have cross-clade neutralizing efficacy and inhibited viral entry by preventing the pH mediated conformational change of HA. Furthermore, mouse-human chimeric MAb 9F4 was found to retain high degrees of neutralizing activity. In this study, through escape mutant generation and in-silico prediction, it was revealed that MAb 9F4 binds to a novel epitope in the vestigial esterase sub-domain of HA comprising at least three non-continuous amino acid residues, arginine (R) at position 62, tryptophan (W) at position 69 and phenylalanine (F) at position 79, which interacted with MAb 9F4 in a conformation-dependent manner. Binding and neutralization studies suggested that R62 is the critical residue for MAb 9F4 binding whereas W69 and F79 seem to cooperate with R62 to stabilize the epitope. Mutation of either R62 or W69 did not affect replicative fitness of the virus in vitro. Interestingly, MAb 9F4 retained neutralizing efficacy against a clade 2.3.2.1a H5N1 virus consisting of an arginine to lysine substitution at position 62 in HA. PMID- 28633989 TI - Efficacy and cytotoxicity in cell culture of novel alpha-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H. AB - Chronic Hepatitis B virus (HBV) infection is a major worldwide public health problem. Current direct-acting anti-HBV drugs target the HBV DNA polymerase activity, but the equally essential viral ribonuclease H (RNaseH) activity is unexploited as a drug target. Previously, we reported that alpha-hydroxytropolone compounds can inhibit the HBV RNaseH and block viral replication. Subsequently, we found that our biochemical RNaseH assay underreports efficacy of the alpha hydroxytropolones against HBV replication. Therefore, we conducted a structure activity analysis of 59 troponoids against HBV replication in cell culture. These studies revealed that antiviral efficacy is diminished by larger substitutions on the tropolone ring, identified key components in the substitutions needed for high efficacy, and revealed that cytotoxicity correlates with increased lipophilicity of the alpha-hydroxytropolones. These data provide key guidance for further optimization of the alpha-hydroxytropolone scaffold as novel HBV RNaseH inhibitors. PMID- 28633990 TI - Cellular Gauge Symmetry and the Li Organization Principle: A Mathematical Addendum. Quantifying energetic dynamics in physical and biological systems through a simple geometric tool and geodetic curves. AB - The present Addendum complements the accompanying paper "Cellular Gauge Symmetry and the Li Organization Principle"; it illustrates a recently-developed geometrical physical model able to assess electronic movements and energetic paths in atomic shells. The model describes a multi-level system of circular, wavy and zigzag paths which can be projected onto a horizontal tape. This model ushers in a visual interpretation of the distribution of atomic electrons' energy levels and the corresponding quantum numbers through rather simple tools, such as compasses, rulers and straightforward calculations. Here we show how this geometrical model, with the due corrections, among them the use of geodetic curves, might be able to describe and quantify the structure and the temporal development of countless physical and biological systems, from Langevin equations for random paths, to symmetry breaks occurring ubiquitously in physical and biological phenomena, to the relationships among different frequencies of EEG electric spikes. Therefore, in our work we explore the possible association of binomial distribution and geodetic curves configuring a uniform approach for the research of natural phenomena, in biology, medicine or the neurosciences. PMID- 28633991 TI - The path to timelessness: Insight, assignment conditions and strong anticipation. AB - This paper focusses on the notions of time and timelessness in Eastern and Western thought traditions. The Introduction addresses the Eastern differentiation between the mind, which does not operate in a successive manner and is therefore not caught in time, and the time-laden successively operating mind and brain. I also describe how Jiddu Krishnamurti reconciles the two through insight, an event which restructures the brain and culminates in an eternal Now. In the following sections, I draw analogies to Western notions of timelessness and insight. Insight-induced transition from time to timelessness can be described in terms of a fractal temporal perspective which is void of succession. Insight is defined as sheer simultaneity: zero succession and infinite simultaneity. Another path to timelessness focusses on decoupling the successively operating mind from outward movement as a way of ceasing all inward movement and with it, all internal time. According to Krishnamurti, if we cannot focus our life on 'the outward', the inward movement and all internal time will cease. However, the noise of the observer turns out to be an insurmountable obstacle. Next, Daniel Dubois' concept of strong anticipation, i.e. delay compensation, is described from both the fractal endo- and the exo-perspective. Timelessness is defined as zero succession and infinite simultaneity. Finally, I describe - again with a fractal model - Otto Rossler's notion of assignment conditions as a second causation as a way of describing Krishnamurti's eternal Now through interfacial shifts. PMID- 28633992 TI - Eating out in four Nordic countries: National patterns and social stratification. AB - Using a survey conducted in four Nordic countries (Denmark, Finland, Norway and Sweden) in 2012, we investigated whether eating out in cafes and restaurants in these countries is best characterized as a workday pattern activity or a leisure activity; and, whether frequent eating at cafes and restaurants is related to socio-demographic factors and factors relevant to the organization of daily life. We found that eating out is not a fundamental part of everyday eating. It is something which takes place occasionally. This may be taken to suggest that eating out in the Nordic countries is primarily a leisure activity. However, while this is an accurate portrayal of Denmark and Norway, eating out in Finland and Sweden is somewhat more common and linked to work-life. This difference probably reflects contrasting historical-institutional paths: in Finland and Sweden a food culture emphasizing cooked lunches and dedicated public policies supporting the provisioning of lunches outside the home may have promoted eating out. Multivariate analysis revealed that eating out declines with age. An urbanization effect exists, as residence in a capital city increases the propensity to eat out. There were socio-economic differences in all countries. We hypothesized that education and status would not significantly explain eating out activity after people's gastronomic interest had been controlled for. However, education was statistically significant in Sweden and Norway, and surprisingly status was negatively associated with eating out in Sweden. As expected, eating out was positively associated with income, and it was more frequent among the higher salariat and the self-employed (although not in Norway). PMID- 28633993 TI - Microfluidics as a Strategic Player to Decipher Single-Cell Omics? AB - Most cell studies are performed at a population level, relying on the assumption of a normal distribution of the function and fate of a cell among a population. However, technologies allowing single-cell analysis (SCA) have recently arisen and have led to increasing evidence of cell population heterogeneity and its importance. Tremendous amounts of new data could now be uncovered to redefine our understanding of cell omics. Microfluidics has emerged as a major technological player in this new era and is gradually increasing in use among biology laboratories, mainly due to the single-cell high-throughput handling solutions it offers. In this review, we assess its use and relevance for omics analysis at the single-cell level, with a specific focus on compartment-based microfluidic approaches. PMID- 28633994 TI - T lymphocytes infiltration promotes blood-brain barrier injury after experimental intracerebral hemorrhage. AB - T lymphocytes migrate into the brain after intracerebral hemorrhage (ICH) and promote cerebral inflammation, thus exacerbating neuronal injury. However, the relationship between of T lymphocytes infiltration and blood-brain barrier (BBB) injury after ICH has not been clarified. In this study, we investigated the spatial-temporal distribution of infiltrating T lymphocytes after ICH in C57BL/6 mice by immunofluorescence and flow cytometry, and the accompanying change rules of BBB permeability were detected by Evans blue dye leakage and tight junction protein expression. Furthermore, T lymphocyte-deficient nude mice and T lymphocyte-decreased C57BL/6 mice treated with fingolimod were used to verify the relationship between T lymphocytes infiltration and BBB leakage after ICH. Here, we reported that brain-infiltrating T lymphocytes in the hemorrhagic hemisphere began to accumulate on the first day and peaked on the fifth day after ICH; BBB leakage also at peaked on the fifth day. Moreover, T lymphocyte-deficient nude mice showed minor BBB leakage after ICH compared with C57BL/6 control mice. Similarly, fingolimod treatment can significantly decrease T lymphocyte infiltration and promote BBB integrity compared with a vehicle control. Overall, our results suggested that suppression of T lymphocyte infiltration may be a novel way to improve BBB integrity after ICH. PMID- 28633995 TI - Quantitative MRI study of the permeability of peritumoral brain edema in lung cancer patients with brain metastases. AB - PURPOSE: To use Ktrans to evaluate the aggressiveness and vascular permeability of peritumoral edema in cases of lung cancer brain metastases. MATERIALS AND METHODS: A total of 68 lung cancer patients with 92 metastatic brain lesions were enrolled (20 metastatic lesions only in the gray matter - group 1; and 72 metastatic lesions located in the gray and white matter junction - group 2). All patients underwent MRI examination, which involved a dual angle (2 degrees and 15 degrees ) enhanced T1W-VIBE (volume interpolated breath-hold examination) sequence to calculate the T1 parameter map. We used the enhanced T1-3D sequence to measure the tumor volume. The vascular permeability coefficient (Ktrans) was calculated using the single-compartment Tofts model, motion registration, and quick input mode. We examined the correlations of Ktrans with the edema index (EI), Ktrans with the tumor volume, and Ktrans with the histological expression of MMP-9 or VEGF in the original lung tumor using Pearson's' correlation analysis. RESULTS: Ktrans and EI were highly correlated in group 2 (r=0.66687; P<0.001) and not correlated in group 1 (r=0.33096; P=0.15405). Ktrans was also moderately related to the positive expression of MMP-9 (r=0.50912; P<0.001) and VEGF (r=0.36995; P=0.00138) There is statistical correlation between Ktrans and EI for group 2, and no statistical correlation between Ktrans and EI for group 1. CONCLUSION: The Ktrans of the peritumoral brain edema may be used to indicate the aggressiveness and vascular permeability of brain metastases in patients with lung cancer. PMID- 28633997 TI - Nicotinamide inhibits the growth of P. falciparum and enhances the antimalarial effect of artemisinin, chloroquine and pyrimethamine. AB - Nicotinamide (vitamin B3) - is a water soluble amide derivative of nicotinic acid, which has been used at high doses for a variety of therapeutic applications. However, its antimalarial effect has not been intensively explored. In this work we analysed the effect of nicotinamide alone and in combination with artemisinin, chloroquine andpyrimethamine on the growth of blood stages of P. falciparum. Our results demonstrate that nicotinamide effectively inhibits the growth of blood stage parasites with IC50 of 6.9+/-0.1mM and 2.2+/-0.3mM for CS2 and 3G8 strains, respectively. The combination of nicotinamide with artemisinin, chloroquine and pyrimethamine demonstrated synergistic effects at IC 10-90%. Treatment of uninfected red blood cells with high dose of nicotinamide (60mM) did not provoke the significant LDH release, demonstrating its non-toxicity for erythrocytes. Nicotinamide acts below the level of tolerance and reduces the effective concentration of anti-malarial drugs due to synergism. These in vitro results suggest that nicotinamide might be useful not only as a vitamin supplement but also as an enhancer of the anti-parasitic effect of common antimalarial drugs including artemisinin, chloroquine and pyrimethamine. PMID- 28633996 TI - Effects of monoaminergic drugs on training-induced motor cortex plasticity in older adults. AB - Primary motor cortex (M1) plasticity is involved in motor learning and stroke motor recovery, and enhanced by increasing monoaminergic transmission. Age impacts these processes but there is a paucity of systematic studies on the effects of monoaminergic drugs in older adults. Here, in ten older adults (age 61+4years, 4 males), we determine the effects of a single oral dose of carbidopa/levodopa (DOPA), d-amphetamine (AMPH), methylphenidate (MEPH) and placebo (PLAC) on M1 excitability and motor training-induced M1 plasticity. M1 plasticity is defined as training related long lasting changes in M1 excitability and kinematics of the trained movement. At peak plasma level of the drugs, subjects trained wrist extension movements for 30min. Outcome measures were motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation at increasing intensity (stimulus response curve, SRC) and peak acceleration of the trained wrist extension movements. Measures were obtained before and after completion of training. The curve parameters plateau (MEPmax), inflection point, and slope were extracted from SRC. At baseline drugs had a differential effect on curve parameters, while kinematics remained unchanged. Training alone (PLAC) increased MEPmax but did not improve kinematics. Drugs affected training-related changes of the curve parameters differently, but did not enhance them or kinematics when compared to PLAC. The results demonstrate that in the older adults, MEPH, DOPA, or AMPH have differential effects on baseline M1 excitability and training-related M1 plasticity but fail to enhance them above the naive level. PMID- 28633999 TI - Characteristics of a Mild Traumatic Brain Injury Sample Recruited Using Amazon's Mechanical Turk. AB - BACKGROUND: Several barriers exist in the recruitment of individuals with a history of mild traumatic brain injury (mTBI). The current study is the first to examine whether crowdsourcing, which has been used in other clinical populations, is useful in the recruitment of those with mTBI. OBJECTIVE: To examine whether Amazon's Mechanical Turk (MTurk), an online crowdsourcing platform, is a useful tool in the recruitment of individuals with a history of mTBI and to examine the injury and psychological characteristics of individuals who report a history of mTBI. DESIGN: Retrospective, cross-sectional study. SETTING: Online. PARTICIPANTS: A total of 468 MTurk workers (215 who reported mTBI history on the screener, 253 who did not). METHODS: Comparison of MTurk participants ("workers") who report a history of mTBI on a one-item screener and/or a more comprehensive mTBI assessment tool (ie, the Ohio State University Traumatic Brain Injury Identification Method [OSU TBI-ID]) with workers who do not report mTBI history. MAIN OUTCOME MEASURES: Prevalence rates of mTBI in the MTurk sample (one-item screener and/or OSU TBI-ID), associations between self-reported mTBI with history of psychological disorders and current psychological symptoms (ie, selected Patient-Reported Outcomes Measurement Information System scales). RESULTS: Of workers who reported a history of mTBI on the screener, 169 (79%) met mTBI criteria on the OSU TBI-ID. Compared with those who denied history of mTBI on both the screener and OSU TBI-ID, workers who reported a history of mTBI on both measures were more likely to have a history of diagnosed depression (P = .008), anxiety (P = .007) or attention deficit-hyperactivity disorder (P = .04), and were more likely to currently experience cognitive (P = .01) and sleep disorder symptoms (P = .003). CONCLUSIONS: Workers recruited via MTurk with history of mTBI show similar rates of psychological disorder history and current symptoms to samples recruited via noncrowdsourcing methods in previous studies. MTurk may be a useful recruitment tool in the mTBI population and should be used in future studies of outcomes after mTBI. LEVEL OF EVIDENCE: III. PMID- 28633998 TI - Changes in risk behaviours during and following treatment for hepatitis C virus infection among people who inject drugs: The ACTIVATE study. AB - BACKGROUND: The risk of hepatitis C virus (HCV) reinfection due to continued injecting risk behaviours might remain a barrier to HCV treatment among people who inject drugs. We aimed to evaluate changes in risk behaviours during and following HCV treatment among people with ongoing injecting drug use or receiving opioid substitution treatment (OST). METHODS: ACTIVATE was an international multicentre clinical trial conducted between 2012 and 2014. Participants with HCV genotypes 2/3 infection were treated with peg-interferon/ribavirin for 12 or 24 weeks and completed a self-administered behavioural questionnaire at each study visit. The impact of time in treatment and follow-up on longitudinally measured recent (past month) behavioural outcomes was evaluated using generalized estimating equations. RESULTS: Among 93 enrolled participants (83% male, median age 41 years), 55 (59%) had injected in the past month. Any injecting drug use decreased during HCV treatment and follow-up (OR 0.89 per incremental study visit; 95% CI 0.83-0.95). No significant changes were found in >=daily injecting (OR 0.98; 95% CI 0.89-1.07), use of non-sterile needles (OR 0.94; 95% CI 0.79 1.12), sharing of injecting paraphernalia (OR 0.87; 95% CI 0.70-1.07) or non injecting drug use (OR 1.01; 95% CI 0.92-1.10). Hazardous alcohol use decreased throughout (OR 0.56; 95% CI 0.40-0.77) and OST increased between enrolment and end of treatment (OR 1.48; 95% CI 1.07-2.04). CONCLUSIONS: Recent injecting drug use and hazardous alcohol use decreased, while OST increased during and following HCV treatment among participants with ongoing injecting drug use. These findings support further expansion of HCV care among PWID. PMID- 28634000 TI - Dose-Dependent Effects of AbobotulinumtoxinA (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study. AB - BACKGROUND: AbobotulinumtoxinA has beneficial effects on spasticity and active movements in hemiparetic adults with upper limb spasticity (ULS). However, evidence-based information on optimal dosing for clinical use is limited. OBJECTIVE: To describe joint-specific dose effects of abobotulinumtoxinA in adults with ULS. DESIGN: Secondary analysis of a phase 3 study (NCT01313299). SETTING: Multicenter, international, double-blind, placebo-controlled clinical trial. PARTICIPANTS: A total of 243 adults with ULS >6 months after stroke or traumatic brain injury, aged 52.8 (13.5) years and 64.3% male, randomized 1:1:1 to receive a single-injection cycle of placebo or abobotulinumtoxinA 500 U or 1000 U (total dose). METHODS: The overall effects of injected doses were assessed in the primary analysis, which showed improvement of angles of catch in finger, wrist, and elbow flexors and of active range of motion against these muscle groups. This secondary analysis was performed at each of the possible doses received by finger, wrist, and elbow flexors to establish possible dose effects. MAIN OUTCOME MEASURES: Angle of arrest (XV1) and angle of catch (XV3) were assessed with the Tardieu Scale, and active range of motion (XA). RESULTS: At each muscle group level (finger, wrist, and elbow flexors) improvements in all outcome measures assessed (XV1, XV3, XA) were observed. In each muscle group, increases in abobotulinumtoxinA dose were associated with greater improvements in XV3 and XA, suggesting a dose-dependent effect. CONCLUSIONS: Previous clinical trials have established the clinical efficacy of abobotulinumtoxinA by total dose only. The wide range of abobotulinumtoxinA doses per muscle groups used in this study allowed observation of dose-dependent improvements in spasticity and active movement. This information provides a basis for future abobotulinumtoxinA dosing recommendations for health care professionals based on treatment objectives and quantitative assessment of spasticity and active range of motion at individual joints. LEVEL OF EVIDENCE: I. PMID- 28634001 TI - The Effect of Preoperative Cognitive Behavior and Exercise Therapy for a Patient With an Implanted Left Ventricular Assist Device in Korea. AB - : Left ventricular assist devices (LVADs) are used in patients with progressive heart failure symptoms to provide circulatory support. Patients with LVADs are referred to inpatient cardiac rehabilitation to prevent postoperative complications and improve aerobic capacity and quality of life. Preoperative exercise therapy for cardiac patients is an emerging treatment modality, and several studies have reported that it improves postoperative outcomes, such as length of hospital stay and postoperative complications. This case report describes the benefits of preoperative cognitive behavioral and exercise therapy in a Korean patient undergoing LVAD implantation. LEVEL OF EVIDENCE: V. PMID- 28634002 TI - Acupressure Therapy for Acute Ankle Sprains: A Randomized Clinical Trial. AB - BACKGROUND: Ankle sprains occur frequently among young and active people, accounting for almost 2 million injuries per year. Previous reports suggest that acupressure therapy for acute ankle sprains may shorten the recovery time. OBJECTIVE: To evaluate whether acupressure therapy can improve ankle sprain recovery compared with standard RICE (rest, ice, compression, and elevation) treatment. DESIGN: A randomized controlled trial was conducted. The study protocol was registered in the Chinese Clinical Trial Registry with the study registration number: ChiCTR-TRC-14004794. SETTING: Department of Traditional Chinese Medicine Orthopedics, PLA No.60 Center Hospital, Dali, China, and Department of Orthopedics, Xixi Hospital of Hangzhou, Hangzhou China, between June 2014 and January 2016. PATIENTS: A total of 68 patients with acute ankle sprains were assessed for study eligibility, and a total of 62 patients were included in the present study. METHODS: All patients with ankle sprains seen by the Orthopedics Department within 48 hours since the time of injury were identified. Consenting patients were randomized to either (1) standard treatment (ST group), (2) standard treatment + acupressure (AP group), or (3) standard treatment + mock acupressure (mock AP group). MAIN OUTCOME MEASUREMENTS: Outcomes of interest included a volumetric measurement of the foot, ankle, and lower leg), range of ankle movement, and visual analog pain scores. The American Orthopedic Foot and Ankle Score) and SF12v2 scores were used to assess quality of life. RESULTS: Among the 62 randomized patients, the mean (95% confidence interval [CI]) volumetric measurement of the foot, ankle, and lower leg in the AP group decreased from 185.24 (95% CI 142.80-227.67) to 62.14 (95% CI 44.03-80.25) after 3 sessions of acupressure treatment. This was a statistically significant difference (P < .01) compared with the means of ST group (119.00; 95% CI 89.14 148.86) and mock AP group (118.18; 95% CI 83.99-152.37). After the first treatment, the mean range of ankle movement, visual analog pain scores, and American Orthopedic Foot and Ankle Scores of the AP group were 31.67 (95% CI 27.78-35.55), 3.33 (95% CI 2.97-3.70), and 55.86 (95% CI 50.03-61.69), respectively. These scores were statistically better (P < .01) than the mean of the ST and mock AP group scores. In addition, the mean SF12v2 scores of AP group at 4 and 8 weeks were 109.95 (95% CI 107.29-112.62) and 119.67 (95% CI 119.27 120.05), respectively. These scores were also significantly greater than those of the ST group and mock AP groups (P < .01). CONCLUSION: Acupressure therapy may improve recovery after acute ankle sprain injury, yielding shortened time of disability and improved quality of life. LEVEL OF EVIDENCE: I. PMID- 28634003 TI - Spasticity Video Challenge: A Look at Methods for Addressing Difficult Cases. AB - As seen in this CME online activity (available at http://courses.elseviercme.com/spasticity/662e), treatment of patients with spasticity due to upper motor neuron syndromes, including traumatic brain injury, stroke, and cerebral palsy, is multifaceted, involving chemodenervation, systemic medications, surgical therapy, rehabilitation efforts, and home care. Optimal care begins with the recognition that each patient's impairments are unique and must be assessed carefully to determine the impact of muscle overactivity, loss of dexterity, and weakness on passive and active function in the context of the patients' goals. While botulinum toxin plays a major role in providing symptomatic relief and functional improvement from hypertonia, it should rarely be used as a standalone treatment. PMID- 28634004 TI - Minyoo Matata - The Vicious Worm - A Taenia solium Computer-Based Health Education Tool - in Swahili. AB - Lack of knowledge is one of the main risk factors for the spread of the zoonotic parasite Taenia solium. The computer-based health-education tool 'The Vicious Worm' was developed to create awareness and provide evidence-based health education as a specific measure in control strategies. To increase the reach of the tool, a new version in Swahili was developed and can now be downloaded for free from http://theviciousworm.sites.ku.dk. PMID- 28634005 TI - Semaphorin 3E Alleviates Hallmarks of House Dust Mite-Induced Allergic Airway Disease. AB - Semaphorins are an essential family of guidance cues ubiquitously expressed in various organs, which play diverse developmental, homeostatic, and pathological roles. Semaphorin 3E (Sema3E), initially identified as a neuronal chemorepellent, is involved in the regulation of cell migration, proliferation, and angiogenesis. However, expression and function of Sema3E in allergic asthma has not been extensively investigated. We determined the expression of Sema3E in the airways and its effect on airway inflammation, hyperresponsiveness, and remodeling as pathological features of allergic asthma provoked by house dust mite in vivo. Our data indicate that exposure to house dust mite markedly reduces Sema3E expression in mouse airways. More important, replenishment of Sema3E by intranasal administration of exogenous Sema3E protects mice from allergic asthma by reducing eosinophilic inflammation, serum IgE level, and T helper cell 2/T helper cell 17 cytokine response. The regulatory effect of Sema3E on cytokine response was sustained on allergen recall response in the lymph nodes and spleen. Furthermore, goblet cell hyperplasia, collagen deposition, and airway hyperresponsiveness were significantly diminished on Sema3E treatment. The inhibitory effect of Sema3E was associated with a reduction of pulmonary CD11b+ conventional dendritic cells and regulation of CD4+ T-cell cytokine response. Collectively, our data represent a novel approach to treating allergic asthma via regulation of immune response to house dust mite. PMID- 28634006 TI - Testosterone Differentially Affects T Cells and Neurons in Murine and Human Models of Neuroinflammation and Neurodegeneration. AB - The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. Although s.c. treatment with testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated initial course of disease, similar treatment administered therapeutically exacerbated chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic phase. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase-independent fashion, but also exacerbated cell death in induced pluripotent stem cell-derived primary human neurons under oxidative stress conditions in an aromatase inhibitor-dependent manner. Thus, through the alleviation of inflammatory processes and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiologic sex differentials observed in MS prevalence and course. PMID- 28634007 TI - Gene Expression Differences between Ductal Carcinoma in Situ with and without Progression to Invasive Breast Cancer. AB - To understand the molecular alterations driving the progression of ductal carcinoma in situ (DCIS), we compared patients with pure DCIS and patients with DCIS and synchronous invasive breast cancer (IBC). Twelve patients with extensive pure DCIS were included as a representation of indolent lesions with limited invasive capacity. These cases were matched with 12 patients with a limited DCIS component and IBC, representing lesions with a high invasive potential. Matching included age and surrogate DCIS subtypes. Gene expression profiling was performed on DCIS cells to identify transcriptional differences between these two groups. The identified genes were validated by immunohistochemistry. Nine genes showed significantly different expression. Most of these genes were highly expressed in DCIS samples with IBC, including PLAU (P = 0.002), COL1A1 (P = 0.006), KRT81 (P = 0.009), S100A7 (P = 0.015), SCGB1D2 (P = 0.023), KRT18 (P = 0.029), and NOTCH3 (P = 0.044), whereas EGFR and CXCL14 showed a higher expression in cases with pure DCIS (P = 0.015 and P = 0.028, respectively). This difference was only significant for SCGB1D2 (P = 0.009). Hierarchical clustering revealed distinct clustering of patients with and without invasion. Patients with pure DCIS have a different gene expression pattern as compared to patients with DCIS and synchronous IBC. These genes may pinpoint to driver pathway(s) that play an important role in DCIS progression. PMID- 28634008 TI - Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases. AB - The natural aging process and various pathologies correlate with alterations in the composition and the structural and mechanical integrity of the connective tissue. Collagens represent the most abundant matrix proteins and provide for the overall stiffness and resilience of tissues. The structural changes of collagens and their susceptibility to degradation are associated with skin wrinkling, bone and cartilage deterioration, as well as cardiovascular and respiratory malfunctions. Here, matrix metalloproteinases (MMPs) are major contributors to tissue remodeling and collagen degradation. During aging, collagens are modified by mineralization, accumulation of advanced glycation end-products (AGEs), and the depletion of glycosaminoglycans (GAGs), which affect fiber stability and their susceptibility to MMP-mediated degradation. We found a reduced collagenolysis in mineralized and AGE-modified collagen fibers when compared to native fibrillar collagen. GAGs had no effect on MMP-mediated degradation of collagen. In general, MMP digestion led to a reduction in the mechanical strength of native and modified collagen fibers. Successive fiber degradation with MMPs and the cysteine-dependent collagenase, cathepsin K (CatK), resulted in their complete degradation. In contrast, MMP-generated fragments were not or only poorly cleaved by non-collagenolytic cathepsins such as cathepsin V (CatV). In conclusion, our data indicate that aging and disease-associated collagen modifications reduce tissue remodeling by MMPs and decrease the structural and mechanic integrity of collagen fibers, which both may exacerbate extracellular matrix pathology. PMID- 28634009 TI - The fish parasite Ichthyophthirius multifiliis - Host immunology, vaccines and novel treatments. AB - Ichthyophthirius multifiliis, the causative agent of white spot disease (ichthyophthiriasis) is a major burden for fish farmers and aquarists globally. The parasite infects the skin and the gills of freshwater fish, which may acquire a protective adaptive immune response against this disease, making vaccine strategies feasible. However, there is no prophylactic treatment available and repetitive treatments with auxiliary substances are needed to control the infection. Historically, a variety of drugs and chemicals have been used to combat the disease but due to changing regulations and recognition of carcinogenic and environmentally damaging effects the most efficient compounds are prohibited. A continuous search for novel substances, which are highly effective against the parasites and harmless for the fish is ongoing. These compounds should be environmentally friendly and cost-effective. This review presents recent progress within host immunology, vaccinology and a description of novel substances, which have been tested as treatments against ichthyophthiriasis. PMID- 28634010 TI - LAMP-1-chimeric DNA vaccines enhance the antibody response in Japanese flounder, Paralichthys olivaceus. AB - DNA vaccination is one method to protect farmed fish from viral and bacterial diseases. Chimeric antigens encoded by DNA vaccines have been shown to increase the resistance to viral diseases. Here, we sequenced the gene encoding lysosome associated membrane protein-1 from Japanese flounder, Paralichthys olivaceus, (JfLAMP-1) and assessed its use in a chimeric DNA vaccine fused with the major capsule protein (MCP) from red seabream iridovirus (RSIV). JfLAMP-1 cDNA has a length of 1248 bp encoding 415 aa, which contains transmembrane and cytoplasmic domains. JfLAMP-1 is constitutively expressed in several tissues and its expression in spleen was upregulated following injection of formalin-killed cells (FKC) of Edwardsiella tarda. Immunofluorescence analysis showed that JfLAMP-1 is distributed in the small and large granules in the cytoplasm and groups close to the nucleus. The DNA encoding the luminal domain of JfLAMP-1 was replaced with the gene for the RSIV MCP, and the construct was cloned in an expression vector (pCIneo). Fish vaccinated with pCLAMP-MCP had significantly higher antibody levels than fish vaccinated with pCIneo vector harboring the MCP gene (p < 0.05) at day 30 post-vaccination. PMID- 28634011 TI - Immunomodulatory properties of Concholepas concholepas hemocyanin against francisellosis in a zebrafish model. AB - The development of vaccines for aquaculture has been an important milestone in providing a continuous and sustainable production. Most of the vaccines currently on the market for aquaculture include oil as adjuvant. Nevertheless, several studies reported an occurrence of side effects after their use in farmed fish. As a result, there is a need for new and improved adjuvants that can stimulate the immune system while causing as few side-effects as possible. Hemocyanins are versatile macromolecules with strong immunogenic and immunomodulatory properties. Due to these characteristics, hemocyanin from Concholepas concholepas (CCH) has been biochemically characterized and evaluated as vaccine adjuvant in mice and humans. Francisellosis is a chronic granulomatous disease, which can result in high mortality depending on the host. The disease is caused by the facultative intracellular Gram-negative bacteria Francisella noatunensis, which remains an unsolved problem for the aquaculture, as no efficient vaccines are available. The aim of the present work was to investigate the immunoregulatory properties of CCH against francisellosis in an experimental zebrafish model. When immunized with CCH, zebrafish were protected from subsequent challenge with a lethal dose of Francisella noatunensis subsp. orientalis. Subsequently the mRNA expression levels of several immune-related genes were studied, including mhcii, il12a, tnfalpha and ifng1-1. Taken together, the data report the immunoregulatory properties of CCH and its potential use as a vaccine adjuvant for aquaculture. PMID- 28634012 TI - Different expression of sox17 gene during gametogenesis between scallop Chlamys farreri and vertebrates. AB - SOX17, a member of SRY-related high-mobility-group box (SOX) family, involves in endoderm formation, angiogenesis and carcinogenesis, and its expression characteristics are different in spermatogenesis among several vertebrates. In this study, we cloned a full-length cDNA sequence of sox17 from Zhikong scallop Chlamys farreri, and determined its expression characteristics in gonad at mRNA and protein levels. The cDNA sequence was 2802 bp in length, predicted to encode a protein of 511 amino acids and contained a conservative HMG-box of SOX family, while lacked the C-terminal region of SOX17 comparing to vertebrates. Semi quantitative RT-PCR showed that C. farreri sox17 (Cf-sox17) mRNA exhibited a different tissue distribution, and the transcript abundance was the highest in the gonads. In situ hybridization determined that the Cf-sox17 mRNA was located in various germ cells in testis and ovary. Similar result of Cf-SOX17 protein was also observed by immunohistochemical detection. The location in gonad is different from that of mammals and fish in which SOX17 is only located in some specific germ cells. Our finding revealed a different characteristic of sox17 expression in gametogenesis between scallop and vertebrates, which implied that Cf-sox17 may involve in gametogenesis of bivalves and the function may differ from that in vertebrates. PMID- 28634013 TI - Breast implant associated anaplastic large cell lymphoma: Impact and implications. PMID- 28634014 TI - Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice. AB - BACKGROUND: The role of chemotherapy in the setting of resected colorectal cancer pulmonary metastases (CRCPM) is not well defined. Here we describe utilization of peri-operative chemotherapy and outcomes among patients with resected CRCPM in the general population. METHODS: All cases of CRCPM who underwent resection from 2002 to 2009 were identified using the Ontario Cancer Registry (OCR). Electronic treatment records identified peri-operative chemotherapy delivered within 16 weeks before or after pulmonary metastasectomy (PM). Modified Poisson regression was used to evaluate factors associated with chemotherapy delivery. Cox proportional models were used to explore the association between post-operative chemotherapy and cancer-specific (CSS) and overall survival (OS). RESULTS: The study population included 420 patients. Thirty-six percent of patients (151/420) received peri-operative chemotherapy. Among these patients, 75% (113/151) received post-operative chemotherapy. Factors that were independently associated with use of post-operative chemotherapy included higher socioeconomic status (SES) and no prior adjuvant chemotherapy (p < 0.01). In adjusted analyses post operative chemotherapy was not associated with improved CSS (HR 0.99, 95% CI 0.67 1.47) or OS (HR 0.93 95% CI 0.66-1.31). In exploratory analyses, among those patients who did not receive previous adjuvant therapy for the primary colorectal cancer, post-operative chemotherapy following lung metastasectomy was associated with HR 0.50 (95% CI 0.27-0.95) for OS and HR 0.59 (95% CI 0.27-1.27) for CSS. CONCLUSION: One third of patients with resected CRCPM in routine practice receive peri-operative chemotherapy. A randomized controlled trial is warranted to evaluate whether chemotherapy following resection of CRCPM is associated with improved survival. PMID- 28634016 TI - First Case of Mole in the Horn. PMID- 28634015 TI - Case Report: Three-Dimensional Printed Model for Deep Infiltrating Endometriosis. AB - The combination of a thorough physical examination and imaging with either magnetic resonance imaging (MRI) or pelvic ultrasound are important in the preoperative planning for deep infiltrating endometriosis (DIE). A 2-dimensional (2D) rendering of the pathology by imaging does not always accurately represent intraoperative findings. The detailed topographical relationship and extent of surrounding tissue invasion can be better appreciated by 3-dimensional (3D) modeling. A 49-year-old patient with history of endometriosis and persistent pain underwent preoperative MRI that showed features consistent with DIE endometriosis. Surgery was performed, and the findings were documented. A 3D printed model of the DIE was generated from the MRI and retrospectively compared with intraoperative findings. The 3D model demonstrated both the laterality and spatial relationship of the endometriotic nodule to the posterior uterine wall and rectum. Three-dimensional printing of DIE may be a beneficial adjunct to 2D imaging and can identify further structural relationships to support surgical planning. PMID- 28634017 TI - The Conditional Survival with Time of Intravesical Recurrence of Upper Tract Urothelial Carcinoma. AB - PURPOSE: Since conditional survival analysis provides better estimates of survival time at each followup, we assessed changes in conditional intravesical recurrence-free survival rates after radical nephroureterectomy. We also sought to determine how the impact of well-known risk factors evolves with time, particularly in patients with localized upper tract urothelial carcinoma. MATERIALS AND METHODS: We identified 364 patients with Ta-3N0M0 localized upper tract urothelial carcinoma who underwent open or laparoscopic radical nephroureterectomy at 1 of our 3 institutions. Conditional intravesical recurrence-free and cancer specific survival rates were calculated using the Kaplan-Meier method. The changing impact of parameters on intravesical recurrence with time was assessed by multivariate Cox regression analysis. RESULTS: Intravesical recurrence after radical nephroureterectomy was detected in 176 patients (48.4%) and 93 (25.5%) died of localized upper tract urothelial carcinoma. Five-year intravesical recurrence-free and cancer specific survival rates after surgery were 41.5% and 72.9%, respectively. Based on 1, 2, 3 and 4 year survivorship the 5-year conditional intravesical recurrence-free survival rate increased from 41.5% to 60.5%, 73.4%, 79.5% and 96.7%, respectively. The 5 year conditional cancer specific survival rate also improved from 72.9% to 78.4%, 85.4%, 90.9% and 95.5% at 1, 2, 3 and 4 years, respectively. The effects of well known predictive factors on estimated conditional survival decreased with time for intravesical recurrence. In contrast, the impact of T2 or lower pathological stage and laparoscopic radical nephroureterectomy sustained statistical power with time. CONCLUSIONS: Conditional survival analysis revealed that the probability of intravesical recurrence-free survival increased with time in patients with localized Ta-3N0M0 upper tract urothelial carcinoma after radical nephroureterectomy. Patients with T2 or lower T stage who undergo laparoscopic radical nephroureterectomy may be recommended for longer followup to detect subsequent intravesical recurrence. PMID- 28634019 TI - Economic evaluation of epinephrine auto-injectors for peanut allergy. AB - BACKGROUND: Three commercial epinephrine auto-injectors were available in the United States in the summer of 2016: EpiPen, Adrenaclick, and epinephrine injection, USP auto-injector. OBJECTIVE: To describe the variation in pharmacy costs among epinephrine auto-injector devices in New England and evaluate the additional expense associated with incremental auto-injector costs. METHODS: Decision analysis software was used to evaluate costs of the most and least expensive epinephrine auto-injector devices for children with peanut allergy. To evaluate regional variation in epinephrine auto-injector costs, a random sample of New England national and corporate pharmacies was compared with a convenience sample of pharmacies from 10 Canadian provinces. RESULTS: Assuming prescriptions written for 2 double epinephrine packs each year (home and school), the mean costs of food allergy over the 20-year model horizon totaled $58,667 (95% confidence interval [CI] $57,745-$59,588) when EpiPen was prescribed and $45,588 (95% CI $44,873-$46,304) when epinephrine injection, USP auto-injector was prescribed. No effectiveness differences were evident between groups, with 17.19 (95% CI 17.11-17.27) quality-adjusted life years accruing for each subject. The incremental cost per episode of anaphylaxis treated with epinephrine over the model horizon was $12,576 for EpiPen vs epinephrine injection, USP auto-injector. EpiPen costs were lowest at Canadian pharmacies ($96, 95% CI $85-$107). There was price consistency between corporate and independent pharmacies throughout New England by device brand, with the epinephrine injection, USP auto-injector being the most affordable device. CONCLUSION: Cost differences among epinephrine auto injectors were significant. More expensive auto-injector brands did not appear to provide incremental benefit. PMID- 28634018 TI - Distribution, subtype population, and IgE positivity of mast cells in chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) has been categorized into 2 subtypes in the Asian population: eosinophilic chronic rhinosinusitis (ECRS; similar to CRSwNP in Western countries) and non-ECRS (characterized by inflammation dominated by T-helper cell type 1). The pathogenesis of CRSwNP and the role of mast cells are poorly understood. OBJECTIVE: To investigate the distribution, phenotypes, and immunoglobulin E (IgE) positivity of mast cells in these 2 subtypes of CRSwNP. METHODS: We collected nasal tissue from patients with CRSwNP and control subjects. The mRNA for mast cell proteases tryptase and chymase was measured using real-time polymerase chain reaction, and the distribution of each type of protease-positive mast cell was examined using immunohistochemistry and immunofluorescence. IgE distribution on mast cells was determined using double-immunofluorescent staining for IgE and tryptase. RESULTS: Expression of tryptase mRNA was significantly increased in nasal polyps from patients with the 2 subtypes of CRSwNP compared with controls. Immunohistochemistry showed increased numbers of tryptase-positive mast cells in the epithelium, glands, and submucosa of ECRS polyps, whereas the number of tryptase- and chymase-positive mast cells was increased in the glands and submucosa of non-ECRS polyps. IgE-positive mast cells were abundant in the epithelial, glandular, and submucosal regions of ECRS polyps but few were detected in non-ECRS polyps. CONCLUSION: The present study demonstrates that the distribution, subtype population, and IgE positivity of mast cells is different between ECRS and non-ECRS nasal polyps. Our results suggest a role for IgE mediated mast cell activation in the pathogenesis of ECRS. PMID- 28634020 TI - Accumulated evidence on Helicobacter pylori infection and the risk of asthma: A meta-analysis. AB - BACKGROUND: Helicobacter pylori (H pylori) infection has been suggested to be related to a decreased risk of asthma, but findings in the literature are inconsistent. OBJECTIVE: To quantitatively summarize the existing evidence on the association between H pylori infection and asthma risk. METHODS: The PubMed database was searched for observational studies of H pylori infection in relation to the risk of asthma published in English through May 2017. Measurements of association were pooled using a meta-analytic approach and expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: Twenty-four studies were identified in this meta-analysis, including 8 case-control studies composed of 1,247 cases and 2,410 controls, and 16 cross-sectional studies composed of 50,290 participants (4,185 cases and 46,105 noncases). The average H pylori infection rates were 40.01% and 48.74% in case-control and cross-sectional studies, respectively. Five studies subcategorized H pylori infection according to CagA status, in which 59.37% of H pylori-infected participants were identified as having CagA positivity. Helicobacter pylori infection was significantly inversely associated with the risk of asthma in case-control studies (OR 0.83, 95% CI 0.71-0.98) but was borderline significant in cross-sectional studies (OR 0.88, 95% CI 0.76-1.02). The observed inverse association persisted for CagA positive H pylori infection (OR 0.77, 95% CI 0.63-0.93, P for interaction = .03) but not for CagA-negative strains (OR 1.08, 95% CI 0.66-1.78). No significant difference was observed across age or region subgroups. CONCLUSION: The accumulated evidence supports that H pylori infection, especially CagA-positive H pylori infection, is inversely associated with the risk of asthma. PMID- 28634021 TI - Mycoplasma pneumoniae and health outcomes in children with asthma. AB - BACKGROUND: Acute infections with Mycoplasma pneumoniae (Mp) have been associated with worsening asthma in children. Mp can be present in the respiratory tract for extended periods; it is unknown whether the long-term persistence of Mp in the respiratory tract affects long-term asthma control. OBJECTIVE: To determine the effect of Mp on asthma control. METHODS: We enrolled 31 pediatric subjects 3 to 10 years of age with persistent asthma who completed up to 8 visits over a 24 month period. We detected Mp by antigen capture and polymerase chain reaction. Primary outcome measurements included symptom scores, quality of life, medication scores, oral corticosteroid use, health care usage, school absences, and exhaled breath condensate pH. RESULTS: Low levels of Mp community-acquired respiratory distress syndrome toxin were detected in 20 subjects (64.5%) at enrollment. Subjects with Mp positivity at a given visit had a .579 probability of remaining Mp positive at the subsequent visit, whereas those with Mp negativity had a .348 probability of becoming Mp positive at the following visit. The incidence of Mp overall was higher in the spring and summer months. Overall, we found no significant relation between the detection of Mp and worse outcome measurements at the same visit or at subsequent visits. CONCLUSION: The long-term persistence of Mp in the respiratory tract is common in children with asthma. However, the detection of Mp was not associated significantly with worse asthma symptoms, quality of life, health care usage, school absences, or exhaled breath condensate pH in this pediatric asthma cohort. PMID- 28634022 TI - Goals and objectives of the Italian Network for Tumor Biotherapy (NIBIT). AB - The explosion in the immuno-oncology field, exemplified by the clinical implementation of immune checkpoint inhibitor blockade and other immunotherapeutic strategies was quickly recognized by the Italian biomedical community, thanks to the networking activities of the Italian Network for Tumor Biotherapy (NIBIT), which has been active since 2004 in the diffusion of new scientific and clinical findings in the fields of tumor immunology and immunotherapy. Numerous activities of NIBIT have also helped to overcome the hurdles associated with the clinical implementation of cancer immune biotherapeutic strategies at the national and international levels. Looking forward, a concerted interaction of NIBIT with existing European networks focused on cancer bio-immunotherapy will further contribute to the development of improved therapies in the immuno-oncology field. This Introduction briefly summarizes the history and objectives of NIBIT, as well as the current activities of the Network. PMID- 28634024 TI - Follow the glow. PMID- 28634023 TI - Antibiotic stewardship in burns patients: ISBI guidelines. PMID- 28634025 TI - Impaired cerebral autoregulation in preoperative newborn infants with congenital heart disease. AB - OBJECTIVES: To characterize cerebral autoregulation (CA) in preoperative newborn infants with congenital heart disease (CHD). METHODS: This was a prospective, pilot study of term newborns with CHD who required intensive care. Continuous mean arterial blood pressure (MAP), cerebral tissue oxygen saturation (SCTO2) via near-infrared spectroscopy, and arterial oxygen saturation (SaO2) were collected. Significant low-frequency coherence between MAP and SCTO2 was used to define impaired CA in 20-minute epochs. Cerebral fractional tissue oxygen extraction (FTOE) = (SaO2 - SCTO2)/SaO2 was calculated. Spearman's and rank bi-serial correlations and logistic linear models accounting for multiple measures were used to identify associations with impaired CA and coherence. RESULTS: Twenty four term neonates were evaluated for 23.4 +/- 1.8 hours starting the first day of life. Periods of SaO2 variability >5% were excluded, leaving 63 +/- 10 epochs per subject, 1515 total for analysis. All subjects demonstrated periods of abnormal CA, mean 15.3% +/- 12.8% of time studied. Significant associations with impaired CA per epoch included greater FTOE (P = .02) and lack of sedation (P = .02), and associations with coherence included greater FTOE (P = .03), lack of sedation (P = .03), lower MAP (P = .006), and lower hemoglobin (P = .02). CONCLUSIONS: Term newborns with CHD display time-varying CA abnormalities. Associations seen between abnormal CA and greater FTOE, lack of sedation, and lower hemoglobin suggest that impaired oxygen delivery and increased cerebral metabolic demand may overwhelm autoregulatory capacity in these infants. Further studies are needed to determine the significance of impaired CA in this population. PMID- 28634026 TI - The analogy between the timing of renal replacement therapy and mechanical circulatory intervention. PMID- 28634027 TI - A novel aortic clamp distributing equal pressure along the jaws. PMID- 28634028 TI - A how-to-do-it message from the strategic surgical command center. PMID- 28634029 TI - Discovery of SCORs: Anciently derived, highly conserved gene-associated repeats in stony corals. AB - Stony coral (Scleractinia) genomes are still poorly explored and many questions remain about their evolution and contribution to the success and longevity of reefs. We analyzed transcriptome and genome data from Montipora capitata, Acropora digitifera, and transcriptome data from 20 other coral species. To our surprise, we found highly conserved, anciently derived, Scleractinia COral specific Repeat families (SCORs) that are abundant in all the studied lineages. SCORs form complex secondary structures and are located in untranslated regions and introns, but most abundant in intergenic DNA. These repeat families have undergone frequent duplication and degradation, suggesting a 'boom and bust' cycle of invasion and loss. We speculate that due to their surprisingly high sequence identities across deeply diverged corals, physical association with genes, and dynamic evolution, SCORs might have adaptive functions in corals that need to be explored using population genomic and function-based approaches. PMID- 28634030 TI - Effects of membrane curvature and pH on proton pumping activity of single cytochrome bo3 enzymes. AB - The molecular mechanism of proton pumping by heme-copper oxidases (HCO) has intrigued the scientific community since it was first proposed. We have recently reported a novel technology that enables the continuous characterisation of proton transport activity of a HCO and ubiquinol oxidase from Escherichia coli, cytochrome bo3, for hundreds of seconds on the single enzyme level (Li et al. J Am Chem Soc 137 (2015) 16055-16063). Here, we have extended these studies by additional experiments and analyses of the proton transfer rate as a function of proteoliposome size and pH at the N- and P-side of single HCOs. Proton transport activity of cytochrome bo3 was found to decrease with increased curvature of the membrane. Furthermore, proton uptake at the N-side (proton entrance) was insensitive to pH between pH6.4-8.4, while proton release at the P-side had an optimum pH of ~7.4, suggesting that the pH optimum is related to proton release from the proton exit site. Our previous single-enzyme experiments identified rare, long-lived conformation states of cytochrome bo3 where protons leak back under turn-over conditions. Here, we analyzed and found that ~23% of cytochrome bo3 proteoliposomes show DeltapH half-lives below 50s after stopping turnover, while only ~5% of the proteoliposomes containing a non-pumping mutant, E286C cytochrome bo3 exhibit such fast decays. These single-enzyme results confirm our model in which HCO exhibit heterogeneous pumping rates and can adopt rare leak states in which protons are able to rapidly flow back. PMID- 28634031 TI - Does atopy affect the course of viral pneumonia? AB - BACKGROUND: The presence of atopy is considered as a risk factor for severe respiratory symptoms in children. The objective of this study was to examine the effect of atopy on the course of disease in children hospitalised with viral pneumonia. METHODS: Children between the ages of 1 and 6 years hospitalised due to viral pneumonia between the years of 2013 and 2016 were included to this multicentre study. Patients were classified into two groups as mild-moderate and severe according to the course of pneumonia. Presence of atopy was evaluated with skin prick tests. Groups were compared to evaluate the risk factors associated with severe viral pneumonia. RESULTS: A total of 280 patients from nine centres were included in the study. Of these patients, 163 (58.2%) were male. Respiratory syncytial virus (29.7%), Influenza A (20.5%), rhinovirus (18.9%), adenovirus (10%), human metapneumovirus (8%), parainfluenza (5.2%), coronavirus (6%), and bocavirus (1.6%) were isolated from respiratory samples. Eighty-five (30.4%) children had severe pneumonia. Atopic sensitisation was found in 21.4% of the patients. Ever wheezing (RR: 1.6, 95% CI: 1.1-2.4), parental asthma (RR: 1.5, 95% CI: 1.1-2.2), other allergic diseases in the family (RR: 1.8, 95% CI: 1.2-2.9) and environmental tobacco smoke (RR: 1.6, 95% CI: 1.1-3.5) were more common in the severe pneumonia group. CONCLUSIONS: When patients with mild-moderate pneumonia were compared to patients with severe pneumonia, frequency of atopy was not different between the two groups. However, parental asthma, ever wheezing and environmental tobacco smoke exposure are risk factors for severe viral pneumonia in children. PMID- 28634033 TI - Nickel Sulfate Promotes IL-17A Producing CD4+ T Cells by an IL-23-Dependent Mechanism Regulated by TLR4 and Jak-STAT Pathways. AB - Allergic contact dermatitis, caused by nickel, is a delayed-type hypersensitivity reaction, and 14.5% of the general population may be affected in Europe. Among a wide range of cytokines, the IL-12 family has unique structural and immunological characteristics. Whereas IL-12p70 promotes T helper (Th) 1 cell polarization, IL 23 promotes Th17 cell development and both have been isolated from nickel allergic patients. In this work, we were interested in understanding the mechanism behind nickel-induced Th17 cell development. We showed that nickel induced an early production of IL-23 in human monocyte-derived dendritic cells along with an increase in the expression of il-23p19 and il-12p40 mRNA. However, the production of a significant level of IL-12p70 required an additional signal such as IFN-gamma. Moreover, nickel-treated monocyte-derived dendritic cells induced an increase in the percentage of IL-17A+ CD4+ T cells, an effect reduced by IL-23 neutralization. We then investigated the molecular mechanism of IL-23 production. Our results showed that toll-like receptor 4, p38 mitogen-activated protein kinase, and NF-kappaB were involved in IL-23 production induced by nickel. However, Jak-signal transducer and activator of transcription activation seems to maintain the IL-23/IL-12p70 balance by limiting IL-23 production and promoting Th1 polarization. These results indicate that nickel-induced Th17 cell development is dependent on the production of IL-23 by human monocyte-derived dendritic cells via toll-like receptor 4, p38 mitogen-activated protein kinase, NF-kappaB, and Jak-signal transducer and activator of transcription pathways. PMID- 28634032 TI - Cyclosporine Use in Epidermal Necrolysis Is Associated with an Important Mortality Reduction: Evidence from Three Different Approaches. AB - Several immunomodulatory agents are used in the treatment of epidermal necrolysis, but evidence of their efficacy is limited. The Autonomous Community of Madrid has two reference burn units to which all patients with epidermal necrolysis are referred. One burn unit has mostly used cyclosporine (CsA), and the other has used non-CsA therapies (mainly high-dose intravenous immunoglobulin). The allocation of patients to one or the other burn unit was mainly based on proximity, resembling a random assignment. Thus, we took advantage of this "natural experiment" to estimate the mortality risk ratio (MRR) of CsA (n = 26) compared with non-CsA (n = 16) treatment using hospital as an instrumental variable over the period from 2001 to 2015. We also computed the observed versus expected (O/E) MRR in a case series of 49 CsA-treated patients (including 23 patients from other regions treated in Madrid), and using the Score for Toxic Epidermal Necrolysis (i.e., SCORTEN) scale to estimate the expected values. The instrumental variable-based MRR of CsA versus non-CsA was 0.09 (95% confidence interval = 0.00-0.49). The O/E analysis also showed a reduction in mortality risk (MRROE = 0.42; 95% confidence interval = 0.14-0.99). We identified five other case series of CsA-treated patients providing MRROE and meta-analyzed their results. The pooled MRROE (including from this study) was 0.41 (95% confidence interval = 0.21-0.80). All three approaches consistently show that CsA reduces the mortality in epidermal necrolysis patients. PMID- 28634034 TI - Absence of gamma-Chain in Keratinocytes Alters Chemokine Secretion, Resulting in Reduced Immune Cell Recruitment. AB - Loss-of-function mutations in the common gamma (gammac) chain cytokine receptor subunit give rise to severe combined immunodeficiency characterized by lack of T and natural killer cells and infant death from infection. Hematopoietic stem cell transplantation or gene therapy offer a cure, but despite successful replacement of lymphoid immune lineages, a long-term risk of severe cutaneous human papilloma virus infections persists, possibly related to persistent gammac-deficiency in other cell types. Here we show that keratinocytes, the only cell type directly infected by human papilloma virus, express functional gammac and its co receptors. After stimulation with the gammac-ligand IL-15, gammac-deficient keratinocytes show significantly impaired secretion of specific chemokines including CXCL1, CXCL8, and CCL20, resulting in reduced chemotaxis of dendritic cells and CD4+ T cells. Furthermore, gammac-deficient keratinocytes also exhibit defective induction of T-cell chemotaxis in a model of stable human papilloma virus-18 infection. These findings suggest that persistent gammac-deficiency in keratinocytes alters immune cell recruitment to the skin, which may contribute to the development and persistence of warts in this condition and would require different treatment approaches. PMID- 28634036 TI - The influence of sex and age on ventricular arrhythmia in a population-based registry. AB - BACKGROUND: Post-hoc analyses of clinical trials and population-based studies have shown no difference in mortality between men and women, but often show that men are more likely to receive appropriate ICD therapy. We utilized a population based registry to investigate the interaction of sex and age and the occurrence of ventricular arrhythmia in an ICD population. METHODS AND RESULTS: A total of 776 consecutive patients receiving an ICD for primary or secondary prevention in a provincial ICD registry were studied. No significant mortality difference was found between men and women (27.5% versus 23.7%, p=0.39). Overall, men were more likely to receive appropriate ICD therapy compared to women (39.3% versus 26.7%, p=0.006). The hazard ratio for appropriate therapy in men vs. women <60years of age was 3.22, CI 95% (1.56-6.65), p=0.002, and the same comparison in men vs. women over the age of 60 showed no significant difference (HR 1.11, CI 95% [0.74 1.65], p=0.61). This interaction between age and sex remained significant when adjusted for New York Heart Associated Class, ejection fraction, coronary artery disease and indication for ICD (p=0.02). CONCLUSIONS: This study demonstrates that the risk of appropriate ICD therapy increases as women are older, reaching similar risk as men in that age group. Further study of the mechanism of the interaction of age and sex as they modulate the occurrence of ventricular arrhythmia may be warranted. PMID- 28634035 TI - Psoriasis-Associated Late Cornified Envelope (LCE) Proteins Have Antibacterial Activity. AB - Terminally differentiating epidermal keratinocytes express a large number of structural and antimicrobial proteins that are involved in the physical barrier function of the stratum corneum and provide innate cutaneous host defense. Late cornified envelope (LCE) genes, located in the epidermal differentiation complex on chromosome 1, encode a family of 18 proteins of unknown function, whose expression is largely restricted to epidermis. Deletion of two members, LCE3B and LCE3C (LCE3B/C-del), is a widely-replicated psoriasis risk factor that interacts with the major psoriasis-psoriasis risk gene HLA-C*06. Here we performed quantitative trait locus analysis, utilizing RNA-seq data from human skin and found that LCE3B/C-del was associated with a markedly increased expression of LCE3A, a gene directly adjacent to LCE3B/C-del. We confirmed these findings in a 3-dimensional skin model using primary keratinocytes from LCE3B/C-del genotyped donors. Functional analysis revealed that LCE3 proteins, and LCE3A in particular, have defensin-like antimicrobial activity against a variety of bacterial taxa at low micromolar concentrations. No genotype-dependent effect was observed for the inside-out or outside-in physical skin barrier function. Our findings identify an unknown biological function for LCE3 proteins and suggest a role in epidermal host defense and LCE3B/C-del-mediated psoriasis risk. PMID- 28634038 TI - IDF releases report of global survey on access to medicines and supplies for people with diabetes. PMID- 28634037 TI - Clinical benefit of drugs targeting mitochondrial function as an adjunct to reperfusion in ST-segment elevation myocardial infarction: A meta-analysis of randomized clinical trials. AB - AIMS: To perform a systematic review and meta-analysis of randomized clinical trials (RCT) comparing the effectiveness of drugs targeting mitochondrial function vs. placebo in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical coronary reperfusion. METHODS: Inclusion criteria: RCTs enrolling STEMI patients treated with primary percutaneous coronary intervention (PCI) and comparing drugs targeting mitochondrial function vs. placebo. Odds ratios (OR) were computed from individual studies and pooled with random-effect meta-analysis. RESULTS: Fifteen studies were identified involving 5680 patients. When compared with placebo, drugs targeting mitochondrial component/pathway were not associated with significant reduction of cardiovascular and all-cause mortality (OR 0.9, 95% CI 0.7-1.17 and OR 0.92, 95% CI 0.69-1.23, respectively). However, these agents significantly reduced hospital admission for heart failure (HF) (OR 0.64; 95% CI 0.45-0.92) and increased left ventricular ejection fraction (LVEF) (OR 1.44; 95% CI 1.15-1.82). After analysis for subgroups according to the mechanism of action, drugs with direct/selective action did not reduce any outcome. Conversely, those with indirect/unspecific action showed a significant effect on cardiovascular mortality (0.65, 95% CI 0.46 0.92), all-cause mortality (OR 0.69, 95% CI 0.52-0.92), hospital readmission for HF (OR 0.41, 95% CI 0.28-0.6) and LVEF (OR 1.49, 95% CI 1.09-2.05). CONCLUSIONS: Administration of drugs targeting mitochondrial function in STEMI patients undergoing primary PCI appear to have no effect on mortality, but may reduce hospital readmission for HF. The drugs with a broad-spectrum mechanism of action seem to be more effective in reducing adverse events. PMID- 28634039 TI - Synthesis and biological activity of peptide proline-boronic acids as proteasome inhibitors. AB - On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC50 values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors. PMID- 28634040 TI - 1,2,4-Triazole and 1,3,4-oxadiazole analogues: Synthesis, MO studies, in silico molecular docking studies, antimalarial as DHFR inhibitor and antimicrobial activities. AB - 1,2,4-Triazole and 1,3,4-oxadiazole analogues are of interest due to their potential activity against microbial and malarial infections. In search of suitable antimicrobial and antimalarial compounds, we report here the synthesis, characterization and biological activities of 1,2,4-triazole and 1,3,4-oxadiazole analogues (SS 1-SS 10). The molecules were characterized by IR, mass, 1H NMR, 13C NMR and elemental analysis. The in vitro antimicrobial activity was investigated against pathogenic strains, the results were explained with the help of DFT and PM6 molecular orbital calculations. In vitro cytotoxicity and genotoxicity of the molecules were studied against S. pombe cells. In vitro antimalarial activity was studied. The active compounds were further evaluated for enzyme inhibition efficacy against the receptor Pf-DHFR computationally as well as in vitro to prove their candidature as lead dihydrofolate reductase inhibitors. PMID- 28634041 TI - A Machine-Learning Algorithm Toward Color Analysis for Chronic Liver Disease Classification, Employing Ultrasound Shear Wave Elastography. AB - The purpose of the present study was to employ a computer-aided diagnosis system that classifies chronic liver disease (CLD) using ultrasound shear wave elastography (SWE) imaging, with a stiffness value-clustering and machine learning algorithm. A clinical data set of 126 patients (56 healthy controls, 70 with CLD) was analyzed. First, an RGB-to-stiffness inverse mapping technique was employed. A five-cluster segmentation was then performed associating corresponding different-color regions with certain stiffness value ranges acquired from the SWE manufacturer-provided color bar. Subsequently, 35 features (7 for each cluster), indicative of physical characteristics existing within the SWE image, were extracted. A stepwise regression analysis toward feature reduction was used to derive a reduced feature subset that was fed into the support vector machine classification algorithm to classify CLD from healthy cases. The highest accuracy in classification of healthy to CLD subject discrimination from the support vector machine model was 87.3% with sensitivity and specificity values of 93.5% and 81.2%, respectively. Receiver operating characteristic curve analysis gave an area under the curve value of 0.87 (confidence interval: 0.77-0.92). A machine-learning algorithm that quantifies color information in terms of stiffness values from SWE images and discriminates CLD from healthy cases is introduced. New objective parameters and criteria for CLD diagnosis employing SWE images provided by the present study can be considered an important step toward color-based interpretation, and could assist radiologists' diagnostic performance on a daily basis after being installed in a PC and employed retrospectively, immediately after the examination. PMID- 28634042 TI - Routine Ultrasound Quality Assurance in a Multi-Unit Radiology Department: A Retrospective Evaluation of Transducer Failures. AB - The importance of quality assurance (QA) in medical ultrasound (US) has been widely recognized and recommendations concerning technical QA have been published over the years. However, the demonstrated impact of a properly working QA protocol on clinical routine has been scarce. We investigated the transducer write-off causes for a 5-y period in a multi-unit radiology department with an annual average of 230 transducers in demanding diagnostic use. The transducer faults and the initial observers of the faults leading to transducer write-offs were traced and categorized. The most common cause of transducer write-off was an image uniformity problem or element failure. Mechanical faults or excessive leakage current and defects in the lens constituted smaller yet substantial shares. Our results suggest that a properly working routine QA program can detect majority of the faults before they are reported by users. PMID- 28634043 TI - The roles of integrin alphavbeta6 in cancer. AB - Integrins are a family of heterodimeric cell surface receptors that are expressed in most cells, where they mediate cell-cell and cell-extracellular matrix (ECM) interactions. Integrin alphavbeta6 is a heterodimer with alphav and beta6 subunits. It is epithelial-specific and strongly induced during wound healing, inflammation and carcinogenesis. Integrin alphavbeta6 is considered to be a prognostic indicator because it is up-regulated in various types of cancers and integrin alphavbeta6 expression correlates with the survival time of patients. A large body of evidence suggests that integrin alphavbeta6 is of great significance in tumor progression, as integrin alphavbeta6 has been demonstrated to modulate numerous malignant behaviors of tumor cells. A number of classic oncogenic signaling pathways are involved in integrin alphavbeta6-mediated tumor progression. The expression characteristics and vital effects of integrin alphavbeta6 in the progression of tumors has led studies to focus on integrin alphavbeta6-targeted tumor imaging and tumor therapy, which have subsequently made integrin alphavbeta6 a promising target for clinical examination and treatment. This review provides an overview of the current understanding of the roles and underlying mechanisms of integrin alphavbeta6 in tumors. Furthermore, the common links as well as discrepancies between independent studies are also discussed. PMID- 28634044 TI - miR-218 suppresses gastric cancer cell cycle progression through the CDK6/Cyclin D1/E2F1 axis in a feedback loop. AB - Studies in several cancers have suggested that miR-218 has anti-tumor activities, but its function is yet to be elucidated. In this study, we investigated the regulation and function of miR-218 (miR-218-5p) in the cell cycle progression of gastric cancer (GC). We found that miR-218 could suppress proliferation of gastric cancer cells, induce cell cycle arrest at the G1 phase and inhibit tumor growth and metastasis in vivo. We also demonstrated that miR-218 specifically targeted the 3'-UTR regions of CDK6 and cyclin D1 and inhibited the expression of these molecules, which in turn repressed the pRb/E2F1 signaling pathway. Overexpression of CDK6 and Cyclin D1 reversed miR-218-mediated inhibition of pRB/E2F1 signaling and attenuated the miR-218-induced cell cycle arrest. More importantly, miR-218 expression was significantly reduced and inversely correlated with the levels of CDK6 and Cyclin D1 in gastric cancer tissues. Decreased miR-218 expression was also correlated with advanced clinical stage, lymph node metastasis, and poor prognosis in gastric cancer patients. Furthermore, we showed that miR-218 expression was directly activated by E2F1 through the transactivation of miR-218 host genes, SLIT2 and SLIT3, revealing a negative feedback regulation of miR-218 expression. Taken together, our results describe a regulatory loop miR-218-CDK6/CyclinD1-E2F1 whose disruption may contribute to cell cycle progression in gastric cancer and indicate the potential application of miR-218 in cancer therapy. PMID- 28634046 TI - Tumor antigen PRAME is up-regulated by MZF1 in cooperation with DNA hypomethylation in melanoma cells. AB - Elevated expression of preferentially expressed antigen in melanoma (PRAME) has been implicated in disease progression in a variety of cancers. However, the mechanisms underlying the transcriptional regulation of PRAME remain largely unexplored. Initially, we observed that PRAME was elevated in proportion to the malignant potential of melanoma cells. From the in silico prediction of PRAME gene structure, we identified the putative myeloid zinc finger 1 (MZF1) binding sites, which overlap with a CpG-rich region located in the first intron. The transcription factor MZF1 increased PRAME expression via its direct binding to the intron DNA. Upon treatment with a DNA methylation inhibitor, 5-aza-2' deoxycitidine (5-azaC), together with ectopic expression of MZF1, PRAME expression was significantly enhanced at both the protein and mRNA levels. More pronounced MZF1 binding to the PRAME DNA was observed in the presence of 5-azaC. DNA methylation was inversely correlated with PRAME expression in melanoma cells. Finally, we observed that MZF1, like PRAME, promotes the colony-forming ability in melanoma cells. Overall, our findings suggest that MZF1, via stimulation of PRAME expression, may be a potential prognostic and therapeutic target in melanoma. PMID- 28634045 TI - EGFR/EGFRvIII remodels the cytoskeleton via epigenetic silencing of AJAP1 in glioma cells. AB - EGFR amplification and mutations are the most common oncogenic events in GBM. EGFR overexpression correlates with GBM invasion, but the underlying mechanisms are poorly understood. In a previous study, we showed that AJAP1 is involved in regulating F-actin to inhibit the invasive ability of GBM. In addition, in a GBM cell line, the AJAP1 promoter was highly bound by H3K27me3 and, through bioinformatics analysis, we found that AJAP1 expression was negatively correlated with EGFR. In this study, we found that the pathway downstream of EGFR had a higher activation level in GBM cell lines, which led to excessive tumor suppressor silencing. Therefore, we deduced that in glioma cells, the pathway downstream of EGFR remodels the cytoskeleton via AJAP1 epigenetic silencing to enhance invasion. Furthermore, MK2206 reversed AJAP1 downregulation by inhibiting the EGFR pathway. In vivo, MK2206 also inhibited the proliferation and local invasion of 87-EGFRvIII. These data suggest that activation of the EGFR signal transduction pathway genetically silences anti-oncogenes to enhance GBM malignancy. MK2206 might be a promising therapeutic for EGFR/EGFRvIII-positive GBMs. PMID- 28634047 TI - The study of the intervertebral disc microstructure in matured rats with diffusion kurtosis imaging. AB - OBJECTIVES: The aim of this study was to use DKI to detect the microstructural change of the discs in matured normal rats. METHODS: Total 24 normal SD rats (12 males/12 females) underwent DWI/DKI and T2 sequences with a 3T MRI scanner to get the values of ADC, FA, MD, Da, Dr, MK, Ka and Kr. The discs were categorized using a five-grade degeneration grading system in the T2-images. The height of the discs and the parameters in DWI/DKI were measured to compare between the different grades and sexes. The histological images and the images of fiber tracking were also done in the discs. RESULTS: There were 30 Grade 1 and 18 Grade 2 in the discs. Compared with Grade 1, decreased ADC, increased FA and MK values were observed in Grade 2 (P<0.05). By the ROC analysis of grades of the discs, there was low diagnostic accuracy in ADC value, while FA and MK showed higher accuracy. In Grade 1, there were lower ADC value, lower Dr, higher MK, Ka and Kr in male's group than them in female's group. There were no differences in the parameters except the ADC value in the two sexes in Grade 2. The different microstructure of the normal discs in the male and female rats had been proved by the histological images and the images of fiber tracking. CONCLUSION: DKI is a noninvasive and sustainable means to test the changes of intervertebral discs. The discs in Grade 2 were also found in the normal matured SD rat tails. The assessment of the grade of the discs in T2-images should be done before the experimental management. There was microstructural difference in the nucleus pulposus in the discs in Grade 1 and 2. FA and MK showed higher diagnostic accuracy. The laboratory rats should be the same sex because the microstructure of the normal discs weren't the same. PMID- 28634048 TI - Activation volume vs BOLD signal change as measures of fMRI activation - Its impact on GABA - fMRI activation correlation. AB - PURPOSE: To explore the relative robustness of functional MRI (fMRI) activation volume and blood oxygen level-dependent (BOLD) signal change as fMRI metric, and to study the effect of relative robustness on the correlation between fMRI activation and cortical gamma amino butyric acid (GABA) in healthy controls and patients with multiple sclerosis (MS). METHODS: fMRI data were acquired from healthy controls and patients with MS, with the subjects peforming self paced bilateral finger tapping in block design. GABA spectroscopy was performed with voxel placed on the area of maximum activation during fMRI. Activation volume and BOLD signal changes at primary motor cortex (M1), as well as GABA concentration were calculated for each patient. RESULTS: Activation volume correlated with BOLD signal change in healthy controls, but no such correlation was observed in patients with MS. This difference was likely the result of higher intersubject noise variance in the patient population. GABA concentration correlated with M1 activation volume in patients but not in controls, and did not correlate with any fMRI metric in patients or controls. CONCLUSION: Our data suggest that activation volume is a more robust measure than BOLD signal change in a group with high intersubject noise variance as in patients with MS. Additionally, this study demonstrated difference in correlation behavior between GABA concentration and the 2 fMRI metrics in patients with MS, suggesting that GABA - activation volume correlation is more appropriate measure in the patient group. PMID- 28634049 TI - Training individuals with speech and hearing impairment in basic life support: A pilot study. PMID- 28634050 TI - Was capnographic waveform the gold standard to confirm the endotracheal intubation? We need more proofs. PMID- 28634051 TI - Revisiting Interdialytic Weight Gain and Mortality Association With Serum Albumin Interactions: The Japanese Dialysis Outcomes and Practice Pattern Study. AB - BACKGROUND: The dialysis practice guideline in Japan sets a limit on the allowed interdialytic weight gain (IDWG) <6%. However, the effects of relative gain of fluid volume to body weight may differ in presence of morbid conditions. Here, we examined whether or not the associations between IDWG and mortality differ by serum albumin (sAlb), a nutritional and illness marker. DESIGN: The study type used was prospective cohort study. SUBJECTS: Patients who participated in the Japan Dialysis Outcomes and Practice Pattern Study (phase 1-4 [1999-2011]) and received thrice-weekly hemodialysis. METHODS: IDWG was the exposure of interest and was collected every 4 months, divided into 7 categories as follows: <2%, 2% to 3%, 3% to 4% (reference), 4% to 5%, 5% to 6%, 6% to 7%, and >7%. sAlb was treated as both an effect modifier and confounder and dichotomized into >=3.8 g/dL and <3.8 g/dL segments, according to the protein-energy wasting criteria proposed by the International Society of Renal Nutrition and Metabolism. MAIN OUTCOME MEASURE: The outcome in this study was all-cause mortality. RESULTS: A total of 8,661 patients were analyzed. Time-varying Cox regression analyses revealed that, when sAlb was >=3.8 g/dL, an IDWG >7% was associated with greater risk of mortality (adjusted hazard ratio [AHR] 2.74; 95% confidence interval [CI], 1.49-5.05). When sAlb was <3.8 g/dL, however, IDWGs <2% (AHR 1.89; 95% CI, 1.50-2.39) and 4% to 5% (AHR 0.75; 95% CI, 0.58-0.96) were associated with mortality (P for interaction = .001). Cubic spline analyses showed that the mortality increased when IDWG exceeded 6% for patients with sAlb >=3.8 g/dL; in contrast, for patients with sAlb <3.8 g/dL, the mortality increased when IDWG was <3% and decreased when IDWG was between 4% and 6%. LIMITATION: The main limitation was possible residual confounding. CONCLUSIONS: The direction and magnitude of the associations between IDWG and mortality were modified by sAlb. Dialysis experts should take these results into account when revising the clinical practice guidelines. PMID- 28634052 TI - Management of wide-based renal artery aneurysms using noncovered stent-assisted coil embolization. AB - OBJECTIVE: This study describes the safety and midterm efficacy of a noncovered stent-assisted embolization (SAE) technique in treating patients with wide-base renal artery aneurysms (RAAs). METHODS: Between February 2011 and June 2014, 34 RAAs in 28 consecutive patients were treated with noncovered SAE in our center. RESULTS: Technical success was 100%. During an average follow-up of 19 months, the systolic and diastolic blood pressures were significantly decreased. Serum creatinine was significantly decreased, and the glomerular filtration rate was significantly increased at the 6 and 12 month follow-up compared with the baseline. The aneurysm sac thrombosis ratio was obviously increased at 1, 6, and 12 months of follow-up. Complications occurred in four patients, including one major, two minor, and one late complication. Computed tomography angiography or digital subtraction angiography demonstrated that the primary patency at 1, 6, and 12 months was 100%, 96%, and 100%, respectively, and primary assisted and secondary patency was 100%, without endoleaks. CONCLUSIONS: SAE can be safely and effectively performed in patients with wide-based RAAs or those with critical anatomy. It showed a midterm reduction of blood pressure and improvement of renal function in RAA patients. PMID- 28634053 TI - Using short-term bioassays to evaluate the endocrine disrupting capacity of the pesticides linuron and fenoxycarb. AB - Several short-term whole-organism bioassays based on transgenic aquatic models are now under validation by the OECD (Organization for Economic Co-operation and Development) to become standardized test guidelines for the evaluation of the endocrine activity of substances. Evaluation of the endocrine disrupting capacity of pesticides will be a domain of applicability of these future reference tests. The herbicide linuron and the insecticide fenoxycarb are two chemicals commonly used in agricultural practices. While numerous studies indicate that linuron is likely to be an endocrine disruptor, there is little information available on the effect of fenoxycarb on vertebrate endocrine systems. Using whole-organism bioassays based on transgenic Xenopus laevis tadpoles and medaka fry we assessed the potential of fenoxycarb and linuron to disrupt thyroid, androgen and estrogen signaling. In addition we used in silico approach to simulate the affinity of these two pesticides to human hormone receptors. Linuron elicited thyroid hormone like activity in tadpoles at all concentrations tested and, showed an anti estrogenic activity in medaka at concentrations 2.5mg/L and higher. Our experiments suggest that, in addition to its previously established anti androgenic action, linuron exhibits thyroid hormone-like responses, as well as acting at the estrogen receptor level to inhibit estrogen signaling. Fenoxycarb on the other hand, did not cause any changes in thyroid, androgen or estrogen signaling at the concentrations tested. PMID- 28634054 TI - Effect of Endothelin-1 on proliferation, migration and fibrogenic gene expression in human RPE cells. AB - The pathology of the fibrotic proliferative vitreoretinopathy (PVR) membrane represents an excessive wound healing response characterised by cells' proliferation, migration and secretion of extracellular matrix molecules (ECMs). Retinal pigment epithelial (RPE) cells are a major cellular component of the fibrotic membrane. Endothelin-1 (ET-1) has been reported to be involved in the development of PVR in vivo research. However, little is known about the role of ET-1 in RPE cells in vitro. In the present study, we investigated the role of ET 1 in the proliferation, migration and secretion of ECMs (such as type I collagen and fibronectin) in RPE cells in vitro. Our results illustrated that ET-1 promoted the proliferation, migration and secretion of ECMs through the protein kinase B (Akt) and extracellular signal-regulated kinase (Erk) signaling pathways in RPE cells in vitro. These findings strongly suggested that ET-1 may play a vital role in the development of PVR. PMID- 28634055 TI - An insight on the association of glycation with hepatocellular carcinoma. AB - Hepato-cellular carcinoma (HCC) is one of the frequent cause of cancer-related death worldwide and dominant form of primary liver cancer. However, the reason behind a steady increase in the incidence of this form of cancer remains elusive. Glycation has been reported to play a significant role in the induction of several chronic diseases including cancer. Several risk factors that could induce HCC have been reported in the literature. Deciphering the complex patho physiology associated with HCC is expected to provide new targets for the early detection, prevention, progression and recurrence. Even-though, some of the causative aspects of HCC is known, the advanced glycation end products (AGEs) related mechanism still needs further research. In the current manuscript, we have tried to uncover the possible role of glycation in the induction of HCC. In the light of the available scientific literature, we advocate in-depth comprehensive studies which will shed light towards mechanistic association of glycation with HCC. PMID- 28634057 TI - Evaluation of the biotechnological potential of a novel purified protease BS1 from Bacillus safensis S406 on the chitin extraction and detergent formulation. AB - An extracellular alkaline stable protease BS1 from a new bacteria strain, Bacillus safensis S406, isolated from the Sfax solar saltern, was purified and characterized. The enzyme was purified to homogeneity by ammonium sulfate precipitation, Sephadex G-75 gel filtration, Mono-Q anion-exchange chromatography and ultrafiltration, with a 12.70-fold increase in specific activity and 20.29% recovery. The enzyme has a molecular weight of 29kDa and appeared as a single band on native-PAGE. The optimum pH and temperature values of its proteolytic activity were pH 11.0 and 60 degrees C, respectively. BS1 was tested for the deproteinization of shrimp wastes to extract chitin. An enzyme-protein ratio of 10U/mg of proteins allows to eliminate 93% of protein linked to the chitin after 3h hydrolysis at 45 degrees C. Being very active in alkaline conditions, the potential application of BS1 in laundry formulation was investigated. The enzyme showed high stability in the presence of non-ionic surfactants and some commercial liquid and solid detergents, suggesting its eventual use in detergent formulations. PMID- 28634056 TI - New and Accurate Predictive Model for the Efficacy of Extracorporeal Shock Wave Therapy in Managing Patients With Chronic Plantar Fasciitis. AB - OBJECTIVE: To identify factors for the outcome of a minimum clinically successful therapy and to establish a predictive model of extracorporeal shock wave therapy (ESWT) in managing patients with chronic plantar fasciitis. DESIGN: Randomized, controlled, prospective study. SETTING: Outpatient of local medical center settings. PARTICIPANTS: Patients treated for symptomatic chronic plantar fasciitis between 2014 and 2016 (N=278). INTERVENTIONS: ESWT was performed by the principal authors to treat chronic plantar fasciitis. ESWT was administered in 3 sessions, with an interval of 2 weeks (+/-4d). In the low-, moderate-, and high intensity groups, 2400 impulses total of ESWT with an energy flux density of 0.2, 0.4, and 0.6mJ/mm2, respectively (a rate of 8 impulses per second), were applied. MAIN OUTCOME MEASURES: The independent variables were patient age, sex, body mass index, affected side, duration of symptoms, Roles and Maudsley score, visual analog scale (VAS) score when taking first steps in the morning, edema, bone spurs, and intensity grade of ESWT. A minimal reduction of 50% in the VAS score was considered as minimum clinically successful therapy. The correlations between the achievement of minimum clinically successful therapy and independent variables were analyzed. The statistically significant factors identified were further analyzed by multivariate logistic regression, and the predictive model was established. RESULTS: The success rate of ESWT was 66.9%. Univariate analysis found that VAS score when taking first steps in the morning, edema, and the presence of heel spur in radiograph significantly affected the outcome of the treatment. Logistic regression drew the equation: minimum clinically successful therapy=(1+e[.011+42.807*heel spur+.109*edema+5.395*VASscore])-1.The sensitivity of the predictive factors was 96.77%, 87.63%, and 86.02%, respectively. The specificity of the predictive factors was 45.65%, 42.39%, and 85.87%, respectively. The area under the curve of the predictive factors was .751, .650, and .859, respectively. The Youden index was .4243, .3003, and .7189, respectively. The Hosmer-Lemeshow test showed a good fitting of the predictive model, with an overall accuracy of 89.6%. CONCLUSIONS: This study establishes a new and accurate predictive model for the efficacy of ESWT in managing patients with chronic plantar fasciitis. The use of these parameters, in the form of a predictive model for ESWT efficacy, has the potential to improve decision-making in the application of ESWT. PMID- 28634058 TI - Apoptotic gene expression profiles and DNA damage levels in rat liver treated with perfluorooctane sulfonate and protective role of curcumin. AB - Perfluorinated compounds (PFCs) such as PFOS and PFOA, are xenobiotics that can be detected worldwide in the environment and humans. PFOS (C8F17SO3-) is a fluorinated organic compound has been used for decades in industrial and commercial products. We investigated the genotoxic and apoptotic impact of PFOS in rat liver using comet assay, micronucleus test and apoptotic gene expression methods for caspase 3, caspase 8 and the protective role of curcumin on the PFOS- induced damage under chronic exposure. In this study, rats were treated either with three different PFOS doses only (0.6, 1.25 and 2.5mg/kg) or one dose of curcumin (80mg/kg) or three different doses of PFOS combined with 80mg/kg dose of curcumin by gavage for 30days at 48h intervals. We evaluated the DNA damage via comet assay and micronucleus test. Doses of PFOS increased micronucleus frequency (p<0.05) and strongly induced DNA damage in liver in two different parameters; i: the damaged cell percentage and ii: genetic damage index. Curcumin prevented the formation of DNA damage induced by PFOS and curcumin substance applied with PFOS caused a decrease in the micronucleus frequency. PFOS increased apoptotic gene expression but curcumin decreased the expression levels of caspase 3 and 8. PMID- 28634059 TI - A pumpkin polysaccharide induces apoptosis by inhibiting the JAK2/STAT3 pathway in human hepatoma HepG2 cells. AB - The purpose of this study is to investigate the effect of a purified polysaccharide (PPPF) from pumpkin fruit on the Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling during apoptotic process. The results showed that PPPF or STAT3 siRNA inhibits the cell growth of HepG2 cells via induction of apoptosis. Moreover, PPPF is able to suppress both constitutive and IL-6-induced phosphorylation of STAT3 (on Tyr705) and subsequent nuclear translocation in cancer cells. Such inhibition is found to be achieved through down-regulation of constitutive phosphorylation of JAK2, but not JAk1, c-Src, ERK1/2, and Akt, which means STAT3 tyrosine phosphorylation in HepG2 cells following PPPF treatment is associated with a reduction in JAK2 activity. In addition, the protein expression of SHP-1 was increased in cells in response to PPPF treatment, whereas SHP-2, SOCS-1 and SCOS-3 protein expression remain unchanged. In vivo animal experiment also indicated that PPPF had a potent inhibitory effect on tumor growth in mice bearing HepG2 xenograft tumors. Thus we can conclude that PPPF directly induces apoptotic cell death of HepG2 cells via down-regulation of the JAK2/STAT3 signal transduction pathways, which may facilitates the development of a therapeutic strategy for treating HCC. PMID- 28634060 TI - Potent inhibitions of monoamine oxidase A and B by acacetin and its 7-O-(6-O malonylglucoside) derivative from Agastache rugosa. AB - Five compounds were isolated from the leaves of Agastache rugosa and tested for monoamine oxidase (MAO) inhibitory activity. Acacetin, a flavonoid, potently inhibited recombinant human MAO-A and MAO-B (IC50=0.19 and 0.17MUM, respectively), and reversibly and competitively inhibited MAO-A and MAO-B (Ki=0.045 and 0.037MUM, respectively). Acacetin 7-O-(6-O-malonylglucoside) (AMG) was also found to effectively inhibit MAO-A and MAO-B (IC50=2.34 and 1.87MUM, respectively), and to reversibly and competitively inhibit MAO-A and MAO-B (Ki=1.06 and 0.38MUM, respectively). Tilianin (a glucoside derivative of acacetin) had little inhibitory activity, but the introduction of a malonyl group at sugar moiety significantly increased inhibitory activity. Molecular docking simulation revealed the binding energy of acacetin for MAO-B (-44.2kcal/mol) was greater than its energy for MAO-A (-27.0kcal/mol), and that the Cys172 residue of MAO-B was important for hydrogen bonding with acacetin. AMG was predicted to bind to MAO-B with an energy of -23.1kcal/mol by possible hydrogen-bond formation between an oxygen atom of Ile477 residue and a hydrogen atom (H17) of AMG. However, the interaction between AMG and MAO-A was not verified by the docking simulation. This study suggests acacetin and AMG be viewed as new reversible MAO inhibitors, and useful lead compounds for the inhibitor development. PMID- 28634061 TI - Isolation of a protease-resistant and pH-stable alpha-galactosidase displaying hydrolytic efficacy toward raffinose family oligosaccharides from the button mushroom Agaricus bisporus. AB - A 45-kDa monomeric acidic alpha-galactosidase with a specific activity of 193.12 units/mg was isolated from the fruiting bodies of Agaricus bisporus. Blast search of internal peptide sequences suggested that it is a member of GH family 27 and it is most similar to hypothetical protein AGABI2DRAFT_70106. The enzyme displayed maximal activity at pH 4.0 and 60 degrees C, respectively. The enzyme remained stable within the pH range 2.0-9.0 but its activity was markedly suppressed in the presence of Cu2+, Hg2+, Fe3+ and Ag+ ions. It displayed resistance to alpha-chymotrypsin and neutral protease. Moreover, it manifested degradative activity toward both oligosaccharides and polysaccharides. The enzyme manifested Km values of 0.30mM, 10.65mM and 19.21mM, toward pNPGal, stachyose and raffinose respectively. These results suggest that Agaricus bisporus alpha galactosidase is a promising candidate for elimination of raffinose oligosaccharides (RFOs) in biotechnological applications. PMID- 28634062 TI - Site-directed mutagenesis of GH10 xylanase A from Penicillium canescens for determining factors affecting the enzyme thermostability. AB - In order to investigate factors affecting the thermostability of GH10 xylanase A from Penicillium canescens (PcXylA) and to obtain its more stable variant, the wild-type (wt) enzyme and its mutant forms, carrying single amino acid substitutions, were cloned and expressed in Penicillium verruculosum B1-537 (niaD ) auxotrophic strain under the control of the cbh1 gene promoter. The recombinant PcXylA-wt and I6V, I6L, L18F, N77D, Y125R, H191R, S246P, A293P mutants were successfully expressed and purified for characterization. The mutations did not affect the enzyme specific activity against xylan from wheat as well as its pH optimum of activity. One mutant (L18F) displayed a higher thermostability relative to the wild-type enzyme; its half-life time at 50-60 degrees C was 2-2.5 fold longer than that for the PcXylA-wt, and the melting temperature was 60.0 and 56.1 degrees C, respectively. Most of other mutations led to decrease in the enzyme thermostability. This study, together with data of other researchers, suggests that multiple mutations should be introduced into GH10 xylanases in order to dramatically improve their stability. PMID- 28634063 TI - Occipital Nerve Stimulation for the Treatment of Refractory Occipital Neuralgia: A Case Series. AB - BACKGROUND: Occipital neuralgia is a chronic pain syndrome characterized by sharp, shooting pains in the distribution of the occipital nerves. Although relatively rare, it associated with extremely debilitating symptoms that drastically affect a patient's quality of life. Furthermore, it is extremely difficult to treat as the symptoms are refractory to traditional treatments, including pharmacologic and procedural interventions. A few previous case studies have established the use of a neurostimulation of the occipital nerves to treat occipital neuralgia. OBJECTIVE: The following expands on that literature by retrospectively reviewing the results of occipital nerve stimulation in a relatively large patient cohort (29 patients). METHODS: A retrospective review of 29 patients undergoing occipital nerve stimulation for occipital neuralgia from 2012 to 2017 at a single institution with a single neurosurgeon. RESULTS: Of those 29 patients, 5 were repair or replacement of previous systems, 4 did not have benefit from trial stimulation, and 20 saw benefit to their trial stage of stimulation and went on to full implantation. Of those 20 patients, even with a history of failed procedures and pharmacological therapies, there was an overall success rate of 85%. The average preoperative 10-point pain score dropped from 7.4 +/- 1.7 to a postoperative score of 2.9 +/- 1.7. However, as with any peripheral nerve stimulation procedure, there were complications (4 patients), including infection, hardware erosion, loss of effect, and lead migration, which required revision or system removal. CONCLUSION: Despite complications, the results suggest, overall, that occipital nerve stimulation is a safe and effective procedure for refractory occipital neuralgia and should be in the neurosurgical repertoire for occipital neuralgia treatment. PMID- 28634064 TI - Subarachnoid Hemorrhage in Advanced Age: Comparison of Patients Aged 70-79 Years and 80 Years and Older. AB - BACKGROUND: Clinical routine shows an increasing admission rate of elderly patients suffering from subarachnoid hemorrhage (SAH). OBJECTIVE: Aim of the study was to identify differences in outcome and prognostic factors to better anticipate clinical course and therefore treat this special subgroup better. METHODS: We retrospectively compared patients aged 70-79 and older than 80 years (80+). Patients were entered into a prospectively collected database. Between 1999 and June 2014, 191 patients aged >=70 years suffered from SAH. We stratified between patients aged from 70 to 79 years (n = 138) and 80+ years (n = 53). Outcome was assessed by modified Rankin Scale 6 months after SAH. RESULTS: During the observation period, the rate of elderly patients increased from 9% to 24%. Patients aged 80+ years less often showed significant early hydrocephalus, cerebral vasospasm, and shunt dependence. A total of 51% of all patients were treated by coiling, whereupon also treatment modality had no influence on outcome. By comparing clinical outcomes, no significant differences could be detected. However, mortality rate was not significantly greater in patients 80+ years. Clinical status at time of admission statistically was a prognostic factor in elderly patients as well as the extent of blood clots and an early hydrocephalus. Patients aged 80+ years suffered less from severe cerebral vasospasm, which statistically was no prognostic factor for a favorable outcome in this group. CONCLUSIONS: Patients aged 80+ years with SAH also can achieve a favorable outcome. There was no difference in clinical outcome comparing both groups, but several pathophysiological mechanisms in elderly patients (especially 80+ years) seem to have a positive influence on typical complications after SAH, such as cerebral vasospasm, early hydrocephalus, and shunt dependence. PMID- 28634065 TI - Remote Lesions of Synchronous Sacral and Cervical Dural Arteriovenous Fistulas: A Case Report. AB - BACKGROUND: Spinal dural arteriovenous fistula (DAVF) is a rare disease, and multiple concurrent lesions are extremely rare. Such multiple spinal DAVFs have similar outflow routes at neighboring levels. However, there have been no reported cases of remote lesions of multiple spinal DAVFs. The authors herein report a case of double synchronous cervical and sacral DAVFs. CASE DESCRIPTION: A 56-year-old man with no previous history of disease presented with progressive myelopathy, and spinal magnetic resonance imaging showed extensive edema of the spinal cord from the conus to T7. The initial angiography incidentally revealed a C1 DAVF, but the sacral DAVF was not diagnosed. The C1 DAVF was treated surgically, because of the risk of subarachnoid hemorrhage. A second angiography was performed 2 months after the first surgery because of high clinical suspicion, and the sacral DAVF was diagnosed at that time. The sacral DAVF was treated surgically, and the symptoms gradually resolved within 6 months after surgery. CONCLUSIONS: Spinal DAVF is a rare disease, but clinicians should be aware of the possibility of the concurrence of multiple spinal fistulas located at different levels in the same patient. PMID- 28634066 TI - Recent biotechnology developments and trends in the Russian Federation. AB - This paper addresses recent government initiatives in biotechnology and various federal and regional initiatives. It presents an overview of the most visible industrial biotechnology projects under implementation and highlights changes in legislation affecting development of the bioeconomy in the Russian Federation. PMID- 28634067 TI - Magnetic graphene coated inorganic-organic hybrid nanocomposite for enhanced preconcentration of selected pesticides in tomato and grape. AB - The new magnetic graphene based hybrid silica-N-[3 (trimethoxysilyl)propyl]ethylenediamine (MG@SiO2-TMSPED) nanocomposite was synthesized via sol-gel process, and used as an effective adsorbent in magnetic solid phase extraction (MSPE) of three selected pesticides followed by gas chromatography micro-electron capture detection (GC-MUECD). The adsorbent was characterized using Fourier transform-infrared spectroscopy (FT-IR), Brunauer Emmett-Teller (BET), Barrett-Joyner-Halenda (BJH), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and energy dispersive X-ray spectroscopy (EDXS) techniques. The analytical validity of the developed method was evaluated under optimized conditions and the following figures of merit were obtained: linearity, 1-20MUgkg-1 with good determination coefficients (R2=0.995 0.999); limits of detection (LODs), 0.23-0.30MUgkg-1 (3*SD/m, n=3); and limits of quantitation (LOQ), 0.76-1.0MUgkg-1 (10*SD/m, n=3). The precision (RSD%) of the proposed MSPE method was studied based on intra-day (3.43-8.83%, n=3) and inter day (6.68-8.37%, n=12) precisions. Finally, the adsorbent was applied to determination of pesticides in tomato and grape samples and good recoveries were obtained in the range from 82 to 113% (RSDs 5.1-8.1%, n=3). PMID- 28634068 TI - Investigation of changes in endocannabinoids and N-acylethanolamides in biofluids, and their correlations with female infertility. AB - Female infertility is a worldwide medical problem, and the scarcity of infertility biomarkers has hindered the ability to launch preventive and therapeutic measures in a timely manner. Intriguingly, alterations in endocannabinoids (eCBs) and N-acylethanolamides (NAEs) have been observed in the biofluids of infertile females. Therefore, a hypothesis of using eCB and NAEs in biofluids as infertility biomarkers was proposed by several researchers; however, little evidence exists to verify the hypothesis. To investigate their correlations with female infertility, we developed a magnetic liquid microextraction-chemical derivatization (MLME-CD) method coupled with liquid chromatography-tandem mass spectrometry for the quantification of eCBs and NAEs in biofluids. The target compounds were first purified with magnetic toluene as sorbents, and then labeled with 4-(N,N-dimethyamino)benzoyl chloride (4-DMABC). The MLME-CD method offered several advantages, including reliable quantification results by preventing the isomerization of eCB, high throughput by requiring 20min for sample preparation, and good sensitivity with limits of detection at 3.0-54.3 fmol. The intra-day and inter-day relative standard deviations were below 14.5%, and the recoveries were 87.4%-117.9%. Concentrations of eCBs and NAEs in the serum of 49 infertile women and 53 fertile women (controls), and in the ovarian follicular fluid of 21 infertile women and 20 controls were then quantified. Using unpaired t test analysis indicated significant differences in AEA and PEA in serum, and OEA in follicular fluid between infertile women and healthy controls, and the areas under the curve were in the range of 0.605-0.707. PMID- 28634069 TI - High through-put liquid chromatography - mass spectrometry requires new strategies for the management of fluid at the interface. PMID- 28634070 TI - High and low concentration of 17alpha-estradiol protect cerebellar granule neurons in different time windows. AB - 17alpha-estradiol is a hormonally inactive isomer of 17beta-estradiol, but with similar potency as neuroprotector. However, we have previously reported that pretreatment with high concentration (10 MUM) of both estrogens abolishes their neuroprotection in rat cerebellar granule neurons. Here, we have examined neuroprotective properties of 17alpha-estradiol against glutamate-induced excitotoxicity in chicken cerebellar granule neurons using low (1 nM) and high concentration.17alpha-Estradiol, 1 nM, was neuroprotective when glutamate was administered after a pretreatment period of 24 h, but not when coadministered with glutamate. In contrast, 10 MUM was protective when coadministered with glutamate, but was not efficient when glutamate was administered after a pretreatment period. The difference in protection was linked to a stronger calcium response during glutamate exposure in the non-protective treatments. In addition, the pretreatment period with 10 MUM was accompanied by increased protein level of the N-methyl-d-aspartate receptor subunit NR2B and reduced glutathione level. Thus, 17alpha-estradiol has a concentration and time dependent protective effect against glutamate-induced cell death. PMID- 28634071 TI - The novel YAP target gene, SGK1, upregulates TAZ activity by blocking GSK3beta mediated TAZ destabilization. AB - YAP (Yes-associated protein) and TAZ (transcription activator with PDZ binding motif) are important in tissue regeneration and cancer development, highlighting the importance of discovering partners that regulate their oncogenicity. SGK1 (serum/glucocorticoid regulated kinase 1), initially identified as a homolog of Akt in phosphoinositide 3-kinase signaling, acts as a serine/threonine protein kinase in multiple oncogenic pathways. However, possible links between SGK1 and Hippo-YAP/TAZ signaling remain unexplored. Here, we reveal that SGK1 is a potential positive feedback regulator of YAP and TAZ, showing that the TEAD YAP/TAZ complex directly activates SGK1 transcription by binding to the distal enhancer of SGK1, and SGK1, in turn, stabilizes YAP/TAZ. Moreover, we demonstrate that expression of YAP/TAZ target genes is positively regulated by SGK1. Mechanistically, SGK1 inhibits ubiquitin-mediated degradation of TAZ by inhibiting GSK3beta activity. These findings expand our understanding of YAP/TAZ regulation to include the novel downstream target of YAP, SGK1. PMID- 28634072 TI - Mitochondrial dynamics coordinate cell differentiation. AB - Cells differentiate into specific and functional lineages to build up tissues. It has been shown in several tissues that mitochondrial morphology, levels of "mitochondria-shaping" proteins, and mitochondrial functions change upon differentiation. In this review, we highlight the significance of mitochondrial dynamics and functions in tissue development, cell differentiation, and reprogramming processes. Signalling cascades are critical for tissue stem cell maintenance and cell fate determination, and growing evidence demonstrates mitochondria could act as a centre of intra and extracellular signals to coordinate signalling pathways, such as Notch, Wnt, and YAP/TAZ signalling. Just an organelle, however, emerges as a master regulator of cell differentiation, and can be a target to manipulate cell fates. PMID- 28634073 TI - Long noncoding RNA MEG3 mediated angiogenesis after cerebral infarction through regulating p53/NOX4 axis. AB - OBJECTIVE: This study aimed to explore the mechanism of lncRNA MEG3 on angiogenesis after cerebral infarction (CI). METHODS: The rat brain microvascular endothelial cells (RBMVECs) isolated from rat was used to establish CI model, which were treated with oxygen-glucose deprivation/reoxygenation (OGD/R). The genes mRNA and protein expression levels in RBMVECs were determined by the quantitative real-time polymerase chain reaction (RT-qPCR) and western blot, respectively. The flow cytometry was used to measured cell apoptosis and intracellular reactive oxygen species (ROS) generation. The RBMVECs activities was detected by MTT method. The RNA-immunoprecipitation (RIP) assay was used to detect the interaction between MEG3 and p53, and the relationship between p53 and NOX4 was proved by chromatin co-immunoprecipitation (chip) assay. RESULTS: The results showed that OGD or OGD/R increased MEG3 and NOX4 expression, and there was positive correlation between MEG3 and NOX4 expression in RBMVECs. Next, knockdown of MEG3 indicated that inhibition of MEG3 was conducive to protect RBMVECs against OGD/R-induced apoptosis, with decreased NOX4 and p53 expression, further enhanced pro-angiogenic factors (HIF-1alpha and VEGF) expression, and reduced intracellular ROS generation. And then the RIP and CHIP assay demonstrated that MEG3 could interacted with p53 and regulated its expression, and p53 exerted significant binding in the promoters for NOX4, suggesting that MEG3 regulated NOX4 expression via p53. At last, knockdown of NOX4 indicated that inhibition of NOX4 protected RBMVECs against OGD/R-induced apoptosis, with increased cell viability and pro-angiogenic factors expression, and reduced ROS generation. CONCLUSION: LncRNA MEG3 was an important regulator in OGD/R induced RBMVECs apoptosis and the mechanism of MEG3 on angiogenesis after CI was reduced ROS by p53/NOX4 axis. PMID- 28634074 TI - Distinct regulation of activity-dependent transcription of immediate early genes in cultured rat cortical neurons. AB - The activity-regulated expression of immediate early genes (IEGs) contributes to long-lasting neuronal functions underlying long-term memory. However, their response properties following neuronal activity are unique and remain poorly understood. To address this knowledge gap, here we further investigated the response properties of two representative IEGs, c-fos and brain-derived neurotrophic factor (Bdnf). Treatment of cultured cortical cells with KCl produces a depolarization process that results in the increase of intracellular calcium concentration in a KCl concentration-dependent manner. Consistent with this increase, c-fos expression was induced in a KCl concentration-dependent manner. In contrast, however, Bdnf expression was optimally activated by both 25 and 50 mM concentration of KCl. Similar results were observed when the cells were treated with okadaic acid, which inhibits protein phosphatases and elicits the hyper-phosphorylation of signaling molecules. Thus, Bdnf expression is strictly regulated by a neuronal activity threshold in an all or nothing manner, whereas c fos expression is activated in a neuronal activity-dependent manner. Our findings also suggest that these differential responses might be due to the presence or absence of a TATA box. PMID- 28634075 TI - Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice. AB - Breast cancer is one of the most common cancers in women in the world. Although breast cancer is well treatable at the early stage, patients with distant metastases show a poor prognosis. Data from recent studies using transplantation models indicate that Mint3/APBA3 might promote breast cancer malignancy. However, whether Mint3 indeed contributes to tumor development, progression, or metastasis in vivo remains unclear. To address this, here we examined whether Mint3 depletion affects tumor malignancy in MMTV-PyMT breast cancer model mice. In MMTV PyMT mice, Mint3 depletion did not affect tumor onset and tumor growth, but attenuated lung metastases. Experimental lung metastasis of breast cancer Met-1 cells derived from MMTV-PyMT mice also decreased in Mint3-depleted mice, indicating that host Mint3 expression affected lung metastasis of MMTV-PyMT derived breast cancer cells. Further bone marrow transplant experiments revealed that Mint3 in bone marrow-derived cells promoted lung metastasis in MMTV-PyMT mice. Thus, targeting Mint3 in bone marrow-derived cells might be a good strategy for preventing metastasis and improving the prognosis of breast cancer patients. PMID- 28634076 TI - lncRNA HULC promotes the growth of hepatocellular carcinoma cells via stabilizing COX-2 protein. AB - Highly upregulated in liver cancer (HULC), a lncRNA overexpressed in hepatocellular carcinoma (HCC), has been demonstrated to be involved in the carcinogenesis and progression of HCC. However, the mechanisms of HULC promoting the abnormal growth of HCC cells are still not well elucidated. In the present study, we for the first time demonstrated that HULC promoted the growth of HCC cells through elevating COX-2 protein. Moreover, the study of the corresponding mechanism by which HULC upregulated COX-2 showed that HULC enhanced the level of ubiquitin-specific peptidase 22 (USP22), which decreased ubiquitin-mediated degradation of COX-2 protein by removing the conjugated polyubiquitin chains from COX-2 and finally stabilized COX2 protein. In addition, knockdown of USP22 or COX 2 attenuated HULC-mediated abnormal growth of HCC cells. In conclusion, our results demonstrated that "USP22/COX-2" axis played an important role in HULC promoting growth of HCC cells. The identification of this novel pathway may pave a road for developing new potential anti-HCC strategies. PMID- 28634077 TI - DEPDC1 promotes cell proliferation and tumor growth via activation of E2F signaling in prostate cancer. AB - DEP domain containing 1 (DEPDC1) is recently reported to be overexpressed in several types of human cancer; however the role of DEPDC1 in prostate cancer remains to be investigated. Herein, we identified that the DEPDC1 mRNA and protein expression levels were dramatically increased in prostate cancer tissues and cell lines. Overexpression of DEPDC1 promoted, but depletion of DEPDC1 inhibited cell proliferation by regulating the G1-S phase cell cycle transition. Importantly, we found that DEPDC1 was essential for the tumor growth and formation of bone metastases of prostate cancer cells in vivo. Finally, we demonstrated that DEPDC1 interacted with E2F1 and increased its transcriptional activity, leading to hyper-activation of E2F signaling in prostate cancer cells. Our findings reveal an oncogenic role of DEPDC1 in prostate cancer progression via activation of E2F signaling, and suggest DEPDC1 might be a potential therapeutic target against the disease. PMID- 28634078 TI - Astrocytes regulate the expression of Sp1R3 on oligodendrocyte progenitor cells through Cx47 and promote their proliferation. AB - Many degenerative diseases of the central nervous system are associated with demyelination. Oligodendrocyte progenitor cells (OPCs) are potential stem cells that can differentiate into various cell types, including oligodendrocytes (OLs). Promoting the proliferation and differentiation of OPCs into mature OLs that can myelinate axons is the key to stimulate remyelination. Here, we report that astrocytes (ASTs) increase the number of sphingosine-1-phosphate receptors 3 (S1pR3) on OPCs and promote OPCs proliferation through a direct contact via connexin 47 (Cx47). Our results demonstrate that ASTs can regulate the proliferation of OPCs through Cx47-mediated induction of S1pR3 expression on OPCs. Cx47/S1pR3 remarkably increases the number of OPCs and promotes cell transition from the G1 to the S phase. Furthermore, inhibiting either Cx47 or S1pR3 decreases OPC proliferation. In summary, ASTs regulate the expression of S1pR3 in OPCs via Cx47, which could be a valuable approach for promoting OPC proliferation. This strategy may therefore represent a potential treatment for neurological diseases caused by OLs death and demyelination. PMID- 28634079 TI - Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties. AB - BACKGROUND: Relaxin-2 (RLX) is a peptide hormone that exerts beneficial anti fibrotic and anti-inflammatory effects in diverse models of cardiovascular disease. The goal of this study was to determine the effects of RLX treatment on the susceptibility to atrial fibrillation (AF) after myocardial infarction (MI). METHODS: Mice with cryoinfarction of the left anterior ventricular wall were treated for two weeks with either RLX (75 MUg/kg/d) or vehicle (sodium acetate) delivered via subcutaneously implanted osmotic minipumps. RESULTS: RLX treatment significantly attenuated the increase in AF-inducibility following cryoinfarction and reduced the mean duration of AF episodes. Furthermore, epicardial mapping of both atria revealed an increase in conduction velocity. In addition to an attenuation of atrial hypertrophy, chronic application of RLX reduced atrial fibrosis, which was linked to a significant reduction in atrial mRNA expression of connective tissue growth factor. Transcript levels of the pro-inflammatory cytokines interleukin-6 and interleukin-1beta were reduced in RLX treated mice, but macrophage infiltration into atrial myocardium was similar in the vehicle and RLX treated groups. CONCLUSION: Treatment with RLX in mice after MI reduces susceptibility to AF due to anti-inflammatory and anti-fibrotic properties. Because to these favorable actions, RLX may become a new therapeutic option in the treatment of AF, even when complicating MI. PMID- 28634080 TI - nonG, a constituent of the nonactin biosynthetic gene cluster, regulates nocardamine synthesis in Streptomyces albus J1074. AB - Many factors regulate the expression of specialised secondary metabolite biosynthetic gene clusters, which have been recognised as important for the discovery of novel microbial natural products. A cosmid library based on genomic DNA of the marine-derived Streptomyces puniceus Act1085 was constructed and screened to identify a short gene cluster similar to the nonactin biosynthetic cluster. The ORFs of the gene cluster isolated had high amino acid sequence identity, from 82% to 96%, with corresponding ORFs of the nonactin biosynthetic gene cluster from S. griseus subsp. griseus ETH A7796. Despite the expectation that nonactin or its derivatives would be made from heterologous expression of the gene cluster found in S. albus J1074, nocardamine was isolated. The heterologous expression data indicate that the production of nocardamine in S. albus J1074 is due to an ortholog of nonG, a TetR family transcriptional regulator, from S. puniceus Act1085. PMID- 28634081 TI - Quantitative proteomic reveals the dynamic of protein profile during final oocyte maturation in zebrafish. AB - The molecular mechanisms underlying final oocyte maturation in zebrafish (Danio rerio) remain poorly understood. The present study aimed to employ iTRAQ approach for a comprehensive characterization of during zebrafish oocyte maturation proteome and for comparison between fully-grow immature and mature oocytes prior to ovulation. A total of 1568 proteins were identified, which was representing the largest zebrafish isolated oocytes proteome dataset to date. Differential expression analysis revealed 190 proteins significantly changes between immature and mature oocytes, which 136 proteins were up-regulated and 54 proteins were down-regulated in mature oocytes comparison with immature oocytes. Functional analysis revealed that these differential proteins were mostly involved in cellular response to estrogen stimulus, cellular components, extracellular region, and enzyme regulator activity, etc. The revealed differentially changes in protein expression patterns associated with oocyte maturation suggest that several of the examined proteins, such as vitellogenin(Vtg3), protein S100(S100A10), 17-beta hydroxysteroid dehydrogenase(HSD17B1), pentaxin, zona pellucida (ZP3.2), elongation factor1-alpha, caluemnin B, and 14-3-3 protein may play a specific role during zebrafish final oocyte maturation. These data will provide powerful information for understanding the molecular mechanism underlying zebrafish oocyte maturation, and these proteins may potentially act as markers to predict control oocyte maturation of zebrafish oocytes. PMID- 28634082 TI - Cytokine modulation by stress hormones and antagonist specific hormonal inhibition in rainbow trout (Oncorhynchus mykiss) and gilthead sea bream (Sparus aurata) head kidney primary cell culture. AB - A tight interaction between endocrine and immune systems takes place mainly due to the key role of head kidney in both hormone and cytokine secretion, particularly under stress situations in which the physiological response promotes the synthesis and release of stress hormones which may lead into immunomodulation as side effect. Although such interaction has been previously investigated, this study evaluated for the first time the effect of stress-associated hormones together with their receptor antagonists on the expression of cytokine genes in head kidney primary cell culture (HKPCC) of the freshwater rainbow trout (Oncorhynchus mykiss) and the seawater gilthead sea bream (Sparus aurata). The results showed a striking difference when comparing the response obtained in trout and seabream. Cortisol and adrenocorticotropic hormone (ACTH) decreased the expression of immune-related genes in sea bream but not in rainbow trout and this cortisol effect was reverted by the antagonist mifepristone but not spironolactone. On the other hand, while adrenaline reduced the expression of pro inflammatory cytokines (IL-1beta, IL-6) in rainbow trout, the opposite effect was observed in sea bream showing an increased expression (IL-1beta, IL-6). Interestingly, this effect was reverted by antagonist propranolol but not phentolamine. Overall, our results confirm the regional interaction between endocrine and cytokine messengers and a clear difference in the sensitivity to the hormonal stimuli between the two species. PMID- 28634083 TI - Effects of the soya isoflavone genistein in early life stages of the Senegalese sole, Solea senegalensis: Thyroid, estrogenic and metabolic biomarkers. AB - This study examines the effects induced by environmentally relevant concentrations of the isoflavone genistein (3mg/L and 10mg/L) during early life stages of the Senegalese sole. Throughout the hypothalamus-pituitary-thyroid (HPT) axis, several neurohormonal regulatory thyroid signalling patterns (thyroglobulin/Tg, thyroid peroxidase/TPO, transthyretin/TTR, thyroid receptors/TRbeta, and iodothrynonine deiodinases, Dio2 and Dio3) were analysed. Furthermore, the expression patterns of estrogen receptor ERbeta and haemoprotein Cyp1a were also evaluated. In the control larvae, progressive increases of constitutive hormonal signalling pathways have been evidenced from the pre metamorphosis phase onwards, reaching the highest expression basal levels at the metamorphosis (Tg, TPO, Dio2) and/or during post-metamorphosis (TTR, TRbeta, ERbeta). When the early larvae were exposed to both genistein concentrations (3mg/L and 10mg/L), a statistically significant down-regulation of TPO, TTR and Tg mRNA levels was clearly detected at the metamorphic stages. In addition, the Dio2 and Dio3 transcript expression levels were also down and up-regulated when exposed to both genistein concentrations. In the larvae exposed to genistein, no statistically significant responses were recorded for the TRbeta expression patterns. Nevertheless, the ERbeta and Cyp1a transcript levels were up-regulated at the middle metamorphic stage (S2, at 16 dph) in the larvae exposed to high genistein concentrations and, only the ERbeta was down-regulated (S1, at 12dph) at the lower doses. Finally, all these pointed out imbalances were only temporarily disrupted by exposure to genistein, since most of the modulated transcriptional signals (i.e. up or down-regulation) were quickly restored to the baseline levels. Additionally, the control and genistein-exposed Senegalese sole specimens showed characteristic ontogenetic patterns and completely suitable for an optimal development, metamorphosis, and growth. PMID- 28634085 TI - Use of the Furosemide Fludrocortisone Test to Clinically Assess Distal Tubular Acidification. PMID- 28634086 TI - Towards building a more complex view of the lateral geniculate nucleus: Recent advances in understanding its role. AB - The lateral geniculate nucleus (LGN) has often been treated in the past as a linear filter that adds little to retinal processing of visual inputs. Here we review anatomical, neurophysiological, brain imaging, and modeling studies that have in recent years built up a much more complex view of LGN. These include effects related to nonlinear dendritic processing, cortical feedback, synchrony and oscillations across LGN populations, as well as involvement of LGN in higher level cognitive processing. Although recent studies have provided valuable insights into early visual processing including the role of LGN, a unified model of LGN responses to real-world objects has not yet been developed. In the light of recent data, we suggest that the role of LGN deserves more careful consideration in developing models of high-level visual processing. PMID- 28634084 TI - Drug delivery to melanoma brain metastases: Can current challenges lead to new opportunities? AB - Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease. While these studies are encouraging, there remains significant room for improvement in the treatment of MBM, given the lack of durable response and the development of resistance to current therapies. Critical questions remain regarding mechanisms that lead to this lack of durable response and development of resistance, and how those mechanisms may differ in systemic sites versus brain metastases. One issue that may not be fully appreciated is that the delivery of several small molecule molecularly-targeted therapies to the brain is often restricted due to active efflux at the blood-brain barrier (BBB) interface. Inadequate local drug concentrations may be partially responsible for the development of unique patterns of resistance at metastatic sites in the brain. It is clear that there can be local, heterogeneous BBB breakdown in MBM, as exemplified by contrast enhancement on T1-weighted MR imaging. However, it is possible that the successful treatment of MBM with small molecule targeted therapies will depend, in part, on the ability of these therapies to penetrate an intact BBB and reach the protected micro-metastases (so called "sub-clinical" disease) that escape early detection by contrast-enhanced MRI, as well as regions of tumor within MRI detectable metastases that may have a less compromised BBB. The emergence of resistance in MBM may be related to several diverse, yet interrelated, factors including the distinct microenvironment of the brain and inadequate brain penetration of targeted therapies to specific regions of tumor. The tumor microenvironment has been ascribed to play a key role in steering the course of disease progression, by dictating changes in expression of tumor drivers and resistance-related signaling mechanisms. Therefore, a key issue to consider is how changes in drug delivery, and hence local drug concentrations within a metastatic microenvironment, will influence the development of resistance. Herein we discuss our perspective on several critical questions that focus on many aspects relevant to the treatment of melanoma brain metastases; the answers to which may lead to important advances in the treatment of this devastating disease. PMID- 28634088 TI - Duration of untreated psychosis and neurocognition in first-episode psychosis: A meta-analysis. AB - Neurocognitive impairment is a well-established feature of first-episode psychosis (FEP). Neurotoxicity hypothesis of psychosis suggests that untreated psychosis before the initiation of first effective treatment is associated with loss of acquired cognitive abilities. However, the outcome of the studies investigating the relationship between duration of untreated psychosis (DUP) and cognitive impairment in FEP remains inconclusive. No previous meta-analysis investigating the relationship between DUP and cognitive impairment in FEP has been published. Following the systematic review of FEP studies, a random-effects meta-analysis of the relationship between DUP and neurocognition in schizophrenia was conducted. Current meta-analysis included 27 studies including 3127 patients with first-episode psychosis. Overall, DUP and cognitive abilities were not significantly related, with the exception of evidence for a weak relationship with a single cognitive domain. There was a very small but significant association between longer DUP and reduced performance in planning/problem solving ability (r=-0.09, CI=-0.14 to -0.03). Current findings do not provide support for the neurotoxicity hypothesis of psychosis. PMID- 28634087 TI - Treatment with levetiracetam improves cognition in a ketamine rat model of schizophrenia. AB - Imbalance in neural excitation and inhibition is associated with behavioral dysfunction in individuals with schizophrenia and at risk for this illness. We examined whether targeting increased neural activity with the antiepileptic agent, levetiracetam, would benefit memory performance in a preclinical model of schizophrenia that has been shown to exhibit hyperactivity in the hippocampus. Adult rats exposed to ketamine subchronically during late adolescence showed impaired hippocampal-dependent memory performance. Treatment with levetiracetam dose-dependently improved memory performance of the ketamine-exposed rats. In contrast, the antipsychotic medication risperidone was not effective in this assessment. Levetiracetam remained effective when administered concurrently with risperidone, supporting potential viability of adjunctive therapy with levetiracetam to treat cognitive deficits in schizophrenia patients under concurrent antipsychotic therapy. In addition to its pro-cognitive effect, levetiracetam was also effective in attenuating amphetamine-induced augmentation of locomotor activity, compatible with the need for therapeutic treatment of positive symptoms in schizophrenia. PMID- 28634089 TI - Wedelolactone, a plant coumarin, prevents vascular smooth muscle cell proliferation and injury-induced neointimal hyperplasia through Akt and AMPK signaling. AB - Wedelolactone (WDL) is a natural compound derived from Chinese herbal medicine Eclipta prostrate L, and has been reported to exhibit various effects potentially beneficial for human health. However, the possible preventive effects of WDL toward vascular remodeling and mechanisms involved have not been investigated to date. In this study, we investigated the effects of WDL on proliferation induced by platelet-derived growth factor (PDGF) in primary rat aortic smooth muscle cells (VSMCs) and on neointimal hyperplasia resulted from balloon injury in rats. WDL exhibited strong inhibitory effects against PDGF-induced VSMC proliferation. Cell cycle analysis revealed that WDL induced G0/G1 arrest and prevented cell cycle from entering S phase. Immunoblot analysis suggested that the cell cycle arrest induced by WDL was through Akt suppression and adenosine 5'-monophosphate activated protein kinase (AMPK) activation, with a subsequent cyclin-dependent kinase inhibitor p21 induction and cyclin D1 inhibition. We also observed that WDL notably reduced neointima-to-media area ratio of balloon-injured rat common carotid arteries (CCAs) in comparison with those untreated balloon-injured CCAs. The regulation of WDL on protein expressions of Akt, AMPK and cyclin D1 in vivo were also consistent with that in vitro. Taken together, our results suggest WDL exhibits potential preventive effects toward vascular remodeling and neointimal hyperplasia through the reduction of VSMC proliferation via inhibition of Akt and activation of AMPK. PMID- 28634090 TI - Evaluation of the effect of 3-month bladder basic advice in children with monosymptomatic nocturnal enuresis. AB - INTRODUCTION: Advice (BBA) into the standards of patients' care in both monosymptomatic and non-monosymptomatic nocturnal enuresis. Although the idea of this recommendation was clear and reflects clinical experience, duration and efficacy have not been definitely established. Recent data have demonstrated the lack of efficacy of BBA and a fierce discussion has ensued. The present study was aimed to assess the efficacy of BBA in a group of previously untreated children with primary monosymptomatic nocturnal enuresis (MNE). STUDY DESIGN: The study was a prospective interventional multicenter trial in a cohort of previously untreated MNE patients. Forty-nine children (36 males, 13 females, mean age 7.2 years) were included in the analysis. The treatment efficacy was assessed at the 30th, 60th, and 90th days of BBA. RESULTS: We discovered that the mean number of wet nights decreased significantly (p < 0.001) only after 3 months of BBA from 8.9 to 5.9 episodes every 2 weeks. BBA was fully successful in 2% o the children after 30 day, 12% after 60 days, and 18% after 90 days (Figure). Partial response (by ICCS) was assessed for 8%, 20%, and 34% of the patients. We noted a relatively high rate of non-responders that decreased from 90% to 47% after 90 days. We detected no differences in BBA efficacy between children with night-time polyuria or decreased maximal voided volume. A lower number of wet nights initially predicted the response to the BBA. DISCUSSION: Our study confirmed rather limited efficacy of BBA, similarly to previous observations, but provided more information on isolated MNE, because of a more specific study group and longer period of observation. The limitation of the study was lack of randomization. CONCLUSION: Our study revealed that in treatment-naive children with monosymptomatic enuresis basic bladder training had a low (18%) and late effect, mostly pronounced after the third month of therapy. It seems that only if the patient presents with a favorable profile of bedwetting, occasionally and with a high maximum voided volume, it is worth maintaining BBA for a longer period of up to 3 months before initiating second-line therapy. In an unfavorable initial profile desmopressin or an alarm may be introduced much earlier. PMID- 28634091 TI - A Simple Method Associated With Reduced Opioid Consumption After Total Knee Arthroplasty. AB - BACKGROUND: Most patients experience moderate to severe pain after total knee arthroplasty (TKA). We hypothesized that intraoperative treatment of cut bone surfaces with local anesthetic (preimplantation immersion anesthesia, PIA) would lead to decreased postoperative pain and opioid consumption. METHODS: Records of 76 patients who underwent unilateral, cemented TKA were retrospectively reviewed. For PIA patients, surgical wounds were immersed in local anesthetic solution immediately prior to component implantation. Both PIA (n = 43) and control (n = 33) groups received multimodal pain management, including intra-articular local anesthetic injections. Endpoints were opioid consumption and mean pain scores for postoperative day (POD) 0, 1, and 2. Demographic, medical, and social factors were included in multivariate analyses. RESULTS: PIA patients reported significantly lower mean pain scores than controls on PODs 0 and 1 (both P < .005). Pain scores on POD 2 were similar. PIA patients used 45%-33% less opioids on PODs 0, 1, and 2 (all P < .005). POD 0 pain scores showed a significant interaction between PIA treatment and preoperative opioid use (P = .013). On POD 1, PIA was the only factor associated with lower mean pain scores (P < .001). No factors were significant for POD 2. PIA was the only factor associated with lower postoperative opioid consumption on PODs 0 and 2 (both P < .005). For POD 1, PIA and increasing age (both P <= .005) were associated with lower postoperative opioid consumption. CONCLUSION: PIA was associated with significant reductions in opioid use and mean pain scores after TKA. PMID- 28634092 TI - Alarmingly High Rate of Implant Fractures in One Modular Femoral Stem Design: A Comparison of Two Implants. AB - BACKGROUND: Reports of implant fracture at the modular junction have been seen in modular neck designs, stem-sleeve modular femoral stems, and diaphyseal engaging bi-body modular stems. To date, however, there has never been a direct comparison between 2 different implant designs from the same modular family. The purpose of this study is to compare the rate of implant failure of 2 such stem-sleeve modular femoral stem designs, the S-ROM and Emperion, to further identify factors which increase the risk of this mode of failure. METHODS: A retrospective, single surgeon, review of our institutional database was performed to compare the 2 groups of patients. RESULTS: A total of 1168 total hip arthroplasty procedures were included in our analysis, 547 (47%) with Emperion and 621 (53%) with S-ROM. Eight (1.5%) fractures in 7 patients occurred in the Emperion group compared to 1 (0.2%) fracture in the S-ROM group (P = .015). CONCLUSION: The precise cause of the stem fractures in our study remains unknown and is likely multifactorial. Given the unexpectedly high rate of catastrophic implant failures in the form of stem fracture at the stem-sleeve junction, we recommend more judicious use of modularity in primary total hip arthroplasty. PMID- 28634093 TI - Total Hip Arthroplasty After Transtrochanteric Rotational Osteotomy for Osteonecrosis of the Femoral Head: A Mean 10-Year Follow-Up. AB - BACKGROUND: The objective of the present study was to investigate clinical, quality of life, and radiographic outcomes of patients who underwent total hip arthroplasty (THA) after transtrochanteric rotational osteotomy (TRO) for osteonecrosis of the femoral head (ONFH). METHODS: We performed a case-control study. The participants were 29 patients (34 hips) who underwent THA after TRO (TRO group). These patients had a mean age at surgery of 51.6 years (range, 30-72 years) and underwent postoperative follow-up for a mean period of 10.5 years (range, 3-19 years). For the control group (primary group), we included 58 patients (68 hips) who underwent primary THA for ONFH, matching for age and gender. RESULTS: The Harris Hip Scores at the last follow-up were significantly poorer in the TRO group than in the primary group. Similarly, preoperative and postoperative hip range of motion was significantly poorer in the TRO group than in the primary group. Quality of life (Short Form-36, Oxford Hip Score, and Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire) and complication rates were not significantly different between the groups. The survival rates at 10 years, with revision for any reason as the endpoint, were 81% in the TRO group and 91% in the primary group, showing no significant difference between the groups. The TRO group had a larger average postoperative leg length discrepancy and a higher rate of stem malalignment than the primary group. CONCLUSION: The clinical outcomes of THA after TRO for ONFH were poorer than those of primary THA. PMID- 28634094 TI - Regional Anesthesia in Total Joint Arthroplasty: What Is the Evidence? AB - Total joint arthroplasty is one of the most common surgical procedures performed for end-stage osteoarthritis. The increasing demand for knee and hip arthroplasties along with the improvement in life expectancy has created a substantial medical and economic impact on the society. Effective planning of health care for these individuals is vital. The best method for providing anesthesia and analgesia for total joint arthroplasty has not been defined. Yet, emerging evidence suggests that the type of anesthesia can affect morbidity and mortality of patients undergoing these procedures. PMID- 28634095 TI - Comparative Effectiveness and Safety of Drug Prophylaxis for Prevention of Venous Thromboembolism After Total Knee Arthroplasty. AB - BACKGROUND: Rates of venous thromboembolism in contemporary studies of primary total knee arthroplasty (TKA) have been reported to be as high as 3.5%. Although drug prophylaxis is effective, the best option among these regimens is not well established. The purpose of this study was to evaluate the comparative effectiveness and safety of aspirin, low-molecular-weight heparin, synthetic pentasaccharide factor Xa inhibitors, and vitamin K antagonist. METHODS: Data were from a US total joint replacement registry, with 30,499 patients receiving unilateral TKA from May 16, 2006, to December 31, 2013. Patients received either aspirin (324-325 mg daily), enoxaparin (40-60 mg daily), fondaparinux (2.5 mg daily), or warfarin (all doses) and were followed up 90 days postoperatively on several outcomes: deep vein thrombosis, pulmonary embolism, major bleeding, wound complications, infection, and death. RESULTS: There was no evidence that fondaparinux, enoxaparin, or warfarin were superior to aspirin in the prevention of pulmonary embolism, deep vein thrombosis, or venous thromboembolism or that aspirin was safer than these alternatives. However, enoxaparin was found to be as safe as aspirin with respect to bleeding, and fondaparinux was as safe as aspirin for risk of wound complications. CONCLUSION: Among TKA patients, we did not find evidence for decreased effectiveness or increased safety with use of aspirin, but enoxaparin had comparable safety to aspirin for bleeding and fondaparinux had comparable safety to aspirin for wound complications. PMID- 28634096 TI - Reconstruction of Disrupted Extensor Mechanism After Total Knee Arthroplasty. AB - BACKGROUND: Disruption of the extensor mechanism after total knee arthroplasty (TKA) is a debilitating complication that results in extension lag, limited range of motion, difficulty in walking, frequent falls, and chronic pain. This study presents the clinical and radiographic results of reconstruction after extensor mechanism disruption in TKA patients. METHODS: Consecutive patients with allograft reconstruction of extensor mechanism after TKA were identified retrospectively from an academic tertiary center for revision TKA. RESULTS: Sixteen patients with a mean age of 61 +/- 14 years at extensor mechanism reconstruction with a minimum of 2-year follow-up were included. The mean follow up was 3.3 +/- 2.2 years. Knee Society score (KSS), before and at final follow-up extension lag, range of motion, and radiographic change in patellar height were reviewed. There were statistically significant improvements between preoperative and final follow-up KSS (P < .001; KSS for pain, preoperative 40 +/- 14 points to final follow-up 67 +/- 15 points [P < .001]; KSS for function, preoperative 26 +/ 21 points to final follow-up 48 +/- 25 points [P < .001]). The extension lag was also reduced from 35 degrees +/- 16 degrees preoperatively to 14 degrees +/- 18 degrees (P < .001) at final follow-up. There was an average proximal patellar migration of 8 +/- 10 mm. Five (31%) cases had an extensor lag of >30 degrees or revision surgery for repeat extensor mechanism reconstruction, infection, or arthrodesis. CONCLUSION: Our 10-year experience using allografts during extensor mechanism reconstruction demonstrates reasonable outcomes, but failures are to be anticipated in approximately one-third of patients. PMID- 28634097 TI - Acetabular Reconstruction With the Medial Protrusio Technique for Complex Primary and Revision Total Hip Arthroplasties. AB - BACKGROUND: In the setting of acetabular deficiency during total hip arthroplasty (THA), the medial protrusio technique (MPT) allows for increased component coverage while avoiding excessive component abduction or elevation of the hip center. The technique involves controlled reaming through the medial acetabular wall while maintaining the continuity of the anterior and posterior columns. The purpose of this study is to analyze the results of the largest reported series to date of primary and revision THAs using the MPT. METHODS: A retrospective review of THAs performed by a single surgeon from July 2004 to July 2010 identified 102 patients who underwent THA necessitating the use of the MPT (primary 86 and revision 16), with at least 2 years follow-up. RESULTS: This study reports the largest series to date of primary and revision THAs using the MPT for acetabular deficiency. Postoperatively, mean Harris hip score was 86 (range 31-96). There was no correlation with degree of medialization and change in Harris hip score (P = .12). At mean follow-up of 41.1 months (range 24-92 months), there were no intrapelvic structure injuries and no acetabular components required revision. The MPT provided a safe and effective method for addressing acetabular deficiency and avoiding component malposition. CONCLUSION: The MPT provided a safe and effective method for addressing acetabular deficiency in this large series of patients. The technique was successful at improving component coverage while maintaining an anatomic hip center and avoiding excessive component abduction. Fixation remained durable with no cases of loosening at final follow-up. PMID- 28634098 TI - Sepsis Within 30 Days of Geriatric Hip Fracture Surgery. AB - BACKGROUND: Sepsis after hip fracture typically develops from one of the 3 potential infectious sources: urinary tract infection (UTI), pneumonia, and surgical site infection (SSI). The purpose of this investigation is to determine (1) the proportion of cases of sepsis that arises from each of these potential infectious sources; (2) baseline risk factors for developing each of the potential infectious sources; and (3) baseline risk factors for developing sepsis. METHODS: The National Surgical Quality Improvement Program database was searched for geriatric patients (aged >65 years) who underwent surgery for hip fracture during 2005-2013. Patients subsequently diagnosed with sepsis were categorized according to concomitant diagnosis with UTI, SSI, and/or pneumonia. Multivariate regression was used to test for associations while adjusting for baseline characteristics. RESULTS: Among the 466 patients who developed sepsis (2.4% of all patients), 157 (33.7%) also had a UTI, 135 (29.0%) also had pneumonia, and 36 (7.7%) also had SSI. The rate of sepsis was elevated in patients who developed UTI (13.0% vs 1.7%; P < .001), pneumonia (18.2% vs 1.8%; P < .001), or SSI (14.8% vs 2.3%; P < .001). The mortality rate was elevated among those who developed sepsis (21.0% vs 3.8%; P < .001). CONCLUSION: Sepsis occurs in about 1 in 40 patients after geriatric hip fracture surgery. Of these septic cases, 1 in 3 is associated with UTI, 1 in 3 with pneumonia, and 1 in 15 with SSI. The cause of sepsis is often unknown on clinical diagnosis, and this distribution of potential infectious sources allows clinicians for direct identification and treatment. PMID- 28634099 TI - Fatal anaphylaxis caused by gadolinium due to beta-tryptase-induced hemorragic diathesis. PMID- 28634100 TI - Anaphylactic shock due to brentuximab-vendotin confirmed by skin test and in vitro tests. PMID- 28634101 TI - First-dose anaphylaxis to infliximab: a case of mammalian meat allergy. PMID- 28634102 TI - Depression and Asthma Outcomes in Older Adults: Results from the National Health and Nutrition Examination Survey. AB - BACKGROUND: Older adults have high rates of asthma morbidity and mortality, as well as increased rates of depression. There are no nationally representative studies describing the association of depression on key asthma outcomes such as emergency department (ED) visits among older adults. OBJECTIVE: The objective of this study was to determine the association of depression with asthma outcomes in older adults (age >= 55) from the National Health and Nutrition Examination Survey (NHANES). METHODS: Data from the NHANES survey (2007-2012) were analyzed. Bivariate analyses and multivariate Poisson regression models were used to examine associations between depression and asthma outcomes among adults above the age of 55. RESULTS: Approximately 7.01% (n = 509) of the sample reported a physician diagnosis of asthma. Older adults with asthma and depression (n = 196) had increased asthma episodes (prevalence ratio [PR], 1.53; 95% confidence interval [CI], 1.00-2.35), ED/urgent care visits for asthma (PR, 2.24; 95% CI, 1.15-4.34), sleep disturbances due to asthma (PR 2.75; 95% CI, 1.54-4.92), and activity limitation (PR, 1.77; 95% CI, 1.00-3.18; P = .05) compared with older asthmatics without depression. They also reported worse health-related quality of life measures across 4 domains including days of poor general health, physical health, mental health, and inactivity (P < .001 for all). No significant differences in spirometric values were observed. CONCLUSIONS: Older adults with asthma and depression are nearly twice as likely to have poor asthma outcomes across several indicators, including asthma-related ED/urgent care visits compared with those without depression. Screening for depression and providing supportive resources may decrease the burden of asthma among older adults. PMID- 28634103 TI - Undetectable Mannose Binding Lectin and Corticosteroids Increase Serious Infection Risk in Rheumatoid Arthritis. AB - BACKGROUND: Infection is the leading cause of death in rheumatoid arthritis (RA). Corticosteroid (CS) use is a known and important risk factor for serious infections (SIs). Mannose binding lectin (MBL) is a genetically determined component of the innate immune system implicated in neonatal infections. OBJECTIVE: Our aim was to determine whether MBL deficiency is a risk factor for SIs in RA and to compare it with CS use and also synthetic and biologic disease modifying antirheumatic drug (DMARD) therapy. METHODS: Data on 228 patients with RA were collected for up to 7 years (median = 5.9 years). Serum MBL concentrations were determined in all patients receiving synthetic (n = 96) or biologic (n = 132) DMARD therapy. RESULTS: High rates of SIs were observed in RA irrespective of treatment (17%). Similar rates of SIs were observed in synthetic and biologic DMARD users. The rates of single and multiple SIs were similar, irrespective of the use of a biologic agent. Undetectable MBL (<56 ng/mL) concentrations and maintenance prednisolone at 10 mg per day or higher were associated with an increased risk for an SI, with incident risk ratio of 4.67 (P = .001) and 4.70 (P < .001), respectively. CONCLUSIONS: Undetectable MBL and prednisolone confer a high risk for an SI. The use of biologic DMARDs did not confer substantial SI risk in this observational study. MBL deficiency is hitherto an unrecognized risk factor for an SI in RA. PMID- 28634104 TI - Natural Language Processing for Asthma Ascertainment in Different Practice Settings. AB - BACKGROUND: We developed and validated NLP-PAC, a natural language processing (NLP) algorithm based on predetermined asthma criteria (PAC) for asthma ascertainment using electronic health records at Mayo Clinic. OBJECTIVE: To adapt NLP-PAC in a different health care setting, Sanford Children Hospital, by assessing its external validity. METHODS: The study was designed as a retrospective cohort study that used a random sample of 2011-2012 Sanford Birth cohort (n = 595). Manual chart review was performed on the cohort for asthma ascertainment on the basis of the PAC. We then used half of the cohort as a training cohort (n = 298) and the other half as a blind test cohort to evaluate the adapted NLP-PAC algorithm. Association of known asthma-related risk factors with the Sanford-NLP algorithm-driven asthma ascertainment was tested. RESULTS: Among the eligible test cohort (n = 297), 160 (53%) were males, 268 (90%) white, and the median age was 2.3 years (range, 1.5-3.1 years). NLP-PAC, after adaptation, and the human abstractor identified 74 (25%) and 72 (24%) subjects, respectively, with 66 subjects identified by both approaches. Sensitivity, specificity, positive predictive value, and negative predictive value for the NLP algorithm in predicting asthma status were 92%, 96%, 89%, and 97%, respectively. The known risk factors for asthma identified by NLP (eg, smoking history) were similar to the ones identified by manual chart review. CONCLUSIONS: Successful implementation of NLP-PAC for asthma ascertainment in 2 different practice settings demonstrates the feasibility of automated asthma ascertainment leveraging electronic health record data with a potential to enable large-scale, multisite asthma studies to improve asthma care and research. PMID- 28634105 TI - Genetic diversity in the C-terminus of merozoite surface protein 1 among Plasmodium knowlesi isolates from Selangor and Sabah Borneo, Malaysia. AB - Plasmodium knowlesi, a malaria parasite of macaques, has emerged as an important parasite of humans. Despite the significance of P. knowlesi malaria in parts of Southeast Asia, very little is known about the genetic variation in this parasite. Our aim here was to explore sequence variation in a molecule called the 42kDa merozoite surface protein-1 (MSP-1), which is found on the surface of blood stages of Plasmodium spp. and plays a key role in erythrocyte invasion. Several studies of P. falciparum have reported that the C-terminus (a 42kDa fragment) of merozoite surface protein-1 (MSP-142; consisting of MSP-119 and MSP-133) is a potential candidate for a malaria vaccine. However, to date, no study has yet investigated the sequence diversity of the gene encoding P. knowlesi MSP-142 (comprising Pk-msp-119 and Pk-msp-133) among isolates in Malaysia. The present study explored this aspect. Twelve P. knowlesi isolates were collected from patients from hospitals in Selangor and Sabah Borneo, Malaysia, between 2012 and 2014. The Pk-msp-142 gene was amplified by PCR and directly sequenced. Haplotype diversity (Hd) and nucleotide diversity (l) were studied among the isolates. There was relatively high genetic variation among P. knowlesi isolates; overall Hd and l were 1+/-0.034 and 0.01132+/-0.00124, respectively. A total of nine different haplotypes related to amino acid alterations at 13 positions, and the Pk-MSP-119 sequence was found to be more conserved than Pk-msp-133. We have found evidence for negative selection in Pk-msp-42 as well as the 33kDa and 19kDa fragments by comparing the rate of non-synonymous versus synonymous substitutions. Future investigations should study large numbers of samples from disparate geographical locations to critically assess whether this molecule might be a potential vaccine target for P. knowlesi. PMID- 28634106 TI - Biology, evolution, and medical importance of polyomaviruses: An update. AB - The family Polyomaviridae encompasses non-enveloped viruses with a circular dsDNA genome that is typically approximately 5000bp in length. Originally isolated from mammals, polyomavirus sequences have now been detected in invertebrates, fish, amphibians, reptiles and birds, although it remains to be determined whether all these animals are genuine hosts. The genomes of all polyomaviruses encode at least two regulatory proteins (large and small tumour antigen) and two structural proteins (capsid proteins VP1 and VP2) whose functions have been defined. The large and small tumour antigens have domains conserved among the polyomaviruses, which are responsible for specific interactions with cellular proteins and may result in alteration of the cell cycle. Additional open reading frames (ORFs) are present in the genomes of the different polyomavirus species. Some of these ORFs are transcribed and translated in viral proteins, but their functions remain poorly understood. Polyomaviruses have a restricted host specificity. This may indicate that co-divergence with their hosts, which has been demonstrated in a few cases, was an important factor during polyomavirus diversification. However, a strict co-divergence scenario fails to explain family-wide patterns of diversity, suggesting an important contribution of lineage duplication and, possibly to a lesser extent, recombination and cross-species transmission. Polyomaviruses are pathogens that can cause various malignant and non-malignant diseases in birds and mammals, including humans, but so far they have not been linked to disease in lower vertebrates. In immunosuppressed individuals, reactivation of polyomavirus BK or JC can cause serious disease of the urogenital tract and brain, respectively, while Merkel cell polyomavirus is most probably associated with the development of a highly aggressive neuroendocrine skin tumour in elderly or patients with pre-existing conditions. This review provides an update on the life cycle, prevalence, disease association, and evolution of the viruses belonging to this family. PMID- 28634107 TI - Chronic pramipexole treatment induces compulsive behavior in rats with 6-OHDA lesions of the substantia nigra and ventral tegmental area. AB - Dopamine replacement therapy (DRT) reduces motor symptoms in Parkinson's disease (PD), but also induces impulsive-compulsive behavior (ICB) in up to 25% of PD patients. These non-motor side effects of DRT generally follow a gradual transition from impulsive to compulsive-like-i.e. repetitive, compelled, and non pleasurable-behavior. Here, we investigated the effect of chronic pramipexole (PPX) treatment on the onset of compulsive-like behavior, measured via the post training signal attenuation (PTSA) procedure, in rats with dopaminergic lesions. Accordingly, we aimed to mimic chronic DRT in a PD context, and obtain data on the brain regions that potentially sustain this type of compulsive behavior pattern in rats. We observed that the lesion or treatment alone did not induce compulsive lever pressing in rats. However, rats with lesions of the substantia nigra and ventral tegmental area as well as with chronic PPX treatment developed strong compulsive lever-pressing behavior, as measured via PTSA. Furthermore, when chronic PPX treatment was discontinued before the PTSA test, the lesioned rats showed the same level of compulsive behavior as sham-operated rats. In fact, lesioned, treated, and compulsive-like rats showed significantly higher Fos expression in the orbitofrontal cortex and dorsal striatum. Thus, chronic PPX treatment in PD rats induced a strong compulsive-like behavior. Furthermore, Fos expression mapping suggests that the behavior was sustained via the activation of the orbitofrontal cortex and dorsal striatum. PMID- 28634108 TI - Disturbances of novel object exploration and recognition in a chronic ketamine mouse model of schizophrenia. AB - Schizophrenia is a chronic and devastating disease with an overall lifetime risk of 1%. While positive symptoms of schizophrenia such as hallucinations and delusions are reduced by antipsychotic medication based on the inhibition of type 2 dopaminergic receptors (D2R), negative symptoms (e.g. reduced motivation) and cognitive symptoms (e.g. impaired working memory) of schizophrenia are not effectively treated by current medication. This dichotomy might arise in part because of our limited understanding of the pathophysiology of negative and cognitive symptoms in schizophrenia. In addition to genetic approaches, chronic systemic application of NMDA inhibitors such as ketamine have been used to generate rodent models, which displayed several relevant endophenotypes related to negative and cognitive symptoms and might thus facilitate mechanistic studies into the underlying pathophysiology. In this context, previous behavioral testing identified impairments in novel object recognition memory as a key feature in chronic NMDA-inhibitor schizophrenia rodent models. Using a chronic ketamine mouse model, we have however identified are more complex behavioral phenotype including deficits in novel space and novel object exploration in combination deficits in short-term novel object recognition memory. These impairments in novelty discrimination are in line with prefrontal and hippocampal reductions in parvalbumin-expression as well as reduced expression of the early immediate gene c-fos after novel-object exploration in hippocampal areas in our model. Our results indicate that adult C57Bl6N mice chronically treated with ketamine display combined impairments in novelty exploration and recognition, which might represent both motivational (negative) and cognitive symptoms of schizophrenia. PMID- 28634109 TI - Cannabis-associated psychosis: Neural substrate and clinical impact. AB - Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia-like psychoses. Early onset of use, daily use of high-potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk-increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta-9-tetrahydrocannabinol (THC), can produce transient, dose-dependent, psychotic symptoms, as well as an array of psychosis-relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled "A New Dawn in Cannabinoid Neurobiology". PMID- 28634111 TI - Levels of plasma selenium and urinary total arsenic interact to affect the risk for prostate cancer. AB - This study investigated whether plasma selenium levels modified the risk for prostate cancer (PC) related to arsenic exposure. We conducted a case-control study that included 318 PC patients and 318 age-matched, healthy control subjects. Urinary arsenic profiles were examined using HPLC-HG-AAS and plasma selenium levels were measured by ICP-MS. We found that plasma selenium levels displayed a significant dose-dependent inverse association with PC. The odds ratio (OR) and 95% confidence interval (CI) for PC was 0.07 (0.04-0.13) among participants with a plasma selenium level >28.06 MUg/dL vs. <=19.13 MUg/dL. A multivariate analysis showed that participants with a urinary total arsenic concentration >29.28 MUg/L had a significantly higher OR (1.75, 1.06-2.89) for PC than participants with <=29.89 MUg/L. The combined presence of a low plasma selenium level and a high urinary total arsenic concentration exponentially increased the OR for PC, and additively interacted with PSA at levels >=20 ng/mL. This is the first epidemiological study to examine the combined effects of plasma selenium and urinary total arsenic levels on the OR for PC. Our data suggest a low plasma selenium level coupled with a high urinary total arsenic concentration creates a significant risk for aggressive PC. PMID- 28634112 TI - Concentrations of environmental organic contaminants in meat and meat products and human dietary exposure: A review. AB - Meat and meat products is one of the most relevant food groups in an important number of human diets. Recently, the IARC, based on results of a number of epidemiological studies, classified the consumptions of red meat and processed meat as "probably carcinogenic to humans" and as "carcinogenic to humans", respectively. It was suggested that the substances responsible of the potential carcinogenicity would be mainly generated during meat processing, such as curing and smoking, or when meat is heated at high temperatures. However, the exposure to environmental pollutants through meat consumption was not discussed. The purpose of the present paper was to review recent studies reporting the concentrations of PCDD/Fs, DL-PCBs and PAHs in meat and meat products, as well as the human exposure to these pollutants through the diet. It is concluded that the health risks derived from exposure to carcinogenic environmental contaminants must be considered in the context of each specific diet, which besides meat and meat products, includes other foodstuffs containing also chemical pollutants, some of them with carcinogenic potential. Anyhow, meat and meat products are not the main food group responsible of the dietary exposure to carcinogenic (or probably carcinogenic) environmental organic pollutants. PMID- 28634110 TI - Restoration of CFTR Activity in Ducts Rescues Acinar Cell Function and Reduces Inflammation in Pancreatic and Salivary Glands of Mice. AB - BACKGROUND & AIMS: Sjogren's syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjogren's syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl- channel essential for ductal fluid and HCO3- secretion. We used these models to ask the following questions: is CFTR expression altered in these diseases, does correction of CFTR correct gland function, and most notably, does correcting ductal function correct acinar function? METHODS: We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini. RESULTS: In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca2+ signaling, Orai1, inositol triphosphate receptors, Aquaporin 5 expression, and fluid secretion were restored by rescuing ductal CFTR. CONCLUSIONS: Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjogren's syndrome and pancreatitis. PMID- 28634113 TI - Vitamin D3 supplementation attenuates the early stage of mouse hepatocarcinogenesis promoted by hexachlorobenzene fungicide. AB - Hexachlorobezene (HCB), a fungicide widely distributed in the environment, promotes the development of hepatocellular preneoplastic lesions (PNL) and tumors in rodents. In contrast, vitamin D3 (VD3) supplementation presents a potential role for the prevention/treatment of chronic liver diseases. Thus, we investigated whether VD3 supplementation attenuates the early stage of HCB promoted hepatocarcinogenesis. Female Balb/C mice were injected a single dose of diethylnitrosamine (DEN, 50 mg/kg) at postnatal day 15. From day 40 onwards, mice were fed with a standard diet containing 0.02% HCB alone or supplemented with VD3 (10,000 or 20,000 IU/Kg diet) for 20 weeks. Untreated mice were fed just standard diet. After this period, mice were euthanized and liver and serum samples were collected. Compared to the untreated group, DEN/HCB treatment decreased total hepatic glutathione levels and glutathione peroxidase (GSH-Px) activity while increased lipid peroxidation, p65 protein expression, cell proliferation/apoptosis and the PNL development. In contrast, dietary VD3 supplementation enhanced vitamin D receptor (VDR) protein expression, total glutathione levels and GSH-Px activity while diminished lipid hydroperoxide levels. Also, VD3 supplementation decreased p65 protein expression, hepatocyte proliferation, the size and the liver area occupied by PNL. Therefore, our findings indicate that VD3 supplementation attenuates the early stage of HCB promoted hepatocarcinogenesis. PMID- 28634114 TI - Peanut digestome: Identification of digestion resistant IgE binding peptides. AB - Stability to proteolytic degradation in the digestive tract is considered a general feature shared by most food allergens. Current digestibility models exclusively utilize purified allergen proteins, neglecting the relevant effects of matrix that occur for foodstuff systems. In the present study, we investigated digestion stability of the major peanut allergens directly in the natural matrix using an in vitro static model that simulates the gastrointestinal digestion including the oral, gastric, duodenal and intestinal (brush border membrane enzymes) phases. Immunogenicity was evaluated by Western Blot using N=8 pooled sera of peanut allergic pediatric subjects. Immunoreactive, large-sized and fragments of Ara h 2, Ara h 6 and Ara h 3 survived hydrolysis as assessed by SDS PAGE. Smaller resistant peptides mainly arising from Ara h 3 and also Ara h 1 were detected and further identified by LC-high resolution-MS/MS. RP-HPLC purification followed by dot-blot analysis and MS/MS-based identification demonstrated that stable IgE-binding peptides derived from Ara h 3. These results provide a more realistic picture of the potentially allergenic determinants of peanuts that survived the human digestion, taking into account the role of the food matrix, which may significantly affect gastrointestinal breakdown of peanut allergens. PMID- 28634115 TI - Delineating the roles of cellular and innate antiviral immune parameters mediating ranavirus susceptibility using rainbow trout cell lines. AB - Frog virus 3 is the type species of the Ranavirus genus and the causative agent of massive mortalities of aquatic species worldwide. A critical step in limiting virus replication, particularly early in infection, is the innate immune response. Presently, little is known regarding what innate immune strategies limit FV3 at the cellular level. To this end, the present study uses two rainbow trout cell lines, RTG-2 and RTgutGC, which demonstrate susceptible and relatively resistant phenotypes to FV3 infection, to elucidate susceptibility factors to FV3. RTG-2 demonstrated a lower LD50 and significantly higher virus transcript production compared to RTgutGC. The mode of cell death appeared to be apoptosis for both cell lines; however, RTG-2 did not demonstrate fragmented nuclei typical of apoptosis in cell culture. Next, the source of RTG-2's enhanced susceptibility was pursued, in hopes of highlighting unique features of this virus-host interaction that would predispose a cell to susceptibility. The type I interferon (IFN) response is the keystone mechanism used by the innate immune system to limit virus replication. FV3 induced very low to no levels of IFNs and interferon stimulated genes (ISGs) in either cell line, nor did inducing IFNs prior to infection inhibit virus-induced cell death. A dsRNA-induced antiviral state did reduce virus replication however. UV-inactivated FV3 was also able to kill RTG-2; thus, susceptibility to FV3-induced cell death observed in RTG-2 was independent of virus replication or the cell's ability, or lack thereof, to produce an IFN response. Importantly, RTG-2 showed greater viral entry compared to RTgutGC, suggesting non-innate immune factors, such as surface receptor expression or endocytic mechanism rates, may be key contributors to FV3 susceptibility. These findings contribute to our understanding of cell-level susceptibility to this environmentally important aquatic animal pathogen. PMID- 28634116 TI - Succinate-induced neuronal mitochondrial fission and hexokinase II malfunction in ischemic stroke: Therapeutical effects of kaempferol. AB - Mitochondrial dysfunction is known as one of causative factors in ischemic stroke, leading to neuronal cell death. The present work was undertaken to investigate whether succinate induces neuron apoptosis by regulating mitochondrial morphology and function. In neurons, oxygen-glucose deprivation induced succinate accumulation due to the reversal of succinate dehydrogenase (SDH) activation, leading to mitochondrial fission. Kaempferol inhibited mitochondrial fission and maintained mitochondrial HK-II through activation of Akt, and thereby protected neurons from succinate-mediated ischemi injury. Knockdown of Akt2 with siRNA diminished the effect of kaempferol, indicating that kaempferol suppressed dynamin-related protein 1 (Drp1) activation and promoted HK II mitochondrial binding dependently on Akt. Moreover, we demonstrated that kaempferol potentiated autophagy during oxygen and glucose deprivation, contributing to protecting neuron survival against succinate insult. In vivo, oral administration of kaempferol in mice attenuated the infract volume after ischemic and reperfusion (I/R) injury and reproduced the similar mitochondrial protective effect in the brain infract area. This study indicates that succinate accumulation plays a pivotal role in I/R injury-induced neuronal mitochondrial dysfunction, and suggests that modulation of Drp1 phosphorylation might be potential therapeutic strategy to protect neuron mitochondrial integrity and treat ischemic stroke. PMID- 28634117 TI - To assess the effects of parathyroidectomy (TPTX versus TPTX+AT) for Secondary Hyperparathyroidism in chronic renal failure: A Systematic Review and Meta Analysis. AB - BACKGROUND: Secondary Hyperparathyroidism (SHPT) requiring parathyroidectomy (PTX) occurs more commonly in patients with progressive chronic kidney disease and in those on long-term lithium therapy. Successful PTX often results in a dramatic drop of parathyroid hormone level, relieves the patient from clinical symptoms, and reduces mortality. However, there is an ongoing debate on the optimal surgical treatment of SHPT. Currently, no clinical guidelines or trials have definitely answered the question of whether Total Parathyroidectomy (TPTX) is superior or equal to Total Parathyroidectomy with Autotransplantation (TPTX + AT). OBJECTIVE: The aims of the study were to compare the efficacy of two different surgical procedures and to develop evidence-based practice guidelines for the treatment of SHPT. METHODS: Citations were identified in the Medline, Cochrane, EMBASE, and Chinese Biomedical Literature databases through November 2016. The Newcastle-Ottawa Scale (NOS) score was used to assess the methodological quality of the studies included. All data were analyzed using Review Manager 5.3. RESULTS: A total of nine cohort studies and one Randomized Controlled Trials (RCT), comprising 1283 patients, were identified. The NOS score of all the studies included was 5 or above. Compared with TPTX + AT, patients in the TPTX group had lower rates of "recurrence" (OR = 0.20; 95%CI, 0.11-0.38; P < 0.01), "recurrence or persistence" (OR = 0.18; 95%CI, 0.10-0.33; P < 0.01), "reoperation due to recurrence or persistence" (OR = 0.17; 95%CI, 0.06-0.54; P = 0.002), and shorter "operative time" (WMD = -17.30; 95%CI, -30.53 to -4.06; P < 0.05), except for a higher risk of "hypoparathyroidism" (OR = 2.97; 95%CI, 1.09 8.08; P = 0.01). However, none of the patients had developed permanent hypocalcemia or adynamic bone disease. No significant difference was found for "symptomatic improvement", "complications", "drug requirements", and "hospital stay" (P > 0.05). CONCLUSION: The findings indicate that TPTX is superior to TPTX + AT, while referring to the rate of recurrent SHPT. However, this conclusion needs to be tested in large-scale confirmatory trials. TPTX seems to be a feasible alternative therapeutic option for the surgical treatment of refractory SHPT. PMID- 28634118 TI - Identification of chickpea seed proteins resistant to simulated in vitro human digestion. AB - : Proteins and peptides able to resist gastrointestinal digestion and reach the intestinal mucosa have the potential to influence human health. Chickpea (Cicer arietinum L.) seed proteins are able to resist cooking (86.9% total protein) and/or in vitro simulated human digestion (15.9% total protein resists soaking, cooking and digestion with pepsin and pancreatin). To identify and characterize proteins resisting digestion we made use of different MS methodologies. The efficiency of several proteases (trypsin, AspN, chymotrypsin and LysC) was tested, and two technologies were employed (MALDI-MS/MS and LC-nESI-MS/MS). Digestion with trypsin and AspN were most successful for the identification of seed proteins. When analyzed by MALDI- MS/MS, trypsin allowed the identification of at least one protein in 60% of the polypeptide bands, while AspN allows the identification in 48%. The use of LC-nESI-MS/MS, allowed the identification of much more proteins/polypeptides from digested seeds (232 vs 17 using trypsin). The majority of the proteins found to be able to resist simulated digestion were members of the 7S vicilin and 11S legumin seed storage protein classes, which are reported to contain bio-active functions. In addition, we have found proteins that had not yet been described as potentially able to cause an impact on human health. SIGNIFICANCE: This is the first proteomic study to analyze the effect of processing and simulated human gastrointestinal digestion on the proteome of chickpea seed. Chickpea is reported to have anti-nutritional effects as well as nutraceutical properties, so the identification and characterization of the proteins able to resist digestion is crucial to understand the targets underlying such properties. PMID- 28634119 TI - An ultrasensitive stain for negative protein detection in SDS-PAGE via 4',5' Dibromofluorescein. AB - A highly sensitive method for brief and economical staining of proteins in 1-D and 2-D sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) by 4',5'-Dibromofluorescein (DBF) was developed in this study. Down to 0.025-0.05ng protein could be detected within 10min (only 2 steps) by DBF stain, which is approximately 10-fold more sensitive than those of Eosin Y (EY) and SYPRO Ruby stains, and 20-fold more sensitive than that of imidazole-zinc (IZ) negative stain. In addition, the LC-MS/MS results indicated that the newly developed staining method is compatible with the downstream protein identification. Moreover, the mechanism of DBF stain was investigated by molecular docking. PMID- 28634120 TI - Highly reproducible improved label-free quantitative analysis of cellular phosphoproteome by optimization of LC-MS/MS gradient and analytical column construction. AB - Expanding the sequencing depth of the peptides with a statistically significant quantitative change derived from a biological stimulation is critical. Here we demonstrate that optimization of LC gradient and analytical column construction can reveal over 30,000 unique peptides and 23,000 phosphopeptides at high confidence. The quantitative reproducibility of different analytical workflows was evaluated by comparing the phosphoproteome of CD3/4 stimulated and unstimulated T-cells as a model system. A fritless, 50cm-long column packed with 1.9MUm particles operated with a standard pressure HPLC significantly improved the sequencing depth 51% and decreased the selected ion chromatogram peak spreading. Most importantly, under the optimal workflow we observed an improvement of over 300% in detection of significantly changed phosphopeptides in the stimulated cells compared with the other workflows. The discovery power of the optimized column configuration was illustrated by identification of significantly altered phosphopeptides harboring novel sites from proteins previously established as important in T cell signaling including A-Raf, B-Raf, c Myc, CARMA1, Fyn, ITK, LAT, NFAT1/2/3, PKCalpha, PLCgamma1/2, RAF1, and SOS1. Taken together, our results reveal the analytical power of optimized chromatography using sub 2MUm particles for the analysis of the T cell phosphoproteome to reveal a vast landscape of significantly altered phosphorylation changes in response to T cell receptor stimulation. PMID- 28634121 TI - Population Pharmacokinetics of Tobramycin Inhalation Solution in Pediatric Patients With Cystic Fibrosis. AB - Tobramycin inhalation solution given as a twice daily inhalation of nebulized aerosols of 300 mg is approved for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis patients over 6 years of age. To investigate tobramycin pharmacokinetics (PK) after inhalation of tobramycin in pediatric cystic fibrosis patients below 7 years, a population PK approach was used to evaluate tobramycin PK data in patients 6 months to 44 years of age from 4 clinical studies. The final model used a 2-compartmental, first-order absorption model with effect of body mass index on the apparent central volume of distribution. Relative bioavailability in patients between 6 months and 7 years increased with age by a linear relationship, and was modeled as a ratio to that of patients over 7 years. Simulation showed that steady-state concentrations of tobramycin are lower in pediatric patients 6 months to 6 years than those in patients over 6 years. However, systemic exposure is not predictive of clinical efficacy due to direct dosing at the infection site. P aeruginosa eradication rate and safety profile in patients less than 7 years of age were similar to patients older than 6 years; therefore, no dose adjustment is warranted in the younger pediatric patients. PMID- 28634122 TI - Mapping the Binding Interface in a Noncovalent Size Variant of a Monoclonal Antibody Using Native Mass Spectrometry, Hydrogen-Deuterium Exchange Mass Spectrometry, and Computational Analysis. AB - Variants of monoclonal antibody containing an extra light chain have been reported in protein products. Due to potential impact on potency and immunogenicity, it is important to understand the formation mechanism of such variants so that appropriate control strategies can be implemented to assure product quality. In a model monoclonal antibody, we observed a size variant with an extra light chain noncovalently associated with the monomer (later named as "1.2mer"). The interaction between monomer and the extra light chain was characterized by native spray and hydrogen-deuterium exchange mass spectrometry techniques. The goal is to understand the nature of the noncovalent interaction, to map out the interaction interface and regions of potential conformational distortions. In addition, computational modeling was used to aid in binding site identification. The combined results identify the interaction interface to be located in the heavy chain region 38-57 and in the extra light chain region 30 50. To the best of our knowledge, this study is the first to characterize noncovalent interaction of a size variant comprising an antibody monomer and an extra light chain. Structural knowledge generated in this research work is invaluable for process development and construct design of antibody-based biopharmaceuticals. PMID- 28634124 TI - Cell disruption and lipid extraction for microalgal biorefineries: A review. AB - The microalgae-based biorefinement process has attracted much attention from academic and industrial researchers attracted to its biofuel, food and nutraceutical applications. In this paper, recent developments in cell-disruption and lipid-extraction methods, focusing on four biotechnologically important microalgal species (namely, Chlamydomonas, Haematococcus, Chlorella, and Nannochloropsis spp.), are reviewed. The structural diversity and rigidity of microalgal cell walls complicate the development of efficient downstream processing methods for cell-disruption and subsequent recovery of intracellular lipid and pigment components. Various mechanical, chemical and biological cell disruption methods are discussed in detail and compared based on microalgal species and status (wet/dried), scale, energy consumption, efficiency, solvent extraction, and synergistic combinations. The challenges and prospects of the downstream processes for the future development of eco-friendly and economical microalgal biorefineries also are outlined herein. PMID- 28634123 TI - Clinical Utility of Chromosomal Aneusomy in Individuals at High Risk of Lung Cancer. AB - INTRODUCTION: Low-dose computed tomography screening for lung cancer has a high false-positive rate with frequent discovery of indeterminate pulmonary nodules. Noninvasive biomarkers are needed to reduce false positives and improve risk stratification. A retrospective longitudinal evaluation was performed to assess chromosomal aneusomy in sputum by fluorescence in situ hybridization (CA-FISH) in four nested case-control studies. METHODS: Receiver operating characteristic analysis resulted in two grouped cohorts: a high-risk cohort (Colorado High-Risk Cohort and Colorado Nodule Cohort [68 case patients and 69 controls]) and a screening cohort (American College of Radiology Imaging Network/National Lung Screening Trial and Pittsburgh Lung Screening Study [97 case patients and 185 controls]). The CA-FISH assay was a four-target DNA panel encompassing the EGFR and v-myc avian myelocytomatosis viral oncogene homolog (MYC) genes, and the 5p15 and centromere 6 regions or the fibroblast growth factor 1 gene (FGFR1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA). A four-category scale (normal, probably normal, probably abnormal, and abnormal) was applied. Sensitivity, specificity, and positive and negative likelihood ratios (LRs) (with 95% confidence intervals [CIs]) were estimated for each cohort. RESULTS: Sensitivity and specificity were, respectively, 0.67 (95% CI: 0.55-0.78) and 0.94 (95% CI: 0.85-0.98) for high-risk participants and 0.20 (95% CI: 0.13-0.30) and 0.84 (95% CI: 0.78-0.89) for screening participants. The positive and negative LRs were, respectively, 11.66 (95% CI: 4.44-30.63) and 0.34 (95% CI: 0.24-0.48) for high-risk participants and 1.36 (95% CI: 0.81-2.28) and 0.93 (95% CI: 0.83-1.05) for screening participants. CONCLUSION: The high positive LR of sputum CA-FISH indicates that it could be a useful adjunct to low dose computed tomography for lung cancer in high-risk settings. For screening, however, its low positive LR limits clinical utility. Prospective assessment of CA-FISH in the incidentally identified indeterminate nodule setting is ongoing in the Colorado Pulmonary Nodule Biomarker Trial. PMID- 28634125 TI - Metabolic engineering of yeast for fermentative production of flavonoids. AB - Yeast Saccharomyces cerevisiae was engineered for de novo production of six different flavonoids (naringenin, liquiritigenin, kaempferol, resokaempferol, quercetin, and fisetin) directly from glucose, without supplementation of expensive intermediates. This required reconstruction of long biosynthetic pathways, comprising up to eight heterologous genes from plants. The obtained titers of kaempferol 26.57+/-2.66mgL-1 and quercetin 20.38+/-2.57mgL-1 exceed the previously reported titers in yeast. This is also the first report of de novo biosynthesis of resokaempferol and fisetin in yeast. The work demonstrates the potential of flavonoid-producing yeast cell factories. PMID- 28634126 TI - Biosorption of high-concentration Cu (II) by periphytic biofilms and the development of a fiber periphyton bioreactor (FPBR). AB - In this study, a kind of microbial aggregates: periphytic biofilms were used for Cu removal and immobilized onto fiber for developing a novel bioreactor. Results show that periphyton can effectively entrap Cu at initial concentrations of 2 20mgL-1 due to the overproduction of EPS and porous structure of periphyton, and biosorption was the primary mechanism of Cu removal. Cu (mainly Cu3(OH)42+, Cu2(OH)22+ and Cu2+) adsorption onto periphytic biofilms followed the pseudo second order kinetic model. The biosorption process fitted the Freundlich, Langmuir and Dubinin-Radushkevich Isotherm models well and was thermodynamically spontaneous. The fiber substrate used in the periphyton bioreactor greatly increased the Cation Exchange Capacity (CEC) of the system. This study indicates that immobilization of periphytic biofilms onto fiber for novel bioreactor development is a feasible way of entrapping high-concentration Cu from wastewater. PMID- 28634127 TI - Application of advanced techniques for the assessment of bio-stability of biowaste-derived residues: A minireview. AB - Bio-stability is a key feature for the utilization and final disposal of biowaste derived residues, such as aerobic compost or vermicompost of food waste, bio dried waste, anaerobic digestate or landfilled waste. The present paper reviews conventional methods and advanced techniques used for the assessment of bio stability. The conventional methods are reclassified into two categories. Advanced techniques, including spectroscopic (fluorescent, ultraviolet-visible, infrared, Raman, nuclear magnetic resonance), thermogravimetric and thermochemolysis analysis, are emphasized for their application in bio-stability assessment in recent years. Their principles, pros and cons are critically discussed. These advanced techniques are found to be convenient in sample preparation and to supply diversified information. However, the viability of these techniques as potential indicators for bio-stability assessment ultimately lies in the establishment of the relationship of advanced ones with the conventional methods, especially with the methods based on biotic response. Furthermore, some misuses in data explanation should be noted. PMID- 28634128 TI - Growth stimulation and synthesis of lipids, pigments and antioxidants with magnetic fields in Chlorella kessleri cultivations. AB - This study aimed at applying different intensities (30 and 60mT) and exposure times (24 and 1hd-1) of MF to cultures of Chlorella kessleri and evaluated their effects on cell growth, proximate composition of biomass, pigment production and antioxidant activity. The condition of 60mT for 1hd-1 stimulated biomass concentration of 83.2% by comparison with control culture (CC). Besides stimulated 13.7% lipid synthesis, 38.9% chlorophyll a and 59.1% chlorophyll b, 25.0% total carotenoids and antioxidants up to 185.7%. Thus MF application is an excellent alternative to stimulate cell growth and high biotechnological interest biocompounds. PMID- 28634129 TI - State of the art review of biofuels production from lignocellulose by thermophilic bacteria. AB - Biofuels, including ethanol and butanol, are mainly produced by mesophilic solventogenic yeasts and Clostridium species. However, these microorganisms cannot directly utilize lignocellulosic materials, which are abundant, renewable and non-compete with human demand. More recently, thermophilic bacteria show great potential for biofuels production, which could efficiently degrade lignocellulose through the cost effective consolidated bioprocessing. Especially, it could avoid contamination in the whole process owing to its relatively high fermentation temperature. However, wild types thermophiles generally produce low levels of biofuels, hindering their large scale production. This review comprehensively summarizes the state of the art development of biofuels production by reported thermophilic microorganisms, and also concludes strategies to improve biofuels production including the metabolic pathways construction, co culturing systems and biofuels tolerance. In addition, strategies to further improve butanol production are proposed. PMID- 28634130 TI - The inhibitory impacts of Lactobacillus rhamnosus GG-derived extracellular vesicles on the growth of hepatic cancer cells. AB - Bacterial extracellular vesicles (EVs) have come forth into notice as possible important agent to mediate host-pathogen interactions. In this scientific research, the authors have tried to find out the effect of EVs derived from Lactobacillus rhamnosus GG (LDEVs) on the apoptosis induction in HepG2 cell line. The EVs were purified from the conditioned medium of Lactobacillus rhamnosus GG using ultrafiltration and confirmed by transmission electron microscopy (TEM). The HepG2 cells were treated with different concentrations of purified LDEVs and the cytotoxicity and their effects on the expression of bcl-2 and bax genes were assessed by the MTT assay and semi-quantitative RT-PCR, respectively. The MTT assay showed that only 100 MUg/ml of LDEVs had a significant cytotoxic effect on cancer cells (p < 0.05). The apoptotic index (bax/bcl2 expression ratio) was significantly increased after treating with 50 and 100 MUg/ml LDEVs (p < 0.05). Increased bax/bcl-2 ratio was led to cancer cell death. PMID- 28634132 TI - Diagnosis of Autoimmune Pancreatitis: The Evolution of Diagnostic Criteria for a Rare Disease. PMID- 28634131 TI - Cost Effectiveness of Pre- vs Post-Liver Transplant Hepatitis C Treatment With Direct-Acting Antivirals. AB - BACKGROUND & AIMS: Oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV) treatment offer new hope to both pre- and post-liver transplant (LT) patients. However, whether to treat HCV patients before vs after LT is not clear because treatment can improve liver function but could reduce the chance of receiving an LT while on the waiting list. Our objective was to evaluate the cost effectiveness of pre-LT vs post-LT HCV treatment with oral DAAs in decompensated cirrhotic patients on the LT waiting list. METHODS: We used a validated mathematical model that simulated a virtual trial comparing long-term clinical and cost outcomes of pre-LT vs post-LT HCV treatment with oral DAAs. Model parameters were estimated from United Network for Organ Sharing data, SOLAR-1 and 2 trials, and published studies. For each strategy, we estimated the quality adjusted life-year, life expectancy, cost, and the incremental cost-effectiveness ratio. RESULTS: For lower MELD scores, quality-adjusted life-years were higher with pre-LT HCV treatment compared with post-LT treatment. Pre-LT HCV treatment was cost saving in patients with MELD scores of 15 or less, and cost effective in patients with MELD scores of 16 to 21. In contrast, post-LT HCV treatment was cost effective in patients with MELD scores of 22 to 29 and cost saving if MELD scores were 30 or higher. Results varied by drug prices and by United Network for Organ Sharing regions. CONCLUSIONS: For cirrhotic patients awaiting LT, pre-LT HCV treatment with DAAs is cost effective/saving in patients with MELD scores of 21 or lower, whereas post-LT HCV treatment is cost effective/saving in patients with MELD scores of 22 or higher. PMID- 28634133 TI - Acute Severe Gastrointestinal Tract Bleeding Is Associated With an Increased Risk of Thromboembolism and Death. AB - BACKGROUND & AIMS: We performed a retrospective cohort study of patients with and without gastrointestinal bleeding (GIB) to determine whether GIB increases the risks of thromboembolism and death. METHODS: We collected data from 522 patients with acute severe GIB and 1044 patients without GIB (control subjects, matched for age, sex, year of diagnosis, history of thromboembolism, and use of antithrombotic drugs) who underwent endoscopy at the National Center for Global Health and Medicine in Japan from January 2009 through December 2014. Hazard ratios of GIB for thromboembolism and mortality risk were estimated, adjusting for confounders. We also compared standardized mortality ratios between the GIB cohort and the age- and sex-matched general population in Japan. RESULTS: During a mean follow up of 23.7 months, thromboembolism was identified in 11.5% of patients with GIB and 2.4% of control subjects (hazard ratio, 5.3; 95% confidence interval, 3.3-8.5; P < .001). Multivariate analysis revealed GIB as a risk factor for all-thromboembolic events, cerebrovascular events, and cardiovascular events. During a mean follow-up of 24.6 months, 15.9% of patients with GIB and 8.6% of control subjects died (hazard ratio, 2.1; 95% confidence interval, 1.6-2.9; P < .001). Multivariate analysis revealed GIB as a risk factor for all-cause mortality. Compared with the general population, patients with GIB were at increased risk of death (standardized mortality ratio, 12.0). CONCLUSIONS: In a retrospective analysis of patients undergoing endoscopy in Japan, we identified acute GIB was a significant risk factor for late thromboembolism and death, compared with patients without GIB. GIB also increased risk of death compared with the general population. PMID- 28634134 TI - A Terminal Rectal Mass Ultimately Identified by Histopathology Examination. PMID- 28634135 TI - Outcomes and Role of Urgent Endoscopy in High-Risk Patients With Acute Nonvariceal Gastrointestinal Bleeding. AB - BACKGROUND & AIMS: We investigated clinical outcomes in high-risk patients with acute nonvariceal upper gastrointestinal bleeding (UGIB), and determined if urgent endoscopy is effective. METHODS: Consecutive patients with a Glasgow Blatchford score greater than 7 who underwent endoscopy for acute nonvariceal UGIB at the emergency department from January 1, 2005, to December 31, 2014, were included. Urgent (<6 h) and elective (6-48 h) endoscopies were defined according to the time to endoscopy after the initial presentation. The primary outcomes were mortality and rebleeding within 28 days of admission. RESULTS: Among 961 patients, 571 patients underwent urgent endoscopy. The 28-day mortality rate was 2.5%, and the rebleeding rate was 10.4%. There were significant differences in mortality rate (1.6% vs 3.8%), the number of transfused packed red blood cells (2.6 +/- 2.5 vs 2.3 +/- 2.1 packs), need for intervention (69.5% vs 53.5%), and embolization (2.8% vs 0.5%), but no differences in rebleeding, intensive care unit admission, vasopressor use, and length of stay between the urgent and elective endoscopy groups. Mortality was associated with malignancy (odds ratio [OR], 3.58; 95% confidence interval [CI], 1.33-9.62), cirrhosis (OR, 4.67; 95% CI, 1.85-11.76), urgent endoscopy (OR, 0.36; 95% CI, 0.14-0.95), failed primary endoscopic treatment (OR, 15.03; 95% CI, 4.63-48.82), and rebleeding (OR, 2.77; 95% CI, 1.03-7.45). Rebleeding was associated with Forrest I ulcers (OR, 7.67; 95% CI, 2.71-21.69), Forrest II ulcers (OR, 2.34; 95% CI, 1.51-3.60), and coagulopathy (OR, 2.34; 95% CI, 1.51-3.60). CONCLUSIONS: Urgent endoscopy was an independent predictor of lower mortality rate but was not associated with rebleeding in high-risk patients with acute nonvariceal UGIB. PMID- 28634137 TI - Comparison of Patterns and Outcomes of Liver Resection for Hepatocellular Carcinoma: East vs West. PMID- 28634136 TI - Tongxie Formula Reduces Symptoms of Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal disorder, yet few drugs are effective in reducing symptoms. Approximately 50% of patients with IBS attempt herbal therapy at least once. We performed a randomized controlled trial to compare the efficacy of the herb formulation tongxie vs placebo or pinaverium (an antispasmodic agent) in reducing symptoms of IBS. METHODS: We performed a trial of 1044 adult patients with IBS (based on Rome III criteria) at 5 hospitals in China, from August 2012 through January 2015. Subjects were randomly assigned (1:1:1) to groups given tongxie (a combination of A macrocephalae, P lactiflora, C reticulata, S divaricata, C pilosula, C wenyujin, C medica, and P cocos, along with other herbs, based on patient features), placebo, or pinaverium (50 mg tablets) 3 times daily for 4 weeks. Primary end points were significantly greater reductions in abdominal pain and Bristol stool score (before vs after the 4-week study period) in patients given tongxie compared with patients given placebo or pinaverium. Secondary end points were reductions in pain and stool frequencies and abdominal discomfort and its frequency. RESULTS: Subjects given tongxie had significant reductions, before vs after the study period, in all 6 symptoms assessed, compared to patients given placebo (P < .001). A significantly higher proportion of patients given tongxie had increased stool consistency (75.6%) than patients given pinaverium (50.6%), and a significantly higher proportion of patients given tongxie had fewer daily stools (72.7%) than subjects given pinaverium (58.3%) (P < .001 for both). However, significantly higher proportions of patients given pinaverium had reduced pain (63.5%) and pain frequency (69.5%) than patients given tongxie (51.4% and 58.6%, respectively; P < .005 for both). CONCLUSIONS: In a randomized controlled trial of patients with IBS in China, we found 4 weeks of tongxie to produce significantly greater reduction in symptoms than placebo, and greater increases in stool consistency and reductions in stool frequency, than patients given pinaverium. Tongxie can therefore be considered an effective alternative therapy for patients with IBS who do not respond well to conventional therapies. Clinicaltrials.gov no: NCT01641224. PMID- 28634138 TI - Intracellular and transdermal protein delivery mediated by non-covalent interactions with a synthetic guanidine-rich molecular carrier. AB - The impermeability of the cell plasma membrane is one of the major barriers for protein transduction into mammalian cells, and it also limits the use of proteins as therapeutic agents. Protein transduction has usually been achieved based on certain invasive processes or cell penetrating peptides (CPP). Herein we report our study in which a synthetic guanidine-rich molecular carrier is used as a delivery vector for intracellular and transdermal delivery of proteins. First a sorbitol-based molecular carrier having 8 guanidine units (Sor-G8) was synthesized, and then was simply mixed with a cargo protein of varying sizes to form the non-covalent complex of carrier-cargo proteins. These ionic complexes were shown to have efficient cellular uptake properties. The optimum conditions including the molar ratio between cargo protein and carrier, and the treatment time have been defined. Several protein cargoes were successfully examined with differing sizes and molecular weights: green fluorescent protein (MW 27kDa), albumin (66kDa), concanavalin A (102kDa), and immunoglobulin G (150kDa). These non-covalent complexes were also found to have excellent transdermal penetration ability into the mouse skin. The skin penetration depth was studied histologically by light microscopy as well as two-photon microscopy thus generating a depth profile. These complexes were largely found in the epidermis and dermis layers, i.e. down to ca. 100MUm depth of the mouse skin. Our synthetic Sor-G8 carrier was found to be substantially more efficient that Arg8 in both the intracellular transduction and the transdermal delivery of proteins. The mechanism of the cellular uptake of the complex was briefly studied, and the results suggested macropinocytosis. PMID- 28634139 TI - Ocular disposition of ciprofloxacin from topical, PEGylated nanostructured lipid carriers: Effect of molecular weight and density of poly (ethylene) glycol. AB - Ciprofloxacin (CIP) is an antibacterial agent prescribed for the treatment of ocular infections. The objective of the present project is to investigate the effect of surface PEG functionalization of the Nano structured lipid carriers (NLCs) on formulation stability, ocular penetration and distribution. CIP NLCs were tested with different molecular weight (poly ethylene glycol) PEGs ranging from (2K to 20K) grafted onto the phospholipid and with different chain lengths (14-18 carbons) of phospholipids derivatized with PEG-2K. Drug load in the formulations was maintained at 0.3%w/v. Formulations prepared were evaluated with respect to in vitro release, transcorneal permeation, autoclavability, morphological characteristics and in vivo ocular tissue distribution. Scanning Transmission electron microscopy (STEM) studies revealed that the PEG-CIP-NLCs were spherical in shape. Transcorneal penetration of CIP was optimum with PEG molecular weight in between 2K-10K. Carbon chain length of the phospholipid, however, did not affect transcorneal penetration of CIP. In vivo ocular tissue CIP concentrations attained from the various formulations was consistent with the in vitro data obtained. The results suggest that surface functionalization of PEGs, within a specified range of molecular weight and surface packing density, significantly enhance trans-ocular penetration and impart sterilization stabilization characteristics into the formulations. PMID- 28634140 TI - Novel nanoparticles based on chitosan-dicarboxylate conjugates via tandem ionotropic/covalent crosslinking with tripolyphosphate and subsequent evaluation as drug delivery vehicles. AB - Chitosan-based nanoparticles prepared by ionotropic gelation are prone to stability issues. The aim of this work is to chemically modify chitosan by grafting to succinate, phthalate, glutarate and phenylsuccinate moieties and to investigate the suitability of the resulting polymers as covalently-crosslinked nanocarriers. Corresponding nanoparticles (NPs) were formulated by ionotropic gelation using tripolyphosphate (TPP) anion then they were covalently crosslinked using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). Infrared and thermal analysis confirmed the formation of phosphoramide bonds within the NPs indicating the involvement of TPP in covalent crosslinking. This is the first time to report phosphormide covalent crosslinking within nanoparticles matrices. The resulting NPs were found to resist drastic pH and calcium ion conditions. Size analysis indicated the NPs to be spherical and less than 500nm in diameter. Loading studies using Safranine O showed enhanced NPs drug loading upon covalent crosslinking compared to ionotropic gelling. Doxorubicin-loaded NPs were of superior cytotoxic properties compared to free doxorubicin. PMID- 28634141 TI - One step preparation of spherical drug particles by contamination-free dry milling technique with corn starch beads. AB - The novel dry milling technique has been developed by using a mechanical powder processor for improving the dissolution properties of poorly water-soluble drugs. It was found that the drug crystals were well pulverized by co-processing with fine particles of corn starch (CS). The morphological observation and particle size evaluation revealed that the processed products formed the composite particles with ordered-mixed structure, having double-layered particles with a core of CS and a coating layer of phenytoin (Phe), as a model drug. This result suggested that the drug crystals were selectively micronized and the resultant miniaturized Phe particles were adhered/fixed on the surface of un-milled CS particles. The mechanical characteristics detected by the indentation test assumed that the brittle Phe crystals sandwiched between elastic CS particles would be successfully crushed down by high shearing stress in the processor. The newly-established dispersion-sedimentation test indicated that the fine Phe particles were immediately detached from the composite particles in aqueous phase, constructing the suspension. The dissolution behavior from the processed particles was found to be improved and strongly dependent on the size and amount of detached Phe particles. Such milling and ordered-mixturization have been also successfully done by using recrystallized larger Phe particles than 100MUm. These results would propose the contamination-free dry milling technique without using hard milling balls or beads. The mechanism of the current milling and ordered mixing phenomena is also provided in this report. PMID- 28634143 TI - PCR-based verification of positive rapid diagnostic tests for intestinal protozoa infections with variable test band intensity. AB - Stool-based rapid diagnostic tests (RDTs) for pathogenic intestinal protozoa (e.g. Cryptosporidium spp. and Giardia intestinalis) allow for prompt diagnosis and treatment in resource-constrained settings. Such RDTs can improve individual patient management and facilitate population-based screening programmes in areas without microbiological laboratories for confirmatory testing. However, RDTs are difficult to interpret in case of 'trace' results with faint test band intensities and little is known about whether such ambiguous results might indicate 'true' infections. In a longitudinal study conducted in poor neighbourhoods of Port Elizabeth, South Africa, a total of 1428 stool samples from two cohorts of schoolchildren were examined on the spot for Cryptosporidium spp. and G. intestinalis using an RDT (Crypto/Giardia DuoStrip; Coris BioConcept). Overall, 121 samples were positive for G. intestinalis and the RDT suggested presence of cryptosporidiosis in 22 samples. After a storage period of 9-10 months in cohort 1 and 2-3 months in cohort 2, samples were subjected to multiplex PCR (BD MaxTM Enteric Parasite Panel, Becton Dickinson). Ninety-three percent (112/121) of RDT-positive samples for G. intestinalis were confirmed by PCR, with a correlation between RDT test band intensity and quantitative pathogen load present in the sample. For Cryptosporidium spp., all positive RDTs had faintly visible lines and these were negative on PCR. The performance of the BD MaxTM PCR was nearly identical in both cohorts, despite the prolonged storage at disrupted cold chain conditions in cohort 1. The Crypto/Giardia DuoStrip warrants further validation in communities with a high incidence of diarrhoea. PMID- 28634142 TI - Cysteamine polysaccharide hydrogels: Study of extended ocular delivery and biopermanence time by PET imaging. AB - Cystinosis is a rare autosomal recessive disorder in which cystine crystals accumulate within the lysosomes of various organs, including the cornea. Ocular treatment is based on the administration of cysteamine eye drops, requiring its instillation several times per day. We have introduced the cysteamine in two types of previously developed ocular hydrogels (ion sensitive hydrogel with the polymers gellan gum and kappa-carrageenan and another one composed of hyaluronic acid), aiming at increasing the ocular retention in order to extend the dosing interval. The biopermanence studies (direct measurements and PET/CT) show that these formulations present a high retention time on the ocular surface of rats. From the in vitro release study we determined that both hydrogels can control the release of cysteamine over time, showing a zero order kinetics during four hours. At the same time, these hydrogels could act as corneal absorption promoters, as they allow a higher permeation of cysteamine through bovine cornea compared to a solution. HET-CAM test and cytotoxicity assays show no irritation on the ocular surface. These results demonstrate that the developed formulations present a high potential as vehicles for the topical ocular administration of cysteamine. PMID- 28634144 TI - Development of a multiplex PCR assay for the detection and differentiation of Burkholderia pseudomallei, Burkholderia mallei, Burkholderia thailandensis, and Burkholderia cepacia complex. AB - Two species of Burkholderia pseudomallei complex (Bpc), B. pseudomallei and B. mallei, can cause severe life-threatening infections. Rapidly discerning individual species within the group and separating them from other opportunistic pathogens of the Burkholderia cepacia complex (Bcc) is essential to establish a correct diagnosis and for epidemiological surveillance. In this study, a multiplex PCR assay based on the detection of an individual set of chromosomal beta-lactamase genes for single-step identification and differentiation of B. pseudomallei, B. mallei, B. thailandensis, and Bcc was developed. Two pairs of primers specific to a distinct class of B metallo-beta-lactamase genes and a pair of primers specific to the oxacillin-hydrolyzing class D beta-lactamase gene were demonstrated to successfully discriminate species within Bpc and from Bcc. The assay sensitivity was 9561 genomic equivalents (GE) for B. pseudomallei, 7827 GE for B. mallei, 8749 GE for B. thailandensis and 6023 GE for B. cepacia. PMID- 28634145 TI - Taeniasis caused by Taenia saginata in Gianyar town and Taenia solium in Karangasem villages of Bali, Indonesia, 2011-2016: How to detect tapeworm carriers, anamnesis or microscopy? AB - From January 2011 until September 2016, screening of taeniasis carriers was carried out in a town in Gianyar District (Taenia saginata) and in villages which consisted of several Banjars (the smallest community units) on the eastern slope of Mt. Agung, Karangasem District (Taenia solium) in Bali, Indonesia. Fecal samples from all community members who chose to participate were examined microscopically for detection of taeniid eggs each person completedwith a questionnaire to determine if they had seen whitish, noodle-like proglottids (anamnesis) in their feces. Members with egg positive feces, and those with anamnesis, were treated with niclosamide (Yomesan(r), Bayer). A total of 39T. saginata tapeworm carriers were confirmed in Gianyar after deworming based on anamnesis (100%, 39/39). Only three of them (3/39, 7.7%) and 3/173 participants (1.7%) were identified by fecal microscopy. In contrast, 20T. solium carriers including one migrated to Gianyar were confirmed from 12 patients with eggs in their feces and from another 8 persons of 12 persons suspected to be infected due anamnesis only (8/12,66.7%) in Karangasem. The majority of carriers (12/20, 60.0%) identified by microscopy included 4 (33.3%) and 8 (66.7%) carriers confirmed microscopically with and without anamnesis, respectively. The prevalence rate was 12/1090 (1.10%) of participants. The results indicate that anamnesis is reliable for detection of T. saginata carriers, whereas it is not so reliable for detection of T. solium taeniasis (8/12, 66.7%) and that microscopy is more informative than anamnesis for T. solium. Eggs were detected more frequently in T. solium carriers (4/12, 33.3%) than in patients infected with T. saginata (3/39, 7.7%). T. solium carriers have so far been confirmed from nine of 13 Banjars examined in Karangasem. This study reveals that anamnesis is highly useful for screening of T. saginata carriers, whereas microscopy is a more valuable tool for detection of T. solium carriers. PMID- 28634146 TI - Sub-chronic oral toxicity of Cuminum cyminum L.'s essential oil in female Wistar rats. AB - The current study was performed to evaluate the toxicity of Cuminum cyminum L. (C. cyminum)'s essential oil after 23 days and 45 days of repeated oral administration in female Wistar rats. A total of 80 healthy female Wistar rats were randomly selected and divided into 4 groups. The rats were gavaged with C. cyminum's essential oil at dose levels of 0, 250, 500 and 1000 mg/kg/day. Clinical signs, body weight, hematology, serum biochemistry and organ histopathology were assessed once after 23 days and again after 45 days passed from the start of the intervention. Oral administration of C. cyminum's essential oil had no observed adverse effects on clinical signs, mortality, body weight, hematology, biochemistry and organ histology (liver, kidneys, spleen and lungs) in a sample of healthy female Wistar rats after 23 days and 45 days from the start of the study. However, an increase in serum levels of alanine transaminase (ALT) was found only at dose level of 1000 mg/kg/d C. cyminum's essential oil, after the 23-days interval. We conservatively defined the non-observed adverse effect level (NOAEL) for C. cyminum's essential oil as 500 mg/kg/d in female Wistar rats. The present study results should be treated with cautious in terms of the other organs' toxicity. PMID- 28634147 TI - CSAHi study-2: Validation of multi-electrode array systems (MEA60/2100) for prediction of drug-induced proarrhythmia using human iPS cell-derived cardiomyocytes: Assessment of reference compounds and comparison with non clinical studies and clinical information. AB - With the aim of reconsidering ICH S7B and E14 guidelines, a new in vitro assay system has been subjected to worldwide validation to establish a better prediction platform for potential drug-induced QT prolongation and the consequent TdP in clinical practice. In Japan, CSAHi HEART team has been working on hiPS-CMs in the MEA (hiPS-CMs/MEA) under a standardized protocol and found no inter facility or lot-to-lot variability for proarrhythmic risk assessment of 7 reference compounds. In this study, we evaluated the responses of hiPS-CMs/MEA to another 31 reference compounds associated with cardiac toxicities, and gene expression to further clarify the electrophysiological characteristics over the course of culture period. The hiPS-CMs/MEA assay accurately predicted reference compounds potential for arrhythmogenesis, and yielded results that showed better correlation with target concentrations of QTc prolongation or TdP in clinical setting than other current in vitro and in vivo assays. Gene expression analyses revealed consistent profiles in all samples within and among the testing facilities. This report would provide CiPA with informative guidance on the use of the hiPS-CMs/MEA assay, and promote the establishment of a new paradigm, beyond conventional in vitro and in vivo assays for cardiac safety assessment of new drugs. PMID- 28634148 TI - Iodine and freeze-drying enhanced high-resolution MicroCT imaging for reconstructing 3D intraneural topography of human peripheral nerve fascicles. AB - BACKGROUND: The precise annotation and accurate identification of the topography of fascicles to the end organs are prerequisites for studying human peripheral nerves. NEW METHOD: In this study, we present a feasible imaging method that acquires 3D high-resolution (HR) topography of peripheral nerve fascicles using an iodine and freeze-drying (IFD) micro-computed tomography (microCT) method to greatly increase the contrast of fascicle images. RESULTS: The enhanced microCT imaging method can facilitate the reconstruction of high-contrast HR fascicle images, fascicle segmentation and extraction, feature analysis, and the tracing of fascicle topography to end organs, which define fascicle functions. COMPARISON WITH EXISTING METHODS: The complex intraneural aggregation and distribution of fascicles is typically assessed using histological techniques or MR imaging to acquire coarse axial three-dimensional (3D) maps. However, the disadvantages of histological techniques (static, axial manual registration, and data instability) and MR imaging (low-resolution) limit these applications in reconstructing the topography of nerve fascicles. CONCLUSIONS: Thus, enhanced microCT is a new technique for acquiring 3D intraneural topography of the human peripheral nerve fascicles both to improve our understanding of neurobiological principles and to guide accurate repair in the clinic. Additionally, 3D microstructure data can be used as a biofabrication model, which in turn can be used to fabricate scaffolds to repair long nerve gaps. PMID- 28634149 TI - A non-invasive restraining system for awake mouse imaging. AB - BACKGROUND: Preclinical neuroimaging allows for the assessment of brain anatomy, connectivity and function in laboratory animals, such as mice and rats. Most of these studies are performed under anesthesia to avoid movement during the scanning sessions. METHOD: Due to the limitations associated with anesthetized imaging, recent efforts have been made to conduct rodent imaging studies in awake animals, habituated to the restraint systems used in these instances. As of now, only one such system is commercially available for mouse scanning (Animal Imaging Research, Boston, MA, USA) integrating the radiofrequency coil electronics with the restraining element, an approach which, although effective in reducing head motion during awake imaging, has some limitations. In the current report, we present a novel mouse restraining system that addresses some of these limitations. RESULTS/COMPARISON TO OTHER METHODS: The effectiveness of the restraining system was evaluated in terms of three-dimensional linear head movement across two consecutive functional MRI scans (total 20min) in 33 awake mice. Head movement was minimal, recorded in roughly 12% of the time-series. Respiration rate during the acclimation procedure dropped while the bolus count remained unchanged. Body movement during functional acquisitions did not have a significant effect on magnetic field (B0) homogeneity. CONCLUSION/NOVELTY: Compared to the commercially available system, the benefit of the current design is two-fold: 1) it is compatible with a range of commercially-available coils, and 2) it allows for the pairing of neuroimaging with other established techniques involving intracranial cannulation (i.e. microinfusion and optogenetics). PMID- 28634150 TI - Molecular phylogenetics and biogeography of the ambush bugs (Hemiptera: Reduviidae: Phymatinae). AB - The ambush bugs (Heteroptera: Reduviidae: Phymatinae) are a diverse clade of predators known for their cryptic hunting behavior and morphologically diverse raptorial forelegs. Despite their striking appearance, role as pollinator predators, and intriguing biogeographic distribution, phylogenetic relationships within Phymatinae are largely unknown and the evolutionary history of the subfamily has remained in the dark. We here utilize the most extensive molecular phylogeny of ambush bugs to date, generated from a 3328 base pair molecular dataset, to refine our understanding of phymatine relationships, estimate dates of divergence (BEAST 2), and uncover historical biogeographic patterns (S-DIVA and DEC). This taxon set (39 species of Phymatinae and six outgroups) allowed reevaluation of the proposed sister group of Phymatinae and tribal-level relationships within the group, and for the first time proposes species-level relationships within Phymata Latreille, the largest genus of ambush bugs (~109spp.). Available evidence suggests that Phymata originated in the Neotropical region, with subsequent dispersals to the Nearctic and Palearctic regions. This study provides a framework for future research investigating the evolutionary history of ambush bugs, as well as ecological and microevolutionary investigations. PMID- 28634151 TI - Speech and swallowing abnormalities in adults with POLG associated ataxia (POLG A). AB - BACKGROUND: Mutations in the nuclear-encoded mitochondrial DNA polymerase gamma (POLG) can result in a wide spectrum of neurological deficits. A common presentation is progressive ataxia (POLG-A) which includes impaired speech and swallowing. The nature, severity and impact of these deficits in POLG-A is not known. A comprehensive quantitative and qualitative characterization of dysarthria and dysphagia in this recurrent ataxia disorder will assist in diagnostics, provide insights into the underlying pathology, and establish the foundation for future therapy trials. METHODS: 14 consecutive patients with POLG (9 females, mean age=50.1y, SD=11.2) and 34 healthy controls were enrolled. Comprehensive assessments of motor speech and swallowing function, acoustic analysis of speech, videofluoroscopy and measures of quality of life were conducted. RESULTS: The speech profile of individuals with POLG-A was characterized by poor control of pitch and strain-strangled voice quality, reduced rate of speech and longer variable silences between words, and articulatory breakdown including imprecise consonants and vowel distortions. Swallowing deficits included slower initiation of the swallow reflex, poor control of bolus and late epiglottic closure. Speech and swallowing related quality of life was worse than healthy controls. CONCLUSIONS: The dysarthria and dysphagia profiles in POLG-A are largely symptomatic of impaired timing, indicating a mainly spinocerebellar deficit. Dysarthria and dysphagia contribute to a significant impairment in functional quality of life, and progress distinctly from other POLG-A dysfunctions like ataxia or cognitive impairment. Our assessments establish meaningful patient focused outcome measures that will be suitable for use in natural history studies and clinical trials. PMID- 28634152 TI - Ensuring Inclusion of Adolescent Key Populations at Higher Risk of HIV Exposure: Recommendations for Conducting Biological Behavioral Surveillance Surveys. AB - Ending acquired immune deficiency syndrome (AIDS) depends on greater efforts to reduce new human immunodeficiency virus (HIV) infections and prevent AIDS-related deaths among key populations at highest HIV risk, including males who have sex with males, sex workers, and people who inject drugs. Although adolescent key populations (AKP) are disproportionately affected by HIV, they have been largely ignored in HIV biological behavioral surveillance survey (BBSS) activities to date. This paper reviews current ethical and sampling challenges and provides suggestions to ensure AKP are included in surveillance activities, with the aim being to enhance evidence-informed, strategic, and targeted funding allocations and programs toward ending AIDS among AKP. HIV BBSS, conducted every few years worldwide among adult key populations, provide information on HIV and other infections' prevalence, HIV testing, risk behaviors, program coverage, and when at least three of these surveys are conducted, trend data with which to evaluate progress. We provide suggestions and recommendations on how to make the case to ethical review boards to involve AKP in surveillance while assuring that AKP are properly protected. We also describe two widely used probability sampling methods, time location sampling and respondent driven sampling, and offer considerations of feature modifications when sampling AKP. Effectively responding to AKP's HIV and sexual risks requires the inclusion of AKP in HIV BBSS activities. The implementation of strategies to overcome barriers to including AKP in HIV BBSS will result in more effective and targeted prevention and intervention programs directly suited to the needs of AKP. PMID- 28634153 TI - Beyond Basic Feedback in Mobile Brief Interventions: Designing SMS Message Content for Delivery to Young Adults During Risky Drinking Events. AB - BACKGROUND: Brief interventions can reduce alcohol consumption in young people through screening and delivery of personally relevant feedback. Recently, Web and mobile platforms have been harnessed to increase the reach of brief interventions. Existing literature on mobile-based alcohol brief interventions indicates mixed use of theory in developing interventions. There is no research available to guide the development of SMS text messaging (short message service, SMS) interventions delivered during risky drinking events. OBJECTIVE: The aim of this study was to develop and pilot an alcohol-related risk-reduction brief intervention delivered by SMS to Australian young adults during drinking events. This paper describes the development of intervention message content, with specific focus on the context of delivery during drinking events. METHODS: A sample of 42 young adults attended 4 workshops; these comprised focus-group style discussion on drinking habits and motivations, discussion of intervention design, analysis of existing alcohol media campaigns, and participant development of message content. Data were analyzed thematically. RESULTS: Participants described a focus on having fun and blocking out any incongruent negative influences during drinking episodes. For content to be acceptable, nonjudgmental and non authoritative language was deemed essential. A preference for short, actionable messages was observed, including suggestions for reminders around drinking water, organizing transport home, checking on friends, and plans the next day. Participants were excited about the potential for messages to be tailored to individuals, as previous alcohol-related campaigns were deemed too generic and often irrelevant. Normative-based messages were also perceived as largely irrelevant as participants felt that they understood the drinking-related norms of their immediate peers already. CONCLUSIONS: Findings from this study offer insights into young adults' drinking events and practical advice for designing alcohol-related brief interventions. During our formative development process, we demonstrated a neat correspondence between young people's preferences for alcohol harm reduction interventions and the theoretical principles of brief interventions, including acceptable topics and message style. PMID- 28634154 TI - Improving Consensus Scoring of Crowdsourced Data Using the Rasch Model: Development and Refinement of a Diagnostic Instrument. AB - BACKGROUND: Diabetic retinopathy (DR) is a leading cause of vision loss in working age individuals worldwide. While screening is effective and cost effective, it remains underutilized, and novel methods are needed to increase detection of DR. This clinical validation study compared diagnostic gradings of retinal fundus photographs provided by volunteers on the Amazon Mechanical Turk (AMT) crowdsourcing marketplace with expert-provided gold-standard grading and explored whether determination of the consensus of crowdsourced classifications could be improved beyond a simple majority vote (MV) using regression methods. OBJECTIVE: The aim of our study was to determine whether regression methods could be used to improve the consensus grading of data collected by crowdsourcing. METHODS: A total of 1200 retinal images of individuals with diabetes mellitus from the Messidor public dataset were posted to AMT. Eligible crowdsourcing workers had at least 500 previously approved tasks with an approval rating of 99% across their prior submitted work. A total of 10 workers were recruited to classify each image as normal or abnormal. If half or more workers judged the image to be abnormal, the MV consensus grade was recorded as abnormal. Rasch analysis was then used to calculate worker ability scores in a random 50% training set, which were then used as weights in a regression model in the remaining 50% test set to determine if a more accurate consensus could be devised. Outcomes of interest were the percent correctly classified images, sensitivity, specificity, and area under the receiver operating characteristic (AUROC) for the consensus grade as compared with the expert grading provided with the dataset. RESULTS: Using MV grading, the consensus was correct in 75.5% of images (906/1200), with 75.5% sensitivity, 75.5% specificity, and an AUROC of 0.75 (95% CI 0.73-0.78). A logistic regression model using Rasch-weighted individual scores generated an AUROC of 0.91 (95% CI 0.88-0.93) compared with 0.89 (95% CI 0.86-92) for a model using unweighted scores (chi-square P value<.001). Setting a diagnostic cut-point to optimize sensitivity at 90%, 77.5% (465/600) were graded correctly, with 90.3% sensitivity, 68.5% specificity, and an AUROC of 0.79 (95% CI 0.76-0.83). CONCLUSIONS: Crowdsourced interpretations of retinal images provide rapid and accurate results as compared with a gold standard grading. Creating a logistic regression model using Rasch analysis to weight crowdsourced classifications by worker ability improves accuracy of aggregated grades as compared with simple majority vote. PMID- 28634155 TI - Perceptions of HIV Seriousness, Risk, and Threat Among Online Samples of HIV Negative Men Who Have Sex With Men in Seven Countries. AB - BACKGROUND: Rates of new HIV infections continue to increase worldwide among men who have sex with men (MSM). Despite effective prevention strategies such as condoms and pre-exposure prophylaxis (PrEP), low usage of both methods in many parts of the world hinder prevention efforts. An individual's perceptions of the risk of acquiring HIV and the seriousness they afford to seroconversion are important drivers of behavioral risk-taking. Understanding the behavioral factors suppressing the uptake of HIV prevention services is a critical step in informing strategies to improve interventions to combat the ongoing HIV pandemic among MSM. OBJECTIVE: The study aimed to examine cross-national perceptions of HIV/AIDS seriousness, risk, and threat and the association between these perceptions and sociodemographic characteristics, relationships, and high-risk sexual behaviors among MSM. METHODS: Participants in Australia, Brazil, Canada, Thailand, South Africa, the United Kingdom, and the United States were recruited for a self administered survey via Facebook (N=1908). Respondents were asked to rate their perceived seriousness from 1 (not at all serious) to 5 (very serious) of contracting HIV, their perceived risk from 1 (no risk) to 10 (very high risk) of contracting HIV based on their current behavior, and their perception of the threat of HIV-measured as their confidence in being able to stay HIV-negative throughout their lifetimes-on a scale from 1 (will not have HIV by the end of his lifetime) to 5 (will have HIV by the end of his lifetime). Covariates included sociodemographic factors, sexual behavior, HIV testing, drug use, and relationship status. Three ordered logistic regression models, one for each outcome variable, were fit for each country. RESULTS: Contracting HIV was perceived as serious (mean=4.1-4.6), but perceptions of HIV risk (mean=2.7-3.8) and threat of HIV (mean=1.7-2.2) were relatively low across countries. Older age was associated with significantly lower perceived seriousness of acquiring HIV in five countries (Australia: odds ratio, OR 0.97, 95% CI 0.94-0.99; Brazil: OR 0.95, 95% CI 0.91-0.98; Canada: OR 0.96, 95% CI 0.93-0.98; South Africa: OR 0.96, 95% CI 0.94-0.98; United Kingdom: OR 0.95, 95% CI 0.92-0.98). Being in a male male sexual relationship was associated with significantly lower perceived risk of HIV in four countries (Australia: OR 0.47, 95% CI 0.30-0.75; Canada: OR: 0.54, 95% CI 0.35-0.86; United Kingdom: OR 0.38, 95% CI 0.24-0.60; United States: OR 0.5, 95% CI 0.31-0.82). Drug use in the previous year was associated with greater threat of contracting HIV in two countries (Canada: OR 1.81, 95% CI 1.13-2.91; United Kingdom: OR 1.7, 95% CI 1.06-2.74). CONCLUSIONS: Few measures of behavioral or sexual risk-taking were significantly associated with perceived HIV seriousness, risk, or threat across countries. Overall, low levels of reported risk were identified, and results illustrate important gaps in the understanding of risk among MSM across societies that could be addressed through culturally tailored prevention messaging. PMID- 28634156 TI - Classifying Chinese Questions Related to Health Care Posted by Consumers Via the Internet. AB - BACKGROUND: In question answering (QA) system development, question classification is crucial for identifying information needs and improving the accuracy of returned answers. Although the questions are domain-specific, they are asked by non-professionals, making the question classification task more challenging. OBJECTIVE: This study aimed to classify health care-related questions posted by the general public (Chinese speakers) on the Internet. METHODS: A topic-based classification schema for health-related questions was built by manually annotating randomly selected questions. The Kappa statistic was used to measure the interrater reliability of multiple annotation results. Using the above corpus, we developed a machine-learning method to automatically classify these questions into one of the following six classes: Condition Management, Healthy Lifestyle, Diagnosis, Health Provider Choice, Treatment, and Epidemiology. RESULTS: The consumer health question schema was developed with a four-hierarchical-level of specificity, comprising 48 quaternary categories and 35 annotation rules. The 2000 sample questions were coded with 2000 major codes and 607 minor codes. Using natural language processing techniques, we expressed the Chinese questions as a set of lexical, grammatical, and semantic features. Furthermore, the effective features were selected to improve the question classification performance. From the 6-category classification results, we achieved an average precision of 91.41%, recall of 89.62%, and F1 score of 90.24%. CONCLUSIONS: In this study, we developed an automatic method to classify questions related to Chinese health care posted by the general public. It enables Artificial Intelligence (AI) agents to understand Internet users' information needs on health care. PMID- 28634158 TI - Stem cell therapy for enhancement of bone consolidation in distraction osteogenesis: A contemporary review of experimental studies. AB - OBJECTIVES: Distraction osteogenesis (DO) mobilises bone regenerative potential and avoids the complications of other treatments such as bone graft. The major disadvantage of DO is the length of time required for bone consolidation. Mesenchymal stem cells (MSCs) have been used to promote bone formation with some good results. METHODS: We hereby review the published literature on the use of MSCs in promoting bone consolidation during DO. RESULTS: Studies differed in animal type (mice, rabbit, dog, sheep), bone type (femur, tibia, skull), DO protocols and cell transplantation methods. CONCLUSION: The majority of studies reported that the transplantation of MSCs enhanced bone consolidation or formation in DO. Many questions relating to animal model, DO protocol and cell transplantation regime remain to be further investigated. Clinical trials are needed to test and confirm these findings from animal studies.Cite this article: Y. Yang, S. Lin, B. Wang, W. Gu, G. Li. Stem cell therapy for enhancement of bone consolidation in distraction osteogenesis: A contemporary review of experimental studies. Bone Joint Res 2017;6:385-390. DOI: 10.1302/2046-3758.66.BJR-2017-0023. PMID- 28634159 TI - A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans. AB - Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hyper sensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signaling pathways. Hyper-sensitivity to IR also occurs when other genes mediating NMD are mutated. The hyper-sensitivity to bleomycin, a drug known to induce DSBs, further supports that NMD pathway mutants are defective in DSB repair. Hyper-sensitivity was not observed upon treatment with alkylating agents or UV irradiation. We show that SMG-1 mainly acts in mitotically dividing germ cells, and during late embryonic and larval development. Based on epistasis experiments, SMG-1 does not appear to act in any of the three major pathways known to mend DNA DSBs, namely homologous recombination (HR), nonhomologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ). We speculate that SMG-1 kinase activity could be activated following DNA damage to phosphorylate specific DNA repair proteins and/or that NMD inactivation may lead to aberrant mRNAs leading to synthesis of malfunctioning DNA repair proteins. PMID- 28634160 TI - High-Throughput Characterization of Cascade type I-E CRISPR Guide Efficacy Reveals Unexpected PAM Diversity and Target Sequence Preferences. AB - Interactions between Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) RNAs and CRISPR-associated (Cas) proteins form an RNA-guided adaptive immune system in prokaryotes. The adaptive immune system utilizes segments of the genetic material of invasive foreign elements in the CRISPR locus. The loci are transcribed and processed to produce small CRISPR RNAs (crRNAs), with degradation of invading genetic material directed by a combination of complementarity between RNA and DNA and in some cases recognition of adjacent motifs called PAMs (Protospacer Adjacent Motifs). Here we describe a general, high-throughput procedure to test the efficacy of thousands of targets, applying this to the Escherichia coli type I-E Cascade (CRISPR-associated complex for antiviral defense) system. These studies were followed with reciprocal experiments in which the consequence of CRISPR activity was survival in the presence of a lytic phage. From the combined analysis of the Cascade system, we found that (i) type I-E Cascade PAM recognition is more expansive than previously reported, with at least 22 distinct PAMs, with many of the noncanonical PAMs having CRISPR-interference abilities similar to the canonical PAMs; (ii) PAM positioning appears precise, with no evidence for tolerance to PAM slippage in interference; and (iii) while increased guanine-cytosine (GC) content in the spacer is associated with higher CRISPR-interference efficiency, high GC content (>62.5%) decreases CRISPR interference efficiency. Our findings provide a comprehensive functional profile of Cascade type I-E interference requirements and a method to assay spacer efficacy that can be applied to other CRISPR-Cas systems. PMID- 28634161 TI - Oncolytic adenovirus expressing bispecific antibody targets T-cell cytotoxicity in cancer biopsies. AB - Oncolytic viruses exploit the cancer cell phenotype to complete their lytic life cycle, releasing progeny virus to infect nearby cells and repeat the process. We modified the oncolytic group B adenovirus EnAdenotucirev (EnAd) to express a bispecific single-chain antibody, secreted from infected tumour cells into the microenvironment. This bispecific T-cell engager (BiTE) binds to EpCAM on target cells and cross-links them to CD3 on T cells, leading to clustering and activation of both CD4 and CD8 T cells. BiTE transcription can be controlled by the virus major late promoter, limiting expression to cancer cells that are permissive for virus replication. This approach can potentiate the cytotoxicity of EnAd, and we demonstrate using primary pleural effusions and peritoneal malignant ascites that infection of cancer cells with the BiTE-expressing EnAd leads to activation of endogenous T cells to kill endogenous tumour cells despite the immunosuppressive environment. In this way, we have armed EnAd to combine both direct oncolysis and T cell-mediated killing, yielding a potent therapeutic that should be readily transferred into the clinic. PMID- 28634162 TI - Linking the content to demographic reach of online advertising of electronic nicotine delivery systems. AB - INTRODUCTION: Recent studies have separately examined the content and demographic reach of the advertising of electronic nicotine delivery systems (ENDS). No study to our knowledge has linked the two in investigating whether racial/ethnic groups are differentially exposed to the comparative messages conveyed in online ENDS advertisements. METHODS: 932 unique ENDS advertisements (6311 total), which were posted on 3435 websites between December, 2009 and October, 2015, were categorized as either comparative or non-comparative with respect to the traditional cigarette. The race/ethnicity of website visitors was obtained from a proprietary source and used in constructing variables for racial/ethnic viewership. The variables for advertising content and website racial/ethnic viewership were then linked yielding a final sample of 551 unique ENDS advertisements (2498 total) on 1206 websites. A two-level hierarchical generalized linear model, used in estimating website racial/ethnic viewership as a predictor of comparative advertising, accounted for the nesting of advertisements (level 1) within 152 ENDS brands (level 2). RESULTS: In contrast to racial/ethnic minorities, a greater proportion of non-Hispanic whites visited websites with ENDS advertisements than the overall proportion of nonHispanic white U.S. Internet users. Yet, it was the advertisements on websites that appealed to Hispanics that had greater odds of comparing ENDS to traditional cigarettes. CONCLUSIONS: The lower exposure to ENDS advertising among racial/ethnic minorities versus non-Hispanic whites is consistent with survey data. Yet, the greater odds of comparative advertising of ENDS on websites that appeal to racial/ethnic minorities (ie, Hispanics) could impact the longterm health of minority smokers. IMPLICATIONS: This study's findings have important implications for the uptake of ENDS among minority smokers. If the comparative advertising yields greater interest and eventual use of ENDS, then minority smokers could either benefit from smoking cessation because they switch to ENDS, or adopt dual tobacco use. The fate of comparative advertising of ENDS versus the traditional cigarette will depend on the Food and Drug Administration enforcement of its deeming rules and the ensuing changes in the ENDS marketplace. PMID- 28634163 TI - Reducing tobacco-related harm: FDA's proposed product standard for smokeless tobacco. AB - This Special Communication discusses the Food and Drug Administration's (FDA's) proposed rule that would limit N-nitrosonornicotine (NNN) levels in smokeless tobacco products. It argues that finalising and implementing this first 'product standard' would mark a significant step forward in the FDA's efforts to reduce tobacco-related harms. PMID- 28634164 TI - Medical school entry requirements discriminate against poorer students. PMID- 28634166 TI - Development and Validation of the Pediatric Medical Complexity Algorithm (PMCA) Version 2.0. AB - BACKGROUND AND OBJECTIVES: The Pediatric Medical Complexity Algorithm (PMCA) was developed to stratify children by level of medical complexity. We sought to refine PMCA and evaluate its performance based on the duration of eligibility and completeness of Medicaid data. METHODS: PMCA version 1.0 was applied to a cohort of 299 children insured by Washington State Medicaid with >=1 Seattle Children's Hospital outpatient, emergency department, and/or inpatient encounter in 2012. Blinded assessment of the validation cohort's PMCA category was performed by using medical records. In-depth review of discrepant cases was performed and informed the development of PMCA version 2.0. The sensitivity and specificity of PMCA version 2.0 were assessed. RESULTS: Using Medicaid data, the sensitivity of PMCA version 2.0 was 74% for complex chronic disease (C-CD), 60% for noncomplex chronic disease (NC-CD), and 87% for those without chronic disease (CD). Specificity was 84% to 91% in Medicaid data for all 3 groups. Medicaid data were most complete for children that had primarily fee-for-service claims and were less complete for those with some managed care encounter data. PMCA version 2.0 performed optimally when children had a longer duration of coverage (25 to 36 months) with fee-for-service reimbursement, identifying children with C-CD with 85% sensitivity and 75% specificity, children with NC-CD with 55% sensitivity and 88% specificity, and children without CD with 100% sensitivity and 97% specificity. CONCLUSIONS: PMCA version 2.0 identifies children with C-CD with good sensitivity and very good specificity when applied to Medicaid data. Data quality is a critical consideration when using PMCA. PMID- 28634167 TI - Improved Toys to Identify Pediatric Complexity in the Administrative Data Sandbox. PMID- 28634169 TI - 60 seconds on . . . the Carlisle method. PMID- 28634168 TI - Contributions of Children With Multiple Chronic Conditions to Pediatric Hospitalizations in the United States: A Retrospective Cohort Analysis. AB - BACKGROUND: Children with multiple chronic conditions (CMCC) are increasingly using hospital care. We assessed how much of US pediatric inpatient care is used by CMCC and which chronic conditions are the key drivers of hospital use. METHODS: A retrospective analysis of all 2.3 million US acute-care hospital discharges in 2012 for children age 0 to 18 years in the Kids' Inpatient Database. The ~4.5 million US hospitalizations for pregnancy, childbirth, and newborn and neonatal care were not assessed. We adapted the Agency for Healthcare Research and Quality's Chronic Condition Indicators to classify hospitalizations for children with no, 1, or multiple chronic conditions, and to determine which specific chronic conditions of CMCC are associated with high hospital resource use. RESULTS: Of all pediatric acute-care hospitalizations, 34.3% were of children with no chronic conditions, 36.5% were of those with 1 condition, and 29.3% were of CMCC. Of the $23.6 billion in total hospital costs, 19.7%, 27.4%, and 53.9% were for children with 0, 1, and multiple conditions, respectively, and similar proportions were observed for hospital days. The three populations accounted for the most hospital days were as follows: children with no chronic condition (20.9%), children with a mental health condition and at least 1 additional chronic condition (20.2%), and children with a mental health condition without an additional chronic condition (13.3%). The most common mental health conditions were substance abuse disorders and depression. CONCLUSIONS: CMCC accounted for over one-fourth of acute-care hospitalizations and one-half of all hospital dollars for US pediatric care in 2012. Substantial CMCC hospital resource use involves children with mental health-related conditions. PMID- 28634170 TI - I am a better doctor for allowing myself to stop, reflect, and grieve. PMID- 28634172 TI - Identifying an Oxygenation Index Threshold for Increased Mortality in Acute Respiratory Failure. AB - BACKGROUND: The objective of this work was to examine current oxygenation index (OI) data and outcomes using electronic medical record data to identify a specific OI value associated with mortality. METHODS: This study was a retrospective electronic medical record data review from the pediatric ICU of Phoenix Children's Hospital, with data mining for variables to calculate OIs on subjects age 1 month to 20 y mechanically ventilated > 24 h, excluding those with known intracardiac shunts or cyanotic heart disease. Age, length of hospital stay, duration of mechanical ventilation, and outcomes were also assessed. The Wilcoxon signed-rank test was used to compare continuous variables, receiver operating characteristic analysis was used in determining discriminant ability, and logistic regression was conducted to determine the odds ratio (OR) for risk of death with increasing OI. RESULTS: OI was calculated on 65 subjects, of whom 6 died (9%). The median maximum OI was 10 for all subjects, 17 for non-survivors, and 8 for survivors (P = .14 via Wilcoxon rank-sum test). ORs indicated a 2.4 fold increase in the odds of death (P = .09, 95% CI 0.9-6.6) for each increasing point in maximum OI. Mean OI OR revealed a 1.9-fold increase in the odds of death (P = .25, 95% CI 0.6-5.9). Receiver operating characteristic analysis indicated a higher discriminate ability for maximum OI (area under the curve = 0.68) than mean OI (area under the curve = 0.58). OI cut-points for mortality were established. Mortality was unchanged until maximum OI > 17, for which mortality nearly tripled at a value of 18% versus 6-7% for range 0-17. CONCLUSIONS: Limitations exist in obtaining serial OI values from current electronic medical records. Serial assessment of OI values may allow creation of alert values for increased mortality risk. Consideration of escalation of therapies for respiratory failure, such as high-frequency ventilation, inhaled nitric oxide, or extracorporeal membrane oxygenation may be warranted at lower OIs than historically reported. PMID- 28634171 TI - Preoperative Functional Status Is Associated With Unplanned Intubations Following Thyroidectomies. AB - BACKGROUND: Unplanned postoperative intubation is an important event that may influence the outcome of thyroid- and parathyroidectomies. We performed a focused study on the association of preoperative functional status with unplanned intubation outcomes in these relatively common surgeries. METHODS: Utilizing data from the National Surgical Quality Improvement Program database from 2007 to 2013, a propensity score-matched retrospective cohort study was performed assessing this outcome in the functionally independent versus dependent groups. Kaplan-Meier survival analysis and a Cox proportional hazards model were performed to assess the difference. RESULTS: There were a total of 98,035 thyroid and parathyroidectomies identified from the National Surgical Quality Improvement Program from 2007 to 2013. After propensity score matching, there were 1,862 and 931 cases in the independent and dependent group, respectively. There were 11 versus 33 per 1,000 persons in the independent and dependent group, respectively, who experienced an unplanned intubation within 30 d following surgery (P < .001). The dependent group showed worse intubation-free survival over 30 d (P < .001). There were no differences in this outcome during postoperative days 0-1 (P = .17). Dependent functional status was statistically significantly associated with unplanned intubations up to 30 d postoperatively (hazard ratio 2.4, 95% CI 1.4-4.18, P = .002). CONCLUSIONS: Preoperative functional status is a good marker for identifying patients at risk for re intubation after thyroid- and parathyroidectomy. PMID- 28634173 TI - A Comparison of 2 Respiratory Devices for Sputum Clearance in Adults With Non Cystic Fibrosis Bronchiectasis. AB - BACKGROUND: Airway clearance techniques are a vital part of routine care for patients with bronchiectasis. There is no clear superior modality. The Flutter combines oscillations (6-20 Hz) and positive expiratory pressure; the Lung Flute combines positive expiratory pressure and low frequency acoustic waves (18-22 Hz), to augment clearance. This project aimed to compare these devices. METHODS: This was a randomized crossover study of adult subjects with stable non-cystic fibrosis bronchiectasis (expectorating > 25 mL/d). Subjects attended 2 separate out-patient visits, 1 week apart, and completed a supervised sputum clearance regime and Lickert scale (8 questions regarding subjects' perception of the experience using each device). Total sputum expectorated during supervised intervention (T1) and after 30 min from the end of T1 (T2) was recorded as wet sputum weight. Total wet sputum weight desiccated in a microwave (10 min at 300 watts), allowed measurement of total dry sputum weight. Data were compared using paired t test. RESULTS: We recruited 40 subjects with a mean +/- SD age of 63 +/- 16 y. Overall, there was no significant difference in wet sputum weight (Flutter, 5.78 +/- 6.47 g; Lung Flute, 5.75 +/- 0.22 g) and dry sputum weight (Flutter, 0.40 +/- 0.86 g; Lung Flute, 0.22 +/- 0.21 g). At T1, wet sputum weight was higher for the Flutter (5.10 +/- 6.26 g) compared with the Lung Flute (3.74 +/- 3.44 g) (P = .038). At T2, wet sputum weight was higher for the Lung Flute (2.02 +/- 3.01 g) compared with the Flutter (0.68 +/- 0.75 g) (P = .001). Subjects perceived the Flutter as being significantly better at clearing secretions (P = .01), easy to understand (P = .03), and simple to use (P = .01) compared with the Lung Flute. CONCLUSIONS: Both devices were well-tolerated and successfully augmented secretion clearance. Most subjects preferred the Flutter because of increased speed of secretion clearance, and greater ease of use. PMID- 28634174 TI - Prognostic Value of Uric Acid for Pulmonary Thromboembolism. AB - BACKGROUND: Pulmonary thromboembolism is a serious cardiovascular condition with considerable morbidity and mortality. Clinical studies have indicated that hyperuricemia is an independent risk factor for cardiovascular events. The aim of this study was to investigate possible value of the serum levels of uric acid (UA) in predicting 30-d pulmonary thromboembolism-related mortality. METHODS: Pulmonary thromboembolism was confirmed by computed tomography pulmonary angiography, demographic data, troponin, systolic pressure and pulse on admission, and simplified pulmonary embolism severity index assessment. UA levels were analyzed on admission. The primary end point was all-cause mortality during the first 30 d. RESULTS: A total of 337 acute pulmonary thromboembolism subjects, of whom 59% were females, were enrolled. The median (interquartile range) serum UA level was 5.35 (4.1-7.3) mg/dL. Serum UA levels of deceased subjects were higher than those of alive subjects during the study period (6.9 [4.6-10.0] mg/dL vs 5.2 [4.1-7.0] mg/dL, P = .038). In the receiver operating characteristic analysis, the area under the curve was 0.650 (CI 0.732-0.960) for UA levels for all-cause mortality. A level of serum UA >= 5 mg/dL showed 73% sensitivity and 88% negative predictive value for all-cause 30-d mortality. A weak correlation was determined between the UA levels and age (r = 0.25, P < .001) and any troponin (r = 0.267, P < .001). Serum UA level was an independent predictor of short-term mortality in pulmonary thromboembolism (odds ratio 1.2, P = .002). CONCLUSIONS: Serum UA levels may be a potential biomarker for predicting outcome in patients with acute pulmonary thromboembolism. PMID- 28634177 TI - Pneumococcal pulmonary valve endocarditis. AB - Pulmonary valve endocarditis is an rare type of infective endocarditis (IE). Streptococcus pneumoniae is a pathogen that is uncommonly associated with IE. A 50 year-old man was referred to us to an incidental echocardiographic finding of a pulmonary valve vegetation. He had a recent admission for drainage of a scrotal abscess from which streptococcus pneumoniae was isolated, complicated by hospital acquired pneumonia and pulmonary embolism. Analysis using Polymerase Chain Reaction of the surgically resected mass revealed signs of 16S rDNA consistent with Streptococcus pneumoniae infection. This is the first confirmed case of pneumococcal pulmonary valve IE presenting entirely asymptomatically in the absence of any known risk factors. PMID- 28634176 TI - Impact of Glycemic Variability on Chromatin Remodeling, Oxidative Stress, and Endothelial Dysfunction in Patients With Type 2 Diabetes and With Target HbA1c Levels. AB - Intensive glycemic control (IGC) targeting HbA1c fails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66Shc, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA1c >7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbA1c of <=7.0%. Brachial artery flow mediated dilation (FMD), urinary 8-isoprostaglandin F2alpha (8-isoPGF2alpha), and epigenetic regulation of p66Shc were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8 isoPGF2alpha, and p66Shc upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF2alpha, and p66Shc expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66Shc promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66Shc-related epigenetic changes. MAGE and AUCpp but not HbA1c were independently associated with the altered epigenetic profile on the p66Shc promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA1c levels. PMID- 28634175 TI - Inter-relations between 3-hydroxypropionate and propionate metabolism in rat liver: relevance to disorders of propionyl-CoA metabolism. AB - Propionate, 3-hydroxypropionate (3HP), methylcitrate, related compounds, and ammonium accumulate in body fluids of patients with disorders of propionyl-CoA metabolism, such as propionic acidemia. Although liver transplantation alleviates hyperammonemia, high concentrations of propionate, 3HP, and methylcitrate persist in body fluids. We hypothesized that conserved metabolic perturbations occurring in transplanted patients result from the simultaneous presence of propionate and 3HP in body fluids. We investigated the inter-relations of propionate and 3HP metabolism in perfused livers from normal rats using metabolomic and stable isotopic technologies. In the presence of propionate, 3HP, or both, we observed the following metabolic perturbations. First, the citric acid cycle (CAC) is overloaded but does not provide sufficient reducing equivalents to the respiratory chain to maintain the homeostasis of adenine nucleotides. Second, there is major CoA trapping in the propionyl-CoA pathway and a tripling of liver total CoA within 1 h. Third, liver proteolysis is stimulated. Fourth, propionate inhibits the conversion of 3HP to acetyl-CoA and its oxidation in the CAC. Fifth, some propionate and some 3HP are converted to nephrotoxic maleate by different processes. Our data have implications for the clinical management of propionic acidemia. They also emphasize the perturbations of the liver intermediary metabolism induced by supraphysiological, i.e., millimolar, concentrations of labeled propionate used to trace the intermediary metabolism, in particular, inhibition of CAC flux and major decreases in the [ATP]/[ADP] and [ATP]/[AMP] ratios. PMID- 28634178 TI - Ascorbate protects the diheme enzyme, MauG, against self-inflicted oxidative damage by an unusual antioxidant mechanism. AB - Ascorbate protects MauG from self-inactivation that occurs during the autoreduction of the reactive bis-FeIV state of its diheme cofactor. The mechanism of protection does not involve direct reaction with reactive oxygen species in solution. Instead, it binds to MauG and mitigates oxidative damage that occurs via internal transfer of electrons from amino acid residues within the protein to the high-valent hemes. The presence of ascorbate does not inhibit the natural catalytic reaction of MauG, which catalyzes oxidative post translational modifications of a substrate protein that binds to the surface of MauG and is oxidized by the high-valent hemes via long-range electron transfer. Ascorbate was also shown to prolong the activity of a P107V MauG variant that is more prone to inactivation. A previously unknown ascorbate peroxidase activity of MauG was characterized with a kcat of 0.24 s-1 and a Km of 2.2 uM for ascorbate. A putative binding site for ascorbate was inferred from inspection of the crystal structure of MauG and comparison with the structure of soybean ascorbate peroxidase with bound ascorbate. The ascorbate bound to MauG was shown to accelerate the rates of both electron transfers to the hemes and proton transfers to hemes which occur during the multistep autoreduction to the diferric state which is accompanied by oxidative damage. A structural basis for these effects is inferred from the putative ascorbate-binding site. This could be a previously unrecognized mechanism by which ascorbate mitigates oxidative damage to heme dependent enzymes and redox proteins in nature. PMID- 28634179 TI - Lessons from bacterial homolog of tubulin, FtsZ for microtubule dynamics. AB - FtsZ, a homolog of tubulin, is found in almost all bacteria and archaea where it has a primary role in cytokinesis. Evidence for structural homology between FtsZ and tubulin came from their crystal structures and identification of the GTP box. Tubulin and FtsZ constitute a distinct family of GTPases and show striking similarities in many of their polymerization properties. The differences between them, more so, the complexities of microtubule dynamic behavior in comparison to that of FtsZ, indicate that the evolution to tubulin is attributable to the incorporation of the complex functionalities in higher organisms. FtsZ and microtubules function as polymers in cell division but their roles differ in the division process. The structural and partial functional homology has made the study of their dynamic properties more interesting. In this review, we focus on the application of the information derived from studies on FtsZ dynamics to study microtubule dynamics and vice versa. The structural and functional aspects that led to the establishment of the homology between the two proteins are explained to emphasize the network of FtsZ and microtubule studies and how they are connected. PMID- 28634180 TI - A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors. AB - The genetics behind predisposition to small intestinal neuroendocrine tumors (SI NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs. PMID- 28634181 TI - Outcomes after observation stays among older adult Medicare beneficiaries in the USA: retrospective cohort study. AB - Objective To characterize rates and trends over time of emergency department treatment-and-discharge stays, repeat observation stays, inpatient stays, any hospital revisit, and death within 30 days of discharge from observation stays.Design Retrospective cohort study.Setting 4750 hospitals in the USA.Participants Nationally representative sample of Medicare fee for service beneficiaries aged 65 or over discharged after 363 037 index observation stays, 2 540 000 index emergency department treatment-and-discharge stays, and 2 667 525 index inpatient stays from 2006-11.Main outcome measures Rates of emergency department treatment-and-discharge stays, observation stays, inpatient stays, any hospital revisit, and death within 30 days of discharge from index observation stays. Rates were compared with corresponding outcomes within 30 days of discharge from both index emergency department treatment-and-discharge stays and index inpatient stays.Results Among 363 037 index observation stays resulting in discharge from 2006-11, 30 day rates of emergency department treatment-and discharge stays were 8.4%, repeat observation stays were 2.9%, inpatient stays were 11.2%, any hospital revisit was 20.1%, and death was 1.8%. Of all revisits, 49.7% were for inpatient stays. Revisit rates for emergency department treatment and-discharge stays, repeat observation stays, and any hospital revisit increased from 2006-11 (P<0.001 for trend), while 30 day rates of inpatient stays (P=0.054 for trend) and 30 day mortality (P=0.091 for trend) were both unchanged. Averaged over the study period, 30 day rates of any hospital revisit were similar after discharge from index emergency department treatment-and-discharge stays (19.9%) and index observation stays (20.1%), as was 30 day mortality (1.8% for both). Rates of any hospital revisit (21.8%) and death (5.2%) were highest after discharge from index inpatient stays.Conclusions Hospital revisits are common after discharge from observation stays, frequently result in inpatient hospitalizations, and have increased over time among Medicare beneficiaries. As revisit rates are similar after emergency department and observation stays, strategies shown to enhance emergency department transitional care may be reasonable starting points to improve post-observation outcomes. PMID- 28634183 TI - Syk inhibitors interfere with erythrocyte membrane modification during P falciparum growth and suppress parasite egress. AB - Band 3 (also known as the anion exchanger, SLCA1, AE1) constitutes the major attachment site of the spectrin-based cytoskeleton to the erythrocyte's lipid bilayer and thereby contributes critically to the stability of the red cell membrane. During the intraerythrocytic stage of Plasmodium falciparum's lifecycle, band 3 becomes tyrosine phosphorylated in response to oxidative stress, leading to a decrease in its affinity for the spectrin/actin cytoskeleton and causing global membrane destabilization. Because this membrane weakening is hypothesized to facilitate parasite egress and the consequent dissemination of released merozoites throughout the bloodstream, we decided to explore which tyrosine kinase inhibitors might block the kinase-induced membrane destabilization. We demonstrate here that multiple Syk kinase inhibitors both prevent parasite-induced band 3 tyrosine phosphorylation and inhibit parasite promoted membrane destabilization. We also show that the same Syk kinase inhibitors suppress merozoite egress near the end of the parasite's intraerythrocytic lifecycle. Because the entrapped merozoites die when prevented from escaping their host erythrocytes and because some Syk inhibitors have displayed long-term safety in human clinical trials, we suggest Syk kinase inhibitors constitute a promising class of antimalarial drugs that can suppress parasitemia by inhibiting a host target that cannot be mutated by the parasite to evolve drug resistance. PMID- 28634184 TI - Patients in Wales to take control of medical records. PMID- 28634182 TI - SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells. AB - Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal (SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS. PMID- 28634185 TI - Low-Dose Aspirin and Pancreatic Cancer Risk-Reply. PMID- 28634186 TI - Telomere Length and Pancreatic Cancer Risk-Letter. PMID- 28634187 TI - Telomere Length and Pancreatic Cancer Risk-Reply. PMID- 28634188 TI - Low-Dose Aspirin and Pancreatic Cancer Risk-Letter. PMID- 28634190 TI - A GP's experience of the Grenfell Tower fire. PMID- 28634189 TI - Reduced platelet count, but no major platelet function abnormalities, are associated with loss-of-function ATP-binding cassette-1 gene mutations. AB - Loss-of-function mutations of the the ATP-binding cassette-1 (ABCA1) gene are the cause of Tangier disease (TD) in homozygous subjects and familial HDL deficiency (FHD) in heterozygous subjects. These disorders are characterized by reduced plasma HDL-cholesterol (HDL-C) and altered efflux of cholesterol from cells. Previous studies in TD patients and ABCA1-/- murine models reported defects in platelet count, morphology, and function, but the issue is still controversial. We analyzed three subjects with low to very low HDL-C levels due to the loss-of function mutations of the ABCA1 gene. Two related patients with FHD were heterozygous carriers of two mutations on the same ABCA1 allele; one, with TD, was homozygous for a different mutation. Mild to moderate thrombocytopenia was observed in all the patients. No morphological platelet abnormalities were detected under optical or EM. History of moderate bleeding tendency was recorded only in one of the FHD patients. Only limited alterations in platelet aggregation and activation of the integrin alphaIIbbeta3 were observed in one FHD patient. While alpha-granule secretion (P-selectin), content, and secretion of platelet delta-granules (serotonin, ATP, and ADP) and thromboxane (TX) A2 synthesis were normal in all the patients, the expression of lysosomal CD63, in response to some agonists, was reduced in TD patients. In conclusion, three patients carrying ABCA1 genetic variants had low platelet count, with the lowest values observed in TD, not associated with major alterations in platelet morphology and response to agonists or bleeding. PMID- 28634191 TI - Cd36 knockout mice are protected against lithogenic diet-induced gallstones. AB - The scavenger receptor and multiligand transporter CD36 functions to promote cellular free fatty acid uptake and regulates aspects of both hepatic and intestinal cholesterol metabolism. However, the role of CD36 in regulating canalicular and biliary cholesterol transport and secretion is unknown. Here, we show that germline Cd36 knockout (KO) mice are protected against lithogenic diet (LD)-induced gallstones compared with congenic (C57BL6/J) controls. Cd36 KO mice crossed into congenic L-Fabp KO mice (DKO mice) demonstrated protection against LD-induced gallstones, reversing the susceptibility phenotype observed in L-Fabp KO mice. DKO mice demonstrated reduced biliary cholesterol secretion and a shift into more hydrophophilic bile acid species, without changes in either BA pool size or fecal excretion. In addition, we found that the mean and maximum force of gallbladder contraction was increased in germline Cd36 KO mice, and gallbladder lipid content was reduced compared with wild-type controls. Finally, whereas germline Cd36 KO mice were protected against LD-induced gallstones, neither liver nor intestine-specific Cd36 KO mice were protected. Taken together, our findings show that CD36 plays an important role in modifying gallstone susceptibility in mice, at least in part by altering biliary lipid composition, but also by promoting gallbladder contractility. PMID- 28634192 TI - A new enzyme-linked immunosorbent assay system for human serum hepatic triglyceride lipase. AB - There is no established method for measuring human hepatic triglyceride (TG) lipase (HTGL) concentration in serum. In this study, we developed new monoclonal Abs (MoAbs) (9A1 mouse MoAb and 141A1 rat MoAb) that react with HTGL both in serum and in postheparin plasma (PHP) and established a novel ELISA system for measuring serum HTGL and PHP-HTGL concentrations. To confirm the specificity of MoAbs, we performed immunoprecipitation-immunoblotting analysis. Both 9A1 mouse MoAb and 141A1 rat MoAb were able to immunoprecipitate not only recombinant HTGL and PHP-HTGL but also serum HTGL, demonstrating that HTGL exists in serum obtained without heparin injection. This method yielded intra- and interassay coefficients of variation of <6% and showed no cross-reactivity with LPL or endothelial lipase. In clinical analysis on 42 male subjects with coronary artery disease, there were strong positive correlations of serum HTGL concentration to PHP-HTGL concentration (r = 0.727, P < 0.01). Serum HTGL concentrations showed positive correlations to serum TGs (r = 0.314, P < 0.05) and alanine aminotransferase (r = 0.406, P < 0.01), and tendencies toward positive correlations to LDL cholesterol, small dense LDL, and gammaGTP. These results suggest that this new ELISA method for measuring serum HTGL is applicable in daily clinical practice. PMID- 28634193 TI - Design Improvements for Personal Protective Equipment Used in Ebola and Other Epidemic Outbreaks. PMID- 28634194 TI - ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death. AB - Innate sensing of influenza virus infection induces activation of programmed cell death pathways. We have recently identified Z-DNA-binding protein 1 (ZBP1) as an innate sensor of influenza A virus (IAV). ZBP1-mediated IAV sensing is critical for triggering programmed cell death in the infected lungs. Surprisingly, little is known about the mechanisms regulating ZBP1 activation to induce programmed cell death. Here, we report that the sensing of IAV RNA by retinoic acid inducible gene I (RIG-I) initiates ZBP1-mediated cell death via the RIG-I-MAVS IFN-beta signaling axis. IAV infection induces ubiquitination of ZBP1, suggesting potential regulation of ZBP1 function through posttranslational modifications. We further demonstrate that ZBP1 senses viral ribonucleoprotein (vRNP) complexes of IAV to trigger cell death. These findings collectively indicate that ZBP1 activation requires RIG-I signaling, ubiquitination, and vRNP sensing to trigger activation of programmed cell death pathways during IAV infection. The mechanism of ZBP1 activation described here may have broader implications in the context of virus-induced cell death. PMID- 28634195 TI - Setting Sights on Chlamydia Immunity's Central Paradigm: Can We Hit a Moving Target? PMID- 28634196 TI - Reply to Vicetti Miguel et al., "Setting Sights on Chlamydia Immunity's Central Paradigm: Can We Hit a Moving Target?" PMID- 28634198 TI - The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection. AB - BACKGROUND AND AIM: Chronic HCV infection is associated with several extrahepatic manifestations (EHMs). Data on the effect of sustained virological response (SVR) on the risk of EHMs are limited. METHODS: We conducted a retrospective cohort study using data of patients from the US Veterans Affairs HCV Clinical Case Registry who had a positive HCV RNA test (10/1999-08/2009). Patients receiving interferon-based antiviral therapy (AVT) were identified. SVR was defined as negative HCV RNA at least 12 weeks after end of AVT. Risks of eight incident EHMs were evaluated in Cox regression models. RESULTS: Of the 160 875 HCV-infected veterans, 31 143 (19.4%) received AVT, of whom 10 575 (33.9%) experienced SVR. EHM risk was reduced in the SVR group compared with untreated patients for mixed cryoglobulinaemia (adjusted HR (aHR)=0.61; 95% CI 0.39 to 0.94), glomerulonephritis (aHR=0.62; 95% CI 0.48 to 0.79), porphyria cutanea tarda (PCT) (aHR=0.41; 95% CI 0.20 to 0.83), non-Hodgkin's lymphoma (NHL) (aHR=0.64; 95% CI 0.43 to 0.95), diabetes (aHR=0.82; 95% CI 0.76 to 0.88) and stroke (aHR=0.84; 95% CI 0.74 to 0.94), but not for lichen planus (aHR=1.11; 95% CI 0.78 to 1.56) or coronary heart disease (aHR=1.12; 95% CI 0.81 to 1.56). Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, PCT and diabetes. Significant reductions in the magnitude of aHRs towards the null with increasing time to initiation of AVT after HCV diagnosis were observed for glomerulonephritis, NHL and stroke. CONCLUSIONS: Risks of several EHMs of HCV infection are reduced after AVT with SVR. However, early initiation of AVT may be required to reduce the risk of glomerulonephritis, NHL and stroke. PMID- 28634200 TI - Is it possible to use acupressure to reduce adverse effects related to radiotherapy? PMID- 28634199 TI - Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues. AB - OBJECTIVE: To elucidate the genetic architecture of gene expression in pancreatic tissues. DESIGN: We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison. RESULTS: We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis-eQTLs appeared to be specific for tumour-derived and normal derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p<=0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8*10-8) and tumour derived (p=8.3*10-5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the 'O' mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO 'O' mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. CONCLUSIONS: We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues. PMID- 28634201 TI - Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes. AB - Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry-based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALKDelta2-17). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRalpha phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRalpha expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res; 77(16); 4279-92. (c)2017 AACR. PMID- 28634205 TI - Macrophages don't take more than they can eat. AB - Innate immune signaling feeds forward to control the rate at which macrophages phagocytose bacteria. PMID- 28634202 TI - Hemoglobin A1c Variability Predicts Symptoms of Depression in Elderly Individuals With Type 2 Diabetes. AB - OBJECTIVE: This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) over years with subsequent depressive symptoms. RESEARCH DESIGN AND METHODS: Subjects (n = 837) were participants of the Israel Diabetes and Cognitive Decline (IDCD) study, which aimed to examine the relationship of characteristics of long-term type 2 diabetes with cognitive decline. All pertain to a diabetes registry established in 1998, which contains an average of 18 HbA1c measurements per subject. The results presented here are based on the IDCD baseline examination. Symptoms of depression were assessed using the 15-item version of the Geriatric Depression Scale (GDS). To quantify the association between variability in glycemic control (measured as the SD of HbA1c measurements [HbA1c-SD]) since 1998 with the number of depression symptoms at IDCD baseline, incidence rate ratios (IRRs) and corresponding 95% CIs were estimated via negative binomial regression modeling and used to account for the overdispersion in GDS scores. RESULTS: Subjects' ages averaged 72.74 years (SD 4.63 years), and the mean number of years in the diabetes registry was 8.7 (SD 2.64 years). The mean GDS score was 2.16 (SD 2.26); 10% of subjects had a GDS score >=6, the cutoff for clinically significant depression. Mean HbA1c significantly correlated with HbA1c-SD (r = 0.6625; P < 0.0001). The SD, but not the mean, of HbA1c measurements was significantly associated with the number of subsequent depressive symptoms. For each additional 1% increase in HbA1c-SD, the number of depressive symptoms increased by a factor of 1.31 (IRR = 1.31 [95% CI 1.03-1.67]; P = 0.03). CONCLUSIONS: Variability in glycemic control is associated with more depressive symptoms. PMID- 28634207 TI - Dazed and confused from infection. AB - TNF-alpha produced by circulating CX3CR1high monocytes causes the problems that infected individuals have with learning and remembering. PMID- 28634208 TI - Ligand- and voltage-gated Ca2+ channels differentially regulate the mode of vesicular neuropeptide release in mammalian sensory neurons. AB - Neuropeptides released from dorsal root ganglion (DRG) neurons play essential roles in the neurotransmission of sensory inputs, including those underlying nociception and pathological pain. Neuropeptides are released from intracellular vesicles through two modes: a partial release mode called "kiss-and-run" (KAR) and a full release mode called "full fusion-like" (FFL). Using total internal reflection fluorescence (TIRF) microscopy, we traced the release of pH-sensitive green fluorescent protein-tagged neuropeptide Y (pHluorin-NPY) from individual dense-core vesicles in the soma and axon of single DRG neurons after Ca2+ influx through either voltage-gated Ca2+ channels (VGCCs) or ligand-gated transient receptor potential vanilloid 1 (TRPV1) channels. We found that Ca2+ influx through VGCCs stimulated FFL and a greater single release of neuropeptides. In contrast, Ca2+ influx through TRPV1 channels stimulated KAR and a pulsed but prolonged release of neuropeptides that was partially mediated by Dynamin 1, which limits fusion pore expansion. Suppressing the Ca2+ gradient to an extent similar to that seen after TRPV1 activation abolished the VGCC preference for FFL. The findings suggest that by generating a steeper Ca2+ gradient, VGCCs promote a more robust fusion pore opening that facilitates FFL. Thus, KAR and FFL release modes are differentially regulated by the two principal types of Ca2+ permeable channels in DRG neurons. PMID- 28634211 TI - Grenfell Tower fire: why we cannot ignore the political determinants of health. PMID- 28634209 TI - Genetic evidence that beta-arrestins are dispensable for the initiation of beta2 adrenergic receptor signaling to ERK. AB - The beta2-adrenergic receptor (beta2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that beta-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of beta-arrestin 1 (beta arr1) and beta-arr2 in beta2AR internalization, trafficking, and signaling to ERK. We found that only beta-arr2 was essential for beta2AR internalization. Unexpectedly, beta-arr1 and beta-arr2 and receptor internalization were dispensable for ERK activation. Instead, beta2AR signaled through Galphas and Gbetagamma subunits through a pathway that involved the tyrosine kinase SRC, the adaptor protein SHC, the guanine nucleotide exchange factor SOS, the small GTPase RAS, and the kinases RAF and MEK, which led to ERK activation. These findings provide a molecular framework for beta2AR signaling through beta-arrestin independent pathways in key physiological functions and under pathological conditions. PMID- 28634210 TI - The glycosylation pathway is required for the secretion of Slit and for the maintenance of the Slit receptor Robo on axons. AB - Slit proteins act as repulsive axon guidance cues by activating receptors of the Roundabout (Robo) family. During early neurogenesis in Drosophila melanogaster, Slit prevents the growth cones of longitudinal tract neurons from inappropriately crossing the midline, thus restricting these cells to trajectories parallel to the midline. Slit is expressed in midline glial cells, and Robo is present in longitudinal axon tracts and growth cones. We showed that the enzyme Mummy (Mmy) controlled Slit-Robo signaling through mechanisms that affected both the ligand and the receptor. Mmy was required for the glycosylation of Slit, which was essential for Slit secretion. Mmy was also required for maintaining the abundance and spatial distribution of Robo through an indirect mechanism that was independent of Slit secretion. Moreover, secretion of Slit was required to maintain the fasciculation and position of longitudinal axon tracts, thus maintaining the hardwiring of the nervous system. Thus, Mmy is required for Slit secretion and for maintaining Robo abundance and distribution in the developing nervous system in Drosophila. PMID- 28634214 TI - Effects of microRNA-146a on the proliferation and apoptosis of human osteochondrocytes by targeting TRAF6 through the NF- kappaB signalling pathway. AB - MicroRNAs are important cellular mediators of mRNA degradation and translation repression, which in turn can have an impact on various processes and, if their function is perturbed, can cause disease. Here, we summarize the recent manuscript by Zhong et al. [(2017) Biosci. Rep. 37, BSR20160578], which explores microRNA-146a and how it may play an indirect yet vital role in the proliferation of osteoarthritis (OA) chondrocytes. The data presented by the authors could have important implications for future OA therapies. PMID- 28634212 TI - Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation. AB - Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct-ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the multidrug resistance gene 2-knockout (Mdr2-/-) mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2-/- mice exposed to darkness or melatonin treatment or in male patients with PSC and healthy controls. Mdr2-/- mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine N-acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells in vitro, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2-/- mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. MicroRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2-/- mice and patients with PSC compared with controls and decreased in Mdr2-/- mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2-/- ablates biliary proliferation, liver fibrosis, and angiogenesis. In vitro, overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.-Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation. PMID- 28634213 TI - Omega-3 fatty acids increase the unfolded protein response and improve amyloid beta phagocytosis by macrophages of patients with mild cognitive impairment. AB - Macrophages (Mphis) of patients with Alzheimer's disease and mild cognitive impairment (MCI) are defective in amyloid-beta1-42 (Abeta) phagocytosis and have low resistance to apoptosis by Abeta. Omega-3 fatty acids (omega-3s) in vitro and in vivo and the omega-3 mediator, resolvin D1, in vitro increase Abeta phagocytosis by Mphis of patients with MCI. We have investigated the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress by Mphis in a longitudinal study of fish-derived, omega-3-supplemented patients with MCI. Patients in the apolipoprotein E (ApoE)e3/e3 subgroup over time exhibited an increase of protein kinase RNA-like ER kinase (PERK) expression, Abeta phagocytosis, intermediate M1-M2 Mphi type, and a Mini-Mental State Examination (MMSE) rate of change of +1.8 points per year, whereas patients in the ApoEe3/e4 subgroup showed individually divergent results with an MMSE rate of change of 3.2 points per year. In vitro treatment of Mphis by fish-derived omega-3 emulsion increased Abeta phagocytosis, PERK expression, and UPR RNA signature, and decreased ER stress signature. Augmented genes in the UPR signature included chaperones, lectins, foldases, and N-linked glycosylation enzymes. In summary, fish-derived omega-3s increase cytoprotective genes and decrease proapoptotic genes, improve immune clearance of Abeta, and are associated with an improved MMSE rate of change in ApoEe3/e3 vs. ApoEe3/e4 patients.-Olivera-Perez, H. M., Lam, L., Dang, J., Jiang, W., Rodriguez, F., Rigali, E., Weitzman, S., Porter, V., Rubbi, L., Morselli, M., Pellegrini, M., Fiala, M. Omega-3 fatty acids increase the unfolded protein response and improve amyloid-beta phagocytosis by macrophages of patients with mild cognitive impairment. PMID- 28634215 TI - Vaccination with High-Affinity Epitopes Impairs Antitumor Efficacy by Increasing PD-1 Expression on CD8+ T Cells. AB - Antitumor vaccines encoding self-antigens generally have low immunogenicity in clinical trials. Several approaches are aimed at improving vaccine immunogenicity, including efforts to alter encoded epitopes. Immunization with epitopes altered for increased affinity for the major histocompatibility complex (MHC) or T-cell receptor (TCR) elicits greater numbers of CD8 T cells but inferior antitumor responses. Our previous results suggested that programmed death 1 (PD-1) and its ligand (PD-L1) increased on antigen-specific CD8 T cells and tumor cells, respectively, after high-affinity vaccination. In this report, we use two murine models to investigate whether the dose, MHC affinity, or TCR affinity of an epitope affected the antitumor response via the PD-1/PD-L1 axis. T cells activated with high-affinity epitopes resulted in prolonged APC:T-cell contact time that led to elevated, persistent PD-1 expression, and expression of other checkpoint molecules, in vitro and in vivo Immunization with high-affinity epitopes also decreased antitumor efficacy in the absence of PD-1 blockade. Thus, APC:T-cell contact time can be altered by epitope affinity and lead to therapeutically relevant changes in vaccine efficacy mediated by changes in PD-1 expression. These findings have implications for the use of agents targeting PD-1 expression or function whenever high-affinity CD8 T cells are elicited or supplied by means of vaccination or adoptive transfer. Cancer Immunol Res; 5(8); 630-41. (c)2017 AACR. PMID- 28634216 TI - Respecting patient choices: using the 'Go Wish' cards as a teaching tool. AB - BACKGROUND: Individuals have different values and priorities that can have an important impact on their medical management. Understanding this concept can help physicians provide medical care that is in line with the goals of their patients. Communicating this message effectively to students is challenging. OBJECTIVE: To report our experience with using Go Wish cards in the medical education setting. DESIGN: A thematic analysis of student reflection papers using grounded theory. SETTING/SUBJECTS: Second-year medical students participated in an activity using the Go Wish cards as part of a course module on palliative care. The activity aimed to encourage students to reflect on their own choices at the end of life and to highlight that different people have different priorities. RESULTS: Forty two students (42%) mentioned the Go Wish activity in their reflections on the module. They reported that the activity demonstrated the different priorities at the end of life, it illustrated the importance of providing personalised care, it promoted self-discovery, it transformed their view of death and dying, and it increased their appreciation of the importance of palliative care. CONCLUSION: Go Wish cards can be used to help illustrate the variability in priorities of patients. They can be used as an effective to teach medical students about the importance of considering patient preferences when illness progresses. PMID- 28634218 TI - High-Quality Statin Trials Support the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines After the HOPE-3 Trial (Heart Outcomes Prevention Evaluation-3): MESA (The Multiethnic Study of Atherosclerosis). PMID- 28634219 TI - Early Use of N-acetylcysteine With Nitrate Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST-Segment-Elevation Myocardial Infarction Reduces Myocardial Infarct Size (the NACIAM Trial [N-acetylcysteine in Acute Myocardial Infarction]). AB - BACKGROUND: Contemporary ST-segment-elevation myocardial infarction management involves primary percutaneous coronary intervention, with ongoing studies focusing on infarct size reduction using ancillary therapies. N-acetylcysteine (NAC) is an antioxidant with reactive oxygen species scavenging properties that also potentiates the effects of nitroglycerin and thus represents a potentially beneficial ancillary therapy in primary percutaneous coronary intervention. The NACIAM trial (N-acetylcysteine in Acute Myocardial Infarction) examined the effects of NAC on infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated the effects of intravenous high-dose NAC (29 g over 2 days) with background low-dose nitroglycerin (7.2 mg over 2 days) on early cardiac magnetic resonance imaging assessed infarct size. Secondary end points included cardiac magnetic resonance determined myocardial salvage and creatine kinase kinetics. RESULTS: Of 112 randomized patients with ST-segment-elevation myocardial infarction, 75 (37 in NAC group, 38 in placebo group) underwent early cardiac magnetic resonance imaging. Median duration of ischemia pretreatment was 2.4 hours. With background nitroglycerin infusion administered to all patients, those randomized to NAC exhibited an absolute 5.5% reduction in cardiac magnetic resonance-assessed infarct size relative to placebo (median, 11.0%; [interquartile range 4.1, 16.3] versus 16.5%; [interquartile range 10.7, 24.2]; P=0.02). Myocardial salvage was approximately doubled in the NAC group (60%; interquartile range, 37-79) compared with placebo (27%; interquartile range, 14-42; P<0.01) and median creatine kinase areas under the curve were 22 000 and 38 000 IU.h in the NAC and placebo groups, respectively (P=0.08). CONCLUSIONS: High-dose intravenous NAC administered with low-dose intravenous nitroglycerin is associated with reduced infarct size in patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention. A larger study is required to assess the impact of this therapy on clinical cardiac outcomes. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. URL: http://www.anzctr.org.au/. Unique identifier: 12610000280000. PMID- 28634221 TI - Public's distrust of medicines needs urgent action, says academy. PMID- 28634222 TI - The Role of Procalcitonin in Diagnosis of Sepsis and Antibiotic Stewardship: Opportunities and Challenges. PMID- 28634220 TI - Tidal changes on CT and progression of ARDS. AB - BACKGROUND: Uncertain prediction of outcome in acute respiratory distress syndrome (ARDS) impedes individual patient management and clinical trial design. OBJECTIVES: To develop a radiological metric of injurious inflation derived from matched inspiratory and expiratory CT scans, calibrate it in a model of experimental lung injury, and test it in patients with ARDS. METHODS: 73 anaesthetised rats (acid aspiration model) were ventilated (protective or non protective) for up to 4 hours to generate a spectrum of lung injury. CT was performed (inspiratory and expiratory) at baseline each hour, paired inspiratory and expiratory images were superimposed and voxels tracked in sequential scans. In nine patients with ARDS, paired inspiratory and expiratory CT scans from the first intensive care unit week were analysed. RESULTS: In experimental studies, regions of lung with unstable inflation (ie, partial or reversible airspace filling reflecting local strain) were the areas in which subsequent progression of injury was greatest in terms of progressive infiltrates (R=0.77) and impaired compliance (R=0.67, p<0.01). In patients with ARDS, a threshold fraction of tissue with unstable inflation was apparent: >28% in all patients who died and <=28% in all who survived, whereas segregation of survivors versus non-survivors was not possible based on oxygenation or lung mechanics. CONCLUSIONS: A single set of superimposed inspiratory-expiratory CT scans may predict progression of lung injury and outcome in ARDS; if these preliminary results are validated, this could facilitate clinical trial recruitment and individualised care. PMID- 28634217 TI - Incident Cardiovascular Disease Among Adults With Blood Pressure <140/90 mm Hg. AB - BACKGROUND: Data from before the 2000s indicate that the majority of incident cardiovascular disease (CVD) events occur among US adults with systolic and diastolic blood pressure (SBP/DBP) >=140/90 mm Hg. Over the past several decades, BP has declined and hypertension control has improved. METHODS: We estimated the percentage of incident CVD events that occur at SBP/DBP <140/90 mm Hg in a pooled analysis of 3 contemporary US cohorts: the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), the MESA (Multi-Ethnic Study of Atherosclerosis), and the JHS (Jackson Heart Study) (n=31 856; REGARDS=21 208; MESA=6779; JHS=3869). Baseline study visits were conducted in 2003 to 2007 for REGARDS, 2000 to 2002 for MESA, and 2000 to 2004 for JHS. BP was measured by trained staff using standardized methods. Antihypertensive medication use was self-reported. The primary outcome was incident CVD, defined by the first occurrence of fatal or nonfatal stroke, nonfatal myocardial infarction, fatal coronary heart disease, or heart failure. Events were adjudicated in each study. RESULTS: Over a mean follow-up of 7.7 years, 2584 participants had incident CVD events. Overall, 63.0% (95% confidence interval [CI], 54.9-71.1) of events occurred in participants with SBP/DBP <140/90 mm Hg; 58.4% (95% CI, 47.7-69.2) and 68.1% (95% CI, 60.1-76.0) among those taking and not taking antihypertensive medication, respectively. The majority of events occurred in participants with SBP/DBP <140/90 mm Hg among those <65 years of age (66.7%; 95% CI, 60.5-73.0) and >=65 years of age (60.3%; 95% CI, 51.0-69.5), women (61.4%; 95% CI, 49.9-72.9) and men (63.8%; 95% CI, 58.4-69.1), and for whites (68.7%; 95% CI, 66.1-71.3), blacks (59.0%; 95% CI, 49.5-68.6), Hispanics (52.7%; 95% CI, 45.1-60.4), and Chinese-Americans (58.5%; 95% CI, 45.2-71.8). Among participants taking antihypertensive medication with SBP/DBP <140/90 mm Hg, 76.6% (95% CI, 75.8-77.5) were eligible for statin treatment, but only 33.2% (95% CI, 32.1-34.3) were taking one, and 19.5% (95% CI, 18.5-20.5) met the SPRINT (Systolic Blood Pressure Intervention Trial) eligibility criteria and may benefit from a SBP target goal of 120 mm Hg. CONCLUSIONS: Although higher BP levels are associated with increased CVD risk, in the modern era, the majority of incident CVD events occur in US adults with SBP/DBP <140/90 mm Hg. While absolute risk and cost effectiveness should be considered, additional CVD risk-reduction measures for adults with SBP/DBP <140/90 mm Hg at high risk for CVD may be warranted. PMID- 28634223 TI - Refining Measurement of Hemoglobin A1c. PMID- 28634224 TI - IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors. AB - Burkitt lymphoma/leukemia cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC-positive Burkitt lymphoma cells accumulate a high number of potentially lethal DNA double-strand breaks (DSB) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR) mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with diminished HR activity and hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary Burkitt lymphoma xenografts. In conclusion, IGH/MYC-positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies.Implications: This study postulates that IGH/MYC-induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpgMol Cancer Res; 15(8); 967-72. (c)2017 AACR. PMID- 28634225 TI - Homeobox Transcription Factor NKX2-1 Promotes Cyclin D1 Transcription in Lung Adenocarcinomas. AB - The known oncogene cyclin D1 (CCND1) participates in progression of the cell cycle from G1 to S-phase. Expression of cyclin D1 is frequently promoted in multiple human cancers including non-small cell lung cancer (NSCLC). However, a relationship between cyclin D1 expression and the prognosis of NSCLC has not been confirmed. NKX2-1 is a homeobox transcription factor involved in pulmonary development as a differentiation-promoting factor. In NSCLC, it acts as a metastasis suppressor and correlates with a good prognosis. Here, NKX2-1-binding motifs were identified in the cyclin D1 promoter, but it has not been clarified whether NKX2-1 is involved in cyclin D1 expression in NSCLC. To shed light on this issue, endogenous NKX2-1 was depleted in NSCLC cell lines, which resulted in decreased cyclin D1 mRNA and protein. In contrast, forced overexpression of NKX2 1 increased cyclin D1 levels. Moreover, NKX2-1 directly bound to the cyclin D1 promoter and enhanced its activity. Finally, using human NSCLC clinical specimens, it was determined that both NKX2-1 protein and mRNA were significantly correlated with cyclin D1 expression status in adenocarcinomas. These results indicate that NKX2-1 directly and positively regulates transcription of cyclin D1 Finally, expression of NKX2-1, but not cyclin D1, was significantly associated with metastatic incidence as an independent good prognostic factor of adenocarcinoma.Implications: NKX2-1-expressing adenocarcinomas, whereas NKX2-1 promoted cyclin D1 expression, may show good prognosis features by the metastasis inhibition potency of NKX2-1 regardless cyclin D1 expression. Mol Cancer Res; 15(10); 1388-97. (c)2017 AACR. PMID- 28634227 TI - Evidence based medicine manifesto for better healthcare. PMID- 28634226 TI - Phostine PST3.1a Targets MGAT5 and Inhibits Glioblastoma-Initiating Cell Invasiveness and Proliferation. AB - Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3 hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2lambda5 [1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the beta1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFbetaR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial-mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. Mol Cancer Res; 15(10); 1376-87. (c)2017 AACR. PMID- 28634228 TI - Spatial Mapping and Profiling of Metabolite Distributions during Germination. AB - Germination is a highly complex process by which seeds begin to develop and establish themselves as viable organisms. In this study, we utilize a combination of gas chromatography-mass spectrometry, liquid chromatography-fluorescence, and mass spectrometry imaging approaches to profile and visualize the metabolic distributions of germinating seeds from two different inbreds of maize (Zea mays) seeds, B73 and Mo17. Gas chromatography and liquid chromatography analyses demonstrate that the two inbreds are highly differentiated in their metabolite profiles throughout the course of germination, especially with regard to amino acids, sugar alcohols, and small organic acids. Crude dissection of the seed followed by gas chromatography-mass spectrometry analysis of polar metabolites also revealed that many compounds were highly sequestered among the various seed tissue types. To further localize compounds, matrix-assisted laser desorption/ionization mass spectrometry imaging was utilized to visualize compounds in fine detail in their native environments over the course of germination. Most notably, the fatty acyl chain-dependent differential localization of phospholipids and triacylglycerols was observed within the embryo and radicle, showing correlation with the heterogeneous distribution of fatty acids. Other interesting observations include unusual localization of ceramides on the endosperm/scutellum boundary and subcellular localization of ferulate in the aleurone. PMID- 28634229 TI - Akt activation by Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in ovarian cancer cells. AB - Hyperactivation of Akt is associated with oncogenic changes in the growth, survival, and chemoresistance of cancer cells. The PI3K/phosphoinositide dependent kinase (PDK) 1 pathway represents the canonical mechanism for phosphorylation of Akt at its primary activation site, Thr-308. We observed that Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (beta) (CaMKK2) is highly expressed in high-grade serous ovarian cancer, and we investigated its role in Akt activation in ovarian cancer (OVCa) cell lines (OVCAR-3, SKOV-3, and Caov-3). Knockdown or pharmacological inhibition of CaMKK2 produced phenotypes expected of Akt inhibition, including reductions in cell growth and cell viability and in the regulation of Akt downstream targets involved in G1/S transition and apoptosis. CaMKK2 knockdown or inhibition decreased Akt phosphorylation at Thr-308 and Ser 473 to extents similar to those of PDK1 knockdown or PI3K inhibition. Combined CaMKK2 and PDK1 knockdown or CaMKK and PI3K inhibition, respectively, produced additive effects on p-Akt and cell growth, consistent with direct Akt phosphorylation by CaMKK2. This conclusion was supported by the absence of effects of CaMKK2 knockdown/inhibition on alternative means of activating Akt via p-Akt Thr-450, p-PDK1 Ser-241, or p-IRS1 Ser-636/639. Recombinant CaMKK2 directly activated recombinant Akt by phosphorylation at Thr-308 in a Ca2+/CaM-dependent manner. In OVCa cells, p-Akt Thr-308 was significantly inhibited by intracellular Ca2+i chelation or CaM inhibition. Ionomycin-induced Ca2+ influx promoted p-Akt, an effect blocked by PDK1, and/or CaMKK2, siRNAs, and by PI3K and/or CaMKK inhibitors. CaMKK2 knockdown potentiated the effects of the chemotherapeutic drugs carboplatin and PX-866 to reduce proliferation and survival of OVCa cells. PMID- 28634230 TI - Similarity in gene-regulatory networks suggests that cancer cells share characteristics of embryonic neural cells. AB - Cancer cells are immature cells resulting from cellular reprogramming by gene misregulation, and redifferentiation is expected to reduce malignancy. It is unclear, however, whether cancer cells can undergo terminal differentiation. Here, we show that inhibition of the epigenetic modification enzyme enhancer of zeste homolog 2 (EZH2), histone deacetylases 1 and 3 (HDAC1 and -3), lysine demethylase 1A (LSD1), or DNA methyltransferase 1 (DNMT1), which all promote cancer development and progression, leads to postmitotic neuron-like differentiation with loss of malignant features in distinct solid cancer cell lines. The regulatory effect of these enzymes in neuronal differentiation resided in their intrinsic activity in embryonic neural precursor/progenitor cells. We further found that a major part of pan-cancer-promoting genes and the signal transducers of the pan-cancer-promoting signaling pathways, including the epithelial-to-mesenchymal transition (EMT) mesenchymal marker genes, display neural specific expression during embryonic neurulation. In contrast, many tumor suppressor genes, including the EMT epithelial marker gene that encodes cadherin 1 (CDH1), exhibited non-neural or no expression. This correlation indicated that cancer cells and embryonic neural cells share a regulatory network, mediating both tumorigenesis and neural development. This observed similarity in regulatory mechanisms suggests that cancer cells might share characteristics of embryonic neural cells. PMID- 28634231 TI - Hyperactivity of the Arabidopsis cryptochrome (cry1) L407F mutant is caused by a structural alteration close to the cry1 ATP-binding site. AB - Plant cryptochromes (cry) act as UV-A/blue light receptors. The prototype, Arabidopsis thaliana cry1, regulates several light responses during the life cycle, including de-etiolation, and is also involved in regulating flowering time. The cry1 photocycle is initiated by light absorption by its FAD chromophore, which is most likely fully oxidized (FADox) in the dark state and photoreduced to the neutral flavin semiquinone (FADH degrees ) in its lit state. Cryptochromes lack the DNA-repair activity of the closely related DNA photolyases, but they retain the ability to bind nucleotides such as ATP. The previously characterized L407F mutant allele of Arabidopsis cry1 is biologically hyperactive and seems to mimic the ATP-bound state of cry1, but the reason for this phenotypic change is unclear. Here, we show that cry1L407F can still bind ATP, has less pronounced photoreduction and formation of FADH degrees than wild type cry1, and has a dark reversion rate 1.7 times lower than that of the wild type. The hyperactivity of cry1L407F is not related to a higher FADH degrees occupancy of the photoreceptor but is caused by a structural alteration close to the ATP-binding site. Moreover, we show that ATP binds to cry1 in both the dark and the lit states. This binding was not affected by cry1's C-terminal extension, which is important for signal transduction. Finally, we show that a recently discovered chemical inhibitor of cry1, 3-bromo-7-nitroindazole, competes for ATP binding and thereby diminishes FADH degrees formation, which demonstrates that both processes are important for cry1 function. PMID- 28634232 TI - The phosphocarrier protein HPr of the bacterial phosphotransferase system globally regulates energy metabolism by directly interacting with multiple enzymes in Escherichia coli. AB - The histidine-phosphorylatable phosphocarrier protein (HPr) is an essential component of the sugar-transporting phosphotransferase system (PTS) in many bacteria. Recent interactome findings suggested that HPr interacts with several carbohydrate-metabolizing enzymes, but whether HPr plays a regulatory role was unclear. Here, we provide evidence that HPr interacts with a large number of proteins in Escherichia coli We demonstrate HPr-dependent allosteric regulation of the activities of pyruvate kinase (PykF, but not PykA), phosphofructokinase (PfkB, but not PfkA), glucosamine-6-phosphate deaminase (NagB), and adenylate kinase (Adk). HPr is either phosphorylated on a histidyl residue (HPr-P) or non phosphorylated (HPr). PykF is activated only by non-phosphorylated HPr, which decreases the PykF Khalf for phosphoenolpyruvate by 10-fold (from 3.5 to 0.36 mm), thus influencing glycolysis. PfkB activation by HPr, but not by HPr-P, resulted from a decrease in the Khalf for fructose-6-P, which likely influences both gluconeogenesis and glycolysis. Moreover, NagB activation by HPr was important for the utilization of amino sugars, and allosteric inhibition of Adk activity by HPr-P, but not by HPr, allows HPr to regulate the cellular energy charge coordinately with glycolysis. These observations suggest that HPr serves as a directly interacting global regulator of carbon and energy metabolism and probably of other physiological processes in enteric bacteria. PMID- 28634233 TI - Structural analyses of human thymidylate synthase reveal a site that may control conformational switching between active and inactive states. AB - Thymidylate synthase (TS) is the sole enzyme responsible for de novo biosynthesis of thymidylate (TMP) and is essential for cell proliferation and survival. Inhibition of human TS (hTS) has been extensively investigated for cancer chemotherapy, but several aspects of its activity and regulation are still uncertain. In this study, we performed comprehensive structural and biophysical studies of hTS using crystallography and thermal shift assay and provided the first detailed structural information on the conformational changes induced by ligand binding to the hTS active site. We found that upon binding of the antifolate agents raltitrexed and nolatrexed, the two insert regions in hTS, the functions of which are unclear, undergo positional shifts toward the catalytic center. We investigated the inactive conformation of hTS and found that the two insert regions are also involved in the conformational transition between the active and inactive state of hTS. Moreover, we identified a ligand-binding site in the dimer interface, suggesting that the cavity in the dimer interface could serve as an allosteric site of hTS to regulate the conformational switching between the active and inactive states. On the basis of these findings, we propose a regulatory mechanism of hTS activity that involves allosteric regulation of interactions of hTS with its own mRNA depending on cellular demands for TMP. PMID- 28634234 TI - The thioreduction component CcmG confers efficiency and the heme ligation component CcmH ensures stereo-specificity during cytochrome c maturation. AB - In many Gram-negative bacteria, including Rhodobacter capsulatus, cytochrome c maturation (Ccm) is carried out by a membrane-integral machinery composed of nine proteins (CcmA to I). During this process, the periplasmic thiol-disulfide oxidoreductase DsbA is thought to catalyze the formation of a disulfide bond between the Cys residues at the apocytochrome c heme-binding site (CXXCH). Subsequently, a Ccm-specific thioreductive pathway involving CcmG and CcmH reduces this disulfide bond to allow covalent heme ligation. Currently, the sequence of thioredox reactions occurring between these components and apocytochrome c and the identity of their active Cys residues are unknown. In this work, we first investigated protein-protein interactions among the apocytochrome c, CcmG, and the heme-ligation components CcmF, CcmH, and CcmI. We found that they all interact with each other, forming a CcmFGHI-apocytochrome c complex. Using purified wild-type CcmG, CcmH, and apocytochrome c, as well as their respective Cys mutant variants, we determined the rates of thiol-disulfide exchange reactions between selected pairs of Cys residues from these proteins. We established that CcmG can efficiently reduce the disulfide bond of apocytochrome c and also resolve a mixed disulfide bond formed between apocytochrome c and CcmH. We further show that Cys-45 of CcmH and Cys-34 of apocytochrome c are most likely to form this mixed disulfide bond, which is consistent with the stereo specificity of the heme-apocytochrome c ligation reaction. We conclude that CcmG confers efficiency, and CcmH ensures stereo-specificity during Ccm and present a comprehensive model for thioreduction reactions that lead to heme-apocytochrome c ligation. PMID- 28634235 TI - Mechanistic elucidation of the mycofactocin-biosynthetic radical S adenosylmethionine protein, MftC. AB - Ribosomally synthesized and posttranslationally modified peptide (RiPP) pathways produce a diverse array of natural products. A subset of these pathways depends on radical S-adenosylmethionine proteins to modify the RiPP-produced peptide. Mycofactocin biosynthesis is one example of an S-adenosylmethionine protein dependent RiPP pathway. Recently, it has been shown that MftC catalyzes the oxidative decarboxylation of the C-terminal tyrosine (Tyr-30) on the mycofactocin precursor peptide MftA; however, this product has not been verified by techniques other than MS. Herein, we provide a more detailed study of MftC catalysis and report a revised mechanism for MftC chemistry. We show that MftC catalyzes the formation of two isomeric products. Using a combination of MS, isotope labeling, and 1H and 13C NMR techniques, we established that the major product, MftA*, is a tyramine-valine-cross-linked peptide formed by MftC through two S adenosylmethionine-dependent turnovers. In addition, we show that the hydroxyl group on MftA Tyr-30 is required for MftC catalysis. Furthermore, we show that a substitution in the penultimate MftA Val-29 position causes the accumulation of an MftA** minor product. The 1H NMR spectrum indicates that this minor product contains an alphabeta-unsaturated bond that likely arises from an aborted intermediate of MftA* synthesis. The finding that MftA* is the major product formed during MftC catalysis could have implications for the further elucidation of mycofactocin biosynthesis. PMID- 28634236 TI - Alternative Evolutionary Pathways for Drug-Resistant Small Colony Variant Mutants in Staphylococcus aureus. AB - Staphylococcus aureus is known to generate small colony variants (SCVs) that are resistant to aminoglycoside antibiotics and can cause persistent and recurrent infections. The SCV phenotype is unstable, and compensatory mutations lead to restored growth, usually with loss of resistance. However, the evolution of improved growth, by mechanisms that avoid loss of antibiotic resistance, is very poorly understood. By selection with serial passaging, we isolated and characterized different classes of extragenic suppressor mutations that compensate for the slow growth of small colony variants. Compensation occurs by two distinct bypass mechanisms: (i) translational suppression of the initial SCV mutation by mutant tRNAs, ribosomal protein S5, or release factor 2 and (ii) mutations that cause the constitutive activation of the SrrAB global transcriptional regulation system. Although compensation by translational suppression increases growth rate, it also reduces antibiotic susceptibility, thus restoring a pseudo-wild-type phenotype. In contrast, an evolutionary pathway that compensates for the SCV phenotype by activation of SrrAB increases growth rate without loss of antibiotic resistance. RNA sequence analysis revealed that mutations activating the SrrAB pathway cause upregulation of genes involved in peptide transport and in the fermentation pathways of pyruvate to generate ATP and NAD+, thus explaining the increased growth. By increasing the growth rate of SCVs without the loss of aminoglycoside resistance, compensatory evolution via the SrrAB activation pathway represents a threat to effective antibiotic therapy of staphylococcal infections.IMPORTANCE Small colony variants (SCVs) of Staphylococcus aureus are a significant clinical problem, causing persistent and antibiotic-resistant infections. However, SCVs are unstable and can rapidly evolve growth-compensated mutants. Previous data suggested that growth compensation only occurred with the loss of antibiotic resistance. We have used selection with serial passaging to uncover four distinct pathways of growth compensation accessible to SCVs. Three of these paths (reversion, intragenic suppression, and translational suppression) increase growth at the expense of losing antibiotic resistance. The fourth path activates an alternative transcriptional program and allows the bacteria to produce the extra ATP required to support faster growth, without losing antibiotic resistance. The importance of this work is that it shows that drug-resistant SCVs can evolve faster growth without losing antibiotic resistance. PMID- 28634237 TI - The Pseudomonas aeruginosa PSL Polysaccharide Is a Social but Noncheatable Trait in Biofilms. AB - Extracellular polysaccharides are compounds secreted by microorganisms into the surrounding environment, and they are important for surface attachment and maintaining structural integrity within biofilms. The social nature of many extracellular polysaccharides remains unclear, and it has been suggested that they could function as either cooperative public goods or as traits that provide a competitive advantage. Here, we empirically tested the cooperative nature of the PSL polysaccharide, which is crucial for the formation of biofilms in Pseudomonas aeruginosa We show that (i) PSL is not metabolically costly to produce; (ii) PSL provides population-level benefits in biofilms, for both growth and antibiotic tolerance; (iii) the benefits of PSL production are social and are shared with other cells; (iv) the benefits of PSL production appear to be preferentially directed toward cells which produce PSL; (v) cells which do not produce PSL are unable to successfully exploit cells which produce PSL. Taken together, this suggests that PSL is a social but relatively nonexploitable trait and that growth within biofilms selects for PSL-producing strains, even when multiple strains are on a patch (low relatedness at the patch level).IMPORTANCE Many studies have shown that bacterial traits, such as siderophores and quorum sensing, are social in nature. This has led to an impression that secreted traits act as public goods, which are costly to produce but benefit both the producing cell and its surrounding neighbors. Theories and subsequent experiments have shown that such traits are exploitable by asocial cheats, but we show here that this does not always hold true. We demonstrate that the Pseudomonas aeruginosa exopolysaccharide PSL provides social benefits to populations but that it is nonexploitable, because most of the fitness benefits accrue to PSL-producing cells. Our work builds on an increasing body of work showing that secreted traits can have both private and public benefits to cells. PMID- 28634238 TI - Electron Transport Chain Is Biochemically Linked to Pilus Assembly Required for Polymicrobial Interactions and Biofilm Formation in the Gram-Positive Actinobacterium Actinomyces oris. AB - The Gram-positive actinobacteria Actinomyces spp. are key colonizers in the development of oral biofilms due to the inherent ability of Actinomyces to adhere to receptor polysaccharides on the surface of oral streptococci and host cells. This receptor-dependent bacterial interaction, or coaggregation, requires a unique sortase-catalyzed pilus consisting of the pilus shaft FimA and the coaggregation factor CafA forming the pilus tip. While the essential role of the sortase machine SrtC2 in pilus assembly, biofilm formation, and coaggregation has been established, little is known about trans-acting factors contributing to these processes. We report here a large-scale Tn5 transposon screen for mutants defective in Actinomyces oris coaggregation with Streptococcus oralis We obtained 33 independent clones, 13 of which completely failed to aggregate with S. oralis, and the remainder of which exhibited a range of phenotypes from severely to weakly defective coaggregation. The former had Tn5 insertions in fimA, cafA, or srtC2, as expected; the latter were mapped to genes coding for uncharacterized proteins and various nuo genes encoding the NADH dehydrogenase subunits. Electron microscopy and biochemical analyses of mutants with nonpolar deletions of nuo genes and ubiE, a menaquinone C-methyltransferase-encoding gene downstream of the nuo locus, confirmed the pilus and coaggregation defects. Both nuoA and ubiE mutants were defective in oxidation of MdbA, the major oxidoreductase required for oxidative folding of pilus proteins. Furthermore, supplementation of the ubiE mutant with exogenous menaquinone-4 rescued the cell growth and pilus defects. Altogether, we propose that the A. oris electron transport chain is biochemically linked to pilus assembly via oxidative protein folding.IMPORTANCE The Gram positive actinobacterium A. oris expresses adhesive pili, or fimbriae, that are essential to biofilm formation and Actinomyces interactions with other bacteria, termed coaggregation. While the critical role of the conserved sortase machine in pilus assembly and the disulfide bond-forming catalyst MdbA in oxidative folding of pilins has been established, little is known about other trans-acting factors involved in these processes. Using a Tn5 transposon screen for mutants defective in coaggregation with Streptococcus oralis, we found that genetic disruption of the NADH dehydrogenase and menaquinone biosynthesis detrimentally alters pilus assembly. Further biochemical characterizations determined that menaquinone is important for reactivation of MdbA. This study supports the notion that the electron transport chain is biochemically linked to pilus assembly in A. oris via oxidative folding of pilin precursors. PMID- 28634239 TI - The Dual Activity Responsible for the Elongation and Branching of beta-(1,3) Glucan in the Fungal Cell Wall. AB - beta-(1,3)-Glucan, the major fungal cell wall component, ramifies through beta (1,6)-glycosidic linkages, which facilitates its binding with other cell wall components contributing to proper cell wall assembly. Using Saccharomyces cerevisiae as a model, we developed a protocol to quantify beta-(1,6)-branching on beta-(1,3)-glucan. Permeabilized S. cerevisiae and radiolabeled substrate UDP (14C)glucose allowed us to determine branching kinetics. A screening aimed at identifying deletion mutants with reduced branching among them revealed only two, the bgl2Delta and gas1Delta mutants, showing 15% and 70% reductions in the branching, respectively, compared to the wild-type strain. Interestingly, a recombinant Gas1p introduced beta-(1,6)-branching on the beta-(1,3)-oligomers following its beta-(1,3)-elongase activity. Sequential elongation and branching activity of Gas1p occurred on linear beta-(1,3)-oligomers as well as Bgl2p catalyzed products [short beta-(1,3)-oligomers linked by a linear beta-(1,6) linkage]. The double S. cerevisiae gas1Delta bgl2Delta mutant showed a drastically sick phenotype. An ScGas1p ortholog, Gel4p from Aspergillus fumigatus, also showed dual beta-(1,3)-glucan elongating and branching activity. Both ScGas1p and A. fumigatus Gel4p sequences are endowed with a carbohydrate binding module (CBM), CBM43, which was required for the dual beta-(1,3)-glucan elongating and branching activity. Our report unravels the beta-(1,3)-glucan branching mechanism, a phenomenon occurring during construction of the cell wall which is essential for fungal life.IMPORTANCE The fungal cell wall is essential for growth, morphogenesis, protection, and survival. In spite of being essential, cell wall biogenesis, especially the core beta-(1,3)-glucan ramification, is poorly understood; the ramified beta-(1,3)-glucan interconnects other cell wall components. Once linear beta-(1,3)-glucan is synthesized by plasma membrane-bound glucan synthase, the subsequent event is its branching event in the cell wall space. Using Saccharomyces cerevisiae as a model, we identified GH72 and GH17 family glycosyltransferases, Gas1p and Bgl2p, respectively, involved in the beta (1,3)-glucan branching. The sick phenotype of the double Scgas1Delta bgl2Delta mutant suggested that beta-(1,3)-glucan branching is essential. In addition to ScGas1p, GH72 family ScGas2p and Aspergillus fumigatus Gel4p, having CBM43 in their sequences, showed dual beta-(1,3)-glucan elongating and branching activity. Our report identifies the fungal cell wall beta-(1,3)-glucan branching mechanism. The essentiality of beta-(1,3)-glucan branching suggests that enzymes involved in the glucan branching could be exploited as antifungal targets. PMID- 28634240 TI - Leucine Biosynthesis Is Involved in Regulating High Lipid Accumulation in Yarrowia lipolytica. AB - The yeast Yarrowia lipolytica is a potent accumulator of lipids, and lipogenesis in this organism can be influenced by a variety of factors, such as genetics and environmental conditions. Using a multifactorial study, we elucidated the effects of both genetic and environmental factors on regulation of lipogenesis in Y. lipolytica and identified how two opposite regulatory states both result in lipid accumulation. This study involved comparison of a strain overexpressing diacylglycerol acyltransferase (DGA1) with a control strain grown under either nitrogen or carbon limitation conditions. A strong correlation was observed between the responses on the transcript and protein levels. Combination of DGA1 overexpression with nitrogen limitation resulted in a high level of lipid accumulation accompanied by downregulation of several amino acid biosynthetic pathways, including that of leucine in particular, and these changes were further correlated with a decrease in metabolic fluxes. This downregulation was supported by the measured decrease in the level of 2-isopropylmalate, an intermediate of leucine biosynthesis. Combining the multi-omics data with putative transcription factor binding motifs uncovered a contradictory role for TORC1 in controlling lipid accumulation, likely mediated through 2-isopropylmalate and a Leu3-like transcription factor.IMPORTANCE The ubiquitous metabolism of lipids involves refined regulation, and an enriched understanding of this regulation would have wide implications. Various factors can influence lipid metabolism, including the environment and genetics. We demonstrated, using a multi-omics and multifactorial experimental setup, that multiple factors affect lipid accumulation in the yeast Yarrowia lipolytica Using integrative analysis, we identified novel interactions between nutrient restriction and genetic factors involving regulators that are highly conserved among eukaryotes. Given that lipid metabolism is involved in many diseases but is also vital to the development of microbial cell factories that can provide us with sustainable fuels and oleochemicals, we envision that our report introduces foundational work to further unravel the regulation of lipid accumulation in eukaryal cells. PMID- 28634241 TI - Psl Produced by Mucoid Pseudomonas aeruginosa Contributes to the Establishment of Biofilms and Immune Evasion. AB - Despite years of research and clinical advances, chronic pulmonary infections with mucoid Pseudomonas aeruginosa remain the primary concern for cystic fibrosis patients. Much of the research on these strains has focused on the contributions of the polysaccharide alginate; however, it is becoming evident that the neutral polysaccharide Psl also contributes to biofilm formation and the maintenance of chronic infections. Here, we demonstrate that Psl produced by mucoid strains has significant roles in biofilm structure and evasion of immune effectors. Though mucoid strains produce less Psl than nonmucoid strains, the Psl that is produced is functional, since it mediates adhesion to human airway cells and epithelial cell death. Additionally, Psl protects mucoid bacteria from opsonization and killing by complement components in human serum. Psl production by mucoid strains stimulates a proinflammatory response in the murine lung, leading to reduced colonization. To determine the relevance of these data to clinical infections, we tested Psl production and biofilm formation of a panel of mucoid clinical isolates. We demonstrated three classes of mucoid isolates, those that produce Psl and form robust biofilms, those that did not produce Psl and have a poor biofilm phenotype, and exopolysaccharide (EPS) redundant strains. Collectively, these experimental results demonstrate that Psl contributes to the biofilm formation and immune evasion of many mucoid strains. This is a novel role for Psl in the establishment and maintenance of chronic pulmonary infections by mucoid strains.IMPORTANCE Cystic fibrosis patients are engaged in an ongoing battle against chronic lung infections by the bacterium Pseudomonas aeruginosa One key factor contributing to the maintenance of chronic infections is the conversion to a mucoid phenotype, where the bacteria produce copious amounts of the polysaccharide alginate. Once the bacteria become mucoid, existing treatments are poorly effective. We proposed that mucoid bacteria produce an additional polysaccharide, Psl, which is important for their establishment and maintenance of chronic infections. This work demonstrates that Psl enhances attachment of mucoid bacteria to lung surfaces and leads to inflammation and damage in the lung. Additionally, we find that 50% of mucoid bacteria isolated from patients with chronic infections rely on Psl for the structure of their biofilm communities, suggesting that treatments against Psl should be investigated to enhance the success of current therapies. PMID- 28634243 TI - Erratum for Perkowski et al., "The EXIT Strategy: an Approach for Identifying Bacterial Proteins Exported during Host Infection". PMID- 28634242 TI - Type II Secretion Substrates of Legionella pneumophila Translocate Out of the Pathogen-Occupied Vacuole via a Semipermeable Membrane. AB - Legionella pneumophila replicates in macrophages in a host-derived phagosome, termed the Legionella-containing vacuole (LCV). While the translocation of type IV secretion (T4S) effectors into the macrophage cytosol is well established, the location of type II secretion (T2S) substrates in the infected host cell is unknown. Here, we show that the T2S substrate ProA, a metalloprotease, translocates into the cytosol of human macrophages, where it associates with the LCV membrane (LCVM). Translocation is detected as early as 10 h postinoculation (p.i.), which is approximately the midpoint of the intracellular life cycle. However, it is detected as early as 6 h p.i. if ProA is hyperexpressed, indicating that translocation depends on the timing of ProA expression and that any other factors necessary for translocation are in place by that time point. Translocation occurs with all L. pneumophila strains tested and in amoebae, natural hosts for L. pneumophila It was absent in murine bone marrow-derived macrophages and murine macrophage cell lines. The ChiA chitinase also associated with the cytoplasmic face of the LCVM at 6 h p.i. and in a T2S-dependent manner. Galectin-3 and galectin-8, eukaryotic proteins whose localization is influenced by damage to host membranes, appeared within the LCV of infected human but not murine macrophages beginning at 6 h p.i. Thus, we hypothesize that ProA and ChiA are first secreted into the vacuolar lumen by the activity of the T2S and subsequently traffic into the macrophage cytosol via a novel mechanism that involves a semipermeable LCVM.IMPORTANCE Infection of macrophages and amoebae plays a central role in the pathogenesis of L. pneumophila, the agent of Legionnaires' disease. We have previously demonstrated that the T2S system of L. pneumophila greatly contributes to intracellular infection. However, the location of T2S substrates within the infected host cell is unknown. This report presents the first evidence of a L. pneumophila T2S substrate in the host cell cytosol and, therefore, the first evidence of a non-T4S effector trafficking out of the LCV. We also provide the first indication that the LCV is not completely intact but is instead semipermeable and that this occurs in human but not murine macrophages. Given this permeability, we hypothesize that other T2S substrates and LCV lumenal contents can escape into the host cell cytosol. Thus, these substrates may represent a battery of previously unidentified effectors that can interact with host factors and contribute to intracellular infection by L. pneumophila. PMID- 28634245 TI - Targeting Nectin-4 in Bladder Cancer. AB - Preliminary findings from a phase I clinical trial indicate that enfortumab vedotin, an investigational antibody-drug conjugate targeting nectin-4, shows considerable efficacy in metastatic urothelial carcinoma. Robust responses were seen even among patients with disease progression on platinum chemotherapy and/or immune checkpoint blockade. PMID- 28634244 TI - Simple Expression Domains Are Regulated by Discrete CRMs During Drosophila Oogenesis. AB - Eggshell patterning has been extensively studied in Drosophila melanogaster However, the cis-regulatory modules (CRMs), which control spatiotemporal expression of these patterns, are vastly unexplored. The FlyLight collection contains >7000 intergenic and intronic DNA fragments that, if containing CRMs, can drive the transcription factor GAL4. We cross-listed the 84 genes known to be expressed during D. melanogaster oogenesis with the ~1200 listed genes of the FlyLight collection, and found 22 common genes that are represented by 281 FlyLight fly lines. Of these lines, 54 show expression patterns during oogenesis when crossed to an UAS-GFP reporter. Of the 54 lines, 16 recapitulate the full or partial pattern of the associated gene pattern. Interestingly, while the average DNA fragment size is ~3 kb in length, the vast majority of fragments show one type of spatiotemporal pattern in oogenesis. Mapping the distribution of all 54 lines, we found a significant enrichment of CRMs in the first intron of the associated genes' model. In addition, we demonstrate the use of different anteriorly active FlyLight lines as tools to disrupt eggshell patterning in a targeted manner. Our screen provides further evidence that complex gene patterns are assembled combinatorially by different CRMs controlling the expression of genes in simple domains. PMID- 28634246 TI - Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome. AB - BACKGROUND AND OBJECTIVES: The emerging association of assisted reproductive techniques (ART) with imprinting disorders represents a major issue in the scientific debate on infertility treatment and human procreation. We studied the prevalence of Beckwith-Wiedemann syndrome (BWS) in children conceived through ART to define the specific associated relative risk. METHODS: Patients with BWS born in Piemonte, Italy, were identified and matched with the general demographic data and corresponding regional ART registry. RESULTS: Between 2005 and 2014, live births in Piemonte were 379 872, including 7884 from ART. Thirty-eight patients with BWS were born, 7 from ART and 31 naturally conceived. BWS birth prevalence in the ART group was significantly higher than that of the naturally conceived group (1:1126 vs 1:12 254, P < .001). The absolute live birth risk in the ART group was 887.9 per 1 000 000 vs 83.3 per 1 000 000 in the naturally conceived group, providing a relative risk of 10.7 (95% confidence interval 4.7-24.2). During the 1997-2014 period, 67 patients were diagnosed with BWS out of 663 834 newborns (1:9908 live births). Nine out of the 67 BWS patients were conceived through ART (13.4%), and 8 were molecularly tested, with 4 having an imprinting center 2 loss of methylation, 2 with 11p15.5 paternal uniparental disomy, and 2 negative results. CONCLUSIONS: ART entails a 10-fold increased risk of BWS and could be implicated in the pathogenesis of genomic events besides methylation anomalies. These data highlight the need for awareness of ART-associated health risk. PMID- 28634247 TI - Clinicians' Perceptions of Screening for Food Insecurity in Suburban Pediatric Practice. AB - BACKGROUND: National organizations recommend pediatricians screen for food insecurity (FI). Although there has been growing research in urban practices, little research has addressed FI screening in suburban practices. We evaluated the feasibility, acceptability, and impact of screening in suburban practices. METHODS: We conducted a mixed methods study that implemented FI screening in 6 suburban pediatric primary care practices. We included all children presenting for either a 2-, 15-, or 36-month well-child visit (N = 5645). Families who screened positive were eligible to be referred to our community partner that worked to connect families to the Supplemental Nutrition Assistance Program. We conducted focus groups with clinicians to determine their perceptions of screening and suggestions for improvement. RESULTS: Of the 5645 children eligible, 4371 (77.4%) were screened, of which 122 (2.8%) screened positive for FI (range: 0.9%-5.9% across practices). Of the 122 food-insecure families, only 1 received new Supplemental Nutrition Assistance Program benefits. In focus groups, 3 themes emerged: (1) Time and workflow were not barriers to screening, but concerns about embarrassing families and being unable to provide adequate resources were; (2) Clinicians reported that parents felt the screening showed caring, which reinforced clinicians' continued screening; (3) Clinicians suggested implementing screening before the visit. CONCLUSIONS: We found it is feasible and acceptable for clinicians to screen for FI in suburban practices, but the referral method used in this study was ineffective in assisting families in obtaining benefits. Better approaches to connect families to local resources may be needed to maximize the effectiveness of screening in suburban settings. PMID- 28634248 TI - Suburban Families' Experience With Food Insecurity Screening in Primary Care Practices. AB - BACKGROUND: Food insecurity (FI) remains a major public health problem. With the rise in suburban poverty, a greater understanding of parents' experiences of FI in suburban settings is needed to effectively screen and address FI in suburban practices. METHODS: We conducted 23 semistructured interviews with parents of children <4 years of age who presented for well-child care in 6 suburban pediatric practices and screened positive for FI. In the interviews, we elicited parents' perceptions of screening for FI, how FI impacted the family, and recommendations for how practices could more effectively address FI. All interviews were audio recorded and transcribed. We used a modified grounded theory approach to code the interviews inductively and identified emerging themes through an iterative process. Interviews continued until thematic saturation was achieved. RESULTS: Of the 23 parents interviewed, all were women, with 39% white and 39% African American. Three primary themes emerged: Parents expressed initial surprise at screening followed by comfort discussing their unmet food needs; parents experience shame, frustration, and helplessness regarding FI, but discussing FI with their clinician helped alleviate these feelings; parents suggested practices could help them more directly access food resources, which, depending on income, may not be available to them through government programs. CONCLUSIONS: Although most parents were comfortable discussing FI, they felt it was important for clinicians to acknowledge their frustrations with FI and facilitate access to a range of food resources. PMID- 28634249 TI - David Oliver: Towards a GP consensus on the future of UK general practice. PMID- 28634251 TI - News Feature: Radiation redux. PMID- 28634253 TI - Role of autophagy in tumor necrosis factor-alpha-induced apoptosis of osteoblast cells. AB - The aim of this study is to investigate the role of tumor necrosis factor-alpha (TNF-alpha) in apoptosis and autophagy of mouse osteoblast MC3T3-E1 cells, as well as the crosstalk between autophagy and apoptosis. Mouse osteoblast MC3T3-E1 cells were cultured in vitro and treated with 5-fluorouracil (5-FU), rapamycin, 3 methyl adenine (3-MA) and TNF-alpha either alone or in combination, respectively. MTT assays were used to monitor the cell viability upon different treatments. Annexin-V-FITC/propidium iodide (PI) staining was used to detect the apoptotic rate of osteoblasts. Autophagic structure and apoptotic bodies were visualized by transmission electron microscopy (TEM). Western blot analysis was performed to detect the autophagic marker LC3-II/I, p62 and apoptotic marker cleaved caspase 3. TNF-alpha inhibits MC3T3-E1 cell viability in a dose-dependent and time dependent manner. Annexin-V-FITC/PI staining, coupled with TEM, showed that TNF alpha induced cell apoptosis and autophagy in MC3T3-E1 cells. The autophagy inducer rapamycin ameliorated TNF-alpha-induced apoptosis. In contrast, 3-MA, which is an autophagy inhibitor, caused an exaggerated induction of TNF-alpha induced apoptosis. TNF-alpha upregulated autophagy marker LC3-II/I, but downregulated p62 in osteoblasts. Combined treatment of rapamycin and TNF-alpha further exaggerated this effect, whereas co-treatment of 3-MA and TNF-alpha decreased LC3-II/I, but increased p62 compared with TNF-alpha alone. In addition, TNF-alpha caused an induction of apoptotic marker cleaved caspase-3. TNF-alpha mediated induction of cleaved caspase-3 was downregulated by rapamycin, but upregulated by 3-MA, respectively. TNF-alpha induced both autophagy and apoptosis in osteoblasts, and upregulated autophagy protects the cell by reducing TNF-alpha induced apoptosis. PMID- 28634254 TI - Widespread paleopolyploidy, gene tree conflict, and recalcitrant relationships among the carnivorous Caryophyllales. AB - PREMISE OF STUDY: The carnivorous members of the large, hyperdiverse Caryophyllales (e.g., Venus flytrap, sundews, and Nepenthes pitcher plants) represent perhaps the oldest and most diverse lineage of carnivorous plants. However, despite numerous studies seeking to elucidate their evolutionary relationships, the early-diverging relationships remain unresolved. METHODS: To explore the utility of phylogenomic data sets for resolving relationships among the carnivorous Caryophyllales, we sequenced 10 transcriptomes, including all the carnivorous genera except those in the rare West African liana family Dioncophyllaceae. We used a variety of methods to infer the species tree, examine gene tree conflict, and infer paleopolyploidy events. KEY RESULTS: Phylogenomic analyses supported the monophyly of the carnivorous Caryophyllales, with a crown age of 68-83 million years. In contrast to previous analyses, we recovered the remaining noncore Caryophyllales as nonmonophyletic, although the node supporting this relationship contained a significant amount of gene tree discordance. We present evidence that the clade contains at least seven independent paleopolyploidy events, previously unresolved nodes from the literature have high levels of gene tree conflict, and taxon sampling influences topology even in a phylogenomic data set, regardless of the use of coalescent or supermatrix methods. CONCLUSIONS: Our data demonstrate the importance of carefully considering gene tree conflict and taxon sampling in phylogenomic analyses. Moreover, they provide a remarkable example of the propensity for paleopolyploidy in angiosperms, with at least seven such events in a clade of less than 2500 species. PMID- 28634255 TI - Population genetic structure of Bromus tectorum in the mountains of western North America. AB - PREMISE OF THE STUDY: Invasive species are often initially restricted to a narrow range and may then expand through any of multiple mechanisms including phenotypic plasticity, in situ evolution, or selection on traits preadapted for new habitats. Our study used population genetics to explore possible processes by which the highly selfing invasive annual grass Bromus tectorum has expanded into montane environments. METHODS: We used 69 single nucleotide polymorphic (SNP) markers to genotype ca. 20 individuals from each of 38 montane cheatgrass populations from throughout the Intermountain West and to identify characteristic SNP haplotypes and examine their distribution. KEY RESULTS: Five invariant SNP haplotypes were dominant in montane cheatgrass populations, making up 59% of genotyped individuals, with each haplotype present in 12 to 21 populations. Four of these were absent or present at low frequency in low elevation populations, while the fifth was also sometimes dominant at low elevation. Sixteen haplotypes made up 78% of all genotyped individuals. These haplotypes were distributed across several haplogroups within the clade that also includes most sagebrush steppe lineages. CONCLUSIONS: The wide geographic distribution of several common haplotypes almost completely restricted to montane habitats suggests that dominant lineages in montane populations may possess adaptive syndromes that are preserved through reduced outcrossing rates or negative selection on outcrossed progeny. However, conclusive evidence of such local adaptation requires reciprocal seeding experiments and further characterization of adaptive traits and breeding system characteristics. Other lineages have likely risen to dominance in montane populations through selectively neutral processes. PMID- 28634256 TI - Molecular systematics and historical biogeography of Maianthemum s.s. AB - PREMISE OF THE STUDY: Understanding the underlying mechanisms for the evolution of intercontinental disjunct patterns has long fascinated botanists. We present a molecular phylogenetic reconstruction of Maianthemum s.l. (including Smilacina) with a focus on Maianthemum s.s. species, which have a disjunct distribution between Eurasia and North America. Within this evolutionary framework, we clarify the systematic classification and biogeographical history of Maianthemum s.s. METHOD: Data from two nuclear and five chloroplast DNA regions were analyzed using the programs PAUP*, RAxML, MrBayes, BEAST, and RASP. KEY RESULTS: Our molecular phylogeny supports Maianthemum s.s. as monophyletic. Maianthemum bifolium and M. canadense are grouped according to their taxonomic species, but the accessions of M. dilatatum are divided into two well-defined groups, i.e., one comprising western North American accessions, and the other composed of northeast Asian accessions. Molecular dating and biogeographic reconstructions suggest a northeast Asian origin for Maianthemum s.s. and that a complicated pattern of divergent evolution began approximately in the late Miocene. Intercontinental disjunctions of Maianthemum s.s. in the Northern Hemisphere appear to have occurred two times during the Pliocene. CONCLUSIONS: Based on our results, two possible ways to treat Maianthemum s.s. species can be envisioned: (1) elevate Asian populations of M. dilatatum to specific rank; or (2) combine the three Maianthemum s.s. species into a broadly defined single species. We recommend treatment of Maianthemum s.s. as a single species. The biogeographic patterns of Maianthemum s.s. coupled with molecular dating suggest both vicariance and long-distance dispersal events as key mechanisms for diversification of the clade. PMID- 28634257 TI - Two fossil species of Metrosideros (Myrtaceae) from the Oligo-Miocene Golden Fleece locality in Tasmania, Australia. AB - PREMISE OF THE STUDY: The capsular-fruited genus Metrosideros (Myrtaceae) is one of the most widely distributed flowering plant genera in the Pacific but is extinct in Australia today. The center of geographic origin for the genus and the reason for and timing of its extinction in Australia remain uncertain. We identify fossil Metrosideros fruits from the newly discovered Golden Fleece fossil flora in the Oligo-Miocene of Tasmania, Australia, shedding further light on these problems. METHODS: Standard paleopalynological techniques were used to date the fossil-bearing sediments. Scanning electron microscopy and an auto montage camera system were used to take high-resolution images of fossil and extant fruits taken from herbarium specimens. Fossils are identified using a nearest-living-relative approach. KEY RESULTS: The fossil-bearing sediments are palynostratigraphically dated as being Proteacidites tuberculatus Zone Equivalent (ca. 33-16 Ma) in age and provide a confident Oligo-Miocene age for the macrofossils. Two new fossil species of Metrosideros are described and are here named Metrosideros dawsonii sp. nov. and Metrosideros wrightii sp. nov. CONCLUSIONS: These newly described fossil species of Metrosideros provide a second record of the genus in the Cenozoic of Australia, placing them in the late Early Oligocene to late Early Miocene. It is now apparent not only that Metrosideros was present in Australia, where the genus is now extinct, but that at least several Metrosideros species were present during the Cenozoic. These fossils further strengthen the case for an Australian origin of the genus. PMID- 28634258 TI - Margaret McCartney: To the best of humankind, thank you. PMID- 28634259 TI - Effectiveness of an online SUpport PRogramme (SUPR) for older hearing aid users: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: An educational SUpport PRogramme called SUPR has been developed for hearing aid users (HAUs) and their communication partners (CPs) offering care beyond hearing aid fitting. SUPR teaches its users communication strategies, hearing aid handling skills and personal adjustment to hearing impairment. METHODS/DESIGN: Using a cluster randomised controlled trial design, 70 Dutch hearing aid dispenser practices were randomised into hearing aid fitting (care as usual, 34 practices) and hearing aid fitting including SUPR (36 practices). The aim was to recruit a total of 569 older (aged 50+ years) first-time (n=258) and experienced (n=311) HAUs and their CPs. SUPR consists of a Practical Support Booklet and online material offered via email over a period of 6-7 months. The booklet provides practical information on hearing aids, advice on communication strategies and home exercises. The online material consists of educational videos on hearing aid functionality and usage, communication strategies and peer testimonials. Finally, noncommittal email contact with the dispenser is offered. Every HAU is asked to assign a CP who is advised to be involved intensively. Effect measurements for HAUs and their CPs will occur at baseline and at 6, 12 and 18 months follow-up via online questionnaires. The primary outcomes for HAUs will be the use of communication strategies as measured by the subscales of the Communication Profile for the Hearing Impaired. A process evaluation will be performed. ETHICS AND DISSEMINATION: The study was approved by the Dutch Institutional Review Board of the VU Medical University Center Amsterdam. This intervention could contribute to lowering the hearing impairment burden in our ageing society. The results will be disseminated through peer-reviewed publications and scientific conferences. TRIAL REGISTRATION NUMBER: ISRCTN77340339; Pre-results. PMID- 28634260 TI - Did the suicide barrier work after all? Revisiting the Bloor Viaduct natural experiment and its impact on suicide rates in Toronto. AB - OBJECTIVE: This research aims to determine the long-term impact of the Bloor Street Viaduct suicide barrier on rates of suicide in Toronto and whether media reporting had any impact on suicide rates. DESIGN: Natural experiment. SETTING: City of Toronto, Canada; records at the chief coroner's office of Ontario 1993 2003 (11 years before the barrier) and 2004-2014 (11 years after the barrier). PARTICIPANTS: 5403 people who died by suicide in the city of Toronto. MAIN OUTCOME MEASURE: Changes in yearly rates of suicide by jumping at Bloor Street Viaduct, other bridges including nearest comparison bridge and walking distance bridges, and buildings, and by other means. RESULTS: Suicide rates at the Bloor Street Viaduct declined from 9.0 deaths/year before the barrier to 0.1 deaths/year after the barrier (incidence rate ratio (IRR) 0.005, 95% CI 0.0005 to 0.19, p=0.002). Suicide deaths from bridges in Toronto also declined significantly (IRR 0.53, 95% CI 0.40 to 0.71, p<0.0001). Media reports about suicide at the Bloor Street Viaduct were associated with an increase in suicide by-jumping from bridges the following year. CONCLUSIONS: The current study demonstrates that, over the long term, suicide-by-jumping declined in Toronto after the barrier with no associated increase in suicide by other means. That is, the barrier appears to have had its intended impact at preventing suicide despite a short-term rise in deaths at other bridges that was at least partially influenced by a media effect. Research examining barriers at other locations should interpret short-term results with caution. PMID- 28634262 TI - RASSF4: Regulator of plasma membrane PI(4,5)P2. AB - Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a negatively charged phospholipid that plays a major role in recruiting and regulating proteins at the plasma membrane-cytosol interface. In this issue, Chen et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201606047) demonstrate that RAS association domain family 4 (RASSF4) positively influences PI(4,5)P2 synthesis through ARF6 dependent regulation of PIP5K. PMID- 28634263 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Short reflections on the discovery of the mineralocorticoid receptor. PMID- 28634264 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The scientific impact of cloning the mineralocorticoid receptor: 30 years on. PMID- 28634261 TI - Autophagy gene FIP200 in neural progenitors non-cell autonomously controls differentiation by regulating microglia. AB - Recent studies have shown important roles for autophagy genes in the regulation of different tissue stem cells, including neural stem/progenitor cells (NSCs). However, little is known about whether autophagy can regulate NSCs through cell extrinsic mechanisms. Here, we show that deletion of an essential autophagy gene, FIP200, in NSCs increased expression of Ccl5 and Cxcl10 in a p53-independent manner, mediating increased infiltration of microglia into the subventricular zone of both FIP200hGFAP conditional knockout (cKO) and FIP200;p53hGFAP 2cKO mice. The microglia exhibited an activated M1 phenotype consistent with their potential to inhibit differentiation of FIP200-null NSCs. Blocking either microglia infiltration or activation rescued the deficient differentiation of FIP200-null NSCs from FIP200;p53hGFAP 2cKO mice. Lastly, we showed that increased chemokine expression in FIP200-null NSCs was induced by abnormal p62 aggregate formation and activation of NF-kappaB signaling. Our results suggest that autophagy plays a crucial role in regulating neurogenesis and restricting local immune response in postnatal NSCs through non-cell autonomous mechanisms. PMID- 28634265 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Coregulators as mediators of mineralocorticoid receptor signalling diversity. AB - The cloning of the mineralocorticoid receptor (MR) 30 years ago was the start of a new era of research into the regulatory processes of MR signalling at target genes in the distal nephron, and subsequently in many other tissues. Nuclear receptor (NR) signalling is modified by interactions with coregulatory proteins that serve to enhance or inhibit the gene transcriptional responses. Over 400 coregulatory proteins have been described for the NR super family, many with functional roles in signalling, cellular function, physiology and pathophysiology. Relatively few coregulators have however been described for the MR although recent studies have demonstrated both ligand and/or tissue selectivity for MR-coregulator interactions. A full understanding of the cell, ligand and promoter-specific requirements for MR-coregulator signalling is an essential first step towards the design of small molecular inhibitors of these protein-protein interactions. Tissue-selective steroidal or non-steroidal modulators of the MR are also a desired therapeutic goal. Selectivity, as for other steroid hormone receptors, will probably depend on differential expression and recruitment of coregulatory proteins. PMID- 28634266 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The brain mineralocorticoid receptor: a saga in three episodes. AB - In 1968, Bruce McEwen discovered that 3H-corticosterone administered to adrenalectomised rats is retained in neurons of hippocampus rather than those of hypothalamus. This discovery signalled the expansion of endocrinology into the science of higher brain regions. With this in mind, our contribution highlights the saga of the brain mineralocorticoid receptor (MR) in three episodes. First, the precloning era dominated by the conundrum of two types of corticosterone binding receptors in the brain, which led to the identification of the high affinity corticosterone receptor as the 'promiscuous' MR cloned in 1987 by Jeff Arriza and Ron Evans in addition to the classical glucocorticoid receptor (GR). Then, the post-cloning period aimed to disentangle the function of the brain MR from that of the closely related GR on different levels of biological complexity. Finally, the synthesis section that highlights the two faces of brain MR: Salt and Stress. 'Salt' refers to the regulation of salt appetite, and reciprocal arousal, motivation and reward, by a network of aldosterone-selective MR expressing neurons projecting from nucleus tractus solitarii (NTS) and circumventricular organs. 'Stress' is about the limbic-forebrain nuclear and membrane MRs, which act as a switch in the selection of the best response to cope with a stressor. For this purpose, activation of the limbic MR promotes selective attention, memory retrieval and the appraisal process, while driving emotional expressions of fear and aggression. Subsequently, rising glucocorticoid concentrations activate GRs in limbic-forebrain circuitry underlying executive functions and memory storage, which contribute in balance with MR-mediated actions to homeostasis, excitability and behavioural adaptation. PMID- 28634269 TI - Human development, heredity and evolution. AB - From March 27-29 2017, the RIKEN Center for Developmental Biology held a symposium entitled 'Towards Understanding Human Development, Heredity, and Evolution' in Kobe, Japan. Recent advances in technologies including stem cell culture, live imaging, single-cell approaches, next-generation sequencing and genome editing have led to an expansion in our knowledge of human development. Organized by Yoshiya Kawaguchi, Mitinori Saitou, Mototsugu Eiraku, Tomoya Kitajima, Fumio Matsuzaki, Takashi Tsuji and Edith Heard, the symposium covered a broad range of topics including human germline development, epigenetics, organogenesis and evolution. This Meeting Review provides a summary of this timely and exciting symposium, which has convinced us that we are moving into the era of science targeted on humans. PMID- 28634267 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature. AB - Since the mineralocorticoid receptor (MR) was cloned 30 years ago, it has become clear that MR is expressed in extra-renal tissues, including the cardiovascular system, where it is expressed in all cells of the vasculature. Understanding the role of MR in the vasculature has been of particular interest as clinical trials show that MR antagonism improves cardiovascular outcomes out of proportion to changes in blood pressure. The last 30 years of research have demonstrated that MR is a functional hormone-activated transcription factor in vascular smooth muscle cells and endothelial cells. This review summarizes advances in our understanding of the role of vascular MR in regulating blood pressure and vascular function, and its contribution to vascular disease. Specifically, vascular MR contributes directly to blood pressure control and to vascular dysfunction and remodeling in response to hypertension, obesity and vascular injury. The literature is summarized with respect to the role of vascular MR in conditions including: pulmonary hypertension; cerebral vascular remodeling and stroke; vascular inflammation, atherosclerosis and myocardial infarction; acute kidney injury; and vascular pathology in the eye. Considerations regarding the impact of age and sex on the function of vascular MR are also described. Further investigation of the precise molecular mechanisms by which MR contributes to these processes will aid in the identification of novel therapeutic targets to reduce cardiovascular disease (CVD)-related morbidity and mortality. PMID- 28634268 TI - 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development. AB - The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct. The salient example is eplerenone, first described in 1987, coincidentally with the cloning of MR cDNA. Its launch on the market in 2003 paralleled intensive drug discovery programs for a new generation of non-steroidal MRAs. Now, 30 years after the cDNA cloning of MR and 60 years of clinical use of steroidal MRAs, novel non-steroidal MRAs such as apararenone, esaxerenone and finerenone are in late-stage clinical trials in patients with heart failure, chronic kidney disease (CKD), hypertension and liver disease. Finerenone has already been studied in over 2000 patients with heart failure plus chronic kidney disease and/or diabetes, and in patients with diabetic kidney disease, in five phase II clinical trials. Here, we reflect on the history of the various generations of MRAs and review characteristics of the most important steroidal and non-steroidal MRAs. PMID- 28634270 TI - Making muscle: skeletal myogenesis in vivo and in vitro. AB - Skeletal muscle is the largest tissue in the body and loss of its function or its regenerative properties results in debilitating musculoskeletal disorders. Understanding the mechanisms that drive skeletal muscle formation will not only help to unravel the molecular basis of skeletal muscle diseases, but also provide a roadmap for recapitulating skeletal myogenesis in vitro from pluripotent stem cells (PSCs). PSCs have become an important tool for probing developmental questions, while differentiated cell types allow the development of novel therapeutic strategies. In this Review, we provide a comprehensive overview of skeletal myogenesis from the earliest premyogenic progenitor stage to terminally differentiated myofibers, and discuss how this knowledge has been applied to differentiate PSCs into muscle fibers and their progenitors in vitro. PMID- 28634271 TI - Development of the thyroid gland. AB - Thyroid hormones are crucial for organismal development and homeostasis. In humans, untreated congenital hypothyroidism due to thyroid agenesis inevitably leads to cretinism, which comprises irreversible brain dysfunction and dwarfism. Elucidating how the thyroid gland - the only source of thyroid hormones in the body - develops is thus key for understanding and treating thyroid dysgenesis, and for generating thyroid cells in vitro that might be used for cell-based therapies. Here, we review the principal mechanisms involved in thyroid organogenesis and functional differentiation, highlighting how the thyroid forerunner evolved from the endostyle in protochordates to the endocrine gland found in vertebrates. New findings on the specification and fate decisions of thyroid progenitors, and the morphogenesis of precursor cells into hormone producing follicular units, are also discussed. PMID- 28634274 TI - Btbd7 branches out across multiple organs. PMID- 28634275 TI - Female fertility: no bed of ROS(es). PMID- 28634272 TI - The secreted MSP domain of C. elegans VAPB homolog VPR-1 patterns the adult striated muscle mitochondrial reticulum via SMN-1. AB - The major sperm protein domain (MSPd) has an extracellular signaling function implicated in amyotrophic lateral sclerosis. Secreted MSPds derived from the C. elegans VAPB homolog VPR-1 promote mitochondrial localization to actin-rich I bands in body wall muscle. Here we show that the nervous system and germ line are key MSPd secretion tissues. MSPd signals are transduced through the CLR-1 Lar like tyrosine phosphatase receptor. We show that CLR-1 is expressed throughout the muscle plasma membrane, where it is accessible to MSPd within the pseudocoelomic fluid. MSPd signaling is sufficient to remodel the muscle mitochondrial reticulum during adulthood. An RNAi suppressor screen identified survival of motor neuron 1 (SMN-1) as a downstream effector. SMN-1 acts in muscle, where it colocalizes at myofilaments with ARX-2, a component of the Arp2/3 actin-nucleation complex. Genetic studies suggest that SMN-1 promotes Arp2/3 activity important for localizing mitochondria to I-bands. Our results support the model that VAPB homologs are circulating hormones that pattern the striated muscle mitochondrial reticulum. This function is crucial in adults and requires SMN-1 in muscle, likely independent of its role in pre-mRNA splicing. PMID- 28634273 TI - The C. elegans VAPB homolog VPR-1 is a permissive signal for gonad development. AB - VAMP/synaptobrevin-associated proteins (VAPs) contain an N-terminal major sperm protein domain (MSPd) that is associated with amyotrophic lateral sclerosis. VAPs have an intracellular housekeeping function, as well as an extracellular signaling function mediated by the secreted MSPd. Here we show that the C. elegans VAP homolog VPR-1 is essential for gonad development. vpr-1 null mutants are maternal effect sterile due to arrested gonadogenesis following embryo hatching. Somatic gonadal precursor cells and germ cells fail to proliferate fully and complete their respective differentiation programs. Maternal or zygotic vpr-1 expression is sufficient to induce gonadogenesis and fertility. Genetic mosaic and cell type-specific expression studies indicate that vpr-1 activity is important in the nervous system, germ line and intestine. VPR-1 acts in parallel to Notch signaling, a key regulator of germline stem cell proliferation and differentiation. Neuronal vpr-1 expression is sufficient for gonadogenesis induction during a limited time period shortly after hatching. These results support the model that the secreted VPR-1 MSPd acts at least in part on gonadal sheath cell precursors in L1 to early L2 stage hermaphrodites to permit gonadogenesis. PMID- 28634276 TI - Sox2+ pituitary stem cells on the MAP(K). PMID- 28634277 TI - A new model for single-cell delamination. PMID- 28634278 TI - MSPd signalling: new roles in muscle and reproduction. PMID- 28634279 TI - In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism. AB - OBJECTIVE: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events. DESIGN AND METHODS: Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments. RESULTS: Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the 'English founder', with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9-113 generations, equivalent to 225-2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability. CONCLUSIONS: The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein-protein interactions and AIP protein stability. PMID- 28634281 TI - Margaret McCartney: Health inequality has to be political. PMID- 28634280 TI - Surgical clipping or endovascular coiling for unruptured intracranial aneurysms: a pragmatic randomised trial. AB - BACKGROUND: Unruptured intracranial aneurysms (UIAs) are increasingly diagnosed and are commonly treated using endovascular treatment or microsurgical clipping. The safety and efficacy of treatments have not been compared in a randomised trial. How to treat patients with UIAs suitable for both options remains unknown. METHODS: We randomly allocated clipping or coiling to patients with one or more 3 25 mm UIAs judged treatable both ways. The primary outcome was treatment failure, defined as: initial failure of aneurysm treatment, intracranial haemorrhage or residual aneurysm on 1-year imaging. Secondary outcomes included neurological deficits following treatment, hospitalisation >5 days, overall morbidity and mortality and angiographic results at 1 year. RESULTS: The trial was designed to include 260 patients. An analysis was performed for slow accrual: 136 patients were enrolled from 2010 through 2016 and 134 patients were treated. The 1-year primary outcome, available for 104 patients, was reached in 5/48 (10.4% (4.5% 22.2%)) patients allocated surgical clipping, and 10/56 (17.9% (10.0%-29.8%)) patients allocated endovascular coiling (OR: 0.54 (0.13-1.90), p=0.40). Morbidity and mortality (modified Rankin Scale>2) at 1 year occurred in 2/48 (4.2% (1.2% 14.0%)) and 2/56 (3.6% (1.0%-12.1%)) patients allocated clipping and coiling, respectively. New neurological deficits (15/65 vs 6/69; OR: 3.12 (1.05-10.57), p=0.031), and hospitalisations beyond 5 days (30/65 vs 6/69; OR: 8.85 (3.22 28.59), p=0.0001) were more frequent after clipping. CONCLUSION: Surgical clipping or endovascular coiling of UIAs did not show differences in morbidity at 1 year. Trial continuation and additional randomised evidence will be necessary to establish the supposed superior efficacy of clipping. PMID- 28634283 TI - Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors. AB - Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1-blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.Experimental Design: Utomilumab (0.45-5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.Results: Twenty-three patients received combination treatment with no dose limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders.Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349-57. (c)2017 AACRSee related commentary by Perez-Ruiz et al., p. 5326. PMID- 28634282 TI - Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence. AB - Purpose: Patients with anaplastic thyroid cancer (ATC) have a very high death rate. In contrast, deaths from non-anaplastic thyroid (NAT) cancer are much less common. The genetic alterations in fatal NAT cancers have not been reported.Experimental Design: We performed next-generation sequencing of 410 cancer genes from 57 fatal NAT primary cancers. Results were compared with The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTCs) and to the genomic changes reported in ATC.Results: There was a very high prevalence of TERT promoter mutations, comparable with that of ATC, and these co-occurred with BRAF and RAS mutations. A high incidence of chromosome 1q gain was seen highlighting its importance in tumor aggressiveness. Two novel fusion genes DLG5 RET and OSBPL1A-BRAF were identified. There was a high frequency of mutations in MED12 and these were mutually exclusive to TERT promoter mutations and also to BRAF and RAS mutations. In addition, a high frequency of mutations in RBM10 was identified and these co-occurred with RAS mutations and PIK3CA mutations. Compared with the PTCs in TCGA, there were higher frequencies of mutations in TP53, POLE, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases.Conclusions: These data support a model, whereby fatal NAT cancers arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities. The high rate of TERT promoter mutations, MED12 mutations, RBM10 mutations, and chromosome 1q gain highlight their likely association with tumor virulence. Clin Cancer Res; 23(19); 5970-80. (c)2017 AACR. PMID- 28634284 TI - Co-administration of RANKL and CTLA4 Antibodies Enhances Lymphocyte-Mediated Antitumor Immunity in Mice. AB - Purpose: Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination RANKL and CTLA4 blockade in antitumor immunity has been suggested by recent case reports in melanoma. Here, we provide a rationale for this combination in mouse models of cancer.Experimental Design: The efficacy and mechanism of a combination of RANKL and CTLA4 blockade was examined by tumor-infiltrating lymphocyte analysis, tumor growth, and metastasis using a variety of neutralizing antibodies and gene-targeted mice.Results: RANKL blockade improved the efficacy of anti-CTLA4 mAbs against solid tumors and experimental metastases, with regulatory T-cell (Treg)-depleting anti-CTLA4 mAbs of the mouse IgG2a isotype showing greatest combinatorial activity. The optimal combination depended on the presence of activating Fc receptors and lymphocytes (NK cells for metastatic disease and predominantly CD8+ T cells for subcutaneous tumor control), whereas anti-RANKL alone did not require FcR. The significantly higher T-cell infiltration into solid tumors post anti-RANKL and anti-CTLA4 was accompanied by increased T-cell effector function (cytokine polyfunctionality), and anti-RANKL activity occurred independently of Treg depletion. The majority of RANKL expression in tumors was on T cells whereas RANK-expressing cells were mostly tumor-associated macrophages (TAM), with some expression also observed on dendritic cells (DC) and myeloid-derived suppressor cells (MDSC).Conclusions: These results provide a rationale for the further investigation of RANKL-RANK interactions in tumor immunity and a basis for development of translational markers of interest in human clinical trials. Clin Cancer Res; 23(19); 5789-801. (c)2017 AACR. PMID- 28634285 TI - Frequency of chest pain in primary care, diagnostic tests performed and final diagnoses. AB - OBJECTIVE: Observational study of patients with chest pain in primary care: determination of incidence, referral rate, diagnostic tests and (agreement between) working and final diagnoses. METHODS: 118 general practitioners (GPs) in the Netherlands and Belgium recorded all patient contacts during 2weeks. Furthermore, patients presenting with chest pain were registered extensively. A follow-up form was filled in after 30 days. RESULTS: 22 294 patient contacts were registered. In 281 (1.26%), chest pain was a reason for consulting the GP (mean age for men 54.4/women 53 years). In this cohort of 281 patients, in 38.1% of patients, acute coronary syndrome (ACS) was suspected at least temporarily during consultation, 40.2% of patients were referred to secondary care and 512 diagnostic tests were performed by GPs and consulted specialists. Musculoskeletal pain was the most frequent working (26.1%) and final diagnoses (33.1%). Potentially life-threatening diseases as final diagnosis (such as myocardial infarction) accounted for 8.4% of all chest pain cases. In 23.1% of cases, a major difference between working and final diagnoses was found, in 0.7% a severe disease was initially missed by the GP. CONCLUSION: Chest pain was present in 281 patients (1.26% of all consultations). Final diagnoses were mostly non-life threatening. Nevertheless, in 8.4% of patients with chest pain, life-threatening underlying causes were identified. This seems reflected in the magnitude and wide variety of diagnostic tests performed in these patients by GPs and specialists, in the (safe) overestimation of life-threatening diseases by GPs at initial assessment and in the high referral rate we found. PMID- 28634287 TI - Antibiotics for urinary tract infection in pregnant women. PMID- 28634286 TI - Conjugate Vaccine Immunotherapy for Substance Use Disorder. AB - Substance use disorder, especially in relation to opioids such as heroin and fentanyl, is a significant public health issue and has intensified in recent years. As a result, substantial interest exists in developing therapeutics to counteract the effects of abused drugs. A promising universal strategy for antagonizing the pharmacology of virtually any drug involves the development of a conjugate vaccine, wherein a hapten structurally similar to the target drug is conjugated to an immunogenic carrier protein. When formulated with adjuvants and immunized, the immunoconjugate should elicit serum IgG antibodies with the ability to sequester the target drug to prevent its entry to the brain, thereby acting as an immunoantagonist. Despite the failures of first-generation conjugate vaccines against cocaine and nicotine in clinical trials, second-generation vaccines have shown dramatically improved performance in preclinical models, thus renewing the potential clinical utility of conjugate vaccines in curbing substance use disorder. This review explores the critical design elements of drug conjugate vaccines such as hapten structure, adjuvant formulation, bioconjugate chemistry, and carrier protein selection. Methods for evaluating these vaccines are discussed, and recent progress in vaccine development for each drug is summarized. PMID- 28634288 TI - qSVA framework for RNA quality correction in differential expression analysis. AB - RNA sequencing (RNA-seq) is a powerful approach for measuring gene expression levels in cells and tissues, but it relies on high-quality RNA. We demonstrate here that statistical adjustment using existing quality measures largely fails to remove the effects of RNA degradation when RNA quality associates with the outcome of interest. Using RNA-seq data from molecular degradation experiments of human primary tissues, we introduce a method-quality surrogate variable analysis (qSVA)-as a framework for estimating and removing the confounding effect of RNA quality in differential expression analysis. We show that this approach results in greatly improved replication rates (>3*) across two large independent postmortem human brain studies of schizophrenia and also removes potential RNA quality biases in earlier published work that compared expression levels of different brain regions and other diagnostic groups. Our approach can therefore improve the interpretation of differential expression analysis of transcriptomic data from human tissue. PMID- 28634289 TI - Sex-specific early survival drives adult sex ratio bias in snowy plovers and impacts mating system and population growth. AB - Adult sex ratio (ASR) is a central concept in population biology and a key factor in sexual selection, but why do most demographic models ignore sex biases? Vital rates often vary between the sexes and across life history, but their relative contributions to ASR variation remain poorly understood-an essential step to evaluate sex ratio theories in the wild and inform conservation. Here, we combine structured two-sex population models with individual-based mark-recapture data from an intensively monitored polygamous population of snowy plovers. We show that a strongly male-biased ASR (0.63) is primarily driven by sex-specific survival of juveniles rather than adults or dependent offspring. This finding provides empirical support for theories of unbiased sex allocation when sex differences in survival arise after the period of parental investment. Importantly, a conventional model ignoring sex biases significantly overestimated population viability. We suggest that sex-specific population models are essential to understand the population dynamics of sexual organisms: reproduction and population growth are most sensitive to perturbations in survival of the limiting sex. Overall, our study suggests that sex-biased early survival may contribute toward mating system evolution and population persistence, with implications for both sexual selection theory and biodiversity conservation. PMID- 28634292 TI - Monte Carlo sampling for stochastic weight functions. AB - Conventional Monte Carlo simulations are stochastic in the sense that the acceptance of a trial move is decided by comparing a computed acceptance probability with a random number, uniformly distributed between 0 and 1. Here, we consider the case that the weight determining the acceptance probability itself is fluctuating. This situation is common in many numerical studies. We show that it is possible to construct a rigorous Monte Carlo algorithm that visits points in state space with a probability proportional to their average weight. The same approach may have applications for certain classes of high-throughput experiments and the analysis of noisy datasets. PMID- 28634290 TI - Geospatial analysis of nonmedical vaccine exemptions and pertussis outbreaks in the United States. AB - Because of increased numbers of recorded pertussis cases in the United States, this study sought to understand the role of nonmedical vaccine exemptions and waning immunity may have had on the resurgence of pertussis in the United States at the community level. We used geospatial scan statistics, SaTScan, version 9.4, to analyze nonmedical vaccine exemptions of children entering kindergarten in 2011 and 2012 and reported pertussis cases in 2012 for children in age groups 5 years and younger and 10 to 14 years. Eight statistically significant clusters of nonmedical vaccine exemptions in kindergarteners and 11 statistically significant clusters of pertussis cases in children and adolescents were identified and geospatially linked. Forty-five percent of the counties in the study had high rates of nonmedical vaccine exemptions. The proportion of kindergarteners with nonmedical vaccine exemptions was 2.8 times larger in the identified exemption clusters. In addition, 31 counties had geographic clusters of high rates of pertussis in children ages 10 to 14 years old, consistent with waning immunity. Our findings are consistent with the view that geographic clusters of nonmedical vaccine exemptions and waning immunity may have been factors contributing to community-level pertussis outbreaks. PMID- 28634291 TI - Rhodium metalloinsertor binding generates a lesion with selective cytotoxicity for mismatch repair-deficient cells. AB - The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)]2+ (Rh-PPO). We find that Rh-PPO binding induces a lesion that triggers the DNA damage response (DDR). DDR activation results in cell-cycle blockade and inhibition of DNA replication and transcription. Significantly, the lesion induced by Rh-PPO is not repaired in MMR deficient cells, resulting in selective cytotoxicity. The Rh-PPO mechanism is reminiscent of DNA repair enzymes that displace mismatched bases, and is differentiated from other DNA-targeted chemotherapeutics such as cisplatin by its potency, cellular mechanism, and selectivity for MMR-deficient cells. PMID- 28634293 TI - Intrinsic map dynamics exploration for uncharted effective free-energy landscapes. AB - We describe and implement a computer-assisted approach for accelerating the exploration of uncharted effective free-energy surfaces (FESs). More generally, the aim is the extraction of coarse-grained, macroscopic information from stochastic or atomistic simulations, such as molecular dynamics (MD). The approach functionally links the MD simulator with nonlinear manifold learning techniques. The added value comes from biasing the simulator toward unexplored phase-space regions by exploiting the smoothness of the gradually revealed intrinsic low-dimensional geometry of the FES. PMID- 28634294 TI - Hidden electrostatic basis of dynamic allostery in a PDZ domain. AB - Allosteric effect implies ligand binding at one site leading to structural and/or dynamical changes at a distant site. PDZ domains are classic examples of dynamic allostery without conformational changes, where distal side-chain dynamics is modulated on ligand binding and the origin has been attributed to entropic effects. In this work, we unearth the energetic basis of the observed dynamic allostery in a PDZ3 domain protein using molecular dynamics simulations. We demonstrate that electrostatic interaction provides a highly sensitive yardstick to probe the allosteric modulation in contrast to the traditionally used structure-based parameters. There is a significant population shift in the hydrogen-bonded network and salt bridges involving side chains on ligand binding. The ligand creates a local energetic perturbation that propagates in the form of dominolike changes in interresidue interaction pattern. There are significant changes in the nature of specific interactions (nonpolar/polar) between interresidue contacts and accompanied side-chain reorientations that drive the major redistribution of energy. Interestingly, this internal redistribution and rewiring of side-chain interactions led to large cancellations resulting in small change in the overall enthalpy of the protein, thus making it difficult to detect experimentally. In contrast to the prevailing focus on the entropic or dynamic effects, we show that the internal redistribution and population shift in specific electrostatic interactions drive the allosteric modulation in the PDZ3 domain protein. PMID- 28634295 TI - Population-genomic inference of the strength and timing of selection against gene flow. AB - The interplay of divergent selection and gene flow is key to understanding how populations adapt to local environments and how new species form. Here, we use DNA polymorphism data and genome-wide variation in recombination rate to jointly infer the strength and timing of selection, as well as the baseline level of gene flow under various demographic scenarios. We model how divergent selection leads to a genome-wide negative correlation between recombination rate and genetic differentiation among populations. Our theory shows that the selection density (i.e., the selection coefficient per base pair) is a key parameter underlying this relationship. We then develop a procedure for parameter estimation that accounts for the confounding effect of background selection. Applying this method to two datasets from Mimulus guttatus, we infer a strong signal of adaptive divergence in the face of gene flow between populations growing on and off phytotoxic serpentine soils. However, the genome-wide intensity of this selection is not exceptional compared with what M. guttatus populations may typically experience when adapting to local conditions. We also find that selection against genome-wide introgression from the selfing sister species M. nasutus has acted to maintain a barrier between these two species over at least the last 250 ky. Our study provides a theoretical framework for linking genome-wide patterns of divergence and recombination with the underlying evolutionary mechanisms that drive this differentiation. PMID- 28634296 TI - 1T-TaS2 as a quantum spin liquid. AB - 1T-TaS2 is unique among transition metal dichalcogenides in that it is understood to be a correlation-driven insulator, where the unpaired electron in a 13-site cluster experiences enough correlation to form a Mott insulator. We argue, based on existing data, that this well-known material should be considered as a quantum spin liquid, either a fully gapped [Formula: see text] spin liquid or a Dirac spin liquid. We discuss the exotic states that emerge upon doping and propose further experimental probes. PMID- 28634297 TI - SUPERMAN prevents class B gene expression and promotes stem cell termination in the fourth whorl of Arabidopsis thaliana flowers. AB - The molecular and genetic networks underlying the determination of floral organ identity are well studied, but much less is known about how the flower is partitioned into four developmentally distinct whorls. The SUPERMAN gene is required for proper specification of the boundary between stamens in whorl 3 and carpels in whorl 4, as superman mutants exhibit supernumerary stamens but usually lack carpels. However, it has remained unclear whether extra stamens in superman mutants originate from an organ identity change in whorl 4 or the overproliferation of whorl 3. Using live confocal imaging, we show that the extra stamens in superman mutants arise from cells in whorl 4, which change their fate from female to male, while floral stem cells proliferate longer, allowing for the production of additional stamens. PMID- 28634298 TI - Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP signaling modules in T cells. AB - Specific functions for different cyclic nucleotide phosphodiesterases (PDEs) have not yet been identified in most cell types. Conventional approaches to study PDE function typically rely on measurements of global cAMP, general increases in cAMP dependent protein kinase (PKA), or the activity of exchange protein activated by cAMP (EPAC). Although newer approaches using subcellularly targeted FRET reporter sensors have helped define more compartmentalized regulation of cAMP, PKA, and EPAC, they have limited ability to link this regulation to downstream effector molecules and biological functions. To address this problem, we have begun to use an unbiased mass spectrometry-based approach coupled with treatment using PDE isozyme-selective inhibitors to characterize the phosphoproteomes of the functional pools of cAMP/PKA/EPAC that are regulated by specific cAMP-PDEs (the PDE-regulated phosphoproteomes). In Jurkat cells we find multiple, distinct PDE regulated phosphoproteomes that can be defined by their responses to different PDE inhibitors. We also find that little phosphorylation occurs unless at least two different PDEs are concurrently inhibited in these cells. Moreover, bioinformatics analyses of these phosphoproteomes provide insight into the unique functional roles, mechanisms of action, and synergistic relationships among the different PDEs that coordinate cAMP-signaling cascades in these cells. The data strongly suggest that the phosphorylation of many different substrates contributes to cAMP-dependent regulation of these cells. The findings further suggest that the approach of using selective, inhibitor-dependent phosphoproteome analysis can provide a generalized methodology for understanding the roles of different PDEs in the regulation of cyclic nucleotide signaling. PMID- 28634299 TI - Biosynthesis of isonitrile lipopeptides by conserved nonribosomal peptide synthetase gene clusters in Actinobacteria. AB - A putative lipopeptide biosynthetic gene cluster is conserved in many species of Actinobacteria, including Mycobacterium tuberculosis and M. marinum, but the specific function of the encoding proteins has been elusive. Using both in vivo heterologous reconstitution and in vitro biochemical analyses, we have revealed that the five encoding biosynthetic enzymes are capable of synthesizing a family of isonitrile lipopeptides (INLPs) through a thio-template mechanism. The biosynthesis features the generation of isonitrile from a single precursor Gly promoted by a thioesterase and a nonheme iron(II)-dependent oxidase homolog and the acylation of both amino groups of Lys by the same isonitrile acyl chain facilitated by a single condensation domain of a nonribosomal peptide synthetase. In addition, the deletion of INLP biosynthetic genes in M. marinum has decreased the intracellular metal concentration, suggesting the role of this biosynthetic gene cluster in metal transport. PMID- 28634300 TI - Understanding the mechanical response of double-stranded DNA and RNA under constant stretching forces using all-atom molecular dynamics. AB - Multiple biological processes involve the stretching of nucleic acids (NAs). Stretching forces induce local changes in the molecule structure, inhibiting or promoting the binding of proteins, which ultimately affects their functionality. Understanding how a force induces changes in the structure of NAs at the atomic level is a challenge. Here, we use all-atom, microsecond-long molecular dynamics to simulate the structure of dsDNA and dsRNA subjected to stretching forces up to 20 pN. We determine all of the elastic constants of dsDNA and dsRNA and provide an explanation for three striking differences in the mechanical response of these two molecules: the threefold softer stretching constant obtained for dsRNA, the opposite twist-stretch coupling, and its nontrivial force dependence. The lower dsRNA stretching resistance is linked to its more open structure, whereas the opposite twist-stretch coupling of both molecules is due to the very different evolution of molecules' interstrand distance with the stretching force. A reduction of this distance leads to overwinding in dsDNA. In contrast, dsRNA is not able to reduce its interstrand distance and can only elongate by unwinding. Interstrand distance is directly correlated with the slide base-pair parameter and its different behavior in dsDNA and dsRNA traced down to changes in the sugar pucker angle of these NAs. PMID- 28634301 TI - Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity. AB - Galactosaminogalactan and Pel are cationic heteropolysaccharides produced by the opportunistic pathogens Aspergillus fumigatus and Pseudomonas aeruginosa, respectively. These exopolysaccharides both contain 1,4-linked N-acetyl-d galactosamine and play an important role in biofilm formation by these organisms. Proteins containing glycoside hydrolase domains have recently been identified within the biosynthetic pathway of each exopolysaccharide. Recombinant hydrolase domains from these proteins (Sph3h from A. fumigatus and PelAh from P. aeruginosa) were found to degrade their respective polysaccharides in vitro. We therefore hypothesized that these glycoside hydrolases could exhibit antibiofilm activity and, further, given the chemical similarity between galactosaminogalactan and Pel, that they might display cross-species activity. Treatment of A. fumigatus with Sph3h disrupted A. fumigatus biofilms with an EC50 of 0.4 nM. PelAh treatment also disrupted preformed A. fumigatus biofilms with EC50 values similar to those obtained for Sph3h In contrast, Sph3h was unable to disrupt P. aeruginosa Pel-based biofilms, despite being able to bind to the exopolysaccharide. Treatment of A. fumigatus hyphae with either Sph3h or PelAh significantly enhanced the activity of the antifungals posaconazole, amphotericin B, and caspofungin, likely through increasing antifungal penetration of hyphae. Both enzymes were noncytotoxic and protected A549 pulmonary epithelial cells from A. fumigatus-induced cell damage for up to 24 h. Intratracheal administration of Sph3h was well tolerated and reduced pulmonary fungal burden in a neutropenic mouse model of invasive aspergillosis. These findings suggest that glycoside hydrolases can exhibit activity against diverse microorganisms and may be useful as therapeutic agents by degrading biofilms and attenuating virulence. PMID- 28634303 TI - Structural characterization of the Rabphilin-3A-SNAP25 interaction. AB - Membrane fusion is essential in a myriad of eukaryotic cell biological processes, including the synaptic transmission. Rabphilin-3A is a membrane trafficking protein involved in the calcium-dependent regulation of secretory vesicle exocytosis in neurons and neuroendocrine cells, but the underlying mechanism remains poorly understood. Here, we report the crystal structures and biochemical analyses of Rabphilin-3A C2B-SNAP25 and C2B-phosphatidylinositol 4,5-bisphosphate (PIP2) complexes, revealing how Rabphilin-3A C2 domains operate in cooperation with PIP2/Ca2+ and SNAP25 to bind the plasma membrane, adopting a conformation compatible to interact with the complete SNARE complex. Comparisons with the synaptotagmin1-SNARE show that both proteins contact the same SNAP25 surface, but Rabphilin-3A uses a unique structural element. Data obtained here suggest a model to explain the Ca2+-dependent fusion process by membrane bending with a myriad of variations depending on the properties of the C2 domain-bearing protein, shedding light to understand the fine-tuning control of the different vesicle fusion events. PMID- 28634302 TI - Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions. AB - In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell based studies to provide structure-function properties of a mitochondrial cysteine desulfurase. Unlike prokaryotic cysteine desulfurases, the SDA structure adopts an unexpected architecture in which a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies. The different quaternary structure results in an incompletely formed substrate channel and solvent-exposed pyridoxal 5'-phosphate cofactor and provides a rationale for the allosteric activator function of FXN in eukaryotic systems. The structure also reveals the 4'-phosphopantetheine conjugated acyl-group of ACP occupies the hydrophobic core of ISD11, explaining the basis of ACP stabilization. The unexpected architecture for the SDA complex provides a framework for understanding interactions with acceptor proteins for sulfur-containing biosynthetic pathways, elucidating mechanistic details of eukaryotic Fe-S cluster biosynthesis, and clarifying how defects in Fe-S cluster assembly lead to diseases such as Friedreich's ataxia. Moreover, our results support a lock-and-key model in which LYR proteins associate with acyl-ACP as a mechanism for fatty acid biosynthesis to coordinate the expression, Fe-S cofactor maturation, and activity of the respiratory complexes. PMID- 28634304 TI - Redox-dependent interaction between thaumatin-like protein and beta-glucan influences malting quality of barley. AB - Barley is the cornerstone of the malting and brewing industry. It is known that 250 quantitative trait loci (QTLs) of the grain are associated with 19 malting quality phenotypes. However, only a few of the contributing genetic components have been identified. One of these, on chromosome 4H, contains a major malting QTL, QTL2, located near the telomeric region that accounts, respectively, for 28.9% and 37.6% of the variation in the beta-glucan and extract fractions of malt. In the current study, we dissected the QTL2 region using an expression- and microsynteny-based approach. From a set of 22 expressed sequence tags expressed in seeds at the malting stage, we identified a candidate gene, TLP8 (thaumatin like protein 8), which was differentially expressed and influenced malting quality. Transcript abundance and protein profiles of TLP8 were studied in different malt and feed varieties using quantitative PCR, immunoblotting, and enzyme-linked immunosorbent assay (ELISA). The experiments demonstrated that TLP8 binds to insoluble (1, 3, 1, 4)-beta-D glucan in grain extracts, thereby facilitating the removal of this undesirable polysaccharide during malting. Further, the binding of TLP8 to beta-glucan was dependent on redox. These findings represent a stride forward in our understanding of the malting process and provide a foundation for future improvements in the final beer-making process. PMID- 28634305 TI - Data-Driven Extraction of a Nested Model of Human Brain Function. AB - Decades of cognitive neuroscience research have revealed two basic facts regarding task-driven brain activation patterns. First, distinct patterns of activation occur in response to different task demands. Second, a superordinate, dichotomous pattern of activation/deactivation, is common across a variety of task demands. We explore the possibility that a hierarchical model incorporates these two observed brain activation phenomena into a unifying framework. We apply a latent variable approach, exploratory bifactor analysis, to a large set of human (both sexes) brain activation maps (n = 108) encompassing cognition, perception, action, and emotion behavioral domains, to determine the potential existence of a nested structure of factors that underlie a variety of commonly observed activation patterns. We find that a general factor, associated with a superordinate brain activation/deactivation pattern, explained the majority of the variance (52.37%) in brain activation patterns. The bifactor analysis also revealed several subfactors that explained an additional 31.02% of variance in brain activation patterns, associated with different manifestations of the superordinate brain activation/deactivation pattern, each emphasizing different contexts in which the task demands occurred. Importantly, this nested factor structure provided better overall fit to the data compared with a non-nested factor structure model. These results point to a domain-general psychological process, representing a "focused awareness" process or "attentional episode" that is variously manifested according to the sensory modality of the stimulus and degree of cognitive processing. This novel model provides the basis for constructing a biologically informed, data-driven taxonomy of psychological processes.SIGNIFICANCE STATEMENT A crucial step in identifying how the brain supports various psychological processes is a well-defined categorization or taxonomy of psychological processes and their interrelationships. We hypothesized that a nested structure of cognitive function, in terms of a canonical domain general cognitive process, and various subfactors representing different manifestations of the canonical process, is a fundamental organization of human cognition, and we tested this hypothesis using fMRI task-activation patterns. Using a data-driven latent-variable approach, we demonstrate that a nested factor structure underlies a large sample of brain activation patterns across a variety of task domains. PMID- 28634306 TI - Representations of Time-Varying Cochlear Implant Stimulation in Auditory Cortex of Awake Marmosets (Callithrix jacchus). AB - Electrical stimulation of the auditory periphery organ by cochlear implant (CI) generates highly synchronized inputs to the auditory system. It has long been thought such inputs would lead to highly synchronized neural firing along the ascending auditory pathway. However, neurophysiological studies with hearing animals have shown that the central auditory system progressively converts temporal representations of time-varying sounds to firing rate-based representations. It is not clear whether this coding principle also applies to highly synchronized CI inputs. Higher-frequency modulations in CI stimulation have been found to evoke largely transient responses with little sustained firing in previous studies of the primary auditory cortex (A1) in anesthetized animals. Here, we show that, in addition to neurons displaying synchronized firing to CI stimuli, a large population of A1 neurons in awake marmosets (Callithrix jacchus) responded to rapid time-varying CI stimulation with discharges that were not synchronized to CI stimuli, yet reflected changing repetition frequency by increased firing rate. Marmosets of both sexes were included in this study. By comparing directly each neuron's responses to time-varying acoustic and CI signals, we found that individual A1 neurons encode both modalities with similar firing patterns (stimulus-synchronized or nonsynchronized). These findings suggest that A1 neurons use the same basic coding schemes to represent time varying acoustic or CI stimulation and provide new insights into mechanisms underlying how the brain processes natural sounds via a CI device.SIGNIFICANCE STATEMENT In modern cochlear implant (CI) processors, the temporal information in speech or environmental sounds is delivered through modulated electric pulse trains. How the auditory cortex represents temporally modulated CI stimulation across multiple time scales has remained largely unclear. In this study, we compared directly neuronal responses in primary auditory cortex (A1) to time varying acoustic and CI signals in awake marmoset monkeys (Callithrix jacchus). We found that A1 neurons encode both modalities using similar coding schemes, but some important differences were identified. Our results provide insights into mechanisms underlying how the brain processes sounds via a CI device and suggest a candidate neural code underlying rate-pitch perception limitations often observed in CI users. PMID- 28634308 TI - [Variations of the Endoscopic Keyhole Transcranial Approach]. PMID- 28634307 TI - Prefrontal Neurons Encode a Solution to the Credit-Assignment Problem. AB - To adapt successfully to our environments, we must use the outcomes of our choices to guide future behavior. Critically, we must be able to correctly assign credit for any particular outcome to the causal features which preceded it. In some cases, the causal features may be immediately evident, whereas in others they may be separated in time or intermingled with irrelevant environmental stimuli, creating a potentially nontrivial credit-assignment problem. We examined the neuronal representation of information relevant for credit assignment in the dorsolateral prefrontal cortex (dlPFC) of two male rhesus macaques performing a task that elicited key aspects of this problem. We found that neurons conveyed the information necessary for credit assignment. Specifically, neuronal activity reflected both the relevant cues and outcomes at the time of feedback and did so in a manner that was stable over time, in contrast to prior reports of representational instability in the dlPFC. Furthermore, these representations were most stable early in learning, when credit assignment was most needed. When the same features were not needed for credit assignment, these neuronal representations were much weaker or absent. These results demonstrate that the activity of dlPFC neurons conforms to the basic requirements of a system that performs credit assignment, and that spiking activity can serve as a stable mechanism that links causes and effects.SIGNIFICANCE STATEMENT Credit assignment is the process by which we infer the causes of our successes and failures. We found that neuronal activity in the dorsolateral prefrontal cortex conveyed the necessary information for performing credit assignment. Importantly, while there are various potential mechanisms to retain a "trace" of the causal events over time, we observed that spiking activity was sufficiently stable to act as the link between causes and effects, in contrast to prior reports that suggested spiking representations were unstable over time. In addition, we observed that this stability varied as a function of learning, such that the neural code was more reliable over time during early learning, when it was most needed. PMID- 28634309 TI - [Investigation of Repeatability of Residual Urine Volume Measurement for Lower Urinary Tract Disorder in Patients with Lumbar Degenerative Disorders]. AB - STUDY DESIGN: prospective study OBJECTIVE:To evaluate repeatability of residual urine(RU)volume measurement(RUM)in patients with lumbar degenerative disorders. SUMMARY OF BACKGROUND DATA: RUM by abdominal echo is a non-invasive modality to evaluate lower urinary tract disorder(LUTD), repeatability of which is not found in urological disorders. Additionally, its repeatability has not been confirmed in spinal disorders. The authors examined repeatability of RUM for evaluation of LUTD in patients with lumbar degenerative disorders. METHODS: Thirty-four patients with lumbar degenerative disorders and 7 normal adult volunteers entered our study. RUM was performed at least twice(two to seven times; average 3.6 times). According to urological guidelines, RU over 50 cc is defined as abnormal. Thirty-four patients were divided into two groups:the U+group with lower urinary tract lesion(16 patients)and the U-group without such a lesion(18 patients). RESULTS: In normal adult volunteers:In all volunteers, there was no abnormal RU. Repeatability of RUM was 100%. Average RU volume was 1.6 cc. In patients with lumbar degenerative disorders:Repeatability of RUM was 94.4% in the U group(average RU volume was 35.2 cc)and 50% in the U+group(average RU volume was 50.1 cc). In all patients with lumbar degenerative disorders, repeatability of RUM was 73.5%(average RU volume was 43.0 cc). CONCLUSIONS: Repeatability of RUM in patients with lumbar degenerative disorders was 73.5%. Especially, in patients without lower urinary tract lesion, high repeatability of RUM was confirmed. According to the present study, RUM seemed to be a dependable modality to evaluate LUTD in patients with lumbar degenerative disorders. PMID- 28634310 TI - [A Case of Coexistent Glossopharyngeal Neuralgia and Hemifacial Spasm Successfully Treated with Transposition of the Vertebral Artery]. AB - A case of coexistent glossopharyngeal neuralgia and hemifacial spasm was treated by transposition of the vertebral artery. A 60-year-old man was referred to our hospital due to pain in the left posterior part of the tongue that was difficult to control with oral medication at a local hospital. The diagnosis was left glossopharyngeal neuralgia based on the symptoms, imaging findings, and lidocaine test results. Moreover, the patient had left hemifacial spasm. Microvascular decompression was performed, which confirmed that the vertebral artery was compressing the lower cranial nerve and the posterior inferior cerebellar artery was compressing the root exit zone of the facial nerve. The vertebral artery and posterior inferior cerebellar artery were transposed using TachoSil(r). After the surgery, both glossopharyngeal neuralgia and hemifacial spasm disappeared, and the patient was discharged. PMID- 28634311 TI - [Bevacizumab-Related Hyperintense Lesions on Diffusion-Weighted Imaging at Different Locations in a Patient with Malignant Glioma]. AB - We report the case of a 60-year-old man who first presented with transient difficulty of word recall. Subsequent MRI revealed an invasive brain tumor in the left frontal lobe. The patient underwent open biopsy, and diffuse astrocytoma(WHO grade II)was diagnosed. However, the malignant potential of this tumor was not particularly low because of a few enhancement on preoperative evaluation, and radiation therapy was initially performed. Four months after ending irradiation, temozolomide treatment was introduced for tumor regrowth. After another 2 months, combined chemotherapy with bevacizumab was also started due to tumor enlargement, which was evaluated as malignant transformation to glioblastoma. Two focal lesions with signal hyperintensity on DWI appeared in the frontal and temporal lobes at different locations 3 months after starting bevacizumab. The left temporal lesion subsequently changed to a ring-enhanced tumor, and glioblastoma(WHO grade IV)was finally diagnosed at decompressive surgery. Another frontal lesion, however, continued to maintain a favorable course without any changes in signal despite appearing as similar signal-hyperintense lesions. The temporal hyperintense lesion may undergo malignant transformation into glioblastoma with typical radiological appearance. Recent studies on image changes following bevacizumab treatment have attracted widespread attention, and the clinical significance of such hyperintense lesions has gained attention. This present case was thought to be valuable because of the contradistinctive aspects at the same time, in which the hyperintense lesions of the frontal and temporal lobes seemed to represent antitumor activity or drug refractory effects based on bevacizumab treatment. PMID- 28634312 TI - [A Case of Dural Arteriovenous Fistula in the Anterior Cranial Fossa that Developed Remote from the Craniotomy Site after Surgery]. AB - Dural arteriovenous fistula(dAVF)is relatively rare, and its etiology remains uncertain. Generally, dAVF is thought to be acquired and has been reported to develop secondary to sinus thrombosis, head injury, infection, and surgery. We report a rare case of dAVF in the anterior cranial fossa that developed remote from the craniotomy site after surgery. A 52-year-old man underwent surgery for hypertensive intracerebral hemorrhage 4 years prior. Perioperative imaging modalities demonstrated no abnormal vascular malformation except for an un ruptured anterior communicating artery aneurysm. Four years later, follow-up magnetic resonance angiography showed abnormal vascular malformation in the anterior cranial fossa, and cerebral angiography demonstrated dAVF. dAVF and aneurysm were successfully treated. Possible formation of a dAVF should be considered after craniotomy. PMID- 28634313 TI - [A Case of Bilateral Traumatic Carotid-Cavernous Fistula]. AB - Bilateral traumatic carotid-cavernous fistula(CCF)is rare. It is most commonly caused by a direct head or face injury involving the cavernous sinus and develops immediately after trauma. We report a case of bilateral traumatic CCF that occurred as an intracerebral hematoma(ICH)mimicking apoplexy 5 months later. We treated the patient with point occlusion of venous reflux causing an ICH using coil embolization to remove the hematoma. Three days after we performed trans venous occlusion of the intercavernous connection and right cavernous sinus using coil embolization through the right inferior petrosal vein, it was identified that the left CCF was occluded after first embolization into the left sylvian vein. The mechanism of delayed development of traumatic CCF and spontaneous disappearance of CCF after occlusion of venous reflux are discussed. PMID- 28634314 TI - [A Case of Moyamoya Disease Associated with SAPHO Syndrome]. AB - Moyamoya disease is a unique occlusive disease of the internal carotid artery(ICA)with moyamoya vessels that can lead to transient ischemic attacks and hemorrhagic stroke. When other inherited or acquired disorders and conditions occur in conjunction with moyamoya disease, the syndrome is known as quasi moyamoya disease. We report the case of a 34-year-old woman with a past history of SAPHO(Synovitis-Acne-Pustulosis-Hyperostosis-Osteomyelitis)syndrome, who presented with arm weakness and headache. Magnetic resonance angiography revealed severe terminal stenosis of the left ICA with moyamoya vessels, and she was diagnosed as moyamoya disease associated with SAPHO syndrome. She underwent superficial temporal artery-middle cerebral artery anastomosis and her arm weakness improved postoperatively. Postoperative course was uneventful, although she showed transient right paresthesia, which improved with conservative therapy. Autoimmune response could contribute to the development of this moyamoya disease, and we discuss its mechanism with a literature review. PMID- 28634315 TI - [A Case of Metastatic Brain Tumor Complicated by Multiple Repeated Hemorrhages]. AB - Metastatic brain tumor occasionally results in multiple cerebral hemorrhages. Here, we report a case of metastatic brain tumor complicated by multiple repeated cerebral hemorrhages. An 80-year-old man with a history of removal of lung cancer was admitted to our hospital because of disturbed consciousness following headache. A brain CT revealed a mass lesion of 40-mm diameter in the left cerebellum and a mass lesion of 2-mm diameter in the right temporal lobe. The cerebellar mass lesion showed homogeneous iso-density, indicating a subacute phase hemorrhage. Two days later, a follow-up CT revealed that the mass lesion had become high-density, indicating complication by a fresh hemorrhage. Hematoma was removed and histological examination was performed on the cerebellar lesion. There was leakage of dark-red liquid intraoperatively, and histological examination revealed an adenocarcinoma, indicating metastasis of the lung cancer. Additionally, necrosis and hemorrhage were identified. Postoperatively, whole brain irradiation was performed. The right temporal lesion gradually enlarged but disappeared after irradiation. In conclusion, multiple brain metastases may result in multiple cerebral hemorrhages. Repeated hemorrhage from necrosis of the carcinoma causes a slowly growing hematoma. PMID- 28634316 TI - [Pre- and Intra-Operative Supporting Technology for Brain Tumors(8)Microsurgery and Endoscopic Surgery for Deep-seated Brain Tumor]. PMID- 28634319 TI - Common hepatic artery quadrifurcation associated with right hepatic artery from superior mesenteric artery during laparoscopic total splenopancreasectomy. AB - : Hepatobiliopancreatic surgery is challenging becouse of the complexity of resections and reconstructions and variability of vascular anatomy. The arterial vascularization of the liver is susteined by the common hepatic artery (CHA) that originates from the celiac trunk (CT). The CHA bifurcates into the gastroduodenal artery (GDA) and proper hepatic artery (PHA) 0.5-1 cm medial to the common bile duct (CBD), and the PHA bifurcates into a right and a left branch at hepatic hilum. The most frequent variants are the right hepatic artery (RHA) from the superior mesenteric artery (SMA), the left hepatic artery (LHA) from the left gastric artery (LGA) or a combination of these two variants. Herein, we describe the case of a 70 years old woman affected by IPMN of the pancreas with a quadrifurcation of CHA, associated with a RHA off the SMA. KEY WORDS: Anatomic variant Hepatic artery variant, Hepatic anatomy, Hepatic vascular anatomy. PMID- 28634318 TI - Evaluation and validation of the diagnostic value of the apparent diffusion coefficient for differentiating early-stage endometrial carcinomas from benign mimickers at 3T MRI. AB - Previous researchers obtained various apparent diffusion coefficient (ADC) cutoff values to differentiate endometrial carcinoma from benign mimickers with 1.5T magnetic resonance imaging (MRI). Few studies have used 3T MRI or validated the effectiveness of these cutoff ADC values prospectively. This study was designed in two stages to obtain a cutoff ADC value at 3T MRI and to validate prospectively the role of the ADC value. First, we conducted a retrospective study of 60 patients to evaluate the diagnostic value of ADC by obtain a theoretical cutoff ADC value for differentiating between benign and malignant endometrial lesions. Student's t test revealed that ADC values for stage I endometrial carcinomas were significantly lower than those for benign lesions. The area under the curve value of the receiver operating characteristic curve was 0.993, and the cutoff ADC value was 0.98 * 10-3 mm2/s. The sensitivity, specificity, and overall accuracy of diagnosing stage I endometrial carcinoma were 100%, 97.1%, and 98.3%, respectively. Second, we conducted a prospective study of 26 patients to validate the use of the cutoff ADC value obtained in the study's first stage. The sensitivity, specificity, and overall accuracy for differentiating malignant from benign endometrial lesions based on the cutoff ADC value obtained earlier were as follows: radiologist 1 attained 86.67%, 100.0%, and 92.31%, respectively; radiologist 2 attained 86.67%, 91.0%, and 88.5%, respectively. Our results suggest that ADC values could be a potential biomarker for use as a quantitative and qualitative tool for differentiating between early stage endometrial carcinomas and benign mimickers. PMID- 28634320 TI - Comparison of 2 Analgesia Modalities in Total Knee Replacement Surgery: Is There an Effect on Knee Function Rehabilitation? AB - BACKGROUND We compared the effects of continuous femoral nerve block (CFNB) and continuous intraarticular block (CIAB) on pain, functional recovery and adverse effects after total knee arthroplasty (TKA). MATERIAL AND METHODS We prospectively randomized 54 patients undergoing TKA into 2 groups: CFNB (Group F) and CIAB (Group I). Surgery was performed under spinal anesthesia. All patients received patient-controlled analgesia (PCA) with morphine, diclofenac, and acetaminophen for the first 72 h postoperatively. Pain was assessed with a visual analog scale (VAS), 48-h morphine consumption and 72-h local anesthetic dosage were recorded, motor blockade was assessed, maximum range of motion (ROM) was measured, and adverse effect profiles were recorded. RESULTS There was no significant difference in postoperative pain at rest, in passive motion, active motion, or active movement (2-min walk test (2MWT)) between study groups. Group I had less opioid usage in the first 24 h postoperatively (p<0.05). No significant difference was found between the groups in the postoperative local anesthetic dosage (p>0.05). Significantly lower scores of Bromage scale in Group I in 72 h after surgery (p<0.05) were found. Group I had superior passive maximum ROM in 1 month after surgery and superior active maximum ROM on day 7 and at 1 month after surgery (p<0.05). CONCLUSIONS Both CFNB and CIAB are effective postoperative analgesia methods after TKA. CIAB leads to lower postoperative opioid usage in the first 24 h, lower motor blockade in the first 72 h, and better knee function on day 7 and at 1 month after surgery. PMID- 28634322 TI - Helium Irradiation and Implantation Effects on the Structure of Amorphous Silicon Oxycarbide. AB - Despite recent interest in amorphous ceramics for a variety of nuclear applications, many details of their structure before and after irradiation/implantation remain unknown. Here we investigated the short-range order of amorphous silicon oxycarbide (SiOC) alloys by using the atomic pair distribution function (PDF) obtained from electron diffraction. The PDF results show that the structure of SiOC alloys are nearly unchanged after both irradiation up to 30 dpa and He implantation up to 113 at%. TEM characterization shows no sign of crystallization, He bubble or void formation, or segregation in all irradiated samples. Irradiation results in a decreased number of Si-O bonds and an increased number of Si-C and C-O bonds. This study sheds light on the design of radiation-tolerant materials that do not experience helium swelling for advanced nuclear reactor applications. PMID- 28634321 TI - A central mechanism enhances pain perception of noxious thermal stimulus changes. AB - Pain perception temporarily exaggerates abrupt thermal stimulus changes revealing a mechanism for nociceptive temporal contrast enhancement (TCE). Although the mechanism is unknown, a non-linear model with perceptual feedback accurately simulates the phenomenon. Here we test if a mechanism in the central nervous system underlies thermal TCE. Our model successfully predicted an optimal stimulus, incorporating a transient temperature offset (step-up/step-down), with maximal TCE, resulting in psychophysically verified large decrements in pain response ("offset-analgesia"; mean analgesia: 85%, n = 20 subjects). Next, this stimulus was delivered using two thermodes, one delivering the longer duration baseline temperature pulse and the other superimposing a short higher temperature pulse. The two stimuli were applied simultaneously either near or far on the same arm, or on opposite arms. Spatial separation across multiple peripheral receptive fields ensures the composite stimulus timecourse is first reconstituted in the central nervous system. Following ipsilateral stimulus cessation on the high temperature thermode, but before cessation of the low temperature stimulus properties of TCE were observed both for individual subjects and in group-mean responses. This demonstrates a central integration mechanism is sufficient to evoke painful thermal TCE, an essential step in transforming transient afferent nociceptive signals into a stable pain perception. PMID- 28634323 TI - Intestinal microbial dysbiosis aggravates the progression of Alzheimer's disease in Drosophila. AB - Neuroinflammation caused by local deposits of Abeta42 in the brain is key for the pathogenesis and progression of Alzheimer's disease. However, inflammation in the brain is not always a response to local primary insults. Gut microbiota dysbiosis, which is recently emerging as a risk factor for psychiatric disorders, can also initiate a brain inflammatory response. It still remains unclear however, whether enteric dysbiosis also contributes to Alzheimer's disease. Here we show that in a Drosophila Alzheimer's disease model, enterobacteria infection exacerbated progression of Alzheimer's disease by promoting immune hemocyte recruitment to the brain, thereby provoking TNF-JNK mediated neurodegeneration. Genetic depletion of hemocytes attenuates neuroinflammation and alleviated neurodegeneration. We further found that enteric infection increases the motility of the hemocytes, making them more readily attracted to the brain with an elevated oxidative stress status. This work highlights the importance of gut brain crosstalk as a fundamental regulatory system in modulating Alzheimer's disease neurodegeneration.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease. PMID- 28634324 TI - Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo. AB - Ficolins are a family of pattern recognition molecules that are capable of activating the lectin pathway of complement. A limited number of reports have demonstrated a protective role of ficolins in animal models of infection. In addition, an immune modulatory role of ficolins has been suggested. Yet, the contribution of ficolins to inflammatory disease processes remains elusive. To address this, we investigated ficolin deficient mice during a lipopolysaccharide (LPS)-induced model of systemic inflammation. Although murine serum ficolin was shown to bind LPS in vitro, there was no difference between wildtype and ficolin deficient mice in morbidity and mortality by LPS-induced inflammation. Moreover, there was no difference between wildtype and ficolin deficient mice in the inflammatory cytokine profiles after LPS challenge. These findings were substantiated by microarray analysis revealing an unaltered spleen transcriptome profile in ficolin deficient mice compared to wildtype mice. Collectively, results from this study demonstrate that ficolins are not involved in host response to LPS-induced systemic inflammation. PMID- 28634325 TI - In Utero and Lactational Exposure Study in Rats to Identify Replacements for Di(2 ethylhexyl) Phthalate. AB - Di(2-ethylhexyl) phthalate (DEHP) and other phthalates are ubiquitous environmental contaminants with endocrine disrupting properties. Two novel plasticizers, 1,4 butanediol dibenzoate (BDB) and dioctyl succinate (DOS), have been proposed as potential replacements. Both have desirable properties as plasticizers and minimal in vitro biological effects. Herein, we present an in utero and lactational exposure study comparing DEHP with BDB, DOS, and 1,2 cyclohexane dicarboxylic acid diisononyl ester (DINCH), a commercial alternative. Timed-pregnant Sprague-Dawley rats were gavaged with vehicle or one of these chemicals at 30 or 300 mg/kg/day from gestational day 8 until postnatal day (PND) 21. The offspring were examined for effects on developmental and endocrine markers until PND 46. DEHP treatment (300 mg/kg) decreased heart weights in dams and induced a significant decrease in anogenital index and an increase in hemorrhagic testes and multinucleated gonocytes in PND 3 male pups. An increase in the incidence of hemorrhagic testes was also observed on PND 8 after exposure to DINCH (30 and 300 mg/kg). The only other effects observed were decreases in serum alanine transaminase and magnesium in BDB 30 exposed dams. These data suggest that both BDB and DOS are viable alternative plasticizers. PMID- 28634326 TI - A Chrysoporthe cubensis enzyme cocktail produced from a low-cost carbon source with high biomass hydrolysis efficiency. AB - Low cost and high efficiency cellulolytic cocktails can consolidate lignocellulosic ethanol technologies. Sugarcane bagasse (SCB) is a low cost agro industrial residue, and its use as a carbon source can reduce the costs of fungi cultivation for enzyme production. Chrysoporthe cubensis grown under solid state fermentation (SSF) with wheat bran has potential to produce efficient enzymatic extracts for SCB saccharification. This fungus was grown under submersed fermentation (SmF) and SSF with in natura SCB, pretreated with acid or alkali and with others carbon sources. In natura SCB induced the highest carboxymethylcellulase (CMCase), xylanase, beta-xylosidase, alpha-galactosidase and mannanase activities by C. cubensis under SSF. In natura and washed SCB, inducers of enzyme production under SSF, did not induce high cellulases and hemicellulases production by C. cubensis in SmF. The C. cubensis enzymatic extract produced under SSF with in natura SCB as a carbon source was more efficient for lignocelulolic biomass hydrolysis than extracts produced under SSF with wheat bran and commercial cellulolytic extract. Chrysoporthe cubensis showed high potential for cellulases and hemicellulases production, especially when grown under SSF with in natura SCB as carbon source. PMID- 28634327 TI - High quality factor confined Tamm modes. AB - We demonstrate that quality factors up to 5000 can be obtained in Tamm-like hybrid metal/semiconductor structures. To do this, a Bragg mirror is covered by a thin transparent layer and a metallic film. The reduced losses of these modes are related to an intermediate behavior between conventional Tamm plasmon and Bragg modes lying deeper in the semiconductor medium. One of the most striking features of this approach is that these super Tamm modes can still be spatially confined with the metal. Confinement on micrometric scale is experimentally demonstrated. The simplicity and versatility of high-Q mode control by metal structuration open perspectives for lasing and polaritonic applications. PMID- 28634328 TI - Multiple magnetoelectric coupling effect in BaTiO3/Sr2CoMoO6 heterostructures. AB - Due to the demand of controlling magnetism by electric fields for future storage devices, materials with magnetoelectric coupling are of great interests. Based on first-principles calculations, we study the electronic and magnetic properties of a double perovskite Sr2CoMoO6 (SCMO) in a hybrid heterostructure combined with BaTiO3 (BTO) in different polarization states. The calculations show that by introducing ferroelectric state in BTO, SCMO transforms from an antiferromagnetic semiconductor to a half-metal. Specially, altering the polarization direction not only controls the interfacial magnetic moment, but also changes the orbital occupancy of the Co-3d state. This novel multiple magnetoelectric coupling opens possibilities for designing new type of spintronic and microelectronic devices with controllable degree of freedom of interfacial electrons in the heterostructures. PMID- 28634330 TI - Increase in predation risk and trophic level induced by nocturnal visits of piscivorous fishes in a temperate seagrass bed. AB - The majority of surveys on food webs of aquatic ecosystems have been conducted during the day owning to difficulties in sampling animals at night. In this study, to examine diurnal changes in predator-prey interactions in a temperate seagrass Zostera marina bed, a quantitative day/night survey of fish, the dominant animal community, coupled with acoustic telemetry of their predators, was conducted. The number of species, abundance, and biomass of piscivorous predators and mean trophic level during the night were significantly higher than those in the day in all seasons. Analysis of the stomach contents of 182 piscivorous predators showed that no fish predation occurred during the day whereas predation occurred during the night in winter, spring, and summer. Acoustic telemetry demonstrated nocturnal visits by dominant piscivorous fish species (rockfishes and conger eel) to the seagrass bed. We conclude that the nocturnal visits by piscivorous fishes increased the predation risk and trophic level in the fish nursery. The ecological functions of seagrass beds should be reevaluated accounting for day/night changes in food webs; these areas serve as nurseries for juvenile and small-sized fishes during the day and as foraging grounds for predators during the night. PMID- 28634329 TI - Long days enhance recognition memory and increase insulin-like growth factor 2 in the hippocampus. AB - Light improves cognitive function in humans; however, the neurobiological mechanisms underlying positive effects of light remain unclear. One obstacle is that most rodent models have employed lighting conditions that cause cognitive deficits rather than improvements. Here we have developed a mouse model where light improves cognitive function, which provides insight into mechanisms underlying positive effects of light. To increase light exposure without eliminating daily rhythms, we exposed mice to either a standard photoperiod or a long day photoperiod. Long days enhanced long-term recognition memory, and this effect was abolished by loss of the photopigment melanopsin. Further, long days markedly altered hippocampal clock function and elevated transcription of Insulin like Growth Factor2 (Igf2). Up-regulation of Igf2 occurred in tandem with suppression of its transcriptional repressor Wilm's tumor1. Consistent with molecular de-repression of Igf2, IGF2 expression was increased in the hippocampus before and after memory training. Lastly, long days occluded IGF2-induced improvements in recognition memory. Collectively, these results suggest that light changes hippocampal clock function to alter memory, highlighting novel mechanisms that may contribute to the positive effects of light. Furthermore, this study provides insight into how the circadian clock can regulate hippocampus dependent learning by controlling molecular processes required for memory consolidation. PMID- 28634331 TI - Genotoxicity and cytotoxicity of the plasma jet-treated medium on lymphoblastoid WIL2-NS cell line using the cytokinesis block micronucleus cytome assay. AB - Despite growing interest in the application of atmospheric plasma jets as medical treatment strategies, there has been comparatively little research on the potential genotoxic and cytotoxic effects of plasma jet treatment. In this study, we have employed the cytokinesis block micronucleus cytome (CBMN-Cyt) assay with WIL2-NS B lymphoblastoid cells to test the potential genotoxicity, as well as the cytotoxicity, of toxic species generated in cell culture media by an argon (Ar) plasma jet. Elevated levels of cell death (necrosis) and occurrence of chromosomal damage (micronuclei MN, nculeoplasmic bridge NPBs and nuclear bus, Nbuds) were observed when cells were exposed to plasma jet-treated media. These results provide a first insight into how we might measure the genotoxic and cytotoxic effect of plasma jet treatments (both indirect and direct) in dividing human cells. PMID- 28634332 TI - Predicting the potential risk area of illegal vaccine trade in China. AB - Since the disclosure of the "Illegal vaccine operation series case in Jinan, Shandong" in March, 2016, this issue has attracted a great deal of attention and has led to public concerns about the safety and efficacy of the vaccines involved in this case. The main purpose of this paper is to scientifically and scrupulously predict the possible geographic distribution of illegal vaccines in China, and provide a foundation to guide future governmental policies and actions. A species distribution model was used because of the advantages of using presence/pseudo-absence or presence-only data, and it performs well with incomplete species distribution data. A series of socioeconomic variables were used to simulate habitat suitability distribution. Maxent (Maximum Entropy Model) and GARP (Genetic Algorithm for Rule set Production) were used to predict the risks of illegal vaccines in China, and define the spatial distribution and significant factors of the area at risk from illegal vaccines. Jackknife tests were used to evaluate the relative importance of socioeconomic variables. It was found that: (1) Shandong, Hebei, Henan, Jiangsu and Anhui are the main high-risk areas impacted by the vaccines involved in Jinan case. (2) Population density and industrial structure are the main socioeconomic factors affecting areas which may be at risk from illegal vaccines. PMID- 28634333 TI - Atomic rearrangement of a sputtered MoS2 film from amorphous to a 2D layered structure by electron beam irradiation. AB - We synthesised a crystalline MoS2 film from as-sputtered amorphous film by applying an electron beam irradiation (EBI) process. A collimated electron beam (60 mm dia.) with an energy of 1 kV was irradiated for only 1 min to achieve crystallisation without an additional heating process. After the EBI process, we observed a two-dimensional layered structure of MoS2 about 4 nm thick and with a hexagonal atomic arrangement on the surface. A stoichiometric MoS2 film was confirmed to grow well on SiO2/Si substrates and include partial oxidation of Mo. In our experimental configuration, EBI on an atomically thin MoS2 layer stimulated the transformation from a thermodynamically unstable amorphous structure to a stable crystalline nature with a nanometer grain size. We employed a Monte Carlo simulation to calculate the penetration depth of electrons into the MoS2 film and investigated the atomic rearrangement of the amorphous MoS2 structure. PMID- 28634334 TI - Image-guided transplantation of single cells in the bone marrow of live animals. AB - Transplantation of a single hematopoietic stem cell is an important method for its functional characterization, but the standard transplantation protocol relies on cell homing to the bone marrow after intravenous injection. Here, we present a method to transplant single cells directly into the bone marrow of live mice. We developed an optical platform that integrates a multiphoton microscope with a laser ablation unit for microsurgery and an optical tweezer for cell micromanipulation. These tools allow image-guided single cell transplantation with high spatial control. The platform was used to deliver single hematopoietic stem cells. The engraftment of transplants was tracked over time, illustrating that the technique can be useful for studying both normal and malignant stem cells in vivo. PMID- 28634335 TI - Ordered hydroxyls on Ca3Ru2O7(001). AB - As complex ternary perovskite-type oxides are increasingly used in solid oxide fuel cells, electrolysis and catalysis, it is desirable to obtain a better understanding of their surface chemical properties. Here we report a pronounced ordering of hydroxyls on the cleaved (001) surface of the Ruddlesden-Popper perovskite Ca3Ru2O7 upon water adsorption at 105 K and subsequent annealing to room temperature. Density functional theory calculations predict the dissociative adsorption of a single water molecule (E ads = 1.64 eV), forming an (OH)ads group adsorbed in a Ca-Ca bridge site, with an H transferred to a neighboring surface oxygen atom, Osurf. Scanning tunneling microscopy images show a pronounced ordering of the hydroxyls with (2 * 1), c(2 * 6), (1 * 3), and (1 * 1) periodicity. The present work demonstrates the importance of octahedral rotation and tilt in perovskites, for influencing surface reactivity, which here induces the ordering of the observed OH overlayers.As ternary perovskite-type oxides are increasingly used in fuel cells and catalysis, greater understanding of their surface chemical properties is required. Here the authors report a pronounced ordering of hydroxyls on the cleaved (001) surface of Ca3Ru2O7 perovskite induced by O-octahedral rotation and tilt. PMID- 28634336 TI - LC-MS/MS quantification of sulfotransferases is better than conventional immunogenic methods in determining human liver SULT activities: implication in precision medicine. AB - This study aims to determine whether enzyme activities are correlated with protein amounts and mRNA expression levels of five major human sulfotransferase (SULT) enzymes in 10 matched pericarcinomatous and hepatocellular carcinoma liver samples. The MRM UHPLC-MS/MS method, Western blot and RT-PCR were used along with SULT activity measurement using probe substrates. The LC-MS/MS method was specific for all five tested SULTs, whereas Western blot was specific for only two isoforms. The activities of SULT1A1, SULT1B1, SULT1E1 and SULT2A1 in 9 of 10 samples showed a significant decrease in tumor tissues relative to matched pericarcinomatous tissues, whereas the activities of SULT1A3 in 7 of 10 samples increased. The turnover numbers of SULTs did not change, except for SULT1A1. A generally high degree of correlations was observed between SULT activities and protein amounts (r2 >= 0.59 except one), whereas a low degree of correlations was observed between SULT activities and mRNA expression levels (r2 <= 0.48 except one). HCC reduced the SULT activities via impaired protein amounts. LC-MS/MS quantification of SULTs is highly reliable measurement of SULT activities, and may be adopted for implementing precision medicine with respect to drugs mainly metabolized by SULTs in healthy and HCC patients. PMID- 28634337 TI - Evolutionary and network analysis of virus sequences from infants infected with an Australian recombinant strain of human parechovirus type 3. AB - We present the near complete virus genome sequences with phylogenetic and network analyses of potential transmission networks of a total of 18 Australian cases of human parechovirus type 3 (HPeV3) infection in infants in the period from 2012 2015. Overall the results support our previous finding that the Australian outbreak strain/lineage is a result of a major recombination event that took place between March 2012 and November 2013 followed by further virus evolution and possibly recombination. While the nonstructural coding region of unknown provenance appears to evolve significantly both at the nucleotide and amino acid level, the capsid encoding region derived from the Yamagata 2011 lineage of HPeV3 appears to be very stable, particularly at the amino acid level. The phylogenetic and network analyses performed support a temporal evolution from the first Australian recombinant virus sequence from November 2013 to March/April 2014, onto the 2015 outbreak. The 2015 outbreak samples fall into two separate clusters with a possible common ancestor between March/April 2014 and September 2015, with each cluster further evolving in the period from September to November/December 2015. PMID- 28634338 TI - Coumarin-benzimidazole hybrids as a potent antimicrobial agent: synthesis and biological elevation. AB - Molecular hybridization approach is an emerging tool in drug discovery for designing new pharmacophores with biological activity. A novel, new series of coumarin-benzimidazole hybrids were designed, synthesized and evaluated for their broad spectrum antimicrobial activity. Among all the synthesized molecules, compound (E)-3-(2-1H-benzo[d]imidazol-1-yl)-1-((4-chlorobenzyl)oxy)imino)ethyl) 2H-chromen-2-one showed the most promising broad spectrum antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris. In addition, it has showed no cytotoxicity and hemolysis at 10 times the MIC concentration. SAR studies indicate that position of the chlorine atom in the hybrid critically determines the antibacterial activity. PMID- 28634339 TI - Effective Synthesis of Highly Oxidized Graphene Oxide That Enables Wafer-scale Nanopatterning: Preformed Acidic Oxidizing Medium Approach. AB - Demand for rapid and massive-scale exfoliation of bulky graphite remains high in graphene commercialization and property manipulation. We report a procedure utilizing "preformed acidic oxidizing medium (PAOM)" as a modified version of the Hummers' method for fast and reliable synthesis of graphene oxide. Pre-mixing of KMnO4 and concentrated H2SO4 prior to the addition of graphite flakes enables the formation of effectively and efficiently oxidized graphene oxide (EEGO) featured by its high yields and suspension homogeneity. PAOM expedites diffusion of the Mn oxidants into the graphite galleries, resulting in the rapid graphite oxidation, capable of oxidizing bulky graphite flakes (~0.8 mm in diameter) that can not be realized by the Hummers' method. In the scale-up tests, ten-time amount of graphite can be completely exfoliated by PAOM without need of extended reaction time. The remarkable suspension homogeneity of EEGO can be exploited to deposit ultra-flat coating for wafer-scale nanopatterning. We successfully fabricated GO optical gratings with well-defined periodicity (300 nm) and uniform thickness (variation <7 nm). The combination of the facile and potent PAOM approach with the wafer-scale patterning technique may realize the goal for massive throughput graphene nanoelectronics. PMID- 28634340 TI - Dispersal ability determines the scaling properties of species abundance distributions: a case study using arthropods from the Azores. AB - Species abundance distributions (SAD) are central to the description of diversity and have played a major role in the development of theories of biodiversity and biogeography. However, most work on species abundance distributions has focused on one single spatial scale. Here we used data on arthropods to test predictions obtained with computer simulations on whether dispersal ability influences the rate of change of SADs as a function of sample size. To characterize the change of the shape of the SADs we use the moments of the distributions: the skewness and the raw moments. In agreement with computer simulations, low dispersal ability species generate a hump for intermediate abundance classes earlier than the distributions of high dispersal ability species. Importantly, when plotted as function of sample size, the raw moments of the SADs of arthropods have a power law pattern similar to that observed for the SAD of tropical tree species, thus we conjecture that this might be a general pattern in ecology. The existence of this pattern allows us to extrapolate the moments and thus reconstruct the SAD for larger sample sizes using a procedure borrowed from the field of image analysis based on scaled discrete Tchebichef moments and polynomials. PMID- 28634341 TI - Terahertz circular Airy vortex beams. AB - Vortex beams have received considerable research interests both in optical and millimeter-wave domain since its potential to be utilized in the wireless communications and novel imaging systems. Many well-known optical beams have been demonstrated to carry orbital angular momentum (OAM), such as Laguerre-Gaussian beams and high-order Bessel beams. Recently, the radially symmetric Airy beams that exhibit an abruptly autofocusing feature are also demonstrated to be capable of carrying OAM in the optical domain. However, due to the lack of efficient devices to manipulate terahertz (THz) beams, it could be a challenge to demonstrate the radially symmetric Airy beams in the THz domain. Here we demonstrate the THz circular Airy vortex beams (CAVBs) with a 0.3-THz continuous wave through 3D printing technology. Assisted by the rapidly 3D-printed phase plates, individual OAM states with topological charge l ranging from l = 0 to l = 3 and a multiplexed OAM state are successfully imposed into the radially symmetric Airy beams. We both numerically and experimentally investigate the propagation dynamics of the generated THz CAVBs, and the simulations agree well with the observations. PMID- 28634342 TI - Natural canopy bridges effectively mitigate tropical forest fragmentation for arboreal mammals. AB - Linear infrastructure development and resulting habitat fragmentation are expanding in Neotropical forests, and arboreal mammals may be disproportionately impacted by these linear habitat clearings. Maintaining canopy connectivity through preservation of connecting branches (i.e. natural canopy bridges) may help mitigate that impact. Using camera traps, we evaluated crossing rates of a pipeline right-of-way in a control area with no bridges and in a test area where 13 bridges were left by the pipeline construction company. Monitoring all canopy crossing points for a year (7,102 canopy camera nights), we confirmed bridge use by 25 mammal species from 12 families. With bridge use beginning immediately after exposure and increasing over time, use rates were over two orders of magnitude higher than on the ground. We also found a positive relationship between a bridge's use rate and the number of species that used it, suggesting well-used bridges benefit multiple species. Data suggest bridge use may be related to a combination of bridge branch connectivity, multiple connections, connectivity to adjacent forest, and foliage cover. Given the high use rate and minimal cost, we recommend all linear infrastructure projects in forests with arboreal mammal populations include canopy bridges. PMID- 28634343 TI - Falling Direction can Predict the Mechanism of Recurrent Falls in Advanced Parkinson's Disease. AB - Falls are a common and disabling symptom in patients with Parkinson's disease (PD). For prevention, it is important to understand the pathophysiology of falls in PD patients, but the predictors for the possible mechanisms underlying such falls have not been clearly elucidated. In this prospective observational study, we investigated the implications of falling direction to predict the mechanisms of recurrent falls in PD patients. We enrolled 62 recurrent fallers with PD and divided them into two groups according to the main falling directions: 45 PD fallers who fell forward (forward fallers), and 17 PD fallers who fell in the other directions (non-forward fallers). Although there was no difference in demographic data, parkinsonism, or frontal lobe function, forward fallers showed more severe falls and tended to fall during walking or turning, while non-forward fallers usually fell during sitting/standing or turning. Additionally, forward fallers revealed higher score on a freezing of gait (FOG) questionnaire. Logistic regression analysis demonstrated that FOG was associated with falling forward, while balance impairment, akinetic-rigid subtype, and neuropsychiatric symptoms were associated with falling into the other directions. Our results indicate that FOG and balance impairment are two major mechanisms for recurrent falling in PD patients, and falling direction is an important predictor for these mechanisms. PMID- 28634344 TI - OmniGA: Optimized Omnivariate Decision Trees for Generalizable Classification Models. AB - Classification problems from different domains vary in complexity, size, and imbalance of the number of samples from different classes. Although several classification models have been proposed, selecting the right model and parameters for a given classification task to achieve good performance is not trivial. Therefore, there is a constant interest in developing novel robust and efficient models suitable for a great variety of data. Here, we propose OmniGA, a framework for the optimization of omnivariate decision trees based on a parallel genetic algorithm, coupled with deep learning structure and ensemble learning methods. The performance of the OmniGA framework is evaluated on 12 different datasets taken mainly from biomedical problems and compared with the results obtained by several robust and commonly used machine-learning models with optimized parameters. The results show that OmniGA systematically outperformed these models for all the considered datasets, reducing the F1 score error in the range from 100% to 2.25%, compared to the best performing model. This demonstrates that OmniGA produces robust models with improved performance. OmniGA code and datasets are available at www.cbrc.kaust.edu.sa/omniga/. PMID- 28634346 TI - Generating conditional gene knockouts in Plasmodium - a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR/Cas9. AB - Successful establishment of CRISPR/Cas9 genome editing technology in Plasmodium spp. has provided a powerful tool to transform Plasmodium falciparum into a genetically more tractable organism. Conditional gene regulation approaches are required to study the function of gene products critical for growth and erythrocyte invasion of blood stage parasites. Here we employ CRISPR/Cas9 to facilitate use of the dimerisable Cre-recombinase (DiCre) that is frequently used to mediate the excision and loss of loxP-flanked DNA sequences in a rapamycin controlled manner. We describe novel CRISPR/Cas9 transfection plasmids and approaches for the speedy, stable and marker-free introduction of transgenes encoding the DiCre recombinase into genomic loci dispensable for blood stage development. Together these plasmids form a toolkit that will allow the rapid generation of transgenic DiCre-expressing P. falciparum lines in any genetic background. Furthermore, the newly developed 3D7-derived parasite lines, constitutively and stably expressing DiCre, generated using this toolkit will prove useful for the analysis of gene products. Lastly, we introduce an improved treatment protocol that uses a lower rapamycin concentration and shorter treatment times, leading to loxP-guided recombination with close to 100% efficiency within the same replication cycle. PMID- 28634345 TI - Sirtuin 3 deficiency does not alter host defenses against bacterial and fungal infections. AB - Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase. SIRT3 regulates cell metabolism and redox homeostasis, and protects from aging and age-associated pathologies. SIRT3 may drive both oncogenic and tumor-suppressive effects. SIRT3 deficiency has been reported to promote chronic inflammation-related disorders, but whether SIRT3 impacts on innate immune responses and host defenses against infections remains essentially unknown. This aspect is of primary importance considering the great interest in developing SIRT3-targeted therapies. Using SIRT3 knockout mice, we show that SIRT3 deficiency does not affect immune cell development and microbial ligand-induced proliferation and cytokine production by splenocytes, macrophages and dendritic cells. Going well along with these observations, SIRT3 deficiency has no major impact on cytokine production, bacterial burden and survival of mice subjected to endotoxemia, Escherichia coli peritonitis, Klebsiella pneumoniae pneumonia, listeriosis and candidiasis of diverse severity. These data suggest that SIRT3 is not critical to fight infections and support the safety of SIRT3-directed therapies based on SIRT3 activators or inhibitors for treating metabolic, oncologic and neurodegenerative diseases without putting patients at risk of infection. PMID- 28634347 TI - Decreased circulating Zinc levels in Parkinson's disease: a meta-analysis study. AB - There is no consensus on the involvement of zinc (Zn) dysfunctions in Parkinson's Disease (PD). We performed a meta-analysis to evaluate whether circulating Zn levels in the serum, plasma, and cerebrospinal fluid (CSF) are altered in PD. Twenty-three published studies were selected by searching the databases of PubMed and China National Knowledge Infrastructure (CNKI). A total of 803 PD patients and 796 controls, 342 PD patients and 392 controls, and 135 PD patients and 93 controls were included to study Zn levels in the serum, plasma, and CSF, respectively. Our meta-analysis showed that the serum Zn levels were significantly lower in PD patients compared with health controls (SMD = -0.59; 95% CI [-1.06, -0.12]; P = 0.014). A reduced Zn levels in PD patients were found when serum and plasma studies were analyzed together (SMD = -0.60, 95% CI [-0.98; -0.22]; p = 0.002). PD patients had a tendency toward reduced CSF Zn levels compared with health controls (SMD = -0.50; 95% CI [-1.76, 0.76]; P = 0.439), but no statistical significance was obtained and this data did not allow conclusions due to a small sample size of CSF studies. This study suggests that reduced Zn levels in the serum and plasma are associated with an increased risk for PD. PMID- 28634348 TI - Distinct arsenic metabolites following seaweed consumption in humans. AB - Seaweeds contain arsenic primarily in the form of arsenosugars, which can be metabolized to a wide range of arsenic compounds. To characterize human exposure to arsenic from seaweed consumption, we determined concentrations of arsenic species in locally available seaweeds, and assessed urinary arsenic compounds in an experimental feeding study. A total of 11 volunteers consumed 10 g per day of three types of seaweeds (nori, kombu, and wakame) for three days each, while abstaining from rice and seafood following a three-day washout period. Urinary arsenosugars and their metabolites (including dimethyl arsenate (DMA), thio dimethylarsinoylethanol (thio-DMAE), thio-dimethylarsinoylacetate (thio-DMAA), and thio-DMA) were measured in spot urine samples prior to seaweed consumption, and in 24-hour urine samples while consuming seaweed. Commercial products made from whole seaweed had substantial concentrations of arsenic (12-84 ug/g), dominated by arsenosugars. Intact arsenosugars along with DMA, thio-DMAA, thio DMAE all increased in urine after ingesting each type of seaweed, and varied between seaweed types and between individuals. Only trace levels of the known toxic metabolite, thio-DMA, were observed, across individuals. Thio-DMAE and thio DMAA are unique products of arsenosugar breakdown, thus assessment of these compounds may help to identify dietary intake of arsenic from seaweed from other exposure pathways. PMID- 28634349 TI - Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson's disease. AB - Recent studies have demonstrated that hyperphosphorylation of tau protein plays a role in neuronal toxicities of alpha-synuclein (ASYN) in neurodegenerative disease such as familial Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease. Using a transgenic mouse model of Parkinson's disease (PD) that expresses GFP-ASYN driven by the PDGF-beta promoter, we investigated how accumulation of ASYN impacted axonal function. We found that retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF) in DIV7 cultures of E18 cortical neurons was markedly impaired at the embryonic stage, even though hyperphosphorylation of tau was not detectable in these neurons at this stage. Interestingly, we found that overexpressed ASYN interacted with dynein and induced a significant increase in the activated levels of small Rab GTPases such as Rab5 and Rab7, both key regulators of endocytic processes. Furthermore, expression of ASYN resulted in neuronal atrophy in DIV7 cortical cultures of either from E18 transgenic mouse model or from rat E18 embryos that were transiently transfected with ASYN-GFP for 72 hrs. Our studies suggest that excessive ASYN likely alters endocytic pathways leading to axonal dysfunction in embryonic cortical neurons in PD mouse models. PMID- 28634350 TI - A subset of cerebrovascular pericytes originates from mature macrophages in the very early phase of vascular development in CNS. AB - Pericytes are believed to originate from either mesenchymal or neural crest cells. It has recently been reported that pericytes play important roles in the central nervous system (CNS) by regulating blood-brain barrier homeostasis and blood flow at the capillary level. However, the origin of CNS microvascular pericytes and the mechanism of their recruitment remain unknown. Here, we show a new source of cerebrovascular pericytes during neurogenesis. In the CNS of embryonic day 10.5 mouse embryos, CD31+F4/80+ hematopoietic lineage cells were observed in the avascular region around the dorsal midline of the developing midbrain. These cells expressed additional macrophage markers such as CD206 and CD11b. Moreover, the CD31+F4/80+ cells phagocytosed apoptotic cells as functionally matured macrophages, adhered to the newly formed subventricular vascular plexus, and then divided into daughter cells. Eventually, these CD31+F4/80+ cells transdifferentiated into NG2/PDGFRbeta/desmin-expressing cerebrovascular pericytes, enwrapping and associating with vascular endothelial cells. These data indicate that a subset of cerebrovascular pericytes derive from mature macrophages in the very early phase of CNS vascular development, which in turn are recruited from sites of embryonic hematopoiesis such as the yolk sac by way of blood flow. PMID- 28634351 TI - A Dynamical Model for Activating and Silencing the Mitotic Checkpoint. AB - The spindle assembly checkpoint (SAC) is an evolutionarily conserved mechanism, exclusively sensitive to the states of kinetochores attached to microtubules. During metaphase, the anaphase-promoting complex/cyclosome (APC/C) is inhibited by the SAC but it rapidly switches to its active form following proper attachment of the final spindle. It had been thought that APC/C activity is an all-or nothing response, but recent findings have demonstrated that it switches steadily. In this study, we develop a detailed mathematical model that considers all 92 human kinetochores and all major proteins involved in SAC activation and silencing. We perform deterministic and spatially-stochastic simulations and find that certain spatial properties do not play significant roles. Furthermore, we show that our model is consistent with in-vitro mutation experiments of crucial proteins as well as the recently-suggested rheostat switch behavior, measured by Securin or CyclinB concentration. Considering an autocatalytic feedback loop leads to an all-or-nothing toggle switch in the underlying core components, while the output signal of the SAC still behaves like a rheostat switch. The results of this study support the hypothesis that the SAC signal varies with increasing number of attached kinetochores, even though it might still contain toggle switches in some of its components. PMID- 28634352 TI - Differences in sequences between HBV-relaxed circular DNA and covalently closed circular DNA. AB - The hepatitis B virus (HBV) genome exists in two forms: circular covalently closed DNA (cccDNA) and relaxed circular DNA (RCDNA). Here, we investigated the presence of differences in the sequences of both forms in paired samples of serum and liver tissue. The serum and liver biopsy samples were collected at the same time from 67 chronically infected patients. The genotyping of the RCDNA and cccDNA was performed using mass spectrometry analysis. The HBV mutations located in the HBV pol (P) and the HBV basal core promoter/pre-core (BCP/PC) regions were included. The BCP/PC and P sequences of the RCDNA extracted from liver and blood samples were different in 39% and 16% of patients, respectively. Differences were also found between RCDNA and cccDNA extracted from the same liver specimen. Moreover, the cccDNA BCP/PC region sequence had an impact on various virological and clinical parameters. We demonstrated that there are differences between the RCDNA and cccDNA sequences that were extracted from the same liver tissue. However, further investigations are needed to analyze whether the mutations in the cccDNA are conserved and whether cccDNA serves as a 'mutation storage' pool for HBV. This result could have profound implications for the subsequent therapy choices for treatment-experienced patients. PMID- 28634353 TI - Coronavirus HKU15 in respiratory tract of pigs and first discovery of coronavirus quasispecies in 5'-untranslated region. AB - Coronavirus HKU15 is a deltacoronavirus that was discovered in fecal samples of pigs in Hong Kong in 2012. Over the past three years, Coronavirus HKU15 has been widely detected in pigs in East/Southeast Asia and North America and has been associated with fatal outbreaks. In all such epidemiological studies, the virus was generally only detected in fecal/intestinal samples. In this molecular epidemiology study, we detected Coronavirus HKU15 in 9.6% of the nasopharyngeal samples obtained from 249 pigs in Hong Kong. Samples that tested positive were mostly collected during winter. Complete genome sequencing of the Coronavirus HKU15 in two nasopharyngeal samples revealed quasispecies in one of the samples. Two of the polymorphic sites involved indels, but the other two involved transition substitutions. Phylogenetic analysis showed that the two nasopharyngeal strains in the present study were most closely related to the strains PDCoV/CHJXNI2/2015 from Jiangxi, China, and CH/Sichuan/S27/2012 from Sichuan, China. The outbreak strains in the United States possessed highly similar genome sequences and were clustered monophyletically, whereas the Asian strains were more diverse and paraphyletic. The detection of Coronavirus HKU15 in respiratory tracts of pigs implies that in addition to enteric infections, Coronavirus HKU15 may be able to cause respiratory infections in pigs and that in addition to fecal-oral transmission, the virus could possibly spread through the respiratory route. The presence of the virus in respiratory samples provides an alternative clinical sample to confirm the diagnosis of Coronavirus HKU15 infection. Quasispecies were unprecedentedly observed in the 5'-untranslated region of coronavirus genomes. PMID- 28634354 TI - Primary osteomyelitis caused by an NDM-1-producing K. pneumoniae strain of the highly virulent sequence type 23. PMID- 28634355 TI - Longitudinal study of Middle East Respiratory Syndrome coronavirus infection in dromedary camel herds in Saudi Arabia, 2014-2015. AB - Two herds of dromedary camels were longitudinally sampled with nasal and rectal swabs and serum, between September 2014 and May 2015, and the samples were tested for Middle East Respiratory Syndrome (MERS) coronavirus RNA and antibodies. Evidence of MERS-CoV infection was confirmed in one herd on the basis of detection of virus RNA in nasal swabs from three camels and significant increases in the antibody titers from three others. The three viruses were genetically identical, thus indicating introduction of a single virus into this herd. There was evidence of reinfection of camels that were previously seropositive, thus suggesting that prior infection does not provide complete immunity from reinfection, a finding that is relevant to camel vaccination strategies as a means to prevent zoonotic transmission. PMID- 28634356 TI - An outbreak of echovirus 18 encephalitis/meningitis in children in Hebei Province, China, 2015. PMID- 28634357 TI - Astroviruses in bats, Madagascar. PMID- 28634358 TI - HIV-1 gp41-targeting fusion inhibitory peptides enhance the gp120-targeting protein-mediated inactivation of HIV-1 virions. AB - Protein- or peptide-based viral inactivators are being developed as novel antiviral drugs with improved efficacy, pharmacokinetics and toxicity profiles because they actively inactivate cell-free human immunodeficiency virus type 1 (HIV-1) virions before attachment to host cells. By contrast, most clinically used antiviral drugs must penetrate host cells to inhibit viral replication. In this study, we pre-treated HIV-1 particles with a gp120-targeting bispecific multivalent protein, 2Dm2m or 4Dm2m, in the presence or absence of the gp41 targeting HIV-1 fusion inhibitory peptides enfuvirtide (T20), T2635, or sifuvirtide (SFT). HIV-1 virions were separated from the inhibitors using PEG 6000, followed by testing of the residual infectivity of the HIV-1 virions. 2Dm2m and 4Dm2m exhibited significant inactivation activity against all HIV-1 strains tested with EC50 values at the low nanomolar level, whereas none of the gp41 targeting peptides showed inactivation activity at concentrations up to 250 nM. Notably, these three peptides significantly enhanced protein-mediated inactivation against cell-free HIV-1 virions, including HIV-1 laboratory-adapted and primary HIV-1 strains, as well as those resistant to T20 or T2635 and virions released from reactivated latently HIV-1-infected cells. These results indicate that the gp120-targeting bispecific multivalent proteins 2Dm2m and 4Dm2m have potential for further development as HIV-1 inactivator-based antiviral drugs for use in the clinic, either alone or in combination with a gp41-targeting HIV-1 fusion inhibitor such as T20, to treat patients with HIV-1 infection and AIDS. PMID- 28634359 TI - Infections of horses and shrews with Bornaviruses in Upper Austria: a novel endemic area of Borna disease. AB - Borna disease, a lethal infection with Borna disease virus-1 (BoDV-1), was diagnosed in four horses from Upper Austria in 2015 and 2016. All cases occurred in winter (two cases in February 2015 and two cases in December 2016), and the maximal distance of the affected stables was 17 km. To demonstrate whether the causative agent was also harbored by its reservoir host, the bicolored white toothed shrew (Crocidura leucodon), 28 shrews from this geographic area were collected in 2015 and investigated for the presence of BoDV-1. The shrew species were identified according to taxonomic clues and molecular barcodes. Affected horses and all shrews were investigated using histology, immunohistochemistry (IHC) and reverse transcription PCR. The horses exhibited severe nonpurulent encephalitis. Large amounts of BoDV-1 antigen were identified in their CNS. Among the 28 shrews, nine were identified as C. leucodon and 13 as Sorex araneus (Common shrew; Eurasian shrew). Six C. leucodon (66.7%) and one S. araneus (7.7%) had BoDV-1 infections. In accordance with previous findings, the IHC of C. leucodon exhibited a high amount of viral antigen in many neural and extraneural tissues. By contrast, the single positive S. araneus had an exclusively neural staining pattern. Of all positive samples, whole-genome BoDV-1 sequences were generated. The acquired sequences of the affected shrews were not identical to each other and clustered around the sequences of the diseased horses belonging, surprisingly, to the German 'strain V' cluster. PMID- 28634360 TI - Missing magnetism in Sr4Ru3O10: Indication for Antisymmetric Exchange Interaction. AB - Metamagnetism occuring inside a ferromagnetic phase is peculiar. Therefore, Sr4Ru3O10, a T C = 105 K ferromagnet, has attracted much attention in recent years, because it develops a pronounced metamagnetic anomaly below T C for magnetic fields applied in the crystallographic ab-plane. The metamagnetic transition moves to higher fields for lower temperatures and splits into a double anomaly at critical fields H c1 = 2.3 T and H c2 = 2.8 T, respectively. Here, we report a detailed study of the different components of the magnetization vector as a function of temperature, applied magnetic field, and varying angle in Sr4Ru3O10. We discover for the first time a reduction of the magnetic moment in the plane of rotation at the metamagnetic transition. The anomaly shifts to higher fields by rotating the field from H ? c to H || c. We compare our experimental findings with numerical simulations based on spin reorientation models taking into account magnetocrystalline anisotropy, Zeeman effect and antisymmetric exchange interactions. While Magnetocrystalline anisotropy combined with a Zeeman term are sufficient to explain a metamagnetic transition in Sr4Ru3O10, a Dzyaloshinskii-Moriya term is crucial to account for the reduction of the magnetic moment as observed in the experiments. PMID- 28634361 TI - Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice. AB - Uridine, one of the four components that comprise RNA, has attracted attention as a novel therapeutic modulator of inflammation. However, very little is known about its effect on intestinal inflammation. The aim of the present study was to investigate the potential protective effect of intracolonic administered uridine against DSS induced colitis in male C57BL/6 mice. Intracolonic instillation of 3 doses of uridine 1 mg/Kg (lower dose), 5 mg/Kg (medium dose), and 10 mg/Kg (higher dose) in saline was performed daily. Uridine at medium and high dose significantly reduced the severity of colitis (DAI score) and alleviated the macroscopic and microscopic signs of the disease. The levels of proinflammatory cytokines IL-6, IL-1beta and TNF in serum as well as mRNA expression in colon were significantly reduced in the uridine treated groups. Moreover, colon tissue myloperoxidase activities, protein expression of IL-6, TNF- alpha, COX-2, P-NFkB and P-Ikk-betaalpha in the colon tissues were significantly reduced in medium and high dose groups. These findings demonstrated that local administration of uridine alleviated experimental colitis in male C57BL/6 mice accompanied by the inhibition of neutrophil infiltration and NF-kappaB signaling. Thus, Uridine may be a promising candidate for future use in the treatment of inflammatory bowel disease. PMID- 28634362 TI - Reconstructing the phylogeny of Blattodea: robust support for interfamilial relationships and major clades. AB - Cockroaches are among the most recognizable of all insects. In addition to their role as pests, they play a key ecological role as decomposers. Despite numerous studies of cockroach phylogeny in recent decades, relationships among most major lineages are yet to be resolved. Here we examine phylogenetic relationships among cockroaches based on five genes (mitochondrial 12S rRNA, 16S rRNA, COII; nuclear 28S rRNA and histone H3), and infer divergence times on the basis of 8 fossils. We included in our analyses sequences from 52 new species collected in China, representing 7 families. These were combined with data from a recent study that examined these same genes from 49 species, resulting in a significant increase in taxa analysed. Three major lineages, Corydioidea, Blaberoidea, and Blattoidea were recovered, the latter comprising Blattidae, Tryonicidae, Lamproblattidae, Anaplectidae, Cryptocercidae and Isoptera. The estimated age of the split between Mantodea and Blattodea ranged from 204.3 Ma to 289.1 Ma. Corydioidea was estimated to have diverged 209.7 Ma (180.5-244.3 Ma 95% confidence interval [CI]) from the remaining Blattodea. The clade Blattoidea diverged from their sister group, Blaberoidea, around 198.3 Ma (173.1-229.1 Ma). The addition of the extra taxa in this study has resulted in significantly higher levels of support for a number of previously recognized groupings. PMID- 28634363 TI - Long-term health outcomes in patients with Prader-Willi Syndrome: a nationwide cohort study in Denmark. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a rare congenital disease that affects growth, sexual development, cognitive function and behavior. Individuals exhibit food preoccupation and hyperphagia, which may lead to obesity with premature morbidity and mortality. The aim of this work was to evaluate the risk of venous thromboembolisms (VTEs), myocardial infarction, pulmonary hypertension, sleep apnea, depression, anxiety and all-cause mortality among persons with PWS as compared with an age- and sex-matched general-population cohort. METHODS: All persons diagnosed with PWS (n=155) were identified in the Danish Health Registries; an age- and sex-matched comparison group was selected from the general population of Denmark (n=15 500); diseases of interest were identified through the health registry and cause of death register. Follow-up began on date of birth or first medical record availability through to first occurrence of an outcome of interest; follow-up ceased at emigration from Denmark or end of study. Incidence rates (IRs) were calculated and Cox's proportional hazards models were used to understand the relative risk (RR) of disease. RESULTS: The IRs for VTE among patients with PWS was 144 (60-347) per 100 000 person-years. Risks for VTE events and all-cause mortality were 9.4 times (95% confidence interval (CI): 3.7 23.5) and 11.0 times (95% CI: 5.7-21.1) higher, respectively, for patients with PWS versus the general population. Increased risks were also found individually for deep venous thromboses (DVTs) (RR: 9.1; 95% CI: 3.2-25.2), pulmonary embolisms (RR: 11.0; 95% CI: 1.4-86.9), myocardial infarction (RR: 7.2; 95% CI: 1.7-30.2) and anxiety (RR: 2.8; 95% CI: 1.0-7.5). No cases of pulmonary hypertension, sleep apnea or depressive disorders were identified within this PWS cohort. CONCLUSIONS: Multiple cardiovascular and behavioral illnesses are more likely to occur among patients with PWS than within the general population. These increased risks may provide an impetus for enhanced disease prevention, screening, diagnosis and treatment. PMID- 28634364 TI - Lipid changes 8 years post gastric bypass in adolescents with severe obesity (FABS-5+ study). AB - OBJECTIVE: Severe obesity in adolescents is increasing and few effective treatments exist. Bariatric surgery is one option, but the extent to which surgery influences cardiovascular risk factors over time in youth is not clear. We hypothesized that Roux-en Y gastric bypass (RYGB) would be associated with sustained improvements in lipids over time (>5 years). PARTICIPANTS/METHODS: Youth who underwent RYGB from 2001 to 2007 were recruited for the Follow-up of Adolescent Bariatric Surgery-5+ (FABS-5+) in 2011-2014. Baseline body mass index (BMI) and lipids were abstracted from medical records. Follow-up data were obtained at a research visit. Analyses included paired t-tests to assess changes in BMI and lipids over time. General linear models were used to evaluate predictors of high-density lipoprotein (HDL) and non-HDL-cholesterol at follow up. A non-operative group was recruited for comparison. RESULTS: Surgical participants (n=58) were a mean+/-s.d. age of 17+/-2 years at baseline and 25+/-2 years at long-term follow-up. Eighty-six percent were Caucasian and 64% were female. At long-term follow-up BMI decreased by 29% and all lipids (except total cholesterol) significantly improved (P<0.01). Female sex was a significant predictor of non-HDL-cholesterol level at 1 year, while change in BMI from 1 year to long-term follow-up was a significant predictor of non-HDL-cholesterol and HDL cholesterol during the same interval (P<0.05). In the non-operative group, BMI increased by 8% and lipid parameters were unchanged. CONCLUSIONS: This is the longest and most complete follow-up of youth following RYGB. Weight loss maintenance over time was significantly associated with improvements in lipid profile over 5 years. PMID- 28634365 TI - Different levels of blood pressure, different benefit from dual antiplatelet therapy in minor stroke or TIA patients. AB - The study aimed to evaluate whether the benefits of dual antiplatelet therapy would be influenced by blood pressure (BP) levels, among acute minor stroke or transient ischemic attack (TIA). In CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling cerebrovascular Events) trail, Patients were stratified by systolic BP (SBP) and diastolic BP (DBP) level measured on admission, respectively, using the supine position BP within 24 hours after symptoms onset. The primary efficacy outcome was stroke recurrence, bleeding was the safety outcome. Patients with SBP >= 140 mmHg, dual antiplatelet treatment could reduce the risk of stroke recurrence significantly (HR 0.654, 95% CI 0.529-0.793, p < 0.001) than mono antiplatelet therapy. And patients with DBP >= 90 mmHg, clopidogrel-aspirin significantly reduced the risk of recurrent stroke (HR 0.588, 95% CI 0.463-0.746, p < 0.001), compared with aspirin alone. However, in patients with SBP < 140 mmHg or DBP < 90 mmHg, no significant difference was observed between clopidogrel plus aspirin and aspirin alone. there was no difference in bleeding episodes by treatment assignment across categories of SBP or DBP. Patients with SBP >= 140 mmHg or DBP >= 90 mmHg after minor stroke or TIA got more benefits from dual antiplatelet therapy. Bleeding risk from dual antiplatelet treatment did not increase among patients with higher BP level on admission. PMID- 28634366 TI - Quantifying non-ergodicity of anomalous diffusion with higher order moments. AB - Anomalous diffusion is being discovered in a fast growing number of systems. The exact nature of this anomalous diffusion provides important information on the physical laws governing the studied system. One of the central properties analysed for finite particle motion time series is the intrinsic variability of the apparent diffusivity, typically quantified by the ergodicity breaking parameter EB. Here we demonstrate that frequently EB is insufficient to provide a meaningful measure for the observed variability of the data. Instead, important additional information is provided by the higher order moments entering by the skewness and kurtosis. We analyse these quantities for three popular anomalous diffusion models. In particular, we find that even for the Gaussian fractional Brownian motion a significant skewness in the results of physical measurements occurs and needs to be taken into account. Interestingly, the kurtosis and skewness may also provide sensitive estimates of the anomalous diffusion exponent underlying the data. We also derive a new result for the EB parameter of fractional Brownian motion valid for the whole range of the anomalous diffusion parameter. Our results are important for the analysis of anomalous diffusion but also provide new insights into the theory of anomalous stochastic processes. PMID- 28634367 TI - Proteomic analysis reveals large amounts of decomposition enzymes and major metabolic pathways involved in algicidal process of Trametes versicolor F21a. AB - A recent algicidal mode indicates that fungal mycelia can wrap and eliminate almost all co-cultivated algal cells within a short time span. However, the underlying molecular mechanism is rarely understood. We applied proteomic analysis to investigate the algicidal process of Trametes versicolor F21a and identified 3,754 fungal proteins. Of these, 30 fungal enzymes with endo- or exoglycosidase activities such as beta-1,3-glucanase, alpha-galactosidase, alpha glucosidase, alginate lyase and chondroitin lyase were significantly up regulated. These proteins belong to Glycoside Hydrolases, Auxiliary Activities, Carbohydrate Esterases and Polysaccharide Lyases, suggesting that these enzymes may degrade lipopolysaccharides, peptidoglycans and alginic acid of algal cells. Additionally, peptidase, exonuclease, manganese peroxidase and cytochrome c peroxidase, which decompose proteins and DNA or convert other small molecules of algal cells, could be other major decomposition enzymes. Gene Ontology and KEGG pathway enrichment analysis demonstrated that pyruvate metabolism and tricarboxylic acid cycle pathways play a critical role in response to adverse environment via increasing energy production to synthesize lytic enzymes or uptake molecules. Carbon metabolism, selenocompound metabolism, sulfur assimilation and metabolism, as well as several amino acid biosynthesis pathways could play vital roles in the synthesis of nutrients required by fungal mycelia. PMID- 28634368 TI - Preparation and Properties of A Hyperbranch-Structured Polyamine adsorbent for Carbon Dioxide Capture. AB - A fibrous adsorbent with amino-terminated hyperbranch structure (PP-AM-HBP-NH2) was prepared by grafting hyperbranched polyamine (HBP-NH2) onto the acrylamide modified polypropylene (PP) fibers. The grafting of AM on PP fibers provided the active sites for introducing HBP-NH2 onto the PP fibers. This kind of "grafting to" procedure to synthesize hyperbranch-structured fiber could overcome the disadvantages of stepwise growth procedure, avoiding the complicated synthesis process and the requirement of strict experimental conditions. The grafted HBP NH2 was three-dimensional dentritic architecture and had a large number of pores existing within the grafted polymers, which is favorable for CO2 molecules to diffuse into the HBP-NH2. Therefore, the as-prepared PP-AM-HBP-NH2 fibers showed a high adsorption capacity (5.64 mmol/g) for CO2 in the presence of water at 25 degrees C, and the utilization efficiency of alkyl amino groups could reach 88.2%, demonstrating that the hyperbranched structure of adsorbents can greatly promote adsorption capacity and efficiency. This could be attributed to better swelling properties and lower mass transfer resistance to CO2 of the hyperbranched adsorbent. PP-AM-HBP-NH2 also showed excellent regeneration performance, and it could maintain the same adsorption capacity for CO2 after 15 recycle numbers as the fresh adsorbent. PMID- 28634369 TI - Forecasting Effusive Dynamics and Decompression Rates by Magmastatic Model at Open-vent Volcanoes. AB - Effusive eruptions at open-conduit volcanoes are interpreted as reactions to a disequilibrium induced by the increase in magma supply. By comparing four of the most recent effusive eruptions at Stromboli volcano (Italy), we show how the volumes of lava discharged during each eruption are linearly correlated to the topographic positions of the effusive vents. This correlation cannot be explained by an excess of pressure within a deep magma chamber and raises questions about the actual contributions of deep magma dynamics. We derive a general model based on the discharge of a shallow reservoir and the magmastatic crustal load above the vent, to explain the linear link. In addition, we show how the drastic transition from effusive to violent explosions can be related to different decompression rates. We suggest that a gravity-driven model can shed light on similar cases of lateral effusive eruptions in other volcanic systems and can provide evidence of the roles of slow decompression rates in triggering violent paroxysmal explosive eruptions, which occasionally punctuate the effusive phases at basaltic volcanoes. PMID- 28634370 TI - Microbial Antigens Stimulate Metalloprotease-7 Secretion in Human B-Lymphocytes Using mTOR-Dependent and Independent Pathways. AB - Metalloproteinases (MMPs) contribute to tissue remodeling and acute inflammation not only by degrading extracellular matrix proteins but also by controlling the influx of chemokines through the regulation and shedding of syndecans. B lymphocytes, in addition to their well-known function as antibody producing cells, participate in the innate immune response by secreting inflammatory cytokines and chemokines. However, there is little information about the role of B-lymphocytes in the regulation of MMPs; consequently, herein we investigated whether activated human circulating B-lymphocytes contributed to the secretion of MMPs. We demonstrate that B-lymphocytes activated by un-methylated CpG motifs, found in bacterial DNA, and beta-glucans, found in the cell wall of fungi, both induced MMP-7. Interestingly, while CpG-stimulated cells activated the mTOR pathway via TLR9 receptor to induced MMP-7, beta-glucan-stimulated cells were mTOR-independent and used Dectin-1 receptor. B-lymphocytes did not seem to have a major role in the secretion of tissue inhibitors of metalloproteinases (TIMPs). However, secreted MMP-7 participated in the shedding of Syndecan-4 from the surface of B-lymphocytes. In conclusion, circulating human B-lymphocytes contribute to the regulation of the innate immune system by participating in the secretion of MMP-7 which in turn is important for the shedding of Syndecan-4 in response to infectious stimuli. PMID- 28634371 TI - Factors related to good asthma control using different medical adherence scales in Latvian asthma patients: an observational study. AB - : One of the main challenges in asthma control is adherence to pharmaceutical treatment. The aim of this study was to test the association between adherence to asthma medication, control and medical beliefs, cognitive and emotional perceptions using three different validated questionnaires. Beliefs about asthma medicine, cognitive and emotional factors were determined in a cross-sectional survey of patients attending outpatient pulmonologist practices in Latvia (n = 352). The validated Beliefs about Medicines Questionnaire and the Brief Illness Perception Questionnaire were used. Adherence to asthma medication was assessed using the Morisky Medication Adherence Scale and two different versions of the Medication Adherence Reporting Scale. Several questions about necessity or concerns related to pharmaceutical treatment were able to predict poor adherence according to the Morisky scale. If the patient felt that without the asthma medication his life would be impossible, his risk to have poor treatment adherence was 46% reduced (odds ratio 0.54; 95% confidence interval 0.33-0.89). Furthermore, asthma patients who were convinced that their health depends on the asthma treatment were less likely to have poor treatment adherence (odds ratio 0.56: 95% confidence interval 0.32-0.97). In case the patient was concerned by the need to constantly use asthma medication or sometimes concerned by long-term effects of asthma medication the odds of poor treatment adherence were 1.96 (95% confidence interval 1.19-3.24) and 2.43 (95% confidence interval 1.45-4.08), respectively. In conclusion, medication beliefs, particularly concerns and necessity of asthma treatment were associated with poor treatment adherence when assessed with the Morisky or 5-item Medication Adherence Reporting Scale. ASTHMA TREATMENT: INVESTIGATING POOR ADHERENCE IN THE LATVIAN POPULATION: Concerns about treatment necessity and uses of asthma medication are key factors influencing poor treatment adherence in Latvia. There are multiple psychological and behavioral reasons why patients do not adhere to asthma treatment courses, including social and religious beliefs, and perceptions of chronic illness. Patient questionnaires and 'adherence scales' can help predict whether patients are likely to follow advice, but their efficacy differs for individual nations. Dins Smits at Riga Stradins University, Latvia, and co-workers analyzed responses to three questionnaires completed by 352 asthma patients to assess treatment perceptions and the best questionnaire option for the Latvian population. Concerns about the use of asthma medication and beliefs about treatment necessity were key factors in poor adherence. These were picked up by the Morisky and MARS 5-item scales, which the authors recommend for future use. PMID- 28634372 TI - DNA methylation changes in endometrium and correlation with gene expression during the transition from pre-receptive to receptive phase. AB - The inner uterine lining (endometrium) is a unique tissue going through remarkable changes each menstrual cycle. Endometrium has its characteristic DNA methylation profile, although not much is known about the endometrial methylome changes throughout the menstrual cycle. The impact of methylome changes on gene expression and thereby on the function of the tissue, including establishing receptivity to implanting embryo, is also unclear. Therefore, this study used genome-wide technologies to characterize the methylome and the correlation between DNA methylation and gene expression in endometrial biopsies collected from 17 healthy fertile-aged women from pre-receptive and receptive phase within one menstrual cycle. Our study showed that the overall methylome remains relatively stable during this stage of the menstrual cycle, with small-scale changes affecting 5% of the studied CpG sites (22,272 out of studied 437,022 CpGs, FDR < 0.05). Of differentially methylated CpG sites with the largest absolute changes in methylation level, approximately 30% correlated with gene expression measured by RNA sequencing, with negative correlations being more common in 5' UTR and positive correlations in the gene 'Body' region. According to our results, extracellular matrix organization and immune response are the pathways most affected by methylation changes during the transition from pre receptive to receptive phase. PMID- 28634373 TI - An Assessment of Mobile Predator Populations along Shallow and Mesophotic Depth Gradients in the Hawaiian Archipelago. AB - Large-bodied coral reef roving predators (sharks, jacks, snappers) are largely considered to be depleted around human population centers. In the Hawaiian Archipelago, supporting evidence is primarily derived from underwater visual censuses in shallow waters (<=30 m). However, while many roving predators are present or potentially more abundant in deeper strata (30-100 m+), distributional information remains sparse. To partially fill that knowledge gap, we conducted surveys in the remote Northwestern Hawaiian Islands (NWHI) and populated Main Hawaiian Islands (MHI) from 2012-2014 using baited remote underwater stereo video. Surveys between 0-100 m found considerable roving predator community dissimilarities between regions, marked conspicuous changes in species abundances with increasing depth, and largely corroborated patterns documented during shallow water underwater visual censuses, with up to an order of magnitude more jacks and five times more sharks sampled in the NWHI compared to the MHI. Additionally, several species were significantly more abundant and larger in mesophotic versus shallow depths, which remains particularly suggestive of deep water refugia effects in the MHI. Stereo-video extends the depth range of current roving predator surveys in a more robust manner than was previously available, and appears to be well-suited for large-scale roving predator work in the Hawaiian Archipelago. PMID- 28634374 TI - Behavioural responses to potential dispersal cues in two economically important species of cereal-feeding eriophyid mites. AB - Passively dispersing organisms should optimise the time and direction of dispersal by employing behaviours that increase their probability of being successfully transported by dispersal agents. We rigorously tested whether two agriculturally important passively-dispersing eriophyoid species, wheat curl mite (WCM) and cereal rust mite (CRM), display behaviours indicating their readiness to depart from current host plants in the presence of potential dispersal cues: wind, an insect vector and presence of a fresh plant. Contrary to our expectations, we found that both species decreased their general activity in the presence of wind. When exposed to wind, WCM (but not CRM) significantly increased behaviour that has previously been considered to facilitate dispersal (in this case, standing vertically). Our study provides the first sound test of the function of what have been interpreted as dispersal-related behaviours of eriophyid mites. The low proportion of WCM exhibiting dispersal behaviour suggests there may be predisposed dispersers and residents in the population. Moreover, we found that WCM was generally more active than CRM, which is likely a contributing factor to its high invasive potential. PMID- 28634375 TI - Sea-level projections representing the deeply uncertain contribution of the West Antarctic ice sheet. AB - There is a growing awareness that uncertainties surrounding future sea-level projections may be much larger than typically perceived. Recently published projections appear widely divergent and highly sensitive to non-trivial model choices. Moreover, the West Antarctic ice sheet (WAIS) may be much less stable than previous believed, enabling a rapid disintegration. Here, we present a set of probabilistic sea-level projections that approximates the deeply uncertain WAIS contributions. The projections aim to inform robust decisions by clarifying the sensitivity to non-trivial or controversial assumptions. We show that the deeply uncertain WAIS contribution can dominate other uncertainties within decades. These deep uncertainties call for the development of robust adaptive strategies. These decision-making needs, in turn, require mission-oriented basic science, for example about potential signposts and the maximum rate of WAIS induced sea-level changes. PMID- 28634376 TI - Structural basis to stabilize the domain motion of BARD1-ARD BRCT by CstF50. AB - BRCA1 associated ring domain protein 1(BARD1) is a tumor suppressor protein having a wide role in cellular processes like cell-cycle checkpoint, DNA damage repair and maintenance of genomic integrity. Germ-line mutation Gln 564 His discovered in linker region of BARD1 leads to loss of binding to Cleavage stimulating factor (CstF50), which in turn instigates the premature mRNA transcript formation and apoptosis. We have studied the dynamics of ARD domain present in the BARD1 wild-type and mutant protein in association with CstF50 using biophysical, biochemical and molecular dynamics simulations. It has been observed that the ARD domain is relatively more flexible than the BRCT domain of BARD1. Further relative orientations of both the ARD and BRCT domains varies due to the highly flexible nature of the connecting linker region present between the domains. It has been observed that mutant ARD domain is more dynamic in nature compared to wild-type protein. Molecular docking studies between BARD1 Gln 564 His mutant and CstF50 shows the loss of interactions. Furthermore, domain motion of ARD present in BARD1 was stabilized when complexed with CstF50. PMID- 28634377 TI - Hepatoprotective and in vitro antioxidant effects of native depolymerised exopolysaccharides derived from Termitomyces albuminosus. AB - In this study, native depolymerised-exopolysaccharides (DEPS) were successfully derived from the exopolysaccharides (EPS) of Termitomyces albuminosus, and its hepatoprotective effects against a high-fat emulsion and in vitro antioxidant activities were investigated. Based on the results of in vitro assays, DEPS showed superior antioxidant activities compared with EPS dose-dependently. According to the in vivo assays both EPS and DEPS significantly decreased the lipid levels, improved the enzymatic activities, and reduced lipid peroxidation in both serum and hepatic homogenates. Furthermore, EPS and DEPS attenuated the high-fat emulsion-induced histopathological injury to the liver. Both EPS and DEPS might be used as natural drugs to treat and protect against hyperlipidaemia and liver injury induced by a high-fat emulsion. In addition, based on the results of GC and HPLC analyses, rhamnose and low molecular weight compounds may play an important role in contributing to the antioxidant activities of EPS and DEPS. PMID- 28634378 TI - Compact acceleration of energetic neutral atoms using high intensity laser-solid interaction. AB - Recent advances in high-intensity laser-produced plasmas have demonstrated their potential as compact charge particle accelerators. Unlike conventional accelerators, transient quasi-static charge separation acceleration fields in laser produced plasmas are highly localized and orders of magnitude larger. Manipulating these ion accelerators, to convert the fast ions to neutral atoms with little change in momentum, transform these to a bright source of MeV atoms. The emittance of the neutral atom beam would be similar to that expected for an ion beam. Since intense laser-produced plasmas have been demonstrated to produce high-brightness-low-emittance beams, it is possible to envisage generation of high-flux, low-emittance, high energy neutral atom beams in length scales of less than a millimeter. Here, we show a scheme where more than 80% of the fast ions are reduced to energetic neutral atoms and demonstrate the feasibility of a high energy neutral atom accelerator that could significantly impact applications in neutral atom lithography and diagnostics. PMID- 28634379 TI - The effect of weak acid anions on the selective catalytic wet air oxidation of aqueous ammonia to nitrogen. AB - In this work, the effect of weak acid anions on the ammonia removal has been extensively studied for the process of selective catalytic wet air oxidation (CWAO) of ammonia to nitrogen. It is found that the presence of weak acid anions can effectively enhance the ammonia conversion and selectivity towards nitrogen. The combination between the weak acid anions and H+ to produce weak acid molecules is responsible for such enhancement. Firstly, the H+ consumption of weak acid anions can increase the NH3 concentration and thus the reactivity of ammonia oxidation, due to the shift to NH3 on the equilibrium of NH4+/NH3. Secondly, the competition combination with H+ between the weak acid anions and NO2- can increase the concentration of NO2- and thus boosts the disproportionation reaction between NH4+ and NO2- to produce nitrogen. PMID- 28634380 TI - Late-onset Circulatory Collapse and Continuous Positive Airway Pressure are Useful Predictors of Treatment-requiring Retinopathy of Prematurity: A 9-year Retrospective Analysis. AB - Visual loss caused by retinopathy of prematurity (ROP) will be prevented if treatment-requiring ROP (TR-ROP) can be predicted. In this retrospective study including 418 infants with <=32 weeks of gestational age (GA) and/or <=1500 grams of birthweight, we attempted to identify useful predictors. We also examined the efficiency of significant predictors compared with existing predictive models, ROPScore and CHOP model. Multivariable logistic regression analyses supported the following factors were useful for predicting TR-ROP from all infants and infants with any ROP: GA (odds ratio [OR], 0.47 and 0.48), history of late-onset circulatory collapse (LCC) (OR, 2.76 and 2.44) and use of continuous positive airway pressure (CPAP) at 35 weeks of postmenstrual age (OR, 3.78 and 4.50). The comparison of areas under receiver operating characteristic curves indicated the combination of LCC, CPAP and ROPScore was better than ROPScore to predict TR-ROP from all infants and infants with any ROP (P = 0.007 and 0.02) and the combination of LCC, CPAP and CHOP model was also better than CHOP model to predict TR-ROP from all infants and infants with any ROP (P = 0.01 and 0.02). Our results suggested infants with a history of LCC and a long CPAP support have a high incidence of TR-ROP. PMID- 28634381 TI - Impact of initial active engagement in self-monitoring with a telemonitoring device on glycemic control among patients with type 2 diabetes. AB - This study aimed to investigate the effect of patient engagement in self monitoring with a telemonitoring device on glycemic control among patients with type 2 diabetes. We conducted a subanalysis of the telemonitoring device study in Kaiser Permanente Northern California members. We divided the telemonitoring group into 53 frequent and 54 infrequent users based on self-monitoring of blood glucose (SMBG) frequency of the first 6 weeks. The frequency of SMBG transmitted from the telemonitoring device was examined over 24 weeks. Clinic and laboratory tests were collected at baseline, 6 weeks and 6 months. There was no significant difference in baseline HbA1c level between the two groups. After 6 months, change in HbA1c was -2.4 +/- 1.6% among frequent users and -1.5 +/- 1.5% among infrequent users (p = 0.003). The proportion of patients achieving target HbA1C level at 6 months was significantly higher among frequent users than among infrequent users. An increased frequency of SMBG was significantly correlated with a reduction in HbA1c at 6 months. In conclusion, initial active engagement in self-monitoring with a telemonitoring device could provide incremental improvement of glycemic control over 6 months. PMID- 28634382 TI - Expression of P301L-hTau in mouse MEC induces hippocampus-dependent memory deficit. AB - Intracellular accumulation of abnormally phosphorylated tau in different types of neurons is a pathological characteristic of Alzheimer's disease (AD). While tau modification and associated neuronal loss and hypometabolism start in the entorhinal cortex (EC) in early AD patients, the mechanism by which mutant P301L hTau leads to dementia is not fully elucidated. Here, we studied the effects of P301L hTau transduction in the medial EC (MEC) of mice on tau phosphorylation and accumulation, and cognitive deficit. We found that the exogenous mutant tau protein was restricted in MEC without spreading to other brain regions at one month after transduction. Interestingly, expression of the mutant tau in MEC induces endogenous tau hyperphosphorylation and accumulation in hippocampus and cortex, and inhibits neuronal activity with attenuated PP-DG synapse plasticity, leading to hippocampus-dependent memory deficit with intact olfactory function. These findings suggest a novel neuropathological mechanism of early AD, which is initiated by tau accumulation in MEC, and demonstrate a tau pathological model of early stage AD. PMID- 28634383 TI - Discrepancy between objective and subjective cognition in adults with major depressive disorder. AB - This study aimed to determine: i) the correlation between objective and subjective cognition, ii) the correlates of objective and subjective cognition and iii) the predictors of discrepancy between objective and subjective cognition. Participants were non-elderly patients with major depressive disorder (MDD). We assessed subjective cognition using the Perceived Deficit Questionnaire for Depression (PDQ-D) and objective cognition using Face I and Face II tests of the Wechsler Memory Scale, 3rd edition and Digit Span and Matrix Reasoning tests of the Wechsler Intelligence Scale for Adults, 3rd edition. The discrepancy between objective and subjective cognition was estimated. Participants were 57 outpatients with MDD. PDQ-D scores were not correlated with composite neurocognitive test (NCT) z scores. Years of education significantly predicted composite NCT z scores, as did age. The 9-item Patient Health Questionnaire (PHQ 9) scores significantly predicted PDQ-D scores, as did antidepressant treatment. Age significantly predicted discrepancy scores, as did PHQ-9 scores. In conclusion, objective and subjective cognition in patients with MDD are not correlated. Age and education predict objective cognition. Depression. severity and antidepressant treatment predict subjective cognition. Age and depression severity may predict the discrepancy between objective and subjective cognition. PMID- 28634384 TI - Alternative splicing regulates distinct subcellular localization of Epithelial splicing regulatory protein 1 (Esrp1) isoforms. AB - Epithelial-Splicing-Regulatory-Protein 1 (Esrp1) is a cell-type specific RNA binding protein (RBP) that is essential for mammalian development through maintenance of epithelial cell properties including barrier function. Esrp1 also regulates splicing during the epithelial to mesenchymal transition (EMT). It contains three highly conserved RNA recognition motifs (RRMs) in the absence of other clearly defined protein domains. Esrp1 itself is also alternatively spliced to produce multiple protein isoforms. Here we determined that two competing alternative 5' splice sites in exon 12 yield Esrp1 isoforms with differential nucleocytoplasmic localization. We carried out a detailed characterization of the Esrp1 peptide that is sufficient to confer nuclear localization. Furthermore, we identified splice variants encoding distinct nuclear and cytoplasmic isoforms of fusilli, the D. Melanogaster Esrp1 ortholog. Our observations demonstrate that the production of both nuclear and cytoplasmic Esrp1 isoforms through alternative splicing is phylogenetically conserved; strongly suggesting it is biologically significant. Thus, while previous studies have described extensive regulation by nuclear Esrp1 to promote epithelial specific splicing, it will be of great interest to study the contribution of cytoplasmic Esrp1 in maintenance of epithelial cell functions. PMID- 28634385 TI - Vertical and bevel-structured SiC etching techniques incorporating different gas mixture plasmas for various microelectronic applications. AB - This study presents a detailed fabrication method, together with validation, discussion, and analysis, for state-of-the-art silicon carbide (SiC) etching of vertical and bevelled structures by using inductively coupled plasma reactive ion etching (ICP-RIE) for microelectronic applications. Applying different gas mixtures, a maximum bevel angle of 87 degrees (almost vertical), large-angle bevels ranging from 40 degrees to 80 degrees , and small-angel bevels ranging from 7 degrees to 17 degrees were achieved separately using distinct gas mixtures at different ratios. We found that SF6 with additive O2 was effective for vertical etching, with a best etching rate of 3050 A/min. As for the large angle bevel structures, BCl3 + N2 gas mixtures show better characteristics, exhibiting a controllable and large etching angle range from 40 degrees to 80 degrees through the adjustment of the mixture ratio. Additionally, a Cl2 + O2 mixture at different ratios is applied to achieve a small-angel bevels ranging from 7 degrees to 17 degrees . A minimum bevel angel of approximately 7 degrees was achieved under the specific volume of 2.4 sccm Cl2 and 3.6 sccm O2. These results can be used to improve performance in various microelectronic applications including MMIC via holes, PIN diodes, Schottky diodes, JFETs' bevel mesa, and avalanche photodiode fabrication. PMID- 28634386 TI - Shape and Composition Control of Monodisperse Hybrid Pt-CoO Nanocrystals by Controlling the Reaction Kinetics with Additives. AB - Here, we report the effect of Fe(CO)5 additives in the synthesis of branched Pt CoO nanowires (NWs) and core@shell concave nanocubes (NCs), in a one-pot system. Key to the success of this synthesis is control over the shape of the Pt seeds by controlling the quantity of Fe(CO)5 additive. In the absence of Fe(CO)5, branched Pt-CoO NWs were synthesized through the attachment of small Pt seed particles, followed by the growth of CoO by deposition. On the other hand, Pt@CoO concave NCs were obtained in the presence of Fe(CO)5 because of the stronger adsorption of Co on the Pt (100) surfaces than on the closely packed (111) surfaces. Also, various other conditions including the control of reducing agents, precursor concentrations, and stabilizing agents, were used to verify the effects of reaction kinetics on the synthesis of Pt-CoO nanoparticles. Compared to Pt/graphene oxide (GO) catalyst, branched Pt-CoO NWs supported on GO showed enhanced specific activity toward the oxygen reduction reaction (ORR). PMID- 28634387 TI - Quasiparticle and optical properties of strained stanene and stanane. AB - Quasiparticle band structures and optical properties of two dimensional stanene and stanane (fully hydrogenated stanene) are studied by the GW and GW plus Bethe Salpeter equation (GW-BSE) approaches, with inclusion of the spin-orbit coupling (SOC). The SOC effect is significant for the electronic and optical properties in both stanene and stanane, compared with their group IV-enes and IV-anes counterparts. Stanene is a semiconductor with a quasiparticle band gap of 0.10 eV. Stanane has a sizable band gap of 1.63 eV and strongly binding exciton with binding energy of 0.10 eV. Under strain, the quasiparticle band gap and optical spectrum of both stanene and stanane are tunable. PMID- 28634388 TI - Mito-xenophagic killing of bacteria is coordinated by a metabolic switch in dendritic cells. AB - Chlamydiae are bacterial pathogens that grow in vacuolar inclusions. Dendritic cells (DCs) disintegrate these compartments, thereby eliminating the microbes, through auto/xenophagy, which also promotes chlamydial antigen presentation via MHC I. Here, we show that TNF-alpha controls this pathway by driving cytosolic phospholipase (cPLA)2-mediated arachidonic acid (AA) production. AA then impairs mitochondrial function, which disturbs the development and integrity of these energy-dependent parasitic inclusions, while a simultaneous metabolic switch towards aerobic glycolysis promotes DC survival. Tubulin deacetylase/autophagy regulator HDAC6 associates with disintegrated inclusions, thereby further disrupting their subcellular localisation and stability. Bacterial remnants are decorated with defective mitochondria, mito-aggresomal structures, and components of the ubiquitin/autophagy machinery before they are degraded via mito-xenophagy. The mechanism depends on cytoprotective HSP25/27, the E3 ubiquitin ligase Parkin and HDAC6 and promotes chlamydial antigen generation for presentation on MHC I. We propose that this novel mito-xenophagic pathway linking innate and adaptive immunity is critical for effective DC-mediated anti-bacterial resistance. PMID- 28634389 TI - Novel indolyl-chalcone derivatives inhibit A549 lung cancer cell growth through activating Nrf-2/HO-1 and inducing apoptosis in vitro and in vivo. AB - Increasing evidence indicates that Nrf-2, named the nuclear factor-erythroid 2 related factor, may perform anticancer function. In this study, a series of novel substituted phenyl- (3-methyl-1H-indol-2-yl)-prop-2-en-1-one (indolyl-chalcone) derivatives were synthesized and their effects on Nrf-2 activity were observed. We found that compounds 3a-3d and 6c elevated Nrf-2 activity. Then we evaluated their anticancer activities in vitro and in vivo by utilizing human lung cancer cell line A549. The in vitro results showed that among the compounds, 3d performed effectively anti-growth activity by inducing A549 lung cancer cell apoptosis and activating Nrf-2/HO-1 (heme oxygenase-1) pathway. In vivo, we proved that compound 3d inhibited the tumor growth effectively through inducing cell apoptosis without affecting CAM normal angiogenesis. These data suggest that our discovery of a novel Nrf-2 activator compound 3d would provide a new point of human lung cancer treatment. PMID- 28634390 TI - Increased Glutamate in Somatosensory Cortex in Functional Dyspepsia. AB - Functional Dyspepsia-Post-prandial Distress Syndrome (FD-PDS) was associated with mood-related increases in resting activity and lowered activation threshold in the somatosensory cortex (SSC), insula and perigenual anterior cingulate cortex(pgACC) in functional imaging studies. The underlying cortical neurochemical changes are unknown. We performed proton Magnetic Resonance Spectroscopy (1H-MRS) on 17 consecutive tertiary clinic-recruited psychotropic naive Rome III FD-PDS female and 17 age-sex matched healthy controls. Voxels were placed on bilateral pgACC, left insula and SSC. Water-suppressed spectra were acquired using PRESS with short echo time (TE) (T = 24 ms) to separately quantify glutamate (Glu) and glutamine (Gln). Main outcome measure was regional Glu/Cr + PCr. Severity of depression, anxiety, somatization, and dyspepsia were also assessed. We found significantly increased SSC Glu/Cr + PCr in FD-PDS subjects compared to controls. SSC Glu/Cr + PCr correlated significantly with postprandial distress chronicity, dyspeptic symptoms severity and anxiety. The SSC Glu/Cr + PCr - dyspepsia correlations became insignificant after controlling for anxiety but were independent of depression. Gln/Glu ratio, which indicates glial Glu cycling failure, was unchanged. No between-group differences were noted in other regional metabolite concentrations. Our findings suggested enhanced SSC glutamate transmission in FD-PDS that was linked to post-prandial distress chronicity and severity and anxiety. PMID- 28634391 TI - Two alternative pathways for docosahexaenoic acid (DHA, 22:6n-3) biosynthesis are widespread among teleost fish. AB - Docosahexaenoic acid (DHA) plays important physiological roles in vertebrates. Studies in rats and rainbow trout confirmed that DHA biosynthesis proceeds through the so-called "Sprecher pathway", a biosynthetic process requiring a Delta6 desaturation of 24:5n-3 to 24:6n-3. Alternatively, some teleosts possess fatty acyl desaturases 2 (Fads2) that enable them to biosynthesis DHA through a more direct route termed the "Delta4 pathway". In order to elucidate the prevalence of both pathways among teleosts, we investigated the Delta6 ability towards C24 substrates of Fads2 from fish with different evolutionary and ecological backgrounds. Subsequently, we retrieved public databases to identify Fads2 containing the YXXN domain responsible for the Delta4 desaturase function, and consequently enabling these species to operate the Delta4 pathway. We demonstrated that, with the exception of Delta4 desaturases, fish Fads2 have the ability to operate as Delta6 desaturases towards C24 PUFA enabling them to synthesise DHA through the Sprecher pathway. Nevertheless, the Delta4 pathway represents an alternative route in some teleosts and we identified the presence of putative Delta4 Fads2 in a further 11 species and confirmed the function as Delta4 desaturases of Fads2 from medaka and Nile tilapia. Our results demonstrated that two alternative pathways for DHA biosynthesis exist in teleosts. PMID- 28634392 TI - The traditional Chinese medicine Achyranthes bidentata and our de novo conception of its metastatic chemoprevention: from phytochemistry to pharmacology. AB - Our recent biosystems analysis revealed similarities between embryonic implantation and cancer cell adhesion, which suggests that abortifacients may be good for safe and effective metastatic chemoprevention targeting circulating tumor cells (CTC). Here we test the hypothesis by using the well-known abortion herb Achyranthes bidentata Blume (A. bidentata). Five compounds were separated from the herb root. Among them, ginsenoside Ro was the most potent in inhibiting embryonic implantation within non-cytotoxic concentrations. It specifically inhibited the metastatic dissemination capability of colon cancer cells HT29, including the migration and invasion ability, and their adhesion to human endothelium through inhibiting integrin alphavbeta6, MMP-2, MMP-9, and ERK phosphorylation by HT29. Pretreatment of nude mice with oral ginsenoside Ro followed by HT29 intravenous inoculation and 40-day oral ginsenoside Ro significantly prevented lung metastasis with downregulation of integrin alphavbeta6 and no toxicity. The present study firstly introduces the new conception of utilizing safe and effective abortion botanic medicines for CTC based metastatic chemoprevention. PMID- 28634393 TI - A small-molecule DS44170716 inhibits Ca2+-induced mitochondrial permeability transition. AB - Mitochondria are involved in a variety of physiological and pathological processes. Ca2+ uptake is one of the important functions of the organelle for maintenance of cellular Ca2+ homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca2+ overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT. Here we report upon a small-molecule compound DS44170716 that inhibits Ca2+-induced MPT in rat liver isolated mitochondria. DS44170716 protects human liver HepG2 cells from Ca2+-induced death with a level of protection similar to cyclosporin A (CsA). The inhibitory mechanism of DS44170716 against MPT is independent on PPIF, a target of CsA. DS44170716 blocks Ca2+ flux into the mitochondria by decreasing mitochondrial membrane potential, while potently inhibiting mitochondrial complex III activities and weakly inhibiting complex IV and V activities. Similarly, complex III inhibitor antimycin A, complex IV inhibitor KCN or complex V inhibitor oligomycin inhibits Ca2+ uptake of isolated mitochondria. These results show that DS44170716 is a novel class inhibitor of MPT by blocking of mitochondrial complexes and Ca2+-overload into mitochondria. PMID- 28634394 TI - The roles of Toll-like receptor 4 in the pathogenesis of pathogen-associated biliary fibrosis caused by Clonorchis sinensis. AB - Pathogen-associated biliary fibrosis (PABF) is a type of liver fibrosis characterized by injuries of cholangiocytes and extra cellular matrix (ECM) deposition around bile ducts caused by various bacteria, fungi, virus and parasites. Recent studies show that TLR4 plays an important role in several other types of liver fibrosis, but the mechanism of TLR4 in PABF is yet really unclear. In the present study, a PABF mouse model was established by a trematode infection Clonorchis sinensis which dwells in the bile ducts and causes severe biliary fibrosis of mice. The results showed that the levels of collagen depositions, alpha-SMA and hydroxyproline (Hyp) contents in TLR4 mut mice infected by C. sinensis were significantly lower than in those of TLR4 wild ones. Furthermore, we found that the activation of TGF-beta signaling was impaired in the TLR4 mut mice, compared with wild mice when they were challenged to the same dose of C. sinensis metacercariae. Moreover, the mice with TLR4 mutation showed a decreased activation of hepatic stellate cells indicated by the expression of alpha-SMA, when compared with TLR4 wild mice. These data demonstrate that TLR4 contributes to PABF caused by C. sinensis and TLR4 signaling may be a potential medical target for treatment of PABF. PMID- 28634395 TI - Seven-Membered Lactam Derivatives of Podophyllotoxins as New Pesticidal Agents. AB - As a continuation of our efforts to discover and develop natural-product-based insecticidal agents, three novel and unusual 7-membered lactam derivatives of podophyllotoxin were prepared by thionyl chloride-mediated ring-expanded Beckmann rearrangement. The steric configurations of 3a-c were unambiguously identified by X-ray crystallography. It demonstrated that the configuration of the picropodophyllotoxin C4-oximes could also be confirmed by the corresponding C ring expansion products via Beckmann rearrangement. Moreover, it was obviously further testified that when picropodophyllones reacted with hydroxylamine hydrochloride, only E configuration of picropodophyllotoxin C4-oximes was selectively produced. Compounds 3b and 3c showed more potent pesticidal activity than toosendanin against oriental armyworm, Mythimna separata (Walker). PMID- 28634396 TI - Epigenetic silencing of downstream genes mediated by tandem orientation in lung cancer. AB - Epigenetic deregulation is of importance in tumorigenesis. In particular CpG islands (CGI), are frequently hypermethylated. Here, genome-wide DNA-methylation profiles of 480,000 CpGs in lung cancer cells were generated. It was observed that intra- and intergenic CGI exhibited higher methylation compared to normal cells. The functional annotation of hypermethylated CGI revealed that the hypermethylation was associated with homeobox domain genes and targets marked by repressive histone modifications. The strongest methylation variation was observed in transitional areas of CGI, termed shores. 5'-shores of promoter associated CGI in lung cancer cell lines were higher methylated than 3'-shores. Within two tandem-oriented genes, a significant hypermethylation of the downstream-located CGI promoters was revealed. Hypermethylation correlates with the length of the intergenic region between such tandem genes. As the RASSF1A tumor suppressor gene represents such a downstream tandem gene, its silencing was analyzed using an inducible system. It was determined that the induction of an upstream gene led to a repression of RASSF1A through a process involving histone deacetylases and CPSF1. A tumor-specific increase in expression of histone deacetylases and CPSF1 was detected in lung cancer. Our results suggest that the downstream gene could be susceptible to epigenetic silencing when organized in a tandem orientation. PMID- 28634397 TI - One-pot hydrothermal synthesis of CdS decorated CuS microflower-like structures for enhanced photocatalytic properties. AB - CdS decorated CuS structures have been controllably synthesized through a one-pot hydrothermal method. The morphologies and compositions of the as-prepared samples could be concurrently well controlled by simply tuning the amount of CdCl2 and thiourea. Using this strategy, the morphology of the products experienced from messy to flower-like morphologies with multiple porous densities, together with the phase evolution from pure CuS to the CdS/CuS composites. Serving as a photocatalyst, the samples synthesized with the addition of 1 mmol cadmium chloride and 3 mmol thiourea during synthetic process, showed the best photocatalytic activity, which could reach a maximum photocatalytic efficiency of 93% for methyl orange (MO) photodegradation after 150 min. The possible mechanism for the high photocatalytic efficiency of the sample was proposed by investigating the composition, surface area, structure, and morphology before and after photocatalytic reaction. PMID- 28634398 TI - Mutations in human AID differentially affect its ability to deaminate cytidine and 5-methylcytidine in ssDNA substrates in vitro. AB - Activation-induced cytidine deaminase (AID) is known for its established role in antibody production. AID induces the diversification of antibodies by deaminating deoxycytidine (C) within immunoglobulin genes. The capacity of AID to deaminate 5 methyldeoxycytidine (5 mC) and/or 5-hydroxymethyldeoxycytidine (5 hmC), and consequently AID involvement in active DNA demethylation, is not fully resolved. For instance, structural determinants of AID activity on different substrates remain to be identified. To better understand the latter issue, we tested how mutations in human AID (hAID) influence its ability to deaminate C, 5 mC, and 5 hmC in vitro. We showed that each of the selected mutations differentially affects hAID's ability to deaminate C and 5 mC. At the same time, we did not observe hAID activity on 5 hmC. Surprisingly, we found that the N51A hAID mutant, with no detectable activity on C, efficiently deaminated 5 mC, which may suggest different requirements for C and 5 mC deamination. Homology modeling and molecular dynamics simulations revealed that the pattern of enzyme-substrate recognition is one of the important factors determining enzyme activity on C and 5 mC. Consequently, we have proposed mechanisms that explain why wild type hAID more efficiently deaminates C than 5 mC in vitro and why 5 hmC is not deaminated. PMID- 28634399 TI - Terrestrial water load and groundwater fluctuation in the Bengal Basin. AB - Groundwater-level fluctuations represent hydraulic responses to changes in groundwater storage due to aquifer recharge and drainage as well as to changes in stress that include water mass loading and unloading above the aquifer surface. The latter 'poroelastic' response of confined aquifers is a well-established phenomenon which has been demonstrated in diverse hydrogeological environments but is frequently ignored in assessments of groundwater resources. Here we present high-frequency groundwater measurements over a twelve-month period from the tropical, fluvio-deltaic Bengal Aquifer System (BAS), the largest aquifer in south Asia. The groundwater level fluctuations are dominated by the aquifer poroelastic response to changes in terrestrial water loading by processes acting over periods ranging from hours to months; the effects of groundwater flow are subordinate. Our measurements represent the first direct, quantitative identification of loading effects on groundwater levels in the BAS. Our analysis highlights the potential limitations of hydrogeological analyses which ignore loading effects in this environment. We also demonstrate the potential for employing poroelastic responses in the BAS and across other tropical fluvio deltaic regions as a direct, in-situ measure of changes in terrestrial water storage to complement analyses from the Gravity and Climate Experiment (GRACE) mission but at much higher resolution. PMID- 28634400 TI - Chronic treatment with cisplatin induces chemoresistance through the TIP60 mediated Fanconi anemia and homologous recombination repair pathways. AB - The Fanconi anemia pathway in coordination with homologous recombination is essential to repair interstrand crosslinks (ICLs) caused by cisplatin. TIP60 belongs to the MYST family of acetyltransferases and is involved in DNA repair and regulation of gene transcription. Although the physical interaction between the TIP60 and FANCD2 proteins has been identified that is critical for ICL repair, it is still elusive whether TIP60 regulates the expression of FA and HR genes. In this study, we found that the chemoresistant nasopharyngeal carcinoma cells, derived from chronic treatment of cisplatin, show elevated expression of TIP60. Furthermore, TIP60 binds to the promoters of FANCD2 and BRCA1 by using the chromatin immunoprecipitation experiments and promote the expression of FANCD2 and BRCA1. Importantly, the depletion of TIP60 significantly reduces sister chromatid exchange, a measurement of HR efficiency. The similar results were also shown in the FNACD2-, and BRCA1-deficient cells. Additionally, these TIP60 deficient cells encounter more frequent stalled forks, as well as more DNA double strand breaks resulting from the collapse of stalled forks. Taken together, our results suggest that TIP60 promotes the expression of FA and HR genes that are important for ICL repair and the chemoresistant phenotype under chronic treatment with cisplatin. PMID- 28634401 TI - OhrR of Mycobacterium smegmatis senses and responds to intracellular organic hydroperoxide stress. AB - Organic hydroperoxide reductase regulator (OhrR) in bacteria is a sensor for organic hydroperoxide stress and a transcriptional regulator for the enzyme organic hydroperoxide reductase (Ohr). In this study we investigated, using a GFP reporter system, whether Mycobacterium smegmatis OhrR has the ability to sense and respond to intracellular organic hydroperoxide stress. It was observed that M. smegmatis strains bearing the pohr-gfpuv fusion construct were able to express GFP only in the absence of an intact ohrR gene, but not in its presence. However, GFP expression in the strain bearing pohr-gfpuv with an intact ohrR gene could be induced by organic hydroperoxides in vitro and in the intracellular environment upon ingestion of the bacteria by macrophages; indicating that OhrR responds not only to in vitro but also to intracellular organic hydroperoxide stress. Further, the intracellular expression of pohr driven GFP in this strain could be abolished by replacing the intact ohrR gene with a mutant ohrR gene modified for N-terminal Cysteine (Cys) residue, suggesting that OhrR senses intracellular organic hydroperoxides through Cys residue. This is the first report demonstrating the ability of OhrR to sense intracellular organic hydroperoxides. PMID- 28634402 TI - Enhanced antiviral and antifibrotic effects of short hairpin RNAs targeting HBV and TGF-beta in HBV-persistent mice. AB - The hepatitis B virus (HBV) causes acute and chronic liver infection, which may lead to liver cirrhosis and hepatocellular carcinoma. Current treatments including interferons and nucleotide analogs, have limited therapeutic effects, underscoring the need to identify effective therapeutic options to inhibit HBV replication and prevent complications. Previous animal models mimicking chronic HBV infection do not faithfully reflect disease progression in humans. Here, we used our established HBV-persistent mouse line with liver fibrosis to evaluate the efficacy of novel therapies. The combination of two short hairpin RNAs (dual shRNA) against different coding regions of HBV delivered by a self-complementary AAV vector showed better antiviral effects than single shRNA both in vitro and in HBV-persistent mice. The dual-shRNA also exhibited stronger antifibrotic activity in vivo. Vector carrying shRNA against TGF-beta, though did not inhibit HBV replication alone, enhanced the antiviral and antifibrotic activities of single and dual HBV shRNAs. Co-administration of TGF-beta shRNA and HBV dual-shRNA decreased HBV DNA, HBV RNA, HBsAg, HBeAg, and liver fibrosis markers in serum and tissues, and improved liver morphology more effectively than single treatments. Our results suggest that the combination of shRNAs against HBV and TGF-beta could be developed into a viable treatment for human HBV infection. PMID- 28634404 TI - Modelled responses of the Kalahari Desert to 21st century climate and land use change. AB - Drylands are home to over 2 billion people globally, many of whom use the land for agricultural and pastoral activities. These vulnerable livelihoods could be disrupted if desert dunefields become more active in response to climate and land use change. Despite increasing knowledge about the role that wind, moisture availability and vegetation cover play in shaping dryland landscapes, relatively little is known about how drylands might respond to climatic and population pressures over the 21st century. Here we use a newly developed numerical model, which fully couples vegetation and sediment-transport dynamics, to simulate potential landscape evolution at three locations in the Kalahari Desert, under two future emissions scenarios: stabilising (RCP 4.5) and high (RCP 8.5). Our simulations suggest that whilst our study sites will experience some climatically induced landscape change, the impacts of climate change alone on vegetation cover and sediment mobility may be relatively small. However, human activity could strongly exacerbate certain landscape trajectories. Fire frequency has a primary impact on vegetation cover, and, together with grazing pressure, plays a significant role in modulating shrub encroachment and ensuing land degradation processes. Appropriate land management strategies must be implemented across the Kalahari Desert to avoid severe environmental and socio-economic consequences over the coming decades. PMID- 28634403 TI - Fine Particulate Air Pollution and First Hospital Admissions for Ischemic Stroke in Beijing, China. AB - The primary objective of this study was to assess the association between short term changes in ambient fine particulate matter (PM2.5) and first hospital admissions for ischemic stroke. We identified 63,956 first hospital admissions for ischemic stroke from the Beijing Medical Claim Data for Employees from January 1, 2010, through June 30, 2012. A generalized additive Poisson model was applied to explore the association between PM2.5 and admissions for ischemic stroke. We also explore the effect modification of risk by age and gender. The exposure-response relationship between PM2.5 and admissions for ischemic stroke was approximately linear, with a relatively stable response at lower concentrations (<100 MUg/m3) and a steeper response at higher concentrations. A 10 MUg/m3 increase in the same-day PM2.5 concentration was associated with 0.31% (95% CI, 0.17-0.45%, P < 1.57 * 10-5) increase in the daily admissions for ischemic stroke. The association was also statistically significant at lag 1, 2, 3, 0-2 and 0-4 days. Subgroup analyses showed that the association was not different between patients >=65 years and <65 years old or between males and females. In conclusion, short-term exposure to PM2.5 was positively associated with first hospital admissions for ischemic stroke in Beijing, China. PMID- 28634405 TI - Shedding new light on an old molecule: quinophthalone displays uncommon N-to-O excited state intramolecular proton transfer (ESIPT) between photobases. AB - Excited state dynamics of common yellow dye quinophthalone (QPH) was probed by femtosecond transient absorption spectroscopy. Multi-exponential decay of the excited state and significant change of rate constants upon deuterium substitution indicate that uncommon nitrogen-to-oxygen excited state intramolecular proton transfer (ESIPT) occurs. By performing density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations, we found that adiabatic surface crossing between the S1 and S2 states takes place in the photoreaction. Unlike most cases of ESIPT, QPH does not exhibit tautomer emission, possibly due to internal conversion or back-proton transfer. The ESIPT of QPH presents a highly interesting case also because the moieties participating in ESIPT, quinoline and aromatic carbonyl, are both traditionally considered as photobases. PMID- 28634406 TI - Enhancing KCC2 function counteracts morphine-induced hyperalgesia. AB - Morphine-induced hyperalgesia (MIH) is a severe adverse effect accompanying repeated morphine treatment, causing a paradoxical decrease in nociceptive threshold. Previous reports associated MIH with a decreased expression of the Cl- extruder KCC2 in the superficial dorsal horn (SDH) of the spinal cord, weakening spinal GABAA/glycine-mediated postsynaptic inhibition. Here, we tested whether the administration of small molecules enhancing KCC2, CLP257 and its pro-drug CLP290, may counteract MIH. MIH was typically expressed within 6-8 days of morphine treatment. Morphine-treated rats exhibited decreased withdrawal threshold to mechanical stimulation and increased vocalizing behavior to subcutaneous injections. Chloride extrusion was impaired in SDH neurons measured as a depolarizing shift in E GABA under Cl- load. Delivering CLP257 to spinal cord slices obtained from morphine-treated rats was sufficient to restore Cl- extrusion capacity in SDH neurons. In vivo co-treatment with morphine and oral CLP290 prevented membrane KCC2 downregulation in SDH neurons. Concurrently, co treatment with CLP290 significantly mitigated MIH and acute administration of CLP257 in established MIH restored normal nociceptive behavior. Our data indicate that enhancing KCC2 activity is a viable therapeutic approach for counteracting MIH. Chloride extrusion enhancers may represent an effective co-adjuvant therapy to improve morphine analgesia by preventing and reversing MIH. PMID- 28634407 TI - Analysis of survival and hatching transcriptomes from potato cyst nematodes, Globodera rostochiensis and G. pallida. AB - Potato cyst nematodes (PCNs), Globodera rostochiensis and G. pallida, cause important economic losses. They are hard to manage because of their ability to remain dormant in soil for many years. Although general knowledge about these plant parasitic nematodes has considerably increased over the past decades, very little is known about molecular events involved in cyst dormancy and hatching, two key steps of their development. Here, we have studied the progression of PCN transcriptomes from dry cysts to hatched juveniles using RNA-Seq. We found that several cell detoxification-related genes were highly active in the dry cysts. Many genes linked to an increase of calcium and water uptake were up-regulated during transition from dormancy to hydration. Exposure of hydrated cysts to host plant root exudates resulted in different transcriptional response between species. After 48 h of exposure, G. pallida cysts showed no significant modulation of gene expression while G. rostochiensis had 278 differentially expressed genes. The first G. rostochiensis significantly up-regulated gene was observed after 8 h and was coding for a transmembrane metalloprotease. This enzyme is able to activate/inactivate peptide hormones and could be involved in a cascade of events leading to hatching. Several known effector genes were also up regulated during hatching. PMID- 28634408 TI - A tightly regulated IL-22 response maintains immune functions and homeostasis in systemic viral infection. AB - Interleukin-22 (IL-22) plays an important role in host immunity and tissue homeostasis in infectious and inflammatory diseases. However, the function and regulation of IL-22 in viral infection remain largely unknown. Here, we report that viral infection triggered early IL-22 production from the liver and lymphoid organs. gammadelta T cells are the main immune cells to produce IL-22 in the liver, a process mediated by the IL-23/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. In the presence of IL 23, IL-22 production is independent of aryl hydrocarbon receptor (AhR) signaling. In acute and persistent viral infections, IL-22 deficiency resulted in thymic and splenic hypertrophy, while excessive IL-22 induced atrophy in these lymphoid organs. Moreover, IL-22 deficiency enhanced T cell responses to promote viral clearance, but increased IL-22 in vivo decreased T cell numbers and functions in the liver and lymphoid tissues. Together, our findings reveal a significant effect of the IL-23/PI3K/mTORC1 axis on regulating IL-22 production and also identify a novel role of IL-22 in controlling antiviral T cell responses in the non-lymphoid and lymphoid organs during acute and persistent viral infections. PMID- 28634409 TI - Characterization of the 3D structure of a cultivated land surface and its influence on wheat seedlings growth using Kinect. AB - The quality of wheat emergence has a significant impact on the subsequent growth and development of seedlings. The structure of cultivated land surfaces is an important factor influencing wheat seedlings growth. However, few studies have investigated this. In this study, three-dimensional structural parameters of cultivated land surfaces were collected using 3D imaging equipment, and the effects of different grades of lands on the emergence and growth of wheat were evaluated. The evaluation criteria for the soil blocks was designed according to the ISO-25178-2 standard, and the wheat emergence rate, speed, tillering capacity per plant, dry weight per plant, and final yields of different grades of cultivated land were investigated. The results indicated that the three dimensional information obtained through the Kinect sensors was reliable. The deviation of measured values from the factual values was trivial. The value of R2 was greater than 0.99**. The value of RMSE was less than 2 mm. These results describe a method for obtaining three-dimensional structures of land surfaces using 3D cameras and the evaluation of wheat emergence capacity. It can be used as a reference for obtaining three-dimensional cultivated land structures or other similar objects. PMID- 28634411 TI - Stomach: A chief role for Lgr5+ cells. PMID- 28634410 TI - Climate response to the 8.2 ka event in coastal California. AB - A fast-growing stalagmite from the central California coast provides a high resolution record of climatic changes synchronous with global perturbations resulting from the catastrophic drainage of proglacial Lake Agassiz at ca. 8.2 ka. High frequency, large amplitude variations in carbon isotopes during the 8.2 ka event, coupled with pulsed increases in phosphorus concentrations, indicate more frequent or intense winter storms on the California coast. Decreased magnesium-calcium ratios point toward a sustained increase in effective moisture during the event, however the magnitude of change in Mg/Ca suggests this event was not as pronounced on the western North American coast as anomalies seen in the high northern latitudes and monsoon-influenced areas. Nevertheless, shifts in the White Moon Cave record that are synchronous within age uncertainties with cooling of Greenland, and changes in global monsoon systems, suggest rapid changes in atmospheric circulation occurred in response to freshwater input and associated cooling in the North Atlantic region. Our record is consistent with intensification of the Pacific winter storm track in response to North Atlantic freshwater forcing, a mechanism suggested by simulations of the last deglaciation, and indicates this intensification led to increases in precipitation and infiltration along the California coast during the Holocene. PMID- 28634413 TI - Topical Fibronectin Improves Wound Healing of Irradiated Skin. AB - Wound healing is significantly delayed in irradiated skin. To better understand global changes in protein expression after radiation, we utilized a reverse phase protein array (RPPA) to identify significant changes in paired samples of normal and irradiated human skin. Of the 210 proteins studied, fibronectin was the most significantly and consistently downregulated in radiation-damaged skin. Using a murine model, we confirmed that radiation leads to decreased fibronectin expression in the skin as well as delayed wound healing. Topically applied fibronectin was found to significantly improve wound healing in irradiated skin and was associated with decreased inflammatory infiltrate and increased angiogenesis. Fibronectin treatment may be a useful adjunctive modality in the treatment of non-healing radiation wounds. PMID- 28634414 TI - Monitoring and analysis of coastal reclamation from 1995-2015 in Tianjin Binhai New Area, China. AB - Increasing coastal reclamation activities have been undertaken to solve the conflict between people and land resources, creating significant challenges for coordinating coastal reclamation, economic development and environmental protection. This paper analyzes the effects of coast reclamation on Gross Domestic Product growth and the quality of inshore seawater in the Tianjin Binhai New Area. Remote sensing and a Geographic Information System were used to extract the information of coastal reclamation. The correlation between the area of coastal reclamation, GDP growth and the quality of inshore seawater was analyzed and a decoupling elasticity model was used to explore trends in the relationship between economic development and coastal reclamation. Results showed that coastal reclamation activities played an important role in promoting economic development, but greatly damaged the ecological environment. Although the relationship between coastal reclamation and economic development has weakened during the last three periods, the influence on the environment will continue because of the cumulative effects of pollution. To maintain a balance between coastal reclamation, economic development and environmental protection, (1) coastal reclamation planning must address both economic and environmental outcomes; (2) environmental deficiencies from existing coastal reclamation projects must be rectified; and (3) the legal system regulating coastal reclamation needs to be refined and strengthened. PMID- 28634412 TI - Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets. AB - Extracellular vesicles (EVs) are membranous vesicles originating from different cells in the liver. The pathophysiological role of EVs is increasingly recognized in liver diseases, including alcoholic liver disease, NAFLD, viral hepatitis and hepatocellular carcinoma. EVs, via their cargo, can provide communication between different cell types in the liver and between organs. EVs are explored as biomarkers of disease and could also represent therapeutic targets and vehicles for treatment delivery. Here, we review advances in understanding the role of EVs in liver diseases and discuss their utility in biomarker discovery and therapeutics. PMID- 28634415 TI - Force-induced increased osteogenesis enables accelerated orthodontic tooth movement in ovariectomized rats. AB - As the number of elderly orthodontic patients increases, the impact of postmenopausal osteoporosis on orthodontic tooth movement (OTM) has attracted a great deal of attention because OTM relies on alveolar bone remodeling. The question of whether OTM causes subsequent alveolar bone loss and is harmful to alveolar bone health under osteoporotic conditions remains to be answered. The present study aimed to clarify the influences of OTM on alveolar bone in osteoporotic rats. OTM was accelerated in ovariectomized (OVX) rats as a result of increased bone resorption in the pressure area. At the same time, anabolic bone formation was promoted in the tension area during OTM in OVX rats. Micro-CT analysis of alveolar bone revealed a decrease in BMD, BV/TV and Tb.Th. in the OTM group compared with that in non-OTM rats on day 21 of OTM, suggesting that OTM caused alveolar bone loss in OVX rats during OTM. However, the OTM-induced bone loss could be recovered 3 months after OTM in OVX rats. Thus, our findings suggest that increased osteogenesis may compensate for the increased bone resorption during and after OTM and enable effective accelerated OTM in OVX rats. PMID- 28634416 TI - New climatic targets against global warming: will the maximum 2 degrees C temperature rise affect estuarine benthic communities? AB - The Paris Agreement signed by 195 countries in 2015 sets out a global action plan to avoid dangerous climate change by limiting global warming to remain below 2 degrees C. Under that premise, in situ experiments were run to test the effects of 2 degrees C temperature increase on the benthic communities in a seagrass bed and adjacent bare sediment, from a temperate European estuary. Temperature was artificially increased in situ and diversity and ecosystem functioning components measured after 10 and 30 days. Despite some warmness effects on the analysed components, significant impacts were not verified on macro and microfauna structure, bioturbation or in the fluxes of nutrients. The effect of site/habitat seemed more important than the effects of the warmness, with the seagrass habitat providing more homogenous results and being less impacted by warmness than the adjacent bare sediment. The results reinforce that most ecological responses to global changes are context dependent and that ecosystem stability depends not only on biological diversity but also on the availability of different habitats and niches, highlighting the role of coastal wetlands. In the context of the Paris Agreement it seems that estuarine benthic ecosystems will be able to cope if global warming remains below 2 degrees C. PMID- 28634417 TI - Expression Status of PIWIL1 as a Prognostic Marker of Colorectal Cancer. AB - The PIWI-like protein 1 (PIWIL1) plays a crucial role in stem cell proliferation, embryogenesis, growth, and development, as well as differentiation and maturation in multiple organisms. The relationships between PIWIL1 expression and clinicopathological features of colorectal cancer (CRC) patients were analyzed by us. Survival analysis was performed using the Kaplan-Meier method and Cox's proportional hazards model. The high expression rate of PIWIL1 in the cancer tissue was obviously higher than that in the corresponding adjacent tissue. The expression of PIWIL1 was closely related to the tumor differentiation degree, infiltration depth, lymphovascular invasion, lymph node metastasis, and TNM stage. The Kaplan-Meier survival model suggested that the survival time of CRC patients in the high PIWIL1 expression group was notably lower than that in the low PIWIL1 expression group. High PIWIL1 expression suggests a poor prognosis for CRC patients, and PIWIL1 can serve as an important molecular marker for predicting the prognosis of CRC patients. PMID- 28634419 TI - Elevated Plasma Levels of sIL-2R in Complex Regional Pain Syndrome: A Pathogenic Role for T-Lymphocytes? AB - The immune system has long been thought to be involved in the pathophysiology of complex regional pain syndrome (CRPS). However, not much is known about the role of the immune system and specifically T-cells in the onset and maintenance of this disease. In this study, we aimed to evaluate T-cell activity in CRPS by comparing blood soluble interleukin-2 receptor (sIL-2R) levels between CRPS patients and healthy controls. CRPS patients had statistically significant elevated levels of sIL-2R as compared to healthy controls (median sIL-2R levels: 4151 pg/ml (Q3 - Q1 = 5731 pg/ml - 3546 pg/ml) versus 1907 pg/ml (Q3 - Q1: 2206 pg/ml - 1374 pg/ml), p < 0.001, resp.). Furthermore, sIL-2R level seems to be a good discriminator between CRPS patients and healthy controls with a high sensitivity (90%) and specificity (89.5%). Our finding indicates increased T-cell activity in patients with CRPS. This finding is of considerable relevance as it could point towards a T-cell-mediated inflammatory process in this disease. This could pave the way for new anti-inflammatory therapies in the treatment of CRPS. Furthermore, sIL-2R could be a promising new marker for determining inflammatory disease activity in CRPS. PMID- 28634420 TI - Characterization of the Proinflammatory Profile of Synovial Fluid-Derived Exosomes of Patients with Osteoarthritis. AB - The purpose of this study is to characterize synovial fluid- (SF-) derived exosomes of patients with gonarthrosis comparing two methods of isolation and to investigate their immune regulatory properties. Extracellular vesicles (EVs) have been isolated from inflamed SF by polymer precipitation method and quantified by Exocet kit and by nanoparticle tracking analysis. Vesicles expressed all the specific exosomal markers by immunoblot and FACS. After isolation with Exoquick, a relevant contamination by immune complexes was detected, which required further magnetic bead-based purification to remove. SF-derived exosomes significantly stimulated the release of several inflammatory cytokines and chemokines and metalloproteinases by M1 macrophages but did not influence the expression of CD80 and CD86 costimulatory molecules. In conclusion, we characterized purified exosomes isolated from inflamed SF and demonstrate that purified exosomes are functionally active in their ability to stimulate the release of proinflammatory factors from M1 macrophages. Our data indicate that SF-derived exosomes from gonarthrosis patients play a role in disease progression. PMID- 28634418 TI - Long Noncoding RNAs as Biomarkers in Cancer. AB - Long noncoding RNAs (lncRNAs) are a relatively well-characterized class of noncoding RNA (ncRNA) molecules, involved in the regulation of various cell processes, including transcription, intracellular trafficking, and chromosome remodeling. Their deregulation has been associated with the development and progression of various cancer types, the fact which makes them suitable as biomarkers for cancer diagnosis and prognosis. In recent years, detection of cancer-associated lncRNAs in body fluids of cancer patients has proven itself as an especially valuable method to effectively diagnose cancer. Cancer diagnosis and prognosis employing circulating lncRNAs are preferential when compared to classical biopsies of tumor tissues, especially due to their noninvasiveness, and have great potential for routine usage in clinical practice. Thus, this review focuses on summarizing the perspectives of lncRNAs as biomarkers in cancer, based on evaluating their expression profiles determined in body fluids of cancer patients. PMID- 28634423 TI - Tumor RAS Gene Expression Levels Are Influenced by the Mutational Status of RAS Genes and Both Upstream and Downstream RAS Pathway Genes. AB - The 3 human RAS genes play pivotal roles regulating proliferation, differentiation, and survival in normal cells and become mutated in 15% to 20% of all human tumors and amplified in many others. In this report, we examined data from The Cancer Genome Atlas to investigate the relationship between RAS gene mutational status and messenger RNA expression. We show that all 3 RAS genes exhibit increased expression when they are mutated in a context-dependent manner. In the case of KRAS, this increase is manifested by a larger proportional increase in KRAS4A than KRAS4B, although both increase significantly. In addition, the mutational status of RAS genes can be associated with expression changes in other RAS genes, with most of these cases showing decreased expression. The mutational status associations with expression are recapitulated in cancer cell lines. Increases in expression are mediated by both copy number variation and contextual differences, including mutational status of epidermal growth factor receptor (EGFR) and BRAF. These findings potentially reveal an adaptive response during tumor evolution that is dependent on the mutational status of proximal genes in the RAS pathway and cellular context. Cell contextual differences in these adaptations may influence therapeutic responsiveness and alternative resistance mechanisms. PMID- 28634422 TI - Lipopolysaccharide-Binding Protein Downregulates Fractalkine through Activation of p38 MAPK and NF-kappaB. AB - BACKGROUND: LBP and fractalkine are known to be involved in the pathogenesis of ARDS. This study investigated the relationship between LBP and fractalkine in LPS induced A549 cells and rat lung tissue in an ARDS rat model. METHODS: A549 cells were transfected with LBP or LBP shRNA plasmid DNA or pretreated with SB203580 or SC-514 following LPS treatment. An ARDS rat model was established using LPS with or without LBPK95A, SB203580, or SC-514 treatment. RT-PCR, western blotting, ELISA, immunofluorescence, coimmunoprecipitation, and immunohistochemical staining were used to study the expression of fractalkine and LBP and p38 MAPK and p65 NF-kappaB activities. RESULTS: LPS increased LBP and reduced fractalkine. LBP overexpression further decreased LPS-induced downregulation of fractalkine and p38 MAPK and p65 NF-kappaB activation; LBP gene silencing, SB203580, and SC 514 suppressed LPS-induced downregulation of fractalkine and p38 MAPK and p65 NF kappaB activation in A549 cells. LBP and fractalkine in lung tissue were increased and decreased, respectively, following LPS injection. LBPK95A, SB203580, and SC-514 ameliorated LPS-induced rat lung injury and suppressed LPS induced downregulation of fractalkine by decreasing phospho-p38 MAPK and p65 NF kappaB. CONCLUSIONS: The results indicate that LBP downregulates fractalkine expression in LPS-induced A549 cells and in an ARDS rat model through activation of p38 MAPK and NF-kappaB. PMID- 28634424 TI - Overexpression and Knockdown of Hypoxia-Inducible Factor 1 Disrupt the Expression of Steroidogenic Enzyme Genes and Early Embryonic Development in Zebrafish. AB - Hypoxia is an important environmental stressor leading to endocrine disruption and reproductive impairment in fish. Although the hypoxia-inducible factor 1 (HIF 1) is known to regulate the transcription of various genes mediating oxygen homeostasis, its role in modulating steroidogenesis-related gene expression remains poorly understood. In this study, the regulatory effect of HIF-1 on the expression of 9 steroidogenic enzyme genes was investigated in zebrafish embryos using a "gain-of-function and loss-of-function" approach. Eight of the genes, CYP11a, CYP11b2, 3beta-HSD, HMGCR, CYP17a1, 17beta-HSD2, CYP19a, and CYP19b, were found to be differentially upregulated at 24 and 48 hpf following zHIF-1alpha DeltaODD overexpression (a mutant zebrafish HIF-1alpha protein with proline-414 and proline-557 deleted). Knockdown of zHIF-1alpha also affected the expression pattern of the steroidogenic enzyme genes. Overexpression of zHIF-1alpha and hypoxia exposure resulted in downregulated StAR expression but upregulated CYP11a and 3beta-HSD expression in zebrafish embryos. Conversely, the expression patterns of these 3 genes were reversed in embryos in which zHIF-1alpha was knocked down under normoxia, suggesting that these 3 genes are regulated by HIF 1. Overall, the findings from this study indicate that HIF-1-mediated mechanisms are likely involved in the regulation of specific steroidogenic genes. PMID- 28634421 TI - The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy. AB - Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation. Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis. The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions. Moreover, VWF and ADAMTS13 have been recently proposed as prognostic biomarkers in cardiovascular, metabolic, and inflammatory diseases, such as diabetes, stroke, myocardial infarction, and sepsis. All these features make VWF an attractive therapeutic target in thromboinflammation. Several lines of research have recently investigated "tailor-made" inhibitors of VWF. Results from animal models and clinical studies support the potent anti-inflammatory and antithrombotic effect of VWF antagonism, providing reassuring data on its safety profile. This review describes the role of VWF in vascular inflammation "from bench to bedside" and provides an updated overview of the drugs that can directly interfere with the VWF/ADAMTS13 axis. PMID- 28634426 TI - Prevalence and Consequences of Perinatal Substance Use-Growing Worldwide Concerns. PMID- 28634425 TI - A Transcriptional Regulatory Role for the Membrane Type-1 Matrix Metalloproteinase in Carcinogen-Induced Inflammasome Gene Expression. AB - Signal-transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation associated cancer cell functions including migration, proliferation, and survival. Aside from upregulation of the inflammation biomarker cyclooxygenase-2 (COX-2) expression, MT1-MMP's role in relaying intracellular signals triggered by extracellular pro-inflammatory cues remains poorly understood. Here, we triggered inflammation in HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), an inducer of COX-2 and of MT1-MMP. To assess the global transcriptional regulatory role that MT1-MMP may exert on inflammation biomarkers, we combined gene array screens with a transient MT1-MMP gene silencing strategy. Expression of MT1-MMP was found to exert both stimulatory and repressive transcriptional control of several inflammasome-related biomarkers such as interleukin (IL)-1B, IL-6, IL-12A, and IL-33, as well as of transcription factors such as EGR1, ELK1, and ETS1/2 in PMA-treated cells. Among the signal-transducing pathways explored, the silencing of MT1-MMP prevented PMA from phosphorylating extracellular signal regulated kinase, inhibitor of kappaB, and p105 nuclear factor kappaB (NF-kappaB) intermediates. We also found a signaling axis linking MT1-MMP to MMP-9 transcriptional regulation. Altogether, our data indicate a significant involvement of MT1-MMP in the transcriptional regulation of inflammatory biomarkers consolidating its contribution to signal transduction functions in addition to its classical hydrolytic activity. PMID- 28634427 TI - Leveraging Food and Drug Administration Adverse Event Reports for the Automated Monitoring of Electronic Health Records in a Pediatric Hospital. AB - The objective of this study was to determine whether the Food and Drug Administration's Adverse Event Reporting System (FAERS) data set could serve as the basis of automated electronic health record (EHR) monitoring for the adverse drug reaction (ADR) subset of adverse drug events. We retrospectively collected EHR entries for 71 909 pediatric inpatient visits at Cincinnati Children's Hospital Medical Center. Natural language processing (NLP) techniques were used to identify positive diseases/disorders and signs/symptoms (DDSSs) from the patients' clinical narratives. We downloaded all FAERS reports submitted by medical providers and extracted the reported drug-DDSS pairs. For each patient, we aligned the drug-DDSS pairs extracted from their clinical notes with the corresponding drug-DDSS pairs from the FAERS data set to identify Drug-Reaction Pair Sentences (DRPSs). The DRPSs were processed by NLP techniques to identify ADR-related DRPSs. We used clinician annotated, real-world EHR data as reference standard to evaluate the proposed algorithm. During evaluation, the algorithm achieved promising performance and showed great potential in identifying ADRs accurately for pediatric patients. PMID- 28634428 TI - Marketization in Long-Term Care: A Cross-Country Comparison of Large For-Profit Nursing Home Chains. AB - This article presents cross-country comparisons of trends in for-profit nursing home chains in Canada, Norway, Sweden, United Kingdom, and the United States. Using public and private industry reports, the study describes ownership, corporate strategies, costs, and quality of the 5 largest for-profit chains in each country. The findings show that large for-profit nursing home chains are increasingly owned by private equity investors, have had many ownership changes over time, and have complex organizational structures. Large for-profit nursing home chains increasingly dominate the market and their strategies include the separation of property from operations, diversification, the expansion to many locations, and the use of tax havens. Generally, the chains have large revenues with high profit margins with some documented quality problems. The lack of adequate public information about the ownership, costs, and quality of services provided by nursing home chains is problematic in all the countries. The marketization of nursing home care poses new challenges to governments in collecting and reporting information to control costs as well as to ensure quality and public accountability. PMID- 28634429 TI - Exploration of Spinal Cord Aging-Related Proteins Using a Proteomics Approach. AB - How aging affects the spinal cord at a molecular level is unclear. The aim of this study was to explore spinal cord aging-related proteins that may be involved in pathological mechanisms of age-related changes in the spinal cord. Spinal cords of 2-year-old and 8-week-old female Sprague-Dawley rats were dissected from the animals. Protein samples were subjected to 2-dimentional polyacrylamide gel electrophoresis followed by mass spectrometry. Screened proteins were further investigated with immunohistochemistry and Western blotting. Among the screened proteins, we selected alpha-crystallin B-subunit (alphaB-crystallin) and peripherin for further investigation because these proteins were previously reported to be related to central nervous system pathologies. Immunohistochemistry and Western blotting revealed significant upregulation of alphaB-crystallin and peripherin expression in aged rat spinal cord. Further exploration is needed to elucidate the precise mechanism and potential role of these upregulated proteins in spinal cord aging processes. PMID- 28634430 TI - Evaluation of Four Bait Traps for Sampling Wireworm (Coleoptera: Elateridae) Infesting Cereal Crops in Montana. AB - The basic principles of a reliable integrated pest management program include pest identification, monitoring, and distribution. Selecting the appropriate sampling protocol to monitor wireworm for research or applied entomology depends on the objective, including simply detecting the presence or absence of wireworm, surveying the composition of wireworm assemblages, or estimating spatial and temporal population densities. In this study, the efficacy of pitfall, stocking, pot, and canister traps baited with wheat and barley mixtures was evaluated for monitoring wireworm populations in four commercial cereal fields in Montana. Pitfall and stocking traps collected greater numbers of wireworm (1625 and 1575, respectively) followed by pot-type and canister-type traps (1173 and 725, respectively). The 5098 wireworm collected from four sites included seven species: Aeolus mellillus, Agriotes sp, Dalopius sp, Hypnoidus bicolor, Limonius californicus, Limonius infuscatus, and S. aeripennis. PMID- 28634431 TI - The Aftermath of a Hepatic Artery Aneurysm-A Rare Etiology of Biliary Obstruction! AB - BACKGROUND: Hepatic artery aneurysms (HAAs) constitute 14% to 20% of visceral artery aneurysms. Most HAAs are asymptomatic. Although rare, obstructive jaundice due to external bile duct compression or rupture of the HAA into the biliary tree with occlusion of the lumen from blood clots has been reported. CASE PRESENTATION: A 56-year-old white man presented to an outside hospital with symptoms of obstructive jaundice, including abdominal pain and yellowing of the skin. Imaging showed a large HAA. Patient was transferred to our hospital where an endoscopic retrograde cholangiopancreatography with biliary stenting was performed. This was followed by coil embolization of the HAA with improvement in symptoms and liver chemistries. CONCLUSIONS: Most clinicians agree that management of HAA is highly variable and depends on clinical presentation and anatomic location. Biliary stenting provides temporary relief for patients with obstructive jaundice. Definitive options include open aneurysmal repair versus endovascular therapy. Hepatic artery aneurysms represent a significant risk for hemorrhage and therefore must be addressed promptly once discovered. PMID- 28634432 TI - Effect of Ice Bag Application to Femoral Region on Pain in Patients Undergoing Percutaneous Coronary Intervention. AB - AIMS: The aim of this study is to determine the pain reduction effectiveness of ice bag applications to the femoral region in patients undergoing percutaneous coronary intervention. MATERIAL AND METHODS: A randomized controlled trial with repeated measures and two-group design. The study was completed with a total of 104 patients who met the inclusion criteria: 52 each in the experimental group and the control group. The pain experienced by the patients was evaluated before and during removal and again while the nurse applied pressure on the catheter site after removal. The NRS scores were identified as NRS1, NRS2, and NRS3 for the three assessment, respectively. RESULTS: The NRS1 score was similar between the two groups. It increased at the 2nd measurement, and a statistically significant difference was determined between the two groups (4.0 (3.0-4.0) in the experimental group and 6.0 (4.0-7.0) in the control group) (p < 0.001). CONCLUSIONS: The results of the study revealed that ice bag application to femoral region was effective in reducing pain induced by femoral catheter removal in patients undergoing percutaneous coronary intervention. Local ice bag application may therefore be recommended as a nursing intervention for pain control in such cases. PMID- 28634433 TI - The Draft Genome of the Non-Host-Associated Methanobrevibacter arboriphilus Strain DH1 Encodes a Large Repertoire of Adhesin-Like Proteins. AB - Methanobrevibacter arboriphilus strain DH1 is an autotrophic methanogen that was isolated from the wetwood of methane-emitting trees. This species has been of considerable interest for its unusual oxygen tolerance and has been studied as a model organism for more than four decades. Strain DH1 is closely related to other host-associated Methanobrevibacter species from intestinal tracts of animals and the rumen, making this strain an interesting candidate for comparative analysis to identify factors important for colonizing intestinal environments. Here, the genome sequence of M. arboriphilus strain DH1 is reported. The draft genome is composed of 2.445.031 bp with an average GC content of 25.44% and predicted to harbour 1964 protein-encoding genes. Among the predicted genes, there are also more than 50 putative genes for the so-called adhesin-like proteins (ALPs). The presence of ALP-encoding genes in the genome of this non-host-associated methanogen strongly suggests that target surfaces for ALPs other than host tissues also need to be considered as potential interaction partners. The high abundance of ALPs may also indicate that these types of proteins are more characteristic for specific phylogenetic groups of methanogens rather than being indicative for a particular environment the methanogens thrives in. PMID- 28634434 TI - An Acidic Exopolysaccharide from Haloarcula hispanica ATCC33960 and Two Genes Responsible for Its Synthesis. AB - A 1.1 * 106 Da acidic exopolysaccharide (EPS) was purified from an extremely halophilic archaeon Haloarcula hispanica ATCC33960 with a production of 30 mg L-1 when grown in AS-168 medium, which mainly composed of mannose and galactose with a small amount of glucose in a molar ratio of 55.9 : 43.2 : 0.9. Two glycosyltransferase genes (HAH_1662 and HAH_1667) were identified to be responsible for synthesis of the acidic EPS. Deletion of either HAH_1662 or HAH_1667 led to loss of the acidic EPS. The mutants displayed a different cell surface morphology, retarded growth in low salty environment, an increased adhesion, and swimming ability. Our results suggest that biosynthesis of the acidic EPS might act as an adaptable mechanism to protect the cells against harsh environments. PMID- 28634435 TI - The Clinical Uses of Electrocochleography. AB - The clinical uses of electrocochleography are reviewed with some technical notes on the apparatus needed to get clear recordings under different conditions. Electrocochleography can be used to estimate auditory thresholds in difficult to test children and a golf club electrode is described. The same electrode can be used to obtain electrical auditory brainstem responses (EABR). Diagnostic testing in the clinic can be performed with a transtympanic needle electrode, and a suitable disposable monopolar electrode is described. The use of tone bursts rather than click stimuli gives a better means of diagnosis of the presence of endolymphatic hydrops. Electrocochleography can be used to monitor the cochlear function during surgery and a long coaxial cable, which can be sterilized, is needed to avoid electrical artifacts. Recently electrocochleography has been used to monitor cochlear implant insertion and to record residual hearing using an electrode on the cochlear implant array as the non-inverting (active) electrode. PMID- 28634436 TI - Dual Coding Theory Explains Biphasic Collective Computation in Neural Decision Making. AB - A central question in cognitive neuroscience is how unitary, coherent decisions at the whole organism level can arise from the distributed behavior of a large population of neurons with only partially overlapping information. We address this issue by studying neural spiking behavior recorded from a multielectrode array with 169 channels during a visual motion direction discrimination task. It is well known that in this task there are two distinct phases in neural spiking behavior. Here we show Phase I is a distributed or incompressible phase in which uncertainty about the decision is substantially reduced by pooling information from many cells. Phase II is a redundant or compressible phase in which numerous single cells contain all the information present at the population level in Phase I, such that the firing behavior of a single cell is enough to predict the subject's decision. Using an empirically grounded dynamical modeling framework, we show that in Phase I large cell populations with low redundancy produce a slow timescale of information aggregation through critical slowing down near a symmetry-breaking transition. Our model indicates that increasing collective amplification in Phase II leads naturally to a faster timescale of information pooling and consensus formation. Based on our results and others in the literature, we propose that a general feature of collective computation is a "coding duality" in which there are accumulation and consensus formation processes distinguished by different timescales. PMID- 28634437 TI - Latent Growth Curve Models for Biomarkers of the Stress Response. AB - Objective: The stress response is a dynamic process that can be characterized by predictable biochemical and psychological changes. Biomarkers of the stress response are typically measured over time and require statistical methods that can model change over time. One flexible method of evaluating change over time is the latent growth curve model (LGCM). However, stress researchers seldom use the LGCM when studying biomarkers, despite their benefits. Stress researchers may be unaware of how these methods can be useful. Therefore, the purpose of this paper is to provide an overview of LGCMs in the context of stress research. We specifically highlight the unique benefits of using these approaches. Methods: Hypothetical examples are used to describe four forms of the LGCM. Results: The following four specifications of the LGCM are described: basic LGCM, latent growth mixture model, piecewise LGCM, and LGCM for two parallel processes. The specifications of the LGCM are discussed in the context of the Trier Social Stress Test. Beyond the discussion of the four models, we present issues of modeling nonlinear patterns of change, assessing model fit, and linking specific research questions regarding biomarker research using different statistical models. Conclusions: The final sections of the paper discuss statistical software packages and more advanced modeling capabilities of LGCMs. The online Appendix contains example code with annotation from two statistical programs for the LCGM. PMID- 28634439 TI - Inconsistency in Abnormal Brain Activity across Cohorts of ADHD-200 in Children with Attention Deficit Hyperactivity Disorder. AB - Many papers have shown results from the multi-site dataset of resting-state fMRI (rs-fMRI) in attention deficit hyperactivity disorder (ADHD), a data-sharing project named ADHD-200. However, few studies have illustrated that to what extent the pooled findings were consistent across cohorts. The present study analyzed three voxel-wise whole-brain metrics, i.e., amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality (DC) based on the pooled dataset as well as individual cohort of ADHD-200. In addition to the conventional frequency band of 0.01-0.08 Hz, sub-frequency bands of 0-0.01, 0.01-0.027, 0.027-0.073, 0.073-0.198, and 0.198-0.25 Hz, were assessed. While the pooled dataset showed abnormal activity in some brain regions, e.g., the bilateral sensorimotor cortices, bilateral cerebellum, and the bilateral lingual gyrus, these results were highly inconsistent across cohorts, even across the three cohorts from the same research center. The standardized effect size was rather small. These findings suggested a high heterogeneity of spontaneous brain activity in ADHD. Future studies based on multi-site large-sample dataset should be performed on pooled data and single cohort data, respectively and the effect size must be shown. PMID- 28634438 TI - Computational Models of Anterior Cingulate Cortex: At the Crossroads between Prediction and Effort. AB - In the last two decades the anterior cingulate cortex (ACC) has become one of the most investigated areas of the brain. Extensive neuroimaging evidence suggests countless functions for this region, ranging from conflict and error coding, to social cognition, pain and effortful control. In response to this burgeoning amount of data, a proliferation of computational models has tried to characterize the neurocognitive architecture of ACC. Early seminal models provided a computational explanation for a relatively circumscribed set of empirical findings, mainly accounting for EEG and fMRI evidence. More recent models have focused on ACC's contribution to effortful control. In parallel to these developments, several proposals attempted to explain within a single computational framework a wider variety of empirical findings that span different cognitive processes and experimental modalities. Here we critically evaluate these modeling attempts, highlighting the continued need to reconcile the array of disparate ACC observations within a coherent, unifying framework. PMID- 28634441 TI - Roles of Pannexin-1 Channels in Inflammatory Response through the TLRs/NF-Kappa B Signaling Pathway Following Experimental Subarachnoid Hemorrhage in Rats. AB - Background: Accumulating evidence suggests that neuroinflammation plays a critical role in early brain injury after subarachnoid hemorrhage (SAH). Pannexin 1 channels, as a member of gap junction proteins located on the plasma membrane, releases ATP, ions, second messengers, neurotransmitters, and molecules up to 1 kD into the extracellular space, when activated. Previous studies identified that the opening of Pannexin-1 channels is essential for cellular migration, apoptosis and especially inflammation, but its effects on inflammatory response in SAH model have not been explored yet. Methods: Adult male Sprague-Dawley rats were divided into six groups: sham group (n = 20), SAH group (n = 20), SAH + LV Scramble-ShRNA group (n = 20), SAH + LV-ShRNA-Panx1 group (n = 20), SAH + LV-NC group (n = 20), and SAH + LV-Panx1-EGFP group (n = 20). The rat SAH model was induced by injection of 0.3 ml fresh arterial, non-heparinized blood into the prechiasmatic cistern in 20 s. In SAH + LV-ShRNA-Panx1 group and SAH + LV-Panx1 EGFP group, lentivirus was administered via intracerebroventricular injection (i.c.v.) at 72 h before the induction of SAH. The Quantitative real-time polymerase chain reaction, electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting were performed to explore the potential interactive mechanism between Pannexin-1 channels and TLR2/TLR4/NF-kappaB-mediated signaling pathway. Cognitive and memory changes were investigated by the Morris water maze test. Results: Administration with LV-ShRNA-Panx1 markedly decreased the expression levels of TLR2/4/NF-kappaB pathway-related agents in the brain cortex and significantly ameliorated neurological cognitive and memory deficits in this SAH model. On the contrary, administration of LV-Panx1-EGFP elevated the expressions of TLR2/4/NF-kappaB pathway-related agents, which correlated with augmented neuronal apoptosis. Conclusion: Pannexin-1 channels may contribute to inflammatory response and neurobehavioral dysfunction through the TLR2/TLR4/NF-kappaB-mediated pathway signaling after SAH, suggesting a potential role of Pannexin-1 channels could be a potential therapeutic target for the treatment of SAH. PMID- 28634440 TI - Cysteines as Redox Molecular Switches and Targets of Disease. AB - Thiol groups can undergo numerous modifications, making cysteine a unique molecular switch. Cysteine plays structural and regulatory roles as part of proteins or glutathione, contributing to maintain redox homeostasis and regulate signaling within and amongst cells. Not surprisingly therefore, cysteines are associated with many hereditary and acquired diseases. Mutations in the primary protein sequence (gain or loss of a cysteine) are most frequent in membrane and secretory proteins, correlating with the key roles of disulfide bonds. On the contrary, in the cytosol and nucleus, aberrant post-translational oxidative modifications of thiol groups, reflecting redox changes in the surrounding environment, are a more frequent cause of dysregulation of protein function. This essay highlights the regulatory functions performed by protein cysteine residues and provides a framework for understanding how mutation and/or (in)activation of this key amino acid can cause disease. PMID- 28634443 TI - The Narrow Abdomen Ion Channel Complex Is Highly Stable and Persists from Development into Adult Stages to Promote Behavioral Rhythmicity. AB - The sodium leak channel NARROW ABDOMEN (NA)/ NALCN is an important component of circadian pacemaker neuronal output. In Drosophila, rhythmic expression of the NA channel regulator Nlf-1 in a subset of adult pacemaker neurons has been proposed to contribute to circadian regulation of channel localization or activity. Here we have restricted expression of Drosophila NA channel subunits or the Nlf-1 regulator to either development or adulthood using the temperature-inducible tubulin-GAL80ts system. Surprisingly, we find that developmental expression of endogenous channel subunits and Nlf-1 is sufficient to promote robust rhythmic behavior in adults. Moreover, we find that channel complex proteins produced during development persist in the Drosophila head with little decay for at least 5-7 days in adults. In contrast, restricting either endogenous or transgenic gene expression to adult stages produces only limited amounts of the functional channel complex. These data indicate that much of the NA channel complex that functions in adult circadian neurons is normally produced during development, and that the channel complex is very stable in most neurons in the Drosophila brain. Based on these findings, we propose that circadian regulation of NA channel function in adult pacemaker neurons is mediated primarily by post-translational mechanisms that are independent of Nlf-1. PMID- 28634442 TI - Mild Traumatic Brain Injury Evokes Pyramidal Neuron Axon Initial Segment Plasticity and Diffuse Presynaptic Inhibitory Terminal Loss. AB - The axon initial segment (AIS) is the site of action potential (AP) initiation, thus a crucial regulator of neuronal activity. In excitatory pyramidal neurons, the high density of voltage-gated sodium channels (NaV1.6) at the distal AIS regulates AP initiation. A surrogate AIS marker, ankyrin-G (ankG) is a structural protein regulating neuronal functional via clustering voltage-gated ion channels. In neuronal circuits, changes in presynaptic input can alter postsynaptic output via AIS structural-functional plasticity. Recently, we showed experimental mild traumatic brain injury (mTBI) evokes neocortical circuit disruption via diffuse axonal injury (DAI) of excitatory and inhibitory neuronal systems. A key finding was that mTBI-induced neocortical electrophysiological changes involved non-DAI/ intact excitatory pyramidal neurons consistent with AIS-specific alterations. In the current study we employed Thy1-yellow fluorescent protein (YFP)-H mice to test if mTBI induces AIS structural and/or functional plasticity within intact pyramidal neurons 2 days after mTBI. We used confocal microscopy to assess intact YFP+ pyramidal neurons in layer 5 of primary somatosensory barrel field (S1BF), whose axons were continuous from the soma of origin to the subcortical white matter (SCWM). YFP+ axonal traces were superimposed on ankG and NaV1.6 immunofluorescent profiles to determine AIS position and length. We found that while mTBI had no effect on ankG start position, the length significantly decreased from the distal end, consistent with the site of AP initiation at the AIS. However, NaV1.6 structure did not change after mTBI, suggesting uncoupling from ankG. Parallel quantitative analysis of presynaptic inhibitory terminals along the postsynaptic perisomatic domain of these same intact YFP+ excitatory pyramidal neurons revealed a significant decrease in GABAergic bouton density. Also within this non-DAI population, patch-clamp recordings of intact YFP+ pyramidal neurons showed AP acceleration decreased 2 days post-mTBI, consistent with AIS functional plasticity. Simulations of realistic pyramidal neuron computational models using experimentally determined AIS lengths showed a subtle decrease is NaV1.6 density is sufficient to attenuate AP acceleration. Collectively, these findings highlight the complexity of mTBI-induced neocortical circuit disruption, involving changes in extrinsic/presynaptic inhibitory perisomatic input interfaced with intrinsic/postsynaptic intact excitatory neuron AIS output. PMID- 28634444 TI - Experience-Dependency of Reliance on Local Visual and Idiothetic Cues for Spatial Representations Created in the Absence of Distal Information. AB - Spatial encoding in the hippocampus is based on a range of different input sources. To generate spatial representations, reliable sensory cues from the external environment are integrated with idiothetic cues, derived from self movement, that enable path integration and directional perception. In this study, we examined to what extent idiothetic cues significantly contribute to spatial representations and navigation: we recorded place cells while rodents navigated towards two visually identical chambers in 180 degrees orientation via two different paths in darkness and in the absence of reliable auditory or olfactory cues. Our goal was to generate a conflict between local visual and direction specific information, and then to assess which strategy was prioritized in different learning phases. We observed that, in the absence of distal cues, place fields are initially controlled by local visual cues that override idiothetic cues, but that with multiple exposures to the paradigm, spaced at intervals of days, idiothetic cues become increasingly implemented in generating an accurate spatial representation. Taken together, these data support that, in the absence of distal cues, local visual cues are prioritized in the generation of context specific spatial representations through place cells, whereby idiothetic cues are deemed unreliable. With cumulative exposures to the environments, the animal learns to attend to subtle idiothetic cues to resolve the conflict between visual and direction-specific information. PMID- 28634446 TI - Are Distal and Proximal Visual Cues Equally Important during Spatial Learning in Mice? A Pilot Study of Overshadowing in the Spatial Domain. AB - Animals use distal and proximal visual cues to accurately navigate in their environment, with the possibility of the occurrence of associative mechanisms such as cue competition as previously reported in honey-bees, rats, birds and humans. In this pilot study, we investigated one of the most common forms of cue competition, namely the overshadowing effect, between visual landmarks during spatial learning in mice. To this end, C57BL/6J * Sv129 mice were given a two trial place recognition task in a T-maze, based on a novelty free-choice exploration paradigm previously developed to study spatial memory in rodents. As this procedure implies the use of different aspects of the environment to navigate (i.e., mice can perceive from each arm of the maze), we manipulated the distal and proximal visual landmarks during both the acquisition and retrieval phases. Our prospective findings provide a first set of clues in favor of the occurrence of an overshadowing between visual cues during a spatial learning task in mice when both types of cues are of the same modality but at varying distances from the goal. In addition, the observed overshadowing seems to be non reciprocal, as distal visual cues tend to overshadow the proximal ones when competition occurs, but not vice versa. The results of the present study offer a first insight about the occurrence of associative mechanisms during spatial learning in mice, and may open the way to promising new investigations in this area of research. Furthermore, the methodology used in this study brings a new, useful and easy-to-use tool for the investigation of perceptive, cognitive and/or attentional deficits in rodents. PMID- 28634445 TI - Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment. AB - Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70-120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease. PMID- 28634448 TI - From Behavioral Facilitation to Inhibition: The Neuronal Correlates of the Orienting and Reorienting of Auditory Attention. AB - Successful adaptive behavior relies on the ability to automatically (bottom-up) orient attention to different locations in the environment. This results in a biphasic pattern in which reaction times (RT) are faster for stimuli that occur in the same spatial location (valid) for the first few hundred milliseconds, which is termed facilitation. This is followed by faster RT for stimuli that appear in novel locations (invalid) after longer delays, termed inhibition of return. The neuronal areas and networks involved in the transition between states of facilitation and inhibition remain poorly understood, especially for auditory stimuli. Functional magnetic resonance imaging (fMRI) data were therefore collected in a large sample of healthy volunteers (N = 52) at four separate auditory stimulus onset asynchronies (SOAs; 200, 400, 600, and 800 ms). Behavioral results indicated that facilitation (valid RT < invalid RT) occurred at the 200 ms SOA, with inhibition of return (valid RT > invalid RT) present at the three longer SOAs. fMRI results showed several brain areas varying their activation as a function of SOA, including bilateral superior temporal gyrus, anterior thalamus, cuneus, dorsal anterior cingulate gyrus, and right ventrolateral prefrontal cortex (VLPFC)/anterior insula. Right VLPFC was active during a behavioral state of facilitation, and its activation (invalid - valid trials) further correlated with behavioral reorienting at the 200 ms delay. These results suggest that right VLPFC plays a critical role when auditory attention must be quickly deployed or redeployed, demanding heightened cognitive and inhibitory control. In contrast to previous work, the ventral and dorsal frontoparietal attention networks were both active during valid and invalid trials across SOAs. These results suggest that the dorsal and ventral networks may not be as specialized during bottom-up auditory orienting as has been previously reported during visual orienting. PMID- 28634447 TI - The Moving Rubber Hand Illusion Reveals that Explicit Sense of Agency for Tapping Movements Is Preserved in Functional Movement Disorders. AB - Functional movement disorders (FMD) are characterized by motor symptoms (e.g., tremor, gait disorder, and dystonia) that are not compatible with movement abnormalities related to a known organic cause. One key clinical feature of FMD is that motor symptoms are similar to voluntary movements but are subjectively experienced as involuntary by patients. This gap might be related to abnormal self-recognition of bodily action, which involves two main components: sense of agency and sense of body ownership. The aim of this study was to systematically investigate whether this function is altered in FMD, specifically focusing on the subjective feeling of agency, body ownership, and their interaction during normal voluntary movements. Patients with FMD (n = 21) and healthy controls (n = 21) underwent the moving Rubber Hand Illusion (mRHI), in which passive and active movements can differentially elicit agency, ownership or both. Explicit measures of agency and ownership were obtained via a questionnaire. Patients and controls showed a similar pattern of response: when the rubber hand was in a plausible posture, active movements elicited strong agency and ownership; implausible posture of the rubber hand abolished ownership but not agency; passive movements suppressed agency but not ownership. These findings suggest that explicit sense of agency and body ownership are preserved in FMD. The latter finding is shared by a previous study in FMD using a static version of the RHI, whereas the former appears to contrast with studies demonstrating altered implicit measures of agency (e.g., sensory attenuation). Our study extends previous findings by suggesting that in FMD: (i) the sense of body ownership is retained also when interacting with the motor system; (ii) the subjective experience of agency for voluntary tapping movements, as measured by means of mRHI, is preserved. PMID- 28634449 TI - Electromyography Data Processing Impacts Muscle Synergies during Gait for Unimpaired Children and Children with Cerebral Palsy. AB - Muscle synergies calculated from electromyography (EMG) data identify weighted groups of muscles activated together during functional tasks. Research has shown that fewer synergies are required to describe EMG data of individuals with neurologic impairments. When considering potential clinical applications of synergies, understanding how EMG data processing impacts results and clinical interpretation is important. The aim of this study was to evaluate how EMG signal processing impacts synergy outputs during gait. We evaluated the impacts of two common processing steps for synergy analyses: low pass (LP) filtering and unit variance scaling. We evaluated EMG data collected during barefoot walking from five muscles of 113 children with cerebral palsy (CP) and 73 typically-developing (TD) children. We applied LP filters to the EMG data with cutoff frequencies ranging from 4 to 40 Hz (reflecting the range reported in prior synergy research). We also evaluated the impact of normalizing EMG amplitude by unit variance. We found that the total variance accounted for (tVAF) by a given number of synergies was sensitive to LP filter choice and decreased in both TD and CP groups with increasing LP cutoff frequency (e.g., 9.3 percentage points change for one synergy between 4 and 40 Hz). This change in tVAF can alter the number of synergies selected for further analyses. Normalizing tVAF to a z-score (e.g., dynamic motor control index during walking, walk-DMC) reduced sensitivity to LP cutoff. Unit variance scaling caused comparatively small changes in tVAF. Synergy weights and activations were impacted less than tVAF by LP filter choice and unit variance normalization. These results demonstrate that EMG signal processing methods impact outputs of synergy analysis and z-score based measures can assist in reporting and comparing results across studies and clinical centers. PMID- 28634450 TI - Leonurine Improves Age-Dependent Impaired Angiogenesis: Possible Involvement of Mitochondrial Function and HIF-1alpha Dependent VEGF Activation. AB - Objective: Advanced age is associated with impaired angiogenesis in part because of mitochondrial dysfunction. We have recently reported that leonurine exerts protective effects in neuron via regulation of mitochondrial function. The aim of this study was to explore whether leonurine is able to attenuate mitochondrial dysfunction and to enhance angiogenesis in old rats with hindlimb ischemia. Methods and Results: At day 14 after surgery, hypoxia-inducible factor (HIF) 1alpha and vascular endothelial growth factor (VEGF) expression was decreased in the ischemic muscle of aged animals, which was accompanied by enhanced oxidative stress, increased mitochondrial damage, decreased capillary density, and reduced limb perfusion compared with young mice. Importantly, these effects were inhibited by leonurine treatment in old animals. In vitro, we showed that the functional activities (migration and tube formation) of human umbilical vein endothelial cells (HUVECs) were significantly impaired in senescent compared to young. However, leonurine rescued HUVECs functional activities in senescent HUVECs. Mechanistically, we found that leonurine restored the age-dependent reduction in HIF activity and subsequent reduced VEGF expression in senescent HUVECs. Moreover, the mitochondrial oxidative stress was significantly augmented in senescent HUVECs, in association with reduced mitochondrial function. However, leonurine significantly reduced the mitochondrial oxidative stress and restored the mitochondrial membrane potential. Conclusion: Our results demonstrate that leonurine protects against age-dependent impairment of angiogenesis possibly through attenuation of mitochondrial dysfunction and subsequent VEGF up regulation impairment. PMID- 28634451 TI - Berberine Ameliorates Diabetes-Associated Cognitive Decline through Modulation of Aberrant Inflammation Response and Insulin Signaling Pathway in DM Rats. AB - Background: Memory-impairment was one of the common characteristics in patients with diabetes mellitus. The release of chronic inflammation mediators and insulin resistance in diabetic brain gave rise to the generation of toxic factor Abeta42 which was the marker of Alzheimer's disease. In addition, the impairment of memory in diabetes mellitus was also correlated predominantly with uptake/metabolism of glucose in medial prefrontal cortex (mPFC). Previously, anti inflammation and hypoglycemic effects of berberine (BBr) have been described in peripheral tissues. For better understanding the effects of BBr on cognitive action in diabetics, we investigated the functions of BBr involved in anti inflammation and ameliorating insulin resistance in prefrontal cortex of diabetic rats. Methods: Intragastric administration of BBr (187.5 mg/Kg/d) was used in diabetic rats. Fear-condition assay was applied for cognitive assessment, and relative protein expressions were detected by western-blot. The glucose uptake in prefrontal cortex of diabetic rats was tested by Positron-Emission Tomography imaging. The levels of inflammation mediators were determined by commercial ELISA kits. Results: The inflammation mediator release and insulin resistance in the mPFC of diabetic rats was inhibited by BBr. The activation of PI3K/Akt/mTOR and MAPK signaling pathway, as well as two novel isoforms PKCeta and PKC?? and the translocation of NF-kappaB in neuron were also down-regulated by BBr; furthermore, the neuron specific glucose transporter GLUT3 was remarkably augmented by 2-3 times when compared with diabetic group; meanwhile, BBr also promoted glucose uptake in the brain. Additionally BBr decreased the expressions of amyloid precursor protein and BACE-1, and the production of oligomeric Abeta42. Finally, it accelerates the reinforcement of the information and ameliorates cognitive impairment. Conclusion: BBr inhibited the activation of inflammation pathway and insulin resistance in the mPFC of diabetic rats. Finally, it improved the lesion of cognition in diabetic rats. PMID- 28634452 TI - Establishing the Basis for Mechanobiology-Based Physical Therapy Protocols to Potentiate Cellular Healing and Tissue Regeneration. AB - Life is mechanobiological: mechanical stimuli play a pivotal role in the formation of structurally and functionally appropriate body templates through mechanobiologically-driven cellular and tissue re/modeling. The body responds to mechanical stimuli engendered through physical movement in an integrated fashion, internalizing and transferring forces from organ, through tissue and cellular length scales. In the context of rehabilitation and therapeutic outcomes, such mechanical stimuli are referred to as mechanotherapy. Physical therapists use mechanotherapy and mechanical interventions, e.g., exercise therapy and manual mobilizations, to restore function and treat disease and/or injury. While the effect of directed movement, such as in physical therapy, is well documented at the length scale of the body and its organs, a number of recent studies implicate its integral effect in modulating cellular behavior and subsequent tissue adaptation. Yet the link between movement biomechanics, physical therapy, and subsequent cellular and tissue mechanoadaptation is not well established in the literature. Here we review mechanoadaptation in the context of physical therapy, from organ to cell scale mechanotransduction and cell to organ scale extracellular matrix genesis and re/modeling. We suggest that physical therapy can be developed to harness the mechanosensitivity of cells and tissues, enabling prescriptive definition of physical and mechanical interventions to enhance tissue genesis, healing, and rehabilitation. PMID- 28634453 TI - Relaxin-Family Peptide Receptors 1 and 2 Are Fully Functional in the Bovine. AB - In most mammals the peptide hormone relaxin is a key physiological component regulating early pregnancy and birth. However, synteny analysis shows that the gene encoding ovarian relaxin-2 is deleted in cows and sheep. While, these ruminants appear to exhibit a relaxin-like physiology, as in other mammals, until now a molecular understanding of this has been lacking. Cloning and expression analysis of the cognate bovine receptor for relaxin, RXFP1, as well as of the structurally related receptor, RXFP2, in female tissues, shows that these are expressed in a similar way to other mammals. RXFP1 transcripts are found in ovarian theca cells, endometrium, and myometrium, whereas RXFP2 transcripts are expressed in ovarian theca cells, oocytes, as well as in myometrium. Transfection of receptor-expressing gene constructs into HEK293 cells indicates that bovine RXFP1 has a greater EC50 at 10-50 nM for porcine or human relaxin, compared to human RXFP1. For bovine RXFP2, in contrast, the EC50 is <1 nM for its cognate ligand, bovine INSL3, but also 10-30 nM for porcine or human relaxin. Functional analysis shows that bovine myometrial cells are able to respond to exogenous relaxin and INSL3 with a significant increase in cAMP. Although expressing mRNA for both RXFP1 and RXFP2, bovine follicular theca cells only respond to INSL3 with a dose-dependent increase in cAMP. Altogether the results suggest that the cow is able to compensate for the missing hormone, and moreover imply that relaxin analogs could offer an important therapeutic option in treating female ruminant infertility. PMID- 28634455 TI - Fertilizing a Patient Engagement Ecosystem to Innovate Healthcare: Toward the First Italian Consensus Conference on Patient Engagement. AB - Currently we observe a gap between theory and practices of patient engagement. If both scholars and health practitioners do agree on the urgency to realize patient engagement, no shared guidelines exist so far to orient clinical practice. Despite a supportive policy context, progress to achieve greater patient engagement is patchy and slow and often concentrated at the level of policy regulation without dialoguing with practitioners from the clinical field as well as patients and families. Though individual clinicians, care teams and health organizations may be interested and deeply committed to engage patients and family members in the medical course, they may lack clarity about how to achieve this goal. This contributes to a wide "system" inertia-really difficult to be overcome-and put at risk any form of innovation in this filed. As a result, patient engagement risk today to be a buzz words, rather than a real guidance for practice. To make the field clearer, we promoted an Italian Consensus Conference on Patient Engagement (ICCPE) in order to set the ground for drafting recommendations for the provision of effective patient engagement interventions. The ICCPE will conclude in June 2017. This document reports on the preliminary phases of this process. In the paper, we advise the importance of "fertilizing a patient engagement ecosystem": an oversimplifying approach to patient engagement promotion appears the result of a common illusion. Patient "disengagement" is a symptom that needs a more holistic and complex approach to solve its underlined causes. Preliminary principles to promote a patient engagement ecosystem are provided in the paper. PMID- 28634454 TI - The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease. AB - The sodium and potassium gradients across the plasma membrane are used by animal cells for numerous processes, and the range of demands requires that the responsible ion pump, the Na,K-ATPase, can be fine-tuned to the different cellular needs. Therefore, several isoforms are expressed of each of the three subunits that make a Na,K-ATPase, the alpha, beta and FXYD subunits. This review summarizes the various roles and expression patterns of the Na,K-ATPase subunit isoforms and maps the sequence variations to compare the differences structurally. Mutations in the Na,K-ATPase genes encoding alpha subunit isoforms have severe physiological consequences, causing very distinct, often neurological diseases. The differences in the pathophysiological effects of mutations further underline how the kinetic parameters, regulation and proteomic interactions of the Na,K-ATPase isoforms are optimized for the individual cellular needs. PMID- 28634457 TI - Perceptual Categories Derived from Reid's "Common Sense" Philosophy. AB - The 18th-century Scottish 'common sense' philosopher Thomas Reid argued that perception can be distinguished on several dimensions from other categories of experience, such as sensation, illusion, hallucination, mental images, and what he called 'fancy.' We extend his approach to eleven mental categories, and discuss how these distinctions, often ignored in the empirical literature, bear on current research. We also score each category on five properties (ones abstracted from Reid) to form a 5 * 11 matrix, and thus can generate statistical measures of their mutual dependencies, a procedure that may have general interest as illustrating what we can call 'computational philosophy.' PMID- 28634456 TI - Absolute and Relative Training Load and Its Relation to Fatigue in Football. AB - The aim of the study was to assess the relationship of external and internal training load (TL) indicators with the objective and subjective fatigue experienced by 15 semi-professional football players, over eight complete weeks of the competition period in the 2015-2016 season, which covered microcycles from 34th to 41st. The maximum heart rate (HRmax) and maximum speed (Vmax) of all the players were previously measured in specific tests. The TL was monitored via questionnaires on rating of perceived exertion (RPE), pulsometers and GPS devices, registering the variables: total distance (TD), player load 2D (PL2D), TD at >80% of the Vmax (TD80), TD in deceleration at < -2 m?sec-2 (TDD <-2), TD in acceleration >2 m?sec-2 (TDA >2), Edwards (ED), time spent at between 50 and 80% (50-80% HRmax), 80-90% (80-90% HRmax), and >90% of the HRmax (>90% HRmax), and RPE both respiratory/thoracic (RPEres) and leg/muscular (RPEmus). All the variables were analyzed taking into account both the absolute values accumulated over the week and the normalized values in relation to individual mean competition values. Neuromuscular fatigue was measured objectively using the countermovement jump test and subjectively via the Total Quality Recovery (TQR) scale questionnaire. Analytical correlation techniques were later applied within the general linear model. There is a correlation between the fatigue experienced by the player, assessed objectively and subjectively, and the load accumulated over the week, this being assessed in absolute and relative terms. Specifically, the load relative to competition correlated with the physical variables TD ( 0.279), PL2D (-0.272), TDD < -2 (-0.294), TDA >2 (-0.309), and sRPEmus (-0.287). The variables related to heart rate produced a higher correlation with TQR. There is a correlation between objectively and subjectively assessed fatigue and the accumulated TL of a player over the week, with a higher sensitivity being shown when compared to the values related to the demands of competition. Monitoring load and assessing fatigue, we are closer to knowing what the prescription of an adequate dose of training should be in order for a player to be as fresh as possible and in top condition for a match. Normalizing training demands with respect to competition could be an appropriate strategy for individualizing player TL. PMID- 28634460 TI - Children's Self-Regulation in Cultural Contexts: The Role of Parental Socialization Theories, Goals, and Practices. AB - Self-regulation is a complex multidimensional construct which has been approached mainly in Western cultural contexts. The present contribution examines the importance of considering the culture-sensitive nature of self-regulation by reviewing theory and research on the development of children's self-regulation in different cultural contexts. This review of theory and research allows to suggest that widely shared values in a cultural group influence parental socialization theories, goals, and practices, which in turn have an impact on how children learn to self-regulate, the forms of self-regulation they develop, and the goals associated with self-regulation. Thus, this article concludes that more specific research is required to relate both the developmental and the cultural aspects of children's self-regulation. PMID- 28634459 TI - Cognitive Correlates of Different Mentalizing Abilities in Individuals with High and Low Trait Schizotypy: Findings from an Extreme-Group Design. AB - Mentalizing or Theory of Mind (ToM) deficits in schizophrenia have been studied to great extent, but studies involving samples of trait schizotypy yield ambiguous results. Executive functions like cognitive inhibition, cognitive flexibility, and agency are all prerequisites of mentalizing, and it is assumed that the impairment of these functions contributes to ToM deficits in schizophrenia. Whether these impairments influence the ToM performance of people with high trait schizotypy remains unclear. Although impaired self-agency has repeatedly been identified in people with schizotypy, its role in mentalizing is yet to be investigated. The main aim of this study was to explore whether deficits in cognitive and affective ToM can be found in high trait schizotypy, and to identify in what way these deficits are related to the positive and negative dimensions of schizotypy. The secondary aim was to examine whether these deficits correlate with executive functions. Based on the dimensional view of the schizophrenia spectrum, an extreme-group design was applied to non-clinical volunteers demonstrating high (N = 39) and low (N = 47) trait schizotypy. Affective and cognitive ToM were investigated using the Movie for Assessment of Social Cognition, a sensitive and video-based measurement. Cognitive inhibition was assessed using the Stroop Test, and cognitive flexibility was analyzed using the Trail-Making Test. Agency was measured using a computerized self-agency paradigm. Participants in the high-schizotypy group performed significantly worse in the affective ToM task (d = 0.79), and their overall ToM performance was significantly impaired (d = 0.60). No between-group differences were found with regards to cognitive ToM, executive functions, and self-agency. Cognitive flexibility correlated negatively with positive schizotypy, and contributed to a worse overall and affective ToM. Impaired cognitive inhibition contributed to undermentalizing-type errors. It was found that non-clinical participants with high trait (positive) schizotypy - especially those with slight executive function deficits - may have difficulties in understanding the emotional state of others and consequently in functioning in social situations. PMID- 28634458 TI - Phone Conversation while Processing Information: Chronometric Analysis of Load Effects in Everyday-media Multitasking. AB - This is a pilot study that examined the effect of cell-phone conversation on cognition using a continuous multitasking paradigm. Current theorizing argues that phone conversation affects behavior (e.g., driving) by interfering at a level of cognitive processes (not peripheral activity) and by implying an attentional-failure account. Within the framework of an intermittent spare utilized capacity threading model, we examined the effect of aspects of (secondary-task) phone conversation on (primary-task) continuous arithmetic performance, asking whether phone use makes components of automatic and controlled information-processing (i.e., easy vs. hard mental arithmetic) run more slowly, or alternatively, makes processing run less reliably albeit with the same processing speed. The results can be summarized as follows: While neither expecting a text message nor expecting an impending phone call had any detrimental effects on performance, active phone conversation was clearly detrimental to primary-task performance. Crucially, the decrement imposed by secondary-task (conversation) was not due to a constant slowdown but is better be characterized by an occasional breakdown of information processing, which differentially affected automatic and controlled components of primary-task processing. In conclusion, these findings support the notion that phone conversation makes individuals not constantly slower but more vulnerable to commit attention failure, and in this way, hampers stability of (primary-task) information processing. PMID- 28634461 TI - Sensitivity to Acceleration in the Human Early Visual System. AB - It is widely believed that the human visual system is insensitive to acceleration in moving stimuli. This notion is supported by evidence that detection sensitivity for velocity modulation in moving stimuli is a lowpass function of the velocity modulation's temporal frequency. However, the lowpass function might be a mixture of detection by attention-based tracking and low-level mechanisms sensitive to acceleration. To revisit the issue of acceleration perception in relation to attentive tracking, we measured detection sensitivities for velocity modulations at various temporal frequencies (0.25-8 Hz) by using drifting gratings within long or short spatial windows that make the tracking of grating easier or more difficult respectively. Results showed that modulation sensitivity is lowpass for gratings with long windows but bandpass for gratings with short windows (peak at ~1 Hz). Moreover, we found that lowpass sensitivity becomes bandpass when we removed observer attention by a concurrent letter identification task. An additional visual-search experiment showed that a target dot moving with a velocity modulation at relatively high temporal frequencies (~2-4 Hz) was most easily detected among dots moving at various constant velocities. These results support the notion that high sensitivity to sluggish velocity modulation is a product of attentively tracking of moving stimuli and that the visual system is directly sensitive to accelerations and/or decelerations at the preattentive level. PMID- 28634462 TI - Gender Invariance of the Gambling Behavior Scale for Adolescents (GBS-A): An Analysis of Differential Item Functioning Using Item Response Theory. AB - As there is a lack of evidence attesting the equivalent item functioning across genders for the most employed instruments used to measure pathological gambling in adolescence, the present study was aimed to test the gender invariance of the Gambling Behavior Scale for Adolescents (GBS-A), a new measurement tool to assess the severity of Gambling Disorder (GD) in adolescents. The equivalence of the items across genders was assessed by analyzing Differential Item Functioning within an Item Response Theory framework. The GBS-A was administered to 1,723 adolescents, and the graded response model was employed. The results attested the measurement equivalence of the GBS-A when administered to male and female adolescent gamblers. Overall, findings provided evidence that the GBS-A is an effective measurement tool of the severity of GD in male and female adolescents and that the scale was unbiased and able to relieve truly gender differences. As such, the GBS-A can be profitably used in educational interventions and clinical treatments with young people. PMID- 28634463 TI - Protective Effect of N-Acetylcysteine Amide on Blast-Induced Increase in Intracranial Pressure in Rats. AB - Blast-induced traumatic brain injury is associated with acute and possibly chronic elevation of intracranial pressure (ICP). The outcome after TBI is dependent on the progression of complex processes which are mediated by oxidative stress. So far, no effective pharmacological protection against TBI exists. In this study, rats were exposed to a single or repetitive blast overpressure (BOP) at moderate intensities of 72 or 110 kPa in a compressed air-driven shock tube. The degree and duration of the increase in ICP were proportional to the intensity and frequency of the blast exposure(s). In most cases, a single dose of antioxidant N-acetylcysteine amide (NACA) (500 mg/kg) administered intravenously 2 h after exposure to BOP significantly attenuated blast-induced increase in ICP. A single dose of NACA was not effective in improving the outcome in the group of animals that were subjected to repetitive blast exposures at 110 kPa on the same day. In this group, two treatments with NACA at 2 and 4 h post-BOP exposure resulted in significant attenuation of elevated ICP. Treatment with NACA prior to BOP exposure completely prevented the elevation of ICP. The findings indicate that oxidative stress plays an important role in blast-induced elevated ICP as treatment with NACA-ameliorated ICP increase, which is frequently related to poor functional recovery after TBI. PMID- 28634464 TI - Anti-Inflammatory and Neuroprotective Effects of Co-UltraPEALut in a Mouse Model of Vascular Dementia. AB - Vascular dementia (VaD), the second most common cause of cognitive impairment in the population, is a disease that results from reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Co-ultramicronized PEALut (co-ultra PEALut) is a new compound with beneficial effects, which include anti-inflammatory and antioxidant properties. Recently, co-ultraPEALut has been shown to exhibit neuroprotective effects in models of Parkinson's disease, cerebral ischemia and Alzheimer's disease. However, its effects on VaD remain unknown. Therefore, the purpose of the present study was to highlight the potential neuroprotective actions of co-ultraPEALut containing N palmitoylethanolamine (PEA) and the antioxidant flavonoid luteolin (Lut) (10:1 by mass) in a mouse model of VaD induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, mice were orally treated with 1 mg/kg co-ultraPEALut daily for 15 days. On the 15th day, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Our results clearly demonstrate that co-ultraPEALut improved learning, memory ability, locomotor activity, and the reciprocal social interaction. In addition, the mice subjected to VaD and treated with the co-ultraPEALut showed a reorganization of CA1 and CA3 regions of the hippocampus and restored the number of hippocampal neurons as evidenced by NeuN expression, a specific marker of neurons. Furthermore following carotid arteries ligation, mice treated with co ultraPEALut showed a modification of proinflammatory, proapoptotic proteins and of oxidative stress as evidenced by the expression of IkappaB-alpha, NF-kappaB p65, Bax, Bcl-2, inducible nitric oxide synthase, and cyclooxygenase-2. In order, co-ultraPEALut treatment restored VaD-induced loss of brain-derived neurotrophic factor and neurotrophins 3 (NT-3) expression in mice. These results confirmed that the neuroprotective effects of co-ultraPEALut were associated with its anti inflammatory and antioxidant properties. PMID- 28634465 TI - Abnormal Resting-State Functional Connectivity in Progressive Supranuclear Palsy and Corticobasal Syndrome. AB - BACKGROUND: Pathological and MRI-based evidence suggests that multiple brain structures are likely to be involved in functional disconnection between brain areas. Few studies have investigated resting-state functional connectivity (rsFC) in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In this study, we investigated within- and between-network rsFC abnormalities in these two conditions. METHODS: Twenty patients with PSP, 11 patients with CBS, and 16 healthy subjects (HS) underwent a resting-state fMRI study. Resting-state networks (RSNs) were extracted to evaluate within- and between-network rsFC using the Melodic and FSLNets software packages. RESULTS: Increased within-network rsFC was observed in both PSP and CBS patients, with a larger number of RSNs being involved in CBS. Within-network cerebellar rsFC positively correlated with mini mental state examination scores in patients with PSP. Compared to healthy volunteers, PSP and CBS patients exhibit reduced functional connectivity between the lateral visual and auditory RSNs, with PSP patients additionally showing lower functional connectivity between the cerebellar and insular RSNs. Moreover, rsFC between the salience and executive-control RSNs was increased in patients with CBS compared to HS. CONCLUSION: This study provides evidence of functional brain reorganization in both PSP and CBS. Increased within-network rsFC could represent a higher degree of synchronization in damaged brain areas, while between-network rsFC abnormalities may mainly reflect degeneration of long-range white matter fibers. PMID- 28634466 TI - Abnormal Temporal Coupling of Tactile Perception and Motor Action in Parkinson's Disease. AB - Evidence shows altered somatosensory temporal discrimination threshold (STDT) in Parkinson's disease in comparison to normal subjects. In healthy subjects, movement execution modulates STDT values through mechanisms of sensory gating. We investigated whether STDT modulation during movement execution in patients with Parkinson's disease differs from that in healthy subjects. In 24 patients with Parkinson's disease and 20 healthy subjects, we tested STDT at baseline and during index finger abductions (at movement onset "0", 100, and 200 ms thereafter). We also recorded kinematic features of index finger abductions. Fifteen out of the 24 patients were also tested ON medication. In healthy subjects, STDT increased significantly at 0, 100, and 200 ms after movement onset, whereas in patients with Parkinson's disease in OFF therapy, it increased significantly at 0 and 100 ms but returned to baseline values at 200 ms. When patients were tested ON therapy, STDT during index finger abductions increased significantly, with a time course similar to that of healthy subjects. Differently from healthy subjects, in patients with Parkinson's disease, the mean velocity of the finger abductions decreased according to the time lapse between movement onset and the delivery of the paired electrical stimuli for testing somatosensory temporal discrimination. In conclusion, patients with Parkinson's disease show abnormalities in the temporal coupling between tactile information and motor outflow. Our study provides first evidence that altered temporal processing of sensory information play a role in the pathophysiology of motor symptoms in Parkinson's disease. PMID- 28634467 TI - Brain Network Activation Technology Does Not Assist with Concussion Diagnosis and Return to Play in Football Athletes. AB - BACKGROUND: Concussion diagnosis and management remains a largely subjective process. This investigation sought to evaluate the utility of a novel neuroelectric measure for concussion diagnosis and return to play decision making. HYPOTHESIS: Brain Network Activation (BNA) scores obtained within 72-h of injury will be lower than the athlete's preseason evaluation and that of a matched control athlete; and the BNA will demonstrate ongoing declines at the return to play and post-season time points, while standard measures will have returned to pre-injury and control athlete levels. DESIGN: Case-control study. METHODS: Football athletes with a diagnosed concussion (n = 8) and matched control football athletes (n = 8) completed a preseason evaluation of cognitive (i.e., Cogstate Computerized Cognitive Assessment Tool) and neuroelectric function (i.e., BNA), clinical reaction time, SCAT3 self-reported symptoms, and quality of life (i.e., Health Behavior Inventory and Satisfaction with Life Scale). Following a diagnosed concussion, injured and control athletes completed post-injury evaluations within 72-h, once asymptomatic, and at the conclusion of the football season. RESULTS: Case analysis of the neuroelectric assessment failed to provide improved diagnostics beyond traditional clinical measures. Statistical analyses indicated significant BNA improvements in the concussed and control groups from baseline to the asymptomatic timepoint. CONCLUSION: With additional attention being placed on rapid and accurate concussion diagnostics and return to play decision-making, the addition of a novel neuroelectric assessment does not appear to provide additional clinical benefit at this time. Clinicians should continue to follow the recommendations for the clinical management of concussion with the assessment of the symptom, cognitive, and motor control domains. PMID- 28634468 TI - Fragile X Syndrome: Prevalence, Treatment, and Prevention in China. AB - Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the leading monogenic cause of autism spectrum disorder. Although FXS has been studied for several decades, there is relatively little basic science or clinical research being performed on FXS in China. Indeed, there is a large gap between China and Western countries in the FXS field. China has a potentially large number of FXS patients. However, many of them are underdiagnosed or even misdiagnosed, and treatments are not always administered in the Chinese population. This review discusses the prevalence, treatment, and prevention of FXS in China to facilitate an understanding of this disease in the Chinese population. PMID- 28634469 TI - Alexander Disease Mutations Produce Cells with Coexpression of Glial Fibrillary Acidic Protein and NG2 in Neurosphere Cultures and Inhibit Differentiation into Mature Oligodendrocytes. AB - BACKGROUND: Alexander disease (AxD) is a rare disease caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). The disease is characterized by presence of GFAP aggregates in the cytoplasm of astrocytes and loss of myelin. OBJECTIVES: Determine the effect of AxD-related mutations on adult neurogenesis. METHODS: We transfected different types of mutant GFAP into neurospheres using the nucleofection technique. RESULTS: We find that mutations may cause coexpression of GFAP and NG2 in neurosphere cultures, which would inhibit the differentiation of precursors into oligodendrocytes and thus explain the myelin loss occurring in the disease. Transfection produces cells that differentiate into new cells marked simultaneously by GFAP and NG2 and whose percentage increased over days of differentiation. Increased expression of GFAP is due to a protein with an anomalous structure that forms aggregates throughout the cytoplasm of new cells. These cells display down-expression of vimentin and nestin. Up-expression of cathepsin D and caspase-3 in the first days of differentiation suggest that apoptosis as a lysosomal response may be at work. HSP27, a protein found in Rosenthal bodies, is expressed less at the beginning of the process although its presence increases in later stages. CONCLUSION: Our findings seem to suggest that the mechanism of development of AxD may not be due to a function gain due to increase of GFAP, but to failure in the differentiation process may occur at the stage in which precursor cells transform into oligodendrocytes, and that possibility may provide the best explanation for the clinical and radiological images described in AxD. PMID- 28634470 TI - The Dark Side of the Mushroom Spring Microbial Mat: Life in the Shadow of Chlorophototrophs. II. Metabolic Functions of Abundant Community Members Predicted from Metagenomic Analyses. AB - Microbial mat communities in the effluent channels of Octopus and Mushroom Springs within the Lower Geyser Basin of Yellowstone National Park have been extensively characterized. Previous studies have focused on the chlorophototrophic organisms of the phyla Cyanobacteria and Chloroflexi. However, the diversity and metabolic functions of the other portion of the community in the microoxic/anoxic region of the mat are poorly understood. We recently described the diverse but extremely uneven microbial assemblage in the undermat of Mushroom Spring based on 16S rRNA amplicon sequences, which was dominated by Roseiflexus members, filamentous anoxygenic chlorophototrophs. In this study, we analyzed the orange-colored undermat portion of the community of Mushroom Spring mats in a genome-centric approach and discuss the metabolic potentials of the major members. Metagenome binning recovered partial genomes of all abundant community members, ranging in completeness from ~28 to 96%, and allowed affiliation of function with taxonomic identity even for representatives of novel and Candidate phyla. Less complete metagenomic bins correlated with high microdiversity. The undermat portion of the community was found to be a mixture of phototrophic and chemotrophic organisms, which use bicarbonate as well as organic carbon sources derived from different cell components and fermentation products. The presence of rhodopsin genes in many taxa strengthens the hypothesis that light energy is of major importance. Evidence for the usage of all four bacterial carbon fixation pathways was found in the metagenome. Nitrogen fixation appears to be limited to Synechococcus spp. in the upper mat layer and Thermodesulfovibrio sp. in the undermat, and nitrate/nitrite metabolism was limited. A closed sulfur cycle is indicated by biological sulfate reduction combined with the presence of genes for sulfide oxidation mainly in phototrophs. Finally, a variety of undermat microorganisms have genes for hydrogen production and consumption, which leads to the observed diel hydrogen concentration patterns. PMID- 28634471 TI - A Chitin-binding Protein Purified from Moringa oleifera Seeds Presents Anticandidal Activity by Increasing Cell Membrane Permeability and Reactive Oxygen Species Production. AB - Candida species are opportunistic pathogens that infect immunocompromised and/or immunosuppressed patients, particularly in hospital facilities, that besides representing a significant threat to health increase the risk of mortality. Apart from echinocandins and triazoles, which are well tolerated, most of the antifungal drugs used for candidiasis treatment can cause side effects and lead to the development of resistant strains. A promising alternative to the conventional treatments is the use of plant proteins. M. oleifera Lam. is a plant with valuable medicinal properties, including antimicrobial activity. This work aimed to purify a chitin-binding protein from M. oleifera seeds and to evaluate its antifungal properties against Candida species. The purified protein, named Mo CBP2, represented about 0.2% of the total seed protein and appeared as a single band on native PAGE. By mass spectrometry, Mo-CBP2 presented 13,309 Da. However, by SDS-PAGE, Mo-CBP2 migrated as a single band with an apparent molecular mass of 23,400 Da. Tricine-SDS-PAGE of Mo-CBP2 under reduced conditions revealed two protein bands with apparent molecular masses of 7,900 and 4,600 Da. Altogether, these results suggest that Mo-CBP2 exists in different oligomeric forms. Moreover, Mo-CBP2 is a basic glycoprotein (pI 10.9) with 4.1% (m/m) sugar and it did not display hemagglutinating and hemolytic activities upon rabbit and human erythrocytes. A comparative analysis of the sequence of triptic peptides from Mo CBP2 in solution, after LC-ESI-MS/MS, revealed similarity with other M. oleifera proteins, as the 2S albumin Mo-CBP3 and flocculating proteins, and 2S albumins from different species. Mo-CBP2 possesses in vitro antifungal activity against Candida albicans, C. parapsilosis, C. krusei, and C. tropicalis, with MIC50 and MIC90 values ranging between 9.45-37.90 and 155.84-260.29 MUM, respectively. In addition, Mo-CBP2 (18.90 MUM) increased the cell membrane permeabilization and reactive oxygen species production in C. albicans and promoted degradation of circular plasmid DNA (pUC18) from Escherichia coli. The data presented in this study highlight the potential use of Mo-CBP2 as an anticandidal agent, based on its ability to inhibit Candida spp. growth with apparently low toxicity on mammalian cells. PMID- 28634473 TI - Toxic Effects of Prodigiosin Secreted by Hahella sp. KA22 on Harmful Alga Phaeocystis globosa. AB - Application of algicidal compounds secreted by bacteria is a promising and environmentally friendly strategy to control harmful algal blooms (HABs). Years ago prodigiosin was described as an efficient algicidal compound, but the details about the effect of prodigiosin on algal cells are still elusive. Prodigiosin shows high algicidal activity on Phaeocystis globosa, making it a potential algicide in HAB control. When P. globosa were treated with prodigiosin at 5 MUg/mL, algae cells showed cytoplasmic hypervacuolization, chloroplast and nucleus rupture, flagella missing, and cell fracture, when observed by scanning electron microscope and transmission electron microscopy. Prodigiosin induced a reactive oxygen species (ROS) burst in P. globosa at 2 h, which could result in severe oxidative damage to algal cells. Chlorophyll a (Chl a) fluorescence decreased significantly after prodigiosin treatment; about 45.3 and 90.0% of algal cells lost Chl a fluorescence at 24 and 48 h. The Fv/Fm value, reflecting the status of the photosystem II electron flow also decreased after prodigiosin treatment. Quantitative polymerase chain reaction (PCR) analysis psbA and rbcS expression indicated that photosynthesis process was remarkably inhibited by prodigiosin. The results indicated that the inhibition of photosynthesis may produce excessive ROS causing cell necrosis. This study is the first report about algal lysis mechanism of prodigiosin on harmful algae. Our results could increase our knowledge on the interaction between algicidal compounds and harmful algae, which could lead to further studies in the microcosm. PMID- 28634472 TI - Antifungal Activity against Filamentous Fungi of Ts1, a Multifunctional Toxin from Tityus serrulatus Scorpion Venom. AB - Antimicrobial peptides (AMPs) are ubiquitous and multipotent components of the innate immune defense arsenal used by both prokaryotic and eukaryotic organisms. The search for new AMPs has increased in recent years, due to the growing development of microbial resistance to therapeutical drugs. In this work, we evaluate the effects of Tityus serrulatus venom (Tsv), its fractions and its major toxin Ts1, a beta-neurotoxin, on fungi growth. The fractions were obtained by ion-exchange chromatography of Tsv. The growth inhibition of 11 pathogenic and non-pathogenic filamentous fungi (Aspergillus fumigatus, A. nidulans, A. niger, A. terreus, Neurospora crassa, Penicillium corylophilum, P. ochrochloron, P. verrucosum, P. viridicatum, P. waksmanii, and Talaromyces flavus) was evaluated by quantitative microplate reader assay. Tsv (100 and 500 MUg/well, which correspond to 1 and 5 mg/mL, respectively, of total soluble protein) was active in inhibiting growth of A. nidulans, A. terreus, P. corylophilum, and P. verrucosum, especially in the higher concentration used and at the first 30 h. After this period, fungi might have used Tsv components as alternative sources of nutrients, and therefore, increased their growth tax. Only fractions IX, X, XI, XIIA, XIIB (3 and 7.5 MUg/well, which correspond to 30 and 75 MUg/mL, respectively, of total soluble protein) and Ts1 (1.5, 3, and 6 MUg/well, which correspond to 2.18, 4.36, and 8.72 MUM, respectively) showed antifungal activity. Ts1 showed to be a non-morphogenic toxin with dose-dependent activity against A. nidulans, inhibiting 100% of fungal growth from 3 MUg/well (4.36 MUM). The inhibitory effect of Ts1 against A. nidulans growth was accompanied by fungistatic effects and was not amended by 1 mM CaCl2 or tetrodotoxin (46.98 and 93.96 MUM). The structural differences between Ts1 and drosomycin, a potent cysteine-rich antifungal peptide, are discussed here. Our results highlight the antifungal potential of the first cysteine-containing scorpion toxin. Since Ts1 is a multifunctional toxin, we suggest that it could be used as a template in the design of engineered scorpion AMPs and in the search for new mechanisms of action of antifungal drugs. PMID- 28634474 TI - Different Dynamic Distribution in Chickens and Ducks of the Hypervirulent, Novel Genotype Fowl Adenovirus Serotype 4 Recently Emerged in China. AB - A hypervirulent fowl adenovirus serotype 4 (FAdV-4) has caused hepatitis hydropericardium syndrome (HHS) with mortalities that range from 30 to 80% in outbreaks across China since 2015. The FAdV-4 strain was characterized as a novel genotype based on the specific genome characteristics. However, our understanding of the dynamic distribution, tissue tropism, and pathogenesis of the novel FAdV-4 is incomplete. In this study, a new, sensitive and FAdV-4-specific real-time PCR was developed and applied to detect the dynamic distribution of the duck origin, novel FAdV-4 strain HLJDAd15 in experimentally infected special-pathogen free (SPF) chickens and ducks. Notably, the pathogenicity and replication pattern of HLJDAd15 were completely different between chickens and ducks. Severe hydropericardium and 10% mortality were induced in chickens, whereas no clinical signs were observed in any duck. The virus replicated was detected throughout the study in both chickens and ducks. However, only one replication peak with a high virus concentration appeared in chickens at 5 days post infection (dpi), whereas two peaks with relatively low virus titres appeared in ducks at 7 and 21 dpi. Thus, ducks could be a natural reservoir of the novel FAdV-4 absent of clinical signs, and a new transmission route from ducks shedding FAdV-4 continually to chickens was revealed, which might aggravate the outbreak of HHS in chickens. This study provides the first accurate quantitative data for the replication kinetics of the novel FAdV-4 in different hosts. The different pathogenicity, dynamic distribution and replication pattern in chickens and ducks provide a foundation for further clarification of the pathogenesis of the novel FAdV-4. PMID- 28634475 TI - Cesarean or Vaginal Birth Does Not Impact the Longitudinal Development of the Gut Microbiome in a Cohort of Exclusively Preterm Infants. AB - The short and long-term impact of birth mode on the developing gut microbiome in neonates has potential implications for the health of infants. In term infants, the microbiome immediately following birth across multiple body sites corresponds to birth mode, with increased Bacteroides in vaginally delivered infants. We aimed to determine the impact of birth mode of the preterm gut microbiome over the first 100 days of life and following neonatal intensive care unit (NICU) discharge. In total, 867 stool samples from 46 preterm infants (21 cesarean and 25 vaginal), median gestational age 27 weeks, were sequenced (V4 region 16S rRNA gene, Illumina MiSeq). Of these, 776 samples passed quality filtering and were included in the analysis. The overall longitudinal alpha-diversity and within infant beta-diversity was comparable between cesarean and vaginally delivered infants. Vaginally delivered infants kept significantly more OTUs from 2 months of life and following NICU discharge, but OTUs lost, gained, and regained were not different based on birth mode. Furthermore, the temporal progression of dominant genera was comparable between birth modes and no significant difference was found for any genera following adjustment for covariates. Lastly, preterm gut community types (PGCTs) showed some moderate differences in very early life, but progressed toward a comparable pattern by week 5. No PGCT was significantly associated with cesarean or vaginal birth. Unlike term infants, birth mode was not significantly associated with changes in microbial diversity, composition, specific taxa, or overall microbial development in preterm infants. This may result from the dominating effects of NICU exposures including the universal use of antibiotics immediately following birth and/or the lack of Bacteroides colonizing preterm infants. PMID- 28634476 TI - Changes in N:P Supply Ratios Affect the Ecological Stoichiometry of a Toxic Cyanobacterium and Its Fungal Parasite. AB - Human activities have dramatically altered nutrient fluxes from the landscape into receiving waters. As a result, not only the concentration of nutrients in surface waters has increased, but also their elemental ratios have changed. Such shifts in resource supply ratios will alter autotroph stoichiometry, which may in turn have consequences for higher trophic levels, including parasites. Here, we hypothesize that parasite elemental composition will follow changes in the stoichiometry of its host, and that its reproductive success will decrease with host nutrient limitation. We tested this hypothesis by following the response of a host-parasite system to changes in nitrogen (N) and phosphorus (P) supply in a controlled laboratory experiment. To this end, we exposed a fungal parasite (the chytrid Rhizophydium megarrhizum) to its host (the freshwater cyanobacterium Planktothrix rubescens) under control, low N:P and high N:P conditions. Host N:P followed treatment conditions, with a decreased N:P ratio under low N:P supply, and an increased N:P ratio under high N:P supply, as compared to the control. Shifts in host N:P stoichiometry were reflected in the parasite stoichiometry. Furthermore, at low N:P supply, host intracellular microcystin concentration was lowered as compared to high N:P supply. In contrast to our hypothesis, zoospore production decreased at low N:P and increased at high N:P ratio as compared to the control. These findings suggest that fungal parasites have a relatively high N, but low P requirement. Furthermore, zoospore elemental content, and thereby presumably their size, decreased at high N:P ratios. From these results we hypothesize that fungal parasites may exhibit a trade-off between zoospore size and production. Since zooplankton can graze on chytrid zoospores, changes in parasite production, stoichiometry and cell size may have implications for aquatic food web dynamics. PMID- 28634477 TI - Metabolomic Analysis and Mode of Action of Metabolites of Tea Tree Oil Involved in the Suppression of Botrytis cinerea. AB - Tea tree oil (TTO), a volatile essential oil, has been widely used as an antimicrobial agent. However, the mechanism underlying TTO antifungal activity is not fully understood. In this study, a comprehensive metabolomics survey was undertaken to identify changes in metabolite production in Botrytis cinerea cells treated with TTO. Significant differences in 91 metabolites were observed, including 8 upregulated and 83 downregulated metabolites in TTO-treated cells. The results indicate that TTO inhibits primary metabolic pathways through the suppression of the tricarboxylic acid (TCA) cycle and fatty acid metabolism. Further experiments show that TTO treatment decreases the activities of key enzymes in the TCA cycle and increases the level of hydrogen peroxide (H2O2). Membrane damage is also induced by TTO treatment. We hypothesize that the effect of TTO on B. cinerea is achieved mainly by disruption of the TCA cycle and fatty acid metabolism, resulting in mitochondrial dysfunction and oxidative stress. PMID- 28634478 TI - Transcriptional and Antagonistic Responses of Biocontrol Strain Lysobacter enzymogenes OH11 to the Plant Pathogenic Oomycete Pythium aphanidermatum. AB - Lysobacter enzymogenes is a ubiquitous, beneficial, plant-associated bacterium emerging as a novel biological control agent. It has the potential to become a new source of antimicrobial secondary metabolites such as the Heat-Stable Antifungal Factor (HSAF), which is a broad-spectrum antimycotic with a novel mode of action. However, very little information about how L. enzymogenes detects and responds to fungi or oomycetes has been reported. An in vitro confrontation bioassay between the pathogenic oomycete Pythium aphanidermatum and the biocontrol bacterial strain L. enzymogenes OH11 was used to analyze the transcriptional changes in the bacteria that were induced by the oomycetes. Analysis was performed at three time points of the interaction, starting before inhibition zone formation until inhibition zone formation. A L. enzymogenes OH11 DNA microarray was constructed for the analysis. Microarray analysis indicated that a wide range of genes belonging to 14 diverse functions in L. enzymogenes were affected by P. aphanidermatum as critical antagonistic effects occurred. L. enzymogenes detected and responded to the presence of P. aphanidermatum early, but alteration of gene expression typically occurred after inhibition zone formation. The presence of P. aphanidermatum increased the twitching motility and HSAF production in L. enzymogenes. We also performed a contact interaction between L. enzymogenes and P. aphanidermatum, and found that HSAF played a critical role in the interaction. Our experiments demonstrated that L. enzymogenes displayed transcriptional and antagonistic responses to P. aphanidermatum in order to gain advantages in the competition with this oomycete. This study revealed new insights into the interactions between bacteria and oomycete. PMID- 28634479 TI - Whole Blood Profiling of Bacillus Calmette-Guerin-Induced Trained Innate Immunity in Infants Identifies Epidermal Growth Factor, IL-6, Platelet-Derived Growth Factor-AB/BB, and Natural Killer Cell Activation. AB - Vaccination of infants with bacillus Calmette-Guerin (BCG) activates both the innate and adaptive arms of the immune response. The antimycobacterial effects of these responses most likely account for the ability of BCG to protect against childhood forms of tuberculosis (TB). There is also evidence for a heterologous protective effect of BCG vaccination against TB-unrelated mortality in low birth weight infants. A possible mechanism of action of this effect, the induction of trained innate immunity, has been demonstrated when cells from BCG-vaccinated adults are restimulated in vitro with non-related microbial stimuli. Our aim was to examine an extensive panel of secreted immune biomarkers to characterize the profile of trained innate immunity in infants. Stimulation of whole blood for 48 h was performed 4 months after BCG vaccination, or in control unvaccinated infants. Stimulants were lipopolysaccharide; Pam3Cys (P3C); heat-killed Candida albicans, Staphylococcus aureus, Escherichia coli, and a lysate of Mycobacterium tuberculosis. Culture supernatants were tested for secreted cytokines and chemokines by 42-plex bead array and monocytes and natural killer (NK) cells assessed for expression of activation markers by flow cytometry. BCG-vaccinated infants displayed increases in 11 cytokines and chemokines in response to different non-specific innate immunity stimuli: epidermal growth factor (EGF); eotaxin; IL-6; IL-7; IL-8; IL-10; IL-12p40; monocyte chemotactic protein-3; macrophage inflammatory protein-1alpha; soluble CD40 ligand and platelet-derived growth factor (PDGF)-AB/BB. Although each stimulant induced a distinct response profile, three analytes, EGF, IL-6, and PDGF-AB/BB, were commonly higher after stimulation with Pam3Cys, C. albicans, and S. aureus. Conversely, certain cytokines such as interferon gamma-inducible protein-10, IL-2, IL-13, IL-17, GM CSF, and GRO were suppressed in BCG-vaccinated infants, while no increases in TNFalpha or IL-1beta production were detected. We did not observe a concomitant, BCG-associated change in monocyte surface activation markers in response to non specific stimuli, but we detected a significant increase in CD69 expression on NK cells in response to Pam3Cys. Pam3Cys-induced NK cell activation correlated with the magnitude of IL-12p40 and IL-10 responses to the same stimulant. This study reveals a novel cytokine/chemokine biomarker signature of BCG-induced trained innate immunity in infants and the involvement of NK cells in these responses. PMID- 28634480 TI - Fc-Galactosylation of Human Immunoglobulin Gamma Isotypes Improves C1q Binding and Enhances Complement-Dependent Cytotoxicity. AB - Binding of the complement component C1q to the CH2 domain of antigen-bound immunoglobulin gamma (IgG) activates the classical complement pathway and depends on its close proximity to Fc fragments of neighboring antibodies. IgG subclasses contain a highly conserved asparagine 297 (N)-linked biantennary glycan within their CH2 domains, the core structure of which can be extended with terminal galactose and sialic acid residues. To investigate whether Fc-glycosylation regulates effector functions of human IgG subclasses, we cloned the antigen binding region of the CD20-specific monoclonal antibody rituximab into IgG isotype expression vectors. We found that Fc-galactosylation enhances the efficacy of CD20-targeting complement-fixing antibodies for C1q binding and complement-mediated tumor cell lysis. Increased efficacies were restricted to IgG1 and IgG3 subclasses indicating that Fc-galactosylation alone is not sufficient for IgG2 and IgG4 to acquire complement-fixing properties. Addition of terminal galactose to the N-glycan specifically improved binding of C1q without changing antigen- and FcgammaRIIIa-binding affinities of IgG isotypes. These data indicate that Fc galactosylation can be harnessed to enhance the complement activating properties of IgG1 and IgG3 antibodies. PMID- 28634481 TI - Genome-Wide Analysis of the RAV Family in Soybean and Functional Identification of GmRAV-03 Involvement in Salt and Drought Stresses and Exogenous ABA Treatment. AB - Transcription factors play vital roles in plant growth and in plant responses to abiotic stresses. The RAV transcription factors contain a B3 DNA binding domain and/or an APETALA2 (AP2) DNA binding domain. Although genome-wide analyses of RAV family genes have been performed in several species, little is known about the family in soybean (Glycine max L.). In this study, a total of 13 RAV genes, named as GmRAVs, were identified in the soybean genome. We predicted and analyzed the amino acid compositions, phylogenetic relationships, and folding states of conserved domain sequences of soybean RAV transcription factors. These soybean RAV transcription factors were phylogenetically clustered into three classes based on their amino acid sequences. Subcellular localization analysis revealed that the soybean RAV proteins were located in the nucleus. The expression patterns of 13 RAV genes were analyzed by quantitative real-time PCR. Under drought stresses, the RAV genes expressed diversely, up- or down-regulated. Following NaCl treatments, all RAV genes were down-regulated excepting GmRAV-03 which was up-regulated. Under abscisic acid (ABA) treatment, the expression of all of the soybean RAV genes increased dramatically. These results suggested that the soybean RAV genes may be involved in diverse signaling pathways and may be responsive to abiotic stresses and exogenous ABA. Further analysis indicated that GmRAV-03 could increase the transgenic lines resistance to high salt and drought and result in the transgenic plants insensitive to exogenous ABA. This present study provides valuable information for understanding the classification and putative functions of the RAV transcription factors in soybean. PMID- 28634482 TI - Whole Plant Temperature Manipulation Affects Flavonoid Metabolism and the Transcriptome of Grapevine Berries. AB - Among environmental factors, temperature is the one that poses serious threats to viticulture in the present and future scenarios of global climate change. In this work, we evaluated the effects on berry ripening of two thermal regimes, imposed from veraison to harvest. Potted vines were grown in two air-conditioned greenhouses with High Temperature (HT) and Low Temperature (LT) regimes characterized by 26 and 21 degrees C as average and 42 and 35 degrees C as maximum air daily temperature, respectively. We conducted analyses of the main berry compositional parameters, berry skin flavonoids and berry skin transcriptome on HT and LT berries sampled during ripening. The two thermal conditions strongly differentiated the berries. HT regime increased sugar accumulation at the beginning of ripening, but not at harvest, when HT treatment contributed to a slight total acidity reduction and pH increase. Conversely, growing temperatures greatly impacted on anthocyanin and flavonol concentrations, which resulted as strongly reduced, while no effects were found on skin tannins accumulation. Berry transcriptome was analyzed with several approaches in order to identify genes with different expression profile in berries ripened under HT or LT conditions. The analysis of whole transcriptome showed that the main differences emerging from this approach appeared to be more due to a shift in the ripening process, rather than to a strong rearrangement at transcriptional level, revealing that the LT temperature regime could delay berry ripening, at least in the early stages. Moreover, the results of the in-depth screening of genes differentially expressed in HT and LT did not highlight differences in the expression of transcripts involved in the biosynthesis of flavonoids (with the exception of PAL and STS) despite the enzymatic activities of PALs and UFGT being significantly higher in LT than HT. This suggests only a partial correlation between molecular and biochemical data in our conditions and the putative existence of post-transcriptional and post-translational mechanisms playing significant roles in the regulation of flavonoid metabolic pathways and in particular of anthocyanins. PMID- 28634483 TI - Elicitor-Induced Biochemical and Molecular Manifestations to Improve Drought Tolerance in Rice (Oryza sativa L.) through Seed-Priming. AB - Rice (Oryza sativa L.) is one of the major grain cereals of the Indian subcontinent which face water-deficit stress for their cultivation. Seed-priming has been reported to be a useful approach to complement stress responses in plants. In the present study, seed-priming with hormonal or chemical elicitor [viz. methyl jasmonate (MJ), salicylic acid (SA), paclobutrazol (PB)] showed significant increase in total phenolic content, antioxidant activity and expression of Rice Drought-responsive (RD1 and RD2) genes (of AP2/ERF family) in contrasting rice genotypes (Nagina-22, drought-tolerant and Pusa Sugandh-5, drought-sensitive) under drought stress. However, decrease in lipid peroxidation and protein oxidation was observed not only under the stress but also under control condition in the plants raised from primed seeds. Expression analyses of RD1 and RD2 genes showed upregulated expression in the plants raised from primed seeds under drought stress. Moreover, the RD2 gene and the drought-sensitive genotype showed better response than that of the RD1 gene and the drought tolerant genotype in combating the effects of drought stress. Among the elicitors, MJ was found to be the most effective for seed-priming, followed by PB and SA. Growth and development of the plants raised from primed seeds were found to be better under control and drought stress conditions compared to that of the plants raised from unprimed seeds under the stress. The present study suggests that seed-priming could be one of the useful approaches to be explored toward the development of simple, cost-effective and farmer-friendly technology to enhance rice yield in rainfed areas. PMID- 28634484 TI - Manipulation of Metabolic Pathways to Develop Vitamin-Enriched Crops for Human Health. AB - Vitamin deficiencies are major forms of micronutrient deficiencies, and are associated with huge economic losses as well as severe physical and intellectual damages to humans. Much evidence has demonstrated that biofortification plays an important role in combating vitamin deficiencies due to its economical and effective delivery of nutrients to populations in need. Biofortification enables food plants to be enriched with vitamins through conventional breeding and/or biotechnology. Here, we focus on the progress in the manipulation of the vitamin metabolism, an essential part of biofortification, by the genetic modification or by the marker-assisted selection to understand mechanisms underlying metabolic improvement in food plants. We also propose to integrate new breeding technologies with metabolic pathway modification to facilitate biofortification in food plants and, thereby, to benefit human health. PMID- 28634485 TI - Nitrogen Can Alleviate the Inhibition of Photosynthesis Caused by High Temperature Stress under Both Steady-State and Flecked Irradiance. AB - Nitrogen is one of the most important elements for plants and is closely related to photosynthesis. High temperature stress significantly inhibits photosynthesis under both steady-state and flecked irradiance. However, it is not known whether nitrogen can affect the decrease in photosynthesis caused by high temperature, especially under flecked irradiance. In the present study, a pot experiment was conducted under two nitrogen (N) supplies with rice plants, and the steady-state and dynamic photosynthesis rates were measured under 28 and 40 degrees C. High temperature significantly increased leaf hydraulic conductance (Kleaf) under high N supply (HN) but not under low N supply (LN). The increased Kleaf maintained a constant leaf water potential (Psileaf) and steady-state stomatal conductance (gs,sat) under HN, while the Psileaf and gs,sat significantly decreased under high temperature in LN conditions. This resulted in a more severe decrease in steady-state photosynthesis (Asat) under high temperature in the LN conditions. After shifting from low to high light, high temperature significantly delayed the recovery of photosynthesis, which resulted in more carbon loss under flecked irradiance. These effects were obtained under HN to a lesser extent than under LN supply. Therefore, it is concluded that nitrogen can alleviate the inhibition of photosynthesis caused by high temperature stress under both steady-state and flecked irradiance. PMID- 28634487 TI - Dynamic Inertia Weight Binary Bat Algorithm with Neighborhood Search. AB - Binary bat algorithm (BBA) is a binary version of the bat algorithm (BA). It has been proven that BBA is competitive compared to other binary heuristic algorithms. Since the update processes of velocity in the algorithm are consistent with BA, in some cases, this algorithm also faces the premature convergence problem. This paper proposes an improved binary bat algorithm (IBBA) to solve this problem. To evaluate the performance of IBBA, standard benchmark functions and zero-one knapsack problems have been employed. The numeric results obtained by benchmark functions experiment prove that the proposed approach greatly outperforms the original BBA and binary particle swarm optimization (BPSO). Compared with several other heuristic algorithms on zero-one knapsack problems, it also verifies that the proposed algorithm is more able to avoid local minima. PMID- 28634486 TI - beta-Cell Replacement Strategies: The Increasing Need for a "beta-Cell Dogma". AB - Type 1 diabetes is an auto-immune disease resulting in the loss of pancreatic beta-cells and, consequently, in chronic hyperglycemia. Insulin supplementation allows diabetic patients to control their glycaemia quite efficiently, but treated patients still display an overall shortened life expectancy and an altered quality of life as compared to their healthy counterparts. In this context and due to the ever increasing number of diabetics, establishing alternative therapies has become a crucial research goal. Most current efforts therefore aim at generating fully functional insulin-secreting beta-like cells using multiple approaches. In this review, we screened the literature published since 2011 and inventoried the selected markers used to characterize insulin secreting cells generated by in vitro differentiation of stem/precursor cells or by means of in vivo transdifferentiation. By listing these features, we noted important discrepancies when comparing the different approaches for the initial characterization of insulin-producing cells as true beta-cells. Considering the recent advances achieved in this field of research, the necessity to establish strict guidelines has become a subject of crucial importance, especially should one contemplate the next step, which is the transplantation of in vitro or ex vivo generated insulin-secreting cells in type 1 diabetic patients. PMID- 28634488 TI - Antiherding in Financial Decision Increases Valuation of Return on Investment: An Event-Related Potential Study. AB - Using event-related potentials, this study investigated how financial herding or antiherding affected the valuation of subsequent outcomes. For each trial, subjects decided whether to buy the stock according to its net money flow information which could be used to reflect the strength of buying power or selling power of the stock. The return on investment (ROI) as feedback included the increase or decrease percentage after subjects' responses. Results showed that, compared with herding, antiherding induced larger discrepancies of FRN and P300 amplitude between positive ROI and negative ROI, indicating that individuals under antiherding condition had stronger motivation and paid more attention in the evaluation process of ROI. Moreover, only for positive ROI, the amplitudes of FRN and P300 were modulated by two kinds of behaviors. We suggested that individuals making antiherd decisions were more confident with their own ability and choices, which reduced the positive outcome prediction error and gave more mental resources to evaluate positive outcome. However, negative outcomes evoked no different motivational meaning and negative emotion for individuals between herding and antiherding. The study may provide new insights into neurocognitive processes of herding and antiherding in financial market. PMID- 28634489 TI - A Study of Patients with Primary Mediastinal Germ Cell Tumors Treated Using Multimodal Therapy. AB - OBJECTIVES: Primary mediastinal germ cell tumors (PMGCTs) are rare, which often makes them difficult to treat. Herein, we examined patients with PMGCTs who underwent multimodal treatment. METHODS: We examined 6 patients (median age: 25 years, range: 19-27 years) with PMGCTs who underwent multimodal treatment between April 2001 and March 2015. Three patients had seminomas, 2 patients had yolk sac tumors, and 1 patient had choriocarcinoma. The median observation period was 32.5 months (range: 8-84 months). RESULTS: Three of the 6 patients received initial operation followed by 3-4 courses of chemotherapy (bleomycin, etoposide, and cisplatin (BEP) or etoposide and cisplatin (EP)). One patient developed multiple lung metastases 17 months after surgery; received salvage chemotherapy with vinblastine, ifosfamide, and cisplatin; and achieved complete remission. The remaining 3 patients received initial BEP and EP chemotherapy. Multiple lung metastases and supraclavicular lymph node metastases were detected in 2 of these patients at the initial diagnosis. The patients underwent resections to remove residual tumor after treatment, and no viable tumor cells were found. CONCLUSIONS: Reliable diagnosis and immediate multimodal treatments are necessary for patients with PMGCTs. The 6 patients treated in our hospital have never experienced recurrence after the multimodal treatment. PMID- 28634490 TI - Associations of Pet Ownership with Older Adults Eating Patterns and Health. AB - Pet ownership has been shown to improve quality of life for older adults. The objective of this cross-sectional study was to compare older pet owners and older non-pet owners and assess differences between groups. This study was conducted on adults over 50 years of age, who owned either one cat or one dog versus nonowners based on age, race, gender, and education. Matched older pet owners (OPO) versus non-pet owners (NPO) pairs (n = 84), older cat owners (OCO) versus non-cat owners (NCO) (n = 29), and older dog owners (ODO) versus non-dog owners (NDO) pairs (n = 55) were analyzed. No differences were found between OPO and NPO for dietary, activity, or lifestyle, except OPO had fewer health conditions [p < 0.03]. Total OCO had greater body mass indices [BMI] (MU = 29.6 +/- 8.2) than ODO (MU = 23.2 +/- 5.2) [p < 0.02], less activity [p < 0.02], and shorter duration of activity [p < 0.05] and took fewer supplements [p < 0.003]. OCO and NCO differed on health conditions (MU = 0.8 +/- 0.9 versus MU = 1.9 +/- 1.3, [p < 0.008]) and ODO versus NDO differed on BMI (MU = 25 +/- 4 versus MU = 27 +/- 6, [p < 0.04]). Although there are limitations to this study, data may be useful for targeting marketing and health messages to older persons. PMID- 28634491 TI - More Favorable Metabolic Impact of Three-Times-Weekly versus Daily Growth Hormone Treatment in Naive GH-Deficient Children. AB - OBJECTIVE: To evaluate whether two different regimens of weekly injections could lead to similar auxological and metabolic effects in children with growth hormone deficiency (GHD). DESIGN: 32 GHD children (25 males, mean age 10.5 +/- 2.2 yr) were randomly assigned to receive daily (group A, 16 patients) or TIW (group B, 16 patients) GHT for 12 months. METHODS: Auxological parameters, insulin-like growth factor-I (IGF-I), glucose and insulin during OGTT, glycosylated hemoglobin (HbA1c), lipid profile, the oral disposition index (DIo), the homeostasis model assessment estimate of insulin resistance (Homa-IR), and the insulin sensitivity index (ISI). RESULTS: After 12 months, both groups showed a significant and comparable improvement in height (p < 0.001) and IGF-I (p < 0.001). As regards the metabolic parameters, in both groups, we found a significant increase in fasting insulin (p < 0.001 and p = 0.026) and Homa-IR (p < 0.001 and p = 0.019). A significant increase in fasting glucose (p = 0.001) and a decrease in ISI (p < 0.001) and DIo (p = 0.002) were only found in group A. CONCLUSIONS: The TIW regimen is effective and comparable with the daily regimen in improving auxological parameters and has a more favorable metabolic impact in GHD children. This trial is registered with ClinicalTrials.gov NCT03033121. PMID- 28634493 TI - An Exceptional Case of Intraparotid Plexiform Neurofibroma Originating from Autonomic Fibers of the Auriculotemporal Nerve. AB - Plexiform neurofibromas are benign tumors that tend to occur in patients suffering from neurofibromatosis type 1 (NF-1). This report addresses a rare case where the tumor affected the parotid gland, deriving almost exclusively from the peripheral portion of the facial nerve. A 6-year-old male was referred to us complaining about a gradually enlarging swelling over the right parotid area. Imaging localized the lesion to the superficial lobe of the parotid gland, suggesting a neurofibroma. Cosmetic disfigurement and a functional deficit led us to perform complete surgical resection. Meticulous surgical dissection as well as auriculotemporal nerve origin made complete extirpation possible with almost zero morbidity and ensured alleviation of both aesthetic impairment and pain. This is the first case of an intraparotid PN in a pediatric NF-1 patient, which originated from branches of the auriculotemporal nerve and particularly from fibers of the autonomic nervous system. Radical surgical excision was decided according to established decision-making algorithms. PMID- 28634492 TI - Effectiveness of Different Preventive Programs in Cariogram Parameters of Young Adults at High Caries Risk. AB - OBJECTIVE: To evaluate the effectiveness of different preventive programs in young adults at high caries risk using Cariogram software. METHODS: Sixty-six young adults with high caries risk were evaluated. Dental caries risk for all subjects was determined according to WHO criteria. Subjects were divided into three different preventive groups (control: OH, fluoride varnish: FV, and chlorhexidine varnish: CV). They were followed for 12 weeks (baseline: T0, 1 week: T1, 4 weeks: T2, and 12 weeks: T3). Plaque index, diet frequency, and salivary chairside tests (to record the flow rate, buffer capacity, and mutans streptococci and lactobacillus counts) were performed at each visit. Based on these data, ten caries-related variables were collected and inserted into the Cariogram software to calculate the predicted chance of avoiding caries for each subject. RESULTS: Significant changes were obtained about the Cariogram parameters (diet, bacteria, susceptibility, circumstances, and Cariogram risk group). No significant differences were found between the three methods regarding mean Cariogram scores after 3 months (p > 0.05). CONCLUSIONS: The regular and effective short-term (three months) use of 1450 ppm fluoridated toothpaste, one visit application of fluoride, and chlorhexidine varnishes were effective for reducing caries risk in young adults, which can be clearly demonstrated using Cariogram software. PMID- 28634494 TI - Antiviral Activity of Fridericia formosa (Bureau) L. G. Lohmann (Bignoniaceae) Extracts and Constituents. AB - A phytochemical study of Fridericia formosa (Bignoniaceae) ethanol extracts of leaves, stems, and fruits was guided by in vitro assays against vaccinia virus Western Reserve (VACV-WR), human herpes virus 1 (HSV-1), murine encephalomyocarditis virus (EMCV), and dengue virus type 2 (DENV-2) by the MTT method. All the ethanol extracts were active against DENV-2, HSV-1, and VACV-WR with best results for the fruits extract against DENV-2 (SI > 38.2). For VACV-WR and HSV-1, EC50 values > 200 MUg mL-1 were determined, while no inhibition of the cytopathic effect was observed with EMCV. Five compounds were isolated and identified as the C-glucosylxanthones mangiferin (1), 2'-O-trans caffeoylmangiferin (2), 2'-O-trans-coumaroylmangiferin (3), 2'-O-trans cinnamoylmangiferin (5), and the flavonoid chrysin (4). The most active compound was 2'-O-trans-coumaroylmangiferin (3) with SI > 121.9 against DENV-2 and 108.7 for HSV-1. These results indicate that mangiferin cinnamoyl esters might be potential antiviral drugs. PMID- 28634495 TI - Choking Hazards: Are Current Product Testing Methods for Small Parts Adequate? AB - Choking on small parts remains one of the leading causes of death and injury in infants and toddlers. The current method of testing for small parts, created by the Consumer Product Safety Commission (CPSC), has become outdated and has yet to be changed despite the many deaths and injuries of children. The method uses a device called the small parts test fixture (SPTF) that is supposed to mimic the size of a fully expanded throat of a toddler. If a product does not fit inside the cavity of the SPTF, then it is deemed safe to play with because it "will not fit" in the esophagus of a child. The present study obtains a dataset of products recalled by the CPSC within the last twelve years due to choking hazards/incidents and discovers that a noteworthy amount of the children's products have parts that are larger than the fixture size and are still capable of causing choking. This study indicates that a larger SPTF size must be implemented by the CPSC in order to prevent future choking incidents on small parts. PMID- 28634496 TI - Household Response to Inadequate Sewerage and Garbage Collection Services in Abuja, Nigeria. AB - Provision of sanitation and garbage collection services is an important and yet challenging issue in the rapidly growing cities of developing countries, with significant human health and environmental sustainability implications. Although a growing number of studies have investigated the consequences of inadequate delivery of basic urban services in developing countries, few studies have examined how households cope with the problems. Using the Exit, Voice, Loyalty, and Neglect (EVLN) model, this article explores how households respond to inadequate sewerage and garbage collection services in Abuja, Nigeria. Based on a qualitative study, data were gathered from in-depth interviews with sixty households, complemented with personal observation. The findings from grounded analysis indicated that majority (62%) and about half (55%) of the respondents have utilized the informal sector for sewerage services and garbage collection, respectively, to supplement the services provided by the city. While 68% of the respondents reported investing their personal resources to improve the delivery of existing sewerage services, half (53%) have collectively complained to the utility agency and few (22%) have neglected the problems. The paper concludes by discussing the public health and environmental sustainability implications of the findings. PMID- 28634497 TI - Weighted Polynomial Approximation for Automated Detection of Inspiratory Flow Limitation. AB - Inspiratory flow limitation (IFL) is a critical symptom of sleep breathing disorders. A characteristic flattened flow-time curve indicates the presence of highest resistance flow limitation. This study involved investigating a real-time algorithm for detecting IFL during sleep. Three categories of inspiratory flow shape were collected from previous studies for use as a development set. Of these, 16 cases were labeled as non-IFL and 78 as IFL which were further categorized into minor level (20 cases) and severe level (58 cases) of obstruction. In this study, algorithms using polynomial functions were proposed for extracting the features of IFL. Methods using first- to third-order polynomial approximations were applied to calculate the fitting curve to obtain the mean absolute error. The proposed algorithm is described by the weighted third-order (w.3rd-order) polynomial function. For validation, a total of 1,093 inspiratory breaths were acquired as a test set. The accuracy levels of the classifications produced by the presented feature detection methods were analyzed, and the performance levels were compared using a misclassification cobweb. According to the results, the algorithm using the w.3rd-order polynomial approximation achieved an accuracy of 94.14% for IFL classification. We concluded that this algorithm achieved effective automatic IFL detection during sleep. PMID- 28634498 TI - Evaluation of in vitro cytotoxicity, biocompatibility, and changes in the expression of apoptosis regulatory proteins induced by cerium oxide nanocrystals. AB - Cerium oxide nanocrystals (CeO2-NCs) exhibit superoxide dismutase and catalase mimetic activities. Based on these catalytic activities, CeO2-NCs have been suggested to have the potential to treat various diseases. The crystalline size of these materials is an important factor that influences the performance of CeO2 NCs. Previous reports have shown that several metal-based nanocrystals, including CeO2-NCs, can induce cytotoxicity in cancer cells. However, the underlying mechanisms have remained unclear. To characterize the anticancer activities of CeO2-NCs, several assays related to the mechanism of cytotoxicity and induction of apoptosis has been performed. Here, we have carried out a systematic study to characterize CeO2-NCs phase purity (X-ray diffraction), morphology (electron microscopy), and optical features (optical absorption, Raman scattering, and photoluminescence) to better establish their potential as anticancer drugs. Our study revealed anticancer effects of CeO2-NCs in HT29 and SW620 colorectal cancer cell lines with half-maximal inhibitory concentration (IC50) values of 2.26 and 121.18 MUg ml-1, respectively. Reductions in cell viability indicated the cytotoxic potential of CeO2-NCs in HT29 cells based on inverted and florescence microscopy assessments. The mechanism of cytotoxicity confirmed by estimating possible changes in the expression levels of Bcl2, BclxL, Bax, PARP, cytochrome c, and beta-actin (control) proteins in HT29 cells. Down-regulation of Bcl2 and BclxL and up-regulation of Bax, PARP, and cytochrome c proteins suggested the significant involvement of CeO2-NCs exposure in the induction of apoptosis. Furthermore, biocompatibility assay showed minimum effect of CeO2-NCs on human red blood cells. PMID- 28634499 TI - Three-input gate logic circuits on chemically assembled single-electron transistors with organic and inorganic hybrid passivation layers. AB - Single-electron transistors (SETs) are sub-10-nm scale electronic devices based on conductive Coulomb islands sandwiched between double-barrier tunneling barriers. Chemically assembled SETs with alkanethiol-protected Au nanoparticles show highly stable Coulomb diamonds and two-input logic operations. The combination of bottom-up and top-down processes used to form the passivation layer is vital for realizing multi-gate chemically assembled SET circuits, as this combination enables us to connect conventional complementary metal oxide semiconductor (CMOS) technologies via planar processes. Here, three-input gate exclusive-OR (XOR) logic operations are demonstrated in passivated chemically assembled SETs. The passivation layer is a hybrid bilayer of self-assembled monolayers (SAMs) and pulsed laser deposited (PLD) aluminum oxide (AlO[Formula: see text]), and top-gate electrodes were prepared on the hybrid passivation layers. Top and two-side-gated SETs showed clear Coulomb oscillation and diamonds for each of the three available gates, and three-input gate XOR logic operation was clearly demonstrated. These results show the potential of chemically assembled SETs to work as logic devices with multi-gate inputs using organic and inorganic hybrid passivation layers. PMID- 28634500 TI - Stroke Performance Measures Do Not Predict Functional Outcome. AB - BACKGROUND AND PURPOSE: Poststroke functional outcome is critical to stroke survivors. We sought to determine whether adherence to current stroke performance measures is associated with better functional outcome 90 days after an ischemic stroke. METHODS: Utilizing the Brain Attack Surveillance in Corpus Christi cohort, we examined adherence to 7 ischemic stroke performance measures from February 2009 to June 2012. Adherence to the measures was analyzed in aggregate using a binary defect-free score and an opportunity score, representing the proportion of eligible measures met. The opportunity score ranges from 0 to 1, with values closer to 1 implying better adherence. Functional outcome, defined by an activities of daily living and instrumental activities of daily living (ADL/IADL) score (range 1-4, higher scores worse), was ascertained at 90 days poststroke. Tobit regression models were fitted to examine the associations between the performance measures and functional outcome, adjusting for demographic and clinical characteristics, including stroke severity. RESULTS: There were 565 patients with ischemic stroke included in the analysis. The median ADL/IADL score was 2.32 (interquartile range [IQR]: 1.41-3.41). The median opportunity score was 1 (IQR: 0.8-1), and 58.4% of the patients received defect free care. After adjustment, the opportunity score (P = .67) and defect-free care (P = .92) were not associated with functional outcome. CONCLUSION: In this population, adherence to a composite of current stroke performance measures was not associated with poststroke functional outcome after adjustment for other factors. Performance measures that are associated with improved functional outcome should be developed and incorporated into stroke quality measures. PMID- 28634501 TI - Subarachnoid Hemorrhage and Long-Term Stroke Risk After Traumatic Brain Injury. AB - BACKGROUND: Recent studies suggest that traumatic brain injury (TBI) is a risk factor for subsequent ischemic stroke, even years after the initial insult. The mechanisms of the association remain unclear. The presence of traumatic subarachnoid hemorrhage (tSAH) may mediate the effect of TBI on long-term stroke risk, as it has previously been linked to short-term vasospasm and delayed cerebral ischemia. METHODS: Using administrative claims data, we conducted a retrospective cohort study of acute care hospitalizations. Patients discharged with a first-recorded diagnosis of tSAH were followed for a primary diagnosis of stroke. They were matched to patients with TBI but not tSAH. Cox proportional hazards modeling was used to assess the association between tSAH and stroke while adjusting for covariates. RESULTS: We identified 40 908 patients with TBI (20 454 patients with tSAH) who were followed for a mean of 4.3 + 1.8 years. A total of 531 had an ischemic stroke after discharge. There was no significant difference in stroke risk between those with tSAH (1.79%; 95% confidence interval [CI] 1.54% 2.08%) versus without tSAH (2.12%; 95% CI 1.83%-2.44%). The same pattern was found in adjusted analyses even when the group was stratified by age-group or by proxies of TBI severity. CONCLUSIONS: Our findings do not support a role of tSAH in mediating the association between TBI and protracted stroke risk. Further study is required to elucidate the mechanisms of long-term increased stroke risk after TBI. PMID- 28634502 TI - Impact of Neurological Follow-Up on Early Hospital Readmission Rates for Acute Ischemic Stroke. AB - INTRODUCTION: Despite advances in stroke care, readmission rates for patients with ischemic stroke remain high. Although factors such as age, diabetes, and continuous use of antiplatelet agents have been found to predict readmission rates, the impact of after-hospital care has not been examined. METHODS: The present study reviewed the charts of 416 patients with acute ischemic stroke and recorded stroke-related comorbidities, neurology follow-up within 21 days, readmission at 0 to 30 days, readmission at 31 to 90 days, and any reasons for readmission. RESULTS: For those readmitted within 0 to 30 days, reasons for readmission were other medical conditions (62.5%), recurrent stroke (30.4%), and elective procedure (7.1%). For those readmitted within 31 to 90 days, reasons for readmission were other medical conditions (62.3%), recurrent stroke (15.1%), and elective procedure (22.6%). There was no significant relationship between being evaluated within 21 days and readmission at 0 to 30 or 31 to 90 days. However, those who did have a neurology follow-up at any point in time had a lower readmission rate of 10.6% compared to those who never came back (19.2%, P = .017). Patients with coronary artery disease and diabetes had a significantly higher likelihood of readmission within 0 to 30 days. CONCLUSION: The present study suggests that neurology follow-up at any point in time for patients with acute ischemic stroke may reduce short-term readmissions, but special attention to optimizing management of other underlying medical conditions, coronary artery disease, or diabetes may also help reduce overall readmissions. Patients with stroke, therefore, may benefit from a follow-up with both the primary care and neurology in a coordinated fashion to prevent early readmissions at 30 days. PMID- 28634503 TI - Monitoring the Diagnostic Process on an Inpatient Neurology Service. AB - The Institute of Medicine report Improving Diagnosis in Health Care called for tools to monitor physicians' diagnostic process. We addressed this need by developing a tool for clinicians to record and analyze their diagnostic process. The tool was a secure web application in which clinicians used a structured grading system to assess the relative impact of clinical, laboratory, and neuroimaging data for every new diagnosis. Four neurohospitalists used the tool for 6.5 months on a general neurology ward service at a single tertiary-level teaching hospital. Process measures of tool use included number of diagnoses entered, time spent on each data entry, and concordance of diagnoses compared to the medical record. We also aggregated the data across clinicians to examine the average process scores across common inpatient disorders. The 4 clinicians entered 254 new diagnoses that took approximately 3 minutes per patient. In 50 randomly chosen cases, the neurohospitalists' diagnoses entered into the tool agreed with 92% of diagnoses in the medical record, which was better than the agreement between billing code and medical record diagnoses (74%). The diagnostic process varied across disease categories, showing a spectrum of clinical-dominant (eg, headache), laboratory-dominant (eg, encephalitis), and neuroimaging-dominant (eg, stroke) disorders. This study demonstrated the feasibility of a clinician driven diagnostic process monitoring system, along with preliminary characterization of the process for common disorders. The tracking of diagnostic process has the potential to promote reflection on clinical practice, deconstruct neurologists' clinical decision-making, and improve health-care safety. PMID- 28634504 TI - The Reemergence of EEG Reactivity After Cardiac Arrest. AB - Electroencephalogram (EEG) reactivity has been increasingly utilized in prognostication after cardiac arrest. Recent studies have demonstrated a false positive rate of 0% in predicting poor outcome with a nonreactive EEG. The reemergence of reactivity after an initial nonreactive EEG has been noted in cases of drug intoxication, rewarming after hypothermia, and after discontinuing sedation. This is the first case describing the reemergence of EEG reactivity without the confounding factors listed above. We describe a case of resuscitated cardiac arrest with initial EEG demonstrating a lack of reactivity. A repeat EEG completed 3 days later revealed a reemergence of reactivity in the setting of normothermia, a negative drug screen, and the absence of sedation. The delayed recovery of EEG reactivity without previously established confounding factors is novel. Serial EEGs may be beneficial as the available literature on reactivity and prognostication is based on an average of 24 to 48 hours of EEG tracing. Prognostication after cardiac arrest continues to require a multimodal approach. PMID- 28634505 TI - A 57-Year-Old Man With Headache, Numbness, and Weakness. AB - We present the case of a 57-year-old man with headache, numbness, and weakness. We review the differential diagnosis and discuss the relevant imaging. Once the diagnosis is evident, we review the natural history and evidence in support of each possible treatment. PMID- 28634506 TI - Meningovascular Syphilis. PMID- 28634507 TI - Susceptibility-Weighted Imaging Diagnosis of Cerebral Fat Embolism. PMID- 28634508 TI - Reversible Rhombencephalitis in Neuro-Behcet's Disease. PMID- 28634509 TI - Movements Here Today, Gone Tomorrow: Images in Clinical Neurology Case of Hyperglycemic Hemichorea. PMID- 28634510 TI - Internal Carotid Artery and Sphenoidal Emissary (Vesalian) Vein Fistula Mimicking a Carotid-Cavernous Sinus Fistula. PMID- 28634511 TI - Extreme Delta Brush in NMDA Receptor Encephalitis. PMID- 28634512 TI - Diffusion weighted imaging for the detection and evaluation of cholesteatoma. AB - Cholesteatoma is a collection of keratinous debris and stratified squamous epithelium. It is trapped in the middle ear and can lead to bony erosion. The disease is treated surgically often followed by a second-look procedure to check for residual tissue or recurrence. Cholesteatoma has specific signal-intensity characteristics on magnetic resonance imaging with very high signal intensity on diffusion weighted imaging (DWI). Various DWI techniques exist: Echo-planar imaging (EPI)-based and non-EPI-based techniques as well as new approaches like multi-shot EPI DWI. This article summarizes all techniques, discusses the significance in detecting cholesteatoma and mentions actual studies. Further recommendations for daily clinical practise are provided. PMID- 28634513 TI - Correlation of lumbar lateral recess stenosis in magnetic resonance imaging and clinical symptoms. AB - AIM: To assess the correlation of lateral recess stenosis (LRS) of lumbar segments L4/5 and L5/S1 and the Oswestry Disability Index (ODI). METHODS: Nine hundred and twenty-seven patients with history of low back pain were included in this uncontrolled study. On magnetic resonance images (MRI) the lateral recesses (LR) at lumbar levels L4/5 and L5/S1 were evaluated and each nerve root was classified into a 4-point grading scale (Grade 0-3) as normal, not deviated, deviated or compressed. Patient symptoms and disability were assessed using ODI. The Spearman's rank correlation coefficient was used for statistical analysis (P < 0.05). RESULTS: Approximately half of the LR revealed stenosis (grade 1-3; 52% at level L4/5 and 42% at level L5/S1) with 2.2% and 1.9% respectively reveal a nerve root compression. The ODI score ranged from 0%-91.11% with an arithmetic mean of 34.06% +/- 16.89%. We observed a very weak statistically significant positive correlation between ODI and LRS at lumbar levels L4/5 and L5/S1, each bilaterally (L4/5 left: rho < 0.105, P < 0.01; L4/5 right: rho < 0.111, P < 0.01; L5/S1 left: rho 0.128, P < 0.01; L5/S1 right: rho < 0.157, P < 0.001). CONCLUSION: Although MRI is the standard imaging tool for diagnosing lumbar spinal stenosis, this study showed only a weak correlation of LRS on MRI and clinical findings. This can be attributed to a number of reasons outlined in this study, underlining that imaging findings alone are not sufficient to establish a reliable diagnosis for patients with LRS. PMID- 28634514 TI - Cystic lesions of peripheral nerves: Are we missing the diagnosis of the intraneural ganglion cyst? AB - AIM: To highlight the salient magnetic resonance imaging (MRI) features of the intraneural ganglion cyst (INGC) of various peripheral nerves for their precise diagnosis and to differentiate them from other intra and extra-neural cystic lesions. METHODS: A retrospective analysis of the magnetic resonance (MR) images of a cohort of 245 patients presenting with nerve palsy involving different peripheral nerves was done. MR images were analyzed for the presence of a nerve lesion, and if found, it was further characterized as solid or cystic. The serial axial, coronal and sagittal MR images of the lesions diagnosed as INGC were studied for their pattern and the anatomical extent along the course of the affected nerve and its branches. Its relation to identifiable anatomical landmarks, intra-articular communication and presence of denervation changes in the muscles supplied by involved nerve was also studied. RESULTS: A total of 45 cystic lesions in the intra or extraneural locations of the nerves were identified from the 245 MR scans done for patients presenting with nerve palsy. Out of these 45 cystic lesions, 13 were diagnosed to have INGC of a peripheral nerve on MRI. The other cystic lesions included extraneural ganglion cyst, paralabral cyst impinging upon the suprascapular nerve, cystic schwannoma and nerve abscesses related to Hansen's disease involving various peripheral nerves. Thirteen lesions of INGC were identified in 12 patients. Seven of these affected the common peroneal nerve with one patient having a bilateral involvement. Two lesions each were noted in the tibial and suprascapular nerves, and one each in the obturator and proximal sciatic nerve. An intra-articular connection along the articular branch was demonstrated in 12 out of 13 lesions. Varying stages of denervation atrophy of the supplied muscles of the affected nerves were seen in 7 cases. Out of these 13 lesions in 12 patients, 6 underwent surgery. CONCLUSION: INGC is an important cause of reversible mono-neuropathy if diagnosed early and surgically treated. Its classic MRI pattern differentiates it from other lesions of the peripheral nerve and aid in its therapeutic planning. In each case, the joint connection has to be identified preoperatively, and the same should be excised during surgery to prevent further cyst recurrence. PMID- 28634516 TI - Online table of contents. PMID- 28634515 TI - Transarterial chemoembolization using 40 um drug eluting beads for hepatocellular carcinoma. AB - AIM: To assess the safety and efficacy of transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) using a new generation of 40 MUm drug eluting beads in patients not eligible for curative treatment. METHODS: Drug eluting bead TACE (DEB-TACE) using a new generation of microspheres (embozene tandem, 40 MUm) preloaded with 100 mg of doxorubicin was performed on 48 early or intermediate HCC patients with compensated cirrhosis. Response to therapy was assessed with Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) guidelines applied to computed tomography or magnetic resonance imaging. Eleven out of the 48 treated patients treated progressed on to receive liver orthotopic transplantation (OLT). This allowed for histological analysis on the treated explanted nodules. RESULTS: DEB-TACE with 40 MUm showed a good safety profile without major complications or 30-d mortality. The objective response rate of treated tumors was 72.6% and 26.7% according to mRECIST and RECIST respectively. Histological examination in 11 patients assigned to OLT showed a necrosis degree > 90% in 78.6% of cases. The overall time to progression was 13 mo (11-21). CONCLUSION: DEB-TACE with 40 MUm particles is an effective treatment for the treatment of HCC in early-intermediate patients (Barcelona Clinic Liver Cancer stage A/B) with a good safety profile and good results in term of objective response rate and necrosis. PMID- 28634517 TI - Introduction of a quality improvement curriculum in the Department of Internal Medicine, Lincoln Medical Center. AB - Community hospitals with limited resources struggle to engage physicians in Quality improvement initiatives. We introduced Quality Improvement (QI) curriculum for residents in response to ACGME requirements and surveyed the residents understanding of QI and their involvement in QI projects before and after the introduction of the curriculum. The current article describes our experiences with the process, the challenges and possible solutions to have a successful resident led QI initiative in a community hospital. Methods: A formal QI curriculum was introduced in the Department of Internal Medicine from September to October 2015 using the Model for Improvement from Institute for Health care Improvement (IHI). Learners were expected to read the online modules, discuss in small group sessions and later encouraged to draft their QI projects using the Charter form and PDSA form available on the HI website. Online surveys were conducted a week prior and 3 months after completion of the curriculum Results: 80% (100/117) of residents completed the pre-curriculum survey and 52% (61/117) completed the survey post curriculum. 96.7% of residents report that physicians should lead QI projects and training rather than the hospital administrators. Residents had 20% increase in understanding and confidence in leading quality improvement projects post curriculum once initiated. Most Residents (72%) feel QI should be taught during residency. Active involvement of residents with interest was seen after the initiation of Open School Institute of health improvement (IHI) curriculum as compared to Institutional led QI's. The resident interventions, pitfalls with change processes with an example of PDSA cycle are discussed. Conclusion: A Dedicated QI curriculum is necessary to prepare the physicians deliver quality care in an increasing complex health care delivery system. The strength of the curriculum is the ease of understanding the material, easily available to all, and can be easily replicated in a Community Hospital program with limited resources. Participation in QI by residents may promote constructive competitiveness among related hospitals in public system to improve delivery of safe care. Abbreviations: ACGME: Accreditation Council for Graduate Medical Education; IHI: Institute of Healthcare Improvement; PDSA: Plan Do-Study-Act; PGY: QI: Quality improvement. PMID- 28634518 TI - Role of albumin in cirrhosis: from a hospitalist's perspective. AB - Albumin, a negatively charged globular protein encoded on chromosome 4, is one of the most abundant proteins in the plasma and accounts for approximately 75% of plasma oncotic pressure. The role of albumin in the management of various disease states has shown to be beneficial historically. Low serum albumin is a predictor of mortality and poor outcomes. In cirrhotics undergoing paracentesis, albumin infusion prevents rapid re-accumulation of ascitic fluid while simultaneously decreasing the risk of post-paracentesis related circulatory dysfunction. Additionally, albumin is utilized in patients with hepatorenal syndrome (HRS) and spontaneous bacterial peritonitis (SBP). Overall, albumin appears to be an effective pharmacological agent in the management of cirrhosis and its complications. PMID- 28634519 TI - Prevalence and risk factors of heart failure in the USA: NHANES 2013 - 2014 epidemiological follow-up study. AB - Background: Heart Failure (HF) is a progressive epidemic associated with considerable morbidity and mortality. Self-reported data from the National Health and Nutrition Examination Survey (NHANES) provides a unique representation of individuals suffering from HF. The purpose of this study is to analyze updated NHANES 2013-2014 data to identify any changes in the prevalence and current risk factors of HF, especially given the novel lifestyles and increased medical awareness of current generations. Methods: NHANES uses a multistage probability sampling design under the Centers for Disease Control and Prevention (CDC). The Student's t-test and Chi-square test/ Fisher's exact test was used for analysis of variables. A multiple logistic regression model was used to identify statistically significant risk factors for HF. Analyses were performed with the use of SAS software, version 9.4. Results: Based on our analysis, the primary risk factor was coronary artery disease followed by hypertension, diabetes mellitus, age >= 65 years, and obesity. Conclusion: The findings revealed that despite improved population awareness and advancements in diagnostics and therapeutics, the same risk factors continue to persist. This provided an insight into the path towards which our resources need to be directed, so as to effectively tackle the aforementioned risk factors. PMID- 28634520 TI - Effect of heartfulness meditation on burnout, emotional wellness, and telomere length in health care professionals. AB - Background: Burnout poses significant challenges during training years in residency and later in the career. Meditation is a tool to treat stress-related conditions and promote wellness. Telomere length may be affected by burnout and stress. However, the benefits of meditation have not been fully demonstrated in health care professionals. Objective: We assessed the effects of a 12-week 'Heartfulness Meditation' program on burnout, emotional wellness, and telomere length in residents, faculty members, and nurses at a large community teaching hospital during the 2015-16 academic year. Methods: All subjects completed a baseline Maslach Burnout Inventory (MBI) and Emotional Wellness Assessment (EWA) at the beginning of the study. Meditators received instructions in Heartfulness Meditation. At week 12, subjects completed a follow up MBI and EWA scores. Salivary telomere length was measured at baseline and week 12. Results: Twenty seven out of a total 155 residents (17.4%) along with eight faculty physicians and 12 nurses participated in the study. Thirty-five enrolled as meditators and 12 as controls. At 12 weeks, the meditators had statistically significant improvement in all measures of burnout and in nearly all attributes of EWA. Controls showed no statistically significant changes in either burnout or emotional wellness scores. Relative telomere length increased with statistical significance in a younger subset of meditators. Conclusion: Our results indicate that meditation offers an accessible and efficient method by which physician and nurse burnout can be ameliorated and wellness can be enhanced. The increased telomere length is an interesting finding but needs to be confirmed with further research. Abbreviations: EWA: Emotional wellness assessment; MBI: Maslach burnout inventory; EE: Emotional exhaustion; DP: Depersonalization; PA: Personal accomplishment; PI: Prinicipal investigator; JT: Jayaram Thimmapuram. PMID- 28634521 TI - A review of echocardiograms in hypertensive patients greater than 60 years in a community based family medicine program. AB - Background: Heart disease as a result of Hypertension is known to occur. Anatomical and functional changes of the heart can easily be detected by echocardiography, which is a safe and readily available study. Objectives: The aims of this study were to evaluate the prevalence of common echocardiographic changes in chronic hypertensive patients and to compare these changes in male and female populations. Design/methods: The study was a community-based cross sectional study, on 227 hypertensive patients, 60 years and older, seen in St. Joseph's Family Medicine at Clifton, with integrated clinical and echocardiographic data. Results: Study population consisted of 227 hypertensive patients, over the age of 60 years who had echocardiography done. Overall 92.5% of the echocardiograms had abnormal findings including but not limited to TR, Diastolic dysfunction, MR, and LVH. There was significant difference between the rate of MR in male and female population. Conclusion: A variety of echocardiographic abnormalities can be found in hypertensive patients. Drug selection in hypertension should be driven by the underlying cardiac pathology. Certain drugs have more effectiveness for diastolic dysfunction, LVH, systolic dysfunction and pulmonary hypertension and are superior choices when these conditions are present. Echocardiogram is a non-invasive and easily available tool in order to help us to select the best treatment strategy to optimize hypertensive control in the challenging group of elderly patients. The results of our study should influence us to liberally use echocardiography in these patients to guide treatment decision and drug selection. Abbreviations: LVH: left ventricular hypertrophy; MR: mitral valve regurgitation; TR: tricuspidvalve regurgitation; LVD: left ventricular dilation; LVEF: left ventricular ejection fraction. PMID- 28634522 TI - Popliteal arterial thrombosis in nephrotic syndrome: a case report. AB - Thrombosis is a frequent cause of morbidity and mortality in patients with nephrotic syndrome (NS). Though venous thromboses are common in NS, arterial thromboses are relatively rare. Commonly involved arteries include coronary, iliac, femoral, renal, cerebral, pulmonary, mesenteric, and axillary arteries, and the aorta. Arterial thromboses are associated with poor prognosis; treatment options are limited and patients may not always be amenable to treatment. We present the case of a 39-year-old female with NS who presented with thigh pain and was found to have sub-acute popliteal artery thrombosis. PMID- 28634523 TI - Mallory-Weiss tear after violent hiccups: a rare association. AB - We present an unusual case of a 44-year-old male who developed violent hiccups soon after a ureteroscopy for nephrolithiasis; later, the forceful hiccups were followed by hematemesis. Upper esophagogastroduodenoscopy revealed Mallory-Weiss tears and esophageal erosions in the lower esophagus. Esophageal biopsy was unremarkable. The patient did not have a prior history of the gastrointestinal disorder. Although extracorporeal shock wave lithotripsy has on rare occasion been implicated in the development of gastrointestinal erosions, no such correlation exists for ureteroscopy and upper gastrointestinal bleeding in the management of nephrolithiasis. It was the development of violent hiccups for several hours before the onset of hematemesis that likely led to the upper gastrointestinal bleed. PMID- 28634524 TI - A rare case of pylephlebitis after colonic polypectomy. AB - Pylephlebitis or infective suppurative thrombosis of the portal mesenteric venous system is an uncommon condition that can potentially be deadly if not recognized and treated early. Although most commonly associated with pancreatitis and diverticulitis, any intra-abdominal or pelvic infection occurring in the region drained by the portal venous system can cause this rare entity. We report a case of a 75-year-old woman who developed post polypectomy pylephlebitis following colonoscopy, a condition rarely reported in the literature. PMID- 28634526 TI - Concurrent babesiosis and serological evidence of Lyme disease in a young patient. AB - Human babesiosis co-infected with Lyme disease in a young patient is an important condition. Here, we describe a case of a 39-year-old male patient with concurrent babesiosis and Lyme disease. Co-infections of tick borne diseases are often difficult to diagnose and underreported, and resulting in significant morbidity and mortality to patients. While co-infections have been infrequently described, it is of paramount importance that clinicians should be able to diagnose early and treat them effectively according to the patient geographical area and history of tick bite. PMID- 28634525 TI - Pseudomembranous aspergillar tracheobronchitis in a non-neutropenic critically ill patient in the intensive care unit. AB - Invasive aspergillosis is an important cause of morbidity and mortality among immunocompromised patients. Prolonged neutropenia is the most common risk factor. It has rarely been reported to occur in non-neutropenic critically ill patients in the intensive care unit setting. Mortality rate in this group has been reported to be as high as 92%. We report a case of tracheobronchial aspergillosis in a non-neutropenic critically ill patient to highlight the fact that critically ill patients admitted in the intensive care unit can develop opportunistic infections such as invasive aspergillosis even in the absence of classic risk factors and prior history of immunosuppression. Early diagnosis and prompt initiation of antifungal therapy may improve the outcome and decrease mortality rate. PMID- 28634527 TI - An atypical presentation of a re-emerging disease. AB - Often referred to as 'The Great Mimicker', syphilis infections have been on the rise since 2000 including cases of primary and secondary syphilis where 19,999 were reported in the USA in 2014. The increase in cases has led the USPSTF to recommend screening for syphilis infection in persons who are at increased risk of infection. Changes in screening and re-emergence of the disease necessitates review of the multitude of circumstances a patient can present for care. Immunocompetent patients begin to show classic symptoms within 10-90 days following infection with the spirochete. In the immunocompromised patient, the presenting symptoms are often atypical and more complex. With the rise in HIV infections, syphilitic infections have become increasingly common worldwide and several atypical presentations have been observed. The following case is an atypical presentation of syphilis involving both central and peripheral nervous system findings in a patient without significant medical history. PMID- 28634528 TI - Squamous cell carcinoma of the ascending colon: two cases. AB - Squamous cell carcinoma (SCC) of the colon without known primary source is a rare finding that needs aggressive management. We report two cases of SCC of the colon without any clear extra-colonic source despite extensive workup. In our experience, the clinical course and prognosis are largely dependent on the presence of metastatic disease at diagnosis. The main treatment is surgery, with chemotherapy having less defined role. PMID- 28634529 TI - Duodenal diverticulum: incidental finding with potentially dangerous outcomes. AB - We present the case of an 83-year-old woman with a past medical history significant for schizoaffective disorder, presenting to our emergency department with the complaint of 'pain'. Given the non-specific complaint and the limited history obtained, CT imaging was performed on her chest and abdomen which incidentally found a large duodenal diverticulum. This manuscript discusses the incidence of duodenal diverticula and the potential associated complications. PMID- 28634530 TI - The role of medical education in the development of the scientific practice of medicine. AB - The authors describe the important role of medical schools and graduate medical education programs (residencies) in relationship to the advances in Medicine witnessed during the twentieth century; diagnosis, prognosis and treatment were revolutionized. This historical essay details the evolution of the education system and the successful struggle to introduce a uniform, science-based curriculum and bedside education. The result was successive generations of soundly educated physicians prepared with a broad knowledge in science, an understanding of laboratory methods and the ability to practice medicine at the bedside. These changes in medical education created a foundation for the advancement of medicine. PMID- 28634531 TI - Smallpox vaccination: an early start of modern medicine in America. AB - Smallpox was eradicated by the World Health Organization in 1980. Before its eradication thedisease had a mortality rate upwards of 50% and had a significant impact on society. During theAmerican Revolutionary war, smallpox outbreaks were impeding the American war effort until1777 when George Washington carried out a mass inoculation campaign in the ContinentalArmy that reduced the mortality from smallpox to less than 2%. Inoculation was an early formof vaccination that used live virus from active pustules to induce a milder, but still sometimesdeadly, case of disease. Washington has been credited with helping to ease the burden ofsmallpox on the Army which improved the odds of success against the British. When EdwardJenner's vaccine reached America it was more readily accepted by political and medical leadersdue the success of Washington's inoculation campaign. The Founding Fathers argued thatsmallpox vaccination was the greatest discovery in modern medicine and they were likely correctthat it helped to usher in the modern era of vaccinology. PMID- 28634533 TI - A study to evaluate the prevalence of impaired awareness of hypoglycaemia in adults with type 2 diabetes in outpatient clinic in a tertiary care centre in Singapore. AB - BACKGROUND: Impaired awareness of hypoglycaemia (IAH) predisposes affected patients to severe hypoglycaemia. There are few data on prevalence of IAH in adults with insulin-treated type 2 diabetes in Asia. We aim to ascertain the prevalence of IAH among insulin-treated patients with type 2 diabetes in an outpatient clinic in a tertiary care centre in Singapore. METHODS: A total of 374 patients with insulin-treated type 2 diabetes attending the outpatient diabetes clinic in a tertiary referral centre in Singapore were recruited over a 4-month period. Participants completed a questionnaire to document baseline characteristics and assess their hypoglycaemia awareness status, using a combination of the Clarke, Gold and Pedersen-Bjergaard methods. RESULTS: Using the Clarke, Gold and Pedersen-Bjergaard methods, prevalence of IAH in our cohort was 9.6%, 13.4% and 33.2% respectively. Overall, 7.2% of participants suffered from severe hypoglycaemia in the preceding year. The IAH group had more episodes of severe hypoglycaemia across all three methods, compared with the normal awareness group (p < 0.01). There were no significant differences in mean HbA1c, duration of diabetes and insulin treatment between the IAH and normal awareness groups. CONCLUSIONS: IAH is prevalent in adults with insulin-treated type 2 diabetes in Asia, and is associated with significantly increased risk of severe hypoglycaemia. PMID- 28634534 TI - Etiological factors of short stature in children and adolescents: experience at a tertiary care hospital in Egypt. AB - BACKGROUND: Accurate anthropometric measurements and critical analysis of growth data allow the clinician to promptly recognize children with short stature. The aim of this study was to determine the frequency of etiological factors causing short stature among children referred to the pediatric endocrinology clinic of Assiut University Children's Hospital, the main tertiary care center in Upper Egypt. METHODS: We conducted this descriptive observational study from May 2012 to December 2015, to analyze 637 children (boys 354, girls 283) with short stature. Evaluation included: detailed medical history, physical examination, laboratory tests, bone age and chromosomal analysis. RESULTS: Endocrinological causes accounted for 26% of short stature [of them, 11.8% had growth hormone deficiency (GHD)], 63.6% had normal variants of growth [of them, 42% had familial short stature (FSS), 15.8% had constitutional growth delay (CGD) and 5.5% a combination of both]. Interestingly, celiac disease (CD) constituted 6.6% of children with short stature in our cohort. CONCLUSIONS: Although potentially treatable causes such as GHD, hypothyroidism and CD accounted for a considerable percentage of short stature in our study, the majority of short stature in children had normal variations of growth. Growth hormone treatment in children, however, should be promptly initiated with specific clinical indications. CD is a not uncommon cause of short stature. PMID- 28634532 TI - Cellularizing hydrogel-based scaffolds to repair bone tissue: How to create a physiologically relevant micro-environment? AB - Tissue engineering is a promising alternative to autografts or allografts for the regeneration of large bone defects. Cell-free biomaterials with different degrees of sophistication can be used for several therapeutic indications, to stimulate bone repair by the host tissue. However, when osteoprogenitors are not available in the damaged tissue, exogenous cells with an osteoblast differentiation potential must be provided. These cells should have the capacity to colonize the defect and to participate in the building of new bone tissue. To achieve this goal, cells must survive, remain in the defect site, eventually proliferate, and differentiate into mature osteoblasts. A critical issue for these engrafted cells is to be fed by oxygen and nutrients: the transient absence of a vascular network upon implantation is a major challenge for cells to survive in the site of implantation, and different strategies can be followed to promote cell survival under poor oxygen and nutrient supply and to promote rapid vascularization of the defect area. These strategies involve the use of scaffolds designed to create the appropriate micro-environment for cells to survive, proliferate, and differentiate in vitro and in vivo. Hydrogels are an eclectic class of materials that can be easily cellularized and provide effective, minimally invasive approaches to fill bone defects and favor bone tissue regeneration. Furthermore, by playing on their composition and processing, it is possible to obtain biocompatible systems with adequate chemical, biological, and mechanical properties. However, only a good combination of scaffold and cells, possibly with the aid of incorporated growth factors, can lead to successful results in bone regeneration. This review presents the strategies used to design cellularized hydrogel-based systems for bone regeneration, identifying the key parameters of the many different micro-environments created within hydrogels. PMID- 28634535 TI - Effectiveness and safety of daptomycin in patients with infective endocarditis undergoing heart valve replacement: a subgroup analysis from real-world data. AB - BACKGROUND: European Cubicin(r) Outcomes Registry and Experience (EU-CORE) was a retrospective, non-interventional, multicenter registry that collected real-world clinical outcomes following daptomycin use for the treatment of Gram-positive infections. EU-CORE data from patients with infective endocarditis (IE) who underwent heart valve replacement were analysed. METHODS: Clinical outcomes were assessed as success (cured or improved), failure, or non-evaluable. Adverse events (AEs) were recorded for up to 30 days after daptomycin treatment. RESULTS: Of 610 patients with IE, 198 [32.5%; left-sided IE (LIE), 166 (83.8%); right sided IE (RIE), 21 (10.6%); both LIE and RIE, 11 (5.6%)] underwent heart valve replacement. Other than cardiovascular disease, renal disease (18.2%), sepsis (16.2%), and diabetes mellitus (15.2%) were the most significant underlying diseases. Major pathogens in patients with positive culture results (68.0%) were Staphylococcus aureus [36.8%; methicillin-resistant S. aureus (MRSA), 12.8%] and coagulase-negative staphylococci (CoNS; 31.6%). Daptomycin treatment [median duration (range), 21 days (1-112)] resulted in high clinical success in patients with S. aureus (88.4%; MRSA, 80.0%) and CoNS (81.1%) infections, with an overall success rate of 83.3%. Clinical success rate was high (90.0%) in patients who received daptomycin dose >6 mg/kg/day. Overall clinical success rate in patients followed for up to 2 years was 90.7%. AEs and serious AEs possibly related to daptomycin were reported in 6 (3.0%) and 4 (2.0%) patients, respectively. CONCLUSIONS: Daptomycin treatment was effective and well tolerated with a sustained response in patients with IE who underwent heart valve surgery. A trend towards better clinical outcomes was observed with higher daptomycin doses. PMID- 28634537 TI - A meta-analysis of antibacterial envelope use in prevention of cardiovascular implantable electronic device infection. AB - OBJECTIVES: Cardiac implantable electronic device (CIED) infection has been a major clinical problem in addition to being a major financial burden. In spite of antimicrobial prophylaxis, CIED infection rates have been increasing disproportionately. We therefore conducted this meta-analysis to assess the role of TYRX antibiotic envelope for the prevention of CIED infection. METHODS: Using extensive online search, we conducted a meta-analysis of studies reporting CIED infections with versus without the use of TYRX antibiotic envelope. A random effect model was used, and between studies heterogeneity was estimated with I2. All analyses were performed with RevMan (version 5.0.20). RESULTS: Five cohort studies were included in this meta-analysis. The pooled odds ratio (OR) of included studies was 0.29 [95% confidence interval (CI): 0.09-0.94; p < 0.004]. There was evidence of heterogeneity with I2 of 58%. There was also evidence of publication bias on funnel plot analysis. On sensitivity analysis, no statistically significant difference was noted when stratified by study design or duration of follow-up. CONCLUSION: The results of our study demonstrate a significant beneficial effect of TYRX antibiotic envelope for the prevention of CIED infections. PMID- 28634536 TI - Telavancin: a novel semisynthetic lipoglycopeptide agent to counter the challenge of resistant Gram-positive pathogens. AB - Telavancin (TD-6424), a semisynthetic lipoglycopeptide vancomycin-derivative, is a novel antimicrobial agent developed by Theravance for overcoming resistant Gram positive bacterial infections, specifically methicillin-resistant Staphylococcus aureus (MRSA). The US Food and Drug Administration (USFDA) had approved telavancin in 2009 for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria, including MRSA (S. aureus, Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus anginosus group, or Enterococcus faecalis). Telavancin has two proposed mechanisms of action. In vitro, telavancin has a rapid, concentration-dependent bactericidal effect, due to disruption of cell membrane integrity. Telavancin has demonstrable in vitro activity against aerobic and anaerobic Gram-positive bacteria. Telavancin and vancomycin have similar spectra of activity. Gram-negative bacteria are usually non-susceptible to telavancin. Telavancin has been successfully tested in various animal models of bacteremia, endocarditis, meningitis, and pneumonia. Phase II Telavancin versus Standard Therapy for Treatment of Complicated Skin and Soft Tissue Infections due to Gram-Positive Bacteria (FAST 1 and FAST 2) and phase III [Assessment of Telavancin in Complicated Skin and Skin Structure Infections 1 (ATLAS 1 and ATLAS 2)] clinical trials have been conducted for evaluating telavancin's efficacy and safety in cSSSIs. Phase III clinical trials have been carried out for evaluating telavancin's safety and efficacy in nosocomial pneumonia [Assessment of Telavancin for Treatment of Hospital acquired Pneumonia 1 and 2 (ATTAIN 1 and ATTAIN 2)]. A phase II randomized, double-blind, clinical trial has been carried out for evaluating telavancin's safety and efficacy in uncomplicated S. aureus bacteremia [Telavancin for Treatment of Uncomplicated S. aureus Bacteremia (ASSURE)]. Pacemaker lead-related infective endocarditis due to a vancomycin intermediate S. aureus (VISA) strain (non-daptomycin susceptible) was successfully treated with parenteral telavancin for 8 weeks. Telavancin extensively binds to serum albumin (~93%) and has a relatively small volume of distribution. Telavancin is not biotransformed by any cytochrome P450 microsomal enzymes and excreted mainly in the urine. Though well-tolerated, worrisome adverse effects, including renal dysfunction and QTc prolongation are of potential concern. Given its extensive binding to plasma proteins, long half life, and a long post-antibiotic effect, it represents a promising addition to the therapeutic armamentarium in combating infections caused by resistant Gram positive pathogens, namely, MRSA. PMID- 28634538 TI - Prevalence and clinical impact of vitamin D deficiency on abdominal tuberculosis. AB - BACKGROUND: Vitamin D is recognised to have multiple actions, including role in immune modulation. The prevalence and impact of vitamin D deficiency (VDD) in abdominal tuberculosis is unknown. METHODS: We report the prevalence and clinical impact of VDD in patients with abdominal tuberculosis. The patients were divided into two groups: VDD (<20 ng/ml) or vitamin D sufficient (VDS) (?20 ng/ml). Groups were compared for extent (abdominal alone or extra-abdominal also) of disease and pattern of involvement (intestinal, peritoneal or both) and inflammatory response [serum C-reactive protein (CRP)]. RESULTS: Of 63 patients, 53 had complete data (mean age: 36.3 +/- 14.43, 31 males). Fourty-five (84.9%) patients had VDD and mean VD levels were 11.1 +/- 10.1 ng/ml. Of 8 patients with VDS, 1 (12.5%) had extra-abdominal involvement while 13 (28.9%) with VDD had extra-abdominal involvement (p = 0.066). The mean CRP in patients with VDD was 42.9 +/- 34.9 mg/dl vis-a-vis 105.38 +/- 64.8 in VDS (p ? 0.05). All seven patients with both intestinal and peritoneal involvement had VDD. CONCLUSION: VDD is common in abdominal tuberculosis and may be associated with more extensive involvement albeit a reduced inflammatory response. PMID- 28634539 TI - Using mHealth technologies to improve the identification of behavioral health problems in urban primary care settings. AB - INTRODUCTION: Behavioral health disorders remain under recognized and under diagnosed among urban primary care patients. Screening patients for such problems is widely recommended, yet is challenging to do in a brief primary care encounter, particularly for this socially and medically complex patient population. METHODS: In 2013, intervention patients at an urban Connecticut primary clinic were screened for post-traumatic stress disorder, depression, and risky drinking (n = 146) using an electronic tablet-based screening tool. Screening data were compared to electronic health record data from control patients (n = 129) to assess differences in the prevalence of behavioral health problems, rates of follow-up care, and the rate of newly identified cases in the intervention group. RESULTS: Results from logistic regressions indicated that both groups had similar rates of disorder at baseline. Patients in the intervention group were five times more likely to be identified with depression (p < 0.05). Post-traumatic stress disorder was virtually unrecognized among controls but was observed in 23% of the intervention group (p < 0.001). The vast majority of behavioral health problems identified in the intervention group were new cases. Follow-up rates were significantly higher in the intervention group relative to controls, but were low overall. CONCLUSION: This tablet-based electronic screening tool identified significantly higher rates of behavioral health disorders than have been previously reported for this patient population. Electronic risk screening using patient-reported outcome measures offers an efficient approach to improving the identification of behavioral health problems and improving rates of follow-up care. PMID- 28634540 TI - Improvement of walking ability during postoperative rehabilitation with the hybrid assistive limb after total knee arthroplasty: A randomized controlled study. AB - OBJECTIVE: We aimed to compare the efficacies of rehabilitation with the hybrid assistive limb and conventional rehabilitation after total knee arthroplasty. MATERIALS AND METHODS: A total of 37 consecutive patients who underwent primary total knee arthroplasty for knee osteoarthritis were enrolled. Seven patients withdrew from the study after randomization, and 30 patients (hybrid assistive limb group: n = 16; conventional group: n = 14) completed the randomized controlled trial. Patients in the hybrid assistive limb group underwent ten 20 min rehabilitation sessions with the hybrid assistive limb as well as 20-min conventional sessions over the course of 2 weeks, whereas patients in the conventional group received ten 40-min conventional sessions during the same period. The primary outcome measure was walking speed, whereas the secondary outcome measures included quadriceps strength and knee pain assessed using a numerical rating scale. The outcome measures were evaluated prior to surgery and on postoperative weeks 1, 2, and 3. RESULTS: In the early postoperative period, rehabilitation after total knee arthroplasty with the hybrid assistive limb resulted in a significantly greater improvement in walking speed (weeks 1 and 2: p = 0.045), quadriceps strength (weeks 1 and 2; weeks 1 and 3: p < 0.0001), and numerical rating scale scores (week 1: p = 0.03) than conventional rehabilitation. CONCLUSION: Rehabilitation with the hybrid assistive limb after total knee arthroplasty led to greater improvements in walking speed, quadriceps strength, and pain scores than conventional rehabilitation. PMID- 28634541 TI - Campylobacter jejuni myocarditis: A journey from the gut to the heart. AB - OBJECTIVES: Campylobacter jejuni is an unusual cause of myocarditis and could easily be missed. METHODS: We describe a case of a 25 year old man, who presented with 3 day history of vomiting and diarrhoea, followed by chest pain and significant high sensitive troponin rise. RESULTS: The patient's profuse diarrhoea was accompanied by raised inflammatory markers, electrocardiogram changes and evidence of cardiomyopathy on transthoracic echocardiogram. Various aetiological viral serologies which were tested for came back negative. However, stool culture was positive for the bacteria, Campylobacter jejuni. He was successfully treated with antibiotics and made an uneventful recovery. CONCLUSIONS: Campylobacter jejuni gastroenteritis has a worldwide prevalence. Therefore, prompt diagnosis and treatment is crucial when this organism is implicated in myocarditis. PMID- 28634542 TI - Angioedema: Perioperative management. AB - OBJECTIVE: To describe the perioperative management of a patient with acquired angioedema (AAE). METHODS: A 66-year-old Caucasian male presented from an outside hospital with a history of acquired angioedema and gastrointestinal stromal tumor related intractable urticaria and mastocytosis. He was admitted for urgent laparoscopic partial gastrectomy, secondary to gastric outlet obstruction symptomatology. Previous combined attacks were characterized by a widespread rash, abdominal pain and respiratory distress resulting in hospitalization. Following preoperative consultation with the patient's allergist and a hospital pharmacist, he was treated preoperatively with fresh frozen plasma and his home prednisone dose. C1-inhibitor (Berinert(r)) was on standby along with epinephrine, given that the underlying etiology (C1- inhibitor deficiency vs histaminergic) was not known. RESULTS: There were no intraoperative complications, and the patient was discharged home 3 days after the procedure. CONCLUSIONS: Optimization of perioperative outcomes in patients, especially during urgent or emergent surgery, with a history of angioedema requires the development of a patient-specific perioperative plan, including prophylaxis, rescue therapies and opioid-sparing strategies. PMID- 28634543 TI - Cannabis and cognitive functioning in multiple sclerosis: The role of gender. AB - BACKGROUND: Cognitive function in people with multiple sclerosis (PwMS) is associated with gender differences and the use of smoked/ingested cannabis. OBJECTIVE: The objective of this report is to explore a possible gender-cannabis interaction associated with cognitive dysfunction in PwMS. METHODS: A retrospective analysis was undertaken of cognitive data collected from 140 PwMS. A general linear model was conducted to determine gender and cannabis effects on processing speed (SDMT), verbal (CVLT-II) and visual (BVMT-R) memory, and executive functions (D-KEFS), while controlling for age and years of education. RESULTS: Cannabis was smoked at least once a month by 33 (23.6%) participants. Cannabis users were more impaired on the SDMT (p = 0.044). Men, who comprised 30.7% of the entire sample and 42.2% of cannabis users, were more impaired on the CVLT-II (total learning, p = 0.001; delayed recall, p = 0.004). A cannabis-gender interaction was found with the CVLT-II delayed recall (p = 0.049) and BVMT-R total learning (p = 0.014), where male cannabis users performed more poorly than female. CONCLUSION: Males with MS may be particularly vulnerable to the cognitive side effects of smoked cannabis use. PMID- 28634544 TI - Efficacy of Subconjunctival Bevacizumab Injections before and after Surgical Excision in Preventing Pterygium Recurrence. AB - PURPOSE: To evaluate the efficacy of subconjunctival bevacizumab injections, before and after surgical excision with bare sclera technique, in preventing postoperative pterygium recurrence. MATERIAL AND METHODS: 83 eyes of 83 patients affected with primary pterygia underwent surgical excision. 42 eyes received two subconjunctival bevacizumab injections, at the dosage of 2.5 mg/0.1 ml, one week prior surgery and one week after intervention. Recurrence rate was evaluated among the two groups. Moreover, modifications of pterygium size and grade one week after the first injection were evaluated. RESULTS: At 6 months after surgery, the recurrence rate was 7.14% in the bevacizumab group and 24.39% in the control group. Significant changes of pterygium size and grade were reported after the first injection. No important complications related to bevacizumab subconjunctival injections were registered. CONCLUSIONS: The application of subconjunctival bevacizumab injections, at the dosage of 2.5 mg/0.1 ml, before and after surgical pterygium excision, may be useful in preventing lesion recurrence after bare scleral procedures. Furthermore, bevacizumab subconjunctival administration is well tolerated and may represent a safer alternative if compared with other surgical techniques and adjunctive drugs. This trial is retrospectively registered with ISRCTN Registry on 18 April 2017, TRN: ISRCTN11424742. PMID- 28634545 TI - Herbal and Alternative Medicine Use in Tanzanian Adults Admitted with Hypertension-Related Diseases: A Mixed-Methods Study. AB - BACKGROUND: Hypertension is increasingly common in sub-Saharan Africa where traditional medicine use is also common. We conducted a hospital-based, mixed methods study to determine prevalence, pattern, and correlates of herbal and alternative medicine use in Tanzanian adults hospitalized with hypertension. METHODS: A standardized questionnaire was administered. In-depth interviews were performed on a subset of participants. Factors associated with herbal medicine use were determined by logistic regression. The association between traditional medicine uses and allopathic medication adherence was determined using ordinal logistic regression. Qualitative data were analyzed according to grounded theory. RESULTS: Of 213 adults enrolled, 52 (24.4%) reported using herbs during the previous month and 47 (22.1%) reported concurrent use of herbs and allopathic medicines. Lower educational level, nonprofessional employment, and lack of health insurance were significantly associated with herbal medicine use. Alternative medicines use was not associated with lower medication adherence. Qualitative interviews identified several important themes including reasons for herbal medicine use. CONCLUSION: The use of traditional medicines is very common among patients with hypertension. Adults from low socioeconomic status, those with misunderstandings about hypertension, and those without health insurance were more likely to take herbs. Open, nonjudgmental communication between healthcare workers and patients regarding use of traditional medicines must be encouraged in Africa. PMID- 28634546 TI - Low Hemoglobin among Pregnant Women in Midwives Practice of Primary Health Care, Jatinangor, Indonesia: Iron Deficiency Anemia or beta-Thalassemia Trait? AB - Low hemoglobin (Hb) or anemia is common among pregnant women in developing countries which may cause adverse pregnancy outcomes and maternal deaths. Our study aimed to assess Hb level measured by midwives in primary health care facility at rural area of Jatinangor, Indonesia, and to explore whether the anemia was due to iron deficiency (IDA) or beta-thalassemia trait (beta-TT). Pregnant women (n = 105) had finger prick test for Hb level during a regular antenatal care examination from October to November 2016. Hb level by finger prick test was compared with venous blood, measured by complete blood count (CBC). Indices including MCV and MCH and indices of Shine & Lal, Mentzer, Srivastava, Engels & Frase, Ehsani, and Sirdah were analyzed to differentiate anemia due to IDA and anemia due to suspect beta-TT. HbA2 was measured to confirm beta-TT. Anemic pregnant women were found in 86.7% by finger prick test compared to 21.9% (n = 23) by CBC. The prevalence of beta-TT in our study was 5.7%. Hb measurement among pregnant women in low resource area is highly important; however, finger prick test in this study showed a high frequency of anemia which may lead to iron oversupplementation. A standard CBC is encouraged; MCV and MCH would help midwives to identify beta-TT. PMID- 28634547 TI - Kinesiophobia, Pain, Muscle Functions, and Functional Performances among Older Persons with Low Back Pain. AB - OBJECTIVES: This study aims (1) to determine the association between kinesiophobia and pain, muscle functions, and functional performances and (2) to determine whether kinesiophobia predicts pain, muscle functions, and functional performance among older persons with low back pain (LBP). METHODS: This is a correlational study, involving 63 institutionalized older persons (age = 70.98 +/ 7.90 years) diagnosed with LBP. Anthropometric characteristics (BMI) and functional performances (lower limb function, balance and mobility, and hand grip strength) were measured. Muscle strength (abdominal and back muscle strength) was assessed using the Baseline(r) Mechanical Push/Pull Dynamometer, while muscle control (transverse abdominus and multifidus) was measured by using the Pressure Biofeedback Unit. The pain intensity and the level of kinesiophobia were measured using Numerical Rating Scale and Tampa Scale of Kinesiophobia, respectively. Data were analyzed using Pearson's correlation coefficients and multivariate linear regressions. RESULTS: No significant correlations were found between kinesiophobia and pain and muscle functions (all p > 0.05). Kinesiophobia was significantly correlated with mobility and balance (p = 0.038, r = 0.263). Regressions analysis showed that kinesiophobia was a significant predictor of mobility and balance (p = 0.038). CONCLUSION: We can conclude that kinesiophobia predicted mobility and balance in older persons with LBP. Kinesiophobia should be continuously assessed in clinical settings to recognize the obstacles that may affect patient's compliance towards a rehabilitation program in older persons with LBP. PMID- 28634548 TI - Decline in Memory, Visuospatial Ability, and Crystalized Cognitive Abilities in Older Adults: Normative Aging or Terminal Decline? AB - The aim of this study is to explore the pattern of change in multiple measures of cognitive abilities in a sample of oldest-old adults, comparing two different time metrics (chronological age and time to death) and therefore examining both underlying conceptual assumptions (age-related change and terminal decline). Moreover, the association with individual characteristics as sex, education, and dementia diagnosis was also examined. Measures of cognitive status (Mini-Mental State Examination and the Swedish Clock Test) and tests of crystallized (knowledge and synonyms), memory (verbal memory, nonverbal long-term memory, recognition and correspondence, and short-term memory), and visuospatial ability were included. The sample consisted of 671 older Swedish adult participants of the OCTO Twin Study. Linear mixed models with random coefficients were used to analyse change patterns and BIC indexes were used to compare models. Results showed that the time to death model was the best option in analyses of change in all the cognitive measures considered (except for the Information Test). A significant cognitive decline over time was found for all variables. Individuals diagnosed with dementia had lower scores at the study entrance and a faster decline. More educated individuals performed better in all the measures of cognition at study entry than those with poorer education, but no differences were found in the rate of change. Differences were found in age, sex, or time to death at baseline across the different measures. These results support the terminal decline hypothesis when compared to models assuming that cognitive changes are driven by normative aging processes. PMID- 28634549 TI - A Qualitative Study of Quality of Life Concerns following a Melanoma Diagnosis. AB - The goal of this study was to identify a relevant and inclusive list of quality of life issues among long-term survivors of melanoma. Individuals diagnosed with stage I-III cutaneous melanoma and had survived 1-5 years, ages 18-65 years at diagnosis, were recruited. Five focus groups were conducted with 33 participants in total. Discussions centered on participants' experiences at diagnosis, as well as ongoing physical, emotional, and social concerns, and behavioral changes since diagnosis. The majority of participants reported shock, fear, and feeling overwhelmed at the time of diagnosis. Some reported lingering physical concerns, including pain, numbness, and lymphedema, while a few reported no lasting issues. Emotional concerns were common, with most reporting anxiety. Several also noted feeling lonely and isolated. Social concerns included alteration of activities to avoid sun exposure, issues with family communication, and frustration with the lack of appreciation of the seriousness of melanoma by others. Finally, while many participants reported changes to their sun exposure and UV-protection behaviors, some reported little to no change. The shared experiences among participants in this study confirm the unique nature of melanoma and the need for interventions designed to improve the health and quality of life of melanoma survivors. PMID- 28634550 TI - Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer's Disease Patients Carrying the APOE Epsilon 4 Allele. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Abeta) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Abeta/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by gamma-secretase (but not beta-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro. PMID- 28634551 TI - Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction. AB - Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1 targeting protein enriched in the postsynaptic density of striatal dendritic spines. Spinophilin association with PP1 is increased concurrent with decreases in PP1 activity in an animal model of PD. Using proteomic-based approaches, we observed dopamine depletion-induced decreases in spinophilin binding to multiple protein classes in the striatum. Specifically, there was a decrease in the association of spinophilin with neurofilament medium (NF-M) in dopamine-depleted striatum. Using a heterologous cell line, we determined that spinophilin binding to NF-M required overexpression of the catalytic subunit of protein kinase A and was decreased by cyclin-dependent protein kinase 5. Functionally, we demonstrate that spinophilin can decrease NF-M phosphorylation. Our data determine mechanisms that regulate, and putative consequences of, pathological changes in the association of spinophilin with NF-M that are observed in animal models of PD. PMID- 28634553 TI - Acute Lymphoblastic Leukemia with Infective Endocarditis Presented with Unusual Intracardiac Mass. AB - Acute lymphoblastic leukemia (ALL) is a systemic disease that is presented with different symptoms and signs. Cardiac manifestation is rare in ALL, but it is very important and needs appropriate management. It usually presents as leukemic myocardial infiltration and in the presence of cardiac mass comprehensive evaluation for other etiologies is mandatory. We reported on a 6-year-old boy in remission phase of ALL and large cardiac mass in the right atrium with obscure early symptoms and signs, in whom infective endocarditis (IE) was diagnosed and appropriate medical treatment was performed. Because the mass was sustained, surgical resection was considered for the patient. PMID- 28634554 TI - False Positive Transit Time Flowmetry Graft Failure in Multivessel Coronary Spasm following Off-Pump Coronary Artery Bypass Grafting. AB - Intraoperative Transit Time Flowmetry is currently recommended to assess graft patency during coronary artery bypass grafting (CABG), especially in presence of haemodynamic instability or inability to wean the patient from cardiopulmonary bypass, new regional wall motion abnormalities, or significant ventricular arrhythmias. The VeriQTM system is one of the currently available systems, which detects imperfections that may be corrected by graft revision. In this case report, multivessel coronary spasm (CS) post-CABG interferes with these intraoperative parameters misleading initially into false results. Cardiac surgeons should bear in mind the limit of VeriQ in distinguishing between graft failure and CS. Angiography may be considered in patients with decreased graft flow despite revision of anastomosis and vasodilatory treatment for the definitive diagnosis. PMID- 28634552 TI - Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy. AB - Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis. PMID- 28634555 TI - A Rare Case of Pneumopericardium in the Setting of Tuberculous Constrictive Pericarditis. AB - A 28-year-old Filipino male was admitted due to high-grade fevers and dyspnea on a background of chronic cough and weight loss. Due to clinical and echocardiographic signs of cardiac tamponade, emergency pericardiocentesis was performed on his first hospital day. Five days after, chest radiographs showed new pockets of radiolucency within the cardiac shadow, indicative of pneumopericardium. On repeat echo, air microbubbles admixed with loculated effusion were visualized in the anterior pericardial space. Constrictive physiology was also supported by a thickened pericardium, septal bounce, exaggerated respiratory variation in AV valve inflow, and IVC plethora. A chest CT scan confirmed the presence of an air-fluid level within the pericardial sac. The patient was started on a quadruple antituberculosis regimen and IV piperacillin-tazobactam to cover for superimposed acute bacterial pericarditis. Pericardiectomy was performed as definitive management, with stripped pericardium measuring 5-7 mm thick and caseous material extracted from the pericardial sac. Histopathology was consistent with tuberculosis. This report highlights pneumopericardium as a rare complication of pericardiocentesis. We focused on the utility of echocardiography for diagnosing and monitoring this condition on a background of tuberculous constrictive pericarditis, ultimately convincing us that pericardiectomy was necessary, instead of the usual conservative measures for pneumopericardium. PMID- 28634556 TI - Central Venous Line Insertion Revealing Partial Anomalous Pulmonary Venous Return: Diagnosis and Management. AB - Central venous line malposition is a well-known complication of line insertion. Rarely, it can be mal-positioned in an anomalous pulmonary vein. We present an unusual case of a 56-year-old woman that was found to have partial anomalous pulmonary venous return on central venous line insertion. In this report, we describe a systematic approach to diagnosis and management of this unusual situation. PMID- 28634557 TI - Dental Management of a Child with Incidentally Detected Hemophilia: Report of a Clinical Case. AB - Children with hemophilia (A or B) are at risk for bleeding episodes, which rank from mild mucosal/soft tissues bleeding to life-threatening hemorrhages. This report describes the dental/medical management provided to an 8.10-year-old patient suffering from uncontrolled bleeding after a surgical procedure to expose both permanent upper central incisors, in which hemophilia was a pure incidental finding. Additionally, diverse precautions to be considered during the dental clinical treatment of hemophilic children are discussed. PMID- 28634559 TI - Malignant Pleural Mesothelioma with Marked Lymphatic Involvement: A Report of Two Autopsy Cases. AB - We herein report two cases of malignant pleural mesothelioma with marked lymphangiosis. The patients included a 68-year-old man and a 67-year-old man who both had a history of exposure to asbestos. Computed tomography (CT) on admission showed pleural effusion with pleural thickening. In both cases, a histopathological examination of the pleura confirmed the diagnosis of epithelioid malignant mesothelioma. They received chemotherapy, but the treatment was only palliative. The chest CT assessments during admission revealed marked pleural effusion and mediastinal lymphadenopathy. CT also showed a consolidative mass with bronchovascular bundle and septal thickening in the lungs suggesting pulmonary parenchymal involvement and the lymphangitic spread of the tumor. These CT findings mimicked lung cancer with pleuritis and lymphangitic carcinomatosis. Autopsy was performed in both cases. Macroscopically, the tumor cells infiltrated the lung with the marked lymphatic spread of the tumor. Microscopy also revealed that the tumor had invaded the pulmonary parenchyma with the marked lymphatic spread of the tumor. Although this growth pattern is unusual, malignant pleural mesothelioma should be considered as the differential diagnosis, especially in patients with pleural lesions. PMID- 28634558 TI - Plesiomonas shigelloides: An Unusual Cause of Septic Abortion. AB - Plesiomonas shigelloides, the only oxidase-positive Enterobacteriaceae, is an inhabitant of freshwater and estuary ecosystems. We report the first possible case of Plesiomonas shigelloides-induced septic abortion. This 24-year-old female was successfully treated by dilatation and curettage as well as antimicrobial therapy. PMID- 28634560 TI - Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma Developed in a Patient with Progressive Muscular Dystrophy: A Case Report and Review of the Literature. AB - BACKGROUND: Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLS) is an intermediate or locally aggressive form of adipocytic soft tissue sarcoma. Muscular dystrophy (MD) is characterized by progressive muscle atrophy and its replacement by adipose and fibrous tissue. Recently, some authors have reported that MD genes are related to neoplastic formation, but there have been no detailed clinical reports of ALT associated with MD. CASE PRESENTATION: A 73-year old woman with a diagnosis of limb-girdle MD visited our department for recurrence of a huge tumor in her left thigh. She had undergone resection of a lipoma at the same site more than 20 years earlier. Imaging studies revealed a lipomatous tumor in her left thigh. We performed marginal resection including the adjacent muscles. Histological diagnosis was atypical lipomatous tumor. The postoperative course was uneventful, with no recurrence at 36 months of follow up. CONCLUSION: We encountered a huge atypical tumor in a patient with MD. This is the first detailed report to describe an association between ALT and MD. We hypothesize that degenerative changes occurring in adipose tissue during muscle atrophy can cause lipomatous neoplasms and moreover that the mutation of MD related genes may lead to the proliferation of tumor cells or to malignancy. PMID- 28634561 TI - Custom-Made Alumina Ceramic Total Talar Prosthesis for Idiopathic Aseptic Necrosis of the Talus: Report of Two Cases. AB - Two women aged 65 years and 78 years presented to our center with idiopathic necrosis of the talus. In both cases, imaging examinations showed collapse and sclerotic changes of the talar body caused by the necrosis. Both women underwent resection and placement of a third-generation custom-made alumina ceramic total talar prosthesis. Immobilization of the ankle in a short-leg cast for 3 weeks was followed by early rehabilitation. One year and 6 months after surgery, both women were able to walk without pain. Their Japanese Society for Surgery of the Foot ankle-hindfoot scale scores improved from 22 and 29/100 points to 90 and 95/100 points, respectively. To the best of our knowledge, the successful treatments of these two rare cases of idiopathic necrosis of the talus are among only a few reported cases of using a third-generation alumina ceramic prosthesis. PMID- 28634562 TI - A Simple Bone Cyst in Cervical Vertebrae of an Adolescent Patient. AB - INTRODUCTION: Spinal simple bone cysts, also known as solitary cysts, are extremely unusual benign primary bone tumors with few cases reported in the literature. CASE PRESENTATION: Incidental Magnetic Resonance Imaging (MRI) finding of a C2 Simple bone cyst in a 13-year-old female patient is reported. Complementary studies suggested the benign nature of the lesion. Patient underwent cervical curettage followed by tumor excision. A lateral submandibular approach to the upper cervical spine was used and careful bone resection was possible with a radiofrequency assisted burr and no instrumentation or fixation was required. The stability of the defect was ensured by filling it with bone allograft and by prescribing a postsurgical plastic cervical collar to maintain neck immobilization. Histological examination supported the diagnosis of simple bone cyst. At 6-12-month follow-up the patient presented no recurrence or symptomatology. CONCLUSIONS: Solitary bone cysts are infrequent entities in the cervical vertebrae and preservation of spine stability without instrumentation to avoid neurological complications is often challenging. In this case, the proximity of the cyst to the right vertebral artery and the risk of injury were high; however the surgical approach used was successful and no recurrence or instability was evidenced on postoperative MRI. PMID- 28634563 TI - Aspiration of Aluminum Beverage Can Tab: Case Report and Literature Review. AB - We describe the case of a 16-year-old male who aspirated a beverage can tab resulting in significant functional impairment. Since the introduction of beverage can opening tabs ("pop-tops" or "pull-tabs") nearly 50 years ago, five cases of their aspiration have been reported in the literature and this is the first case to report tracheal lodgment. We describe the clinical course for this patient including the inadequacy of radiographic evaluation and a significant delay in diagnosis. We highlight unique features of small aluminum foreign bodies that require consideration and mention a potential change in epidemiology associated with evolving product design. Our primary objective is increased awareness among otolaryngologists that radiography is unreliable for diagnosis or localization of small aluminum foreign bodies. The patient history must therefore be incorporated with other imaging modalities and/or endoscopic evaluation. Also, given the marked prevalence of aluminum beverage cans, we suspect that the inadvertent aspiration of can tabs is more common than indicated by the paucity of published reports. PMID- 28634564 TI - PAX8 Distinguishes Diffuse Large B-Cell Lymphoma Mimicking Sarcoma. AB - PAX8 is important for embryogenesis of the thyroid, Mullerian system, and upper urinary/renal tract, and expression of PAX8 has been described in carcinomas from each of these sites. The sensitivity and specificity of the polyclonal PAX8 antibody in a large cohort of epithelial tumors as well as lymphomas have been previously determined, the latter because polyclonal PAX8 is known to be immunoreactive in nonneoplastic B-cell lymphocytes which are often used as the positive internal control for immunohistochemistry. In this case report, PAX8 was a diagnostic clue for revising a previous diagnosis of unclassified high grade sarcoma to diffuse large B-cell lymphoma. This case report demonstrates a pitfall for PAX8 immunoreactivity and acts as a reminder that lymphoma should be included in the differential diagnosis of a PAX8 positive, epithelial cell marker negative tumor of unknown primary origin. PMID- 28634565 TI - Home-Based Telepsychiatry in US Urban Area. AB - Telepsychiatry expands access to psychiatric care. However, telepsychiatry for elderly adults is only reimbursed in the US if the patient is assessed while in a clinical setting. This case study presents a homebound older woman previously hospitalized for schizophrenia who had not seen a psychiatrist in over 20 years. Care was provided with hybrid telepsychiatry (team-based practice with social worker traveling to the home with electronic tablet for connection with psychiatrist). The intervention resulted in detecting unrecognized depression and complex trauma. The treatment plan included adding an antidepressant and therapy plan, eliminating one psychiatric medication, and reducing dosage of pain medication. The outcomes were improved function and quality of life. The patient and caregiver were both highly satisfied with the services. This hybrid telepsychiatry is a reasonable option for homebound elderly patients living in urban areas and less expensive than nursing home admission. PMID- 28634566 TI - Adhesive-Enhanced Sternal Closure: Feasibility and Safety of Late Sternal Reentry. AB - This clinical case report describes sternal reentry performed years after adhesive-enhanced sternal closure using Kryptonite bone cement. This report provides novel data on the late effects of this innovation. We observed that sternal reentry is feasible and safe. The adhesive did not weaken from biodegradation over a period of several years. There was no evidence of adherence to adjacent soft tissues or other nonbony deep mediastinal structures. Surgeons who receive patients who require redoing cardiac surgery after adhesive-enhanced closure with Kryptonite can be reassured that sternal reentry is safe and feasible. PMID- 28634567 TI - AAA Rupture and Psoas Hematoma due to Type II Endoleak from Inferior Mesenteric Artery "Unusual" Collaterals. AB - Although endovascular aneurysm repair (EVAR) in the abdominal aorta has reduced the perioperative mortality when compared with open repair, the need for reintervention after complications such as endoleak may be presented in up to 20% of the cases. Type II endoleak from branch vessels is often benign but can potentially be associated with progressive abdominal aortic aneurysm growth and sac expansion. We present a rare case of a patient who presented with sac expansion and psoas hematoma due to Type II endoleak from "unusual" collaterals of IMA and was treated successfully with endoleak microembolization and percutaneous decompression of the hematoma. PMID- 28634568 TI - Sirtuin-2 Protects Neural Cells from Oxidative Stress and Is Elevated in Neurodegeneration. AB - Sirtuins are highly conserved lysine deacetylases involved in ageing, energy production, and lifespan extension. The mammalian SIRT2 has been implicated in Parkinson's disease (PD) where studies suggest SIRT2 promotes neurodegeneration. We therefore evaluated the effects of SIRT2 manipulation in toxin treated SH-SY5Y cells and determined the expression and activity of SIRT2 in postmortem brain tissue from patients with PD. SH-SY5Y viability in response to oxidative stress induced by diquat or rotenone was measured following SIRT2 overexpression or inhibition of deacetylase activity, along with alpha-synuclein aggregation. SIRT2 in human tissues was evaluated using Western blotting, immunohistochemistry, and fluorometric activity assays. In SH-SY5Y cells, elevated SIRT2 protected cells from rotenone or diquat induced cell death and enzymatic inhibition of SIRT2 enhanced cell death. SIRT2 protection was mediated, in part, through elevated SOD2 expression. SIRT2 reduced the formation of alpha-synuclein aggregates but showed minimal colocalisation with alpha-synuclein. In postmortem PD brain tissue, SIRT2 activity was elevated compared to controls but also elevated in other neurodegenerative disorders. Results from both in vitro work and brain tissue suggest that SIRT2 is necessary for protection against oxidative stress and higher SIRT2 activity in PD brain may be a compensatory mechanism to combat neuronal stress. PMID- 28634569 TI - Epidemiology and Management of Atrial Fibrillation and Stroke: Review of Data from Four European Countries. AB - In Europe, 1-3% of the population suffers from atrial fibrillation (AF) and has increased stroke risk. By 2060 a doubling in number of cases and great burden in managing this medical condition are expected. This paper offers an overview of data on epidemiology and management of AF and stroke in four European countries as well as the interconnection between these dimensions. A search index was developed to access multiple scientific and "grey" literatures. Information was prioritised based on strength of evidence and date. Information on country reports was double-checked with national experts. The overall prevalence of AF is consistent across countries. France has the lowest stroke incidence and mortality, followed by Netherland and UK, while Romania has higher rates. GPs or medical specialists are responsible for AF treatment; exception are the special thrombosis services in the Netherlands. Prevention measurements are only present in UK through screening programs. Although international and national guidelines are available, undertreatment is present in all countries. Despite differences in healthcare systems and management of AF, epidemiology is comparable between three of the countries. Romania is an outlier, by being limited in data accessibility. This knowledge can contribute to improved AF care in Europe. PMID- 28634571 TI - Current Immunotherapeutic Strategies to Enhance Oncolytic Virotherapy. AB - Oncolytic viruses (OV) represent a promising strategy to augment the spectrum of cancer therapeutics. For efficacy, they rely on two general mechanisms: tumor specific infection/cell-killing, followed by subsequent activation of the host's adaptive immune response. Numerous OV genera have been utilized in clinical trials, ultimately culminating in the 2015 Food and Drug Administration approval of a genetically engineered herpes virus, Talminogene laherparepvec (T-VEC). It is generally accepted that OV as monotherapy have only modest clinical efficacy. However, due to their ability to elicit specific antitumor immune responses, they are prime candidates to be paired with other immune-modulating strategies in order to optimize therapeutic efficacy. Synergistic strategies to enhance the efficacy of OV include augmenting the host antitumor response through the insertion of therapeutic transgenes such as GM-CSF, utilization of the prime boost strategy, and combining OV with immune-modulatory drugs such as cyclophosphamide, sunitinib, and immune checkpoint inhibitors. This review provides an overview of these immune-based strategies to improve the clinical efficacy of oncolytic virotherapy. PMID- 28634570 TI - To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents. AB - Ischemic strokes are major causes of death and disability. Searching for potential therapeutic strategies to prevent and treat stroke is necessary, given the increase in overall life expectancy. Epidemiological reports indicate that metformin is an oral antidiabetic medication that can reduce the incidence of ischemic events in patients with diabetes mellitus. Its mechanism of action has not been elucidated, but metformin pleiotropic effects involve actions in addition to glycemic control. AMPK activation has been described as one of the pharmacological mechanisms that explain the action of metformin and that lead to neuroprotective effects. Most experiments done in the cerebral ischemia model, via middle cerebral artery occlusion in rodents (MCAO), had positive results favoring metformin's neuroprotective role and involve several cellular pathways like oxidative stress, endothelial nitric oxide synthase activation, activation of angiogenesis and neurogenesis, autophagia, and apoptosis. We will review the pharmacological properties of metformin and its possible mechanisms that lead to neuroprotection in cerebral ischemia. PMID- 28634572 TI - A Helicobacter pylori Homolog of Eukaryotic Flotillin Is Involved in Cholesterol Accumulation, Epithelial Cell Responses and Host Colonization. AB - The human pathogen Helicobacter pylori acquires cholesterol from membrane raft domains in eukaryotic cells, commonly known as "lipid rafts." Incorporation of this cholesterol into the H. pylori cell membrane allows the bacterium to avoid clearance by the host immune system and to resist the effects of antibiotics and antimicrobial peptides. The presence of cholesterol in H. pylori bacteria suggested that this pathogen may have cholesterol-enriched domains within its membrane. Consistent with this suggestion, we identified a hypothetical H. pylori protein (HP0248) with homology to the flotillin proteins normally found in the cholesterol-enriched domains of eukaryotic cells. As shown for eukaryotic flotillin proteins, HP0248 was detected in detergent-resistant membrane fractions of H. pylori. Importantly, H. pylori HP0248 mutants contained lower levels of cholesterol than wild-type bacteria (P < 0.01). HP0248 mutant bacteria also exhibited defects in type IV secretion functions, as indicated by reduced IL-8 responses and CagA translocation in epithelial cells (P < 0.05), and were less able to establish a chronic infection in mice than wild-type bacteria (P < 0.05). Thus, we have identified an H. pylori flotillin protein and shown its importance for bacterial virulence. Taken together, the data demonstrate important roles for H. pylori flotillin in host-pathogen interactions. We propose that H. pylori flotillin may be required for the organization of virulence proteins into membrane raft-like structures in this pathogen. PMID- 28634573 TI - Tick Bioactive Molecules as Novel Therapeutics: Beyond Vaccine Targets. PMID- 28634574 TI - Reducing Viability Bias in Analysis of Gut Microbiota in Preterm Infants at Risk of NEC and Sepsis. AB - Necrotising enterocolitis (NEC) and sepsis are serious diseases of preterm infants that can result in feeding intolerance, the need for bowel resection, impaired physiological and neurological development, and high mortality rates. Neonatal healthcare improvements have allowed greater survival rates in preterm infants leading to increased numbers at risk of developing NEC and sepsis. Gut bacteria play a role in protection from or propensity to these conditions and have therefore, been studied extensively using targeted 16S rRNA gene sequencing methods. However, exact epidemiology of these conditions remain unknown and the role of the gut microbiota in NEC remains enigmatic. Many studies have confounding variables such as differing clinical intervention strategies or major methodological issues such as the inability of 16S rRNA gene sequencing methods to determine viable from non-viable taxa. Identification of viable community members is important to identify links between the microbiota and disease in the highly unstable preterm infant gut. This is especially important as remnant DNA is robust and persists in the sampling environment following cell death. Chelation of such DNA prevents downstream amplification and inclusion in microbiota characterisation. This study validates use of propidium monoazide (PMA), a DNA chelating agent that is excluded by an undamaged bacterial membrane, to reduce bias associated with 16S rRNA gene analysis of clinical stool samples. We aim to improve identification of the viable microbiota in order to increase the accuracy of clinical inferences made regarding the impact of the preterm gut microbiota on health and disease. Gut microbiota analysis was completed on stools from matched twins (n = 16) that received probiotics. Samples were treated with PMA, prior to bacterial DNA extraction. Meta-analysis highlighted a significant reduction in bacterial diversity in 68.8% of PMA treated samples as well as significantly reduced overall rare taxa abundance. Importantly, overall abundances of genera associated with protection from and propensity to NEC and sepsis such as: Bifidobacterium; Clostridium, and Staphylococcus sp. were significantly different following PMA-treatment. These results suggest non-viable cell exclusion by PMA-treatment reduces bias in gut microbiota analysis from which clinical inferences regarding patient susceptibility to NEC and sepsis are made. PMID- 28634575 TI - Association between Plasmatic Ceramides Profile and AST/ALT Ratio: C14:0 Ceramide as Predictor of Hepatic Steatosis in Adolescents Independently of Obesity. AB - OBJECTIVE: To assess the association between plasma ceramides and hepatic steatosis (HS) in adolescents, independently of obesity. MATERIALS AND METHODS: Ninety-four adolescents from two previous studies conducted and published by our crew were included. Study subjects were stratified in three groups: normal weight (n = 18), obesity (n = 34), and obesity + HS (n = 42). The presence of HS was defined when ALT/AST ratio was <1. Ceramides subspecies (C14:0, C16:0, C18:0, C24:0, and C24:1) were determined by LC/MS. RESULTS: All ceramides correlated directly with ALT levels and inversely with ALT/AST ratio; the strongest correlation was observed among C14:0 ceramide (r = 0.41 and r = -0.54, resp.; P < 0.001). Furthermore, significant correlations were observed between cholesterol and all ceramides except for C24:1 ceramide. Interestingly ceramides C14:0, C18:0, and C24:1 correlated directly with both fasting insulin and HOMA-IR index. For assessing HS, a cut-off point of 10.3 nmol/L for C14:0 ceramide reported a sensitivity of 92.7% and a specificity of 73.5% when normal weight and obesity groups (n = 52) were compared against obesity + HS group (n = 42). Positive and negative predictive values were 77.5% and 90.2%, respectively. CONCLUSIONS: Plasma ceramides are closely associated with hepatic steatosis in adolescents. C14:0 ceramide could be a novel biomarker of HS independently of obesity. PMID- 28634577 TI - Commentary: Impact of Fecal Calprotectin Measurement on Decision-Making in Children with Inflammatory Bowel Disease. PMID- 28634576 TI - Disability in Patients with Inflammatory Bowel Disease: Correlations with Quality of Life and Patient's Characteristics. AB - BACKGROUND: Inflammatory bowel diseases may cause significant disability. However, little is known regarding the life domains where patients encounter most limitations. OBJECTIVES: To assess patients' overall disability and determine the life domains where most restrictions were applied. Secondarily, we sought for possible relationships among disability, quality of life (HRQoL), and population characteristics. METHOD: The study lasted for two years (2013-2015) and included 200 patients [52% ulcerative colitis (UC)] from a referral centre. Disability was evaluated using the 36-item version of WHODAS 2.0 questionnaire. The influence of population characteristics on overall disability was assessed with linear regression. RESULTS: Crohn's disease (CD) patients showed greater overall disability compared to UC (19.22 versus 15.01, p = 0.001), with higher scores in the domains of relationships, life activities, and participation. Disability was negatively associated with HRQoL (p < 0.001). Long activity, extensive disease, rural residence, and employment independently influenced the overall disability in both groups. Additionally, significant influence was recorded for lower education in the UC and for operation and celibacy in the CD group. CONCLUSIONS: CD patients were facing more limitations compared to those with UC, especially in the domains of relationships, activities, and participation. Other than clinical factors, sociodemographic characteristics were also associated with increased disability. PMID- 28634578 TI - Neonatal Venous Thromboembolism. AB - Neonates are the pediatric population at highest risk for development of venous thromboembolism (VTE), and the incidence of VTE in the neonatal population is increasing. This is especially true in the critically ill population. Several large studies indicate that the incidence of neonatal VTE is up almost threefold in the last two decades. Central lines, fluid fluctuations, sepsis, liver dysfunction, and inflammation contribute to the risk profile for VTE development in ill neonates. In addition, the neonatal hemostatic system is different from that of older children and adults. Platelet function, pro- and anticoagulant proteins concentrations, and fibrinolytic pathway protein concentrations are developmentally regulated and generate a hemostatic homeostasis that is unique to the neonatal time period. The clinical picture of a critically ill neonate combined with the physiologically distinct neonatal hemostatic system easily fulfills the criteria for Virchow's triad with venous stasis, hypercoagulability, and endothelial injury and puts the neonatal patient at risk for VTE development. The presentation of a VTE in a neonate is similar to that of older children or adults and is dependent upon location of the VTE. Ultrasound is the most common diagnostic tool employed in identifying neonatal VTE, but relatively small vessels of the neonate as well as frequent low pulse pressure can make ultrasound less reliable. The diagnosis of a thrombophilic disorder in the neonatal population is unlikely to change management or outcome, and the role of thrombophilia testing in this population requires further study. Treatment of neonatal VTE is aimed at reducing VTE-associated morbidity and mortality. Recommendations for treating, though, cannot be extrapolated from guidelines for older children or adults. Neonates are at risk for bleeding complications, particularly younger neonates with more fragile intracranial vessels. Developmental alterations in the coagulation proteins as well as unique pharmacokinetics must also be taken into consideration when recommending VTE treatment. In this review, epidemiology of neonatal VTE, pathophysiology of neonatal VTE with particular attention to the developmental hemostatic system, diagnostic evaluations of neonatal VTE, and treatment guidelines for neonatal VTE will be reviewed. PMID- 28634579 TI - Precision in Setting Cancer Prevention Priorities: Synthesis of Data, Literature, and Expert Opinion. AB - Cancer will continue to be a leading cause of ill health and death unless we can capitalize on the potential for 30-40% of these cancers to be prevented. In this light, cancer prevention represents an enormous opportunity for public health, potentially saving much of the pain, anguish, and cost associated with treating cancer. However, there is a challenge for governments, and the wider community, in prioritizing cancer prevention activities, especially given increasing financial constraints. This paper describes a method for identifying cancer prevention priorities. This method synthesizes detailed cancer statistics, expert opinion, and the published literature for the priority setting process. The process contains four steps: assessing the impact of cancer types; identifying cancers with the greatest impact; considering opportunities for prevention; and combining information on impact and preventability. The strength of our approach is that it is straightforward, transparent and reproducible for other settings. Applying this method in Western Australia produced a priority list of seven adult cancers which were identified as having not only the biggest impact on the community but also the best opportunities for prevention. Work conducted in an additional project phase went on to present data on these priority cancers to a public consultation and develop an agenda for action in cancer prevention. PMID- 28634580 TI - Tobacco Use during Pregnancy and Its Associated Factors in a Mountain District of Eastern Nepal: A Cross-Sectional Questionnaire Survey. AB - BACKGROUND: Tobacco using among women is more prevalent in Nepal as compared to other South-East Asian countries. The effect of its use is seen not only on the pregnant women, but also health of the growing fetus is compromised. Currently, little is known about the tobacco use among women especially during pregnancy in Nepal. This study explored the tobacco use prevalence and its associated factors during pregnancy. MATERIALS AND METHODS: A cross-sectional study was conducted in Sankhuwasabha, a mountain district of eastern Nepal. Representative sample of 436 women of reproductive age group with infant were selected by stratified simple random sampling. Data were collected by face-to-face interviews of selected participants. Data were analyzed with SPSS version 16.0. Binary logistic regression was used to analyze the relationship among variables. RESULTS: The study revealed that the prevalence of tobacco use during pregnancy was 17.2%. Only one fifth of the research participants were asked to quit tobacco by health workers during last pregnancy. Multivariable analyses revealed that illiteracy (AOR: 2.31, CI: 1.18-4.52), more than two parity (AOR: 2.45, CI: 1.19-5.07), alcohol use during last pregnancy (AOR: 3.99, CI: 1.65-9.68), and having tobacco user within family (AOR: 2.05, CI: 1.11-3.78) are more likely to use tobacco during pregnancy. CONCLUSION: Tobacco use during pregnancy was widely prevalent. Tobacco-focused interventions are required for antenatal women to promote cessation among user and prevent initiation with focus on overcoming problems like illiteracy, high parity, alcohol use, and having other tobacco user family members in family. PMID- 28634581 TI - Commentary: Surveillance of Crimean-Congo Haemorrhagic Fever in Pakistan. PMID- 28634582 TI - Cancer Stem Cells in Moderately Differentiated Lip Squamous Cell Carcinoma Express Components of the Renin-Angiotensin System. AB - AIM: We investigated the expression of the renin-angiotensin system (RAS) by cancer stem cell (CSC) subpopulations we have identified in moderately differentiated lip squamous cell carcinoma (MDLSCC). METHOD: Ten MDLSCC samples underwent 3,3-diaminobenzidine (DAB) and immunofluorescent immunohistochemical (IHC) staining for (pro)renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin II receptor 1 (ATIIR1), and receptor 2 (ATIIR2). NanoString analysis and Western blotting (WB) were performed on six MDLSCC samples for gene and protein expression, respectively. RESULTS: IHC staining showed expression of PRR, ATIIR1, and ATIIR2 on cells within the tumor nests (TNs) and the stroma. ACE was localized to the microvessels within the stroma. WB detected PRR, ACE, and ATIIR2. NanoString analysis confirmed gene expression of PRR, ACE, and ATIIR1. CONCLUSION: Components of the RAS: PRR, ATIIR1, and ATIIR2 are expressed on two CSC subpopulations in MDLSCC, one within the TNs and the other within the stroma. The endothelium of the microvessels within the stroma expresses ACE. PMID- 28634584 TI - Effect of Chitosan Edible Coating on the Biochemical and Physical Characteristics of Carp Fillet (Cyprinus carpio) Stored at -18 degrees C. AB - The effect of an edible coating (EC) with 1.5% chitosan as an additive, on common carp (Cyprinus carpio) fillet, was determined evaluating the biochemical, physicochemical, textural, microbiological, and nutritional characteristics periodically during its storage in the freezer (-18 degrees C), observing a decrease in the rate of biochemical reactions related to degradation (p < 0.05), hydroperoxides content (HPC) (0.8324 nM hydroperoxides/mg of protein versus 0.5540 nM/mg with regard to the EC sample), as well as protein carbonyl content (PCC) (0.5860 nM versus 0.4743 nM of reactive carbonyl groups/mg of protein of noncoated material), keeping properties for a longer period of time, and a lower protein solubility (7.8 mg of supernatant protein/mg of total protein versus 6.8 mg/mg) and less loss of moisture (8% less, with regard to EC); for the nutritional characteristics of the fillet, lysine is the limiting aminoacid in the sample without EC, while leucine is the limiting aminoacid for the EC sample. According to microbial growth, the count was 2.2 * 105 CFU/g of sample in mesophiles versus 4.7 * 104 in the EC sample. The results indicate that the use of EC added with chitosan maintains the quality of the product regarding lipid and protein oxidation until fourth month of storage, maintaining moisture content without variation for at least 3 months, and inhibits microbial growth up to 2 logarithmic units, during five months of frozen storage. PMID- 28634583 TI - Circular RNAs: Biogenesis, Function and Role in Human Diseases. AB - Circular RNAs (circRNAs) are currently classed as non-coding RNA (ncRNA) that, unlike linear RNAs, form covalently closed continuous loops and act as gene regulators in mammals. They were originally thought to represent errors in splicing and considered to be of low abundance, however, there is now an increased appreciation of their important function in gene regulation. circRNAs are differentially generated by backsplicing of exons or from lariat introns. Unlike linear RNA, the 3' and 5' ends normally present in an RNA molecule have been joined together by covalent bonds leading to circularization. Interestingly, they have been found to be abundant, evolutionally conserved and relatively stable in the cytoplasm. These features confer numerous potential functions to circRNAs, such as acting as miRNA sponges, or binding to RNA-associated proteins to form RNA-protein complexes that regulate gene transcription. It has been proposed that circRNA regulate gene expression at the transcriptional or post transcriptional level by interacting with miRNAs and that circRNAs may have a role in regulating miRNA function in cancer initiation and progression. circRNAs appear to be more often downregulated in tumor tissue compared to normal tissue and this may be due to (i) errors in the back-splice machinery in malignant tissues, (ii) degradation of circRNAs by deregulated miRNAs in tumor tissue, or (iii) increasing cell proliferation leading to a reduction of circRNAs. circRNAs have been identified in exosomes and more recently, chromosomal translocations in cancer have been shown to generate aberrant fusion-circRNAs associated with resistance to drug treatments. In addition, though originally thought to be non coding, there is now increasing evidence to suggest that select circRNAs can be translated into functional proteins. Although much remains to be elucidated about circRNA biology and mechanisms of gene regulation, these ncRNAs are quickly emerging as potential disease biomarkers and therapeutic targets in cancer. PMID- 28634585 TI - High Plasma Glucagon Levels Correlate with Waist-to-Hip Ratio, Suprailiac Skinfold Thickness, and Deep Subcutaneous Abdominal and Intraperitoneal Adipose Tissue Depots in Nonobese Asian Indian Males with Type 2 Diabetes in North India. AB - We aimed to correlate plasma glucagon levels with anthropometric measures and abdominal adipose tissue depots. Nonobese males (n = 81; BMI < 25 kg/m2) with T2DM of less than one-year duration and nonobese males without diabetes (n = 30) were evaluated for the following: anthropometry (BMI, waist circumference, W-HR, and truncal skinfolds), whole-body DEXA (for body fat and fat-free mass), and MRI scan (for volumes of subcutaneous abdominal adipose tissue (SCAT) including superficial and deep, intra-abdominal visceral adipose tissue (including intraperitoneal adipose tissue (IPAT), retroperitoneal adipose tissue, liver span and fatty liver, and pancreatic volume)). Plasma glucose and glucagon, serum insulin, hepatic transaminases, and lipid profile were measured. Significantly higher levels of fasting and postprandial glucagon (p < 0.001) and fasting and postprandial insulin (p < 0.001) were seen in patients with T2DM. The mean values of fasting and postprandial plasma glucagon levels were higher in T2DM patients with NAFLD (n = 37) as compared to T2DM patients without NAFLD (n = 44). Four independent predictors were derived for fasting glucagon levels in patients with T2DM, namely, W-HR, suprailiac skinfold thickness, IPAT, and deep SCAT (p < 0.05; r2 = 0.84). These observations in Asian Indians may have significance for diabetes therapies which impact glucagon levels. PMID- 28634586 TI - The Referral System between Primary and Secondary Health Care in Saudi Arabia for Patients with Type 2 Diabetes: A Systematic Review. AB - BACKGROUND: In Saudi Arabia, the mortality of diabetes is currently reported at 6%. A well-administered referral system is crucial in aiding the management of this disease. METHOD: A single reviewer employed a systematic approach to searching the literature databases with regard to the question: what are the attributes of referral systems in Saudi Arabia for patients with type 2 diabetes (T2D)? The results were analysed in order to provide recommendations to improve the Saudi health system. RESULTS: Twelve primary studies were identified from a systematic search. Overall, the 12 studies did not clearly mention any of the factors of a good referral system. The referral problems identified by this study included patients' unnecessary requests for referral, unstructured referral letters, and unclear dissemination guidelines for referral. CONCLUSIONS: This research attempted to identify the efficiency of the referral processes that were implemented for patients with T2D. The majority of the included studies were completely silent on the main referral factors for patients. If this review is representative of the referral system in Saudi Arabia, then, in the context of T2D, current referrals are unsafe. Further research on the quality of the referral system, taking into account at least some of the WHO referral guidelines, is required. PMID- 28634587 TI - Exercise Metabolism in Nonobese Patients with Type 2 Diabetes Following the Acute Restoration of Normoglycaemia. AB - This study investigated how acute restoration of normoglycaemia affected energy metabolism during exercise in nonobese patients with type 2 diabetes. Six subjects (mean +/- SEM) aged 56.2 +/- 2.7 years, with a BMI of 24.5 +/- 1.5 kg/m2 and a VO2 peak of 28.7 ml/kg/min, attended the lab on two randomised occasions for a four-hour resting infusion of insulin or saline, followed by 30 minutes cycling at 50% VO2 peak. During the 4 h resting infusion, there was a greater (P < 0.0001) reduction in blood glucose in insulin treatment (INS) (from 11.2 +/- 0.6 to 5.6 +/- 0.1 mmol/l) than in saline treatment/control (CON) (from 11.5 +/- 0.7 to 8.5 +/- 0.6 mmol/l). This was associated with a lower (P < 0.05) resting metabolic rate in INS (3.87 +/- 0.17) than in CON (4.39 +/- 0.30 kJ/min). During subsequent exercise, blood glucose increased significantly in INS from 5.6 +/- 0.1 at 0 min to 6.3 +/- 0.3 mmol/l at 30 min (P < 0.01), which was accompanied by a lower blood lactate response (P < 0.05). Oxygen uptake, rates of substrate utilization, heart rate, and ratings of perceived exertion were not different between trials. Insulin-induced normoglycaemia increased blood glucose during subsequent exercise without altering overall substrate utilization. PMID- 28634588 TI - Antitumor Effect of KML-B-Treated Dendritic Cells via Induction of Lymphocyte Activation. AB - Lectins are carbohydrate-binding proteins with various biological activities, such as antitumor and immunomodulatory effects. Although lectins have various biological activities, they are still limited by cytotoxicity in normal cells. To overcome this problem, we used the noncytotoxic part of Korean mistletoe lectin B chain (KML-B) to induce maturation of dendritic cells (DCs). A previous study reported that KML-B induces DC maturation by triggering TLR-4, including expression of costimulatory molecules (CD40, CD80, and CD86), MHC II, and secretion of cytokines in DCs. Additionally, matured DCs by KML-B induced T helper (Th) cell activation and differentiation toward Th1 cells. However, the interaction of KML-B-treated DCs with CD8+ T cells is still poorly understood. In this study, we confirmed the ability of matured DCs by KML-B to stimulate cytotoxic T cells using OT-1 mouse-derived CD8+ T cells. KML-B induced MHC I expression in DCs, stimulation of CD8+ T cell activation and proliferation, and IFN-gamma secretion. Moreover, tumor sizes were reduced by KML-B treatment during vaccination of OVA257-264-pulsed DCs. Here, we confirmed induction of CD8+ T cell activation and the antitumor effect of KML-B treatment in DCs. PMID- 28634590 TI - The Immune Epitope Database: How Data Are Entered and Retrieved. AB - Easy access to a vast collection of experimental data on immune epitopes can greatly facilitate the development of therapeutics and vaccines. The Immune Epitope Database and Analysis Resource (IEDB) was developed to provide such a resource as a free service to the biomedical research community. The IEDB contains epitope and assay information related to infectious diseases, autoimmune diseases, allergic diseases, and transplant/alloantigens for humans, nonhuman primates, mice, and any other species studied. It contains T cell, B cell, MHC binding, and MHC ligand elution experiments. Its data are curated primarily from the published literature and also include direct submissions from researchers involved in epitope discovery. This article describes the process of capturing data from these sources and how the information is organized in the IEDB data. Different approaches for querying the data are then presented, using the home page search interface and the various specialized search interfaces. Specific examples covering diverse applications of interest are given to highlight the power and functionality of the IEDB. PMID- 28634589 TI - HLA Class Ia and Ib Polyreactive Anti-HLA-E IgG2a Monoclonal Antibodies (TFL-006 and TFL-007) Suppress Anti-HLA IgG Production by CD19+ B Cells and Proliferation of CD4+ T Cells While Upregulating Tregs. AB - The anti-HLA-E IgG2a mAbs, TFL-006 and TFL-007, reacted with all HLA-I antigens, similar to the therapeutic preparations of IVIg. Indeed, IVIg lost its HLA reactivity, when its HLA-E reactivity was adsorbed out. US-FDA approved IVIg to reduce antibodies in autoimmune diseases. But the mechanism underlying IVIg mediated antibody reduction could not be ascertained due to the presence of other polyclonal antibodies. In spite of it, the cost prohibitive high or low IVIg is administered to patients waiting for donor organ and for allograft recipients for lowering antiallograft antibodies. A mAb that could mimic IVIg in lowering Abs, with defined mechanism of action, would be highly beneficial for patients. Demonstrably, the anti-HLA-E mAbs mimicked several functions of IVIg relevant to suppressing the antiallograft Abs. The mAbs suppressed activated T cells and anti HLA antibody production by activated B cells, which were dose-wise superior to IVIg. The anti-HLA-E mAb expanded CD4+, CD25+, and Foxp3+ Tregs, which are known to suppress T and B cells involved in antibody production. These defined functions of the anti-HLA-E IgG2a mAbs at a level superior to IVIg encourage developing their humanized version to lower antibodies in allograft recipients, to promote graft survival, and to control autoimmune diseases. PMID- 28634592 TI - Euglycemic Diabetic Ketoacidosis With Prolonged Glucosuria Associated With the Sodium-Glucose Cotransporter-2 Canagliflozin. AB - Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control by a reversible inhibition of the sodium-glucose cotransporters in the renal proximal tubules resulting in increased urinary glucose. This unique mechanism, independent of insulin secretion and beta cell function, has made this class of medication desirable in patients with type 2 diabetes. However in May 2015, the US Food and Drug Administration issued a safety warning pertaining to the development of diabetic ketoacidosis (DKA) with the use of SGLT2 inhibitors. DKA associated with SGLT2 inhibitors frequently develops in the absence of hyperglycemia, which makes the diagnosis more challenging. Due to the reversible inhibition of SGLT2 by this class of medication, a quick recovery of glucosuria after cessation of medication is expected. In this article, we present a case of a 50-year-old woman with type 2 diabetes who developed euglycemic DKA after initiating therapy with canagliflozin. This case of DKA associated with SGLT2 inhibitor use was unique due to her hypoglycemic presentation and persistent glucosuria. SGLT2 inhibitors such as canagliflozin may predispose patients not only to diabetic ketoacidosis but also to prolonged glucosuria. PMID- 28634591 TI - Examination of the Microbial Spectrum in the Etiology of Erythema Nodosum: A Retrospective Descriptive Study. AB - Even though infections are the most common cause of erythema nodosum (EN), only certain microorganisms take the great interest such as streptococci in knowledge. Our aim was to examine the frequency and type of infections in EN, to determine the characteristics of patients with an infectious etiology, and to discuss the role of these microbes in EN pathology in the context of their interactions with humans. Charts of 81 patients with EN who were seen between 2003 and 2017 were retrospectively reviewed. Identified etiological factors were classified into three groups: infectious, noninfectious, and idiopathic. While there were no significant demographic and clinical differences between the infectious and idiopathic groups, systemic symptoms (p = 0.034) and the number of EN lesions (p = 0.016) were significantly lower; the mean erythrocyte sedimentation rate was significantly higher (p = 0.049), but the mean aspartate aminotransferase value was significantly lower in the infectious group compared to the noninfectious group (p = 0.019). Besides streptococci, many other microbes, including the ones living on and inside us, were identified in the etiology of EN. There is a need for large-scale prospective studies involving control groups for a better understanding of the microbial immunopathology of EN. PMID- 28634593 TI - Carcinoid Heart Disease: Starting From Heart Failure. AB - Carcinoid syndrome is the constellation of symptoms mediated by humoral factors produced by some carcinoid tumors. It consists primarily of vasomotor symptoms, gastrointestinal hypermotility, hypotension, and bronchospasm, due to the production and release of vasoactive substances. Carcinoid heart disease occurs in more than 50% of patients with carcinoid syndrome; in some cases, it represents the initial manifestation of the disease. We report the case of a 75 year-old woman with a metastatic neuroendocrine tumor admitted to the emergency room for fatigue and heart failure. Transthoracic echocardiography showed severe tricuspid and pulmonic regurgitation suggesting carcinoid heart disease. A hypervascular retroperitoneal mass was found on abdominal computed tomography, which seemed to arise from the mesenteric artery, anteriorly to the abdominal aorta. Unfortunately, our patient was neither a candidate for mass resection nor for cardiac surgery due to advanced metastatic disease and poor clinical condition. Additionally, we performed a systematic literature review of carcinoid heart disease focusing on typical echocardiographic findings. PMID- 28634594 TI - Pancreatic Cancer Heralded by Worsening Glycemic Control: A Report of Two Cases. AB - Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. Since it is usually diagnosed at an advanced stage, its prognosis remains poor. The initial presentation varies according to the tumor location. The most common presenting signs are weight loss, jaundice, and pain. Several epidemiological, clinical, and experimental studies over the past 2 decades have shown that long-standing diabetes is a modest risk factor for pancreatic cancer. However, new-onset diabetes has also been observed to be an early manifestation of pancreatic cancer. We report 2 cases where worsening glycemic control led to the diagnosis of pancreatic cancer. PMID- 28634596 TI - Study on Drive System of Hybrid Tree Harvester. AB - Hybrid tree harvester with a 60 kW diesel engine combined with a battery pile could be a "green" forest harvesting and transportation system. With the new design, the diesel engine maintains a constant engine speed, keeping fuel consumption low while charging the batteries that drive the forwarder. As an additional energy saving method, the electric motors work as generators to charge the battery pile when the vehicle moves downhill. The vehicle is equipped with six large wheels providing high clearance over uneven terrain while reducing ground pressure. Each wheel is driven via a hub gear by its own alternating current motor, and each of the three wheel pairs can be steered independently. The combination of the diesel engine and six electric motors provides plenty of power for heavy lifting and pulling. The main component parameters of the drive system are calculated and optimized with a set of dynamics and simulated with AVL Cruise software. The results provide practical insights for the fuel tree harvester and are helpful to reduce the structure and size of the tree harvester. Advantage Environment provides information about existing and future products designed to reduce environmental impacts. PMID- 28634595 TI - Role of Repeat Muscle Compartment Pressure Measurements in Chronic Exertional Compartment Syndrome of the Lower Leg. AB - BACKGROUND: The diagnostic gold standard for diagnosing chronic exertional compartment syndrome (CECS) is a dynamic intracompartmental pressure (ICP) measurement of the muscle. The potential role of a repeat ICP (re-ICP) measurement in patients with persistent lower leg symptoms after surgical decompression or with ongoing symptoms after an earlier normal ICP is unknown. PURPOSE: To study whether re-ICP measurements in patients with persistent CECS like symptoms of the lower leg may contribute to the diagnosis of CECS after both surgical decompression and a previously normal ICP measurement. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Charts of patients who underwent re ICP measurement of lower leg compartments (anterior [ant], deep posterior [dp], and/or lateral [lat] compartments) between 2001 and 2013 were retrospectively studied. CECS was diagnosed on the basis of generally accepted cutoff pressures for newly onset CECS (Pedowitz criteria: ICP at rest >=15 mmHg, >=30 mmHg after 1 minute, or >=20 mmHg 5 minutes after a provocative test). Factors predicting recurrent CECS after surgery or after a previously normal ICP measurement were analyzed. RESULTS: A total of 1714 ICP measurements were taken in 1513 patients with suspected CECS over a 13-year observation period. In all, 201 (12%) tests were re-ICP measurements for persistent lower leg symptoms. Based on the proposed ICP cutoff values, CECS recurrence was diagnosed in 16 of 62 previously operated compartments (recurrence rate, 26%; 53 patients [64% female]; median age, 24 years; age range, 15-78 years). Recurrence rates were not different among the 3 lower leg CECS compartments (ant-CECS, 17%; dp-CECS, 33%; lat-CECS, 30%; chi2 = 1.928, P = .381). Sex (chi2 = 0.058, P = .810), age (U = 378, z = 1.840, P = .066), bilaterality (chi2 = 0.019, P = .889), and prefasciotomy ICP did not predict recurrence. Re-ICP measurements evaluating 20 compartments with previously normal ICP measurements (15 patients [53% female]; mean age, 31 +/- 10 years) detected CECS in 3 compartments (15%, all ant-CECS). CONCLUSION: Previous fasciotomy for lower leg CECS or previously normal muscle pressure (ICP) do not rule out CECS as a cause of persisting lower leg symptoms. Repeat ICP measurement may have a potential role in the evaluation of patients with persistent lower leg complaints. However, other reasons for lower leg exertional pain must always be considered prior to secondary surgery. PMID- 28634597 TI - Molecular Characterization of Salmonella from Human and Animal Origins in Uganda. AB - Sporadic Salmonella outbreaks with varying clinical presentations have been on the rise in various parts of Uganda. The sources of outbreaks and factors underlying the different clinical manifestation are curtailed by paucity of information on Salmonella genotypes and the associated virulence genes. This study reports molecular diversity of Salmonella enterica and their genetic virulence profiles among human and animal isolates. Characterization was done using Kauffman-White classification scheme and virulence genes analysis using multiplex PCR. Overall, 52% of the isolates belonged to serogroup D, 16% to serogroup E, 15% to poly F, H-S, and 12% to serogroup B. Serogroups A, C1, and C2 each consisted of only one isolate representing 5%. Virulence genes located on SPI-1 [spaN and sipB] and on SPI-2 [spiA] in addition to pagC and msgA were equally distributed in isolates obtained from all sources. Plasmid encoded virulence gene spvB was found in <5% of isolates from both human epidemic and animal origins whereas it occurred in 80% of clinical isolates. This study reveals that serogroup D is the predominant Salmonella serogroup in circulation and it is widely shared among animals and humans and calls for joint and coordinated surveillance for one health implementation in Uganda. PMID- 28634598 TI - Previously unrecognized behavioral phenotype in Gaucher disease type 3. AB - OBJECTIVE: To provide a comprehensive description of abnormal behaviors in patients with Gaucher disease type 3 (GD3) and relate these behaviors to demographic, neurodevelopmental, and neurologic characteristics. METHODS: Thirty four Egyptian patients with GD3 (mean age of 7.9 years) were enrolled in the study. They were selected based on parent report and/or physician observation of one or more abnormal behaviors documented in 2 settings and by 2 different individuals and/or by video recording. Behaviors were grouped into 4 categories: Crying/Withdrawal, Impatience/Overactivity, Anger/Aggression, and Repetitive Acts. Baseline and follow-up 6-12 monthly neurologic evaluations included IQ assessment and an EEG. All patients were receiving enzyme replacement therapy (30 60 IU/kg every 2 weeks) and were followed for periods of 3-10 years. RESULTS: Supranuclear palsy of horizontal gaze, and of both horizontal and vertical gaze, bulbar symptoms, seizures, convergent strabismus, abnormal gait, and neck retroflexion were present in 97.1%, 50%, 55.9%, 29.4%, 29.4%, 20.6%, and 4.4% of patients, respectively. The most abnormal behavioral features were excessive anger (88.2%) and aggression (64.7%), and both were significantly higher in males. Anger/Aggression scores were highly correlated with IQ but not with either EEG/Seizure status or neurologic signs. CONCLUSIONS: We describe behavioral problems with a unique pattern of excessive anger and aggression in patients with GD3. Defining these components using quantitative behavioral scoring methods holds promise to provide a marker of neurologic disease progression and severity. PMID- 28634599 TI - Editorial: Clinical dentistry is coming of age. PMID- 28634600 TI - Oral mucous membrane pemphigoid associated with hypothyroidism: A retrospective study and a case report. AB - OBJECTIVE: The purpose of the study was to evaluate the relationship between mucous membrane pemphigoid and a state of hypothyroidism. The study included analysis of the dental charts of 40 subjects with clinically and histologically confirmed diagnosis of mucous membrane pemphigoid and 35 age- and gender-matched subjects, from the same clinic, with no diagnosis of vesiculo-ulcerative lesions. RESULTS: Thirteen subjects from the pemphigoid group (32%) had a hypothyroid condition, compared to four subjects (11%) from the control group (P = .030). Within the mucous membrane pemphigoid subjects who had a history of hypothyroidism, 83% were females. Although cases of hypothyroidism and autoimmune blistering oral disorders such as lichen planus were described in the past, this is the first report of an association between mucous membrane pemphigoid and hypothyroidism. A case report describes a patient who presented with desquamative gingivitis and vesicular lesions, and was diagnosed with mucous membrane pemphigoid and Hashimoto's thyroiditis. CONCLUSION: The general dental provider should be familiar with mucous membrane pemphigoid and the potential association with hypothyroidism. Early diagnosis of hypothyroidism is significant because replacement may prevent a significant morbidity associated with this condition. Therefore, the general dental provider should be aware of oral conditions presented as desquamative gingivitis and their potential association with hypothyroidism. PMID- 28634601 TI - An annealing-free aqueous-processed anatase TiO2 compact layer for efficient planar heterojunction perovskite solar cells. AB - A facile aqueous-based fabrication scheme is developed for producing annealing free anatase TiO2 (AF-TiO2) films that exhibit efficient electron transport properties in planar heterojunction perovskite solar cells (PSCs). AF-TiO2 films are fabricated by spin coating on a substrate a colloidal solution of anatase TiO2 nanoparticles (NPs) prepared via a low temperature hydrolytic sol-gel method. The resultant AF-TiO2 films show low electrical resistance, high transmittance in the visible and near-infrared regions and facilitation of high quality perovskite film formation, which can be attributed to their homogeneous surface morphology and nanocrystallinity. The AF-TiO2 based PSCs achieve a power conversion efficiency (PCE) of 18.29 +/- 0.18%, showing significant improvement compared to the control PSCs (PCE = 11.33 +/- 0.32%) based on TiO2 films made by high-temperature annealing of amorphous TiO2 (HTA-TiO2). PMID- 28634602 TI - Recent advances in the computational chemistry of soft porous crystals. AB - Here we highlight recent progress in the field of computational chemistry of nanoporous materials, focusing on methods and studies that address the extraordinary dynamic nature of these systems: the high flexibility of their frameworks, the large-scale structural changes upon external physical or chemical stimulation, and the presence of defects and disorder. The wide variety of behavior demonstrated in soft porous crystals, including the topical class of metal-organic frameworks, opens new challenges for computational chemistry methods at all scales. PMID- 28634603 TI - High-resolution and multi-range particle separation by microscopic vibration in an optofluidic chip. AB - An optofluidic chip is demonstrated in experiments for high-resolution and multi range particle separation through the optically-induced microscopic vibration effect, where nanoparticles are trapped in loosely overdamped optical potential wells created with combined optical and fluidic constraints. It is the first demonstration of separating single nanoparticles with diameters ranging from 60 to 100 nm with a resolution of 10 nm. Nanoparticles vibrate with an amplitude of 3-7 MUm in the loosely overdamped potential wells in the microchannel. The proposed optofluidic device is capable of high-resolution particle separation at both nanoscale and microscale without reconfiguring the device. The separation of bacteria from other larger cells is accomplished using the same chip and operation conditions. The unique trapping mechanism and the superb performance in high-resolution and multi-range particle separation of the proposed optofluidic chip promise great potential for a diverse range of biomedical applications. PMID- 28634604 TI - Semithiobambus[6]uril is a transmembrane anion transporter. AB - Semithiobambus[6]uril is shown to be an efficient transmembrane anion transporter. Although all bambusuril analogs (having either O, S or N atoms in their portals) are excellent anion binders, only the sulfur analog is also an effective anion transporter capable of polarizing lipid membranes through selective anion uniport. This notable divergence reflects significant differences in the lipophilic character of the bambusuril analogs. PMID- 28634605 TI - Functionalised cyclodextrin-based metal-organic frameworks. AB - CD-MOF, an extended framework incorporating the C8 symmetric cyclic oligosaccharide, gamma-cyclodextrin (gamma-CD), is based on the coordination of alkali metal cations to alternating alpha-1,4-linked d-glucopyranosyl units on the primary and secondary faces of the gamma-CD tori. Here, we report the synthesis and characterisation of an amino-functionalised CD-MOF that is isostructural with pristine CD-MOF and adsorbs CO2 permanently. PMID- 28634606 TI - A new AIE multi-block polyurethane copolymer material for subcellular microfilament imaging in living cells. AB - A multi-block fluorescent amphiphilic polyurethane copolymer (TPE-PU), self assembling into hairy, water-soluble micelles, is used as a subcellular microfilament probe in living cells. PMID- 28634607 TI - A high throughput microfluidic platform for size-selective enrichment of cell populations in tissue and blood samples. AB - Numerous applications in biology and medicine require the efficient and reliable separation of cells for disease diagnosis, genetic analysis, drug screening, and therapeutics. In this work, we demonstrate a novel technology that integrates a passive and an active device to separate, enrich and release cells on-demand from a complex blood sample, or cancer cells derived from a tissue biopsy. We exploit the high throughput (>1 mL min-1), size-based sorting capability of the passive spiral inertial microfluidic (iMF) device to focus particles/cells towards an active lateral cavity acoustic transducer (LCAT) device for size-selective enrichment. We demonstrate that this platform is capable of efficiently (>90%) removing smaller cells, such as RBCs in a blood sample or smaller cancer cells in a heterogeneous cell line, and providing 44 000* enrichment from the remaining sample within 5 min of device operation. Finally, we use this platform for two applications: selective enrichment of the side-population of DU-145 cells from tissue biopsy and isolation of larger monocytes from blood. Our platform integrates the high throughput (processing rate) capacity of spiral iMF with the high selectivity of LCAT, thereby offering a unique route for highly-selective, label-free particle/cell sorting, with potential application in lab-on-chip platforms for liquid biopsy and diagnostics applications. PMID- 28634608 TI - Hexagonal boron nitride supported mesoSiO2-confined Ni catalysts for dry reforming of methane. AB - Based on the superior chemical and thermal stability of hexagonal boron nitride (h-BN), we design and synthesize h-BN supported mesoSiO2-confined Ni catalysts with a stable architecture. The as-prepared catalyst exhibits excellent coke- and sintering-resistance performance in the dry reforming of methane, and especially, there is almost no loss of activity even after a 100 h stability test due to the synergistic effects of the h-BN interface and Ni nanoparticles. PMID- 28634610 TI - Efficiently mapping structure-property relationships of gas adsorption in porous materials: application to Xe adsorption. AB - Designing better porous materials for gas storage or separations applications frequently leverages known structure-property relationships. Reliable structure property relationships, however, only reveal themselves when adsorption data on many porous materials are aggregated and compared. Gathering enough data experimentally is prohibitively time consuming, and even approaches based on large-scale computer simulations face challenges. Brute force computational screening approaches that do not efficiently sample the space of porous materials may be ineffective when the number of possible materials is too large. Here we describe a general and efficient computational method for mapping structure property spaces of porous materials that can be useful for adsorption related applications. We describe an algorithm that generates random porous "pseudomaterials", for which we calculate structural characteristics (e.g., surface area, pore size and void fraction) and also gas adsorption properties via molecular simulations. Here we chose to focus on void fraction and Xe adsorption at 1 bar, 5 bar, and 10 bar. The algorithm then identifies pseudomaterials with rare combinations of void fraction and Xe adsorption and mutates them to generate new pseudomaterials, thereby selectively adding data only to those parts of the structure-property map that are the least explored. Use of this method can help guide the design of new porous materials for gas storage and separations applications in the future. PMID- 28634609 TI - SNAr catalysis enhanced by an aromatic donor-acceptor interaction; facile access to chlorinated polyfluoroarenes. AB - Selective catalytic SNAr reaction of polyfluoroaryl C-F bonds with chloride is shown. Stoichiometric TMSCl makes the reaction exergonic and allows catalysis, which involves ground state elevation of chloride, aromatic donor-acceptor interactions, and stabilization of the Meisenheimer complex. Traditional cross coupling of the products is now possible and demonstrates the utility. PMID- 28634611 TI - Micro- and nano-patterned conductive graphene-PEG hybrid scaffolds for cardiac tissue engineering. AB - A lack of electrical conductivity and structural organization in currently available biomaterial scaffolds limits their utility for generating physiologically representative models of functional cardiac tissue. Here we report on the development of scalable, graphene-functionalized topographies with anisotropic electrical conductivity for engineering the structural and functional phenotypes of macroscopic cardiac tissue constructs. Guided by anisotropic electroconductive and topographic cues, the tissue constructs displayed structural property enhancement in myofibrils and sarcomeres, and exhibited significant increases in the expression of cell-cell coupling and calcium handling proteins, as well as in action potential duration and peak calcium release. PMID- 28634612 TI - Pd(0)-Catalyzed intramolecular arylative dearomatization of beta-naphthols. AB - An efficient Pd(0)-catalyzed intramolecular arylative dearomatization of beta naphthols is described. Using Q-Phos as a ligand, the arylative dearomatization reaction proceeded smoothly affording excellent yields and chemoselectivity even when the catalyst loading was reduced to 0.1 mol%. This method offers an efficient access to a series of structurally diverse spirocarbocycles. Preliminary investigation indicates that an enantioselective reaction is feasible in the presence of a chiral phosphoramidite ligand. PMID- 28634613 TI - Breathing-induced new phase transition in an MIL-53(Al)-NH2 metal-organic framework under high methane pressures. AB - The high pressure methane sorption tests on a flexible metal-organic framework [MIL-53(Al)-NH2] reveal a new phase transition to a large pore (lp) phase above 45 bar. The mixed-ligand strategy and pressure cycling tests are suggested to reduce the pressure requirement of such a phase transition for applications in natural gas storage. PMID- 28634614 TI - Detection of the circulating tumor DNAs in angioimmunoblastic T- cell lymphoma. AB - Recent genetic studies identified that the disease-specific G17V RHOA mutation, together with mutations in TET2, DNMT3A, and IDH2, is a hallmark of angioimmunoblastic T cell lymphomas (AITL). The diagnostic value of these mutations is now being investigated. Circulating tumor DNAs (ctDNAs) may offer a non-invasive testing for diagnosis and disease monitoring of cancers. To investigate whether these mutations are useful markers for ctDNAs in AITL and its related lymphomas, we performed targeted sequencing for TET2, RHOA, DNMT3A, and IDH2 in paired tumors and cell-free DNAs from 14 patients at diagnosis. Eighty three percent of mutations detected in tumors were also observed in cell-free DNAs. During the disease course, mutations were detectable in cell-free DNAs in a refractory case, while they disappeared in a chemosensitive case. These data suggest that the disease-specific gene mutations serve as sensitive indicators for ctDNAs and may also be applicable for non-invasive monitoring of minimal residual diseases in AITL. PMID- 28634615 TI - ABO genotype-phenotype discrepancy due to chimerism resolved by clonal separation. PMID- 28634617 TI - Liver transplantation for hepatocellular carcinoma. AB - Over the last several years, liver transplantation has evolved to become a widely used treatment for hepatocellular carcinoma (HCC). The criteria used were developed in order to have acceptable outcomes for transplant with survival similar to other indications for transplant. These criteria are discussed in detail along with alternate options, including surgical resection and downstaging of HCC in cirrhotics. Technical considerations of liver transplantation must be considered, and living donor liver transplant is a possibility for treatment. PMID- 28634616 TI - Lineage switch from B acute lymphoblastic leukemia to acute monocytic leukemia with persistent t(4;11)(q21;q23) and cytogenetic evolution under CD19-targeted therapy. PMID- 28634618 TI - CT and MRI findings in focal eosinophilic infiltration of the liver. AB - OBJECTIVES: To investigate the findings of computed tomography (CT) and magnetic resonance imaging (MRI) of focal eosinophilic infiltration (FEI) of the liver. METHODS: A retrospective study including 29 patients with confirmed FEI of the liver was performed. We evaluated the lesions' number, distribution, size, shape, margin, attenuation or signal intensity characteristics, the enhancement pattern, and some special features. Spearman correlation analysis was used to analyze the correlation between the number of lesions and the eosinophil counts in peripheral blood. RESULTS: In all, 108 lesions were detected in 29 cases, including two cases with single lesion and the remaining 27 cases with multiple lesions. The mean size of all lesions was 34 mm (range, from 3 to 61 mm). 95 (88%) lesions were located in subcapsular parenchyma or surrounding the portal vein. Most (66%) subcapsular lesions were wedge shaped and all lesions surrounding portal vein were round shaped. However, the hepatic parenchymal lesions were irregular or round shaped. All lesions showed ill-defined margins. On pre-contrast CT images, the lesions showed slightly low attenuation or iso-attenuating. On T1-weighted and T2-weighted images, the lesions were slightly iso-/hypointense and hyperintense, respectively. A total of 23 (79.3%) cases were gradually enhanced. Branches of portal vein went through the lesions in all cases; 12 had 'stripe sign' and 16 had 'halo ring sign.' Spearman analysis indicated a significant correlation between the number of lesions and the increased eosinophils in peripheral blood (r = 0.627, p = 0.0003). CONCLUSIONS: Special CT and MRI features and increased eosinophils may strongly suggest the diagnosis of FEI of the liver. PMID- 28634619 TI - Implementation of LI-RADS into a radiological practice. AB - Since its introduction in 2011, Liver Imaging Reporting and Data System (LI-RADS) has become an increasingly utilized method for radiologists to categorize lesions for hepatocellular carcinoma (HCC) in patients at risk (American College of Radiology, www.acr.org/quality-safety/resources/lirads 2016). This overview article presents insight into methods of incorporating LI-RADS into an existing clinical practice, highlighting concrete ways to establish this system as a mainstay in any radiologist's evidence-based armamentarium. We will focus on the importance of standardization to improve the value of our reporting. We will also discuss specific opportunities to favor adoption of LI-RADS including building a community of users composed of radiologists and referring physicians, forming a strategic vision, enlisting a team leader, overcoming barriers to adoption, communicating successes, integrating the system into the departmental culture, and learning from mistakes. The 2017 version of LI-RADS is the most recent update and is based on the most current medical imaging evidence. The details of these updates are described in other articles in this journal's edition. Efforts should be made to increase adherence and to enhance standardized use of LI-RADS internationally. Ultimately, the objective of LI-RADS is to prioritize patient care and optimize medical outcomes. PMID- 28634620 TI - New data on Neodiplostomum americanum Chandler and Rausch, 1947 (Digenea: Diplostomidae), in the Great Horned Owl Bubo virginianus Gmelin, 1788 and the Eastern Screech Owl Megascops asio Linnaeus, 1758 in Mississippi, USA. AB - Neodiplostomum americanum Chandler and Rausch, 1947 has been reported from six species of owls in North America. At present, there are no molecular data for this species and gene sequence data from Neodiplostomum Railliet, 1919 are limited. A freshly deceased specimen of the Great Horned Owl Bubo virginianus Gmelin, 1788 and a freshly deceased specimen of the Eastern Screech Owl Megascops asio Linnaeus, 1758 were collected in Oktibbeha County, Mississippi in 2014 and 2016, respectively. Neodiplostomum americanum were recovered from both hosts. Herein, updated morphological descriptions are supplemented with gene sequence data from conserved (18S, ITS1-5.8S, ITS2, and 28S rRNA) and fast-evolving (cytochrome c oxidase subunit 1 mtDNA) regions. Preliminary phylogenetic analysis of the genus based on cytochrome c oxidase subunit 1 gene sequence data supports the placement of N. americanum within a discrete phylogroup of the family Diplostomidae. The life history of N. americanum is unknown and currently limited to the description of the adult stage in avian hosts. The molecular data generated in this study offer insight into the phylogenetic placement of N. americanum within the Diplostomatidae and will aid in identifying different life stages in putative intermediate hosts. PMID- 28634621 TI - Role of MRI in predicting meniscal tear reparability. AB - OBJECTIVE: To elucidate the role of MRI in predicting meniscal tear reparability according to tear type and location in relation to vascular zones. MATERIALS AND METHODS: In this retrospective study, two readers evaluated 79 pre-surgical MRIs of meniscal tears arthroscopically treated with meniscectomy or meniscal repair. Tears were classified according to type into vertical, horizontal, radial, complex, flaps and bucket handle and were considered reparable if the distance measured from the tear to the menisco-capsular junction was less than or equal to 5 mm. Predictions were compared with the surgical procedure performed in arthroscopy. We assessed the diagnostic performance of MRI, agreement between MRI and arthroscopy, and interrater agreement. Then, we conducted an ROC analysis on the distances measured by the first reader and built a multivariate logistic regression model. RESULTS: MRI had a sensitivity, specificity, PPV, NPV and accuracy, respectively, of 85%, 79%, 86%, 76% and 83% in predicting meniscal tear reparability. Correct predictions for the specific tear pattern were 76% for vertical, 84% for horizontal, 88% for radial, 86% for complex, 84% for flaps and 86% for bucket handle. Agreement between the two readers' predictions and arthroscopy was good (k = 0.65 and 0.61, respectively). Inter-rater agreement was almost excellent (k = 0.79). The ROC analysis revealed sensitivity and specificity of 73% and 83% with a cutoff value of <4 mm (p < 0.001). Anterior cruciate ligament injury and medial meniscal tear increased the likelihood of meniscal tear reparability. CONCLUSIONS: MRI can be a reliable and accurate tool to predict the reparability of meniscal tears, with higher prediction rates for bucket-handle tears. PMID- 28634622 TI - Burned-out seminoma revealed by solitary rib bone metastasis. AB - Burned-out tumor is a rare phenomenon in which a testicular tumor regresses in the primary lesion and progresses in a metastatic lesion. We report the case of a 30-year-old male with burned-out seminoma revealed by open biopsy of solitary 10th rib bone metastasis. He underwent inguinal orchiectomy, which revealed hyalinization, indicating a spontaneously regressed testicular tumor. Chemotherapy for seminoma was administered in three cycles of bleomycin + etoposide + cisplatin therapy. The chemotherapy was effective, and wide resection of the rib was subsequently performed. No postoperative chemotherapy was performed, and there has been no evidence of recurrence for 3 years postoperatively. PMID- 28634623 TI - Knot integrity using different suture types and different knot-tying techniques for reconstructive pelvic floor procedures. AB - INTRODUCTION AND HYPOTHESIS: Surgeons use a variety of sutures and knot-tying methods during pelvic reconstructive procedures. We hypothesized that knot strength integrity will be similar with regards to type of knot, type of suture, and the knot-tying process. METHODS: Using six different suture materials, flat square knots and slip knots were tied robotically and by hand by two surgeons. Knot integrity was evaluated using an Instron 5544 machine. We measured force and elongation at suture failure or knot slippage (whichever came first) as well as force at 3-mm displacement. RESULTS: Four hundred and thirty-two knots were tie; one unraveled before the analysis, and 431 were tested. Three hundred and ninety two knots reached or surpassed tensile strength of 30 N, the force at which tissue itself will fail. Knots tied with polyglyconate suture achieved the greatest tensile strength and those with OO-polydioxanone had the lowest. Hand tied knots, regardless of technique and suture material, had greater tensile strength but greater elongation than robotically tied knots. Slip knots and flat square knots have similar integrity regardless of the tying technique. CONCLUSION: Hand-tied knots had greater tensile strength than robotic knots, but the strength to break all knots required supraphysiological conditions. The decision to use a specific type of suture based on strength is not supported by our results, suggesting that surgeons may choose sutures based on other characteristics and personal comfort. PMID- 28634624 TI - Population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space. AB - Animal models of the rhesus macaque (Macaca mulatta), the most widely used nonhuman primate, have been irreplaceable in neurobiological studies. However, a population-averaged macaque brain diffusion tensor imaging (DTI) atlas, including comprehensive gray and white matter labeling as well as bony and facial landmarks guiding invasive experimental procedures, is not available. The macaque white matter tract pathways and microstructures have been rarely recorded. Here, we established a population-averaged macaque brain atlas with high-resolution ex vivo DTI integrated into in vivo space incorporating bony and facial landmarks, and delineated microstructures and three-dimensional pathways of major white matter tracts in vivo MRI/DTI and ex vivo (postmortem) DTI of ten rhesus macaque brains were acquired. Single-subject macaque brain DTI template was obtained by transforming the postmortem high-resolution DTI data into in vivo space. Ex vivo DTI of ten macaque brains was then averaged in the in vivo single-subject template space to generate population-averaged macaque brain DTI atlas. The white matter tracts were traced with DTI-based tractography. One hundred and eighteen neural structures including all cortical gyri, white matter tracts and subcortical nuclei, were labeled manually on population-averaged DTI-derived maps. The in vivo microstructural metrics of fractional anisotropy, axial, radial and mean diffusivity of the traced white matter tracts were measured. Population averaged digital atlas integrated into in vivo space can be used to label the experimental macaque brain automatically. Bony and facial landmarks will be available for guiding invasive procedures. The DTI metric measurements offer unique insights into heterogeneous microstructural profiles of different white matter tracts. PMID- 28634625 TI - Serum antioxidant capacity, biochemical profile and body composition of breast cancer survivors in a randomized Mediterranean dietary intervention study. AB - PURPOSE: Increasing evidence suggests that Mediterranean Diet (MD) is correlated with reduced risk of breast cancer (BC) and cancer mortality, since it modifies patients' serum antioxidant capacity, body composition and biochemical parameters. The aim of the study was to investigate whether a dietary intervention based on MD has a beneficial effect on these factors. METHODS: In this intervention study, seventy female BC survivors were randomly assigned to (1) the intervention group (personalized dietary intervention based on MD) and (2) the control group (received the updated American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention and ad libitum diet). Both groups were assessed twice [beginning, end of study (after 6 months)] regarding their anthropometric and biochemical parameters, serum vitamin C, vitamin A, a tocopherol and CoQ10 levels, dietary intake and adherence to MD. An additional intermediate analysis was conducted on participants' body composition and biochemical profile. RESULTS: Concerning the intervention group, body weight, body fat mass, waist circumference, body mass index as well as HDL-cholesterol were significantly decreased (P < 0.2%). An increase was observed in the vitamin C levels in blood (P < 0.2%). In the control group, body weight, body fat mass and serum total cholesterol rose (P < 0.2%). At the end of the study the two groups were significantly different considering blood glucose, vitamin C, polyunsaturated fatty acids, vitamin A and a-tocopherol levels. CONCLUSIONS: This randomized dietary intervention based on MD managed to ameliorate serum antioxidant capacity, body composition, adherence to MD and glycemic profile of postmenopausal BC survivors. PMID- 28634626 TI - Hepatic shear wave elastography in children under free-breathing and breath-hold conditions. AB - OBJECTIVES: To compare hepatic 2D shear wave elastography (2D SWE) in children between free-breathing and breath-hold conditions, in terms of measurement agreement and time expenditure. METHODS: A cohort of 57 children (12.7+/-4.3 years) who underwent standardized 2D SWE between May and October 2015 were retrospectively evaluated. Liver elastograms were obtained under free-breathing and breath-hold conditions and time expenditure was measured. Median stiffness, interquartile range (IQR), and IQR/median ratio were calculated based on 12, six, and three elastograms. Results were compared using Pearson correlation coefficient, intraclass correlation coefficient (ICC), Bland-Altman analysis, and Student's t. RESULTS: Median liver stiffness under free-breathing and breath-hold conditions correlated strongly (7.22+/-4.5kPa vs. 7.21+/-4.11kPa; r=0.97, P<0.001). Time to acquire 12 elastograms with free-breathing was lower than that with breath-holding (79.3+/-32.5sec vs. 143.7+/-51.8sec, P<0.001). Results for median liver stiffness based of 12, six, and three elastograms demonstrated very high agreement for free-breathing (ICC 0.993) and for breath-hold conditions (ICC 0.994). CONCLUSIONS: Hepatic 2D SWE performed with free-breathing yields results similar to the breath-hold condition. With a substantially lower time requirement, which can be further reduced by lowering the number of elastograms, the free-breathing technique may be suitable for infants and less cooperative children not capable of breath-holding. KEY POINTS: * Hepatic 2D SWE performed with free-breathing yields results similar to breath-hold condition. * Benefit of the free-breathing approach is the substantially lower time requirement. * Lowering the number of elastograms can further reduce time expenditure. * Free breathing 2D SWE is suitable in children with suspected liver disease. PMID- 28634627 TI - Influence of multiple stapler firings used for rectal division on colorectal anastomotic leak rate. AB - BACKGROUND: Anastomotic leakage following colorectal resection remains one of the most significant complications with relevant morbidity and mortality. There is evidence that a higher number of stapler firings for rectal division can affect the leak rate in double stapling anastomosis. However, there are no data concerning compression anastomosis. We present our institutional experience addressing this issue. DESIGN: This is a retrospective review of a prospective institutional database of patients undergoing colonic and rectal resection for benign and malignant indications between January 2008 and December 2014 at the surgical department of the St. John of God Hospital, Vienna. Inclusion criteria were rectal division with linear stapling devices and construction of anastomosis to the rectal stump using a circular stapler or compression device. RESULTS: Three hundred eighty two (196 female; 51.3%) patients were included. Mean age was 65.8 years (range: 18-95) Indications for the operation included diverticular disease (44.8%), colorectal carcinoma (51.6%), inflammatory bowel disease (1.8%), and adenoma (1.8%). A laparoscopic approach was employed in 334 cases (87.4%); in 170 patients (44.9%), a compression anastomosis was created. One, two, and three or more stapler cartridges were used for rectal division in 58.4, 33.5, and 8.1%, respectively. Male gender, neoadjuvant therapy, rectal cancer as an underlying disease, laparoscopic surgical approach, and duration of operation longer than 200 min are leading causes for the usage of more than one stapler cartridge. Overall leak rate was 4.7% (18/382). The only factor associated with the occurrence of leakage was the use of three or more stapler cartridges for the closure of the rectal stump (p = 0.002). CONCLUSION: Our data support that multiple stapler firings for rectal division following colorectal resection has a major impact on anastomotic leak rate. Especially in laparoscopic surgery efforts should be made to minimize the number of stapler cartridges used. PMID- 28634629 TI - Medical malpractice claims in laparoscopic gynecologic surgery: a Dutch overview of 20 years. AB - BACKGROUND: The success of newly introduced surgical techniques is generally primarily assessed by surgical outcome measures. However, data on medical liability should concomitantly be used to evaluate provided care as they give a unique insight into substandard care from patient's point of view. The aim of this study was to analyze the number and type of medical claims after laparoscopic gynecologic procedures since the introduction of advanced laparoscopy two decades ago. Secondly, our objective was to identify trends and/or risk factors associated with these claims. METHODS: To identify the claims, we searched the databases of the two largest medical liability mutual insurance companies in The Netherlands (MediRisk and Centramed), covering together 96% of the Dutch hospitals. All claims related to laparoscopic gynecologic surgery and filed between 1993 and 2015 were included. RESULTS: A total of 133 claims met our inclusion criteria, of which 54 were accepted claims (41%) and 79 rejected (59%). The number of claims remained relatively constant over time. The majority of claims were filed for visceral and/or vascular injuries (82%), specifically to the bowel (40%) and ureters (20%). More than one third of the injuries were entry related (38%) and 77% of the claims were filed after non-advanced procedures. A delay in diagnosing injuries was the primary reason for financial compensation (33%). The median sum paid to patients was ?12,000 (500-848,689). In 90 claims, an attorney was defending the patient (83% for the accepted claims; 57% for the rejected claims). CONCLUSION: The number of claims remained relatively constant during the study period. Most claims were provoked by bowel and ureter injuries. Delay in recognizing injuries was the most encountered reason for granting financial compensation. Entering the abdominal cavity during laparoscopy continues to be a potential dangerous step. As a result, gynecologists are recommended to thoroughly counsel patients undergoing any laparoscopic procedure, even regarding the risk of entry-related injuries. PMID- 28634628 TI - Standardizing hysteroscopy teaching: development of a curriculum using the Delphi method. AB - BACKGROUND: Hysteroscopy is performed often and in many indications but is challenging to learn. Hands-on training in live patients faces ethical, legal, and economic obstacles. Virtual reality simulation may hold promise as a hysteroscopy training tool. No validated curriculum specific in hysteroscopy exists. The aim of this study was to develop a hysteroscopy curriculum, using the Delphi method to identify skill requirements. METHODS: Based on a literature review using the key words "curriculum," "simulation," and "hysteroscopy," we identified five technical and non-technical areas in which skills were required. Twenty hysteroscopy experts from different French hospital departments participated in Delphi rounds to select items in these five areas. The rounds were to be continued until 80-100% agreement was obtained for at least 60% of items. A curriculum was built based on the selected items and was evaluated in residents. RESULTS: From November 2014 to April 2015, 18 of 20 invited experts participated in three Delphi rounds. Of the 51 items selected during the first round, only 25 (49%) had 80-100% agreement during the second round, and a third round was therefore conducted. During this last round, 80-100% agreement was achieved for 31 (61%) items, which were used to create the curriculum. All 14 residents tested felt that a simulator training session was acceptable and helped them to improve their skills. CONCLUSIONS: We describe a simulation-based hysteroscopy curriculum focusing on skill requirements identified by a Delphi procedure. Its development allows standardization of training programs offered to residents. PMID- 28634630 TI - Development and validation of a tool for non-technical skills evaluation in robotic surgery-the ICARS system. AB - BACKGROUND: Non-technical skills (NTS) are being increasingly recognised as vital for safe surgical practice. Numerous NTS rating systems have been developed to support effective training and assessment. Yet despite the additional challenges posed by robotic surgery, no NTS rating systems have been developed for this unique surgical environment. This study reports the development and validation of the first NTS behavioural rating system for robotic surgery. METHODS: A comprehensive index of all relevant NTS behaviours in robotic surgery was developed through observation of robotic theatre and interviews with robotic surgeons. Using a Delphi methodology, a panel of 16 expert surgeons was consulted to identify behaviours important to NTS assessment. These behaviours were organised into an appropriate assessment template. Experts were consulted on the feasibility, applicability and educational impact of ICARS. An observational trial was used to validate ICARS. 73 novice, intermediate and expert robotic surgeons completed a urethrovesical anastomosis within a simulated operating room. NTS were tested using four scripted scenarios of increasing difficulty. Performances were video recorded. Robotic and NTS experts assessed the videos post hoc using ICARS and the standard behavioural rating system, NOn-Technical Skills for Surgeons (NOTSS). RESULTS: 28 key non-technical behaviours were identified by the expert panel. The finalised behavioural rating system was organised into four principle domains and seven categories. Expert opinion strongly supported its implementation. ICARS was found to be equivalent to NOTSS on Bland-Altman analysis and accurately differentiated between novice, intermediate and expert participants, p = 0.01. Moderate agreement was found between raters, Krippendorff's alpha = 0.4. The internal structure of ICARS was shown to be consistent and reliable (median Cronbach alpha = 0.92, range 0.85 0.94). CONCLUSION: ICARS is the first NTS behavioural rating system developed for robotic surgery. Initial validation has shown it to be an effective and reliable tool. Implementation of ICARS will supported structured training and assessment of NTS within the robotic surgical curriculum. PMID- 28634631 TI - SAGES University MASTERS Program: a structured curriculum for deliberate, lifelong learning. AB - BACKGROUND: Postgraduate training has been haphazard to date. Surgeons have relied on attendance to annual meetings and multiple choice study guides to demonstrate maintenance of certification and continuing medical education. METHODS: SAGES held a retreat to develop the concept and scope of the Masters Program. Surveys were sent to SAGES members to guide curriculum development and selection of anchoring operations. RESULTS: SAGES has developed an educational curriculum across eight domains (Acute Care, Biliary, Bariatric, Colorectal, Hernia, Foregut, Flex Endoscopy, and Robotic Surgery) incorporating SAGES educational materials and guidelines, social media, coaching and mentoring. CONCLUSIONS: Deliberate, lifelong learning should be a better way to teach and learn. PMID- 28634633 TI - Erratum to: Nd:YAG laser irradiation associated with fluoridated gels containing photo absorbers in the prevention of enamel erosion. PMID- 28634632 TI - Can a virtual reality surgical simulation training provide a self-driven and mentor-free skills learning? Investigation of the practical influence of the performance metrics from the virtual reality robotic surgery simulator on the skill learning and associated cognitive workloads. AB - BACKGROUND: While it is often claimed that virtual reality (VR) training system can offer self-directed and mentor-free skill learning using the system's performance metrics (PM), no studies have yet provided evidence-based confirmation. This experimental study investigated what extent to which trainees achieved their self-learning with a current VR simulator and whether additional mentoring improved skill learning, skill transfer and cognitive workloads in robotic surgery simulation training. METHODS: Thirty-two surgical trainees were randomly assigned to either the Control-Group (CG) or Experiment-Group (EG). While the CG participants reviewed the PM at their discretion, the EG participants had explanations about PM and instructions on how to improve scores. Each subject completed a 5-week training using four simulation tasks. Pre- and post-training data were collected using both a simulator and robot. Peri-training data were collected after each session. Skill learning, time spent on PM (TPM), and cognitive workloads were compared between groups. RESULTS: After the simulation training, CG showed substantially lower simulation task scores (82.9 +/- 6.0) compared with EG (93.2 +/- 4.8). Both groups demonstrated improved physical model tasks performance with the actual robot, but the EG had a greater improvement in two tasks. The EG exhibited lower global mental workload/distress, higher engagement, and a better understanding regarding using PM to improve performance. The EG's TPM was initially long but substantially shortened as the group became familiar with PM. CONCLUSION: Our study demonstrated that the current VR simulator offered limited self-skill learning and additional mentoring still played an important role in improving the robotic surgery simulation training. PMID- 28634634 TI - Pain and fracture-related limitations persist 6 months after a fragility fracture. AB - Our objective was to examine the experience of pain after a fracture beyond the conventional healing duration of 6 months. We conducted a phenomenological study in participants who were deemed high risk for future fracture and recruited through an urban fracture clinic in Toronto, Canada. In-depth interviews were conducted with questions addressing the experience of pain, the status of recovery from the fracture, ways in which the fracture affected one's daily activities, and interactions with health care providers. Two researchers coded the transcripts within the phenomenological perspective to develop a structure of the pain experience, promoting rigour through the use of multiple analysts, searching for negative cases, and supporting claims with direct quotations from participants. We interviewed 21 participants who had sustained fractures of the wrist (n = 4), hip (n = 6), vertebrae (n = 2), and multiple or other locations (n = 9). All patients were ambulatory, had a range of socioeconomic status, and lived in the community. Eleven of the 21 participants reported persistent pain at the site of the fracture. Of the 10 participants who reported no pain, four indicated they had ongoing difficulties with range of motion and specific activities and two others described persistent pain from a previous fracture or reliance on a scooter for mobility. Our study demonstrated that over two-thirds of older adults reported fracture-related pain and/or limitations at, or beyond, 6 months post-fracture. We suggest that health care providers ask questions about post-fracture pain and/or limitations when assessing fracture status beyond 6 months. PMID- 28634635 TI - Erratum to: Long-term success of dental implant-supported dentures in postirradiated patients treated for neoplasms of the maxillofacial skeleton: a retrospective study. PMID- 28634636 TI - Farmers' Willingness to Adopt Conservation Agriculture: New Evidence from Lebanon. AB - With increasing food insecurity and climate change, conservation agriculture has emerged as a sustainable alternative to intensive conventional agriculture as a source of food supply. Yet the adoption rate of conservation agriculture is still low. Our paper analyses the factors affecting farmers' willingness to adopt conservation agriculture in Lebanon. The findings show that household characteristics-years of farming and farm size affect conservation agriculture adoption. However, household characteristics alone were insufficient to explain conservation agriculture adoption. We found that farming experience, information sources, frequency of irrigation, and severity of weed infestation in the past, participation in specific trainings, and farmers' perception about the long-term impact of conservation agriculture, were key determinants of conservation agriculture adoption. Our paper encourages policymakers to invest in conservation agriculture to overcome food insecurity and environmental changes affecting food systems in the Middle East. The paper also informs agribusiness firms to view conservation agriculture as a viable alternative to strengthen their business relationship with farmers in arid and semi-arid regions. PMID- 28634637 TI - Managing neurogenic orthostatic hypotension with droxidopa in a patient with Parkinson disease, atrial fibrillation, and hypertension. PMID- 28634638 TI - Co-existence of Anaerobic Ammonium Oxidation Bacteria and Denitrifying Anaerobic Methane Oxidation Bacteria in Sewage Sludge: Community Diversity and Seasonal Dynamics. AB - Anaerobic ammonium oxidation (ANAMMOX) and denitrifying anaerobic methane oxidation (DAMO) have been recently discovered as relevant processes in the carbon and nitrogen cycles of wastewater treatment plants. In this study, the seasonal dynamics of ANAMMOX and DAMO bacterial community structures and their abundance in sewage sludge collected from wastewater treatment plants were analysed. Results indicated that ANAMMOX and DAMO bacteria co-existed in sewage sludge in different seasons and their abundance was positively correlated (P < 0.05). The high abundance of ANAMMOX and DAMO bacteria in autumn and winter indicated that these seasons were the preferred time to favour the growth of ANAMMOX and DAMO bacteria. The community structure of ANNAMOX and DAMO bacteria could also shift with seasonal changes. The "Candidatus Brocadia" genus of ANAMMOX bacteria was mainly recovered in spring and summer, and an unknown cluster was primarily detected in autumn and winter. Similar patterns of seasonal variation in the community structure of DAMO bacteria were also observed. Group B was the dominant in spring and summer, whereas in autumn and winter, group A and group B presented almost the same proportion. The redundancy analysis revealed that pH and nitrate were the most significant factors affecting community structures of these two groups (P < 0.01). This study reported the diversity of ANAMMOX and DAMO in wastewater treatment plants that may be the basis for new nitrogen removal technologies. PMID- 28634639 TI - The Curious Case of Achromobacter eurydice, a Gram-Variable Pleomorphic Bacterium Associated with European Foulbrood Disease in Honeybees. AB - Honeybees are prone to parasite and pathogen infestations/infections due to their social colony life. Bacterial pathogens in particular lead to destructive infections of the brood. European foulbrood is caused by the bacterium Melissococcus plutonius in combination with several other Gram-positive bacteria (Achromobacter eurydice, Bacillus pumilus, Brevibacillus laterosporus, Enterococcus faecalis, Paenibacillus alvei, Paenibacillus dendritiformis) involved as secondary invaders following the initial infection. More than a century ago, A. eurydice was discovered to be associated with European foulbrood and morphologically and biochemically characterized. However, since the 1950s 1960s, only a few studies are known covering the biological relevance of this bacterium. Here, we review the biology, ecology, morphology, and biochemistry and discuss the still unclear systematic classification of A. eurydice. PMID- 28634640 TI - The Microbiome of Eucalyptus Roots under Different Management Conditions and Its Potential for Biological Nitrogen Fixation. AB - Eucalyptus plantations offer a cost-effective and renewable source of raw material. There is substantial interest in improving forestry production, especially through sustainable strategies such as the use of plant growth promoting bacteria. However, little is known about Eucalyptus microbiology. In this study, the endophytic bacterial community was assessed in Eucalyptus urograndis roots using culture-dependent and culture-independent techniques with plants grown under different conditions. Three phyla accounted for approximately 95% of the community, with Actinobacteria corresponding to approximately 59%. This contrasts with previous studies in which Actinobacteria accounted for only 5 to 10%. Our data also revealed a high diversity of bacteria, with 359 different genera but a high level of dominance. Six genera, Mycobacterium, Bradyrhizobium, Streptomyces, Bacillus, Actinospica, and Burkholderia, accounted for more than 50% of the classified sequences. We observed a significant influence of the treatments on some genera, causing changes in the bacterial community structure. The obtained data also suggest that Eucalyptus may benefit from biological nitrogen fixation, with many abundant genera being closely related to nitrogen fixing bacteria. Using N-depleted media, we also cultured 95 bacterial isolates, of which 24 tested positive for the nifH gene and were able to maintain growth without any N source in the medium. PMID- 28634641 TI - A novel technique for ultrasound-guided central venous catheterization under short-axis out-of-plane approach: "stepwise flashing with triangulation". AB - In ultrasound-guided central venous catheterization, there is no standard technique either for the needle tip visualization or for the adequate needle angle and entry to the skin with short-axis view under out-of-plane technique. In the present study, we propose a novel technique named "stepwise flashing with triangulation", and the efficacy of this technique is assessed. Before and after a didactic session in which the technique was explained, 12 novice residents were asked to position the needle tip on or into the imitation vessels and to avoid deeper penetration by using an agar tissue phantom with ultrasound guidance. "Stepwise flashing" technique was for stepwise visualization of the needle tip, and "triangulation" technique was for adequate needle angle and entry to the skin. After the session, the success rate was increased and a deeper penetration rate was decreased. This technique will help us to facilitate vascular access and to avoid complications in clinical settings. PMID- 28634642 TI - Determinants of change in polypharmacy status in Switzerland: the population based CoLaus study. AB - OBJECTIVES: This study aimed to assess the prevalence, the change, and the determinants of change in polypharmacy in a population-based sample. METHODS: Baseline (2003-2006) and follow-up (2009-2012) data are from 4679 participants aged between 35 and 75 years (53.5% women, mean age 52.6 +/- 10.6 years) from the population of Lausanne, Switzerland. Polypharmacy was defined by the regular use of >=5 drugs. Four categories of change were defined: never (no polypharmacy at baseline and follow-up), initiating (no polypharmacy at baseline but at follow up), maintaining, or quitting. RESULTS: Polypharmacy increased from 7.7% at baseline to 15.3% at follow-up. Cardiovascular drugs were the most prescribed medicines at baseline and follow-up. Gender, age, obesity, smoking, previously diagnosed hypertension, or diabetes or dyslipidemia were significantly and independently associated with initiating and maintaining polypharmacy. CONCLUSION: In a population-based sample, prevalence of polypharmacy doubled over a 5.6-year period. The main determinants of initiating polypharmacy were age, overweight and obesity, smoking status, and previously diagnosed cardiovascular risk factors. PMID- 28634643 TI - Acute high-caffeine exposure increases autophagic flux and reduces protein synthesis in C2C12 skeletal myotubes. AB - Caffeine is a highly catabolic dietary stimulant. High caffeine concentrations (1 10 mM) have previously been shown to inhibit protein synthesis and increase protein degradation in various mammalian cell lines. The purpose of this study was to examine the effect of short-term caffeine exposure on cell signaling pathways that regulate protein metabolism in mammalian skeletal muscle cells. Fully differentiated C2C12 skeletal myotubes either received vehicle (DMSO) or 5 mM caffeine for 6 h. Our analysis revealed that caffeine promoted a 40% increase in autolysosome formation and a 25% increase in autophagic flux. In contrast, caffeine treatment did not significantly increase the expression of the skeletal muscle specific ubiquitin ligases MAFbx and MuRF1 or 20S proteasome activity. Caffeine treatment significantly reduced mTORC1 signaling, total protein synthesis and myotube diameter in a CaMKKbeta/AMPK-dependent manner. Further, caffeine promoted a CaMKII-dependent increase in myostatin mRNA expression that did not significantly contribute to the caffeine-dependent reduction in protein synthesis. Our results indicate that short-term caffeine exposure significantly reduced skeletal myotube diameter by increasing autophagic flux and promoting a CaMKKbeta/AMPK-dependent reduction in protein synthesis. PMID- 28634645 TI - Comparative Evaluation of Preliminary Screening Methods for Colorectal Cancer in a Mass Program. AB - BACKGROUND: The fecal immunochemical test (FIT) has been widely used in preliminary screening for colorectal cancer (CRC). The high-risk factor questionnaire (HRFQ) and quantitative risk-assessment method (QRAM) are recommended for estimating the risk of CRC qualitatively and quantitatively in China. AIM: We aimed to prospectively compare the diagnostic values of CRC preliminary screening methods to identify which method is preferable as a screening strategy. METHODS: Individuals aged 40-74 years old were enrolled in a mass CRC screening program from January 1, 2007 to December 31, 2014, in Jiashan County, Zhejiang Province, China. FIT of two stool specimens at 1-week intervals was performed by laboratory personnel and face-to-face interviews were conducted by trained investigators. Screening data in the program were linked to a CRC surveillance and registry system, and CRC cases reported in the system were regarded as true patients. RESULTS: A total of 96,043 subjects were included. The sensitivity and specificity of FIT for detecting CRC cases were 75.49% (95% CI 69.84-80.39) and 90.36% (95% CI 90.17-90.54), respectively. QRAM was more sensitive (p < 0.001) and less specific (p < 0.001) than HRFQ. The sensitivity and specificity of FIT along with HRFQ were 86.56% (95% CI 81.81-90.22) and 81.37% (95% CI 81.12-81.62), and those of FIT along with QRAM were 88.93% (95% CI 84.47-92.23) and 73.95% (95% CI 73.67-74.23). CONCLUSIONS: Our findings suggest that CRC preliminary screening with FIT and QRAM in parallel has high sensitivity and satisfactory specificity, and is a useful strategy in mass screening programs. PMID- 28634644 TI - Minimal Clinically Important Differences (MCID) in Assessing Outcomes of Post Traumatic Stress Disorder. AB - This study sought to determine the minimal clinically important difference (MCID) for two frequently used measures of symptom severity in Post-Traumatic Stress Disorder: the Clinician Administered PTSD Scale (CAPS) and the PTSD Symptom Checklist (PCL). Data from a randomized clinical trial of antipsychotic medication in military-related treatment-resistant PTSD (N= 267) included assessments 4 times over 26 weeks. Methods for estimating the MCID were based on both the anchor-based approach, using the Clinical Global Impressions (CGI) severity and improvement scales, rated by both clinicians and patients; and the distribution-based approach (based on standardized z-scores). Severity and change scores on the CAPS and PCL were converted to z-scores and compared across CGI levels using analysis of variance. The average difference in CAPS z-scores between each of three CGI levels between "moderate" to "severe" and from "no change" to "much improved" was 0.758 for clinician CGI ratings and 0.525 for patient CGI ratings and were similar for the PCL (0.483 and 0.471) with all differences significant at p<.0001). Clinically meaningful CAPS and PCL severity and change z-scores range between 0.5-0.8 standard deviations. The MCID estimates suggested here provide an empirical basis for determining whether statistically significant changes in CAPS and PCL scores are clinically meaningful. PMID- 28634646 TI - The Role of Robotics in the Invasive Management of Bladder Cancer. AB - Robot-assisted radical cystectomy (RARC) has been adopted widely in many centres, owed largely to the success of robot-assisted laparoscopic prostatectomy (RALP). It aims to replicate the oncological outcomes of open radical cystectomy (ORC), while providing a shorter recovery period. Despite this, previous RCTs have failed to show a benefit for RARC over ORC. These trials have compared extracorporeal RARC (eRARC) with ORC, which requires a further incision to mobilise the bowel for urinary reconstruction with an open technique. For intracorporeal RARC (iRARC), this urinary reconstruction is performed robotically without further incisions. There are theoretical benefits to this approach such as reduced recovery time for the bowel and reduced ileus rates, but no level 1 evidence currently exists to support this. While there has been an improvement in patient outcomes since the adoption of RARC, various other factors, such as enhanced recovery programmes and surgical learning curve, have made it difficult to attribute this solely to the robotic approach as many centres performing ORC have also shown similar improvements. In this review, we will discuss implementation of RARC as well as perioperative measures that have helped improve outcomes, offer a comparison of outcomes between ORC and RARC and highlight upcoming RCTs that may offer new evidence for or against a paradigm shift in the future of bladder cancer surgery. PMID- 28634648 TI - Fasciola hepatica-a "Diver" in the Biliary Tree. AB - Fasciola hepatica is an endemic trematode that affects millions of people worldwide. The human being can be an accidental host through consumption of contaminated food or water. The authors present a case of hepatic fascioliasis in a 69-year-old Portuguese woman who recently traveled from Egypt, Brazil, and India. PMID- 28634649 TI - Assessment of cabozantinib treatment on QT interval in a phase 3 study in medullary thyroid cancer: evaluation of indirect QT effects mediated through treatment-induced changes in serum electrolytes. AB - PURPOSE: This study evaluated factors impacting QTc interval in a phase 3 trial of cabozantinib in progressive, metastatic, medullary thyroid cancer (MTC). METHODS: Electrocardiogram (12-lead ECG) measurements were obtained at screening, and at pre-dose, and 2, 4, and 6 h post-dose on Days 1 and 29 in a phase 3 study in patients with MTC treated with cabozantinib (140 mg/day). Central tendency analyses were conducted on baseline-corrected QTc values. Linear and nonlinear mixed-effects models were used to evaluate potential factors affecting the QTc interval, including serum electrolytes, patient demographics, and cabozantinib concentration. RESULTS: Central tendency analysis showed that oral cabozantinib (140 mg/day) produced a 10-15 ms increase in delta-delta Fridericia corrected QT (??QTcF) and delta-delta study-specific corrected QT (??QTcS) on Day 29, but not on Day 1. Further analysis showed that QTcS provided a slightly more accurate QT correction than QTcF. Mixed-effects models evaluating serum electrolytes, age, sex, and cabozantinib concentration showed that decreased serum calcium and potassium could explain the majority of cabozantinib treatment-associated QTcS prolongation observed in this study. CONCLUSIONS: Cabozantinib treatment prolongs the ??QTcF interval by 10-15 ms. There was the absence of a strong relationship between cabozantinib concentration and QTcS prolongation. Cabozantinib treatment effects on serum calcium and potassium best explain the QTcS prolongation observed in this study. PMID- 28634647 TI - Erratum to: Training guidelines for endovascular stroke intervention: an international multi-society consensus document. PMID- 28634651 TI - Focus issue European Journal of Trauma and Emergency Surgery on "Volume Resuscitation and Coagulation" : Focus on volume resuscitation and coagulation to improve outcomes in acute trauma haemorrhage. PMID- 28634650 TI - A randomized phase II study of gemcitabine plus Z-360, a CCK2 receptor-selective antagonist, in patients with metastatic pancreatic cancer as compared with gemcitabine plus placebo. AB - BACKGROUND: We investigated the efficacy and safety of 60, 120, or 240 mg of Z 360, which is a highly potent cholecystokinin2-receptor-selective antagonist, combined with gemcitabine in patients with metastatic pancreatic cancer. METHODS: Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups. Patients received 1000 mg/m2 gemcitabine for each cycle and Z-360 tablets of 60 mg (GZ 60 mg group), 120, 240 mg or placebo tablets (Gem group) orally twice daily. The primary endpoint was overall survival (OS). RESULTS: The median OS was 1.3 months longer in the GZ 60 mg group compared with the Gem group (8.5 vs. 7.2 months) and the risk of death was reduced by 19% compared with the Gem group, although there were no statistically significant differences. The study treatments were well tolerated. CONCLUSIONS: In this Phase II study, no statistically significant differences between the GZ groups and Gem group were detected in any analysis. However, Z-360 in dose of 60 mg tends to improve OS in patients with metastatic pancreatic cancer with low toxic effect. Further exploratory trials with other agents such as gemcitabine plus nab-paclitaxel might be beneficial. PMID- 28634652 TI - A multi-source approach to determine SMA incidence and research ready population. AB - In spinal muscular atrophy (SMA), degeneration of motor neurons causes progressive muscular weakness, which is caused by homozygous deletion of the SMN1 gene. Available epidemiological data on SMA are scarce, often outdated, and limited to relatively small regions or populations. Combining data from different sources including genetic laboratories and patient registries may provide better insight of the disease epidemiology. To investigate the incidence of genetically confirmed SMA, and the number of patients who are able and approachable to participate in new clinical trials and observational research, we used both genetic laboratories, the TREAT-NMD Global SMA Patient Registry and the Care and Trial Sites Registry (CTSR). In Europe, 4653 patients were genetically diagnosed by the genetic laboratories in the 5-year period 2011 to 2015, with 992 diagnosed in 2015 alone. The data provide an estimated incidence of SMA in Europe of 1 in 3900-16,000 live births. Patient numbers in the national patient registries and CTSR were considerably lower. By far, most patients registered in the national patient registries and the CTSR live in Europe and are reported to have SMA type II. Considerable differences between countries in patient participation in the registries were observed. Our findings indicate that not all patients with SMA are accessed by specialist healthcare services and these patients may not have access to research opportunities and optimal care. PMID- 28634653 TI - Assessing the Combined Toxicity of BMAA and Its Isomers 2,4-DAB and AEG In Vitro Using Human Neuroblastoma Cells. AB - The non-protein amino acid (NPAA) beta-methylamino-L-alanine (BMAA) is produced by a diverse range of cyanobacteria, diatoms and dinoflagellates, and is present in both aquatic and terrestrial ecosystems globally. Exposure to BMAA has been implicated in the development of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). BMAA is often found in nature along with its structural isomers 2,4 diaminobutyric acid (2,4-DAB) and aminoethylglycine (AEG); however, the toxicity of these NPAAs in combination has not been examined. We have previously demonstrated that BMAA induces endoplasmic reticulum (ER) stress and increases caspase and cathepsin activity in human neuroblastoma cells (SH-SY5Y), effects consistent with proteotoxic stress due to disturbances in protein synthesis, folding or turnover. The current study investigates whether 2,4-DAB and AEG share a similar mechanism of toxicity to BMAA, and if simultaneous exposure of cells to BMAA and its isomers results in increased toxicity in vitro. We show that a 48-h treatment with both 500 MUM BMAA and 2,4-DAB decreases cell viability in vitro whereas AEG was not cytotoxic under the same conditions. Treatment of SH-SY5Y cells with 2,4-DAB did not increase expression of ER stress markers. Combined treatment of cells with BMAA and 2,4-DAB resulted in increased caspase activity and increased apoptosis above that of BMAA or 2,4-DAB on their own. These results suggest that 2,4-DAB does not share the same mechanism of toxicity as BMAA but the presence of 2,4-DAB increases the toxicity of BMAA to human cells in vitro. PMID- 28634654 TI - Improvement in latent variable indirect response modeling of multiple categorical clinical endpoints: application to modeling of guselkumab treatment effects in psoriatic patients. AB - Exposure-response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure response of guselkumab, a human IgG1 monoclonal antibody in clinical development that blocks IL-23. A Phase 2b study was conducted in 238 patients with psoriasis for which disease severity was assessed using Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores. A latent variable Type I IDR model was developed to evaluate the therapeutic effect of guselkumab dosing on 75, 90 and 100% improvement of PASI scores from baseline and PGA scores, with placebo effect empirically modeled. The results showed that the joint model is able to describe the observed data better with fewer parameters compared with the common approach of separately modeling the endpoints. PMID- 28634655 TI - Effect of Adherence on Pharmacokinetic/Pharmacodynamic Relationships of Oral Targeted Anticancer Drugs. AB - The emergence of oral targeted anticancer agents transformed several cancers into chronic conditions with a need for long-term oral treatment. Although cancer is a life-threatening condition, oncology medication adherence-the extent to which a patient follows the drug regimen that is intended by the prescriber-can be suboptimal in the long term, as in any other chronic disease. Poor adherence can impact negatively on clinical outcomes, notably because most of these drugs are given as a standard non-individualized dosage despite marked inter-individual variabilities that can lead to toxic or inefficacious drug concentrations. This has been especially studied with the prototypal drug imatinib. In the context of therapeutic drug monitoring (TDM), increasingly advocated for oral anticancer treatment optimization, unreported suboptimal adherence affecting drug intake history may lead to significant bias in the concentration interpretation and inappropriate dosage adjustments. In the same way, suboptimal adherence may also bias the results of pharmacokinetic modeling studies, which will affect in turn Bayesian TDM interpretation that relies on such population models. Detailed knowledge of the influence of adherence on plasma concentrations in pharmacokinetic studies or in routine TDM programs is however presently missing in the oncology field. Studies on this topic are therefore eagerly awaited to better pilot the treatment of cancer with the new targeted agents and to find their optimal dosage regimen. Hence, the development and assessment of effective medication adherence programs are warranted for these treatments. PMID- 28634656 TI - Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Alliance clinical trials. AB - PURPOSE: Clinical practice guidelines on chemotherapy-induced peripheral neuropathy (CIPN) use the NCI Common Terminology Criteria for Adverse Events (CTCAE), while recent clinical trials employ a potentially superior measure, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN twenty-item scale (QLQ-CIPN20), a patient-reported outcome (PRO). Practitioners and researchers lack guidance, regarding how QLQ-CIPN20 results relate to the traditional CTCAE during the serial assessment of patients undergoing chemotherapy. METHODS: Two large CIPN clinical trial datasets (538 patients) pairing QLQ-CIPN20 and CTCAE outcomes were analyzed using a multivariable linear mixed model with QLQ-CIPN20 score as the outcome variable, CTCAE grade as the main effect, and patient as random effect (accounting for internal correlation of serial measures). RESULTS: The association between QLQ CIPN20 scores and CTCAE grades was strong (p < 0.0001), whereby patients with higher CTCAE grade had worse QLQ-CIPN20 scores. Some variation of QLQ-CIPN20 scores was observed based on drug, treatment, and cycle. While there was a marked difference in the mean QLQ-CIPN20 scores between CTCAE grades, the ranges of QLQ CIPN20 scores within each CTCAE grade were large, leading to large overlap in CIPN20 scores across CTCAE grades. CONCLUSIONS: A strong positive association of QLQ-CIPN20 scores and CTCAE grade provides evidence of convergent validity as well as practical guidance, as to how to quantitatively interpret QLQ-CIPN20 scores at the study level in terms of the traditional CTCAE. The present results also highlight an important clinical caveat, specifically, that conversion of a specific QLQ-CIPN20 score to a specific CTCAE score may not be reliable at the level of an individual patient. PMID- 28634657 TI - Longitudinal perceptions of the side effects of chemotherapy in patients with gynecological cancer. AB - PURPOSE: This study aimed to assess the incidence and difference of side effects among six courses of chemotherapy (C/T) in gynecological cancer patients. METHODS: The study period was from Sep. 2010 to Dec. 2011 at the Kaohsiung Veterans General Hospital in Taiwan. The treating protocols, courses, and drugs of C/T in patient were considered according to the different malignant cancers and clinical conditions. The patient data of age, marriage status, education, religion, and experiences of C/T were collected. The patients' or their families' reported side effects of C/T were recorded daily from the beginning of C/T to the 10th day after C/T in each cycle and every course of C/T. RESULTS: Total 89 patients enrolled into the study received total 450 courses of C/T. The mean age was 54.52 +/- 11.02. Ovarian cancer was the most common malignant disease (64.0%). The most often combination of drugs used was Taxol and carboplatin (40.9%). Patients complained peripheral numbness of limbs, with the highest incidence of 58.6%. The side effects with incidence about 50% were decreased fatigue (55.0%) and hair loss (49.9%). Other side effects with different levels of incidence were also noticed, such as lack of appetite, changes in taste, and muscle ache. The incidences of peripheral limb numbness and hair loss were increased with following courses of C/T. The high incidence of fatigue did not show variation between different courses of C/T. CONCLUSION: This study revealed the incidence of side effects and occurrence timing during C/T in patients with gynecological cancer. These data provide substantial information to patients and their families to understand the potential side effects of C/T courses, which might increase their compliance in receiving adjuvant C/T. Relieving the side effects in C/T would be important to improve their quality of daily life and treatment willingness. PMID- 28634658 TI - The UTCI and the ISB. AB - Thermal effects of the environment are the most prominent environmental influences on the human body. Keeping the body core temperature in a narrow optimum range is the dominating physiological process. Thus, assessing thermal environments has been a major field in biometeorology for many decades, which is also reflected in the number of respective articles and their citations. In the early days of thermal assessments, simple indices only considering a few environmental parameters were used. The next step has been the development of heat budget models describing all relevant heat/energy fluxes to and from the human body. One of the first was PET, which has been presented in the most cited IJBM publication ever (1999). All of these models created by individual scientists have some shortcomings and confinements in their application. In order to overcome such restrictions and to bring the state of the art scientists of thermal modelling together a working group to define a "universal" thermal climate index (UTCI) has been founded, backed and driven by an own commission of the International Society of Biometeorology. This working group has developed a comprehensive open source tool to calculate UTCI for the assessment of outdoor thermal environments for biometeorological applications (see the IJBM special issue 56 (2012) on UTCI). PMID- 28634659 TI - Effects of single moor baths on physiological stress response and psychological state: a pilot study. AB - Moor mud applications in the form of packs and baths are widely used therapeutically as part of balneotherapy. They are commonly given as therapy for musculoskeletal disorders, with their thermo-physical effects being furthest studied. Moor baths are one of the key therapeutic elements in our recently developed and evaluated 3-week prevention program for subjects with high stress level and increased risk of developing a burnout syndrome. An embedded pilot study add-on to this core project was carried out to assess the relaxing effect of a single moor bath. During the prevention program, 78 participants received a total of seven moor applications, each consisting of a moor bath (42 degrees C, 20 min, given between 02:30 and 05:20 p.m.) followed by resting period (20 min). Before and after the first moor application in week 1, and the penultimate moor application in week 3, salivary cortisol was collected, blood pressure and heart rate were measured, and mood state (Multidimensional Mood State Questionnaire) was assessed. A Friedman test of differences among repeated measures was conducted. Post hoc analyses were performed using the Wilcoxon signed-rank test. A significant decrease in salivary cortisol concentration was seen between pre- and post-moor bath in week 1 (Z = -3.355, p = 0.0008). A non-significant decrease was seen between pre- and post-moor bath in week 3. Mood state improved significantly after both moor baths. This pilot study has provided initial evidence on the stress-relieving effects of single moor baths, which can be a sensible and recommendable therapeutic element of multimodal stress-reducing prevention programs. The full potential of moor baths still needs to be validated. A randomized controlled trial should be conducted comparing this balneo-therapeutic approach against other types of stress reduction interventions. PMID- 28634660 TI - Should I Convince My Partner to Go on Pre-Exposure Prophylaxis (PrEP)? The Role of Personal and Relationship Factors on PrEP-Related Social Control among Gay and Bisexual Men. AB - An estimated 35-68% of new HIV infections among gay, bisexual, and other men who have sex with men (GBM) are transmitted through main partnerships. Pre-exposure prophylaxis (PrEP) is highly effective in reducing HIV seroconversion, yet PrEP uptake has been modest. PrEP-naive GBM with HIV-negative, PrEP-naive main partners enrolled in One Thousand Strong (n = 409), a U.S. national cohort of GBM, were asked about (1) the importance of partner PrEP use and (2) their willingness to convince their partner to initiate PrEP. On average, participants thought partner PrEP was only modestly important and were only moderately willing to try to convince their partner to initiate PrEP. Personal PrEP uptake willingness and intentions were the strongest indicators of partner PrEP outcomes. Being in a monogamish relationship arrangement (as compared to a monogamous arrangement) and the experience of intimate partner violence victimization were associated with increased willingness to persuade a partner to initiate PrEP. PMID- 28634663 TI - Transthoracic echography assessment of the superior vena cava flow: a pilot study. PMID- 28634662 TI - HIV Stigma and Substance Use Among HIV-Positive Russians with Risky Drinking. AB - The link between HIV stigma with substance use is understudied. We characterized individuals with high HIV stigma and examined whether HIV stigma contributes to substance use among HIV-positive Russians reporting risky alcohol use. We analyzed data from HERMITAGE, a randomized controlled trial of 700 people living with HIV/AIDS (PLWHA) with past 6-month risky sex and risky alcohol use in St. Petersburg, Russia (2007-2011). Participants who were female and reported depressive symptoms and lower social support were more likely to endorse high HIV stigma (all p's < 0.001). In adjusted models, high HIV stigma was not significantly associated with the primary outcome unhealthy substance use and was not consistently associated with secondary substance use outcomes. Interventions to enhance social and mental health support for PLWHA, particularly women, may reduce stigma, though such reductions may not correspond to substantial decreases in substance use among this population. PMID- 28634661 TI - Depression and ART Initiation Among HIV Serodiscordant Couples in Kenya and Uganda. AB - Depression is a known barrier for antiretroviral therapy (ART) adherence, but less is understood about its effects on ART initiation. We followed 1013 HIV infected individuals participating in the Partners Demonstration Project, an open label study of integrated pre-exposure prophylaxis (PrEP) and ART delivery for HIV serodiscordant couples in Kenya and Uganda. Associations between depression, measured annually with the Hopkins Symptoms Checklist-Depression (HSCL-D), and ART initiation were assessed with Cox proportional hazards regression. At enrollment, 162 participants (16.0%) reported symptoms consistent with probable depression, defined by a HSCL-D mean score >1.75, and this proportion decreased during study follow-up (6.7 and 3.6% at 12- and 24-months, respectively; p value < 0.001). Greater depressive symptom severity was associated with a greater likelihood of ART initiation overall (adjusted hazard ratio [aHR] 1.32, 95% CI 1.01-1.73) and among participants with CD4 count <= 350 cells/ul (aHR 1.30, 95% CI 1.01-1.67). Depression decreased 6 months after ART initiation (adjusted odds ratio [aOR] 0.34, 95% CI 0.23-0.51). Among East African HIV-infected persons in HIV serodiscordant couples, depression was not a barrier to ART initiation. ART initiation was associated with improved depressive symptoms in this setting. PMID- 28634664 TI - High variability of treatments for paediatric status asthmaticus: a retrospective study in PICUs. PMID- 28634665 TI - Usefulness of Mapping Biopsy in the Treatment of Penoscrotal Extramammary Paget's Disease. PMID- 28634666 TI - CT Density in the Pancreas is a Promising Imaging Predictor for Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: Fatty pancreas (FP) was recently recognized as a risk factor for pancreatic ductal adenocarcinoma (PDAC). It is unclear whether computed tomography (CT) can be used to make a FP diagnosis. This study investigated whether CT could provide a predictive value for PDAC by diagnosing FP. METHODS: The study included 183 consecutive patients who underwent distal pancreatectomy from February 2007 to January 2017, including 75 cases of PDAC and 108 cases of other pancreatic disease. Pancreatic CT density (pancreatic index; PI) at the initial diagnosis was calculated by dividing the CT number in the pancreas by the number in the spleen. To assess whether CT could be used to detect FP, 43 cases were evaluated pathologically for FP. We investigated the correlation between FP and PI, and determined the optimal PI cutoff value for detecting FP using receiver operating characteristics analysis. We then investigated whether the PI value could be used as a predictor for PDAC. RESULTS: Fourteen cases (32.6%) were pathologically diagnosed with FP. PI was significantly lower in the FP group versus the non-FP group (0.51 vs. 0.83; p = 0.0049). ROC analysis indicated that the PI had good diagnostic accuracy for FP diagnosis (cutoff value 0.70; sensitivity 0.79, specificity 0.79). Low PI (<=0.70) was identified in the multivariate analysis as an independent risk factor for PDAC (odds ratio 2.31; p = 0.023). CONCLUSIONS: PI was strongly associated with pathological FP, which was independently associated with PDAC. PI shows promise as an imaging predictor for PDAC. PMID- 28634667 TI - Elevated Interleukin-13 Receptor Alpha 1 Expression in Tumor Cells Is Associated with Poor Prognosis in Patients with Invasive Breast Cancer. AB - BACKGROUND: Interleukin (IL)-13 is an immunoregulatory, anti-inflammatory cytokine that is produced by numerous immune cells, and plasma membrane receptor for IL-13 (IL-13R) is known to be expressed in various human malignancies and in immune cells. METHODS: The authors evaluated the expression of IL-13R alpha 1 (IL 13Ralpha1, an IL-13R subtype) by immunohistochemistry in tissue microarrays of 1213 invasive breast cancer (IBC) samples to determine the prognostic value of IL 13Ralpha1 expression. RESULTS: High IL-13Ralpha1 expression was observed in 619 (51%) cases and was found to be associated with an older (>=50 years) age (p = 0.022), lymph node metastasis (p = 0.015), ductal and micropapillary histologic subtypes (p < 0.001), lymphovascular invasion (p = 0.012), HER2 positivity (p < 0.001), and a high (>20%) Ki-67 index (p = 0.039). No significant correlation was found between IL-13Ralpha1 expression and clinicopathological variables, including tumor size, histological grade, hormone receptor expressions, and tumor infiltrating lymphocyte levels. Patients with high IL-13Ralpha1 expression showed poorer overall survival (p = 0.044) and disease-free survival (DFS, p = 0.001) than those with low/negative expression. Subgroup analysis revealed an association between IL-13Ralpha1 expression and survival for HER2-negative, but not for HER2-positive tumors. Multivariate analysis showed high IL-13Ralpha1 expression was an independent negative prognostic factor of DFS (p = 0.019). CONCLUSIONS: The results of this study suggest the IL-13 and IL-13Ralpha1 interaction promotes cancer cell growth and metastasis, and IL-13Ralpha1 expression is a potential prognostic marker in IBC. PMID- 28634668 TI - Black-and-white snub-nosed monkey (Rhinopithecus bieti) feeding behavior in a degraded forest fragment: clues to a stressed population. AB - Rapid global deforestation has forced many of the world's primates to live in fragmented habitats, making the understanding of their behavioral responses to degraded and fragmented habitats a key challenge for their future protection and management. The black-and-white snub-nosed monkey (Rhinopithecus bieti) is an endangered species endemic to southwest China. The forest habitat ranges from near-continuous to fragmented. In this study, we investigated the activity budget and diet of a R. bieti population that live in an isolated and degraded habitat patch at Mt. Lasha in Yunnan Province, near the current southern limit of the species. We used our data along with data from six other sites in more-continuous habitats across its range to model factors that predict stress, including feeding effort and time feeding on lichens against potential predictive parameters. Models showed feeding effort across all sites increased with increasing altitude and latitude, and with decreasing food species diversity. There was also a strong positive relationship between feeding effort and time feeding lichens. The Mt. Lasha R. bieti population exploited a total of 36 food species, spending 80.2% of feeding time feeding on lichens, Bryoria spp. and Usnea longissima. These figures are more comparable to those living in the north than those living in the mid- and southern part of the species' range. Given the models for feeding effort and time feeding on lichens, the unexpectedly high time spend feeding on lichens and feeding effort relative to latitude and elevation are suggestive of a stressed population at Mt. Lasha. PMID- 28634669 TI - Yttrium-90 (Y-90) Resin Microsphere Therapy for Patients with Unresectable Hepatocellular Carcinoma: a Single-Center Experience. AB - BACKGROUND/AIM: Selective intraarterial radionuclide therapy (SIRT) with yttrium 90 (Y-90) resin microspheres presently has successful results in primary or metastatic inoperable liver tumors. This procedure, which is also known as radioembolisation, delivers high doses of radiation selectively to hepatic tumors while minimum healthy liver exposure. The aim of this study was to present our clinical experience of radiomicrosphere therapy for the treatment of patients with unresectable hepatocellular carcinoma (HCC). METHODS: We performed 40 Y-90 microsphere therapies in 28 patients (5 females, 23 males; mean age +/- SD 48 +/- 8) with HCC during the period from April 2008 through December 2016. Pretreatment Tc-99m microaggregated albumin (MAA) scintigraphy was performed to all patients in order to detect eligibility for SIRT. All patients had pre- and post biochemical tests (hemogram and serologic tests) and imaging methods (CT or MRI or PET/CT) at regular intervals to detect any possible complication and determine response rates. RESULTS: The mean shunting to the lungs on MAA scan was 6.5% and the mean +/- SD administered dose of Y-90 was 1.55 +/- 0.32 GBq in all patients. The estimated doses to the target tumors, normal liver parenchyma and lungs were 105.7 +/- 55.3, 25.5 +/- 8.2 and 5.8 +/- 1.7 Gy, respectively. No significant complication was observed during or early after (first week) the treatment procedure and it was well tolerated by all the patients. Only one patient developed a treatment-related gastroduodenal ulcer 3 weeks after the treatment. In control imaging tests (MRI or FDG PET/CT) performed 2.5 months after the treatment, we observed complete response in 2 (7%) patients, partial response in 10 (36%) patients, stable disease in 5 (18%) patients and progressive disease in 11 (39%) patients. CONCLUSION: According to our clinical experience, we can conclude that Y-90 microsphere therapy is a safe and effective treatment option for the patients with unresectable HCC without any serious side effects. PMID- 28634670 TI - Surveillance of the Patients with High Risk of Hepatocellular Cancer. PMID- 28634671 TI - Venous Thromboembolism Is an Independent Predictor of Mortality Among Patients with Gastric Cancer. AB - BACKGROUND: Venous thromboembolism (VTE) is an independent predictor of death among patients with cancer. Patients with gastric cancer (GC) are at higher risk for VTE when compared to other solid tumors, and if one considers its prevalence, GC may be responsible for one of the highest incidences of cancer-associated thrombosis. The impact of VTE on mortality is not well defined among patients with GC. AIM: The aim of this study is to measure the impact of VTE as independent predictor of GC mortality. METHODS: Chart review of patients with GC treated in the Department of Oncology at John Stroger Hospital between the years of 2010 and 2015. VTE events were objectively confirmed with imaging in all cases. Active GC was defined as biopsy-proven metastatic disease or on active chemotherapy. Along with cancer-specific data, we abstracted risk assessments tools, non-GC-specific, validated for VTE and mortality prediction cancer, including the Khorana score (KRS), platelet lymphocyte ratio (PLR), and neutrophil lymphocyte ratio (NLR). Continuous variables are expressed by the median as appropriate according to normality. Categorical variables are expressed as percentages. SPSS version 22 was used and chi-square, Mann-Whitney U, Kaplan Meier curve, and Cox proportional hazard with forward modeling were applied. RESULTS: We included 112 patients in the analysis. The patients were predominantly men (66%), 58-year-old, with adenocarcinoma (84%) and advanced disease (59%). The median follow-up was 21.3 months (IQR 8.9-42.4). Cumulative incidence of VTE at 1 year was 9%. The median time from diagnosis to VTE occurrence was 59 days (IQR 36 to 258). Patients with VTE had worse OS when compared to the non-VTE group (medians 11.87 vs 29.97 months, p = 0.02). Patients stratified as high risk by the PLR had worse OS (medians 22.6 vs 42.77 months, p = 0.02). There was no statistical difference in OS among patients stratified as high risk by the KRS (medians 23.7 vs 42.5, p = 0.16) and NLR (medians 24.1 vs 42.7 months, p = 0.21). In multivariate analysis, the independent predictors of mortality were VTE (hazard ratio (HR), 2.9; 95% CI, 1.4 to 6.6; p < 0.01), adenocarcinoma (HR, 3.1; 95% CI, 1.1 to 9.0; p = 0.03), advanced disease (HR, 2.8; 95% CI, 1.4 to 5.8; p < 0.01), and PLR (HR, 2.2; 95% CI, 1.3 to 3.8; p < 0.01). CONCLUSION: VTE is associated with worse survival among patients with GC along with adenocarcinoma, advanced disease, and PLR. Moreover, these findings were independent of other cancer- and treatment-specific variables. Although potentially predictive in other cancer types, NLR and KRS were not associated with worse survival in this cohort. PMID- 28634672 TI - HCC Locoregional Therapies: Yttrium-90 (Y-90) Selective Internal Radiation Therapy (SIRT). PMID- 28634673 TI - B-mode and Doppler ultrasound of chronic kidney disease in dogs and cats. AB - Ultrasound is the imaging test of choice for renal evaluation, because it provides information about the position, size, shape, internal architecture and hemodynamics of the kidneys without harming the patient. In chronic kidney disease, the main findings observed in B-mode ultrasound images are increased cortical echogenicity, loss of corticomedullary differentiation, reduced renal volume and irregular renal contour, and when these changes are associated, they are indicative of end-stage renal disease. However, the cause of kidney disease cannot be determined by ultrasonography, but must be confirmed by means of biopsy, although the presence of ultrasonographic changes indicative of the end stage of the disease may contraindicate this procedure. The Doppler ultrasound test complements the ultrasonic B-mode examination and enables the assessment of renal perfusion based on a calculation of the hemodynamic indices, which are increased in cases of chronic kidney lesions, with higher values in the most severe cases. Thus, ultrasound examinations are not only useful in diagnostics but also play an important role in defining the prognosis of patients with chronic kidney disease. PMID- 28634674 TI - Prognostic impact of nutritional status assessed by the Controlling Nutritional Status score in patients with stable coronary artery disease undergoing percutaneous coronary intervention. AB - BACKGROUND: Recently, malnutrition has been shown to be related to worse clinical outcomes in patients with heart failure. However, the association between nutritional status and clinical outcomes in patients with coronary artery disease (CAD) remains unclear. We investigated the prognostic value of malnutrition assessed by the Controlling Nutritional Status (CONUT; range 0-12, higher = worse, consisting of serum albumin, cholesterol and lymphocytes) score in patients with CAD. METHODS: The CONUT score was measured on admission in a total of 1987 patients with stable CAD who underwent elective percutaneous coronary intervention (PCI) between 2000 and 2011. Patients were divided into two groups according to their CONUT score (0-1 vs. >=2). The incidence of major adverse cardiac events (MACE), including all-cause death and non-fatal myocardial infarction, was evaluated. RESULTS: The median CONUT score was 1 (interquartile range 0-2). During the median follow-up of 7.4 years, 342 MACE occurred (17.2%). Kaplan-Meier curves revealed that patients with high CONUT scores had higher rates of MACE (log-rank p < 0.0001). High CONUT scores showed a significant increase in the incidence of MACE compared with low CONUT scores, even after adjusting for confounding factors (hazard ratio: 1.64, 95% confidence interval 1.30-2.07, p < 0.0001). Adding CONUT scores to a baseline model with established risk factors improved the C-index (p = 0.02), net reclassification improvement (p = 0.004) and integrated discrimination improvement (p = 0.0003). CONCLUSIONS: Nutritional status assessed by the CONUT score was significantly associated with long-term clinical outcomes in patients with CAD. Pre-PCI assessment of the CONUT score may provide useful prognostic information. PMID- 28634675 TI - Wild capuchin monkeys anticipate the amount of ripe fruit in natural trees. AB - Tropical forests have a high diversity of tree species which have very low densities and vary across time in their seasons of peak fruiting and maturation rates. As evidence of the ability of primates to track or anticipate changes in fruit production at individual trees, researchers have used the increased speed of primate groups toward more rewarding food patches. We analyzed the speed of approach to natural trees of wild capuchin monkeys under the effect of scramble competition, after excluding any plausible visual, olfactory and auditory cues. We conducted all-day group follows of three habituated capuchin groups at Iguazu National Park, Argentina, collecting data on ranging behavior and patterns of visits to fruit trees in relation with their location and fruit availability. Travel speed varied according to the expected reward at a feeding tree, increasing as rewards increased from low values, but decreasing again at very high values. Also, travel speed varied with time of day, decreasing from the time of first activity as the monkeys became less hungry, and increasing again toward late afternoon. Measures of unripe fruit cover did not explain variation in travel speed at any distance from a focal tree. Our data imply that, after excluding sensory cues, capuchins appear to anticipate time-varying ripe fruit quantity of natural resources, suggesting that they use memory of tree location and anticipation of fruit maturation. We also confirm that speed is a good measure about expectations of resources, as has been shown in previous studies. PMID- 28634677 TI - P5 medicine and justice: the future is now. PMID- 28634676 TI - Evaluation of the psychometric properties of the EORTC chemotherapy-induced peripheral neuropathy questionnaire (QLQ-CIPN20). AB - PURPOSE: To investigate the scale structure and psychometrics of the EORTC chemotherapy-induced peripheral neuropathy module (QLQ-CIPN20). METHODS: Using confirmatory factor analyses (CFA), we tested two hypothesized scale structure models of the QLQ-CIPN20 in 473 patients with non-small cell lung cancer, 281 patients with heterogeneous cancer diagnoses, and 500 patients with colorectal cancer. We also modeled the two hypothesized models as bi-factor models. These included a general factor, in addition to the specific domain factors. Additional models were investigated with exploratory factor analysis (EFA). Known groups validity was evaluated where justified. RESULTS: CFA could not confirm the two hypothesized models (Model 1: CFI < 0.926; TLI < 0.914; RMSEA > 0.077 and Model 2: CFI < 0.906; TLI < 0.887; RMSEA > 0.105) in any of the three samples. Including a general factor to these two hypothesized models to produce a bi factor model also did not yield satisfactory results. Using EFA, we identified four different factor structures in the three samples that were unstable due to cross loadings of the items. When scoring the QLQ-CIPN20 as a simple, additive checklist evidence was found for known groups validity in the first two samples based on Common Toxicity Criteria (CTC-AE), and in the third sample based on exposure to CIPN-inducing chemotherapy. CONCLUSIONS: Neither CFA nor EFA yielded support for a stable subscale structure for the QLQ-CIPN20. Scoring the questionnaire as a simple additive checklist results in acceptable validity. PMID- 28634678 TI - The iliac crest in forensic age estimation: evaluation of three methods in pelvis X-rays. AB - Age assessment in children and young adults is a relevant forensic issue. It is requested not only in evaluating criminal responsibility in youths without proper identification documents, often in relation to age thresholds, but also for release of a residency permit, and asylum seekers of minors. The analysis of the Risser sign and the iliac crest ossification process has been proposed as a useful tool for forensic age estimation. We evaluated the applicability of three different age estimation methods on a sample of 497 pelvic radiographs of Italian individuals between 10 and 25 years of age. Each method showed high reliability for both reproducibility and repeatability. The staging technique inspired by Kreitner and Kellinghaus methods (KK-MS) is easier than the Risser method in applicability, as it is not affected by the variations of ossification. We observed that all subjects who attained stage 3c of KK-MS and 5 of Risser Fr were >14 years, suggesting the benefits of these methods for that age threshold. The applicability of the area measurement method, inspired by Cameriere's approach, ranged between 12 and 20 years, but the statistical analysis showed only a moderate correlation with age. In order to evaluate the possible use of this approach it is therefore necessary to clarify and exclude external factors influencing the parameter. In conclusion, the iliac crest ossification is of interest in age estimation for forensic purposes. The evaluation of the pelvis X ray, in addition to the other common dental and skeletal methods, could become a useful supplementary tool in age estimation for the 14 year threshold in order to fulfill forensic-level requirements. PMID- 28634679 TI - Establishment of two forensic medicine OSCE stations on the subject of external post-mortem examination. AB - An improvement in quality of medical external post-mortem examinations among others can be achieved by more intensive training of medical students. Modern learning and teaching methods such as e-learning modules and SkillsLab stations should be used for this. The introduction of corresponding methods of assessment such as the OSCE procedure is necessary to test the success of learning. In Halle (Germany), two OSCE stations on the subject of external post-mortem examinations were introduced in 2016. The 'practical external post-mortem examination' station test skills and abilities students have learned during practical external post mortem examination in small group classes on a simulation doll. At the 'death certificate' station, an original death certificate must be filled in, testing the knowledge, skills and abilities learned in the SkillsLab station and during e learning. A total of 148 students took part in the test. At both stations, at least two thirds of the students (69.5 and 81.7%) were able to show good or very good test results. In addition to the strengths, a detailed evaluation of the test results showed that there were still deficits in terms of the corresponding courses (e.g. inspection of the neck region in the small group classes), which will have to be remedied in the future. When analysing the test concept and the test implementation, objectivity was nearly perfect. There was a satisfactory internal consistency and stability over 8 months. Ultimately, in addition to several strengths (such as good understanding and transparency of the checklists) the evaluation of the examiners also showed further potential areas for improvement (e.g. harmonisation of the degree of difficulty for the individual rotations) when designing the OSCE stations. Overall, it was possible to determine that the OSCE testing format is a suitable tool to test external post mortem examination skills and that conclusions about improvements in teaching can also be drawn from this. PMID- 28634680 TI - Stability of upper face sexual dimorphism in central European populations (Czech Republic) during the modern age. AB - One of the most fundamental issues in forensic anthropology is the determination of sex and population affinity based on various skeletal elements. Therefore, we compared the sexual dimorphism of the upper facial skeleton from a recent Czech population (twenty-first century) with that of a population from Early Modern Age Bohemia (sixteenth to eighteenth centuries). Methods of geometric morphometrics were applied. According to the results, sexual dimorphism in terms of size, shape, and form was statistically significant in both populations. The best results of sex estimation originated from analyses of form. Thus, both size and shape differences should be taken into account for determination of the sex. The accuracy of prediction achieved 91.1% for individuals in the recent population and 87.5% for individuals from the early modern population. Only minor differences were found between sexual dimorphism in the studied populations. We conclude that sexual dimorphism of the upper facial skeleton is stable during the relatively short time period. PMID- 28634682 TI - Searching for the "sweet spot": the foot rotation and parallel engagement of ankle ligaments in maximizing injury tolerance. AB - Ligament sprains, defined as tearing of bands of fibrous tissues within ligaments, account for a majority of injuries to the foot and ankle complex in field-based sports. External rotation of the foot is considered the primary injury mechanism of syndesmotic ankle sprains with concomitant flexion and inversion/eversion associated with particular patterns of ligament trauma. However, the influence of the magnitude and direction of loading vectors to the ankle on the in situ stress state of the ligaments has not been quantified in the literature. The objective of the present study was to search for the maximum injury tolerance of a human foot with an acceptable subfailure distribution of individual ligaments. We used a previously developed and comprehensively validated foot and ankle model to reproduce a range of combined foot rotation experienced during high-risk sports activities. Biomechanical computational investigation was performed on initial foot rotation from [Formula: see text] of plantar flexion to [Formula: see text] of dorsiflexion, and from [Formula: see text] of inversion to [Formula: see text] of eversion prior to external rotation. Change in initial foot rotation shifted injury initiation among different ligaments and resulted in a wide range of injury tolerances at the structural level (e.g., 36-125 Nm of rotational moment). The observed trend was in agreement with a parallel experimental study that initial plantar flexion decreased the incidence of syndesmotic injury compared to a neutral foot. A mechanism of distributing even loads across ligaments subjected to combined foot rotations was identified. This mechanism is potential to obtain the maximum load-bearing capability of a foot and ankle while minimizing the injury severity of ligaments. Such improved understanding of ligament injuries in athletes is necessary to facilitate injury management by clinicians and countermeasure development by biomechanists. PMID- 28634681 TI - Microtubule affinity-regulating kinases are potential druggable targets for Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects normal functions of the brain. Currently, AD is one of the leading causes of death in developed countries and the only one of the top ten diseases without a means to prevent, cure, or significantly slow down its progression. Therefore, newer therapeutic concepts are urgently needed to improve survival and the quality of life of AD patients. Microtubule affinity-regulating kinases (MARKs) regulate tau-microtubule binding and play a crucial role in neurons. However, their role in hyperphosphorylation of tau makes them potential druggable target for AD therapy. Despite the relevance of MARKs in AD pathogenesis, only a few small molecules are known to have anti-MARK activity and not much has been done to progress these compounds into therapeutic candidates. But given the diverse role of MARKs, the specificity of novel inhibitors is imperative for their successful translation from bench to bedside. In this regard, a recent co-crystal structure of MARK4 in association with a pyrazolopyrimidine-based inhibitor offers a potential scaffold for the development of more specific MARK inhibitors. In this manuscript, we review the biological role of MARKs in health and disease, and draw attention to the largely unexplored area of MARK inhibitors for AD. PMID- 28634683 TI - Players of 'hypoxia orchestra' - what is the role of FMISO? PMID- 28634684 TI - Heterogeneity index evaluated by slope of linear regression on 18F-FDG PET/CT as a prognostic marker for predicting tumor recurrence in pancreatic ductal adenocarcinoma. AB - PURPOSE: 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been investigated as a method to predict pancreatic cancer recurrence after pancreatic surgery. We evaluated the recently introduced heterogeneity indices of 18F-FDG PET/CT used for predicting pancreatic cancer recurrence after surgery and compared them with current clinicopathologic and 18F FDG PET/CT parameters. METHODS: A total of 93 pancreatic ductal adenocarcinoma patients (M:F = 60:33, mean age = 64.2 +/- 9.1 years) who underwent preoperative 18F-FDG PET/CT following pancreatic surgery were retrospectively enrolled. The standardized uptake values (SUVs) and tumor-to-background ratios (TBR) were measured on each 18F-FDG PET/CT, as metabolic parameters. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were examined as volumetric parameters. The coefficient of variance (heterogeneity index-1; SUVmean divided by the standard deviation) and linear regression slopes (heterogeneity index-2) of the MTV, according to SUV thresholds of 2.0, 2.5 and 3.0, were evaluated as heterogeneity indices. Predictive values of clinicopathologic and 18F-FDG PET/CT parameters and heterogeneity indices were compared in terms of pancreatic cancer recurrence. RESULTS: Seventy patients (75.3%) showed recurrence after pancreatic cancer surgery (mean recurrence = 9.4 +/- 8.4 months). Comparing the recurrence and no recurrence patients, all of the 18F-FDG PET/CT parameters and heterogeneity indices demonstrated significant differences. In univariate Cox regression analyses, MTV (P = 0.013), TLG (P = 0.007), and heterogeneity index-2 (P = 0.027) were significant. Among the clinicopathologic parameters, CA19-9 (P = 0.025) and venous invasion (P = 0.002) were selected as significant parameters. In multivariate Cox-regression analyses, MTV (P = 0.005), TLG (P = 0.004), and heterogeneity index-2 (P = 0.016) with venous invasion (P < 0.001, 0.001, and 0.001, respectively) demonstrated significant results. CONCLUSIONS: The heterogeneity index obtained using the linear regression slope, could be an effective predictor of pancreatic cancer recurrence after pancreatic cancer surgery, in addition to 18F-FDG PET/CT volumetric parameters and clinicopathologic parameters. PMID- 28634685 TI - Poor predictive value of positive interim FDG-PET/CT in primary mediastinal large B-cell lymphoma. AB - PURPOSE: Though commonly used to assess response to therapy, the prognostic value of interim FDG-PET/CT in Primary Mediastinal Large B-cell Lymphoma (PMBCL) is unclear. METHODS: We conducted a retrospective study on 36 consecutive patients treated at our institution for a PMBCL between 2006 and 2014. All patients with a positive interim FDG-PET/CT had undergone histological restaging consisting either in a surgical debulking of the residual lesion (15 patients) or a CT guided core needle biopsy (two patients). All FDG-PET/CT were secondarily reviewed according to the more recent Deauville criteria. RESULTS: Interim FDG PET/CT was considered positive in 17/36 patients using visual evaluation. Among these patients, 14 had a Deauville score of 4. Histological restaging was negative in all but one case, showing inflammation and/or fibrosis. After a median follow-up of 48.5 months, a total of five patients have relapsed, two patients in the positive FDG-PET/CT group, and three patients in the negative FDG PET/CT group, respectively. CONCLUSIONS: These data indicate that a positive interim FDG-PET/CT does not reflect persistence of active disease in the vast majority of PMBCL cases. The relapse rate appears similar regardless of interim FDG-PET/CT results and interpretation criteria. This suggests that interim FDG PET/CT has a poor positive predictive value, thus kt should be used with caution in PMBCL. PMID- 28634686 TI - Respiratory Uptake and Depuration Kinetics of Perfluorooctanesulfonate (PFOS) in a Marine Sandworm Species. AB - We determined the respiratory uptake and depuration kinetics of perfluorooctanesulfonate (PFOS) in Perinereis wilsoni, a polychaete sandworm used as a model species to investigate the fate of chemical pollutants in coastal environments. The sandworms were kept in gravel-packed containers, and the water levels were varied cyclically to mimic the tides. We used seawater kept at 17.1 degrees C. A 7-day exposure period was followed by a 9-day depuration period. The dissolved PFOS concentration averaged 28 ng/L during the exposure period. Sandworm samples were collected regularly for analysis of PFOS concentrations, and a first-order-kinetics model was applied to the concentrations. The respiratory absorption efficiency of PFOS was estimated to be 11% that of oxygen, which is higher than the corresponding estimates reported for several fish species. The estimated depuration half-life of 15 days was comparable to previously reported estimates for fish and oligochaete species. The bioconcentration factor was 470. PMID- 28634687 TI - Noninvasive serum models to predict significant liver related events in chronic hepatitis C. AB - AIM: We aim to compare 20 noninvasive fibrosis scores (NIFS), derived from routine blood tests, for predicting significant liver-related adverse events (SLRE) in patients with chronic hepatitis C (CHC) after anti-viral treatment (AVT) with the goal to identify independent predictors for these outcomes. METHODS: From 1605 patients who received AVT (pegylated interferon and ribavirin) from January 2002 to June 2014, 20 NIFS were calculated from routine blood tests prior to AVT. Areas under the receiver-operating characteristic curve (AUROC) were calculated for each of these NIFS for predicting non-response to AVT and development of SLRE on follow-up. RESULTS: Mean age was 41.9 +/- 9.7 years, and patients were predominantly genotype 4 (65%). After AVT, there were 1089 (67.8%) responders, 482 (30%) non-responders and 34 (2.1%) relapsers. After median follow up of 6580.5 patient-years, 60 (3.8%) had SLRE, 52 (3.2%) had decompensation, and 11 (0.7%) had hepatocellular carcinoma (HCC). The predictive accuracy of NIFS and liver biopsy (LB) for non-response to AVT was low. FIB-4, FibroQ and King score showed high accuracy for predicting adverse events. For predicting decompensation, HCC and SLRE, FibroQ (0.881), King score (0.905) and FibroQ (0.877) had the highest AUROC, respectively. On multivariate analysis, independent predictors for treatment non-response (age, ALT, GGT, platelet count), HCC (albumin, GGT) and SLRE (albumin, GGT, platelet count) were identified. CONCLUSIONS: Some simple pretreatment blood parameters and NIFS showed high accuracy for predicting development of SLRE post treatment. Application of these simple scores can improve assessment of long-term liver prognosis for CHC. PMID- 28634688 TI - Acute variceal bleeding: risk stratification and management (including TIPS). AB - Acute variceal bleeding should be suspected in all patients with cirrhosis presenting with upper gastrointestinal bleeding. Vasoactive drugs and prophylactic antibiotics must be started as soon as possible, even before performing the diagnostic endoscopy. Once the patient is hemodynamically stable, upper gastrointestinal endoscopy should be performed in order to confirm the diagnosis and provide endoscopic therapy (preferably banding ligation). After this initial approach, the most appropriate therapy to prevent both early and late rebleeding must be instituted following a risk stratification strategy. The present chapter will focus on the initial management of patients with acute variceal bleeding, including general management and hemostatic therapies, as well as the available treatments in case of failure to control bleeding or development of rebleeding. PMID- 28634689 TI - Survival, Intestinal Mucosa Adhesion, and Immunomodulatory Potential of Lactobacillus plantarum Strains. AB - Survival during transit through the gastrointestinal track, intestinal mucosa adhesion, and a potential immunomodulatory effect of Lactobacillus plantarum strains 2035 and ACA-DC 2640 were investigated in a rat model. According to microbiological and multiplex PCR analysis, both strains were detected in feces 24 h after either single-dose or daily administration for 7 days. Intestinal mucosa adhesion of L. plantarum 2035 was noted in the large intestine at 24 h after single-dose administration, while it was not detected at 48 h. Daily dosing, prolonged detection of the strain up to 48 h post-administration, and expanded adhesion to the small intestine. Adhesion of L. plantarum ACA-DC 2640 to the intestinal mucosa after single-dose administration was prolonged and more extended compared to L. plantarum 2035. Daily dosing increased both the levels and the rate of positive cultures of the strains compared to those of the single dose scheme. In addition, both strains increased total IgG while decreased IgM and IgA serum levels. In conclusion, L. plantarum 2035 and L. plantarum ACA-DC 2640 survived transit through the gastrointestinal track, exhibited transient distinct adhesion to the intestinal mucosa and modulated the systemic immune response. PMID- 28634690 TI - Long-term retromuscular and intraperitoneal mesh size changes within a randomized controlled trial on incisional hernia repair, including a review of the literature. AB - : Purpose Ingrowth of fibroblasts in a polypropylene mesh may cause contraction and a later recurrence. We assessed mesh contraction in intraabdominal and retromuscular implantation after incisional hernia repair. METHODS: A cohort of patients within an RCT on laparoscopic (LHR) versus open hernia repair (OHR) had their mesh borders marked with metal clips. X-ray was performed on postoperative day 1 and after 1 year. Total length, width, and dislocation were measured. A tacker fixated large-pore polypropylene mesh was used in LHR, and a retromuscular small-pore heavy-weight mesh was sutured to the midline in OHR. Patient's pain was assessed before surgery and after 1 year. RESULTS: For analysis 37/47 patients remained: 20 LHR and 17 OHR. Hernia defect area was median 41 cm2 in LHR and 25 cm2 in OHR (p < 0.140). Implanted mesh size was 300 cm2 for LHR and 240 cm2 for OHR (p < 0.341). After 1 year the mesh area decreased by 4.4% and 0.5% in LHR and OHR, respectively (p < 0.063). Longitudinal distance decreased by 2.8% in LHR and by 2.6% in OHR (p < 0.269). Transverse distance decreased by 1.6% in LHR but increased by 3.1% in OHR (p < 0.005). Dislocation was seen in four LHR and one OHR. Two recurrent and one port-site hernia were diagnosed after LHR. Measurements between observers were identical in 58% and consensus was made in the remainder. Pain was not correlated to mesh area change. CONCLUSIONS: Mesh contraction after 1 year is not a clinical issue for an intraperitoneal large pore mesh or a retromuscular small-pore mesh. It is not correlated to postoperative pain. PMID- 28634692 TI - CRISPR-Cas orthologues and variants: optimizing the repertoire, specificity and delivery of genome engineering tools. AB - Robust and cost-effective genome editing in a diverse array of cells and model organisms is now possible thanks to the discovery of the RNA-guided endonucleases of the CRISPR-Cas system. The commonly used Cas9 of Streptococcus pyogenes shows high levels of activity but, depending on the application, has been associated with some shortcomings. Firstly, the enzyme has been shown to cause mutagenesis at genomic sequences resembling the target sequence. Secondly, the stringent requirement for a specific motif adjacent to the selected target site can limit the target range of this enzyme. Lastly, the physical size of Cas9 challenges the efficient delivery of genomic engineering tools based on this enzyme as viral particles for potential therapeutic applications. Related and parallel strategies have been employed to address these issues. Taking advantage of the wealth of structural information that is becoming available for CRISPR-Cas effector proteins, Cas9 has been redesigned by mutagenizing key residues contributing to activity and target recognition. The protein has also been shortened and redesigned into component subunits in an attempt to facilitate its efficient delivery. Furthermore, the CRISPR-Cas toolbox has been expanded by exploring the properties of Cas9 orthologues and other related effector proteins from diverse bacterial species, some of which exhibit different target site specificities and reduced molecular size. It is hoped that the improvements in accuracy, target range and efficiency of delivery will facilitate the therapeutic application of these site-specific nucleases. PMID- 28634691 TI - Modulation of rotavirus severe gastroenteritis by the combination of probiotics and prebiotics. AB - Annual mortality rates due to infectious diarrhea are about 2.2 million; children are the most vulnerable age group to severe gastroenteritis, representing group A rotaviruses as the main cause of disease. One of the main factors of rotavirus pathogenesis is the NSP4 protein, which has been characterized as a viral toxin involved in triggering several cellular responses leading to diarrhea. Furthermore, the rotavirus protein NSP1 has been associated with interferon production inhibition by inducing the degradation of interferon regulatory factors IRF3, IRF5, and IRF7. On the other hand, probiotics such as Bifidobacterium and Lactobacillus species in combination with prebiotics such as inulin, HMO, scGOS, lcFOS have been associated with improved generalized antiviral response and anti-rotavirus effect by the reduction of rotavirus infectivity and viral shedding, decreased expression of NSP4 and increased levels of specific anti-rotavirus IgAs. Moreover, these probiotics and prebiotics have been related to shorter duration and severity of rotavirus diarrhea, to the prevention of infection and reduced incidence of reinfections. In this review we will discuss in detail about the rotavirus pathogenesis and immunity, and how probiotics such as Lactobacillus and Bifidobacterium species in combination with prebiotics have been associated with the prevention or modulation of rotavirus severe gastroenteritis. PMID- 28634693 TI - rhEPO Enhances Cellular Anti-oxidant Capacity to Protect Long-Term Cultured Aging Primary Nerve Cells. AB - Erythropoietin (EPO) may protect the nervous system of animals against aging damage, making it a potential anti-aging drug for the nervous system. However, experimental evidence from natural aging nerve cell models is lacking, and the efficacy of EPO and underlying mechanism of this effect warrant further study. Thus, the present study used long-term cultured primary nerve cells to successfully mimic the natural aging process of nerve cells. Starting on the 11th day of culture, cells were treated with different concentrations of recombinant human erythropoietin (rhEPO). Using double immunofluorescence labeling, we found that rhEPO significantly improved the morphology of long-term cultured primary nerve cells and increased the total number of long-term cultured primary cells. However, rhEPO did not improve the ratio of nerve cells. A 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure nerve cell activity and showed that rhEPO significantly improved the activity of long-term cultured primary nerve cells. Moreover, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double immunofluorescence labeling flow cytometry revealed that rhEPO reduced the apoptotic rate of long-term cultured primary nerve cells. Senescence-associated beta-galactosidase (SA-beta-gal) immunohistochemistry staining showed that rhEPO significantly reduced the aging rate of long-term cultured primary nerve cells. Immunochemistry revealed that rhEPO enhanced intracellular superoxide dismutase (SOD) activity and glutathione (GSH) abundance and reduced the intracellular malondialdehyde (MDA) level. In addition, this effect depended on the dose, was maximized at a dose of 100 U/ml and was more pronounced than that of vitamin E. In summary, this study finds that rhEPO protects long-term cultured primary nerve cells from aging in a dose dependent manner. The mechanism of this effect may be associated with the enhancement of the intracellular anti-oxidant capacity. These findings provide a theoretical basis to further the anti-aging mechanism of EPO in the nervous system, and they provide experimental evidence at the cellular level for the clinical application of EPO to protect the nervous system from aging. PMID- 28634694 TI - Clinical background including anticoagulant therapy in patients with atrial fibrillation in a community-based survey: the Saitama AF Registry. AB - Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, and carries an increased risk of cardiogenic embolism. Oral anticoagulants (OACs) including warfarin and/or non-vitamin K antagonists can prevent the majority of these events. The Saitama AF Registry was a community-based survey of patients with AF in Saitama City, which represents an urban community in Japan. A total of 75 institutions participated in the registry and attempted to enroll consecutive patients with AF from September 2014 to August 2015. The aim of the present study was to examine the clinical characteristics of patients with AF using data of the Saitama AF Registry. In addition, we investigated the difference in clinical characteristics of the patients between small-sized hospitals and large-sized hospitals. A total of 3591 patients were enrolled; 57.7% of all patients were enrolled from small-sized hospitals, whereas 42.3% were from large-sized hospitals. The patients from small-sized hospitals had higher CHADS2 score than those from large-sized hospitals. Approximately, 80% of all patients were treated with OACs, and the prescription rate was higher in patients with CHADS2 score >= 2 from both small-sized hospitals and large-sized hospitals. In conclusion, the present study demonstrated an appropriate use of OACs for high-risk patients with CHADS2 score >=2 in Saitama City regardless of hospital size. PMID- 28634696 TI - Prominent midfoot involvement in children with enthesitis-related arthritis category of juvenile idiopathic arthritis. AB - Foot involvement is common in juvenile idiopathic arthritis (JIA) but is often unrecognized and difficult to treat. This study was done to assess clinical and radiological involvement of the feet and its impact on function in Indian children with enthesitis-related arthritis (ERA). We enrolled consecutive children with ERA with disease duration of less than 5 years. All patients underwent clinical examination of the feet and filled the juvenile arthritis foot index (JAFI) questionnaire. Ultrasound (US) of foot joints and entheses and extremity magnetic resonance imaging (MRI) scan of one foot were done. Fifty-five patients (53 boys), with median 14 years and disease duration 1.9 years, were included. Thirty-seven of 46 were HLA-B27-positive. Mean juvenile spondyloarthritis disease activity (JSpADA) index and juvenile idiopathic arthritis disease activity scrore-10 (JADAS10) scores were 4 and 14.25. Forty-six had history of foot pain, 36 had foot involvement on examination (15 ankle, 8 subtalar, 24 midfoot, 10 forefoot, and 21 tendoachilles), and 7 had plantar fascia involvement. On US (N = 55), 16 had ankle involvement and 8 had subtalar involvement, and 19 patients had midfoot arthritis, 24 had tendoachilles enthesitis, and 11 had plantar fasciitis. On MRI (N = 50), 27 had midfoot involvement. Thirty-three had bone edema. Fourteen had midfoot enthesitis and 17 had tenosynovitis. Clinical and US had 82% concordance at the midfoot and 90% at the ankle. MRI had 74% concordance with examination and 72% with US at the midfoot. The median JAFI scores were as follows: total JAFI = 4 (0-11), impairment = 1, activity limitation = 2, and participation restriction = 1. JAFI total and individual domains correlated with JADAS10, JSpADAS, and childhood health assessment questionnaire (CHAQ) but not duration of foot disease. JAFI was higher in children with midfoot arthritis on US. Foot joints and entheses are involved in a substantial proportion of patients with ERA patients and the midfoot is commonly involved. Foot disease produces significant functional limitation. PMID- 28634695 TI - Assessment of early diastolic intraventricular pressure gradient in the left ventricle among patients with repaired tetralogy of Fallot. AB - Assessment of left ventricular (LV) dysfunction is vital in patients with repaired tetralogy of Fallot (rTOF). The early diastolic intraventricular pressure gradient (IVPG) in the LV plays an important role in diastolic function. IVPG is calculated as the intraventricular pressure difference divided by the LV length, which allows to account for differences in LV size and therefore calculate IVPG in children. We aimed to investigate the mechanisms of LV diastolic dysfunction by measuring mid-to-apical IVPG as an indicator of the active suction force sucking blood from the left atrium into the LV. We included 38 rTOF patients and 101 healthy controls. The study population was stratified based on age group into children (4-9 years), adolescents (10-15 years), and adults (16-40 years). IVPGs were calculated based on mitral inflow measurements obtained using color M-mode Doppler echocardiography. Although total IVPGs did not differ between rTOF patients and controls, mid-to-apical IVPGs in adolescents and adults were smaller among rTOF patients than among controls (0.15 +/- 0.05 vs. 0.21 +/- 0.06 mmHg/cm, p < 0.05; 0.09 +/- 0.07 vs. 0.17 +/- 0.05 mmHg/cm, p < 0.001; respectively). Additionally, only mid-to-apical IVPG correlated linearly with peak circumferential strain (rho = 0.217, p = 0.011), longitudinal strain (rho = -0.231, p = 0.006), torsion (rho = -0.200, p = 0.018), and untwisting rate in early diastole (rho = -0.233, p = 0.006). In rTOF, the mechanisms underlying diastolic dysfunction involve reduced active suction force, which correlates with reduced LV deformation in all directions. PMID- 28634697 TI - In psoriatic arthritis Dkk-1 and PTH are lower than in rheumatoid arthritis and healthy controls. AB - Psoriatic Arthritis (PsA) is characterized by bone erosive damage often associated with exuberant bone formation especially in enthesial sites. Dkk-1 and sclerostin are the main inhibitors of the WNT/beta-catenin signaling pathway and play a key role in the regulation of both bone formation and resorption. We performed this study in order to compare the serum levels of the WNT-pathway regulators along with bone turnover markers (BTM) and parathyroid hormone (PTH) between three different groups: one group of female patients affected by PsA, one group of female patients affected by rheumatoid arthritis (RA), and healthy female controls (HC). This is a cross-sectional study including 33 patients with PsA classified with the CASPAR criteria, 35 HC, and 28 patients with RA classified with the ACR/EULAR 2010 criteria. Intact N-propeptide of type I collagen (PINP), C-terminal telopeptide of type I collagen (CTX-I), Dickkopf related-protein 1 (Dkk-1), sclerostin, PTH, and 25OH-vitamin D serum levels were dosed. The PsA group showed significantly lower Dkk-1 levels when compared to the HC and RA groups. Dkk-1 in the RA group was significantly higher than HC. A similar trend was documented for PTH. In the PsA group, CTX-I was found to be lower than in both the RA and HC groups. This study demonstrated for the first time that Dkk-1 levels in PsA are lower than HC, in contrast with RA, in which they are increased. These results might contribute to explain the different bone involvement of the two different diseases. PMID- 28634698 TI - Association between characteristics of pain and stiffness and the functional status of patients with incident polymyalgia rheumatica from primary care. AB - This paper aims to examine the relationship between different characteristics of pain and stiffness and the functional status of patients with newly diagnosed polymyalgia rheumatica (PMR). Baseline analysis of an inception cohort study was conducted. Patients aged >=18 years, with a new diagnosis of PMR were recruited from 382 English general practices. Participants were mailed a baseline questionnaire, including separate pain and stiffness manikins and numerical rating scales (NRS), a question on their ability to raise their arms above their head and the modified Health Assessment Questionnaire (mHAQ) to examine participants' functional status. Linear regression analysis, reported as regression co-efficients (95% confidence intervals (95% CI)), was used to assess the association of pain and stiffness with function, initially unadjusted and then adjusted for age, gender, deprivation status, smoking status, BMI, anxiety and depression. Six hundred fifty two patients responded to the baseline survey (88.5%). The majority (88.2%) reported no, or mild impairment in their functional status. Adjusted linear regression analysis demonstrated that high (NRS >=8) pain (0.20 (95% CI 0.10-0.28)) or stiffness (0.18 (0.09-0.26)) ratings, an increasing number of sites of pain (0.18 (0.06-0.29)) or stiffness (0.19 (0.08-0.31)) and shoulder pain (0.18 (0.05-0.31)), stiffness (0.10 (0.01-0.20)) and difficulty raising arms above one's head (0.19 (0.10-0.28)) were all associated with increased functional impairment. The majority of newly diagnosed PMR patients reported no or minimal functional difficulty. However, those who experience severe or widespread pain or stiffness often have significant functional limitation in performing their daily activities and may be a subset worthy of additional focus in primary care. PMID- 28634700 TI - Management of Tuberous Breast Deformities: Review of Long-term Outcomes and Patient Satisfaction with BREAST-Q. AB - BACKGROUND: The treatment of a tuberous breast deformity has changed over the years, with a large variety of procedures described. However, maintaining a long lasting breast contour is an ongoing challenge. The aim of this study was to evaluate the long-term results of tuberous breast corrections, focusing on the incidence of secondary procedures and patient satisfaction. MATERIALS AND METHODS: Forty-six patients who underwent correction of a tuberous breast deformity from 2000 through 2013 were considered. Age, degree of deformity, asymmetry, BMI, pregnancy, first surgical technique used, complications and further surgical procedures were evaluated. Statistical analysis was conducted to identify predicting factors for multiple procedures. Patient satisfaction was evaluated with BREAST-Q. RESULTS: Eighty-eight breasts were treated: 57 breasts underwent implant-based corrections, whereas 31 breasts underwent autologous procedures. A multi-step procedure was initially planned in 7 breasts only, and 41 breasts underwent secondary procedures: 33 out of 53 breasts (62.3%) were re operated in the implant-based group, whereas 8 out of 28 breasts (28.6%) were re operated in the autologous group. Statistical analysis showed a correlation between the number of procedures and young age (P = 0.0253) and between the number of procedures and the primary surgical technique (P = 0.0132). The BREAST Q evaluation suggested that patient satisfaction was comparable. CONCLUSIONS: The question of time is one of the main issues in breast surgery. The management of tuberous breast deformities requires a customized strategy considering all parameters to improve the longevity of the result in the long term. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28634699 TI - Cost-effective analysis of disease-modifying anti-rheumatic drugs in rheumatoid arthritis. AB - The main objective of the study was to perform the pharmacoeconomic analysis of synthetic disease-modifying anti-rheumatic drugs in rheumatoid arthritis patients. A prospective, observational study was conducted in 98 rheumatoid arthritis (RA) patients meeting 2010 Rheumatoid Arthritis Classification Criteria. Treatment-naive RA patients were initiated on synthetic disease modifying anti-rheumatic drugs (DMARD/s) and followed up for 3 months. Average cost-effectiveness analysis was done by taking Health Assessment Questionnaire Disability Index (HAQ-DI) score as a measure of effectiveness. Out of the 98 RA patients, 15.30% were males and 84.69% females. 80.61% RA patients are seropositive. Majority of the study population patients (55%) were on combination of three synthetic DMARDs and almost a quarter (24.48%) were on combination of two synthetic DMARDs. The mean value of DAS 28 at baseline was 6.07 +/- 1.33 and after 3 months treatment, the mean was 3.84 +/- 1.11. The mean disability index measured by HAQ-DI was significantly reduced from 1.43 +/- 0.71 to 0.81 +/- 0.61, p < 0.001, after 3 months treatment. The direct medical cost of treatment of RA per month is 997.05 rupees. The average cost-effectiveness ratio of combination of synthetic DMARDs was 1533.92 rupees. Treatment of RA with synthetic DMARDs controls disease activity and improves disability with reasonable cost of treatment. The majority of the direct medical cost is attributable to cost of medicine and laboratory investigation. Use of quality generic drugs and an early diagnosis would minimize the economic burden on the patient. PMID- 28634701 TI - The 50 Most Cited Articles in Facial Plastic Surgery. AB - Bibliometric analysis is a common method to determine the most influential articles in medical specialties, as it is an objective measure of peer recognition of scientific work. This study is the first bibliometric analysis of the literature in facial plastic surgery, to determine the most cited papers in the field. Bibliometric analysis was performed using the Science Citation Index from the Institute for Scientific Information, accessed through the Web of ScienceTM. Filter terms relevant to the field of facial plastic surgery were used to identify the 50 most cited journal articles between 1900 and 2016. The median number of citations was 150 (range 116-1091). The articles spanned a wide range of topics in the field, with the most common topics being free flap reconstruction (n = 10), nasal surgery (n = 9), and rhytidectomy (n = 6). The majority of these articles (n = 29) presented findings supported by level IV or V evidence. This analysis provides an overview of the most cited articles in facial plastic surgery, many of which introduced some of the most fundamental principles and techniques in the field. These landmark articles represent important educational points that should be reviewed by all clinicians and trainees in this field. Level of Evidence III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28634702 TI - Rectus Abdominis Fat Transfer (RAFT) in Lipoabdominoplasty: A New Technique to Achieve Fitness Body Contour in Patients that Require Tummy Tuck. AB - OBJECTIVE: To describe a new technique to achieve a fit-look in lipoabdominoplasty patients through liposculpture and rectus abdominis fat transfer (RAFT). METHODS: Patients with a body mass index under 26 and of both genders scheduled for abdominoplasty or body lift were selected for this procedure. Fat was transferred directly to the rectus abdominis muscle after flap elevation during lipoabdominoplasty. RESULTS: A total of 26 patients were operated on with this technique. No complications attributable to the fat grafting were noticed. All patients had a high satisfaction level with the procedure. Demonstrative cases are shown. DISCUSSION: The RAFT technique is a useful and effective technique to improve results in standard lipoabdominoplasty. Its main limitation is the adequate selection of the patient. The RAFT technique can be incorporated easily to common day practice. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28634703 TI - Isoperistaltic versus antiperistaltic side-to-side anastomosis after right laparoscopic hemicolectomy for cancer (ISOVANTI) trial: study protocol for a randomised clinical trial. AB - BACKGROUND: It is believed that loosing ileocecal valve is well tolerated in patients who do not have short bowel syndrome or Crohn disease. From the hypothesis of colonic peristalsis and transit is regulated by that ileocecal valvular mechanism, we try to find out if the creation of a new pseudo-valvular mechanism as antiperistaltic anastomosis could be considered after right hemicolectomy can cause any short- or long-term changes in gastrointestinal habits. PURPOSE: The purpose of the study at primary endpoint is to compare early (occurring within 30 days of surgery) and late (occurring during the follow-up) postoperative complications between both groups The purpose of the study at secondary endpoint is to compare intraoperative and postoperative events between experimental and control groups in terms of operating time, first oral tolerance day, first flatus and faeces, length of hospital stay and orocecal transit; comparing rates of gastrointestinal life quality and comparing mortality rates between both groups. METHODS: The ISOVANTI trial is a randomized controlled single-centre trial comparing isoperistaltic versus antiperistaltic side-to-side anastomosis after right laparoscopic hemicolectomy. It is designed as a parallel group superiority trial. CONCLUSIONS: It is unknown if a pseudo-valvular mechanism as antiperistaltic anastomosis can be considered has short- or long term consequences in gastrointestinal habit. Considering the impact that ileocolic anastomosis configuration could have on the restitution of bowel transit after right hemicolectomy, we think it is indicated and necessary a randomized trial comparing iso- and antiperistaltic modalities. TRIAL REGISTRATION: NCT02309931. PMID- 28634704 TI - Teprotumumab: a new avenue for the management of moderate-to-severe and active Graves' orbitopathy? PMID- 28634705 TI - How does pregnancy affect the patients with pituitary adenomas: a study on 113 pregnancies from Turkey. AB - OBJECTIVE: Data regarding pregnancies in relation to pituitary tumors are limited. The effects of pregnancy on pituitary adenomas and the effects of adenoma itself (hormonal activity, mass effects and pituitary insufficiency) and/or treatment on the ongoing gestation and developing fetus were evaluated. METHODS: The study was a retrospective study. A questionnaire involving questions regarding medical history before index gestation, history of related pregnancy, result of index gestation and postpartum follow-up of the patients was filled by the investigator in one of the eight Referral Endocrinology Centers from Turkey. RESULTS: One hundred and thirteen (83 prolactinoma, 21 acromegaly, 8 NFPA and 1 plurihormonal pituitary adenoma) pregnancies of 87 (60 prolactinoma, 19 acromegaly, 7 NFPA and 1 plurihormonal pituitary adenoma) patients were reviewed. The clinically important pregnancy-related tumor growth of pituitary adenomas was found to be low in previously treated adenomas. Prolactinomas were more likely to increase in size during pregnancy especially if effective prior treatment was lacking. The risk of hypopituitarism is also minimal due to pituitary adenomas during pregnancy. The results of pregnancies did not differ in patients who were on medical treatment or not for prolactinomas and acromegaly during gestation. Neural tube defect and microcephaly associated with maternal cabergoline use; Down syndrome and corpus callosum agenesis associated with maternal bromocriptine use; unilateral congenital cataract, craniosynostosis and microcephaly associated with maternal acromegaly were detected for the first time. CONCLUSION: Medical treatment can be safely done stopped in patients with prolactinoma and acromegaly when pregnancy is confirmed and reinstituted when necessary. Prospective studies may help to determine the effects of medical treatment during gestation on the mother and fetus. PMID- 28634706 TI - Parenting a Child with ASD: Comparison of Parenting Style Between ASD, Anxiety, and Typical Development. AB - Parenting children with ASD has a complex history. Given parents' increasingly pivotal role in children's treatment, it is critical to consider parental style and behaviours. This study (1) compares parenting style of parents of children with ASD, parents of children with anxiety disorders, and parents of typically developing (TD) children and (2) investigates contributors to parenting style within and between groups. Parents of children with anxiety had a distinct parenting style compared to ASD and TD parents. Unique relationships between child symptoms and parenting behaviours emerged across the three groups. Understanding factors that impact parenting between and within clinical groups can guide the development of interventions better tailored to support the needs of parents, particularly parents of children with ASD. PMID- 28634707 TI - Parent Support of Preschool Peer Relationships in Younger Siblings of Children with Autism Spectrum Disorder. AB - Preschool-aged siblings of children with ASD are at high-risk (HR) for ASD and related challenges, but little is known about their emerging peer competence and friendships. Parents are the main providers of peer-relationship opportunities during preschool. Understanding parental challenges supporting early peer relationships is needed for optimal peer competence and friendships in children with ASD. We describe differences in peer relationships among three groups of preschool-aged children (15 HR-ASD, 53 HR-NonASD, 40 low-risk, LR), and examine parent support activities at home and arranging community-based peer activities. Children with ASD demonstrated precursors to poor peer competence and friendship outcomes. Parents in the HR group showed resilience in many areas, but providing peer opportunities for preschool-age children with ASD demanded significant adaptations. PMID- 28634709 TI - Incidental durotomy in decompression for lumbar spinal stenosis: incidence, risk factors and effect on outcomes in the Spine Tango registry. AB - PURPOSE: The three aims of this Spine Tango registry study of patients undergoing decompression for spinal stenosis were to: report the rate of dural tear (DT) stratified by treatment centre; find factors associated with an increased likelihood of incurring a DT; and compare treatment outcomes in relation to DT (none vs. repaired vs. unrepaired DT). METHODS: Multivariate logistic regression was used to assess the association between DT and patient and treatment characteristics. Patient-rated and surgical outcomes were compared in patients with no DT, repaired DT, and unrepaired DT, while adjusting for case-mix. RESULTS: DT occurred in 328/3254 (10.1%) of included patients. The rate for all 29 contributing hospitals was within 95% confidence intervals of the average. The likelihood of DT increased by 2% per year of age, 1.78 times with previous spine surgery, 1.67 for a minimally/less invasive surgery, 1.58 times with laminectomy, and 1.40, and 2.12 times for BMI 31-35, and >35 in comparison with BMI 26-30, respectively. The majority of DTs (272/328; 82.9%) were repaired. Repairing the DT was associated with a longer duration of surgery (p < 0.001). More patients with repaired than with unrepaired DTs were satisfied with treatment, but the difference was not statistically significant. There was no association between DT and patient-reported outcomes. CONCLUSION: The unadjusted rate of incidental DT during decompression for LSS was homogeneous across the participating centres and was associated with age, BMI, previous surgery at the same spinal level, minimally/less invasive surgery, and laminectomy. Non-repair of DTs had no negative association with treatment outcome; however, the unrepaired DTs may have been those that were smaller in size. PMID- 28634708 TI - Speaker-Versus Listener-Oriented Disfluency: A Re-examination of Arguments and Assumptions from Autism Spectrum Disorder. AB - We re-evaluate conclusions about disfluency production in high-functioning forms of autism spectrum disorder (HFA). Previous studies examined individuals with HFA to address a theoretical question regarding speaker- and listener-oriented disfluencies. Individuals with HFA tend to be self-centric and have poor pragmatic language skills, and should be less likely to produce listener-oriented disfluency. However, previous studies did not account for individual differences variables that affect disfluency. We show that both matched and unmatched controls produce fewer repairs than individuals with HFA. For silent pauses, there was no difference between matched controls and HFA, but both groups produced more than unmatched controls. These results identify limitations in prior research and shed light on the relationship between autism spectrum disorders and disfluent speech. PMID- 28634710 TI - Pharmacodynamic and pharmacokinetic assessment of electronic cigarettes, combustible cigarettes, and nicotine gum: implications for abuse liability. AB - RATIONALE: Electronic cigarettes (ECs) are becoming popular alternatives for smokers, but there has been limited study of their abuse liability. OBJECTIVES: The objective of this study was to evaluate the abuse liability of three Vuse Solo ECs, ranging from 14 to 36 mg in nicotine content, relative to high- and low abuse liability comparator products (usual brand combustible cigarettes and nicotine gum, respectively) in a group of 45 EC-naive smokers. METHODS: Enrolled subjects' ratings of subjective effects and nicotine uptake over 6 h were used to measure abuse liability and pharmacokinetics following in-clinic use of each EC. RESULTS: Use of Vuse Solo resulted in subjective measures and nicotine uptake that were between those of combustible cigarettes and nicotine gum, although generally closer to nicotine gum. Compared to combustible cigarettes, use of Vuse Solo resulted in significantly lower scores in measures of product liking, positive effects, and intent to use again. These pharmacodynamic findings were consistent with the pharmacokinetic data, showing that cigarettes produced substantially faster and higher levels of nicotine uptake as compared to Vuse Solo and nicotine gum. Vuse Solo resulted in more rapid initial uptake of nicotine compared to nicotine gum, but peak concentration and long-term extent of uptake were not different or were lower with Vuse. CONCLUSIONS: Collectively, these findings suggest that Vuse Solo likely has an abuse liability that is somewhat greater than nicotine gum but lower than cigarettes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02269514. PMID- 28634711 TI - alpha-Pyrone Derivatives from a Streptomyces Strain Resensitize Tamoxifen Resistance in Breast Cancer Cells. AB - Tamoxifen resistance (TamR) is the underlying cause of treatment failure in many breast cancer patients receiving tamoxifen. In order to look for noncytotoxic natural products with the ability to reverse TamR, an extract from strain Streptomyces sp. KIB-H0495 was detected to be active. Subsequent large scale fermentation and isolation led to the isolation of four alpha-pyrone derivatives including two new compounds, violapyrones J (2) and K (3), and two known analogues, violapyrones B (1) and I (4). Further bioactivity assays indicated that only 1 and 3 exerted potent resensitization effects on MCF-7/TamR cells at a concentration of 1 MUM. Owing to the simple structures of 1 and 3, these two compounds might have potential for further investigation as novel tamoxifen resensitization agent in breast cancer chemotherapy. PMID- 28634712 TI - Site-directed mutagenesis under the direction of in silico protein docking modeling reveals the active site residues of 3-ketosteroid-Delta1-dehydrogenase from Mycobacterium neoaurum. AB - 3-Ketosteroid-Delta1-dehydrogenases (KsdD) from Mycobacterium neoaurum could transform androst-4-ene-3,17-dione (AD) to androst-1,4-diene-3,17-dione. This reaction has a significant effect on the product of pharmaceutical steroid. The crystal structure and active site residues information of KsdD from Mycobacterium is not yet available, which result in the engineering of KsdD is tedious. In this study, by the way of protein modeling and site-directed mutagenesis, we find that, Y122, Y125, S138, E140 and Y541 from the FAD-binding domain and Y365 from the catalytic domain play a key role in this transformation. Compared with the wild type, the decline in AD conversion for mutants illustrated that Y125, Y365, and Y541 were essential to the function of KsdD. Y122, S138 and E140 contributed to the catalysis of KsdD. The following analysis revealed the catalysis mechanism of these mutations in KsdD of Mycobacterium. These information presented here facilitate the manipulation of the catalytic properties of the enzyme to improve its application in the pharmaceutical steroid industry. PMID- 28634713 TI - Characterization and in vitro antibacterial activity of saponin-conjugated silver nanoparticles against bacteria that cause burn wound infection. AB - Saponins are glycosides, which destabilize the membrane by altering the membrane permeability. Thus, the present study was aimed to fabricate the silver nanoparticles (AgNPs) using fenugreek derived saponin (SN) against multi-drug resistant bacteria. This study has optimized the concentration of SN (240 mg/mL) for the synthesis of an effective AgNPs against the test organism Escherichia coli. The SN reduced AgNPs produced a reddish-brown colour and displayed UV absorption at 416 nm. The bio-reducing efficiency of SN (62.76%) was calculated from the HPLC quantitation of free SN in the colloidal solution of AgNPs. The FESEM-EDAX analysis of SN-AgNPs revealed a spherical shape and showed signals for elemental silver along with carbon and oxygen. The spherical morphology of SN AgNPs was also confirmed from its TEM and AFM micrographs and their sizes were found in between 2-15 nm. The hydrodynamic size, zeta potential and crystalline nature of SN-AgNPs were studied by DLS and XRD analyses and were found to be 9-30 nm, -18 mV and fcc crystallinity respectively. The FT-IR analysis of SN-AgNPs revealed that the functional groups such as C-O, C=C, C=O and O-H of SN are involved in the reduction and stability of AgNPs. The SN-AgNPs have depicted a notable in vitro structural stability and showed a remarkable antibacterial activity against the bacterial species, related to severe burn wound infections. In conclusion, the findings of our study clearly demonstrate that the SN-AgNPs conjugate would be a novel effective antibacterial agent for the prevention/eradication of multi-drug resistant bacterial infections in severe burn wounds. PMID- 28634714 TI - Microbial community shift in a suspended stuffing biological reactor with pre attached aerobic denitrifier. AB - Bioaugmentation is substantially determined by pre-attached communities in biological stuffing systems. However, the inevitable changes of microbial community shift occurred between pre-attached microorganisms on stuffing material and other existing communities in wastewater. Targeting at nitrogen removal in aerobic denitrification reactors, biological augmentation was built by polyurethane supporting material and aerobic denitrification bacteria of Pseudomonas stutzeri strains were primarily colonized. The total nitrogen removal reached a high efficiency of 77 +/- 6%, resulting from a relative high nitrate removal (90%) and a low nitrite production of 24 mg l-1. The nitrate removal was kept 10% higher using preattached strains than that using wastewater communities. During the bioaugmentation process, abundant bacteria related to nitrogen removal were evolutively enriched to compete with preattached Pseudomonas stutzeri. The most abundant bacteria growing up in the biofilm belonged to various Classes of Proteobacteria Phylum. A noticeable nitrite production with a relative low TN removal efficiency occurred when Brucella sp. and Brevundimonas sp. were simultaneously enriched in place of Pseudomonas, because Brevundimonas also accumulated nitrite during denitrification under an aerobic condition. The results indicated that pre-attached denitrifiers in comprehensive communities on stuffing material can be established for the efficient nitrogen and COD removal in aerobic denitrification reactors. PMID- 28634715 TI - Regulatory element-based prediction identifies new susceptibility regulatory variants for osteoporosis. AB - Despite genome-wide association studies (GWASs) have identified many susceptibility genes for osteoporosis, it still leaves a large part of missing heritability to be discovered. Integrating regulatory information and GWASs could offer new insights into the biological link between the susceptibility SNPs and osteoporosis. We generated five machine learning classifiers with osteoporosis associated variants and regulatory features data. We gained the optimal classifier and predicted genome-wide SNPs to discover susceptibility regulatory variants. We further utilized Genetic Factors for Osteoporosis Consortium (GEFOS) and three in-house GWASs samples to validate the associations for predicted positive SNPs. The random forest classifier performed best among all machine learning methods with the F1 score of 0.8871. Using the optimized model, we predicted 37,584 candidate SNPs for osteoporosis. According to the meta-analysis results, a list of regulatory variants was significantly associated with osteoporosis after multiple testing corrections and contributed to the expression of known osteoporosis-associated protein-coding genes. In summary, combining GWASs and regulatory elements through machine learning could provide additional information for understanding the mechanism of osteoporosis. The regulatory variants we predicted will provide novel targets for etiology research and treatment of osteoporosis. PMID- 28634717 TI - Morphological diversification among island populations of intertidal mites (Acari, Oribatida, Fortuyniidae) from the Galapagos archipelago. AB - The intertidal oribatid mite species Alismobates galapagoensis and Litoribates caelestis occur on the archipelago of Galapagos. To test for morphological variation between populations of different islands, a comprehensive morphometric study was performed. Four A. galapagoensis populations from the islands Bartolome, Isabela, Santa Cruz and San Cristobal, as well as two L. caelestis populations from Bartolome and Santa Cruz were investigated. The L. caelestis populations did not show any significant differences whereas the A. galapagoensis populations exhibited clear divergences indicating speciation. Differences in overall size of A. galapagoensis apparently followed a gradient from East to West, with specimens from San Cristobal being the largest and individuals from Bartolome and Isabela being the smallest. Apart from size, significant shape differences were found in the epimeral region and females showed stronger variation among islands than males. The degree of morphological divergence seems to correlate with geographic distance, i.e. populations from islands located closer to each other showed fewer differences than populations from distant islands. Based on this correlation we suggest that transport between islands has happened mainly by drifting on ocean currents. PMID- 28634716 TI - From prenatal anxiety to parenting stress: a longitudinal study. AB - The objective of this study was to explore how maternal mood during pregnancy, i.e., general anxiety, pregnancy-specific anxiety, and depression predicted parenting stress 3 months after giving birth, thereby shaping the child's early postnatal environmental circumstances. To this end, data were used from 1073 women participating in the Dutch longitudinal cohort Generations2, which studies first-time pregnant mothers during pregnancy and across the transition to parenthood. Women filled out the State Trait Anxiety Inventory (STAI), Pregnancy Related Anxiety Questionnaire-revised (PRAQ-R), and Beck Depression Index (BDI) three times during pregnancy: at 12, 22, and 32 weeks gestational age. Three months postpartum, a parenting stress questionnaire was filled out yielding seven different parenting constructs. Latent scores were computed for each of the repeatedly measured maternal mood variables with Mplus and parenting stress constructs were simultaneously regressed on these latent scores. Results showed that trait anxiety and pregnancy-specific anxiety were uniquely related to almost all parenting stress constructs, taking depression into account. Early prevention and intervention to reduce maternal anxiety in pregnancy could hold the key for a more advantageous trajectory of early postnatal parenting. PMID- 28634718 TI - Mite communities (Acari: Mesostigmata) in young and mature coniferous forests after surface wildfire. AB - Density, diversity and assemblage structure of Mesostigmata (cohorts Gamasina and Uropodina) were investigated in Scots pine forests differing in forest age (young: 9-40 years and mature: 83-101 years) in which wildfire occurred. This animal group belongs to the dominant acarine predators playing a crucial role in soil food webs and being important as biological control agents. In total, six forests (three within young and three within mature stands) were inspected in Puszcza Knyszynska Forest Complex in May 2015. At each forest area, sampling was done from burned and adjacent control sites with steel cylinders for heat extraction of soil fauna. Data were analyzed statistically with nested ANOVA. We found a significant effect on mite density of both fire and forest age, with more mites in mature forests and control plots. In total, 36 mite taxa were identified. Mite diversity differed significantly between forest ages but not between burned versus control. Our study indicated that all studied forests are characterized by unique mite species and that the mite communities are dominated by different mite species depending on age forest and surface wildfire occurrence. Finally, canonical correspondence analysis ranked the mite assemblages from control mature, through burned young and burned mature, away from the control young. PMID- 28634720 TI - The financial impact and drivers of hospital charges in contralateral prophylactic mastectomy and reconstruction: a Nationwide Inpatient Sample hospital analysis. AB - PURPOSE: Rates of contralateral prophylactic mastectomy (CPM) have increased over the last decade; it is important for surgeons and hospital systems to understand the economic drivers of increased costs in these patients. This study aims to identify factors affecting charges in those undergoing CPM and reconstruction. METHODS: Analysis of the Healthcare Cost and Utilization Project National Inpatient Sample was undertaken (2009-2012), identifying women aged >=18 with unilateral breast cancer undergoing unilateral mastectomy with CPM and immediate breast reconstruction (IBR) (CPM group), in addition to unilateral mastectomy and IBR alone (UM group). Generalized linear modeling with gamma regression and a log link function provided mean marginal hospital charge (MMHC) estimates associated with the presence or absence of patient, hospital and operative characteristics, postoperative complications, and length of stay (LOS). RESULTS: Overall, 70,695 women underwent mastectomy and reconstruction for unilateral breast cancer; 36,691 (51.9%) in the CPM group, incurring additional MMHCs of $20,775 compared to those in the UM group (p < 0.001). In the CPM group, MMHCs were reduced in those aged >60 years (p < 0.001), while African American or Hispanic origin increased MMHCs (p < 0.001). Diabetes, depression, and obesity increased MMHCs (p < 0.001). MMHCs increased with larger (p < 0.001) hospitals, Western location (p < 0.001), greater household income (p < 0.001), complications (p < 0.001), and increasing LOS (p < 0.001). MMHCs decreased in urban teaching hospitals and Midwest or Southern regions (p < 0.001). CONCLUSION: There are many patient and hospital factors affecting charges; this study provides surgeons and hospital systems with transparent, quantitative charge data in patients undergoing contralateral prophylactic mastectomy and immediate breast reconstruction. PMID- 28634719 TI - A sugarcane pathogenesis-related protein, ScPR10, plays a positive role in defense responses under Sporisorium scitamineum, SrMV, SA, and MeJA stresses. AB - KEY MESSAGE: A pathogenesis-related gene, ScPR10 , was isolated from sugarcane and its bio-function was characterized, demonstrating that ScPR10 was involved in plant defense responses to Sporisorium scitamineum , SrMV, SA, and MeJA stresses. Plant fungal and viral diseases are the major concerns in sugarcane industry. Many anti-fungal and antivirus components, including pathogenesis-related (PR) proteins, have been identified. The pathogenesis-related protein 10 (PR10) is the dominant group in PR families, involved in the plant defense mechanism. In this study, ScPR10 (GenBank Acc. No. KT887884), a 701-bp-length PR10 gene with a 483 bp-length open reading frame, was isolated from sugarcane. Its transient expression in the leaves of Nicotiana benthamiana indicated that the function role of ScPR10 is likely in the nucleus, and it increased the level of H2O2 accumulation in leaf cells. Moreover, ScPR10 could also enhance the resistance of N. benthamiana leaves to infection by Pseudomonas solanacearum and Fusarium solani var. coeruleum. Quantitative real-time PCR analysis revealed that ScPR10 was not constitutively expressed in sugarcane tissues due to its high expression in the buds and scant presence in root tips. In addition, the transcript of ScPR10 could be induced by a pathogenic fungus (Sporisorium scitamineum) and a virus (Sorghum mosaic virus, SrMV) in the resistant sugarcane cultivars, while it was down-regulated in the susceptible ones. After exposure to salicylic acid (SA) and methyl jasmonate (MeJA), ScPR10 peaked at 6 and 12 h, respectively. These results suggest that ScPR10 can play a positive role in sugarcane defense responses to S. scitamineum, SrMV, SA, and MeJA stresses. PMID- 28634721 TI - The mystery of the old acid man. PMID- 28634722 TI - Three Novel Bile Alcohols of Mature Male Sea Lamprey (Petromyzon marinus) Act as Chemical Cues for Conspecifics. AB - Sea lamprey, Petromyzon marinus, rely heavily on chemical cues that mediate their life history events, such as migration and reproduction. Here, we describe petromyzone A-C (1-3), three novel bile alcohols that are highly oxidized and sulfated, isolated from water conditioned with spermiated male sea lamprey. Structures of these compounds were unequivocally established by spectroscopic analyses and by comparison with spectra of known compounds. Electro-olfactogram recordings showed that 1 at 10-11 M was stimulatory to the adult sea lamprey olfactory epithelium, while 2 and 3 were stimulatory at 10-13 M. Behavioral assays indicated that 1 is attractive, 2 is not attractive or repulsive, and 3 is repulsive to ovulated female sea lamprey. The results suggest that 1 and 2 may be putative pheromones that mediate chemical communication in sea lamprey. The identification of these three components enhances our understanding of the structures and functions of sex pheromone components in this species and may provide useful behavioral manipulation tools for the integrated management of sea lamprey, a destructive invader in the Laurentian Great Lakes. PMID- 28634724 TI - DARMA: Software for dual axis rating and media annotation. AB - Continuous measurement systems provide a means of measuring dynamic behavioral and experiential processes as they play out over time. DARMA is a modernized continuous measurement system that synchronizes media playback and the continuous recording of two-dimensional measurements. These measurements can be observational or self-reported and are provided in real-time through the manipulation of a computer joystick. DARMA also provides tools for reviewing and comparing collected measurements and for customizing various settings. DARMA is a domain-independent software tool that was designed to aid researchers who are interested in gaining a deeper understanding of behavior and experience. It is especially well-suited to the study of affective and interpersonal processes, such as the perception and expression of emotional states and the communication of social signals. DARMA is open-source using the GNU General Public License (GPL) and is available for free download from http://darma.jmgirard.com . PMID- 28634723 TI - Combinational use of hepatitis B viral antigens predicts responses to nucleos(t)ide analogue/peg-interferon sequential therapy. AB - BACKGROUND: This prospective cohort study searched for factors associated with a response to nucleos(t)ide analogue/peg-interferon (NUC/peg-IFN) sequential therapy. METHODS: A total of 95 patients with chronic hepatitis B being treated with NUCs were enrolled. Immediately following NUC cessation, peg-IFN was administered at 180 ug/dose weekly for 48 weeks. RESULTS: Twenty-six patients (27%) were judged to be responders at 48 weeks after the completion of peg-IFN. Analysis of baseline factors revealed that hepatitis B surface antigen (HBsAg) <3.1 log IU/ml and HB core-related antigen (HBcrAg) <3.9 log U/ml were significant indicators of a treatment response. The levels of the markers decreased in both responders and non-responders during peg-IFN therapy but continued falling in responders only after halting peg-IFN. Lower HBsAg (<2.0 log IU/ml) and HBcrAg (<3.8 log U/ml) levels at the time of response judgment were also significantly associated with a favorable response. While lower HBcrAg at baseline was the sole predictor of decreased HBcrAg levels at judgment, lower HBsAg, lower HBcrAg, and the use of adefovir dipivoxil at baseline predicted decreased HBsAg levels at the study endpoint. The use of adefovir dipivoxil was also associated with higher serum IFN-lambda3, which might have contributed to the reduction in patient HBsAg levels. CONCLUSIONS: The combinational use of HBsAg and HBcrAg levels at baseline and their changes throughout sequential therapy may be useful for predicting a response to NUC/peg-IFN sequential therapy. PMID- 28634725 TI - Analyzing individual growth with clustered longitudinal data: A comparison between model-based and design-based multilevel approaches. AB - To prevent biased estimates of intraindividual growth and interindividual variability when working with clustered longitudinal data (e.g., repeated measures nested within students; students nested within schools), individual dependency should be considered. A Monte Carlo study was conducted to examine to what extent two model-based approaches (multilevel latent growth curve model - MLGCM, and maximum model - MM) and one design-based approach (design-based latent growth curve model - D-LGCM) could produce unbiased and efficient parameter estimates of intraindividual growth and interindividual variability given clustered longitudinal data. The solutions of a single-level latent growth curve model (SLGCM) were also provided to demonstrate the consequences of ignoring individual dependency. Design factors considered in the present simulation study were as follows: number of clusters (NC = 10, 30, 50, 100, 150, 200, and 500) and cluster size (CS = 5, 10, and 20). According to our results, when intraindividual growth is of interest, researchers are free to implement MLGCM, MM, or D-LGCM. With regard to interindividual variability, MLGCM and MM were capable of producing accurate parameter estimates and SEs. However, when D-LGCM and SLGCM were applied, parameter estimates of interindividual variability were not comprised exclusively of the variability in individual (e.g., students) growth but instead were the combined variability of individual and cluster (e.g., school) growth, which cannot be interpreted. The take-home message is that D-LGCM does not qualify as an alternative approach to analyzing clustered longitudinal data if interindividual variability is of interest. PMID- 28634727 TI - Safety and efficacy of chemosaturation in patients with primary and secondary liver tumors. AB - BACKGROUND: Chemosaturation with percutaneous hepatic perfusion (CS-PHP; hepatic CHEMOSAT(r) delivery system; Delcath Systems Inc, USA) is a novel medical device, which delivers high doses of melphalan directly to the liver in patients with primary and secondary liver tumors while limiting systemic toxicity through hemofiltration of the hepatic venous blood. The aim of this study was to analyze the safety and efficacy of the second-generation CS-PHP after 54 treatments at Hannover Medical School, Germany. METHODS: Overall response rates (ORR) were assessed according to response evaluation criteria in solid tumors (RECIST1.1). Overall survival (OS), progression-free survival (PFS), and hepatic PFS (hPFS) were analyzed using the Kaplan-Meier estimation. RESULTS: 29 patients were treated with CS-PHP as last-line therapy up to five sessions. 19 patients had unresectable hepatic metastases from solid tumors [ocular melanoma (OM) n = 11; colorectal carcinoma n = 2; pancreatic adenocarcinoma n = 2; periampular carcinoma n = 2; breast and endometrial cancer each n = 1] and 10 patients were diagnosed with hepatocellular or cholangiocarcinoma (HCC/CCA). ORR was 19.2%. Patients with OM had the highest ORR (33.3%). Similar to patients with OM, patients with hepatobiliary tumors had durable disease stabilization (40%). Median OS, PFS, and hPFS were 261, 117, and 135 days, respectively. Tumor volume negatively correlated with OS. Complications and toxicities included thrombocytopenia, cardiovascular events, ulcerous bleeding, and edema. CONCLUSION: Second-generation CS-PHP seems to be effective and tolerable. Patient selection based on tumor volume and entity is of importance. Particularly, patients with OM and hepatobiliary tumors represent promising candidates for CS PHP. PMID- 28634728 TI - Aroma oil therapy in palliative care: a pilot study with physiological parameters in conscious as well as unconscious patients. AB - OBJECTIVE: The aim of this pilot study is to analyze the reactions of healthy test persons and conscious as well as unconscious palliative patients to aroma stimuli. PATIENTS AND METHODS: In a randomized controlled study, healthy probands, conscious and unconscious palliative patients were exposed to two essential oils (lemon, lavender). Water was used as the control stimulus. Physiological parameters (breathing rate and heart rate, oxygen saturation, systolic, diastolic and mean arterial pressure) were measured. RESULTS: 10 test persons (control group), 15 conscious patients and 5 unconscious palliative patients were exposed to the stimuli. Healthy test persons reacted to lemon oil with a significant increase in respiration rate, heart rate and diastolic blood pressure, whereas to lavender oil with a significant decrease in respiration rate was measured. There were no significant reactions concerning the other parameters. Conscious and unconscious patients reacted with a significant increase in all measured parameters to lemon oil and with a significant decrease in all parameters except for oxygen saturation to lavender oil. No significant differences in the reactions were measured between the conscious and unconscious patients and no significant reactions to control stimuli were detected. All physiological reactions were very short and only detectable during stimulus presentation. CONCLUSION: Significant physiological reactions were measured after simulation with aroma oils in all three groups in this study. Healthy probands showed different reactions than palliative patients irrespective to their conscious state. PMID- 28634729 TI - Analysis of gender-based differences among surgeons in Japan: results of a survey conducted by the Japan Surgical Society. Part 1: Working style. AB - PURPOSE: To assess the working styles of men and women working as surgeons in Japan. METHODS: In July, 2014, the Japan Surgical Society invited all their members (n = 29,861), through an internet campaign, to participate in a nationwide survey of surgeons. The items investigated in this descriptive study included demographic information and working styles, based on a questionnaire. RESULTS: In total, 6211 surgeons participated (response rate 20.8%, 5586 men and 625 women). The largest age stratum was 40-49 years for men and 30-39 years for women. Overall, respondents identified their labor contract, including salary and work hours, as the highest priority for improvement. Women with children were more likely to be part-time employees, work fewer hours, and take fewer house calls/on-calls than their male counterparts. Moreover, women of all ages earned a lower annual income than men, irrespective of whether they had children. Perception scores for discrimination related to work and promotion were significantly higher among women than men (p < 0.01 and p = 0.011, respectively). CONCLUSIONS: A significant difference in working style was observed between men and women working as surgeons in Japan. PMID- 28634726 TI - Connexin Channels at the Glio-Vascular Interface: Gatekeepers of the Brain. AB - Neuronal survival, electrical signaling and synaptic activity require a well balanced micro-environment in the central nervous system. This is achieved by the blood-brain barrier (BBB), an endothelial barrier situated in the brain capillaries, that controls near-to-all passage in and out of the brain. The endothelial barrier function is highly dependent on signaling interactions with surrounding glial, neuronal and vascular cells, together forming the neuro-glio vascular unit. Within this functional unit, connexin (Cx) channels are of utmost importance for intercellular communication between the different cellular compartments. Connexins are best known as the building blocks of gap junction (GJ) channels that enable direct cell-cell transfer of metabolic, biochemical and electric signals. In addition, beyond their role in direct intercellular communication, Cxs also form unapposed, non-junctional hemichannels in the plasma membrane that allow the passage of several paracrine messengers, complementing direct GJ communication. Within the NGVU, Cxs are expressed in vascular endothelial cells, including those that form the BBB, and are eminent in astrocytes, especially at their endfoot processes that wrap around cerebral vessels. However, despite the density of Cx channels at this so-called gliovascular interface, it remains unclear as to how Cx-based signaling between astrocytes and BBB endothelial cells may converge control over BBB permeability in health and disease. In this review we describe available evidence that supports a role for astroglial as well as endothelial Cxs in the regulation of BBB permeability during development as well as in disease states. PMID- 28634730 TI - Phase III trial comparing UFT + PSK to UFT + LV in stage IIB, III colorectal cancer (MCSGO-CCTG). AB - PURPOSE: Oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) is not inferior to standard weekly fluorouracil and folinate for stage II/III colon cancer. However, protein-bound polysaccharide K (PSK) has been evaluated as postoperative adjuvant therapy for colorectal cancer. This report is the first of MCSGO-CCTG, which compared UFT/LV to UFT/PSK as adjuvant chemotherapy for stage IIB or III colorectal cancer in patients who had undergone Japanese D2/D3 lymph node dissection. METHODS: The primary endpoint was the 3-year disease-free survival (DFS). A randomized non-inferiority study compared UFT/LV to UFT/PSK. The overall survival, adverse events, compliance, and quality of life were also investigated as the secondary endpoints. RESULTS: Between March 2006 and December 2010, 357 patients were randomized to UFT/PSK (n = 178) or UFT/LV (n = 179) (median age 65 years, colon/rectum 67.4/32.6%, stage IIB/IIIA/IIIB/IIIC 11.1/15.7/55.0/18.2%). The 3-year DFS rate was 82.3% in those receiving UFT/LV and 72.1% in those receiving UFT/PSK. The non-inferiority of UFT/PSK adjuvant therapy to UFT/LV therapy was not verified (-9.06%, 90% confidence interval 17.06 to -1.06%). The 3-year overall survival rate was 95.4% in those receiving UFT/LV and 90.7% in those receiving UFT/PSK. CONCLUSIONS: As adjuvant chemotherapy for stage IIB and III colorectal cancer patients, UFT/PSK adjuvant therapy was not non-inferior to UFT/LV therapy with respect to the DFS. PMID- 28634731 TI - Frey's procedure for chronic pancreatitis improves the nutritional status of these patients. AB - PURPOSE: The aim of surgical intervention for chronic pancreatitis (CP) is to relieve symptoms and improve quality of life. However, the precise effect of surgery on the nutritional status of CP patients, which is often impaired by exocrine and endocrine pancreatic dysfunction, has not been elucidated. We conducted this study to evaluate whether Frey's procedure improves the nutritional status of CP patients. METHODS: The nutritional status of 35 patients who underwent Frey's procedure for CP at our institute between April 2005 and December 2014, was assessed by the controlling nutritional status (CONUT) scoring before and 1 year after the surgery, and compared with that of seven CP patients who underwent pancreatoduodenectomy. The occurrence of postoperative hepatic steatosis was also monitored. RESULTS: The nutritional status improved after Frey's procedure, but not after pancreatoduodenectomy. The median postoperative CONUT score after Frey's procedure was significantly lower than the preoperative score (1.0 +/- 0.5 vs. 4.0 +/- 2.5; p < 0.001). CONCLUSION: Frey's procedure is superior to pancreatoduodenectomy for improving the nutritional status of CP patients. PMID- 28634733 TI - Dynamic Properties of Human Tympanic Membrane After Exposure to Blast Waves. AB - Blast overpressure causes dynamic damage to middle ear components, and tympanic membrane (TM) rupture is the most frequent middle ear injury. However, it is unclear how the blast waves change mechanical properties of the TM and affect sound transmission through the ear. This paper reports the current study on dynamic properties of the TM after exposure to blast waves by using acoustic loading and laser Doppler vibrometry (LDV). The TM specimens were prepared from human temporal bones following exposures to blast overpressure. Vibration of the TM specimen induced by acoustic loading was measured by LDV over a frequency range of 200-8000 Hz. An inverse-problem solving method with finite element modeling was used to determine the complex modulus of the TM specimen. The post blast storage modulus ranged from 23.1 to 26.9 MPa, and loss modulus ranged from 0.09 to 3.78 MPa as frequency increased from 200 to 8000 Hz. Compared to the complex modulus of normal TM reported in the literature, the post-blast storage and loss modulus decreased significantly across the frequency range. The scanning electron microscopy (SEM) images of the post-blast TM samples showed microstructural changes of the tissue, which explained the alteration of mechanical properties of the TM samples. PMID- 28634741 TI - Erratum to: Zidovudine: An Update of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy. PMID- 28634732 TI - Engineering poly(lactic-co-glycolic acid) (PLGA) micro- and nano-carriers for Controlled Delivery of 17beta-Estradiol. AB - With menopause, circulating levels of 17beta-estradiol (E2) markedly decrease. E2 based hormone therapy is prescribed to alleviate symptoms associated with menopause. E2 is also recognized for its beneficial effects in the central nervous system (CNS), such as enhanced cognitive function following abrupt hormonal loss associated with ovariectomy. For women with an intact uterus, an opposing progestogen component is required to decrease the risk of developing endometrial hyperplasia. While adding an opposing progestogen attenuates these detrimental effects on the uterus, it can attenuate the beneficial effects of E2 in the CNS. Poly(lactic-co-glycolic acid) (PLGA) micro- and nano- carriers (MNCs) have been heavily investigated for their ability to enhance the therapeutic activity of hydrophobic agents following exogenous administration, including E2. Multiple PLGA MNC formulation parameters, such as composition, molecular weight, and type of solvent used, can be altered to systematically manipulate the pharmacokinetic and pharmacodynamic profiles of encapsulated agents. Thus, there is an opportunity to enhance the therapeutic activity of E2 in the CNS through controlled delivery from PLGA MNCs. The aim of this review is to consider the fate of exogenously administered E2 and discuss how PLGA MNCs and route of administration can be used as strategies for controlled E2 delivery. PMID- 28634734 TI - Exploring the digital technology preferences of teenagers and young adults (TYA) with cancer and survivors: a cross-sectional service evaluation questionnaire. AB - PURPOSE: Digital technology has the potential to support teenagers and young adults (TYAs) with cancer from the onset of their disease into survivorship. We aimed to establish (1) the current pattern of use of TYA digital technologies within our service-user population, and (2) their preferences regarding digital information and support within the service. METHODS: A cross-sectional survey was administered as a paper and online self-completed questionnaire to TYAs aged 13 24 accessing outpatient, inpatient, and day care cancer services at a regional specialist centre over a 4-week period. RESULTS: One hundred two TYAs completed the survey (55.7% male; 39.8% female; 83.3% paper; 16.7% online; mean age 18.5 years [SD = 3.51]). Of the TYAs, 41.6% rated the importance of digital communication as "essential" to their lives. Half (51.0%) kept in contact with other patients they had met during treatment, and 12.0% contacted patients they had not met in person. Respondents wanted to receive clinical information online (66.3%) and use online chat rooms (54.3%). Future online services desired included virtual online groups (54.3%), online counselling or psychological support (43.5%), and receiving (66.3%) and sharing (48.9%) clinical information online. CONCLUSIONS: Young people with cancer are digital natives. A significant subgroup expressed a desire for digital resources from oncology services, though existing resources are also highly valued. Digital resources have potential to improve patient experience and engagement. IMPLICATIONS FOR CANCER SURVIVORS: There is considerable scope to develop digital resources with which TYAs can receive information and connect with both professionals and fellow patients, following diagnosis, through treatment and survivorship. PMID- 28634742 TI - Outcomes of coronoid-first repair in terrible triad injuries of the elbow. AB - BACKGROUND: Clinical outcomes of terrible triad injuries (TTIs) of the elbow are historically poor. To date, it is still debatable whether the coronoid needs to be fixed and if so, how and in which sequence. METHODOLOGY: Between 2010 and 2013, 13 patients were treated surgically for acute TTIs of the elbow at a Tertiary Level 1 Trauma Centre by a single surgeon, using a standardized protocol, which included coronoid-brachialis complex fixation via pull-through trans-osseous sutures, radial head fixation or prosthetic replacement and a repair of the lateral ulnar collateral ligament. Repair of the medial collateral ligament (MCL) was done if valgus-stress test demonstrated persistent instability. Patients were then followed-up with clinical and radiological evaluation by the senior author until fracture union and elbow range of motion reached a plateau. Outcomes measured were range of motion, DASH scores and MEPS, as well as surgical complications. RESULTS: Intraoperative stability was achieved in all 13 cases, MCL repair was required in 3 cases and application of external fixation was not required in any case. Patients were followed-up for an average length of 27.7 months and the minimum follow-up period was 12 months. The average age of patients was 46.4 years (range 35-79 years old) at the time of trauma. This included eight Regan-Morrey Type I and five Regan-Morrey Type II coronoid fractures, with ten Mason Type I/II and three Mason Type III radial head fractures. The average arc of ulno-humeral motion was 105.0 degrees (range 80 degrees -135 degrees ). The average flexion contracture was 15.0 degrees (range 0 degrees -40 degrees ). The average supination-pronation arc was 114.9 degrees (range 0 degrees -180 degrees ). The average MEPS was 85 of 100 (range 45-100) and the average DASH score was 21.2 of 100 (range 1.7-61.2). A single case of radio-ulnar synostosis, heterotropic ossification and two cases of recurrent elbow instability were noted. CONCLUSIONS: The coronoid-first surgical approach, using a suture-lasso fixation method, has technical benefits for us and showed good clinical success in our series. This is important with postero-medial rotatory instability being common in our series of TTIs. We emphasize not to miss a TTI in an apparently isolated low Mason class radial head fracture. PMID- 28634743 TI - Comminuted olecranon fractures: biomechanical testing of locked versus minifragment non-locked plate fixation. AB - INTRODUCTION: Open reduction and internal fixation has long been accepted as optimal treatment for displaced olecranon fractures based on poor results seen with conservative management. With the presence of comminution, tension-band wiring constructs are contraindicated due to tendency to compress through fragments, thereby shortening the articular segment. Therefore, plate fixation is typically employed. Our hypothesis was that in a comminuted fracture model, 2.7 mm reconstruction plating without locking screws will perform equally to 3.5 mm locked plating in terms of fracture displacement and rotation (shear). MATERIALS AND METHODS: A three-part comminuted olecranon fracture pattern was created in nine matched pairs of cadaveric specimen using an oscillating saw in standardized, reproducible fashion. Each matched pair was then randomized to receive either 2.7 mm reconstruction plating or 3.5 mm proximal ulna locked plating. Random allocation software was used to assign the 2.7 mm plate construct to either the right or left side of each pair with the contralateral receiving the 3.5 mm plate construct. Specimens were cyclically loaded simulating passive range of motion exercises commonly performed during rehabilitation. Displacement and rotation in relation to the long axis of the ulna were measured through motion capture. Fragment gapping and rotation was quantified following 100 cycles at 10 N and again following 100 cycles at 500 N. RESULTS: No significant differences were detected between the 2.7 and 3.5 mm plates in fracture rotation or gapping following loads at 10 N (0.5 degrees and 0.7 degrees ; 0.6 and 1.2 mm; respectively; p > 0.05) or 500 N (2.3 degrees and 1.6 degrees ; 3.8 and 3.1 mm; respectively; p > 0.05) loading. Fragment rotation and gapping were positively correlated within each plate construct (R 2 > 0.445; p < 0.05). CONCLUSIONS: 2.7 mm plating is an alternative to 3.5 mm locked plating with decreased plate prominence without significantly sacrificing displacement and rotational control. This is beneficial in fracture patterns where the traditional dorsal plating does not offer optimal screw trajectory. PMID- 28634744 TI - Gain-of-function SNPs in NLRP3 and IL1B genes confer protection against obesity and T2D: undiscovered role of inflammasome genetics in metabolic homeostasis? PMID- 28634746 TI - Screening and identification of a specific peptide binding to cervical cancer cells from a phage-displayed peptide library. AB - OBJECTIVES: To screen and identify the probe markers specifically binding to human cervical cancer, a phage-displayed 12-mer peptide library was used for biopanning of SiHa cells. RESULTS: After four rounds of whole-cell subtraction biopanning, the phage recovery was 21-fold higher (from 3.9 * 10-5 to 8.3 * 10-4) than that of the first round, and specific phage clones were significantly enriched. 57 randomly selected phage clones were tested by ELISA, and 36 phage clones were identified as positive clones. After sequencing of positive clones, six different peptide sequences were obtained and CSP3 showed best affinity and specificity to SiHa cells via immunofluorescence assay. CONCLUSIONS: Peptide, CSP3, bound to SiHa cells specifically and sensitively. It may be a potential candidate for molecular imaging detection and targeting therapy of cervical cancer. PMID- 28634745 TI - Prolactin function and putative expression in the brain. AB - INTRODUCTION: Prolactin is a peptide hormone mainly synthetized and secreted by the anterior pituitary gland, but also by extrapituitary tissues, such as mammary gland, decidua, prostate, skin, and possibly the brain. Similarly, prolactin receptor is expressed in the pituitary gland, many peripheral tissues, and in contrast to prolactin, its receptor has been consistently detected in several brain regions, such as cerebral cortex, olfactory bulb, hypothalamus, hippocampus, amygdala, among others. Classically, prolactin function has been related to the stimulation of lactogenesis and galactopoiesis, however, it is well known that prolactin induces a wide range of functions in different brain areas. PURPOSE: The aim of this review is to summarize recent reports on prolactin and prolactin receptor synthesis and localization, as well as recapitulate both the classic functions attributed to this hormone in the brain and the recently described functions such as neurogenesis, neurodevelopment, sleep, learning and memory, and neuroprotection. CONCLUSION: The distribution and putative expression of prolactin and its receptors in several neuronal tissues suggests that this hormone has pleiotropic functions in the brain. PMID- 28634747 TI - Evaluation of vaccination strategies for SIR epidemics on random networks incorporating household structure. AB - This paper is concerned with the analysis of vaccination strategies in a stochastic susceptible [Formula: see text] infected [Formula: see text] removed model for the spread of an epidemic amongst a population of individuals with a random network of social contacts that is also partitioned into households. Under various vaccine action models, we consider both household-based vaccination schemes, in which the way in which individuals are chosen for vaccination depends on the size of the households in which they reside, and acquaintance vaccination, which targets individuals of high degree in the social network. For both types of vaccination scheme, assuming a large population with few initial infectives, we derive a threshold parameter which determines whether or not a large outbreak can occur and also the probability of a large outbreak and the fraction of the population infected by a large outbreak. The performance of these schemes is studied numerically, focusing on the influence of the household size distribution and the degree distribution of the social network. We find that acquaintance vaccination can significantly outperform the best household-based scheme if the degree distribution of the social network is heavy-tailed. For household-based schemes, when the vaccine coverage is insufficient to prevent a major outbreak and the vaccine is imperfect, we find situations in which both the probability and size of a major outbreak under the scheme which minimises the threshold parameter are larger than in the scheme which maximises the threshold parameter. PMID- 28634748 TI - Exposure-response relationship of ramucirumab in East Asian patients from RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer. AB - BACKGROUND: Ramucirumab is a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor-2. Second-line ramucirumab, in conjunction with paclitaxel (ramucirumab 8 mg/kg or placebo in combination with 80 mg/m2 paclitaxel), has been shown to be effective and safe in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in RAINBOW, a global phase III randomized clinical trial. We conducted an exploratory exposure-response analysis of efficacy and safety of ramucirumab in East Asian patients from the RAINBOW trial. METHODS: Using sparse pharmacokinetic samples collected in the RAINBOW trial, a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C min,ss) using a nonlinear mixed-effect modeling approach. Kaplan-Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (C min,ss) and efficacy relationship by overall survival and progression-free survival. Exposure-safety relationships were assessed descriptively. RESULTS: Two hundred and twenty-two East Asian patients were included in this exposure response analysis. Higher ramucirumab C min,ss was associated with longer overall survival (p = 0.0115) and progression-free survival (p = 0.0179) in this patient cohort. Patients with higher ramucirumab C min,ss (>=56.87 ng/ml median) had higher incidences of grade >=3 leukopenia and neutropenia, but not febrile neutropenia or hypertension. CONCLUSIONS: This exploratory analysis suggests a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in East Asian patients from RAINBOW, consistent with the overall exposure-response analysis from this trial. A regimen with a higher dosage of ramucirumab warrants further consideration for East Asian patients with gastric/GEJ cancer. PMID- 28634749 TI - The King laryngeal tube: a mimic of esophageal intubation in the emergency department. AB - The King Airway is a temporary airway device used primarily in the pre-hospital setting and typically exchanged for an endotracheal tube upon arrival to the emergency department. Since this usually occurs before imaging, many radiologists are unfamiliar with the King Airway. This lack of familiarity can have important consequences for the patient and treating team. The purpose of this article is to raise awareness of the King Airway among radiologists, emphasize appropriate positioning, and review the imaging complications of incorrect positioning. PMID- 28634750 TI - T135I substitution in the nonstructural protein 2C enhances foot-and-mouth disease virus replication. AB - The foot-and-mouth disease virus (FMDV) nonstructural protein 3A plays an important role in viral replication, virulence, and host range. It has been shown that deletions of 10 or 19-20 amino acids in the C-terminal half of 3A attenuate serotype O and C FMDVs, which replicate poorly in bovine cells but normally in porcine-derived cells, and the C-terminal half of 3A is not essential for serotype Asia1 FMDV replication in BHK-21 cells. In this study, we constructed a 3A deletion FMDV mutant based on a serotype O FMDV, the wild-type virus O/YS/CHA/05, with a 60-amino acid deletion in the 3A protein sequence, between residues 84 and 143. The rescued virus O/YS/CHA/05-Delta3A exhibited slower growth kinetics and formed smaller plaques compared to O/YS/CHA/05 in both BHK-21 and IBRS-2 cells, indicating that the 60-amino acid deletion in the 3A protein impaired FMDV replication. After 14 passages in BHK-21 cells, the replication capacity of the passaged virus O/YS/CHA/05-Delta3A-P14 returned to a level similar to the wild-type virus, suggesting that amino acid substitutions responsible for the enhanced replication capacity occurred in the genome of O/YS/CHA/05-Delta3A-P14. By sequence analysis, two amino acid substitutions, P153L in VP1 and T135I in 2C, were found in the O/YS/CHA/05-Delta3A-P14 genome compared to the O/YS/CHA/05-Delta3A genome. Subsequently, the amino acid substitutions VP1 P153L and 2C T135I were separately introduced into O/YS/CHA/05 Delta3A to rescue mutant viruses for examining their growth kinetics. Results showed that the 2C T135I instead of the VP1 P153L enhanced the virus replication capacity. The 2C T135I substitution also improved the replication of the wild type virus, indicating that the effect of 2C T135I substitution on FMDV replication is not associated with the 3A deletion. Furthermore, our results showed that the T135I substitution in the nonstructural protein 2C enhanced O/YS/CHA/05 replication through promoting viral RNA synthesis. PMID- 28634751 TI - Herpesviral vectors and their application in oncolytic therapy, vaccination, and gene transfer. AB - Herpesviruses are enveloped DNA viruses that infect vertebrate cells. Their high potential cloning capacity and the lifelong persistence of their genomes in various host cells make them attractive platforms for vector-based therapy. In this review, we would like to highlight recent advances of three major areas of herpesvirus vector development and application: (i) oncolytic therapy, (ii) recombinant vaccines, and (iii) large capacity gene transfer vehicles. PMID- 28634752 TI - Comparison of three treatment strategies for cesarean scar pregnancy. AB - PURPOSE: To explore the optimal treatment for cesarean scar pregnancy. METHOD: In total, 86 women diagnosed with a cesarean scar pregnancy were divided into three groups according to treatment. The human chorionic gonadotrophin (hCG) decline percentage, intraoperative blood loss and success rate were analyzed in Group A [combination of uterine arterial embolization (UAE), local methotrexate (MTX) injection and dilation & curettage (D&C)], Group B (combination of UAE and local MTX injection) and Group C (D&C). Then, the best treatment was carefully analyzed, and recommendations were provided. RESULTS: The success rate was highest in Group A (97.5%) compared with Group B (76%) and Group C (63.15%). The reduction in hCG was greatest in Group A (86.62%, 44.0-99.97%) compared with group B (67.83%, 18.0-98.03%) and Group C (68.21%, 27.0-93.24%). The intraoperative blood loss was lowest in Group A (44.881, 5-200 ml) compared with Group C (224.737, 10-1000 ml). Additionally, we found that the best time to perform D&C in group A depended on the hCG reduction percentage, and a 35% reduction after UAE and local MTX injection could be used as the indicator to perform D&C. CONCLUSIONS: The combination of UAE, local MTX injection and D&C for CSP patients is the optimal treatment strategy. A 35% reduction in hCG after UAE and local MTX injection can be recommended as the indicator to perform D&C. PMID- 28634753 TI - Fetal cephaloceles: prenatal diagnosis and course of pregnancy in 65 consecutive cases. AB - PURPOSE: To scrutinize the characteristics of all cases with antenatally established diagnosis of cephalocele in two tertiary referral centers. METHODS: We retrospectively reviewed 65 cases diagnosed with cephaloceles and tabulated sonographic findings and autopsy recordings as well as medical charts of all survivors in terms of clinical outcome. RESULTS: The case notes of 65 fetuses were available for final analysis. Gestational age (GA) at diagnosis ranged from 10.4 to 38.1 weeks. Of our cohort, 53/65 cases (80%) had occipital protrusions, 10 (15%) were found to have frontal lesions, and another two had parietal cephaloceles. A total of 52 pregnancies were terminated or resulted in intrauterine fetal demise (78%). In 18 cases (11%), the cephalocele was part of underlying syndromic disorders (e.g., Meckel-Gruber syndrome). Thirteen pregnancies were continued until term, out of which all affected individuals were live-born. Neurosurgical intervention was prompted within the first 7 months postnatally. CONCLUSIONS: In general, the outcome of fetuses with cephaloceles is rather poor as four out of five pregnancies were terminated. Postnatal outcome of all survivors in our cohort was rather determined by localization of the cele and more important by the presence and severity of concomitant malformations than the extent of the lesion. PMID- 28634754 TI - Value of endometrial thickness assessed by transvaginal ultrasound for the prediction of endometrial cancer in patients with postmenopausal bleeding. AB - PURPOSE: Histological confirmation of endometrial cancer by dilatation/curettage (D/C) in women with postmenopausal bleeding (PMB) can be challenging due to anesthesiological and/or surgical risks. Thus, less invasive methods for diagnostics are required to identify patients with minimal risk for endometrial cancer (EC) to avoid unnecessary surgical intervention. The objective of this single-center cohort study was to assess the diagnostic validity of transvaginal ultrasound (TVUS) measurements of endometrial thickness (ET) in patients with PMB for the detection of EC. METHODS: A retrospective analysis of data from patients presenting between January 2005 and August 2014 at the Department of Obstetrics and Gynecology, University Hospital Ulm, Germany, with PMB and subsequent D/C was performed. Complete data with TVUS documentation of ET and histological results of tissue samples were available from 254 patients. In addition, data on age, body mass index (BMI), ASA-score, diabetes, hypertension, and hematological laboratory values (for a smaller subsample) were recorded. To identify independent risk factors, a multivariate logistic regression with endometrial cancer as binary response variable (yes/no) was performed. Diagnostic efficacy data for different ET cutoff points (<=1 to <=26 mm) were obtained by a receiver operator characteristic (ROC) curve analysis. RESULTS: The multivariate logistic regression revealed a significant independent predictive value for age and ET. However, none of the analyzed ET cutoff points showed optimal diagnostic validity, as all cutoff points with sensitivity rates above 90% (<=1 to <=5 mm) had false positive rates of 70% and higher. CONCLUSIONS: There is no ET cutoff point that provides good diagnostic accuracy and/or reliably excludes the presence of endometrial cancer in patients with PMB. Thus, our data analysis supports the actual German approach of histological evaluation of any PMB to confirm or exclude EC. PMID- 28634755 TI - Rhabdomyosarcoma of the lower female genital tract: an analysis of 144 cases. AB - PURPOSE: The aim of the present study was to elucidate the clinico-pathological characteristics of female patients with lower genital tract rhabdomyosarcoma (RMS) stratified by age group and investigate their prognosis, using a multi institutional database. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was accessed (1973-2013) and a cohort of females diagnosed with RMS of the lower genital tract (vulva, vagina, cervix) was drawn. Five-year overall survival (OS) rate was estimated following generation of Kaplan-Meier curves and compared with the log-rank test. RESULTS: A total of 144 eligible cases were identified; 51.4 and 48.6% originated from the vagina/vulva and the cervix, respectively. Median patient age was 16 years and distant metastases were rare (ten cases). The majority of tumors were of embryonal histology (75.7%). Non-embryonal RMS was more prevalent in the older patient groups. Tumors originating from the cervix were more common among adolescents and premenopausal women. Rate of LN involvement was 52.9 and 20% for vulvovaginal and cervical tumors (p = 0.02). Five-year OS rate was 68.4%; factors associated with better OS were younger age, absence of distant metastasis, embryonal histology, negative LNs, and performance of surgery. For prepubertal girls and adolescents, radical surgery did not confer a survival benefit compared to local tumor excision. CONCLUSION: RMS of the lower genital tract primarily affects prepubertal girls and adolescents, who have excellent survival rates; however, outcomes for adults remain poor. PMID- 28634756 TI - A high throughput targeted and non-targeted method for the analysis of microcystins and anatoxin-A using on-line solid phase extraction coupled to liquid chromatography-quadrupole time-of-flight high resolution mass spectrometry. AB - Microcystins are cyclic heptapeptide hepatotoxins produced by cyanobacteria in freshwater. Sample preparation for the analysis of these cyanotoxins in water from algal blooms can take up to several days due to the matrix complexity and the low detection limits required to comply with current legislation. Moreover, there is a large number of unknown microcystins that could potentially exist in the environment resulting from different amino acid substitutions into the microcystin skeletal structure. To tackle these problems, the present study involved the development of a high throughput method based on on-line solid phase extraction coupled to liquid chromatography that could provide quantitative results for 12 microcystin variants (LR, YR, RR, HtyR, HilR, WR, LW, LA, LF, LY, Dha7-LR, and Dha7-RR) and anatoxin-A in less than 3 h with detection limits between 0.004 and 0.01 MUg L-1 and expanded uncertainty between 4 and 14%. Data dependent acquisition was employed for the non-targeted analysis of these cyanotoxins. Filtering the data based on structure diagnostic fragments, two unknown microcystin variants not previously reported in the literature were detected. The structures Leu1-microcystin-Met(O)R and Leu1-microcystin-LY were fully characterized by accurate mass measurement, collision-induced dissociation, and fragmentation prediction software. PMID- 28634757 TI - A UHPLC-MS/MS method for profiling multifunctional steroids in human hair. AB - It is important to profile steroids in many physiological and pathological processes. Recently, hair has been used for the long-term measurement of endogenous steroid hormones. Analyzing hair has advantages of being noninvasive and time sequential compared with other bio-specimens. Liquid chromatography-mass spectrometry (LC-MS) techniques have been widely used over the past decades; however, it is challenging to profile estrogens in hair by LC-MS, and more comprehensive steroid profiling is required. In this paper, an ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to simultaneously profile 28 multifunctional steroids, including corticosteroids (n = 6), estrogens (n = 13), androgens (n = 5) and progestogens (n = 4), in human scalp hair in a single run. To optimize the sample preparation procedure, we evaluated extraction time, post-incubation purification and hair fragment length; 30 mg hair samples were washed with hexane, cut into 5 mm pieces and incubated in methanol for 18 h at 25 degrees C. Methanol extraction derivatized using Girard P and dansyl chloride reagent was analyzed within 25 min using an automated injection program combined with a diverter valve switch and step analysis (AIDSA). The method was well validated in terms of linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, matrix effect and recovery, and was successfully applied to a steroid profile from male and female hairs. Significant differences were observed between genders. In addition, steroids showed a declining trend from the proximal to more distal hair segments; thus, care should be taken when obtaining hair samples for analysis to account for this difference in steroid levels along the length of hair. Graphical Abstract The workflow of the estabished UHPLC-MS/MS method. PMID- 28634758 TI - A general double library SELEX strategy for aptamer selection using unmodified nonimmobilized targets. AB - Aptamer discovery for unmodified nonimmobilized targets has been constantly presenting itself as a significant challenge to the research community. We demonstrate here a novel double library (DL) SELEX strategy and its usefulness and generality toward discovering both ssDNA- and RNA-based aptamers with nanomolar binding affinities toward unmodified targets of both small (e.g., doxycycline) and large (e.g., VEGF165) sizes. The same selection strategy further allows for concurrent selection of an aptamer pair, recognizing discrete epitopes on the same protein, from the same selection cycles for the sandwich aptamer pair based biosensor development (e.g., one aptamer for the recognition and the other for the signal transduction). These results establish the DL-SELEX method developed here as a valuable and highly accessible selection strategy for aptamer discovery, especially when chemical modifications of target molecules are not preferred or simply impossible. PMID- 28634759 TI - Current applications of high-resolution mass spectrometry for the analysis of new psychoactive substances: a critical review. AB - The proliferation of new psychoactive substances (NPS) in recent years has resulted in the development of numerous analytical methods for the detection and identification of known and unknown NPS derivatives. High-resolution mass spectrometry (HRMS) has been identified as the method of choice for broad screening of NPS in a wide range of analytical contexts because of its ability to measure accurate masses using data-independent acquisition (DIA) techniques. Additionally, it has shown promise for non-targeted screening strategies that have been developed in order to detect and identify novel analogues without the need for certified reference materials (CRMs) or comprehensive mass spectral libraries. This paper reviews the applications of HRMS for the analysis of NPS in forensic drug chemistry and analytical toxicology. It provides an overview of the sample preparation procedures in addition to data acquisition, instrumental analysis, and data processing techniques. Furthermore, it gives an overview of the current state of non-targeted screening strategies with discussion on future directions and perspectives of this technique. Graphical Abstract Missing the bullseye - a graphical respresentation of non-targeted screening. Image courtesy of Christian Alonzo. PMID- 28634761 TI - Unveiling the compositional variety of cardiolipins in Rhodobacter sphaeroides by liquid chromatography with electrospray ionization and multistage collision induced dissociation mass spectrometry. AB - Cardiolipins (CL) contained in the lipid extracts of the photosynthetic bacterium Rhodobacter sphaeroides (strain R26) were systematically characterized by reversed-phase liquid chromatography coupled to electrospray ionization mass spectrometry, performed in single (MS), tandem (MS/MS) and sequential (MS3) modes using a linear ion trap mass spectrometer. The total number of carbon atoms and C=C bonds of each CL and, subsequently, those related to each of the constituting phosphatidic acid (PA) units, along with the location of the latter on the central glycerol backbone, were inferred from MS and MS/MS data, respectively. Moreover, the composition and location of both acyl chains on the glycerol backbone of each PA unit was obtained by MS3 measurements, an approach used for the first time for the structural elucidation of CL in R. sphaeroides. As a result, an unprecedented profile of CL in this bacterium was obtained, with 27 main species characterized, many of which are represented by compositional or regiochemical isomers. Interestingly, such a variability is generated from a limited number of different acyl chains, either saturated (i.e. 12:0, 16:0, 17:0, 18:0, 19:0) or mono-unsaturated (16:1, 18:1). The absence of polyunsaturated chains, more susceptible to oxidation damage, appeared to be indirectly related to the lack of carotenoids potentially acting as antioxidant agents, a specific feature of R. sphaeroides R26. The occurrence of odd-numbered acyl chains was ascribed to the need to guarantee membrane fluidity, through a less compact packing of CL, thus compensating for the lack of CL bearing polyunsaturated side chains. Graphical abstract Representation of MS signals due to carboxylate anions that would be detected, as separate couples, in the fragmentation spectra of the anions resulting from the two phosphatidic acid units included in a cardiolipin molecule bearing four different acyl chains. PMID- 28634762 TI - Rapid preconcentration of viable bacteria using magnetic ionic liquids for PCR amplification and culture-based diagnostics. AB - In this study, a series of magnetic ionic liquids (MILs) were investigated for the extraction and preconcentration of bacteria from aqueous samples. By dispersing small volumes (e.g., 15 MUL) of MIL within an aqueous cell suspension, bacteria were rapidly extracted and isolated using a magnetic field. Of the seven hydrophobic MILs examined, the trihexyl(tetradecyl)phosphonium Ni(II) hexafluoroacetylacetonate ([P66614+][Ni(hfacac)3-]) MIL exhibited the greatest enrichment of viable Escherichia coli K12 when coupled with microbiological culture as the detection method. The MIL-based strategy was applied for the preconcentration of E. coli from aqueous samples to obtain enrichment factors (E F) as high as 44.6 in less than 10 min. The MIL extraction approach was also interfaced with polymerase chain reaction (PCR) amplification where the positive detection of E. coli was achieved with the [P66614+][Co(hfacac)3-], [P66614+][Ni(hfacac)3-], [P66614+][Dy(hfacac)4-], and [P66614+][Nd(hfacac)4-] MILs. While direct sampling of an aqueous cell suspension at a concentration of 1.68 * 104 colony-forming units (CFUs) mL-1 yielded no amplicon when subjected to PCR, extraction of the sample with the [P66614+][Ni(hfacac)3-] MIL under optimized conditions provided sufficient enrichment of E. coli for amplicon detection. Importantly, the enrichment of bacteria using the Ni(II)-, Co(II)-, and Dy(III)-based MILs was compatible with real-time quantitative PCR amplification to dramatically improve sample throughput and lower detection limits to 1.0 * 102 CFUs mL-1. The MIL-based method is much faster than existing enrichment approaches that typically require 24-h cultivation times prior to detection and could potentially be applied for the preconcentration of a variety of Gram-negative bacteria from aqueous samples. Graphical abstract Magnetic ionic liquid solvents rapidly preconcentrate viable E. coli cells for unambiguous pathogen detection using microbiological culture and qPCR. PMID- 28634763 TI - Results of an interlaboratory method performance study for the size determination and quantification of silver nanoparticles in chicken meat by single-particle inductively coupled plasma mass spectrometry (sp-ICP-MS). AB - Single-particle inductively coupled plasma mass spectrometry (sp-ICP-MS) promises fast and selective determination of nanoparticle size and number concentrations. While several studies on practical applications have been published, data on formal, especially interlaboratory validation of sp-ICP-MS, is sparse. An international interlaboratory study was organized to determine repeatability and reproducibility of the determination of the median particle size and particle number concentration of Ag nanoparticles (AgNPs) in chicken meat. Ten laboratories from the European Union, the USA, and Canada determined particle size and particle number concentration of two chicken meat homogenates spiked with polyvinylpyrrolidone (PVP)-stabilized AgNPs. For the determination of the median particle diameter, repeatability standard deviations of 2 and 5% were determined, and reproducibility standard deviations were 15 and 25%, respectively. The equivalent median diameter itself was approximately 60% larger than the diameter of the particles in the spiking solution. Determination of the particle number concentration was significantly less precise, with repeatability standard deviations of 7 and 18% and reproducibility standard deviations of 70 and 90%. PMID- 28634764 TI - Are Wrongful Life Actions Threatening the Value of Human Life? AB - Most courts around the world have been refusing wrongful life actions. The main argument invoked is that the supposed compensable injury cannot be classified as such, since life is always a blessing no matter how hard and painful it is.In opposition to mainstream scholars and the dominant case law, this article sustains that life must be distinguished from living conditions, the former being the real injury at stake, since some living conditions are so intolerable that in themselves they justify a compensation within wrongful life actions. PMID- 28634765 TI - A 450-Year-Old Turkish Poem on Medical Ethics. AB - The Ottoman physician-poet Nidai of Ankara (1509 to post-1567) studied medicine in Crimea and served as a court physician in Istanbul during the reign of Sultan Selim II. Nidai marked the classical period of Ottoman medicine particularly with his acclaimed works and translations in Turkish, among which Manafi al-Nas (Benefits of People, 1566) became widely known. The final chapter of Manafi al Nas also is known independently under the name Vasiyyetname (Last Will), which is a remarkable guide on medical ethics. This didactic, sixty-eight-line poem includes Nidai's moral advice to physicians that they should be well mannered, trustworthy, and competent in their arts and should treat their patients with modesty, honesty, and compassion. Even after 450 years of existence, Vasiyyetname retains its ethical and artistic relevance and still serves as a vehicle for the transmission of humanistic ideals far beyond the time and place it was written. PMID- 28634766 TI - Political Minimalism and Social Debates: The Case of Human-Enhancement Technologies. AB - A faulty understanding of the relationship between morality and politics encumbers many contemporary debates on human enhancement. As a result, some ethical reflections on enhancement undervalue its social dimensions, while some social approaches to the topic lack normative import. In this essay, I use my own conception of the relationship between ethics and politics, which I call "political minimalism," in order to support and strengthen the existing social perspectives on human-enhancement technologies. PMID- 28634767 TI - Including People with Dementia in Research: An Analysis of Australian Ethical and Legal Rules and Recommendations for Reform. AB - Research is crucial to advancing knowledge about dementia, yet the burden of the disease currently outpaces research activity. Research often excludes people with dementia and other cognitive impairments because researchers and ethics committees are concerned about issues related to capacity, consent, and substitute decision-making. In Australia, participation in research by people with cognitive impairment is governed by a national ethics statement and a patchwork of state and territorial laws that have widely varying rules. We contend that this legislative variation precludes a consistent approach to research governance and participation and hinders research that seeks to include people with impaired capacity. In this paper, we present key ethical principles, provide a comprehensive review of applicable legal rules in Australian states and territories, and highlight significant differences and ambiguities. Our analysis includes recommendations for reform to improve clarity and consistency in the law and reduce barriers that may exclude persons with dementia from participating in ethically approved research. Our recommendations seek to advance the national decision-making principles recommended by the Australian Law Reform Commission, which emphasize the rights of all adults to make their own decisions and for those with impaired capacity to have access to appropriate supports to help them make decisions that affect their lives. PMID- 28634768 TI - Futile Treatment-A Review. AB - The main goal of intensive care medicine is helping patients survive acute threats to their lives, while preserving and restoring life quality. Because of medical advancements, it is now possible to sustain life to an extent that would previously have been difficult to imagine. However, the goals of medicine are not to preserve organ function or physiological activity but to treat and improve the health of a person as a whole. When dealing with medical futilities, physicians and other members of the care team should be aware of some ethical principles. Knowing these principles could make decision-making easier, especially in cases where legal guidelines are insufficient or lacking. Understanding of these principles can relieve the pressure that healthcare professionals feel when they have to deal with medical futility. Efforts should be made to promote an ethics of care, which means caring for patients even after further invasive treatment has been deemed to be futile. Treatments that improve patients' comfort and minimize suffering of both patients and their families are equally as important as those aimed at saving patients' lives. PMID- 28634769 TI - Decision-Making Capacity and Unusual Beliefs: Two Contentious Cases : Australasian Association of Bioethics and Health Law John McPhee (Law) Student Essay Prize 2016. AB - Decision-making capacity is a vital concept in law, ethics, and clinical practice. Two legal cases where capacity literally had life and death significance are NHS Trust v Ms T [2004] and Kings College Hospital v C [2015]. These cases share another feature: unusual beliefs. This essay will critically assess the concept of capacity, particularly in relation to the unusual beliefs in these cases. Firstly, the interface between capacity and unusual beliefs will be examined. This will show that the "using and weighing of information" is the pivotal element in assessment. Next, this essay will explore the relationship between capacity assessment and a decision's "rationality." Then, in light of these findings, the essay will appraise the judgments in NHS v T and Kings v C, and consider these judgments' implications. More broadly, this essay asks: Does capacity assessment examine only the decision-making process (as the law states), or is it also influenced by a decision's rationality? If influenced by rationality, capacity assessment has the potential to become "a search and disable policy aimed at those who are differently orientated in the human life world" (Gillett 2012, 233). In contentious cases like these, this potential deserves attention. PMID- 28634770 TI - Medical Negligence Determinations, the "Right to Try," and Expanded Access to Innovative Treatments. AB - This article considers the issue of expanded access to innovative treatments in the context of recent legislative initiatives in the United Kingdom and the United States. In the United Kingdom, the supporters of legislative change argued that the common law principles governing medical negligence are a barrier to innovation. In an attempt to remove this perceived impediment, two bills proposed that innovating doctors sued for negligence should be able to rely in their defence on the fact that their decision to innovate was "responsible." A decision to innovate would be regarded as responsible if it followed a specified process. Although these changes to the law of medical negligence were not passed, this article argues that the idea of a process-based approach was sound. In the United States, a number of states have passed "Right to Try" laws that permit doctors to prescribe and companies to provide investigational products without the need for FDA approval. These laws do not purport to and nor are they able to alter the obligations of individuals and companies under federal law. They are consequently unlikely to achieve their stated aim of expanding access to investigational products. This article argues that they nevertheless have a cogent rationale in so far as they highlight the need for rights-based reform to federal regulations governing access. PMID- 28634771 TI - Off-pump versus on-pump coronary surgery in patients with chronic kidney disease: a meta-analysis. AB - BACKGROUND: Patients with chronic kidney disease (CKD) have worse adverse cardiovascular outcomes after coronary artery bypass grafting (CABG). However, the adverse cardiovascular outcomes between off-pump coronary artery bypass grafting (OPCAB) versus on-pump coronary artery bypass grafting (ONCAB) in these patients have been a subject of debate. METHODS: We undertook a comprehensive literature search of PubMed, Embase, and the Cochrane Library database to identify all relevant studies comparing techniques between OPCAB and ONCAB in CKD patients. We pooled the odds ratios (ORs) and hazard ratios (HRs) from individual studies and conducted heterogeneity, quality assessment, and publication bias analyses. RESULTS: This meta-analysis includes 17 studies with 201,889 patients. In CKD patients, OPCAB was associated with significantly lower early mortality as compared to ONCAB (OR 0.88; 95% CI 0.82-0.93; p < 0.0001). OPCAB was associated with decreased risk of atrial fibrillation (OR 0.57; 95% CI 0.34-0.97; p = 0.04), cerebrovascular accident (OR 0.46; 95% CI 0.22-0.95; p = 0.04), blood transfusion (OR 0.20; 95% CI 0.08-0.49; p = 0.0005), pneumonia, prolonged ventilation, and shorter hospital stays. No difference was found regarding long-term survival (HR 1.08; 95% CI 0.86-1.36; p = 0.51) or myocardial infarction (OR 0.65; 95% CI 0.30 1.38; p = 0.26). CONCLUSIONS: Compared with ONCAB, OPCAB is associated with superior postoperative morbidity and the early mortality in CKD patients. Long term survival is comparable between the two surgical revascularizations. PMID- 28634772 TI - The effect of desensitization therapy in kidney transplantation. AB - BACKGROUND: Desensitization therapy may enable the patient to get allograft in sensitized recipient or solve the organ shortage in ABO-incompatible relationship in kidney transplantation (KT). However, the graft outcome and morbidity remains unclear. METHODS: We retrospectively analyzed 845 KT patients from January 2010 to February 2016 at Seoul National University Hospital. The patients were divided into three groups as follows: HLA-incompatible (HLAi) group, ABO-incompatible (ABOi) group, and control group. The HLAi group comprised patients who received desensitization therapy due to the presence of donor-specific antibodies (DSAs) or high panel reactive antibodies (PRAs). The ABOi group is defined as those undergoing preoperative desensitization therapy for anti-ABO antibodies. RESULTS: Of the total of 845 recipients, 48 (5.6%) were HLAi KTs and 71 (13.9%) were ABOi KTs, respectively. Pre-emptive KT is done more frequently in ABOi group, therefore, they had shorter dialysis duration than the others. HLAi recipients had a higher proportion of women than the ABOi group and a higher proportion of re-transplantation. During the 38.4 (0.4-76.9) months of follow-up, there were more acute antibody-mediated rejections (AAMRs) in the HLAi (6.7%) and ABOi (8.5%) groups than in the control group (1.9%) (P = 0.001). However, there was no difference in graft survival, patient survival, and annual allograft among three groups. CONCLUSIONS: Despite the higher incidence of AAMRs, HLAi and ABOi KTs showed a favorable graft and patient outcome after desensitization therapy. PMID- 28634773 TI - Development and validation of a Fall Risk Assessment Index for dialysis patients. AB - BACKGROUND: Dialysis patients often have low physical performance due to uremic sarcopenia, protein energy wasting (PEW), and incidence intradialytic hypotension (IDH), which are indicated as risk factors for falling. The objective of this study was to develop a symptom-encompassing evaluation form to predict falls with high sensitivity for dialysis patients. METHODS: A total of 251 patients who had been receiving maintenance hemodialysis therapy three times a week were enrolled in the study. Demographics, malnutrition and inflammatory status, dialytic therapeutic management situation, physical function and performance, and inquiries about falling were recorded. The Cox proportional hazards analysis evaluated the impact of falls. Calculated hazard ratios were converted to weighted scores, using approximate multiples of 0.5 and an evaluation form was created, which we called the Dialysis Fall Risk Index (DFRI). Kaplan-Meier survival analyses with the log-rank test and the Cox proportional hazard analysis were performed to evaluate the validity of the DFRI. RESULTS: The DFRI consisted of seven items and a total of 12 points. The predictive validity of DFRI included hazard ratios for quartile 3 and 4 of 2.65 and 3.84, respectively, compared with quartile 1 as a reference point. The cut-off point of the DFRI showed the highest sensitivity and specificity among other screening indices. DISCUSSION: The present study included the development of a new evaluation form that encompasses symptoms of end-stage kidney disease to predict falls in dialysis patients. PMID- 28634774 TI - Learning from Synthetic Models of Extracellular Matrix; Differential Binding of Wild Type and Amyloidogenic Human Apolipoprotein A-I to Hydrogels Formed from Molecules Having Charges Similar to Those Found in Natural GAGs. AB - Among other components of the extracellular matrix (ECM), glycoproteins and glycosaminoglycans (GAGs) have been strongly associated to the retention or misfolding of different proteins inducing the formation of deposits in amyloid diseases. The composition of these molecules is highly diverse and a key issue seems to be the equilibrium between physiological and pathological events. In order to have a model in which the composition of the matrix could be finely controlled, we designed and synthesized crosslinked hydrophilic polymers, the so called hydrogels varying the amounts of negative charges and hydroxyl groups that are prevalent in GAGs. We checked and compared by fluorescence techniques the binding of human apolipoprotein A-I and a natural mutant involved in amyloidosis to the hydrogel scaffolds. Our results indicate that both proteins are highly retained as long as the negative charge increases, and in addition it was shown that the mutant is more retained than the Wt, indicating that the retention of specific proteins in the ECM could be part of the pathogenicity. These results show the importance of the use of these polymers as a model to get deep insight into the studies of proteins within macromolecules. PMID- 28634775 TI - Hydrophilic Acylated Surface Protein A (HASPA) of Leishmania donovani: Expression, Purification and Biophysico-Chemical Characterization. AB - Hydrophilic acylated surface proteins (HASPs) are acidic surface proteins which get localized on the surface of Leishmania parasite during infective stages through a "non-classical" pathway. In this study, we report the heterologous expression and purification of Leishmania donovani HASPA (r-LdHASPA) in E. coli system and its partial characterization. The structural aspects of the purified protein were analyzed using CD spectroscopy and modeling studies which indicate that r-LdHASPA consists of random coils. Studies in mouse macrophage RAW264.7 cell lines indicate that r-LdHASPA enhances reactive oxygen species (ROS) production. Co-immunoprecipitation (IP) studies indicate that r-LdHASPA interacts with certain macrophage proteins which however could not be identified unambiguously. The present study provides key insights into the structural and functional aspects of an important Leishmania protein, HASPA, which we believe could be useful for further research on vaccine/drug development. PMID- 28634776 TI - Evidence Supporting the Internal Validity of the Proposed ND-PAE Disorder. AB - The internal validity of the proposed Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE) was evaluated in children diagnosed with either Fetal Alcohol Syndrome (FAS) or partial FAS who were 3-10 years of age and had enrolled in a math intervention study. Symptoms were coded as present or absent using assessments conducted in the study, including standardized measures of neurocognitive and behavioral functioning, parent interview, and direct observations of the child. The number of endorsed ND-PAE symptoms was not related to environmental factors but was moderately related to the child's age. ND-PAE symptoms were highly consistent and this did not vary by age. Evidence suggested the ND-PAE adaptive symptoms may be too restrictive and only one symptom from this domain may be sufficient. Impulsiveness was not related to an endorsement of the ND-PAE disorder but research is needed with other clinical groups to establish the discriminative validity of this symptom. PMID- 28634777 TI - Healthy and Unhealthy Food Prices across Neighborhoods and Their Association with Neighborhood Socioeconomic Status and Proportion Black/Hispanic. AB - This paper evaluates variation in food prices within and between neighborhoods to improve our understanding of access to healthy foods in urbanized areas and potential economic incentives and barriers to consuming a higher-quality diet. Prices of a selection of healthier foods (dairy, fruit juice, and frozen vegetables) and unhealthy foods (soda, sweets, and salty snacks) were obtained from 1953 supermarkets across the USA during 2009-2012 and were linked to census block group socio-demographics. Analyses evaluated associations between neighborhood SES and proportion Black/Hispanic and the prices of healthier and unhealthy foods, and the relative price of healthier foods compared with unhealthy foods (healthy-to-unhealthy price ratio). Linear hierarchical regression models were used to explore geospatial variation and adjust for confounders. Overall, the price of healthier foods was nearly twice as high as the price of unhealthy foods ($0.590 vs $0.298 per serving; healthy-to-unhealthy price ratio of 1.99). This trend was consistent across all neighborhood characteristics. After adjusting for covariates, no association was found between food prices (healthy, unhealthy, or the healthy-to-unhealthy ratio) and neighborhood SES. Similarly, there was no association between the proportion Black/Hispanic and healthier food price, a very small positive association with unhealthy price, and a modest negative association with the healthy-to-unhealthy ratio. No major differences were seen in food prices across levels of neighborhood SES and proportion Black/Hispanic; however, the price of healthier food was twice as expensive as unhealthy food per serving on average. PMID- 28634778 TI - How are socio-demographic and psycho-social factors associated with the prevalence and chronicity of severe pain in 14 different body sites? A cross sectional population-based survey. AB - BACKGROUND: Severe pain and chronic pain have a high impact on individuals and society. Body location of pain is important with regard to perception, articulation, and underlying biological, mental or social causes of pain. METHODS: A cross-sectional survey was performed in the general Austrian population with 15,474 personally interviewed subjects aged 15 years and older. RESULTS: The 1-year period prevalence of severe pain in any body site was 38.6% and of chronic pain 24.9%. In all, 8.1% had pain in at least three body sites. Subjects aged 65 years and older (52.2%), those with low education (43.4%), unemployed subjects (50.4%), retired subjects (52.4%), those with anxiety/depression (67.7%), and subjects with lack of social support (49.6%) were sub-populations with high pain prevalence. In multivariate analyses, depression/anxiety was associated with prevalence and chronicity of severe pain in all body sites (range of ORs 1.89-5.01), while such associations were found for lack of social support (range of ORs 1.33-1.65), female sex (range of ORs 1.38-2.34), higher age (range of ORs 1.09-1.18 for 5 year intervals), as well as low educational (range of ORs 1.47-2.06 primary vs. tertiary education) and unemployment status (range of ORs 1.50-2.62) in most body sites. Being born in non-EU or EFTA states was associated with pain in many body sites (range of ORs 1.38-2.10). CONCLUSIONS: Psychosocial factors are associated with pain presence in similar ways irrespective of location. Regarding socio-demographic factors, differences towards the magnitude and the direction in the association with pain frequency and chronicity in different body sites emerged. PMID- 28634780 TI - Echocardiographic Inferior Vena Cava Measurement As An Alternative to Central Venous Pressure Measurement in Neonates. AB - OBJECTIVES: To evaluate the correlation between echocardiographic inferior vena cava (IVC) measurements and central venous pressure (CVP) in neonates. Also, to evaluate the correlation between IVC measurements and gestational age (GA) and body weight (BW). METHODS: This cross sectional analytical study was conducted from June 2014 through June 2016 in a level III NICU. All neonates requiring intensive hemodynamic monitoring and having umbilical venous catheter (UVC) in place for clinical indications were enrolled in the study. IVC measurements were recorded by echocardiography (ECHO) and CVP was measured concomitantly in neonates having appropriate sized UVC in place. IVC measurements were evaluated and compared for any correlation with the CVP, GA and BW. RESULTS: Fifty neonates with median gestation of 37 wk [Q1 = 29.2, Q3 = 37.8, interquartile range (IQR) = 8.6 wk] and median birth weight of 2420 g (Q1 = 923.5, Q3 = 2850, IQR = 1926.5 g) were included in the study. A strong negative linear correlation was observed between IVC collapsibility index (IVC-CI) and CVP (r = -0.968, r2 = -0.937, p 0.000). No correlation was observed between IVC-CI and GA or BW. IVC minimum and IVC maximum diameters did not correlate with CVP but correlated well with GA and BW. CONCLUSIONS: Echocardiographic IVC-CI measurement has a good correlation with CVP measurement in neonates. The clinical use will depend on the ability of IVC CI to predict surrogate markers of tissue perfusion in shock. PMID- 28634783 TI - The treatment for the first branchial cleft anomalies in children. AB - The objective of this study is to make a clinical analysis for first branchial cleft anomalies (FBCAs), especially introduce the relationship between the Type I/II FBCA with the facial nerve and to demonstrate the importance of using intraoperative microscope and facial nerve monitoring. This is a retrospective review of patients with FBCAs treated in Beijing Children's Hospital, from Jan 2013 to Dec 2015. Clinical data of patients, including sex, age, chief complains, history of surgery, incision and drainage, the relationship with the facial nerve, pre and post-operative facial paralysis, recurrent rate and complications were recorded. FBCAs were divided into two subtypes according to Work's Classification. All patients had an MRI examination for diagnosis and to locate the lesions before surgery. Both microscope and facial nerve monitors were routinely used for detecting and protecting the facial nerve. The study cohort included 42 patients with ages ranging from 10 months to 14 years. The chief complaint was recurrent swelling or abscess near the ear or angle of mandibular. 76.2% of them (32/42) had incision and drainage histories. Two of them had suffered from facial palsy during the infectious period. Seven patients had undergone surgeries once or twice in other hospitals. Four patients with Type II FBCAs developed temporary facial palsy. We had follow-ups for each patient from 3 months to 3 years. 4 (9.5%) patients with Type I FBCA had got postoperative external auditory canal (EAC) stenosis. There were no cases of recurrence. Type II FBCAs has closer relationship with facial nerve than Type I FBCAs. The facial nerve of Type II FBCAs may lie more superficially and ascending to the fistula. Intraoperative microscope and facial nerve monitoring were necessary for protecting the facial nerve and decreasing the recurrent rate. PMID- 28634784 TI - Attentional weights in vision as products of spatial and nonspatial components. AB - The relationship between visual attentional selection of items in particular spatial locations and selection by nonspatial criteria was investigated in a partial report experiment with report of letters (as many as possible) from brief postmasked exposures of circular arrays of letters and digits. The data were fitted by mathematical models based on Bundesen's (Psychological Review, 97, 523 547, 1990) theory of visual attention (TVA). Both attentional weights of targets (letters) and attentional weights of distractors (digits) showed strong variations across the eight possible target locations, but for each of the ten participants, the ratio of the weight of a distractor at a given location to the weight of a target at the same location was approximately constant. The results were accommodated by revising the weight equation of TVA such that the attentional weight of an object equals a product of a spatial weight component (weight due to being at a particular location) and a nonspatial weight component (weight due to having particular features other than locations), the two components scaling the effects of each other multiplicatively. PMID- 28634781 TI - Infectious Disease Surveillance in the Woylie (Bettongia penicillata). AB - Wild populations of the critically endangered woylie (Bettongia penicillata) recently declined by 90% in southwest Western Australia. Increased predation is the leading hypothesis for decline, but disease may be playing a role increasing susceptibility to predation. To explore this possibility, we surveyed woylie populations in the wild, in captivity and in a predator-free sanctuary for exposure to, and infection with, four known pathogens of macropods: herpesviruses, Wallal and Warrego orbiviruses, and Toxoplasma gondii. Our study found two of 68 individuals positive for neutralizing antibodies against known macropodid alphaherpesviruses. Three of 45 individuals were PCR positive for a herpesvirus that was shown to be a novel gammaherpesvirus or a new strain/variant of Potoroid Herpesvirus 1. Further sequence information is required to definitively determine its correct classification. There was no evidence of antibodies to orbivirus Wallal and Warrego serogroups, and all serological samples tested for T. gondii were negative. This is the first report of PCR and serological detection of herpesviruses in the woylie. Positive individuals did not demonstrate clinical signs of herpesviral diseases; therefore, the clinical significance of herpesviruses to wild woylie populations remains unclear. Further monitoring for herpesvirus infections will be important to inform disease risk analysis for this virus and determine temporal trends in herpesvirus activity that may relate to population health and conservation outcomes. PMID- 28634785 TI - [Imaging and preoperative planning for osteotomies around the knee]. AB - Physiologic alignment of the human lower leg is well defined. The etiology for malalignment comprises constitutional, degenerative and posttraumatic conditions. Osteotomies around the knee can correct the malalignment, provided that the origin of deviation is in proximity of the knee center. Crucial factors for the evaluation of axis deviation are the weight-bearing line, the mechanical axes of femur and tibia, the joint line angles and the center of the hip, knee and upper ankle joint. Careful preoperative planning is mandatory for reproducible clinical results. For the treatment of varus osteoarthritis of the knee, a slight overcorrection to the 62% width of the lateral tibial plateau is frequently advocated. In valgus knees, a correction of the postoperative weight-bearing line to physiologic conditions (44% of the lateral tibial width) is regarded to be sufficient. Recently, individualized planning of the correction angle is advocated to better address the underlying pathology of each patient. PMID- 28634786 TI - Inhibition of NF-kappaB activity by aminoguanidine alleviates neuroinflammation induced by hyperglycemia. AB - Neuroinflammation is a key feature of cerebral complication which is associated with diabetes mellitus (DM). Inducible nitric oxide synthase (iNOS) is implicated in the pathogenesis of neuroinflammation. However, how iNOS facilitates the development of inflammation in brain is still unidentified. The aim of the present study was to investigate the association of iNOS and neuroinflammation in diabetic mice, and elucidate the potential mechanisms underlying aminoguanidine (AG), the selective inhibitor of iNOS, protected neurons against inflammation in diabetic mice. In present experiment, diabetic mice model were established by a single intraperitoneal injection of streptozotocin (STZ). AG was administered to diabetic mice for ten weeks after this disease induction. Then we measured iNOS activity in the serum and brain, detected the glial fibrillary acidic protein (GFAP) and ionised calcium binding adaptor molecule-1 (Iba-1) expressions in the brain. Moreover, nuclear factor-kappa B (NF-kappaB) in cytoplasm and nucleus were tested by IP and WB. Results revealed that high expression of iNOS in serum and brain could be reversed by AG treatment. Furthermore, AG could also inhibit GFAP and Iba-1 expressions, and NF-kappaB nuclear translocation by inhibiting it from binding to iNOS in cytoplasm. Our findings indicated that iNOS can combine with NF-kappaB in cytoplasm and promote its nuclear transfer in diabetic mice. Furthermore, AG decreased neuroinflammation through inhibiting iNOS activity and reducing NF-kappaB nuclear translocation by promoting its dissociation with iNOS in cytoplasm. PMID- 28634788 TI - Consistent reconstruction of 4D fetal heart ultrasound images to cope with fetal motion. AB - PURPOSE: 4D ultrasound imaging of the fetal heart relies on reconstructions from B-mode images. In the presence of fetal motion, current approaches suffer from artifacts, which are unrecoverable for single sweeps. METHODS: We propose to use many sweeps and exploit the resulting redundancy to automatically recover from motion by reconstructing a 4D image which is consistent in phase, space, and time. An interactive visualization framework to view animated ultrasound slices from 4D reconstructions on arbitrary planes was developed using a magnetically tracked mock probe. RESULTS: We first quantified the performance of 10 4D reconstruction formulations on simulated data. Reconstructions of 14 in vivo sequences by a baseline, the current state-of-the-art, and the proposed approach were then visually ranked with respect to temporal quality on orthogonal views. Rankings from 5 observers showed that the proposed 4D reconstruction approach significantly improves temporal image quality in comparison with the baseline. The 4D reconstructions of the baseline and the proposed methods were then inspected interactively for accessibility to clinically important views and rated for their clinical usefulness by an ultrasound specialist in obstetrics and gynecology. The reconstructions by the proposed method were rated as 'very useful' in 71% and were statistically significantly more useful than the baseline reconstructions. CONCLUSIONS: Multi-sweep fetal heart ultrasound acquisitions in combination with consistent 4D image reconstruction improves quality as well as clinical usefulness of the resulting 4D images in the presence of fetal motion. PMID- 28634787 TI - Insulin resistance in ischemic stroke. AB - Insulin resistance often refers to a pathological condition in which cells fail to respond to the normal actions of insulin. Increasing literature has noted a critical role of insulin resistance in the pathogenesis of ischemic stroke. Insulin resistance plays an important role in the pathogenesis of ischemic stroke via enhancing advanced changes of atherosclerosis. A variety of literature indicates that insulin resistance enhances platelet adhesion, activation and aggregation which are conducive to the occurrence of ischemic stroke. Insulin resistance also induces hemodynamic disturbances and contributes to the onset of ischemic stroke. In addition, insulin resistance may augment the role of the modifiable risk factors in ischemic stroke and induce the occurrence of ischemic stroke. Preclinical and clinical studies have supported that improving insulin resistance may be an effective measure to prevent or delay ischemic stroke. PMID- 28634789 TI - Detection and grading of prostate cancer using temporal enhanced ultrasound: combining deep neural networks and tissue mimicking simulations. AB - PURPOSE : Temporal Enhanced Ultrasound (TeUS) has been proposed as a new paradigm for tissue characterization based on a sequence of ultrasound radio frequency (RF) data. We previously used TeUS to successfully address the problem of prostate cancer detection in the fusion biopsies. METHODS : In this paper, we use TeUS to address the problem of grading prostate cancer in a clinical study of 197 biopsy cores from 132 patients. Our method involves capturing high-level latent features of TeUS with a deep learning approach followed by distribution learning to cluster aggressive cancer in a biopsy core. In this hypothesis generating study, we utilize deep learning based feature visualization as a means to obtain insight into the physical phenomenon governing the interaction of temporal ultrasound with tissue. RESULTS : Based on the evidence derived from our feature visualization, and the structure of tissue from digital pathology, we build a simulation framework for studying the physical phenomenon underlying TeUS based tissue characterization. CONCLUSION : Results from simulation and feature visualization corroborated with the hypothesis that micro-vibrations of tissue microstructure, captured by low-frequency spectral features of TeUS, can be used for detection of prostate cancer. PMID- 28634790 TI - Cellulose Acetate Butyrate: Ammonio Methacrylate Copolymer Blends as a Novel Coating in Osmotic Tablets. AB - The objective of this work was the preparation of osmotic tablets using polymer blends of cellulose acetate butyrate (CAB) or ethylcellulose with ammonio methacrylate copolymer (Eudragit(r) RL). The advantage of these coatings in comparison to the traditionally used cellulose acetate is their solubility in safer organic solvents like ethanol. Polymer films were characterized with respect to their water uptake, dry mass loss, and mechanical properties. The effect of the polymer blend ratio on drug release and on the rupture force of the coating was investigated. In addition, the effect of drug solubility and content, pH and agitation rate of the release medium, and coating level and plasticizer content on the release were studied. With increased Eudragit(r) RL content in the coating blends, higher medium uptake of the film was observed, resulting in shorter lag times and faster drug release from the osmotic tablets. Replacing ethylcellulose with cellulose acetate butyrate as a coating material led to shorter lag times and faster drug release due to increased film permeability. In addition, CAB-based films had a higher strength and flexibility. The drug release was osmotically controlled and decreased with increasing coating level. It increased with increased drug solubility, plasticizer content, change of buffer species (acetate > phosphate), and decreased coating level. Agitation rate and drug content had no effect on the drug release. A 20% w/w coating level was sufficient for the tablet to tolerate forces of more than five times of the gastric destructive force reported in literature. PMID- 28634791 TI - Erratum to: Toxic potential of the emerging contaminant nicotine to the aquatic ecosystem. PMID- 28634792 TI - Impairments of cadmium on vitellogenin accumulation in the hepatopancreas of freshwater crab Sinopotamon henanense. AB - During ovary maturation of crabs, vitellogenin (Vg), a precursor molecule of vitellin (Vn) needed for embryogenesis, can be produced in large quantities in the hepatopancreas and then transported to the ovary by the hemolymph. In the present study, effects of Cd on Vg accumulation in the hepatopancreas and Vg transportation of the freshwater crab Sinopotamon henanense were investigated. We also studied the impacts of Cd on the mRNA expression of genes involved in energy metabolism, protein metabolism, and metallothionein (MT) and glutathione (GSH) synthesis. After Cd treatment, the Vg concentration and the Vg mRNA expression in the hepatopancreas were downregulated. Pearson's correlation coefficient showed that the Vg level in the hepatopancreas correlated positively with those of the ovary and hemolymph (correlation coefficients 0.844 and 0.749, respectively), suggesting that the Vg transport from the hepatopancreas to the ovary can be impaired by Cd. The levels of carbohydrate and protein in the hepatopancreas of Cd-exposed crabs were decreased, and an inhibited protein metabolism was also observed. Energy production related isocitrate dehydrogenase and cytochrome C oxidase mRNA expressions, and MT and GSH synthesis increased after 10 days of Cd treatment and decreased after 20 days. Cd also caused a time-dependent upregulation of malondialdehyde. Our findings showed that Cd decreased Vg accumulation in the hepatopancreas due to partially excessive energy consumption and an activated defense system in the hepatopancreas, suggesting a possible regulatory mechanism in S. henanense which is the competitive advantage of energy reserves in metabolic Cd stress responses over the high-energy flux during vitellogenesis to ensure a continuous supply of metabolic energy. Moreover, the damage of Vg accumulation in the hepatopancreas caused by Cd could lead to an insufficient accumulation of Vn in the ovary and cause a retardation of oocyte development. PMID- 28634793 TI - Arsenic sorption by red mud-modified biochar produced from rice straw. AB - Red mud-modified biochar (RM-BC) has been produced to be utilized as a novel adsorbent to remove As because it can effectively combine the beneficial features of red mud (rich metal oxide composition and porous structure) and biochar (large surface area and porous structure properties). SEM-EDS and XRD analyses demonstrated that red mud had loaded successfully on the surface of biochar. With the increasing of pH in solution, arsenate (As(V)) adsorption on RM-BC decreased while arsenite (As(III)) increased. Arsenate adsorption kinetics process on RM-BC fitted the pseudo-second-order model, while that of As(III) favored the Elovich model. All sorption isotherms produced superior fits with the Langmuir model. RM BC exhibited improved As removal capabilities, with a maximum adsorption capacity (Qmax) for As(V) of 5923 MUg g-1, approximately ten times greater than that of the untreated BC (552.0 MUg g-1). Furthermore, it has been indicated that the adsorption of As(V) on RM-BC may be strongly associated with iron oxides (hematite and magnetite) and aluminum oxides (gibbsite) by X-ray absorption near edge spectroscopy (XANES), which was possibly because of surface complexation and electrostatic interactions. RM-BC may be used as a valuable adsorbent for removing As in the environment due to the waste materials being relatively abundant. PMID- 28634794 TI - Evaluation in situ of genotoxicity and stress in South American common toad Rhinella arenarum in environments related to fluorite mine. AB - Little attention has been paid to the impact of wastewater generated by mining activities on fluoride. In this study, we evaluated the hematology responses of common South American toad Rhinella arenarum inhabiting natural and artificial environments associated with a fluorite mine from central Argentina. We analyzed three sampling stations associated with the fluorite mine: (I) Los Cerros Negros stream (CN), which runs on granitic rock with a high fluorite content; (II) Los Vallecitos stream (LV), which runs on metamorphic rock with low fluorite content; and (III) artificial decantation ponds (DP) containing sediments produced by fluorite flotation process. We calculated frequencies of micronuclei, erythrocyte nuclear abnormalities, mitosis, and immature erythrocytes. In addition, we performed a differential leukocyte count and determined neutrophils/lymphocyte ratio as a stress response estimator. We found high micronucleus (MN) and erythrocyte nuclear abnormality (ENA) frequencies in DP and CN but low frequencies in LV. The neutrophil/lymphocyte ratio was different among sites, with a significant increase in individuals from DP. Values registered in DP could be caused by exposure to mixture of compounds registered in dams that hold wastewater, while high values registered in CN stream might be due to natural concentrations of fluoride. Our results suggest that blood is an effective and non-destructive sensitive indicator for monitoring genotoxic agents in freshwater ecosystems. PMID- 28634795 TI - High toxicity of camphene and gamma-elemene from Wedelia prostrata essential oil against larvae of Spodoptera litura (Lepidoptera: Noctuidae). AB - The development of eco-friendly biopesticides in the fight against agricultural pests is an important challenge nowadays. The essential oil of Wedelia prostrata Hemsl. is known for its multipurpose biological activities in Chinese folk medicine. However, limited efforts attempted to understand the potential insecticidal activity of its main individual constituents and related mechanism of action. In this research, we investigated the insecticidal activity of W. prostrata against the crop pest Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae). Toxicity on 4th instar larvae was assessed after 24 h of exposure. The LC50 and LC90 of the W. prostrata essential oil were 167.46 and 322.12 MUg/ml, respectively. GC-MS analyses were carried out to shed light on the oil chemical composition. Main constituents were the monoterpene camphene (9.6%) and the sesquiterpenes gamma-elemene (7.6%), alpha-humulene (6.9%), and (E,E)-alpha farnesene (7.3%). The pure constituents were evaluated for their insecticidal activity on S. litura 4th instar larvae. The most toxic molecule was camphene (LC50 = 6.28 MUg/ml), followed by gamma-elemene, (LC50 = 10.64 MUg/ml), alpha humulene (LC50 = 12.89 MUg/ml), and (E,E)-alpha-farnesene (LC50 = 16.77 MUg/ml). Overall, our experiments highlighted the promising potential of camphene and gamma-elemene from W. prostrata essential oil against larvae of S. litura, allowing us to propose these two compounds for the development of newer pesticides in the fight against crop pests. Further studies aimed at evaluating the potential synergy between these two molecules, as well as their stability in field conditions are ongoing. PMID- 28634796 TI - Effects of perfluorooctanoic acid and perfluorooctane sulfonate on acute toxicity, superoxide dismutase, and cellulase activity in the earthworm Eisenia fetida. AB - Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are the two best-known perfluorinated chemicals and have received much attention due to their ubiquity in the environment. In the present study, we evaluated the effects of PFOS and PFOA on acute toxicity, superoxide dismutase (SOD), and cellulase activities in Eisenia fetida. The results of acute toxicity testing using a filter paper contact test and a natural field soil test showed that PFOA and PFOS exhibited acute toxicity in earthworms, and the toxic effect of PFOS was greater than that of PFOA. The results also showed that avoidance behavior is a more sensitive and easy operation biomarker than acute toxicity and will give us information for early diagnosis of soil pollution, well before the lethal effect becomes apparent. Subchronic exposure to PFOA or PFOS resulted in changes in SOD and cellulase activities in E. fetida, and SOD activity was more sensitive than cellulase activity during early exposure. Based on these findings, we suggest that avoidance behavior and SOD activity in earthworms are suitable biomarkers for evaluating the toxicity of PFOA- and PFOS-contaminated soils. These results indicate that exposure to PFOA and PFOS has a potential impact on soil animals and their environment. PMID- 28634797 TI - Distribution, transfer, and health risks of polycyclic aromatic hydrocarbons (PAHs) in soil-wheat systems of Henan Province, a typical agriculture province of China. AB - In order to investigate the distribution, transfer, and human health risks of polycyclic aromatic hydrocarbons (PAHs) in the soil-wheat systems, soil samples from 20 farmlands and corresponding wheat tissues were collected from selected regions of Henan Province in June 2013 and were analyzed to estimate the concentration of PAHs. The total concentrations of 15 PAHs (?15 PAHs) in soils from Henan Province varied from 6.91 to 72.4 ng/g. Moreover, two-ring to three ring PAHs (1.59-29.1 ng/g) were the major species in soils, occupying 56.2% of total PAHs. Principal component analysis (PCA)-multiple linear regression (MLR) revealed that fossil fuel burning dominated the input of PAHs in agricultural soils of Henan Province. The range of ?15 PAHs concentrations in wheat tissues was 13.9-50.9 ng/g, which decreased along the root-straw-grain. Positive correlation among PAHs of soil and wheat tissues showed that PAHs in wheat mainly came from soil and then migrated along root-straw-grain. Moreover, PAHs were accumulated highest in root and lowest in grain. Two-ring to three-ring PAHs were easier to transfer from soil to wheat than five-ring to six-ring PAHs. Consumption of wheat grain created potential risk of cancer in Henan Province. PMID- 28634799 TI - Assessment of heat-inactivated marine Aspergillus flavus as a novel biosorbent for removal of Cd(II), Hg(II), and Pb(II) from water. AB - A novel marine fungus was isolated and classified as Aspergillus flavus strain EGY11. The heat-inactivated form of isolated Aspergillus flavus was investigated and evaluated as a new eco-friendly and highly efficient biosorbent for removal of toxic heavy metals such as Cd(II), Hg(II), and Pb(II) from aqueous solutions. The SEM morphological studies of biosorbent-loaded metal ions confirmed their direct binding on the surface of heat-inactivated Aspergillus flavus. The metal biosorption capacity values were determined and optimized by the batch technique in the presence of various experimental controlling factors such as pH, contact time, biosorbent dosage, initial metal ion concentration, and coexisting species. The maximum metal capacity values of Cd(II), Hg(II), and Pb(II) were cauterized as 1550 (pH 7.0), 950 (pH 7.0), and 1000 MUmol g-1 (pH 6.0), respectively. The equilibrium time for removal of metal ions was identified as 40 min. The maximum sorption capacity values (1200.0-4000.0 MUmol g-1) were established by 5.0 mg as the optimum mass of biosorbent. The collected biosorption data obtained from the equilibrium studies using the initial metal ion concentration were described by the Langmuir, Freundlich, Brunauer-Emmett-Teller (BET), and Dubinin-Radushkevich isotherm (D-R) isotherm models. The potential implementation of heat-inactivated Aspergillus flavus biosorbent for heavy metal removal from different water samples was successfully accomplished using multistage microcolumn technique. The results refer to excellent percentage recovery values in the ranges 92.7-99.0, 91.3-95.6, and 95.3-98.2% for the biosorptive removal of Cd(II), Hg(II), and Pb(II), respectively, from the examined environmental samples. PMID- 28634798 TI - Value of biochars from Miscanthus x giganteus cultivated on contaminated soils to decrease the availability of metals in multicontaminated aqueous solutions. AB - The objective of this study was to evaluate the sorption efficiency of eight biochars, made from Miscanthus x giganteus cultivated on contaminated agricultural soil, in aqueous solutions contaminated with metals alone or mixed with polycyclic aromatic hydrocarbons. These biochars were produced in different pyrolysis conditions (temperature, 400/600 degrees C; heating rate, 5/10 degrees C min-1; duration, 45/90 min) and compared with an uncontaminated commercialized biochar made of wood. The physicochemical characterization of the Miscanthus biochars confirmed the impact of the pyrolysis on the biochar parameters with substantial differences between the biochars in terms of pH, cation exchange capacity, and specific surface area. The sorption experiment showed higher sorption efficiency of Cd, Pb, and Zn for the Miscanthus biochars produced at 600 degrees C compared with the biochars produced at 400 degrees C when the aqueous solutions were mono- or multicontaminated. Furthermore, the desorption study showed that the sorption process was largely irreversible. Therefore, the high sorption capacity of Miscanthus biochars and the low sorption reversibility confirmed that these biochars are a suitable sorbent for metals. PMID- 28634801 TI - Ameliorating soil acidity and physical properties of two contrasting texture Ultisols with wastewater sludge biochar. AB - The production of biochar is a safe and beneficial disposal way for wastewater sludge. The biochar produced from wastewater sludge can be used as soil amendments for improving soil properties and for increasing crop yield. This work investigated the influences of wastewater sludge biochar (WSB) on the pH, exchangeable acidity, and physical properties of strongly acidic Ultisols with contrasting texture (clayey soil and sandy loam). Two soils were mixed with WSB at the rate of 0, 10, 20, and 40 g biochar kg-1 soil and incubated for 240 days at 75% field water capacity. Incubation experimental results indicated that WSB significantly increased soil pH and exchangeable Ca2+ and Mg2+ contents, and decreased soil exchangeable H+ and Al3+, compared with the control. The application of WSB enhanced the formation of 5-2-mm macroaggregate, and decreased the content of <0.25-mm microaggregate. WSB application significantly increased aggregate stability of soils, determined by mean weight diameter (MWD) of aggregate. WSB increased the field water capacity and available water content (AWC) of sandy loam while WSB was not found to increase significantly water holding capacity and AWC of clayey soil. WSB significantly reduced plastic index and tensile strength (TS) of clayey soil and did not alter the TS of sandy loam. Overall results suggest that WSB is a suitable amendment for strongly acidic Ultisols with poor physical properties. However, the soil texture affected greatly the improvement effect of WSB on poor physical properties in soils. PMID- 28634800 TI - Impact of chemical leaching on permeability and cadmium removal from fine-grained soils. AB - The aim of this study was to investigate the influence of chemical leaching on permeability and Cd removal from fine-grained polluted soils. Column leaching experiments were conducted using two types of soils (i.e., artificially Cd polluted loam and historically polluted silty loam). Chemical agents of CaCl2, FeCl3, citric acid, EDTA, rhamnolipid, and deionized water were used to leach Cd from the soils. Results showed that organic agents reduced permeability of both soils, and FeCl3 reduced permeability of loam soil, compared with inorganic agents and deionized water. Entrapment and deposition of colloids generated from the organic agents and FeCl3 treatments reduced the soil permeability. The peak Cd effluence from the artificially polluted loam columns was retarded. For the artificially polluted soils treated with EDTA and the historically polluted soils with FeCl3, Cd precipitates were observed at the bottom after chemical leaching. When Cd was associated with large colloid particles, the reduction of soil permeability caused Cd accumulation in deeper soil. In addition, the slow process of disintegration of soil clay during chemical leaching might result in the retardation of peak Cd effluence. These results suggest the need for caution when using chemical-leaching agents for Cd removal in fine-grained soils. PMID- 28634802 TI - Alkaline-treated sawdust as an effective material for cationic dye removal from textile effluents under dynamic conditions: breakthrough curve prediction and mechanism exploration. AB - This paper deals with the methylene blue molecule (MB) removal from synthetic and real textile wastewaters by alkali-treated orange tree sawdust (ATOS) under different dynamic conditions. Experimental results showed that MB removal efficiencies by ATOS increased when increasing initial dye concentrations and bed depths but decreased with the increase of the applied flow rates with a maximum adsorption capacity of about 110 mg g-1. Moreover, various empirical models were applied to predict the experimental breakthrough curves (BTCs) and to determine the characteristic adsorption parameters. The applied models successfully fitted data in the following order: Thomas ([Formula: see text] = 0.969), dose response ([Formula: see text] = 0.949), and Clark ([Formula: see text] = 0.874). ATOS was also found to efficiently remove dyes and other mineral pollutants such as chlorides, nitrates, and phosphates from real wastewaters. MB removal by ATOS involved not only cationic exchange but also complexation with acidic and basic functional groups. Moreover, important MB desorption yields from ATOS (more than 93%) were obtained when using saline solutions. All these results confirmed that NaOH-treated orange tree sawdust can be considered as a promising material for the removal of cationic dyes from industrial wastewaters. PMID- 28634803 TI - A method for reducing environmental pollution by using essential oils in rodent pest management program. AB - Strong-smelling plant extracts, such as essential oils, have a variety of feeding effects on mammals. Considering current concerns over long-term health issues and environmental effects of chemicals, plant-based products with repellent or antifungal activities may represent good solutions for improvement of rodent pest control programs. The present study was therefore focused on examining the effects of bergamot, lavender, and thyme essential oils as additional bait components on daily intakes of cereal-based baits by wild house mice. Lavender essential oil, containing linalool and linalyl acetate as main components, and thyme essential oil with a prevailing thymol component had no effects on house mice diet. Bergamot essential oil, whose main components were linalool, limonene, and linalyl acetate, showed a repellent effect on house mouse diet. PMID- 28634804 TI - Biocontrol of the wheat pathogen Zymoseptoria tritici using cyclic lipopeptides from Bacillus subtilis. AB - Innovation toward ecofriendly plant protection products compatible with sustainable agriculture and healthy food is today strongly encouraged. Here, we assessed the biocontrol activity of three cyclic lipopeptides from Bacillus subtilis (mycosubtilin, M; surfactin, S; fengycin, F) and two mixtures (M + S and M + S + F) on wheat against Zymoseptoria tritici, the main pathogen on this crop. Foliar application of these biomolecules at a 100-mg L-1 concentration on the wheat cultivars Dinosor and Alixan, 2 days before fungal inoculation, provided significant reductions of disease severity. The best protection levels were recorded with the M-containing formulations (up to 82% disease reduction with M + S on Dinosor), while S and F treatments resulted in lower but significant disease reductions. In vitro and in planta investigations revealed that M-based formulations inhibit fungal growth, with half-maximal inhibitory concentrations of 1.4 mg L-1 for both M and M + S and 4.5 mg L-1 for M + S + F, thus revealing that the observed efficacy of these products may rely mainly on antifungal property. By contrast, S and F had no direct activity on the pathogen, hence suggesting that these lipopeptides act on wheat against Z. tritici as resistance inducers rather than as biofungicides. This study highlighted the efficacy of several lipopeptides from B. subtilis to biocontrol Z. tritici through likely distinct and biomolecule-dependent modes of action. PMID- 28634806 TI - Household water insecurity and its cultural dimensions: preliminary results from Newtok, Alaska. AB - Using a relational approach, I examine several cultural dimensions involved in household water access and use in Newtok, Alaska. I describe the patterns that emerge around domestic water access and use, as well as the subjective lived experiences of water insecurity including risk perceptions, and the daily work and hydro-social relationships involved in accessing water from various sources. I found that Newtok residents haul water in limited amounts from a multitude of sources, both treated and untreated, throughout the year. Household water access is tied to hydro-social relationships predicated on sharing and reciprocity, particularly when the primary treated water access point is unavailable. Older boys and young men are primarily responsible for hauling water, and this role appears to be important to male Yupik identity. Many interviewees described preferring to drink untreated water, a practice that appears related to cultural constructions of natural water sources as pure and self-purifying, as well as concerns about the safety of treated water. Concerns related to the health consequences of low water access appear to differ by gender and age, with women and elders expressing greater concern than men. These preliminary results point to the importance of understanding the cultural dimensions involved in household water access and use. I argue that institutional responses to water insecurity need to incorporate such cultural dimensions into solutions aimed at increasing household access to and use of water. PMID- 28634805 TI - Comparative prevalence of Escherichia coli carrying virulence genes and class 1 and 2 integrons in sub-tropical and cool temperate freshwater. AB - Aquatic environments are now recognized secondary habitat of potentially pathogenic Escherichia coli. In this study, PCR-based analyses were used to determine the phylogenetic composition and frequency of occurrence of eight clinically significant virulence genes (VGs) in E. coli isolates from sub tropical Brisbane and cool temperate Tasmania freshwater in Australia. In Brisbane, non-commensal E. coli isolates belonging to the B2 and D phylogenetic group were dominant (72%). A significantly higher number (P < 0.05) of E. coli carrying VGs were detected in the sub-tropical freshwaters compared to the cool temperate water. Furthermore, diarrheagenic pathotype (EHEC) was also observed in the sub-tropical freshwater. The genes east1 and eaeA were significantly more common (P < 0.00001) than other VGs. The eaeA gene which codes for intimin protein along with toxin genes east1, stx 1 , stx 2 , and LT1 were mostly detected in phylogenetic groups B2 and D. The ANOVA results also suggested a statistically significant difference (P < 0.016) between the VGs carried by phylogenetic groups B2 and D. Class 1 integrase (intl1) and class 2 integrase (intl2) genes were detected in 38 (24.83%) and 23 (15.03%) of E. coli isolates, respectively. The Gretna site (Tasmania) with known fecal input from bovine and ovine sources had the highest number of E. coli carrying intl1 (29%) and intl2 (13%) genes. In addition, class 2 integron was more commonly detected in the phylogenetic group B2. The results of this study highlight the need to better understand sources and reasons for the high prevalence of E. coli carrying clinically significant VGs in a sub-tropical environment and its public health implications. PMID- 28634807 TI - Differential diagnosis between benign and malignant soft tissue tumors utilizing ultrasound parameters. AB - PURPOSE: Preoperative discrimination between benign and malignant soft tissue tumors is critical for the prevention of excess application of magnetic resonance imaging and biopsy as well as unplanned resection. Although ultrasound, including power Doppler imaging, is an easy, noninvasive, and cost-effective modality for screening soft tissue tumors, few studies have investigated reliable discrimination between benign and malignant soft tissue tumors. METHODS: To establish a modality for discrimination between benign and malignant soft tissue tumors using ultrasound, we extracted the significant risk factors for malignancy based on ultrasound information from 40 malignant and 56 benign pathologically diagnosed soft tissue tumors and established a scoring system based on these risk factors. RESULTS: The maximum size, tumor margin, and vascularity evaluated using ultrasound were extracted as significant risk factors. Using the odds ratio from a multivariate regression model, a scoring system was established. Receiver operating characteristic analyses revealed a high area under the curve value (0.85), confirming the accuracy of the scoring system. CONCLUSION: Ultrasound is a useful modality for establishing the differential diagnosis between benign and malignant soft tissue tumors. PMID- 28634808 TI - Mapping of genetic locus for leaf trichome in Brassica oleracea. AB - KEY MESSAGE: The genetic locus for leaf trichome was identified via marker-based mapping and SNP microarray assay, and a functional marker was developed to facilitate the breeding for hairiness in Brassica oleracea. Plant trichomes are involved in various functions particularly in protecting plants against some biotic and abiotic damages. In the present study, an F2 segregating population was developed from the cross between a glabrous cultivated B. oleracea (CC, 2n = 18) and a hairy wild relative, B. incana (CC, 2n = 18). A 1:3 segregation pattern between glabrous and hairy plants was detected among 1063 F2 genotypes, and the locus for hairiness was mapped in a 4.3-cM genetic region using 267 SSR markers among 149 F2 genotypes, corresponding to a 17.6-Mb genomic region on chromosome C01. To narrow the genetic region for hairiness, the Brassica 60 K SNP Bead Chip Arrays were applied to genotype 64 glabrous and 30 hairy F2 plants, resulting in a 1.04-Mb single peak region located in the 17.6-Mb interval. A candidate gene, BoTRY, was identified by qRT-PCR which revealed significant higher expression in glabrous F2 genotypes as compared with that in hairy plants. A cleaved amplified polymorphic site marker was successfully developed to distinguish the sequence variations of BoTRY between hairy and glabrous plants. Our study will be helpful for molecular breeding for hairiness in B. oleracea. PMID- 28634809 TI - Genetic and transcriptomic analyses of lignin- and lodging-related traits in Brassica napus. AB - KEY MESSAGE: Candidate genes associated with lignin and lodging traits were identified by combining phenotypic, genotypic, and gene expression data in B. napus. Brassica napus is one of the world's most important oilseed crops, but its yield can be dramatically reduced by lodging, bending, and falling of its vertical stems. Lignin has been shown to contribute to stem mechanical strength. In this study, we found that the syringyl/guaiacyl (S/G) monolignol ratio exhibits a significant negative correlation with disease and lodging resistance. A total of 92 and 50 SNP and SSR loci, respectively, were found to be significantly associated with five traits, breaking force, breaking strength, lodging coefficient, acid detergent lignin content, and the S/G monolignol ratio using GWAS. To identify novel genes involved in lignin biosynthesis, transcriptome sequencing of high- (H) and low (L)-ADL content accessions was performed. The up-regulated genes were mainly involved in glycoside catabolic processes (especially glucosinolate catabolism) and cell wall biogenesis, while down-regulated genes were involved in glucosinolate biosynthesis, indicating that crosstalk exists between glucosinolate metabolic processes and lignin biosynthesis. Integrating this differential expression with the GWAS analysis, we identified four candidate genes regulating lignin, including glycosyl hydrolase (BnaA01g00480D), CYT1 (BnaA04g22820D), and two encoding transcription factors, SHINE1 (ERF family) and DAR6 (LIM family). This study provides insight into the genetic control of lodging and lignin in B. napus. PMID- 28634811 TI - [Methodological limitations in the use of human donor eyes exemplified by age related alterations in cell density of the retinal pigment epithelium]. PMID- 28634810 TI - microRNA Regulation of Skeletal Development. AB - PURPOSE OF REVIEW: Osteogenesis is a complex process involving the specification of multiple progenitor cells and their maturation and differentiation into matrix secreting osteoblasts. Osteogenesis occurs not only during embryogenesis but also during growth, after an injury, and in normal homeostatic maintenance. While much is known about osteogenesis-associated regulatory genes, the role of microRNAs (miRNAs), which are epigenetic regulators of protein expression, is just beginning to be explored. While miRNAs do not abrogate all protein expression, their purpose is to finely tune it, allowing for a timely and temporary protein down-regulation. RECENT FINDINGS: The last decade has unveiled a multitude of miRNAs that regulate key proteins within the osteogenic lineage, thus qualifying them as "ostemiRs." These miRNAs may endogenously target an activator or inhibitor of differentiation, and depending on the target, may either lead to the prolongation of a progenitor maintenance state or to early differentiation. Interestingly, cellular identity seems intimately coupled to the expression of miRNAs, which participate in the suppression of previous and subsequent differentiation steps. In such cases where key osteogenic proteins were identified as direct targets of miRNAs in non-bone cell types, or through bioinformatic prediction, future research illuminating the activity of these miRNAs during osteogenesis will be extremely valuable. Many bone-related diseases involve the dysregulation of transcription factors or other proteins found within osteoblasts and their progenitors, and the dysregulation of miRNAs, which target such factors, may play a pivotal role in disease etiology, or even as a possible therapy. PMID- 28634812 TI - Semi-industrial Scale Production of a New Yeast with Probiotic Traits, Cryptococcus sp. YMHS, Isolated from the Red Sea. AB - A new yeast strain with promising probiotic traits was isolated from the Red Sea water samples. The isolate (YMHS) was subjected to genetic characterization and identified as Cryptococcus sp. Nucleotide sequence analysis of the rRNA gene internal transcribed spacer regions showed 95% sequence similarity between the isolate and Cryptococcus albidus. Cryptococcus sp. YMHS exhibited desirable characteristics of probiotic microorganisms; it has tolerance to low pH in simulated gastric juice, resistance to bile salts, hydrophobic characteristics, broad antimicrobial activity, and in vitro ability to degrade cholesterol. The isolate grew well in a semi-defined medium composed of yeast extract, glucose, KH2PO4, (NH4)2SO4, and MgSO4, yielding cell mass of 2.32 and 5.82 g/l in shake flask and in bioreactor cultures, respectively. Fed-batch cultivation, with controlled pH, increased the biomass gradually in culture, reaching 28.5 g/l after 32 h cultivation. Beside the feasible use as a probiotic, the new strain also could be beneficial in the development of functional foods or novel food preservatives. To our knowledge, this is the first report of yeast with probiotic properties isolated from the Red Sea. PMID- 28634813 TI - Long-Term Excessive Selenium Supplementation Induces Hypertension in Rats. AB - Selenium (Se) is an essential trace element involved in several biological pathways, naturally found in rocks, soils, and food. Even though the daily requirement of Se is achieved through a balanced diet, the use of Se supplements has been frequent. Due to the risk of toxic effects of having Se in excess, supplementation is still under debate. The aim was to evaluate the effects of long-term Se supplementation upon systolic blood pressure (SBP) and redox status of rats exposed to sodium selenite. Male Wistar rats were exposed to 2 and 6 mg/L of sodium selenite in drinking water for 85 days. SBP and body weight were evaluated weekly; oxidative stress biomarkers were measured in blood or plasma; and Se levels were assessed in blood, plasma, kidney, and liver. Se supplementation (2 and 6 mg/L) induced significant increase in the SBP in rats from the 42nd day until the end of the study. This increase on SBP was not associated with significant changes in oxidative stress biomarkers. A significant increase in Se levels was found in whole blood, kidney, and liver from both groups of rats receiving Se supplementation when compared to control. Although the exact mechanisms underlying this augment in SBP are not clear, they are potentially related to other Se biological routes besides the synthesis of selenoproteins, such as GSH-Px. Due to the negative effects upon blood pressure, precautionary measures are advised, since the selling of supplements does not require a medical prescription. PMID- 28634814 TI - Assessment of Waterborne Amine-Coated Silver Nanoparticle (Ag-NP)-Induced Toxicity in Labeo rohita by Histological and Hematological Profiles. AB - Silver nanoparticles (Ag-NPs) have wide applications in the medical field; however, the toxicological effects are still poorly studied. The study was aimed to determine the effects of 15.78 nm spherical and amine-coated Ag-NPs on hematology and histology of gills and liver tissues in 28 days treated Labeo rohita (L. rohita). It was found that Ag-NPs induced alterations in the hematological parameters in a dose dependent manner. The Ag-NPs also induced histological alterations in a dose-dependent manner. In gill tissues, it induced fusion of secondary lamellae, separation of gill epithelium, fusion and necrosis of lamellar cells, hyperplasia, deformed cartilaginous skeleton, separation and lifting of epithelium, and curling of lamellae in a dose dependent manner. In the liver, Ag-NPs produced abnormalities in hepatic tissues by reducing the size of hepatocytes and nuclei, and stimulated the production of necrotic and apoptotic bodies. It was concluded that Ag-NPs are toxic to aquatic organisms and induce hematotoxicity and histopathological conditions in exposed fish. PMID- 28634815 TI - Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. AB - Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect. PMID- 28634817 TI - Identification of the acclimation genes in transcriptomic responses to heat stress of White Pekin duck. AB - White Pekin duck is an important meat resource in the livestock industries. However, the temperature increase due to global warming has become a serious environmental factor in duck production, because of hyperthermia. Therefore, identifying the gene regulations and understanding the molecular mechanism for adaptation to the warmer environment will provide insightful information on the acclimation system of ducks. This study examined transcriptomic responses to heat stress treatments (3 and 6 h at 35 degrees C) and control (C, 25 degrees C) using RNA-sequencing analysis of genes from the breast muscle tissue. Based on three distinct differentially expressed gene (DEG) sets (3H/C, 6H/C, and 6H/3H), the expression patterns of significant DEGs (absolute log2 > 1.0 and false discovery rate < 0.05) were clustered into three responsive gene groups divided into upregulated and downregulated genes. Next, we analyzed the clusters that showed relatively higher expression levels in 3H/C and lower levels in 6H/C with much lower or opposite levels in 6H/3H; we referred to these clusters as the adaptable responsive gene group. These genes were significantly enriched in the ErbB signaling pathway, neuroactive ligand-receptor interaction and type II diabetes mellitus in the KEGG pathways (P < 0.01). From the functional enrichment analysis and significantly regulated genes observed in the enriched pathways, we think that the adaptable responsive genes are responsible for the acclimation mechanism of ducks and suggest that the regulation of phosphoinositide 3-kinase genes including PIK3R6, PIK3R5, and PIK3C2B has an important relationship with the mechanisms of adaptation to heat stress in ducks. PMID- 28634818 TI - SG2NA is a regulator of endoplasmic reticulum (ER) homeostasis as its depletion leads to ER stress. AB - SG2NA belongs to a three-member striatin subfamily of WD40 repeat superfamily of proteins. It has multiple protein-protein interaction domains involved in assembling supramolecular signaling complexes. Earlier, we had demonstrated that there are at least five variants of SG2NA generated by alternative splicing, intron retention, and RNA editing. Such versatile and dynamic mode of regulation implicates it in tissue development. In order to shed light on its role in cell physiology, total proteome analysis was performed in NIH3T3 cells depleted of 78 kDa SG2NA, the only isoform expressing therein. A number of ER stress markers were among those modulated after knockdown of SG2NA. In cells treated with the ER stressors thapsigargin and tunicamycin, expression of SG2NA was increased at both mRNA and protein levels. The increased level of SG2NA was primarily in the mitochondria and the microsomes. A mouse injected with thapsigargin also had an increase in SG2NA in the liver but not in the brain. Cell cycle analysis suggested that while loss of SG2NA reduces the level of cyclin D1 and retains a population of cells in the G1 phase, concurrent ER stress facilitates their exit from G1 and traverse through subsequent phases with concomitant cell death. Thus, SG2NA is a component of intrinsic regulatory pathways that maintains ER homeostasis. PMID- 28634816 TI - Critical biological parameters modulate affinity as a determinant of function in T-cell receptor gene-modified T-cells. AB - T-cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T cells. Using a model for altered antigen recognition, we determined how TCR-pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR-pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR-pMHC affinity did not always predict or dictate IFNgamma release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR-pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients. PMID- 28634819 TI - Establishment of a tagged variant of Lgr4 receptor suitable for functional and expression studies in the mouse. AB - Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4) is produced in a broad spectrum of mouse embryonic and adult tissues and its deficiency results in embryonal or perinatal lethality. The LGR4 function was mainly related to its potentiation of canonical Wnt signaling; however, several recent studies associate LGR4 with additional signaling pathways. To obtain a suitable tool for studying the signaling properties of Lgr4, we generated a tagged variant of the Lgr4 receptor using gene targeting in the mouse oocyte. The modified Lgr4 allele expresses the Lgr4 protein fused with a triple hemagglutinin (3HA) tag located at the extracellular part of the protein. The allele is fully functional, enabling tracking of Lgr4 expression in the mouse tissues. We also show that via surface labeling, the 3HA tag allows direct isolation and analysis of living Lgr4 positive cells obtained from the small intestinal crypts. Finally, the HA tag specific antibody can be employed to characterize the biochemical features of Lgr4 and to identify possible biding partners of the protein in cells derived from various mouse tissues. PMID- 28634820 TI - The first lady president of the ISPN: Prof. Dr. Graciela Zuccaro and her journey through pediatric neurosurgery. AB - The International Society for Pediatric Neurosurgery (ISPN) was founded in 1972 in Chicago, IL, USA. It has been 45 years since the creation of the ISPN, but it is not until now that the pediatric neurosurgery community has been led by a female neurosurgeon. PMID- 28634821 TI - Cavernous malformations of central nervous system in pediatric patients: our single-centered experience in 50 patients and review of literature. AB - PURPOSE: Cavernous malformations (CMs) are rare developmental cerebrovascular malformations of the central nervous system with a childhood prevalence of 0.3 to 0.53%. Our purpose was to assess the clinical features and microsurgical outcome in pediatric central nervous system (CNS) CMs. MATERIAL AND METHODS: We retrospectively enrolled all the CM patients admitted to our institute from 1 January 2001 to 31 December 2014. Data was analyzed for their clinical features and surgical outcome. RESULTS: A total of 50 patients with CMs (30 supratentorial, 14 infratentorial, and 6 spinal) with a mean age of 14 years (3 18 years, SD +/-4.64) were enrolled into the study. Most of these patients (78%) were male. Size varied from 1.2 to 6 cm. Three patients had multiple CMs. Symptoms of CMs were site specific. Seizure was the most common symptom (63.3%) of CMs at supratentorial location followed by headache (46%) and neurodeficiency (26%), while all brainstem and spinal CMs presented with neurodeficiencies. History of clinically significant acute hemorrhage was present in 19.2% of supratentorial (ST) superficial CMs, 50% of ST deep CMs, 25% of cerebellar CMs, 44.4% of brainstem CMs, and 50% of spinal CMs. Forty-five CMs in 44 patients were surgically excised. Their follow-up ranged from 6 to 162 months (mean 47.2 months, SD +/-53). All supratentorial CM patients showed improvement in their symptoms. Patients with preoperative seizure showed good seizure control with Engel scale I in 16 (94.1%) and Engel scale II in 1 (5.9%). In infratentorial (IT) and spinal CM patients, 92.3 and 66.7% had improvement in their neurodeficiencies, respectively. There was no mortality in our series. CONCLUSION: Microsurgical excision of CNS CM results in excellent neurological outcome in pediatric patients. Early intervention is necessary in spinal CMs for better outcome. PMID- 28634822 TI - The Ratio of Eicosapentaenoic Acid (EPA) to Arachidonic Acid may be a Residual Risk Marker in Stable Coronary Artery Disease Patients Receiving Treatment with Statin Following EPA Therapy. AB - BACKGROUND: We investigated the relationship between the eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio and non-high-density lipoprotein cholesterol (non-HDL-C) level, a major residual risk of coronary artery disease (CAD), in statin-treated CAD patients following EPA therapy. METHODS: We conducted a 6 month, prospective, randomized clinical trial to investigate the effect of the additional administration of EPA on the EPA/AA ratio and the serum non-HDL-C level in stable CAD patients receiving statin treatment. We assigned CAD patients already receiving statin therapy to an EPA group (1800 mg/day; n = 50) or a control group (n = 50). RESULTS: A significant reduction in the serum non-HDL-C level was observed in the EPA group, compared with the control group (-9.7 vs. 1.2%, p = 0.01). A multiple-regression analysis with adjustments for coronary risk factors revealed that achieved EPA/AA ratio was more reliable as an independent and significant predictor of a reduction in the non-HDL-C level at a 6-month follow-up examination (beta = -0.324, p = 0.033) than the absolute change in the EPA/AA ratio. Interestingly, significant negative correlations were found between the baseline levels and the absolute change values of both non-HDL-C and triglyceride-rich lipoproteins, both markers of residual risk of CAD, indicating that patients with a higher baseline residual risk achieved a greater reduction. CONCLUSION: The present results suggest that the achieved EPA/AA ratio, but not the absolute change in EPA/AA ratio, following EPA therapy might be a useful marker for the risk stratification of CAD among statin-treated patients with a high non-HDL-C level. CLINICAL TRIAL REGISTRATION: UMIN ( http://www.umin.ac.jp/ ) Study ID: UMIN000010452. PMID- 28634823 TI - A nationwide study of the incidence rate of herb-induced liver injury in Korea. AB - Discrepant incidence has been reported regarding the incidence of herb-induced liver injury (HILI). To address the growing worldwide concern of HILI, we evaluated the risk of HILI in a nationwide prospective study. Between April 2013 and January 2016, 1001 inpatients (360 males and 641 females) from 10 tertiary hospitals throughout South Korea were treated with herbal drugs and had their liver enzymes periodically measured. A total of six patients met the criteria for HILI with RUCAM scores ranging from 4 to 7. All these participants were women and developed the hepatocellular type of HILI. One HILI participant met the criteria for Hy's law; however, none of six cases presented clinical symptoms related to liver injury. This is the first nationwide prospective study that estimated the extent of the incidence of HILI [total: 0.60%, 95% confidence interval (CI) 0.12 1.08; women: 0.95%, 95% CI 0.19-1.68] and described its features in hospitalized participants. PMID- 28634824 TI - Association of Parkinsonism or Parkinson Disease with Polypharmacy in the Year Preceding Diagnosis: A Nested Case-Control Study in South Korea. AB - INTRODUCTION: Published studies on the association between polypharmacy and parkinsonism or Parkinson disease are very limited. OBJECTIVE: The objective of this study was to investigate whether polypharmacy is associated with parkinsonism or Parkinson disease in elderly patients. METHODS: From a South Korean national health insurance sample cohort database for 2002-2013, we matched parkinsonism cases (defined by diagnosis codes for parkinsonism/Parkinson disease) and Parkinson disease cases (patients who had records for both Parkinson disease diagnosis and anti-Parkinson disease drug prescriptions) with controls. Logistic regression analysis evaluated the associations of parkinsonism/Parkinson disease with polypharmacy (i.e., five or more prescribed daily drugs) during the year preceding parkinsonism/Parkinson disease diagnosis, medications potentially associated with parkinsonism, and comorbidity status (using the Charlson Comorbidity Index score and hospitalization records). RESULTS: The study population included 6209 cases and 24,836 controls for parkinsonism and 1331 cases and 5324 controls for Parkinson disease. In univariate logistic regression, odds ratios for parkinsonism/Parkinson disease increased significantly with increased polypharmacy, medications potentially associated with parkinsonism, Charlson Comorbidity Index score, or prior hospitalizations. In multiple logistic regression, odds ratios for parkinsonism/Parkinson disease (adjusted for medications potentially associated with parkinsonism and comorbidities) also increased with increased polypharmacy. Odds ratios (95% confidence interval) for Parkinson disease were higher than those for parkinsonism with stronger statistical significance: 1.41 (1.28-1.55) and 2.17 (1.84-2.57) for parkinsonism and 2.87 (2.30-3.58) and 4.75 (3.39-6.66) for Parkinson disease for between five and ten prescribed daily drugs and ten or more drugs, respectively. CONCLUSIONS: Polypharmacy in the year preceding diagnosis may be associated with an increased risk for parkinsonism/Parkinson disease. Medications potentially associated with parkinsonism were assumed to increase the risk for parkinsonism/Parkinson disease, but more studies are required to confirm this relationship. PMID- 28634825 TI - A rapid and cost-effective approach for the development of polymorphic microsatellites in non-model species using paired-end RAD sequencing. AB - As one of the most informative and versatile DNA-based markers, microsatellites have been widely used in population and conservation genetic studies. However, the development of microsatellites has traditionally been laborious, time consuming, and expensive. In the present study, a rapid and cost-effective "RAD seq-Assembly-Microsatellite" approach was developed to identify abundant microsatellite markers in non-model species using the roughskin sculpin Trachidermus fasciatus as a representative. Overlapping paired-end Illumina reads generated by restriction-site-associated DNA sequencing (RAD-seq) were clustered based on the similarity of reads containing the restriction enzyme recognition site and then assembled into contigs, which were used for microsatellite discovery and primer design. A total of 121,750 RAD contigs were generated with a mean length of 522 bp, and 19,782 contigs contained microsatellite motifs. A total of 156,150 primer pairs were successfully designed based on 16,497 contigs containing priming sites. Experimental validation of 52 randomly selected microsatellite loci demonstrated that 45 (86.54%) loci were successfully amplified and polymorphic in two geographically isolated populations of T. fasciatus. Compared with traditional approaches based on DNA cloning and other approaches based on next-generation sequencing, our newly developed approach could yield thousands of microsatellite loci with much higher successful amplification rate and lower costs, especially for non-model species with shallow background of genomic information. The "RAD-seq-Assembly-Microsatellite" approach holds great promise for microsatellite development in future ecological and evolutionary studies of non-model species. PMID- 28634827 TI - Highly functionalized cyclic beta-amino acid moieties as promising scaffolds in peptide research and drug design. AB - Peptide-based drug research has received high attention in the field of medicinal chemistry over the past decade. For drug design, to improve proteolytic stability, it is desirable to include unnatural building blocks, such as conformationally restricted beta-amino acid moieties, into the peptide sequence. Accordingly, the synthesis and incorporation of such conformationally rigid systems into novel type of peptides has gained large interest. Our research group has designed highly efficient methods for the construction of potential antimicrobial peptides. Moreover, a number of synthetic approaches have been developed for the synthesis of various pharmacologically interesting cyclic beta amino acid derivatives as monomers with multiple stereogenic centers. PMID- 28634826 TI - TAI vacuolar invertase orthologs: the interspecific variability in tomato plants (Solanum section Lycopersicon). AB - Understanding the genetic mechanisms underlying carbohydrate metabolism can promote the development of biotechnological advances in fruit plants. The flesh tomato fruit represents an ideal system for examining the role of sucrose cleavage enzymes in fruit development, and wild tomato species differing in storage sugars serve as an excellent research material for this purpose. Plant vacuolar invertase is a key enzyme of sucrose metabolism in the sink organs. In the present study, we identified complete gene sequences encoding the TAI vacuolar invertase in 11 wild and one cultivated tomato accessions of the Solanum section Lycopersicon. The average level of interspecific polymorphism in TAI genes was 8.58%; however, in the green-fruited tomatoes, the TAI genes contained 100 times more SNPs than those in the red-fruited accessions. The TAI proteins demonstrated 8% variability, whereas the red-fruited species had none. A TAI based phylogenetic tree revealed two main clusters containing self-compatible and self-incompatible species, which concurs with the previous crossability-based division and demonstrates that the TAI genes reflect the evolutionary relationships between the red- and green-fruited tomatoes. Furthermore, we detected differential expression patterns of the TAI genes in the fruits of wild and cultivated tomatoes, which corresponded to sugar composition. The polymorphism analysis of the TAI acid invertases of Solanum section Lycopersicon species will contribute to the understanding of the genetic potential of TAI genes to impact tomato breeding through genetic engineering of the carbohydrate composition in the fruit. PMID- 28634828 TI - Donation and back-donation analyzed through a charge transfer model based on density functional theory. AB - The net charge transfer process that occurs between two species, A and B, interacting with each other, may be decomposed into two processes: one in which A receives charge from B, which can be identified as the electrophilic channel for A or the nucleophilic channel for B, and a second in which A donates charge to B, which can be identified as the nucleophilic channel for A or the electrophilic channel for B. By determining the amount of charge associated with both processes through the minimization of the interaction energy associated with each case, the expressions for the amount of charge involved in each case can be expressed in terms of the directional chemical potentials and the hardnesses of the interacting species. The correlation between the charges obtained for the interaction between phosphine ligands of the type PRR'R'' and Ni, and the A1 carbonyl stretching frequency provides support for their interpretation as measures of the electrophilicity and nucleophilicity of a chemical species, and, at the same time, allows one to describe the donation and back-donation processes in terms of the density functional theory of chemical reactivity. PMID- 28634829 TI - Potential inhibitory effect of indolizine derivatives on the two enzymes: nicotinamide phosphoribosyltransferase and beta lactamase, a molecular dynamics study. AB - Nicotinamide phosphoribosyl-transferases (NAMPT) are enzymes that play a role in targeting cancer metabolism, while beta lactamases are involved in bacterial resistance to beta-lactam antibiotics. Many protein inhibitors exhibit such property which is often correlated with their cellular potency. In order to understand such a phenomenon, the present article conducts an analysis of the dynamic behavior of complexes formed by the inhibitors, that is indolizine derivatives, with the studied enzymes. Both docking and molecular dynamics led to identification of their interactions and showed the mechanism of inhibition of the two studied enzymes. The differences in the behavior of ligand at the active sites of beta lactamases and nicotinamide phosphoribosyl-transferases are indicated by structural and enthalpy values. PMID- 28634830 TI - The microRNA effector RNA-induced silencing complex in hidradenitis suppurativa: a significant dysregulation within active inflammatory lesions. AB - Recently, we could show that the expression levels of the key regulators of the microRNA (miRNA) maturation and transport were dysregulated in inflamed hidradenitis suppurativa (HS) tissue (Heyam et al. in Wiley Interdiscip Rev RNA 6:271-289, 2015). The RNA-induced silencing complex (RISC) is the central element of the miRNA pathway and regulates miRNA formation and function. We investigated the expression of the RISC components, namely transactivation-responsive RNA binding protein-1 (TRBP1), TRBP2, protein activator (PACT) of the interferon induced protein kinase R, Argonaute RISC Catalytic Component-1 (AGO1) and Component-2 (AGO2), metadherin, and staphylococcal nuclease and Tudor domain containing-1 (SND1) in inflamed HS tissue compared to healthy and psoriatic controls by real-time reverse transcription polymerase chain reaction. Expression levels of all investigated components were significantly lower in lesional HS skin (n = 18) compared to healthy controls (n = 10). TRBP1, PACT, AGO1, AGO2, and SND1 expression levels were significantly down-regulated in lesional HS skin compared to healthy-appearing perilesional skin (n = 7). TRBP2 and SND1 expression levels were significantly lower in healthy-appearing perilesional skin compared to healthy controls. In lesional HS skin, expression levels of PACT, AGO1, and AGO2 were significantly lower compared to psoriatic skin (n = 10). In summary, our data showed that all investigated components of RISC are dysregulated in the skin of HS patients, providing support for the hypothesis that miRNAs may have a pathological role in the inflammatory pathogenesis of HS. PMID- 28634831 TI - Malaria 2017: Update on the Clinical Literature and Management. AB - PURPOSE OF REVIEW: Malaria is a prevalent disease in travelers to and residents of malaria-endemic regions. Health care workers in both endemic and non-endemic settings should be familiar with the latest evidence for the diagnosis, management and prevention of malaria. This article will discuss the recent malaria epidemiologic and medical literature to review the progress, challenges, and optimal management of malaria. RECENT FINDINGS: There has been a marked decrease in malaria-related global morbidity and mortality secondary to malaria control programs over the last few decades. This exciting progress is tempered by continued levels of high transmission in some regions, the emergence of artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia, and the lack of a highly protective malaria vaccine. In the United States (US), the number of travelers returning with malaria infection has increased over the past few decades. Thus, US health care workers need to maintain expertise in the diagnosis and treatment of this infection. The best practices for treatment and prevention of malaria need to be continually updated based on emerging data. Here, we present an update on the recent literature on malaria epidemiology, drug resistance, severe disease, and prevention strategies. PMID- 28634832 TI - The fragility of randomized controlled trials in intracranial hemorrhage. AB - Fragility of randomized controlled trials (RCTs) has been evaluated using a novel metric called fragility index (FI), which measures how many events the statistical significance of a dichotomous outcome depends on. This study aimed to evaluate the fragility of RCTs in intracranial hemorrhage. Literature search (PubMed/Embase) identified all RCTs of intracranial hemorrhage since 2006. The overall distribution of FI was evaluated. Subgroup and spearman correlation analyses were made to explore potential factors that may affect FI value. All the included RCTs were divided into two groups (positive and negative trials) according to the statistical significance of selected outcomes. Finally, 47 positive and 51 negative trials were included. Both the median FI ([2; IQR, 1-4] vs. [6; IQR, 4-9], p < 0.001) and the proportion of trials with FI <=1 (2 vs. 18, p < 0.001) in positive trials were smaller than negative trials. In subgroup comparison within positive trials, sample size ([165; IQR, 87-200] vs. [83; IQR, 60-120], p = 0.015) and number of events ([35; IQR, 20-72] vs. [24; IQR, 11-32], p = 0.015) were higher in subgroup with FI >1 than the subgroup with FI <=1. Weak positive correlations were found between FI and sample size and number of events. In the field of intracranial hemorrhage, trials reporting significant conclusions often depend on a small number of events. Compared to sample size, this phenomenon is more likely to be affected by statistical approach and trial methodology. PMID- 28634834 TI - Acute demyelinating neuropathy associated with rituximab treatment in a patient with relapsing nephrotic syndrome. PMID- 28634833 TI - A case of renal dysfunction caused by pelvic organ prolapse. AB - Pelvic organ prolapse (POP) is the descent of pelvic organs through the vagina, and sometimes causes hydronephrosis. Although the association between POP and hydronephrosis has long been recognized, severe hydronephrosis and renal dysfunction are rarely seen. We report a case of 66-year-old woman who had a vaginal delivery presented with externalized uterine and bladder prolapse during the previous 2 years. She had a 3-day history of hypophagia and vomiting, and laboratory analysis resulted in serum creatinine of 5.75 mg/dL and blood urea of 78.1 mg/dL. The patient was treated urgently with vaginal pessary to return the uterine and bladder into the pelvis. After 2 weeks, her serum creatinine dropped to 3.66 mg/dL, but chronic renal failure persisted. Hydronephrosis caused by POP may lead to renal dysfunction and can advance to irreversible renal damage if left untreated. Important is early evaluation of renal function and images of the kidney and ureter. PMID- 28634835 TI - Impact of mechanical stimulation on the chondrogenic processes in human bone marrow aspirates modified to overexpress sox9 via rAAV vectors. AB - BACKGROUND: Evaluation of gene-based approaches to target human bone marrow aspirates in conditions of mechanical stimulation that aim at reproducing the natural joint environment may allow to develop improved treatments for articular cartilage injuries. In the present study, we investigated the potential of rAAV mediated sox9 gene transfer to enhance the chondrogenic differentiation processes in human bone marrow aspirates under established hydrodynamic conditions compared with the more commonly employed static culture conditions. METHODS: Fresh human bone marrow aspirates were transduced with rAAV-FLAG-hsox9 (40 MUl) and maintained for up to 28 days in chondrogenic medium under mechanically-induced conditions in dynamic flow rotating bioreactors that permit tissue growth and matrix deposition relative to static culture conditions. The samples were then processed to examine the potential effects of sox9 overexpression on the cellular activities (matrix synthesis, proliferation) and on the chondrogenic differentiation potency compared with control treatments (absence of rAAV vector; reporter rAAV-lacZ, rAAV-RFP, and rAAV-luc gene transfer). RESULTS: Prolonged, significant sox9 overexpression via rAAV was achieved in the aspirates for at least 28 days when applying the rAAV-FLAG-hsox9 construct, leading to higher, prolonged levels of matrix biosynthesis and to enhanced chondrogenic activities relative to control treatments especially when maintaining the samples under mechanical stimulation. Administration of sox9 however did not impact the indices of proliferation in the aspirates. Remarkably, sox9 gene transfer also durably delayed hypertrophic and osteogenic differentiation in the samples regardless of the conditions of culture applied versus control treatments. CONCLUSIONS: The current observations show the value of genetically modifying human bone marrow aspirates upon mechanical stimulation by rAAV sox9 as a promising strategy for future treatments to improve cartilage repair by implantation in lesions where the tissue is submitted to natural mechanical forces. PMID- 28634836 TI - Test-retest reproducibility of [11C]-L-deprenyl-D2 binding to MAO-B in the human brain. AB - BACKGROUND: [11C]-L-deprenyl-D2 is a positron emission tomography (PET) radioligand for measurement of the monoamine oxidase B (MAO-B) activity in vivo brain. The estimation of the test-retest reproducibility is important for accurate interpretation of PET studies. RESULTS: We performed two [11C]-L deprenyl-D2 scans for six healthy subjects and evaluated the test-retest variability of this radioligand. MAO-B binding was quantified by two tissue compartment model (2TCM) with three rate constants (K 1, k 2, k 3) using metabolite-corrected plasma radioactivity. The lambdak 3 defined as (K 1/k 2) * k 3 was also calculated. The correlation between MAO-B binding and age, and the effect of partial volume effect correction (PVEc) for the reproducibility were also estimated. %difference of k 3 was 2.6% (medial frontal cortex) to 10.3% (hippocampus), and that of lambdak 3 was 5.0% (thalamus) to 9.2% (cerebellum). Mean %difference of all regions were 5.3 and 7.0% in k 3 and lambdak 3, respectively. All regions showed below 10% variabilities except the hippocampus in k 3 (10.3%). Intraclass correlation coefficient (ICC) of k 3 was 0.78 (hippocampus) to 0.98 (medial frontal cortex), and that of lambdak 3 was 0.78 (hippocampus) to 0.95 (thalamus). Mean ICC were 0.94 and 0.89 in k 3 and lambdak 3, respectively. The highest positive correlation with age was observed in the hippocampus, as r = 0.75 in k 3 and 0.76 in lambdak 3. After PVEc, mean %difference were 5.6 and 7.2% in k 3 and lambdak 3, respectively. Mean ICC were 0.92 and 0.90 for k 3 and lambdak 3, respectively. These values were almost the same as those before PVEc. CONCLUSIONS: The present results indicate that k 3 and lambdak 3 of [11C]-L-deprenyl-D2 are reliable parameters for test-retest reproducibility with healthy subjects both before and after PVEc. The studies with patients of larger sample size are required for further clinical applications. PMID- 28634837 TI - Heterocyclic Quinodimethanes. AB - This chapter describes a series of heterocyclic quinodimethanes mainly containing O, N, S and Si atoms in their frameworks with either closed- or open-shell electronic structures in the ground state. Their syntheses, structural characterizations and chemical and physical properties are comprehensively reviewed. Some of them are used as materials for dyes/pigments and semiconductors for organic electronics. Some of them show an open-shell singlet diradical character with unusual properties. The purpose of this chapter is to provide fundamental understanding on the structure-property relationships of quinoidal pi conjugated compounds and give some insight into the rational design of such molecules with desirable properties. PMID- 28634838 TI - Superselective Transarterial Chemoembolization as an Alternative to Surgery in Symptomatic/Enlarging Liver Hemangiomas. AB - BACKGROUND: Transarterial embolization of liver hemangiomas has not been considered to be consistently effective. METHODS: The charts of 25 patients who underwent superselective transarterial chemoembolization with the bleomycin lipiodol emulsion were evaluated retrospectively. RESULTS: Twenty-two patients had abdominal pain; asymptomatic/vaguely symptomatic enlargement was the treatment indication in three patients. A single session was conducted in 17 patients, two sessions in 7 and three sessions in one. After the first session, lesion volume decreased by median (range) 51% (10-92%) from median (range) 634 (226-8435) to 372(28-4710) cm3 (p < 0.01), after a median period of 4 months (range 2-8). A second session was performed in eight patients (median (range) initial volume 1276 (441-8435) cm3) with persistent complaints and/or large lesions receiving feeders from both right and left hepatic arteries (staged treatment). Median (range) lesion size decreased further from 806 (245-4710) to 464 (159-2150) cm3 (p < 0.01). Three patients experienced a postembolization syndrome that persisted after the first week. Seventeen of the 22 symptomatic patients (77%) reported resolution or marked amelioration of complaints. Regrowth after initial regression was not observed during median (range) 14 (8-39) months of follow-up (n:18). CONCLUSION: Transarterial chemoembolization with the bleomycin-lipiodol emulsion is a potential alternative to surgery for symptomatic/enlarging liver hemangiomas. Volume reduction is universal, and symptom control is satisfactory. Centrally located and very large (>1000 cm3) lesions may require two sessions. PMID- 28634839 TI - Outcomes of Kidney Donors over 60 Years Old: A Single-Center Cohort Study. AB - AIM: To evaluate outcomes and post-donation kidney function of older living kidney donors (LKD). METHODS: Retrospective analysis of prospective database including all consecutive LKD undergoing laparoscopic nephrectomy in a single center (09/1998-12/2013). LKD aged >=60 years were compared to younger LKD. Renal function assessed by creatinine levels and estimated glomerular filtration rates (eGFR). Surgical complications classified according to the Clavien-Dindo classification. Bivariate and multivariate analyses using linear mixed effect models were performed to determine factors (age, gender, hypertension status, BMI, choice of better functioning kidney for donation) that might impinge on renal function after donation. RESULTS: 213 LKD were identified: 49 older (median age: 66 years, range: 60-79) and 164 younger (median age: 46, range: 25-59). Mean operative time (149 vs. 152 min, p = 0.69), conversion to laparotomy (n = 1 vs. 3, p = 0.92), grade III-IV complications (n = 4 vs. 2, p = 0.36) were similar. Older had more grade I-II complications (n = 18 vs. 4, p < 0.001). Despite similar pre-donation eGFR (80 vs. 84 ml/min/1.73 m2), older donors presented significantly lower eGFR during inpatient period (46 vs. 51 ml/min/1.73 m2, p = 0.0003), at 1 month (51 vs. 58 ml/min/1.73 m2, p = 0.002) and at 1 year (54 vs. 62 ml/min/1.73 m2, p = 0.001). Multivariate analysis adjusted to gender, hypertension status, BMI and choice of better functioning kidney for donation showed that at 1 year, age >=60 affected renal function by a coefficient of 0.91 (p < 0.001). CONCLUSION: Despite renal function improvement after discharge, LKD >= 60 years presented lower eGFR than younger at one year and had more grade I-II surgical complications. PMID- 28634840 TI - Self-Inflicted Abdominal Stab Wounds Have a Higher Rate of Non-therapeutic Laparotomy/Laparoscopy and a Lower Risk of Injury. AB - BACKGROUND: The profile and management of self-inflicted abdominal stab wounds (SI-ASW) patients is still obscure. METHODS: The National Trauma Data Bank (2012) was queried for adults with abdominal stab wounds (n = 9544). Patients with SI ASW (n = 1724) and non-SI-ASW (n = 7820) were compared. Predictors for non therapeutic laparotomy/laparoscopy (non-TL) in SI-ASW patients were identified. RESULTS: SI-ASW patients were older, had more females and behavioral disorders, similar physiology, but a lower Injury Severity Score. They had more laparotomies overall (54 versus 48%, p < 0.0001) and more non-TL (42 versus 32%, p < 0.0001), but less injuries (43 versus 53%, p < 0.0001), although peritoneal violation rate was similar. Complications and mortality were similar. In the SI-ASW cohort, non TL patients were more likely to be female and younger, and to have Glasgow Coma Scale (GCS) >=13 and a higher systolic blood pressure. History of psychiatric, drug and alcohol disorders was associated with SI-ASW, but did not independently predict the need for treatment in adjusted models. CONCLUSION: Patients with SI ASW underwent more non-TL than patients with non-SI-ASW. Female gender, younger age, and a higher GCS and systolic blood pressure predicted non-TL in this group. PMID- 28634841 TI - Patient-Related Risk Factors for Postoperative Infection After Cholecystectomy. AB - BACKGROUND: The impact of patient-related risk factors on the incidence of postoperative infection after cholecystectomy is relatively unknown. AIM: The aim of this study was to explore potential patient-related risk factors for surgical site infection (SSI) and septicaemia following cholecystectomy. MATERIALS AND METHODS: All cholecystectomies registered in the Swedish national population based register for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks) 2006-2014 were identified. The study cohort was cross-matched with the Swedish National Patient Register in order to obtain data on patient history and postoperative infections. Simple and multiple logistic regression analyses were performed in order to assess the impact of various comorbidities on the risk for SSI and septicaemia. RESULTS: A total of 94,557 procedures were registered. A SSI was seen following 5300 procedures (5.6%), and septicaemia following 661 procedures (0.7%). There was a significantly increased risk for SSI in patients with connective tissue disease (odds ratio [OR] 1.404, 95% confidence interval [CI] 1.208-1.633), complicated diabetes (OR 1.435, CI 1.205-1.708), uncomplicated diabetes (OR 1.391, CI 1.264 1.530), chronic kidney disease (OR 1.788, CI 1.458-2.192), cirrhosis (OR 1.764, CI 1.268-2.454) and obesity (OR 1.630, CI 1.475-1.802). There was a significantly higher risk for septicaemia in patients with chronic kidney disease (OR 3.065, CI 2.120-4.430) or cirrhosis (OR 5.016, CI 3.019-8.336). CONCLUSION AND DISCUSSION: Certain comorbidities have an impact on the risk for postoperative infection after cholecystectomy, especially SSI. This should be taken into account when planning the procedure and when deciding on prophylactic antibiotic treatment. PMID- 28634843 TI - Primary Recurrence in the Lung is Related to Favorable Prognosis in Patients with Pancreatic Cancer and Postoperative Recurrence. AB - BACKGROUND: The pattern of recurrence affects the clinical outcome in tumor patients. However, the clinical significance of lung metastasis as the primary recurrence site after resection in patients with pancreatic cancer remains unclear. This study aimed to clarify the clinical significance of the primary recurrence site in patients with pancreatic cancer, in terms of prognosis and clinicopathological features. METHODS: This retrospective cohort study included 220 patients with postoperative recurrence after pancreatectomy for pancreatic cancer and classified by primary site of recurrence. We focused on patients with lung metastasis as the primary recurrence and investigated its correlation with prognosis and clinicopathological factors. RESULTS: Twenty-four (11%) patients had lung metastasis as the primary recurrence. This recurrence pattern had the best prognosis among all recurrence patterns, including liver metastasis and local recurrence. Patients with lung metastasis as the primary recurrence had favorable overall survival and survival from the date of recurrence compared with patients with other primary recurrence sites in both univariate (P = 0.0008 and P = 0.0005) and multivariate analyses (P = 0.0051 and P = 0.0068). In terms of clinicopathological features of resected pancreatic tumors, lung metastasis as the primary recurrence was associated with lower tumor stage and histologic grade, and less vascular invasion and residual tumor volume than liver metastasis. CONCLUSIONS: Pancreatic cancer patients with lung metastasis as the primary recurrence after pancreatectomy have a better prognosis than those with other recurrence patterns. PMID- 28634842 TI - Evaluation of Open and Minimally Invasive Adrenalectomy: A Systematic Review and Network Meta-analysis. AB - BACKGROUND: Adrenalectomy can be performed via open and various minimally invasive approaches. The aim of this systematic review was to summarize the current evidence on surgical techniques of adrenalectomy. METHODS: Systematic literature searches (MEDLINE, EMBASE, Web of Science, Cochrane Library) were conducted to identify randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing at least two surgical procedures for adrenalectomy. Statistical analyses were performed, and meta-analyses were conducted. Furthermore, an indirect comparison of RCTs and a network meta-analysis of CCTs were carried out for each outcome. RESULTS: Twenty-six trials (1710 patients) were included. Postoperative complication rates did not show differences for open and minimally invasive techniques. Operation time was significantly shorter for open adrenalectomy than for the robotic approach (p < 0.001). No differences were found between laparoscopic and robotic approaches. Network meta-analysis showed open adrenalectomy to be the fastest technique. Blood loss was significantly reduced in the robotic arm compared with open and laparoscopic adrenalectomy (p = 0.01). Length of hospital stay (LOS) was significantly lower after conventional laparoscopy than open adrenalectomy in CCTs (p < 0.001). Furthermore, both retroperitoneoscopic (p < 0.001) and robotic access (p < 0.001) led to another significant reduction of LOS compared with conventional laparoscopy. This difference was not consistent in RCTs. Network meta-analysis revealed the lowest LOS after retroperitoneoscopic adrenalectomy. CONCLUSION: Minimally invasive adrenalectomy is safe and should be preferred over open adrenalectomy due to shorter LOS, lower blood loss, and equivalent complication rates. The retroperitoneoscopic access features the shortest LOS and operating time. Further high-quality RCTs are warranted, especially to compare the posterior retroperitoneoscopic and the transperitoneal robotic approach. PMID- 28634844 TI - Thrombospondin-1 Production Regulates the Inflammatory Cytokine Secretion in THP 1 Cells Through NF-kappaB Signaling Pathway. AB - Thrombospondin-1 (TSP-1) is upregulated in several inflammatory diseases. Recent data have shown that macrophages from TSP-1-deficient mice have a reduced inflammatory phenotype, suggesting that TSP-1 plays a part in macrophage activation. DNA microarray approach revealed that Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) may induce the enhanced TSP-1 expression in human monocytes, suggesting a role of TSP-1-mediated pathogenesis in periodontitis. Until recently, the function of TSP-1 has been a matter of debate. In this study, we explored the role of TSP-1 in inflammatory cytokine secretions and its putative mechanism in pathogenesis of periodontitis. We demonstrated that TSP-1 expression was significantly upregulated in gingival tissues with periodontitis and in P. gingivalis LPS-stimulated THP-1 cells. Deficiency of TSP 1 by transfecting siRNAs decreased IL-6, IL-1beta, and TNF-alpha secretions in THP-1 cells, whereas overexpression of TSP-1 resulted in an upregulation of IL-6, IL-1beta, and TNF-alpha productions. Additional experiments showed that Pyrrolidine dithiocarbamate (PDTC) inhibited IL-6, IL-1beta, and TNF-alpha expression induced by overexpression of TSP-1, accompanying with downregulation of phosphorylated p65 and IkappaBalpha protein levels in response to P. gingivalis LPS. These results indicated that TSP-1 played a significant role in P. gingivalis LPS-initiated inflammatory cytokines (IL-6, IL-1beta, and TNF alpha) secretions of THP-1 cells, and the NF-kappaB signaling is involved in its induction of expression. Thus, TSP-1 effectively elevated P. gingivalis LPS induced inflammation mediated by the NF-kappaB pathway and may be critical for pathology of periodontitis. PMID- 28634845 TI - Histomorphometric and immunohistochemical evaluation of collagen containing xenogeneic bone blocks used for lateral bone augmentation in staged implant placement. AB - BACKGROUND: The osteoconductive properties of collagen containing xenogeneic bone blocks (CCXBB) remain unclear. The aim of this prospective single-arm clinical study was to assess the histological outcomes of CCXBB blocks used as bone replacement grafts for lateral bone augmentation procedures. METHODS: In 15 patients with severe horizontal alveolar ridge resorption, lateral augmentation procedures were performed using CCXBB as bone replacement grafts. Twenty-six weeks postoperatively, a re-entry procedure was performed to evaluate the bone width for adequate implant placement and two histological specimens were retrieved from each patient, one being processed for ground sectioning and the other for decalcified paraffin-included sections. In non-decalcified sections, the relative proportions occupied by bone, biomaterials, and connective tissue present in the biopsies were identified. In de-calcified sections, structures and cells positive for osteopontin (OPN), tartrate-resistant acid phosphatase activity (TRAP), osteocalcin (OSC), and alkaline phosphatase (ALP) were assessed. RESULTS: Soft tissue dehiscence occurred during the follow-up in 5 out of 15 patients (33.3%). The mean crest width at baseline was 2.78 mm (SD 0.57) and the mean crest width at re-entry was 6.90 mm (SD 1.22), with a mean ridge width increase of 4.12 mm (SD 1.32). Twenty-six bone biopsies were obtained from 13 patients. Histomorphometric analysis showed a mean of 26.90% (SD 12.21) of mineralized vital bone (MVB), 21.37% (SD 7.36) of residual CCXBB, 47.13% (SD 19.15) of non-mineralized tissue, and 0.92% of DBBM. The immunohistochemical analysis revealed a large number of OPN-positive cells 8.12% (SD 4.73), a lower proportion of TRAP positive multinuclear cells 5.09% (SD 4.91), OSC-positive cells 4.09% (SD 4.34), and a limited amount of ALP positive cells 1.63% (SD 2). CONCLUSIONS: CCXBB achieved significant horizontal crestal width allowing for staged implant placement in most of the patients. In light of the histological outcomes and implant failures, special attention must be placed to prevent soft tissue dehiscence when CCXBB is used in severe atrophic alveolar crests. PMID- 28634846 TI - Lipid accumulation and metabolic analysis based on transcriptome sequencing of filamentous oleaginous microalgae Tribonema minus at different growth phases. AB - Filamentous oleaginous microalgae specie Tribonema minus is a promising feedstock for biodiesel production. However, the metabolic mechanism of lipid production in this filamentous microalgal specie remains unclear. Here, we compared the lipid accumulation of T. minus at different growth phases, and described the de novo transcriptome sequencing and assembly and identified important pathways and genes involved in TAG production. Total lipid increased by 2.5-fold and its TAG level in total lipid reached 81.1% at stationary phase. Using the genes involved in the lipid metabolism, the TAG biosynthesis pathways were generated. Moreover, results also demonstrated that, in addition to the observed overexpression of the fatty acid synthesis pathway, TAG production at stationary growth phase was bolstered by repression of the beta-oxidation pathway, up-regulation of genes that funnels acetyl-CoA to lipid biosynthesis, especially gene encoding for phospholipid:diacylglycerol acyltransferase (PDAT) which funnels DAG to TAG biosynthesis. PMID- 28634847 TI - Carbon nanotubes embedded in embryoid bodies direct cardiac differentiation. AB - We embedded carbon nanotubes (CNTs) in mouse embryoid bodies (EBs) for modulating mechanical and electrical cues of the stem cell niche. The CNTs increased the mechanical integrity and electrical conductivity of the EBs. Measured currents for the unmodified EBs (hereafter, EBs) and the EBs-0.25 mg/mL CNTs were 0.79 and 26.3 mA, respectively, at voltage of 5 V. The EBs had a Young's modulus of 20.9 +/- 6.5 kPa, whereas the Young's modulus of the EB-0.1 mg/mL CNTs was 35.2 +/- 5.6 kPa. The EB-CNTs also showed lower proliferation and greater differentiation rates compared with the EBs as determined by the expression of pluripotency genes and the analysis of EB sizes. Interestingly, the cardiac differentiation of the EB-CNTs was significantly greater than that of the EBs, as confirmed by high throughput gene analysis at day 5 of culture. Applying electrical stimulation to the EB-CNTs specifically enhanced the cardiac differentiation and beating activity of the EBs. PMID- 28634848 TI - Erratum to: Towards novel Cry toxins with enhanced toxicity/broader: a new chimeric Cry4Ba / Cry1Ac toxin. PMID- 28634849 TI - Characterization of new recombinant 3-ketosteroid-Delta1-dehydrogenases for the biotransformation of steroids. AB - 3-Ketosteroid-Delta1-dehydrogenases (KstDs [EC 1.3.99.4]) catalyze the Delta1 dehydrogenation of steroids and are a class of important enzymes for steroid biotransformations. In this study, we cloned 12 putative KstD-encoding (kstd) genes from both fungal and Gram-positive microorganisms and attempted to overproduce the recombinant proteins in E. coli BL21(DE3). Five successful recombinant enzymes catalyzed the Delta1-desaturation of a variety of steroidal compounds such as 4-androstene-3,17-dione (AD), 9alpha-hydroxy-4-androstene-3,17 dione (9-OH-AD), hydrocortisone, cortisone, and cortexolone. However, the substrate specificity and catalytic efficiency of the enzymes differ depending on their sources. The purified KstD from Mycobacterium smegmatis mc2155 (MsKstD1) displayed high catalytic efficiency toward hydrocortisone, progesterone, and 9-OH AD, where it had the highest affinity (K m 36.9 +/- 4.6 MUM) toward 9-OH-AD. On the other hand, the KstD from Rhodococcus erythropolis WY 1406 (ReKstD) exhibited high catalytic efficiency toward androst-4,9(11)-diene-3,17-dione (Diene), 21 acetoxy-pregna-4,9(11),16-triene-3,20-dione (Triene), and cortexolone, where in all three cases the K m values (12.3 to 17.8 MUM) were 2.5-4-fold lower than that toward hydrocortisone (46.3 MUM). For both enzymes, AD was a good substrate although ReKstD had a 3-fold higher affinity than MsKstD1. Reaction conditions were optimized for the biotransformation of AD or hydrocortisone in terms of pH, temperature, and effects of hydrogen peroxide, solvent, and electron acceptor. For the biotransformation of hydrocortisone with 20 g/L wet resting E. coli cells harboring MsKstD1 enzyme, the yield of prednisolone was about 90% within 3 h at the substrate concentration of 6 g/L, demonstrating the application potential of the newly cloned KstDs. PMID- 28634850 TI - Novel vitamin B12-producing Enterococcus spp. and preliminary in vitro evaluation of probiotic potentials. AB - Vitamin B12 is an essential nutrient required for crucial metabolic processes in humans. Vitamin B12-producing lactic acid bacteria (LAB) have been attracting increased attentions currently because of the generally recognized as safe (GRAS) status. Most of recent studies focused on Lactobacillus, and little is known about B12-producing Enterococcus. In the present study, five Enterococcus strains isolated from infant feces were identified as vitamin B12 producers. Among them, Enterococcus faecium LZ86 had the highest B12 production (499.8 +/- 83.7 MUg/L), and the B12 compound from LZ86 was identified as the biological active adenosylcobalamin, using reversed phase high-performance liquid (RP-HPLC) chromatogram. We examined basic probiotic and safety properties of E. faecium LZ86 and found that it was able to survive harsh environmental conditions (hot temperature, cold temperature, ethanol and osmotic stresses), tolerate gastric acid (pH 2.0, 3 h) and bile salts (0.3%), and adhere to Caco-2 cells. We also showed that E. faecium LZ86 is devoid of transferable antibiotic resistance and potential virulence factors. Together, here we report a B12-producing E. faecium strain LZ86 firstly, which has desirable probiotic properties and may serve as a good candidate for vitamin B12 fortification in food industry. PMID- 28634851 TI - Multi-step biocatalytic depolymerization of lignin. AB - Lignin is a biomass-derived aromatic polymer that has been identified as a potential renewable source of aromatic chemicals and other valuable compounds. The valorization of lignin, however, represents a great challenge due to its high inherent functionalization, what compromises the identification of chemical routes for its selective depolymerization. In this work, an in vitro biocatalytic depolymerization process is presented, that was applied to lignin samples obtained from beech wood through OrganoCat pretreatment, resulting in a mixture of lignin-derived aromatic monomers. The reported biocracking route comprises first a laccase-mediator system to specifically oxidize the Calpha hydroxyl group in the beta-O-4 structure of lignin. Subsequently, selective beta-O-4 ether cleavage of the oxidized beta-O-4 linkages is achieved with beta-etherases and a glutathione lyase. The combined enzymatic approach yielded an oily fraction of low-molecular-mass aromatic compounds, comprising coniferylaldehyde and other guaiacyl and syringyl units, as well as some larger (soluble) fractions. Upon further optimization, the reported biocatalytic route may open a valuable approach for lignin processing and valorization under mild reaction conditions. PMID- 28634852 TI - Incidence of prolonged QTc and severe hypoglycemia in type 1 diabetes: the EURODIAB Prospective Complications Study. AB - AIMS: To assess the independent role of severe hypoglycemia on 7-year cumulative incidence of prolonged QTc in a large cohort of patients with type 1 diabetes. METHODS: People with type 1 diabetes recruited by the EURODIAB Prospective Complications Study who had normal QTc were examined at baseline and after 7 years with standardized methods (n = 1415; mean age +/- SD 32.1 +/- 9.6 years; diabetes duration 14.2 +/- 8.8 years). Hypoglycemic episodes were assessed by a questionnaire. QTc was calculated according to Bazett's formula. In logistic regression analysis, we examined the role of severe hypoglycemia (none, 1-2, or 3 and more episodes/year) on the cumulative incidence of prolonged QTc, independently of age, sex, HbA1c, blood pressure, BMI, physical activity, distal symmetrical and autonomic neuropathy. RESULTS: In total, 264/1415 (17%) patients had incident prolonged QTc. Compared to those with persistently normal QTc, a greater proportion of incident cases had 3 and more hypoglycemic episodes at baseline (16.3 vs 11.2%, p = 0.03) and after 7 years (15.2 vs 9.6%, p = 0.01). In logistic regression analysis, 3 or more episodes of severe hypoglycemia at baseline did not increase cumulative incidence of prolonged QTc (OR 1.34, 95% CI 0.88-2.03). By contrast, severe hypoglycemia at the follow-up examination was associated with higher incidence of QTc prolongation (OR 1.68, 1.09-2.58), which reverted to not significant after adjustment for diabetic neuropathy. CONCLUSIONS: Severe hypoglycemia was not associated with incidence QTc prolongation in type 1 diabetic patients from the EURODIAB PCS. PMID- 28634853 TI - Chloroplast aggregation during the cold-positioning response in the liverwort Marchantia polymorpha. AB - Under low-light conditions, chloroplasts localize along periclinal cell walls at temperatures near 20 degrees C, but they localize along anticlinal cell walls near 5 degrees C. This phenomenon is known as the cold-positioning response. We previously showed that chloroplasts move as aggregates rather than individually during the cold-positioning response in the fern Adiantum capillus-veneris. This observation suggested that chloroplasts physically interact with each other during the cold-positioning response. However, the physiological processes underlying chloroplast aggregation are unclear. In this report, we characterized chloroplast aggregation during the cold-positioning response in the liverwort Marchantia polymorpha. Confocal laser microscopy observations of transgenic liverwort plants expressing a fluorescent fusion protein that localizes to the chloroplast outer envelope membrane (OEP7-Citrine) showed that neighboring chloroplast membranes did not fuse during the cold-positioning response. Transmission electron microscopy analysis revealed that a distance of at least 10 nm was maintained between neighboring chloroplasts during aggregation. These results indicate that aggregated chloroplasts do not fuse, but maintain a distance of at least 10 nm from each other during the cold-positioning response. PMID- 28634854 TI - MicroRNAs associated with inflammation in shoulder tendinopathy and glenohumeral arthritis. AB - Inflammation is associated with glenohumeral arthritis and rotator cuff tendon tears. Epigenetically, miRNAs tightly regulate various genes involved in the inflammatory response. Alterations in the expression profile of miRNAs and the elucidation of their target genes with respect to the pathophysiology could improve the understanding of their regulatory role and therapeutic potential. Here, we screened key miRNAs that mediate inflammation and linked with JAK2/STAT3 pathway with respect to the coincidence of glenohumeral arthritis in patients suffering from rotator cuff injury (RCI). Human resected long head of the biceps tendons were examined for miRNA profile from two groups of patients: Group 1 included the patients with glenohumeral arthritis and massive rotator cuff tears and the Group 2 patients did not have arthritis or rotator cuff tears. The miRNA profiling revealed that 235 miRNAs were highly altered (fold change less than -3 and greater than +2 were considered). Data from the NetworkAnalyst program revealed the involvement and interaction between 3,430 different genes associated with inflammation out of which 284 genes were associated with JAK2/STAT3 pathway and interconnect 120 different pathways of inflammation. Around 1,500 miRNAs were found to play regulatory role associated with these genes of inflammatory responses and 77 miRNAs were found to regulate more than 10 genes. Among them, 25 genes with less than tenfold change were taken to consideration which altogether constitute for the regulation of 102 genes. Targeting these miRNAs and the underlying regulatory mechanisms may advance our knowledge to develop promising therapies in the management of shoulder tendon pathology. PMID- 28634855 TI - Alpha linolenic acid decreases apoptosis and oxidized phospholipids in cardiomyocytes during ischemia/reperfusion. AB - The omega-3 fatty acid, alpha linolenic acid (ALA) found in plant-derived foods induces significant cardiovascular benefits when ingested. ALA may be cardioprotective during ischemia; however, the mechanism(s) responsible for this effect is unknown. Isolated adult rat cardiomyocytes were exposed to medium containing ALA for 24 h and then exposed to non-ischemic (control), simulated ischemia (ISCH), or simulated ischemia/reperfusion (IR) conditions. Cardiomyocyte phospholipids were extracted and analyzed by an HPLC/electrospray ionization tandem mass spectrometry system. Pre-treatment of cells with ALA resulted in a significant incorporation of ALA within cardiomyocyte phosphatidylcholine. Cell death, DNA fragmentation and caspase-3 activity increased during ischemia and ischemia/reperfusion. Two pro-apoptotic oxidized phosphatidylcholine (OxPC) species, 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) were significantly increased during both ischemia and ischemia/reperfusion. Pre-treatment of the cells with ALA resulted in a significant reduction in cell death during ischemia and ischemia/reperfusion challenge. Apoptosis was also inhibited during ischemia and ischemia/reperfusion as shown by reduced DNA fragmentation and decreased caspase activation. ALA pre-treatment significantly decreased the production of POVPC and PGPC during ischemia and ischemia/reperfusion. ALA pre-treatment also significantly increased in resting Ca2+ during ischemia or ischemia/reperfusion but did not improve Ca2+ transients. ALA protects the cardiomyocyte from apoptotic cell death during simulated ISCH and IR by inhibiting the production of specific pro-apoptotic OxPC species. OxPCs represent a viable interventional target to protect the heart during ischemic challenge. PMID- 28634857 TI - Computational Modelling of Cancer Development and Growth: Modelling at Multiple Scales and Multiscale Modelling. AB - In this paper, we present two mathematical models related to different aspects and scales of cancer growth. The first model is a stochastic spatiotemporal model of both a synthetic gene regulatory network (the example of a three-gene repressilator is given) and an actual gene regulatory network, the NF-[Formula: see text]B pathway. The second model is a force-based individual-based model of the development of a solid avascular tumour with specific application to tumour cords, i.e. a mass of cancer cells growing around a central blood vessel. In each case, we compare our computational simulation results with experimental data. In the final discussion section, we outline how to take the work forward through the development of a multiscale model focussed at the cell level. This would incorporate key intracellular signalling pathways associated with cancer within each cell (e.g. p53-Mdm2, NF-[Formula: see text]B) and through the use of high performance computing be capable of simulating up to [Formula: see text] cells, i.e. the tissue scale. In this way, mathematical models at multiple scales would be combined to formulate a multiscale computational model. PMID- 28634856 TI - Estrogen receptor alpha gene polymorphism and vascular complications in girls with type 1 diabetes mellitus. AB - The effect of estrogens is mediated by activation of estrogen receptors (ERs). Because ER-alpha gene polymorphisms may exert different effects in childhood, we analyzed the associations between the IVS1 -397T>C (PvuII) polymorphism and systemic inflammatory state, proangiogenic factors, frequency of monocyte subsets, lipid profile, blood pressure, and vascular complications in girls with type 1 diabetes mellitus (DM1). We examined 180 young girls with DM1 and 120 healthy age-matched controls. The analysis concerned PvuII polymorphism of the ER alpha gene as well as the levels of serum inflammatory markers (CRP, IL-6, TNF alpha), proangiogenic factors (VEGF, angiogenin), 17beta-estradiol, values of monocyte subsets (CD14++CD16- and CD14+CD16+), lipid profile, and blood pressure. In our study, girls with CC genotype had lower level of inflammatory and angiogenic factors and lower frequencies of CD14+CD16+ monocytes in comparison to CT or TT carriers. Simultaneously, the CC carriers had a greater population of CD14++CD16- monocytes, increased blood pressure, and serum levels of: estrogen, total cholesterol, triglycerides, and low-density lipoprotein cholesterol than girls bearing CT or TT genotype. Our study suggests a pleiotropic effect of PvuII polymorphic CC variant on diabetic vasculopathies. Although the CC genotype carriers demonstrate less inflammatory and angiogenic activity, they seem to display less favorable cardiometabolic features. Based on our study, we cannot distinguish PvuII ER-alpha genotype that could be useful in identification of DM1 girls that are more prone to develop of late vascular complications, before the occurrence of first clinical symptoms. PMID- 28634858 TI - Distal pain and carpal tunnel syndrome diagnosis among cashiers: a longitudinal study. AB - OBJECTIVE: To estimate in a longitudinal study the yearly incidence of carpal tunnel syndrome (CTS) in a cohort of women working as cashiers. METHOD: A total of 198 cashiers, belonging to a cohort investigated in 2011-2012 for arm pain, were screened for re-assessment in 2015 (at least 40 months from the first examination), and 156 women had complete demographic, personal and working data allowing to be included in this study. On the basis of self- and clinician administered questionnaires investigating the presence of CTS, all symptomatic patients underwent clinical and neurophysiological [nerve conduction studies (NCS) of median and ulnar nerves] assessments. RESULTS: NCS confirmed the presence of CTS in 17 out of 149 workers; however, seven of them already received the diagnosis of CTS at the previous assessment in 2011-2012, leading to an overall incidence of new cases equal to 7.0%. Cumulative working time at the cashier of the women with CTS in the period 2012-2015 was highly variable (1744 4479 h) without an evident association with the severity of CTS. No differences in general demographic data were found in the women with vs. without CTS. Comorbidities potentially associated with increased risk of CTS were present in 21 women in the entire cohort (14.0% of the population, 40.0% in the subgroup of women with newly assessed CTS). Overweight/obesity and hypothyroidism were the most frequent comorbidities. CONCLUSION: The results of this prospective study showed that the annualized incidence of CTS in our population of cashier was 2.0%; 40% of the new CTS cases had comorbidities. PMID- 28634859 TI - Erratum to: Erythropoietin Rescues Memory Impairment in a Rat Model of Chronic Cerebral Hypoperfusion via the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3beta Pathway. PMID- 28634861 TI - Retraction Note to: The Critical Role of SRPK1 in EMT of Human Glioblastoma in the Spinal Cord. PMID- 28634860 TI - Molecular Chaperone Hsp70 and Its Constitutively Active Form Hsc70 Play an Indispensable Role During Eye Development of Drosophila melanogaster. AB - In the present study, we demonstrate that molecular chaperone Hsp70 and Hsc70 is essential for normal organization and development of ommatidial cells in Drosophila melanogaster eye. An exogenously expressed dominant negative mutant of Hsp70 (K71E) and Hsc70.4 (K71S and D206S) in an eye-specific manner resulted in eye degeneration that includes loss of eye pigment, disorganized ommatidia, abnormality in bristle cell arrangement and reduction in the eye size. The developmental organization of ommatidial cells (cone, photoreceptor, pigment, and bristle cell complex) was disturbed in Hsp70 and Hsc70 mutants. Acridine orange (AO) and caspase 3 staining showed an increased cell death in Hsp70 and Hsc70 mutant eyes. Genetic interaction study of Hsp70 and Hsc70 mutants with candidate genes of JNK signaling pathway and immunocytochemistry study using phospho-JNK antibody suggested that mutation in Hsp70 and Hsc70 results in ectopic activation of JNK signaling in fly eye. Further, anti-PH3 staining in Hsp70 and Hsc70 mutant eyes revealed a reduced number of mitotic cells in second mitotic wave (SMW) of developing eye and anti-Rh1 staining showed reduced Rh1 expression, accumulation of Rh1 in the cytoplasm, and rhabdomere degeneration. Thus, on the basis of results, it was concluded that molecular chaperone Hsp70 and Hsc70 play an indispensable role during Drosophila eye development. PMID- 28634862 TI - Effect of GAPT extract on expression of tau protein and its phosphorylation related enzymes in hippocampal neurons of APPV717I transgenic mice. AB - OBJECTIVE: To investigate the effect of GAPT, an extract mixture from Radix Ginseng, Rhizoma Acor tatarinowii, Radix Polygalae and Radix Curcuma (containing ingredient of turmeric), etc. on expression of tau protein and its phosphorylation related enzyme in hippocampal neurons of APPV717I transgenic mice. METHODS: Sixty three-month-old APPV717I transgenic mice were randomly divided into model group, donepezil group [0.92 mg/(kg*d)], the low, medium and high dosage of GAPT groups [0.075, 0.15, 0.30 g/(kg*d), 12 in each group], and 12 three-month-old C57BL/6J mice were set as a normal control group, treatments were administered orally once a day respectively, and both the normal group and model group were given 0.5% sodium carboxymethyl cellulose solution. Immunohistochemistry (IHC) and Western blot analysis were used to detect the expression of total tau protein (Tau-5), cyclin-dependent kinase 5 (CDK5) and protein phosphatase 2A (PP2A) in hippocampal neurons of experimental mice after 8 month drug administration (11 months old). RESULTS: In the model group, the expression of Tau-5 and CDK5 were increased, whereas the expression of PP2A was decreased in hippocampal neurons, which were signifificantly different compared with that in the normal group (all P<0.01). IHC test indicated the number and area of either Tau-5 or CDK5 positive cells were decreased with a dose-depended way in GAPT groups, and an increase of PP2A. Compared with the model group, the changes were signifificant in GAPT groups (P<0.05 or P<0.01). Similar results were shown by Western blot. CONCLUSION: GAPT could attenuate abnormal hyperphosphorylation of tau protein in hippocampal neurons of APPV717I transgenic mice via inhibiting the expression of CDK5 and activating the expression of PP2A. PMID- 28634864 TI - Diagnostic Indicators for Blood Stasis Syndrome Patients with Gynaecological Diseases. AB - OBJECTIVE: To investigate the important diagnostic indicators for blood stasis syndrome (BSS) in patients of childbearing age with gynaecological diseases. METHODS: A partial least squared-discriminant analysis (PLS-DA) were applied to BSS symptoms data of patients with gynaecological diseases, and the diagnostic indicators used by doctors of Korean medicine (DKMs) among BSS patients with gynaecological diseases were also investigated. RESULTS: A total of 103 patients of childbearing age with gynaecological diseases and 40 healthy controls were enrolled. Among the 103 patients, 63 (61.7%) and 40 (38.8%) were diagnosed with BSS and non-BSS, respectively, and BSS patients exhibited a more severe extent of disease. A score plot of PLS-DA showed clearly different patterns among the 3 groups. Based on the variable importance on projection of PLS-DA model, menstrual pains, dark lumps in the menstrual blood, ileocoecal tenderness and resistance, sharp pains, and sublingual varicosities were selected as the top five most important indicators. Moreover, more than 75% of DKMs chose dark lumps in menstrual blood, menstrual pain, and dark menstrual blood as the diagnostic indicators of BSS in patients with gynaecological diseases, and more than 49% of them also considered sharp pains, dark red tongue, sublingual varicosities, and tendency to bruise easily as diagnostic indicators of BSS. CONCLUSION: DKMs focused on menstrual symptoms and certain gynaecological symptoms to diagnose BSS patients of childbearing age with female diseases. PMID- 28634863 TI - High-Tech Acupuncture for Prevention of Lifestyle Diseases-A Sino-Austrian Cooperation Research Protocol on Heart Rate Variability. AB - BACKGROUND: Acupuncture can not only be used for well-known diseases, but also for so-called modern lifestyle-related diseases. Using innovative methods like e.g. new analyses of heart rate variability (HRV), it is also possible to investigate diseases like burnout syndrome, ie., qi deficiency in Chinese medicine (CM). OBJECTIVE: The main object of this research protocol is to perform research on the relationship of burnout syndrome and heart rate (HR) and HRV. METHODS: A total of 175 patients with burnout syndrome (qi deficiency syndrome) in five groups and 35 healthy volunteers will be investigated. Based on random numbers generated by computer and concealed in opaque envelops, the patients will be assigned to four acupuncture groups using Zusanli (ST 36) acupuncture stimulation, Guanyuan (CV4) acupuncture stimulation, both points, and both points with Streitberger device respectively, and a moxibustion group using both points mentioned above, with 35 cases in each group. Altogether four different experiments are planned. Experiment 1 includes 70 subjects and is a comparison between a burnout group and a control group (healthy volunteers). The evaluation parameters are different scores and indices of HR and HRV. Experiment 2 includes 140 subjects and compares the efficacy of different acupuncture points. In experiment 3 (105 subjects), acupuncture and moxibustion should be compared to healthy volunteers. Experiment 4 (70 subjects) investigates the long-term therapeutic effects of acupuncture and moxibustion on the scores of qi deficiency and HR/HRV in qi deficiency patients. In both the acupuncture and moxibustion groups, a total of 10 treatments will be performed. CONCLUSIONS: The joint research aims at the scientific evaluation of CM, mainly in the field of HRV. This parameter could be a very good indicator of the state of health and can be inflfluenced by different acupuncture methods, as shown in the past. PMID- 28634865 TI - Dynamics of tobacco DNA topoisomerases II in cell cycle regulation: to manage topological constrains during replication, transcription and mitotic chromosome condensation and segregation. AB - KEY MESSAGE: The topoisomerase II expression varies as a function of cell proliferation. Maximal topoisomerase II expression was tightly coupled to S phase and G2/M phase via both transcriptional and post-transcriptional regulation. Investigation in meiosis using pollen mother cells also revealed that it is not the major component of meiotic chromosomes, it seems to diffuse out once meiotic chromosomal condensation is completed. Synchronized tobacco BY-2 cell cultures were used to study the role of topoisomerase II in various stages of the cell cycle. Topoisomerase II transcript accumulation was observed during the S- and G2/M- phase of cell cycle. This biphasic expression pattern indicates the active requirement of topoisomerase II during these stages of the cell cycle. Through immuno-localization of topoisomerase II was observed diffusely throughout the nucleoplasm in interphase nuclei, whereas, the nucleolus region exhibited a more prominent immuno-positive staining that correlated with rRNA transcription, as shown by propidium iodide staining and BrUTP incorporation. The immuno-staining analysis also showed that topoisomerase II is the major component of mitotic chromosomes and remain attached to the chromosomes during cell division. The inhibition of topoisomerase II activity using specific inhibitors revealed quite dramatic effect on condensation of chromatin and chromosome individualization from prophase to metaphase transition. Partially condensed chromosomes were not arranged on metaphase plate and chromosomal perturbations were observed when advance to anaphase, suggesting the importance of topoisomerase II activity for proper chromosome condensation and segregation during mitosis. Contrary, topoisomerase II is not the major component of meiotic chromosomes, even though mitosis and meiosis share many processes, including the DNA replication, chromosome condensation and precisely regulated partitioning of chromosomes into daughter cells. Even if topoisomerase II is required for individualization and condensation of meiotic chromosomes, it seems to diffuse out once meiotic chromosomal condensation is completed. PMID- 28634866 TI - Differential chromosomal organization between Saguinus midas and Saguinus bicolor with accumulation of differences the repetitive sequence DNA. AB - Saguinus is the largest and most complex genus of the subfamily Callitrichinae, with 23 species distributed from the south of Central America to the north of South America with Saguinus midas having the largest geographical distribution while Saguinus bicolor has a very restricted one, affected by the population expansion in the state of Amazonas. Considering the phylogenetic proximity of the two species along with evidence on the existence of hybrids between them, as well as cytogenetic studies on Saguinus describing a conserved karyotypic macrostructure, we carried out a physical mapping of DNA repeated sequences in the mitotic chromosome of both species, since these sequences are less susceptible to evolutionary pressure and possibly perform an important function in speciation. Both species presented 2n = 46 chromosomes; in S. midas, chromosome Y is the smallest. Multiple ribosomal sites occur in both species, but chromosome pairs three and four may be regarded as markers that differ the species when subjected to G banding and distribution of retroelement LINE 1, suggesting that it may be cytogenetic marker in which it can contribute to identification of first generation hybrids in contact zone. Saguinus bicolor also presented differences in the LINE 1 distribution pattern for sexual chromosome X in individuals from different urban fragments, probably due to geographical isolation. In this context, cytogenetic analyses reveal a differential genomic organization pattern between species S. midas and S. bicolor, in addition to indicating that individuals from different urban fragments have been accumulating differences because of the isolation between them. PMID- 28634867 TI - A risk assessment study of water quality, biota, and legacy sediment prior to small dam removal in a tributary to the Delaware River. AB - The proposed removal of three run-of-river dams (all <=5-m height) in eastern Pennsylvania along lower Bushkill Creek, a tributary of the Delaware River, has provided a valuable opportunity for multidisciplinary research involving the collection of more than 5 years of pre-removal monitoring data, analysis of heavy metals in legacy sediment cores, and associated toxicity assays to determine the singular and interactive effects of lead, copper, and cadmium on survival and behavior of a common macroinvertebrate found in Bushkill Creek. Monitoring data were collected from sites approximately 35 m upstream and downstream of dams and reference sites located approximately 5 km upstream of all dams. Results indicate that oxygen levels, macroinvertebrate diversity, and proportion of sensitive taxa were significantly lower upstream and downstream of dams in comparison with upstream reference reaches. The strong correlation between water quality and macroinvertebrates in this system implies that removal of the lower three dams would lead to improvements in water quality, biotic integrity, and resilience in lower Bushkill Creek. Sediment analyses and toxicity assays suggest that dam removal and sediment mobilization may route contaminated sediments downstream at concentrations that may harm more sensitive biota. However, macroinvertebrate mortality and behavior were not significantly different from clean water controls for the large majority of toxicity assays. All together, these results suggest that dams 1-3 are good candidates for successful stream restoration but that the removals would best be planned in a way that mitigates potential impacts of contaminated legacy sediment. PMID- 28634868 TI - Occurrence, removal and health risk assessment of phthalate esters in the process streams of two different wastewater treatment plants in Lagos and Ogun States, Nigeria. AB - Phthalate esters (PEs) are one of the environmentally active organic pollutants capable of causing endocrine disruption. The levels of PE congeners were determined in the influent and effluent from Covenant Oxidation Pond (COP) and Ikeja Wastewater Treatment Plant (IWWTP). Standard methods were adopted for determining the physical and chemical parameters of the water samples. The water samples for PE congener's determination were collected, acidified and stored at 4 degrees C prior to liquid-liquid extraction and analysis by gas chromatograph. The possible health risk associated with the usage of effluent-polluted river water was also investigated. The pH and temperature ranges were within the Federal Ministry of Environment (FME) 2001 guideline limits while the dissolved oxygen, biochemical oxygen demand and chemical oxygen demand were above the limits. The IWWTP performed better at removing PEs at 54% compared to 43.3% on average at COP. The health risk of individual PE congener showed no non-cancer effects (HQ) as the values varied from 5.01E-05 (DAP) to 1.52E-02 (DEHP) for adults and 1.17E-04 (DAP) to 3.76E-03 (DBP) for children at COP, while at IWWTP, it ranged from 8.06E-05 (DIBP) to 1.09E-02 (DEHP) for adults and 5.68E-04 (MMP) to 2.54E-02 (DEHP) for children. Notwithstanding, the usage of effluent-polluted river water by local communities downstream may result in carcinogenic effects due to the cumulative effects of the PE congeners as the values obtained for adults and children for the ingestion and dermal routes for the two waste process streams ranged from 4.67E-06 (IWWTP) to 6.22E-05 (IWWTP) and 2.18E-05 (IWWTP) to 7.18E-05 (COP), respectively. PMID- 28634869 TI - Discharge permit market and farm management nexus: an approach for eutrophication control in small basins with low-income farmers. AB - The economic concerns of low-income farmers are barriers to nutrient abatement policies for eutrophication control in surface waters. This study brings up a perspective that focuses on integrating multiple-pollutant discharge permit markets with farm management practices. This aims to identify a more economically motivated waste load allocation (WLA) for non-point sources (NPS). For this purpose, we chose the small basin of Zrebar Lake in western Iran and used the soil and water assessment tool (SWAT) for modeling. The export coefficients (ECs), effectiveness of best management practices (BMPs), and crop yields were calculated by using this software. These variables show that low-income farmers can hardly afford to invest in BMPs in a typical WLA. Conversely, a discharge permit market presents a more cost-effective solution. This method saves 64% in total abatement costs and motivates farmers by offering economic benefits. A market analysis revealed that nitrogen permits mostly cover the trades with the optimal price ranging from $6 to $30 per kilogram. However, phosphorous permits are limited for trading, and their price exceeds $60 per kilogram. This approach also emphasizes the establishment of a regional institution for market monitoring, dynamic pricing, fair fund reallocation, giving information to participants, and ensuring their income. By these sets of strategies, a WLA on the brink of failure can turn into a cost-effective and sustainable policy for eutrophication control in small basins. PMID- 28634870 TI - Assessing different sources of uncertainty in hydrological projections of high and low flows: case study for Omerli Basin, Istanbul, Turkey. AB - This study investigates the assessment of uncertainty contribution in projected changes of high and low flows from parameterization of a hydrological model and inputs of ensemble regional climate models (RCM). An ensemble of climate projections including 15 global circulation model (GCM)/RCM combinations and two bias corrections (change factor (CF) and bias correction in mean (BC)) was used to generate streamflow series for a reference and future period using the Hydrologiska Byrans Vattenbalansavdelning (HBV) model with the 25 best-fit parameter sets based on four objective functions. The occurrence time of high flows is also assessed through seasonality index calculation. Results indicated that the inputs of hydrological model from ensemble climate models accounts for greater contribution to the uncertainty related to projected changes in high flows comparing to the contribution from hydrological model parameterization. However, the uncertainty contribution is opposite for low flows, particularly for CF method. Both CF and BC increases the total mean variance of high and low flows. The variability in the occurrence time of high flows through RCMs is greater than the variability resulted from hydrological model parameters with and without statistical downscaling. The CF provides more accurate timing than BC and it shows the most pronounced changes in flood seasonality. PMID- 28634871 TI - Rabies virus co-localizes with early (Rab5) and late (Rab7) endosomal proteins in neuronal and SH-SY5Y cells. AB - Rabies virus (RABV) is a highly neurotropic virus that follows clathrin-mediated endocytosis and pH-dependent pathway for trafficking and invasion into endothelial cells. Early (Rab5, EEA1) and late (Rab7, LAMP1) endosomal proteins play critical roles in endosomal sorting, maturity and targeting various molecular cargoes, but their precise functions in the early stage of RABV neuronal infection remain elusive. In this study, the relationship between enigmatic entry of RABV with these endosomal proteins into neuronal and SH-SY5Y cells was investigated. Immunofluorescence, TCID50 titers, electron microscopy and western blotting were carried out to determine the molecular interaction of the nucleoprotein (N) of RABV with early or late endosomal proteins in these cell lines. The expression of N was also determined by down-regulating Rab5 and Rab7 in both cell lines through RNA interference. The results were indicative that N proficiently colocalized with Rab5/EEA1 and Rab7/LAMP1 in both cell lines at 24 and 48 h post-infection, while N titers significantly decreased in early infection of RABV. Down-regulation of Rab5 and Rab7 did not inhibit N expression, but it prevented productive infection via blocking the normal trafficking of RABV in a low pH environment. Ultrathin sections of cells studied by electron microscope also verified the close association of RABV with Rab5 and Rab7 in neurons. From the data it was concluded that primary entry of RABV strongly correlates with the kinetics of Rab-proteins present on early and late vesicles, which provides helpful clues to explain the early events of RABV in nerve cells. PMID- 28634872 TI - Predictive Markers of Response to Everolimus and Sunitinib in Neuroendocrine Tumors. AB - Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques. PMID- 28634873 TI - Evaluating Two Evidence-Based Intervention Strategies to Promote CRC Screening Among Latino Adults in a Primary Care Setting. AB - Regular use of colorectal cancer screening can reduce incidence and mortality, but participation rates remain low among low-income, Spanish-speaking Latino adults. We conducted two distinct pilot studies testing the implementation of evidence-based interventions to promote fecal immunochemical test (FIT) screening among Latinos aged 50-75 years who were not up-to-date with CRC screening (n = 200) at a large Federally Qualified Health Center (FQHC) in San Diego, CA. One pilot focused on an opportunistic clinic visit "in-reach" intervention including a 30-min session with a patient navigator, review of an educational "flip-chart," and a take-home FIT kit with instructions. The second pilot was a system-level "outreach" intervention consisting of mailed materials (i.e., FIT kit, culturally and linguistically tailored instructions, and a pre-paid return envelope). Both received follow-up calls to promote screening completion and referrals for additional screening and treatment if needed. The primary outcome was FIT kit completion and return within 3 months assessed through electronic medical records. The in-reach pilot consisted of mostly insured (85%), women (82%), and Spanish-speaking (88%) patients. The outreach pilot consisted of mostly of Spanish-speaking (73%) women (64%), half of which were insured (50%). At a 3 month follow-up, screening completion was 76% for in-reach and 19% for outreach. These data demonstrate that evidence-based strategies to promote CRC screening can be implemented successfully within FQHCs, but implementation (particularly of mailed outreach) may require setting and population-specific optimization. Patient, provider, and healthcare system related implementation approaches and lessons learned from this study may be implemented in other primary care settings. PMID- 28634874 TI - The Childcare Center: an Untapped Opportunity to Engage and Educate Families in Healthy Behaviors. AB - Obesity rates in preschool children are high and disproportionately affect low income children of color in the USA. Since 80% of preschool children spend ~40 h/week in out-of-the home childcare, childcare centers are promising sites for obesity prevention interventions. Mixed methods were used to develop, implement, and assess the feasibility of an obesity prevention program for children 2-5 years. The intervention which consisted of brief (1-3 min), interactive, educational modules was developed by content experts and parents (n = 20) and targeted four areas (milk, sugar sweetened beverages, screen time, and physical activity). The modules were delivered by community health workers in the childcare center during pick-up and drop-off times, in small groups and home visits upon request. Focus groups with childcare center staff (n = 28) assessed satisfaction and interest in incorporating the intervention into care. Between February 2013 and March 2014, 354 caregivers (~73%) at six centers participated in one or more educational sessions. Of children, 37.4% in 2013 and 35.9% in 2014 were overweight or obese. Children entering preschool in 2014 were more likely to be overweight/obese than children who had been in the center since 2013 (36.2 vs 23.2%, p < 0.05). Childcare staff endorsed the intervention and received training to continue the program. Brief, interactive health-related behavior-change interventions engaged large numbers of low-income caregivers at childcare centers and resonated with center staff. Childcare center staff represent an underutilized resource to combat the childhood obesity epidemic. PMID- 28634875 TI - Mental Health Care Disparities Now and in the Future. AB - In 2014, the USA spent $3 trillion dollars in health care the most per capita in the world. However, the USA lacks universal health coverage, and lags behind other highly developed and wealthy countries in life expectancy (even some "non wealthy" countries have better outcomes). The USA also has deficits in other health outcome measures. Health care costs in the USA continue to rise annually and many patients receive only mediocre care. In addition, clear disparities exist across different communities, socioeconomic groups, and race and ethnicity groups. As a result, individuals with mental illness are at an increased risk of being homeless, committing suicide, and having problems maintaining a job. This paper will address mental health disparities and review the efforts some states are taking to improve the lifesaving services offered to citizens with mental illness, in order for them to recover and reach their full potentials. PMID- 28634877 TI - Socioeconomic Status, Financial Strain, and Leukocyte Telomere Length in a Sample of African American Midlife Men. AB - BACKGROUND: African American men in the USA experience poorer aging-related health outcomes compared to their White counterparts, partially due to socioeconomic disparities along racial lines. Greater exposure to socioeconomic strains among African American men may adversely impact health and aging at the cellular level, as indexed by shorter leukocyte telomere length (LTL). This study examined associations between socioeconomic factors and LTL among African American men in midlife, a life course stage when heterogeneity in both health and socioeconomic status are particularly pronounced. METHODS: Using multinomial logistic regression, we examined associations between multiple measures of SES and tertiles of LTL in a sample of 92 African American men between 30 to 50 years of age. RESULTS: Reports of greater financial strain were associated with higher odds of short versus medium LTL (odds ratio (OR)=2.21, p = 0.03). Higher income was associated with lower odds of short versus medium telomeres (OR=0.97, p = 0.04). Exploratory analyses revealed a significant interaction between educational attainment and employment status (chi 2 = 4.07, p = 0.04), with greater education associated with lower odds of short versus long telomeres only among those not employed (OR=0.10, p = 0.040). CONCLUSION: Cellular aging associated with multiple dimensions of socioeconomic adversity may contribute to poor aging-related health outcomes among African American men. Subjective appraisal of financial difficulty may impact LTL independently of objective dimensions of SES. Self-appraised success in fulfilling traditionally masculine gender roles, including being an economic provider, may be a particularly salient aspect of identity for African American men and have implications for cellular aging in this population. PMID- 28634876 TI - Life Expectancy Gain Due to Employment Status Depends on Race, Gender, Education, and Their Intersections. AB - PURPOSE: Despite the well-established health effects of socioeconomic status (SES), SES resources such as employment may differently influence health outcomes across sub-populations. This study used a national sample of US adults to test if the effect of baseline employment (in 1986) on all-cause mortality over a 25-year period depends on race, gender, education level, and their intersections. METHODS: Data came from the Americans' Changing Lives (ACL) study, which followed 2025 Whites and 1156 Blacks for 25 years from 1986 to 2011. The focal predictor of interest was baseline employment (1986), operationalized as a dichotomous variable. The main outcome of interest was time to all-cause mortality from 1986 to 2011. Covariates included baseline age, health behaviors (smoking, drinking, and exercise), physical health (obesity, chronic disease, function, and self rated health), and mental health (depressive symptoms). A series of Cox proportional hazard models were used to test the association between employment and mortality risk in the pooled sample and based on race, gender, education, and their intersections. RESULTS: Baseline employment in 1986 was associated with a lower risk of mortality over a 25-year period, net of covariates. In the pooled sample, baseline employment interacted with race (HR = .69, 95% CI = .49-.96), gender (HR = .73, 95% CI = .53-1.01), and education (HR = .64, 95% CI = .46-.88) on mortality, suggesting diminished protective effects for Blacks, women, and individuals with lower education, compared to Whites, men, and those with higher education. In stratified models, the association was significant for Whites (HR = .71, 95%CI = .59-.90), men (HR = .60, 95%CI = .43-.83), and individuals with high education (HR = .66, 95%CI = .50-.86) but not for Blacks (HR = .77, 95%CI = .56 1.01), women (HR = .88, 95%CI = .69-1.12), and those with low education (HR = .92, 95%CI = .67-1.26). The largest effects of employment on life expectancy were seen for highly educated men (HR = .50, 95%CI = .32-.78), White men (HR = .55, 95%CI = .38-.79), and highly educated Whites (HR = .63, 95%CI = .46-.84). The effects were non-significant for Black men (HR = 1.10, 95%CI = .68-1.78), Whites with low education (HR = 1.01, 95%CI = .67-1.51), and women with low education (HR = 1.06, 95%CI = .71-1.57). CONCLUSION: In the USA, the health gain associated with employment is conditional on one's race, gender, and education level, along with their intersections. Blacks, women, and individuals with lower education gain less from employment than do Whites, men, and highly educated people. More research is needed to understand how the intersections of race, gender, and education alter health gains associated with socioeconomic resources. PMID- 28634879 TI - When Notes Fall from a Page. PMID- 28634878 TI - Can music-based movement therapy improve motor dysfunction in patients with Parkinson's disease? Systematic review and meta-analysis. AB - This study aimed to quantify whether there is association between music-based movement therapy and motor dysfunction in patients with Parkinson's disease, and, if so, whether music-based movement therapy can be used as first-line non pharmacological treatment. To conduct a systematic review and meta-analysis of clinical trials that examined the effect of music-based movement therapy on patient-relevant and disease-specific outcomes. Comprehensive literature was searched of PubMed, EMbase, and the Cochrane Library from inception to November 2016. Randomized controlled trial of patients with Parkinson's disease was searched to identify trials comparing music-based movement therapy with no music care. A total of 8 studies (11 analyses, 241 subjects) were included; all of them had acceptable quality by PEDro scale score. Studies based on any type of Parkinson's disease patients were combined and subgroup analyzed. Compared with the control group, the SMD of Berg Balance Scale score was 0.85(0.46 to 1.25), 0.60 (-0.98 to -0.22) in Parkinson Disease Questionnaire-39 summary index, -0.90s (-1.56 to -0.23) in Time Up and Go text, and -0.43 (-1.11 to 0.25) in Unified Parkinson's Disease Rating Scale Motor Subscale 3 as instrument methods for motor function. Secondary outcomes included cognitive function and quality of life. There was positive evidence to support the use of music-based movement therapy on treatment of motor function; there was neutral evidence to support the use of music for the treatment of cognitive function quality of life. PMID- 28634880 TI - Erratum to: An RCT Investigating Patient-Driven Versus Physician-Driven Titration of BIAsp 30 in Patients with Type 2 Diabetes Uncontrolled Using NPH Insulin. PMID- 28634881 TI - Drowning and near drowning - definitions and terminology. PMID- 28634883 TI - A Minimal Continuous-Time Markov Pharmacometric Model. AB - In this work, an alternative model to discrete-time Markov model (DTMM) or standard continuous-time Markov model (CTMM) for analyzing ordered categorical data with Markov properties is presented: the minimal CTMM (mCTMM). Through a CTMM reparameterization and under the assumption that the transition rate between two consecutive states is independent on the state, the Markov property is expressed through a single parameter, the mean equilibration time, and the steady state probabilities are described by a proportional odds (PO) model. The mCTMM performance was evaluated and compared to the PO model (ignoring Markov features) and to published Markov models using three real data examples: the four-state fatigue and hand-foot syndrome data in cancer patients initially described by DTMM and the 11-state Likert pain score data in diabetic patients previously analyzed with a count model including Markovian transition probability inflation. The mCTMM better described the data than the PO model, and adequately predicted the average number of transitions per patient and the maximum achieved scores in all examples. As expected, mCTMM could not describe the data as well as more flexible DTMM but required fewer estimated parameters. The mCTMM better fitted Likert data than the count model. The mCTMM enables to explore the effect of potential predictive factors such as drug exposure and covariates, on ordered categorical data, while accounting for Markov features, in cases where DTMM and/or standard CTMM is not applicable or conveniently implemented, e.g., non uniform time intervals between observations or large number of categories. PMID- 28634882 TI - Gingipain of Porphyromonas gingivalis manipulates M1 macrophage polarization through C5a pathway. AB - Gingipains secreted by Porphyromonas gingivalis (P. gingivalis, Pg) play an important role in maintaining macrophage infiltrating. And, this study is to evaluate effects of gingipain on M1 macrophage polarization after exposure to Porphyromonas gingivalis (P. gingivalis, Pg) and if these effects are through complement component 5a (C5a) pathway. Mouse RAW264.7 macrophages were exposed to gingipain extracts, Escherichia coli lipopolysaccharides (Ec-LPS), Pg-LPS with or without the C5aR antagonist: PMX-53 for 24 h. Then, gene expressions and protein of IL-12, IL-23, iNOS, IL-10, TNF-alpha, IL-1beta, and IL-6 were determined by qRT-PCR and ELISA assays. Surface markers CD86 for M1 and CD206 for M2 were also evaluated by flow cytometry. The results show that gingipain extracts alone increased expressions of IL-12, IL-23, iNOS, TNF-alpha, IL-1beta, and IL-6, but not IL-10. Gingipain extracts plus Ec-LPS decreased expressions of IL-12, IL-23, iNOS, TNF-alpha, IL-1beta, and IL-6 in which Ec-LPS induced increase. For gingipain extracts plus Pg-LPS-treated RAW264.7, macrophages, gingipain extracts enhanced expressions of IL-12 and IL-23 in which Pg-LPS induced increase, but not iNOS and IL-10 while gingipain extracts decreased expressions of TNF-alpha, IL 1beta, and IL-6 in which Pg-LPS induced increase. Interestingly, PMX-53 increased expressions of IL-12, IL-23, and iNOS when RAW264.7 macrophages were treated with gingipain extracts plus Ec-LPS or Pg-LPS and PMX-53, while PMX-53 decreased expressions of TNF-alpha, IL-1beta, and IL-6. Changes of CD86-positive macrophages were consistent with cytokine changes. Our data indicate that gingipain is a critical regulator, more like a promoter to manipulate M1 macrophage polarization in order to benefit P. gingivalis infection through the C5a pathway. PMID- 28634884 TI - A Nanosensor Based on Carbon Dots for Recovered Fluorescence Detection Clenbuterol in Pork Samples. AB - Clenbuterol (CLB), a member of beta-agonist family, has now been a serious threat to human health due to its illegal usage in the animal feed. In this paper, we designed a fluorescence resonance energy transfer (FRET) system consisting of carbon dots (C-dots) and gold nanoparticles (AuNPs) for recovered fluorescence detecting of CLB. In the presence of CLB, CLB molecules can interact with AuNPs via Au-N bonds, preventing the interaction of C-dots and AuNPs, which induced the recover of the fluorescent intensity. Under the optimal conditions, the limit of detection for CLB was 3 nM, with a wide concentration linear range of 8-200 nM (S/N = 3). Meanwhile, the proposed method was successfully applied to detect CLB in pork samples, illustrating it could be used as a reliable, rapid, and cost effective method for the determination of CLB residues in pork samples. PMID- 28634885 TI - Colorimetric Determination of Pb2+ in Perfect Aqueous Solution Using Carminic Acid as a Selective Chemosensor. AB - The commercially available natural organic dye, carminic acid (CA), an anthraquinone derivative bearing hydroxyl and carboxyl groups as recognition sites was found to be a colorimetric probe for Pb2+ in perfect aqueous solution under neutral conditions with specific selectivity and high sensitivity. Upon addition of Pb2+, the absorption maximum of CA showed a large red shift, and the resulted color change from red to purple could be easily identified even by the naked eye. The chemical stoichiometric ratio between CA and Pb2+ was determined to be 1:2 through Job plot, Pb2+ titration, and kinetic experiments. Moreover, other environmental relevant metal ions induced no or minimal spectral and color changes. The reversibility of Pb2+ to CA with EDTA even through several cycles was established for practical applications. The results indicated that CA can be a good candidate for simple, convenient and reversible colorimetric detection of Pb2+ in aqueous solution even though it was hard to be applied to determine Pb2+ on the water testing by US EPA. PMID- 28634886 TI - Subcortical brain atrophy in Gulf War Illness. AB - Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990-1991 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. Although brain dysfunction in GWI has been well documented (EBioMedicine 12:127-32, 2016), abnormalities in brain structure have been debated. Here we report a substantial (~10%) subcortical brain atrophy in GWI comprising mainly the brainstem, cerebellum and thalamus, and, to a lesser extent, basal ganglia, amygdala and diencephalon. The highest atrophy was observed in the brainstem, followed by left cerebellum and right thalamus, then by right cerebellum and left thalamus. These findings indicate graded atrophy of regions anatomically connected through the brainstem via the crossed superior cerebellar peduncle (left cerebellum -> right thalamus, right cerebellum -> left thalamus). This distribution of atrophy, together with the observed systematic reduction in volume of other subcortical areas (basal ganglia, amygdala and diencephalon), resemble the distribution of atrophy seen in toxic encephalopathy (Am J Neuroradiol 13:747-760, 1992) caused by a variety of substances, including organic solvents. Given the potential exposure of Gulf War veterans to "a wide range of biological and chemical agents including sand, smoke from oil-well fires, paints, solvents, insecticides, petroleum fuels and their combustion products, organophosphate nerve agents, pyridostigmine bromide, ..." (Institute of Medicine National Research Council. Gulf War and Health: Volume 1. Depleted uranium, pyridostigmine bromide, sarin, and vaccines. National Academies Press, Washington DC, 2000), it is reasonable to suppose that such exposures, alone or in combination, could underlie the subcortical atrophy observed. PMID- 28634887 TI - Aberrant connections between climbing fibres and Purkinje cells induce alterations in the timing of an instrumental response in the rat. AB - Cerebellar participation in timing and sensory-motor sequences has been supported by several experimental and clinical studies. A relevant role of the cerebellum in timing of conditioned responses in the range of milliseconds has been demonstrated, but less is known regarding the role of the cerebellum in supra second timing of operant responses. A dissociated role of the cerebellum and striatum in timing in the millisecond and second range had been reported, respectively. The climbing fibre-Purkinje cell synapse is crucial in timing models; thus, the aberrant connection between these cellular elements is a suitable model for evaluating the contribution of the cerebellum in timing in the supra-second range. The aberrant connection between climbing fibres and Purkinje cells was induced by administration of the antagonist of NMDA receptors MK-801 to Sprague-Dawley rats at postnatal days 7-14. The timing of an operant response with two fixed intervals (5 and 8 s) and egocentric sequential learning was evaluated in 60-day-old adult rats. The aberrant connections caused a reduced accuracy in the timing of the instrumental response that was more evident in the 8-s interval and a reduced number of successive correct responses (responses emitted in the correct second without any other response between them) in the 8-s interval. In addition, an inability to incorporate new information in a sequence previously learned in egocentric-based sequence learning was apparent in rats with aberrant CF-PC synapses. These results support a relevant role for the cerebellum in the fine-tuning of the timing of operant responses in the supra second range. PMID- 28634888 TI - Saccades evoked in response to electrical stimulation of the posterior bank of the arcuate sulcus. AB - To test the hypothesis that the premotor cortex in and behind the caudal bank of the arcuate sulcus can generate saccades, we stimulated electrically the periarcuate region of alert rhesus monkeys. We were able to produce saccades from sites of the premotor cortex that were contiguous with the frontal eye fields and extended up to 2 mm behind the smooth pursuit area. However, premotor sites often elicited saccades with ipsiversive characteristic vectors, lower peak velocities, and flatter velocity profiles when compared to saccades evoked from the frontal eye field. PMID- 28634889 TI - The efficacy of airflow and seat vibration on reducing visually induced motion sickness. AB - Visually induced motion sickness (VIMS) is a well-known sensation in virtual environments and simulators, typically characterized by a variety of symptoms such as pallor, sweating, dizziness, fatigue, and/or nausea. Numerous methods to reduce VIMS have been previously introduced; however, a reliable countermeasure is still missing. In the present study, the effect of airflow and seat vibration to alleviate VIMS was investigated. Eighty-two participants were randomly assigned to one of four groups (airflow, vibration, combined airflow and vibration, and control) and then exposed to a 15 min long video of a bicycle ride shot from first-person view. VIMS was measured using the Fast Motion Sickness Scale (FMS) and the Simulator Sickness Questionnaire (SSQ). Results showed that the exposure of airflow significantly reduced VIMS, whereas the presence of seat vibration, in contrast, did not have an impact on VIMS. Additionally, we found that females reported higher FMS scores than males, however, this sex difference was not found in the SSQ scores. Our findings demonstrate that airflow can be an effective and easy-to-apply technique to reduce VIMS in virtual environments and simulators, while vibration applied to the seat is not a successful method. PMID- 28634890 TI - CCL11 (Eotaxin-1) Levels Predict Long-Term Functional Outcomes in Patients Following Ischemic Stroke. AB - Circulating levels of the pro-inflammatory cytokine C-C motif chemokine 11 (CCL11, also known as eotaxin-1) are increased in several animal models of neuroinflammation, including traumatic brain injury and Alzheimer's disease. Increased levels of CCL11 have also been linked to decreased neurogenesis in mice. We hypothesized that circulating CCL11 levels would increase following ischemic stroke in mice and humans, and that higher CCL11 levels would correlate with poor long-term recovery in patients. As predicted, circulating levels of CCL11 in both young and aged mice increased significantly 24 h after experimental stroke. However, ischemic stroke patients showed decreased CCL11 levels compared to controls 24 h after stroke. Interestingly, lower post-stroke CCL11 levels were predictive of increased stroke severity and independently predictive of poorer functional outcomes in patients 12 months after ischemic stroke. These results illustrate important differences in the peripheral inflammatory response to ischemic stroke between mice and human patients. In addition, it suggests CCL11 as a candidate biomarker for the prediction of acute and long-term functional outcomes in ischemic stroke patients. PMID- 28634891 TI - A scoping review of the public health impact of vitamin D-fortified dairy products for fracture prevention. AB - PURPOSE: Dairy products are rich in nutrients that positively influence bone health and hence fracture risk, and have therefore been recommended and used for fracture prevention. To help decision makers to efficiently allocate scare resources, it is further important to assess the public health and economic impact of any health intervention. In recent years, several studies have been conducted to estimate the public health and/or economic impact of dairy products but no overview is currently available. This article aims therefore to summarize evidence and review articles that estimated the public health and/or economic impact of vitamin D-fortified dairy products for fracture prevention. METHODS: A literature review was conducted using PubMed to identify original studies that assessed the public health and/or economic impact of dairy products (or of calcium/vitamin D supplementation) for fracture prevention up to January 15, 2017. RESULTS: Seven articles were identified. Different strategies were used by the authors to model the economic/public health impact of dairy products. The four studies assessing the public health impact of dairy products revealed a substantial benefit in terms of fracture prevented, life years, disability adjusted life years and/or quality-adjusted life years gained. Studies assessing the cost-effectiveness revealed that the use of dairy products is generally cost effective in the general population aged above 70 years, and from the age of 60 years in populations at high risk of fractures. CONCLUSION: This systematic review suggests that the use of dairy products could substantially reduce the burden of osteoporotic fractures and seem to be an economically beneficial strategy. PMID- 28634892 TI - Lung Clearance Index (LCI) is Stable in Most Primary Ciliary Dyskinesia (PCD) Patients Managed in a Specialist Centre: a Pilot Study. AB - Primary ciliary dyskinesia is a condition in which abnormal cilia structure or function leads to reduced mucociliary clearance and obstructive lung disease. Twenty-nine patients had lung clearance index (LCI) measured in 2009 and we attempted to perform a 5-year follow-up. Only 12 patients could be re-recruited, but in this small group LCI was stable over the 5 years, which confirms previous data showing that spirometry is also stable in these patients over the medium term. The two patients with the highest LCI in 2009 had since died, despite one having relatively preserved spirometry at the time. These data may be used to inform sample size calculations of future studies. PMID- 28634894 TI - Pearls: Never Write a Research Grant Alone. PMID- 28634893 TI - Geriatric Assessment and Functional Decline in Older Patients with Lung Cancer. AB - PURPOSE: Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS). METHODS: At baseline, GA was performed in patients >=70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined. RESULTS: Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS. CONCLUSIONS: Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis. PMID- 28634895 TI - CORR Insights(r): Teaching the Basics: Development and Validation of a Distal Radius Reduction and Casting Model. PMID- 28634896 TI - Cochrane in CORR (r): Industry Sponsorship and Research Outcome. PMID- 28634897 TI - The Effect of Surgical Technique and Spacer Texture on Bone Regeneration: A Caprine Study Using the Masquelet Technique. AB - BACKGROUND: The Masquelet-induced-membrane technique is a commonly used method for treating segmental bone defects. However, there are no established clinical standards for management of the induced membrane before grafting. QUESTIONS/PURPOSES: Two clinically based theories were tested in a chronic caprine tibial defect model: (1) a textured spacer that increases the induced membrane surface area will increase bone regeneration; and (2) surgical scraping to remove a thin tissue layer of the inner induced-membrane surface will enhance bone formation. METHODS: Thirty-two skeletally mature female goats were assigned to four groups: smooth spacer with or without membrane scraping and textured spacer with or without membrane scraping. During an initial surgical procedure (unilateral, left tibia), a defect was created excising bone (5 cm), periosteum (9 cm), and muscle (10 g). Segments initially were stabilized with an intramedullary rod and an antibiotic-impregnated polymethylmethacrylate spacer with a smooth or textured surface. Four weeks later, the spacer was removed and the induced-membrane was either scraped or left intact before bone grafting. Bone formation was assessed using micro-CT (total bone volume in 2.5-cm central defect region) as the primary outcome; radiographs and histologic analysis as secondary outcomes, with the reviewer blinded to the treatment groups of the samples being assessed 12 weeks after grafting. All statistical tests were performed using a linear mixed effects model approach. RESULTS: Micro-CT analysis showed greater bone formation in defects with scraped induced membrane (mean, 3034.5 mm3; median, 1928.0 mm3; quartile [Q]1-Q3, 273.3-2921.1 mm3) compared with defects with intact induced membrane (mean, 1709.5 mm3; median, 473.8 mm3; Q1-Q3, 132.2 1272.3 mm3; p = 0.034). There was no difference in bone formation between textured spacers (mean, 2405.5 mm3; median, 772.7 mm3; Q1-Q3, 195.9-2743.8 mm3) and smooth spacers (mean, 2473.2 mm3; median, 1143.6 mm3; Q1-Q3, 230.2-451.1 mm3; p = 0.917). CONCLUSIONS: Scraping the induced-membrane surface to remove the innermost layer of the induced-membrane increased bone regeneration. A textured spacer that increased the induced-membrane surface area had no effect on bone regeneration. CLINICAL RELEVANCE: Scraping the induced membrane during the second stage of the Masquelet technique may be a rapid and simple means of improving healing of segmental bone defects, which needs to be confirmed clinically. PMID- 28634898 TI - Role of Obesity in Asthma: Mechanisms and Management Strategies. AB - PURPOSE OF REVIEW: Obesity is a commonly reported comorbidity in asthma, particularly in severe asthma. Obese asthmatics are highly symptomatic with a poor quality of life, despite using high-dose inhaled corticosteroids. While the clinical manifestations have been documented, the aetiologies of obese-asthma remain unclear. RECENT FINDINGS: Several potential mechanisms have been proposed, including poor diet quality, physical inactivity and consequent accrual of excess adipose tissue. Each of these factors independently activates inflammatory pathways, potentially exerting effects in the airways. Because the origins of obesity are multifactorial, it is now believed there are multiple obese-asthma phenotypes, with varied aetiologies and clinical consequences. In this review, we will describe the clinical implications of obesity in people with asthma, our current understanding of the mechanisms driving this association and describe recently proposed obese-asthma phenotypes. We will then discuss how asthma management is complicated by obesity, and provide graded recommendations for the management of obesity in this population. PMID- 28634899 TI - Primary Prevention of Food Allergy. AB - PURPOSE OF REVIEW: This article summarises recent developments on the prevention of food allergy in terms of the 5 D's of the development of food allergy: dry skin, diet, dogs, dribble, and vitamin D. RECENT FINDINGS: While several advances have improved our understanding of the development of food allergy, few preventive strategies have been implemented beyond changes in infant feeding guidelines. These now state that the introduction of allergenic solids such as peanuts should occur in the first year of life. Results from randomised controlled trials on other allergenic solids, vitamin D supplementation, BCG immunisation at birth and eczema prevention are eagerly anticipated in order to inform further preventative strategies. PMID- 28634900 TI - Review of Physical Urticarias and Testing Methods. AB - PURPOSE OF REVIEW: This review aims to update the information available on the prevalence, clinical picture, diagnostic methods, and treatment of urticarias induced by external physical stimuli. RECENT FINDINGS: Physical urticarias are present in up to 5% of the general population, and in 10 to 50% of patients with chronic urticaria. Recent investigations have provided evidence that the presence of physical urticaria alone or when comorbid with chronic spontaneous urticaria is associated with a worse prognosis and duration. Most frequent subtypes of physical urticaria are dermographism and delayed pressure urticaria. The diagnosis is established through specific provocation tests and the management encompasses avoidance measures, pharmacologic therapy with nonsedating antihistamines, and alternative medications in refractory cases. PMID- 28634901 TI - Changes in plasma miR-9, miR-16, miR-205 and miR-486 levels after non-small cell lung cancer resection. AB - PURPOSE: The majority of non-small cell lung cancer (NSCLC) patients presents with an advanced-stage disease and, consequently, exhibits a poor overall survival rate. We aimed to assess changes in plasma miR-9, miR-16, miR-205 and miR-486 levels and their potential as biomarkers for the diagnosis and monitoring of NSCLC patients. METHODS: Plasma was collected from 50 healthy donors and from NSCLC patients before surgery (n = 61), 1 month after surgery (n = 37) and 1 year after surgery (n = 14). microRNA levels were quantified using qRT-PCR. RESULTS: We found in NSCLC patients before treatment, both with squamous cell carcinoma (SQCC) and adenocarcinoma (ADC), significantly higher plasma miR-16 and miR-486 levels than in healthy individuals. Pre-treatment miR-205 concentrations were found to be significantly higher in SQCC than in ADC patients, and only SQCC patients presented significantly higher circulating miR-205 levels than healthy donors. SQCC plasma miR-9 levels were not different from normal control levels, but in ADC they were found to be significantly decreased. A combination of plasma miR-16, miR-205 and miR-486 measurements was found to discriminate NSCLC patients from healthy persons, with a specificity of 95% and a sensitivity of 80%. Following tumor resection, we found that the miR-9 and miR-205 levels significantly decreased, even below the normal level, whereas the increased miR 486 level persisted up to one year after surgery, and the miR-16 level decreased to normal. After tumor resection, none of the miR levels tested was found to relate to recurrence. CONCLUSIONS: Our data indicate that miR-9, miR-16, miR-205 and miR-486 may serve as NSCLC biomarkers. The observed cancer-related pre- and post-operative changes in their plasma levels may not only reflect the presence of a primary cancer, but also of a systemic response to cancer. PMID- 28634903 TI - Capsule Commentary on Borrero et al., Unintended Pregnancy and Contraceptive Use among Women Veterans: The ECUUN Study. PMID- 28634904 TI - Capsule Commentary on Balaban et al., Impact of a Patient Navigator Program on Hospital-Based and Outpatient Utilization Over 180 Days in a Safety-Net Health System. PMID- 28634905 TI - Capsule Commentary on Rigotti et al., Interactive Voice Response Calls to Promote Smoking Cessation after Hospital Discharge: Pooled Analysis of Two Randomized Clinical Trials. PMID- 28634902 TI - Therapeutic Potential of Baicalein in Alzheimer's Disease and Parkinson's Disease. AB - Alzheimer's disease and Parkinson's disease are the two most common, progressive central neurodegenerative diseases affecting the population over the age of 60 years. Apart from treatments that temporarily improve symptoms, there is no medicine currently available to inhibit or reverse the progression of Alzheimer's disease and Parkinson's disease. In traditional Chinese medicine, the root of Scutellaria baicalensis Georgi is a classic compatible component in the decoction of herbal medicine used for treating central nervous system diseases. Modern pharmacokinetic studies have confirmed that baicalein (5,6,7-trihydroxyflavone) is a major bioactive flavone constituent root of S. baicalensis Georgi. Studies showed that baicalein possesses a range of key pharmacological properties, such as reducing oxidative stress, anti-inflammatory properties, inhibiting aggregation of disease-specific amyloid proteins, inhibiting excitotoxicity, stimulating neurogenesis and differentiation action, and anti-apoptosis effects. Based on these properties, baicalein shows therapeutic potential for Alzheimer's disease and Parkinson's disease. In this review, we summarize the pharmacological protective actions of baicalein that make it suitable for the treatment of Alzheimer's disease and Parkinson's disease, and discuss the potential mechanisms underlying the effects. PMID- 28634906 TI - Delivery of Brief Cognitive Behavioral Therapy for Medically Ill Patients in Primary Care: A Pragmatic Randomized Clinical Trial. AB - BACKGROUND: Few studies have examined the practical effectiveness and implementation potential of brief psychotherapies that integrate mental and physical health. OBJECTIVE: To determine whether an integrated brief cognitive behavioral therapy (bCBT), delivered by mental health providers in primary care, would improve depression, anxiety and quality of life for medically ill veterans. DESIGN: Pragmatic patient-randomized trial comparing bCBT to enhanced usual care (EUC). PARTICIPANTS: A total of 302 participants with heart failure and/or chronic obstructive pulmonary disease (COPD) with elevated symptoms of depression and/or anxiety were enrolled from two Veterans Health Administration primary care clinics. INTERVENTION: bCBT was delivered to 180 participants by staff mental health providers (n = 19). bCBT addressed physical and emotional health using a modular, skill-based approach. bCBT was delivered in person or by telephone over 4 months. Participants randomized to EUC (n = 122) received a mental health assessment documented in their medical record. MAIN MEASURES: Primary outcomes included depression (Patient Health Questionnaire) and anxiety (Beck Anxiety Inventory). Secondary outcomes included health-related quality of life. Assessments occurred at baseline, posttreatment (4 months), and 8- and 12-month follow-up. KEY RESULTS: Participants received, on average, 3.9 bCBT sessions with 63.3% completing treatment (4+ sessions). bCBT improved symptoms of depression (p = 0.004; effect size, d = 0.33) and anxiety (p < 0.001; d = 0.37) relative to EUC at posttreatment, with effects maintained at 8 and 12 months. Health-related quality of life improved posttreatment for bCBT participants with COPD but not for heart failure. Health-related quality of life outcomes were not maintained at 12 months. CONCLUSIONS: Integrated bCBT is acceptable to participants and providers, appears feasible for delivery in primary care settings and is effective for medically ill veterans with depression and anxiety. Improvements for both depression and anxiety were modest but persistent, and the impact on physical health outcomes was limited to shorter-term effects and COPD participants. Clinical trials.Gov identifier: NCT01149772. PMID- 28634907 TI - Incidence and Predictors of Repeat Bone Mineral Densitometry: A Longitudinal Cohort Study. AB - BACKGROUND: Existing guidelines for repeat screening and treatment monitoring intervals regarding the use of dual-energy x-ray absorptiometry (DXA) scans are conflicting or lacking. The Choosing Wisely campaign recommends against repeating DXA scans within 2 years of initial screening. It is unclear how frequently physicians order repeat scans and what clinical factors contribute to their use. OBJECTIVE: To estimate cumulative incidence and predictors of repeat DXA for screening or treatment monitoring in a regional health system. DESIGN: Retrospective longitudinal cohort study PARTICIPANTS: A total of 5992 women aged 40-84 years who received initial DXA screening from 2006 to 2011 within a regional health system in Sacramento, CA. MAIN MEASURES: Two- and five-year cumulative incidence and hazard rations (HR) of repeat DXA by initial screening result (classified into three groups: low or high risk of progression to osteoporosis, or osteoporosis) and whether women were prescribed osteoporosis drugs after initial DXA. KEY RESULTS: Among women not treated after initial DXA, 2-year cumulative incidence for low-risk, high-risk, and osteoporotic women was 8.0%, 13.8%, and 19.6%, respectively, increasing to 42.9%, 60.4%, and 57.4% by 5 years after initial screening. For treated women, median time to repeat DXA was over 3 years for all groups. Relative to women with low-risk initial DXA, high risk initial DXA significantly predicted repeat screening for untreated women [adjusted HR 1.67 (95% CI 1.40-2.00)] but not within the treated group [HR 1.09 (95% CI 0.91-1.30)]. CONCLUSIONS: Repeat DXA screening was common in women both at low and high risk of progression to osteoporosis, with a substantial proportion of women receiving repeat scans within 2 years of initial screening. Conversely, only 60% of those at high-risk of progression to osteoporosis were re screened within 5 years. Interventions are needed to help clinicians make higher value decisions regarding repeat use of DXA scans. PMID- 28634908 TI - An Entrustable Professional Activity (EPA)-Based Framework to Prepare Fourth-Year Medical Students for Internal Medicine Careers. AB - The purpose of the fourth year of medical school remains controversial. Competing demands during this transitional phase cause confusion for students and educators. In 2014, the Association of American Medical Colleges (AAMC) released 13 Core Entrustable Professional Activities for Entering Residency (CEPAERs). A committee comprising members of the Clerkship Directors in Internal Medicine and the Association of Program Directors in Internal Medicine applied these principles to preparing students for internal medicine residencies. The authors propose a curricular framework based on five CEPAERs that were felt to be most relevant to residency preparation, informed by prior stakeholder surveys. The critical areas outlined include entering orders, forming and answering clinical questions, conducting patient care handovers, collaborating interprofessionally, and recognizing patients requiring urgent care and initiating that care. For each CEPAER, the authors offer suggestions about instruction and assessment of competency. The fourth year of medical school can be rewarding for students, while adequately preparing them to begin residency, by addressing important elements defined in the core entrustable activities. Thus prepared, new residents can function safely and competently in supervised postgraduate settings. PMID- 28634909 TI - Categorical Risk Perception Drives Variability in Antibiotic Prescribing in the Emergency Department: A Mixed Methods Observational Study. AB - BACKGROUND: Adherence to evidence-based antibiotic therapy guidelines for treatment of upper respiratory tract infections (URIs) varies widely among clinicians. Understanding this variability is key for reducing inappropriate prescribing. OBJECTIVE: To measure how emergency department (ED) clinicians' perceptions of antibiotic prescribing risks affect their decision-making. DESIGN: Clinician survey based on fuzzy-trace theory, a theory of medical decision making, combined with retrospective data on prescribing outcomes for URI/pneumonia visits in two EDs. The survey predicts the categorical meanings, or gists, that individuals derive from given information. PARTICIPANTS: ED physicians, residents, and physician assistants (PAs) who completed surveys and treated patients with URI/pneumonia diagnoses between August 2014 and December 2015. MAIN MEASURES: Gists derived from survey responses and their association with rates of antibiotic prescribing per visit. KEY RESULTS: Of 4474 URI/pneumonia visits, 2874 (64.2%) had an antibiotic prescription. However, prescribing rates varied from 7% to 91% for the 69 clinicians surveyed (65.2% response rate). Clinicians who framed therapy-prescribing decisions as a categorical choice between continued illness and possibly beneficial treatment ("why not take a risk?" gist, which assumes antibiotic therapy is essentially harmless) had higher rates of prescribing (OR 1.28 [95% CI, 1.06-1.54]). Greater agreement with the "antibiotics may be harmful" gist was associated with lower prescribing rates (OR 0.81 [95% CI, 0.67-0.98]). CONCLUSIONS: Our results indicate that clinicians who perceive prescribing as a categorical choice between patients remaining ill or possibly improving from therapy are more likely to prescribe antibiotics. However, this strategy assumes that antibiotics are essentially harmless. Clinicians who framed decision-making as a choice between potential harms from therapy and continued patient illness (e.g., increased appreciation of potential harms) had lower prescribing rates. These results suggest that interventions to reduce inappropriate prescribing should emphasize the non-negligible possibility of serious side effects. PMID- 28634922 TI - Erratum to: Maclobemide. PMID- 28634910 TI - The Complex Biology of the Aryl Hydrocarbon Receptor and Its Role in the Pituitary Gland. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor best known for its ability to mediate the effects of environmental toxins such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), polycyclic aromatic hydrocarbons (PAHs), benzene, and polychlorinated biphenyls (PCBs) through the initiation of transcription of a number of metabolically active enzymes. Therefore, the AHR has been studied mostly in the context of xenobiotic signaling. However, several studies have shown that the AHR is constitutively active and plays an important role in general cell physiology, independently of its activity as a xenobiotic receptor and in the absence of exogenous ligands. Within the pituitary, activation of the AHR by environmental toxins has been implicated in disruption of gonadal development and fertility. Studies carried out predominantly in mouse models have revealed the detrimental influence of several environmental toxins on specific cell lineages of the pituitary tissue mediated by activation of AHR and its downstream effectors. Activation of AHR during fetal development adversely affected pituitary development while adult models exposed to AHR ligands demonstrated varying degrees of pituitary dysfunction. Such dysfunction may arise as a result of direct effects on pituitary cells or indirect effects on the hypothalamic-pituitary-gonadal axis. This review offers in-depth analysis of all aspects of AHR biology, with a particular focus on its role and activity within the adenohypophysis and specifically in pituitary tumorigenesis. A novel mechanism by which the AHR may play a direct role in pituitary cell proliferation and tumor formation is postulated. This review therefore attempts to cover all aspects of the AHR's role in the pituitary tissue, from fetal development to adult physiology and the pathophysiology underlying endocrine disruption and pituitary tumorigenesis. PMID- 28634911 TI - Novel insights into a reputably irreversible process: combined mRNA and miRNA profiling of tissue from vesicourethral anastomotic stenosis after radical prostatectomy. AB - PURPOSE: Until recently, tissue fibrosis-ultimately leading to permanent scaring has been considered an irreversible process. However, recent findings indicate that it may be reversible after all. Vesicourethral anastomotic stenosis (VUAS) as fibrous narrowing is a frequent complication after radical prostatectomy with high recurrence rates and requires invasive treatment. The pathophysiology is poorly understood. Therefore, a combined mRNA and miRNA transcription profiling in tissue from VUAS was performed using nCounter technology. METHODS: To assess tissue morphology and fiber composition, histochemical staining was performed. RNA expression of healthy and fibrotic tissue of twelve patients was analyzed using the human miRNA panel v3 and mRNA PanCancer pathway panel on the nCounter gene1 system and qRT-PCR. Differential expression data analysis was performed using the nSolver software implementing the R-based advanced pathway analysis tool. miRWalk2.0 was used for miRNA target prediction. RESULTS: More linearized tissue architecture, increased collagens, and decreased elastic fibers were observed in VUAS samples. 23 miRNAs and 118 protein coding genes were differentially expressed (p < 0.01) in fibrotic tissue. miRNA target prediction and overlap analysis indicated an interaction of the strongest deregulated miRNAs with 29 deregulated mRNAs. Pathway analysis revealed alterations in DNA repair, cell cycle regulation, and TGF-beta signaling. qRT-PCR confirmed differential expression of top deregulated miRNAs and mRNAs. CONCLUSIONS: In VUAS tissue, severe alterations on mRNA and miRNA level are found. These consistent changes give insights into the pathogenesis of VUAS after radical prostatectomy and point to future options for transcriptomics-based risk stratification and targeted therapies. PMID- 28634924 TI - Chondroblastoma in adult age. AB - PURPOSE: Chondroblastoma (CB) is a rare benign tumor that occurs most commonly in the second decade of life. No studies on CB in adulthood have been reported. Our purposes were to report a single-institution experience on CB in adults and to discuss the clinical and imaging findings, type of treatment, oncologic and functional outcomes. PATIENTS AND METHODS: All patients diagnosed and treated for CB from 1981 to 2014 were reviewed. The main inclusion criterion was patients above their 30 years of age at diagnosis. Clinical presentation, imaging, surgical treatment, complications and functional outcome were evaluated. Local recurrences were recorded. RESULTS: There were 15 males (65%) and 8 females (35%) with a mean age of 40 years (range 30-59 years). Tumor involved the small bones (talus, calcaneus, acromion, cuneiform, metatarsals) in 15 patients (65%) and the long bones in eight patients (35%). Treatment consisted of curettage only (6 cases), curettage plus phenol (13 cases), curettage plus radiotherapy (one patient with vertebral tumor), resection (two patients with CB of the acromion) and chopart amputation (one patient with a metatarsal tumor). At a mean follow-up of 8.4 years (range 3-30 years), twenty patients (87%) remained continuously disease-free, whereas three had local recurrences. None of the patients received chemotherapy. CONCLUSION: This study confirms that the occurrence and outcome of adult patients with CB are similar with those affecting younger patients. The main difference consists of the involved bones; flat bones and short tubular bones of the foot, especially the talus and calcaneus, are most commonly involved as opposed to long tubular bones. LEVEL OF EVIDENCE: Therapeutic study, level IV 1 (case series). PMID- 28634923 TI - Osteoblastoma of the elbow: analysis of 13 patients and literature review. AB - PURPOSE: To analyze the clinical and radiographic characteristics, treatment, and outcome of patients with elbow osteoblastoma. PATIENTS AND METHODS: We present 13 patients (7 males and 6 females; mean age, 28 years) diagnosed and treated for an elbow osteoblastoma from 1975 to 2012. Mean follow-up was 29 months (range 12-60 months). Clinical presentation, imaging, surgical treatment, complications, range of elbow motion, and functional outcome were evaluated. The MSTS, DASH, and OXFORD scores were used. RESULTS: Main symptom was pain (all patients) accompanied by stiffness (8 patients) and swelling or tumefaction (7 patients), with a median duration of symptoms of 32 months (range 6-96 months). Distal humerus was affected in 10 patients, proximal ulna in 2 patients, and proximal radius in one patient. All patients underwent surgical therapy that consisted of curettage of the lesion (7 patients), curettage and bone allografting (3 patients), wide resection (2 patients; total distal humerus and resection of the radial head), and radiofrequency thermal ablation (1 patient). One patient experienced a recurrence after surgical treatment. The mean MSTS score after treatment was 87% (range 50-100%), which corresponds to excellent results. CONCLUSIONS: Intralesional surgery is successful in tumor control in most patients with osteoblastoma of the elbow. Thermal ablation may be successful for smaller lesions. Most of the patients had a good-to-excellent functional outcome even if they had tumor-related elbow stiffness at diagnosis. LEVEL OF EVIDENCE: Therapeutic study, Level IV-1. PMID- 28634925 TI - Technical efficiency of selected hospitals in Eastern Ethiopia. AB - This study examines the relative technical efficiency of 12 hospitals in Eastern Ethiopia. Using six-year-round panel data for the period between 2007/08 and 2012/13, this study examines the technical efficiency, total factor productivity, and determinants of the technical inefficiency of hospitals. Data envelopment analysis (DEA) and DEA- based Malmquist productivity index used to estimate relative technical efficiency, scale efficiency, and total factor productivity index of hospitals. Tobit model used to examine the determinants of the technical inefficiency of hospitals. The DEA Variable Returns to Scale (VRS) estimate indicated that 6 (50%), 5 (42%), 3 (25%), 3 (25%), 4 (33%), and 3 (25%) of the hospitals were technically inefficient while 9 (75%), 9 (75%), 7 (58%), 7 (58%), 7 (58%) and 8 (67%) of hospitals were scale inefficient between 2007/08 and 2012/13, respectively. On average, Malmquist Total Factor Productivity (MTFP) of the hospitals decreased by 3.6% over the panel period. The Tobit model shows that teaching hospital is less efficiency than other hospitals. The Tobit regression model further shows that medical doctor to total staff ratio, the proportion of outpatient visit to inpatient days, and the proportion of inpatients treated per medical doctor were negatively related with technical inefficiency of hospitals. Hence, policy interventions that help utilize excess capacity of hospitals, increase doctor to other staff ratio, and standardize number of inpatients treated per doctor would contribute to the improvement of the technical efficiency of hospitals. PMID- 28634926 TI - Aging effect on the instrumented Timed-Up-and-Go test variables in nursing home women aged 80-93 years. AB - Although the total "Timed-Up-and Go" test (TUG) performance time can characterize an age-related decline of general mobility, this result alone doesn't give any detailed information about the test subtasks. The primary objective of the study was to identify in nursing home women a variable extracted from instrumented TUG (iTUG) that is the best predictor of age. The secondary objective was to assess whether this variable is associated with the results of the isometric knee extension peak torque (IKEPT); lower limb strength measured by the 30-s chair stand test (30sCST), and walking capacity measured by the 6-min walk test (6MWT). Twenty-six women (mean +/- SD: age-85.8 +/- 3.6 years; body weight-59.4 +/- 12.3 kg; body height-151.0 +/- 7.3 cm; BMI-26.0 +/- 4.9 kg/m2) performed iTUG (while wearing a body-fixed inertial sensor) and functional tests. Total iTUG performance time significantly correlated with age (r = 0.484; p < 0.05), 30sCST (r = -0.593; p < 0.01), and 6MWT (r = -0.747; p < 0.001) but not with absolute nor relative IKEPT (p > 0.05). Additionally, the subjects' age correlated with 30sCST (r = -0.422; p < 0.05), 6MWT (r = -0.482; p < 0.05), IKEPT (r = -0.392; p < 0.05) and IKEPT/FFM (r = -0.407; p < 0.05). Five out of 16 analyzed iTUG variables were significantly related to age, and multiple regression analysis showed the best correlation with the sit-to-stand vertical acceleration range (STSVAR) (r2 = 0.430; SEE = 3.041; beta = -0.544 +/- 0.245; B = -1.204 +/- 0.543; p < 0.05). Moreover, STSVAR was significantly associated with %Fat (r = 0.415; p < 0.05), 30sCST (r = 0.519; p < 0.01), 6MWT (r = 0.585; p < 0.01) but not with absolute nor relative IKEPT (p > 0.05). The obtained results suggest that in the oldest old group of nursing home women an age-related decline in TUG performance is mainly associated with a reduction of "explosive" strength of lower limb muscles. PMID- 28634927 TI - Nine pairs of megastigmane enantiomers from the leaves of Eucommia ulmoides Oliver. AB - Nine pairs of megastigmane enantiomers (1a/1b-9a/9b), comprising two new compounds (6S,9R)-blumenol C (7b), (6S,9S)-blumenol C (8b), two pairs of enantiomers (+)-(6R)-eucomegastigmane A (1a), (-)-(6S)-eucomegastigmane A (1b), (+)-(3S,4S)-eucomegastigmane B (5a), (-)-(3R,4R)-eucomegastigmane B (5b) isolated by chiral resolution firstly, and twelve known compounds, were isolated from the leaves of Eucommia ulmoides Oliver. Their structures were elucidated based on extensive spectroscopic analysis. Absolute configurations of the megastigmane enantiomers were assigned by comparing experimental ECD and OR with calculated ECD and OR. Docking-based virtual screening of all compounds showed that megastigmane enantiomers have weak intermolecular interactions with the binding site residues of angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R). PMID- 28634928 TI - Comparison of formulas and methods for high myopia patients requiring intraocular lens powers less than six diopters. AB - PURPOSE: To determine the best method to minimize postoperative hyperopia and achieve mild myopia in patients requiring low-powered (<6.00 D) MN60MA intraocular lenses (IOLs). METHODS: This retrospective non-comparative case series consists of 32 eyes (20 patients). Postoperative spherical equivalent (SE) refractions were compared using four methods: standard formulas with varying target refractions (Haigis -1.00 D, Hoffer Q -1.75 D, Holladay 1 -1.50 D and SRK/T -1.00 and -1.25 D), axial length adjustment methods for standard formulas targeted for both plano and -0.50 D, Barrett Universal II formula and the Haigis formula using separate constants for plus and minus IOLs (Haigis +/-). SE (mean, standard deviation, median, range), median absolute error (MedAE), prediction errors, percentage SE less than 0.25 D and greater than -1.00 D, percentage SE within +/-0.50 and +/-1.00 D of the targeted refraction were calculated. RESULTS: All methods and formulas gave acceptable mean SE refractions ranging from -0.04 to -0.68 D. The Barrett Universal II, Haigis +/-, standard Haigis formula targeted for -1.00 D and the Holladay 1 formula targeted for -1.50 D met stricter criteria of final SE between 0.25 and -1.00 D in 94-100% of eyes and MedAE between 0.37 and 0.51 D. Other methods had more myopic or hyperopic outliers. CONCLUSIONS: For these eyes with high myopia, the Barrett Universal II, Haigis +/ , standard Haigis targeted for -1.00 D and the standard Holladay 1 targeted for 1.50 D formulas produce the best results exceeding established benchmark criteria and minimizing hyperopic surprises. PMID- 28634929 TI - Factors associated with multiple recurrences of nonspecific orbital inflammation aka orbital pseudotumor. AB - OBJECTIVE: To assess clinical characteristics of patients at risk for recurrent nonspecific orbital inflammation (NSOI). METHODS: This was a retrospective comparison study with a 24-month follow-up, in a clinic-based population in rural India. The medical records at two eye care centers were searched from March 2001 2014. A total of 153 patients with recurrent NSOI, 107 of whom had a single recurrence (Group 1) and 46 of whom had multiple recurrences (Group 2). Clinical and demographic data were compared between both groups. Comparisons of mean values were done with multiple 2-tailed independent T tests, and differences in proportions were compared using Chi-squared tests. A multivariate logistic regression model was used to determine which factors were predictive of patients having multiple recurrences. RESULTS: Several factors were independently related to multiple recurrences (P < 0.05 for all): age <=16 years (2.5 OR, 95% CI 1.3 3.6), bilateral disease (3.2 OR 95% CI 1.4-5.1), presence of optic disc edema or T-sign on B-scan ultrasonography (3.9 OR 95% CI 1.8-6.2), sclerosing variant (8.5 OR 95% CI 5.4-11.3), corticosteroid taper <4 weeks long (2.8 OR 95% CI 1.1-4.2), autoimmune disease among 1st degree relatives (2.2 OR 95% CI 1.2-3.3). In patients with recurrent disease, the interval between the initial episode and the first recurrence was predictive of further recurrences: <=3 months (3.2 OR, 95% CI 2.0-4.5) and >=12 months (0.21 OR, 95% CI 0.01-0.39). CONCLUSION: Younger patients and those with bilateral disease are more apt to have recurrences of NSOI. Other factors that increase the risk of multiple recurrences include a T sign, optic disc edema, poor initial response to steroids, a sclerosing variant, a recurrence within 3 months, and those who underwent a rapid steroid taper. PMID- 28634931 TI - 3D Cell Culture: An Introduction. AB - 3D cell culture is an invaluable tool in developmental, cell, and cancer biology. By mimicking crucial features of in vivo environment, including cell-cell and cell-extracellular matrix interactions, 3D cell culture enables proper structural architecture and differentiated function of normal tissues or tumors in vitro. Thereby 3D cell culture realistically models in vivo tissue conditions and processes, and provides in vivo like responses. Since its early days in the 1970s, 3D cell culture has revealed important insights into mechanisms of tissue homeostasis and cancer, and accelerated translational research in cancer biology and tissue engineering. PMID- 28634930 TI - What are the priorities for improving cataract surgical outcomes in Africa? Results of a Delphi exercise. AB - PURPOSE: The quality of cataract surgery delivered in sub-Saharan Africa (SSA) is a significant constraint to achieving the elimination of avoidable blindness. No published reports from routine SSA cataract services attain the WHO benchmarks for visual outcomes; poor outcomes (<6/60) often comprise 20% in published case series. This Delphi exercise aimed to identify and prioritise potential interventions for improving the quality of cataract surgery in SSA to guide research and eye health programme development. METHODS: An initial email open question survey created a ranked list of priorities for improving quality of surgical services. A second-round face-to-face discussion facilitated at a Vision 2020 Research Mentorship Workshop in Tanzania created a refined list for repeated ranking. RESULTS: Seventeen factors were agreed that might form target interventions to promote quality of cataract services. Improved training of surgeons was the top-ranked item, followed by utilisation of biometry, surgical equipment availability, effective monitoring of outcomes of cataract surgery by the surgeon, and well-trained support staff for the cataract pathway (including nurses seeing post-operative cases). CONCLUSION: Improving the quality of cataract surgery in SSA is a clinical, programmatic and public health priority. In the absence of other evidence, the collective expert opinion of those involved in ophthalmic services regarding the ranking of factors to promote quality improvement, refined through this Delphi exercise, provides us with candidate intervention areas to be evaluated. PMID- 28634932 TI - Preparation of Decellularized Biological Scaffolds for 3D Cell Culture. AB - The biggest challenge of designing and implementing an in vitro study is developing a microenvironment that most closely represents the interactions observed in vivo. Decellularization of tissues and organs has been shown to be an effective method for the removal of potentially immunogenic constituents while preserving essential growth factors and extracellular matrix (ECM ) proteins necessary for proper cell function. Enzymatic digestion of decellularized tissues allows these tissue-specific components to be reconstituted into bioactive hydrogels through a physical crosslinking of collagen. In the following protocol, we describe unique decellularization methods for both dermis and urinary bladder matrix (UBM) derived from porcine tissues. We then provide details for hydrogel formation and subsequent three-dimensional (3D) culture of two cell types: NIH 3T3 fibroblasts and C2C12 myoblasts . PMID- 28634933 TI - 3D Cell Culture in Interpenetrating Networks of Alginate and rBM Matrix. AB - Altered tissue mechanical properties have been implicated in many key physiological and pathological processes. Hydrogel-based materials systems, made with native extracellular matrix (ECM) proteins, nonnative biopolymers, or synthetic polymers are often used to study these processes in vitro in 3D cell culture experiments. However, each of these materials systems present major limitations when used in mechanobiological studies. While native ECM-based hydrogels may enable good recapitulation of physiological behavior, the mechanics of these hydrogels are often manipulated by increasing or decreasing the protein concentration. This manipulation changes cell adhesion ligand density, thereby altering cell signaling. Alternatively, synthetic polymer-based hydrogels and nonnative biopolymer-based hydrogels can be mechanically tuned and engineered to present cell adhesion peptide motifs, but still may not fully promote physiologically relevant behavior. Here, we combine the advantages of native ECM proteins and nonnative biopolymers in interpenetrating network (IPN) hydrogels consisting of rBM matrix, which contains ligands native to epithelial basement membrane, and alginate, an inert biopolymer derived from seaweed. The following protocol details the generation of IPNs for mechanical testing or for 3D cell culture. This biomaterial system offers the ability to tune the stiffness of the 3D microenvironment without altering cell adhesion ligand concentration or pore size. PMID- 28634934 TI - Hydrogel-Based In Vitro Models of Tumor Angiogenesis. AB - In situ forming hydrogels prepared from multi-armed poly(ethylene glycol) (PEG), glycosaminoglycans (GAG) and various peptides enable the development of advanced three dimensional (3D) culture models. Herein, we report methods for the PEG-GAG gel-based 3D co-cultivation of human umbilical vein endothelial cells, mesenchymal stromal cells, and different cancer cell lines. The resulting constructs allow for the exploration of interactions between solid tumors with 3D vascular networks in vitro to study the mechanistic aspects of cancer development and to perform drug testing. PMID- 28634935 TI - Generation of Induced Pluripotent Stem Cells in Defined Three-Dimensional Hydrogels. AB - Since the groundbreaking discovery of induced pluripotent stem cells (iPSCs) many research groups have attempted to improve the efficiency of the classical cell reprogramming process. Surprisingly, the contribution of the three-dimensional (3D) microenvironment to iPSC generation has been largely overlooked. Here we describe a protocol for the generation of iPSCs in defined poly(ethylene glycol) (PEG)-based hydrogels that, besides allowing higher reprogramming efficiency, are also a powerful tool to study the influence of biophysical parameters on iPSC generation. PMID- 28634936 TI - Calcium Phosphate Foams: Potential Scaffolds for Bone Tissue Modeling in Three Dimensions. AB - The present method describes the procedure to fabricate calcium phosphate foams with suitable open porosity, pore size, and composition to perform three dimensional (3D) cell cultures with the objective to simulate the bone tissue microenvironment in vitro. Foams with two compositions but equivalent porosity can be fabricated. On the one hand, hydroxyapatite foams obtained by hydrolysis at 37 degrees C, with microstructure that mimics the small crystal size of the mineral component of bones, and on the other hand, beta tricalcium phosphate foams with polygonal grains obtained by sintering at 1100 degrees C. In the first part of the chapter the calcium phosphate foams are briefly described. Afterwards, the foaming process is described in detail, including alternatives to overcome processing problems than can arise. Finally, insights are provided on how to perform 3D cell cultures using the calcium phosphate foams as substrates. PMID- 28634937 TI - Establishment of 3D Intestinal Organoid Cultures from Intestinal Stem Cells. AB - The intestinal epithelium is the most rapidly renewed tissue in adult mammals, and its renewal is strictly controlled by intestinal stem cells. Extensive studies using genetic models of intestinal epithelium have revealed the mechanisms underlying the self-renewal of intestinal stem cells. Exploiting this knowledge, we developed a novel 3D culture system that enables the outgrowth of intestinal Lgr5+ stem cells derived from mouse and human tissues into ever expanding crypt-villus mini-guts, known as intestinal epithelial organoids. These organoids are maintained by the self-renewal of stem cells and give rise to all differentiated cell types of the intestinal epithelium. Once established, organoids can be cryopreserved and thawed when needed. This culture system has been widely used for studying stem cell behavior and gene function and for disease modeling. PMID- 28634938 TI - 3D Coculture of Mammary Organoids with Fibrospheres: A Model for Studying Epithelial-Stromal Interactions During Mammary Branching Morphogenesis. AB - Mammary gland is composed of branched epithelial structure embedded within a complex stroma formed by several stromal cell types, including fibroblasts, and extracellular matrix (ECM). Development of mammary gland is tightly regulated by bidirectional epithelial-stromal interactions that include paracrine signaling, ECM remodeling and mechanosensing. Importantly, these interactions play crucial role in mammary gland homeostasis and when deregulated they contribute to tumorigenesis. Therefore, understanding the mechanisms underlying epithelial stromal interactions is critical for elucidating regulation of normal mammary gland development and homeostasis and revealing novel strategies for breast cancer therapy. To this end, several three-dimensional (3D) cell culture models have been developed to study these interactions in vitro. In this chapter, a novel 3D organoid-fibrosphere coculture model of mammary gland is described with the capacity for studying not only the qualitative and quantitative aspects of interactions between mammary fibroblasts and epithelial organoids but also their radius and directionality. PMID- 28634939 TI - An Organotypic 3D Assay for Primary Human Mammary Epithelial Cells that Recapitulates Branching Morphogenesis. AB - We have developed a three-dimensional organotypic culture system for primary human mammary epithelial cells (HMECs) in which the cells are cultured in free floating collagen type I gels. In this assay, luminal cells predominantly form multicellular spheres, while basal/myoepithelial cells form complex branched structures resembling terminal ductal lobular units (TDLUs), the functional units of the human mammary gland in situ. The TDLU-like organoids can be cultured for at least 3 weeks and can then be passaged multiple times. Subsequently, collagen gels can be stained with carmine or by immunofluorescence to allow for the analysis of morphology, protein expression and polarization, and to facilitate quantification of structures. In addition, structures can be isolated for gene expression analysis. In summary, this technique is suitable for studying branching morphogenesis, regeneration, and differentiation of HMECs as well as their dependence on the physical environment. PMID- 28634940 TI - 3D Primary Culture Model to Study Human Mammary Development. AB - We present a protocol for expanding human mammary tissues from primary patient derived cells in three-dimensional (3D) cultures. The primary epithelial cells are seeded into 3D hydrogels with defined components, which include both proteins and carbohydrates present in mammary tissue. Over a span of 10-14 days, the seeded cells form mammary tissues with complex ductal-lobular topologies and include luminal and basal cells in the correct orientation, together with cells that stain positively for stem cell markers. In addition to recapitulating key architectural features of human mammary tissue, the expanded tissues also respond to lactogenic hormones including estrogen, progesterone, and prolactin. We anticipate that these cultures will prove useful for studies of mammary development and breast cancer. PMID- 28634941 TI - Lungosphere Assay: 3D Culture of Lung Epithelial Stem/Progenitor Cells. AB - Lung epithelium contains distinctive subpopulations of lung stem/progenitor cells (LSPCs) that are essential for lung epithelial maintenance and repair in vivo. Hence, LSPCs are in the center of interest of lung biology due to their promising therapeutic applications. To reach this goal, proper characterization of LSPCs, understanding of their proliferation and differentiation potentials and elucidation of mechanisms that control them are necessary. Therefore, development of reliable in vitro clonogenic assays has been needed. We established lungosphere assay, an in vitro sphere-forming 3D culture assay that enables to evaluate stem/progenitor cell activity, self-renewal and differentiation capacity of LSPCs and to conveniently test the effect of various treatments on LSPCs. Here we provide a detailed description of procedures for isolation of adult mouse lung epithelial cells, their culture in non-adherent conditions to form LSPC-derived spheroids (lungospheres) and for embedding of lungospheres into 3D extracellular matrix to model processes of lung tissue maintenance in a physiologically relevant microenvironment. PMID- 28634942 TI - 3D Hanging Drop Culture to Establish Prostate Cancer Organoids. AB - Three-dimensional (3D) cell culture enables the growth of cells in a multidimensional and multicellular manner compared to conventional cell culture techniques. Especially in prostate cancer research there is a big need for more tissue-recapitulating models to get a better understanding of the mechanisms driving prostate cancer as well as to screen for more efficient drugs that can be used for treatment. In this chapter we describe a 3D hanging drop system that can be used to culture prostate cancer organoids as tumor epithelial monocultures and as epithelial-stromal cocultures. PMID- 28634943 TI - 3D-Dynamic Culture Models of Multiple Myeloma. AB - 3D-dynamic culture models represent an invaluable tool for a better comprehension of tumor biology and drug response, as they accurately re-create/preserve the complex multicellular organization and the dynamic interactions of the parental microenvironment, which can affect tumor fate and drug sensitivity. Hence, development of models that recapitulate tumor within its embedding microenvironment is an imperative need. This is particularly true for multiple myeloma (MM), which survives almost exclusively in the bone marrow (BM). To meet this need, we have previously exploited and validated an innovative 3D-dynamic culture technology, based on the use of the Rotary Cell Culture System (RCCS TM) bioreactor . Here, we describe, step by step, the procedures we have employed to establish two human MM ex vivo models, i.e., the culture of human BM-derived isolated cells and of MM tissues from patients. PMID- 28634944 TI - Preparation of a Three-Dimensional Full Thickness Skin Equivalent. AB - In vitro test systems are a promising alternative to animal models. Due to the use of human cells in a three-dimensional arrangement that allows cell-cell or cell-matrix interactions these models may be more predictive for the human situation compared to animal models or two-dimensional cell culture systems. Especially for dermatological research, skin models such as epidermal or full thickness skin equivalents (FTSE) are used for different applications. Although epidermal models provide highly standardized conditions for risk assessment, FTSE facilitate a cellular crosstalk between the dermal and epidermal layer and thus can be used as more complex models for the investigation of processes such as wound healing, skin development, or infectious diseases. In this chapter, we describe the generation and culture of an FTSE, based on a collagen type I matrix and provide troubleshooting tips for commonly encountered technical problems. PMID- 28634945 TI - Analysis of Breast Cancer Cell Invasion Using an Organotypic Culture System. AB - Metastasis is the main cause of cancer patient mortality. Local tumor invasion is a key step in metastatic dissemination whereby cancer cells dislodge from primary tumors, migrate through the peritumoral stroma and reach the circulation. This is a highly dynamic process occurring in three dimensions that involves interactions between tumor, stromal cells, and the extracellular matrix. Here we describe the organotypic culture system and its utility to study breast cancer cell invasion induced by cancer-associated fibroblasts. This is a three-dimensional model that reproduces the biochemical and physiological properties of real tissue and allows for investigating the molecular and cellular mechanisms involving tumor and its microenvironment, and their contribution to cancer cell invasion . This system provides a robust, accurate, and reproducible method for measuring cancer cell invasion and represents a valuable tool to improve the mechanistic understanding of the initial steps in metastasis . PMID- 28634946 TI - 3D Coculture Model of the Brain Parenchyma-Metastasis Interface of Brain Metastasis. AB - Central nervous system (CNS ) metastasis is not only an increasing but still a very unsatisfying clinical problem, with very few treatment options nowadays and an unmet clinical need. Additionally, the patients suffer from severe neurological symptoms. Furthermore the preclinical studies are limited and thus innovative methods are needed to study the mechanism of CNS metastasis during the final steps. Especially nowadays, the most critical step during metastasis seems to be the contention of the microenvironment of host organs with the cancer cells coming from other organs. More and more data indicate that this contention often leads to apoptosis of the pre-metastatic cells and prevents successful metastasis. However, this important step is barely understood. To further improve our knowledge about this important step of metastasis we developed a new experimental tool where we coculture an organotypic brain slice with a 3D tumor cell plug embedded in Matrigel for 3-4 days.This model especially mimics the interactions of cancer cells and glial cells at the interface of the brain parenchyma and the metastatic tissue. Therefore this coculture method with an organotypic brain slice and a tumor cell plug allows us to visualize and/or manipulate the interactions at this very important zone. Furthermore, it also allows us to use brain tissue from genetically engineered mice and/or genetically modified tumor cells to investigate genes of interest in the microenvironment or in cancer cells. Moreover this method avoids the use of a large number of animals and is especially useful in identifying the invasiveness of different tumor cell lines into the brain parenchyma as well as in studying the effect of specific treatments against brain metastasis progression during the final and most critical steps of metastasis. PMID- 28634947 TI - 3D Neural Culture in Dual Hydrogel Systems. AB - 3D in vitro culture systems may yield physiological outcomes that more closely approximate in vivo behavior. A number of fabrication techniques and hydrogel scaffold materials are available to researchers, but often their implementation is complex and seemingly prohibitive. Herein, we describe a simplistic and adaptable dual hydrogel photolithography method utilized to engineer advanced in vitro systems for studies of neuronal development and characterization. PMID- 28634948 TI - 3D Cell Culture in Micropatterned Hydrogels Prepared by Photomask, Microneedle, or Soft Lithography Techniques. AB - Despite the advantages of three-dimensional (3D) hydrogels for cell culture over traditional 2D plates, their clinical application is limited by inability to recapitulate the micro-architecture of complex tissues. Micropatterning can be employed to modify the homogenous micro-architecture of hydrogels. Three techniques for cell encapsulation in 3D micropatterned gels are described. The photomask and micromold techniques are used for cell encapsulation in relatively shallow patterns like disks or short rectangles but due to the presence of PDMS mold, the resolution of micromold technique is potentially higher than the photomask. The microneedle technique is often used for cell encapsulation in relatively deep microchannels within any geometry. PMID- 28634949 TI - 3D Stem Cell Niche Engineering via Two-Photon Laser Polymerization. AB - A strategy to modulate the behavior of stem cells in culture is to mimic structural aspects of the native cell-extracellular matrix (ECM) interaction. An important example of such artificial microenvironments for stem cell culture is the so-called "synthetic niche." Synthetic niches can be defined as polymeric culture systems mimicking at least one aspect of the interactions between stem cells and the extracellular surroundings, including biochemical factors (e.g., the delivery of soluble factors) and/or biophysical factors (e.g., the microarchitecture of the ECM). Most of the currently available approaches for scaffold fabrication, based on self-assembly methods, do not allow for a submicrometer control of the geometrical structure of the substrate, which might play a crucial role in stem cell fate determination. A novel technology that overcomes these limitations is laser two-photon polymerization (2PP). Femtosecond laser 2PP is a mask-less direct laser writing technique that allows manufacturing three dimensional arbitrary microarchitectures using photosensitive materials. Here, we report on the development of an innovative culture substrate, called the "nichoid," microfabricated in a hybrid organic-inorganic photoresist called SZ2080, to study mesenchymal stem cell mechanobiology. PMID- 28634950 TI - Microfluidic-Based Generation of 3D Collagen Spheres to Investigate Multicellular Spheroid Invasion. AB - During tumor progression, cancer cells acquire the ability to escape the primary tumor and invade adjacent tissues. They migrate through the stroma to reach blood or lymphatics vessels that will allow them to disseminate throughout the body and form metastasis at distant organs. To assay invasion capacity of cells in vitro, multicellular spheroids of cancer cells, mimicking primary tumor, are commonly embedded in collagen I extracellular matrix, which mimics the stroma. However, due to their higher density, spheroids tend to sink at the bottom of the collagen droplets, resulting in the spreading of the cells on two dimensions. We developed an innovative method based on droplet microfluidics to embed and control the position of multicellular spheroids inside spherical droplets of collagen. In this method cancer cells are exposed to a uniform three-dimensional (3D) collagen environment resulting in 3D cell invasion. PMID- 28634951 TI - High-Throughput Cancer Cell Sphere Formation for 3D Cell Culture. AB - Three-dimensional (3D) cell culture is critical in studying cancer pathology and drug response. Though 3D cancer sphere culture can be performed in low-adherent dishes or well plates, the unregulated cell aggregation may skew the results. On contrary, microfluidic 3D culture can allow precise control of cell microenvironments, and provide higher throughput by orders of magnitude. In this chapter, we will look into engineering innovations in a microfluidic platform for high-throughput cancer cell sphere formation and review the implementation methods in detail. PMID- 28634952 TI - High-Throughput 3D Tumor Culture in a Recyclable Microfluidic Platform. AB - Three-dimensional (3D) tumor culture miniaturized platforms are of importance to biomimetic model construction and pathophysiological studies. Controllable and high-throughput production of 3D tumors is desirable to make cell-based manipulation dynamic and efficient at micro-scale. Moreover, the 3D culture platform being reusable is convenient to research scholars. In this chapter, we describe a dynamically controlled 3D tumor manipulation and culture method using pneumatic microstructure-based microfluidics, which has potential applications in the fields of tissue engineering, tumor biology, and clinical medicine in a high throughput way. PMID- 28634953 TI - High-Throughput Microfluidic Platform for 3D Cultures of Mesenchymal Stem Cells. AB - The design of innovative tools for generating physiologically relevant three dimensional (3D) in vitro models has been recently recognized as a fundamental step to study cell responses and long-term tissue functionalities thanks to its ability to recapitulate the complexity and the dimensional scale of the cellular microenvironment, while directly integrating high-throughput and automatic screening capabilities.This chapter addresses the development of a poly(dimethylsiloxane)-based microfluidic platform to (1) generate and culture 3D cellular microaggregates under continuous flow perfusion while (2) conditioning them with different combinations/concentrations of soluble factors (i.e., growth factors, morphogens or drug molecules), in a high-throughput fashion. The proposed microfluidic system thus represents a promising tool for establishing innovative high-throughput models for drug screening, investigation of tissues morphogenesis, and optimization of tissue engineering protocols. PMID- 28634954 TI - 3D Anastomosed Microvascular Network Model with Living Capillary Networks and Endothelial Cell-Lined Microfluidic Channels. AB - This protocol describes detailed practical procedures for generating 3D intact and perfusable microvascular network that connects to microfluidic channels without appreciable leakage. This advanced 3D microvascular network model incorporates different stages of vascular development including vasculogenesis, endothelial cell (EC) lining, sprouting angiogenesis, and anastomosis in sequential order. The capillary network is first induced via vasculogenesis in a middle tissue chamber and then EC linings along the microfluidic channel on either side serve as artery and vein. The anastomosis is then induced by sprouting angiogenesis to facilitate tight interconnection between the artery/vein and the capillary network. This versatile device design and its robust construction methodology establish a physiological microcirculation transport model of interconnected perfused vessels from artery to vascularized tissue to vein. PMID- 28634955 TI - Human Lung Small Airway-on-a-Chip Protocol. AB - Organs-on-chips are microfluidic cell culture devices created using microchip manufacturing techniques that contain hollow microchannels lined by living cells, which recreate specialized tissue-tissue interfaces, physical microenvironments, and vascular perfusion necessary to recapitulate organ-level physiology in vitro. Here we describe a protocol for fabrication, culture, and operation of a human lung "small airway-on-a-chip," which contains a differentiated, mucociliary bronchiolar epithelium exposed to air and an underlying microvascular endothelium that experiences fluid flow. First, microengineering is used to fabricate a multilayered microfluidic device that contains two parallel elastomeric microchannels separated by a thin rigid porous membrane; this requires less than 1 day to complete. Next, primary human airway bronchiolar epithelial cells isolated from healthy normal donors or patients with respiratory disease are cultured on the porous membrane within one microchannel while lung microvascular endothelial cells are cultured on the opposite side of the same membrane in the second channel to create a mucociliated epithelium-endothelium interface; this process take about 4-6 weeks to complete. Finally, culture medium containing neutrophils isolated from fresh whole human blood are flowed through the microvascular channel of the device to enable real-time analysis of capture and recruitment of circulating leukocytes by endothelium under physiological shear; this step requires less than 1 day to complete. The small airway-on-a-chip represents a new microfluidic tool to model complex and dynamic inflammatory responses of healthy and diseased lungs in vitro. PMID- 28634956 TI - Microfluidic Bioprinting of Heterogeneous 3D Tissue Constructs. AB - 3D bioprinting is an emerging field that can be described as a robotic additive biofabrication technology that has the potential to build tissues or organs. In general, bioprinting uses a computer-controlled printing device to accurately deposit cells and biomaterials into precise architectures with the goal of creating on demand organized multicellular tissue structures and eventually intra organ vascular networks. The latter, in turn, will promote the host integration of the engineered tissue/organ in situ once implanted. Existing biofabrication techniques still lay behind this goal. Here, we describe a novel microfluidic printing head-integrated within a custom 3D bioprinter-that allows for the deposition of multimaterial and/or multicellular within a single scaffold by extruding simultaneously different bioinks or by rapidly switching between one bioink and another. The designed bioprinting method effectively moves toward the direction of creating viable tissues and organs for implantation in clinic and research in lab environments. PMID- 28634957 TI - Bioprinting of 3D Tissue Models Using Decellularized Extracellular Matrix Bioink. AB - Bioprinting provides an exciting opportunity to print and pattern all the components that make up a tissue-cells and extracellular matrix (ECM) material-in three dimensions (3D) to generate tissue analogues. A large number of materials have been used for making bioinks; however, majority of them cannot represent the complexity of natural ECM and thus are unable to reconstitute the intrinsic cellular morphologies and functions. We present here a method for making of bioink from decellularized extracellular matrices (dECMs) and a protocol for bioprinting of cell-laden constructs with this novel bioink. The dECM bioink is capable of providing an optimized microenvironment that is conducive to the growth of 3D structured tissue. We have prepared bioinks from different tissues, including adipose, cartilage and heart tissues and achieved high cell viability and functionality of the bioprinted tissue structures using our novel bioink. PMID- 28634958 TI - Bioprinting Cartilage Tissue from Mesenchymal Stem Cells and PEG Hydrogel. AB - Bioprinting based on thermal inkjet printing is one of the most attractive enabling technologies for tissue engineering and regeneration. During the printing process, cells, scaffolds , and growth factors are rapidly deposited to the desired two-dimensional (2D) and three-dimensional (3D) locations. Ideally, the bioprinted tissues are able to mimic the native anatomic structures in order to restore the biological functions. In this study, a bioprinting platform for 3D cartilage tissue engineering was developed using a commercially available thermal inkjet printer with simultaneous photopolymerization . The engineered cartilage demonstrated native zonal organization, ideal extracellular matrix (ECM ) composition, and proper mechanical properties. Compared to the conventional tissue fabrication approach, which requires extended UV exposure, the viability of the printed cells with simultaneous photopolymerization was significantly higher. Printed neocartilage demonstrated excellent glycosaminoglycan (GAG) and collagen type II production, which was consistent with gene expression profile. Therefore, this platform is ideal for anatomic tissue engineering with accurate cell distribution and arrangement. PMID- 28634959 TI - Real-Time Cell Cycle Imaging in a 3D Cell Culture Model of Melanoma. AB - Aberrant cell cycle progression is a hallmark of solid tumors; therefore, cell cycle analysis is an invaluable technique to study cancer cell biology. However, cell cycle progression has been most commonly assessed by methods that are limited to temporal snapshots or that lack spatial information. Here, we describe a technique that allows spatiotemporal real-time tracking of cell cycle progression of individual cells in a multicellular context. The power of this system lies in the use of 3D melanoma spheroids generated from melanoma cells engineered with the fluorescent ubiquitination-based cell cycle indicator (FUCCI). This technique allows us to gain further and more detailed insight into several relevant aspects of solid cancer cell biology, such as tumor growth, proliferation, invasion, and drug sensitivity. PMID- 28634960 TI - Revealing 3D Ultrastructure and Morphology of Stem Cell Spheroids by Electron Microscopy. AB - Cell culture methods have been developed in efforts to produce biologically relevant systems for developmental and disease modeling, and appropriate analytical tools are essential. Knowledge of ultrastructural characteristics represents the basis to reveal in situ the cellular morphology, cell-cell interactions, organelle distribution, niches in which cells reside, and many more. The traditional method for 3D visualization of ultrastructural components, serial sectioning using transmission electron microscopy (TEM), is very labor intensive due to contentious TEM slice preparation and subsequent image processing of the whole collection. In this chapter, we present serial block-face scanning electron microscopy, together with complex methodology for spheroid formation, contrasting of cellular compartments, image processing, and 3D visualization. The described technique is effective for detailed morphological analysis of stem cell spheroids, organoids, as well as organotypic cell cultures. PMID- 28634961 TI - Quantitative Phenotypic Image Analysis of Three-Dimensional Organotypic Cultures. AB - Glandular epithelial cells differentiate into three-dimensional (3D) multicellular or acinar structures, particularly when embedded in laminin-rich extracellular matrix (ECM). The spectrum of different multicellular morphologies formed in 3D is a reliable indicator for the differentiation potential of normal, non-transformed cells compared to different stages of malignant progression. Motile cancer cells may actively invade the matrix, utilizing epithelial, mesenchymal, or mixed modes of motility. Dynamic phenotypic changes involved in 3D tumor cell invasion are also very sensitive to small-molecule inhibitors that, e.g., target the actin cytoskeleton. Our strategy is to recapitulate the formation and the histology of complex solid cancer tissues in vitro, based on cell culture technologies that promote the intrinsic differentiation potential of normal and transformed epithelial cells, and also including stromal fibroblasts and other key components of the tumor microenvironment. We have developed a streamlined stand-alone software solution that supports the detailed quantitative phenotypic analysis of organotypic 3D cultures. This approach utilizes the power of automated image analysis as a phenotypic readout in cell-based assays. AMIDA (Automated Morphometric Image Data Analysis) allows quantitative measurements of a large number of multicellular structures, which can form a multitude of different organoid shapes, sizes, and textures according to their capacity to engage in epithelial differentiation programs or not. At the far end of this spectrum of tumor-relevant differentiation properties, there are highly invasive tumor cells or multicellular structures that may rapidly invade the surrounding ECM, but fail to form higher-order epithelial tissue structures. Furthermore, this system allows us to monitor dynamic changes that can result from the extraordinary plasticity of tumor cells, e.g., epithelial-to-mesenchymal transition in live cell settings. Furthermore, AMIDA supports an automated workflow, and can be combined with quality control and statistical tools for data interpretation and visualization. Our approach supports the growing needs for user-friendly, straightforward solutions that facilitate cell-based organotypic 3D assays in basic research, drug discovery, and target validation. PMID- 28634962 TI - Automatic auditory disambiguation of visual awareness. AB - Multisensory integration can play a critical role in producing unified and reliable perceptual experience. When sensory information in one modality is degraded or ambiguous, information from other senses can crossmodally resolve perceptual ambiguities. Prior research suggests that auditory information can disambiguate the contents of visual awareness by facilitating perception of intermodally consistent stimuli. However, it is unclear whether these effects are truly due to crossmodal facilitation or are mediated by voluntary selective attention to audiovisually congruent stimuli. Here, we demonstrate that sounds can bias competition in binocular rivalry toward audiovisually congruent percepts, even when participants have no recognition of the congruency. When speech sounds were presented in synchrony with speech-like deformations of rivalling ellipses, ellipses with crossmodally congruent deformations were perceptually dominant over those with incongruent deformations. This effect was observed in participants who could not identify the crossmodal congruency in an open-ended interview (Experiment 1) or detect it in a simple 2AFC task (Experiment 2), suggesting that the effect was not due to voluntary selective attention or response bias. These results suggest that sound can automatically disambiguate the contents of visual awareness by facilitating perception of audiovisually congruent stimuli. PMID- 28634963 TI - Leucopenia associated with metamizole: a case-control study. AB - AIMS OF THE STUDY: The aim of this study was to identify possible risk factors for the development of leucopenia associated with metamizole use. METHODS: A retrospective case-control study was performed. Cases of metamizole-associated leucopenia managed at a single centre (2005-2013) were characterised and compared with matched controls who took metamizole without developing complications. RESULTS: Fifty-seven cases and 139 controls were identified. Of the cases, 32 were postoperative and these were compared to age-, sex- and ward-matched postoperative controls (n = 64). The remaining cases (n = 25) were compared to sex-matched, non-postoperative controls (n = 75). The number of patients with a positive allergy history was higher among postoperative cases than controls (p = 0.004) as was the number with previous leucopenic episodes (p = 0.03). The prevalence of diagnosed hepatitis C infection was 9% among all cases compared with 1% among all controls (p = 0.005). The use of concomitant cytostatic agents (even at immunosuppressive doses) was significantly higher among non postoperative cases than controls (p = 0.011). There was no association between renal function and the development of leucopenia. CONCLUSIONS: A history of allergies, previous leucopenic episodes, hepatitis C infection and concomitant cytostatic agents are possible risk factors for leucopenia associated with metamizole use. PMID- 28634965 TI - The treatment of iron deficiency without anaemia (in otherwise healthy persons). AB - Iron deficiency is the most widespread and frequent nutritional disorder in the world. It affects a high proportion of children and women in developing countries and is also significantly prevalent in the industrialised world, with a clear predominance in adolescents and menstruating females. Iron is essential for optimal cognitive function and physical performance, not only as a binding site of oxygen but also as a critical constituent of many enzymes. Therefore iron deficiency at all its levels - nonanaemic iron deficiency, iron deficiency with microcytosis or hypochromia and iron deficiency anaemia - should be treated. In the presence of normal stores, however, preventative iron administration is inefficient, has side effects and seems to be harmful. In symptomatic patients with fatigue or in a population at risk for iron deficiency (adolescence, heavy or prolonged menstruation, high performance sport, vegetarian or vegan diet, eating disorder, underweight), a baseline set of blood tests including haemoglobin concentration, haematocrit, mean cellular volume, mean cellular haemoglobin, percentage of hypochromic erythrocytes and serum ferritin levels are important to monitor iron deficiency. To avoid false negative results (high ferritin levels in spite of iron deficiency), an acute phase reaction should be excluded by history and measurement of C-reactive protein. An algorithm leads through this diagnostic process and the decision making for a possible treatment. For healthy males and females aged >15 years, a ferritin cut-off of 30 ug/l is appropriate. For children from 6-12 years and younger adolescents from 12-15 years, cut-offs of 15 and 20 ug/l, respectively, are recommended. As a first step in treatment, counselling and oral iron therapy are usually combined. Integrating haem and free iron regularly into the diet, looking for enhancers and avoiding inhibitors of iron uptake is beneficial. In order to prevent reduced compliance, mainly as a result of gastrointestinal side effects of oral treatment, the use of preparations with reasonable but not excessive elemental iron content (28-50 mg) seems appropriate. Only in exceptional cases will an intravenous injection be necessary (e.g., concomitant disease needing urgent treatment, repeated failure of first-step therapy).To measure the success of treatment, the basic blood tests should be repeated after 8 to 10 weeks. Patients with repeatedly low ferritin will benefit from intermittent oral substitution to preserve iron stores and from long term follow-up, with the basic blood tests repeated every 6 or 12 months to monitor iron stores. Long-term daily oral or intravenous iron supplementation in the presence of normal or even high ferritin values is, however, not recommended and is potentially harmful. PMID- 28634966 TI - Prevalence of tobacco smoking in Switzerland: do reported numbers underestimate reality? AB - QUESTION UNDER STUDY: Surveys on tobacco consumption represent an important decision aid for public health policy related to smoking. Although Switzerland's tobacco control policies and regulations are among the weakest, its reported smoking prevalence is among the lowest in Europe. However, there appears to be a discrepancy between reported prevalence and aggregate data on national cigarette consumption. Our purpose was to closely look at this discrepancy and study its significance. METHODS: Calculation of national aggregate tobacco consumption by Switzerland's resident population for the years 2012 to 2015 and comparison with reported consumption derived from survey results on smoking prevalence and intensity. Comparison with similar data for France for year 2014. Evaluation of several hypotheses to explain the discrepancy between survey results and national aggregate consumption data. RESULTS: There was a large discrepancy of about 45% between reported smoking consumption implied by survey results and estimated actual consumption derived from aggregate data on sales. Whereas survey results suggest smoking prevalence in Switzerland to be around 25% and rather stable during the period 2012 to 2015, true prevalence could be greater than 31%. CONCLUSION: The results of surveys aiming to estimate smoking prevalence and intensity in Switzerland may substantially suffer from underreporting, misreporting and sampling bias. Survey methodology needs to be examined to see whether such reporting discrepancy can be reduced. PMID- 28634967 TI - Sleep-disordered breathing: clinical features, pathophysiology and diagnosis. AB - In recent decades, the association between sleep-disordered breathing (SDB) and cardio- and cerebrovascular diseases (including hypertension, coronary heart disease and stroke) has been the focus of interest of both clinicians and researchers. A growing concern is the increasing prevalence of SDB in the general population, which can be partly explained by the rise in obesity prevalence and population aging, as well as by the development of enhanced diagnostic tools and approaches. Because of evidence of adverse long-term effects of SDB on cardiovascular morbidity and overall mortality, systematic screening for SDB should be considered for populations at risk. The evidence of a long-term benefit of treatment for SDB, however, is still controversial and the best management approaches are still unclear. This article summarises available epidemiological data and focuses on the main pathophysiological mechanisms linking SDB to cardio- and cerebrovascular disorders. We will also give a critical overview of the current diagnostic procedures. The available treatment approaches and their prognostic effects on cardio- and cerebrovascular health will be discussed in a second paper. PMID- 28634968 TI - Adapting the "Chester step test" to predict peak oxygen uptake in children. AB - AIM OF THE STUDY: Maximal exercise testing may be difficult to perform in clinical practice, especially in obese children who have low cardiorespiratory fitness and exercise tolerance. We aimed to elaborate a model predicting peak oxygen consumption (VO2) in lean and obese children with use of the submaximal Chester step test. METHODS: We performed a maximal step test, which consisted of 2-minute stages with increasing intensity to exhaustion, in 169 lean and obese children (age range: 7-16 years). VO2 was measured with indirect calorimetry. A statistical Tobit model was used to predict VO2 from age, gender, body mass index (BMI) z-score and intensity levels. Estimated VO2peak was then determined from the heart rate-VO2 linear relationship extrapolated to maximal heart rate (220 minus age, in beats.min-1). RESULTS: VO2 (ml/kg/min) can be predicted using the following equation: VO2 = 22.82 - [0.68*BMI z-score] - [0.46*age (years)] - [0.93*gender (male = 0; female = 1)] + [4.07*intensity level (stage 1, 2, 3 etc.)] - [0.24*BMI z-score *intensity level] - [0.34*gender*intensity level]. VO2 was lower in participants with high BMI z-scores and in female subjects. CONCLUSION: The Chester step test can assess cardiorespiratory fitness in lean and obese children in clinical settings. Our adapted equation allows the Chester step test to be used to estimate peak aerobic capacity in children. PMID- 28634969 TI - Diagnosis and assessment of renal fibrosis: the state of the art. AB - Chronic kidney disease (CKD) is defined as an alteration of kidney function and/or structure lasting for more than 3 months and is a major public health issue. Histologically, the severity of CKD correlates with the magnitude of kidney cortical interstitial fibrosis. Estimation of kidney fibrosis is crucial to assess prognosis and guide therapy in both native and allograft kidneys. Biopsy is currently the gold standard for assessing fibrosis with histological techniques. Although this procedure has become safer over recent years, complications and limitations remain. Given these restrictions, new, noninvasive techniques are necessary for the evaluation and follow-up of CKD patients. Radiological methods such as ultrasound and magnetic resonance imaging are emerging for assessment kidney fibrosis. These two techniques have advantages but also limitations. In addition to radiological assessment of fibrosis, urinary and plasma biomarkers are being developed and tested as predictive tools for histological lesions in the kidney. This article reviews the current evidence for these novel techniques in the evaluation of kidney interstitial fibrosis. PMID- 28634970 TI - Severe injection site reactions after subcutaneous administration of Sayana(c). AB - PURPOSE: Sayana(r) was introduced as the first depot medroxyprogesterone acetate containing contraceptive that is administered via subcutaneous injection. Within 10 months, the Regional Pharmacovigilance Centre (RPVC) Zurich received several anonymous reports of serious local reactions after Sayana(r) administration. In this retrospective study, individual case safety reports (ICSRs) on local adverse drug reactions (ADRs) related to Sayana(r) were analysed from the WHO pharmacovigilance database. METHODS: International, national and regional ICSRs during Sayana(r) administration up to 1 January 2016 were examined. Data on ADRs were retrieved from the WHO Global Database VigiBaseTM. Demographic data, drug administration information, duration of Sayana(r) treatment, latency time of the ADR, and its course, severity and outcomes were analysed. RESULTS: Worldwide, 398 ICSRs after Sayana(r) use were registered in the database. We identified 20 reported terms that were potentially used to describe a persistent lipodystrophy. When only cases containing one or more of these 20 reported terms were selected, 323 (81.2%) international ICSRs remained for analysis. Of those, 91.6% (n = 296) were categorised as serious. The majority of the reactions (n = 193, 54.4%) did not recover. In the 67 Swiss ICSRs, 77 ADRs were reported using 10 different terms including severe or persistent local reactions like lipodystrophy, atrophy or fat necrosis. Thirty-two patients (47.7%) did not recover. All 11 regional cases reported to the RPVC Zurich were categorised as serious ADRs. For the majority of the patients (n = 7, 63.6%) the interval between the application of Sayana(r) and development of the lipodystrophy was between 2 and 4 months. Most of the reactions were irreversible (n = 9, 81.8%). One patient underwent plastic surgery for artificial infill of the dent. CONCLUSIONS: Persistent local injection site reactions such as lipodystrophy, fat tissue necrosis or atrophy occur frequently after subcutaneous Sayana(r) use. These adverse drug reactions were recently integrated in the Swiss product information. Physicians and patients should be informed and advised about these potentially irreversible effects. PMID- 28634971 TI - Impact of growing cohorts of adults with con-genital heart disease on clinical workload: a 20-year experience at a tertiary care centre. AB - BACKGROUND: Population based studies show a steady increase in adult patients with congenital heart defects. The aim of this study was to assess the evolution of such a patient cohort and its burden on clinical care at a dedicated tertiary care centre. METHODS: All patients with congenital heart disease followed up by a dedicated multidisciplinary team at our institution were identified (n = 1725). Disease characteristics, the increase in patient numbers and interventions and the increase in selected complications were analysed and compared between the first (1996-2005) and second (2006-2015) decades of the study period. RESULTS: Between the two decades of the study period, the number of patients in follow-up increased by 109%, the number of patients who died or underwent transplantation more than doubled and the number of outpatient visits increased by 195%. One fourth of all patients underwent at least one surgical procedure and 14% had at least one percutaneous intervention. The increase in surgical procedures between the two decades was 27% and the increase in percutaneous interventions 159%. Between the two decades the number of patients requiring direct current cardioversion increased from 32 to 95 (+197%), the number of patients requiring admission for infective endocarditis increased from 7 to 29 (+314%) and the number of women followed up during pregnancy increased from 18 to 115 (+539%). CONCLUSION: As a result of the increasing number and complexity of adult survivors with congenital heart disease more resources will be needed to cope with the demands of this novel cohort of complex patients in adult cardiology. PMID- 28634972 TI - Predictors of re-exacerbation after an index exacerbation of chronic obstructive pulmonary disease in the REDUCE randomised clinical trial. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) compromise physical activity and quality of life and contribute significantly to health care costs. Systemic glucocorticoids benefit clinical outcome in AECOPD, and the REDUCE trial demonstrated noninferiority of a 5-day treatment course with prednisone compared with 14 days therapy regarding clinical outcome over 6 months of follow-up. Unexpectedly, we found an inverse correlation between circulating cortisol levels and exacerbation risk during a 6-month follow-up period. OBJECTIVE: To evaluate whether additional predictors of COPD re-exacerbation can be identified after the index exacerbation in the REDUCE cohort. METHODS: Of 314 patients with AECOPD randomised to 5 or 14 days of prednisone treatment, 311 were included in the analysis. Parameters tested as predictors of re-exacerbation were sex, age, smoking status, forced expiratory volume in one second (FEV1), dyspnoea as assessed with the Medical Research Council (MRC) dyspnoea scale, home oxygen therapy, pretreatment with systemic glucocorticoids, pretreatment with antibiotics, duration of hospitalisation, blood pressure, oxygen saturation, admission to the Intensive Care Unit (ICU) and relevant infections in follow-up. The risks for re-exacerbation were estimated by means of logistic regression and Cox proportional hazard models and expressed as odds ratios and hazard ratios, respectively. RESULTS: After multivariate adjustment, significant predictors at hospital discharge for COPD re-exacerbation during follow-up were: duration of hospital stay >8 days (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.03 2.28); FEV1 <30% predicted (HR 1.76, 95% CI 1.06-2.91); hypertension (HR 2.39, 95% CI 1.04-5.48) and MRC dyspnoea scale (HR 1.61, 95% CI 1.30-2.01, per unit increment). Present cigarette smoking (HR 0.60, 95% CI 0.38-0.92) was negatively associated with re-exacerbation. CONCLUSION: In addition to biochemical suppression of the adrenal glands, other standard clinical parameters predict re exacerbation in patients admitted to the emergency department with AECOPD. (REDUCE trial registration: ISRCTN29646069). PMID- 28634973 TI - The role of a surveillance programme for intro-ducing peripherally inserted central catheters: a 2-year observational study in an academic hospital. AB - AIMS OF THE STUDY: In our hospital, a previous attempt to introduce peripherally inserted central catheters (PICC) was aborted after a nonsystematic approach, seemingly accompanied by high rates of complications. The goal of this new interdisciplinary project was to introduce PICCs in an academic hospital, with an embedded interdisciplinary surveillance programme for both infectious and noninfectious outcomes. METHODS: We prospectively collected data for this surveillance study from all patients who underwent PICC insertion from 1 January 2014 and had the catheter removed by 31 December 2015 in our 950-bed academic hospital (Bern University Hospital, Switzerland). Infectious complications were defined according to Centers for Disease Control and Prevention / National Healthcare Safety Network criteria. PICCs were restricted to cancer and infectious disease patients, and were followed up irrespective of the management setting (inpatient, outpatient or intermittently hospitalised after insertion). An interdisciplinary team reviewed the outcomes on a routine basis and discussed changes to the process to improve outcomes, if necessary. RESULTS: One hundred and thirty-five PICCs were inserted in 124 patients, the majority of whom were patients from the medical oncology department (n = 107, 86.3%). Indications for PICC insertion included: chemotherapy (n = 97, 71.9%), antibiotic therapy (n = 24, 17.8%), total parenteral nutrition (n = 8, 5.9%), blood product transfusion (n = 4, 3.0%) and palliative care (n = 2, 1.5%). During a total of 10 402 catheter-days (median dwell time 62 days), there were five central line associated bloodstream infections, including one mucosal barrier injury laboratory-confirmed bloodstream infection and two exit-site infections, yielding incidence rates of 0.48 and 0.19 infections per 1000 catheter-days, respectively. Incidence rates were 0.67 per 1000 catheter-days (n = 7) for radiologically documented deep venous thrombosis, 0.96 (n = 10) for tip dislocation and 0.67 (n = 7) for catheter occlusion. The overall rate of complications was 4.5 per 1000 catheter-days. Seventeen catheters (12.6%) were removed because of any complication. CONCLUSION: We successfully introduced PICCs in an academic hospital by implementing a systematic surveillance programme for complications. Both infectious and noninfectious complications were rare. Infection prevention specialists should be actively involved during the introduction of new intravascular devices in order to provide quality indicators and assure patient safety. PMID- 28634974 TI - Markers of subclinical atherosclerosis in schoolchildren with obesity and metabolic syndrome. AB - BACKGROUND: Although increased carotid intima-media thickness (cIMT), soluble adhesion molecules and proinflammatory biomarkers are strongly implicated in the development of atherosclerotic lesions, the role of obesity and metabolic syndrome (MetS) in atherogenicity and inflammation among schoolchildren is not well investigated. AIM: To determine the levels of cIMT, endothelial dysfunction and inflammatory biomarkers in a group of schoolchildren with obesity and MetS. METHODS: Eighty-seven schoolchildren (age 10-15 years) were categorised into three groups: normal bodyweight group, obese group and severely obese with MetS group (17 boys and 12 girls in each group). Levels of cIMT were measured with high-resolution B-mode ultrasound. Serum proinflammatory cytokines interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL 1beta), and soluble adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1(ICAM-1) were measured. RESULTS: Mean cIMT levels were significantly higher (p ?0.05) among severely obese schoolchildren with MetS (0.49 +/- 0.02 mm) compared with both the obese (0.43 +/- 0.03 mm) and the normal bodyweight counterparts (0.36 +/- 0.03 mm). Serum levels of IL-6, TNF-alpha, IL-1beta, E-selectin, VCAM-1 and ICAM-1 were significantly higher (p ?0.05) in severely obese with MetS and obese children compared with the normal bodyweight group. However, no significant differences (p >0.05) were found between the severely obese schoolchildren with MetS and the obese without MetS. CONCLUSIONS: Severely obese schoolchildren having MetS exhibited higher cIMT levels than obese and normal bodyweight counterparts. Biomarkers of inflammation and endothelial dysfunction were higher in obese schoolchildren, but biomarkers were not increased any further by the degree of obesity nor the MetS cluster. PMID- 28634975 TI - Promoting bioethics in the Eastern Mediterranean Region. PMID- 28634976 TI - Satisfaction levels with family physician services: a pilot national health programme in the Islamic Republic of Iran. AB - Family physicians in the Islamic Republic of Iran have been providing health and medical services to residents from rural areas since 2005, and from 2011 these services have been delivered to urban residents in Fars and Mazandaran provinces. This study was conducted in 2014 to measure the rate of user satisfaction with services provided by family physicians to the rural and urban population of the second most populated county in Fars province (Marvdasht county, population > 330 000). In urban and rural areas, 1650 houses (825 in rural and 825 in urban areas) were selected, of which 1561 houses were inhabited (2908 individuals in urban and 3062 individuals in rural areas) and an interview-administered doorstep questionnaire was completed. Overall satisfaction rate was 59.2%: 54.5% for urban areas and 63.2% for rural areas. This study suggests that satisfaction is higher among rural residents and that better quality services from family physicians are needed in both rural and urban communities. PMID- 28634977 TI - Effect of Ramadan fasting on glucose level, lipid profile, HbA1c and uric acid among medical students in Karachi, Pakistan. AB - To assess the effect of Ramadan fasting on blood pressure, fasting glucose, lipid profile, uric acid, HbA1c, body mass index, body adiposity index and visceral adiposity index among fasting medical students, 35 students were recorded before, during and after Ramadan (August) 2011, for their blood pressure, anthropometric measurements, questionnaire response and blood sample. A blood sample was taken at each visit for glucose, lipid profile and HbA1c. Total physical activity, weight-to-height ratio, body adiposity index and visceral adiposity index were calculated for insulin sensitivity. Changes in anthropometric measurements were not statistically significant. However, physical activities increased significantly after Ramadan. Changes in blood pressure, fasting blood sugar, total cholesterol, HbA1c, uric acid and triglyceride were not statistically significant. Mean high density lipoprotein decreased significantly in Ramadan, while low density lipoprotein increased significantly. PMID- 28634978 TI - Correlation between hepatitis C viral load and hepatitis C Core antigenaemia among Egyptians. AB - Hepatitis C virus (HCV) infection is widespread in Egypt. This study compared HCV RNA with HCVcAg for the detection and quantification of viraemia among a sample of Egyptians. Sera from 80 suspected HCVpositive individuals were tested simultaneously for HCV-RNA load using real-time polymerase chain reaction (PCR) and HCVcAg level using ELISA. Of the 80 samples, 25% were HCV-RNA-negative. HCVcAg was detected in all samples: range 0.4-2462 ng/mL, mean 460 (SD 506) ng/mL. The sensitivity and specificity of HCVcAg were 96.7% and 90.9%, respectively. There was a significant correlation between serum HCV-RNA and HCVcAg levels (r = 0.4, P < 0.0001). HCV-RNA remains the gold standard for diagnosis of active HCV infection but HCVcAg can be used where PCR is not available. PMID- 28634979 TI - Interpretation of symptoms as a cause of delays in patients with acute myocardial infarction, Istanbul, Turkey. AB - This cross-sectional study aimed to assess interpretation of symptoms as a cause of delays in patients with acute myocardial infarction (AMI). It was conducted at a university hospital in Istanbul, Turkey. The sample included 93 patients: 73 male, mean age 57.89 (12.13) years. Prehospital delay time ranged from 15 minutes to 10 days, with a median of 2 hours (interquartile range: 9.50). Patients waited for pain to go away (48.4%) and tried to calm down (39.8%). Most patients attributed AMI-related symptoms to a reason other than heart disease. In a multivariate logistic regression analysis, the type of AMI was classified based on electrocardiography findings (odds ratio 5.18, 95% confidence interval: 1.69 15.91, P=0.004) and was independently associated with a long prehospital delay time, indicating that patients with ST segment elevation MI would seek early medical care. Misinterpretation of symptoms and misconceptions about emergency treatment during AMI cause delays in admission and may affect treatment. PMID- 28634980 TI - Association of rotating night shift with lipid profile among nurses in an Egyptian tertiary university hospital. AB - The main objective was to identify whether night shift nurses are more prone to dyslipidaemia than day shift nurses. One hundred and fifty female nurses aged 20 49 years were recruited from Ain Shams University Hospitals, Egypt, from January to March 2016: 64 day shift and 86 night shift. Diet type was assessed by interview questionnaire and job satisfaction was assessed using the job satisfaction survey. Triglyceride (TG), low-density lipoprotein (LDL) and high density lipoprotein (HDL) were measured in all nurses. The predictors of high TG level were ages 30-39 and >= 40 years and night shift. The only predictor of high LDL level (> 130 mg/dl) was age >= 40 years. An unhealthy diet and night shift were predictors of risky HDL levels. Seventy nurses were unsatisfied with their jobs, and 137 ate a semi-healthy diet. The findings emphasize that night shift nurses are at risk of abnormal lipid profile, therefore an occupational programme to help nurses cope with their employment conditions is necessary. PMID- 28634981 TI - Improving influenza vaccination rates of healthcare workers: a multipronged approach in Qatar. AB - We assessed whether an influenza vaccination (IV) campaign was effective at increasing vaccination rate in healthcare workers (HCWs) in 2 hospitals in Doha, Qatar that had no mandatory IV policy. The campaign comprised promotional, educational and vaccine delivery interventions; a dedicated IV team; telephone hotline; free IV with improved access, leadership involvement; incentives; group educational sessions; and reporting/tracking activities. During the 2014/15 influenza season, IV rates according to hospital and HCW category were calculated and compared with the 2 seasons before the intervention. The combined mean rate for IV for both hospitals increased for 2014/15 (64.3%) compared with 2013/14 (37.2%) and 2012/13 (28.4%). There was increased IV uptake among doctors and nurses at each hospital, and the IV rate for the 2 hospitals (59.1 and 69.5%) were higher than in 2013/14 (21.1% and 53.2%) and 2012/13 (17.2% and 39.6%). The findings highlight the importance of improving IV rates among HCWs in hospitals with no mandatory vaccination policies through multicomponent interventions. PMID- 28634982 TI - Zika in Singapore: implications for Saudi Arabia. PMID- 28634983 TI - La resistance a la sectorisation : exemple du gouvernorat de Nabeul en Tunisie. AB - Sectorisation was introduced in Tunisia in 1999. The objective of this study was to examine the difficulties and resistance to the sectorisation of psychiatric care in the state of Nabeul. A transversal study was conducted over a period of 5 months from 1 November 2014 to 31 March 2015 on 96 patients resident in the state of Nabeul and treated at Razi hospital. Patients were aged between 18 and 69 years old ( sex ratio equal to one), 55.2% were single and 46% had a low socioeconomic level (n=44). Chronic psychotic disorder was diagnosed in 64.3% , depression in 12.3%, bipolar disorder in 18.8% and mental retardation in 3% of cases. Most of them refused to continue psychiatric treatment in the second or the first line of care. Resistance to sectorisation was associated with a low socioeconomic level (P = 0.039), availability of a companion (P = 0.04), celibacy (P = 0.04), gender (P = 0.05) and negatively correlated to psychotic disorder diagnosis. It was concluded that the environment plays an important role in the choice of the place of care. Subjects treated for mental illness were found to have greater trust in the structures that treated the acute episode of their illness, and paradoxically felt less stigmatized in Razi hospital. PMID- 28634984 TI - Reply To: Higher Intelligence and Later Maternal Age: Which Way Does the Causal Direction Go? PMID- 28634985 TI - A performance comparison between the two language versions of the Affective Go/No Go test: A randomised crossover study. AB - The purpose of this randomised crossover study is to validate the Korean version of the Affective Go/No-go (AGN) test. The Korean words for the AGN test were selected after careful evaluation of emotional valences, word length and frequency. Fifteen Korean advanced learners of English were administered both Korean and English versions, yielding 30 data points. The performance of both language versions was compared for each of the AGN test parameters (response latency, commission error and omission error) using two-way analysis of variance (ANOVA). Intraclass correlation coefficients (ICCs) were estimated to evaluate associations between the two versions. The ICCs were high for response latencies of all valences and commission errors of positive and neutral words, but not for that of negative words and omission errors of all valences. A similar pattern of test results, as revealed by the high ICCs and non-significant interaction effects between language and word valence, suggests that the psychometric properties of the AGN test may be comparable over different language versions. PMID- 28634986 TI - Proteomic analysis of red blood cells from donors exhibiting high hemolysis demonstrates a reduction in membrane-associated proteins involved in the oxidative response. AB - BACKGROUND: The development of hemolysis during ex vivo hypothermic storage is multifaceted. Standardization of collection and production processes is used to minimize variability in biologics manufacturing and to maximize product quality. However, the influence of various donor characteristics on product quality is often difficult to evaluate and to control. Using a proteomic approach, we aimed to decipher relevant donor characteristics that may predict red blood cell (RBC) quality during storage. STUDY DESIGN AND METHODS: Ten healthy volunteer donors exhibiting repeated high hemolysis at outdate (>0.8%; RBCHH ) and 10 age- and sex matched control donors (RBCCtrl ) were studied. Common quality variables were measured on Days 5, 14, 21, 28, and 42 of storage. Protein profiles of hemoglobin depleted membrane fractions from RBCHH and RBCCtrl donors were analyzed using a quantitative proteomics approach based on iTRAQ (isobaric tags for relative and absolute quantitation). RESULTS: Time-dependent lesion development was apparent in both donor populations. RBCHH exhibited reduced 2,3-bisphosphoglycerate levels (p < 0.001) and morphologic score (p < 0.001), but displayed elevated hemolysis level (p < 0.001), RBC-derived microvesicle formation (p < 0.001), and mean corpuscular fragility (p < 0.001) compared to RBCCtrl , indicating notable differences at the membrane between the two donor populations. Proteomic findings revealed a significant reduction in the level of proteins involved in oxidative response pathways at early time points in RBCHH compared to that of RBCCtrl . CONCLUSION: The recruitment of these candidate proteins might be part of a response mechanism altered in RBCHH donors and therefore may be useful as a donor screening tool. PMID- 28634987 TI - Dietary TiO2 particles modulate expression of hormone-related genes in Bombyx mori. AB - Silkworm (Bombyx mori) is an economically beneficial insect. Its growth and development are regulated by endogenous hormones. In the present study, we found that feeding titanium dioxide nanoparticles (TiO2 NP) caused a significant increase of body size. TiO2 NP stimulated the transcription of several genes, including the insulin-related hormone bombyxin, PI3K/Akt/TOR (where PI3K is phosphatidylinositol 3-kinase and TOR is target of rapamycin), and the adenosine 5'-monophosphateactivated protein kinase (AMPK)/target of rapamycin (TOR) pathways. Differentially expressed gene (DEG) analysis documented 26 developmental hormone signaling related genes that were differentially expressed following dietary TiO2 NP treatment. qPCR analysis confirmed the upregulation of insulin/ecdysteroid signaling genes, such as bombyxin B-1, bombyxin B-4, bombyxin B-7, MAPK, P70S6K, PI3k, eIF4E, E75, ecdysteroid receptor (EcR), and insulin related peptide binding protein precursor 2 (IBP2). We infer from the upregulated expression of bombyxins and the signaling network that they act in bombyxin stimulated ecdysteroidogenesis. PMID- 28634989 TI - Growth of Au Nanoparticles on 2D Metalloporphyrinic Metal-Organic Framework Nanosheets Used as Biomimetic Catalysts for Cascade Reactions. AB - Inspired by the multiple functions of natural multienzyme systems, a new kind of hybrid nanosheet is designed and synthesized, i.e., ultrasmall Au nanoparticles (NPs) grown on 2D metalloporphyrinic metal-organic framework (MOF) nanosheets. Since 2D metalloporphyrinic MOF nanosheets can act as the peroxidase mimics and Au NPs can serve as artificial glucose oxidase, the hybrid nanosheets are used to mimic the natural enzymes and catalyze the cascade reactions. Furthermore, the synthesized hybrid nanosheets are used to detect biomolecules, such as glucose. This study paves a new avenue to design nanomaterial-based biomimetic catalysts with multiple complex functions. PMID- 28634988 TI - Panax notoginseng Preparations for Unstable Angina Pectoris: A Systematic Review and Meta-Analysis. AB - This paper assessed the evidence of Panax notoginseng preparations in patients suffering from UAP using meta-analysis and systematic review methods. Methods were according to the Cochrane Handbook and analysed using Revman 5.3. A search of PubMed, Cochrane Library, Embase, MEDLINE, Chinese national knowledge infrastructure (CNKI), Vip information database, Wanfang data and Chinese Biomedical Literature Database (SinoMed) was conducted to identify randomized controlled trials (RCTs) of P. notoginseng preparations on UAP regardless of blinding, sex and language. The outcomes include all-cause mortality, cardiac mortality, cardiovascular events, UAP symptoms, improvement of electrocardiogram and adverse events. Eighteen RCTs including 1828 patients were identified. The level of reporting is generally poor. Among 18 studies, 16 studies were prescribed P. notoginseng injections, and two studies were oral P. notoginseng preparations. Reduction of cardiovascular events (RR:0.35;95% CI:0.13 to 0.94), alleviation of angina pectoris symptoms (RR:1.23;95% CI 1.18 to 1.29), improvement of ECG (RR:1.22;95% CI 1.15 to 1.28) and reduced frequency of angina pectoris (MD:-1.48; 95% CI -2.49 to -0.48) were observed. Cardiac mortality and duration of angina pectoris were not statistically significant. Panax notoginseng is beneficial to UAP patients; the results of these reviews may have important implications to clinical work. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28634990 TI - Clinical assessment to determine the risk of bowel cancer using Symptoms, Age, Mass and Iron deficiency anaemia (SAMI). AB - BACKGROUND: The aim of this study was to identify characteristics with independent predictive value for bowel cancer for use in the clinical assessment of patients attending colorectal outpatient clinics. METHODS: This was a 22-year (1986-2007) retrospective cohort analysis of data collected prospectively from patients who attended colorectal surgical outpatient clinics in Portsmouth. The data set was split randomly into two groups of patients to generate and validate a predictive model. Multivariable logistic regression was used to create and validate a system to predict outcome. Receiver operating characteristic (ROC) curves and Hosmer-Lemeshow test were used to evaluate the model's predictive capability. The likelihood of bowel cancer was expressed as the odds ratio (OR). RESULTS: Data from 29 005 patients were analysed. Discrimination of the model for bowel cancer was high in the development (C-statistic 0.87, 95 per cent c.i. 0.85 to 0.88) and validation (C-statistic 0.86, 0.84 to 0.87) groups. The most important co-variables in the final model were: age (OR 3.17-27.10), rectal (OR 31.48) or abdominal (OR 1.83-8.45) mass, iron deficiency anaemia (IDA) (OR 4.42 8.38), rectal bleeding and change in bowel habit in combination (OR 5.37), change in bowel habit without rectal bleeding, with or without abdominal pain (OR 2.12 2.52), and rectal bleeding with no perianal symptoms and without change in bowel habit (OR 2.91). Some 91.5 per cent of bowel cancers presented with these characteristics, 40.4 per cent with a mass and/or IDA. In patients with at least one of these characteristics the overall risk of having cancer was 10.0 (range 6.5-50.4) per cent, compared with 1.1 (0.3-2.3) per cent in patients without them. CONCLUSION: A clinical assessment that systematically identifies or excludes four symptom-age combinations, a mass and IDA (SAMI) stratifies patients as having a low and higher risk of having bowel cancer. This could improve patient selection for referral and investigation. PMID- 28634991 TI - Experiences and psychological distress of spouses of prostate cancer patients at time of diagnosis and primary treatment. AB - We studied experiences and psychological distress of partners of prostate cancer patients at the time of diagnosis and primary treatment and investigated associates of their psychological wellbeing and the emotional social support they give to and receive from the patient. Using a quantitative questionnaire we studied the spouses' experiences (psychological response and sources of information and emotional support at diagnosis; impacts of prostate cancer on partnership and sex life; impact of side effects of treatment) and the emotional support given and received, and measured their psychological symptom distress. Many spouses reported distressing experiences and all psychological symptoms. Two thirds perceived no impact of the cancer on the partnership while 29% no change in sex life. Distress was associated with a shock, fear of the man's death and impact of side effects, whereas emotional support from a doctor predicted less distress. More support given to the patient was associated with information and emotional support received from a doctor and the patient's sexual dysfunction and pain, and less with experiences of depression, no impact on the partnership and the patient's irritableness. The spouses' distress was relieved by emotional support from a doctor, which along with received information also enhanced their capability to support the patient. PMID- 28634992 TI - The real thing: preschoolers prefer actual activities to pretend ones. AB - Pretend play is a quintessential activity of early childhood, and adults supply children with many toys to encourage it. Do young children actually prefer to pretend, or do they do it because they are unable to engage in some activities for real? Here we examined, for nine different activities, American middle-class preschoolers' preferences for pretend and real activities. The 100 children we tested (M = 58.5 months, range 36 to 82 months) overwhelmingly preferred real activities to pretend ones, and this preference increased from age 3 to age 4, then remained steady through age 6. Children provided cogent justifications for their preferences. The results are discussed with reference to other domains in which children show reality preferences and with respect to the content of preschool curricula. PMID- 28634993 TI - Eu3+ -doped polystyrene and polyvinylidene fluoride nanofibers made by electrospinning for photoluminescent fabric designing. AB - Eu3+ -doped polystyrene and polyvinylidene fluoride (PVDF/Eu3+ and PS/Eu3+ ) nanofibers were made using electrospinning. These fibers were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT IR), energy dispersive spectroscopy (EDX) and photoluminescence (PL). Spectral analysis of PVDF/Eu3+ and PS/Eu3+ nanofibers was based on their emission spectra. A bright red emission was noticed from Eu3+ that was assigned to the hypersensitive 5 D0 -> 7 F2 transition. The enhanced intensity ratios of 5 D0 > 7 F2 to 5 D0 -> 7 F1 transitions in the nanofibers indicated a more polarized chemical environment for the Eu3+ ions and greater hypersensitivity for the 5 D0 -> 7 F2 transition, which showed the potential for application in various polymer optoelectronic devices. The Eu3+ -doped polymer (PVDF/Eu3+ and PS/Eu3+ ) nanofibers are suitable for the photoluminescent white light fabric design of smart textiles. This paper focuses on the potential application of smart fabrics to address challenges in human life. PMID- 28634994 TI - Concentration- and flux-based dose-responses of isoprene emission from poplar leaves and plants exposed to an ozone concentration gradient. AB - Concentration- and flux-based O3 dose-responses of isoprene emission from single leaves and whole plants were developed. Two poplar clones differing in O3 sensitivity were exposed to five O3 levels in open-top chambers for 97 d: charcoal-filtered ambient air (CF), non-filtered ambient air (NF) and NF plus 20 ppb (NF + 20), 40 ppb (NF + 40) and 60 ppb (NF + 60). At both leaf and plant level, isoprene emission was significantly decreased by NF + 40 and NF + 60 for both clones. Although intra-specific variability was found when the emissions were up-scaled to the whole plant, both leaf- and plant-level emissions decreased linearly with increasing concentration-based (AOT40, cumulative exposure to hourly O3 concentrations >40 ppb) and flux-based indices (PODY , cumulative stomatal uptake of O3 > Y nmol O3 m-2 PLA s-1 ). AOT40- and POD7 -based dose responses performed equally well. The two clones responded differently to AOT40 and similarly to PODY (with a slightly higher R2 for POD7 ) when the emission was expressed as change relative to clean air. We thus recommend POD7 as a large scale risk assessment metric to estimate isoprene emission responses to O3 in poplar. PMID- 28634995 TI - The Longitudinal Association Between Early Childhood Obesity and Fathers' Involvement in Caregiving and Decision-Making. AB - OBJECTIVE: Fathers have increased their involvement in child caregiving; however, their changing role in childhood obesity is understudied. This study assessed the longitudinal association between changes in obesity among children aged 2 to 4 years and changes in fathers' involvement with raising children. METHODS: Longitudinal data from the Early Childhood Longitudinal Study-Birth Cohort were used to conduct child fixed-effects linear and logistic regression analyses to assess the association between changes in childhood obesity-related outcomes (sugar-sweetened beverage consumption, screen time, BMI z score, overweight/obesity, obesity) and fathers' involvement with raising children (caregiving and influencing child-related decisions). Fixed-effects models control for all time-invariant characteristics. Analyses were controlled for time varying confounders, including child age, maternal and paternal employment, and family poverty status. RESULTS: Children whose fathers increased their frequency of taking children outside and involvement with physical childcare experienced a decrease in their odds of obesity from age 2 to age 4. Obesity-related outcomes were not associated with fathers' decision-making influence. CONCLUSIONS: Increases in fathers' involvement with some aspects of caregiving may be associated with lower odds of childhood obesity. Encouraging fathers to increase their involvement with raising children and including fathers in childhood obesity prevention efforts may help reduce obesity risk among young children. PMID- 28634996 TI - Molecular regulation and pharmacological targeting of the beta-catenin destruction complex. AB - : The beta-catenin destruction complex is a dynamic cytosolic multiprotein assembly that provides a key node in Wnt signalling regulation. The core components of the destruction complex comprise the scaffold proteins axin and adenomatous polyposis coli and the Ser/Thr kinases casein kinase 1 and glycogen synthase kinase 3. In unstimulated cells, the destruction complex efficiently drives degradation of the transcriptional coactivator beta-catenin, thereby preventing the activation of the Wnt/beta-catenin pathway. Mutational inactivation of the destruction complex is a major pathway in the pathogenesis of cancer. Here, we review recent insights in the regulation of the beta-catenin destruction complex, including newly identified interaction interfaces, regulatory elements and post-translationally controlled mechanisms. In addition, we discuss how mutations in core destruction complex components deregulate Wnt signalling via distinct mechanisms and how these findings open up potential therapeutic approaches to restore destruction complex activity in cancer cells. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc. PMID- 28634999 TI - Plasticity in gas-exchange physiology of mature Scots pine and European larch drive short- and long-term adjustments to changes in water availability. AB - Adjustment mechanisms of trees to changes in soil-water availability over long periods are poorly understood, but crucial to improve estimates of forest development in a changing climate. We compared mature trees of Scots pine (Pinus sylvestris) and European larch (Larix decidua) growing along water-permeable channels (irrigated) and under natural conditions (control) at three sites in inner-Alpine dry valleys. At two sites, the irrigation had been stopped in the 1980s. We combined measurements of basal area increment (BAI), tree height and gas-exchange physiology (Delta13 C) for the period 1970-2009. At one site, the Delta13 C of irrigated pine trees was higher than that of the control in all years, while at the other sites, it differed in pine and larch only in years with dry climatic conditions. During the first decade after the sudden change in water availability, the BAI and Delta13 C of originally irrigated pine and larch trees decreased instantly, but subsequently reached higher levels than those of the control by 2009 (15 years afterwards). We found a high plasticity in the gas exchange physiology of pine and larch and site-specific responses to changes in water availability. Our study highlights the ability of trees to adjust to new conditions, thus showing high resilience. PMID- 28635001 TI - Electro- and Liquid Phase-Separations (ITP 2016). PMID- 28634997 TI - Working toward precision medicine: Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges. AB - Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype-phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype-phenotype relationships. PMID- 28634998 TI - Dietary glycaemic index and glycaemic load and upper gastrointestinal disorders: results from the SEPAHAN study. AB - BACKGROUND: Little is known about the effects of carbohydrate, particularly any association between dietary glycaemic index or glycaemic load and uninvestigated heartburn or uninvestigated chronic dyspepsia in the community. The present study aimed to determine associations between dietary glycaemic index or glycaemic load and uninvestigated heartburn or uninvestigated chronic dyspepsia. METHODS: This cross-sectional study was conducted in 2987 adults. Dietary glycaemic index and glycaemic load were estimated using a validated food-frequency questionnaire. Uninvestigated heartburn and uninvestigated chronic dyspepsia were determined using a modified and validated version of the Rome III questionnaire. RESULTS: After controlling for various confounders, high glycaemic load was associated with an increased risk of uninvestigated heartburn [odds ration (OR) = 1.75; 95% confidence interval CI = 1.03, 2.97; P = 0.04] and uninvestigated chronic dyspepsia (OR = 2.14; 95% CI: 1.04, 4.37; P = 0.04) in men but not in women. In normal-weight individuals, high glycaemic index was related to an increased risk of uninvestigated heartburn (OR = 1.52; 95% CI: 1.07, 2.15; P = 0.02) and high glycaemic load to an increased risk of uninvestigated chronic dyspepsia (OR=1.78; 95% CI: 1.05, 3.01; P = 0.03). No significant associations were observed in subjects with excess body weight. CONCLUSIONS: Our data suggest that there are body mass index- and sex-specific associations between dietary carbohydrate quality with uninvestigated heartburn and uninvestigated chronic dyspepsia. PMID- 28635002 TI - Impact of changing global political landscape on women's health priorities. PMID- 28635003 TI - Anchoring on Self and Others During Social Inferences. AB - When making inferences about similar others, people anchor and adjust away from themselves (Tamir & Mitchell, 2013). However, research on relational self theory (Andersen & Chen, 2002) suggests the possibility of using knowledge about others as an anchor when they are more similar to a target. We investigated whether social inferences are made on the basis of significant other knowledge through an anchoring and adjustment process, and whether anchoring on a significant other is more effortful than anchoring on the self. Participants answered questions about their likes and habits, as well as the likes and habits of a significant other, a target similar to their significant other, and a yoked control. We found that prediction differences between the significant other and similar target led to longer response times, and we found the opposite effect for self and target differences, suggesting anchoring and adjustment from the significant other rather than the self. These effects were moderated by the source-relative salience of the dimension being evaluated. The evidence was mixed with respect to the question of whether anchoring on a significant other is more effortful than anchoring on the self. PMID- 28635005 TI - The World Health Organization's Ninth Director-General: The Leadership of Tedros Adhanom. PMID- 28635004 TI - Observation period for changes in proteinuria and risk prediction of end-stage renal disease in general population. AB - AIM: Proteinuria is known to be an independent risk factor of end-stage renal disease (ESRD). But the associations between changes in dipstick proteinuria and the risk of ESRD in the general population and its appropriate observation period to predict incident ESRD are unknown. METHODS: We assessed the changes in dipstick proteinuria in 69 021 participants aged >=20 years who participated in health check-ups from 1993 and more than once until 1996 in Okinawa, Japan. Development of ESRD until 2011 was identified using dialysis registry. Cox proportional hazards model and receiver operating characteristic (ROC) curve were used. RESULTS: At baseline, proteinuria (+/-) and >=(1+) were observed in 2.4% and 1.2% of total subjects. 1.5% of subjects had decreased and 9.4% of subjects had increased their proteinuria level after 2 years. After adjustment for confounding factors, hazard ratios (95% confidence interval) of ESRD for subjects with proteinuria change <= - 1, +1, +2, +3, and +4 level during 2 years compared to subjects with no change were 0.89 (0.43-1.87), 3.18 (2.21-4.60), 8.01 (5.55 11.55), 11.17 (6.59-19.95), and 16.59 (5.95-46.25), respectively. Heterogeneity existed between changes in proteinuria level during 1 or 3 years and the risk of ESRD among baseline proteinuria. Area under the ROC curve (95%CI) to predict ESRD by increase in proteinuria level during 1, 2, and 3 years were 0.650 (0.623 0.679), 0.779 (0.751-0.808), and 0.778 (0.748-0.808), respectively. CONCLUSIONS: The changes in dipstick proteinuria were an independent predictor of ESRD in the general population. Changes in proteinuria over 2 years may be appropriate for the risk prediction of ESRD. PMID- 28635006 TI - The care burden and coping levels of chronic psychiatric patients' caregivers. AB - PURPOSE: This descriptive study was conducted in order to determine care burden of caregivers of chronic psychiatric patients and their levels of coping with stress. METHODS: The study was conducted with 134 caregivers of chronic psychiatric patients. The following data collection tools were used: the personal information form, the ZBI and SCI. The study participants were selected from the population by using an improbable random sampling method. RESULTS: The average age of the caregivers was 49.95+/-13.68 and the majority were married and primary school graduates. CONCLUSION: This study determined that caregivers experienced a high level of burden. However, while the deal with their difficulties of providing effective care was found to have more coping methods they use. PMID- 28635007 TI - The intricate anatomy of the periodontal ligament and its development: Lessons for periodontal regeneration. AB - The periodontal ligament (PDL) connects the tooth root and alveolar bone. It is an aligned fibrous network that is interposed between, and anchored to, both mineralized surfaces. Periodontal disease is common and reduces the ability of the PDL to act as a shock absorber, a barrier for pathogens and a sensor of mastication. Although disease progression can be stopped, current therapies do not primarily focus on tissue regeneration. Functional regeneration of PDL may be achieved using innovative techniques, such as tissue engineering. However, the complex fibrillar architecture of the PDL, essential to withstand high forces, makes PDL tissue engineering very challenging. This challenge may be met by studying PDL anatomy and development. Understanding PDL anatomy, development and maintenance provides clues regarding the specific events that need to be mimicked for the formation of this intricate tissue. Owing to the specific composition of the PDL, which develops by self-organization, a different approach than the typical combination of biomaterials, growth factors and regenerative cells is necessary for functional PDL engineering. Most specifically, the architecture of the new PDL to be formed does not need to be dictated by textured biomaterials but can emerge from the local mechanical loading conditions. Elastic hydrogels are optimal to fill the space properly between tooth and bone, may house cells and growth factors to enhance regeneration and allow self-optimization by the alignment to local stresses. We suggest that cells and materials should be placed in a proper mechanical environment to initiate a process of self-organization resulting in a functional architecture of the PDL. PMID- 28635008 TI - Assisted Reproductive Technology and Birth Defects: Effects of Subfertility and Multiple Births. AB - BACKGROUND: Assisted reproductive technology (ART) has been associated with birth defects, but the contributions of multiple births and underlying subfertility remain unclear. We evaluated the effects of subfertility and mediation by multiple births on associations between ART and nonchromosomal birth defects. METHODS: We identified a retrospective cohort of Massachusetts live births and stillbirths from 2004 to 2010 among ART-exposed, ART-unexposed subfertile, and fertile mothers using linked information from fertility clinics, vital records, hospital discharges, and birth defects surveillance. Log-binomial regression was used to estimate prevalence ratios and 95% confidence intervals (CIs). Mediation analyses were performed to deconstruct the ART-birth defects association into the direct effect of ART, the indirect effect of multiple births, and the effect of ART-multiples interaction. RESULTS: Of 17,829 ART-exposed births, 355 had a birth defect, compared with 162 of 9431 births to subfertile mothers and 6183 of 445,080 births to fertile mothers. The adjusted prevalence ratio was 1.5 (95% CI, 1.3-1.6) for ART and 1.3 (95% CI, 1.1-1.5) in subfertile compared with fertile deliveries. We observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects. CONCLUSION: Although the risk of birth defects with ART is small, a substantial portion of the relative effect is mediated through multiple births, with subfertility contributing an important role. Future research is needed to determine the impact of newer techniques, such as single embryo transfer, on these risks. Birth Defects Research 109:1144-1153, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28635009 TI - Female GADD34 mice develop age-related inflammation and hepatocellular carcinoma. AB - AIM: To analyze the impact of sex on GADD34 function, we studied the aging of female GADD34-deficient mice and compared them with male GADD34-deficient mice. METHODS: We used GADD34-deficient mice on a C57BL/6 background. These mice were fed a normal diet throughout their life. Alternatively, they were fed a high-fat diet at 3 months-of-age. Liver tissues taken from mice were analyzed by hematoxylin-eosin staining and immunohistochemical methods. Fresh liver cells were analyzed by flow cytometry. RESULTS: We found that female GADD34-deficient mice did not develop obesity or fatty livers. However, female GADD34-deficient mice had infiltrations of myeloid cells in the liver, followed by liver atrophy. Many female GADD34-deficient mice developed hepatocellular carcinoma, whereas female wild-type (WT) mice did not show hepatocellular carcinoma during aging. Female GADD34-deficient mice and female WT mice developed the same percentages of lymphoma. Although a high-fat diet induced a higher level of steatosis in young male GADD34-deficient mice compared with WT mice, a high-fat diet induced the same level of steatosis in young female GADD34-deficient mice compared with WT mice. However, GADD34-deficient female young mice had a higher level of infiltration of myeloid cells and myofibroblasts than WT mice. CONCLUSIONS: In contrast to male GADD34-deficient mice, female GADD34-deficient mice did not show obesity as they aged. However, similar to the males, they developed inflammation followed by hepatocellular carcinoma. Geriatr Gerontol Int 2017; 17: 2593-2601. PMID- 28635010 TI - A case of presumed autoimmune subepidermal blistering dermatosis treated with oclacitinib. AB - BACKGROUND: Autoimmune subepidermal blistering dermatoses (ASBD) are a group of severe autoimmune dermatoses rarely described in dogs. Their treatment usually necessitates the long term use of medications potentially associated with adverse effects. In humans, Janus Kinase (JAK) inhibitors have been demonstrated to be of value in some cases of autoimmune skin disease. HYPOTHESIS/OBJECTIVES: To evaluate oral oclacitinib, a JAK-1 predominant inhibitor, in one case of ASBD in a dog. CASE REPORT: A 5-year-old German shepherd cross-bred dog was presented with an acute onset of ulcerative and blistering skin lesions on the face, oral cavity, lateral trunk and limbs. Associated systemic signs were not seen. A clinical diagnosis of ASBD was supported by the finding of subepidermal clefts and visualization of the epidermal basement membrane zone at the bottom of the clefts on histopathological examination. Treatment was initiated with prednisolone at 1.2 mg/kg twice daily. Because of severe adverse effects and relapse, when the prednisolone dose was reduced, oclacitinib therapy was administered at 0.5 mg/kg twice a day. A complete resolution of clinical signs was noted after one month and no relapse was observed after twelve months of treatment. No adverse effects were reported. CONCLUSION: The use of oclacitinib may be useful for the treatment of some autoimmune skin diseases in dogs. Further controlled studies are needed to confirm our findings. PMID- 28635011 TI - Radiotherapy-assisted tumor selective metronomic oral chemotherapy. AB - Chemotherapy have commonly been used in maximum tolerated dose to completely eradicate the cancer. However, such treatments often failed due to the complex and dynamic nature of cancer. Therefore, it has been suggested that cancer should be treated as a chronic disease, controlling its growth by providing continuous therapeutic pressure for long-term. Such an approach, however, requires a therapy that is non-toxic and orally available with sufficient potency. Herein, we propose a radiotherapy-assisted orally available metronomic apoptosis-targeted chemotherapy, which delivers doxorubicin continuously to the irradiated tumor with high selectivity while causing minimal toxicities to the normal tissues. DEVD-S-DOX/DCK complex is the anticancer prodrug for our strategy that could selectively release doxorubicin in the irradiated tumor tissue with sufficient oral bioavailability. The prodrug was completely inactive by itself, but displayed potent anticancer activity when coupled with radiotherapy. Consequently, the daily oral administration of DEVD-S-DOX/DCK in combination with the low-dose radiotherapy effectively suppressed the growth of tumor in vivo with no significant systemic toxicities despite that the accumulated dose of doxorubicin exceeded 150 mg/kg. Therefore, the our novel therapy using DEVD-S DOX/DCK complex is considered as an outstanding treatment option for treating cancer for long-term attributed to its oral availability and low-toxicity profile as well as the potent anticancer effect. PMID- 28635012 TI - Keratitis-ichthyosis-deafness syndrome accompanied by disseminated cutaneous fungal infection. AB - Keratitis-ichthyosis-deafness (KID) syndrome is a rare genodermatosis. It is mostly associated with mutations of the connexin 26 gene, resulting in keratitis, erythrokeratoderma and neurosensory deafness. In addition to the clinical triad, the KID syndrome patients are at high risk for infectious complications, while the mechanisms are poorly understood. In the present article, we described an Asian case of KID syndrome accompanied by fungal infection. The present study was designed to define the mutation type, and further to explore the interaction between the innate immunity response and the infectious complication of KID syndrome. Genomic DNA was extracted from peripheral blood for mutation analysis. Isolation and identification of the species were carried out to confirm the infectious microorganism. Three biopsy specimens from different parts of the body (right thigh, abdomen and forehead, respectively) were carried out for histopathological and immunohistochemical analysis. Furthermore, quantitative polymerase chain reaction (PCR) was carried out to study the expression of Toll like receptor 2 (TLR2) on the epidermis of the right thigh. We identified a mutation (p.G12R) in the GJB2 gene in this patient with Trichophyton rubrum infection. Immunohistochemistry staining revealed a lower expression of TLR2 and no significant difference in TLR4. Meanwhile, PCR showed a relatively slight increase of TLR2 RNA expression. These results indicated that GJB2 mutation (p.G12R) in this case of KID syndrome, which was susceptible to T. rubrum infection, might be attributed to a limited native immune response. PMID- 28635013 TI - Demographic characteristics and pregnancy outcomes in adolescents - Experience from an Australian perinatal centre. AB - BACKGROUND: Adolescent pregnancy is defined as pregnancy in girls aged 10-19 years and can be associated with increased risks. AIM: To investigate obstetric and perinatal outcomes in a cohort of adolescent girls from a major Australian tertiary centre. MATERIALS AND METHODS: This was a nine-year retrospective cohort study of women who birthed at the Mater Mother's Hospital (MMH) in Brisbane, Australia between 1 January 2007 and 31 December 2015. The adolescent cohort was aged <19 years and the control group was aged 20-24 years. RESULTS: Over the study period the total study cohort comprised 8904 women. Of these, the adolescent cohort consisted of 1625 girls (18.2%) and the control group consisted of 7279 women (81.8%). Adolescents were more likely to be nulliparous, single, of Indigenous ethnicity or to have refugee status. They had higher rates of smoking, asthma, diabetes mellitus and thyroid disease. They were more likely to have an uncomplicated spontaneous vaginal delivery but were less likely to have an intact perineum and had higher rates of pre-term delivery and low birth weight babies. There were no differences in rates of postpartum haemorrhage. CONCLUSIONS: Teenage pregnancy results in poorer obstetric and perinatal outcomes. A focus on optimising maternal health care and providing culturally appropriate antenatal and intrapartum care is imperative to improving outcomes. PMID- 28635014 TI - Haemolysis during sodium dimercaptosulphonate therapy for Wilson's disease in G6PD-deficient patients: First report of two cases. AB - WHAT IS KNOWN AND OBJECTIVE: Wilson's disease (WD) is an inherited disorder in which defective biliary excretion of copper leads to its accumulation. Sodium dimercaptosulphonate (DMPS) is used as the primary therapy in China. CASE DESCRIPTION: We report two cases, with WD and G6PD deficiency, who developed haemolysis on treatment with DMPS, without any other known risk. After withdrawal of DMPS and administration of dexamethasone and packed red blood cells, the patients recovered. WHAT IS NEW AND CONCLUSION: Clinicians should keep in mind haemolysis as a potentially life-threatening side effect of DMPS in patients with G6PD. PMID- 28635015 TI - A retrospective analysis of the comparative effectiveness of smoking cessation medication among individuals with mental illness in community-based mental health and addictions treatment settings. AB - : WHAT IS KNOWN ON THE SUBJECT?: Persons with different mental illnesses smoke for reasons based on their particular diagnosis. As compared to those without, persons with mental illnesses are less able to quit smoking when using smoking cessation medications. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This paper shows that there may be differences in the ability to quit smoking between persons with different mental illness diagnoses. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Clinicians should be aware that persons with anxiety disorders may find it more difficult to quit smoking as compared to those with other mental illnesses. Clinicians should be aware that of all medications, varenicline seems to help those with mood disorders to quit the best. Clinicians should be aware that persons with psychotic disorders likely need longer treatment durations for smoking cessation as compared to persons with other mental illnesses. ABSTRACT: Introduction Individuals with mental illnesses (MI) have diagnosis-specific reasons for smoking and achieve low smoking cessation when using cessation medications. Aim To assess differences in smoking cessation outcomes by MI diagnosis and cessation medications in outpatient mental health and addictions treatment settings in Vancouver, Canada. Method This is a retrospective analysis of tobacco treatment outcomes from 539 participants. The programme consists of cessation pharmacotherapy with 8 to 12 weeks of behavioural counselling and 12 weeks of support group. Smoking cessation was verified by expired carbon monoxide levels. Generalized estimating equations models assessed differences in cessation by type of medication in both total and stratified samples. Results There were no significant differences in cessation by pharmacotherapy in the total sample. Individuals with a mood disorder were two times more likely to achieve cessation as compared to those with an anxiety disorder. Among individuals with mood disorders, receiving varenicline alone resulted in three times the likelihood of cessation as compared to receiving single NRT. Discussion The differences in outcomes by MI diagnosis suggest the need for more diagnosis-specific approaches to optimize cessation. Implications for Practice Compared with other diagnoses, persons with anxiety disorders may have a greater challenge quitting and those with a psychotic disorder may require longer treatment durations. PMID- 28635016 TI - Enucleation of solid pseudopapillary tumor with a preoperative nasopancreatic drainage stent in a child. AB - Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor with low-grade malignancy in children. A complete surgical resection can achieve a favorable prognosis. Although several reports have indicated that enucleation is considered a safe and effective treatment, the most significant complication is injury to the main pancreatic duct. The usefulness and safety of tumor enucleation after preoperative placement of an endoscopic nasopancreatic drainage stent (NPDS) has recently been reported. We present the case of SPT in a 10-year-old girl. To avoid and detect injury to the main pancreatic duct during operation, an NPDS was endoscopically placed before laparotomy. The patient underwent a complete enucleation of the tumor with the guidance of an NPDS. Our case is the first report of a successful enucleation of an SPT with a preoperative placement of an NPDS. This procedure may lead to safe enucleation of a pancreatic tumor with low malignancy, such as SPT, in children. PMID- 28635017 TI - Clinical features and outcomes in patients with thrombotic microangiopathy not associated with severe ADAMTS13 deficiency. AB - BACKGROUND: The a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 (ADAMTS13) activity assay has become important in distinguishing autoimmune thrombotic thrombocytopenic purpura from other forms of thrombotic microangiopathy (TMA). Although the significance of severe deficiency in ADAMTS13 (activity levels 10% or less) has been well defined, little data are available on the clinical importance of mild to moderate deficiency (activity levels 11%-70%) among patients with TMA. STUDY DESIGN AND METHODS: We conducted a retrospective study using the Harvard TMA Research Collaborative Registry. Among 254 patients who met the inclusion criteria for TMA, 186 patients with ADAMTS13 activity levels greater than 10% were divided into moderate-deficiency (11%-40%), mild-deficiency (41%-70%), and no-deficiency (greater than 70%). RESULTS: Compared with mild or no deficiency, moderate ADAMTS13 deficiency correlated with older age; higher bilirubin and international normalized ratio; and increased frequency of sepsis, shock, or multiorgan failure. Platelet counts, lactate dehydrogenase levels, and the presence of renal or neurologic dysfunction did not vary across the three patient cohorts. While moderate ADAMTS13 deficiency was associated with increased 90-day mortality in univariate analysis, this association was no longer significant in multivariate analysis. Variables that independetly predicted 90-day mortality in this cohort of patients included Charlson comorbidity index, alanine aminotransferase level, platelet count, creatinine, and the presence of sepsis, shock, or multiorgan failure. CONCLUSION: Moderately deficient ADAMTS13 activity identifies a cohort of patients with TMA who are at increased risk for 90-day mortality. The ADAMTS13 activity level in this group is not an independent predictor of poor outcomes but instead appears to be a marker of disease acuity. PMID- 28635018 TI - Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial. AB - BACKGROUND: Guselkumab, an anti-interleukin-23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials. OBJECTIVES: To evaluate the efficacy and safety of guselkumab in patients with moderate-to severe plaque psoriasis who had an inadequate response to ustekinumab. METHODS: In this phase III, randomized, double-blind study, 871 patients received open label ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to ustekinumab [Investigator's Global Assessment (IGA) >= 2] were randomized (double-blind) to guselkumab 100 mg or to continue ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open label ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two-grade improvement (from week 16) from week 28 to week 40. Improvement >= 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed. RESULTS: The mean number of visits at which patients achieved IGA 0/1 and at least a two-grade improvemen (week 28-40) was significantly greater in the guselkumab group vs. the randomized ustekinumab group (1.5 vs. 0.7; P < 0.001); greater proportions of patients in the guselkumab group achieved IGA 0/1 and at least a two-grade improvement at week 28 (31.1% vs. 14.3%; P = 0.001) and week 52 (36.3% vs. 17.3%; P < 0.001). Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52. After week 16, 64.4% of patients in the guselkumab group and 55.6% in the ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type. Overall, 6.7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4.5% (n = 6) for the ustekinumab group. CONCLUSIONS: Patients treated with ustekinumab who did not achieve an IGA of 0/1 by week 16 derived significant benefit from switching to guselkumab. PMID- 28635019 TI - Highly Stretchable, Shape Memory Organohydrogels Using Phase-Transition Microinclusions. AB - Shape memory effect in polymer materials has attracted considerable attention due to its promising applications in a variety of fields. However, shape memory polymers prepared by conventional strategy suffer from a common problem, in which high strain capacity and excellent shape memory behavior cannot be simultaneously achieved. This study reports a general and synergistic strategy to fabricate high strain and tough shape memory organohydrogels that feature binary cooperative phase. The phase- transition micro-organogels and elastic hydrogel framework act synergistically to provide excellent thermomechanical performance and shape memory effect. During shape memory process, the organohydrogels exhibit high strain capacity, featuring fully recoverable stretching deformation by up to 2600% and compression by up to 85% beneath a load ~20 times the organohydrogel's weight. Furthermore, owing to the micro-organogel and hydrogel heterostructures, the interfacial tension derived from heterophases dominates the shape recovery of the organohydrogel material. Simple processing and smart surface patterning of the shape memory behavior and multiple shape memory effects can also be realized. Meanwhile, these organohydrogels are also nonswellable in water and oil, which is important for multimedia applications. PMID- 28635020 TI - Fentanyl novel derivative-related deaths. AB - OBJECTIVE: Fentanyl (FEN) is a potent, synthetic narcotic used as an anaesthetic and a pain reliever, but also illegally manufactured. For diversion purpose, it is being steadily modified to produce new analogous compounds and derivatives (FENS), categorised as novel psychoactive substances. While potential FEN abuse is already known, even in the absence of a clear lethal dosage, there is still a shortage of data on its derivatives. METHODS: A literature review of FENS-related deaths was performed, to better understand potential damage and future perspectives of FEN congeners. RESULTS: Epidemiological data, pathological findings, administration routes, average concentrations and lethal doses, toxicological issues, trends in misuses, comparison among FENS, and possible explanation for FENS abuse are reviewed and discussed in depth. CONCLUSIONS: This study provides a medical-legal and toxicological assessment of this phenomenon in order to understand the role of illegal fentanyl and its congeners in deaths from FENS overdose. PMID- 28635021 TI - The object of my aggression: Sexual objectification increases physical aggression toward women. AB - Objectification involves reducing someone to a sexual object, rather than seeing them as a full person. Despite numerous theoretical claims that people are more aggressive toward the objectified, and empirical evidence that objectification is linked to high willingness to aggress, rape proclivity, and aggressive attitudes, no research has examined a causal link between objectification and physical aggression, particularly in the context of provocation. In two experiments, we examined this predicted link. In Experiment 1, using a 2 (objectification: no/yes) * 2 (provocation: no/yes) factorial between-subjects design, we investigated the effects of objectification, induced via body focus during a face to-face interaction, and provocation on physical aggression toward a female confederate. Our results revealed a significant main effect of provocation, a marginal main effect of objectification, and a significant interaction between these variables. In the absence of a provocation, focusing on a woman's body increased aggression toward her. Experiment 2 replicated Experiment 1 using a video of a target woman instead of a face-to-face interaction. Again, our results showed a significant two-way interaction between objectification and provocation, wherein objectification increased aggression in the absence of provocation. Overall, this research indicates that objectification can lead to heightened physical aggression toward objectified women. PMID- 28635022 TI - Food culture of faith communities and potential impact on childhood obesity. AB - OBJECTIVE: To explore the food culture within faith communities (FC) in order to examine the consumption of away-from-home foods, and to provide an evidence base for the future development of healthy away-from-home meal initiatives though FCs. DESIGN AND SAMPLE: A qualitative descriptive design informed by an ethnographic method of free listing was utilized. A purposive sample of 34 FC leaders from seven distinct FCs participated in this study. RESULTS: The top five salience scores for five research questions are considered in detail. Of note, food is provided at multiple FC events including at worship time and Bible or group study, but also as part of school, youth programming, and special events. The purposes of serving food were reported to be not only for modes of entertainment and fellowship but also for promoting attendance and providing basic nutrition needs. CONCLUSIONS: Professionals practicing in public health, faith community nursing, or in community health nursing are apt to engage in focused dialogues regarding the multidimensional health problem of childhood obesity. This research study directs nurses to consider food culture as a dimension of importance, especially within FCs. Appreciating FC food culture is important because many families engage in the settings for years, decades, and possibly a life span. PMID- 28635023 TI - Risk stratification of patients with left atrial appendage thrombus prior to catheter ablation of atrial fibrillation: An approach towards an individualized use of transesophageal echocardiography. AB - INTRODUCTION: The need for transesophageal echocardiography (TEE) before catheter ablation of atrial fibrillation (CA-AF) is still being questioned. The aim of this study is to analyze patients' (patients) risk factors of left atrial appendage thrombus (LAAT) prior to CA-AF in daily clinical practice, according to oral anticoagulation (OAC) strategies recommended by current guidelines. METHODS AND RESULTS: All patients scheduled for CA-AF from 01/2015 to 12/2016 in our center were included and either treated with NOACs (novel-OAC; paused 24-hours preablation) or continuous vitamin K antagonists (INR 2.0-3.0). All patients received a preprocedural TEE at the day of ablation. Two groups were defined: (1) patients without LAAT, (2) patients with LAAT. The incidence of LAAT was 0.78% (13 of 1,658 patients). No LAAT was detected in patients with a CHA2 DS2 -VASc score of <=1 (n = 640 patients) irrespective of the underlying AF type. Independent predictors for LAAT are: higher CHA2 DS2 -VASc scores (odds ratio [OR] 1.54, 95%-confidence interval [CI]: 1.07-2.23, P = 0.0019), a history of nonparoxysmal AF (OR 7.96, 95%-CI: 1.52-146.64, P = 0.049), hypertrophic cardiomyopathy (HCM; OR 9.63, 95% CI: 1.36-43.05, P = 0.007), and a left ventricular ejection fraction (LVEF) < 30% (OR 8.32, 95% CI: 1.18-36.29, P = 0.011). The type of OAC was not predictive (P = 0.70). CONCLUSIONS: The incidence of LAAT in patients scheduled for CA-AF is low. Therefore, periprocedural OAC strategies recommended by current guidelines seem feasible. Preprocedural TEE may be dispensed in patients with a CHA2 DS2 -VASc score <=1. However, a CHA2 DS2 VASc score >=2, reduced LVEF, HCM, or history of nonparoxysmal AF are independently associated with an increased risk for LAAT. PMID- 28635024 TI - A small molecule activator of Nav 1.1 channels increases fast-spiking interneuron excitability and GABAergic transmission in vitro and has anti-convulsive effects in vivo. AB - Nav 1.1 (SCN1A) channels primarily located in gamma-aminobutyric acid (GABA)ergic fast-spiking interneurons are pivotal for action potential generation and propagation in these neurons. Inappropriate function of fast-spiking interneurons, leading to disinhibition of pyramidal cells and network desynchronization, correlates with decreased cognitive capability. Further, reduced functionality of Nav 1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Nav 1.1 channels available for studying pharmacological modulation of interneuron function. In the current study, we identified a small molecule Nav 1.1 activator, 3-amino-5-(4 methoxyphenyl)thiophene-2-carboxamide, named AA43279, and provided an in vitro to in vivo characterization of the compound. In HEK-293 cells expressing human Nav 1.1 channels, AA43279 increased the Nav 1.1-mediated current in a concentration dependent manner mainly by impairing the fast inactivation kinetics of the channels. In rat hippocampal brain slices, AA43279 increased the firing activity of parvalbumin-expressing, fast-spiking GABAergic interneurons and increased the spontaneous inhibitory post-synaptic currents (sIPSCs) recorded from pyramidal neurons. When tested in vivo, AA43279 had anti-convulsive properties in the maximal electroshock seizure threshold test. AA43279 was tested for off-target effects on 72 different proteins, including Nav 1.2, Nav 1.4, Nav 1.5, Nav 1.6 and Nav 1.7 and exhibited reasonable selectivity. Taken together, AA43279 might constitute a valuable tool compound for revealing biological functions of Nav 1.1 channels. PMID- 28635025 TI - Arabidopsis WRKY2 and WRKY34 transcription factors interact with VQ20 protein to modulate pollen development and function. AB - Plant male gametogenesis is tightly regulated, and involves complex and precise regulations of transcriptional reprogramming. WRKY transcription factors have been demonstrated to play critical roles in plant development and stress responses. Several members of this family physically interact with VQ motif containing proteins (VQ proteins) to mediate a plethora of programs in Arabidopsis; however, the involvement of WRKY-VQ complexes in plant male gametogenesis remains largely unknown. In this study, we found that WRKY2 and WKRY34 interact with VQ20 both in vitro and in vivo. Further experiments displayed that the conserved VQ motif of VQ20 is responsible for their physical interactions. The VQ20 protein localizes in the nucleus and specifically expresses in pollens. Phenotypic analysis showed that WRKY2, WRKY34 and VQ20 are crucial for pollen development and function. Mutations of WRKY2, WRKY34 and VQ20 simultaneously resulted in male sterility, with defects in pollen development, germination and tube growth. Further investigation revealed that VQ20 affects the transcriptional functions of its interacting WRKY partners. Complementation evidence supported that the VQ motif of VQ20 is essential for pollen development, as a mutant form of VQ20 in which LVQK residues in the VQ motif were replaced by EDLE did not rescue the phenotype of the w2-1 w34-1 vq20-1 triple-mutant plants. Further expression analysis indicated that WRKY2, WRKY34 and VQ20 co-modulate multiple genes involved in pollen development, germination and tube growth. Taken together, our study provides evidence that VQ20 acts as a key partner of WRKY2 and WKRY34 in plant male gametogenesis. PMID- 28635026 TI - Efficacy and safety of ixekizumab treatment in Japanese patients with moderate-to severe plaque psoriasis: Subgroup analysis of a placebo-controlled, phase 3 study (UNCOVER-1). AB - The present study describes a subgroup analysis of 33 Japanese patients participating in UNCOVER-1, an international, placebo-controlled, phase 3 study of ixekizumab in patients with moderate-to-severe psoriasis. Patients were randomized to a placebo (n = 13) or ixekizumab 80 mg every 4 (IXEQ4W, n = 12) or 2 (IXEQ2W, n = 8) weeks, from week 0-12. At week 12, ixekizumab-treated patients with a static Physician Global Assessment score 0 or 1 (sPGA [0,1]; n = 16) were re-randomized to a placebo (n = 6), ixekizumab 80 mg every 12 (IXEQ12W, n = 5) or 4 (IXEQ4W, n = 5) weeks, from week 12-60. At week 12, more ixekizumab-treated versus placebo-treated patients achieved sPGA (0,1) (>=66.7% vs 0%), >=75% improvement in Psoriasis Area and Severity Index (>=75% vs 0%), and sPGA (0) or 100% improvement in Psoriasis Area and Severity Index (both >=33.3% vs 0%), with improved symptoms and quality of life. At week 60, 100% (IXEQ4W), 40.0% (IXEQ12W) and 16.7% (placebo) had maintained sPGA (0,1). From week 0-12, treatment-emergent adverse events were 76.9% (placebo), 75.0% (IXEQ4W) and 87.5% (IXEQ2W), and from week 12-60 were 66.7% (placebo) and 100% (IXEQ12W, IXEQ4W). Ixekizumab-treated patients had no severe treatment-emergent adverse events, and one serious TEAE (IXEQ4W); infection was the most frequent treatment-emergent adverse event. In conclusion, ixekizumab for 60 weeks was effective and safe for Japanese patients with moderate-to-severe psoriasis, in line with the overall findings from UNCOVER 1. PMID- 28635027 TI - Towards the use of bioresorbable fibers in time-domain diffuse optics. AB - In the last years bioresorbable materials are gaining increasing interest for building implantable optical components for medical devices. In this work we show the fabrication of bioresorbable optical fibers designed for diffuse optics applications, featuring large core diameter (up to 200 MUm) and numerical aperture (0.17) to maximize the collection efficiency of diffused light. We demonstrate the suitability of bioresorbable fibers for time-domain diffuse optical spectroscopy firstly checking the intrinsic performances of the setup by acquiring the instrument response function. We then validate on phantoms the use of bioresorbable fibers by applying the MEDPHOT protocol to assess the performance of the system in measuring optical properties (namely, absorption and scattering coefficients) of homogeneous media. Further, we show an ex-vivo validation on a chicken breast by measuring the absorption and scattering spectra in the 500-1100 nm range using interstitially inserted bioresorbable fibers. This work represents a step toward a new way to look inside the body using optical fibers that can be implanted in patients. These fibers could be useful either for diagnostic (e. g. for monitoring the evolution after surgical interventions) or treatment (e. g. photodynamic therapy) purposes. Picture: Microscopy image of the 100 MUm core bioresorbable fiber. PMID- 28635028 TI - Gases for establishing pneumoperitoneum during laparoscopic abdominal surgery. AB - BACKGROUND: This is an update of the review published in 2013.Laparoscopic surgery is now widely performed to treat various abdominal diseases. Currently, carbon dioxide is the most frequently used gas for insufflation of the abdominal cavity (pneumoperitoneum). Although carbon dioxide meets most of the requirements for pneumoperitoneum, the absorption of carbon dioxide may be associated with adverse events. People with high anaesthetic risk are more likely to experience cardiopulmonary complications and adverse events, for example hypercapnia and acidosis, which has to be avoided by hyperventilation. Therefore, other gases have been introduced as alternatives to carbon dioxide for establishing pneumoperitoneum. OBJECTIVES: To assess the safety, benefits, and harms of different gases (i.e. carbon dioxide, helium, argon, nitrogen, nitrous oxide, and room air) used for establishing pneumoperitoneum in participants undergoing laparoscopic general abdominal or gynaecological pelvic surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 9), Ovid MEDLINE (1950 to September 2016), Ovid Embase (1974 to September 2016), Science Citation Index Expanded (1970 to September 2016), Chinese Biomedical Literature Database (CBM) (1978 to September 2016), ClinicalTrials.gov (September 2016), and World Health Organization International Clinical Trials Registry Platform (September 2016). SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing different gases for establishing pneumoperitoneum in participants (irrespective of age, sex, or race) undergoing laparoscopic abdominal or gynaecological pelvic surgery under general anaesthesia. DATA COLLECTION AND ANALYSIS: Two review authors identified the trials for inclusion, collected the data, and assessed the risk of bias independently. We performed the meta-analyses using Review Manager 5. We calculated risk ratio (RR) for dichotomous outcomes (or Peto odds ratio for very rare outcomes), and mean difference (MD) or standardised mean difference (SMD) for continuous outcomes with 95% confidence intervals (CI). We used GRADE to rate the quality of evidence, MAIN RESULTS: We included nine RCTs, randomising 519 participants, comparing different gases for establishing pneumoperitoneum: nitrous oxide (three trials), helium (five trials), or room air (one trial) was compared to carbon dioxide. Three trials randomised participants to nitrous oxide pneumoperitoneum (100 participants) or carbon dioxide pneumoperitoneum (96 participants). None of the trials was at low risk of bias. There was insufficient evidence to determine the effects of nitrous oxide and carbon dioxide on cardiopulmonary complications (RR 2.00, 95% CI 0.38 to 10.43; two studies; 140 participants; very low quality of evidence), or surgical morbidity (RR 1.01, 95% CI 0.18 to 5.71; two studies; 143 participants; very low quality of evidence). There were no serious adverse events related to either nitrous oxide or carbon dioxide pneumoperitoneum (three studies; 196 participants; very low quality of evidence). We could not combine data from two trials (140 participants) which individually showed lower pain scores (a difference of about one visual analogue score on a scale of 1 to 10 with lower numbers indicating less pain) with nitrous oxide pneumoperitoneum at various time points on the first postoperative day, and this was rated asvery low quality .Four trials randomised participants to helium pneumoperitoneum (69 participants) or carbon dioxide pneumoperitoneum (75 participants) and one trial involving 33 participants did not state the number of participants in each group. None of the trials was at low risk of bias. There was insufficient evidence to determine the effects of helium or carbon dioxide on cardiopulmonary complications (RR 1.46, 95% CI 0.35 to 6.12; three studies; 128 participants; very low quality of evidence) or pain scores (visual analogue score on a scale of 1 to 10 with lower numbers indicating less pain; MD 0.49 cm, 95% CI -0.28 to 1.26; two studies; 108 participants; very low quality of evidence). There were three serious adverse events (subcutaneous emphysema) related to helium pneumoperitoneum (three studies; 128 participants; very low quality of evidence).One trial randomised participants to room air pneumoperitoneum (70 participants) or carbon dioxide pneumoperitoneum (76 participants). The trial was at unclear risk of bias. There were no cardiopulmonary complications or serious adverse events observed related to either room air or carbon dioxide pneumoperitoneum (both outcomes very low quality of evidence). The evidence of lower hospital costs and reduced pain during the first postoperative day with room air pneumoperitoneum compared with carbon dioxide pneumoperitoneum (a difference of about one visual analogue score on a scale of 1 to 10 with lower numbers indicating less pain, was rated as very low quality of evidence. AUTHORS' CONCLUSIONS: The quality of the current evidence is very low. The effects of nitrous oxide and helium pneumoperitoneum compared with carbon dioxide pneumoperitoneum are uncertain. Evidence from one trial of small sample size suggests that room air pneumoperitoneum may decrease hospital costs in people undergoing laparoscopic abdominal surgery. The safety of nitrous oxide, helium, and room air pneumoperitoneum has yet to be established.Further trials on this topic are needed, and should compare various gases (i.e. nitrous oxide, helium, argon, nitrogen, and room air) with carbon dioxide under standard pressure pneumoperitoneum with cold gas insufflation for people with high anaesthetic risk. Future trials should include outcomes such as complications, serious adverse events, quality of life, and pain. PMID- 28635029 TI - Coping With Racism: Moderators of the Discrimination-Adjustment Link Among Mexican-Origin Adolescents. AB - What strategies help ethnic minority adolescents to cope with racism? The present study addressed this question by testing the role of ethnic identity, social support, and anger expression and suppression as moderators of the discrimination adjustment link among 269 Mexican-origin adolescents (Mage = 14.1 years), 12-17 years old from the Midwestern U.S. Results from multilevel moderation analyses indicated that ethnic identity, social support, and anger suppression, respectively, significantly attenuated the relations between discrimination and adjustment problems, whereas outward anger expression exacerbated these relations. Moderation effects differed according to the level of analysis. By identifying effective coping strategies in the discrimination-adjustment link at specific levels of analysis, the present findings can guide future intervention efforts for Latino youth. PMID- 28635030 TI - Plasticity of thermoregulatory behavior in leopard geckos (Eublepharis macularius, Blyth 1954). AB - Studies on thermoregulation in nocturnal lizards have shown that their thermal regimes are similar to those of diurnal lizards, even though they hide during the daytime and are active mostly at night, when heat sources are very scarce. As a result, nocturnal lizards display an active thermoregulatory behavior consisting of seeking warm shelters to hide during the daytime, using accumulated heat for the nocturnal activity. Based on this information, we hypothesize that when leopard geckos (Eublepharis macularius, Blyth 1954) are presented with the choice of safety in cool shelters or vulnerability in heated open areas, suitable temperature will prevail in importance, i.e. they will trade the advantages provided by the shelter for an exposed, but physiologically necessary heat source. Data on the time juvenile E. macularius spent in shelters, and in open areas along a thermal gradient and under a 12/12 hr photoperiod, from eight individuals confirmed our hypothesis. We found that, not only did they select heat sources over shelters, but, along with the light/dark cycle, temperature may also represent a cue for activity. Additionally we found that substrate moisture plays an important role in shelter preference. PMID- 28635031 TI - Finding the disorder in binge eating disorder. PMID- 28635032 TI - Amino-Functionalized ZIF-7 Nanocrystals: Improved Intrinsic Separation Ability and Interfacial Compatibility in Mixed-Matrix Membranes for CO2 /CH4 Separation. AB - Highly permeable and selective, as well as plasticization-resistant membranes are desired as promising alternatives for cost- and energy-effective CO2 separation. Here, robust mixed-matrix membranes based on an amino-functionalized zeolitic imidazolate framework ZIF-7 (ZIF-7-NH2 ) and crosslinked poly(ethylene oxide) rubbery polymer are successfully fabricated with filler loadings up to 36 wt%. The ZIF-7-NH2 materials synthesized from in situ substitution of 2 aminobenzimidazole into the ZIF-7 structure exhibit enlarged aperture size compared with monoligand ZIF-7. The intrinsic separation ability for CO2 /CH4 on ZIF-7-NH2 is remarkably enhanced as a result of improved CO2 uptake capacity and diffusion selectivity. The incorporation of ZIF-7-NH2 fillers simultaneously makes the neat polymer more permeable and more selective, surpassing the state-of the-art 2008 Robeson upper bound. The chelating effect between metal (zinc) nodes of fillers and ester groups of a polymer provides good bonding, enhancing the mechanical strength and plasticization resistance of the neat polymer membrane. The developed novel ZIF-7 structure with amino-function and the resulting nanocomposite membranes are very attractive for applications like natural-gas sweetening or biogas purification. PMID- 28635033 TI - Effects of Copaiba Oil Topical Administration on Oral Wound Healing. AB - The effects of topical copaiba oil extract and topical corticosteroid were assessed on oral wound healing in an in vivo model using 96 male Wistar rats. Traumatic ulcers were caused in the dorsum of the tongue using a 3-mm punch tool. The animals were divided into: Control; Corticosteroid; Placebo and Copaiba oil Group. The animals received two daily applications of the products. The control group received only daily handling. Six rats in each group were euthanized at days 3, 5, 10 and 14. The animals were monitored daily to determine wound status. The weigh was assessed at day 0 and euthanasia day. The percentage of repair was calculated, and histopathological aspects were analyzed. The Kruskal-Wallis test was used to compare the results between groups and times of evaluation. Closing time was assessed through the log-rank test. The corticosteroid group lost more weight at days 10 and 14 than the control group (p < 0.05). Moreover, the healing time of corticosteroid group was longer than the control group (p = 0.007). No differences were observed between the copaiba oil group and the control group. We concluded that topical copaiba oil, in spite of being safe, did not accelerate the process of oral wound healing. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28635034 TI - Modular transmit/receive arrays using very-high permittivity dielectric resonator antennas. AB - PURPOSE: Dielectric resonator antenna (DRAs) are compact structures that exhibit low coupling between adjacent elements and therefore can be used as MRI transmit arrays. In this study, we use very high permittivity materials to construct modular flexible transceive arrays of a variable numbers of elements for operation at 7T. METHODS: DRAs were constructed using rectangular blocks of ceramic (lead zirconate titanate, epsilonr = 1070) with the transverse electric (TE)01 mode tuned to 298 MHz. Finite-difference time-domain simulations were used to determine the B1 and specific absorption rate distributions. B1+ maps were acquired in a phantom to validate the simulations. Performance was compared to an equally sized surface coil. In vivo images were acquired of the wrist (four elements), ankle (seven elements), and calf muscle (16 elements). RESULTS: Coupling between DRAs spaced 5 mm apart on a phantom was -18.2 dB compared to 9.1 dB for equivalently spaced surface coils. DRAs showed a higher B1+ intensity close to the antenna but a lower penetration depth compared to the surface coil. CONCLUSION: DRAs show very low coupling compared to equally sized surface coils and can be used in transceive arrays without requiring decoupling networks. The penetration depth of the current DRA geometry means they are ideally suited to imaging of extremities. Magn Reson Med 79:1781-1788, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 28635035 TI - Effect of Selective CF3 Substitution on the Physical and Chemical Properties of Gold Corroles. AB - Gold corroles are not readily accessible and they display no interesting physical or chemical properties. A facile methodology has now been developed for obtaining selectively CF3 -substituted gold(III) corroles and the introduction of these groups has been found to have an immense effect on the structures of the complexes, their photophysical and redox properties, and on their ability to participate in catalytic processes. PMID- 28635036 TI - Time-driven activity-based costing to estimate cost of care at multidisciplinary aerodigestive centers. AB - OBJECTIVES/HYPOTHESIS: Providing high-value healthcare to patients is increasingly becoming an objective for providers including those at multidisciplinary aerodigestive centers. Measuring value has two components: 1) identify relevant health outcomes and 2) determine relevant treatment costs. Via their inherent structure, multidisciplinary care units consolidate care for complex patients. However, their potential impact on decreasing healthcare costs is less clear. The goal of this study was to estimate the potential cost savings of treating patients with laryngeal clefts at multidisciplinary aerodigestive centers. STUDY DESIGN: Retrospective chart review. METHODS: Time-driven activity based costing was used to estimate the cost of care for patients with laryngeal cleft seen between 2008 and 2013 at the Massachusetts Eye and Ear Infirmary Pediatric Aerodigestive Center. Retrospective chart review was performed to identify clinic utilization by patients as well as patient diet outcomes after treatment. Patients were stratified into neurologically complex and neurologically noncomplex groups. RESULTS: The cost of care for patients requiring surgical intervention was five and three times as expensive of the cost of care for patients not requiring surgery for neurologically noncomplex and complex patients, respectively. Following treatment, 50% and 55% of complex and noncomplex patients returned to normal diet, whereas 83% and 87% of patients experienced improved diets, respectively. Additionally, multidisciplinary team based care for children with laryngeal clefts potentially achieves 20% to 40% cost savings. CONCLUSIONS: These findings demonstrate how time-driven activity based costing can be used to estimate and compare patient costs in multidisciplinary aerodigestive centers. LEVEL OF EVIDENCE: 2c. Laryngoscope, 127:2152-2158, 2017. PMID- 28635037 TI - Novel role and regulation of HDAC4 in cocaine-related behaviors. AB - Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction-related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)-key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm-a process controlled in large part by changes in phosphorylation of conserved residues. Cocaine triggers a transient nuclear accumulation of HDAC5 that functions to limit the development of cocaine reward behavior. However, the role and regulation of the close family member, HDAC4, in cocaine behaviors remain largely unknown. In this study, we report that cocaine and cAMP signaling in striatum produced differential phosphorylation and subcellular localization of HDAC4 and HDAC5. Unlike HDAC5, cocaine exposure induced a modest hyperphosphorylation and nuclear export of HDAC4. Genetic deletion of HDAC4 in the nucleus accumbens reduced acute cocaine-produced locomotion, maximum locomotor sensitization and cocaine reward-related behavior. Interestingly, overexpression of an HDAC4 cytoplasm-concentrated mutant (S266E) increased cocaine reward behavior in the cocaine conditioned place preference assay, suggesting that cocaine-induced nuclear export of HDAC4 might function to facilitate the development of cocaine reward behaviors through a role in the cell cytoplasm. Together, our findings suggest that, despite high sequence homology, HDAC4 and HDAC5 are oppositely regulated by cocaine-induced signaling in vivo and have distinct roles in regulating cocaine behaviors. PMID- 28635038 TI - Trifluoromethyl- and Fluoroalkylselenolations of Alkynyl Copper(I) Compounds. AB - The successful perfluoroalkylselenolation of alkynyl copper(I) compounds is described herein. The reaction occurs under oxidant free conditions at room temperature. This convenient one-pot procedure is based on the in situ generation of trifluoromethylselenyl chlorides. The developed system shows high functional group tolerance and also promotes the employment of fluoroalkyl derivatives. PMID- 28635039 TI - Rational Design of Na(Li1/3 Mn2/3 )O2 Operated by Anionic Redox Reactions for Advanced Sodium-Ion Batteries. AB - In an effort to develop high-energy-density cathodes for sodium-ion batteries (SIBs), low-cost, high capacity Na(Li1/3 Mn2/3 )O2 is discovered, which utilizes the labile O 2p-electron for charge compensation during the intercalation process, inspired by Li2 MnO3 redox reactions. Na(Li1/3 Mn2/3 )O2 is systematically designed by first-principles calculations considering the Li/Na mixing enthalpy based on the site preference of Na in the Li sites of Li2 MnO3 . Using the anionic redox reaction (O2- /O- ), this Mn-oxide is predicted to show high redox potentials (~4.2 V vs Na/Na+ ) with high charge capacity (190 mAh g-1 ). Predicted cathode performance is validated by experimental synthesis, characterization, and cyclic performance studies. Through a fundamental understanding of the redox reaction mechanism in Li2 MnO3 , Na(Li1/3 Mn2/3 )O2 is designed as an example of a new class of promising cathode materials, Na(Li1/3 M2/3 )O2 (M: transition metals featuring stabilized M4+ ), for further advances in SIBs. PMID- 28635040 TI - Verbal communication of families with cancer patients at end of life: A questionnaire survey with bereaved family members. AB - OBJECTIVE: To clarify the verbal communication of feelings between families and patients in Japanese palliative care units from the perspective of bereaved family members by examining (1) proportions of families' and patients' verbalization of six feelings (gratitude, love, seeking forgiveness, giving forgiveness, wishes after death, and continuing bonds), (2) recognition of receiving these feelings through verbalization from the family's perspective, and (3) the specific attitudes of family members that influence their verbalizations. METHODS: In 2010, a cross-sectional survey was conducted with 968 bereaved families of cancer patients in palliative care units across Japan. RESULTS: Five hundred thirty-seven responses were analyzed. (1) "Gratitude" was verbalized most often (families: 47%; patients: 61%), and "expressing forgiveness" least often (families: 16%; patients: 11%). (2) Even if the words were not used, 81.2% to 88.2% of families answered that they had received the patient's feelings, and 71.8% to 85.4% of families felt the patient had received their feelings. (3) Multiple logistic regression analyses indicated that the strongest attitudes determining verbalizing were "not wanting to say farewell without conveying feelings," "a daily basis of expressing," and "heart-to-heart communication" (ishin-denshin). CONCLUSIONS: For both families and patients, verbalizing feelings was difficult. Our results showed that families' and patients' verbalizing and receiving of feelings must be aligned to understand their communication at the end of life in Japan. Future research is needed to verify how attitude helps promote or inhibit verbalization. PMID- 28635041 TI - Neuro-Protective Effects of Resveratrol on Carbon Monoxide-Induced Toxicity in Male Rats. AB - Acute carbon monoxide (CO) poisoning causes neurotoxicity through induction of necrosis, apoptosis, lipid peroxidation and oxidative stress. Resveratrol (RES) is a natural polyphenolic phytoalexin that exhibits neuroprotective effects in ischemia/reperfusion due to its anti-apoptotic, anti-necrotic and strong anti oxidant properties as well as its ability to activate pro-survival pathways. In this study, rats were exposed to CO 3000 ppm for 1 h. Immediately after poisoning and on the next four consecutive days, RES (1, 5 and 10 mg/kg) was administered intraperitoneally. On the fifth day, animals' brains were excised, and necrosis, lipid peroxidation level and the level of Akt, BAX and BCL2 expression were evaluated. The results showed that RES 10 mg/kg significantly reduced lipid peroxidation, but RES 1 and 5 mg/kg had no significant effect on this parameter. Furthermore, RES 5 and 10 mg/kg significantly increased Akt expression level, while BAX/BCL2 ratio was reduced by RES 1, 5 and 10 mg/kg. Moreover, RES reduced necrotic foci in the brain, but the best results were seen following treatment with RES 10 mg/kg. In summary, RES showed neuroprotective effect in CO-poisoned rats as it decreased necrosis and BAX/BCL2 ratio and increased Akt expression levels. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28635042 TI - Palpation for pressure ulcers: examining the bony prominence and physical properties of the wound. PMID- 28635043 TI - Live imaging of X chromosome inactivation and reactivation dynamics. AB - The epigenetic phenomenon called X chromosome inactivation plays critical roles in female development in eutherian mammals, and has attracted attention in the fields of developmental biology and regenerative biology in efforts to understand the pluripotency of stem cells. X chromosome inactivation is routinely studied after cell fixation, but live imaging is increasingly being required to improve our understanding of the dynamics and kinetics of X chromosome inactivation and reactivation processes. Here, we describe our live imaging method to monitor the epigenetic status of X chromosomes using a gene knock-in mouse strain named "Momiji" and give an overview of the application of this strain as a resource for biological and stem cell research. PMID- 28635044 TI - Experience and psychological impact of anal cancer screening in gay, bisexual and other men who have sex with men: a qualitative study. AB - OBJECTIVE: Human papillomavirus-related anal cancer rates are increasing and are particularly high in gay, bisexual and other men who have sex with men (GBM/MSM), especially HIV-positive individuals. Although screening programs for high-risk populations have been advocated, concerns about possible adverse psychological consequences exist. This study aimed to investigate GBM/MSM's experience, understanding and emotional response to screening techniques for anal cancer to determine how best to minimise psychological distress in future programs. METHODS: In-depth qualitative face-to-face interviews were conducted with 21 GBM/MSM participating in the "Study of the Prevention of Anal Cancer" in Sydney, Australia, between June 2013 and June 2014. Nonrandom, purposive sampling was used to ensure heterogeneity with respect to HIV status and screening test results. Framework analysis method was used to organise the data and identify emerging themes. RESULTS: Knowledge about anal cancer, human papillomavirus and the link between them was limited. Abnormal screening results affected participants' sense of well-being and were associated with anxiety and concern about developing anal cancer. HIV-negative men receiving abnormal results showed higher levels of distress compared to their HIV-positive counterparts. Consultations with general practitioners about abnormal results had an important role in increasing participants' understanding and in moderating their anxiety. CONCLUSION: Anal cancer screening should be accompanied by health education around anal cancer, its aetiology and the meaning of associated test results. Simple and effective communication strategies should be encouraged. Collaboration with general practitioners could assist the process of education and reporting test results. PMID- 28635045 TI - Management of alopecia areata: Updates and algorithmic approach. AB - Alopecia areata is a chronic, recurrent and non-scarring alopecia. The prognoses of patients are very diverse. The larger the area of hair loss, the poorer the treatment response and greater the probability of chronic disease progression. Numerous treatments have been introduced, but curative treatments have yet to be established. The long-term efficacy of the current treatments is minimal, and the therapeutic response varies widely. Recent clinical trials have attempted to apply therapeutic metrics, such as the Severity of Alopecia Tool, and many have been designed as randomized controlled studies, enabling a more precise evaluation of existing treatments. There have been updates in practice, efficacy or indications of therapeutics that have been previously used. Moreover, the use of novel treatments such as biologics has recently been introduced. Commonly, the most important factor in determining the treatment modality for alopecia areata has been the extent of hair loss. However, if the disease activity is high and likely to progress, combination therapy with adjuvant modalities will be more desirable. This review will discuss the therapeutic effects of existing and newly introduced treatments based on their quantity, quality of evidence and expected complications. In addition, an algorithmic approach to management of alopecia areata is proposed according to clinical subtype, severity, onset and activity of the disease. PMID- 28635046 TI - Three-year outcomes and reconnection patterns after initial contact force guided pulmonary vein isolation for paroxysmal atrial fibrillation. AB - BACKGROUND AND OBJECTIVE: Contact force (CF) sensing is a novel technology used for catheter ablation of atrial fibrillation (AF). We compared the single procedure success of CF-guided pulmonary vein isolation (PVI) with that of non-CF guided PVI during a 3-year (1,095 days) follow up period and analyzed the pattern of pulmonary vein (PV) reconnection. METHODS: A cohort of 167 subjects (68 CF vs. 99 non-CF) with paroxysmal AF were included in the study. Atrial arrhythmia (AA) recurrence was defined as documented AF, atrial flutter, or atrial tachycardia lasting >30 seconds and occurring after 90 days. RESULTS: Subjects in the CF group showed a statistically nonsignificant improvement in AA free survival compared to those in the non-CF group (66.2% vs. 51.5%; P value: 0.06). A greater propensity for reconnection was noted around the right-sided PVs compared to left sided PVs related in both catheter ablation groups. For example, in the CF group 36% of right-sided segments reconnected compared to 16% of left-sided segments (P value <0.01). CONCLUSIONS: A greater propensity for reconnection was noted around the right sided PV segments in both the CF and non-CF groups. The explanation for this finding was related to greater catheter instability around the right sided veins. Further research is needed to explore the utility of a "real-time" composite indicator that includes RF energy, CF and catheter stability in predicting transmural lesion formation during catheter ablation. PMID- 28635047 TI - Feeding Asian pangolins: An assessment of current diets fed in institutions worldwide. AB - Pangolins are ant specialists which are under intense threat from the illegal wildlife trade. Nutrition has notoriously been their downfall in captivity and is still an issue in regards to rescue and rehabilitation. We analyzed the nutrient content of diets used by institutions that are successfully keeping Asian pangolins and to assess the variety of the ingredients and nutrients, compared these with the nutritional requirements of potential nutritional model species. We performed intake studies at five institutions and also had data from three other institutions. We also analyzed five different wild food items to use as a proxy of wild diet. We observed two categories of captive diets: those mostly or completely composed of insects and those high in commercial feeds or animal meat. Nutrient values were broad and there was no clear rule. The non-protein energy to protein energy ratio of the diets were much higher than the wild food items, more so for those which receive less insects. The average contribution of carbohydrate, fat and protein energy were also further away from the wild samples the less insects they contained. The previously suggested nutritional model for pangolins is the domestic dog which is supported by our relatively large nutrient ranges of apparently successful diets, however due to their highly carnivorous nature; the upper most nutrient intake data are not consistent with this and favor the feline nutrient recommendations. We are unable to render a conclusion of what model is more appropriate based on our data collected. PMID- 28635048 TI - Prophylactic chorioretinectomy for eye injuries with high proliferative vitreoretinopathy risk. AB - With its incidence exceeding 60%, proliferative vitreoretinopathy (PVR) remains the most important pathology responsible for loss of vision, even the eyeball, after certain types of severe trauma. In this article, we present results obtained using our novel surgical technique, prophylactic chorioretinectomy (PCR), to prevent the development of PVR. Data on severely injured eyes at high risk for PVR [rupture, posterior laceration, deep-impact intraocular foreign body (IOFB) trauma, perforating injury] were collected prospectively. All eyes underwent vitrectomy (PPV) by PCR within 100 hr of the trauma. Eyes were excluded if they presented with endophthalmitis or if the reconstructive surgery was performed outside this time frame. Forty eyes of 40 consecutive patients were analyzed; full follow-up information was obtained for all of them. The injury was rupture in 27%, penetrating in 15%, (deep-impact) IOFB in 35%, and perforating in 23%. PPV-PCR was performed during primary (wound closure) surgery in 59% of cases. All eyes had at least minimal vitreous hemorrhage, and none had a true posterior vitreous detachment. At the time of PPV, 30% of the eyes had a retinal detachment. Sixteen percent developed PVR, but none from the site of the PCR procedure. In 20%, silicone oil remained in the eye at the last follow-up. The visual acuity improved in 93% of eyes and worsened in none; the improvement was mostly due to surgical clearing of the media opacity. In this subgroup of eyes with severe open-globe trauma, over 60% are expected to develop PVR. PPV/PCR performed within 100 hr reduced the PVR risk significantly, so currently it remains the best option for the surgeon. Clin. Anat. 31:28-38, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28635049 TI - A neural network model for development of reaching and pointing based on the interaction of forward and inverse transformations. AB - Pointing is one of the communicative actions that infants acquire during their first year of life. Based on a hypothesis that early pointing is triggered by emergent reaching behavior toward objects placed at out-of-reach distances, we proposed a neural network model that acquires reaching without explicit representation of 'targets'. The proposed model controls a two-joint arm in a horizontal plane, and it learns a loop of internal forward and inverse transformations; the former predicts the visual feedback of hand position and the latter generates motor commands from the visual input through random generation of the motor commands. In the proposed model, the motor output and visual input were represented by broadly tuned neural units. Even though explicit 'targets' were not presented during learning, the simulation successfully generated reaching toward visually presented objects at within-reach and out-of-reach distances. PMID- 28635052 TI - Bis-Tridentate Ir(III) Metal Phosphors for Efficient Deep-Blue Organic Light Emitting Diodes. AB - Emissive Ir(III) metal complexes possessing two tridentate chelates (bis tridentate) are known to be more robust compared to those with three bidentate chelates (tris-bidentate). Here, the deep-blue-emitting, bis-tridentate Ir(III) metal phosphors bearing both the dicarbene pincer ancillary such as 2,6 diimidazolylidene benzene and the 6-pyrazolyl-2-phenoxylpyridine chromophoric chelate are synthesized. A deep-blue organic light-emitting diode from one phosphor exhibits Commission Internationale de l'Eclairage (CIE(x,y) ) coordinates of (0.15, 0.17) with maximum external quantum efficiency (max. EQE) of 20.7% and EQE = 14.6% at the practical brightness of 100 cd m-2 . PMID- 28635050 TI - Prediction of sustained fetal toxicity induced by ketoprofen based on PK/PD analysis using human placental perfusion and rat toxicity data. AB - AIM: We encountered a case of fetal toxicity due to ductus arteriosus (DA) constriction in a 36-week pregnant woman who had applied multiple ketoprofen patches. The aim of the present study was to present the case and develop a model to predict quantitatively the fetal toxicity risk of transdermal administration of ketoprofen. METHODS: Human placenta perfusion studies were conducted to estimate transplacental pharmacokinetic (PK) parameters. Using a developed model and these parameters, human fetal plasma concentration profiles of ketoprofen administered to mothers were simulated. Using pregnant rats, DA constriction and fetal plasma drug concentration after ketoprofen administration were measured, fitted to an Emax model, and extrapolated to humans. RESULTS: Transplacental transfer value at the steady state of ketoprofen was 4.82%, which was approximately half that of antipyrine (passive marker). The model and PK parameters predicted almost equivalent mother and fetus drug concentrations at steady state after transdermal ketoprofen administration in humans. Maximum DA constriction and maximum plasma concentration of ketoprofen after administration to rat dams were observed at different times: 4 h and 1 h, respectively. The model accurately described the delay in DA constriction with respect to the fetal ketoprofen concentration profile. The model with effect compartment and the obtained parameters predicted that use of multiple ketoprofen patches could potentially cause severe DA constriction in the human fetus, and that fetal toxicity might persist after ketoprofen discontinuation by the mother, as observed in our case. CONCLUSION: The present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen. PMID- 28635051 TI - Substitution determination of Fmoc-substituted resins at different wavelengths. AB - In solid-phase peptide synthesis, the nominal batch size is calculated using the starting resin substitution and the mass of the starting resin. The starting resin substitution constitutes the basis for the calculation of a whole set of important process parameters, such as the number of amino acid derivative equivalents. For Fmoc-substituted resins, substitution determination is often performed by suspending the Fmoc-protected starting resin in 20% (v/v) piperidine in DMF to generate the dibenzofulvene-piperidine adduct that is quantified by ultraviolet-visible spectroscopy. The spectrometric measurement is performed at the maximum absorption wavelength of the dibenzofulvene-piperidine adduct, that is, at 301.0 nm. The recorded absorption value, the resin weight and the volume are entered into an equation derived from Lambert-Beer's law, together with the substance-specific molar absorption coefficient at 301.0 nm, in order to calculate the nominal substitution. To our knowledge, molar absorption coefficients between 7100 l mol-1 cm-1 and 8100 l mol-1 cm-1 have been reported for the dibenzofulvene-piperidine adduct at 301.0 nm. Depending on the applied value, the nominal batch size may differ up to 14%. In this publication, a determination of the molar absorption coefficients at 301.0 and 289.8 nm is reported. Furthermore, proof is given that by measuring the absorption at 289.8 nm the impact of wavelength accuracy is reduced. (c) 2017 The Authors Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd. PMID- 28635053 TI - Protective Effects of Lepidium meyenii (Maca) Aqueous Extract and Lycopene on Testosterone Propionate-Induced Prostatic Hyperplasia in Mice. AB - The inhibitory effect of maca extractant, lycopene, and their combination was evaluated in benign prostatic hyperplasia (BPH) mice induced by testosterone propionate. Mice were divided into a saline group, solvent control group and testosterone propionate-induced BPH mice [BPH model group, solvent BPH model group, benzyl glucosinolate group (1.44 mg/kg), maca group (60 mg/kg), lycopene treated (15, 5, and 2.5 mg/kg), maca (30 mg/kg) combine lycopene treated (7.5, 2.5, and 1.25 mg/kg), and finasteride treated]. Benzyl glucosinolate was used in order to evaluate its pharmacological activity on BPH to find out whether it is the major active component of maca aqueous extract. Finasteride was used as positive control. The compounds were administered once for 30 successive days. Compared with solvent BPH model group, BPH mice fed with maca (30 mg/kg) and lycopene (7.5 mg/kg) combination exhibited significant reductions in the prostatic index, prostatic acid phospatase, estradiol, testosterone, and dihydrotestosterone levels in serum. They also had similar histological compared with those aspects observed in the mice in the solvent control group. The results indicated that combination of maca and lycopene synergistically inhibits BPH in mice. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28635054 TI - Spectroscopic Observation of the Triplet Diradical State of a Cyclobutadiene. AB - Tetrakis(trimethylsilyl)cyclobuta-1,3-diene (1) was subjected to a temperature dependent EPR study to allow the first spectroscopic observation of a triplet diradical state of a cyclobutadiene (2). From the temperature dependent EPR absorption area we derive a singlet->triplet (1->2) energy gap, EST , of 13.9 kcal mol-1 , in agreement with calculated values. The zero-field splitting parameters D=0.171 cm-1 , E=0 cm-1 are accurately reproduced by DFT calculations. The triplet diradical 2 is thermally accessible at moderate temperatures. It is not an intermediate in the thermal cycloreversion of cyclobutadiene to two acetylene molecules. PMID- 28635055 TI - Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR). AB - A 43-year-old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against alpha4 integrins. To investigate the risk-exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004 2014), a FDA Advisory Committee Meeting Report, and peer-reviewed publications. In the United States, the manufacturer maintains an FDA-mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab-treated patients. We statistically compared reporting completeness for natalizumab-associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab-associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21-74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab-treated MS patients who developed biopsy-confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38-48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1-77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8 possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab-treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature. PMID- 28635056 TI - High-resolution deep functional imaging of the whole mouse brain by photoacoustic computed tomography in vivo. AB - Photoacoustic computed tomography (PACT) is a non-invasive imaging technique offering high contrast, high resolution, and deep penetration in biological tissues. We report a PACT system equipped with a high frequency linear transducer array for mapping the microvascular network of a whole mouse brain with the skull intact and studying its hemodynamic activities. The linear array was scanned in the coronal plane to collect data from different angles, and full-view images were synthesized from the limited-view images in which vessels were only partially revealed. We investigated spontaneous neural activities in the deep brain by monitoring the concentration of hemoglobin in the blood vessels and observed strong interhemispherical correlations between several chosen functional regions, both in the cortical layer and in the deep regions. We also studied neural activities during an epileptic seizure and observed the epileptic wave spreading around the injection site and the wave propagating in the opposite hemisphere. PMID- 28635057 TI - Pill testing or drug checking in Australia: Acceptability of service design features. AB - INTRODUCTION AND AIMS: This study aimed to determine design features of a drug checking service that would be feasible, attractive and likely to be used by Australian festival and nightlife attendees. DESIGN AND METHODS: Web survey of 851 Australians reporting use of psychostimulants and/or hallucinogens and attendance at licensed venues past midnight and/or festivals in the past year (70% male; median age 23 years). RESULTS: A drug-checking service located at festivals or clubs would be used by 94%; a fixed-site service external to such events by 85%. Most (80%) were willing to wait an hour for their result. Almost all (94%) would not use a service if there was a possibility of arrest, and a majority (64%) would not use a service that did not provide individual feedback of results. Drug-checking results were only slightly more attractive if they provided comprehensive quantitative results compared with qualitative results of key ingredients. Most (93%) were willing to pay up to $5, and 68% up to $10, per test. One-third (33%) reported willingness to donate a whole dose for testing: they were more likely to be male, younger, less experienced, use drugs more frequently and attend venues/festivals less frequently. DISCUSSION AND CONCLUSIONS: In this sample, festival- or club-based drug-checking services with low wait times and low cost appear broadly attractive under conditions of legal amnesty and individualised feedback. Quantitative analysis of ecstasy pills requiring surrender of a whole pill may appeal to a minority in Australia where pills are more expensive than elsewhere. [Barratt MJ, Bruno R, Ezard N, Ritter A. Pill testing or drug checking in Australia: Acceptability of service design features. Drug Alcohol Rev 2017;00:000-000]. PMID- 28635058 TI - Preparation and evaluation of regioselectively substituted amylose derivatives for chiral separations. AB - Six novel regioselectively substituted amylose derivatives with a benzoate at 2 position and two different phenylcarbamates at 3- and 6-positions were synthesized and their structures were characterized by 1 H nuclear magnetic resonance (NMR) spectroscopy. Their enantioseparation abilities were then examined as chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC) after they were coated on 3-aminopropyl silica gels. Investigations indicated that the substituents at the 3- and 6-positions played an important role in chiral recognition of these amylose 2-benzoate serial derivatives. The derivatives demonstrated characteristic enantioseparation and some racemates were better resolved on these derivatives than on Chiralpak AD, which is one of the most efficient CSPs, utilizing coated amylose tris(3,5 dimethylphenylcarbamate) as the chiral selector. Among the derivatives prepared, amylose 2-benzoate-3-(phenylcarbamate/4-methylphenylcarbamate)-6-(3,5 dimethylphenylcarbamate) exhibited chiral recognition abilities comparable to that of Chiralpak AD and may be useful CSPs in the future. The effect of mobile phase on chiral recognition was also studied. In general, with the decreased concentration of 2-propanol, better resolutions were obtained with longer retention times. Moreover, when ethanol was used instead of 2-propanol, poorer resolutions were often achieved. However, in some cases, improved enantioselectivity was achieved with ethanol rather than 2-propanol as the mobile phase modifier. PMID- 28635059 TI - Contribution to the reduction-induced fluorescence enhancement of natural organic matter: Aromatic ketones outweigh quinones. AB - This work involves the comparison of the fluorescence excitation - emission matrices of different low-molecular-weight carbonyl compounds and natural organic matter (NOM). The aim is to determine if quinone or aromatic ketone groups are more responsible for the reduction-induced fluorescence enhancement of NOM. After reduction, the aromatic ketones showed a significantly greater fluorescence change than the quinones, proving that the former play a more important role. Further analysis of the fluorescence of the NOM samples after re-oxidization by oxygen with a Cu2+ catalyst, provided additional reliable evidence in support of the dominant role of aromatic ketones in the fluorescence change. This work demonstrates that aromatic ketone moieties should be given more attention when considering the physicochemical properties of NOM and related environmental processes. PMID- 28635060 TI - Stress and coping in Japanese mothers whose infants required congenital heart disease surgery. AB - BACKGROUND: With the growing number of severe congenital heart disease (CHD) surgeries, some hospitals in Japan are experiencing difficulty meeting the demand for CHD surgery. As a result, CHD surgery preparation is difficult for mothers of these infants. AIMS: To examine the stress and coping of mothers whose infants needed CHD surgery and to identify the factors that influenced maternal coping. METHODS: Semistructured interviews were conducted with 11 mothers whose infants had undergone CHD surgery. Qualitative analyses of transcribed interviews were performed. RESULTS: The coping of mothers for surgery began when mothers received news of their infant's CHD diagnosis. Maternal stress appraisal and coping changed as surgery approached. In particular, maternal coping was influenced by diagnosis event, symptoms of their child, anticipated number of surgeries, presence of chromosomal abnormality, and infant age. CONCLUSION: The stressors and coping challenges of mothers whose infants needed CHD surgery changed as the surgery date approached, and these were influenced by 5 factors. PMID- 28635061 TI - Editorial: Writing for the Reader. PMID- 28635062 TI - Mobile phone text messaging to improve knowledge and practice of diabetic foot care in a developing country: Feasibility and outcomes. AB - PURPOSE: To test the feasibility and effectiveness of using mobile phone text messaging to reinforce learning and the practice of diabetic foot care in a developing country. METHODS: Ongoing learning reinforcement (2-3 times weekly) by text messaging followed an informal class on diabetic foot care in a community clinic setting. Subjects with cell phone access and no history of diabetic foot wounds or current wounds were recruited for participation (N = 225). Foot examinations and pretesting by survey occurred just before patients departed the clinic; the posttest survey and a final foot examination occurred 12 weeks later. The survey included basic demographic items along with items to measure knowledge and current foot care practices. One sample t tests (raw scores) and Wilcoxon signed-rank tests compared knowledge and practice before and after intervention. RESULTS: Initially, a majority of the sample (76%) reported poor levels of foot care. After 12 weeks <1% reported poor foot care practices. Statistical testing showed significant gains in knowledge (by score and level) and nearly unanimous compliance with daily foot examination. CONCLUSION: Mobile phone text messaging is an economical, feasible, and effective method for educators to improve diabetic self-care, even in a developing country. PMID- 28635063 TI - Association between physical and depressive symptoms during the first 6 months postpartum. AB - AIM: To examine the relationship between physical symptoms and depressive symptoms among new mothers during the first 6 months postpartum. METHODS: Prospective cohort study design was used in this study. Participants were recruited in 13 Japanese hospitals between 2012 and 2013. A total of 2709 women (response rate of those invited 71.9%) provided longitudinal data using self report questionnaires at 5 time points: during the hospital stay and at 1, 2, 4, and 6 months postpartum. Depressive symptoms were measured using the Japanese version of the Edinburgh Postnatal Depression Scale. Also, 37 physical symptoms were measured using a yes-or-no checklist. To examine the association between physical symptoms and depressive symptoms, logistic regression analysis was used. RESULTS: There was a significant positive association between physical symptoms and depressive symptoms during the first 6 months postpartum. Fifteen physical symptoms were associated with significantly increased odds of depression at 1, 2, 4, and 6 months post-partum. These symptoms included: loss of appetite, tiredness/languor, and palpitation/shortness of breath. CONCLUSION: Multiple physical symptoms after childbirth were associated with depressive symptomatology. Health professionals should assess for postpartum depression when puerperal women report multiple physical symptoms as independent complaints. PMID- 28635064 TI - Postpartum maternal function and parenting stress: Comparison by feeding methods. AB - AIM: This cross-sectional and longitudinal study explored primiparous mothers' functioning and parenting stress on the basis of infant-feeding method over the first 6 months postpartum. METHODS: Participants were Japanese primiparae who delivered live singleton infants (N = 1120). Questionnaires, completed at 1, 2, 4, and 6 months postpartum, included demographics, feeding method, frequency of feedings, time required from infant's feeding to falling asleep, mother's sleep time, Postnatal Accumulated Fatigue Scale, and the original Japanese version of Parenting Stress Short-Form Scale. Chi-square tests and Welch F tests for one-way analysis of variance were conducted. RESULTS: Exclusively breastfeeding mothers fed their infants more frequently, but required less time from infant's feeding to falling asleep than either mixed or formula-feeding mothers. Mixed feeding mothers required more time for infant feeding and reported more severe fatigue and greater parenting stress than breastfeeding mothers at 1 and 2 months postpartum. Exclusively formula-feeding mothers required more time to get their infant back to sleep and reported greater parenting stress than the other groups at 6 months postpartum. Nearly 25% of mothers continued breastfeeding exclusively through the first 6 months postpartum. Mothers often changed feeding methods, with many exclusively breastfeeding by 6 months. CONCLUSION: Feeding methods may affect maternal functioning and parenting stress across the postpartum period. PMID- 28635065 TI - Evaluating cultural competence among Japanese clinical nurses: Analyses of a translated scale. AB - This paper describes the factor analysis testing and construct validation of the Japanese version of the Caffrey Cultural Competence Health Services (J-CCCHS). The inventory, composed of 28 items, was translated using language and subject matter experts. Psychometric testing (exploratory factor, alpha reliability, and confirmatory factor analyses) was undertaken with nurses (N = 7494, 92% female, mean age 32.6 years) from 19 hospitals across Japan. Principal components extraction with varimax rotation yielded a 5-factor solution (62.31% variance explained) that was labeled: knowledge, comfort-proximal, comfort-distal, awareness, and awareness of national policy. Cronbach alpha for the subscales ranged from 0.756 to 0.892. In confirmatory factor analysis using the robust maximum likelihood estimator, the chi-square test was as follows: chi2 (340) = 14604.44, P < .001. After correlated errors were introduced, there was evidence of improved model fit (chi2 (335) = 8681.61, P < .05) but the other indices showed improvement (RMSEA = .058 [90% CI, 0.057-0.059], TLI = .891, CFI = .903, and SRMR = .059). The discriminating power of the J-CCCHS was indicated by statistically mean differences in J-CCCHS subscale scores between predefined groups. Taking into consideration that this is the first foray into construct validation for this instrument, and that fit was improved when a subsequent data driven model was tested, and it has the ability to distinguish between known groups that are expected to differ in cultural competence, the instrument can be of value to clinicians and educators alike. PMID- 28635066 TI - Consensus development of quality indicators for end-of-life care for elders in Japan. AB - AIMS AND OBJECTIVES: Quality indicators for end-of-life care have been published; however, none have been developed specifically for nursing in the cultural and traditional context of Japan. This study aimed to develop and build a consensus of quality indicators for end-of-life care for elders in Japan from the perspective of nursing science. METHODS: To develop the quality indicators, we used a literature review, expert panel process, and the Delphi technique among clinical nurse specialists in geriatrics. RESULTS: Quality indicators were identified in 7 major areas: advance directives and surrogate continuity, ethical daily care, care preferences and decisions about life-sustaining treatment, assessment and management of pain and other symptoms, daily care for the dying, family care, and institutional systems for end-of-life care. CONCLUSIONS: These quality indicators represent the first attempt to develop a best practices approach toward improving the quality of elderly end-of-life care in nursing. PMID- 28635067 TI - Maternal coping with the prospect of liver transplant among their school-age children. AB - The purpose of the current study was to describe the following: maternal coping with the prospect of becoming the living-donor liver transplant for their child; the daily lives of school-age children surviving biliary atresia with their native liver; and to explore the relationship between these individuals. Semistructured interviews were conducted with 6 school-age children surviving biliary atresia with their native liver and their mothers. The interviews were conducted from June to August 2014, and a qualitative content analysis was used. Results showed that mothers realized a possible need for transplantation in the future, which contributes to emotional and practical uncertainties. The mothers coexisted with this uncertainty and preferred to use a buffering strategy. In contrast, the children did not consider their illness and future and did not adhere to a therapeutic regimen. It is suggested that living with uncertainty about the health and survival of their children is advantageous for mothers. However, problems related to the psychosocial aspect and child's adherence may occur in the future. In addition, problem-solving coping strategies for mothers and the independence of chronically ill children with liver disease should be promoted. PMID- 28635068 TI - Selective Growth of Metal-Free Metallic and Semiconducting Single-Wall Carbon Nanotubes. AB - A major obstacle for the use of single-wall carbon nanotubes (SWCNTs) in electronic devices is their mixture of different types of electrical conductivity that strongly depends on their helical structure. The existence of metal impurities as a residue of a metallic growth catalyst may also lower the performance of SWCNT-based devices. Here, it is shown that by using silicon oxide (SiOx ) nanoparticles as a catalyst, metal-free semiconducting and metallic SWCNTs can be selectively synthesized by the chemical vapor deposition of ethanol. It is found that control over the nanoparticle size and the content of oxygen in the SiOx catalyst plays a key role in the selective growth of SWCNTs. Furthermore, by using the as-grown semiconducting and metallic SWCNTs as the channel material and source/drain electrodes, respectively, all-SWCNT thin-film transistors are fabricated to demonstrate the remarkable potential of these SWCNTs for electronic devices. PMID- 28635069 TI - Exciton coupling between enones: Quassinoids revisited. AB - The electronic circular dichroism (ECD) spectra of two previously reported quassinoids containing a pair of enone chromophores are revisited to gain insight into the consistency and applicability of the exciton chirality method. Our study is based on time-dependent Density Functional Theory calculations, transition and orbital analysis, and numerical exciton coupling calculations. In quassin (1) the enone/enone exciton coupling is quasi-degenerate, yielding strong rotational strengths that account for the observed ECD spectrum in the enone pi-pi* region. In perforalactone C (2) the nondegenerate coupling produces weak rotational strengths, and the ECD spectrum is dominated by other mechanisms of optical activity. We remark the necessity of a careful application of the nondegenerate exciton coupling method in similar cases. PMID- 28635070 TI - Adjuvant Treatment with Qilin Pill for Men with Oligoasthenospermia: A Meta Analysis of Randomized Controlled Trials. AB - Qilin pill has been used in the management of oligoasthenospermia. This meta analysis aimed to evaluate the effects of Qilin pill as an adjunctive therapy on semen parameters in oligoasthenospermic men. A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, Wanfang, CNKI, and VIP databases until June 2016. Randomized controlled trials (RCTs) that evaluated Qilin pill as an adjunctive therapy in oligoasthenospermic were included. Dichotomous data and continuous data were calculated as the risk ratio (RR) and mean difference (MD) with their 95% confidence interval (CI), respectively. Eight RCTs involving 778 patients were identified. Adjunctive treatment with Qilin pill significantly improved the semen volume (MD 0.50 mL; 95% CI 0.42-0.59), sperm concentration (MD 5.01 * 106 /mL; 95% CI 3.28-6.75), sperm motility (MD 7.54%; 95% CI 5.64-9.45), grade A sperm (MD 9.75%; 95% CI 4.05-15.45), serum testosterone level (MD 1.66 nM; 95% CI 0.40-2.92), and pregnancy rate (RR 1.46; 95% CI 1.08-1.99) during follow-up. However, differences in the serum follicle stimulating and luteinizing hormone levels were not significant. Adjunctive treatment with Qilin pill significantly improves the sperm quality in patients with oligoasthenospermia. However, further trials are necessary to investigate the efficacy of Qilin pill on oligoasthenospermia-induced male infertility. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28635071 TI - Total laryngectomy: A new lateral cervical approach. PMID- 28635073 TI - Oncologists', nurses', and social workers' strategies and barriers to identifying suicide risk in cancer patients. AB - OBJECTIVE: To identify oncologists', nurses', and social workers' strategies and barriers in identifying suicide risk in cancer patients. METHODS: Sixty-one oncology healthcare professionals (HCPs) at 2 cancer centers were interviewed. We used the grounded theory method (GT) of data collection and analysis. Analysis involved line-by-line coding, and was inductive, with codes and categories emerging from participants' narratives. RESULTS: The majority of oncologists and nurses reported that they had encountered at least 1 patient who had committed suicide during their careers (56% and 55%, respectively) and/or had suicidal ideation (65% and 75%, respectively). Social workers reported having fewer suicides in their practices (22%), but similar rates of suicidal ideation among patients (66%). Strategies to identifying suicide risk included paying attention to patients' verbal indicators, explicit actions, and mental health distress. In addition HCPs reported that mental health disorders and other patient characteristics increased their likelihood to assess suicidality among patients. Reported barriers to identification included patient factors such as patients giving no warning, patients concealing suicidality, and patients failing to come in. HCP barriers to identification included lack of training and awareness, difficulty in differentiating suicidality from mental health distress, lack of time with patients, fear of asking about suicidality, and lack of coping resources to deal with suicidal patients. CONCLUSIONS: HCPs reports of their lack of training and awareness on identifying suicide risk is alarming given the higher risk of suicide among cancer patients. Training programs should incorporate the successful strategies used by HCPs and overcome barriers to identifying suicide risk. PMID- 28635072 TI - PlGF enhances TLR-dependent inflammatory responses in human mononuclear phagocytes. AB - PROBLEM: Levels of placental growth factor (PlGF) peak during third trimester of pregnancy, a time when women are at increased risk of virus-induced morbidity. We hypothesized PlGF might contribute to an exaggerated inflammatory response to Toll-like receptor (TLR) activation. METHOD OF STUDY: Primary human adult and cord blood CD14+ cells were cultured in the presence of TLR ligands and/or PlGF. RESULTS: PlGF significantly enhanced the magnitude and duration of TNF messenger RNA and protein production by TLR-7/8-activated monocytes, and increased subsequent production of TNF-independent inflammatory cytokines. This PlGF/TLR effect involved multiple inflammatory cytokines/chemokines and was seen with the majority of TLR agonists. PlGF enhanced phosphorylation of IkappaB kinase (IKK) in monocytes stimulated with the TLR-7/8 agonist R848, and IKK inhibition completely suppressed the PlGF effect. CONCLUSION: PlGF enhances TLR-signaling upstream of IKK and contributes to an exaggerated pathologic pro-inflammatory state in response to activation of maternal and fetal mononuclear phagocytes by specific TLR agonists. PMID- 28635075 TI - Salts Influence Cathechins and Flavonoids Encapsulation in Liposomes: A Molecular Dynamics Investigation. AB - Cathechins and flavonoids are responsible of numerous health benefits. Two of the most representatives' compounds for their antioxidant and therapeutic effects are Epigallocatechin 3-Gallate (EGCG), from green tea extracts, and morelloflavone (MF), from Garcinia dulcis. Here we explore, by atomistic Molecular Dynamics simulations, how EGCG and MF interact with lipid bilayers and we show the salts' influence on their encapsulation degree in neutral liposomes. As a result, we found out that EGCGs naturally bind to the hydrophilic regions of phospholipids, positioning themselves mostly at the interface between water and lipid phases. The presence of a salt clearly influences the EGCG molecules' absorption and the total effect depends strongly on the salt nature and concentration. Beside, for MF, we observed a high stability of the intermolecular MFs aggregates in water that strongly penalizes the flavonoid's interaction with the lipid polar heads. However, salts can influence MF's liposomal penetration, even if they are not able to promote completely its absorption inside the bilayer. For both compounds, the increase of penetration is more marked in presence of magnesium chloride, whilst calcium chloride showed the opposite effect. PMID- 28635074 TI - Do sleep disturbances mediate the association between work-family conflict and depressive symptoms among nurses? A cross-sectional study. AB - WHAT IS KNOWN ON THE SUBJECT: Nurses are at a high risk for work-family conflict due to long and irregular work hours and multiple physical and psychosocial stressors in their work environment. Nurses report higher rates of depressive symptoms than the general public, leading to a high rate of burnout, absenteeism, and turnover. Work-family conflict is associated with negative consequences in nurses including physical illnesses and mental disorders. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE: Past research on this topic has not examined the mechanisms for the effect of work family conflict on depression. Studies rarely examine the influence of health behaviors such as sleep in explaining this association. Our study identified significant association of sleep disturbances with both work family conflict and depressive symptoms in nurses. Our main contribution is reporting the important role of sleep disturbances in translating the effect of work-family conflict on depressive symptoms among nurses. WHAT ARE THE IMPLICATIONS FOR PRACTICE: Nurses need to receive training in best practices for maintaining their own sleep and mental health. Organizations should include sleep health education and training in workplace health programs. Evidence-based interventions to promote healthy sleep practices such as cognitive behavioral therapy and complementary and integrative approaches should be evaluated for their effectiveness in addressing the impact of work-family conflict on the mental health of nurses. Healthcare organizations should incorporate mental health services as part of their Employee Assistance Program for nurses and include psychological and sleep disorders screening, counseling, and follow-up. ABSTRACT: Introduction Depression has been identified as the leading cause of disability worldwide. Nurses report higher rates of depression than the general public. Work-family conflict is challenging for nurses and may lead to depression and poor health. However, the mechanisms for the effect of work-family conflict on depression have not been well understood. Aim The objective is to use a cross sectional design to examine the role of sleep disturbances in the association between work-family conflict and depressive symptoms in nurses. Methods Questionnaires, measuring working conditions, work-family conflict, sleep disturbances and depressive symptoms were collected from 397 nurses at a not-for profit community hospital in the north-eastern United States. Results We observed a significant association between work-family conflict and depressive symptoms (beta = 2.22, p < .001) among nurses. Sleep disturbances partially mediated this association by 40.54%. Discussion Sleep disturbances play an important role in translating work-family conflict into depressive symptoms. Implications Evidence based interventions to promote healthy sleep practices should be evaluated for their effectiveness in addressing the impact of work-family conflict on mental health. Organizations should include sleep education and training as a component of workplace health promotion and employee assistance programmes to mitigate the effect of work-family conflict and promote overall health in nurses. PMID- 28635076 TI - Supernumeraries in Nicolaides-Baraitser Syndrome. AB - BACKGROUND: Nicolaides-Baraitser Syndrome(NCBRS) is an extremely rare condition which has been reported in only a few cases. NCBRS is a distinct clinical condition with typical clinical features of pre- and post-natal global developmental delay, impaired speech, and seizures. Microcephaly, sparse hair, anteverted alae nasi, undefined philtrum, prominence of distal phalanges and interphalangeal joints, and short metacarpals are also typical of NCBRS. CASE REPORT: There are no reported cases in the literature of patients with NCBRS presenting with multiple dental impactions, and to the authors' knowledge, this is the 28th fully documented case of NCBRS and only 75 cases identified as potentially having NCBRS. The clinical features, diagnosis, and course of management are also described. CONCLUSION: Although NCBRS is very rare, it is important to assess dental development in view of the possibility of multiple supernumerary teeth which can have detrimental effects on the occlusion. PMID- 28635077 TI - Self-Disgust within Eating Disordered Groups: Associations with Anxiety, Disgust Sensitivity and Sensory Processing. AB - This study aimed to assess the relationship between self-disgust and sensory processing within eating psychopathology. Five hundred and ninety-one women with a self-reported diagnosis of anorexia nervosa, bulimia nervosa or who had no previous history of an eating disorder completed a battery of online questionnaires measuring disgust, emotion and sensory variables. Those with an eating disorder reported significantly higher rates of self-disgust than those with no history of disordered eating. In groups of women with self-reported bulimia, self-disgust was associated with sensation avoidance and sensation seeking. Within the group with anorexia nervosa, self-disgust was associated with low registration and sensation seeking. This report is the first to examine the expression of the emotion self-disgust within eating psychopathology and examine associations of this factor with sensory processing. The emotion self-disgust needs to be further examined to understand its possible role in the onset and maintenance of disordered eating. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28635079 TI - Oxygen Vacancy-Mediated Photocatalysis of BiOCl: Reactivity, Selectivity, and Perspectives. AB - Semiconductor photocatalysis is a trustworthy approach to harvest clean solar light for energy conversions, while state-of-the-art catalytic efficiencies are unsatisfactory because of the finite light response and/or recombination of robust charge carriers. Along with the development of modern material characterization techniques and electronic-structure computations, oxygen vacancies (OVs) on the surface of real photocatalysts, even in infinitesimal concentration, are found to play a more decisive role in determining the kinetics, energetics, and mechanisms of photocatalytic reactions. This Review endeavors to clarify the inherent functionality of OVs in photocatalysis at the surface molecular level using 2D BiOCl as the platform. Structure sensitivity of OVs on reactivity and selectivity of photocatalytic reactions is intensely discussed via confining OVs onto prototypical BiOCl surfaces of different structures. The critical understanding of OVs chemistry can help consolidate and advance the fundamental theories of photocatalysis, and also offer new perspectives and guidelines for the rational design of catalysts with satisfactory performance. PMID- 28635078 TI - Prevalence of Orofacial Clefts among Live Births in China: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Orofacial clefts (OFCs) are common human birth defects in China. However, studies on the prevalence of OFCs present inconsistent results. The overall prevalence and geographic distribution of OFCs are poorly described in China. Thus, we conducted a systematic review and meta-analysis to estimate the prevalence of OFCs. METHODS: The systematic review and meta-analysis were conducted on the basis of an established protocol (PROSPERO 2015: CRD42015030198). We systematically searched for articles in four electronic databases, including Embase, PubMed, Wanfang Database, and China National Knowledge Infrastructure (CNKI) to identify relevant studies about prevalence of OFCs in China. Meta-analysis, including subgroup analysis, was conducted to estimate the pooled prevalence. RESULTS: A total of 41 studies published between 1986 and 2015 were included in our analysis. The sample size ranged from 2,586 to 4,611,808 live births. The random-effects model of meta-analysis showed that the overall prevalence of OFCs in China was 1.4 per 1000 live births (95% confidence interval [CI], 1.1-1.7). In subgroup analysis based on geographic regions, we found that OFC prevalence in Southwest (2.3 per 1000 live births, 95% CI, 1.1 4.7) was higher than that in other regions of China. There were no significant time trends of OFCs during the study period (p-value = 0.47). CONCLUSION: The overall prevalence of OFCs in China was 1.4 per 1000 live births. No significant secular trend of prevalence has been found in this analysis. Further studies need to be conducted to explore the etiology of OFC to better control the risk of this common birth defect. Birth Defects Research 109:1011-1019, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28635080 TI - Neuroadaptations of presynaptic and postsynaptic GABAB receptor function in the paraventricular nucleus in response to chronic unpredictable stress. AB - BACKGROUND AND PURPOSE: Chronic stress impairs GABAA (GABA type A) receptor mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABAB receptor function is also altered. We hypothesize that chronic stress alters GABAB receptor function in PVN corticotrophin-releasing hormone (CRH) neurons to control hypothalamus-pituitary-adrenal axis activity. EXPERIMENTAL APPROACH: Whole-cell patch clamp recordings were made of PVN-CRH neurons expressing eGFP driven by CRH promoter in brain slices from unstressed rats and rats exposed to chronic unpredictable mild stress (CUMS). KEY RESULTS: CUMS elevated the basal circulating corticosterone levels and increased the basal firing activity of PVN-CRH neurons. Microinjection of GABAB receptor agonist baclofen into the PVN suppressed the increased corticosterone levels in CUMS rats compared with unstressed rats. CUMS blunted the baclofen-induced inhibition on PVN-CRH neurons and outward currents in these neurons. Furthermore, CUMS reduced expression of GABAB1 (GABAB R1) protein in the PVN. Blocking NMDA receptors with AP5 restored the reduced baclofen-induced currents in CUMS rats but had no effect on GABAB1 expression. Furthermore, CUMS treatment augmented the baclofen-induced decrease in the frequency of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitor postsynaptic currents in PVN-CRH neurons. The GABAB receptor antagonist CGP55845 increased the firing activity of PVN-CRH neurons only in CUMS-treated rats and not in unstressed rats. CONCLUSIONS AND IMPLICATIONS: These findings suggest that chronic stress impairs postsynaptic GABAB receptor function but augments presynaptic GABAB receptor function in controlling glutamatergic and GABAergic synaptic inputs in PVN-CRH neurons. PMID- 28635081 TI - Understanding and improving photo-control of ion channels in nociceptors with azobenzene photo-switches. AB - BACKGROUND AND PURPOSE: The photo-isomerizable local anaesthetic, quaternary ammonium-azobenzene-quaternary ammonium (QAQ), provides rapid, optical control over pain signalling without involving genetic modification. In darkness or in green light, trans-QAQ blocks voltage-gated K+ and Na+ channels and silences action potentials in pain-sensing neurons. Upon photo-isomerization to cis with near UV light, QAQ blockade is rapidly relieved, restoring neuronal activity. However, the molecular mechanism of cis and trans QAQ blockade is not known. Moreover, the absorption spectrum of QAQ requires UV light for photo-control, precluding use deep inside neural tissue. EXPERIMENTAL APPROACH: Electrophysiology and molecular modelling were used to characterize the binding of cis and trans QAQ to voltage-gated K+ channels and to develop quaternary ammonium-ethylamine-azobenzene-quaternary ammonium (QENAQ), a red-shifted QAQ derivative controlled with visible light. KEY RESULTS: trans QAQ was sixfold more potent than cis QAQ, in blocking current through Shaker K+ channels. Both isomers were use-dependent, open channel blockers, binding from the cytoplasmic side, but only trans QAQ block was slightly voltage dependent. QENAQ also blocked native K+ and Na+ channels preferentially in the trans state. QENAQ was photo-isomerized to cis with blue light and spontaneously reverted to trans within seconds in darkness, enabling rapid photo-control of action potentials in sensory neurons. CONCLUSIONS AND IMPLICATIONS: Light-switchable local anaesthetics provide a means to non-invasively photo-control pain signalling with high selectivity and fast kinetics. Understanding the mode of action of QAQ and related compounds will help to design of drugs with improved photo-pharmacological properties. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. PMID- 28635082 TI - Targeting risk factors for type 2 diabetes in American Indian youth: the Tribal Turning Point pilot study. AB - BACKGROUND: American Indian (AI) youth are at high risk for type 2 diabetes. OBJECTIVES: To partner with Eastern Band of Cherokee Indians and Navajo Nation to develop a culturally sensitive behavioural intervention for youth (Tribal Turning Point; TTP) and assess feasibility in an 8-month randomized pilot study. METHODS: We enrolled 62 overweight/obese AI children (7-10 years) who participated with >=1 parent/primary caregiver. Intervention participants (n = 29) attended 12 group classes and five individual sessions. Control participants (n = 33) attended three health and safety group sessions. We analysed group differences for changes in anthropometrics (BMI, BMI z-score, waist circumference), cardiometabolic (insulin, glucose, blood pressure) and behavioural (physical activity and dietary self-efficacy) outcomes. RESULTS: Study retention was 97%, and intervention group attendance averaged 84%. We observed significant treatment effects (p = 0.02) for BMI and BMI z-score: BMI increased in control (+1.0 kg m-2 , p < 0.001) but not intervention participants (+0.3 kg m-2 , p = 0.13); BMI z score decreased in intervention (-0.17, p = 0.004) but not control participants (0.01, p = 0.82). There were no treatment effects for cardiometabolic or behavioural outcomes. CONCLUSIONS: We demonstrated that a behavioural intervention is feasible to deliver and improved obesity measures in AI youth. Future work should evaluate TTP for effectiveness, sustainability and long-term impact in expanded tribal settings. PMID- 28635083 TI - Clinically distinct trajectories of fatigue and their longitudinal relationship with the disturbance of personal goals following a cancer diagnosis. AB - OBJECTIVES: Most studies on fatigue in patients with cancer aggregate its prevalence and severity on a group level, ignoring the possibility that subgroups of patients may differ widely in their development of fatigue. This study aimed to identify subgroups of patients with clinically distinct trajectories of fatigue from diagnosis to 18 months post-diagnosis. As fatigue might trigger goal disturbance, the study also identified trajectories of concrete and abstract goal disturbance and longitudinally examined their co-occurrence with fatigue. DESIGN: Prospective design with quantitative and qualitative method of data collection. METHODS: Patients with colorectal cancer (n = 183) reported on their levels of fatigue and goal disturbance shortly after diagnosis (T1 ) and at 7 months (T2 ) and 18 months (T3 ) post-diagnosis. Growth mixture model analyses were performed to identify trajectories of fatigue and goal disturbance. Guidelines for the clinical relevance of fatigue were applied. RESULTS: Four clinically distinct trajectories of fatigue were identified as follows: (1) persistent severe fatigue (25.4%), (2) moderate fatigue (56.1%), (3) no fatigue (13.8%), and (4) rapidly improving fatigue (4.7%). The majority of patients with cancer reported high disturbance of their concrete goals, while high disturbance of abstract goals was less evident. Fatigue and concrete goal disturbance co-occurred longitudinally. CONCLUSIONS: The fatigue and goal disturbance experienced from diagnosis to 18 months post-diagnosis differ considerably for subgroups of patients with cancer. Fatigue and concrete goal disturbance are persistent burdens in the majority of patients. Investigating symptom burden beyond average trends can guide clinicians to identify patients most in need for treatment. Targeting goal disturbance might benefit the psychological well-being in patients suffering from persistent symptoms. Statement of contribution What is already known on this subject? Fatigue is a common and distressing symptom at all stages of the cancer experience. Earlier studies suggest that many patients recover from fatigue after treatment completion. Patients with cancer experience disturbance in their personal goals, which is related to poor psychological well-being. What does this study add? Developments of fatigue and goal disturbance differ between subgroups of patients with cancer but co-occur within these subgroups. About 30% of the patients experience severe fatigue after diagnosis, of which only few patients recover within 18 months post-diagnosis. Targeting goal disturbance might benefit patients with severe and ongoing symptoms. PMID- 28635085 TI - Venous thromboembolism management in Northeast Melbourne: how does it compare to international guidelines and data? AB - BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality with significant heterogeneity in its management, both within our local practice and in international guidelines. AIMS: To provide a holistic evaluation of 'real-world' Australian experience in the warfarin era, including how we compare to international guidelines. METHODS: Retrospective evaluation of VTE from July 2011 to December 2012 at two major hospitals in Melbourne, Australia. These results were compared to recommendations in the international guidelines. RESULTS: A total of 752 episodes involving 742 patients was identified. Contrary to international guidelines, an unwarranted heritable thrombophilia screen was performed in 22.0% of patients, amounting to a cost of AU$29 000. The duration of anticoagulation was longer compared to international recommendations, although the overall recurrence (3.2/100 person-years) and clinically significant bleeding rates (2.4/100 person-years) were comparable to 'real-world' data. Unprovoked VTE (hazard ratio 2.06; P = 0.01) was a risk factor for recurrence, and there was no difference in recurrence between major VTE (proximal deep vein thrombosis (DVT) and/or pulmonary embolism) and isolated distal DVT (3.02 vs 3.94/100 person years; P = 0.25). Fourteen patients were subsequently diagnosed with malignancy, and patients with recurrent VTE had increased risk of prospective cancer diagnosis (relative risk 6.68; P < 0.001). CONCLUSIONS: While our 'real-world' VTE experience during the warfarin era largely correlates with international guidelines, there remains heterogeneity in the management strategies, including excessive thrombophilia screening and longer duration of anticoagulation. This audit highlights the need for national VTE guidelines, as well as prospective auditing of VTE management, in the direct oral anticoagulant era for future comparison. PMID- 28635084 TI - Primary tumor sites in relation to ultraviolet radiation exposure and skin visibility correlate with survival in cutaneous melanoma. AB - The prognostic value of detailed anatomic site and ultraviolet radiation (UVR) exposure patterns has not been fully determined in cutaneous melanoma. Thus, we reviewed medical records for detailed site in a population-based retrospective Swedish patient cohort diagnosed with primary invasive melanoma 1976-2003 (n = 5,973). We followed the patients from date of diagnosis until death, emigration or December 31st 2013, and evaluated melanoma-specific survival by subsite in a multivariable regression model adjusting for established prognostic factors. We found that melanoma on chronic UVR exposure sites (face, dorsum of hands; adjusted HR 0.6; CI 0.4-0.7) and moderately intermittent UVR sites (lateral arms, lower legs, dorsum of feet; HR 0.7; CI 0.6-0.8) were associated with a favorable prognosis compared with highly intermittent sites (chest, back, neck, shoulders and thighs). Further, melanoma on poorly visible skin sites upon self-examination (scalp, retroauricular area, back, posterior upper arms and thighs, buttocks, pubic area; HR 1.3; CI 1.1-1.5) had a worse prognosis than those on easily visible sites (face, chest, abdomen, anterior upper arms and thighs, lower arms and legs, dorsum of hands and feet, palms). In conclusion, highly intermittent UVR exposure sites and poor skin visibility presumably correlate with reduced melanoma survival, independent of established tumor characteristics. A limitation of the study was the lack of information on actual individual UVR exposure. PMID- 28635088 TI - Arts and cultural activity: A vital part of the health and care system. AB - This article discusses how the arts and cultural activities are a vital part of a health and care system and have potential to fulfil the theme of active ageing. The changing nature of care provision in response to demographic change, fiscal pressure and increasingly consumerist attitudes on the part of care users, is considered. Selected examples of how participation in arts and cultural activities increases not only well-being but also health outcomes are then outlined. The article highlights the potential of 'cultural commissioning' and within that 'arts on prescription' - public funding of arts-related activities for people with care needs - and advocates investment in arts and cultural activities to better meet the demands of health, social care and aged care. Concluding remarks are made, and a way forward is suggested. PMID- 28635086 TI - Attitudes towards intergenerational equity: Preliminary Australian evidence. PMID- 28635089 TI - Comparison of fall-related traumatic brain injury in residential aged care and community-dwelling older people: A population-based study. AB - OBJECTIVE: To compare trends, causes, and outcomes of fall-related traumatic brain injury (TBI) between community-dwelling (CD) individuals and residential aged care facility (RACF) residents. METHODS: Hospitalisation and RACF administrative data for 6635 individuals aged >=65 years admitted to all NSW hospitals for fall-related TBI from 2008-2009 to 2012-2013 were linked. RESULTS: Of the 6944 hospitalisations, 20.8% were for RACF residents. Age-standardised hospitalisation rates were almost fourfold higher for RACF residents than CD individuals (standardised rate ratio 3.7; 95% CI 3.4-4.1); but increased at a similar annual rate of 9.2% (95% CI 0.3-19.0) and 7.2% (95% CI 5.6-8.9), respectively. Compared to CD individuals: a higher proportion of falls in RACF residents were furniture-related (21.4% vs 9.9%); resulted in haemorrhage (82.5% vs 73.7%); and death (23.1% vs 14.9%). Overall, 7.7% of hospitalisations for CD individuals resulted in new permanent RACF placement. CONCLUSION: Residential aged care facility residents have higher hospitalisation rates and poorer health outcomes than their CD counterparts. PMID- 28635091 TI - Perceptions of health-care professionals' treatment of older people. PMID- 28635092 TI - Well-being of older Aboriginal Australians: The importance of 'keeping spirit strong'. PMID- 28635093 TI - Role of art centres for Aboriginal Australians living with dementia in remote communities. AB - OBJECTIVE: To explore the role art centres in remote communities play for Aboriginal and Torres Strait Islander Australians living with dementia. METHODS: A comprehensive literature search was undertaken, with no restrictions on articles regarding year of publication. RESULTS: Art programmes have been found to be of benefit to both people living with dementia and their carers, particularly when programmes are administered in environments that are culturally revered. Findings indicate remote art centres play a key role in maintaining traditions, culture and practices unique to Aboriginal and Torres Strait Islanders, but there is a gap in knowledge regarding how they cater for the needs of people with dementia. CONCLUSION: Addressing this gap will be helpful in remote areas where prevalence of dementia is up to five times that of non Aboriginal people, and there are limited health and support services. Further research is required to explore strengths and gaps of current practices. PMID- 28635094 TI - Is there anything to worry about? PMID- 28635095 TI - Age discrimination in the workplace: The more things change .... PMID- 28635096 TI - What happens to your submission at Australasian Journal on Ageing? PMID- 28635098 TI - Venous loops: a benign feature of diabetic retinopathy or cause for concern? PMID- 28635099 TI - Effects of electronic device overuse by university students in relation to clinical status and anatomical variations of the median nerve and transverse carpal ligament. AB - INTRODUCTION: This study investigates the results of a questionnaire, provocative tests, and ultrasonographic measurements of carpal tunnel morphological parameters in intensive and nonintensive electronic device users. METHODS: Forty eight university students (equal numbers of intensive and nonintensive users, >=5 h/day and <5 h/day of electronic device usage, respectively) were randomly selected after questionnaire responses were received and evaluated clinically and by ultrasonography. All participants were right-handed. RESULTS: Intensive users had significantly more positive results in Phalen's and Durkan's tests and reported more wrist/hand pain compared with nonintensive users (P < 0.05). Intensive users also had significantly larger median nerve cross-sectional areas, flattening ratios, and perimeters as well as greater bowing of the transverse carpal ligament compared with nonintensive users (P < 0.05). DISCUSSION: Overuse of electronic devices may adversely affect the median nerve within the carpal tunnel and the transverse carpal ligament, resulting in numbness, tingling, and pain in the hand. Caution may be warranted when using handheld electronic devices. Muscle Nerve 56: 873-880, 2017. PMID- 28635100 TI - A new system for classifying accessory canal morphology. AB - Thorough knowledge of anatomical complexities of the root canal system has a direct impact on the effectiveness of canal preparation and filling, and is an essential prerequisite for successful root canal treatment. A wide range of complex variations in root canal anatomy exists, including root canal configuration type, developmental anomalies and minor canal morphology such as accessory canals and apical deltas. Accessory canals and apical deltas have been associated with pulp disease, primary canal infection, canal reinfection and post treatment disease. The current definitions of accessory canal anatomy are not standardized and potentially confusing. Given their role in endodontic disease and their impact on treatment outcomes, there is a need to have a simple classification of their anatomy to provide an accurate description of their position and path from the canal to the external surface of the root. The purpose of this article is to introduce a new system for classifying accessory canal morphology for use in research, clinical practice and training. PMID- 28635101 TI - A simply synthesized biphenyl substituted piperidin-4-one for the fluorescence chemosensing of Cd2. AB - Ion-induced change in fluorescence is a straight-forward method for detection of toxic metal ions showing immediate response. Cadmium ions are toxic to the environment. We report in this paper a piperidine-4-one-based fluorescent chemosensor of Cd2+ ions, designed and synthesized by a simple method. The compound is characterized using infra-red (IR) and 1 H-NMR spectral techniques. The chemosensor showed Cd2+ ion selectivity and sensitivity in aqueous solution. The stoichiometry and the binding constants were determined using fluorescence spectroscopy. Piperidine-4-one shows a 1:1 stoichiometric binding to Cd2+ . The limit of detection of Cd2+ was reported. PMID- 28635102 TI - Ratiometric analysis of optical coherence tomography-measured in vivo retinal layer thicknesses for the detection of early diabetic retinopathy. AB - Influence of diabetes mellitus (DM) and diabetic retinopathy (DR) on parafoveal retinal thicknesses and their ratios was evaluated. Six retinal layer boundaries were segmented from spectral-domain optical coherence tomography images using open-source software. Five study groups: (1) healthy control (HC) subjects, and subjects with (2) controlled DM, (3) uncontrolled DM, (4) controlled DR and (5) uncontrolled DR, were identified. The one-way analyses of variance (ANOVA) between adjacent study groups (i. e. 1 with 2, 2 with 3, etc) indicated differences in retinal thicknesses and ratios. Overall retinal thickness, ganglion cell layer (GCL) thickness, inner plexiform layer (IPL) thickness, and their combination (GCL+ IPL), appeared to be significantly less in the uncontrolled DM group when compared to controlled DM and controlled DR groups. Although the combination of nerve fiber layer (NFL) and GCL, and IPL thicknesses were not different, their ratio, (NFL+GCL)/IPL, was found to be significantly higher in the controlled DM group compared to the HC group. Comparisons of the controlled DR group with the controlled DM group, and with the uncontrolled DR group, do not show any differences in the layer thicknesses, though several significant ratios were obtained. Ratiometric analysis may provide more sensitive parameters for detecting changes in DR. Picture: A representative segmented OCT image of the human retina is shown. PMID- 28635104 TI - Response to letter to the editor: Persistent neuropsychiatric impairment in HCV patients-or educational mismatch? PMID- 28635103 TI - Uncovering the dispersion history, adaptive evolution and selection of wheat in China. AB - Wheat was introduced to China approximately 4500 years ago, where it adapted over a span of time to various environments in agro-ecological growing zones. We investigated 717 Chinese and 14 Iranian/Turkish geographically diverse, locally adapted wheat landraces with 27 933 DArTseq (for 717 landraces) and 312 831 Wheat660K (for a subset of 285 landraces) markers. This study highlights the adaptive evolutionary history of wheat cultivation in China. Environmental stresses and independent selection efforts have resulted in considerable genome wide divergence at the population level in Chinese wheat landraces. In total, 148 regions of the wheat genome show signs of selection in at least one geographic area. Our data show adaptive events across geographic areas, from the xeric northwest to the mesic south, along and among homoeologous chromosomes, with fewer variations in the D genome than in the A and B genomes. Multiple variations in interdependent functional genes such as regulatory and metabolic genes controlling germination and flowering time were characterized, showing clear allelic frequency changes corresponding to the dispersion of wheat in China. Population structure and selection data reveal that Chinese wheat spread from the northwestern Caspian Sea region to South China, adapting during its agricultural trajectory to increasingly mesic and warm climatic areas. PMID- 28635105 TI - Do we need vasoconstrictors up to 5 days after successful hemostasis by ligation of bleeding varices? PMID- 28635106 TI - Long noncoding RNA and its contribution to autism spectrum disorders. AB - Recent studies have indicated that long noncoding RNAs (lncRNAs) play important roles in multiple processes, such as epigenetic regulation, gene expression regulation, development, nutrition-related and other diseases, toxic response, and response to drugs. Although the functional roles and mechanisms of several lncRNAs have been discovered, a better understanding of the vast majority of lncRNAs remains elusive. To understand the functional roles and mechanisms of lncRNAs is critical because these transcripts represent the majority of the transcriptional output of the mammalian genome. Recent studies have also suggested that lncRNAs are more abundant in the human brain and are involved in neurodevelopment and neurodevelopmental disorders, including autism spectrum disorders (ASDs). In this study, we review several known functions of lncRNAs and the potential contribution of lncRNAs to ASDs and to other genetic syndromes that have a similar clinical presentation to ASDs, such as fragile X syndrome and Rett syndrome. PMID- 28635107 TI - New Space-Time Metaphors Foster New Nonlinguistic Representations. AB - What is the role of language in constructing knowledge? In this article, we ask whether learning new relational language can create new ways of thinking. In Experiment 1, we taught English speakers to talk about time using new vertical linguistic metaphors, saying things like "breakfast is above dinner" or "breakfast is below dinner" (depending on condition). In Experiment 2, rather than teaching people new metaphors, we relied on the left-right representations of time that our American college student participants have already internalized through a lifetime of visuospatial experience reading and writing text from left to right. In both experiments, we asked whether the representations (whether newly acquired from metaphor or acquired over many years of visuospatial experience) are susceptible to verbal interference. We found that (a) learning new metaphors created new space-time associations that could be detected in a nonlinguistic implicit association task; (b) these newly learned representations were not susceptible to verbal interference; and (c) with respect to both verbal and visual interference, representations newly learned from linguistic metaphor behaved just like those on the left-right axis that our participants had acquired through years of visuospatial experience. Taken together, these results suggest that learning new relational language can be a powerful tool in constructing new representations and expanding our cognitive repertoire. PMID- 28635108 TI - Oropharyngeal dysphagia in older adults: The well-known tale. PMID- 28635109 TI - Dietary diversity decreases the risk of cognitive decline among elderly Japanese. PMID- 28635110 TI - Applied botulinum neurotoxin injection in a patient with dementia to reduce hypersalivation. PMID- 28635111 TI - Factor XI deficiency as a result of a novel Tyr347Stop nonsense mutation in an elderly Japanese woman. PMID- 28635112 TI - Effectiveness and safety of inpatient respite care for caregivers of disabled patients in an acute care hospital. PMID- 28635113 TI - Dietary diversity and the risk reduction of mild cognitive impairment/dementia in older adults. PMID- 28635114 TI - Longitudinal changes in peripheral oxidative markers in patients with Alzheimer's disease, with or without cardiovascular disease. PMID- 28635115 TI - Emphysematous cystitis in an elderly diabetic patient. PMID- 28635116 TI - Maternal Smoking, Alcohol, and Caffeine Exposures and Risk of Hypospadias. AB - BACKGROUND: We examined the association of hypospadias risk with maternal smoking and consumption of alcohol and caffeine. METHODS: We analyzed data from mothers of 2437 moderate/severe cases and 5472 nonmalformed controls born from 1997 to 2011 who participated in the National Birth Defects Prevention Study (NBDPS). Exposures were assessed by maternal telephone interviews. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for mother's age, parity, race-ethnicity, education, vitamin/mineral supplement intake, obesity, and study center. RESULTS: Active smoking during the first month of pregnancy was associated with reduced risk, with smaller ORs for increasing quantity smoked; the OR for smoking >1/2 pack/day was 0.7 (95% CI, 0.5 0.9). Among nonsmokers, the OR for any secondhand smoke exposure was 0.8 (95% CI, 0.7-0.9). ORs for alcohol and caffeine consumption were near one and CIs included 1.0. In an analysis of joint exposures to smoking and alcohol and caffeine consumption, the only OR for which the 95% CI excluded 1.0 was for women who smoked, drank, and had low caffeine consumption (OR, 0.6; 95% CI, 0.4-0.8). CONCLUSION: Maternal exposure to cigarette smoke was associated with reduced risk, and women who smoked, drank, and had low caffeine intake were at lowest risk. We do not interpret these results to suggest that these exposures have overall benefit to a pregnant woman or developing fetus. They may, however, offer clues to help us understand mechanisms that lead to hypospadias. Birth Defects Research 109:1127-1133, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28635117 TI - Relationship Between Fish Consumption and Disease Activity in Rheumatoid Arthritis. AB - OBJECTIVE: To assess whether more frequent fish consumption is associated with lower rheumatoid arthritis (RA) disease activity scores among participants in an RA cohort. METHODS: We conducted a cross-sectional analysis using baseline data from participants in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis cohort study. Frequency of fish consumption was assessed by a baseline food frequency questionnaire assessing usual diet in the past year. Multivariable, total energy-adjusted linear regression models provided effect estimates and 95% confidence intervals (95% CIs) for frequency of fish consumption (i.e., never to <1 time/month, 1 time/month to <1 time/week, 1 time/week, and >=2 times/week) on baseline Disease Activity Score in 28 joints (DAS28) using the C-reactive protein (CRP) level. We also estimated the difference in DAS28-CRP associated with increasing fish consumption by 1 serving per week. RESULTS: Among 176 participants, the median DAS28-CRP score was 3.5 (interquartile range 2.9-4.3). In an adjusted linear regression model, subjects consuming fish >=2 times/week had a significantly lower DAS28-CRP compared with subjects who ate fish never to <1 time/month (difference -0.49 [95% CI -0.97, -0.02]). For each additional serving of fish per week, DAS28-CRP was significantly reduced by 0.18 (95% CI -0.35, -0.004). CONCLUSION: Our findings suggest that higher intake of fish may be associated with lower disease activity in RA patients. PMID- 28635118 TI - Incidental papillary fibroelastoma of the tricuspid valve. PMID- 28635119 TI - The detection and prevention of unintentional consumption of DOx and 25x-NBOMe at Portugal's Boom Festival. AB - OBJECTIVE: This paper describes the misrepresentation of LSD at Portugal's Boom Festival 2014 and the prevention of unintentional consumption of DOx and 25x NBOMe among LSD consumers attending a drug-checking service. METHODS: Two hundred forty-five drug samples expected to contain LSD were submitted to the drug checking service for chemical analysis. One hundred ten post-test questionnaires were successfully matched with test results. RESULTS: About 67.3% of the alleged LSD samples tested contained only LSD; 0.8% contained LSD combined with adulterants; 24.1% did not contain LSD but did contain another psychoactive substance, including 11.4% that were 2,5-dimethoxyamphetamine derivatives and 9.8% that were N-benzyl-2,5-dimethoxyphenethylamine derivatives; and no psychoactive substance was detected in 7.8%. The majority of service users who received unexpected test results regarding their alleged LSD (74.2%) reported that they did not intend to consume the drug. Following dissemination of alerts on day 2, a larger than expected proportion of all tests conducted were for LSD, when comparing the 2014 festival to 2012, where no such alert was disseminated. CONCLUSIONS: Although these results support the provision of integrated drug checking services in party settings, evidence of their utility and effectiveness would be improved through future research incorporating more robust measures of outcomes following provision of drug-checking results. PMID- 28635120 TI - Diffractive corneal inlay for presbyopia. AB - A conceptually new type of corneal inlays for a customized treatment of presbyopia is presented. The diffractive inlay consists on a small aperture disc having an array of micro-holes distributed inside the open zones of a Fresnel zone plate. In this way, the central hole of the disc lets pass the zero order diffraction and produces an extension of the depth of far focus of the eye, while the diffracted light through the holes in the periphery produce the near focus. Additionally, the micro-holes in the inlay surface fulfill the essential requirement of allowing the flow of nutrients through it to the cells of the corneal stroma. Theoretical and optical-bench experimental results for the polychromatic axial Point Spread Function (PSF) were obtained, showing an improved performance compared to the small aperture corneal inlay currently in the market (Kamra). Images of a test object, obtained at several vergences in the surroundings of the far and near foci, are also shown. Picture: Simulation of the appearance of the Diffractive corneal inlay on a real eye. PMID- 28635121 TI - Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism. AB - BACKGROUND: Valproic acid (VPA) is the most teratogenic anticonvulsant drug in clinical use today. Children exposed prenatally to VPA have previously been shown to have dysmorphic craniofacial features, identified subjectively but not by anthropometric methods. Exposure to VPA has also been associated with an increased frequency of autism spectrum disorder (ASD). An increased cephalic index (the ratio of the cranial lateral width to the cranial anterior-posterior length) has been observed in children with ASD. METHODS: Forty-seven children exposed to VPA during the first trimester of pregnancy were evaluated for dysmorphic facial features, identified subjectively and by measurements. Each VPA exposed child was evaluated for ASD using the Social Communication Questionnaire, Autism Diagnostic Interview-Revised, and Autism Diagnostic Observation Schedule. The same physical examination was carried out on an unexposed comparison group of 126 children. The unexposed children also had testing for cognitive performance by the Wechsler Intelligence Scale for Children. RESULTS: Several dysmorphic craniofacial features, including telecanthus, wide philtrum, and increased length of the upper lip were identified subjectively. Anthropometric measurements confirmed the increased intercanthal distance and documented additional findings, including an increased cephalic index and decreased head circumference/height index. There were no differences between the craniofacial features of VPA-exposed children with and without ASD. CONCLUSION: An increased frequency of dysmorphic craniofacial features was identified in children exposed to VPA during the first trimester of pregnancy. The most consistent finding was a larger cephalic index, which indicates a disproportion of increased width of the skull relative to the shortened anterior-posterior length. Birth Defects Research 109:1134-1143, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28635122 TI - Sketching the Invisible to Predict the Visible: From Drawing to Modeling in Chemistry. AB - Sketching as a scientific practice goes beyond the simple act of inscribing diagrams onto paper. Scientists produce a wide range of representations through sketching, as it is tightly coupled to model-based reasoning. Chemists in particular make extensive use of sketches to reason about chemical phenomena and to communicate their ideas. However, the chemical sciences have a unique problem in that chemists deal with the unseen world of the atomic-molecular level. Using sketches, chemists strive to develop causal mechanisms that emerge from the structure and behavior of molecular-level entities, to explain observations of the macroscopic visible world. Interpreting these representations and constructing sketches of molecular-level processes is a crucial component of student learning in the modern chemistry classroom. Sketches also serve as an important component of assessment in the chemistry classroom as student sketches give insight into developing mental models, which allows instructors to observe how students are thinking about a process. In this paper we discuss how sketching can be used to promote such model-based reasoning in chemistry and discuss two case studies of curricular projects, CLUE and The Connected Chemistry Curriculum, that have demonstrated a benefit of this approach. We show how sketching activities can be centrally integrated into classroom norms to promote model based reasoning both with and without component visualizations. Importantly, each of these projects deploys sketching in support of other types of inquiry activities, such as making predictions or depicting models to support a claim; sketching is not an isolated activity but is used as a tool to support model based reasoning in the discipline. PMID- 28635123 TI - Measuring fitness heritability: Life history traits versus morphological traits in humans. AB - OBJECTIVES: Traditional interpretation of Fisher's Fundamental Theorem of Natural Selection is that life history traits (LHT), which are closely related with fitness, show lower heritabilities, whereas morphological traits (MT) are less related with fitness and they are expected to show higher heritabilities. In humans, although few studies have examined the heritability of LHT and MT, none of them have analyzed the same sample for comparative purposes. Here we assessed, for the first time, the heritability, additive genetic variance (VA ), residual variance (VR ) and coefficient of genetic additive variation (CVA ) values of LHT and MT in a singular collection of identified skulls with associated demographic records from Hallstatt (Austria). MATERIALS AND METHODS: LHT, such as lifespan, number of offspring, age at birth of first and last child, reproductive span, and lifetime reproductive success, were estimated from 18,134 individuals from the Hallstatt Catholic parish records, which represent seven generations and correspond to a time span of 400 years. MT were assessed through 17 craniofacial indices and 7 angles obtained from 355 adult crania from the same population. Heritability, VA , VR , and CVA values of LHT and MT were calculated using restricted maximum likelihood methods. RESULTS: LHT heritabilities ranged from 2.3 to 34% for the whole sample, with men showing higher heritabilities (4-45%) than women (0-23.7%). Overall, MT presented higher heritability values than most of LHT, ranging from 0 to 40.5% in craniofacial indices, and from 13.8 to 32.4% in craniofacial angles. LHT showed considerable additive genetic variance values, similar to MT, but also high environmental variance values, and most of them presenting a higher evolutionary potential than MT. DISCUSSION: Our results demonstrate that, with the exception of lifespan, LHT show lower heritability values, than MT. The lower heritability of LHT is explained by a higher influence of environmental and cultural factors. PMID- 28635125 TI - State transitions: a major mortality risk for seasonal species. AB - Ageing results from the accumulation of multifactorial damage over time. However, the temporal distribution of this damage remains unknown. In seasonal species, transitions between seasons are critical periods of massive physiological remodelling. We hypothesised that these recurrent peaks of physiological remodelling are costly in terms of survival. We tested whether captive small primates exposed to an experimentally increased frequency of seasonal transitions die sooner than individuals living under natural seasonality. The results show that experiencing one additional season per year increases the mortality hazard by a factor of 3 to 4, whereas the expected number of seasons lived is only slightly impacted by the seasonal rhythm. These results demonstrate that physiological transitions between periods of high and low metabolic activity represent a major mortality risk for seasonal organisms, which has been ignored until now. PMID- 28635126 TI - Reinterpreting maximum entropy in ecology: a null hypothesis constrained by ecological mechanism. AB - Simplified mechanistic models in ecology have been criticised for the fact that a good fit to data does not imply the mechanism is true: pattern does not equal process. In parallel, the maximum entropy principle (MaxEnt) has been applied in ecology to make predictions constrained by just a handful of state variables, like total abundance or species richness. But an outstanding question remains: what principle tells us which state variables to constrain? Here we attempt to solve both problems simultaneously, by translating a given set of mechanisms into the state variables to be used in MaxEnt, and then using this MaxEnt theory as a null model against which to compare mechanistic predictions. In particular, we identify the sufficient statistics needed to parametrise a given mechanistic model from data and use them as MaxEnt constraints. Our approach isolates exactly what mechanism is telling us over and above the state variables alone. PMID- 28635124 TI - Regular aerobic exercise reduces endothelin-1-mediated vasoconstrictor tone in overweight and obese adults. AB - NEW FINDINGS: What is the central question of this study? Does aerobic exercise training reduce endothelin-1 (ET-1)-mediated vasoconstrictor tone in overweight/obese adults? And, if so, does lower ET-1 vasoconstriction underlie the exercise-related enhancement in endothelium-dependent vasodilatation in overweight/obese adults? What is the main finding and its importance? Regular aerobic exercise reduces ET-1-mediated vasoconstrictor tone in previously sedentary overweight/obese adults, independent of weight loss. Decreased ET-1 vasoconstriction is an important mechanism underlying the aerobic exercise induced improvement in endothelium-dependent vasodilator function in overweight/obese adults. Endothelin-1 (ET-1)-mediated vasoconstrictor tone is elevated in overweight and obese adults, contributing to vasomotor dysfunction and increased cardiovascular disease risk. Although the effects of habitual aerobic exercise on endothelium-dependent vasodilatation in overweight/obese adults have been studied, little is known regarding ET-1-mediated vasoconstriction. Accordingly, the aims of the present study were to determine the following: (i) whether regular aerobic exercise training reduces ET-1 mediated vasoconstrictor tone in overweight and obese adults; and, if so, (ii) whether the reduction in ET-1-mediated vasoconstriction contributes to exercise induced improvement in endothelium-dependent vasodilatation in this population. Forearm blood flow (FBF) in response to intra-arterial infusion of selective ETA receptor blockade (BQ-123, 100 nmol min-1 for 60 min), acetylcholine [4.0, 8.0 and 16.0 MUg (100 ml tissue)-1 min-1 ] in the absence and presence of ETA receptor blockade and sodium nitroprusside [1.0, 2.0 and 4.0 MUg (100 ml tissue) 1 min-1 ] were determined before and after a 3 month aerobic exercise training intervention in 25 (16 men and nine women) overweight/obese (body mass index 30.1 +/- 0.5 kg m-2 ) adults. The vasodilator response to BQ-123 was significantly lower (~25%) and the FBF responses to acetylcholine were ~35% higher after exercise training. Before the exercise intervention, the co-infusion of acetylcholine plus BQ-123 resulted in a greater vasodilator response than acetylcholine alone; however, after the exercise intervention the FBF response to acetylcholine was not significantly increased by ETA receptor blockade. These results demonstrate that regular aerobic exercise reduces ET-1-mediated vasoconstrictor tone in previously sedentary overweight and obese adults. Moreover, decreased ET-1-mediated vasoconstriction is an important mechanism underlying the aerobic exercise-induced improvement in endothelium-dependent vasodilator function in overweight/obese adults. PMID- 28635127 TI - Cardiovascular risk score is linked to subcutaneous adipocyte size and lipid metabolism. AB - OBJECTIVE: Although white adipose tissue mass and distribution correlates with cardiovascular disease, the fat cell-specific perturbations underlying this association are not known. We determined the relationship between adipocyte size and lipid metabolism with cardiovascular risk. DESIGN/SUBJECTS: Adipocyte size as well as spontaneous (basal) and hormone-stimulated effects on adipocyte lipid metabolism (lipolysis and lipogenesis) were investigated in abdominal subcutaneous adipose tissue of 304 men and 775 women. Subjects were classified into five categories according to Adult Treatment Panel III (ATPIII) metabolic syndrome criteria. RESULTS: Adipocyte size increased with increasing ATPIII score (P < 0.0001). For lipolysis, there was a gradual increase in basal and catecholamine-stimulated lipolysis and a decrease in insulin-mediated inhibition of stimulated lipolysis with ATPIII (P < 0.0001). In contrast, the lipolytic action of atrial natriuretic peptide was similar between ATPIII classes. Basal and insulin-stimulated lipogenesis decreased with increasing score (P < 0.0001). Circulating free fatty acid levels were 50% higher in the top risk category (4-5) compared with the lowest score (P < 0.0001). Fat cell size correlated positively with increasing ATPIII score and lipolysis but negatively with lipogenesis. All these differences were independent of age, sex and body weight status (P < 0.0001 to 0.02 after correction). When all functional measures were put together, maximum insulin-stimulated lipogenesis, insulin-antilipolytic sensitivity and basal lipolysis together explained about 20% in the variation of ATPIII in score. CONCLUSIONS: Independently of sex, age and body weight status, a high cardiovascular risk score associates with increased circulating free fatty acid levels and hormone-specific alterations of lipolysis/lipogenesis in enlarged subcutaneous fat cells. PMID- 28635129 TI - microRNAs involved in auxin signalling modulate male sterility under high temperature stress in cotton (Gossypium hirsutum). AB - Male sterility caused by long-term high-temperature (HT) stress occurs widely in crops. MicroRNAs (miRNAs), a class of endogenous non-coding small RNAs, play an important role in the plant response to various abiotic stresses. To dissect the working principle of miRNAs in male sterility under HT stress in cotton, a total of 112 known miRNAs, 270 novel miRNAs and 347 target genes were identified from anthers of HT-insensitive (84021) and HT-sensitive (H05) cotton cultivars under normal-temperature and HT conditions through small RNA and degradome sequencing. Quantitative reverse transcriptase-polymerase chain reaction and 5'-RNA ligase mediated rapid amplification of cDNA ends experiments were used to validate the sequencing data. The results show that miR156 was suppressed by HT stress in both 84021 and H05; miR160 was suppressed in 84021 but induced in H05. Correspondingly, SPLs (target genes of miR156) were induced both in 84021 and H05; ARF10 and ARF17 (target genes of miR160) were induced in 84021 but suppressed in H05. Overexpressing miR160 increased cotton sensitivity to HT stress seen as anther indehiscence, associated with the suppression of ARF10 and ARF17 expression, thereby activating the auxin response that leads to anther indehiscence. Supporting this role for auxin, exogenous Indole-3-acetic acid (IAA) leads to a stronger male sterility phenotype both in 84021 and H05 under HT stress. Cotton plants overexpressing miR157 suppressed the auxin signal, and also showed enhanced sensitivity to HT stress, with microspore abortion and anther indehiscence. Thus, we propose that the auxin signal, mediated by miRNAs, is essential for cotton anther fertility under HT stress. PMID- 28635128 TI - Development of a classification model for non-alcoholic steatohepatitis (NASH) using confocal Raman micro-spectroscopy. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in developed countries [1]. A subset of individuals with NAFLD progress to non alcoholic steatohepatitis (NASH), an advanced form of NAFLD which predisposes individuals to cirrhosis, liver failure and hepatocellular carcinoma. The current gold standard for NASH diagnosis and staging is based on histological evaluation, which is largely semi-quantitative and subjective. To address the need for an automated and objective approach to NASH detection, we combined Raman micro spectroscopy and machine learning techniques to develop a classification model based on a well-established NASH mouse model, using spectrum pre-processing, biochemical component analysis (BCA) and logistic regression. By employing a selected pool of biochemical components, we identified biochemical changes specific to NASH and show that the classification model is capable of accurately detecting NASH (AUC=0.85-0.87) in mice. The unique biochemical fingerprint generated in this study may serve as a useful criterion to be leveraged for further validation in clinical samples. PMID- 28635130 TI - Prothrombin complex concentrate for emergent reversal of warfarin: an international survey of hospital protocols. AB - For emergent warfarin reversal, four-factor prothrombin complex concentrates (4FPCCs) are recommended by many international guidelines. We surveyed international clinical sites including members of the Biomedical Excellence for Safer Transfusion (BEST) Collaborative. Most sites have emergent warfarin reversal protocols (53% use PCC, 25% use PCC+ plasma and 2% use plasma alone); however, variation between adjusted dosing and fixed dosing was observed. PMID- 28635131 TI - Characterization of pharyngeal peristaltic pressure variability during volitional swallowing in healthy individuals. AB - BACKGROUND: Recent technological advances incorporated in high resolution manometry have justifiably heightened interest in manometric evaluation of the pharynx. Despite this interest, from both physiologic and clinical perspective there remain a number of unanswered questions regarding the magnitude of variability of pharyngeal pressure phenomena. Therefore, the aim of the present study was to characterize in healthy individuals the inter-subject and recording site specific variability of pharyngeal peristaltic pressure phenomena. METHODS: We studied 32 healthy subjects (age: 21-83 years,20 under 35 years) during dry,5 and 10 mL water swallows *3. Pharyngeal peristaltic pressures were recorded using a high resolution (HR) manometric system and a catheter assembly with 36 circumferential sensors spaced at 1 cm intervals positioned trans-nasally to traverse the pharynx, UES and proximal esophagus. KEY RESULTS: Both site-specific pressure data and the Pharyngeal contractile integral (PhCI) showed wide dispersion ranging between values under 50 mm Hg to over 300 mm Hg and 100-600 mm Hg/cm/s,respectively. There was also wide range of dispersion of data for both the standard deviations and the coefficient of variation for all sites (P=.001). The coefficient of variation for PhCI ranged between 0.02 and 0.25 representing data dispersion of 2-25 percent of the mean among subjects (P=.001). Position, age and volume of swallowed fluid did not influence the magnitude of variability. CONCLUSIONS: Deglutitive Pharyngeal peristalsis generates pressures with significant degree of site-related and inter-subject variability. This variability is not influenced by age, position and volume of swallowed fluid. PMID- 28635132 TI - The fabrication of iron oxide nanoparticle-nanofiber composites by electrospinning and their applications in tissue engineering. AB - This paper reviews the use of iron oxide nanoparticle-nanofiber composites in tissue engineering with a focus on the electrospinning technique. Electrospinning is an established method of scaffold fabrication offering a number of key advantages which include its facile nature, with electrospun materials offering a high surface area to volume ratio, potential for the release of drugs and antimicrobials, controllable fiber diameters and high porosity and permeability. A number of different techniques for the preparation of iron oxide nanoparticles including their functionalization are discussed along with their applications in the biomedical field. The review then focusses on the fabrication of nanoparticle nanofiber composite scaffolds formed using electrospinning. The advantages and disadvantages of current fabrication techniques are discussed including the fabrication of nanofibers using pre-synthesized nanoparticles and post-treatment synthesized nanoparticles. We demonstrate that emerging in-situ synthesis techniques show promise by offering a reduced number of steps and simpler procedures for the production of magnetic scaffolds. These scaffolds have a number of applications in tissue engineering, allowing for improved bone and tissue repair. PMID- 28635134 TI - Locomotor sensitization is expressed by ghrelin and D1 dopamine receptor agonist in the nucleus accumbens core in amphetamine pre-exposed rat. AB - Ghrelin modulates mesolimbic dopaminergic pathways in the brain in addition to its role in feeding. We investigated what roles ghrelin in the nucleus accumbens (NAcc) core may play in mediating locomotor activating effects of amphetamine (AMPH). First, when rats were administered with AMPH (1 mg/kg, i.p.) following a bilateral microinjection of ghrelin (0.1 or 0.5 MUg/side) into the NAcc core, their locomotor activity was significantly enhanced, while these effects were blocked by co-microinjection of ghrelin receptor antagonist (0.5 MUg/side) into this site. Second, we pre-exposed rats to saline or amphetamine (1 mg/kg, i.p.) every 2 to 3 days for a total of four times. After 2 weeks of drug-free withdrawal period, we examined the effect of saline, ghrelin (0.5 MUg/side), D1 dopamine receptor agonist, SKF81297 (0.5 MUg/side) or ghrelin (0.5 MUg/side) + SKF81297 (0.5 MUg/side) directly microinjected into the NAcc core on locomotor activity. When we measured rats' locomotor activity for 1 hour immediately following microinjections, only ghrelin + SKF81297 produces sensitized locomotor activity, while all others have no effects. These results suggest that ghrelin may have a distinct role in the NAcc core to provoke the sensitized locomotor activity induced by psychomotor stimulants, and further, it may produce these effects by interaction with D1 dopamine receptors. PMID- 28635133 TI - Critical role of glioma-associated oncogene homolog 1 in maintaining invasive and mesenchymal-like properties of melanoma cells. AB - Cutaneous melanoma is the most aggressive form of skin cancer. This aggressiveness appears to be due to the cancer cells' ability to reversibly switch between phenotypes with non-invasive and invasive potential, and microphthalmia-associated transcription factor (MITF) is known to play a central role in this process. The transcription factor glioma-associated oncogene homolog 1 (GLI1) is a component of the canonical and noncanonical sonic hedgehog pathways. Although GLI1 has been suggested to be involved in melanoma progression, its precise role and the mechanism underlying invasion remain unclear. Here we investigated whether and how GLI1 is involved in the invasive ability of melanoma cells. Gli1 knockdown (KD) melanoma cell lines, established by using Gli1-targeting lentiviral short hairpin RNA, exhibited a markedly reduced invasion ability, but their MITF expression and activity were the same as controls. Gli1 KD melanoma cells also led to less lung metastasis in mice compared with control melanoma cells. Furthermore, the Gli1 KD melanoma cells underwent a mesenchymal-to-epithelial-like transition, accompanied by downregulation of the epithelial-to-mesenchymal transition (EMT)-inducing transcription factors (EMT-TF) Snail1, Zeb1 and Twist1, but not Snail2 or Zeb2. Collectively, these results indicate that GLI1 is important for maintaining the invasive and mesenchymal-like properties of melanoma cells independent of MITF, most likely by modulating a subset of EMT-TF. Our findings provide new insight into how heterogeneity and plasticity are achieved and regulated in melanoma. PMID- 28635135 TI - The gene expression landscape of pine seedling tissues. AB - Conifers dominate vast regions of the Northern hemisphere. They are the main source of raw materials for timber industry as well as a wide range of biomaterials. Despite their inherent difficulties as experimental models for classical plant biology research, the technological advances in genomics research are enabling fundamental studies on these plants. The use of laser capture microdissection followed by transcriptomic analysis is a powerful tool for unravelling the molecular and functional organization of conifer tissues and specialized cells. In the present work, 14 different tissues from 1-month-old maritime pine (Pinus pinaster) seedlings have been isolated and their transcriptomes analysed. The results increased the sequence information and number of full-length transcripts from a previous reference transcriptome and added 39 841 new transcripts. In total, 2376 transcripts were ubiquitously expressed in all of the examined tissues. These transcripts could be considered the core 'housekeeping genes' in pine. The genes have been clustered in function to their expression profiles. This analysis reduced the number of profiles to 38, most of these defined by their expression in a unique tissue that is much higher than in the other tissues. The expression and localization data are accessible at ConGenIE.org (http://v22.popgenie.org/microdisection/). This study presents an overview of the gene expression distribution in different pine tissues, specifically highlighting the relationships between tissue gene expression and function. This transcriptome atlas is a valuable resource for functional genomics research in conifers. PMID- 28635136 TI - Knockdown of TOR causing ovarian diapause in a genetically stable brachypterous strain of Nilaparvata lugens. AB - Brown planthopper (BPH), Nilaparvata lugens (Stal) (Hemiptera: Delphacidae), is one of the most damaging pests of rice crops. BPH is a migratory insect with a delayed ovarian development in migrants classified as reproductive diapause. The molecular mechanism of reproductive diapause remains unclear, although we suspect it might be regulated by one or more nutrient signaling pathways. The target of rapamycin (TOR) pathway regulates cell growth in response to nutritional information, which raised a hypothesis that TOR mediates BPH reproductive diapause. We used a pure brachypterous strain (BS) and a predominantly macropterous strain (MS) to investigate the roles of NlTOR in BPH reproductive diapause. We found that NlTOR is expressed from the nymphal to adult stages, with a higher expression level of NlTOR in BS adults at 1, 2, and 4 days posteclosion than in MS at the same time points. Injection of dsNlTOR into BS nymphs resulted in the termination of BPH female ovary development and the retardation of nymph development. We infer that TOR signaling functions in BPH reproductive diapause by regulating the expression of NlFoxA and NlVitellogenin. PMID- 28635137 TI - Effect of body position, eyelid manipulation, and manual jugular compression on intraocular pressure in clinically normal cats. AB - OBJECTIVE: To determine the effect of body position, eyelid manipulation, and manual jugular compression on intraocular pressure (IOP) in clinically normal cats. ANIMAL STUDIED: TWENTY-ONE ADULT CLIENT-OWNED DOMESTIC SHORTHAIR CATS: PROCEDURES: The IOP was measured by means of rebound tonometer. A baseline IOP was measured in all cats in ventral recumbency with normal head position (horizontal to the ground) with no pressure on the neck or eyelids. To measure the IOP in dorsal recumbency, each cat was held in the dorsal recumbency position for 5 min. Four different manipulations were used, including maximal dorsoventral extension of the eyelids, lateral eyelid extension, manual compression of the ipsilateral jugular vein, and manual compression of both jugular veins. IOP after all the manipulations was measured in ventral recumbency. RESULTS: Overall the mean +/- SD IOP values of all eyes in ventral recumbency, dorsal recumbency, maximal dorsoventral extension of the eyelids, lateral eyelid extension, compression of the right jugular vein, compression of the left jugular vein, and compression of the both jugular veins were 16.1 +/- 2.9 mmHg, 17.1 +/- 5.0 mmHg, 21.7 +/- 5.8 mmHg, 22.4 +/- 5.6 mmHg, 15.0 +/- 3.7 mmHg, 14.9 +/- 3.7 mmHg, and 16.1 +/- 4.6 mmHg, respectively. IOP was increased significantly in maximal dorsoventral extension of the eyelids (P = 0.001) and lateral eyelid extension (P = 0.001) compared to baseline. CONCLUSIONS: Results of this study may be beneficial for clinicians to be aware of the effects of body position, traction, and compression of the eyelids and neck on IOP during ophthalmic examination in cats. PMID- 28635138 TI - Snake spectacle vessel permeability to sodium fluorescein. AB - OBJECTIVE: Assess vascular permeability of the snake spectacle to sodium fluorescein during resting and shedding phases of the ecdysis cycle. ANIMAL STUDIED: Ball python (Python regius). PROCEDURES: The snake was anesthetized, and spectral domain optic coherence tomography was performed prior to angiographic procedures. An electronically controlled digital single-lens reflex camera with a dual-head flash equipped with filters suitable for fluorescein angiography was used to make images. Sodium fluorescein (10%) solution was administered by intracardiac injection. Angiographic images were made as fluorescein traversed the vasculature of the iris and spectacle. Individually acquired photographic frames were assessed and sequenced into pseudovideo image streams for further evaluation CONCLUSIONS: Fluorescein angiograms of the snake spectacle were readily obtained. Vascular permeability varied with the phase of ecdysis. Copious leakage of fluorescein occurred during the shedding phase. This angiographic method may provide diverse opportunities to investigate vascular aspects of snake spectacle ecdysis, dysecdysis, and the integument in general. PMID- 28635139 TI - Improving precision of ability estimation: Getting more from response times. AB - By considering information about response time (RT) in addition to response accuracy (RA), joint models for RA and RT such as the hierarchical model (van der Linden, 2007) can improve the precision with which ability is estimated over models that only consider RA. The hierarchical model, however, assumes that only the person's speed is informative of ability. This assumption of conditional independence between RT and ability given speed may be violated in practice, and ignores collateral information about ability that may be present in the residual RTs. We propose a posterior predictive check for evaluating the assumption of conditional independence between RT and ability given speed. Furthermore, we propose an extension of the hierarchical model that contains cross-loadings between ability and RT, which enables one to take additional collateral information about ability into account beyond what is possible in the standard hierarchical model. A Bayesian estimation procedure is proposed for the model. Using simulation studies, the performance of the model is evaluated in terms of parameter recovery, and the possible gain in precision over the standard hierarchical model and an RA-only model is considered. The model is applied to data from a high-stakes educational test. PMID- 28635140 TI - Noradrenergic signaling in the VTA modulates cocaine craving. AB - Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha1 -adrenergic and alpha2 -adrenergic receptors (alpha1 -ARs and alpha2 -ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague-Dawley rats was attenuated by intra-VTA prazosin or terazosin-two selective alpha1 -AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective alpha1 -AR agonist phenylephrine as well as alpha2 -AR antagonist RX 821002, whereas the selective beta-AR antagonist propranolol had no effects. In addition, blockade of alpha1 -AR in the VTA prevented alpha2 -AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA alpha1 -AR and alpha2 -AR but not beta-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving. PMID- 28635141 TI - High sensitivity non-invasive detection of calcifications deep inside biological tissue using Transmission Raman Spectroscopy. AB - The aim of this research was to develop a novel approach to probe non-invasively the composition of inorganic chemicals buried deep in large volume biological samples. The method is based on advanced Transmission Raman Spectroscopy (TRS) permitting chemical specific detection within a large sampling volume. The approach could be beneficial to chemical identification of the breast calcifications detected during mammographic X-ray procedures. The chemical composition of a breast calcification reflects the pathology of the surrounding tissue, malignant or benign and potentially the grade of malignancy. However, this information is not available from mammography, leading to excisional biopsy and histopathological assessment for a definitive diagnosis. Here we present, for the first time, a design of a new high performance deep Raman instrument and demonstrate its capability to detect type II calcifications (calcium hydroxyapatite) at clinically relevant concentrations and depths of around 40 mm in phantom tissue. This is around double the penetration depth achieved with our previous instrument design and around two orders of magnitude higher than that possible when using conventional Raman spectroscopy. PMID- 28635143 TI - Controlling the Photonic Properties of Cholesteric Cellulose Nanocrystal Films with Magnets. AB - The self-assembly of cellulose nanocrystals is a powerful method for the fabrication of biosourced photonic films with a chiral optical response. While various techniques have been exploited to tune the optical properties of such systems, the presence of external fields has yet to be reported to significantly modify their optical properties. In this work, by using small commercial magnets (~ 0.5-1.2 T) the orientation of the cholesteric domains is enabled to tune in suspension as they assemble into films. A detailed analysis of these films shows an unprecedented control of their angular response. This simple and yet powerful technique unlocks new possibilities in designing the visual appearance of such iridescent films, ranging from metallic to pixelated or matt textures, paving the way for the development of truly sustainable photonic pigments in coatings, cosmetics, and security labeling. PMID- 28635142 TI - Protective Effects Induced by Microwave-Assisted Aqueous Harpagophytum Extract on Rat Cortex Synaptosomes Challenged with Amyloid beta-Peptide. AB - Harpagophytum procumbens is a plant species that displays anti-inflammatory properties in multiple tissues. The iridoid glycosides arpagoside, harpagide, and procumbide appear to be the most therapeutically important constituents. In addition, harpagoside treatment exerted neuroprotective effects both in vitro and in vivo. Considering these findings, the aim of the present work is to explore the possible protective role of the previously described microwave-assisted aqueous extract of H. procumbens on rat hypothalamic (Hypo-E22) cells, and in rat cortex challenged with amyloid beta-peptide (1-40). In this context, we assayed the protective effects induced by H. procumbens by measuring the levels of malondialdehyde, 3-hydroxykynurenine (3-HK), brain-derived neurotrophic factor, and tumor necrosis factor-alpha, 3-HK. Finally, we evaluated the effects of H. procumbens treatment on cortex levels of dopamine, norepinephrine, and serotonin. H. procumbens extract was well tolerated by Hypo-E22 cells and upregulated brain derived neurotrophic factor gene expression but down-regulated tumor necrosis factor-alpha gene expression. In addition, the extract reduced amyloid beta peptide stimulation of malondialdehyde and 3-HK and blunted the decrease of dopamine, norepinephrine, and serotonin, in the cortex. In this context, our work supports further studies for the evaluation and confirmation of Harpagophytum in the management of the clinical symptoms related to Alzheimer's disease. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28635144 TI - Not all cultural values are created equal: Cultural change in China reexamined through Google books. AB - Given its major transformations in recent decades, China has figured prominently in research on cultural change. Previous research converges in showing a general trend towards individualism in contemporary China while noting that rising individualism tends to coexist with enduring collectivism. To further understand this, we tested whether perceived traditional importance of cultural values would modulate the trajectory of cultural change reflected in word usage frequencies in published books. We re-analysed Google's Chinese corpus since 1980 based on a broad sample of words associated with individualism-collectivism. We replicated the pattern of rising individualism and declining collectivism among words of modest and low perceived traditional importance. Most important, however, collectivistic words of high perceived traditional importance increased in usage frequencies with time, thus departing from the general trend towards individualism. Overall, our research underscores the role of core culture in cultural maintenance during times of rapid cultural change. PMID- 28635145 TI - Chemical Vapor Deposition of Bernal-Stacked Graphene on a Cu Surface by Breaking the Carbon Solubility Symmetry in Cu Foils. AB - The synthesis of Bernal-stacked multilayer graphene over large areas is intensively investigated due to the value of this material's tunable electronic structure, which makes it promising for use in a wide range of optoelectronic applications. Multilayer graphene is typically formed via chemical vapor deposition onto a metal catalyst, such as Ni, a Cu-Ni alloy, or a Cu pocket. These methods, however, require sophisticated control over the process parameters, which limits the process reproducibility and reliability. Here, a new synthetic method for the facile growth of large-area Bernal-stacked multilayer graphene with precise layer control is proposed. A thin Ni film is deposited onto the back side of a Cu foil to induce controlled diffusion of carbon atoms through bulk Cu from the back to the front. The resulting multilayer graphene exhibits a 97% uniformity and a sheet resistance of 50 Omega sq-1 with a 90% transmittance after doping. The growth mechanism is elucidated and a generalized kinetic model is developed to describe Bernal-stacked multilayer graphene growth by the carbon atoms diffused through bulk Cu. PMID- 28635146 TI - The effect of CT scanners in the trauma room - an observational study. AB - BACKGROUND: A CT scanner incorporated in the trauma resuscitation bay may benefit trauma patients by fastening work-up times; however, evidence in the area is still sparse. We assessed if time from admission to first CT scan was lower after incorporation of a CT scanner in the resuscitation bay. METHODS: We included trauma patients admitted in two 1-year periods, before and after a major rebuilding of the trauma room. Beforehand, one CT scanner was located in an adjacent room. After the rebuilding, two mobile CT scanners were placed in the resuscitation bays, where a moving gantry was combined with a trauma resuscitation table. Subgroup analyses were performed on severely injured and patients with traumatic brain injury. RESULTS: We included 784 patients before and 742 patients after the reconstruction. Case-mix differed between study periods as there was a higher proportion of severe injuries, traumatic brain injury and penetrating trauma in the after period. We found a minor increase in time to CT in the after period (20 vs. 21 min, P = 0.008). In a multivariate regression analysis adjusted for differences in case-mix and with time to CT as outcome, period was an insignificant explanatory variable [beta (before vs. after): 0.96 min 95% CI: 0.9-1.02, P = 0.3]. In both subgroups, we found no significant difference in time to CT. CONCLUSION: We found no reduction in time to CT scan, when comparing a period with mobile CT scanners incorporated in the resuscitation bay to an earlier period with a CT scanner next to the trauma room. PMID- 28635147 TI - Life-threatening aortic dissection with cardiac tamponade during catheter ablation for ventricular tachycardia originating from left coronary cusp. PMID- 28635148 TI - How common are cranial sesamoids among squamates? AB - Sesamoids are elements that originate as intratendinous structures due to genetic and epigenetic factors. These elements have been reported frequently in vertebrates, although cranial sesamoids have been recorded almost exclusively in non-tetrapod Osteichthyes. The only tetrapod cranial sesamoids reported until now have been the transiliens cartilage (of crocodiles and turtles), and another one located in the quadrate-mandibular joint of birds. Here, we examined seven squamate species using histological sections, dissections of preserved specimens, dry skeletons, cleared and stained specimens, computed tomographies (CT), and report the presence of other cranial sesamoids. One is attached to the cephalic condyle of the quadrate, embedded in the bodenaponeurosis and jaw adductor muscles of Ophiodes intermedius (Anguidae). The other sesamoid is found at the base of the basicranium of several squamates, capping the sphenoccipital tubercle, on the lateral side of the basioccipital-basisphenoid suture. This bone has previously been reported as "element X." We reinterpret it as a basicranial sesamoid, as it is associated with tendons of the cranio-cervical muscles. This bone seems to have the function of resisting tension-compression forces generated by the muscle during flexion the head. This element was previously known in several squamates, and we confirmed its presence in three additional squamate families: Gymnophthalmidae, Gekkonidae, and Pygopodidae. The evidence suggests that cranial sesamoids are a widespread character in squamates, and it is possible that this feature has been present since the origin of the group. PMID- 28635149 TI - Underuse of risk assessment and overuse of computed tomography pulmonary angiography in patients with suspected pulmonary thromboembolism. AB - BACKGROUND: Evidence suggests the potential overuse of computed tomography pulmonary angiography (CTPA) in patients with suspected pulmonary thromboembolism (PTE) in the absence of consistent use of pre-test clinical prediction rules and D-dimer assays. AIM: To evaluate use and diagnostic utility of clinical prediction rules and D-dimer assay in patients with suspected PTE and quantify potentially avoidable overuse of CTPA in low risk patients. METHODS: A total of 344 consecutive patients undergoing CTPA at a tertiary hospital was studied with regards to the use of D-dimer assays and clinical prediction rules for PTE. For each patient, a modified Wells score (mWS), revised Geneva score and PISA model were calculated retrospectively; performance characteristics for each rule for PTE were determined with reference to results of CTPA. Results for the mWS and D dimer assays (when performed) were used to estimate the overuse of CTPA according to risk category. RESULTS: Use of a clinical prediction rule was documented in only 5.0% of cases. Of 269 low-risk patients who had a calculated mWS <=4, only 64 (23.8%) had a D-dimer assay performed, with 30 (11.1%) having a PTE on CTPA. Among 75 patients with an mWS >4, 23 (30.7%) had a PTE on CTPA (P < 0.001). Compared to other prediction rules, an mWS>4 had the highest positive predictive value (31.0%) for PTE; all rules demonstrated similar negative predictive values for low-risk scores (87-89%). After adjusting for an 11% false negative rate for PTE in patients with low-risk mWS, overuse of CTPA was reported in up to 190 (55.2%) patients. CONCLUSION: More than 50% of patients with suspected PTE may be subject to unwarranted use of CTPA in the absence of pre-test clinical prediction rules coupled with D-dimer assays. PMID- 28635150 TI - A pilot study of "post-seclusion and/or restraint review" intervention with patients and staff in a mental health setting. AB - PURPOSE: To develop and evaluate a "post-seclusion and/or restraint review" (PSRR) intervention implemented in an acute psychiatric care unit. DESIGN AND METHODS: Twelve staff members and three patients were enrolled in a participatory case study. To evaluate PSRR intervention, qualitative analysis was carried out. Seclusion and restraint use 6 months before and after the PSRR implementation was compared. FINDINGS: Nurses reported that they were able to explore the patient's feelings during the PSRR intervention with patients, which led to restoration of the therapeutic relationship. PSRR with the treatment team was perceived as a learning opportunity, which allowed to improve the therapeutic intervention. Both the use of seclusion and the time spent in seclusion were significantly reduced 6 months after the implementation of PSRR intervention. PRACTICE IMPLICATION: Our results suggest the efficacy of PSRR in overcoming the discomfort perceived by both staff and patient and, in the meantime, in reducing the need for coercive procedures. Systematic PSRR could permit to improve the quality of care and the safety of aggressiveness management. PMID- 28635151 TI - Propagation of Gaussian and Laguerre-Gaussian vortex beams through mouse brain tissue. AB - Light transmission of Gaussian (G) and Laguerre-Gaussian (LG) vortex beams in mouse brain tissue is investigated. Transmittance is measured with different orbital angular momentums (OAM) at various tissue thicknesses. In both ballistic and diffusive regions, transmittances of G and LG beams show no significant difference. The transition point from ballistic to diffusive region for the mouse brain tissue is determined at about 480 MUm. The observed transmittances of the G and LG beams show independence on OAM modes, which may be attributed to poorly understood interference effects from brain tissue. PMID- 28635152 TI - A DNA Structure Containing AgI -Mediated G:G and C:C Base Pairs. AB - Metal-mediated base pairs have been extensively utilized in many research fields, including genetic-code extension, novel therapeutics development, and nanodevice design. Compared to other cations, AgI is more flexible in pairing with natural base pairs. Herein, we present a DNA structure containing two C-AgI -C pairs and the first reported G-AgI -G pair in a short 8mer DNA strand. This structure not only provides detailed insight into these AgI -mediated base-pairing patterns in DNA, but also represents the first nonhelical DNA structure driven by heavy-metal ions, thus further contributing to the structural diversity of DNA. This unique complex structure is highly sequence-dependent, thus implying functional potentials as a new DNA aptamer that can bind and recognize silver ions. These results not only advance our understanding of the interactions between AgI and nucleobases, but also provide a unique structural component for the rational design of new DNA nanodevices. PMID- 28635153 TI - Topical Silymarin Administration for Prevention of Capecitabine-Induced Hand-Foot Syndrome: A Randomized, Double-Blinded, Placebo-Controlled Clinical Trial. AB - Hand-foot syndrome (HFS) is a frequent dose-limiting adverse reaction of capecitabine in patient with gastrointestinal cancers. Silymarin is a polyphenolic flavonoid extracted from the Silybum marianum that exhibits strong antioxidant and antiinflammatory activities. In this study, we evaluated silymarin efficacy in prevention of capecitabine-induced HFS in patients with gastrointestinal cancers, as the first human study. During this pilot, randomized, double-blinded, placebo-controlled clinical trial, the effect of silymarin gel 1%, which is applied on the palms and soles twice daily starting at the first day of chemotherapy for 9 weeks, on HFS occurrence was assessed. Forty patients fulfilled the inclusion criteria assigned to the silymarin or placebo group. World Health Organization HFS grading scale scores were recorded at baseline and every 3 weeks during these 9 weeks. The median WHO HFS scores were significantly lower in silymarin group at the end of the 9th week (p < 0.05). The scores increased significantly in both placebo and silymarin groups during chemotherapy, but there was a delay for HFS development and progression in silymarin group. Prophylactic administration of silymarin topical formulation could significantly reduce the severity of capecitabine-induced HFS and delays its occurrence in patients with gastrointestinal cancer after 9 weeks of application. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28635154 TI - Chiral Responsive Liquid Quantum Dots. AB - How to convert the weak chiral-interaction into the macroscopic properties of materials remains a huge challenge. Here, this study develops highly fluorescent, selectively chiral-responsive liquid quantum dots (liquid QDs) based on the hydrophobic interaction between the chiral chains and the oleic acid-stabilized QDs, which have been designated as (S)-1810-QDs. The fluorescence spectrum and liquidity of thermal control demonstrate the fluorescence properties and the fluidic behavior of (S)-1810-QDs in the solvent-free state. Especially, (S)-1810 QDs exhibit a highly chiral-selective response toward (1R, 2S)-2-amino-1,2 diphenyl ethanol. It is anticipated that this study will facilitate the construction of smart chiral fluidic sensors. More importantly, (S)-1810-QDs can become an attractive material for chiral separation. PMID- 28635155 TI - Representation and Computation in Cognitive Models. AB - One of the central issues in cognitive science is the nature of human representations. We argue that symbolic representations are essential for capturing human cognitive capabilities. We start by examining some common misconceptions found in discussions of representations and models. Next we examine evidence that symbolic representations are essential for capturing human cognitive capabilities, drawing on the analogy literature. Then we examine fundamental limitations of feature vectors and other distributed representations that, despite their recent successes on various practical problems, suggest that they are insufficient to capture many aspects of human cognition. After that, we describe the implications for cognitive architecture of our view that analogy is central, and we speculate on roles for hybrid approaches. We close with an analogy that might help bridge the gap. PMID- 28635156 TI - Pyoderma gangrenosum and underlying diseases in Japanese patients: A regional long-term study. AB - Pyoderma gangrenosum (PG) is a chronic inflammatory disease of unknown cause that presents as an inflammatory and ulcerative disorder of the skin. PG is often associated with an underlying systemic disease. However, the frequencies of the underlying diseases are unclear in Japanese patients. In this retrospective, observational study, all patients diagnosed with PG who visited dermatology departments of nine regional hospitals in and around Ibaraki Prefecture were collected from 1982 to 2011 or 2014. The diagnoses of PG were based on the characteristic clinical and histological appearances and ruling out of infection. Sixty-two PG patients, including 29 males and 33 females, were identified. The ages of onset were 16-89 years, and the mean age was 50.2 years. Fifty (80%) of the 62 patients presented with an ulcerative PG, and the lower leg was the most common site (74%). Forty-six (74%) PG patients had underlying diseases. The most frequent was ulcerative colitis (32%), followed by myelodysplastic syndrome (11%), rheumatoid arthritis (6%) and aortitis syndrome (5%). For treatment, 54 cases (87%) received systemic corticosteroids and 10 received additional treatment with cyclosporin. There was no significant correlation between underlying diseases and response to the initial treatment. Multivariate analysis revealed that the number of affected sites negatively correlated with successful initial treatment. Fifteen (24%) of the 62 cases relapsed. In conclusion, ulcerative colitis and hematological disorders were frequently associated with PG while approximately a quarter of the cases were idiopathic. PMID- 28635157 TI - Longitudinal study on the use of dried blood spots for home monitoring in children after kidney transplantation. AB - The use of DBSs for home monitoring has been limited due to unsatisfactory blood sampling and analytical difficulties. The aim of this longitudinal feasibility trial was to assess the utility of DBS to monitor TAC and Cr at home in transplant recipients. A total of 30 participants (2-21 years, mean+/-SD, 13.6+/ 5.4 year) were enrolled over 12 months. Eighteen were males. Monthly DBS samples were obtained at home and mailed to the central laboratory for analysis of TAC and Cr. Nineteen patients completed the study, and 216 cards were received in the laboratory from a total of 279 cards expected, with 416/519 (80%) blood spots being suitable for analysis. We found a high correlation between blood TAC and Cr levels by DBS and the clinical laboratory, R2 =.81 and .95, respectively. Fifteen parents and 15 youth completed measures of satisfaction with and preference for DBS testing. All but one parent/caregiver and youth reported satisfaction and preference for this method of testing over laboratory blood draws. We conclude that home DBS monitoring is a feasible method to monitor TAC and Cr in pediatric transplant recipients. PMID- 28635159 TI - Nutrition in Renal Supportive Care: Patient-driven and flexible. AB - Renal Supportive Care is an alternative treatment pathway in advanced chronic kidney disease that is being increasingly adopted, particularly in the elderly. Renal Supportive Care uses principles of palliative care and has been developed to enhance the care for dialysis patients with a high symptom burden and those being managed on a non-dialysis pathway. Nutrition management is often an under recognized component of care and can play an important role in improving patients' quality of life to reduce symptom burden, support physical function and independence and provide appropriate counselling to patients and their families to ensure the goals of Renal Supportive Care are met. Nutrition interventions need to target patient and treatment goals, with frequent monitoring to ensure patient needs are being met. This review outlines available literature on this topic and suggests some practical ways in which nutrition can be enhanced for these patients. PMID- 28635161 TI - The contribution of unrecorded alcohol to health harm. PMID- 28635162 TI - Chlamydia trachomatis Is Responsible for Lipid Vacuolation in the Amniotic Epithelium of Fetal Gastroschisis. AB - BACKGROUND: Vacuolated amniotic epithelium with lipid droplets in gastroschisis placentas is an unusual finding. Mass spectrometry of lipid droplets identified triglycerides, ester-linked to an unusual pattern of fatty acids. We hypothesize that these findings result from a Chlamydia trachomatis infection during the periconceptional period. The rising incidence of chlamydia infections has paralleled the increasing prevalence of gastroschisis among women less than 25 years of age. Histologically, young women are at greatest risk for a chlamydia infection due to their immature columnar epithelium, the preferential site for attachment of Chlamydia trachomatis infectious particle (elementary body). METHODS: Chlamydia trachomatis survive in an inclusion, relying on its host to acquire essential nutrients, amino acids, and nucleotides for survival and replication. If essential nutrients are not available, the bacteria cannot replicate and may be trafficked to the lysosome for degradation or remain quiescent, within the inclusion, subverting innate immunologic clearance. RESULTS: Chlamydiae synthesize several lipids (phosphatidylethanolamine, phosphatidylserine, and phosphoatidylglycerol); however, their lipid content reveal eukaryotic lipids (sphingomyelin, cholesterol, phosphatidylcholine, and phosphatidylinositol), evidence that chlamydiae "hijack" host lipids for expansion and replication. CONCLUSION: The abnormal amniotic epithelial findings are supported by experimental evidence of the trafficking of host lipids into the chlamydiae inclusion. If not lethal, what harm will elementary bodies inflict to the developing embryo? Do these women have a greater pro-inflammatory response to an environmental exposure, whether cigarette smoking, change in partner, or a pathogen? Testing the hypothesis that Chlamydia trachomatis is responsible for amniotic epithelium vacuoles will be a critical first step. Birth Defects Research 109:1003-1010, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28635158 TI - Prepregnancy overweight and obesity are associated with impaired child neurodevelopment. AB - The authors examined the relationship of prepregnancy body mass index (BMI) and gestational weight gain (GWG) with child neurodevelopment. Mother-child dyads were a subgroup (n = 2,084) of the Child Health and Development Studies from the Oakland, California, area enrolled during pregnancy from 1959 to 1966 and followed at child age 9 years. Linear regression was used to examine associations between prepregnancy BMI, GWG, and standardized Peabody Picture Vocabulary Test and Raven Progressive Matrices scores and to evaluate effect modification of GWG by prepregnancy BMI. Before pregnancy, 77% of women were normal weight, 8% were underweight, 11% were overweight, and 3% were obese. Associations between GWG and child outcomes did not vary by prepregnancy BMI, suggesting no evidence for interaction. In multivariable models, compared to normal prepregnancy BMI, prepregnancy overweight and obesity were associated with lower Peabody scores (b: -1.29; 95% CI [-2.6, -0.04] and b: -2.7; 95% CI [-5.0, -0.32], respectively). GWG was not associated with child Peabody score [b: -0.03 (95% CI: -0.13, 0.07)]. Maternal BMI and GWG were not associated with child Raven score (all P >0.05). Maternal prepregnancy overweight and obesity were associated with lower scores for verbal recognition in mid-childhood. These results contribute to evidence linking maternal BMI with child neurodevelopment. Future research should examine the role of higher prepregnancy BMI values and the pattern of pregnancy weight gain in child cognitive outcomes. PMID- 28635164 TI - Assessing the toxicological significance of new psychoactive substances in fatalities. AB - The number of new psychoactive substances (NPS) has increased significantly, especially within the last 5 years. The EMCDDA conducts risks assessments of such substances, especially in relation to serious adverse events. Examination of the individual health risks of a substance is a fundamental requirement of the process. Based on a number of considerations, the Toxicological Significance Score has been developed to support the risk assessment of NPS by allowing the role of a substance in deaths to be better assessed and classified. PMID- 28635163 TI - Early pregnancy body mass index modifies the association of pre-pregnancy dietary patterns with serum polyunsaturated fatty acid concentrations throughout pregnancy in Brazilian women. AB - Dietary patterns (DPs) have been described as an important factor that may influence polyunsaturated fatty acid (PUFA) concentrations and body mass index (BMI) during pregnancy. We aim to evaluate the association between pre-pregnancy DPs and serum PUFA percentages throughout pregnancy considering early pregnancy BMI as a possible effect modifier. A prospective cohort of 154 pregnant women was followed (5th-13th, 20th-26th, and 30th-36th gestational weeks). Serum PUFA concentrations (total n-3 and total n-6, eicosapentaenoic + docosahexaenoic acids) were measured in each trimester and expressed as percentages. The n-6/n-3 ratio was calculated. Longitudinal linear mixed-effects models including interaction terms between DPs and early pregnancy BMI were employed. Serum PUFA percentages declined, whereas the n-6/n-3 ratio, monounsaturated, and saturated percentages increased throughout pregnancy for all BMI categories. Three pre pregnancy DPs were identified by principal component analysis (common Brazilian, healthy, and processed). Overweight women with higher adherence to the common Brazilian and to the healthy DPs presented reduced n-3 PUFA percentage and increased n-6 percentages and n-6/n-3 ratio compared to under or normal weight women. Obese women with higher adherence to the processed DP presented a more pronounced decrease of total n-3 percentage compared to under or normal weight women. Early pregnancy BMI modified the effect of pre-pregnancy DPs on PUFA profile throughout gestation. Higher adherence to the healthy pattern was associated with increased n-3 percentage, except for overweight women. Only for processed DP was the behaviour of PUFA the same for all BMI categories, showing a worse evolution profile, that is, increased n-6 and reduced n-3 fractions. PMID- 28635165 TI - Therapeutic targeting of the mitochondrial reactive oxygen species engine prevents portal hypertension and hepatic fibrogenesis. PMID- 28635166 TI - HBV reactivation after HCV eradication: Deja Vu. PMID- 28635167 TI - Response to Lipopolysaccharide binding protein predicts decompensated cirrhosis mortality? It is too early. PMID- 28635168 TI - Malignant potential of hepatocellular adenoma. PMID- 28635169 TI - Potential drug-drug interactions in older adults: A population-based study. AB - AIM: To evaluate the potential drug-drug interactions (PDDI) between drugs used by older adults, any associated factors and recommended clinical management. METHODS: A cross-sectional, population-based study was carried out through a home survey of 934 older adults (from December 2009 to April 2010). A questionnaire was applied, and the participants were asked to show all the drugs used and their respective prescriptions, thus providing data to identify polypharmacy, self medication and PDDI. PDDI, their consequences, severity and clinical management were identified using Micromedex. RESULTS: Overall, 2846 drugs and 665 PDDI were identified, 71.0% of which were moderate and 22.4% serious. The prevalence of PDDI was 36.9%. Drugs with a narrow therapeutic index were involved in 17.0% of the PDDI. The variables female sex (PR = 1.11, 95% CI 1.02-1.20), age >=80 years (PR = 1.15, 95% CI 1.03-1.28), no polypharmacy (PR = 0.72, 95% CI 0.67-0.78) and no hospitalization in the past year (PR = 0.90, 95% CI 0.82-0.97) remained associated with the presence of three or more PDDI in the final multivariate analysis model. CONCLUSIONS: Most PDDI were related to routinely used drugs (enalapril, hydrochlorothiazide, calcium, captopril, levothyroxine and simvastatin), and more than one-third of the older adults were exposed to PDDI with the possible risk of serious health consequences. Drugs with a narrow therapeutic index were involved in several PDDI, with increased risk of toxicity. The clinical management procedures most recommended are dose adjustment and dosing changes, control of the drugs' serum levels, and monitoring of the clinical conditions. Geriatr Gerontol Int 2017; 17: 2336-2346. PMID- 28635170 TI - Alginate oligosaccharides modify hyphal infiltration of Candida albicans in an in vitro model of invasive human candidosis. AB - AIMS: A novel alginate oligomer (OligoG CF-5/20) has been shown to potentiate antifungal therapy against a range of fungal pathogens. The current study assessed the effect of this oligomer on in vitro virulence factor expression and epithelial invasion by Candida species. METHODS AND RESULTS: Plate substrate assays and epithelial models were used to assess Candida albicans (CCUG 39343 and ATCC 90028) invasion, in conjunction with confocal laser scanning microscopy and histochemistry. Expression of candidal virulence factors was determined biochemically and by quantitative PCR (qPCR). Changes in surface charge of C. albicans following OligoG treatment were analysed using electrophoretic light scattering. OligoG induced marked alterations in hyphal formation in the substrate assays and reduced invasion in the epithelial model (P < 0.001). Significant dose-dependent inhibition of phospholipase activity in C. albicans was evident following OligoG treatment (P < 0.05). While OligoG binding failed to affect alterations in surface charge (P > 0.05), qPCR demonstrated a reduction in phospholipase B (PLB2) and SAPs (SAP4 and SAP6) expression. CONCLUSION: OligoG CF 5/20 reduced in vitro virulence factor expression and invasion by C. albicans. SIGNIFICANCE AND IMPACT OF THE STUDY: These results, and the previously described potentiation of antifungal activity, define a potential therapeutic opportunity in the treatment of invasive candidal infections. PMID- 28635171 TI - Replacing PAPS: In vitro phase II sulfation of steroids with the liver S9 fraction employing ATP and sodium sulfate. AB - In vitro technologies provide the capacity to study drug metabolism where in vivo studies are precluded due to ethical or financial constraints. The metabolites generated by in vitro studies can assist anti-doping laboratories to develop protocols for the detection of novel substances that would otherwise evade routine screening efforts. In addition, professional bodies such as the Association of Official Racing Chemists (AORC) currently permit the use of in vitro-derived reference materials for confirmation purposes providing additional impetus for the development of cost effective in vitro metabolism platforms. In this work, alternative conditions for in vitro phase II sulfation using human, equine or canine liver S9 fraction were developed, with adenosine triphosphate (ATP) and sodium sulfate in place of the expensive and unstable co-factor 3' phosphoadenosine-5'-phosphosulfate (PAPS), and employed for the generation of six representative steroidal sulfates. Using these conditions, the equine in vitro phase II metabolism of the synthetic or so-called designer steroid furazadrol ([1',2']isoxazolo[4',5':2,3]-5alpha-androstan-17beta-ol) was investigated, with ATP and Na2 SO4 providing comparable metabolism to reactions using PAPS. The major in vitro metabolites of furazadrol matched those observed in a previously reported equine in vivo study. Finally, the equine in vitro phase II metabolism of the synthetic steroid superdrol (methasterone, 17beta-hydroxy-2alpha,17alpha dimethyl-5alpha-androstan-3-one) was performed as a prediction of the in vivo metabolic profile. PMID- 28635172 TI - Doxorubicin kinetics and effects on lung cancer cell lines using in vitro Raman micro-spectroscopy: binding signatures, drug resistance and DNA repair. AB - Raman micro-spectroscopy is a non-invasive analytical tool, whose potential in cellular analysis and monitoring drug mechanisms of action has already been demonstrated, and which can potentially be used in pre-clinical and clinical applications for the prediction of chemotherapeutic efficacy. To further investigate such potential clinical application, it is important to demonstrate its capability to differentiate drug mechanisms of action and cellular resistances. Using the example of Doxorubicin (DOX), in this study, it was used to probe the cellular uptake, signatures of chemical binding and subsequent cellular responses, of the chemotherapeutic drug in two lung cancer cell lines, A549 and Calu-1. Multivariate statistical analysis was used to elucidate the spectroscopic signatures associated with DOX uptake and subcellular interaction. Biomarkers related to DNA damage and repair, and mechanisms leading to apoptosis were also measured and correlated to Raman spectral profiles. Results confirm the potential of Raman spectroscopic profiling to elucidate both drug kinetics and pharmacodynamics and differentiate cellular drug resistance associated with different subcellular accumulation rates and subsequent cellular response to DNA damage, pointing towards a better understanding of drug resistance for personalised targeted treatment. PMID- 28635173 TI - Laparoscopic surgery for sigmoid colon cancer after multiple operations including urinary diversion with Indiana pouch: A case report. AB - A 73-year-old man with lower abdominal pain was diagnosed at our hospital with sigmoid colon cancer. He had previously undergone radical cystectomy with Indiana pouch construction and gastrectomy to treat bladder cancer and gastric cancer, respectively. We performed a laparoscopic Hartmann's operation with Japanese D3 lymph node dissection. We observed severe adhesion in the abdominal cavity; adhesions between the urostomy and sigmoid colon were particularly severe. The tumor had invaded to the distal rectum, which had adhered to the pubic bone and the previously reconstructed urinary pouch. By performing careful and persistent laparoscopic dissection, we completed the operation without damaging the urostomy and with no remnant tumor tissue (R0). The postoperative course was uneventful, and the patient was doing well with no evidence of cancer recurrence 1 year after surgery. PMID- 28635175 TI - Abstractband anlasslich der 25. Jahrestagung der Arbeitsgemeinschaft Dermatologische Histologie (ADH), 23. bis 25. Juni 2017 in Stuttgart-Bad Cannstatt. PMID- 28635174 TI - Flash Light Millisecond Self-Assembly of High chi Block Copolymers for Wafer Scale Sub-10 nm Nanopatterning. AB - One of the fundamental challenges encountered in successful incorporation of directed self-assembly in sub-10 nm scale practical nanolithography is the process compatibility of block copolymers with a high Flory-Huggins interaction parameter (chi). Herein, reliable, fab-compatible, and ultrafast directed self assembly of high-chi block copolymers is achieved with intense flash light. The instantaneous heating/quenching process over an extremely high temperature (over 600 degrees C) by flash light irradiation enables large grain growth of sub-10 nm scale self-assembled nanopatterns without thermal degradation or dewetting in a millisecond time scale. A rapid self-assembly mechanism for a highly ordered morphology is identified based on the kinetics and thermodynamics of the block copolymers with strong segregation. Furthermore, this novel self-assembly mechanism is combined with graphoepitaxy to demonstrate the feasibility of ultrafast directed self-assembly of sub-10 nm nanopatterns over a large area. A chemically modified graphene film is used as a flexible and conformal light absorbing layer. Subsequently, transparent and mechanically flexible nanolithography with a millisecond photothermal process is achieved leading the way for roll-to-roll processability. PMID- 28635176 TI - Genetic loss of the muscarinic M3 receptor markedly alters bile formation and cholestatic liver injury in mice. AB - AIM: Hepatic innervation represents a potentially underestimated regulator of liver function and regeneration. The muscarinic 3 receptor (M3 -R) is the primary cholangiocyte receptor for the afferent parasympathetic innervation of bile ducts. We aimed to determine the specific role of the M3 -R in bile formation and models for cholestatic liver disease in mice. METHODS: We compared bile flow and composition in M3 -R knock-out mice (M3 -R-/- ) and wild type littermates (WT). Furthermore, we compared liver inury of M3 -R-/- and WT mice after 3,5 diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding, a well-characterized preclinical model of cholestatic liver disease. To analyze the possible role of the M3 -R as a therapeutic target, we treated 4-week-old Mdr2-/- mice, a preclinical model for sclerosing cholangitis, with the M3 -R agonist bethanechol for 4 weeks. RESULTS: M3 -R-/- mice showed significantly reduced bile flow compared to WT mice, most likely due to decreased biliary HCO3- secretion. However, even aged M3 -R-/- mice did not spontaneously develop liver injury or cholestasis. Challenging M3 -R-/- and WT littermates with DDC feeding showed substantially aggravated liver injury in M3 -R-/- mice. After 4 weeks bethanechol treatment, Mdr2-/- mice showed less liver injury compared to controls. CONCLUSION: Our experimental findings suggest that M3 -R-signalling significantly influences bile formation. Loss of the M3 -R increases susceptibility to cholestatic injury in DDC-fed mice. Since treatment of Mdr2-/- mice with a M3 -R agonist decreases liver injury, M3-R signaling may represent a therapeutic target in specific cholangiopathies. PMID- 28635177 TI - Engineering human bone grafts with new macroporous calcium phosphate cement scaffolds. AB - Bone engineering opens the possibility to grow large amounts of tissue products by combining patient-specific cells with compliant biomaterials. Decellularized tissue matrices represent suitable biomaterials, but availability, long processing time, excessive cost, and concerns on pathogen transmission have led to the development of biomimetic synthetic alternatives. We recently fabricated calcium phosphate cement (CPC) scaffolds with variable macroporosity using a facile synthesis method with minimal manufacturing steps and demonstrated long term biocompatibility in vitro. However, there is no knowledge on the potential use of these scaffolds for bone engineering and whether the porosity of the scaffolds affects osteogenic differentiation and tissue formation in vitro. In this study, we explored the bone engineering potential of CPC scaffolds with two different macroporosities using human mesenchymal progenitors derived from induced pluripotent stem cells (iPSC-MP) or isolated from bone marrow (BMSC). Biomimetic decellularized bone scaffolds were used as reference material in all experiments. The results demonstrate that, irrespective of their macroporosity, the CPC scaffolds tested in this study support attachment, viability, and growth of iPSC-MP and BMSC cells similarly to decellularized bone. Importantly, the tested materials sustained differentiation of the cells as evidenced by increased expression of osteogenic markers and formation of a mineralized tissue. In conclusion, the results of this study suggest that the CPC scaffolds fabricated using our method are suitable to engineer bone grafts from different cell sources and could lead to the development of safe and more affordable tissue grafts for reconstructive dentistry and orthopaedics and in vitro models for basic and applied research. PMID- 28635178 TI - Assessing inhibitory control in early-stage Alzheimer's and Parkinson's disease using the Hayling Sentence Completion Test. AB - The ability to inhibit irrelevant information is essential for coping with the demands of everyday life. Inhibitory deficits are present in all stages of dementia and commonly observed in people with Parkinson's disease (PwPD). Inhibition is frequently tested with the Stroop test, but this may lack ecological validity. This study investigates inhibitory control in people with Alzheimer's disease dementia (PwD) and PwPD using the Hayling Sentence Completion Test (HSCT), which aspires to be a more ecologically valid task. A total of 117 people completed the HSCT, a test where participants have to complete a sentence with an unrelated word. The sample comprised 30 PwD, 33 PwPD, and 54 healthy older controls. We compared response times and the number and type of errors across the three groups. Completion time in Part B (Inhibition) did not distinguish between PwD, PwPD, and controls when controlling for the initiation speed, but a higher proportion of Category A errors (producing a word that fits the sentence when instructed otherwise) was a unique characteristic of inferior performance in PwD and PwPD. While not part of the standard test scoring protocol, controlling for the initiation speed and distinguishing between speed and accuracy in test performance appear to be essential for accurate evaluation of the inhibitory control in HSCT in older people. The findings suggest that the HSCT may be sensitive to verbal suppression deficits and may provide insight into inhibitory control in PwD and PwPD. PMID- 28635179 TI - Changing Trends in Opioid Use Among Patients With Rheumatoid Arthritis in the United States. AB - OBJECTIVE: Opioid prescribing recently has come under intense scrutiny. However, longitudinal patterns of prescription opioid receipt in a population-based cohort of patients with chronic pain, such as those with rheumatoid arthritis (RA), have not been well characterized. The aim of this study was to examine both trends over time and variability in individual physician prescribing of short-term and long-term use of opioids. METHODS: We identified a cohort of RA patients based on 2006-2014 Medicare data and evaluated longitudinal time trends in "regular" use of opioids. A separate analysis conducted in 2014 assessed rheumatologist specific variability in regular use of opioid prescriptions in patients with RA. RESULTS: We identified 97,859 RA patients meeting the eligibility criteria. The mean age of the patients was 67 years, 80% were female, 82% were white, and 12% were African American. The most commonly used opioids were those that combined acetaminophen with hydrocodone or propoxyphene. Regular opioid prescribing increased slowly but peaked in 2010 before propoxyphene was withdrawn from the market. Following the withdrawal of propoxyphene, receipt of hydrocodone and tramadol increased commensurately, and overall opioid use declined only slightly. Factors associated with regular use of opioids included younger age, female sex, African American race, back pain, fibromyalgia, anxiety, and depression. Variability between US rheumatologists (n = 4,024) in prescribing the regular use of opioids for their RA patients was high; in the average rheumatologist's practice, 40% of RA patients used prescription opioids regularly. In almost half of the patients, at least some opioid prescriptions were written by a rheumatologist, and 14% received opioids that were co-prescribed concurrently by more than 1 physician. CONCLUSION: In the US, opioid use in older patients with RA peaked in 2010 and is now declining slightly. Withdrawal of propoxyphene from the US market in 2010 had minimal effect on overall opioid use, because use of propoxyphene was replaced by increased use of other opioids. PMID- 28635180 TI - Renal vascularization indexes and fetal hemodynamics in fetuses with growth restriction. AB - OBJECTIVE: To identify the correlation between the renal vascularization index (VI), the flow index (FI) and the vascularization and flow index (VFI) and placental and fetal hemodynamics in fetuses with growth restriction. METHOD: Bidimensional ultrasound and three-dimensional power Doppler with the VOCAL technique were used to determine the renal vascular indexes and fetal and placental hemodynamics in fetuses below the 10th percentile for fetal weight. Partial correlation analysis (controlled for renal depth and gestational age) was performed. The fetuses were divided into four groups according to their hemodynamic picture, and renal indexes were compared between the groups. RESULTS: Eighty-one fetuses were evaluated. VI, FI and VFI showed negative correlation with the ductus venosus pulsatility index. VI and VFI showed positive correlations with the amniotic fluid index. The group of fetuses with the worst hemodynamic picture (abnormal umbilical artery, middle cerebral artery and ductus venosus pulsatility indexes) showed significantly lower VI and VFI than the group with no changes in these pulsatility indexes. CONCLUSIONS: Renal vascularization indexes were inversely correlated with ductus venosus pulsatility indexes and were diminished in fetuses showing hemodynamic compromise. These changes might be related to postnatal renal impairment. (c) 2017 John Wiley & Sons, Ltd. PMID- 28635181 TI - Buprenorphine requires concomitant activation of NOP and MOP receptors to reduce cocaine consumption. AB - Buprenorphine's clinical use is approved for the treatment of heroin addiction; however, evidence supporting its efficacy in cocaine abuse also exists. While for heroin it has been demonstrated that the effect of buprenorphine is mediated by its ability to activate MU-opioid peptide receptor (MOP) receptors, the mechanism through which it attenuates cocaine intake remains elusive. We explored this mechanism using operant models where rodents were trained to chronically self administer cocaine for 2 hours daily. Buprenorphine (0.3, 1.0 and 3.0 mg/kg) given intraperitoneally 90 minutes before access to cocaine significantly and dose dependently reduced its intake. Pre-treatment with naltrexone or with the selective nociceptin/orphanin FQ peptide (NOP) antagonist SB-612111 did not prevent buprenorphine-induced reduction of cocaine intake. However, when naltrexone and SB-612111 were combined, the effect of buprenorphine on cocaine was completely prevented. To confirm that co-activation of MOP and NOP receptors is the underlying mechanism through which buprenorphine reduces cocaine intake, three compounds, namely, AT-034, AT-201 and AT-202, with a range of affinity and intrinsic activity profiles for MOP and NOP receptors, but weak ability for kappa opioid peptide receptor (KOP) transmission, were tested. Consistent with our hypothesis based on buprenorphine's effects, results demonstrated that AT-034 and AT-201, which co-activate MOP and NOP receptors, reduced cocaine self administration like buprenorphine. AT-202, which selectively stimulates NOP receptors, was not effective. Together, these data demonstrate that for buprenorphine, co-activation of MOP and NOP receptors is essential to reduce cocaine consumption. These results open new vistas on the treatment of cocaine addiction by developing compounds with mixed MOP/NOP agonist properties. PMID- 28635182 TI - The effect of flaxseed supplementation on body weight and body composition: a systematic review and meta-analysis of 45 randomized placebo-controlled trials. AB - Flaxseed consumption may be inversely associated with obesity; however, findings of available randomized controlled trials (RCTs) are conflicting. The present study aimed to systematically review and analyse RCTs assessing the effects of flaxseed consumption on body weight and body composition. PubMed, Medline via Ovid, SCOPUS, EMBASE and ISI Web of Sciences databases were searched up to November 2016. Mean changes in body composition indices including body weight, body mass index (BMI) and waist circumference were extracted. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI). Heterogeneity between studies was assessed with the I2 test. Publication bias and subgroup analyses were also performed. The quality of articles was assessed via the Jadad scale. A total of 45 RCTs were included. Meta-analyses suggested a significant reduction in body weight (WMD: -0.99 kg, 95% CI: -1.67, -0.31, p = 0.004), BMI (WMD: -0.30 kg m-2 , 95% CI: -0.53, -0.08, p = 0.008) and waist circumference (WMD: -0.80 cm, 95% CI: -1.40, -0.20, p = 0.008) following flaxseed supplementation. Subgroup analyses showed that using whole flaxseed in doses >=30 g d-1 , longer-term interventions (>=12 weeks) and studies including participants with higher BMI (>= 27 kg m-2 ) had positive effects on body composition. Whole flaxseed is a good choice for weight management particularly for weight reduction in overweight and obese participants. PMID- 28635183 TI - Cetuximab-conjugated nanodiamonds drug delivery system for enhanced targeting therapy and 3D Raman imaging. AB - In this study, a multicomponent nanodiamonds (NDs)-based targeting drug delivery system, cetuximab-NDs-cisplatin bioconjugate, combining both specific targeting and enhanced therapeutic efficacy capabilities, is developed and characterized. The specific targeting ability of cetuximab-NDs-cisplatin system on human liver hepatocellular carcinoma (HepG2) cells is evaluated through epidermal growth factor receptor (EGFR) blocking experiments, since EGFR is over-expressed on HepG2 cell membrane. Besides, cytotoxic evaluation confirms that cetuximab-NDs cisplatin system could significantly inhibit the growth of HepG2 cells, and the therapeutic activity of this system is proven to be better than that of both nonspecific NDs-cisplatin conjugate and specific EGF-NDs-cisplatin conjugate. Furthermore, a 3-dimensional (3D) Raman imaging technique is utilized to visualize the targeting efficacy and enhanced internalization of cetuximab-NDs cisplatin system in HepG2 cells, using the NDs existing in the bioconjugate as Raman probes, based on the characteristic Raman signal of NDs at 1332 cm-1 . These advantageous properties of cetuximab-NDs-cisplatin system propose a prospective imaging and treatment tool for further diagnostic and therapeutic purposes. PMID- 28635184 TI - Design, Synthesis, and Biological Evaluation of Isothiosemicarbazones with Antimycobacterial Activity. AB - A series of benzaldehyde and salicylaldehyde-S-benzylisothiosemicarbazones was synthesized and tested against 12 different strains of mycobacteria, Gram positive and Gram-negative bacteria, and the significant selectivity toward mycobacteria was proved. Twenty-eight derivatives were evaluated for the inhibition of isocitrate lyase, which is a key enzyme of the glyoxylate cycle necessary for latent tuberculosis infection, and their iron-chelating properties were investigated. Two derivatives, 5-bromosalicylaldehyde-S-(4-fluorobenzyl) isothiosemicarbazone and salicylaldehyde-S-(4-bromobenzyl)-isothiosemicarbazone, influenced the isocitrate lyase activity and caused a better inhibition at 10 MUmol/L than 3-nitropropionic acid, a standard inhibitor. The compounds were also found to act as exogenous chelators of iron, which is an obligate cofactor for many mycobacterial enzymes. Due to their low cytotoxicity, together with the activity against isocitrate lyase and the ability to sequester iron ions, the compounds belong to potential antibiotics with the main effect on mycobacteria. PMID- 28635185 TI - Antipulverization Electrode Based on Low-Carbon Triple-Shelled Superstructures for Lithium-Ion Batteries. AB - The realization of antipulverization electrode structures, especially using low carbon-content anode materials, is crucial for developing high-energy and long life lithium-ion batteries (LIBs); however, this technology remains challenging. This study shows that SnO2 triple-shelled hollow superstructures (TSHSs) with a low carbon content (4.83%) constructed by layer-by-layer assembly of various nanostructure units can withstand a huge volume expansion of ~231.8% and deliver a high reversible capacity of 1099 mAh g-1 even after 1450 cycles. These values represent the best comprehensive performance in SnO2 -based anodes to date. Mechanics simulations and in situ transmission electron microscopy suggest that the TSHSs enable a self-synergistic structure-preservation behavior upon lithiation/delithiation, protecting the superstructures from collapse and guaranteeing the electrode structural integrity during long-term cycling. Specifically, the outer shells during lithiation processes are fully lithiated, preventing the overlithiation and the collapse of the inner shells; in turn, in delithiation processes, the underlithiated inner shells work as robust cores to support the huge volume contraction of the outer shells; meanwhile, the middle shells with abundant pores offer sufficient space to accommodate the volume change from the outer shell during both lithiation and delithiation. This study opens a new avenue in the development of high-performance LIBs for practical energy applications. PMID- 28635186 TI - Catheter ablation of atrial fibrillation with box isolation of fibrotic areas: Lessons on fibrosis distribution and extent, clinical characteristics, and their impact on long-term outcome. AB - INTRODUCTION: The BIFA concept (box isolation of fibrotic areas) supplementing pulmonary vein isolation (PVI) was implemented in atrial fibrillation (AF) patients with fibrotic atrial cardiomyopathy (FACM) to improve catheter ablation outcomes. METHODS AND RESULTS: Ninety-two patients with FACM underwent PVI + BIFA. We investigated patient characteristics (58 persistent/34 paroxysmal, 68 +/ 8 years, LA 44 +/- 7 mm, CHA2 DS2 -VASc 2.6 +/- 1.3, FACM I: 15.2%, II: 53.3%, III: 26.1%, IV: 5.4%), periprocedural data concerning fibrosis extent/distribution, and their impact on outcome. Based on severe fibrosis areas (SFAs) of 13.5 +/- 13.9 cm2 detected by voltage mapping, 1.4 +/- 0.5 boxes (n = 1 3, 2.2-35.3 cm2 ) were applied in the left atrium. With higher grade FACM, SFAs increased and maximum voltage decreased (I/IV: 6.29/3.18 mV). Anterior (ant.) SFAs were found to be more common and larger than posterior (post.) SFAs (58.3% vs. 42.6%, ant. 8.0 +/- 8.0 vs. post. 4.7 +/- 6.8 cm2 ). In 40 of 92 (43%) patients, both atrial walls were affected with rare cases of solely post. fibrosis (6 of 92, 6.6%). Women (39 of 92, 42%) showed FACM III+IV more often than men (P = 0.022) and can still present paroxysmal while persistent males are more likely to have FACM I-II. Single and multiple procedure (1.2/patient) success was 69% and 83% after 16 +/- 8 months with an unfavorable impact of large SFA size, both-sided fibrosis and reduced maximum voltage, independently of patient characteristics and AF type. CONCLUSION: FACM patients are a challenging AF subgroup for catheter ablation. Women seem to show FACM III+IV more often than men. The distribution of left atrial fibrosis is variable but more pronounced anteriorly. Atrial disease is characterized by SFA size but also maximum voltage reduction, both with implications on ablation outcome. Using BIFA, success rates of patients without fibrosis can be approached but are limited in FACM III+IV. PMID- 28635187 TI - The Viologen Cation Radical Pimer: A Case of Dispersion-Driven Bonding. AB - The pi bonds between organic radicals have generated excitement as an orthogonal interaction for designing self-assembling architectures in water. A systematic investigation of the effect of the viologen cation radical structure on the strength and nature of the pimer bond is provided. A striking and unexpected feature of this pi bond is that the bond strength is unchanged by substitution with electron-donating groups or withdrawing groups or with increased conjugation. Furthermore, the interaction is undiminished by sterically bulky N alkyl groups. Theoretical modeling indicates that strong dispersion forces dominate the interaction between the radicals, rationalizing the insensitivity of the bonding interaction to substituents: The stacking of polarizable pi radicals leads to attractive dispersion forces in excess of typical dispersion interactions of small molecules and helps overcome the Coulombic repulsion of bringing two cationic species into contact. PMID- 28635189 TI - A new deal for the Monaldi Archives for Chest Disease. AB - The Editors: Antonio Spanevello, Bruno Balbi, Francesco Fattirolli, Furio Colivicchi.This issue marks a change in the Editorial Board of Monaldi Archives for Chest Disease. We would like to take this opportunity to impart some news on the current status of the journal. Our submissions are increasing, citations to our papers are rising, and recognition of the journal is broadening. Overall, 2016 has been a good year for the journal. Several changes are being made and several more are coming soon. Yet, focussing on the results achieved only is not our main goal, hence we now direct our efforts toward reaching an even greater impact. PMID- 28635190 TI - Characteristics of structured physical training currently provided in cardiac patients: insights from the Exercise Training in Cardiac Rehabilitation (ETCR) Italian survey. AB - BACKGROUND: Uncertainty exists about current delivery levels of exercise training (ET) during Cardiac Rehabilitation (CR) programmes. AIM OF THE STUDY: To evaluate ET modalities in the real world of CR facilities in Italy. METHODS: This was an observational survey of aggregate data, collected from CR facilities on a voluntary basis. Snapshots of a single working day at a local site were made, in terms of characteristics of patients and ET programmes delivered. RESULTS. Overall, 612 patients from 26 CR units were included, with an in-patient vs. out patient ratio of 3:1. Coronary artery disease (57.6%), heart failure (20.3%), and valve disease/surgery (22.1%) were the most represented target groups. The prevalence of endurance continuous training, interval training, and resistance/strength training was 66.7%, 11.1%, and 9.0%; other non-aerobic endurance and non-resistance training modalities such as respiratory muscle training and calisthenics were reported in 39.9% and 42.9% of cases respectively. Workloads for endurance exercise training were determined by cardiopulmonary test, conventional 12-leads ECG exercise testing, 6min-walking test, theoretical determination of heart rate, and rating of perceived exertion in 9%, 8%, 27%, 9%, and 40% of cases respectively. The average duration of the programmes (on an intention to treat basis) was 25 sessions of 42+/-11 minutes, with a frequency of >4 sessions/week in 67% of patients. CONCLUSIONS: Despite advances in CR interventions, there is a significant need for improvement of functional evaluation and exercise training prescription, and consideration of a wider range of training modalities in Italy. . PMID- 28635188 TI - The financial and quality-of-life cost to patients living with a chronic wound in the community. AB - Chronic wounds are associated with financial and personal costs. The system level expense associated with chronic wounds has been established, however, the out-of pocket cost incurred by individuals who self-fund has not been the focus of extensive investigation. Recently, there has been renewed interest in evaluating quality of life, in line with the shift to patient enablement and self-care in chronic disease management. The objectives of this research were to describe the out-of-pocket wound treatment costs and the quality of life of people who have chronic wounds. A questionnaire incorporating the Cardiff Wound Impact Schedule and purpose-designed instruments was completed by a non-probability, convenience sample of 113 people in Australia and Wales. Data was analysed using descriptive statistics. The sample was on average 63.6 years of age and had wounds that were on an average 109 weeks duration. Participants had spent on average AU$2475 on wound dressing products since the wound started, and AU$121.82 in the most recent 28 days which represented 10% of their disposable income. Health-related quality of life was sub-optimal, 6/10 (ave) according to the Cardiff Wound Impact Schedule. Younger participants reported significantly poorer quality of life on all CWIS sub-scales when compared to older participants. This study found that chronic wounds present a significant financial cost to individuals who must self fund their wound dressings and other wound treatment related expenses. Participants who had access to wound product subsidisation also experienced personal financial costs. People who have chronic wounds experience sub-optimal quality of life therefore this condition is also costly to the individual's well being. The quality of life of younger people has not received adequate attention and requires further consideration given the many years that younger people may have to live with this debilitating and often recurrent condition. Continued action is required to reduce the financial and personal costs experienced by people who have chronic wounds. It is imperative that healthcare funding is directed to people who have chronic wounds, in particular to alleviate the out-of pocket costs experienced by self-funders. Continued attention to the quality of life of people who have chronic wounds is required to minimise the negative effects of this condition and enhance well-being. PMID- 28635191 TI - Impact of a nutrition/educational program in a group of type 2 diabetes patients, already involved in a wider "Group Care" plan and not achieving complete target: an observational study. AB - Type 2 diabetes is one of the most frequent chronic degenerative diseases in the world (5.4% in Italy); it has many chronic consequences with a significant impact either on expectation or quality of life. About 80-90% of type 2 diabetes patients is either overweight or obese, condition that can cause many more negative consequences than in individuals in the same conditions but with normal weight. The aim of the research is to assess if diabetic people who cannot reach the goals of glycemic control, good eating habits and weight loss can eventually obtain, with an individualized care plan, long lasting improvements. This study involved a little group of diabetic patients who did not achieve an optimal therapeutic target. These patients have been individually followed by a dietician for six months through a program of dietetic counseling and regular controls and at the end we compare the results of another group of diabetic people, involved in the Group Care Plan (but without the support of the dietitian). The nutrition educational program determined a significant weight loss (- 4.62 kg vs + 3.46 kg; p<0.05), a reduction of waist circumference (-5.34 cm vs + 4.15 cm; p<0.05), an improvement of glycemic control (Hb1Ac: - 0.67 % vs + 0.57%; p<0.05), lipidic profile (total cholesterol: - 1 mg/dl vs + 12.85 mg/dl; p<0.05) and perceived quality of life (Test Att 19: 0 subjects vs 6 subjects). An individualized nutrition educational program in patients with type 2 diabetes not achieving a therapeutic target can optimize global care of the disease. PMID- 28635192 TI - Incidence of primary spontaneous pneumothorax is not associated with microclimatic variations. Results of a seven-year survey in a temperate climate area. AB - Some diseases, such as renal colic and atrial fibrillation, display an association with microclimatic variations. In particular, despite a correlation has been reported between incidence of primary spontaneous pneumothorax (PSP) and meteorological variations, the evidence remains poor and conflictual. The aim of this study was to assess the influence of day-by-day meteorological variations on the number of visits for PSP in the Emergency Department (ED). All PSP cases were retrieved from the hospital database from January 2008 to December 2014. For all the observational days, meteorological data about the Parma Province were obtained from the Environment and Climate Regional Agency. The correlation between ED visits for PSP and variation of air temperature (T degrees ), atmospheric pressure (hPa) and humidity (%) was then tested. The chronological data of all the visits for PSP were correlated with climate data by univariate linear regressions analysis. A total number of 608.215 ED visits were recorded during the observational period, with an average of 238 patients per day. Overall, 257 PSP cases were observed (mean age 37+/-21 years), 79% males and 21% females. No significant correlation between average daily visits for SP and daily change of average temperature, humidity, or atmospheric pressure was observed throughout the observational period (p>0.05 for all). The results of the study show that the incidence of PSP is not significantly associated with changes of microclimatic variables. PMID- 28635193 TI - Comparing the effect of cardiac biomarkers on the outcome of normotensive patients with acute pulmonary embolism. AB - Acute pulmonary embolism (PE) is a cardiovascular challenge with potentially fatal consequences. This study was designed to observe the association of novel cardiac biomarkers with outcome in this setting. In this prospective study, from 86 patients with a confirmed diagnosis of PE, 59 patients met the inclusion criteria (22 men, 37 women; mean age, 63.36+/-15.04 y).The plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), growth differentiation factor-15 (GDF-15), heart-type fatty acid-binding protein (H-FABP), tenascin-C, and D-dimer were measured at the time of confirmed diagnosis. The endpoints of the study were defined as the short-term adverse outcome and long-term all-cause mortality. Totally, 11.8% (7/59) of the patients had the short-term adverse outcome. The mean value of logNT-proBNP was 6.40+/-1.66 pg/ml. Among all the examined biomarkers, only the mean value of logNT-proBNP was significantly higher in the patients with the short-term adverse outcome (7.88+/-0.67 vs. 6.22+/- 1.66 pg/ml; OR, 2.359; 95% CI, 1.037 to 5.367; P=0.041). After adjustment, a threefold increase in the short-term adverse outcome was identified (OR, 3.239; 95% CI, 0.877 to 11.967; P=0.078).Overall, 18.64% (11/59) of the patients had expired by the long-term follow-up. Moreover, adjustment revealed an evidence regarding association between increased logNT-proBNP levels and long-term mortality (HR, 2.163; 95%CI, 0.910 to 5.142; P=0.081). Our study could find evidences on association between increased level of NT-proBNP and short-term adverse outcome and/or long-term mortality in PE. This biomarker may be capable of improving prediction of outcome and clinical care in non-high-risk PE. PMID- 28635195 TI - A study to estimate prevalence and risk factors of Obstructive Sleep Apnoea Syndrome in a semi-urban Indian population. AB - Obstructive Sleep Apnea Syndrome (OSAS) has been recognised as a major cause of morbidity and mortality in developing countries like India. There is still a paucity of Indian studies regarding the prevalence of OSAS. The current single centre prospective cross-sectional study was undertaken to know prevalence estimates for key symptoms and features that can indicate the presence of OSAS in an Indian population. A survey was conducted on subjects with age groups >= 25 years at King George's Medical University, Lucknow, Uttar Pradesh, India from August 2009 to July 2011. Data was recorded during the interview on the basis of Berlin Questionnaire (BQ). Risk factors for OSAS were also evaluated. Risk group categorization for OSAS was done with the help of a questionnaire and overnight polysomnography was performed in each group to measure apnea and hypopnea index (AHI). Out of 1816 subjects, 1512 (response rate 83.3%) finally participated in the survey with mean age 42.6+/-11.2 years, males 67.9% and females 32.1%. Of them 6.2% were found to be at high-risk OSAS; 12.2% were obese (Body Mass Index >=30 kg/m2) and 33.5% of the obese population were at high-risk OSAS. Among high risk patients with OSAS, 62.4% had hypertension. Statistically significant and independent risk factors found for OSAS were obesity, large neck size, alcoholism and use of sedatives/tranquillizers. High-risk category predicted an AHI >=5 with a sensitivity of 86.3% (95% CI 73.1-93.8), specificity of 93.1% (95% CI 89.1 95.7), positive and negative predictive values of 70.9% (95% CI 57.9-81.4) and 97.2% (95% CI 94.1-98.8) respectively. It can be concluded that BQ questionnaire can still be used as a pre-assessment tool for predicting persons at risk for OSAS in clinical practice. Further studies on estimation of prevalence of OSAS by applying BQ are warranted in near future from other regions of India. PMID- 28635194 TI - Volitional rehabilitative assessments in patients admitted in a post-intensive care step down unit. A feasibility study. AB - A high variability in functional tests and activities used during the pulmonary rehabilitation has been observed in post-intensive care unit (ICU) patients, and the best battery of tests to adopt has not been described yet. We tested in patients admitted in a post-ICU Step Down Unit the ability to perform the more frequent functional volitional tests. The relations of each single volitional test with general disability and dyspnea at discharge were also evaluated. Ten volitional tests including: bedside spirometry test (ST: FEV1%, FVC%), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), Peak Expiratory Flow during Cough (PCEF), Quadriceps Muscle Strength (QMS), latissimus Dorsi and teres Major Strength (DMS), Brachial biceps Muscle Strength (BMS), effort tolerance measured by sit-to-stand test, Takahashi test and 6-Min Walking Test (6MWT), were evaluated in post-ICU patients at entry and discharge from in hospital rehabilitation. General disability was assessed by Barthel Index, while dyspnea by Borg scale. At admission, >70% of subjects performed muscle strength test, while <25% performed respiratory and effort tolerance tests. At discharge, feasibility of spirometry, respiratory muscle strength and effort tolerance tests improved (all, p<0.001); 6MWT was the least feasible. At discharge, cardiorespiratory patients were more capable to perform tests compared to neurological ones. All outcome measures, with exception of FEV1%, and FVC%, were significantly related to the disability score. Peripheral muscle exercises showed the highest feasibility, spirometry and leg effort tolerance the lowest. Motor disability was explained mainly by the peripheral muscle strength. The study of non-volitional outcome measures and tests linked to a protocol-driven intervention should be performed in this specific population. PMID- 28635196 TI - Direct oral anticoagulants in patients undergoing cardioversion: insight from randomized clinical trials. AB - Anticoagulation, reducing the risk of thromboembolic events in patients undergoing cardioversion, is a cornerstone of peri-cardioversion management in patients with atrial fibrillation. We aimed to analyse published data on the efficacy and safety of direct oral anticoagulants (DOACs) in patients undergoing cardioversion. We performed a systematic review of randomized prospective clinical trials (RCTs) comparing DOACs with warfarin and reporting data on post cardioversion outcomes of interest. Outcomes of interest were stroke, systemic thromboembolic events and major bleeding. We reviewed a total of six RCTs including 3900 cardioversions performed using a DOAC for thromboembolic prophylaxis. These studies reported a low incidence overall of adverse outcomes associated with the use of DOACs (around 1% in all studies, except the ROCKET post-hoc study which included ablation procedures). The incidence rate of adverse events during DOAC treatment was found to be very similar to that observed with warfarin anticoagulation. In RCTs DOAC treatment in patients undergoing cardioversion appears to be effective and safe. However, because evidence in this clinical setting is still weak, observational reports could be useful in providing further data about peri-procedural outcomes. PMID- 28635197 TI - Depression, anxiety and chronic pain in patients with chronic obstructive pulmonary disease: the influence of breath. AB - Chronic obstructive pulmonary disease (COPD) is a major public health problems, causing significant mortality and morbidity in the world. It is a complex and progressive disease, characterized by chronic inflammation and dysfunction of the respiratory airways. The article reviews the available information on the potential role of the diaphragm in this disease. The purpose is to identify a potential correlation between symptoms such as depression, anxiety and chronic pain, frequently observed in COPD, with the activity of the diaphragm. The morphology and metabolism of the diaphragm are usually modified in the presence of COPD: a correlation between this symptoms and a pathological adaptation of breathing can be hypothesized. The management of these conditions should always be multidisciplinary, in order to have a global vision of the patient. PMID- 28635198 TI - Two foreign bodies embedded in the intraventricular septum: A case report. AB - A 23-year old male was presented at the outpatient clinic of our department reporting that he had been subjected to insertion of foreign bodies in his chest. Physical examination was unremarkable. Imaging studies revealed the presence of two bodies in the subcutaneous tissue of the anterior chest wall and two needle shaped intramyocardial bodies that were impacted in the intraventricular septum. Due to late appearance, the position, and because of the absence of symptoms, it was decided that the patient should be managed conservatively. Today, five years after the incident, the patient remains asymptomatic and he is followed-up regularly. PMID- 28635199 TI - A case of obstructive sleep apnea syndrome associated with floppy eyelid syndrome: positive effect of CPAP therapy. AB - The obstructive sleep apnoea syndrome (OSAS) may be associated with several eyes disorders, among which the most common is the floppy eyelid syndrome (FES). We intended to highlight the association between OSAS and FES and evaluate the effect of FES treatment with Continuous Positive Airway Pressure (CPAP). A 50 year patient with a 10-year history of snoring, sleep fragmentation and daytime sleepiness associated with several comorbidities has been studied. For six months, several ocular symptoms were present, particularly on waking up in the morning. An overnight respiratory polygraphy was performed at baseline and after CPAP titration. The treatment with CPAP corrects apnea/hypopnea events and rapidly improves patient's daytime sleepiness and eyes FES-related symptoms. This improvement is already evident after a very short period of treatment. PMID- 28635200 TI - Unusual symptomatic late onset presentation of aberrant right subclavian artery: report of two cases and short literature review. AB - Aberrant subclavian arteries are congenital vascular anomalies that usually do not cause any symptoms. When symptomatic they are considered as a rare cause of dysphagia. This presentation is known as dysphagia lusoria. They are diagnosed by barium swallow or contrast-enhanced computed tomography, although it may be an incidental finding. Management varies from life modifications and drug therapy to surgical intervention. We report two cases of the unusual form of late onset symptomatic presentation because of the presence of aberrant right subclavian artery. Main symptom was chest pain without dysphagia. Due to age and medical comorbidities both patients where managed conservatively. PMID- 28635201 TI - Hamman-Rich syndrome: a forgotten entity. AB - The following report outlines the case of a 76-year-old gentleman who presented to the hospital with acute interstitial pneumonitis, a rare and rapidly progressive type of idiopathic interstitial pneumonia. The patient initially presented with a three-week history of progressive shortness of breath and cough which was diagnosed as community acquired pneumonia. Treatment with oral antibiotics was unsuccessful resulting in re-presentation the following week with type one respiratory failure. Investigations revealed widespread inflammatory changes consistent with an acute inflammatory process. Intravenous steroids, antibiotics and antiviral medications were initiated before an urgent transfer to the intensive care unit was required for intubation. An open lung biopsy, in conjunction with the clinical picture, confirmed the diagnosis of acute interstitial pneumonitis. The significance of this report is to highlight the rapid and destructive clinical course of a rare type of pneumonitis, which initially presented as a routine and innocuous diagnosis in our patient. PMID- 28635202 TI - Palliative treatment of life-threatening hemoptysis with silicone stent insertion in advanced lung cancer. AB - Massive hemoptysis is a stressful and life-threatening event that can occur in lung cancer patients. The management of this event is usually challenging, and can involve surgery, embolization, and bronchoscopy. Unfortunately, while surgery can offer a definitive solution to hemoptysis, lung cancer patients are often excluded from this approach. On the other hand, bronchial arterial embolization rarely results in long-term control of bleeding. Endoscopy allows a skilled physician to perform mechanical tamponade or laser photocoagulation of bleeding lesions and preserve the main airways. While endoscopic stent placement is usually performed in order to treat stenosis, it has been occasionally employed to isolate and mechanically block the bleeding sites within the bronchial tree. We present the cases of two patients suffering from lung cancer-related life threatening hemoptysis; both patients were successfully treated by positioning a silicone stent during emergency bronchoscopy. Subsequently, we present a concise review of the available literature. PMID- 28635203 TI - Post-pneumonectomy and post-lobectomy syndromes: case series and review of the literature. AB - The post-pneumonectomy syndrome is a rare complication consisting of rotation and herniation of the mediastinal structures, the remaining lung and the respective bronchi, into the contralateral hemithorax. This situation may produce symptomatic airway obstruction and varies in its presentation and severity. We describe one case of right and one of left pneumonectomy syndrome as well as one case of post-lobectomy syndrome. We review the literature on the pathophysiology, the clinical, radiological and bronchoscopic characteristics of this rare entity and discuss all available therapeutic alternatives. PMID- 28635204 TI - Esophago-pulmonary fistula manifesting as recurrent pneumonias and migrating mediastinal calcifications. AB - A 43-year old man presented with recurrent pneumonias, episodes of hemoptysis and an enlarging right lower lobe mass. A clear diagnosis was not previously established in spite of multiple radiological evaluations and biopsies. Meticulous review of his CT imaging showed that he had subcarinal calcification on his prior CT scans, which had decreased in size and now multiple new small areas of calcifications were seen in the right lower lobe lesion. An esophago pulmonary fistula due to migration of mediastinal calcifications was suspected which was identified on careful review of the CT chest and confirmed by esophagogastroduodenoscopy. Patient had surgical repair with complete recovery. PMID- 28635205 TI - Recurrence of right lower lobe pneumonia 3 years after the first episode in an otherwise healthy 13-year-old girl. AB - Recurrent pneumonia is one of the most frequent reasons for referral to paediatric chest physicians. The diagnostic work-up is dependent on whether infection repeatedly occurs in the same lung lobe, or affects multiple lobes and/or different areas in different episodes. A 13-year-old girl was admitted with a second episode of right lower lobe pneumonia. The chest x-ray demonstrated an inhomogeneous opacity, without a clearly recognizable segmental distribution. A contrast-enhanced CT scan, was therefore performed that showed a polycyclic consolidation with blood supply from a systemic artery, originated from the thoracic aorta. A diagnosis of superinfection of an intralobar sequestration was made. The patient was treated with systemic antibiotics and, four weeks later, a segmental resection of the lesion was performed. The histological evaluation of the surgical specimen confirmed the diagnosis. PMID- 28635206 TI - Integrated care of chronic degenerative non-communicable diseases and rehabilitation: the odd couple? AB - Chronic degenerative non-communicable diseases affecting different organs and systems are considered by the World Health Organization (WHO) as the emergent epidemic in the third millennium... PMID- 28635207 TI - Integrating the care of the complex COPD patient. AB - Proceedings of the European Seminars in Respiratory Medicine course, Long-Term Integrated Care of COPD Patients held in Stresa, Italy, on 16-17 June, 2016. PMID- 28635208 TI - Association of clinical characteristics of patients presenting with influenza like illness or severe acute respiratory illness with development of acute respiratory distress syndrome. AB - Clinical judgement and suspicion of influenza based on signs and symptoms of influenza-like illness and severe acute respiratory illness are critical for better patient outcome. Whether clinical characteristics of patients are associated with the development of acute respiratory distress syndrome and PCR positivity of samples was the aim of this study. We included all patients (n=37) presenting with influenza like illness (ILI) or severe acute respiratory illness (SARI) to a tertiary care hospital in northwest Pakistan during December 2015 until the end of January 2016. Each patient was assessed for signs and symptoms, clinical features, treatment, complications and outcome of ILI and SARI. Throat or nasopharyngeal swabs were obtained from 36 patient and analyzed for the presence of Influenza virus by quantitative PCR. Patients presenting with ILI or SARI were febrile (p<0.001, one sample t-test), significantly tachypneic (p<0.001) and had critically lower oxygen saturation (p<0.001). Nasal congestion at presentation (p=0.006, chi-square test for association) and infiltrates on chest radiographs (p=0.025) were significantly associated with acute respiratory distress syndrome. Likelihood of the occurrence of ARDS was significantly increased with decrease in oxygen saturation (Odds ratio; 0.75, 95% CI; 0.46, 1.21, p=0.048) and marginally significantly increased in lower age (Odds ratio; 0.82, 95% CI; 0.58, 1.15, p=0.055) and higher white cell count (Odds ratio; 1.001, 95% CI; 0.99, 1.002, p=0.054). The presence of Influenza type A/H1N1pdm09 strains was confirmed in 7/11 patients. However no significant difference was observed in the clinical features and complications of PCR positive and negative patients. Clinical signs and symptoms of influenza-like illness or severe acute respiratory illness significantly predict the development of complications irrespective of the positivity or negativity of laboratory qPCR reports. PMID- 28635209 TI - [Advantage of otorhinolaryngologist in managing advanced differentiated thyroid carcinoma]. PMID- 28635210 TI - [The strategy and significance of individualized stratified therapy for differentiated thyroid carcinoma]. PMID- 28635211 TI - [Problems and countermeasures in the treatment of medullary thyroid carcinoma]. PMID- 28635212 TI - [Clinical features of postoperative cervical lymph nodes recurrence in papillary thyroid carcinoma]. AB - Objective: To analyse the postoperative metastasis or recurrence of cervical lymph nodes in individual neck levels for papillary thyroid carcinoma and to evaluate the outcomes and complications of re-surgery. Methods: A retrospective cohort study of 259 patients who underwent lymph node dissection for PTC relapse from January 2010 to June 2011. Lymph node metastases in each of neck levels were detected, postoperative complications were evaluated, and the patients were followed up with examining thyroglobulin levels to assess the therapeutic effect.Continuous variables were compared with t test.Categorical variables were compared with Fisher's exact test. Results: Lymph node metastasis was found in 259 cases and lymph node metastasis rates in levels II, III, IV, V and VI were 43.2%, 50.2%, 45.6%, 8.1% and 59.1% respectively. In 44 cases received the neck dissection of level II, the metastasis rates in the levels IIa and IIb were respectively (52.3% vs 18.2%, P=0.887). Recurrence in unilateral lateral neck was more common than that in bilateral lateral neck (73.1% vs 20.6%, P<0.001). The lymph nodes in lateral neck were more likely to metastasize than those in central region (80.7% vs 59.1%, P<0.001). There were 47 cases (18.1%) had postoperative complications, including 10 cases with permanent hypocalcemia. Conclusions: The scope of re-operation for neck metastasis or recurrence in papillary thyroid carcinoma should include the dissection of levels II-IV and VI. The incidence of postoperative complications for re-surgery is high, and re-surgery should be performed by experienced surgeon. PMID- 28635213 TI - [Risk factors for central neck lymph node metastases of papillary thyroid carcinoma]. AB - Objective: To investigate the impact factors for central neck lymph node metastases(CLNM) of papillary thyroid carcinoma(PTC). Methods: A total of 498 patients with PTC who underwent total or hemi-thyroidectomy plus central neck lymph node dissection between January 2014 and July 2016 were included. Univariate and multivariate analyses were performed to identify clinicopathological characteristics, thyroid function parameters and US findings that associated with CLNM of PTC. A nomogram was developed to predict the probability of CLNM. The receiver operating characteristic curve(ROC) was used to estimate the efficiency of the nomogram. Results: Among 498 patients, 284 patients were affected by CNLM. The sensitivity and specificity of US in predicting PTC metastasis in the central neck were 31.3% and 88.3%, respectively. Univariate and multivariate analyses showed that gender, age, number and size of suspicious malignant nodules in thyroid, and suspicious lymph node metastasis detected by ultrasonography were independently correlated with CLNM. The ROC showed that the AUC was 0.748, with sensitivity of 80.8%, and specificity of 59.8%. Conclusions: Gender, age, number and size of suspicious malignant nodules in thyroid, suspicious lymph node metastasis were predictive factors for CLNM in patients with PTC. The nomogram developed based on related factors with CLNM is more sensitive than sonographic central neck lymph node features in predicting the probability of CLNM. PMID- 28635214 TI - [Clinicopathological characteristics of papillary thyroid microcarcinoma and risk factors for central lymph node metastasis]. AB - Objective: To analyze the clinicopathological characteristics of papillary thyroid microcarcinoma (PTMC) and risk factors for central lymph node metastasis(CLNM) in PTMC. Methods: The data of 900 patients with PTMC initially treated in our hospital from January 2004 to December 2015 were retrospectively analyzed. Chi-square test and Logistic regression analysis were performed to determine the risk factors for CLNM. Results: CLNM affected 162 (22.9%) of 707 patients treated with central lymph node dissection. Age, maximum tumor size, multifocality, bilaterality, and extracapsular spread (ECS) were significantly correlated with CLNM (all P<0.01). Age<45 years, maximum tumor size>5 mm, multifocality, bilaterality, and extracapsular spread were independently correlated with CLNM. Conclusion: A prophylactic central lymph node dissection should be considered in PTMC patients with age<45 years, maximum tumor size>5 mm, multifocality, bilaterality, and extracapsular spread. PMID- 28635215 TI - [Retrospective comparison of screening criteria for active surveillance for papillary thyroid microcarcinoma]. AB - Objective: To investigate the rationality of management of active surveillance for papillary thyroid microcarcinoma (PTMC) and the main indications for active surveillance for PTMC. Methods: In this study, two criteria were used to evaluate patients with PTMC: low-risk PTMC conditions defined by Kuma hospital and Chinese Association of Thyroid Oncology (CATO) consensus on PTMC management of active surveillance. The patients had received surgical treatment. Clinicopathological characteristics and prognosis of the patients in different groups were compared. Results: A total of 778 patients were enrolled in the study, 565 (72.6%) of them met Kuma screening criteria and only 112 (14.4%) met CATO screening criteria. Kuma low-risk subgroup had lower incidence of cervical lymph node metastasis than Kuma high-risk PTMC subgroup(30.6% vs 47.9%, P<0.05). There were significant differences in multifocal lesions(6.3% vs 16.4%), extrathyroidal extension (1.8% vs 7.5%) and cervical lymph node metastasis(19.6% vs 38.0%) between low-risk and high-risk CATO PTMC subgroups. Patients in the CATO low-risk PTMC subgroup had lower recurrence and longer disease-free survival (DFS) than those in the CATO high-risk PTMC subgroup. But there was no significant difference in recurrence or DFS between Kuma low-risk and high-risk Kuma PTMC subgroups.The Chi-square test of Fisher's exact probabilities test was used to compare clinicopathological characteristics of patients between different groups.Rates of disease-free survival were calculated using the Kaplan-Meier method. Conclusion: CATO screening criteria is relatively strict and may be more suitable for Chinese patients with active surveillance for PTMC. PMID- 28635216 TI - [RET/PTC rearrangement affects multifocal formation of papillary thyroid carcinoma]. AB - Objective:RET/PTC gene rearrangement can lead to aberrant activation of tyrosine kinase receptors, which is a common mutation in papillary thyroid carcinoma (PTC). This study focuses on the association of RET/PTC rearrangements with PTC clinical factors. Methods: From January 2011 to December 2013, a total of 114 patients with PTC were enrolled in this study. Clinicopathological parameters, lifestyle, and thyroid hormone levels were collected. RET/PTC rearrangements were detected by TaqMan PCR and verified by Sanger sequencing.Data were analyzed with SPSS software, including chi-square test, Fisher's exact test, Mann-Whitney U test, Student's t-test, and Logistic regression. Results:RET/PTC rearrangements were not found in all paracancerous normal thyroid tissues, and were detected in 23.68% (27/114) of PTC. Further analysis revealed no correlation between RET/PTC rearrangement and thyroid function, clinicopathologic parameters, and lifestyle in the total PTC group or in the subgroup of patients with concomitant diseases (including Hashimoto's thyroiditis and nodular goiter). But in the subgroup of PTC without concomitant disease, RET/PTC rearrangement was associated with tumor multifocal (P=0.018), and RET/PTC-positive PTC patients had an increased risk of tumor multifocal (OR=5.57, 95% CI 1.39-22.33). It was also found that RET/PTC rearrangement was associated with an abnormal increase in TSH level of one month after surgery (P= 0.037). Conclusion: Nodular goiter and Hashimoto 's thyroiditis may be a confounding factor in PTC. RET/PTC rearrangement may play an important role in the occurrence of thyroid carcinoma multifocal after exclusion of this confounding factor. PMID- 28635217 TI - [The exploration on optimization of two alternatives between roll test and Dix Hallpike test in benign paroxysmal positional vertigo]. AB - Objective: To analyze the objective characteristics of roll test and Dix-Hallpike test in benign paroxysmal positional vertigo(BPPV)patients, discussing the premier solution of positional test. Methods: A total of 230 patients with BPPV, whereas 170 posterior semicircular canal canalithiasis (PSC-Can) BPPV and 60 horizontal semicircular canal canalithiasis (HSC-Can) BPPV were involved respectively. The induced nystagmus in roll test and Dix-Hallpike test was recorded by video nystagmuo graph (VNG), and the direction, intensity and time characteristics of nystagmus were compared in various BPPV.SPSS19.0 software was used for statistical analysis. Results: Vertically upward nystagmus was induced by hanging in 170 PSC-Can Dix-Hallpike test, and the nystagmus reversed and turned weaker when the subjects came to sit. The intensity of nystagmus at turning to lesion side by hanging and sitting were (30.3+/-14.1) degrees /s and (12.6+/-7.5) degrees /s respectively, the difference was statistically significant (t=20.153, P<0.05). However, no nystagmus was induced in PSC-Can roll test. Horizontal nystagmus in the same direction with turning was induced in 60 HSC-Can roll test. The intensity of nystagmus at turning to lesion side and normal side was (42.0+/-18.0) degrees /s and (20.3+/-8.7) degrees /s respectively, the difference was statistically significant (t=12.731, P<0.05). Furthermore, horizontal nystagmus in the same direction with turning was induced in 57 HSC-Can Dix-Hallpike. The coherence was 95% with the results of roll test. Conclusions: Dix-Hallpike test can not only be used to diagnose PSC-Can, but also induce nystagmus in HSC-Can effectively. Whereas the roll test only show significance in diagnosing HSC-Can. To avoid uncomfortable stimulation to patients as much as possible, we suggest to use Dix-Hallpike test at first, and to judge whether using roll test based on the result of the horizontal nystagmus. PMID- 28635218 TI - [Nasal irrigation for the treatment of vasomotor rhinitis: a pilot study]. AB - Objective: To observe the therapeutic effect of simple 3.0% saline nasal irrigation and combined treatment of 3.0% saline nasal irrigation and budesonide nasal spray for vasomotor rhinitis (VMR), and explore the long-term effect for VMR. Through examination of levels of substance P (SP) and mucin (MUC)5B in nasal lavage fluid, the mechanisms of nasal irrigation treatment for VMR was discussed. Methods: One hundred and one patients from Department of Otorhinolaryngology Head and Neck Surgery, Huashan Hospital of Fudan University with VMR were randomly divided into 4 groups. The number of patients was 24 in control group, 25 in budesonide nasal spray treatment group (budesonide group), 25 in nasal irrigation treatment group (nasal irrigation group) and 27 in budesonide nasal spray + nasal irrigation group (combined treatment group). Control patients were left untreated. Budesonide group was under budesonide nasal spray treatment, nasal irrigation group was treated using 3.0% saline with a temperature of 40C and combined treatment group was given both treatments. The duration of the intervention period was 3 months (90 days). Visual Analog Scale (VAS) was used to evaluate nasal symptoms, and the health-related quality of life was assessed using the 12-item Short Form Health Survey version 2.0 (SF-12v2). Enzyme-linked immunosorbent assay (ELISA) was used to assess the contents of SP and MUC5B in nasal lavage fluid before and after 3-month treatments in budesonide and nasal irrigation group in the study. MUC5B in nasal lavage fluid after the SP challenge and anticholinergic drug intervention in control group were also evaluated with ELISA. Results: Nighty out of 101 patients completed the study. In the budesonide and combined treatment group after relevant interventions, the total VAS score of nasal symptoms decreased (5.91+/-0.21 vs 3.82+/-0.15, 6.18+/-0.17 vs 3.92+/-0.15, t value was 8.193, 10.060, respectively, all P<0.05) and SF-12v2 score increased (146.00+/-1.23 vs 152.30+/-0.97, 146.00+/-1.08 vs 155.40+/-0.90, t value was 3.982, 6.697, respectively, all P<0.05), with both scores showed no significant differences in the nasal irrigation group (5.96+/-0.17 vs 5.72+/-0.15, 146.10+/ 1.17 vs 147.00+/-0.94, t value was 1.038, 0.607, respectively, all P>0.05) after the first month. In the budesonide and combined treatment group after relevant interventions, the total VAS score of nasal symptoms decreased (5.91+/-0.21 vs 5.05+/-0.15, 6.18+/-0.17 vs 5.10+/-0.12, t value was 3.374, 5.351, respectively, all P<0.05) and SF-12v2 score increased (146.00+/-1.23 vs 150.90+/-0.76, 146.00+/ 1.08 vs 153.60+/-0.94, t value was 3.373, 5.343, respectively, all P<0.05), with both scores showed no significant differences in the nasal irrigation group (5.96+/-0.17 vs 5.78+/-0.17, 146.10+/-1.17 vs 148.10+/-0.80, t value was 0.716, 1.438, respectively, all P>0.05) after the second month. By the end of the third month, in nasal irrigation and combined treatment group, the VAS score was diminished (5.96+/-0.17 vs 4.80+/-0.12, 6.18+/-0.17 vs 4.44+/-0.13, t value was 5.485, 8.264, respectively, all P<0.05) and SF-12v2 score was elevated (146.10+/ 1.17 vs 150.80+/-0.96, 146.00+/-1.08 vs 152.90+/-0.85, t value was 3.163, 5.008, respectively, all P<0.05), but there were no significant differences in budesonide group (5.91+/-0.21 vs 5.68+/-0.18, 146.00+/-1.23 vs 148.40+/-0.85, t value was 0.819, 1.587, respectively, all P>0.05). Additionally, SP in nasal lavage fluid decreased and MUC5B showed no statistical changes in budesonide group after three months, however, SP showed no any changes and MUC5B reduced significantly in nasal lavage fluid in nasal irrigation group. Furthermore, the anticholinergic drug could not decrease the concentration of MUC5B after the SP challenge in nasal cavity in control group. Conclusions: The therapeutic effect of simple nasal irrigation with 3.0% saline or combined treatment of 3.0% saline nasal irrigation and nasal corticosteroids is superior to simple nasal corticosteroids. Nasal corticosteroids plays a role in the inhibition of sensory nerve endings in nasal mucosa, but neurotransmitter plays a limited role in the pathogenesis of VMR. PMID- 28635219 TI - [Olfactory function in children with adenoid hypertrophy who underwent adenotonsillectomy during pre- and post-operative period]. AB - Objective: To assess the olfactory function in children with adenoid hypertrophy and investigate the changes of both olfactory function and appetite in children with adenoid hypertrophy before and after adenoidectomy. Methods: Forty-four children with adenoid hypertrophy admitted for adenoidectomy, aged 7-12 years, mean age (10.0+/-2.0) years were tested by Sniffin' Sticks test and visual analog scale(VAS) of the children's appetite preoperatively between March and August 2015.In a appointment 6 months after operation, all of them returned and were tested again. The control group consisted of 40 healthy children, aged 7-12 years, mean age (11.2+/-0.8) years.SPSS 13.0 software was used for statistical analysis Results: The olfactory function of the study group TDI scores (32.4+/ 3.5) preoperatively were significantly lower in comparison with the results of the control group TDI scores (37.3+/-2.8)(t=7.057, P<0.001). Significant improvement of olfaction TDI scores (36.8+/-1.9) was observed in the follow-up appointment(t=13.573, P<0.001). The VAS of the children's appetite during post adenoidectomy was higher compared to pre-adenoidectomy(t=16.765, P<0.001). There was a strong correlation between the increase in appetite of children and the change of TDI score (r=0.59, P<0.01). Conclusions: Children with adenoid hypertrophy have a reduced ability of both olfactory function and appetite. Surgery had a greater impact on olfaction and appetite. PMID- 28635221 TI - [Treatment of intractable aspiration after partial laryngectomy by cuffed tracheostomy tube with inner cannula]. AB - Objective: To evaluate the efficacy of cuffed tracheostomy tube with inner cannula for the treatment of intractable aspiration after partial laryngectomy. Methods: From May 2010 to June 2015, 15 patients with intractable aspiration after partial laryngectomy of laryngeal and hypopharyngeal carcinoma were enrolled. Cuffed tracheostomy tube with inner cannula was used in the 15 patients for treatment of intractable aspiration. The patients and their family were trained to manage the cuffed tracheostomy tube with inner cannula and to eat since the 14th day after surgery. Cuff was initially inflated with 10 ml air and then deflated of 0.5 ml air every 2-3 days. Until the inflation of cuff was no longer required, the cuffed tracheostomy tube was replaced by metal tracheostomy tube. The patients' swallowing function and aspiration were evaluated 6 months after treatment. Results: The 15 cases with intractable aspiration were treated with cuffed tracheostomy tube with inner cannula and after 2-3 months, 14 of them replaced the cuffed tracheostomy tubes with inner cannula by metal tracheostomy tubes and recovered oral eating, and tracheostomy tubes were no longer required for 12 of 14 patients in following 3-6 months, showing a total decannulation rate of 80% in the patients with refractory aspiration. Conclusion: It was safe and effective to treat aspiration after laryngeal and hypopharyngeal surgery with cuffed tracheostomy tube with inner cannula. PMID- 28635220 TI - [The bisphenol A-enhanced activity of thyroid carcinoma cell line B-CPAP is inhibited by Icarrin]. AB - Objective: To investigate the effect of icariin (ICA) on the bisphenol A (BPA) enhanced proliferation function of thyroid carcinoma cell B-CPAP and underlying mechanism. Methods: The proliferation of Gastric B-CPAP cell line was evaluated by cell counting kit-8 (CCK-8). Apoptosis and ROS expression in B-CPAP cells were detected by flow cytometry. The expression of superoxide dismutase (SOD) and malondialdehyde (MDA) in B-CPAP cells were measured by individual assay kits. The expressions of Bcl-2 and gamma-HA2X were detected by Western blot. SPSS 18.0 software was used to analyze the data. Results: B-CPAP cell activity was promoted by treatment with 3*10(-7)mol/L BPA for 48 h, with significant difference in absorbance between BPA and control groups (1.089+/-0.053 vs 0.935+/-0.010, P<0.05). The cell activities of BPA+ ICA(25), BPA+ ICA(50), BPA+ ICA(100) and BPA+ ICA(200) groups was 0.780+/-0.036, 1.007+/-0.050, 0.958+/-0.033 and 0.625+/ 0.064, respectively (all P<0.01). The proliferation of B-CPAP cells treated with BPA for 72 hours showed a similar trend to 48 hours. There was no significant difference between all treatment groups in 24 hours. The apoptosis rate was (19.272+/-0.186)% in BPA-treated cells, and was (22.412+/-0.238)% in control cells (P<0.05). The apoptosis rates of BPA+ ICA(50) and BPA+ ICA(200) groups were (23.688+/-0.412)% and (30.270+/-0.696)%, respectively (P<0.01). The intracellular accumulation of ROS in BPA, BPA+ ICA(50), and BPA+ ICA(200) groups were 806+/-21, 1 772+/-37, 2 041+/-16, respectively (P<0.01). The expressions of anti-apoptotic protein Bcl-2 in control, BPA, BPA+ ICA(50), BPA+ ICA(200) groups were 7 120+/ 151, 9 801+/-286, 5 902+/-171 and 4 203+/-216, respectively (P<0.01). Conclusion: BPA can promote the proliferation of thyroid carcinoma B-CPAP cells and decrease the apoptosis of cells, and this effect can be inhibited by ICA. The possible mechanism is to induce high expression of intracellular ROS and inhibit the expression of antioxidase system, leading to cell oxidative damage, thereby inducing apoptosis. PMID- 28635222 TI - [Clinical analysis of glossopharyngeal neuralgia associated with abnormal styloid process: report of 8 cases]. PMID- 28635223 TI - [Recurrent nasal adenoid cystic carcinoma with local invasion: report of two cases]. PMID- 28635224 TI - [One case report for branchial cleft carcinoma]. PMID- 28635225 TI - [Modification factors associated with maternally inherited non-syndromic hearing loss]. AB - Mutations in the mitochondrial DNA have been certified to be one of the most important causes of maternally inherited sensorineural hearing loss. Among these, mitochondrial 12S rRNA1555A>G, 1494C>T and other mutations are associated with both nonsyndromic and drug induced hearing loss caused by aminoglycosides. Individuals carrying 1555A>G or 1494C>T mutation have a variety of clinical manifestations, which implies that the 1555A>G or 1494C>T mutation is a chief factor underlying the development of deafness but insufficient to produce the clinical phenotype. Therefore other modifier factors, such as aminoglycosides, mitochondrial haplotypes, secondary mutation or nuclear modifier genes, may play an important role in the phenotypic expression of the deafness-associated mitochondrial 12S rRNA1555A>G or 1494C>T mutation. In this review, the modifier factors for the phenotypic expression of deafness-associated mitochondrial 12S rRNA1555A>G or 1494C>T mutations were summarized and proposed the pathogenesis of maternally inherited deafness. PMID- 28635226 TI - [Principles and strategies in surgical management of differentiated thyroid cancer invading upper areodigestive tracts]. PMID- 28635227 TI - [Mechanism and clinical efficacy of third-generation epidermal growth factor receptor tyrosine kinase inhibitor in non-small cell lung cancer]. AB - Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, most of patients will develop resistance to TKIs treatment due to the emergence of the T790M mutation. The third-generation EGFR TKI is highly selective and efficient for activating mutants (EGFR sensitive mutations) and resistance mutant (T790M+ ). This review summarizes the mechanism and clinical efficacy of the third-generation EGFR-TKI in NSCLC patients. PMID- 28635228 TI - [Mechanism of long non-coding RNA-metastasis associated lung adenocarcinoma transcript 1 induced invasion and metastasis of esophageal cancer cell EC-109]. AB - Objective: To investigate the effect and mechanism of long non-coding RNA metastasis associated lung adenocarcinoma transcript 1, (LncRNA-MALAT1) on invasion and metastasis of esophageal cancer cell EC-109. Methods: EC-109 cells were transfected with lentiviral vector carrying short hairpin RNA of MALAT1( shRNA-MALAT1) or a nonspecific shRNA control (shRNA-control). The expressions of MALAT1, microRNA-200a, ZEB1 and ZEB2 were detected by qRT-PCR. The effect of shRNA-MALAT1 on invasion of EC-109 cells was determined by transwell assay. The expressions of components of epithelial-msenchymal transition pathway in EC-109 cells were determined by immunofluorescence array and western blotting. The expression relationship between MALAT1 and miR-200a in EC-109 cells was detected by dual-luciferase reporter assay. Results: The result of qRT-PCR showed that the expressions levels of MALAT1, ZEB1 and ZEB2 in shRNA-MALAT1 group were 0.43+/ 0.06, 0.64+/-0.04 and 0.51+/-0.04, respectively, significantly lower than 0.97+/ 0.08, 1.06+/-0.07 and 0.98+/-0.05 in shRNA-control group and 1 in control group, respectively(all P<0.05). Transwell assay showed that the number of invaded cells in shRNA MALAT1 group was (96.81+/-10.43) per low-power field, markedly lower than that of (278.44+/-13.28) per low-power field in shRNA-control group (P<0.01). Immunofluorescence staining and Western blotting showed that MALAT1 downregulation significantly reduced the expressions of proteins related to EMT signal pathway in EC-109 cells.Dual luciferase reporter assay showed that compared to negative control, the activities of luciferase reporter in EC-109 cells co-transfected with pmirGLO-MALAT1-wt and miR-200a were significantly down regulated. While co-transfected pmirGLO-MALAT1-mut with miR-200a mimics had no effect on the luciferase reporter activities of MALAT1. Conclusion: LncRNA MALAT1 functions as a competing endogenous RNA to regulate the expressions of ZEB1 and ZEB2 by sponging miR-200a and promotes invasion and migration of esophageal cancer cells through inducing epithelial-mesenchymal transition. PMID- 28635229 TI - [Macrophage colony stimulating factor enhances non-small cell lung cancer invasion and metastasis by promoting macrophage M2 polarization]. AB - Objective: To investigate the key cytokine which polarizes M2 macrophages and promotes invasion and metastasis in non-small cell lung cancer (NSCLC). Methods: After co-culture with A549 cells in vitro, the proportion of CD14(+) CD163(+) M2 macrophages in monocytes and macrophage colony stimulating factor (M-CSF) levels in culture supernatant were detected by flow cytometry, ELISA assay and real-time qPCR, respectively. The effects of CD14(+) CD163(+) M2 macrophages on invasion of A549 cells and angiogenesis of HUVEC cells were measured by transwell assay and tubule formation assay, respectively. The clinical and prognostic significance of M-CSF expression in NSCLC was further analyzed. Results: The percentage of CD14(+) CD163(+) M2 macrophages in monocytes and the concentration of M-CSF in the supernatant followed by co-culture was (12.03+/-0.46)% and (299.80+/ 73.76)pg/ml, respectively, which were significantly higher than those in control group [(2.80+/-1.04)% and (43.07+/-11.22)pg/ml, respectively, P< 0.05]. Human recombinant M-CSF promoted M2 polarization of macrophages in vitro. M2 macrophages enhanced the invasion of A549 cells (66 cells/field vs. 26 cells/field) and the angiogenesis of HUVEC cells (22 tubes/field vs. 8 tubes/field). The mRNA expression of M-CSF in stage I-II patients (16.23+/-4.83) was significantly lower than that in stage III-IV (53.84+/-16.08; P<0.05). M-CSF levels were associated with poorer overall survival and disease-free survival in NSCLC patients (P<0.05). Conclusions: Tumor-derived M-CSF can induce CD14(+) CD163(+) M2 polarization of macrophages, which can further promote the metastasis and angiogenesis of NSCLC. M-CSF could be used as a potential therapeutic target of NSCLC. PMID- 28635230 TI - [The expression of programmed death receptor 1 in non-small cell lung cancer and its clinicopathological features and prognosis showed a connection with epidermal growth factor receptor gene mutations]. AB - Objective: To investigate the relationships between the expression of programmed death 1 (PD-1) and the epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC). The study also attempted to investigate the clinicopathological features and prognosis in NSCLC patients. Methods: The expression of PD-1 protein in 88 cases of NSCLC tumor tissues and adjacent tissues was detected by immunohistochemistry. The mutations of EGFR in NSCLC were detected by Polymerase Chain Reaction-Amplification Refractory Mutation System(PCR-ARMS) method. The expression of PD-1 and patients' clinical characteristics and prognosis were analyzed. Results: PD-1 was positive in 63.6%(56/88) NSCLC tumor tissues, which was significantly higher than that in adjacent normal tissues (21.6%, 19/88) (P<0.05). EGFR gene mutations were found in 43 cases (48.9%), in which 30 cases (69.8%)were PD-1 positive expression. 45 cases had the wild types of EGFR gene, in which 26 cases (57.8%) were PD-1 positive. There were 24 cases of 19Del EGFR mutations, including 20 cases (83.3%) of PD-1 positive expression. 19 patients had 21L858 EGFR mutations, including 10 cases (52.6%) of PD-1 positive expression. The expression of PD-1 in NSCLC was related to patients' smoking status, lymph node metastasis and EGFR gene mutations (P<0.05). The median progression-free survival time of patients with PD 1 positive and negative expression was 7.03 and 18.66 months, respectively (P=0.007). In patients with wild-type EGFR gene, the median progression-free survival time of PD-1 positive and negative expression was 25.21 and 38.24 months, respectively. The difference was statistically significant (P=0.024). The median progression-free survival time in 43 cases of EGFR mutant patients with PD 1 positive and negative expression was 21.23 and 31.44 months. The difference was not statistically significant (P=0.128). Conclusions: PD-1 expresses in both EGFR mutant and wild-type NSCLC, and its expression levelis different with various EGFR mutations. The expression of PD-1 in NSCLC is related to the prognosis of patients, and the prognosis of patients with positive PD-1 expression was poor. PMID- 28635231 TI - [Comparison of paired box genes 8 and 2 expression in epithelium tissues and the related tumors]. AB - Objective: To explore the expressional differences between paired box genes 2(Pax2) and 8 (Pax8) protein in different kinds of epitheliums and tumors, and to investigate the clinicopathologic significance. Methods: Expression levels of Pax2 and Pax8 protein were detected in 75 cases of different human epithelium tissues and 255 cases of different tumors on tissue microarray by immunohistochemistry. Results: Pax2 and Pax8 selectively expressed in different tissues. The positive rates of Pax8 protein expressed in the normal epithelium of the thyroid, urinary system and female reproductive system were 100% (2/2), 60.0% (3/5) and 76.9% (10/13), respectively. The positive rates of Pax2 expressed in the epithelium tissues of urinary system and the female reproductive system were 40.0% (2/5) and 38.5% (5/13) respectively. However, the expression of Pax2 protein was not detected in the normal thyroid epithelium. The positive rate of Pax8 protein expressing in the epithelium of reproductive system was significantly higher than that of Pax2 protein (P<0.05). The tumors derived from different tissues also expressed different levels of protein Pax2 and Pax8. The positive rates of Pax8 in renal cell carcinoma, thyroid carcinoma and endometrial adenocarcinoma were 65.2% (15/23), 66.7% (10/15) and 80.0% (4/5), respectively. The positive rates of Pax2 in renal cell carcinoma, thyroid carcinoma and endometrial adenocarcinoma were 34.8% (8/23), 13.3% (2/15) and 20.0% (1/5), respectively. The positive rates of Pax8 protein expressed in renal cell carcinoma, thyroid carcinoma and endometrial adenocarcinoma were significantly higher than those of Pax2 protein (P<0.05). The positive rates of Pax8 in ovarian serous carcinoma, endometrial carcinoma and clear cell carcinoma were 92.9% (26/28), 81.8% (9/11) and 82.4% (14/17), respectively. The positive rates of Pax2 in ovarian serous carcinoma, endometrial carcinoma and clear cell carcinoma were 28.6% (8/28), 9.1% (1/11) and 17.6% (3/17), respectively. The positive rates of Pax8 protein expressed in ovarian serous carcinoma, endometrial carcinoma and clear cell carcinomawere significantly higher than those of Pax2 protein (P<0.05). Conclusions: Pax2 and Pax8 are specifically expressed in female reproductive system and uritany system. However, the positive expression of Pax8 is superior to that of Pax2. The combined expression of Pax8 and Pax2 can be used in the differential diagnosis of epithelial tumors derived from different origins. PMID- 28635232 TI - [Analysis of the clinicopathological characteristics and prognosis in 674 cases of breast intraductal papillary tumor]. AB - Objective: Breast intraductal papillary tumors are clinically common diseases derived from the ducts. The aim of this study is to investigate the clinicopathological characteristics of intraductal papillary tumors and risk factors for carcinogenesis. Methods: The clinicopathological data of 674 patients with breast intraductal papillary tumors, who underwent surgery in the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences from January 2010 to July 2015, were retrospectively analyzed. Results: The median follow-up time was 46 months. The 674 cases were classified into 547 intraductal papilloma, 88 cases of intraductal papillary carcinoma, 32 cases of intracystic papillary carcinoma, and 7 cases of solid papillary carcinoma of breast. After a median follow-up time of 46 months, 13 out of 547 (2.4%) intraductal papillomas had local recurrence in the original dissected quadrat, another 10 cases developed breast cancer in the original dissected quadrat. The 3-year recurrence-free survival rates in intraductal papilloma and intraductal papilloma accompanied with atypical ductal hyperplasia were 97.7% and 93.5%, respectively, the recurrence-free survival curves showed a significant difference (P=0.011). Multivariate analysis indicated that atypical ductal hyperplasia was a major prognostic factor affecting the recurrence-free survival of intraductal papilloma (RR=0.183, 95%CI=0.054 to 0.777, P=0.020). Four cases (3.1%) of intraductal papillary carcinoma had local recurrence. The logistic analysis showed that patient aged >45 years, clinical manifestations of a breast lump, maximum tumor diameter greater than 2 cm are possible clinical manifestation of malignant breast intraductal papillary tumors (RR=1.735, 95%CI=1.007-2.990, P=0.047; RR=2.849, 95%CI=1.207-6.711, P=0.017; RR=3.792, 95%CI=2.162-6.653, P<0.001). Conclusions: Intraductal papillary tumors have a certain recurrence rate. Age, clinical features and tumor size may be predictive factors of intraductal papillary carcinoma. PMID- 28635233 TI - [Clinical characteristics and prognosis of anaplastic thyroid carcinoma]. AB - Objective: To investigate the clinical characteristics, treatment outcomes and prognostic factors in patients with anaplastic thyroid cancer. Methods: Clinical data of 56 patients with anaplastic thyroid cancer at Zhejiang Cancer Hospital from January 2006 to June 2016 were retrospectively reviewed and followed up. Results: Of the 56 patients, there were 24 male and 32 female. The median age was 65 years old. At diagnosis, 10 patients have different degrees of breathing difficulty; 8 patients have varying degrees of dysphagia, and 12 patients have hoarseness. Distant metastases were found in 23 patients at presentation. Patient staging was performed in accordance with the tumor-node-metastasis system as follows: stage IVA (n=19), stage IVB (n=14) and stage IVC (n=23). The median survival time of 56 patients was 4.5 months.The overall 1-year survival rate was 5.4%. Univariate analysis showed that radiotherapy and multimodality therapy were prognostic factors for 1-year overall survival (both of P<0.05). The overall 1 year survival rate of the patients who received precision radiotherapy was 16.7%, which was higher than who received the other radiation therapy (4.0%, P=0.040). Furthermore, the overall 1-year survival rate of the patients who received surgery combined with radiotherapy was 12.5%, which was higher than who received the other treatments(4.2%, P=0.040). Multivariate analysis indicated that radiotherapy was independently associated with improved survival (P=0.020). Conclusions: Patients with anaplastic thyroid cancer should receive multimodality therapies combining surgery with radiotherapy. Radiotherapy is independently associated with improved overall survival. Notably, the precision radiotherapy that based on image guidance has a significantly beneficial impact on the prognosis of patients. PMID- 28635234 TI - [Clinicopathological features and prognosis of malignant peripheral nerve sheath tumor: a retrospective study of 140 cases]. AB - Objective: To investigate the clinicopathological features and prognosis of malignant peripheral nerve sheath tumors (MPNST). Methods: We retrospectively reviewed the clinical data of MPNST patients who were treated at Cancer Institute & Hospital, Chinese Academy of Medical Science from January 1999 to January 2016. A total of 140 patients with 66 male and 74 female with MPNST were enrolled in the study. The median age was 40 at the time of diagnosis. Survival analysis were estimated by Kaplan-Meier method and Log rank test. Multivariate analysis were estimated by Cox proportional hazards regression model. Results: The median follow-up time was 43.0 months. The 3- and 5-year overall survival (OS) rates were 56.4% and 48.6%, respectively. The 3-year local recurrence (LR) rate and distant metastasis (DM) rates were 42.9% and 49.3%, respectively. Univariate analysis showed that the tumor location, AJCC stage, S-100, radiotherapy and margin status affected 5-year OS rate (all P<0.05). The tumor location, AJCC stage, S-100, Ki-67 staining, margin status, radiotherapy and chemotherapy affected 3-year LR rate (all P<0.05). The tumor location, AJCC stage, S-100, Ki 67 staining and margin status affected 3-year DM rate (all P<0.05). Multivariate analysis showed that the tumor location, AJCC stage, S-100 were independent factors for 5-year OS rate (all P<0.05). The tumor location, Ki-67 staining and chemotherapy were independent factors for LR (all P<0.05) while the AJCC stage, margin status and Ki-67 staining were independent factors for DM (all P<0.05). Conclusions: MPSNT is an aggressive tumor with poor prognosis. Multiple factors were identified in this study. Patients with the tumor located at head and neck, advanced AJCC stage and negative S-100 usually have a low 5-year overall survival rate. Patients with the tumor located at head and neck, Ki-67 staining >= 20% and without chemotherapy had a higher tendency of local recurrence. Poor prognosis factors for DM were advanced AJCC stage, positive margin and Ki-67 staining >= 20%. PMID- 28635235 TI - [The role of postmastectomy radiotherapy in clinical T1-3N1M0 breast cancer patients with pathological negative lymph nodes after neoadjuvant chemotherapy and mastectomy]. AB - Objective: To analyze the outcomes of clinical T1-3N1M0 breast cancer patients with pathological negative axillary lymph nodes (ypN0) after neoadjuvant chemotherapy (NAC) and mastectomy, and investigate the role of postmastectomy radiotherapy (PMRT). Methods: A total of 185 patients with clinical T1-3N1M0 breast cancer treated between 1999 and 2013 were retrospectively reviewed. All patients were treated with NAC and mastectomy, and achieved ypN0. Of them, 89 patients received additional PMRT and 96 patients did not. 101 patients had clinical stage II disease. 84 patients had clinical stage III disease. The rates of locoregional recurrence (LRR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS) were calculated using the Kaplan-Meier method, and differences were compared using the log-rank test. Univariate analysis was used to interpret the impact of clinical features and treatment on patients' outcome. Results: The 5-year rates of LRR, DM, DFS, and OS for all patients were 4.5%, 10.4%, 86.6%, and 97.1%, respectively. For patients with and without PMRT, the 5-year LRR rates were 1.1% and 7.5% (P=0.071), the 5-year DM rates were 5.1% and 15.0% (P=0.023), the 5-year DFS rates were 95.0% and 79.0% (P=0.008), and the 5-year OS rates were 100.0% and 94.5% (P=0.089) respectively. In univariate analysis, lymph-vascular space invasion (LVSI) was poor prognostic factor of LRR (P=0.001), < 40 years old and lack of PMRT was a poor prognostic factor for DM (P<0.05), lack of PMRT was a poor prognostic factor for DFS (P=0.008), primary lesion residual and mild-moderate pathological response to NAC were poor prognostic factors for OS (P<0.05). In the subgroup of Stage III disease, for patients with and without PMRT, the 5-year LRR rates were 1.9% and 14.4% (P=0.041), the 5-year DFS rates were 91.9% and 67.4% (P=0.022), respectively. In the subgroup of Stage II disease, for patients with and without PMRT, the 5-year DM rates were 0 and 11.5% (P=0.044), the 5-year DFS rates were 100.0% and 84.9% (P=0.023), respectively. Conclusions: The LRR rate of clinical T1-3N1M0 breast cancer patients who achieved ypN0 after NAC and mastectomy was low. PMRT decreased the DM rate and increased DFS rate in all patients, and significantly decreased the LRR rate in Stage III disease. PMRT should be considered for patients with Stage III disease, and further research is warranted to investigate the benefit of PMRT for Stage II disease. PMID- 28635236 TI - [Efficacy and safety of Xiaoaiping combined with chemotherapy in the treatment of advanced esophageal cancer]. AB - Objective: To evaluate the efficacy and safety of Xiaoaiping combined with chemotherapy in the treatment of advanced esophageal cancer. Methods: This is a multi-center, randomized, open label and parallel controlled study. A total of 124 advanced esophageal cancer patients with Karnofsky Performance Status (KPS) score >=60 and expected survival time>=3 months were enrolled. We adopted design and divided the patients into study and control group. The patients in study group received Xiaoaiping combined with S-1 and cisplatin. The control group received S-1 and cisplatin. Each group included 62 patients and 21 days as a treatment cycle. The efficacy and adverse events in patients of the two groups were observed and compared. Results: 57 patients in the study group and 55 in the control group were included in efficacy assessment. The response rate was 54.4% and 34.5% in the study group and control group, respectively(P<0.05). Disease control rates were 86.0% and 69.1%, respectively(P<0.05). The median progression free survival (PFS) was 7.97 in the study group and 6.43 months in the control group(P<0.05). The median overall survival(OS) was 12.93 in the study group and 10.93 months in the control group(P<0.05). The most common adverse events in the two groups were nausea and vomiting, thrombocytopenia, anemia, neutropenia, liver damage, pigmentation, oral mucositis, renal impairment and diarrhea. The incidences of nausea, vomiting, thrombocytopenia, leukopenia, neutropenia and diarrhea in the study group were significantly higher than those in the control group(P<0.05). Conclusion: Xiaoaiping combined with S-1 and cisplatin significantly increased response rate, and prolongedpatients' survival in patients with advanced esophageal cancer. PMID- 28635237 TI - [Comparison of the short-term and long-term outcomes of laparoscopic surgery and open surgery for early-stage cervical cancer]. AB - Objective: To evaluate the short-term and long-term outcomes after laparoscopic surgery compared with traditional laparotomy in cases of stage IA2-IIA2 cervical cancer. Methods: We conducted a retrospective study on the clinical data of 1 863 patients diagnosed as FIGO stages IA2-IIA2 cervical cancer in 6 third-grade class A hospitals in Guangxi province between January 2007 and May 2014. One thousand and seventy-one received laparoscopy, and 792 received laparotomy. T-test, U-test and chi(2) test were used to compare the short-term and long-term outcomes. The short-term outcomes included surgical related outcomes and operative complications, and the long-term outcomes included quality of life (pelvic floor functions and sexual functions), survival and recurrence. Pelvic floor function and sexual function were assessed with the International Consultation on Incontinence Quesonnaire Female Lower Urinary tract(ICIQ-FLUTS) and the Female Sexual Function Inventory (FSFI), respectively. Survival rates were estimated by Kaplan-Meier analysis. The survival curves were compared with Log-rank test. Cox regression analysis was used to evaluaterisk factors for prognosis. Results: (1)The short-term outcomes : There were significant difference in operative time([(257+/-69) vs(238+/-56)min], estimated blood loss[(358+/-314) vs(707+/ 431)ml], anus exhausting time[(2.5+/-0.9) vs (2.9+/-0.8)d], preserved days of catheter[(15+/-7) vs(18+/-9)d], and post-operative length of stay[(19+/-16) vs (30+/-21)d] between the laparoscopic surgery group and the opensurgery group(P<0.05). There was no significant difference in lymph nodes yielded[(21+/ 9) vs (21+/-11)], left parametrial width[(2.5+/-0.8) vs (2.7+/-0.7)cm], right parametrial width [(2.6+/-0.3) vs (2.7+/-0.2)cm], vaginal cuff length[(2.4+/-0.7) vs (2.2+/-0.7)cm] between the laparoscopic surgery group and the opensurgery group(P>0.05). The intra-operative complications occurred in 8.1%(87/1 071)in the laparoscopic surgery group and in 10.7%(85/792)in the open surgery group(P>0.05). However, the complications of vascular injury in the laparoscopic surgery group[2.6%(28/1 071)]was lower than that in the open surgery group[7.7%(61/792), P<0.001]. The laparoscopic surgery exhibited lower post- operative complication rate [33.8%(362/1 071)vs 40.2%(318/792), P<0.05] and poorer wound healing rate [0.7%(7/1 071)vs 4.0%(32/792), P<0.05]. (2)The long-term outcomes(Hierarchical analysis): The overall incontinence in ICIQ-FLUTS questionnaire in nerve-sparing laparoscopic group [28.4%(67/236)] was lower than that in the open surgery group [35.9%(71/198), P=0.004] . However, There was no significant difference in degree of incontinence between the two groups(P>0.05). The overall sexual dysfunction in FSFI questionnaire after 12 months of postoperative in the nerve-sparing laparoscopic group [47.0%(111/236)]was lower than that in the open surgery group [58.6%(116/198), P=0.001], and the six different dimension scores in the laparoscopic surgery group were higher than that in the open surgery group (P<0.05). The recurrence rate was 3.5%(35/1 007)in the laparoscopicsurgery group and 4.7%(35/740)in the open surgery group(P>0.05). The 5-year OS was 94.0% for the laparoscopic surgery group and 90.2% for the open surgery group(P>0.05), and the 5-year DFS was 93.9% for the laparoscopic surgery group and 89.1% for the open surgery group(P>0.05). (3) Prognostic fators: In univariate analysis, tumor dimension, clinical stage, deep stromal invasion, LVSI, and retroperitoneal lymph node metastasis signficantly affected 5-year OS and 5-year DFS(P<0.05); In multivariate analyses, LVSI, deep stromal invasion and LN metastasis were independent prognostic factors(P<0.05). Conclusions: Laparoscopy can reduceestimated blood loss, accelerate postoperative recovery and improve the quality of life after surgery compared to laparotomy, and it ensures the same oncological results as open surgery. Laparoscopic approach is a safe and effective treatment for early-stage cervical cancer. PMID- 28635239 TI - [An analysis of incidence trends and characteristics of soft tissue sarcoma in Beijing, 1999-2013]. AB - Objective: To analyze the incidence trends and to describe the characteristics of soft tissue sarcoma (STS) among residents in Beijing from 1999 to 2013. Methods: Medical information of the cases diagnosed as STS(ICD10: C47&C49) from 1999 to 2013 in Beijing was extracted from the population-based database of Beijing Cancer Registry.Crude incidence rate, age-standardized incidence rates to Chinese population (ASRC)and the world population(ASRW) were calculated. The characteristics of the STS cases in different gender and age groups from urban and rural areas were respectively analyzed.The incidence trends and annual percentage changes (APC) during last 15 years were analyzed by using JoinPoint 3.4.3 software. Results: A total of 2 048 cases were diagnosed as STS during the study period and the incidence rate of STS was 1.15 per 100 000 person-years. The ASRC was 0.74 per 100 000 person-years and ASRW was 0.86 per 100 000 person years, respectively. Except for the impact of changes in the age composition, the APC of ASRW from 1999 to 2013 was 3.95%. For males, the incidence rate was increased from 0.65 per 100 000 in 1999 to 1.51 per 100 000 in 2013, and the APC was 4.27% (P<0.05); For females, the incidence rate was increased from 0.61 per 100 000 in 1999 to 0.91 per 100 000 in 2013, and the APC was 3.38% (P<0.05). In urban area, the incidence rate increased from 1.14 per 100 000 in 2000 to 1.35 per 100 000 in 2013, and the APC was 2.70% (P=0.05); In rural area, the incidence rate increased from 0.57 per 100 000 in 2000 to 0.98 per 100 000 in 2013, and the APC was 4.66% (P=0.04). 85.89%cases were pathologically diagnosed.Among them, undifferentiated pleomorphic sarcoma was the most common subtype, which accounting for 19.22%, followed by liposarcoma (19.04%), malignantnerve sheath tumor (10.18%), fibrosarcoma (10.06%)and sarcoma without definite type(7.22%). Conclusions: The incidence rate of STS is still increasing, especially in the rural area of Beijing. The most common subtypes of STS in different age-groups were different. Further study is needed to explore the high risks of STS in the population with specific characteristics. PMID- 28635238 TI - [Comparison of vacuum bag fixation and Orfit rack with thermoplastic membrane fixation for image-guided cervical cancer radiotherapy]. AB - Objective: To compare the difference of displacement between the vacuum bag fixation and the Orfit rack with thermoplastic membrane fixation of the cervical cancer patients, and to explore the individual fixation of the patients. Methods: We retrospectively analyzed the clinical data of 66 patients diagnosed as cervical cancer in Zhangzhou Municipal Hospital of Fujian Province from December 2014 to April 2016. Among them, 33 patients were fixed with vacuum bag, 33 patients were fixed with the Orfit rack with thermoplastic membrane. The cone beam computed tomography (CBCT) images were acquired daily for the first three times of the radiotherapy, followed by once every other day for a total of 15 times. The CBCT scan images were matched with the CT scan images, and the matching results were recorded and analyzed. Results: The absolute value of the displacement in the left and right directions of the vacuum bag group was (0.28+/ 0.30) cm, significantly lower than (0.38+/-0.46) cm in the Orfit rack with thermoplastic membrane group(P<0.001). The absolute value of the displacement in the anteroposterior direction of the vacuum bag group was (0.28+/-0.32) cm, with no significant difference of (0.27+/-0.23) cm in the Orfit rack with thermoplastic membrane group (P=0.580). The absolute value of the displacement in the up and down directions was (0.33+/-0.60) cm, with no statistically significant difference of (0.27+/-0.48) cm in the Orfit rack with thermoplastic membrane group (P=0.150). During the three times of CBCT scans, the differences of displacement in the left and right directions of the vacuum bag group were negligible, while apparently varied in the anteroposterior and up and down directions, however, the differences were not statistically significant (P>0.05). The change of the displacement in the three-dimensional direction in the Orfit rack with thermoplastic membrane group was marginal, and all of the differences were not significant(all P>0.05). Conclusions: Both the vacuum bag fixation and the Orfit rack with thermoplastic membrane fixation are suitable for the cone beam CT image-guided radiotherapy of cervical cancer patients. However, the displacement in the left and right directions of the vacuum bag fixation is smaller than the Orfit rack with thermoplastic membrane fixation. During the period of treatment, the mean value of the difference of displacement in the anterior and posterior directions of the Orfit rack with thermoplastic membrane fixation is mild, which can be used individually by the patients with a flexible body and good tolerance. PMID- 28635240 TI - [Two cases of lung cancer with bone metastasis of hand]. PMID- 28635242 TI - [Towards a neuropsychological approach to autism] AB - Neuropsychology attributes mental activity to brain functioning. An inventory of the every-day life of the autist confirms a breakdown in behavior adapted to the world around him. Deficiency in the contribution of the right hemisphere, compromising social life, is accompanied by a mental life that is detached from reality, favorizing preconceived ideas that are inscribed in the logic governing the left hemispheric function. Inside each hemisphere homologous areas of the cerebral cortex, receiving and sharing the same information, react to messages according to their own mode. The left hemisphere applies itself to elementary information, treated sequentially, while the right hemisphere continuously brings up to date temporal and spatial synthesis coming from the sensorale contribution. Attachment to an object or attentiveness to the world: this alternative mode is the key to understanding. The disorder responsible for autism occurs in the perinatal period. It compromizes the maturation of right hemisphere functions where interaction with the surrounding environment should take precedence over attention to objects. Besides its interest in the orientation of research, the neuropsychological approach of Pervasive Development Disorder has the merit of demystifying the drama associated with autism. A better understanding of the nature of this disorder would be of great assistance in circumventing it. PMID- 28635241 TI - [Alpha-fetoprotein-producing pancreatic cancer: a case report]. PMID- 28635244 TI - [Malaria is still a leading cause of fever and death among children and pregnant women in Africa in 2015]. AB - The prevalence and morbidity of P. vivax, P. ovale (curisi et wallikeri) and P. malariae remain underestimated. However important progress has been made. According to the WHO World Malaria report between 2000 and 2015 the malaria incidence has decreased by 42% while the incidence of malaria deaths has decreased by 66%. This is the result of the important progress made in scaling up the main interventions such the rapid diagnosis test, Artemisinin-based combination therapies, long lasting insecticide treated nets, indoor residual house spraying, intermittent preventive treatment during pregnancy (IPTp-SP), Seasonal Malaria Chemoprophylaxis with combined antimalarial (SMClAQ-SP). In the Sahel region with a highly seasonal transmission, the use of SMC resulted in a reduction of malaria morbidity for 80% and a reduce mortality for 58%. Malaria elimination efforts are going on in many countries in Swaziland, South Africa, Namibia, Zanzibar (United Republic of Tanzania), Bioko Island (Equatorial Guinea), Sao Tome and Principe, Cape Verde, and maybe Senegal. For the time being only countries in Northern Africa and few in East Africa (Mauritius) have reached the elimination of local transmission. Despite the progress made near 500,000 malaria deaths occur annually in the African Region with 10-15% leading to disabling sequels and low school performance in children. Reaching the target of 80% for preventive and treatment interventions remain a challenge in many countries in Africa. It's important to keep in mind that the Abuja targets and MGDs were not reached by most African countries. In addition, among 12 million children eligible for SMC only 35% were covered despite the availability of resources in 2014. A huge global stock out of ACT. AQ-SP is possible. The development of an effective vaccine has been disappointing with a limited effectiveness of the RTS,S. The emerging resistance to Artemisinin derivate in South-East Asia and its possible expansion to Africa is of big concern. Anopheles gambiae resistance to pyrethroid make to situation even more complex. The situation can worsen because of factor such as climate change and socio-political crisis. Therefore the malaria situation in Africa is still of big concern despite the progress highlighted. Innovative a robust approach is needed with strong government commitment and partners support to lead battle. A new hope is emerging with the development of candidate vaccine from whole sporozoite, the other candidates vaccines blocking the transmission in phase 1b and the new SMC Plus strategy (AQ-SP+Azithromycine). Conclusion: lessons learnt from the malaria eradication era in the 50s must be factored in while developing the malaria elimination strategy for Africa by 2030. PMID- 28635245 TI - Focus on lung cancer screening program at Campus Bio-Medico of Rome: update on over 3250 patients. PMID- 28635246 TI - Patient-specific cardiac electrophysiology. PMID- 28635247 TI - Spontaneous coronary dissection of left anterior descending artery complicated by retrograde extension of dissection and involvement of left main artery: successful management with percutaneous coronary intervention. PMID- 28635248 TI - Safety, feasibility, tips and tricks of permanent pacemaker implantation in patients with isolated persistent left superior vena cava. PMID- 28635249 TI - Perfluorocarbon/Gold Loading for Noninvasive in Vivo Assessment of Bone Fillers Using 19F Magnetic Resonance Imaging and Computed Tomography. AB - Calcium phosphate cement (CPC) is used in bone repair because of its biocompatibility. However, high similarity between CPC and the natural osseous phase results in poor image contrast in most of the available in vivo imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). For accurate identification and localization during and after implantation in vivo, a composition with enhanced image contrast is needed. In this study, we labeled CPC with perfluoro-15-crown-5-ether-loaded (PFCE) poly(latic-co-glycolic acid) nanoparticles (hydrodynamic radius 100 nm) and gold nanoparticles (diameter 40 nm), as 19F MRI and CT contrast agents, respectively. The resulting CPC/PFCE/gold composite is implanted in a rat model for in vivo longitudinal imaging. Our findings show that the incorporation of the two types of different nanoparticles did result in adequate handling properties of the cement. Qualitative and quantitative long-term assessment of CPC/PFCE/gold degradation was achieved in vivo and correlated to the new bone formation. Finally, no adverse biological effects on the bone tissue are observed via histology. In conclusion, an easy and efficient strategy for following CPC implantation and degradation in vivo is developed. As all materials used are biocompatible, this CPC/PFCE/gold composite is clinically applicable. PMID- 28635250 TI - Highly Stimuli-Responsive Au Nanorods/Poly(N-isopropylacrylamide) (PNIPAM) Composite Hydrogel for Smart Switch. AB - To achieve both fast response and structural integrity during the repeating volume changes are the most significant challenges for thermoresponsive hydrogels. In this work, AuNRs/PNIPAM composite hydrogel with fast thermal/optical response and structural integrity is facilely prepared by electrospinning and following a curing treatment. By combining the photothermal property of AuNRs and thermal-responsive effect of PNIPAM, the composite hydrogel shows fast thermal/photoresponse, high heating rate, and high structural integrity with fierce size change. When laser irradiation begins, the temperature of the film increases from room temperature to 34.5 degrees C in 1 s and will further increase even to 60 degrees C in 5 s. Both the porous structure of the hydrogel and the assemble effect of AuNRs within the PNIPAM fibers facilitate the fast responsibility. Furthermore, to take advantage of this fibrous hydrogel adequately, one novel kind of thermal/photocontrolled switch based on the composite hydrogel is prepared, which exhibits fast responsivity and high stability even under acidic or basic conditions. PMID- 28635251 TI - Molecular Adsorbates Switch on Heterogeneous Catalysis: Induction of Reactivity by N-Heterocyclic Carbenes. AB - We report the N-heterocyclic carbene (NHC)-induced activation of an otherwise unreactive Pd/Al2O3 catalyst. Surface analysis techniques demonstrate the NHC being coordinated to the palladium particles and affecting their electronic properties. Ab initio calculations provide further insight into the electronic effect of the coordination with the NHC injecting electron density into the metal nanocluster thus lowering the barrier for bromobenzene activation. By this NHC modification, the catalyst could be successfully applied in the Buchwald-Hartwig amination of aryl chlorides, bromides, and iodides. Various heterogeneity tests could additionally show that the reaction proceeds via a heterogeneous active species. PMID- 28635252 TI - Proton-Fueled, Reversible DNA Hybridization Chain Assembly for pH Sensing and Imaging. AB - Design of DNA self-assembly with reversible responsiveness to external stimuli is of great interest for diverse applications. We for the first time develop a pH responsive, fully reversible hybridization chain reaction (HCR) assembly that allows sensitive sensing and imaging of pH in living cells. Our design relies on the triplex forming sequences that form DNA triplex with toehold regions under acidic conditions and then induce a cascade of strand displacement and DNA assembly. The HCR assembly has shown dynamic responses in physiological pH ranges with excellent reversibility and demonstrated the potential for in vitro detection and live-cell imaging of pH. Moreover, this method affords HCR assemblies with highly localized fluorescence responses, offering advantages of improving sensitivity and better selectivity. The proton-fueled, reversible HCR assembly may provide a useful approach for pH-related cell biology study and disease diagnostics. PMID- 28635253 TI - Discovery and Characterization of Histidine Oxidation Initiated Cross-links in an IgG1 Monoclonal Antibody. AB - Novel cross-links between an oxidized histidine and intact histidine, lysine, or cysteine residues were discovered and characterized from high-molecular weight (HMW) fractions of an IgG1 monoclonal antibody (mAb). The mAb HMW fractions were collected using preparative size-exclusion chromatography (SEC) and extensively characterized to understand the mechanism of formation of the nonreducible and covalently linked portion of the HMWs. The HMW fractions were IdeS digested, reduced, and analyzed by size-exclusion chromatography coupled with mass spectrometry (SEC-MS). The nonreducible cross-links were found to be enriched in the fragment crystallizable (Fc) region of the heavy chain, with a net mass increase of 14 Da. Detailed peptide mapping revealed as many as seven covalent cross-links in the HMW fractions, where oxidized histidines react with intact histidine, lysine, and free cysteine to form cross-links. It is the first time that histidine-cysteine (His-Cys) and histidine-lysine (His-Lys) in addition to histidine-histidine (His-His) cross-links were discovered in monoclonal antibody HMW species. The histidine oxidation hot spots were identified, which include conserved histidine residues His292 and His440 in the Fc region and His231 in the hinge region of the IgG1 mAb heavy chain. Their cross-linking partners include His231, His292, His440, and Cys233 in the hinge region and Lys297 in the Fc region. A cross-linking mechanism has been proposed that involves nucleophilic addition by histidine, cysteine, or lysine residues to the carbonyl-containing histidine oxidation intermediates to form the cross-links. PMID- 28635254 TI - Sudoku-like Lab-on-Paper Cyto-Device with Dual Enhancement of Electrochemiluminescence Intermediates Strategy. AB - This paper describes the design and construction of a sudoku-like lab-on-paper platform, in which dual enhancement of reaction intermediates strategy was incorporated for multiplexed competitive electrochemiluminescence (ECL) cyto assay. Benefiting from the sudoku-like structure, integrated multifunctions were obtained on such an elaborately devised platform, including specific reagents storage, multiple samples immobilization, residual automatic washing, and signal collection. By utilizing semicarbazide (SE) and silver nanoparticles (AgNPs) as dual enhancers, more ECL intermediates could be obtained in the graphene quantum dots (GQDs) and peroxydisulfate system, resulting in the production of more excited-state GQDs to emit light. Moreover, the double-stranded DNA nanowire with multiple branched arms (MBdsDNA) was chosen as an efficient nanocarrier to load more GQDs and AgNPs. Via immobilizing AgNPs on the end of the plentiful branched arms, Ag-MBdsDNA were obtained and trapped on the sensing interface through the valid competitive interactions between target cells and Ag-MBdsDNA. Afterward, abundant GQDs were attached to the three-dimensional (3D) DNA skeleton of the captured Ag-MBdsDNA via pi-pi stacking. Due to their good self-catalytic activity of labeled AgNPs, more silver was deposited on the Ag-MBdsDNA@GQDs, giving rise to further amplification of expected signal. With four types of cancer cells as models, MCF-7, CCRF-CEM, HeLa, and K562 cells were assayed in the ranges of 1.0 * 102-1.0 * 107, 1.5 * 102-2.0 * 107, 2.0 * 102-5.0 * 106, and 1.2 * 102-2.0 * 106 cells mL-1 with the detection limits of 38, 53, 67, and 42 cells mL-1, respectively. Notably, this strategy supplies a simple and versatile platform for sensitive determination of multiple targeted cells, which would play a crucial role in point-of-care diagnostic fields. PMID- 28635255 TI - Characterization and Immunomodulatory Activity of a Novel Peptide, ECFSTA, from Wheat Germ Globulin. AB - A novel peptide was extracted from wheat germ globulin and purified using ion exchange chromatography, gel filtration chromatography, and semi-preparative reversed-phase high-performance liquid chromatography (RP-HPLC). The sequence of the peptide was found to be Glu-Cys-Phe-Ser-Thr-Ala (ECFSTA). Its immunomodulatory effects were evaluated, and the results showed that ECFSTA could enhance phagocytosis of RAW 264.7 cells and significantly increase their secretion of nitric oxide (NO), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and reactive oxygen species (ROS). ECFSTA activated macrophages mainly through the pattern recognition receptors (PRRs) of toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4), and the production of ROS simultaneously stimulated macrophages to produce TNF-alpha. Thus, ECFSTA could be used as an immunomodulator and might be a promising component of functional foods. PMID- 28635256 TI - In Situ Gelation-Induced Death of Cancer Cells Based on Proteinosomes. AB - Hydrogels are an excellent type of material that can be utilized as a platform for cell culture. However, when a bulky hydrogel forms on the inside of cancer cells, the result would be different. In this study, we demonstrate a method for in situ gelation inside cancer cells that can efficiently induce cell death. Glutathione-responsive proteinosomes with good biocompatibility were prepared as carriers for sodium alginate to be endocytosed by cancer cells, where the chelation between sodium alginate and free calcium ions in the culture medium occurs during the diffusion process. The uptake of the hydrogel-loaded proteinosomes into the cancer cells, and then the triggered release of hydrogel with concomitant aggregation, was well-confirmed by monitoring the change of the Young's modulus of the cells based on AFM force measurements. Accordingly, when a large amount of hydrogel formed in cells, the cell viability would be inhibited by ~90% by MTT assay at a concentration of 5.0 MUM of hydrogel-loaded proteinosomes after 48 h incubation, which clearly proves the feasibility of the demonstrated method for killing cancer cells. Although more details regarding the mechanism of cell death should be conducted in the near future, such a demonstrated method of in situ gelation inside cells provides another choice for killing cancer cells. PMID- 28635258 TI - Mucin-Inspired Lubrication on Hydrophobic Surfaces. AB - In the human body, high-molecular-weight glycoproteins called mucins play a key role in protecting epithelial surfaces against pathogenic attack, controlling the passage of molecules toward the tissue and enabling boundary lubrication with very low friction coefficients. However, neither the molecular mechanisms nor the chemical motifs of those biomacromolecules involved in these fundamental processes are fully understood. Thus, identifying the key features that render biomacromolecules such as mucins outstanding boundary lubricants could set the stage for creating versatile artificial superlubricants. We here demonstrate the importance of the hydrophobic terminal peptide domains of porcine gastric mucin (MUC5AC) and human salivary mucin (MUC5B) in the processes of adsorbing to and lubricating a hydrophobic PDMS surface. Tryptic digestion of those mucins results in removal of those terminal domains, which is accompanied by a loss of lubricity as well as surface adsorption. We show that this loss can in part be compensated by attaching hydrophobic phenyl groups to the glycosylated central part of the mucin macromolecule. Furthermore, we demonstrate that the simple biopolysaccharide dextran can be functionalized with hydrophobic groups which confers efficient surface adsorption and good lubricity on PDMS to the polysaccharide. PMID- 28635257 TI - Circular Bivalent Aptamers Enable in Vivo Stability and Recognition. AB - Aptamers are powerful candidates for molecular imaging and targeted therapy of cancer based on such appealing features as high binding affinity, high specificity, site-specific modification and rapid tumor penetration. However, aptamers are susceptible to plasma exonucleases in vivo. This seriously affects their in vivo applications. To overcome this key limitation, we herein report the design and development of circular bivalent aptamers. Systematic studies reveal that cyclization of aptamers can improve thermal stability, nuclease resistance and binding affinity. In vivo fluorescence imaging further validates the efficient accumulation and retention of circular bivalent aptamers in tumors compared to "mono-aptamers". Therefore, this study provides a simple and efficient strategy to boost in vivo aptamer applications in cancer diagnosis and therapy. PMID- 28635259 TI - Delivery System Targeting Hemagglutinin of Influenza Virus A to Facilitate Antisense-Based Anti-H1N1 Therapy. AB - Antisense oligonucleotides (ODNs) are therapeutic molecules that hybridize to complementary target mRNA sequences. To further overcome the poor cellular uptake of ODNs, we proposed a novel strategy to deliver ODNs by conjugating the anti influenza A virus (IAV) ODN with a peptide showing high affinity to the hemagglutinin (HA) on the surface of IAV particles or the IAV-infected host cells. The HA-specific binding peptides were selected by phage display, and the individual binding clones are characterized by DNA sequencing, and the selected phage was further assayed by enzyme-linked immunosorbent assay. The final selected HA-binding peptide, SHGRITFAYFAN, was conjugated to an anti-IAV ODN. The delivery efficiency and the anti-IAV effects of the conjugated molecule were evaluated in a cell-culture and a mouse-infection model. The conjugated molecule was successfully delivered into IAV-infected host cells more efficiently than the anti-IAV ODN in vitro and in vivo. Furthermore, the conjugated molecule protected 80% of the mice from lethal challenge and inhibited the plaque count by 75% compared to the unconjugated molecule (60% and 40%). These findings demonstrate that the delivery of antisense oligodeoxynucleotides to infected tissues by a virus-binding peptide-mediated system is a potential therapeutic strategy against IAV. PMID- 28635261 TI - Novel Protein-Based Solid-Biosensor for Determining Pro-oxidant Activity of Phenolic Compounds. AB - To develop a protein-based biosensor measuring the pro-oxidant activities of phenolic compounds, egg white proteins were precipitated with calcium chloride to obtain an insoluble calcium proteinate complex. This biosensor was used for the determination of Cu(II)-induced pro-oxidant activity of antioxidants such as gallic acid, catechin, epicatechin, quercetin, chlorogenic acid and myricetin, and ascorbic acid. This assay involved the reduction of Cu(II) ions to Cu(I) by antioxidant compounds (simultaneously giving rise to reactive oxygen species) and binding of the formed Cu(I) to the solid biosensor. The protein-bound Cu(I), an indicator of pro-oxidant activity of antioxidants on proteins, was colorimetrically determined at 450 nm with neocuproine (Nc). The method was applied to synthetic mixtures and herbal (sage, green tea, mint, and marjoram) infusions, and its findings were compared to those of a modified carbonyl detection assay. This low-cost biosensor can be prepared in large quantities and used for a long time. PMID- 28635262 TI - Enormous Hydrogen Bond Strength Enhancement through pi-Conjugation Gain: Implications for Enzyme Catalysis. AB - Surprisingly large resonance-assistance effects may explain how some enzymes form extremely short, strong hydrogen bonds to stabilize reactive oxyanion intermediates and facilitate catalysis. Computational models for several enzymic residue-substrate interactions reveal that when a pi-conjugated, hydrogen bond donor (XH) forms a hydrogen bond to a charged substrate (Y-), XH can become significantly more pi-electron delocalized, and this "extra" stabilization may boost the [XH...Y-] hydrogen bond strength by >=15 kcal/mol. This reciprocal relationship departs from the widespread pKa concept (i.e., the idea that short, strong hydrogen bonds form when the interacting moieties have matching pKa values), which has been the rationale for enzymic acid-base reactions. The findings presented here provide new insight into how short, strong hydrogen bonds could form in enzymes. PMID- 28635260 TI - Development, Validation, and Interlaboratory Evaluation of a Quantitative Multiplexing Method To Assess Levels of Ten Endogenous Allergens in Soybean Seed and Its Application to Field Trials Spanning Three Growing Seasons. AB - As part of the regulatory approval process in Europe, comparison of endogenous soybean allergen levels between genetically engineered (GE) and non-GE plants has been requested. A quantitative multiplex analytical method using tandem mass spectrometry was developed and validated to measure 10 potential soybean allergens from soybean seed. The analytical method was implemented at six laboratories to demonstrate the robustness of the method and further applied to three soybean field studies across multiple growing seasons (including 21 non-GE soybean varieties) to assess the natural variation of allergen levels. The results show environmental factors contribute more than genetic factors to the large variation in allergen abundance (2- to 50-fold between environmental replicates) as well as a large contribution of Gly m 5 and Gly m 6 to the total allergen profile, calling into question the scientific rational for measurement of endogenous allergen levels between GE and non-GE varieties in the safety assessment. PMID- 28635263 TI - Crystalline Nanochannels with Pendant Azobenzene Groups: Steric or Polar Effects on Gas Adsorption and Diffusion? AB - An azobenzene-containing, zirconium-based metal-organic framework (AzoMOF), upon irradiation with ultraviolet (UV) light at 365 +/- 10 nm, underwent trans-to-cis isomerization of its azobenzene pendants to furnish the cis-isomer content of 21% (AzoMOF21%) in 30 min at the photostationary state and underwent backward isomerization into AzoMOF1% upon either irradiation with visible light (420-480 nm) or heating. When the cis-isomer content increased, the diffusion rate and amount of CO2 adsorbed into the nanochannels of AzoMOF decreased considerably. When erythrosine B, a polarity-probing guest, was used, it showed a red shift upon exposure of AzoMOF20%?EB to visible light, indicating that the interior environment of AzoMOF turns less polar as the trans-isomer content becomes higher. In sharp contrast, the adsorption profiles of AzoMOF15% and AzoMOF1% for Ar having an analogous kinetic diameter to CO2 but no quadrupole moment and a smaller polarizability were virtually identical to one another. Therefore, it is likely that CO2 experiences a dominant effect of a polar effect rather than a steric effect in the crystalline nanochannels. PMID- 28635264 TI - Cadmium Accumulation Risk in Vegetables and Rice in Southern China: Insights from Solid-Solution Partitioning and Plant Uptake Factor. AB - Solid-solution partitioning coefficient (Kd) and plant uptake factor (PUF) largely determine the solubility and mobility of soil Cd to food crops. A four year regional investigation was conducted in contaminated vegetable and paddy fields of southern China to quantify the variability in Kd and PUF. The distributions of Kd and PUF characterizing transfers of Cd from soil to vegetable and rice are probabilistic in nature. Dynamics in soil pH and soil Zn greatly affected the variations of Kd. In addition to soil pH, soil organic matter had a major influence on PUF variations in vegetables. Heavy leaching of soil Mn caused a higher Cd accumulation in rice grain. Dietary ingestion of 85.5% of the locally produced vegetable and rice would have adverse health risks, with rice consumption contributing 97.2% of the risk. A probabilistic risk analysis based on derived transfer function reveals the amorphous Mn oxide content exerts a major influence on Cd accumulation in rice in pH conditions below 5.5. Risk estimation and field experiments show that to limit the Cd concentration in rice grains, soil management strategies should include improving the pH and soil Mn concentration to around 6.0 and 345 mg kg-1, respectively. Our work illustrates that re-establishing a balance in trace elements in soils' labile pool provides an effective risk-based approach for safer crop practices. PMID- 28635265 TI - Metabolic Oligosaccharide Engineering with Alkyne Sialic Acids Confers Neuraminidase Resistance and Inhibits Influenza Reproduction. AB - Metabolic incorporation of azide- or alkyne-modified sialic acids into the cellular glycosylation pathway enables the study of sialoglycan expression, localization, and trafficking via bioorthogonal chemistry. Herein, we report that such modifications of the sialic acid sugar can have a profound influence on their hydrolysis by neuraminidases (sialidase). Azidoacetyl (Az)-modified sialic acids were prone to neuraminidase cleavage, whereas propargyloxycarbonyl (Poc) modified sialic acids were largely resistant to cleavage. Because the influenza virus infection cycle depends on the hydrolysis of host-cell-surface sialic acids, influenza cell-to-cell transmission was strongly reduced in Poc sialic acid glycoengineered host cells. The use of Poc sialic acids may disturb biological processes involving neuraminidase cleavage but also provides perspective for use in applications in which sialic acid hydrolysis is not desired, such as antibody modification, viral infection, etc. PMID- 28635266 TI - Boosting the Thermoelectric Performance of (Na,K)-Codoped Polycrystalline SnSe by Synergistic Tailoring of the Band Structure and Atomic-Scale Defect Phonon Scattering. AB - We report the high thermoelectric performance of p-type polycrystalline SnSe obtained by the synergistic tailoring of band structures and atomic-scale defect phonon scattering through (Na,K)-codoping. The energy offsets of multiple valence bands in SnSe are decreased after Na doping and further reduced by (Na,K) codoping, resulting in an enhancement in the Seebeck coefficient and an increase in the power factor to 492 MUW m-1 K-2. The lattice thermal conductivity of polycrystalline SnSe is decreased by the introduction of effective phonon scattering centers, such as point defects and antiphase boundaries. The lattice thermal conductivity of the material is reduced to values as low as 0.29 W m-1 K 1 at 773 K, whereas ZT is increased from 0.3 for 1% Na-doped SnSe to 1.2 for 1% (Na,K)-codoped SnSe. PMID- 28635267 TI - Cytochrome c Provides an Electron-Funneling Antenna for Efficient Photocurrent Generation in a Reaction Center Biophotocathode. AB - The high quantum efficiency of photosynthetic reaction centers (RCs) makes them attractive for bioelectronic and biophotovoltaic applications. However, much of the native RC efficiency is lost in communication between surface-bound RCs and electrode materials. The state-of-the-art biophotoelectrodes utilizing cytochrome c (cyt c) as a biological wiring agent have at best approached 32% retained RC quantum efficiency. However, bottlenecks in cyt c-mediated electron transfer have not yet been fully elucidated. In this work, protein film voltammetry in conjunction with photoelectrochemistry is used to show that cyt c acts as an electron-funneling antennae that shuttle electrons from a functionalized rough silver electrode to surface-immobilized RCs. The arrangement of the two proteins on the electrode surface is characterized, revealing that RCs attached directly to the electrode via hydrophobic interactions and that a film of six cyt c per RC electrostatically bound to the electrode. We show that the additional electrical connectivity within a film of cyt c improves the high turnover demands of surface bound RCs. This results in larger photocurrent onset potentials, positively shifted half-wave reduction potentials, and higher photocurrent densities reaching 100 MUA cm-2. These findings are fundamental for the optimization of bioelectronics that utilize the ubiquitous cyt c redox proteins as biological wires to exploit electrode-bound enzymes. PMID- 28635268 TI - Isotope-Controlled Selectivity by Quantum Tunneling: Hydrogen Migration versus Ring Expansion in Cyclopropylmethylcarbenes. AB - Using the tunneling-controlled reactivity of cyclopropylmethylcarbene, we demonstrate the viability of isotope-controlled selectivity (ICS), a novel control element of chemical reactivity where a molecular system with two conceivable products of tunneling exclusively produces one or the other, depending only on isotopic composition. Our multidimensional small-curvature tunneling (SCT) computations indicate that, under cryogenic conditions, 1 methoxycyclopropylmethylcarbene shows rapid H-migration to 1-methoxy-1 vinylcyclopropane, whereas deuterium-substituted 1-methoxycyclopropyl-d3 methylcarbene undergoes ring expansion to 1-d3-methylcyclobutene. This predicted change in reactivity constitutes the first example of a kinetic isotope effect that discriminates between the formation of two products. PMID- 28635269 TI - Reduction Potentials of [FeFe]-Hydrogenase Accessory Iron-Sulfur Clusters Provide Insights into the Energetics of Proton Reduction Catalysis. AB - An [FeFe]-hydrogenase from Clostridium pasteurianum, CpI, is a model system for biological H2 activation. In addition to the catalytic H-cluster, CpI contains four accessory iron-sulfur [FeS] clusters in a branched series that transfer electrons to and from the active site. In this work, potentiometric titrations have been employed in combination with electron paramagnetic resonance (EPR) spectroscopy at defined electrochemical potentials to gain insights into the role of the accessory clusters in catalysis. EPR spectra collected over a range of potentials were deconvoluted into individual components attributable to the accessory [FeS] clusters and the active site H-cluster, and reduction potentials for each cluster were determined. The data suggest a large degree of magnetic coupling between the clusters. The distal [4Fe-4S] cluster is shown to have a lower reduction potential (~ < -450 mV) than the other clusters, and molecular docking experiments indicate that the physiological electron donor, ferredoxin (Fd), most favorably interacts with this cluster. The low reduction potential of the distal [4Fe-4S] cluster thermodynamically restricts the Fdox/Fdred ratio at which CpI can operate, consistent with the role of CpI in recycling Fdred that accumulates during fermentation. Subsequent electron transfer through the additional accessory [FeS] clusters to the H-cluster is thermodynamically favorable. PMID- 28635270 TI - Understanding the Effects of Genotype, Growing Year, and Breeding on Tunisian Durum Wheat Allergenicity. 2. The Celiac Disease Case. AB - The aim of this study was to compare immunogenic and toxic gluten peptides related to celiac disease (CD). 100 accessions of genotypes selected during the 20th century in Tunisia were in vitro digested and then analyzed by UPLC/ESI-MS technique using an isotopically labeled internal standard. The first MANOVA confirmed a high variability in the content of immunogenic and toxic peptides reflecting high genetic diversity in the germplasm released during the past century in Tunisia, consistently with PCA and clustering analysis results. Our finding showed also important variability in CD epitopes due to growing season's climate scenarios. Moreover, the second MANOVA revealed significant differences between abandoned and modern cultivars' CD-related peptide amounts. Although we could not conclude that there was an augment of allergens in newly selected durum wheat lines compared to abandoned ones, we demonstrated that modern genotype peptides were less sensitive to climate variation, which is a useful indicator for wheat breeders. PMID- 28635272 TI - Efficient Flame-Retardant and Smoke-Suppression Properties of Mg-Al-Layered Double-Hydroxide Nanostructures on Wood Substrate. AB - Improving the flame retardancy of wood is an imperative yet highly challenging step in the application of wood in densely populated spaces. In this study, Mg-Al layered double-hydroxide (LDH) coating was successfully fabricated on a wood substrate to confer flame-retardant and smoke-suppression properties. The chemical compositions and bonding states characterized by energy-dispersive X-ray spectroscopy and X-ray photoelectron spectroscopy confirmed the coating constituents of Mg-Al LDH. The coating evenly covered the sample wood surfaces and provided both mechanical enhancement and flame-retardancy effects. The limiting oxygen index of the Mg-Al LDH-coated wood increased to 39.1% from 18.9% in the untreated wood. CONE calorimetry testing revealed a 58% reduction in total smoke production and a 41% reduction in maximum smoke production ratio in the Mg Al LDH-coated wood compared to the untreated wood; the peak heat release rate and total heat release were also reduced by 49% and 40%, respectively. The Mg-Al LDH coating is essentially hydrophilic, but simple surface modification by fluoroalkyl silane could make it superhydrophobic, with a water contact angle of 152 degrees and a sliding angle of 8.6 degrees . The results of this study altogether suggest that Mg-Al LDH coating is a feasible and highly effective approach to nanoconstructing wood materials with favorable flame-retardant and smoke-suppression properties. PMID- 28635271 TI - Emerging Chemistry Strategies for Engineering Native Chromatin. AB - Chromosomes present one of most challenging of all substrates for biochemical study. This is because genomic DNA is physically associated with an astonishing collection of nuclear factors, which serve to not only store the nucleic acid in a stable form, but also grant access to the information it encodes when needed. Understanding this complex molecular choreography is central to the field of epigenetics. One of the great challenges in this area is to move beyond correlative type information, which is now in abundant supply, to the point where we can truly connect the dots at the molecular level. Establishing such causal relationships requires precise manipulation of the covalent structure of chromatin. Tools for this purpose are currently in short supply, creating an opportunity that, as we will argue in this Perspective, is well suited to the sensibilities of the chemist. PMID- 28635273 TI - A Direct Bandgap Copper-Antimony Halide Perovskite. AB - Since the establishment of perovskite solar cells (PSCs), there has been an intense search for alternative materials to replace lead and improve their stability toward moisture and light. As single-metal perovskite structures have yielded unsatisfactory performances, an alternative is the use of double perovskites that incorporate a combination of metals. To this day, only a handful of these compounds have been synthesized, but most of them have indirect bandgaps and/or do not have bandgaps energies well-suited for photovoltaic applications. Here we report the synthesis and characterization of a unique mixed metal ?111? oriented layered perovskite, Cs4CuSb2Cl12 (1), that incorporates Cu2+ and Sb3+ into layers that are three octahedra thick (n = 3). In addition to being made of abundant and nontoxic elements, we show that this material behaves as a semiconductor with a direct bandgap of 1.0 eV and its conductivity is 1 order of magnitude greater than that of MAPbI3 (MA = methylammonium). Furthermore, 1 has high photo- and thermal-stability and is tolerant to humidity. We conclude that 1 is a promising material for photovoltaic applications and represents a new type of layered perovskite structure that incorporates metals in 2+ and 3+ oxidation states, thus significantly widening the possible combinations of metals to replace lead in PSCs. PMID- 28635275 TI - Infrared Determination of the Protonation State of a Key Histidine Residue in the Photosynthetic Water Oxidizing Center. AB - Photosynthetic water oxidation is performed at the Mn4CaO5 cluster in photosystem II (PSII). The protonation structures of amino acid residues and water molecules around the Mn4CaO5 cluster are crucial in water oxidation reactions. In this study, we determined the protonation state of a key His residue in water oxidation, D1-H337, that is directly hydrogen-bonded with the oxygen atom of the Mn4CaO5 cluster, using polarized attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Flash-induced polarized ATR-FTIR difference spectra upon the S1 -> S2 transition of oriented PSII membranes showed broad negative and positive features at about 2600 and 2900 cm-1, respectively, with large dichroic ratios, accompanied by several minor peaks attributable to the Fermi resonance of a His NH vibration. Quantum mechanics/molecular mechanics (QM/MM) calculations well reproduced the characteristics of these features as the NtauH stretching vibrations of D1-H337 in its protonated cation form. The spectral features were reversed in the S3 -> S0 transition, indicating that this His remains protonated during the S-state cycle. The redox potential (Em) of the Mn4CaO5 cluster in the S1 -> S2 transition, which was estimated from the QM/MM calculations, was found to be comparable to that of water oxidation when D1-H337 is protonated cation. It was thus concluded that the positive charge on the protonated D1-H337 plays an important role in retaining a high Em value of the Mn4CaO5 cluster throughout the reaction cycle to enable water oxidation. PMID- 28635274 TI - Oxidation-State-Dependent Binding Properties of the Active Site in a Mo Containing Formate Dehydrogenase. AB - Molybdenum-containing formate dehydrogenase H from Escherichia coli (EcFDH-H) is a powerful model system for studies of the reversible reduction of CO2 to formate. However, the mechanism of FDH catalysis is currently under debate, and whether the primary Mo coordination sphere remains saturated or one of the ligands dissociates to allow direct substrate binding during turnover is disputed. Herein, we describe how oxidation-state-dependent changes at the active site alter its inhibitor binding properties. Using protein film electrochemistry, we show that formate oxidation by EcFDH-H is inhibited strongly and competitively by N3-, OCN-, SCN-, NO2-, and NO3-, whereas CO2 reduction is inhibited only weakly and not competitively. During catalysis, the Mo center cycles between the formal Mo(VI)?S and Mo(IV)-SH states, and by modeling chronoamperometry data recorded at different potentials and substrate and inhibitor concentrations, we demonstrate that both formate oxidation and CO2 reduction are inhibited by selective inhibitor binding to the Mo(VI)?S state. The strong dependence of inhibitor-binding affinity on both Mo oxidation state and inhibitor electron donor strength indicates that inhibitors (and substrates) bind directly to the Mo center. We propose that inhibitors bind to the Mo following dissociation of a selenocysteine ligand to create a vacant coordination site for catalysis and close by considering the implications of our data for the mechanisms of formate oxidation and CO2 reduction. PMID- 28635276 TI - Dynamic Viscoelastic Functions of Liquid-Crystalline Chitin Nanofibril Dispersions. AB - The dynamic viscoelastic functions of aqueous chitin nanofibril (ChNF) dispersions are defined by their liquid-crystalline fibril arrangement. Four ChNF dispersions with different structures were prepared from squid-pen beta-chitin, by sonication in aqueous acetic acid at pH 3 for 4-40 min. Squid-pen beta-chitin was disintegrated into randomly oriented bundles of ChNFs during the initial stage of sonication and then became more finely dispersed with further sonication up to 8 min. The additional sonication resulted in the individualization of the approximately 3 nm-wide ChNFs. The individual ChNFs self-organized into a nematic liquid crystalline phase. All ChNF dispersions showed power-law concentration c dependences of their storage moduli G' at a certain angular frequency omega (Gomega' = Acalpha). The front factor A was positively correlated with the degree of disintegration. The exponent alpha increased from 2.7 to 3.8-3.9, as the ChNF dispersion self-organized from the randomly dispersed structure into the nematic ordered fibril arrangement. This demonstrated an enhancement in the solid concentration dependence. PMID- 28635278 TI - Reflections on 2016 and Projecting Forward. PMID- 28635281 TI - Reactions of Criegee Intermediates with Alcohols at Air-Aqueous Interfaces. AB - The fate of Criegee intermediates (CIs) from the gas-phase ozonolysis of unsaturated organic compounds in the troposphere is largely controlled by their reactions with water vapor. We recently found that against all expectations carboxylic acids compete at millimolar concentrations with water for CIs at the air-liquid interface of aqueous organic media. This outcome is consistent with both the low water concentration in the outermost interfacial layers and the enrichment of the competing acids therein. Here we show, via online electrospray mass spectrometric detection, that CIs generated in situ in the fast ozonolysis of sesquiterpenes (C15H24) on the surface of water:acetonitrile microjets react with n >= 4 linear alcohols CnH2n+1OH to produce high molecular weight C15+n ethers in one step. The OH group of 1-octanol proved to be ~25 times less reactive than that of n-octanoic toward CIs at the same bulk molar concentration, revealing that the reactivity of hydroxylic species depends on both acidities and interfacial affinities. CI interfacial reactions with surface-active hydroxylic species, by bypassing water, represent shortcuts to molecular complexity in atmospheric aerosols. PMID- 28635280 TI - Antiadhesive Activity and Metabolomics Analysis of Rat Urine after Cranberry (Vaccinium macrocarpon Aiton) Administration. AB - Cranberry (Vaccinium macrocarpon Aiton) is used to treat noncomplicated urinary tract infections (UTIs). A-type procyanidins (PAC-A) are considered the active constituents able to inhibit bacterial adhesion to the urinary epithelium. However, the role of PAC-A in UTIs is debated, because of their poor bioavailability, extensive metabolism, limited knowledge about urinary excretion, and contradictory clinical trials. The effects of 35-day cranberry supplementation (11 mg/kg PAC-A, 4 mg/kg PAC-B) were studied in healthy rats using a ultra performance liquid chromatography-mass spectrometry (UPLC-MS)-based metabolomics approach. Microbial PAC metabolites, such as valeric acid and valerolactone derivatives, were related to cranberry consumption. An increased urinary excretion of glucuronidated metabolites was also observed. In a further experiment, urine samples were collected at 2, 4, 8, and 24 h after cranberry intake and their antiadhesive properties were tested against uropathogenic Escherichia coli. The 8 h samples showed the highest activity. Changes in urinary composition were studied by ultra performance liquid chromatography-time-of flight (UPLC-QTOF), observing the presence of PAC metabolites. The PAC-A2 levels were measured in all collected samples, and the highest amounts, on the order of ng/mL, were found in the samples collected after 4 h. Results indicate that the antiadhesive activity against uropathogenic bacteria observed after cranberry consumption is ascribable to PAC-A metabolites rather than to a direct PAC-A effect, as the measured PAC-A levels in urine was lower than those reported as active in the literature. PMID- 28635282 TI - Fining of Red Wine Monitored by Multiple Light Scattering. AB - This work describes a new approach based on multiple light scattering to study red wine clarification processes. The whole spectral signal (1933 backscattering points along the length of each sample vial) were fitted by a multivariate kinetic model that was built with a three-step mechanism, implying (1) adsorption of wine colloids to fining agents, (2) aggregation into larger particles, and (3) sedimentation. Each step is characterized by a reaction rate constant. According to the first reaction, the results showed that gelatin was the most efficient fining agent, concerning the main objective, which was the clarification of the wine, and consequently the increase in its limpidity. Such a trend was also discussed in relation to the results achieved by nephelometry, total phenols, zeta-potential, color, sensory, and electronic nose analyses. Also, higher concentrations of the fining agent (from 5 to 30 g/100 L) or higher temperatures (from 10 to 20 degrees C) sped up the process. Finally, the advantage of using the whole spectral signal vs classical univariate approaches was demonstrated by comparing the uncertainty associated with the rate constants of the proposed kinetic model. Overall, multiple light scattering technique showed a great potential for studying fining processes compared to classical univariate approaches. PMID- 28635283 TI - Piezoresistive Effect in the [Fe(Htrz)2(trz)](BF4) Spin Crossover Complex. AB - We report on the effect of hydrostatic pressure on the electrical conductivity and dielectric permittivity of the [Fe(Htrz)2(trz)](BF4) (Htrz = 1H-1,2,4, triazole) spin crossover complex. Variable-temperature and -pressure broad-band impedance spectrometry revealed a piezoresistive effect of more than 1 order of magnitude for pressures as low as 500 bar, associated with a large pressure induced hysteresis of 1700 bar. The origin of the piezoresistive effect has been attributed to the pressure-induced spin state switching in the complex, and the associated P,T phase diagram was determined. PMID- 28635284 TI - Competing Stereocomplexation and Homocrystallization of Poly(l-lactic acid)/Poly(d-lactic acid) Racemic Mixture: Effects of Miscible Blending with Other Polymers. AB - Promoting the stereocomplexation ability of high-molecular-weight poly(l-lactic acid) (PLLA) and poly(d-lactic acid) (PDLA) is an efficient way to improve the thermal resistance of the resulting materials. Herein, we studied the competing crystallization kinetics, polymorphic crystalline structure, and lamellae structure of the PLLA/PDLA component in its miscible blends with poly(vinyl acetate) (PVAc) and proposed a method to improve the stereocomplexation ability of PLLA and PDLA through miscible blending with the other polymer. Crystallization of the PLLA/PDLA component is suppressed after the addition of PVAc, due to the dilution effect. The stereocomplexation ability of PLLA and PDLA is enhanced by blending with PVAc; this becomes more obvious at a high PVAc content (>=50 wt %) but less significant with the further increase of PLLA, PDLA molecular weights. Almost exclusive formation of SCs is achieved for PLLA and PDLA after blending with a large proportion of PVAc (e.g., 75 wt %). Incorporation of PVAc also facilitates the HC-to-SC structural reorganization upon heating. The increased chain mobility, decreased equilibrium melting point, and enhanced intermolecular interactions may account for the preferential stereocomplexation in PLLA/PDLA/PVAc blends. PMID- 28635285 TI - Triazole/Triazine-Functionalized Mesoporous Silica As a Hybrid Material Support for Palladium Nanocatalyst. AB - Noble and precious metal catalysts are sought for their remarkable efficiency in catalyzing numerous reactions in heterogeneous phase. However, they are costly and require the development of high-surface-area supports that favor their strong immobilization, dispersion, and stability. Toward this end, mesoporous silica based materials can be regarded as unique supports for nanometric-sized noble metal catalysts provided they are functionalized with appropriate ligands. In this work, mesoporous silica SBA-15 was prepared and modified with 3 azidopropyltriethoxysilane and then clicked with alkyne derivatives of 1,3,5 triazine complex ligand. The resulting hybrid material contains triazole and triazine moieties covalently bound to the mesoporous silica network. The triazole/triazine minidendron was immobilized through a 1,3-dipolar cycloaddition click reaction, which was monitored by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The heterocyclic ligand-functionalized SBA 15 material served as a hybrid reactive platform for in situ deposition of palladium nanoparticles whose size is 3.154 +/- 0.49 nm as assessed by X-ray diffraction and confirmed by transmission electron microscopy. The catalytic performance of the final palladium-decorated hybrid triazole/triazine functionalized SBA-15 support was evaluated in the model reduction of 4 nitrophenol to 4-aminophenol by catalytic hydrogenation and stoichiometric reduction. Excellent catalytic performances were achieved, with reduction rate constant (Kapp) of 16.8 * 10-3 s-1 for this model reaction. Moreover, the hybrid catalyst can be produced in high yield and recycled. PMID- 28635287 TI - Configurational Disorder of Water Hydrogen-Bond Network at the Protein Dynamical Transition. AB - We introduce a novel strategy to quantify the disorder of extended water-water hydrogen-bond (HB) networks sampled in particle-based computer simulations. The method relies on the conformational clustering of the HB connectivity states. We successfully applied it to unveil the fine relationship among the protein dynamical transition in hydrated powder, which marks the activation of protein flexibility at Td ~ 240 K, and the sudden increase in the configurational disorder of the water HB network enveloping the proteins. Our finding links, in the spirit of the Adam-Gibbs relationship, the diffusivity of protein atoms, as quantified by the hydrogen mean-square displacements, and the thermodynamic solvent configurational entropy. PMID- 28635288 TI - Color Control of Pr3+ Luminescence by Electron-Hole Recombination Energy Transfer in CaTiO3 and CaZrO3. AB - Controlling luminescence in phosphors able to produce several emissions from different stable excited states determines their use in optical devices. We investigate the color control mechanism that quenches the greenish-blue emission in favor of the red one in the archetype phosphor CaTiO3:Pr3+. State-of-the-art ab initio calculations indicate that direct host-to-dopant energy transfer (released by electron-hole recombination following the interband excitation and structural reorganization) selectively populates the 1D2 red luminescent state of Pr3+ and bypasses the 3P0 greenish-blue emitter. Local defects can modulate the electron-hole recombination energy and therefore increase the red emission efficiency, as experimentally observed. The selection of red emission does not happen in CaZrO3:Pr3+ because the electron-hole recombination energy is much higher. The calculations could not support the widely accepted color control mechanism based on metal-to-metal charge transfer states. The conclusion sets new points of view for the color control of lanthanide activated inorganic phosphors. PMID- 28635286 TI - Utilization of an Active Site Mutant Receptor for the Identification of Potent and Selective Atypical 5-HT2C Receptor Agonists. AB - Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1 ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist. PMID- 28635290 TI - Bare and Effective Charge of Mesoporous Silica Particles. AB - We develop and combine a novel numerical model, within the Poisson-Boltzmann framework, with classical experimental titration techniques for mesoporous silica particles to study the charging behavior as both pH and the amount of monovalent salt are varied. One key finding is that these particles can be considered to have an effectively or apparent electroneutral inner core with an effectively charged rim. As a consequence, the total apparent charge of the particle is several orders of magnitude smaller than that of the bare silica charge, which accounts only for the charged silanol groups of the mesoporous silica particles and which has its major contribution from the interior. Hence, the interior dictates the mesoporous silicas' bare charge while the rim its effective charge. We furthermore report density, charge, and accumulated charge profiles across the particle's interface. PMID- 28635289 TI - Exploring the Drug Resistance of HCV Protease. AB - Hepatitis C virus (HCV) currently affects several million people across the globe. One of the major classes of drugs against HCV inhibits the NS3/4A protease of the polyprotein chain. Efficacy of these drugs is severely limited due to the high mutation rate that results in several genetically related quasispecies. The molecular mechanism of drug resistance is frequently deduced from structural studies and binding free energies. However, prediction of new mutations requires the evaluation of both binding free energy of the drug as well as the parameters (kcat and KM) for the natural substrate. The vitality values offer a good approach to investigate and predict mutations that render resistance to the inhibitor. A successful mutation should only affect the binding of the drug and not the catalytic activity and binding of the natural substrate. In this article, we have calculated the vitality values for four known drug inhibitors that are either currently in use or in clinical trials, evaluating binding free energies by the relevant PDLD/S-LRA method and activation barriers by the EVB method. The molecular details pertaining to resistance are also discussed. We show that our calculations are able to reproduce the catalytic effects and binding free energies in a good agreement with the corresponding observed values. Importantly, previous computational approaches have not been able to achieve this task. The trend for the vitality values is in accordance with experimental findings. Finally, we calculate the vitality values for mutations that have either not been studied experimentally or reported for some inhibitors. PMID- 28635291 TI - Fractal Model for Wettability of Rough Surfaces. AB - This paper presents a fractal model to describe wettability on multiscale randomly rough surfaces. Hydrophobic or superhydrophobic surfaces, produced by processes such as electrodeposition and etching, lead to the creation of random roughness at multiple length scales on the surface. This paper considers the description of such surfaces with a fractal asperity model based on the Weierstrass-Mandelbrot (W-M) function, where the fractal parameters are uniquely determined from a power spectrum of the surface. By use of this description, a model is presented to evaluate the apparent contact angle in the different wetting regimes. The model is predictive in that it does not use any empirical or correlatory fitting of parameters to experimental data. Experimental validation of the model predictions is presented on various hydrophobic and superhydrophobic surfaces generated on several materials under different processing conditions. The contact angle is found be strongly dependent on the range of asperity length scale and weakly dependent on the fractal dimension for a surface with stable Cassie state. Based on the fractal description, desired surface roughness characteristics for generating superhydrophobicity on a particular substrate are also derived. PMID- 28635292 TI - Assembly, Morphology, Diffusivity, and Indentation of Hydrogel-Supported Lipid Bilayers. AB - Recognizing the limitations of solid-supported lipid bilayers to reproduce the behavior of cell membranes, including bendability, transmembrane protein inclusion, and virus entry, this study describes a novel biomimetic system for cell membranes with the potential to overcome these and other limitations. The developed strategy utilizes a hydrogel with tunable mechanical behavior that resembles those of living cells as the soft support for the phospholipid bilayer, while a polyelectrolyte multilayer film serves as an intermediate layer to facilitate the self-assembly of the lipid bilayer on the soft cushion. Quartz crystal microbalance studies show that, upon coming into contact with the polyelectrolyte film, vesicles fuse and rupture to yield a robust lipid bilayer. Fluorescence recovery after photobleaching confirms the formation of a membrane, while atomic force microscopy shows a low adhesion between the indenting probe and the bilayer. More importantly, in comparison to the solid-supported lipid bilayer, the response of this biomimetic system to nanoindentation demonstrates its increased mechanical stability and bendability when assembled on a soft cushion. Hence, the developed hydrogel-supported lipid bilayers can mimic biomechanical properties of cell membranes, which will enable scientists to study and to understand biophysicochemical interactions between cell membranes and extracellular entities. PMID- 28635293 TI - Probing the Importance of Charge Flux in Force Field Modeling. AB - We analyze the conformational dependence of atomic charges and molecular dipole moments for a selection of ~900 conformations of peptide models of the 20 neutral amino acids. Based on a set of reference density functional theory calculations, we partition the changes into effects due to changes in bond distances, bond angles, and torsional angles and into geometry and charge flux contributions. This allows an assessment of the limitations of fixed charge force fields and indications for how to design improved force fields. The torsional degrees of freedom are the main contribution to conformational changes of atomic charges and molecular dipole moments, but indirect effects due to change in bond distances and angles account for ~25% of the variation. Charge flux effects dominate for changes in bond distances and are also the main component of the variation in bond angles, while they are ~25% compared to the geometry variations for torsional degrees of freedom. The geometry and charge flux contributions to some extent produce compensating effects. PMID- 28635295 TI - Coarse-Grained Models of Aqueous and Pure Liquid Alkanes. AB - A model for linear alkanes is presented in which interaction sites are only on the carbon atoms, and the range of the potential is reduced using the Stillinger Weber potential. The model is optimized for aqueous and liquid alkane properties and can match thermodynamic and structural properties, including solvation free energies, liquid densities, and liquid/vapor and liquid/water surface tensions for alkanes over a range of lengths. The results for long alkanes indicate that such models can be useful as accurate, yet efficient, coarse-grained potentials for macromolecules in water and other environments. PMID- 28635294 TI - Tunable Anisotropic Photon Emission from Self-Organized CsPbBr3 Perovskite Nanocrystals. AB - We report controllable anisotropic light emission of photons originating from vertically aligned transition dipole moments in spun-cast films of CsPbBr3 nanocubes. By depositing films of nanocrystals on precoated substrates we can control the packing density and resultant radiation pattern of the emitted photons. We develop a technical framework to calculate the average orientation of light emitters, i.e., the angle between the transition dipole moment vector (TDM) and the substrate. This model is applicable to any emissive material with a known refractive index. Theoretical modeling indicates that oriented emission originates from an anisotropic alignment of the valence band and conduction band edge states on the ionic crystal lattice and demonstrates a general path to model the experimentally less accessible internal electric field of a nanosystem from the photoluminescent anisotropy. The uniquely accessible surface of the perovskite nanoparticles allows for perturbation of the normally isotropic emissive transition. The reported sensitive and tunable TDM orientation and control of emitted light will allow for applications of perovskite nanocrystals in a wide range of photonic technologies inaccessible to traditional light emitters. PMID- 28635297 TI - Medical Students Leading Quality Improvement: A Lean Six Sigma Approach to Pain Management. PMID- 28635298 TI - Letter to the Editor: Response to "Quantifying Medical Student Education and Exposure to Otolaryngology". PMID- 28635296 TI - Benzoxaborole Antimalarial Agents. Part 5. Lead Optimization of Novel Amide Pyrazinyloxy Benzoxaboroles and Identification of a Preclinical Candidate. AB - Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development. PMID- 28635299 TI - Prevalence and Geographic Variations of Polypharmacy Among West Virginia Medicaid Beneficiaries. AB - BACKGROUND: West Virginia (WV) residents are at high risk for polypharmacy given its considerable chronic disease burdens. OBJECTIVE: To evaluate the prevalence, correlates, outcomes, and geographic variations of polypharmacy among WV Medicaid beneficiaries. METHODS: In this cross-sectional study, we analyzed 2009-2010 WV Medicaid fee-for-service (FFS) claims data for adults aged 18-64 (N=37,570). We defined polypharmacy as simultaneous use of drugs from five or more different drug classes on a daily basis for at least 60 consecutive days in one year. Multilevel logistic regression was used to explore the individual- and county level factors associated with polypharmacy. Its relationship with healthcare utilization was assessed using negative binomial regression and logistic regression. The univariate local indicators of spatial association method was applied to explore spatial patterns of polypharmacy in WV. RESULTS: The prevalence of polypharmacy among WV Medicaid beneficiaries was 44.6%. High-high clusters of polypharmacy were identified in southern WV, indicating counties with above-average prevalence surrounded by counties with above-average prevalence. Polypharmacy was associated with being older, female, eligible for Medicaid due to cash assistance or medical eligibility, having any chronic conditions or more chronic conditions, and living in a county with lower levels of education. Polypharmacy was associated with more hospitalizations, emergency department visits, and outpatient visits, as well as higher non-drug medical expenditures. CONCLUSIONS: Polypharmacy was prevalent among WV Medicaid beneficiaries and was associated with substantial healthcare utilization and expenditures. The clustering of high prevalence of polypharmacy in southern WV may suggest targeted strategies to reduce polypharmacy burden in these areas. PMID- 28635301 TI - Stem Cell-Mediated Paracrine Signaling Alters Fibroplasia in Human Vocal Fold Fibroblasts in Vitro. AB - OBJECTIVES: Interactions between mesenchymal stem cells (MSCs) and native vocal fold fibroblasts (VFFs) have not been described in spite of promising preliminary data regarding the effects of MSCs on vocal fold repair in vivo. The current study employed a conditioned media (CM) model to investigate the paracrine effects of bone marrow-derived mesenchymal stem cells (BMSCs) on VFFs. METHODS: Human VFFs were treated with transforming growth factor-beta1 (TGF-beta1; 10 ng/mL), CM from human BMSCs following 48 hours of TGF-beta1 stimulation, or CM+TGF-beta1. Proliferation, immunocytochemistry for alpha smooth muscle actin (alphaSMA), migration, and collagen gel contraction were quantified as well as transcription of components of the TGF-beta signaling pathway. RESULTS: Transforming growth factor-beta1 accelerated proliferation and induced alphaSMA in VFFs; these effects were suppressed with CM ( P = .009, P < .001, respectively). The CM+TGF-beta1 condition increased cell migration ( P = .02) and decreased gel contraction; CM+TGF-beta1 also inhibited TGF-beta signaling via significant upregulation of NR4A1 as well as downregulation of S MAD3 and TGF beta1 relative to TGF-beta1 stimulation in the absence of CM ( P = .002, P < .001, and P = .005, respectively). CONCLUSIONS: Conditioned media affected many profibrotic cell activities in TGF-beta1-stimulated VFFs, likely related to altered TGF-beta signaling. These data provide preliminary insight regarding the antifibrotic effects of MSCs and further support their progression to clinical utility. PMID- 28635302 TI - High Resting Heart Rate and High BMI Predicted Severe Coronary Atherosclerosis Burden in Patients With Stable Angina Pectoris by SYNTAX Score. AB - We investigated the independent and combined association of resting heart rate (RHR expressed as beats/min, bpm) and body mass index (BMI) with SYNTAX score (SS) in patients with stable angina. We divided 312 patients into 4 groups according to RHR quartiles: Q1 (<65 bpm), Q2 (65-69 bpm), Q3 (70-79 bpm), and Q4 (>=80 bpm). The SS (12.0 +/- 9.0, 16.0 +/- 15.5, 18.0 +/- 16.5, and 20.0 +/- 27.5; P < .001) was significantly higher for those in Q4 than for those in Q1, Q2, and Q3. Multivariate logistic regression analysis indicated that each 10-bpm increment in RHR was significantly associated with SS (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.27-2.06). Patients with high RHR and high BMI had significantly greater odds ratio (OR) of high SS (4.03, 95% CI 2.00-8.14), compared to participants with low RHR and low BMI. Both RHR and BMI were independent predictors of coronary atherosclerosis as assessed by SS. RHR in combination with BMI and multivariate logistic regression analysis emphasized the importance of the correlation between RHR and SS in patients with stable angina pectoris. PMID- 28635303 TI - Increased Pulse Wave Velocity in Systemic Lupus Erythematosus: A Meta-Analysis. AB - Systemic lupus erythematosus (SLE) is associated with increased cardiovascular risk. This study aims to derive a more precise estimation on pulse wave velocity (PWV) level in patients with SLE and related factors. A literature search was performed using PubMed, EMBASE, and The Cochrane Library databases, studies published up to February 28, 2017, in English. Pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated by fixed-effect or random-effect model analysis. Heterogeneity test was performed by the Q statistic and quantified using I2; publication bias was evaluated using a funnel plot and Egger's linear regression test. Of 156 studies found, 27 met eligibility criteria, and 14 studies were finally included in the meta-analysis. Meta analysis revealed that the SLE group had significantly higher PWV levels than the control group; SMD = 0.56 and 95% CI (0.30-0.82). Subgroup analyses showed that body mass index (BMI), sample size, and disease duration were associated with PWV in patients with SLE. Overall, our study suggests that patients with SLE have a higher PWV level, and it is associated with BMI, sample size, and disease duration. PMID- 28635304 TI - The Relationship Between the Neutrophil-Lymphocyte Ratio and In-Stent Restenosis in Patients With Femoropopliteal Chronic Total Occlusions. AB - We investigated the relationship between the neutrophil-lymphocyte ratio (NLR) and in-stent restenosis (ISR) in patients with femoropopliteal chronic total occlusions (CTOs). The study enrolled 180 patients who had undergone successful stenting treatment for femoropopliteal CTO. Patients with ISR were subsequently classified into 2 groups: early-ISR (within 1 year) and late-ISR (after 1 year). The clinical characteristics, angiographic data, and follow-up data were recorded. The baseline NLR was significantly higher in the early-ISR group than that in the non-ISR group [3.96(2.14) and 3.33(2.73), p = .04]. Receiver operating characteristic curve analysis suggested an optimum early ISR NLR cutoff point of 3.62, which showed a sensitivity and specificity of 73.4% and 80.4%, respectively (area under the curve: 0.707, 95% confidence interval: 0.603-0.792, P < .001). A subgroup analysis was performed based on the NLR value (<3.62 vs >=3.62). In the NLR >=3.62 subgroup, the incidence of early ISR was higher than that of late ISR ( P < .01). In the multivariate analysis, NLR >=3.62 was independently and positively associated with a higher risk of early ISR. In conclusion, NLR is independently associated with early ISR after stent implantation in patients with femoropopliteal CTO. PMID- 28635305 TI - Factors modifying performance of a novel citizen text message alert system in improving survival of out-of-hospital cardiac arrest. AB - AIMS: Recently we found that the text message alert system increases survival of sudden out-of-hospital cardiac arrest. The aim of the present study is to explore the contribution of the system to survival specifically in resuscitation settings with prolonged delay of start of resuscitation. METHODS AND RESULTS: Data were used from consecutive patients resuscitated for out-of-hospital cardiac arrest during a two-year period in the Dutch province Limburg. Survival of 291 cases with out-of-hospital cardiac arrest where one or more volunteers attended (Scenario 2) was compared with survival of 131 cases with out-of-hospital cardiac arrest where no volunteers attended and only standard care was given (Scenario 1). Multivariable logistic regression models including terms for interaction between scenario and the covariate coding for resuscitation setting were used to test for effect modification. The highest impact on survival of the alert system was observed in cases of (a) witnessed arrests (odds ratio=2.25; 95% confidence interval: 1.27-4.00; p=0.005); (b) arrests that occurred in the home (odds ratio=2.28; 95% confidence interval: 1.21-4.28; p=0.011); (c) arrival of the ambulance with a delay of 7-10 min (odds ratio=2.63; 95% confidence interval: 1.09-6.35; p=0.032); and (d) arrests at evening/night (odds ratio=3.07; 95% confidence interval: 1.34-7.03; p=0.008). Due to the low sample size, p-values from tests for interaction were non-significant. CONCLUSION: The contribution of the alert system to survival is most substantial in cases of witnessed arrest, in the home situation, at slightly delayed arrival of the first ambulance and during the evening/night. PMID- 28635306 TI - Self-injurious behaviors in children with autism spectrum disorder enrolled in the Study to Explore Early Development. AB - We assessed potential factors associated with "current" or "ever" self-injurious behaviors, reported in the Autism Diagnostic Interview-Revised, among children with autism spectrum disorder (n = 692) from the Study to Explore Early Development. Data on factors examined were obtained from questionnaires, standardized clinical instruments, and birth certificates. We employed a log binomial regression to assess these associations. Although most associations were quite similar for currently and ever exhibiting self-injurious behaviors, a few differences were noted. We documented previously unreported associations of current self-injurious behaviors with maternal age and cesarean delivery, and ever self-injurious behaviors with maternal age, child sex, gestational age, and maternal race. We also confirmed previously reported associations with adaptive skills, somatic conditions (sleep, gastrointestinal, and sensory abnormalities), and other behavioral problems. These findings are informative for clinical practice and future research. PMID- 28635300 TI - Pyridine Dinucleotides from Molecules to Man. AB - SIGNIFICANCE: Pyridine dinucleotides, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), were discovered more than 100 years ago as necessary cofactors for fermentation in yeast extracts. Since that time, these molecules have been recognized as fundamental players in a variety of cellular processes, including energy metabolism, redox homeostasis, cellular signaling, and gene transcription, among many others. Given their critical role as mediators of cellular responses to metabolic perturbations, it is unsurprising that dysregulation of NAD and NADP metabolism has been associated with the pathobiology of many chronic human diseases. Recent Advances: A biochemistry renaissance in biomedical research, with its increasing focus on the metabolic pathobiology of human disease, has reignited interest in pyridine dinucleotides, which has led to new insights into the cell biology of NAD(P) metabolism, including its cellular pharmacokinetics, biosynthesis, subcellular localization, and regulation. This review highlights these advances to illustrate the importance of NAD(P) metabolism in the molecular pathogenesis of disease. CRITICAL ISSUES: Perturbations of NAD(H) and NADP(H) are a prominent feature of human disease; however, fundamental questions regarding the regulation of the absolute levels of these cofactors and the key determinants of their redox ratios remain. Moreover, an integrated topological model of NAD(P) biology that combines the metabolic and other roles remains elusive. FUTURE DIRECTIONS: As the complex regulatory network of NAD(P) metabolism becomes illuminated, sophisticated new approaches to manipulating these pathways in specific organs, cells, or organelles will be developed to target the underlying pathogenic mechanisms of disease, opening doors for the next generation of redox-based, metabolism targeted therapies. Antioxid. Redox Signal. 28, 180-212. PMID- 28635308 TI - Combined HQSAR, topomer CoMFA, homology modeling and docking studies on triazole derivatives as SGLT2 inhibitors. AB - AIM: Sodium-glucose cotransporter 2 (SGLT2) is a promising target for diabetes therapy. We aimed to develop computational approaches to identify structural features for more potential SGLT2 inhibitors. MATERIALS & METHODS: In this work, 46 triazole derivatives as SGLT2 inhibitors were studied using a combination of several approaches, including hologram quantitative structure-activity relationships (HQSAR), topomer comparative molecular field analysis (CoMFA), homology modeling, and molecular docking. HQSAR and topomer CoMFA were used to construct models. Molecular docking was conducted to investigate the interaction of triazole derivatives and homology modeling of SGLT2, as well as to validate the results of the HQSAR and topomer CoMFA models. RESULTS: The most effective HQSAR and topomer CoMFA models exhibited noncross-validated correlation coefficients of 0.928 and 0.891 for the training set, respectively. External predictions were made successfully on a test set and then compared with previously reported models. The graphical results of HQSAR and topomer CoMFA were proven to be consistent with the binding mode of the inhibitors and SGLT2 from molecular docking. CONCLUSION: The models and docking provided important insights into the design of potent inhibitors for SGLT2. PMID- 28635307 TI - Synthesis, evaluation and modeling of some triazolothienopyrimidinones as anti inflammatory and antimicrobial agents. AB - AIM: New triazolotetrahydrobenzothienopyrimidinone derivatives were synthesized. EXPERIMENTAL: Their structures were confirmed, and their anti-inflammatory, antimicrobial activities and ulcerogenic potentials were evaluated. RESULTS: Compounds 7a, 10a and 11a showed minimal ulcerogenic effect and high selectivity toward human recombinant COX-2 over COX-1 enzyme with IC50 values of 1.39, 1.22 and 0.56 MUM, respectively. Their docking outcome correlated with their biological activity and confirmed the high selectivity binding toward COX-2. Compound 12b displayed antimicrobial activity comparable to that of ampicillin against Escherichia coli while compounds 6 and 11c were similar to ampicillin against Staphylococcus aureus. In addition, compounds 7a, 9a, 10b and 11c showed dual anti-inflammatory/antimicrobial activities. CONCLUSION: This work represents a promising matrix for developing new potential anti-inflammatory, antimicrobial and dual antimicrobial/anti-inflammatory candidates. [Formula: see text]. PMID- 28635309 TI - Rheumatoid arthritis is associated with negatively variable impacts on domains of female sexual function: evidence from a systematic review and meta-analysis. AB - To systematically review the literature to identify the impact of rheumatoid arthritis (RA) on specific female sexual function domains. A meta-analysis was performed and the related literature were searched in MEDLINE, EMBASE, Cochrane Library, CNKI, CBM and Web of Science databases, and in reference lists of articles and systematic reviews. Score of the Female Sexual Function Index (FSFI) was used as the outcome measurement, and mean differences (MD) with 95% confidence intervals (CI) were calculated. Five studies were included, including 346 women with RA and 237 healthy female controls. Each domain of the FSFI score: lubrication (MD, -2.48; 95% CI, -3.69, -1.28), orgasm-1.71 (-2.09, -1.33), sexual desire-1.27 (-1.59, -0.95), satisfaction-1.67 (-2.18, -1.16), arousal-1.83 ( 2.85, -0.82), pain-1.57 (-2.43, -0.70) and the total score -8.84 (-11.88, -5.79) were lower in RA women than healthy controls. Furthermore, lubrication dimension was most severely affected especially. This meta-analysis showed that female RA patients scored lower in each dimension of FSFI, mostly in the lubrication domain. It demonstrated that targeted interventions should be done to improve their sexual function. Future well-designed researches with larger sample sizes are necessary to evaluate the potential risk factors which determine female sexual dysfunction. PMID- 28635310 TI - How can tricyclic sophoridinic derivatives be used as autophagy inhibitors for cancer treatments? PMID- 28635311 TI - Type D personality, but not Type A behavior pattern, is associated with coronary plaque vulnerability. AB - Personality traits are associated with major adverse coronary events (MACE) in patients with coronary artery disease (CAD). However, the link between personality traits and intravascular morphology in CAD patients is poorly understood. This study investigated the relationship between personality traits, specifically Type A behavior pattern and Type D personality, and plaque vulnerability. After adjustment for demographic and clinical factors, multivariable regression analysis showed no association between Type A and optical coherence tomography indices. However, Type D personality was independently associated with lipid plaque, thin cap fibroatheroma (TCFA), and fibrous cap thickness. More specifically, negative affectivity of Type D was related to lipid plaque, TCFA and fibrous cap thickness, and social inhibition was associated with plaque rupture. Our results show that Type D personality was associated with plaque vulnerability, independent of clinical factors. Measurement of negative affectivity and social inhibition will increase our understanding of the progressive phase of the plaque vulnerability, which can contribute to the early identification of high risk patients and reduce the incidence of MACE. PMID- 28635312 TI - Predictors of adherence to aerobic exercise in rectal cancer patients during and after neoadjuvant chemoradiotherapy. AB - This pilot study explored predictors of adherence to exercise during and after neoadjuvant chemoradiotherapy (NACRT) in rectal cancer patients. Eighteen rectal cancer patients were prescribed three supervised aerobic exercise sessions/week during NACRT followed by >=150 min/week of unsupervised aerobic exercise after NACRT. Although not statistically significant, adherence to supervised exercise during NACRT was meaningfully better for patients who were women (d = .82; P = .12), younger (d = -.62; P = .30), married (d = .62; P = .42), with better mental health (r = .32; P = .21), fewer diarrhea symptoms (r = .48; P = .052), and higher anticipated enjoyment (r = .31; P = .23), support (r = .32; P = .22), and motivation (r = .31; P = .23). After NACRT, adherence was significantly better for patients who reported worse mental health (r = -.56; P = .046) and meaningfully better for patients who were women (d = .54; P = .38), better educated (d = .77; P = .22), had no comorbidities (d = -.63; P = .17), and exercised at baseline (d = 1.05; P = .12). Demographics, tumor side effects, and motivational variables may predict adherence to exercise during and after NACRT. PMID- 28635313 TI - Reliability and validity of the Chinese version of the Breathlessness Beliefs Questionnaire. AB - The aim of this article is to evaluate the reliability and validity of the Chinese version of the Breathlessness Beliefs Questionnaire (BBQ) for use among patients with respiratory diseases in China. The BBQ is an instrument for assessing specific dyspnoea-related fears and may have predictive value for chronic obstructive pulmonary disease outcomes beyond general anxiety measures. This instrument has not previously been translated into Chinese or tested in mainland China. This was a cross-sectional validation study with a 1-week test of reproducibility. A total of 252 Chinese patients with respiratory diseases recruited from pulmonary outpatient and inpatient departments completed the BBQ. Demographic characteristics, pulmonary function and degree of dyspnoea were also measured. Cronbach's alpha was 0.82 for the total BBQ score; 0.72 for the somatic focus subscale and 0.73 for the activity avoidance subscale. Test-retest reliability was satisfactory, with intraclass correlation coefficient scores for the BBQ overall and for each subscale ranging from 0.96 to 0.98 ( p < 0.001). After exploratory factor analyses, the Chinese version of the BBQ was found to be similar to the original Dutch version. The Chinese version of the BBQ is a reliable tool to assess dyspnoea-related fear in patients with respiratory diseases in mainland China. PMID- 28635315 TI - Age stereotypes, flexible goal adjustment, and well-being among Chinese older adults. AB - Previous studies have examined the independent roles of positive age stereotypes (PAS) and negative age stereotypes (NAS) in successful aging. This study aimed to examine the joint effect of PAS and NAS on the well-being of Chinese older adults, and to further examine whether this effect was moderated by flexible goal adjustment (FGA). Using a cross-sectional design, 279 Chinese older adults (age range 60-97 years) completed measures related to age stereotypes, FGA, and well being. The results showed that PAS interacted with NAS to predict well-being. In addition, the joint effect of PAS and NAS was moderated by FGA. Specially, for older adults with low FGA, NAS weakened the positive association between PAS and well-being; whereas, for older adults with high FGA, NAS could not influence the association between PAS and well-being. Tailored interventions to modify aging perceptions and to enhance coping flexibility competence might be helpful for promoting the well-being of older adults. PMID- 28635314 TI - Fluorescent-labeled bioconjugates of the opioid peptides biphalin and DPDPE incorporating fluorescein-maleimide linkers. AB - AIM: The conjugation of fluorescent labels to opioid peptides is an extremely challenging task, which needs to be overcome to create new classes of probes for biological assays. MATERIALS & METHODS: Three opioid peptide analogs of biphalin and [D-Pen2,5]-Enkephalin (DPDPE) containing a fluorescein-maleimide motif were synthesized. RESULTS & DISCUSSION: The biphalin analog 17 binds to opioid receptors with KiMU = 530 +/- 90 nM and Kidelta = 69.8 +/- 16.4 nM. We then tested the ability of the compounds to stimulate G-protein-coupling, 17 activated MU-receptor expressing cells (EC50 = 16.7 +/- 6.7 nM, EMax = 76 +/- 4%) as well as delta-receptor expressing cells (EC50 = 42 +/- 10 nM, EMax = 34 +/- 8%). However, 17 was not able to fluorescently label receptor in live or fixed cells. CONCLUSION: Our data suggest that the biphalin scaffold could be employed to develop fluorescent ligands with the appropriate fluorescent motif, and suggest a means for further probe development. PMID- 28635316 TI - Complications Following Collagenase Treatment for Dupuytren Contracture. AB - BACKGROUND: Collagenase Clostridium histolyticum (CCH) injection and manipulation is a relatively new method for treating Dupuytren contracture that is growing in popularity. Although side effects such as swelling and ecchymosis are common, they are typically mild and self-limited. Major complications are rare but have included flexor tendon rupture and complex regional pain syndrome. METHODS: This study describes a case report of 2 patients seen at our institution. RESULTS: Here, we report 2 patients seen at our institution each with different, yet serious complications after CCH injection and manipulation. One patient had extensive skin loss and chose amputation over reconstruction. The other patient had loss of perfusion and required finger amputation. CONCLUSIONS: Although it is unclear how directly the administration of CCH is connected to the observed complications, physicians should recognize the potential for serious rare complications in any treatment of Dupuytren contracture. PMID- 28635317 TI - Beyond the wall: can D-amino acids and small molecule inhibitors eliminate infections? PMID- 28635318 TI - What structural modifications can be used for BRD4 inhibitors for their use in leukemia therapy? PMID- 28635319 TI - A Case of Topical Ruxolitinib Treatment Failure in Alopecia Areata. AB - Alopecia areata (AA) is an autoimmune-mediated, nonscarring form of hair loss. Despite its prevalence, current management options are limited, especially when the disease has progressed to alopecia totalis (AT) or alopecia universalis (AU). Recent evidence that janus kinase (JAK) signaling contributes to AA pathogenesis prompted the investigation of JAK inhibitors such as tofacitinib and ruxolitinib as possible oral treatments. However, the potential for significant adverse effects with systemic JAK inhibition makes local administration a more attractive option. Yet, a paucity of data exists on topical JAK inhibition in AA. A success of topical ruxolitinib (0.6% cream) use in a young patient with AU has been reported to date. Here we report the treatment of a 66-year-old with AA with the same formulation of topical ruxolitinib, where it failed to induce hair growth. Our report demonstrates the importance of examining the factors contributing to variation in treatment response in a clinical trial of topical JAK inhibitors in AA. It is likely that both intrinsic factors specific to individual patients and extrinsic factors relating to treatment regimen are involved. Furthermore, characterisation of the specific JAKs overexpressed in AA may better target medication. Finally, this report highlights the need to compare the outcomes of topical vs oral ruxolitinib administration in patients with severe AA, AT, and AU and may support the possibility that extensive disease is more adequately treated with oral administration of ruxolitinib. PMID- 28635322 TI - The Art of Health Promotion. PMID- 28635323 TI - Preserving Employee Privacy in Wellness. AB - The proposed "Preserving Employee Wellness Programs Act" states that the collection of information about the manifested disease or disorder of a family member shall not be considered an unlawful acquisition of genetic information. The bill recognizes employee privacy protections that are already in place and includes specific language relating to nondiscrimination based on illness. Why did legislation expressly intending to "preserve wellness programs" generate such antipathy about wellness among journalists? This article argues that those who are committed to preserving employee wellness must be equally committed to preserving employee privacy. Related to this, we should better parse between discussions and rules about commonplace health screenings versus much less common genetic testing. PMID- 28635325 TI - Effect of salt loading on baroreflex sensitivity in reduced renal mass hypertension. AB - BACKGROUND: High dietary salt, as well as renal mass reduction, is known to decrease baroreflex sensitivity in rats. However, the effect of high salt intake on baroreflex sensitivity is unknown in reduced renal mass (RRM) hypertension; therefore, the aim of this study was to investigate the effects of salt loading on arterial baroreflex sensitivity and mean arterial pressure (MAP) in RRM hypertension. METHODS: Both RRM and sham-operated control (SO) rats were loaded with 0.25 or 0.5% NaCl for five weeks. Plasma Na+, K+, and creatinine levels were measured, and baroreflex sensitivity was evaluated before and after beta1 blockade. In addition, cardiac vagal tone and intrinsic heart rate (IHR) were measured. RESULTS: RRM decreased full baroreflex sensitivity of the tachycardic response under 0.5% NaCl loading and the parasympathetic bradycardic response under 0% NaCl loading. The NaCl loading did not affect the severity of RRM hypertension. Cardiac vagal tone and IHR decreased in RRM rats versus SO controls under all NaCl loading conditions. RRM decreased plasma K+ under 0% NaCl loading and increased plasma Na+ under 0.5% NaCl loading. High (0.5%) NaCl loading decreased IHR and increased plasma creatinine and left ventricular weight in RRM rats. CONCLUSIONS: RRM in combination with 0.5% NaCl loading led to a decrease in the sensitivity of full baroreflex and of the parasympathetic component of baroreflex. Changes in plasma Na+ and K+ levels, due to NaCl loading, may have contributed to the decrease in baroreflex sensitivities and IHR but had no effect upon MAP in RRM rats. PMID- 28635324 TI - Gliptins Suppress Inflammatory Macrophage Activation to Mitigate Inflammation, Fibrosis, Oxidative Stress, and Vascular Dysfunction in Models of Nonalcoholic Steatohepatitis and Liver Fibrosis. AB - AIMS: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, liver fibrosis, and increased cardiovascular mortality. Dipeptidyl peptidase-4 inhibitors (gliptins) are indirect glucagon-like peptide 1 agonists with antidiabetic and anti-inflammatory activity, used for the treatment of type 2 diabetes. Their potential and underlying mechanisms to treat metabolic liver inflammation and fibrosis as well as the associated vascular dysfunction remain to be explored. RESULTS: In the methionine/choline-deficient (MCD) diet and Mdr2-/- models of NASH and liver fibrosis, treatment with sitagliptin and linagliptin significantly decreased parameters of steatosis and inflammation, which was accompanied by suppression of hepatic transcript levels reflecting metabolic inflammation and fibrosis, including SREBP-1c, FAS, TNFalpha, iNOS, alpha-SMA, Col1alpha1, and MMP-12. Moreover, gliptins reduced the number of liver infiltrating CD11b+Ly6Chi proinflammatory monocytes/macrophages and liver resident F4/80+ macrophages, with an increase of Ym1+ alternative macrophages and (anti-inflammatory) macrophage markers Arg1 and IL-10. This was paralleled by decreased hepatic and aortic reactive oxygen species (ROS) production and NOX-2 mRNA expression, a normalization of endothelial dysfunction, cardiac NADPH oxidase activity, mitochondrial ROS formation, and whole blood oxidative burst in the MCD model. Innovation and Conclusions: Gliptins via suppression of inflammation decrease steatosis, apoptosis, oxidative stress, and vascular dysfunction in murine models of NASH and liver fibrosis, with mild direct antifibrotic properties. They reduce the numbers of liver and vascular inflammatory monocytes/macrophages and induce their alternative polarization, with beneficial effect on NASH-associated hepatic and cardiovascular complications. Therefore, gliptins qualify as drugs for treatment of NASH and associated liver fibrosis and cardiovascular complications. Antioxid. Redox Signal. 28, 87-109. PMID- 28635326 TI - Encapsulins: molecular biology of the shell. AB - Compartmentalization is both a fundamental principle of cellular organization and an emerging theme in prokaryotic biology. Work in the past few decades has shown that protein-based organelles called microcompartments enhance the function of encapsulated cargo proteins. More recently, the repertoire of known prokaryotic organelles has expanded beyond microcompartments to include a new class of smaller proteinaceous compartments, termed nanocompartments (also known as encapsulins). Nanocompartments are icosahedral capsids that are smaller and less complex than microcompartments. Encapsulins are formed by a single species of shell protein that self-assembles and typically encapsulates only one type of cargo protein. Significant progress has been made in understanding the structure of nanocompartment shells and the loading of cargo to the interior. Recent analysis has also demonstrated the prevalence of encapsulin genes throughout prokaryotic genomes and documented a large diversity of cargo proteins with a variety of novel functions, suggesting that nanocompartments play an important role in many microbes. Here we review the current understanding of encapsulin structure and function and highlight exciting open questions of physiological significance. PMID- 28635327 TI - Within-visit blood pressure variability and cardiovascular risk factors in hypertensive patients with non-dialysis chronic kidney disease. AB - : As there may be an association between within-visit blood pressure (BP) variability and cardiovascular disease (CVD), we investigated the clinical significance of this BP variability in non-dialysis chronic kidney disease (CKD) patients. MATERIALS AND METHODS: According to the median of coefficient of variation (CV) of three systolic BP (SBP) readings within a single visit, we divided hypertensive patients with stage G1-4 CKD already treated with antihypertensive therapy into the high SBP-CV group and the low SBP-CV group. Univariate and multivariate linear regression analyses were also performed to explore the contributing factors to within-visit BP variability. RESULTS: In the high SBP-CV group, the clinic BP, total cholesterol level, dyslipidemia, and past history of CVD were significantly greater, while alpha1-blockers and renin angiotensin system (RAS) inhibitors usage were significantly reduced compared with the lower SBP-CV group. Within-visit BP variability was significantly and positively correlated with total cholesterol (R = 0.392, P < 0.001) and low density lipoprotein cholesterol (R = 0.284, P = 0.013). Total cholesterol (beta = 0.269, P = 0.024), alpha1-blockers usage (beta = -0.260, P = 0.015), and RAS inhibitors usage (beta = -0.266, P = 0.017) were shown to independently contribute to the within-visit BP variability after adjustment for age, sex, presence of diabetes, CVD history, statins usage, and clinic SBP. CONCLUSIONS: We show that within-visit BP variability may be a clinically relevant factor of CVD risk, and lipid lowering and/or anti-hypertensive therapies using RAS inhibitors and alpha1-blockers may be associated with the improved within-visit BP variability observed in non-dialysis CKD patients. PMID- 28635328 TI - Dietary implications for patients receiving long-term oral anticoagulation therapy for treatment and prevention of thromboembolic disease. AB - INTRODUCTION: The effectiveness of oral anticoagulation therapy with warfarin (a vitamin K antagonist) in the treatment of thromboembolic disease, including stroke prophylaxis in patients with atrial fibrillation is well recognised. However, warfarin has a narrow therapeutic window and an unpredictable anticoagulation response, which make it difficult to achieve and maintain optimal anticoagulation. Various dietary factors, including sudden changes in eating patterns, can significantly alter anticoagulation control, thereby potentially exposing patients to the risk of bleeding or thromboembolic complications. Dietary vitamin K intake is a particularly important factor, given the mechanism of action of warfarin. Areas covered: In this article, we cover the sources of vitamin K and their potential effect of dietary vitamin K on anticoagulation response to warfarin. We also discuss the results of studies on the effect of vitamin K supplementation on anticoagulation stability. Expert commentary: A stable dietary vitamin K, promoted by daily oral vitamin K supplementation, can improve anticoagulation stability in patients on warfarin therapy. There is experimental evidence in animals that dietary vitamin K affects anticoagulation response to the direct thrombin inhibitor, ximelagatran. Whether dietary vitamin K affects anticoagulation response to the currently licensed direct oral anticoagulants (DOACs) in man remains to be investigated. PMID- 28635329 TI - Lead induces Siberian tiger fibroblast apoptosis by interfering with intracellular homeostasis. AB - Lead (Pb2+) is a poisonous heavy metal that causes many pathophysiological effects in living systems. Its toxicological effects are well known as it causes apoptosis of several cell types and tissues. This study aimed to determine the criteria required for early diagnosis of Pb2+ poisoning in the Siberian tiger using a tiger population in China, to identify a safety Pb2+ concentration threshold, and to provide suggestions for preventing Pb2+ poisoning in Siberian tigers. We investigated the apoptotic effects of Pb2+ (0, 32, 64, and 125 MUM) for 12-48 h on Siberian tiger fibroblasts in vitro. Typical apoptotic effects were observed after Pb2+ exposure. Pb2+ strongly blocked DNA synthesis in the G0/G1 phase and induced cell apoptosis in a dose- and time-dependent manner. Intracellular free calcium (Ca2+) levels, reactive oxygen species levels, and efflux of extracellular Ca2+ were increased. The mitochondrial membrane potential was lowered. Caspase-3, -8, and -9 activities were increased when fibroblasts were treated with 32, 64, and 125 MUM Pb2+. The gene expression levels of Bax, caspase-3, -8, Fas, and p53 were increased, while that of Bcl-2 was decreased. Calcium homeostasis and mitochondrial function were disturbed. Ca2+ efflux, oxidative damage, activation of caspases, and regulation of Bax, Bcl-2, caspase 3, -8, Fas, and p53 gene expression played an important role in the apoptotic effects. The disorder of intracellular homeostasis was the trigger for apoptosis in Siberian tiger fibroblasts. PMID- 28635330 TI - Multiple functions of insulin-degrading enzyme: a metabolic crosslight? AB - Insulin-degrading enzyme (IDE) is a ubiquitous zinc peptidase of the inverzincin family, which has been initially discovered as the enzyme responsible for insulin catabolism; therefore, its involvement in the onset of diabetes has been largely investigated. However, further studies on IDE unraveled its ability to degrade several other polypeptides, such as beta-amyloid, amylin, and glucagon, envisaging the possible implication of IDE dys-regulation in the "aggregopathies" and, in particular, in neurodegenerative diseases. Over the last decade, a novel scenario on IDE biology has emerged, pointing out a multi-functional role of this enzyme in several basic cellular processes. In particular, latest advances indicate that IDE behaves as a heat shock protein and modulates the ubiquitin proteasome system, suggesting a major implication in proteins turnover and cell homeostasis. In addition, recent observations have highlighted that the regulation of glucose metabolism by IDE is not merely based on its largely proposed role in the degradation of insulin in vivo. There is increasing evidence that improper IDE function, regulation, or trafficking might contribute to the etiology of metabolic diseases. In addition, the enzymatic activity of IDE is affected by metals levels, thus suggesting a role also in the metal homeostasis (metallostasis), which is thought to be tightly linked to the malfunction of the "quality control" machinery of the cell. Focusing on the physiological role of IDE, we will address a comprehensive vision of the very complex scenario in which IDE takes part, outlining its crucial role in interconnecting several relevant cellular processes. PMID- 28635331 TI - Network meta-analysis of liraglutide versus dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes in Japanese patients. AB - AIMS: To determine the comparative efficacy and safety of liraglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors as antidiabetics for Japanese patients with uncontrolled type 2 diabetes (T2DM). METHODS AND MATERIALS: We searched for randomized controlled trials (RCTs) evaluating outcomes among Japanese adults with uncontrolled T2DM and including liraglutide or DPP-4 inhibitors up to August 2016. We extracted data on trial and patient characteristics, and the following outcomes: HbA1c, weight, patients meeting HbA1c <7%, patients experiencing hypoglycemic events, microalbuminuria, estimated glomerular filtration rate (eGFR) and creatinine. We synthesized data using network meta-analyses (NMA) using a Bayesian framework. Continuous outcomes were modeled using normal likelihoods and an identity link, while dichotomous outcomes were modeled using a binomial likelihood and a logit link. RESULTS: The systematic literature review yielded 39 publications pertaining to 38 trials. A total of 27 trials (5032 patients) reported change in HbA1c at 12 weeks and at 24 weeks 9 trials (2091 patients). All treatments showed statistically significant reductions in HbA1c relative to placebo at 12 and 24 weeks. Liraglutide 0.9 mg was statistically superior to all DPP-4 interventions (vildagliptin, sitagliptin, linagliptin, alogliptin, teneligliptin, trelagliptin and omarigliptin) at 12 weeks and 24 weeks among those reporting. Treatments were not statistically differentiable with respect to weight change and risk of hypoglycemia. Finally, no comparisons of eGFR and microalbuminuria were conducted, as this data was reported in too few trials to conduct analyses. LIMITATIONS: Some important outcomes were limited by poor reporting (eGFR and microalbuminuria) or low event rates (hypoglycemia). The follow-up time was relatively short. Clinically, the 24 week time point is more important as it demonstrates more sustained results. CONCLUSIONS: Our research suggests that liraglutide 0.9 mg offers a more efficacious treatment option for T2DM than the DPP-4 inhibitors among adult Japanese patients and that it is a viable option for this population. PMID- 28635333 TI - Molecular biomarkers to guide precision medicine in localized prostate cancer. AB - INTRODUCTION: Major advances through tumor profiling technologies, that include next-generation sequencing, epigenetic, proteomic and transcriptomic methods, have been made in primary prostate cancer, providing novel biomarkers that may guide precision medicine in the near future. Areas covered: The authors provided an overview of novel molecular biomarkers in tissue, blood and urine that may be used as clinical tools to assess prognosis, improve selection criteria for active surveillance programs, and detect disease relapse early in localized prostate cancer. Expert commentary: Active surveillance (AS) in localized prostate cancer is an accepted strategy in patients with very low-risk prostate cancer. Many more patients may benefit from watchful waiting, and include patients of higher clinical stage and grade, however selection criteria have to be optimized and early recognition of transformation from localized to lethal disease has to be improved by addition of molecular biomarkers. The role of non-invasive biomarkers is challenging the need for repeat biopsies, commonly performed at 1 and 4 years in men under AS programs. PMID- 28635332 TI - 50% Ethanol extract of Orthosiphon stamineus modulates genotoxicity and clastogenicity induced by mitomycin C. AB - Herbal products contain a variety of compounds which may be useful in protecting against cellular damage caused by mutagens. Orthosiphon stamineus (O.s) also known as Cat whiskers. The herb has been shown anti-oxidative properties and can modulate key cellular proteins that have cytoprotective effect. The study aimed to evaluate the effects of different doses (250, 500 and 1000 mg kg-1) of 50% ethanol extract of O.s (Et. O.s) on micro-nucleated polychromatic erythrocytes (MNPCE), Polychromatic to normachromatic erythrocytes ratio (PCE/NCE), Mitotic index (MI), and Chromosomal aberration (CA) in Bab/c mice. Moreover, these parameters were used to evaluate the anti-genotoxic and clastogenic potencies of (Et. O.s) against mitomycin c (MMC) that interact with biological molecules and induce genotoxic and clastogenic disorders in non-tumor cells. MMC (4 mg kg-1) was injected intraperitoneally (i.p.) to the mice before and after treatment with three different doses of (Et. O.s). The results indicated that the extract at different doses did not show significant (p >= 0.05) differences in (MNPCE), (PCE/NCE) ratios, and (CA) values. The higher doses sowed high (MI) values compared with untreated control group. MMC showed significant increase (p <= 0.001) in (MNPCE), (CA) and reduce (PCE/NCE) and (MI) values compared with untreated control group. Treatment with (Et. O.s) at different doses before and after MMC injection showed to modulate MNPCE, PCE/NCE ratios, CA and MI values in mice bone marrow cells suggesting genoprotective potential of this plant extract. PMID- 28635334 TI - Timing of food intake during simulated night shift impacts glucose metabolism: A controlled study. AB - Eating during the night may increase the risk for obesity and type 2 diabetes in shift workers. This study examined the impact of either eating or not eating a meal at night on glucose metabolism. Participants underwent four nights of simulated night work (SW1-4, 16:00-10:00 h, <50 lux) with a daytime sleep opportunity each day (10:00-16:00 h, <3 lux). Healthy males were assigned to an eating at night (NE; n = 4, meals; 07:00, 19:00 and 01:30 h) or not eating at night (NEN; n = 7, meals; 07:00 h, 09:30, 16:10 and 19:00 h) condition. Meal tolerance tests were conducted post breakfast on pre-night shift (PRE), SW4 and following return to day shift (RTDS), and glucose and insulin area under the curve (AUC) were calculated. Mixed-effects ANOVAs were used with fixed effects of condition and day, and their interactions, and a random effect of subject identifier on the intercept. Fasting glucose and insulin were not altered by day or condition. There were significant effects of day and condition * day (both p < 0.001) for glucose AUC, with increased glucose AUC observed solely in the NE condition from PRE to SW4 (p = 0.05) and PRE to RTDS (p < 0.001). There was also a significant effect of day (p = 0.007) but not condition * day (p = 0.825) for insulin AUC, with increased insulin from PRE to RTDS in both eating at night (p = 0.040) and not eating at night (p = 0.006) conditions. Results in this small, healthy sample suggest that not eating at night may limit the metabolic consequences of simulated night work. Further study is needed to explore whether matching food intake to the biological clock could reduce the burden of type 2 diabetes in shift workers. PMID- 28635335 TI - A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified, DOX-loaded PAMAM dendrimer. AB - Glioma is the most common primary malignant brain tumour and the effect of chemotherapy is hampered by low permeability across the blood-brain-barrier (BBB). Borneol is a time-honoured 'Guide' drug in traditional Chinese medicine and has been proved to be capable of promoting free drugs into the brain efficiently, but there are still risks that free drugs, especially anti-glioma drugs, may be disassembled and metabolised before penetrating the BBB and caused the whole brain distribution. The purpose of this paper was to investigate whether borneol intervention could facilitate the BBB penetration and assist glioma treatment by combining with doxorubicin (DOX) loaded PAMAM dendrimers drug delivery system modified with Angiopep-2 (a ligand of the low-density lipoprotein receptor-related protein, which overexpress both in the BBB and gliomas). The results demonstrated that Angiopep-2 modification could actually enhance the affinity between the dendrimers and the targeting cells and finally increase the cell uptake and boost the anti-tumour ability. Borneol physical combination could further enhance the anti-tumour efficiency of this targeting drug delivery system (TDDS) after penetrating BBB. Compared with free DOX solution, this TDDS illustrated obviously sustained and pH-dependent drug release. This suggested that this synergetic strategy provided a promising way for glioma therapy. PMID- 28635336 TI - New advances in focal therapy for early stage prostate cancer. AB - INTRODUCTION: Prostate focal therapy offers men the opportunity to achieve oncological control while preserving sexual and urinary function. The prerequisites for successful focal therapy are to accurately identify, localize and completely ablate the clinically significant cancer(s) within the prostate. We aim to evaluate the evidence for current and upcoming technologies that could shape the future of prostate cancer focal therapy in the next five years. Areas covered: Current literature on advances in patient selection using imaging, biopsy and biomarkers, ablation techniques and adjuvant treatments for focal therapy are summarized. A literature search of major databases was performed using the search terms 'focal therapy', 'focal ablation', 'partial ablation', 'targeted ablation', 'image guided therapy' and 'prostate cancer'. Expert commentary: Advanced radiological tools such as multiparametric magnetic resonance imaging (mpMRI), multiparametric ultrasound (mpUS), prostate-specific membrane-antigen positron emission tomography (PSMA-PET) represent a revolution in the ability to understand cancer function and biology. Advances in ablative technologies now provide a menu of modalities that can be rationalized based on lesion location, size and perhaps in the near future, pre-determined resistance to therapy. However, these need to be carefully studied to establish their safety and efficacy parameters. Adjuvant strategies to enhance focal ablation are under development. PMID- 28635337 TI - Population-Based Genetic Study of beta-Thalassemia Mutations in Mardan Division, Khyber Pakhtunkhwa Province, Pakistan. AB - beta-Thalassemia (beta-thal) is the most prevalent hereditary blood disorder in Pakistan with a carrier rate of 5.0-8.0%. The homozygous affected children require frequent blood transfusions for their survival. This autosomal recessive disease can only be prevented through awareness programs, carrier screening, mutation detection, genetic counseling and prenatal diagnosis (PND). The present study aimed to determine the prevalence of various mutations causing beta-thal and also to detect carriers of these mutations in families living in the Mardan Division, Khyber Pakhtunkhwa (KP) Province, Pakistan. The study was conducted at the Department of Biochemistry, Abdul Wali Khan University Mardan, Pakistan. Blood samples of beta-thalassemic families were collected from various transfusion centers in Mardan Division. Using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique, all samples were analyzed for the six most common mutations causing beta-thal in this area. Six different mutant primers for the detection of different mutations were used. The most common mutations detected in thalassemic patients were frameshift codons (FSC) 8/9 (+G) (HBB: c.27_28insG), codons 41/42 (-TTCT) (HBB: c.126_129delCTTT), and IVS-I-5 (G>C) (HBB: c.92+5G>C). The predominant mutation for carrying the mutant genes for beta-thal were FSC 8/9, IVS-I-5, codons 41/42, IVS-I-1. It was also found that 66.7% of marriages were consanguineous. The FSC 8/9 mutation was found to be the most common beta-thal mutation with a frequency of 44.4%. This research project provides a strong incentive for the establishment of large scale mutation detection and PND services in the Mardan Division. PMID- 28635338 TI - Risk of stroke/systemic embolism, major bleeding and associated costs in non valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population. AB - OBJECTIVE: To compare the risk and cost of stroke/systemic embolism (SE) and major bleeding between each direct oral anticoagulant (DOAC) and warfarin among non-valvular atrial fibrillation (NVAF) patients. METHODS: Patients (>=65 years) initiating warfarin or DOACs (apixaban, rivaroxaban, and dabigatran) were selected from the Medicare database from 1 January 2013 to 31 December 2014. Patients initiating each DOAC were matched 1:1 to warfarin patients using propensity score matching to balance demographics and clinical characteristics. Cox proportional hazards models were used to estimate the risks of stroke/SE and major bleeding of each DOAC vs. warfarin. Two-part models were used to compare the stroke/SE- and major-bleeding-related medical costs between matched cohorts. RESULTS: Of the 186,132 eligible patients, 20,803 apixaban-warfarin pairs, 52,476 rivaroxaban-warfarin pairs, and 16,731 dabigatran-warfarin pairs were matched. Apixaban (hazard ratio [HR] = 0.40; 95% confidence interval [CI] 0.31, 0.53) and rivaroxaban (HR = 0.72; 95% CI 0.63, 0.83) were significantly associated with lower risk of stroke/SE compared to warfarin. Apixaban (HR = 0.51; 95% CI 0.44, 0.58) and dabigatran (HR = 0.79; 95% CI 0.69, 0.91) were significantly associated with lower risk of major bleeding; rivaroxaban (HR = 1.17; 95% CI 1.10, 1.26) was significantly associated with higher risk of major bleeding compared to warfarin. Compared to warfarin, apixaban ($63 vs. $131) and rivaroxaban ($93 vs. $139) had significantly lower stroke/SE-related medical costs; apixaban ($292 vs. $529) and dabigatran ($369 vs. $450) had significantly lower major bleeding-related medical costs. CONCLUSIONS: Among the DOACs in the study, only apixaban is associated with a significantly lower risk of stroke/SE and major bleeding and lower related medical costs compared to warfarin. PMID- 28635339 TI - Methods for estimating costs in patients with hyperlipidemia experiencing their first cardiovascular event in the United Kingdom. AB - AIMS: Methods for integrating external costs into clinical databases are not well characterized. The purpose of this research was to describe and implement methods for estimating the cost of hospitalizations, prescriptions, and general practitioner and specialist visits used to manage hyperlipidemia patients experiencing cardiovascular (CV) events in the United Kingdom (UK). METHODS: This study was a retrospective cohort study using the Clinical Practice Research Datalink and Hospital Episode Statistics data. Costs were incorporated based on reference costs from the National Health Service, and labor costs from the Personal Social Services Research Unit. The study population included patients seen by general practitioners in the UK from 2006-2012. Patients >=18 years were selected at the time of their first CV-related hospitalization defined as myocardial infarction, ischemic stroke, heart failure, transient ischemic attack, unstable angina, or revascularization. To be included, patients must have received >=2 lipid-lowering therapies. Outcome measures included healthcare utilization and direct medical costs for hospitalizations, medications, general practitioner visits, and specialist visits during the 6-month acute period, starting with the CV hospitalization, and during the subsequent 30-month long term period. RESULTS: There were 24,093 patients with a CV hospitalization included in the cohort. This study identified and costed 69,240 hospitalizations, 673,069 GP visits, 32,942 specialist visits, and 2,572,792 prescriptions, representing 855 unique drug and dose combinations. The mean acute period and mean annualized long-term period costs (2014L) were L4,060 and L1,433 for hospitalizations, L377 and L518 for GP visits, L59 and L103 for specialist visits, and L98 and L209 for medications. CONCLUSIONS: Hospital costs represent the largest portion of acute and long-term costs in this population. Detailed costing using utilization data is feasible and representative of UK clinical practice, but is labor intensive. The availability of a standardized coding system in the UK drug costing data would greatly facilitate drug costing. PMID- 28635341 TI - Erratum. PMID- 28635340 TI - From seed to cooked pasta: influence of traditional and non-conventional transformation processes on total antioxidant capacity and phenolic acid content. AB - The aim of this work was to compare the traditional with a non-conventional (i.e. kernel micronisation) durum wheat milling process by monitoring the content of bound, conjugated and free phenolic acids (PAs) and the level of the total antioxidant capacity (TAC) occurring in the durum wheat pasta production chain, from seed to cooked pasta. The traditional transformation processes negatively influenced TAC and PA content (40% and 89% decrease from seed to cooked pasta, respectively), mainly during the milling process (25% and 84% decrease of TAC and PA, respectively), which has been related to the removal of external layers of kernels. Conversely, the micronisation applied on durum wheat kernels allowed to obtain whole-wheat pasta that preserved the seed endowment of antioxidant compounds even in cooked pasta. These results indicate the micronisation as a valuable approach to produce pasta with improved nutritional value and potential health-promoting effects compared to the traditional pasta. PMID- 28635342 TI - Healthcare costs in psoriasis and psoriasis sub-groups over time following psoriasis diagnosis. AB - AIMS: To quantify healthcare costs in patients with psoriasis overall and in psoriasis patient sub-groups, by level of disease severity, presence or absence of psoriatic arthritis, or use of biologics. METHODS: Administrative data from Truven Health Analytics MarketScan Research Database were used to select adult patients with psoriasis from January 2009 to January 2014. The first psoriasis diagnosis was set as the index date. Patients were required to have >=6 months of continuous enrollment with medical and pharmacy benefits pre-index and >=12 months post-index. Patients were followed from index until the earliest of loss to follow-up or study end. All-cause healthcare costs and outpatient pharmacy costs were calculated for the overall psoriasis cohort and for the six different psoriasis patient sub-groups: (a) patients with moderate-to-severe disease and mild disease, (b) patients with psoriatic arthritis and those without, and (c) patients on biologics and those who are not. Costs are presented per-patient-per year (PPPY) and by years 1, 2, 3, 4, and 5 of follow-up, expressed in 2014 US dollars. RESULTS: A total of 108,790 psoriasis patients were selected, with a mean age of 46.0 years (52.7% females). Average follow-up was 962 days. All-cause healthcare costs were $12,523 PPPY. Outpatient pharmacy costs accounted for 38.6% of total costs. All-cause healthcare costs were highest for patients on biologics ($29,832), then for patients with psoriatic arthritis ($23,427) and those with moderate-to-severe disease ($21,481). Overall, all-cause healthcare costs and outpatient pharmacy costs presented an upward trend over a 5-year period. CONCLUSIONS: Psoriasis is associated with significant economic burden, which increases over time as the disease progresses. Patients with moderate-to-severe psoriasis, those with psoriatic arthritis, or use of biologics contributes to higher healthcare costs. Psoriasis-related pharmacy expenditure is the largest driver of healthcare costs in patients with psoriasis. PMID- 28635343 TI - Primary psychopathy and alcohol pathology in college students: The role of protective behavioral strategies. AB - OVERVIEW: Though not an official diagnosis, psychopathy has become an important area of research due to the litany of deleterious outcomes associated with this aspect of temperament. Psychopathy is composed of primary and secondary traits. Research consistently links psychopathy to alcohol pathology, though often only via secondary traits which are comprised of intractable aspects of behavior (e.g., poor impulse control). In contrast, primary psychopathy is comprised of behaviors that can be learned and thus may be more malleable (i.e., low harm reduction behaviors). OBJECTIVES: The current study examines associations between primary psychopathic traits and alcohol involvement as a function of Protective Behavioral Strategies (PBS) utilization in a sample of college students. METHOD: Participants (n = 936 college student drinkers; 66.56% female) completed a series of questionnaires assessing primary psychopathy, alcohol involvement, and PBS use. RESULTS: There was a significant positive association between primary psychopathy and alcohol consumption and pathology. This association was partially mediated via diminished PBS use. PBS use also moderated the relationship between alcohol consumption and pathology. The indirect effects from psychopathy to alcohol outcomes were attenuated at high (+1SD) PBS and potentiated at low (-1SD) PBS. CONCLUSION: The current findings suggest that some of the alcohol pathology associated with psychopathy is a function of lower harm reduction strategies among individuals with more psychopathic traits. These findings suggest that interventions targeting PBS use may be one way to reduce alcohol problems among those with higher levels of primary psychopathy. PMID- 28635344 TI - Trajectories of remission and mortality over 13 years after intake to substance use treatment. AB - BACKGROUND: Little is known about the relationships between long-term patterns of substance use and mortality risk among substance use disorder (SUD) patients. OBJECTIVE: To determine distinct patterns of remission and relapse of SUD over time and examine their relationship with mortality. METHODS: The study site was Kaiser Permanente of Northern California. Data for 997 adults who entered substance use treatment between 1994 and 1996 and 4,241 non-SUD patients with similar demographic distributions (35% women in both groups) were analyzed. Latent class growth analysis identified distinct remission trajectory groups over 13 years among SUD patients, and survival analyses were conducted to examine the risk of death between remission trajectory groups, and SUD and non-SUD patients within each remission trajectory group. RESULTS: Three distinct remission trajectory groups were identified among SUD patients: 1) early relapse-low remission probabilities; 2) declining remission-decreasing remission probabilities; and 3) stable remission-stable remission probabilities across all time points. Among the SUD patients, the early relapse group had a higher risk of death than those stably remitted; stable and declining remission groups did not differ. Comparisons within each remission trajectory group showed that SUD patients in the early relapse and stable remission groups had higher risks of death compared with non-SUD patients; there were no differences within the declining group. CONCLUSIONS: SUD patients in the stable remission group had lower survival rates compared with non-SUD patients. These findings underline the importance of continuously addressing healthcare needs of individuals with SUD, even in the presence of long-term remission. PMID- 28635345 TI - Avatar-assisted therapy: a proof-of-concept pilot study of a novel technology based intervention to treat substance use disorders. AB - BACKGROUND: Avatar-assisted therapy (AAT) is a novel and emerging technology that uses the Internet to enable clinicians and clients in substance abuse treatment to participate in group counseling sessions from separate and remote locations in real time through the use of avatars and virtual environments. OBJECTIVES: The current study is a pilot proof-of-concept feasibility study involving individuals in outpatient substance abuse treatment. This report addresses two questions: (1) are individuals who present for substance abuse treatment interested in receiving AAT and (2) what factors are associated with better treatment success. METHODS: Individuals who presented at the treatment clinic who met study eligibility criteria, and provided their written informed consent to participate, were included in the current study (N = 59; 78% male). RESULTS: Twenty-eight (47.5%) participants completed 16 weeks of treatment and attended more sessions compared to non-completers (M = 14.3 vs. 7.5 p < .05). Those individuals who completed treatment were less likely to have a positive urine drug screen at baseline (21.5 vs. 78.6%; p < .05). Furthermore, those individuals who successfully completed treatment were less likely to have positive urine drug screens during treatment compared to those who did not complete (29.7% vs. 70.3%, p < .05). There were no arrests during treatment for completers and non-completers. CONCLUSION: Poor retention in substance use disorder treatment has long been a major problem for public health. AAT is a feasible approach that has the potential to expand treatment to individuals who might have difficulty accessing treatment. Moreover, AAT may be appealing to clients who are concerned about anonymity and confidentiality. PMID- 28635346 TI - Effect of drug-related cues on response inhibition through abstinence: A pilot study in male heroin abstainers. AB - BACKGROUND: Chronic heroin use can cause a deficit of inhibitory function, leading to a loss of control over drug use. Exposure to drug-related cues is considered as one of the contributing factors. However, it is unclear whether there are dynamic changes on the effect of drug-related cues on response inhibition following prolonged abstinence. OBJECTIVE: The present study investigated the effect of drug-related cues on response inhibition in heroin abstainers at different abstinent phases. METHODS: 26 shorter-term (2-6 months) and 26 longer-term (19-24 months) male heroin abstainers performed on a modified two-choice Oddball task, which included two conditions: in the cued condition, neutral pictures served as the background of standard stimuli (yellow frame) and heroin-related pictures served as the background of deviant stimuli (blue frame), reversed in the controlled conditions. RESULTS: Compared to longer-term abstainers, mean reaction time (RT) for drug deviants in shorter-term abstainers was significantly longer. Shorter-term abstainers also showed markedly slower response to neutral deviants relative to drug deviants, but this tendency was not observed in longer-term abstainers. Nevertheless, both groups had similar RT for standard stimuli regardless of their paired background pictures. CONCLUSION: Effect of drug-related cues on response inhibition remains at the early stage of abstinence; however, this effect may be reduced following a longer period of drug abstinence. Our findings highlight the importance of assessing and improving the ability of inhibiting drug-related cue reactivity during treatment. PMID- 28635347 TI - Ketamine and international regulations. AB - BACKGROUND: Ketamine is an anesthetic commonly used in low-income countries and has recently been shown to be effective for treatment-resistant depression. However, the illicit manufacturing, trafficking, and nonmedical use of ketamine are increasing globally, and its illicit use poses major public health challenges in many countries. OBJECTIVES: To review the nonmedical use of ketamine in selected countries and its regulatory control. METHODS: We conducted a review of literature identified from searches of the China National Knowledge Infrastructure (CNKI) (1979-2016) and PubMed databases, supplemented by additional references identified by the authors. Special attention was given to the regulation of ketamine. RESULTS: Illicit manufacturing, trafficking, and use of ketamine appear to have begun on a large scale in several Asian nations, and it has subsequently spread to other regions. Regulations governing availability of ketamine vary across countries, but there is a clear trend toward tighter regulations. CONCLUSIONS: As nonmedical use of ketamine and its harmful consequences have worsened globally, stricter controls are necessary. Appropriate regulation of ketamine is important for international efforts to control ketamine's cross-border trafficking and its nonmedical use. PMID- 28635348 TI - Hope, coping skills, and the prefrontal cortex in alcohol use disorder recovery. AB - BACKGROUND: Alcohol use disorders adversely affect individual and societal health. These disorders are a chronic brain disease, and protective factors against relapse should be studied. Prefrontal cortex (PFC) dysfunction is evident in alcohol use disorders, and research that explores recovery of the PFC in alcohol use disorders is needed, specifically in regard to how psychological and behavioral factors can augment medicalized treatments and protect against relapse. For example, hope or a belief that recovery is possible is an important cognitive construct-thought to precede behavioral action-that has been associated with relapse. OBJECTIVES: In this study, associations between healthy coping skills and hope (psychological/behavioral factors) and PFC regional activation in response to alcohol cue exposure were examined. It was also examined whether such associations were unique to alcohol cues. METHODS: Forty-two participants, 32 males and nine females in recovery from an alcohol use disorder (AUD), were administered a subjective hope and coping in recovery measure. They also viewed alcohol, positive, negative, and neutral cues during functional near-infrared spectroscopy (fNIR) PFC assessment. RESULTS: Levels of healthy coping skills positively correlated with activation in the right dorsomedial prefrontal cortex (DMPFC) in response to alcohol cues. This finding was unique to alcohol cues. CONCLUSION: The association between coping skills and activation of the right DMPFC in response to alcohol cues may reflect greater action restraint and top down PFC control processing that may protect against relapse. PMID- 28635350 TI - Corrigendum. PMID- 28635349 TI - The association between alcohol use trajectories from adolescence to adulthood and cannabis use disorder in adulthood: a 22-year longitudinal study. AB - BACKGROUND: Due to the increasing prevalence of cannabis use disorder (CUD), the impact of cannabis use on public health may be significant. OBJECTIVE: The present study seeks the possible precursors (e.g., alcohol use) of CUD in order to minimize the potential negative consequences of CUD such as impaired coordination and performance. METHOD: The Harlem Longitudinal Development Study included 674 participants (53% African Americans, 47% Puerto Ricans), with 60% females (n=405) from a six wave survey. We used a growth mixture model to obtain the trajectories of alcohol use from the mean ages of 14 to 36. To examine the associations between alcohol use trajectories and CUD, we used logistic regression analyses with the indicator of CUD as the dependent variable and the indicator of membership in each trajectory group as the independent variables. RESULTS: A three alcohol use trajectory group model was selected. Male gender, higher frequency of cannabis use in adolescence, and a lower educational level were associated with an increased likelihood of having CUD. Membership in the increasing alcohol use group (OR=27.44, p < .01; AOR=15.54, p < .01) and the moderate alcohol use group (OR=10.40, p < .05; AOR=8.63, p < .05) were associated with an increased likelihood of having CUD compared with the membership in the no or low alcohol use group. CONCLUSIONS: The findings of our study support the hypothesis that addressing alcohol use at an early age could impact later CUD. PMID- 28635351 TI - Assessing the quality of bereavement care after perinatal death: development and piloting of a questionnaire to assess parents' experiences. AB - Understanding parents' experience of care is essential to develop high-quality perinatal bereavement services. This study aimed at developing a questionnaire to identify parents' needs and record their experience of care. The patient experience questionnaire was developed by professionals and parents, and piloted in a tertiary maternity unit. Responses were received from 58 parents. Sensitivity and kindness of staff and time spent with their baby were ranked as 'very important' by 95% of parents. Care in these areas largely met their needs (90%), although 5% of respondents stated that partners could have been more involved. Between 8% and 15% of respondents did not feel that language used at the diagnosis of fetal death was sensitive, clear and unambiguous. Parents did not always receive written information about their care (5%) or post-mortem (13%). Analysis of bereaved parents' responses identified areas for improvement including greater involvement of partners and a need for timely information. Impact statement What is already known on this subject?: Good quality bereavement care after perinatal death reduces the negative emotional, psychological and social effects for parents. Description of parents' experiences is a potential means to improve the quality of perinatal bereavement care. What do the results of this study add?: Parents' needs and experiences of care after perinatal death were recorded using a patient-experience questionnaire designed by a multi professional team and parents. Staff behaviour, particularly sensitivity and kindness was highly valued by parents. Giving both verbal and written information could be improved. Training is needed for professionals, particularly those who come into contact with bereaved parents less frequently. What are the implications of these findings for clinical practice and/or further research?: Description of parents' priorities and views can be used to identify areas for improvement in perinatal bereavement care. Parents' views should be regularly sought and used to develop local services in an iterative process. PMID- 28635352 TI - A randomized controlled trial comparing two types of retractors at caesarean delivery. AB - The aim of this study was to determine if the use of a self-retaining, symmetrical retractor (OB/Mobius(r)) during caesarean delivery is associated with differences in post-operative pain experience. Consenting women undergoing caesarean delivery were randomly assigned to OB/Mobius(r) versus conventional retraction instruments. Women were blinded to retractor type and filled out surgical pain surveys each post-operative day. Additional outcome variables were collected through a provider survey and chart review. Of the 154 randomised women, 144 completed the study. There was no difference in the symmetry, quality or intensity of postoperative pain based on the method of retraction. The OB/Mobius(r) retractor did not confer an improvement in the quality or intensity of post-caesarean discomfort in the first three days following delivery. Nor did the groups differ in operative times, blood loss or pain medication usage. However, the retractor may offer improved visualisation and retraction in obese women. Impact statement Use of a plastic sheath self-retaining retractor has been minimally studied in caesarean deliveries. Recently it was found that the use of such a retractor reduced wound infection, but another study in obese women did not show improved rates of infection (Hinkson et al. 2016 ; Scolari Childress et al. 2016 ). The study of sheath self-retaining retractors to decrease post operative pain has not been reported previously. This study offers an investigation into a generalisable population of parturients who undergo caesarean delivery and if the primary use of a self-retaining retractor versus sole use of traditional hand-held retractors decreased post-operative pain while in the hospital. Although this study did not show an improvement in post operative pain, provider experience reports demonstrated some improvement in visualisation, particularly in the obese population with the use of this novel retractor, thus making it an option for providers who do caesarean deliveries without an assistant and find hand-held retractors inadequate. PMID- 28635353 TI - A Systematic Review of Supported Accommodation Programs for People Released From Custody. AB - One of the challenges that people recently released from custody face is securing housing. Many individuals rely on supported accommodation programs for housing in the immediate post-release period. However, the value of supported accommodation programs in producing positive criminal justice and health outcomes for people released from custody has not been widely examined. This article reviews the current literature on supported accommodation programs and the elements of these services that contribute to positive outcomes for individuals released from custody. We focused on programs that provided temporary, transitional group residences for adults recently released from a correctional setting. The systematic review identified only nine publications that met the inclusion criteria. Studies were frequently at high risk of bias and few consistent findings emerged about either effectiveness of accommodation programs or program characteristics associated with participant outcomes. Methodologically rigorous research is needed to determine the effectiveness of post-release supported accommodation programs. PMID- 28635354 TI - The effects of food on opioid-induced nausea and vomiting and pharmacological parameters: a systematic review. AB - Opioids remain the standard of care for treating moderate to severe pain resulting from surgery or injury in cases of acute pain, and are recommended for patients who have not responded to nonopioid analgesics. Effective management of pain has an impact on clinical course and often depends on achieving an acceptable balance between opioid efficacy, safety, and tolerability. Common opioid-related adverse events such as nausea and vomiting are associated with an overall lower achievement of effective pain management and patient satisfaction. However, in practice, clinicians employ various strategies to maximize efficacy, minimize these adverse effects, and ensure the careful, judicious, and evidence based use of opioids for patients who require them. Typical strategies for management and minimization of these types of adverse events include dose reduction, dose titration, opioid rotation, prescription for an antiemetic, and recommending the patient take opioids with food. Overall, the most straightforward approach that clinicians tend to employ that does not require additional visits or adjustment of prescriptions, is to recommend patients take opioids with food. However, given the current climate with opioids, it is critical and imperative that decisions for use of opioids be grounded in a solid and thorough evidence-base. In fact, several opioids are recommended to be taken explicitly with or without food because of interactions with abuse-deterrent technologies that can cause increased adverse events or inadequate analgesia. Therefore, we sought to review, synthesize, and summarize the literature for randomized, controlled trials and other studies to support the hypothesis that taking opioids with food reduces opioid-related events such as nausea and vomiting. Based on the current evidence we surveyed, the recommendation to take opioids with food does not appear to consistently and unequivocally reduce nausea and vomiting and, in many cases, increases the frequency of these adverse events in the studies we examined. PMID- 28635355 TI - Aberrant Wnt signaling: a special focus in CNS diseases. AB - Wnt signals regulate cell proliferation, migration and differentiation during development, as well as synaptic transmission and plasticity in the adult brain. Abnormal Wnt signaling is central to a number of brain pathologies. We review here, the significance of this pathway focused in the contribution of the most frequent alterations in receptors, secretable modulators and downstream targets in Alzheimer's disease (AD) and Glioblastoma (GBM). beta-catenin and GSK3 levels are pivotal in the neurodegeneration associated to AD contributing to memory deficits, tau phosphorylation, increased beta-amyloid production and modulation of Apolipoprotein E in the brain. In consequence, beta-catenin and GSK3 are targets for potential treatments in AD. Also, Wnt pathway components and secreted molecules interfering with this signaling contribute to the progression of tumoral cells. Wnt pathway activation is a bad prognosis in brain cancer; however, mutations in WNT or Frizzled (FZD) genes do not account for the cases of GBM. Instead, recent studies indicate that epigenetic modifications contribute to the development of GBMs opening novel strategies to study GBM progression. PMID- 28635356 TI - Simultaneous ABO-incompatible living-donor liver transplantation and splenectomy without plasma exchange in China: Two case reports. AB - ABO-incompatible (ABO-i) living-donor liver transplantation (LDLT) is performed if an ABO-compatible graft cannot be obtained. However, a perfect desensitization protocol has not been established worldwide, especially for simultaneous ABO-i LDLT and splenectomy. We herein report two cases of ABO-i LDLT. To the best of our knowledge, this is the first case report of ABO-i LDLT in an adult patient in China. Splenectomy and T-cell-targeted immunosuppression (basiliximab) was used to overcome the blood group barrier in these recipients. The patients had good graft function without signs of antibody-mediated rejection throughout the 12 month follow-up. Thus, ABO-i LDLT with splenectomy is undoubtedly life-saving when an ABO-compatible graft cannot be obtained for patients in critical condition. PMID- 28635357 TI - Hypertrophy of the ligamentum flavum and expression of transforming growth factor beta. AB - Objective To explore the relationship between cellular apoptosis and hypertrophy of the ligamentum flavum in the lumbar region. Methods Thirty patients with lumbar spinal stenosis were evaluated. Hypertrophy of the ligamentum flavum was present in 15 patients and absent in 15. Hematoxylin-eosin staining and transforming growth factor beta (TGF-beta) immunohistochemical testing were applied to compare these two groups. Results Derangement of fibrous alignment, fibrocartilage changes, and infiltration of inflammatory cells were observed in the patients with hypertrophy of the ligamentum flavum, while fibrous alignment was normal and few inflammatory cells were observed in patients without hypertrophy. Immunohistochemical studies showed positive expression of TGF-beta in patients with hypertrophy, while expression was negative in patients without hypertrophy. The integrated optical density was 2.6556708 in the hypertrophy group and 23104671 in the normal controls. Conclusions Expression of TGF-beta was closely related to hypertrophy of the ligamentum flavum. Appropriate application of the TGF-beta expression level can be used to predict progression of hypertrophy of the ligamentum flavum. PMID- 28635358 TI - Disability and the impact of need for periodontal care on quality of life: A cross-sectional study. AB - Objective The need for periodontal care may negatively impact daily life. We compared the need for periodontal care and its impact on daily life between disabled and healthy adults in the Eastern Province, Saudi Arabia. Methods In this cross-sectional study of 819 adults, a questionnaire was used to assess personal background factors; the impact of periodontitis on pain, avoiding foods, embarrassment, sleeplessness, work absence, and discontinuing daily activities; and risk factors (smoking, diabetes, toothbrushing, insurance, professional tooth cleaning, and dental visits). The outcome was clinically assessed need for periodontal care impacting daily life. The relationship between the outcome and risk factors adjusted for personal background and disability was assessed using ordinal regression. Results Healthy and disabled persons had a high need for periodontal care (66.8%). Current smokers had a higher likelihood and health insured persons had a lower likelihood of need for periodontal care impacting daily life regardless of whether disability was considered. Conclusions Most adults needed periodontal care, and disabled persons experienced a greater impact on life. Current smokers and uninsured persons were more likely to need periodontal care impacting daily life. Our findings are important for the prevention of periodontitis through tobacco cessation and extending insurance coverage. PMID- 28635359 TI - Thoracic paravertebral block versus intravenous patient-controlled analgesia for pain treatment in patients with multiple rib fractures. AB - Objectives To assess the effect of thoracic paravertebral block (PVB) on pain management and preservation of pulmonary function compared with intravenous, patient-controlled analgesia (IVPCA) in patients with multiple rib fractures (MRFs). Methods Ninety patients with unilateral MRFs were included in this prospective study and randomly assigned to the TPVB or IVPCA group. The visual analogue scale (VAS) pain score, blood gas analysis, and bedside spirometry were measured and recorded at different time points after analgesia. Results TPVB and IVPCA provided good pain relief. VAS scores were significantly lower in the TPVB group than in the IVPCA group at rest and during coughing ( P < 0.05). Patients in the TPVB group had a higher PaO2 and PaO2/FiO2 and lower P(A-a)O2 compared with the IVPCA group ( P < 0.05). Moreover, patients in the TPVB group showed higher FVC, FEV1/FVC, and PEFR, and fewer complications than did the IVPCA group ( P < 0.05). Conclusion TPVB is superior to IVPCA in pain relief and preservation of pulmonary function in patients with MRFs. PMID- 28635360 TI - The association between apolipoprotein A1-C3-A5 gene cluster promoter polymorphisms and risk of ischemic stroke in the northern Chinese Han population. AB - Objective Given its effects on lipid metabolism, the apolipoprotein A1-C3-A5 ( APOA1-C3-A5) gene cluster is thought to play an important role in ischemic stroke pathogenesis. Here, we evaluated whether the APOA1-C3-A5 cluster is associated with ischemic stroke in the northern Chinese Han population. Methods This case control study analyzed 812 patients with ischemic stroke and 844 healthy controls with regard to four APOA1-C3-A5 cluster promoter single nucleotide polymorphisms (SNPs), rs670, rs2854116, rs2854117, and rs662799, using the SNaPshot Multiplex sequencing assay. Potential associations among ischemic stroke, genotyping, and allele frequencies were assessed. Results APOA1 rs670 CT/TT genotypes, APOA5 rs662799 AG/GG genotypes, and the APOC3 rs2854116 CC genotype were associated with an increased risk of ischemic stroke according to multivariate logistic analysis after adjusting for confounding factors. A significantly increased risk for ischemic stroke was also identified among high-risk haplotypes (C-C-T-A and T T-C-A) for rs670-rs2854116-rs2854117-rs662799. Conclusion This study showed that rs670, rs2854116, and rs662799 SNPs of the APOA1-C3-A5 cluster are associated with ischemic stroke in the northern Chinese Han population. PMID- 28635361 TI - Role of licochalcone A in VEGF-induced proliferation of human airway smooth muscle cells: implications for asthma. AB - Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodeling, which is associated with increased airway smooth muscle (ASM) mass. Licochalcone A is the predominant characteristic chalcone in licorice root. We found that licochalcone A inhibited vascular endothelial growth factor (VEGF)-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed via inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity, but not that of Akt. Furthermore, licochalcone A treatment inhibited VEGF-induced activation of VEGF receptor 2 (VEGFR2) and ERK and blocked the downregulation of caveolin-1 in a concentration-dependent manner. Collectively, our findings suggested that licochalcone A inhibited VEGF-induced ASM cell proliferation by suppressing VEGFR2 and ERK1/2 activation and downregulating caveolin-1. Further studies of these mechanisms are needed to facilitate the development of treatments for smooth muscle hyperplasia-associated diseases of the airway, such as asthma. PMID- 28635362 TI - Costs and effectiveness of fingolimod versus alemtuzumab in the treatment of highly active relapsing-remitting multiple sclerosis in the UK: re-treatment, discount, and disutility. AB - OBJECTIVE: Patients with relapsing-remitting multiple sclerosis (RRMS) treated with disease modifying therapies (DMTs) who continue to experience disease activity may be considered for escalation therapies such as fingolimod, or may be considered for alemtuzumab. Previous economic modeling used Markov models; applying one alternative technique, discrete event simulation (DES) modeling, allows re-treatment and long-term adverse events (AEs) to be included in the analysis. METHODS: A DES was adapted to model relapse-triggered re-treatment with alemtuzumab and the effect of including ongoing quality-adjusted life year (QALY) decrements for AEs that extend beyond previous 1-year Markov cycles. As the price to the NHS of fingolimod in the UK is unknown, due to a confidential patient access scheme (PAS), a variety of possible discounts were tested. The interaction of re-treatment assumptions for alemtuzumab with the possible discounts for fingolimod was tested to determine which DMT resulted in lower lifetime costs. The lifetime QALY results were derived from modeled treatment effect and short- and long-term AEs. RESULTS: Most permutations of fingolimod PAS discount and alemtuzumab re-treatment rate resulted in fingolimod being less costly than alemtuzumab. As the percentage of patients who are re-treated with alemtuzumab due to experiencing a relapse approaches 100% of those who relapse whilst on treatment, the discount required for fingolimod to be less costly drops below 5%. Consideration of treatment effect alone found alemtuzumab generated 0.2 more QALYs/patient; the inclusion of AEs up to a duration of 1 year reduced this advantage to only 0.14 QALYs/patient. Modeling AEs with a lifetime QALY decrement found that both DMTs generated very similar QALYs with the difference only 0.04 QALYs/patient. CONCLUSIONS: When the model captured alemtuzumab re-treatment and long-term AE decrements, it was found that fingolimod is cost-effective compared to alemtuzumab, assuming application of only a modest level of confidential PAS discount. PMID- 28635363 TI - Early mortality risk in incident Chinese hemodialysis patients: a retrospective cohort study. AB - BACKGROUND: Early mortality risk of maintenance hemodialysis (MHD) patients varies by country and ethnicity. Here, early mortality in incident Chinese HD patients were studied. METHODS: Data from 1 January 2007 to 31 December 2013 were pulled from Beijing dialysis registry system. All included patients were followed to the end of 2013. This time period of dialysis was divided into six intervals (<=120, 121-365 days; 1-2, 2-3, 3-4, >=5 years). Patients' demographics, primary cause of end-stage renal disease (ESRD), date of first HD, date of death, cause for death, date and cause of censoring were extracted from the registry database. All-cause mortality (per 100 patient-years) was calculated for each period stratified by sex, age and cause of ESRD. Monthly mortality rates were also calculated. RESULTS: A total of 11,955 patients were included, 6738 were males and 5217 were females. The mean age at dialysis initiation was 57.7 +/- 16.1 years. The median follow-up time was 19.8 months. There were total 2555 deaths. The overall mortality rate was 8.2 per 100 patient-years. Mortality rates were 18.7, 7.5, 6.9, 6.9, 6.5 and 6.2 in each period. The first 2 months mortality rates were 41.9 and 16.6 per 100 patient-years. Higher mortality was observed in patients who were older, female, diabetic and hypertensive. CONCLUSIONS: The most critical period was the first 2 months of dialysis initiation. Patients who were older, female, diabetic and hypertensive had higher risk of early mortality. Our analysis highlighted that the transitional period from sever CKD stages to dialysis initiation, when optimal supportive care should be adopted, was crucial for patients' survival. PMID- 28635364 TI - The impact of motivational interviewing on behavior stages of nulliparous pregnant women preparing for childbirth: a randomized clinical trial. AB - OBJECTIVE: To examine the effectiveness of motivational interviewing (MI) on the stages of behavior change among nulliparous pregnant women who were preparing for childbirth. METHODS: In this randomized clinical trial, 234 pregnant women were studied in two intervention groups (MI and lecture), and one control group at three stages. In weeks 16-19 of pregnancy, two counseling sessions were held for the MI group, and one lecturing session was held for the lecture group. In weeks 21 and 37 of pregnancy, the three groups were reevaluated. RESULTS: At baseline, more than 70% of women were at pre-contemplation and contemplation stages. In week 21 of pregnancy, in MI 71% were at preparation stage, whereas in the lecture and control groups, 51.9% and 49.4% were at the contemplation stage, respectively. In week 37 of pregnancy, in MI, lecture and control groups, 90%, 59.7% and 27.3% were at the action stage, respectively (p < .001). The result of generalized estimating equation (GEE) analysis using a Poisson model indicated that the incident rate for lecture group was 1.7 (95% CI: 1.2-2.5) times the incident rate for the MI group. Also, the incident rate for control group was 3.4 (95% CI: 2.2-5.0) times the incident rate for the MI group. CONCLUSIONS: Motivational interviewing was effective in guiding nulliparous mothers toward positive behavior stages. PMID- 28635366 TI - Redox biology of Leishmania and macrophage targeted nanoparticles for therapy. AB - Intramacrophage parasite 'Leishmania' has developed various mechanisms for proficient uptake into macrophages and phagosome regulation to avoid macrophage's oxidative burst induced by peroxide, hydroxyl radical, hypochlorous acid and peroxynitrite production. One major barrier for impairing the accession of old fashioned anti-Leishmanial drugs is intrinsic incapability to pass through cell membranes and limiting their abilities to ultimately destroy intracellular pathogens. Receptor-mediated targeted drug delivery to the macrophages by using nanoparticles emerges as promising strategy to improve therapeutic efficacy of old-fashioned drug. Receptor-mediated targeted nanoparticles can migrate across the cell membrane barriers and release enclosed drug cargo at sites of infection. This review is focusing on Leishmania-macrophage signaling alterations, its association with drug resistance and role of nanoparticles for receptor mediated macrophage targeting. PMID- 28635367 TI - In vivo and in vitro depolymerizations of intracellular medium-chain-length poly 3-hydroxyalkanoates produced by Pseudomonas putida Bet001. AB - In vivo and in vitro depolymerizations of intracellular medium-chain-length poly 3-hydroxyalkanoates (mcl-PHA) in Pseudomonas putida Bet001 grown on lauric acid was studied. Both processes were studied under optimum conditions for mcl-PHA depolymerization viz. 0.2 M Tris-HCl buffer, pH 9, ionic strength (I) = 0.2 M at 30 degrees C. For in vitro depolymerization studies, cell-free system was obtained from lysing bacterial cells suspension by ultrasonication at optimum conditions (frequency 37 kHz, 30% of power output, <25 degrees C for 120 min). The comparison between in vivo and in vitro depolymerizations of intracellular mcl-PHA was made. In vitro depolymerization showed lower depolymerization rate but higher yield compared to in vivo depolymerization. The monomer liberation rate reflected the mol% distribution of the initial polymer subunit composition, and the resulting direct individual products of depolymerization were identical for both in vivo and in vitro processes. It points to exo-type reaction for both processes, and potential biological route to chiral molecules. PMID- 28635365 TI - Nucleosomal organization and DNA base composition patterns. AB - Nucleosomes are the basic units of chromatin. They compact the genome inside the nucleus and regulate the access of proteins to DNA. In the yeast genome, most nucleosomes occupy well-defined positions, which are maintained under many different physiological situations and genetic backgrounds. Although several short sequence elements have been described that favor or reduce the affinity between histones and DNA, the extent to which the DNA sequence affects nucleosome positioning in the genomic context remains unclear. Recent analyses indicate that the base composition pattern of mononucleosomal DNA differs among species, and that the same sequence elements have a different impact on nucleosome positioning in different genomes despite the high level of phylogenetic conservation of histones. These studies have also shown that the DNA sequence contributes to nucleosome positioning to the point that it is possible to design synthetic DNA molecules capable of generating regular and species-specific nucleosomal patterns in vivo. PMID- 28635368 TI - Efficacy and safety of autologous cell therapies for knee cartilage defects (autologous stem cells, chondrocytes or the two): randomized controlled trial design. AB - AIM: The main aim of this trial is to test the safety and efficacy of autologous stromal/stem cells, chondrocytes or the two combined in the treatment of knee cartilage defects. PATIENTS & METHODS: Patients with symptomatic chondral/osteochondral defects will be randomized to cell therapy treatment with one of three cell populations (1:1:1). The primary efficacy outcome is a functional knee score (Lysholm) at 15 months post-treatment and the primary safety outcome is the incidence of adverse events. Secondary objectives are to analyze repair tissues, quality of life and cost-utility assessments. Exploratory objectives are to identify predictors for success/potency and dose-response relationships. RESULTS & CONCLUSION: This trial has been carefully designed so that valuable scientific and clinical information can be gathered throughout and in the final analysis. PMID- 28635369 TI - Comparison of Knotless Barbed Suture Versus Monofilament Suture in the Oral Cavity of Cats. AB - The present study compares a knotless, barbed, absorbable suture material against a conventional monofilament absorbable suture material in oral mucosal wound closure. The parameters measured include time of closure and differences in healing at 2 and 4 weeks postoperatively. A prospective study comparing a knotless, barbed suture system with conventional absorbable sutures was undertaken in 19 cats. Nineteen cats had full mouth extractions performed. Following the extraction procedures, the incisions in the arcades (maxillary and mandibular) were apposed with the barbed, knotless suture system in a continuous pattern on one side and with a conventional smooth suture in an interrupted pattern on the other. Suturing times for each arcade were recorded. The material used to close the first side of each cat varied. Healing, dehiscence, and other complications were assessed at 2 and 4 weeks postoperatively. The average closure time (+/- standard deviation) per quadrant with conventional monofilament suture was 8.7 (+/-1.3) minutes, while barbed suture required an average of 5.1 (+/-1.1) minutes per quadrant to complete the suture. This difference (95% confidence interval) of 3.6 (+/-3.2-4.1) minutes per quadrant was statistically significant ( P < .001). Dehiscence and ranula-like swelling formation were noted as uncommon postoperative complications, but the differences were not significant between the groups. Barbed, knotless sutures resulted in faster closure times than conventional, simple interrupted, monofilament sutures with similar healing and complication rates. To the author's knowledge, there is no current literature comparing conventional absorbable monofilament sutures to a knotless, barbed, absorbable suture system for closure of oral mucosal incisions in cats. PMID- 28635370 TI - Evaluation of the comprehensive palatability of Japanese sake paired with dishes by multiple regression analysis based on subdomains. AB - Many factors contribute to palatability. In order to evaluate the palatability of Japanese alcohol sake paired with certain dishes by integrating multiple factors, here we applied an evaluation method previously reported for palatability of cheese by multiple regression analysis based on 3 subdomain factors (rewarding, cultural, and informational). We asked 94 Japanese participants/subjects to evaluate the palatability of sake (1st evaluation/E1 for the first cup, 2nd/E2 and 3rd/E3 for the palatability with aftertaste/afterglow of certain dishes) and to respond to a questionnaire related to 3 subdomains. In E1, 3 factors were extracted by a factor analysis, and the subsequent multiple regression analyses indicated that the palatability of sake was interpreted by mainly the rewarding. Further, the results of attribution-dissections in E1 indicated that 2 factors (rewarding and informational) contributed to the palatability. Finally, our results indicated that the palatability of sake was influenced by the dish eaten just before drinking. PMID- 28635371 TI - Deoxynivalenol and zearalenone in unprocessed cereals and soybean from different cultivation regions in Croatia. AB - The aim of this study was to investigate the occurrence of deoxynivalenol (DON) and zearalenone (ZEN) in unprocessed cereals and soybean sampled in 2014 and 2015 from different fields located in Croatian regions. A total of 306 samples were analysed for DON and 415 samples for ZEN concentrations using quantitative ELISA methods. In 2014, DON and ZEN were determined in all samples in the mean concentrations of 1,461 +/- 2,265 ug/kg and 656 +/- 853 ug/kg, respectively, while in 2015 these means were 2,687 +/- 2,731 ug/kg and 1,140 +/- 1,630 ug/kg, respectively. The cultivation year significantly (p < 0.05) influenced mycotoxin concentrations, whereas the influence of cultivation region was seen with ZEN for all cereals except soybean, and not seen with DON at all. A higher contamination determined during 2015 could be explained by high to extreme humidity evidenced in the period of cereals' growth and harvesting. PMID- 28635372 TI - Peptide-functionalized nanoparticles for the selective induction of apoptosis in target cells. AB - AIM: The study developed a prohibitin (PHB) targeted nanotherapy for selective induction of apoptosis in target cells. METHODS: Gold nanoparticles (AuNPs) were bifunctionalized with adipose homing and proapoptotic peptides. The efficacy and mode of cell death induced by the AuNPs were investigated in vitro on three cancer cell lines. RESULTS: The antiproliferative activity of PHB-targeted bifunctionalized AuNPs was more pronounced on cells that express the PHB receptor, and demonstrated receptor-mediated targeting and selectivity. The bifunctionalized AuNPs induced cell death by apoptosis. CONCLUSION: The PHB targeted nanotherapy under study could potentially be used for treatment of diseases that are characterized by overexpression of PHB. As such, further investigations will be conducted in vivo. PMID- 28635373 TI - Relative risk of hemorrhage during pregnancy in patients with brain arteriovenous malformations. AB - Background It is unclear whether the risk of bleeding from brain arteriovenous malformations is higher during pregnancy, delivery, or puerperium. We compared occurrence of brain arteriovenous malformation hemorrhage in women during this period with occurrence of hemorrhage outside this period during their fertile years. Methods We included all women with ruptured brain arteriovenous malformations (16-41 years) from a retrospective database of patients with brain arteriovenous malformations in four Dutch university hospitals (n = 95) and from the population-based Scottish Audit of Intracranial Vascular Malformations (n = 44). We estimated the relative rate of brain arteriovenous malformation rupture (before any treatment) during exposed time (pregnancy, delivery, puerperium) versus non-exposed time during fertile years, using the case-crossover design as primary analysis, and the self-controlled case-series design as secondary analysis. Results In 17 of 95 Dutch women and in 3 of 44 Scottish women, hemorrhages occurred while pregnant; none occurred during delivery or puerperium. In Dutch women, the relative rate of brain arteriovenous malformation rupture during pregnancy, delivery, or puerperium was 6.8 (95% confidence interval 3.6 13) according to the case-crossover method and 7.1 (95% confidence interval 3.4 13) using the self-controlled case-series method. In Scottish women, the relative rate was 1.3 (95% confidence interval 0.39-4.1) using the case-crossover method and 1.7 (95% confidence interval 0.0-4.4) according to the self-controlled case series method. Because of limited overlap of confidence intervals, we refrained from pooling the cohorts. Conclusions Case-crossover and self-controlled case series analyses reveal an increase in relative rate of brain arteriovenous malformation rupture during pregnancy in the Dutch cohort but not in the Scottish cohort. Since point estimates varied between both cohorts and numbers are relatively small, the clinical implications of our findings are uncertain. PMID- 28635374 TI - Sepsis favors high-on-clopidogrel platelet reactivity. AB - High-on-treatment platelet reactivity (HPR) is associated with ischemic events in patients on antiplatelet therapy with a history of cardiovascular disease. On the other hand, recent data have associated sepsis with adverse cardiovascular events in patients admitted with bacteremia or respiratory infection. We aimed to assess P2Y12-mediated platelet reactivity (PR) during sepsis and recovery in patients under clopidogrel. This was a prospective observational study. Incoming patients presenting with signs/symptoms of sepsis already on a maintenance dose of clopidogrel of 75 mg qd for cardiovascular events were included in this study. Patients were assessed for their PR on presentation and following septic syndrome, using the VerifyNow point-of-care P2Y12 assay. Patients were excluded in the presence of evidence of noncompliance to antiplatelet regimen or in need of discontinuation during this study. Twenty-two septic patients on clopidogrel were included in this study (Supplemental Figure S1). Clopidogrel was administered for previous stroke, coronary, and peripheral artery disease in 27.3, 40.9, and 31.8% of patients, respectively. The main site of infection was respiratory tract followed by urinary tract, while the same amounts of gram negative and -positive pathogens were isolated. HPR was noted in 77% and 29% of patients during sepsis and recovery, respectively, presenting a significant decrease in P2Y12 reaction units values during follow-up [240.7 +/- 58.3 versus 179.5 +/- 58.4, 95% CI (-102.7, -39.76), p = 0.0002]. Five patients died of infection, while no adverse cardiovascular events were noted in our study. Our study shows that sepsis may favor HPR, which is reversed when recovery occurs. This finding may underlie the adverse cardiovascular events in patients admitted with sepsis, possibly requiring alteration of antiplatelet regimen during the inflammation period. PMID- 28635375 TI - Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy. AB - A growing body of research suggests that traumatic events lead to persisting personality change characterized by increased neuroticism. Relevantly, enduring improvements in Post-Traumatic Stress Disorder (PTSD) symptoms have been found in response to 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. There is evidence that lasting changes in the personality feature of "openness" occur in response to hallucinogens, and that this may potentially act as a therapeutic mechanism of change. The present study investigated whether heightened Openness and decreased Neuroticism served as a mechanism of change within a randomized trial of MDMA-assisted psychotherapy for chronic, treatment resistant PTSD. The Clinician-Administered PTSD Scale (CAPS) Global Scores and NEO PI-R Personality Inventory (NEO) Openness and Neuroticism Scales served as outcome measures. Results indicated that changes in Openness but not Neuroticism played a moderating role in the relationship between reduced PTSD symptoms and MDMA treatment. Following MDMA-assisted psychotherapy, increased Openness and decreased Neuroticism when comparing baseline personality traits with long-term follow-up traits also were found. These preliminary findings suggest that the effect of MDMA-assisted psychotherapy extends beyond specific PTSD symptomatology and fundamentally alters personality structure, resulting in long-term persisting personality change. Results are discussed in terms of possible mechanisms of psychotherapeutic change. PMID- 28635376 TI - Advances in understanding the role of disease-associated proteins in spinal muscular atrophy. AB - INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disorder characterized by alpha motor neuron loss in the spinal cord due to reduced survival motor neuron (SMN) protein level. While the genetic basis of SMA is well described, the specific molecular pathway underlying SMA is still not fully understood. Areas covered: This review discusses the recent advancements in understanding the molecular pathways in SMA using different omics approaches and genetic modifiers identified in both vertebrate and invertebrate systems. The findings that are summarized in this article were deduced from original articles and reviews with a particular focus on the latest advancements in the field. Expert commentary: The identification of genetic modifiers such as PLS3 and NCALD in humans or of SMA modulators such as Elavl4 (HuD), Copa, Uba1, Mapk10 (Jnk3), Nrxn2 and Tmem41b (Stasimon) in various SMA animal models improved our knowledge of impaired cellular pathways in SMA. Inspiration from modifier genes and their functions in motor neuron and neuromuscular junctions may open a new avenue for future SMA combinatorial therapies. PMID- 28635377 TI - How are we applying nanogel composites in biomedicine? PMID- 28635379 TI - Corrigendum. AB - : Gilliam, T. B. (2016). RESPONSE: Workplace Health & Safety, 64(11), 521. (Original doi: 10.1177/2165079916676829) This response incorrectly referred in the text to the lead author of the letter to the editor "Concerns With Medical and Pharmacy Costs for New Hire Nurses" as Churchill. This author's surname should have been listed as Burchill. PMID- 28635378 TI - People With Autism Spectrum Conditions Make More Consistent Decisions. AB - People with autism spectrum conditions (ASC) show reduced sensitivity to contextual stimuli in many perceptual and cognitive tasks. We investigated whether this also applies to decision making by examining adult participants' choices between pairs of consumer products that were presented with a third, less desirable "decoy" option. Participants' preferences between the items in a given pair frequently switched when the third item in the set was changed, but this tendency was reduced among individuals with ASC, which indicated that their choices were more consistent and conventionally rational than those of control participants. A comparison of people who were drawn from the general population and who varied in their levels of autistic traits revealed a weaker version of the same effect. The reduced context sensitivity was not due to differences in noisy responding, and although the ASC group took longer to make their decisions, this did not account for the enhanced consistency of their choices. The results extend the characterization of autistic cognition as relatively context insensitive to a new domain, and have practical implications for socioeconomic behavior. PMID- 28635380 TI - Inorganic nanoparticles as potential regulators of immune response in dendritic cells. AB - AIM: The spontaneous adsorption of proteins on nanoparticles (NPs) in biological media is exploited to prepare complexes of NPs and proteins from cancer cells' lysates for application in cancer immunotherapy. MATERIALS & METHODS: Gold (Au) and silica NPs were synthesized, incubated with cancer cells' lysates and characterized. Dendritic cells (DCs) were challenged with protein-coated NPs, their maturation, viability and morphology were evaluated and lymphocytes T proliferation was determined. RESULTS: Silica and Au NPs bound different pools of biomolecules from lysates, and are therefore promising selective carriers for antigens. When incubated with immature DCs, NPs were efficiently endocytosed without cytotoxicity. Finally, protein-coated AuNPs promoted DC maturation and DC mediated lymphocyte proliferation, at variance with lysate alone and protein coated silica NPs, that did not promote DCs maturation. CONCLUSION: These results demonstrate that the spontaneous formation of protein coronas on NPs represents a possible approach to fast, easy, cost-effective DCs stimulation. PMID- 28635381 TI - Provoked Eagle syndrome after dental procedure: A review of the literature. AB - Eagle syndrome is an uncommon condition caused by an elongated ossified styloid process. The majority of individuals with an elongated ossified styloid process are asymptomatic. Therefore, this condition is diagnosed based on clinical presentation, with radiologic imaging serving to confirm the diagnosis. The styloid process is considered elongated if measuring greater than 3 cm, but there is little correlation between length of the styloid process and severity of symptoms. This syndrome was originally described in post-tonsillectomy patients, but has since been seen in other clinical settings. We present a case of Eagle syndrome that became symptomatic after a dental procedure (wisdom teeth removal). A literature review performed with focus on various etiologies of Eagle syndrome diagnosis found a previously published case of Eagle syndrome presenting as pain of dental origin;1 however, no case reports of symptoms arising in a patient post dental procedure were found in our search. PMID- 28635383 TI - Rendering LGBTQ+ Visible in Nursing: Embodying the Philosophy of Caring Science. AB - Although health care institutions continue to address the importance of diversity initiatives, the standard(s) for treatment remain historically and institutionally grounded in a sociocultural privileging of heterosexuality. As a result, lesbian, gay, bisexual, transgender, and queer (LGBTQ+) communities in health care remain largely invisible. This marked invisibility serves as a call to action, a renaissance of thinking within redefined boundaries and limitations. We must therefore refocus our habits of attention on the wholeness of persons and the diversity of their storied experiences as embodied through contemporary society. By rethinking current understandings of LGBTQ+ identities through innovative representation(s) of the media, music industry, and pop culture within a caring science philosophy, nurses have a transformative opportunity to render LGBTQ+ visible and in turn render a transformative opportunity for themselves. PMID- 28635382 TI - White cell and platelet content affects the release of bioactive factors in different blood-derived scaffolds. AB - Platelet-derived factors are biomaterials that might accelerate healing process in oral, maxillofacial, and several other applications. Release of specific factors by platelet concentrates is critical to achieving a successful outcome. Here, we have shown that platelet-rich fibrin (PRF) clots were beneficial sources of leukocytes, which may directly affect the release of chemokines and growth factors. When compared with the standard leukocyte-PRF (L-PRF), the experimental low-force modified procedure [defined as advanced-PRF (A-PRF)] entrapped the same content of viable leukocytes, released a similar amount of inflammatory cytokines, but secreted 3-, 1.6-, 3-, and 1.2-fold higher levels of Eotaxin, CCL5, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), respectively. A leukocyte-free scaffold, such as plasma rich in growth factors (PRGF), released only platelet-specific factors and, in particular, the F3 fraction, the richest in growth factors, secreted higher amount of CCL5 and PDGF compared to F1 and F2 fractions. In conclusion, different procedures and leukocyte content affect cytokine, chemokines, and growth factor release from platelet derivatives, which may be helpful in different clinical settings. PMID- 28635384 TI - ? PMID- 28635385 TI - ? PMID- 28635386 TI - ? PMID- 28635387 TI - ? PMID- 28635388 TI - ? PMID- 28635389 TI - ? PMID- 28635390 TI - ? PMID- 28635391 TI - ? PMID- 28635392 TI - ? PMID- 28635393 TI - ? PMID- 28635394 TI - ? PMID- 28635395 TI - ? PMID- 28635396 TI - MicroRNA-34a inhibits tumor invasion and metastasis in osteosarcoma partly by effecting C-IAP2 and Bcl-2. AB - Osteosarcoma is a common primary malignant bone tumor that occurs mainly in children and adolescents. Recent evidence has demonstrated that miR-34a is involved in the invasion and metastasis of osteosarcoma. This study aims to explore the effect of biological behavior of miR-34a on osteosarcoma. First, we collect osteosarcoma and adjacent specimens, and the relative expression of miR 34a and C-IAP2 messenger RNA was quantitated by real-time polymerase chain reaction. Furthermore, miR-34a stimulant is synthesized and transfected onto osteosarcoma MG-63 cells. The effect of overexpression of miR-34a on osteosarcoma was detected by colony-forming assay, Annexin V-fluorescein isothiocyanate Apoptosis Detection Kit I, Transwell assay, and animal experiment in vivo. Finally, the relative levels of C-IAP2 and Bcl-2 protein were checked by western blot, and the activity of caspase-3 and caspase-9 was tested by spectrophotometry assay. In conclusion, miR-34a was downregulated in osteosarcoma cells. And the expression of C-IAP2 and Bcl-2 protein was drastically inhibited, and the activities of caspase-3 and caspase-9 were significantly increased after transfecting miR-34a onto osteosarcoma MG-63 cells. And the overexpression of miR 34a can inhibit cell invasion and metastasis, promote cell apoptosis, and arrest cells in G0/G1 period. And the animal experiment in vivo demonstrated that the overexpression of miR-34a could significantly inhibit the growth of osteosarcoma in animal skin. Taken together, we indicated that miR-34a can inhibit tumor invasion and metastasis in osteosarcoma, and its mechanism may be partly related to downregulating the expression of C-IAP2 and Bcl-2 protein directly or indirectly. PMID- 28635397 TI - Induction of apoptosis and autophagy by calcifying nanoparticles in human bladder cancer cells. AB - Calcifying nanoparticles have been linked to various types of human disease, but how they contribute to disease processes is unclear. Here, we examined whether and how calcifying nanoparticles isolated from patients with kidney stones are cytotoxic to human bladder cancer cells. Calcifying nanoparticles were isolated from midstream urine of patients with renal calcium oxalate stones and examined by electron microscopy. Human bladder cancer cells (EJ cells) were cultured in the presence of calcifying nanoparticles or nanohydroxyapatites for 12 and 72 h and examined for toxicity using the Cell Counting Kit-8, for autophagy using transmission electron microscopy and confocal microscopy, and for apoptosis using fluorescence microscopy, transmission electron microscopy, and flow cytometry. Changes in protein expression were analyzed by Western blotting. The results showed that the size and shape of the isolated calcifying nanoparticles were as expected. Calcifying nanoparticles were cytotoxic to EJ cells, more so than nanohydroxyapatites, and this was due, at least in part, to the production of intracellular reactive oxygen species. Transmission electron microscopy showed that calcifying nanoparticles were packaged into vesicles and autolysosomes. Calcifying nanoparticles induced greater autophagy and apoptosis than nanohydroxyapatites. Our findings demonstrate that calcifying nanoparticles can trigger bladder cancer cell injury by boosting reactive oxygen species production and stimulating autophagy and apoptosis. PMID- 28635398 TI - GPX2 overexpression indicates poor prognosis in patients with hepatocellular carcinoma. AB - Glutathione peroxidase 2 has important role of tumor progression in lots of carcinomas, yet little is known about the prognosis of glutathione peroxidase 2 in hepatocellular carcinoma. Glutathione peroxidase 2 expression was assessed by immunohistochemistry in hepatocellular carcinoma tissues. The association between glutathione peroxidase 2 expression with clinicopathological/prognostic value was examined. Glutathione peroxidase 2 overexpression was correlated with alpha fetoprotein level, larger tumor, BCLC stage, and tumor recurrence. Kaplan-Meier analysis showed that glutathione peroxidase 2 was an independent predictor for overall survival and time to recurrence. glutathione peroxidase 2 overexpression was correlated with poor prognosis in patient subgroups stratified by tumor size, differentiation, tumor-node-metastasis, and BCLC stage. Moreover, stratified analysis showed that tumor-node-metastasis stage-I patients with high glutathione peroxidase 2 expression had poor prognosis than those with low glutathione peroxidase 2 expression. Additionally, combination of glutathione peroxidase 2 and serum alpha-fetoprotein was correlated with prognosis in hepatocellular carcinoma. In conclusion, glutathione peroxidase 2 overexpression contributes to poor prognosis of hepatocellular carcinoma patients and helps to identify the high-risk hepatocellular carcinoma patients. PMID- 28635399 TI - Overexpression of long non-coding RNA MEG3 suppresses breast cancer cell proliferation, invasion, and angiogenesis through AKT pathway. AB - Long non-coding RNA MEG3 has been identified as a tumor suppressor which plays important roles in tumorigenesis; however, its potential role in breast cancer has not been fully examined. Here, we showed that MEG3 was downregulated in breast cancer tissues and cell lines. Overexpression of MEG3 inhibited breast cancer cell proliferation and invasion, suggesting that MEG3 played an important role in breast cancer progression and metastasis. Moreover, MEG3 upregulation caused marked inhibition of angiogenesis-related factor expression. Conditioned medium derived from MEG3 overexpressed breast cancer cells significantly decreased the capillary tube formation of endothelial cells. Furthermore, elevated expression of MEG3 in breast cancer inhibits in vivo tumorigenesis and angiogenesis in a nude mouse xenograft model. Mechanistically, overexpression of MEG3 results in downregulation of AKT signaling, which is pivotal for breast cancer cell growth, invasion, and tumor angiogenesis. Collectively, these results suggest that MEG3 might suppress the tumor growth and angiogenesis via AKT signaling pathway and MEG3 may serve as a potential novel diagnostic and therapeutic target of breast cancer. PMID- 28635400 TI - The long noncoding RNA FOXCUT promotes proliferation and migration by targeting FOXC1 in nasopharyngeal carcinoma. AB - Long noncoding RNAs play an important role in various biological processes, including tumorigenesis. FOXC1 (Forkhead box C1) is a member of the Forkhead box family of transcription factors and plays a crucial role in nasopharyngeal carcinoma. In this study, a novel long noncoding RNA (FOXCUT) located upstream of FOXC1 was investigated in 42 nasopharyngeal carcinoma patients. Our analysis revealed that the expression levels of FOXCUT and FOXC1 in nasopharyngeal carcinoma tissues were significantly higher than those observed in chronic nasopharyngitis tissues and that FOXCUT expression was positively correlated with FOXC1 expression. Additionally, knockdown of FOXCUT significantly inhibited proliferation and migration of nasopharyngeal carcinoma cell lines and resulted in downregulated expression of the matrix metalloproteinase 7 and matrix metalloproteinase 9, as well as vascular endothelial growth factor A and beta catenin. Our findings suggested that FOXCUT expression contributed to the development and progression of nasopharyngeal carcinoma by targeting FOXC1 and that FOXCUT might be useful as a potential nasopharyngeal carcinoma biomarker and therapeutic target. PMID- 28635401 TI - Inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer. AB - This study explored the mechanism underlying long non-coding RNA ROR regulating autophagy on Tamoxifen resistance in breast cancer. Cancer tissues and adjacent normal tissues were collected from 74 breast cancer patients. Human breast cancer BT474 cells were assigned into blank, phosphate buffered saline, Tamoxifen, negative control + Tamoxifen, siROR + Tamoxifen, 3-methyladenine + Tamoxifen, and siROR + 3-methyladenine + TA groups. The expression of long non-coding RNA ROR and expressions of multi-drug resistance-associated P-glycoprotein and glutathione S-transferase-pi messenger RNA were detected using quantitative real time polymerase chain reaction. The expressions of light chain 3, Beclin 1, multi drug resistance-associated P-glycoprotein, and glutathione S-transferase-pi protein were determined using western blotting. Cell proliferation, invasion, and migration abilities were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, Transwell assay, and scratch test, respectively. The long non-coding RNA ROR expression was higher in the breast cancer tissues than that in the adjacent normal tissues. Compared with the blank group, light chain 3 and Beclin 1 expressions were increased in the siROR + Tamoxifen group but decreased in the 3-methyladenine + Tamoxifen group; these data indicated that downregulated long non-coding RNA ROR promoted autophagy. In comparison with the blank group, multi-drug resistance-associated P-glycoprotein and glutathione S-transferase-pi messenger RNA and protein expressions were reduced in the siROR + Tamoxifen group but elevated in the 3-methyladenine + Tamoxifen group, suggesting that downregulated long non-coding RNA ROR suppressed the drug resistance to Tamoxifen and the inhibition of autophagy reversed the effect of long non-coding RNA ROR on drug resistance. Compared with the Tamoxifen, negative control, and siROR + 3-methyladenine + Tamoxifen groups, the cell proliferation, invasion, and migration in the siROR + Tamoxifen group were much decreased; these results implied that downregulated long non-coding RNA ROR suppressed BT474 cell proliferation, invasion, and migration and reversed the effect of Tamoxifen on the BT474 cells. These results indicate that inhibition of long non-coding RNA ROR reverses resistance to Tamoxifen by inducing autophagy in breast cancer. PMID- 28635402 TI - Analysing the vocal behaviour of teachers during classroom teaching using a portable voice accumulator. AB - PURPOSE: Teachers are at a considerable risk of developing vocal health problems due to intensive voice use during teaching. This study investigated factors related to the teacher's voice during a teaching situation. METHODS: Overall, 113 teachers were recorded during a typical class lesson, lasting on average 48 min. A portable voice dosimeter (VoxLog System) was used to measure the sound pressure level (SPL) of the noise in the classroom, the teacher's voice SPL, the fundamental frequency (fo) and the phonation time. General conditions of each lesson such as number of pupils, lesson subject and the educational level of the class were also collected. For the analysis, vocal loading doses and correlations between teacher's voice and noise SPL were calculated. RESULTS: Voice and noise SPL values varied across the lesson subjects, with highest levels measured in sports lessons. The mean noise SPL changed throughout a lesson with highest values at the beginning and at the end of the lessons. The correlation analysis of voice and noise SPL identified two groups of teachers with different vocal SPL behaviours. For some teachers, the voice SPL varied with the noise SPL. For others, voice SPL was constantly high. A regression model on the teacher's voice SPL yielded a strong correlation with fo, the classroom noise SPL, and the individual vocal SPL behaviour. CONCLUSIONS: Classroom noise SPL and individual vocal SPL behaviour were significantly associated with teachers' voice SPL during teaching. Addressing these factors could be important steps in reducing the vocal load in teachers. PMID- 28635403 TI - Psychomotor skills assessment by motion analysis in minimally invasive surgery on an animal organ. AB - BACKGROUND: A high level of psychomotor skills is required to perform minimally invasive surgery (MIS) safely. To be able to measure these skills is important in the assessment of surgeons, as it enables constructive feedback during training. The aim of this study was to test the validity of an objective and automatic assessment method using motion analysis during a laparoscopic procedure on an animal organ. MATERIAL AND METHODS: Experienced surgeons in laparoscopy (experts) and medical students (novices) performed a cholecystectomy on a porcine liver box model. The motions of the surgical tools were acquired and analyzed by 11 different motion-related metrics, i.e., a total of 19 metrics as eight of them were measured separately for each hand. We identified for which of the metrics the experts outperformed the novices. RESULTS: In total, two experts and 28 novices were included. The experts achieved significantly better results for 13 of the 19 instrument motion metrics. CONCLUSIONS: Expert performance is characterized by a low time to complete the cholecystectomy, high bimanual dexterity (instrument coordination), a limited amount of movement and low measurement of motion smoothness of the dissection instrument, and relatively high usage of the grasper to optimize tissue positioning for dissection. PMID- 28635404 TI - Safety and efficacy of HepaSphere 50-100 MUm in the treatment of hepatocellular carcinoma. AB - AIM: To evaluate the effects of HepaSphere 50-100 MUm (Merit Medical) as a doxorubicin carrier and embolization agent for the treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS: A prospective analysis of 18 patients recruited from a national cancer center was conducted. This analysis evaluated the efficacy and safety of HepaSphere, as expressed by the treatment response rate (measured by the modified Response Evaluation Criteria in Solid Tumors, mRECIST) and by the prevalence of treatment-related adverse events, respectively. RESULTS: The cohort was predominantly male, with a mean age of 69 years. The objective response rate (complete + partial response) was 53.3%. The variable most likely to be associated with objective response was Barcelona Clinic Liver Cancer (BCLC) staging. The most prevalent adverse events were nausea, vomiting and abdominal pain. CONCLUSION: HepaSphere chemoembolization yielded a substantial objective response rate with an acceptable toxicity profile and should be considered an option for HCC treatment. PMID- 28635406 TI - Concept design of robotic modules for needlescopic surgery. AB - BACKGROUND: Many minimally invasive surgical procedures and assisting robotic systems have been developed to further minimize the number and size of incisions in the body surface. This paper presents a new idea combining the advantages of modular robotic surgery, single incision laparoscopic surgery and needlescopic surgery. MATERIAL AND METHODS: In the proposed concept, modules carrying therapeutic or diagnostic tools are inserted in the abdominal cavity from the navel as in single incision laparoscopic surgery and assembled to 3-mm needle shafts penetrating the abdominal wall. RESULTS: A three degree-of-freedom robotic module measuring 16 mm in diameter and 51 mm in length was designed and prototyped. The performance of the three connected robotic modules was evaluated. CONCLUSION: A new idea of modular robotic surgery was proposed, and demonstrated by prototyping a 3-DOF robotic module. The performance of the connected robotic modules was evaluated, and the challenges and future work were summarized. PMID- 28635405 TI - Effects of microwave ablation on T-cell subsets and cytokines of patients with hepatocellular carcinoma. AB - OBJECTIVES: To investigate the effects of microwave ablation on T-lymphocyte subsets and cytokines in patients with hepatocellular carcinoma. MATERIAL AND METHODS: Peripheral blood was collected from 45 patients with hepatocellular carcinoma treated by microwave ablation before treatment, one week and one month after treatment. T cells (CD3+, CD4+ and CD8+ cells), CD4+ CD25+ Tregs, and CD16+ CD56+ NK cells were analyzed by flow cytometry. Levels of cytokines (IL-2, IFN gamma, TNF-alpha, IL-12, IL-4, IL-6, IL-8, and IL-10) were determined by a Luminex 200 analyzer. RESULTS: Compared with before treatment, CD3+ cells, CD4+ cells and IL-12 increased significantly at one month after the microwave ablation treatment, while IL-4, IL-10 decreased significantly. CONCLUSIONS: Microwave ablation could relieve the suppression of immune function caused by tumors, promote the deviation of Th2/Th1, and improve immune dysfunction in patients with hepatocellular carcinoma. PMID- 28635407 TI - Ovarian reserve after fibroid embolization in premenopausal women. AB - OBJECTIVE: To investigate the effect of uterine artery embolization (UAE) for fibroids on ovarian pool of premenopausal women. STUDY DESIGN: Prospective case control study. MATERIAL AND METHODS: One-hundred and twenty premenopausal women, aged between 40 and 50 years, who underwent UAE for symptomatic uterine fibroids and the same number of women, aged between 40 and 50 years, with symptomatic uterine fibroids, who were not offered treatment were recruited for this study. Hormonal status and ovarian reserve were evaluated by means of anti-Mullerian hormone (AMH) and follicle stimulating hormone (FSH) pre-procedural, three months, six months and 12 months after UAE. RESULTS: No statistically significant decrease was noted in AMH values 12 months post procedure and no statistical significant alterations in AMH values between the two groups. CONCLUSIONS: Even though the study results may not be able to confirm the preservation of ovarian reserve and normal menstruation after UAE in premenopausal women, it should be considered as a friendly to normal menstruation treatment option of symptomatic fibroids. PMID- 28635408 TI - Assisted reproductive technologies and the Iranian community attitude towards infertility. AB - Since the late 1990s, assisted reproductive technologies (ARTs) have been legitimized in Iran through an official religious endorsement. Iran, under the dominant authority of the Shia sect, is now the most enthusiastic adopter of ARTs in the Muslim world, permitting all forms of treatments, including third party donation. This study examined the public perception of assisted conception and its influence on the adoption of these methods in Iran. The study was questionnaire-based and conducted in 2012 in Shiraz, the most populated city in the south of Iran. It included 405 Iranian residents selected through the cluster sampling method. The results indicated that respondents did not support all types of assisted reproduction. Amongst modern infertility treatment methods, IVF (using husband's sperm and wife's egg) was the most widely accepted. Gestational surrogacy and the use of donated gametes were less accepted. Demographic variables including gender, marital status, age, education and employment status were linked to significant differences in public opinion. It was concluded that members of the public require better information about gamete donation and surrogacy, as this could shape infertile couples' decision-making. PMID- 28635409 TI - Confronting infertility in Iranian clients: a grounded theory. AB - The present study examined how infertile Iranian clients confront infertility. Research on infertility has confirmed the significance of a socio-cultural context in the formation of responses to infertility. This study used the grounded theory approach to explore the experiences of infertile individuals presenting at the Royan Institute in Iran from October 2013 to September 2014. Clients with infertility of at least two years in duration were recruited using purposive sampling followed by theoretical sampling. A total of 41 interviews were conducted with 36 people. Data were collected through in-depth unstructured interviews and field notes. Data analysis was performed using MAXQDA 2007. A sense of 'insecurity about personal and family identity' shaped in the context of 'facing the cultural-economic dilemmas' was identified as the main concern of infertile clients. The clients dealt with this concern through a series of strategies that included gradual acceptance of infertility, seeking information and consultation, pursuing treatment, focusing on saving the marriage, self control and resilience and fighting inner turmoil. All these approaches suggest 'protecting personal and family identity' as the core concept. The findings highlight the need for the health care system to treat infertility as a broad concept than mere individual and biological dysfunction. PMID- 28635410 TI - Pelvic floor dysfunction and polycystic ovary syndrome. AB - The purpose of this study was to compare the prevalence of pelvic floor dysfunction (PFD) symptoms in patients with and without polycystic ovary syndrome (PCOS) and among different PCOS phenotypes. This was a case-control study. All participants were assessed using ultrasonography to determine the presence or absence of polycystic ovaries (PCO) and allocated to the case or control group (having healthy females whose husbands were diagnosed with male infertility). The case group was then further subdivided into the three phenotypes according to the presence or absence of menstrual dysfunction (M), hyperandrogenism (HA) and PCO on ultrasonography. Pelvic floor dysfunction was assessed by the Pelvic Floor Distress Inventory-20 (PFDI-20). Briefly, the reported pelvic organ prolapse (POP) symptoms were higher in PCOS group (p = 0.05). The mean PFD score in the HA + M + PCO group was higher compared to other phenotypes although the difference did not reach significant level (p > 0.05). However, there was a significant positive correlation between luteinising hormone (LH) level and the POP symptom portion of the PFDI-20 (p < 0.05). The reported POP symptoms were higher in PCOS group especially in HA + M + PCO phenotype. The findings suggest that higher levels of LH might correlate to symptoms of POP. PMID- 28635411 TI - Single-nucleotide polymorphisms in the human RAD21L gene may be a genetic risk factor for Japanese patients with azoospermia caused by meiotic arrest and Sertoli cell-only syndrome. AB - Genetic mechanisms are implicated in some cases of male infertility. Recently, it was demonstrated that male mice lacking the gene for RAD21L exhibited azoospermia caused by meiotic arrest. Mouse RAD21L is a functionally relevant meiotic alpha kleisin that is essential for male fertility. Therefore, we hypothesized that RAD21L mutations or polymorphisms may be associated with male infertility, especially azoospermia secondary to meiotic arrest. To determine if RAD21L defects are associated with azoospermia in groups of patients with meiotic arrest, we performed direct sequencing of the RAD21L coding regions in 38 Japanese patients with meiotic arrest and in 200 normal controls. Three coding single-nucleotide polymorphisms (SNP1-SNP3) were detected in the meiotic arrest patient group. Sertoli cell-only syndrome is considered a common cause of non obstructive azoospermia. For comparison, the RAD21L coding regions in which SNP1 SNP3 were detected were sequenced in 140 patients with Sertoli cell-only syndrome. Statistical analyses were used to compare the two groups of patients with the control group. Genotype and allele frequencies of SNP2 and SNP3 were notably higher in the two patient groups compared with the control group (Bonferroni adjusted p value <0.016). These results suggest a critical role for RAD21L in human spermatogenesis. PMID- 28635412 TI - Gamete donors' reasons for, and expectations and experiences of, registration with a voluntary donor linking register. AB - This paper reports on a study of the views and experiences of 21 sperm donors and five egg donors registered with UK DonorLink (UKDL), a voluntary DNA-based contact register established to facilitate contact between adults who wish to identify and locate others to whom they are genetically related following donor conception. Specifically, the paper examines donors' reasons for searching for, or making information about themselves available to donor-conceived offspring. Their expectations of registration with UKDL, experiences of being registered and finally, the experiences of those who had contacted donor-conceived offspring and other genetic relatives are investigated. While most respondents reported largely positive experiences of registration, the study found significant issues relating to concerns about donation, DNA testing, possible linking with offspring and expectations of any relationship that might be established with offspring that have implications for support, mediation and counselling. Research that puts the experiences, perceptions and interests of gamete donors as the central focus of study is a relatively recent phenomenon. This study contributes to this debate and highlights directions for future research in this area. PMID- 28635413 TI - The high responder: a review of pathophysiology and outcomes during IVF treatment. AB - This review attempts to summarize the known literature on high responders to ovarian stimulation during assisted reproductive techniques (ART). Response to gonadotrophins is subject to significant interindividual and intercycle variation, thus carrying a risk of high response or poor response to ovarian stimulation regimens. The main risk for high responders is the development of ovarian hyperstimulation syndrome (OHSS) which is associated with significant morbidity. Hence, the definition of high responders in the literature has primarily focussed on risk factors for OHSS. Strategies to reduce OHSS including tailoring of the ovarian stimulation regimens and adjusting gonadotrophin doses according to patient characteristics and findings during the cycle of stimulation. In addition, modifying the type of ovulation trigger used and adjuvant therapies, such as metformin, intravenous colloids and vascular endothelial growth factor blockers, have also been studied as options to reduce OHSS. Apart from the risk of OHSS, high response also appears to have an adverse impact on the oocyte and endometrium, though there is a paucity of data regarding the extent and mechanisms behind this impact. PMID- 28635414 TI - Core-shell PLA-PVA porous microparticles as carriers for bacteriocin nisin. AB - This work is focused on preparation of novel porous type of core-shell-structured microparticles based on polylactide (shell) and poly(vinyl alcohol) cross-linked with glutaric acid (GA) (core) prepared by water-in-oil-in-water solvent evaporation technique. The microparticle systems were used as delivery systems for immobilisation of model antibacterial agent - nisin. The effect of cross linking and the initial amount of nisin on their morphology was investigated using scanning electron microscopy, BET analysis, zeta potential measurement and Fourier transform infra-red spectroscopy. Encapsulation efficiency and release profile of nisin from the microparticles were studied by high performance liquid chromatography. Antibacterial activity of the prepared systems was tested by dilution and spread plate technique. Results showed the microparticles in the size range of 9-16 MUm in diameter with spherical multi-hollow core-shell structure. The presence of cross-linking agent GA influences the release profile of the peptide and has synergistic effect on Listeria monocytogenes growth reduction. PMID- 28635416 TI - Arsenic and fluoride co-contamination in shallow aquifers from agricultural suburbs and an industrial area of Punjab, Pakistan: Spatial trends, sources and human health implications. AB - Release of arsenic (As) and fluoride (F-) species into groundwater is a serious health concern around the world. The present study was the first systematic baseline study conducted in Rahim Yar Khan district, Punjab, focusing on As and F contamination in groundwater. A total of 51 representative groundwater samples comprising of 44 samples from agricultural suburbs and 7 from an industrial base were analysed. Statistical parameters, principal component analysis-multiple linear regression (PCA-MLR) and health risk assessment model were used to investigate the hydro geochemistry, spatial patterns, interrelation, source contribution and associated health risks of high As and F- in groundwater of the study area. Results showed high risk of F- exposure to people of the study area, with all samples exceeding the WHO standard of 1.5 mg/L, and for As, 32.5% of the studied groundwater samples exceeded the WHO standard (10 ug/L). The maximum As (107.23 ug/L) and F- (26.4 mg/L) levels were observed in samples close to the agricultural and smelting areas, implicating the frequent use of fertilizers and influence of industrial effluents in the study area. The PCA-MLR receptor model quantitatively illustrates that the majority of As and F- comes from natural sources, while, among anthropogenic sources, industrial and agricultural activities contributed the most. Health risk assessment revealed a high risk of As and F- contamination to the exposed population; therefore, detailed control strategies and policies are required in order to mitigate the health risks. PMID- 28635417 TI - Suicide Attempts Among Individuals With Specific Learning Disorders: An Underrecognized Issue. AB - Several studies have linked specific learning disorders (SLDs) with suicidal ideation, but less is known about the disorders' association with suicide attempts. This gap in the literature is addressed via the 2012 nationally representative Canadian Community Health Survey ( n = 21,744). The prevalence of lifetime suicide attempts among those with an SLD was much higher than those without (11.1% vs. 2.7%, p < .001). In comparison with their peers without SLDs, adults with SLDs had 46% higher odds of having ever attempted suicide, even after adjusting for most known risk factors (e.g., childhood adversities, history of mental illness and substance abuse, sociodemographics; odds ratio = 1.46, 95% CI [1.05, 2.04]). The largest attenuation in the association between SLD and suicidal attempts was accounted for by adverse childhood experiences. Among those with SLDs ( n = 745), a history of witnessing chronic parental domestic violence and ever having had a major depressive disorder were associated with substantially higher odds of suicide attempts. PMID- 28635415 TI - Known and unknown cerebral arteriovenous malformations in pregnancies: haemorrhage risk and influence on obstetric management. AB - Objective The objective of this study was to evaluate the haemorrhage risk of known and unknown cerebral arteriovenous malformations and their obstetric management. Methods A retrospective review was performed and analysed 67 consecutive cases of arteriovenous malformation with pregnancy history. Results Sixty-seven cases of arteriovenous malformation with pregnancy histories were identified. In 14 cases (20.9%) of arteriovenous malformation diagnosed before pregnancy, 11 cases were treated (10 embolisation and one surgery), there was no haemorrhage in 14 pregnancies, 14 healthy babies were delivered by caesarean section in 12 pregnancies (85.7%) and vaginal delivery in two pregnancies (14.3%). In 53 cases (89.1%) of arteriovenous malformation diagnosed during/after pregnancy, there was one (1.6%) case of subarachnoid haemorrhage at 38 weeks' gestation in 64 pregnancies, 64 healthy babies were delivered by caesarean section in 11 pregnancies (17.2%) and vaginal delivery in 53 pregnancies (82.8%). This resulted in 1.6% (95% confidence interval 0-4.6%) haemorrhage rate per pregnancy in unknown arteriovenous malformations. Known arteriovenous malformation gravida was prone to caesarean section; however, vaginal delivery did not increase the haemorrhage risk in unknown arteriovenous malformation gravidas (1.8% vs. 0%, P = 1.000). Conclusion Prior treatment for ruptured arteriovenous malformation could prevent its haemorrhage during pregnancy and the haemorrhage risk of unruptured arteriovenous malformation in pregnancies is low. Although known arteriovenous malformation gravida is prone to caesarean section, vaginal delivery seems not to increase the haemorrhage risk in unknown arteriovenous malformation gravidas. PMID- 28635418 TI - Infantile Spasms and Injuries of Prematurity: Short-Term Treatment-Based Response and Long-Term Outcomes. AB - The association of infantile spasms and periventricular leukomalacia and/or intraventricular hemorrhage is well documented. Data regarding early treatment based and long-term outcomes are limited. A retrospective chart review identified children with infantile spasms born prematurely (<37 weeks) with diagnoses of periventricular leukomalacia and/or intraventricular hemorrhage. Thirteen children were included. Median gestational age was 30 weeks and age of onset of infantile spasms was 8 months. Nine children had intraventricular hemorrhage, 10 had periventricular leukomalacia, and 6 children had both. Twelve of 13 children had resolution of spasms. In responders, the successful medication was adrenocorticotropic hormone (ACTH) in 7, topiramate in 3, and vigabatrin in 2. Follow-up after a median of 7.1 years found that all patients had developmental delay but only 1 had refractory epilepsy. Standard therapies (ACTH and vigabatrin) appeared to be more effective than other treatments. Developmental delay is common in children with periventricular leukomalacia / intraventricular hemorrhage and infantile spasms, but refractory epilepsy might be less frequent. PMID- 28635419 TI - Multimodal imaging Gd-nanoparticles functionalized with Pittsburgh compound B or a nanobody for amyloid plaques targeting. AB - AIM: Gadolinium-based nanoparticles were functionalized with either the Pittsburgh compound B or a nanobody (B10AP) in order to create multimodal tools for an early diagnosis of amyloidoses. MATERIALS & METHODS: The ability of the functionalized nanoparticles to target amyloid fibrils made of beta-amyloid peptide, amylin or Val30Met-mutated transthyretin formed in vitro or from pathological tissues was investigated by a range of spectroscopic and biophysics techniques including fluorescence microscopy. RESULTS: Nanoparticles functionalized by both probes efficiently interacted with the three types of amyloid fibrils, with KD values in 10 micromolar and 10 nanomolar range for, respectively, Pittsburgh compound B and B10AP nanoparticles. Moreover, they allowed the detection of amyloid deposits on pathological tissues. CONCLUSION: Such functionalized nanoparticles could represent promising flexible and multimodal imaging tools for the early diagnostic of amyloid diseases, in other words, Alzheimer's disease, Type 2 diabetes mellitus and the familial amyloidotic polyneuropathy. PMID- 28635420 TI - The Most Common Comorbidities in Dandy-Walker Syndrome Patients: A Systematic Review of Case Reports. AB - OBJECTIVE: Dandy-Walker syndrome (DWS) is a rare neurologic multi-entity malformation. This review aimed at reporting its main nonneurologic comorbidities. METHODS: Following PRISMA guidelines, search in Medline was conducted (2000-2014, keyword: dandy-walker). Age, sex, country, DWS type, consanguinity or siblings with DWS, and recorded coexistent conditions (by ICD10 category) were extracted for 187 patients (46.5% male, 43% from Asia) from 168 case reports. RESULTS: Diagnosis was most often set in <1 year old (40.6%) or >12 years old (27.8%). One-third of cases had a chromosomal abnormality or syndrome (n = 8 PHACE), 27% had a cardiovascular condition (n = 7 Patent Ductus Arteriosus), 24% had a disease of eye and ear (n = 9 cataract); most common malignancy was nephroblastoma (n = 8, all Asian). Almost one-fifth had a mental illness diagnosis; only 6.4% had mild or severe intellectual disability. CONCLUSION: The spread of comorbidities calls for early diagnosis and multidisciplinary research and practice, especially as many cases remain clinically asymptomatic for years. PMID- 28635421 TI - Seeing the diagnosis on karyotype-SOX2 and eye development. PMID- 28635422 TI - Metallothionein polymorphisms in a Northern Spanish population with neovascular and dry forms of age-related macular degeneration. AB - BACKGROUND: To elucidate the potential role of single nucleotide polymorphisms (SNPs) in the metallothionein (MT) genes in Northern Spanish patients with age related macular degeneration (AMD). METHODS: A total of 130 unrelated Northern Spanish natives diagnosed with AMD (46 dry, 35 neovascular, and 49 mixed) and 96 healthy controls, matched by age and ethnicity, were enrolled in a case-control study. DNA was isolated from peripheral blood and genotyped for 14 SNPs located at 5 MT genes (MT1A: rs11076161, rs 11640851, rs8052394, and rs7196890; MT1B: rs8052334, rs964372, and rs7191779; MT1M: rs2270836 and rs9936741; MT2A: rs28366003, rs1610216, rs10636, and rs1580833; MT3: rs45570941) using TaqMan probes. The association study was performed using the HaploView 4.0 software. RESULTS: The allelic and genotypic frequencies analysis revealed that rs28366003 at MT2A gene is significantly associated with dry AMD. The frequency of genotype AG was significantly higher in dry AMD than in control cases (p = 2.65 * 10-4; AG vs. AA) conferring more than ninefold increased risk to dry AMD (OR = 9.39, 95% CI: 2.11-41.72), whereas the genotype AA confers disease protection (OR = 0.82, 95% CI: 0.71-0.95). No statistically significant differences were observed between AMD subjects and controls in the rest of the 14 SNPs analyzed. CONCLUSIONS: The present study is the first to investigate the potential association of SNPs at MT genes with susceptibility to AMD. We found a significant association of SNP rs28366003 at MT2A gene with susceptibility to the dry form of AMD in a Northern Spanish population. PMID- 28635423 TI - Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1. AB - BACKGROUND: Mutations in the BRCA1-associated protein required for the ataxia telangiectasia mutated (ATM) activation-1 (BRAT1) gene cause lethal neonatal rigidity and multifocal seizure syndrome characterized by rigidity and intractable seizures and a milder phenotype with intellectual disability, seizures, nonprogressive cerebellar ataxia or dyspraxia, and cerebellar atrophy. To date, nystagmus, cortical visual impairment, impairment of central vision, optic nerve hypoplasia, and optic atrophy have been described in this condition. This article describes the retinal findings in a patient with biallelic deleterious sequence variants in BRAT1. MATERIALS AND METHODS: Case report of a child with biallelic sequence variants in the BRAT1 gene. RESULTS: This patient had developmental delay, microcephaly, nystagmus, and esotropia, and full-field electroretinography (ERG) revealed an inner retinal dystrophy. She was found on exome sequencing to have compound heterozygous sequence variants in the BRAT1 gene: one maternally inherited frameshift variant (c.294dupA, predicting p.Leu99Thrfs*92), which has previously been reported, and one paternally inherited novel missense variant (c.803G>A, p.Arg268His), which is likely to affect protein function. CONCLUSIONS: Biallelic sequence variants in BRAT1 have been reported to cause a variety of ocular and systemic manifestations, but to our knowledge, this is the first report of inner retinal dysfunction manifest as selective loss of full-field ERG scotopic and photopic b-wave amplitudes. PMID- 28635426 TI - Shared learning in an interconnected world: the role of international health partnerships. PMID- 28635424 TI - Genome-wide linkage and haplotype sharing analysis implicates the MCDR3 locus as a candidate region for a developmental macular disorder in association with digit abnormalities. AB - BACKGROUND: Developmental macular disorders are a heterogeneous group of rare retinal conditions that can cause significant visual impairment from childhood. Among these disorders, autosomal dominant North Carolina macular dystrophy (NCMD) has been mapped to 6q16 (MCDR1) with recent support for a non-coding disease mechanism of PRDM13. A second locus on 5p15-5p13 (MCDR3) has been implicated in a similar phenotype, but the disease-causing mechanism still remains unknown. METHODS: Two families affected by a dominant developmental macular disorder that closely resembles NCMD in association with digit abnormalities were included in the study. Family members with available DNA were genotyped using the Affymetrix GeneChip Human Mapping 250K Sty array. A parametric multipoint linkage analysis assuming a fully penetrant dominant model was performed using MERLIN. Haplotype sharing analysis was carried out using the non-parametric Homozygosity Haplotype method. Whole-exome sequencing was conducted on selected affected individuals. RESULTS: Linkage analysis excluded MCDR1 from the candidate regions (LOD < -2). There was suggestive linkage (LOD = 2.7) at two loci, including 9p24.1 and 5p15.32 that overlapped with MCDR3. The haplotype sharing analysis in one of the families revealed a 5 cM shared IBD segment at 5p15.32 (p value = 0.004). Whole exome sequencing did not provide conclusive evidence for disease-causing alleles. CONCLUSIONS: These findings do not exclude that this phenotype may be allelic with NCMD MCDR3 at 5p15 and leave the possibility of a non-coding disease mechanism, in keeping with recent findings on 6q16. Further studies, including whole-genome sequencing, may help elucidate the underlying genetic cause of this phenotype and shed light on macular development and function. PMID- 28635425 TI - Multimodal imaging in CABP4-related retinopathy. AB - PURPOSE: Multimodal imaging has not been documented for CABP4-related retinopathy. In this study, we describe optical coherence tomography (OCT) and fundus autofluorescence findings for five genetically confirmed cases. METHODS: Retrospective case series. RESULTS: Four patients with the previously described homozygous Saudi CABP4 founder mutation c.81_82insA (p.Pro28ThrfsX44) and one patient with the homozygous mutation c.1A>G (p.Met1?) in CABP4 were examined. The ages ranged between 9 and 16 years at last follow-up, and the duration of follow up ranged from 2 to 12 years. Foveal thickness was reduced ranging between 175 and 212 micrometers. Wide field imaging including fundus autofluorescence was unremarkable. All patients presented with a negative electroretinogram, with a variable amount of cone and rod dysfunction. Over follow-up, there was no electroretinographic indication of any progressive retinal dysfunction. CONCLUSIONS: Foveal thinning is a feature of CABP4 retinopathy. Normal autofluorescence is consistent with inner retinal dysfunction and suggests the condition could be amenable to gene therapy. Retinal dysfunction was stable throughout follow-up. PMID- 28635431 TI - Independent mental health advocacy: the right to be heard - context, values and good practice. PMID- 28635427 TI - The divergence of minimum unit pricing policy across the UK: opportunities for public health policy development. PMID- 28635432 TI - Psychological resilience in people experiencing schizophrenia and suicidal thoughts and behaviours. AB - BACKGROUND: Negative stressors can aggravate the impact of schizophrenia. However, some people find ways of combating such stressors. There is a dearth of research examining factors which enable individuals with schizophrenia to show psychological resilience. AIMS: The goal of this study was to investigate resilience to negative stressors in people with disorders on the schizophrenia spectrum using a qualitative methodology. METHODS: Data were collected from 23 participants who had experienced schizophrenia and suicidal thoughts and behaviours. Semi-structured interviews followed a topic guide. Participants were asked (i) what resilience meant to them, (ii) which stressors they had experienced over 12 months and (iii) how they had counteracted those stressors. Thematic analysis was conducted to identify re-occurring themes across interviews. RESULTS: A continuum of psychological mechanisms described participants' views about the meaning of resilience which ranged from passive acceptance to resistance (e.g. withstanding pressure), and then to active strategies to counter stressors (e.g. confronting). These themes were also evident in narratives expressing personal resilience strategies but, additionally, included emotional coping techniques. External factors were highlighted that supported resilience including social support, reciprocity and religious coping. CONCLUSIONS: People with schizophrenia develop ways of being resilient to negative events which should inform therapeutic interventions. PMID- 28635434 TI - Mental health professionals and media professionals: a survey of attitudes towards one another. AB - BACKGROUND: The general public regard mass media as their main source of information about mental illness. Psychiatrists are reluctant to engage with the media. There is little understanding of why this is the case. AIMS: The paper looks to explore attitudes of mental health clinicians and the media towards one another. METHOD: Media and mental health clinicians in the southwest of England completed self-report surveys. RESULTS: Of 119 questionnaires returned 85 were mental health clinicians and 34 media professionals. Both groups agreed that stigma is a major issue and clinicians have a key role influencing media portrayal of mental illness. The media view their reporting to be more balanced than clinicians and lack awareness of clinician mistrust towards them. Those clinicians with media training (13%) felt significantly more comfortable talking to media and significantly less mistrustful of them. Clinicians who had experience of working with media felt more comfortable doing media work. Only 15% of media professionals had received mental health awareness training. CONCLUSIONS: Media training and experience are associated with an increased willingness of mental health professionals to engage with the media. Reciprocal awareness training between media and mental health professionals may be a simple intervention worth pursuing. PMID- 28635435 TI - GPs' views and perspectives on patient non-adherence to treatment in primary care prior to suicide. AB - BACKGROUND: Individuals who do not adhere to their treatment regimens may be at greater risk of suicide but these issues are relatively unexplored in primary care services. AIM: To explore GPs' views and perspectives on the reasons why patients who were in contact with mental health services in the year prior to suicide was non-adherent to treatment prior to their death. METHOD: In total, 198 semi-structured face-to-face interviews with GPs of people who had died by suicide. Interviews were transcribed verbatim and analyzed using a thematic approach. RESULTS: The following themes were conceptualized from GP interviews: (i) "Lack of insight or denial?" relates to what GPs perceived as their patients lack of insight into their psychiatric illness; (ii) "Lack of treatment choices" discusses GPs' understanding of patient treatment choices; (iii) "Services for comorbidity and dual diagnosis" refers to treatment availability for suicidal patients with two or more mental health diagnoses. CONCLUSIONS: For suicide prevention, it is crucial for health professionals to assess patients and manage the possible causes of non-adherence. Policies for increasing treatment adherence, improving services for dual diagnosis, or providing alternative treatments to meet individual patient needs may help to achieve the best health outcomes and could potentially prevent suicide. PMID- 28635436 TI - Changes in the nature and intensity of stress following employment among people with severe mental illness receiving individual placement and support services: an exploratory qualitative study. AB - BACKGROUND: Most people with severe mental illness (SMI) want to work. Individual placement and support (IPS) programs have proven effective in helping them obtain and keep competitive jobs. Yet, practitioners often fear that competitive jobs might be too stressful. AIMS: To explore how the nature and intensity of stress experienced by IPS clients changed after the transition from looking for work to being employed. METHODS: Semi-structured interviews explored the experiences of 16 clients of an IPS program who had recently been competitively employed. Grounded theory was used to structure the analysis. RESULTS: Most participants reported that their stress level decreased once they found work. Stress following work was associated with fear of failure, pressure to perform and uncertainty. The support that people perceived in their return-to-work project, and where they were on their recovery journey, modulated their perception of stress. Many cited IPS as a source of support. CONCLUSIONS: Competitive work changed the nature of stress and was mostly associated with a decrease in stress level. Adjunctive interventions aiming to buffer self-stigma or help participants use more adaptive coping mechanisms may merit investigation. PMID- 28635437 TI - Assessment of diagnostic information and quality of working alliance with clients diagnosed with personality disorders during the mental health intake. AB - BACKGROUND: A primary purpose of diagnostic systems is to improve care, yet, little is known about how providers use it routine clinical care. AIMS: We investigated specific DSM-IV personality disorders (PDs) diagnostic information therapists collected during intake visits and the association between a therapist PD diagnosis and clients' and therapists' reports of the quality of working alliance during the intake. METHOD: A total of 122 intakes (n = 34, 27.9% were diagnosed with PD) in four community mental health clinics in Israel were audiotaped. Immediately following the intake, clients and therapists completed the working alliance inventory (WAI). Independent clinicians coded the intakes using an information checklist. RESULTS: Despite the relatively high prevalence of PD in regular psychiatric care, very limited PD diagnostic information was directly assessed during the intake. Therapists evaluated the quality of the working alliance when they saw a client they diagnosed with PD as significantly lower than the rating of a client without a PD, while the clients' ratings did not differ as a result of their diagnosis. CONCLUSIONS: Therapists do not collect sufficient explicit diagnostic information to base their PD diagnostic decisions. Yet, the presence of PD diagnosis affects their rapport with their clients as early as the intake. PMID- 28635438 TI - Resilience mediated the association between acculturation and psychological growth in college students from Hong Kong to Guangzhou, China. AB - BACKGROUND: The number of Hong Kong citizens living in mainland China is increasing. The process of acculturation may create opportunities for psychological growth. AIMS: This study aimed at examining whether resilience mediated the effects of acculturation on psychological growth in college students from Hong Kong to Guangzhou. METHOD: In this cross-sectional survey, 164 college students in Guangzhou who were Hong Kong permanent residents (female: 46%, age: 21.09 +/- 1.50) joined the study. RESULTS: The integration group reported more psychological growth than the assimilation, separation, and marginalization groups. Resilience partially mediated the effect of integration on psychological growth and fully mediated the effect of marginalization on psychological growth. CONCLUSIONS: Resilience represents one of the mechanisms to explain beneficial effects of integration on psychological growth in college students from Hong Kong to Guangzhou. Theoretical considerations to rethink the acculturation model, implications for developing intervention programs, and recommendations for future research are discussed. PMID- 28635439 TI - Social and occupational factors associated with psychological wellbeing among occupational groups affected by disaster: a systematic review. AB - BACKGROUND: The psychological impact of disasters has been well-documented; less attention has been paid to factors affecting the wellbeing of those exposed to disasters as occupational groups. AIMS: To conduct a systematic literature review identifying social and occupational factors affecting the wellbeing of disaster exposed employees; to use these factors to identify recommendations for potential interventions. METHOD: Four electronic literature databases were searched; reference lists of relevant papers were hand-searched. RESULTS: A total of 18 005 papers were found, 571 full texts were read and 36 included in the review. The psychological impact of disasters on employees was associated with pre-disaster factors (experience/training; income; life events/health; job satisfaction), peri disaster factors (exposure; peri-traumatic experiences; perceptions of safety; injury), social factors (organisational support; social support generally) and post-disaster factors (impact on life). CONCLUSIONS: It is important to build a resilient workforce outside of a crisis. Pre-disaster training in recognising signs of distress, understanding vulnerability factors such as those described above, which may put certain employees at greater risk of distress and how to support colleagues may be useful. Further research into the effectiveness of post disaster interventions is needed. PMID- 28635440 TI - Adding an accredited exercise physiologist role to a new model of care at a secure extended care mental health service: a qualitative study. AB - BACKGROUND: Accredited exercise physiologists (AEPs) are emerging as essential members of allied health in the management of non-communicable chronic diseases. People diagnosed with severe mental illness (SMI) are at greater risk of cardiovascular diseases. Secure extended care units (SECUs) provide treatment, supervision and support for people with SMI whose needs cannot be met adequately in the community. However, the role of AEPs in SECUs has not been described. AIM: Describe the processes and outcomes of adding an AEP to a new model of care at a SECU. METHODS: An exploratory study with emphasis on qualitative data. Interviews with a purposive sample of SECU staff. RESULTS: Participants articulated concern about poor physical health of which two themes emerged (1) the development of the AEP role; a calculated gamble and (2) the practical application of the role. CONCLUSIONS: An AEP was identified as the role to best implement the organisations vision to improve physical health of people with SMI. Implementation and practical application of the role relied on an informed calculated gamble. Yet, once embedded in the service, the AEP role was able to capacity build among clinical staff, develop a treatment pathway, and implement consumer specific physical health interventions. PMID- 28635444 TI - Older people less likely to receive talking therapy for mental health. AB - Too few older people are being referred for talking therapies for common mental health conditions, a study has found. PMID- 28635443 TI - Corrigendum. PMID- 28635441 TI - The extension of a set of needs-led mental health clusters to accommodate people accessing UK intellectual disability health services. AB - BACKGROUND: A development of a needs-led mental health classification system based on the Health of the National Outcome Scales (HoNOS) has previously been developed. AIMS: To extend the needs-based mental health (MH) clusters to accommodate the additional needs of people accessing UK intellectual disabilities health services. METHOD: Hierarchical cluster analysis was performed on assessment data from 18 National Health Service (NHS) provider organisations. The statistical results were clinically shaped through multi-disciplinary workshops. The resulting clusters were combined with six independently rated measures for a second data collection exercise. Based on these data, refinements were made before performing internal and external validity checks. RESULTS: Eight additional clusters for people with health needs associated with their intellectual disabilities were produced. Three described primarily physical health (PH) needs, four described needs arising from behaviours which challenged (with/without autism) whilst one described people with generally low needs. Together, these covered 83.4% of cases with only a 10% overlap. The clusters were replicable and had clinical utility and validity. CONCLUSIONS: It was possible to extend the needs-led mental health classification system to capture the additional needs of people accessing UK intellectual disability services. PMID- 28635445 TI - 'My diabetes nurse has always gone beyond the call of duty'. AB - Three years ago I nearly died from complications related to diabetes, but specialist nurse Kathy Taylor, pictured, and her excellent team helped to save my life. PMID- 28635446 TI - Child deaths from diarrhoea down but stay highest in poorest nations. AB - The number of child deaths caused by diarrhoea globally has fallen by a third in ten years, research shows. PMID- 28635447 TI - 'Your core nursing skills are vital'. AB - After taking up a nursing career in his thirties, Major Rob Instrell qualified in Southampton in 2002. He worked mainly in emergency care, and is now lead practitioner in critical care outreach at Blackpool Teaching Hospitals NHS Foundation Trust. In his military career, he has served as a troop commander and as the unit adjutant for 335 Medical Evacuation, and has been the regiment's clinical lead for the past four years. PMID- 28635448 TI - Let's talk about your weight.... AB - A significant proportion of nurses in the UK are overweight or obese and the problem is, in every sense, a growing one. PMID- 28635449 TI - Nursing care after death in Northern Ireland. AB - Essential facts According to the Registrar General Annual Report, there were 15,548 deaths in Northern Ireland in 2015. Almost two thirds of these were of people aged 75 or over, and almost half occurred in NHS hospitals, with a further 20% in other hospitals or nursing homes. There are significant differences between what happens after death in Northern Ireland and in other UK countries. For example, in Northern Ireland it is common practice to hold a wake, where family and friends come together to view the deceased person in their home. There is also an expectation that funerals can be arranged within three or four days of death. PMID- 28635450 TI - You don't have to know the answers to write poetry. AB - It's a great pleasure to be able to spend the next six months as the RCN's first ever writer in residence. My role is part of an exciting new project at the RCN Library and Archive called Service Scrapbooks: Nursing, Storytelling and the First World War, which is funded by a L60,600 grant from the Heritage Lottery Fund. PMID- 28635451 TI - Delivering person-centred care in police custody. AB - The custody nurse role was introduced in 2003 following changes to legislation, which allowed nurses and paramedics to care for people in police custody. Before this, the work was done solely by doctors. PMID- 28635452 TI - Reflective practice. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article focused on reflection, which is an essential tool for nurses that can be used in their personal and professional development, while reinforcing continuous learning. PMID- 28635455 TI - Chemicals in cigarette smoke shown to damage foetal liver cells. AB - Chemicals in cigarette smoke constitute a risk to the foetus if the mother smokes during pregnancy, and can damage foetal liver cells, a study has shown. PMID- 28635456 TI - Nurses tell of horrific scenes as they helped those injured in London tower block fire. AB - Two nurses have told of their struggle to care for patients following a huge tower block fire in London. PMID- 28635457 TI - The perils of making snap judgements. AB - Trust is one of the foundations of nursing. Whether it is with colleagues or the people you nurse, your ability to form trusting relationships can affect significantly the quality of care someone receives. PMID- 28635458 TI - Mature fall-out will be costly. AB - I was disappointed to read that about 6,000 fewer mature students have applied to start nursing courses this autumn (analysis, June 7). PMID- 28635459 TI - Pay must be overhauled, says re-elected nurse MP. AB - Nurses should be able to expect the same pay for doing the same job wherever they work, a re-elected nurse MP has said. PMID- 28635460 TI - Changing the agenda. AB - Conservative MP Maria Caulfield raises concerns about nurses' pay but claims it's not about total money in the system but 'what's being done with it'. PMID- 28635461 TI - Cut fossil fuel links and curb burden on the NHS. AB - At a time when the NHS is struggling to meet demand, it is easy to regard the health impact of climate change as less urgent than the immediate needs of patients. However, action now to limit the effects of climate change would also reduce demands on the health service and help us to meet the healthcare needs of future generations. PMID- 28635463 TI - An overview of the evidence-based practice process for novice researchers. AB - This article explores how nurses can use evidence-based practice to critique and evaluate the rationale and evidence for specific nursing procedures or practices. Through the development of a focused research question and search strategy, nurses can select and critique relevant research articles to answer the research question, which can support the provision of optimal practice and high-quality care. This article demonstrates the process of evidence-based practice, with the aim of increasing novice researchers' confidence in applying this process in practice. The article evaluates the rationale for the use of an early-warning score system in the identification of patients at risk of deterioration, in particular the identification of sepsis and septic shock in the emergency setting. In this article, one research article will be selected and critiqued; however, in practice several appropriate articles should be reviewed to draw firm conclusions. Some of the barriers to the implementation of evidence-based practice and the dissemination of research will be discussed. PMID- 28635464 TI - Cancer survival rates higher when travelling further to a GP. AB - Patients in rural areas and those in urban areas who have to travel further to see a GP have better cancer survival rates, research has found. PMID- 28635465 TI - One in three patients with hypertension shun medication. AB - One in three patients with high blood pressure are failing to take the medication they are given to control it, research suggests. PMID- 28635466 TI - A profession to be proud of. AB - We have to admire the responses of individuals and organisations to the Grenfell Tower fire and the recent terrorist attacks, where major incident plans were activated. Our colleagues, nurses and the wider healthcare teams showed heroism, expertise, compassion and commitment. PMID- 28635467 TI - Health secretary to meet with RCN over nurse pay. AB - Health secretary Jeremy Hunt will meet with the RCN to talk about nurses' pay, health leaders at the NHS Confederation conference heard last week. PMID- 28635469 TI - Brexit alliance will be 'voice of healthcare'. AB - An alliance has been set up to put healthcare at the heart of Brexit negotiations. PMID- 28635468 TI - A smile to help in the tough times. AB - At the start of my second year of training I was working on a cardiac ward where I helped to care for a young teenager who was awaiting surgery. PMID- 28635471 TI - Off camera. AB - Wearing body cameras at work is a terrible idea, especially in settings where establishing a trusting therapeutic relationship is vital (readers' panel, 14 June). PMID- 28635473 TI - England risks losing its place as leading role model in education. AB - The International Council of Nurses (ICN) held its biennial meeting in Barcelona in May. I was invited as an official observer of the Council of Nurse Representatives, and learned first-hand how the ICN operates. PMID- 28635474 TI - Approaching the issue. AB - Pre-registration students are not registered with the Nursing and Midwifery Council (NMC), so you cannot report them to the regulator. The NMC issues guidance on professional conduct for nursing and midwifery students, but it cannot take any action until the person is on, or applies to join, the register. PMID- 28635476 TI - Newly qualified nurses could prescribe early in their careers, suggests NMC. AB - Newly qualified nurses may be able to undertake training to prescribe under proposals set out by the Nursing and Midwifery Council (NMC). PMID- 28635477 TI - Crystal Oldman among nurses named in Queen's birthday honours list. AB - Queen's Nursing Institute chief executive Crystal Oldman has been made a CBE for services to the charity and community nursing. She joins other nurses recognised in the 2017 Queen's birthday honours. PMID- 28635478 TI - Let's celebrate the feel-good factor. AB - I am ignored. Disregarded. A non-person. Part of the furniture. But I don't mind. In fact, it gives me a warm glow. PMID- 28635479 TI - Help with housing costs. AB - Nurses working in the London area have benefited from a London 'weighting' for as long as many can remember. It can be the difference between being able to live and work in the capital and being forced to move elsewhere by the high cost of housing. PMID- 28635480 TI - Leadership styles in nursing. AB - Nurses are often asked to think about leadership, particularly in times of rapid change in healthcare, and where questions have been raised about whether leaders and managers have adequate insight into the requirements of care. This article discusses several leadership styles relevant to contemporary healthcare and nursing practice. Nurses who are aware of leadership styles may find this knowledge useful in maintaining a cohesive working environment. Leadership knowledge and skills can be improved through training, where, rather than having to undertake formal leadership roles without adequate preparation, nurses are able to learn, nurture, model and develop effective leadership behaviours, ultimately improving nursing staff retention and enhancing the delivery of safe and effective care. PMID- 28635481 TI - Readers' panel - Should mentors be replaced by supervisors and assessors? AB - Our experts consider a hot topic of the day. PMID- 28635482 TI - Diagnosis and management of myasthenia gravis. AB - Myasthenia gravis is a rare long-term neurological condition that is characterised by fluctuating skeletal muscle weakness and fatigue, as well as respiratory difficulties. It is both an acquired autoimmune disease and a chronic neuromuscular disorder. Because of its rarity, myasthenia gravis is relatively unknown and may be unfamiliar to many nurses. While there are various types of myasthenia, this article focuses on myasthenia gravis, exploring its symptoms, diagnosis and treatment, and examining the nurse's role in managing the condition. The symptoms of myasthenic crisis and cholinergic crisis are also explained, and the experience of patients with myasthenia gravis in hospital and community settings is illustrated using case studies. PMID- 28635483 TI - Student life - Imposter syndrome. AB - I will never forget the first time I stepped onto a ward as a nursing student in my freshly ironed new uniform. Everything was going well. This was it, I was living my dream. And then an older woman called out for a nurse, looked at me, and I froze. I wasn't a 'real' nurse, so what on earth was I to do? PMID- 28635484 TI - Political losses. AB - I am gutted Labour didn't win the election, as they promised to reintroduce the bursary. I put my nursing degree on hold for 16 months due to my daughter's illness. The new term begins in September, but I have lost my bursary and maintenance grant entitlement. I can no longer afford to do the course. PMID- 28635485 TI - Letter. AB - Why is it 'interesting' that three of the nurse MPs are Conservative (Election wins boost nurse numbers in the Commons, news, 14 June)? PMID- 28635487 TI - HUG. AB - Created by a woman who found little support after losing a baby, this app aims to help anyone following the loss of a baby at any gestation. PMID- 28635486 TI - Letter. AB - I was disappointed to see that Jeremy Hunt had been reappointed as health secretary. PMID- 28635489 TI - Trusts 'at risk' after Brexit are already losing EU nurses. AB - More than half of NHS trusts in England identified as being most vulnerable to workforce problems post-Brexit have already seen falls in EU nurse numbers. PMID- 28635488 TI - Falling EU nurse figures spark fresh concerns over Brexit. AB - Concern about the effect of Brexit on the UK nursing workforce could intensify, with new figures showing fewer EU nurses in post at certain NHS trusts and fewer registering to work in the UK. PMID- 28635490 TI - Beloved Old Age and What to Do About It: Margery Allingham's The Relay Handed on to Julia Jones Jones Julia Beloved Old Age and What to Do About It: Margery Allingham's The Relay Handed on to Julia Jones 192pp L10.99 Golden Duck 9781899262298 1899262296 [Formula: see text]. AB - This book offers the perspectives of two people caring for older family members: novelist Margery Allingham in the 1950s and her biographer Julia Jones, whose mother is in her nineties and currently living in supported housing. PMID- 28635491 TI - Community Care and Inclusion for People with an Intellectual Disability Jackson Robin & Lyons Maria (Eds) Community Care and Inclusion for People with an Intellectual Disability 256pp L25.00 Floris Books 9781782503330 1782503331 [Formula: see text]. AB - This book includes reflective and philosophical accounts that explore the widest context of community care. It is a collection of personal views and experiences from several authors. Many examples focus on the provision of the Camphill Village model across the world, and these provide a philosophical continuity throughout the book. PMID- 28635492 TI - Grenfell Tower tragedy echoes the public safety issues of Mid Staffs. AB - The Grenfell Tower fire and associated loss of life has shocked the nation, and prompted a public inquiry that will make recommendations on how to prevent a repeat. Let's hope it will prove more effective in this respect than similar inquiries covering scandals in healthcare. PMID- 28635495 TI - Analysis of audiometric notch as a noise-induced hearing loss phenotype in US youth: data from the National Health And Nutrition Examination Survey, 2005-2010. AB - OBJECTIVE: Bilateral audiometric notch (BN) at 4000-6000 Hz was identified as a noise-induced hearing loss (NIHL) phenotype for genetic association analysis in college-aged musicians. This study analysed BN in a sample of US youth. DESIGN: Prevalence of the BN within the study sample was determined and logistic regression analyses were performed to identify audiologic and other demographic factors associated with BN. Computer-simulated "flat" audiograms were used to estimate potential influence of false-positive rates in estimating the prevalence of the BN. STUDY SAMPLE: 2348 participants (12-19 years) following the inclusion criteria were selected from the National Health and Nutrition Examination Survey data (2005-2010). RESULTS: The prevalence of BN was 16.6%. Almost 55.6% of the participants showed notch in at least one ear. Noise exposure, gender, ethnicity and age showed significant relationship with the BN. Computer simulation revealed that 5.5% of simulated participants with "flat" audiograms showed BN. CONCLUSION: Association of noise exposure with BN suggests that it is a useful NIHL phenotype for genetic association analyses. However, further research is necessary to reduce false-positive rates in notch identification. PMID- 28635494 TI - Urea cycle disorder misdiagnosed as multiple sclerosis: a case report and review of the literature. AB - Urea cycle disorders are a group of inborn errors of metabolism caused by dysfunction of any of the six enzymes or two transport proteins involved in urea biosynthesis. In this paper, we report a patient who presented with neurological dysfunction and coma in the immediate postpartum period. She was misdiagnosed for many years as a case of multiple sclerosis. The importance of reporting this case is to illustrate that the wrong diagnosis of patients as being affected with multiple sclerosis for many years due to magnetic resonance imaging abnormalities rather than the classic relapsing-remitting nature of the disease may lead to catastrophic consequences. The patient was treated with intravenous steroids several times, which is contraindicated in patients with urea cycle disorders as it may precipitate acute hyperammonemic attacks. In addition, the management of urea cycle disorder could have started earlier and avoided multiple admissions to the intensive care unit. We believe that the presence of symmetric hyperintense insular cortical changes are seen in multiple hyperammonemic processes, and in the context of the clinical presentation and high ammonia levels can be suggestive of a urea cycle disorder. For any patient presenting with atypical clinical features, images should be reviewed and discussed in detail with an experienced neuroradiologist. In addition, the ammonia levels should be checked if a urea cycle disorder is suspected. PMID- 28635493 TI - The structure of lamin filaments in somatic cells as revealed by cryo-electron tomography. AB - Metazoan nuclei are equipped with nuclear lamina - a thin layer of intermediate filaments (IFs) mostly built of nuclear lamins facing the inner nuclear membrane (INM). The nuclear lamina serves as an interaction hub for INM-proteins, soluble nuclear factors and DNA. It confers structural and mechanical stability to the nucleus, transduces mechanical forces and biochemical signals across the nuclear envelope (NE) and regulates the organization of chromatin. By using cryo-electron tomography (cryo-ET), we recently provided an unprecedented view into the 3D organization of lamin filaments within the lamina meshwork in mammalian somatic cells. Through implementation of averaging procedures, we resolved the rod and globular Ig-fold domains of lamin filaments. The density maps suggested that they assemble into 3.5 nm thick filaments. Our analysis revealed interesting structural differences between nucleoplasmic and cytoplasmic intermediate filaments, raising the question of which molecular cues define their assembly modes inside the cell. PMID- 28635496 TI - Internet-based peer support for Meniere's disease: a summary of web-based data collection, impact evaluation, and user evaluation. AB - OBJECTIVE: This paper presents a summary of web-based data collection, impact evaluation, and user evaluations of an Internet-based peer support program for Meniere's disease (MD). DESIGN: The program is written in html-form. The data are stored in a MySQL database and uses machine learning in the diagnosis of MD. The program works interactively with the user and assesses the participant's disorder profile in various dimensions (i.e., symptoms, impact, personal traits, and positive attitude). The inference engine uses a database to compare the impact with 50 referents, and provides regular feedback to the user. Data were analysed using descriptive statistics and regression analysis. STUDY SAMPLE: The impact evaluation was based on 740 cases and the user evaluation on a sample of 75 cases of MD respectively. RESULTS: The web-based system was useful in data collection and impact evaluation of people with MD. Among those with a recent onset of MD, 78% rated the program as useful or very useful, whereas those with chronic MD rated the program 55%. CONCLUSIONS: We suggest that a web-based data collection and impact evaluation for peer support can be helpful while formulating the rehabilitation goals of building the self-confidence needed for coping and increasing social participation. PMID- 28635497 TI - Desynchronisation of auditory steady-state responses related to changes in interaural phase differences: an objective measure of binaural hearing. AB - OBJECTIVE: Binaural processing can be measured objectively as a desynchronisation of phase-locked neural activity to changes in interaural phase differences (IPDs). This was reported in a magnetoencephalography study for 40 Hz amplitude modulated tones. The goal of this study was to measure this desynchronisation using electroencephalography and explore the outcomes for different modulation frequencies. DESIGN: Auditory steady-state responses (ASSRs) were recorded to pure tones, amplitude modulated at 20, 40 or 80 Hz. IPDs switched between 0 and 180 degrees at fixed time intervals. STUDY SAMPLE: Sixteen young listeners with bilateral normal hearing thresholds (<=25 dB HL at 125-8000 Hz) participated in this study. RESULTS: Significant ASSR phase desynchronisations to IPD changes were detected in 14 out of 16 participants for 40 Hz and in 8, respectively 9, out of 13 participants for 20 and 80 Hz modulators. Desynchronisation and restoration of ASSR phase took place significantly faster for 80 Hz than for 40 and 20 Hz. CONCLUSIONS: ASSR desynchronisation to IPD changes was successfully recorded using electroencephalography. It was feasible for 20, 40 and 80 Hz modulators and could be an objective tool to assess processing of changes in binaural information. PMID- 28635498 TI - Effect of age-related hearing loss on the click-rate-induced facilitation of acoustic reflex thresholds. AB - OBJECTIVE: This investigation was designed to evaluate the effect of age-related hearing loss on the click-rate-induced improvement in the acoustic reflex thresholds. DESIGN: Case-control study. STUDY SAMPLE: Data from five different adults ear-groups (15 ears each) were included in the study: 1. Younger with normal hearing. 2. Older with normal hearing. 3. Older with mild high-frequency loss. 4. Older with moderate high-frequency loss. 5. Older with low- and high frequency loss. Ipsilateral acoustic reflex thresholds were obtained from the left and/or right ear/s by presenting clicks at the repetition rates of 50, 100, 150, 200 and 300 clicks/s. The rate-induced facilitation (RIF) was calculated by subtracting the lowest acoustic reflex threshold from the highest reflex threshold obtained across the various click-rates. RESULTS: The click-RIF is significantly reduced in older individuals compared to younger adults. There is no significant difference in RIF across the four older adult groups suggesting that an age-related, mild to moderate hearing loss has no significant effect on the click RIF of the acoustic reflex thresholds. CONCLUSIONS: Click-RIF may allow us to document the effect of ageing on temporal processing within the auditory brainstem area, in a time-efficient and objective manner using commercially available equipment. PMID- 28635499 TI - Hearing aid fine-tuning based on Dutch descriptions. AB - OBJECTIVE: The aim of this study was to derive an independent fitting assistant based on expert consensus. Two questions were asked: (1) what (Dutch) terms do hearing impaired listeners use nowadays to describe their specific hearing aid fitting problems? (2) What is the expert consensus on how to resolve these complaints by adjusting hearing aid parameters? DESIGN: Hearing aid dispensers provided descriptors that impaired listeners use to describe their reactions to specific hearing aid fitting problems. Hearing aid fitting experts were asked "How would you adjust the hearing aid if its user reports that the aid sounds...?" with the blank filled with each of the 40 most frequently mentioned descriptors. STUDY SAMPLE: 112 hearing aid dispensers and 15 hearing aid experts. The expert solution with the highest weight value was considered the best solution for that descriptor. Principal component analysis (PCA) was performed to identify a factor structure in fitting problems. RESULTS: Nine fitting problems could be identified resulting in an expert-based, hearing aid manufacturer independent, fine-tuning fitting assistant for clinical use. CONCLUSIONS: The construction of an expert-based, hearing aid manufacturer independent, fine tuning fitting assistant to be used as an additional tool in the iterative fitting process is feasible. PMID- 28635502 TI - Hearing aid technology: model-based concepts and assessment. PMID- 28635500 TI - A systematic review of stimulus parameters for eliciting distortion product otoacoustic emissions from adult humans. AB - OBJECTIVE: The objective of this study is to review the scientific literature to determine if a set of stimulus parameters can be described to elicit distortion product otoacoustic emissions (DPOAEs) of higher absolute level and/or greater reliability in healthy adult humans and higher sensitivity and specificity in adults with cochlear lesions. DESIGN: Systematic review. STUDY SAMPLE: Searches of four electronic databases yielded 47 studies that had used different parameters to elicit DPOAEs from within or between-groups of adult humans. RESULTS: The wide range of stimulus parameters used in the reviewed studies saw a wide range of reported values for DPOAE level, reliability, and sensitivity and specificity to cochlear lesions. CONCLUSION: The most commonly used stimulus parameters for eliciting DPOAEs from adult humans have included frequency ratios for the two primary tones (f2/f1) of between 1.04 and 1.4 and levels (L1/L2) of 65/55 dB SPL. The most commonly used parameters for eliciting DPOAEs of higher level in healthy adults appear to be linked to f2/f1 values between 1.20 and 1.22 and L1/L2 levels of 75/75 dB SPL. The stimulus parameters for eliciting DPOAEs of greater reliability in healthy adults and higher sensitivity and specificity in adults with cochlear lesions have yet to be clearly determined. PMID- 28635503 TI - Practical guidelines to minimise language and cognitive confounds in the diagnosis of CAPD: a brief tutorial. AB - OBJECTIVE: To provide audiologists with strategies to minimise confounding cognitive and language processing variables and accurately diagnose central auditory processing disorder (CAPD). DESIGN: Tutorial. STUDY SAMPLE: None. RESULTS: Strategies are reviewed to minimise confounding cognitive and language processing variables and accurately diagnose CAPD. CONCLUSIONS: Differential diagnosis is exceedingly important and can be quite challenging. Distinguishing between two or more conditions presenting with similar symptoms or attributes requires multidisciplinary, comprehensive assessment. To ensure appropriate interventions, the audiologist is a member of the multidisciplinary team responsible for determining whether there is an auditory component to other presenting deficits or whether one condition is responsible for the symptoms seen in another. Choice of tests should be guided both by the symptoms of the affected individual, as established in an in-depth interview and case history, the individual's age and primary language, and by the specific deficits reported to be associated with specific clinical presentations. Knowing which tests are available, their strengths and limitations, the processes assessed, task and response requirements, and the areas of the central auditory nervous system (CANS) to which each test is most sensitive provides the audiologist with critical information to assist in the differential diagnostic process. PMID- 28635504 TI - Applying Rasch model analysis in the development of the cantonese tone identification test (CANTIT). AB - OBJECTIVE: Applying Rasch analysis to evaluate the internal structure of a lexical tone perception test known as the Cantonese Tone Identification Test (CANTIT). DESIGN: A 75-item pool (CANTIT-75) with pictures and sound tracks was developed. Respondents were required to make a four-alternative forced choice on each item. A short version of 30 items (CANTIT-30) was developed based on fit statistics, difficulty estimates, and content evaluation. Internal structure was evaluated by fit statistics and Rasch Factor Analysis (RFA). STUDY SAMPLE: 200 children with normal hearing and 141 children with hearing impairment were recruited. RESULTS: For CANTIT-75, all infit and 97% of outfit values were < 2.0. RFA revealed 40.1% of total variance was explained by the Rasch measure. The first residual component explained 2.5% of total variance in an eigenvalue of 3.1. For CANTIT-30, all infit and outfit values were < 2.0. The Rasch measure explained 38.8% of total variance, the first residual component explained 3.9% of total variance in an eigenvalue of 1.9. CONCLUSIONS: The Rasch model provides excellent guidance for the development of short forms. Both CANTIT-75 and CANTIT 30 possess satisfactory internal structure as a construct validity evidence in measuring the lexical tone identification ability of the Cantonese speakers. PMID- 28635505 TI - Social inequalities in pure-tone hearing assessed using occupational stratification schemes. AB - OBJECTIVE: The objective of this study is to analyse the performance of two occupational stratification approaches and the impact of social position on adult hearing. DESIGN: The prevalence of hearing impairment, pure-tone averages (PTA) and prevalence ratios (PR) for relative hearing loss, which focuses on the position of one's PTA in the age- and gender-specific distribution, were compared in groups defined by ISCO Skill Level and the International Socio-Economic Index (ISEI). STUDY SAMPLE: About 1571 subjects aged 30-89, including 677 highly screened adults, from the cross-sectional study HORSTAT. RESULTS: ISCO Skill Level and ISEI yielded qualitatively the same results. The prevalence difference between the socially least and most advantaged group ranges between 10 and 16%, varying with the scheme applied. Low- and high-frequency PTA and PR for relative hearing loss confirm the gradient. Screening reduced, but did not negate the social differences. The prevalence difference dropped to 6-7% in the otologically normal subsample. CONCLUSIONS: Social groups defined by hierarchical, occupational measures differ in their pure-tone hearing, even if the main risk factors are controlled for. This underlines the need for population-based sampling, the relevance of reporting the study group's social composition and the importance of advancing the discussion on appropriate social measures in hearing research. PMID- 28635506 TI - An individualised acoustically transparent earpiece for hearing devices. AB - OBJECTIVE: An important and often still unresolved problem of hearing devices such as assistive listening devices and hearing aids is limited user acceptance - a primary reason is poor conservation quality of the acoustic environment. Approaching a possible solution to this problem, an earpiece prototype is presented and evaluated. The prototype is individually and automatically calibrated in situ to provide acoustical transparency, i.e., achieving an audio perception alike to the open ear. DESIGN: A comprehensive evaluation was performed, comprising technical measurements on an advanced dummy head and listening tests, in which listeners directly compared sound perception through the prototype and a simulated open ear canal reference. STUDY SAMPLE: Ten normal hearing subjects, including five expert listeners, participated in the listening test. RESULTS: The technical evaluation verified good achievement of acoustical transparency. The psychoacoustic results showed that a reliable distinction between the two conditions presented was not possible for relevant communication sounds. CONCLUSION: The prototype can be described as an initial realisation of an acoustically transparent hearing system, i.e. a device that does not disturb the perception of external sounds. In further developments, the device can be considered as the basis for systems integrating high sound quality, hearing support and other desired modifications. PMID- 28635507 TI - Cochlear implant effectiveness in postlingual single-sided deaf individuals: what's the point? AB - OBJECTIVES: By extending the indication criteria for cochlear implants (CI), the population of CI candidates increased in age, as well as range and type of hearing loss. This qualitative study identified factors that contributed to seek CI treatment in single-sided deaf individuals and gained insights how single sided deafness (SSD) and hearing with a CI affect their lives. DESIGN: An open ended questionnaire and a standardised inventory (IOI-HA) were used. Qualitative data reflecting the reasons to seek CI treatment and the individual experiences after CI switch-on were collected. STUDY SAMPLE: A total of 19 postlingually deafened single-sided deaf CI users. RESULTS: Participants use their CI daily and stated that their life satisfaction increased since CI activation. The analysis of the qualitative data revealed four core categories: sound localisation, tinnitus and noise sensitivity, fear to lose the second ear and quality of life. CONCLUSIONS: Our results show how strongly and diversely quality of hearing and quality of life is affected by acquired SSD and improved after CI activation. Our data suggest that the fear of hearing loss (HL) on the normal hearing (NH) ear is an important but so far neglected reason to seek treatment with a CI in individuals with postlingual SSD. PMID- 28635510 TI - The Effects on Obesity Related Peptides of Laparoscopic Gastric Band Applications in Morbidly Obese Patients. AB - BACKGROUND: The aim of this study was to examine the relationship between weight loss and resistin, apelin, chemerin, and visfatin after laparoscopic adjustable gastric banding (LAGB). METHODS: The study group consisted of 19 patients who were operated on for morbid obesity (BMI: 48.7 +/- 6.6 kg/m2), and 22 healthy, normal-weight (BMI: 22.9 +/- 2.5 kg/m2) subjects formed the control group. We obtained blood samples from the study subjects at three different times: before undergoing surgery and at one month and 6 months after surgery. Blood was obtained once from the control group. RESULTS: Significant weight loss was achieved at one and 6 months after surgery. Plasma levels of apelin, resistin, chemerin, and visfatin were higher in morbidly obese patients compared with the control group. Obesity-related peptides decreased one month and 6 months after surgery. CONCLUSIONS: Elevated plasma resistin, apelin, chemerin, and visfatin levels in morbidly obese patients are gradually reduced after weight loss. According to these findings, LAGB surgery is found to be an important and efficient means for morbidly obese patients both to lose weight and to develop a better metabolic risk profile in a short time period. PMID- 28635509 TI - Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Adult Common Marmoset Fibroblasts. AB - The common marmoset monkey (Callithrix jacchus; Cj) is an advantageous nonhuman primate species for modeling age-related disorders, including Parkinson's disease, due to their shorter life span compared to macaques. Cj-derived induced pluripotent stem cells (Cj-iPSCs) from somatic cells are needed for in vitro disease modeling and testing regenerative medicine approaches. Here we report the development of a novel Cj-iPSC line derived from adult marmoset fibroblasts. The Cj-iPSCs showed potent pluripotency properties, including the development of mesodermal lineages in tumors after injection to immunocompromised mice, as well as ectoderm and endoderm lineages after in vitro differentiation regimens, demonstrating differentiated derivatives of all three embryonic layers. In addition, expression of key pluripotency genes (ZFP42, PODXL, DNMT3B, C-MYC, LIN28, KLF4, NANOG, SOX2, and OCT4) was observed. We then tested the neural differentiation capacity and gene expression profiles of Cj-iPSCs and a marmoset embryonic stem cell line (Cj-ESC) after dual-SMAD inhibition. Exposure to CHIR99021 and sonic hedgehog (SHH) for 12 and 16 days, respectively, patterned the cells toward a ventralized midbrain dopaminergic phenotype, confirmed by expression of FOXA2, OTX2, EN-1, and tyrosine hydroxylase. These results demonstrate that common marmoset stem cells will be able to serve as a platform for investigating regenerative medicine approaches targeting the dopaminergic system. PMID- 28635511 TI - The Immunohistochemical Expression MTA 1 Protein and its Prognostic Value in Pancreatic Cancer. AB - : Purpose/aim: To examine with immunohistochemical assay MTA1 protein expression levels in pancreatic cancer tissues defining its prognostic value. MATERIAL AND METHODS: The specimens derived from 51 patients who underwent surgery. The levels of MTA1 protein were compared with the age of the patients, their survival, and prognosis. Also, we studied clinical and histopathological factors such as the degree of tumor differentiation and its stage in correlation with MTA1 protein levels. In parallel, there was correlation between the expression of the MUTauAlpha1 protein and the aforementioned factors regarding survival rate. Furthermore, we independently correlated the patient's survival in relation to whether they had undergone adjuvant chemotherapy or not. RESULTS: It has been found to be low, moderate, or high expression of MTA1 levels in 48 out of 51 cancer tissues. Specifically, 49.0% of patients had low expression, 33.3% moderate, and 11.8% high expression of MTA1. Regarding the expression of MTA1 protein in correlation with various clinical and histopathological factors, a statistically significant correlation was observed with the degree of differentiation (p = 0.0068) and with the stage of the disease (p = 0.0173), but not with survival (p = 0.0740) or the age of them (p = 0.1547). Finally, it was found that overexpression of the MTA1protein is a prognostic factor for shorter survival in patients with pancreatic cancer (average 4.67 +/- 0.95 months). CONCLUSIONS: MTA 1 protein may constitute an important prognostic marker in pancreatic cancer and could improve prognosis and treatment. PMID- 28635512 TI - Effect of Simvastatin on Lipid Accumulation and the Expression of CXCL16 and Nephrin in Podocyte Induced by Oxidized LDL. AB - OBJECTIVE: To investigate the effect of simvastatin on lipid accumulation and the expression of CXCL16 and Nephrin in murine podocytes induced by oxidized LDL (OxLDL) in order to explore the mechanism of protection. METHODS: Murine podocytes (MPC5) were incubated with OxLDL (80 MUg/ml) at different concentrations of simvastatin (0, 1.0, and 2.0 MUg/ml) for 48 hours. Oil red O staining was used for the assessment of lipid accumulation in podocytes, and colorimetric cholesterol detection kit was used for the quantitative measurement. CXCL16 and Nephrin expression were detected by using Western blot. RESULTS: OxLDL treated MPC5 cells exhibited significantly higher intracellular lipid accumulations compared with the untreated group. Colorimetric detection found that total cholesterol was 90.3 +/- 30.1 MUg/ml in untreated cells and 226.5 +/- 21.6 MUg/ml in OxLDL-treated cells. The difference was statistically significant (p < .01). While cells were treated with both OxLDL and simvastatin, we observed little lipid accumulation. Total cholesterol in OxLDL + simvastatin cells were 151.8 +/- 6.8 MUg/ml and 135.5 +/- 26.9 MUg/ml under 1.0 MUg/ml or 2.0 MUg/ml of simvastatin treatment, respectively. Both were statistically significantly lower than that of the OxLDL treated cells (p < .05). Western blot analysis showed that CXCL16 expression was significantly increased (p < .05) in OxLDL-treated cells compared with the untreated cells, and was significantly inhibited by application of simvastatin (p < .05). The analysis of nephrin expression showed that there were no changes in group simvastatin compared with that of control group (p > .05). Nephrin expression was significantly reduced by treatment with OxLDL (p < .01), and was significantly increased by application of simvastatin (p < .05). CONCLUSION: Simvastatin treatment could significantly decrease lipid accumulation in murine podocytes and this protective effect was realized through inhibition of the expression of CXCL16 and increase in the expression of nephrin. PMID- 28635513 TI - Evaluation of Platelet Indices and Red Cell Distribution Width as New Biomarkers for the Diagnosis of Acute Appendicitis. AB - BACKGROUND: Debate around the value of laboratory tests in establishing the diagnosis of acute appendicitis (AA) still continues. This prospective study aimed to investigate the changes in mean platelet volume (MPV), platelet distribution width (PDW), and red cell distribution width (RDW) with the diagnosis of acute appendicitis. METHOD: 200 patients who underwent emergency appendectomy were included. According to postoperative histology, patients were divided into three groups: acute non-complicated, acute complicated appendicitis (positive appendicectomy groups), and negative appendectomy group. White blood cell (WBC), neutrophil, lymphocyte count, neutrophil-to-lymphocyte ratio (NLR), platelets (PLT) count, MPV, PDW, RDW, and C-reactive protein (CRP) were compared among the groups. RESULTS: One hundred twenty-five (62.5%) patients had non complicated acute appendicitis, 20 (10%) had complicated acute appendicitis, while 55 (27.5%) had normal appendix. WBC (p <.001), neutrophil (p <.001), NLR (p <.001), PDW (p =.003), and CRP (p =.001) were higher, while lymphocyte (p <.001) and PLT counts (p =.020) were lower in positive appendectomy compared with negative appendectomy patients. MPV levels were insignificantly different across the groups. RDW level was significantly higher in complicated compared with non complicated acute appendicitis (p =.006); however, no significant difference was found between positive and negative appendectomy groups. Using receiver operating characteristic analysis, sensitivity, specificity, and diagnostic accuracy respectively were 44.83, 100.0, and 72.415% for WBC count, 72.41, 81.82, and 77.115% for neutrophil count, 48.28, 90.91, and 69.595% for PDW, 89.66, 63.64, and 76.65% for CRP. CONCLUSIONS: Increased PDW combined with elevated WBC and neutrophil counts maybe used as diagnostic tests in the cases of acute appendicitis, while MPV and RDW levels were not useful diagnostic markers. PMID- 28635514 TI - Effects of Thyroid Hormone Therapy on Cut-Surface Healing of the Remnant Stomach with Short-Term Weight Loss Alterations after Sleeve Gastrectomy. AB - BACKGROUND: The hypothalamic-pituitary-tyhroid axis is directly affected by drastic changes in energy stores. The aim of the present study was to determine the effects of triiodothyronine (T3) treatment on cut-surface healing of remnant stomach with weight loss alterations after sleeve gastrectomy (SG). METHODS: Thirty male Wistar Albino rats were divided into three groups: sham (n = 6), control (n = 12), and experimental (n = 12). Control and experimental group rats underwent sleeve gastrectomy. Experimental group rats received a single dose of T3 (400 mg/100 g) on the first postoperative day whereas control group rats received 0.9% NaCl. All rats were sacrificed on the seventh postoperative day. RESULTS: In the group of rats receiving T3, levels of FT3 were significantly higher and that of FT4 were significantly lower compared with both the control and sham group rats (p <.05). No significant difference was found between control and T3 group rats in terms of weight loss (p >.05). Microscopic examination of the cut surface of remnant stomach in the control group rats revealed significantly more severe tissue necrosis, edema, and disruption of mucosal epithelium than in the T3 group rats (p <.05). On the other hand, bridging of the submucosal and muscular layers, tissue granulation, fibroblast accumulation, neoangiogenesis, and collagen deposition in the T3 group rats were significantly higher than in the control group rats (p <.05). CONCLUSIONS: Sleeve gastrectomy did not significantly alter thyroid hormone levels in short term. T3 hormone therapy seems to deliver constructive therapeutic effects for wound healing while causing no adverse effect on weight reduction. PMID- 28635515 TI - An Effective Treatment for Heart Failure Caused by Valvular Heart Diseases: Thoracic Sympathetic Block. AB - BACKGROUND: The pilot study is designed to investigate the effect of continuous thoracic sympathetic block (TSB) on cardiac function, reconstruction, and hemodynamic parameters in patients with heart failure resulting from valvular heart disease. METHOD: The cardiac function parameters, including left ventricle ejection fraction (LVEF), left ventricle end-diastole diameter (LVEDD), fractional shortening (FS), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), were measured in 19 patients before and after TSB treatment. The patients were also classified on the basis of NYHA classification system. RESULTS: 4 weeks of TSB administration improved cardiac function in 18 of 19 patients (94.74%). The patients' LVEF, LVEDD, and NT-proBNP were all improved significantly after treatment. CONCLUSIONS: The favorable clinical outcome of TSB administration suggests an alternative treatment for the patients with heart failure caused by valvular dysfunctions. PMID- 28635516 TI - Concentration of UHCL1 in the Serum of Children with Acute Appendicitis, Before and After Surgery, and Its Correlation with CRP and Prealbumin. AB - : Ubiquitin-mediated protein degradation plays a crucial role in various cellular processes, including signal transduction, cell differentiation, and stress response. Ubiquitin C-terminal hydrolase 1 (UCHL1) is a unique deubiquitinating enzyme that has both hydrolase and ligase activities. The aim of this study was the determination of UCHL1 concentration in serum of children with appendicitis, before and after the surgery. MATERIAL AND METHODS: 42 children with acute appendicitis, who were managed at the Pediatric Surgery Department, between 2013 and 2014, were randomly included into the study (age 9 months up to 14 years, mean age 2.5 + 1 years). There were 15 girls and 27 boys. 18 healthy, age-matched subjects, admitted for planned surgeries served as controls. Exclusion criteria were: severe preexisting infections, immunological or cardiovascular diseases that required long-term medication, and complicated cases of appendicitis with perforation of appendix and/or peritonitis. RESULTS: The UCHL1 concentrations in the blood plasma of patients with acute appendicitis, were highest before the surgery, and were above the range of concentrations measured in controls, the difference was statistically significant. The UCHL1 concentration measured 24 and 72 h after the operation, slowly decreased over time, and still did not reach the normal range, when compared with the concentration measured in controls (p < 0.05). CONCLUSIONS: UCHL1 concentration may reflect the metabolic response to acute state inflammation, and the process of gradual ebbing of the inflammation. The method of operation-classic open appendectomy, or laparoscopic appendectomy, does not influence the general trend in UCHL1 concentration in children with appendicitis. There is strong negative correlation between prealbumin and UCHL1 concentrations. PMID- 28635517 TI - A Primer for Oncoimmunology (Immunooncology). AB - Oncoimmunology (or immunooncology) is a burgeoning specialty of precision ("personalized") medicine designed to heighten the antitumor response of the immune system against molecules expressed excessively or only by tumor cells. This focus is necessary, as cancers are polyclonal tissues comprised of antigenically heterogeneous cells, the exact composition of which is shaped by the balance between antitumor immunity and tumor-promoting inflammation. Key targets include enhancing immune system (especially T cell) reactivity, inhibiting immune checkpoints, and promoting tumor cytolysis. Therapeutic modalities to address these targets include administering antibodies, cytokines, or small molecules that directly stimulate the immune system, attack tumor associated antigens, or interfere with tumor-stroma interactions; adoptive transfer of autologous T cells following ex vivo selection/expansion/activation (typically after lymphoid-depleting regimens and in conjunction with immunostimulatory therapy); and vaccination (against tumor antigens). Pathology involvement in oncoimmunology product development is critical to assess expression of target molecules in tumor cells, stromal cells, and tumor infiltrating leukocytes. PMID- 28635518 TI - Complete resolution of mycosis fungoides tumors with imiquimod 5% cream: a case series. AB - OBJECTIVE: To demonstrate the clinical efficacy of topical 5% imiquimod for mycosis fungoides (MF) tumors. BACKGROUND: Treatment of tumor-stage MF represents a therapeutic challenge because of a limited number of effective topical therapies. Single tumors can be treated with localized radiation but may recur. Systemic therapies are also an option but are associated with serious adverse effects. Imiquimod is a topical agent whose efficacy has been documented in treating MF patches and plaques as well as one case of tumor-stage disease. METHODS: We present two stage IIB MF patients, including one with large cell transformation, whose tumors were treated with imiquimod 5% cream after failing prior therapies. RESULTS: The MF tumors in both patients demonstrated a complete response to imiquimod 5% cream without recurrence over 8 years and 2 years of follow-up, respectively. One patient experienced application site irritation and flu-like symptoms as adverse effects. CONCLUSIONS: Our case series is only the second report in the literature demonstrating complete resolution of MF tumors with topical imiquimod. An additional therapeutic option for tumor-stage MF, imiquimod may represent an effective alternative to localized radiation for isolated MF tumors and warrants further investigation in the treatment of various stages of MF. PMID- 28635519 TI - The Elicitor Protein AsES Induces a Systemic Acquired Resistance Response Accompanied by Systemic Microbursts and Micro-Hypersensitive Responses in Fragaria ananassa. AB - The elicitor AsES (Acremonium strictum elicitor subtilisin) is a 34-kDa subtilisin-like protein secreted by the opportunistic fungus Acremonium strictum. AsES activates innate immunity and confers resistance against anthracnose and gray mold diseases in strawberry plants (Fragaria * ananassa Duch.) and the last disease also in Arabidopsis. In the present work, we show that, upon AsES recognition, a cascade of defense responses is activated, including: calcium influx, biphasic oxidative burst (O2?- and H2O2), hypersensitive cell-death response (HR), accumulation of autofluorescent compounds, cell-wall reinforcement with callose and lignin deposition, salicylic acid accumulation, and expression of defense-related genes, such as FaPR1, FaPG1, FaMYB30, FaRBOH-D, FaRBOH-F, FaCHI23, and FaFLS. All these responses occurred following a spatial and temporal program, first induced in infiltrated leaflets (local acquired resistance), spreading out to untreated lateral leaflets, and later, to distal leaves (systemic acquired resistance). After AsES treatment, macro-HR and macro oxidative bursts were localized in infiltrated leaflets, while micro-HRs and microbursts occurred later in untreated leaves, being confined to a single cell or a cluster of a few epidermal cells that differentiated from the surrounding ones. The differentiated cells initiated a time-dependent series of physiological and anatomical changes, evolving to idioblasts accumulating H2O2 and autofluorescent compounds that blast, delivering its content into surrounding cells. This kind of systemic cell-death process in plants is described for the first time in response to a single elicitor. All data presented in this study suggest that AsES has the potential to activate a wide spectrum of biochemical and molecular defense responses in F. ananassa that may explain the induced protection toward pathogens of opposite lifestyle, like hemibiotrophic and necrotrophic fungi. PMID- 28635520 TI - Information for Clinicians: Approach to the patient with progressive radioactive iodine refractory thyroid cancer- When to use systemic therapy. AB - N/A. PMID- 28635521 TI - Assessment of an Innovative Voluntary Substance Abuse Treatment Program Designed to Replace Compulsory Drug Detention Centers in Malaysia. AB - BACKGROUND: As part of an ongoing initiative by the Malaysian government to implement alternative approaches to involuntary detention of people who use drugs, the National Anti-Drug Agency has created new voluntary drug treatment programs known as Cure and Care (C&C) Centers that provide free access to addiction treatment services, including methadone maintenance therapy, integrated with social and health services. OBJECTIVES: We evaluated early treatment outcomes and client satisfaction among patients accessing C&C treatment and ancillary services at Malaysia's second C&C Center located in Kota Bharu, Kelantan. METHODS: In June-July 2012, a cross-sectional convenience survey of 96 C&C inpatients and outpatients who entered treatment >30 days previously was conducted to assess drug use, criminal justice experience, medical co morbidities, motivation for seeking treatment, and attitudes towards the C&C. Drug use was compared for the 30-day-period before C&C entry and the 30-day period before the interview. RESULTS: Self-reported drug use levels decreased significantly among both inpatient and outpatient clients after enrolling in C&C treatment. Higher levels of past drug use, lower levels of social support, and more severe mental health issues were reported by participants who were previously imprisoned. Self-reported satisfaction with C&C treatment services was high. Conclusions/Importance: Preliminary evidence of reduced drug use and high levels of client satisfaction among C&C clients provide support for Malaysia's ongoing transition from compulsory drug detention centers (CDDCs) to these voluntary drug treatment centers. If C&C centers are successful, Malaysia plans to gradually transition away from CDDCs entirely. PMID- 28635522 TI - Dietary Intake Among Opioid- and Alcohol-Using Pregnant Women. AB - BACKGROUND: Substance abuse in nonpregnant adults has been associated with increased intake in calories and decreased intake of nutrient-dense foods; however, studies examining dietary intake in opioid-using and alcohol-using pregnant women are lacking. OBJECTIVE: The objective of this study was to evaluate dietary intake in opioid-using pregnant women with or without concurrent light-to-moderate alcohol use as compared to abstaining controls. METHODS: This prospective birth cohort included 102 pregnant women classified into four study groups: controls (n = 27), medication-assisted treatment (MAT; n = 26), alcohol (ALC; n = 22), and concurrent use of both substances (MAT + ALC; n = 27). Percentage differences in macro- and micronutrient intake were estimated from the food frequency questionnaire and compared among the study groups. Proportions of participants with intakes below the estimated average requirements (EAR) based on diet and diet with supplements were estimated. RESULTS: Three exposed groups had lower prevalence of multivitamin use in periconceptional period (11.5-31.8%) than controls (44.4%). Unadjusted mean energy intake was significantly higher in the MAT + ALC group compared to controls, while micronutrient intake per 1000 kcal was the highest in the control group for almost all of the micronutrients analyzed. After adjustment for energy intake and sociodemographic characteristics, MAT group had lower estimated dietary intake of iron (-15.0%, p = 0.04) and folate (-16.8%, p = 0.04) compared to controls. A high proportion of participants in all study groups had dietary intake below the EAR for vitamin E, iron, and folate. CONCLUSION: Results highlight the need for targeted dietary interventions for opioid-using pregnant women. PMID- 28635523 TI - Long-Term Paired Associative Stimulation Enhances Motor Output of the Tetraplegic Hand. AB - A large proportion of spinal cord injuries (SCI) are incomplete. Even in clinically complete injuries, silent non-functional connections can be present. Therapeutic approaches that can strengthen transmission in weak neural connections to improve motor performance are needed. Our aim was to determine whether long-term delivery of paired associative stimulation (PAS, a combination of transcranial magnetic stimulation [TMS] with peripheral nerve stimulation [PNS]) can enhance motor output in the hands of patients with chronic traumatic tetraplegia, and to compare this technique with long-term PNS. Five patients (4 males; age 38-68, mean 48) with no contraindications to TMS received 4 weeks (16 sessions) of stimulation. PAS was given to one hand and PNS combined with sham TMS to the other hand. Patients were blinded to the treatment. Hands were selected randomly. The patients were evaluated by a physiotherapist blinded to the treatment. The follow-up period was 1 month. Patients were evaluated with Daniels and Worthingham's Muscle Testing (0-5 scale) before the first stimulation session, after the last stimulation session, and 1 month after the last stimulation session. One month after the last stimulation session, the improvement in the PAS-treated hand was 1.02 +/- 0.17 points (p < 0.0001, n = 100 muscles from 5 patients). The improvement was significantly higher in PAS-treated than in PNS-treated hands (176 +/- 29%, p = 0.046, n = 5 patients). Long-term PAS might be an effective tool for improving motor performance in incomplete chronic SCI patients. Further studies on PAS in larger patient cohorts, with longer stimulation duration and at earlier stages after the injury, are warranted. PMID- 28635524 TI - Serology and protein electrophoresis for evidence of exposure to 12 mink pathogens in free-ranging American mink (Neovison vison) in Argentina. AB - BACKGROUND: Basic pathologic characteristics for farmed minks were previously reported worldwide. However, its status in the wild has not been studied in detail. OBJECTIVE: Serology and electrophoresis were carried out for evidence of exposure to 12 mink pathogens on two different locations. ANIMALS AND METHODS: Serology was done in 87 wild minks by reference techniques against Toxoplasma gondii, Encephalitozoon cuniculi, Neospora caninum, Brucella abortus, Mycobacterium bovis, Leptospira interrogans, canine distemper virus (CDV), canine adenovirus (CAV), canine parvovirus (CPV), rabies virus (RV), Influenza A virus (FLUAV) and Aleutian disease virus (ADV). Hypergammaglobulinemia, the ADV main clinical feature, was determined by conventional electrophoresis. RESULTS: Seventy-one percent of the 87 sera had antibodies against one or more pathogens. ADV accounted for the highest seroprevalence (29%), followed by T. gondii (26%), L. interrogans (14%), M. bovis (12%), B. abortus (9%), N. caninum (3%), CPV (3%) and CDV (2%). Seroprevalence was influenced by location but not sex or age. Additionally, 16% of the seropositive samples for ADV had gammaglobulin levels >40.0 g/L. Antibody titers for CDV and CPV were low and difficult to interpret as almost all these cases had borderline concentrations. CONCLUSION: A cautious interpretation of the results is urged as the epidemiological role of the wild mink is largely unexplored for most of these agents. Nevertheless, the information may be clinically relevant.. PMID- 28635525 TI - The role of prenatal, obstetric, and post-partum factors in the parenting stress of mothers and fathers of 9-month old infants. AB - INTRODUCTION: The aim of this paper was to examine the role of perinatal, obstetric and post partum factors on maternal and paternal stress. It will present the first examination of the role of prenatal, obstetric, post-partum, and demographic variables in parenting stress for mothers and fathers at 9 months. METHODS: Data from 6821 parental dyads of 9-month-old infants were extracted from the Growing Up in Ireland National Longitudinal Study of Children. Participants completed the Parental Stress Scale, the Dyadic Adjustment Scale, the Quality of Attachment Sub-scale from the Maternal and Paternal Postnatal Attachment Scales, and a single item health status question from the Short Form 12 Health Survey. Information on prenatal care, pregnancy complications, obstetric outcomes, infant health, and participant demographics were also collected. Separate hierarchical linear regressions were conducted for mothers and fathers Results: Mothers reported higher levels of parenting stress than fathers (p < 0.001). Maternal parenting stress was predicted by attachment, own health status, average sleep, occupation, household income, and having a very rapid labor. Paternal parenting stress was predicted by attachment and own health status. DISCUSSION: A range of perinatal factors was associated with an increased risk of higher parenting stress at 9 months post-partum and the roles of these factors differ between mothers and fathers. These findings are important for predicting and reducing risk of parenting stress in both genders. PMID- 28635526 TI - A randomized lifestyle intervention preventing gestational diabetes: effects on self-rated health from pregnancy to postpartum. AB - INTRODUCTION: The purpose was to examine the effects of a randomized lifestyle intervention on self-rated health from pregnancy to postpartum in participants at high risk for gestational diabetes mellitus. METHODS: We included 266 women with a history of gestational diabetes and/or prepregnancy BMI >=30 kg/m2. The intervention group (n = 144) received individualized counseling on diet, physical activity, and weight management from trained nurses at six timepoints between the first trimester of pregnancy and 12 months postpartum, and met three times with a dietitian. The control group (n = 122) received standard antenatal care. We assessed self-rated health at the six timepoints by means of a single question with five response options ranging from good (1) to poor (5). Baseline-adjusted mean changes in self-rated health level were assessed with a mixed model for repeated measure methods. RESULTS: The mean (SD) for self-rated health at baseline was 1.8 (0.8) in the intervention group and 2.1 (0.9) in the control group (p = 0.006). Self-rated health varied over time (time effect p < 0.001) and was the poorest in the third trimester. The sample indicated that self-rated health improved in the intervention group and deteriorated in the control group from the first trimester to 12 months postpartum, but the difference between the groups did not reach statistical significance (group effect p = 0.064). DISCUSSION: The self-rated health level varied over time from the first trimester of pregnancy to 12 months postpartum in women at risk for gestational diabetes. Improving self-rated health among high-risk pregnant women through lifestyle intervention calls for further research. PMID- 28635527 TI - Whose fault is it? Blame predicting psychological adjustment and couple satisfaction in couples seeking fertility treatment. AB - Infertility bears psychological and relational consequences for couples who face this problem. Few studies have examined the role of self- and partner blaming to explain psychological and relationship adjustment in couple presenting with a fertility problem. This study used a dyadic approach to explore the links between blaming oneself and one's partner and both partners' symptoms of depression and anxiety, and couple satisfaction in 279 couples enrolled in fertility treatments. Partners were questioned about the extent to which they blamed themselves and their partner for the fertility problem. They also completed the Dyadic Adjustment Scale and the Index of Psychological Symptoms. Path analyses based on the Actor-Partner Interdependence Model showed that self-blame predicted anxiety and depression symptoms in both men and women. Men's self-blame also predicted their own lower relationship satisfaction, whereas women's self-blame predicted more depression and anxiety in their partner. Partner blame in women predicted their own and their partner lower relationship satisfaction. Women's tendency to blame their partner also predicted their own depression symptoms. Clinical implications of these findings are discussed. PMID- 28635528 TI - Clinical, social and ethical issues associated with non-invasive prenatal testing for aneuploidy. AB - Non-invasive prenatal testing (NIPT), based on analysis of cell-free foetal DNA, is rapidly becoming a preferred method to screen for chromosomal aneuploidy with the technology now available in over 90 countries. This review provides an up-to date discussion of the key clinical, social and ethical implications associated with this revolutionary technology. Stakeholders are positive about a test that is highly accurate, safe, can be perfomed early in pregnancy, identifies affected pregnancies that might otherwise have been missed and reduces the need for invasive testing. Nevertheless, professional societies currently recommend it as an advanced screening test due to the low false positive rate (FPR). Despite the practical and psychological benefits, a number of concerns have been raised which warrant attention. These include the potential for routinisation of testing and subsequent impact on informed decision-making, an "easy" blood test inadvertently contributing to women feeling pressured to take the test, fears NIPT will lead to less tolerance and support for those living with Down syndrome and the heightened expectation of having "perfect babies". These issues can be addressed to some extent through clinician education, patient information and establishing national and international consensus in the development of comprehensive and regularly updated guidelines. As the number of conditions we are able to test for non invasively expands it will be increasingly important to ensure pre-test counselling can be delivered effectively supported by knowledgeable healthcare professionals. PMID- 28635529 TI - Major obstetric hemorrhage: a follow-up survey on quality of life of women and their partners. AB - INTRODUCTION: A description is given of the quality of life (QOL) of women who were treated with peripartum embolization or hysterectomy for major obstetric hemorrhage (MOH). METHODS: Questionnaires assessing QOL, combined with questionnaires and drawings assessing illness perceptions, were used to compare women with MOH to reference groups provided by the questionnaires. RESULTS: Women who experienced MOH have similar scores on QOL questionnaires compared to reference groups. Women treated with arterial embolization scored better than women treated with hysterectomy. Partners of women with MOH scored better on QOL questionnaires than reference groups. Drawings reflect the major emotional impact of MOH. DISCUSSION: MOH does not seem to have a negative effect on QOL 6-8 years after the event, although drawings and verbalizations indicate major emotional impact. More extensive follow-up is advised for early recognition of the need for psychological help. Women after embolization seem to have better QOL compared to women after hysterectomy. PMID- 28635530 TI - The effect of voluntary termination of pregnancy on female sexual and emotional well-being in different age groups. AB - INTRODUCTION: To evaluate the impact of voluntary termination of pregnancy (VTOP) on the psycho-sexological well-being of females before/six months after the abortion. METHODS: A sample of 194 women was recruited from three obstetrics and gynaecological divisions. The women were evaluated for the variables "sexual functioning" with the Female Sexual Function Index (FSFI), "depression" with the Beck Depression Inventory (BDI-II), and "anxiety state" with the Self-Rating Anxiety Scale (SAS) at time 0 (the beginning of the abortion procedure) and time 1 (six months after the abortion). Since 24 women refused to fill out the questionnaires, the final sample was composed of 170 women. RESULTS: The women showed a slight although significant improvement in the mean FSFI score from time 0 (16.7 +/- 12.9) to time 1 (20.9 +/- 13.8) (p < 0.001) which paralleled with a slight decrease in the incidence of clinically significant sexual dysfunction [49% (84/170) (time 0) versus 34.1% (58/170) (time 1)], (McNemar's test; p = 0.0241). The sub-group of younger women (18-25) showed a lesser increase in FSFI score from time 0 to time 1. In addition, both depression (p = 0.048) and anxiety (p < 0.001) significantly decreased over time. However, the female sexuality remained impaired since more than two thirds (69.5%) of women were sexually dysfunctional six months after VTOP. DISCUSSION: Voluntary TOP may influence the sexuality of younger females differently from how it influences that of older women. Hence, the sexuality of younger female should be regularly supervised in follow-up examinations. PMID- 28635531 TI - Drug exposure in early pregnancy might be related to the effects of increased maternal progesterone in implantation period. AB - AIM: This short communication aims to evaluate the relation in between drug exposure time and early pregnancy regarding gestational weeks. METHODS: The study covers the referrals made to the Department of Pharmacology for a teratogenic consultation in a 3-year period. From the recordings of pregnant women, the last menstrual period and the starting date of medication were used to determine the time of prescription with regard to gestational weeks. RESULTS: In all of the three years, potentially teratogenic medication was prescribed more frequently in the 3rd, 4th and 5th gestational weeks (in between 15-35 days of pregnancy). Approximately 75% of the pregnant women in the study were prescribed with drugs, most frequently with analgesics, antibiotics, gastrointestinal drugs and antidepressants, in these gestational weeks. CONCLUSIONS: The timing of prescriptions in early pregnancy frequently coincides with the increased levels of maternal progesterone in implantation period. Progesterone may lead to negative mood symptoms of an increased pain perception, anxiety, irritability and aggression in some of the pregnant women and therefore causes an increased stress condition which in turn may result in pain, infection and inflammation in the individual. Taking the frequently used medications into consideration, the reason for prescriptions in this period might be related to the symptoms originating from the effects of progesterone. Future studies are needed to better demonstrate this association of drug exposure and effects of maternal progesterone in early pregnancy. PMID- 28635532 TI - Assessing physical symptoms during the postpartum period: reliability and validity of the primary health questionnaire somatic symptom subscale (PHQ-15). AB - INTRODUCTION: This study aimed at establishing the reliability and validity of the primary health questionnaire (PHQ-15) somatic symptom severity subscale for postpartum women. METHODS: Women (N = 495) completed the PHQ-15 approximately 6 weeks postpartum during the baseline phase of a randomized controlled trial evaluating a writing intervention for postnatal health in England. Reliability was assessed using internal consistency statistics and convergent validity by comparing differences in self-reported physical health, health-related quality of life (QoL) and primary care usage by PHQ-15 symptom severity category. RESULTS: Cronbach's alpha for the PHQ-15 was 0.73 and item-total statistics met recommended guidelines. Validity analyzes showed 6% of women reported severe symptoms, 17% medium, 50% low and 27% minimal symptoms. Women with severe symptoms reported poorer overall physical health, poorer physical health-related QoL and greater use of primary care. Women with severe symptoms also rated their baby's health as worse and used primary care more for their baby. DISCUSSION: This study suggests the PHQ-15 has the potential to be a useful and valid measure of physical symptoms in postpartum women in high-income countries. PMID- 28635533 TI - The burden of endometriosis symptoms on health-related quality of life in women in the United States: a cross-sectional study. AB - INTRODUCTION: To examine the symptomatic burden of endometriosis on health related quality of life (HRQL) in women in the United States (US). METHODS: A cross sectional web-based survey study was conducted among women using survey panels. The survey included study-specific questions and standardized HRQL questionnaires. Participants reviewed a list of endometriosis symptoms and selected all symptoms they had ever or were currently experiencing. For current symptoms, participants rated the severity and bothersomeness of each symptom. Participants completed the endometriosis health profile (EHP-30) core questionnaire. Descriptive analyzes were performed and multivariate regressions were run with each EHP subscale as a dependent variable to examine the impact of symptoms while controlling for age and comorbid conditions. RESULTS: Mean age of the 1269 women was 34.3 +/- 0.3; 78% were white. At least 75% reported having ever experienced: pelvic pain/cramping during their menstrual period, anxiety/stress, lower back pain or fatigue/weariness/anemia. EHP-30 scores ranged from 33.6 (95% CI: 31.4, 35.8) (social support) to 37.8 (95% CI: 35.5, 40.1) (control and powerlessness), indicating moderate HRQL impact. For all but one domain and one symptom, EHP-30 scores were significantly higher (worse) for women who had individual endometriosis-related symptoms than for those who did not. EHP 30 scores consistently deteriorated with each increase in the number of symptoms experienced and by increasing perceived disease severity. Pelvic pain/cramping during menstrual period, irregular periods and general abdominal pain were significantly associated with the EHP-30 domain scores in the regression models. CONCLUSION: Experiencing endometriosis symptoms is associated with lower HRQL. Importantly, as symptom severity and number of symptoms increase, HRQL further deteriorates. PMID- 28635534 TI - Exploring premenstrual dysphoric disorder (PMDD) in the work context: a qualitative study. AB - This study aims to explore women's experience of premenstrual dysphoric disorder (PMDD) in the workplace, and identify if organizations can do anything to help. Analysis of 15 semi-structured interviews, using an inductive thematic analysis approach, revealed the most common symptoms women experience at work include difficulty in concentrating, self-doubt, paranoia, fatigue, tearfulness, a heightened sensitivity to the environment and people, outbursts, and finding social interaction particularly difficult during this premenstrual "episode" phase. It is these symptoms that contribute to observed presenteeism and absenteeism in the work context. After symptoms disappear (with onset of menstruation), women reported feelings of guilt and engage in over-compensatory behaviors such as working longer hours and taking work home during the remainder of the menstrual cycle (i.e. post-episode phase). Women alternate between these phases every month, which over time, accumulate and have additional consequences. Women are leaving the workforce through voluntary and/or involuntary turnover, sometimes giving up on careers entirely. The interviews also highlighted that organizations need greater awareness and support mechanisms in place for helping female employees with this condition. These findings could be of interest and have relevance to researchers, employers, policymakers, and health professionals. PMID- 28635535 TI - Effect of the previous reproductive outcomes in subfertile women after in vitro fertilization (IVF) and/or intracytoplasmic sperm injection (ICSI) treatments on perinatal anxious and depressive symptomatology. AB - INTRODUCTION: The present study aims to investigate the effects of previous reproductive outcomes on the levels of depression, anxiety and perceived social support in subfertile women who conceived after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment. METHODS: A prospective cohort study was developed. Data were collected on subfertile patients who conceived after IVF/ICSI treatment. All demographic and clinical data were recorded. The Edinburgh Postnatal Depression Scale, the State-Trait Anxiety Inventory-Y and the Multidimensional Scale of Perceived Social Support at 22 and 32 weeks of gestation and 15 days after delivery were completed. Data were analyzed comparing patients who conceived at their first IVF/ICSI cycle, after one unsuccessful ARTs cycle, and after multiple unsuccessful IVF/ICSI cycles. RESULTS: A significant increase in state anxiety and depression scores from 22 gestational weeks of gestation to 15 days after delivery was observed in patients who received multiple unsuccessful IVF/ICSI cycles compared with other groups. No significant difference in perceived social support was detected among groups. The differences in depression and anxiety scores remained consistent after controlling for perceived social support. DISCUSSION: A history of unsuccessful IVF/ICSI treatments seems to leave women more vulnerable in facing the duties of the new parental role. Such possibility underlies the importance of the availability of a psychological support for these women, even after a successful medical treatment for infertility. PMID- 28635536 TI - Women's experiences with vaginal examinations during labor in the Netherlands. AB - INTRODUCTION: Vaginal digital examination (VE) is a routine medical procedure during labor to assess the start and progression of labor. This study explores women's experiences with VE's during labor in the Netherlands. METHODS: An exploratory anonymous online survey was distributed among Dutch women who underwent a trial of labor and gave birth to a living term child in the previous six months. Unadjusted odds ratios are calculated to establish associations between women's characteristics and reporting a negative experience with VE's. RESULTS: Of the 159 women who met the inclusion criteria, 56 women (35.2%) reported a negative experience with the VE. These women reported more pain, embarrassment, not being able to relax, not feeling respected and not feeling the possibility to stop the examination. The odds of reporting negative experiences increased by giving birth in hospital, an instrumental delivery, more examinations, more different caretakers performing the examination and caregivers not introducing themselves before the examination. About 41.7% of the women reported being examined more often than advised in national and international guidelines (every two to four hours). DISCUSSION: Although our study is limited, it shows that experiences with the VE during labor can be negative and should be considered carefully. We promote research of and teaching the use of additional noninvasive methods to assess progression of labor in daily clinical practice. We conclude that the number of VE's during labor should be restricted as much as possible. VE's should only be performed in the interest of the woman in labor, after her informed consent and preferably performed by as few different caregivers as possible. PMID- 28635537 TI - Prenatal diagnosis tests and women's risk perception: a cross-sectional study. AB - OBJECTIVE: To investigate women's decision to undergo non-invasive and/or invasive tests for prenatal diagnosis depending on the procedure-related risk and the risk of carrying a foetus with Down syndrome (DS). Both risks are rated in terms of numerical relevance and acceptability. METHOD: A sample of 448 consecutive women with low-risk pregnancies were interviewed to collect social and clinical variables and to determine their perceptions of the risks of invasive procedure-related miscarriage and carrying a foetus with DS. The risks were scored numerically in terms of their relevance and acceptability using a 10 point rating scale. RESULTS: The factors related to the use of non-invasive tests were age >=35 years, not being treated at a public service, rating the risk of carrying a foetus with DS as having high numerical relevance and low acceptability, and rating the risk of miscarriage as having high acceptability. These relationships were still present when the use of invasive tests was considered, except in terms of the numerical relevance of the risk of carrying a foetus with DS. CONCLUSION: Perceived acceptability affects the interpretation of a given risk more than the numerical relevance of the risk. PMID- 28635538 TI - Clomipramine trial for treatment-resistant persistent genital arousal disorder: a case series. AB - INTRODUCTION: Treatment of persistent genital arousal disorder (PGAD), as a chronic and disabling condition, implicates substantial compelling complexities. METHODS: In this case series, seven women diagnosed with PGAD who were referred to the Sexual Dysfunction Unit of Psychotherapy Outpatient Clinic of Bakirkoy Research and Training Hospital for Psychiatry, Neurology, and Neurosurgery, Istanbul, Turkey between 2006 and 2009 were included. All patients were previously resistant to other antidepressants, antipsychotics and antiepileptics. The additional details of PGAD onset, frequency, type and duration of arousal, previous pharmacological interventions, and maximum and maintenance doses of clomipramine were recorded. RESULTS: All patients achieved a substantial symptomatic improvement with clomipramine within the follow-up period of 2-9 years. DISCUSSION: Based on our study results, we recommend clomipramine in combination with psychotherapy as the treatment of choice in PGAD and to be used before any invasive procedure such as electroconvulsive therapy (ECT) or surgery. PMID- 28635539 TI - An Old Challenge with New Promises: A Systematic Review on Comprehensive Geriatric Assessment in Long-Term Care Facilities. AB - Comprehensive geriatric assessment (CGA) is a multidimensional and multidisciplinary diagnostic process focused on determining the clinical profile, pathological risk, residual skills, short- and long-term prognosis, and personalized therapeutic and care plan of the functionally compromised and frail older subjects. Previous evidence suggested that the effectiveness of CGA programs may be influenced by settings where the CGA is performed [i.e., hospital, posthospital discharge/long-term care facilities (LTCFs), or community/home] as well as the specific clinical conditions of older frail individuals. In this scenario, CGA and quality of care in LTCFs have been a challenge for decades. In the present article, we systematically reviewed evidence from the last three decades of clinical research devoted to systematic implementation of CGA programs in LTCFs, that is, nursing homes, care homes, residential homes, and rehabilitation facilities. In the United States, all LTC residents must undergo a CGA on a regular basis on admission to a facility, prompting the development of the Resident Assessment Instrument (RAI) Minimum Data Set, a specific CGA-based assessment tool in this population. In the LTCF setting, the present reviewed evidence suggested that most complex older subjects may benefit from a CGA in terms of improved quality of care and reduced hospitalization events and that CGA must be standardized across healthcare settings to promote greater health system integration and coordination. In the LTCF setting, particularly in nursing homes, other new and promising CGA programs have also been proposed to develop rapid screening CGA-based tools to enhance in the future the ability of primary care physicians to recognize and treat geriatric syndromes in this setting. However, at present, the interRAI suite of instruments represented an integrated health information system that has the potential to provide person-centered information transcending healthcare settings. PMID- 28635540 TI - Reduced serum VGF levels were reversed by antidepressant treatment in depressed patients. AB - OBJECTIVES: VGF, a non-acronymic neuropeptide, is important in the pathogenesis of major depressive disorder (MDD) and in the functioning and efficacy of some antidepressant drugs. In this study we assessed whether serum VGF levels change in MDD patients and if antidepressant treatments can restore these changes. METHODS: We measured serum VGF concentrations using sandwich ELISA in drug-free MDD patients before treatment began (n = 26) and at 8 weeks after antidepressant treatment (n = 26) with escitalopram and duloxetine, two common antidepressants. The severity of depression was assessed with the 17-item Hamilton Depression Rating Scale (HDRS). RESULTS: VGF serum levels were significantly lower in MDD patients compared to controls (P = .002), even after controlling for the effects of age and education (P = .037), and they were reversed by 8 weeks of drug treatment (P < .0001). Both escitalopram and duloxetine restored the decreased serum VGF levels (P < .05). We observed no correlation between VGF levels and HDRS scores in pre-treatment MDD patients (P = .879). CONCLUSIONS: The results suggest that VGF may be implicated in the pathophysiology of MDD and in the mechanisms underlying the action of antidepressants, and serum VGF may be regarded as a trait parameter for MDD. PMID- 28635541 TI - Association between abnormal brain functional connectivity in children and psychopathology: A study based on graph theory and machine learning. AB - OBJECTIVES: One of the major challenges facing psychiatry is how to incorporate biological measures in the classification of mental health disorders. Many of these disorders affect brain development and its connectivity. In this study, we propose a novel method for assessing brain networks based on the combination of a graph theory measure (eigenvector centrality) and a one-class support vector machine (OC-SVM). METHODS: We applied this approach to resting-state fMRI data from 622 children and adolescents. Eigenvector centrality (EVC) of nodes from positive- and negative-task networks were extracted from each subject and used as input to an OC-SVM to label individual brain networks as typical or atypical. We hypothesised that classification of these subjects regarding the pattern of brain connectivity would predict the level of psychopathology. RESULTS: Subjects with atypical brain network organisation had higher levels of psychopathology (p < 0.001). There was a greater EVC in the typical group at the bilateral posterior cingulate and bilateral posterior temporal cortices; and significant decreases in EVC at left temporal pole. CONCLUSIONS: The combination of graph theory methods and an OC-SVM is a promising method to characterise neurodevelopment, and may be useful to understand the deviations leading to mental disorders. PMID- 28635542 TI - Gene expression study of mitochondrial complex I in schizophrenia and paranoid personality disorder. AB - OBJECTIVES: The aetiology and molecular mechanisms of schizophrenia (SCZ) and paranoid personality disorder (PPD) are not yet clarified. The present study aimed to assess the role of mitochondrial complex I and cell bioenergetic pathways in the aetiology and characteristics of SCZ and PPD. METHODS: mRNA levels of all genomic and mitochondrial genes which encode mitochondrial complex I subunits (44 genes) were assessed in blood in 634 SCZ, 340 PPD patients and 528 non-psychiatric subjects using quantitative real-time PCR, and associated comprehensive psychiatric, neurological and biochemical assessments. RESULTS: Significant expression changes of 18 genes in SCZ patients and 11 genes in PPD patients were detected in mitochondrial complex I. Most of these genes were novel candidate genes for SCZ and PPD. Several correlations between mRNA levels and severity of symptoms, drug response, deficits in attention, working memory, executive functions and brain activities were found. CONCLUSIONS: Deregulations of both core and supernumerary subunits of complex I are involved in the aetiology of SCZ and PPD. These deregulations have effects on brain activity as well as disorder characteristics. PMID- 28635544 TI - Heparin: new life for an old drug. AB - Heparin is one of the oldest drugs, which nevertheless remains in widespread clinical use as an inhibitor of blood coagulation. The history of its identification a century ago unfolded amid one of the most fascinating scientific controversies turning around the distribution of credit for its discovery. The composition, purification and structure-function relationship of this naturally occurring glycosaminoglycan regarding its classical role as anticoagulant will be dealt with before proceeding to discuss its therapeutic potential in, among other, inflammatory and infectious disease, cancer treatment, cystic fibrosis and Alzheimer's disease. The first bibliographic reference hit using the words 'nanomedicine' and 'heparin' is as recent as 2008. Since then, nanomedical applications of heparin have experienced an exponential growth that will be discussed in detail, with particular emphasis on its antimalarial activity. Some of the most intriguing potential applications of heparin nanomedicines will be exposed, such as those contemplating the delivery of drugs to the mosquito stages of malaria parasites. PMID- 28635545 TI - Current asthma, respiratory symptoms and airway infections among students in relation to the school and home environment in Japan. AB - OBJECTIVE: To study associations between the school and home environment and current asthma, respiratory symptoms and airway infections among Japanese students. METHODS: Japanese students (12-15 y) (N = 1048) in four schools responded to a questionnaire on respiratory health, allergy and the home environment. Temperature, relative air humidity (RH) and student density (students/m2 floor area) was measured in the classrooms: dust was collected from floors and in classroom air and analysed for cat (Fel d 1) and dog (Can f 1) allergens. Health associations were analysed by multi-level logistic regression. RESULTS: Doctor's diagnosed asthma was common (13.4%), 8.8% reported cat allergy and 6.1% dog allergy. The median level in floor dust was 41 ng/g (IQR 23-92) for Fel d 1 and 101 ng/g (IQR 54-101) for Can f 1. The median level in air was 18.6 ng/ m2/ day (IQR5.9-25.1) for Fel d 1 and 18.6 ng/ m2/ day (IQR 6.0-13.3) for Can f 1. High RH, high student density and airborne cat allergen was associated with airway infections. In the home environment, recent indoor painting, new floor materials, odour, having cats as pets, window pane condensation in winter, and dampness in floor construction were associated with respiratory illness. CONCLUSION: High relative air humidity, high student density and airborne cat allergens at school may increase the risk of airway infections. Having cats as pets, chemical emissions from paint and new floor materials, odour and dampness can constitute domestic risk factors for respiratory symptoms while having dogs as pets could be protective. PMID- 28635543 TI - Anxiety modulates the relation between attention-deficit/hyperactivity disorder severity and working memory-related brain activity. AB - OBJECTIVES: Individuals with attention-deficit/hyperactivity disorder (ADHD) often have heightened levels of anxiety, which has been associated with worse performance on working memory tasks. Knowledge of the neural pathways underlying the combined presence of ADHD and anxiety may aid in a better understanding of their co-occurrence. Therefore, we investigated how anxiety modulates the effect of ADHD severity on neural activity during a visuospatial working memory (VSWM) task. METHODS: Neuroimaging data were available for 371 adolescents and young adults participating in the multicentre cohort study NeuroIMAGE (average age 17.1 years). We analysed the effects of ADHD severity, anxiety severity and their interaction on-task accuracy, and on neural activity associated with working memory (VSWM trials minus baseline), and memory load (high memory load trials minus low load trials). RESULTS: Anxiety significantly modulated the relation between ADHD severity and neural activity in the cerebellum for the working memory contrast, and bilaterally in the striatum and thalamus for the memory load contrast. CONCLUSIONS: We found that ADHD with co-occurring anxiety is associated with lowered neural activity during a VSWM task in regions important for information gating. This fits well with previous theorising on ADHD with co occurring anxiety, and illustrates the neurobiological heterogeneity of ADHD. PMID- 28635546 TI - Physical activity and asthma: A longitudinal and multi-country study. AB - OBJECTIVE: To investigate the impact of physical activity on asthma in middle aged adults, in one longitudinal analysis, and one multi-centre cross-sectional analysis. METHODS: The Respiratory Health in Northern Europe (RHINE) is a population-based postal questionnaire cohort study. Physical activity, height and weight were self-reported in Bergen, Norway, at RHINE II (1999-2001) and all centres at RHINE III (2010-2012). A longitudinal analysis of Bergen data investigated the association of baseline physical activity with follow-up asthma, incident asthma and symptoms, using logistic and zero-inflated Poisson regression (n = 1782). A cross-sectional analysis of all RHINE III centres investigated the association of physical activity with concurrent asthma and symptoms (n = 13,542) using mixed-effects models. Body mass index (BMI) was categorised (<20, 20-24.99, 25-29.99, 30+ kg/m2) and physical activity grouped by amount and frequency of lighter (no sweating/heavy breathing) and vigorous (sweating/heavy breathing) activity. RESULTS: In the Bergen longitudinal analysis, undertaking light activity 3+ times/week at baseline was associated with less follow-up asthma (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.22, 0.89), whilst an effect from undertaking vigorous activity 3+ times/week was not detected (OR 1.22, 95% CI 0.44, 2.76). The associations were attenuated with BMI adjustment. In the all centre cross-sectional analysis an interaction was found, with the association between physical activity and asthma varying across BMI categories. CONCLUSION: These findings suggest potential longer-term benefit from lighter physical activity, whilst improvement in asthma outcomes from increasing activity intensity was not evident. Additionally, it appears the benefit from physical activity may differ according to BMI. PMID- 28635547 TI - "Healthcare seems to vary a lot": A focus group study among parents of children with severe allergy. AB - BACKGROUND: Living with an allergic disease has consequences for both affected children and their families. The aim of this qualitative study was to gain deeper knowledge of what life is like for families of children with severe allergic disease, in order to improve care and thereby reduce the consequences of living with a chronic disease. METHODS: Four focus group interviews were performed with Swedish parents of children, aged 6-11 and 12-16 years, with severe allergic disease (from one or more allergic conditions, such as food allergy/eczema/hay fever/asthma). The participants were attending a family support weekend. Interviews were analyzed with a qualitative method. RESULTS: Based on parental experiences, the following themes were presented in the analysis: limitations, control, injustices, and fear and anxiety. It was evident that the families lived isolated lives and experienced different kinds of limitations. Parents felt a need to have control of their child's everyday life and described a feeling of constantly being on guard. They also suggested that understanding of the child's allergies was lacking in preschool/school and that healthcare did not provide adequate support. They felt that the same care should be offered to children and families, no matter where they lived. CONCLUSIONS: Based on parental experiences, having a child with severe allergic disease implies a need to constantly be on guard. In order to improve the care of children with severe allergy and their families, a more person- and family-centered approach is needed. PMID- 28635548 TI - Th-17 regulatory cytokines IL-21, IL-23, and IL-6 enhance neutrophil production of IL-17 cytokines during asthma. AB - BACKGROUND: In a subset of severe asthma patients, chronic airway inflammation is associated with infiltration of neutrophils, Th-17 cells and elevated expression of Th-17-derived cytokines (e.g., interleukin [IL]-17, IL-21, IL-22). Peripheral neutrophils from allergic asthmatics are known to express higher IL-17 cytokine levels than those from healthy subjects, but the regulatory mechanisms involved are not well understood. We hypothesize that Th-17 regulatory cytokines could modulate IL-17 expression in neutrophils. METHODS: Peripheral blood neutrophils isolated from asthmatics were stimulated with IL-21, IL-23, and IL-6 cytokines and their ability to produce IL-17A and IL-17F was determined relative to healthy controls. Signal transducer and activator of transcription 3 (STAT3) phosphorylation levels were measured in stimulated neutrophil using flow cytometry. The requirement for STAT3 phosphorylation was determined by blocking its activation using a specific chemical inhibitor. RESULTS: Stimulating asthmatic neutrophils with IL-21, 23, and 6 enhanced the production of IL-17A and IL-17F at significantly higher levels comparatively to healthy controls. Stimulating neutrophils with IL-21, IL-23, and IL-6 cytokines enhanced STAT3 phosphorylation, in all cases. Interestingly, inhibiting STAT3 phosphorylation using a specific chemical inhibitor dramatically blocked the ability of neutrophils to produce IL-17, demonstrating that STAT3 activation is the major factor mediating IL-17 gene expression. CONCLUSIONS: These findings suggest that neutrophil infiltration in lungs of severe asthmatics may represent an important source of pro-inflammatory IL-17A and -F cytokines, a production enhanced by Th 17 regulatory cytokines, and thus providing a feedback mechanism that sustains inflammation. Our results suggest that STAT3 pathway could be a potential target for regulating neutrophilic inflammation during severe asthma. PMID- 28635549 TI - A missed primary care appointment correlates with a subsequent emergency department visit among children with asthma. AB - OBJECTIVE: Since the Affordable Care Act's implementation, emergency department (ED) visits have increased. Poor asthma control increases the risk of acute exacerbations and preventable ED visits. The Centers for Medicare and Medicaid Services support the reduction of preventable ED visits to reduce healthcare spending. Implementation of interventions to avoid preventable ED visits has become a priority for many healthcare systems yet little data exist examining children's missed asthma management primary care (PC) appointments and subsequent ED visits. METHODS: Longitudinal, retrospective review at a children's hospital was conducted for children with diagnosed asthma (ICD-9 493.xx), ages 2-18 years, scheduled for a PC visit between January 1, 2010, and June 30, 2012 (N = 3895). Records were cross-referenced with all asthma-related ED visits from January 1, 2010 to December 31, 2012. Logistic regression with maximum likelihood estimation was conducted. RESULTS: None of the children who completed a PC appointment experienced an ED visit in the subsequent 6 months whereas 2.7% of those with missed PC appointments had an ED visit (chi2 = 64.28, p <.0001). Males were significantly more likely to have an ED visit following a missed PC appointment than females (chi2 = 34.37, p <.0001). There was a statistically significant interaction of sex * age. Younger children (<12 years) made more visits than older children. CONCLUSIONS: The importance of adherence to PC appointments for children with asthma as one mechanism for preventing ED visits was demonstrated. Interventions targeting missed visits could decrease asthma-related morbidity, preventable ED visits, and healthcare costs. PMID- 28635550 TI - Peptide grafted and self-assembled poly(gamma-glutamic acid)-phenylalanine nanoparticles targeting camptothecin to glioma. AB - AIM: To synthesize cRGDfK peptide conjugated poly(gamma-glutamic acid) phenylalanine nanoparticles to improve the therapeutic efficacy of camptothecin (CPT) against glioblastoma multiforme. METHODS: Peptide-conjugated, drug-loaded nanoparticles (cRGDfK-conjugated camptothecin-loaded PGA-PA nanoparticles [RCPN]) were prepared and physico-chemically characterized using different techniques. Nanoparticles were evaluated for in vitro anticancer activity, cellular uptake, induction of apoptosis and wound healing cell migration against U87MG human glioblastoma cells. RESULTS: RCPN, with a particle size of <100 nm and 65% CPT encapsulation efficiency, exhibited a dose- and time-dependent cytotoxicity to glioblastoma cells. Compared with native CPT or unconjugated nanoparticles, RCPN induced apoptosis, increased reactive oxygen species generation and inhibited U87MG cell migration. CONCLUSION: cRGDfK-mediated and amphiphilic copolymer-based nanomedicines represent a new approach for improved delivery of anticancer drugs to and treatment of glioblastoma multiforme. PMID- 28635551 TI - New strategies in melanoma therapy: can nanoparticles overcome chemoresistance? PMID- 28635552 TI - Temporal variations of fine and coarse particulate matter sources in Jeddah, Saudi Arabia. AB - : This study provides the first comprehensive analysis of the seasonal variations and weekday/weekend differences in fine (aerodynamic diameter <2.5 MUm; PM2.5) and coarse (aerodynamic diameter 2.5-10 MUm; PM2.5-10) particulate matter mass concentrations, elemental constituents, and potential source origins in Jeddah, Saudi Arabia. Air quality samples were collected over 1 yr, from June 2011 to May 2012 at a frequency of three times per week, and analyzed. The average mass concentrations of PM2.5 (21.9 MUg/m3) and PM10 (107.8 MUg/m3) during the sampling period exceeded the recommended annual average levels by the World Health Organization (WHO) for PM2.5 (10 MUg/m3) and PM10 (20 MUg/m3), respectively. Similar to other Middle Eastern locales, PM2.5-10 is the prevailing mass component of atmospheric particulate matter at Jeddah, accounting for approximately 80% of the PM10 mass. Considerations of enrichment factors, absolute principal component analysis (APCA), concentration roses, and backward trajectories identified the following source categories for both PM2.5 and PM2.5 10: (1) soil/road dust, (2) incineration, and (3) traffic; and for PM2.5 only, (4) residual oil burning. Soil/road dust accounted for a major portion of both the PM2.5 (27%) and PM2.5-10 (77%) mass, and the largest source contributor for PM2.5 was from residual oil burning (63%). Temporal variations of PM2.5-10 and PM2.5 were observed, with the elevated concentration levels observed for mass during the spring (due to increased dust storm frequency) and on weekdays (due to increased traffic). The predominant role of windblown soil and road dust in both the PM2.5 and PM2.5-10 masses in this city may have implications regarding the toxicity of these particles versus those in the Western world where most PM health assessments have been made in the past. These results support the need for region-specific epidemiological investigations to be conducted and considered in future PM standard setting. IMPLICATIONS: Temporal variations of fine and coarse PM mass, elemental constituents, and sources were examined in Jeddah, Saudi Arabia, for the first time. The main source of PM2.5-10 is natural windblown soil and road dust, whereas the predominant source of PM2.5 is residual oil burning, generated from the port and oil refinery located west of the air sampler, suggesting that targeted emission controls could significantly improve the air quality in the city. The compositional differences point to a need for health effect studies to be conducted in this region, so as to directly assess the applicability of the existing guidelines to the Middle East air pollution. PMID- 28635553 TI - Bridging generation gaps in medical education: a "light bulb moment" at the Association for Medical Education in Europe annual conference in Barcelona. AB - Generation gaps have been described before and so have ways to deal with them. But they were mainly focused on the teachers. We would like to bridge these generation gaps, not only by creating awareness but also by learning from each other. This leads to better equipped doctors across all generations and promotes lifelong learning instantaneously. PMID- 28635554 TI - Summary of the Bill Morgan Memorial Symposium - part 1: biology, epidemiology and radiation protection. PMID- 28635555 TI - Personality disorders: patient characteristics and level of outpatient treatment service. AB - BACKGROUND: In this naturalistic study, patients with personality disorders (N = 388) treated at Stolpegaard Psychotherapy Center, Mental Health Services, Capital Region of Denmark were allocated to two different kinds of treatment: a standardized treatment package with a preset number of treatment hours (basic hospital service) and 2: a specialized treatment program for the most severely affected patients without a predetermined restricted number of treatment hours and significantly more individual psychotherapy (regional specialized hospital services). AIMS: To investigate patient characteristics associated with clinicians' allocation of patients to the two different personality disorder services. METHODS: Patient characteristics across eight domains were collected in order to study whether there were systematic differences between patients allocated to the two different treatments. Patient characteristics included measures of symptom severity, personality pathology, trauma and socio-demographic characteristics. Significance testing and binary regression analysis were applied to identify important predictors. RESULTS: Patient characteristics on fifteen variables differed significantly, all in the expected direction, with patients in regional specialized hospital services showing more pathology and psychosocial problems. In the regression model, only age and two variables capturing psychosocial functioning remained significant predictors of allocation. DISCUSSION: The finding that younger age was the most significant predictor of longer treatment replicates an earlier finding of allocation to treatment for personality disorder. Overall, this study therefore lends further support to the importance of demographic and social contextual factors in clinicians' allocation of patients to different treatment services for personality disorder. PMID- 28635556 TI - Executive control in schizophrenia: a preliminary study on the moderating role of COMT Val158Met for comorbid alcohol and substance use disorders. AB - BACKGROUND: A functional polymorphism in the catechol-O-methyltransferase (COMT) gene (Val158Met) appears to influence cognition in people with alcohol/substance use disorders (AUD/SUD) and in those with psychosis. METHODS: To explore the potential moderating effect of these factors, a cross-sectional study was conducted, randomly recruiting subjects with DSM-IV diagnosis of schizophrenia. AUD/SUD was rigorously assessed, as well as COMT Val158Met polymorphism. Executive control functioning was measured using the Intra-Extra Dimensional Set Shift (IED). The effect of a possible interaction between comorbid AUD/SUD and COMT Val158Met polymorphism on IED scores was explored. RESULTS: Subjects with schizophrenia, comorbid AUD/SUD, and MetMet carriers for SNP rs4680 of the COMT gene showed worse performance on IED completed stages scores, as compared with individuals with ValVal genotype. However, among subjects without AUD/SUD, those with the MetMet variant performed better than people carrying ValVal genotype. CONCLUSIONS: This study is the first to date examining the impact of COMT on cognition in a highly representative sample of people with schizophrenia and comorbid AUD/SUD. Differential moderating effects of COMT Val/Met genotype variations may similarly influence executive functions in people with schizophrenia and comorbid AUD/SUD. PMID- 28635558 TI - Identifying Criminogenic Needs Using the Personality Assessment Inventory With Males Who Have Sexually Offended. AB - The present study investigated the relationships between the scales of the Personality Assessment Inventory (PAI) and variables relevant to recidivism risk and criminogenic need to inform clinicians' use of the PAI for purposes of treatment planning and risk management. PAI profiles, risk measure and domain scores, and recidivism data were collected for 158 males who have been convicted of sexually offending. Data were analyzed to investigate whether select clinical scales of the PAI correlated with conceptually relevant domains of risk and/or recidivism. Our findings demonstrated that the antisocial scales were consistently associated with risk constructs and recidivism, while very few clinical and personality scales showed relationships with risk constructs. The PAI seems to include select scales that represent risk-related needs, but also, other scales that may be more related to responsivity issues, and therefore may have utility to address two of the risk, need, and responsivity principles. PMID- 28635557 TI - Cellular immune responses of older adults to four influenza vaccines: Results of a randomized, controlled comparison. AB - Cellular immunity is important for protection against the serious complications of influenza in older adults. As it is unclear if newer influenza vaccines elicit greater cellular responses than standard vaccines, we compared responses to 2 standard and 2 newer licensed trivalent inactivated vaccines (TIVs) in a randomized trial in older adults. Non-frail adults >= 65 y old were randomly assigned to receive standard subunit, MF59-adjuvanted subunit, standard split virus or intradermal split-virus TIV. Peripheral blood mononuclear cells (PBMC) harvested pre- and 3-weeks post-vaccination were stimulated with live A/H3N2 virus. PBMC supernatants were tested for interleukin 10 (IL-10) and interferon gamma (IFN-gamma), and lysates for granzyme B (GrB). Flow cytometry identified CD4+ and CD8+ T- cells expressing intracellular IL-2, IL-10, IFN-gamma, GrB, or perforin. Differences following immunization were assessed for paired subject samples and among vaccines. 120 seniors participated, 29-31 per group, which were well matched demographically. Virus-stimulated PBMCs were GrB-rich before and after vaccination, with minimal increases evident. Immunization did not increase secretion of IFN-gamma or IL-10. However, cytolytic effector T-cells (CD8+GrB+perforin+) increased significantly in percentage post-vaccination in all groups, to similar mean values across groups. CD4+GrB+perforin+ T-cells also increased significantly after each vaccine, to similar mean values among vaccines. Vaccination did not increase the low baseline percentages of CD4+ or CD8+ T-cells expressing IFN-gamma, IL-2 or IL-10 . In conclusion, participants had pre-existing cellular immunity to H3N2 virus. All 4 vaccines boosted cellular responses to a similar but limited extent, particularly cytolytic effector CD8+ T cells associated with clinical protection against influenza. PMID- 28635559 TI - Purification of antibody against Ara h 2 by a homemade immunoaffinity chromatography column. AB - Antibodies are used extensively in numerous applications both in vivo and in vitro. To purify anti-Ara h 2 polyclonal antibody, a homemade immunoaffinity chromatography (IAC) column method was established. The properties of homemade column were compared with those of the mAb affinity protein G (MPG) agarose high flow, a commercially available column successfully used in capturing polyclonal antibodies. During antibody purification from rabbits' antiserum against Ara h 2, the column capacity, recovery, and purification factor were characterized for IAC and MPG. The homemade IAC could separate the corresponding antibody with higher specificity and lower cost but with lower recovery and column capacity than those of MPG. Thus, the homemade IAC is a specific, inexpensive, and suitable method that can be used for various laboratory purifications. PMID- 28635561 TI - Patient handling in the healthcare sector. PMID- 28635560 TI - Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma. AB - BACKGROUND: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC. METHODS: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7-5.6], and median OS was 5.0 months [confidence interval 0.7-5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%. CONCLUSIONS: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and radioactive iodine-refractory DTC. PMID- 28635564 TI - Arthroscopic fixation of acute acromioclavicular joint disruption with TightRopeTM: Outcome and complications after minimum 2 (2-5) years follow-up. AB - PURPOSE: To evaluate the midterm results of arthroscopic reconstruction of acute acromioclavicular (AC) joint disruption using TightRopeTM system. METHODS AND MATERIAL: We retrospectively assess the results of 24 patients of acute AC joint dislocation who were operated using TightRope system. Constant and University of California, Los Angeles (UCLA) scores and coracoclavicular distance were calculated pre- and postoperatively. Data was entered into MS excel and analyzed using the SPSS version 17. RESULTS: The mean follow-up was 39.45 months. Constant and UCLA scores were significantly increased postoperatively. Six patients had partial loss of reduction within 3-6 months and two patients had a failure of construct. Constant score was significantly lower in these patients. CONCLUSION: TightRope reconstruction of the AC joint is a reproducible and safe alternative to many other techniques of AC joint reconstruction. Early subluxation remains a concern and may reflect the need for technique modification. PMID- 28635562 TI - Nanoformulated natural therapeutics for management of streptozotocin-induced diabetes: potential use of curcumin nanoformulation. AB - AIM: The goal of this study was to improve curcumin (CUR) aqueous solubility and bioavailability via nanoformulation, and then study its activity and mechanism of action as an antidiabetic agent. METHODS: CUR-loaded pluronic nanomicelles (CURnp) were prepared and characterized. Biochemical assessments were performed as well as histological, confocal and RTPCR studies on pancreatic target tissues. RESULTS: CURnp with a diameter of 333 +/- 6 nm and zeta potential of -26.1 mv were obtained. Antidiabetic action of CURnp was attributed to significant upregulation of Pdx-1 and NKx6.1 gene expression and achievement of optimum redox balance, which led to alleviation of streptozotocin-induced beta-cell damage via a significant upregulation in insulin gene expression proved by RTPCR studies and by the presence of 40% insulin positive cells through confocal microscope studies on pancreatic tissue. PMID- 28635566 TI - Stone size is a predictor for residual stone and multiple procedures of endoscopic combined intrarenal surgery. AB - OBJECTIVES: The aim of this study was to identify the predictors of treatment results after endoscopic combined intrarenal surgery (ECIRS). MATERIALS AND METHODS: A retrospective analysis was conducted of 75 patients with renal stones who underwent ECIRS and a preoperative non-contrast computed tomography (NCCT) examination. The stone-free rate (SFR), number of primary procedures and perioperative complications were investigated, and the predictors contributing to these three outcomes were analyzed. Stone-free status was determined within 3 months postoperatively using NCCT. The number of primary procedures (defined as ECIRS and/or conventional transurethral lithotripsy) and perioperative complications were reviewed using the medical records. RESULTS: The final SFR after further treatment was 69.3% (52/75 cases). About 70% of all cases underwent only one primary procedure, and the average number of primary procedures was 1.41. From multivariate analysis, increasing stone size (p < 0.001), increasing Charlson Comorbidity Index (p = 0.043) and unfavorable nephrostomy tract (p = 0.046) were independent significant predictors of residual stones, and increasing stone size was the only independent significant predictor of two or more primary procedures (p = 0.017). Overall, 24 out of 75 patients (32%) experienced one or more perioperative complications. Based on multivariate analysis, female gender (p = 0.014) and increasing Hounsfield units (p = 0.006) were significantly associated with perioperative complications. CONCLUSIONS: Increasing stone size was an independent predictor for residual stone and multiple procedures of ECIRS. In contrast, increasing number of involved calyces was not predictive, which may be responsible for the combined antegrade and retrograde access. Female gender and increasing Hounsfield units of the stone were significantly associated with perioperative complications of ECIRS, and ECIRS for these patients requires careful attention. PMID- 28635565 TI - Prostate cancer stem cells: from theory to practice. AB - None of the generally accepted theories on prostate cancer development can fully explain many distinguishing features of the disease, such as intratumoral heterogeneity, metastatic growth, drug resistance and tumor relapse. Prostate stem cells are a heterogeneous and small subpopulation of self-renewing cells which can actively proliferate in response to changes in the androgen level and give rise to all the cell lineages that build the prostate epithelium. According to the cancer stem cell hypothesis, prostate cancer could be a stem cell disease. Prostate cancer stem cells, which represent only a minimal percentage of the tumor mass, are characterized by a markedly increased clonogenicity and therapeutic resistance. These tumor-initiating cells reside in dynamic niches distributed within the prostate but at a higher concentration in proximal regions of the prostatic ducts. Several markers have been used to identify prostate cancer stem cells. Nevertheless, a definitive profile has not yet been established owing to specificity issues. As cancer stem cells play determining roles in the birth and burst of prostate malignancy, strategies that selectively target them have gained huge clinical attention. Unraveling the mechanisms underlying the physiological functions of cancer stem cells and gaining fundamental insights into their putative involvement in the pathogenesis of prostate tumors provide novel opportunities for the development of efficient and sophisticated therapeutic strategies in the future. PMID- 28635567 TI - Management of neobladder complications: endoscopy comes first. AB - OBJECTIVE: The aim of this study was to report the functional outcome after endoscopic management of neobladder complications. MATERIALS AND METHODS: Out of 197 patients who underwent radical cystectomy and orthotopic ileal neobladder reconstruction between 2007 and 2013, 30 patients with delayed postoperative complications were enrolled in this study. Complications were in the form of: eight patients with outflow obstruction, 12 with ureteroenteric stricture, nine with neobladder calculi and one with an isolated recurrent papillary tumor inside the neobladder. Patients were followed up regularly to assess the outcomes of endoscopic treatment. RESULTS: The mean maximum flow rate and postvoiding residual urine after endoscopic treatment of outflow obstruction were 18.2 +/- 3.9 ml/s and 28.7 +/- 11 ml, respectively. Ten patients with ureteroenteric stricture showed resolution of hydronephrosis after antegrade dilatation and JJ stent fixation, with two patients requiring open surgery owing to impassable strictures. Complete clearance of neobladder calculi occurred after endoscopic neocystolithotripsy, with two patients requiring two sessions owing to large calculi. Transurethral resection of the neobladder for isolated tumor recurrence was performed in one patient over two sessions, followed by adjuvant chemoirradiation. CONCLUSIONS: Endourological management of orthotopic neobladder problems is the safest choice. It avoids the difficulties and complications of open surgery and has durable results. PMID- 28635568 TI - Additional value of magnetic resonance-targeted biopsies to standard transrectal ultrasound-guided biopsies for detection of clinically significant prostate cancer. AB - OBJECTIVE: The aim of this study was to evaluate the additional value of magnetic resonance imaging-targeted biopsy (MRI-TB) to standard transrectal ultrasound guided biopsy (SB) for detection of clinically significant prostate cancer (PCa). An additional aim was to compare the biopsy results to MRI evaluation using a Likert scale. MATERIALS AND METHODS: Patients with newly diagnosed localized PCa (n = 53) by clinical routine SB were prospectively included. The majority of the patients were scheduled for curative therapy before enrollment. The patients underwent multiparametric MRI (mpMRI) at 3 T using an endorectal coil followed by two MRI-TBs, using ultrasound with cognitive fusion. All included patients underwent MRI-TB, even those who had low to very low suspicion of significant PCa on mpMRI. The detection rate of significant cancer on SB versus SB + MRI-TB was compared in the 53 included patients and with whole-mounted histopathology as reference in 34 cases. Comparison of the biopsy results to MRI evaluation and interreader agreement calculation of five-point Likert score evaluation were performed. RESULTS: In total, 32 significant (Gleason >=7) PCa were detected by SB, while SB + MRI-TB detected an additional five significant PCa. MRI-TB alone detected 20 and missed 17 significant PCa. Ten of the significant PCa cases missed by MRI-TB had a Likert score of 3 or lower. Interreader agreement using the Likert scale was high, with a kappa value of 0.77 (95% confidence interval 0.63-0.92, p < 0.0001). CONCLUSION: Detection of significant PCa increased by adding MRI-TB to SB. This may not be of enough clinical value to justify the use of targeted biopsies in this patient group. PMID- 28635569 TI - Stratification model based on early postprostatectomy prostate-specific antigen kinetics may help to reduce the risk of overtreatment in candidates for adjuvant radiotherapy. AB - OBJECTIVE: The aim of this study was to construct a stratification model based on early postoperative kinetics of prostate-specific antigen (PSA) to select the most suitable high-risk patients for early intervention after radical prostatectomy (RP). MATERIALS AND METHODS: The study evaluated 205 men who had undergone RP without any adjuvant treatment. All of the patients had positive surgical margins, extracapsular extension and/or seminal vesicle invasion. The patients underwent multiple ultrasensitive PSA measurements on days 14, 30, 60 and 90 after RP, and subsequently at 3 month intervals. The ability of particular PSA measurements to predict biochemical recurrence (BCR) was assessed using the area under the curve (AUC). A sequential mathematical decision procedure was constructed to create a stratification model. RESULTS: During the median follow up of 45.9 months, 106 patients (51%) experienced BCR. Prediction of BCR in terms of the AUC for PSA measurements on days 14, 30, 60 and 90 after the surgery was 0.61, 0.70, 0.80 and 0.82, respectively. In the multivariate analysis, only PSA after RP remained as a predictor of progression-free survival (p < 0.001). The stratification model based on calculated cut-off values for PSA on day 30 (0.068 ng/ml) and PSA on day 60 (0.015 ng/ml) reduced the potential overtreatment rate by 37%. CONCLUSIONS: The results imply that ultrasensitive PSA values obtained very early after RP correlate with the presence of recurrent disease in high-risk patients. Incorporating these readily available variables into risk stratification models may help to individualize the administration of adjuvant radiotherapy and thus to minimize overtreatment. PMID- 28635570 TI - Quality dementia care: Prerequisites and relational ethics among multicultural healthcare providers. AB - BACKGROUND: Many nursing homes appear as multicultural workplaces where the majority of healthcare providers have an ethnic minority background. This environment creates challenges linked to communication, interaction and cultural differences. Furthermore, the healthcare providers have varied experiences and understanding of what quality care of patients with dementia involves. PURPOSE: The aim of this study is to illuminate multi-ethnic healthcare providers' lived experiences of their own working relationship, and its importance to quality care for people with dementia. RESEARCH DESIGN: The study is part of a greater participatory action research project: 'Hospice values in the care for persons with dementia'. The data material consists of extensive notes from seminars, project meetings and dialogue-based teaching. The text material was subjected to phenomenological-hermeneutical interpretation. Participants and research context: Participants in the project were healthcare providers working in a nursing home unit. The participants came from 15 different countries, had different formal qualifications, varied backgrounds and ethnic origins. Ethical considerations: The study is approved by the Norwegian Regional Ethics Committee and the Norwegian Social Science Data Services. FINDINGS: The results show that good working relationships, characterized by understanding each other's vulnerability and willingness to learn from each other through shared experiences, are prerequisites for quality care. The healthcare providers further described ethical challenges as uncertainty and different understandings. DISCUSSION: The results are discussed in the light of Logstrup's relational philosophy of ethics and the concepts of vulnerability, ethic responsibility, trust and openness of speech. CONCLUSION: The prerequisite for quality care for persons with dementia in a multicultural working environment is to create arenas for open discussions between the healthcare providers. Leadership is of great importance. PMID- 28635571 TI - Comparison of the Seventh and Eighth Editions of the American Joint Committee on Cancer/Union for International Cancer Control Tumor-Node-Metastasis Staging System for Differentiated Thyroid Cancer. AB - OBJECTIVE: To evaluate the efficacy and prognostic validity for disease-specific survival (DSS) of the eighth edition American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis (TNM) staging system (TNM-8) compared to the seventh edition (TNM-7) in patients with differentiated thyroid carcinoma (DTC). METHODS: The seventh and eighth editions of the TNM staging system were applied to 1613 DTC patients who underwent thyroid surgery between 1996 and 2003. The proportion of variation explained and Harrell's c-index were evaluated to compare the predictive capability of DSS. RESULTS: The mean age of the patients was 44.7 years, and the median follow-up period was 11.2 years. When TNM-8 was applied, 63% of T3 and 3% of N1b DTCs were downgraded to T1/T2 and N1a, respectively. About 38% of patients were downstaged according to TNM-8. The 10 year DSS rates in TNM-7 stages I, II, III, and IV were 99.7%, 98.2%, 98.8%, and 83.2%, respectively. Those in TNM-8 stages I, II, III, and IV were 99.6%, 95.4%, 72.3%, and 48.6%, respectively. The proportion of variation explained values of TNM-7 and TNM-8 were 6.0% and 7.0%, respectively. The Harrell's c-index of TNM-7 was 0.86 and that of TNM-8 was 0.88. CONCLUSIONS: A significant number of patients were reclassified to lower stages with the application of TNM-8 compared to TNM-7. Applying TNM-8 could improve the accuracy of the staging system for predicting DSS in patients with DTC. PMID- 28635573 TI - [Colonic ischaemia - a condition with an atypical clinical presentation; timely recognition and treatment improve prognosis]. AB - The incidence of colonic ischaemia has risen in recent decades because of the ageing population. Patients with colonic ischaemia present with mild abdominal pain, rectal blood loss and/or diarrhoea. However, no pathognomonic signs have been described. Signs of peritonitis are often absent and serum lactate may be normal. This makes prompt recognition and diagnosis difficult, while early treatment with close monitoring is important to optimise prognosis. Computed tomography may have suggestive findings and exclude other causes of abdominal pain, but endoscopy remains the gold standard for confirming the diagnosis. Colonic ischaemia is mostly located in the left colon and has a relatively good prognosis. However, the presence of right-sided ischaemic colitis should alert physicians, because these patients have a worse prognosis, increased need for surgery and they also experience higher mortality rates. PMID- 28635574 TI - [It is all about the form - adrenaline in anaphylaxis: intravenous or intramuscular administration?] AB - BACKGROUND: Medication errors are a frequent problem in the accident and emergency (A&E) department. CASE DESCRIPTION: A 17-year-old boy was referred to our A&E department with an anaphylactic reaction to peanuts. Because of various shortcomings in the care process in A&E, adrenaline was administered intravenously instead of intramuscularly, resulting in a broad complex tachycardia. We analysed these shortcomings using the 'Prevention and recovery information system for monitoring and analysis' (PRISMA) method. CONCLUSION: Medication errors are usually a result of shortcomings in non-technical skills, such as communication and situational awareness. Training these skills by applying the concept 'Crew resource management' may reduce medication errors and improve patient safety. PMID- 28635575 TI - [High-risk obstetrics in tertiary centres: anaesthetist, hybrid operating suite and obstetric critical care unit]. AB - The frequency of pregnancy-related morbidity has increased over recent decades, as has the number of patients with complex congenital cardiac anomalies reaching fertile age, resulting in an increasing number of high-risk pregnancies. In order to optimalise maternal and foetal outcome in these patients, not only is the availability of optimal in-hospital facilities (e.g. obstetric critical care unit, hybrid operating suite) important, but also a multidisciplinary approach which is mandatory for successful maternal and foetal outcome. The role of a dedicated obstetric anaesthetist in this multidisciplinary team is essential. In contrast with other Western countries, in the Netherlands this has so far been underestimated. Obstetric anaesthetists should also be part of multidisciplinary obstetric care in high-risk patients during pregnancy, thus optimalising conditions for successful delivery and maternal and foetal outcome. PMID- 28635576 TI - [A man with an anomaly in his ear]. AB - A 65-year-old man presented with an anomaly in his left ear. He had no complaints, but was ashamed of the lesion. On physical examination a pigmented, pedunculated, polypoid tumour of approximately 2 x 2.5 cm was seen, which filled the whole cavum conchae. After excision, histopathological examination showed a verruca seborrhoica. PMID- 28635577 TI - [An intraoral swelling located in the buccal mucosa]. AB - A 69-year-old woman presented with a bony hard swelling inside her left cheek. After clinical and radiographic examination, the diagnosis sialolithiasis of the main duct of the parotid gland was made. Surgical removal relieved her complaints. PMID- 28635578 TI - [Healthcare professionals back in the driving seat]. AB - This commentary discusses the increasingly observed managerilisation of healthcare. Managerilisation frequently results in a framework of rules, regulations and accompanying time-consuming forms and procedures to guide decision-making. Although likely developed with the best of intentions in mind, this framework may be of limited value and tends to leave healthcare professionals feeling frustrated and distrusted. In addition, overzealous bureaucracy and rigid adherence to protocols may be disadvantageous to patient care and outcomes. Instead, we advocate a renewed focus on common sense and in particular on a renewed trust in healthcare professionals. Their professional judgement is based on many years of education and bedside experience. Hospital management should once again seek to embrace their expertise, while healthcare professionals should actively seek to regain the reins when it comes to delivering healthcare. PMID- 28635579 TI - [Fish oil in pregnancy: can it prevent asthma in children?] AB - Taking fish oil supplements in the third trimester of pregnancy was associated with significantly less wheezing or asthma in the child at the age of 3-5 years, according to a randomized clinical trial by Bisgaard et al., NEJM 2017. However, the results of this study should be interpreted with caution. The primary end points were modified at a late stage in the study, and two primary end points, eczema in the first 3 years of life and allergic sensitization at 18 months of age, were demoted to secondary end points, and showed no significant effect of treatment. Furthermore, the age range for the published primary end point, persistent wheeze, differed from that in the protocol. Additional concerns include the emphasis on outcomes by omega-3 fatty acid levels in the blood, a post hoc subgroup analysis not included in the protocol. In our opinion, this study does not justify advising routine fish oil supplements in pregnancy. PMID- 28635580 TI - Hide and "sick": Self-concealment, shame and distress in the setting of psycho oncology. AB - : ABSTRACTObjective:Both trait and contextual self-concealment, as well as shame- and guilt-proneness, have previously been found to be associated with psychological distress. However, findings regarding the associations between these variables among patients with cancer and among the spouses of patients with cancer are limited. The aim of the current study was therefore to investigate the relationship between shame-proneness and psychological distress (anxiety and depression) by examining the mediating role of both trait and contextual self concealment among patients with cancer and among the spouses of patients with cancer. METHOD: The current study was part of a large-scale cross-sectional study on self-concealment among patients with cancer and spouses of patients with cancer. It was based on two independent subsamples: patients with cancer and spouses of patients with cancer, who were not dyads. A total of 80 patients with cancer and 80 spouses of (other) patients with cancer completed questionnaires assessing shame- and guilt-proneness, trait and contextual self-concealment, anxiety, and depression. RESULTS: Results indicate that spouses reported both greater shame-proneness and anxiety than did patients (main effect of role). Female participants reported greater shame-proneness, higher levels of contextual self-concealment, and greater depression and anxiety than did male participants (main effect of gender). No group differences (role/gender) were found for guilt proneness and trait self-concealment. Trait and contextual self-concealment partially mediated the relationship between shame-proneness and distress, pointing out the need to further examine additional mediators. SIGNIFICANCE OF RESULTS: Findings suggest that contextual self-concealment and shame-proneness are important variables to consider when assessing distress in the setting of psycho-oncology. Study results may have significant clinical implications regarding the need to identify patients and spouses who are more prone to shame and self-concealment behavior in order to better tailor interventions for them. PMID- 28635581 TI - First report on the successful hybridization of Pangasianodon hypophthalmus (Sauvage, 1878) and Clarias gariepinus (Burchell, 1822). AB - Breeding and larval performance of novel hybrids from reciprocal crosses of Asian catfish Pangasianodon hypophthalmus (Sauvage, 1878) and African catfish Clarias gariepinus (Burchell, 1822) were investigated in this study. Spawning was by hormonal injection of brood fish, artificial fertilization, and incubation in triplicate aquarium tanks (0.5 * 0.5 * 0.5 m3) with continuous aeration. Reciprocal crosses (?C. gariepinus * ?P. hypophthalmus and ?P. hypophthalmus * ?C. gariepinus) had lower hatchability (<=50%) than their pure siblings (>=75%). Fish from all crosses survived until the juvenile stage but survival at 35 days post hatching (dph) was higher for pure C. gariepinus sib. ?C. gariepinus * ?P. hypophthalmus was observed to be less resistant to degradation of water quality than the other crosses, however it had higher body weight compared with the other crosses that showed similar performance. Morphological comparison of surviving juvenile at 35 dph, showed that all ?P. hypophthalmus * ?C. gariepinus and 13% of the ?C. gariepinus * ?P. hypophthalmus exhibited the very same morphology as that of their maternal parent species, while the other portion of the ?C. gariepinus * ?P. hypophthalmus cross exhibited morphological traits that were intermediate between those of both parent species. This study been the first successful attempt to hybridize both species and therefore, laid the groundwork for further studies on the aquaculture potentials of the novel hybrids. PMID- 28635582 TI - Protective effects of ethanol extracts of Artemisia asiatica Nakai ex Pamp. on ageing-induced deterioration in mouse oocyte quality. AB - Following ovulation, oocytes undergo a time-dependent deterioration in quality referred to as post-ovulatory ageing. Although various factors influence the post ovulatory ageing of oocytes, oxidative stress is a key factor involved in deterioration of oocyte quality. Artemisia asiatica Nakai ex Pamp. has been widely used in East Asia as a food ingredient and traditional medicine for the treatment of inflammation, cancer, and microbial infections. Recent studies have shown that A. asiatica exhibits antioxidative effects. In this study, we investigated whether A. asiatica has the potential to attenuate deterioration in oocyte quality during post-ovulatory ageing. Freshly ovulated mouse oocytes were cultured with 0, 50, 100 or 200 MUg/ml ethanol extracts of A. asiatica Nakai ex Pamp. After culture for up to 24 h, various ageing-induced oocyte abnormalities, including morphological changes, reactive oxygen species (ROS) accumulation, apoptosis, chromosome and spindle defects, and mitochondrial aggregation were determined. Treatment of oocytes with A. asiatica extracts reduced ageing-induced morphological changes. Moreover, A. asiatica extracts decreased ROS generation and the onset of apoptosis by preventing elevation of the Bax/Bcl-2 expression ratio during post-ovulatory ageing. Furthermore, A. asiatica extracts attenuated the ageing-induced abnormalities including spindle defects, chromosome misalignment and mitochondrial aggregation. Our results demonstrate that A. asiatica can relieve deterioration in oocyte quality and delay the onset of apoptosis during post-ovulatory ageing. PMID- 28635583 TI - Cigarette smoke is associated with altered expression of antioxidant enzymes in granulosa cells from women undergoing in vitro fertilization. AB - This study was undertaken to evaluate whether cigarette smoke is associated with changes in the expression of antioxidant enzymes in granulosa cells of women undergoing IVF treatments. For this aim, the expression of three antioxidant enzymes (SOD1, SOD2 and catalase) in non-smokers (n = 20) and smokers (n = 20) was analyzed. There was a statistically significant overexpression of SOD2 and catalase mRNA levels in smokers in comparison with non-smokers. Cigarette smoking was associated with a lower fertilization rate, implantation rate and pregnancy rate in comparison with non-smokers. There was no effect on retrieved oocytes number, metaphase II oocytes number, quality of embryos transferred and live birth rate. These findings suggest that cigarette smoke initiates oxidative stress in granulosa cells. PMID- 28635584 TI - The Patient Dignity Inventory: Just another evaluation tool? Experiences with advanced cancer patients. AB - OBJECTIVE: The Patient Dignity Inventory (PDI) evaluates sources of distress related to the feeling of loss of dignity and was designed for patients at the end of life. The aim of the present work was to generate a better understanding of the experiences of healthcare staff when using the PDI. METHOD: An exploratory qualitative study is presented about the experience of 4 professionals who applied the PDI to 124 advanced-cancer patients. Our study consisted of an analysis of their experiences, taken from information generated in a focus group. A thematic analysis was performed on the information generated at that meeting by two researchers working independently. RESULTS: The initial experiences with the PDI on the part of the professionals led them to systematically administer the questionnaire as part of an interview instead of having patients fill it out themselves in written form. What started out as an evaluation very often led to a profound conversation on the meaning of life, dignity, and other sensitive, key issues related to the process of the illness. SIGNIFICANCE OF RESULTS: The PDI has intrinsic therapeutic value and is useful in clinical practice, and it is also a way of examining issues related to dignity and the meaning of life within the context of advanced-stage illness. There is a need for studies that examine patient experiences through a PDI-based interview. PMID- 28635585 TI - The meaning and experience of bereavement support: A qualitative interview study of bereaved family caregivers. AB - : ABSTRACTObjective:Experiences of bereavement can be stressful and are frequently complicated by emotional, familial, and financial issues. Some-though not all-caregivers may benefit from bereavement support. While considered standard within palliative care services in Australia, bereavement support is not widely utilized by family caregivers. There is little research focused on the forms of bereavement support desired or required by family caregivers, how such care is viewed, and/or how bereavement support is experienced. This study examined the experiences of bereaved family caregivers and their impressions of and interactions with bereavement support. METHOD: This paper reports on one aspect of a broader study designed to explore a range of experiences of patients and caregivers to and through palliative care. Focusing on experiences of bereavement, it draws on qualitative semistructured interviews with 15 family caregivers of palliative care patients within a specialist palliative care unit of an Australian metropolitan hospital. The interviews for this stage of the study were initiated 3-9 months after an initial interview with a family caregiver, during which time the palliative patient had died, and they covered family caregivers' experiences of bereavement and bereavement support. Interviews were digitally audiotaped and transcribed in full. A thematic analysis was conducted utilizing the framework approach wherein interview transcripts were reviewed, key themes identified, and explanations developed. RESULTS: The research identified four prevalent themes: (1) sociocultural constructions of bereavement support as for the incapable or socially isolated; (2) perceptions of bereavement support services as narrow in scope; (3) the "personal" character of bereavement and subsequent incompatibility with formalized support, and (4) issues around the timing and style of approaches to being offered support. SIGNIFICANCE OF RESULTS: Systematic pre-bereavement planning and careful communication about the services offered by palliative care bereavement support centers may improve receipt of support among bereaved family caregivers in need. PMID- 28635587 TI - ICTV Virus Taxonomy Profile: Ophioviridae. AB - The Ophioviridae is a family of filamentous plant viruses, with single-stranded negative, and possibly ambisense, RNA genomes of 11.3-12.5 kb divided into 3-4 segments, each encapsidated separately. Virions are naked filamentous nucleocapsids, forming kinked circles of at least two different contour lengths. The sole genus, Ophiovirus, includes seven species. Four ophioviruses are soil transmitted and their natural hosts include trees, shrubs, vegetables and bulbous or corm-forming ornamentals, both monocots and dicots. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Ophioviridae, which is available at http://www.ictv.global/report/ophioviridae. PMID- 28635586 TI - GC-1: A Thyromimetic With Multiple Therapeutic Applications in Liver Disease. AB - Thyroid hormones (THs), namely, 3,5,3'-triiodo-l-thyronine (T3) and 3,5,3',5' tetraiodo-l-thyronine (thyroxine or T4), influence a variety of physiological processes that have important implications in fetal development, metabolism, cell growth, and proliferation. While THs elicit several beneficial effects on lipid metabolism and improve myocardial contractility, these therapeutically desirable effects are associated to a thyrotoxic state that severely limits the possible use of THs as therapeutic agents. Therefore, several efforts have been made to develop T3 analogs that could retain the beneficial actions (triglyceride, cholesterol, obesity, and body mass lowering) without the adverse TH-dependent side effects. This goal was achieved by the synthesis of TRbeta-selective agonists. In this review, we summarize the current knowledge on the effects of one of the best characterized TH analogs, the TRbeta1-selective thyromimetic, GC 1. In particular, we review some of the effects of GC-1 on different liver disorders, with reference to its possible clinical application. A brief comment on the possible therapeutic use of GC-1 in extrahepatic disorders is also included. PMID- 28635588 TI - Genome sequence variation in the constricta strain dramatically alters the protein interaction and localization map of Potato yellow dwarf virus. AB - The genome sequence of the constricta strain of Potato yellow dwarf virus (CYDV) was determined to be 12 792 nt long and organized into seven ORFs with the gene order 3'-N-X-P-Y-M-G-L-5', which encodes the nucleocapsid, phospho, movement, matrix, glyco, and RNA-dependent RNA polymerase proteins, respectively, except for X, which is of unknown function. Cloned ORFs for each gene, except L, were used to construct a protein interaction and localization map (PILM) for this virus, which shares greater than 80 % amino acid similarity in all ORFs except X and P with the sanguinolenta strain of this species (SYDV). Protein localization patterns and interactions unique to each viral strain were identified, resulting in strain-specific PILMs. Localization of CYDV and SYDV proteins in virus infected cells mapped subcellular loci likely to be sites of replication, morphogenesis and movement. PMID- 28635589 TI - Regulation of Escherichia coli Pathogenesis by Alternative Sigma Factor N. AB - sigmaN (also sigma54) is an alternative sigma factor subunit of the RNA polymerase complex that regulates the expression of genes from many different ontological groups. It is broadly conserved in the Eubacteria with major roles in nitrogen metabolism, membrane biogenesis, and motility. sigmaN is encoded as the first gene of a five-gene operon including rpoN (sigmaN), ptsN, hpf, rapZ, and npr that has been genetically retained among species of Escherichia, Shigella, and Salmonella. In an increasing number of bacteria, sigmaN has been implicated in the control of genes essential to pathogenic behavior, including those involved in adherence, secretion, immune subversion, biofilm formation, toxin production, and resistance to both antimicrobials and biological stressors. For most pathogens how this is achieved is unknown. In enterohemorrhagic Escherichia coli (EHEC) O157, Salmonella enterica, and Borrelia burgdorferi, regulation of virulence by sigmaN requires another alternative sigma factor, sigmaS, yet the model by which sigmaN-sigmaS virulence regulation is predicted to occur is varied in each of these pathogens. In this review, the importance of sigmaN to bacterial pathogenesis is introduced, and common features of sigmaN-dependent virulence regulation discussed. Emphasis is placed on the molecular mechanisms underlying sigmaN virulence regulation in E. coli O157. This includes a review of the structure and function of regulatory pathways connecting sigmaN to virulence expression, predicted input signals for pathway stimulation, and the role for cognate sigmaN activators in initiation of gene systems determining pathogenic behavior. PMID- 28635590 TI - Imbalance between innate antiviral and pro-inflammatory immune responses may contribute to different outcomes involving low- and highly pathogenic avian influenza H5N3 infections in chickens. AB - In order to gain further insight into the early virus-host interactions associated with highly pathogenic avian influenza virus infections in chickens, genome-wide expression profiling of chicken lung and brain was carried out at 24 and 72 h post-inoculation (h p.i.). For this purpose two recombinant H5N3 viruses were utilized, each possessing a polybasic HA0 cleavage site but differing in pathogenicity. The original rH5N3 P0 virus, which has a low-pathogenic phenotype, was passaged six times through chickens to give rise to the derivative rH5N3 P6 virus, which is highly pathogenic (Diederich S, Berhane Y, Embury-Hyatt C, Hisanaga T, Handel K et al.J Virol 2015;89:10724-10734). The gene-expression profiles in lung were similar for both viruses, although they varied in magnitude. While both viruses produced systemic infections, differences in clinical disease progression and viral tissue loads, particularly in brain, where loads of rH5N3 P6 were three orders of magnitude higher than rH5N3 P0 at 72 .p.i., were observed. Although genes associated with gene ontology (GO) categories INFalpha and INFbeta biosynthesis, regulation of innate immune response, response to exogenous dsRNA, defence response to virus, positive regulation of NF-kappaB import into the nucleus and positive regulation of immune response were up-regulated in rH5N3 P0 and rH5N3 P6 brains, fold changes were higher for rH5N3 P6. The additional up-regulation of genes associated with cytokine production, inflammasome and leukocyte activation, and cell-cell adhesion detected in rH5N3 P6 versus rH5N3 P0 brains, suggested that the balance between antiviral and pro-inflammatory innate immune responses leading to acute CNS inflammation might explain the observed differences in pathogenicity. PMID- 28635591 TI - CamOptimus: a tool for exploiting complex adaptive evolution to optimize experiments and processes in biotechnology. AB - Multiple interacting factors affect the performance of engineered biological systems in synthetic biology projects. The complexity of these biological systems means that experimental design should often be treated as a multiparametric optimization problem. However, the available methodologies are either impractical, due to a combinatorial explosion in the number of experiments to be performed, or are inaccessible to most experimentalists due to the lack of publicly available, user-friendly software. Although evolutionary algorithms may be employed as alternative approaches to optimize experimental design, the lack of simple-to-use software again restricts their use to specialist practitioners. In addition, the lack of subsidiary approaches to further investigate critical factors and their interactions prevents the full analysis and exploitation of the biotechnological system. We have addressed these problems and, here, provide a simple-to-use and freely available graphical user interface to empower a broad range of experimental biologists to employ complex evolutionary algorithms to optimize their experimental designs. Our approach exploits a Genetic Algorithm to discover the subspace containing the optimal combination of parameters, and Symbolic Regression to construct a model to evaluate the sensitivity of the experiment to each parameter under investigation. We demonstrate the utility of this method using an example in which the culture conditions for the microbial production of a bioactive human protein are optimized. CamOptimus is available through: (https://doi.org/10.17863/CAM.10257). PMID- 28635592 TI - Type-specific L1 virus-like particle-mediated protection of horses from experimental bovine papillomavirus 1-induced pseudo-sarcoid formation is long lasting. AB - Equine sarcoids are common therapy-resistant skin tumours induced by bovine papillomavirus type 1 or 2 (BPV1, BPV2) infection. We have previously shown that prophylactic vaccination with BPV1 L1 virus-like particles (VLPs) efficiently protects horses from experimental BPV1-induced pseudo-sarcoid development. Here, we assessed BPV1 L1 VLP vaccine-mediated long-term protection from experimental tumour formation in seven horses 5 years after immunization with three different doses of BPV1 L1 VLPs, and three unvaccinated control animals. Horses were challenged by intradermal inoculation with infectious BPV1 virions at 10 sites on the neck (106 virions per injection). In vaccinated horses, BPV1 challenge did not result in any apparent lesions irrespective of vaccine dosage and BPV1 neutralizing antibody titres that had dropped considerably over time and below the detection limit in one individual. Control horses developed pseudo-sarcoids at all inoculation sites. We conclude that immunization of horses with BPV1 L1 VLPs induces long-lasting protection against experimental BPV1 virion-induced disease. PMID- 28635593 TI - The protein Slr1143 is an active diguanylate cyclase in Synechocystis sp. PCC 6803 and interacts with the photoreceptor Cph2. AB - Cyclic-di-GMP is an ubiquitous second messenger in bacteria. Several c-di-GMP receptor proteins have been identified to date, and downstream signalling pathways are often mediated through protein-protein interactions. The photoreceptor Cph2 from the cyanobacterium Synechocystis sp. PCC 6803 comprises three domains related to c-di-GMP metabolism: two GGDEF and one EAL domain. It has been shown that the C-terminal GGDEF domain acts as blue-light triggered c-di GMP producer thereby inhibiting motility of the cells in blue light. The specific function of the other two c-di-GMP related domains remained unclear. In this study, we test knockout mutants of potential interaction partners of Cph2 for altered phototactic behaviour. Whereas wild-type cells are non-motile under high intensity red light of 640 nm, the mutant Deltaslr1143 displays positive phototaxis. This phenotype can be complemented by overexpression of full-length Slr1143, which also results in an increased cellular c-di-GMP concentration. However, the non-motile phenotype of wild-type cells under high-intensity red light appears not to be due to an elevated cellular c-di-GMP content. Using co precipitation and yeast two-hybrid assays, we demonstrate that the GGDEF domain of Slr1143 interacts with the EAL and the GGDEF domains of Cph2. However, under the test conditions, the interaction of the two proteins is not light-dependent. We conclude that Slr1143 is a new Cph2-interacting regulatory factor which modulates motility under red light and accordingly we propose Cip1 (Cph2 interacting protein 1) as a new designation for this gene product. PMID- 28635595 TI - What is a Global Britain? PMID- 28635594 TI - Translation repression via modulation of the cytoplasmic poly(A)-binding protein in the inflammatory response. AB - Gene expression is precisely regulated during the inflammatory response to control infection and limit the detrimental effects of inflammation. Here, we profiled global mRNA translation dynamics in the mouse primary macrophage mediated inflammatory response and identified hundreds of differentially translated mRNAs. These mRNAs' 3'UTRs have enriched binding motifs for several RNA-binding proteins, which implies extensive translational regulatory networks. We characterized one such protein, Zfp36, as a translation repressor. Using primary macrophages from a Zfp36-V5 epitope tagged knock-in mouse generated by CRISPR/Cas9-mediated genome editing, we found that the endogenous Zfp36 directly interacts with the cytoplasmic poly(A)-binding protein. Importantly, this interaction is required for the translational repression of Zfp36's target mRNAs in resolving inflammation. Altogether, these results uncovered critical roles of translational regulations in controlling appropriate gene expression during the inflammatory response and revealed a new biologically relevant molecular mechanism of translational repression via modulating the cytoplasmic poly(A) binding protein. PMID- 28635596 TI - Breast cancer targeted therapy: successes and challenges. PMID- 28635597 TI - Kenya's nurses strike takes its toll on health-care system. PMID- 28635598 TI - Sickle cell disease: tipping the balance of genomic research to catalyse discoveries in Africa. PMID- 28635600 TI - Offline: The Donald Trump Promise. PMID- 28635599 TI - A global research agenda on migration, mobility, and health. PMID- 28635601 TI - Access to abortion in the USA-the legal battle. PMID- 28635602 TI - Preparedness for natural disasters in Colombia. PMID- 28635603 TI - Exposure to lead in petrol and increased incidence of dementia. PMID- 28635604 TI - Exposure to lead in petrol and increased incidence of dementia. PMID- 28635605 TI - Exposure to lead in petrol and increased incidence of dementia - Authors' reply. PMID- 28635606 TI - Stroke in ICD-11: the end of a long exile. PMID- 28635607 TI - CONACYT's freeze on postgraduate fellowships in Mexico. PMID- 28635608 TI - The protective role of folic acid against testicular dysfunction in lead intoxicated rat model. AB - There is an increasing concern over male reproductive toxicity caused by lead exposure. Folic acid (FA) is supposed to be a promising therapeutic strategy against lead toxicity. Therefore, the aim of this experimental study was to shed light on the potential protective role of FA on lead-induced testicular dysfunction in rats and its possible underlying mechanistic pathways. Rats (n = 24) were divided into four groups: Control, FA, Lead, and FA+Lead group. After 4 weeks, lead intoxication resulted in a marked reduction in the relative testicular weight and the serum level of testosterone, an impairment in the characters of semen analysis, and an increased content of lead, malondialdehyde and both interleukin-6 and -10 and a decreased antioxidant enzyme levels in the testicular tissue homogenate. Furthermore, marked degenerative histological changes and an increased expression of NF-kappaB were also noticed in the testicular tissue of Lead group. Supplementation of FA in association with lead considerably alleviated these adverse outcome responses most probably owing to its cytoprotective ability as emerged from combating the oxidative stress and inflammatory reactions. We concluded that FA could act as a highly effective fighting approach against lead-associated testicular toxicity. PMID- 28635609 TI - Gastroprotective effect of ghrelin against indomethacin-induced gastric injury in rats: possible role of heme oxygenase-1 pathway. AB - Ghrelin has been shown to ameliorate gastric injury by several mechanisms in experimental animal models. The present study aimed to investigate the effect of pretreatment with ghrelin on indomethacin-induced gastric injury in rats and the role of heme oxygenase-1(HO-1) pathway as a novel mechanism underlying the gastroprotective effect of ghrelin. In all groups studied, ulcer score (U.S), ulcer index (U.I) and preventive index (P.I) were evaluated and the gastric inflammatory biomarkers including levels of tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and myeloperoxidase (MPO) activity as well as prostaglandin E2 (PGE2), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), HO-1 and bilirubin as an indicator of heme oxygenase activity were measured. Indomethacin induced significant elevation in U.S and U.I as well as the inflammatory and the oxidative markers and reduced the PGE2 in addition to HO-1 level and activity. Pretreatment with ghrelin reversed these results. In order to elucidate the possible role of HO-1 in mediating the protective effects of ghrelin, tin protoporphyrin (SnPP) HO-1 blocker was administrated; it significantly attenuated the gastroprotective effect of ghrelin. In conclusion HO 1 activity significantly contributes toward ghrelin-mediated gastroprotection. PMID- 28635610 TI - Chemical components, antioxidant potential and hepatoprotective effects of Artemisia campestris essential oil against deltamethrin-induced genotoxicity and oxidative damage in rats. AB - In the present study, we evaluated the antioxidant potential of Artemisia campestris essential oil (ACEO) and the possible protective effects against deltamethrin induced hepatic toxic effects. The ACEO showed radical scavenging activity with IC50 = 47.66 +/- 2.51 ug/ml, ferric reducing antioxidant power (FRAP) potential (EC50 = 5.36 +/- 0.77 ug/ml), superoxide scavenging activity (IC50 = 0.175 +/- 0.007 ug/ml) and OH scavenging activity (IC50 = 0.034 +/- 0.007 ug/ml). The obtained results of phenolic profile demonstrated that phenolic compounds are the major contributor to the antioxidant activity of ACEO. GC-MS analysis revealed the presence of 61 components in which monoterpene hydrocarbons constitute the major fraction (38.85%). In in vivo study, deltamethrin exposure caused an increase of serum AST, ALT and ALP activities, hepatic malondialdehyde (MDA) (measured as TBARS) and conjugated dienes markers of lipid peroxidation (LPO), while antioxidant enzyme activities (SOD, CAT and GPx) decreased significantly. Furthermore, it induces DNA damage as indicated by DNA fragmentation accompanied with severe histological changes in the liver tissues. The treatment with vitamin E or ACEO significantly improved the hepatic toxicity induced by deltamethrin. It can be concluded that vitamin E and ACEO are able to improve the hepatic oxidative damage induced by deltamethrin. Therefore, ACEO is an important product in reducing the toxic effects of deltamethrin. PMID- 28635611 TI - Modulatory effects of naringin on hepatic key enzymes of carbohydrate metabolism in high-fat diet/low-dose streptozotocin-induced diabetes in rats. AB - We evaluated the modulatory effects of naringin on altered hepatic key enzymes of carbohydrate metabolism in high-fat diet/low-dose streptozotocin-induced diabetic rats. Oral treatment of naringin at a doses of 20, 40 and 80 mg/kg body weight to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, blood glycosylated hemoglobin and increase in the levels of plasma insulin and blood hemoglobin. The altered activities of the hepatic key enzymes of carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase, glycogen phosphorylase and glycogen content of diabetic rats were significantly reverted to near normal levels by the treatment of naringin in a dose-dependent manner. Naringin at a dose of 80 mg/kg body weight showed the highest significant effect than the other two doses (20 and 40 mg/kg). Further, immunohistochemical observation of pancreas revealed that naringin-treated diabetic rats showed the increased number of insulin immunoreactive beta-cells, which confirmed the biochemical findings. These findings revealed that naringin has potential antihyperglycemic activity in high-fat diet/low-dose streptozotocin induced diabetic rats. PMID- 28635612 TI - Consequences of lipopolysaccharide and n-3 polyunsaturated fatty acid administration on aortic function of spontaneously hypertensive rats. AB - The aim of the work was to study the delayed effect of lipopolysaccharide (LPS) administration on endothelial function of the aorta of rats with genetic hypertension. Further, the possibility to ameliorate LPS-induced changes by n-3 polyunsaturated fatty acids (n-3 PUFA) was tested. Rats received a bolus of 1 mg/kg LPS i.p.; n-3 PUFA were administered in the dose of 30 mg/kg daily for 10 days p.o.. Ten days after receiving of LPS, the body weight gain of rats was statistically lower compared to control rats (p < 0.05). n-3 PUFA administration to LPS rats had no effect on this parameter. The TBARS and NAGA concentrations in plasma were significantly increased in the LPS group (p < 0.05) and n-3 PUFA administration returned them to control values. In functional studies, phenylephrine (PE, 1 umol/l) evoked contraction of aortas which was not statistically different among experimental groups. However, endothelium-dependent relaxation was depressed in the LPS group (p < 0.05) and n-3 PUFA slightly recovered it to control values. In conclusion, oxidative stress seems to be responsible for aortic endothelial dysfunction detected 10 days after administration of LPS to rats. n-3 PUFA slightly improved the function of the endothelium injured by LPS, probably thanks to their antioxidant properties. Prolonged administration of higher doses of n-3 PUFA should defend the vascular endothelium against detrimental effect of bacterial inflammation. PMID- 28635613 TI - Association of the S267F variant on NTCP gene and treatment response to pegylated interferon in patients with chronic hepatitis B: a multicentre study. AB - BACKGROUND: Sodium taurocholate co-transporting polypeptide (NTCP) is a cell receptor for HBV. The S267F variant on the NTCP gene is inversely associated with the chronicity of HBV infection, progression to cirrhosis and hepatocellular carcinoma in East Asian populations. The aim of this study was to determine whether the S267F variant was associated with response to pegylated interferon (PEG-IFN) in patients with chronic HBV infection. METHODS: A total of 257 patients with chronic HBV, treated with PEG-IFN for 48 weeks, were identified from 13 tertiary hospitals included in the hepatitis B database of the Thai Association for the Study of the Liver (THASL). RESULTS: Of these, 202 patients were infected with HBV genotype C (84.9%); 146 patients were hepatitis B e antigen (HBeAg)-positive (56.8%). Genotypic frequencies of the S267F polymorphism were 85.2%, 14.8% and 0% for the GG, GA and AA genotypes, respectively. S267F GA was associated with sustained alanine aminotransferase (ALT) normalization (OR = 3.25, 95% CI 1.23, 8.61; P=0.02) in HBeAg-positive patients. Patients with S267F variant tended to have more virological response, sustained response with hepatitis B surface antigen (HBsAg) loss at 24 weeks following PEG-IFN treatment. There was no association between the S267F variant and improved patient outcomes in HBeAg-negative patients. CONCLUSIONS: The S267F variant on the NTCP gene is independently associated with sustained normalization of ALT following treatment with PEG-IFN in patients with HBV infection who are HBeAg-positive. The findings of this study provide additional support for the clinical significance of the S267F variant of NTCP beyond HBV entry. PMID- 28635614 TI - Advanced treatment planning using direct 4D optimisation for pencil-beam scanned particle therapy. AB - We report on development of a new four-dimensional (4D) optimisation approach for scanned proton beams, which incorporates both irregular motion patterns and the delivery dynamics of the treatment machine into the plan optimiser. Furthermore, we assess the effectiveness of this technique to reduce dose to critical structures in proximity to moving targets, while maintaining effective target dose homogeneity and coverage. The proposed approach has been tested using both a simulated phantom and a clinical liver cancer case, and allows for realistic 4D calculations and optimisation using irregular breathing patterns extracted from e.g. 4DCT-MRI (4D computed tomography-magnetic resonance imaging). 4D dose distributions resulting from our 4D optimisation can achieve almost the same quality as static plans, independent of the studied geometry/anatomy or selected motion (regular and irregular). Additionally, current implementation of the 4D optimisation approach requires less than 3 min to find the solution for a single field planned on 4DCT of a liver cancer patient. Although 4D optimisation allows for realistic calculations using irregular breathing patterns, it is very sensitive to variations from the planned motion. Based on a sensitivity analysis, target dose homogeneity comparable to static plans (D5-D95 <5%) has been found only for differences in amplitude of up to 1 mm, for changes in respiratory phase <200 ms and for changes in the breathing period of <20 ms in comparison to the motions used during optimisation. As such, methods to robustly deliver 4D optimised plans employing 4D intensity-modulated delivery are discussed. PMID- 28635616 TI - Fermi-to-Bose crossover in a trapped quasi-2D gas of fermionic atoms. AB - The physics of many-body systems where particles are restricted to move in two spatial dimensions is challenging and even controversial: on one hand, neither long-range order nor Bose condensation may appear in infinite uniform 2D systems at finite temperature, on the other hand this does not prohibit superfluidity or superconductivity. Moreover, 2D superconductors, such as cuprates, are among the systems with the highest critical temperatures. Ultracold atoms are a platform for studying 2D physics. Unique from other physical systems, quantum statistics may be completely changed in an ultracold gas: an atomic Fermi gas may be smoothly crossed over into a gas of Bose molecules (or dimers) by tuning interatomic interactions. We review recent experiments where such crossover has been demonstrated, as well as critical phenomena in the Fermi-to-Bose crossover. We also present simple theoretical models describing the gas at different points of the crossover and compare the data to these and more advanced models. PMID- 28635615 TI - Topography on a subcellular scale modulates cellular adhesions and actin stress fiber dynamics in tumor associated fibroblasts. AB - Cells can sense and adapt to mechanical properties of their environment. The local geometry of the extracellular matrix, such as its topography, has been shown to modulate cell morphology, migration, and proliferation. Here we investigate the effect of micro/nanotopography on the morphology and cytoskeletal dynamics of human pancreatic tumor-associated fibroblast cells (TAFs). We use arrays of parallel nanoridges with variable spacings on a subcellular scale to investigate the response of TAFs to the topography of their environment. We find that cell shape and stress fiber organization both align along the direction of the nanoridges. Our analysis reveals a strong bimodal relationship between the degree of alignment and the spacing of the nanoridges. Furthermore, focal adhesions align along ridges and form preferentially on top of the ridges. Tracking actin stress fiber movement reveals enhanced dynamics of stress fibers on topographically patterned surfaces. We find that components of the actin cytoskeleton move preferentially along the ridges with a significantly higher velocity along the ridges than on a flat surface. Our results suggest that a complex interplay between the actin cytoskeleton and focal adhesions coordinates the cellular response to micro/nanotopography. PMID- 28635617 TI - The dosimetric impact of gadolinium-based contrast media in GBM brain patient plans for a MRI-Linac. AB - Dosimetric effects of gadolinium based contrast media (Gadovist) were evaluated for the Elekta MRI linear accelerator using the research version of the Monaco treatment planning system (TPS). In order to represent a gadolinium uptake, the contrast was manually assigned to a phantom as well as to the gross tumour volume (GTV) of 6 glioblastoma multiforme (GBM) patients. A preliminary estimate of the dose enhancement, due to gadolinium, was performed using the phantom irradiated with a single beam. A more complicated assessment was performed for the GBM patients using a 7 field IMRT technique. The material table in Monaco was modified in order to identify the presence of a non-biological material. The dose distribution was modelled using GPUMCD (MC algorithm in Monaco) for an unmodified (or default) material table (DMT) as well as for a modified (or custom) material table (CMT) for both the phantom and patients. Various concentrations ranging between 8 and 157 mg ml-1 were used to represent the gadolinium uptake in the patient's GTV. It was assumed that the gadolinium concentration remained the same for the entire course of radiation treatment. Results showed that at the tissue Gadovist interface, inside the phantom, dose scored using the DMT was 7% lower compared to that using the CMT for 157 mg ml-1 concentration of gadolinium. Dosimetric differences in the case of the patient study were measured using the DVH parameters. D 50% was higher by 6% when the DMT was used compared to the CMT for dose modelling for a gadolinium concentration of 157 mg ml-1. This difference decreased gradually with decreasing concentration of gadolinium. It was concluded that dosimetric differences can be quantified in Monaco if the tumour-gadolinium concentration is more than 23 mg ml-1. If the gadolinium concentration is lower than 23 mg ml-1, then a correction for the presence of gadolinium may not be necessary in the TPS. PMID- 28635618 TI - Nickel cobaltite nanosheets strongly anchored on boron and nitrogen co-doped graphene for high-performance asymmetric supercapacitors. AB - Strongly coupled boron and nitrogen co-doped graphene (BN-G) hybrids with nickel cobaltite (NiCo2O4) nanosheets (NCO/BN-G) were fabricated by a facile soft chemical method for asymmetric supercapacitors with high-performance. The strong interaction between BN-G and NiCo2O4 nanosheets are explored by various techniques. The effect of heteroatom doping on electrochemical properties of the hybrids is systematically investigated. The strong synergistic effect between NiCo2O4 and BN-G leads to a specific capacitance of 106.5 mA h g-1 at the current density of 0.5 A g-1 and capacitance retention of 96.8% after 10 000 cycles at 5 A g-1, much better than those of the pure NiCo2O4 and its hybrid with N-doped graphene. Moreover, an asymmetric supercapacitor device, assembled with NCO/BN-G and activated carbon (NCO/BN-G//AC), exhibits a maximum energy density of 45.6 Wh kg-1 and an excellent cycling stability. The improved electrochemical performance of the NCO/BN-G hybrid is attributed to the good conductivity of BN-G and the synergistic effect between NiCo2O4 nanosheets and BN-G combined together through a plane-to-plane contact mode. PMID- 28635619 TI - On the importance of accurate quantification of individual volatile metabolites in exhaled breath. AB - It is argued that shortcomings of certain approaches to breath analysis research based on superficial interpretation of non-quantitative data are inadvertently inhibiting the progression of non-invasive breath analysis into clinical practice. The objective of this perspective is to suggest more clinically profitable approaches to breath research. Thus, following a discourse on the challenges and expectations in breath research, a brief indication is given of the analytical techniques currently used for the analysis of very humid exhaled breath. The seminal work that has been carried out using GC-MS revealed that exhaled breath comprises large numbers of trace volatile organic compounds, VOCs. Unfortunately, analysis of these valuable GC-MS data is mostly performed using chemometrics to distinguish the VOC content of breath samples collected from patients and healthy controls, and reliable quantification of the VOCs is rarely deemed necessary. This limited approach ignores the requirements of clinically acceptable biomarkers and misses the opportunity to identify relationships between the concentrations of individual VOCs and certain related physiological or metabolic parameters. Therefore, a plea is made for more effort to be directed towards the positive identification and accurate quantification of individual VOCs in exhaled breath, which are more physiologically meaningful as best exemplified by the quantification of breath nitric oxide, NO. Support for the value of individual VOC quantification is illustrated by the SIFT-MS studies of breath hydrogen cyanide, HCN, a biomarker of Pseudomonas aeruginosa infection, breath acetic acid as an indicator of airways acidification in cystic fibrosis patients, and n-pentane as a breath biomarker of inflammation in idiopathic bowel disease patients. These single VOCs could be used as non-invasive monitors of the efficacy of therapeutic intervention. The increase of breath methanol following the ingestion of a known amount of the sweetener aspartame impressively shows that accurate breath analysis is a reliable indicator of blood concentrations. However, using individual VOCs for specific disease diagnosis does have its problems and it is, perhaps, more appropriate to see their concentrations as proxy markers of general underlying physiological change. We dedicate this perspective to Lars Gustafsson for his seminal work on breath research and especially for his pioneering work on nitric oxide measurements in exhaled breath in asthma, which best shows the utility and value of the quantification of individual breath biomarkers on which this perspective focuses. PMID- 28635620 TI - Anomalous dielectric response of short hydrogen bonds under pressure: the case of (Mn,Fe)2+AlPO4(OH)2H2O. AB - An anomalous increase in the real part of dielectric response is observed in Mn0.5Fe0.5AlPO4(OH)2H2O while cooling to ~70 K. This is addressed to field induced proton dynamics in a short hydrogen bond of 2.480(3) A. The absence of discontinuities in heat capacity curves above the Neel temperature (T N ~ 7 K) excludes a paraelectric to antiferroelectric phase transition. Upon the application of mild hydrostatic pressures below 1.6 GPa, the maximum in the dielectric response is shifted from 70 K to lower temperatures near 2 K. This explains a narrow correlation between proton transfer and the compression of the short hydrogen bond length. PMID- 28635621 TI - The charge and spin transport properties in hexagonal silicene nanorings. AB - Based on the tight-binding model, charge and spin transport properties of hexagonal silicene rings are investigated within the nonequilibrium Green's function technique. The effects of external electric, magnetic and exchange fields are taken into account. The calculated results reveal that the hexagonal silicene nanorings act as a controllable spin filter. The near-perfect spin polarization can be achieved by adjusting the electric, magnetic and exchange fields. The calculated results offer new possibilities for silicene ring based spin nanodevices. PMID- 28635622 TI - The Arabidopsis GPR1 Gene Negatively Affects Pollen Germination, Pollen Tube Growth, and Gametophyte Senescence. AB - Genes essential for gametophyte development and fertilization have been identified and studied in detail; however, genes that fine-tune these processes are largely unknown. Here, we characterized an unknown Arabidopsis gene, GTP BINDING PROTEIN RELATED1 (GPR1). GPR1 is specifically expressed in ovule, pollen, and pollen tube. Enhanced green fluorescent protein-tagged GPR1 localizes to both nucleus and cytoplasm, and it also presents in punctate and ring-like structures. gpr1 mutants exhibit no defect in gametogenesis and seed setting, except that their pollen grains are pale in color. Scanning electron microscopy analyses revealed a normal patterned but thinner exine on gpr1 pollen surface. This may explain why gpr1 pollen grains are pale. We next examined whether GPR1 mutation affects post gametogenesis processes including pollen germination, pollen tube growth, and ovule senescence. We found that gpr1 pollen grains germinated earlier, and their pollen tubes elongated faster. Emasculation assay revealed that unfertilized gpr1 pistil expressed the senescence marker PBFN1:GUS (GUS: a reporter gene that encodes beta-glucuronidase) one-day earlier than the wild type pistil. Consistently, ovules and pollen grains of gpr1 mutants showed lower viability than those of the wild type at 4 to 5 days post anthesis. Together, these data suggest that GPR1 functions as a negative regulator of pollen germination, pollen tube growth, and gametophyte senescence to fine-tune the fertilization process. PMID- 28635623 TI - Compressed-Sensing Reconstruction Based on Block Sparse Bayesian Learning in Bearing-Condition Monitoring. AB - Remote monitoring of bearing conditions, using wireless sensor network (WSN), is a developing trend in the industrial field. In complicated industrial environments, WSN face three main constraints: low energy, less memory, and low operational capability. Conventional data-compression methods, which concentrate on data compression only, cannot overcome these limitations. Aiming at these problems, this paper proposed a compressed data acquisition and reconstruction scheme based on Compressed Sensing (CS) which is a novel signal-processing technique and applied it for bearing conditions monitoring via WSN. The compressed data acquisition is realized by projection transformation and can greatly reduce the data volume, which needs the nodes to process and transmit. The reconstruction of original signals is achieved in the host computer by complicated algorithms. The bearing vibration signals not only exhibit the sparsity property, but also have specific structures. This paper introduced the block sparse Bayesian learning (BSBL) algorithm which works by utilizing the block property and inherent structures of signals to reconstruct CS sparsity coefficients of transform domains and further recover the original signals. By using the BSBL, CS reconstruction can be improved remarkably. Experiments and analyses showed that BSBL method has good performance and is suitable for practical bearing-condition monitoring. PMID- 28635624 TI - Effects of Type 1 Diabetes Risk Alleles on Immune Cell Gene Expression. AB - Genetic studies have identified 61 variants associated with the risk of developing Type 1 Diabetes (T1D). The functions of most of the non-HLA (Human Leukocyte Antigen) genetic variants remain unknown. We found that only 16 of these risk variants could potentially be linked to a protein-coding change. Therefore, we investigated whether these variants affected susceptibility by regulating changes in gene expression. To do so, we examined whole transcriptome profiles of 600 samples from the Type 1 Diabetes Genetics Consortium (T1DGC). These comprised four different immune cell types (Epstein-Barr virus (EBV) transformed B cells, either basal or after stimulation; and cluster of differentiation (CD)4+ and CD8+ T cells). Many of the T1D-associated risk variants regulated expression of either neighboring (cis-) or distant (trans-) genes. In brief, 24 of the non-HLA T1D variants affected the expression of 31 nearby genes (cis) while 25 affected 38 distant genes (trans). The effects were highly significant (False Discovery Rate p < 0.001). In addition, we searched in public databases for expression effects of T1D single nucleotide polymorphisms (SNPs) in other immune cell types such as CD14+ monocytes, lipopolysaccharide (LPS) stimulated monocytes, and CD19+ B cells. In this paper, we review the (expression quantitative trait loci (eQTLs) associated with each of the 60 T1D variants and provide a summary of the genes impacted by T1D risk alleles in various immune cells. We then review the methodological steps involved in analyzing the function of genome wide association studies (GWAS)-identified variants, with emphasis on those affecting gene expression. We also discuss recent advancements in the methodologies and their advantages. We conclude by suggesting future study designs that will aid in the study of T1D risk variants. PMID- 28635625 TI - Soil Moisture Content Estimation Based on Sentinel-1 and Auxiliary Earth Observation Products. A Hydrological Approach. AB - A methodology for elaborating multi-temporal Sentinel-1 and Landsat 8 satellite images for estimating topsoil Soil Moisture Content (SMC) to support hydrological simulation studies is proposed. After pre-processing the remote sensing data, backscattering coefficient, Normalized Difference Vegetation Index (NDVI), thermal infrared temperature and incidence angle parameters are assessed for their potential to infer ground measurements of SMC, collected at the top 5 cm. A non-linear approach using Artificial Neural Networks (ANNs) is tested. The methodology is applied in Western Crete, Greece, where a SMC gauge network was deployed during 2015. The performance of the proposed algorithm is evaluated using leave-one-out cross validation and sensitivity analysis. ANNs prove to be the most efficient in SMC estimation yielding R2 values between 0.7 and 0.9. The proposed methodology is used to support a hydrological simulation with the HEC HMS model, applied at the Keramianos basin which is ungauged for SMC. Results and model sensitivity highlight the contribution of combining Sentinel-1 SAR and Landsat 8 images for improving SMC estimates and supporting hydrological studies. PMID- 28635627 TI - Molecular Quantum Similarity, Chemical Reactivity and Database Screening of 3D Pharmacophores of the Protein Kinases A, B and G from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis remains one of the world's most devastating pathogens. For this reason, we developed a study involving 3D pharmacophore searching, selectivity analysis and database screening for a series of anti-tuberculosis compounds, associated with the protein kinases A, B, and G. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these compounds, with anti-tuberculosis activity. Using the Molecular Quantum Similarity field and reactivity descriptors supported in the Density Functional Theory, it was possible to measure the quantification of the steric and electrostatic effects through the Overlap and Coulomb quantitative convergence (alpha and beta) scales. In addition, an analysis of reactivity indices using global and local descriptors was developed, identifying the binding sites and selectivity on these anti-tuberculosis compounds in the active sites. Finally, the reported pharmacophores to PKn A, B and G, were used to carry out database screening, using a database with anti-tuberculosis drugs from the Kelly Chibale research group (http://www.kellychibaleresearch.uct.ac.za/), to find the compounds with affinity for the specific protein targets associated with PKn A, B and G. In this regard, this hybrid methodology (Molecular Mechanic/Quantum Chemistry) shows new insights into drug design that may be useful in the tuberculosis treatment today. PMID- 28635626 TI - Adiponectin, a Therapeutic Target for Obesity, Diabetes, and Endothelial Dysfunction. AB - Adiponectin is the most abundant peptide secreted by adipocytes, whose reduction plays a central role in obesity-related diseases, including insulin resistance/type 2 diabetes and cardiovascular disease. In addition to adipocytes, other cell types, such as skeletal and cardiac myocytes and endothelial cells, can also produce this adipocytokine. Adiponectin effects are mediated by adiponectin receptors, which occur as two isoforms (AdipoR1 and AdipoR2). Adiponectin has direct actions in liver, skeletal muscle, and the vasculature.Adiponectin exists in the circulation as varying molecular weight forms, produced by multimerization. Several endoplasmic reticulum ER-associated proteins, including ER oxidoreductase 1-alpha (Ero1-alpha), ER resident protein 44 (ERp44), disulfide-bond A oxidoreductase-like protein (DsbA-L), and glucose regulated protein 94 (GPR94), have recently been found to be involved in the assembly and secretion of higher-order adiponectin complexes. Recent data indicate that the high-molecular weight (HMW) complexes have the predominant action in metabolic tissues. Studies have shown that adiponectin administration in humans and rodents has insulin-sensitizing, anti-atherogenic, and anti inflammatory effects, and, in certain settings, also decreases body weight. Therefore, adiponectin replacement therapy in humans may suggest potential versatile therapeutic targets in the treatment of obesity, insulin resistance/type 2 diabetes, and atherosclerosis. The current knowledge on regulation and function of adiponectin in obesity, insulin resistance, and cardiovascular disease is summarized in this review. PMID- 28635629 TI - Light Emitting Marker for Robust Vision-Based On-The-Spot Bacterial Growth Detection. AB - Simple methods using the striped pattern paper marker and FFT (fast Fourier transformation) have been proposed as alternatives to measuring the optical density for determining the level of bacterial growth. The marker-based method can be easily automated, but due to image-processing-base of the method, the presence of light or the color of the culture broth can disturb the detection process. This paper proposes a modified version of marker-FFT-based growth detection that uses a light emitting diode (LED) array as a marker. Since the marker itself can emit the light, the measurements can be performed even when there is no light source or the bacteria are cultured in a large volume of darkly colored broth. In addition, an LED marker can function as a region of interest (ROI) indicator in the image. We expect that the proposed LED-based marker system will allow more robust growth detection compared to conventional methods. PMID- 28635628 TI - Identification and Validation of Reference Genes for Seashore Paspalum Response to Abiotic Stresses. AB - Seashore paspalum (Paspalum vaginatum) is among the most salt- and cadmium tolerant warm-season perennial grass species widely used as turf or forage. The objective of this study was to select stable reference genes for quantitative real-time polymerase chain reaction (qRT-PCR) analysis of seashore paspalum in response to four abiotic stresses. The stability of 12 potential reference genes was evaluated by four programs (geNorm, NormFinder, BestKeeper, and RefFinder). U2AF combined with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) showed stable expression in Cd-treated leaves and cold-treated roots. U2AF and FBOX were the most stable reference genes in Cd-treated roots and cold-treated leaves. In Polyethylene Glycol (PEG)- or salt-treated roots, the reference gene U2AF paired with either ACT or CYP were stable. SAND and CACS exhibited the most stability in salt-treated leaves, and combining UPL, PP2A, and EF1a was most suitable for PEG treated leaves. The stability of U2AF and instability of UPL and TUB was validated by analyzing the expression levels of four target genes (MT2a, VP1, PIP1, and Cor413), and were shown to be capable of detecting subtle changes in expression levels of the target genes in seashore paspalum. This study demonstrated that FBOX, U2AF, and PP2A could be used in future molecular studies that aim to understand the mechanisms of abiotic stress tolerance in seashore paspalum. PMID- 28635630 TI - Development of a High-Density SNP-Based Linkage Map and Detection of QTL for beta Glucans, Protein Content, Grain Yield per Spike and Heading Time in Durum Wheat. AB - High-density genetic linkage maps of crop species are particularly useful in detecting qualitative and quantitative trait loci for important agronomic traits and in improving the power of classical approaches to identify candidate genes. The aim of this study was to develop a high-density genetic linkage map in a durum wheat recombinant inbred lines population (RIL) derived from two elite wheat cultivars and to identify, characterize and correlate Quantitative Trait Loci (QTL) for beta-glucan, protein content, grain yield per spike and heading time. A dense map constructed by genotyping the RIL population with the wheat 90K iSelect array included 5444 single nucleotide polymorphism (SNP) markers distributed in 36 linkage groups. Data for beta-glucan and protein content, grain yield per spike and heading time were obtained from replicated trials conducted at two locations in southern Italy. A total of 19 QTL were detected in different chromosome regions. In particular, three QTL for beta-glucan content were detected on chromosomes 2A and 2B (two loci); eight QTL controlling grain protein content were detected on chromosomes 1B, 2B, 3B (two loci), 4A, 5A, 7A and 7B; seven QTL for grain yield per spike were identified on chromosomes 1A, 2B, 3A (two loci), 3B (two loci) and 6B; and one marker-trait association was detected on chromosome 2A for heading time. The last was co-located with a beta-glucan QTL, and the two QTL appeared to be negatively correlated. A genome scan for genomic regions controlling the traits and SNP annotated sequences identified five putative candidate genes involved in different biosynthesis pathways (beta glucosidase, GLU1a; APETALA2, TaAP2; gigantea3, TaGI3; 14-3-3 protein, Ta14A; and photoperiod sensitivity, Ppd-A1). This study provides additional information on QTL for important agronomic traits that could be useful for marker-assisted breeding to obtain new genotypes with commercial and nutritional relevance. PMID- 28635631 TI - Ag Nanoparticles Drop-Casting Modification of Screen-Printed Electrodes for the Simultaneous Voltammetric Determination of Cu(II) and Pb(II). AB - A new silver nanoparticle modified screen-printed electrode was developed and applied to the simultaneous determination of Pb(II) and Cu(II). Two different types of silver nanoparticles with different shapes and sizes, Ag nanoseeds and Ag nanoprisms, were microscopically characterized and three different carbon substrates, graphite, graphene and carbon nanofibers, were tested. The best analytical performance was achieved for the combination of Ag nanoseeds with a carbon nanofiber modified screen-printed electrode. The resulting sensor allowed the simultaneous determination of Pb(II) and Cu(II) at trace levels and its applicability to natural samples was successfully tested with a groundwater certified reference material, presenting high reproducibility and trueness. PMID- 28635632 TI - Glucose and Lipid Dysmetabolism in a Rat Model of Prediabetes Induced by a High Sucrose Diet. AB - Glucotoxicity and lipotoxicity are key features of type 2 diabetes mellitus, but their molecular nature during the early stages of the disease remains to be elucidated. We aimed to characterize glucose and lipid metabolism in insulin target organs (liver, skeletal muscle, and white adipose tissue) in a rat model treated with a high-sucrose (HSu) diet. Two groups of 16-week-old male Wistar rats underwent a 9-week protocol: HSu diet (n = 10)-received 35% of sucrose in drinking water; Control (n = 12)-received vehicle (water). Body weight, food, and beverage consumption were monitored and glucose, insulin, and lipid profiles were measured. Serum and liver triglyceride concentrations, as well as the expression of genes and proteins involved in lipid biosynthesis were assessed. The insulin stimulated glucose uptake and isoproterenol-stimulated lipolysis were also measured in freshly isolated adipocytes. Even in the absence of obesity, this rat model already presented the main features of prediabetes, with fasting normoglycemia but reduced glucose tolerance, postprandial hyperglycemia, compensatory hyperinsulinemia, as well as decreased insulin sensitivity (resistance) and hypertriglyceridemia. In addition, impaired hepatic function, including altered gluconeogenic and lipogenic pathways, as well as increased expression of acetyl-coenzyme A carboxylase 1 and fatty acid synthase in the liver, were observed, suggesting that liver glucose and lipid dysmetabolism may play a major role at this stage of the disease. PMID- 28635633 TI - New Insights in Thyroid Cancer and p53 Family Proteins. AB - Thyroid cancers are common endocrine malignancies that comprise tumors with different clinical and histological features. Indeed, papillary and follicular thyroid cancers are slow-growing, well-differentiated tumors, whereas anaplastic thyroid cancers are undifferentiated neoplasias that behave much more aggressively. Well-differentiated thyroid carcinomas are efficiently cured by surgery and radioiodine, unlike undifferentiated tumors that fail to uptake radioactive iodine and are usually resistant to chemotherapy. Therefore, novel and more effective therapies for these aggressive neoplasias are urgently needed. Whereas most genetic events underlying the pathogenesis of well-differentiated thyroid cancers have been identified, the molecular mechanisms that generate undifferentiated thyroid carcinomas are still unclear. To date, one of the best characterized genetic alterations leading to the development of poorly differentiated thyroid tumors is the loss of the p53 tumor suppressor gene. In addition, the existence of a complex network among p53 family members (p63 and p73) and their interactions with other factors that promote thyroid cancer progression has been well documented. In this review, we provide an update on the current knowledge of the role of p53 family proteins in thyroid cancer and their possible use as a therapeutic target for the treatment of the most aggressive variants of this disease. PMID- 28635635 TI - Identifying Bird Remains Using Ancient DNA Barcoding. AB - Bird remains that are difficult to identify taxonomically using morphological methods, are common in the palaeontological record. Other types of challenging avian material include artefacts and food items from endangered taxa, as well as remains from aircraft strikes. We here present a DNA-based method that enables taxonomic identification of bird remains, even from material where the DNA is heavily degraded. The method is based on the amplification and sequencing of two short variable parts of the 16S region in the mitochondrial genome. To demonstrate the applicability of this approach, we evaluated the method on a set of Holocene and Late Pleistocene postcranial bird bones from several palaeontological and archaeological sites in Europe with good success. PMID- 28635636 TI - Cell Selection Technique for Millimeter-Wave Cellular Systems with Hybrid Beamforming. AB - In this paper, a cell selection technique for millimeter-wave (mm-wave) cellular systems with hybrid beamforming is proposed. To select a serving cell, taking into account hybrid beamforming structures in a mm-wave cellular system, the angles of arrival and departure for all candidate cells need to be estimated in the initialization stage, requiring a long processing time. To enable simultaneous multi-beam transmissions in a multi-cell environment, a cell and beam synchronization signal (CBSS) is proposed to carry beam IDs in conjunction with cell IDs. A serving cell maximizing the channel capacity of the hybrid beamformer is selected with the estimated channel information and the optimum precoder. The performance of the proposed technique is evaluated by a computer simulation with a spatial channel model in a simple model of a mm-wave cellular system. It is shown by simulation that the proposed technique with the CBSS can significantly reduce the processing time for channel estimation and cell selection, and can achieve additional gains in channel capacity, or in bit error rate, compared to that obtained by conventional techniques. PMID- 28635634 TI - Despite Inflammation, Supplemented Essential Amino Acids May Improve Circulating Levels of Albumin and Haemoglobin in Patients after Hip Fractures. AB - Essential amino acids (EAAs) are nutritional substrates that promote body protein synthesis; thus we hypothesised that their supplementation may improve circulating albumin (Alb) and haemoglobin (Hb) in rehabilitative elderly patients following hip fractures (HF). Out of the 145 HF patients originally enrolled in our study, 112 completed the protocol. These subjects were divided into two randomised groups, each containing 56 patients. For a period of two months, one group (age 81.4 +/- 8.1 years; male/female 27/29) received a placebo, and the other (age 83.1 +/- 7.5 years; male/female 25/31) received 4 + 4 g/day oral EAAs. At admission, the prevalence of both hypoAlb (<3.5 g/dL) and hypoHb (<13 g/dL male, <12 g/dL female) was similar in the placebo group (64.3% hypoAlb, 66% hypoHb) and the treated group of patients (73.2% hypoAlb, 67.8% hypoHb). At discharge, however, the prevalence of hypoAlb had reduced more in EAAs than in placebo subjects (31.7% in EAAs vs. 77.8% in placebo; p < 0.001). There was a 34.2% reduction of anaemia in hypoHb in EAA subjects and 18.9% in placebo subjects, but the difference was not statistically significant. Oral supplementation of EAAs improves hypoAlb and, to a lesser extent, Hb in elderly rehabilitative subjects with hip fractures. Anaemia was reduced in more than one third of patients, which, despite not being statistically significant, may be clinically relevant. PMID- 28635637 TI - A Short-Term Biological Indicator for Long-Term Kidney Damage after Radionuclide Therapy in Mice. AB - Folate receptor (FR)-targeted radionuclide therapy using folate radioconjugates is of interest due to the expression of the FR in a variety of tumor types. The high renal accumulation of radiofolates presents, however, a risk of radionephropathy. A potential option to address this challenge would be to use radioprotectants, such as amifostine. Methods for early detection of kidney damage that-in this case-cannot be predicted based on dose estimations, would facilitate the development of novel therapies. The aim of this study was, therefore, to assess potentially changing levels of plasma and urine biomarkers and to determine DNA damage at an early stage after radiofolate application. The identification of an early indicator for renal damage in mice would be useful since histological changes become apparent only several months after treatment. Mice were injected with different quantities of 177Lu-folate (10 MBq, 20 MBq and 30 MBq), resulting in mean absorbed kidney doses of ~23 Gy, ~46 Gy and ~69 Gy, respectively, followed by euthanasia two weeks (>85% of the mean renal radiation dose absorbed) or three months later. Whereas all investigated biomarkers remained unchanged, the number of gamma-H2AX-positive nuclei in the renal cortex showed an evident dose-dependent increase as compared to control values two weeks after treatment. Comparison with the extent of kidney injury determined by histological changes five to eight months after administration of the same 177Lu folate activities suggested that the quantitative assessment of double-strand breaks can be used as a biological indicator for long-term radiation effects in the kidneys. This method may, thus, enable faster assessment of radiopharmaceuticals and protective measures by preventing logistically challenging long-term investigations to detect kidney damage. PMID- 28635638 TI - Antibiotic Concentrations Decrease during Wastewater Treatment but Persist at Low Levels in Reclaimed Water. AB - Reclaimed water has emerged as a potential irrigation solution to freshwater shortages. However, limited data exist on the persistence of antibiotics in reclaimed water used for irrigation. Therefore, we examined the fate of nine commonly-used antibiotics (ampicillin, azithromycin, ciprofloxacin, linezolid, oxacillin, oxolinic acid, penicillin G, pipemidic acid, and tetracycline) in differentially treated wastewater and reclaimed water from two U.S. regions. We collected 72 samples from two Mid-Atlantic and two Midwest treatment plants, as well as one Mid-Atlantic spray irrigation site. Antibiotic concentrations were measured using liquid-chromatography- tandem mass spectrometry. Data were analyzed using Mann-Whitney-Wilcoxon tests and Kruskal Wallis tests. Overall, antibiotic concentrations in effluent samples were lower than that of influent samples. Mid-Atlantic plants had similar influent but lower effluent antibiotic concentrations compared to Midwest plants. Azithromycin was detected at the highest concentrations (of all antibiotics) in influent and effluent samples from both regions. For most antibiotics, transport from the treatment plant to the irrigation site resulted in no changes in antibiotic concentrations, and UV treatment at the irrigation site had no effect on antibiotic concentrations in reclaimed water. Our findings show that low-level antibiotic concentrations persist in reclaimed water used for irrigation; however, the public health implications are unclear at this time. PMID- 28635640 TI - Analysis of Maneuvering Targets with Complex Motions by Two-Dimensional Product Modified Lv's Distribution for Quadratic Frequency Modulation Signals. AB - For targets with complex motion, such as ships fluctuating with oceanic waves and high maneuvering airplanes, azimuth echo signals can be modeled as multicomponent quadratic frequency modulation (QFM) signals after migration compensation and phase adjustment. For the QFM signal model, the chirp rate (CR) and the quadratic chirp rate (QCR) are two important physical quantities, which need to be estimated. For multicomponent QFM signals, the cross terms create a challenge for detection, which needs to be addressed. In this paper, by employing a novel multi scale parametric symmetric self-correlation function (PSSF) and modified scaled Fourier transform (mSFT), an effective parameter estimation algorithm is proposed referred to as the Two-Dimensional product modified Lv's distribution (2D-PMLVD) for QFM signals. The 2D-PMLVD is simple and can be easily implemented by using fast Fourier transform (FFT) and complex multiplication. These measures are analyzed in the paper, including the principle, the cross term, anti-noise performance, and computational complexity. Compared to the other three representative methods, the 2D-PMLVD can achieve better anti-noise performance. The 2D-PMLVD, which is free of searching and has no identifiability problems, is more suitable for multicomponent situations. Through several simulations and analyses, the effectiveness of the proposed estimation algorithm is verified. PMID- 28635639 TI - Immune Checkpoints as a Target for Colorectal Cancer Treatment. AB - Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies. We present an updated review of the biological background and clinical development of immune checkpoint inhibitors in colorectal cancer (CRC). Early trial results on PD1 and PD-L1 blockade appear promising, especially in CRC patients with microsatellite instability (MSI). Clinical trials are ongoing to confirm these preliminary results, evaluate combination strategies and identify biomarkers to predict which patients are most likely to benefit from, or show resistance to, the effects of checkpoint inhibition. PMID- 28635641 TI - The Fate of Pollutants in Porous Asphalt Pavements, Laboratory Experiments to Investigate Their Potential to Impact Environmental Health. AB - Pervious Paving Systems (PPS) are part of a sustainable approach to drainage in which excess surface water is encouraged to infiltrate through their structure, during which potentially toxic elements, such as metals and hydrocarbons are treated by biodegradation and physical entrapment and storage. However, it is not known where in the PPS structure these contaminants accumulate, which has implications for environmental health, particularly during maintenance, as well as consequences for the recycling of material from the PPS at the end-of-life. A 1 m3 porous asphalt (PA) PPS test rig was monitored for 38 months after monthly additions of road sediment (RS) (367.5 g in total) and unused oil (430 mL in total), characteristic of urban loadings, were applied. Using a rainfall simulator, a typical UK rainfall rate of 15 mm/h was used to investigate its efficiency in dealing with contamination. Water quality of the effluent discharged from the rig was found to be suitable for discharge to most environments. On completion of the monitoring, a core was taken down through its surface, and samples of sediment and aggregate were taken. Analysis showed that most of the sediment remained in the surface course, with metal levels lower than the original RS, but higher than clean, unused aggregate or PA. However, even extrapolating these concentrations to 20 years' worth of in-service use (the projected life of PPS) did not suggest their accumulation would present an environmental pollution risk when carrying out maintenance of the pavement and also indicates that the material could be recycled at end-of-life. PMID- 28635642 TI - Lack of Association between Serum Vitamin B6, Vitamin B12, and Vitamin D Levels with Different Types of Glaucoma: A Systematic Review and Meta-Analysis. AB - Although vitamins play a major role in health, and their deficiency may be linked to symptoms of optic-nerve dysfunction, the association between serum vitamin levels and glaucoma in humans remains controversial. In this study, articles in the PubMed, Web of Science, and EMBASE databases were searched up to 25March 2017. Nine studies on primary open-angle glaucoma (POAG), four studies on normal tension glaucoma (NTG), and six studies on exfoliative glaucoma (EXG) were retrieved. The combined results showed no differences in the levels of serum vitamin B6 between POAG (p = 0.406) and EXG (p = 0.139) patients and controls. The weighted mean differences (WMDs) with 95% confidence intervals (CIs) were 2.792 ng/mL (-3.793 to 9.377) and 1.342 ng/mL (-3.120 to 0.436), respectively. There was no difference between POAG (p = 0.952), NTG (p = 0.757), or EXG (p = 0.064) patients and controls in terms of serum vitamin B12. The WMDs with 95% CIs were 0.933 pg/mL (-31.116 to 29.249), 6.652 pg/mL (-35.473 to 48.777), and 49.946 pg/mL (-102.892 to 3.001), respectively. The serum vitamin D levels exhibited no differences (p = 0.064) between POAG patients and controls; the WMD with 95% CI was 2.488 ng/mL (-5.120 to 0.145). In conclusion, there was no association found between serum vitamin B6, vitamin B12, or vitamin D levels and the different types of glaucoma. PMID- 28635643 TI - A Multi-Wavelength Opto-Electronic Patch Sensor to Effectively Detect Physiological Changes against Human Skin Types. AB - Different skin pigments among various ethnic group people have an impact on spectrometric illumination on skin surface. To effectively capture photoplethysmographic (PPG) signals, a multi-wavelength opto-electronic patch sensor (OEPS) together with a schematic architecture of electronics were developed to overcome the drawback of present PPG sensor. To perform a better in vivo physiological measurement against skin pigments, optimal illuminations in OEPS, whose wavelength is compatible with a specific skin type, were optimized to capture a reliable physiological sign of heart rate (HR). A protocol was designed to investigate an impact of five skin types in compliance with Von Luschan's chromatic scale. Thirty-three healthy male subjects between the ages of 18 and 41 were involved in the protocol implemented by means of the OEPS system. The results show that there is no significant difference (p: 0.09, F = 3.0) in five group tests with the skin types across various activities throughout a series of consistent measurements. The outcome of the present study demonstrates that the OEPS, with its multi-wavelength illumination characteristics, could open a path in multiple applications of different ethnic groups with cost-effective health monitoring. PMID- 28635644 TI - PD-1/PD-L1 Blockade Therapy for Tumors with Downregulated MHC Class I Expression. AB - The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary resistance developed. To enhance its efficacy in treated patients, predictive biomarkers are searched for and various combination treatments are intensively investigated. As the downregulation of major histocompatibility complex (MHC) class I molecules is one of the most frequent mechanisms of tumor escape from the host's immunity, it should be considered in PD-1/PD-L1 checkpoint inhibition. The potential for the use of a PD-1/PD-L1 blockade in the treatment of tumors with aberrant MHC class I expression is discussed, and some strategies of combination therapy are suggested. PMID- 28635645 TI - Cembrene Diterpenoids with Ether Linkages from Sarcophyton ehrenbergi: An Anti Proliferation and Molecular-Docking Assessment. AB - Three new cembrene diterpenoids, sarcoehrenbergilid A-C (1-3), along with four known diterpenoids, sarcophine (4), (+)-7alpha,8beta-dihydroxydeepoxysarcophine (5), sinulolide A (6), and sinulolide B (7), and one steroid, sardisterol (8), were isolated and characterized from a solvent extract of the Red Sea soft coral Sarcophyton ehrenbergi. Chemical structures were elucidated by NMR and MS analyses with absolute stereochemistry determined by X-ray analysis. Since these isolated cembrene diterpenes contained 10 or more carbons in a large flexible ring, conformer stabilities were examined based on density functional theory calculations. Anti-proliferative activities for 1-8 were evaluated against three human tumor cell lines of different origins including the: lung (A549), colon (Caco-2), and liver (HepG2). Sardisterol (8) was the most potent of the metabolites isolated with an IC50 of 27.3 uM against the A549 cell line. Since an elevated human-cancer occurrence is associated with an aberrant receptor function for the epidermal growth factor receptor (EGFR), molecular docking studies were used to examine preferential metabolite interactions/binding and probe the mode of-action for metabolite-anti tumor activity. PMID- 28635646 TI - Synthesis and Bioactivity Characterization of Scutellarein Sulfonated Derivative. AB - Scutellarin (1) has been widely used to treat acute cerebral infarction in clinic, but poor aqueous solubility decreases its bioavailability. Interestingly, scutellarin (1) could be metabolized into scutellarein (2) in vivo. In this study, a sulfonic group was introduced at position C-8 of scutellarein (2) to enhance the aqueous solubility of the obtained derivative (3). DPPH (1,1-diphenyl 2-picrylhydrazyl)-radical scavenging ability and antithrombic activity were also conducted to determine its bioactivity. The result showed that scutellarein derivate (3) could be a better agent for ischemic cerebrovascular disease treatment. PMID- 28635647 TI - Virulence Genes of S. aureus from Dairy Cow Mastitis and Contagiousness Risk. AB - Staphylococcus aureus (S. aureus) is a major agent of dairy cow intramammary infections: the different prevalences of mastitis reported might be related to a combination of S. aureus virulence factors beyond host factors. The present study considered 169 isolates from different Italian dairy herds that were classified into four groups based on the prevalence of S. aureus infection at the first testing: low prevalence (LP), medium-low (MLP), medium-high (MHP) and high (HP). We aimed to correlate the presence of virulence genes with the prevalence of intramammary infections in order to develop new strategies for the control of S. aureus mastitis. Microarray data were statistically evaluated using binary logistic regression and correspondence analysis to screen the risk factors and the relationship between prevalence group and gene. The analysis showed: (1) 24 genes at significant risk of being detected in all the herds with infection prevalence >5%, including genes belonging to microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), immune evasion and serine proteases; and (2) a significant correlation coefficient between the genes interacting with the host immune response and HP isolates against LP ones. These results support the hypothesis that virulence factors, in addition to cow management, could be related to strain contagiousness, offering new insights into vaccine development. PMID- 28635649 TI - The Sea Urchin Arbacia lixula: A Novel Natural Source of Astaxanthin. AB - Several echinoderms, including sea urchins, are valuable sources of bioactive compounds but their nutraceutical potential is largely unexplored. In fact, the gonads of some sea urchin species contain antioxidants including carotenoids and polyhydroxylated naphthoquinones (PHNQ's), such as echinochrome A. Astaxanthin is known to have particular bioactivity for the prevention of neurodegenerative diseases. This carotenoid is produced by microalgae, while several marine invertebrates can bioaccumulate or synthetize it from metabolic precursors. We determined the carotenoid content and analyzed the bioactivity potential of non harvested Atlantic-Mediterranean sea urchin Arbacia lixula. The comparison of methanol crude extracts obtained from eggs of farmed and wild specimens revealed a higher bioactivity in farmed individuals fed with a customized fodder. HPLC analysis revealed a high concentration of astaxanthin (27.0 MUg/mg), which was the only pigment observed. This study highlights the potential of farmed A. lixula as a new source of the active stereoisomer of astaxanthin. PMID- 28635648 TI - Deoxyelephantopin and Isodeoxyelephantopin as Potential Anticancer Agents with Effects on Multiple Signaling Pathways. AB - Cancer is the 2nd leading cause of death worldwide. The development of drugs to target only one specific signaling pathway has limited therapeutic success. Developing chemotherapeutics to target multiple signaling pathways has emerged as a new prototype for cancer treatment. Deoxyelephantopin (DET) and isodeoxyelephantopin (IDET) are sesquiterpene lactone components of "Elephantopus scaber and Elephantopus carolinianus", traditional Chinese medicinal herbs that have long been used as folk medicines to treat liver diseases, diabetes, diuresis, bronchitis, fever, diarrhea, dysentery, cancer, and inflammation. Recently, the anticancer activity of DET and IDET has been widely investigated. Here, our aim is to review the current status of DET and IDET, and discuss their anticancer activity with specific emphasis on molecular targets and mechanisms used by these compounds to trigger apoptosis pathways which may help to further design and conduct research to develop them as lead therapeutic drugs for cancer treatments. The literature has shown that DET and IDET induce apoptosis through multiple signaling pathways which are deregulated in cancer cells and suggested that by targeting multiple pathways simultaneously, these compounds could selectively kill cancer cells. This review suggests that DET and IDET hold promising anticancer activity but additional studies and clinical trials are needed to validate and understand their therapeutic effect to develop them into potent therapeutics for the treatment of cancer. PMID- 28635650 TI - The Application of Heptamethine Cyanine Dye DZ-1 and Indocyanine Green for Imaging and Targeting in Xenograft Models of Hepatocellular Carcinoma. AB - Near infrared fluorescence (NIRF) imaging has strong potential for widespread use in noninvasive tumor imaging. Indocyanine green (ICG) is the only Food and Drug Administration (FDA) -approved NIRF dye for clinical diagnosis; however, it is unstable and poorly targets tumors. DZ-1 is a novel heptamethine cyanine NIRF dye, suitable for imaging and tumor targeting. Here, we compared the fluorescence intensity and metabolism of DZ-1 and ICG. Additionally, we assayed their specificities and abilities to target tumor cells, using cultured hepatocellular carcinoma (HCC) cell lines, a nude mouse subcutaneous xenograft model of liver cancer, and a rabbit orthotopic transplantation model. We found that DZ-1 accumulates in tumor tissue and specifically recognizes HCC in subcutaneous and orthotopic models. The NIRF intensity of DZ-1 was one order of magnitude stronger than that of ICG, and DZ-1 showed excellent intraoperative tumor targeting in the rabbit model. Importantly, ICG accumulated at tumor sites, as well as in the liver and kidney. Furthermore, DZ-1 analog-gemcitabine conjugate (NIRG) exhibited similar tumor-specific targeting and imaging properties, including inhibition of tumor growth, in HCC patient-derived xenograft (PDX) mice. DZ-1 and NIRG demonstrated superior tumor-targeting specificity, compared to ICG. We show that DZ-1 is an effective molecular probe for specific imaging, targeting, and therapy in HCC. PMID- 28635651 TI - Effects of Tetrodotoxin in Mouse Models of Visceral Pain. AB - Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor-specific Nav1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Nav1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain. PMID- 28635652 TI - Fucaceae: A Source of Bioactive Phlorotannins. AB - Fucaceae is the most dominant algae family along the intertidal areas of the Northern Hemisphere shorelines, being part of human customs for centuries with applications as a food source either for humans or animals, in agriculture and as remedies in folk medicine. These macroalgae are endowed with several phytochemicals of great industrial interest from which phlorotannins, a class of marine-exclusive polyphenols, have gathered much attention during the last few years due to their numerous possible therapeutic properties. These compounds are very abundant in brown seaweeds such as Fucaceae and have been demonstrated to possess numerous health-promoting properties, including antioxidant effects through scavenging of reactive oxygen species (ROS) or enhancement of intracellular antioxidant defenses, antidiabetic properties through their acarbose-like activity, stimulation of adipocytes glucose uptake and protection of beta-pancreatic cells against high-glucose oxidative stress; anti-inflammatory effects through inhibition of several pro-inflammatory mediators; antitumor properties by activation of apoptosis on cancerous cells and metastasis inhibition, among others. These multiple health properties render phlorotannins great potential for application in numerous therapeutical approaches. This review addresses the major contribution of phlototannins for the biological effects that have been described for seaweeds from Fucaceae. In addition, the bioavailability of this group of phenolic compounds is discussed. PMID- 28635653 TI - Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis Inhibitors. AB - Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents. The hierarchical filters in the pipeline (i.e., similarity search, a pharmacophore model, a shape-based model, and molecular docking) rendered 13 potential hits from Specs chemical library. By using PC12 cells (exposed to rotenone) as a cell model for bioassay, we first identified that AK-918/42829299, AN-465/41520984, and AT-051/43421517 were able to protect PC12 cells from rotenone-induced cell death. Molecular docking suggested these hit compounds were likely to bind to hPgk1 in a similar mode to terazosin. In summary, we not only present a versatile VS pipeline for potential apoptosis inhibitors discovery, but also provide three novel-scaffold hit compounds that are worthy of further development and biological study. PMID- 28635654 TI - The Identification of a SIRT6 Activator from Brown Algae Fucus distichus. AB - Brown seaweeds contain many bioactive compounds, including polyphenols, polysaccharides, fucosterol, and fucoxantin. These compounds have several biological activities, including anti-inflammatory, hepatoprotective, anti-tumor, anti-hypertensive, and anti-diabetic activity, although in most cases their mechanisms of action are not understood. In this study, extracts generated from five brown algae (Fucus dichitus, Fucus vesiculosus (Linnaeus), Cytoseira tamariscofolia, Cytoseira nodacaulis, Alaria esculenta) were tested for their ability to activate SIRT6 resulting in H3K9 deacetylation. Three of the five macroalgal extracts caused a significant increase of H3K9 deacetylation, and the effect was most pronounced for F. dichitus. The compound responsible for this in vitro activity was identified by mass spectrometry as fucoidan. PMID- 28635655 TI - From Farm to Pharma: An Overview of Industrial Heparin Manufacturing Methods. AB - The purification of heparin from offal is an old industrial process for which commercial recipes date back to 1922. Although chemical, chemoenzymatic, and biotechnological alternatives for this production method have been published in the academic literature, animal-tissue is still the sole source for commercial heparin production in industry. Heparin purification methods are closely guarded industrial secrets which are not available to the general (scientific) public. However by reviewing the academic and patent literature, we aim to provide a comprehensive overview of the general methods used in industry for the extraction of heparin from animal tissue. PMID- 28635656 TI - Screening and Identification of the Metabolites in Rat Plasma and Urine after Oral Administration of Areca catechu L. Nut Extract by Ultra-High-Pressure Liquid Chromatography Coupled with Linear Ion Trap-Orbitrap Tandem Mass Spectrometry. AB - Areca catechu L. nut, a well-known toxic traditional herbal medicine, has been widely used to treat various diseases in China and many other Asian countries for centuries. However, to date the in vivo absorption and metabolism of its multiple bioactive or toxic components still remain unclear. In this study, liquid chromatography coupled with tandem mass spectrometry was used to analyze the major components and their metabolites in rat plasma and urine after oral administration of Areca catechu L. nut extract (ACNE). A total of 12 compounds, including 6 alkaloids, 3 tannins and 3 amino acids, were confirmed or tentatively identified from ACNE. In vivo, 40 constituents, including 8 prototypes and 32 metabolites were identified in rat plasma and urine samples. In summary, this study showed an insight into the metabolism of ACNE in vivo, which may provide helpful chemical information for better understanding of the toxicological and pharmacological profiles of ACNE. PMID- 28635658 TI - Asperentin B, a New Inhibitor of the Protein Tyrosine Phosphatase 1B. AB - In the frame of studies on secondary metabolites produced by fungi from deep-sea environments we have investigated inhibitors of enzymes playing key roles in signaling cascades of biochemical pathways relevant for the treatment of diseases. Here we report on a new inhibitor of the human protein tyrosine phosphatase 1B (PTP1B), a target in the signaling pathway of insulin. A new asperentin analog is produced by an Aspergillussydowii strain isolated from the sediment of the deep Mediterranean Sea. Asperentin B (1) contains an additional phenolic hydroxy function at C-6 and exhibits an IC50 value against PTP1B of 2 MUM in vitro, which is six times stronger than the positive control, suramin. Interestingly, asperentin (2) did not show any inhibition of this enzymatic activity. Asperentin B (1) is discussed as possible therapeutic agents for type 2 diabetes and sleeping sickness. PMID- 28635660 TI - Diverse Regulation of Vitamin D Receptor Gene Expression by 1,25-Dihydroxyvitamin D and ATRA in Murine and Human Blood Cells at Early Stages of Their Differentiation. AB - Vitamin D receptor (VDR) is present in multiple blood cells, and the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is essential for the proper functioning of the immune system. The role of retinoic acid receptor alpha (RARalpha) in hematopoiesis is very important, as the fusion of RARalpha gene with PML gene initiates acute promyelocytic leukemia where differentiation of the myeloid lineage is blocked, followed by an uncontrolled proliferation of leukemic blasts. RARalpha takes part in regulation of VDR transcription, and unliganded RARalpha acts as a transcriptional repressor to VDR gene in acute myeloid leukemia (AML) cells. This is why we decided to examine the effects of the combination of 1,25D and all-trans-retinoic acid (ATRA) on VDR gene expression in normal human and murine blood cells at various steps of their development. We tested the expression of VDR and regulation of this gene in response to 1,25D or ATRA, as well as transcriptional activities of nuclear receptors VDR and RARs in human and murine blood cells. We discovered that regulation of VDR expression in humans is different from in mice. In human blood cells at early stages of their differentiation ATRA, but not 1,25D, upregulates the expression of VDR. In contrast, in murine blood cells 1,25D, but not ATRA, upregulates the expression of VDR. VDR and RAR receptors are present and transcriptionally active in blood cells of both species, especially at early steps of blood development. PMID- 28635661 TI - Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1alpha-GRP78-Akt Axis. AB - Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such effects remain unclear. This study aimed to uncover the potential mechanism involving 78-kDa glucose regulated protein (GRP78) to explain the enhanced MSC bioactivity and survival in hindlimb ischemia. Under hypoxia (2% O2), the expression of GRP78 was significantly increased via hypoxia-inducible factor (HIF)-1alpha. Hypoxia induced GRP78 promoted the proliferation and migration potential of MSCs through the HIF-1alpha-GRP78-Akt signal axis. In a murine hind-limb ischemia model, hypoxic preconditioning enhanced the survival and proliferation of transplanted MSCs through suppression of the cell death signal pathway and augmentation of angiogenic cytokine secretion. These effects were regulated by GRP78. Our findings indicate that hypoxic preconditioning promotes survival, proliferation, and angiogenic cytokine secretion of MSCs via the HIF-1alpha-GRP78-Akt signal pathway, suggesting that hypoxia-preconditioned MSCs might provide a therapeutic strategy for MSC-based therapies and that GRP78 represents a potential target for the development of functional MSCs. PMID- 28635657 TI - Selection of Nucleic Acid Aptamers Targeting Tumor Cell-Surface Protein Biomarkers. AB - Aptamers are nucleic acids referred to as chemical antibodies as they bind to their specific targets with high affinity and selectivity. They are selected via an iterative process known as 'selective evolution of ligands by exponential enrichment' (SELEX). Aptamers have been developed against numerous cancer targets and among them, many tumor cell-membrane protein biomarkers. The identification of aptamers targeting cell-surface proteins has mainly been performed by two different strategies: protein- and cell-based SELEX, when the targets used for selection were proteins and cells, respectively. This review aims to update the literature on aptamers targeting tumor cell surface protein biomarkers, highlighting potentials, pitfalls of protein- and cell-based selection processes and applications of such selected molecules. Aptamers as promising agents for diagnosis and therapeutic approaches in oncology are documented, as well as aptamers in clinical development. PMID- 28635659 TI - dIvergEnt: How IgE Axis Contributes to the Continuum of Allergic Asthma and Anti IgE Therapies. AB - Asthma is an airway disease characterised by chronic inflammation with intermittent or permanent symptoms including wheezing, shortness of breath, chest tightness, and cough, which vary in terms of their occurrence, frequency, and intensity. The most common associated feature in the airways of patients with asthma is airway inflammation. In recent decades, efforts have been made to characterise the heterogeneous clinical nature of asthma. The interest in improving the definitions of asthma phenotypes and endotypes is growing, although these classifications do not always correlate with prognosis nor are always appropriate therapeutic approaches. Attempts have been made to identify the most relevant molecular and cellular biomarkers underlying the immunopathophysiological mechanisms of the disease. For almost 50 years, immunoglobulin E (IgE) has been identified as a central factor in allergic asthma, due to its allergen-specific nature. Many of the mechanisms of the inflammatory cascade underlying allergic asthma have already been elucidated, and IgE has been shown to play a fundamental role in the triggering, development, and chronicity of the inflammatory responses within the disease. Blocking IgE with monoclonal antibodies such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic asthma. A better understanding of the multiple contributions of IgE to the inflammatory continuum of asthma could contribute to the development of novel therapeutic strategies for the disease. PMID- 28635662 TI - Development of a Dunaliella tertiolecta Strain with Increased Zeaxanthin Content Using Random Mutagenesis. AB - Zeaxanthin is a xanthophyll pigment that is regarded as one of the best carotenoids for the prevention and treatment of degenerative diseases. In the worldwide natural products market, consumers prefer pigments that have been produced from biological sources. In this study, a Dunaliella tertiolecta strain that has 10-15% higher cellular zeaxanthin content than the parent strain (zea1), was obtained by random mutagenesis using ethyl methanesulfonate (EMS) as a mutagen. This mutant, mp3, was grown under various salinities and light intensities to optimize culture conditions for zeaxanthin production. The highest cellular zeaxanthin content was observed at 1.5 M NaCl and 65-85 MUmol photons.m 2.s-1, and the highest daily zeaxanthin productivity was observed at 0.6 M NaCl and 140-160 MUmol photons.m-2.s-1. The maximal yield of zeaxanthin from mp3 in fed-batch culture was 8 mg.L-1, which was obtained at 0.6 M NaCl and 140-160 MUmol photons.m-2.s-1. These results suggest that random mutagenesis with EMS is useful for generating D. tertiolecta strains with increased zeaxanthin content, and also suggest optimal culture conditions for the enhancement of biomass and zeaxanthin production by the zeaxanthin accumulating mutant strains. PMID- 28635663 TI - Assessing Genetic Diversity and Population Differentiation of Colored Calla Lily (Zantedeschia Hybrid) for an Efficient Breeding Program. AB - Plastome-genome incompatibility (PGI) is prevalent in several plants including the Zantedeschia species, a worldwide commercial flower crop native to South Africa. Generally, hybrids suffering from PGI appear less vigorous and more susceptible than normal plants. Previous reports revealed that the PGI level in interspecific hybrids is correlated with the relatedness of the parental species in the genus Zantedeschia. To provide a basis for utilizing and improving resources in breeding programs, a total of 117 accessions of colored calla lily (Zantedeschia hybrid), collected from New Zealand, the Netherlands and the United States, were genotyped using 31 transferable expressed sequence tags-simple sequence repeats (EST-SSR) markers from the white calla lily (Zantedeschia aethiopica). A moderately high level of genetic diversity was observed, with 111 alleles in total, an observed/expected heterozygosity (Ho/He) of 0.453/0.478, and polymorphism information content (PIC) of 0.26. Genetic distance and STRUCTURE based analysis further clustered all accessions into four subgroups (G-Ia, G-Ib, G-IIa and G-IIb), which mostly consisted of Zantedeschia pentlandii, Zantedeschia elliotiana, Zantedeschia albomaculata and Zantedeschia rehmannii, respectively. Significant genetic differentiation was observed between all inferred subgroup pairs, with the Fst ranging from 0.142 to 0.281. Finally, the accessions assigned into G-IIb (Z. rehmannii) were recommended as top priority parents in efficient Zantedeschia breeding program designs. PMID- 28635664 TI - Adolescent Exposure to the Synthetic Cannabinoid WIN 55212-2 Modifies Cocaine Withdrawal Symptoms in Adult Mice. AB - Chronic cannabinoid consumption is an increasingly common behavior among teenagers and has been shown to cause long-lasting neurobehavioral alterations. Besides, it has been demonstrated that cocaine addiction in adulthood is highly correlated with cannabis abuse during adolescence. Cocaine consumption and subsequent abstinence from it can cause psychiatric symptoms, such as psychosis, cognitive impairment, anxiety, and depression. The aim of the present research was to study the consequences of adolescent exposure to cannabis on the psychiatric-like effects promoted by cocaine withdrawal in adult mice. We pre treated juvenile mice with the cannabinoid CB1 receptor agonist WIN 55212-2 (WIN) and then subjected them to a chronic cocaine treatment during adulthood. Following these treatments, animals were tested under cocaine withdrawal in the following paradigms: pre-pulse inhibition, object recognition, elevated plus maze, and tail suspension. The long-term psychotic-like actions induced by WIN were not modified after cocaine cessation. Moreover, the memory impairments induced by cocaine withdrawal were not altered by previous adolescent WIN intake. However, WIN pre-treatment prevented the anxiogenic effects observed after cocaine abstinence, and led to greater depressive-like symptoms following cocaine removal in adulthood. This study is the first to show the long-lasting behavioral consequences of juvenile exposure to WIN on cocaine withdrawal in adult mice. PMID- 28635665 TI - Towards a Uniform Metrological Assessment of Grating-Based Optical Fiber Sensors: From Refractometers to Biosensors. AB - A metrological assessment of grating-based optical fiber sensors is proposed with the aim of providing an objective evaluation of the performance of this sensor category. Attention was focused on the most common parameters, used to describe the performance of both optical refractometers and biosensors, which encompassed sensitivity, with a distinction between volume or bulk sensitivity and surface sensitivity, resolution, response time, limit of detection, specificity (or selectivity), reusability (or regenerability) and some other parameters of generic interest, such as measurement uncertainty, accuracy, precision, stability, drift, repeatability and reproducibility. Clearly, the concepts discussed here can also be applied to any resonance-based sensor, thus providing the basis for an easier and direct performance comparison of a great number of sensors published in the literature up to now. In addition, common mistakes present in the literature made for the evaluation of sensor performance are highlighted, and lastly a uniform performance assessment is discussed and provided. Finally, some design strategies will be proposed to develop a grating based optical fiber sensing scheme with improved performance. PMID- 28635666 TI - Host Adaptation of Soybean Dwarf Virus Following Serial Passages on Pea (Pisum sativum) and Soybean (Glycine max). AB - Soybean Dwarf Virus (SbDV) is an important plant pathogen, causing economic losses in soybean. In North America, indigenous strains of SbDV mainly infect clover, with occasional outbreaks in soybean. To evaluate the risk of a US clover strain of SbDV adapting to other plant hosts, the clover isolate SbDV-MD6 was serially transmitted to pea and soybean by aphid vectors. Sequence analysis of SbDV-MD6 from pea and soybean passages identified 11 non-synonymous mutations in soybean, and six mutations in pea. Increasing virus titers with each sequential transmission indicated that SbDV-MD6 was able to adapt to the plant host. However, aphid transmission efficiency on soybean decreased until the virus was no longer transmissible. Our results clearly demonstrated that the clover strain of SbDV-MD6 is able to adapt to soybean crops. However, mutations that improve replication and/or movement may have trade-off effects resulting in decreased vector transmission. PMID- 28635667 TI - A Review of Flaviviruses that Have No Known Arthropod Vector. AB - Most viruses in the genus Flavivirus are horizontally transmitted between hematophagous arthropods and vertebrate hosts, but some are maintained in arthropod- or vertebrate-restricted transmission cycles. Flaviviruses maintained by vertebrate-only transmission are commonly referred to as no known vector (NKV) flaviviruses. Fourteen species and two subtypes of NKV flaviviruses are recognized by the International Committee on Taxonomy of Viruses (ICTV), and Tamana bat virus potentially belongs to this group. NKV flaviviruses have been isolated in nature almost exclusively from bats and rodents; exceptions are the two isolates of Dakar bat virus recovered from febrile humans and the recent isolations of Sokoluk virus from field-collected ticks, which raises questions as to whether it should remain classified as an NKV flavivirus. There is evidence to suggest that two other NKV flaviviruses, Entebbe bat virus and Yokose virus, may also infect arthropods in nature. The best characterized bat- and rodent associated NKV flaviviruses are Rio Bravo and Modoc viruses, respectively, but both have received limited research attention compared to many of their arthropod infecting counterparts. Herein, we provide a comprehensive review of NKV flaviviruses, placing a particular emphasis on their classification, host range, geographic distribution, replication kinetics, pathogenesis, transmissibility and molecular biology. PMID- 28635668 TI - The Role of cccDNA in HBV Maintenance. AB - Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide; it can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. The molecular mechanisms determining HBV persistence are not fully understood, but these appear to be multifactorial and the unique replication strategy employed by HBV enables its maintenance in infected hepatocytes. Both the stability of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the hepatocyte nucleus, and the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. Since a true cure of HBV requires clearance of intranuclear cccDNA from infected hepatocytes, understanding the mechanisms involved in cccDNA biogenesis, regulation and stability is mandatory to achieve HBV eradication. This review will summarize the state of knowledge on these mechanisms including the impact of current treatments on the cccDNA stability and activity. We will focus on events challenging cccDNA persistence in dividing hepatocytes. PMID- 28635669 TI - Modulation of Human beta-Defensin-1 Production by Viruses. AB - While initially identified as a broad-spectrum antimicrobial peptide, constitutively expressed in epithelia, human beta-defensin (hBD)-1 is now recognized to have a more complex pattern of expression of its gene, DEFB1, as well as activities that extend beyond direct antimicrobial. These observations suggest a complex role for hBD-1 in the host defense against viral infections, as evidenced by its expression in cells involved in viral defense, and its gene regulation in response to viral challenge. This regulation is observed both in vitro and in vivo in humans, as well as with the murine homolog, mBD-1. While numerous reviews have summarized the existing literature on beta-defensin gene expression and activity, here we provide a focused review of relevant studies on the virus-mediated regulation of hBD-1 and how this regulation can provide a crucial aspect of the innate immune defense against viral infection. PMID- 28635670 TI - Single-Lead Fetal ECG Extraction Based on a Parallel Marginalized Particle Filter. AB - This paper presents a novel method for extracting the fetal ECG (FECG) from a single-lead abdominal signal. A dynamical model for a modified abdominal signal is proposed, in which both the maternal ECG (MECG) and the FECG are modeled, and then a parallel marginalized particle filter (par-MPF) is used for tracking the abdominal signal. Finally, the FECG and MECG are simultaneously separated. Several experiments are conducted using both simulated and clinical signals. The results indicate that the method proposed in this paper effectively extracts the FECG and outperforms other Bayesian filtering algorithms. PMID- 28635672 TI - Towards the Internet of Smart Trains: A Review on Industrial IoT-Connected Railways. AB - Nowadays, the railway industry is in a position where it is able to exploit the opportunities created by the IIoT (Industrial Internet of Things) and enabling communication technologies under the paradigm of Internet of Trains. This review details the evolution of communication technologies since the deployment of GSM R, describing the main alternatives and how railway requirements, specifications and recommendations have evolved over time. The advantages of the latest generation of broadband communication systems (e.g., LTE, 5G, IEEE 802.11ad) and the emergence of Wireless Sensor Networks (WSNs) for the railway environment are also explained together with the strategic roadmap to ensure a smooth migration from GSM-R. Furthermore, this survey focuses on providing a holistic approach, identifying scenarios and architectures where railways could leverage better commercial IIoT capabilities. After reviewing the main industrial developments, short and medium-term IIoT-enabled services for smart railways are evaluated. Then, it is analyzed the latest research on predictive maintenance, smart infrastructure, advanced monitoring of assets, video surveillance systems, railway operations, Passenger and Freight Information Systems (PIS/FIS), train control systems, safety assurance, signaling systems, cyber security and energy efficiency. Overall, it can be stated that the aim of this article is to provide a detailed examination of the state-of-the-art of different technologies and services that will revolutionize the railway industry and will allow for confronting today challenges. PMID- 28635671 TI - Rab33B Controls Hepatitis B Virus Assembly by Regulating Core Membrane Association and Nucleocapsid Processing. AB - Many viruses take advantage of cellular trafficking machineries to assemble and release new infectious particles. Using RNA interference (RNAi), we demonstrate that the Golgi/autophagosome-associated Rab33B is required for hepatitis B virus (HBV) propagation in hepatoma cell lines. While Rab33B is dispensable for the secretion of HBV subviral envelope particles, its knockdown reduced the virus yield to 20% and inhibited nucleocapsid (NC) formation and/or NC trafficking. The overexpression of a GDP-restricted Rab33B mutant phenocopied the effect of deficit Rab33B, indicating that Rab33B-specific effector proteins may be involved. Moreover, we found that HBV replication enhanced Rab33B expression. By analyzing HBV infection cycle steps, we identified a hitherto unknown membrane targeting module in the highly basic C-terminal domain of the NC-forming core protein. Rab33B inactivation reduced core membrane association, suggesting that membrane platforms participate in HBV assembly reactions. Biochemical and immunofluorescence analyses provided further hints that the viral core, rather than the envelope, is the main target for Rab33B intervention. Rab33B-deficiency reduced core protein levels without affecting viral transcription and hampered core/NC sorting to envelope-positive, intracellular compartments. Together, these results indicate that Rab33B is an important player in intracellular HBV trafficking events, guiding core transport to NC assembly sites and/or NC transport to budding sites. PMID- 28635673 TI - Toxicity of Naphthalene and Benzene on Tribollium castaneum Herbst. AB - Naphthalene and benzene are widely-used volatile organic compounds. The aim of this research was to examine the toxicological effects of naphthalene and benzene against Tribolium castaneum as an animal model. Adult insects were exposed to these aromatic compounds to assess mortality after 4-48 h of exposure. The lethal concentration 50 (LC50) for naphthalene, naphthalin, and benzene were 63.6 uL/L, 20.0 uL/L, and 115.9 uL/L in air, respectively. Real-time polymerase chain reaction (PCR) analysis revealed expression changes in genes related to oxidative stress and metabolism [Glutathione S-Transferase (Gst), and Cytochrome P450 6BQ8 (Cyp6bq8)]; reproduction and metamorphosis [Hormone receptor in 39-like protein (Hr39), Ecdysone receptor: (Ecr), and Chitin synthase 2 (Chs2)]; and neurotransmission [Histamine-gated chloride channel 2 (Hiscl2)] in insects exposed for 4 h to 70.2 uL/L naphthalene. Adults exposed to benzene (80 uL/L; 4 h) overexpressed genes related to neurotransmission [GABA-gated anion channel (Rdl), Hiscl2, and GABA-gated ion channel (Grd)]; reproduction and metamorphosis [Ultraspiracle nuclear receptor (USP), Ecr; and Hr39]; and development (Chs2). The data presented here provides evidence that naphthalene and benzene inhalation are able to induce alterations on reproduction, development, metamorphosis, oxidative stress, metabolism, neurotransmission, and death of the insect. PMID- 28635674 TI - Exploring Wound-Healing Genomic Machinery with a Network-Based Approach. AB - The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and for selecting potential drug targets. We start by selecting literature-relevant genes in murine wound healing, and inferring from them a Protein-Protein Interaction (PPI) network. Then, we analyze the network to rank wound healing-related genes according to their topological properties. Lastly, we perform a procedure for in-silico simulation of a treatment action in a biological pathway. The findings obtained by applying the developed pipeline, including gene expression analysis, confirms how a network-based bioinformatics method is able to prioritize candidate genes for in vitro analysis, thus speeding up the understanding of molecular mechanisms and supporting the discovery of potential drug targets. PMID- 28635676 TI - Comment on: "Melanisation of Aspergillus terreus-Is Butyrolactone I Involved in the Regulation of Both DOPA and DHN Types of Pigments in Submerged Culture? Microorganisms 2017, 5, 22". AB - A recent article by Palonen et al. describes the effect of butyrolactone I on the expression of a secondary metabolite biosynthesis gene cluster from Aspergillus terreus that shows similarities to fusarubin biosynthesis gene clusters from Fusarium species. The authors claim that two different types of pigments are formed in Aspergillus terreus conidia, whereby one pigment is termed a DOPA-type melanin and the second a DHN-type melanin. Unfortunately, the terminology of the classification of melanin-types requires revision as Asp-melanin present in A. terreus conidia is clearly distinct from DOPA-melanins. In addition, some hypotheses in this manuscript are based on questionable data published previously, resulting in incorrect conclusions. Finally, as biochemical data are lacking and metabolite production is only deduced from bioinformatics and transcriptomic data, the production of a second pigment type in A. terreus conidia appears highly speculative. PMID- 28635675 TI - Co-Infection with Marek's Disease Virus and Reticuloendotheliosis Virus Increases Illness Severity and Reduces Marek's Disease Vaccine Efficacy. AB - Marek's disease virus (MDV) and reticuloendotheliosis virus (REV) cause Marek's disease (MD) and reticuloendotheliosis (RE), respectively. Co-infection with MDV and REV is common in chickens, causing serious losses to the poultry industry. However, experimental studies of such co-infection are lacking. In this study, Chinese field strains of MDV (ZW/15) and REV (JLR1501) were used as challenge viruses to evaluate the pathogenicity of co-infection and the influence of MD vaccination in chickens. Compared to the MDV-challenged group, the mortality and tumor rates increased significantly by 20.0% (76.7 to 96.7%) and 26.7% (53.3 to 80.0%), in the co-challenged group, respectively. The protective index of the MD vaccines CVI988 and 814 decreased by 33.3 (80.0 to 47.7) and 13.3 (90.0 to 76.7), respectively. These results indicated that MDV and REV co-infection significantly increased disease severity and reduced the vaccine efficacy. The MDV genome load showed no difference in the feather pulps and spleen, and pathogenicity-related MDV gene expression (meq, pp38, vIL-8, and ICP4) in the spleen significantly increased at some time points in the co-challenged group. Clearly, synergistic pathogenicity occurred between MDV and REV, and the protective efficacy of existing MD vaccines was attenuated by co-infection with Chinese field MDV and REV strains. PMID- 28635677 TI - T-Cell Manipulation Strategies to Prevent Graft-Versus-Host Disease in Haploidentical Stem Cell Transplantation. AB - Allogeneic haematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical donor can be curative for eligible patients with non-malignant and malignant haematological disorders. HSCT from alternative donor sources, such as HLA-mismatched haploidentical donors, is increasingly considered as a viable therapeutic option for patients lacking HLA-matched donors. Initial attempts at haploidentical HSCT were associated with vigorous bidirectional alloreactivity, leading to unacceptably high rates of graft rejection and graft-versus-host disease (GVHD). More recently, new approaches for mitigating harmful T-cell alloreactivity that mediates GVHD, while preserving the function of tumour-reactive natural killer (NK) cells and gammadelta T cells, have led to markedly improved clinical outcomes, and are successfully being implemented in the clinic. This article will provide an update on in vitro strategies and in vivo approaches aimed at preventing GVHD by selectively manipulating key components of the adaptive immune response, such as T-cell receptor (TCR)-alphabeta T cells and CD45RA-expressing naive T cells. PMID- 28635678 TI - Evaluation of Classifier Performance for Multiclass Phenotype Discrimination in Untargeted Metabolomics. AB - Statistical classification is a critical component of utilizing metabolomics data for examining the molecular determinants of phenotypes. Despite this, a comprehensive and rigorous evaluation of the accuracy of classification techniques for phenotype discrimination given metabolomics data has not been conducted. We conducted such an evaluation using both simulated and real metabolomics datasets, comparing Partial Least Squares-Discriminant Analysis (PLS DA), Sparse PLS-DA, Random Forests, Support Vector Machines (SVM), Artificial Neural Network, k-Nearest Neighbors (k-NN), and Naive Bayes classification techniques for discrimination. We evaluated the techniques on simulated data generated to mimic global untargeted metabolomics data by incorporating realistic block-wise correlation and partial correlation structures for mimicking the correlations and metabolite clustering generated by biological processes. Over the simulation studies, covariance structures, means, and effect sizes were stochastically varied to provide consistent estimates of classifier performance over a wide range of possible scenarios. The effects of the presence of non normal error distributions, the introduction of biological and technical outliers, unbalanced phenotype allocation, missing values due to abundances below a limit of detection, and the effect of prior-significance filtering (dimension reduction) were evaluated via simulation. In each simulation, classifier parameters, such as the number of hidden nodes in a Neural Network, were optimized by cross-validation to minimize the probability of detecting spurious results due to poorly tuned classifiers. Classifier performance was then evaluated using real metabolomics datasets of varying sample medium, sample size, and experimental design. We report that in the most realistic simulation studies that incorporated non-normal error distributions, unbalanced phenotype allocation, outliers, missing values, and dimension reduction, classifier performance (least to greatest error) was ranked as follows: SVM, Random Forest, Naive Bayes, sPLS-DA, Neural Networks, PLS-DA and k-NN classifiers. When non normal error distributions were introduced, the performance of PLS-DA and k-NN classifiers deteriorated further relative to the remaining techniques. Over the real datasets, a trend of better performance of SVM and Random Forest classifier performance was observed. PMID- 28635679 TI - The Role of Angiogenesis in Cancer Treatment. AB - A number of anti-angiogenesis drugs have been FDA-approved and are being used in cancer treatment, and a number of other agents are in different stages of clinical development or in preclinical evaluation. However, pharmacologic anti angiogenesis strategies that arrest tumor progression might not be enough to eradicate tumors. Decreased anti-angiogenesis activity in single mechanism-based anti-angiogenic strategies is due to the redundancy, multiplicity, and development of compensatory mechanism by which blood vessels are remodeled. Improving anti-angiogenesis drug efficacy will require identification of broad spectrum anti-angiogenesis targets. These strategies may have novel features, such as increased porosity, and are the result of complex interactions among endothelial cells, extracellular matrix proteins, growth factors, pericyte, and smooth muscle cells. Thus, combinations of anti-angiogenic drugs and other anticancer strategies such as chemotherapy appear essential for optimal outcome in cancer patients. This review will focus on the role of anti-angiogenesis strategies in cancer treatment. PMID- 28635681 TI - Antimicrobial Activity of Nitric Oxide-Releasing Ti-6Al-4V Metal Oxide. AB - Titanium and titanium alloy materials are commonly used in joint replacements, due to the high strength of the materials. Pathogenic microorganisms can easily adhere to the surface of the metal implant, leading to an increased potential for implant failure. The surface of a titanium-aluminum-vanadium (Ti-6Al-4V) metal oxide implant material was functionalized to deliver an small antibacterial molecule, nitric oxide. S-nitroso-penicillamine, a S-nitrosothiol nitric oxide donor, was covalently immobilized on the metal oxide surface using self-assembled monolayers. Infrared spectroscopy was used to confirm the attachment of the S nitrosothiol donor to the Ti-Al-4V surface. Attachment of S-nitroso-penicillamine resulted in a nitric oxide (NO) release of 89.6 +/- 4.8 nmol/cm2 under physiological conditions. This low concentration of nitric oxide reduced Escherichia coli and Staphylococcus epidermidis growth by 41.5 +/- 1.2% and 25.3 +/- 0.6%, respectively. Combining the S-nitrosothiol releasing Ti-6Al-4V with tetracycline, a commonly-prescribed antibiotic, increased the effectiveness of the antibiotic by 35.4 +/- 1.3%, which allows for lower doses of antibiotics to be used. A synergistic effect of ampicillin with S-nitroso-penicillamine-modified Ti-6Al-4V against S. epidermidis was not observed. The functionalized Ti-6Al-4V surface was not cytotoxic to mouse fibroblasts. PMID- 28635683 TI - Blastic Plasmacytoid Dendritic Cell Neoplasm with Pulmonary Involvement and Atypical Skin Lesion. AB - BACKGROUND Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematodermic malignancy neoplasm with highly aggressive course and poor prognosis. This disease typically presents with cutaneous involvement as the first manifestation, with subsequent or simultaneous spread to bone marrow and peripheral blood. CASE REPORT Here, we report the case of a 51-year-old woman who presented a violaceus skin lesion on the lateral region of the right thigh, weight loss, fever, and lymphadenopathies. Computed tomography (CT) displayed thoracic and abdominal lymph node and alveolar bleeding. Flow cytometry from circulating blastic cells was compatible with BPDCN (CD4+, CD56+ and CD123+). She underwent 5 cycles of hyper-CVAD alternating with high-dose methotrexate and cytarabine, but the patient died due to alveolar bleeding and sepsis. CONCLUSIONS We report a rare case of BPDCN characterized by an aggressive course, presence of atypical skin lesion, a finding suggestive of pulmonary infiltration, and nonresponse to induction chemotherapy, leading to late diagnosis and therapeutic management. Because of the late recognition of the skin lesion, neoplastic cells infiltrated the dermis and spread as the disease progressed rapidly to a fatal course. PMID- 28635682 TI - Relationship Between Human mutL Homolog 1 (hMLH1) Hypermethylation and Colorectal Cancer: A Meta-Analysis. AB - BACKGROUND Hypermethylation of CpG islands in gene promoter regions is an important mechanism of gene inactivation in cancers. Promoter hypermethylation of human mutL homolog 1 (hMLH1) has been implicated in a subset of colorectal cancers that show microsatellite instability (MSI), while the connection of the epigenetic inactivation of hMLH1 in colorectal cancers remains unknown. The aim of this study was to evaluate the relationship between the promoter hypermethylation of hMLH1 and colorectal cancers by performing a meta-analysis. MATERIAL AND METHODS Eligible studies were identified through searching PubMed, Cochrane Library, Web of Science, and Google Scholar databases. R Software including meta packages was used to calculate the pooled and odds ratios (ORs) with corresponding confidence intervals (CIs). Funnel plots were also performed to evaluate publication bias. RESULTS This meta-analysis obtained 45 articles, including 4096 colorectal cancer patients, and identified a significant association between hMLH1 hypermethylation and colorectal cancer risk using the fixed-effects model (OR=8.3820; 95% CI, 6.9202~10.1527; z=21.7431; P<0.0001) and random effects model pooled (OR=10.0963; 95% CI, 6.1919~16.4626; z=9.2688; P<0.0001). The significant relationship was found in subgroup analyses. CONCLUSIONS The results of this meta-analysis show a significant association between hMLH1 hypermethylation and colorectal cancer risk. PMID- 28635684 TI - [Spatial analysis of syphilis and gonorrhea infections in a Public Health Service in Madrid]. AB - OBJECTIVE: Sexually transmitted diseases are a significant public health problem. Within the Madrid Autonomous Region, the districts with the highest syphilis and gonorrhea incidences are part of the same Public Health Service (Servicio de Salud Publica del Area 7, SSPA 7). The objective of this study was to identify, by spatial analysis, clusters of syphilis and gonorrhea infections in this SSPA in Madrid. METHODS: All confirmed syphilis and gonorrhea cases registered in SSPA 7 in Madrid were selected. Moran's I was calculated in order to identify the existence of spatial autocorrelation and a cluster analysis was performed. Clusters and cumulative incidences (CI) per health zone were mapped. RESULTS: The district with most cases was Centro (CI: 67.5 and 160.7 per 100.000 inhabitants for syphilis and gonorrhea, respectively) with the highest CI (120.0 and 322.6 per 100.000 inhabitants) in the Justicia health zone.91.6% of all syphilis cases and 89.6% of gonorrhea cases were among men who have sex with men (MSM). Moran's I was 0.54 and 0.55 (p=0.001) for syphilis and gonorrhea, respectively. For syphilis, a cluster was identified including the six health zones of the Centro district, with a relative risk (RR)of 6.66 (p=0.001). For gonorrhea, a cluster was found including the Centro district, three health zones of the Chamberi district and one of Latina (RR 5.05; p=0.001). CONCLUSIONS: Centro was the district with most cases of syphilis and gonorrhea and the most affected population were MSM. For both infections, clusters were found with an important overlap. By identifying the most vulnerable health zones and populations, these results can help to design public health measures for preventing sexually transmitted diseases. PMID- 28635680 TI - Saturated Fatty Acids and Cardiovascular Disease: Replacements for Saturated Fat to Reduce Cardiovascular Risk. AB - Dietary recommendations to decrease the risk of cardiovascular disease (CVD) have focused on reducing intake of saturated fatty acids (SFA) for more than 50 years. While the 2015-2020 Dietary Guidelines for Americans advise substituting both monounsaturated and polyunsaturated fatty acids for SFA, evidence supports other nutrient substitutions that will also reduce CVD risk. For example, replacing SFA with whole grains, but not refined carbohydrates, reduces CVD risk. Replacing SFA with protein, especially plant protein, may also reduce CVD risk. While dairy fat (milk, cheese) is associated with a slightly lower CVD risk compared to meat, dairy fat results in a significantly greater CVD risk relative to unsaturated fatty acids. As research continues, we will refine our understanding of dietary patterns associated with lower CVD risk. PMID- 28635685 TI - [Perineal wounds management after abdominoperineal extirpation of the rectum (experience of local negative pressure application)]. PMID- 28635686 TI - [Diagnosis and treatment of dirofilariasis of soft tissue of the lower extremities]. PMID- 28635687 TI - [The titanium-containing mesh as a perspective group of implants for abdominal wall repair]. PMID- 28635688 TI - [Establishment of the neurorehabilitation research center]. PMID- 28635689 TI - [Etude for surgical press history in Russia. On the 120th anniversary of the journal 'Surgery. N.I. Pirogov Journal' (1897-1945). Part 1]. PMID- 28635690 TI - [Pulmonary hemorrhage in blunt chest trauma]. PMID- 28635691 TI - [Review of the guidelines for doctors "Diagnosis and Treatment of Zenker's diverticulum', St. Petersburg, 2016]. PMID- 28635692 TI - [Some aspects of nosocomial infections dissemination in intensive care units of different profile]. PMID- 28635693 TI - [Chiasm and optic nerve glioma manifested as hemorrhage (two clinical cases and a literature review)]. AB - The article presents two rare clinical cases of low-grade (WHO grade I-II) glioma of the anterior visual pathway structures, the chiasm and optic nerves, in adults. The feature of these cases was the benign nature of a chiasm and optic nerve glioma in adults as well as its presentation in the form of hemorrhage to the tumor and parenchymal and subarachnoid space, which to some extent complicated making the correct diagnosis. Removal of an intracerebral hematoma and open tumor biopsy were performed in one case, and removal of a hematoma and partial tumor resection followed by radiotherapy were performed in the other case. PMID- 28635694 TI - [Improvement of visual functions after successful microsurgical exclusion of a giant aneurysm of the right internal carotid artery using revascularization techniques]. AB - We describe a clinical case of successful treatment of a female patient with a giant paraclinoid aneurysm of the right ICA. The aneurysm had a pseudotumoral course and manifested as pronounced progressive visual impairments. The patient underwent microsurgery including trapping/clipping of the right ICA aneurysm after creation of an EICMA and a high-flow anastomosis between the ECA and the M2 segment of the MCA. The surgery enabled decompression of the optic nerves, avoiding their injury. Postoperatively, the patient underwent transcutaneous electrical stimulation of the optic nerves. The case feature was that the patient developed gradual restoration of the blind eye vision. PMID- 28635696 TI - [Combined surgical treatment of cavernous internal carotid artery pseudoaneurysm]. AB - We describe a clinical case of surgical treatment of a cavernous internal carotid artery (ICA) pseudoaneurysm that developed due to damage to the artery during transsphenoidal resection of pituitary adenoma. Clinically, the aneurysm presented with episodes of profuse epistaxis that required tight nasal packing. Given the presence of an open circle of Willis, the patient underwent staged surgery that included the creation of a high-flow extra-intracranial anastomosis, subsequent endovascular ICA occlusion at the pseudoaneurysm level using balloon assisted coiling, and endoscopic debridement of the nasal cavity. The combined surgical treatment of this rare complication successfully excluded the pseudoaneurysm from the bloodstream, which led to complete regression of nasal bleeding. PMID- 28635695 TI - [Giant partially thrombosed aneurysm of the vertebral artery: a case report and literature review]. AB - INTRODUCTION: Giant partially thrombosed aneurysms of the vertebral artery are recalcitrant to treatment by microsurgical trapping and thrombectomy. Application of endovascular interventions is limited due to substantial brainstem compression and cranial nerve neuropathy. Combined endovascular exclusion and microsurgical excision provides an approach to treatment of these lesions. CLINICAL CASE: A 48 year-old female patient presented with progressive complaints of ataxia, diplopia in left lateral gaze, and dysphagia. Imaging studies (CT, MRI, angiography) revealed a giant partially thrombosed aneurysm of the right vertebral artery and pronounced brainstem compression. TREATMENT: The initial phase of treatment involved endovascular occlusion of the vertebral artery and aneurysm trapping that did not lead to changes in the postoperative patient's neurological status. MRI demonstrated complete aneurysm thrombosis and a weak TOF signal in the vertebral artery near the proximal aneurysm neck region. Because of persistent brainstem compression, the patient underwent right suboccipital craniectomy and hemilaminectomy of the CI arch for aneurysm excision one week after endovascular occlusion. After isolating the aneurysmal sac, the vertebral artery was transected, and two small branches extending from the aneurysm neck to the brainstem were also coagulated and transected, followed by aneurysm excision. Numerous vasa vasorum in the wall of the proximal vertebral artery and aneurysm neck were coagulated to stop bleeding. After surgery, the patient developed neurological symptoms (right leg ataxia and dysphagia worsening) due to lateral medullary infarction (confirmed by MRI) that presumably resulted from coagulation of two small perforating branches coming from the aneurysm neck to the brainstem. Recovery of the patient's neurological functions was observed during conservative treatment. The patient was discharged with mild right leg ataxia and preoperative left-sided abducens paresis. CONCLUSION: Medulla oblongata compression associated with a giant thrombosed aneurysm of the vertebral artery can be eliminated by endovascular trapping followed by surgical excision of the aneurysm. Preserving the vasa vasorum feeding the brainstem is crucial for prevention of ischemic complications. PMID- 28635697 TI - [Clinical guidelines for treatment of unruptured asymptomatic brain aneurysms]. PMID- 28635698 TI - [Unruptured cerebral aneurysms]. AB - The problem of high disability and mortality due to subarachnoid hemorrhage (SAH) from cerebral aneurysms has led to the fact that surgical treatment of unruptured aneurysms has been considered in Western Europe, Japan, and the United States as a method for prevention of subarachnoid hemorrhage for many years. The introduction of the so-called surgical SAH prophylaxis in Russia is a challenge that requires defining the principles of patient selection and choosing a treatment technique for unruptured cerebral aneurysms. The article highlights the modern approaches to treatment of asymptomatic unruptured cerebral aneurysms based on the concepts of aneurysm epidemiology and natural progression. PMID- 28635699 TI - [Decompressive craniotomy in patients with intracranial aneurysmal hemorrhage]. AB - Decompressive craniotomy (DCT) has been used for treatment of patients with acute aneurysmal subarachnoid hemorrhage (SAH) for more than 20 years. But so far, the attitude to this surgery is controversial, and the indications and contraindications for it are not clearly defined. The article reviews the domestic and foreign literature devoted to the issues of validity and efficacy of DCT in treatment of cerebral edema and intracranial hypertension in patients with aneurysmal SAH. PMID- 28635700 TI - [The promising directions for the further development of halotherapy in pediatric medicine]. AB - This article is focused on the modern possibilities for the application of halotherapy with a view to prevention, treatment and rehabilitation of the children with special reference to the main bio-physical properties of the principal active factors of halotherapy including dry finely-dispersed sodium chloride aerosols and specific features of the mechanism of their therapeutic action. The extensive studies have been underway in the recent years for the purpose of development of the new effective methods for the reconstitution of the aerodispersive environment. Halotherapy can be provided either on an individual (haloinhalation) or a group (exposition in the halochambers and halorooms basis. Halotherapy has been shown to produce well apparent anti-inflammatory, draining, mucolytic, immunomodulatory, and sanogenetic action. The high effectiveness of halotherapy for the prophylactic application in the frequently ill children is emphasized together with the possibility of its extensive use for the treatment of acute respiratory diseases and combined medical rehabilitation of the children presenting with chronic ENT disorders, respiratory and skin diseases. The optimal technologies for the clinical application of various types of halotherapy are discussed. PMID- 28635701 TI - [Diagnosis and treatment of acquired tracheomalacia in patients with cicatrical tracheal stenosis]. PMID- 28635702 TI - [Laparoscopic adhesiolysis and prevention of abdominal adhesions by using mechanical barriers]. AB - Adhesions commonly result from abdominal and pelvic surgical procedures and may result in intestinal obstruction, infertility, chronic pain, or complicate subsequent operations. Laparoscopy produces less peritoneal trauma than does conventional laparotomy and may result in decreased adhesion formation. We present a review of the available data on laparoscopy and adhesion formation, as well as laparoscopic adhesiolysis. We also review current adjuvant techniques that may be used by practicing laparoscopists to prevent adhesion formation. PMID- 28635703 TI - [External duodenal fistula]. PMID- 28635704 TI - [Review of the monograph of N.A. Kuznetsov 'Surgical risk: decision-making'. M.: Litterra; 2015.] PMID- 28635705 TI - [The influence of the climatic and weather conditions on the mechanisms underlying the formation of enhanced meteosensitivity (a literature review)]. AB - The present review concerns the problem of the influence of the climatic conditions on the human body, the creation of the medical weather forecast service, the development of non-pharmacological methods for the correction of meteopathic disorders, and the reduction of the risk of the complications provoked by the unfavourable weather conditions. The literature data are used to analyse the influence of climatic and weather factors on the formation of enhanced meteosensitivity and the development of exacerbations of chronic non communicable diseases under the influence of weather conditions. It is concluded that marked changes of the weather may lead to an increased frequency of exacerbations of the chronic non-communicable diseases. The influence of weather and climate on human health is becoming an increasingly important factor under the current conditions bearing in mind the modern tendency toward variations of the global climatic conditions and their specific regional manifestations. The authors emphasize the necessity of the identification and evaluation of the predictors of the development of high meteosensitivity for the prognostication of the risks of the meteopathic reactions and the complications associated with the changes in weather conditions as well as the importance of the improvement of the existing and the development of new methods for the non-pharmacological prevention and correction of enhanced meteosensitivity with the application of the natural and preformed physical factors. PMID- 28635706 TI - [The physical methods for the prevention and management of weather-dependent pathological reactions (a literature review)]. AB - The review presents data on the non-pharmacological methods and technologies for the prevention and management of meteopathic reactions (MPR) applied in Russia for the treatment of the patients suffering from obstructive and cardiovascular diseases. It is assumed, based on the concept of heliogeophysical imprinting, that the major factors responsible for the development of MPR are the disturbances of electromagnetic homeostasis. The acupuncture points and channels are regarded as a system designed for the maintenance of electromagnetic balance in the human body. In this context, it is proposed to encourage the application of the methods of electro-diagnostics and reflexology for the prevention and correction of meteopathic reactions. PMID- 28635707 TI - [The medical rehabilitation of the children presenting with atopic dermatitis (a literature review)]. AB - Atopic dermatitis takes the predominant position in the structure of skin pathologies in the children of various age. Both the scientifically based forecasts and the data of numerous investigations give evidence not only of the significant increase in the number of patients presenting with this condition but also of the growing severity of this disease. Taken together, these facts account for the serious medico-social importance of the problems arising in connection with this pathology. The introduction of the eliminative actions, a hypoallergenic diet, local and systemic pharmacotherapeutic modalities do not always allow to prevent or arrest the inflammatory process and achieve the long standing remission. The high frequency of undesirable reactions to the pharmacological products turns the attention of many clinicians to the application of the non-pharmacological factors and methods for the treatment of atopic dermatitis in the children. The main objectives of physical therapy in the case of atopic dermatitis include the normalization of the state of the central and vegetative nervous system, the achievement of hyposensitization, sedative, anti-toxic, and anti-inflammatory effects, as well as the application of the dissolving, trophic, and antipruritogenic agents, strengthening of the general health status of the children. PMID- 28635708 TI - [The early diagnosis of neurodegenerative changes in multiple sclerosis and clinically isolated syndrome based on optical coherence tomography of the retina]. AB - AIM: To study signs of neurodegeneration in the retina in multiple sclerosis. MATERIAL AND METHODS: We studied the retinal nerve fiber layer (RNFL) in 265 (524 eyes) patients. RESULTS AND CONCLUSION: We identified a reliable thinning of RNFL of both eyes in patients with relapsing-remitting multiple sclerosis (MS). A comparative analysis by sectors revealed a specific decrease in RNFL in temporal segments and papillomacular beam. Mean values of RNFL in patients with clinically isolated syndrome did not differ from those in controls. Thickening of RNFL of low segments (NI i TI) and decrease in the thickness of the upper temporal segment (TS) were found. The results have demonstrated that neurodegenerative signs in the retina may be early appearances of MS. Optical coherence tomography allows to perform objective and rapid screening of retinal neurodegenerative changes. PMID- 28635709 TI - [Regional metabolic changes of supraventricular tissue in patients with relapsing remitting and secondary-progressive multiple sclerosis]. AB - AIM: To evaluate and compare the intensity of changes in a regional meta-analysis in relapsing-remitting and secondary-progressive multiple sclerosis (RRS and SPMS). MATERIAL AND METHODS: The results of longitudinal studies of multiple sclerosis (MS) using positron emission tomography, magnetic resonance spectroscopy and diffusion tensor imaging are presented. RESULTS: In MS, metabolic changes precede the structural ones. The markers of neuronal and axonal dysfunction (a decrease in NAA/Cr ratios in the white and grey matters, without the structural changes) are recorded in the early stages. The metabolic changes in the grey matter were recorded mostly in the middle frontal gyrus and posterior cingulate cortex. With the increase of duration and severity of MS, the metabolic changes spread to the other regions of supraventricular areas. The distribution of degeneration zones is related to MS course. CONCLUSION: There is substantial evidence on the irreversible damage of neurons in the medial prefrontal cortex in SPMS that confirms the vulnerability of the frontal cingulate gyrus in MS. PMID- 28635710 TI - [A retrospective analysis of the effect of pregnancy on the course of multiple sclerosis]. AB - AIM: For a long time it was believed that pregnancy worsens the clinical course of multiple sclerosis. In several European countries, there have been several studies that have demonstrated remission of autoimmune aggression during pregnancy. We studied the effect of pregnancy on the course of multiple sclerosi. MATERIAL AND METHODS: A retrospective analysis of disease course of 279 patients was performed for the first time in three major Russian centers (Moscow, Novosibirsk, Tyumen). RESULTS AND CONCLUSION: There was a remission of autoimmune aggression during pregnancy. The use of DMT before pregnancy was a predictor of a more favorable course of the disease after delivery. An earlier beginning of DMT after delivery led to a significant risk reduction of relapses. PMID- 28635711 TI - [A study of the relation between the sCD40-sCD40L system and the course of multiple sclerosis]. AB - AIM: To determine the relationship between the level of soluble CD40 and CD40L (sCD40, sCD40L) and key characteristics of the course of multiple sclerosis. MATERIAL AND METHODS: A comparative cross-sectional study covered 80 patients with multiple sclerosis diagnosed according to 2005 McDonald criteria. Enzyme immunoassay method was applied to measure the concentration of sCD40 and sCD40L in venous blood serum. RESULTS: No significant changes in sCDL or sSD levels were found during acute MS periods in comparison to remission periods. The positive correlation between the frequency of exacerbations and the level of sCDL was shown. CONCLUSION: No evidence for the association between indexes of activity of the sCD40-sCD40L system in blood and both exacerbation of MS, severity and rate of neurological impairment in this disease was demonstrated. PMID- 28635712 TI - [A prospective, open, non-randomized study on the safety and efficacy of natalizumab (tisabri) in the Russian population of patients with relapsing remitting multiple sclerosis]. AB - AIM: To evaluate safety and efficacy of natalizumab (tisabri) in the RUSTYS study of patients with relapsing-remitting multiple sclerosis (RRMS) during one year. MATERIAL AND METHODS: This prospective, open, non-randomized clinical study included 100 RRMS patients treated with natalizumab in dose 300 mg intravenously every 4 weeks during 48 weeks. The safety was assessed by the percentage of patients with infusion reactions as well as by the distribution of undesirable effects (UE). Before treatment and after 48 weeks, antibodies to JC virus (JCV) were determined. The efficacy was evaluated by the frequency of relapses, progression of disability, MRI results and quality of life indices. RESULTS: After treatment, 87% of the patients had no relapses, disease progression assessed by EDSS was not observed in 96% . To 48th week, 71% of patients had no MRI changes in T2 lesions and 79.6% - in T1 hypointense lesions. Quality of life has been improved. At least one UE, including the development of tuberculosis in one patient, was noted. Infections (upper respiratory tract infection, nasopharyngitis, flu) were recorded in 25% of the patients. Three out of 28 (10.7%) of the patients with negative results of JCV analysis at baseline had the seroconversion with the change of the negative status to the 48th week. No cases of progressive multifocal leukoencephalopathy related to natalizumab were found. CONCLUSION: The results are in line with those of earlier studies in patients with RRMS with high disease activity. PMID- 28635713 TI - [Intravenous immunoglobulins: perspectives in multiple sclerosis (a literature review with own results)]. AB - In this review, we have analyzed a role of intravenous immunoglobulins (IVIGs) in multiple sclerosis (MS) therapy. Main mechanisms of IVIGs are elucidated and the results of the most prominent investigations of IVIGs in MS are reported. Based on these data, we discuss a role of IVIGs as second line therapy in MS. We also present results of our own open observational study of IVIG therapy of 41 patients with relapsing-remitting and secondary progressive with relapses MS, in which a clear decrease of relapse rate (by 2-3 times) and disability (in average by 0.38-0.48 EDSS points) were revealed. We found some differences between complex IVIGs and pure IgG IVIGs clinical efficacy with some prevalence of complex IVIGs that were discussed. High IVIGs safety and tolerability (only slight transitory side effects in up to 14% of patients) were found. PMID- 28635714 TI - [Supplement. Criteria of non-efficacy of treatment and withdrawal of first line DMD and switching to second-line drugs]. PMID- 28635715 TI - [The International Baikal seminar 'Innovations in neurology and neurosurgery' 2015']. PMID- 28635716 TI - [The First World War and the development of Russian psychiatry]. PMID- 28635717 TI - [Neuroimaging of functional abnormalities in apathy]. AB - Apathy is a common comorbid condition in neurologic and somatic disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis, frontotemporal dementia, senile dementia, HIV) and a symptom of many psychiatric disorders. Neurophysiologic research in this area aims to examine the specific features to differentiate the apathy from main disorder. This paper reviews neuroimaging studies of functional abnormalities in apathy. PMID- 28635718 TI - [Assessment of need in nutritional support in patients with the consequences of central nervous system injuries]. AB - Traumatic brain injury (TBI) and spinal cord injury (SCI) are most common causes of death and disability in young patients. Metabolic changes occur immediately after the acute injury of the central nervous system. However hypermetabolic response in SCI is less pronounced compared to that in TBI that could be explained by the weakness of denervated muscles and hypodynamia. Following SCI, the level of resting energy expenditure is lower comparison to that calculated using the Harris-Benedict formula. Indirect calorimetry corresponded to class II (B) medical evidence, is recommended as a method for assessment of energy expenditure in the acute stage of TBI and SCI as well as in their consequences. Nutritional support is favorable and safe and therefore, it should be used as soon as possible. Many studies provide evidence that nutritional support leads to the replenishment of energy expenditure, reduce catabolic processes and nitrogen loss thus minimizing the risk of complications that in future decrease the extent of disability and increase quality-of-life of patients with the consequences of central nervous system injuries. PMID- 28635719 TI - [Neurodevelopmental disorders in children with epilepsy]. AB - Neurodevelopmental disorders, including intellectual disability, autistic spectrum disorders, speech disorders, attention deficit hyperactivity disorder (ADHD), learning disabilities, are more prevalent in children with epilepsy compared with the general population. Marked developmental delay and regression of acquired skills are characteristic of epileptic encephalopathies. Conditions, in which neurodevelopmental disorders are associated with the marked epileptiform EEG activity, while clinical epileptic seizures are absent, represent a serious problem. The authors consider the features of epilepsy with electrical status epilepticus during slow-wave sleep, pseudo-Lennox syndrome, Landau-Kleffner syndrome, children autistic epileptiform regression, autosomal-dominant rolandic epilepsy with verbal dispraxy and a combination of epilepsy and subclinical epileptiform EEG activity with developmental dysphasia and ADHD. In addition to the optimization of basic treatment with antiepileptic drugs (AEDs), nootropic drugs which do not increase epileptiform activity (hopantenic acid), are recommended. PMID- 28635720 TI - [Poststroke depression - a common medical and social problem]. AB - Poststroke depression (PD) is considered as a common medical and social problem. Depression is estimated to occur in 30-35% of the patients during the first year after stroke. Despite the high level of comorbidity, PD is frequently undetectedand and untreated. Psychological impairment from stroke has a negative effect on functional outcome, rehabilitation and quality of live. On the basis of literature review present prevalence, etiology, pathogenesis,diagnosis of PD and summarize current recommendations for therapeutic intervention. A rational approach to the treatment and prevention of PD is proposed. PMID- 28635721 TI - [A.A. Skoromets, D.G. German, M.V. Iretskaya, L.L. Brandman 'Tunnel compressive/ischemic mono- and multineuropathies' 3rd Ed. Revised. M.: GEOTAR Media; 2015;376.] PMID- 28635722 TI - [Epidemiology of neuroendocrine neoplasms]. PMID- 28635723 TI - [XII Congress of Russian Surgeons]. PMID- 28635724 TI - [Etudes of surgical press history in Russia. On the 120th anniversary of "Surgery" journal (1946-2015). Part 2]. PMID- 28635725 TI - [Solitary fibrous tumor of pleura and lung: case reports and literature review]. PMID- 28635726 TI - [The role and place of talc in malignant pleuritis management (literature review)]. PMID- 28635727 TI - [Chronic cerebrovascular diseases and metabolic syndrome: approaches to pathogenic therapy of cognitive dysfunction]. AB - Cognitive decline comprises one of the most important symptoms of chronic cerebral hypoperfusion. It leads not only to social disability of the patients with a subsequent decline in life quality but also to a decrease in adequate control of the course of both vascular pathology and comorbid states. Pathogenetic therapy and prevention of cerebrovascular disease progression, along with general medical measures, should include the drugs normalizing different symptoms of metabolic syndrome (arterial hypertension, diabetes mellitus etc) as well as complex drugs with multiple actions (hemangioma correction, antithrombotic, antioxidant and vasoactive) actions. PMID- 28635728 TI - [Cognitive dysfunction after coronary artery bypass grafting]. AB - Despite the advances in surgical and anesthetic techniques for coronary artery bypass grafting (CABG), the incidence of neurological complications, including postoperative cognitive dysfunction (POCD), remains high. CABG is performed more often in elderly patients with severe comorbidities. However, comprehensive prevention measures and POCD rehabilitation have not yet been developed. Physical training is an effective and safe method for correcting endothelial dysfunction, severe systemic inflammatory response syndrome, lipid peroxidation, i.e. mechanisms contributing to the development and severity of POCD. PMID- 28635729 TI - [Correction of pathological conditions associated with insulin-resistant hyperglycaemia]. AB - High level of glucose in the blood in hypoxic-ischemic states is one of the main factors that complicates the degree of brain damage. An increased level of reactive oxygen species and impaired functioning of the endogenous antioxidant system are the consequences of the hyperglycemic-ischemic condition. Medical treatment is necessary to compensate for the development of cerebrovascular disorders in ischemia comorbid to diabetes mellitus. The use of antioxidants (2 ethyl-6-methyl-3-hydroxypyridine succinate) is the most therapeutically effective. PMID- 28635730 TI - [The relationship between schizophrenia and epilepsy: the history and current state of the problem]. AB - The review deals with the background and current state of the relationship between schizophrenia and epilepsy. The author presents results of recent epidemiological, neuropsychological, neurophysiological and genetic studies, indicating that these diseases may be different clinical variants of a common etiologic process (neurodevelopmental brain abnormalities), while epilepsy with chronic psychotic symptoms can be considered as an experimental model of schizophrenia pathogenesis. PMID- 28635732 TI - [Review of "Histology and embryology of human oral cavity organs" by V.L. Bykov]. PMID- 28635731 TI - [Gerpes viruses and multiple sclerosis]. AB - AIM: To study the efficacy of L-lysine aescinat in the treatment of vascular and microvascular disorders in patients with cerebral venous dystonia. MATERIAL AND METHODS: Sixty-eight patients, 25 male and 43 female, aged from 25 to 56 years, with disturbances of venous cerebral blood circulation and venous outflow difficulties were examined. The examination included the assessment of cerebral hemodynamics using the algorithm of complex ultrasound examinations and functional status of the microcirculation by the laser Doppler flowmetry (LDF) at baseline and 10 days after treatment with L-lysine aescinat. RESULTS AND CONCLUSION: L-lysine aescinat improves intracranial venous outflow, significantly improves the functioning of microcirculation, while not affecting the normal type of microcirculation or changing it in the direction of improvement of hemodynamic parameters, has a modulating effect on the autonomic response, and can be recommended in the complex treatment of young and middle aged patients with disturbances of cerebral venous blood circulation with the predominance of vagotonia as well as hypersympathicotonia. PMID- 28635734 TI - [Diagnosis of Acanthamoeba keratitis]. AB - The Acanthamoeba keratitis is a relatively rare, but dangerous disease of the cornea. Its development is thought to be associated with contact lens wearing as well as corneal microwounds contaminated with soil or water. The disease has no evident distinctive clinical features and is, therefore, difficult to be distinguished from herpetic or fungal keratitis. Nevertheless, Acanthamoeba infection can be suspected judging from anamnestic data (i.e. contact lens use and corneal injury with subsequent contamination of the wound), inadequately strong pain syndrome, ring-shaped infiltration of the cornea and ineffectiveness of conventional therapy. Also helpful may be such measures as isolating the bacteria using the method of biocultures, morphological examination of corneal biopsy material (using light and luminescent microscopy), genetic testing, and in vivo confocal microscopy of the cornea. Other promising methods are also listed in this article. A widely accepted diagnostic technique is yet, however, missing. PMID- 28635733 TI - [Optical coherence tomography angiography in glaucoma diagnosis]. AB - According to literature data, vascular dysfunction may well contribute to the development of glaucomatous optic neuropathy, which makes it reasonable to search for new imaging techniques capable of early diagnosis and monitoring of glaucoma through assessment of retinal, optic nerve head (ONH), and choroidal perfusion. Optical coherence tomography angiography (OCTA), a recently introduced method based on the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm, enables evaluation of both retinal and choroidal blood flow in peripapillary and macular areas. The first studies involving OCTA have revealed a decrease in retinal blood flow in glaucoma. It has also been shown that visual field indices correlate better with the peripapillary flow index than with morphometric parameters of the optic nerve head (ONH) and peripapillary retina. OCT angiography has great potential for ONH blood flow assessment during physiological tests, which is an important step towards understanding pathogenesis of glaucoma. PMID- 28635735 TI - [Treatment of Acanthamoeba keratitis]. AB - In recent years, Acanthamoeba keratitis (AK) has became a clinically significant problem because of the broad use of contact lenses that are the major risk factor of the disease. The treatment presents considerable difficulties due to similarity of clinical manifestations of AK to other keratites (bacterial, herpetic, and fungal). This often leads to late diagnosis and formation of drug resistant cysts. There is currently no specific drug universally suitable for monotherapy of AK. Instead, 2 agents (usually chlorhexidine and poligexametilen biguanide) are used that, if combined, are effective against both trophozoites and cysts. If necessary (severe keratitis, insufficient treatment effect), diamidines (propamidine and its analogs), antifungals (fluconazole, itrakonazol), certain antibiotics (Neomycinum), and iodine-containing medications (povidone iodine) can be prescribed. The use of corticosteroids is considered unjustified because of the risk of rapid progression (due to disturbance of local immunity and also provocation of excystation of the amoebas). The penetrative keratoplasty may be required, especially if a descemetocele or corneal perforation occurs, however, its results are generally worse than those in other keratites because of a higher risk of complications (iridocyclitis, secondary glaucoma, AK recurrence in the graft). In some cases, good results are achieved with minimally invasive surgeries, such as mechanical epithelial debridement, conjunctivoplasty and cryopreserved amniotic membrane transplantation, excimer laser phototherapeutic keratectomy, and cross-linking. In the future, gene therapy and specific chemotherapy of AK may well be developed. PMID- 28635736 TI - [Hypothesis of immune privilege of the cornea and pathophysiology of graft rejection]. AB - Transplantation of donated cornea is a radical and pathogenetically oriented measure of rehabilitation for patients with corneal blindness. Unlike other transplantation surgeries, keratoplasty is usually done without tissue typing and systemic immunosuppression. Even so, in the absence of risk factors, grafts can remain clear in as many as 90% of cases. The phenomenon is explained by immune privilege of the cornea. The hypothesis of immune privilege comprises several interrelated mechanisms that ensure long-lasting transparency of the graft. These include transfer limits of immunogenic stimuli to peripheral lymphoid tissues, deviation of the immune response, and neutralization of immune effector elements within the host-graft interface by immunosuppressive ocular environment. A change in any of the said components leads to loss of the immune-privilege status of the cornea, thus, significantly increasing the risk of graft rejection. We know several stages of the response activation cascade in graft rejection that can be influenced therapeutically, namely, antigen absorption, processing, and presentation as well as T-cell expansion and cellular inflow to the eye. The first two stages take place in the eye itself and are susceptible to instillation drugs and gene therapy. New highly selective medications aimed at specific signals from the immune cells and their pathways may be able to help restore the immune privilege of the cornea and improve the results of optical and reconstructive surgeries in high-risk patients. PMID- 28635737 TI - [Modern treatments for purulent corneal ulcers]. AB - This review covers the most widely used modern treatment methods, minimally invasive and surgical, for therapy-resistant purulent corneal ulcers. PMID- 28635738 TI - [Embryological aspects of clinical presentations of congenital lens and vitreous anomalies]. AB - This report gives a general overview of embryological features of the human eye. Key literature sources published during the last century on evaluation of congenital changes in the vitreous body and identification of signs of its 'underdevelopment' in certain types of congenital cataracts have been studied. The said changes were analyzed in terms of general pathology of the human body as well as local morphological manifestations. According to the authors, such an approach justifies the need for comparison of clinical manifestations of congenital lens and vitreous changes with possible embryonic defects. PMID- 28635739 TI - [Mental health disorders in the first years of life: disorders mostly related with psychogenic factors]. AB - In the literature review the authors present current data on the clinical features, prevalence and general approaches to treatment and prevention of mental disorders related with environmental factors in early childhood. A quite new class of the disorders, which are specific for early childhood: attachment disorders, clinical specifics of posttraumatic stress disorder, clinical manifestations of sleep disorders and feeding disorders is considered. It is emphasized that disturbed parent-child relations can be one of the predictors of early mental disorders in children. The modern models of psychotherapy for children of early age are presented. PMID- 28635740 TI - [Functional disorders: pathogenesis and systematic of clinical presentation]. AB - Functional disorders hold a prominent place in the clinical practice of physicians of different specialties. The difficulties in the diagnosis of functional disorders need expensive examinations, and standard treatment is, as a rule, is not effective. Currently, the pathogenesis of these disorders is considered in the frames of the biopsychosocial model. In this literature review, the authors present modern concepts of terminology, classification, main features and general trends of the course of functional disorders. Special attention is drawn to comorbidity, a role of psychogenic factors and cerebral mechanisms of the pathogenesis including cognitive aspects. PMID- 28635741 TI - [A place of first-line drugs in treatment of multiple sclerosis]. AB - A rapidly changing set of drugs for treatment of multiple sclerosis (MS) leads to the necessity of searching for predictors of their efficacy. Understanding of pathogenetic processes in MS and mechanisms of action of different drugs play an important role in the search for markers of potential responders. The author analyses the presently accumulated information on the original drug copaxone (glatiramer acetate) including current concepts on the mechanism of action, long term safety and efficacy. Data on the frequency and significance of adverse effects during treatment with glatiramer acetate as well as on the influence of the drug on pregnancy, postpartum course of MS and development of the infant who received glatiramer acetate prenatally compared to other disease-modifying drugs are presented. PMID- 28635742 TI - [A review of drugs for treatment of Alzheimer's disease in clinical trials: main trends]. AB - Development of drugs for treatment of neurodegenerative diseases, including Alzheimer's disease (AD), is thought to be a complicated problem of current medical chemistry. According to current concepts, AD is proteinopathy due to impairments in the metabolism of amyloid precursor protein and tau-protein that results in the pathological protein aggregation in the brain. The author describes about 130 compound used in clinical trials of AD in 2015 and presents major characteristics of their action. It has allowed to find the following trends in a search for drugs for AD: 1. Development of disease modifying drugs, 2. Drugs, which act on several molecular targets simultaneously, 3. Search for new possibilities of using known drugs (drug reposition). PMID- 28635743 TI - [Clinical efficacy of neuropeptides in cerebrovascular pathology]. AB - Great value in the treatment of ischemic stroke (IS) is given for neuroprotection. When ischemic neuroprotection aims to increase the period of 'therapeutic window' and stop the cascade of pathological reactions. The neuroprotection is defined as the continuous adaptation of the neuron to new functional conditions, as the key to reducing damage to brain tissue caused by ischemia, it acts at the level of the molecular cascade leading to the dysfunction and death of neurons. Special attention is paid to the study of the properties of low molecular weight neuropeptides that penetrate through the hematoencephalitic barrier and exert a multiple effect on the Central nervous system (CNS) even in small concentrations. One of neuropeptide of cytoprotectors, is Cortexin, containing a complex of low molecular weight peptides (with mass from 1 to 10 kDa), which is optimally balanced and close to the metabolism of brain neurons (organotropic) that exert tissue-specific, regulatory and restorative effect on the cerebral cortex. The article presents data on the effectiveness purpose of Cortexin in patients with IS. It is shown that the optimal scheme for the purpose of Cortexin includes: intramuscular administration of Cortexin in the dose of 20 mg (10 mg morning + 10 mg evening) for 10 days, with a repeat the same course within 10 days after the first, since the first 6 h after the onset of stroke symptoms. The observation period is more than 2 months. PMID- 28635744 TI - [Biological basis of suicidal behavior]. AB - Based on current clinical and classification concepts of suicidality, the biological parameters characteristic of suicidal behavior, completed and uncompleted suicides reported in the last few decades are discussed. The results obtained in the studies of neurotransmitter and other brain systems, immune system, lipid and other types of metabolism as well as data of neuroimaging brain studies and post-mortem investigation of brain structures are presented. PMID- 28635745 TI - [Genetic aspects of binge eating disorder Part 2. Molecular genetics and pharmacogenetic approaches]. AB - Genetic risk of binge eating disorder (VED) is a consequence of joint participation of many genes, the contribution of each one is small, but the total (additive) effect is significant and greatly influences the age at onset, clinical dynamics and the level of treatment resistance. It is assumed that the carriers of different polymorphic variants of genes and their combinations have different levels of genetic risk. No Genom Wide Association studies of VED has been performed and the analysis of the results of candidate genes studies gives reason to believe that pathogenetically substantiated panel of genes, including serotonin system, BDNF and, especially dopamine and endogenous opioid system, would be most useful, taking into account the mechanism of action of drugs for the VED treatment. Genetic studies with this panel if using evidence-based design, detailed and quantitative analysis of the family history of binge eating can give good results for: 1) assessment of the genetic risk of VED for primary prevention programs; 2) identification of the specific clinical forms of development and course of VED with significant genetic influence; 3) identification of the specific genetic variants that increase the effectiveness of personalized pharmacotherapy of VED within pharmacogenetic approach. PMID- 28635746 TI - [Discirculatory encephalopathy and small vessel disease]. AB - The report examines the practicability of the term 'discirculatory encephalopathy' used in the Russian Federation to designate the chronic cerebral ischemia of different origin. The authors discuss the state of small vessel disease which manifests itself through slowly progressive cerebral changes. On the basis of their own research results and literature review the authors conclude that a standardized extract of Ginkgo biloba EGb761 (tanakan) can be effectively used in patients with small vessel disease. PMID- 28635747 TI - [Diploptic treatment of concomitant strabismus]. AB - This is a literature review on the use of diploptic treatment in concomitant strabismus. PMID- 28635748 TI - [Treating severe keratoconjunctivitis sicca]. AB - Keratoconjunctivitis sicca is a widespread disease with a complex multifactorial pathogenesis. Current understanding of its pathogenesis and existing treatments are summarized in this literature review. PMID- 28635749 TI - [Purulent corneal ulcers: clinical presentation, diagnosis, and conservative treatment]. AB - This is a detailed review of purulent corneal ulcer signs and symptoms, problems in diagnosis, and conservative treatment options. PMID- 28635750 TI - [M.R. Bogomil'sky, I.V. Rakhmanova, E.I. Zelikovich, M.M. Polunin, A.G. Matrsokin 'The atlas of clinical roentgenoanatomy of the temporal bone in breast-fed newborns and young children'. M: Ritm 2014]. PMID- 28635751 TI - [Effects of body positioning in patients with non-traumatic intracranial hemorrhages]. AB - The article presents an analysis of different methods of positioning patients with acute cerebral pathology. Changing of 'head-of-the bed' position is a routine and simple method of correction of intracranial hypertension. For the majority of patients with cerebral damage, regardless of the etiological factor, 15-30 degrees 'head - of - the bed' position is preferable. However, in some cases head-of-bed manipulation can lead to the irreversible ischemic damage due to the reduction in systemic and perfusion pressure and cerebral blood flow. Thus, the selection of the optimal body position in different types of acute cerebral pathology remains a debated issue. PMID- 28635752 TI - [Results and promises of genetics of cognitive impairment in schizophrenia: molecular-genetic approaches]. AB - This review highlights the basic paradigms and directions of molecular genetic studies of cognitive deficits in schizophrenia. Along with the traditional approach based on functional candidate genes, it covers genome-wide association studies (GWAS) for cognition in general population and schizophrenic patients, attempts to integrate GWAS results in polygenic profiles that can be used in personalized care of schizophrenic patients, and a search for biological pathways implicated in the development of cognitive impairments with bioinformatics methods. However, despite significant advances in understanding the genetic basis of the disease and a rapidly growing amount of data on genes associated with cognitive functions, most of the variability of cognitive impairments in patients remains unexplained. The data on the functional complexity of the genome accumulated in the fields of molecular biology and genetics underscore the importance of studying epigenetic mechanisms of cognitive deficits in schizophrenia. PMID- 28635753 TI - [Predictors and modifiers of impulse control disorders in Parkinson's disease]. AB - Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson's disease (PD). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses. Possible predictor's for ICDs include male sex, younger age and younger age at PD onset, use of dopaminergic agents. Modifiers of ICDs are pharmacological (medication) and non-pharmacological (surgical, behavioral) treatments. PMID- 28635754 TI - [Cerebral plasticity and connectopathies: mechanisms of comorbidity of neurological diseases and depression]. AB - In this theoretical study, the concept of connectome and connectopathy was used for the analysis of the data related to molecular mechanisms of the pathogenesis and comorbidities of neurological and psychiatric diseases (in particular, depression), as well as approaches to their pharmacotherapy. A scheme of main network levels underlying connectome is provided, including subcellular and molecular levels. Neuronal networks forming connectome are based on several 'lower' network levels, the state and interactions of these levels stipulating the state and functioning of the connectome as well as its dynamic changes. Similarly, network levels are demonstrated for connectopathies. Common network mechanisms of connectopathies, particularly depressive disorders and neurodegenerative diseases, are not only underlying the comorbidity, but also suggest common potential pharmacotherapeutic approaches. PMID- 28635755 TI - [Characteristics of structural and functional organization of the brain]. AB - Current conceptions on the fundamental mechanisms underlying brain functioning in normal conditions and pathological states are considered. The author emphasizes that a great progress in the field has been achieved after the implementation of neuroimaging methods in clinical practice. During the last time, attention is drawn to the connections between separate neurons as well as between different brain regions. Functional specialization and functional integration of different brain regions are key concepts of the higher brain function organization. The significance of the resting state of the brain, which is in fact the active process, is analyzed. The state of cerebral functions determines internal processes in the neuronal tissue. Different aspects of energy metabolism determining the normal functioning of cerebral structures are considered. The expediency of using the drugs influencing the energy metabolism, one of which is 2-ethyl-6-methyl-3-hydroxypyridine succinate (mexidol), is highlighted. PMID- 28635756 TI - [Specifics of the use of NSAIDs in senior age]. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) have a strong analgesic and anti inflammatory effects and are widely used in clinical practice. Patients with chronic disorders of the joints, in particular the spine, are main consumers of NSAIDs. However, risk factors for side-effects should be taken into consideration in the treatment with NSAIDs, especially in patients of old age. The careful control of treatment taking into account the risk of developing gastrointestinal and cardiovascular events is needed. PMID- 28635757 TI - [A role of the gastrointestinal tract microbiota in the pathogenesis of Parkinson's disease]. AB - Microbiota is a community of microorganisms, viruses, protozoa, colonizing the gut. There are tight phylogenetic relationships between the gut microbiota and the human body, the disturbance of which may lead to the CNS dysfunction as well as to the development of neurodegenerative diseases. This review focuses on general and specific aspects of the influence of gut microbiota on the pathogenesis of Parkinson's disease (PD). Current theories and models of the relationship between microbiota and brain structures in PD are presented with a specific focus on neurochemical and immunological aspects of the problem. PMID- 28635759 TI - [Second All-Russian Scientific and Practical Conference on Current Approaches to the Morphological Diagnosis of Human Neoplasms]. PMID- 28635761 TI - [Interview with A.A. Skoromets]. PMID- 28635760 TI - [The current problems related to Meniere's disease]. AB - Over 150 years have elapsed since Prosper Meniere's described for the first time the clinical symptoms of the disease that is called by his name at the present time. Nevertheless, the etiology of this pathological condition remains unknown. It has been believed during many decades that the cause of Meniere's disease Is the presence of an excess fluid (hydrops) in the endolymphatic space of the inner ear leading to the rupture of membranes responsible for hearing impairment and vestibular disorders. The recent histopathological studies have demonstrated that endolymphatic hydrops (RH) is not necessarily associated with the clinical manifestations of Meniere's disease. During the last decades, certain authors have undertaken attempts to elaborate new theories of etiology, pathogenesis, and mechanisms underlying the development of dizziness associated with Meniere's disease. These are the theory of genetic predisposition to this condition, the viral and autoimmune theories, and the theory of disturbance of the longitudinal endolymph flow. However, none of these theories was adequately substantiated. The ongoing experimental and morphological studies appear to give evidence that the aquaporin water channels may play a role in the formation of hydrops. Moreover, the mechanisms underlying episodes of dizziness remain to be elucidated. In the light of recent progress in normal physiology and pathological physiology of the ear, the theory of ruptures proposed by H. Schuknecht tends to be considered increasingly less attractive and appears to be replaced by new hypotheses providing an alternative explanation for the mechanism behind the development of Meniere's disease giving priority to the role of contamination of perilymph with calcium ions. PMID- 28635762 TI - [The philosophy of rapid rehabilitation in thoracoabdominal surgery]. PMID- 28635763 TI - [What surgeon is necessary today?] PMID- 28635764 TI - [Thrombosis of the cerebral veins in gynecological practice]. AB - The review presents literature data on the risk factors of cerebral venous thrombosis (CVT), a rare life threatening disorder. Currently, the diagnosis of CVT is made more often due to the possibility of using neuroimaging methods of cerebral structures. Pregnancy, postpartum period, use of oral contraceptives are risk factors of CVT. A role of thrombophilia, in particular Factor V Leiden mutations and the prothrombin G20210A polymorphism, in the CVT pathogenesis is confirmed. The development of CVT is an example of the interaction between persistent risk factors increasing the likelihood of thrombotic complications and acquired risk factors. A focal neurological deficit during pregnancy, delivery and postpartum period is the best indicator of CVT diagnosis. Possibilities of the use of anticoagulants in treatment and prevention of CVT are analyzed. PMID- 28635765 TI - [Interview with prof. L.B. Novikova]. PMID- 28635766 TI - [Contemporary paradigm of rational stroke treatment]. AB - Stroke was and remains one of the world's leading medical and social problems. Nowadays we are watching permanent sometimes cardinal changes in view about etiology, pathogenetic mechanisms and therapy of patients with stroke. In this work there have been elucidated contemporary theoretical and practical aspects of stroke treatment and prophylaxis based on the results of multicenter clinical trials and experience of leading foreign and native specialists. Much attention is devoted to the pharmacotherapy of patients with stroke. It is showed that application of neuroprotective drugs is of great importance, among which antihypoxants with pleiotropic action play a crucial role (mexidol). PMID- 28635767 TI - [Experience of Regional Vascular Centre in assisting patients with severe cerebrovascular accidents in Novosibirsk]. AB - The analysis of the work of the neurological department of the Novosibirsk regional vascular center of City Clinical Hospital #1 for the period from 2013 to 2015 was done. We analyzed the annual reports of the regional vascular center, dynamics of cerebrovascular disease patterns, lethality, about the provision of medical care to patients with stroke, the use of high-tech methods of diagnosis and treatment. Ascertain the progress achieved and the perspectives of further improving the quality of care to patients with stroke due to wider use of methods of rehabilitation in the acute stage of stroke. PMID- 28635768 TI - [Methods for alveolar bone density assessment and its value for long-term prosthetic functioning]. PMID- 28635769 TI - [Modern wound dressings in oral surgery]. AB - In this review the modern wound dressings used in surgical dentistry and maxillofacial surgery are studied. We describe the tupes of wound dressings and their properties. The results of clinical use in various surgical procedures in the oral cavity are presented. PMID- 28635770 TI - [The resolution of the expert body for the section on demyelinating diseases of the Russian Society of Neurologists and Russian Executive Committee of multiple sclerosis researchers (Kazan, 19 november 2015) on the 'Current principles and optimization of treatment of patients with relapsing-remitting multiple sclerosis with glatiramer acetate']. PMID- 28635771 TI - [A.N. Boiko, M.E. Guseva, S.A. Sivertseva 'Non-medical treatment and life style in multiple sclerosis']. PMID- 28635772 TI - [Navigation systems in neurosurgery]. AB - When preparing the review, we analyzed publications available at the Medline database; a total of 1,083 publications related to the review's subject were analyzed. After more careful analysis, we selected 117 publications devoted to the development of neuronavigation in craniocerebral surgery, historical prerequisites of neuronavigation emergence, current trends, and future perspectives of the technique. PMID- 28635774 TI - [Yu.A. Molin 'The human body as the main incriminating evidence'. Sankt Petersburg: Severnaya Zvezda, 2014]. PMID- 28635773 TI - [Prevention and treatment of postoperative epidural scar adhesions]. AB - Postoperative epidural scar adhesions remain one of the most frequent late complications of microdiscectomy, which deteriorates the overall outcome in treatment of herniated lumbosacral discs. Despite a large number of conservative and surgical treatment options for epidural scar adhesions, the treatment outcome not always satisfies the patient and doctor. The review's aim was to systematize the available data on this complication and to facilitate the choice of appropriate tactics for its treatment. PMID- 28635775 TI - [Interview with prof. N.A. Shamalov]. PMID- 28635776 TI - [No-touch pancreatectomy and radical antegrade modular pancreatosplenectomy: a systematic review]. AB - AIM: To summarize the data of 'no-touch isolation technique' (NIT) for pancreatoduodenectomy and radical antegrade modular pancreato-splenectomy (RAMPS) for pancreatic malignancies. MATERIAL AND METHODS: We looked through Pubmed and Cochrane databases for scientific papers published from January 2000 until September 2014. RESULTS: Eight studies were included. There were 7 retrospective cohort studies and one randomized controlled trial (RCT). Mean operation time and blood loss were 267 min (198-386 min) and 132 ml (331-744 ml) respectively. Mean morbidity rate was 35% (17-58%). There was no 30-day mortality. Mean incidence of R0-resection varied from 50% to 97% with average value 84%. Median survival was reported in 3 studies (17, 18 and 26 months). Five-year actuarial overall survival was reported in 4 studies (31, 36, 40 and 53%). CONCLUSION: Positive results of NIT and RAMPS might justify further evaluation of the method in pancreatic cancer. Prospective randomized controlled trials needs to be done to demonstrate the oncological value of this novel surgical technique. PMID- 28635777 TI - [The role of Oppel's shool in the national military surgery]. PMID- 28635778 TI - [Characteristics of dizziness in elderly]. AB - Clinical features of the main diseases that may cause dizziness in elderly and approaches to its treatment are reviewed. The treatment plan and increase of its effectiveness as well as prevention of the complications and improvement of quality of life of patients should be based on these features. PMID- 28635779 TI - [Creutzfeldt-Jakob disease: clinical and diagnostic aspects]. AB - In this article, authors analyzed a modern approach to the diagnosis of Creutzfeldt-Jakob disease (CJD) based on the clinical signs, cerebrospinal fluid markers, electroencephalography and magnetic resonance imaging. It was demonstrated for the first time that patients with late-onset CJD differed from younger CJD patients with respect to MRI profiles and initial clinical presentation. To date, cerebrospinal fluid (CSF) analysis, particularly protein 14-3-3 testing, presents an important approach to the identification of disease cases. A spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions. Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein. Recent studies applied the RT-QuIC methodology to CSF for the diagnosis of human prion diseases. PMID- 28635780 TI - [Characteristics of the clinical picture and treatment of moderate or severe Alzheimer's disease]. AB - Alzheimer's disease (AD) is the most frequent cause of dementia and one of the most frequent disease in elderly patients. Pathomorphological data have demonstrated that AD is a sole cause in 40% of patients with dementia and in about 15-20% of cases with vascular comorbidity. We consider the evolution of cognitive and mental disorders in moderate and severe stages of AD and describe new approaches to treatment of late AD stages using high doses of cholinesterase inhibitors (in particular, a new form of rivastigmine transdermal system (15 cm2) releasing 13,3 mg of active substance per day), and combinations of cholinesterase inhibitors and memantine with non-pharmacological correction of behavioral disorders the clinical assessment of treatment efficacy. Attention is drawn to the formation of the adequate level of expectations in caregivers. PMID- 28635781 TI - [Classification and diagnosis of apraxia]. AB - Apraxia is one of the most frequent clinical presentations of vascular, traumatic, infectious, tumor and neurodegenerative diseases of the brain. However neurologists have difficulties with diagnosis. The author presents a review of current classifications of apraxia and methods of its clinical diagnosis. PMID- 28635782 TI - [Validation of the Russian version of the modified Addenbrooke's cognitive examination for Alzheimer's disease diagnosis]. AB - AIM: To evaluate the validity of the Russian version of the modified Addenbrooke's cognitive examination (ACE-m) for Alzheimer's disease (AD) diagnosis. MATERIAL AND METHODS: ACE-m and MMSE, as a comparison scale, were administered to 78 patients including 49 patients with AD and 29 healthy people. RESULTS AND CONCLUSION: ACE-m demonstrated the high validity in the diagnosis of dementia in AD. Cronbach's alpha was 0.89. ACE-m is a brief and simple in use test that measures a wide spectrum of cognitive functions, gives a general impression about cognitive deficit and diagnoses dementia in AD with the greater validity compared to MMSE. This scale is useful not only in diagnosis of AD but also in differentiation with other causes of dementia. PMID- 28635783 TI - [Melatonin in correction of REM-sleep behavior disorders in Parkinson's disease]. AB - : Objective - to estimate efficacy and safety of melatonin in REM-sleep behavior disorders (RBD) in patients with Parkinson's disease (PD). MATERIAL AND METHODS: We examined 60 patients with RBD and I-III stages of PD. Neuropsychological examination was performed before and after treatment. RBD was confirmed by polysomnography in 30 patients. RESULTS: After the treatment with melatonin in dose of 3-6 mg for 4 weeks, 84% of patients reported reduction of RBD symptoms, daytime sleepiness, anxiety and depression. CONCLUSION: Melatonin can be used for RBD treatment in PD patients. PMID- 28635784 TI - [Methods for evaluating of olfactory function in patients with Parkinson's disease]. AB - Olfactory disorder takes a special place among non-motor symptoms of Parkinson's disease (PD) as one of earliest signs of the disease. Based on literature data, authors suggest that simple and structured tests for detection of olfactory disorders should be part of diagnostic algorithm for early detection of PD) and occupy a special place in differential diagnosis of diseases of the extrapyramidal system. Literature on the methods of study of olfactory function recommended as an additional instrument for PD diagnosis is presented. PMID- 28635785 TI - [Event-related potentials in Parkinson's disease]. AB - Cognitive deterioration is not an initial symptom of Parkinson's disease but occurs over the course of the disease with the incidence of dementia. The P300 component of event-related potentials appears to be sensitive to cognitive impairment, and has been used to examine cognitive functions in Parkinson's disease. Although many studies have shown that P300 latency and amplitude are correlated with cognitive functions, there is a sufficient amount of controversial results. The authors have reviewed the results and suggested that the method should be used only in the combination with clinical and neuropsychological examinations. Further studies are needed. PMID- 28635786 TI - [Gait disorders in Parkinson's disease]. AB - Gait and posture disorders are frequent signs of Parkinson's disease. Authors reviewed clinical and pathophysiological results reported for these disorders as well as the methods of investigation and treatment approaches including rehabilitation measures. PMID- 28635787 TI - [Is hyperlipidemia a risk factor of Parkinson's disease?] AB - AIM: To assess the relationship of the lipid spectrum, smoking, coffee drinking and brachiocephalic artery intima-media thickness with clinical characteristics of Parkinson's disease (PD). MATERIAL AND METHODS: Authors examined 46 patients with PD, I-IV stages according to the Hoehn and Yahr scale, and 30 people without extrapyramidal pathology or cardiovascular diseases (controls). RESULTS AND CONCLUSION: Patients with PD had lower levels of triglycerides and lower intima media complex thickness compared to the controls. There was a trend towards the lower levels of total blood cholesterol, the differences were most marked in the late stage of PD. It can be suggested that the factors studied do not play a significant role in the development of degenerative process in PD. The marked differences may be related to a possible influence of antiparkinsonian treatment on the indicators of lipid metabolism. PMID- 28635788 TI - [Pramipexole in Parkinson's disease]. AB - Pramipexole is non-ergoline dopamine receptor agonist. There is accumulating evidence for the efficacy of pramipexole in treatment of Parkinson's disease (PD). Authors have summarized the results concerning the optimal start treatment, the using of pramipexole in early and advanced PD stages, effects of pramipexole on tremor, cognitive impairment, affective functions and safety pramipexole. PMID- 28635789 TI - [Pharmacotherapy accompanied by deep brain stimulation of the subthalamic nucleus in patients with Parkinson's disease]. AB - AIM: To analyze pharmacotherapy accompanied by deep brain stimulation of the subthalamic nucleus. MATERIAL AND METHODS: The study included 54 patients, who underwent bilateral STN DBS from 2003 to 2012. The severity of motor disturbances, activities of daily living and complications of dopaminergic therapy were estimated in accordance with II, III and IV parts of the Unified Parkinson's Disease Rating Scale (UPDRS) before operation and one, three and four years after it. L-dopa equivalent daily dose (LEDD) was assessed along with an analysis of the pharmacotherapy in whole. RESULTS AND CONCLUSION: By the end of the 1st year, the severity of motor disturbances in OFF-period decreased by 52.3% and remained stable for 3 years (51.8%), a slight increase of severity of motor disturbances was observed later, however it didn't reach the pre-operative level. The severity of motor fluctuations and drug-induced dyskinesia fell by 64.9%, 70.7% and 42.7% by the end of the first, third and fourth year of observation. The maximal decrease in LEDD was reached by the end of the 1st year and accounted for 57.7%; by the end of the third and fourth years it was 52.4% and 38.2%, respectively. During the 1st year, 16.7% of patients didn't take levodopa. The dose of pure levodopa decreased by the end of the 1st year by 64.6%, and by 56.7% and 43.7% by the end of the 3rd and 4th years, respectively. Monotherapy by an agonist of dopamine receptors (ADR) was received by 12.9% of patients, thus the share of ADR as part of the combined therapy increased in the postoperative period from 24.1% to 35.2%. PMID- 28635790 TI - [Meeting on the problem of diagnostic and treatment of Alzheimer's disease in Russian Federation]. PMID- 28635792 TI - [Tonsillitis and tonsillogenic conditions]. AB - The objective of the present study was to analyze and summarize the literature publications concerning tonsillitis and related (tonsillogenic) pathological conditions. The retrospective analysis of these materials made it possible to collect and summarize information about the influence of palatine tonsillar pathology (chronic tonsillitis) on the function of various organs and their systems. It has been shown that pathogenesis of a great variety of disease is underlain by pathology of palatine tonsils. Also, the possibility to stabilize the pathological processes in certain organs and systems by the conservative and/or surgical treatment of chronic tonsillitis has been demonstrated. It is concluded that the patients presenting with chronic tonsillitis make up a group of risk of development of many serious somatic diseases and require enhanced attention not only of otorhinolaryngologists but also specialists representing other medical disciplines. The multidisciplinary approach to the management of such patients is the sole way to reduce the frequency ofgeneral complications in the patients with chronic tonsillitis. PMID- 28635793 TI - [The higher education at the post-Soviet territories: the long echo of the Bologna process]. AB - The objective of the present work was to analyze the possibilities envisaged by the Bologna system for the improvement of the quality of higher medical education at the post-Soviet territories. Any academic innovations including, in the first place, the accession to the Bologna process should be assessed in terms of their influence on the quality of education. This article describes the main factors responsible for the impaired quality of specialist training and the unjustified growth in the number of students in the combination with the loss of motivation to study. The arguments are provided in support of the opinion that the principles of the Bologna Declaration work fairly well only In the framework of the western educational model, but even there their widespread implementation not infrequently gives rise to contradictory and conflicting attitudes. At the same time, the two-level training systems deserve attention, firstly as a mechanism facilitating transition of a student to another speciality after he (she) completes the first-level course and, secondly as a means to shorten the total length of training. It is demonstrated that the competency-based model regarded as an exclusively European innovation has actually been borrowed from the Soviet higher education system. The devastating consequences of the total transition to the modular education are discussed. PMID- 28635794 TI - [Neurological and psychiatric disorders in Behcet's disease]. AB - The data of the literature on epidemiology, clinical manifestations, diagnosis and treatment of Behcet's disease are presented. Particular attention is paid to international recommendations (2014) on the classification, diagnostic criteria and treatment of neurological symptoms of Behcet disease. PMID- 28635795 TI - [Current approaches to optimize treatment of dementia and Alzheimer's disease]. AB - Currently, substitution therapy is the main focus in the treatment of Alzheimer's disease (AD). It is aimed at overcoming neurotransmitter deficits in a variety of neuronal systems affected in AD. To overcome the cholinergic insufficiency, acetylcholinesterase inhibitors (rivastigmine, donepezil and galantamine) are primarily used. The efficacy and safety of these drugs in AD have been convincingly shown in numerous clinical trials in different countries. Memantine is the main drug in glutamatergic strategies in the treatment of AD, which has a neuroprotective effect and relieves symptoms at the level of the remaining glutamatergic synapses. Some other formulations (cerebrolysin, nicergoline etc) can be also applied as vasoactive and neuroprotective agents. PMID- 28635796 TI - [The assessment of the efficacy of citicoline in the early and recovery stages of stroke]. AB - The review presents data on the evaluation of the efficacy of citicoline in ischemic stroke. It presents research findings about the effect of citicoline to reduce infarct volume in animal models of cerebral ischemia. Long-term treatment of CDP-choline initiated 24 hours after stroke contributes to the increased plasticity of neurons in intact brain areas (functionally associated with the damaged areas) and accelerated functional recovery. The oral administration of citicoline within the first 24 hours after the onset of symptoms in moderate and severe stroke increases the probability of complete recovery in 3 months. A neuroprotective effect of citicoline in acute and early restorative stages of stroke accompanied by cognitive impairment was shown. According to the results of clinical trials of the dosage regimen, citicoline administered in the dose of 1000 mg/day for 8 weeks accelerates the regression of hemiplegia; the intravenous injection in the dose of 750 mg/day for 10 days, starting with the first 48 hours of stroke onset symptoms, promotes the recovery of motor and cognitive functions; the intravenous injection in the dose of 1 g within 14 days improves the recovery of consciousness, general condition and functional status. PMID- 28635797 TI - [Treatment of benign paroxysmal positional vertigo]. AB - Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder. BPPV is easily diagnosed by positioning tests and effectively treated by repositioning maneuvers. The authors focus on the treatment of BPPV, when different canals are affected, including canalo- and cupulolithiasias. Complications of BPPV and surgery of cases, resistant to conservative treatment, are also discussed. PMID- 28635798 TI - [Differential diagnosis between mechanical and inflammatory lower back pain, therapy options]. AB - The article presents the differential diagnosis between mechanical and inflammatory lower back pain based on clinical and paraclinical evidence. The results of comparative studies of amtolmetinum guacilum (AMG) and celecoxib, as well the CORONA study of its efficacy and cardiovascular safety in ankylosing spondylitis, are also discussed. PMID- 28635800 TI - [Carbohydrate metabolism in patients with acromegaly and Itsenko-Cushing disease]. AB - The relevance of investigating carbohydrate metabolism (CM) in patients with acromegaly and Itsenko-Cushing disease is attributable to frequent glucose metabolic disturbances, on the one hand, and to difficulties in choosing sugar lowering therapy in these categories of patients, on the other. The efficiency of hyperglycemia treatment in these patients may be reduced due to problems in achieving remission/cure of the underlying disease and to specific therapy favoring hyperglycemia. The top-priority tasks are to search for ways of reducing the frequency of CM abnormalities in patients with neuroendocrine diseases and to elaborate sugar-lowering therapy regimens. There is a growing interest in studies of the role of the incretin system in the pathogenesis of secondary hyperglycemias associated with neuroendocrine diseases. Nevertheless, few works have been published on this subject matter because of its novelty. There is a need for a further closer study of the specific features of incretin system function and the pharmacodynamics of incretin mimetics that are potential candidates as first-line drugs to treat secondary hyperglycemias. This paper attempts to summarize the available data obtained from studies into CM in neuroendocrine diseases. PMID- 28635799 TI - [Algorithms of mono- and polytherapy in clinical epileptology. Part 1. General principles of drug choice]. AB - The large number of antiepileptic drugs (AEDs) at the physician's disposal provides not only a broad therapeutic potential in the treatment of epilepsy (EP), but creates difficulties in the adequate choice of AED. The sufficient experience in the management of patients with epilepsy has been gained so far in the world, based on which the International League Against Epilepsy (ILAE), updated classification, adopted the basic definition of efficiency, remission, resistance, evidence of research on the effectiveness of AED therapy, and introduced the concept of "resolved" epilepsy. In this article, a group of Russian experts suggest recommendations on the main steps in the choice of therapy in epilepsy. Possible drug interactions between different AEDs and other drugs as well as main characteristics of mono- and polytherapy of epilepsy are described. Some features of the use of AEDs in the elderly, characteristics of the "female" epilepsy related to the reproductive function and basic requirements for the therapy of epilepsy in children are presented. PMID- 28635801 TI - [The concurrence of diabetes mellitus and gallstone disease]. AB - The article presents an update on the concurrence of diabetes mellitus (DM) and gallstone disease (GSD), on the mechanisms for the development of GSD in patients with type 2 DM (T2DM), on the risk factors of DM in GSD. The role of diabetic autonomic neuropathy of the gallbladder in the development of cholelithiasis is assessed in patients with T2DM. The impact of impaired secretion of neurohormones in the gastrointestinal tract in the development of DM in GSD is analyzed. PMID- 28635802 TI - [Asthma and metabolic syndrome: Clinical and pathogenetic relationships]. AB - Asthma and metabolic syndrome (MS) are common and social diseases. External and internal factors influencing the development and manifestations of asthma are identified; among which there is obesity that is a major risk factor for MS. Accordingly, the concurrence of asthma and MS and to study their clinical and pathogenetic relationships are a topical problem. There is a tendency to identify a particular asthma phenotype that is characterized by later-onset disease in the presence of obesity; the low prevalence of atopy, low serum level of IgE, and a poorly-controlled course with a trend of standard therapy resistance. It is necessary to understand the essence of asthma cause-effect relationships in the presence of obesity for defining management tactics for this group of patients. PMID- 28635803 TI - [Hereditary pheochromocytoma-associated syndromes. Part 2]. AB - Pheochromocytoma (PCC)/paraganglioma is a catecholamine-secreting tumor of the paraganglion. The hereditary variants of PCC have been previously considered to occur in 10% of cases. The latest researches have clearly demonstrated that the hereditary cause of chromaffin tumors is revealed in a much larger number of patients. There have been the most investigated NF, RET, VHL, SDHD, SDHC, and SDHB gene mutations. New EGLN1/PHD2, KIF1V, SDH5/SDHAF2, IDH1, TMEM127, SDHA, MAX, and HIF2A gene mutations have been recently discovered. This review describes the most common PCC-associated syndromes in detail and considers the specific features of new mutations. PMID- 28635804 TI - [Some issues of the diagnosis and treatment of gastroesophageal reflux disease]. AB - The clinical inefficacy of proton pump inhibitors (PPIs) is very frequently encountered in nonerosive gastroesophageal reflux disease (NERD) in particular. Postprandial acid pocket, weak-acid or alkaline reflux, etc. are one of the causes of resistance to antisecretory drugs. Alginates serve as a good alternative to PPIs in treating NERD and gastroesophageal reflux in children and pregnant women. The alginate test may help diagnose NERD. PMID- 28635805 TI - [The North School of neurologists]. PMID- 28635806 TI - [Main directions of research activity]. PMID- 28635807 TI - [The history of surgical treatment of epilepsy in the Russian Federation]. PMID- 28635808 TI - [Interview with N.N. Spirin]. PMID- 28635809 TI - [Current tendencies in surgery for inguinal hernias: world experience]. PMID- 28635810 TI - [Platelet rich plasma in bones defects regeneration]. PMID- 28635811 TI - [E.I. Gusev, A.N. Konovalova, V.I. Skvortsova 'Neurology and neurosurgery'. Textbook, 4th Ed]. PMID- 28635812 TI - [Prognostic value of biomarkers in chronic heart failure with preserved left ventricular ejection fraction]. AB - The paper reviews major biomarkers for determining the prognosis in patients with chronic heart failure and preserved ejection fraction. It also considers cystatin C, one of the novel and probably the most practically important biomarkers. PMID- 28635813 TI - [The role of inflammation in the pathogenesis of chronic heart failure]. AB - The review considers the main points of the concept of progressive chronic heart failure (CHF). The neurohumoral model of CHF pathogenesis could create novel approaches to treating these patients. However, recent studies have shown that the ways of activating the neurohumoral systems in CHF are much more complex. The increased local synthesis of hormones causes the activation of proinflammatory cytokines and proto-oncogenes, which have a number of negative effects. Multiple studies have formulated the immunoinflammatory concept of CHF pathogenesis, according to which the increased concentration of interleukin-6 is a marker of poor prognosis in CHF, and the level of tumor necrosis factor-alpha directly correlates with the severity of its clinical manifestations and the activity of the neurohumoral background in decompensation. The review gives a classification of cytokines and describes the reasons for their elevated plasma concentration, their possible role in the occurrence and progression of CHF, and their prognostic significance. The pathogenesis of CHF, which includes cytokine aggression, requires further studies of the effect of the inflammatory component on the course of heart failure. PMID- 28635814 TI - [The biological activity of high-density lipoprotein fractions and their role in the development of cardiovascular diseases]. AB - Increasing the human plasma concentration of high-density lipoproteins (HDL) may be part of strategy for control of cardiovascular diseases (CVD). HDL particles vary in their structure, metabolism, and biological activity. The review describes major HDL fractions (subpopulations) and discusses new findings on the antiatherogenic properties of HDL particles. The whole spectrum of HDL fractions, small, dense, protein-rich lipoproteins, has atheroprotective properties that are determined by the presence of specialized groups of proteins and lipids; however, this activity may be decreased in atherogenic lesion. Comprehensive structural and compositional analysis of HDL may provide key information to identify the fractions that have characteristic biological properties and lose their functionality in CVD. These fractions may be also biomarkers for the risk of CVD and hence represent pharmacological targets. PMID- 28635815 TI - [Assessment of arterial wall stiffness by 24-hour blood pressure monitoring]. AB - Arterial wall stiffness is an early marker of cardiovascular diseases. The gold standard for assessment of the stiffness of large vessels is presently pulse wave velocity (PWV). Work is in progress on the study of the reference values of PWV in people of different genders and ages. 24-hour blood pressure (BP) monitoring is not only a procedure that can estimate diurnal BP variability, but also monitor the indicators of vascular wall stiffness in a number of cases over a 24 hour period. The given review highlights the pathophysiology of arterial stiffness, methods for its assessment, and the aspects of use in therapeutic practice. PMID- 28635816 TI - [Occupational factors and a risk of cardiovascular diseases]. AB - The paper gives Russian and foreign authors' data on a relationship between occupational factors and cardiovascular diseases. It considers the impact of psychosocial stress on the risk of hypertension, coronary heart disease, and cardiovascular events in representatives of different professional groups. PMID- 28635818 TI - [Gut microbiota and obesity: Pathogenetic relationships and ways to normalize the intestinal microflora]. AB - The review demonstrates mechanisms in the relationship of obesity to gut microbiota, as well as possible therapeutic measures to normalize the intestinal microflora. There is evidence that the latter makes a great contribution to the pathogenesis of obesity and related diseases. Investigations have shown the role of the nature of consumed foods (fatty foods) in reducing the amount of bifidobacteria and lactobacilli, as well as the effects of bacterial lipopolysaccharides and metabolites from the intestinal microflora (trimethylamine-N-oxide, bile acids, etc.). The use of prebiotics, probiotics and ursodeoxycholic acid preparations and fecal transplantation are promising in correcting the microflora and in providing their positive effect on metabolic disturbances. Certain probiotic strains are effective in treating dyslipidemia, diabetes mellitus, obesity, and metabolic syndrome. Gut microbiota is impaired in obesity and contributes to the development of cardiovascular diseases. The control of the gut microbiota and the use of drugs altering the composition of the microflora may become a novel approach to reducing the risk of cardiovascular diseases. PMID- 28635817 TI - [Dizziness and anxiety disorders in the elderly]. AB - Perhaps each dizzy patient feels anxiety. Varying emotional disorders are particularly common in elderly patients with dizziness. The causes of the frequent concurrence of dizziness and mental disorders (anxiety and depression) are diverse. Amongst these there are two chief conditions: 1) vestibular vertigo may cause anxiety to a greater extent than many other symptoms; 2) anxiety and depression are themselves frequently manifested by the sensations resembling vestibular ones that patients are inclined to call dizziness. On the contrary, anxiety may appear in some cases as the sensations resembling dizziness. Besides the latter, the patient may present a lot of complaints, which serves as a manifestation of psychoautonomic syndrome (the basis for which is anxiety and depression). At the same time, the term 'phobic postural instability' is proposed to describe psychogenic disorders, in which dizziness becomes virtually the only chief complaint. The treatment of dizziness and anxiety disorders in the elderly encompasses a few areas: vestibular rehabilitation, drug therapy, and psychotherapy. The paper describes the possibilities of using anvifen as a pathogenetically sound treatment in patients with anxiety disorders, as anvifen is a GABA-ergic medication. PMID- 28635819 TI - [Comment on the article by Onishchenko A.L. et al. 'Reasons for intraocular pressure to resist hypotensive therapy in glaucoma patients']. PMID- 28635820 TI - [Not just substitution of concepts]. PMID- 28635821 TI - [Further studies are required]. PMID- 28635822 TI - [Terms and epithets. Flight of thought or scholasticism]. PMID- 28635823 TI - [En face' optical coherence tomography guided focal navigated laser photocoagulation]. AB - : Aim - to prove the feasibility of focal navigated laser photocoagulation (LP) for central serous chorioretinopathy (CSC) that relies only on the data provided by optical coherence tomography (OCT) without considering fluorescein angiography (FA). MATERIAL AND METHODS: Two patients with CSC were treated with focal navigated LP (NAVILAS laser system) basing on macular OCT findings (RTVue 100). Before the procedure, FA was not performed. RESULTS: In both cases the leaking point was recognized by a solitary focal detachment of the pigment epithelium in 'en face' OCT scans. OCT images were then imported into the laser photocoagulator unit and superimposed on the basic image of the fundus, thus, enabling accurate focal LP. In both cases the serous retinal detachment resolved completely within 9-14 days. CONCLUSION: In some CSC patients, 'en face' OCT data allow focal navigated laser photocoagulation without prior fluorescein angiography. PMID- 28635824 TI - [Blepharoptosis: diagnostic tests]. AB - The article discusses diagnostic algorithms for blepharoptosis in patients with Horner's syndrome, myasthenia, chronic progressive ophthalmoplegia, myotonic dystrophy, and acute neurovascular events. Basic methods for evaluating the upper eyelid position and ptosis severity as well as special pharmacologic stress tests to reveal the true etiology of the condition and make the best treatment choice are described. PMID- 28635825 TI - [Diagnostic approach to choroidal metastases]. AB - : Intraocular metastases account for 64-67% of all metastatic ocular tumors, of them 88-90.7% are found in the choroid. By the time the metastasis is diagnosed, 30-44% of patients usually have their primary lesion identified. In oncology patients with multiple and/or bilateral choroidal involvement, the diagnosis can be easily determined at ophthalmoscopy, while in those whose anamnesis is unburdened, this task is quite challenging. Aim - to define diagnostic criteria of choroidal metastases that would consider data provided by state-of-the-art instrumental assessment. MATERIAL AND METHODS: The study enrolled 5 patients (3 women and 2 men) with choroidal metastases of different origin. The mean patient age at the time of ocular involvement was 47.8 years (38-60 years). Oncological anamnesis was burdened in only 2 cases. RESULTS: Due to the small number of cases and diverse clinical presentation, we considered appropriate to describe each case separately. CONCLUSION: The absence of a known pre-existing lesion is typical of the younger age group. By analyzing optical coherence tomography data, we are able to list the most common signs of all choroidal metastases: hummocky profile of the choroid and a high neuroepithelium detachment accompanied by edema and photoreceptor damage. Fluorescein angiography diagnostic criteria are the following: spotted hyperfluorescence that begins in the arterial phase and gradually increases in intensity, while choroidal fluorescence is blocked during the whole examination; almost confluent hyperfluorescence with brighter pin points along the margin of the lesion seen in the later phases. Evaluation of autofluorescence is auxiliary, but can provide an idea of the disease duration. PMID- 28635826 TI - [Primary granulocytic sarcoma of lacrimal gland]. AB - The article presents clinical description and instrumental findings (ultrasound examination and multi-slice computed tomography of the orbits) of a rare lacrimal gland tumor, which precedes or concurs with acute myeloblastic leukemia. Due to the low incidence of myeloid (granulocytic) sarcoma, it is not possible to develop a proper algorithm for its diagnosis and treatment. Few descriptions that are available in the literature neither give an idea of the variety of manifestations and the order of organ involvement, nor allow any vital prognosis. Verification of the diagnosis can only be based on immunohistochemical findings of the primary tumor and bone marrow biopsy material. The authors emphasize the importance of combination treatment (radiation therapy of the orbits and chemotherapy) in the prevention of leukemia. PMID- 28635827 TI - [Idiopathic epiretinal membranes: visual function impairment, morphological and functional features of retinal involvement]. AB - By affecting different retinal layers, an idiopathic epiretinal membrane (iERM) produces changes in macular architectonics and functioning. Morphological and functional assessment of these patients using modern visualization methods and electroretinography contributes to a better understanding of pathogenetic mechanisms of iERM. PMID- 28635828 TI - [Modern methods of minimally invasive glaucoma surgery]. AB - Over the years, glaucoma surgery has improved from iridectomy by A. Graefe and traumatizing procedures performed without magnification tools or microsurgical instrument to high-technology interventions that are not only microscopic, but also pathogenetically oriented. Various modifications of trabeculectomy, initially introduced by J. Cairns back in 1968, had been the gold standard for several decades and were notable for pronounced and stable hypotensive effects. However, there was also a strong association with such complications as choroidal detachment and hyphema, thus, boosting the development of so called nonfistulizing surgeries. Of the latter, the most widely used are non-penetrating procedures, including deep sclerectomy and viscocanalostomy. Although very safe, they appear unable to produce a truly long-lasting hypotensive effect. Moreover, just as fistulizing trabeculectomy, non-penetrating procedures damage the limbus and adjacent conjunctiva reducing the possibility of a second intervention. This fact together with other drawbacks mentioned above, on the one hand, and technical progress, on the other, were essential prerequisites for the appearance of a new type of surgery - minimally invasive glaucoma surgery (MIGS). Parameters that should be met for a procedure to be considered minimally invasive are debated. The main requirement has, however, been established: ab interno approach through a corneal incision. As surgical tools are enhanced and new techniques arise, options for glaucoma treatment widen greatly, ensuring our future move to higher level standards in the field. This review contains all recent data on minimally invasive techniques currently in use in glaucoma surgery or those under investigation. The authors have also analyzed effectiveness reports and present their conclusions regarding the current state of MIGS worldwide. PMID- 28635830 TI - [Causes of maternal deaths and reserves for their reduction at the present stage. A manual for physicians (2nd enlarged edition) edited by A.P. Milovanov, I.O. Bushtyreva]. PMID- 28635829 TI - [Ocular tuberculosis]. AB - Ocular tuberculosis (OTB) is a specific infectious (bacterial) disease dealt with by ophthalmologists and phthisiatricians. This is a serious illness with chronic, persistent course and extremely doubtful prognosis. Chemotherapy, even if effective, can still be followed by a decrease in visual acuity. Clinical recovery is often unstable. Ocular tuberculosis is largely associated with permanent disability and, as a result, a decline in quality of life of these patients. Statistical reporting does not always reflect the true prevalence of the disease as it sometimes develops in patients with pre-existing specific pulmonary involvement. This article discusses all pathogenetic mechanisms of OTB that have been described so far. Attention is paid to modern diagnostic methods, including spectral optical coherence tomography. Positive results of endonasal electrophoresis for the treatment of OTB are described. PMID- 28635831 TI - [The 2015-2016 epidemic season in Russia and the world: Circulation of influenza viruses, trends in incidence, clinical aspects, and treatment algorithm]. AB - In the 2015-2016 epidemic season, there were dominant influenza A(H1N1)pdm09 strains (over 90%) among the circulating influenza viruses in most countries of the Northern Hemisphere and in Russia. A study of the antigenic properties of influenza A(H1N1)pdm09 strains revealed no differences in those of vaccine virus. Sequencing showed that there were amino acid substitutions in hemagglutinin (receptor binding and Sa sites) and in the genes encoding internal proteins (PA, NP, M1, and NS1). The rise in the incidence in the Russian Federation, which was etiologically associated with influenza viruses, was registered in January February 2016 with its maximum being observed at 4-5 weeks of 2016. Within the framework of the epidemiological surveillance of circulating influenza viruses in the Russian Federation, which was conducted by the WHO European Office, the D.I. Ivanovsky Institute of Virology, Honorary Academician N.F. Gamaleya Federal Research Centre for Epidemiology and Microbiology, Ministry of Health of Russia, and the Research Institute of Influenza, Ministry of Health of Russia, monitored at the Infectious Diseases Hospital One (IDH-1), Moscow Healthcare Department. Among 1491 examinees, influenza was verified in 104 (21.3%) adults, 208 (42.5%) pregnant women, and 177 (36.2%) children. Influenza A(H1N1)pdm09 was more often diagnosed in the age group of 15-40 years (63.7%); the proportion of influenza patients aged over 50 years increased (22.1%). Most adult patients had moderate influenza; pneumonia complicated the disease in 27.4%. Influenza in the pregnant women was complicated by pneumonia in 4.8% of cases. Influenza was more frequently diagnosed in infants and preschool children aged 0 to 3 years (42.9%), 4 to 6 years (41.2%), and older (15.9%), namely: 7-9 years (10%) and 10-12 years (5.9%). Influenza in the children was complicated by acute tonsillitis (19.4%) and varying degrees of laryngeal stenosis (12.4%). Bronchial obstructive syndrome developed in 2.5%, the rate of pneumonia was 6.2%. Antiviral therapy (AVT) in the early stages of the disease reduces the risk of its severity, the frequency of secondary complications, and the duration and degree of clinical symptoms of influenza. AVT with oseltamivir, zanamivir, imidazolyl ethanamide pentandioic acid (ingavirin), and interferon-a2b (viferon) has been performed in the patients hospitalized at Moscow IDH-1 in the 2015-2016 epidemic season. PMID- 28635832 TI - [Use of succinate-containing agents in the treatment of infectious diseases]. AB - The review gives data that reveal the role of succinic acid in providing cells with energy and oxygen under hypoxic conditions. It presents the results of clinical and experimental studies to evaluate the efficacy of succinate containing drugs in the combination therapy of infectious diseases. The spectrum of biological effects of these drugs, which is provided by the synergy of their active ingredients, is considered. PMID- 28635833 TI - [Infective endocarditis in the elderly: The current view of the problem]. AB - The review gives the current views of the etiology and risk factors of infective endocarditis (IE) in the elderly. It reports the specific clinical picture of the disease at this age, including clinically apparent syndromes, comorbidity, and various clinical signs and peculiarities of IE. Particular emphasis is placed on the diagnosis of an endocardial infectious lesion, which is based on the use of the modified Duke criteria. The methods of IE diagnosis, particularly microbiological examination, imaging techniques, among which echocardiography in different modes plays a particular role, are listed. The treatment of the disease is based on the latest recommendations for antibiotic therapy with and without regard to a specific etiological factor. The issues of surgical intervention, as well as approaches to preventing IE in elderly people are discussed. PMID- 28635834 TI - [Chronic HCV infection: An internist's opinion (Part 2)]. AB - Hepatitis C virus (HCV) infection results in not only chronic hepatitis and subsequent complications as liver cirrhosis and hepatocellular carcinoma, but also in a significant number of other diseases, the so-called extrahepatic manifestations of chronic HCV infection. In addition to lymphoproliferative and autoimmune disorders discussed in Part 1 of this review, many other diseases turned to be associated with chronic HCV infection. Part 2 of this review is dedicated to the analysis of the relationship of chronic HCV-infection to the development of some endocrine diseases, such as thyroiditis and diabetes mellitus, and cardiovascular disorders. It also provides the characteristics of the currently available antiviral agents and considers whether they may be used in patents with extrahepatic manifestations of chronic HCV infection. PMID- 28635835 TI - [Diagnostic possibilities of methods for the evaluation of liver fibrosis in chronic viral hepatitis]. AB - The paper reviews the diagnostic possibilities of different methods for the evaluation of liver fibrosis in chronic viral hepatitis from the point of view of their clinical application. Histological examination retains its value as the gold standard method in evaluating the liver. Transient elastography is a rather effective tool for identifying severe liver fibrosis. PMID- 28635837 TI - [Nutritional status in patients with cystic fibrosis: Possibilities of correction]. AB - The major risk factor for death in cystic fibrosis (CF) is a progressive lung injury; however, low nutritional status (NS) remains an important and underestimated problem in the management of these patients. The NS of a patient with CF is impaired by many factors, such as chronic malabsorption, pancreatic failure, chronic inflammation, and recurrent pulmonary infection - they all lead to higher energy demand in the presence of lower intake of nutrients. The NS of those with CF plays an important role in maintaining lung function. The patients with higher NS have longer life expectancies. According to the Russian National Registry, both pediatric and adult patients with CF have shorter life expectancies. The article discusses various nutritional support regimens and their impact on lung function parameters. PMID- 28635836 TI - [Possibilities of using cepeginterferon alpha-2b in double (cepeginterferon alfa 2b and ribavirin) and triple (simeprevir, cepeginterferon alpha-2b, and ribavirin) antiviral therapy regimens for chronic hepatitis C. A review of clinical trials and experience of everyday clinical practice]. AB - Since the incidence of chronic hepatitis C (CHC) increases steadily, the priority of national health care is to provide antiviral therapy (AVT) for the maximum number of patients infected with hepatitis C virus (HCV). The regimens including pegylated interferons (PEG-IFN) are still in demand in the Russian Federation. A number of clinical trials have been conducted to evaluate the efficacy and safety of cepeginterferon alpha-2b (cePEG-IFN alpha-2b), an original PEG-IFN-alpha developed in the Russian Federation. Their results have shown that cePEG-IFN alpha-2b in the two-component AVT regimen has at least no less clinical efficacy than PEG-IFN alpha-2b and PEG-INF alpha-2a in HCV monoinfected and HCV/HIV co infected patients. The pooled analysis of data has indicated that the use of cePEG-IFN alpha-b in combination with ribavirin allows an average of 80% of the patients with HCV genotypes 2 and 3 and 62% of those with HCV genotype 1 to achieve a sustained virological response (SVR). In clinical practice when the two component AVT regimen (cePEG-IFN alpha-b and ribavirin) was used in patients with early-stage CHC and mild fibrosis, SVR was recorded in 90.7% of the patients with HCV genotype 2/3 and in 75% of those with HCV genotype 1. The experience in using cePEG-IFN alpha-2b as a component of the three-component AVT regimen (simeprevir, cePEG IFN alfa-2b, and ribavirin) has been published. The observational program manly covered young patients with mild or moderate fibrosis. SVR was observed in 94% of the patients. Another paper describes the experience with the triple AVT therapy (simeprevir, cePEG-IFN alfa-2b, and ribavirin) in 22 patients, the majority of whom had advanced fibrosis. SVR was recorded in 71.4% of those who had completed treatment. Thus, an individual approach and assessment of predictive response factors to two- or three-component AVT regimens including cePEG-IFN alpha 2b can achieve successful treatment outcomes in most patients with CHC, which is, in some cases, more economically sound than interferon-free regimens used as first-line therapy. PMID- 28635838 TI - [The impact of tuberculosis and chemotherapy on female reproductive health]. AB - The paper outlines a concise review of Russian and foreign literature on the specific features of the course of respiratory tuberculosis in reproductive-aged women. It shows the impact of active tuberculosis and massive chemotherapy on the reproductive system, analyzes clinical symptoms, immediate and long-term consequences, and prognosis of future reproductive function. The timely diagnosis and optimal correction of reproductive disorders in women with respiratory tuberculosis can improve their quality of life, fertile capacities, and birth of a successive healthy offspring. PMID- 28635839 TI - [Surgical treatment of patients with oral leukoplakia]. AB - The aim of the study was to elaborate lingual nerve sparing procedure of submandibular gland duct stones extraction. The study involved 43 patients with syalolithiasis treated in Oral Surgery Unit of Central Research Institute of Dentistry and Maxillofacial Surgery in 2013-2015. It was shown that to prevent lingual nerve and artery injury submandibular salivary gland duct should be dissected to the level of obstruction thus allowing adequate visualization of anatomical correlations especially when removing stones from the distal part of the duct. PMID- 28635840 TI - [Review of Journal of Dental Materials publications on world trends in dental ceramic materials studies]. PMID- 28635841 TI - [State and perspectives of studies on osteoplastic materials]. AB - Article highlights the state and the main directions of researches on osteoplastic materials used for filling of bone defects, types of these materials, effects and mechanisms of their interaction with the recipient tissues, defines objectives and prospects for further researches on the issue. PMID- 28635842 TI - [Methods of restoring the integrity the lower jaw in children with post-resection defects']. AB - The review deals with modern concepts on surgical treatment of post-resection defects of the mandible in children. The analysis of domestic and foreign literature. Describes the various classification of tumor lesions in children and post-resection defects of the mandible. Highlighted the advantages and disadvantages, and the prospects for recovery of integrity of the mandible in children. PMID- 28635843 TI - [Hygienic aspects of dental caries and its prevention]. AB - This review summarizes fluoride content in surface water sources of various Russian regions and its relationship with the prevalence of caries in the population. Low Fluoride content in almost all water sources of Russia highlights the importance of individual prevention of dental caries above all by the use of fluorinated toothpaste. From the standpoint of evidence-based medicine the tooth brushing with fluorinated paste twice daily has the highest level of efficiency of caries reduction. PMID- 28635844 TI - [Thyrotropin-producing adenomas and thyrotropic hyperplasia (clinical case reports and the review of the literature)]. AB - An increased blood level of the thyroid stimulating hormone (TSH) is usually associated with primary hypothyroidism (PHT) but can also be observed in such rare cases as TSH-secreting pituitary tumor. The article describes four clinical cases of elevated TSH blood levels: 1) TSH-secreting pituitary adenoma with hyperthyroidism; 2) TSH-secreting adenoma with hypothyroidism; 3) hormonally inactive pituitary adenoma combined with primary hypothyroidism; 4) reversible thyrotropic hyperplasia. These clinical situations substantiate the importance of considering different diagnoses in a patient with a pituitary gland tumor associated with an increased TSH blood level. PMID- 28635845 TI - [Neurosurgery in a patient on dual antiplatelet therapy. Case report and the review of the literature]. AB - INTRODUCTION: A neurosurgical intervention in a patient on dual antiplatelet therapy is a serious challenge for both the neurosurgeon and anesthesiologist.. MATERIAL AND METHODS: The article describes a clinical case of a successful urgent neurosurgical intervention (ventriculoperitoneostomy for obstructive hydrocephalus caused by a large meningioma of the posterior surface of the petrous pyramid) in a patient on dual antiplatelet therapy (DAT) due to a recently placed coronary stent.. CONCLUSION: Given a high risk of coronary stent thrombosis, the surgery was performed in the presence of ongoing DAT. There were no intracranial hemorrhagic complications, but subcutaneous hemorrhagic complications developed. The article discusses the features of managing similar patients whose number is growing. PMID- 28635846 TI - [Evolution of surgical approaches to the anterior and middle cranial fossa: from extended craniotomy to the supraorbital keyhole approach]. AB - At early history of neurosurgery, the use of extended craniotomy was dictated by poor illumination, inadequate visualization, and the lack of accurate diagnosis. The technological progress development and the emergence of highly informative neuroimaging, microscopy, and neuroendoscopy minimized neurosurgical approaches and, accordingly, approach-associated complications. At present, the fundamental philosophy of minimally invasive surgery is of particular topicality because this surgery contributes to rapid recovery of patients and reduces the period of hospital treatment. The aim of the article is to provide a brief historical overview of the evolution of surgical approaches to the skull base, ranging from extended craniotomy to minimally invasive interventions. PMID- 28635847 TI - [Epidemiology, diagnosis, clinical symptoms, and classification of malignant primary skull base tumors]. AB - A review of literature presents up-to-date information on the prevalence, incidence, clinical manifestations, diagnosis, and classification of malignant primary skull base tumors (MPSBTs). In the structure of total cancer incidence, malignant head and neck tumors account for 5% of all annual cancer deaths in the USA and are among the 5 most common groups of tumors in males worldwide. These tumors develop most often in the sixth decade of life, occurring 2 times more often in males than in females. In Russia, the MPSBT incidence (as of 2012) was 0.62% out of all newly diagnosed malignant tumors. The incidence rate amounts to 0.66 per 100 000 population and is significantly higher than the global rate (0.44 per 100 000). About half of all malignant skull base tumors have the epithelial nature and affect the anterior parts of the skull base. The most frequent histological types of malignant skull base tumors are squamous cell carcinoma, adenocarcinoma, and non-Hodgkin's B cell lymphoma. Treatment of skull base tumors is an interdisciplinary problem and the area of interest of otolaryngologists, dentists, ophthalmologists, neurosurgeons, plastic surgeons, radiologists, and chemotherapists. Physical and endoscopic examinations, endoscopic transnasal biopsy, CT, MRI, PET/CT, and ultrasound are typically used for verification of the diagnosis, tumor staging, and selection of the treatment approach. The review describes the criteria for TNM staging of malignant tumors of the nasal cavity and paranasal sinuses in accordance with the 7th version of the TNM recommendations of the American Joint Committee on Cancer (AJCC). The TNM based staging depends on the location (maxillary sinus, nasal cavity, or ethmoid labyrinth) and histological structure of the tumor, which, in turn, determines the tactics of comprehensive treatment and a prognosis group. PMID- 28635848 TI - [Stress adaptive effects after traumatic brain injury]. AB - Neuroendocrine dysfunction, in particular impaired synthesis of anterior pituitary hormones, is a common complication of traumatic brain injury. Deficiency of tropic pituitary hormones entails a hypofunction of the related peripheral endocrine glands and can be accompanied by persistent endocrine and metabolic disorders. In particular, the hypophyseal mechanisms are the key ones in implementation of most stress effects. Adequate implementation of these mechanisms largely determines a favorable outcome in the acute stage of disease. Traumatic brain injury (as well as any significant injury) initiates a stress response that can not develop in full in the case of pituitary gland failure. It is logical to suppose that the course of the acute phase of stress in the presence of hypopituitarism is different to a certain extent from the typical course, which inevitably affects certain adaptation elements. In this review, we analyzed the adaptive effects of stress after traumatic brain injury. PMID- 28635849 TI - [Radio-visualization of non-specific postmortem changes in the cardiovascular system]. AB - This paper presents a review of the literature concerning radio-visualization of non-specific postmortem changes in the cardiovascular system during computed tomography and magnetic resonance imaging. The peculiar radiological characteristics of postmortem blood clots and cadaveric hypostases in the internal organs are described. It is emphasized that postmortem CT and MRI can not replace the pathological anatomical studies and forensic medical autopsy. Roentgenologists engaged in the postmortem examination of the bodies must have relevant knowledge of pathological anatomy and forensic medicine (namely, they must be aware of the non-specific postmortem changes) to be able to adequately interpret the tomograms obtained and correctly establish the diagnosis. It is recommended that the postmortem CT and MRI images should be used as an additional material for the traditional autopsy, e.g. as a preliminary 'guide' preceding the postmortem examination. PMID- 28635850 TI - [The All-Russian scientific and practical conference 'Organization of the forensic medical service of Russia in the current period: problems, approaches to their solution, and results'. Voronezh, 20-22 April, 2016]. PMID- 28635851 TI - [Modern views on myopic maculopathy]. AB - Most of world's scientists consider the fast-growing incidence of myopia a problem of great social importance due to associated increase in complicated myopia that leads to disability among the working-age population. This is a review on complicated myopia and myopic maculopathy that covers the history of research in this field, principles of classification, and etiological factors. It also deals with choroidal neovascularization (CNV), which often follows, and its treatment options, including anti-VEGF therapy. Possible complications of the latter are described as well. Literature search was done using PubMed, eLIBRARY, and Scopus text databases. A total of 61 sources, both Russian and foreign, were analyzed. Current clinical knowledge of different types of myopic maculopathy is still insufficient and the gaps are likely to be filled using modern methods of detailed in vivo examination of both sclera and choroidea. Anti-VEGF therapy has proved most effective in treating myopic maculopathy-associated neovascularization, however, a systematic approach to patient selection and management is yet needed. PMID- 28635852 TI - [Molecular mechanisms and pathogenetic treatment of mitochondrial optic neuropathies]. AB - The article presents a review of literature on inherited optic neuropathies (ION), namely, Leber's hereditary optic neuropathy and autosomal dominant optic neuropathy. Their molecular genetic characteristics and pathogenetic mechanisms such as mitochondrial respiratory chain deficiency, oxidative stress, mitochondrial dynamics, and biogenesis are covered. Prospects of ION treatment are described. PMID- 28635853 TI - [41st Border Extension Session of the Central Research Institute of Gastroenterology]. PMID- 28635854 TI - [The canonical Wnt/beta-catenin pathway: From the history of its discovery to clinical application]. AB - The Wnt/beta signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/beta-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis. PMID- 28635855 TI - [Diabetes mellitus and the central nervous system]. AB - The review considers the current views on the central nervous system (CNS) in diabetes mellitus (DM). It discusses an attitude towards the term 'diabetic encephalopathy'. The data of investigations of cognitive functions in types 1 and 2 DM and the brain structural imaging results obtained using up-to-date technologies are considered. The results of studies of the factors that induce cerebral changes in DM and their associated cognitive impairments are given. There is evidence that hyperglycemia has a more considerable impact on the above processes than hypoglycemia; other possible factors, apart from blood glucose control, are set out. The current views on the function of insulin in the CNS and the relationship of central insulin resistance to Alzheimer's disease are outlined. There are current data on intranasal insulin application that is still exploratory, but, as might be judged from the findings, may by a promising method for the treatment and prevention of cognitive decline in both patients with DM and those without this condition. PMID- 28635856 TI - [MiRNAs in the diagnosis of cardiovascular diseases associated with type 2 diabetes mellitus and obesity]. AB - Worldwide, the number of patients with type 2 diabetes mellitus (T2DM), obesity, and cardiovascular diseases (CVD) continues to increase steadily. Despite long term studies of obesity and concomitant diseases, the molecular genetic bases for the development of these pathological conditions have remained the subject of numerous investigations so far. Recent investigations point to the involvement of miRNAs as dynamic modifiers of the pathogenesis of various pathological conditions, including obesity, T2DM, and CVD. MicroRNAs are involved in various biological processes underlying the development of CVDs, including endothelial dysfunction, cell adhesion, and atherosclerotic plaque formation and rupture. Some of them are considered as potential sensitive diagnostic markers of coronary heart disease and acute myocardial infarction. Approximately 1,000 microRNAs are found in the human body. It has been determined that miRNAs regulate 30% of all human genes. Among them there are about 50 circulating miRNAs presumably associated with cardiovascular diseases. This review provides recent data on the participation of some miRNAs in various pathological and physiological states associated with CVD in DM and obesity. An extended and exact understanding of the function of miRNAs in the gene regulatory networks associated with cardiovascular risk in obesity will be able to reveal new mechanisms for the progression of disease, to predict its development, and to elaborate innovative therapeutic strategies. PMID- 28635857 TI - [Obesity in metabolic syndrome, as well as kidney dysfunction]. AB - The presence of metabolic syndrome (MS) in a patient allows him to be assigned to a group at high risk for atherosclerosis, cardiovascular events, coronary heart disease, and type 2 diabetes mellitus. In addition, MS negatively affects not only the heart and vessels, but also kidney function, which leads to chronic kidney disease (CKD). MS is pathogenetically associated with CKD and is an independent prognostic factor of the development of the latter, namely, the involvement of the kidney frequently determines prognosis and quality of life in these patients. The paper gives a modern view on the concept of MS and CKD and considers its main diagnostic criteria, etiology, and pathogenesis. The study of the relationships between MS and CKD may suggest that the high prevalence of kidney dysfunction in the general population is largely determined by metabolic nephropathies, including obesity-related nephropathy. The identification of risk factors and poor prognostic markers in this category of patients seems to be extremely important for the early diagnosis of the disease and their timely elimination is one of the main approaches to the comprehensive prevention of CKD in these patients. PMID- 28635858 TI - [Nutrition in obesity: Target criteria and monitoring of weight loss]. AB - The review paper gives in details the current clinical guidelines for evaluation of the impact of nutrition on the correction of increased body mass index (BMI) and obesity, an overview of the efficacy of specific commercial diets, target criteria for weight loss, and monitoring the status of a patient who participates in a weight loss program. The current clinical guidelines suggest that today there is no optimal diet in terms of its impact on the correction of overweight and further maintenance of the weight loss achieved. There is a need for both the improvement of the professional capacity of healthcare workers in advising patients about nutrition and the population's awareness about the principles of a healthy diet. The complex nature of the problem requires that a medical community should interact closely with politicians to make a legislative decision on a number of issues relating to healthy eating. PMID- 28635859 TI - [Chronic hepatitis C virus infection: An internist's opinion (Part 1)]. AB - Hepatitis C virus (HCV) infection results in not only chronic hepatitis and subsequent complications as liver cirrhosis and hepatocellular carcinoma, but also in a significant number of other diseases, the so-called extrahepatic manifestations of chronic HCV infection. This is because of viral hepatotropicity and lymphotropicity. The most striking example of the course of chronic HCV infection, in which the infectious and inflammatory processes are concurrent with autoimmune disorders and carcinogenesis, is mixed cryoglobulinemia and B-cell non Hodgkin's lymphoma. The pathogenesis of these diseases is based on the clonal expansion of B cells, which occurs under their prolonged stimulation with the virus or viral proteins. Part 1 of this review is devoted to the analysis of a correlation of chronic HCV infection with lymphoproliferative and autoimmune disorders, as well as its association with kidney injury. PMID- 28635860 TI - [Antithrombotic treatment as primary and secondary prevention of stroke]. AB - The use of antithrombotic drugs (ATD) is necessary in the treatment and prevention of thrombosis. The correction of risk factors of ischemic stroke (IS) and transitory ischemic attacks (TIA) is important as well. The drugs inhibiting the activation and aggregation of thrombocytes allow to decrease the number of myocardial infarctions by 35%, stroke by 25% and mortality from cardiovascular causes by 15%. Currently, the clinical efficacy of acetylsalicylic acid (ASA), thienopyridines (ticlopidine, clopidogrel), dipyridamole or the combination of dipyridamole and ASA as well as glycoprotein antagonists IIb-IIIa for intravenous introduction have been confirmed. A review of experimental and clinical studies confirming the efficacy of dipyridamole in the treatment of acute stage of stroke and primary and secondary prevention of II is presented. PMID- 28635861 TI - [Intrathecal administration of drugs]. AB - The article summarizes the introduction of drugs into the cerebrospinal fluid. Indications and contraindications for the administration of pharmaceuticals in the cerebrospinal fluid spaces are presented. Main groups of pharmacological agents used for endolumbar introduction and conditions under which they are used, as well as advantages and disadvantages of this treatment are considered. The authors describe a method of administration of antibiotics for bacterial and fungal infections of the central nervous system. The need to assess the intracranial pressure prior to cisternal puncture and exclude blocking of cerebrospinal fluid pathways is emphasized. Information about intrathecal administration of anticancer and cytostatic drugs in primary and metastatic brain lesions as well as data on the significant positive effect of oxygen-ozone mixture in the treatment of victims of traumatic brain injury in its acute period are presented. Of interest are the results of the study, which showed a statistically significant reduction in the severity of neurological deficit after the introduction of cerebrolysin in the lumbar space in the first days after the onset of cerebral infarction. Possible complications of the described method of drug delivery, measures taken against them and methods of preventionare described. PMID- 28635862 TI - [Neurological disorders in eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome)]. AB - Eosinophilic granulomatosis with polyangiitis - EGPA (Churg-Strauss syndrome) is a rare autoimmune disorder. The pathogenesis of the disease includes production of anti-neutrophil cytoplasmic antibodies directed against myeloperoxidase with the development of small-vessel necrotizing vasculitis and eosinophilic infiltration of organs. The involvement of peripheral and central nervous system is observed in more than 3/4 of cases. The authors describe three patients with EGPA. In a 53-year-old male patient, EGPA manifested with multiple neuropathies, which regressed after treatment with corticosteroids and cytostatics. In a 34 year-old woman, cerebral sinus thrombosis and cerebral infarction developed in the non-active period of long-term EGPA. The patient was treated with anticoagulants. A 77-year-old woman with a newly diagnosed EGPA, confirmed by bone marrow examination for eosinophilia, developed ischemic stroke and polyneuropathy. The causes and mechanisms of development as well as dynamics and outcomes of neurological disorders, differential diagnosis, treatment and prognosis of eosinophilic granulomatosis with polyangiitis are discussed. PMID- 28635863 TI - [Modern approaches to treatment of psychosis in Parkinson's disease]. AB - Psychotic disorders in Parkinson's disease (PDPD) are common and significantly influence the quality of life and disability level. The pathogenesis of PDPD is complex and not yet fully understood. Taking into consideration the features of the Parkinson's disease (usually older patients with a risk of cognitive decline), and the pharmacodynamics of the antiparkinsonian and traditional antipsychotic drugs, the management of PDPD is a challenging issue of clinical neurology and psychiatry. In this systematic review, scientific publications for the period 2014-2016 were analyzed within two bibliographic databases: MEDLINE/PubMed and eLIBRARY.RU. Additionally, the guidelines of the International Parkinson and Movement Disorders Society, American Academy of Neurology and European Academy of Neurology were included in the analysis. Clozapine is recommended to use in the treatment of PDPD, quetiapine is possible to use, pimavanserin will probably become a remedy of choice. Nonpharmacological approaches have positive effects on the general condition of the patients with PDPD, however the efficacy of such approaches to treat psychosis is unclear. PMID- 28635864 TI - [Pharmacotherapy and dementia]. AB - The review considers treatment aspects of dementia in Alzheimer's disease (DAD), vascular dementia (VD) and some other forms of dementia. Pathogenetic pharmacotherapy of DAD aims to maintain the activity of cholinergic neurons with anticholinesterase drugs including donepezil, which is used most often. The main objective of VD treatment is prevention of new cerebral infarctions using cardiotropic medications, antiaggregants, anticoagulants, hypotensive drugs and statins. In Russia, patients with DAD and VD receive polymodal drugs as well. These drugs have been included in the list of antidementia medications due to their wide use in treatment of discirculatory encephalopathy and chronic brain ischemia. PMID- 28635866 TI - [Hippocampal sclerosis: pathogenesis, clinical features, diagnosis, and treatment]. AB - Hippocampal sclerosis, also known as Ammon horn sclerosis or mesial temporal sclerosis, is usually associated with intractable epilepsy and characterized by specific patterns of neuronal loss and gliosis in the medial temporal lobe structures. Hippocampal sclerosis manifests clinically as epilepsy, often intractable epilepsy; in most cases, this condition is surgically treatable. As the most common histological diagnosis in adult patients subjected to epilepsy surgery, hippocampal sclerosis is characterized by complex pathogenesis and requires a multidisciplinary approach to its diagnosis and treatment. This article reviews the pathologic features, natural history, pathogenesis, and electroclinical and MRI signs of hippocampal sclerosis. PMID- 28635865 TI - [Modern treatments for degenerative disc diseases of the lumbosacral spine. A literature review]. AB - Many researchers consider degenerative diseases of the spine as a pandemic of the XXIst century. Herniated intervertebral discs of the lumbosacral spine occur in 61% of patients with degenerative spine diseases. Of these, 15% of patients have herniated discs at the LII-LIII level, 10% of patients at the LIII-LIV level, and 40% of patients at the LIV-LV and LV-SI levels. A high cost of conservative treatment of degenerative spine disease symptoms and its low efficacy in reducing the intensity and duration of pain necessitate the development of new methods of surgical treatment. In this paper, we analyze the literature data on minimally invasive spine surgery and demonstrate the main advantages of percutaneous endoscopic surgical techniques. PMID- 28635867 TI - [The investigations into the amino acid composition of the tooth for the purpose of forensic medical personality identification]. AB - The increasingly greater requirements for the new approaches to the forensic medical personality identification necessitate the extensive search for and the development of the precise methods enabling the experts to determine the general personality signs in the cases of mass mortality and the large number of victims with the conspicuous post-mortem changes in their appearance including those associated with putrefaction and strong fragmentation of the bodies. This article presents the analytical review demonstrating that determination of the victims' age in the combination with the analysis of the amino acid composition of dental tissues provides a promising tool for the investigations not only in the fields of archeology and anthropology but also for the purpose of personality identification in forensic medicine. PMID- 28635868 TI - [The modern possibilities for the application of photogrammetry in forensic medical traumatology]. AB - The authors discuss the modern possibilities and prospects for the application of photogrammetry (FM) in forensic medical traumatology based on the results of the analysis of the many-year experience reported in the foreign periodicals with special reference to road traffic injuries, gunshot wounds, and animals' bites. The examples of objective difficulties and promising prospects for the further application of the FM techniques in the practical work of forensic medical experts and medical criminalists are considered with reference to the use of various FM-based methods and equipment including 3D laser scanners, chambers, stereoscopic mounting attachments, etc. Special attention is given to the contribution of the current scientific and technical progress to the solution of the practical problems facing forensic medical experts with reference to the unique opportunities provided by the modern computed technologies enabling the specialists to considerably improve the quality of expert examination. PMID- 28635869 TI - [The topical problems of expert mistakes and evaluation of the quality of forensic medical expertises based on the analysis of the reports published in the journal 'Sudebno-meditsinskaya ekspertiza' (Forensic Medical Expertise) during the period from 1958 till 2015]. AB - The objective of the present study was the thematic analysis of the reports published in the journal 'Sudebno-meditsinskaya ekspertiza' (Forensic Medical Expertise) during the period from 1958 till 2015 that contain the authors' characteristics of the mistakes made in connection with the performance of various forms of forensic medical expertise with special reference to their quality and time schedules. A total of 268 issues of the journal were looked through from which 25 articles were selected dealing with the analysis of expert mistakes. The present work continues the series of publications having the objectives to elucidate logical errors encountered in expert conclusions, text books, guidelines, and other methodological materials concerning forensic medical expertise for the purpose of their further in-depth investigation. PMID- 28635870 TI - [The problems of pediatric pathological anatomy and new pathology orders]. PMID- 28635871 TI - [The modern possibilities for the treatment of the patients presenting with benign and tumour-like diseases of the larynx]. AB - Rehabilitation of the patients presenting with benign and tumour-like diseases of the larynx (BLT) is currently a serious challenge for modern otorhinolaryngology in view of the high prevalence of this pathology. Dysphonia is a leading clinical symptom of the diseases that considerably deteriorates the quality of life of the patients. Certain benign conditions of the larynx exhibit a tendency toward malignization. The treatment of the patients presenting with benign and tumour like diseases of the larynx requires a combined approach including the surgical, therapeutic, and phonopedic modalities for the rehabilitation of the vocal function. This article presents a review of the literature on the modern high energy techniques for the treatment of the patients presenting with benign and tumour-like diseases of the larynx, The advantages and disadvantages of each method are discussed. PMID- 28635872 TI - [The current views of the problem of the plastic correction of the laryngo tracheal defects in the patients presenting with combined laryngeal stenoses]. AB - The present review of the literature is designed to analyze the currently available methods for the plastic correction of the laryngo-tracheal defects in the patients presenting with combined laryngeal stenoses at the concluding stage of their medical rehabilitation. We looked through 56 literature sources including 28 publications of the foreign authors. The different approaches to the plastic correction of the laryngo-tracheal defects have been critically considered with special reference to their advantages and disadvantages. The importance of the problem under consideration arises from the necessity of the search for the new methods of plastic correction of the laryngo-tracheal defects. PMID- 28635873 TI - [A role of P-glycoprotein in neurology]. AB - On the basis of the analysis of literature data, the authors show a role of P glycoprotein in the pathogenesis, pharmacotherapy and a prophylaxis of neurologic diseases (Alzheimer's disease, Parkinson's disease, epilepsy, stroke). PMID- 28635874 TI - [Subclavian steal syndrome]. AB - Literature data on the etiology, clinical picture, diagnostic variants and treatment of subclavian steal syndrome are reviewed. Different clinical variants and neurological symptoms of the syndrome are described. Multispiral computed tomography, along with ultrasound examination, is important in the diagnosis of the syndrome and its causes. The use of other methods is necessary for more accurate diagnosis and prevention of perioperative complications. The character of damage of subclavian arteries and brachiocephalic stem should be taken into account in the choice of an optimal method of surgical treatment. PMID- 28635875 TI - [Disturbances of gait and postural stability in chronic cerebral ischemia]. AB - Disturbances of gait and postural stability are characteristic of the chronic progressive vascular lesion of the brain observed in moderate to severe stages of cerebrovascular disease. Disconnections between the prefrontal cortex, basal ganglia and cerebellum due to the damage of the white matter (vascular leukoencephalopathy) underlie disturbances of gait and postural stability (shorter stride length, wider gait). There are difficulties in starting with possible stoppings during the walking, waiting in front of small barriers as well as difficulties in concentration (e.g., talk during walking worsen the gait). In contrast to Parkinson's disease, associated movements of hands are observed. The severity of gait disturbances is usually correlated with the severity of vascular cognitive impairment unified by the common underlying substrate - the dysfunction of the frontal brain lobes. Approaches to treatment of patients with vascular movement disorders are discussed. PMID- 28635876 TI - [Salivation after stroke]. AB - Salivation after stroke (sialorrhea, hypersalivation, ptyalism) can be caused by the overproduction or a lack of utilization of saliva. Patients after stroke often have sialorrhea as a result of dysphagia. Neurogenic dysphagia in acute period after stroke occurs in 25-65% of patients. The mortality rate among people with post-stroke dysphagia and tube feeding ranges from 20 to 24%. Patients who suffering from profuse salivation have difficulties with articulation and swallowing, bad breath, irritation and maceration of perioral area, contamination of clothing and bed linen. Profuse salivation increases caregiver burden as well. Psychologically, profuse salivation leads to lower self-esteem and social isolation. Pulmonary aspiration is the most serious complication of sialorrhea. Injections of botulinum toxins in the large salivary glands and the m. cricopharyngeus are the most effective method of treatment. PMID- 28635877 TI - [A neuropathic component of lumboischialgia: mechanisms of development and treatment approaches]. AB - Low back pain (LBP) is accompanied by the development of pain syndrome that spreads into the leg in 25-57% of patients. This is an important factor predicting the risk of transition of pain from acute to chronic and is an indirect indicator of disease severity. It is often impossible to specify the primary mechanism facilitated pain irradiation in lumboischialgia because many structures can cause analogous symptoms. Mechanisms of development of LBP are represented by nociceptive, neuropathic and psychogenic components. Currently, the term 'neuropathic back pain' remains rather ambiguous. Existing data suggest that the term 'neuropathic LBP is not confined to classic radiculopathy and is realized through several pathophysiological mechanisms. Lumboischialgia is a clinical appearance of these mechanisms. The authors present main mechanisms of the development of lumboischialgia, discuss clinical markers of neuropathic component of LBP, approaches to its diagnosis and treatment. PMID- 28635878 TI - [Helicobacter pylori infection and extragastroduodenal diseases]. AB - At present, the clinical significance of Helicobacter pylori infection has been validly determined within the development of a diversity of gastroduodenal diseases, including chronic gastritis, gastroduodenal ulcer, MALT lymphoma, and gastric adenocarcinoma. The Expert Council's Maastricht IV consensus (2010) determining international standards for the diagnosis and treatment of H. pylori infection is that there is evidence that the latter may be associated with the development of a number of extragastroduodenal diseases (EGDDs) presented by iron deficiency anemia of unspecified etiology, idiopathic thrombocytopenic purpura, and vitamin B12 deficiency. In these diseases, it is recommended that infection with H. pylori be diagnosed and, if the test is positive, this microorganism be eradicated. A large number of investigations have been recently conducted to examine the association of H. pylori infection with other EGDDs. This paper reviews theoretical and epidemiological data on the association of H. pylori with diseases of the cardiovascular (atherosclerosis, myocardial infarction) and central nervous (Alzheimer's disease, Parkinson's disease) systems, pancreas (autoimmune pancreatitis, pancreatic cancer), oncological (colonic adenomas, colorectal cancer, hepatocellular carcinoma), dermatological (chronic spontaneous urticaria), and other EGDDs. The review highlights the potential protective role of H. pylori in diseases with the atopic element of genesis and a complicated course of gastroesophageal reflux disease (Barrett's esophagus, esophageal adenocarcinoma). PMID- 28635879 TI - [Cachexia syndrome: The present state of the problem and importance in clinical practice]. AB - Available updates have changed our idea about cachexia as a terminal condition, which could consider it as a combined metabolic syndrome that gives rise to the worse course of the underlying disease, the lower efficiency of specific therapy, and higher death rates. Chronic inflammatory factors are recognized to be the main mechanisms for the development of cachexia syndrome (CS). In addition, diagnostic criteria for this pathological condition are well defined. These criteria are rather simple for use in clinical practice and they should be assessed by physicians at all stages of a follow-up of patients with severe chronic diseases, since cachexia may develop long before the appearance of the so called extreme emaciation. The earlier the physician will anticipate the onset of CS, the more successful attempts to correct the latter and accordingly the better prognosis of the underlying disease will be. Available updates on the possibilities of correcting cachexia - anorexia are considered although there are no established standards for the management and treatment of patients with CS now. The elaboration of a step-by-step algorithm for following up the patients and a search for medications with proven clinical efficacy are relevant. PMID- 28635880 TI - [The development of functional gastrointestinal diseases: Genetic aspects]. AB - Motility disorders of the upper and lower gastrointestinal tract encompass a very wide range of structurally different diseases. Functional dyspepsia and irritable bowel syndrome (IBS) are the most common functional gastrointestinal disorders in clinical practice. In spite of the considerable prevalence of these functional diseases, the knowledge of their development mechanisms is very scarce. Recent investigations of the impact of the motor and sensory components of the pathogenesis of these diseases have demonstrated that the development of IBS is associated with serotonin transporter gene (5-HTTLPR) impairment and that the patients with IBS show the inadequate response to nonselective cannabinoid receptor agonists, which is caused by cannabinoid receptor gene (CNR1) polymorphism. Most investigations (mainly trials with small sample sizes) dealing with the identification of pharmacogenetic features have indicated that there is a preponderance of patients with intermediary metabolism among those with functional gastrointestinal diseases. However, larger investigations are necessary for a more exact understanding of this aspect. PMID- 28635881 TI - [Type 2 diabetes mellitus: Clinical aspects of genetics, nutrigenetics, and pharmacogenetics]. AB - The review gives modern knowledge of the genetics, pharmacogenetics and nutrigenetics of type 2 diabetes mellitus. The knowledge of genetic determinants can refine our understanding of the pathogenesis of this disease and introduce pharmacogenetic and nutrigenetic approaches to its effective therapy and prevention. PMID- 28635883 TI - [A meeting on Parkinson,s disease in the Media Sphera Publishing House with the participation of prof. E.A. Katunina and prof. I.V. Litvinenko]. PMID- 28635882 TI - [Change in the organ of vision in somatic diseases]. AB - The functional or morphological changes associated with systemic diseases make up the bulk of eye pathology. Accordingly, systemic drug therapy for these diseases can affect the eye. Changes of the organ of vision and appropriate ophthalmological advice can assist an internist to diagnose and adequately treat the patient. The article considers possible changes in the organ of vision in the presence of somatic diseases, as well as alterations resulting from drug therapy for these diseases. PMID- 28635884 TI - [Idiopathic pulmonary fibrosis: The current state of the problem]. AB - Idiopathic pulmonary fibrosis (IPF) is a severe lung disease, with death occurring within 2-5 years after its onset. IPF affects people in the second half of life. Its causes are unknown. Before 1999, IPF was out from the group of idiopathic interstitial lung diseases as a separate nosological entity. Practitioners very often (80%) make diagnostic errors in IPF and prescribe antibiotics, anti-inflammatory drugs, which worsen the course of this disease. The distinctive feature of the pathogenesis of IPF is the absence of inflammation, which is clinically manifested by the inefficacy of glucocorticosteroids and other anti-inflammatory drugs. Pharmacological agents for the treatment of IPF have been designed since 2000. One of them has been registered and permitted for use in the Russian Federation. This paper is a review of an update on the problem of IPF, which should facilitate the appropriate orientation of physicians in diagnosing and treating this severe disease. PMID- 28635885 TI - [Enoxaparin is a low-molecular-weight heparin with a complex chemical structure and various non-anticoagulant properties]. AB - The paper discusses the non-anticoagulant properties of unfractionated heparin and enoxaparin and their relation to their chemical structures. It is emphasized that enoxaparin has multiple, often interrelated, non-anticoagulant effects that can complement its antithrombotic activity and enhance the efficiency of therapy in patients receiving the drug for various indications. The realization of these effects requires the complex structure with the standard distribution of molecular weight (Mw) (average Mw, about 4500 Da, as well as Mw of less than 2000 Da (<20%), 2000 to 8000 Da (>68%), and more than 8000 Da (<18%), and with the standard content of 1.6-anhidro rings (15-25%), which is determined by the source of raw materials and by the production technology of the original drug and cannot be fully reproduced when designing its bioanalogues. PMID- 28635886 TI - [Depression, anxiety, stress, and mortality]. AB - The analytical paper summarizes the main results of recent investigations of the relationships of depression, anxiety, and stress with overall and cardiovascular mortality. It shows that depression and stress are associated with an increased risk of death mainly from cardiovascular diseases, and depression treatment and stress control can increase life expectancy. PMID- 28635887 TI - [Hereditary afibrinogenemia: A literature review and clinical observations]. AB - Afibrinogenemia is a rare congenital coagulopathy that leads to life-threatening bleeding. In afibrinogenemia, plasma fibrinogen levels are less than 0.1 g/L. The clinical manifestations of the disease can be both bleeding and thromboses of different localizations, which is determined by the multifunctional role of fibrinogen in hemostasis. The described cases demonstrate different clinical phenotypes of the disease. In both cases the diagnosis was confirmed by genetic examinations that revealed homozygous mutations in the fibrinogen A genes. The nature of the mutations assumes consanguineous marriages, as confirmed by the results of a genealogical analysis. Fibrinogen preparations are promising in treating afibrinogenemia in Russia. PMID- 28635888 TI - [Adiponectin in health and disease]. AB - Over the past 20 years after the discovery of adiponectin, much knowledge about its effect in health and disease has been gained. Adiponectin has antidiabetic, antiatherogenic, anti-inflammatory, immunomodulatory, metabolic, vasoprotective, and antiapoptotic properties. However, an understanding stems from the given literature review that much remains to be explored. Adiponectin has not yet commonly used in clinical practice, but cardiologists, endocrinologists, pediatricians, oncologists, and physicians of many specialties are interested in its preventive and therapeutic applications. PMID- 28635889 TI - [Small bowel injuries due to nonsteroidal anti-inflammatory drugs and antiplatelet therapy. Approaches to prevention and treatment]. AB - Nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injuries (NSAID enteropathies) become clinically important. Videocapsule endoscopy shows that the small bowel is involved in NSAID-related gastrointestinal tract (GIT) injury in almost two-thirds of all cases. Due to a large number of patients who receive NSAIDs, combined antiplatelet therapy, or long use anticoagulants, GIT injury prevention becomes an actual problem. Treatment for NSAID enteropathy is different from that for NSAID gastropathy. In NSAID enteropathy, it is advisable to use drugs that are able to increase the production of prostaglandins and mucus, to restore intestinal epithelial permeability, and to exert anti inflammatory and antioxidant effects. Rebamipide that produces many pleiotropic effects and also has cytoprotective properties may become the drug of choice for treating patients with NSAID enteropathy. In addition, rebamipide has no effects on various cytochrome P-450 enzyme systems, by reducing the risk of drug interactions. PMID- 28635891 TI - [Meloxicam in Russia: 20 years together]. AB - Meloxicam is one of the most commonly used representatives of the group of nonsteroidal anti-inflammatory drugs prescribed in our country. It has been used in Russian clinical practice for 20 years and established itself as an effective and rather safe analgesic and anti-inflammatory medications. During this period almost 48 million packages of brand-name meloxicam have been sold; millions of people in our country have been successfully treated with this drug. During this period, there have been at least 29 Russian clinical trials of brand-name meloxicam, which covered 3,736 patients. In all the trials, meloxicam has demonstrated a good therapeutic potential (a substantial improvement in more than 75% of patients) and a low incidence of side effects, which averaged 6.4% (30.5% in the control groups). The good tolerability of brand-name meloxicam (Movalis) is confirmed by a total of 120 spontaneous reports of the adverse events due to this drug, which were sent to the Federal Service for Health Supervision in December 2008 to July 2015 (over the last 7 years). This number seems negligible (nearly 30 million packages) if the amount of meloxicam sold over the period is taken into account. Extensive experience in clinical practice with this drug and a wide series of national clinical trials support the good reputation of brand name meloxicam among Russian physicians and patients. This review briefly gives the data of Russian and main foreign clinical trials of the therapeutic effect and safety of meloxicam. PMID- 28635890 TI - [Use of probiotics and probiotic-based immunomodulators as adjuvant therapy for Helicobacter pylori eradication]. AB - At present, Helicobacter pylori (Nr) infection is the most common chronic bacterial infection in humans, the pathogen of which colonizes approximately 50% of the world's population. Hp eradication is required to control complications of Hp-related diseases (gastric and duodenal ulcers). Nevertheless, a number of investigations have demonstrated widespread antibacterial therapy inefficiency due to Hp antibiotic resistance and patient non-compliance with treatment regimens. Due to the growing need to elaborate alternative eradication regimens, some researchers have drawn their attention to probiotics and immunomodulators derived from Lactobacillus in particular for eradication therapy in Np-positive patients to enhance the effect of antibacterial drugs. The review analyzes the results of 10 meta-analyses of randomized clinical trials with a similar design, which were published in 2007 to 2015, and other clinical trials assessing the role of probiotics and probiotic-based immunomodulators as an adjuvant therapy for Hp eradication. The results of the analysis have established that Lactobacillus strain-containing probiotics, both monocomponent probiotics and those as part of multicomponent ones, when used as an adjunct to anti-Hp therapy, significantly increase the level of Np eradication by 8.1-20.0% (p<0.05; Level of Evidence, 1A; Recommendation Grade A). The use of N-acetylglucosaminyl-N acetylmuramyl dipeptide (Licopid, a Lactobacillus bulgaricus-based immunomodulator) 0.001 and 0.01 g/day as an adjuvant to first-line triple anti-Hp therapy was shown to increase the level of Hp eradication by 7.1-8.9%. The intake of licopid 0.001 and 0.01 g/day during 7-day triple anti-Hp therapy results in the absence of recurrent Hp infection, as compared with 7- and 14-day treatment protocols without licopid, and leads to a significantly low incidence of Hp reinfection within 2-5 years after successful bacterial eradication, as compared with the 7-day protocol without adjuvant therapy with glucosaminylmuramyl dipeptide (p<0.05). PMID- 28635892 TI - [Central regulation of pain in patients with joint disease and approaches to therapy]. AB - The paper reviews investigations studies that have demonstrated that chronic pain syndrome is mixed in rheumatic diseases. The nervous system is involved in its pathogenesis with different frequency and different mechanisms. Under the influence of afferent pain impulses from damaged joints, there are changes in the excitability of spinal cord neurons, which is called central sensitization (CS). A number of patients have enhanced CS and clinical manifestations as neuropathic sensitive phenomena. The mixed model of the development of chronic pain in joint diseases and its presence along with nociceptive (inflammatory) and neuropathic pain components may explain the discrepancy between joint inflammatory and structural changes and pain intensity, the presence of distant pain and sensitive disorders in the areas outside the joint, and sometimes the efficiency of anti inflammatory therapy. The presence of the neuropathic pain component serves as a rationale for combined therapy by adding centrally acting drugs, such as anticonvulsants. PMID- 28635893 TI - [Nosocomial obstetric infections: Yesterday, today, tomorrow]. AB - Antibiotic resistance of microorganisms is one of the most acute problems of modern obstetrics. The paper analyzes current antibiotic resistance. It considers the mechanisms of its formation and ways to overcome the resistance. PMID- 28635894 TI - [Department of Otorhinolaryngology at the Kazan State Medical Academy]. PMID- 28635895 TI - [The paranasal sinuses as the nitric oxide depot]. AB - This paper was designed to report the currently available data on physiology of the nasal cavity and paranasal sinuses together with the results of national and international investigations on the computer modeling of the air flow in these structures. Also discussed are the gas composition in the paranasal sinuses and the potential factors responsible for the changes in the concentration of nitric oxide with the chemical formula of NO in the nasal cavity and paranasal sinuses. PMID- 28635896 TI - [The response of the upper respiratory tract to the impact of atmospheric pollution]. AB - The present literature review characterizes the environmental conditions in the Russian Federation in general and the Republic of Tatarstan in particular with special reference to the influence of atmospheric pollution on the development and the clinical picture of the diseases of the respiratory organs including pathology of the upper respiratory tract in the populations of the industrial centres and other environmentally unfriendly areas. The views of the domestic and foreign authors concerning the role of the environmental factors in the clinical picture of the upper respiratory tract disorders are described in detail. The authors emphasize the necessity of the further investigationsinto this problem and the development of the methods for the prevention of diseases of the upper respiratory react. PMID- 28635897 TI - [The functional disturbances in the vegetative nervous system associated with nasal and paranasal sinuses pathology]. AB - The authors undertook the analysis of the literature data on the functional state of the vegetative nervous system (VNS) in the patients presenting with otorhinolaryngological pathology. These data suggest the participation of VNS in the origin and development of many ENT diseases. Moreover, they demonstrate the absence of commonly accepted approaches to the study of VNS and the assessment of clinical manifestations of vegetative dysfunction syndrome. The necessity of the further investigationsinto this problem is emphasized taking into consideration various types of vegetative constitution in the patients suffering from diseases of the upper respiratory tract. PMID- 28635898 TI - [The modern transplants for the restoration of bone defects in rhinology]. AB - The author presents the results of the analysis of the data from the domestic and foreign literature concerning the potential of the osteoplastic methods for the restoration of bone defects in the nasal septum. All types of the osteoplastic materials finding the application in rhinologyare described. PMID- 28635899 TI - [The role of the perinatal transmission and persistence of human papilloma virus in the development of juvenile respiratory papillomatosis]. AB - This review paper presents the results of the recent studies designed to elucidate the etiopathogenetic role ofhuman papilloma virus infection in the development of respiratory papillomatosis in the children. Special attention is given to the possible pathways and mechanisms of the mother-to-child transmission of papilloma virus, its frequency and risk factors during pregnancy and in the postnatal period. The results of investigations into the frequency of papilloma virus infection in the children are presented along withrisk factors contributing to its persistence and the development ofjuvenile respiratory papillomatosis. The possible approaches to the management of this condition are proposed. PMID- 28635900 TI - [Chronic rhinosinusitis with nasal polyps. The recent trend in the studies of the pathogenesis, diagnosis and treatment of this disease]. AB - A review of the current problems of nasal polyposis has been presented. The results of an analysis mainly of foreign literature have been given, which is reflected in EPOS 2012. PMID- 28635901 TI - [Alimskiy A.V. Modern advances in new imaging techniques prompting diagnostics and treatment of oral pathology (by prof. A.P. Arzhantsev)]. PMID- 28635902 TI - [Risk factors, clinical presentations, prevention, and treatment of corneal graft rejection]. AB - Corneal transplantation is the most common and successful type of allotransplantation surgery. Post-transplant immune response in keratoplasty is less pronounced than that in other transplantation procedures, which is accounted for by anatomical features of the cornea and, also, its low antigenic potential and active immunosuppression. However, the immune privilege of the cornea can be violated by neovascularization, inflammation, or trauma. Patients who require keratoplasty to restore their sight and whose immune privilege is disturbed, fall into a high-risk group and are likely to demonstrate tissue incompatibility and non-transparent engraftment. Two approaches exist as to how graft rejection can be prevented. One of them involves induction of donor-specific tolerance, the other - non-specific suppression of the recipient's immune response. To avoid tissue incompatibility, measures can be taken to restore the immune privilege of the cornea as well as to induce antigen-specific tolerance, which is considered a promising, thought yet experimental, area of modern transplantology. In clinical practice, one pays most attention to improvement of non-specific immune suppression methods based on interfering in the metabolism of immunocompetent cells. Thus, timely prescriptions and proper immunosuppressive tactics with account to possible risk factors determine the outcome in high-risk patients undergoing corneal transplantation surgery. PMID- 28635903 TI - [Structural and functional characteristics of vitrectomized eyes]. AB - The article describes the potential effects of vitrectomy on clinical refraction, refraction of the cornea and its biomechanical parameters, the state of the lens, intraocular pressure, and biometric parameters of the anterior eye segment. PMID- 28635904 TI - [Myocardial fibrosis: Current aspects of the problem]. AB - Fibrosis is one of the main components in the progression of most cardiovascular diseases, including coronary heart disease, by causing structural changes in the myocardium and vascular wall. The quantitative and qualitative characteristics of fibrosis of the myocardium are responsible for decreasing its elastic properties, developing diastolic dysfunction, impairing myocardial contractility, developing systolic dysfunction and cardiac arrhythmias, and worsening coronary blood flow in patients with heart failure of different etiologies. The important aspect of studying fibrosis is not only its interpretation as a model of the typical pathological process, but also its consideration as a systemic lesion of various organs and tissues. At the same time, the identification of myocardial fibrosis biomarkers that are available for their determination in circulating blood is of particular interest. Since there was evidence for the role of fibrosis in developing dysfunction of various organs and ensuring the systematicity of most diseases, especially at their development stages, the process of fibrosis came to be regarded as a promising therapeutic target. It is relevant to further investigate myocardial fibrosis, which is aimed at increasing the efficiency of its diagnosis and predicting its course and pathogenetically sound therapy. PMID- 28635905 TI - [Algorithm for the management of patients with stable coronary artery disease and high-grade ventricular arrhythmias]. AB - The paper gives an original algorithm for the management of patients with stable coronary artery disease, preserved/moderately reduced left ventricular systolic function, and high-grade ventricular arrhythmias from the first registration of the latter to the choice of treatment policy. Great attention is paid to the assessment of a private clinical case, by determining the nature of arrhythmias, and to the involvement of autonomic regulation in the genesis of ventricular arrhythmias. The importance of topical diagnosis of ventricular arrhythmias and identification of psychological disorders is emphasized. Diagnostic problems are solved in a step-by-step fashion using up-to-date techniques. The key point of the algorithm proposed is to prevent sudden cardiac death. PMID- 28635906 TI - [Obstructive sleep apnea at high altitude]. AB - Obstructive sleep apnea (OSA) is an important and socially relevant problem of modern medicine, which is referred to as a most common pathological condition. The problem of OSA is especially urgent for inhabitants of high mountainous regions, as a combination of climatic, social, and cultural factors can significantly affect the course of the disease in both indigenous highlanders and people temporarily residing at high altitude. The paper reviews the current literature covering the problem of OSA at high altitude. It gives the data of Russian and foreign literature on the pathogenesis and clinical presentation of OSA. The author also analyzes an update on the impact of high altitude on the course of OSA in indigenous highlanders and people temporarily living at high altitude. She emphasizes the role of hypobaric hypocapnia as the most important factor for the development of central sleep apnea in the presence of conditions that are obstructive and aggravating the course of the disease. PMID- 28635907 TI - [The problem of obstructive sleep apnea syndrome in asthmatic patients]. AB - Asthma and obstructive sleep apnea syndrome (OSAS) are one of the most common chronic respiratory diseases. These have common risk factors that include obesity, gastroesophageal reflux disease (GERD) and impaired nasal breathing (allergic rhinitis, sinusitis). At the same time, experimental evidence demonstrates common pathophysiological mechanisms of these diseases, such as involvement in the process of the respiratory tract, a systemic inflammatory response, and implementation of neuromechanical reflexes. Thus, there is an obvious synergism between these conditions, which affects symptoms, response to therapy, and prognosis. The available data allow discussion on whether there is a need to identify and treat OSAS in asthmatic patients. By keeping in mind the high incidence of OSAS in patients with severe asthma, it may be suggested that treatment for OSAS can reduce the number of exacerbations, improve the quality of life, and decline the number of obstinate asthma cases. It is very important for general practitioners to assess risk factors, such as body weight, nasal stuffiness, and GERD, and to utilize screening tools for more efficient use of healthcare resources. Considering the known positive effects of CPAP therapy in short-term studies, future investigations should focus on the impact of CPAP therapy on asthma symptoms in the long-term, as well as on the effects of asthma drugs on the course of OSAS. PMID- 28635908 TI - [Idiopatic pulmonary fibrosis: A new paradigm]. AB - Idiopathic pulmonary fibrosis ((IPF) is the most common disease from a group of interstitial lung diseases, which occurs mainly in middle-aged and elderly people. Over the past decade, there have been considerable changes in approaches to diagnosing and treating IPF. The paper presents an update on the epidemiology of IPF, the results of new studies of its pathogenesis, and main approaches to diagnosing the disease. In addition, there is new evidence on therapy for IPF. PMID- 28635909 TI - [Chronic obstructive pulmonary disease concurrent with metabolic syndrome: Pathophysiological and clinical features]. AB - Chronic obstructive pulmonary disease (COPD) still remains a serious public health problem, which is a common cause of disability and death in the able bodied population. Furthermore, the number of patients with metabolic syndrome (MS) is steadily increasing worldwide. Recently, there is also an increase in the number of patients with COPD concurrent with MS, which is a mutually confounding risk factor for concomitant cardiovascular disease and adversely affects prognosis in these patients. Systemic subclinical inflammation is a common link between COPD and the components of MS. Systemic inflammation in patients with comorbidity is complemented by an inflammatory process in the abdominal visceral adipose tissue that serves as a source of proinflammatory adipokines (leptin, resistin, and tumor necrosis factor-alpha). Patients with COPD in the presence of MS components have in general higher ventilation needs, more obvious clinical manifestations of bronchopulmonary diseases, and more frequent COPD exacerbations and frequently require higher doses of inhaled glucocorticosteroids. As compared with normal-weight patients with COPD, obese patients with this condition have more limited physical activity and much more exercise intolerance. There are currently no practical recommendations for the management of patients with comorbidity; patients with COPD concurrent with MS need an individual therapeutic approach. It is important to elaborate a package of preventive measures to improve quality of life in patients, to reduce the incidence of systemic complications, and to achieve symptomatic improvements. Thus, to develop and implement practical guidelines for physicians and patients are an urgent issue. PMID- 28635910 TI - [Involvement of the hepatobiliary system and pancreas in obesity]. AB - The article provides an overview of current views on the involvement of the liver, gallbladder, and pancreas in patients with overweight and obesity. It considers the general issues of the pathogenesis of these conditions, their clinical features and diagnostic methods. PMID- 28635911 TI - [The modern possibilities for the application of photogrammetry in the forensic medical practice and scientific researches]. AB - The authors consider the modern possibilities for the application of photogrammetry in the domestic forensic medical practice and scientific researches as exemplified by the use of 3D-laser scanning and the single-chamber photogrammetric technique for the visualization of various objects including the places of road traffic accidents and other events. Special emphasis is laid on the objective difficulties likely to be encountered in this work and the prospects for the further application of photogrammetric methods in the work of experts in various fields of human activities. The important role of scientific and technical progress in the solution of practical expert problems is illustrated based on the utilization of the unique up-to-date computed technologies capable of improving the quality of expert support of investigative activities. PMID- 28635912 TI - [The age-dependent changes of sella turcica, frontal and sphenoid sinuses]. AB - This article is designed to report the results of analysis of the literature publications concerning age-specific changes in the configuration of the sella turcica, frontal and sphenoid sinuses during the life span of a human being. It is shown that the subjects above the age of 20-25 years undergo age-dependent variations of the morphometric characteristics of the sella turcica, frontal and sphenoid sinuses. It suggests the necessity of the further development of the research methods with a view to increasing the number of techniques used in forensic medicine designed to enhance the accuracy of estimation of the human biological age. PMID- 28635914 TI - [All-Russian scientific-practical conference with international participation 'Child and adolescent psychiatry: current issues of diagnosis, therapy, prevention and rehabilitation' (St. Petersburg, 19-21 November 2014)]. PMID- 28635913 TI - [Lipid metabolism in patients with hematologic cancers]. AB - It is considered that hypercholesterolemia is life-threatening and low cholesterol levels are a positive factor. However, taking into consideration the fact that cholesterol plays a key role in cell proliferation, it should be remembered that its low blood level may be linked to high cholesterol demands from neoplastic cells. The literature review analyzes the results of recent investigations of lipid metabolism in patients with hematologic cancers and their other types. All given investigations show a significant reduction in the serum levels of total cholesterol and high-density lipoproteins in patients with hematological disease at its onset. The data for other indicators of the lipid transport system are ambiguous. Such changes have been elucidated to be associated with the accumulation of cholesterol in the leukemia cells due to enhanced synthesis de novo, a more active absorption from circulation and blocked release of its surplus. If the disease runs a favorable course, lipid metabolic parameters become normalized and, in case of remission, correspond to those seen in healthy individuals. They continue to decline in patients with disease progression. This allows the consideration of cholesterol, its fractions, and apolipoproteins as biochemical prognostic markers in hematological cancer patients and as indicators for assessment of treatment results. In addition, there is evidence for the effect of chemotherapeutic agents on lipid metabolism. Recent attempts to elaborate new treatment strategies, by using the current knowledge on the role of lipid metabolism in cancers, are considered. PMID- 28635915 TI - [Preparation of training base in Izhevsk in 1941 for evacuation of Moscow State Dental Institute]. AB - The paper describes the history of preparation for the evacuation of Moscow State Dental Institute in 1941. Training base assumed in Izhevsk was not required because of the retreat of German troops. PMID- 28635916 TI - [Tunnel technique in oral surgery]. AB - The article is aimed to analyze the advantages of the tunnel operative approach in dental surgery. It is shown that the application of the tunnel technique can enhance tissue regeneration and revascularization, achieve better aesthetic and functional results, offer higher treatment quality. PMID- 28635917 TI - [Cone beam CT in diagnostics of facial trauma]. AB - The article provides a review of domestic and international scientific literature to reveal the possibilities of cone-beam computed tomography in facial trauma diagnostics. The ratio of maxillofacial trauma continues to grow progressively. The current situation increases the need for high-quality, fast and extremely informative radiology diagnosis for such conditions. At the moment the possibilities of multislice computed tomography are well examined in the facial trauma diagnosis. But the potential of cone-beam computed tomography aren't fully known yet by radiologists and maxillofacial surgeons. This review presents an analysis of the method's technical features, its advantages, disadvantages and special application aspects in facial trauma. PMID- 28635918 TI - [Risk factors for vertical root fractures after endodontic treatment]. AB - The review sought to describe the main risk factors for vertical root fracture predisposition in teeth after root canal treatment: altered mechanical characteristics of dentine due to loss of moisture and use of aggressive irrigation agents, insufficient amount of remaining dentine tissue after mechanical preparation of root canals, damage to the remaining tooth structure due to the effects of posts of different materials. According to the reviewed studies it is difficult to reveal the main factor predisposing to vertical root fractures. It is likely that in each case there is an interaction of several factors. PMID- 28635919 TI - [Video capsule endoscopy is one more step towards improving the diagnosis of small intestinal diseases]. AB - AIM: To estimate the value of video capsule endoscopy (VCE) in the diagnosis of small intestine (SI) diseases.. SUBJECTS AND METHODS: A total of 134 patients, including 72 (53.7%) women and 62 (46.3%) men whose mean age was 41.48+/-9.33 years. Group 1 included 73 patients who were examined using an algorithm for the diagnosis of SI diseases, 61 patients underwent VCE by the referrals handed in other healthcare facilities. RESULTS: In the patients of Group 1, pathological SI changes were revealed by VCE by almost 4 times more frequently than in those of Group 2. VCE provides a possibility of establishing the sources of bleeding, Crohn's disease, and other inflammatory diseases, which are inaccessible to other diagnostic methods. SI arteriovenous malformations, polyps, and diverticula, parasitic infections, and nonsteroidal anti-inflammatory drug-associated enteropathy may be causes of obscure SI bleeding and anemia. In celiac disease, VCE may estimate the extent of SI mucosal atrophy and reveal its disintegration as erosions and ulcers, which are inherent in its refractory form. CONCLUSION: VCE is a highly informative method for examining the SI, but, in view of the specific features of its performance and the high cost of hardware, VCE is recommended to be performed in accordance with the proposed diagnostic algorithm. PMID- 28635920 TI - [Myocardial injury associated with chronic hepatitis C: Clinical types and pathogenetic components]. AB - Heart injury is one of the extrahepatic manifestations of chronic hepatitis C (CHC). The paper gives Russian and foreign authors' data on a relationship between CHC and myocardial injury. It discusses different pathogenetic components (the direct effect of the virus, immunological components), through which hepatitis C virus can induce myocarditis and cardiomyopathies in patients with CHC. PMID- 28635921 TI - [Promising markers for the risk and prognosis of gestational diabetes mellitus]. AB - The review provides information on the molecular genetic mechanisms for the development gestational diabetes mellitus (GDM). It gives data on the genetic identity of GDM and type 2 diabetes mellitus and considers a role of some adipokines and incretin hormones in the development of GDM. There is evidence for the role of magnesium and vitamin D deficiencies in the pathogenesis of gestational carbohydrate metabolic disturbances. PMID- 28635922 TI - [Molecular genetics of maturity-onset diabetes of the young]. AB - To verify the type of diabetes mellitus (DM) remains an extremely important problem in endocrinology, as along with types 1 and 2 DM there are rarer hereditary types of DM, including maturity-onset diabetes of the young (MODY). The latter is a genetic type of DM, which is characterized by an autosomal dominant inheritance. Eleven types of MODY (MODY 1 to MODY13) are identified; each is associated with mutations in the certain gene: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11 and ABCC8. A molecular genetic testing for suspected MODY is conducted to verify the diagnosis and to define a subtype of MODY, patient management tactics, to predict the outcome of the disease and its complications in relation to the found subtype of MODY. It is also important to seek mutation causing MODY in terms of the early detection of MODY in the first-degree relatives of a proband, appropriate therapy of the disease, and prevention of its complications. PMID- 28635923 TI - [Hepatosplenic T-cell lymphoma: The problems of diagnosis and treatment]. AB - In the past decade, a notable advance has been made in the understanding of the pathogenesis of NK/T-cell lymphomas; however, their diagnosis remains difficult because of their rarity and clinical and morphological variabilities. The paper generalizes the ten-year experience of the Hematology Research Center, Ministry of Health of Russia, in diagnosing and treating hepatosplenic T-cell lymphoma (HSTL), considers the problems of differential diagnosis with other hematological diseases occurring with similar clinical and laboratory symptoms, and lays down current approaches to the diagnosis and treatment of this condition. A clinician's view of the problem of diagnosis and treatment of this disease is given. HSTL is shown to be a heterogeneous group of diseases differing in a T cell receptor chain gene rearrangement, the clinical course of the disease, and overall survival (OS). According to our data, 3-year OS was 12%; the median survival was 26 months. Two-year OS for gammadelta and alphabeta HSTL was equal to 25 and 70%, respectively. The difference in OS for the variants of HSTL failed to reach statistical significance (because the sample might be insufficient). PMID- 28635924 TI - [Pregravid preparation of diabetic women]. AB - Pregnancy in women with type 1 or 2 diabetes mellitus (DM) is associated with an increased risk for complications in both the mother and her fetus. The impact of these complications on modifiable risk factors may substantially improve pregnancy outcomes and reduce malformation rates in children. This is a goal of pregravid preparation (PGP) in this category of patients. The review gives the main points of PGP in patients with types 1 and DM and shows the results of main studies providing evidence for PGP in DM. In particular, by the moment of conception, DM patients should achieve a glycosylated hemoglobin (HbA1c) goal of <6% no later than 4 weeks before conception and during the first trimester of pregnancy, take folic acid in a high dose (at least 4000 ug, or 4 mg, daily), quit tobacco smoking and alcohol use, receive potentially teratogenic drugs, and, if need be, lose weight (the target body mass index of <27 kg/m2). PMID- 28635925 TI - [Postoperative analgesia: realities and prospects]. PMID- 28635926 TI - [Subcutaneous port systems with intraperitoneal catheter 'BBraun' in combined treatment of advanced stomach cancer]. PMID- 28635927 TI - [Mechanisms of corneal neovascularization and modern options for its suppression]. AB - Quite a number of pathological factors exist that can disturb the balance between anti-angiogenic and proangiogenic mechanisms, thus causing vascularization of the cornea. The neovessels are immature, ill-formed, and show increased permeability, which is dangerous of corneal edema, lipid deposition, and opacification. Moreover, as known, corneal neovascularization (CNV; preexisting or postoperative) may contribute to immune response against the transplant. Suppression of neovascularization is able to decrease the risk of corneal transplant rejection. In order to identify the principal strategy for struggling against CNV, we should first get a better understanding of its etiology, pathogenesis, and role in transplant immunity as well as mechanisms of action of available treatment methods. PMID- 28635928 TI - [Changes in hemostasis-related parameters of blood and lacrimal fluid in patients with retinal vein occlusion]. AB - High prevalence of retinal vein occlusion in young people as well as treatment complexity and inadequate control of hemostatic parameters of blood and lacrimal fluid determine the significance of relevant research in patients with retinal vascular pathology. The data thus obtained may be useful for disease prognosis, severity evaluation and therapy control. This review is aimed to study hemostasis related parameters of blood and lacrimal fluid in such patients. PMID- 28635929 TI - [Retinal vascular occlusion and polymorphisms in genes coding for components of vitamin K cycle]. AB - In recent years, more and more attention has been paid to the role of polymorphisms in genes that code for the components of vitamin K cycle in the development of retinal vascular occlusion. Vitamin K serves as a cofactor for a number of blood coagulation factors, namely, factor II, VII, IX, and X, and also for anticoagulation proteins C and S. According to the literature, 1639G4A polymorphism of the vitamin K epoxide reductase complex subunit 1 gene (VKORC1) is likely to be a new risk factor of retinal vascular occlusion. PMID- 28635931 TI - [M. Thali, R. Dirnhofer, P. Vock. The Virtopsy Approach. 3D optical and radiological scanning and reconstruction in forensic medicine (CRC Press, Boca Raton, Fl: CRC Press. London NW. 2009)]. PMID- 28635930 TI - [Vascular endothelial growth factors (VEGF): role in pathological processes]. AB - Russian and foreign literature sources on vascular endothelial growth factors (VEGF) from different parts of the human body, their prevalence and involvement in pathological processes were analyzed. A conclusion has been drawn that further research on different types of VEGF is needed. PMID- 28635932 TI - [Electroporation: characteristics and therapeutic application of the method (a review)]. AB - The article briefly summarizes the currently available information on electroporation and electroporation-based therapy. We consider the definition and the biophysical basis of the method as well as the possible mechanisms underlying the formation of pores under the influence of the application of a pulsed electric field. The characteristics of the devices for electroporation are described and the most typical examples of the use of electroporation and electrochemotherapy in experimental and clinical oncology, dermatology, cosmetology, and other fields of medicine are provided. PMID- 28635933 TI - [A role of carotid endarterectomy in prevention of cerebral ischemic damage]. AB - Authors present a literature review on the prevalence, clinical presentations, diagnosis and outcome of surgical treatment of atherosclerotic stenosis of the internal carotid artery. PMID- 28635934 TI - [An interview with prof. L.I. Volkova]. PMID- 28635935 TI - [Mental health disorders in the first years of life: autism spectrum disorders, constitutional and residual-organic abnormalities]. AB - In the first part of a literature review, new approaches to multidisciplinary diagnoses of mental health disorders in early childhood are considered. The opportunities for standardization of clinical, psychological and social indicators on the basis of international Diagnostic classification of mental health and developmental disorders of infancy and early childhood (DC:0-3R) are emphasized. The main assessment of diagnostic techniques of this psycho pathological class in the first years of life are considered. An analysis of current data on autism spectrum disorders (ASD) and data about different variants of ASD course are presented. The analysis of current publications in the field of early constitutional and residual-organic abnormalities showed the congruence between them and 'regulation disorders of sensory processing', described in DC:0 3R. PMID- 28635936 TI - [Pathogenetic approaches to treatment of cognitive disorders in patients with diabetes mellitus]. AB - The article presents the currents concepts on the mechanisms of brain lesions and development of cognitive impairment in diabetes mellitus (DM) including DM type 2. Metabolic and vascular mechanisms, oxidative stress, hyperglycemia, glutamate excitotoxicity, insulin insufficiency and brain insulin resistance, general vascular and microcirculatory disturbances, death of cortical neurons, decrease in the newly synthesized acetylcholine, activation of lipid peroxidation are considered. A review of the main domestic and international drugs used in clinical practice for treatment of cognitive impairment in patients with DM is presented. PMID- 28635937 TI - [A role of the MAO-B inhibitor rasagiline in treatment of Parkinson's disease]. AB - The current medications for Parkinson's disease (PD) treatment have predominantly symptomatic action. They reduce the severity of main motor symptoms and delay the disability and fatal outcome but do not able to prevent the late stages characterized by multiple motor and non-motor disorders. A search for new drugs, which are able to slow disease progression at the early stage and promote effective treatment of symptoms at the late stage, is extremely urgent. Rasagiline (azilect), a new generation MAO-B inhibitor, helps to solve the problems at different stages of PD. PMID- 28635938 TI - [Methods of assessment of movement functions in the upper limb]. AB - An analysis of the results of domestic and foreign studies as well as the own data on the movement impairment in the paretic arm due to the stroke is presented. Advantages and shortcomings of commonly used scales for the assessment of upper limb functioning and possibilities of their using in different stages of stroke are analyzed. PMID- 28635939 TI - [Childhood maltreatment and its impact on the mental health]. AB - This review covers the literature of the last 25 years on the impact of childhood maltreatment on the mental health throughout the individual's life. Child abuse increases the risk of many mental disorders including depression, suicidal ideation and suicidal behavior, anxiety-related disorders, psychoses as well as alcohol and other drug abuse. The impact of child trauma on the mental health is largely due to structural and functional changes in the hippocampus, amygdala and prefrontal cortex. Early preventive interventions play a great role in the prevention of mental disorders associated with childhood adversities. PMID- 28635940 TI - [Genetics factors in pathogenesis and clinical genetics of binge eating disorder]. AB - Genetic studies have shown that binge eating disorder (VED) aggregates in families, heritability was estimated as about 60% and additive genetic influences on BED up to 50%. Using a genetic approach has proved useful for verifying the diagnostic categories of BED using DSM-IV criteria and supporting the validity of considering this pathology as a separate nosological category. The results confirmed the genetic and pathogenic originality of BED as a separate psychopathological phenomenon, but not a subtype of obesity. It seems fruitful to considerate BED as a disease with hereditary predisposition with significant genetic influence and a complex psychopathological syndrome, including not only eating disorders, but also depressive and addictive component. A possible mechanism of pathogenesis of BED may be the interaction of the neuroendocrine and neurotransmitters systems including the active involvement of the reward system in response to a variety of chronic stress influences with the important modulatory role of specific personality traits. The high level of genetic influence on the certain clinical manifestations of BED confirms the ability to identify the subphenotypes of BED on genetic basis involving clinical criteria. It can not only contribute to further genetic studies, taking into account more homogeneous samples, but also help in finding differentiated therapeutic approaches. PMID- 28635941 TI - [Algorithms of mono- and polytherapy in clinical epileptology]. AB - The large number of antiepileptic drugs (AEDs) at the physician's disposal provides not only a broad therapeutic potential in the treatment of epilepsy (EP), but creates difficulties in the adequate choice of AED. The sufficient experience in the management of patients with epilepsy has been gained so far in the world, based on which the International League Against Epilepsy (ILAE), updated classification, adopted the basic definition of efficiency, remission, resistance, evidence of research on the effectiveness of AED therapy, and introduced the concept of "resolved" epilepsy. In this article, a group of Russian experts suggest recommendations on the main steps in the choice of therapy in epilepsy. Possible drug interactions between different AEDs and other drugs as well as main characteristics of mono- and polytherapy of epilepsy are described. Some features of the use of AEDs in the elderly, characteristics of the "female" epilepsy related to the reproductive function and basic requirements for the therapy of epilepsy in children are presented. PMID- 28635942 TI - [Morphological diagnosis of viral damage to a kidney transplant]. AB - Due to the development of organ transplantation and its accompanying immunosuppression, recent years have been marked by the higher incidence of opportunistic viral infections that are of considerable importance among posttransplantation complications. A variety of viral infections, the possibility of their concomitant or subtle course, and the ability to cause life-threatening complications in recipients make relevant the description of existing diagnostic methods. The article summarizes the data available in the literature on the etiology, clinical symptoms, and morphological manifestations of viral infections, such as polyomaviruses, adenoviruses, herpesviruses, including HSV-1, HSV-2, cytomegalovirus (CMV), and Epstein-Barr virus. It describes the principles of differential diagnosis of kidney transplant damage caused by these viruses and that with acute cellular and humoral rejection, which plays an important role due to opposite approaches to treating these diseases. PMID- 28635943 TI - [Fabry's disease: Neurological disorders]. AB - The paper considers the pathogenesis and clinical features of Fabry's disease. It is stressed that along with cardiovascular system damage and kidney injury, there are peripheral and central nervous system lesions in this disease. In Fabry's disease, great attention is paid to cerebrovascular diseases that frequently give rise to disability. Peripheral neuropathy is mainly due to involvement of minor fibers and autonomic disorders. Signs that allow this disease to be diagnosed are given. PMID- 28635944 TI - [Role of microRNA in oncogenesis of pituitary tumors and their practical significance]. AB - Microribonucleic acids (miRNAs) are a class of noncoding RNAs that regulate posttranscriptional gene expression. These molecules are regulators of cell proliferation, metabolism, apoptosis, and differentiation. MiRNAs are not degraded by RNAases and their concentrations can be measured in different body fluids, including serum. The expression of miRNAs varies in intact tissues and tumors, including pituitary adenomas. Pituitary tumors are encountered in 22.5% of the population and, in a number of cases, may be asymptomatic, but in case of invasion or/and hormone overproduction, their clinical presentation is severe with multiple symptoms leading to disability and even death. The mechanisms for the development and progression of pituitary tumors and the markers for remission and recurrence have not been adequately investigated. This literature review discusses the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers. PMID- 28635945 TI - [Neuroprotective and nephroprotective effects of remote postconditioning: Prospects for clinical use]. AB - The results of experimental and clinical studies strongly suggest that remote ischemic preconditioning (RIP) has no neuroprotective effect during cardiac surgery performed under extracorporeal circulation. Remote preconditioning (RP) has no neuroprotective effect in hemorrhagic stroke. A randomized multicenter study is needed to evaluate the efficiency RIP in patients with ischemic stroke. RP reduces the severity of ischemia/reperfusion kidney injury during transplantation. RIP has been established to prevent contrast-induced nephropathy. There is a need for a multicenter trial to evaluate the efficiency of RIP in patients with abdominal aortic aneurysm repair. Analysis of the presented data indicates that RIP fails to prevent cardiorenal syndrome in infants and children during cardiac surgery. The data available in the literature on the capacity of RIP to provide nephroprotective effect in patients after coronary artery bypass surgery are discordant and indicative of the advisability of a multicenter study. PMID- 28635946 TI - A clinical nutritionist's experience and expectations. PMID- 28635947 TI - In situ dynamic observations of perovskite crystallisation and microstructure evolution intermediated from [PbI6]4- cage nanoparticles. AB - Hybrid lead halide perovskites have emerged as high-performance photovoltaic materials with their extraordinary optoelectronic properties. In particular, the remarkable device efficiency is strongly influenced by the perovskite crystallinity and the film morphology. Here, we investigate the perovskites crystallisation kinetics and growth mechanism in real time from liquid precursor continually to the final uniform film. We utilize some advanced in situ characterisation techniques including synchrotron-based grazing incident X-ray diffraction to observe crystal structure and chemical transition of perovskites. The nano-assemble model from perovskite intermediated [PbI6]4- cage nanoparticles to bulk polycrystals is proposed to understand perovskites formation at a molecular- or nano-level. A crystallisation-depletion mechanism is developed to elucidate the periodic crystallisation and the kinetically trapped morphology at a mesoscopic level. Based on these in situ dynamics studies, the whole process of the perovskites formation and transformation from the molecular to the microstructure over relevant temperature and time scales is successfully demonstrated. PMID- 28635948 TI - Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles. AB - Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18 1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming deficient mutant. NEM rescues synaptic transmission in munc13-1 null and munc18 1/2SWAP synapses, in acute munc13-1 null slices and even partially in munc13-1/2 double null synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming. PMID- 28635949 TI - Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis. AB - Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype phenotype correlation of the disease. PMID- 28635950 TI - Genetically predicted high body mass index is associated with increased gastric cancer risk. AB - Epidemiological studies have linked body mass index (BMI) with risk of gastrointestinal cancers. However, for gastric cancer, the relationship is more controversial. In particular, it is unclear whether the observed association is due to confounding or bias inherent in conventional observational studies. To investigate whether BMI is causally associated with gastric cancer risk, we applied Mendelian randomization using individual-level data from 2631 gastric cancer cases and 4373 cancer-free controls. We derived a weighted genetic risk score (wGRS) using 37 BMI-associated genetic variants as an instrumental variable. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between genetically predicted BMI and gastric cancer risk. We observed that higher genetically determined BMI was associated with increased gastric cancer risk (per standard deviation (SD) increase in the wGRS: OR=1.07, 95% CI: 1.02-1.13, P=4.94 * 10-3). Compared with individuals in the bottom tertile of the BMI wGRS, those in the top tertile had 1.14-fold (95% CI: 1.01-1.29) increased risk of developing gastric cancer. Sensitivity analyses using alternative causal inference measures demonstrated consistent association. Our study indicated that genetically high BMI was associated with increased gastric cancer risk, suggesting that high BMI may have a causal role in the etiology of gastric cancer. PMID- 28635951 TI - New insights into the imprinted MEG8-DMR in 14q32 and clinical and molecular description of novel patients with Temple syndrome. AB - The chromosomal region 14q32 contains several imprinted genes, which are expressed either from the paternal (DLK1 and RTL1) or the maternal (MEG3, RTL1as and MEG8) allele only. Imprinted expression of these genes is regulated by two differentially methylated regions (DMRs), the germline DLK1/MEG3 intergenic (IG) DMR (MEG3/DLK1:IG-DMR) and the somatic MEG3-DMR (MEG3:TSS-DMR), which are methylated on the paternal and unmethylated on the maternal allele. Disruption of imprinting in the 14q32 region results in two clinically distinct imprinting disorders, Temple syndrome (TS14) and Kagami-Ogata syndrome (KOS14). Another DMR with a yet unknown function is located in intron 2 of MEG8 (MEG8-DMR, MEG8:Int2 DMR). In contrast to the IG-DMR and the MEG3-DMR, this somatic DMR is methylated on the maternal chromosome and unmethylated on the paternal chromosome. We have performed extensive methylation analyses by deep bisulfite sequencing of the IG DMR, MEG3-DMR and MEG8-DMR in different prenatal tissues including amniotic fluid cells and chorionic villi. In addition, we have studied the methylation pattern of the MEG8-DMR in different postnatal tissues. We show that the MEG8-DMR is hypermethylated in each of 13 non-deletion TS14 patients (seven newly identified and six previously published patients), irrespective of the underlying molecular cause, and is always hypomethylated in the four patients with KOS14, who have different deletions not encompassing the MEG8-DMR itself. The size and the extent of the deletions and the resulting methylation pattern suggest that transcription starting from the MEG3 promoter may be necessary to establish the methylation imprint at the MEG8-DMR. PMID- 28635952 TI - Yunis-Varon syndrome caused by biallelic VAC14 mutations. AB - Yunis-Varon syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5) bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varon syndrome. PMID- 28635953 TI - Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians. AB - Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10-3). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 * 10-3). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected. PMID- 28635954 TI - Phenotypic extremes of BICD2-opathies: from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features. AB - Heterozygous variants in BICD cargo adapter 2 (BICD2) cause autosomal dominant spinal muscular atrophy, lower extremity-predominant 2 (SMALED2). The disease is usually characterized by a benign or slowly progressive, congenital or early onset muscle weakness and atrophy that mainly affects the lower extremities, although some affected individuals show involvement of the arms and the shoulder girdle. Here we report unusual extremes of BICD2-related diseases: A severe form of congenital muscular atrophy with arthrogryposis multiplex, respiratory insufficiency and lethality within four months. This was caused by three BICD2 variants, (c.581A>G, p.(Gln194Arg)), (c.1626C>G, p.(Cys542Trp)) and (c.2080C>T, p.(Arg694Cys)), two of which were proven to be de novo. Affected individuals showed reduced fetal movement, weak muscle tone and sparse or no spontaneous activity after birth. Despite assisted ventilation, the condition led to early death. At the other extreme, we identified an asymptomatic woman with a known BICD2 variant (c.2108C>T, p.(Thr703Met)). Radiological examination showed fatty degeneration of selected thigh and calf muscles without clinical consequences. Instead, her son carrying the same variant is affected by a mild childhood onset disease with myopathic and neurogenic features. Mechanisms leading to variable expressivity and onset of BICD2-related disease may include alterations in molecular interactions of BICD2 and suggest the presence of genetic modifiers that may act in a protective fashion to ameliorate or abrogate disease. Our data define an additional severe disease type caused by BICD2 and emphasize a possibly variable etiology of BICD2-opathies with regard to primary muscle and neuronal involvement. PMID- 28635955 TI - Corrigendum: Double-flow focused liquid injector for efficient serial femtosecond crystallography. AB - This corrects the article DOI: 10.1038/srep44628. PMID- 28635956 TI - Self-assembled three dimensional network designs for soft electronics. AB - Low modulus, compliant systems of sensors, circuits and radios designed to intimately interface with the soft tissues of the human body are of growing interest, due to their emerging applications in continuous, clinical-quality health monitors and advanced, bioelectronic therapeutics. Although recent research establishes various materials and mechanics concepts for such technologies, all existing approaches involve simple, two-dimensional (2D) layouts in the constituent micro-components and interconnects. Here we introduce concepts in three-dimensional (3D) architectures that bypass important engineering constraints and performance limitations set by traditional, 2D designs. Specifically, open-mesh, 3D interconnect networks of helical microcoils formed by deterministic compressive buckling establish the basis for systems that can offer exceptional low modulus, elastic mechanics, in compact geometries, with active components and sophisticated levels of functionality. Coupled mechanical and electrical design approaches enable layout optimization, assembly processes and encapsulation schemes to yield 3D configurations that satisfy requirements in demanding, complex systems, such as wireless, skin-compatible electronic sensors. PMID- 28635958 TI - Origin of fast ion diffusion in super-ionic conductors. AB - Super-ionic conductor materials have great potential to enable novel technologies in energy storage and conversion. However, it is not yet understood why only a few materials can deliver exceptionally higher ionic conductivity than typical solids or how one can design fast ion conductors following simple principles. Using ab initio modelling, here we show that fast diffusion in super-ionic conductors does not occur through isolated ion hopping as is typical in solids, but instead proceeds through concerted migrations of multiple ions with low energy barriers. Furthermore, we elucidate that the low energy barriers of the concerted ionic diffusion are a result of unique mobile ion configurations and strong mobile ion interactions in super-ionic conductors. Our results provide a general framework and universal strategy to design solid materials with fast ionic diffusion. PMID- 28635957 TI - ITK signalling via the Ras/IRF4 pathway regulates the development and function of Tr1 cells. AB - Type 1 regulatory T (Tr1) cells differentiate in response to signals engaging the T cell receptor (TCR), express high levels of the immunosuppressive cytokine IL 10, but not Foxp3, and can suppress inflammation and promote immune tolerance. Here we show that ITK, an important modulator of TCR signalling, is required for the TCR-induced development of Tr1 cells in various organs, and in the mucosal system during parasitic and viral infections. ITK kinase activity is required for mouse and human Tr1 cell differentiation. Tr1 cell development and suppressive function of Itk deficient cells can be restored by the expression of the transcription factor interferon regulatory factor 4 (IRF4). Downstream of ITK, Ras activity is responsible for Tr1 cell induction, as expression of constitutively active HRas rescues IRF4 expression and Tr1 cell differentiation in Itk-/- cells. We conclude that TCR/ITK signalling through the Ras/IRF4 pathway is required for functional development of Tr1 cells. PMID- 28635959 TI - Optogenetic activation of Plexin-B1 reveals contact repulsion between osteoclasts and osteoblasts. AB - During bone remodelling, osteoclasts induce chemotaxis of osteoblasts and yet maintain spatial segregation. We show that osteoclasts express the repulsive guidance factor Semaphorin 4D and induce contact inhibition of locomotion (CIL) in osteoblasts through its receptor Plexin-B1. To examine causality and elucidate how localized Plexin-B1 stimulation may spatiotemporally coordinate its downstream targets in guiding cell migration, we develop an optogenetic tool for Plexin-B1 designated optoPlexin. Precise optoPlexin activation at the leading edge of migrating osteoblasts readily induces local retraction and, unexpectedly, distal protrusions to steer cells away. These morphological changes are accompanied by reorganization of Myosin II, PIP3, adhesion and active Cdc42. We attribute the resultant repolarization to RhoA/ROCK-mediated redistribution of beta-Pix, which activates Cdc42 and promotes protrusion. Thus, our data demonstrate a causal role of Plexin-B1 for CIL in osteoblasts and reveals a previously unknown effect of Semaphorin signalling on spatial distribution of an activator of cell migration. PMID- 28635960 TI - Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis. AB - Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases. PMID- 28635962 TI - Growth of organic crystals via attachment and transformation of nanoscopic precursors. AB - A key requirement for the understanding of crystal growth is to detect how new layers form and grow at the nanoscale. Multistage crystallization pathways involving liquid-like, amorphous or metastable crystalline precursors have been predicted by theoretical work and have been observed experimentally. Nevertheless, there is no clear evidence that any of these precursors can also be relevant for the growth of crystals of organic compounds. Herein, we present a new growth mode for crystals of DL-glutamic acid monohydrate that proceeds through the attachment of preformed nanoscopic species from solution, their subsequent decrease in height at the surface and final transformation into crystalline 2D nuclei that eventually build new molecular layers by further monomer incorporation. This alternative mechanism provides a direct proof for the existence of multistage pathways in the crystallization of molecular compounds and the relevance of precursor units larger than the monomeric constituents in the actual stage of growth. PMID- 28635961 TI - Hypoxia-induced mobilization of NHE6 to the plasma membrane triggers endosome hyperacidification and chemoresistance. AB - The pH-dependent partitioning of chemotherapeutic drugs is a fundamental yet understudied drug distribution mechanism that may underlie the low success rates of current approaches to counter multidrug resistance (MDR). This mechanism is influenced by the hypoxic tumour microenvironment and results in selective trapping of weakly basic drugs into acidified compartments such as the extracellular environment. Here we report that hypoxia not only leads to acidification of the tumour microenvironment but also induces endosome hyperacidification. The acidity of the vesicular lumen, together with the alkaline pH of the cytoplasm, gives rise to a strong intracellular pH gradient that drives intravesicular drug trapping and chemoresistance. Endosome hyperacidification is due to the relocalization of the Na+/H+ exchanger isoform 6 (NHE6) from endosomes to the plasma membrane, an event that involves binding of NHE6 to the activated protein kinase C-receptor for activated C kinase 1 complex. These findings reveal a novel mechanism of hypoxia-induced MDR that involves the aberrant intracellular distribution of NHE6. PMID- 28635963 TI - Single-molecule analysis of steroid receptor and cofactor action in living cells. AB - Population-based assays have been employed extensively to investigate the interactions of transcription factors (TFs) with chromatin and are often interpreted in terms of static and sequential binding. However, fluorescence microscopy techniques reveal a more dynamic binding behaviour of TFs in live cells. Here we analyse the strengths and limitations of in vivo single-molecule tracking and performed a comprehensive analysis on the intranuclear dwell times of four steroid receptors and a number of known cofactors. While the absolute residence times estimates can depend on imaging acquisition parameters due to sampling bias, our results indicate that only a small proportion of factors are specifically bound to chromatin at any given time. Interestingly, the glucocorticoid receptor and its cofactors affect each other's dwell times in an asymmetric manner. Overall, our data indicate transient rather than stable TF cofactors chromatin interactions at response elements at the single-molecule level. PMID- 28635964 TI - Elastically driven intermittent microscopic dynamics in soft solids. AB - Soft solids with tunable mechanical response are at the core of new material technologies, but a crucial limit for applications is their progressive aging over time, which dramatically affects their functionalities. The generally accepted paradigm is that such aging is gradual and its origin is in slower than exponential microscopic dynamics, akin to the ones in supercooled liquids or glasses. Nevertheless, time- and space-resolved measurements have provided contrasting evidence: dynamics faster than exponential, intermittency and abrupt structural changes. Here we use 3D computer simulations of a microscopic model to reveal that the timescales governing stress relaxation, respectively, through thermal fluctuations and elastic recovery are key for the aging dynamics. When thermal fluctuations are too weak, stress heterogeneities frozen-in upon solidification can still partially relax through elastically driven fluctuations. Such fluctuations are intermittent, because of strong correlations that persist over the timescale of experiments or simulations, leading to faster than exponential dynamics. PMID- 28635965 TI - Identification, genealogical structure and population genetics of S-alleles in Malus sieversii, the wild ancestor of domesticated apple. AB - The self-incompatibility (SI) gene that is specifically expressed in pistils encodes the SI-associated ribonuclease (S-RNase), functioning as the female specificity determinant of a gametophytic SI system. Despite extensive surveys in Malus domestica, the S-alleles have not been fully investigated for Malus sieversii, the primary wild ancestor of the domesticated apple. Here we screened the M. sieversii S-alleles via PCR amplification and sequencing, and identified 14 distinct alleles in this species. By contrast, nearly 40 are present in its close wild relative, Malus sylvestris. We further sequenced 8 nuclear genes to provide a neutral reference, and investigated the evolution of S-alleles via genealogical and population genetic analyses. Both shared ancestral polymorphism and an excess of non-synonymous substitution were detected in the S-RNases of the tribe Maleae in Rosaceae, indicating the action of long-term balancing selection. Approximate Bayesian Computations based on the reference neutral loci revealed a severe bottleneck in four of the six studied M. sieversii populations, suggesting that the low number of S-alleles found in this species is mainly the result of diversity loss due to a drastic population contraction. Such a bottleneck may lead to ambiguous footprints of ongoing balancing selection detected at the S locus. This study not only elucidates the constituents and number of S-alleles in M. sieversii but also illustrates the potential utility of S-allele number shifts in demographic inference for self-incompatible plant species. PMID- 28635966 TI - Testing models of refugial isolation, colonization and population connectivity in two species of montane salamanders. AB - Pleistocene glaciations have profoundly affected patterns of genetic diversity within many species. Temperate alpine organisms likely experienced dramatic range shifts, given that much of their habitat was glaciated during this time. While the effects of glaciations are relatively well understood, the spatial locations of refugia and processes that gave rise to current patterns of diversity are less well known. We use a microsatellite data set to test hypotheses of population connectivity and refugial isolation in the web-toed salamanders (Hydromantes) of the Sierra Nevada. We reject models of refugia with subsequent expansion into either the high southern Sierra or low-elevation Owens Valley, in favor of a simple isolation model with no migration between current populations. We find no evidence of migration at even moderate spatial scales using a variety of analyses in the southern Sierra, and limited migration in the northern Sierra. These results suggest that divergence in isolation following fragmentation is the dominant process structuring genetic variation in these salamander species. In the context of anthropogenic climate change and habitat degradation, these results imply that salamanders and other low-vagility alpine organisms are at risk of decline as they are unlikely to migrate across large distances. PMID- 28635967 TI - Social behaviour involving drug resistance: the role of initial density, initial frequency and population structure in shaping the effect of antibiotic resistance as a public good. AB - Bacteria sometimes cooperate with co-inhabiting cells. Pathogenic bacteria, for example, often produce and excrete virulence factors, eventually benefitting both producer and non-producer cells. The role of social interactions involving antibiotic resistance, however, has been more elusive. Enzymes that inactivate beta-lactam antibiotics such as ampicillin or penicillin (beta-lactamases) are good candidates as public goods. Nonetheless, it has been claimed that bacteria harbouring plasmids of natural origin coding for beta-lactamase almost do not protect sensitive bacteria. This does not fit with the fact that ampicillin sensitive bacteria can be isolated from subjects undergoing ampicillin treatment. We hypothesised that there are two non-exclusive explanations for the discrepancy between previous works: (1) the range of values of demographic conditions (such as initial strain frequency, initial total cell density or habitat structure) has not been broad enough to include most scenarios, or (2) there are interactions between some of these factors. We performed experiments with Escherichia coli bacterial cells to measure the degree of protection of sensitive cells when co cultured with cells harbouring RP4, R16a or the R1 plasmids, all of natural origin and coding for beta-lactamases, and in presence of ampicillin. In these co cultures, performed in structured and non-structured environments, both the initial total cell density and the initial frequency of sensitive cells spanned four orders of magnitude. We found protection of sensitive cells in 63% of tested conditions. All factors (plasmid, structure, frequency and density) significantly affect levels of protection. Moreover, all factors interact, with interactions revealing large or very large effect sizes. PMID- 28635969 TI - Erratum: Collective modes in multi-Weyl semimetals. AB - This corrects the article DOI: 10.1038/srep34023. PMID- 28635968 TI - Sex-biased dispersal creates spatial genetic structure in a parthenogenetic ant with a dependent-lineage reproductive system. AB - Reproduction and dispersal are key aspects of species life history that influence spatial genetic structure in populations. Several ant species in the genus Cataglyphis have evolved a unique breeding system in which new reproductives (that is, queens and males) are produced asexually by parthenogenesis; in contrast, non-reproductives (that is, workers) are produced via sexual reproduction by mates from distinct genetic lineages. We investigated how these two coexisting reproductive methods affect population-level spatial genetic structure using the ant Cataglyphis mauritanica as a model. We obtained genotypes for queens and their male mates from 338 colonies, and we found that the two lineages present in the study population occurred with equal frequency. Furthermore, analysis of spatial genetic structure revealed strong sex-biased dispersal. Because queens were produced by parthenogenesis and because they dispersed over short distances, there was an extreme level of spatial structuring: a mosaic of patches composed of clonal queens was formed. Males, on the other hand, dispersed over several hundred metres and, thus, across patches, ensuring successful interlineage mating. PMID- 28635970 TI - Expansion of the Tibetan Plateau during the Neogene. AB - The appearance of detritus shed from mountain ranges along the northern margin of the Tibetan Plateau heralds the Cenozoic development of high topography. Current estimates of the age of the basal conglomerate in the Qaidam basin place this event in Paleocene-Eocene. Here we present new magnetostratigraphy and mammalian biostratigraphy that refine the onset of basin fill to ~25.5 Myr and reveal that sediment accumulated continuously until ~4.8 Myr. Sediment provenance implies a sustained source in the East Kunlun Shan throughout this time period. However, the appearance of detritus from the Qilian Shan at ~12 Myr suggests emergence of topography north of the Qaidam occurred during the late Miocene. Our results imply that deformation and mountain building significantly post-date Indo-Asian collision and challenge the suggestion that the extent of the plateau has remained constant through time. Rather, our results require expansion of high topography during the past 25 Myr. PMID- 28635971 TI - Exercise Among Women With Ovarian Cancer: A Feasibility and Pre-/Post-Test Exploratory Pilot Study. AB - PURPOSE/OBJECTIVES: To establish the feasibility and acceptability of completing a higher dose of the planned physical activity volume among women with ovarian cancer, including those undergoing active treatment. ?. DESIGN: A pre-/post-test exercise intervention. All participants were asked to complete 225 minutes per week of physical activity for 26 weeks. Multiple supports were provided, including exercise DVDs, self-reported logs, and an objective physical activity tracker (Fitbit(r)).?. SETTING: Home-based exercise intervention with in-person training and telephone follow-ups.?. SAMPLE: 10 women with ovarian cancer who were treated within Penn Medicine in Philadelphia, Pennsylvania.?. METHODS: Home based, in-person exercise counseling was provided by an exercise trainer weekly for the first six weeks and then monthly for a total of 26 weeks. Weekly follow up telephone calls were used to assess exercise adherence and barriers to completing exercise, review symptom changes, and provide behavioral support. ?. MAIN RESEARCH VARIABLES: Feasibility and acceptability.?. FINDINGS: Eight participants completed the study and achieved at least 80% of the prescribed exercise dose. Five participants were undergoing chemotherapy simultaneously. Participants experienced no adverse events during the 26-week intervention. Compared to baseline, average steps increased by 1,593 per day and moderate intensity physical activity increased by 15 minutes per day. ?. CONCLUSIONS: A 225-minutes-per-week exercise program is feasible and acceptable in a population of patients with ovarian cancer. Participants significantly improved their physical activity during the 26-week intervention.?. IMPLICATIONS FOR NURSING: The findings suggest that nursing professionals could recommend that women with ovarian cancer exercise 225 minutes per week regardless of cancer and/or treatment trajectory. For those experiencing aches and pains, behavioral supports and suggestions of a lower exercise dose are needed to maintain physical activity. PMID- 28635972 TI - Experiences and Concerns of Lesbian, Gay, or Bisexual Survivors of Colorectal Cancer. AB - PURPOSE/OBJECTIVES: To identify the experiences and needs of lesbian, gay, or bisexual (LGB) survivors of colorectal cancer (CRC) and to expand the current understanding of LGB survivorship by obtaining in-depth knowledge of survivorship among individuals with a cancer other than breast or prostate. ?. RESEARCH APPROACH: Qualitative, semistructured individual interviews via telephone.?. SETTING: Participants were recruited using social media, flyers, word of mouth, and contact with LGB and cancer organizations during a four-month period.?. PARTICIPANTS: Eight LGB individuals with a diagnosis of stage III CRC from 2009 2014. ?. METHODOLOGIC APPROACH: All interviews were audio recorded and then transcribed verbatim. Thematic analysis performed by more than one analyst was used for the interview transcripts. ?. FINDINGS: Participants described experiences with social support and isolation, cancer care from an LGB perspective, and substantial economic impacts of their cancer diagnosis. In addition, they reported struggles with health insurance coverage, employment, and housing during and after their treatment for CRC. ?. CONCLUSIONS: In addition to issues regarding sexual identity disclosure and social support, economic impacts of CRC exist; these are likely critical to healthy survivorship in LGB men and women. ?. INTERPRETATION: Attention should be paid to the economic impact of CRC on LGB individuals, along with issues of social support and sexual identity disclosure. Oncology nurses could play an important role in determining the economic and social needs of patients with CRC, accepting the often nontraditional support networks of LGB individuals, and facilitating disclosure of an LGB identity. PMID- 28635974 TI - Conceptual Issues Surrounding Quality of Life in Oncology Nursing. AB - Quality of life (QOL) is a critical, prevalent, and enduring concept in oncology nursing research and practice. QOL is a paramount issue in the consideration of treatment, goal planning, and decision making for individuals with cancer, their families, and their care providers. Journals, well-developed valid and reliable instruments, and multiple conceptual models and frameworks are devoted to QOL. This column will review two broad conceptual aspects to consider in relation to QOL. First, conceptual considerations will be discussed for the definition and measurement of QOL. Second, conceptual issues related to QOL as an outcome will be discussed. PMID- 28635973 TI - Deconstructing Decisions to Initiate, Maintain, or Discontinue Adjuvant Endocrine Therapy in Breast Cancer Survivors: A Mixed-Methods Study. AB - PURPOSE/OBJECTIVES: Adjuvant endocrine therapy (AET) has been shown to improve survival in hormone receptor-positive breast cancer survivors, but as many as half do not complete recommended treatment. Management of medication-related side effects and engagement with providers are two potentially modifiable factors, but their associations with adherence are not well understood. The aims were to build on survey results to qualitatively explore survivors' experiences with prescribed AET to (a) describe appraisal and management of AET side effects and (b) deconstruct decisions to initiate, discontinue, or maintain AET.?. RESEARCH APPROACH: The authors used a mixed-methods explanatory sequence research design with a qualitative emphasis.?. SETTING: Survivors were recruited from a clinical cancer registry maintained at the University of Texas Southwestern Medical Center, which includes the Harold C. Simmons Comprehensive Cancer Center (National Cancer Institute-designated), in Dallas.?. PARTICIPANTS: 452 survivors completed a survey, and 30 took part in telephone interviews.?. METHODOLOGIC APPROACH: Qualitative methods were used in which the authors recorded and transcribed interviews for analysis and used open coding to reduce data into themes.?. FINDINGS: Among adherent survivors, the themes of tolerance of side effects and perseverance were strong. Nonadherent survivors expressed more difficulty managing side effects and perceived fewer benefits when side effects were bothersome. The most common side effects mentioned by all survivors were menopausal symptoms and joint pain; less common side effects were cognitive decline and cardiac distress. Some sought advice from their oncology team. Nonadherent survivors appeared initially motivated to maintain AET but identified a tolerance limit for side effects after which a provider's recommendation was less influential in their decision to maintain or discontinue AET.?. INTERPRETATION: This study elucidated adherence as a complex continuum of behaviors, appraisals, and decision points. These insights may be particularly useful in counseling survivors taking AET and promoting timely delivery of clinical interventions to enhance adherence.?. IMPLICATIONS FOR NURSING: Nurses should be involved in the planning and implementation of clinical interventions to manage side effects and other barriers to AET adherence. PMID- 28635975 TI - Our Responsibility to Our Research Participants. AB - As the readers of this journal know all too well, conducting a study takes a lot of time, energy, commitment, and, most of all, work. I do not have to list the myriad steps that need to be taken, often with delays in between, to take a study from good idea to analysis. There are often sweat and tears, if not blood, and, at the end of the process, there may be exhaustion. Then the piles of paper and data-rich files languish on a desk or computer, never to see the light of day. Or, perhaps, a manuscript is written and submitted and then rejected or needs extensive revision. And it languishes again. Many of us have been in this position and remember what that rejection felt like and how hard it was to revise and submit again, or not.?. PMID- 28635976 TI - Supporting Change in Oncology Nursing Practice in Kuwait. AB - As countries around the world struggle to provide oncology care and treatment to their populations, nurses, as the largest healthcare workforce, are faced with the challenge of obtaining, maintaining, and developing specialized oncology nursing knowledge and expertise. Strategies that can be deployed at a local level to support nurses with integrating new knowledge into practice are important in meeting and overcoming this challenge. This article describes a theory-based model for implementing oncology nursing best practices in the Middle Eastern country of Kuwait. ?. PMID- 28635977 TI - Chemotherapy-Induced Peripheral Neuropathy Assessment Tools: A Systematic Review. AB - PROBLEM IDENTIFICATION: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting chemotherapy toxicity, which has a long-lasting effect and decreases quality of life. Although several tools have been developed to detect CIPN, the study quality, psychometric properties, and practicality of CIPN assessment tools have not been systematically reviewed.?. LITERATURE SEARCH: Electronic searches using keywords were conducted in Medline, PubMed, CINAHL(r), and Cochrane Library for articles published from 1980-2015. Eligible studies were included if they involved patients with cancer receiving chemotherapy, provided CIPN assessment tools with psychometric properties, and were published in English.?. DATA EVALUATION: Data were extracted, and study quality was assessed. CIPN tools were evaluated in terms of psychometric properties and practicality.?. SYNTHESIS: A total of 19 studies describing 20 tools were reviewed. The quality of studies varied from strong to weak. The validity ranged from low to high, and the reliability with internal consistency ranged from 0.56-0.96. Poor inter-rater agreement was found. Not all of the tools were deemed practical.?. CONCLUSIONS: Considering the psychometric properties and practicality, two tools (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG Ntx] and Total Neuropathy Score [TNS]) are recommended for assessing CIPN.?. IMPLICATIONS FOR NURSING: Routine assessment of CIPN and choosing appropriate assessment tools are imperative. The FACT/GOG-Ntx and TNS are recommended for clinical use. PMID- 28635978 TI - Vaginal Testosterone for Management of Aromatase Inhibitor-Related Sexual Dysfunction: An Integrative Review. AB - PROBLEM IDENTIFICATION: Women taking aromatase inhibitors (AIs) as part of the management of hormone receptor-positive breast cancer experience more symptoms of sexual dysfunction, including vaginal atrophy, as opposed to postmenopausal women and women treated with tamoxifen (Nolvadex(r)). Vaginal testosterone could be an alternative to estrogen, which is contraindicated in this population.?. LITERATURE SEARCH: A systematic review was completed by searching PubMed and Scopus databases.?. DATA EVALUATION: 64 search results were reduced to a final sample of 3 articles after applying inclusion and exclusion criteria.?. SYNTHESIS: Published results suggest that vaginally applied testosterone doses of 150 mcg and 300 mcg improve symptoms of sexual dysfunction in women taking AIs. Minimal side effects are observed, and estradiol levels are not affected by vaginally applied testosterone. Additional research is needed to evaluate vaginal testosterone in women taking AIs.?. CONCLUSIONS: Vaginal testosterone shows preliminary promise as an option to manage sexual side effects of AI therapy in postmenopausal cancer survivors; however, available data are too limited to draw practice-changing conclusions.?. IMPLICATIONS FOR RESEARCH: Large-scale randomized, controlled trials need to be completed to evaluate the efficacy and safety of vaginal testosterone in women taking AIs. PMID- 28635979 TI - Response to "Patient-Inspired Research: A Better Way to Go?" AB - I would like to thank Anne Katz for her thoughtful editorial on the importance of patient opinion in defining research questions. Nurse researchers choose to study specific topics for a variety of reasons. These reasons often relate to research funding priorities. It costs a lot of money to do research; topics may be chosen not because they are necessarily the passion of the researcher, but because that is where the funding dictates.?. PMID- 28635980 TI - Improving Self-Efficacy and Self-Care in Adult Patients With a Urinary Diversion: A Pilot Study. AB - PURPOSE/OBJECTIVES: To evaluate the feasibility and acceptability of a multimodality educational intervention for improving self-efficacy (SE) and self care in patients with a new urinary diversion (UD).?. DESIGN: Two-arm randomized, controlled trial.?. SETTING: Academic medical center in New York.?. SAMPLE: 8 adults diagnosed with bladder cancer requiring UD.?. METHODS: A multimodality educational intervention consisting of video, Microsoft PowerPoint(r) slides, and medical illustrations was developed. SE was assessed pre- and postintervention related to care of the UD. Education scale scores provided evidence for intervention acceptability and assessment of UD self-care skills.?. MAIN RESEARCH VARIABLES: Feasibility, acceptability, results of SE, and self-care scales.?. FINDINGS: Enrollment and retention was 100%. All participants took part in every aspect of the study. No issues were apparent with administration of the study; however, a lack of self-care independence was noted between the study arms. The control group was younger in age than the intervention group.?. CONCLUSIONS: A supplemental multimethod educational intervention is acceptable in this population and feasible to integrate into hospital care or into an appropriately powered study.?. IMPLICATIONS FOR NURSING: A need exists for ongoing postdischarge support and education in this population. Additional studies are needed to determine the best approach for this. PMID- 28635981 TI - Patient-Perceived Access to Care When Actively Seeking Treatment. AB - PURPOSE/OBJECTIVES: To examine predictors of perceived access to care and reported barriers to care of patients with cancer actively seeking treatment.?. DESIGN: Retrospective secondary data analysis.?. SETTING: U.S. Medical Expenditure Panel Survey, a national survey with questions about healthcare coverage and access.?. SAMPLE: 1,170 adults with cancer actively seeking treatment.?. METHODS: A retrospective analysis of data. Bivariate tests for significant association between individual characteristics and low perceived access to care were conducted using a chi-square test. ?. MAIN RESEARCH VARIABLES: The dependent variable was perceived access to care. The independent variables included sex, age, race, poverty status, education level, marital status, cancer site, comorbidities, and insurance status.?. FINDINGS: Those with Medicaid insurance or no health insurance had significantly lower perceived access to care compared to those with Medicare. Institutional barriers to treatment, such as financial or insurance, were the most common reported barriers.?. CONCLUSIONS: Most adults with cancer reported adequate access to medical care and medications, but a small yet vulnerable population expressed difficulties in accessing treatment.?. IMPLICATIONS FOR NURSING: To effectively advocate for vulnerable populations with Medicaid or no insurance, nurses may require specialized knowledge beyond the scope of general oncology nursing. PMID- 28635982 TI - Research Ethics in Big Data. AB - The ethical conduct of research includes, in part, patient agreement to participate in studies and the protection of health information. In the evolving world of data science and the accessibility of large quantities of web-based data created by millions of individuals, novel methodologic approaches to answering research questions are emerging. This article explores research ethics in the context of big data. PMID- 28635983 TI - Risk Factors for Re-Excision Following Breast-Conserving Surgery. AB - PURPOSE/OBJECTIVES: To identify previously unstudied factors predicting re excision following breast-conserving surgery (BCS) and to assess the feasibility of obtaining data about breast density for predictive modeling.?. DESIGN: Retrospective secondary data analysis.?. SETTING: Data were obtained from the cancer registry and electronic health records (EHRs) at Texas Health Harris Methodist Hospital, a large, urban, private, nonprofit hospital in North Texas.?. SAMPLE: 244 patients choosing BCS from 2011-2012.?. METHODS: Data were subjected to univariate analyses (chi-square) followed by logistic regression.?. MAIN RESEARCH VARIABLES: The primary dependent variable was re-excision following BCS. Predictors of interest included lifestyle factors, time from diagnosis to surgery, surgical approach, patient age, and breast density, and controlled for covariates, such as assay results.?. FINDINGS: Three factors predicted re excision with 87% accuracy. CONCLUSIONS: Women younger than 60 years whose surgery included placement of a wire for localization of tissue to be removed and who underwent surgery soon after diagnosis are the least likely to require reoperation after BCS. Data integrity is critical to the success of research using EHRs and registry information.?. IMPLICATIONS FOR NURSING: Nurses may improve patient outcomes by helping women considering BCS solve problems that may delay surgery. Nurses can contribute to the success of nursing research by thoroughly and accurately recording patient information in EHRs. PMID- 28635984 TI - Anxiety and Depression Associated With Burden in Caregivers of Patients With Brain Metastases. AB - PURPOSE/OBJECTIVES: To describe and examine the relationship between caregiver burden and the affective disorders anxiety and depression in caregivers of patients with brain metastases.?. DESIGN: Cross-sectional, descriptive, correlational.?. SETTING: Moores Cancer Center at the University of California, San Diego. ?. SAMPLE: 56 family caregivers of patients with brain metastases from solid tumors at other primary sites.?. METHODS: Self-administered survey.?. MAIN RESEARCH VARIABLES: Caregiver burden, anxiety, and depression.?. FINDINGS: With the exception of caregiver esteem, no statistically significant relationships were noted between impact on schedule, a dimension of caregiver burden, and screening positive for affective disorders.?. CONCLUSIONS: Findings from this study support previous reports indicating that the odds of having anxiety and depressive symptoms are greater in family caregivers who report higher levels of caregiver burden.?. IMPLICATIONS FOR NURSING: The identification and management of caregiver burden are important considerations for a comprehensive cancer care program. Addressing the needs of the cancer caregiver, who is at heightened risk for various psychological, physical, financial, and social problems, is increasingly vital. PMID- 28635985 TI - Experiences of Women With Gestational Trophoblastic Neoplasia Treated With High Dose Chemotherapy and Stem Cell Transplantation: A Qualitative Study. AB - PURPOSE/OBJECTIVES: To explore the experiences of women with gestational trophoblastic neoplasia during and after treatment to understand their perspectives, priorities, and concerns.?. RESEARCH APPROACH: A descriptive, exploratory study using in-depth semistructured interviews.?. SETTING: All interviews were conducted in a quiet, designated room at Weston Park Hospital in Sheffield, South Yorkshire.?. PARTICIPANTS: Women with gestational trophoblastic neoplasia who had received stem cell transplantation from 2003 to 2013. Ten patients were eligible, and eight agreed to participate.?. METHODOLOGIC APPROACH: Interviews were carried out over the phone and were recorded and transcribed verbatim. Framework analysis was carried out to generate in-depth descriptions of participants' experiences.?. FINDINGS: Participants described significant physical, psychological, and social effects during and following treatment. Recovery was slow, and treatment had long-term effects on sexuality and body image. The impact of the women's diagnosis and treatment on their children was a primary concern.?. INTERPRETATION: The study provided insight into the multidimensional impact of stem cell transplantation, which can continue after treatment. The need for family-centered services for patients with dependent children was identified.?. IMPLICATIONS FOR NURSING: Nurses need to develop services that effectively communicate the challenges of stem cell transplantation to patients and provide family-centered care and late effects and rehabilitation services. PMID- 28635986 TI - Optimism, Symptom Distress, Illness Appraisal, and Coping in Patients With Advanced-Stage Cancer Diagnoses Undergoing Chemotherapy Treatment. AB - PURPOSE/OBJECTIVES: To explore the relationships between optimism, self-efficacy, symptom distress, treatment complexity, illness appraisal, coping, and mood disturbance in patients with advanced-stage cancer.?. DESIGN: Cross-sectional study.?. SETTING: Smilow Cancer Hospital at Yale New Haven in Connecticut, an outpatient comprehensive cancer center.?. SAMPLE: A convenience sample of 121 adult patients with stages III-IV cancer undergoing active chemotherapy.?. METHODS: Participants completed common self-report questionnaires to measure variables. Treatment hours and visits were calculated from data retrieved from medical record review. Mediation and path analysis were conducted to identify direct and indirect pathways from the significant antecedent variables to mood disturbance.?. MAIN RESEARCH VARIABLES: Dispositional optimism, self-efficacy, social support, treatment complexity, symptom distress, illness appraisal, coping, and mood disturbance.?. FINDINGS: Greater optimism and self-efficacy were associated with less negative illness appraisal, less avoidant coping, and decreased mood disturbance. Conversely, greater symptom distress was associated with greater negative illness appraisal, greater avoidant coping, and greater mood disturbance. In the final model, optimism and symptom distress had direct and indirect effects on mood disturbance. Indirect effects were partially mediated by illness appraisal.?. CONCLUSIONS: Mood disturbance resulted from an interaction of disease stressors, personal resources, and cognitive appraisal of illness. Avoidant coping was associated with greater disturbed mood, but neither avoidant nor active coping had a significant effect on mood in the multivariate model. ?. IMPLICATIONS FOR NURSING: Illness appraisal, coping style, and symptom distress are important targets for intervention. Optimism is a beneficial trait and should be included, along with coping style, in comprehensive nursing assessments of patients with cancer. PMID- 28635987 TI - Integrative Review of Facility Interventions to Manage Compassion Fatigue in Oncology Nurses. AB - PROBLEM IDENTIFICATION: Oncology nurses are regularly exposed to high-stress situations that may lead to compassion fatigue, and many institutions have implemented interventions to reduce burnout in nurses, but knowledge on the feasiblity, effectiveness, and nurses' experience of interventions is lacking.?. LITERATURE SEARCH: Electronic search of literature published from 1992-2015 was performed to evaluate in-facility interventions to manage compassion fatigue in oncology nurses. Databases used included CINAHL(r), PubMed, Web of Science, Google Scholar, and PsycINFO(r). ?. DATA EVALUATION: The goal was to evaluate the effectiveness, feasibility, and nurses' experience of interventions to manage compassion fatigue. The study designs, methods, and limitations were independently screened by the authors. ?. SYNTHESIS: Of 164 studies, 31 met eligibility criteria. ?. CONCLUSIONS: The majority of the studies were conducted in Western countries, which suggests the need for additional research in other settings to determine effective interventions that address compassion fatigue and stress cross-culturally. Quantitative and qualitative studies failed to gain high scores in terms of quality. Limited conclusions can be drawn from small studies that report on outcomes with many confounding variables, such as turnover rate or general health of nurses, from a single institution. ?. IMPLICATIONS FOR RESEARCH: Lack of empirical precision in evaluating the effectiveness, feasibility, and nurses' experiences of interventions indicates a need for future, more rigorously designed experimental studies. Because of the global increase in the number of patients being diagnosed and living with cancer, oncology nurses should be able to recognize and manage compassion fatigue. PMID- 28635988 TI - Salivary epithelial-myoepithelial carcinoma: clinical, morphological and molecular features. AB - Epithelial-myoepithelial carcinoma (EMC) is a rare biphasic tumor accounting for less than 2% of all salivary gland malignancies. It presents as a slowly growing, asymptomatic small size mass, with ulceration of overlying mucosa in some cases. Microscopically, it is characterized by glands lined by the simultaneous presence of two different cell components, inner epithelial cells and outer myoepithelial cells. Immunohistochemical staining of myoepithelial cells is variably positive for vimentin, Smooth Muscle Actin (SMA), Muscle Specific Actin (MSA), S100, Smooth Muscle Myosin Heavy Chain I(SM-MHC), calponin and p63. Several molecular alterations, mainly point mutations, have been described. Mutations of HRAS, AKT1, CTNNB1 and PIK3CA were highlighted in variable percentage of EMC samples. EMC is considered a low-grade malignant tumor with a 5-year survival rate of 94% that may commonly recur locally after resection in 30-50% of cases. At the moment, adequate resection with negative margins is the minimum recommended and necessary treatment. PMID- 28635989 TI - Sinonasal tumor pathology: what's new? AB - The sinonasal tract is an anatomical region affected by a wide variety of tumors with different clinical behavior, histologic and molecular features. Substantial advances have been made in the field of sinonasal tumor pathology in recent years, including improvement in the diagnosis, treatment and genetic characterization. In this article, a review of the histological features of new distinctive pathologic entities as well as newly described molecular alterations of these rare tumors is presented. PMID- 28635990 TI - Neuroendocrine neoplasms of the head and neck and olfactory neuroblastoma. Diagnosis and classification. AB - Neuroendocrine neoplasms (NENs) of the head and neck are a rare group of heterogeneous epithelial neoplastic proliferations arising in virtually all of the different organs of this region, particularly in the nasal cavity, the paranasal sinuses, the nasopharynx, the larynx, the salivary glands, and the middle ear. They encompass a wide spectrum of entities ranging from very indolent neuroendocrine tumors to highly aggressive neuroendocrine carcinomas. They may represent a challenge for radiologists, oncologists, and pathologists and a correct diagnosis is crucial for the management of patients. The nomenclature and classification of cervicocephalic NENs is currently under debate and for this reason a different diagnostic terminology has been used over the years, creating confusions among clinicians and pathologists. Olfactory neuroblastoma is a rare neuroectodermal neoplasm arising in the nasal cavity showing some challenging diagnostic aspects. In this review we give an update of the more relevant criteria for diagnosing head and neck NENs and olfactory neuroblastomas focusing on the critical use of morphological parameters and immunohistochemical staining. PMID- 28635991 TI - The papillomas of the sinonasal tract. A comprehensive review. AB - Papillomas are uncommon tumors of the sinonasal tract histologically derived from the Schneiderian membrane. Three distinctive variants are described, the exophytic, the inverting and the oncocytic types. On physical examination, their appearance varies from exophytic-fungiform seen in the exophytic variant, to polypoid-papillary in both the inverting and oncocytic variant. The presence of an asymptomatic mass or epistaxis and unilateral nasal obstruction are the typical presenting symptoms. Clinically they tend to recur and, although benign, they may erode the bone laminas by pressure, especially the inverting type, causing proptosis and other co-morbidities. Malignant transformation is seen both synchronously, on a pre-existing papilloma, and metachronously after several recurrences of papilloma. Schneiderian papillomas are at a date a topic of controversy regarding their etiology, pathogenesis and biological behavior. Furthermore, histologic criteria to assess dysplasia and malignant transformation are ill-defined. The present study aims to comparatively review the histologic types of papillomas, their etiology, the currently available criteria for malignant transformation, their treatment and prognosis. PMID- 28635992 TI - Odontogenic tumors: a retrospective clinicopathological study from two Italian centers. AB - Objective: The aim of this retrospective study was to perform an epidemiological analysis of all odontogenic tumors treated in the University Hospitals "Ospedali Riuniti" in Ancona and "Policlinico" in Bari, from 1990 to 2015. Materials and methods: A retrospective survey of 277 patients treated for odontogenic tumors from 1990 to 2015 was performed. Data were retrieved from the archives of the above quoted Sections of Pathology. The lesions were classified according to 2005 WHO histological classification, and the following variables were analyzed: age, sex, histopathological diagnosis, site distribution, tumor size, and relapses. Peripheral odontogenic tumors were analyzed considering these lesions separately from their central counterparts. Results: In a total of 344 surgical specimens, there were 277 primary tumors and 67 recurrences. As regards primary lesions, there were 185 odontogenic keratocysts (keratocystic odontogenic tumors) (66.8%), 49 ameloblastomas (17.7%), and 40 other benign odontogenic tumors (14.4%). As to malignant tumors, only 3 ameloblastic carcinomas were found (1.1%). The mean age was 46.7 years, with a M:F ratio of 1.8:1. The mandible was the most common site of localization, with 211 cases (76.2%). Also, 21 cases of peripheral odontogenic tumors were found, ameloblastomas being the most common (8 cases, 38.1%). Conclusions: There is a wide variety of cysts, some of which are subject to variations according to sex, localization, and age. Odontogenic tumors are rare neoplasms and appear to show variations according to sex, localization, and age, and may be useful to the clinicians who need to make clinical judgments before biopsy about the most probable diagnosis. PMID- 28635993 TI - Head and neck vascular anomalies. A multidisciplinary approach and diagnostic criteria. AB - Vascular anomalies represent a heterogeneous group of pathologies of the circulatory system that can affect any type of hematic and /or lymphatic vessel of different diameter or anatomic site. The extreme variability of tissue types and districts involved by these lesions determines a wide heterogeneity of clinical manifestations, resulting in involvement of different medical expertise. In this context, a commonly agreed terminology is crucial for the appropriate evaluation and multidisciplinary management of patients. The ISSVA Classification that has its roots in the previous Classification of Mulliken and Glowacky distinguishes vascular anomalies in two main groups: vascular tumors and vascular malformations. In head and neck, where vascular anomalies are the most common benign lesions of infancy and childhood, correct diagnosis with the use of unequivocal terminology is more crucial for treatment considering the relevance of structures that can be involved. The aim of this work has been to clarify information and knowledges currently available in the field of vascular anomalies. Referring to ISSVA Classification, clinico- histopathological aspects of each entity have been elucidated. PMID- 28635994 TI - Oral field cancerization: history and future perspectives. AB - Notwithstanding extended surgical approaches or adjuvant chemoradiotherapy, the development of multiple neoplastic lesions arising in the oral cavity after treatment still represents a critical clinical challenge in the management of patients with oral squamous cell carcinoma. Such clinical behavior of oral squamous cell carcinoma is nowadays better known as "field" cancerization effect as suggested by Slaughter, the author that for the first time tried to describe it in a scientific paper. Field cancerization is now widely accepted not only in head and neck oncology but also in other anatomical districts as well as in different types of epithelial neoplasia. A brief history of the theory of field cancerization is here proposed and future perspectives deriving from new molecular techniques are discussed. PMID- 28635995 TI - Open access publication in the fields of human fertility, infertility and early pregnancy. AB - The study of human fertility has expanded dramatically since the birth of IVF and with it, the body of literature. That said, the availability of open access publication in the field remains somewhat limited. Fertility Research and Practice offers a new open access, peer-reviewed venue for quality clinical, basic science and translational studies and scholarly reviews in human fertility, infertility and early pregnancy. The journal specifically encourages works from international contributors and from investigators in less-resourced environments and has gathered an editorial board with a breadth of geographic representation to support this mission. PMID- 28635996 TI - Reply to Engelthaler and Meyer, "Furthering the Continental Drift Speciation Hypothesis in the Pathogenic Cryptococcus Species Complexes". PMID- 28635997 TI - A spin column-free approach to sodium hydroxide-based glycan permethylation. AB - Glycan permethylation was introduced as a tool to facilitate the study of glycans in 1903. Since that time, permethylation procedures have been continually modified to improve permethylation efficiency and qualitative applicability. Typically, however, either laborious preparation steps or cumbersome and uneconomical spin columns have been needed to obtain decent permethylation yields on small glycan samples. Here we describe a spin column-free (SCF) glycan permethylation procedure that is applicable to both O- and N-linked glycans and can be employed upstream to intact glycan analysis by MALDI-MS, ESI-MS, or glycan linkage analysis by GC-MS. The SCF procedure involves neutralization of NaOH beads by acidified phosphate buffer, which eliminates the risk of glycan oxidative degradation and avoids the use of spin columns. Optimization of the new permethylation procedure provided high permethylation efficiency for both hexose (>98%) and HexNAc (>99%) residues-yields which were comparable to (or better than) those of some widely-used spin column-based procedures. A light vs. heavy labelling approach was employed to compare intact glycan yields from a popular spin-column based approach to the SCF approach. Recovery of intact N-glycans was significantly better with the SCF procedure (p < 0.05), but overall yield of O glycans was similar or slightly diminished (p < 0.05 for tetrasaccharides or smaller). When the SCF procedure was employed upstream to hydrolysis, reduction and acetylation for glycan linkage analysis of pooled glycans from unfractionated blood plasma, analytical reproducibility was on par with that from previous spin column-based "glycan node" analysis results. When applied to blood plasma samples from stage III-IV breast cancer patients (n = 20) and age-matched controls (n = 20), the SCF procedure facilitated identification of three glycan nodes with significantly different distributions between the cases and controls (ROC c statistics > 0.75; p < 0.01). In summary, the SCF permethylation procedure expedites and economizes both intact glycan analysis and linkage analysis of glycans from whole biospecimens. PMID- 28635998 TI - Heterogeneous catalytic hydrogenation of CO2 by metal oxides: defect engineering perfecting imperfection. AB - Metal oxides with their myriad compositions, structures and bonding exhibit an incredibly diverse range of properties. It is however the defects in metal oxides that endow them with a variety of functions and it is the ability to chemically tailor the type, population and distribution of defects on the surface and in the bulk of metal oxides that delivers utility in different applications. In this Tutorial Review, we discuss how metal oxides with designed defects can be synthesized and engineered, to enable heterogeneous catalytic hydrogenation of gaseous carbon dioxide to chemicals and fuels. If this approach to utilization and valorization of carbon dioxide could be developed at industrially significant rates, efficiencies and scales and made economically competitive with fossil based chemicals and fuels, then carbon dioxide refineries envisioned in the future would be able to contribute to the reduction of greenhouse gas emissions, ameliorate climate changes, provide energy security and enable protection of the environment. This would bring the vision of a sustainable future closer to reality. PMID- 28635999 TI - Carbon dots promoted vanadium flow batteries for all-climate energy storage. AB - We report a one-pot solvothermal method to prepare a carbon dots decorated graphite felt (CDs/GF) electrode. The resulting CDs/GF shows excellent wettability and greatly enhanced activity towards vanadium redox couples. VFB with the CDs/GF electrode exhibits outstanding rate performance, superior cycling stability, and broad temperature adaptability from -20 to 60 degrees C. PMID- 28636001 TI - WatAA: Atlas of Protein Hydration. Exploring synergies between data mining and ab initio calculations. AB - Water molecules represent an integral part of proteins and a key determinant of protein structure, dynamics and function. WatAA is a newly developed, web-based atlas of amino-acid hydration in proteins. The atlas provides information about the ordered first hydration shell of the most populated amino-acid conformers in proteins. The data presented in the atlas are drawn from two sources: experimental data and ab initio quantum-mechanics calculations. The experimental part is based on a data-mining study of a large set of high-resolution protein crystal structures. The crystal-derived data include 3D maps of water distribution around amino-acids and probability of occurrence of each of the identified hydration sites. The quantum mechanics calculations validate and extend this primary description by optimizing the water position for each hydration site, by providing hydrogen atom positions and by quantifying the interaction energy that stabilizes the water molecule at the particular hydration site position. The calculations show that the majority of experimentally derived hydration sites are positioned near local energy minima for water, and the calculated interaction energies help to assess the preference of water for the individual hydration sites. We propose that the atlas can be used to validate water placement in electron density maps in crystallographic refinement, to locate water molecules mediating protein-ligand interactions in drug design, and to prepare and evaluate molecular dynamics simulations. WatAA: Atlas of Protein Hydration is freely available without login at . PMID- 28636002 TI - Electronic structure and time-dependent description of rotational predissociation of LiH. AB - The adiabatic potential energy curves of the 1Sigma+ and 1Pi states of the LiH molecule were calculated. They correlate asymptotically to atomic states, such as 2s + 1s, 2p + 1s, 3s + 1s, 3p + 1s, 3d + 1s, 4s + 1s, 4p + 1s and 4d + 1s. A very good agreement was found between our calculated spectroscopic parameters and the experimental ones. The dynamics of the rotational predissociation process of the 11Pi state were studied by solving the time-dependent Schrodinger equation. The classical experiment of Velasco [Can. J. Phys., 1957, 35, 1204] on dissociation in the 11Pi state is explained for the first time in detail. PMID- 28636005 TI - Mass, mobility and MSn measurements of single ions using charge detection mass spectrometry. AB - Charge detection mass spectrometry is used to measure the mass, charge, MSn and mobility of an individual ion produced by electrospray ionization of a 8 MDa polyethylene glycol sample. The charge detection mass spectrometer is an electrostatic ion trap that uses cone electrodes and a single tube detector and can detect ions for up to the full trapping time of 4.0 s. The time-domain signal induced on the detector tube by a single multiply charged ion can be complex owing to sequential fragmentation of the original precursor ion as well as increasing oscillation frequencies of the single ion owing to collisions with background gas that reduce the kinetic energy of the ion inside the trap. Simulations show that the ratio of the time for the ion to turn around inside the cone region of the trap to the time for the ion to travel through the detector tube is constant with m/z and increases with the ion energy per charge. By measuring this ratio, the kinetic energy of an ion can be obtained with good precision (~1%) and this method to measure ion kinetic energies eliminates the necessity of ion energy selection prior to trapping for high precision mass measurement of large molecules in complex mixtures. This method also makes it possible to measure the masses of each sequential fragment ion formed from the original precursor ion. MS7 of a single multiply charged PEG molecule is demonstrated, and from these ion energy measurements and effects of collisions on the ion motion inside the trap, information about the ion mobility of the precursor ion and its fragments is obtained. PMID- 28636003 TI - In vitro modulation of gut microbiota by whey protein to preserve intestinal health. AB - The effect of several types of whey milk - cow, sheep, goat and a mixture of them (60 : 20 : 20, respectively) - was assessed in the human gut microbiota. The prebiotic potential of these substrates was evaluated through in vitro gastrointestinal digestion following faecal batch culture fermentations (mimicking colonic fermentation) for 48 hours, using faeces from normal-weight (NW) and obese (OB) donors. Throughout the fermentation process, pH, gas production, short chain and branched fatty acids (SCFA-BCFA) were measured, as well as the changes of microbiota using qPCR. The pH decreased in all whey samples during the fermentation process. Gas production was higher in all whey samples than in controls, especially at 12 hours (p < 0.05). The diversity of SCFA and BCFA production was significantly different between the donors, in particular cow and mixed whey. Whey milk had a strong prebiotic effect on the gut microbiota of NW and OB donors, showing a significant increase of Bifidobacterium (p < 0.05) with cow, sheep and mixed whey and increase in the Lactobacillus group, particularly in OB donors. Bacteria associated with obesity did not show an increase in any of the groups of donors. Therefore, supplementing a diet with these types of whey can selectively stimulate the growth of probiotic bacteria, enhancing SCFA production, which could improve intestinal disorders. In addition, it may be an interesting approach to the prevention of overweight and obesity and related diseases. Whey milk has a potent prebiotic effect. It can selectively stimulate desirable bacteria and SCFA profile, in both OB and NW donors, contributing to improved intestinal health and reducing obesity. PMID- 28636006 TI - Copper ion interaction with the RNase catalytic site fragment of the angiogenin protein: an experimental and theoretical investigation. AB - The angiogenin protein (Ang) is a member of the vertebrate-specific secreted ribonucleases and one of the most potent angiogenic factors known. Ang is a normal constituent of human plasma and its concentration increases under some physiological and pathological conditions to promote neovascularization. Ang was originally identified as an angiogenic tumour factor, but its biological activity has been found to extend from inducing angiogenesis to promoting cell survival in different neurodegenerative diseases. Ang exhibits weak ribonucleolytic activity, which is critical for its biological functions. The RNase catalytic sites are two histidine residues, His-13 and His-114, and the lysine Lys-40. Copper is also an essential cofactor in angiogenesis and influences angiogenin's biological properties. The main Cu(ii) anchoring site of Ang is His-114, where metal binding inhibits RNase activity of the protein. To reveal the Cu(ii) coordination environment in the C-terminal domain of the Ang protein, we report on the characterization, by means of potentiometric, voltammetric, and spectroscopic (CD, UV-Vis and EPR) methods and DFT calculations, of Cu(ii) complexes formed with a peptide fragment including the Ang sequence 112-117 (PVHLDQ). Potentiometric titrations indicated that [CuLH-2] is the predominant species at physiological pH. EPR, voltammetric data and DFT calculations are consistent with a CuN3O2 coordination mode in which a distorted square pyramidal arrangement of the peptide was observed with the equatorial positions occupied by the nitrogen atoms of the deprotonated amides of the Asp and Leu residues, the delta-N atom of histidine and the oxygen atom of the aspartic carboxylic group. Moreover, two analogous peptides encompassing the PVHLNQ and LVHLDQ sequences were also characterized by using thermodynamic, spectroscopic and DFT studies to reveal the role they play in Cu(ii) complex formation by the carboxylate side chain of the Asp and Pro residues, a known breaking-point in metal coordination. PMID- 28636007 TI - Analysis of association of gene variants with obesity traits in New Zealand European children at 6 years of age. AB - Childhood obesity is a public health problem, which is associated with a long term increased risk of cardiovascular disease and premature mortality. Several gene variants have previously been identified that have provided novel insights into biological factors that contribute to the development of obesity. As obesity tracks through childhood into adulthood, identification of the genetic factors for obesity in early life is important. The objective of this study was to identify putative associations between genetic variants and obesity traits in children at 6 years of age. We recruited 1208 children of mothers from the New Zealand centre of the international Screening for Pregnancy Endpoints (SCOPE) study. Eighty common genetic variants associated with obesity traits were evaluated by the Sequenom assay. Body mass index standardised scores (BMI z scores) and percentage body fat (PBF; measured by bio-impedance assay (BIA)) were used as anthropometric measures of obesity. A positive correlation was found between BMI z-scores and PBF (p < 0.001, r = 0.756). Two subsets of gene variants were associated with BMI z-scores (HOXB5-rs9299, SH2B1-rs7498665, NPC1-rs1805081 and MSRA-rs545854) and PBF (TMEM18-rs6548238, NPY-rs17149106, ETV-rs7647305, NPY rs16139, TIMELESS-rs4630333, FTO-rs9939609, UCP2-rs659366, MAP2K5-rs2241423 and FAIM2-rs7138803) in the genotype models. However, there was an absence of overlapping association between any of the gene variants with BMI z-scores and PBF. A further five variants were associated with BMI z-scores (TMEM18-rs6548238, FTO-rs9939609 and MC4R-rs17782313) and PBF (SH2B1-rs7498665 and FTO-rs1421085) once separated by genetic models (additive, recessive and dominant) of inheritance. This study has identified significant associations between numerous gene variants selected on the basis of prior association with obesity and obesity traits in New Zealand European children. PMID- 28636008 TI - Highly efficient electroluminescent PtII ppy-type complexes with monodentate ligands. AB - Functional PtII ppy-type complexes (ppy = 2-phenylpyridine anion) with pyridine and chloride monodentate ligands are prepared, which show high electroluminescence efficiencies. PMID- 28636010 TI - Engineering multi-functional bacterial outer membrane vesicles as modular nanodevices for biosensing and bioimaging. AB - Outer membrane vesicles (OMVs) are proteoliposomes derived from the outer membrane and periplasmic space of many Gram-negative bacteria including E. coli as part of their natural growth cycle. Inspired by the natural ability of E. coli to sort proteins to both the exterior and interior of OMVs, we reported here a one-pot synthesis approach to engineer multi-functionalized OMV-based sensors for both antigen binding and signal generation. SlyB, a native lipoprotein, was used a fusion partner to package nanoluciferase (Nluc) within OMVs, while a previously developed INP-Scaf3 surface scaffold was fused to the Z-domain for antibody recruiting. The multi-functionalized OMVs were used for thrombin detection with a detection limit of 0.5 nM, comparable to other detection methods. Using the cohesin domains inserted between the Z-domain and INP, these engineered OMVs were further functionalized with a dockerin-tagged GFP for cancer cell imaging. PMID- 28636013 TI - New insights into the solubility of graphene oxide in water and alcohols. AB - One of the main advantages of graphene oxide (GO) over its non-oxidized counterpart is its ability to form stable solutions in water and some organic solvents. At the same time, the nature of GO solutions is not completely understood; the existing data are scarce and controversial. Here, we demonstrate that the solubility of GO, and the stability of the as-formed solutions depend not just on the solute and solvent cohesion parameters, as commonly believed, but mostly on the chemical interactions at the GO/solvent interface. By the DFT and QTAIM calculations, we demonstrate that the solubility of GO is afforded by strong hydrogen bonding established between GO functional groups and solvent molecules. The main functional groups taking part in hydrogen bonding are tertiary alcohols; epoxides play only a minor role. The magnitude of the bond energy values is significantly higher than that for typical hydrogen bonding. The hydrogen bond energy between GO functional groups and solvent molecules decreases in the sequence: water > methanol > ethanol. We support our theoretical results by several experimental observations including solution calorimetry. The enthalpy of GO dissolution in water, methanol and ethanol is -0.1815 +/- 0.0010, -0.1550 +/- 0.0012 and -0.1040 +/- 0.0010 kJ g-1, respectively, in full accordance with the calculated trend. Our findings provide an explanation for the well-known, but poorly understood solvent exchange phenomenon. PMID- 28636012 TI - Does H4SO5 exist? AB - The possible existence of H4SO5 in aqueous sulfuric acid is analyzed in detail. For bare H4SO5, the computed free energy barrier for the exergonic transformation of H4SO5 into the H2SO4H2O complex is only 3.8 kcal mol-1. The presence of water or sulfuric acid catalyzes the dehydration to such an extent that it becomes almost a barrierless process. In the gas phase, dehydration of H4SO5 is an autocatalytic reaction as the water molecule produced by the decomposition of one H4SO5 molecule induces further dissociation. Thus, in solution, the surrounding water molecules make the para-sulfuric acid a very vulnerable species to exist. The simulated Raman spectra also corroborate the absence of H4SO5 in solution. PMID- 28636017 TI - Effect of cisplatin on the transport activity of PII-type ATPases. AB - Cisplatin (cis-diamminedichlorido-Pt(ii)) is extensively used as a chemotherapeutic agent against various types of tumors. However, cisplatin administration causes serious side effects, including nephrotoxicity, ototoxicity and neurotoxicity. It has been shown that cisplatin can interact with P-type ATPases, e.g., Cu+-ATPases (ATP7A and ATP7B) and Na+,K+-ATPase. Cisplatin-induced inhibition of Na+,K+-ATPase has been related to the nephrotoxic effect of the drug. To investigate the inhibitory effects of cisplatin on the pumping activity of PII-type ATPases, electrical measurements were performed on sarcoplasmic reticulum Ca2+-ATPase (SERCA) and Na+,K+-ATPase embedded in vesicles/membrane fragments adsorbed on a solid-supported membrane. We found that cisplatin inhibits SERCA and Na+,K+-ATPase only when administered without a physiological reducing agent (GSH); in contrast, inhibition was also observed in the case of Cu+-ATPases in the presence of 1 mM GSH. Our results indicate that cisplatin is a much stronger inhibitor of SERCA (with an IC50 value of 1.3 MUM) than of Na+,K+ ATPase (with an IC50 value of 11.1 MUM); moreover, cisplatin inhibition of Na+,K+ ATPase is reversible, whereas it is irreversible in the case of SERCA. In the absence of a physiological substrate, while Cu+-ATPases are able to translocate cisplatin, SERCA and Na+,K+-ATPase do not perform ATP-dependent cisplatin displacement. PMID- 28636018 TI - Fluorescence lifetime microscopy reveals the biologically-related photophysical heterogeneity of oxyblepharismin in light-adapted (blue) Blepharisma japonicum cells. AB - The step-up photophobic response of the heterotrich ciliate Blepharisma japonicum is mediated by a hypericinic pigment, blepharismin, which is not present in any of the known six families of photoreceptors, namely rhodopsins, phytochromes, xanthopsins, cryptochromes, phototropins, and BLUF proteins. Upon irradiation, native cells become light-adapted (blue) by converting blepharismin into the photochemically stable oxyblepharismin (OxyBP). So far, OxyBP has been investigated mainly from a photophysical point of view in vitro, either alone or complexed with proteins. In this work, we exploit the vivid fluorescence of OxyBP to characterize its lifetime emission in blue B. Japonicum cells, on account of the recognized role of the fluorescence lifetime to provide physicochemical insights into the fluorophore environment at the nanoscale. In a biological context, OxyBP modifies its emission lifetime as compared to isotropic media. The phasor approach to fluorescence lifetime microscopy in confocal mode highlights that fluorescence originates from two excited states, whose relative balance changes throughout the cell body. Additionally, Cilia and kinetids, i.e., the organelles involved in photomovement, display lifetime asymmetry between the anterior and posterior part of the cell. From these data, some hypotheses on the phototransduction mechanism are proposed. PMID- 28636019 TI - Wavelength-selective and high-contrast multicolour fluorescence photoswitching in a mixture of photochromic nanoparticles. AB - Herein, we report on wavelength-selective and high-contrast multicolour fluorescence photoswitching between white-, orange-, cyan-, and dark-colours in a mixture of two distinguishable emission-coloured photochromic nanoparticles composed of different pairs of a photoswitching unit and a fluorescence unit. PMID- 28636028 TI - Supramolecular functional assemblies: dynamic membrane transporters and peptide nanotubular composites. AB - The fabrication of functional molecular devices constitutes one of the most important current challenges for chemical sciences. The complex processes accomplished by living systems continuously demand the assistance of non-covalent interactions between molecular building blocks. Additionally, these building blocks (proteins, membranes, nucleotides) are also constituted by self-assembled structures. Therefore, supramolecular chemistry is the discipline required to understand the properties of the minimal self-assembled building blocks of living systems and to develop new functional smart materials. In the first part of this feature article, we highlight selected examples of the preparation of supramolecular membrane transporters with special emphasis on the application of dynamic covalent bonds. In the second section of the paper we review recent breakthroughs in the preparation of peptide nanotube hybrids with functional applications. The development of these devices constitutes an exciting process from where we can learn how to understand and manipulate supramolecular functional assemblies. PMID- 28636030 TI - Base-promoted, deborylative secondary alkylation of N-heteroaromatic N-oxides with internal gem-bis[(pinacolato)boryl]alkanes: a facile derivatization of 2,2' bipyridyl analogues. AB - A base-promoted, secondary alkylation of N-heteroaromatic N-oxides using internal gem-bis[(pinacolato)boryl]alkanes as alkylation reagents is reported. The reaction exhibits a broad scope, providing deoxygenated secondary alkylated N heteroaromatic compounds with high efficiency. The usefulness of the developed protocol is evidenced by the sequential direct alkylation of 2,2'-bipyridine-N oxide. PMID- 28636029 TI - Cross-impact of surface and interaction anisotropy in the self-assembly of organic adsorption monolayers: a Monte Carlo and transfer-matrix study. AB - Using a simple lattice gas model we study the features of self-assembly in adsorption layers where both "molecule-surface" and "molecule-molecule" interactions are anisotropic. Based on the example of adsorption layers of mono functional organic molecules on the heterogeneous surface with strip-like topography, we have revealed plenty of possible self-assembled structures in this simple system, such as discrete, linear, zigzag, chess board-like, two dimensional porous and close-packed patterns. However, the phase behavior of the adsorption layer is much richer, if the interactions between functional and non functional parts of adjacent adsorbed molecules have comparable strength and opposite signs. It is demonstrated that filling of the strips composed of relatively "strong" adsorption sites with the increase of chemical potential can be non-monotonic. This effect is associated with surface anisotropy and results from the changing of the driving force of the self-assembly process - interactions between the adsorbed molecule and the surface dominate at low surface coverages, but intermolecular forces prevail at higher ones. Additionally, when the width of the strip composed of "strong" adsorption sites is two or more times greater than that of the adsorbed molecule, a local assembly of the ordered phases on the "strong" adsorption sites is observed. Our results suggest strategies for controlling the self-assembly in experiments involving mono-functional organic molecules on a strip-like heterogeneous surface. PMID- 28636031 TI - Attaining resistive switching characteristics and selector properties by varying forming polarities in a single HfO2-based RRAM device with a vanadium electrode. AB - This study proposes a method for a HfO2-based device to exhibit both resistive switching (RS) characteristics as resistive random access memory (RRAM) and selector characteristics by introducing vanadium (V) as the top electrode. This simple V/HfO2/TiN structure can demonstrate these two different properties depending on forming polarities. The RS mechanism is activated by a positive forming bias. In contrast, the selector property is induced by a negative forming bias. The material analyses firstly confirm the existence of V in the top electrode. Then the electrical measurements for the same V/HfO2/TiN structures but with different forming polarities were carried out to further investigate their DC sweeping characteristics to act as either a selector or RRAM device. Furthermore, reliability tests for both selector and RRAM devices were also conducted to confirm their switching stabilities. Finally, current fitting methods and temperature influence experiments were performed to investigate the carrier transport mechanisms. Finally, physical models were proposed to illustrate the selector property and RS mechanism for selector and RRAM devices, respectively. This simple device structure with its easy operating method accomplishes a significant advancement of devices combining both selector properties and RRAM for remarkable real applications in the near future. PMID- 28636032 TI - Reline aqueous solutions behaving as liquid mixtures of H-bonded co-solvents: microphase segregation and formation of co-continuous structures as indicated by Brillouin and 1H NMR spectroscopies. AB - Deep eutectic solvents (DESs) offer a suitable alternative to conventional solvents in terms of both performance and cost-effectiveness. Some DESs also offer certain green features, the greenness of which is notoriously enhanced when combined with water. Aqueous DES dilutions are therefore attracting great attention as a novel green medium for biotechnological processes, with the aqueous dilutions of reline - a DES composed of urea and choline chloride - being one of the most studied systems. Despite their macroscopic homogeneous appearance, both 1H NMR spectroscopic studies and molecular dynamics simulations have revealed the occurrence of certain dynamic heterogeneity at a microscopic molecular level. Ultrasonic measurements were also used with the aim of getting further insights but nonconclusive results were obtained. Herein, we have studied aqueous reline dilutions by Brillouin spectroscopy given its proved suitability for detecting local structure rearrangements in liquid mixtures of H-bonded co solvents. Brillouin spectroscopy revealed the formation of a co-continuous structure resulting from local structure rearrangements and micro-segregation into aqueous and DES phases. Interestingly, there is agreement between 1H NMR and Brillouin spectroscopy when pointing to the DES content where microphase segregation and formation of co-continuous structures occurred. PMID- 28636034 TI - Upregulation of heme oxygenase-1 mediates the anti-inflammatory activity of casein glycomacropeptide (GMP) hydrolysates in LPS-stimulated macrophages. AB - Recently, we have shown that casein glycomacropeptide hydrolysates (GHP) exhibit both anti-inflammatory and anti-oxidative activities in vitro. However, whether heme oxygenase-1 (HO-1) is involved in the cytoprotective effect of GHP against the inflammatory status remains unclear. Therefore, we hypothesized that HO-1 is a potential target of GHP, which mediates its anti-inflammatory effect. Here, GHP inhibited the intracellular reactive oxygen species (ROS) accumulation and NADPH oxidase 2 (NOX2) expression and enhanced reduced glutathione (GSH) levels in LPS stimulated RAW264.7 macrophages. GHP also suppressed the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) stimulated by lipopolysaccharide (LPS). However, zinc(ii)-protoporphyrin IX (ZnPPIX), a selective inhibitor of HO-1, restored the GHP-mediated suppression of ROS production and NOX2, TNF-alpha, IL-1beta, IL-6 and iNOS expression. GHP treatment inhibited the LPS-induced nuclear transcription factor kappa-B (NF-kappaB) translocation, which was markedly reversed by ZnPPIX. Furthermore, GHP induced the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), Akt and p38. Pharmacological inhibition of Akt, ERK1/2, and p38 abrogated GHP-induced nuclear localization of NF-E2-related factor-2 (Nrf2) and the expression of HO-1. In summary, GHP inhibits the LPS-induced inflammatory status through upregulating HO-1 expression via PI3K/Akt, ERK1/2 and p38 signaling pathways in RAW264.7 macrophages. PMID- 28636035 TI - Development of air-stable hydrogen evolution catalysts. AB - Obtaining abundant pure hydrogen by reduction of water has an important implication in the development of clean and renewable energy. Hence research focused on the development of non-noble metal based facile and energy efficient catalysts for proton reduction is on the rise. However, for practical utilization, it is necessary that these complexes function unabated in the presence of atmospheric oxygen and other common contaminants in abundant water sources. There has been very little activity towards the development of oxygen tolerant hydrogen producing catalysts. This article aims to draw attention to this issue of oxygen sensitivity in the HER and highlights the development of a few air-stable HER catalysts (enzymatic as well as artificial) elaborating the challenges involved and the techniques discovered to overcome this significant deterrent to large-scale hydrogen production by electrolysis from abundant water sources. PMID- 28636039 TI - A convenient method for multicolour labelling of proteins with BODIPY fluorophores via tyrosine residues. AB - Fluorescence is an essential imaging modality for labelling and visualising cells and sub-cellular structures. Multicolour labelling is especially challenging due to differences in physicochemical and photophysical behaviour of structurally unrelated fluorophores in the heterogeneous environments found in sub-cellular compartments. Herein, we report the conjugation of three azide-bearing BODIPYs with similar core structures but widely different emission wavelengths (green, red and NIR) to tyrosine residues of a model globular protein (BSA) via a common linking methodology. The resulting BODIPY-BSA conjugates have demonstrated multi wavelength fluorescence emission for biological applications. Fluorescence imaging was performed in HeLa cells through live cell confocal microscopy imaging, with good intracellular location visualisation observed. PMID- 28636040 TI - Tamoxifen-like metallocifens target the thioredoxin system determining mitochondrial impairment leading to apoptosis in Jurkat cells. AB - Tamoxifen-like metallocifens (TLMs) of the group-8 metals (Fe, Ru, and Os) show strong anti-proliferative activity on cancer cell lines resistant to apoptosis, owing to their unique redox properties. In contrast, the thioredoxin system, which is involved in cellular redox balance, is often overexpressed in cancer cells, especially in tumour types resistant to standard chemotherapies. Therefore, we investigated the effect of these three TLMs on the thioredoxin system and evaluated the input of the metallocene unit in comparison with structurally related organic tamoxifens. In vitro, all three TLMs became strong inhibitors of the cytosolic (TrxR1) and mitochondrial (TrxR2) isoforms of thioredoxin reductase after enzymatic oxidation with HRP/H2O2 while none of the organic analogues was effective. In Jurkat cells, TLMs inhibited mainly TrxR2, resulting in the accumulation of oxidized thioredoxin 2 and cell redox imbalance. Overproduction of ROS resulted in a strong decrease in the mitochondrial membrane potential, translocation of cytochrome c to the cytosol and activation of caspase 3, thus leading to apoptosis. None of these events occurred with organic tamoxifens. The mitochondrial fraction of cells exposed to TLMs contained a high amount of the corresponding metal, as quantified by ICP-OES. The lipophilic and cationic character associated with the singular redox properties of the TLMs could explain why they alter the mitochondrial function. These results provide new insights into the mechanism of action of tamoxifen-like metallocifens, underlying their prodrug behaviour and the pivotal role played by the metallocenic entity in their cytotoxic activity associated with the induction of apoptosis. PMID- 28636041 TI - Fluorescence properties of aurone derivatives: an experimental and theoretical study with some preliminary biological applications. AB - In this paper, we explored the fluorescence properties of eight aurone derivatives bearing methoxy groups and bromine atoms as substituents in the benzene rings. All derivatives showed strong solvatochromic absorption and emission properties in solvents of different polarities. Some of them showed high fluorescence quantum yields, which make them potential compounds for sensing applications. The position of the methoxy groups in the benzofuranone moiety and the presence of bromine atoms in the benzene ring had a strong influence on the fluorescence behaviour of the aurones. DFT calculations allowed us to explain the emission properties of aurones and their solvatochromism, which was related to an excited state with strong charge-transfer character. Aurone 4 has the most promising characteristics showing a large difference in the quantum yields and large Stokes shifts depending on the solvent polarities. These results prompted us to explore some preliminary biological applications for aurone 4 such as the sensing of hydrophobic pockets of a protein and its thermotropic behaviour in liposomes. PMID- 28636046 TI - Lead(ii) soaps: crystal structures, polymorphism, and solid and liquid mesophases. AB - The long-chain members of the lead(ii) alkanoate series or soaps, from octanoate to octadecanoate, have been thoroughly characterized by means of XRD, PDF analysis, DSC, FTIR, ssNMR and other techniques, in all their phases and mesophases. The crystal structures at room temperature of all of the members of the series are now solved, showing the existence of two polymorphic forms in the room temperature crystal phase, different to short and long-chain members. Only nonanoate and decanoate present both forms, and this polymorphism is proven to be monotropic. At higher temperature, these compounds present a solid mesophase, defined as rotator, a liquid crystal phase and a liquid phase, all of which have a similar local arrangement. Since some lead(ii) soaps appear as degradation compounds in oil paintings, the solved crystal structures of lead(ii) soaps can now be used as fingerprints for their detection using X-ray diffraction. Pair distribution function analysis on these compounds is very similar in the same phases and mesophases for the different members, showing the same short range order. This observation suggests that this technique could also be used in the detection of these compounds in disordered phases or in the initial stages of formation in paintings. PMID- 28636047 TI - Decoding the regulatory mechanism of glucose and insulin induced phosphatidylinositol 3,4,5-trisphosphate dynamics in beta-cells. AB - In MIN6 pancreatic beta-cells, glucose and insulin act in a synergistic manner to regulate the dynamics of Phosphatidylinositol (3,4,5)-trisphosphate (PIP3). However, the precise regulatory mechanism behind such an experimentally observed synergy is poorly understood. In this article, we propose a phenomenological mathematical model for studying the glucose and insulin driven PIP3 activation dynamics under various stimulatory conditions to unfold the mechanism responsible for the observed synergy. The modeling study reveals that the experimentally observed oscillation in PIP3 dynamics with disparate time scales for different external glucose doses is mainly orchestrated by the complex dynamic regulation of cytosolic Ca2+ in beta-cells. The model accounts for the dose-dependent activation of PIP3 as a function of externally added insulin, and further shows that even in the absence of Ca2+ signaling, externally added glucose can still maintain a basal level of endogenous insulin secretion via the fatty acid metabolism pathway. Importantly, the model analysis suggests that the glucose mediated ROS (reactive oxygen species) activation often contributes considerably to the synergistic activation of PIP3 by glucose and insulin in a context dependent manner. Under the physiological conditions that keep beta-cells in an insulin responsive state, the effect of glucose induced ROS signaling plays a moderate role in PIP3 activation. As beta-cells approach an insulin resistant state, the glucose induced ROS signaling significantly affects the PIP3 dynamics. Our findings provide a plausible mechanistic insight into the experimentally observed synergy, and can lead to novel therapeutic strategies. PMID- 28636048 TI - Supramolecular surface functionalization via catechols for the improvement of cell-material interactions. AB - Optimization of cell-material interactions is crucial for the success of synthetic biomaterials in guiding tissue regeneration. To do so, catechol chemistry is often used to introduce adhesiveness into biomaterials. Here, a supramolecular approach based on ureido-pyrimidinone (UPy) modified polymers is combined with catechol chemistry in order to achieve improved cellular adhesion onto supramolecular biomaterials. UPy-modified hydrophobic polymers with non-cell adhesive properties are developed that can be bioactivated via a modular approach using UPy-modified catechols. It is shown that successful formulation of the UPy catechol additive with the UPy-polymer results in surfaces that induce cardiomyocyte progenitor cell adhesion, cell spreading, and preservation of cardiac specific extracellular matrix production. Hence, by functionalizing supramolecular surfaces with catechol functionalities, an adhesive supramolecular biomaterial is developed that allows for the possibility to contribute to biomaterial-based regeneration. PMID- 28636049 TI - Neutral mixed-metal coordination polymers based on a ditopic acetylacetonate, Mg(ii) and Ag(i): syntheses, characterization and solvent-dependent topologies. AB - The complex [Mg(acacCN)2(H2O)2] (acacCN = 3-cyanoacetylacetonate) has been synthesized in good yield and fully characterized. It represents a versatile labile precursor for an anionic tris(ligand) complex which is crosslinked with Ag(i) to five different neutral bimetallic networks; all of them are solvates. Four of these extended structures share the same framework stoichiometry Ag[Mg(acacCN)3] and only differ in their solvent content. The co-crystallized solvent molecules decide the topological outcome of the crosslinking: the four compounds can be classified into two isomorphous 3D networks and two non isomorphous but related 2D layer structures. The individual structures suggest preferred inclusion of dichloromethane, followed by acetone; direct competition experiments confirm these considerations. An additional coordination polymer shows the framework stoichiometry Ag2[Mg(acacCN)2(MeOH)2][Mg(acacCN)3]2; this binodal 3D network is associated with the unprecedented vertex symbol (109.1011.1013)(103.107.107.107.108.1010). PMID- 28636050 TI - Photoelectrochemical ion concentration polarization: membraneless ion filtration based on light-driven electrochemical reactions. AB - In this article we report a microelectrochemical system that is able to partially desalinate water. The underlying principles are similar to previous reports in which a local electric field resists passage of ions. However, in the present case, no membrane is required and, most interestingly, much of the power for desalination originates from light rather than electricity. This could greatly increase the power efficiency for desalination. The device is based on a TiO2 photoanode coupled to a Pt cathode. Illumination of the photoanode drives faradaic reactions at the cathode that lead to an ion depletion zone. The resulting local electric field limits transport of charged species. In situ conductivity and fluorescence measurements demonstrate the effectiveness of the device. PMID- 28636053 TI - Evidence of bad recycling practices: BFRs in children's toys and food-contact articles. AB - Brominated flame retardants (BFRs) have been used intentionally in a wide range of plastics, but are now found in an even wider range of such materials (including children's toys and food contact articles) as a result of recycling practices that mix BFR-containing waste plastics with "virgin" materials. In this study Br was quantified in toy and food contact samples on the assumption that its concentration can be used as a metric for BFR contamination. Subsequently, compound specific determination of BFRs was performed to evaluate the validity of the aforementioned assumption, crucial to render rapid, inexpensive, in situ Br determination in non-laboratory environments (such as waste handling facilities) a viable option for sorting wastes according to their BFR content. We report semi quantitative compound specific BFR concentrations to give an overview of the distribution of individual BFRs in the analyzed samples. Finally, we evaluated the correlations between waste electrical and electronic equipment (WEEE) related substances (Ca, Sb and rare earth elements (REEs)) and Br as a proxy for identifying poor sorting practices in different waste streams. 26 samples of toys, food-contact articles and WEEE were analyzed with a suite of different techniques in order to obtain comprehensive information about their elemental and molecular composition. The information obtained from principal component analysis about WEEE-related compounds provides new insights into the influence of sorting practices on the extent of products' contamination and bringing out polymer related trends in the pollutants' signature. 61% of all samples were Br positive: of these samples, 45% had decaBDE concentrations exceeding the concentration limits for PBDEs and their main constituent polymer was - according to the REE signature of such samples - Acrylonitrile Butadiene Styrene (ABS), uses of which include copying equipment, laptops and computers. The ability to better track chemicals of concern and their trends in products is the main requirement for high-level management and control of material cycles to become non-toxic in the future as proposed in the EU's 7th Environmental Action Plan. PMID- 28636054 TI - Guidelines for surgical approaches for minimally invasive plate osteosynthesis in cats. AB - OBJECTIVES: Minimally invasive plate osteosynthesis (MIPO) is one of the most recent fixation techniques that embody the concept of biological osteosynthesis. Several studies evaluating MIPO in dogs have been published in the recent years. However, there are few clinical reports of MIPO in cats and no description of the surgical approaches. The purpose of our study was to describe the safe corridors for plate insertion in cats using the MIPO technique. METHODS: The surgical approaches for the humerus, radius-ulna, femur and tibia were developed after reviewing the described techniques and surgical approaches for MIPO in dogs, while considering any relevant anatomical difference between dogs and cats. Following the MIPO approaches, the limbs were anatomically dissected and the relationship between proximal and distal positions of the implants and neurovascular structures was noted. RESULTS: The surgical approaches developed for the humerus and radius-ulna differed from what had been reported previously, because relevant anatomical differences were found between dogs and cats. Anatomical landmarks for safe plate application were described for all the major long bones in cats. No damage to vital structures following plate insertion was detected in the dissection. CLINICAL SIGNIFICANCE: In this cadaveric study, we evaluated the safety of the surgical approaches for MIPO in cats. By respecting the anatomical landmarks described in this report, damage to the neurovascular structures can be avoided performing the MIPO technique in cats. PMID- 28636052 TI - Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC). AB - Cyclin-dependent kinase 9 (CDK9), a member of the cyclin-dependent protein kinase (CDK) family, is involved in transcriptional elongation of several target genes. CDK9 is ubiquitously expressed and has been shown to contribute to a variety of malignancies such as pancreatic, prostate and breast cancers. Here we report the development of a heterobifunctional small molecule proteolysis targeting chimera (PROTAC) capable of cereblon (CRBN) mediated proteasomal degradation of CDK9. In HCT116 cells, it selectively degrades CDK9 while sparing other CDK family members. This is the first example of a PROTAC that selectively degrades CDK9. PMID- 28636055 TI - Effect of headless compression screw on construct stability for centre of rotation and angulation-based levelling osteotomy. Biomechanical testing in flexion and torsion. AB - OBJECTIVE: To compare the biomechanical properties of bone and implant constructs when used for the centre of rotation and angulation (CORA) based levelling osteotomy, with and without implantation of a trans-osteotomy headless compression screw tested under three-point flexural and torsional forces; thereby determining the contribution of a trans-osteotomy headless compression screw with regards to stability of the construct. METHODS: Experimental biomechanical study utilizing 12 pairs of cadaveric canine tibias. Using the CORA based levelling osteotomy (CBLO) procedure, the osteotomy was stabilized with either a standard non-locking CBLO bone plate augmented with a headless compression screw (HCS) or a CBLO bone plate alone. Tibial constructs were mechanically tested in three point craniocaudal flexural testing or in torsion. RESULTS: In three-point flexural testing, the difference between the two constructs was not significant. In torsion, the difference in the angle of failure between constructs with a HCS (48.46 degrees ) and constructs without a HCS (81.65 degrees ) was significant (p = 0.036). Maximum torque achieved by constructs with a HCS (21.7 Nm) was greater than those without (18.7 Nm) (p = 0.056). Stiffness differences between both groups in torsion and bending were not significant. Use of a HCS did increase the stability of the CBLO construct in torsional testing, but not in flexural testing. PMID- 28636056 TI - Comparison of complications following tibial tuberosity advancement and tibial plateau levelling osteotomy in very large and giant dogs 50 kg or more in body weight. AB - OBJECTIVES: To analyse and compare major complications in dogs >=50 kg undergoing tibial tuberosity advancement (TTA) or tibial plateau levelling osteotomy (TPLO) for treatment of cranial cruciate ligament disease. METHODS: Medical records and radiographs of client-owned dogs (>=50 kg) treated for cranial cruciate ligament disease with either TTA or TPLO between January 2011 and November 2015 were reviewed. Ninety-one TTA cases and 54 TPLO cases met the study inclusion criteria. All complications within one year of surgery were recorded. Major complications were those requiring surgical revision or intervening medical therapy to resolve. Logistic regression analysis evaluated for associations with major complication occurrence. Major complications were statistically compared between TTA and TPLO treatment groups. RESULTS: Incidence of major complications following TTA and TPLO surgery were 19.8% and 27.8%, respectively. Surgical site infection (SSI) was the single most common major complication following both TTA (15.4%) and TPLO (25.9%) surgery. There were no significant differences between TTA and TPLO treatment regarding the rate of SSI, surgical revision, or overall occurrence of major complications. Postoperative antibiotic therapy significantly reduced the risk of a major complication in all dogs >=50 kg (p = 0.015; OR: 0.201: 95%CI: 0.055-0.737). CLINICAL SIGNIFICANCE: Major complications occurred frequently following TTA and TPLO treatment of cranial cruciate ligament disease in dogs >=50 kg. The increased chance for SSI should be considered and postoperative antibiotic therapy is recommended. PMID- 28636057 TI - Symmetrical brachydactyly in a dog. AB - Congenital malformations of the canine manus and pes are infrequently reported in the veterinary literature. This includes brachydactyly which is a general term used to indicate the shortening of digits due to abnormal development of the phalanges, metacarpals, or metatarsals. This case report describes isolated brachydactyly in a one-year-old male Maremma Sheepdog affecting all of the phalanges, metacarpals, and metatarsals of digits two through five. This condition was confirmed by determining the length of each phalanx, metacarpal, and metatarsal of the affected dog as well as an unaffected littermate. The affected dog's metacarpal, metatarsal, and phalanx lengths ranged from 50% to 77% of that of the unaffected sibling. Other abnormalities found on physical examination as well as on radiographic imaging are discussed. PMID- 28636058 TI - Percutaneous tibial physeal fracture repair in small animals: technique and 17 cases. AB - OBJECTIVES: To retrospectively describe cases treated via percutaneous tibial physeal fracture repair (PTPFR), using intra-operative fluoroscopy (IFL) or digital radiography (DR). To describe a technique ("spiking"), used to treat tibial tuberosity avulsion fractures. METHODS: Clinical data of 14 dogs and three cats were included. The "spiking" technique was described. RESULTS: Intra operative fluoroscopy (n = 11) and DR (n = 6) were successfully used in 11 tibial tuberosity avulsion fractures, one combined proximal physeal and tibial tuberosity avulsion fracture, and five distal tibial/fibular physeal fractures. Surgery times ranged from eight to 54 minutes. The "spiking" technique was successfully applied in six tibial tuberosity avulsion fracture cases. Return to function was at a mean (+/- standard deviation) of 1.9 (+/- 1.6) weeks. Long-term (>12 months; n = 17) follow-up was available at a mean of 40.6 (+/- 13.4) months. Major complications consisted of skin irritation from a pin (distal tibia / fibula physeal fracture case; 8 weeks post-PTPFR), and a bilateral grade II medial patella luxation (tibial tuberosity avulsion fracture case; 1.5 years post PTPFR). One case developed a mild tibial tuberosity avulsion fracture re avulsion. All conditions in these three cases were not of clinical concern at follow-up and final outcome was graded as good in these and excellent in the other 14 cases. CLINICAL SIGNIFICANCE: Percutaneous tibial physeal fracture repair can be considered as a technique to treat tibial physeal fractures. The "spiking" technique was successfully applied in six dogs. A larger, prospective case series is indicated to provide additional clinical information. PMID- 28636059 TI - Clinical outcome and complications of thoracic and pelvic limb stump and socket prostheses. AB - OBJECTIVES: To describe the use, quality of life, compliance, complications, and outcome of animals fitted with stump socket prostheses. METHODS: Medical records of dogs fitted with a stump socket prosthesis were reviewed. Functional outcome, quality of life and complications were retrospectively assessed from an owner questionnaire. RESULTS: Thirteen stump socket prostheses (12 dogs) were fitted for a variety of reasons including trauma, congenital abnormalities, and neoplasia. Eight dogs had a good outcome overall and four a poor outcome. Quality of life (QOL) remained good or excellent in 10/12 dogs. Nine complications were seen in 7/12 dogs, most were manageable; surgical wound complications (n = 2) and pressures sores (n = 4) were the most frequently encountered. One dog suffered multiple complications. Thoracic and pelvic limb stump socket prostheses had a similar complication rate, however all animals with a poor outcome had a thoracic limb stump socket prosthesis; two were small breed dogs (under 10 kg) and two had bilateral thoracic limb abnormalities. CLINICAL SIGNIFICANCE: Stump socket prostheses are feasible and versatile in animals. In correctly selected cases, good to excellent outcomes are possible. However, complications are frequent but often manageable. Further investigations are required into the risk factors for poor outcomes and prospective studies are required to assess changes in biomechanics, function, and QOL before and after fitting of a stump socket prosthesis. Until further evidence is available, careful consideration should be given before fitting bilateral thoracic limb stump socket prostheses or thoracic limb stump socket prostheses to small breed dogs. PMID- 28636060 TI - Developing Mobile Clinical Decision Support for Nursing Home Staff Assessment of Urinary Tract Infection using Goal-Directed Design. AB - BACKGROUND: Unique characteristics of nursing homes (NHs) contribute to high rates of inappropriate antibiotic use for asymptomatic bacteriuria (ASB), a benign condition. A mobile clinical decision support system (CDSS) may support NH staff in differentiating urinary tract infections (UTI) from ASB and reducing antibiotic days. OBJECTIVES: We used Goal-Directed Design to: 1) Characterize information needs for UTI identification and management in NHs; 2) Develop UTI Decide, a mobile CDSS prototype informed by personas and scenarios of use constructed from Aim 1 findings; 3) Evaluate the UTI Decide prototype with NH staff. METHODS: Focus groups were conducted with providers and nurses in NHs in Denver, Colorado (n= 24). Qualitative descriptive analysis was applied to focus group transcripts to identify information needs and themes related to mobile clinical decision support for UTI identification and management. Personas representing typical end users were developed; typical clinical context scenarios were constructed using information needs as goals. Usability testing was performed using cognitive walk-throughs and a think-aloud protocol. RESULTS: Four information needs were identified including guidance regarding resident assessment; communication with providers; care planning; and urine culture interpretation. Design of a web-based application incorporating a published decision support algorithm for evidence-based UTI diagnoses proceeded with a focus on nursing information needs during resident assessment and communication with providers. Certified nursing assistant (CNA) and registered nurse (RN) personas were constructed in 4 context scenarios with associated key path scenarios. After field testing, a high fidelity prototype of UTI Decide was completed and evaluated by potential end users. Design recommendations and content recommendations were elicited. CONCLUSIONS: Goal-Directed Design informed the development of a mobile CDSS supporting participant-identified information needs for UTI assessment and communication in NHs. Future work will include iterative deployment and evaluation of UTI Decide in NHs to decrease inappropriate use of antibiotics for suspected UTI. PMID- 28636061 TI - Impact of femoral varus on complications and outcome associated with corrective surgery for medial patellar luxation. AB - OBJECTIVES: To evaluate the association of femoral varus with postoperative complications and outcome following standard corrective surgery for medial patellar luxation (MPL) without distal femoral osteotomy (DFO) in dogs. METHODS: In a retrospective study spanning a 12 year period, 87 stifles with MPL that were treated by standard surgical techniques were included. Inclination angle (ICA), femoral varus angle (FVA), anatomical lateral distal femoral angle (aLDFA), and mechanical lateral distal femoral angle (mLDFA) were measured. Postoperative complications were noted and outcome evaluated. Associations between potential risk factors and both complication rate and outcome were assessed. RESULTS: Postoperative complications occurred in 19 stifles, five of which were major. There was no evidence of an association between FVA (p = 0.41) or aLDFA (p = 0.38) and any complication. There was also no evidence of an association between FVA (p = 0.31) or aLDFA (p = 0.38) and any major complication. Dogs with a larger aLDFA had increased odds of a poorer outcome (p = 0.01) as did dogs that suffered a major complication (p = 0.0001). CLINICAL SIGNIFICANCE: Based on radiographic measurements, there is no evidence of an association between FVA and the incidence of postoperative complications following standard MPL correction. Traditional surgical techniques appear to be appropriate for most cases of MPL and further work is required to better define selection criteria for including DFO in the treatment of these cases. PMID- 28636062 TI - A structural numerical model for the optimization of double pelvic osteotomy in the early treatment of canine hip dysplasia. AB - BACKGROUND: Double pelvic osteotomy (DPO) planning is usually performed by hip palpation, and on radiographic images which give a poor representation of the complex three-dimensional manoeuvre required during surgery. Furthermore, bone strains which play a crucial role cannot be foreseen. OBJECTIVE: To support surgeons and designers with biomechanical guidelines through a virtual model that would provide bone stress and strain, required moments, and three-dimensional measurements. METHODS: A multibody numerical model for kinematic analyses has been coupled to a finite element model for stress/strain analysis on deformable bodies. The model was parametrized by the fixation plate angle, the iliac osteotomy angle, and the plate offset in ventro-dorsal direction. Model outputs were: acetabular ventro-version (VV) and lateralization (L), Norberg (NA) and dorsal acetabular rim (DAR) angles, the percentage of acetabular coverage (PC), the peak bone stress, and moments required to deform the pelvis. RESULTS: Over 150 combinations of cited parameters and their respective outcome were analysed. Curves reporting NA and PC versus VV were traced for the given patient. The optimal VV range in relation to NA and PC limits was established. The 25 degrees DPO plate results were the most similar to 20 degrees TPO. The output L grew for positive iliac osteotomy inclinations. The 15 degrees DPO plate was critical in relation to DAR, while very large VV could lead to bone failure. CLINICAL SIGNIFICANCE: Structural models can be a support to the study and optimization of DPO as they allow for foreseeing geometrical and structural outcomes of surgical choices. PMID- 28636064 TI - Side-scattered finger-photoplethysmography: experimental investigations toward practical noninvasive measurement of blood glucose. AB - The aim of this study was to discover a simple/convenient geometrical arrangement of radiation sources and detector to acquire finger-photoplethysmograms (PPGs) with wavelength regions of blood glucose (BGL) absorption, toward practical noninvasive BGL measurement. First, we compared PPGs with three wavelengths: 808 nm (without water absorption), 1160 nm (with weak water absorption), and 1600 nm (with nearly peak BGL absorption and strong water absorption), while the source detector spacing was successively increased circumferentially around a fingertip. In 10 healthy subjects, we observed clear cardiac-related pulsatile components of PPG signals at 808 and 1160 nm in any incident positions with more than 15 dB of signal-to-noise ratio ( S / N ), but reliable PPG detections at 1600 nm with more than 10 dB of S / N was only possible when the source-detector distance was less than 3 mm around the fingertip circumference. Second, with this arrangement, an experiment was performed using six wavelengths to cover glucose absorption bands (from 1550 to 1749 nm), obtaining pulsatile PPG signals with more or less 15 dB of S / N . Through the present experiments, this orthogonal arrangement of the source and detector to detect forward- and side-scattered radiation through the tissue is appropriate for PPG measurements with wavelength regions where there is potential for BGL measurement. PMID- 28636063 TI - Solving Interoperability in Translational Health. Perspectives of Students from the International Partnership in Health Informatics Education (IPHIE) 2016 Master Class. AB - BACKGROUND: In the summer of 2016 an international group of biomedical and health informatics faculty and graduate students gathered for the 16th meeting of the International Partnership in Health Informatics Education (IPHIE) masterclass at the University of Utah campus in Salt Lake City, Utah. This international biomedical and health informatics workshop was created to share knowledge and explore issues in biomedical health informatics (BHI). OBJECTIVE: The goal of this paper is to summarize the discussions of biomedical and health informatics graduate students who were asked to define interoperability, and make critical observations to gather insight on how to improve biomedical education. METHODS: Students were assigned to one of four groups and asked to define interoperability and explore potential solutions to current problems of interoperability in health care. RESULTS: We summarize here the student reports on the importance and possible solutions to the "interoperability problem" in biomedical informatics. Reports are provided from each of the four groups of highly qualified graduate students from leading BHI programs in the US, Europe and Asia. CONCLUSION: International workshops such as IPHIE provide a unique opportunity for graduate student learning and knowledge sharing. BHI faculty are encouraged to incorporate into their curriculum opportunities to exercise and strengthen student critical thinking to prepare our students for solving health informatics problems in the future. PMID- 28636066 TI - Assessment of the "cross-bridge"-induced interaction of red blood cells by optical trapping combined with microfluidics. AB - Red blood cell (RBC) aggregation is an intrinsic property of the blood that has a direct effect on the blood viscosity and circulation. Nevertheless, the mechanism behind the RBC aggregation has not been confirmed and is still under investigation with two major hypotheses, known as "depletion layer" and "cross bridging." We aim to ultimately understand the mechanism of the RBC aggregation and clarify both models. To measure the cell interaction in vitro in different suspensions (including plasma, isotonic solution of fibrinogen, isotonic solution of fibrinogen with albumin, and phosphate buffer saline) while moving the aggregate from one solution to another, an approach combining optical trapping and microfluidics has been applied. The study reveals evidence that RBC aggregation in plasma is at least partly due to the cross-bridging mechanism. The cell interaction strength measured in the final solution was found to be significantly changed depending on the initial solution where the aggregate was formed. PMID- 28636065 TI - Automatic motion correction for in vivo human skin optical coherence tomography angiography through combined rigid and nonrigid registration. AB - When using optical coherence tomography angiography (OCTA), the development of artifacts due to involuntary movements can severely compromise the visualization and subsequent quantitation of tissue microvasculatures. To correct such an occurrence, we propose a motion compensation method to eliminate artifacts from human skin OCTA by means of step-by-step rigid affine registration, rigid subpixel registration, and nonrigid B-spline registration. To accommodate this remedial process, OCTA is conducted using two matching all-depth volume scans. Affine transformation is first performed on the large vessels of the deep reticular dermis, and then the resulting affine parameters are applied to all depth vasculatures with a further subpixel registration to refine the alignment between superficial smaller vessels. Finally, the coregistration of both volumes is carried out to result in the final artifact-free composite image via an algorithm based upon cubic B-spline free-form deformation. We demonstrate that the proposed method can provide a considerable improvement to the final en face OCTA images with substantial artifact removal. In addition, the correlation coefficients and peak signal-to-noise ratios of the corrected images are evaluated and compared with those of the original images, further validating the effectiveness of the proposed method. We expect that the proposed method can be useful in improving qualitative and quantitative assessment of the OCTA images of scanned tissue beds. PMID- 28636067 TI - Dynamic time warping-based averaging framework for functional near-infrared spectroscopy brain imaging studies. AB - We investigate the problem related to the averaging procedure in functional near infrared spectroscopy (fNIRS) brain imaging studies. Typically, to reduce noise and to empower the signal strength associated with task-induced activities, recorded signals (e.g., in response to repeated stimuli or from a group of individuals) are averaged through a point-by-point conventional averaging technique. However, due to the existence of variable latencies in recorded activities, the use of the conventional averaging technique can lead to inaccuracies and loss of information in the averaged signal, which may result in inaccurate conclusions about the functionality of the brain. To improve the averaging accuracy in the presence of variable latencies, we present an averaging framework that employs dynamic time warping (DTW) to account for the temporal variation in the alignment of fNIRS signals to be averaged. As a proof of concept, we focus on the problem of localizing task-induced active brain regions. The framework is extensively tested on experimental data (obtained from both block design and event-related design experiments) as well as on simulated data. In all cases, it is shown that the DTW-based averaging technique outperforms the conventional-based averaging technique in estimating the location of task-induced active regions in the brain, suggesting that such advanced averaging methods should be employed in fNIRS brain imaging studies. PMID- 28636068 TI - Parent-Child association in physical activity and sedentary behaviour. AB - BACKGROUND: Parents influence the physical activity and sedentary behaviour of their children. This analysis examines associations between parental role modeling and support and children's physical activity and sedentary behaviour. DATA AND METHODS: The sample consists of 1,328 biological parent-child pairs from the first three cycles of the Canadian Health Measures Survey (2007 through 2013). Data on physical activity and sedentary behaviour were collected using a questionnaire and by accelerometer. Pearson correlation and linear regression analyses were completed to examine associations between parents' and children's measured physical activity and sedentary time and reported screen-based activities. Analyses were adjusted for variables indicating parental support and household lifestyle characteristics. RESULTS: Accelerometer-measured physical activity and sedentary time were correlated in all parent-child pairs. Parents' measured moderate-to-vigorous physical activity (MVPA) was associated with children's MVPA (beta = 0.28, p < 0.001). For every 20-minute increase in a parent's MVPA, the child's MVPA increased by 5 to 10 minutes. Parents' measured sedentary time was associated with that of their daughters on weekends, and with that of their sons during the after-school period. Parents' reported screen time was associated with that of their daughters. INTERPRETATION: This study confirms parents' influence on their children's physical activity. Parental role modeling and support have independent effects on a child's level of physical activity. PMID- 28636069 TI - Parent-Child association in body weight status. AB - BACKGROUND: The prevalence of overweight and obesity among children and adults has risen in Canada. Studies suggest that parent obesity is a risk factor for overweight and obesity in children. This analysis examines associations between biological parent and child body mass index (BMI) in a nationally representative sample of Canadian children. DATA AND METHODS: The analysis is based on data collected for 1,563 children aged 6 to 10 in the first three cycles of the Canadian Health Measures Survey (2007 to 2013). BMI was calculated using measured height and weight. Pearson correlation, logistic, and linear regression analyses examined associations between biological parent and child BMI and obesity status, controlling for other risk factors. RESULTS: Biological parent and child BMI were correlated. When risk factors were taken into account, a child's average BMI increased as their parent's BMI increased. Parent BMI explained 2% of the variance in boys' BMI and 12% of the variance in girls' BMI. Boys and girls with a biological parent who was obese were at increased risk of being overweight or obese. Girls were also at increased risk of being overweight or obese if a biological parent was overweight. INTERPRETATION: Children's body weight status is associated with that of at least one of their biological parents. Having an obese parent increases the risk of overweight or obesity among children in Canada. PMID- 28636070 TI - Development of a population-based microsimulation model of body mass index. AB - BACKGROUND: The increasing prevalence of overweight and obesity has necessitated the development of body mass index (BMI) projection models such as the POpulation HEalth Model (POHEM). This study describes the POHEM-BMI model, a microsimulation tool that can be used to support evidence-based health policy making for obesity reduction. DATA AND METHODS: The National Population Health Survey, the Canadian Community Health Survey (CCHS), and the Canadian Health Measures Survey (CHMS) were used to develop and validate a predictive model of BMI for adults and childhood BMI history. Models were incorporated into POHEM and used to transition BMI over time in a fully dynamic simulated Canadian population. RESULTS: POHEM BMI projections of self-reported and measured adult BMI and childhood BMI history agree well with CCHS and CHMS validation estimates. Among men and women, average BMI is projected to increase by more than one BMI unit between 2001 and 2030. Projections of self-reported BMI show that 59% of the adult population will be overweight or obese by 2030; projections of measured BMI show that the percentage will be 66%. INTERPRETATION: Using empirically developed BMI prediction models for adults and childhood BMI history integrated into the POHEM framework, validated projections of BMI for the Canadian population can be produced. Projections of BMI trends could have important applications in tracking the prevalence of related diseases, and in planning and comparing intervention strategies. PMID- 28636071 TI - The role of homocysteine in seminal vesicles remodeling in rat. AB - INTRODUCTION: Elevated plasma homocysteine (Hcy) levels have been associated with several tissue injuries including heart and liver fibrosis. In these diseases, hyperhomocysteinemia (Hhcy) plays a major role in modulating the alteration of the balance between matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMPs), leading to the pathological accumulation of extracellular matrix (ECM) proteins. Since the effect of Hhcy on ECM of seminal vesicle was not studied, the aim of our research was to check if Hcy can induce a remodeling within seminal vesicles ECM. MATERIAL AND METHODS: The study was conducted in 22 adult male Wistar rats. The rats were divided into two groups: a control group, which received standard diet and tap water; the treated group received the same diet and water supplemented with solution of L-methionine (200 mg/kg b.w./day) for 6 months. Plasma homocysteine concentration was measured. Histological changes were observed with light microscope. The presence of collagen I and III and metalloproteinases (2, 3, 7 and 9) in the seminal vesicles was examined using immunohistochemistry and Western blotting. RESULTS: Plasma Hcy levels increased significantly after methionine treatment and interfered significantly with body weight in treated rats. The content of fibrillar collagens (I and III) in the wall of seminal vesicles was elevated in hyperhomocysteinemic rats. Moreover, we found that hyperhomocysteinemia increased the expression of MMP-2, -3, -7 and -9 in seminal vesicles of experimental rats. CONCLUSIONS: Increased plasma concentration of Hcy accompanied by the accumulation of collagen and upregulation of MMPs in rat seminal vesicles might contribute to the remodeling of seminal vesicles. PMID- 28636072 TI - Using Chief Complaint in Addition to Diagnosis Codes to Identify Falls in the Emergency Department. AB - OBJECTIVES: To compare incidence of falls in an emergency department (ED) cohort using a traditional International Classification of Diseases, Ninth Revision (ICD 9) code-based scheme and an expanded definition that included chief complaint information and to examine the clinical characteristics of visits "missed" in the ICD-9-based scheme. DESIGN: Retrospective electronic record review. SETTING: Academic medical center ED. PARTICIPANTS: Individuals aged 65 and older seen in the ED between January 1, 2013, and September 30, 2015. MEASUREMENTS: Two fall definitions were applied (individually and together) to the cohort: an ICD-9 based definition and a chief complaint definition. Admission rates and 30-day mortality (per encounter) were measured for each definition. RESULTS: Twenty three thousand eight hundred eighty older adult visits occurred during the study period. Using the most-inclusive definition (ICD-9 code or chief complaint indicating a fall), 4,363 visits (18%) were fall related. Of these visits, 3,506 (80%) met the ICD-9 definition for a fall-related visit, and 2,664 (61%) met the chief complaint definition. Of visits meeting the chief complaint definition, 857 (19.6%) were missed when applying the ICD-9 definition alone. Encounters missed using the ICD-9 definition were less likely to lead to an admission (42.9%, 95% confidence interval (CI) = 39.7-46.3%) than those identified (54.4%, 95% CI = 52.7-56.0%). CONCLUSION: Identifying individuals in the ED who have fallen based on diagnosis codes underestimates the true burden of falls. Individuals missed according to the code-based definition were less likely to have been admitted than those who were captured. These findings call attention to the value of using chief complaint information to identify individuals who have fallen in the ED-for research, clinical care, or policy reasons. PMID- 28636073 TI - Chanarin-Dorfman syndrome. PMID- 28636074 TI - Optimizing outcomes in pancreas transplantation: Impact of organ preservation time. AB - Recent changes to pancreas graft allocation policy have increased the number of organs available for regional and distant sharing, which results in a corresponding increase in preservation time. We sought to systematically assess the impact of cold ischemia time (CIT) on outcomes post-transplant. A retrospective review of 1253 pancreas transplants performed at a single transplant center was performed to correlate CIT to transplant outcomes. The rate of technical failure (TF) increased with 20+ hours of CIT, with a 2.7-fold to 6.2 fold increased rate of TF for pancreas after kidney (PAK), simultaneous pancreas and kidney (SPK), and pancreas transplants overall. Long-term graft survival was best with <12 hours of CIT; graft failure increased 1.2-fold to 1.4-fold with 12 24 hours of CIT and 2.2-fold with 24+ hours. CIT had less influence on the pancreas transplant alone category than either SPK or PAK and had markedly more influence on grafts from older (age >25 years) and overweight (body mass index >25) donors. In the final analysis, grafts with <12 hours of CIT performed the best overall, and strategies that reduce CIT (such as early allocation, pre recovery cross-matching, and chartered flights for organs) should be considered whenever possible. PMID- 28636076 TI - Prevalence and impact of obesity in people with haemophilia: Review of literature and expert discussion around implementing weight management guidelines. AB - Obesity affects more than 35% of Americans, increasing the risk of more than 200 comorbid conditions, impaired quality of life and premature mortality. This review aimed to summarize literature published over the past 15 years regarding the prevalence and impact of obesity in people with haemophilia (PWH) and to discuss implementing general guidelines for weight management in the context of the haemophilia comprehensive care team. Although few studies have assessed the effects of obesity on haemophilia-specific outcomes, existing evidence indicates an important impact of weight status on lower extremity joint range of motion and functional disability, with potentially important effects on overall quality of life. Data regarding bleeding tendency in PWH with coexisting obesity are largely inconclusive; however, some individuals may experience reduced joint bleeds following moderate weight loss. Additionally, conventional weight-based dosing of factor replacement therapy leads to increased treatment costs for PWH with obesity or overweight, suggesting pharmacoeconomic benefits of weight loss. Evidence-based recommendations for weight loss include behavioural strategies to reduce caloric intake and increase physical activity, pharmacotherapy and surgical therapy in appropriate patients. Unique considerations in PWH include bleed-related risks with physical activity; thus, healthcare professionals should advise patients on types and intensities of, and approaches to, physical activity, how to adjust treatment to accommodate exercise and how to manage potential activity-related bleeding. Increasing awareness of these issues may improve identification of PWH with coexisting obesity and referral to appropriate specialists, with potentially wide-ranging benefits in overall health and well being. PMID- 28636075 TI - Molecular cloning, mRNA expression and biological activity of the pheromone biosynthesis activating neuropeptide (PBAN) from the European corn borer, Ostrinia nubilalis. AB - Pheromone biosynthesis activating neuropeptide (PBAN) is a member of the pyrokinin (FXPRLamide) insect neuropeptides. Here, we report the cloning of the gene Ostnu-PBAN from the E and Z pheromone strains of the European corn borer (ECB), Ostrinia nubilalis (Lepidoptera: Crambidae), a major pest of maize. The Ostnu-PBAN genomic sequence is > 5 kb in length and consists of six exons. The deduced amino acid sequence revealed a 200-residue precursor protein including a signal peptide, a 24-amino acid (aa) diapause hormone, a 37-aa PBAN and three other FXPRLamide neuropeptides. Our in vivo assays suggest that the 37-aa synthetic Ostnu-PBAN is hormonally active in the pheromone gland. It restores sex pheromone production to normal levels in mated females and decapitated virgins of both E and Z cultures. The results of a real-time PCR analysis indicated that Ostnu-PBAN mRNA levels reached a plateau in the brain-suboesophageal ganglion complexes 1 day after eclosion, and mating did not affect the mRNA expression. Three size classes of Ostnu-PBAN mRNA (1.9, 2.0 and 2.1 kb) were obtained, differing only in the length of the 3' untranslated region. However, there was no correlation between sequence divergence and the pheromone composition, voltinism or geographical origin (Hungary, Slovenia, Sweden, Turkey) of ECB moths. PMID- 28636077 TI - Arabidopsis shaker pollen inward K+ channel SPIK functions in SnRK1 complex regulated pollen hydration on the stigma. AB - Pollen hydration is a critical step that determines pollen germination on the stigma. KINbetagamma is a plant-specific subunit of the SNF1-related protein kinase 1 complex (SnRK1 complex). In pollen of the Arabidopsis kinbetagamma mutant, the levels of reactive oxygen species were decreased which lead to compromised hydration of the mutant pollen on the stigma. In this study, we analyzed gene expression in kinbetagamma mutant pollen by RNA-seq and found the expression of inward shaker K+ channel SPIK was down-regulated in the kinbetagamma pollen. Furthermore, we showed that the pollen hydration of the Arabidopsis spik mutant was defective on the wild-type stigma, although the mutant pollen demonstrated normal hydration in vitro. Additionally, the defective hydration of spik mutant pollen could not be rescued by the wild-type pollen on the stigma, indicating that the spik mutation deprived the capability of pollen absorption on the stigma. Our results suggest that the Arabidopsis SnRK1 complex regulates SPIK expression, which functions in determining pollen hydration on the stigma. PMID- 28636078 TI - Microbial lipopeptide production and purification bioprocesses, current progress and future challenges. AB - Lipopeoptides are amphiphilic compounds combining interesting physicochemical properties and biological activities. Due to their high foaming capacity in aerated bioreactor, the development of scalable bioprocesses for their production is a major bottleneck. In addition, the genes involved in the biosynthesis of these lipopeptides are mainly regulated by the quorum sensing, a global regulatory mechanism depending on cell density and known to be activated in biofilms. Several approaches have thus been considered in literature taking into account two criteria, on one side, to favor, control or avoid foam formation and on the other side, to use planktonic or immobilized (biofilm) cells. These different bioprocesses are discussed in the present review along with the purification strategies proposed for extracting and concentrating these biosurfactants. PMID- 28636079 TI - Amelanotic melanoma in a child, the importance of suspecting the disease. PMID- 28636080 TI - Case of successful treatment of subcutaneous granuloma annulare with local hyperthermia. PMID- 28636081 TI - Cell size and wall dimensions drive distinct variability of earlywood and latewood density in Northern Hemisphere conifers. AB - Interannual variability of wood density - an important plant functional trait and environmental proxy - in conifers is poorly understood. We therefore explored the anatomical basis of density. We hypothesized that earlywood density is determined by tracheid size and latewood density by wall dimensions, reflecting their different functional tasks. To determine general patterns of variability, density parameters from 27 species and 349 sites across the Northern Hemisphere were correlated to tree-ring width parameters and local climate. We performed the same analyses with density and width derived from anatomical data comprising two species and eight sites. The contributions of tracheid size and wall dimensions to density were disentangled with sensitivity analyses. Notably, correlations between density and width shifted from negative to positive moving from earlywood to latewood. Temperature responses of density varied intraseasonally in strength and sign. The sensitivity analyses revealed tracheid size as the main determinant of earlywood density, while wall dimensions become more influential for latewood density. Our novel approach of integrating detailed anatomical data with large scale tree-ring data allowed us to contribute to an improved understanding of interannual variations of conifer growth and to illustrate how conifers balance investments in the competing xylem functions of hydraulics and mechanical support. PMID- 28636083 TI - Editorial Comment to Predictive value of different prostate-specific antigen based markers in men with baseline total prostate-specific antigen <2.0 ng/mL. PMID- 28636082 TI - Salvianolic acid B protects against acute lung injury by decreasing TRPM6 and TRPM7 expressions in a rat model of sepsis. AB - This study aimed to investigate the protective effects of salvianolic acid B (SA B) on acute lung injury (ALI) through decreasing the expressions of channel kinase's TRPM6 and TRPM7. Wistar Septic rat models were established by lipopolysaccharide (LPS), which were separated into the control, lipopolysaccharide (LPS), SA-B, SA-B + si-TRPM6, SA-B + si-TRPM7, si-TRPM6, and si-TRPM7 groups. Arterial blood gas, protein content, total white blood cell (WBC) count and the percentage of polymorphonuclear neutrophils (PMN%) were measured. Levels of TNF-alpha and IL-6 levels in bronchoalveolar lavage fluid (BALF) were monitored. Lung coefficient, myeloperoxidase (MPO) and superoxide dismutase (SOD) activity were conducted by MPO and SOD kit. The mRNA expressions of TRPM6 and TRPM7 were detected by qRT-PCR. Compared with the control group, the PaO2 and PaO2 /FiO2 values exhibited decreases in other group, while the PaCO2 value, protein content, total WBC, PMN%, TNF-alpha, IL-6 levels and lung coefficient values all increased. MPO activity in lung tissue increased, while SOD activity decreased. TRPM6 and TRPM7 expressions increased significantly. Compared with the LPS group, the SA-B, SA-B + si-TRPM6, SA-B + si-TRPM7, si TRPM6, and si-TRPM7 groups had increased PaO2 and the PaO2 /FiO2 , while decreased PaCO2, protein content, total WBC, PMN%, TNF-alpha, IL-6 levels, and lung coefficient. MPO activity in lung tissue decreased while SOD activity increased. Decreased mRNA expressions of TRPM6 and TRPM7 in the SA-B, SA-B + si TRPM6, and SA-B + si-TRPM6 groups were observed. Through decreasing the expressions of the channel kinase TRPM6 and TRPM7, SA-B protects against ALI in septic rats. PMID- 28636084 TI - Co-morbidities and bleeding in elderly patients with haemophilia-A survey of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). AB - BACKGROUND: Nowadays patients with haemophilia survive longer due to improvements in haemophilia care. It has been hypothesized that the bleeding type and frequency may vary with age and are influenced by co-morbidities and co medication in elderly patients. OBJECTIVES: To investigate a large group of patients older than 60 years of age with haemophilia concerning haemophilia treatment, bleeding pattern changes, co-morbidities, co-medication, bleeding sites and patient mortality. METHODS: A retrospective multi-centre data collection study was initiated on behalf of the German, Austrian and Swiss Society of Thrombosis and Haemostasis Research (GTH). Parameters of interest were investigated over the 5 years prior to study entry. RESULTS: A total of 185 haemophilia patients (mean age, 69.0+/-7.0 years, 29% with severe haemophilia) were included in the study. Regular prophylaxis was performed in 30% of the patients with severe haemophilia. In total, the annual bleeding rate was 2.49 and in patients with severe haemophilia 5.61, mostly caused by joint bleeds. Hypertension was the most common co-morbidity, but it occurred significantly less frequently than in an age-matched general population older than 70 years; 12% of the patients suffered from ischaemic heart disease, and 13% of the patients received anticoagulant or antiplatelet therapy. Within the observation period, 17% of the patients with severe haemophilia developed a higher frequency of bleeding symptoms, which was significantly associated with the use of antiplatelet or anticoagulant drugs. CONCLUSIONS: The most common co-morbidity of the patient population was hypertension, a considerable part had ischemic heart disease and antiplatelet or anticoagulant drugs. PMID- 28636085 TI - Herbivore performance and plant defense after sequential attacks by inducing and suppressing herbivores. AB - It is well known that herbivore-induced plant defenses alter host plant quality and can affect the behavior and performance of later arriving herbivores. Effects of sequential attacks by herbivores that either suppress or induce plant defenses are less well studied. We sequentially infested leaves of tomato plants with a strain of the phytophagous spider mite Tetranychus urticae that induces plant defenses and the closely related Tetranychus evansi, which suppresses plant defenses. Plant quality was quantified through oviposition of both spider mite species and by measuring proteinase inhibitor activity using plant material that had been sequentially attacked by both herbivore species. Spider-mite oviposition data show that T. evansi could suppress an earlier induction of plant defenses by T. urticae, and T. urticae could induce defenses in plants previously attacked by T. evansi in 1 day. Longer attacks by the second species did not result in further changes in oviposition. Proteinase inhibitor activity levels showed that T. evansi suppressed the high activity levels induced by T. urticae to constitutive levels in 1 day, and further suppressed activity to levels similar to those in plants attacked by T. evansi alone. Attacks by T. urticae induced proteinase inhibitor activity in plants previously attacked by T. evansi, eventually to similar levels as induced by T. urticae alone. Hence, plant quality and plant defenses were significantly affected by sequential attacks and the order of attack does not affect subsequent performance, but does affect proteinase inhibitor activity levels. Based on our results, we discuss the evolution of suppression of plant defenses. PMID- 28636086 TI - Selective and Tunable Near-Infrared and Visible Light Transmittance of MoO3-x Nanocomposites with Different Crystallinity. AB - In this Communication, we report MoO3-x nanocomposites in which the near-infrared and visible light transmittance can be selectively modulated through the crystallinity. The MoO3-x nanocomposites were fabricated by a hydrothermal method, and their optical properties were characterized by UV-Vis spectrometer. The obtained results proved the possibility to tune the nanocomposite's optical properties in the UV/Visible spectral region: crystalline MoO3 mainly regulates the near-infrared range (800-2600 nm), and amorphous MoO3-x mainly changes the visible range from 350 nm to 800 nm and MoO3-x , with semi-crystalline structures mainly modulating around 800-1000 nm. These kinds of optical modulations could be attributed to small polar absorption, free electron absorption and plasmon absorption according to different crystallinity. Our work may create new possibilities for future applications such as photochromism, photocatalysis, and electrochromism. PMID- 28636087 TI - Extended inferior antrostomy for maxillary sinus surgery. PMID- 28636088 TI - Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses. AB - Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core-shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-kappaB (NF-kappaB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-beta (TGF-beta)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes. PMID- 28636089 TI - Geographic substructure in craniometric estimates of admixture for contemporary American populations. AB - OBJECTIVES: This study investigates heterogeneity in craniometrically-derived estimates of admixture in order to reveal population substructure in a sample of Black, White, Hispanic, and Native American individuals from the FDB. It reports evidence of spatial trends in population-specific patterns of admixture and contextualizes its results in terms of demographic diversity in the United States. MATERIALS AND METHODS: The FDB was sampled to capture the population variation within forensic casework, skeletal collections, and the U.S. population at-large. Individuals were selected for the availability of population identifier, sex, and geographic information. Variation in inferred admixture proportions was evaluated, per population and by sex, for evidence of geographic substructure. Comparative data was sourced from the U.S. Census. RESULTS: This analysis identifies significant associations between the estimated Black, Native American and White component memberships and place of birth and recovery. The sampled populations differ significantly in admixture proportions, in a systematic way. Admixture patterns vary in accordance with the densities and relative proportions of the U.S. census populations. DISCUSSION: There is considerable variation in admixture estimates, not just between, but notably within, all four of the populations. This substructure can be explained by differences in geography, including regions, divisions, and states. This article's findings agree with census trends and speak broadly to admixture dynamics and ancestral diversity among contemporary Americans. They are also specifically relevant to those cases in the FDB. The presence of subpopulations has implications for cranial research, forensic identification, and studies of biological variation in the United States. PMID- 28636090 TI - Chronic inflammatory acantholytic dermatosis: a previously under-recognized or emerging variant of Grover disease. PMID- 28636091 TI - Biodegradable stents in the treatment of benign biliary strictures: Does one size fit all? PMID- 28636092 TI - Impact of diagnosis of von Willebrand disease on patient outcomes: Analysis of medical insurance claims data. AB - The inherited bleeding disorder von Willebrand disease (VWD) is challenging to diagnose owing to disease heterogeneity, lack of a definitive laboratory test and variations in diagnostic criteria. We evaluated the impact of diagnosis and diagnostic delay on patient outcomes. The PharMetrics Plus Database was interrogated for medical claims for VWD (ICD-9 286.4) and bleeding events between 1 January 2006 and 30 June 2015. Longitudinal analysis was performed of patients newly diagnosed with VWD (>=9 months' continuous enrolment before first VWD claim) through 24 months following diagnosis. In total, 32 028 diagnosed, including 18 182 newly diagnosed, patients were identified. Most patients (72%) were female. Prediagnosis, bleeding symptoms were most commonly managed by a hospitalist/emergency room physician. Misrecognition of VWD was common, with 25% of patients visiting the same specialist type at least twice for an episodic bleed before diagnosis. Thirty-seven percentage of patients had no diagnostic laboratory test within 24 months of their initial diagnostic claim. Bleed claims reduced following diagnosis: 41% and 26% of female and male patients, respectively, had claims in the year prediagnosis, falling to 21% and 9% of patients at 1-2 years postdiagnosis. The proportion of patients with multiple bleed claims also decreased, from 17% to 6% (females) and 7% to 3% (males). Serially misrecognized patients continued to have more bleeding episodes than other patients, although bleed frequency was lower than before diagnosis. There is a need for improved patient management from bleeding presentation onward to reduce the time to VWD diagnosis and to enhance patient outcomes. PMID- 28636093 TI - Introspection Plays an Early Role in Children's Explicit Theory of Mind Development. AB - This study assessed children's (N = 236) ability to introspect the mental states of seeing and knowing relative to their ability to attribute each state to others. Children could introspect seeing 10 months before they could introspect knowing. Two- and 3-year-olds correctly reported their own seeing states, whereas 3- and 4-year-olds correctly reported their own knowing states. For each mental state, there was a 7-month difference before children could correctly attribute that state to another. These findings indicate that knowing is more difficult to introspect than seeing and that the ability to introspect each mental state emerges prior to the ability to correctly attribute them to others. Theoretical implications for self-other differences in theory-of-mind development are considered. PMID- 28636094 TI - Characterisation of clonal Philadelphia-negative cytogenetic abnormalities in a large cohort of chronic myeloid leukaemia. AB - BACKGROUND: Clonal Philadelphia (Ph)-negative cytogenetic abnormalities (CPCA) have been reported in chronic myeloid leukaemia (CML) patients treated with either interferon or tyrosine kinase inhibitor (TKI). However, the incidences and types of these cytogenetic abnormalities after treatment vary due to the limited populations enroled. METHODS: We analysed the frequency and types of CPCA in a cohort of 607 CML patients in the chronic phase after TKI treatment. We also followed up these CPCA with a median of 31.8 months (range from 11 to 63 months) from diagnosis and investigated their effects on disease progression. RESULTS: We found 18 out of 607 CML patients had cytogenetic abnormality in the Ph-negative cells with an incidence of 3%. In total, six types of chromosomal abnormalities have been identified in these 18 patients with the majority of them aneuploidy abnormalities, especially the trisomy 8. Four of 18 patients (22.2%) were noted to have several abnormalities in the Ph-negative cells. Furthermore, follow-up studies of these CPCA showed that they could be either persistent or transient (15 vs 3 patients), and may not affect disease progression since none of them developed transformed myelodysplasia or transformed acute myeloid leukaemia. CONCLUSION: Three percent of CML patients in the chronic phase were observed to have CPCA during TKI treatment. Our results suggest that the detection of CPCA in CML may not predict disease progression. PMID- 28636095 TI - Suppression or knockout of SaF/SaM overcomes the Sa-mediated hybrid male sterility in rice. AB - Hybrids between the indica and japonica subspecies of rice (Oryza sativa) are usually sterile, which hinders utilization of heterosis in the inter-subspecific hybrid breeding. The complex locus Sa comprises two adjacently located genes, SaF and SaM, which interact to cause abortion of pollen grains carrying the japonica allele in japonica-indica hybrids. Here we showed that silencing of SaF or SaM by RNA interference restored male fertility in indica-japonica hybrids with heterozygous Sa. We further used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based genome editing to knockout the SaF and SaM alleles, respectively, of an indica rice line to create hybrid-compatible lines. The resultant artificial neutral alleles did not affect pollen viability and other agricultural traits, but did break down the reproductive barrier in the hybrids. We found that some rice lines have natural neutral allele Sa-n, which was compatible with the typical japonica or indica Sa alleles in hybrids. Our results demonstrate that SaF and SaM are required for hybrid male sterility, but are not essential for pollen development. This study provides effective approaches for the generation of hybrid-compatible lines by knocking out the Sa locus or using the natural Sa-n allele to overcome hybrid male sterility in rice breeding. (c) 2017 The Authors. Bioelectromagnetics published by Wiley Periodicals, Inc. PMID- 28636096 TI - Continuous recording of oblique-view dermoscopy images enables observation of the convergence of the fibrillar into the parallel furrow pattern and to differentiate melanocytic naevi from acral melanoma. PMID- 28636097 TI - Digest: Finding new homes: Multilevel selection on birth timing and growth in North American red squirrels. PMID- 28636100 TI - Plantar wart-like Candida granuloma in a patient with myelodysplastic syndrome. PMID- 28636099 TI - Spectators or participants: How can SETAC become more engaged in international climate change research programs? AB - Environmental toxicologists and chemists have been crucial to evaluating the chemical fate and toxicological effects of environmental contaminants, including chlorinated pesticides, before and after Rachel Carson's publication of Silent Spring in 1962. Like chlorinated pesticides previously, global climate change is widely considered to be one of the most important environmental challenges of our time. Over the past 30 yr, climate scientists and modelers have shown that greenhouse gases such as CO2 and CH4 cause radiative forcing (climate forcing) and lead to increased global temperatures. Despite significant climate change research efforts worldwide, the climate science community has overlooked potential problems associated with chemical contaminants, in particular how climate change could magnify the ecological consequences of their use and disposal. It is conceivable that the impacts of legacy or new chemical contaminants on wildlife and humans may be exacerbated when climate changes, especially if global temperatures rise as predicted. This lack of attention to chemical contaminants represents an opportunity for environmental toxicologists and chemists to become part of the global research program, and our objective is to highlight the importance of and ways for that to occur. Environ Toxicol Chem 2017;36:1971-1977. (c) 2017 SETAC. PMID- 28636098 TI - Repeated procedures at the generator pocket are a determinant of implantable cardioverter-defibrillator infection. AB - BACKGROUND: Rates of cardiac-device infections have increased in recent years, but the current incidence and risk factors for infection in patients with implantable cardioverter-defibrillators (ICDs) are not well known. HYPOTHESIS: The increasing number of ICD infections is related to accumulated pocket manipulations over time. METHODS: This single-center, prospective study included patients that underwent ICD implantation from 2008 to 2015. The endpoint was time to infection. Multivariate analysis was performed to identify independent risk factors related to infection. RESULTS: The study included a total of 570 patients, of whom 419 (73.5%) underwent a first implantation. Mean age was 59 +/- 14 years, and 80% were male. During a median follow-up of 36 months (interquartile range, 18-61 months; 1887 patient-years), infection was identified in 26 patients (4.56%), an incidence of 14.9 * 1000 patient-years. Median time to infection was 9.7 months (interquartile range, 1.35-23.4 months), and 38.5% were late infections (beyond 12 months of follow-up). In patients with replacement implants, the incidence was 3-fold higher than in first implantations (27.7 vs 9.1 * 1000 patient-years; P = 0.002). Cox regression identified 2 independent predictors of ICD infection: cumulative number of interventions at the generator pocket (hazard ratio: 1.92, 95% confidence interval: 1.42-2.6, P < 0.001) and pocket hematoma (hazard ratio: 7.0, 95% confidence interval: 2.7-17.9, P < 0.0001). CONCLUSIONS: The incidence of infection in ICD patients is greater than previously reported, largely due to late infections. Each new cumulative intervention at the same generator pocket nearly doubles the risk of infection. PMID- 28636101 TI - Knockdown of lncRNA MEG3 inhibits viability, migration, and invasion and promotes apoptosis by sponging miR-127 in osteosarcoma cell. AB - Osteosarcoma (OS) is one of the most common bone malignancies and occurs almost exclusively in children and adolescents. This study aimed to explore the role of lncRNA maternally expressed gene 3 (MEG3) in OS cells growth and metastasis, and to uncover the possible underlying mechanism. In this study, the expressions of MEG3 in five OS cell lines (MG63, OS-732, SaOS, G292, and 143B) and in a human osteoblast cell line hFOB1.19 were measured by qRT-PCR analysis. The expressions of MEG3, miR-127, and ZEB1 in OS-732 cells were overexpressed or suppressed by transfection. Cell viability, migration, invasion, and apoptosis were then assessed. The results showed that MEG3 was highly expressed in OS cell lines when compared to hFOB1.19 cell. MEG3 silence significantly suppressed OS-732 cells growth and metastasis, as evidenced by the decreases in cell viability, migration, invasion, and increase in apoptotic cell rate. MEG3 acted as an endogenous sponge by binding to miR-127. More interestingly, MEG3 silence could not suppress OS-732 cells growth and metastasis when miR-127 was knocked down. ZEB1 was a target gene of miR-127, and miR-127 overexpression-induced impairments in cell growth and metastasis were attenuated when ZEB1 was overexpressed. Moreover,miR-127 suppression activated JNK and Wnt signaling pathways, while these activations were recovered by ZEB1 silence. To conclude, our findings suggest that lncRNA MEG3 promoted OS cells growth and metastasis in vitro through sponging miR-127. This study provides the evidence that MEG3 may be a potential therapeutic target for OS. PMID- 28636102 TI - Does the portal of entry determine our view? Interfaces between dyadic and three way assessment of a clinical family transitioning to parenthood. AB - The purpose of this interface was to explore the influences of dyadic and three way observation on clinical assessment of young families. Three independent clinicians observed a clinically referred family using semistructured play paradigms, each with only a limited view of the family. One had only the data on dyadic interactions, the second only had data on the family triad, and the third observed both the dyads and the triad. Interactions were scored using standardized measures as well as the clinical impressions of the three practitioners. The various ports of entry yielded similar impressions in some instances, but each port also provided a richness of information not available from the other portal. Clinical implications are discussed, including not only the benefits of each port for assessment but also the implications for therapy in this case example. PMID- 28636103 TI - Interfaces between intersubjectivity and attachment: Three perspectives on a mother-infant inpatient case. AB - Despite much new literature on clinical early intervention, background theoretical issues have received less critical attention. In this study, we look at a single mother-infant case from different perspectives. To give the discussion a viable focus, we draw upon two types of specific material: an Adult Attachment Interview (M. Main & R. Goldwyn, 1985-1998) and a video of mother infant interaction. We elaborate some alternative conceptualizations of this material, noting similarities, contrasts, and differences in emphasis in these frameworks. A brief series of practical implications for clinical treatment is summarized in conclusion. PMID- 28636104 TI - Attachment disorders in family and social context. AB - Serious disturbances of attachment in young children have been increasingly studied in the past decade as they arise in atypical rearing environments. The purpose of this review is to provide an update on recent findings and to consider their implications. Research on children raised in institutions, children adopted out of institutions, and young children who have experienced neglect in families is considered. Reactive attachment disorder may be identified reliably in a minority of children being raised in severely neglectful environments. The emotionally withdrawn/inhibited pattern and the indiscriminately social/disinhibited pattern arise in similar conditions of risk, but respond differently to intervention and appear to have different correlates. Much has been learned about the emotionally withdrawn/inhibited pattern of reactive attachment disorder and the indiscriminately social/disinhibited pattern. Much less is known about so-called secure base distortions or relational disorders of attachment. PMID- 28636105 TI - The clinical relevance of infancy: A progress report. AB - In the past few decades, findings from infant observations have played a key role in the following selected areas: (a) The emphasis now is on interpersonal and intersubjective processes rather than on intrapsychic processes. This is a paradigm shift towards a two-person psychology. (b) The elaboration of the attachment domain has reoriented our views of development and treatment. (c) The success of extended home-visiting programs as a preventive measure for parents and infants at risk has brought an agonizing reappraisal of what makes prevention (and therapy) work. (d) By default, the baby's world is nonverbal. This has led to a productive reexploration of unconsciousness, especially the domain of implicit knowledge. For the future, the following are some of the areas of great promise: (a) Attachment, love and "holding" must be disentangled. (b) We must study how and when the mirror neuron system gets micro- and macroregulated. One is not always open to empathic reception. (c) The articulation between the nonverbal (implicit) with the verbal (explicit) needs far more study. (d) The nonspecific factors of psychotherapy seem to be the most important in bringing about change and prevention. We need a greater systematic study of the nonspecific. (e) The triad and quartet, and so on need further exploration. (f) There are many more, but the beauty of research is that you can't know where it will go next. PMID- 28636106 TI - Infant's triangular communication in "two for one" versus "two against one" family triangles: Case illustrations. AB - Infants use their social competence very early to communicate not only in dyads but also in triads, in particular in the triangle they form with their mother and father. The development of this triangular communication is largely shaped by the ways the parents support or undermine each other in relation to their child. Whereas triangular communication is facilitated in "two for one" alliances, it is recruited in the service of regulating the parents' conflicts in "two against one" coalitions. These processes are manifest in toddlerhood and may be traced back to the coparenting alliance in formation during pregnancy. PMID- 28636107 TI - The infant's relational worlds: Family, community, and culture. PMID- 28636108 TI - Understanding the influences and impact of patient-clinician communication in cancer care. AB - BACKGROUND: Patient-clinician communication is thought to be central to care outcomes, but when and how communication affects patient outcomes is not well understood. OBJECTIVE: We propose a conceptual model and classification framework upon which the empirical evidence base for the impact of patient-clinician communication can be summarized and further built. DESIGN: We use the proposed model and framework to summarize findings from two recent systematic reviews, one evaluating the use of shared decision making (SDM) on cancer care outcomes and the other evaluating the role of physician recommendation in cancer screening use. KEY RESULTS: Using this approach, we identified clusters of studies with positive findings, including those relying on the measurement of SDM from the patients' perspective and affective-cognitive outcomes, particularly in the context of surgical treatment decision making. We also identify important gaps in the literature, including the role of SDM in post-surgical treatment and end-of life care decisions, and those specifying particular physician communication strategies when recommending cancer screening. CONCLUSIONS: Transparent linkages between key conceptual domains and the influence of methodological approaches on observed patient outcomes are needed to advance our understanding of how and when patient-clinician communication influences patient outcomes. The proposed conceptual model and classification framework can be used to facilitate the translation of empirical evidence into practice and to identify critical gaps in knowledge regarding how and when patient-clinician communication impacts care outcomes in the context of cancer and health care more broadly. PMID- 28636109 TI - Xq26.1-26.3 duplication including MOSPD1 and GPC3 identified in boy with short stature and double outlet right ventricle. AB - Xq25q26 duplication syndrome has been reported in individuals with clinical features such as short stature, intellectual disability, syndromic facial appearance, small hands and feet, and genital abnormalities. The symptoms are related to critical chromosome regions including Xq26.1-26.3. In this particular syndrome, no patient with congenital heart disease was previously reported. Here, we report a 6-year-old boy with typical symptoms of Xq25q26 duplication syndrome and double outlet right ventricle (DORV) with pulmonary atresia (PA). He had the common duplicated region of Xq25q26 duplication syndrome extending to the distal region including the MOSPD1 locus. MOSPD1 regulates transforming growth factor beta (TGFbeta) 2,3 and may be responsible for cardiac development including DORV. In the patient's lymphocytes, mRNA expression of TGFbeta2 was lower than control, and might cause DORV as it does in TGFbeta2-deficient mice. Therefore, MOSPD1 is a possible candidate gene for DORV, probably in combination with GPC3. Further studies of the combined functions of MOSPD1 and GPC3 are needed, and identification of additional patients with MOSPD1 and GPC3 duplication should be pursued. PMID- 28636110 TI - Cumulative toxicity of neonicotinoid insecticide mixtures to Chironomus dilutus under acute exposure scenarios. AB - Extensive agricultural use of neonicotinoid insecticide products has resulted in the presence of neonicotinoid mixtures in surface waters worldwide. Although many aquatic insect species are known to be sensitive to neonicotinoids, the impact of neonicotinoid mixtures is poorly understood. In the present study, the cumulative toxicities of binary and ternary mixtures of select neonicotinoids (imidacloprid, clothianidin, and thiamethoxam) were characterized under acute (96-h) exposure scenarios using the larval midge Chironomus dilutus as a representative aquatic insect species. Using the MIXTOX approach, predictive parametric models were fitted and statistically compared with observed toxicity in subsequent mixture tests. Single-compound toxicity tests yielded median lethal concentration (LC50) values of 4.63, 5.93, and 55.34 MUg/L for imidacloprid, clothianidin, and thiamethoxam, respectively. Because of the similar modes of action of neonicotinoids, concentration-additive cumulative mixture toxicity was the predicted model. However, we found that imidacloprid-clothianidin mixtures demonstrated response-additive dose-level-dependent synergism, clothianidin thiamethoxam mixtures demonstrated concentration-additive synergism, and imidacloprid-thiamethoxam mixtures demonstrated response-additive dose-ratio dependent synergism, with toxicity shifting from antagonism to synergism as the relative concentration of thiamethoxam increased. Imidacloprid-clothianidin thiamethoxam ternary mixtures demonstrated response-additive synergism. These results indicate that, under acute exposure scenarios, the toxicity of neonicotinoid mixtures to C. dilutus cannot be predicted using the common assumption of additive joint activity. Indeed, the overarching trend of synergistic deviation emphasizes the need for further research into the ecotoxicological effects of neonicotinoid insecticide mixtures in field settings, the development of better toxicity models for neonicotinoid mixture exposures, and the consideration of mixture effects when setting water quality guidelines for this class of pesticides. Environ Toxicol Chem 2017;36:3091-3101. (c) 2017 SETAC. PMID- 28636111 TI - Microalbuminuria is associated with increased choroidal thickness in type 1 diabetes mellitus patients without diabetic retinopathy. PMID- 28636113 TI - Linking ReI and PtII Chromophores with Aminopyridines: A Simple Route to Achieve a Complicated Photophysical Behavior. AB - The bifunctional aminopyridine ligands H2 N-(CH2 )n -4-C5 H4 N (n=0, L1; 1, L2; 2, L3) have been utilized for the preparation of the rhenium complexes [Re(phen)(CO)3 (L1-L3)]+ (1-3; phen=phenanthroline). Complexes 2 and 3 with NH2 coordinated L2 and L3, respectively, were coupled with cycloplatinated motifs {Pt(ppy)Cl} and {Pt(dpyb)}+ (ppy=2-phenylpyridine, dpyb=dipyridylbenzene) to give the bimetallic species [Re(phen)(CO)3 (MU-L2/L3)Pt(ppy)Cl]+ (4, 6) and [Re(phen)(CO)3 (MU-L2/L3)Pt(dpyb)]2+ (5, 7). In solution, complexes 4 and 6 show 3 MLCT {Re}-based emission at 298 K, which changes to the 3 IL(ppy) state at 77 K. The photophysical properties of compounds 5 and 7 display a pronounced concentration dependence, presumably due to the formation of bimolecular aggregates. Analysis of the spectroscopic data, combined with TD-DFT simulations, suggest that unconventional heteroleptic {Re(phen)}???{Pt(dpyb)} pi-pi stacking operates as the driving force for ground-state association. The latter, together with intra- and intermolecular energy-transfer processes, determines the appearance of multiple emission bands and results in nonlinear relaxation kinetics of the excited states. PMID- 28636112 TI - Fluorescent carbon nanoparticles obtained from charcoal via green methods and their application for sensing Fe3+ in an aqueous medium. AB - Two green methods (microwave and hydrothermal) were employed for the preparation of water dispersible fluorescent carbon nanoparticles (CNPs) from activated charcoal. Microwave and hydrothermally synthesized carbon nanoparticles, (MW CNPs) and (HT-CNPs), respectively were characterized by microscopic and spectroscopic techniques. A detailed study of their fluorescence characteristics was made. MW-CNPs and HT-CNPs were tested for metal ion selectivity in aqueous medium. MW-CNPs showed selectivity for Fe3+ among the tested metal ions and important studies such as for interference, linear range and limit of detection were carried out. The application of MW-CNPs for detection of Fe3+ in water was demonstrated. PMID- 28636114 TI - SET/I2PP2A overexpression induces phenotypic, molecular, and metabolic alterations in an oral keratinocyte cell line. AB - The multifunctional SET/I2PP2A protein is known to be overexpressed in head and neck squamous cell carcinoma. However, SET has been reported to have apparently conflicting roles in promoting cancer cell survival under oxidative stress conditions and preventing invasion and metastasis, complicating efforts to understand the contribution of SET to carcinogenesis. In the present study, we overexpressed SETin a spontaneously immortalized oral keratinocyte cell line (NOK SI SET) and demonstrated that SET upregulation alone was sufficient to transform cells. In comparison with NOK-SI cells, NOK-SI SET cells demonstrated increased levels of phosphorylated Akt, c-Myc and inactive/phosphorylated Rb, together with decreased total Rb protein levels. In addition, NOK-SI SET cells presented the following: (a) a spindle-cell shape morphology compared with the polygonal morphology of NOK-SI cells; (b) loss of mesenchymal stem cell markers CD44 and CD73, and epithelial cell markers CD71 and integrin alpha6/beta4; (c) the ability to form xenograft tumors in nude mice; and (d) increased mitochondrial respiration accompanied by decreased ROSlevels. Overall, our results show that SEToverexpression promotes morphological and oncogenic cell transformation of an oral keratinocyte cell. PMID- 28636115 TI - SiRNA-Mediated Down-Regulation of CLIC4 Gene Inhibits Cell Proliferation and Accelerates Cell Apoptosis of Mouse Liver Cancer Hca-F and Hca-P Cells. AB - This study explored the effects involved in silencing CLIC4 on apoptosis and proliferation of mouse liver cancer Hca-F and Hca-P cells. A CLIC4-target small interfering RNA (siRNA) was designed to compound into two individual complementary oligonucleotide chains. A process of annealing and connection to a pSilencer vector was followed by transfection with Hca-F and Hca-P cells. Quantitative real-time polymerase chain reaction and Western blotting techniques were used to determine CLIC4 mRNA and protein expressions. CCK8 assay and flow cytometry were employed for analysis of the survival and apoptosis rate as well as the cell cycle in an octreotide-induced apoptosis model. Expressions of caspase 3, caspase 9, and cleaved PARP were measured using Western blotting. The CLIC4 mRNA and protein expressions in Hca-F and Hca-P cells transfected by pSilencer-CLIC4 siRNA plasmid in the blank group displayed remarkably decreased levels of expression, when compared with both the control and negative control (NC) groups. Decreased survival rates and cleaved PARP expression, increased cell apoptosis rate,expressions of caspase 3 and caspase 9 in Hca-F and Hca-P cells were detected in groups that had been cultured in a medium containing octreotide. The pSilencer-CLIC4 siRNA-2 group when compared with the control and NC groups exhibited decreased survival rates, cleaved PARP expression, increased cell apoptosis rates, and increased expressions of caspase 3 and caspase 9 of Hca-F and Hca-P cells. The results demonstrated that siRNA-induced down-regulation of CLIC4 could proliferation, while in turn promoting apoptosis of mouse liver cancer Hca-F and Hca-P cells. J. Cell. Biochem. 119: 659-668, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28636117 TI - Infant irritability: The impact of fetal alcohol exposure, maternal depressive symptoms, and low emotional support from the husband. AB - OBJECTIVES: The aim of this study was to investigate the impact of fetal alcohol exposure, maternal depressive symptoms, and low emotional support from the husband on infant irritability in the first one and a half years of life. Four models describing the interplay of these factors were assessed: A direct effect model, an interaction or threshold model, a mediational model and a transactional model. METHOD: A sample of initially 458 women was assessed in a prospective 3 wave study across the first 17 months after childbirth. Fetal alcohol exposure was questioned retrospectively six weeks after birth. Infant irritability was reported by the mothers and fathers. RESULTS: Support for the direct effect model and the interaction model could be found: Fetal alcohol exposure and low emotional support from the husband were associated with increased infant irritability at 5 months. The impact of fetal alcohol exposure was moderated by postnatal depressive symptoms. More irritability was reported if both risk factors, prenatal alcohol exposure and maternal depressive symptoms, were present. Infant irritability and maternal depressive symptoms were associated cross-sectionally. At the age of 17 months only a main effect of prenatal alcohol exposure on irritability could be found. CONCLUSION: Direct effects of fetal alcohol exposure, maternal depressive symptoms, and low emotional support from the husband on infant irritability as well as an interaction between fetal alcohol exposure and maternal depressive symptoms were revealed. The interaction can be understood in terms of a diathesis-stress model. However, no longitudinal associations between maternal depressive symptoms and infant irritability could be found. PMID- 28636116 TI - Curriculum content and assessment of pre-clinical dental skills: A survey of undergraduate dental education in Europe. AB - INTRODUCTION: Since 1981, the qualifications for various healthcare professionals across the European Union have enjoyed mutual recognition in accordance with the EU Directive 81/1057/EEC. Whilst the directive includes dental practitioners, it is recognised that significant variation exists in curriculum structure, content and scope of practice across institutions. This article aimed to explore pan European practice in relation to curriculum content, teaching and learning strategies and assessment of pre-clinical dental skills. METHOD: A request to complete an online questionnaire, in English, was sent electronically to skills leads at all Association of Dental Education in Europe member schools. The questionnaire collected information in relation to institution and country, regulatory requirements to demonstrate safety, details of specific pre-clinical skills courses, learning materials and teaching staff. RESULTS: Forty-eight institutions, from 25 European countries responded. Seven countries (n=7, 28%) reported no requirement to demonstrate student operative safety prior to patient treatment. Several core and operative clinical skills are common to the majority of institutions. The most commonly taught core skills related directly to the clinical environment such as cross-infection control and hand washing. The least common were skills that indirectly related to patient care, such as communication skills and working as a team. CONCLUSION: There are clear differences within European pre-clinical dental education, and greater efforts are needed to demonstrate that all European students are fit to practice before they start treating patients. Learning outcomes, teaching activities and assessment activities of pre-clinical skills should be shared collaboratively to further standardise curricula. PMID- 28636118 TI - Mental health in infants with esophageal atresia. AB - Chronic somatic illness in infancy may challenge the development of mental health and impinge the infant's capability to form close interpersonal relationships. Esophageal atresia (EA) is a congenital anomaly requiring neonatal surgery, medical aftertreatment, and extended hospitalization. The aim of the study was to assess mental health and to find prognostic factors for mental health among infants with EA. Thirty-nine infants treated consecutively during 2000 to 2003 and their mothers were included. Infant mental health was assessed by Diagnostic Classification: 0-3 (Zero to Three, 1994). Medical and environmental data were collected from medical records and semistructured interview with the mothers. Child development was assessed with the Bayley scales, second edition (N. Bayley, 1993). Maternal psychological distress, anxiety, and child temperament were assessed by self-report questionnaires: the General Health Questionnaire, 30-item version (D. Goldberg & P. Williams, 1988); the State Trait Anxiety Inventory (C.D. Spielberger, R. Gorsuch, & R. Lushene, 1970); and the Infant Behaviour Questionnaire (M.K. Rothbart, 1981). Thirty-one percent of the infants with EA showed mental health disorders by 1 year of age. Prognostic factors predicting mental health were posttraumatic symptoms reported by mother, more than one operation, mechanical ventilation beyond 1 day, and moderate/severe chronic family strain. Relational trauma, vulnerable attachment, and impaired self development are highlighted as possible pathways for psychopathology. Children with EA are vulnerable to mental health disorders, and this study may help clinicians to identify children at risk. PMID- 28636119 TI - Termination as a therapeutic intervention when treating children who have experienced multiple losses. AB - Children who have endured traumatizing events often have a history of prior disruptions and losses which also have been experienced as traumatic. Termination of therapy with these children, therefore, provides a unique opportunity for the clinician to provide the traumatized child and his or her caregiver with a new experience of loss; one that is controlled, predictable, and paced. Through this experience, the child and caregiver can develop a new model for loss, one that permits for losses that are a natural part of healthy growth and change. This article outlines one approach to utilizing termination as an integral component of the therapeutic process with infants, toddlers, and preschoolers and their caregivers. Using a psychodynamic model and working dyadically with the child and the caregiver, termination is approached as a primary intervention, pivotal to the successful treatment of this vulnerable population. PMID- 28636120 TI - Promoting infant well-being in the context of maternal depression by supporting the father. AB - Maternal depression is recognized as posing a significant risk to the healthy development of infants. Guided by attachment theory, interventions have focused on the distressed mother's relationship with her infant. While interventions which include fathers are reported in the literature, the processes involved in the fathers' support of a distressed mother and in his interactions with his infant in the context of maternal depression remain unexplored. In the case study described here, home-visiting support was directed to the father in a couple in which the mother had been treated for depression after the birth. The observed effects of the intervention on father-infant interaction and the "knock-on" effects on the mothers' parenting suggest that targeting support to fathers in distressed families should be considered. Points for a service protocol are provided to incorporate fathers into the identification and treatment of maternal distress. PMID- 28636121 TI - Young children's responses to September 11th: The New York City experience. AB - Although the knowledge base regarding very young children's responses to trauma has been expanding, descriptions of their responses to terrorism remain sparse. Yet, their vulnerability makes this an important group to study. Recent events in the United States (9/11, Hurricane Katrina) make this question highly relevant. This study aims to provide extensive descriptions of how children 5 years or younger on September 11th who were living in close proximity to Ground Zero responded that day and in the following months. Sixty-seven New York City parents (with 104 children) participated in focus groups between November 2001 and May 2002. Focus groups also provided a foundation for an in-depth study examining young children's adaptation following 9/11 and changes in parenting behaviors after the disaster. Findings on children's behavioral and emotional reactions on 9/11 and in the 8 months after as well as their need to return to normalcy are reported. Consistent with current understanding of trauma symptoms in young children, parents reported behaviors including chronic sleep disruptions, fearful reactions, development of new fears, and increased clinginess and separation anxiety following the disaster. On the actual day, children's responses were described as ranging from calm and cooperative to difficult and panicky. Implications for working with parents and young children affected by terrorism or community-level trauma and directions for future research are discussed. PMID- 28636122 TI - Hidradenitis Suppurativa in Down Syndrome: A Case Series. AB - BACKGROUND/OBJECTIVES: Many dermatologic and systemic diseases have been reported in association with hidradenitis suppurativa, but its association with Down syndrome is rarely mentioned in the literature. The objective of the current study was to assess the frequency of hidradenitis suppurativa in patients with Down syndrome who visited our clinic over 4 years. METHODS: We recorded the presenting complaints and dermatologic problems of patients with Down syndrome who visited our clinic from January 2011 to December 2014. Medical photographs were taken. Patients with hidradenitis suppurativa were assessed according to severity and treated with topical and systemic medications. RESULTS: Twenty-nine new patients with Down syndrome visited our clinic during this period. Eleven had hidradenitis suppurativa. Disease severity included Hurley stages I and II. CONCLUSION: The presence of hidradenitis suppurativa in 38% of patients with Down syndrome is far higher than would be expected by chance alone. PMID- 28636123 TI - SEM imaging of the stimulatory response of RAW264.7 cells against Porphyromonas gingivalis using a simple technique employing new conductive materials. AB - In the medical biology, it is essential to understand not only biological morphology but also the interaction between biological materials and agents. To study these, electron microscopy (EM) is often utilized. However, sample preparation techniques for EM require a high level of skill and a considerable time. Here, we conducted EM using a simple technique employing a conductive liquid, BEL-1, and compared the results with another simple technique employing an ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4 ]). BEL-1 was used for sample pretreatment, and the morphologies of the mouse RAW 264.7 cell line, Porphyromonas gingivalis, and the RAW 264.7 cell line were stimulated via co-incubation with P. gingivalis and observed using field emission scanning EM (FE-SEM). In the present study, the inflammation-induced system of P. gingivalis was successfully established. FE-SEM results revealed the fine morphology of the RAW 264.7 cell line and P. gingivalis and confirmed a morphological change in the RAW 264.7 cell line caused by P. gingivalis stimulation. Using the developed sample preparation technique employing BEL-1, high-contrast and high-resolution observations of deformable biological materials were conducted without any difficulty or the necessity for complicated technique. This morphological information and the developed techniques can contribute to reveal the interaction between biological materials and agents and thereby accelerate drug formulation and disease treatment. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1280-1285, 2018. PMID- 28636124 TI - The IPS-scale: A new soft tissue assessment scale for percutaneous and transcutaneous implants for bone conduction devices. PMID- 28636125 TI - Forensic application of stable isotope delta values: Proposed minimum requirements for method validation. PMID- 28636126 TI - Bilateral diffuse uveal melanocytic proliferation: Case report and literature review. AB - Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic intraocular disease that causes progressive visual loss in patients driven by an IgG factor associated with an underlying malignancy. Characteristic ocular findings include exudative retinal detachment, rapid cataract formation and uveal melanocytic tumours. The awareness and documentation of BDUMP has increased during the past decade, and the increasing amount of data collected demonstrates the effect of treatment with plasmapheresis and the value of diagnostic tools in BDUMP such as genetic and immunologic investigations. The literature of BDUMP has not been reviewed since 2003, and there is a growing need for an updated review on diagnosis and management of BDUMP. We review the literature and report a case of BDUMP with a white ciliary body tumour, iris rubeosis, increased iris pigmentation and cataract. PMID- 28636127 TI - Nonmediated, Label-Free Based Detection of Cardiovascular Biomarker in a Biological Sample. AB - Direct electrochemical (EC) monitoring in a cell culture medium without electron transporter as called mediator is attractive topic in vitro organoid based on chip with frequently and long-time monitoring since it can avoid to its disadvantage as stability, toxicity. Here, direct monitoring with nonmediator is demonstrated based on impedance spectroscopy under the culture medium in order to overcome the limitation of mediator. The applicability of EC monitoring is shown by detecting alpha-1-anti trypsin (A1AT) which is known as biomarkers for cardiac damage and is widely chosen in organoid cardiac cell-based chip. The validity of presented EC monitoring is proved by observing signal processing and transduction in medium, mediator, medium-mediator complex. After the observation of electron behavior, A1AT as target analyte is immobilized on the electrode and detected using antibody-antigen interaction. As a result, the result indicates limit of detection is 10 ng mL-1 and linearity for the 10-1000 ng mL-1 range, with a sensitivity of 3980 nF (log [g mL])-1 retaining specificity. This EC monitoring is based on label-free and reagentless detection, will pave the way to use for continuous and simple monitoring of in vitro organoid platform. PMID- 28636128 TI - Phosphonium Salts as Pseudohalides: Regioselective Nickel-Catalyzed Cross Coupling of Complex Pyridines and Diazines. AB - Heterobiaryls are important pharmacophores that are challenging to prepare by traditional cross-coupling methods. An alternative approach is presented where pyridines and diazines are converted into heteroaryl phosphonium salts and coupled with aryl boronic acids. Nickel catalysts are unique for selective heteroaryl transfer, and the reaction has a broad substrate scope that includes complex pharmaceuticals. Phosphonium ions also display orthogonal reactivity in cross-couplings compared to halides, enabling chemoselective palladium- and nickel-catalyzed coupling sequences. PMID- 28636129 TI - The 52nd International Conference on Medicinal Chemistry (RICT 2016) of the French Medicinal Chemistry Society (SCT) Held in Caen (Normandy). AB - Outstanding Medchem in France: Guest editors Janos Sapi, Luc Van Hjfte, and Patrick Dallemagne look back at the 52nd International Conference on Medicinal Chemistry (RICT 2016) held in Caen, France. They discuss the history of the French Medicinal Chemistry Society (Societe de Chimie Therapeutique, SCT) and provide highlights of last year's events, including some key presentations now collected in this Special Issue. PMID- 28636130 TI - Microstructural changes in the fovea following autologous internal limiting membrane transplantation surgery for large macular holes. PMID- 28636131 TI - State, trait, and dental anxiety in caregivers of individuals with disabilities. AB - PURPOSE: The aim of this study was to compare state anxiety, trait anxiety, and dental anxiety in caregivers of patients with special needs and caregivers of pediatric patients without special needs at dental clinics. MATERIALS AND METHODS: A quantitative, cross-sectional study was conducted. Data were collected using a semistructured questionnaire. All respondents were older than 18 years of age. Individuals with cognitive impairment and those taking anxiolytics, antidepressants, or sleep-inducing medication were excluded from the study. The sample consisted of 55 caregivers of patients with special needs and 55 caregivers of pediatric dental patients. A questionnaire was administered to determine the sociodemographic profile of the patients based on the 2015 Brazilian Economic Classification Criteria. Anxiety regarding dental treatment was measured using the dental anxiety scale. The state-trait anxiety inventory was used to identify state and trait anxiety levels. RESULTS: Caregivers of individuals with disabilities had a similar level of anxiety as caregivers of pediatric dental patients. Most caregivers of individuals with disabilities were mothers with an older age and a greater frequency of trait anxiety, especially when these mothers had health problems. State anxiety was associated with a lower education level. CONCLUSIONS: Higher dental anxiety levels were found among caregivers with a higher level of trait anxiety, independently of the type of patient to which care was given. PMID- 28636133 TI - Association of chronic hypertension with birth of small-for-gestational-age neonate. AB - OBJECTIVE: To examine the effect of chronic hypertension (CH), with and without superimposed pre-eclampsia (PE), on the incidence of a small-for-gestational-age (SGA) neonate and to explore the possible mechanism for such association. METHODS: Data for this study were derived from prospective screening for adverse pregnancy outcomes in women with singleton pregnancy attending their first routine hospital visit at 11-13 weeks' gestation, which included recording of maternal characteristics and medical history and measurement of mean arterial pressure (MAP). Birth-weight Z-score, adjusted for gestational age and maternal and pregnancy characteristics, and incidence of SGA were compared between those with and those without CH in the total population and in the subgroups of pregnancies with and without PE. Regression analysis was used to examine the relationship between MAP and birth-weight Z-score and incidence of SGA and PE in those with and those without CH. RESULTS: The study population constituted 74 226 pregnancies, including 1052 (1.4%) with CH and 73 174 without CH. PE developed in 233 (22.1%) cases of the group with CH and in 1662 (2.3%) of those without CH. In the group that developed PE, there was no significant difference for either median birth-weight Z-score or incidence of SGA between those with CH and those without CH. In the group without PE, the incidence of SGA was twice as high in those with CH than in those without. There was a significant association between log10 MAP multiples of the median and incidence of SGA and PE, which was more marked in those with CH than in those without. CONCLUSION: CH is associated with an increased risk of SGA and PE and this is related to MAP at 11-13 weeks' gestation. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28636134 TI - Cerebrovascular diseases in hemophiliacs: A real, but underestimated risk. PMID- 28636132 TI - TRPC1- and TRPC3-dependent Ca2+ signaling in mouse cortical astrocytes affects injury-evoked astrogliosis in vivo. AB - Following brain injury astrocytes change into a reactive state, proliferate and grow into the site of lesion, a process called astrogliosis, initiated and regulated by changes in cytoplasmic Ca2+ . Transient receptor potential canonical (TRPC) channels may contribute to Ca2+ influx but their presence and possible function in astrocytes is not known. By RT-PCR and RNA sequencing we identified transcripts of Trpc1, Trpc2, Trpc3, and Trpc4 in FACS-sorted glutamate aspartate transporter (GLAST)-positive cultured mouse cortical astrocytes and subcloned full-length Trpc1 and Trpc3 cDNAs from these cells. Ca2+ entry in cortical astrocytes depended on TRPC3 and was increased in the absence of Trpc1. After co expression of Trpc1 and Trpc3 in HEK-293 cells both proteins co-immunoprecipitate and form functional heteromeric channels, with TRPC1 reducing TRPC3 activity. In vitro, lack of Trpc3 reduced astrocyte proliferation and migration whereas the TRPC3 gain-of-function moonwalker mutation and Trpc1 deficiency increased astrocyte migration. In vivo, astrogliosis and cortex edema following stab wound injury were reduced in Trpc3-/- but increased in Trpc1-/- mice. In summary, our results show a decisive contribution of TRPC3 to astrocyte Ca2+ signaling, which is even augmented in the absence of Trpc1, in particular following brain injury. Targeted therapies to reduce TRPC3 channel activity in astrocytes might therefore be beneficial in traumatic brain injury. PMID- 28636135 TI - Job satisfaction mediates subjective social status and turnover intention among Chinese nurses. AB - Nurse turnover is one of the reasons for the global nurse shortage. Although previous studies have examined the determinants of turnover intention in detail, there is limited knowledge on the effect of subjective social status on nurse turnover intention. Therefore, in this study, we examined this relationship, including job satisfaction as a mediator, among Chinese nurses. This cross sectional study employed questionnaires to assess subjective social status, job satisfaction, and turnover intention in 581 nurses who were randomly recruited from 10 hospitals in Jinan, China. The results partially supported our model. Although subjective social status exerted no significant direct effect on turnover intention, it exerted a significant indirect effect through job satisfaction. These results provide a new insight into why nurses leave their jobs, and possible new solutions to the nurse turnover problem. Efforts should be made to improve nurses' subjective social status. PMID- 28636136 TI - Capillary zone electrophorsis for the analysis of naturally occurring 2 hydroxycitric acids and their lactones. AB - A simple capillary zone electrophoresis method with direct ultraviolet detection has been developed for the analysis of naturally occurring diastereomeric 2 hydroxycitric acid lactones. Using 50 mM sodium phosphate buffer of pH 7, a baseline resolution Rs > 3.0 was observed for all organic acids selected for the present study. This method was employed for the quantitative determination of title acids present in the plant sources namely Garcinia cambogia fruit rinds and Hibiscus sabdariffa calyx. Conversion of 2-hydroxycitric acids to their lactones on heating the above plant sources is deliberated. The Hydrolysis of hydroxycitric acid lactones in aqueous solution is reported for the first time. PMID- 28636138 TI - Dermoscopy for improving the diagnosis of pretibial pruritic papular dermatitis. PMID- 28636137 TI - The experience of waiting for a kidney transplant: A qualitative study. AB - BACKGROUND: In Australia over 1100 people are living on dialysis while waiting for a kidney transplant from a deceased donor. Worldwide there are an estimated 170,000 people who wait an average of three years before an organ becomes available. OBJECTIVE: To provide an understanding of the lived experience of people waiting on dialysis for a kidney transplant from a deceased donor. APPROACH: A qualitative descriptive research design was used. Participants were recruited from a large metropolitan hospital. Two focus groups were conducted with six participants ranging in age from 29-63 years, with dialysis experience of 10-72 months. Data saturation was achieved and thematic analysis was used to interpret the data providing a descriptive account of the experience of waiting for a kidney transplant. FINDINGS: Waiting for a kidney transplant takes place in the context of living on dialysis. Four main themes were identified: living on dialysis is physically and mentally demanding; living with uncertainty; altered relationship dynamics; and feelings towards the deceased donor. CONCLUSIONS: This study provides a descriptive summary of what it is like to live on dialysis while waiting for a kidney transplant from a deceased donor from the perspective of the person waiting. People are burdened by; uncertainty; the experience of the dialysis therapy; and the thought of the human cost of transplantation. These findings suggest that this cohort may benefit from strategies to relieve uncertainty such as effective communication from the treating team and peer support from the dialysis community. PMID- 28636139 TI - Review of HPLC and LC-MS/MS assays for the determination of various nonsteroidal anti-androgens used in the treatment of prostate cancer. AB - Prostate cancer is the most common cancer and one of the leading causes of cancer deaths in men. One of the commonly used approaches to treat metastatic prostate cancer was via first-generation nonsteroidal anti-androgens (NSAAs), namely flutamide, nilutamide, bicalutamide and topilutamide. Most prostate cancer patients who are initially responsive develop the most aggressive form of disease called castration-resistant prostate cancer. Second-generation NSAA receptor antagonists (enzalutamide, apalutamide and darolutamide) are emerging as additional new options to treat castration-resistant prostate cancer. The objective of this work was to review the literature on the bioanalytical methods for the quantification of first- and second-generation NSAA inhibitors in clinical (human plasma) and preclinical (mouse plasma, rat plasma, urine and tissue homogenates etc.) studies along with relevant case studies for some chosen drugs. Based on the review, it was concluded that the published methodologies using either HPLC or LC-MS/MS are well suited for the quantification of NSAA inhibitors in various biological fluids to delineate pharmacokinetic data. PMID- 28636140 TI - Case of recalcitrant nail psoriasis unresponsive to adalimumab but successfully treated with infliximab. PMID- 28636141 TI - Binocular facilitation of cone-specific visual evoked potentials in colour deficiency. AB - BACKGROUND: Neural compensatory mechanisms have been proposed, which preserve the binocular visual field in glaucoma, as well as cognition in Alzheimer's disease and motor function in Parkinson's disease. It is conceivable that comparable mechanisms operate to preserve function in congenital and/or dystrophic disease. In hereditary colour vision deficiency (CVD), we observed significant facilitation in the amplitude of the binocular cone-specific visual evoked potential (VEP) compared to the monocular amplitude for the cone type corresponding to the CVD. We propose that this finding may reflect preservation of function in hereditary colour vision deficiency. METHODS: Binocular and monocular L, M and S cone-specific VEPs were recorded from 12 colour vision deficient subjects and 17 with normal colour vision, confirmed to be CVD or normal on a battery of colour vision tests. Binocular VEP amplitudes were compared to monocular amplitudes within subjects and between subject groups. RESULTS: Subjects with CVDs showed binocular facilitation of VEP amplitude (enhancement more than 2.0 times; mean: 2.8 times, p = 0.0003) for the cone type corresponding to their CVD. Mean facilitation of 2.8 times exceeded binocular enhancement for other cone types within CVDs (2.8 times versus 1.2 times) and compared to colour vision normals (2.8 times versus 1.2 times). CONCLUSIONS: Hereditary CVDs show binocular facilitation of cone VEP signals for the cone type corresponding to their CVD. As CVD is typically assessed with foveal stimuli, our findings using wider-field binocular stimulation suggest that enhanced colour perception may occur in CVD across a more extensive area of visual field. These results may relate to binocular visual field enhancement in glaucoma and improved colour vision in CVD at supra-threshold levels of stimulation. PMID- 28636142 TI - Clinical development of immunotherapy for prostate cancer. AB - Prostate cancer is the most common cancer in men, and the second leading cause of cancer-related death in Western countries. Prostate cancer-related death occurs in patients with metastatic castration-resistant prostate cancer. Although several new drugs for castration-resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed. PMID- 28636144 TI - Preface. PMID- 28636143 TI - Tetratricopeptide repeat protein Pyg7 is essential for photosystem I assembly by interacting with PsaC in Arabidopsis. AB - Although progress has been made in determining the structure and understanding the function of photosystem I (PSI), the PSI assembly process remains poorly understood. PsaC is an essential subunit of PSI and participates in the transfer of electrons to ferredoxin. However, how PsaC is assembled during accumulation of the PSI complex is unknown. In the present study, we showed that Pyg7 localized to the stromal thylakoid and associated with the PSI complex. We also showed that Pyg7 interacted with PsaC. Furthermore, we found that the PSI assembly process was blocked following formation of the PsaAB heterodimer in the pyg7 mutant. In addition, the analyses of PSI stability in Pyg7RNAi plants showed that Pyg7 is involved in maintaining the assembled PSI complex under excess-light conditions. Moreover, we demonstrated that decreased Pyg7 content resulted in decreased efficiency of PSI assembly in Pyg7RNAi plants. These findings suggest that the role of Pyg7 in PSI biogenesis has evolved as an essential assembly factor by interacting with PsaC in Arabidopsis, in addition to being a stability factor for PSI as seen in Synechocystis. PMID- 28636145 TI - European Academy of Neurology - Resident and Research Fellow Section: innovations and future direction in 2017. PMID- 28636146 TI - Recent climatic drying leads to age-independent growth reductions of white spruce stands in western Canada. AB - Since 2001, climatic conditions have been notably drier than normal across large areas of the western Canadian interior, leading to widespread impacts on the forests of this region. This poses a major concern for the future, given climate change projections for continued warming and drying. We conducted tree-ring analysis in 75 pure stands of white spruce (Picea glauca) across Alberta and west central Saskatchewan to examine the effects of recent climatic drying on the growth of this important boreal tree species. Allometric equations were used to calculate annual growth in aboveground tree biomass (GBM ) from ring width measurements. Results showed an increasing trend in GBM from the 1960s to the 1990s, followed by a sharp decline during the severe drought of 2001-2002. Of the 75 stands, only 18 recovered sufficiently to cause an increase in mean GBM from the predrought decade of 1991-2000 to the subsequent decade of 2001-2010. The remaining 57 stands exhibited a decline in mean GBM between these decades. Climatic drying was a major cause of the growth decline, as shown by the significant stand-level relationship between percentage change in decadal mean GBM and the change in decadal mean values of a climate moisture index from 1991 2000 to 2001-2010. Subsequent analyses of boreal stands sampled across Alberta during 2015 revealed that white spruce growth had declined even further as drought conditions intensified during 2014-2015. Overall, there was a 38% decrease in mean GBM between 1997 and 2015, but surprisingly, the percentage decrease was not significantly different for young, productive stands compared with older, less productive stands. Thus, stand ageing cannot explain the observed decline in white spruce growth during the past quarter century, suggesting that these forests are at risk if the trend towards more frequent, severe drought continues in the region. PMID- 28636147 TI - Digest: Floral ambush in the sun: Evolution of flower-dwelling and UV-white reflectance in crab spiders. PMID- 28636148 TI - Magnetostructural Characterization of Oxalamide Dihalo-Bridged Copper Dimers: Intra- and Interdimer Interactions Studied by Single-Crystal Electron Spin Resonance Spectroscopy. AB - Detailed single-crystal electron spin resonance (ESR) analysis of oxalamide complexes with halogen-bridged copper dimers, supported by X-ray, magnetic susceptibility, and powder ESR studies, is reported. Four complexes with two different ligands are synthesized: [CuLA (MU-X)]2 and [CuLV (MU-X)]2 , for which LA =N-(l-alanine methyl ester)-N'-[(2-pyridine-2-yl)methyl]oxalamide and LV =N-(l valine methyl ester)-N'-[(2-pyridine-2-yl)methyl]oxalamide, for which X=Cl or Br. X-ray analysis shows that the geometry at each copper(II) ion is square pyramidal, whereas two pyramids share one base-to-apex edge with parallel basal planes. The complexes are linked by hydrogen bonds into infinite chains and are further linked into a 3D network. Susceptibility measurements show that the copper centers in the dimers are weakly antiferromagnetically coupled (|J|~1-2 cm 1 ). From powder ESR spectroscopy, the g values and dx2-y2 orbital as the ground state of the unpaired electron are determined. The complexes show unusual anisotropic splitting and merging of the ESR lines if their single crystals rotate in a magnetic field. The observation of this partially resolved intradimer dipolar splitting enables estimation of the weak interdimer exchange interaction parameter |J'|~0.001 cm-1 . PMID- 28636150 TI - Multiple milia associated with use of the tyrosine kinase inhibitor dovitinib. PMID- 28636149 TI - Photocatalytic interaction of aminophylline-riboflavin leads to ROS-mediated DNA damage and cell death: A novel phototherapeutic mechanism for cancer. AB - The accompanied tissue devastation and systemic toxicity of chemotherapy has shifted the quest for having an effective and palliative cancer therapy towards photodynamic therapy (PDT). Riboflavin (Rf), an essential micronutrient is emerging as a potent tool of PDT, due to its excellent photosensitizing properties. It can be used as an efficient adjuvant for various anticancer drugs. The hemolytic and proteolytic effect of photoilluminated aminophylline (Am), a xanthine derivative, and Rf is well documented in literature. In this study, using human peripheral lymphocytes we have demonstrated the strong pro-oxidant effects of photocatalytic interaction between Am and Rf. The photo degradation kinetics of Am in the presence of Rf was monitored using UV spectroscopy, fluorescence spectroscopy, and Fourier transform infrared spectroscopy. The resultant pro-oxidant action of Am was monitored through various assays like lipid peroxidation, protein carbonylation, and reactive oxygen species (ROS) generation. Furthermore, the cytotoxic potential of this system was studied using comet and MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. Treated lymphocytes were visualized using fluorescence and scanning electron microscopy to further validate apoptosis. ROS scavengers ameliorated the oxidative damage caused by this system suggesting pivotal role of ROS in causing apoptotic cell death. As cancer cells exhibit increased absorption of Rf as well as are very sensitive in any further ROS level increment, this putative pathway can serve as an effective anodyne phototherapeutic strategy for cancer treatment. (c) 2017 IUBMB Life, 69(8):611-622, 2017. PMID- 28636151 TI - Method of teaching undergraduate students to perform root canal treatment: It's influence on the quality of root fillings. AB - INTRODUCTION: This study aimed to assess whether the method of teaching endodontology influenced the quality of root fillings made by undergraduate students. MATERIALS AND METHODS: The method of teaching endodontology at our institution was revised. Changes concerned: the programme (ie method of clinical training and summative assessment), and the supervision whilst performing root canal treatment on patients. An intermediate cohort (N=91) comprised partly students attending the former programme (involving patients) and partly students attending the revised programme (without patients). After succeeding in the summative assessment, the quality of the first root filling made by the student in a patient under supervision of either a general dental practitioner or an endodontist was evaluated according to pre-determined criteria. Data were analysed using Cohen's Kappa, Chi-square, Fisher's exact, Mann-Whitney and Kruskal-Wallis tests. RESULTS: Sixty-two per cent (47 of 76) of root fillings made by students who attended the revised programme were of good quality, in comparison with 47% (seven of 15) of those made by students who attended the former programme (P=.274). Less complex treatments had better quality root fillings if students were supervised by endodontists (88% (14 of 16) good quality) than supervised by general dental practitioners (59% (22 of 37) good quality) (P=.045). Complex treatments did not differ in quality of root fillings for the supervision types (P=.825). CONCLUSION: The quality of root fillings made by students who attended the revised programme seems at least as high as that of those who attended the former programme. Higher quality root fillings might be obtained under supervision of endodontists than under supervision of general dental practitioners. PMID- 28636152 TI - Dynamics and origin of cytokinins involved in plant manipulation by a leaf-mining insect. AB - Several herbivorous insects and plant-associated microorganisms control the phytohormonal balance, thus enabling them to successfully exploit the plant by inhibiting plant defenses and withdrawing plant resources for their own benefit. The leaf-mining moth Phyllonorycter blancardella modifies the cytokinin (CK) profile of mined leaf-tissues, and the insect symbiotic bacteria Wolbachia is involved in the plant manipulation to the benefit of the insect host. To gain a deeper understanding into the possible origin and dynamics of CKs, we conducted an extensive characterization of CKs in larvae and in infected apple leaves. Our results show the enhanced CK levels in mines, both on green and yellow leaves, allowing insects to control their nutritional supply under fluctuating environmental conditions. The spatial distribution of CKs within the mined leaves shows that hormone manipulation is strictly limited to the mine suggesting the absence of CK translocation from distant leaf areas toward the insect feeding site. Mass spectrometry analyses reveal that major CK types accumulating in mines and larvae are similar to what is observed for most gall-inducers, suggesting that strategies underlying the plant manipulation may be shared between herbivorous insects with distinct life histories. Results further show that CKs are detected in the highest levels in larvae, reinforcing our hypothesis that CKs accumulating in the mines originate from the insect itself. Presence of bacteria specific methylthio-CKs is consistent with previous results suggesting that insect bacterial symbionts contribute to the observed phenotype. Our study provides key findings toward the understanding of molecular mechanisms underlying this intricate plant-insect-microbe interaction. PMID- 28636153 TI - Special Section: From Genes to Bedside and Back. PMID- 28636154 TI - Multiple-opposing rotation flaps for the scalp defect including hair whorl. PMID- 28636155 TI - The use of Transnasal Humidified Rapid-Insufflation Ventilatory Exchange in 17 cases of subglottic stenosis. PMID- 28636156 TI - Pathways from infant exposure to marital conflict to parent-toddler role reversal. AB - We know that exposure to marital conflict places infants at risk, but we know less about processes. One process may be role reversal, when a distressed parent looks to the child to meet unmet needs for comfort, intimacy, or companionship. A parent in marital conflict may be particularly prone to role reversal, which in turn adversely affects child development. The current study examined pathways from infants' exposure to marital conflict at 12 months to role reversal at 24 months. We sampled low-middle socioeconomic status (SES) families with their first child (N = 128). Independent observers assessed marital conflict (in a problem-solving task) and role reversal (in a story-telling task). We found that each parent's conflict behavior predicted the other parent's role reversal. In a direct pathway, mother's conflict behavior towards father led directly to father's role reversal with the child. In an indirect pathway, father's conflict behavior towards mother led to his withdrawal from her, which in turn led to mother's role reversal with the child. Clinical implications are discussed within a developmental psychopathology framework in terms of preventive interventions to offset the deleterious effect of marital conflict and role reversal on child development. PMID- 28636157 TI - Meeting the emotional needs of infants and toddlers in foster care: The collaborative mental health care experience. AB - This paper describes a partnership between an infant mental health consultation program and child welfare authorities, with a special focus on the use of a consultation model to support infants and toddlers in foster care. The authors describe a model of practice that incorporates the transactional model with a developmental perspective to help foster parents understand and address the emotional needs of these children. The clinical implications section reviews strategies for addressing attachment and relationship disturbances, promoting self-regulation, and enhancing social competence in infants and young foster children. PMID- 28636158 TI - Reflection in thought and action: Maternal parenting reflectivity predicts mind minded comments and interactive behavior. AB - Recent research has identified mothers' mental reflective functioning and verbal mind-minded comments as important predictors of subsequent infant attachment security. In the present study, we examine associations between mothers' (N = 95) parenting reflectivity expressed in an interview and observed parenting behavior, including verbal mind-minded comments and interactive behavior during interaction with their 7-month-old infants. Parenting reflectivity was coded from the Working Model of the Child Interview. Maternal behavior was assessed via observations of mother-infant interaction during free play and structured teaching tasks. Both maternal appropriate mind-minded comments as well as other indicators of maternal interactive behavior were coded. Parenting reflectivity was positively correlated with mind-minded comments and behavioral sensitivity. Hierarchical multiple regression analyses indicated that parenting reflectivity contributed to maternal behavior beyond the contributions of mothers' educational status and depression symptoms. Discussion emphasizes the importance of individual differences in parental capacity to accurately perceive and mentalize their infants' experience, and the consequences of these differences for caregiving behavior. PMID- 28636159 TI - The Chances for Children Teen Parent-Infant Project: Results of a pilot intervention for teen mothers and their infants in inner city high schools. AB - Adolescent motherhood poses serious challenges to mothers, to infants, and ultimately to society, particularly if the teen mother is part of a minority population living in an urban environment. This study examines the effects of a treatment intervention targeting low-income, high-risk teen mothers and their infants in the context of public high schools where daycare is available onsite. Our findings confirm the initial hypothesis that mothers who received intervention would improve their interactions with their infants in the areas of responsiveness, affective availability, and directiveness. In addition, infants in the treatment group were found to increase their interest in mother, respond more positively to physical contact, and improve their general emotional tone, which the comparison infants did not. Importantly, these findings remain even within the subset of mothers who scored above the clinical cutoff for depression on the Center for Epidemiological Studies-Depression Scale (CES-D; L. Radloff, 1977), confirming that it is possible to improve mother-infant interaction without altering the mother's underlying depression. The implications of these findings are significant both because it is more difficult and requires more time to alter maternal depression than maternal behavior and because maternal depression has been found to have such devastating effects on infants. PMID- 28636160 TI - Species-specific metabolism of naphthalene and phenanthrene in 3 species of marine teleosts exposed to Deepwater Horizon crude oil. AB - The 2 most abundant polycyclic aromatic hydrocarbons (PAHs) measured in Deepwater Horizon crude oil, naphthalene and phenanthrene, and their associated homologs have both been shown to be acutely toxic in fish. Although fish have a relatively high metabolic capacity for PAHs, hydroxylated PAH (OH-PAH) derivatives formed during the initial metabolic response can negatively impact the health of fish. Species-specific metabolism of naphthalene and phenanthrene was evaluated in 3 marine teleosts, red drum (Scianops ocellatus), Florida pompano (Trachinotus carolinus), and southern flounder (Paralichthys lethostigma). Fish were exposed to Deepwater Horizon crude oil by intraperitoneal injections at time 0 and 48 h, with bile sampling events at 24 and 72 h post injection. The data suggested metabolic induction in Florida pompano and red drum, whereas southern flounder may have demonstrated metabolic fatigue. By 24 h post injection, overall profiles of red drum and southern flounder were dominated by hydroxylated phenanthrene metabolites; conversely, the Florida pompano profiles were dominated by monohydroxylated naphthalenes. In addition, Florida pompano had faster overall relative biotransformation rates, suggesting their potential decreased susceptibility to adverse effects. Red drum and southern flounder had much lower relative biotransformation rates, indicating their probable susceptibility to adverse outcomes after naphthalene and phenanthrene exposures. To our knowledge, the present study is the first to investigate monohydroxylated PAHs in fish exposed to Deepwater Horizon oil. Environ Toxicol Chem 2017;36:3168-3176. (c) 2017 (c) 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 28636162 TI - Cobalt-Catalyzed ortho-C-H Functionalization/Alkyne Annulation of Benzylamine Derivatives: Access to Dihydroisoquinolines. AB - A practical picolinamide-directed C-H functionalization/alkyne annulation of benzylamine derivatives enabling access to the previously elusive 1,4 dihydroisoquinoline skeleton was developed using molecular O2 as the sole oxidant and Co(OAc)2 as precatalyst. The method is compatible with both internal and terminal alkynes and shows high versatility and functional-group tolerance. Furthermore, full preservation of enantiopurity is observed when using non racemic alpha-substituted benzylamine derivatives. Kinetic analysis of the reagents and catalyst, labeling experiments, and the isolation and identification of catalytically competent Co-complexes revealed important insights about the mechanism. PMID- 28636163 TI - The PU-PROM: A patient-reported outcome measure for peptic ulcer disease. AB - OBJECTIVE: Patient-reported outcome measure (PROM) conceived to enable description of treatment-related effects, from the patient perspective, bring the potential to improve in clinical research, and to provide patients with accurate information. Therefore, the aim of this study was to develop a patient-centred peptic ulcer patient-reported outcome measure (PU-PROM) and evaluate its reliability, validity, differential item functioning (DIF) and feasibility. METHOD: To develop a conceptual framework and item pool for the PU-PROM, we performed a literature review and consulted other measures created in China and other countries. Beyond that, we interviewed 10 patients with peptic ulcers, and consulted six key experts to ensure that all germane parameters were included. In the first item selection phase, classical test theory and item response theory were used to select and adjust items to shape the preliminary measure completed by 130 patients and 50 controls. In the next phase, the measure was evaluated used the same methods with 492 patients and 124 controls. Finally, we used the same population in the second item reselection to assess the reliability, validity, DIF and feasibility of the final measure. RESULTS: The final peptic ulcer PRO measure comprised four domains (physiology, psychology, society and treatment), with 11 subdomains, and 54 items. The Cronbach's alpha coefficient of each subdomain for the measure was >0.800. Confirmatory factory analysis indicated that the construct validity fulfilled expectations. Model fit indices, such as RMR, RMSEA, NFI, NNFI, CFI and IFI, showed acceptable fit. The measure showed a good response rate. CONCLUSIONS: The peptic ulcer PRO measure had good reliability, validity, DIF and feasibility, and can be used as a clinical research evaluation instrument with patients with peptic ulcers to assess their condition focus on treatment. This measure may also be applied in other health areas, especially in clinical trials of new drugs, and may be helpful in clinical decision making. PMID- 28636164 TI - A Nanostructured Microfluidic Immunoassay Platform for Highly Sensitive Infectious Pathogen Detection. AB - Rapid and simultaneous detection of multiple potential pathogens by portable devices can facilitate early diagnosis of infectious diseases, and allow for rapid and effective implementation of disease prevention and treatment measures. The development of a ZnO nanorod integrated microdevice as a multiplex immunofluorescence platform for highly sensitive and selective detection of avian influenza virus (AIV) is described. The 3D morphology and unique optical property of the ZnO nanorods boost the detection limit of the H5N2 AIV to as low as 3.6 * 103 EID50 mL-1 (EID50 : 50% embryo infectious dose), which is ~22 times more sensitive than conventional enzyme-linked immunosorbent assay. The entire virus capture and detection process could be completed within 1.5 h with excellent selectivity. Moreover, this microfluidic biosensor is capable of detecting multiple viruses simultaneously by spatial encoding of capture antibodies. One prominent feature of the device is that the captured H5N2 AIV can be released by simply dissolving ZnO nanorods under slightly acidic environment for subsequent off-chip analyses. As a whole, this platform provides a powerful tool for rapid detection of multiple pathogens, which may extent to the other fields for low cost and convenient biomarker detection. PMID- 28636165 TI - A feasibility and safety study of intracoronary hemodilution during primary coronary angioplasty in order to reduce reperfusion injury in myocardial infarction. AB - OBJECTIVES: We designed a pilot study to evaluate safety and feasibility of an inexpensive and simple approach to intracoronary hemodilution during primary angioplasty (PPCI) to reduce reperfusion injury. INTRODUCTION: Early revascularization in acute myocardial infarction decreases infarct size and improves outcomes. However, abrupt restoration of coronary flow results in myocardial reperfusion injury and increased final infarct size. Dilution of coronary blood during revascularization may help reduce this damage. If proved effective, such an approach would need to be simple and suitable for widespread adoption. METHODS: Ten patients presenting with STEMI underwent intracoronary dilution with room temperature Hartmann's solution delivered through the guiding catheter during primary angioplasty (PPCI). Infusion of perfusate began prior to crossing the occluded artery with the guidewire, continuing until 10 min after completion of the balloon and stenting procedure. Infusion was briefly interrupted for contrast injection and pressure monitoring. The outcome measures were safety, including intracoronary temperature reduction and volume of intracoronary perfusate infused, and technical feasibility. RESULTS: There were no significant symptomatic, hemodynamic, ECG ST/T segment or rhythm changes observed during perfusate administration. The median (interquartile range) volume of perfusate administered was 550 mL (350-725 mL) and the median intracoronary temperature reduction observed was 3.4 degrees Celsius. Myocardial salvage was 0.54 (0.43-0.65). CONCLUSIONS: Transcatheter intracoronary hemodilution with room temperature perfusate during PPCI is feasible and appears safe. Such a strategy is simple and inexpensive, with potential to be widely applied. Further mechanistic and subsequent outcome powered studies are required to evaluate whether this strategy can reduce reperfusion injury in STEMI. PMID- 28636166 TI - Could intradialytic nutrition improve refractory anaemia in patients undergoing haemodialysis? AB - BACKGROUND: This prospective randomised study was designed to evaluate the efficacy of intradialytic parenteral nutrition (IDPN) therapy in malnourished patients with refractory anaemia. METHODS: Forty patients who were malnourished with a BMI not greater than 23 (17-23) kg/m2 , undergoing regular HD were included. Of those, 20 patients received 500-1000 ml of IDPN at a rate of 250-300 ml/h at each HD session three days per week for six consecutive months. The other 20 patients did not receive IDPN infusion. The malnutrition inflammation score (MIS) and haematological parameters were recorded at baseline and after three and six months. RESULTS: Mean haemoglobin levels, BMI and serum albumin were significantly increased while MIS was significantly decreased after the 3rd and 6th months of IDPN. CONCLUSION: IDPN has a good role in improving refractory anaemia by significantly increasing haemoglobin levels, body weight, and serum albumin levels. The intervention also significantly decreases the MIS of patients. PMID- 28636167 TI - Berberine ameliorates collagen-induced arthritis in rats by suppressing Th17 cell responses via inducing cortistatin in the gut. AB - Berberine, an isoquinoline alkaloid, has been reported to ameliorate various autoimmune diseases including rheumatoid arthritis by oral administration. However, its mechanism remains mysterious due to an extremely low bioavailability. The fact that berberine readily accumulates in the gut, the largest endocrine organ in the body, attracted us to explore its anti-arthritic mechanism in view of the induction of intestinal immunosuppressive neuropeptides. In this study, berberine (200 mg.kg-1 , i.g.) was shown to ameliorate collagen induced arthritis in rats, which was manifested by the reduction of clinical signs and joint destruction, as well as marked down-regulation of Th17 cell frequency and interleukin-17 level in blood. In contrast, an intravenous injection of berberine failed to affect arthritis in rats, implying that its anti arthritic effect was gut-dependent. Further studies revealed that oral berberine selectively elevated the levels of cortistatin, of five gut-derived neuropeptides tested, in the intestines and sera of arthrititic rats. Antagonists of ghrelin/growth hormone secretagogue receptor 1 (a subtype of cortistatin receptor) almost completely abolished the ameliorative effect of berberine on arthritis and Th17 cell responses in rats. In vitro, berberine showed a moderate ability to promote the expression of cortistatin in nerve cells, which was strengthened when the nerve cells were cocultured with enteroendocrine cells to induce an autocrine/paracrine environment. In summary, oral berberine exerted anti-arthritic effect through inhibiting the Th17 cell response, which was closely associated with the induction of cortistatin generation from gut through augmenting autocrine/paracrine action between enteric nerve cells and endocrine cells. PMID- 28636168 TI - Improved hemodialysis with hemocompatible polyethersulfone hollow fiber membranes: In vitro performance. AB - We show that addition of nanozeolite (NZ) and vitamin E D-alpha-Tocopherol polyethylene glycol succinate (TPGS or T) considerably improves the performance of polyethersulfone (PES or P) hollow fiber membrane (HFM) for hemodialysis. Nanocomposite HFMs were manufactured using PES as a polymer, TPGS as an additive and NZ as a filler to give a composite membrane called PT-NZ. HFMs were spun by dry-wet spinning principle based on liquid-liquid phase separation. TPGS and NZ were successfully incorporated in HFMs, as confirmed by EDX elemental mapping. The resultant PT-NZ HFMs had improved hemocompatibility: lower percent hemolysis (0.28% in batch mode and 0.32% in continuous mode), lower platelet adhesion, higher coagulation time and lower protein adsorption (16.34 ug/cm2 ), compared with P, PT, and commercial (F60S) HFMs. The ultrafiltration coefficient of PT-NZ HFM-based module (274.59 mL/m2 /h/mmHg) was ~1.5-times higher than that of F60S membranes (151.67 mL/m2 /h/mmHg), and the solute rejection of both the membranes was comparable. The toxin clearance performance of lab-scale PT-NZ HFM-based hemodialyzer with uremic toxin spiked goat blood was remarkably higher (five times) than that of F60S. Hence, the synthesized PT-NZ HFMs are a potentially attractive membrane material for hemodialysis application, particularly due to decreased treatment time and minimal side reactions. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1286-1298, 2018. PMID- 28636169 TI - A novel double nucleotide variant in the ferritin-L iron-responsive element in a Finnish patient with hereditary hyperferritinaemia-cataract syndrome. AB - PURPOSE: To present a novel Finnish double nucleotide variant in the iron responsive element (IRE) of the ferritin L-chain gene (FTL) leading to hyperferritinaemia-cataract syndrome (HHCS). METHODS: Genomic DNA extracted from peripheral blood leucocytes and synthetized with three different primers flanking the IRE in the FTL 5'-untranslated region of the FTL was used in polymerase chain reaction (PCR). Thereafter, Sanger sequencing was performed on the 487-bp and 602 bp PCR amplification products with specific primers to reveal FTL IRE mutations. RESULTS: A 58-year-old female patient with elevated serum ferritin level (1339 MUg/l) was diagnosed with HHCS after extensive workup. Genetic testing identified a novel double point mutation g.48965355G>C (chr19, hg19) and g.48965356G>T (chr19, hg19) in the lower stem region of the IRE canonical structure of the FTL. CONCLUSION: After excluding other causes, elevated serum ferritin level in a person with early onset cataract is indicative for HHCS, a genetic disorder caused by mutation in the IRE of the FTL. PMID- 28636170 TI - Apathy in a sunburnt country: Understanding the skin cancer and sun protection knowledge and practises of Australian doctors. PMID- 28636171 TI - Pulsed food resources, but not forest cover, determine lifetime reproductive success in a forest-dwelling rodent. AB - The relative contributions of habitat and food availability on fitness may provide evidence for key habitat features needed to safeguard population persistence. However, defining habitat quality for a species can be a complex task, especially if knowledge on the relationship between individual performance and habitat quality is lacking. Here, we determined the relative importance of the availability of suitable forest habitat, body mass and food from masting tree species on female lifetime reproductive success (LRS) of Siberian flying squirrels (Pteromys volans). We calculated LRS of 500 female flying squirrels based on a 22-year-long longitudinal dataset of two populations from western Finland. We assessed with generalised additive models the potential effects of availability of suitable habitat and cumulative lifetime availability of food from masting tree species on female LRS, longevity and fecundity. On a reduced dataset, we evaluated the importance of female winter body mass and conducted a piecewise path analysis to determine how variables were connected. According to generalised additive models female longevity, fecundity and LRS were mainly determined by variation in cumulative lifetime availability of food from masting alder and birch. Instead, habitat and body mass had a smaller role. The path analysis indicated that lifetime food availability had a direct effect on longevity and fecundity, and these had an equal effect on LRS at both study sites. Our results on LRS show that the occurrence of tree masting events during a female flying squirrel's lifetime has a profoundly larger effect on LRS than the cover of suitable forest habitat. Furthermore, this study emphasises the importance of both fecundity and longevity, and the indirect effects of food availability via those components, as determinants of lifetime fitness in female flying squirrels. PMID- 28636172 TI - A Phos-tag-based micropipette-tip method for rapid and selective enrichment of phosphopeptides. AB - Phosphorylated peptides are attractive targets in the study of the phosphoproteome. Here, we introduce a simple and convenient micropipette-tip method for the separation of phosphorylated and nonphosphorylated peptides by using a phosphate-binding zinc(II) complex of 1,3-bis(pyridin-2 ylmethylamino)propan-2-olate (Phos-tag). A 200-MUL micropipette tip containing 10 MUL of swollen agarose beads functionalized with Phos-tag moieties was prepared. All steps in the phosphate-affinity separation (binding, washing, and elution) were conducted by using aqueous buffers at neutral pH values. The entire separation protocol required less than 30 min per sample. By means of three independent separation experiments, followed by mass spectrometric (MS) analyses, we identified 1,649 non-redundant phosphopeptides from the lysates of human embryonic kidney cells (the peptides sample derived from 25 MUg proteins per an MS analysis). The average ratio of identified phosphopeptides to total peptides in the respective experiments was >90%, showing a high selectivity. Furthermore, the high correlation between the triplicate analyses was confirmed by scatter plots based on the normalized abundance of each peptide, as calculated by a label free peptide relative quantification analysis in Progenesis QI. This micropipette tip method would be thus used preferentially as an alternative to existing tools for the reliable enrichment of phosphopeptides. PMID- 28636173 TI - Patient-reported outcome measures in amblyopia and strabismus: a systematic review. AB - BACKGROUND: Many patient-reported outcome measures (PROMs) have been developed and/or used to measure the impact of amblyopia and strabismus on quality of life (QoL). Identifying the one with superior quality is important for evaluating the effectiveness of novel therapy for amblyopia and for directing improved clinical decision-making in adults considering strabismic surgery. Therefore, the aim of this review is to identify all PROMs previously developed/used to study the impact of amblyopia and/or strabismus on QoL and to appraise the quality and comprehensiveness of content of the disease-specific instruments. METHODS: A systematic search was carried out in the electronic databases of PubMed, Cochrane, Web of Science and PsycINFO. The quality of content and measurement properties of all the disease-specific instruments were assessed using established quality standards. Further, the content of the instruments were examined for comprehensiveness by categorising each item across the eight ophthalmic QoL domains (activity limitation, concerns, emotional well-being, social well-being, economic, convenience, symptoms and mobility). RESULTS: Seventy-one PROMs were identified, out of which 32 were amblyopia- and/or strabismus-specific. Out of all the disease-specific instruments, just four have been subjected to modern psychometric tests and only the adult strabismus questionnaire (AS-20) demonstrated good measurement properties. Most of the amblyopia-specific instruments measured the impact of the treatment of amblyopia on children, while most of the strabismus-specific instruments measured concerns related to appearance and treatment outcome in adults. All instruments have gaps in their content and failed to address QoL comprehensively. CONCLUSION: All the existing amblyopia- and/or strabismus-specific instruments fall short of desired quality and/or comprehensiveness of content. The review identifies the need for developing an instrument with superior quality and discusses potential directions of future research. PMID- 28636174 TI - Shared minds: Effects of a mother's imitation of her child on the mother-child interaction. AB - Children with Autistic Spectrum Disorders (ASD) have impaired social interaction right from early development. Previous studies (Dawson & Adams, 1984; Tiegerman & Primavera, 1981, 1984) have suggested that imitating children with ASD is effective in facilitating their social behaviors. The present case report, through a 6-month intervention, investigated how a home-based intervention of helping a mother imitate her 21-month-old child with ASD impacted the child's development of social communication outside the experimental settings. Our results show that the mother's imitation of her child might be associated with the development of nonverbal joint attention skills. Positive changes in the mother's emotion towards her child and the mother-child interaction also were noted and represent other important effects of parental involvement in therapeutic interventions for children with ASD. PMID- 28636175 TI - Competencies for infant mental health therapists: A survey of expert opinion. AB - We report on data provided by a nationwide panel of 23 infant mental health (IMH) experts who provided numerical ratings of the relative importance of 143 competencies desirable for licensed mental health therapists working with infants/children birth to 5 years of age and their families/caregivers. The competencies were developed based on prior state and national efforts and our own experience in training IMH therapists. The competencies were grouped conceptually into seven areas: (a) Normal infant and toddler development; (b) Atypical development (perturbations in development); (c) Emotional/behavioral disorders in infants and young children; (d) Assessment; (e) Intervention; (f) Community resources and referrals; and (g) Organization, communication, and collaboration. We calculated means, SDs, 95% confidence intervals to rank order each competency. We conducted reliability analyses and tested for mean differences in ratings for the seven areas. Interrater and intraclass correlations were modest, likely the result of restriction of range in the ratings. The seven areas showed high levels of internal consistency and, with few exceptions, did not significantly differ in the means of their ratings. The utility of the competencies are discussed as a framework for training and professional development for IMH clinicians. PMID- 28636176 TI - Caregivers' disrupted representations of the unborn child predict later infant caregiver disorganized attachment and disrupted interactions. PMID- 28636177 TI - Developmental history of care and control, depression and anger: Correlates of maternal sensitivity in toddlerhood. AB - This study examined maternal sensitivity in response to toddler distress in relation to mothers' childhood care and control experiences with parents, maternal depression, and maternal anger. Fifty-two mothers and infants participated. Mothers reported childhood care and control experiences prenatally. At 21/2 years, mothers reported depressive symptoms and anger on questionnaires, and reported maternal behavior in a daily diary for 1 week, yielding ratings of maternal sensitivity to fear and anger. Results were as follows: (a) Mothers' acceptance during childhood correlated negatively with both maternal depression and maternal anger, and positively with maternal sensitivity to fear at 21/2 years; (b) maternal anger mediated the association between childhood care and maternal sensitivity to fear at 21/2 years; and (c) the interaction of maternal and paternal control during childhood predicted maternal sensitivity to anger at 21/2 years, controlling for maternal education. When maternal control was low, paternal control was positively associated with maternal sensitivity to anger whereas when maternal control was high, paternal control was negatively associated with maternal sensitivity to anger. Results are discussed in relation to prior studies, with particular emphasis on attachment theory. Implications for preventive intervention efforts are considered. PMID- 28636178 TI - The intergenerational effects of trauma from terror: A real possibility. AB - The goals of this article are to discuss the potential risk of children whose parents were traumatized by terror, to present literature on parenting in the context of terror, and to consider factors that may mediate the transmission of trauma-effects from parents to children. Mediators considered are parents' traumatic distress, disturbed parent-child interactions, trauma-related disturbances in parents' thinking, and effects of stress on children's neural functioning. Also discussed are genetic and environmental factors that may moderate the transmission of intergenerational effects and promote children's risk and resilience. Points raised during the discussion are illustrated with segments from interviews of women who were pregnant or gave birth some time after direct exposure to a terror attack. The authors conclude that empirical studies are needed to learn more about the intergenerational transmission of trauma effects and processes that underlie it. The authors join others in the call to improve evaluation, treatment, and support of trauma victims and their children to stymie the transmission of problems from one generation to the next. PMID- 28636179 TI - Discontinuation and non-publication of neurodegenerative disease trials: a cross sectional analysis. AB - BACKGROUND AND PURPOSE: Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases. METHODS: ClinicalTrials.gov was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication. RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with <=100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41 10.83). Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63). CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice. PMID- 28636180 TI - Characterization of Herpes Simplex Virus Infections Seen in the Pediatric Dermatology Office. AB - BACKGROUND/OBJECTIVES: Atypical and severe clinical manifestations of primary and recurrent herpes simplex virus (HSV) infections may present to a pediatric dermatologist for evaluation. The purpose of this study was to characterize the clinical features of the population diagnosed with HSV referred to a pediatric dermatology office. METHODS: This retrospective case series examined patients diagnosed with HSV in a pediatric dermatology practice at an academic medical center from 2005 to 2015. Characteristics of the population were collected and analyzed. RESULTS: In this study of 48 children diagnosed with HSV, 33% presented at age 2 years or younger, with approximately half having exhibited initial symptoms before 2 years of age; 39.6% of the population had six or more outbreaks per year. The outbreaks were equally divided between unifocal and multifocal presentations, with 60% of children without any labial or mucosal involvement. Suppressive treatment was initiated in 33% of patients; the average age at initiation was 6 years. CONCLUSION: Our data characterize a subset of immunocompetent young children who present to pediatric dermatologists with frequent HSV outbreaks that are often multifocal and involve cutaneous sites, with or without mucosal involvement. PMID- 28636181 TI - Identification of Biomarkers for Early Diagnosis of Acute Myocardial Infarction. AB - Acute myocardial infarction (AMI) is a common disease with serious consequences in mortality and cost. Here we aim to screen the differentially expressed genes (DEGs) as biomarkers for early diagnosis of AMI. The microarray data of AMI was downloaded from Gene Expression Omnibus (GEO), including two independent types of research GSE66360 and GSE62646. The DEGs between control and processed samples were screened out by using limma package. Meanwhile, we performed functional analysis of GO terms and/or KEGG pathways to observe the enriched pathways of the DEGs. Finally, regression analysis of raw data was performed by using packet affyPLM in R language. Dataset GSE62646 contained 53 DEGs (FC log2>1 and P value <0.05) between first-day samples from 28 STEMI patients and control samples from 14 patients without myocardial infarction history. There were 12 up-regulated and 41 down-regulated genes, 35 DEGs annotated. In GSE66360, a total of 3034 DEGs between 32 AMI patients and 38 healthy persons were obtained, including 1861 up regulated and 1173 down-regulated DEGs. The comparison of the DEGs in two datasets revealed four common up-regulated genes (EGR1, STAB1, SOCS3, TMEM176A). In enrichment analysis, STAB1, SOCS3, EGR1 involved in metabolic regulation and signaling pathways related to coronary artery disease with a characteristic change (P < 0.05). The DEGs, especially the four up-regulated common genes, could serve as biomarkers for early diagnosis of AMI. Additionally, the relative biological pathways these DEGs enriched in might provide a good reference to explore the molecular expression mechanism of AMI. J. Cell. Biochem. 119: 650 658, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28636182 TI - Effects of green tea on lipid metabolism in overweight or obese people: A meta analysis of randomized controlled trials. AB - SCOPE: The effects of green tea on lipid metabolism were inconsistent. The objective of this meta-analysis was to evaluate the effects of green tea on lipid metabolism in overweight or obese people. METHODS AND RESULTS: We searched randomized controlled trials (RCTs) comparing green tea with a control on lipid metabolism on PUBMED and WEB OF SCIENCE (January 1990 to September 2016), COCHRANE and EMBASE (updated to October 2016), and the Chinese databases CNKI, WanFang and CBMD. Twenty-one articles studying 1704 overweight or obese subjects were selected for this meta-analysis. The pooled results demonstrated that green tea significantly decreased plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels in overweight or obese people. The weighted mean difference was -3.38 mg/dl for TC (95% CI: -6.42, -0.33 mg/dL) and -5.29 mg/dL for LDL (95% CI: -7.92, -2.6 6 mg/dL), respectively. Green tea intake, however, showed no effect on plasma triglyceride (TG) and high-density lipoprotein cholesterol(HDL) levels in overweight or obese people with a relatively high heterogeneity. CONCLUSION: The meta-analysis shows that drinking green tea can lower plasma TC and LDL levels significantly. Nevertheless, green tea's effect on plasma TG and HDL must be further evaluated by additional high quality and large-scale RCTs. PMID- 28636183 TI - Ordination with any dissimilarity measure: a weighted Euclidean solution. AB - The classical approach to ordination is to use variants of the Euclidean distance to measure differences between samples (e.g., sites in a community study) based on their observation vectors (e.g., abundance counts for a set of species). Examples include Euclidean distance on standardized or log-transformed data, on which principal component analysis and redundancy analysis are based; chi-square distance, on which (canonical) correspondence analysis is based; and Hellinger distance, using square roots of relative values in each multivariate vector. Advantages of the Euclidean approach include the neat decomposition of variance and the ordination's optimal biplot display. To extend this approach to any non Euclidean or nonmetric dissimilarity, a simple solution is proposed, consisting of the estimation of a weighted Euclidean distance that optimally approximates the dissimilarities. This preliminary step preserves the good properties of the classical approach while giving two additional benefits as by-products. Firstly, the estimated species weights, quantifying each species' contribution to the dissimilarities, can be interpreted, and weights equal or close to zero can assist in variable selection. Secondly, the dimensionality remains that of the number of species, not the dimensionality inherent in the dissimilarities, which depends on the number of samples and can be considerably higher. PMID- 28636184 TI - Pharmacokinetics and pharmacodynamics of bococizumab, a monoclonal antibody to PCSK9, after single subcutaneous injection at three sites [NCT 02043301]. AB - AIM: To characterize the single-dose pharmacokinetics (PK) and pharmacodynamics (PD) of bococizumab, a monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), administered subcutaneously (s.c.) to the abdomen, thigh, or upper arm (NCT02043301). METHODS: Seventy-five adults with low density lipoprotein cholesterol (LDL-C) >=130 mg/dL and not on background lipid lowering therapy were randomized (1:1:1) to a single 150-mg s.c. dose of bococizumab administered to the abdomen, thigh, or upper arm. Blood samples for bococizumab and lipids were collected for 12 weeks postdose. RESULTS: Plasma bococizumab concentration-time profiles and PK parameters were generally similar across injection sites. Mean maximum observed concentration (Cmax ) ranged from 8.14 to 11.9 MUg/mL, and area under the concentration-time curve (AUCinf ) ranged from 160.3 to 198.9 ug?day/mL. The median time to Cmax (Tmax ) ranged from 4.25 to 6.93 days. Similar LDL-C concentration-time profiles were observed across injection sites, with mean (% coefficient of variation) maximum reductions in LDL C of -57.5% (15.8), -57.0% (25.9), and -55.0% (24.1) for the abdomen, thigh, and upper arm, respectively. Adverse events (AEs) were mostly mild and generally similar across injection sites. Commonly reported AEs were upper respiratory tract infection (9.3%), headache (6.7%), and injection site reaction (6.7%). One serious AE was reported (ischemic colitis), which was not considered related to study drug. CONCLUSIONS: Similar PK profiles and robust LDL-C reductions were observed following a single 150-mg s.c. injection of bococizumab administered to the abdomen, thigh, or upper arm in untreated subjects with LDL-C >=130 mg/dL. Bococizumab was generally well tolerated following a single 150-mg s.c. administration in this subject population. PMID- 28636185 TI - Decarboxylative Alkynylation. AB - The development of a new decarboxylative cross-coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel- and iron-based catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well-established alkyne syntheses. The reaction is operationally simple and broad in scope while providing succinct and scalable avenues to previously reported synthetic intermediates. PMID- 28636187 TI - Dual-labeled chemiluminescence enzyme immunoassay for simultaneous measurement of total prostate specific antigen (TPSA) and free prostate specific antigen (FPSA). AB - The specificity for early diagnostic of prostate-specific antigen (PSA) is low because the current technology mostly allows the detection of only one biomarker at one time. In this work, a dual-labeled chemiluminescence enzyme immunoassay (CLEIA) for simultaneous measurement of total PSA (TPSA) and free PSA (FPSA) was proposed. Anti-PSA McAb (Mab1) was immobilized on a microplate as the solid phase, horseradish peroxidase (HRP)-labeled anti-TPSA monoclonal antibody (McAb2) and alkaline phosphatase (ALP)-labeled anti-FPSA McAb3 were used as detection antibodies. Two chemiluminescence reactions of HRP with luminol and ALP with 4 methoxy-4-(3-phosphate-phenyl)-spiro-(1,2-dioxetane-3,2'-adamantane) (AMPPD) were used as the signal detecting system. Based on a sandwich model, the amount of FPSA and TPSA could be determined simultaneously. The effects of several physico chemical parameters were studied and optimized. Cross-reactivities of six common tumor markers in serum were studied. The proposed method presented the sensitivity of 0.03 ng ml-1 and 0.05 ng ml-1 for FPSA and TPSA respectively, with low cross-reactivities. Compared with the results from commercial chemiluminescent kits there was good correlation, indicating that this established method could be used to simultaneously to measure the concentrations of FPSA and TPSA in one serum sample and also could greatly facilitate the early diagnosis for PCa in clinical practice. PMID- 28636186 TI - Views of general practice staff about the use of a patient-oriented treatment decision aid in shared decision making for patients with type 2 diabetes: A mixed methods study. AB - BACKGROUND: Decision aids can be used to support shared decision making (SDM). A patient-oriented treatment decision aid (DA) was developed for type 2 diabetes but its use by general practice staff appeared to be limited. OBJECTIVES: To explore views of practice staff towards SDM and the DA. DESIGN: A mixed-methods study within the Dutch PORTDA-diab trial. SETTING AND PARTICIPANTS: Included were 17 practices with staff members who were responsible for routine diabetes care and had worked with the DA, and 209 of their patients. METHODS: Interviews were conducted focusing on applicability, usefulness and feasibility of the DA. Interviews were tape-recorded, transcribed verbatim and subjected to content analysis for identifying and classifying views. Patient-reported data about the use of the DA were collected. Associations between specific views and use of the DA were tested using Pearson point-biserial correlation. RESULTS: The majority of practice staff expressed positive views towards SDM, which was associated with making more use of the DA. Most of the staff expressed that the DA stimulated a two-way conversation. By using the DA, several became aware of their paternalistic approach. Some staff experienced a conflict with the content of the DA, which was associated with making less use of the DA. CONCLUSIONS: The DA was considered useful by practice staff to support SDM. A positive view towards SDM was a facilitator, whereas experiencing a conflict with the content of the DA was a barrier for making use of the DA. PMID- 28636188 TI - Selective laser trabeculoplasty as replacement therapy in medically controlled glaucoma patients. AB - PURPOSE: We examined selective laser trabeculoplasty (SLT) as a replacement therapy for medically controlled open-angle glaucoma (OAG) or ocular hypertensive patients. METHODS: A prospective randomized interventional clinical trial on 143 glaucoma patients. Patients were randomized to either receiving SLT or to the control group that continued on pressure lowering medication. Data were recorded 1 hr, 1 week, 1, 3, 6, 12 and 18 months after SLT. Primary outcome was number of medications at 12 and 18 months while maintaining a predetermined target intraocular pressure (IOP). RESULTS: Selective laser trabeculoplasty (SLT) reduced number of medications from a mean of 1.5 at baseline, to 0.35 after 12 months and 0.29 after 18 months. Meanwhile, SLT achieved more than 20% IOP lowering in 95% of eyes and more than 30% IOP lowering in 86% of eyes after 18 months. Seventy-seven per cent of our eyes no longer needed any medication after SLT at 18 months. CONCLUSION: Selective laser trabeculoplasty (SLT) enabled a reduction in number of medications while maintaining good IOP control. Selective laser trabeculoplasty (SLT) was able to completely replace medical therapy in 77% of eyes after 18 months. Selective laser trabeculoplasty (SLT) as replacement therapy may reduce local and systemic side-effects and prevent adherence issues. PMID- 28636189 TI - Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors. AB - Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1 inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors. Among them, the most potent compound corresponds to hexamidine (IC50 = 5.9 +/- 1.7 MUm), which is an antimicrobial agent. The binding between hexamidine and PRMT1 was further validated by thermal shift assays and nuclear magnetic resonance (NMR) experiments. Molecular docking and NMR assays indicated that hexamidine occupied the substrate binding pocket. Furthermore, hexamidine effectively blocked cell proliferation in cancer cell lines related to PRMT1 overexpression. Taken together, this study has provided a druggable scaffold targeting PRMT1 as well as a new way to repurpose old drugs which is a complementary tool for the discovery of new lead compounds. PMID- 28636191 TI - "Fast Track" Development and Approval Process for Heart Failure Therapeutics. AB - Heart failure (HF) is a global epidemic, with a high mortality and morbidity burden. In such diseases, earlier access to lifesaving therapeutic regimens is imperative, and could be accomplished by improving the drug development and approval process, without jeopardizing patient safety. The US Food and Drug Administration (FDA) has already established mechanisms facilitating the latter, but further guidance to enhance and expedite the process holds promise to further improve patient outcomes. PMID- 28636190 TI - UCH-L1 promotes invasion of breast cancer cells through activating Akt signaling pathway. AB - As a de-ubiquitin enzyme, ubiquitin C-terminal hydrolase (UCH)-L1 has been shown to be overexpressed in several human cancers. However, the function of UCH-L1 in invasion of breast cancers is still unclear. Here we report that the expression of UCH-L1 is significantly higher in cancer cells with higher invasive ability. While ectopic UCH-L1 expression failed to alter cell proliferation in MCF-7 cells, it caused a significant upregulation of cellular invasion. Furthermore, siRNA mediated knockdown of UCH-L1 led to suppression of invasion in UCH-L1 overexpressing MCF-7 cells. In order to identify molecular mechanisms underlying these observations, a novel in vitro proximity-dependent biotin identification method was developed by fusing UCH-L1 protein with a bacterial biotin ligase (Escherichia coli BirA R118G, BioID). Streptavidin magnetic beads pulldown assay revealed that UCH-L1 can interact with Akt in MCF-7 cells. Pulldown assay with His tagged recombinant UCH-L1 protein and cell lysate from MCF-7 cells further demonstrated that UCH-L1 preferentially binds to Akt2 for Akt activation. Finally, we demonstrated that overexpression of UCH-L1 led to activation of Akt as evidenced by upregulation of phosphorylated Akt. Thus, these findings demonstrated that UCH-L1 promotes invasion of breast cancer cells and might serve as a potential therapeutic target for treatment of human patients with breast cancers. PMID- 28636192 TI - Intestinal barrier integrity and inflammatory bowel disease: Stem cell-based approaches to regenerate the barrier. AB - Disruption of normal barrier function is a fundamental factor in the pathogenesis of inflammatory bowel disease, which includes increased epithelial cell death, modified mucus configuration, altered expression and distribution of tight junction proteins, along with a decreased expression of antimicrobial peptides. Inflammatory bowel disease is associated with life-long morbidity for affected patients, and both the incidence and prevalence is increasing globally, resulting in substantial economic strain for society. Mucosal healing and re-establishment of barrier integrity are associated with clinical remission, as well as with an improved patient outcome. Hence, these factors are vital treatment goals, which conventionally are achieved by a range of medical treatments, although none are effective in all patients, resulting in several patients still requiring surgery at some point. Therefore, novel treatment strategies to accomplish mucosal healing and to re-establish normal barrier integrity in inflammatory bowel disease are warranted, and luminal stem cell-based approaches might have an intriguing potential. Transplantation of in vitro expanded intestinal epithelial stem cells derived either directly from mucosal biopsies or from directed differentiation of human pluripotent stem cells may constitute complementary treatment options for patients with mucosal damage, as intestinal epithelial stem cells are multipotent and may give rise to all epithelial cell types of the intestine. This review provides the reader with a comprehensive state-of-the-art overview of the intestinal barrier's role in healthy and diseased states, discussing the clinical application of stem cell-based approaches to accomplish mucosal healing in inflammatory bowel disease. PMID- 28636193 TI - The role of maternal responsiveness in predicting infant affect during the still face paradigm with infants born very low birth weight. AB - There is limited empirical literature addressing infants' response to a standardized stressor with infants born very low birth weight (VLBW). The purpose of this study was to assess the relative strength of maternal responsiveness in predicting infant affect in response to the Still Face (SF) paradigm in a cross sectional cohort of ethnically diverse infants born VLBW and their mothers (N = 50; infants 6-8 months old). Infant affect and maternal responsiveness were coded in 1-s intervals while dyads participated in the SF. In addition, perinatal medical status, developmental status, and infant temperament were assessed. Findings revealed that positive infant affect during and after the SF stressor were strongly associated with baseline infant positive affect and maternal responsiveness at the reunion episode, respectively. In contrast, when predicting negative infant affect during and after the SF stressor, prior infant negative affect was strongly and uniquely significant. Infant positive affect, negative affect, and maternal responsiveness were not significantly associated with gender, infant perinatal medical history, developmental status, or temperament. Future research is warranted to determine how these findings relate to infants' stress reactions in naturalistic settings and if relationship-focused interventions may reverse infant negative emotionality, enhance positive emotionality, and thereby improve self-regulation and longer term social and cognitive developmental outcomes in medically at-risk infants. PMID- 28636194 TI - Evaluation of the psychometrics properties of the alarm distress baby scale among 122 Brazilian children. AB - The Alarm Distress Baby Scale (ADBB) aims at assessing infant withdrawal behavior. A previous validation study revealed acceptable reliability and validity indices. The present study investigated the psychometric properties of the scale in a larger sample from a culturally different population. Pediatricians evaluated the behavior of 122 infants, 2 and 19 months old, using the ADBB during routine physical consultation. Four investigators (two pediatricians and two nurses not specialized in pediatric care) examined video recordings of the evaluations. Results showed good interrater reliability coefficients among pediatricians and poor correlation when all professionals were grouped together. Test-retest reliability revealed good intraexaminer agreement (r = 0.91). The pediatricians' evaluation using the ADBB was compared with a psychiatric examination to investigate the scale's criterion validity. The cutoff point of 5 provided the best clinical validity (sensitivity of 79%, specificity of 81%). Results from construct validity showed that the scale had three dimensions. Comparison of the factor solution with other construct validity studies of the same instrument revealed similarities and differences. Results suggest that the ADBB may be a useful screening instrument to detect signs of psychiatric alterations related to withdrawal behavior in primary care services, and it is likely to provide consistent information. PMID- 28636195 TI - Effectiveness of the home-start parenting support program: Behavioral outcomes for parents and children. AB - This study examined effectiveness of Home-Start, a program designed to support parents with young children. The aims were (a) to examine whether Home-Start improved maternal well-being and (b) to examine whether Home-Start led to changes in the behavior of mothers or children. Self-reported and observational data were collected in two waves, using data from 54 mothers and their children between 1.5 and 3.5 years of age who participated in this intervention program for 6 months. These data were compared to 51 comparison families who reported need for parenting support. The results showed a significant improvement in perceived parenting competence, but no effects on maternal depressive moods. Mixed results were found for parenting behavior: Parental consistency and observed sensitivity improved significantly in the Home-Start group whereas no effects were found on the other parenting variables. Child behavioral problems seemed to diminish at the second measurement in both groups, and therefore these changes cannot be attributed to Home-Start. PMID- 28636196 TI - Play and emotional availability in young children with Down syndrome. AB - This study investigates mother-child interaction and its associations with play in children with Down syndrome (DS). There is consensus that mother-child interaction during play represents an important determinant of typical children's play development. Concerning children with DS, few studies have investigated mother-child interaction in terms of the overall emotional quality of dyadic interaction and its effect on child play. A sample of 28 children with DS (M age = 3 years) took part in this study. In particular, we studied whether the presence of the mother in an interactional context affects the exploratory and symbolic play of children with DS and the interrelation between children's level of play and dyadic emotional availability. Children showed significantly more exploratory play during collaborative play with mothers than during solitary play. However, the maternal effect on child symbolic play was higher in children of highly sensitive mothers relative to children whose mothers showed lower sensitivity, the former displaying more symbolic play than the latter in collaborative play. Results offer some evidence that dyadic emotional availability and child play level are associated in children with DS, consistent with the hypothesis that dyadic interactions based on a healthy level of emotional involvement may lead to enhanced cognitive functioning. PMID- 28636197 TI - Consistency in infant sleeping arrangements and mother-infant interaction. AB - This study examined the association between infant sleeping arrangements (i.e., habitual co-sleeping, inconsistent co-sleeping, and non-co-sleeping) and quality of mother-infant interaction during play in a sample of mothers, each with a typically developing infant (N=70). Mother-infant dyads who experienced consistency in infant sleeping arrangements in a typical week at 6 months (i.e., habitual co-sleeping or non-co-sleeping) were characterized by more positive maternal and infant behavior and dyadic quality of interaction at 9 months compared with dyads who experienced inconsistency in sleeping arrangements. Additionally, a greater amount of co-sleeping per week was associated with an increased duration of breastfeeding, mothers working fewer hours, less infant temperamental intensity, and less maternal depression. This study underscores the advantages of empirically based studies that consider consistency in infant sleep experience as a factor that is associated with more positive mother-child interaction. PMID- 28636199 TI - Widespread occurrence and potential for biodegradation of bioactive contaminants in Congaree National Park, USA. AB - Organic contaminants with designed molecular bioactivity, such as pesticides and pharmaceuticals, originate from human and agricultural sources, occur frequently in surface waters, and threaten the structure and function of aquatic and terrestrial ecosystems. Congaree National Park in South Carolina (USA) is a vulnerable park unit due to its location downstream of multiple urban and agricultural contaminant sources and its hydrologic setting, being composed almost entirely of floodplain and aquatic environments. Seventy-two water and sediment samples were collected from 16 sites in Congaree National Park during 2013 to 2015, and analyzed for 199 and 81 targeted organic contaminants, respectively. More than half of these water and sediment analytes were not detected or potentially had natural sources. Pharmaceutical contaminants were detected (49 total) frequently in water throughout Congaree National Park, with higher detection frequencies and concentrations at Congaree and Wateree River sites, downstream from major urban areas. Forty-seven organic wastewater indicator chemicals were detected in water, and 36 were detected in sediment, of which approximately half are distinctly anthropogenic. Endogenous sterols and hormones, which may originate from humans or wildlife, were detected in water and sediment samples throughout Congaree National Park, but synthetic hormones were detected only once, suggesting a comparatively low risk of adverse impacts. Assessment of the biodegradation potentials of 8 14 C-radiolabeled model contaminants indicated poor potentials for some contaminants, particularly under anaerobic sediments conditions. Environ Toxicol Chem 2017;36:3045-3056. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28636198 TI - Actin filament reorganisation controlled by the SCAR/WAVE complex mediates stomatal response to darkness. AB - Stomata respond to darkness by closing to prevent excessive water loss during the night. Although the reorganisation of actin filaments during stomatal closure is documented, the underlying mechanisms responsible for dark-induced cytoskeletal arrangement remain largely unknown. We used genetic, physiological and cell biological approaches to show that reorganisation of the actin cytoskeleton is required for dark-induced stomatal closure. The opal5 mutant does not close in response to darkness but exhibits wild-type (WT) behaviour when exposed to abscisic acid (ABA) or CaCl2 . The mutation was mapped to At5g18410, encoding the PIR/SRA1/KLK subunit of the ArabidopsisSCAR/WAVE complex. Stomata of an independent allele of the PIR gene (Atpir-1) showed reduced sensitivity to darkness and F1 progenies of the cross between opal5 and Atpir-1 displayed distorted leaf trichomes, suggesting that the two mutants are allelic. Darkness induced changes in the extent of actin filament bundling in WT. These were abolished in opal5. Disruption of filamentous actin using latrunculin B or cytochalasin D restored wild-type stomatal sensitivity to darkness in opal5. Our findings suggest that the stomatal response to darkness is mediated by reorganisation of guard cell actin filaments, a process that is finely tuned by the conserved SCAR/WAVE-Arp2/3 actin regulatory module. PMID- 28636201 TI - An exploration of the relationship between use of safety-seeking behaviours and psychosis: A systematic review and meta-analysis. AB - Safety-seeking behaviours are responses employed to protect against perceived threat. In relation to anxiety disorders, safety-seeking behaviours have been implicated in both the formation and maintenance of distress. Several studies have highlighted similar findings in relation to psychosis; however, this literature has not yet been synthesized. This review is, therefore, being conducted in order to synthesize the literature on safety seeking in people with psychosis to increase the understanding of this relationship. A systematic search identified and included 43 studies comprising 2,592 participants, published between 1995 and 2015. The results indicated that people experiencing psychosis commonly respond to their experiences with behavioural and cognitive strategies intended to manage their difficulties. In relation to safety seeking, avoidance, and resistance, there was a pattern that these responses are associated with increased distress and appraisals of threat. The results relating to engagement response styles showed the opposite pattern. These results provide support for cognitive models of safety seeking and psychosis with many of the meta-analyses reported here showing a clear pattern of association between behavioural responses and distress. However, the results reported within individual studies are mixed. This appears to be particularly true with the response style of distraction, with our analyses unable to clarify this relationship. It is possible that the mixed results could reflect the complexities in defining safety seeking and distinguishing it from coping in this population. The clinical implications of this are discussed. PMID- 28636200 TI - Functional Impairment: An Unmeasured Marker of Medicare Costs for Postacute Care of Older Adults. AB - OBJECTIVES: To assess the effects of preadmission functional impairment on Medicare costs of postacute care up to 365 days after hospital discharge. DESIGN: Longitudinal cohort study. SETTING: Health and Retirement Study (HRS). PARTICIPANTS: Nationally representative sample of 16,673 Medicare hospitalizations of 8,559 community-dwelling older adults from 2000 to 2012. MEASUREMENTS: The main outcome was total Medicare costs in the year after hospital discharge, assessed according to Medicare claims data. The main predictor was functional impairment (level of difficulty or dependence in activities of daily living (ADLs)), determined from HRS interview preceding hospitalization. Multivariable linear regression was performed, adjusted for age, race, sex, income, net worth, and comorbidities, with clustering at the individual level to characterize the association between functional impairment and costs of postacute care. RESULTS: Unadjusted mean Medicare costs for 1 year after discharge increased with severity of impairment in a dose-response fashion (P < .001 for trend); 68% had no functional impairment ($25,931), 17% had difficulty with one ADL ($32,501), 7% had dependency in one ADL ($39,928), and 8% had dependency in two or more ADLs ($45,895). The most severely impaired participants cost 77% more than those with no impairment; adjusted analyses showed attenuated effect size (33% more) but no change in trend. Considering costs attributable to comorbidities, only three conditions were more expensive than severe functional impairment (lymphoma, metastatic cancer, paralysis). CONCLUSION: Functional impairment is associated with greater Medicare costs for postacute care and may be an unmeasured but important marker of long-term costs that cuts across conditions. PMID- 28636202 TI - Squamous cell carcinoma of the temporal bone in 30 patients: Difference in presentation and treatment in de novo disease vs radiation associated disease. PMID- 28636203 TI - Directional Matrix Nanotopography with Varied Sizes for Engineering Wound Healing. AB - Topographic features play a crucial role in the regulation of physiologically relevant cell and tissue functions. Here, an analysis of feature-size-dependent cell-nanoarchitecture interactions is reported using an array of scaffolds in the form of uniformly spaced ridge/groove structures for engineering wound healing. The ridge and groove widths of nanopatterns are varied from 300 to 800 nm and the nanotopography features are classified into three size ranges: dense (300-400 nm), intermediate (500-600 nm), and sparse (700-800 nm). On these matrices, fibroblasts demonstrate a biphasic trend of cell body and nucleus elongation showing the maximum at intermediate feature density, whereas maximum migration speed is observed at the dense case with monotonic decrease upon increasing feature size. The directional organization of cell-synthesized fibronectin fibers can be regulated differently via the nanotopographical features. In an in vitro wound healing model, the covering rate of cell-free regions is maximized on the dense nanotopography and decreased with increasing feature size, showing direct correlation with the trend of migration speed. It is demonstrated that the properties of repaired tissue matrices in the process of wound healing may be controlled via the feature-size-dependent cell-nanoarchitecture interactions, which can be an important consideration for designing tissue engineering scaffolds. PMID- 28636204 TI - Aerobic exercise training for adults with fibromyalgia. AB - BACKGROUND: Exercise training is commonly recommended for individuals with fibromyalgia. This review is one of a series of reviews about exercise training for people with fibromyalgia that will replace the "Exercise for treating fibromyalgia syndrome" review first published in 2002. OBJECTIVES: * To evaluate the benefits and harms of aerobic exercise training for adults with fibromyalgia* To assess the following specific comparisons ? Aerobic versus control conditions (eg, treatment as usual, wait list control, physical activity as usual) ? Aerobic versus aerobic interventions (eg, running vs brisk walking) ? Aerobic versus non exercise interventions (eg, medications, education) We did not assess specific comparisons involving aerobic exercise versus other exercise interventions (eg, resistance exercise, aquatic exercise, flexibility exercise, mixed exercise). Other systematic reviews have examined or will examine these comparisons (Bidonde 2014; Busch 2013). SEARCH METHODS: We searched the Cochrane Library, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Physiotherapy Evidence Database (PEDro), Thesis and Dissertation Abstracts, the Allied and Complementary Medicine Database (AMED), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and the ClinicalTrials.gov registry up to June 2016, unrestricted by language, and we reviewed the reference lists of retrieved trials to identify potentially relevant trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in adults with a diagnosis of fibromyalgia that compared aerobic training interventions (dynamic physical activity that increases breathing and heart rate to submaximal levels for a prolonged period) versus no exercise or another intervention. Major outcomes were health-related quality of life (HRQL), pain intensity, stiffness, fatigue, physical function, withdrawals, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data, performed a risk of bias assessment, and assessed the quality of the body of evidence for major outcomes using the GRADE approach. We used a 15% threshold for calculation of clinically relevant differences between groups. MAIN RESULTS: We included 13 RCTs (839 people). Studies were at risk of selection, performance, and detection bias (owing to lack of blinding for self-reported outcomes) and had low risk of attrition and reporting bias. We prioritized the findings when aerobic exercise was compared with no exercise control and present them fully here.Eight trials (with 456 participants) provided low-quality evidence for pain intensity, fatigue, stiffness, and physical function; and moderate-quality evidence for withdrawals and HRQL at completion of the intervention (6 to 24 weeks). With the exception of withdrawals and adverse events, major outcome measures were self-reported and were expressed on a 0 to 100 scale (lower values are best, negative mean differences (MDs)/standardized mean differences (SMDs) indicate improvement). Effects for aerobic exercise versus control were as follows: HRQL: mean 56.08; five studies; N = 372; MD -7.89, 95% CI -13.23 to -2.55; absolute improvement of 8% (3% to 13%) and relative improvement of 15% (5% to 24%); pain intensity: mean 65.31; six studies; N = 351; MD -11.06, 95% CI -18.34 to -3.77; absolute improvement of 11% (95% CI 4% to 18%) and relative improvement of 18% (7% to 30%); stiffness: mean 69; one study; N = 143; MD -7.96, 95% CI -14.95 to -0.97; absolute difference in improvement of 8% (1% to 15%) and relative change in improvement of 11.4% (21.4% to 1.4%); physical function: mean 38.32; three studies; N = 246; MD -10.16, 95% CI -15.39 to -4.94; absolute change in improvement of 10% (15% to 5%) and relative change in improvement of 21.9% (33% to 11%); and fatigue: mean 68; three studies; N = 286; MD -6.48, 95% CI -14.33 to 1.38; absolute change in improvement of 6% (12% improvement to 0.3% worse) and relative change in improvement of 8% (16% improvement to 0.4% worse). Pooled analysis resulted in a risk ratio (RR) of moderate quality for withdrawals (17 per 100 and 20 per 100 in control and intervention groups, respectively; eight studies; N = 456; RR 1.25, 95%CI 0.89 to 1.77; absolute change of 5% more withdrawals with exercise (3% fewer to 12% more).Three trials provided low quality evidence on long-term effects (24 to 208 weeks post intervention) and reported that benefits for pain and function persisted but did not for HRQL or fatigue. Withdrawals were similar, and investigators did not assess stiffness and adverse events.We are uncertain about the effects of one aerobic intervention versus another, as the evidence was of low to very low quality and was derived from single trials only, precluding meta-analyses. Similarly, we are uncertain of the effects of aerobic exercise over active controls (ie, education, three studies; stress management training, one study; medication, one study) owing to evidence of low to very low quality provided by single trials. Most studies did not measure adverse events; thus we are uncertain about the risk of adverse events associated with aerobic exercise. AUTHORS' CONCLUSIONS: When compared with control, moderate-quality evidence indicates that aerobic exercise probably improves HRQL and all-cause withdrawal, and low-quality evidence suggests that aerobic exercise may slightly decrease pain intensity, may slightly improve physical function, and may lead to little difference in fatigue and stiffness. Three of the reported outcomes reached clinical significance (HRQL, physical function, and pain). Long-term effects of aerobic exercise may include little or no difference in pain, physical function, and all-cause withdrawal, and we are uncertain about long-term effects on remaining outcomes. We downgraded the evidence owing to the small number of included trials and participants across trials, and because of issues related to unclear and high risks of bias (performance, selection, and detection biases). Aerobic exercise appears to be well tolerated (similar withdrawal rates across groups), although evidence on adverse events is scarce, so we are uncertain about its safety. PMID- 28636205 TI - Progressive SCAR14 with unclear speech, developmental delay, tremor, and behavioral problems caused by a homozygous deletion of the SPTBN2 pleckstrin homology domain. AB - We report on nine members of a consanguineous Pakistani family with primary presentation of intellectual disability, developmental delay, limb and gait ataxia, behavioral and speech problems, and tremor. By linkage mapping and exome sequencing we identified novel homozygous splicing variant c.6375-1G>C in SPTBN2. To date, only two other SPTBN2 mutations with recessive pattern of inheritance causing SCAR14 (spinocerebellar ataxia, autosomal recessive 14) that manifest with developmental ataxia and cognitive impairment, or cerebellar ataxia, mental retardation, and pyramidal signs have been reported. The mutation we identified is predicted to lead to the deletion of just the pleckstrin homology domain; thus, the earlier onset and more progressive nature of the disease in the presented family, as compared to earlier reports, were unexpected. No other mutation that could possibly explain the features that were unusual for SCAR14 arched palate, limb hypotonia, climacophobia, and behavioral problems-was identified. The disease was more severe in males than females. Our findings expand the recessive SPTBN2 mutation phenotype. We also review SPTBN2 mutation phenotypes. The gene encodes beta-III spectrin, which forms tetramers with alpha II spectrin. The manifestations of this third recessive mutation suggest that for recessive mutations either no mutant protein is synthesized because the transcript is subject to nonsense-mediated decay or the mutant protein does not bind membrane proteins and, thus, does not exert a negative effect in heterozygotes, whereas the dominant mutations causing SCA5 form defective tetramers that compete with the native tetramers in binding membrane proteins, but are unable to anchor them. PMID- 28636206 TI - Retinal vascular injuries and intravitreal human embryonic stem cell-derived haemangioblasts. AB - OBJECTIVE: To investigate whether intravitreally applied haemangioblasts (HB) derived from human embryonic stem cells (hESCs) are helpful for the repair of vascular damage caused in animals by an oxygen-induced retinopathy (OIR), by an induced diabetic retinopathy (DR) or by an induced retinal ischaemia with subsequent reperfusion. METHODS: Human embryonic stem cell-derived HBs were transplanted intravitreally into C57BL/6J mice (OIR model), into male Wistar rats with an induced DR and into male Wistar rats undergoing induced retinal ischaemia with subsequent reperfusion. Control groups of animals received an intravitreal injection of endothelial cells (ECs) or phosphate-buffered saline (PBS). We examined the vasculature integrity in the mice with OIR, the blood-retina barrier in the rats with induced DR, and retinal thickness and retinal ganglion cell density in retina flat mounts of the rats with the retinal ischaemic-reperfusion retinopathy. RESULTS: In the OIR model, the study group versus control groups showed a significantly (p < 0.001) smaller retinal avascular area [5.1 +/- 2.7%;n = 18 animals versus 12.2 +/- 2.8% (PBS group; n = 10 animals) and versus 11.8 +/- 3.7% (EC group; n = 8 animals)] and less retinal neovascularization [6.3 +/- 2.5%;n = 18 versus 15.2 +/- 6.3% (n = 10; PBS group) and versus 15.8 +/- 3.3% (n = 8; EC group)]. On retinal flat mounts, hESC-HBs were integrated into damaged retinal vessels and stained positive for PECAM (CD31) as EC marker. In the DR model, the study group versus the EC control group showed a significantly (p = 0.001) better blood-retina barrier function as measured at 2 days after the intravitreal injections [study group: 20.2 +/- 12.8 MUl/(g * hr); n = 6; versus EC control group: 52.9 +/- 9.9 MUl/(g * hr; n = 6)]. In the retinal ischaemia reperfusion model, the groups did not differ significantly in retinal thickness and retinal ganglion cell density at 2, 5 and 7 days after baseline. CONCLUSION: By integrating into damaged retinal vessels and differentiating into ECs, intravitreally administered hESC-HBs may have partially repaired a retinal vascular injury caused by OIR model and DR. PMID- 28636207 TI - Specificity of, and influence of hemolysis, lipemia, and icterus on serum lipase activity as measured by the v-LIP-P slide. AB - BACKGROUND: Measurement of pancreatic lipase in serum is being used for the diagnosis of pancreatitis. OBJECTIVES: The aims of this study were to measure serum lipase activity by the v-LIP-P slide and serum canine pancreatic lipase immunoreactivity (cPLI) concentration by Spec cPL in dogs with exocrine pancreatic insufficiency (EPI) and in serum samples that were hemolyzed, lipemic, or icteric. METHODS: Serum samples from 50 dogs with EPI, 8 samples spiked with canine hemoglobin, Intralipid, or ditaurobilirubin, and 8 samples from dogs with severe hypertriglyceridemia were evaluated using v-LIP-P and Spec cPL assays. RESULTS: Serum lipase activity (v-LIP-P) was in the lower 20% of the RI in 58% of EPI dogs, while serum cPLI (as measured by Spec cPL) was in the lower 20% of the RI in 98% of EPI dogs. The mean (+/-SD) observed-to-expected ratios for serum samples spiked with canine hemoglobin, Intralipid, or ditaurobilirubin were 63.0 +/- 25.1%, 489.2 +/- 469.7%, and 80.2 +/- 11.6% for the v-LIP-P slide, respectively, and 99.3 +/- 6.8%, 96.9 +/- 9.4%, and 98.7 +/- 11.0% for Spec cPL, respectively. However, naturally occurring hypertriglyceridemia did not appear to have a significant effect on serum lipase activity as measured by the v-LIP-P slide. CONCLUSIONS: These results show that Spec cPL is specific for pancreatic lipase, while the v-LIP-P slide is not. In addition, hemolysis and lipemia had no effect on Spec cPL, while severe icterus resulted in a slight decrease in Spec cPL. Hemolysis and icterus had a significant effect on the v-LIP-P slide. The effect of lipemia on the v-LIP-P slide cannot be conclusively established based on this study. PMID- 28636209 TI - A case of acquired reactive perforating collagenosis. PMID- 28636208 TI - A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers. AB - AIM: To evaluate the safety, tolerability, and pharmacokinetics/pharmacodynamics of PRN1008, a novel Bruton's tyrosine kinase (BTK) inhibitor, in healthy volunteers, and thus determine the dose range for future clinical studies. METHODS: This was a two-part randomized, placebo controlled study in healthy volunteers using a liquid formulation. Part I was a single ascending dose design with dose levels of 50-1200 mg (n = 6 active, two placebos per cohort); Part II was a multiple ascending dose design, with dose regimens ranging from 300 to 900 mg daily, either four times or twice daily for 10 days. Plasma pharmacokinetics, adverse events, vital signs, electrocardiograms and laboratory parameters were assessed. BTK occupancy in peripheral blood mononuclear cells was evaluated as a marker of target engagement. RESULTS: PRN1008 was rapidly absorbed following oral administration, and was safe and well tolerated in all dose regimens evaluated in both single and multiple doses. PRN1008 demonstrated a large volume of distribution, and a half-life of approximately 3-4 h. BTK occupancy of >90% was observed within 4 h after dosing in both single and multiple dose regimens, and was closely linked to maximum plasma concentration. BTK occupancy decay was slow (-1.6% h-1 ), and occupancy was sustained despite drug concentrations being undetectable. No severe or serious adverse events occurred, and the most common adverse events were gastrointestinal in nature. CONCLUSIONS: PRN1008 was safe and well-tolerated following oral administration, and achieved high, sustained levels of BTK occupancy in peripheral blood mononuclear cells. PMID- 28636210 TI - Graphical displays. PMID- 28636212 TI - Digest: Ecological opportunity, competition, and diversity dependence in macroevolution. PMID- 28636211 TI - Resolution of donor non-alcoholic fatty liver disease following liver transplantation. AB - INTRODUCTION: Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes. METHODS: Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS >=15%, while all recipients received postoperative liver biopsies for cause. RESULTS: The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients. CONCLUSIONS: High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets. PMID- 28636213 TI - Distribution and hypoxia-regulation of haemocyanin in springtails (Collembola). AB - Haemocyanin is the copper-containing respiratory protein present in many arthropods. In the hexapods, respiratory proteins had long been considered unnecessary as sufficient O2 was thought to be obtained via the trachea. Nevertheless, many ametabolous and hemimetabolous hexapod species actually possess haemocyanin. Here we investigated the occurrence of haemocyanin in Collembola (springtails). Haemocyanin was found in 22 collembolan species of the suborders Symphypleona, Tomoceroidea and Entomobryomorpha, demonstrating its widespread occurrence. No haemocyanin was identified in 16 species of these taxa, and it appears to be absent in Poduromorpha. The presence of haemocyanin does not correlate with either the phylogenetic history or lifestyle of the investigated species. We further investigated the function of haemocyanin in Folsomia candida (Entomobryomorpha) by applying different hypoxia regimes. Whereas short-term (1 h) and mild (10% O2 ) hypoxia led to a decrease in haemocyanin mRNA, strong hypoxia (24 h, 1.5% O2 ) resulted in a ~4300-fold increase in haemocyanin expression. Hypoxia induction of haemocyanin could not be demonstrated in evolutionarily more advanced Hexapoda, where it is restricted to the embryo. The results indicate (1) an important role of haemocyanin in the oxygen supply of F. candida, which may be adaptive in the potentially hypoxic environment in the soil, and (2) a change in haemocyanin function in hexapod evolution. PMID- 28636214 TI - National home infusion teaching guidelines will improve quality of care and patient outcomes in haemophilia treatment centres across the USA. PMID- 28636215 TI - Case of generalized pustular psoriasis presenting with both pleural effusion and pericardial effusion collection. PMID- 28636216 TI - Imaging of haemophilic arthropathy: Awareness of pitfalls and need for standardization. PMID- 28636217 TI - Research on potential biomarker correlates for suicidal behavior: A review. AB - Suicide is a world health priority. Studies over the last few decades have revealed the complexity underlying the neurobiological mechanisms of suicide. Researchers have found dysregulations in the serotonergic system, the stress system, neural plasticity, lipid metabolism, and cell signaling pathways in relation to suicidal behaviors. These findings have provided more insight into the final path leading to suicide, at which medical intervention should be applied to prevent the action. However, because these molecular mechanisms have been implicated in both depression and suicide, the specificity of the mechanisms has been obscured. In this review, we summarize the main findings of studies on molecular mechanisms of suicidal behavior from the last 2 decades, with particular emphasis on the potential, independent role of each mechanism that is not contingent upon an underlying psychopathology, such as depression. The act of suicide is multifactorial; no single molecular mechanism is sufficient to fully account for the act. Knowledge of the reciprocal interactions among these molecular mechanisms and studying them in the context of brain circuitry by using neuroimaging techniques will provide a better understanding of the neurobiology of suicide. PMID- 28636218 TI - Maternal depression and anxiety effects on the human fetus: Preliminary findings and clinical implications. AB - Newborns of depressed and anxious mothers show biobehavioral abnormalities suggesting that maternal psychological distress has negative effects on the fetus. Two studies examined the fetuses of depressed and nondepressed mothers: (a) a cross-sectional investigation of fetal activity during the second and third trimesters and (b) an examination of behavioral and heart rate response to vibratory stimulation in late-gestation fetuses. Fetuses of depressed mothers were more active during the fifth, sixth, and seventh gestational months. Assessment of late-term fetuses consisted of a baseline, trials of vibratory stimulation directed towards measuring habituation, and a poststimulation period. During baseline, the fetuses of depressed mothers exhibited a lower heart rate. During stimulation trials, they showed less total movement and appeared to habituate more often. Approximately 35% of the variance in fetal behavior was accounted for by the mothers' depression and anxiety symptoms. Maternal depression may be linked to greater fetal activity during the second and third trimesters and decreased behavioral responsivity during late gestation. The response of late-term fetuses of depressed mothers to vibratory stimulation may reflect "receptor adaptation/effector fatigue" and not true habitation. Future studies should examine the value of clinical interventions provided to the pregnant mother. PMID- 28636219 TI - A mother-infant therapy group model for postpartum depression. AB - This pilot study examined the feasibility and efficacy of a manualized, 12-week mother-infant therapy group (M-ITG) model for women with moderate to severe depressive symptoms during the postpartum period. Study participants were referred to the psychiatric clinic of a university medical center for assessment and treatment for postpartum depression. Results of pre- and post comparisons utilizing self-report and observational measures showed that women in the M-ITG groups (n = 18) reported significantly fewer depressive symptoms and experienced their infants as more reinforcing following 12 weeks of treatment than did the depressed women in the waitlist control group (WLCG) (n = 14). Mothers in the M ITG group also were rated as exhibiting significantly more positive affective involvement and communication in interactions with their infants following treatment than did mothers in the WLCG. The M-ITG model is described, and the implications of utilizing a mother-infant treatment approach for postpartum depression that focuses on the relationships as well as the mother's depressive symptoms is discussed. The importance of further examining the efficacy of the M ITG model for women with postpartum depression and their families in a large scale, randomized clinical trial is underscored. PMID- 28636221 TI - Treatment of postpartum depression in mothers: Secondary benefits to the infants. AB - This study examined the quality of mother-infant interaction and levels of perceived stress and parenting efficacy in association with mothers' levels of depression among mothers with significant depressive symptoms during the postpartum period, who were followed prospectively during treatment, and their infants less than 6 months old. Mothers with postpartum depression (n = 19) were treated with medication, and the mothers were observed with their infants prior to treatment and 3 and 6 months later. A comparison group of nondepressed mothers (n = 25) was included to control for the normal developmental changes associated with the postpartum period. The depressed women experienced a significant reduction in depressive symptoms and did not differ significantly from well mothers 6 months after beginning treatment. Despite initial levels of parenting quality and depression, mothers' reduced levels of depression, after 12 weeks of treatment, were associated with improvements in the quality of their interactions with their infants and with improvements in their infants' quality of play. For both perceived stress and parenting efficacy beliefs, both depressed and well mothers showed a significant improvement from the initial to the 12-week visit, and there were no significant differences between depressed and well mothers' perceived stress or efficacy beliefs at the 12-week visit. Depression at the 12 week visit did not predict perceived stress or efficacy beliefs beyond the variance accounted for by initial levels of those variables and depression. The impact of reducing levels of maternal depression symptoms supports theoretical models of the role of parenting in the association between maternal depression and child functioning. Further, these findings support the benefits to infants of reducing depression in mothers. PMID- 28636220 TI - Six-week postpartum maternal depressive symptoms and 4-month mother-infant self- and interactive contingency. AB - Associations of 6-week maternal depressive symptoms [Center for Epidemiological Studies Depression Scale (CES-D)] with 4-month mother-infant self- and interactive contingency patterns during face-to-face play were investigated in 132 dyads. Self- and interactive contingency (auto- and lagged cross-correlation, respectively) were assessed by multilevel time-series analysis. Infant and mother gaze, facial and vocal affect, touch, and spatial orientation behaviors were coded second-by-second from split-screen videotape, and a multimodal measure of facial-visual "engagement" was constructed, generating nine modality pairings. With higher CES-D, the self-contingency of both partners was lowered in most modalities. With higher CES-D, interactive contingency values were both heightened (in some modalities) and lowered (in others), varying by partner. These results are consistent with an optimal midrange model. With higher CES-D, interactive contingency showed the following patterns: (a) Mothers and their infants had a reciprocal orientational sensitivity; (b) mothers and infants manifested a reciprocal intermodal discordance in attention versus affect coordination, lowering gaze coordination, but heightening affective coordination; (c) infants heightened, but mothers lowered, touch coordination with partner touch-an "infant approach-mother withdraw" touch pattern. Nonlinear analyses indicated that altered self- and interactive contingency were similar at both the low ("denial") as well as the high ("endorsement") poles of depressive symptoms, in half the findings. These complex, multimodal findings define different aspects of communication disturbance, with relevance for therapeutic intervention. PMID- 28636223 TI - Mother-infant psychotherapy: Examining the therapeutic process of change. PMID- 28636222 TI - Recent progress in immunotherapy for urological cancer. AB - Cancer immunotherapy for urological tumors had made progress for several decades, but recent advances in immunotherapy, as therapeutic vaccines or immune checkpoint inhibitors, have drastically changed the present treatment strategy. Recently, nivolumab and atezolizumab have been approved by the Food and Drug Administration for treatment of urological cancers. Additional immune checkpoint inhibitors and vaccines are being tested in clinical trials. Despite advances in these therapeutic modalities, benefits are limited to a subset of patients. New agents and novel combinations will also continue to create new immunotherapy strategies. Further development of biomarkers for predicting response is required to achieve optimal efficacy with these therapeutic interventions. PMID- 28636224 TI - Early emotional development in infants and toddlers: Perspectives of Early Head Start staff and parents. AB - As part of a curriculum-development project, focus groups were implemented with Early Head Start staff and with parents of infants and toddlers enrolled in Early Head Start. Focus groups were designed to identify staff and parent beliefs about early emotional development. Three major themes were identified that crossed the staff and parent focus groups: (a) Infants' and toddlers' abilities to have emotions and to be aware of others' emotions; (b) roles of parents as advocates, teachers, and disciplinarians; and (c) parental reflectivity about their own experiences as influences on their parenting. The findings suggest that parents participating in Early Head Start have some knowledge about basic emotions and the developmental nature of emotions, but may easily misinterpret emotional displays only as attempts at manipulation rather than as valid expressions of feelings; expectations for gender-appropriate emotional expressiveness begin early; more empowered parents may view themselves as role models and teachers for their children; and more reflective parents are better prepared to engage in the sensitive interactions needed to guide young children's growing awareness of their own and others' emotions. Implications for parenting education and program planning utilizing an infant mental health perspective are discussed. PMID- 28636225 TI - Video interaction guidance inviting transcendence of postpartum depressed mothers' self-centered state and holding behavior. AB - By sometimes evoking self-absorbed and avoidance behaviors in new mothers, postnatal depression affects the quality of mother-infant interaction, which in turn may invoke distress and avoidance in the infant and cause even more lasting impairment in the child's development. Three depressed mothers, A, B, and C, are reported upon after having been offered counseling in accordance with the Marte Meo approach through jointly watching with the therapist video replays of themselves interacting with their newborns. Clinical vignettes are offered which indicate how empathic and positive support of a sensitive therapist can be helpful in inviting the mother's recognition of her importance to her infant and facilitating mutually gratifying interaction between mother and child. Protocol analyses of select sessions of video-related therapy reveal that two of the mothers sometimes complete the therapist's unfinished statements in an other centered manner, thereby transcending their initial self-centered state. This is most dramatic in the case of Mother A, who starts out in the first session almost incapable of speech, merely nodding or shaking her head. In addition to other indications of improved mother-infant interaction, comparison of pre- and postguidance windows regarding the three mothers' holding behaviors reveals a shift from an avoidance or anxious stance to closer and more secure holding. PMID- 28636226 TI - Satellite babies in transnational families: A study of parents' decision to separate from their infants. AB - This study examines a practice which is characteristic of an era of intensifying globalization: As part of a transnational lifestyle, an increasing number of immigrants to North America send infants thousands of miles back to their country of origin to be raised by members of their extended families-a culturally sanctioned tradition. After several years of separation, the children return to the biological parents to attend school in the adopted country, a custom which, according to Western mental health models, could have significant sequelae for attachment relationships and other facets of development. This practice is particularly prevalent among immigrants from the People's Republic of China, but a modified version of it can be found in other groups as well. The work described here is the first phase of a longitudinal project that explores the advantages and potential repercussions, for both infants and parents, of a transnational lifestyle. The current study reviews the decision-making process of a group of Chinese Canadian immigrant parents who are considering a separation from their infants. Preliminary findings show that the expected concerns about disrupting attachment relationships are embedded in more salient considerations of economic need and cultural perspective. These exploratory data exemplify an emergent field of culture-focused research and practice in infant mental health, and support the call for innovative models to situate infant developmental pathways in global and transcultural contexts. PMID- 28636227 TI - Triadic nonverbal communication in mother-infant consultations: Two contrasted cases. AB - The aim of the present case study was to present and discuss the analysis of triadic nonverbal communication between mother, infant, and therapist in two early consultations as an indicator of the therapeutic alliance. The analysis explored nonverbal triadic interactions (body positions and facial orientations of the mother, infant, and therapist, and expressive behaviors of the infant) and triadic affective sharing (via a microanalytic interview of the therapist). The quality of the therapeutic alliance and clinical outcome for each case are described. The description of the two cases illustrates the importance of the progressive development of nonverbal "engagement" by the three people (triadic alliance) and of moments with triadic emotional sharing. The contribution of the therapist appears to be crucial, in particular via his or her body and affective engagement with the infant. The triadic alliance appears to be both an indicator of the therapeutic alliance and an element that can foster it. PMID- 28636228 TI - Learning to sleep through the night: Solution or strain for mothers and young children? AB - Is the process of helping infants and young children learn to sleep through the night a solution to family sleep problems or does it exacerbate matters for mother and child? Retrospective and current accounts from a nonclinical, convenience sample of 102 mothers of preschool-aged children provided information on sleep issues from early infancy through preschool age. Child, mother, and parenting characteristics, along with family sleep arrangements, were differentially related to the age at which children learned to sleep through the night and to the extent of difficulty that characterized this experience. Mothers who indicated more difficulty as their children learned to sleep through the night also reported more depressive symptoms and more strain in the mother-child relationship. Later age at sleeping through the night was more common among early bedsharers, but timing of sleeping through the night was not associated with preschool children's reported independence in several nonsleep domains. Sleep arrangements and the importance placed on sleeping through the night were the strongest contributors to variance explained in whether children learned to sleep through the night during infancy or toddlerhood. When advising parents about sleep interventions, practitioners should seek to understand whether families' parenting values fit their nighttime sleep practices. PMID- 28636230 TI - Quantification of fatty acids in erythrocytes and plasma by fast gas chromatography. AB - As a result of the heterogeneous nature of lipid classes in complex biological matrices such as plasma and erythrocytes, it is imperative to have a robust and validated methodology for fatty acid quantification. The effective method presented here combines available methodology of fast gas chromatography and an improvement of the sample preparation methodology before injection into the gas chromatograph. This methodology ensures complete transesterification and quantification of total and individual fatty acids (and not only in relative amounts) by addition of internal standards. We considered sample preparation key, and we established the use of lysis buffer and ethanol for erythrocytes and plasma sample preparation, respectively. Fatty acid profile was determined by acid methylation and fast gas chromatography equipped with a flame ionization detector. The triacylglycerol 13:0, phosphatidylcholine 23:0, and methyl esters 21:0 were used as internal standards. Within the linearity of the calibration, the ratio of the peak area of each fatty acid over the peak area of the internal standard was constant (coefficient of variation <= 2.5). Satisfactory repeatability <15% and intermediate reproducibility < 15% were observed. Finally, this validated method was applied to a pre-clinical trial that investigated the impact of dietary fats on accretion of specific fatty acids in plasma and erythrocytes. PMID- 28636229 TI - Recovery from reproductive and morphological abnormalities in medaka (Oryzias latipes) following a 14-day exposure to diclofenac. AB - Mating pairs of medaka (Oryzias latipes) were exposed to diclofenac at measured concentrations of 0 (control), 7.1, 37, and 78 MUg/L for 14 d under static renewal conditions. Effects on reproductive success, as well as morphological abnormalities, of the fish were assessed. During the exposure period, both fecundity and fertility were significantly decreased in the 37- and 78-MUg/L treatment groups, and swollen abdomens in females were observed in all exposure groups. Notably, a defect of the lower jaw was also observed in 4 male fish: 2 at 37 MUg/L and 2 at 78 MUg/L of diclofenac. Subsequently, we investigated whether the reproductive and morphological abnormalities induced by diclofenac would be permanent or reversible once the medaka were returned to clean water. The reproductive ability of paired medaka was gradually restored to fish that were cultured in clean water for 14 d. After this period in clean water, we also observed a noticeable decrease in swollen abdomens in females; however, mandibular defects in the males remained, even after the 14-d recovery period. Radiographic and histochemical examinations revealed that diclofenac might affect bone remodeling in the lower jaw of male medaka because of a disruption in osteoclast function. These results suggest that reproductive impairments in pairs of medaka exposed to diclofenac may be reversible but that skeletal deformities (i.e., mandibular defect) in males may be persistent. Environ Toxicol Chem 2017;36:3277-3283. (c) 2017 SETAC. PMID- 28636231 TI - Orchestration at the beginning: mitosis in sea urchin embryo. PMID- 28636233 TI - Green Synthesis of A2 SiF6 (A=Li-Cs) Nanoparticles using Ionic Liquids as Solvents and as Fluorine Sources: A Simple Approach without HF. AB - In this Communication, nanoparticles of the fluoridosilicates A2 SiF6 (A=Li, Na, K, Rb, Cs), which are extremely promising host lattices for future LEDs, are presented for the first time. The preparation method we introduce here is a very simple and energy and time saving one, moreover the usage of toxic HF or elemental fluorine is avoided. In detail, the ionic liquid [Bmim]PF6 was used both as solvent and fluoride source in an ionothermally assisted microwave synthesis. The small size of the so-obtained nanoparticles is of huge relevance for their applications as thin films or for the coverage of surfaces, for example in next-generation white LEDs upon doping with Mn4+ . PMID- 28636232 TI - A genetic stochastic process model for genome-wide joint analysis of biomarker dynamics and disease susceptibility with longitudinal data. AB - Unraveling the underlying biological mechanisms or pathways behind the effects of genetic variations on complex diseases remains one of the major challenges in the post-GWAS (where GWAS is genome-wide association study) era. To further explore the relationship between genetic variations, biomarkers, and diseases for elucidating underlying pathological mechanism, a huge effort has been placed on examining pleiotropic and gene-environmental interaction effects. We propose a novel genetic stochastic process model (GSPM) that can be applied to GWAS and jointly investigate the genetic effects on longitudinally measured biomarkers and risks of diseases. This model is characterized by more profound biological interpretation and takes into account the dynamics of biomarkers during follow-up when investigating the hazards of a disease. We illustrate the rationale and evaluate the performance of the proposed model through two GWAS. One is to detect single nucleotide polymorphisms (SNPs) having interaction effects on type 2 diabetes (T2D) with body mass index (BMI) and the other is to detect SNPs affecting the optimal BMI level for protecting from T2D. We identified multiple SNPs that showed interaction effects with BMI on T2D, including a novel SNP rs11757677 in the CDKAL1 gene (P = 5.77 * 10-7 ). We also found a SNP rs1551133 located on 2q14.2 that reversed the effect of BMI on T2D (P = 6.70 * 10-7 ). In conclusion, the proposed GSPM provides a promising and useful tool in GWAS of longitudinal data for interrogating pleiotropic and interaction effects to gain more insights into the relationship between genes, quantitative biomarkers, and risks of complex diseases. PMID- 28636234 TI - Association of recent gay-related stressful events and emotional distress with suicidal behaviors over 12 months in Chinese men who have sex with men. AB - INTRODUCTION: The study was designed to assess the association of gay-related stressful events (GRSEs) and emotional distress with suicidal behaviors over a 12 month period in Chinese men who have sex with men (MSM). METHODS: A total of 807 MSM were recruited using a respondent-driven sampling method from 4 cities in northeastern China. The GRSEs were measured using the Gay-related Stressful Life Events Scale, depression using the Self-rating Depression Scale, and anxiety using the Self-rating Anxiety Scale. RESULTS: A total of 26.0% of study participants experienced GRSEs during the 3 months, and their average Self-rating Depression Scale and Self-rating Anxiety Scale scores were significantly lower than the national norms. Over a 12-month period, the prevalence of suicidal ideation, plan, and attempt was 9.7%, 4.0%, and 3.0%, respectively, each of which is at least 3 to 4 times greater than that of male adults in the general population of China. Multiple logistic regression analysis showed that GRSEs significantly increased the risk of suicidal ideation (odds ratio [OR] = 2.3, 95% confidence interval [CI], 1.4-3.7) and plan (OR = 2.8, 95% CI, 1.3-6.0). Depressive symptoms significantly increased the risk of suicidal ideation (OR = 3.5, 95% CI, 2.1-5.8), plan (OR = 4.4, 95% CI, 2.0-9.6), and attempt (OR = 5.6, 95% CI, 21.94.8). Anxiety symptoms (OR = 3.4, 95% CI, 1.4-8.4) and cohabitation with a same sex partner (OR = 3.0, 95% CI, 1.2-7.9) significantly increased the risk of suicide attempt. DISCUSSION: More efforts to reduce GRSE are worth investigating as a strategy to reduce suicidal thoughts and behaviors in Chinese MSM. PMID- 28636235 TI - Stem cell-based tooth and periodontal regeneration. AB - Currently regeneration of tooth and periodontal damage still remains great challenge. Stem cell-based tissue engineering raised novel therapeutic strategies for tooth and periodontal repair. Stem cells for tooth and periodontal regeneration include dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), stem cells from the dental apical papilla (SCAPs), and stem cells from human exfoliated deciduous teeth (SHEDs), dental follicle stem cells (DFSCs), dental epithelial stem cells (DESCs), bone marrow mesenchymal stem cells (BMMSCs), adipose-derived stem cells (ADSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). To date, substantial advances have been made in stem cell-based tooth and periodontal regeneration, including dentin pulp, whole tooth, bioroot and periodontal regeneration. Translational investigations have been performed such as dental stem cell banking and clinical trials. In this review, we present strategies for stem cell-based tissue engineering for tooth and periodontal repair, and the translational studies. PMID- 28636236 TI - Assessment of silibinin as a potential antifungal agent and investigation of its mechanism of action. AB - Silibinin, which is derived from Silybum marianum (milk thistle), has used as a traditional remedy for liver or biliary disorders and known to have superior antioxidant activity. In addition, silibinin was recently reported to have antifungal effect related to fungal apoptosis against Candida albicans and the interest in the therapeutic effect is increasing. In this study, we found another mode of antifungal action of silibinin and its antibiofilm activity on C. albicans. To investigate influence on fungal plasma membrane, propidium iodide and bis-(1, 3-dibutylbarbituric acid) trimethineoxonol [DiBAC4 (3)] assay were primarily carried out. After 5-h incubation with silibinin (50, 100, 150, or 200 ug/mL), the propidium iodide fluorescent percentages increased by 11.90%, 28.50%, 34.10%, and 44.52%, respectively, and the DiBAC4 (3) fluorescent percentages increased by 13.18%, 34.64%, 46.99%, and 57.15%, respectively. As a result, we thought that silibinin concentrations of more than 100 ug/mL have a membrane damaging effect. Subsequently, to estimate the degree of membrane damage, we used Fluorescein isothiocyanate-labelled dextrans (FDs) of various sizes and the results indicated that silibinin allowed penetration of molecules smaller than approximately FD20 (3.3 nm). In addition, silibinin inhibited the dimorphic transition of C. albicans and resulted in the inhibition of biofilm development at an early stage. In conclusion, we found membrane-damaging effect of silibinin and its antibiofilm effect in C. albicans. (c) 2017 IUBMB Life, 69(8):631-637, 2017. PMID- 28636237 TI - Microperforate hymen presenting with incomplete abortion: A case report. AB - A 20-year-old patient with 3 months of amenorrhea presented in the labor room with bleeding per vaginum and having experienced lower abdominal pain for 2 h. She had a history of difficult intercourse and prolonged menstrual flow. Inspection revealed a bleeding point over an obstructing membrane at the level of the vaginal introitus. Subsequent vaginal examination confirmed the diagnosis of microperforate hymen. Her urine pregnancy test was positive and an ultrasound examination revealed the presence of retained products of conception in the endometrial cavity. Hymenectomy was carried out to evacuate the retained products of conception and the margins of the hymen were sutured to prevent restenosis. The outcome was uneventful. This case study suggests that even though subocclusive hymenal anomalies, such as microperforate hymen, can interfere with normal vaginal intercourse, it does not lead to infertility and can permit pregnancy. Hence, awareness about this rare entity may lead to early detection and improvement in the patient's quality of life. PMID- 28636238 TI - Segmental, Domain-Selective Perdeuteration and Small-Angle Neutron Scattering for Structural Analysis of Multi-Domain Proteins. AB - Multi-domain proteins play critical roles in fine-tuning essential processes in cellular signaling and gene regulation. Typically, multiple globular domains that are connected by flexible linkers undergo dynamic rearrangements upon binding to protein, DNA or RNA ligands. RNA binding proteins (RBPs) represent an important class of multi-domain proteins, which regulate gene expression by recognizing linear or structured RNA sequence motifs. Here, we employ segmental perdeuteration of the three RNA recognition motif (RRM) domains in the RBP TIA-1 using Sortase A mediated protein ligation. We show that domain-selective perdeuteration combined with contrast-matched small-angle neutron scattering (SANS), SAXS and computational modeling provides valuable information to precisely define relative domain arrangements. The approach is generally applicable to study conformational arrangements of individual domains in multi domain proteins and changes induced by ligand binding. PMID- 28636239 TI - Forensic issues in infant mental health: Challenging systems, clinical risk, future collaborations. AB - Much clinical work in infant mental health includes working with families of young children involved in the complex arenas of the legal and child protection systems. These systems have their own distinctive languages, cultures, and values, but they share a concern with clinicians about the best interest of the child. This special issue explores selected topics in this area, calling attention to research, policy, and clinical issues in forensic infant mental health. The purpose of the issue is to stimulate additional thinking and additional scholarly attention to these vital issues that have such importance for families around the world. PMID- 28636240 TI - Predictors of permanent loss of custody for mothers of infants and toddlers in foster care. AB - The maltreating mothers of abused and neglected infants and toddlers were evaluated as part of an intensive intervention program. The purpose of this study was to examine cumulative risk versus specific risk factors that led to permanent loss of custody by mothers, predicated upon decisions by the Juvenile Court with regard to permanency planning. The following risk factors were analyzed as potential predictors of placement outcomes: maternal education, maternal history of abuse as a child, history of psychiatric difficulties, substance-abuse history, conviction history (excluding child-abuse charges), depressive symptomatology, degree of partner violence experienced, and cumulative number of risks the mother experienced. Results indicated that mothers who lost custody had significantly more risk factors than those who were reunified with their children. Cumulative risk was a stronger predictor than specific risk factors. Implications for intervention are discussed. PMID- 28636241 TI - A judicial-mental health partnership to heal young children in juvenile court. AB - In this article, we describe the background and issues to be addressed related to dependent children in juvenile court. In an important effort to systematically examine developmental functioning and treatment needs in maltreated and violence exposed young children, the Prevention and Evaluation of Early Neglect and Trauma (PREVENT) initiative of the Dependency Court Intervention Program for Family Violence, a national demonstration project in the Miami-Dade Juvenile Court, developed a program to evaluate all infants, toddlers, and preschoolers who are adjudicated dependent by the court. The goal of the intervention is to raise awareness of the needs of infants and toddlers in juvenile court and to work toward healing the child. The PREVENT program involved the evolution of a judicial-mental health partnership designed to assist the court in making more informed decisions about the best interest of the child by adding scientific knowledge about development, prevention, intervention, evaluation, and treatment. The outcome of the partnership and multidisciplinary approach is illustrated through presenting a case vignette of a mother and baby showing the challenges and strengths of intervention. Finally, we consider overall outcomes of the intervention and directions for the future. PMID- 28636242 TI - Infant mental health, child maltreatment, and the law: A jurisprudent therapy analysis. AB - Scholarly and clinical discussions of the legal issues facing infant mental health professionals typically focus on the seemingly intractable differences in philosophies, goals, and approaches inherent in the law and the mental health professions. We argue that forensically informed approaches to practice with very young children can potentially enhance many mental health and child welfare outcomes. This article describes the relatively new conceptual frameworks known as "therapeutic jurisprudence" and "jurisprudent therapy." Using these conceptual frameworks, we analyze representative problems that are typical in infant mental health practice with maltreated children through case examples drawn from their evaluations of children and families in the child protection and legal systems. Demonstrations of how such dilemmas can be approached with enhanced analytic decision-making and practice approaches are presented. We argue that applying such jurisprudent therapy approaches opens up fresh perspectives for evidence based practices that facilitate creative, rigorous, and intellectually stimulating clinical work. PMID- 28636243 TI - The infant protection system in France: How does it work? AB - The French system for protection of infants and toddlers relies on the collaboration of several different partners for preventing, screening, assessing, intervening in, and treating cases of infant abuse and neglect. This article first provides a brief historic overview and some data about the protection of infants in France, with data focused on the Parisian area. We then describe the tasks and interconnections of these different agencies and administrations, and offer some reflections on the actual functioning of the system. Finally, some suggestions for changes are provided. Discussion should begin on a theoretical level regarding whether we should continue with institutionalization of infants for long periods of time, as is still the case in Paris. Discussion also should take place regarding which is the higher priority when infants and children are in situations of danger, abuse, and/or neglect of infants: (a) the hope of reestablishing parental rights or (b) the need of the infant for a secure and stable attachment relationship. The process of evaluating parental caregiving skills would benefit from more clinical observation as well as structured methods of assessment. PMID- 28636244 TI - Filicide: Historical review and prevention of child death by parent. AB - Filicide has occurred throughout the world since before recorded history. Although rates have declined in developed nations, it remains a leading cause of child death with approximately equal numbers of children killed by fathers and mothers. A large percentage of filicides is associated with mental illness, particularly postpartum depression and psychosis. The remainder results from child abuse and neglect. Men convicted of filicide are usually incarcerated whereas female perpetrators are more likely to receive treatment-oriented sentences. Individuals working with families and children should be trained to recognize risk factors and intervene to protect endangered children. PMID- 28636245 TI - Weight gain in the first week of life predicts overweight at 2 years: A prospective cohort study. AB - In formula-fed infants, rapid weight gain during the first week of life is associated with later obesity. To examine the association between weight gain during the first week and overweight at age 2 among infants with various feeding practices and the relationship between exclusive breastfeeding in early infancy and overweight, we enrolled a prospective cohort of healthy mother-infant dyads and followed them for 2 years. We enrolled 450 mother/infant pairs and obtained information on 306 infants at year 2. Weight change during the first week of life and detailed feeding information were collected during the first month of life. Anthropometric measures were collected at 2 years. Overweight was defined as body mass index (BMI) >=85th percentile for age. At 2 years, 81% had normal weights and 19% were overweight. Maternal pre-pregnancy BMI; infant birth weight; maternal education; and Women, Infants, and Children status were associated with the risk of overweight at age 2. Children who gained more than 100 g during the first week were 2.3 times as likely after adjustment (p = .02) to be overweight at age 2 compared to infants who lost weight. There was no association between feeding type and BMI, but feeding type was significantly associated with change in weight at week 1 and anthropometric measurements at age 2. Infant weight gain in the first week of life is related to overweight at age 2, and exclusively breastfed infants are least likely to gain >=100 g. PMID- 28636246 TI - A Stretchable Electrochemical Sensor for Inducing and Monitoring Cell Mechanotransduction in Real Time. AB - Existing methods offer little direct and real-time information about stretch triggered biochemical responses during cell mechanotransduction. A novel stretchable electrochemical sensor is reported that takes advantage of a hierarchical percolation network of carbon nanotubes and gold nanotubes (CNT AuNT). This hybrid nanostructure provides the sensor with excellent time reproducible mechanical and electrochemical performances while granting very good cellular compatibility, making it perfectly apt to induce and monitor simultaneously transient biochemical signals. This is validated by monitoring stretch-induced transient release of small signaling molecules by both endothelial and epithelial cells cultured on this sensor and submitted to stretching strains of different intensities. This work demonstrates that the hybrid CNT-AuNT platform offers a versatile and highly sensitive way to characterize and quantify short-time mechanotransduction responses. PMID- 28636247 TI - Predicting developmental deficiencies at the age of four based on data from the first seven months of life. AB - The study examines very young children with the aim of identifying precursors of developmental problems during the first 7 months of age. Information from screening and observations in the birth clinic, in the first level of health care, and from parents was collected on five different occasions. The information that was included concerning the child and family was defined as either optimal or nonoptimal. At the age of 4 years, a clinical group was identified (11.1% of the total population). Logistic regression analyses were performed to detect risk factors. Twenty-one precursors were used to create a screening questionnaire that provided useful information (sensitivity = 56.1%, specificity = 98.8%) for predicting developmental problems of the children. The contribution of sociodemographic data was significant; medical information was less significant. The highest prediction rate surprisingly was found in the moderate clinical subgroup (62.1%), compared to the group with more severe problems that had a slightly lower rate (46.7%). The conclusion of the study is that it is possible to detect infants in need of early intervention using a continuous process of observation and screening. PMID- 28636248 TI - Attachment in foster children associated with caregivers' sensitivity and behavioral problems. AB - This study focused on attachment of foster children by examining factors associated with attachment relationships of children raised from birth by the same parents. The sample included 61 children between 26 to 88 months of age and their foster caregivers. Attachment security and caregiver sensitivity were coded on the basis of, respectively, a home-observation (Attachment Q-Set) and a laboratory procedure (Three boxes). Other measures included caregiver reports of child externalizing and internalizing behavior problems and symptoms of attachment disorder, including inhibited and disinhibited attachment as well as secure base distortions. For a subsample of children, teacher ratings of behavior problems also were available. Foster parent sensitivity was positively associated with attachment security, but only if symptoms of disordered attachment were partialled out. Symptoms of inhibited and disinhibited attachment as well as secure base distortions were positively related to parent reports of externalizing and internalizing behavior problems whereas attachment security was negatively related to teacher reports of externalizing behavior problems. Attachment theoretical tenets appeared valid with foster parent-child relationships, except for children with symptoms of attachment disorder. PMID- 28636249 TI - Posttraumatic stress symptoms following childbirth and mothers' perceptions of their infants. AB - Postpartum psychological distress can adversely affect the early mother-infant relationship; however, this has not been investigated in relation to posttraumatic stress disorder (PTSD) following childbirth. This article explores whether PTSD symptoms relating to labor and delivery are associated with mothers' early perceptions of their infant. Using labor and childbirth as the stressor criterion, 211 women were assessed at 6 weeks' postpartum for symptoms of intrusions, avoidance, and hyperarousal. Their perceptions of their infants, of mother-to-infant attachment, and infant behavioral characteristics also were evaluated. In sum, 3.8% of the women fulfilled full diagnostic criteria, and a further 21.3% reported clinically significant symptoms on at least one dimension of PTSD. Those meeting full or partial criteria perceived their attachment relationships to be significantly less optimal and reported more negative maternal representations in terms of their infants being less warm and more invasive. They also rated them as being temperamentally more difficult, prone to distress, and less easy to soothe. However, when the effects of depression were partialled, only the effect for perceived warmth remained. Posttraumatic stress symptoms relating to labor and delivery may adversely influence maternal perceptions of infants, with potentially adverse implications for the developing mother-infant relationship. The overlap with depressive symptoms requires further exploration. PMID- 28636250 TI - Parents' attachment styles, mental representations, and institutionalization of children in Bulgaria. AB - We first summarize the history, extent, and characteristics of institutionalization of non-orphan children in Bulgaria. Then we describe a study of certain psychological characteristics of mothers who use institutionalization compared with mothers similar in ethnicity and close-to-poverty circumstances, those using state daycare programs, and those using weekly care programs for their children. Institutionalizing mothers had been institutionalized themselves far more often than had the other mothers. On two attachment measures, as expected, institutionalizing mothers were less secure and more insecure than daycare mothers, with weekly care mothers intermediate. On a parental representation task, results were somewhat more equivocal. Results suggest that psychological characteristics, especially attachment style, are important in decisions to use institutionalization as a means of child care. PMID- 28636251 TI - Influences of maternal postpartum depression on fathers and on father-infant interaction. AB - Maternal postpartum depression (PPD) has been shown to negatively influence mother-infant interaction; however, little research has explored how fathers and father-infant interaction are affected when a mother is depressed. This study examined the influence of maternal PPD on fathers and identified maternal and paternal factors associated with father-infant interaction in families with depressed as compared with nondepressed mothers. A convenience sample of 128 mother-father-infant triads, approximately half of which included women with significant symptoms of PPD at screening, were recruited from a screening sample of 790 postpartum women. Mothers and fathers completed measures of depression, marital satisfaction, and parenting stress at 2 to 3 months' postpartum and were each videotaped interacting with their infants. Results indicate that maternal PPD is associated with increased paternal depression and higher paternal parenting stress. Partners of depressed women demonstrated less optimal interaction with their infants, indicating that fathers do not compensate for the negative effects of maternal depression on the child. Although mother-infant interaction did not influence father-infant interaction, how the mother felt about her relationship with the infant did, even more so than maternal depression. The links between maternal PPD, fathers, and father-infant interaction indicate a need for further understanding of the reciprocal influences between mothers, fathers, and infants. PMID- 28636252 TI - Influence of analyzed lubricant volumes on the amount and characteristics of generated wear particles from three different types of polyethylene liner materials. AB - The articulating components of artificial joints consist mainly of metals, ceramics, or polymers. Resulting abrasive wear particles can promote osteolysis and aseptic loosening of the endo-prosthetic implants. Ultra-high-molecular weight-polyethylene is the material used most for bearing couples in total hip replacement. In the present study, three types of polyethylene (PE) liners varying in material composition, i.e., (1) conventional PE (C-PE), (2) sequentially cross-linked PE (SX-PE), (3) cross-linked PE blended with vitamin E (EX-PE) articulating with two types of femoral heads were used. After ultrasound treatment of each simulator lubricant, different concentrations (0.1/0.25/0.5/1.0 mL) were taken and dissolved in hydrochloric acid (37%) in a similar manner. The aim was to analyze the characteristics of wear particles generated in a hip simulator, with respect to different volumes of the lubricant. Within the scope of particle analysis, distinct alterations for particle characteristics were determined in the lubricant volumes and types of PE material used. A significant decrease in particle number for SX-PE liners, compared to the C-PE inserts and even more for EX-PE inserts, was detected at each lubricant volume. Particle morphologies varied depending on PE material. Alterations in particle size and other morphologic parameters between the four tested volumes, could be proven for each PE type. In general, particle sizes and parameters (e.g., length and width) increased with increasing serum volumes. In conclusion, the chosen volume of the simulator lubricant used for particle analysis has a crucial influence on detected particle number, size distribution, and morphologic parameters. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1299 1306, 2018. PMID- 28636254 TI - Histological and reference system for the analysis of mouse intervertebral disc. AB - A new scoring system based on histo-morphology of mouse intervertebral disc (IVD) was established to assess changes in different mouse models of IVD degeneration and repair. IVDs from mouse strains of different ages, transgenic mice, or models of artificially induced IVD degeneration were assessed. Morphological features consistently observed in normal, and early/later stages of degeneration were categorized into a scoring system focused on nucleus pulposus (NP) and annulus fibrosus (AF) changes. "Normal NP" exhibited a highly cellularized cell mass that decreased with natural ageing and in disc degeneration. "Normal AF" consisted of distinct concentric lamellar structures, which was disrupted in severe degeneration. NP/AF clefts indicated more severe changes. Consistent scores were obtained between experienced and new users. Altogether, our scoring system effectively differentiated IVD changes in various strains of wild-type and genetically modified mice and in induced models of IVD degeneration, and is applicable from the post-natal stage to the aged mouse. This scoring tool and reference resource addresses a pressing need in the field for studying IVD changes and cross-study comparisons in mice, and facilitates a means to normalize mouse IVD assessment between different laboratories. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:233-243, 2018. PMID- 28636253 TI - Estimation of vanadium water quality benchmarks for the protection of aquatic life with relevance to the Athabasca Oil Sands region using species sensitivity distributions. AB - Elevated vanadium (V) concentrations in oil sands coke, which is produced and stored on site of some major Athabasca Oil Sands companies, could pose a risk to aquatic ecosystems in northern Alberta, Canada, depending on its future storage and utilization. In the present study, V toxicity was determined in reconstituted Athabasca River water to various freshwater organisms, including 2 midge species (Chironomus dilutus and Chironomus riparius; 4-d and 30-d to 40-d exposures) and 2 freshwater fish species (Oncorhynchus mykiss and Pimephales promelas; 4-d and 28-d exposures) to facilitate estimation of water quality benchmarks. The acute toxicity of V was 52.0 and 63.2 mg/L for C. dilutus and C. riparius, respectively, and 4.0 and 14.8 mg V/L for P. promelas and O. mykiss, respectively. Vanadium exposure significantly impaired adult emergence of C. dilutus and C. riparius at concentrations >=16.7 (31.6% reduction) and 8.3 (18.0% reduction) mg/L, respectively. Chronic toxicity in fish presented as lethality, with chronic 28-d LC50s of 0.5 and 4.3 mg/L for P. promelas and O. mykiss, respectively. These data were combined with data from the peer-reviewed literature, and separate acute and chronic species sensitivity distributions (SSDs) were constructed. The acute and chronic hazardous concentrations endangering only 5% of species (HC5) were estimated as 0.64 and 0.05 mg V/L, respectively. These new data for V toxicity to aquatic organisms ensure that there are now adequate data available for regulatory agencies to develop appropriate water quality guidelines for use in the Athabasca Oil Sands region and elsewhere. Until then, the HC5 values presented in the present study could serve as interim benchmarks for the protection of aquatic life from exposure to hazardous levels of V in local aquatic environments. Environ Toxicol Chem 2017;36:3034-3044. (c) 2017 SETAC. PMID- 28636255 TI - Recombinant human serum albumin for corneal preservation. AB - PURPOSE: To study the performance of a completely synthetic organ culture (OC) preservation system containing recombinant human serum albumin (rHSA) for preservation of human donor corneas. METHODS: Twenty-four paired donor corneas were randomly collected, and one cornea from each donor was preserved in synthetic (experimental) and serum-based media (control). The tissues were assessed at day 0; after 6 days of preservation at room temperature (RT) in Cornea Trans(r) and Cornea Prep II(r) ; after 28 days at 31 degrees C in Cornea Syn(r) [with rHSA] and Cornea Max(r) [with foetal calf serum (FCS)] and; 4-day post deswelling in Cornea Trans(r) and Cornea Jet(r) . Thickness was determined with optical coherence tomography (OCT) and transparency with a validated, custom device. Morphology, endothelial cell density (ECD) and mortality were observed after treating the tissues with Trypan blue and sucrose. Glucose uptake by the cells was analysed. Data were compared using non-parametric paired Wilcoxon tests with p < 0.05 deemed significant. Histology using periodic acid-schiff (PAS), expressions of p63, CK12, alphaSMA and ZO-1 were analysed, and cell apoptosis postpreservation was studied. RESULTS: Corneas stored in synthetic media showed a higher and statistically significant value as compared to serum-based media in terms of viable endothelial cell density (VECD), mortality, morphology and glucose uptake postpreservation. Histology showed presence of all the layers, all the markers were expressed, and no apoptosis was observed in either media. CONCLUSION: The new synthetic preservation system containing rHSA (and other confidential constituents) showed better preservation effects than traditional media containing serum. PMID- 28636256 TI - Optical coherence tomography angiography in choroidal haemangioma: small case series. PMID- 28636257 TI - Covalent attachment and Pro-Pro endopeptidase (PPEP-1)-mediated release of Clostridium difficile cell surface proteins involved in adhesion. AB - In the past decade, Clostridium difficile has emerged as an important gut pathogen. This anaerobic, Gram-positive bacterium is the main cause of infectious nosocomial diarrhea. Whereas much is known about the mechanism through which the C. difficile toxins cause diarrhea, relatively little is known about the dynamics of adhesion and motility, which is mediated by cell surface proteins. This review will discuss the recent advances in our understanding of the sortase-mediated covalent attachment of cell surface (adhesion) proteins to the peptidoglycan layer of C. difficile and their release through the action of a highly specific secreted metalloprotease (Pro-Pro endopeptidase 1, PPEP-1). Specific emphasis will be on a model in which PPEP-1 and its substrates control the switch from a sessile to motile phenotype in C. difficile, and how this is regulated by the cyclic dinucleotide c-di-GMP (3'-5' cyclic dimeric guanosine monophosphate). PMID- 28636258 TI - Plant products for practising procedural dermatology. PMID- 28636259 TI - Variants in KAT6A and pituitary anomalies. PMID- 28636260 TI - Lichenoid keratosis is frequently misdiagnosed as basal cell carcinoma. AB - Lichenoid keratosis (LK), also known as benign lichenoid keratosis or lichen planus-like keratosis, is a solitary, pink to red-brown scaly plaque representing a host immunological response to a variety of precursor lesions. LK is often misdiagnosed as a dermatological malignancy owing to its clinical resemblance to basal cell carcinoma (BCC) or Bowen disease. We performed a retrospective analysis of the pathology records of a series of LK lesions with reference to the demographic features and accuracy of clinical diagnosis. The pathology records from 2008 to 2009 of 263 consecutive patients with a histological diagnosis of LK from a specialized skin laboratory were retrieved. Data relating to clinical diagnosis, age, sex, anatomical location, time of year of presentation and any coexistent pathological lesions adjacent to the LK were recorded. Mean age at presentation was 64 years (range 34-96), and 58% of patients were female. The most common anatomical site was the chest/anterior torso, followed by the back and legs. The most common coexisting lesion was solar keratosis at 14%, followed by seborrhoeic keratosis (SK) at 7.8%. The correct clinical diagnosis of LK was made in 29.5% of cases. The most common clinical diagnosis was BCC (47%), while SK was the preferred diagnosis in 18%. A clinical diagnosis was not given in 5.5% of cases. In conclusion, it appears that LK is frequently misdiagnosed, with misdiagnosis occurring in > 70% of cases in this study. PMID- 28636261 TI - Characteristics of corneal biomechanical responses detected by a non-contact scheimpflug-based tonometer in eyes with glaucoma. AB - PURPOSE: To determine the corneal biomechanical properties in eyes with glaucoma using a non-contact Scheimpflug-based tonometer. METHODS: Corneal biomechanical responses were examined using a non-contact Scheimpflug-based tonometer. The tonometer parameters of the normal control group (n = 75) were compared with those of the glaucoma group (n = 136), including an analysis of glaucoma subgroups categorized by visual field loss. RESULTS: After adjusting for potential confounding factors, including the intraocular pressure (IOP), central corneal thickness (CCT), age and axial length, the deformation amplitude was smaller in the glaucoma group (1.09 +/- 0.02 mm) than in the normal control group (1.12 +/- 0.02 mm; p value = 0.031). The deformation amplitude and the deflection amplitude of the severe glaucoma group (1.12 +/- 0.02 mm and 0.92 +/- 0.01 mm) were significantly greater than that of the early glaucoma group (1.07 +/- 0.01 mm and 0.88 +/- 0.11 mm, p = 0.006 and p = 0.031), whereas that of the moderate glaucoma group (1.09 +/- 0.02 mm and 0.90 +/- 0.02 mm) was greater than that of the early glaucoma group, but this difference was not statistically significant. The deformation amplitude showed a negative correlation with the CCT in the normal control group (r = -0.235), with a weaker negative relationship observed in the early glaucoma group (r = -0.099). However, in the moderate and severe glaucoma groups, the deformation amplitude showed a positive relationship with the CCT, showing an inverse relationship. The duration and number of antiglaucomatous eyedrops used had negative correlations with the CCT in eyes with moderate and severe glaucoma. CONCLUSION: Overall, the glaucoma group showed significantly less deformable corneas than did the normal controls, even after adjusting for the IOP, CCT, age and axial length. However, there were also differences according to the severity of glaucoma, where the corneal deformation amplitude was greater in the severe glaucoma group compared to the early glaucoma group. The combined effects of stiffening due to glaucoma and increased viscoelastic properties caused by the chronic use of antiglaucomatous eyedrops may have resulted in the present findings. PMID- 28636262 TI - Increased renal concentrating ability after long-term oral desmopressin lyophilisate treatment contributes to continued success for monosymptomatic nocturnal enuresis. AB - OBJECTIVES: To investigate renal concentrating ability after long-term fast melting oral desmopressin lyophilisate treatment in children with monosymptomatic nocturnal enuresis. METHODS: The present retrospective study involved 58 children (43 boys, 15 girls; aged 6-12 years) with nocturnal enuresis receiving oral desmopressin lyophilisate. After treatment for 4 weeks with a complete response, patients were placed on a reduced dose of 120 MUg on alternate days. Moring urine osmolality was measured using urine samples obtained after medication and non medication dry nights. Patients who experienced >=1 wet nights/month during alternate-day oral desmopressin lyophilisate treatment or within 6 months after its cessation were assigned to the relapse group, whereas those who experienced <1 wet night/month were assigned to the continued success group. RESULTS: The continued success and relapse groups included 41 and 17 patients, respectively. The mean duration of treatment was 18.5 and 18.3 months in the continued success group and relapse group, respectively. There was no significant difference in morning urine osmolality after medication nights between the continued success and relapse groups; however, morning urine osmolality after non-medication nights was significantly higher in the continued success group than in the relapse group (P < 0.0001). Similarly, nocturnal urine volume was significantly higher in the relapse group than in the continued success group (P = 0.046). CONCLUSIONS: These results suggest that patients receiving long-term oral desmopressin lyophilisate treatment develop increased nocturnal renal concentrating ability, which results in sustained dryness even after treatment cessation. PMID- 28636263 TI - Acute bilateral myopia caused by lamotrigine-induced uveal effusions. PMID- 28636265 TI - Full Selectivity Control in Cobalt(III)-Catalyzed C-H Alkylations by Switching of the C-H Activation Mechanism. AB - Selectivity control in hydroarylation-based C-H alkylation has been dominated by steric interactions. A conceptually distinct strategy that exploits the programmed switch in the C-H activation mechanism by means of cobalt catalysis is presented, which sets the stage for convenient C-H alkylations with unactivated alkenes. Detailed mechanistic studies provide compelling evidence for a programmable switch in the C-H activation mechanism from a linear-selective ligand-to-ligand hydrogen transfer to a branched-selective base-assisted internal electrophilic-type substitution. PMID- 28636264 TI - Desmopressin in haemophilia: The need for a standardised clinical response and individualised test regimen. AB - INTRODUCTION: Due to interindividual variation in desmopressin response, non severe haemophilia A patients require desmopressin testing prior to therapeutic treatment. However, adequate response or frequency of blood sampling is not standardised in international guidelines. Consequently, various definitions and blood sampling protocols are currently applied. Interestingly, sustainability of desmopressin response is not incorporated into these definitions. AIM: To study desmopressin response rates in a cohort of non-severe haemophilia A patients using currently accepted desmopressin response definitions. This, in order to formulate a standardised, uniform response which includes information on sustainability and to design a standardised blood sampling protocol. METHODS: Currently used desmopressin responses in non-severe haemophilia A patients were derived from a literature search. Actual desmopressin response rates were individualised in 105 non-severe HA patients from the Erasmus University Medical Centre and classified according to current varying definitions. RESULTS: Five response definitions were evaluated, three of which included only factor VIII (FVIII):C cut-off levels and two also incorporated FVIII:C-fold increase over baseline. FVIII: C-fold increase showed no association with desmopressin response sustainability. FVIII: C 1 hour after infusion (<0.30, >=0.30-0.49, >=0.50-0.79 and >=0.80 IU/mL) was, however, indicative of desmopressin response after 6 hours. CONCLUSION: We suggest standardised desmopressin response based on clinically relevant FVIII:C levels, e.g. 0.30 and 0.50 IU/mL. In addition, patients with <0.30 IU/mL FVIII:C after 1 hour (non-responder) or >=0.80 IU/mL (sustained responder) do not require subsequent blood sampling. However, patients with >=0.30-0.79 IU/mL FVIII:C after 1 hour should undergo blood sampling after 6 hours to additionally determine response sustainability. PMID- 28636266 TI - MaRAP2-4, a waterlogging-responsive ERF from Mentha, regulates bidirectional sugar transporter AtSWEET10 to modulate stress response in Arabidopsis. AB - As waterlogging and successive events severely influence growth and development of economically important plants, we attempted to characterize the role of a waterlogging-responsive group I (A-6) ethylene response factor (MaRAP2-4) from Mentha arvensis. Waterlogging, ethylene and methyl jasmonate rapidly induced the expression of MaRAP2-4. MaRAP2-4 interacted with multiple cis-elements like dehydration response elements (DRE1/2), anoxia/jasmonic acid response element (JARE) and GCC box showing its involvement in multiple responses. MaRAP2-4 localizes in the nucleus and acts as a transcriptional activator. Truncation and internal deletion identified a 20 amino acids potential transactivation domain (PLPSSVDAKLEAICQSLAIN) in MaRAP2-4. MaRAP2-4 transgenic Arabidopsis showed enhanced waterlogging and subsequent oxidative stress tolerance. Microarray analysis revealed that within up-regulated genes 483, 212 and 132 promoters carry either single or multiple copies of DRE, JARE and GCC cis-element/s, respectively. Within these promoters, a large section belongs to carbohydrate metabolism/transport, including many SWEET transporters. Further analysis showed MaRAP2-4 specifically targets two positions in AtSWEEET10 promoter carrying DRE and/or GCC box that might regulate carbohydrate availability and waterlogging tolerance. These results demonstrate that MaRAP2-4 is a positive regulator of waterlogging tolerance, and as energy-consuming processes such as carbohydrate biosynthesis are reduced under waterlogging-induced hypoxia, sugar transport through SWEETs may be the primary option to make sugar available to the required tissue. PMID- 28636267 TI - Strontium-releasing fluorapatite glass-ceramics: Crystallization behavior, microstructure, and solubility. AB - The purpose of this work was to investigate the effect of strontium partial replacement for calcium on the crystallization behavior, microstructure and solubility of fluorapatite glass-ceramics. Four glass compositions were prepared with increasing amounts of strontium partially replacing calcium. The crystallization behavior was analyzed by differential scanning calorimetry and X ray diffraction (XRD). The microstructure was investigated by scanning electron microscopy. The chemical solubility was quantified according to ISO standard 10993-14. The amount of strontium released in solution after incubation in TRIS HCl or citric acid buffer was measured by atomic absorption spectroscopy. XRD analyses revealed that partially substituted strontium-fluorapatite and strontium akermanite crystallized after strontium additions. The lattice cell volume of both phases increased linearly with the amount of strontium in the composition. Strontium additions led to a reduction in crystal size and an increase in crystal number density. The chemical solubility and amount of strontium released in solution increased linearly with the amount of strontium present in the composition in both TRIS-HCl and citric acid buffers. Total amounts of strontium released reached a maximum of 547 +/- 80 ppm in TRIS-HCl and 1252 +/- 290 ppm in citric acid buffer for the glass composition with the highest amount of strontium. For all strontium-containing compositions, the amount released in TRIS HCl continued to increase between 70 and 120 h, indicating sustained release rather than burst release. (c) 2017 Wiley Periodicals, Inc. J Biomater Res Part B: 106B: 1421-1430, 2018. PMID- 28636268 TI - High throughput sequencing reveals Drosophila suzukii responses to insecticides. AB - Global climate change and acquired resistance to insecticides are threats to world food security. Drosophila suzukii, a devastating invasive pest in many parts of the world, causes substantial economic losses to fruit production industries, forcing farmers to apply broad-spectrum insecticides frequently. This could lead to the development of insecticide resistance. We determined the Lethal Concentration 50 (median lethal concentration, LC50 ) values of zeta cypermethrin, spinosad, and malathion insecticides against D. suzukii colonies established from Clarke and Pierce county Georgia, United States. The LC50 values were 3 fold higher in the Pierce county population for all insecticide treatments. We then used RNA sequencing to analyze the responses of Pierce and Clarke population flies surviving a LC50 treatment of the 3 insecticides. We identified a high number of differentially expressed genes that are likely involved in detoxification and reduced cuticular penetration, especially in the Pierce population, with extensive overlap in differentially expressed genes between the 3 insecticide treatments. Finally, we predicted fewer nonsynonymous single nucleotide variants having deleterious effects on protein function among detoxification, insecticide target, and cuticular protein encoding genes in Pierce flies. Thus a combination of increased gene expression and fewer deleterious single nucleotide variants highlights molecular mechanisms underlying the higher LC50 values for Pierce population flies. PMID- 28636269 TI - Commentary on R&D Trends Away from General Medicine/Cardiovascular Drugs: Can the FDA Help Reverse the Trend? AB - In the latter part of the 20th century, drug development in cardiovascular diseases (CVDs) was a paragon of "modern" therapeutics, bringing about a substantial number of effective, well-tolerated agents targeting some of the most prevalent diseases of the Western world. These drugs were often examples of rational drug development targeting specific pathophysiologic pathways previously elucidated through basic research (e.g., targeting of the renin-angiotensin system or the cholesterol synthesis pathway). The widespread adoption of these ground-breaking medications in practice and into medical guidelines undoubtedly played a role in the fall of morbidity and mortality from CVD in the United States in recent decades. For instance, the combined, age-adjusted rates of death due to heart disease and CVD fell in the United States from an aggregate of 329.6 per 100,000 in 1999 to 203.5 in 2014. Although lifestyle trends (e.g., decreased smoking prevalence) contributed to this decline, the impact of safe and effective medications for common CVD conditions cannot be dismissed. Yet, despite the drop in CVD morbidity and mortality, CVDs remain a leading cause of morbidity and mortality in the United States and, therefore, a large area of unmet medical need. PMID- 28636270 TI - C-Reactive protein and progression of vision loss in retinitis pigmentosa. AB - PURPOSE: Chronic inflammation is involved in retinitis pigmentosa (RP). We demonstrated previously that intraocular inflammatory levels, as measured by slit lamp ophthalmoscopy or laser flare photometry, are inversely correlated with central visual function in patients with RP. Here, we investigated the relationship between serum high-sensitivity C-reactive protein (hs-CRP) and visual parameters in RP. METHODS: We studied 58 consecutive typical patients with RP <40 years old and 29 age- and gender-matched controls. High-sensitivity C reactive protein (hs-CRP) was detected by immunoturbidimetry. The relationships between hs-CRP and visual parameters including best-corrected visual acuity (BCVA), mean deviation (MD) of static perimetry tests (Humphrey Field Analyzer, the central 10-2 programme) and VA changes over the prior 5 years and MD changes over the prior 3 years were analysed in the patients with RP. RESULTS: The serum hs-CRP levels of the patients with RP were significantly higher than those of the controls (0.06 +/- 0.08 versus 0.03 +/- 0.04 mg/dl, p = 0.0119). In the patients with RP, there was no correlation of hs-CRP with cross-sectionally assessed VA or MD, but the baseline hs-CRP was significantly correlated with the MD deterioration (r = -0.4073, p = 0.0314). CONCLUSION: The average serum hs-CRP was significantly increased in the patients with RP, and higher hs-CRP was associated with faster deterioration of central visual function. These results suggest that the systemic inflammatory profile is altered and may be associated with disease progression in RP. PMID- 28636271 TI - Dietary patterns are associated with the prevalence of alexithymia. AB - Recent evidence supports the association between healthy dietary patterns and a reduced risk of depression. The objective was: (1) to examine the associations between dietary patterns and alexithymic features; and (2) investigate whether these possible associations are explained by depressive symptoms in a cross sectional study among the Finnish general population aged 25-65 years. The study population was a part of the population-based Kuopio Depression Study (KUDEP) conducted in central-eastern Finland (n = 1747). Dietary data were collected using a food frequency questionnaire and dietary patterns from 22 predefined food groups, which were extracted by factor analysis. Alexithymia was assessed using the 20-item Toronto Alexithymia Scale (TAS-20) and depression using the 21-item Beck Depression Inventory (BDI-21). Altogether, 173 of the study subjects (9.9%) were alexithymic. Three dietary patterns were identified: "prudent," "Western" and "traditional." Lower scores for a healthy prudent dietary pattern and higher scores for an unhealthy Western dietary pattern were associated with an increased likelihood of belonging to the alexithymic group among subjects with elevated depressive symptoms. Among subjects without depressive symptoms, alexithymia was associated with lower scores in the prudent dietary pattern, but also with higher scores in the traditional dietary pattern. General population subjects with alexithymic features may have unhealthier dietary patterns than non-alexithymic subjects. PMID- 28636272 TI - Development of biotic ligand model-based freshwater aquatic life criteria for lead following us environmental protection agency guidelines. AB - The US Environmental Protection Agency's (USEPA's) current ambient water quality criteria (AWQC) for lead (Pb) in freshwater were developed in 1984. The criteria are adjusted for hardness, but more recent studies have demonstrated that other parameters, especially dissolved organic carbon (DOC) and pH, have a much stronger influence on Pb bioavailability. These recent studies have been used to support development of a biotic ligand model (BLM) for Pb in freshwater, such that acute and chronic Pb toxicity can be predicted over a wide range of water chemistry conditions. Following USEPA guidelines for AWQC development and using a methodology consistent with that used by the USEPA in developing its recommended BLM-based criteria for copper in 2007, we propose acute and chronic BLM-based AWQC for Pb in freshwater. In addition to the application of the BLM approach that can better account for site-specific Pb bioavailability, the toxicity data sets presented are much more robust than in 1984, and there are now sufficient chronic Pb toxicity data available that use of an acute-to-chronic ratio is no longer necessary. Over a range of North American surface waters with representative water chemistry conditions, proposed acute BLM-based Pb criteria ranged from approximately 20 to 1000 MUg/L and chronic BLM-based Pb criteria ranged from approximately 0.3 to 40 MUg/L. The lowest criteria were for water with low DOC (1.2 mg/L), pH (6.7), and hardness (4.3 mg/L as CaCO3), whereas the highest criteria were for water with high DOC (9.8 mg/L), pH (8.2), and hardness (288 mg/L as CaCO3 ). Environ Toxicol Chem 2017;36:2965-2973. (c) 2017 SETAC. PMID- 28636273 TI - Long-term belowground effects of grassland management: the key role of liming. AB - The functioning of human-managed grassland ecosystems strongly depends on how common management practices will affect grassland "belowground compartment" including soil biogeochemistry and plant roots. Key questions remain about how animal grazing, liming (e.g., the addition of CaCO3 to soils), and nutrient fertilization might affect, in the long-term, soil nutrient cycling and multiple root traits. Here we focus on a mesotrophic grassland located in Berkshire, UK, where contrasting levels of rabbit grazing, liming, and different inorganic fertilizers have been applied since 1991. We ask how (1) soil nitrogen (N) availability and cycling, (2) total root mass, (3) root mass decomposition, and (4) arbuscular mycorrhizal fungal (AMF) root colonization might respond to 22 years of very different management. We found that liming strongly affected total root mass, root decomposition, root AMF colonization as well as soil N availability and cycling and that these effects were mainly driven by liming induced increases in soil pH. Increases in soil pH were associated with significant (1) decreases in root mass, (2) increases in root mass decomposability and in the mineralization of N in decomposing root detritus, and (3) increases in AMF infection. Soil pH was also significantly related to greater N availability (i.e., soil NO3 levels) and to lower delta15 N natural abundance, which suggests more efficient N uptake by plants in limed soils as we found in our study. The application of multiple nutrients (N, P, K, Mg) also reduced total root mass, while N-only fertilization was associated with greater AMF infection. Surprisingly the long-term impact of grazing was generally weak and not significant on most plant and soil parameters. Despite soil pH affecting most belowground variables, changes in soil pH were not associated with any change in soil C and N stocks. Because liming can improve nutrient cycling (and benefits soil pH and grass yields) without negatively affecting soil C sequestration, we suggest that regular liming applications may provide management solutions for increasing the long-term sustainability of permanent grassland. PMID- 28636274 TI - Marfan syndrome with a homozygous FBN1 splicing mutation. PMID- 28636275 TI - Efficacy of aflibercept for polypoidal choroidal vasculopathy in Caucasians. PMID- 28636276 TI - Covariate selection with group lasso and doubly robust estimation of causal effects. AB - The efficiency of doubly robust estimators of the average causal effect (ACE) of a treatment can be improved by including in the treatment and outcome models only those covariates which are related to both treatment and outcome (i.e., confounders) or related only to the outcome. However, it is often challenging to identify such covariates among the large number that may be measured in a given study. In this article, we propose GLiDeR (Group Lasso and Doubly Robust Estimation), a novel variable selection technique for identifying confounders and predictors of outcome using an adaptive group lasso approach that simultaneously performs coefficient selection, regularization, and estimation across the treatment and outcome models. The selected variables and corresponding coefficient estimates are used in a standard doubly robust ACE estimator. We provide asymptotic results showing that, for a broad class of data generating mechanisms, GLiDeR yields a consistent estimator of the ACE when either the outcome or treatment model is correctly specified. A comprehensive simulation study shows that GLiDeR is more efficient than doubly robust methods using standard variable selection techniques and has substantial computational advantages over a recently proposed doubly robust Bayesian model averaging method. We illustrate our method by estimating the causal treatment effect of bilateral versus single-lung transplant on forced expiratory volume in one year after transplant using an observational registry. PMID- 28636277 TI - ESRRB plays a crucial role in the promotion of porcine cell reprograming. AB - The estrogen-related receptor b (ESRRB) is an orphan nuclear receptor and targets many genes involved in self-renewal and pluripotency. In mouse ES cells, overexpression of ESRRB can maintain LIF-independent self-renewal in the absence of Nanog. However, the fundamental features of porcine ESRRB remain elusive. In this study, we revealed the expression profiles of ESRRB in both porcine pluripotent stem cells and early stage embryos and dissected the functional domains of ESRRB protein to prove that ESRRB is a key transcription factor that enhanced porcine pluripotent gene activation. Addition of ESRRB into the cocktail of core pluripotent factors Oct4, Sox2, Klf4, and c-Myc (OSKM + E) could significantly enhance the reprograming efficiency and the formation of alkaline phosphatase positive colonies. Conversely, knockdown of ESRRB in piPSCs significantly reduced the expression level of pluripotent genes, minimized the alkaline phosphatase activity, and initiated the porcine induced pluripotent stem cell differentiation. Therefore, porcine ESRRB is a crucial transcription factor to improve the self-renewal of piPSCs. PMID- 28636278 TI - RNA Activation: A Diamond in the Rough for Genome Engineers. AB - The ability to develop efficient and versatile technologies for manipulating gene expression is a fundamental issue both in biotechnology and therapeutics. The endogenous RNA interference (RNAi) pathway which mediates gene silencing was discovered at the end of the 20th century and it is nowadays considered as an essential strategy for knockdown of specific genes and for studying gene function. Remarkably, during the past decade, a RNA-induced mechanism of gene activation has also been reported. Likewise RNAi, the RNA activation (RNAa) process is also mediated by sequence-specific double-stranded RNA (dsRNA) molecules, and interesting resemblances between both RNA-based transcriptional mechanisms have been described. Small activating RNAs (saRNAs) and related molecules have been used for targeting of genes in species that are as different as nematodes and humans, and similar dsRNA-induced activation phenomena have also been observed in plants. The aim of this letter is to highlight recent molecular insights into yet unexplored RNAa mechanism and its potential for manipulating transcriptional activity. J. Cell. Biochem. 119: 247-249, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28636279 TI - Effects of in ovo injection of chrysin, quercetin and ascorbic acid on hatchability, somatic attributes, hepatic oxidative status and early post-hatch performance of broiler chicks. AB - An experiment was conducted to evaluate the effects of in ovo injection of chrysin, quercetin and ascorbic acid on hatchability, somatic attributes, hepatic antioxidant status and early post-hatch growth performance of broiler chicks. Four hundred and eighty embryonated broiler breeder eggs containing live 18-day old embryos were divided into six groups of 80 eggs each. One group remained intact and served as a control group (i), whereas the other five groups were injected with the prepared injection solutions as follows: (ii) 0.05 ml distilled water; (iii) 0.05 ml distilled water containing 6 mg ascorbic acid; (iv) 0.05 ml dimethyl sulfoxide (DMSO); (v) 0.05 ml DMSO containing 4.5 mg quercetin; and (vi) 0.05 ml DMSO containing 4.5 mg chrysin. The hatchability rate, hatching weight, residual yolk sac weight, yolk sac-free body weight, liver weight, hepatic glutathione peroxidase and total superoxide dismutase activities, as well as malondialdehyde concentrations, were not affected by the injected solutions. There were no differences between chicks hatched from the control and in ovo injected eggs in weight gain, feed intake and feed conversion ratio from 0 to 11 days of age. However, the specific contrast performed between the in ovo injected groups and intact eggs revealed that in ovo injection significantly increased hatchability rate (p = .0493). This finding also implies that our injection procedure was harmless. In conclusion, the intra-egg injection of chrysin, quercetin or ascorbic acid at the injection rates used in this study did not have a significant effect on hatchability, somatic characteristics, early growth performance and hepatic antioxidant status of broiler chicks. However, the overall hatchability was higher in the in ovo injected eggs as compared to non injected ones. These findings also confirmed the harmlessness of the procedure developed for in ovo injection in this study. PMID- 28636280 TI - Getting on the same page: Communication, patient involvement and shared understanding of "decisions" in oncology. AB - BACKGROUND: Patients and clinicians do not often agree on whether a decision has been made about cancer care. This could be explained by factors related to communication quality and/or the type of decision being made. METHODS: We used a self-developed coding scheme to code a random sample of 128 encounters in which patients and clinicians either agreed (n=64) or disagreed (n=64) that a cancer care decision was made and tested for associations between concordance and key communication behaviours. We also identified and characterized cancer care decisions by topic and level of patient involvement and looked for trends. RESULTS: We identified 378 cancer care decisions across 128 encounters. Explicit decisions were most commonly made about topics wherein decision control could be easily delegated to a clear and present expert (eg either the patient or the clinician). Related to this, level of patient involvement varied significantly by decision topic. Explicit decisions were rarely made in an observable way about social, non-clinical or self-management related topics, although patients and clinicians both reported having made a cancer care decision in encounters where no decisions were observed. We found no association between communication behaviours and concordance in our sample. CONCLUSIONS: What counts as a "decision" in cancer care may be constructed within disparate social roles that leave many agendas unaddressed and decisions unmade. Changing the content of conversations to encourage explicit decisions about self-management and life context-related topics may have greater value in enabling shared understanding than promoting communication behaviours among already high-performing communicators. PMID- 28636281 TI - Aryl- and heteroaryl-substituted phenylalanines as AMPA receptor ligands. AB - A series of racemic unnatural amino acids was rationally designed on the basis of recently published X-ray structures of the GluA2 LBD with bound phenylalanine based antagonists. Twelve new diaryl- or aryl/heteroaryl-substituted phenylalanine derivatives were synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most interesting compound in this series, (RS)-2-amino-3-(3'-hydroxy-5-(1H-pyrazol-4-yl)-[1,1' biphenyl]-3-yl)propanoic acid 7e, showed the binding affinity of 4.6 MUm for native AMPA receptors and over fourfold lower affinity for kainic acid receptors. Furthermore, 7e was evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. Recently reported X-ray structures 5CBR and 5CBS, representing two distinct antagonist binding modes, were used as templates for molecular docking of the synthesized series. Binding data supported with molecular modeling confirmed that aryl/heteroaryl-substituted phenylalanine analogues effectively bind to AMPA receptors with low micromolar affinity and high selectivity over native NMDA and kainate receptors. These properties make 7e a promising lead for the further development of new AMPA receptor ligands. PMID- 28636282 TI - The predictive value of different infant attachment measures for socioemotional development at age 5 years. AB - The predictive value of different infant attachment measures was examined in a community-based sample of 111 healthy children (59 boys, 52 girls). Two procedures to assess infant attachment, the Attachment Q-Set (applied on a relatively short observation period) and a shortened version of the Strange Situation Procedure (SSSP), were applied to the children at age 15 months and related to a comprehensive set of indicators of the children's socioemotional development at age 5 years. Three attachment measures were used as predictors: AQS security, SSSP security, and SSSP attachment disorganization. AQS security and SSSP security jointly predicted the security of the children's attachment representation at age 5. Apart from that, SSSP attachment disorganization was a better predictor of the children's later socioemotional development than were the other two early attachment measures. First, attachment disorganization was the only attachment measure to predict the children's later ego-resiliency, school adjustment, and dissociation. Second, as for the socioemotional measures at age 5 that also were related to AQS or SSSP security (i.e., peer social competence and externalizing problems), the attachment security measures did not explain any extra variance beyond what was explained by attachment disorganization. PMID- 28636283 TI - Attachment in substance-exposed toddlers: The role of caregiving and exposure. AB - Prenatal substance exposure is linked to adverse outcomes in children. Some adverse outcomes may result from insecure attachment and low-quality caregiving rather than from substance exposure. Little is known about the caregiving of polysubstance-using mothers. To address this, low-income mothers (n = 41) with their substance-exposed 12-month-olds were compared with a nonexposed group case matched for other risk factors. Maternal sensitivity and involvement were analyzed from 2 hr of videotaped interaction. Attachment was assessed using the Attachment Q-Set. Attachment security and quality of caregiving were quite low for both groups, with no significant differences. In addition, regression analyses revealed that quality of caregiving predicted attachment, but amount of alcohol and cocaine exposure did not. These results suggest that among toddlers with social risk, substance exposure may not predict insecure attachment. Previous research linking attachment to exposure may be better explained by low quality caregiving. Implications are that substance-exposed children, and nonexposed children with comparable social risk, are likely to need intervention to enhance maternal sensitivity and involvement to improve psychiatric outcomes. PMID- 28636284 TI - Young infants' triangular communication with their parents in the context of maternal postpartum psychosis: Four case studies. AB - With increasing data on the dynamics of normative couples as they transition to parenthood and become a triad, the need for greater understanding of the impact of parental psychopathology on this transition has become clear. The goal of the current article is to begin exploring this area that has received little attention to date, by describing case examples from a study of clinical families as they transitioned to parenthood. Four representative cases were selected from a pool of 13 mother-father-baby triads, for whom the mother had been hospitalized conjointly with her infant due to a psychotic episode during the postpartum period. The families were observed as part of a clinical consultation that included a semistructured play paradigm known as the Lausanne Trilogue Play (LTP; E. Fivaz-Depeursinge, & A. Corboz-Warnery, 1999). Interactions were scored using standardized measures as well as clinical impressions. All families from the clinical sample were noted to struggle and frequently failed to achieve the goals of play. The impact on the infants in terms of their developing sense of self as well as their defensive strategies in this context are discussed, with clinical implications explored. PMID- 28636285 TI - Caregiving behavior and interactions of prenatally depressed mothers (antidepressant-treated and non-antidepressant-treated) during newborn acute pain. AB - This exploratory study aimed to examine time-based measures of the behaviors and interactions of prenatally depressed serotonin reuptake inhibitors (SRI) medicated mothers to their infant's pain (n = 10) by comparing them with similar measures obtained from prenatally depressed nonmedicated mothers and their infants (n = 10), and nondepressed mothers and their infants (n = 10). During the second trimester of their pregnancy, the 30 study mothers were assessed for depression and anxiety, with no further measures of maternal mood taken. Maternal and infant interactions were continuously videorecorded while the infant underwent a scheduled heel lance for routine blood screening that occurred when study infants were between the ages of 24 and 60 hr. Maternal behavior and infant cry, for all 30 cases, were coded second-by-second for the full duration of each infant's heel lance using a reliable coding system and analyzed using odds ratio and regression analyses. Infants exposed to prenatal SRIs and depressed maternal mood were more likely to have lower Apgar scores and to exhibit weak and absent cry. Even when duration of the heel lance was controlled for, women with depression during the second trimester were more likely to exhibit depressed behavior at 2 days' postpartum despite sustained SRI antidepressant treatment. Both groups of prenatally depressed mothers were more likely to exhibit diminished response to their infants' pain cue although nonmedicated mothers' expressions of depressed behavior were more similar to healthy controls. Comprehensive understanding is essential to optimize the clinical care of mothers and their infants in this complex setting. This study contributes preliminary new findings that warrant prospective and longitudinal studies to clarify further the impacts of prenatal SRI and maternal mental mood (e.g., chronic depression and anxiety) effects on the mother-infant interaction and infant pain and stress reactivity. PMID- 28636286 TI - Maternal correlates of 2-year-old American Indian children's social-emotional development in a Northern Plains tribe. AB - The developmental experiences of very young American Indian children today are not well documented in the current literature. The present study sought to explore the social-emotional development of American Indian toddlers living on a Northern Plains reservation, as a function of maternal variables. Mothers completed self-report questionnaires about their experiences and their children's development. Observer ratings of children's development also were conducted. Maternal stress, substance use/abuse, perceptions of stress in the mother-child relationship, social support, and American Indian cultural identity were significantly related to children's social-emotional development. This study is the first to explore these relationships in a Northern Plains American Indian sample of young children and their mothers. Results suggest possible points of intervention for improving the developmental outcomes of very young American Indian children. PMID- 28636287 TI - The spectrum of aseptic central nervous system infections in southern Germany - demographic, clinical and laboratory findings. AB - BACKGROUND AND PURPOSE: Aseptic infections of the central nervous system (CNS) are frequently observed in Germany. However, no study has systematically addressed the spectrum of aseptic CNS infections in Germany. METHODS: Data on 191 adult patients diagnosed from January 2007 to December 2014 with aseptic meningitis or encephalitis/meningoencephalitis at our hospital were collected by chart review and analyzed for demographic, clinical and laboratory findings. Patients were stratified according to the causative virus and findings were compared between groups. RESULTS: In our cohort, meningitis was caused in 36% by enterovirus (EV), 15% by herpes simplex virus (HSV), 12% by varicella zoster virus (VZV) and 5% by tick borne encephalitis (TBE). Encephalitis/meningoencephalitis was caused in 13% by HSV, 13% by VZV, and three out of 11 tested patients were positive for TBE. The highest incidence of EV infections was between 25 and 35 years and of HSV infections between 30 and 60 years. VZV infections had a bimodal distribution peaking below 30 and above 70 years. VZV and EV infections were more frequently observed during summer, whereas HSV infections showed no seasonal preference. Inflammatory changes in cerebrospinal fluid (CSF) were highest in HSV and lowest in EV infections. CONCLUSIONS: Polymerase chain reaction tests for HSV, VZV and EV in CSF and TBE serology determined the causative virus in over 60% of tested patients. The age of affected patients, seasonal distribution, disease course and inflammatory changes in CSF differ between groups of patients affected by the most common viral infections. PMID- 28636288 TI - Total Synthesis of Ovafolinins A and B: Unique Polycyclic Benzoxepin Lignans through a Cascade Cyclization. AB - Ovafolinins A and B, isolated from Lyonia ovalifolia var. elliptica, are lignans that contain a unique bridged structure containing a penta- and tetracyclic benzoxepin and an aryl tetralin. We report the first total synthesis of these natural products in which an acyl-Claisen rearrangement was initially utilized to construct the lignan backbone with correct relative stereochemistry. Judicious use of a bulky protecting group placed reactive moieties in the correct orientation, thereby resulting in a cascade reaction to form the bridged benzoxepin/aryl tetralin from a linear precursor in a single step. Modification of this route allowed the enantioselective synthesis of (+)-ovafolinins A and B, which confirmed the absolute stereochemistry, and comparison of optical rotation suggests that these compounds are found as scalemic mixtures in nature. PMID- 28636289 TI - Loss of idealism or realistic optimism? A cross-sectional analysis of dental hygiene students' and registered dental hygienists' professional identity perceptions. AB - OBJECTIVES: The dental hygiene profession in the U.S. is in the process of establishing a direct access model of care and contributing to the creation of the profession of a dental therapist. The objectives were to analyse the professional role perceptions of dental hygiene students and registered dental hygienists in these times of change. Specifically, it was explored whether dental hygiene students' current professional identities differ (i) from their expected future identities, and (ii) from dental hygienists' current and (iii) past identities. METHODS: Survey data were collected from 215 dental hygiene students concerning their present and future role perceptions, and from 352 registered dental hygienists concerning their present and past professional identity perceptions. RESULTS: Students' future professional identity perceptions were even more positive than their very positive current perceptions of their professional role components. Students' current perceptions of professional pride, professional ambition, work ethic and patient relations were more positive than dental hygienists' current perceptions of these professional role components. A comparison of students' current perceptions with dental hygienists' current and retrospective descriptions showed that students were more positive than dental hygienists in each case. CONCLUSIONS: The fact that dental hygienists had less positive role perceptions than dental hygiene students might lead to the conclusion that a loss of idealism occurs over the course of a professional lifespan. However, dental hygienists actually improved their role perceptions over time and students' future descriptions were more positive than their current descriptions, supporting the interpretation that realistic optimism dominates professional role perceptions in these times of change. PMID- 28636291 TI - ? PMID- 28636290 TI - Sulforaphane protection against the development of doxorubicin-induced chronic heart failure is associated with Nrf2 Upregulation. AB - BACKGROUND: Doxorubicin (DOX) is an anthracycline antitumor drug. However, its clinical use is limited by dose-dependent cardiotoxicity and even progresses to chronic heart failure (CHF). OBJECTIVE: This study aims to investigate whether the Nrf2 activator, sulforaphane (SFN), can prevent DOX-induced CHF. METHODS: Male Sprague-Dawley rats which received treatment for 6 weeks were divided into four groups (n=30 per group): control, SFN, DOX and DOX plus SFN group. RESULTS: Results revealed that DOX induced progressive cardiac damage as indicated by increased cardiac injury markers, cardiac inflammation, fibrosis and oxidative stress. SFN significantly prevented DOX-induced progressive cardiac dysfunction between 2-6 weeks and prevented DOX-induced cardiac function deterioration. Furthermore, it significantly decreased ejection fraction and increased the expression of brain natriuretic peptide. SFN also almost completely prevented DOX induced cardiac oxidative stress, inflammation and fibrosis. SFN upregulated NF E2-related factor 2 (Nrf2) expression and transcription activity, which was reflected by the increased mRNA expression of Nrf2 and its downstream genes. Furthermore, in cultured H9c2 cardiomyocytes, the protective effect of SFN against DOX-induced fibrotic and inflammatory responses was abolished by Nrf2 silencing. CONCLUSION: We arrived at the conclusion that DOX-induced CHF can be prevented by SFN through the upregulation of Nrf2 expression and transcriptional function. PMID- 28636292 TI - [Head and neck cancer : promising results of immunotherapy]. AB - Immunotherapy, especially checkpoint inhibitors such as anti-PD1 and anti-PDL1 antibodies, has changed the standard of care and the prognosis of melanoma, but also more recently of lung cancer, renal cancer and Hodgkin lymphoma. Results of preliminary studies in head and neck squamous cell carcinoma (HNSCC) as well as in less frequent tumors of the region, such as nasopharyngeal carcinoma and high grade salivary gland carcinoma, are also promising. Indeed, in a recent phase 3 study, the PD1 inhibitor nivolumab has recently demonstrated a significant improvement in overall survival for platin-resistant recurrent and/or metastatic HNSCC. PMID- 28636293 TI - [Treatment of advanced hepatocellular carcinoma : Novel agents and role of local therapy]. AB - The incidence of hepatocellular carcinoma (HCC) is increasing in Switzerland and its treatment is a challenge. The purpose of this article is to summarize the different therapeutic approaches in the metastatic stage, as well as the perspectives of targeted treatments and immunotherapy. Until recently, the only recognized therapeutic standard for these patients with metastatic CHC was sorafenib, a tyrosine kinase inhibitor. If the patient was to progress under sorafenib, no other recognized therapeutic option was available as second line. We present in this article the recent data on regorafenib, also an inhibitor of tyrosine kinases, the first systemic therapy showing an increase in survival for patients progressing under sorafenib. Then we will discuss promising data and progress made in treatments checkpoints inhibitors and therapies combining local and systematic approaches. PMID- 28636294 TI - [Selective therapeutic de-escalation in early stage breast cancer]. AB - The survival of patients with breast cancer has improved considerably thanks to adjuvant radiotherapy and systemic treatments. Due to the potential adverse events associated with these treatments, a de-escalation effort was undertaken concerning surgery and more recently the adjuvant treatments. Conservative breast surgery and the avoidance of axillary dissection were possible for the majority of the patients without detrimental effect on survival. New radiotherapy techniques and the consideration of cancer biology allowed to better protect the peripheral organs and even to avoid treatment in certain low-risk patients. The refinement of prognostic and predictive criteria helped reducing the use of chemotherapy and adapting the duration of endocrine therapy to the risk. PMID- 28636295 TI - [Screening of ovarian cancer : not for tomorrow]. AB - As the worldwide incidence of cancer continuously rises, one of the measures to reduce mortality is early diagnosis while the disease is still curable. Colonoscopy screening and PAP-smears are worthwhile examples illustrating the impact of early diagnosis on mortality. Ovarian cancer is the first cause of mortality by gynecological cancers in Switzerland (incidence of 600 new cases / year), mostly diagnosed at advanced stages with a poor prognosis. Could surveillance measures improve survival ? Three large-scale randomized control trials failed to show mortality reduction from ovarian cancer with the methods currently available. A better comprehension of pathogenesis can allow the development of new strategies of screening. PMID- 28636296 TI - [Follow-up of the long-term cancer survivor]. AB - Improvements in diagnosis and treatments explain the notable increase in patients chronically affected or recovering from cancer. This is a fragile population, who is physically, psychologically and socially affected by the consequences of the disease and the associated treatments. In addition to detecting a possible relapse, oncologists and primary care physicians have to deal with a variety of issues like psychological distress, sexual dysfunction, cardiotoxicity, cognitive impairment, fatigue and, in some cases, a second primary cancer. This is a real challenge for modern medical oncology, with an important financial impact. A long term structured follow-up could improve the management of patients with a history of cancer and favour their physical recovery and psychosocial integration. PMID- 28636297 TI - [Supportive care in oncology: a real change for patients?] AB - With the increased incidence of cancers due to an aging population, and a prolonged survival thanks to advances in cancer treatments, new therapeutic challenges have arisen. The management of symptoms, the tolerance of increasingly effective oncologic treatments and, finally, quality of life are central concerns of patients and their loved ones. Supportive care in oncology has helped meet these challenges, offering a holistic approach, encompassing somatic, psychiatric and social aid. Inaugurated in 2005, the oncologic supportive care unit of the Geneva University Hospitals allows many cancer patients access to a team of multidisciplinary care-givers to help meet their needs. PMID- 28636298 TI - [Renal toxicities in oncology therapies]. AB - Development of oncological treatments has progressively and significantly reduced both mortality and morbidity. Chemotherapy and more recently immunotherapy may have short- and long-term side effects among which, renal involvement is one of the most frequent complications, which may alter therapeutic options and quality of life. High cumulative doses of chemotherapy, concomitant administration of nephrotoxic treatment and pre-existing nephropathy are to be carefully considered. This article intends to review some practical considerations concerning therapies from a nephrological point of view. PMID- 28636299 TI - [Sprain of the thumb metacarpal-phalangeal with lesion of the ulnar collateral ligament]. AB - The sprain of the thumb metacarpal-phalangeal joint must be treated in an adapted way in order to avoid chronic laxity. The comparative and bilateral clinical exam is the main element that will allow to detect laxity. In the case of non laxity, a conservative treatment with a splint makes sense. In the case of laxity with Stener effect, a surgical procedure is recommended in order to reintegrate the collateral ligament. In the case of laxity without Stener effect, the choice of treatment is contentious. A US or MRI would be useful if the Stener effect could be underlying. For whichever treatment opted, rehabilitation is to be started as soon as at week 4, in order to reduce risks of stiffness. The return to any sport or training will depend on the sprain stage and on the possibility to wear a rigid splint or not. PMID- 28636300 TI - ? PMID- 28636301 TI - ? PMID- 28636302 TI - ? PMID- 28636303 TI - ? PMID- 28636304 TI - ? PMID- 28636305 TI - ? PMID- 28636308 TI - Redox-Sensitive Nanoscale Coordination Polymers for Drug Delivery and Cancer Theranostics. AB - Nanoscale coordination polymers (NCPs), with inherent biodegradability, chemical diversities, and porous structures, are a promising class of nanomaterials in the nanomedicine field. Herein, a unique type of redox-sensitive NCPs is constructed with manganese ions (Mn2+) and dithiodiglycolic acid as the disulfide (SS) containing organic bridging ligand. The obtained Mn-SS NCPs with a mesoporous structure could be efficiently loaded with doxorubicin (DOX), a chemotherapeutics. The yielded Mn-SS/DOX nanoparticles are coated with a layer of polydopamine (PDA) and then modified by poly(ethylene glycol) (PEG). In such a Mn SS/DOX@PDA-PEG NCP structure, the disulfide linkage (SS) within dithiodiglycolic acid can be cleaved in the presence of glutathione (GSH), leading to efficient redox-responsive dissociation of NCPs and the subsequent drug release. Meanwhile, Mn2+ in Mn-SS/DOX@PDA-PEG NCPs would offer a strong T1 contrast in magnetic resonance (MR) imaging, Upon intravenous injection, these Mn-SS/DOX@PDA-PEG NCPs show efficient tumor homing, as revealed by MR imaging, and offer an obviously improved in vivo therapeutic outcome compared to that achieved with free DOX. PMID- 28636310 TI - Sensing Mechanisms in the Redox-Regulated, [2Fe-2S] Cluster-Containing, Bacterial Transcriptional Factor SoxR. AB - Bacteria possess molecular biosensors that enable responses to a variety of stressful conditions, including oxidative stress, toxic compounds, and interactions with other organisms, through elaborately coordinated regulation of gene expression. In Escherichia coli and related bacteria, the transcription factor SoxR functions as a sensor of oxidative stress and nitric oxide (NO). SoxR protein contains a [2Fe-2S] cluster essential for its transcription-enhancing activity, which is regulated by redox changes in the [2Fe-2S] cluster. We have explored the mechanistic and structural basis of SoxR proteins function and determined how the chemistry at the [2Fe-2S] cluster causes the subsequent regulatory response. In this Account, I describe our recent achievements in three different areas using physicochemical techniques, primarily pulse radiolysis. First, redox-dependent conformational changes in SoxR-bound DNA were studied by site-specifically replacing selected bases with the fluorescent probes 2 aminopurine and pyrrolocytosine. X-ray analyses of the DNA-SoxR complex in the oxidized state revealed that the DNA structure is distorted in the center regions, resulting in local untwisting of base pairs. However, the inactive, reduced state had remained uncharacterized. We found that reduction of the [2Fe 2S] cluster in the SoxR-DNA complex weakens the fluorescence intensity within a region confined to the central base pairs in the promoter region. Second, the reactions of NO with [2Fe-2S] clusters of E. coli SoxR were analyzed using pulse radiolysis. The transcriptional activation of SoxR in E. coli occurs through direct modification of [2Fe-2S] by NO to form a dinitrosyl iron complex (DNIC). The reaction of NO with [2Fe-2S] cluster of SoxR proceeded nearly quantitatively with concomitant reductive elimination of two equivalents S0 atoms. Intermediate nitrosylation products, however, were too unstable to observe. We found that the conversion proceeds through at least two steps, with the faster phase being the first reaction of the NO molecule with the [2Fe-2S] cluster. The slower reaction with the second equivalent NO molecule, however, was important for the formation of DNIC. Third, to elucidate the differences between the distinct responses of SoxR proteins from two different species, we studied the interaction of E. coli and Pseudomonas aeruginosa SoxR with superoxide anion using a mutagenic approach. Despite the homology between E. coli SoxR and P. aeruginosa SoxR, the function of P. aeruginosa SoxR differs from that of E. coli. The substitution of E. coli SoxR lysine residues, located close to [2Fe-2S] clusters, into P. aeruginosa SoxR dramatically affected the reaction with superoxide anion. PMID- 28636309 TI - Quantitative Chemical Proteomic Profiling of the in Vivo Targets of Reactive Drug Metabolites. AB - Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, we describe a quantitative chemical proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogues of four representative hepatotoxic drugs, we demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e.g., lipid/sterol pathways for troglitazone). Site-specific proteomics revealed that acetaminophen reacts with high stoichiometry with several conserved, functional (seleno)cysteine residues throughout the liver proteome. Our findings thus provide an advanced experimental framework to characterize the proteomic reactivity of drug metabolites in vivo, revealing target profiles that may help to explain mechanisms and identify risk factors for drug-induced liver injury. PMID- 28636311 TI - Insights into Integrated Lead Generation and Target Identification in Malaria and Tuberculosis Drug Discovery. AB - New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery. This Account recaps the existing challenges facing antimalarial and antituberculosis drug discovery, including limitations associated with experimental animal models as well as biological complexities intrinsic to the causative pathogens. We enlist various highlights from a body of work within our research group aimed at identifying and characterizing new chemical leads, and navigating these challenges to contribute toward the global drug discovery and development pipeline in malaria and tuberculosis. We describe a catalogue of in house efforts toward deriving safe and efficacious preclinical drug development candidates via cell-based medicinal chemistry optimization of phenotypic whole cell medium and high throughput screening hits sourced from various small molecule chemical libraries. We also provide an appraisal of target-based screening, as invoked in our laboratory for mechanistic evaluation of the hits generated, with particular focus on the enzymes within the de novo pyrimidine biosynthetic and hemoglobin degradation pathways, the latter constituting a heme detoxification process and an associated cysteine protease-mediated hydrolysis of hemoglobin. We further expound on the recombinant enzyme assays, heme fractionation experiments, and genomic and chemoproteomic methods that we employed to identify Plasmodium falciparum falcipain 2 (PfFP2), hemozoin formation, phosphatidylinositol 4-kinase (PfPI4K) and Mycobacterium tuberculosis cytochrome bc1 complex as the targets of the antimalarial chalcones, pyrido[1,2 a]benzimidazoles, aminopyridines, and antimycobacterial pyrrolo[3,4-c]pyridine 1,3(2H)-diones, respectively. In conclusion, we argue for the expansion of chemical space through exploitation of privileged natural product scaffolds and diversity-oriented synthesis, as well as the broadening of druggable spaces by exploiting available protein crystal structures, -omics data, and bioinformatics infrastructure to explore hitherto untargeted spaces like lipid metabolism and protein kinases in P. falciparum. Finally, we audit the merits of both target based and whole-cell phenotypic screening in steering antimalarial and antituberculosis chemical matter toward populating drug discovery pipelines with new lead molecules. PMID- 28636312 TI - Combining Protein and miRNA Quantification for Bladder Cancer Analysis. AB - We combine the telomerase extension reaction and microRNA (miRNA)-induced rolling circle amplification, followed by graphene oxide (GO) and nicking enzyme-assisted signal amplification as a method to analyze telomerase and miRNA-21 in urine samples with the following merits. First, it is a binary assay and can simultaneously output double signals that correspond to the quantities of telomerase and miRNA, respectively. Second, telomerase activity is enhanced by using a DNA molecular beacon probe to inhibit the formation of G-quadruplex. Third, background noise is decreased significantly via introduction of GO. Fourth, performance tests on about 258 urine samples demonstrate that this binary assay can distinguish between urine from bladder cancer patients, those with cystitis, and normal individuals. Finally, this strategy also shows great potential in distinguishing between muscle-invasive bladder cancers and non muscle-invasive bladder cancers. The proposed strategy will greatly contribute to clinical decision-making and individualized treatments. PMID- 28636314 TI - Giant Thermal Rectification from Single-Carbon Nanotube-Graphene Junction. AB - We describe the influence of the geometry parameters on the thermal rectification of single-carbon nanotube-graphene junction. The two-dimensional (2D) distribution of the thermal rectification with respect to the tube length and the side length of the graphene nanosheet are calculated and visualized. The maximum thermal rectification ratios of the designed single-carbon nanotube-graphene junction can reach 1244.1% and 1681.6% at average temperatures of 300 and 200 K, respectively. These values are much higher than those reported for single material nanostructure-based thermal rectifiers. The thermal rectification ratios of the nanotube-graphene junction are fairly sensitive to geometry size and are almost entirely dominated by the degree of overlap of the power spectra under negative thermal bias. These findings could offer useful guidelines for the design and performance improvement of thermal diodes. PMID- 28636315 TI - Fabrication of Hierarchical Macroporous Biocompatible Scaffolds by Combining Pickering High Internal Phase Emulsion Templates with Three-Dimensional Printing. AB - Biocompatible and biodegradable porous scaffolds with adjustable pore structure have aroused increasing interest in bone tissue engineering. Here, we report a facile method to fabricate hierarchical macroporous biocompatible (HmPB) scaffolds by combining Pickering high internal phase emulsion (HIPE) templates with three-dimensional (3D) printing. HmPB scaffolds composed of a polymer matrix of poly(l-lactic acid), PLLA, and poly(epsilon-caprolactone), PCL, are readily fabricated by solvent evaporation of 3D printed Pickering HIPEs which are stabilized by hydrophobically modified silica nanoparticles (h-SiO2). The pore structure of HmPB scaffolds is easily tailored to be similar to natural extracellular matrix (ECM) by varying the fabrication conditions of the Pickering emulsion or adjusting the printing parameters. In addition, in vivo drug release studies which employ enrofloxacin (ENR) as a model drug indicate the potential of HmPB scaffolds as a drug carrier. Furthermore, in vivo cell culture assays prove that HmPB scaffolds that possess good biocompatibility as mouse bone mesenchymal stem cells (mBMSCs) can adhere and proliferate well on them. All the results suggest that HmPB scaffolds hold great potential in bone tissue engineering applications. PMID- 28636316 TI - Novel Melamine/o-Phthalaldehyde Covalent Organic Frameworks Nanosheets: Enhancement Flame Retardant and Mechanical Performances of Thermoplastic Polyurethanes. AB - Covalent organic frameworks (COFs) nanosheets prepared from condensation reaction between melamine and o-phthalaldehyde are first prepared through ball milling and then incorporated into thermoplastic polyurethanes (TPU) by solution mixing. Transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FTIR) spectrometer are applied to characterize COFs nanosheets. It is observed apparently from TEM image that COFs nanosheets are obtained. Successful preparation of COFs nanosheets is proved further by vanishment of typical diffraction peak of COFs at around 23.5 degrees in COFs nanosheets XRD pattern, appearance of quadrant and semicircle stretching of the s-triazine ring at 1568 and 1469 cm-1 in FTIR spectra and N?C bond at 389.5 eV in N1s high-resolution XPS spectra of COFs nanosheets. The thermal property, combustion behavior and mechanical performance of TPU naoncomposites are also investigated. Incorporation of COFs nanosheets into TPU contributes to char forming of TPU under nitrogen atmosphere and 14.3% decrease of peak heat release rate of TPU. Besides, the elongation at break, Young's modulus, and fracture strength of TPU nanocomposites increase sharply compared with that of neat one. PMID- 28636313 TI - Iodine(III) Reagents in Radical Chemistry. AB - The chemistry of hypervalent iodine(III) compounds has gained great interest over the past 30 years. Hypervalent iodine(III) compounds show valuable ionic reactivity due to their high electrophilicity but also express radical reactivity as single electron oxidants for carbon and heteroatom radical generation. Looking at ionic chemistry, these iodine(III) reagents can act as electrophiles to efficiently construct C-CF3, X-CF3 (X = heteroatom), C-Rf (Rf = perfluoroalkyl), X-Rf, C-N3, C-CN, S-CN, and C-X bonds. In some cases, a Lewis or a Bronsted acid is necessary to increase their electrophilicity. In these transformations, the iodine(III) compounds react as formal "CF3+", "Rf+", "N3+", "Ar+", "CN+", and "X+" equivalents. On the other hand, one electron reduction of the I(III) reagents opens the door to the radical world, which is the topic of this Account that focuses on radical reactivity of hypervalent iodine(III) compounds such as the Togni reagent, Zhdankin reagent, diaryliodonium salts, aryliodonium ylides, aryl(cyano)iodonium triflates, and aryl(perfluoroalkyl)iodonium triflates. Radical generation starting with I(III) reagents can also occur via thermal or light mediated homolysis of the weak hypervalent bond in such reagents. This reactivity can be used for alkane C-H functionalization. We will address important pioneering work in the area but will mainly focus on studies that have been conducted by our group over the last 5 years. We entered the field by investigating transition metal free single electron reduction of Togni type reagents using the readily available sodium 2,2,6,6-tetramethylpiperidine-1-oxyl salt (TEMPONa) as an organic one electron reductant for clean generation of the trifluoromethyl radical and perfluoroalkyl radicals. That valuable approach was later successfully also applied to the generation of azidyl and aryl radicals starting with the corresponding benziodoxole (Zhdankin reagent) and iodonium salts. In the presence of alkenes as radical acceptors, vicinal trifluoromethyl-, azido-, and arylaminoxylation products result via a sequence comprising radical addition to the alkene and subsequent TEMPO trapping. Electron-rich arenes also react with I(III) reagents via single electron transfer (SET) to give arene radical cations, which can then engage in arylation reactions. We also recognized that the isonitrile functionality in aryl isonitriles is a highly efficient perfluoroalkyl radical acceptor, and reaction of Rf-benziodoxoles (Togni type reagents) in the presence of a radical initiator provides various perfluoroalkylated N-heterocycles (indoles, phenanthridines, quinolines, etc.). We further found that aryliodonium ylides, previously used as carbene precursors in metal-mediated cyclopropanation reactions, react via SET reduction with TEMPONa to the corresponding aryl radicals. As a drawback of all these transformations, we realized that only one ligand of the iodine(III) reagent gets transferred to the substrate. To further increase atom-economy of such conversions, we identified cyano or perfluoroalkyl iodonium triflate salts as valuable reagents for stereoselective vicinal alkyne difunctionalization, where two ligands from the I(III) reagent are sequentially transferred to an alkyne acceptor. Finally, we will discuss alkynyl-benziodoxoles as radical acceptors for alkynylation reactions. Similar reactivity was found for the Zhdankin reagent that has been successfully applied to azidation of C-radicals, and also cyanation is possible with a cyano I(III) reagent. To summarize, this Account focuses on the design, development, mechanistic understanding, and synthetic application of hypervalent iodine(III) reagents in radical chemistry. PMID- 28636317 TI - Downsizing Proto-oncogene cFos to Short Helix-Constrained Peptides That Bind Jun. AB - The oncogenic transcription factor activator protein-1 (AP-1) is a DNA-binding protein that assembles through dimerization of Fos and Jun protein subunits, their leucine-rich helical sequences entwining into a coiled-coil structure. This study reports on downsizing the proto-oncogene cFos protein (380 residues) to shorter peptides (37-25 residues) modified with helix-inducing constraints to enhance binding to Jun. A crystal structure is reported for a 37-residue Fos derived peptide (FosW) bound to Jun. This guided iterative downsizing of FosW to shorter peptide sequences that were constrained into stable water-soluble alpha helices by connecting amino acid side chains to form cyclic pentapeptide components. Structural integrity in the presence and absence of Jun was assessed by circular dichroism spectroscopy, while the thermodynamics of binding to cFos was measured by isothermal titration calorimetry. A 25-residue constrained peptide, one-third shorter yet 25% more helical than the structurally characterized 37-residue Fos-derived peptide, retained 80% of the binding free energy as a result of preorganization in a Jun-binding helix conformation, with the entropy gain (TDeltaS = +3.2 kcal/mol) compensating for the enthalpy loss. Attaching a cell-penetrating peptide (TAT48-57) and a nuclear localization signal (SV40) promoted cell uptake, localization to the nucleus, and inhibition of the proliferation of two breast cancer cell lines. PMID- 28636318 TI - Inverse Photonic Glasses by Packing Bidisperse Hollow Microspheres with Uniform Cores. AB - A major fabrication challenge is producing disordered photonic materials with an angle-independent structural red color. Theoretical work has shown that such a color can be produced by fabricating inverse photonic glasses with monodisperse, nontouching voids in a silica matrix. Here, we demonstrate a route toward such materials and show that they have an angle-independent red color. We first synthesize monodisperse hollow silica particles with precisely controlled shell thickness and then make glassy colloidal structures by mixing two types of hollow particles with the same core size and different shell thicknesses. We then infiltrate the interstices with index-matched polymers, producing disordered porous materials with uniform, nontouching air voids. This procedure allows us to control the light-scattering form factor and structure factor of these porous materials independently, which is not possible to do in photonic glasses consisting of packed solid particles. The structure factor can be controlled by the shell thickness, which sets the distance between pores, whereas the pore size determines the peak wave vector of the form factor, which can be set below the visible range to keep the main structural color pure. By using a binary mixture of 246 and 268 nm hollow silica particles with 180 nm cores in an index-matched polymer matrix, we achieve angle-independent red color that can be tuned by controlling the shell thickness. Importantly, the width of the reflection peak can be kept constant, even for larger interparticle distances. PMID- 28636319 TI - Green Catanionic Gemini Surfactant-Lichenysin Mixture: Improved Surface, Antimicrobial, and Physiological Properties. AB - Catanionic surfactant mixtures form a wide variety of organized assemblies and aggregates with improved physicochemical and biological properties. The green catanionic mixture NalphaNomega-Bis(Nalphacaproylarginine) alpha,omega propyldiamide (C3(CA)2):Lichenysin (molar ratio 8:2) showed antimicrobial synergies against Yersinia enterocolitica, Bacillus subtilis, Escherichia coli O157:H7, and Candida albicans. Flow cytometry and viability studies indicated that this catanionic mixture increases the probability of Y. enterocolitica (38.2%) and B. subtilis (17.1%) cells entering a viable but nonculturable state. Zeta potential showed that one of the cationic charges of C3(CA)2 is neutralized by Lichenysin. An isotherm study demonstrated the formation of a stable aggregate between the two surfactants. The catanionic aggregate was able to interact with bacterial phospholipids. The lowest hemolysis (22.1 MUM) was obtained with the catanionic mixture, although an irritant potential (0.70) was characterized. According to the therapeutic index, the C3(CA)2:Lichenysin mixture was the formulation least toxic to eukaryotic cells. Partial neutralization of C3(CA)2 by Lichenysin modified the mode of action that enhances the transition of bacterial cells into a viable but nonculturable state (VBNC) and improved the cell selectivity. PMID- 28636320 TI - DNA Loading and Release Using Custom-Tailored Poly(l-lysine) Surfaces. AB - This Article describes the generation and study of surfaces modified with custom crafted poly(l-lysine) (PLL) coatings for use in the loading and delivery of single-stranded DNA (ssDNA). The experimental strategy utilizes bidentate dithiol adsorbates to generate stably bound azide-terminated self-assembled monolayers (SAMs) on gold possessing an oligo(ethylene glycol) (OEG) spacer. Consequent to the molecular assembly on gold, the azide termini are covalently attached to a maleimide linker moiety via a copper-catalyzed azide-alkyne "click" reaction. Functionalization with maleimide provides a platform for the subsequent attachment of cysteine-terminated poly(l-lysine) (PLL), thus forming a suitable surface for the loading of ssDNA via electrostatic interactions. In efforts to maximize DNA loading, we generate SAMs containing mixtures of short and long PLL segments and explore the DNA-loading capability of the various PLL SAMs. We then use thermal increases to trigger the release of the ssDNA from the surface. By examining the loading and release of ssDNA using these new two-dimensional systems, we gain preliminary insight into the potential efficacy of this approach when using three-dimensional gold nanostructure systems in future gene-delivery and biosensing applications. PMID- 28636321 TI - Copper Oxide Nanoparticles Induce Lysogenic Bacteriophage and Metal-Resistance Genes in Pseudomonas aeruginosa PAO1. AB - The intensive use of metal-based nanoparticles results in their continuous release into the environment, leading to potential risks for human health and microbial ecosystems. Although previous studies have indicated that nanoparticles may be toxic to microorganisms, there is a scarcity of data available to assess the underlying molecular mechanisms of inhibitory and biocidal effects of nanoparticles on microorganisms. This study used physiological experiments, microscopy, live/dead staining, and the genome-wide RNA sequencing to investigate the multiple responses of Pseudomonas aeruginosa to the exposure of copper oxide nanoparticles (CuO NPs). The results for the first time show that CuO NPs induce lysogenic bacteriophage, which might render defective within a bacterial host. The presence of CuO NPs causes nitrite accumulation and great increases in N2O emissions. Respiration is likely inhibited as denitrification activity is depleted in terms of decreased transcript levels of most denitrification genes. Meanwhile, CuO NPs exposure significantly up-regulated gene expression for those coding for copper resistance, resistance-nodulation-division, P-type ATPase efflux, and cation diffusion facilitator transporters. Our findings offer insights into the interaction between environmental bacteria and CuO NPs at the transcriptional level and, thus, improve our understanding of potential risks of nanoparticles on microbial ecosystems and public health. PMID- 28636322 TI - Spirally Structured Conductive Composites for Highly Stretchable, Robust Conductors and Sensors. AB - Flexible and stretchable electronics are highly desirable for next generation devices. However, stretchability and conductivity are fundamentally difficult to combine for conventional conductive composites, which restricts their widespread applications especially as stretchable electronics. Here, we innovatively develop a new class of highly stretchable and robust conductive composites via a simple and scalable structural approach. Briefly, carbon nanotubes are spray-coated onto a self-adhesive rubber film, followed by rolling up the film completely to create a spirally layered structure within the composites. This unique spirally layered structure breaks the typical trade-off between stretchability and conductivity of traditional conductive composites and, more importantly, restrains the generation and propagation of mechanical microcracks in the conductive layer under strain. Benefiting from such structure-induced advantages, the spirally layered composites exhibit high stretchability and flexibility, good conductive stability, and excellent robustness, enabling the composites to serve as highly stretchable conductors (up to 300% strain), versatile sensors for monitoring both subtle and large human activities, and functional threads for wearable electronics. This novel and efficient methodology provides a new design philosophy for manufacturing not only stretchable conductors and sensors but also other stretchable electronics, such as transistors, generators, artificial muscles, etc. PMID- 28636323 TI - Ultrafast Dynamic Pressure Sensors Based on Graphene Hybrid Structure. AB - Mechanical flexible electronic skin has been focused on sensing various physical parameters, such as pressure and temperature. The studies of material design and array-accessible devices are the building blocks of strain sensors for subtle pressure sensing. Here, we report a new and facile preparation of a graphene hybrid structure with an ultrafast dynamic pressure response. Graphene oxide nanosheets are used as a surfactant to prevent graphene restacking in aqueous solution. This graphene hybrid structure exhibits a frequency-independent pressure resistive sensing property. Exceeding natural skin, such pressure sensors, can provide transient responses from static up to 10 000 Hz dynamic frequencies. Integrated by the controlling system, the array-accessible sensors can manipulate a robot arm and self-rectify the temperature of a heating blanket. This may pave a path toward the future application of graphene-based wearable electronics. PMID- 28636324 TI - Oxide Film Efficiently Suppresses Dendrite Growth in Aluminum-Ion Battery. AB - Aluminum metal foil is the optimal choice as an anode material for aluminum-ion batteries for its key advantages such as high theoretical capacity, safety, and low cost. However, the metallic nature of aluminum foil is very likely to induce severe dendrite growth with further electrode disintegration and cell failure, which is inconsistent with previous reports. Here, we discover that it is aluminum oxide film that efficiently restricts the growth of crystalline Al dendrite and thus improves the cycling stability of Al anode. The key role of surficial aluminum oxide film in protecting Al metal anode lies in decreasing the nucleation sites, controlling the metallic dendrite growth, and preventing the electrode disintegration. The defect sites in aluminum oxide film provide channels for electrolyte infiltration and further stripping/depositing. Attributed to such a protective aluminum oxide film, the Al-graphene full cells can attain up to 45 000 stable cycles. PMID- 28636326 TI - Experimental Study of the Detection Limit in Dual-Gate Biosensors Using Ultrathin Silicon Transistors. AB - Dual-gate field-effect biosensors (bioFETs) with asymmetric gate capacitances were shown to surpass the Nernst limit of 59 mV/pH. However, previous studies have conflicting findings on the effect of the capacitive amplification scheme on the sensor detection limit, which is inversely proportional to the signal-to noise ratio (SNR). Here, we present a systematic experimental investigation of the SNR using ultrathin silicon transistors. Our sensors operate at low voltage and feature asymmetric front and back oxide capacitances with asymmetry factors of 1.4 and 2.3. We demonstrate that in the dual-gate configuration, the response of our bioFETs to the pH change increases proportional to the asymmetry factor and indeed exceeds the Nernst limit. Further, our results reveal that the noise amplitude also increases in proportion to the asymmetry factor. We establish that the commensurate increase of the noise amplitude originates from the intrinsic low-frequency characteristic of the sensor noise, dominated by number fluctuation. These findings suggest that this capacitive signal amplification scheme does not improve the intrinsic detection limit of the dual-gate biosensors. PMID- 28636325 TI - Challenges and Hallmarks of Establishing Alkylacetylphosphonates as Probes of Bacterial 1-Deoxy-d-xylulose 5-Phosphate Synthase. AB - 1-Deoxy-d-xylulose 5-phosphate (DXP) synthase catalyzes the thiamin diphosphate (ThDP)-dependent formation of DXP from pyruvate and d-glyceraldehyde 3-phosphate. DXP is at a metabolic branch point in bacteria, feeding into the methylerythritol phosphate pathway to indispensable isoprenoids and acting as a precursor for biosynthesis of essential cofactors in central metabolism, pyridoxal phosphate and ThDP, the latter of which is also required for DXP synthase catalysis. DXP synthase follows a unique random sequential mechanism and possesses an unusually large active site. These features have guided the design of sterically demanding alkylacetylphosphonates (alkylAPs) toward the development of selective DXP synthase inhibitors. alkylAPs studied here display selective, low MUM inhibitory activity against DXP synthase. They are weak inhibitors of bacterial growth in standard nutrient rich conditions. However, bacteria are significantly sensitized to most alkylAPs in defined minimal growth medium, with minimal inhibitory concentrations (MICs) ranging from low MUM to low mM and influenced by alkyl chain length. The longest analog (C8) displays the weakest antimicrobial activity and is a substrate for efflux via AcrAB-TolC. The dependence of inhibitor potency on growth environment emphasizes the need for antimicrobial screening conditions that are relevant to the in vivo microbial microenvironment during infection. DXP synthase expression and thiamin supplementation studies offer support for DXP synthase as an intracellular target for some alkylAPs and reveal both the challenges and intriguing aspects of these approaches to study target engagement. PMID- 28636328 TI - Structural Dynamics of Native-Like Ions in the Gas Phase: Results from Tandem Ion Mobility of Cytochrome c. AB - Ion mobility (IM) is a gas-phase separation technique that is used to determine the collision cross sections of native-like ions of proteins and protein complexes, which are in turn used as restraints for modeling the structures of those analytes in solution. Here, we evaluate the stability of native-like ions using tandem IM experiments implemented using structures for lossless ion manipulations (SLIM). In this implementation of tandem IM, ions undergo a first dimension of IM up to a switch that is used to selectively transmit ions of a desired mobility. Selected ions are accumulated in a trap and then released after a delay to initiate the second dimension of IM. For delays ranging from 16 to 33 231 ms, the collision cross sections of native-like, 7+ cytochrome c ions increase monotonically from 15.1 to 17.1 nm2. The largest products formed in these experiments at near-ambient temperature are still far smaller than those formed in energy-dependent experiments (~21 nm2). However, the collision cross section increases by ~2% between delay times of 16 and 211 ms, which may have implications for other IM experiments on these time scales. Finally, two subpopulations from the full population were each mobility selected and analyzed as a function of delay time, showing that the three populations can be differentiated for at least 1 s. Together, these results suggest that elements of native-like structure can have long lifetimes at near-ambient temperature in the gas phase but that gas-phase dynamics should be considered when interpreting results from IM. PMID- 28636327 TI - MALDI MS Guided Liquid Microjunction Extraction for Capillary Electrophoresis Electrospray Ionization MS Analysis of Single Pancreatic Islet Cells. AB - The ability to characterize chemical heterogeneity in biological structures is essential to understanding cellular-level function in both healthy and diseased states, but these variations remain difficult to assess using a single analytical technique. While mass spectrometry (MS) provides sufficient sensitivity to measure many analytes from volume-limited samples, each type of mass spectrometric analysis uncovers only a portion of the complete chemical profile of a single cell. Matrix-assisted laser desorption/ionization (MALDI) MS and capillary electrophoresis electrospray ionization (CE-ESI)-MS are complementary analytical platforms frequently utilized for single-cell analysis. Optically guided MALDI MS provides a high-throughput assessment of lipid and peptide content for large populations of cells, but is typically nonquantitative and fails to detect many low-mass metabolites because of MALDI matrix interferences. CE-ESI-MS allows quantitative measurements of cellular metabolites and increased analyte coverage, but has lower throughput because the electrophoretic separation is relatively slow. In this work, the figures of merit for each technique are combined via an off-line method that interfaces the two MS systems with a custom liquid microjunction surface sampling probe. The probe is mounted on an xyz translational stage, providing 90.6 +/- 0.6% analyte removal efficiency with a spatial targeting accuracy of 42.8 +/- 2.3 MUm. The analyte extraction footprint is an elliptical area with a major diameter of 422 +/- 21 MUm and minor diameter of 335 +/- 27 MUm. To validate the approach, single rat pancreatic islet cells were rapidly analyzed with optically guided MALDI MS to classify each cell into established cell types by their peptide content. After MALDI MS analysis, a majority of the analyte remains for follow-up measurements to extend the overall chemical coverage. Optically guided MALDI MS was used to identify individual pancreatic islet alpha and beta cells, which were then targeted for liquid microjunction extraction. Extracts from single alpha and beta cells were analyzed with CE-ESI-MS to obtain qualitative information on metabolites, including amino acids. Matching the molecular masses and relative migration times of the extracted analytes and related standards allowed identification of several amino acids. Interestingly, dopamine was consistently detected in both cell types. The results demonstrate the successful interface of optical microscopy-guided MALDI MS and CE-ESI-MS for sequential chemical profiling of individual, mammalian cells. PMID- 28636329 TI - Metallic Element Chelated Tag Labeling (MeCTL) for Quantitation of N-Glycans in MALDI-MS. AB - N-glycosylation plays an important role in chief biological and pathological processes. Quantifying the N-glycan is important since glycan alterations are related to many diseases. In this study, we developed a novel N-glycan quantitation approach using metallic element chelated tag labeling (MeCTL) through reductive amination. The MeCTL strategy is of high labeling efficiency and accurate in quantitation with high reproducibility (CV < 17.03%) and good linearity (R2 > 0.99) within 2 orders of magnitude of dynamic range. Additionally, it provides significant cross-ring fragmentation to distinguish N glycan isomers. Furthermore, multiplex quantitation by chelation with several different rare earth elements can be achieved. At last, this strategy has been successfully used for evaluation of N-glycan changes in human serum associated with CRC, indicating its potential in clinical applications including disease N glycome profiling and relative quantitation. PMID- 28636330 TI - Water in Ionic Liquid Lubricants: Friend and Foe. AB - To a greater or lesser extent, most room-temperature ionic liquids (RTILs) absorb water from humid air. Penetration of water into the lubricating nanoscale film may affect its equilibrium structure and dynamic properties and thus influence the ability of RTILs as lubricants to reduce friction between solid surfaces. Here we investigate the impact of hydration on lubrication using nonequilibrium molecular dynamics simulations. Water adsorption changes both the ionic liquid molecules' orientation and the slip conditions at the solid-liquid interfaces, resulting in a reduced resistance against squeezing-out of the lubricant by an external load. For the same normal load, the film becomes thinner when water is present. We show that even small amounts of water can screen the electrostatic interactions between the ions, making RTILs more "fluid" and compressible and hence less resistant to external stress. The impact that screening has on friction involves several aspects that are systematically analyzed in this paper. PMID- 28636331 TI - Doping of Graphene Nanoribbons via Functional Group Edge Modification. AB - We report the on-surface synthesis of 7-armchair graphene nanoribbons (7-AGNRs) substituted with nitrile (CN) functional groups. The CN groups are attached to the GNR backbone by modifying the 7-AGNR precursor. Whereas many of these groups survive the on-surface synthesis, the reaction process causes the cleavage of some CN from the ribbon backbone and the on-surface cycloisomerization of few nitriles onto pyridine rings. Scanning tunneling spectroscopy and density functional theory reveal that CN groups behave as very efficient n-dopants, significantly downshifting the bands of the ribbon and introducing deep impurity levels associated with the nitrogen electron lone pairs. PMID- 28636332 TI - New Insights into the Wavelength Dependence of MALDI Mass Spectrometry. AB - The interplay between the wavelength of the laser and the absorption profile of the matrix constitutes a crucial factor in matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). Numerous studies have shown that typically best analytical results are obtained if the laser wavelength matches the UV absorption band of the matrix in the solid state well. However, many powerful matrices exhibit peak absorptions which differ notably from the standard MALDI laser wavelengths of 337, 349, and 355 nm, respectively. Here we used two wavelength-tunable lasers to investigate the MALDI wavelength dependence with a selected set of such matrices. We studied 3-hydroxypicolinic acid (3-HPA), 2,4,6 trihydroxyacetophenon (THAP), dithranol (1,8-dihydroxy-10H-anthracen-9-on), 2-(4' hydroxybenzeneazo)benzoic acid (HABA), and 6-aza-2-thiothymine (ATT). For analyte systems we investigated DNA oligomers (3-HPA), phospholipids (dithranol, THAP, HABA), and non-covalent peptide-peptide and protein-peptide complexes (ATT). We recorded analyte ion and total ion counts as a function of wavelength and laser fluence between 213 and 600 nm. Although the so-generated comprehensive heat maps generally corroborated the previously made findings, several fine features became notable. For example, despite a still high optical absorption exhibited by some of the matrices in the visible wavelength range, ion yields generally dropped strongly, indicating a change in ionization mechanism. Moreover, the non-covalent complexes were optimally detected at wavelengths corresponding to a relatively low optical absorptivity of the ATT matrix, presumably because of ejection of a particular cold MALDI plume. Our comprehensive data shed useful light into the MALDI mechanisms and could assist in further methodological advancement of the technique. PMID- 28636333 TI - Glycosaminoglycan Analysis by Cryogenic Messenger-Tagging IR Spectroscopy Combined with IMS-MS. AB - We combine ion mobility spectrometry with cryogenic, messenger-tagging, infrared spectroscopy and mass spectrometry to identify different isomeric disaccharides of chondroitin sulfate (CS) and heparan sulfate (HS), which are representatives of two major subclasses of glycosaminoglycans. Our analysis shows that while CS and HS disaccharide isomers have similar drift times, they can be uniquely distinguished by their vibrational spectrum between ~3200 and 3700 cm-1 due to their different OH hydrogen-bonding patterns. We suggest that this combination of techniques is well suited to identify and characterize glycan isomers directly, which presents tremendous challenges for existing methods. PMID- 28636334 TI - Interpreting the Collision Cross Sections of Native-like Protein Ions: Insights from Cation-to-Anion Proton-Transfer Reactions. AB - The effects of charge state on structures of native-like cations of serum albumin, streptavidin, avidin, and alcohol dehydrogenase were probed using cation to-anion proton-transfer reactions (CAPTR), ion mobility, mass spectrometry, and complementary energy-dependent experiments. The CAPTR products all have collision cross-section (Omega) values that are within 5.5% of the original precursor cations. The first CAPTR event for each precursor yields products that have smaller Omega values and frequently exhibit the greatest magnitude of change in Omega resulting from a single CAPTR event. To investigate how the structures of the precursors affect the structures of the products, ions were activated as a function of energy prior to CAPTR. In each case, the Omega values of the activated precursors increase with increasing energy, but the Omega values of the CAPTR products are smaller than the activated precursors. To investigate the stabilities of the CAPTR products, the products were activated immediately prior to ion mobility. These results show that additional structures with smaller or larger Omega values can be populated and that the structures and stabilities of these ions depend most strongly on the identity of the protein and the charge state of the product, rather than the charge state of the precursor or the number of CAPTR events. Together, these results indicate that the excess charges initially present on native-like ions have a modest, but sometimes statistically significant, effect on their Omega values. Therefore, potential contributions from charge state should be considered when using experimental Omega values to elucidate structures in solution. PMID- 28636336 TI - A Mg-CP with in Situ Encapsulated Photochromic Guest as Sensitive Fluorescence Sensor for Fe3+/Cr3+ Ions and Nitro-Explosives. AB - Here we report a fluorescent magnesium coordination polymer (Mg-CP), namely, [CH3 dpb]2[Mg3(1,4-NDC)4(MU-H2O)2(CH3OH)(H2O)].1.5H2O (1, 1,4-H2NDC = 1,4-naphthalene dicarboxylic acid, dpb = 1,4-bis(pyrid-4-yl)benzene). Compound 1 possesses a three-dimensional (3D) host-guest structure constructed by the 1,4-NDC linkers bridging the linear trinuclear secondary building units of [Mg3(COO)8(MU-H2O)2]. The dpb molecules were in situ reacted with CH3OH resulting in photochromic cations of [CH3-dpb]+ that acted as guests located in the channels parallel to the b-axis. Photoluminescence (PL) studies indicated that 1 showed a strong green emission demonstrating sensitive fluorescence sensing of Fe3+/Cr3+ metal ions and nitro-explosive compounds. Compound 1 represents the first PL Mg-CP as a fluorescent probe for detecting metal ions. Moreover, because of the in situ encapsulation of photochromic [CH3-dpb]+ guests, 1 exhibited reversible photochromic behavior. PMID- 28636335 TI - A2B-Miktoarm Glycopolymer Fibers and Their Interactions with Tenocytes. AB - Electrospun biodegradable membranes have attracted great attention for a range of tissue engineering applications. Among them, poly(epsilon-caprolactone) (PCL) is one of the most widely used polymers, owing to its well-controlled biocompatibility and biodegradability. However, PCL also has a number of limitations, such as its hydrophobic nature and the lack of functional groups on its side chain, limiting its ability to interact with cells. Herein, we have designed and prepared a series of well-defined A2B-miktoarm copolymers with PCL and glycopolymer segments to address these limitations. Moreover, copolymers were electrospun to make membranes, which were studied in vitro to investigate cell affinity, toxicity, activity, and adhesion with these materials. The results indicate that incorporating glucose moieties into miktoarm polymers has improved the biocompatibility of the PCL while increasing the cellular interaction with the membrane material. PMID- 28636337 TI - Thermal Annealing to Modulate the Shape Memory Behavior of a Biobased and Biocompatible Triblock Copolymer Scaffold in the Human Body Temperature Range. AB - A biodegradable and biocompatible electrospun scaffold with shape memory behavior in the physiological temperature range is here presented. It was obtained starting from a specifically designed, biobased PLLA-based triblock copolymer, where the central block is poly(propylene azelate-co-propylene sebacate) (P(PAz60PSeb40)) random copolymer. Shape memory properties are determined by the contemporary presence of the low melting crystals of the P(PAz60PSeb40) block, acting as switching segment, and of the high melting crystal phase of PLLA blocks, acting as physical network. It is demonstrated that a straightforward annealing process applied to the crystal phase of the switching element gives the possibility to tune the shape recovery temperature from about 25 to 50 degrees C, without the need of varying the copolymer's chemical structure. The thermal annealing approach here presented can be thus considered a powerful strategy for "ad hoc" programming the same material for applications requiring different recovery temperatures. Fibroblast culture experiments demonstrated scaffold biocompatibility. PMID- 28636338 TI - Contributions of Local Farming to Urban Sustainability in the Northeast United States. AB - Food consumption is an important contributor to a city's environmental impacts (carbon emissions, land occupation, water use, etc.) Urban farming (UF) has been advocated as a means to increase urban sustainability by reducing food-related transport and tapping into local resources. Taking Boston as an illustrative Northeast U.S. city, we developed a novel method to estimate sub-urban, food borne carbon and land footprints using multiregion-input-output modeling and nutritional surveys. Computer simulations utilizing primary data explored UF's ability to reduce these footprints using select farming technologies, building on previous city-scale UF assessments which have hitherto been dependent on proxy data for UF. We found that UF generated meagre food-related carbon footprint reductions (1.1-2.9% of baseline 2211 kg CO2 equivalents/capita/annum) and land occupation increases (<1% of baseline 9000 m2 land occupation/capita/annum) under optimal production scenarios, informing future evidence-based urban design and policy crafting in the region. Notwithstanding UF's marginal environmental gains, UF could help Boston meet national nutritional guidelines for vegetable intake, generate an estimated $160 million U.S. in revenue to growers and act as a pedagogical and community building tool, though these benefits would hinge on large-scale UF proliferation, likely undergirded by environmental remediation of marginal lands in the city. PMID- 28636339 TI - Binding Differences of Two Homochiral [Ru(bpy)2dppz]2+ Complexes with poly(U).poly(A)*poly(U) Triplex RNA. AB - The first investigation of chiral ruthenium(II) complexes Delta- and Lambda [Ru(bpy)2dppz]2+ and triplex RNA poly(U).poly(A)*poly(U) was carried out, which showed that Delta enantiomer displayed significant ability in stabilizing model triplex RNA. PMID- 28636340 TI - Three-Dimensional Modeling of Quasicrystal Structures from X-ray Diffraction: An Icosahedral Al-Cu-Fe Alloy. AB - Quasicrystals (QCs) are well-ordered but aperiodic crystals with classically forbidden symmetries (such as 5-fold). High-dimensional (HD) crystallography is a standard method to locate atom positions explicitly. However, in practice, it is still challenging because of its complexity. Here, we report a new simple approach to three-dimensional (3D) atomic modeling derived from X-ray diffraction data, and apply it to the icosahedral QC Al0.63Cu0.25Fe0.12. Electron density maps were calculated directly from 3D diffraction data indexed with noninteger (fractional) numbers as measured, with proper phases; each of 25 = 32 possible phase assignments for the five strongest reflections was used for Fourier synthesis. This resulted in an initial phasing model based on chemically sensible electron density maps. The following procedure was exactly the same as that used to determine ordinary crystal structures, except that fractional indices were assigned to the reciprocal vectors relative to the three orthogonal 2-fold axes in icosahedral (Ih) symmetry to which the observed diffraction data conformed. Finally, ~30 000 atoms were located within a sphere of a ~48 A radius. Structural motifs or basic repeating units with a hierarchical nature can be found. Isolated icosahedral clusters are surrounded by a concentric dodecahedron, beyond which there is a concentric truncated icosahedron. These are strikingly similar to those obtained via HD crystallography, but show very clear real-space relationships between the clusters. PMID- 28636342 TI - Charge Transfer Properties of Triarylamine Integrated Dimolybdenum Dyads. AB - Three quadruply bonded dimolybdenum complexes equipped with a triarylamine pendant, [(DAniF)3Mo2(MU-O2CC6H4N(C6H4CH3)2] (DAniF = N,N'-di(p anisyl)formamidinate; [OO-ph-N]), [(DAniF)3Mo2(MU-OSCC6H4N(C6H4CH3)2] ([OS-ph N]), and [(DAniF)3Mo2(MU-S2CC6H4N(C6H4CH3)2] ([SS-ph-N]), have been synthesized and characterized by single crystal X-ray diffraction. In electrochemical measurements, the redox couple for the organic amine group becomes irreversible, reflecting the substantially strong electronic interaction between the dimetal center and organic redox site. The potential difference for the two successive redox events, ca. DeltaE1/2(E1/2(2)(N/N*+) - E1/2(1)(Mo2IV/V)), falls in the range of 0.5-0.8 V as estimated from the differential pulse voltammograms. For the monocation radicals [OO-ph-N]+, [OS-ph-N]+, and [SS-ph-N]+, obtained by chemical oxidation of the neutral precursor, a broad ligand (amine) to metal (Mo2) charge transfer (LMCT) absorption band is observed in the near-IR region. Interestingly, analogous to the intervalence charge transfer (IVCT) bands for mixed-valence complexes, the LMCT absorption bands, which are solvent dependent, decrease in energy and bandwidth as the electronic coupling between the two redox sites increases in an order of increasing S content in the chelating group. The electronic coupling matrix elements (Hab) are determined by optical analyses from the generalized Mulliken-Hush (GMH) theory, falling in the range of 400-800 cm-1 in CH2Cl2. These results indicate that in these radical cations the charge is localized. Time-dependent DFT calculations show that the frontier molecular orbitals for these asymmetrical donor-acceptor systems have unbalanced distribution of electron density, and the LMCT bands arise from an electronic transition from the pendant ligand-based to metal-based molecular orbitals, corresponding to donor (N)-acceptor (Mo2) charge transfer. PMID- 28636341 TI - Biochemical Characterization of WbkC, an N-Formyltransferase from Brucella melitensis. AB - It has become increasingly apparent within the last several years that unusual N formylated sugars are often found on the O-antigens of such Gram negative pathogenic organisms as Francisella tularensis, Campylobacter jejuni, and Providencia alcalifaciens, among others. Indeed, in some species of Brucella, for example, the O-antigen contains 1,2-linked 4-formamido-4,6-dideoxy-alpha-d mannosyl groups. These sugars, often referred to as N-formylperosamine, are synthesized in pathways initiating with GDP-mannose. One of the enzymes required for the production of N-formylperosamine, namely, WbkC, was first identified in 2000 and was suggested to function as an N-formyltransferase. Its biochemical activity was never experimentally verified, however. Here we describe a combined structural and functional investigation of WbkC from Brucella melitensis. Four high resolution X-ray structures of WbkC were determined in various complexes to address its active site architecture. Unexpectedly, the quaternary structure of WbkC was shown to be different from that previously observed for other sugar N formyltransferases. Additionally, the structures revealed a second binding site for a GDP molecule distinct from that required for GDP-perosamine positioning. In keeping with this additional binding site, kinetic data with the wild type enzyme revealed complex patterns. Removal of GDP binding by mutating Phe 142 to an alanine residue resulted in an enzyme variant displaying normal Michaelis-Menten kinetics. These data suggest that this nucleotide binding pocket plays a role in enzyme regulation. Finally, by using an alternative substrate, we demonstrate that WbkC can be utilized to produce a trideoxysugar not found in nature. PMID- 28636343 TI - A Six-Coordinate Dysprosium Single-Ion Magnet with Trigonal-Prismatic Geometry. AB - A mononuclar six-coordinate dysprosium complex was synthesized and structurally and magnetically characterized. X-ray structural analyses show trigonal-prismatic coordination geometry of the DyIII center. Slow relaxation of magnetization in the absence of a direct-current field and magnetic hysteresis up to 3.0 K could be observed, indicating its single-ion-magnet behavior. Arrhenius fitting and ab initio calculations suggest that the magnetic relaxation process may not occur through the Orbach process at high temperatures under the experimental conditions. PMID- 28636345 TI - Levels of Organochlorine Pesticides Are Associated with Amyloid Aggregation in Apex Avian Brains. AB - Organochlorine (OC) pesticides pose a significant environmental risk to wildlife and humans and have been associated with Alzheimer's disease (AD). This study aims to spectroscopically analyze brains from free-flying birds and link the results to OC exposure and consequent amyloid aggregation. As long-lived apex predators, predatory birds represent a sentinel species similar to humans. Therefore, the results have implications for both species and may also add to our understanding of the role OC pesticides play in the development of AD. Brains of wild Sparrowhawks were analyzed using ATR-FTIR and Raman spectroscopy and Congo red staining; results were correlated with OC pesticide concentrations in livers. Effects of OC exposure were sex- and age-dependent and associated alterations were seen in lipids and protein secondary structure. A shift from alpha-helix to beta-sheet conformation of proteins indicated that concentrations of OC pesticides >7.18 MUg/g may lead to cerebral amyloid aggregation. PMID- 28636344 TI - Ruthenium Complexes are pH-Activated Metallo Prodrugs (pHAMPs) with Light Triggered Selective Toxicity Toward Cancer Cells. AB - Metallo prodrugs that take advantage of the inherent acidity surrounding cancer cells have yet to be developed. We report a new class of pH-activated metallo prodrugs (pHAMPs) that are activated by light- and pH-triggered ligand dissociation. These ruthenium complexes take advantage of a key characteristic of cancer cells and hypoxic solid tumors (acidity) that can be exploited to lessen the side effects of chemotherapy. Five ruthenium complexes of the type [(N,N)2Ru(PL)]2+ were synthesized, fully characterized, and tested for cytotoxicity in cell culture (1A: N,N = 2,2'-bipyridine (bipy) and PL, the photolabile ligand, = 6,6'-dihydroxybipyridine (6,6'-dhbp); 2A: N,N = 1,10 phenanthroline (phen) and PL = 6,6'-dhbp; 3A: N,N = 2,3-dihydro-[1,4]dioxino[2,3 f][1,10]phenanthroline (dop) and PL = 6,6'-dhbp; 4A: N,N = bipy and PL = 4,4' dimethyl-6,6'-dihydroxybipyridine (dmdhbp); 5A: N,N = 1,10-phenanthroline (phen) and PL = 4,4'-dihydroxybipyridine (4,4'-dhbp). The thermodynamic acidity of these complexes was measured in terms of two pKa values for conversion from the acidic form (XA) to the basic form (XB) by removal of two protons. Single-crystal X-ray diffraction data is discussed for 2A, 2B, 3A, 4B, and 5A. All complexes except 5A showed measurable photodissociation with blue light (lambda = 450 nm). For complexes 1A-4A and their deprotonated analogues (1B-4B), the protonated form (at pH 5) consistently gave faster rates of photodissociation and larger quantum yields for the photoproduct, [(N,N)2Ru(H2O)2]2+. This shows that low pH can lead to greater rates of photodissociation. Cytotoxicity studies with 1A-5A showed that complex 3A is the most cytotoxic complex of this series with IC50 values as low as 4 MUM (with blue light) versus two breast cancer cell lines. Complex 3A is also selectively cytotoxic, with sevenfold higher toxicity toward cancerous versus normal breast cells. Phototoxicity indices with 3A were as high as 120, which shows that dark toxicity is avoided. The key difference between complex 3A and the other complexes tested appears to be higher uptake of the complex as measured by inductively coupled plasma mass spectrometry, and a more hydrophobic complex as compared to 1A, which may enhance uptake. These complexes demonstrate proof of concept for dual activation by both low pH and blue light, thus establishing that a pHAMP approach can be used for selective targeting of cancer cells. PMID- 28636346 TI - Halogenated Flame Retardants in Predator and Prey Fish From the Laurentian Great Lakes: Age-Dependent Accumulation and Trophic Transfer. AB - The identification, persistence, accumulation and trophic transfer of 25 polybrominated diphenyl ether (PBDE) congeners, 23 non-PBDE halogenated flame retardants (NPHFRs), 4 polybrominated-diphenoxybenzenes (PB-DiPhOBzs) and 6 methoxylated (MeO-) PB-DiPhOBzs were investigated in predator and prey fish collected in 2010 from sites in the North American Great Lakes of Ontario (n = 26) and Erie (n = 39). Regardless of locations or species, 20 PBDEs and 12 NPHFRs were quantifiable in at least one of the 65 analyzed samples, and polybrominated 1,4-diphenoxybenzenes (PB-DiPhOBzs) and MeO-PB-DiPhOBzs were not detectable in any of analyzed samples. Among the FRs, the greatest concentrations were the ?PBDE, ranging from 1.06 (Rainbow Smelt, Lake Erie) to 162 (Lake Trout, Lake Ontario) ng/g wet weight (ww), which was followed by mean HBCDD concentrations ranging ND to 17.3 (Lake Trout, Lake Ontario) ng/g ww. The remaining FRs were generally not detectable or at sub-ppb levels. In most of cases, FR concentrations in samples from Lake Ontario were greater than those from Lake Erie. Strong and significant positive linear relationships occurred between log normalized FR concentrations (ww or lipid weight (lw)) and ages of the top predator Lake Trout (n = 16, from Lake Ontario), and the estimated FR doubling ages (T2) were 2.9-6.4 years. For Walleye from Lake Erie, significantly positive linear relationships were also observed for some FRs, but the linear relationships generally became negative after FR concentrations were normalized with lipid weight. This study provides novel information on FR accumulation in aquatic organisms, and for the first time, significant positive linear relationships are reported between log-normalized FR concentrations (lw or ww) and ages of Lake Trout from the Great Lakes. PMID- 28636347 TI - Structure and Dynamics of Alginate Gels Cross-Linked by Polyvalent Ions Probed via Solid State NMR Spectroscopy. AB - Alginate gels are an outstanding biomaterial widely applicable in tissue engineering, medicine, and pharmacy for cell transplantation, wound healing and efficient bioactive agent delivery, respectively. This contribution provides new and comprehensive insight into the atomic-resolution structure and dynamics of polyvalent ion-cross-linked alginate gels in microbead formulations. By applying various advanced solid-state NMR (ssNMR) spectroscopy techniques, we verified the homogeneous distribution of the cross-linking ions in the alginate gels and the high degree of ion exchange. We also established that the two-component character of the alginate gels arises from the concentration fluctuations of residual water molecules that are preferentially localized along polymer chains containing abundant mannuronic acid (M) residues. These hydrated M-rich blocks tend to self aggregate into subnanometer domains. The resulting coexistence of two types of alginate chains differing in segmental dynamics was revealed by 1H-13C dipolar profile analysis, which indicated that the average fluctuation angles of the stiff and mobile alginate segments were about 5-9 degrees or 30 degrees , respectively. Next, the 13C CP/MAS NMR spectra indicated that the alginate polymer microstructure was strongly dependent on the type of cross-linking ion. The polymer chain regularity was determined to systematically decrease as the cross-linking ion radius decreased. Consistent with the 1H-1H correlation spectra, regular structures were found for the gels cross-linked by relatively large alkaline earth cations (Ba2+, Sr2+, or Ca2+), whereas the alginate chains cross-linked by bivalent transition metal ions (Zn2+) and trivalent metal cations (Al3+) exhibited significant irregularities. Notably, however, the observed disordering of the alginate chains was exclusively attributed to the M residues, whereas the structurally well-defined gels all contained guluronic acid (G) residues. Therefore, a key role of the units in M-rich blocks as mediators promoting the self-assembly of alginate chains was experimentally confirmed. Finally, combining 2D 27Al 3Q/MAS NMR spectroscopy with density functional theory (DFT) calculations provided previously unreported insight into the structure of the Al3+ cross-linking centers. Notably, even with a low residual amount of water, these cross-linking units adopt exclusively 6-fold octahedral coordination and exhibit significant motion, which considerably reduces quadrupolar coupling constants. Thus, the experimental strategy presented in this study provides a new perspective on cross-linked alginate structure and dynamics for which high quality diffraction data at the atomic resolution level are inherently unavailable. PMID- 28636349 TI - Water Dynamics from the Surface to the Interior of a Supramolecular Nanostructure. AB - Water within and surrounding the structure of a biological system adopts context specific dynamics that mediate virtually all of the events involved in the inner workings of a cell. These events range from protein folding and molecular recognition to the formation of hierarchical structures. Water dynamics are mediated by the chemistry and geometry of interfaces where water and biomolecules meet. Here we investigate experimentally and computationally the translational dynamics of vicinal water molecules within the volume of a supramolecular peptide nanofiber measuring 6.7 nm in diameter. Using Overhauser dynamic nuclear polarization relaxometry, we show that drastic differences exist in water motion within a distance of about one nanometer from the surface, with rapid diffusion in the hydrophobic interior and immobilized water on the nanofiber surface. These results demonstrate that water associated with materials designed at the nanoscale is not simply a solvent, but rather an integral part of their structure and potential functions. PMID- 28636350 TI - Integrating a Semitransparent, Fullerene-Free Organic Solar Cell in Tandem with a BiVO4 Photoanode for Unassisted Solar Water Splitting. AB - We report an unassisted solar water splitting system powered by a diketopyrrolopyrrole (DPP)-containing semitransparent organic solar cell. Two major merits of this fullerene-free solar cell enable its integration with a BiVO4 photoanode. First is the high open circuit voltage and high fill factor displayed by this single junction solar cell, which yields sufficient power to effect water splitting when serially connected to an appropriate electrode/catalyst. Second, the wavelength-resolved photoaction spectrum of the DPP-based solar cell has minimal overlap with that of the BiVO4 photoanode, thus ensuring that light collection across these two components can be optimized. The latter feature enables a new water splitting device configuration wherein the solar cell is placed first in the path of incident light, before the BiVO4 photoanode, although BiVO4 has a wider bandgap. This configuration is accessed by replacing the reflective top electrode of the standard DPP-based solar cell with a thin metal film and an antireflection layer, thus rendering the solar cell semitransparent. In this configuration, incident light does not travel through the aqueous electrolyte to reach the solar cell or photoanode, and therefore, photon losses due to the scattering of water are reduced. Moreover, this new configuration allows the BiVO4 photoanode to be back-illuminated, i.e., through the BiVO4/back contact interface, which leads to higher photocurrents compared to front illumination. The combination of a semitransparent single-junction solar cell and a BiVO4 photoanode coated with oxygen evolution catalysts in a new device configuration yielded an unassisted solar water splitting system with a solar-to-hydrogen conversion efficiency of 2.2% in water. PMID- 28636348 TI - Development of an Aryloxazole Class of Hepatitis C Virus Inhibitors Targeting the Entry Stage of the Viral Replication Cycle. AB - Reliance on hepatitis C virus (HCV) replicon systems and protein-based screening assays has led to treatments that target HCV viral replication proteins. The model does not encompass other viral replication cycle steps such as entry, processing, assembly and secretion, or viral host factors. We previously applied a phenotypic high-throughput screening platform based on an infectious HCV system and discovered an aryloxazole-based anti-HCV hit. Structure-activity relationship studies revealed several compounds exhibiting EC50 values below 100 nM. Lead compounds showed inhibition of the HCV pseudoparticle entry, suggesting a different mode of action from existing HCV drugs. Hit 7a and lead 7ii both showed synergistic effects in combination with existing HCV drugs. In vivo pharmacokinetics studies of 7ii showed high liver distribution and long half-life without obvious hepatotoxicity. The lead compounds are promising as preclinical candidates for the treatment of HCV infection and as molecular probes to study HCV pathogenesis. PMID- 28636351 TI - Heats of Formation of Medium-Sized Organic Compounds from Contemporary Electronic Structure Methods. AB - Computational electronic structure calculations are routinely undertaken to predict thermodynamic properties of various species. However, the application of highly accurate wave function theory methods, such as the "gold standard" coupled cluster approach including single, double, and partly triple excitations in perturbative fashion, CCSD(T), to large molecules is limited due to high computational cost. In this work, the promising domain based local pair natural orbital coupled cluster approach, DLPNO-CCSD(T), has been tested to reproduce 113 accurate formation enthalpies of medium-sized molecules (few dozens heavy atoms) important for bio- and combustion chemistry via the reaction based Feller Peterson-Dixon approach. For comparison, eight density functional theory (B3LYP, B3LYP-D3, PBE0, PBE0-D3, M06, M06-2X, omegaB97X-D3, and omegaB97M-V) and MP2 based (B2PLYP-D3, PWPB95-D3, B2T-PLYP, B2T-PLYP-D, B2GP-PLYP, DSD-PBEP86-D3, SCS MP2, and OO-SCS-MP2) methods have been tested. The worst performance has been obtained for the standard hybrid DFT functionals, PBE0 (mean unsigned error (MUE)/mean signed error (MSE) = 9.1/6.0 kcal/mol) and B3LYP (MUE/MSE = 13.5/-13.3 kcal/mol). The influence of an empirical dispersion correction term on these functionals' performance is not homogeneous: B3LYP performance is improved (B3LYP D3 (MUE/MSE = 6.0/0.8 kcal/mol)); meanwhile PBE0 performance is worse (PBE0-D3 (MUE/MSE = 14.1/13.6 kcal/mol)). The Minnesota functionals, M06 (MUE/MSE = 3.8/ 2.0 kcal/mol) and M06-2X (MUE/MSE = 3.5/3.0 kcal/mol), and recently developed omegaB97X-D3 (MUE/MSE = 3.2/0.2 kcal/mol) and omegaB97M-V (MUE/MSE = 2.2/1.3 kcal/mol) methods provided significantly better formation enthalpies. Enthalpies of similar quality can also be obtained from some double hybrid methods (B2PLYP D3 (MUE/MSE = 4.7/2.0 kcal/mol), PWPB95-D3 (MUE/MSE = 4.3/3.2 kcal/mol), B2T-PLYP (MUE/MSE = 4.1/-3.0 kcal/mol), and B2T-PLYP-D (MUE/MSE = 3.3/1.7 kcal/mol)). The two spin component scaled (SCS) MP2 methods resulted in even smaller errors (SCS MP2 (MUE/MSE = 1.9/1.2 kcal/mol) and OO-SCS-MP2 (MUE/MSE = 1.6/0.1 kcal/mol)). The best performance was found for the frozen core (FC) DLPNO-CCSD(T) method with a MUE/MSE of 1.6/-1.2 kcal/mol. The performance of the DLPNO-CCSD(T) method can be further improved by running the post-SCF calculations on the B3LYP orbitals: the MUE/MSE for the DLPNO-CCSD(T,B3LYP) approximation is 1.2/-0.4 kcal/mol. We recommend the DLPNO-CCSD(T,B3LYP) method for black box applications in thermodynamics of medium-sized organic molecules when the canonical CCSD(T) calculations with basis sets of reasonable quality are prohibitively expensive. PMID- 28636352 TI - Prevention of Marine Biofouling Using the Natural Allelopathic Compound Batatasin III and Synthetic Analogues. AB - The current study reports the first comprehensive evaluation of a class of allelopathic terrestrial natural products as antifoulants in a marine setting. To investigate the antifouling potential of the natural dihydrostilbene scaffold, a library of 22 synthetic dihydrostilbenes with varying substitution patterns, many of which occur naturally in terrestrial plants, were prepared and assessed for their antifouling capacity. The compounds were evaluated in an extensive screen against 16 fouling marine organisms. The dihydrostilbene scaffold was shown to possess powerful general antifouling effects against both marine microfoulers and macrofoulers with inhibitory activities at low concentrations. The species of microalgae examined displayed a particular sensitivity toward the evaluated compounds at low ng/mL concentrations. It was shown that several of the natural and synthetic compounds exerted their repelling activities via nontoxic and reversible mechanisms. The activities of the most active compounds such as 3,5 dimethoxybibenzyl (5), 3,4-dimethoxybibenzyl (9), and 3-hydroxy-3',4,5' trimethoxybibenzyl (20) were comparable to the commercial antifouling booster biocide Sea-nine, which was employed as a positive control. The investigation of terrestrial allelopathic natural products to counter marine fouling represents a novel strategy for the design of "green" antifouling technologies, and these compounds offer a potential alternative to traditional biocidal antifoulants. PMID- 28636353 TI - Synthesis of 8-Substituted Analogues of Cyclic ADP-4-Thioribose and Their Unexpected Identification as Ca2+-Mobilizing Full Agonists. AB - A series of 8-substituted analogues of cyclic ADP-4-thioribose (cADPtR, 3), which is a stable equivalent of Ca2+-mobilizing second messenger cyclic ADP-ribose (cADPR, 1), were designed as potential pharmacological tools for studies on cADPR modulated Ca2+ signaling pathways. These 8-amino analogue (8-NH2-cADPtR, 4), 8 azido analogue (8-N3-cADPtR, 5), and 8-chloro analogue (8-Cl-cADPtR, 6) were efficiently synthesized, where the stereoselective N1-beta-thioribosyladenine ring closure reaction via an alpha/beta-equilibrium of the 1-aminothioribose derivative and construction of the characteristic 18-membered pyrophosphate ring by Ag+-promoted activation of a phenyl phosphorothioate type substrate were the two key steps. Although 8-NH2-cADPR (2) is a well-known potent antagonist against cADPR-inducing Ca2+-release, the 4-thioribose congener 8-NH2-cADPtR turned out unexpectedly to be a full agonist in sea urchin egg homogenate evaluation system. This important finding suggested that the ring-oxygen in the N1-ribose of cADPR analogues is essential for the antagonistic activity in the Ca2+-signaling pathway, which can contribute to clarify the structure-agonist/antagonist activity relationship. PMID- 28636354 TI - Rational Design of Lithium-Sulfur Battery Cathodes Based on Experimentally Determined Maximum Active Material Thickness. AB - Rational design of conductive carbon hosts for high energy density lithium-sulfur batteries requires an understanding of the fundamental limitations to insulating active material loading. In this work, we investigate the electrochemistry of lithium sulfide films ranging in thickness from 30 to 3500 nm. We show that films thicker than approximately 40 nm cannot be charged at local charge densities above 1 MUA cm-2, and by implication, the maximum useful pore diameter is near 60 nm in a practical cathode. "Activation" overpotentials for Li2S are identified in thicker films, resulting from polysulfide generation, but are shown not to improve the fundamental areal charge limitations. We develop a model for filling of conductive pores with active material to rationally design composites based on local charge density. For low-electrolyte applications, the importance of matching micropore volume to sulfide loading and cycling rate is emphasized. PMID- 28636355 TI - Semisynthetic Flavone-Derived Antimicrobials with Therapeutic Potential against Methicillin-Resistant Staphylococcus aureus (MRSA). AB - A new series of semisynthetic flavone-based small molecules mimicking antimicrobial peptides has been designed from natural icaritin to combat drug resistant Gram-positive bacterial infections. Compound 6 containing two arginine residues exhibited excellent antibacterial activity against Gram-positive bacteria, including MRSA, and very low toxicity to mammalian cells, resulting in a high selectivity of more than 511, comparable to that of several membrane active antibiotics in clinical trials. Our data show for the first time that icaritin derivatives effectively kill bacteria. Meanwhile, this is the first study deploying a biomimicking strategy to design potent flavone-based membrane targeting antimicrobials. 6 showed rapid bactericidal activity by disrupting the bacterial membrane and can circumvent the development of bacterial resistance. Importantly, 6 was highly efficacious in a mouse model of corneal infection caused by MRSA and Staphylococcus aureus. PMID- 28636356 TI - Biomimetic Architectured Graphene Aerogel with Exceptional Strength and Resilience. AB - Materials combining lightweight, robust mechanical performances, and multifunctionality are highly desirable for engineering applications. Graphene aerogels have emerged as attractive candidates. Despite recent progresses, the bottleneck remains how to simultaneously achieve both strength and resilience. While multiscale architecture designs may offer a possible route, the difficulty lies in the lack of design guidelines and how to experimentally achieve the necessary structure control over multiple length scales. The latter is even more challenging when manufacturing scalability is taken into account. The Thalia dealbata stem is a naturally porous material that is lightweight, strong, and resilient, owing to its architecture with three-dimensional (3D) interconnected lamellar layers. Inspired by such, we assemble graphene oxide (GO) sheets into a similar architecture using a bidirectional freezing technique. Subsequent freeze drying and thermal reduction results in graphene aerogels with highly tunable 3D architectures, consequently an unusual combination of strength and resilience. With their additional electrical conductivity, these graphene aerogels are potentially useful for mechanically switchable electronics. Beyond such, our study establishes bidirectional freezing as a general method to achieve multiscale architectural control in a scalable manner that can be extended to many other material systems. PMID- 28636357 TI - Correction to alpha-Glucosidase Inhibitory and Cytotoxic Taxane Diterpenoids from the Stem Bark of Taxus wallichiana. PMID- 28636358 TI - Transferable Atom-Centered Potentials for the Correction of Basis Set Incompleteness Errors in Density-Functional Theory. AB - Recent progress in the accurate calculation of noncovalent interactions has enabled density-functional theory (DFT) to model systems relevant in biological and supramolecular chemistry. The application of DFT methods using atom-centered Gaussian basis sets to large systems is limited by the number of basis functions required to accurately model thermochemistry and, in particular, weak intermolecular interactions. Basis set incompleteness error (BSIE) arising from the use of incomplete basis sets leads to erroneous intermolecular energies, bond dissociation energies, and structures. In this article, we develop a correction for BSIE in DFT calculations using basis set incompleteness potentials (BSIP). BSIPs are atom-based one-electron potentials (ACPs) with the same functional form as effective core potentials (ECP) that are designed to correct the effects of BSIE in properties that are linear mappings of the energy. We present a systematic way of developing general, error-correcting ACPs and apply this technique to generate BSIPs for eight common elements in organic and biological systems (H, C, N, O, F, P, S, and Cl). Two BSIPs were optimized for use with the scaled MINI (MINIs) and MINIs(d) basis sets and were designed to correct for the impacts of BSIE on noncovalent binding energies and intra/intermolecular geometries. BSIPs developed for use with 6-31G*, pc-1, and 6-31+G** basis sets also correct for the effects of BSIE on bond dissociation energies, which enables the study of chemical reactions in very large systems. BSIPs can be used with any density functional in any electronic structure program that implements ECPs. Our BSIPs add very little to the computational cost provided an efficient ECP implementation is used. Our results support the use of BLYP-D3/MINIs-BSIP as a computationally inexpensive and more accurate alternative to other approaches (e.g., B3LYP/6-31G* and BP86/6-31G*) in protein and supramolecular structural studies. PMID- 28636359 TI - Relativistic Approximations to Paramagnetic NMR Chemical Shift and Shielding Anisotropy in Transition Metal Systems. AB - We apply approximate relativistic methods to calculate the magnetic property tensors, i.e., the g-tensor, zero-field splitting (ZFS) tensor (D), and hyperfine coupling (HFC) tensors, for the purpose of constructing paramagnetic nuclear magnetic resonance (pNMR) shielding tensors. The chemical shift and shielding anisotropy are calculated by applying a modern implementation of the classic Kurland-McGarvey theory ( J. Magn. Reson. 1970 , 2 , 286 ), which formulates the shielding tensor in terms of the g- and HFC tensors obtained for the ground multiplet, in the case of higher than doublet multiplicity defined by the ZFS interaction. The g- and ZFS tensors are calculated by ab initio complete active space self-consistent field and N-electron valence-state perturbation theory methods with spin-orbit (SO) effects treated via quasidegenerate perturbation theory. Results obtained with the scalar relativistic (SR) Douglas-Kroll-Hess Hamiltonian used for the g- and ZFS tensor calculations are compared with nonrelativistically based computations. The HFC tensors computed using the fully relativistic four-component matrix Dirac-Kohn-Sham approach are contrasted against perturbationally SO-corrected nonrelativistic results in the density functional theory framework. These approximations are applied on paramagnetic metallocenes (MCp2) (M = Ni, Cr, V, Mn, Co, Rh, Ir), a Co(II) pyrazolylborate complex, and a Cr(III) complex. SR effects are found to be small for g and D in these systems. The HFCs are found to be more influenced by relativistic effects for the 3d systems. However, for some of the 3d complexes, nonrelativistic calculations give a reasonable agreement with the experimental chemical shift and shielding anisotropy. The influence of scalar relativity is strong for the 5d IrCp2 system. This mixed ab initio/DFT technique, with a fully relativistic method used for the critical HFC tensor, should be useful for the treatment of both electron correlation and relativistic effects at a reasonable computational cost to compute the pNMR shielding tensors in transition metal systems. PMID- 28636360 TI - Proneurogenic Effects of Trazodone in Murine and Human Neural Progenitor Cells. AB - Several antidepressants increase adult hippocampal neurogenesis (ahNG) in rodents, primates, and, potentially, humans. This effect may at least partially account for their therapeutic activity. The availability of antidepressants whose mechanism of action involves different neurotransmitter receptors represents an opportunity for increasing our knowledge on their distinctive peculiarities and for dissecting the contribution of receptor subtypes in ahNG modulation. The aim of this study was to evaluate, in vitro, the effects of the antidepressant trazodone (TZD) on ahNG by using primary cultures of murine adult hippocampal neural progenitor cells (ahNPCs) and human induced pluripotent stem cell (iPSC) derived NPCs. We demonstrated that TZD enhances neuronal differentiation of murine as well as human NPCs. TZD is a multimodal antidepressant, which binds with high affinity to 5-HT2a, alpha1, and 5-HT1a and with lower affinity to 5 HT2c, alpha2 and 5-HTT. We demonstrated that TZD proneurogenic effects were mediated by 5-HT2a antagonism both in murine and in human NPCs and by 5-HT2c antagonism in murine cells. Moreover NF-kappaB p50 nuclear translocation appeared to be required for TZD-mediated proneurogenic effects. Interestingly, TZD had no proneurogenic effects in 5-HT depleted ahNPCs. The TDZ bell-shaped dose-response curve suggested additional effects. However, in our model 5-HT1a and alpha1/alpha2 receptors had no role in neurogenesis. Overall, our data also demonstrated that serotoninergic neurotransmission may exert both positive and negative effects on neuronal differentiation of ahNPCs in vitro. PMID- 28636362 TI - Corey-Chaykovsky Reactions of Nitro Styrenes Enable cis-Configured Trifluoromethyl Cyclopropanes. AB - Trifluoromethyl-substituted cyclopropanes are an attractive family of building blocks for the construction of pharmaceutical and agrochemical agents. This work demonstrated the utilization of fluorinated sulfur ylides as versatile reagents for Corey-Chaykovsky cyclopropanation reactions of nitro styrenes. This protocol favored the synthesis of cis-configured trifluoromethyl cyclopropanes for a broad range of substrates with excellent yields and good diastereoselectivities. PMID- 28636361 TI - Machine-Learning-Assisted Approach for Discovering Novel Inhibitors Targeting Bromodomain-Containing Protein 4. AB - Bromodomain-containing protein 4 (BRD4) is implicated in the pathogenesis of a number of different cancers, inflammatory diseases and heart failure. Much effort has been dedicated toward discovering novel scaffold BRD4 inhibitors (BRD4is) with different selectivity profiles and potential antiresistance properties. Structure-based drug design (SBDD) and virtual screening (VS) are the most frequently used approaches. Here, we demonstrate a novel, structure-based VS approach that uses machine-learning algorithms trained on the priori structure and activity knowledge to predict the likelihood that a compound is a BRD4i based on its binding pattern with BRD4. In addition to positive experimental data, such as X-ray structures of BRD4-ligand complexes and BRD4 inhibitory potencies, negative data such as false positives (FPs) identified from our earlier ligand screening results were incorporated into our knowledge base. We used the resulting data to train a machine-learning model named BRD4LGR to predict the BRD4i-likeness of a compound. BRD4LGR achieved a 20-30% higher AUC-ROC than that of Glide using the same test set. When conducting in vitro experiments against a library of previously untested, commercially available organic compounds, the second round of VS using BRD4LGR generated 15 new BRD4is. Moreover, inverting the machine-learning model provided easy access to structure-activity relationship (SAR) interpretation for hit-to-lead optimization. PMID- 28636364 TI - Charge-Shift Corrected Electronegativities and the Effect of Bond Polarity and Substituents on Covalent-Ionic Resonance Energy. AB - Bond dissociation energies and resonance energies for HnA-BHm molecules (A, B = H, C, N, O, F, Cl, Li, and Na) have been determined in order to re-evaluate the concept of electronegativity in the context of modern valence bond theory. Following Pauling's original scheme and using the rigorous definition of the covalent-ionic resonance energy provided by the breathing orbital valence bond method, we have derived a charge-shift corrected electronegativity scale for H, C, N, O, F, Cl, Li, and Na. Atomic charge shift character is defined using a similar approach resulting in values of 0.42, 1.06, 1.43, 1.62, 1.64, 1.44, 0.46, and 0.34 for H, C, N, O, F, Cl, Li, and Na, respectively. The charge-shift corrected electronegativity values presented herein follow the same general trends as Pauling's original values with the exception of Li having a smaller value than Na (1.57 and 1.91 for Li and Na respectively). The resonance energy is then broken down into components derived from the atomic charge shift character and polarization effects. It is then shown that most of the resonance energy in the charge-shift bonds H-F, H3C-F, and Li-CH3 and borderline charge-shift H-OH is associated with polarity rather than the intrinsic atomic charge-shift character of the bonding species. This suggests a rebranding of these bonds as "polar charge-shift" rather than simply "charge-shift". Lastly, using a similar breakdown method, it is shown that the small effect the substituents -CH3, -NH2, OH, and -F have on the resonance energy (<10%) is mostly due to changes in the charge-shift character of the bonding atom. PMID- 28636365 TI - Sustainable Elastomers from Renewable Biomass. AB - Sustainable elastomers have undergone explosive growth in recent years, partly due to the resurgence of biobased materials prepared from renewable natural resources. However, mounting challenges still prevail: How can the chemical compositions and macromolecular architectures of sustainable polymers be controlled and broadened? How can their processability and recyclability be enabled? How can they compete with petroleum-based counterparts in both cost and performance? Molecular-biomass-derived polymers, such as polymyrcene, polymenthide, and poly(epsilon-decalactone), have been employed for constructing thermoplastic elastomers (TPEs). Plant oils are widely used for fabricating thermoset elastomers. We use abundant biomass, such as plant oils, cellulose, rosin acids, and lignin, to develop elastomers covering a wide range of structure property relationships in the hope of delivering better performance. In this Account, recent progress in preparing monomers and TPEs from biomass is first reviewed. ABA triblock copolymer TPEs were obtained with a soft middle block containing a soybean-oil-based monomer and hard outer blocks containing styrene. In addition, a combination of biobased monomers from rosin acids and soybean oil was formulated to prepare triblock copolymer TPEs. Together with the above mentioned approaches based on block copolymers, multigraft copolymers with a soft backbone and rigid side chains are recognized as the first-generation and second generation TPEs, respectively. It has been recently demonstrated that multigraft copolymers with a rigid backbone and elastic side chains can also be used as a novel architecture of TPEs. Natural polymers, such as cellulose and lignin, are utilized as a stiff, macromolecular backbone. Cellulose/lignin graft copolymers with side chains containing a copolymer of methyl methacrylate and butyl acrylate exhibited excellent elastic properties. Cellulose graft copolymers with biomass derived polymers as side chains were further explored to enhance the overall sustainability. Isoprene polymers were grafted from a cellulosic backbone to afford Cell-g-polyisoprene copolymers. Via cross-linking of these graft copolymers, human-skin-mimic elastomers and high resilient elastomers with a well defined network structure were achieved. The mechanical properties of these resilient elastomers could be finely controlled by tuning the cellulose content. As isoprene can be produced by engineering of microorganisms, these elastomers could be a renewable alternative to petroleum products. In summary, triblock copolymer and graft copolymer TPEs with biomass components, skin-mimic elastomers, high resilient biobased elastomers, and engineering of macromolecular architectures for elastomers are discussed. These approaches and design provide us knowledge on the potential to make sustainable elastomers for various applications to compete with petroleum-based counterparts. PMID- 28636363 TI - Distinct Protein Hydration Water Species Defined by Spatially Resolved Spectra of Intermolecular Vibrations. AB - In this molecular dynamics simulation study, we analyze intermolecular vibrations in the hydration shell of a solvated enyzme, the membrane type 1-matrix metalloproteinase, with high spatial resolution. Our approach allows us to characterize vibrational signatures of the local hydrogen bond network, the translational mobility of water molecules, as well as the molecular entropy, in specific local environments. Our study demonstrates the heterogeneity of water properties within the hydration shell of a complex biomolecule. We define a classification scheme based on the vibrational density of states that allows us to distinguish separate classes of hydration water species and facilitates the description of hydration water properties at distinct hydration sites. The results demonstrate that no single characteristic of the protein surface is sufficient to determine the properties of nearby water. The protein surface geometry, quantified here by the number of protein atoms in the vicinity of a hydration water molecule, as well as the chemical nature of a solvated protein functional group, influences dynamic and thermodynamic properties of solvating water molecules. PMID- 28636366 TI - Oxygenation via C-H/C-C Bond Activation with Molecular Oxygen. AB - The selective oxidation of organic molecules is a fundamentally important component of modern synthetic chemistry. In the past decades, direct oxidative C H and C-C bond functionalization has proved to be one of the most efficient and straightforward methods to synthesize complex products from simple and readily available starting materials. Among these oxidative processes, the use of molecular oxygen as a green and sustainable oxidant has attracted considerable attention because of its highly atom-economical, abundant, and environmentally friendly characteristics. The development of new protocols using molecular oxygen as an ideal oxidant is highly desirable in oxidation chemistry. More importantly, the oxygenation reaction of simple molecules using molecular oxygen as the oxygen source offers one of the most ideal processes for the construction of O containing compounds. Aerobic oxidation and oxygenation by enzymes, such as monooxygenase, tyrosinase, and dopamine beta-monooxygenase, have been observed in some biological C-H bond hydroxylation processes. Encouraged by these biological transformations, transition-metal- or organocatalyst-catalyzed oxygenation through dioxygen activation has attracted academic and industrial prospects. In this Account, we describe some advances from our group in oxygenation via C-H/C-C bond activation with molecular oxygen as the oxidant and oxygen source for the synthesis of O-containing compounds. Under an atmosphere of O2 (1 atm) or air (1 atm), we have successfully incorporated one or two O atoms from O2 into simple and readily available substrates through C-H, C-C, C?C, and C=C bond cleavage by transition-metal catalysis, organocatalysis, and photocatalysis. Moreover, we have devised cyclization reactions with molecular oxygen to construct O heterocycles. Most of these transformations can tolerate a broad range of functional groups. Furthermore, on the basis of isotope labeling experiments, electron paramagnetic resonance spectral analysis, and other mechanistic studies, we have demonstrated that a single electron transfer process via a carbon radical, peroxide radical, or hydroxyl radical is involved in these aerobic oxidation and oxygenation reactions. These protocols provide new approaches for the green synthesis of various alpha-keto amides, alpha-keto esters, esters, ketones, aldehydes, formamides, 2-oxoacetamidines, 2-(1H)-pyridones, phenols, tertiary alpha-hydroxy carbonyls, p-quinols, beta-azido alcohols, benzyl alcohols, tryptophols, and oxazoles, which have potential applications in the preparation of natural products, bioactive compounds, and functional materials. In most cases, inexpensive and low-toxicity Cu, Fe, Mn, or NHPI was found to be an efficient catalyst for the transformation. The high efficiency, low cost, high oxygen atom economy, broad substrate scope, and practical operation make the developed oxygenation system very attractive and practical. Moreover, the design of new types of molecular-oxygen- or air-based oxidation and oxygenation reactions can be anticipated. PMID- 28636367 TI - Cobalt-Catalyzed Regioselective Ortho C(sp2)-H Bond Nitration of Aromatics through Proton-Coupled Electron Transfer Assistance. AB - A cobalt-catalyzed proton-coupled electron transfer (PCET) mediated regioselective ortho-specific nitration of aromatic C(sp2)-H bonds using chelation-assisted removable vicinal diamine directing groups was developed. The reaction proceeded under mild conditions in the presence of Co(OAc)2.4H2O as the catalyst with AgNO2 utilized as the nitro source as well as terminal oxidant in the presence of O2 as an external oxidant. No external base or additives were required for this process. Controlled experiments and mechanistic investigations with DFT calculations revealed that the reaction proceeds through a PCET promoted nitro functional group transfer pathway. Moreover, the produced compounds are valuable and pharmaceutically quite relevant. PMID- 28636368 TI - Probing the Mechanism of LAL-32, a Gold Nanoparticle-Based Antibiotic Discovered through Small Molecule Variable Ligand Display. AB - The unrelenting rise of antimicrobial-resistant bacteria has necessitated the search for novel antibiotic solutions. Herein we describe further mechanistic studies on a 2.0-nm-diameter gold nanoparticle-based antibiotic (designated LAL 32). This antibiotic exhibits bactericidal activity against the Gram-negative bacterium Escherichia coli at 1.0 MUM, a concentration significantly lower than several clinically available antibiotics (such as ampicillin and gentamicin), and acute treatment with LAL-32 does not give rise to spontaneous resistant mutants. LAL-32 treatment inhibits cellular division, daughter cell separation, and twin arginine translocation (Tat) pathway dependent shuttling of proteins to the periplasm. Furthermore, we have found that the cedA gene imparts increased resistance to LAL-32, and shown that an E. coli cedA transposon mutant exhibits increased susceptibility to LAL-32. Taken together, these studies further implicate cell division pathways as the target for this nanoparticle-based antibiotic and demonstrate that there may be inherently higher barriers for resistance evolution against nanoscale antibiotics in comparison to their small molecule counterparts. PMID- 28636369 TI - Dynamics of Charged Species in Ionic-Neutral Block Copolymer and Surfactant Complexes. AB - Structure-property relationships of ionic block copolymer (BCP) surfactant complexes are critical toward the progress of favorable engineering design of efficient charge-transport materials. In this article, molecular dynamics simulations are used to understand the dynamics of charged-neutral BCP and surfactant complexes. The dynamics are examined for two different systems: charged-neutral double-hydrophilic and hydrophobic-hydrophilic block copolymers with oppositely charged surfactant moieties. The dynamics of the surfactant head, tails, and charges are studied for five different BCP volume fractions. We observe that the dynamics of the different species solely depend on the balance between electrostatic and entropic interactions between the charged species and the neutral monomers. The favorable hydrophobic-hydrophobic interactions and the unfavorable hydrophobic-hydrophilic interactions determine the mobilities of the monomers. The dynamical properties of the charge species influence complex formation. Structural relaxations exhibit length-scale dependent behavior, with slower relaxation at the radius of gyration length-scale and faster relaxation at the segmental length-scale, consistent with previous results. The dynamical analysis correlates ion-exchange kinetics to the self-assembly behavior of the complexes. PMID- 28636370 TI - Access to Fused Tricyclic gamma-Butyrolactones, A Natural Product-like Scaffold. AB - Serendipitous findings of an acid mediated skeletal rearrangement of bicyclo-beta ketoester having cyclopropyl ring to access fused tricyclic gamma-butyrolactones has been described. This novel transformation has been optimized to 30 mol% p toluenesulfonic acid (p-TSA) in toluene using Dean-Stark apparatus, where the aldol condensation, cyclopropyl ring opening followed by cyclization took place in a single-pot operation. The resulting tricyclic compounds are interesting chemotype with natural product resemblance and may find useful applications in the future. PMID- 28636372 TI - Surface Desorption Dielectric-Barrier Discharge Ionization Mass Spectrometry. AB - A variant of dielectric-barrier discharge named surface desorption dielectric barrier discharge ionization (SDDBDI) mass spectrometry was developed for high efficiency ion transmission and high spatial resolution imaging. In SDDBDI, a tungsten nanotip and the inlet of the mass spectrometer are used as electrodes, and a piece of coverslip is used as a sample plate as well as an insulating dielectric barrier, which simplifies the configuration of instrument and thus the operation. Different from volume dielectric-barrier discharge (VDBD), the microdischarges are generated on the surface at SDDBDI, and therefore the plasma density is extremely high. Analyte ions are guided directly into the MS inlet without any deflection. This configuration significantly improves the ion transmission efficiency and thus the sensitivity. The dependence of sensitivity and spatial resolution of the SDDBDI on the operation parameters were systematically investigated. The application of SDDBDI was successfully demonstrated by analysis of multiple species including amino acids, pharmaceuticals, putative cancer biomarkers, and mixtures of both fatty acids and hormones. Limits of detection (S/N = 3) were determined to be 0.84 and 0.18 pmol, respectively, for the analysis of l-alanine and metronidazole. A spatial resolution of 22 MUm was obtained for the analysis of an imprinted cyclophosphamide pattern, and imaging of a "T" character was successfully demonstrated under ambient conditions. These results indicate that SDDBDI has high-efficiency ion transmission, high sensitivity, and high spatial resolution, which render it a potential tool for mass spectrometry imaging. PMID- 28636374 TI - Correction to "Rate Coefficients of the HCl + OH -> Cl + H2O Reaction from Ring Polymer Molecular Dynamics". PMID- 28636373 TI - Total Synthesis of the Marine Polyketide (-)-Gracilioether F. AB - First asymmetric synthesis of the marine natural product (-)-gracilioether F is described from a d-mannitol derived known compound. The key step involves intramolecular 1,4-conjugate addition of a hydroxymethyl radical generated from Ti (III) mediated ring opening of a terminal epoxy ring tethered to a butenolide to produce stereoselectively a five-membered ring fused bicyclic lactone, the core structure present in gracilioether F. PMID- 28636371 TI - Iron Oxidation and Core Formation in Recombinant Heteropolymeric Human Ferritins. AB - In animals, the iron storage and detoxification protein, ferritin, is composed of two functionally and genetically distinct subunit types, H (heavy) and L (light), which co-assemble in various ratios with tissue specific distributions to form shell-like protein structures of 24 subunits within which a mineralized iron core is stored. The H-subunit possesses a ferroxidase center (FC) that catalyzes Fe(II) oxidation, whereas the L-subunit does not. To assess the role of the L subunit in iron oxidation and core formation, two human recombinant heteropolymeric ferritins, designated H-rich and L-rich with ratios of ~20H:4L and ~22L:2H, respectively, were employed and compared to the human homopolymeric H-subunit ferritin (HuHF). These heteropolymeric ferritins have a composition similar to the composition of those found in hearts and brains (i.e., H-rich) and in livers and spleens (i.e., L-rich). As for HuHF, iron oxidation in H-rich ferritin was found to proceed with a 2:1 Fe(II):O2 stoichiometry at an iron level of 2 Fe(II) atoms/H-subunit with the generation of H2O2. The H2O2 reacted with additional Fe(II) in a 2:1 Fe(II):H2O2 ratio, thus avoiding the production of hydroxyl radical. A MU-1,2-peroxo-diFe(III) intermediate was observed at the FC of H-rich ferritin as for HuHF. Importantly, the H-rich protein regenerated full ferroxidase activity more rapidly than HuHF did and additionally formed larger iron cores, indicating dual roles for the L-subunit in facilitating iron turnover at the FC and in mineralization of the core. The L-rich ferritin, while also facilitating iron oxidation at the FC, additionally promoted oxidation at the mineral surface once the iron binding capacity of the FC was exceeded. PMID- 28636375 TI - One-Pot Synthesis of Functionalized Carbazoles via a CAN-Catalyzed Multicomponent Process Comprising a C-H Activation Step. AB - The microwave-promoted three-component reaction between o-nitrochalcones, primary amines and beta-dicarbonyl compounds in the presence of Ce(IV) ammonium nitrate constitutes the first example of a multicomponent carbazole synthesis. This reaction furnishes highly substituted and functionalized carbazole derivatives via a double annulation process that generates two C-C and two C-N bonds, with water as the only side product. Mechanistically, this transformation has some unusual features that include an intramolecular coupled hydrogenation dehydrogenation process, the functionalization of a C-H group by direct attack onto a nitrogen function and a CAN-catalyzed reduction via hydride transfer from ethanol. The mechanisms of these reactions were studied with the aid of computational techniques. PMID- 28636376 TI - On the Mechanism of the Iodide-Triiodide Exchange Reaction in a Solid-State Ionic Liquid. AB - Efficient charge transport has been observed in iodide-based room-temperature ionic liquids when doped with iodine. To investigate preferred pathways for the iodide (I-)-to-triiodide (I3-) exchange reaction and to clarify the origin of this high ionic conductivity, we have conducted electronic structure calculations in the crystal state of 1-butyl-3-methylimidazolium iodide ([BMIM][I]). Energy barriers for the different stages of the iodine-swapping process, including the reorientation of the I-...I3- moiety, were determined from minimum energy paths as a function of a reaction coordinate. Hirshfeld charges and structural parameters, such as bond lengths and angles, were monitored during the reaction. Several bond-exchange events were observed with energy barriers ranging from 0.17 to 0.48 eV and coinciding with the formation of a twisted I-...I3- complex. Striking similarities were observed in the mechanics and energetics of this charge-transfer process in relation to solid-state superionic conductors. PMID- 28636377 TI - Enthalpies of Formation of Hydrazine and Its Derivatives. AB - Enthalpies of formation, DeltafH298 degrees , in both the gas and condensed phase, and enthalpies of sublimation or vaporization have been estimated for hydrazine, NH2NH2, and its 36 various derivatives using quantum chemical calculations. The composite G4 method has been used along with isodesmic reaction schemes to derive a set of self-consistent high-accuracy gas-phase enthalpies of formation. To estimate the enthalpies of sublimation and vaporization with reasonable accuracy (5-20 kJ/mol), the method of molecular electrostatic potential (MEP) has been used. The value of DeltafH298 degrees (NH2NH2,g) = 97.0 +/- 3.0 kJ/mol was determined from 75 isogyric reactions involving about 50 reference species; for most of these species, the accurate DeltafH298 degrees (g) values are available in Active Thermochemical Tables (ATcT). The calculated value is in excellent agreement with the reported results of the most accurate models based on coupled cluster theory (97.3 kJ/mol, the average of six calculations). Thus, the difference between the values predicted by high-level theoretical calculations and the experimental value of DeltafH298 degrees (NH2NH2,g) = 95.55 +/- 0.19 kJ/mol recommended in the ATcT and other comprehensive reference sources is sufficiently large and requires further investigation. Different hydrazine derivatives have been also considered in this work. For some of them, both the enthalpy of formation in the condensed phase and the enthalpy of sublimation or vaporization are available; for other compounds, experimental data for only one of these properties exist. Evidence of accuracy of experimental data for the first group of compounds was provided by the agreement with theoretical DeltafH298 degrees (g) value. The unknown property for the second group of compounds was predicted using the MEP model. This paper presents a systematic comparison of experimentally determined enthalpies of formation and enthalpies of sublimation or vaporization with the results of calculations. Because of relatively large uncertainty in the estimated enthalpies of sublimation, it was not always possible to evaluate the accuracy of the experimental values; however, this model allowed us to detect large errors in the experimental data, as in the case of 5,5'-hydrazinebistetrazole. The enthalpies of formation and enthalpies of sublimation or vaporization have been predicted for the first time for ten hydrazine derivatives with no experimental data. A recommended set of self consistent experimental and calculated gas-phase enthalpies of formation of hydrazine derivatives can be used as reference DeltafH298 degrees (g) values to predict the enthalpies of formation of various hydrazines by means of isodesmic reactions. PMID- 28636378 TI - What Is the Structure of the Antitubercular Natural Product Eucapsitrione? AB - 1,5,7-Trihydroxy-6H-indeno[1,2-b]anthracene-6,11,13-trione (1), proposed to be the antitubercular natural product eucapsitrione, has been synthesized in 43% overall yield and six steps, including a key Suzuki-Miyaura biaryl coupling and a directed remote metalation (DReM)-initiated cyclization. The physical and spectroscopic properties of 1 do not match the data reported for the natural product. At this time there is insufficient information available to enable a structure reassignment. During the optimization of the Suzuki-Miyaura coupling, an unprecedented biaryl coupling ortho to the borono group was observed. The scope of this unusual reaction has been investigated. PMID- 28636379 TI - A One-Pot Assembly of Fully Substituted Alkyl 5-Aminothiophene-2-carboxylates from Allenes, Isothiocyanates, and Alkyl 2-Bromoacetates. AB - A novel simple approach to highly functionalized multisubstituted thiophenes such as alkyl 4-alkoxy-5-amino-3-methylthiophene-2-carboxylates through the one-pot sequential reaction of alpha-lithiated alkoxyallenes with isothiocyanates and alkyl 2-bromoacetates has been discovered. The process proceeds quickly (30-45 min) via in situ formation and intramolecular cyclization of alkyl 2-[(2 alkoxybuta-2,3-dienimidoyl)sulfanyl]acetates (1-aza-1,3,4-trienes). PMID- 28636380 TI - Free-Radical-Promoted Copper-Catalyzed Decarboxylative Alkylation of alpha,beta Unsaturated Carboxylic Acids with ICH2CF3 and Its Analogues. AB - A novel and efficient free-radical-promoted copper-catalyzed decarboxylative alkylation of alpha,beta-unsaturated carboxylic acids with ICH2CF3 and its analogues has been developed. This methodology provides a convenient access to the synthesis of allylic trifluoromethyl and beta-CF3 ketone containing compounds as well as other biologically useful fluorinated molecules and materials. PMID- 28636381 TI - Density Functional Study of Trimetallic AuxPdyPtz (x + y + z = 7) Clusters and Their Interactions with the O2 Molecule. AB - Density functional theory calculations were performed to investigate the structural and energetic properties of trimetallic AuxPdyPtz clusters with x + y + z = 7. The possible stable geometrical configurations with their electronic states are determined. We analyze the chemical order, binding energies, vertical ionization potential, electron affinity, and HOMO-LUMO gaps as a function of the whole concentration range. The affinity of AuxPdyPtz clusters toward one O2 molecule is also evaluated in terms of the changes in geometry, adsorption energy, and charge transfer. PMID- 28636382 TI - Development of Efficient Chemistry to Generate Site-Specific Disulfide-Linked Protein- and Peptide-Payload Conjugates: Application to THIOMAB Antibody-Drug Conjugates. AB - Conjugation of small molecule payloads to cysteine residues on proteins via a disulfide bond represents an attractive strategy to generate redox-sensitive bioconjugates, which have value as potential diagnostic reagents or therapeutics. Advancement of such "direct-disulfide" bioconjugates to the clinic necessitates chemical methods to form disulfide connections efficiently, without byproducts. The disulfide connection must also be resistant to premature cleavage by thiols prior to arrival at the targeted tissue. We show here that commonly employed methods to generate direct disulfide-linked bioconjugates are inadequate for addressing these challenges. We describe our efforts to optimize direct-disulfide conjugation chemistry, focusing on the generation of conjugates between cytotoxic payloads and cysteine-engineered antibodies (i.e., THIOMAB antibody-drug conjugates, or TDCs). This work culminates in the development of novel, high yielding conjugation chemistry for creating direct payload disulfide connections to any of several Cys mutation sites in THIOMAB antibodies or to Cys sites in other biomolecules (e.g., human serum albumin and cell-penetrating peptides). We conclude by demonstrating that hindered direct disulfide TDCs with two methyl groups adjacent to the disulfide, which have heretofore not been described for any bioconjugate, are more stable and more efficacious in mouse tumor xenograft studies than less hindered analogs. PMID- 28636384 TI - Role of Crystal Structure and Chalcogenide Redox Properties on the Oxidative Assembly of Cadmium Chalcogenide Nanocrystals. AB - Oxidative assembly of metal chalcogenide nanocrystals (NCs) enables the formation of 2-D (dense) and 3-D porous structures without the presence of intervening ligands between particles that can moderate transport properties. This route has been demonstrated to be successful for a range of single-component structures including CdQ, PbQ, and ZnQ (Q = S, Se, Te). En route to the controllable assembly of multicomponent nanostructures, the roles of Q redox properties (2Q2- > Q22- + 2e) responsible for particle cross-linking and the native structure (cubic zinc blende vs hexagonal wurtzite) in the kinetics of assembly in single component CdQ NCs are evaluated using time-resolved dynamic light scattering (TR DLS). For wurtzite CdQ, the rates follow the ease of oxidation, with telluride as the fastest, followed by selenide and sulfide. However, when comparing CdS wurtzite (w) and zinc blende (zb), the cubic NCs exhibit surprisingly slow kinetics. NMR studies reveal the zb structure to have lower ligand coverage (by a factor of 4) relative to that of w, and the formation of free disulfide (the product of ligand oxidation) is slow. This is attributed to differences in the surface energies of w and zb facets, with w having polar (0001) facets of high energy compared to the neutral facets of the zb structure. The zb-CdS NCs prepared by low-temperature synthesis methods are likely to suffer from surface defects that may moderate reactivity. EPR studies suggest that zb-CdS has paramagnetic sulfur vacancies not present in w-CdS. These data suggest that structure plays an unexpectedly large role in the kinetics of CdQ NC oxidative assembly, providing a useful lever to moderate activities in multicomponent assemblies. PMID- 28636385 TI - Sequential Catalysis of Phosphine Oxide for Stereoselective Synthesis of Stereopentads. AB - An efficient method for accessing enantiomerically pure stereopentads via a catalytic asymmetric sequential aldol reaction has been developed for the first time. The enantioselective sequential aldol reaction produces a wide range of chiral stereopentad precursors in good yields with excellent enantioselectivities. The key to success is the use of the sequential catalytic system involving a chiral phosphine oxide catalyst and trichlorosilyl triflate. PMID- 28636383 TI - Gene Expression Profiling in Human Lung Cells Exposed to Isoprene-Derived Secondary Organic Aerosol. AB - Secondary organic aerosol (SOA) derived from the photochemical oxidation of isoprene contributes a substantial mass fraction to atmospheric fine particulate matter (PM2.5). The formation of isoprene SOA is influenced largely by anthropogenic emissions through multiphase chemistry of its multigenerational oxidation products. Considering the abundance of isoprene SOA in the troposphere, understanding mechanisms of adverse health effects through inhalation exposure is critical to mitigating its potential impact on public health. In this study, we assessed the effects of isoprene SOA on gene expression in human airway epithelial cells (BEAS-2B) through an air-liquid interface exposure. Gene expression profiling of 84 oxidative stress and 249 inflammation-associated human genes was performed. Our results show that the expression levels of 29 genes were significantly altered upon isoprene SOA exposure under noncytotoxic conditions (p < 0.05), with the majority (22/29) of genes passing a false discovery rate threshold of 0.3. The most significantly affected genes belong to the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor network. The Nrf2 function is confirmed through a reporter cell line. Together with detailed characterization of SOA constituents, this study reveals the impact of isoprene SOA exposure on lung responses and highlights the importance of further understanding its potential health outcomes. PMID- 28636386 TI - MsViz: A Graphical Software Tool for In-Depth Manual Validation and Quantitation of Post-translational Modifications. AB - Mass spectrometry (MS) has become the tool of choice for the large scale identification and quantitation of proteins and their post-translational modifications (PTMs). This development has been enabled by powerful software packages for the automated analysis of MS data. While data on PTMs of thousands of proteins can nowadays be readily obtained, fully deciphering the complexity and combinatorics of modification patterns even on a single protein often remains challenging. Moreover, functional investigation of PTMs on a protein of interest requires validation of the localization and the accurate quantitation of its changes across several conditions, tasks that often still require human evaluation. Software tools for large scale analyses are highly efficient but are rarely conceived for interactive, in-depth exploration of data on individual proteins. We here describe MsViz, a web-based and interactive software tool that supports manual validation of PTMs and their relative quantitation in small- and medium-size experiments. The tool displays sequence coverage information, peptide spectrum matches, tandem MS spectra and extracted ion chromatograms through a single, highly intuitive interface. We found that MsViz greatly facilitates manual data inspection to validate PTM location and quantitate modified species across multiple samples. PMID- 28636387 TI - Novel Kiteplatin Pyrophosphate Derivatives with Improved Efficacy. AB - Two new Pt(II) derivatives of kiteplatin ([PtCl2(cis-1,4-DACH)]) with pyrophosphate as carrier ligand, one mononuclear (1) and one dinuclear (2), were synthesized with the aim of potentiating the efficacy of kiteplatin. Complex 1 resulted to be remarkably stable at physiological pH, but it undergoes a fast hydrolysis reaction at acidic pH releasing free pyrophosphate and (aquated) kiteplatin. The dinuclear compound 2 resulted to be less stable than 1 at both neutral and acidic pH forming 1 and (aquated) kiteplatin as first step. Both compounds (1 and 2) do not react as such with 5'-GMP, whereas their hydrolysis products readily form adducts with the nucleotide. The in vitro cytotoxicity assays against a panel of six human cancer cell lines showed that complex 2 affects cancer cell viability even at nanomolar concentrations. The cytotoxic activity of 2 is greater (up to 2 orders of magnitude) than that of cisplatin, oxaliplatin, and kiteplatin, whereas the mononuclear complex 1 has shown a cytotoxic activity comparable to that of oxaliplatin and kiteplatin, but higher than cisplatin. The latter result is not surprising, since the presence of two negative charges reduces the uptake of 1 into the tumor cells as compared to the neutral compound 2. The remarkable activity of 2 against the pancreatic cell line BxPC3 (average IC50 = 0.07 MUM) deserves further investigation. PMID- 28636388 TI - Correlation between Photoluminescence and Carrier Transport and a Simple In Situ Passivation Method for High-Bandgap Hybrid Perovskites. AB - High-bandgap mixed-halide hybrid perovskites have higher open-circuit voltage deficits and lower carrier diffusion lengths than their lower-bandgap counterparts. We have developed a ligand-assisted crystallization (LAC) technique that introduces additives in situ during the solvent wash and developed a new method to dynamically measure the absolute intensity steady-state photoluminescence and the mean carrier diffusion length simultaneously. The measurements reveal four distinct regimes of material changes and show that photoluminescence brightening often coincides with losses in carrier transport, such as in degradation or phase segregation. Further, the measurements enabled optimization of LAC on the 1.75 eV bandgap FA0.83Cs0.17Pb(I0.66Br0.34)3, resulting in an enhancement of the photoluminescence quantum yield (PLQY) of over an order of magnitude, an increase of 80 meV in the quasi-Fermi level splitting (to 1.29 eV), an increase in diffusion length by a factor of 3.5 (to over 1 MUm), and enhanced open-circuit voltage and short-circuit current from photovoltaics fabricated from the LAC-treated films. PMID- 28636390 TI - Application of a Heterogeneous Chiral Titanium Catalyst Derived from Silica Supported 3-Aryl H8-BINOL to Enantioselective Alkylation and Arylation of Aldehydes. AB - A 3-aryl H8-BINOL was grafted on the surface of silica gel using a hydrosilane derivative as a precursor, and the resulting silica-supported ligand (6 mol %) was employed in the enantioselective alkylation and arylation of aldehydes in the presence of Ti(OiPr)4. The reactions using Et2Zn, Et3B, and aryl Grignard reagents all afforded the corresponding adducts in high enantioselectivities and yields. The silica-immobilized titanium catalyst could be reused up to 14 times without appreciable deterioration of the activity. PMID- 28636389 TI - Tumor Microenvironment-Responsive Multistaged Nanoplatform for Systemic RNAi and Cancer Therapy. AB - While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, the effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core. When the rationally designed, long circulating polymeric NPs accumulate in tumor tissues after intravenous administration, the targeted siRNA-TCPA complexes can be rapidly released via TME pH-mediated NP disassembly for subsequent specific targeting of tumor cells and cytosolic transport, thus achieving efficient gene silencing. In vivo results further demonstrate that the multistaged NP delivery of siRNA against bromodomain 4 (BRD4), a recently discovered target protein that regulates the development and progression of prostate cancer (PCa), can significantly inhibit PCa tumor growth. PMID- 28636392 TI - Hybrid CPU/GPU Integral Engine for Strong-Scaling Ab Initio Methods. AB - We present a parallel integral algorithm for two-electron contributions occurring in Hartree-Fock and hybrid density functional theory that allows for a strong scaling parallelization on inhomogeneous compute clusters. With a particular focus on graphic processing units, we show that our approach allows an efficient use of CPUs and graphics processing units (GPUs) simultaneously, although the different architectures demand conflictive strategies in order to ensure efficient program execution. Furthermore, we present a general strategy to use large basis sets like quadruple-zeta split valence on GPUs and investigate the balance between CPUs and GPUs depending on l-quantum numbers of the corresponding basis functions. Finally, we present first illustrative calculations using a hybrid CPU/GPU environment and demonstrate the strong-scaling performance of our parallelization strategy also for pure CPU-based calculations. PMID- 28636391 TI - Copper-Catalyzed Direct Nitration on Aryl C-H Bonds by Concomitant Azidation Oxidation with TMS Azide and TBHP under Aerobic Conditions. AB - An unprecedented copper-catalyzed in situ azidation-oxidation for the nitration of anilides and sulfonamides has been developed by direct CAr-H functionalization. This novel and efficient nitration protocol is achieved employing TMSN3 and TBHP without the exclusion of air or moisture. The synthetic applications of the 2-nitroanilides have been explored. PMID- 28636393 TI - Lithium Ion Coupled Electron-Transfer Rates in Superconcentrated Electrolytes: Exploring the Bottlenecks for Fast Charge-Transfer Rates with LiMn2O4 Cathode Materials. AB - The charge-transfer kinetics of lithium ion intercalation into LixMn2O4 cathode materials was examined in dilute and concentrated aqueous and carbonate LiTFSI solutions using electrochemical methods. Distinctive trends in ion intercalation rates were observed between water-based and ethylene carbonate/diethyl carbonate solutions. The influence of the solution concentration on the rate of lithium ion transfer in aqueous media can be tentatively attributed to the process associated with Mn dissolution, whereas in carbonate solutions the rate is influenced by the formation of a concentration-dependent solid electrolyte interface (SEI). Some indications of SEI layer formation at electrode surfaces in carbonate solutions after cycling are detected by X-ray photoelectron spectroscopy. The general consequences related to the application of superconcentrated electrolytes for use in advanced energy storage cathodes are outlined and discussed. PMID- 28636394 TI - Synthesis of RNA 5'-Azides from 2'-O-Pivaloyloxymethyl-Protected RNAs and Their Reactivity in Azide-Alkyne Cycloaddition Reactions. AB - Commercially available 2'-O-pivaloyloxymethyl (PivOM) phosphoramidites were employed in an SPS protocol for RNA 5' azides. The utility of the N3-RNAs in CuAAC and SPAAC was demonstrated by RNA 5' labeling, chemical ligation including fragment joining and cyclization, and bioconjugation. As a result, several new RNA conjugates that may be valuable tools for studies on biological events such as innate immune response (cyclic dinucleotides), post-transcriptional gene regulation (circular RNAs), or mRNA turnover (m7G capped RNAs) were obtained. PMID- 28636395 TI - Synthesis of the Marine Myxobacterial Antibiotic Enhygrolide A. AB - The first synthesis of enhygrolide A, a scarce gamma-alkylidenebutenolide antibiotic of the obligate marine myxobacterium Enhygromyxa salina, was achieved in five steps and 54% overall yield from tetronic acid. Key steps include (i) organocatalytic reductive alkylation, (ii) iron-catalyzed sp2-sp3 cross-coupling, and (iii) vinylogous aldol condensation. Aside from its brevity and reliance on environmentally sustainable processes, the synthesis demonstrates the serviceability of butenolide pivalates in cross-coupling reactions. PMID- 28636396 TI - Copper-Catalyzed Asymmetric Protoboration of beta-Amidoacrylonitriles and beta Amidoacrylate Esters: An Efficient Approach to Functionalized Chiral alpha-Amino Boronate Esters. AB - A copper-catalyzed asymmetric protoboration of both Z-beta-amidoacrylonitriles and ethyl E-beta-amidoacrylates using bis(pinacolato)diboron has been developed for the first time. The process tolerates a vast array of substrates, delivering a series of stable functionalized chiral alpha-amino boronate esters in good yields and enantioselectivities under mild reaction conditions. The current method is also applicable for gram-scale synthesis without erosion of enantioselectivity. This work provides an attractive and complementary approach to synthesizing enantioriched chiral alpha-amino boronate esters. PMID- 28636398 TI - Ultrafast Carrier Trapping in Thick-Shell Colloidal Quantum Dots. AB - It has previously been found that Auger processes can lead to femtosecond carrier trapping in quantum dots, limiting their performance in optoelectronic applications that rely on radiative recombination. Using atomistic simulations, we investigate whether a shell can protect carriers from Auger-assisted trapping. For these studies we investigate CdSe/CdS core-shell quantum dots having total diameters reaching up to 10 nm. We find trapping lifetimes as fast as 1 ps for 2 nm shells, and we report that shells as thick as 6 nm are required to suppress trapping fully. The most efficient recombination mechanism is found to proceed through shallow empty traps, suggesting it can be suppressed by filling the traps through doping or external electrochemical potential. Our findings suggest that to achieve efficient light emission, surface traps have to be completely eliminated, even in thick-shell quantum dots. PMID- 28636397 TI - Comparison of the Structural Response to Pressure of Ionic Liquids with Ether and Alkyl Functionalities. AB - The response of ionic liquids to external perturbations including elevated pressure is a topic of current interest for applications such as tribology. Ionic liquids come in many classes, including those that are amphiphilic and some that are mostly polar having either cationic or anionic tails that are functionalized. The current study compares the effect of elevated pressure on two ionic liquids with different types of cationic tail. 1-Decyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (C10mim+/NTf2-) is amphiphilic whereas isoelectronic ether-functionalized 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3 methylimidazolium bis(trifluoromethylsulfonyl)amide (C7O3mim+/NTf2-) has cationic tails that are more polar and conformationally different. We find that the response to elevated pressure for these two systems is quite unsimilar. Intramolecular conformational changes as well as changes in the structure of liquid nanodomains appear to be significantly more prominent in the case of C10mim+/NTf2-. Whereas both the density of C10mim+/NTf2- and C7O3mim+/NTf2- change at elevated pressure, the change is more dramatic for C10mim+/NTf2-. The very different response for each of these two types of ionic liquids can be clearly gleaned from distribution functions in real space and the partial subcomponents of the X-ray structure function, S(q), in reciprocal space. Liquid structure in the case of C7O3mim+/NTf2-, and the intramolecular conformational structure of C7O3mim+ in particular, appear to be more resilient to pressure changes than those in the isoelectronic amphiphilic analogue. PMID- 28636399 TI - Helium Accepts Back-Donation In Highly Polar Complexes: New Insights into the Weak Chemical Bond. AB - We studied the puzzling stability and short distances predicted by theory for helium adducts with some highly polar molecules, such as BeO or AuF. On the basis of high-level quantum-chemical calculations, we carried out a detailed analysis of the charge displacement occurring upon adduct formation. For the first time we have unambiguously ascertained that helium is able not only to donate electron density, but also, unexpectedly, to accept electron density in the formation of weakly bound adducts with highly polar substrates. The presence of a large dipole moment induces a large electric field at He, which lowers its 2p orbital energy and enables receipt of pi electron density. These findings offer unprecedented important clues toward the design and synthesis of stable helium compounds. PMID- 28636400 TI - Click Biotinylation of PLGA Template for Biotin Receptor Oriented Delivery of Doxorubicin Hydrochloride in 4T1 Cell-Induced Breast Cancer. AB - PLGA was functionalized with PEG and biotin using click chemistry to generate a biotin receptor targeted copolymer (biotinylated-PEG-PLGA) which in turn was used to fabricate ultrafine nanoparticles (BPNP) of doxorubicin hydrochloride (DOX) for effective delivery in 4T1 cell induced breast cancer. However, adequate entrapment of a hydrophilic bioactive like DOX in a hydrophobic polymer system made of PLGA is not usually possible. We therefore modified a conventional W/O/W emulsion method by utilizing NH4Cl in the external phase to constrain DOX in dissolved polymer phase by suppressing DOX's inherent aqueous solubility as per common ion effect. This resulted in over 8-fold enhancement in entrapment efficiency of DOX inside BPNP, which otherwise is highly susceptible to leakage due to its relatively high aqueous solubility. TEM and DLS established BPNP to be sized below 100 nm, storage stability studies showed that BPNP were stable for one month at 4 degrees C, and in vitro release suggested significant control in drug release. Extensive in vitro and in vivo studies were conducted to propound anticancer and antiproliferative activity of BPNP. Plasma and tissue distribution study supplemented by pertinent in vivo fluorescence imaging mapped the exact fate of DOX contained inside BPNP once it was administered intravenously. A comparative safety profile via acute toxicity studies in mice was also generated to out rightly establish usefulness of BPNP. Results suggest that BPNP substantially enhance anticancer activity of DOX while simultaneously mitigating its toxic potential due to altered spatial and temporal presentation of drug and consequently deserve further allometric iteration. PMID- 28636401 TI - One-Step Solvothermal Synthesis of Petalous Carbon-Coated Cu+-Doped CdS Nanocomposites with Enhanced Photocatalytic Hydrogen Production. AB - Metal ion doping and nanocoating a CdS photocatalyst have been proven to be effective strategies to inhibit photocorrosion and improve photocatalytic performance. In this study, carbon-coated Cu+-doped CdS nanocomposites (C-Cu-CdS) with a stable petalous structure and highly uniform size distribution were successfully synthesized via a facile one-step solvothermal method. Both Cu+ doping and carbon coating to the CdS photocatalyst are realized in this one-step strategy. Benefiting from the unique core-shell structure and metal ion doping, the as-prepared C-Cu-CdS catalyst exhibits significantly enhanced photostability and visible-light-driven photocatalytic efficiency. For an optimal Cu+ doping percentage of 1.0%, an average hydrogen production rate of 2796 MUmol h-1 g-1 and an apparent quantum efficiency of 16.0% at a wavelength of 420 nm was observed, the latter of which is nearly 9.3 times higher than that of the carbon-coated CdS product without Cu+ doping. The origin of the improved photocatalytic activity is systematically investigated by examining the effects of Cu+ doping. PMID- 28636402 TI - A Chiral Pentenolide-Based Unified Strategy toward Dihydrocorynantheal, Dihydrocorynantheol, Protoemetine, Protoemetinol, and Yohimbane. AB - An organocatalytic cross-aldol reaction of formaldehyde (formalin) with alkyl aldehydes, followed by the Z-selective Horner-Wadsworth-Emmons (HWE) reaction and immediate lactonization, afforded gamma-alkylated pentenolides in good overall yields and excellent enantioselectivities. Based on this scalable sequence, five quinolizidine alkaloids were synthesized in a unified and concise manner. The development of an in situ activation of a tertiary amide to improve the efficiency of the Bischler-Napieraiski (B-N) reaction was also noteworthy due to the generality to sensitive substrates for a variety of target molecules. PMID- 28636404 TI - Examining the Association Between Health Literacy and Medication Adherence Among Older Adults. AB - Health literacy plays a vital role in patients' understanding of their prescribed medication instructions. To inform strategies to assist providers in communicating in a manner that is easily understood by patients, it would be beneficial to determine the relationship between health literacy and the day-to day aspects of medication adherence. This study identified: 1) differences of health literacy levels in medication adherence; 2) the association between health literacy and medication adherence; and 3) and factors associated with medication adherence score. A convenience sample of older predominantly African-American patients (N = 389), over the age of 60, completed a cross-sectional survey. Chi square analysis assessed health literacy differences in five aspects of medication adherence. Ordinary linear regression analysis determined factors associated with medication adherence score. Patients with limited health literacy were more likely to forget to take their medications and more likely to take less medication than instructed than patients with adequate health literacy (chi2(5) = 15.91, p = .007, chi2(5) = 10.31, p = .036, respectively). REALM score was also significantly associated with medication adherence score (beta= .016, p < .001, beta = .009, p = .033), respectively). Findings suggest that providers seeking to improve medication adherence in older adults, particularly African-American patients, should focus communication on assessing health literacy levels prior to discussing medication instructions. PMID- 28636403 TI - Applying Precision Medicine to Trial Design Using Physiology. Extracorporeal CO2 Removal for Acute Respiratory Distress Syndrome. AB - In clinical trials of therapies for acute respiratory distress syndrome (ARDS), the average treatment effect in the study population may be attenuated because individual patient responses vary widely. This inflates sample size requirements and increases the cost and difficulty of conducting successful clinical trials. One solution is to enrich the study population with patients most likely to benefit, based on predicted patient response to treatment (predictive enrichment). In this perspective, we apply the precision medicine paradigm to the emerging use of extracorporeal CO2 removal (ECCO2R) for ultraprotective ventilation in ARDS. ECCO2R enables reductions in tidal volume and driving pressure, key determinants of ventilator-induced lung injury. Using basic physiological concepts, we demonstrate that dead space and static compliance determine the effect of ECCO2R on driving pressure and mechanical power. This framework might enable prediction of individual treatment responses to ECCO2R. Enriching clinical trials by selectively enrolling patients with a significant predicted treatment response can increase treatment effect size and statistical power more efficiently than conventional enrichment strategies that restrict enrollment according to the baseline risk of death. To support this claim, we simulated the predicted effect of ECCO2R on driving pressure and mortality in a preexisting cohort of patients with ARDS. Our computations suggest that restricting enrollment to patients in whom ECCO2R allows driving pressure to be decreased by 5 cm H2O or more can reduce sample size requirement by more than 50% without increasing the total number of patients to be screened. We discuss potential implications for trial design based on this framework. PMID- 28636405 TI - Conventional Polysomnography Is Not Necessary for the Management of Most Patients with Suspected Obstructive Sleep Apnea. Noninferiority, Randomized Controlled Trial. AB - RATIONALE: Home respiratory polygraphy may be a simpler alternative to in laboratory polysomnography for the management of more symptomatic patients with obstructive sleep apnea, but its effectiveness has not been evaluated across a broad clinical spectrum. OBJECTIVES: To compare the long-term effectiveness (6 mo) of home respiratory polygraphy and polysomnography management protocols in patients with intermediate-to-high sleep apnea suspicion (most patients requiring a sleep study). METHODS: A multicentric, noninferiority, randomized controlled trial with two open parallel arms and a cost-effectiveness analysis was performed in 12 tertiary hospitals in Spain. Sequentially screened patients with sleep apnea suspicion were randomized to respiratory polygraphy or polysomnography protocols. Moreover, both arms received standardized therapeutic decision-making, continuous positive airway pressure (CPAP) treatment or a healthy habit assessment, auto-CPAP titration (for CPAP indication), health-related quality-of life questionnaires, 24-hour blood pressure monitoring, and polysomnography at the end of follow-up. The main outcome was the Epworth Sleepiness Scale measurement. The noninferiority criterion was -2 points on the Epworth scale. MEASUREMENTS AND MAIN RESULTS: In total, 430 patients were randomized. The respiratory polygraphy protocol was noninferior to the polysomnography protocol based on the Epworth scale. Quality of life, blood pressure, and polysomnography were similar between protocols. Respiratory polygraphy was the most cost effective protocol, with a lower per-patient cost of 416.7?. CONCLUSIONS: Home respiratory polygraphy management is similarly effective to polysomnography, with a substantially lower cost. Therefore, polysomnography is not necessary for most patients with suspected sleep apnea. This finding could change established clinical practice, with a clear economic benefit. Clinical trial registered with www.clinicaltrials.gov (NCT 01752556). PMID- 28636406 TI - Protective Effect of Intravitreal Administration of Exosomes Derived from Mesenchymal Stem Cells on Retinal Ischemia. AB - PURPOSE: Exosomes derived from human mesenchymal stem cells (hMSCs) cultured under hypoxic conditions contain proteins and growth factors that promote angiogenesis. This study investigated the effect of intravitreal administration of these exosomes on retinal ischemia using a murine model. METHODS: Oxygen induced retinopathy (OIR) was induced by exposing one-week-old male C57BL/6J mice to 5 days of 75% hyperoxic conditioning, and returning to room air. After hyperoxic conditioning, the right eye of each mouse was injected intravitreally with 1 ul saline or exosomes derived from hMSCs and compared to control mice of the same age raised in room air without OIR injected intravitreally with saline. Two weeks post-injection, fluorescein angiography (FA) and phase-variance optical coherence tomography angiography (pvOCTA) were used to assess retinal perfusion. Retinal thickness was determined by OCT. The extent of retinal neovascularization was quantitated histologically by counting vascular nuclei on the retinal surface. RESULTS: Among eyes with OIR, intravitreal exosome treatment partially preserved retinal vascular flow in vivo and reduced associated retinal thinning; retinal thickness on OCT was 111.1 +/- 7.4um with saline versus 132.1 +/- 11.6um with exosome, p < 0.001. Retinal neovascularization among OIR eyes was reduced with exosome treatment when compared to saline-treated eyes (7.75 +/- 3.68 versus 2.68 +/- 1.35 neovascular nuclei per section, p < 0.0001). No immunogenicity or ocular/systemic adverse effect was associated with intravitreal exosome treatment. CONCLUSIONS: Intravitreal administration of exosomes derived from hMSCs was well tolerated without immunosuppression and decreased the severity of retinal ischemia in this murine model. This appealing novel non-cellular therapeutic approach warrants further exploration. PMID- 28636407 TI - Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary. AB - Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD. PMID- 28636408 TI - Pattern Visual Evoked Potential, Pattern Electroretinogram, and Retinal Nerve Fiber Layer Thickness in Patients with Migraine during and after Aura. AB - PURPOSE: To study pattern visual evoked potential (PVEP), pattern electroretinogram (PERG), and retinal nerve fiber layer (RNFL) thickness in patients with migraine during and after aura. MATERIALS AND METHODS: We included 60 eyes of 60 patients with migraine (Group 1) and 30 healthy volunteers (30 eyes) as controls (Group 2). Group 1 was studied twice, during a visual aura (1 a) and in between attacks (1-b). All participants underwent full ophthalmological examination, PVEP, PERG, and optical coherence tomographyOCT imaging of the RNFL thickness for each patient. RESULTS: RNFL thickness was found to be thinner in patients during the aura compared to controls. It increased significantly post aura but remained lower than the controls. Prolonged P100 latency and decreased amplitude were found in patients during aura compared to controls with significant change in between attacks to values comparable to the controls. We found prolonged N95 latency and decreased amplitude in patients during aura compared to controls with significant change post-aura to values comparable to the controls. There was positive correlation between average RNFL thicknesses and VA and spherical equivalent; but it showed negative correlation with duration of migraine, attack duration, and aura duration. Multiple regression analysis showed that the most important determinants of average RNFL thickness in patients of migraine were attack and aura duration (beta = -0.21 and -0.26 and p = 0.03 and 0.04, respectively). CONCLUSION: Migraine attacks impose both functional and structural retinal changes. The functional changes are fully reversible after the aura but not the structural ones. So, vigorous prevention of migraine attacks would be protective for retina. PMID- 28636409 TI - Subjective well-being of visually impaired older adults living in the community. AB - OBJECTIVES: Vision impairment is one of the most common disabilities among older adults, and it has a substantial impact on well-being. The present study constructs an integrative model to identify which variables derived from four dimensions of life (physical/functional, social, psychological and environmental) combined with sociodemographic variables explain the overall subjective well being (SWB) visually impaired older adults living in the community. METHOD: A total of 121 severe visually impaired persons, aged 60 and over (M = 77.4, range 60-95), participated in the study. Personal, face-to-face interviews were conducted with participants at social centers or at their homes. Research tools consisted of valid and reliable questionnaires. RESULTS: Five variables explained the older adults' variability in SWB: self-rated health, sense of meaning in life, functional independence in activity of daily living (ADL), sense of control of one's environment (Mastery) and the participant's age. The explained variance percentage was found to be high (61%). In contrast to expectations, social environmental variables proved to be only of secondary significance in explaining SWB variability. DISCUSSION: Variables derived from the psychological dimension appear more significant than the social-environmental variables in explaining SWB among visually impaired older adults. These variables should be considered when developing intervention programs intended to increase SWB within this unique population group. PMID- 28636410 TI - Targeting cancer cell mitochondria as a therapeutic approach: recent updates. AB - Mitochondria play a key role in ATP generation, redox homeostasis and regulation of apoptosis. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is considered as an attractive therapeutic strategy. However, metabolic flexibility in cancer cells may enable the upregulation of compensatory pathways, such as glycolysis to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of both targeting mitochondria and inhibiting glycolysis may be particularly useful to overcome such drug-resistant mechanism. This review provides an update on recent development in the field of targeting mitochondria and novel compounds that impact mitochondria, glycolysis or both. Key challenges in this research area and potential solutions are also discussed. PMID- 28636411 TI - Asthma and influenza vaccination in elderly hospitalized patients: Matched case control study in Spain. AB - OBJECTIVES: Influenza infection is an exacerbating factor for asthma, and its prevention is critical in managing asthmatic patients. We investigated the effect of influenza vaccination on asthmatic and non-asthmatic patients hospitalized with laboratory-confirmed influenza in Spain. METHODS: We made a matched case control study to assess the frequency of hospitalization for influenza in people aged >=65 years. Hospitalized patients with unplanned hospital admissions were recruited from 20 hospitals representing seven Spanish regions. Cases were defined as those hospitalized due to a laboratory-confirmed influenza infection and controls were matched by age, sex, and hospital. Data were obtained from clinical records, and patients stratified by clinical asthma history. Vaccination status and asthma due to influenza infection were analyzed according to sociodemographic variables and medical risk conditions. Multivariable analysis was made using conditional logistic regression models. RESULTS: 582 hospitalized patients with influenza (15.8% asthmatic) and 1,570 hospitalized patients without influenza (7.9% asthmatic) were included. In the multivariable conditional logistic regression using unvaccinated and non-asthmatic patients as the reference group, vaccination significantly prevented influenza in non-asthmatic patients (aOR = 0.63; 95% CI: 0.45, 0.88) and also showed a trend for a possibly protective effect in asthmatic patients (aOR = 0.79; 95% CI: 0.34, 1.81). CONCLUSION: Our results suggest that influenza vaccination could be a protective factor for asthmatic patients, although the results are inconclusive and further research is required. Practically, given the better clinical evolution of vaccinated asthma cases, and the lack of better evidence, the emphasis on vaccination of this group should continue. PMID- 28636412 TI - Comparative chemical and biological studies of leaves and pollens of Phoenix canariensis hort. ex Chabaud. AB - AIM: Phoenix canariensis hort. ex Chabaud is one of the most important palm plants. In spite of that, it has not been extensively investigated from a phytochemical or a biological perspective. MATERIALS & METHODS: Air-dried powdered leaves and pollen grains of the plant were extracted using 70% ethanol. The residues were fractionated with different solvents of increasing polarity. Antioxidant, anti-inflammatory, hepatoprotective, anti-hyperglycemic activities were determined using adult male albino rats of wistar strain. RESULTS: Phytochemical investigation of Phoenix canariensis (Arecaceae) leaves and pollens led to the isolation of five compounds; isorhamnetin-3-O-beta-glucoside and isorhamnetin 7-O-rutinoside from the leaves in addition to isorhamnetin-3-O rutinoside and rutin together with beta sitosterol-3-O-beta-D-glucoside from pollens. The 70% ethanolic extracts of both organs were found to possess the highest antioxidant activity followed by their ethyl acetate fractions. Seventy percent ethanolic leaf extract and its ethyl acetate fraction showed the most potent hepatoprotective, anti-inflammatory and anti-hyperglycemic activities as compared with reference drugs. Isorhamnetin-7-O-rutinoside and beta-sitosterol-3 O-beta-D-glucoside were isolated from the genus and from Phoenix canariensis for the first time. CONCLUSION: This study reveals that Phoenix canariensis is an efficient natural source of safe antioxidants, anti-hyperglycemic, anti inflammatory and hepatoprotective agents. PMID- 28636413 TI - Tea consumption is associated with cognitive impairment in older Chinese adults. AB - OBJECTIVE: To explore the association between tea consumption and cognitive impairment (CoI). METHODS: 4579 adults (>=60 years) from the Weitang Geratric Diseases Study were assessed for characteristics of tea consumption and cognitive function by administering questionnaires and the Abbreviated Mental Test (AMT), respectively. We divided the subjects into normal cognitive function group (AMT score >=8) and CoI group (AMT score <=7). The association between tea consumption and risk of CoI was determined by logistic regression models. RESULTS: The least-squared means of the AMT scores for the subjects who seldom consumed tea were less favorable than those who habitually consumed tea. An inverse association was found between tea consumption (of any type) and prevalence of CoI (odds ratio = 0.74, 95% confidence interval = 0.57-0.98, P = 0.032). Interestingly, the protective correlation of tea was more obvious in never smokers (odds ratio = 0.63), but vanished in current/former smokers (odds ratio = 1.10). In never smokers, frequency of tea consumption was significantly associated with CoI (P for trend = 0.010). CONCLUSION: Habitual tea consumption is suggested to be associated with a decreased risk of CoI among elders in Suzhou, and a higher frequency of tea consumption was associated with a lower prevalence of CoI among never smokers. PMID- 28636414 TI - Non-dipping status and selected adipokines concentration in children with primary arterial hypertension. AB - : High blood pressure (BP) in children and adolescents is associated with increased risk of persistent hypertension (HT) in adulthood and, consequently, cardiovascular disease and target organ damage. AIM: The values of selected anthropometric parameters and laboratory test results including leptin and apelin concentration were evaluated with regard to averaged values of office BP measurements and 24-hour ABPM. MATERIAL AND METHODS: The study included 55 children: 23-with primary HT and coexisting overweight or obese (HT-OB), 16-with primary HT and normal weight (HT-NW), and 16 healthy children (C). RESULTS: The concentration of leptin and apelin in HT-OB children was significantly higher than in the C and HT-NW group. A similar finding for leptin level was demonstrated in comparison of HT-NW with C group. In children with HT-OB, the lack of decline in nocturnal DBP was associated with significantly higher BMI and the Cole's Index value. Children with HT-OB and lack of decline in nocturnal SBP showed lower leptin and insulin concentrations, and lower values of HOMA-IR as compared with dipping children. Positive correlation in the whole study group was found between adipokines levels and BP measurements. In conclusion, children with primary HT show higher concentration of adipokines compared with their healthy peers. The data on relationship of serum adipokines levels with anthropometric and BP parameters in children may be helpful to clarify the sequence of disturbances in the cardiovascular system in adults, which requires further examination. PMID- 28636416 TI - AKT modulates the autophagy-lysosome pathway via TFEB. PMID- 28636415 TI - Comprehensive Modeling of Corneal Alkali Injury in the Rat Eye. AB - PURPOSE: To characterize the molecular, clinical, and histopathological profiles in the rat cornea after alkali injury over a 21-day period. METHODS: Alkali injury was induced in one eye of male Lewis rats. Corneal opacity and corneal neovascularization were assessed daily. Real-time qRT-PCR analysis and immunohistochemical staining were conducted to examine inflammation, neovascularization, and fibrosis. RESULTS: We found that within 2 hours of chemical exposure, corneal opacification rapidly developed with an acute increase in various cytokine expressions, while several cytokines demonstrated a secondary peak by day 7. Early neutrophil infiltration peaked at day 1 post-injury while macrophage infiltration peaked at day 7. Throughout the time course of the study, corneal opacity persisted and neovascularization, lymphangiogenesis, and fibrosis progressed. CONCLUSIONS: This study highlights the molecular, clinical, and histopathological changes throughout the progression of alkali injury in the rat cornea. These profiles will assist in the development of new strategies and therapies for ocular alkali injury. PMID- 28636417 TI - A novel antimicrobial approach based on the inhibition of zinc uptake in Salmonella enterica. AB - In this review we discuss evidences suggesting that bacterial zinc homeostasis represents a promising target for new antimicrobial strategies. The ability of the gut pathogen Salmonella enterica sv Typhimurium to withstand the host responses aimed at controlling growth of the pathogen critically depends on the zinc importer ZnuABC. Strains lacking a functional ZnuABC or its soluble component ZnuA display a dramatic loss of pathogenicity, due to a reduced ability to express virulence factors; withstand the inflammatory response; and compete with other gut microbes. Based on this data, ZnuA was chosen as a candidate for the rational design of novel antibiotics. Through a combination of structural and functional investigations, we have provided a proof of concept of the potential of this approach. PMID- 28636419 TI - Poison or Prevention? Understanding the Linkages between Vaccine-Negative Individuals' Knowledge Deficiency, Motivations, and Active Communication Behaviors. AB - The last few decades have seen growing concerns among parents regarding the safety of childhood vaccines, arguably leading to the rise of the anti-vaccine movement. This study is an effort to understand situational and cross-situational factors that influence individuals' negative attitudes toward vaccines, referred to as vaccine negativity. In doing so, this study elucidated how situational and cross-situational factors influence vaccine negativity. Specifically, this study tested how knowledge deficiency, or acceptance of scientifically inaccurate data about vaccines, and institutional trust influenced negative attitudes toward vaccines. Using the situational theory of problem solving as the theoretical framework, this study also identified and tested a knowledge-attitude-motivation behavior framework of vaccine negative individuals' cognitions and behaviors about the issue. PMID- 28636418 TI - DXS as a target for structure-based drug design. AB - In this review, we analyze the enzyme DXS, the first and rate-limiting protein in the methylerythritol 4-phosphate pathway. This pathway was discovered in 1996 and is one of two known metabolic pathways for the biosynthesis of the universal building blocks for isoprenoids. It promises to offer new targets for the development of anti-infectives against the human pathogens, malaria or tuberculosis. We mapped the sequence conservation of 1-deoxy-xylulose-5-phosphate synthase on the protein structure and analyzed it in comparison with previously identified druggable pockets. We provide a recent overview of known inhibitors of the enzyme. Taken together, this sets the stage for future structure-based drug design. PMID- 28636420 TI - TIRR and 53BP1- partners in arms. PMID- 28636421 TI - Analysis of Origins of Admission for Solid Tumor Oncology Inpatients: Disease Severity and Outcomes. AB - PURPOSE: Hospital transfers may affect clinical outcomes. Evaluation of admission by source of transfer, time of admission, and provider type may identify opportunities to improve inpatient outcomes. METHODS: We reviewed charts of patients admitted to the solid tumor oncology service between July and December 2014 from the Cleveland Clinic Foundation (CCF) Main Campus emergency department (ED), CCF Regional EDs, outside hospital (OSH) ED, OSH inpatient services, and CCF outpatient clinics. Data collected included time of admission, mortality and severity risk scores, and provider type. Risk factors were assessed for clinical outcomes, including activations of the Adult Medical Emergency Team, intensive care unit transfers, in-hospital mortality, and length of stay (LOS). RESULTS: Five hundred admissions were included. OSH inpatient transfers had significantly higher disease severity compared with all other origins of admission. OSH inpatient transfers demonstrated significantly longer LOS compared with all other origins of admission, and higher mortality rates compared with the outpatient direct admits and CCF Main Campus ED admits. After adjusting for disease severity and risk of mortality, OSH ED patients remained at higher risk for Adult Medical Emergency Team activation, OSH inpatient transfers had the longest LOS, and CCF Main Campus ED patients had the lowest risk of mortality. Time of admission and provider type were not associated with any of the outcomes. CONCLUSION: Oncology inpatients transferred from an outside health care facility are at higher risk for adverse outcomes. The magnitude of difference is lessened, but still significant, after adjustment for disease severity and risk of mortality. PMID- 28636422 TI - Usurping bacterial virulence factors as self-delivery vehicles for therapeutic use. PMID- 28636423 TI - Fundamental motor skills: A systematic review of terminology. AB - The three aims of this systematic review are to describe: (1) use of the term fundamental motor/movement skills (FMS) in published articles; (2) the quality of definitions; and (3) relative use of process- and product- oriented assessments to measure FMS. The inclusion criteria included: (a) peer-reviewed article, (b) printed in English, (c) published between January 2000 and 31 December 2015, (d) presence of either the term "fundamental motor or movement skill" in the title and/or abstract, and (e) FMS were a measured outcome. There has been an increase in the number of publications on FMS in recent years, with the majority of studies conducted in Australia (n = 41, 33%). Approximately 24% of studies (n = 30) did not provide any explicit definition of FMS. A majority of studies reported the use of process-oriented measures (n = 98, 79%) compared to product oriented measures (n = 23, 19%), and few studies used both (n = 6, 5%). We recommend that researchers provide: (1) an operational definition of FMS that states FMS are the "building blocks" (or similar terminology) of more advanced, complex movements; (2) specific categories of skills that compose FMS; and (3) at least one specific example of a FMS. PMID- 28636424 TI - Fluid shear stress regulates HepG2 cell migration though time-dependent integrin signaling cascade. AB - Hepatocellular carcinoma (HCC) is a subtype of malignant liver cancer with poor prognosis and limited treatment options. It is noteworthy that mechanical forces in tumor microenvironment play a pivotal role in mediating the behaviors and functions of tumor cells. As an instrumental type of mechanical forces in vivo, fluid shear stress (FSS) has been reported having potent physiologic and pathologic effects on cancer progression. However, the time-dependent mechanochemical transduction in HCC induced by FSS remains unclear. In this study, hepatocellular carcinoma HepG2 cells were exposed to 1.4 dyn/cm2 FSS for transient duration (15s and 30s), short duration (5 min, 15 min and 30 min) and long duration (1h, 2h and 4h), respectively. The expression and translocation of Integrins induced FAK-Rho GTPases signaling events were examined. Our results showed that FSS endowed HepG2 cells with higher migration ability via reorganizing cellular F-actin and disrupting intercellular tight junctions. We further demonstrated that FSS regulated the expression and translocation of Integrins and their downstream signaling cascade in time-dependent patterns. The FSS downregulated focal adhesion components (Paxillin, Vinculin and Talin) while upregulated the expression of Rho GTPases (Cdc42, Rac1 and RhoA) in long durations. These results indicated that FSS enhanced tumor cell migration through Integrins-FAK-Rho GTPases signaling pathway in time-dependent manners. Our in vitro findings shed new light on the role of FSS acting in physiologic and pathological processes during tumor progression, which has emerged as a promising clinical strategy for liver carcinoma. PMID- 28636426 TI - Comparison of knowledge, perception and attitudes of concussion in previously concussed versus non-concussed youth soccer players. AB - OBJECTIVES: To examine if history of concussion is correlated with a difference in knowledge, attitude, and perception of concussive injuries in youth soccer players. METHODS: A convenience sample of youth soccer athletes aged 14 to 18 years completed a survey assessing prior history of concussive injury, knowledge of concussive injury, self-reporting attitudes, and perception of the injury. The survey consists of 16 knowledge questions (eleven on a scale of 1-2, and five on a scale of 1-4) and 12 attitude questions (seven on a scale of 1-4, and five on a scale of 1-5). The primary outcomes are the total scores calculated by summing the standardized raw scores for all knowledge questions and attitude questions, respectively. Linear regression was used to estimate the mean difference in the primary outcomes between previously concussed and non-concussed athletes (calculated as previously concussed - non-concussed). RESULTS: Surveys were obtained from 90 athletes, with 32 (36%) previously sustaining at least one concussion. Thirty-one out of these 32 concussions were diagnosed by a medical provider. On average, the mean total raw scores of all knowledge questions are 34.6 (82.2% of 42 possible points) and 33.7 (80.2% of 42 total points) for previously concussed and non-concussed athletes, respectively, and the mean total raw scores of all attitude questions are 38.7 (72.9% of 53 possible points) and 39.6 (74.7% of 53 possible points), respectively. Mean differences estimated from univariate linear regression in the standardized total scores of knowledge questions and attitude questions are 1.56(95% confidence interval: -1.52-4.65) and -1.23 (%95 confidence interval: -4.64-2.19), respectively. Adjusting for age and years of playing soccer gave similar results. CONCLUSION: Although we did not find significant differences between previously concussed and non-concussed athletes in either the knowledge or the attitude questions as measured by their total scores, this study showed a high level of awareness of concussion in youth soccer players, while still highlighting a need for education. Limited distinctions were made among subgroups of players, suggesting directions of future research in investigating the role that outside factors may have on knowledge and perception of concussion. PMID- 28636425 TI - American Thoracic Society/National Heart, Lung, and Blood Institute Asthma Chronic Obstructive Pulmonary Disease Overlap Workshop Report. AB - Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic obstructive lung diseases with an associated high burden of disease. Asthma, which is often allergic in origin, frequently begins in infancy or childhood with variable airflow obstruction and intermittent wheezing, cough, and dyspnea. Patients with COPD, in contrast, are usually current or former smokers who present after the age of 40 years with symptoms (often persistent) including dyspnea and a productive cough. On the basis of age and smoking history, it is often easy to distinguish between asthma and COPD. However, some patients have features compatible with both diseases. Because clinical studies typically exclude these patients, their underlying disease mechanisms and appropriate treatment remain largely uncertain. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the American Thoracic Society, convened a workshop of investigators in San Francisco, California on May 14, 2016. At the workshop, current understanding of asthma-COPD overlap was discussed among clinicians, pathologists, radiologists, epidemiologists, and investigators with expertise in asthma and COPD. They considered knowledge gaps in our understanding of asthma-COPD overlap and identified strategies and research priorities that will advance its understanding. This report summarizes those discussions. PMID- 28636427 TI - Liver-directed therapy in metastatic colorectal cancer. AB - INTRODUCTION: Colorectal cancer is a significant global health issue with over 1 million cases diagnosed annually throughout the world. 15% of patients diagnosed with colorectal cancer will have liver metastases and 60% will develop liver metastases if they have metastatic disease. Oligometastatic colorectal cancer confined to the liver represents an intermediate state in the evolution of metastatic capacity that opens the opportunity for local interventions. Areas covered: The literature supports long-term survival if patients undergo liver resection of colorectal metastases. This article reviews the liver-directed therapeutic strategies available for the management of metastatic liver disease including hepatic arterial infusion therapy, radiofrequency ablation, radiation therapy and transarterial chemoembolization. Expert commentary: Great advances have been made with the use of liver directed therapies. In the USA using hepatic arterial infusions with FUDR and Decadron along with systemic therapy, 5 year survivals after liver resection have improved. In Europe with the use of HAI of Oxaliplatin, more patients have been able to get to resection and have obtained higher survival rates, even in second line therapy. New advances in ablative therapy have improved results to get all disease treated at resection for the treatment of reccurrence. PMID- 28636429 TI - Autograft Versus Allograft for Posterior Cruciate Ligament Reconstruction: An Updated Systematic Review and Meta-analysis. AB - BACKGROUND: Multiple studies have demonstrated a higher risk of graft failure after anterior cruciate ligament reconstruction with allograft, but limited data are available comparing outcomes of posterior cruciate ligament reconstruction (PCLR) with autograft versus allograft. PURPOSE: To compare the clinical outcomes of autograft versus allograft for primary PCLR. STUDY DESIGN: Systematic review. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and EMBASE to locate studies (level of evidence I-III) comparing clinical outcomes of autograft versus allograft in patients undergoing primary PCLR with the conventional transtibial technique. Search terms used were "posterior cruciate ligament," "autograft," and "allograft." Patients were evaluated based on graft failure rate, examination of knee laxity, and patient reported outcome scores (Lysholm, Tegner, subjective International Knee Documentation Committee [IKDC], and objective IKDC scores). RESULTS: Five studies (2 level II, 3 level III) were identified that met inclusion criteria, including a total of 132 patients undergoing PCLR with autograft (semitendinosus-gracilis or bone-patellar tendon-bone) and 110 patients with allograft (tibialis anterior, Achilles tendon, or bone-patellar tendon-bone). No patients experienced graft failure. Average anteroposterior (AP) knee laxity was significantly higher in allograft patients (3.8 mm) compared with autograft patients (3.1 mm) ( P < .01). Subjective IKDC, Lysholm, and Tegner scores improved for both groups across studies, without a significant difference in improvement between groups except in one study, in which Lysholm scores improved to a significantly greater extent in the autograft group ( P < .01). CONCLUSION: Patients undergoing primary PCLR with either autograft or allograft can be expected to experience improvement in clinical outcomes. Autograft patients experienced less AP knee laxity postoperatively, although the clinical significance of this is unclear and subjective outcomes improved substantially and to a similar degree in both groups. PMID- 28636428 TI - FK506-binding proteins 12 and 12.6 (FKBPs) as regulators of cardiac Ryanodine Receptors: Insights from new functional and structural knowledge. AB - Ryanodine Receptors (RyRs) are intracellular Ca2+ channels that mediate Ca2+ flux from the sarco(endo)plasmic reticulum in many cell types. The interaction of RyRs with FK506-binding proteins (FKBPs) has been proposed as an important regulatory mechanism, where the loss of this interaction leads to channel dysfunction. In the heart, phosphorylation of RyR has been suggested to disrupt the RyR-FKBP interaction promoting altered Ca2+ signaling, heart failure and arrhythmias. However, the functional result of FKBP interaction with RyR and how this interaction is regulated remains highly controversial. Recently, high resolution structures of RyR have provided novel aspects to the ongoing debate. This review will discuss the most recent functional data in light of these new structures. PMID- 28636430 TI - When Is Embryonic Arrest Broken in Turtle Eggs? AB - Turtle embryos enter a state of arrested development in the oviduct, allowing the mother greater flexibility in her reproductive schedule. Development recommences once eggs transition from the hypoxic oviduct to the normoxic nest. Significant mortality can occur if turtle eggs are moved between 12 h and 20 d after oviposition, and this is linked to the recommencement of embryonic development. To better understand the timing of developmental arrest and to determine how movement-induced mortality might be avoided, we determined the latency (i.e., time elapsed since oviposition) to recommencement of development following oviposition by exposing the eggs of green turtles (Chelonia mydas) to hypoxia (oxygen tension <8 mmHg) for 3 d, commencing 30 min to 48 h after oviposition. Embryonic development-including development of the characteristic opaque white spot on the eggshell-was halted by hypoxic incubation. When the delay before hypoxic incubation was 12 h or less, hatching success did not differ from a control group. If the hypoxic treatment began after 16 h or more in normoxia, then all embryos died. Thus, by returning eggs to a hypoxic environment before they have broken from arrest (i.e., within 12 h of oviposition), it is possible to extend embryonic arrest for at least 3 d, with no apparent detriment to hatching success. Therefore, hypoxic incubation may provide a new approach for avoidance of movement-induced mortality when conservation or research efforts require the relocation of eggs. Our findings also suggest that movement-induced mortality may have constrained the evolution of viviparity in turtles. PMID- 28636431 TI - Enhanced production of raw starch degrading enzyme using agro-industrial waste mixtures by thermotolerant Rhizopus microsporus for raw cassava chip saccharification in ethanol production. AB - In the present study, solid-state fermentation for the production of raw starch degrading enzyme was investigated by thermotolerant Rhizopus microsporus TISTR 3531 using a combination of agro-industrial wastes as substrates. The obtained crude enzyme was applied for hydrolysis of raw cassava starch and chips at low temperature and subjected to nonsterile ethanol production using raw cassava chips. The agro-industrial waste ratio was optimized using a simplex axial mixture design. The results showed that the substrate mixture consisting of rice bran:corncob:cassava bagasse at 8 g:10 g:2 g yielded the highest enzyme production of 201.6 U/g dry solid. The optimized condition for solid-state fermentation was found as 65% initial moisture content, 35 degrees C, initial pH of 6.0, and 5 * 106 spores/mL inoculum, which gave the highest enzyme activity of 389.5 U/g dry solid. The enzyme showed high efficiency on saccharification of raw cassava starch and chips with synergistic activities of commercial alpha-amylase at 50 degrees C, which promotes low-temperature bioethanol production. A high ethanol concentration of 102.2 g/L with 78% fermentation efficiency was achieved from modified simultaneous saccharification and fermentation using cofermentation of the enzymatic hydrolysate of 300 g raw cassava chips/L with cane molasses. PMID- 28636432 TI - Young Men, Masculinities, and Suicide. AB - Young men constitute one of the highest risk groups for suicide in most countries. This gives reason to explore how meanings attached to masculinity can be evoked and handled when a young man takes his life. In-depth interviews with 5 to 8 informants for each of 10 suicides, as well as suicide notes, were analyzed using Interpretative Phenomenological Analysis. The suicides appeared as signature acts of compensatory masculinity with the following themes: When hope is gone, no one must know; weakness was never allowed; and suicide conducted in a way to present oneself as heroic. The handling of masculinity in triggering suicidal plans and in carrying out suicide is intrinsically connected to avoidance of help-seeking behavior. PMID- 28636433 TI - Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated During Acute HIV Infection. AB - AGS-004 consists of matured autologous dendritic cells co-electroporated with in vitro transcribed RNA encoding autologous HIV antigens. In an open-label, single arm sub-study of AGS-004-003, AGS-004 was administered monthly to suppressed participants who started antiretroviral therapy (ART) during acute HIV infection. HIV-1 specific T cell responses were measured by multicolor flow cytometry after 3-4 doses. The frequency of resting CD4+ T-cell infection (RCI) was measured by quantitative viral outgrowth assay. Participants demonstrating increased immune response postvaccination were eligible for analytic treatment interruption (ATI). AGS-004 induced a positive immune response defined as >=2-fold increase from baseline in the number of multifunctional HIV-1 specific CD28+/CD45RA- CD8+ effector/memory cytoxic T-lymphocytes (CTLs) in all six participants. All participants underwent ATI with rebound viremia at a median of 29 days. Immune correlates between time to viral rebound and the induction of effector CTLs were determined. Baseline RCI was low in most participants (0.043-0.767 IUPM). One participant had a >2-fold decrease (0.179-0.067 infectious units per million [IUPM]) in RCI at week 10. One participant with the lowest RCI had the longest ATI. AGS-004 dendritic cell administration increased multifunctional HIV-specific CD28+/CD45RA- CD8+ memory T cell responses in all participants, but did not permit sustained ART interruption. However, greater expansion of CD28-/CCR7 /CD45RA- CD8+ effector T cell responses correlated with a longer time to viral rebound. AGS-004 may be a useful tool to augment immune responses in the setting of latency reversal and eradication strategies. PMID- 28636434 TI - Selective Breeding and Short-Term Access to a Running Wheel Alter Stride Characteristics in House Mice. AB - Postural and kinematic aspects of running may have evolved to support high runner (HR) mice to run approximately threefold farther than control mice. Mice from four replicate HR lines selectively bred for high levels of voluntary wheel running show many differences in locomotor behavior and morphology as compared with four nonselected control (C) lines. We hypothesized that HR mice would show stride alterations that have coadapted with locomotor behavior, morphology, and physiology. More specifically, we predicted that HR mice would have stride characteristics that differed from those of C mice in ways that parallel some of the adaptations seen in highly cursorial animals. For example, we predicted that limbs of HR mice would swing closer to the parasagittal plane, resulting in a two dimensional measurement of narrowed stance width. We also expected that some differences between HR and C mice might be amplified by 6 d of wheel access, as is used to select breeders each generation. We used the DigiGait Imaging System (Mouse Specifics) to capture high-speed videos in ventral view as mice ran on a motorized treadmill across a range of speeds and then to automatically calculate several aspects of strides. Young adults of both sexes were tested both before and after 6 d of wheel access. Stride length, stride frequency, stance width, stance time, brake time, propel time, swing time, duty factor, and paw contact area were analyzed using a nested analysis of covariance, with body mass as a covariate. As expected, body mass and treadmill speed affected nearly every analyzed metric. Six days of wheel access also affected nearly every measure, indicating pervasive training effects, in both HR and C mice. As predicted, stance width was significantly narrower in HR than C mice. Paw contact area and duty factor were significantly greater in minimuscle individuals (subset of HR mice with 50%-reduced hind limb muscle mass) than in normal-muscled HR or C mice. We conclude that stride characteristics of house mice are adaptable in response to both selective breeding and changes in daily locomotor behavior (activity levels) that occur during as few as 6 d. These results have important implications for understanding the evolution and coadaptation of locomotor behavior and performance. PMID- 28636435 TI - Effects of a contrast training programme on jumping, sprinting and agility performance of prepubertal basketball players. AB - The purpose of this study was to examine the effects of a 10 week contrast training (CT) programme (isometric + plyometric) on jumping, sprinting abilities and agility performance in prepubertal basketball players. Fifty-eight children from a basketball academy (age: 8.72 +/- 0.97 years; body mass index: 17.22 +/- 2.48 kg/m2) successfully completed the study. Participants were randomly assigned to experimental groups (EG, n = 30) and control groups (CG, n = 28). The CT programme was included in the experimental group's training sessions - twice a week - as part of their usual weekly training regime. This programme included 3 exercises: 1 isometric and 2 plyometric. Jumping, sprinting and agility performance were assessed before and after the training programme. Significant differences were found in posttest between EG and CG in sprint and T-test: EG showed better results than CG. Furthermore, there were significant differences in posttest-pretest between EG and CG in squat jump, countermovement jump, drop jump, sprint and T-test with the EG showing better results than CG. The CT programme led to increases in vertical jump, sprint and agility levels, so that the authors suggest that prepubertal children exhibit high muscular strength trainability. PMID- 28636436 TI - Signal-on fluorescent sensor based on N-CQDs for the detection of glutathione in human serum and pharmaceutic preparation. AB - Nitrogen-doped carbon quantum dots (N-CQDs) with citric acid and ethylenediamine as raw materials were synthesized by an efficient one-step strategy. The N-CQDs showed a special property that the fluorescence was quenched by Fe3+. The quenched fluorescence of N-CQDs could be recovered by glutathione (GSH). Therefore, a "signal-on" fluorescent sensor was developed to detect GSH. The fluorescent sensor could favorably avoid the interference of ascorbic acid, dopamine, glucose, oxidized glutathione, and other amino acids in the detecting process of GSH. The proposed sensor showed a great feature that GSH can be accurately detected in the range from 0.001 to 0.1 mol/L and can be applied to detect GSH in the human serum. Therefore, the proposed method has a promising application for monitoring the blood drug concentration of GSH in clinical studies. PMID- 28636437 TI - Tobacco rattle virus (TRV)-Mediated Silencing of Nicotiana benthamiana ARGONAUTES (NbAGOs) Reveals New Antiviral Candidates and Dominant Effects of TRV-NbAGO1. AB - The objective of this study was to determine the contribution of different ARGONAUTE proteins in Nicotiana benthamiana (NbAGOs) to the defense against silencing sensitive GFP-expressing viral constructs based on Tomato bushy stunt virus (TBSV) (Tombusvirus), Sunn-hemp mosaic virus (Tobamovirus), and Foxtail mosaic virus (Potexvirus). Upon Tobacco rattle virus (TRV)-mediated down regulation of NbAGO1, 4, 5, or 6, no effects were noted on susceptibility to any virus construct, whereas knockdown of NbAGO2 specifically prevented silencing of P19-defective TBSV (TGdP19). Down-regulation of a new gene referred to as NbAGO5L showed some reduced silencing for TGdP19 but not for the other two virus constructs, whereas silencing of NbAGO7 gave rise to a subtle increase in susceptibility to all three viruses. Co-infiltrating different TRV-NbAGO constructs simultaneously did not enhance virus susceptibility. However, an unexpected finding was that whenever the TRV-NbAGO1 construct was present, this compromised silencing of genes targeted by co-infiltrated constructs, as shown upon co-infiltration of TRV-NbAGO1 with either TRV-NbAGO2 or TRV-Sul (targeting Magnesium chelatase I). Only after a prolonged period (approximately 2 months) did TRV-Sul-mediated systemic bleaching occur in these co-infected plants, suggesting that TRV-NbAGO1 hinders the silencing ability of other TRV-NbAGO constructs. In conclusion, this study revealed new antiviral NbAGOs and dominant effects of silencing NbAGO1. PMID- 28636438 TI - Oxidative stress mediated by nitrogen at elevated pressure inhibits non-small cell lung cancer growth. AB - : Purpose/Aim: High pressures of gases such as nitrogen enhance production of singlet oxygen. Therefore, we hypothesized that growth of non-small cell lung cancer (NSCLC) A549 cells and a human-derived NSCLC explant could be inhibited by an oxidative stress mechanism using high-pressure nitrogen. MATERIALS AND METHODS: Growth of human NSCLC explants and A549 cells in Matrigel were assessed after implantation into nude mice who were exposed to elevated pressures. RESULTS: Subcutaneous implant growth of NSCLC in nude mice was inhibited by a daily 78-minute protocol using nitrogen/oxygen breathing mixture such that at the maximum pressure of 2.78 atmospheres over ambient, mice breathed oxygen at normal atmospheric pressure. In vivo growth inhibition of A549 cells by high-pressure nitrogen could be abrogated in subcutaneous Matrigel implants when supplemented with 10-mM N-acetylcysteine as an antioxidant. Ex vivo A549 cell exposures exhibited elevated singlet oxygen production, and reactive oxygen species were produced for up to 4 hours after short-term high-pressure nitrogen exposure. CONCLUSIONS: This pilot study demonstrates that elevated normoxic nitrogen pressure can exacerbate oxidative stress in NSCLC to inhibit growth. PMID- 28636439 TI - Functional enrichment of mannanase-treated spent brewer yeast. AB - In this study, the effect of Bacillus amyloliquefaciens-produced beta-mannanase on the nutrient diffusion (release) and antioxidant activity of spent brewer yeast (SBY) was investigated. Three pretreatments were performed: (1) autolysis at 50 degrees C for 24 h; (2) autolysis at 50 degrees C for 24 h, with the addition of beta-mannanase during the autolysis; (3) autolysis at 50 degrees C for 24 h, and the beta-mannanase was added for another 12 h treatment. The pretreatments with the addition of beta-mannanase caused significant cell wall degradation, markedly increased the yield of SBY extracts. More importantly, this study found that polysaccharides were degraded to be oligosaccharides with a considerable reduction in molecular weights. Meanwhile, pretreatment with the enzyme also exhibited a higher antioxidant activity in SBY extract compared to autolysis itself. The current study indicated that pretreatment (3) had a better effect than pretreatment (2) in terms of improving in antioxidant activity in SBY extract. These improved characteristics of SBY extracts isolated through enzymatic treatment appear to show promising features for their prospective use as natural functional agents. PMID- 28636440 TI - Effects of Time to Start Training After Acute Patellar Tendon Enthesis Injuries on Healing of the Injury in a Rabbit Model. AB - BACKGROUND: A patellar tendon injury is a common injury in sports. The optimal time to start training after an acute, proximal patellar enthesis injury is still unclear. HYPOTHESIS: The time to start training after an acute, proximal patellar enthesis injury significantly affects healing of the patellar tendon 4 weeks after the injury. STUDY DESIGN: Controlled laboratory study. METHODS: The left hindlimbs of 35 mature female rabbits were randomly assigned to 5 injury groups including a 4-week natural healing group (NH4W) and 4 training groups that started low-intensity training at 24 hours (POST24), 48 hours (POST48), 72 hours (POST72), and 96 hours (POST96) after an acute patellar tendon injury, with 7 limbs in each group. The right hindlimbs of the NH4W group were used as a control group (CON). An acute, proximal patellar enthesis injury was created in all injury groups. The training groups underwent low-intensity quadriceps training for 2 hours per day and 3 days per week for 4 weeks. Histological and radiographic data were collected and analyzed. RESULTS: The cell densities of the training groups were significantly lower than those of the NH4W and CON groups ( P = .01). The fibrocartilage zone was significantly thicker in the POST24, POST48, and POST72 groups compared with the CON and NH4W groups and was the thickest in the POST24 group ( P = .01). The bone surface to bone volume ratio was significantly higher in all the injury groups compared with the CON group and in the POST24 group compared with the other groups ( P = .01). Trabecular thickness was significantly lower in all the injury groups compared with the CON group and in the POST24 group compared with the other groups ( P = .01). CONCLUSION: Resting without training in the first 96 hours after an acute patellar tendon enthesis injury resulted in the best recovery of cell density in the tendon enthesis 4 weeks after the injury. Starting training 96 hours after the injury resulted in the best recovery of fibrocartilage zone thickness. Starting training 48 to 96 hours after the injury resulted in the best healing of the bone component of the attachment site 4 weeks after the injury. The optimal time to start training may be longer than 96 hours after an acute patellar tendon enthesis injury for the best overall healing of the tendon enthesis 4 weeks after the injury. CLINICAL RELEVANCE: A rest of a minimal 72 hours may be needed for the best healing of a patellar tendon enthesis after an acute injury. Future studies are needed to determine the optimal time to start training after an acute patellar tendon injury. PMID- 28636441 TI - Introduction. PMID- 28636442 TI - The National Ebola Training and Education Center: Preparing the United States for Ebola and Other Special Pathogens. AB - The National Ebola Training and Education Center (NETEC) was established in 2015 in response to the 2014-2016 Ebola virus disease outbreak in West Africa. The US Department of Health and Human Services office of the Assistant Secretary for Preparedness and Response and the US Centers for Disease Control and Prevention sought to increase the competency of healthcare and public health workers, as well as the capability of healthcare facilities in the United States, to deliver safe, efficient, and effective care to patients infected with Ebola and other special pathogens nationwide. NYC Health + Hospitals/Bellevue, Emory University, and the University of Nebraska Medical Center/Nebraska Medicine were awarded this cooperative agreement, based in part on their experience in safely and successfully evaluating and treating patients with Ebola virus disease in the United States. In 2016, NETEC received a supplemental award to expand on 3 initial primary tasks: (1) develop metrics and conduct peer review assessments; (2) develop and provide educational materials, resources, and tools, including exercise design templates; (3) provide expert training and technical assistance; and, to add a fourth task, create a special pathogens clinical research network. PMID- 28636443 TI - Personal Protective Equipment Supply Chain: Lessons Learned from Recent Public Health Emergency Responses. AB - Personal protective equipment (PPE) that protects healthcare workers from infection is a critical component of infection control strategies in healthcare settings. During a public health emergency response, protecting healthcare workers from infectious disease is essential, given that they provide clinical care to those who fall ill, have a high risk of exposure, and need to be assured of occupational safety. Like most goods in the United States, the PPE market supply is based on demand. The US PPE supply chain has minimal ability to rapidly surge production, resulting in challenges to meeting large unexpected increases in demand that might occur during a public health emergency. Additionally, a significant proportion of the supply chain is produced off-shore and might not be available to the US market during an emergency because of export restrictions or nationalization of manufacturing facilities. Efforts to increase supplies during previous public health emergencies have been challenging. During the 2009 H1N1 influenza pandemic and the 2014 Ebola virus epidemic, the commercial supply chain of pharmaceutical and healthcare products quickly became critical response components. This article reviews lessons learned from these responses from a PPE supply chain and systems perspective and examines ways to improve PPE readiness for future responses. PMID- 28636444 TI - A Highly Infectious Disease Care Network in the US Healthcare System. AB - During the 2014-15 Ebola outbreak in West Africa, the United States responded by stratifying hospitals into 1 of 3 Centers for Disease Control and Prevention (CDC)-designated categories-based on the hospital's ability to identify, isolate, assess, and provide care to patients with suspected or confirmed Ebola virus disease (EVD)-in an attempt to position the US healthcare system to safely isolate and care for potential patients. Now, with the Ebola epidemic quelled, it is crucial that we act on the lessons learned from the EVD response to broaden our national perspective on infectious disease mitigation and management, build on our newly enhanced healthcare capabilities to respond to infectious disease threats, develop a more cost-effective and sustainable model of infectious disease prevention, and continue to foster training so that the nation is not in a vulnerable position once more. We propose the formal creation of a US Highly Infectious Disease Care Network (HIDCN) modeled after 2 previous highly infectious disease consensus efforts in the United States and the European Union. A US Highly Infectious Disease Care Network can provide a common platform for the exchange of training, protocols, research, knowledge, and capability sharing among high-level isolation units. Furthermore, we envision the network will cultivate relationships among facilities and serve as a means of establishing national standards for infectious disease response, which will strengthen domestic preparedness and the nation's ability to respond to the next highly infectious disease threat. PMID- 28636445 TI - Developing a CASPER Survey to Assess the Prevalence of Risk Factors for Neglected Tropical Diseases in Texas. AB - While more than a billion people live at risk of neglected tropical diseases in areas of Asia, sub-Saharan Africa, and Latin America, the degree to which such diseases burden countries like the United States is currently unclear. Even though many neglected tropical diseases such as dengue, leishmaniasis, and Chagas disease are not endemic to the United States, the possibility of their emergence is noteworthy, especially in states like Texas, which has high levels of poverty, a large immigrant population, and a climate amenable to the vectors for these diseases and is geographically proximate to endemic areas. Despite the health threat that emerging neglected tropical diseases may pose, little is known about the prevalence of risk factors for them in the United States. Texas House Bill 2055, enacted on September 1, 2015, mandated the establishment of a surveillance program for neglected tropical diseases in Texas. After reviewing the potential risk factors for transmission in Texas, we developed a 41-question survey that could be implemented using the Community Assessment for Public Health Emergency Response (CASPER) method. In concert with public health surveillance and vector population monitoring, data from CASPERs could be used to quickly and cost effectively assess the prevalence of risk factors for 10 neglected tropical diseases in Texas or elsewhere in the United States. The data generated by future CASPERs conducted using this survey could be immediately actionable, guiding public health priority setting and decision making. PMID- 28636446 TI - United States Notifications of Travelers from Ebola-Affected Countries. AB - The International Health Regulations (IHR), an international law under the auspices of the World Health Organization (WHO), mandates that countries notify other countries of "travelers under public health observation." Between November 10, 2014, and July 12, 2015, the US Centers for Disease Control and Prevention (CDC) made 2,374 notifications to the National IHR Focal Points in 114 foreign countries of travelers who were monitored by US health departments because they had been to an Ebola-affected country in West Africa. Given that countries have preidentified focal points as points of contacts for sharing of public health information, notifications could be made by CDC to a trusted public health recipient in another country within 24 hours of receipt of the traveler's information from a US health department. The majority of US health departments used this process, offered by CDC, to notify other countries of travelers intending to leave the United States while being monitored in their jurisdiction. PMID- 28636447 TI - Emerging Viral Infections in Pakistan: Issues, Concerns, and Future Prospects. AB - Emerging infectious diseases pose a serious threat to public health security; this is especially true in the underdeveloped world because of limited resources to combat them. These emerging pathogens are characterized by a novel mode of pathogenesis and, in some cases, a broad host range. Over the past few decades, Pakistan has suffered a great deal from infectious diseases such as dengue, Crimean-Congo fever, hepatitis, measles, and polio. Changing climate conditions, environmental degradation, global warming, loss of biodiversity, and other ecological determinants have a direct effect on these diseases and result in the emergence and reemergence of infectious entities. The causes of such disease outbreaks are complex and often not well understood. Dealing with an outbreak requires an integrated and coordinated approach, with decision making by various state departments. Stringent biosecurity and biosafety protocols can help to reduce the chances of infection dissemination. In order to mitigate the risks associated with emerging pathogens, there is a greater need to understand the interactions of pathogen-host-environment, to monitor molecular evolution and genomic surveillance, and to facilitate the gearing up of scientists across the globe to control these emerging diseases. This article reviews recent outbreaks in Pakistan and challenges for the development of an agile healthcare setup in the country. PMID- 28636448 TI - Ebola Virus Training: A Needs Assessment and Gap Analysis. AB - In response to the 2014 Ebola virus disease outbreak, the Worker Training Program embarked on an assessment of existing training for those at risk for exposure to the virus. Searches of the recent peer-reviewed literature were conducted for descriptions of relevant training. Federal guidance issued during 2015 was also reviewed. Four stakeholder meetings were conducted with representatives from health care, academia, private industry, and public health to discuss issues associated with ongoing training. Our results revealed few articles about training that provided sufficient detail to serve as models. Training programs struggled to adjust to frequently updated federal guidance. Stakeholders commented that most healthcare training focused solely on infection control, and there was an absence of employee health-related training for non-healthcare providers. Challenges to ongoing training included funding and organizational complacency. Best practices were noted where management and employees planned training cooperatively and where infection control, employee health, and hospital emergency managers worked together on the development of protective guidance. We conclude that sustainable training for infectious disease outbreaks requires annual funding, full support from organizational management, input from all stakeholders, and integration of infection control, emergency management, and employee health when implementing guidance and training. PMID- 28636449 TI - Zika Virus in Ontario: Evaluating a Rapid Risk Assessment Tool for Emerging Infectious Disease Threats. AB - To determine the Ontario-specific risk of local and travel-related Zika virus transmission in the context of a public health emergency of international concern, Public Health Ontario (PHO) completed a rapid risk assessment (RRA) on January 29, 2016, using a newly developed RRA guidance tool. The RRA concluded that risk of local mosquito-borne transmission was low, with a high risk of imported cases through travel. The RRA was updated 3 times based on predetermined triggers. An independent evaluation assessed both the application of the RRA guidance tool (process evaluation) and the usefulness of the RRA (outcome evaluation). We conducted face-to-face, semi-structured interviews with 7 individuals who participated in the creation or review of the Zika virus RRA and 4 end-users at PHO and the Ministry of Health and Long-Term Care. An inductive thematic analysis of responses was undertaken, whereby themes were directly informed by the data. The process evaluation determined that most steps outlined in the RRA guidance tool were adhered to, including forming a cross-functional writing team, clarifying the scope and describing context, completing the RRA summary report, and updating the RRA based on predefined triggers. The outcome evaluation found that end-users judged the Zika virus RRA as evidence-informed, useful, consistent, and timely. The evaluation established that the locally tailored guidance tool, adapted from national and international approaches to RRAs, facilitated a systematic, evidence-informed, and timely formal RRA process at PHO for the Zika virus RRA, which met the needs of end-users. Based on the evaluation, PHO will modify future RRAs by incorporating some flexibility into the literature review process to support timeliness of the RRA, explicitly describing the limitations of studies used to inform the RRA, and refining risk algorithms to better suit emerging infectious disease threats. It is anticipated that these refinements will improve upon the timely assessment of novel or reemerging infectious diseases. PMID- 28636450 TI - Impact of mycotoxins on the intestine: are mucus and microbiota new targets? AB - There is an increasing awareness of the deleterious effects attributed to mycotoxins during their fate within the gut, particularly for deoxynivalenol (DON), zearalenone (ZEN), ochratoxin A (OTA), fumonisin B1 (FB1), aflatoxin B1 (AFB1), and patulin (PAT). Evidence indicates that disruption of the epithelial barrier is well established. However, intestinal barrier function on its luminal side involves two other partners, mucus and microbiota, which have rarely been considered in the context of mycotoxin exposure. The current review aimed at providing a summary of DON, ZEN, OTA, FB1, AFB1, and PAT effects on intestinal barrier function, with special focus on mucus and microbiota. DON, ZEN, OTA, FB1, AFB1, and PAT are known to markedly affect epithelial cell integrity and functions. Regarding mucus, DON is the most documentated mycotoxin. In vivo, toxicological impact of DON generally has only been assessed through goblet cell number. Evaluation of the mycotoxins/mucus interplay considering other indicators such as composition, thickness, and penetrability of mucus, mucin O-glycosylation thus warrants further attention. With respect to microbiota, few short-term studies to date have been reported indicating deleterious effects. However, long term exposure to mycotoxins may also produce significant changes in microbiota composition and metabolic activity, which requires further experimentation. In conclusion, mucus and microbiota are key targets for dietary mycotoxins although assessment of induced effects is preliminary. A significant research effort is now underway to determine the adverse consequences of mycotoxins on mucus and microbiota considered as individual but also as tightly connected gut players. PMID- 28636451 TI - Assessing hydrogen peroxide vapor exposure from hospital sterilizers. AB - This study examines the hydrogen peroxide concentrations measured near four models of hydrogen peroxide sterilizers, from two manufacturers, monitored in seven hospitals across the U.S. and Canada over several years. The results showed that the majority of sterilizers do not emit hazardous levels of hydrogen peroxide and none of them exceeded the OSHA PEL of 1 ppm (8-hr time-weighted average (TWA)), however several of the sterilizers exceeded 3 ppm, the short-term exposure limit in two states: Washington and Hawaii. One hospital found brief concentrations of 25-40 ppm hydrogen peroxide from 4 hydrogen peroxide sterilizers each time they opened the sterilizer at the end of its cycle. Although not exceeding the OSHA PEL, these exposures are of concern since this concentration is roughly half the NIOSH IDLH of 75 ppm, and operators in a busy hospital environment may receive these exposures multiple times a day. PMID- 28636452 TI - Epidemiology of NIV for Acute Respiratory Failure in COPD Patients: Results from the International Surveys vs. the "Real World". AB - Non-invasive ventilation (NIV) has been recommended as the first-line ventilation modality for acute respiratory failure (ARF) due to acute exacerbation of chronic obstructive pulmonary disease (AECOPD) based on strong evidence. However, everyday clinical practice may differ from findings of multiple randomized controlled trials. Physicians and respiratory therapists involved in NIV management have been queried about its utilization and effectiveness. In addition to these estimates, cohort studies and analysis of large inpatient dataset of patients with AECOPD and ARF managed with NIV have been extensively published over the last two decades. This review summarizes the perception of medical staff vs. the "real life" data about NIV use for ARF in AECOPD patients. PMID- 28636453 TI - Testing the efficacy of existing force-endurance models to account for the prevalence of obesity in the workforce. AB - This study evaluates whether the existing force-endurance relationship models are predictive of endurance time for overweight and obese individuals, and if not, provide revised models that can be applied for ergonomics practice. Data was collected from 141 participants (49 normal weight, 50 overweight, 42 obese) who each performed isometric endurance tasks of hand grip, shoulder flexion, and trunk extension at four levels of relative workload. Subject-specific fatigue rates and a general model of the force-endurance relationship were determined and compared to two fatigue models from the literature. There was a lack of fit between previous models and the current data for the grip (ICC = 0.8), with a shift toward lower endurance times for the new data. Application of the revised models can facilitate improved workplace design and job evaluation to accommodate the capacities of the current workforce. PMID- 28636454 TI - Anticancer potential of sanguinarine for various human malignancies. AB - Sanguinarine (Sang) - a benzophenanthridine alkaloid extracted from Sanguinaria canadensis - exhibits antioxidant, anti-inflammatory, proapoptotic and growth inhibitory activities on tumor cells of various cancer types as established by in vivo and in vitro studies. Although the underlying mechanism of Sang antitumor activity is yet to be fully elucidated, Sang has displayed multiple biological effects, which remain to suggest its possible use in plant-derived treatments of human malignancies. This review covers the anticancer abilities of Sang including inhibition of aberrantly activated signal transduction pathways, induction of cell death and inhibition of cancer cell proliferation. It also highlights Sang mediated inhibition of angiogenesis, inducing the expression of tumor suppressors, sensitization of cancer cells to standard chemotherapeutics to enhance their cytotoxic effects, while addressing the present need for further pharmacokinetic-based studies. PMID- 28636455 TI - The Role of the Healthcare Chaplain: A Literature Review. AB - Healthcare chaplains operate in many healthcare sites internationally and yet their contribution is not always clearly understood by medical and healthcare staff. This review aims to explore the chaplains' role in healthcare, with a view to informing best practice in future healthcare chaplaincy. Overall the extent of the provision and staffing of chaplaincy service internationally is unclear. From this review, several key spiritual and pastoral roles in healthcare emerge including a potential contribution to ethical decision making at the end of life. Healthcare chaplains are key personnel, already employed in many healthcare organizations, who are in a pivotal position to contribute to future developments of faith-based care, faith-sensitive pastoral, and spiritual care provision. They also have a new and evolving role in ethical support of patient, families and healthcare teams. PMID- 28636456 TI - Healthcare System in Indonesia. AB - The cultural diversity, its archipelago, and the major religion being Muslim have all influenced the development of the healthcare in Indonesia. The authors' objective is to describe the evolution of the healthcare system in Indonesia. Community-based health service, called puskesmas, is the key of the healthcare service in the country. The World Health Organization estimated that 64% of all deaths in Indonesia are caused by noncommunicable diseases, which might relate to the mostly unorganized prehospital care system. The healthcare system in Indonesia continues to improve its care delivery and outcomes by an escalation in the number of health services. PMID- 28636457 TI - NOTCH signaling in lung diseases. AB - NOTCH is a fundamental signaling system that regulates normal embryonic development and tissue homeostasis in adult life. NOTCH receptor is a single-pass transmembrane protein normally triggered via direct cell-to-cell contact, in which NOTCH ligands bind the extracellular domain of the receptor, inducing gamma secretase cleavage and release of intracellular domain. The intracellular domain binds to the transcriptional effector RBPJkappa to activate transcription of target genes that regulate cell differentiation, patterning, and morphogenesis during embryonic development and adult life. Specifically, NOTCH plays an essential role in the development and homeostasis of the lung. Aberrations in NOTCH signaling or components of the signaling system have been linked to various pulmonary pathological conditions. We herein provide a brief overview of collective in vitro and in vivo studies of NOTCH signaling to illustrate its regulatory functions in lung diseases, including asthma, chronic obstructive pulmonary disease, pulmonary arterial hypertension, and lung cancer. We also discuss the mechanisms underlying the regulatory role of NOTCH in these pathological conditions and the potential of NOTCH-targeted therapies for the treatment of these diseases. PMID- 28636458 TI - Contamination of firefighter personal protective equipment and skin and the effectiveness of decontamination procedures. AB - Firefighters' skin may be exposed to chemicals via permeation/penetration of combustion byproducts through or around personal protective equipment (PPE) or from the cross-transfer of contaminants on PPE to the skin. Additionally, volatile contaminants can evaporate from PPE following a response and be inhaled by firefighters. Using polycyclic aromatic hydrocarbons (PAHs) and volatile organic compounds (VOCs) as respective markers for non-volatile and volatile substances, we investigated the contamination of firefighters' turnout gear and skin following controlled residential fire responses. Participants were grouped into three crews of twelve firefighters. Each crew was deployed to a fire scenario (one per day, four total) and then paired up to complete six fireground job assignments. Wipe sampling of the exterior of the turnout gear was conducted pre- and post-fire. Wipe samples were also collected from a subset of the gear after field decontamination. VOCs off-gassing from gear were also measured pre fire, post-fire, and post-decon. Wipe sampling of the firefighters' hands and neck was conducted pre- and post-fire. Additional wipes were collected after cleaning neck skin. PAH levels on turnout gear increased after each response and were greatest for gear worn by firefighters assigned to fire attack and to search and rescue activities. Field decontamination using dish soap, water, and scrubbing was able to reduce PAH contamination on turnout jackets by a median of 85%. Off-gassing VOC levels increased post-fire and then decreased 17-36 min later regardless of whether field decontamination was performed. Median post-fire PAH levels on the neck were near or below the limit of detection (< 24 micrograms per square meter [ug/m2]) for all positions. For firefighters assigned to attack, search, and outside ventilation, the 75th percentile values on the neck were 152, 71.7, and 39.3 ug/m2, respectively. Firefighters assigned to attack and search had higher post-fire median hand contamination (135 and 226 ug/m2, respectively) than other positions (< 10.5 ug/m2). Cleansing wipes were able to reduce PAH contamination on neck skin by a median of 54%. PMID- 28636460 TI - Evaluation of Bovine High-Density SNP Genotyping Array in Indigenous Dairy Cattle Breeds. AB - In total 52 samples of Sahiwal ( 19 ), Tharparkar ( 17 ), and Gir ( 16 ) were genotyped by using BovineHD SNP chip to analyze minor allele frequency (MAF), genetic diversity, and linkage disequilibrium among these cattle. The common SNPs of BovineHD and 54K SNP Chips were also extracted and evaluated for their performance. Only 40%-50% SNPs of these arrays was found informative for genetic analysis in these cattle breeds. The overall mean of MAF for SNPs of BovineHD SNPChip was 0.248 +/- 0.006, 0.241 +/- 0.007, and 0.242 +/- 0.009 in Sahiwal, Tharparkar and Gir, respectively, while that for 54K SNPs was on lower side. The average Reynold's genetic distance between breeds ranged from 0.042 to 0.055 based on BovineHD Beadchip, and from 0.052 to 0.084 based on 54K SNP Chip. The estimates of genetic diversity based on HD and 54K chips were almost same and, hence, low density chip seems to be good enough to decipher genetic diversity of these cattle breeds. The linkage disequilibrium started decaying (r2 < 0.2) at 140 kb inter-marker distance and, hence, a 20K low density customized SNP array from HD chip could be designed for genomic selection in these cattle else the 54K Bead Chip as such will be useful. PMID- 28636459 TI - Inhibition of Fusarium solani Infection in Murine Keratocytes by Lactobacillus salivarius ssp. salivarius JCM1231 Culture Filtrate In Vitro. AB - PURPOSE: To explore the inhibitory activity of Lactobacillus salivarius ssp. salivarius JCM1231 (L. salivarius JCM1231) culture filtrate against Fusarium solani (F. solani) and its effects on murine keratocytes (MKs) infected with F. solani. METHODS: L. salivarius JCM1231 was cultured in an anaerobic incubator for 24 h, and the L. salivarius culture filtrate (LSCF) was prepared .The antifungal activity of L. salivarius JCM1231 against F. solani was determined with a plate overlay assay, agar diffusion assay, and conidial germination inhibition test. The effects of temperature, pH, and proteolytic enzymes on the antifungal activity of LSCF were detected with microtiter plate-well assay and conidial germination inhibition assay. Furthermore, the effects of LSCF on MKs infected with F. solani were detected. Cell activity and apoptosis were measured using methylthiazoletetrazolium assays and flow cytometry analysis, respectively. The levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) cytokines were measured using real-time polymerase chain reactions and enzyme linked immunosorbent assays (ELISA), and mycotoxin production was detected with high-performance liquid chromatography tandem mass spectrometry. RESULTS: Conidial germination and mycelia growth of F. solani were significantly inhibited by LSCF. The antifungal substances produced by L. salivarius JCM1231 were heat unstable, proteinaceous, and sensitive to proteolytic enzymes and were active within a narrow acidic pH range between 2.0 and 4.0. In the presence of 15 ug/ml of LSCF, cell activity was significantly increased, and cell apoptosis, the level of IL-6 and TNF-alpha expressions, and mycotoxin (zearalenone and fumonisin B1) productions were decreased significantly in MKs infected with F. solani. CONCLUSION: L. salivarius JCM1231 culture filtrate can effectively inhibit F. solani growth and protect MKs against F. solani infection. PMID- 28636461 TI - GeNICE: A Novel Framework for Gene Network Inference by Clustering, Exhaustive Search, and Multivariate Analysis. AB - Gene network (GN) inference from temporal gene expression data is a crucial and challenging problem in systems biology. Expression data sets usually consist of dozens of temporal samples, while networks consist of thousands of genes, thus rendering many inference methods unfeasible in practice. To improve the scalability of GN inference methods, we propose a novel framework called GeNICE, based on probabilistic GNs; the main novelty is the introduction of a clustering procedure to group genes with related expression profiles and to provide an approximate solution with reduced computational complexity. We use the defined clusters to perform an exhaustive search to retrieve the best predictor gene subsets for each target gene, according to multivariate criterion functions. GeNICE greatly reduces the search space because predictor candidates are restricted to one gene per cluster. Finally, a multivariate analysis is performed for each defined predictor subset to retrieve minimal subsets and to simplify the network. In our experiments with in silico generated data sets, GeNICE achieved substantial computational time reduction when compared to solutions without the clustering step, while preserving the gene expression prediction accuracy even when the number of clusters is small (about 50) relative to the number of genes (order of thousands). For a Plasmodium falciparum microarray data set, the prediction accuracy achieved by GeNICE was roughly 97%, while the respective topologies involving glycolytic and apicoplast seed genes had a very large intramodularity, very small interconnection between modules, and some module hub genes, reflecting small-world and scale-free topological properties, as expected. PMID- 28636462 TI - Are Commercial Complementary Food Distributions to Refugees and Migrants in Europe Conforming to International Policies and Guidelines on Infant and Young Child Feeding in Emergencies? AB - In 2015, more than one million migrants and refugees arrived in Europe. Commercial complementary foods, processed foods marketed for infants and young children 6-23 months of age, were distributed by various humanitarian actors along migrant routes and in European refugee camps. Unsolicited donations and distributions of commercial complementary food products were problematic and divergent from international policies on infant and young child feeding during humanitarian emergencies. Interim guidance regarding commercial complementary foods was published during the peak of the emergency but implemented differently by various humanitarian actors. Clearer and more technical specifications on commercial complementary foods are needed in order to objectively determine their suitability for operational contexts in Europe and emergency nutrition assistance in the future. PMID- 28636463 TI - Optimization of an anti-HER2 nanobody expression using the Taguchi method. AB - Despite being widely used in immunotherapy of cancer, whole antibodies are limited by several disadvantages. This has led to the advent of novel biomolecules such as nanobodies. Taguchi method is a statistical experimental design to study the effect of multiple variables in biological processes. In an effort to overexpress a recombinant anti-human epidermal growth factor receptor type 2 (HER2) nanobody, we performed a detailed study to find optimal condition of temperature, induction, culture media, vector, and host strain, using Taguchi methodology. A total of 16 various experiments were designed. Total protein of the formulated cultures were assessed by Bradford test and sodium dodecyl sulfate polyacrylamide gel electrophoresis, followed by size exclusion high performance liquid chromatography to quantify the relative concentration of the nanobody in different expression settings. Western blotting was performed to confirm the expression of the anti-HER2 nanobody. When, individually, optimum parameters determined by Taguchi were applied, including SHuffle strain cultured in LB medium, induced with 0.4 mM isopropyl-beta-D-thio-galactoside for 18 h at 24 degrees C, production yield further increased by about 9% (25.4 mg/L), compared to the highest expression setting. Flow cytometry and enzyme-linked immunosorbent assay result indicated improved protein binding in optimized conditions. Overall, our findings provide a basis for further investigations on economical production of recombinant nanobodies to improve production yield and activity. PMID- 28636464 TI - Understanding the pluses of pulses. PMID- 28636466 TI - Erratum. PMID- 28636465 TI - Evaluation of the Xpert Norovirus assay for the rapid detection of norovirus genogroups I and II in faecal specimens within a routine laboratory setting. PMID- 28636467 TI - Normal epithelial cells trigger EphA2-dependent RasV12 cell repulsion at the single cell level. AB - Epithelial cells expressing oncogenic Ras (RasV12) are detected by normal neighbors and are often extruded from tissues. We recently demonstrated that differential EphA2 signaling drives the segregation of mutant cells from normal monolayers via cell repulsion and increased RasV12 cell contractility. EphA2 signaling on RasV12 cells is triggered by ephrin-A ligands presented by normal cells. Here, we show that normal epithelial cells trigger the repulsion and enhanced contractility of Ras-transformed epithelial cells at the single cell level. We also reveal that ephrin-A ligands expressed on RasV12 cells are not required to drive RasV12 cell segregation following interaction with normal cells. Thus, normal-RasV12 cell-cell interaction triggers EphA2 forward signaling in RasV12 cells to drive repulsion and segregation of the transformed cells. PMID- 28636468 TI - Do Ligamentum Teres Tears Portend Inferior Outcomes in Patients With Borderline Dysplasia Undergoing Hip Arthroscopic Surgery? A Match-Controlled Study With a Minimum 2-Year Follow-up. AB - BACKGROUND: Arthroscopic surgery in borderline dysplastic hips remains controversial, but the role of the ligamentum teres (LT) has not been studied in this setting. HYPOTHESIS: Borderline dysplastic patients with LT tears have worse short-term outcomes than those without LT tears. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were prospectively collected on patients who underwent arthroscopic surgery between February 2008 and April 2014. The inclusion criteria were borderline dysplasia (lateral center-edge angle [LCEA], 18 degrees -25 degrees ) and labral tears; arthroscopic treatments including labral preservation and capsular plication; and preoperative patient-reported outcome scores including the modified Harris Hip Score (mHHS), Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Sport-Specific Subscale, and visual analog scale for pain. Patients were excluded for preoperative Tonnis osteoarthritis grade >0, workers' compensation claims, previous ipsilateral hip surgery and conditions, or frank dysplasia (LCEA <18 degrees ). Patients with LT tears were pair-matched to patients without tears for sex, age at surgery +/-10 years, body mass index (<30 kg/m2 vs >=30 kg/m2), labral treatment type, and microfracture. RESULTS: Of 68 eligible patients, 63 (93%) had a minimum 2-year follow-up, and 30 (48%) had LT tears. Twenty patients in each group were pair-matched. The mean follow-up time was 54.3 months (range, 24.2-83.8 months) for the LT tear group and 38.6 months (range, 24.6-70.6 months) for the control group ( P = .002). Ninety percent were female. There were no significant differences regarding demographics or intra operative procedures. The LT tear group trended toward lower postoperative mHHS ( P = .09) and NAHS ( P = .09) values. Mean satisfaction was 8.1 for the LT tear group and 7.9 for the control group. Preoperative and follow-up scores were not significantly different between the groups. The LT tear group had 5 revisions, with 1 revision in the control group. Three patients (15%) in the LT tear group underwent total hip arthroplasty (THA); no patients in the control group required THA. CONCLUSION: In borderline dysplastic patients undergoing hip arthroscopic surgery with labral treatment and capsular plication, LT tears may indicate advanced instability and portend slightly inferior outcomes when compared with a match-controlled group. Borderline dysplastic patients with LT tears may have increased propensities toward revision arthroscopic surgery and conversion to THA. LT tears in these patients may warrant consideration for additional procedures including periacetabular osteotomy and LT reconstruction. PMID- 28636469 TI - Ten new species of Macalpinomyces on Eriachne in northern Australia. AB - Macalpinomyces was established in 1977, with the type species M. eriachnes described from a specimen collected in northern Australia on the grass Eriachne sp. in 1855. Subsequently, M. eriachnes has been reported on more than 21 species of Eriachne in northern Australia. In this study, a polyphasic approach was employed to determine whether M. eriachnes masked cryptic diversity. On the basis of morphology, multilocus phylogeny, and coalescent methods of generalized mixed Yule-coalescent (GMYC) and Poisson tree processes (PTP) models, 26 specimens of Macalpinomyces on 13 species of Eriachne held in Australian herbaria were studied. Consequently, 10 new species of Macalpinomyces that satisfied the phylogenetic species recognition criteria are described. PMID- 28636470 TI - Reply to 'Highly selective A3 adenosine receptor agonists relieve chronic neuropathic pain'. PMID- 28636471 TI - Laparoscopic colectomy in a district hospital: the single surgeon can be safe. AB - BACKGROUND: Several outcome measures have been identified for colorectal surgery and published in the literature. This study sought to compare outcomes of high volume laparoscopic colectomy by a single surgeon in a district hospital with outcomes from tertiary referral centres. METHODS: This was a retrospective review of elective laparoscopic colectomy by a single laparoscopic general surgeon in a district hospital over a 51-month period using a prospectively maintained database. The key outcome measures studied were length of hospital stay, conversion to open, anastomotic leak, wound infection, re-admission and 30-day mortality. RESULTS: 187 elective laparoscopic colectomies were performed at the Kent and Canterbury Hospital between July 2008 and October 2012. The median patient age was 69 years (range 22-90 years). Median length of hospital stay was 4 days (range 1-48 days). Anastomotic leak occurred in 4 (2.1%) patients. Seven (3.7%) patients underwent conversion to open surgery. Re-admission occurred in 4 (2.1%) patients for small bowel obstruction (1), wound infection (1), anastomotic leak (1) and colo-vaginal fistula (1). There was one post-operative death from severe chest infection (0.5%). These results are similar to those published by tertiary referral centres. CONCLUSIONS: This study of outcomes at a district hospital shows that the outcome reported from laparoscopic colorectal surgery in tertiary referral centres is reproducible at the district hospital level by a single surgeon with a high operative volume. PMID- 28636472 TI - Benign tumors of the parotid gland: a retrospective study of 339 patients. AB - AIM: Among 339 patients operated for benign tumor of the parotid gland: the recurrences and the postoperative complications rates were compared WITH those published in literature. MATERIALS AND METHODS: About 339 patients operated: 274 primarily and 65 for recurrence or residual tumor. VARIABLES: sex, age, surgical techniques, pre- or postoperative radiotherapy, histology, size and localization of the tumors, disease free intervals, recurrences and postoperative complications. RESULTS: 177 men and 162 women. Median age: 55 years and mean follow-up: 10.4 years. About 39 patients had adjuvant radiotherapy (11.5%). After primary surgery, four patients experienced recurrences (1.5%). After salvage surgery, eight patients recurred (12.3%). The recurrence rate was the highest among pleomorphic adenomas. Facial paralysis was more frequent after salvage surgery. DISCUSSION: Recurrence rate 10 years later was lower after primary than after salvage surgery (p = 0.01). There was no relation between adjuvant radiotherapy and recurrence rate probably because the low rate of recurrences. CONCLUSION: Recurrence rate after primary surgery is lower after superficial or total parotidectomy than after other surgical techniques. Pleomorphic adenomas have the highest rate of recurrences. Age and sex have no significant influence over the rate of recurrences. The most frequent postoperative complications are facial paralysis and Frey's syndrome. PMID- 28636473 TI - The preventive effect of ambroxol hydrochloride chitosan on postoperative intraperitoneal adhesion formation in a rat model. AB - BACKGROUND: This study aimed to investigate the effects of ambroxol hydrochloride chitosan reduced the degree of peritoneal adhesion. METHODS: A total of 120 Sprague-Dawley (SD) rats were experimented, group A: the damaged peritoneal was covered with ambroxol hydrochloride chitosan, group B: chitosan membrane only, group C: nothing. Enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry (IHC) were used to observe the expression of TNF-alpha and NF-kappaB p65. RESULTS: TNF-alpha and NF-kappaB p65 in group A significantly decreased in comparison with the controls. IHC showed TNF-alpha and NF-kappaB p65 were significantly down-regulated in group A. Adhesion grade in the treatment group was significantly lower than in controls. CONCLUSION: Ambroxol hydrochloride chitosan reduced the degree of peritoneal adhesion. PMID- 28636474 TI - Lumbar artery perforators: an anatomical study based on computed tomographic angiography imaging. AB - BACKGROUND: The free lumbar artery perforator flap has recently been introduced as a potentially valuable option for autologous breast reconstruction in a subset of patients. Up to date, few anatomical studies, exploring the lumbar region as a donor site for perforator- based flaps, have been conducted. METHODS: An anatomical study of the position of the dominant lumbar artery perforator was performed, using the preoperative computed tomographic angiography images of 24 autologous breast reconstruction patients. In total, 61 dominant perforators were determined, 28 on the left and 33 on the right side. A radiologist defined the position of the perforator as coordinates in an xy-grid. RESULTS: Dominant perforators were shown to originate from the lumbar arteries at the level of lumbar vertebrae three or four. Remarkably, approximately 85% of these lumbar artery perforators enter the skin at 7-10 cm lateral from the midline (mean left 8.6 cm, right 8.2 cm). CONCLUSION: This study concludes a rather constant position of the dominant perforator. Therefore, preoperative-computed tomographic angiography is not always essential to find this perforator and Doppler ultrasound could be considered as an alternative, thereby carefully assessing all advantages and disadvantages inherent to either of these imaging methods. PMID- 28636475 TI - Surgical aortic valve replacement for stenosis of TAVI device. AB - We here report the case of a stenosis of the CoreValve(r) system due to reduced mobility of prosthesis cusps for which a surgical replacement of the aortic valve was proposed. The exact mechanism leading to this impaired mobility of the leaflets is yet to be determined. We also underline the fact a transcatheter aortic valve implantation (TAVI) device can be replaced by a surgical replacement without excessive operative risks despite the patient being initially considered as high-risk. PMID- 28636476 TI - An intradural, subpial lipoma. AB - Introduction - patients: Intradural lipomas are rare congenital tumors. A case of intradural lipoma in the absence of any congenital spinal anomalies is reported. Patient presented with spinal cord compression syndrome. Methods - results - conclusions: Treatment of this disorder is still controversial. PMID- 28636477 TI - Three-axial evaluation of whole-body vibration in agricultural telehandlers: The effects of an active cab-suspension system. AB - Agricultural and earth-moving machinery operators are particularly exposed to whole-body vibration (WBV), which has severe effects on health and affects comfort and performance. Few studies have investigated vibrational safety and comfort issues in telescopic handlers. These vehicles are widespread in many off road applications-such as construction, agriculture, and mining-used to handle loads and to lift persons and equipment. This study investigated the effects of an active hydro-pneumatic cab-suspension system fitted to a telehandler on a driver's vibration exposure along the x-, y-, and z-axes, through both objective and subjective assessments. Sixteen healthy professional telehandler drivers took part in the study. Objective measurements were acquired at the operator's seat, and subjective ratings were taken while participants drove the telehandler with either a deactivated or activated suspension system at 12 kph on an ISO 5008 smooth track. The results showed that the activation of the cab-suspension system reduced the root-mean-square acceleration along the x- and z-axes (p =.038 and p =.000, respectively). Moreover, the frequency analysis showed a reduction in the acceleration along the z-axis in the range of 2-25 Hz (p <.05 for all comparisons); in particular, the acceleration was reduced by 50% in the higher frequency range (4-20 Hz). A reduction in the vibration intensity was perceived by the participants along the y- and z-axes (p =.009 and p =.003, respectively). Implications for the future development of suspension systems are discussed. PMID- 28636478 TI - Pathway and rate-limiting step of glyphosate degradation by Aspergillus oryzae A F02. AB - Aspergillus oryzae A-F02, a glyphosate-degrading fungus, was isolated from an aeration tank in a pesticide factory. The pathway and rate-limiting step of glyphosate (GP) degradation were investigated through metabolite analysis. GP, aminomethylphosphonic acid (AMPA), and methylamine were detected in the fermentation liquid of A. oryzae A-F02, whereas sarcosine and glycine were not. The pathway of GP degradation in A. oryzae A-F02 was revealed: GP was first degraded into AMPA, which was then degraded into methylamine. Finally, methylamine was further degraded into other products. Investigating the effects of the exogenous addition of substrates and metabolites showed that the degradation of GP to AMPA is the rate-limiting step of GP degradation by A. oryzae A-F02. In addition, the accumulation of AMPA and methylamine did not cause feedback inhibition in GP degradation. Results showed that degrading GP to AMPA was a crucial step in the degradation of GP, which determines the degradation rate of GP by A. oryzae A-F02. PMID- 28636479 TI - Decrements in knee extensor and flexor strength are associated with performance fatigue during simulated basketball game-play in adolescent, male players. AB - This study quantified lower-limb strength decrements and assessed the relationships between strength decrements and performance fatigue during simulated basketball. Ten adolescent, male basketball players completed a circuit based, basketball simulation. Sprint and jump performance were assessed during each circuit, with knee flexion and extension peak concentric torques measured at baseline, half-time, and full-time. Decrement scores were calculated for all measures. Mean knee flexor strength decrement was significantly (P < 0.05) related to sprint fatigue in the first half (R = 0.65), with dominant knee flexor strength (R = 0.67) and dominant flexor:extensor strength ratio (R = 0.77) decrement significantly (P < 0.05) associated with sprint decrement across the entire game. Mean knee extensor strength (R = 0.71), dominant knee flexor strength (R = 0.80), non-dominant knee flexor strength (R = 0.75), mean knee flexor strength (R = 0.81), non-dominant flexor:extensor strength ratio (R = 0.71), and mean flexor:extensor strength ratio (R = 0.70) decrement measures significantly (P < 0.05) influenced jump fatigue during the entire game. Lower limb strength decrements may exert an important influence on performance fatigue during basketball activity in adolescent, male players. Consequently, training plans should aim to mitigate lower-limb fatigue to optimise sprint and jump performance during game-play. PMID- 28636480 TI - The Emerging Role of Pimavanserin in the Management of Parkinson's Disease Psychosis. AB - : A panel of experts drawn from neurology, psychiatry, geropsychiatry, geriatrics, and pharmacy representatives of 3 health plans convened in New York City on July 30, 2016, with the objective of sharing opinions, ideas, and information regarding the optimal management of Parkinson's disease psychosis (PDP). Three key points emerged from the discussion: (1) Because of the nature of Parkinson's disease and PDP, finding appropriate treatment can prove challenging; (2) emerging therapies may present an opportunity for effective disease management; and (3) moving forward, provider and patient education regarding PDP and available treatment options is essential for well-managed symptoms and better quality of life. The panel reviewed current practices and formulated recommendations on moving forward in the treatment of PDP. DISCLOSURES: This project and manuscript was funded by ACADIA Pharmaceuticals and developed by Magellan Rx Management. Lopes and Farnum are employees of Magellan Rx Management. Kremens has received consulting/speaker fees from Teva Pharmaceuticals, UCB, Sunovion, Impax, Lundbeck, ACADIA, USWorldMeds, Merz, Acorda, Kyowa, Neurocrine, and GE Healthcare. Pagan reports consulting/speaker fees from Teva Nanoscience, AbbVie, Impax, ACADIA, Medtronic, USWorldMeds, Merz, and Cynapsus and research and educational grants from USWorldMeds, Teva, and Medtronic. Patel has received consultant/speaker fees from ACADIA, Allergen, and Avanir. Alva reports research support from Accera, Allergan, Axovant, Eisai, Neurotrope, Genentech, Intra Cellular, Janssen, Lundbeck, Neurim, Novartis, Otsuka, Roche, Suven, and Trans Tech and consultant/speaker fees from ACADIA, Alkermes, Allergan, Avanir, Janssen, Lundbeck, Merck, Nestle, Otsuka, Sunovion, Takeda, and Vanda. The other authors report no potential conflicts of interest, financial or otherwise. PMID- 28636481 TI - Turmoil in the Individual Insurance Market - Where It Came From and How to Fix It. PMID- 28636482 TI - Impact of freeway weaving segment design on light-duty vehicle exhaust emissions. AB - : In the United States, 26% of greenhouse gas emissions is emitted from the transportation sector; these emisssions meanwhile are accompanied by enormous toxic emissions to humans, such as carbon monoxide (CO), nitrogen oxides (NOx), and hydrocarbon (HC), approximately 2.5% and 2.44% of a total exhaust emissions for a petrol and a diesel engine, respectively. These exhaust emissions are typically subject to vehicles' intermittent operations, such as hard acceleration and hard braking. In practice, drivers are inclined to operate intermittently while driving through a weaving segment, due to complex vehicle maneuvering for weaving. As a result, the exhaust emissions within a weaving segment ought to vary from those on a basic segment. However, existing emission models usually rely on vehicle operation information, and compute a generalized emission result, regardless of road configuration. This research proposes to explore the impacts of weaving segment configuration on vehicle emissions, identify important predictors for emission estimations, and develop a nonlinear normalized emission factor (NEF) model for weaving segments. An on-board emission test was conducted on 12 subjects on State Highway 288 in Houston, Texas. Vehicles' activity information, road conditions, and real-time exhaust emissions were collected by on-board diagnosis (OBD), a smartphone-based roughness app, and a portable emission measurement system (PEMS), respectively. Five feature selection algorithms were used to identify the important predictors for the response of NEF and the modeling algorithm. The predictive power of four algorithm-based emission models was tested by 10-fold cross-validation. Results showed that emissions are also susceptible to the type and length of a weaving segment. Bagged decision tree algorithm was chosen to develop a 50-grown-tree NEF model, which provided a validation error of 0.0051. The estimated NEFs are highly correlated with the observed NEFs in the training data set as well as in the validation data set, with the R values of 0.91 and 0.90, respectively. IMPLICATIONS: Existing emission models usually rely on vehicle operation information to compute a generalized emission result, regardless of road configuration. In practice, while driving through a weaving segment, drivers are inclined to perform erratic maneuvers, such as hard braking and hard acceleration due to the complex weaving maneuver required. As a result, the exhaust emissions within a weaving segment vary from those on a basic segment. This research proposes to involve road configuration, in terms of the type and length of a weaving segment, in constructing an emission nonlinear model, which significantly improves emission estimations at a microscopic level. PMID- 28636483 TI - Lumping kinetics of ABE fermentation wastewater treatment by oleaginous yeast Trichosporon cutaneum. AB - Lumping kinetics models were built for the biological treatment of acetone butanol-ethanol (ABE) fermentation wastewater by oleaginous yeast Trichosporon cutaneum with different fermentation temperatures. Compared with high temperature (33 degrees C, 306 K) and low temperature (23 degrees C, 296 K), medium temperature (28 degrees C, 301 K) was beneficial for the cell growth and chemical oxygen demand (COD) degradation during the early stage of fermentation but the final yeast biomass and COD removal were influenced little. By lumping method, the materials in the bioconversion network were divided into five lumps (COD, lipid, polysaccharide, other intracellular products, other extracellular products), and the nine rate constants (k1-k9) for the models can well explain the bioconversion laws. The Gibbs free energy (G) for this bioconversion was positive, showing that it cannot happen spontaneous, but the existence of yeast can after the chemical equilibrium and make the bioconversion to be possible. Overall, the possibility of using lumping kinetics for elucidating the laws of materials conversion in the biological treatment of ABE fermentation wastewater by T. cutaneum has been initially proved and this method has great potential for further application. PMID- 28636484 TI - Bezlotoxumab: anti-toxin B monoclonal antibody to prevent recurrence of Clostridium difficile infection. AB - INTRODUCTION: Clostridium difficile infection (CDI) is the most common nosocomial infection in the U.S. 25% of CDI patients go on to develop recurrent CDI (rCDI) following current standard of care (SOC) therapy, leading to morbidity, mortality and economic loss. The first passive immunotherapy drug targeting C.difficile toxin B (bezlotoxumab) has been approved recently by the FDA and EMA for prevention of rCDI. Areas covered: A body of key studies was selected and reviewed by the authors. The unmet needs in CDI care were ascertained with emphasis in rCDI, including the epidemiology, pathophysiology and current management. The current knowledge about the immune response to C. difficile toxins and how this knowledge led to the development and the clinical use of bezlotoxumab is described. Current and potential future competitors to the drug were examined. Expert commentary: A single 10 mg/kg intravenous infusion of bezlotoxumab has been shown to decrease rCDI by ~40% (absolute reduction ~10%) in patients being treated for primary CDI or rCDI with SOC antibiotics. Targeting C.difficile toxins by passive immunotherapy is a novel mechanism for prevention of C.difficile infection. Bezlotoxumab will be a valuable adjunctive therapy to reduce the burden of CDI. PMID- 28636485 TI - Mineralocorticoids modulate the expression of the beta-3 subunit of the Na+, K+ ATPase in the renal collecting duct. AB - Renal sodium reabsorption depends on the activity of the Na+,K+-ATPase alpha/beta heterodimer. Four alpha (alpha1-4) and 3 beta (beta1-3) subunit isoforms have been described. It is accepted that renal tubule cells express alpha1/beta1 dimers. Aldosterone stimulates Na+,K+-ATPase activity and may modulate alpha1/beta1 expression. However, some studies suggest the presence of beta3 in the kidney. We hypothesized that the beta3 isoform of the Na+,K+-ATPase is expressed in tubular cells of the distal nephron, and modulated by mineralocorticoids. We found that beta3 is highly expressed in collecting duct of rodents, and that mineralocorticoids decreased the expression of beta3. Thus, we describe a novel molecular mechanism of sodium pump modulation that may contribute to the effects of mineralocorticoids on sodium reabsorption. PMID- 28636486 TI - Spirituality, Religion, and Suicidality Among Veterans: A Qualitative Study. AB - This qualitative study explores the relationship between veterans' spirituality/religion and suicide ideation and attempts. Qualitative semi structured interviews were conducted with 30 veterans who either endorsed chronic suicidal ideation or had made suicide attempt(s). Interviews explored the bi directional relationship between spirituality/religion (e.g., beliefs, practices, and experiences), and suicide ideation and behaviors. Interviews were analyzed using thematic analysis. Veterans' responses indicate that spirituality/religion can discourage or permit suicidal ideation, help in coping with ideation, and facilitate meaning making and coping in the presence of self-perceived suffering. Veterans who survived a suicide attempt explored the impact of their spirituality/religion on their recovery. Findings highlight a complex and diverse relationship between spirituality/religion and suicidality. These findings may inform further research on treatment strategies that assess the function of spirituality/religion, and incorporate protective aspects of spirituality/religion into mental health treatment. PMID- 28636487 TI - Internalized Homonegativity, Confucianism, and Self-Esteem at the Emergence of an LGBTQ Identity in Modern Vietnam. AB - We examine the relationships between internalized homonegativity, Confucianism, and self-esteem among LGBTQ adults who grew up during the Open Door Policy, or Doi Moi, in Vietnam. Participants were identified via activist networks and social media groups. They completed online survey focused on internalized homo/transphobia, self-esteem, and Confucian values. The study revealed that more exposure to Confucian values in early life is related to higher levels of internalized homonegativity. Male-born participants also had a higher level of internalized homonegativity than female-born participants. In general, lower levels of self-esteem were also related to higher levels of internalized homonegativity. We discuss the implications of these findings in light of conflicting values between Confucianism and the economic and social transformation that has occurred under Doi Moi. PMID- 28636488 TI - Workers' exposure to bioaerosols from three different types of composting facilities. AB - Composting is a natural dynamic biological process used to valorise putrescible organic matter. The composting process can involve vigorous movements of waste material piles, which release high concentrations of bioaerosols into the surrounding environment. There is a lack of knowledge concerning the dispersal of airborne microorganisms emitted by composting plants (CP) as well as the potential occupational exposure of composting workers. The aim of this study was to investigate the workers exposure to bioaerosols during working activities in three different types of composting facilities (domestic, manure, carcass) using two different quantification methods (cultivation and qPCR) for bacteria and moulds concentrations. As expected, even if there are differences between all CP frameworks, independently of the type of the raw compost used, the production of bioaerosols increases significantly during handling activities. Important concentrations of mesophilic moulds and mesophilic bacteria were noted in the working areas with a respective maximal concentration of 2.3 * 105 CFU/m3 and 1.6 * 105 CFU/m3. A. fumigatus and thermophilic Actinomycetes were also detected in all working areas for the 3 CP. This study emphases the risks for workers to being in contact with aerosolized pathogens such as Mycobacterium and Legionella and more specifically, L. pneumophila. The presence of high concentration of these bacteria in CP suggests a potential occupational health risk. This study may lead to recommendations for the creation of limits for occupational exposure. There is a need for identifying the standards exposure limits to bioaerosols in CP and efficient recommendation for a better protection of workers' health. PMID- 28636489 TI - Evaluation of countermeasures for red light running by traffic simulator-based surrogate safety measures. AB - OBJECTIVE: The conflicts among motorists entering a signalized intersection with the red light indication have become a national safety issue. Because of its sensitivity, efforts have been made to investigate the possible causes and effectiveness of countermeasures using comparison sites and/or before-and-after studies. Nevertheless, these approaches are ineffective when comparison sites cannot be found, or crash data sets are not readily available or not reliable for statistical analysis. Considering the random nature of red light running (RLR) crashes, an inventive approach regardless of data availability is necessary to evaluate the effectiveness of each countermeasure face to face. METHOD: The aims of this research are to (1) review erstwhile literature related to red light running and traffic safety models; (2) propose a practical methodology for evaluation of RLR countermeasures with a microscopic traffic simulation model and surrogate safety assessment model (SSAM); (3) apply the proposed methodology to actual signalized intersection in Virginia, with the most prevalent scenarios increasing the yellow signal interval duration, installing an advance warning sign, and an RLR camera; and (4) analyze the relative effectiveness by RLR frequency and the number of conflicts (rear-end and crossing). RESULTS: All scenarios show a reduction in RLR frequency (-7.8, -45.5, and -52.4%, respectively), but only increasing the yellow signal interval duration results in a reduced total number of conflicts (-11.3%; a surrogate safety measure of possible RLR-related crashes). An RLR camera makes the greatest reduction ( 60.9%) in crossing conflicts (a surrogate safety measure of possible angle crashes), whereas increasing the yellow signal interval duration results in only a 12.8% reduction of rear-end conflicts (a surrogate safety measure of possible rear-end crash). CONCLUSIONS: Although increasing the yellow signal interval duration is advantageous because this reduces the total conflicts (a possibility of total RLR-related crashes), each countermeasure shows different effects by RLR related conflict types that can be referred to when making a decision. Given that each intersection has different RLR crash issues, evaluated countermeasures are directly applicable to enhance the cost and time effectiveness, according to the situation of the target intersection. In addition, the proposed methodology is replicable at any site that has a dearth of crash data and/or comparison sites in order to test any other countermeasures (both engineering and enforcement countermeasures) for RLR crashes. PMID- 28636490 TI - Creating Inclusive Physical Activity Spaces: The Case of Body-Positive Yoga. AB - PURPOSE: Within the modern cultural climate, those in larger bodies face high levels of weight stigma, particularly in sport and physical activity spaces, which serves as a strong barrier to their participation. However, given the strong link between physical activity and general health and well-being for participants, it is important to explore strategies that encourage participation of these individuals. Thus, the current research examined strategies that physical activity instructors use to develop inclusive exercise spaces for all body sizes. METHOD: This study employed a series of semistructured qualitative interviews (n = 9) with instructors of body-inclusive yoga classes to explore the ways in which they encourage participation for those in larger bodies. RESULTS: Emergent themes from the current study suggested support for 6 factors for creating body-inclusive physical activity spaces: authentic leadership, a culture of inclusion, a focus on health, inclusive language, leader social activism, and a sense of community. CONCLUSION: This study revealed that leaders must intentionally cultivate inclusion in their spaces to encourage those in nonconforming bodies to participate. These findings have important health and management implications for the sport and physical activity context and provide a basic outline of practical strategies that practitioners can use to foster inclusion in their spaces. PMID- 28636495 TI - Annual Index, Volume 24. PMID- 28636491 TI - Atherosclerosis Induced by a High-Cholesterol and High-Fat Diet in the Inbred Strain of the Wuzhishan Miniature Pig. AB - Coronary artery disease has a significant genetic predisposition, which mainly results from atherosclerosis. Miniature pig is an excellent model to investigate atherosclerosis. This study investigated whether the occurrence and development of atherosclerosis in the Wuzhishan miniature pigs (WZSPs) that were closely bred 12 generations had better consistency. The WZSPs (n = 9) were fed a high cholesterol and high-fat diet (HCFD). After continuous feeding, 3 WZSPs each were sacrificed at 6, 8, and 12 months, respectively, and the general clinical manifestations and serological indexes were detected. The pathological changes of the major arteries and main organs were recorded. The results showed WZSPs were quite susceptible to the HCFD. At 6 months, plaque lesions appeared in the abdominal aorta and iliac artery, while at 8 months, they appeared in the coronary artery. At 12 months, atherosclerotic lesions could be found in all major arteries, while lipid core, cholesterol precipitation, and calcium deposition appeared in the most serious sites. The progression of arterial lesions and distribution of the lesions were highly consistent in the pigs. However, apparent variations in serum markers were observed. In conclusion, inbred WZSP is a good model to investigate atherosclerosis and has good predictability for the occurrence and development of the disease. PMID- 28636496 TI - The genus Pulveroboletus (Boletaceae, Boletales) in China. AB - Species of Pulveroboletus (Boletaceae, Boletales) in China are investigated on the basis of morphology and molecular phylogenetic analyses of DNA sequences from nuc rDNA region encompassing the internal transcribed spacers 1 and 2, along with the 5.8S rDNA (ITS) and nuc 28S rDNA D1-D2 domains (28S) and sequences from the translation elongation factor 1-alpha gene (TEF1). Nine species are recognized in the country, three of them are described as new: P. flaviscabrosus, P. rubroscabrosus, and P. subrufus, five of them are previous described taxa: P. brunneopunctatus, P. brunneoscabrosus, P. macrosporus, P. reticulopileus, and P. sinensis, the remaining one is tentatively named P. cf. ridleyi, which will be further studied in the future. A key to the Chinese taxa of the genus is provided. Unexpectedly, the current study did not identify disjunct populations of Pulveroboletus species in East Asia and North/Central America. PMID- 28636497 TI - Size-segregated particulate matter and its association with respiratory deposition doses among outdoor exercisers in Dhanbad City, India. AB - : Regular exercise improves physiological processes and yields positive health outcomes. However, it is relatively less known that particulate matter (PM) exposure during outdoor exercises may increase several respiratory health problems depending on PM levels. In this study, the respiratory deposition doses (RDDs) in head airway (HD), tracheobronchial (TB), and alveolar (AL) regions of various PM size fractions (<10, <2.5, and <1 MUm; PM10, PM2.5, and PM1) were estimated in healthy male and female exercisers in urban outdoors and within house premises. The highest RDDs were found for PM during morning hours in winter compared with remaining periods. RDDs in AL region for males and females, respectively, were 34.7 * 10-2 and 28.8 * 10-2 ug min-1 for PM10, 65.7 * 10-2 and 56.9 * 10-2 ug min-1 for PM2.5, and 76.5 * 10-2 and 66.3 * 10-2 ug min-1 for PM1. The RDD values in AL region were significantly higher in PM1 (27%) compared with PM2.5 (13%) and PM10 (2%) during exercise in all periods. This result showed that the morning peak hours in winter are more harmful to urban outdoor exercisers compared with other periods. This study also showed that the AL region would have been the main affected zone through fine particle (PM1) to all the exercisers. IMPLICATIONS: Size-segregated particle concentrations in urban outdoors and within house premises were measured. The highest respiratory deposition doses (RDDs) were found for PM during morning hours in winter compared with remaining periods. During light exercise, the RDD values in alveolar (AL) region for PM10, PM2.5, and PM1 for male exercisers were significantly higher, 20.4%, 15.5%, and 15.4%, respectively, compared with female exercisers during morning peak hours in winter. PMID- 28636498 TI - A Novel Clinical-Simulated Suture Education for Basic Surgical Skill: Suture on the Biological Tissue Fixed on Standardized Patient Evaluated with Objective Structured Assessment of Technical Skill (OSATS) Tools. AB - BACKGROUND: Clinical-simulated training has shown benefit in the education of medical students. However, the role of clinical simulation for surgical basic skill training such as suturing techniques remains unclear. MATERIALS AND METHODS: Forty-two medical students were asked to perform specific suturing tasks at three stations with the different settings within four minutes (Station 1: Synthetic suture pad fixed on the bench, Station 2: Synthetic suture pad fixed on the standardized patient, Station 3: Pig skin fixed on the standardized patient); the OSATS (Objective Structured Assessment of Technical Skill) tool was used to evaluate the performance of students. A questionnaire was distributed to the students following the examination. RESULTS: Mean performance score of Station 3 was significant lower than that of Station 1 and 2 in the general performance including tissue handling, time, and motion. The suturing techniques of students at Station 2 and 3 were not as accurate as that at Station 1. Inappropriate tension was applied to the knot at Station 2 compared with Station 1 and 3. On the questionnaire, 93% of students considered clinical-simulated training of basic surgical skills was necessary and may increase their confidence in future clinical work as surgeons; 98% of students thought the assessment was more objective when OSATS tool was used for evaluation. CONCLUSION: Clinical simulation examination assessed with OSATS might throw a novel light on the education of basic surgical skills and may be worthy of wider adoption in the surgical education of medical students. PMID- 28636499 TI - Monoclonal Antibody Against Toxocara cati Second-Stage Larvae. PMID- 28636500 TI - The Association of rs1047763 and rs1008898 of C1GALT1 with IgA Nephropathy Risk: A Global Meta-Analysis. AB - IgA nephropathy (IgAN) is a globally common primary glomerulonephritis characterized by an elevated level of serum IgA and immune complex deposition in the mesangial area. In the serum of patients with IgAN, the hinge region of IgA1 immunoglobulin contains aberrantly glycosylated O-glycans deficient in galactose, which is normally added to the core 1 O-glycan structure by core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (C1GALT1), the key enzyme in the process of glycosylation. It is unknown if single-nucleotide polymorphisms rs1047763 and rs1008898 of C1GALT1 increase the risk of IgAN. We enrolled 5 subjects in this meta-analysis, including a total of 1693 IgAN patients and 1864 control subjects. We performed meta-analysis on associations between rs1047763, rs1008898, and IgAN using the allele model, dominant model, recessive model, and additive model. We found that there was no relationship between rs1047763 and rs1008898 in C1GALT1 and susceptibility to IgAN. PMID- 28636501 TI - Monoclonal Antibodies Against Canine Distemper Virus. PMID- 28636502 TI - Monoclonal Antibody TX94, Human DNAX Accessory Molecule-1 (CD226). PMID- 28636503 TI - Effects of Instructional Physical Activity Courses on Overall Physical Activity and Mood in University Students. AB - PURPOSE: The aim of this research was to assess the association between university-based instructional physical activity (PA) courses and changes in overall PA levels and negative mood and their interrelations. The study also sought to determine the amount of change in PA required to significantly improve mood in course enrollees. METHOD: Participants were university students initially completing PA below the level recommended for health who were either presently enrolled in an elective instructional PA course (treatment group, n = 52, 69% female) or not presently enrolled in such a course (comparison group, n = 32, 69% female). Validated surveys assessed volumes of PA completed per week and overall negative mood from baseline to course end. Mediation analyses assessed group effects on mood through PA changes and reciprocal relations between PA and mood changes. RESULTS: There was a significantly greater increase in PA and significantly more reduction in negative mood in the treatment group. Change in PA completely mediated the relationship between group and change in negative mood, and change in mood completely mediated the relationship between group and PA. These findings indicated a reciprocal, mutually reinforcing relationship between changes in PA and mood. An increase in PA of at least 2 days/week was associated with a significant reduction in negative mood, with no greater effect for more increase. CONCLUSIONS: Results provided an improved understanding of the effects of university-based instructional PA courses and how they might be leveraged to improve students' mental health and possibly contribute to their academic success. PMID- 28636504 TI - Prognostic value of the new high sensitive cardiac troponin T assay (hs-cTnT) after coronary artery bypass grafting. AB - Background The aim of the study was to assess the value of post-operative cardiac troponin T-levels, measured with a new highly sensitive assay (hs-cTnT), as a suitable parameter to predict patients' outcome after cardiac surgery. With the introduction of the new hs-cTnT assay the correlation between measured levels and the post-operative patient's outcome remains to be evaluated. Methods Patients undergoing coronary artery bypass grafting (n = 213) were included. Perioperative measurements of hs-cTnT and CK-MB were correlated to parameters of clinical outcome and further explored. Patients with an uneventful course were compared with those with post-operative complications, including need of repeat revascularization (RR) or death (RR/death), cardiogenic shock (CS) or death (CS/death) and a combination of all (RR/CS/death). Results Significant results were observed in patients after isolated CABG, where CS/death and RR/CS/death patients had higher post-operative hs-cTnT levels (P < 0.01). Moreover, multivariate analysis of the CABG-group revealed that acute renal failure (OR =14.7, 95% CI =2.7-79.1, P < 0.001), early post-operative hs-cTnT levels higher than the upper quintile (> 1,476.8 pg/ml) (OR =8.1, 95% CI =3.0-22.2, P < 0.001) and unstable angina pectoris (OR =2.4, 95% CI =1.1-5.7, P < 0.05) were the most powerful independent predictors of post-operative complications. Upon discriminant analysis the application of hs-cTnT almost doubled the sensitivity of the outcome prediction. Conclusions The new hs-cTnT assay is a useful diagnostic tool that may significantly enhance the prediction of adverse events after CABG. In our study a hs-cTnT-value >1,476.8 pg/ml proved to be a reliable marker for ongoing post-operative complications. PMID- 28636505 TI - The effect of aerobic interval training and continuous training on exercise capacity and its determinants. AB - Objective We aimed to investigate (1) the effects of aerobic interval training (AIT) and aerobic continuous training (ACT) on (sub)maximal exercise measures and its determinants including endothelial function, muscle strength and cardiac autonomic function, and (2) the relationship between exercise capacity and these determinants. Methods Two-hundred coronary artery disease (CAD) patients (58.4 +/ 9.1 years) were randomized to AIT or ACT for 12 weeks. All patients performed a cardiopulmonary exercise test and endothelial function measurements before and after the intervention; a subpopulation underwent muscle strength and heart rate variability (HRV) assessments. Results The VO2, heart rate and workload at peak and at first and second ventilatory threshold increased (P-time <0.001); the oxygen uptake efficiency slope (P-time <0.001) and half time of peak VO2 (P-time <0.001) improved. Endothelial function and heart rate recovery (HRR) at 1 and 2 min improved (P-time <0.001), while measures of muscle strength and HRV did not change. Both interventions were equally effective. Significant correlations were found between baseline peak VO2 and (1) quadriceps strength (r = 0.44; P < 0.001); (2) HRR at 2 min (r = 0.46; P < 0.001). Changes in peak VO2 correlated significantly with changes in (1) FMD (rho = 0.17; P < 0.05); (2) quadriceps strength (r = 0.23; P < 0.05); (3) HRR at 2 min (rho = 0.18; P < 0.05) and Total power of HRV (rho = 0.41; P < 0.05). Conclusions This multicentre trial shows equal improvements in maximal and submaximal exercise capacity, endothelial function and HRR after AIT and ACT, while these training methods seem to be insufficient to improve muscle strength and HRV. Changes in peak VO2 were linked to changes in all underlying parameters. PMID- 28636506 TI - Incidence and predictors of atrial fibrillation after coronary artery bypass surgery: detection by event loop recorder monitoring from a contemporary multicentre cohort. AB - Background Atrial fibrillation (AF) is a frequent complication after cardiac surgery. We explored the incidence and predictors of post-operative AF at 30-day follow-up in an unselected multi-centre cohort of patients undergoing elective coronary artery bypass grafting (CABG) in contemporary practice. Methods and results We enrolled 740 consecutive patients scheduled for elective CABG with or without valve surgery. Cardiac rhythm was continuously monitored for 15 days after surgery by an ambulatory event loop recorder. Clinical follow-up for the occurrence of arrhythmias was performed for the next 15 days by office visits. The primary end point was the incidence of AF at 30-day follow-up. Mean age was 56.5 +/- 8.9 years; 69.5% were males; 80% had diabetes. All patients completed 30 day follow-up. At the end of 30 days, AF occurred in 77 patients (10.4%). Most episodes (47 out of 77 episodes, 61%) of AF occurred during post-operative day 2. Episodes of AF were very rare after the first 5 post-operative days (3 out of 77 episodes, 3.9%). Multivariable regression analysis identified the following independent predictors of AF at 30-day follow-up: the lack of beta blocker use (hazard ratio 0.37, 95% confidence interval 0.21-0.64, P < 0.001), and the preoperative left atrial volume index (hazard Ratio 2.21, 95% confidence interval 1.79-2.74, P < 0.001). Conclusions In patients undergoing elective CABG, the incidence of post-operative AF at 30-day follow-up is rather low; the lack of beta blocker use in the perioperative period, and the preoperative left atrial volume index independently predicted the occurrence of AF at 30 days. PMID- 28636507 TI - Aorto-right ventricular outflow tract fistula after Bentall repair. PMID- 28636508 TI - How to perform stress/exercise echocardiography in -hypertrophic cardiomyopathy? PMID- 28636509 TI - Evaluation of endothelial dysfunction with flow-mediated dilatation after transradial coronary angiography. AB - Objective Transradial coronary angiography (TRCA) may lead to endothelial dysfunction. Therefore, this study investigated the TRCA-related endothelial dysfunction and its relation to operator experience, the number of punctures and procedure duration. Methods and results A total of 57 patients (42 males and 17 females) who underwent TRCA were included in this single-centre study. Nine months after the procedure, all patients underwent radial artery B-mode ultrasound imaging, and flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) techniques were employed. The non-intervened right radial artery was accepted as control. The percentage change in diameter after FMD was significantly greater in the right radial artery compared to the left radial artery (right 13.6% vs left 10.1%, P = 0.041). The percentage change in diameter after NMD was similar in both right and left radial arteries (right 23.8% vs left 23.4%, P = 0.932). According to the puncture numbers, the percentage change was significantly lower in the intervened artery among patients with more than one puncture (13.3% vs 7.8%, P = 0.005). According to the operator experience, the percentage change in the intervened artery was significantly higher in patients in whom the procedure was performed by experienced operators (13.7% vs 7.6%, P = 0.002). The procedure duration also showed a negative correlation with the percentage change in the intervened artery (r = -0.349, P = 0.008). Conclusions TRCA may lead to endothelial dysfunction represented by FMD. Moreover, higher puncture numbers for sheath insertion, longer procedure durations and less experience in radial interventions may have adverse effects on the endothelial function. PMID- 28636510 TI - The balance of omega-3 polyunsaturated fatty acids for -reducing residual risks in patients with coronary artery disease. AB - Residual risk, which cannot be prevented by statins alone, must be controlled for inhibiting the onset of coronary events. Omega-3 polyunsaturated fatty acids (PUFAs) play an important role in controlling residual risk. The Japan eicosapentaenoic acid (EPA) Lipid Intervention Study demonstrated the inhibitory effect of high-purity EPA preparations on the residual risk of cardiovascular events. Omega-3 PUFAs inhibit coronary artery disease (CAD) through various actions, including triglyceride-lowering action. Besides lipid metabolism, platelet aggregation inhibition, anti-inflammatory effects, improved vascular endothelium function, and anti-hypertensive action contribute to arteriosclerosis inhibition. Conversely, several recent studies did not demonstrate the efficacy of omega-3 PUFAs for CAD prevention. PUFAs levels may need to exceed a threshold for anti-arteriosclerotic action. The efficacy of EPA might depend on the baseline value of the EPA/arachidonic acid (AA) ratio prior to EPA administration. This baseline EPA/AA ratio value varies according to country and region as well as changes of dietary habits. More global research in this field is needed to identify an optimal omega-3 PUFAs administration strategy. PMID- 28636511 TI - Feasibility of low-dose coronary computed tomographic angiography used in atrial fibrillation patients. AB - OBJECTIVE: The diagnosis of coronary artery disease (CAD) in atrial fibrillation (AF) patients using coronary computed tomography angiography (CCTA) requires a large exposure dosage or repeated examinations. This study evaluates the feasibility of using low-dose CCTA in the double prospectively ECG-triggered high pitch spiral acquisition mode (Double Flash Spiral mode). METHODS: Twenty-eight AF patients with suspected CAD were recruited. Double Flash Spiral mode (tube voltage 100 kVp) and iterative reconstruction was used for CCTA examination. Two radiologists cross-evaluated the CCTA image quality. The effective radiation dose was measured for each patient. RESULTS: Twenty-eight AF patients (10 female, 18 male, mean age 68.8 +/- 13.9 y, body mass index 24.3 +/- 2.3 kg/cm2) were recruited and 337 artery segments were evaluated. In total, 98.5% (332/337) of the coronary artery segments and 96.4% (27/28) of the AF patients were rated as diagnostically evaluable. Of these 27 diagnosable patients, 17 patients (63%) were diagnosed with multi-vessel stenosis. Besides, 5 of 28 patients (17.9%) have left atrial appendage thrombus. The quality of the integrated image was significantly better than either of the individual first or the second scans, based on segments (P < 0.001) and patients (P < 0.05). The mean effective radiation dose was 1.5 mSv +/-0.4 mSv. CONCLUSIONS: Using the Double Flash Spiral mode at low radiation dose (mean 1.5 mSv), 98.5% of the coronary segments and 96.4% of the scans were of sufficient diagnostic quality. PMID- 28636512 TI - Isolated mitral valve P3 prolapse with severe regurgitation - transoesophageal 2D/3D echo-guidance in transapical -artificial neochordae implantation in challenging patient. PMID- 28636513 TI - Large left circumflex artery aneurysm and left ventricular-coronary sinus fistula. PMID- 28636514 TI - Duration of dual anti-platelet therapy - State of the art after the DAPT and PEGASUS-TIMI 54 trials. AB - Dual anti-platelet therapy is prescribed in the setting of coronary heart disease for the prevention of stent thrombosis and acute thrombotic events. The optimal duration of dual anti-platelet therapy is still under debate as numerous trials have shown non-inferiority of a strategy of early cessation of one of the agents as compared to the standard practice whereas two larger trials have demonstrated benefit of prolonging dual anti-platelet therapy. PMID- 28636515 TI - A brief period of intensive cardiac rehabilitation improves global longitudinal strain and diastolic function after a first uncomplicated myocardial infarction. AB - Objectives In patients with abnormal left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI), cardiac rehabilitation with physical training prevents cardiac remodelling. To define the role of rehabilitation in the recovery of ventricular function in less severe cases, we studied its effects on more refined indexes of left ventricular function in uncomplicated, low-risk patients. Methods and results Fifty-five patients underwent percutaneous coronary revascularization after uncomplicated first AMI. Thirty-four started cardiac rehabilitation with counselling and physical training; 21 patients did not train, followed a counselling program and were taken as controls. Echocardiography was performed at baseline, after rehabilitation or counselling program and at six months follow-up. We measured: global strain (GS%) with speckle tracking analysis, E/e' by tissue Doppler imaging (TDI), left ventricular elastance (KLV) from the deceleration time (DT), LVEF, systolic and diastolic volumes, wall motion score index (WMSI). At baseline, groups had similar GS%, KLV, LVEF, DT, E/e', systolic and diastolic volumes, WMSI. Rehabilitation increased peak VO2 by 18% (P < 0.05) and improved GS%, KLV, LVEF, E/e' and WMSI (P < 0.02) that were unchanged in controls. The improvement persisted at six months. Conclusions After a first uncomplicated AMI, abnormalities of left systolic and diastolic ventricular function may be present persisting over time despite a normal LVEF, which are fully reverted by cardiac rehabilitation. PMID- 28636516 TI - A rare primary cardiac benign tumour: diagnosis by non-invasive cardiac imaging. PMID- 28636517 TI - Imaging in the field of cardiac resynchronization therapy: a real additive value? PMID- 28636518 TI - A patient with relapsing myocardial ischaemia. PMID- 28636519 TI - How we eat may be as important as what we eat: eating behaviour and heart rate variability. AB - Objective Diet exerts a crucial role on cardiovascular health. Evidence is mainly based on the content and the amount of dietary intakes. Some recent reports demonstrated that eating behaviour may also be of significant importance in cardiovascular health. In this study we aimed to investigate the effects of eating behaviour on heart rate variability (HRV) in healthy subjects. Methods and results In total, 521 healthy subjects with 24-hour Holter ECG recordings filled out a special questionnaire about their eating behaviour and lifestyles. From these patients, 425 subjects were healthy and had recordings suitable for analysis. Five types of eating behaviour were assessed in the questionnaire: (1) adherence to the Mediterranean diet (using the MedDietScore), (2) skipping breakfast, (3) late night eating, (4) having snacks, and (5) rapid eating. Physical exercise level and active working status of the subjects were also assessed. The root mean square of successive differences (RMSSD) was used for assessment of HRV. RMSSD values were lower in subjects skipping breakfast compared to subjects having breakfast regularly (26.32 vs 31.52 P = 0.02). Other behavioural patterns did not have any effect on the HRV parameters. Ageing, male sex, sedentary lifestyle and no active working were also found to be associated with reduced HRV in univariate analysis. In multivariate regression analysis, age and skipping breakfast were the only parameters significantly associated with a lower RMSSD (beta: -0.222, P: 0.008 and beta: -0.191, P: 0.020, respectively) Conclusions The findings of this study showed that skipping breakfast may be a cause of cardiac autonomic dysfunction. PMID- 28636520 TI - Radial Artery Occlusion - Incidence, Predictors and Long-term outcome after TRAnsradial Catheterization: clinico-Doppler ultrasound-based study (RAIL-TRAC study). AB - Background and aim The purpose of this study was to assess incidence, predictors and outcome of radial artery occlusion (RAO) after transradial catheterization (TRC) based on clinical and Doppler ultrasound study. Methods A total of 1,945 consecutive patients undergoing transradial catheterization for diagnostic evaluation or intervention were included. Radial artery examination was based on palpation and colour Doppler study on the day before, 1 day (D1), 1 month (D30) and 6 months (D180) following the procedure. RAO was defined as absence of pulse on palpation and forward flow on Doppler study. Predictors of RAO were found by logistic regression analysis. Results Baseline demographic and procedural data were recorded. The mean radial arterial diameter was 2.56 +/- 0.29 mm. On D1, radial artery Doppler examination revealed RAO in 339 patients (17.4%) but pulse was still palpable in 115 (34%) of them. At D30, these were 221 (11.4%) and 114 (52%), respectively, as no new RAO were noted. Interestingly, 118 (34.8%) patients had spontaneous recanalization of their radial artery as shown by catch up in patency rate. At D180, these were 99 (5.1%) and 68 (69%), respectively, meaning further new catch-up implying further recanalization. Patients with persistent RAO remained asymptomatic. On multivariate analysis, female sex, diabetes, lower BMI, radial artery diameter <=2.2 mm and radial artery-to-sheath ratio (AS ratio) < 1 were predictors of RAO. Conclusion TRC for coronary angiography, ad hoc and staged angioplasty can be performed with similar efficacy and safety though RAO occurs more frequently in patients with prior radial artery cannulation and with larger sheath size. Persistent RAO remains asymptomatic. PMID- 28636521 TI - A proposed role for sepsis in the pathogenesis of myocardial calcification. PMID- 28636522 TI - A "giant" cause of acute myocardial infarction. PMID- 28636523 TI - Emergency percutaneous embolization of iatrogenic right coronary artery-pleural space communication. PMID- 28636524 TI - His-bundle pacing using dual-chamber cardioverter-defibrillator in patients with chronic atrial fibrillation: different pacing and sensing features. PMID- 28636525 TI - Prognostic significance of improvement in right ventricular systolic function during cardiac resynchronization therapy. AB - Objectives There is conflicting evidence concerning the role of right ventricular (RV) systolic dysfunction in the long-term clinical outcome after cardiac resynchronization therapy (CRT). Therefore we aimed to assess evolution of RV systolic function during CRT, covariates associated with its improvement, and its impact on outcome. Methods and results All CRT device implantations (Jan 2009-Dec 2011) in our institution were reviewed. Records of 69 patients (25% female, mean age 62.8 +/- 9.2 years, mean left ventricular (LV) ejection fraction 27 +/- 8%) were analyzed. Baseline RV fractional area change (FAC) < 35% was present in 37 patients (54%). At one year, 24 of them (65%) improved in RV FAC. LV remodeling and mitral regurgitation were significantly associated with the likelihood of RV FAC improvement (OR 4.80, 95% CI 1.13-20.46, P = 0.034 and OR 0.32, 95% CI 0.12 0.89, P = 0.029, respectively). The composite endpoint of death or heart transplantation occurred in 23 patients (33%) over a mean follow-up of 2.8 +/- 1.4 years. RV FAC at one year (HR 0.90, 95% CI 0.86-0.94, P < .001) was, independently of NYHA class and LV remodeling, associated with clinical outcome. Conclusions RV systolic function might improve during CRT. This seems mainly due to changed left-sided hemodynamics and LV remodeling. Good RV systolic function is independently related with better outcome. PMID- 28636526 TI - Does Health Coaching Grow Capacity in Cancer Survivors? A Systematic Review. AB - Interventions that grow patient capacity to do the work of health care and life are needed to support the health of cancer survivors. Health coaching may grow capacity. This systematic review of health coaching interventions explored coaching's ability to grow capacity of cancer survivors. The authors included randomized trials or quasi-experimental studies comparing coaching to alternative interventions, and adhered to PRISMA reporting guidelines. Data were analyzed using the Theory of Patient Capacity (BREWS: Capacity is affected by factors that influence ability to reframe Biography ["B"], mobilize or recruit Resources ["R"], interact with the Environment of care ["E"], accomplish Work ["W"]), and function Socially ["S"]). The authors reviewed 2210 references and selected 12 studies (6 randomized trials and 6 pre-post). These studies included 1038 cancer survivors, mean age 57.2 years, with various type of cancers: breast, colorectal, prostate, and lung. Health coaching was associated with improved quality of life, mood, and physical activity but not self-efficacy. Classified by potential to support growth in patient capacity, 67% of included studies reported statistically significant outcomes that support "B" (quality of life, acceptance, spirituality), 75% "R" (decreased fatigue, pain), 67% "W" (increased physical activity), and 33% "S" (social deprivation index). None addressed changing the patient's environment of care. In cancer survivors, health coaching improved quality of life and supported patient capacity by several mechanisms, suggesting an important role for "Capacity Coaching." Future interventions that improve self efficacy and patients' environments of care are needed. Capacity Coaching may improve health and quality of life of cancer survivors. PMID- 28636527 TI - Evaluating performance over time: Is improving better than being consistently good? AB - In many decision contexts, people evaluate others based on intertemporal performance records and commonly face a choice between two distinct profiles: performance that is consistently high versus performance that improves over time to that high level. We proposed that these two profiles could be appealing for different reasons, and thus evaluators' preferences will differ across decision contexts. In three studies, participants were presented with candidates (e.g., students, employees) displaying the two profiles, and evaluated each candidate in terms of performance, future expectations, and deservingness. The consistent candidate was rated higher on performance, but lower on future expectations, than the improved candidate. Consequently, in achievement-based decisions (e.g., selecting a student for a scholarship), the consistent candidate was viewed as most deserving, whereas in potential-based decisions (e.g., selecting an employee for promotion), the improved candidate was preferred. These effects were mediated by the relative weight that evaluators placed on performance and future expectations. PMID- 28636528 TI - Three dimensional reconstruction of energy stores for jumping in planthoppers and froghoppers from confocal laser scanning microscopy. AB - Jumping in planthopper and froghopper insects is propelled by a catapult-like mechanism requiring mechanical storage of energy and its quick release to accelerate the hind legs rapidly. To understand the functional biomechanics involved in these challenging movements, the internal skeleton, tendons and muscles involved were reconstructed in 3-D from confocal scans in unprecedented detail. Energy to power jumping was generated by slow contractions of hind leg depressor muscles and then stored by bending specialised elements of the thoracic skeleton that are composites of the rubbery protein resilin sandwiched between layers of harder cuticle with air-filled tunnels reducing mass. The images showed that the lever arm of the power-producing muscle changed in magnitude during jumping, but at all joint angles would cause depression, suggesting a mechanism by which the stored energy is released. This methodological approach illuminates how miniaturized components interact and function in complex and rapid movements of small animals. PMID- 28636550 TI - MIF: functions in brain and glioblastoma. PMID- 28636551 TI - Neuroblastoma stem cells and CFC1. PMID- 28636529 TI - Bladder Cancer and Water Disinfection By-product Exposures through Multiple Routes: A Population-Based Case-Control Study (New England, USA). AB - BACKGROUND: Ingestion of disinfection byproducts has been associated with bladder cancer in multiple studies. Although associations with other routes of exposure have been suggested, epidemiologic evidence is limited. OBJECTIVES: We evaluated the relationship between bladder cancer and total, chlorinated, and brominated trihalomethanes (THMs) through various exposure routes. METHODS: In a population based case-control study in New England (n=(1,213) cases; n=(1,418) controls), we estimated lifetime exposure to THMs from ingestion, showering/bathing, and hours of swimming pool use. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression adjusted for confounders. RESULTS: Adjusted ORs for bladder cancer comparing participants with exposure above the 95th percentile with those in the lowest quartile of exposure (based on the distribution in controls) were statistically significant for average daily intake mg/d of total THMs [OR=1.53 (95% CI: 1.01, 2.32), p-trend=0.16] and brominated THMs [OR=1.98 (95% CI: 1.19, 3.29), p-trend=0.03]. For cumulative intake mg, the OR at the 95th percentile of total THMs was 1.45 (95% CI: 0.95, 2.2), p-trend=0.13; the ORs at the 95th percentile for chlorinated and brominated THMs were 1.77 (95% CI: 1.05, 2,.99), p-trend=0.07 and 1.78 (95% CI: 1.05, 3.00), p-trend=0.02, respectively. The OR in the highest category of showering/bathing for brominated THMs was 1.43 (95% CI: 0.80, 2.42), p-trend=0.10. We found no evidence of an association for bladder cancer and hours of swimming pool use. CONCLUSIONS: We observed a modest association between ingestion of water with higher THMs (>95th percentile vs.<25th percentile) and bladder cancer. Brominated THMs have been a particular concern based on toxicologic evidence, and our suggestive findings for multiple metrics require further study in a population with higher levels of these exposures. Data from this population do not support an association between swimming pool use and bladder cancer. https://doi.org/10.1289/EHP89. PMID- 28636563 TI - Activity modifies adult brain maturity. PMID- 28636564 TI - Radiation dosimetry in magnetic fields with Farmer-type ionization chambers: determination of magnetic field correction factors for different magnetic field strengths and field orientations. AB - The aim of this work was to determine magnetic field correction factors that are needed for dosimetry in hybrid devices for MR-guided radiotherapy for Farmer-type ionization chambers for different magnetic field strengths and field orientations. The response of six custom-built Farmer-type chambers irradiated at a 6 MV linac was measured in a water tank positioned in a magnet with magnetic field strengths between 0.0 T and 1.1 T. Chamber axis, beam and magnetic field were perpendicular to each other and both magnetic field directions were investigated. EGSnrc Monte Carlo simulations were compared to the measurements and simulations with different field orientations were performed. For all geometries, magnetic field correction factors, [Formula: see text], and perturbation factors were calculated. A maximum increase of 8.8% in chamber response was measured for the magnetic field perpendicular to chamber and beam axis. The measured chamber response could be reproduced by adjusting the dead volume layer near the chamber stem in the Monte Carlo simulations. For the magnetic field parallel to the chamber axis or parallel to the beam, the simulated response increased by 1.1% at maximum for field strengths up to 1.1 T. A complex dependence of the response was found on chamber radius, magnetic field strength and orientation of beam, chamber axis and magnetic field direction. Especially for magnetic fields perpendicular to beam and chamber axis, the exact sensitive volume has to be considered in the simulations. To minimize magnetic field correction factors and the influence of dead volumes on the response of Farmer chambers, a measurement set-up with the magnetic field parallel to the chamber axis or parallel to the beam is recommended for dosimetry. PMID- 28636565 TI - Porous-carbon-nanotube decorated carbon nanofibers with effective microwave absorption properties. AB - Carbon nanofibers decorated with porous carbon nanotubes were prepared by electrospinning and annealing methods. The microwave reflection loss of the products was investigated in the frequency range of 2-18 GHz. The bandwidth with a reflection loss less than -10 dB covers a wide frequency, ranging from 7.0 to 14.1 GHz with thickness of 3.0-5.5 mm, and the minimum reflection loss is -44.5 dB at 10.7 GHz with thickness of 2.0 mm. The large reflection loss and wide reflection band reveal that the products could be a promising candidate for microwave absorption. PMID- 28636566 TI - Detection of muscle gap by L-BIA in muscle injuries: clinical prognosis. AB - : Sport-related muscle injury classifications are based basically on imaging criteria such as ultrasound (US) and magnetic resonance imaging (MRI) without consensus because of a lack of clinical prognostics for return-to-play (RTP), which is conditioned upon the severity of the injury, and this in turn with the muscle gap (muscular fibers retraction). Recently, Futbol Club Barcelona's medical department proposed a new muscle injury classification in which muscle gap plays an important role, with the drawback that it is not always possible to identify by MRI. Localized bioimpedance measurement (L-BIA) has emerged as a non invasive technique for supporting US and MRI to quantify the disrupted soft tissue structure in injured muscles. OBJECTIVE: To correlate the severity of the injury according to the gap with the RTP, through the percent of change in resistance (R), reactance (Xc) and phase-angle (PA) by L-BIA measurements in 22 muscle injuries. MAIN RESULTS: After grouping the data according to the muscle gap (by MRI exam), there were significant differences in R between grade 1 and grade 2f (myotendinous or myofascial muscle injury with feather-like appearance), as well as between grade 2f and grade 2g (myotendinous or myofascial muscle injury with feather and gap). The Xc and PA values decrease significantly between each grade (i.e. 1 versus 2f, 1 versus 2g and 2f versus 2g). In addition, the severity of the muscle gap adversely affected the RTP with significant differences observed between 1 and 2g as well as between 2f and 2g. SIGNIFICANCE: These results show that L-BIA could aid MRI and US in identifying the severity of an injured muscle according to muscle gap and therefore to accurately predict the RTP. PMID- 28636567 TI - Invariant wide bandgaps in honeycomb monolayer and single-walled nanotubes of IIB VI semiconductors. AB - The search for low-dimensional materials with unique electronic properties is important for the development of electronic devices in the nanoscale. Through systematic first-principles calculations, we found that the band gaps of the two dimensional honeycomb monolayers (HMs) and one-dimensional single-walled nanotubes (SWNTs) of IIB-VI semiconductors (ZnO, CdO, ZnS and CdS) are nearly chirality-independent and weakly diameter-dependent. Based on analysis of the electronic structures, it was found that the conduction band minimum is contributed to by the spherically symmetric s orbitals of cations and the valence band maximum is dominated by the in-plane [Formula: see text] and [Formula: see text] hybridizations. These electronic states are robust against radius curvature, resulting in the invariant feature of the band gaps for the structures changing from HM to SWNTs. The band gaps of these materials range from 2.3 to 4.7 eV, which is of potential application in electronic devices and optoelectronic devices. Our studies show that searching for and designing specific electronic structures can facilitate the process of exploring novel nanomaterials for future applications. PMID- 28636568 TI - Causes of mortality in schizophrenia: An updated review of European studies. AB - BACKGROUND: The excess mortality in schizophrenia is still a phenomenon insufficiently studied on the cross-national level. It is important to analyse current studies on morality in schizophrenia since significant changes have recently taken place in psychiatric health care systems and guidelines of pharmacological treatment have been developed in European countries. SUBJECTS AND METHODS: This article reviews studies addressing mortality in schizophrenia in Europe that were published in English in the Pubmed database in 2009-2014. It aimed at determining countries where studies were conducted, methodologies and tools used, and current main mortality rates, as well as direction of causality in this group of patients. RESULTS: The recently published studies were conducted only in few European countries. The majority of data was obtained from general medical records and death records. The studies indicate that schizophrenia patients are characterized by higher mortality rate than the general population, with natural causes (cardiovascular diseases and cancers) and suicides predominating. The increasing mortality gap with significantly shorter life expectancy of patients with schizophrenia in comparison with the general population is considerable. CONCLUSIONS: Death records are a crucial tool in studies on mortality in schizophrenia patients; however they are insufficiently employed. Recent European reports do not show positive tendencies, indicating that standardized mortality rates in schizophrenia remain on the same level or even increase, particularly for deaths resulting from natural causes. Due to various methodologies used in studies, their direct comparison is difficult. This limitation warrants further discussion on methods used in future studies on schizophrenia mortality in Europe. PMID- 28636569 TI - Diabetic ketoacidosis associated with antipsychotic drugs: case reports and a review of literature. AB - BACKGROUND: Second generation antipsychotics (SGAs) are associated with metabolic disturbances. Diabetic ketoacidosis (DKA) is a rare, but potentially fatal sign of acute glucose metabolism dysregulation linked to the use of SGAs. The aims of this article are to present patients with a history of psychotic disorders and of severe metabolic diabetic ketoacidosis, possibly associated with the use of antipsychotics, and to review the current literature on the topic of antipsychotic-induced DKA. METHOD: PubMed/Medline and EBSCO databases were searched using the keywords: diabetic ketoacidosis, antipsychotics, atypical antipsychotics, second generation antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone, amisulpride and haloperidol. Case reports, case series and reviews of case series were included in the review. RESULTS: The majority of patients who developed DKA following treatment with antipsychotics were treated with olanzapine and clozapine in monotherapy or in combination with other antipsychotics. DKA mostly occurred in the first six months of antipsychotic treatment. Other risk factors included insulin resistance prior to antipsychotic treatment, male gender and middle age. CONCLUSION: Clinicians should consider the risk of DKA when starting treatment with SGAs. Preventive measures for patients with psychotic disorders using antipsychotics should include regular assessment of risk factors and screening for diabetes before and after administering antipsychotics, especially in the first months of treatment. Whenever possible, polypharmacy should be avoided. PMID- 28636570 TI - Use of Electroconvulsive Therapy in Central-Eastern European Countries: an Overview. AB - Though a number of reports on the use of electroconvulsive therapy (ECT) has been published from the Central-Eastern European region over the past two decades, a systematic review of this literature has not been published. Thus the aim of this paper was to review recent trends in ECT practice in Central-Eastern Europe. Systematic literature search was undertaken using the Medline, PSYCHINFO and EMBASE databases covering the period between January 2000 and December 2013. Relevant publications were found from the following countries: Bulgaria, Croatia, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, Slovakia, Ukraine, but none from Albania and Moldova. ECT practice in the region shows a heterogeneous picture in terms of utilization rate, main indications, and the technical parameters of application. On one end of the spectrum is Slovakia where the majority of psychiatric facilities offer ECT, on the other end is Slovenia, where ECT is banned. In about half of the countries schizophrenia is the main indication for ECT. In Ukraine, unmodified ECT is still in use. Clinical training is generally lacking in the region and only 3 countries have a national ECT protocol. Possible ways of improving ECT practice in the region are briefly discussed. PMID- 28636571 TI - Schizophrenia and Bipolar Affective Disorder: a Dimensional Approach. AB - AIM: Schizophrenia (SCH) and bipolar affective disorder (BAD) are currently classified separately according to the DSM (The Diagnostic and Statistical Manual of Mental Disorders) and ICD (International Statistical Classification of Diseases and Related Health Problems) standardized diagnostic guidelines. However, the validity of this categorical approach is controversial because psychotic symptoms may be observed in both diagnoses. The purpose of this study was to compare the clinical and social characteristics in a sample group consisting of patients diagnosed with SCH or BAD to help demonstrate the basic difficulty in the current classification of SCH and BAD as two etiologically distinct diseases. SUBJECTS AND METHODS: The study sample group consisted of 102 patients diagnosed with SCH and 92 patients diagnosed with BAD. All of the participants were evaluated by Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition with regard to beginning symptoms of the disease, the symptoms and signs of active disease period within total disease duration, continuining residual symptoms in intermediate period. The patients were administered the Positive and Negative Syndrome Scale, the Quality of Life Enjoyment and Satisfaction Questionnaire and the Social Functioning Scale. RESULTS: The SCH and BAD groups in this study were statistically similar in terms of sex, length of education, age at disease onset, attempted suicide, quality of life and social functioning. CONCLUSION: Our study findings indicated that the course of disease in patients with BAD-1, in which psychotic features predominate and which exhibits a recurring course, shares various characteristics with SCH. It can be concluded that further phenomenological and neurobiological evaluations are required for intermediate cases with similiar clinical characteristics with schizophrenia and bipolar disorders. PMID- 28636572 TI - Mood Symptoms in Stabilized Patients with Schizophrenia: A Bipolar Type with Predominant Psychotic Features? AB - BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) are traditionally distinguished on the basis of progressive deterioration and long-term outcome, but a more dimensional approach is warranted. There are limited data on the occurrence of manic symptoms in patients with schizophrenia. The aim of the current study was to search for patterns in the clinical symptomatology, which may suggest the presence of one or several mood disorders under the label of schizophrenia. SUBJECTS AND METHODS: Hundred-seventy-five patients diagnosed with schizophrenia according to DSM-5 were included in the study. The psychometric assessment included the Positive and Negative Syndrome Scale, Young Mania Rating Scale, The Montgomery-Asberg Depression Rating Scale and the Calgary Depression Scale. The statistical analysis included MANOVA, Pearson Correlation coefficient and principal components analysis. RESULTS: Significant subthreshold manic symptoms were present in 25.14% of patients. Mood symptoms correlated with positive symptoms. The PCA revealed a complex structure with 15 factors (one positive, negative, somatic, anxiety, neurocognitive, disorganization and manic, five depressive and three psychomotor/excitement/hostility/violence). CONCLUSION: Psychotic mood disorders are often phenotypically indistinguishable from schizophrenia, so it is likely that psychotic affective patients have been misdiagnosed with schizophrenia. The current study suggests that there seem to be patients with mania misdiagnosed as 'schizophrenics' because of the presence of psychotic features, a condition better described as 'schizophreniform bipolar disorder'. PMID- 28636573 TI - Prescribing patterns for inpatients with schizophrenia spectrum disorders in a psychiatric hospital in Slovenia: Results of 16-month prospective, non interventional clinical research. AB - BACKGROUND: In Slovenia, there has been no evidence about the prescribing patterns for inpatients with psychotic disorders. The research aims to analyze drug utilization patterns for inpatients with psychotic disorder that are coded as F20-F29 according to International Classification of Diseases (ICD) 10th revision (schizophrenia spectrum disorders). SUBJECTS AND METHODS: Prospective research was conducted at the Psychiatric Hospital Idrija. The medical records of the inpatients admitted over a 12-month period were collected from the beginning to the end of their hospitalization. RESULTS: A total of 311 inpatients with 446 hospitalizations were included, producing a total of 3954 medication prescriptions. Medications prescribed pro re nata (the use of as needed) were also taken into account. Antipsychotics (N=1149, 43% of prescriptions) were the most often prescribed medications, followed by anxiolytics, antiparkinsonians, antidepressants, mood stabilizers and cardiovascular drugs. A total of 256 (82%) inpatients received at least one pro re nata medication. It was observed that the studied population was treated with one antipsychotic on 27 percent of prescriptions. CONCLUSIONS: Inpatients with schizophrenia spectrum disorders were exposed to a large number of different drugs. They were not received only psychotropic drugs but also other medications. With the knowledge about medications the implementation of clinical pharmacy services to the psychiatrists would significantly improve medication of inpatients with psychotic disorders and polypharmacotherapy. PMID- 28636574 TI - Early intervention programme for patients with psychotic disorders in "Sveti Ivan" Psychiatric hospital (RIPEPP) - sociodemographic and baseline characteristics of the participants. AB - BACKGROUND: Psychiatric hospital "Sveti Ivan" in Zagreb, Croatia, offers an outpatient Early intervention programme for patients with psychotic disorders (RIPEPP), consisting of psychoeducational workshops and group psychodynamic psychotherapy. The aim of this study was to describe sociodemographic and baseline characteristics of the participants, in order to provide better understanding of this population, and to assist with the development of more effective therapeutic approaches. SUBJECTS AND METHODS: Since 2008, a total of 245 patients with first episodes of psychosis and their family members participated in the programme. They filled out several questionnaires within the framework of the programme evaluation, but for the purposes of this study, only data collected on sociodemographic questionnaire and the Health of the Nation Outcome Scales (HoNOS) are presented. RESULTS: Majority of the participants were male (66%), at the average age of 28 (SD=6.6), living with their parents (73.5%). Most of them finished secondary school (45.7%) but almost a quarter of the sample (23.7%) is currently studying at university. The average duration of untreated period was 101.60 days, with a median of 30 days. According to results of HONOS questionnaire, upon entry into the programme, the patients most often listed cognitive functioning (attention, concentration, memory) and professional issues (performance of work tasks and activities tied to work) as the most problematic areas. CONCLUSION: The findings of this study provide more detailed description of the beneficiaries of the RIPEPP programme, which can contribute to forming future programmes for the prevention of psychotic disorders. PMID- 28636575 TI - The temperament and character traits in patients with major depressive disorder and bipolar affective disorder with and without suicide attempt. AB - BACKGROUND: Suicide and mood disorders (especially major depressive disorder (MDD) and bipolar affective disorder (BD)) represent a significant global health burden. Major depressive disorder and bipolar affective disorder have been associated with increased risk for suicide. Some specific suicide risk factors might be found in underlying individual personality traits. Specific personality features may predispose an individual to mood disorders (MDD or BD) hence increased suicide risk. The specificity of this research is in the assessment of personality features during the acute phase of illness immediately after suicide attempt which resulted in psychiatric inpatient treatment. SUBJECTS AND METHODS: The study included 119 unrelated Caucasian participants with MDD-severe depressive episode without psychotic symptoms (MDD) and BD-severe depressive episode without psychotic symptoms (BD-sDE). Both groups of patients with MDD and BD-sDE were divided into the suicide attempters and non-suicidal group. The diagnoses of the severe depressive episode without psychotic symptoms in major depressive disorder (MDD; F32.2) and bipolar disorder (BD-sDE; F31.4) were made according to ICD-10 (WHO 1992) diagnostic criteria. Methods of suicide attempts were also assessed according to ICD-10 and a self-report questionnaire, the Temperament and Character Inventory (TCI) was applied. RESULTS: The participants who exhibited suicide attempt had significantly higher scores on harm-avoidance (HA) (p<0.001), significantly lower score on persistence (PS) (p=0.037) and lower score, however not statistically significant, on novelty-seeking (NS) (p=0.319) regarding temperament dimensions. In character dimensions, the patients with suicidal attempt had significantly lower scores on self-directedness (SD) (p<0.001) and significantly lower scores on cooperativeness (CO) (p=0.001). CONCLUSION: Patients who had suicide attempt may have some significantly different personality traits than non-suicidal patients with mood disorders. The combination of high harm-avoidance (HA) and low self-directedness (SD) may be specific for depressive episode while the combination of high HA, novelty-seeking (NS), and self-transcendence (ST) with low SD may be related to suicide attempts during the depressive episode in bipolar disorder. The novelty-seeking (NS), self transcendence (ST) and self-directedness (SD) may be specific for suicidal group of bipolar patients. PMID- 28636576 TI - Vitamin D Levels and Vitamin D Receptor Gene Polymorphism in Major Depression. AB - BACKGROUND: The aim of this study is to evaluate vitamin D levels and rs2228570 (FokI) polymorphism of vitamin D in patients with established diagnosis of major depressive disorder in order to investigate the impact of vitamin D levels and genetic polymorphisms on etiology and/or severity of the disease. SUBJECTS AND METHODS: The study included 86 patients who were diagnosed with major depressive disorder in Hospital of Balikesir University Faculty of Medicine, Department of Psychiatry, and 89 healthy volunteers with similar age, sex, education level and BMI. Psychiatric diagnosis was established by using Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). For clinical evaluation, sociodemographic data form, Hamilton Depression Rating Scale, Hamilton Anxiety Scale were used. Blood samples were drawn after 12 hours of fasting from the patients volunteered and the control group who were given their informed consent for participation in the study. Vitamin D levels were determined by using the method of ECLIA (Electrochemiluminescent immunoassay). Genotype analysis was performed using the method of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR RFLP). RESULTS: In our study, median vitamin D levels (min-max) of the patient and control groups were 10.3 ng/mL (3.0-42.1) and 11.4 ng/mL (3.0-38.8), respectively. Statistically significant differences as for vitamin D levels between groups were not detected (p=0.729). Similiarly no statistically significant difference between groups in genotype distribution was observed (p=0.396). CONCLUSION: In conclusion, our findings do not support the relationship between depression, vitamin D levels and Fok 1 polymorphism of vitamin D receptor. To test these hypotheses in the light of literature we need further studies to be performed with large number of patients. PMID- 28636577 TI - Comorbidity and Suicidality in Patients Diagnosed with Panic Disorder/Agoraphobia and Major Depression. AB - BACKGROUND: Comorbidity of anxiety and depression (both current and lifetime) is associated with greater chronicity and an increased risk of suicidality. We wished to ascertain which symptom clusters had the strongest association with suicidality. Our aims were (1) to examine the presence of current comorbidity and suicidality in patients diagnosed with panic disorder/agoraphobia (PD/A) and major depression (MD), and their relationship with duration of psychiatric treatment and frequency of hospital admission; and (2) to examine which coexisting symptoms were most strongly predictive of suicidality in sub-groups and the overall group. SUBJECTS AND METHODS: The study sample comprised 100 patients with PD/A and MD. The following assessment instruments were applied: the Panic and Agoraphobia Scale, the Beck Anxiety Inventory, the Beck Depression Inventory-II, the Beck Scale for Suicide Ideation, the Obsessive-Compulsive Inventory-Revised, the Liebowitz Social Anxiety Scale and the Whiteley Index of Hypochondriasis. RESULTS: High rates of current comorbidity were seen in both groups. Patients with MD had significantly higher suicidality scores, but were also older, with a longer duration of psychiatric treatment and more frequent hospitalizations. In the overall group, psychiatric comorbidity was correlated with duration of psychiatric treatment and frequency of hospitalizations (with the exception of hypochondriasis which was not correlated with frequency of hospitalization). In both sub-groups and the overall group, suicidality was correlated with scores for all examined comorbidity (with the exception of hypochondriasis in the PD/A group): however, after multiple regression only obsessive-compulsive symptomatology predicted suicidality in all sub-groups and the overall group, as well as depression in the overall group. Depression supposed as dependent variable and obsessive-compulsive symptomatology as a mediator explained around 37% of the variance in suicidal ideation. CONCLUSION: Patients with PD/A or MD show high rates of current comorbidity. The effect of depression on suicidality was significant, but a non-trivial impact was also mediated by obsessive-compulsive symptomatology. PMID- 28636578 TI - Human neuropsin gene in depression. AB - BACKGROUND: Neuropsin (NP, kallikrein 8, KLK8) - a kallikrein gene-related (KLK) endoprotease - plays a key role in neuroplasticity processes, since intracellular signal cascades and regulation of gene expression are engaged in long-term synaptic plasticity. The main aim of this paper is to compare expression of the human neuropsin gene on the mRNA level in a group of patients diagnosed with depression and in a group of healthy subjects who have never been treated psychiatrically. SUBJECTS AND METHODS: 291 people, aged 18-67, were qualified to participate in the experiment: major recurrent depression group (MRD) and the control group (CG). Designations were carried out for the human NP gene (hNP). RESULTS: For hNP gene expression at the mRNA level was higher in patients with depression than in the CG (p<0.005). A Spearman's rank correlation analysis did not reveal any statistically significant relationship between the intensity of the disease measured using the HDRS scale and expression on the mRNA level for the hNP gene. Expression for the hNP gene in the entire group analysed increased with age of the examined individuals (p<0.005). CONCLUSION: Expression of the hNP gene on the mRNA level, evaluated based on peripheral blood, is significantly higher in the patients with MRD than in the healthy subjects. PMID- 28636579 TI - Regeneration orientation is better than resistance orientation in behaviour activation. Results from an intervention study with psychosomatic patients. AB - The meaning of positive activities in mental health is widely known and found its entrance in therapeutically and empirical work. It also found it's entrance to current therapeutic developments. Different strategies for assessment and promotion of activity level exist. Patients were acquired from a department of psychosomatic medicine in a German rehabilitation center and randomly allocated to two treatment groups ("regeneration" vs "resistance" group). Data from 62 patients in the regeneration group and 65 patients in the resistance group was compared with 43 patients who received a "treatment as usual". All group comparisons were statistically significant, with different results depending on the type of activities. Regarding behavior activation, there tend to be an advantage for the regeneration group. Nothing is said about the transfer after discharge and long term effects. PMID- 28636580 TI - Mediator Effects of Positive Emotions on Social Support and Depression among Adolescents Suffering from Mobile Phone Addiction. AB - BACKGROUND: Depression is a common mental disorder that is widely seen among adolescents suffering from mobile phone addiction. While it is well known that both positive emtions in adolescents wiotions and social support can have a positive impact by helping individuals to maintain a positive attitude, the correlation between positive emotions, social support, and depression among these adolescents remains to be investigated. This study examined the mediator effects of positive emotions on the relationship between social support and depression among adolescents suffering from mobile phone addiction. SUBJECTS AND METHODS: For this study, conducted in 2016, we selected 1,346 adolescent students from three middle schools (ranging from Junior Grade One to Senior Grade Three) in Hunan Province of China, to participate in the survey. Participants were selected using the stratified cluster random sampling method, and all participants remained anonymous throughout the study. Each participant completed the Self-made General Situation Questionnaire, the Social Support Rating Scale, the Positive and Negative Affect Schedule, the Center for Epidemiological Studies Depression Scale, and the Mobile Phone Addiction Tendency Scale. RESULTS: There was significant positive correlation between positive emotions and social support. Both positive emotions and social support demonstrated significant negative correlation with depression. Positive emotions had partial mediator effects on the relationship between social support and depression (P<0.01). CONCLUSIONS: Both social support and positive emotions can lower levels of depression among adolescents suffering from mobile phone addiction. Social support contributes to positive emoth mobile phone addiction, thereby reducing their levels of depression. These findings suggest that more support and care should be given to this particular adolescent population. PMID- 28636582 TI - Bilateral DMPFC-rTMS Leads to Sustained Remission in Geriatric Treatment Resistant Depression: A Case Report. PMID- 28636581 TI - The PsyLOG mobile application: development of a tool for the assessment and monitoring of side effects of psychotropic medication. AB - Mobile health interventions are regarded as affordable and accessible tools that can enhance standard psychiatric care. As part of the mHealth Psycho-Educational Intervention Versus Antipsychotic-Induced Side Effects (mPIVAS) project (www.psylog.eu), we developed the mobile application "PsyLOG" based on mobile "smartphone" technology to monitor antipsychotic-induced side effects. The aim of this paper is to describe the rationale and development of the PsyLOG and its clinical use. The PsyLOG application runs on smartphones with Android operating system. The application is currently available in seven languages (Croatian, Czech, English, French, German, Japanese and Serbian). It consists of several categories: "My Drug Effects", "My Life Styles", "My Charts", "My Medication", "My Strategies", "My Supporters", "Settings" and "About". The main category "My Drug Effects" includes a list of 30 side effects with the possibility to add three additional side effects. Side effects are each accompanied by an appropriate description and the possibility to rate its severity on a visual analogue scale from 0-100%. The PsyLOG application is intended to enhance the link between patients and mental health professionals, serving as a tool that more objectively monitors side-effects over certain periods of time. To the best of our knowledge, no such applications have so far been developed for patients taking antipsychotic medication or for their therapists. PMID- 28636583 TI - Posttraumatic Stress Disorder and Comorbid Sexual Dysfunctions. PMID- 28636584 TI - Proton magnetic resonance spectroscopy in Huntington's disease accompanying neuroborreliosis. PMID- 28636586 TI - Eardrum regeneration: membrane repair. PMID- 28636585 TI - Microbiome: A Potential Component in the Origin of Mental Disorders. AB - It is not surprising to find microbiome abnormalities present in psychiatric disorders such as depressive disorders, bipolar disorders, etc. Evolutionary pressure may provide an existential advantage to the host eukaryotic cells in that it survives in an extracellular environment containing non-self cells (e.g., bacteria). This phenomenon is both positive and negative, as with other intercellular processes. In this specific case, the phenomenal amount of information gained from combined bacterial genome could enhance communication between self and non-self cells. This can be coupled to both pathological processes and healthy ones. In this review, we chose to examine potential associated disorders that may be coupled to the microbiome, from the perspective of their bidirectional communication with eukaryotic cells in the gut. Cognition, being the newest neural networking functionality to evolve, consumes a good amount of organismic energy, 30% of which arises from the gut flora. Furthermore, the mammalian gut is highly innervated and has a highly developed immune component, reflecting brain complexity. The brain-gut axis uses similar molecular messengers as the brain, which affects bacterial processes as well. Thus, any modification of normal bacterial processes may manifest itself in altered behavior/cognition, originating from the gut. The origin of some disorders associated with this bidirectional communication may be harnessed to restore normal functioning. PMID- 28636587 TI - Marching to a new beat. PMID- 28636588 TI - Immunology: The patterns of T-cell target recognition. PMID- 28636589 TI - Identifying specificity groups in the T cell receptor repertoire. AB - T cell receptor (TCR) sequences are very diverse, with many more possible sequence combinations than T cells in any one individual. Here we define the minimal requirements for TCR antigen specificity, through an analysis of TCR sequences using a panel of peptide and major histocompatibility complex (pMHC) tetramer-sorted cells and structural data. From this analysis we developed an algorithm that we term GLIPH (grouping of lymphocyte interactions by paratope hotspots) to cluster TCRs with a high probability of sharing specificity owing to both conserved motifs and global similarity of complementarity-determining region 3 (CDR3) sequences. We show that GLIPH can reliably group TCRs of common specificity from different donors, and that conserved CDR3 motifs help to define the TCR clusters that are often contact points with the antigenic peptides. As an independent validation, we analysed 5,711 TCRbeta chain sequences from reactive CD4 T cells from 22 individuals with latent Mycobacterium tuberculosis infection. We found 141 TCR specificity groups, including 16 distinct groups containing TCRs from multiple individuals. These TCR groups typically shared HLA alleles, allowing prediction of the likely HLA restriction, and a large number of M. tuberculosis T cell epitopes enabled us to identify pMHC ligands for all five of the groups tested. Mutagenesis and de novo TCR design confirmed that the GLIPH identified motifs were critical and sufficient for shared-antigen recognition. Thus the GLIPH algorithm can analyse large numbers of TCR sequences and define TCR specificity groups shared by TCRs and individuals, which should greatly accelerate the analysis of T cell responses and expedite the identification of specific ligands. PMID- 28636590 TI - Host and viral traits predict zoonotic spillover from mammals. AB - The majority of human emerging infectious diseases are zoonotic, with viruses that originate in wild mammals of particular concern (for example, HIV, Ebola and SARS). Understanding patterns of viral diversity in wildlife and determinants of successful cross-species transmission, or spillover, are therefore key goals for pandemic surveillance programs. However, few analytical tools exist to identify which host species are likely to harbour the next human virus, or which viruses can cross species boundaries. Here we conduct a comprehensive analysis of mammalian host-virus relationships and show that both the total number of viruses that infect a given species and the proportion likely to be zoonotic are predictable. After controlling for research effort, the proportion of zoonotic viruses per species is predicted by phylogenetic relatedness to humans, host taxonomy and human population within a species range-which may reflect human wildlife contact. We demonstrate that bats harbour a significantly higher proportion of zoonotic viruses than all other mammalian orders. We also identify the taxa and geographic regions with the largest estimated number of 'missing viruses' and 'missing zoonoses' and therefore of highest value for future surveillance. We then show that phylogenetic host breadth and other viral traits are significant predictors of zoonotic potential, providing a novel framework to assess if a newly discovered mammalian virus could infect people. PMID- 28636591 TI - Infectious diseases: Predictions of virus spillover across species. PMID- 28636592 TI - Quantifiable predictive features define epitope-specific T cell receptor repertoires. AB - T cells are defined by a heterodimeric surface receptor, the T cell receptor (TCR), that mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs). TCRs are generated by genomic rearrangement of the germline TCR locus, a process termed V(D)J recombination, that has the potential to generate marked diversity of TCRs (estimated to range from 1015 (ref. 1) to as high as 1061 (ref. 2) possible receptors). Despite this potential diversity, TCRs from T cells that recognize the same pMHC epitope often share conserved sequence features, suggesting that it may be possible to predictively model epitope specificity. Here we report the in-depth characterization of ten epitope-specific TCR repertoires of CD8+ T cells from mice and humans, representing over 4,600 in frame single-cell-derived TCRalphabeta sequence pairs from 110 subjects. We developed analytical tools to characterize these epitope-specific repertoires: a distance measure on the space of TCRs that permits clustering and visualization, a robust repertoire diversity metric that accommodates the low number of paired public receptors observed when compared to single-chain analyses, and a distance based classifier that can assign previously unobserved TCRs to characterized repertoires with robust sensitivity and specificity. Our analyses demonstrate that each epitope-specific repertoire contains a clustered group of receptors that share core sequence similarities, together with a dispersed set of diverse 'outlier' sequences. By identifying shared motifs in core sequences, we were able to highlight key conserved residues driving essential elements of TCR recognition. These analyses provide insights into the generalizable, underlying features of epitope-specific repertoires and adaptive immune recognition. PMID- 28636594 TI - Surface tension prevails over solute effect in organic-influenced cloud droplet activation. AB - The spontaneous growth of cloud condensation nuclei (CCN) into cloud droplets under supersaturated water vapour conditions is described by classic Kohler theory. This spontaneous activation of CCN depends on the interplay between the Raoult effect, whereby activation potential increases with decreasing water activity or increasing solute concentration, and the Kelvin effect, whereby activation potential decreases with decreasing droplet size or increases with decreasing surface tension, which is sensitive to surfactants. Surface tension lowering caused by organic surfactants, which diminishes the Kelvin effect, is expected to be negated by a concomitant reduction in the Raoult effect, driven by the displacement of surfactant molecules from the droplet bulk to the droplet vapour interface. Here we present observational and theoretical evidence illustrating that, in ambient air, surface tension lowering can prevail over the reduction in the Raoult effect, leading to substantial increases in cloud droplet concentrations. We suggest that consideration of liquid-liquid phase separation, leading to complete or partial engulfing of a hygroscopic particle core by a hydrophobic organic-rich phase, can explain the lack of concomitant reduction of the Raoult effect, while maintaining substantial lowering of surface tension, even for partial surface coverage. Apart from the importance of particle size and composition in droplet activation, we show by observation and modelling that incorporation of phase-separation effects into activation thermodynamics can lead to a CCN number concentration that is up to ten times what is predicted by climate models, changing the properties of clouds. An adequate representation of the CCN activation process is essential to the prediction of clouds in climate models, and given the effect of clouds on the Earth's energy balance, improved prediction of aerosol-cloud-climate interactions is likely to result in improved assessments of future climate change. PMID- 28636593 TI - T cells from patients with Parkinson's disease recognize alpha-synuclein peptides. AB - Genetic studies have shown the association of Parkinson's disease with alleles of the major histocompatibility complex. Here we show that a defined set of peptides that are derived from alpha-synuclein, a protein aggregated in Parkinson's disease, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson's disease. These responses may explain the association of Parkinson's disease with specific major histocompatibility complex alleles. PMID- 28636595 TI - Nlrp9b inflammasome restricts rotavirus infection in intestinal epithelial cells. AB - Rotavirus, a leading cause of severe gastroenteritis and diarrhoea in young children, accounts for around 215,000 deaths annually worldwide. Rotavirus specifically infects the intestinal epithelial cells in the host small intestine and has evolved strategies to antagonize interferon and NF-kappaB signalling, raising the question as to whether other host factors participate in antiviral responses in intestinal mucosa. The mechanism by which enteric viruses are sensed and restricted in vivo, especially by NOD-like receptor (NLR) inflammasomes, is largely unknown. Here we uncover and mechanistically characterize the NLR Nlrp9b that is specifically expressed in intestinal epithelial cells and restricts rotavirus infection. Our data show that, via RNA helicase Dhx9, Nlrp9b recognizes short double-stranded RNA stretches and forms inflammasome complexes with the adaptor proteins Asc and caspase-1 to promote the maturation of interleukin (Il) 18 and gasdermin D (Gsdmd)-induced pyroptosis. Conditional depletion of Nlrp9b or other inflammasome components in the intestine in vivo resulted in enhanced susceptibility of mice to rotavirus replication. Our study highlights an important innate immune signalling pathway that functions in intestinal epithelial cells and may present useful targets in the modulation of host defences against viral pathogens. PMID- 28636596 TI - Selective sp3 C-H alkylation via polarity-match-based cross-coupling. AB - The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the alpha-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry. PMID- 28636598 TI - Astrophysics: Stellar siblings grow closer with age. PMID- 28636597 TI - Phase separation drives heterochromatin domain formation. AB - Constitutive heterochromatin is an important component of eukaryotic genomes that has essential roles in nuclear architecture, DNA repair and genome stability, and silencing of transposon and gene expression. Heterochromatin is highly enriched for repetitive sequences, and is defined epigenetically by methylation of histone H3 at lysine 9 and recruitment of its binding partner heterochromatin protein 1 (HP1). A prevalent view of heterochromatic silencing is that these and associated factors lead to chromatin compaction, resulting in steric exclusion of regulatory proteins such as RNA polymerase from the underlying DNA. However, compaction alone does not account for the formation of distinct, multi-chromosomal, membrane less heterochromatin domains within the nucleus, fast diffusion of proteins inside the domain, and other dynamic features of heterochromatin. Here we present data that support an alternative hypothesis: that the formation of heterochromatin domains is mediated by phase separation, a phenomenon that gives rise to diverse non-membrane-bound nuclear, cytoplasmic and extracellular compartments. We show that Drosophila HP1a protein undergoes liquid-liquid demixing in vitro, and nucleates into foci that display liquid properties during the first stages of heterochromatin domain formation in early Drosophila embryos. Furthermore, in both Drosophila and mammalian cells, heterochromatin domains exhibit dynamics that are characteristic of liquid phase-separation, including sensitivity to the disruption of weak hydrophobic interactions, and reduced diffusion, increased coordinated movement and inert probe exclusion at the domain boundary. We conclude that heterochromatic domains form via phase separation, and mature into a structure that includes liquid and stable compartments. We propose that emergent biophysical properties associated with phase-separated systems are critical to understanding the unusual behaviours of heterochromatin, and how chromatin domains in general regulate essential nuclear functions. PMID- 28636599 TI - Addendum: Immune clearance of highly pathogenic SIV infection. AB - This corrects the article DOI: 10.1038/nature12519. PMID- 28636600 TI - Hidden morphological diversity among early tetrapods. AB - Phylogenetic analysis of early tetrapod evolution has resulted in a consensus across diverse data sets in which the tetrapod stem group is a relatively homogenous collection of medium- to large-sized animals showing a progressive loss of 'fish' characters as they become increasingly terrestrial, whereas the crown group demonstrates marked morphological diversity and disparity. The oldest fossil attributed to the tetrapod crown group is the highly specialized aistopod Lethiscus stocki, which shows a small size, extreme axial elongation, loss of limbs, spool-shaped vertebral centra, and a skull with reduced centres of ossification, in common with an otherwise disparate group of small animals known as lepospondyls. Here we use micro-computed tomography of the only known specimen of Lethiscus to provide new information that strongly challenges this consensus. Digital dissection reveals extremely primitive cranial morphology, including a spiracular notch, a large remnant of the notochord within the braincase, an open ventral cranial fissure, an anteriorly restricted parasphenoid element, and Meckelian ossifications. The braincase is elongate and lies atop a dorsally projecting septum of the parasphenoid bone, similar to stem tetrapods such as embolomeres. This morphology is consistent in a second aistopod, Coloraderpeton, although the details differ. Phylogenetic analysis, including critical new braincase data, places aistopods deep on the tetrapod stem, whereas another major lepospondyl lineage is displaced into the amniotes. These results show that stem group tetrapods were much more diverse in their body plans than previously thought. Our study requires a change in commonly used calibration dates for molecular analyses, and emphasizes the importance of character sampling for early tetrapod evolutionary relationships. PMID- 28636602 TI - Immunology: Gut sensor halts viral attack. PMID- 28636601 TI - Crystal structure of the potassium-importing KdpFABC membrane complex. AB - Cellular potassium import systems play a fundamental role in osmoregulation, pH homeostasis and membrane potential in all domains of life. In bacteria, the kdp operon encodes a four-subunit potassium pump that maintains intracellular homeostasis, cell shape and turgor under conditions in which potassium is limiting. This membrane complex, called KdpFABC, has one channel-like subunit (KdpA) belonging to the superfamily of potassium transporters and another pump like subunit (KdpB) belonging to the superfamily of P-type ATPases. Although there is considerable structural and functional information about members of both superfamilies, the mechanism by which uphill potassium transport through KdpA is coupled with ATP hydrolysis by KdpB remains poorly understood. Here we report the 2.9 A X-ray structure of the complete Escherichia coli KdpFABC complex with a potassium ion within the selectivity filter of KdpA and a water molecule at a canonical cation site in the transmembrane domain of KdpB. The structure also reveals two structural elements that appear to mediate the coupling between these two subunits. Specifically, a protein-embedded tunnel runs between these potassium and water sites and a helix controlling the cytoplasmic gate of KdpA is linked to the phosphorylation domain of KdpB. On the basis of these observations, we propose a mechanism that repurposes protein channel architecture for active transport across biomembranes. PMID- 28636603 TI - Trans-kingdom mimicry underlies ribosome customization by a poxvirus kinase. AB - Ribosomes have the capacity to selectively control translation through changes in their composition that enable recognition of specific RNA elements. However, beyond differential subunit expression during development, evidence for regulated ribosome specification within individual cells has remained elusive. Here we report that a poxvirus kinase phosphorylates serine/threonine residues in the human small ribosomal subunit protein, receptor for activated C kinase (RACK1), that are not phosphorylated in uninfected cells or cells infected by other viruses. These modified residues cluster in an extended loop in RACK1, phosphorylation of which selects for translation of viral or reporter mRNAs with 5' untranslated regions that contain adenosine repeats, so-called polyA-leaders. Structural and phylogenetic analyses revealed that although RACK1 is highly conserved, this loop is variable and contains negatively charged amino acids in plants, in which these leaders act as translational enhancers. Phosphomimetics and inter-species chimaeras have shown that negative charge in the RACK1 loop dictates ribosome selectivity towards viral RNAs. By converting human RACK1 to a charged, plant-like state, poxviruses remodel host ribosomes so that adenosine repeats erroneously generated by slippage of the viral RNA polymerase confer a translational advantage. Our findings provide insight into ribosome customization through trans-kingdom mimicry and the mechanics of species-specific leader activity that underlie poxvirus polyA-leaders. PMID- 28636604 TI - Liquid droplet formation by HP1alpha suggests a role for phase separation in heterochromatin. AB - Gene silencing by heterochromatin is proposed to occur in part as a result of the ability of heterochromatin protein 1 (HP1) proteins to spread across large regions of the genome, compact the underlying chromatin and recruit diverse ligands. Here we identify a new property of the human HP1alpha protein: the ability to form phase-separated droplets. While unmodified HP1alpha is soluble, either phosphorylation of its N-terminal extension or DNA binding promotes the formation of phase-separated droplets. Phosphorylation-driven phase separation can be promoted or reversed by specific HP1alpha ligands. Known components of heterochromatin such as nucleosomes and DNA preferentially partition into the HP1alpha droplets, but molecules such as the transcription factor TFIIB show no preference. Using a single-molecule DNA curtain assay, we find that both unmodified and phosphorylated HP1alpha induce rapid compaction of DNA strands into puncta, although with different characteristics. We show by direct protein delivery into mammalian cells that an HP1alpha mutant incapable of phase separation in vitro forms smaller and fewer nuclear puncta than phosphorylated HP1alpha. These findings suggest that heterochromatin-mediated gene silencing may occur in part through sequestration of compacted chromatin in phase-separated HP1 droplets, which are dissolved or formed by specific ligands on the basis of nuclear context. PMID- 28636605 TI - Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block. AB - The stereoselective oxidation of hydrocarbons is one of the most notable advances in synthetic chemistry over the past fifty years. Inspired by nature, enantioselective dihydroxylations, epoxidations and other oxidations of unsaturated hydrocarbons have been developed. More recently, the catalytic enantioselective allylic carbon-hydrogen oxidation of alkenes has streamlined the production of pharmaceuticals, natural products, fine chemicals and other functional materials. Allylic functionalization provides a direct path to chiral building blocks with a newly formed stereocentre from petrochemical feedstocks while preserving the olefin functionality as a handle for further chemical elaboration. Various metal-based catalysts have been discovered for the enantioselective allylic carbon-hydrogen oxidation of simple alkenes with cyclic or terminal double bonds. However, a general and selective allylic oxidation using the more common internal alkenes remains elusive. Here we report the enantioselective, regioselective and E/Z-selective allylic oxidation of unactivated internal alkenes via a catalytic hetero-ene reaction with a chalcogen based oxidant. Our method enables non-symmetric internal alkenes to be selectively converted into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the resulting multifunctional chiral building blocks highlight the potential for rapidly converting internal alkenes into a broad range of enantioenriched structures that can be used in the synthesis of complex target molecules. PMID- 28636606 TI - Molecular biology: A liquid reservoir for silent chromatin. PMID- 28636607 TI - Three-dimensional cell shapes and arrangements in human sweat glands as revealed by whole-mount immunostaining. AB - Because sweat secretion is facilitated by mechanical contraction of sweat gland structures, understanding their structure-function relationship could lead to more effective treatments for patients with sweat gland disorders such as heat stroke. Conventional histological studies have shown that sweat glands are three dimensionally coiled tubular structures consisting of ducts and secretory portions, although their detailed structural anatomy remains unclear. To better understand the details of the three-dimensional (3D) coiled structures of sweat glands, a whole-mount staining method was employed to visualize 3D coiled gland structures with sweat gland markers for ductal luminal, ductal basal, secretory luminal, and myoepithelial cells. Imaging the 3D coiled gland structures demonstrated that the ducts and secretory portions were comprised of distinct tubular structures. Ductal tubules were occasionally bent, while secretory tubules were frequently bent and formed a self-entangled coiled structure. Whole mount staining of complex coiled gland structures also revealed the detailed 3D cellular arrangements in the individual sweat gland compartments. Ducts were composed of regularly arranged cuboidal shaped cells, while secretory portions were surrounded by myoepithelial cells longitudinally elongated along entangled secretory tubules. Whole-mount staining was also used to visualize the spatial arrangement of blood vessels and nerve fibers, both of which facilitate sweat secretion. The blood vessels ran longitudinally parallel to the sweat gland tubules, while nerve fibers wrapped around secretory tubules, but not ductal tubules. Taken together, whole-mount staining of sweat glands revealed the 3D cell shapes and arrangements of complex coiled gland structures and provides insights into the mechanical contraction of coiled gland structures during sweat secretion. PMID- 28636608 TI - The construct of sexual openness for females in steady intimate relationships. AB - The analysis of open-minded attitudes towards sexuality in general requires a construct based on attitudinal dimensions. Although several existing studies involve sexual attitudes, they differ substantially and standardized conceptual work is missing. Thus, the authors introduce the latent variable sexual openness to develop a construct based on self-oriented attitudes towards different sexual topics. Available survey data of female German students in a steady relationship allowed providing a first empirical test for the applicability of this construct. Five subdimensions are acknowledged central for sexual openness: sexual practices, masturbation, bisexuality, permissiveness, and pornography consumption. Confirmatory factor analysis and correlations confirmed the idea of an underlying mechanism with an impact on all five variables. Though further validation of the construct of sexual openness is required, the findings strongly support the notion of an overarching latent attitude variable, which influences the individual relation to everything sexual. The results were compared to other studies and potential approaches for future analyses were proposed. PMID- 28636609 TI - Genomic and phenotypic characterisation of fluoroquinolone resistance mechanisms in Enterobacteriaceae in Durban, South Africa. AB - Resistance to fluoroquinolones (FQ) is being increasingly reported and found to be mediated by efflux pumps, plasmid-mediated quinolone resistance genes (PMQR) and mutations in gyrA, gyrB, parC and parE. However, studies reporting on FQ resistance mechanisms (FQRM), particularly in Africa, are focused mostly on Salmonella. This study used a whole-genome-based approach to describe FQRM in forty-eight clinical Enterobacteriaceae isolates comprising of Klebsiella pneumoniae (n = 21), Serratia marcescens (n = 12), Enterobacter spp. (n = 10), Citrobacter freundii (n = 3), Escherichia coli (n = 1), and Klebsiella michiganensis (n = 1) with reduced susceptibility to FQ in Enterobacteriaceae. All the isolates exhibited exceptionally high-level resistance (MIC of 4-512mg/L) to all three FQs, which could not be reversed by carbonyl cyanide m-chlorophenyl hydrazine (CCCP), verapamil (VRP) or reserpine (RSP). PMQR genes such as oqxAB (n = 43), aac(6')-Ib-cr (n = 28), and qnr(S1, B1, B2, B9, B49, B66) (n = 23) were identified without transposons or integrons in their immediate environments. Multiple and diverse mutations were found in gyrA (including S83I/Y and T/I83I/T), gyrB, parC and parE, which were clonally specific. There were vertical and horizontal transmission of high-level FQ resistance in Enterobacteriaceae in hospitals in Durban, South Africa, which are mediated by efflux, PMQR genes, and gyrA, gyrB, parC and parE mutations. PMID- 28636610 TI - Chronotypes in the US - Influence of age and sex. AB - An individual's chronotype reflects how the circadian system embeds itself into the 24-h day with rhythms in physiology, cognition and behavior occurring accordingly earlier or later. In view of an increasing number of people working at unusual times and linked health and safety risks, the wide range in human chronotypes may provide opportunities to allow people to work (and sleep) at times that are in synch with their circadian physiology. We aimed at estimating the distribution of chronotypes in the US population by age and sex. Twelve years (2003-2014) of pooled diary data from the American Time Use Survey were used to calculate chronotype based on mid-point of sleep on weekends (MSFWe, n = 53,689). We observed a near-normal distribution overall and within each age group. The distribution's mean value is systematically different with age, shifting later during adolescence, showing a peak in 'lateness' at ~19 years, and shifting earlier thereafter. Men are typically later chronotypes than women before 40, but earlier types after 40. The greatest differences are observed between 15 and 25 for both sexes, equaling more than 50% of the total chronotype difference across all age groups. The variability in chronotype decreases with age, but is generally higher in males than females. This is the first study to estimate the distribution and prevalence of individual chronotypes in the US population based on a large-scale, nationally representative sample. Our finding that adolescents are on average the latest chronotypes supports delaying school start times to benefit their sleep and circadian alignment. The generally wide range in chronotypes may provide opportunities for tailored work schedules by matching external and internal time, potentially decreasing long- and short-term health and safety risks. PMID- 28636611 TI - Unmanned aircraft systems as a new source of disturbance for wildlife: A systematic review. AB - The use of small Unmanned Aircraft Systems (UAS; also known as "drones") for professional and personal-leisure use is increasing enormously. UAS operate at low altitudes (<500 m) and in any terrain, thus they are susceptible to interact with local fauna, generating a new type of anthropogenic disturbance that has not been systematically evaluated. To address this gap, we performed a review of the existent literature about animals' responses to UAS flights and conducted a pooled analysis of the data to determine the probability and intensity of the disturbance, and to identify the factors influencing animals' reactions towards the small aircraft. We found that wildlife reactions depended on both the UAS attributes (flight pattern, engine type and size of aircraft) and the characteristics of animals themselves (type of animal, life-history stage and level of aggregation). Target-oriented flight patterns, larger UAS sizes, and fuel-powered (noisier) engines evoked the strongest reactions in wildlife. Animals during the non-breeding period and in large groups were more likely to show behavioral reactions to UAS, and birds are more prone to react than other taxa. We discuss the implications of these results in the context of wildlife disturbance and suggest guidelines for conservationists, users and manufacturers to minimize the impact of UAS. In addition, we propose that the legal framework needs to be adapted so that appropriate actions can be undertaken when wildlife is negatively affected by these emergent practices. PMID- 28636612 TI - Laminin 211 inhibits protein kinase A in Schwann cells to modulate neuregulin 1 type III-driven myelination. AB - Myelin is required for proper nervous system function. Schwann cells in developing nerves depend on extrinsic signals from the axon and from the extracellular matrix to first sort and ensheathe a single axon and then myelinate it. Neuregulin 1 type III (Nrg1III) and laminin alpha2beta1gamma1 (Lm211) are the key axonal and matrix signals, respectively, but how their signaling is integrated and if each molecule controls both axonal sorting and myelination is unclear. Here, we use a series of epistasis experiments to show that Lm211 modulates neuregulin signaling to ensure the correct timing and amount of myelination. Lm211 can inhibit Nrg1III by limiting protein kinase A (PKA) activation, which is required to initiate myelination. We provide evidence that excessive PKA activation amplifies promyelinating signals downstream of neuregulin, including direct activation of the neuregulin receptor ErbB2 and its effector Grb2-Associated Binder-1 (Gab1), thereby elevating the expression of the key transcription factors Oct6 and early growth response protein 2 (Egr2). The inhibitory effect of Lm211 is seen only in fibers of small caliber. These data may explain why hereditary neuropathies associated with decreased laminin function are characterized by focally thick and redundant myelin. PMID- 28636614 TI - Smartphone dependence classification using tensor factorization. AB - Excessive smartphone use causes personal and social problems. To address this issue, we sought to derive usage patterns that were directly correlated with smartphone dependence based on usage data. This study attempted to classify smartphone dependence using a data-driven prediction algorithm. We developed a mobile application to collect smartphone usage data. A total of 41,683 logs of 48 smartphone users were collected from March 8, 2015, to January 8, 2016. The participants were classified into the control group (SUC) or the addiction group (SUD) using the Korean Smartphone Addiction Proneness Scale for Adults (S-Scale) and a face-to-face offline interview by a psychiatrist and a clinical psychologist (SUC = 23 and SUD = 25). We derived usage patterns using tensor factorization and found the following six optimal usage patterns: 1) social networking services (SNS) during daytime, 2) web surfing, 3) SNS at night, 4) mobile shopping, 5) entertainment, and 6) gaming at night. The membership vectors of the six patterns obtained a significantly better prediction performance than the raw data. For all patterns, the usage times of the SUD were much longer than those of the SUC. From our findings, we concluded that usage patterns and membership vectors were effective tools to assess and predict smartphone dependence and could provide an intervention guideline to predict and treat smartphone dependence based on usage data. PMID- 28636613 TI - In vivo immune signatures of healthy human pregnancy: Inherently inflammatory or anti-inflammatory? AB - Changes in maternal innate immunity during healthy human pregnancy are not well understood. Whether basal immune status in vivo is largely unaffected by pregnancy, is constitutively biased towards an inflammatory phenotype (transiently enhancing host defense) or exhibits anti-inflammatory bias (reducing potential responsiveness to the fetus) is unclear. Here, in a longitudinal study of healthy women who gave birth to healthy infants following uncomplicated pregnancies within the Canadian Healthy Infant Longitudinal Development (CHILD) cohort, we test the hypothesis that a progressively altered bias in resting innate immune status develops. Women were examined during pregnancy and again, one and/or three years postpartum. Most pro-inflammatory cytokine expression, including CCL2, CXCL10, IL-18 and TNFalpha, was reduced in vivo during pregnancy (20-57%, p<0.0001). Anti-inflammatory biomarkers (sTNF-RI, sTNF-RII, and IL-1Ra) were elevated by ~50-100% (p<0.0001). Systemic IL-10 levels were unaltered during vs. post-pregnancy. Kinetic studies demonstrate that while decreased pro inflammatory biomarker expression (CCL2, CXCL10, IL-18, and TNFalpha) was constant, anti-inflammatory expression increased progressively with increasing gestational age (p<0.0001). We conclude that healthy resting maternal immune status is characterized by an increasingly pronounced bias towards a systemic anti-inflammatory innate phenotype during the last two trimesters of pregnancy. This is resolved by one year postpartum in the absence of repeat pregnancy. The findings provide enhanced understanding of immunological changes that occur in vivo during healthy human pregnancy. PMID- 28636615 TI - Family living sets the stage for cooperative breeding and ecological resilience in birds. AB - Cooperative breeding is an extreme form of cooperation that evolved in a range of lineages, including arthropods, fish, birds, and mammals. Although cooperative breeding in birds is widespread and well-studied, the conditions that favored its evolution are still unclear. Based on phylogenetic comparative analyses on 3,005 bird species, we demonstrate here that family living acted as an essential stepping stone in the evolution of cooperative breeding in the vast majority of species. First, families formed by prolonging parent-offspring associations beyond nutritional independency, and second, retained offspring began helping at the nest. These findings suggest that assessment of the conditions that favor the evolution of cooperative breeding can be confounded if this process is not considered to include 2 steps. Specifically, phylogenetic linear mixed models show that the formation of families was associated with more productive and seasonal environments, where prolonged parent-offspring associations are likely to be less costly. However, our data show that the subsequent evolution of cooperative breeding was instead linked to environments with variable productivity, where helpers at the nest can buffer reproductive failure in harsh years. The proposed 2-step framework helps resolve current disagreements about the role of environmental forces in the evolution of cooperative breeding and better explains the geographic distribution of this trait. Many geographic hotspots of cooperative breeding have experienced a historical decline in productivity, suggesting that a higher proportion of family-living species could have been able to avoid extinction under harshening conditions through the evolution of cooperative breeding. These findings underscore the importance of considering the potentially different factors that drive different steps in the evolution of complex adaptations. PMID- 28636616 TI - Temnothorax rugatulus ant colonies consistently vary in nest structure across time and context. AB - A host of animals build architectural constructions. Such constructions frequently vary with environmental and individual/colony conditions, and their architecture directly influences behavior and fitness. The nests of ant colonies drive and enable many of their collective behaviors, and as such are part of their 'extended phenotype'. Since ant colonies have been recently shown to differ in behavior and life history strategy, we ask whether colonies differ in another trait: the architecture of the constructions they create. We allowed Temnothorax rugatulus rock ants, who create nests by building walls within narrow rock gaps, to repeatedly build nest walls in a fixed crevice but under two environmental conditions. We find that colonies consistently differ in their architecture across environments and over nest building events. Colony identity explained 12 40% of the variation in nest architecture, while colony properties and environmental conditions explained 5-20%, as indicated by the condition and marginal R2 values. When their nest boxes were covered, which produced higher humidity and lower airflow, colonies built thicker, longer, and heavier walls. Colonies also built more robust walls when they had more brood, suggesting a protective function of wall thickness. This is, to our knowledge, the first study to explicitly investigate the repeatability of nestbuilding behavior in a controlled environment. Our results suggest that colonies may face tradeoffs, perhaps between factors such as active vs. passive nest defense, and that selection may act on individual construction rules as a mechanisms to mediate colony-level behavior. PMID- 28636617 TI - BackUp: Development and evaluation of a smart-phone application for coping with suicidal crises. AB - BACKGROUND: Suicide is a major public health issue and has large impact on the lives of many people. Innovative technologies such as smartphones could create new possibilities for suicide prevention, such as helping to overcome the barriers and stigma on help seeking in case of suicidal ideation. Due to their omnipresence, smartphone apps can offer suicide prevention tools very fast, they are easily-accessible, low-threshold and can help overcome some of the help seeking barriers suicidal people experience. This article describes the development, testing and implementation of a mobile application for coping with suicidal crisis: BackUp. METHODS: Based on the analysis of literature and existing suicide prevention apps several tools were identified as relevant to include in a suicide prevention app. The selected tools (a safety planning tool, a hope box, a coping cards module, and a module to reach out) are evidence based in a face to face context, and could be easily transferred into a mobile app. The testing of existing apps and the literature also revealed important guidelines for the technical development of the application. RESULTS: BackUp was developed and tested by an expert panel (n = 9) and a panel of end users (n = 21). Both groups rated BackUp as valuable for suicide prevention. Suicidal ideation of the end user group was measured using the Beck Scale for Suicidal Ideation before and after testing BackUp, and showed a small but non-significant decrease. The majority of the testers used BackUp several times. All tools were evaluated as rather or very useable in times of suicidal crisis. CONCLUSION: BackUp was positively evaluated and indicates that self-help tools can have a positive impact on suicidal ideation. Apps in particular create opportunities in approaching people that are not reached by traditional interventions; on the other hand they can contribute to suicide prevention in addition to regular care. However, more research is needed on the impact and effect of suicide prevention apps. PMID- 28636618 TI - De novo transcriptome of the mayfly Cloeon viridulum and transcriptional signatures of Prometabola. AB - Mayflies (Ephemeroptera) display many primitive characters and a unique type of metamorphosis (Prometabola). However, information on the genomes and transcriptomes of this insect group is limited. The RNA sequencing study presented here generated the first de novo transcriptome assembly of Cloeon viridulum (Ephemeroptera: Baetidae), and compared gene expression signatures among the young larva (YL), mature larva (ML), subimago (SI), and imago (IM) stages of this mayfly. The transcriptome, based on 88 Gb of sequence data, comprised a set of 81,185 high quality transcripts. The number of differentially expressed genes (DEGs) in YL vs. ML, ML vs. SI, and SI vs. IM, was 4,825, 1,584, and 1,278, respectively, according to the reads per kilobase of transcript per million mapped reads analysis, assuming a false discovery rate <0.05 and a fold change >2. Gene enrichment analysis revealed that these DEGs were enriched in the "chitin metabolic process", "germ cell development", "steroid hormone biosynthesis", and "cutin, suberine, and wax biosynthesis" pathways. Finally, the expression pattern of a selected group of candidate signature genes for Prometabola, including vestigial, methoprene-tolerant, wingless, and broad complex were confirmed by quantitative real time-PCR analysis. The Q-PCR analysis of larval, subimaginal, and imaginal stages of C. viridulum suggests that the development of mayflies more closely resembles hemimetamorphosis than holometamorphosis. PMID- 28636619 TI - What do computer scientists tweet? Analyzing the link-sharing practice on Twitter. AB - Twitter communication has permeated every sphere of society. To highlight and share small pieces of information with possibly vast audiences or small circles of the interested has some value in almost any aspect of social life. But what is the value exactly for a scientific field? We perform a comprehensive study of computer scientists using Twitter and their tweeting behavior concerning the sharing of web links. Discerning the domains, hosts and individual web pages being tweeted and the differences between computer scientists and a Twitter sample enables us to look in depth at the Twitter-based information sharing practices of a scientific community. Additionally, we aim at providing a deeper understanding of the role and impact of altmetrics in computer science and give a glance at the publications mentioned on Twitter that are most relevant for the computer science community. Our results show a link sharing culture that concentrates more heavily on public and professional quality information than the Twitter sample does. The results also show a broad variety in linked sources and especially in linked publications with some publications clearly related to community-specific interests of computer scientists, while others with a strong relation to attention mechanisms in social media. This refers to the observation that Twitter is a hybrid form of social media between an information service and a social network service. Overall the computer scientists' style of usage seems to be more on the information-oriented side and to some degree also on professional usage. Therefore, altmetrics are of considerable use in analyzing computer science. PMID- 28636620 TI - Risk of ischemic stroke after atrial fibrillation diagnosis: A national sample cohort. AB - Atrial fibrillation (AF) is a major risk factor for ischemic stroke and associated with a 5-fold higher risk of stroke. In this retrospective cohort study, the incidence of and risk factors for ischemic stroke in patients with AF were identified. All patients (>=30 years old) without previous stroke who were diagnosed with AF in 2007-2013 were selected from the National Health Insurance Service-National Sample Cohort. To identify factors that influenced ischemic stroke risk, Cox proportional hazard regression analysis was conducted. During a mean follow-up duration of 3.2 years, 1022 (9.6%) patients were diagnosed with ischemic stroke. The overall incidence rate of ischemic stroke was 30.8/1000 person-years. Of all the ischemic stroke that occurred during the follow-up period, 61.0% occurred within 1-year after AF diagnosis. Of the patients with CHA2DS2-VASc score of >=2, only 13.6% were receiving warfarin therapy within 30 days after AF diagnosis. Relative to no antithrombotic therapy, warfarin treatment for >90 days before the index event (ischemic stroke in stroke patients and death/study end in non-stroke patients) associated with decreased ischemic stroke risk (Hazard Ratio = 0.41, 95%confidence intervals = 0.32-0.53). Heart failure, hypertension, and diabetes mellitus associated with greater ischemic stroke risk. AF patients in Korea had a higher ischemic stroke incidence rate than patients in other countries and ischemic stroke commonly occurred at early phase after AF diagnosis. Long-term (>90 days) continuous warfarin treatment may be beneficial for AF patients. However, warfarin treatment rates were very low. To prevent stroke, programs that actively detect AF and provide anticoagulation therapy are needed. PMID- 28636621 TI - Validation study of the safety attitudes questionnaire (SAQ) in public hospitals of Heilongjiang province, China. AB - PURPOSE: The objective of this study was to validate the reliability and validity of the safety attitudes questionnaire (SAQ) in Heilongjiang province, northern China. METHODS: The SAQ was distributed to 27 public hospitals in five cities across Heilongjiang province. The Cronbach's alpha, item-dimension and dimension dimension correlations were calculated. Descriptive analyses and confirmatory factor analysis were also performed. RESULTS: The recovery rate of the questionnaire was 84.45%. The validity and reliability measures of the SAQ were acceptable. The goodness-of-fit index from the confirmatory factor analysis showed a reasonable model fit (CFI = 0.93, GFI = 0.91, RMSEA = 0.05). The Cronbach's alpha value for the scale was 0.91 and ranged from 0.66 to 0.91 for each of the scales. The SAQ showed good internal consistency reliability. CONCLUSION: The SAQ had satisfactory psychometric properties and could be a useful tool to measure safety attitudes in public hospitals in Heilongjiang province in China. PMID- 28636622 TI - Inhibition of hepatitis B viral entry by nucleic acid polymers in HepaRG cells and primary human hepatocytes. AB - Hepatitis B virus (HBV) infection remains a major public health concern worldwide with 240 million individuals chronically infected and at risk of developing cirrhosis and hepatocellular carcinoma. Current treatments rarely cure chronic hepatitis B infection, highlighting the need for new anti-HBV drugs. Nucleic acid polymers (NAPs) are phosphorothioated oligonucleotides that have demonstrated a great potential to inhibit infection with several viruses. In chronically infected human patients, NAPs administration lead to a decline of blood HBsAg and HBV DNA and to HBsAg seroconversion, the expected signs of functional cure. NAPs have also been shown to prevent infection of duck hepatocytes with the Avihepadnavirus duck hepatitis B virus (DHBV) and to exert an antiviral activity against established DHBV infection in vitro and in vivo. In this study, we investigated the specific anti-HBV antiviral activity of NAPs in the HepaRG human hepatoma cell line and primary cultures of human hepatocytes. NAPs with different chemical features (phosphorothioation, 2'O-methyl ribose, 5-methylcytidine) were assessed for antiviral activity when provided at the time of HBV inoculation or post-inoculation. NAPs dose-dependently inhibited HBV entry in a phosphorothioation-dependent, sequence-independent and size-dependent manner. This inhibition of HBV entry by NAPs was impaired by 2'O-methyl ribose modification. NAP treatment after viral inoculation did not elicit any antiviral activity. PMID- 28636623 TI - The basolateral vesicle sorting machinery and basolateral proteins are recruited to the site of enteropathogenic E. coli microcolony growth at the apical membrane. AB - Foodborne Enteropathogenic Escherichia coli (EPEC) infections of the small intestine cause diarrhea especially in children and are a major cause of childhood death in developing countries. EPEC infects the apical membrane of the epithelium of the small intestine by attaching, effacing the microvilli under the bacteria and then forming microcolonies on the cell surface. We first asked the question where on epithelial cells EPEC attaches and grows. Using models of polarized epithelial monolayers, we evaluated the sites of initial EPEC attachment to the apical membrane and found that EPEC preferentially attached over the cell-cell junctions and formed microcolonies preferentially where three cells come together at tricellular tight junctions. The ability of EPEC to adhere increased when host cell polarity was compromised yielding EPEC access to basolateral proteins. EPEC pedestals contain basolateral cytoskeletal proteins. Thus, we asked if attached EPEC causes reorganization the protein composition of the host cell plasma membrane at sites of microcolony formation. We found that EPEC microcolony growth at the apical membrane resulted in a local accumulation of basolateral plasma membrane proteins surrounding the microcolony. Basolateral marker protein aquaporin-3 localized to forming EPEC microcolonies. Components of the basolateral vesicle targeting machinery were re-routed. The Exocyst (Exo70) was recruited to individual EPEC as was the basolateral vesicle SNARE VAMP-3. Moreover, several Rab variants were also recruited to the infection site, and their dominant-negative equivalents were not. To quantitatively study the recruitment of basolateral proteins, we created a pulse of the temperature sensitive basolateral VSVG, VSVG3-SP-GFP, from the trans-Golgi Network. We found that after release from the TGN, significantly more VSVG3-SP-GFP accumulated at the site of microcolony growth than on equivalent membrane regions of uninfected cells. This suggests that trafficking of vesicles destined for the basolateral membrane are redirected to the apical site of microcolony growth. Thus, in addition to disrupting host cell fence function, local host cell plasma membrane protein composition is changed by altered protein trafficking and recruitment of basolateral proteins to the apical microcolony. This may aid EPEC attachment and subsequent microcolony growth. PMID- 28636624 TI - Metabolically-healthy obesity is associated with higher prevalence of colorectal adenoma. AB - BACKGROUND: The risk of colorectal adenoma (CRA), an important precursor of colorectal cancer, is largely unknown among obese individuals without obesity related metabolic abnormalities, a condition described as metabolically-healthy obese (MHO). The aim of this study was to examine the association among metabolic status, the different categories of body mass index (BMI), and CRA in a large cohort of adults. METHODS: We analyzed the association among metabolic status, BMI categories and CRA in asymptomatic adults who underwent a first-time colonoscopy as part of the comprehensive health check-up program at the Health Promotion Center of Samsung Medical Center, from January 2005 to December 2012. Being metabolically healthy was defined as lacking any metabolic syndrome components and having a homeostasis model assessment of insulin resistance <2.5. RESULTS: The prevalence of "any," "multiple," and "high-risk" CRA was 25.6%, 8.3%, and 4.4% among 9,182 metabolically-healthy participants, and 35.9%, 12.5%, and 7.0% among 17,407 metabolically-unhealthy participants, respectively. Increased BMI showed a significant dose-dependent relationship with the prevalence of "any," "multiple," and "high-risk" CRA, in both metabolically healthy and unhealthy participants. In multivariable-adjusted models that accounted for potential confounders including age, sex, smoking, alcohol, first degree family history of colorectal cancer, and aspirin use, the odds ratio (OR) for any CRA comparing MHO with metabolically-healthy normal-weight (MHNW) participants was 1.25 (95% confidence interval (CI), 1.09-1.43). Further adjustment for metabolic components associated with obesity did not significantly change the association. Similarly, the ORs for multiple CRAs and high risk CRA were higher in MHO participants than MHNW participants [ORs (95% CI), 1.63 (1.31 2.04) and 1.53 (1.14-2.04), respectively]. CONCLUSIONS: The MHO phenotype was closely associated with higher prevalence of CRA, including high-risk adenoma. This finding supports the conclusion that MHO increases the risk of colorectal cancer. PMID- 28636625 TI - Comparison study of exhaust plume impingement effects of small mono- and bipropellant thrusters using parallelized DSMC method. AB - A space propulsion system is important for the normal mission operations of a spacecraft by adjusting its attitude and maneuver. Generally, a mono- and a bipropellant thruster have been mainly used for low thrust liquid rocket engines. But as the plume gas expelled from these small thrusters diffuses freely in a vacuum space along all directions, unwanted effects due to the plume collision onto the spacecraft surfaces can dramatically cause a deterioration of the function and performance of a spacecraft. Thus, aim of the present study is to investigate and compare the major differences of the plume gas impingement effects quantitatively between the small mono- and bipropellant thrusters using the computational fluid dynamics (CFD). For an efficiency of the numerical calculations, the whole calculation domain is divided into two different flow regimes depending on the flow characteristics, and then Navier-Stokes equations and parallelized Direct Simulation Monte Carlo (DSMC) method are adopted for each flow regime. From the present analysis, thermal and mass influences of the plume gas impingements on the spacecraft were analyzed for the mono- and the bipropellant thrusters. As a result, it is concluded that a careful understanding on the plume impingement effects depending on the chemical characteristics of different propellants are necessary for the efficient design of the spacecraft. PMID- 28636626 TI - Digestible lysine requirements of male broilers from 1 to 42 days of age reassessed. AB - Three experiments were conducted separately to estimate the digestible Lys (dig. Lys) requirements of Cobb * Cobb 500 male broilers using different statistical models. For each experiment, 1,200 chicks were housed in 48 floor pens in a completely randomized design with 6 treatments and 8 replicates. Broilers were fed diets with increasing dig. Lys levels from 1 to 12 d (Exp. 1), from 12 to 28 d (Exp. 2), and 28 to 42 d (Exp. 3). Increasing dig. Lys levels were equally spaced from 0.97 to 1.37% in Exp. 1, 0.77 to 1.17% in Exp. 2, and 0.68 to 1.07% in Exp. 3. The lowest dig. Lys diets were not supplemented with L-Lysine and all other essential AA met or exceeded recommendations. In Exp. 3, six birds per pen were randomly selected from each replication to evaluate carcass and breast yields. Digestible Lys requirements were estimated by quadratic polynomial (QP), linear broken-line (LBL), quadratic broken-line (QBL), and exponential asymptotic (EA) models. Overall, dig. Lys requirements varied among response variables and statistical models. Increasing dietary dig. Lys had a positive effect on BW, carcass and breast yields. Levels of dig. Lys that optimized performance using QP, LBL, QBL, and EA models were 1.207, 1.036, 1.113, and 1.204% for BWG and 1.190, 1.027, 1.100, and 1.172% for FCR in Exp. 1; 1.019, 0.853, 0.944; 1.025% for BWG and 1.050, 0.879, 1.032, and 1.167% for FCR in Exp. 2; and 0.960, 0.835, 0.933, and 1.077% for BWG, 0.981, 0.857, 0.963, and 1.146% for FCR in Exp. 3. The QP, LBL, QBL, and EA also estimated dig. Lys requirements as 0.941, 0.846, 0.925, and 1.070% for breast meat yield in Exp. 3. In conclusion, Lys requirements vary greatly according to the statistical analysis utilized; therefore, the origin of requirement estimation must be taken into account in order to allow adequate comparisons between references. PMID- 28636627 TI - Plasma cell neoplasia after kidney transplantation: French cohort series and review of the literature. AB - Although post-transplant lymphoproliferative disorder (PTLD) is the second most common type of cancer in kidney transplantation (KT), plasma cell neoplasia (PCN) occurs only rarely after KT, and little is known about its characteristics and evolution. We included twenty-two cases of post-transplant PCN occurring between 1991 and 2013. These included 12 symptomatic multiple myeloma, eight indolent myeloma and two plasmacytomas. The median age at diagnosis was 56.5 years and the median onset after transplantation was 66.7 months (2-252). Four of the eight indolent myelomas evolved into symptomatic myeloma after a median time of 33 months (6-72). PCN-related kidney graft dysfunction was observed in nine patients, including six cast nephropathies, two light chain deposition disease and one amyloidosis. Serum creatinine was higher at the time of PCN diagnosis than before, increasing from 135.7 (+/-71.6) to 195.9 (+/-123.7) MUmol/l (p = 0.008). Following transplantation, the annual rate of bacterial infections was significantly higher after the diagnosis of PCN, increasing from 0.16 (+/-0.37) to 1.09 (+/-1.30) (p = 0.0005). No difference was found regarding viral infections before and after PCN. Acute rejection risk was decreased after the diagnosis of PCN (36% before versus 0% after, p = 0.004), suggesting a decreased allogeneic response. Thirteen patients (59%) died, including twelve directly related to the hematologic disease. Median graft and patient survival was 31.7 and 49.4 months, respectively. PCN after KT occurs in younger patients compared to the general population, shares the same clinical characteristics, but is associated with frequent bacterial infections and relapses of the hematologic disease that severely impact the survival of grafts and patients. PMID- 28636628 TI - Effects of Spirulina on the functions and redox status of auditory system in senescence-accelerated prone-8 mice. AB - To our knowledge, the effects of Spirulina platensis water extract (SP) on hearing function have not yet been reported. This study investigated the effects of SP on the function and redox status of the auditory system. Auditory brainstem responses and redox status were compared between two groups of 3-month-old senescence-accelerated prone-8 (SAMP8) mice: the control group was fed a normal diet, and the experimental group was fed a normal diet with oral supplementation of SP for 6 weeks. Compared with the control group, the experimental group had significantly lower hearing thresholds according to auditory brainstem responses measured using click sounds and 8-kHz tone burst sound stimulation at the end of this study. The experimental group had a shorter I-III interval of auditory brainstem responses with 16-kHz tone burst stimulation than the control group that was of borderline significance. Additionally, the experimental group had significantly higher mRNA expression of the superoxide dismutase and catalase genes in the cochlea and brainstem and significantly higher mRNA expression of the glutathione peroxidase gene in the cochlea. Further, the experimental group had significantly lower malondialdehyde levels in the cochlea and brainstem than the control group. However, tumor necrosis factor-alpha mRNA expression was not significantly different between the control and experimental groups. SP could decrease hearing degeneration in senescence-accelerated prone-8 mice possibly by increasing superoxide dismutase, catalase, and glutathione peroxidase gene expression and decreasing damage from oxidative stress in the cochlea and brainstem. PMID- 28636629 TI - Minimal oscillating subnetwork in the Huang-Ferrell model of the MAPK cascade. AB - Prompted by the recent growing evidence of oscillatory behavior involving MAPK cascades we present a systematic approach of analyzing models and elucidating the nature of biochemical oscillations based on reaction network theory. In particular, we formulate a minimal biochemically consistent mass action subnetwork of the Huang-Ferrell model of the MAPK signalling that provides an oscillatory response when a parameter controlling the activation of the top-tier kinase is varied. Such dynamics are either intertwined with or separated from the earlier found bistable/hysteretic behavior in this model. Using the theory of stability of stoichiometric networks, we reduce the original MAPK model, convert kinetic to convex parameters and examine those properties of the minimal subnetwork that underlie the oscillatory dynamics. We also use the methods of classification of chemical oscillatory networks to explain the rhythmic behavior in physicochemical terms, i.e., we identify of the role of individual biochemical species in positive and negative feedback loops and describe their coordinated action leading to oscillations. Our approach provides an insight into dynamics without the necessity of knowing rate coefficients and thus is useful prior the statistical evaluation of parameters. PMID- 28636630 TI - Accessibility and socio-economic development of human settlements. AB - Access to facilities, services and socio-economic opportunities plays a critical role in the growth and decline of cities and human settlements. Previous attempts to explain changes in socio-economic indicators by differences in accessibility have not been convincing as countries with highly developed transport infrastructure have only seen marginal benefits of infrastructure improvements. Australia offers an ideal case for investigating the effects of accessibility on development since it is seen as home to some of the most liveable cities in the world while, at the same time, it also has some of the most isolated settlements. We investigate herein the connectivity and accessibility of all 1814 human settlements (population centers exceeding 200 persons) in Australia, and how they relate to the socio-economic characteristics of, and opportunities in, each population center. Assuming population as a proxy indicator of available opportunities, we present a simple ranking metric for a settlement using the number of population and the distance required to access all other settlements (and the corresponding opportunities therein). We find a strikingly unequal distribution of access to opportunities in Australia, with a marked prominence of opportunities in capital cities in four of the eight states. The two largest cities of Sydney and Melbourne have a dominant position across all socio-economic indicators, compared to all the other cities. In general, we observe across all the settlements that a decrease in access to opportunities is associated with relatively greater socio-economic disadvantage including increased median age and unemployment rate and decreased median household income. Our methodology can be used to better understand the potential benefits of improved accessibility based on infrastructure development, especially for remote areas and for cities and towns with many socio-economically disadvantaged population. PMID- 28636631 TI - Incidence and mortality due to snakebite in the Americas. AB - BACKGROUND: Better knowledge of the epidemiological characteristics of snakebites could help to take measures to improve their management. The incidence and mortality of snakebites in the Americas are most often estimated from medical and scientific literature, which generally lack precision and representativeness. METHODOLOGY/PRINCIPAL FINDINGS: Authors used the notifications of snakebites treated in health centers collected by the Ministries of Health of the American countries to estimate their incidence and mortality. Data were obtained from official reports available on-line at government sites, including those of the Ministry of Health in each country and was sustained by recent literature obtained from PubMed. The average annual incidence is about 57,500 snake bites (6.2 per 100,000 population) and mortality is close to 370 deaths (0.04 per 100,000 population), that is, between one third and half of the previous estimates. The incidence of snakebites is influenced by the abundance of snakes, which is related to (i) climate and altitude, (ii) specific preferences of the snake for environments suitable for their development, and (iii) human population density. Recent literature allowed to notice that the severity of the bites depends mainly on (i) the snake responsible for the bite (species and size) and (ii) accessibility of health care, including availability of antivenoms. CONCLUSIONS/SIGNIFICANCES: The main limitation of this study could be the reliability and accuracy of the notifications by national health services. However, the data seemed consistent considering the similarity of the incidences on each side of national boundaries while the sources are distinct. However, snakebite incidence could be underestimated due to the use of traditional medicine by the patients who escaped the reporting of cases. However, gathered data corresponded to the actual use of the health facilities, and therefore to the actual demand for antivenoms, which should make it possible to improve their management. PMID- 28636632 TI - Parasitoid wasp usurps its host to guard its pupa against hyperparasitoids and induces rapid behavioral changes in the parasitized host. AB - Some parasites have an ability to fabricate the behavior of their host and impel the host to guard parasites' offspring, which is popularly called as bodyguard manipulation. Psalis pennatula larva parasitized by a braconid parasitoid wasp Microplitis pennatula exhibits some behavioral changes including the guarding of the parasitoid pupa from its natural enemies. We hypothesized that these behavioral change exhibited by the parasitized host larva are induced by the parasitoid and can be considered as an example of bodyguard manipulation. Even though hyperparasitoids are the more specialized natural enemy of parasitoids than predators, very few studies tested the success of guarding parasitoid pupa against hyperparasitoids. This study analyzed the success of guarding behavior of the parasitized host against hyperparasitoids. The onsets of parasite-induced phenotypic alterations (PIPAs) in the parasitized host were inspected to analyze whether these behavioral changes in the host larva manifests gradually or abruptly. The study concludes that parasitized host larva defends the parasitoid pupa from hyperparasitoids and the PIPAs in the parasitized host develops abruptly only after the egression of parasitoid prepupa. PMID- 28636633 TI - Playing with fire - What is influencing horse owners' decisions to not vaccinate their horses against deadly Hendra virus infection? AB - Hendra virus is a zoonotic paramyxovirus, which causes severe respiratory and neurological disease in horses and humans. Since 2012, the Hendra virus sub-unit G vaccine has been available for horse vaccination in Australia. Uptake of the vaccine has been limited and spill-over events of Hendra virus infection in horses continue to occur. We conducted an online, questionnaire-based cross sectional study of 376 horse owners belonging to a variety of different equestrian clubs in Queensland, Australia, to identify risk factors for non vaccination against Hendra virus. A total of 43.1% (N = 162) of horse owners indicated that they currently did not vaccinate against Hendra virus infection, while 56.9% (N = 214) currently vaccinated against Hendra virus infection. A total of 52 risk factors were evaluated relating to equestrian activities, horse management, perceived risk and severity of horse and human infection with Hendra virus, side effects of Hendra vaccination, other vaccinations conducted by horse owners and horse owners' attitudes towards veterinarians. The final multivariable logistics regression model identified the following risk factors associated with increased odds of non-vaccination against Hendra virus: 1) perceived low risk (compared to high) of Hendra virus infection to horses (considering the horse owners' location and management practices) or horse owners were unsure about the risk of infection, 2) perceived moderate severity (compared to very severe or severe) of Hendra virus infection in humans, 3) horse owners non-vaccination of their pets, 4) horse owners non-vaccination against strangles disease in horses, 5) handling of more than three horses per week (compared to one horse only) and 6) perceived attitude that veterinarians had a high motivation of making money from Hendra virus vaccination (compared to veterinarians having a low motivation of making money from Hendra virus vaccination). Horse owners were more likely to vaccinate against Hendra virus if horses were used for dressage, show jumping or eventing. The study also identified horse owners' concerns about side-effects and about the lack of evidence on vaccine efficacy. PMID- 28636634 TI - Cardiomyopathy development protection after myocardial infarction in rats: Successful competition for major dihydropyridines' common metabolite against captopril. AB - During the last 25 years angiotensin-converting enzyme inhibitors spectacularly conquered the field of cardiovascular diseases therapy. Nevertheless, lack of new studies concerning side effects associated with their chronic administration seems to be rather confusing. In our previous research, we proved that the main furnidipines' metabolite (M-2) possess multiple cardioprotective actions. Currently, we compared effects of post-infarction long-term oral treatment with M 2 and captopril on hemodynamic parameters and "ischemic cardiomyopathy" development in rats. Myocardial infarction was evoked by permanent left anterior descending coronary artery occlusion for 35 days. Surviving rats were treated with captopril (2 * 25 mg/kg) or M-2 (4 mg/kg) from 6th- 35th day. At 35th day rats' hearts were tested on working heart setup, where following parameters were measured: heart rate, preload pressure, aortic systolic and diastolic pressures, aortic maximum rise and fall, aortic and coronary flow, myocardial oxygen consumption and oximetry in perfusate. Subsequently, heart tissue specimens were assessed during morphological estimation. Captopril caused significant heart rate increase and markedly diminished preload pressure in comparison to M-2. Both drugs evoked essential aortic pressure increase. Aortic flow was significantly decreased after M-2, whereas captopril increased this parameter in comparison to M-2. Both agents caused marked coronary flow increase. Morphologic examination in captopril revealed cardiomyopathic process in 70% of hearts, whereas in M-2 this value reached 30%. Neovascularization of post-infarcted myocardium was visible only after M-2 therapy. Concluding, M-2 presented itself as more attractive agent in long-term post-infarction treatment by preventing cardiomyopathy development, angiogenesis stimulation and preserving cardiac performance. PMID- 28636635 TI - MicroRNA-144-3p inhibits autophagy activation and enhances Bacillus Calmette Guerin infection by targeting ATG4a in RAW264.7 macrophage cells. AB - MicroRNAs (miRNAs) are small noncoding nucleotides that play major roles in the response of host immune cells. Autophagy plays a key role in activating the antimicrobial host defense against Mycobacterium tuberculosis (M. tuberculosis). Whether miRNAs specifically influence the activation of macrophage autophagy during M. tuberculosis infection is largely unknown. In the present study, we demonstrate that Mycobacterium bovis Bacillus Calmette-Guerin (BCG) infection of macrophages leads to increased expression of miR-144-3p, which targets autophagy related gene 4a (ATG4a), to inhibit autophagy activation and antimicrobial responses to BCG. Overexpression of miR-144-3p significantly decreased both mRNA and protein levels of ATG4a, inhibited the formation of autophagosomes in RAW264.7 cells and increased intracellular survival of BCG. However, transfection with miR-144-3p inhibitor led to an increase in ATG4a levels, accelerated the autophagic response in macrophages, and decreased BCG survival in macrophages. The experimental results of this study reveal a novel role of miR-144-3p in inhibiting autophagy activation by targeting ATG4a and enhancing BCG infection, and provide potential targets for developing improved treatment. PMID- 28636636 TI - SensiScreen(r)KRAS exon 2-sensitive simplex and multiplex real-time PCR-based assays for detection of KRAS exon 2 mutations. AB - Activating mutations in codon 12 and codon 13 of the KRAS (Kirsten rat sarcoma viral oncogene homolog) gene are implicated in the development of several human cancer types and influence their clinical evaluation, treatment and prognosis. Numerous different methods for KRAS genotyping are currently available displaying a wide range of sensitivities, time to answer and requirements for laboratory equipment and user skills. Here we present SensiScreen(r) KRAS exon 2 simplex and multiplex CE IVD assays, that use a novel real-time PCR-based method for KRAS mutation detection based on PentaBase's proprietary DNA analogue technology and designed to work on standard real-time PCR instruments. By means of the included BaseBlockerTM technology, we show that SensiScreen(r) specifically amplifies the mutated alleles of interest with no or highly subdued amplification of the wild type allele. Furthermore, serial dilutions of mutant DNA in a wild type background demonstrate that all SensiScreen(r) assays display a limit of detection that falls within the range of 0.25-1%. Finally, in three different colorectal cancer patient populations, SensiScreen(r) assays confirmed the KRAS genotype previously determined by commonly used methods for KRAS mutation testing, and notably, in two of the populations, SensiScreen(r) identified additional mutant positive cases not detected by common methods. PMID- 28636637 TI - Plasma kisspeptin levels are associated with insulin secretion in nondiabetic individuals. AB - To evaluate if plasma kisspeptin concentrations are associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders. 261 nondiabetic subjects were stratified into tertiles according to kisspeptin values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT). After adjusting for age, gender, and BMI, subjects in the highest (tertile 3) kisspeptin group exhibited significantly lower values of insulinogenic index, corrected insulin response (CIR30), and Stumvoll indexes for first-phase and second-phase insulin release as compared with low (tertile 1) or intermediate (tertile 2) kisspeptin groups. Univariate correlations between kisspeptin concentration and metabolic variables showed that kisspeptin concentration was significantly and positively correlated with age, blood pressure, and 2-h post-load glucose, and inversely correlated with BMI, and waist circumference. There was an inverse relationship between kisspeptin levels and OGTT-derived indexes of glucose-stimulated insulin secretion. A multivariable regression analysis in a model including all the variables significantly correlated with kisspeptin concentration showed thar age (beta = -0.338, P<0.0001), BMI (beta = 0.272, P<0.0001), 2-h post-load glucose (beta = -0.229, P<0.0001), and kisspeptin (beta = -0.105, P = 0.03) remained associated with insulinogenic index. These factors explained 34.6% of the variance of the insulinogenic index. In conclusion, kisspeptin concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, 2-h post-load glucose, and insulin sensitivity. PMID- 28636638 TI - Outcomes from a large 10 year hepatitis C treatment programme in people who inject drugs: No effect of recent or former injecting drug use on treatment adherence or therapeutic response. AB - BACKGROUND AND AIMS: People who inject drugs (PWID) are historically viewed as having "difficult to treat" hepatitis C disease, with perceived inferior treatment adherence and outcomes, and concerns regarding reinfection risk. We evaluated for differences in treatment adherence and response to Peginterferon alfa-2a/Ribavirin (Peg-IFNalpha/RBV) in a large urban cohort with and without a history of remote or recent injection drug use. METHODS: Patient data was retrospectively reviewed for 1000 consecutive patients-608 former (no injecting drug use for 6 months of therapy), 85 recent (injecting drug use within 6 months) PWID, and 307 non-drug users who were treated for chronic hepatitis C with Peg IFNalpha/RBV. The groups were compared for baseline characteristics, treatment adherence, and outcome. RESULTS: There was no significant difference in treatment non-adherence between the groups (8.4% in PWID vs 6.8% in non-PWIDs; RR = 1.23, CI 0.76-1.99). The overall SVR rate in PWID (64.2%) was not different from non PWIDs (60.9%) [RR = 1.05, 95% CI 0.95-1.17]. There was no significant difference in SVR rates between the groups controlling for genotype (48.4% vs 48.4% for genotype 1; 74.9 vs 73.3% for genotype 3). Former and recent PWID had similar adherence rates. CONCLUSIONS: PWID have comparable treatment adherence and SVR rates when compared to non-drug users treated with Peg-IFNalpha/RBV. These data support a public health strategy of HCV treatment and eradication in PWID in the DAA era. PMID- 28636639 TI - Predictive value of serum transthyretin for outcome in acute ischemic stroke. AB - INTRODUCTION: The impact of choroid plexus with its blood-cerebrospinal fluid barrier in the ischemic stroke pathology is poorly explored. Transthyretin (TTR) is a protein synthesized in liver and just in choroid plexus. OBJECTIVES: The current study was designed to assess the prognostic value of serum TTR for functional outcome (at the time of hospital discharge) and long-term (one-year) overall mortality in ischemic stroke patients. PATIENTS AND METHODS: We conducted a prospective observational study. Patients (n = 81) with acute (< 24 hours of symptoms onset) ischemic stroke consecutively admitted to Stroke Unit were included. An unfavorable outcome was defined as a modified Rankin Scale (mRS) score >= 3. The relationships between serum TTR levels and clinical outcome were analyzed using multivariate analysis. One-year mortality was analyzed by Kaplan Meier survival curves stratified by mean value of TTR. RESULTS: Compared with patients with mRS <3, patients with an unfavorable outcome at hospital discharge had significantly lower TTR levels on admission (P < 0.0001). In non-survivals serum TTR levels were significantly lower compared with patients who survive one year of observation (P = 0.009). Using multivariate analysis, transthyretin emerged as an independent predictor for unfavorable outcome at the day of hospital discharge (adjusted odds ratio = 0.96; 95% CI: 0.9-0.99, P <0.05). A one year mortality of patients with the lower TTR levels was significantly higher than in patients with TTR levels above mean value (P = 0.02). CONCLUSIONS: Serum level of TTR at admission was a predictor of functional outcome after ischemic stroke and was also associated with one-year mortality in stroke survivals. PMID- 28636640 TI - Targeted nanodiamonds for identification of subcellular protein assemblies in mammalian cells. AB - Transmission electron microscopy (TEM) can be used to successfully determine the structures of proteins. However, such studies are typically done ex situ after extraction of the protein from the cellular environment. Here we describe an application for nanodiamonds as targeted intensity contrast labels in biological TEM, using the nuclear pore complex (NPC) as a model macroassembly. We demonstrate that delivery of antibody-conjugated nanodiamonds to live mammalian cells using maltotriose-conjugated polypropylenimine dendrimers results in efficient localization of nanodiamonds to the intended cellular target. We further identify signatures of nanodiamonds under TEM that allow for unambiguous identification of individual nanodiamonds from a resin-embedded, OsO4-stained environment. This is the first demonstration of nanodiamonds as labels for nanoscale TEM-based identification of subcellular protein assemblies. These results, combined with the unique fluorescence properties and biocompatibility of nanodiamonds, represent an important step toward the use of nanodiamonds as markers for correlated optical/electron bioimaging. PMID- 28636641 TI - Development of a range of fluorescent reagentless biosensors for ATP, based on malonyl-coenzyme A synthetase. AB - The range of ATP concentrations that can be measured with a fluorescent reagentless biosensor for ATP has been increased by modulating its affinity for this analyte. The ATP biosensor is an adduct of two tetramethylrhodamines with MatB from Rhodopseudomonas palustris. Mutations were introduced into the binding site to modify ATP binding affinity, while aiming to maintain the concomitant fluorescence signal. Using this signal, the effect of mutations in different parts of the binding site was measured. This mutational analysis revealed three variants in particular, each with a single mutation in the phosphate-binding loop, which had potentially beneficial changes in ATP binding properties but preserving a fluorescence change of ~3-fold on ATP binding. Two variants (T167A and T303A) weakened the binding, changing the dissociation constant from the parent's 6 MUM to 123 MUM and 42 MUM, respectively. Kinetic measurements showed that the effect of these mutations on affinity was by an increase in dissociation rate constants. These variants widen the range of ATP concentration that can be measured readily by this biosensor to >100 MUM. In contrast, a third variant, S170A, decreased the dissociation constant of ATP to 3.8 MUM and has a fluorescence change of 4.2 on binding ATP. This variant has increased selectivity for ATP over ADP of >200-fold. This had advantages over the parent by increasing sensitivity as well as increasing selectivity during ATP measurements in which ADP is present. PMID- 28636642 TI - In vivo evaluation of inter-operator reproducibility of digital dental and conventional impression techniques. AB - PURPOSE: The aim of this study was to evaluate and compare the inter-operator reproducibility of three-dimensional (3D) images of teeth captured by a digital impression technique to a conventional impression technique in vivo. MATERIALS AND METHODS: Twelve participants with complete natural dentition were included in this study. A digital impression of the mandibular molars of these participants was made by two operators with different levels of clinical experience, 3 or 16 years, using an intra-oral scanner (Lava COS, 3M ESPE). A silicone impression also was made by the same operators using the double mix impression technique (Imprint3, 3M ESPE). Stereolithography (STL) data were directly exported from the Lava COS system, while STL data of a plaster model made from silicone impression were captured by a three-dimensional (3D) laboratory scanner (D810, 3shape). The STL datasets recorded by two different operators were compared using 3D evaluation software and superimposed using the best-fit-algorithm method (least squares method, PolyWorks, InnovMetric Software) for each impression technique. Inter-operator reproducibility as evaluated by average discrepancies of corresponding 3D data was compared between the two techniques (Wilcoxon signed rank test). RESULTS: The visual inspection of superimposed datasets revealed that discrepancies between repeated digital impression were smaller than observed with silicone impression. Confirmation was forthcoming from statistical analysis revealing significantly smaller average inter-operator reproducibility using a digital impression technique (0.014+/- 0.02 mm) than when using a conventional impression technique (0.023 +/- 0.01 mm). CONCLUSION: The results of this in vivo study suggest that inter-operator reproducibility with a digital impression technique may be better than that of a conventional impression technique and is independent of the clinical experience of the operator. PMID- 28636643 TI - Neuromuscular electrical stimulation prevents skeletal muscle dysfunction in adjuvant-induced arthritis rat. AB - Skeletal muscle weakness is a prominent feature in patients with rheumatoid arthritis (RA). In this study, we investigated whether neuromuscular electrical stimulation (NMES) training protects against skeletal muscle dysfunction in rats with adjuvant-induced arthritis (AIA). AIA was produced by intraarticular injection of complete Freund's adjuvant into the knees of Wistar rats. For NMES training, dorsiflexor muscles were stimulated via a surface electrode (0.5 ms pulse, 50 Hz, 2 s on/4 s off). NMES training was performed every other day for three weeks and consisted of three sets produced at three min intervals. In each set, the electrical current was set to achieve 60% of the initial maximum isometric torque and the current was progressively increased to maintain this torque; stimulation was stopped when the 60% torque could no longer be maintained. After the intervention period, extensor digitorum longus (EDL) muscles were excised and used for physiological and biochemical analyses. There was a reduction in specific force production (i.e. force per cross-sectional area) in AIA EDL muscles, which was accompanied by aggregation of the myofibrillar proteins actin and desmin. Moreover, the protein expressions of the pro-oxidative enzymes NADPH oxidase, neuronal nitric oxide synthase, p62, and the ratio of the autophagosome marker LC3bII/LC3bI were increased in AIA EDL muscles. NMES training prevented all these AIA-induced alterations. The present data suggest that NMES training prevents AIA-induced skeletal muscle weakness presumably by counteracting the formation of actin and desmin aggregates. Thus, NMES training can be an effective treatment for muscle dysfunction in patients with RA. PMID- 28636644 TI - Longitudinal changes in physical activity, sedentary behavior and body mass index in adolescence: Migrations towards different weight cluster. AB - This study examined longitudinal changes in physical activity, sedentary behavior and body mass index in adolescents, specifically their migrations towards a different weight cluster. A cohort of 755 adolescents participated in a three year study. A clustering Self-Organized Maps Analysis was performed to visualize changes in subjects' characteristics between the first and second assessment, and how adolescents were grouped. Also a classification tree was used to identify the behavioral characteristics of the groups that changed their weight cluster. Results indicated that boys were more active and less sedentary than girls. Boys were especially keen to technological-based activities while girls preferred social-based activities. A moderate competing effect between sedentary behaviors and physical activities was observed, especially in girls. Overweight and obesity were negatively associated with physical activity, although a small group of overweight/obese adolescents showed a positive relationship with vigorous physical activity. Cluster migrations indicated that 22.66% of adolescents changed their weight cluster to a lower category and none of them moved in the opposite direction. The behavioral characteristics of these adolescents did not support the hypothesis that the change to a lower weight cluster was a consequence of an increase in time devoted to physical activity or a decrease in time spent on sedentary behavior. Physical activity and sedentary behavior does not exert a substantial effect on overweight and obesity. Therefore, there are other ways of changing to a lower-weight status in adolescents apart from those in which physical activity and sedentary behavior are involved. PMID- 28636646 TI - Variation in hunting behaviour in neighbouring chimpanzee communities in the Budongo forest, Uganda. AB - Hunting and sharing of meat is seen across all chimpanzee sites, with variation in prey preferences, hunting techniques, frequencies, and success rates. Here, we compared hunting and meat-eating behaviour in two adjacent chimpanzee communities (Pan troglodytes schweinfurthii) of Budongo Forest, Uganda: the Waibira and Sonso communities. We observed consistent between-group differences in prey-species preferences and in post-hunting behaviour. Sonso chimpanzees show a strong prey preference for Guereza colobus monkeys (Colobus guereza occidentalis; 74.9% hunts), and hunt regularly (1-2 times a month) but with large year-to-year and month-to-month variation. Waibira chimpanzee prey preferences are distributed across primate and duiker species, and resemble those described in an early study of Sonso hunting. Waibira chimpanzees (which include ex-Sonso immigrants) have been observed to feed on red duiker (Cephalophus natalensis; 25%, 9/36 hunts), a species Sonso has never been recorded to feed on (18 years data, 27 years observations), despite no apparent differences in prey distribution; and show less rank-related harassment of meat possessors. We discuss the two most likely and probably interrelated explanations for the observed intergroup variation in chimpanzee hunting behaviour, that is, long-term disruption of complex group level behaviour due to human presence and possible socially transmitted differences in prey preferences. PMID- 28636645 TI - Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies. AB - BACKGROUND: Several genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies. METHODOLOGY: A systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality. Beyond outcome measures, information was extracted on the setting for each study, characteristics of population samples and polymorphisms. RESULTS: Fifty studies met eligibility criteria and were used for data extraction. With a single exception, all studies used a candidate gene approach, providing data on 229 polymorphisms in or near 55 different genes. Of variants investigating in independent data sets, only rs2029461 SNP in GRM4, rs3743123 in CX36 and rs3918149 in BRD2 showed a significant association with JME in at least two different background populations. The lack of consistent associations might be due to variations in experimental design and/or limitations of the approach. CONCLUSIONS: Thus, despite intense research evidence established, specific genetic variants in JME susceptibility remain inconclusive. We discussed several issues that may compromise the quality of the results, including methodological bias, endophenotype and potential involvement of epigenetic factors. PROSPERO REGISTRATION NUMBER: CRD42016036063. PMID- 28636647 TI - Hemodynamic and metabolic characteristics associated with development of a right ventricular outflow tract pressure gradient during upright exercise. AB - BACKGROUND: We recently reported a novel observation that many patients with equal resting supine right ventricular(RV) and pulmonary artery(PA) systolic pressures develop an RV outflow tract(RVOT) pressure gradient during upright exercise. The current work details the characteristics of patients who develop such an RVOT gradient. METHODS: We studied 294 patients (59.7+/-15.5 years-old, 49% male) referred for clinical invasive cardiopulmonary exercise testing, who did not have a resting RVOT pressure gradient defined by the simultaneously measured peak-to-peak difference between RV and PA systolic pressures. RESULTS: The magnitude of RVOT gradient did not correspond to clinical or hemodynamic findings suggestive of right heart failure; rather, higher gradients were associated with favorable exercise findings. The presence of a high peak RVOT gradient (90th percentile, >=33mmHg) was associated with male sex (70 vs. 46%, p = 0.01), younger age (43.6+/-17.7 vs. 61.8+/-13.9 years, p<0.001), lower peak right atrial pressure (5 [3-7] vs. 8 [4-12]mmHg, p<0.001), higher peak heart rate (159+/-19 vs. 124+/-26 beats per minute, p<0.001), and higher peak cardiac index (8.3+/-2.3 vs. 5.7+/-1.9 L/min/m2, p<0.001). These associations persisted when treating peak RVOT as a continuous variable and after age and sex adjustment. At peak exercise, patients with a high exercise RVOT gradient had both higher RV systolic pressure (78+/-11 vs. 66+/-17 mmHg, p<0.001) and lower PA systolic pressure (34+/-8 vs. 50+/-19 mmHg, p<0.001). CONCLUSIONS: Development of a systolic RV-PA pressure gradient during upright exercise is not associated with an adverse hemodynamic exercise response and may represent a normal physiologic finding in aerobically fit young people. PMID- 28636648 TI - Cost-effectiveness of pazopanib versus sunitinib for metastatic renal cell carcinoma in the United Kingdom. AB - BACKGROUND: Sunitinib and pazopanib are the only two targeted therapies for the first-line treatment of locally advanced or metastatic renal cell carcinoma (mRCC) recommended by the United Kingdom's National Institute for Health and Care Excellence. Pazopanib demonstrated non-inferior efficacy and a differentiated safety profile versus sunitinib in the phase III COMPARZ trial. The current analysis provides a direct comparison of the cost-effectiveness of pazopanib versus sunitinib from the perspective of the United Kingdom's National Health Service based on data from COMPARZ and other sources. METHODS: A partitioned survival analysis model with three health states (alive with no progression, alive with progression, or dead) was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained for pazopanib versus sunitinib over five years (duration of follow-up for final survival analysis in COMPARZ). The proportion of patients in each health state over time was based on Kaplan-Meier distributions for progression-free and overall survival from COMPARZ. Utility values were based on EQ-5D data from the pivotal study of pazopanib versus placebo. Costs were based on medical resource utilisation data from COMPARZ and unit costs from secondary sources. Probabilistic and deterministic sensitivity analyses were conducted to assess uncertainty of model results. RESULTS: In the base case, pazopanib was estimated to provide more QALYs (0.0565, 95% credible interval [CrI]: -0.0920 to 0.2126) at a lower cost (-L1,061, 95% CrI: -L4,328 to L2,067) versus sunitinib. The probability that pazopanib yields more QALYs than sunitinib was estimated to be 76%. For a threshold value of L30,000 per QALY gained, the probability that pazopanib is cost-effective versus sunitinib was estimated to be 95%. Pazopanib was dominant in most scenarios examined in deterministic sensitivity analyses. CONCLUSIONS: Pazopanib is likely to be a cost effective treatment option compared with sunitinib as first-line treatment of mRCC in the United Kingdom. PMID- 28636649 TI - Factors associated with successful transition among children with disabilities in eight European countries. AB - INTRODUCTION: This research paper aims to assess factors reported by parents associated with the successful transition of children with complex additional support requirements that have undergone a transition between school environments from 8 European Union member states. METHODS: Quantitative data were collected from 306 parents within education systems from 8 EU member states (Bulgaria, Cyprus, Greece, Ireland, the Netherlands, Romania, Spain and the UK). The data were derived from an online questionnaire and consisted of 41 questions. Information was collected on: parental involvement in their child's transition, child involvement in transition, child autonomy, school ethos, professionals' involvement in transition and integrated working, such as, joint assessment, cooperation and coordination between agencies. Survey questions that were designed on a Likert-scale were included in the Principal Components Analysis (PCA), additional survey questions, along with the results from the PCA, were used to build a logistic regression model. RESULTS: Four principal components were identified accounting for 48.86% of the variability in the data. Principal component 1 (PC1), 'child inclusive ethos,' contains 16.17% of the variation. Principal component 2 (PC2), which represents child autonomy and involvement, is responsible for 8.52% of the total variation. Principal component 3 (PC3) contains questions relating to parental involvement and contributed to 12.26% of the overall variation. Principal component 4 (PC4), which involves transition planning and coordination, contributed to 11.91% of the overall variation. Finally, the principal components were included in a logistic regression to evaluate the relationship between inclusion and a successful transition, as well as whether other factors that may have influenced transition. All four principal components were significantly associated with a successful transition, with PC1 being having the most effect (OR: 4.04, CI: 2.43-7.18, p<0.0001). DISCUSSION: To support a child with complex additional support requirements through transition from special school to mainstream, governments and professionals need to ensure children with additional support requirements and their parents are at the centre of all decisions that affect them. It is important that professionals recognise the educational, psychological, social and cultural contexts of a child with additional support requirements and their families which will provide a holistic approach and remove barriers for learning. PMID- 28636650 TI - The formation of lipid droplets favors intracellular Mycobacterium leprae survival in SW-10, non-myelinating Schwann cells. AB - Leprosy is a chronic infectious disease that is caused by the obligate intracellular pathogen Mycobacterium leprae (M.leprae), which is the leading cause of all non-traumatic peripheral neuropathies worldwide. Although both myelinating and non-myelinating Schwann cells are infected by M.leprae in patients with lepromatous leprosy, M.leprae preferentially invades the non myelinating Schwann cells. However, the effect of M.leprae infection on non myelinating Schwann cells has not been elucidated. Lipid droplets (LDs) are found in M.leprae-infected Schwann cells in the nerve biopsies of lepromatous leprosy patients. M.leprae-induced LD formation favors intracellular M.leprae survival in primary Schwann cells and in a myelinating Schwann cell line referred to as ST88 14. In the current study, we initially characterized SW-10 cells and investigated the effects of LDs on M.leprae-infected SW-10 cells, which are non-myelinating Schwann cells. SW-10 cells express S100, a marker for cells from the neural crest, and NGFR p75, a marker for immature or non-myelinating Schwann cells. SW 10 cells, however, do not express myelin basic protein (MBP), a marker for myelinating Schwann cells, and myelin protein zero (MPZ), a marker for precursor, immature, or myelinating Schwann cells, all of which suggests that SW-10 cells are non-myelinating Schwann cells. In addition, SW-10 cells have phagocytic activity and can be infected with M. leprae. Infection with M. leprae induces the formation of LDs. Furthermore, inhibiting the formation of M. leprae-induced LD enhances the maturation of phagosomes containing live M.leprae and decreases the ATP content in the M. leprae found in SW-10 cells. These facts suggest that LD formation by M. leprae favors intracellular M. leprae survival in SW-10 cells, which leads to the logical conclusion that M.leprae-infected SW-10 cells can be a new model for investigating the interaction of M.leprae with non-myelinating Schwann cells. PMID- 28636651 TI - Yield of yearly routine physical examination in HIV-1 infected patients is limited: A retrospective cohort study in the Netherlands. AB - BACKGROUND: Routine physical examinations might be of value in HIV-infected patients, but the yield is unknown. We determined the diagnoses that would have been missed without performing annual routine physical examinations in HIV infected patients with stable disease. METHODS: Data were collected from the medical records of 299 HIV-1-infected patients with CD4 count >350 cells/mm3 if not using combination antiretroviral therapy (cART), or CD4 count >100 cells/mm3 and undetectable viral load if using cART. We defined the diagnoses that would have been missed without performing routine physical examinations on annual check ups in 2010. Exclusion criteria were hepatitis B/C co-infection, start/ switch of cART < 24 weeks, pregnancy, and transgenderism. RESULTS: 215 patients (72%) had positive findings: lipodystrophy (30%), lymphadenopathy (16%) and hypertension (8.4%) were the most common. Two-thirds of all findings were not new or were based on complaints indicating a physical examination even if not routinely scheduled. For 24 patients (8.0%) the routine physical examination led to the finding of a new diagnosis: six-all men who have sex with men (MSM)-had a concurrent sexually transmitted infection, eight had hypertension, and ten others had a large variety of diagnoses. A total atrioventricular block with bradycardia was the most clinically relevant finding. CONCLUSIONS: Annual physical examinations of HIV-infected patients with stable disease brought few new diagnoses that would have been missed without performing a routine examination. Our results suggest that standard assessments could be restricted to six-monthly measuring blood pressure in all patients and annually performing anogenital and digital rectal examination on MSM. PMID- 28636652 TI - Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency. AB - Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2, or NOTCH3 and affected tumor suppressor genes including RB1, PTEN, and KMT2C. Furthermore, we identified putative TGFA enhancer regions. Recurrent SVs that affected the TGFA enhancer region led to enhanced expression of the TGFA oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications. PMID- 28636653 TI - The Ebola virus VP35 protein binds viral immunostimulatory and host RNAs identified through deep sequencing. AB - Ebola virus and Marburg virus are members of the Filovirdae family and causative agents of hemorrhagic fever with high fatality rates in humans. Filovirus virulence is partially attributed to the VP35 protein, a well-characterized inhibitor of the RIG-I-like receptor pathway that triggers the antiviral interferon (IFN) response. Prior work demonstrates the ability of VP35 to block potent RIG-I activators, such as Sendai virus (SeV), and this IFN-antagonist activity is directly correlated with its ability to bind RNA. Several structural studies demonstrate that VP35 binds short synthetic dsRNAs; yet, there are no data that identify viral immunostimulatory RNAs (isRNA) or host RNAs bound to VP35 in cells. Utilizing a SeV infection model, we demonstrate that both viral isRNA and host RNAs are bound to Ebola and Marburg VP35s in cells. By deep sequencing the purified VP35-bound RNA, we identified the SeV copy-back defective interfering (DI) RNA, previously identified as a robust RIG-I activator, as the isRNA bound by multiple filovirus VP35 proteins, including the VP35 protein from the West African outbreak strain (Makona EBOV). Moreover, RNAs isolated from a VP35 RNA-binding mutant were not immunostimulatory and did not include the SeV DI RNA. Strikingly, an analysis of host RNAs bound by wild-type, but not mutant, VP35 revealed that select host RNAs are preferentially bound by VP35 in cell culture. Taken together, these data support a model in which VP35 sequesters isRNA in virus-infected cells to avert RIG-I like receptor (RLR) activation. PMID- 28636654 TI - Characterization of human FCRL4-positive B cells. AB - FCRL4 is an immunoregulatory receptor that belongs to the Fc receptor-like (FCRL) family. In healthy individuals, FCRL4 is specifically expressed by memory B cells (MBCs) localized in sub-epithelial regions of lymphoid tissues. Expansion of FCRL4+ B cells has been observed in blood and other tissues in various infectious and autoimmune disorders. Currently, the mechanisms involved in pathological FCRL4+ B cell generation are actively studied, but they remain elusive. As in vivo FCRL4+ cells are difficult to access and to isolate, here we developed a culture system to generate in vitro FCRL4+ B cells from purified MBCs upon stimulation with soluble CD40 ligand and/or CpG DNA to mimic T-cell dependent and/or T-cell independent activation, respectively. After 4 days of stimulation, FCRL4+ B cells represented 17% of all generated cells. Transcriptomic and phenotypic analyses of in vitro generated FCRL4+ cells demonstrated that they were closely related to FCRL4+ tonsillar MBCs. They strongly expressed inhibitory receptor genes, as observed in exhausted FCRL4+ MBCs from blood samples of HIV infected individuals with high viremia. In agreement, cell cycle genes were significantly downregulated and the number of cell divisions was two-fold lower in in vitro generated FCRL4+ than FCRL4- cells. Finally, due to their reduced proliferation and differentiation potential, FCRL4+ cells were less prone to differentiate into plasma cells, differently from FCRL4- cells. Our in vitro model could be of major interest for studying the biology of normal and pathological FCRL4+ cells. PMID- 28636655 TI - Changes in inflammatory biomarkers in HCV-infected patients undergoing direct acting antiviral-containing regimens with or without interferon. AB - BACKGROUND AND AIMS: Increased levels of chemokine interferon-gamma (IFN-gamma) inducible protein-10 (CXCL10), soluble CD163 (sCD163) and soluble CD14 (sCD14) have been reported in HCV infection. The aim of this study was to compare, sCD163 and sCD14 levels in HCV-infected patients undergoing direct acting antiviral (DAA)-containing regimens with or without interferon (IFN). METHODS: sCD163, sCD14 and CXCL10 were longitudinally measured by ELISA in 159 plasma samples from 25 HCV-infected patients undergoing IFN-based treatment plus telaprevir or boceprevir and 28 HCV infected subjects treated with DAA IFN-free regimens. Twenty-five healthy donors (HD) were included as controls. RESULTS: At baseline CXCL10, sCD163 and sCD14 levels were higher in HCV-infected patients than in HD. CXCL10 and sCD163 levels were significantly decreased in responder (R) patients who achieved sustained virological response (SVR), with both IFN-based and IFN free regimens, while they were persistently elevated in non-responders (NR) patients who stopped IFN-based treatments because of failure or adverse events. Conversely, sCD14 levels were apparently unchanged during therapy, but at the end of treatment the levels reached normal ranges. Comparing the two regimens, the extent of CXCL10 reduction was more pronounced in patients undergoing DAA IFN free therapies, whereas sCD163 and sCD14 reduction was similar in the two groups. Interestingly, only in IFN-based regimens baseline sCD163 levels were significantly higher in NR than in R patients, while in the IFN-free treatment group also patients with high sCD163 plasma levels obtained SVR. At the end of therapy, even if the biomarkers were largely decreased, their levels remained significantly higher compared to HD. Only in the early fibrosis stages, sCD163 values tended to normalize. CONCLUSIONS: These results indicate that IFN-free regimens including newer DAA induce an early and marked decrease in circulating inflammatory biomarkers. However, the full normalization of biomarkers was not obtained, especially in patients with advanced fibrosis, thus underlying the need for a treatment in the early stages of HCV infection. PMID- 28636659 TI - Retraction: A High-Throughput Screening-Compatible Strategy for the Identification of Inositol Pyrophosphate Kinase Inhibitors. PMID- 28636656 TI - Selective propagation of mouse-passaged scrapie prions with long incubation period from a mixed prion population using GT1-7 cells. AB - In our previous study, we demonstrated the propagation of mouse-passaged scrapie isolates with long incubation periods (L-type) derived from natural Japanese sheep scrapie cases in murine hypothalamic GT1-7 cells, along with disease associated prion protein (PrPSc) accumulation. We here analyzed the susceptibility of GT1-7 cells to scrapie prions by exposure to infected mouse brains at different passages, following interspecies transmission. Wild-type mice challenged with a natural sheep scrapie case (Kanagawa) exhibited heterogeneity of transmitted scrapie prions in early passages, and this mixed population converged upon one with a short incubation period (S-type) following subsequent passages. However, when GT1-7 cells were challenged with these heterologous samples, L-type prions became dominant. This study demonstrated that the susceptibility of GT1-7 cells to L-type prions was at least 105 times higher than that to S-type prions and that L-type prion-specific biological characteristics remained unchanged after serial passages in GT1-7 cells. This suggests that a GT1 7 cell culture model would be more useful for the economical and stable amplification of L-type prions at the laboratory level. Furthermore, this cell culture model might be used to selectively propagate L-type scrapie prions from a mixed prion population. PMID- 28636657 TI - Novel siRNA formulation to effectively knockdown mutant p53 in osteosarcoma. AB - OBJECTIVES: The tumor suppressor p53 plays a crucial role in the development of osteosarcoma. The primary objective of this study is to develop and optimize lipid based nanoparticle formulations that can carry siRNA and effectively silence mutant p53 in 318-1, a murine osteosarcoma cell line. METHODS: The nanoparticles were composed of a mixture of two lipids (cholesterol and DOTAP) and either PLGA or PLGA-PEG and prepared by using an EmulsiFlex-B3 high pressure homogenizer. A series of studies that include using different nanoparticles, different amount of siRNAs, cell numbers, incubation time, transfection media volume, and storage temperature was performed to optimize the gene silencing efficiency. KEY FINDINGS: Replacement of lipids by PLGA or PLGA-PEG decreased the particle size and overall cytotoxicity. Among all lipid-polymer nanoformulations, nanoparticles with 10% PLGA showed highest mutant p53 knockdown efficiency while maintaining higher cell viability when a nanoparticle to siRNA ratio equal to 6.8:0.66 and 75 nM siRNA was used. With long term storage the mutant p53 knockdown efficiency decreased to a greater extent. CONCLUSIONS: This study warrants a future evaluation of this formulation for gene silencing efficiency of mutant p53 in tissue culture and animal models for the treatment of osteosarcoma. PMID- 28636658 TI - Efficacy and safety of ultrasound-guided implantation of fiducial markers in the liver for stereotactic body radiation therapy. AB - OBJECTIVE: Stereotactic body radiation therapy (SBRT) for the treatment of a malignancy in the liver requires the perilesional implantation of fiducial markers for lesion detection. The purpose of this study is to evaluate the efficacy and safety of ultrasound (US) -guided marker implantation for SBRT. METHODS: We retrospectively reviewed 299, US-guided, intrahepatic fiducial markers implanted in 101 patients between November 2013 and September 2014. SBRT planning CT images were analyzed to determine the technical success of the implantation, the mean distance between the tumor margin and the marker, with the ideal location of fiducials defined as the distance between a marker and a tumor less than 3 cm and the distance between markers greater than 2 cm according to the tumor conspicuity seen on gray-scale US and the artifact obscuring tumor margins. We also evaluated procedure-related major and minor complications. RESULTS: Technical success was achieved in 291 (97.3%) fiducial marker implantations. The mean distance between the tumor and the marker was 3.1 cm (S.D., 2.1 cm; range, 0-9.5 cm). Of 101 patients, 72 lesions (71.3%, 2.2 +/- 1.0 cm; range, 0-3.0 cm) had fiducial markers located in an ideal location. The ideal location of fiducials was more common in visible lesions than in poorly conspicuous lesions (90.2% vs. 52.0%, P < 0.001). Seventeen markers (5.8%) developed beam-hardening artifacts obscuring the tumor margins. There were no major complications, although 12 patients (11.9%) developed minor complications. CONCLUSIONS: US-guided implantation of fiducial markers in the liver is an effective and safe procedure with only rare complications. PMID- 28636660 TI - Cellular sensitivity to UV-irradiation is mediated by RNA polymerase I transcription. AB - The nucleolus has long been considered to be a pure ribosome factory. However, over the last two decades it became clear that the nucleolus is involved in numerous other functions besides ribosome biogenesis. Our experiments indicate that the activity of RNA polymerase I (Pol I) transcription monitors the integrity of the DNA and influences the response to nucleolar stress as well as the rate of survival. Cells with a repressed ribosomal DNA (rDNA) transcription activity showed an increased and prolonged p53 stabilisation after UVC irradiation. Furthermore, p53 stabilisation after inhibition and especially after UVC-irradiation might be due to abrogation of the HDM2-p53 degradation pathway by ribosomal proteins (RPs). Apoptosis mediated by highly activated p53 is a typical hallmark of Cockayne syndrome cells and transcriptional abnormalities and the following activation of the RP-HDM2-p53 pathway would be a possible explanation. PMID- 28636661 TI - Robust nonparametric quantification of clustering density of molecules in single molecule localization microscopy. AB - We report a robust nonparametric descriptor, J'(r), for quantifying the density of clustering molecules in single-molecule localization microscopy. J'(r), based on nearest neighbor distribution functions, does not require any parameter as an input for analyzing point patterns. We show that J'(r) displays a valley shape in the presence of clusters of molecules, and the characteristics of the valley reliably report the clustering features in the data. Most importantly, the position of the J'(r) valley ([Formula: see text]) depends exclusively on the density of clustering molecules (rhoc). Therefore, it is ideal for direct estimation of the clustering density of molecules in single-molecule localization microscopy. As an example, this descriptor was applied to estimate the clustering density of ptsG mRNA in E. coli bacteria. PMID- 28636662 TI - Differential regulation of polarized synaptic vesicle trafficking and synapse stability in neural circuit rewiring in Caenorhabditis elegans. AB - Neural circuits are dynamic, with activity-dependent changes in synapse density and connectivity peaking during different phases of animal development. In C. elegans, young larvae form mature motor circuits through a dramatic switch in GABAergic neuron connectivity, by concomitant elimination of existing synapses and formation of new synapses that are maintained throughout adulthood. We have previously shown that an increase in microtubule dynamics during motor circuit rewiring facilitates new synapse formation. Here, we further investigate cellular control of circuit rewiring through the analysis of mutants obtained in a forward genetic screen. Using live imaging, we characterize novel mutations that alter cargo binding in the dynein motor complex and enhance anterograde synaptic vesicle movement during remodeling, providing in vivo evidence for the tug-of-war between kinesin and dynein in fast axonal transport. We also find that a casein kinase homolog, TTBK-3, inhibits stabilization of nascent synapses in their new locations, a previously unexplored facet of structural plasticity of synapses. Our study delineates temporally distinct signaling pathways that are required for effective neural circuit refinement. PMID- 28636663 TI - An endophytic Basidiomycete, Grammothele lineata, isolated from Corchorus olitorius, produces paclitaxel that shows cytotoxicity. AB - Grammothele lineata, an endophyte isolated in our laboratory from jute (Corchorus olitorius acc. 2015) was found to be a substantial paclitaxel producer. Taxol and its related compounds, produced by this endophyte were extracted by growing the fungus in simple nutrient media (potato dextrose broth, PDB). Taxol was identified and characterized by different analytical techniques (TLC, HPLC, FTIR, LC-ESI-MS/MS) following its extraction by ethyl acetate. In PDB media, this fungus was found to produce 382.2 MUgL-1 of taxol which is about 7.6 x103 fold higher than the first reported endophytic fungi, Taxomyces andreanae. The extracted taxol exhibited cytotoxic activity in an in vitro culture of HeLa cancer cell line. The fungal extract also exhibited antifungal and antibacterial activities against different pathogenic strains. This is the first report of a jute endophytic fungus harboring the capacity to produce taxol and also the first reported taxol producing species that belongs to the Basidiomycota phylum, so far unknown to be a taxol producer. These findings suggest that the fungal endophyte, Grammothele lineata can be an excellent source of taxol and can also serve as a potential species for chemical and genetic engineering to enhance further the production of taxol. PMID- 28636664 TI - Looking at paintings in the Vincent Van Gogh Museum: Eye movement patterns of children and adults. AB - In the present study, we examined the eye movement behaviour of children and adults looking at five Van Gogh paintings in the Van Gogh Museum, Amsterdam. The goal of the study was to determine the role of top-down and bottom-up attentional processes in the first stages of participants' aesthetic experience. Bottom-up processes were quantified by determining a salience map for each painting. Top down processing was manipulated by first allowing participants to view the paintings freely, then providing background information about each painting, and then allowing them to view the paintings a second time. The salience analysis showed differences between the eye movement behaviour of children and adults, and differences between the two phases. In the children, the first five fixations during the free viewing phase were strongly related to visually salient features of the paintings-indicating a strong role for bottom-up factors. In the second phase, after children had received background information, top-down factors played a more prominent role. By contrast, adults' observed patterns were similar in both phases, indicating that bottom-up processes did not play a major role when they viewed the paintings. In the second phase, children and adults both spent more time looking at regions that were mentioned in the background information. This effect was greater for adults than for children, confirming the notion that adults, when viewing paintings, rely much more on top-down processing than children. PMID- 28636665 TI - Monitoring obesity prevalence in the United States through bookmarking activities in online food portals. AB - Studying the impact of food consumption on people's health is a serious matter for its implications on public policy, but it has traditionally been a slow process since it requires information gathered through expensive collection processes such as surveys, census and systematic reviews of research articles. We argue that this process could be supported and hastened using data collected via online social networks. In this work we investigate the relationships between the online traces left behind by users of a large US online food community and the prevalence of obesity in 47 states and 311 counties in the US. Using data associated with the recipes bookmarked over an 9-year period by 144,839 users of the Allrecipes.com food website residing throughout the US, several hierarchical regression models are created to (i) shed light on these relations and (ii) establish their magnitude. The results of our analysis provide strong evidence that bookmarking activities on recipes in online food communities can provide a signal allowing food and health related issues, such as obesity to be better understood and monitored. We discover that higher fat and sugar content in bookmarked recipes is associated with higher rates of obesity. The dataset is complicated, but strong temporal and geographical trends are identifiable. We show the importance of accounting for these trends in the modeling process. PMID- 28636666 TI - Molecular and microbiological report of a hospital outbreak of NDM-1-carrying Enterobacteriaceae in Mexico. AB - OBJECTIVES: To characterize the microbiological, molecular and epidemiological data of an outbreak of carbapenem-resistant Enterobacteriaceae (CRE) in a tertiary-care hospital in Mexico. METHODS: From September 2014 to July 2015, all CRE clinical isolates recovered during an outbreak in the Hospital Civil "Fray Antonio Alcalde" in Jalisco, Mexico were screened for antimicrobial susceptibility, carbapenemase production, carbapenemase-encoding genes, and plasmid profiles. Horizontal transfer of imipenem resistance; and clonal diversity by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST); as well as biofilm production and the presence of 14 virulence genes were analyzed in selected isolates. RESULTS: Fifty-two carbapenem-resistant isolates corresponding to 5 species were detected, i.e., Klebsiella pneumoniae (n = 46), Enterobacter cloacae (n = 3), Escherichia coli (n = 1), Providencia rettgeri (n = 1) and Citrobacter freundii (n = 1) with carbapenemase encoding genes blaNDM-1 (n = 48), blaVIM (n = 3), blaIMP (n = 1) and blaKPC (n = 1) detected in these isolates. The blaNDM-1 gene was detected in plasmids from 130- to 170-kb in K. pneumoniae (n = 46); E. cloacae (n = 3), E. coli (n = 1) and P. rettgeri (n = 1). The transfer of plasmids harboring the blaNDM-1 gene was obtained in eight transconjugants. One plasmid restriction pattern was detected, with the blaNDM-1 identified in different restriction fragments. Predominant clone A of K. pneumoniae isolates archived 28/46 (60%) isolates and belongs to ST392. Besides, ST307, ST309, ST846, ST2399, and ST2400 were detected for K. pneumoniae; as well as E. cloacae ST182 and E. coli ST10. The fimA and uge genes were more likely to be identified in K. pneumoniae carbapenem-susceptible isolates (p = <0.001) and biofilm production was more liable to be observed in carbapenem-resistant isolates (p = <0.05). CONCLUSIONS: Four Enterobacteriaceae species harboring the blaNDM-1 gene were detected in a nosocomial outbreak in Mexico; horizontal transfer and strain transmission were demonstrated for the blaNDM-1 gene. Given the variation in the size of the plasmid harboring blaNDM-1, complex rearrangements must also be occurring. PMID- 28636667 TI - Voice over: Audio-visual congruency and content recall in the gallery setting. AB - Experimental research has shown that pairs of stimuli which are congruent and assumed to 'go together' are recalled more effectively than an item presented in isolation. Will this multisensory memory benefit occur when stimuli are richer and longer, in an ecological setting? In the present study, we focused on an everyday situation of audio-visual learning and manipulated the relationship between audio guide tracks and viewed portraits in the galleries of the Tate Britain. By varying the gender and narrative style of the voice-over, we examined how the perceived congruency and assumed unity of the audio guide track with painted portraits affected subsequent recall. We show that tracks perceived as best matching the viewed portraits led to greater recall of both sensory and linguistic content. We provide the first evidence that manipulating crossmodal congruence and unity assumptions can effectively impact memory in a multisensory ecological setting, even in the absence of precise temporal alignment between sensory cues. PMID- 28636668 TI - Microbiota in anorexia nervosa: The triangle between bacterial species, metabolites and psychological tests. AB - Anorexia nervosa (AN) is a psychiatric disease with devastating physical consequences, with a pathophysiological mechanism still to be elucidated. Metagenomic studies on anorexia nervosa have revealed profound gut microbiome perturbations as a possible environmental factor involved in the disease. In this study we performed a comprehensive analysis integrating data on gut microbiota with clinical, anthropometric and psychological traits to gain new insight in the pathophysiology of AN. Fifteen AN women were compared with fifteen age-, sex- and ethnicity-matched healthy controls. AN diet was characterized by a significant lower energy intake, but macronutrient analysis highlighted a restriction only in fats and carbohydrates consumption. Next generation sequencing showed that AN intestinal microbiota was significantly affected at every taxonomic level, showing a significant increase of Enterobacteriaceae, and of the archeon Methanobrevibacter smithii compared with healthy controls. On the contrary, the genera Roseburia, Ruminococcus and Clostridium, were depleted, in line with the observed reduction in AN of total short chain fatty acids, butyrate, and propionate. Butyrate concentrations inversely correlated with anxiety levels, whereas propionate directly correlated with insulin levels and with the relative abundance of Roseburia inulinivorans, a known propionate producer. BMI represented the best predictive value for gut dysbiosis and metabolic alterations, showing a negative correlation with Bacteroides uniformis (microbiota), with alanine aminotransferase (liver function), and with psychopathological scores (obsession-compulsion, anxiety, and depression), and a positive correlation with white blood cells count. In conclusion, our findings corroborate the hypothesis that the gut dysbiosis could take part in the AN neurobiology, in particular in sustaining the persistence of alterations that eventually result in relapses after renourishment and psychological therapy, but causality still needs to be proven. PMID- 28636669 TI - Exploring factors associated with ART adherence and retention in care under Option B+ strategy in Malawi: A qualitative study. AB - Although several studies have documented challenges related to inadequate adherence to antiretroviral therapy (ART) and high loss to follow-up (LTFU) among Option B+ women, there is limited understanding of why these challenges occur and how to address them. This qualitative study examines women's experiences with ART adherence and retention in care. Between July and October 2015, in-depth interviews were conducted with 39 pregnant and lactating women who initiated ART at Bwaila Hospital in Lilongwe, Malawi. Study participants included 14 in care and 25 out of care women, according to facility records. Data were analyzed using an inductive, open-coding approach to thematic analysis. Ten of the respondents (7 out of care, 3 in-care) had stopped and re-started treatment before the interview date. One of the most important factors influencing adherence and retention was the strength of women's support systems. In contrast to women in care, most out-of-care women lacked emotional and financial support from male partners, received minimal counseling from providers at initiation, lacked designated guardians to assist with medication refills or clinic appointments, and were highly mobile. Mobility led to difficulties in accessing treatment in new settings. The most common reasons women re-started treatment following interruptions were due to providers' counseling and encouragement and the mother's desire to be healthy. Improved counseling at initiation, active follow up counseling, women's economic empowerment interventions, promotion of peer counseling schemes and meaningful engagement of male partners can help in addressing the identified barriers and promoting sustained retention of Option B+ women. PMID- 28636670 TI - Identification of novel small molecules that inhibit STAT3-dependent transcription and function. AB - Activation of Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to several processes that are critical for oncogenic transformation, cancer progression, cancer cell proliferation, survival, drug resistance and metastasis. Inhibition of STAT3 signaling has shown a striking ability to inhibit cancer cell growth and therefore, STAT3 has become a promising target for anti cancer drug development. The aim of this study was to identify novel inhibitors of STAT-dependent gene transcription. A cellular reporter-based system for monitoring STAT3 transcriptional activity was developed which was suitable for high-throughput screening (Z' = 0,8). This system was used to screen a library of 28,000 compounds (the ENAMINE Drug-Like Diversity Set). Following counter screenings and toxicity studies, we identified four hit compounds that were subjected to detailed biological characterization. Of the four hits, KI16 stood out as the most promising compound, inhibiting STAT3 phosphorylation and transcriptional activity in response to IL6 stimulation. In silico docking studies showed that KI16 had favorable interactions with the STAT3 SH2 domain, however, no inhibitory activity could be observed in the STAT3 fluorescence polarization assay. KI16 inhibited cell viability preferentially in STAT3 dependent cell lines. Taken together, using a targeted, cell-based approach, novel inhibitors of STAT-driven transcriptional activity were discovered which are interesting leads to pursue further for the development of anti-cancer therapeutic agents. PMID- 28636671 TI - Different residues in the SARS-CoV spike protein determine cleavage and activation by the host cell protease TMPRSS2. AB - The spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) mediates viral entry into target cells. Cleavage and activation of SARS S by a host cell protease is essential for infectious viral entry and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease TMPRSS2 cleaves and activates SARS S in cell culture and potentially also in the infected host. Here, we investigated which determinants in SARS S control cleavage and activation by TMPRSS2. We found that SARS S residue R667, a previously identified trypsin cleavage site, is also required for S protein cleavage by TMPRSS2. The cleavage fragments produced by trypsin and TMPRSS2 differed in their decoration with N-glycans, suggesting that these proteases cleave different SARS S glycoforms. Although R667 was required for SARS S cleavage by TMPRSS2, this residue was dispensable for TMPRSS2-mediated S protein activation. Conversely, residue R797, previously reported to be required for SARS S activation by trypsin, was dispensable for S protein cleavage but required for S protein activation by TMPRSS2. Collectively, these results show that different residues in SARS S control cleavage and activation by TMPRSS2, suggesting that these processes are more complex than initially appreciated. PMID- 28636672 TI - Metabolomic profile and nucleoside composition of Cordyceps nidus sp. nov. (Cordycipitaceae): A new source of active compounds. AB - Cordyceps sensu lato is a genus of arthropod-pathogenic fungi, which have been used traditionally as medicinal in Asia. Within the genus, Ophiocordyceps sinensis is the most coveted and expensive species in China. Nevertheless, harvesting wild specimens has become a challenge given that natural populations of the fungus are decreasing and because large-scale culture of it has not yet been achieved. The worldwide demand for products derived from cultivable fungal species with medicinal properties has increased recently. In this study, we propose a new species, Cordyceps nidus, which parasitizes underground nests of trapdoor spiders. This species is phylogenetically related to Cordyceps militaris, Cordyceps pruinosa, and a sibling species of Cordyceps caloceroides. It is found in tropical rainforests from Bolivia, Brazil, Colombia and Ecuador. We also investigated the medicinal potential of this fungus based on its biochemical properties when grown on four different culture media. The metabolic profile particularly that of nucleosides, in polar and non-polar extracts was determined by UPLC, and then correlated to their antimicrobial activity and total phenolic content. The metabolome showed a high and significant dependency on the substrate used for fungal growth. The mass intensities of nucleosides and derivative compounds were higher in natural culture media in comparison to artificial culture media. Among these compounds, cordycepin was the predominant, showing the potential use of this species as an alternative to O. sinensis. Furthermore, methanol fractions showed antimicrobial activity against gram positive bacteria, and less than 3.00 mg of gallic acid equivalents per g of dried extract were obtained when assessing its total phenolic content by modified Folin-Ciocalteu method. The presence of polyphenols opens the possibility of further exploring the antioxidant capacity and the conditions that may enhance this characteristic. The metabolic composition and biochemical activity indicate potential use of C. nidus in pharmaceutical applications. PMID- 28636674 TI - Behavior change communication activities improve infant and young child nutrition knowledge and practice of neighboring non-participants in a cluster-randomized trial in rural Bangladesh. AB - OBJECTIVE: To examine the impact on infant and young child nutrition knowledge and practice of mothers who were neighbors of mothers participating in a nutrition Behavior Change Communication (BCC) intervention in rural Bangladesh. METHODS: We analyzed data from 300 mothers whose neighbor participated in a nutrition BCC intervention and 600 mothers whose neighbor participated in an intervention that did not include BCC. We constructed measures capturing mothers' knowledge of infant and young child nutrition (IYCN) and measures of food consumption by children 6-24m. The effect on these outcomes of exposure to a neighbor receiving a nutrition BCC intervention was estimated using ordinary least squares and probit regressions. The study was registered with ClinicalTrials.gov (Study ID: NCT02237144). RESULTS: Having a neighboring mother participate in a nutrition BCC intervention increased non-participant mothers' IYCN knowledge by 0.17 SD (translating to 0.3 more correct answers). They were 14.1 percentage points more likely to feed their 6-24m children legumes and nuts; 11.6 percentage points more likely to feed these children vitamin A rich fruits and vegetables; and 10.0 percentage points more likely to feed these children eggs. Children of non-participant mothers who had a neighboring mother participate in a nutrition BCC intervention were 13.8 percentage points more likely to meet World Health Organization (WHO) guidelines for minimum diet diversity, 11.9 percentage points more likely to meet WHO guidelines for minimum acceptable diet, and 10.3 percentage points more likely to meet WHO guidelines for minimum meal frequency for children who continue to be breastfed after age 6m. Children aged 0-6m of non-participant mothers who are neighbors of mothers receiving BCC were 7.1 percentage points less likely to have ever consumed water based liquids. CONCLUSIONS: Studies of nutrition BCC that do not account for information spillovers to non-participants may underestimate its benefits in terms of IYCN knowledge and practice. PMID- 28636673 TI - Evaluation of molecular diagnostic approaches for the detection of BRAF p.V600E mutations in papillary thyroid cancer: Clinical implications. AB - Differentiated papillary thyroid cancer (PTC) is the most common cancer of the endocrine system. PTC has a very good prognosis and a high 5 year survival rate; however, some patients are unresponsive to treatment, and their diagnosis eventually results in death. Recent efforts have focused on searching for prognostic and predictive factors that may enable treatment personalization and monitoring across the course of the disease. The presence of the BRAF mutation is considered to contribute to the risk of poor clinical course, according to American Thyroid Association (ATA) recommendations. The method used for genotyping can impact the predicted mutation frequency; however, ATA recommendations do not address this issue. We evaluated the molecular diagnostic (BRAF p.V600E mutation) results of 410 patients treated for PTC. We thoroughly analyzed the impact of three different BRAF mutation detection methods, Sanger Sequencing (Seq), allele-specific amplification PCR (ASA-PCR), and quantitative PCR (qPCR), on the frequency of mutation detection in 399 patients. Using Seq, we detected the BRAF mutation in 37% of patients; however, we were able to detect BRAF mutations in 57% and 60% of patients using the more sensitive ASA-PCR and qPCR technologies, respectively. Differences between methods were particularly marked in the thyroid papillary microcarcinoma group; BRAF p.V600E mutations were found in 37% of patients using Seq and 63% and 66% of patients using ASA-PCR and qPCR, respectively. We also evaluated how these different diagnostic methods were impacted by DNA quality. Applying methods with different sensitivities to the detection of BRAF p.V600E mutations may result in different results for the same patient; such data can influence stratification of patients into different risk groups, leading to alteration of treatment and follow-up schemes. PMID- 28636675 TI - Probabilistic population aging. AB - We merge two methodologies, prospective measures of population aging and probabilistic population forecasts. We compare the speed of change and variability in forecasts of the old age dependency ratio and the prospective old age dependency ratio as well as the same comparison for the median age and the prospective median age. While conventional measures of population aging are computed on the basis of the number of years people have already lived, prospective measures are computed also taking account of the expected number of years they have left to live. Those remaining life expectancies change over time and differ from place to place. We compare the probabilistic distributions of the conventional and prospective measures using examples from China, Germany, Iran, and the United States. The changes over time and the variability of the prospective indicators are smaller than those that are observed in the conventional ones. A wide variety of new results emerge from the combination of methodologies. For example, for Germany, Iran, and the United States the likelihood that the prospective median age of the population in 2098 will be lower than it is today is close to 100 percent. PMID- 28636676 TI - Mitochondrion to endoplasmic reticulum apposition length in zebrafish embryo spinal progenitors is unchanged in response to perturbations associated with Alzheimer's disease. AB - Mutations in the human genes PRESENILIN1 (PSEN1), PRESENILIN2 (PSEN2) and AMYLOID BETA A4 PRECURSOR PROTEIN (APP) have been identified in familial Alzheimer's disease (AD). The length of mitochondrion-endoplasmic reticulum (M-ER) appositions is increased in Psen1-/-/Psen2-/- double knockout murine embryonic fibroblasts and in fibroblasts from AD-affected individuals. Development of an easily accessible, genetically manipulable, in vivo system for studying M-ER appositions would be valuable so we attempted to manipulate M-ER apposition length in zebrafish (Danio rerio) embryos. We injected fertilized zebrafish eggs with antisense morpholino oligonucleotides (MOs) that inhibit expression of zebrafish familial AD gene orthologues psen1 and psen2. Furthermore, we treated zebrafish embryos with DAPT (a highly specific gamma-secretase inhibitor) or with sodium azide (to mimic partially hypoxic conditions). We then analyzed M-ER apposition in an identified, presumably proliferative neural cell type using electron microscopy. Our analysis showed no significant differences in M-ER apposition lengths at 48 hours post fertilization (hpf) between psen1 & psen2 MO co-injected embryos, embryos treated with DAPT, or sodium azide, and control embryos. Instead, the distribution of M-ER apposition lengths into different length classes was close to identical. However, this indicates that it is feasible to reproducibly measure M-ER size distributions in zebrafish embryos. While our observations differ from those of murine and human studies, this may be due to differences in cellular differentiation and metabolic state, cell age, or species-specific responses. In particular, by focusing on a presumably proliferative embryonic cell type, we may have selected a cell heavily already reliant on anaerobic glycolysis and less responsive to factors affecting M-ER apposition. Future examination of more differentiated, more secretory cell types may reveal measurable responses of M-ER apposition to environmental and genetic manipulation. PMID- 28636677 TI - Contextual imitation of intransitive body actions in a Beluga whale (Delphinapterus leucas): A "do as other does" study. AB - Cetaceans are remarkable for exhibiting group-specific behavioral traditions or cultures in several behavioral domains (e.g., calls, behavioral tactics), and the question of whether they can be acquired socially, for example through imitative processes, remains open. Here we used a "Do as other does" paradigm to experimentally study the ability of a beluga to imitate familiar intransitive (body-oriented) actions demonstrated by a conspecific. The participant was first trained to copy three familiar behaviors on command (training phase) and then was tested for her ability to generalize the learned "Do as the other does" command to a different set of three familiar behaviors (testing phase). We found that the beluga (1) was capable of learning the copy command signal "Do what-the-other does"; (2) exhibited high matching accuracy for trained behaviors (mean = 84% of correct performance) after making the first successful copy on command; (3) copied successfully the new set of three familiar generalization behaviors that were untrained to the copy command (range of first copy = 12 to 35 trials); and (4) deployed a high level of matching accuracy (mean = 83%) after making the first copy of an untrained behavior on command. This is the first evidence of contextual imitation of intransitive (body-oriented) movements in the beluga and adds to the reported findings on production imitation of sounds in this species and production imitation of sounds and motor actions in several cetaceans, especially dolphins and killer whales. Collectively these findings highlight the notion that cetaceans have a natural propensity at skillfully and proficiently matching the sounds and body movements demonstrated by conspecifics, a fitness enhancing propensity in the context of cooperative hunting and anti-predatory defense tactics, and of alliance formation strategies that have been documented in these species' natural habitats. Future work should determine if the beluga can also imitate novel motor actions. PMID- 28636679 TI - Towards the analysis of attosecond dynamics in complex systems. AB - We study from a theoretical perspective the ionization of molecules and clusters induced by irradiation of a combined two-color laser field consisting of a train of attosecond XUV pulses in the presence of an IR field. We use time-dependent density-functional theory (TDDFT) in real time and real space as a theoretical tool. The calculated results are compared to experimental data when available. We also compare TDDFT with results obtained using a time-dependent Schrodinger equation (TDSE), which is well suited to simple systems while TDDFT allows dealing with more complex molecules and clusters. As a key observable, we study ionization versus delay time of the XUV pulses with respect to the IR background pulse. Experiments in simple atoms (He and Ar) show a regular modulation of this signal with half the IR period. This feature is recovered by TDDFT as well as by the TDSE (although total ionization differs by an order of magnitude). As more complex systems, we consider a C3 chain molecule and Na clusters. Here we encounter a different picture as the ionization signal develops a more involved pattern with several peaks per half IR period and as the TDSE produces a different pattern to TDDFT. Both effects could be related to the appearance of strong resonance modes in these more complex systems. PMID- 28636680 TI - Unifying the microscopic picture of His-containing turns: from gas phase model peptides to crystallized proteins. AB - The presence in crystallized proteins of a local anchoring between the side chain of a His residue, located in the central position of a gamma- or beta-turn, and its local main chain environment, was assessed by the comparison of protein structures with relevant isolated model peptides. Gas phase laser spectroscopy, combined with relevant quantum chemistry methods, was used to characterize the gamma- and beta-turn structures in these model peptides. A conformer-selective NH stretch infrared study provided evidence for the formation in vacuo of two types of short-range H-bonded motifs, labelled epsilon-6delta and delta-delta7/piH, bridging the His side chain (in its gauche+ rotamer) to the neighbouring NH(i) and CO(i) sites of the backbone; each side chain-backbone motif was found to be specific of the tautomer (epsilon or delta) adopted by the His side chain in its neutral form. A close comparison between beta- and gamma-turns, selected from the Protein Data Bank, and the gas phase models demonstrated that a significant proportion of the gauche+ His rotamer distribution of proteins was well described by the corresponding gas phase H-bonded structures. This is consistent with the persistence of local 6delta and delta7/piH intramolecular interactions in proteins, emphasizing the relevance of gas phase data to secondary structures that are poorly accessible to solvents, e.g., in the case of a specific compact topology (Xxx-His beta-turns). Deviations from the gas phase structures were also observed, mainly in His-Xxx beta-turns, and assigned to solvent accessible turn structures. They were well accounted for by theoretical models of microhydrated turns, in which a few solvent molecules take over the gas phase motifs, constituting a water-mediated local anchoring of the His side chain to the backbone. Finally, the present gas phase benchmark models also pinpointed weaknesses in the protein structure determination by X-ray diffraction analysis; in particular, besides the lack of tautomer information, inaccuracies in the description of imidazole ring flip rotamerism were identified. PMID- 28636681 TI - Thermally induced conformational changes and protein-protein interactions of bovine serum albumin in aqueous solution under different pH and ionic strengths as revealed by SAXS measurements. AB - Thermal-induced conformational changes and protein-protein interactions of bovine serum albumin (BSA) in aqueous solution are assessed by small angle X-ray scattering (SAXS) at two pH values (7.4 and 9.0) and two ionic strengths (0.1 and 0.5). We demonstrate that Guinier analysis in two ranges of the modulus of the scattering vector allows protein melting and aggregation to be monitored simultaneously, thus providing insights into the mechanism of thermal-induced BSA aggregation. Results of the analysis suggest that at room temperature monomeric and dimeric BSA fractions are present in solution. For low concentrations (<10 mg mL-1) the monomeric to dimeric fraction ratio is close to 6, the same value we obtained independently in size-exclusion chromatography experiments. For elevated concentrations (20 mg mL-1 and 40 mg mL-1) a decrease in the dimer fraction occurs. Following heating, dimer formation is observed prior to protein melting, while no higher order aggregates are observed in the 20-60 degrees C temperature range. In the vicinity of the BSA melting point, higher order aggregates appear and protein molecules exhibit an aggregation burst. Higher ionic strength makes the described effects more pronounced - dimer formation increases at lower temperatures, presumably due to partial screening of electrostatic interactions between protein molecules. Moreover, the melting temperature shifts to higher values upon increasing the protein concentration and pH, indicating that repulsive interactions stabilize the protein structure. The suggested model was verified by the assessment of parameters of protein-protein interaction potentials based on DLVO theory using the global fitting procedure. PMID- 28636678 TI - Measurement properties of patient-reported outcome measures (PROMs) used in adult patients with chronic kidney disease: A systematic review. AB - BACKGROUND: Patient-reported outcome measures (PROMs) can provide valuable information which may assist with the care of patients with chronic kidney disease (CKD). However, given the large number of measures available, it is unclear which PROMs are suitable for use in research or clinical practice. To address this we comprehensively evaluated studies that assessed the measurement properties of PROMs in adults with CKD. METHODS: Four databases were searched; reference list and citation searching of included studies was also conducted. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was used to appraise the methodological quality of the included studies and to inform a best evidence synthesis for each PROM. RESULTS: The search strategy retrieved 3,702 titles/abstracts. After 288 duplicates were removed, 3,414 abstracts were screened and 71 full-text articles were retrieved for further review. Of these, 24 full-text articles were excluded as they did not meet the eligibility criteria. Following reference list and citation searching, 19 articles were retrieved bringing the total number of papers included in the final analysis to 66. There was strong evidence supporting internal consistency and moderate evidence supporting construct validity for the Kidney Disease Quality of Life-36 (KDQOL-36) in pre-dialysis patients. In the dialysis population, the KDQOL-Short Form (KDQOL-SF) had strong evidence for internal consistency and structural validity and moderate evidence for test-retest reliability and construct validity while the KDQOL-36 had moderate evidence of internal consistency, test-retest reliability and construct validity. The End Stage Renal Disease-Symptom Checklist Transplantation Module (ESRD-SCLTM) demonstrated strong evidence for internal consistency and moderate evidence for test-retest reliability, structural and construct validity in renal transplant recipients. CONCLUSIONS: We suggest considering the KDQOL-36 for use in pre dialysis patients; the KDQOL-SF or KDQOL-36 for dialysis patients and the ESRD SCLTM for use in transplant recipients. However, further research is required to evaluate the measurement error, structural validity, responsiveness and patient acceptability of PROMs used in CKD. PMID- 28636682 TI - Excited state characterization of carbonyl containing carotenoids: a comparison between single and multireference descriptions. AB - Carotenoids can play multiple roles in biological photoreceptors thanks to their rich photophysics. In the present work, we have investigated six of the most common carbonyl containing carotenoids: echinenone, canthaxanthin, astaxanthin, fucoxanthin, capsanthin and capsorubin. Their excitation properties are investigated by means of a hybrid density functional theory (DFT) and multireference configuration interaction (MRCI) approach to elucidate the role of the carbonyl group: the bright transition is of pipi* character, as expected, but the presence of a C[double bond, length as m-dash]O moiety reduces the energy of npi* transitions which may become closer to the pipi* transition, in particular as the conjugation chain decreases. This can be related to the presence of a low lying charge transfer state typical of short carbonyl-containing carotenoids. The DFT/MRCI results are finally used to benchmark single-reference time-dependent DFT-based methods: among the investigated functionals, the meta-GGA (and in particular M11L and MN12L) functionals show to perform the best for all six investigated systems. PMID- 28636683 TI - The maximum predicted content of cation vacancies in inorganic and organic inorganic perovskites: the role of the tolerance factor. AB - The maximum content of cation vacancies in perovskites determines the maximum adjustment to the physical properties. By using the classical criterion of the tolerance factor, we put forward a new method to obtain the maximum content of cation vacancies in perovskites. The effective ionic radius was calculated using the weighted average method, and the limit of tolerance factors was used to determine the maximum value of the cation vacancies. The calculated results of the La1-xMnO3 and La0.75Sr0.25Mn1-yO3 materials coincide with experimental results. For application, [(A1)1-x(A2)x]1-z1(B1B2)X3 or [(A1)1-x(A2)x](B1B2)1 z2X3 (X = O, F, Cl, Br, I) inorganic and hybrid organic-inorganic perovskite materials with vacancies at the A or B sites were predicted successfully, which provides a new method to improve the physical properties of perovskite materials. PMID- 28636684 TI - Balanced work function as a driver for facile hydrogen evolution reaction - comprehension and experimental assessment of interfacial catalytic descriptor. AB - A major step in the development of (electro)catalysis would be the possibility to estimate accurately the energetics of adsorption processes related to reaction intermediates. Computational chemistry (e.g. using DFT) developed significantly in that direction and allowed the fast prediction of (electro)catalytic activity trends and improved the general understanding of adsorption at electrochemical interfaces. However, building a reliable and comprehensive picture of electrocatalytic reactions undoubtedly requires experimental assessment of adsorption energies. In this way, the results obtained by computational chemistry can be complemented or challenged, which often is a necessary pathway to further advance the understanding of electrochemical interfaces. In this work an interfacial descriptor of the electrocatalytic activity for hydrogen evolution reaction, analogue to the adsorption energy of the Had intermediate, is identified experimentally using in situ probing of the surface potentials of the metals, under conditions of continuous control of the humidity and the gas exposure. The derived activity trends give clear indication that the electrocatalytic activity for hydrogen evolution reaction is a consequence of an interplay between metal-hydrogen and metal-water interactions. In other words it is shown that the M-H bond formation strongly depends on the nature of the metal water interaction. In fact, it seems that water dipoles at the metal/electrolyte interface play a critical role for electron and proton transfer in the double layer. PMID- 28636685 TI - Interfacial memristors in Al-LaNiO3 heterostructures. AB - Memristive devices are promising circuit elements that enable novel computational approaches which go beyond the von-Neumann paradigms. Here by tuning the chemistry at the Al-LaNiO3 (LNO) interface, a metal-metal junction, we engineer good switching behavior with good electroresistance (ON-OFF resistance ratios of 100), and repeatable multiple resistance states. The active material responsible for such a behavior is a self-formed sandwich of an AlxOy layer at the interface obtained by grabbing oxygen by Al from LNO. Using aberration corrected electron microscopy and transport measurements, it is confirmed that the memristive hysteresis occurs due to the electric field driven O2- (or ) cycling between LNO (reservoir) and the interlayer, which drives the redox reactions forming and dissolving Al nanoclusters in the AlxOy matrix. This work provides clear insights into and details on precise oxygen control at such interfaces and can be useful for newer opportunities in oxitronics. PMID- 28636686 TI - Erythema With Nonscarring, Tense Blister Formation Without Circulating Anti-BP180 Antibodies. PMID- 28636688 TI - Reviews and Meta-analyses of Psychotherapy Efficacy for Borderline Personality Disorder. PMID- 28636687 TI - Types of Shade Vary in Protection Just Like Sunscreens. PMID- 28636690 TI - Opioid Use in Trauma: Combating the "Opidemic" Through Thoughtful Prescribing Practices. PMID- 28636689 TI - Antibiotic Resistance in Acne Treatment. AB - Clinical Question: What is the evidence for antibiotic resistance in acne, and how does resistance affect treatment? Bottom Line: Use of topical and systemic antibiotics for acne is associated with formation of resistance in Propionibacterium acnes and other bacteria, with clinical consequences. Guidelines recommend resistance reduction strategies including avoidance of antibiotic monotherapy, combination treatment with topical modalities, and limiting the duration of oral antibiotic use. PMID- 28636691 TI - Starch-Based "Super Food" May Protect Against Variety of Diseases. PMID- 28636693 TI - Setting National Policy Agendas in Light of the Denmark Results for Well-being. PMID- 28636692 TI - Rethinking the Current American Joint Committee on Cancer TNM Staging System for Medullary Thyroid Cancer. AB - Importance: Controversy exists around the American Joint Committee on Cancer (AJCC) TNM staging system for medullary thyroid cancer (MTC). Because of the rarity of the disease and limited available data, the staging system for MTC has been largely extrapolated from staging for differentiated thyroid cancer. Objectives: To evaluate how well the current (seventh and eighth editions) AJCC TNM staging system correlates with survival for patients with MTC and to suggest a possible revision. Design, Setting, and Participants: This population-based retrospective cohort analysis used the National Cancer Database to select patients aged 18 years or older diagnosed with MTC in the United States between 1998 and 2012. Patient demographic and tumor characteristics were assessed, and pathologic tumor stages were provided as T, N, and M categories. Recursive partitioning with bootstrapping was used to divide patients by TNM stages into groups with similar survival. The newly identified groupings were validated in a Surveillance, Epidemiology, and End Results (SEER) cohort. Data analysis was conducted between July 17, 2016, and November 11, 2016. Main Outcomes and Measures: Overall survival and disease-specific survival. Results: Of the 3315 patients with MTC included in the analysis, 1941 (58.6%) were women. The median (interquartile range) age was 54 (42-65) years, and 2839 (85.6%) self-reported their race/ethnicity as white. The current AJCC TNM staging system classified 941 of these patients (28.4%) as stage I, 907 (27.4%) as stage II, 424 (12.9%) as stage III, and 1043 (31.5%) as stage IV. Recursive partitioning analysis yielded 4 TNM groups: stage I (T1N0-1aM0, T2N0M0), stage II (T1N1bM0, T2N1a-bM0, and T3N0M0), stage III (T3N1a-bM0, T4N0-1bM0), and stage IV (T1-4N0-1bM1). Based on these proposed TNM groupings, 1797 of the 3315 patients (54.2%) were classified as stage I, 684 (20.6%) as stage II, 669 (20.2%) as stage III, and 165 (5.0%) as stage IV. Under the proposed TNM groupings, survival differences across TNM groups were more distinct than under the current AJCC TNM staging system. With stage I as the reference, the hazard ratios of the proposed TNM groupings and the current AJCC TNM staging system were 2.19 (95% CI, 1.37-3.12) vs 1.45 (95% CI, 1.09-1.92) for stage II, 4.20 (95% CI, 2.75-5.75) vs 2.17 (95% CI, 1.59-2.89) for stage III, and 10.97 (95% CI, 5.52-18.57) vs 5.33 (95% CI, 4.13-6.86) for stage IV. In a SEER cohort, the proposed TNM groupings were better at discriminating survival than was the current AJCC TNM staging system. Conclusions and Relevance: The current AJCC TNM staging system for MTC appears to be less than optimal in distinguishing risk of mortality among stage groups, upstaging a significant number of patients to stage IV. The current AJCC TNM staging system could be improved with the new TNM groupings proposed here for more accurate risk stratification and potential treatment selection. PMID- 28636695 TI - Translating Patient-Reported Outcomes From Surgical Research to Clinical Care. PMID- 28636694 TI - Placebo Response and Practice Effects in Schizophrenia Cognition Trials. AB - Importance: Patients' previous experience with performance-based cognitive tests in clinical trials for cognitive impairment associated with schizophrenia can create practice-related improvements. Placebo-controlled trials for cognitive impairment associated with schizophrenia are at risk for these practice effects, which can be difficult to distinguish from placebo effects. Objectives: To conduct a systematic evaluation of the magnitude of practice effects on the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) in cognitive impairment associated with schizophrenia and to examine which demographic, clinical, and cognitive characteristics were associated with improvement in placebo conditions. Design, Setting, and Participants: A blinded review was conducted of data from 813 patients with schizophrenia who were treated with placebo in 12 randomized placebo-controlled clinical trials conducted mostly in outpatient clinics in North America, Europe, Asia, and Latin America from February 22, 2007, to March 1, 2014. A total of 779 patients provided data for the primary outcome measure at baseline and at least 1 follow-up. Seven trials had prebaseline assessments wherein the patients knew that they were not receiving treatment, allowing a comparison of practice and placebo effects in the same patients. Interventions: Placebo compared with various experimental drug treatments. Main Outcomes and Measures: Composite score on the MCCB. Results: Of the 813 patients in the study (260 women and 553 men; mean [SD] age, 41.2 [11.5] years), the mean MCCB composite score at baseline was 22.8 points below the normative mean, and the mean (SEM) total change in the MCCB during receipt of placebo was 1.8 (0.2) T score points (95% CI, 1.40-2.18), equivalent to a change of 0.18 SD. Practice effects in the 7 studies in which there was a prebaseline assessment were essentially identical to the postbaseline placebo changes. Baseline factors associated with greater improvements in the MCCB during receipt of placebo included more depression/anxiety (F1,438 = 5.41; P = .02), more motivation (F1,272 = 4.63; P = .03), and less improvement from screening to baseline (F1,421 = 59.32; P < .001). Conclusions and Relevance: Placebo effects were minimal and associated with the number of postbaseline assessments and several patient characteristics. Given that the patients performed 2.28 SDs below normative standards on average at baseline, a mean placebo-associated improvement of less than 0.2 SD provides evidence that ceiling effects do not occur in these trials. These minimal changes in the MCCB could not be responsible for effective active treatments failing to separate from placebo. PMID- 28636696 TI - Incentive Spirometry After Bariatric Surgery-Reply. PMID- 28636698 TI - Corrections to Numbering, Abstract, and Methods. PMID- 28636697 TI - Role of Positive Parenting in the Association Between Neighborhood Social Disadvantage and Brain Development Across Adolescence. AB - Importance: The negative effects of socioeconomic disadvantage on lifelong functioning are pronounced, with some evidence suggesting that these effects are mediated by changes in brain development. To our knowledge, no research has investigated whether parenting might buffer these negative effects. Objective: To establish whether positive parenting behaviors moderate the effects of socioeconomic disadvantage on brain development and adaptive functioning in adolescents. Design, Setting, and Participants: In this longitudinal study of adolescents from schools in Melbourne, Australia, data were collected at 3 assessments between 2004 and 2012. Data were analyzed between August 2016 and April 2017. Exposures: Both family (parental income-to-needs, occupation, and education level) and neighborhood measures of socioeconomic disadvantage were assessed. Positive maternal parenting behaviors were observed during interactions in early adolescence. Main Outcomes and Measures: Structural magnetic resonance imaging scans at 3 times (early, middle, and late adolescence) from ages 11 to 20 years. Global and academic functioning was assessed during late adolescence. We used linear mixed models to examine the effect of family and neighborhood socioeconomic disadvantage as well as the moderating effect of positive parenting on adolescent brain development. We used mediation models to examine whether brain developmental trajectories predicted functional outcomes during late adolescence. Results: Of the included 166 adolescents, 86 (51.8%) were male. We found that neighborhood, but not family, socioeconomic disadvantage was associated with altered brain development from early (mean [SD] age, 12.79 [0.425] years) to late (mean [SD] age, 19.08 [0.460] years) adolescence, predominantly in the temporal lobes (temporal cortex: random field theory corrected; left amygdala: B, -0.237; P < .001; right amygdala: B, -0.209; P = .008). Additionally, positive parenting moderated the effects of neighborhood disadvantage on the development of dorsal frontal and lateral orbitofrontal cortices as well as the effects of family disadvantage on the development of the amygdala (occupation: B, 0.382; P = .004; income-to-needs: B, 27.741; P = .004), with some male-specific findings. The pattern of dorsal frontal cortical development in males from disadvantaged neighborhoods exposed to low maternal positivity predicted increased rates of school noncompletion (indirect effect, 0.018; SE, 0.01; 95% CI, -0.053 to -0.001). Conclusions and Relevance: Our findings highlight the importance of neighborhood disadvantage in influencing brain developmental trajectories. Further, to our knowledge, we present the first evidence that positive maternal parenting might ameliorate the negative effects of socioeconomic disadvantage on frontal lobe development (with implications for functioning) during adolescence. Results have relevance for designing interventions for children from socioeconomically disadvantaged backgrounds. PMID- 28636699 TI - Dynamic measurements of flowing cells labeled by gold nanoparticles using full field photothermal interferometric imaging. AB - We present highly dynamic photothermal interferometric phase microscopy for quantitative, selective contrast imaging of live cells during flow. Gold nanoparticles can be biofunctionalized to bind to specific cells, and stimulated for local temperature increase due to plasmon resonance, causing a rapid change of the optical phase. These phase changes can be recorded by interferometric phase microscopy and analyzed to form an image of the binding sites of the nanoparticles in the cells, gaining molecular specificity. Since the nanoparticle excitation frequency might overlap with the sample dynamics frequencies, photothermal phase imaging was performed on stationary or slowly dynamic samples. Furthermore, the computational analysis of the photothermal signals is time consuming. This makes photothermal imaging unsuitable for applications requiring dynamic imaging or real-time analysis, such as analyzing and sorting cells during fast flow. To overcome these drawbacks, we utilized an external interferometric module and developed new algorithms, based on discrete Fourier transform variants, enabling fast analysis of photothermal signals in highly dynamic live cells. Due to the self-interference module, the cells are imaged with and without excitation in video-rate, effectively increasing signal-to-noise ratio. Our approach holds potential for using photothermal cell imaging and depletion in flow cytometry. PMID- 28636700 TI - Appropriateness, Health Care Reform, and the Surgeon: Perspectives From the Surgical Outcomes Club. PMID- 28636701 TI - The Metabolodiuretic Promise of Sodium-Dependent Glucose Cotransporter 2 Inhibition: The Search for the Sweet Spot in Heart Failure. PMID- 28636702 TI - Analysis of Survival After Initiation of Continuous Renal Replacement Therapy in a Surgical Intensive Care Unit. AB - Importance: Continuous renal replacement therapy (CRRT) benefits patients with renal failure who are too hemodynamically unstable for intermittent hemodialysis. The duration of therapy beyond which continued use is futile, particularly in a population of patients admitted to and primarily cared for by a surgical service (hereinafter referred to as surgical patients), is unclear. Objective: To analyze proportions of and independent risk factors for survival to discharge after initiation of CRRT among patients in a surgical intensive care unit (SICU). Design, Setting, and Participants: This retrospective cohort study included all patients undergoing CRRT from July 1, 2012, through January 31, 2016, in an SICU of an urban tertiary medical center. The population included patients treated before or after general surgery and patients admitted to a surgical service during inpatient evaluation and care before liver transplant. The pretransplant population was censored from further survival analysis on receipt of a transplant. Exposures: Continuous renal replacement therapy. Main Outcomes and Measures: Hospital mortality among patients in an SICU after initiation of CRRT. Results: Of 108 patients (64 men [59.3%] and 44 women [40.7%]; mean [SD] age, 62.0 [12.7] years) admitted to the SICU, 53 were in the general surgical group and 55 in the pretransplant group. Thirteen of the 22 patients in the pretransplant group who required 7 or more days of CRRT died (in-hospital mortality, 59.1%); among the 12 patients in the general surgery group who required 7 or more days of CRRT, 12 died (in-hospital mortality, 100%). In the general surgical group, each day of CRRT was associated with an increased adjusted odds ratio of death of 1.39 (95% CI, 1.01-1.90; P = .04). Conclusions and Relevance: Continuous renal replacement therapy is valuable for surgical patients with an acute and correctable indication; however, survival decreases significantly with increasing duration of CRRT. Duration of CRRT does not correlate with survival among patients awaiting liver transplant. PMID- 28636703 TI - Transforming the National Surgical Quality Improvement Program to the Delivery of Precision Medicine to Improve the Value of Surgical Care: Summary of the John R. Clarke Keynote Address for the Surgical Outcomes Club 2016 Annual Meeting. PMID- 28636704 TI - Trends in Nationwide Herpes Zoster Emergency Department Utilization From 2006 to 2013. AB - Importance: The effect of vaccination on emergency department (ED) utilization for herpes zoster (HZ) has not been examined to date. Objective: To determine trends in US ED utilization and costs associated with HZ. Design, Setting, and Participants: The Nationwide Emergency Department Sample data set was examined for temporal trends in the number of visits and costs for treatment of HZ in EDs in the United States from January 1, 2006, through December 31, 2013. Cases of HZ were identified using validated International Classification of Diseases, Ninth Revision-Clinical Modification diagnosis codes. Patients were stratified by age: less than 20 years (varicella vaccine recommended), 20 to 59 years (no vaccine recommended), and 60 years or older (HZ vaccine recommended). Population-based rates were estimated using sampling weights. Main Outcomes and Measures: Population-based incidence rates of HZ-related ED visits, charge for ED services, and total charges. Results: A total of 1 350 957 ED visits for HZ were identified between 2006 and 2013, representing 0.13% of all US ED visits. Of these patients, 563 200 (51.7%) were male; mean (SE) age was 54.0 (0.1) years. Between 2006 and 2013, the percentage of HZ-related ED visits increased from 0.13% to 0.14% (8.3%). This growth was driven by patients aged 20 to 59 years (increase of 22.8% [from 0.12% to 0.14% of ED visits]) while the proportion of ED HZ visits decreased for patients aged less than 20 years and 60 years or older, from 0.03% to 0.02% (-39.6%) and from 0.28% to 0.25% (-10.9%), respectively. For all age groups, there was an increase from 2006 to 2013 in overall adjusted total (from $92.83 to $202.47 million) and mean charges (from $763 to $1262) for HZ-related ED visits. Conclusions and Relevance: The number of ED visits and total cost associated with HZ increased between 2006 and 2013. Greater use was driven by an increased number of visits by patients aged 20 to 59 years, but populations recommended for vaccination (<20 and >=60 years) demonstrated decreased ED utilization. Per-visit and total costs increased across all age groups. Vaccination may be associated with a reduction of ED utilization. Further research is required to confirm these results and examine the drivers of increased ED costs. PMID- 28636706 TI - Rectus Femoris Tear Presenting as an Unusual Cause of a Subcutaneous Mass. PMID- 28636705 TI - Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder. AB - Importance: For a small percentage of obsessive-compulsive disorder (OCD) cases exhibiting additional neuropsychiatric symptoms, it was proposed that neuroinflammation occurs in the basal ganglia as an autoimmune response to infections. However, it is possible that elevated neuroinflammation, inducible by a diverse range of mechanisms, is important throughout the cortico-striato thalamo-cortical circuit of OCD. Identifying brain inflammation is possible with the recent advance in positron emission tomography (PET) radioligands that bind to the translocator protein (TSPO). Translocator protein density increases when microglia are activated during neuroinflammation and the TSPO distribution volume (VT) is an index of TSPO density. Objective: To determine whether TSPO VT is elevated in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex in OCD. Design, Setting, and Participants: This case-control study was conducted at a tertiary care psychiatric hospital from May 1, 2010, to November 30, 2016. Participants with OCD (n = 20) and age-matched healthy control individuals (n = 20) underwent a fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3 yl)acetamide PET scan. It is a high-quality second-generation TSPO-binding PET radiotracer. All participants were drug and medication free, nonsmoking, and otherwise healthy. Main Outcomes and Measures: The TSPO VT was measured in the dorsal caudate, orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex. Compulsions were assessed with the Yale-Brown Obsessive Compulsive Scale. Results: In the OCD and healthy groups, the mean (SD) ages were 27.4 (7.1) years and 27.6 (6.6) years, respectively, and 11 (55%) and 8 (40%) were women, respectively. In OCD, TSPO VT was significantly elevated in these brain regions (mean, 32%; range, 31%-36% except anterior cingulate cortex, 24%; analysis of variance, effect of diagnosis: P < .001 to P = .004). Slightly lower elevations in TSPO VT (22%-29%) were present in other gray matter regions. The Yale-Brown Obsessive Compulsive Scale measure of distress associated with preventing compulsive behaviors significantly correlated with TSPO VT in the orbitofrontal cortex (uncorrected Pearson correlation r = 0.62; P = .005). Conclusions and Relevance: To our knowledge, this is the first study demonstrating inflammation within the neurocircuitry of OCD. The regional distribution of elevated TSPO VT argues that the autoimmune/neuroinflammatory theories of OCD should extend beyond the basal ganglia to include the cortico striato-thalamo-cortical circuit. Immunomodulatory therapies should be investigated in adult OCD, rather than solely childhood OCD, particularly in cases with prominent distress when preventing compulsions. PMID- 28636708 TI - Improvement of TNM Staging for Medullary Thyroid Cancer. PMID- 28636709 TI - New Editorial Board Members-July 2017. PMID- 28636707 TI - Incidence and Predictors of Opioid Prescription at Discharge After Traumatic Injury. AB - Importance: In the current health care environment with increased scrutiny and growing concern regarding opioid use and abuse, there has been a push toward greater regulation over prescriptions of opioids. Trauma patients represent a population that may be affected by this regulation, as the incidence of pain at hospital discharge is greater than 95%, and opioids are considered the first line of treatment for pain management. However, the use of opioid prescriptions in trauma patients at hospital discharge has not been explored. Objective: To study the incidence and predictors of opioid prescription in trauma patients at discharge in a large national cohort. Design, Setting, and Participants: Analysis of adult (18-64 years), opioid-naive trauma patients who were beneficiaries of Military Health Insurance (military personnel and their dependents) treated at both military health care facilities and civilian trauma centers and hospitals between January 1, 2006, and December 31, 2013, was conducted. Patients with burns, foreign body injury, toxic effects, or late complications of trauma were excluded. Prior diagnosis of trauma within 1 year and in-hospital death were also grounds for exclusion. Injury mechanism and severity, comorbid conditions, mental health disorders, and demographic factors were considered covariates. The Drug Enforcement Administration's list of scheduled narcotics was used to query opioid use. Unadjusted and adjusted logistic regression models were used to determine the predictors of opioid prescription. Data analysis was performed from June 7 to August 21, 2016. Exposures: Injury mechanism and severity, comorbid conditions, mental health disorders, and demographic factors. Main Outcomes and Measures: Prescription of opioid analgesics at discharge. Results: Among the 33 762 patients included in the study (26 997 [80.0%] men; mean [SD] age, 32.9 [13.3] years), 18 338 (54.3%) received an opioid prescription at discharge. In risk adjusted models, older age (45-64 vs 18-24 years: odds ratio [OR], 1.28; 95% CI, 1.13-1.44), marriage (OR, 1.26; 95% CI, 1.20-1.34), and higher Injury Severity Score (>=9 vs <9: OR, 1.40; 95% CI, 1.32-1.48) were associated with a higher likelihood of opioid prescription at discharge. Male sex (OR, 0.76; 95% CI, 0.69 0.83) and anxiety (OR, 0.82; 95% CI, 0.73-0.93) were associated with a decreased likelihood of opioid prescription at discharge. Conclusions and Relevance: The incidence of opioid prescription at discharge (54.3%) closely matches the incidence of moderate to severe pain in trauma patients, indicating appropriate prescribing practices. We advocate that injury severity and level of pain-not arbitrary regulations-should inform the decision to prescribe opioids. PMID- 28636710 TI - Off-label Use of High-Risk Cardiovascular Devices: Widening the Lens. PMID- 28636713 TI - Practice- vs Physician-Level Variation in Use of Active Surveillance for Men With Low-Risk Prostate Cancer: Implications for Collaborative Quality Improvement. PMID- 28636714 TI - Characteristics and Alternative Treatment Outcomes of Antimalarial-Refractory Cutaneous Lupus Erythematosus. PMID- 28636715 TI - Internet-Based Self-Help Interventions for Depression in Routine Care-Reply. PMID- 28636716 TI - Wide Complex Tachycardia in an Elderly Woman. PMID- 28636717 TI - Internet-Based Self-help Interventions for Depression in Routine Care. PMID- 28636721 TI - Evaluating Evolving Technologies in a Time of Rapid Change: The Case of Transcatheter Aortic Valve Replacement. PMID- 28636718 TI - Trends and Outcomes of Off-label Use of Transcatheter Aortic Valve Replacement: Insights From the NCDR STS/ACC TVT Registry. AB - Importance: Transcatheter aortic valve replacement (TAVR) was approved by the US Food and Drug Administration for severe aortic stenosis in patients who cannot undergo surgery and for patients at high operative risk. Use of TAVR for off label indications has not been previously reported. Objective: To evaluate patterns and adverse outcomes of off-label use of TAVR in US clinical practice. Design, Setting and Participants: Patients receiving commercially funded TAVR in the United States are included in the Transcatheter Valve Therapy Registry. A total of 23 847 patients from 328 sites performing TAVR between November 9, 2011, and September 30, 2014, were assessed for this study. Off-label TAVR was defined as TAVR in patients with known bicuspid valve, moderate aortic stenosis, severe mitral regurgitation, severe aortic regurgitation, or subaortic stenosis. Data were linked with the Centers for Medicare & Medicaid Services for 15 397 patients to evaluate 30-day and 1-year outcomes. Exposure: Off-label use of TAVR. Main Outcomes and Measures: Frequency of off-label TAVR use and the association with in-hospital, 30-day, and 1-year adverse outcomes. Results: Among the 23 847 patients in the study (11 876 women and 11 971 men; median age, 84 years [interquartile range, 78-88 years]), off-label TAVR was used in 2272 patients (9.5%). In-hospital mortality was higher among patients receiving off-label TAVR than those receiving on-label TAVR (6.3% vs 4.7%; P < .001), as was 30-day mortality (8.5% vs 6.1%; P < .001) and 1-year mortality (25.6% vs 22.1%; P = .001). Adjusted 30-day mortality was higher in the off-label group (hazard ratio, 1.27; 95% CI, 1.04-1.55; P = .02), while adjusted 1-year mortality was similar in the 2 groups (hazard ratio, 1.11; 95% CI, 0.98-1.25; P = .11). The median rate of off-label TAVR use per hospital was 6.8% (range, 0%-34.7%; interquartile range, 3.4%-12.1%), with hospitals in the highest tertile of off-label use associated with increased 30-day adverse cardiovascular events compared with the lowest tertile. However, this difference was not observed in adjusted 30-day or 1-year outcomes. Conclusions and Relevance: Approximately 1 in 10 patients in the United States have received TAVR for an off-label indication. After adjustment, 1-year mortality was similar in these patients to that in patients who received TAVR for an on-label indication. These results reinforce the need for additional research on the efficacy of off-label TAVR use. PMID- 28636722 TI - Incentive Spirometry After Bariatric Surgery: The Importance of Patient Compliance. PMID- 28636723 TI - Reviews and Meta-analyses of Psychotherapy Efficacy for Borderline Personality Disorder-Reply. PMID- 28636724 TI - Temporal relationships between job strain and low-back pain. AB - Objectives Psychosocial working conditions are suggested risk factors for low back pain, but it is unclear whether these associations are causal. The present study examined whether there are lagged and bidirectional associations between job strain and low-back pain and further controlled for unmeasured time-invariant confounding. Methods The study was based on four biennial waves of data from the Swedish Longitudinal Occupational Survey of Health (SLOSH), including 3084 men and women. Cross-lagged analyses using structural equation modeling (SEM) were conducted on job strain, a combination of high job demands and low control, and any as well as low-back pain severity (how much any problems affected the respondents life). Analogous SEM (dynamic panel) models with fixed effects were also fitted to remove confounding from time-invariant factors (such as non observed individual and environmental factors, eg, genetics, childhood conditions, personality). Results The SEM models indicated bidirectional associations between job strain and any back pain over a 2-year time lag (beta=0.21 and 0.19, P<0.05), when adjusting for a range of covariates. Job strain was also associated with an increase in low-back pain severity and vice versa. However, the SEM models with fixed-effects showed no statistically significant lagged relationships between job strain and any or low-back pain severity (beta=-0.05 and beta=0.00, respectively). Conclusions This study suggests that associations between job strain and low-back pain with a lag of years may be due to residual confounding by time invariant characteristics. Further studies are, however, needed to elucidate short-term relationships. PMID- 28636725 TI - June is National Dysphagia Awareness Month. PMID- 28636726 TI - Endoscopic view of a dumbbell-shaped sphenoid fungal mass. PMID- 28636727 TI - Vocal fold hemorrhage into a physiologic sulcus. PMID- 28636728 TI - Synchronous lesions of the right accessory parotid gland and left main parotid gland. PMID- 28636729 TI - Massive auricular cutaneous horn. PMID- 28636730 TI - Aggressive differentiated thyroid cancer in the geriatric patient. PMID- 28636731 TI - Correlation among external auditory canal anomaly, temporal bone malformation, and hearing levels in patients with microtia. AB - We conducted a retrospective study to evaluate the relationship between external auditory canal (EAC) anomaly, temporal bone abnormality, and hearing levels using objective scoring systems in Chinese patients with microtia. The study population consisted of 106 ears of 94 Chinese patients (67 male and 27 female) aged 5 to 45 years (mean: 12.6) with microtia. The EAC abnormalities were classified into 4 types according to Schuknecht's criteria: type A, type B, type C, and type D. Developmental anomalies of the temporal bone were evaluated by Jahrsdoerfer computed tomography (CT) scoring system using high-resolution CT scans of the temporal bone. Temporal bone malformation parameters were divided into 4 subgroups: ossicular chain development, windows connected to the cochlea, aeration development of the middle ear, and facial nerve aberration. Hearing levels (air conduction and bone conduction) were examined. Outcomes parameters included correlation coefficients (r) and a number of other variables. The total points (10 points) and subtotal points related to ossicles (4 points), windows (2 points), aeration (2 points), and facial nerve (1 point) correlated inversely with the EAC abnormalities. The hearing levels (air conduction, r = 0.396, p <0.01; bone conduction, r = 0.21, p = 0.03) correlated significantly with the EAC abnormalities of Schuknecht's classification. We conclude that the better developed the external auditory canal, the better developed the temporal bone and the better developed the external auditory canal, the better hearing level. The hearing level also can serve as an indicator to determine whether a patient will be suitable for reconstructive surgery. PMID- 28636732 TI - Positron-emission tomography enhancement after vocal fold injection medialization. AB - The potential for the misinterpretation of positron-emission tomography (PET) scans in the context of a possible malignancy has been confirmed in a case report showing increased 18F-fluorodeoxyglucose (FDG) uptake after unilateral vocal fold augmentation medialization. We sought to expand these findings by investigating FDG uptake in a larger cohort of patients via a retrospective chart review. We examined the records of 15 adults-8 men and 7 women-who had undergone vocal fold augmentation for unilateral vocal fold paralysis and at least one subsequent PET scan. The differences in PET standard uptake value (SUV) between the injected and noninjected vocal folds were assessed via the Wilcoxon signed-rank test. A Spearman rank correlation coefficient was then used to estimate the relationship between differences in PET uptake and the length of time between the injection and the follow-up PET scan. The mean SUV of the injected vocal folds was 3.70, and the mean in the noninjected folds was 2.97. The difference did not achieve statistical significance (p = 0.34). In addition, the rank correlation coefficient with regard to the association between the difference in PET uptake and the duration between injection and PET was -0.24, suggesting an inverse relationship. However, the correlation coefficient did not differ significantly from zero (p = 0.34). We conclude that PET uptake after vocal fold augmentation medialization is variable and that it can increase substantially. This information should be considered in the context of the diagnostic accuracy of malignancy on PET. PMID- 28636733 TI - Idiopathic pretracheal deep neck space infection with mediastinal extension: A series of 3 cases and review of the literature. AB - Idiopathic pretracheal deep neck space infection is an extremely rare condition with potentially devastating complications. We present a series of 3 cases of pretracheal deep neck space infection that arose in the absence of trauma or a congenital lesion and that exhibited mediastinal spread. To the best of our knowledge, these cases represent the first reported series of this rare condition to be published in the English-language literature. All cultures grew Streptococcus milleri, and all patients had a favorable outcome. A high index of suspicion for a deep neck space infection is warranted in view of the devastating complications of this condition. Computed tomography is the investigation of choice. Treatment with intravenous antibiotics and surgical drainage, particularly when mediastinitis is present, is recommended. This rare presentation warrants a thorough investigation to identify the source of infection. PMID- 28636734 TI - Is computed tomography perfusion a useful method for distinguishing between benign and malignant neck masses? AB - Evaluation of neck masses is frequent in ear, nose, and throat clinics. Successful outcomes associated with neck mass are directly related to rapid diagnosis and accurate treatment for each patient. Late diagnosis of a malignant mass increases the magnitude of morbidity and the rate of mortality of the disease. Although magnetic resonance imaging and computed tomography (CT) examinations are important tools for evaluating head and neck pathologies, they do not allow functional evaluation. For this reason, CT perfusion (CTP) as a method of functional evaluation for distinguishing benign from malignant masses is gaining attention. The utility of CTP for distinguishing between benign and malignant mass lesions was investigated in 35 patients with masses in the neck (11 benign, 24 malignant). CTP was shown to be a useful method for identifying head and neck tumors and blood volume values to enable the differential diagnosis of benign and malignant head and neck tumors. PMID- 28636735 TI - Salivary epidermal growth factor concentrations in patients with Sjogren syndrome and laryngopharyngeal reflux. AB - Sjogren syndrome was chosen as a clinical model to study acinar salivary deficiencies in the development of laryngopharyngeal reflux (LPR). The objective of this prospective cohort study was to compare salivary epidermal growth factor (EGF) concentrations of patients with Sjogren syndrome with and without LPR and gastroesophageal reflux disease (GERD) with normal controls. LPR was diagnosed with positive scores on the Reflux Symptom Index and Reflux and Reflux Finding Score, corroborated by esophagogastroduodenoscopy and/or 24-hour pH-metry. Salivary EGF concentrations of both unstimulated and mechanically stimulated saliva were established using enzyme-linked immunosorbent assay, and the significance level was set at 95%. Twenty-one patients and 19 controls were studied. All patients had LPR and 60% also had GERD. The mean salivary EGF concentration of unstimulated and stimulated saliva in the control group was 1,751.37 pg/ml and 544.76 pg/ml, respectively. Unstimulated and stimulated salivary EGF concentrations in the study group were 2,534.65 pg/ml and 920.69 pg/ml, respectively. These differences were not statistically significant. Body mass index, presence of erosive esophagitis, or severity of hyposalivation did not significantly influence salivary EGF concentrations. LPR and GERD are highly prevalent in patients with Sjogren syndrome. Unlike previous studies in which significant EGF deficiencies were found in patients with reflux laryngitis and GERD, patients with Sjogren syndrome seem to have reflux caused by a decrease in clearance capacity and not in specific salivary components. PMID- 28636736 TI - The protective effect of intratympanic dexamethasone on streptomycin ototoxicity in rats. AB - The purpose of this experimental study was to investigate the protective role of intratympanically administered dexamethasone on the inner ears of rats that were exposed to streptomycin ototoxicity. Twenty-four adult Wistar albino rats were separated into 4 groups: Group 1 (only streptomycin), Group 2 (only intratympanic dexamethasone), Group 3 (streptomycin and intratympanic dexamethasone), and Group 4 (streptomycin and intratympanic saline). All rats were evaluated with distortion product otoacoustic emissions (DPOAE) tests before the start of treatment and on the day it ended. On the 45th day, after the final DPOAE tests, animals of all groups were sacrificed under general anesthesia. The differences between the amplitudes of DPOAE results were determined, and hearing results were statistically analyzed. Also, the cochleas of each rat were histopathologically evaluated under a light microscope with hematoxylin and eosin staining. In the intratympanic dexamethasone group it was observed that cochlear hair cells were mostly protected. No significant difference was seen between the DPOAE results before and after treatment (p >0.05). On the other hand, loss was observed in the hearing functions and hair cells of the rats that received streptomycin and streptomycin plus intratympanic saline (p <0.05). In the streptomycin plus intratympanic dexamethasone group, the cochlear hair cells were partially protected. A significant difference was observed when the DPOAE results (DP grams) of the streptomycin plus intratypmanic dexamethasone group were compared to those of the streptomycin plus intratympanic saline group (p <0.05). After the experimental study, ototoxic effects of the administration of streptomycin and intratympanic dexamethasone were observed on the rats' cochlear hair cells. We conclude that intratympanic dexamethasone has protective effects against this cochlear damage in rats. PMID- 28636737 TI - Is there an association between migraine and allergic rhinitis? AB - We conducted a prospective study to evaluate nasal signs and symptoms and to perform allergen-specific immunoglobulin E (IgE) testing to investigate the relationship between migraine and allergic rhinitis. Our study group consisted of 40 patients diagnosed with migraine-22 men and 18 women, aged 21 to 38 years (mean: 25.7). We compared their findings with a control group of 40 healthy adults-15 men and 25 women, aged 19 to 36 years (mean: 25.1). Allergen-specific IgE measurements were obtained with six groups of allergens: fungi, grass pollens, tree pollens, wild herbs, house dust mite 1, and house dust mite 2. We found no significant difference between the migraine patients and the controls in the incidence of nasal signs and symptoms (i.e., discharge, congestion, itching, and sneezing) or inferior turbinate signs (i.e., color and edema). According to the IgE assays, 14 migraine patients (35.0%) were sensitized to one or more allergens, compared with 11 of the controls (27.5%); the difference was not statistically significant. Sensitization was highest for the grass pollens panel in both groups. Even though we did not find an association between migraine and allergic rhinitis, the recent literature supports a correlation between migraine and atopy. The two conditions share common neural pathways and common mediators, and they can be linked statistically in patients and their families. A pathophysiologic association between the two conditions seems more likely than an etiologic association. In this regard, future efforts could be focused on the determination of atopy in migraine patients and the therapeutic implications of this diagnosis. PMID- 28636738 TI - Impact of a pediatric anesthesiologist on operating room efficiency during pediatric tonsillectomies and adenotonsillectomies. AB - We conducted a retrospective case review to determine if the presence of an Accreditation Council for Graduate Medical Education (ACGME) fellowship-trained pediatric anesthesiologist improves efficiency during pediatric tonsillectomies and adenotonsillectomies in hospitals that do not have dedicated pediatric operating rooms and, if so, to determine which specific anesthesia practices might account for such a difference. We reviewed the charts of all patients aged 12 years and younger who had undergone a tonsillectomy or adenotonsillectomy from Jan. 1, 2008, through Aug. 1, 2013, at San Francisco General Hospital. A total of 75 cases met our eligibility criteria. We compiled information on patient demographics, surgical time, anesthesia time, and anesthesia practices. Our primary study outcome was the amount of anesthesia-controlled time (ACT), which is the sum of time spent in induction and emergence. Cases were grouped according to whether the operation was staffed by an ACGME fellowship-trained pediatric anesthesiologist or a general anesthesiologist. Data were analyzed for 1 pediatric anesthesiologist and 23 general anesthesiologists. We found that ACT was significantly shorter during the cases staffed by the ACGME fellowship trained pediatric anesthesiologist, although there were no major differences in anesthesia practices between the types of anesthesiologist. We suggest that staffing pediatric tonsillectomy operations with a fellowship-trained pediatric anesthesiologist may be an effective strategy for increasing operating room efficiency. PMID- 28636739 TI - A comparison of tonsillar surface swabbing, fine-needle aspiration core sampling, and dissected tonsillar core biopsy culture in children with recurrent tonsillitis. AB - In recurrent tonsillitis, the pathogenic bacteria are harbored in the tonsil core, and therefore cultures of superficial swab samples are not particularly accurate in identifying specific types of core bacteria. On the other hand, the results of fine-needle aspiration (FNA) cultures of core samples have been closely correlated with the findings of core cultures in excised tonsils, and both methods are far superior to surface swabbing. We conducted a prospective study to compare the accuracy of culture findings from tonsillar tissue obtained by surface swabbing, FNA sampling of the tonsil core in situ, and core sampling of the excised tonsil in children with recurrent tonsillitis. Our patient population was made up of 54 children-22 boys and 32 girls, aged 4 to 14 years (mean: 10.7)-who were undergoing elective tonsillectomy during a 1-year period. On the day of surgery, a surface swab, core FNA sample, and dissected core sample were obtained from each patient and sent for culture. Culture showed that the three methods were in agreement in 34 cases (63.0%). In 9 cases (16.7%) the surface swab culture grew different pathogens from those of the two core cultures, and in 3 other cases (5.6%) the surface swab culture was negative while the two core cultures were positive for the same pathogens. In all, the results of core FNA culture and dissected core culture were in agreement in 46 cases (85.2%); in only 4 cases (7.4%) did the core FNA culture fail to accurately identify the causative pathogens. Overall, the sensitivity and specificity of core FNA sampling were 100 and 50% respectively, compared with 82.9 and 30.8% for the superficial tonsillar swab. We conclude that routine culture of surface swab specimens in patients with chronic or recurrent tonsillitis is neither reliable nor valid. We recommend that core FNA sampling be considered the diagnostic method of choice since it can be done on an outpatient basis, it would reliably allow for culture-directed antibiotic therapy, and it could obviate the need for elective tonsillectomy in many cases. However, its feasibility as an office procedure in children remains to be determined. PMID- 28636740 TI - Initial experience of a hereditary hemorrhagic telangiectasia center of excellence. AB - Our objectives in reviewing the initial experience of a hereditary hemorrhagic telangiectasia center of excellence (HHT COE) were to better understand the interventions being performed in the comprehensive care of these patients and to present the early data as a reference for other tertiary centers considering starting an HHT COE. We conducted a retrospective review of consecutive patients referred to our newly developed HHT COE for evaluation and treatment between May 2010 and June 2013. Clinical presentation, otolaryngologic treatments, and other operative interventions were analyzed. One hundred forty-four of the 198 patients (73%) evaluated at the HHT COE had definite HHT based on the Curacao diagnostic criteria, with 20 additional patients possibly having HHT and undergoing further evaluation to confirm the diagnosis. Sixteen of the 31 patients (52%) referred to otolaryngology required intervention in the operating room for epistaxis. Seventy two of the 164 (44%) patients with definite or possible HHT required other interventions for internal organ arteriovenous malformations (AVMs), with interventional radiology embolization of pulmonary AVMs being the most common procedure. An HHT COE is important in providing comprehensive care for patients with this rare disease, which has significant clinical sequelae. Having an HHT COE allows for early screening and subspecialty referral within a system of specialists experienced in preventing the morbidity and mortality associated with severe epistaxis and internal organ AVMs. PMID- 28636741 TI - Adenoid cystic carcinoma of the head and neck area: Oncologic treatment and plastic-reconstructive options. AB - Adenoid cystic carcinoma of the head and neck area is a rare malignant tumor with acceptable short-term but mediocre long-term prognosis. Radical tumor excision with clear resection margins, and sometimes resection of the facial nerve due to perineural growth, remains the fundamental therapy. We present 3 distinct clinical cases and discuss the current therapeutic options with special focus on plastic-reconstructive techniques. For reconstruction, the full armament of local and free flaps, as well as prosthetics, may be necessary. Adjuvant radiotherapy increases local control in advanced stages or close resection margins. However, systemic treatment options are limited. Further multicenter clinical trials are necessary due to the rare occurrence of the tumor. PMID- 28636742 TI - Results of endonasal dacryocystorhinostomy in pediatric patients. AB - We conducted a prospective interventional study to evaluate the role of endoscopic endonasal dacryocystorhinostomy in children. Our study population was made up of 20 patients-18 boys and 2 girls, aged 2 to 12 years (mean: 5.3)-who presented with signs and symptoms suggestive of nasolacrimal duct blockage that was refractory to conventional medical treatment. In all cases, blockage was confirmed by nasolacrimal duct syringing that demonstrated regurgitation from the opposite punctum. The primary outcome measures for success were resolution of symptoms and duct patency on lacrimal irrigation. At 6 months, 17 patients (85%) experienced complete symptomatic relief, 1 (5%) had partial relief, and 2 (10%) reported no relief. Moreover, the nasolacrimal duct was patent in 17 patients, partially patent in 2, and blocked in 1. We conclude that endoscopic endonasal dacryocystorhinostomy is a safe and effective procedure in children with nasolacrimal duct blockage when medical therapy and probing have been unsuccessful. PMID- 28636743 TI - Infestation of mites in external auditory canal. PMID- 28636744 TI - Parathyroid carcinoma in a patient with three prior parathyroid adenomas. PMID- 28636745 TI - A practical framework for encouraging and supporting positive behaviour change in diabetes. AB - A wide range of diabetes-directed interventions - including novel medications, devices and comprehensive education programmes - have been shown to be effective in clinical trials. But in the real world of diabetes care their efficacy is often dependent upon on how well a clinician is able to support personal engagement and motivation of the person with diabetes to use these new tools and knowledge consistently, and as directed. Although many person-centred motivational and behavioural strategies have been developed, for example, action planning, motivational interviewing and empowerment-based communication, the sheer number and apparent lack of clear differences among them have led to considerable confusion. The primary goal of this review, therefore, is to provide a practical framework that organizes and structures these programmes to enhance their more systematic use in clinical care. Its purpose is to enhance clinician efforts to respectfully encourage and support engagement and motivation for behaviour change in people with diabetes. The three-step framework for organizing and describing the specific clinical processes involved is based on self determination theory and includes: clinician preparation for a different type of clinical encounter, clinician/person with diabetes relationship building, and clinician utilization of specific behavioural tools. We conclude with practical considerations for application of this framework to the real world of clinical care. PMID- 28636747 TI - Do different characteristics of two emasculators make a difference in equine castration? AB - BACKGROUND: The Serra and Reimer emasculators are frequently used in equine orchiectomy. They differ in jaw profile and the mechanism by which they achieve haemostasis. OBJECTIVES: To investigate whether the haemostatic capacities of the Reimer and Serra emasculators in open and closed castration differ, to compare the haemostatic capacities of each emasculator in both open and closed castration, and to assess whether the tensile strength of the parietal tunic in closed castration differs according to whether a Reimer or Serra emasculator is used. STUDY DESIGN: Ex vivo randomised study. METHODS: Eighty equine cadaver testes were randomly assigned to two groups for, respectively, open and closed castration. Each group was divided into two subgroups for castration with a Serra or Reimer castrator, respectively. Testicular artery leaking pressure was measured by dye injection. In closed castration, the tensile strength of the parietal tunic was measured with a tensiometer. RESULTS: In open castration, the Reimer emasculator resisted significantly higher pressure (median: 706.1 mmHg; interquartile range [IQR]: 597.6-735.5 mmHg) than the Serra emasculator (median: 349.4 mmHg; IQR: 261.1-468.9 mmHg) (P<0.001), whereas no difference was found in closed castration (Serra emasculator, median: 382.5 mmHg [IQR: 294.2-568.2 mmHg]; Reimer emasculator, median: 419.2 mmHg [IQR: 294.2-616.0 mmHg]). The Reimer emasculator resisted significantly higher pressure in the open (median: 706.1 mmHg; IQR: 597.6-735.5 mmHg) compared with the closed (median: 419.2 mmHg; IQR: 294.2-616.0 mmHg) technique (P = 0.03). Parietal tunic tensile strength did not differ significantly by emasculator (mean +/- s.d.: Serra, 12.65 +/- 7.35; Reimer, 17.55 +/- 11.76). MAIN LIMITATIONS: Limitations are inherent to the ex vivo study design. Post-surgery implications were investigated only in the short term and no account was taken of tissue inflammation and oedema, which may influence the integrity of the tissue. CONCLUSIONS: These results suggest it may be preferable to use a Reimer emasculator in open castration. In this ex vivo model of closed castration, no differences between the emasculators were observed. PMID- 28636746 TI - Evaluation of the Parent-Report Inventory of Callous-Unemotional Traits in a Sample of Children Recruited from Intimate Partner Violence Services: A Multidimensional Rasch Analysis. AB - OBJECTIVE: Our study applied multidimensional item response theory (MIRT) to compare structural models of the parent-report version of the Inventory of Callous and Unemotional Traits (ICU; English and North American Spanish translations). METHOD: A total of 291 maternal caregivers were recruited from community-based domestic violence services and reported on their children (77.9% ethnic minority; 47% female), who ranged in age from 7 to 12 years (mean = 9.07, standard deviation = 1.64). We compared 9 models that were based on prior psychometric evaluations of the ICU. RESULTS: MIRT analyses indicated that a revised 18-item version comprising 2 factors (callous-unemotional and empathic prosocial) was more suitable for our sample. Differential item functioning was found for several items across ethnic and language groups, but not for child gender or age. Evidence of construct validity was found. CONCLUSION: We recommend continued research and revisions to the ICU to better assess the presence of callous-unemotional traits in community samples of school-age children. PMID- 28636748 TI - E-cadherin mediates ultraviolet radiation- and calcium-induced melanin transfer in human skin cells. AB - Skin pigmentation is directed by epidermal melanin units, characterized by long lived and dendritic epidermal melanocytes (MC) that interact with viable keratinocytes (KC) to contribute melanin to the epidermis. Previously, we reported that MC:KC contact is required for melanosome transfer that can be enhanced by filopodi, and by UVR/UVA irradiation, which can upregulate melanosome transfer via Myosin X-mediated control of MC filopodia. Both MC and KC express Ca2+ -dependent E-cadherins. These homophilic adhesion contacts induce transient increases in intra-KC Ca2+ , while ultraviolet radiation (UVR) raises intra-MC Ca2+ via calcium-selective ORAI1 ion channels; both are associated with regulating melanogenesis. However, how Ca2+ triggers melanin transfer remains unclear. Here we evaluated the role of E-cadherin in UVR-mediated melanin transfer in human skin cells. MC and KC in human epidermis variably express filopodia-associated E-cadherin, Cdc42, VASP and beta-catenin, all of which were upregulated by UVR in human MC in vitro. Knockdown of E-cadherin revealed that this cadherin is essential for UVR-induced MC filopodia formation and melanin transfer. Moreover, Ca2+ induced a dose-dependent increase in filopodia formation and melanin transfer, as well as increased beta-catenin, Cdc42, Myosin X and E cadherin expression in these skin cells. Together, these data suggest that filopodial proteins and E-cadherin, which are upregulated by intracellular (UVR stimulated) and extracellular Ca2+ availability, are required for filopodia formation and melanin transfer. This may open new avenues to explore how Ca2+ signalling influences human pigmentation. PMID- 28636749 TI - Annual direct medical costs associated with diabetes-related complications in the event year and in subsequent years in Hong Kong. AB - AIM: To develop models to estimate the direct medical costs associated with diabetes-related complications in the event year and in subsequent years. METHODS: The public direct medical costs associated with 13 diabetes-related complications were estimated among a cohort of 128 353 people with diabetes over 5 years. Private direct medical costs were estimated from a cross-sectional survey among 1825 people with diabetes. We used panel data regression with fixed effects to investigate the impact of each complication on direct medical costs in the event year and subsequent years, adjusting for age and co-existing complications. RESULTS: The expected annual public direct medical cost for the baseline case was US$1,521 (95% CI 1,518 to 1,525) or a 65-year-old person with diabetes without complications. A new lower limb ulcer was associated with the biggest increase, with a multiplier of 9.38 (95% CI 8.49 to 10.37). New end-stage renal disease and stroke increased the annual medical cost by 5.23 (95% CI 4.70 to 5.82) and 5.94 (95% CI 5.79 to 6.10) times, respectively. History of acute myocardial infarction, congestive heart failure, stroke, end-stage renal disease and lower limb ulcer increased the cost by 2-3 times. The expected annual private direct medical cost of the baseline case was US$187 (95% CI 135 to 258) for a 65 year-old man without complications. Heart disease, stroke, sight-threatening diabetic retinopathy and end-stage renal disease increased the private medical costs by 1.5 to 2.5 times. CONCLUSIONS: Wide variations in direct medical cost in event year and subsequent years across different major complications were observed. Input of these data would be essential for economic evaluations of diabetes management programmes. PMID- 28636750 TI - Comparison of serum vaspin levels and vaspin expression in adipose tissue and smooth muscle tissue in pregnant women with and without gestational diabetes. AB - OBJECTIVE: Vaspin is associated with metabolic parameters and insulin resistance. However, the expression of vaspin in visceral adipose tissue (VAT) in pregnant women with gestational diabetes mellitus (GDM) has not been fully explored, and the contribution of vaspin to the biological mechanisms underlying GDM remains unclear. This study aimed to compare circulating vaspin levels and its expression in different insulin target tissues including subcutaneous adipose tissue (SAT), VAT and smooth muscle tissue (SMT) in pregnant women with and without GDM. DESIGN: A total of 37 women with GDM (GDM group) and 37 normal pregnant women (control group) were selected. Fasting plasma glucose (FPG), fasting insulin (FINS) and serum vaspin levels were quantified at term, and homeostasis model of assessment2-insulin resistance (HOMA2-IR) values were calculated. RT-qPCR and Western blotting were used to measure mRNA and protein levels of vaspin in VAT, SAT and SMT of 15 GDM women and normal pregnant women. RESULTS: In the GDM group, serum vaspin concentrations were significantly higher than in the control group. Serum vaspin levels were positively correlated with HOMA2-IR in the GDM group but not in the control group. In the GDM group, vaspin mRNA and protein expression levels in SAT and VAT were both significantly higher than in controls, but no difference was found in SMT. Moreover, relative mRNA but not protein expression levels of vaspin in SAT were highest among the three tissues in both groups. CONCLUSIONS: Circulating vaspin levels and expression of vaspin in SAT and VAT were higher in GDM women than in normal pregnant women. However, the specific role of vaspin from SAT and VAT in the pathogenesis of GDM needs further study. PMID- 28636752 TI - Comparison of effect sizes between enriched and nonenriched trials of analgesics for chronic musculoskeletal pain: a systematic review. AB - AIMS: To investigate the use of an enriched study design on the estimates of treatment effect in analgesic trials for chronic musculoskeletal pain. METHODS: Database searches were conducted from 2004 to 2014. We included randomized placebo-controlled trials evaluating pain medications for chronic musculoskeletal pain. Methodological quality was assessed using the PEDro scale. The estimates of treatment effect on pain and adverse events were compared between enriched and nonenriched designs. Metaregression was used to assess the association between the effect size estimate and the study design controlling for analgesic dose and methodological quality. RESULTS: We included 108 trials, of which 99 were included in the meta-analysis (n = 44 171). There were no overall differences in effect sizes between enriched and nonenriched designs for pain intensity. There was a significant difference for a reduction in any adverse events favouring enriched designs for opioids, but not for other analgesics or the outcome serious adverse events. There was an association between effect size and methodological quality, with failure to blind the outcome assessor and failure to use intention to-treat analysis being associated with larger effect sizes. CONCLUSIONS: There is no evidence that the use of an enriched study design changes the treatment effect size estimate for pain. There is some evidence that clinical trials that employ enriched designs report a reduced risk of adverse events in trials for chronic musculoskeletal pain, but it is unclear whether enriched designs influence estimates of serious adverse events. Features of trial design and study quality were associated with treatment effect estimates. PMID- 28636751 TI - Using experimentation to understand the 10-year snowshoe hare cycle in the boreal forest of North America. AB - Population cycles have long fascinated ecologists from the time of Charles Elton in the 1920s. The discovery of large population fluctuations in undisturbed ecosystems challenged the idea that pristine nature was in a state of balance. The 10-year cycle of snowshoe hares (Lepus americanus Erxleben) across the boreal forests of Canada and Alaska is a classic cycle, recognized by fur traders for more than 300 years. Since the 1930s, ecologists have investigated the mechanisms that might cause these cycles. Proposed causal mechanisms have varied from sunspots to food supplies, parasites, diseases, predation and social behaviour. Both the birth rate and the death rate change dramatically over the cycle. Social behaviour was eliminated as a possible cause because snowshoe hares are not territorial and do not commit infanticide. Since the 1960s, large-scale manipulative experiments have been used to discover the major limiting factors. Food supply and predation quickly became recognized as potential key factors causing the cycle. Experiments adding food and restricting predator access to field populations have been decisive in pinpointing predation as the key mechanism causing these fluctuations. The immediate cause of death of most snowshoe hares is predation by a variety of predators, including the Canada lynx (Lynx canadensis Kerr). The collapse in the reproductive rate is not due to food shortage as was originally thought, but is a result of chronic stress from predator chases. Five major issues remain unresolved. First, what is the nature of the predator-induced memory that results in the prolonged low phase of the cycle? Second, why do hare cycles form a travelling wave, starting in the centre of the boreal forest in Saskatchewan and travelling across western Canada and Alaska? Third, why does the amplitude of the cycle vary greatly from one cycle to the next in the same area? Fourth, do the same mechanisms of population limitation apply to snowshoe hares in eastern North American or in similar ecosystems across Siberia? Finally, what effect will climatic warming have on all the above issues? The answers to these questions remain for future generations of biologists to determine. PMID- 28636753 TI - Stable Bromiranium Ions with Weakly-Coordinating Counterions as Efficient Electrophilic Brominating Agents. AB - Electrophilic halogenating agents are an important class of reagents in chemical synthesis. Herein, we show that sterically demanding bromiranium ions with weakly coordinating counterions are highly reactive electrophilic brominating agents. Despite their high reactivity these reagents are stable, in one case even under ambient conditions and can be applied in electrophilic halogenations of alkenes as well as heteroatoms. PMID- 28636755 TI - Technical Note: Combination of multiple EPID imager layers improves image quality and tracking performance of low contrast-to-noise objects. AB - PURPOSE: We hypothesized that combining multiple amorphous silicon flat panel layers increases photon detection efficiency in an electronic portal imaging device (EPID), improving image quality and tracking accuracy of low-contrast targets during radiotherapy. METHODS: The prototype imager evaluated in this study contained four individually programmable layers each with a copper converter layer, Gd2 O2 S scintillator, and active-matrix flat panel imager (AMFPI). The imager was placed on a Varian TrueBeam linac and a Las Vegas phantom programmed with sinusoidal motion (peak-to-peak amplitude = 20 mm, period = 3.5 s) was imaged at a frame rate of 10 Hz with one to four layers activated. Number of visible circles and CNR of least visible circle (depth = 0.5 mm, diameter = 7 mm) was computed to assess the image quality of single and multiple layers. A previously validated tracking algorithm was employed for auto-tracking. Tracking error was defined as the difference between the programmed and tracked positions of the circle. Pearson correlation coefficient (R) of CNR and tracking errors was computed. RESULTS: Motion-induced blurring significantly reduced circle visibility. During four cycles of phantom motion, the number of visible circles varied from 11-23, 13-24, 15-25, and 16-26 for one-, two-, three-, and four-layer imagers, respectively. Compared with using only a single layer, combining two, three, and four layers increased the median CNR by factors of 1.19, 1.42, and 1.71, respectively and reduced the average tracking error from 3.32 mm to 1.67 mm to 1.47 mm, and 0.74 mm, respectively. Significant correlations (P~10-9 ) were found between the tracking error and CNR. CONCLUSION: Combination of four conventional EPID layers significantly improves the EPID image quality and tracking accuracy for a poorly visible object which is moving with a frequency and amplitude similar to respiratory motion. PMID- 28636754 TI - Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. AB - AIMS: The MARLINA-T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of care in individuals with type 2 diabetes and albuminuria. METHODS: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/mol), estimated glomerular filtration rate (eGFR) >=30 mL/min/1.73 m2 and urinary albumin-to creatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. RESULTS: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% +/- 0.9% (62.2 +/- 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], 0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P < .0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P = .1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. CONCLUSIONS: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics. PMID- 28636756 TI - Chemical Composition and Allelopathic, Antibacterial, Antifungal, and Antiacetylcholinesterase Activity of Fish-mint (Houttuynia cordataThunb.) from India. AB - Fish-mint (Houttuynia cordataThunb.), belonging to family Saururaceae, has long been used as food and traditional herbal medicine. The present study was framed to assess the changes occurring in the essential-oil composition of H. cordata during annual growth and to evaluate allelopathic, antibacterial, antifungal, and antiacetylcholinesterase activities. The essential-oil content ranged from 0.06 - 0.14% and 0.08 - 0.16% in aerial parts and underground stem, respectively. The essential oils were analysed by GC-FID, GC/MS, and NMR (1 H and 13 C). Major constituents of aerial-parts oil was 2-undecanone (19.4 - 56.3%), myrcene (2.6 - 44.3%), ethyl decanoate (0.0 - 10.6%), ethyl dodecanoate (1.1 - 8.6%), 2 tridecanone (0.5 - 8.3%), and decanal (1.1 - 6.9%). However, major constituents of underground-stem oil were 2-undecanone (29.5 - 42.3%), myrcene (14.4 - 20.8%), sabinene (6.0 - 11.1%), 2-tridecanone (1.8 - 10.5%), beta-pinene (5.3 - 10.0%), and ethyl dodecanoate (0.8 - 7.3%). Cluster analysis revealed that essential-oil composition varied substantially due to the plant parts and season of collection. The oils exhibited significant allelopathic (inhibition: 77.8 - 88.8%; LD50 : 2.45 - 3.05 MUl/plate), antibacterial (MIC: 0.52 - 2.08 MUl/ml; MBC: bacteriostatic) and antifungal (MIC: 2.08 - 33.33 MUl/ml; MFC: 4.16 - 33.33 MUl/ml) activities. The results indicate that the essential oil from H. cordata has a significant potential to allow future exploration and exploitation as a natural antimicrobial and allelopathic agent. PMID- 28636757 TI - Babesiosis: An unusual cause of sepsis after kidney transplantation and review of the literature. AB - We report a unique case of babesiosis presenting as sepsis after kidney transplantation. A 70-year-old female kidney transplant recipient presented with fever, hemolytic anemia, and acute kidney injury, and met three of four systemic inflammatory response syndrome criteria. Serology was positive for Babesia microti, confirmed by polymerase chain reaction. The patient was treated with atovaquone and azithromycin and made a full recovery. Reports of babesiosis after solid organ transplantation are rare, with only four prior cases reported in the literature. We report the first case of babesiosis, to our knowledge, presenting as sepsis that was successfully treated after solid organ transplantation. PMID- 28636759 TI - Rosacea and its association with enteral microbiota in Korean females. AB - Rosacea is a chronic inflammatory dermatosis affecting the face and eyes. An association between systemic comorbidities and rosacea has been reported, but the link to enteral microbiota is uncertain. We aimed to investigate the link between rosacea and enteral microbiota. A cross-sectional study was performed in a sample of Korean women who participated in a health check-up programme at the Kangbuk Samsung Hospital Health Screening Center between 23 June 2014 and 5 September 2014. The gut microbiome was evaluated by 16S rRNA gene and metagenome sequence analyses. A total of 12 rosacea patients and 251 controls were enrolled. We identified links between rosacea and several changes in gut microbiota: reduced abundance of Peptococcaceae family unknown genus, Methanobrevibacter (genus), Slackia (genus), Coprobacillus (genus), Citrobacter (genus), and Desulfovibrio (genus), and increased abundance of Acidaminococcus (genus), Megasphaera (genus), and Lactobacillales order unknown family unknown genus. A link between rosacea and enteral microbiota was observed in this metagenomic study. A large and elaborate study is needed to confirm these findings and to elucidate the mechanisms involved. PMID- 28636758 TI - Fetal overnutrition and offspring insulin resistance and beta-cell function: the Exploring Perinatal Outcomes among Children (EPOCH) study. AB - AIMS: To examine the associations of intrauterine exposure to maternal diabetes and obesity with offspring insulin resistance, beta-cell function and oral disposition index in a longitudinal observational study of ethnically diverse offspring. METHODS: A total of 445 offspring who were exposed (n=81) or not exposed (n=364) to maternal diabetes in utero completed two fasting blood measurements at mean (sd) ages of 10.5 (1.5) and 16.5 (1.2) years, respectively, and an oral glucose tolerance test at the second visit. We used linear mixed models and general linear univariate models to evaluate the associations of maternal diabetes and pre-pregnancy BMI with offspring outcomes. RESULTS: Maternal diabetes in utero predicted increased insulin resistance [18% higher updated homeostatic model assessment of insulin resistance (HOMA2-IR), P=0.01; 19% lower Matsuda index, P=0.01 and 9% greater updated homeostatic model assessment of beta-cell function (HOMA2-beta), P=0.04]. Each 5-kg/m2 increase in pre-pregnancy BMI predicted increased insulin resistance (11% greater HOMA2-IR, P<0.001; 10% lower Matsuda index, P<0.001; 6% greater HOMA2-beta, P<0.001). Similar results were obtained in a combined model with both exposures. After adjustment for offspring BMI, only maternal diabetes was associated with higher HOMA2-IR (beta=1.12, P=0.03) and lower Matsuda index (beta=0.83, P=0.01). Neither exposure was associated with early insulin response or oral disposition index. CONCLUSIONS: Intrauterine exposure to diabetes or obesity is associated with greater offspring insulin resistance than non-exposure, supporting the hypothesis that fetal overnutrition results in metabolic abnormalities during childhood and adolescence. PMID- 28636760 TI - Successful management of refractory diabetic gastroparesis with long-term Aprepitant treatment. AB - BACKGROUND: People with gastroparesis who develop treatment-resistant (refractory) disease pose a difficult challenge, especially in the setting of end stage renal disease (ESRD) or post pancreas transplant. Aprepitant (a neurokinin receptor antagonist) is licensed for the short-term treatment of chemotherapy induced nausea. There is lack of information on its long-term efficacy and safety in people with diabetic gastroparesis. CASE REPORT: Case 1 was 73-year-old man with Type 2 diabetes of 25 years' duration and ESRD requiring dialysis. He was referred to our unit as his severe symptoms of gastroparesis had failed to respond to multiple medications and resulted in frequent hospital admissions. Aprepitant, which can be used in ESRD, resulted in significant improvement in his symptoms of nausea and vomiting within weeks, and he remained on this long term (18 months) with continued benefits and had no further gastroparesis-related hospital admissions. Case 2 was a 44-year-old man with Type 1 diabetes of 41 years' duration with a history of severe hypoglycaemic events that required a pancreas transplant. Despite normoglycaemia, his symptoms of gastroparesis persisted and failed to respond to multiple medications and frequent botulinum toxin injections. He was commenced on aprepitant with significant improvement in symptoms and has remained on treatment for 12 months with sustained benefits. CONCLUSION: We describe two cases in which long-term aprepitant treatment proved effective in alleviating severe symptoms of gastroparesis that had failed to respond to conventional first-line medical treatments. Our cases highlight the need for novel treatments for managing refractory diabetic gastroparesis. PMID- 28636761 TI - Molecular Tools for Facilitative Carbohydrate Transporters (Gluts). AB - Facilitative carbohydrate transporters-Gluts-have received wide attention over decades due to their essential role in nutrient uptake and links with various metabolic disorders, including diabetes, obesity, and cancer. Endeavors directed towards understanding the mechanisms of Glut-mediated nutrient uptake have resulted in a multidisciplinary research field spanning protein chemistry, chemical biology, organic synthesis, crystallography, and biomolecular modeling. Gluts became attractive targets for cancer research and medicinal chemistry, leading to the development of new approaches to cancer diagnostics and providing avenues for cancer-targeting therapeutics. In this review, the current state of knowledge of the molecular interactions behind Glut-mediated sugar uptake, Glut targeting probes, therapeutics, and inhibitors are discussed. PMID- 28636762 TI - European diabetes research and its funding, 2002-2013. AB - AIM: This study examined the outputs of research papers in diabetes from 31 European countries between 2002 and 2013, and their funding. METHODS: Diabetes research papers in the Web of Science were identified by means of a filter based on journals and title words. For 2009-2013 papers, the funders were coded to show their sector and nationality. RESULTS: Europe published 40 547 diabetes papers in the 12 years between 2002 and 2013. Denmark, Sweden and Finland published the most relative to their wealth, but the UK published the most absolutely despite an apparently low burden (as measured by disability-adjusted life years). The largest source of funding was government (30%), followed by the non-profit sector (18%) and industry (13%). The European Commission supported 2.7% of papers, but more in Latvia (33%) and Estonia (16%). Based on an estimated cost per paper of ?260 000, the annual research expenditure in Europe was approximately ?986 million in 2013. CONCLUSIONS: The European diabetes burden in disability-adjusted life years increased by one third between 2002 and 2012, but its output of research papers has decreased from 44% to 36% of the world total. This decrease needs to be reviewed in the context of European non-communicable disease research policy. PMID- 28636763 TI - Sensitive volume effects on Monte Carlo calculated ion chamber response in magnetic fields. AB - PURPOSE: The development of magnetic resonance-guided radiation therapy (MRgRT) necessitates accurate Monte Carlo (MC) models of ion chambers for computing ion chamber corrections to compensate for the presence of the magnetic field. This study evaluates the sensitivity of the ion chamber dose response in a magnetic field on the collection volume used in the MC simulation. METHODS: The EGSnrc system's egs_chamber application is used with a recently developed and validated magnetic field transport code. The calculated dose to the sensitive volume of the chamber per unit incident photon fluence, normalized to that at 0 T, is evaluated as a function of magnetic field for the PTW 30013, PTW 31006, PTW 31010, Exradin A12S, and Exradin A1SL chambers. The sensitive region is varied by excluding the volume corresponding to either 0, 0.5, or 1 mm of distance away from the stem. The photon field, magnetic field, and ion chamber are all oriented perpendicular to each other as in the majority of published experimental works. RESULTS: The calculations for a Co-60 source demonstrate that variations from the 0 mm simulations are on the order of several percent with a maximum deviation, occurring at 0.5 T, of 1.75 +/- 0.03% and 3.39 +/- 0.06% for the 0.5 mm or 1 mm simulations, respectively, for a 0.057 cm3 A1SL chamber. Larger volume chambers showed smaller, but still non-negligible, variations. Simulations of the A1SL chamber with a 7 MV photon source, corresponding to the Elekta MR-linac machine, demonstrate that the effect is slightly reduced but still persists with a maximum deviation of 1.97 +/- 0.08% for the 1 mm reduction. CONCLUSIONS: Usually, the geometric sensitive volume of the ion chamber is used in MC calculation as a substitute for the potentially unknown, smaller, true collection volume (governed by the complex electric field distribution inside the chamber). The calculations in this study demonstrate that even a small variation in simulated volume can lead to fairly large variations in the MC calculated ion chamber response in a magnetic field. This is an important effect that must be addressed to ensure proper calibration of MRgRT machines using MC ion chamber correction factors. This effect may play a role, even where there is no magnetic field, in small field dosimetry when volume averaging effect are important. PMID- 28636764 TI - Socio-economic status and risk of gestational diabetes mellitus among Chinese women. AB - AIMS: The relationship between socio-economic status and gestational diabetes mellitus has received little attention. The purpose of this study was to investigate the association between socio-economic status and risk of gestational diabetes. METHODS: Data were obtained from the ongoing Healthy Baby Cohort study in Hubei Province, China, in 2012-2014. Information on educational level and household income was collected using standard questionnaires during face-to-face interviews. Gestational diabetes was defined based on the International Association of Diabetes and Pregnancy Study Group's criteria. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for gestational diabetes in relation to socio-economic status. RESULTS: Among 6886 participants, 1005 (14.6%) pregnant women were diagnosed with gestational diabetes. Higher educational level was inversely associated with risk of gestational diabetes (OR, 0.74; 95% CI, 0.58, 0.95 for high school and OR, 0.62; 95% CI, 0.50, 0.76 for college or above). After adjustment for potential confounders, the ORs for gestational diabetes were 0.77 (95% CI, 0.59, 1.00) and 0.65 (95% CI, 0.51, 0.83) for women with high school and college or above education, respectively, compared with women with less than high school education. No significant association between household income and gestational diabetes was observed after adjustment for potential confounders. Subgroup analysis showed that the reduced risk of gestational diabetes with higher educational level was more evident among women with a pre-pregnancy BMI < 24 kg/m2 (P for interaction = 0.022). CONCLUSIONS: Our findings suggested that educational level was a more robust predictor of gestational diabetes than household income among Chinese women. PMID- 28636765 TI - Kinetic parameters for the reaction of 1,2,4-trioxolanes and artemisinin with iron(II): New evidence for the source of antimalarial activity. AB - The Fenton-like reductive cleavage of antimalarial peroxides like artemisinin by iron(II) species is a chemical reaction whose mechanistic pathway has not been yet fully understood; it is, however, known that there is considerable production of radical species centered at both the oxygen and carbon, which are important to the therapeutical effects of those compounds. This article reports kinetic data for the reaction of artemisinin and two model 1,2,4-trioxolanes with iron(II) species and also a mechanistic interpretation of this reductive cleavage from transition state thermodynamics. The suggestion of the presence of an enhancing specific factor inside the plasmodium is made. PMID- 28636766 TI - Association of TNFSF13 polymorphisms with IgA nephropathy in a Chinese Han population. AB - BACKGROUND: Our previous genome-wide association study of IgA nephropathy (IgAN) in a Chinese Han population suggested that the TNFSF13 gene may be a novel susceptibility gene for IgAN. In the present study, we aimed to further evaluate the associations of single-nucleotide polymorphisms (SNPs) and expression level of the TNFSF13 gene with the risk and clinical parameters of IgAN. METHODS: Six candidate SNPs were selected for genotyping by Sequenom MassARRAY iPLEX in 1000 IgAN cases and 1000 controls. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) with adjustment for age and sex. Serum APRIL (encoded by the TNFSF13 gene) level was detected by an enzyme-linked immunosorbent assay. RESULTS: We found that rs3803800 was significantly associated with the susceptibility of IgAN after Bonferroni correction [padditive = 0.0009, OR (95% CI) = 1.25 (1.09-1.42); precessive = 0.0006, OR (95% CI) = 1.54 (1.20-1.96)]; however, the association remained only in women after further sex-stratified analysis. Genotype-phenotype correlation analysis showed significant associations of rs3803800 with severe clinicopathological manifestations in IgAN patients after adjusting for age and sex, as well as the other two SNPs (rs4246413 and rs4968210) that were also associated with specific clinical phenotypes. Compared with healthy controls, serum APRIL levels were significantly higher in IgAN patients (p = 0.0001) and associated with severity of disease. CONCLUSIONS: The results of the present study indicate that the genetic variations and gene expression level of TNFSF13 are associated with the susceptibility and severity of IgAN in a Han Chinese population. PMID- 28636768 TI - Driving Aggression and Anxiety: Intersections, Assessment, and Interventions. AB - OBJECTIVE: Driving aggression and anxiety are significant contributors to risky driving and motor vehicle crashes (MVCs), which are leading causes of U.S. morbidity and mortality. Even though aggression and anxiety can be conceptualized as related features of the fight-or-flight response, literature on these topics has not been integrated. Driving aggression and anxiety are also transdiagnostic constructs that span multiple psychiatric disorders. Assessment and treatment of these complex problems must be understood to reduce the public health burden of MVCs. METHOD: A comprehensive literature search was conducted using PsycInfo and Google Scholar. RESULTS: Definitions and prevalence of constructs including driving anger, aggressive driving, posttraumatic stress disorder, driving phobia, and transdiagnostic factors are delineated. Psychosocial correlates and assessment instruments are reviewed. Theoretical models that explicate personological, affective, cognitive, and behavioral components are explored. Differential and shared processes underlying driving aggression and anxiety are examined. Interventions are described, with a focus on promising cognitive behavioral methods. CONCLUSION: Driving aggression and anxiety likely share affective and cognitive characteristics such as emotional reactivity and distorted threat appraisals. Further research is needed to support theoretical models linking driving aggression and anxiety, and to validate assessment instruments that capture both constructs. Epidemiologic studies are needed to determine norms, prevalence, and clinical cutpoints. Integration of interventions for these interrelated problems could ultimately reduce risky driving and MVCs. PMID- 28636767 TI - Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion. AB - Members of the tissue kallikrein-related peptidase (KLK) family not only regulate several important physiological functions, but aberrant expression has also been associated with various malignancies. Clinically, KLKs have been suggested as promising biomarkers for diagnosis and prognosis in many types of cancer. As of yet, expression of KLKs and their role in skin cancers are, however, poorly addressed. Malignant melanoma is an aggressive disease associated with poor prognosis. Hence, diagnostic biomarkers to monitor melanoma progression are needed. Herein, we demonstrate that although mRNA of several KLKs are aberrantly expressed in melanoma cell lines, only the KLK7 protein is highly secreted in vitro. In line with these findings, ectopic expression of KLK7 in human melanomas and its absence in benign nevi were demonstrated by immunohistochemistry in vivo. Interestingly, overexpression of KLK7 induced a significant reduction in melanoma cell proliferation and colony formation. Moreover, KLK7 overexpression triggered an increase in cell motility and invasion associated with decreased expression of E-cadherin and an upregulation of MCAM/CD146. Our results demonstrate, for the first time, that aberrant KLK7 expression leads to a switch from proliferative to invasive phenotype, suggesting a potential role of KLK7 in melanoma progression. Thus, we hypothesize that KLK7 may represent a potential biomarker for melanoma progression. PMID- 28636769 TI - Is cannabis treatment for anxiety, mood, and related disorders ready for prime time? AB - Anxiety and related disorders are the most common mental conditions affecting the North American population. Despite their established efficacy, first-line antidepressant treatments are associated with significant side effects, leading many afflicted individuals to seek alternative treatments. Cannabis is commonly viewed as a natural alternative for a variety of medical and mental health conditions. Currently, anxiety ranks among the top five medical symptoms for which North Americans report using medical marijuana. However, upon careful review of the extant treatment literature, the anxiolytic effects of cannabis in clinical populations are surprisingly not well-documented. The effects of cannabis on anxiety and mood symptoms have been examined in healthy populations and in several small studies of synthetic cannabinoid agents but there are currently no studies which have examined the effects of the cannabis plant on anxiety and related disorders. In light of the rapidly shifting landscape regarding the legalization of cannabis for medical and recreational purposes, it is important to highlight the significant disconnect between the scientific literature, public opinion, and related policies. The aim of this article is to provide a comprehensive review of the current cannabis treatment literature, and to identify the potential for cannabis to be used as a therapeutic intervention for anxiety, mood, and related disorders. Searches of five electronic databases were conducted (PubMed, MEDLINE, Web of Science, PsychINFO, and Google Scholar), with the most recent in February 2017. The effects of cannabis on healthy populations and clinical psychiatric samples will be discussed, focusing primarily on anxiety and mood disorders. PMID- 28636771 TI - Is transvaginal contained tissue extraction for everyone? PMID- 28636770 TI - A technology training protocol for meeting QSEN goals: Focusing on meaningful learning. AB - The purpose of this paper is to describe and discuss how we designed and developed a 12-step technology training protocol. The protocol is meant to improve meaningful learning in technology education so that nursing students are able to meet the informatics requirements of Quality and Safety Education in Nursing competencies. When designing and developing the training protocol, we used a simplified experiential learning model that addressed the core features of meaningful learning: to connect new knowledge with students' prior knowledge and real-world workflow. Before training, we identified students' prior knowledge and workflow tasks. During training, students learned by doing, reflected on their prior computer skills and workflow, designed individualized procedures for integration into their workflow, and practiced the self-designed procedures in real-world settings. The trainer was a facilitator who provided a meaningful learning environment, asked the right questions to guide reflective conversation, and offered scaffoldings at critical moments. This training protocol could significantly improve nurses' competencies in using technologies and increase their desire to adopt new technologies. PMID- 28636772 TI - RNA-dependent RNA polymerase: Addressing Zika outbreak by a phylogeny-based drug target study. AB - Since the first major outbreak of Zika virus (ZIKV) in 2007, ZIKV is spreading explosively through South and Central America, and recent reports in highly populated developing countries alarm the possibility of a more catastrophic outbreak. ZIKV infection in pregnant women leads to embryonic microcephaly and Guillain-Barre syndrome in adults. At present, there is limited understanding of the infectious mechanism, and no approved therapy has been reported. Despite the withdrawal of public health emergency, the WHO still considers the ZIKV as a highly significant and long-term public health challenge that the situation has to be addressed rapidly. Non-structural protein 5 is essential for capping and replication of viral RNA and comprises a methyltransferase and RNA-dependent RNA polymerase (RdRp) domain. We used molecular modeling to obtain the structure of ZIKV RdRp, and by molecular docking and phylogeny analysis, we here demonstrate the potential sites for drug screening. Two metal binding sites and an NS3 interacting region in ZIKV RdRp are demonstrated as potential drug screening sites. The docked structures reveal a remarkable degree of conservation at the substrate binding site and the potential drug screening sites. A phylogeny-based approach is provided for an emergency preparedness, where similar class of ligands could target phylogenetically related proteins. PMID- 28636773 TI - Comparison of different insulin pump makes under routine care conditions in adults with Type 1 diabetes. AB - AIMS: To compare long-term HbA1c changes associated with different insulin pumps during routine care in a large cohort of adults with Type 1 diabetes representative of other clinic populations. METHODS: Observational, retrospective study of 508 individuals starting pump therapy between 1999 and 2014 (mean age, 40 years; 55% women; diabetes duration, 20 years; 94% Type 1 diabetes; median follow-up, 3.7 years). Mixed linear models compared covariate-adjusted HbA1c changes associated with different pump makes. RESULTS: The pumps compared were: 50% Medtronic, 24% Omnipod, 14% Roche and 12% Animas. Overall HbA1c levels improved and improvements were maintained during a follow-up extending to 10 years (HbA1c : pre-continuous subcutaneous insulin infusion (pre-CSII) vs. 12 months post CSII, 71 (61, 82) vs. 66 (56, 74) mmol/mol; 8.7 (7.7, 9.6) vs. 8.2 (7.3, 8.9)%; P < 0.0001). The percentage of individuals with HbA1c >= 64 mmol/mol (8.0%) reduced from a pre-CSII level of 68% to 55%. After adjusting for baseline confounders, there were no between-pump differences in HbA1c lowering (P = 0.44), including a comparison of patch pumps with traditional catheter pumps (P = 0.63). There were no significant (P < 0.05) between-pump differences in HbA1c lowering in pre-specified subgroups stratified by pre-pump HbA1c , age or diabetes duration. HbA1c lowering was positively related to baseline HbA1c (P < 0.001) and diabetes duration (P = 0.017), and negatively related to the number of years of CSII use (P = 0.024). CONCLUSIONS: Under routine care conditions, there were no covariate-adjusted differences in HbA1c lowering when comparing different pump makes, including a comparison of patch pumps vs. traditional catheter pumps. Therefore, the choice of CSII make should not be influenced by the desired degree of HbA1c lowering. PMID- 28636774 TI - Reducing the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis. AB - Pancreatitis is the most common and potentially devastating complication of endoscopic retrograde cholangiopancreatography (ERCP), resulting in significant morbidity, occasional mortality, and increased health-care expenditure. Accordingly, the prevention of post-ERCP pancreatitis (PEP) remains a major clinical and research priority. Strategies to reduce the incidence of PEP include thoughtful patient selection, appropriate risk-stratification, sound procedural technique, prophylactic pancreatic stent placement, and pharmacoprevention. Despite advances in all these areas, however, the incidence of PEP remains as high as 15% in high-risk cases. Thus, additional research towards the goal of eliminating PEP is necessary. Herein is an evidence-based review of strategies to prevent pancreatitis after ERCP, focusing on recent important developments in the field. PMID- 28636775 TI - Role of the tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in autoimmune thyroid disease. AB - BACKGROUND: TNF-like weak inducer of apoptosis (TWEAK), its receptor fibroblast growth factor-inducible 14 (Fn14) and its scavenger receptor CD163 (sCD163) have known associations with many autoimmune diseases. However, the role of the TWEAK axis in autoimmune thyroid disease (AITD) remains unclear. Therefore, the aim of this study was to investigate the role of the TWEAK-Fn14 axis in the pathogenesis of AITD. METHODS: Serum levels of soluble TWEAK (sTWEAK) and sCD163 were measured in 38 patients with Graves' disease (GD), 40 patients with Hashimoto's thyroiditis (HT) and 40 healthy controls (HCs). Additionally, the mRNA expression of TWEAK and Fn14 in peripheral blood mononuclear cells (PBMCs) was explored, and the protein expression of TWEAK and Fn14 in thyroid glands surgically removed from 10 patients with GD, 10 patients with HT and 10 HCs was studied by immunohistochemical staining. RESULTS: The results showed that the serum levels of sTWEAK were significantly reduced in patients with HT and inversely correlated with antithyroid peroxidase antibody (TPOAb) levels. Additionally, high levels of sCD163 and a high sCD163/sTWEAK ratio were positively associated with the TPOAb levels in patients with HT and the thyrotropin receptor antibody (TRAb) levels in patients with GD. TWEAK mRNA expression and protein expression were upregulated in thyroid glands and PBMCs from patients with HT. CONCLUSION: Expression of the TWEAK-Fn14 axis was upregulated in patients with AITD and might play a role in the pathogenesis of AITD. PMID- 28636776 TI - Facile Synthesis and Chain-Length Dependence of the Optical and Structural Properties of Diketopyrrolopyrrole-Based Oligomers. AB - Here, we report the synthesis, optical properties, and solid-state packing of monodisperse oligomers of diketopyrrolopyrrole (DPP) up to five repeating units. The optical properties of DPP oligomers in solution and the solid state were investigated by a combination of steady-state and transient spectroscopy. Transient absorption spectroscopy and time-correlated single photon counting (TCSPC) measurements show that the fluorescence lifetime decreases with an increase in the oligomer size from monomer to trimer, thereby reaching saturation for pentameric DPP oligomers. The solid-state packing and crystallinity were probed by using advanced techniques, which included grazing incidence small-angle X-ray scattering (GISAXS) and X-ray diffraction (XRD) to elucidate the structure property trend. Collectively, our chain-length dependent studies establish the fundamental correlation between the structure and property and provide a comprehensive understanding of the solid-state properties in DPP-DPP based conjugated systems. PMID- 28636777 TI - Biological effects related to geomagnetic activity and possible mechanisms. AB - This review presents contemporary data on the biological effects of geomagnetic activity. Correlations between geomagnetic indices and biological parameters and experimental studies that used simulated geomagnetic storms to detect possible responses of organisms to these events in nature are discussed. Possible mechanisms by which geomagnetic activity influences organisms are also considered. Special attention is paid to the idea that geomagnetic activity is perceived by organisms as a disruption of diurnal geomagnetic variation. This variation, in turn, is viewed by way of a secondary zeitgeber for biological circadian rhythms. Additionally, we discuss the utility of cryptochrome as a biological detector of geomagnetic storms. The possible involvement of melatonin and protein coding by the CG8198 gene in the biological effects of geomagnetic activity are discussed. Perspectives for studying mechanisms by which geomagnetic storms affect organisms are suggested. Bioelectromagnetics. 38:497-510, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28636778 TI - Comment on: Dosimetric comparison of stopping-power calibration with dual-energy CT and single-energy CT in proton therapy treatment planning [Med. Phys. 43(6), 2845-2854 (2016)]. PMID- 28636779 TI - Comparative study shows differences in screen exposure, sleep patterns and sleep disturbances between Jewish and Muslim children in Israel. AB - AIM: This study determined the differences in screen exposure, sleep patterns and sleep disturbances, and the associations between these factors, among Jewish and Muslim children in Israel. METHODS: The participants were 1049 school children - 499 Jewish and 550 Muslim - with a mean age of 9.2 +/- 0.7 years, who attended public schools in both urban and rural residential settings in 2014. They all completed the Sleep Self-Report questionnaire and the Screen Exposure Questionnaire. RESULTS: Muslim children reported increased screen time, despite having fewer televisions and computers in their bedroom than Jewish children. Muslim children also reported earlier bedtimes and longer sleep duration, but greater sleep disturbances. Having screens in bedrooms and non-school days were related to later bedtimes and later wake-up times for all children. Children who spent four or more hours watching television or using a computer on school days reported significantly more sleep disturbances than children with lower usage. CONCLUSION: Muslim children with a mean age of nine years reported longer screen exposure, earlier bedtimes and longer sleep duration, but more sleep disturbances, than Jewish children. Cultural sleep practices may contribute to the differences in sleep patterns and sleep disturbances of Jewish and Muslim children in Israel. PMID- 28636780 TI - Nanoelectrical and Nanoelectrochemical Imaging of Pt/p-Si and Pt/p+ -Si Electrodes. AB - The interfacial properties of electrolessly deposited Pt nanoparticles (Pt-NPs) on p-Si and p+ -Si electrodes were investigated on the nanometer scale using a combination of scanning probe methods. Atomic force microscopy (AFM) showed highly dispersed Pt-NPs with diameters of 20-150 nm on the Si surface. Conductive AFM measurements showed that only approximately half of the particles exhibited measurable contact currents, with a factor of 103 difference in current observed between particles at a given bias. Local current-voltage measurements revealed a rectifying junction with a resistance >=10 MOmega at the Pt-NP/p-Si interface, whereas the Pt-NP/p+ -Si samples formed an ohmic junction with a local resistance >=1 MOmega. The particles were strongly attached to the sample surface in air. However, in an electrolyte, the adhesion of the particles to the surface was substantially lower, and most of the particles had tip-contact currents that varied by a factor of approximately 10. Scanning electrochemical microscopy (SECM) showed smaller but more uniform electrochemical currents for the particles relative to the currents observed by conductive AFM. In accord with the conductive AFM measurements, the SECM measurements showed conductance through the substrate for only a minority of the particles. These results suggest that the electrochemical performance of the electrolessly deposited Pt nanoparticles on Si can be ascribed to: 1) The high resistance of the contact between the particles and the substrate, 2) the low (<50 %) fraction of particles that support high currents, and 3) the low adhesion of the particles to the surface when in contact with the electrolyte. PMID- 28636781 TI - Discovery of two bombinin peptides with antimicrobial and anticancer activities from the skin secretion of Oriental fire-bellied toad, Bombina orientalis. AB - Amphibian skin secretions are known to contain numerous peptides with a large array of biological activities. Bombinins are a group of amphibian-derived peptides with broad spectrum antimicrobial activities that have been only identified from the ancient toad species, Bombina. In this study, we described the identification and characterization of a novel bombinin precursor which encoded a bombinin-like peptide (BLP-7) and a novel bombinin H-type peptide (named as Bombinin H-BO) from the skin secretion of Oriental fire-bellied toad, Bombina orientalis. The primary structures of both mature peptides were determined by combinations of molecular cloning of peptide precursor-encoding cDNAs and mass spectrometry techniques. Secondary structure prediction revealed that both peptides had cationic amphipathic alpha-helical structural features. The synthetic replicate of BLP-7 displayed more potent antimicrobial activity than Bombinin H-BO against Gram-positive and Gram-negative bacteria and yeast. Also, in vitro antitumour assay showed that both peptides possessed obvious antiproliferative activity on three human hepatoma cells (Hep G2/SK-HEP-1/Huh7) at the non-toxic doses. These results indicate the peptide family of bombinins could be a potential source of drug candidates for anti-infection and anticancer therapy. PMID- 28636783 TI - Normal neonatal hearing screening did not preclude sensorineural hearing loss in two-year-old very preterm infants. AB - AIM: Very preterm infants are at risk of neonatal hearing loss. However, it is unknown whether infants with a normal neonatal hearing screening result risk sensorineural hearing loss (SNHL) at a later age. METHODS: This cohort study was conducted at the Erasmus Medical University Center Rotterdam, the Netherlands, on 77 very preterm infants born between October 2005 and September 2008. All infants underwent auditory brainstem response audiometry during neonatal hearing screening and at two years of corrected age. The frequency of SNHL in infants with a normal neonatal hearing screening was analysed and the risk factors associated with newly diagnosed SNHL in these infants were examined. RESULTS: We found that 3.9% (3/77) of the very preterm infants showed permanent hearing loss during their neonatal hearing screening. In addition, a relatively high prevalence of newly diagnosed SNHL (4.3%) was found in three of the 70 infants followed up at the age of two. The total prevalence rate of permanent hearing loss in the cohort was approximately 8%. CONCLUSION: A normal outcome of neonatal hearing screening did not guarantee normal hearing at two years of age in this very preterm cohort and paediatricians should be alert to the possibility of late onset SNHL. PMID- 28636782 TI - Changing trends in complications of chronic hepatitis C. AB - BACKGROUND & AIMS: Chronic hepatitis C virus (HCV)-related complications have increased over the past decade. METHODS: We used join-point regression modelling to investigate trends in these complications from 2006 to 2015, and the impact of demographics on these trends. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we identified points at which the trend significantly changed, and estimated the annual percent change (APC) in rates of cirrhosis, decompensated cirrhosis and all-cause mortality, adjusted by race, sex and age. RESULTS: Among 11,167 adults with chronic HCV infection, prevalence of cirrhosis increased from 20.8% to 27.6% from 2006 to 2015, with adjusted annual percentage change (aAPC) of 1.2 (p <. 01). Although incidence of all-cause mortality increased from 1.8% in 2006 to 2.9% in 2015, a join-point was identified at 2010, with aAPCs of 9.6 before (2006 < 2010; p < .01) and -5.2 after (2010 <= 2015; p < .01), indicating a decrease in mortality from 2010 and onward. Likewise, overall prevalence of decompensated cirrhosis increased from 9.3% in 2006 to 10.4% in 2015, but this increase was confined to patients 60 or older (aAPC = 1.5; p = .023). Asian American and Black/African American patients demonstrated significantly higher rates of cirrhosis than White patients, while older patients and men demonstrated higher rates of cirrhosis and mortality. CONCLUSIONS: Although cirrhosis and mortality among HCV-infected patients in the US have increased over the past decade, all-cause mortality has decreased in recent years. PMID- 28636786 TI - The complement system in kidney diseases. PMID- 28636787 TI - A co-drug conjugate of naringenin and lipoic acid mediates neuroprotection in a rat model of oxidative stress. AB - Using our in vitro and in vivo models of oxidative stress, the current study was designed to determine the neuroprotective potential of naringenin, alone or in combination with lipoic acid. In our mixed neuronal culture exposed to hypoxia and subsequent reoxygenation, naringenin was shown to provide significant neuroprotection against cell death at a concentration of 2.5 MUmol/L. Lipoic acid (LA) did not produce neuroprotection at any concentration tested (0.25-100 MUmol/L). In contrast, when naringenin was covalently combined with LA, producing a novel compound named "VANL-100", significant neuroprotection was observed at a concentration as low as 2*10-2 MUmol/L (100-fold more potent). An ELISA for antioxidant capacity demonstrated that naringenin and VANL-100 likely resulted in neuroprotection by increasing the free radical scavenging capacity of the neuronal cells. Pretreatment of rats with the above compounds prior to middle cerebral artery occlusion (MCAO) followed by reperfusion, showed similar results. Naringenin significantly reduced infarct volume at a dose of 10 mg/kg while VANL 100 produced significant neuroprotection at a dose as low as 1*10-4 mg/kg (10 000-fold more potent). This VANL-100-induced neuroprotection persisted even when administered 1 and 3 hours into the reperfusion time course. Taken together, these results suggest that our novel compound, VANL-100 is neuroprotective, likely via a mechanism that involves increasing the antioxidant capacity of neuronal cells. Our results also show that VANL-100 is 100-10 000-fold more potent than the parent compounds, which adds to the growing evidence in support of combination therapy targeting oxidative stress in neurodegenerative diseases. PMID- 28636784 TI - Audio-computer-assisted survey interview and patient navigation to increase chronic viral hepatitis diagnosis and linkage to care in urban health clinics. AB - Intravenous drug use and sexual practices account for 60% of hepatitis C (HCV) and B (HBV) infection. Disclosing these activities can be embarrassing and reduce risk reporting, blood testing and diagnosis. In diagnosed patients, linkage to care remains a challenge. Audio-computer-assisted survey interview (Audio-CASI) was used to guide HCV and HBV infection testing in urban clinics. Risk reporting, blood testing and serology results were compared to historical controls. A patient navigator (PN) followed up blood test results and provided patients with positive serology linkage to care (LTC). Of 1932 patients surveyed, 574 (30%) were at risk for chronic viral hepatitis. A total of 254 (44.3%) patients were tested, 34 (13.5%) had serology warranting treatment evaluation, and 64% required HBV vaccination. Of 16 patients with infection, seven HCV and three HBV patients started treatment following patient LTC. Of 146 HBV-naive patients, 70 completed vaccination. About 75% and 49% of HCV antibody and HBV surface antigen-positive patients were born between 1945 and 1965. Subsequently, automated HCV testing of patients born between 1945 and 1965 was built into our hospital electronic medical records. Average monthly HCV antibody testing increased from 245 (January June) to 1187 (July-October). Patient navigator directed LTC for HCV antibody positive patients was 61.6%. In conclusion, audio-CASI can identify patients at risk for HCV or HBV infection and those in need of HBV vaccination in urban medical clinics. Although blood testing once a patient is identified at risk for infection needs to increase, a PN is useful to provide LTC of newly diagnosed patients. PMID- 28636785 TI - Sperm competition suppresses gene drive among experimentally evolving populations of house mice. AB - Drive genes are genetic elements that manipulate the 50% ratio of Mendelian inheritance in their own favour, allowing them to rapidly propagate through populations. The action of drive genes is often hidden, making detection and identification inherently difficult. Yet drive genes can have profound evolutionary consequences for the populations that harbour them: most known drivers are detrimental to organismal gamete development, reproduction and survival. In this study, we identified the presence of a well-known drive gene called t haplotype post hoc in eight replicate selection lines of house mice that had been evolving under enforced monandry or polyandry for 20 generations. Previous work on these selection lines reported an increase in sperm competitive ability in males evolving under polyandry. Here, we show that this evolutionary response can be partly attributed to gene drive. We demonstrate that drive carrying males are substantially compromised in their sperm competitive ability. As a consequence, we found that t frequencies declined significantly in the polyandrous lines while remaining at stable, high levels in the monandrous lines. For the first time in a vertebrate, we thus provide direct experimental evidence that the mating system of a species can have important repercussions on the spread of drive genes over evolutionary relevant timescales. Moreover, our work highlights how the covert action of drive genes can have major, potentially unintended impact on our study systems. PMID- 28636788 TI - Role of positively charged residues on the polar and non-polar faces of amphipathic alpha-helical antimicrobial peptides on specificity and selectivity for Gram-negative pathogens. AB - We have designed de novo and synthesized eight 26-residue all D-conformation amphipathic alpha-helical cationic antimicrobial peptides (AMPs), four with "specificity determinants" which provide specificity for prokaryotic cells over eukaryotic cells and four AMPs without specificity determinants. The eight AMPs contain six positively charged Lys residues on the polar face in four different arrangements to understand the role of these residues have on antimicrobial activity against 14 Acinetobacter baumannii strains, seven of which were resistant to polymyxin B and colistin; six diverse Pseudomonas aeruginosa strains and 17 Staphylococcus aureus strains, nine of which were methicillin-sensitive, and eight of which were methicillin-resistant. The four AMPs without specificity determinants are extremely hemolytic. In contrast, the four AMPs with specificity determinants had dramatic improvements in therapeutic indices showing the importance of specificity determinants in removing eukaryotic cell toxicity. The specificity determinants combined with the location of positively charged residues on the polar face provide Gram-negative pathogen selectivity between A. baumannii and S. aureus. Specificity determinants maintain excellent antimicrobial activity in the presence of human sera, whereas the AMPs without specificity determinants were inactive. This study clearly shows the potential of amphipathic alpha-helical AMPs with specificity determinants as therapeutics to replace existing antibiotics. PMID- 28636789 TI - Out of the dark: 350 million years of conservatism and evolution in diel activity patterns in vertebrates. AB - Many animals are active only during a particular time (e.g., day vs. night), a partitioning that may have important consequences for species coexistence. An open question is the extent to which this diel activity niche is evolutionarily conserved or labile. Here, we analyze diel activity data across a phylogeny of 1914 tetrapod species. We find strong phylogenetic signal, showing that closely related species tend to share similar activity patterns. Ancestral reconstructions show that nocturnality was the most likely ancestral diel activity pattern for tetrapods and many major clades within it (e.g., amphibians, mammals). Remarkably, nocturnal activity appears to have been maintained continuously in some lineages for ~350 million years. Thus, we show that traits involved in local-scale resource partitioning can be conserved over strikingly deep evolutionary time scales. We also demonstrate a potentially important (but often overlooked) metric of niche conservatism. Finally, we show that diurnal lineages appear to have faster speciation and diversification rates than nocturnal lineages, which may explain why there are presently more diurnal tetrapod species even though diurnality appears to have evolved more recently. Overall, our results may have implications for studies of community ecology, species richness, and the evolution of diet and communication systems. PMID- 28636790 TI - Controlling Reaction Selectivity through the Surface Termination of Perovskite Catalysts. AB - Although perovskites have been widely used in catalysis, tuning of their surface termination to control reaction selectivity has not been well established. In this study, we employed multiple surface-sensitive techniques to characterize the surface termination (one aspect of surface reconstruction) of SrTiO3 (STO) after thermal pretreatment (Sr enrichment) and chemical etching (Ti enrichment). We show, by using the conversion of 2-propanol as a probe reaction, that the surface termination of STO can be controlled to greatly tune catalytic acid/base properties and consequently the reaction selectivity over a wide range, which is not possible with single-metal oxides, either SrO or TiO2 . Density functional theory (DFT) calculations explain well the selectivity tuning and reaction mechanism on STO with different surface termination. Similar catalytic tunability was also observed on BaZrO3 , thus highlighting the generality of the findings of this study. PMID- 28636791 TI - Isotretinoin and lymecycline treatments modify the skin microbiota in acne. AB - Oral retinoids and tetracyclines have a major role in acne treatment. Here, we report for the first time the effect of isotretinoin and lymecycline therapy on the skin microbiota in cheek, back and armpit swab samples of acne vulgaris patients using 16S ribosomal RNA (16S rRNA) gene amplicon sequencing. Propionibacterium acnes was the most common in sebaceous areas of healthy and untreated acne skin and more abundant in back than cheek samples. Five taxa, including a Streptococcus taxon, differed significantly between the cheek samples of healthy controls and acne patients, and acne severity was positively correlated with the abundance of Propionibacterium. Both treatments reduced clinical acne grades and the abundance of Propionibacterium, while the abundance of several other taxa was significantly higher in treated cheek samples compared with untreated ones. Less variation was observed in back samples and none in armpit samples. There were no differences in alpha diversity between control and acne patients in any of the sampled skin areas, but the diversity of the microbiota on the cheek and the back was significantly increased after acne treatments. This study provides insight into the skin microbiota in acne and how it is modulated by systemic acne treatment. PMID- 28636792 TI - MTF and DQE enhancement using an apodized-aperture x-ray detector design. AB - PURPOSE: Acquisition of high-quality x-ray images using low patient exposures requires detectors with high detective quantum efficiency (DQE). We describe a novel apodized-aperture pixel (AAP) design that increases high-frequency modulation transfer function (MTF) and DQE values. The AAP design makes a separation of physical sensor elements from image pixels by using very small sensor elements (e.g., 0.010-0.025 mm) to synthesize desired larger image pixels (e.g., 0.1-0.2 mm). METHODS: A cascaded systems model of signal and noise propagation is developed to describe the benefits of the AAP approach in terms of the MTF, Wiener noise power spectrum (NPS), and DQE. The theoretical model was validated experimentally using a CMOS/CsI detector with 0.05 mm sensor elements to synthesize 0.20 mm image pixels and a clinical Se detector with 0.07 mm sensor elements to synthesize 0.28 mm pixels. A Monte Carlo study and x-ray images of a star-pattern and rat leg are used to visually compare AAP images. RESULTS: When used with a high-resolution converter layer and sensor elements one quarter the size of image pixels, the MTF is increased by 53% and the DQE by a factor of 2.3* at the image sampling cut-off frequency. Both simulated and demonstration images show improved detectability of high-frequency content and removal of aliasing artifacts. Evidence of Gibbs ringing is sometimes seen near high-contrast edges. CONCLUSIONS: It is shown that the AAP approach preserves the MTF of the small sensor elements and attenuates frequencies above the image sampling cut-off frequency. This has the double benefit of improving the MTF while reducing both signal and noise aliasing, resulting in an increase of the DQE at high spatial frequencies. For optimal implementation, the converter layer must have very high spatial resolution and the detector must have low readout noise. PMID- 28636793 TI - Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity. AB - BACKGROUND: A validated tool for the dynamic severity assessment of hidradenitis suppurativa/acne inversa (HS) is lacking. OBJECTIVES: To develop and validate a novel dynamic scoring system to assess the severity of HS. METHODS: A Delphi voting procedure was conducted among the members of the European Hidradenitis Suppurativa Foundation (EHSF) to achieve consensus towards an initial HS Severity Score System (HS4). Strengths and weaknesses of HS4 were examined by a multicentre prospective study. Multivariate logistic regression, discriminant analysis and receiver operating characteristic curves, as well as examination for correlation (Spearman's rho) and agreement (Cohen's kappa) with existing scores, were engaged to recognize the variables for a new International HS4 (IHS4) that was established by a second Delphi round. RESULTS: Consensus HS4 was based on number of skin lesions, number of skin areas involved and Dermatology Life Quality Index (DLQI), and was evaluated by a sample of 236 patients from 11 centres. Subsequently, a multivariate regression model calculated adjusted odds ratios for several clinical signs. Nodules, abscesses and draining tunnels resulted as the scoring variables. Three candidate scores were presented to the second Delphi round. The resulting IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe disease. Cohen's kappa was fair (kappa = 0.32) compared with Hurley classification, and moderate (kappa = 0.49) compared with Expert Opinion. Correlation was good (rho > 0.6) with Hurley classification, Expert Opinion, Physician's Global Assessment and Modified Sartorius score, and moderate for DLQI (rho = 0.36). CONCLUSIONS: The novel IHS4 is a validated tool to dynamically assess HS severity and can be used both in real-life and the clinical trials setting. PMID- 28636794 TI - Differences and similarities between bronchopulmonary dysplasia and asthma in schoolchildren. AB - BACKGROUND: The long-term respiratory characteristics of ex-preterm children with bronchopulmonary dysplasia (BPD) are not established. The objective of this study was to describe hallmarks of BPD at school age in comparison to children with atopic asthma. METHODS: This study was a cross-sectional descriptive comparative study in a hospital-based setting. Thirty schoolchildren diagnosed with BPD (10.4 years/born at 26.6 weeks' gestation) and 30 age- and sex-matched children with asthma and sensitized to airborne allergens (IgE >0.35 kUA /L) were analyzed. Measurements included fraction of exhaled nitric oxide (FENO, ppb), dynamic and static lung function, and bronchial provocation with methacholine (PD:20) and mannitol (PD:15), as well as an evaluation of respiratory symptoms using the asthma control test (C-ACT). RESULTS: Lung function measures (FEV1% 77 vs 84, FEV1/FVC% 85 vs 91, FEF50% 61 vs 80) and carbon monoxide diffusion capacity (DLCO%, 81 vs 88) were all reduced in children with BPD compared to asthma (P values <0.042). FENO values were also significantly lower in children with BPD (12 vs 23, P = 0.019). The proportion of positive methacholine tests (74% vs 93%, P = 0.14) was comparable between BPD and asthma. However, less responsiveness towards mannitol (19% vs 61%, P = 0.007) and fewer self-reported symptoms (C-ACT, median 26 vs 24, P = 0.003) were found in the BPD group. CONCLUSION: Respiratory hallmarks of BPD at school-age were reduced lung function, limited responsiveness towards indirectly acting mannitol but hyper-responsiveness towards direct acting methacholine and impairment in diffusion capacity. Children with BPD displayed less evidence of airway inflammation compared with atopic asthma. PMID- 28636796 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 27/2017. PMID- 28636795 TI - Cancer-related disease factors and smoking cessation treatment: Analysis of an ongoing clinical trial. AB - OBJECTIVE: Smoking cessation treatment should be an important aspect of cancer care. In this study, we evaluated whether cancer-related disease factors adversely influence smoking cessation treatment. METHODS: Smokers with cancer (within 5 years of diagnosis, any tumor site) were recruited for an ongoing trial of varenicline for smoking cessation. Disease factors, assessed at baseline, included tumor site, cancer treatment, time since diagnosis, and health-related quality of life. Medication adherence was defined by 132 of 165 pills taken and counseling adherence was defined by 4 of 4 behavioral counseling sessions attended. Abstinence was bioverified at Week 12. Using logistic regression analysis, we assessed the relationship between disease factors and 12-week medication adherence, counseling adherence, and abstinence. RESULTS: Of 144 participants, 56% were medication adherent, 74% were counseling adherent, and 39% were abstinent. Health-related quality of life predicted medication adherence (OR: 1.08, 95% CI, 1.01-1.16, P = .019, d = 0.20) but not counseling adherence or 12-week abstinence. Tumor site, cancer treatment, and time since diagnosis did not predict any smoking cessation treatment outcomes. CONCLUSIONS: Cancer-related disease factors did not predict cancer survivors' engagement or success in smoking cessation treatment. Findings support National Comprehensive Cancer Network Clinical Practice guidelines that recommend smoking cessation treatment for all smokers with cancer, regardless of time since diagnosis. PMID- 28636797 TI - Synthesis and Structure of N,N-Dinitroamidoborane Complexes. AB - A general approach to the synthesis of borohydride complexes containing one or two dinitroamide fragments has been suggested. Based on a smooth substitution of halide in haloborane or dibromoborane complexes with N,N-dinitroamide salts, this method provides various N,N-dinitroamidoboranes complexes in good yields and in analytically pure form. By means of spectroscopic and computational methods, it was demonstrated that dinitroamidoborane complexes could form as both B,N- and B,O-isomers, which did not interconvert at ambient temperature. PMID- 28636798 TI - A cCPE-based xenon biosensor for magnetic resonance imaging of claudin-expressing cells. AB - The majority of malignant tumors originate from epithelial cells, and many of them are characterized by an overexpression of claudins (Cldns) and their mislocalization out of tight junctions. We utilized the C-terminal claudin binding domain of Clostridium perfringens enterotoxin (cCPE), with its high affinity to specific members of the claudin family, as the targeting unit for a claudin-sensitive cancer biosensor. To overcome the poor sensitivity of conventional relaxivity-based magnetic resonance imaging (MRI) contrast agents, we utilized the superior sensitivity of xenon Hyper-CEST biosensors. We labeled cCPE for both xenon MRI and fluorescence detection. As one readout module, we employed a cryptophane (CrA) monoacid and, as the second, a fluorescein molecule. Both were conjugated separately to a biotin molecule via a polyethyleneglycol chemical spacer and later via avidin linked to GST-cCPE. Nontransfected HEK293 cells and HEK293 cells stably expressing Cldn4-FLAG were incubated with the cCPE based biosensor. Fluorescence-based flow cytometry and xenon MRI demonstrated binding of the biosensor specifically to Cldn4-expressing cells. This study provides proof of concept for the use of cCPE as a carrier for diagnostic contrast agents, a novel approach for potential detection of Cldn3/-4 overexpressing tumors for noninvasive early cancer detection. PMID- 28636799 TI - Transcriptional mechanisms coordinating tight junction assembly during epithelial differentiation. AB - Epithelial tissues form a selective barrier via direct cell-cell interactions to separate and establish concentration gradients between the different compartments of the body. Proper function and formation of this barrier rely on the establishment of distinct intercellular junction complexes. These complexes include tight junctions, adherens junctions, desmosomes, and gap junctions. The tight junction is by far the most diverse junctional complex in the epithelial barrier. Its composition varies greatly across different epithelial tissues to confer various barrier properties. Thus, epithelial cells rely on tightly regulated transcriptional mechanisms to ensure proper formation of the epithelial barrier and to achieve tight junction diversity. Here, we review different transcriptional mechanisms utilized during embryogenesis and disease development to promote tight junction assembly and maintenance of intercellular barrier integrity. We focus particularly on the Grainyhead-like transcription factors and ligand-activated nuclear hormone receptors, two central families of proteins in epithelialization. PMID- 28636800 TI - Molecular dissection of smooth septate junctions: understanding their roles in arthropod physiology. AB - Smooth septate junctions (sSJs) are cell-cell junctions that are thought to regulate the paracellular pathway of the intestine and renal system in arthropods. The detailed mechanism of action of sSJs is not well understood, because their molecular organization has remained elusive for a long time. Recently, two sSJ-specific membrane proteins, Ssk and Mesh, were identified by screening monoclonal antibodies raised against sSJ-containing membrane fractions isolated from the silkworm midgut. Furthermore, a genetic screen in Drosophila based on microscopic observation of sSJ formation identified Tsp2A as a novel sSJ specific membrane protein. Together with Tsp2A, Ssk and Mesh form a protein complex, and all three proteins are required for sSJ formation, as well as intestinal barrier function in Drosophila. Additional studies are likely to elucidate their roles in (1) the formation and reorganization of sSJs, (2) paracellular barrier functions and permselectivity, and (3) short-term and long term regulation of paracellular functions in arthropod epithelia. PMID- 28636801 TI - Water channels and barriers formed by claudins. AB - Physiological studies in leaky epithelia, like kidney proximal tubules and the small intestine, have documented water transport via both transcellular and paracellular pathways. The discovery of aquaporin water channels provided a molecular basis for transcellular water movement. In contrast, the contribution, or even existence, of a specific paracellular water pathway has been disputed for a long time, until the cation channel-forming tight junction protein claudin-2 was shown to also permit the paracellular passage of water through its pore. In proximal kidney tubules, claudin-2-based water transport contributes 23-30% of the total water transport. Other paracellular ion channels (claudin-10a, -10b, and -17) proved to be impermeable to water, although their pore size would be sufficient for water molecules to pass. Studies of barrier-forming claudins, like claudin-1 and claudin-3, which tighten the paracellular pathway against ions and larger solutes, indicate that changes in the expression of these sealing claudins do not influence transepithelial water permeability. The present genetic, molecular, computational, and physiological studies are just now beginning to probe the mechanisms and regulation of paracellular permeation. PMID- 28636802 TI - 2016 impact factor for Acta Physiologica is 4.9. PMID- 28636803 TI - Atorvastatin attenuates testosterone-induced benign prostatic hyperplasia in rats: role of peroxisome proliferator-activated receptor-gamma and cyclo oxygenase-2. AB - Diabetes and obesity have been reported to alter sex steroid hormone metabolism. In this study, an attempt was made to investigate the protective effect of atorvastatin (ATR) in combination with celecoxib (CEL) or pioglitazone (PIO) on testosterone-induced BPH in rats. Male Wistar rats (200-250 g) were randomly divided into nine groups (n = 8) and orally treated as follows for 28 consecutive days: group 1: vehicle control (10 mL/kg); group 2: vehicle testosterone (10 mL/kg); groups 3 - 5: ATR (0.5, 2.5, and 5 mg/kg, respectively); group 6: CEL (20 mg/kg); group 7: PIO (20 mg/kg); and groups 8-9: ATR 0.5 mg/kg, and 15 min later, animals were given CEL (20 mg/kg) or PIO (20 mg/kg), respectively. One hour post treatment, animals in groups 2-9 were given testosterone propionate (3 mg/kg, s.c.). Twenty-four hours after last treatment on day 28, blood was collected for serum testosterone and prostate-specific antigen (PSA) analysis. Prostate was harvested for biochemical and histological assays. Subcutaneous injection of testosterone increased serum levels of testosterone and PSA which was ameliorated by pretreatments of rat with ATR, celecoxib, or pioglitazone. Similarly, testosterone-induced increase in MDA and reduction in the activity of GSH, superoxide dismutase (SOD), and catalase were attenuated by ATR. Conversely, celecoxib or pioglitazone treatment failed to affect the activity of antioxidant enzymes. The histology of the prostate showed significant improvement in prostatic cells of ATR, celecoxib, or pioglitazone treated. Findings from the study showed that atorvastatin attenuated testosterone-induced BPH. Moreover, synergistic effect was observed when atorvastatin was combined with celecoxib. PMID- 28636804 TI - New insights into global biogeography, population structure and natural selection from the genome of the epipelagic copepod Oithona. AB - In the epipelagic ocean, the genus Oithona is considered as one of the most abundant and widespread copepods and plays an important role in the trophic food web. Despite its ecological importance, little is known about Oithona and cyclopoid copepods genomics. Therefore, we sequenced, assembled and annotated the genome of Oithona nana. The comparative genomic analysis integrating available copepod genomes highlighted the expansions of genes related to stress response, cell differentiation and development, including genes coding Lin12-Notch-repeat (LNR) domain proteins. The Oithona biogeography based on 28S sequences and metagenomic reads from the Tara Oceans expedition showed the presence of O. nana mostly in the Mediterranean Sea (MS) and confirmed the amphitropical distribution of Oithona similis. The population genomics analyses of O. nana in the Northern MS, integrating the Tara Oceans metagenomic data and the O. nana genome, led to the identification of genetic structure between populations from the MS basins. Furthermore, 20 loci were found to be under positive selection including four missense and eight synonymous variants, harbouring soft or hard selective sweep patterns. One of the missense variants was localized in the LNR domain of the coding region of a male-specific gene. The variation in the B-allele frequency with respect to the MS circulation pattern showed the presence of genomic clines between O. nana and another undefined Oithona species possibly imported through Atlantic waters. This study provides new approaches and results in zooplankton population genomics through the integration of metagenomic and oceanographic data. PMID- 28636805 TI - A hybrid phantom system for patient skin and organ dosimetry in fluoroscopically guided interventions. AB - PURPOSE: The purpose of this study was to investigate calibrations for improved estimates of skin dose and to develop software for computing absorbed organ doses for fluoroscopically guided interventions (FGIs) with the use of radiation dose structured reports (RDSR) and the UF/NCI family of hybrid computational phantoms. METHODS AND MATERIALS: Institutional review board approval was obtained for this retrospective study in which ten RDSRs were selected for their high cumulative reference air kerma values. Skin doses were computed using the University of Florida's rapid in-clinic peak skin dose algorithm (or UF-RIPSA). Kerma-area product (KAP) meter calibrations and attenuation of the tabletop with pad were incorporated into the UF-RIPSA. To compute absorbed organ doses the RDSRs were coupled with software to develop Monte Carlo input decks for each irradiation event. The effects of spectrum matching were explored by modeling (a) a polychromatic x-ray energy beam made to match measured first half-value layers of aluminum, (b) an unmatched spectrum, (c) and a mono-energetic beam equivalent to the effective x-ray energy. The authors also considered the practicality of computing organ doses for each irradiation event within a RDSR. RESULTS: The KAP meter is highly dependent on the quality of the x-ray spectra. Monte Carlo based attenuation coefficients for configurations in which the beam is transmitted through the tabletop with pad reduced the amount by which the software overestimated skin doses. For absorbed organ dose computations, the average ratios of computed organ doses for a non-fitted to fitted spectrum and effective energy to fitted spectrum were 0.45 and 0.03, respectively. Monte Carlo simulations on average took 38 min per patient. All in-field organ tallies converged with a relative error of less than 1% and out-of-field organs tallies within 10% relative error. CONCLUSIONS: This work details changes to the UF-RIPSA software that include an expanded library of computational phantoms, attenuation coefficients for tabletop with pad, and calibration curves for the KAP meter. For the computation of absorbed organ dose, it is possible to model each irradiation event separately on a patient-dependent model that best morphometrically matches the patient, thus providing a full report of internal organ doses for FGI patients. PMID- 28636806 TI - pH-dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine prodrugs. AB - Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl-based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells. PMID- 28636807 TI - Targeting protein for Xenopus kinesin-like protein 2 knockdown enhances radiation sensitivity of human lung squamous carcinoma cell. AB - The targeting protein for Xenopus kinesin-like protein 2 (TPX2) has been demonstrated to be associated with the tumourigenesis of many cancers. In the present study, we investigated the role and preliminary mechanism of TPX2 in the resistance of lung squamous carcinoma to radiation therapy. The results showed that SK-MES-1R and NCI-H226R cells were more resistant to X-ray irradiation than the parental cells (SK-MES-1 and NCI-H226). Moreover, TPX2 was upregulated in the radioresistant cells compared with the parental cells. TPX2 knockdown significantly decreased TPX2 expression in SK-MES-1 cells, while TPX2 overexpression increased TPX2 expression in NCI-H226 cells compared with the corresponding control cells. TPX2 knockdown enhanced the radiosensitivity of SK MES-1 and promoted cell apoptosis following exposure to irradiation, whereas TPX2 overexpression decreased the radiosensitivity of NCI-H226 and inhibited cell apoptosis. In in vivo studies, the combination of TPX2 knockdown and irradiation significantly inhibited tumour growth, decreased tumour weight, downregulated TPX2 expression in tumour tissue and induced cell apoptosis in nude mice, while TPX2 overexpression exerted an opposite effect. Our results indicated that TPX2 was correlated with cell radioresistance and it might be served as a therapeutic target to enhance cell radiosensitivity in the radiation therapy of lung squamous carcinoma. PMID- 28636808 TI - Diversity and abundance of human-pathogenic fungi associated with pigeon faeces in urban environments. AB - Pathogenic fungi are a growing health concern worldwide, particularly in large, densely populated cities. The dramatic upsurge of pigeon populations in cities has been implicated in the increased incidence of invasive fungal infections. In this study, we used a culture-independent, high-throughput sequencing approach to describe the diversity of clinically relevant fungi (CRF) associated with pigeon faeces and map the relative abundance of CRF across Seoul, Korea. In addition, we tested whether certain geographical, sociological and meteorological factors were significantly associated with the diversity and relative abundance of CRF. Finally, we compared the CRF diversity of fresh and old pigeon faeces to identify the source of the fungi and the role of pigeons in dispersal. Our results demonstrated that both the composition and relative abundance of CRF are unevenly distributed across Seoul. The green area ratio and the number of multiplex houses were positively correlated with species diversity, whereas wind speed and number of households were negatively correlated. The number of workers and green area ratio were positively correlated with the relative abundance of CRF, whereas wind speed was negatively correlated. Because many CRF were absent in fresh faeces, we inferred that most species cannot survive the gastrointestinal tract of pigeons and instead are likely transmitted through soil or air and use pigeon faeces as a substrate for proliferation. PMID- 28636809 TI - Visible-Light-Driven Aza-ortho-quinone Methide Generation for the Synthesis of Indoles in a Multicomponent Reaction. AB - A visible-light-driven radical-mediated strategy for the in situ generation of aza-ortho-quinone methides from 2-vinyl-substituted anilines and alkyl radical precursors is described. This process enables an efficient multicomponent reaction of 2-vinylanilines, halides, and sulfur ylides, and has a wide substrate scope and good functional group tolerance. Treatment of the cycloaddition products with a base leads to densely functionalized indoles in a single-flask operation. PMID- 28636810 TI - The Sox2: GFP+/- knock-in mouse model does not faithfully recapitulate Sox2 expression in skin. AB - Hair follicle heterogeneity may be regulated by distinct dermal papillae (DP) that represent mesenchymal lineages, which can be defined by Sox2 expression. However, it was recently shown that GFP expression in the Sox2: GFP+/- mouse model occurs in the DPs of all hair follicle types, challenging the idea that hair follicle heterogeneity can be defined by DP heterogeneity. Here, we investigated whether the knock-in mouse model faithfully expresses GFP when compared to endogenous Sox2 expression. The results reveal that GFP expression is aberrant in both the infundibulum of hair follicles and in the DPs. Consequently, we provide an explanation for the aberrant expression of the knock-in gene based on the original cloning strategy for the mouse model in the context of a newly identified regulatory element associated within the coding region of Sox2. PMID- 28636811 TI - Performance evaluation of GPU parallelization, space-time adaptive algorithms, and their combination for simulating cardiac electrophysiology. AB - The use of computer models as a tool for the study and understanding of the complex phenomena of cardiac electrophysiology has attained increased importance nowadays. At the same time, the increased complexity of the biophysical processes translates into complex computational and mathematical models. To speed up cardiac simulations and to allow more precise and realistic uses, 2 different techniques have been traditionally exploited: parallel computing and sophisticated numerical methods. In this work, we combine a modern parallel computing technique based on multicore and graphics processing units (GPUs) and a sophisticated numerical method based on a new space-time adaptive algorithm. We evaluate each technique alone and in different combinations: multicore and GPU, multicore and GPU and space adaptivity, multicore and GPU and space adaptivity and time adaptivity. All the techniques and combinations were evaluated under different scenarios: 3D simulations on slabs, 3D simulations on a ventricular mouse mesh, ie, complex geometry, sinus-rhythm, and arrhythmic conditions. Our results suggest that multicore and GPU accelerate the simulations by an approximate factor of 33*, whereas the speedups attained by the space-time adaptive algorithms were approximately 48. Nevertheless, by combining all the techniques, we obtained speedups that ranged between 165 and 498. The tested methods were able to reduce the execution time of a simulation by more than 498* for a complex cellular model in a slab geometry and by 165* in a realistic heart geometry simulating spiral waves. The proposed methods will allow faster and more realistic simulations in a feasible time with no significant loss of accuracy. PMID- 28636812 TI - A Case of Fluoxetine-Induced Lower Extremity Ecchymosis. PMID- 28636813 TI - Clozapine-Induced Procalcitonin Elevation. PMID- 28636814 TI - Arsenic Compromises Both p97 and Proteasome Functions. AB - Exposure to arsenic is a worldwide problem that affects more than 200 million people. The underlying mechanisms of arsenic toxicity have been difficult to ascertain due to arsenic's pleotropic effects. A number of recent investigations have shown that arsenic can compromise protein quality control through the ubiquitin proteasome system (UPS) or the endoplasmic reticulum associated protein degradation (ERAD) pathway. In this article, a link between arsenic and protein quality control is reported. Biochemical and cellular data demonstrate a misregulation of the ATPase cycle of the ATPase associated with various cellular activities (AAA+) chaperone, p97. Interestingly, the loss of p97 activity is due to the increased rate of ATP hydrolysis, which mimics a collection of pathogenic genetic p97 lesions. Cellular studies, using a well characterized reporter of both the proteasome and p97, show the proteasome to also be compromised. This loss of both p97 and proteasome functions can explain the catastrophic protein quality control issues observed in acute, high level arsenic exposures. PMID- 28636815 TI - Accurate Characterization of the Pore Volume in Microporous Crystalline Materials. AB - Pore volume is one of the main properties for the characterization of microporous crystals. It is experimentally measurable, and it can also be obtained from the refined unit cell by a number of computational techniques. In this work, we assess the accuracy and the discrepancies between the different computational methods which are commonly used for this purpose, i.e, geometric, helium, and probe center pore volumes, by studying a database of more than 5000 frameworks. We developed a new technique to fully characterize the internal void of a microporous material and to compute the probe-accessible and -occupiable pore volume. We show that, unlike the other definitions of pore volume, the occupiable pore volume can be directly related to the experimentally measured pore volumes from nitrogen isotherms. PMID- 28636817 TI - Framework for Optimizing Selection of Interspecies Correlation Estimation Models to Address Species Diversity and Toxicity Gaps in an Aquatic Database. AB - The Chemical Aquatic Fate and Effects (CAFE) database is a tool that facilitates assessments of accidental chemical releases into aquatic environments. CAFE contains aquatic toxicity data used in the development of species sensitivity distributions (SSDs) and the estimation of hazard concentrations (HCs). For many chemicals, gaps in species diversity and toxicity data limit the development of SSDs, which may be filled with Interspecies Correlation Estimation (ICE) models. Optimization of ICE model selection and integration ICE-predicted values into CAFE required a multistep process that involved the use of different types of data to assess their influence on SSDs and HC estimates. Results from multiple analyses showed that SSDs supplemented with ICE-predicted values generally produced HC5 estimates that were within a 3-fold difference of estimates from measured SSDs (58%-82% of comparisons), but that were often more conservative (63%-76% of comparisons) and had lower uncertainty (90% of comparisons). ICE SSDs did not substantially underpredict toxicity (<10% of comparisons) when compared to estimates from measured SSD. The incorporation of ICE-predicted values into CAFE allowed the development of >800 new SSDs, increased diversity in SSDs by an average of 34 species, and augmented data for priority chemicals involved in accidental chemical releases. PMID- 28636816 TI - Impacts of the Mitochondrial Genome on the Relationship of Long-Term Ambient Fine Particle Exposure with Blood DNA Methylation Age. AB - The mitochondrial genome has long been implicated in age-related disease, but no studies have examined its role in the relationship of long-term fine particle (PM2.5) exposure and DNA methylation age (DNAm-age)-a novel measure of biological age. In this analysis based on 940 observations between 2000 and 2011 from 552 Normative Aging Study participants, we determined the roles of mitochondrial DNA haplogroup variation and mitochondrial genome abundance in the relationship of PM2.5 with DNAm-age. We used the GEOS-chem transport model to estimate address specific, one-year PM2.5 levels for each participant. DNAm-age and mitochondrial DNA markers were measured from participant blood samples. Nine haplogroups (H, I, J, K, T, U, V, W, and X) were present in the population. In fully adjusted linear mixed-effects models, the association of PM2.5 with DNAm-age (in years) was significantly diminished in carriers of haplogroup V (Pinteraction = 0.01; beta = 0.18, 95%CI: -0.41, 0.78) compared to noncarriers (beta = 1.25, 95%CI: 0.58, 1.93). Mediation analysis estimated that decreases in mitochondrial DNA copy number, a measure of mitochondrial genome abundance, mediated 12% of the association of PM2.5 with DNAm-age. Our data suggests that the mitochondrial genome plays a role in DNAm-age relationships particularly in the context of long term PM2.5 exposure. PMID- 28636818 TI - Critical Temperature of 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine Monolayers and Its Possible Biological Relevance. AB - Because transmembrane proteins (TMPs) can be obtained with sufficient purity for X-ray diffraction studies more frequently than decades ago, their mechanisms of action may now be elucidated. One of the pending issues is the actual interplay between transmembrane proteins and membrane lipids. There is strong evidence of the involvement of specific lipids with some membrane proteins, such as the potassium crystallographically sited activation channel (KcsA) of Streptomyces lividans and the secondary transporter of lactose LacY of Escherichia coli, the activities of which are associated with the presence of anionic phospholipids such as the phosphatidylglycerol (PG) and phosphatidyethanolamine (PE), respectively. Other proteins such as the large conductance mechanosensitive channel (MscL) of E. coli seem to depend on the adaptation of specific phospholipids to the irregular surface of the integral membrane protein. In this work we investigated the lateral compressibility of two homoacid phosphatidylethanolamines (one with both acyl chains unsaturated (DOPE), the other with the acyl chains saturated (DPPE)) and the heteroacid phosphatidyletanolamine (POPE) and their mixtures with POPG. The liquid expanded (LE) to liquid condensed (LC) transition was observed in POPE at a temperature below its critical temperature (Tc = 36 degrees C). Because Tc lies below the physiological temperature, the occurrence of this phase transition may have something to do with the functioning of LacY. This magnitude is discussed within the context of the experiments carried out at temperatures below the Tc of POPE at which the activity of Lac Y and other TMPs are frequently studied. PMID- 28636819 TI - Superelastic Pseudocapacitors from Freestanding MnO2-Decorated Graphene-Coated Carbon Nanotube Aerogels. AB - In recent years, the demand for emerging electronic devices has driven efforts to develop electrochemical capacitors with high power and energy densities that can preserve capacitance under and after recovery from mechanical deformation. We have developed superelastic pseudocapacitors using ~1.5 mm thick graphene-coated single-walled carbon nanotube (SWCNT) aerogels decorated with manganese oxide (MnO2) as freestanding electrodes that retain high volumetric capacitance and electrochemical stability before, under, and after recovery from 50% compression. Graphene-coated SWCNT aerogels are superelastic and fatigue-resistant with high specific surface area and electrical conductivity. Electrodeposition of MnO2 onto these aerogels does not alter their superelasticity, with full shape recovery even after 10 000 compression-release cycles to 50% strain. Total (utilized) gravimetric capacitances of these aerogels before compression are similar to those under and after recovery from 50% compression over a wide range of scan rates with capacitances reaching 98 (468), 106 (522), and 128 F/g (626 F/g) at a scan rate of 2 mV/s, respectively. These gravimetric capacitances are preserved even after 10 000 compression-release cycles to 50% strain. Further, 50% compression of these aerogels increases the volumetric capacitance from 1.5 to 3.3 F/cm3. Before compression, the lifetime performances of these aerogels remain largely stable, with capacitance degrading by only ~14% over the first 2000 charge-discharge cycles and remains constant for further 8000 cycles. Under 50% compression, capacitance displays a similar trend over 10 000 charge-discharge cycles. After recovery from 10 000 compression-release cycles to 50% strain, the aerogels show slightly greater capacitance loss of ~28% over the first 2000 charge-discharge cycles and an additional ~10% loss over the subsequent 8000 charge-discharge cycles. Finally, substantially higher gravimetric capacitance is achieved through greater MnO2 deposition, facilitated by the large porosity of these aerogels, albeit at a loss of capacitance retention upon compression. These capacitors display the feasibility of coating graphene-coated SWCNT aerogels with various pseudocapacitive materials to create superelastic energy-storage devices. PMID- 28636820 TI - Experimental and Theoretical Study of Ionic Pair Dissociation in a Lithium Ion Linear Polyethylenimine-Polyacrylonitrile Blend for Solid Polymer Electrolytes. AB - Herein, we report the preparation and characterization of a novel polymeric blend between linear polyethylene imine (PEI) and polyacrylonitrile (PAN), with the purpose of facilitating the dissociation of lithium perchlorate salt (LiClO4) and thus to enhance Li ion transport. It is a joint theoretical and experimental procedure for evaluating and thus demonstrating the lithium salt dissociation. The procedure implies the correlation between the theoretical pair distribution function (PDF) and conventional X-ray diffraction (XRD) by means of a molecular dynamics (MD) approach. Additionally, we correlated the experimental and theoretical Raman and infrared spectroscopy for vibrational characterization of the lithium salt after dissociation in the polymeric blend. We also performed confocal Raman microscopy analysis to evidence the homogeneity on the distribution of all components and the LiClO4 dissociation in the polymer blend. The electrochemical impedance analysis confirmed that the Li-PAN-PEI blend presents a slightly better lithium conductivity of ~8 * 10-7 S cm-1. These results suggest that this polymer blend material is promising for the development of novel fluorine-free solid polymer lithium ion electrolytes, and the methodology is suitable for characterizing similar polymeric systems. PMID- 28636821 TI - Insight into Electronic and Structural Reorganizations for Defect-Induced VO2 Metal-Insulator Transition. AB - An oxygen vacancy defect in monoclinic VO2 has been shown to modulate the metal insulator transition (MIT) at room temperature. However, as the electronic and structural reorganizations occur simultaneously, the origin of MIT is still unclear. Here we performed first-principles calculations to examine electronic variations separately from structural reorganizations during MIT. It was found that the oxygen defect induces electronic reorganization by creating polarized 3d orbitial electrons, while structure reorganization makes the conduction band edge states available for occupation. The conduction band states thus hold polarized charges that delocalize over space, bestowing metallic property on the originally insulated VO2. A linear relationship for the number of polarized electrons and the defect concentration is revealed, which would lead to cost-effective control of VO2 MIT behavior by defect engineering. PMID- 28636822 TI - Electrochemical Properties and Speciation in Mg(HMDS)2-Based Electrolytes for Magnesium Batteries as a Function of Ethereal Solvent Type and Temperature. AB - Magnesium batteries are a promising alternative to lithium-ion batteries due to the widespread abundance of magnesium and its high specific volumetric energy capacity. Ethereal solvents such as tetrahydrofuran (THF) are commonly used for magnesium-ion electrolytes due to their chemical compatibility with magnesium metal, but the volatile nature of THF is a concern for practical application. Herein, we investigate magnesium bis(hexamethyldisilazide) plus aluminum chloride (Mg(HMDS)2-AlCl3) electrolytes in THF, diglyme, and tetraglyme at varying temperature. We find that, despite the higher thermal stability of the glyme based electrolytes, THF-based electrolytes have better reversibility at room temperature. Deposition/stripping efficiency is found to be a strong function of temperature. Diglyme-based Mg(HMDS)2-AlCl3 electrolytes are found to not exchange as quickly as THF and tetraglyme, stabilizing AlCl2+ and facilitating undesired aluminum deposition. Raman spectroscopy, 27Al NMR, and mass spectrometry are used to identify solution speciation. PMID- 28636823 TI - How Bacteria Respond to Material Stiffness during Attachment: A Role of Escherichia coli Flagellar Motility. AB - Material stiffness has been shown to have potent effects on bacterial attachment and biofilm formation, but the mechanism is still unknown. In this study, response to material stiffness by Escherichia coli during attachment was investigated with biofilm assays and cell tracking using the Automated Contour base Tracking for in Vitro Environments (ACTIVE) computational algorithm. By comparing the movement of E. coli cells attached on poly(dimethylsiloxane) (PDMS) surfaces of different Young's moduli (0.1 and 2.6 MPa, prepared by controlling the degree of cross-linking) using ACTIVE, attached cells on stiff surfaces were found more motile during early stage biofilm formation than those on soft surfaces. To investigate if motility is important to bacterial response to material stiffness, we compared E. coli RP437 and its isogenic mutants of flagellar motor (motB) and synthesis of flagella (fliC) and type I fimbriae (fimA) for attachment on 0.1 and 2.6 MPa PDMS surfaces. The motB mutant exhibited defects in response to PDMS stiffness (based on cell counting and tracking with ACTIVE), which was recovered by complementing the motB gene. Unlike motB results, mutants of fliC and fimA did not show significant defects on both face-up and face-down surfaces. Collectively, these findings suggest that E. coli cells can actively respond to material stiffness during biofilm formation, and motB is involved in this response. PMID- 28636824 TI - Bicanonical ab Initio Molecular Dynamics for Open Systems. AB - Performing ab initio molecular dynamics simulations of open systems, where the chemical potential rather than the number of both nuclei and electrons is fixed, still is a challenge. Here, drawing on bicanonical sampling ideas introduced two decades ago by Swope and Andersen [ J. Chem. Phys. 1995 , 102 , 2851 - 2863 ] to calculate chemical potentials of liquids and solids, an ab initio simulation technique is devised, which introduces a fictitious dynamics of two superimposed but otherwise independent periodic systems including full electronic structure, such that either the chemical potential or the average fractional particle number of a specific chemical species can be kept constant. As proof of concept, we demonstrate that solvation free energies can be computed from these bicanonical ab initio simulations upon directly superimposing pure bulk water and the respective aqueous solution being the two limiting systems. The method is useful in many circumstances, for instance for studying heterogeneous catalytic processes taking place on surfaces where the chemical potential of reactants rather than their number is controlled and opens a pathway toward ab initio simulations at constant electrochemical potential. PMID- 28636826 TI - Degradation Mechanisms of Magnesium Metal Anodes in Electrolytes Based on (CF3SO2)2N- at High Current Densities. AB - The energy density of rechargeable batteries utilizing metals as anodes surpasses that of Li ion batteries, which employ carbon instead. Among possible metals, magnesium represents a potential alternative to the conventional choice, lithium, in terms of storage density, safety, stability, and cost. However, a major obstacle for metal-based batteries is the identification of electrolytes that show reversible deposition/dissolution of the metal anode and support reversible intercalation of ions into a cathode. Traditional Grignard-based Mg electrolytes are excellent with respect to the reversible deposition of Mg, but their limited anodic stability and compatibility with oxide cathodes hinder their applicability in Mg batteries with higher voltage. Non-Grignard electrolytes, which consist of ethereal solutions of magnesium(II) bis(trifluoromethanesulfonyl)imide (Mg(TFSI)2), remain fairly stable near the potential of Mg deposition. The slight reactivity of these electrolytes toward Mg metal can be remedied by the addition of surface-protecting agents, such as MgCl2. Hence, ethereal solutions of Mg(TFSI)2 salt with MgCl2 as an additive have been suggested as a representative non-Grignard Mg electrolyte. In this work, the degradation mechanisms of a Mg metal anode in the TFSI-based electrolyte were studied using a current density of 1 mA cm-2 and an areal capacity of ~0.4 mAh cm-2, which is close to those used in practical applications. The degradation mechanisms identified include the corrosion of Mg metal, which causes the loss of electronic pathways and mechanical integrity, the nonuniform deposition of Mg, and the decomposition of TFSI- anions. This study not only represents an assessment of the behavior of Mg metal anodes at practical current density and areal capacity but also details the outcomes of interfacial passivation, which was detected by simple cyclic voltammetry experiments. This study also points out the absolute absence of any passivation at the electrode-electrolyte interface for the premise of developing electrolytes compatible with a metal anode. PMID- 28636827 TI - Chromosome identification by new molecular markers and genomic in situ hybridization in the Triticum-Secale-Thinopyrum trigeneric hybrids. AB - It is very important to use chromosome-specific markers for identifying alien chromosomes in advanced generations of distant hybridization. The chromosome specific markers of rye and Thinopyrum elongatum, as well as genomic in situ hybridization, were used to identify the alien chromosomes in eight lines that were derived from the crossing between Triticum trititrigia (AABBEE) and triticale (AABBRR). The results showed that four lines contained all rye chromosomes but no Th. elongatum chromosomes. The line RE36-1 contained all of the rye chromosomes except for chromosome 2R. The lines RE33-2 and RE62-1 contained all rye chromosomes and 1E and 5E translocated chromosome, respectively. The line RE24-4 contained 12 rye chromosomes plus a 7E chromosome or 12 rye chromosomes plus one R-E translocated chromosome. Chromosome identification in the above lines was consistent using chromosome-specific markers and genomic in situ hybridization. These chromosome-specific markers provide useful tools for detecting alien chromosomes in trigeneric hybrids, and these lines could be utilized as valuable germplasm in wheat improvement. PMID- 28636825 TI - A New Mixed All-Atom/Coarse-Grained Model: Application to Melittin Aggregation in Aqueous Solution. AB - We introduce a new mixed resolution, all-atom/coarse-grained approach (AACG), for modeling peptides in aqueous solution and apply it to characterizing the aggregation of melittin. All of the atoms in peptidic components are represented, while a single site is used for each water molecule. With the full flexibility of the peptide retained, our AACG method achieves speedups by a factor of 3-4 for CPU time reduction and another factor of roughly 7 for diffusion. An Ewald treatment permits the inclusion of long-range electrostatic interactions. These characteristics fit well with the requirements for studying peptide association and aggregation, where the system sizes and time scales require considerable computational resources with all-atom models. In particular, AACG is well suited for biologics since changes in peptide shape and long-range electrostatics may play an important role. The application of AACG to melittin, a 26-residue peptide with a well-known propensity to aggregate in solution, serves as an initial demonstration of this technology for studying peptide aggregation. We observed the formation of melittin aggregates during our simulations and characterized the time-evolution of aggregate size distribution, buried surface areas, and residue contacts. Key interactions including pi-cation and pi-stacking involving TRP19 were also examined. Our AACG simulations demonstrated a clear salt effect and a moderate temperature effect on aggregation and support the molten globule model of melittin aggregates. As a showcase, this work illustrates the useful role for AACG in investigations of peptide aggregation and its potential to guide formulation and design of biologics. PMID- 28636828 TI - Pharmacokinetic drug evaluation of extended release lorcaserin for the treatment of obesity. AB - INTRODUCTION: Lorcaserin is a serotonin 2C receptor antagonist that was FDA approved in 2012. Lorcaserin is recently available as an extended-release (ER) formulation for the treatment of obesity as an adjunct to lifestyle modification. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy, and safety of lorcaserin ER will be reviewed. Expert opinion: Lorcaserin ER 20mg daily provides drug exposure bioequivalent to lorcaserin immediate release (IR) 10mg twice daily. Lorcaserin IR is associated with 3.3 and 3.0% placebo-subtracted weight loss in patients without and with diabetes, respectively. A1C was reduced by 0.9% in patients with diabetes. Common side effects include headache, dry mouth, constipation, dizziness, fatigue, and nausea. Lorcaserin provides potential advantages over other antiobesity medications in regards to tolerability and simplicity of medication initiation, but may not be as effective as other options. Lorcaserin ER offers improved ease of administration and anticipated adherence compared to the IR formulation. The place in therapy for lorcaserin ER and other antiobesity medications will be further clarified by results of pending clinical trials addressing cardiovascular outcomes as well as the role pharmacogenomics and comorbid disease states may play in choosing patient specific therapy. PMID- 28636829 TI - Analysis of Minimally Invasive Esophagectomy at a Single Veterans Affairs Medical Center. AB - BACKGROUND: To date, there are no published studies focusing on the benefits of minimally invasive esophagectomy (MIE) versus open esophagectomy at a Veterans Affairs Medical Center (VAMC). Our primary outcome was the incidence of esophageal malignancy in the veteran population and the postoperative morbidity following traditional and MIE for malignancy. DESIGN: Retrospective analysis of the incidence of esophageal malignancy at a Veteran Integrated Service Network (VISN) 5 VAMC reported to the VAMC Esophageal Tumor Registry between 2003 and 2016 and outcomes of the veterans who received esophagectomy for malignancy. Patients were followed for 5 years following diagnosis of esophageal malignancy. RESULTS: The Washington DC VAMC Tumor Registry recorded over 130 individuals with a new diagnosis of esophageal cancer between 2003 and 2016; 18 patients underwent an open transhiatal or Ivor Lewis esophagectomy and nine underwent an Ivor Lewis MIE. Surgical candidates had an average stage less than two (T1-3, N0-1, M0) and nonsurgical candidates had an average stage greater than three. Age, body mass index, smoking status, or renal function at time of surgery was similar between the two surgical groups. Patients who underwent an MIE had less blood loss (222 cc versus 822 cc, P < .001), fewer transfusions (11% versus 56%, P = .027), and more nodes harvested (10.33 versus 2.72, P < .001) with no change in leak rate (11% versus 17%, P = .703) or postoperative mortality (0% versus 6%, P = .490) compared to traditional esophagectomy. CONCLUSIONS: This report supports the migration toward MIE for malignancy and reemphasizes that veterans present with advanced disease. PMID- 28636831 TI - Health Insurance Coverage and Health - What the Recent Evidence Tells Us. PMID- 28636830 TI - Attenuation of hepatic steatosis by purple sweet potato colour is associated with blocking Src/ERK/C/EBPbeta signalling in high-fat-diet-treated mice. AB - Our previous work showed that purple sweet potato colour (PSPC), a class of naturally occurring anthocyanins, effectively improved hepatic glucose metabolic dysfunction in high-fat-diet (HFD)-treated mice. This study investigated the effects of PSPC on HFD-induced hepatic steatosis and the signalling events associated with these effects. Mice were divided into 4 groups: control group, HFD group, HFD+PSPC group, and PSPC group. PSPC was administered daily for 20 weeks at oral doses of 700 mg/(kg.day)-1). Our results showed that PSPC significantly improved obesity and related metabolic parameters, as well as liver injury in HFD-treated mice. Moreover, PSPC dramatically attenuated hepatic steatosis in HFD-treated mice. PSPC markedly prevented oxidative stress-mediated Src activation in HFD-treated mouse livers. Furthermore, PSPC feeding remarkably suppressed mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) signalling and consequent CCAAT/enhancer binding protein beta (C/EBPbeta) activation and restored AMPK activation in HFD-treated mouse livers, which was confirmed by U0126 treatment. Ultimately, PSPC feeding dramatically reduced protein expression of FAS and CD36 and the activation of ACC, and increased the protein expression of CPT1A in the livers of HFD-treated mice, indicating decreased lipogenesis and fatty acid uptake and enhanced fatty acid oxidation. In conclusion, PSPC exhibited beneficial effects on hepatic steatosis, which were associated with blocking Src and C/EBPbeta activation. PMID- 28636832 TI - Nutrient Deficiencies Are Common Prior to Bariatric Surgery. AB - Obesity, defined as a body mass index >30 kg/m2, is a growing worldwide epidemic currently effecting 1 in 10 adults, with rates as high as 40% in the United States. The only proven long-term treatment of severe obesity on a population level is surgical modification of the gastrointestinal anatomy to induce weight loss, termed bariatric surgery. With adequate physician guidance and appropriate candidate criteria, bariatric surgery is an option for effective long-term treatment of obesity and its related comorbidities. Complications of bariatric surgery can be seen in patients who are not compliant to the recommended lifestyle and dietary changes required following bariatric surgery, including nausea, vomiting, dumping syndrome, acid reflux, and nutrition deficiencies. Despite caloric density, the diet of patients prior to bariatric surgery is often of poor nutrition quality and does not meet recommended dietary guidelines for micronutrient intake, making this an at-risk population for micronutrient malnutrition. Currently, improvements are needed in standardization of nutrition assessment as well as micronutrient cutoffs for deficiency and insufficiency. In the meantime, utilizing our current tools to conduct nutrition assessment at baseline and implement supplementation where necessary may improve the nutrition status of patients undergoing bariatric surgery, both before and after surgery, which may improve their surgical outcomes. PMID- 28636833 TI - CHIP-ping Away at Atherosclerosis. PMID- 28636835 TI - Use of Bacteriophages to Control Escherichia coli O157:H7 in Domestic Ruminants, Meat Products, and Fruits and Vegetables. AB - Escherichia coli O157:H7 is an important foodborne pathogen that causes severe bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Ruminant manure is a primary source of E. coli O157:H7 contaminating the environment and food sources. Therefore, effective interventions targeted at reducing the prevalence of fecal excretion of E. coli O157:H7 by cattle and sheep and the elimination of E. coli O157:H7 contamination of meat products as well as fruits and vegetables are required. Bacteriophages offer the prospect of sustainable alternative approaches against bacterial pathogens with the flexibility of being applied therapeutically or for biological control purposes. This article reviews the use of phages administered orally or rectally to ruminants and by spraying or immersion of fruits and vegetables as an antimicrobial strategy for controlling E. coli O157:H7. The few reports available demonstrate the potential of phage therapy to reduce E. coli O157:H7 carriage in cattle and sheep, and preparation of commercial phage products was recently launched into commercial markets. However, a better ecological understanding of the phage E. coli O157:H7 will improve antimicrobial effectiveness of phages for elimination of E. coli O157:H7 in vivo. PMID- 28636834 TI - Implementation of Medical Homes in Federally Qualified Health Centers. AB - BACKGROUND: From 2011 through 2014, the Federally Qualified Health Center Advanced Primary Care Practice Demonstration provided care management fees and technical assistance to a nationwide sample of 503 federally qualified health centers to help them achieve the highest (level 3) medical-home recognition by the National Committee for Quality Assurance, a designation that requires the implementation of processes to improve access, continuity, and coordination. METHODS: We examined the achievement of medical-home recognition and used Medicare claims and beneficiary surveys to measure utilization of services, quality of care, patients' experiences, and Medicare expenditures in demonstration sites versus comparison sites. Using difference-in-differences analyses, we compared changes in outcomes in the two groups of sites during a 3 year period. RESULTS: Level 3 medical-home recognition was awarded to 70% of demonstration sites and to 11% of comparison sites. Although the number of visits to federally qualified health centers decreased in the two groups, smaller reductions among demonstration sites than among comparison sites led to a relative increase of 83 visits per 1000 beneficiaries per year at demonstration sites (P<0.001). Similar trends explained the higher performance of demonstration sites with respect to annual eye examinations and nephropathy tests (P<0.001 for both comparisons); there were no significant differences with respect to three other process measures. Demonstration sites had larger increases than comparison sites in emergency department visits (30.3 more per 1000 beneficiaries per year, P<0.001), inpatient admissions (5.7 more per 1000 beneficiaries per year, P=0.02), and Medicare Part B expenditures ($37 more per beneficiary per year, P=0.02). Demonstration-site participation was not associated with relative improvements in most measures of patients' experiences. CONCLUSIONS: Demonstration sites had higher rates of medical-home recognition and smaller decreases in the number of patients' visits to federally qualified health centers than did comparison sites, findings that may reflect better access to primary care relative to comparison sites. Demonstration sites had larger increases in emergency department visits, inpatient admissions, and Medicare Part B expenditures. (Funded by the Centers for Medicare and Medicaid Services.). PMID- 28636836 TI - Antiviral treatment of hepatitis C in renal transplant patients - safety issues. PMID- 28636838 TI - Searching for Affective and Cognitive Restoration: Examining the Restorative Effects of Casual Video Game Play. AB - OBJECTIVE: We investigated the effects of a passive break, relaxation activity, and casual video game on affect, stress, engagement, and cognitive performance. BACKGROUND: Reducing stress and improving cognitive performance is critical across many domains. Previous studies investigated taking a break, relaxation techniques, or playing a game; however, these methods have not been compared within a single experiment. METHOD: Participants completed a baseline affective and cognitive assessment (ACA), which included the Positive and Negative Affect Schedule, shortened version of the Dundee Stress State Questionnaire, and backward digit-span. Next, participants completed a vigilance task, followed by another ACA. Participants were then assigned at random to complete a break or relaxation activity or play a casual video game, followed by a final ACA. RESULTS: Participants who played the casual video game exhibited greater engagement and affective restoration than the relaxation condition. The break condition slightly decreased affect and prevented cognitive restoration. CONCLUSION: Playing a casual video game even briefly can restore individuals' affective abilities, making it a suitable activity to restore mood in response to stress. However, future research is needed to find activities capable of cognitive restoration. APPLICATION: Many activities in life require sustained cognitive demand, which are stressful and decrease performance, especially for workers in performance-critical domains. Our research suggests some leisure activities are better than others for restoring fatigued affective processes. PMID- 28636837 TI - MicroRNA-101-2-5p targets the ApoB gene in the liver of chicken (Gallus Gallus). AB - Apolipoprotein B (ApoB) is a major protein component of plasma lipoproteins. It is involved in many important biological processes such as lipid transportation, enzyme activity regulation, and receptor recognition. Extensive studies have shown that the expression of ApoB is regulated at multiple levels. However, the regulation of ApoB expression by microRNAs (miRNAs) still remains unknown. In the present study, identified are miRNAs that are predicted to interact with ApoB in chicken. The predicted relationship between the identified miRNAs and ApoB was verified through dual luciferase reporter assay in chicken DF1 cells, and the effect of miRNAs on ApoB expression was analyzed in chicken embryo hepatocytes stimulated by 17beta-estradiol. The results show that miR-101-2-5p was predicted to interact with ApoB. Dual luciferase reporter assay together with the miR-101-2 5p mimics study demostrate that ApoB is the target of miR-101-2-5p, which suppresses the expression of ApoB through binding with the 3'UTR of ApoB. Our experiments suggest that miR-101-2-5p might be involved in lipid metabolism through binding to the 3'UTR of ApoB in the liver of egg-laying chickens. PMID- 28636839 TI - Which Came First: The Hot Flash or the Mood? PMID- 28636840 TI - Influence of sex on performance fatigability of the plantar flexors following repeated maximal dynamic shortening contractions. AB - The purpose was to determine sex differences in fatigability during maximal, unconstrained velocity, shortening plantar flexions. The role of time-dependent measures (i.e., rate of torque development, rate of velocity development, and rate of neuromuscular activation) in such sex-related differences was also examined. By task termination, females exhibited smaller reductions in power and similar changes in rate of neuromuscular activation than males, indicating females were less fatigable than males. PMID- 28636841 TI - Commentary on Salvador et al.: Esophageal Penetration of the Magnetic Sphincter Augmentation Device: History Repeats Itself. PMID- 28636842 TI - DNA-binding mode transition of tau in the presence of Zinc ions. PMID- 28636843 TI - Hospital Inpatient Admissions With Dehydration and/or Malnutrition in Medicare Beneficiaries Receiving Enteral Nutrition: A Cohort Study. AB - BACKGROUND: Enteral nutrition (EN) supports many older and disabled Americans. This study describes the frequency and cost of acute care hospitalization with dehydration and/or malnutrition of Medicare beneficiaries receiving EN, focusing on those receiving home EN. METHODS: Medicare 5% Standard Analytic Files were used to determine Medicare spending for EN supplies and the proportion and cost of beneficiaries receiving EN, specifically home EN, admitted to the hospital with dehydration and/or malnutrition. RESULTS: In 2013, Medicare paid $370,549,760 to provide EN supplies for 125,440 beneficiaries, 55% of whom were also eligible for Medicaid. Acute care hospitalization with dehydration and/or malnutrition occurred in 43,180 beneficiaries receiving EN. The most common principal diagnoses were septicemia (21%), aspiration pneumonitis (9%), and pneumonia (5%). In beneficiaries receiving EN at home, >one-third (37%) were admitted with dehydration and/or malnutrition during a mean observation interval of 231 +/- 187 days. Admitted patients were usually hospitalized more than once with dehydration and/or malnutrition (1.73 +/- 1.30 admissions) costing $23,579 +/- 24,966 per admitted patient, totaling >$129,685,622 during a mean observation interval of 276 +/- 187 days. Mortality in the year following enterostomy tube placement was significantly higher for admitted compared with nonadmitted patients (40% vs 33%; P = .05). CONCLUSION: Acute care hospitalizations with dehydration and/or malnutrition in Medicare beneficiaries receiving EN were common and expensive. Additional strategies to reduce these, with particular focus on vulnerable populations such as Medicaid-eligible patients, are needed. PMID- 28636845 TI - Cancer Immunotherapy Trials Not Immune from Imprecise Selection of Patients. PMID- 28636844 TI - Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. AB - BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. METHODS: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. RESULTS: In nested case control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. CONCLUSIONS: The presence of CHIP in peripheral blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.). PMID- 28636846 TI - Post-Traumatic Stress Disorder. PMID- 28636847 TI - Variations in Databases Used to Assess Academic Output and Citation Impact. PMID- 28636848 TI - Extended Treatment of Venous Thromboembolism. PMID- 28636849 TI - Extended Treatment of Venous Thromboembolism. PMID- 28636852 TI - Maternal Immunization. PMID- 28636853 TI - Maternal Immunization. PMID- 28636856 TI - On Incarceration and Health - Reframing the Discussion. PMID- 28636851 TI - First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. AB - BACKGROUND: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. METHODS: We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. RESULTS: Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS: Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .). PMID- 28636857 TI - Plasmodium falciparum Mortality in Africa between 1990 and 2015. PMID- 28636855 TI - Efficacy of Recombinant Influenza Vaccine in Adults 50 Years of Age or Older. AB - BACKGROUND: Improved influenza vaccines are needed to control seasonal epidemics. This trial compared the protective efficacy in older adults of a quadrivalent, recombinant influenza vaccine (RIV4) with a standard-dose, egg-grown, quadrivalent, inactivated influenza vaccine (IIV4) during the A/H3N2-predominant 2014-2015 influenza season, when antigenic mismatch between circulating and vaccine influenza strains resulted in the reduced effectiveness of many licensed vaccines. METHODS: We conducted a randomized, double-blind, multicenter trial of RIV4 (45 MUg of recombinant hemagglutinin [HA] per strain, 180 MUg of protein per dose) versus standard-dose IIV4 (15 MUg of HA per strain, 60 MUg of protein per dose) to compare the relative vaccine efficacy against reverse-transcriptase polymerase-chain-reaction (RT-PCR)-confirmed, protocol-defined, influenza-like illness caused by any influenza strain starting 14 days or more after vaccination in adults who were 50 years of age or older. The diagnosis of influenza infection was confirmed by means of RT-PCR assay and culture of nasopharyngeal swabs obtained from participants with symptoms of an influenza-like illness. The primary end point was RT-PCR-confirmed, protocol defined, influenza-like illness between 14 days or more after vaccination and the end of the influenza season. RESULTS: A total of 9003 participants were enrolled and underwent randomization; 8855 (98.4%) received a trial vaccine and underwent an efficacy follow-up (the modified intention-to-treat population), and 8604 (95.6%) completed the per protocol follow-up (the modified per-protocol population). Among RIV4 recipients, the RT-PCR-confirmed influenza attack rate was 2.2% (96 cases among 4303 participants) in the modified per-protocol population and 2.2% (96 cases among 4427 participants) in the modified intention-to-treat population. Among IIV4 recipients, the attack rate was 3.2% (138 cases among 4301 participants) in the modified per-protocol population and 3.1% (138 cases among 4428 participants) in the modified intention-to-treat population. A total of 181 cases of influenza A/H3N2, 47 cases of influenza B, and 6 cases of nonsubtypeable influenza A were detected. The probability of influenza-like illness was 30% lower with RIV4 than with IIV4 (95% confidence interval, 10 to 47; P=0.006) and satisfied prespecified criteria for the primary noninferiority analysis and an exploratory superiority analysis of RIV4 over IIV4. The safety profiles of the vaccines were similar. CONCLUSIONS: RIV4 provided better protection than standard-dose IIV4 against confirmed influenza-like illness among older adults. (Funded by Protein Sciences; ClinicalTrials.gov number, NCT02285998 .). PMID- 28636859 TI - Case 19-2017 - A 53-Year-Old Woman with Leg Numbness and Weakness. PMID- 28636858 TI - Plasmodium falciparum Mortality in Africa between 1990 and 2015. PMID- 28636860 TI - Risks of MRI in Patients with a Pacemaker or Defibrillator. PMID- 28636861 TI - Timing of Metastasis in Breast Cancer. PMID- 28636862 TI - Perirenal Extramedullary Hematopoiesis. PMID- 28636863 TI - Coronary-Artery Vasospasm. PMID- 28636865 TI - Reducing the burden of sexually transmissible infections in Papua New Guinea requires strengthening of clinical services and engaging men. AB - In this edition of Sexual Health, Vallely et al. report the results of a cross sectional prevalence survey of sexually transmissible infections (STIs) among women attending their first antenatal visit in three provinces of Papua New Guinea (PNG). This Editorial examines potential reasons for these high prevalence estimates and discusses strategies for addressing high STIs rates in PNG. PMID- 28636866 TI - Prevalence and risk factors of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and other sexually transmissible infections among women attending antenatal clinics in three provinces in Papua New Guinea: a cross sectional survey. AB - : Background Papua New Guinea (PNG) is estimated to have among the highest prevalences of HIV and sexually transmissible infections (STIs) of any Asia Pacific country, and one of the highest burdens of maternal syphilis globally. The prevalence of curable STIs, such as Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV), among pregnant women in PNG is relatively unknown. METHODS: A cross-sectional bio-behavioural survey to investigate the epidemiology of CT, NG, TV and other STIs among pregnant women in three provinces of PNG was undertaken. Women aged 18-35 years attending their first antenatal clinic visit were invited to participate. Participants completed a short interview and provided self-collected vaginal specimens for CT, NG and TV laboratory-based nucleic acid amplification tests and a venepuncture specimen for laboratory testing for syphilis and Herpes simplex virus type-2 (HSV-2) serology. Routine antenatal assessment was conducted according to national guidelines, including HIV counselling and testing and point-of-care syphilis screening. RESULTS: A total of 765 women were enrolled. Overall, 43% (95% confidence interval (CI): 39.2-46.4) had one or more of CT, NG or TV infection. CT was the most prevalent STI (22.9%, 175/765; 95% CI: 19.9-25.9), followed by TV (22.4%, 171/765; 95% CI: 19.4-25.4), and NG (14.2%, 109/765; 95% CI: 11.7-16.7). The prevalence of active syphilis was 2.2% (17/765; 95% CI: 1.2-3.3), HSV-2 was 28.0% (214/765; 95% CI: 24.8-31.2) and HIV, 0.8% (6/765; 95% CI: 0.2-1.4). Prevalences were highest among primigravid women, women aged <25 years, and among those in Central Province. CONCLUSION: High prevalences of curable genital STIs were observed among women attending routine antenatal clinic services in PNG. These infections have been associated with adverse pregnancy outcomes and could be important contributors to poor maternal and neonatal health in this setting. PMID- 28636867 TI - Assortative sexual mixing patterns in male-female and male-male partnerships in Melbourne, Australia: implications for HIV and sexually transmissible infection transmission. AB - BACKGROUND: Assortative mixing patterns have become a new and important focus in HIV/sexually transmissible infection (STI) research in recent years. There are very limited data on sexual mixing patterns, particularly in an Australian population. METHODS: Male-female and male-male partnerships attending the Melbourne Sexual Health Centre (MSHC) between 2011 and 2014 were included. Correlation of age between two individuals within a partnership was examined by using Spearman's rank correlation. The Newman's assortativity coefficient was used as an aggregate quantitative measurement of sexual mixing for number of partners and condom use. RESULTS: 1165 male-female and 610 male-male partnerships were included in the analysis. There was a strong positive correlation of age in both male-female (rho=0.709; P<0.001) and male-male partnerships (rho=0.553; P<0.001). The assortative mixing pattern for number of partners was similar in male-female (r=0.255; 95% CI: 0.221-0.289) and male-male partnerships (r=0.264; 95% CI: 0.218-0.309). There was a stronger assortative mixing pattern for condom use in male-male (r=0.517, 95% CI: 0.465-0.569) compared with male-female (r=0.382; 95% CI: 0.353-0.412) partnerships. CONCLUSION: Male-female and male male partnerships have a high assortativity mixing pattern for age, number of partners and condom use. The sexual mixing pattern is not purely assortative, and hence it may lead to increased HIV and STI transmission in certain risk groups. PMID- 28636868 TI - Deadly Liver Mob: opening the door - improving sexual health pathways for Aboriginal people in Western Sydney. AB - BACKGROUND: The Deadly Liver Mob project (DLM) is an incentive-based, peer-driven health promotion intervention for Aboriginal people, focusing on hepatitis C and offering education and screening for sexually transmissible infections (STI) and blood-borne viruses (BBV). This study aims to assess the DLM effect on attendance and STI/BBV screening, describe BBV risk factors and report infection rates among Aboriginal people attending Western Sydney Sexual Health Centre (WSSHC). METHODS: A retrospective review of Aboriginal clients during the first year of the DLM project was compared with Aboriginal clients who attended during the 5.3 years before implementation of the project. Data on attendance, screening rates, demographics, lifestyle information and STI/BBV results were extracted. RESULTS: There was a 10-fold increase in the number of Aboriginal people attending, via the DLM project (P<0.01). The DLM group were more likely to be male (47 vs 28%),>=35 years (46 vs 27%), report injecting drug use (IDU) (43 vs 26%), a history of incarceration (48 vs 24%) or unsafe tattooing (36 vs 16%) and have comprehensive STI/BBV testing (85 vs 54%); (P<0.01 for all). There were 79 positive results and 30 commenced hepatitis B vaccination in the DLM period, compared with 15 and 19, in the non-DLM period. CONCLUSIONS: The DLM project effectively increased sexual healthcare attendance and screening for Aboriginal people in Western Sydney. The DLM has fostered ongoing care and facilitated service engagement for individuals at high risk of contracting STIs and BBVs. PMID- 28636869 TI - Association between sexual mixing and genital warts in heterosexual men in Australia: the herd protection from the female human papillomavirus vaccination program. AB - Australian-born women aged <=32 years were eligible for the free female human papillomavirus (HPV) vaccination program introduced in 2007. A total of 1165 heterosexual couples attending the Melbourne Sexual Health Centre between 2011 and 2014 were included in this analysis. Findings showed the odds of having penile warts was 0.52-fold lower among men who had a female partner aged <=32 years compared with men who had a female partners aged >32 years. This suggests men would have received herd protection from their female partners and hence they are at lower risk of acquiring genital warts. PMID- 28636870 TI - Adherence to, and acceptability of, Listerine(r) mouthwash as a potential preventive intervention for pharyngeal gonorrhoea among men who have sex with men in Australia: a longitudinal study. AB - We investigated whether men who have sex with men (MSM) would use mouthwash daily to prevent pharyngeal gonorrhoea. Ten MSM attending the Melbourne Sexual Health Centre were asked to use a Listerine(r) alcohol-containing mouthwash daily for 14 days in August 2015. Mouthwash was used at least once daily for 133 of 140 person days (95% of days; 95% confidence interval 90-98%). All 10 men were willing to use mouthwash on a daily basis, and nine men were willing to use mouthwash after oral sex. This study showed that daily use of mouthwash is an acceptable intervention to prevent pharyngeal gonorrhoea in MSM. PMID- 28636871 TI - Pregnane glycosides from Cynanchum menarandrense. AB - Five new pregnane-type steroidal glycosides, named menarandrosides A-E (1-2, 5-7) were isolated from the aerial parts of Cynanchum menarandrense, together with three known compounds, carumbelloside I (3), carumbelloside II (4), and pregnenolone-3-O-gentiobioside (8). Their structures were determined on the basis of spectroscopic analyses including NMR and mass spectrometry, reporting C-21 steroids glycosylated only by one or two glucose moieties. Compounds were then investigated for their potential to stimulate glucagon-like peptide-1 (GLP-1) secretion in intestinal cells; although none of the pure compounds had any influence, the fraction enriched in pregnanes exhibited a significant activity, suggesting a possible synergistic effect. Furthermore, none of the purified compounds affected cell viability. PMID- 28636872 TI - Long-term postnatal steroid effect in very low birth weight infants. AB - We examined whether hydrocortisone exposure<=1week in very low birth weight infants (VLBWI) was associated with poor neurodevelopmental outcomes at corrected 18months. Further, the clinical factors associated with worse long term outcome were also evaluated. Of a total of 191 VLBWI, the clinical data for these infants relating were retrospectively collected for analysis. Among the 191 VLBWI, 115 (60.2%) infants were exposed to early postnatal hydrocortisone<=1week of life in our NICU of Seoul St. Mary's Hospital, The Catholic University of Korea between December 2012 and December 2014. The morbidities were significantly higher in the group with early hydrocortisone exposure group. At corrected age of 18months, 109/183 (59.6%) infants in the early hydrocortisone exposure group had significantly lower scores in all three (cognitive, language and motor) composites of Bayley Scales of Infant and Toddler Development III. The multivariable logistic regression analysis showed that only periventricular leukomalacia (PVL) is consistently associated with poor long-term outcomes. Our results suggest that early hydrocortisone exposure<=1week in VLBWI may not increase the risk for poor long-term outcomes compared to those not exposed. Only PVL is considered as a risk factor for poor long-term neurodevelopmental outcomes. PMID- 28636873 TI - Mimicking natural phytohormones. 26-Hydroxycholestan-22-one derivatives as plant growth promoters. AB - 26-Hydroxycholestan-22-one derivatives with oxygenated functions in the rings A and/or B were successfully synthesized from diosgenin. After the modifications of rings A and B, the spiroketal side chain was selectively opened through a Lewis acid mediated acetolysis to afford the cholestane derivatives. These compounds incorporate pharmacophores, which mimic the activity of natural phytohormones and show high growth promoting activity in Mexican rice cultivars using the rice lamina inclination test. PMID- 28636874 TI - Next generation matrix metalloproteinase inhibitors - Novel strategies bring new prospects. AB - Enzymatic proteolysis of cell surface proteins and extracellular matrix (ECM) is critical for tissue homeostasis and cell signaling. These proteolytic activities are mediated predominantly by a family of proteases termed matrix metalloproteinases (MMPs). The growing evidence in recent years that ECM and non ECM bioactive molecules (e.g., growth factors, cytokines, chemokines, on top of matrikines and matricryptins) have versatile functions redefines our view on the roles matrix remodeling enzymes play in many physiological and pathological processes, and underscores the notion that ECM proteolytic reaction mechanisms represent master switches in the regulation of critical biological processes and govern cell behavior. Accordingly, MMPs are not only responsible for direct degradation of ECM molecules but are also key modulators of cardinal bioactive factors. Many attempts were made to manipulate ECM degradation by targeting MMPs using small peptidic and organic inhibitors. However, due to the high structural homology shared by these enzymes, the majority of the developed compounds are broad-spectrum inhibitors affecting the proteolytic activity of various MMPs and other zinc-related proteases. These inhibitors, in many cases, failed as therapeutic agents, mainly due to the bilateral role of MMPs in pathological conditions such as cancer, in which MMPs have both pro- and anti-tumorigenic effects. Despite the important role of MMPs in many human diseases, none of the broad-range synthetic MMP inhibitors that were designed have successfully passed clinical trials. It appears that, designing highly selective MMP inhibitors that are also effective in vivo, is not trivial. The challenges related to designing selective and effective metalloprotease inhibitors, are associated in part with the aforesaid high structural homology and the dynamic nature of their protein scaffolds. Great progress was achieved in the last decade in understanding the biochemistry and biology of MMPs activity. This knowledge, combined with lessons from the past has drawn new "boundaries" for the development of the next generation MMP inhibitors. These novel agents are currently designed to be highly specific, capable to discriminate between the homologous MMPs and ideally administered as a short-term topical treatment. In this review we discuss the latest progress in the fields of MMP inhibitors in terms of structure, function and their specific activity. The development of novel highly specific inhibitors targeting MMPs paves the path to study complex biological processes associated with ECM proteolysis in health and disease. This article is part of a Special Issue entitled: Matrix Metalloproteinases edited by Rafael Fridman. PMID- 28636875 TI - Effects of prenatal binge-like ethanol exposure and maternal stress on postnatal morphological development of hippocampal neurons in rats. AB - BACKGROUND: Alcohol is one of the most commonly used drugs of abuse negatively affecting human health and it is known as a potent teratogen responsible for fetal alcohol syndrome (FAS), which is characterized by cognitive deficits especially pronounced in juveniles but ameliorating in adults. Searching for the potential morphological correlates of these effects, in this study, we compared the course of developmental changes in the morphology of principal hippocampal neurons in fetal-alcohol (A group), intubated control (IC group), and intact control male rats (C group) over a protracted period of the first two postnatal months. METHODS: Ethanol was administered to the pregnant Wistar dams intragastrically, throughout gestation days (GD) 7-20, at a total dose of 6g/kg/day resulting in the mean blood alcohol concentration (BAC) of 246.6+/ 40.9mg/dl. Ten morphometric parameters of Golgi-stained hippocampal neurons (pyramidal and granule) from CA1, CA3, and DG areas were examined at critical postnatal days (PD): at birth (PD1), at the end of the brain growth spurt period (PD10), in juveniles (PD30), and in young adults (PD60). RESULTS: During postnatal development, the temporal pattern of morphometric changes was shown to be region-dependent with most significant alterations observed between PD1-30 in the CA region and between PD10-30 in the DG region. It was also parameter dependent with the soma size (except for CA3 pyramids), number of primary dendrites, dendrite diameter, dendritic tortuosity and the branch angle demonstrating little changes, while the total dendritic field area, dendritic length, number of dendritic bifurcations, and spine density being highly increased in all hippocampal regions during the first postnatal month. Moderate ethanol intoxication and the maternal intubation stress during gestation, showed similar, transient effects on the neuron development manifested as a smaller soma size in granule cells, reduced dendritic parameters and lower spine density in pyramidal neurons at PD1. Full recovery from these effects took place within the first 10 postnatal days. CONCLUSIONS: This study showed regional and temporal differences in the development of different morphometric features of principal hippocampal neurons in intact subjects over a protracted 2-months postnatal period. It also demonstrated an overlap in the effects of a moderate fetal ethanol intoxication and a mild maternal stress produced by the intragastric intubation, a commonly used method of ethanol administration to the pregnant dams. Fast recovery from the adverse effects on the soma size, dendritic arborization and spines density observed at birth indicates towards the fetal ethanol/stress induced developmental retardation. PMID- 28636876 TI - Tissue alignment enhances remodeling potential of tendon-derived cells - Lessons from a novel microtissue model of tendon scarring. AB - Tendinopathy is a widespread and unresolved clinical challenge, in which associated pain and hampered mobility present a major cause for work-related disability. Tendinopathy associates with a change from a healthy tissue with aligned extracellular matrix (ECM) and highly polarized cells that are connected head-to-tail, towards a diseased tissue with a disorganized ECM and randomly distributed cells, scar-like features that are commonly attributed to poor innate regenerative capacity of the tissue. A fundamental clinical dilemma with this scarring process is whether treatment strategies should focus on healing the affected (disorganized) tissue or strengthen the remaining healthy (anisotropic) tissue. The question was thus asked whether the intrinsic remodeling capacity of tendon-derived cells depends on the organization of the 3D extracellular matrix (isotropic vs anisotropic). Progress in this field is hampered by the lack of suitable in vitro tissue platforms. We aimed at filling this critical gap by creating and exploiting a next generation tissue platform that mimics aspects of the tendon scarring process; cellular response to a gradient in tissue organization from isotropic (scarred/non-aligned) to highly anisotropic (unscarred/aligned) was studied, as was a transient change from isotropic towards highly anisotropic. Strikingly, cells residing in an 'unscarred' anisotropic tissue indicated superior remodeling capacity (increased gene expression levels of collagen, matrix metalloproteinases MMPs, tissue inhibitors of MMPs), when compared to their 'scarred' isotropic counterparts. A numerical model then supported the hypothesis that cellular remodeling capacity may correlate to cellular alignment strength. This in turn may have improved cellular communication, and could thus relate to the more pronounced connexin43 gap junctions observed in anisotropic tissues. In conclusion, increased tissue anisotropy was observed to enhance the cellular potential for functional remodeling of the matrix. This may explain the poor regenerative capacity of tenocytes in chronic tendinopathy, where the pathological process has resulted in ECM disorganization. Additionally, it lends support to treatment strategies that focus on strengthening the remaining healthy tissue, rather than regenerating scarred tissue. PMID- 28636877 TI - Lectin CGL from the sea mussel Crenomytilus grayanus induces Burkitt's lymphoma cells death via interaction with surface glycan. AB - Marine organisms are rich sources of lectins. Lectins are able to bind specifically and reversibly to different types of carbohydrates or glycoproteins. The present study reports the evaluation of glycan binding profile and anti-tumor potential of lectin CGL from the sea mussel Crenomytilus grayanus. Glycan array assay revealed that CGL was able to bind both alpha and beta anomer of galactose, but interaction with the alphaGal-terminated glycans was stronger. Analysis of most common glycan motifs for CGL showed high affinity to Galalpha1-4Galbeta1 4GlcNAc motif similar to globotriose structure (Gb3: Galalpha1-4Galbeta1-4Glc), the epitope of globotriaosylceramide. CGL recognized Gb3 on the surface of Burkitt's lymphoma Raji cells (high Gb3 expression), leading to dose-dependent cytotoxic effect, G2/M phase cell cycle arrest and apoptosis. Lectin had no effect on erythroleukemia K562 cells (no Gb3 expression). The activity of CGL was specifically blocked by alpha-galactoside. Our findings suggest the use of CGL in cancer diagnosis and treatment. PMID- 28636878 TI - Lycium barbarum polysaccharide alleviates nonylphenol exposure induced testicular injury in juvenile zebrafish. AB - Nonylphenol is an endocrine disrupting chemicals that can disrupt the organisms' reproductive system, and exists widely in rivers and lakes. Lycium barbarum polysaccharide (LBP) is the main active constituent (about 10%) in Lycium barbarum, which is used to protect reproductive health. In this study, we investigated whether LBP can alleviate nonylphenol exposure induced testicular injury in juvenile zebrafish. We detected histological alteration, anti-oxidant enzyme profile and P450 gene transcription to assess LBP effect on testicular development. The GSI reduced significantly due to nonylphenol exposure, while LBP can improve the GSI. The densities of sperms increased and non-celluar zone decreased after LBP treatment. Meanwhile, Cyp11b gene was up regulated to NP group, and cyp19a gene was down regulated to NP group. In sum, the LBP could repair the testicular injury in zebrafish. This findings provide a basis research to remit the estrogen effect of artificial endocrine disruptor. PMID- 28636854 TI - Cluster-Randomized, Crossover Trial of Head Positioning in Acute Stroke. AB - BACKGROUND: The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion. METHODS: In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death). RESULTS: The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P<0.001). In a proportional-odds model, there was no significant shift in the distribution of 90 day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P=0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P=0.83). There were no significant between-group differences in the rates of serious adverse events, including pneumonia. CONCLUSIONS: Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours. (Funded by the National Health and Medical Research Council of Australia; HeadPoST ClinicalTrials.gov number, NCT02162017 .). PMID- 28636879 TI - Delineating neuroinflammation, parasite CNS invasion, and blood-brain barrier dysfunction in an experimental murine model of human African trypanosomiasis. AB - Although Trypanosoma brucei spp. was first detected by Aldo Castellani in CSF samples taken from sleeping sickness patients over a century ago there is still a great deal of debate surrounding the timing, route and effects of transmigration of the parasite from the blood to the CNS. In this investigation, we have applied contrast-enhance magnetic resonance imaging (MRI) to study the effects of trypanosome infection on the blood-brain barrier (BBB) in the well-established GVR35 mouse model of sleeping sickness. In addition, we have measured the trypanosome load present in the brain using quantitative Taqman PCR and assessed the severity of the neuroinflammatory reaction at specific time points over the course of the infection. Contrast enhanced-MRI detected a significant degree of BBB impairment in mice at 14days following trypanosome infection, which increased in a step-wise fashion as the disease progressed. Parasite DNA was present in the brain tissue on day 7 after infection. This increased significantly in quantity by day 14 post-infection and continued to rise as the infection advanced. A progressive increase in neuroinflammation was detected following trypanosome infection, reaching a significant level of severity on day 14 post-infection and rising further at later time-points. In this model stage-2 disease presents at 21days post-infection. The combination of the three methodologies indicates that changes in the CNS become apparent prior to the onset of established stage-2 disease. This could in part account for the difficulties associated with defining specific criteria to distinguish stage-1 and stage-2 infections and highlights the need for improved staging diagnostics. PMID- 28636880 TI - Behavioral evidence of oxidative stress by hematophagy in the ocellar system of Rhodnius prolixus Stal, 1859 red-eyed mutants. AB - The photonegative response to light stimulation in Rhodnius prolixus (Reduviidae, Triatominae) is modulated by compound eyes and ocelli. Screening pigments in the visual system have been shown to protect the cellular structures from the oxidative stress damage produced by blood ingestion and light stimulation. Red eyed mutants of Rhodnius prolixus lack screening pigments in their compound eyes and ocelli and are exposed to more oxidative stress. Experiments with Rhodnius prolixus and Triatoma infestans red-eyed mutants reared from the first nymphal stage show damage in the retinas of the compound eyes and a decrease in photonegative responses due to light stimulation. Because ocelli are only present during the imaginal stages, we designed a group of experiments to assess the possible damage to the ocelli by oxidative stress mediated by blood ingestion in Rhodnius prolixus red-eyed mutants and wild-type insects. To test our hypothesis, we carried out behavioral experiments to evaluate the photonegative responses in adults exposed to different treatments, including coverage of either the compound eyes or ocelli, and different blood feeding regimens. Our results show that the ocelli in Rhodnius prolixus adults can modulate photonegative responses in red eyed mutants better than the compound eyes can. In addition, a decrease in photonegative responses was evident when the red-eyed mutants were fed blood continuously for four weeks. Our results confirm that ocelli in Rhodnius prolixus can be considered a parallel pathway that intersects with information from the compound eyes regarding light stimulation and that their screening pigments play important roles in preventing the damage caused by oxidative stress due to blood ingestion. PMID- 28636881 TI - Mitochondrial genome of Helice tientsinensis (Brachyura: Grapsoidea: Varunidae): Gene rearrangements and higher-level phylogeny of the Brachyura. AB - The mitochondrial genome (mt genome) provides important information for understanding molecular evolution and phylogeny. The further understand the molecular evolution and phylogeny of Helice tientsinensis, the complete mt genome was determined. It is 16,212bp long and includes 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes and a control region. The genome composition of H. tientsinensis was highly A+T biased 69.0% and showed negative AT skew (-0.017) and GC skew (-0.289). One PCG, all rRNAs and 12 of the tRNAs appeared to be rearranged with respect to the pancrustacean ground pattern gene order. Tandem duplication, followed by random deletion, is widely considered to explain translocation of mitochondrial genes. Consecutive recombinations events could explain inversions of genes. The phylogenetic analyses showed that H. tientsinensis has close relationships with Eriocheir japonica sinensis, E. j. hepuensis and E. j. japonica; this indicated that H. tientsinensis belongs in the Grapsoidea, part of the Varunidae family. This study provides evidence for a better understanding of gene rearrangements, as well as the evolutionary status of H. tientsinensis and related species. PMID- 28636882 TI - FOXN1 Italian founder mutation in Indian family: Implications in prenatal diagnosis. AB - The Forkhead box N1 (FOXN1) is a transcriptional factor regulating the development, differentiation and function of thymic epithelial cells; maintaining T-lineage progenitors in bone marrow; promoting terminal differentiation of epithelial cells of hair follicles. Mutation in FOXN1 was reported to cause a rare disorder characterized by rudimentary thymus gland, T-cell immunodeficiency, congenital alopecia and nail dystrophy within an Italian community. This is the first report of FOXN1 p.R255X mutation from India, outside this endogamous Italian community. Out of the two affected children, only one was alive during the genetic evaluation and had all the clinical manifestations such as alopecia totalis and nail dystrophy. The proband was homozygous for FOXN1 p.R255X Italian founder mutation. The carrier status of both the parents was established. Immunological study of the proband revealed total absence of T-cells confirming T cell immunodeficiency. Prenatal diagnosis during third pregnancy revealed absence of FOXN1 mutation. To conclude, this is the first report of FOXN1 mutation from India highlighting that diseases once confined to certain geographical areas are spreading across the globe probably due to human migrations. PMID- 28636883 TI - The effects of monocular training on binocular functions in anisometropic amblyopia. AB - Intensive monocular perceptual learning can improve visual acuity, contrast sensitivity, and vernier acuity in the amblyopic eye in adults with amblyopia. It is however not clear how much monocular training can enhance binocular visual functions. In the current study, we aimed to evaluate effects of monocular training on a variety of binocular functions. Nineteen anisometropic amblyopes (18.5+/-1.26yrs, mean+/-s.e.) were trained in a grating contrast detection task near each individual's cutoff spatial frequency for 6-10days (630 trials/day). Visual acuity, stereoacuity, monocular and binocular contrast sensitivity functions (CSF), binocular phase combination and binocular rivalry were tested before and after training. Although monocular training can improve visual acuity and contrast sensitivity and eye dominance of the amblyopic eye, the magnitudes of improvements did not correlate with each other; the impact of monocular training on binocular phase combination was not significant. The results strongly suggest that structured monocular and binocular training is needed to fully recover deficient visual functions in anisometropic amblyopia. PMID- 28636884 TI - Major achievements of evidence-based traditional Chinese medicine in treating major diseases. AB - A long history of use and extensive documentation of the clinical practices of traditional Chinese medicine resulted in a considerable number of classical preparations, which are still widely used. This heritage of our ancestors provides a unique resource for drug discovery. Already, a number of important drugs have been developed from traditional medicines, which in fact form the core of Western pharmacotherapy. Therefore, this article discusses the differences in drug development between traditional medicine and Western medicine. Moreover, the article uses the discovery of artemisinin as an example that illustrates the "bedside-bench-bedside" approach to drug discovery to explain that the middle way for drug development is to take advantage of the best features of these two distinct systems and compensate for certain weaknesses in each. This article also summarizes evidence-based traditional medicines and discusses quality control and quality assessment, the crucial steps in botanical drug development. Herbgenomics may provide effective tools to clarify the molecular mechanism of traditional medicines in the botanical drug development. The totality-of-the-evidence approach used by the U.S. Food and Drug Administration for botanical products provides the directions on how to perform quality control from the field throughout the entire production process. PMID- 28636885 TI - Differential changes in the pharmacokinetics of statins in collagen-induced arthritis rats. AB - The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins. PMID- 28636887 TI - Temporal dynamics of the HPA axis linked to exploratory behavior in a wild European songbird (Parus major). AB - Variation in the reactivity of the endocrine stress axis is thought to underlie aspects of persistent individual differences in behavior (i.e. animal personality). Previous studies, however, have focused largely on estimating baseline or peak levels of glucocorticoids (CORT), often in captive animals. In contrast, the temporal dynamics of the HPA axis-how quickly it turns on and off, for example-may better indicate how an individual copes with stressors. Moreover, these HPA components might be correlated, thereby representing endocrine suites. Using wild-caught great tits (Parus major) we tested birds for exploratory behavior using a standardized novel environment assay that serves as a validated proxy for personality. We then re-captured a subset of these birds (n=85) and characterized four components of HPA physiology: baseline, endogenous stress response, a dexamethasone (DEX) challenge to estimate the strength of negative feedback, and an adrenocorticotropic hormone (ACTH) challenge to estimate adrenal capacity. We predicted that these four HPA responses would be positively correlated and that less exploratory birds would have a more rapid onset of the stress response (a CORT elevation during the baseline bleed) and weaker negative feedback (higher CORT after DEX). We found support for the first two predictions but not the third. All four components were positively correlated with each other and less exploratory birds exhibited an elevation in CORT during the baseline bleed (<3min from capture). Less exploratory birds, however, did not exhibit weaker negative feedback following the DEX challenge, but did exhibit weaker adrenal capacity. Together, our findings provide partial support for the hypothesis that the temporal reactivity of the HPA axis is linked with consistent individual differences in behavior, with more cautious (slower exploring) individuals exhibiting a faster CORT response. PMID- 28636886 TI - SIRT1 enzymatically potentiates 1,25-dihydroxyvitamin D3 signaling via vitamin D receptor deacetylation. AB - The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitated from human embryonic kidney (HEK293) cells displays a dramatic decrease in acetylated receptor in the presence of 1,25D-ligand, sirtuin-1 (SIRT1) deacetylase, or the resveratrol activator of SIRT1. To elucidate the functional significance of VDR deacetylation, vitamin-d responsive-element (VDRE)-based transcriptional assays were performed to determine if deacetylase overexpression affects VDR/VDRE-driven transcription. In HEK293 kidney and TE85 bone cells, co-transfection of low amounts (1-5ng) of a SIRT1-expression vector elicits a reproducible and statistically significant enhancement (1.3- to 2.6-fold) in transcription mediated by VDREs from the CYP3A4 and cyp24a1 genes, where the magnitude of response to 1,25D-ligand is 6- to 30 fold. Inhibition of SIRT1 via EX-527, or utilization of a SIRT1 loss-of-function mutant (H363Y), resulted in abrogation of SIRT1-mediated VDR potentiation. Studies with a novel, non-acetylatable VDR mutant (K413R) showed that the mutant VDR possesses enhanced responsiveness to 1,25D, in conjunction with reduced, but still significant, sensitivity to exogenous SIRT1, indicating that acetylation of lysine 413 is relevant, but that other acetylated residues in VDR contribute to modulation of its activity. We conclude that the acetylation of VDR comprises a negative feedback loop that attenuates 1,25D-VDR signaling. This regulatory loop is reversed by SIRT1-catalyzed deacetylation of VDR to amplify VDR signaling and 1,25D actions. PMID- 28636889 TI - Complications of hematopoietic stem transplantation: Fungal infections. AB - Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and beta-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. PMID- 28636888 TI - Responsiveness of pituitary to galanin throughout the reproductive cycle of male European sea bass (Dicentrarchus labrax). AB - The neuropeptide galanin (Gal) is a putative factor regulating puberty onset and reproduction through its actions on the pituitary. The present study investigated the pituitary responsiveness to galanin and the patterns of galanin receptors (Galrs) expression throughout the reproductive cycle of two years old male European sea bass (Dicentrarchus labrax), an important aquaculture species. Quantitative analysis of pituitary and hypothalamus transcript expression of four galr subtypes revealed differential regulation according to the testicular developmental stage, with an overall decrease in expression from the immature stage to the mid-recrudescence stage. Incubation of pituitary cells with mammalian 1-29Gal peptide induced significant changes in cAMP concentration, with sensitivities that varied according to the testicular development stages. Furthermore 1-29Gal was able to stimulate both follicle stimulating hormone (Fsh) and luteinizing hormone (Lh) release from pituitary cell suspensions. The magnitude of the effects and effective concentrations varied according to reproductive stage, with generalized induction of Fsh and Lh release in animals sampled in January (full spermiation). The differential expression of galrs in pituitary and hypothalamus across the reproductive season, together with the differential effects of Gal on gonadotropins release in vitro strongly suggests the involvement of the galaninergic system in the regulation the hypothalamus pituitary-gonad axis of male sea bass. This is to our knowledge the first clear evidence for the involvement of galanin in the regulation of reproduction in non mammalian vertebrates. PMID- 28636890 TI - Memory T cells: A helpful guard for allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT) and the major cause of nonrelapse morbidity and mortality of AHSCT. In AHSCT, donor T cells facilitate hematopoietic stem cell (HSC) engraftment, contribute to anti-infection immunity, and mediate graft-versus-leukemia (GVL) responses. However, activated alloreactive T cells also attack recipient cells in vital organs, leading to GVHD. Different T-cell subsets, including naive T (TN) cells, memory T (TM) cells, and regulatory T (Treg) cells mediate different forms of GVHD and GVL; TN cells mediate severe GVHD, whereas TM cells do not cause GVHD, but preserve T cell function including GVL. In addition, metabolic reprogramming controls T-cell differentiation and activation in these disease states. This minireview focuses on the role and the related mechanisms of TM cells in AHSCT, and the potential manipulation of T cells in AHSCT. PMID- 28636892 TI - Topical bioavailability of diclofenac from locally-acting, dermatological formulations. AB - Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo - in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated. PMID- 28636893 TI - Controlled release from aspirin based linear biodegradable poly(anhydride esters) for anti-inflammatory activity. AB - This work reports the synthesis of a novel, aspirin-loaded, linear poly (anhydride ester) and provides mechanistic insights into the release of aspirin from this polymer for anti-inflammatory activity. As compared to conventional drug delivery systems that rely on diffusion based release, incorporation of bioactives in the polymer backbone is challenging and high loading is difficult to achieve. In the present study, we exploit the pentafunctional sugar alcohol (xylitol) to provide sites for drug (aspirin) attachment at its non-terminal OH groups. The terminal OH groups are polymerized with a diacid anhydride. The hydrolysis of the anhydride and ester bonds under physiological conditions release aspirin from the matrix. The resulting poly(anhydride ester) has high drug loading (53%) and displays controlled release kinetics of aspirin. The polymer releases 8.5 % and 20%, of the loaded drug in one and four weeks, respectively and has a release rate constant of 0.0035h-0.61. The release rate is suitable for its use as an anti-inflammatory agent without being cytotoxic. The polymer exhibits good cytocompatibility and anti-inflammatory properties and may find applications as injectable or as an implantable bioactive material. The physical insights into the release mechanism can provide development of other drug loaded polymers. PMID- 28636891 TI - Comparison of cyclophosphamide-thalidomide-dexamethasone to bortezomib cyclophosphamide-dexamethasone as induction therapy for multiple myeloma patients in Brazil. AB - OBJECTIVE/BACKGROUND: Chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) remains the standard treatment for multiple myeloma (MM). Thalidomide or bortezomib may be combined with cyclophosphamide and dexamethasone, in what are known as the CTD and VCD protocols, respectively. The objective of this study was to evaluate the clinical characteristics and response rates obtained with CTD and VCD, observing whether the inclusion of bortezomib to treat MM patients in Brazil increases therapeutic efficiency. METHODS: Forty three MM patients treated with induction protocols CTD and VCD between January 2010 and March 2015 were included. The parameters analyzed were staging, frequency of comorbidities prior to treatment, response rates obtained at each induction cycle, progression-free survival, and overall survival of patients. RESULTS: Very good partial response and complete response obtained with the VCD protocol were superior, compared with the CTD treatment. The presence of comorbidities was similar in the two groups, except kidney failure, which prevailed in the VCD group. Also, 78.3% and 48.3% of patients treated with the VCD and CTD protocols underwent autologous HSCT, respectively. In patients given the VCD protocol, 45.5% had complete response before autologous HSCT. Among those given CTD, this number was only 7.1% (p=0.023). Disease progression after autologous HSCT did not differ between the two groups. CONCLUSION: VCD afforded better responses than the CTD protocol, and improved patient condition before autologous HSCT. However, more studies are necessary including more patients and addressing various clinical conditions, besides the analysis of cost effectiveness of these treatments. PMID- 28636894 TI - Effects of HPMC substituent pattern on water up-take, polymer and drug release: An experimental and modelling study. AB - The purpose of this study was to investigate the hydration behavior of two matrix formulations containing the cellulose derivative hydroxypropyl methylcellulose (HPMC). The two HPMC batches investigated had different substitution pattern along the backbone; the first one is referred to as heterogeneous and the second as homogenous. The release of both the drug molecule theophylline and the polymer was determined. Additionally, the water concentrations at different positions in the swollen gel layers were determined by Magnetic Resonance Imaging. The experimental data was compared to predicted values obtained by the extension of a mechanistic Fickian based model. The hydration of tablets containing the more homogenous HPMC batch showed a gradual water concentration gradient in the gel layer and could be well predicted. The hydration process for the more heterogeneous batch showed a very abrupt step change in the water concentration in the gel layer and could not be well predicted. Based on the comparison between the experimental and predicted data this study suggests, for the first time, that formulations with HPMC of different heterogeneities form gels in different ways. The homogeneous HPMC batch exhibits a water sorption behavior ascribable to a Ficks law for the diffusion process whereas the more heterogeneous HPMC batches does not. This conclusion is important in the future development of simulation models and in the understanding of drug release mechanism from hydrophilic matrices. PMID- 28636895 TI - Neurocognitive characteristics of youth with noncomorbid and comorbid forms of conduct disorder and attention deficit hyperactivity disorder. AB - OBJECTIVE: Studies investigating neurocognitive deficits in youth with conduct disorder (CD) and attention deficit hyperactivity disorder (ADHD) are often confounded by the high rates of comorbidity between the two. METHOD: Neurocognitive functioning was examined in three diagnostic groups (ADHD only, CD only, comorbid ADHD and CD) matched by age, sex, IQ, and medication status (n=28 32 per group). RESULTS: No significant differences emerged between the diagnostic groups on measures of risk-taking or response inhibition. Children with CD performed better on a measure of spatial planning than those with comorbid ADHD and CD, and dimensional analyses in the full sample (n=265) revealed a small association between ADHD symptoms and poorer spatial planning. CONCLUSION: These results suggest that deficits in spatial planning may be more pronounced in individuals with ADHD, but that the neurocognitive functioning of youth with noncomorbid and comorbid CD and ADHD are largely similar. PMID- 28636897 TI - Inappropriate use of FIB-4 index for cirrhosis detection in hepatocellular carcinoma patients. PMID- 28636896 TI - Early maladaptive schemas of emotional deprivation, social isolation, shame and abandonment are related to a history of suicide attempts among patients with major depressive disorders. AB - BACKGROUND: Patients with psychiatric disorders have an exceptionally high risk of completed or attempted suicide. This holds particularly true for patients with major depressive disorders. The aim of the present study was to explore whether patients with major depressive disorders (MDD) and a history of suicide attempts differed in their early maladaptive schemas from patients with MDD but without such a history or from healthy controls. METHOD: Ninety participants took part in the study. Of these, 30 were patients with MDD who had made a recent suicide attempt; 30 were patients with MDD but no suicide attempts, and 30 were gender- and age-matched healthy controls. Participants completed questionnaires covering socio-demographic characteristics and the Young Schema Questionnaire (YSQ- RE2R) to assess early maladaptive schemas. Experts rated patients' MDD with the Montgomery-Asberg Depression Rating Scale. RESULTS: Patients did not differ in experts' ratings of symptoms of depression. Compared to healthy controls, patients with MDD recorded higher scores on maladaptive schemas such as recognition seeking, negativity/pessimism, and insufficient self-control. Compared to patients without suicide attempts and healthy controls, those who had made a suicide attempt had higher scores on dimensions such as failure, mistrust, emotional inhibition, social isolation, and abandonment/instability. CONCLUSION: Compared to healthy controls, patients with MDD had more pronounced maladaptive schemas, but this was more marked in patients with a history of suicide attempts. The results suggest that suicide attempts and poorer psychological functioning are related. PMID- 28636898 TI - Reply to: "Hepatocellular carcinoma (HCC) in the absence of cirrhosis in patients with chronic hepatitis B virus infection". PMID- 28636899 TI - Reply to: "Inappropriate use of FIB-4 index for cirrhosis detection in hepatocellular carcinoma patients". PMID- 28636900 TI - Reply to: "How to predict global trends in HCC mortality if neglect more than half the world's cases?" PMID- 28636902 TI - "Riddle Me This": Substrate Channeling Solves the Paradigms of cAMP-Dependent Activation of PKA. PMID- 28636901 TI - The effect of CD34+ cell telomere length and hTERT expression on the outcome of autologous CD34+ cell transplantation in patients with chronic heart failure. AB - Age-related telomere attrition in stem/progenitor cells may diminish their functional capacity and thereby impair the outcome of cell-based therapies. The aim of the present study was to investigate the effect of CD34+ cell telomere length and hTERT expression on the clinical outcome of autologous CD34+ cell transplantation. We studied 43 patients with cardiomyopathy. Their peripheral blood CD34+ cells were mobilized with granulocyte colony-stimulating factor, enriched by immunoselection and delivered transendocardially. Relative telomere length and expression levels of hTERT were measured using a real-time PCR assay. Immunoselected CD34+ cells had longer telomere length compared to leukocytes in leukapheresis products (p=0.001). In multivariate analysis, CD34+ cell telomere length was not associated with the clinical outcome (b=3.306, p=0.540). While hTERT expression was undetectable in all leukapheresis products, 94.4% of the CD34+ enriched cell products expressed hTERT. Higher CD34+hTERT expression was associated with a better clinical outcome on univariate analysis (b=87.911, p=0.047). Our findings demonstrate that CD34+ cell telomere length may not influence the clinical outcome in cardiomyopathy patients treated with autologous CD34+ cell transplantation. Larger studies are needed to validate the impact of the CD34+hTERT expression on the clinical outcome of autologous CD34+ cell transplantation. PMID- 28636903 TI - Tracking Down Kinesin's Achilles Heel with Balls of Gold. PMID- 28636904 TI - Amoebae as Mechanosensitive Tanks. PMID- 28636905 TI - A Kepler Workflow Tool for Reproducible AMBER GPU Molecular Dynamics. AB - With the drive toward high throughput molecular dynamics (MD) simulations involving ever-greater numbers of simulation replicates run for longer, biologically relevant timescales (microseconds), the need for improved computational methods that facilitate fully automated MD workflows gains more importance. Here we report the development of an automated workflow tool to perform AMBER GPU MD simulations. Our workflow tool capitalizes on the capabilities of the Kepler platform to deliver a flexible, intuitive, and user friendly environment and the AMBER GPU code for a robust and high-performance simulation engine. Additionally, the workflow tool reduces user input time by automating repetitive processes and facilitates access to GPU clusters, whose high-performance processing power makes simulations of large numerical scale possible. The presented workflow tool facilitates the management and deployment of large sets of MD simulations on heterogeneous computing resources. The workflow tool also performs systematic analysis on the simulation outputs and enhances simulation reproducibility, execution scalability, and MD method development including benchmarking and validation. PMID- 28636906 TI - Flexible Fitting of Atomic Models into Cryo-EM Density Maps Guided by Helix Correspondences. AB - Although electron cryo-microscopy (cryo-EM) has recently achieved resolutions of better than 3 A, at which point molecular modeling can be done directly from the density map, analysis and annotation of a cryo-EM density map still primarily rely on fitting atomic or homology models to the density map. In this article, we present, to our knowledge, a new method for flexible fitting of known or modeled protein structures into cryo-EM density maps. Unlike existing methods that are guided by local density gradients, our method is guided by correspondences between the alpha-helices in the density map and model, and does not require an initial rigid-body fitting step. Compared with current methods on both simulated and experimental density maps, our method not only achieves greater accuracy for proteins with large deformations but also runs as fast or faster than many of the other flexible fitting routines. PMID- 28636907 TI - EPR Spectroscopy Targets Structural Changes in the E. coli Membrane Fusion CusB upon Cu(I) Binding. AB - Bacterial cells have developed sophisticated systems to deal with the toxicity of metal ions. Escherichia coli CusCFBA is a complex efflux system, responsible for transferring Cu(I) and Ag(I) ions; this system, located in the periplasm, involves four proteins, CusA, CusB, CusC, and CusF. CusA, CusB, and CusC are connected to one another in an oligomerization ratio of 3:6:3 CusA/CusB/CusC to form the CusCBA periplasm membrane transporter. CusB is an adaptor protein that connects the two membrane proteins CusA (inner membrane) and CusC (outer membrane). CusF is a metallochaperone that transfers Cu(I) and Ag(I) to the CusCBA transporter from the periplasm. The crystal structures of CusB, CusC, CusF, and the CusBA complex have been resolved, shedding some light on the efflux mechanism underlying this intriguing system. However, since CusB is an adaptor protein, its role in operating this system is significant, and should be understood in detail. Here, we utilize EPR spectroscopy to target the conformational changes that take place in the full CusB protein upon binding Cu(I). We reveal that CusB is a dimer in solution, and that the orientation of one molecule with respect to the other molecule changes upon Cu(I) coordination, resulting in a more compact CusB structure. These structural and topological changes upon Cu(I) binding probably play the role of a switch for opening the channel and transferring metal ions from CusB to CusC and out of the cell. PMID- 28636908 TI - Schiff Base Proton Acceptor Assists Photoisomerization of Retinal Chromophores in Bacteriorhodopsin. AB - In this study, we investigated the ultrafast dynamics of bacteriorhodopsins (BRs) from Haloquadratum walsbyi (HwBR) and Haloarcula marismortui (HmBRI and HmBRII). First, the ultrafast dynamics were studied for three HwBR samples: wild-type, D93N mutation, and D104N mutation. The residues of the D93 and D104 mutants correspond to the control by the Schiff base proton acceptor and donor of the proton translocation subchannels. Measurements indicated that the negative charge from the Schiff base proton acceptor residue D93 interacts with the ultrafast and substantial change of the electrostatic potential associated with chromophore isomerization. By contrast, the Schiff base proton donor assists the restructuring of the chromophore cavity hydrogen-bond network during the thermalization of the vibrational hot state. Second, the ultrafast dynamics of the wild-types of HwBR, HmBRI, and HmBRII were compared. Measurements demonstrated that the hydrogen-bond network in the extracellular region in HwBR and HmBRII slows the photoisomerization of retinal chromophores, and the negatively charged helices on the cytoplasmic side of HwBR and HmBRII accelerate the thermalization of the vibrational hot state of retinal chromophores. The similarity of the correlation spectra of the wild-type HmBRI and D104N mutant of HwBR indicates that inactivation of the Schiff base proton donor induces a positive charge on the helices of the cytoplasmic side. PMID- 28636909 TI - Electric-Field-Induced Protein Translocation via a Conformational Transition in SecDF: An MD Study. AB - SecDF is an important component of the Sec protein translocation machinery embedded in the bacterial membrane, which is associated with many functions, such as stabilizing other Sec translocon components within the membrane, maintaining the transmembrane (TM) potential, and facilitating the ATP-independent stage of the translocation mechanism. Related studies suggest that SecDF undergoes functionally important conformational changes that involve mainly its P1-head domain and that these changes are coupled with the proton motive force (Deltap). However, there still is not a clear understanding of how SecDF functions, its exact role in the translocation machinery, and how its function is related to Deltap. Here, using all-atom molecular dynamics simulations combined with umbrella sampling, we study the P1-head conformational change and how it is coupled to the proton motive force. We report potentials of mean force along a root-mean-square-distance-based reaction coordinate obtained in the presence and absence of the TM electrical potential. Our results show that the interaction of the P1 domain dipole moment with the TM electrical field considerably lowers the free-energy barrier in the direction of F-form to I-form transition. PMID- 28636910 TI - Prp40 Homolog A Is a Novel Centrin Target. AB - Pre-mRNA processing protein 40 (Prp40) is a nuclear protein that has a role in pre-mRNA splicing. Prp40 possesses two leucine-rich nuclear export signals, but little is known about the function of Prp40 in the export process. Another protein that has a role in protein export is centrin, a member of the EF-hand superfamily of Ca2+-binding proteins. Prp40 was found to be a centrin target by yeast-two-hybrid screening using both Homo sapiens centrin 2 (Hscen2) and Chlamydomonas reinhardtii centrin (Crcen). We identified a centrin-binding site within H. sapiens Prp40 homolog A (HsPrp40A), which contains a hydrophobic triad W1L4L8 that is known to be important in the interaction with centrin. This centrin-binding site is highly conserved within the first nuclear export signal consensus sequence identified in Saccharomyces cerevisiae Prp40. Here, we examine the interaction of HsPrp40A peptide (HsPrp40Ap) with both Hscen2 and Crcen by isothermal titration calorimetry. We employed the thermodynamic parameterization to estimate the polar and apolar surface area of the interface. In addition, we have defined the molecular mechanism of thermally induced unfolding and dissociation of the Crcen-HsPrp40Ap complex using two-dimensional infrared correlation spectroscopy. These complementary techniques showed for the first time, to our knowledge, that HsPrp40Ap interacts with centrin in vitro, supporting a coupled functional role for these proteins in pre-mRNA splicing. PMID- 28636911 TI - Direct Conversion of an Enzyme from Native-like to Amyloid-like Aggregates within Inclusion Bodies. AB - The acylphosphatase from Sulfolobus solfataricus (Sso AcP) is a globular protein able to aggregate in vitro from a native-like conformational ensemble without the need for a transition across the major unfolding energy barrier. This process leads to the formation of assemblies in which the protein retains its native-like structure, which subsequently convert into amyloid-like aggregates. Here, we investigate the mechanism by which Sso AcP aggregates in vivo to form bacterial inclusion bodies after expression in E. coli. Shortly after the initiation of expression, Sso AcP is incorporated into inclusion bodies as a native-like protein, still exhibiting small but significant enzymatic activity. Additional experiments revealed that this overall process of aggregation is enhanced by the presence of the unfolded N-terminal region of the sequence and by destabilization of the globular segment of the protein. At later times, the Sso AcP molecules in the inclusion bodies lose their native-like properties and convert into beta sheet-rich amyloid-like structures, as indicated by their ability to bind thioflavin T and Congo red. These results show that the aggregation behavior of this protein is similar in vivo to that observed in vitro, and that, at least for a predominant part of the protein population, the transition from a native to an amyloid-like structure occurs within the aggregate state. PMID- 28636912 TI - Channeling of cAMP in PDE-PKA Complexes Promotes Signal Adaptation. AB - Spatiotemporal control of the cAMP signaling pathway is governed by both hormonal stimulation of cAMP generation by adenylyl cyclases (activation phase) and cAMP hydrolysis by phosphodiesterases (PDEs) (termination phase). The termination phase is initiated by PDEs actively targeting the protein kinase A (PKA) R subunit through formation of a PDE-PKAR-cyclic adenosine monophosphate (cAMP) complex (the termination complex). Our results using PDE8 as a model PDE, reveal that PDEs mediate active hydrolysis of cAMP bound to its receptor RIalpha by enhancing the enzymatic activity. This accelerated cAMP turnover occurs via formation of a stable PDE8-RIalpha complex, where the protein-protein interface forms peripheral contacts and the central ligand cements this ternary interaction. The basis for enhanced catalysis is active translocation of cAMP from its binding site on RIalpha to the hydrolysis site on PDE8 through direct "channeling." Our results reveal cAMP channeling in the PDE8-RIalpha complex and a molecular description of how this channel facilitates processive hydrolysis of unbound cAMP. Thus, unbound cAMP maintains the PDE8-RIalpha complex while being hydrolyzed, revealing an undiscovered mode for amplification of PKA activity by cAMP-mediated sequestration of the R-subunit by PDEs. This novel regulatory mode explains the paradox of cAMP signal amplification by accelerated PDE-mediated cAMP turnover. This highlights how target effector proteins of small-molecule ligands can promote enzyme-mediated ligand hydrolysis by scaffolding effects. Enhanced activity of the PDE8-RIalpha complex facilitates robust desensitization, allowing the cell to respond to dynamic levels of cAMP rather than steady-state levels. The PDE8-RIalpha complex represents a new class of PDE-based complexes for specific drug discovery targeting the cAMP signaling pathway. PMID- 28636913 TI - Heterogeneous Tau-Tubulin Complexes Accelerate Microtubule Polymerization. AB - Tau is an intrinsically disordered protein with a central role in the pathology of a number of neurodegenerative diseases. Tau normally functions to stabilize neuronal microtubules, although the mechanism underlying this function is not well understood. Of note is that the interaction between tau and soluble tubulin, which has implications both in understanding tau function as well as its role in disease, is underexplored. Here we investigate the relationship between heterogeneity in tau-tubulin complexes and tau function. Specifically, we created a series of truncated and scrambled tau constructs and characterized the size and heterogeneity of the tau-tubulin complexes formed under nonpolymerizing conditions. Function of the constructs was verified by tubulin polymerization assays. We find that, surprisingly, the pseudo-repeat region of tau, which flanks the core microtubule-binding domain of tau, contributes largely to the formation of large, heterogeneous tau tubulin complexes; additional independent tubulin binding sites exist in repeats two and three of the microtubule binding domain. Of particular interest is that we find positive correlation between the size and heterogeneity of the complexes and rate of tau-promoted microtubule polymerization. We propose that tau-tubulin can be described as a "fuzzy" complex, and our results demonstrate the importance of heterogeneous complex formation in tau function. This work provides fundamental insights into the functional mechanism of tau, and more broadly underscores the relevance of heterogeneous and dynamic complexes in the functions of intrinsically disordered proteins. PMID- 28636914 TI - Peptide-Protein Binding Investigated by Far-IR Spectroscopy and Molecular Dynamics Simulations. AB - Molecular dynamics (MD) simulations and far-infrared (far-IR) spectroscopy were combined to study peptide binding by the second PDZ domain (PDZ1) of MAGI1, which has been identified as an important target for the Human Papilloma Virus. PDZ1 recognizes and binds to the C-terminal end of the E6 protein from high-risk Human Papilloma Virus. The far-IR spectra of two forms of the protein, an unbound APO form and a HOLO form (where the PDZ1 is bound to an 11-residue peptide derived from the C terminus of HPV16 E6), were obtained. MD simulations were used to determine the most representative structure of each form and these were used to compute their respective IR spectra by normal mode analysis. Far-UV circular dichroism spectroscopy was used to confirm the secondary structure content and the stability through temperature-dependent studies. Both the experimental and calculated far-IR spectra showed a red shift of the low-frequency peaks upon peptide binding. The calculations show that this is coincident with an increased number of hydrogen bonds formed as the peptide augments the protein beta-sheet. We further identified the contribution of surface-bound water molecules to bands in the far-IR and, through the calculations, identified potential pathways for allosteric communication. Together, these results demonstrate the utility of combining far-IR experiments and MD studies to study peptide binding by proteins. PMID- 28636915 TI - Probing the Structural Dynamics of the NMDA Receptor Activation by Coarse-Grained Modeling. AB - N-Methyl-D-aspartate (NMDA) receptors are glutamate-gated excitatory channels that play essential roles in brain functions. High-resolution structures have been solved for an allosterically inhibited and agonist-bound form of a functional NMDA receptor; however, other key functional states (particularly the active open-channel state) were only resolved at moderate resolutions by cryo electron microscopy (cryo-EM). To decrypt the mechanism of the NMDA receptor activation, structural modeling is essential to provide presently missing information about structural dynamics. We performed systematic coarse-grained modeling using an elastic network model and related modeling/analysis tools (e.g., normal mode analysis, flexibility and hotspot analysis, cryo-EM flexible fitting, and transition pathway modeling) based on an active-state cryo-EM map. We observed extensive conformational changes that allosterically couple the extracellular regulatory and agonist-binding domains to the pore-forming trans membrane domain (TMD), and validated these, to our knowledge, new observations against known mutational and functional studies. Our results predict two key modes of collective motions featuring shearing/twisting of the extracellular domains relative to the TMD, reveal subunit-specific flexibility profiles, and identify functional hotspot residues at key domain-domain interfaces. Finally, by examining the conformational transition pathway between the allosterically inhibited form and the active form, we predict a discrete sequence of domain motions, which propagate from the extracellular domains to the TMD. In summary, our results offer rich structural and dynamic information, which is consistent with the literature on structure-function relationships in NMDA receptors, and will guide in-depth studies on the activation dynamics of this important neurotransmitter receptor. PMID- 28636917 TI - Kinesin Processivity Is Determined by a Kinetic Race from a Vulnerable One-Head Bound State. AB - Kinesin processivity, defined as the average number of steps that occur per interaction with a microtubule, is an important biophysical determinant of the motor's intracellular capabilities. Despite its fundamental importance to the diversity of tasks that kinesins carry out in cells, no existing quantitative model fully explains how structural differences between kinesins alter kinetic rates in the ATPase cycle to produce functional changes in processivity. Here we use high-resolution single-molecule microscopy to directly observe the stepping behavior of kinesin-1 and -2 family motors with different length neck-linker domains. We characterize a one-head-bound posthydrolysis vulnerable state where a kinetic race occurs between attachment of the tethered head to its next binding site and detachment of the bound head from the microtubule. We find that greater processivity is correlated with faster attachment of the tethered head from this vulnerable state. In compliment, we show that slowing detachment from this vulnerable state by strengthening motor-microtubule electrostatic interactions also increases processivity. Furthermore, we provide evidence that attachment of the tethered head is irreversible, suggesting a first passage model for exit from the vulnerable state. Overall, our results provide a kinetic framework for explaining kinesin processivity and for mapping structural differences to functional differences in diverse kinesin isoforms. PMID- 28636919 TI - Monitoring Quantitative Ultrasound Parameter Changes in a Cell Pellet Model of Cell Starvation. AB - Although it has previously been shown that the spectral analysis of ultrasound backscatter data is sensitive to the cellular changes caused by apoptosis, the sensitivity of spectral analysis to oncosis or ischemic cell death had not previously been studied. Whereas many anticancer treatments induce apoptosis, others induce cell starvation, or oncosis. HT-29 colon adenocarcinoma cells were formed into pellets and covered in phosphate-buffered saline at room temperature for 56 h. The pellets were imaged every 8 h with high-frequency (55 MHz) ultrasound and the raw radio-frequency data processed. The lack of nutrients available to the cells induced cell death due to oncosis. The attenuation slope, speed of sound, spectral slope, and midband fit were estimated at each of the eight time points to identify changes as the cells died due to starvation. The spectral slope decreased monotonically over the 56 h, whereas the attenuation slope showed an increase between 1 and 48 h, followed by a slight decrease between 48 and 56 h. The midband fit did not vary over time. The speed of sound increased from 1514 to 1532 m/s over the first 24 h, after which time it plateaued. These in vitro results indicate different trends in ultrasound parameter changes from those of in vitro apoptotic cells, suggesting that these different methods of cell death can be identified not only by morphological markers, but also by specific ultrasound signatures. PMID- 28636916 TI - Structural Behavior of the Peptaibol Harzianin HK VI in a DMPC Bilayer: Insights from MD Simulations. AB - Microsecond molecular dynamics simulations of harzianin HK VI (HZ) interacting with a dimyristoylphosphatidylcholine bilayer were performed at the condition of low peptide-to-lipid ratio. Two orientations of HZ molecule in the bilayer were found and characterized. In the orientation perpendicular to the bilayer surface, HZ induces a local thinning of the bilayer. When inserted into the bilayer parallel to its surface, HZ is located nearly completely within the hydrophobic region of the bilayer. A combination of solid-state NMR and circular dichroism experiments found the latter orientation to be dominant. An extended sampling simulation provided qualitative results and showed the same orientation to be a global minimum of free energy. The secondary structure of HZ was characterized, and it was found to be located in the 310-helical family. The specific challenges of computer simulation of nonpolar peptides are discussed briefly. PMID- 28636920 TI - Nanog Fluctuations in Embryonic Stem Cells Highlight the Problem of Measurement in Cell Biology. AB - A number of important pluripotency regulators, including the transcription factor Nanog, are observed to fluctuate stochastically in individual embryonic stem cells. By transiently priming cells for commitment to different lineages, these fluctuations are thought to be important to the maintenance of, and exit from, pluripotency. However, because temporal changes in intracellular protein abundances cannot be measured directly in live cells, fluctuations are typically assessed using genetically engineered reporter cell lines that produce a fluorescent signal as a proxy for protein expression. Here, using a combination of mathematical modeling and experiment, we show that there are unforeseen ways in which widely used reporter strategies can systematically disturb the dynamics they are intended to monitor, sometimes giving profoundly misleading results. In the case of Nanog, we show how genetic reporters can compromise the behavior of important pluripotency-sustaining positive feedback loops, and induce a bifurcation in the underlying dynamics that gives rise to heterogeneous Nanog expression patterns in reporter cell lines that are not representative of the wild-type. These findings help explain the range of published observations of Nanog variability and highlight the problem of measurement in live cells. PMID- 28636918 TI - Actin Filament Strain Promotes Severing and Cofilin Dissociation. AB - Computational and structural studies have been indispensable in investigating the molecular origins of actin filament mechanical properties and modulation by the regulatory severing protein cofilin. All-atom molecular dynamics simulations of cofilactin filament structures determined by electron cryomicroscopy reveal how cofilin enhances the bending and twisting compliance of actin filaments. Continuum mechanics models suggest that buckled cofilactin filaments localize elastic energy at boundaries between bare and cofilin-decorated segments because of their nonuniform elasticity, thereby accelerating filament severing. Here, we develop mesoscopic length-scale (cofil)actin filament models and evaluate the effects of compressive and twisting loads on strain energy distribution at specific interprotein interfaces. The models reliably capture the filament bending and torsional rigidities and intersubunit torsional flexibility measured experimentally with purified protein components. Buckling is predicted to enhance cofilactin filament severing with minimal effects on cofilin occupancy, whereas filament twisting enhances cofilin dissociation without compromising filament integrity. Preferential severing at actin-cofilactin boundaries of buckled filaments is more prominent than predicted by continuum models because of the enhanced spatial resolution. The models developed here will be valuable for evaluating the effects of filament shape deformations on filament stability and interactions with regulatory proteins, and analysis of single filament manipulation assays. PMID- 28636922 TI - An Experimental Framework for Quantifying Bacterial Tolerance. AB - Antibiotic tolerance and persistence are often associated with treatment failure and relapse, yet are poorly characterized. In distinction from resistance, which is measured using the minimum inhibitory concentration metric, tolerance and persistence values are not currently evaluated in the clinical setting, and so are overlooked when a course of treatment is prescribed. In this article, we introduce a metric and an automated experimental framework for measuring tolerance and persistence. The tolerance metric is the minimum duration for killing 99% of the population, MDK99, which can be evaluated by a statistical analysis of measurements performed manually or using a robotic system. We demonstrate the technique on strains of Escherichia coli with various tolerance levels. We hope that this, to our knowledge, new approach will be used, along with the existing minimum inhibitory concentration, as a standard for the in vitro characterization of sensitivity to antimicrobials. Quantification of tolerance and persistence may provide vital information in healthcare, and aid research in the field. PMID- 28636921 TI - Characterizing Intracellular Ice Formation of Lymphoblasts Using Low-Temperature Raman Spectroscopy. AB - Raman microspectroscopy was used to quantify freezing response of cells to various cooling rates and solution compositions. The distribution pattern of cytochrome c in individual cells was used as a measure of cell viability in the frozen state and this metric agreed well with the population-averaged viability and trypan blue staining experiments. Raman imaging of cells demonstrated that intracellular ice formation (IIF) was common and did not necessarily result in cell death. The amount of intracellular ice as well as ice crystal size played a role in determining whether or not ice inside the cell was a lethal event. Intracellular ice crystals were colocated to the sections of cell membrane in close proximity to extracellular ice. Increasing the distance between extracellular ice and cell membrane decreased the incidence of IIF. Reducing the effective stiffness of the cell membrane by disrupting the actin cytoskeleton using cytochalasin D increased the amount of IIF. Strong intracellular osmotic gradients were observed when IIF was present. These observations support the hypothesis that interactions between the cell membrane and extracellular ice result in IIF. Raman spectromicroscopy provides a powerful tool for observing IIF and understanding its role in cell death during freezing, and enables the development, to our knowledge, of new and improved cell preservation protocols. PMID- 28636924 TI - Epithelial Folding Driven by Apical or Basal-Lateral Modulation: Geometric Features, Mechanical Inference, and Boundary Effects. AB - During embryonic development, epithelial sheets fold into complex structures required for tissue and organ functions. Although substantial efforts have been devoted to identifying molecular mechanisms underlying epithelial folding, far less is understood about how forces deform individual cells to sculpt the overall sheet morphology. Here we describe a simple and general theoretical model for the autonomous folding of monolayered epithelial sheets. We show that active modulation of intracellular mechanics along the basal-lateral as well as the apical surfaces is capable of inducing fold formation in the absence of buckling instability. Apical modulation sculpts epithelia into shallow and V-shaped folds, whereas basal-lateral modulation generates deep and U-shaped folds. These characteristic tissue shapes remain unchanged when subject to mechanical perturbations from the surroundings, illustrating that the autonomous folding is robust against environmental variabilities. At the cellular scale, how cells change shape depends on their initial aspect ratios and the modulation mechanisms. Such cell deformation characteristics are verified via experimental measurements for a canonical folding process driven by apical modulation, indicating that our theory could be used to infer the underlying folding mechanisms based on experimental data. The mechanical principles revealed in our model could potentially guide future studies on epithelial folding in diverse systems. PMID- 28636923 TI - Mechanosensitive Adhesion Explains Stepping Motility in Amoeboid Cells. AB - Cells employing amoeboid motility exhibit repetitive cycles of rapid expansion and contraction and apply coordinated traction forces to their environment. Although aspects of this process are well studied, it is unclear how the cell controls the coordination of cell length changes with adhesion to the surface. Here, we develop a simple model to mechanistically explain the emergence of periodic changes in length and spatiotemporal dynamics of traction forces measured in chemotaxing unicellular amoeba, Dictyostelium discoideum. In contrast to the biochemical mechanisms that have been implicated in the coordination of some cellular processes, we show that many features of amoeboid locomotion emerge from a simple mechanochemical model. The mechanism for interaction with the environment in Dictyostelium is unknown and thus, we explore different cell environment interaction models to reveal that mechanosensitive adhesions are necessary to reproduce the spatiotemporal adhesion patterns. In this modeling framework, we find that the other motility modes, such as smooth gliding, arise naturally with variations in the physical properties of the surface. Thus, our work highlights the prominent role of biomechanics in determining the emergent features of amoeboid locomotion. PMID- 28636925 TI - Achievements and Challenges for Our Society's Journal. PMID- 28636926 TI - Enhanced human bone marrow mesenchymal stromal cell adhesion on scaffolds promotes cell survival and bone formation. AB - : In order to induce an efficient bone formation with human bone marrow mesenchymal stromal cells (hBMSC) associated to a scaffold, it is crucial to determine the key points of the hBMSC action after in vivo transplantation as well as the appropriate features of a scaffold. To this aim we compared the hBMSC behavior when grafted onto two biomaterials allowing different bone potential in vivo. The cancellous devitalized Tutoplast(r)-processed bone (TPB) and the synthetic hydroxyapatite/beta-tricalcium-phosphate (HA/betaTCP) which give at 6weeks 100% and 50% of bone formation respectively. We first showed that hBMSC adhesion is two times favored on TPB in vitro and in vivo compared to HA/betaTCP. Biomaterial structure analysis indicated that the better cell adhesion on TPB is associated to its higher and smooth open pore architecture as well as its content in collagen. Our 6week time course analysis, showed using qPCR that only adherent cells are able to survive in vivo giving thus an advantage in term of cell number on TPB during the first 4weeks after graft. We then showed that grafted hBMSC survival is crucial as cells participate directly to bone formation and play a paracrine action via the secretion of hIGF1 and hRANKL which are known to regulate the bone formation and resorption pathways respectively. Altogether our results point out the importance of developing a smooth and open pore scaffold to optimize hBMSC adhesion and ensure cell survival in vivo as it is a prerequisite to potentiate their direct and paracrine functions. STATEMENT OF SIGNIFICANCE: Around 10% of skeletal fractures do not heal correctly causing nonunion. An approach involving mesenchymal stromal cells (MSC) associated with biomaterials emerges as an innovative strategy for bone repair. The diversity of scaffolds is a source of heterogeneity for bone formation efficiency. In order to better determine the characteristics of a powerful scaffold it is crucial to understand their relationship with cells after graft. Our results highlight that a biomaterial architecture similar to cancellous bone is important to promote MSC adhesion and ensure cell survival in vivo. Additionally, we demonstrated that the grafted MSC play a direct role coupled to a paracrine effect to enhance bone formation and that both of those roles are governed by the used scaffold. PMID- 28636927 TI - Noxious, but not innocuous, thermal stimuli evoke pERK expression in dorsal horn neurons after spared nerve injury in adult rats. AB - Noxious stimulation of sensory afferents evokes phosphorylated extracellular signal regulated kinase (pERK) expression in spinal cord neurons. This study investigated the expression of pERK in the dorsal horn neurons in response to innocuous and noxious cold stimuli in naive versus spared nerve injury (SNI) rats. Noxious cold or hot stimuli (0 or 45 degrees C) elicited pERK expression in laminae I-II whereas cooling stimuli from 32 degrees C to 25, 15 or 5 degrees C produced no or little pERK expression in dorsal horn neurons. Five days after SNI, a time when these animals showed heat hyperalgesia, cold and mechanical hypersensitivity, only noxious heat stimuli produced a significant increase in pERK expression compared to naive rats in spinal cord neurons. Thus, pERK cannot be used as an activity marker for neurons responding to cooling stimuli or cold allodynia; however, these results confirm the role of pERK as an activity marker for heat hyperalgesia. PMID- 28636928 TI - Neurovascular toxicity of N-methyl-d-aspartate is markedly enhanced in the developing mouse central nervous system. AB - Penumbral perfusion is critical to brain viability. Proximal arterial occlusion and deep brain stroke has variable effect on cortical dysfunction. Cortical microvessel collaterals may be recruited and at times sufficient for partial parenchymal perfusion. Postnatal neural and endothelial cells are markedly vulnerable to glutamate excitotoxicity. Early vascular cell stress may promote partial protective neural preconditioning though postnatally a developmental window of the cerebral microvasculature may be particularly vulnerable to injury. We tested the hypothesis that postnatal NMDA excitotoxic injury, when cerebral endothelial cells' central energy source is via glycolysis, is age specific. Neurovascular responses of cortical viability were directly identified with diffuse reflectance patterns of perfusion properties in a non-invasive manner, over time. Histological evaluation for neural and vascular cytoarchitectonic abnormalities were evaluated 4- 7days post injury. Optical diffuse reflectance recordings were obtained at the injection site prior to, immediately after and 48h post injury. Extent of neurovascular injury at the infarct zone was greatest at PND 5 and cortical perfusion responses identified with recordings of pattern change. These data further suggest excitotoxic injury to both neural and vascular cells, in vivo, can enhance CNS injury in the young and neuroprotective strategies may benefit from vascular directed therapies. PMID- 28636929 TI - Intrinsic functional connectivity alteration of dorsal and rostral anterior cingulate cortex in obsessive-compulsive disorder: A resting fMRI study. AB - Cortico-striato-thalamo-cortical (CSTC) circuit has been implicated in OCD pathophysiology by converging neuroimaging findings. The anterior cingulate cortex (ACC), as an important part within CSTC circuit, plays a critical role in OCD etiology. The ACC can be divided into dorsal and rostral parts anatomically, which are involved in cognitive process and emotional function, respectively. However, the diverse function of intrinsic signals from dorsal and rostral ACC regions remains unclear in OCD study. In this work, we applied resting-state functional magnetic resonance imaging (rs-fMRI) technology to investigate and differentiate the functional connectivity (FC) characteristics between dACC and rACC in unmedicated OCD patients. Also, the correlation between the altered FC and clinical symptom severity was analyzed. Decreased FC of rACC-DLPFC and increased FC between dACC and caudate were found. Moreover, the altered dACC caudate FC was positively correlated with total Y-BOCS and compulsion score in OCD patients. Our findings implied the crossed function of dorsal and rostral circuits in the pathophysiologic mechanism of OCD. The dorsal cingulate-striatum functional pathway served as a potential biomarker for OCD symptomatology and merits further investigations. PMID- 28636930 TI - A Tonoplast P3B-ATPase Mediates Fusion of Two Types of Vacuoles in Petal Cells. AB - It is known that plant cells can contain multiple distinct vacuoles; however, the abundance of multivacuolar cells and the mechanisms underlying vacuolar differentiation and communication among different types of vacuoles remain unknown. PH1 and PH5 are tonoplast P-ATPases that form a heteromeric pump that hyper-acidifies the central vacuole (CV) of epidermal cells in petunia petals. Here, we show that the sorting of this pump and other vacuolar proteins to the CV involves transit through small vacuoles: vacuolinos. Vacuolino formation is controlled by transcription factors regulating pigment synthesis and transcription of PH1 and PH5. Trafficking of proteins from vacuolinos to the central vacuole is impaired by misexpression of vacuolar SNAREs as well as mutants for the PH1 component of the PH1-PH5 pump. The finding that PH1-PH5 and these SNAREs interact strongly suggests that structural tonoplast proteins can act as tethering factors in the recognition of different vacuolar types. PMID- 28636931 TI - p53 Prohibits Propagation of Chromosome Segregation Errors that Produce Structural Aneuploidies. AB - The presence of an abnormal karyotype has been shown to be profoundly detrimental at the cellular and organismal levels but is an overt hallmark of cancer. Aneuploidy can lead to p53 activation and thereby prevents proliferation, but the exact trigger for p53 activation has remained controversial. Here, we have used a system to induce aneuploidy in untransformed human cells to explore how cells deal with different segregation errors. We show that p53 is activated only in a subset of the cells with altered chromosome content. Importantly, we find that at least a subset of whole-chromosome aneuploidies can be propagated in p53 proficient cells, indicating that aneuploidy does not always lead to activation of p53. Finally, we demonstrate that propagation of structural aneuploidies (gain or loss of part of a chromosome) induced by segregation errors is limited to p53 deficient cells. PMID- 28636932 TI - Ubiquitination-Linked Phosphorylation of the FANCI S/TQ Cluster Contributes to Activation of the Fanconi Anemia I/D2 Complex. AB - Repair of interstrand crosslinks by the Fanconi anemia (FA) pathway requires both monoubiquitination and de-ubiquitination of the FANCI/FANCD2 (FANCI/D2) complex. In the standing model, the phosphorylation of six sites in the FANCI S/TQ cluster domain occurs upstream of, and promotes, FANCI/D2 monoubiquitination. We generated phospho-specific antibodies against three different S/TQ cluster sites (serines 556, 559, and 565) on human FANCI and found that, in contrast to the standing model, distinct FANCI sites were phosphorylated either predominantly upstream (ubiquitination independent; serine 556) or downstream (ubiquitination linked; serines 559 and 565) of FANCI/D2 monoubiquitination. Ubiquitination linked FANCI phosphorylation inhibited FANCD2 de-ubiquitination and bypassed the need to de-ubiquitinate FANCD2 to achieve effective interstrand crosslink repair. USP1 depletion suppressed ubiquitination-linked FANCI phosphorylation despite increasing FANCI/D2 monoubiquitination, providing an explanation of why FANCD2 de ubiquitination is important for function of the FA pathway. Our work results in a refined model of how FANCI phosphorylation activates the FANCI/D2 complex. PMID- 28636933 TI - Drosophila Neuropeptide F Signaling Independently Regulates Feeding and Sleep Wake Behavior. AB - Proper regulation of sleep-wake behavior and feeding is essential for organismal health and survival. While previous studies have isolated discrete neural loci and substrates important for either sleep or feeding, how the brain is organized to coordinate both processes with respect to one another remains poorly understood. Here, we provide evidence that the Drosophila Neuropeptide F (NPF) network forms a critical component of both adult sleep and feeding regulation. Activation of NPF signaling in the brain promotes wakefulness and adult feeding, likely through its cognate receptor NPFR. Flies carrying a loss-of-function NPF allele do not suppress sleep following prolonged starvation conditions, suggesting that NPF acts as a hunger signal to keep the animal awake. NPF expressing cells, specifically those expressing the circadian photoreceptor cryptochrome, are largely responsible for changes to sleep behavior caused by NPF neuron activation, but not feeding, demonstrating that different NPF neurons separately drive wakefulness and hunger. PMID- 28636934 TI - The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue. AB - Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here, we demonstrate that the gut microbiota-initiated trimethylamine N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel. Further, antisense oligonucleotide-mediated knockdown or genetic deletion of the TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) conferred protection against obesity in mice. Complimentary mouse and human studies indicate a negative regulatory role for FMO3 in the beiging of white adipose tissue. Collectively, our studies reveal a link between the TMAO-producing enzyme FMO3 and obesity and the beiging of white adipose tissue. PMID- 28636936 TI - Strong TCRgammadelta Signaling Prohibits Thymic Development of IL-17A-Secreting gammadelta T Cells. AB - Despite a growing appreciation of gammadelta T cell contributions to numerous immune responses, the mechanisms that underpin their thymic development remain poorly understood. Here, using precursor/product relationships, we identify thymic stages in two distinct developmental pathways that generate gammadelta T cells pre-committed to subsequent secretion of either IL-17A or IFNgamma. Importantly, this framework for tracking gammadelta T cell development has permitted definitive assessment of TCRgammadelta signal strength in commitment to gammadelta T cell effector fate; increased TCRgammadelta signal strength profoundly prohibited the development of all IL-17A-secreting gammadelta T cells, regardless of Vgamma usage, but promoted the development of gammadelta progenitors along the IFNgamma pathway. This clarifies the recently debated role of TCRgammadelta signal strength in commitment to distinct gammadelta T cell effector fates and proposes an alternate methodology for the study of gammadelta T cell development. PMID- 28636935 TI - The Sensory Striatum Is Permanently Impaired by Transient Developmental Deprivation. AB - Corticostriatal circuits play a fundamental role in regulating many behaviors, and their dysfunction is associated with many neurological disorders. In contrast, sensory disorders, like hearing loss (HL), are commonly linked with processing deficits at or below the level of the auditory cortex (ACx). However, HL can be accompanied by non-sensory deficits, such as learning delays, suggesting the involvement of regions downstream of ACx. Here, we show that transient developmental HL differentially affected the ACx and its downstream target, the sensory striatum. Following HL, both juvenile ACx layer 5 and striatal neurons displayed an excitatory-inhibitory imbalance and lower firing rates. After hearing was restored, adult ACx neurons recovered balanced excitatory-inhibitory synaptic gain and control-like firing rates, but striatal neuron synapses and firing properties did not recover. Thus, a brief period of abnormal cortical activity may induce cellular impairments that persist into adulthood and contribute to neurological disorders that are striatal in origin. PMID- 28636937 TI - The Conserved RNA Binding Cyclophilin, Rct1, Regulates Small RNA Biogenesis and Splicing Independent of Heterochromatin Assembly. AB - RNAi factors and their catalytic activities are essential for heterochromatin assembly in S. pombe. This has led to the idea that siRNAs can promote H3K9 methylation by recruiting the cryptic loci regulator complex (CLRC), also known as recombination in K complex (RIKC), to the nucleation site. The conserved RNA binding protein Rct1 (AtCyp59/SIG-7) interacts with splicing factors and RNA polymerase II. Here we show that Rct1 promotes processing of pericentromeric transcripts into siRNAs via the RNA recognition motif. Surprisingly, loss of siRNA in rct1 mutants has no effect on H3K9 di- or tri-methylation, resembling other splicing mutants, suggesting that post-transcriptional gene silencing per se is not required to maintain heterochromatin. Splicing of the Argonaute gene is also defective in rct1 mutants and contributes to loss of silencing but not to loss of siRNA. Our results suggest that Rct1 guides transcripts to the RNAi machinery by promoting splicing of elongating non-coding transcripts. PMID- 28636938 TI - The LDB1 Complex Co-opts CTCF for Erythroid Lineage-Specific Long-Range Enhancer Interactions. AB - Lineage-specific transcription factors are critical for long-range enhancer interactions, but direct or indirect contributions of architectural proteins such as CCCTC-binding factor (CTCF) to enhancer function remain less clear. The LDB1 complex mediates enhancer-gene interactions at the beta-globin locus through LDB1 self-interaction. We find that an LDB1-bound enhancer upstream of carbonic anhydrase 2 (Car2) activates its expression by interacting directly with CTCF at the gene promoter. Both LDB1 and CTCF are required for enhancer-Car2 looping, and the domain of LDB1 contacted by CTCF is necessary to rescue Car2 transcription in LDB1-deficient cells. Genome-wide studies and CRISPR/Cas9 genome editing indicate that LDB1-CTCF enhancer looping underlies activation of a substantial fraction of erythroid genes. Our results provide a mechanism by which long-range interactions of architectural protein CTCF can be tailored to achieve a tissue-restricted pattern of chromatin loops and gene expression. PMID- 28636939 TI - The Super-Enhancer-Derived alncRNA-EC7/Bloodlinc Potentiates Red Blood Cell Development in trans. AB - Enhancer-derived RNAs are thought to act locally by contributing to their parent enhancer function. Whether large domains of clustered enhancers (super-enhancers) also produce cis-acting RNAs, however, remains unclear. Unlike typical enhancers, super-enhancers form large spans of robustly transcribed chromatin, amassing capped and polyadenylated RNAs that are sufficiently abundant to sustain trans functions. Here, we show that one such RNA, alncRNA-EC7/Bloodlinc, is transcribed from a super-enhancer of the erythroid membrane transporter SLC4A1/BAND3 but diffuses beyond this site. Bloodlinc localizes to trans-chromosomal loci encoding critical regulators and effectors of terminal erythropoiesis and directly binds chromatin-organizing and transcription factors, including the chromatin attachment factor HNRNPU. Inhibiting Bloodlinc or Hnrnpu compromises the terminal erythropoiesis gene program, blocking red cell production, whereas expressing Bloodlinc ectopically stimulates this program and can promote erythroblast proliferation and enucleation in the absence of differentiation stimuli. Thus, Bloodlinc is a trans-acting super-enhancer RNA that potentiates red blood cell development. PMID- 28636940 TI - HECTD3 Mediates an HSP90-Dependent Degradation Pathway for Protein Kinase Clients. AB - Inhibition of the ATPase cycle of the HSP90 chaperone promotes ubiquitylation and proteasomal degradation of its client proteins, which include many oncogenic protein kinases. This provides the rationale for HSP90 inhibitors as cancer therapeutics. However, the mechanism by which HSP90 ATPase inhibition triggers ubiquitylation is not understood, and the E3 ubiquitin ligases involved are largely unknown. Using a siRNA screen, we have identified components of two independent degradation pathways for the HSP90 client kinase CRAF. The first requires CUL5, Elongin B, and Elongin C, while the second requires the E3 ligase HECTD3, which is also involved in the degradation of MASTL and LKB1. HECTD3 associates with HSP90 and CRAF in cells via its N-terminal DOC domain, which is mutationally disrupted in tumor cells with activated MAP kinase signaling. Our data implicate HECTD3 as a tumor suppressor modulating the activity of this important oncogenic signaling pathway. PMID- 28636941 TI - Highly Aggressive Metastatic Melanoma Cells Unable to Maintain Telomere Length. AB - Unlimited replicative potential is one of the hallmarks of cancer cells. In melanoma, hTERT (telomerase reverse transcriptase) is frequently overexpressed because of activating mutations in its promoter, suggesting that telomerase is necessary for melanoma development. We observed, however, that a subset of melanoma metastases and derived cell lines had no telomere maintenance mechanism. Early passages of the latter displayed long telomeres that progressively shortened and fused before cell death. We propose that, during melanoma formation, oncogenic mutations occur in precursor melanocytes with long telomeres, providing cells with sufficient replicative potential, thereby bypassing the need to re-activate telomerase. Our data further support the emerging idea that long telomeres promote melanoma formation. These observations are important when considering anticancer therapies targeting telomerase. PMID- 28636942 TI - Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres. AB - Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative. As serial samples of human tumors cannot usually be obtained to monitor telomere length changes, it has previously been impossible to determine whether tumors are truly TLM-deficient, there is a previously unrecognized TLM, or the assay results are false-negative. Here, we show that a subset of high-risk neuroblastomas (with ~50% 5-year mortality) lacked significant TLM activity. Cancer cells derived from these highly aggressive tumors initially had long telomeres and proliferated for >200 population doublings with ever-shorter telomeres. This indicates that prevention of telomere shortening is not always required for oncogenesis, which has implications for inhibiting TLMs for cancer therapy. PMID- 28636943 TI - OPA1 Isoforms in the Hierarchical Organization of Mitochondrial Functions. AB - OPA1 is a GTPase that controls mitochondrial fusion, cristae integrity, and mtDNA maintenance. In humans, eight isoforms are expressed as combinations of long and short forms, but it is unclear whether OPA1 functions are associated with specific isoforms and/or domains. To address this, we expressed each of the eight isoforms or different constructs of isoform 1 in Opa1-/- MEFs. We observed that any isoform could restore cristae structure, mtDNA abundance, and energetic efficiency independently of mitochondrial network morphology. Long forms supported mitochondrial fusion; short forms were better able to restore energetic efficiency. The complete rescue of mitochondrial network morphology required a balance of long and short forms of at least two isoforms, as shown by combinatorial isoform silencing and co-expression experiments. Thus, multiple OPA1 isoforms are required for mitochondrial dynamics, while any single isoform can support all other functions. These findings will be useful in designing gene therapies for patients with OPA1 haploinsufficiency. PMID- 28636944 TI - Transduction of Repetitive Mechanical Stimuli by Piezo1 and Piezo2 Ion Channels. AB - Several cell types experience repetitive mechanical stimuli, including vein endothelial cells during pulsating blood flow, inner ear hair cells upon sound exposure, and skin cells and their innervating dorsal root ganglion (DRG) neurons when sweeping across a textured surface or touching a vibrating object. While mechanosensitive Piezo ion channels have been clearly implicated in sensing static touch, their roles in transducing repetitive stimulations are less clear. Here, we perform electrophysiological recordings of heterologously expressed mouse Piezo1 and Piezo2 responding to repetitive mechanical stimulations. We find that both channels function as pronounced frequency filters whose transduction efficiencies vary with stimulus frequency, waveform, and duration. We then use numerical simulations and human disease-related point mutations to demonstrate that channel inactivation is the molecular mechanism underlying frequency filtering and further show that frequency filtering is conserved in rapidly adapting mouse DRG neurons. Our results give insight into the potential contributions of Piezos in transducing repetitive mechanical stimuli. PMID- 28636945 TI - PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury. AB - Polarized vesicle transport plays an important role in cell polarization, but the mechanisms underlying this process and its role in innate immune responses are not well understood. Here, we describe a phosphorylation-regulated polarization mechanism that is important for neutrophil adhesion to endothelial cells during inflammatory responses. We show that the protein kinase PKN1 phosphorylates RPH3A, which enhances binding of RPH3A to guanosine triphosphate (GTP)-bound RAB21. These interactions are important for polarized localization of RAB21 and RPH3A in neutrophils, which leads to PIP5K1C90 polarization. Consistent with the roles of PIP5K1C90 polarization, the lack of PKN1 or RPH3A impairs neutrophil integrin activation, adhesion to endothelial cells, and infiltration in inflammatory models. Furthermore, myeloid-specific loss of PKN1 decreases tissue injury in a renal ischemia-reperfusion model. Thus, this study characterizes a mechanism for protein polarization in neutrophils and identifies a potential protein kinase target for therapeutic intervention in reperfusion-related tissue injury. PMID- 28636946 TI - Ptbp2 Controls an Alternative Splicing Network Required for Cell Communication during Spermatogenesis. AB - Alternative splicing has essential roles in development. Remarkably, spermatogenic cells express more alternatively spliced RNAs compared to most whole tissues; however, regulation of these RNAs remains unclear. Here, we characterize the alternative splicing landscape during spermatogenesis and reveal an essential function for the RNA-binding protein Ptbp2 in this highly regulated developmental program. We found that Ptbp2 controls a network of genes involved in cell adhesion, migration, and polarity, suggesting that splicing regulation by Ptbp2 is critical for germ cell communication with Sertoli cells (multifunctional somatic cells necessary for spermatogenesis). Indeed, Ptbp2 ablation in germ cells resulted in disorganization of the filamentous actin (F-actin) cytoskeleton in Sertoli cells, indicating that alternative splicing regulation is necessary for cellular crosstalk during germ cell development. Collectively, the data delineate an alternative splicing regulatory network essential for spermatogenesis, the splicing factor that controls it, and its biological importance in germ-Sertoli communication. PMID- 28636947 TI - Assembly, Secretory Pathway Trafficking, and Surface Delivery of Kainate Receptors Is Regulated by Neuronal Activity. AB - Ionotropic glutamate receptor (iGluR) trafficking and function underpin excitatory synaptic transmission and plasticity and shape neuronal networks. It is well established that the transcription, translation, and endocytosis/recycling of iGluRs are all regulated by neuronal activity, but much less is known about the activity dependence of iGluR transport through the secretory pathway. Here, we use the kainate receptor subunit GluK2 as a model iGluR cargo to show that the assembly, early secretory pathway trafficking, and surface delivery of iGluRs are all controlled by neuronal activity. We show that the delivery of de novo kainate receptors is differentially regulated by modulation of GluK2 Q/R editing, PKC phosphorylation, and PDZ ligand interactions. These findings reveal that, in addition to short-term regulation of iGluRs by recycling/endocytosis and long-term modulation by altered transcription/translation, the trafficking of iGluRs through the secretory pathway is under tight activity-dependent control to determine the numbers and properties of surface-expressed iGluRs. PMID- 28636948 TI - PTENalpha Modulates CaMKII Signaling and Controls Contextual Fear Memory and Spatial Learning. AB - PTEN (phosphatase and tensin homology deleted on chromosome 10) has multiple functions, and recent studies have shown that the PTEN family has isoforms. The roles of these PTEN family members in biologic activities warrant specific evaluation. Here, we show that PTENalpha maintains CaMKII in a state that is competent to induce long-term potentiation (LTP) with resultant regulation of contextual fear memory and spatial learning. PTENalpha binds to CaMKII with its distinctive N terminus and resets CaMKII to an activatable state by dephosphorylating it at sites T305/306. Loss of PTENalpha impedes the interaction of CaMKII and NR2B, leading to defects in hippocampal LTP, fear-conditioned memory, and spatial learning. Restoration of PTENalpha in the hippocampus of PTENalpha-deficient mice rescues learning deficits through regulation of CaMKII. CaMKII mutations in dementia patients inhibit CaMKII activity and result in disruption of PTENalpha-CaMKII-NR2B signaling. We propose that CaMKII is a target of PTENalpha phosphatase and that PTENalpha is an essential element in the molecular regulation of neural activity. PMID- 28636949 TI - Cloning, expression, and nutritional regulation of the glutamine synthetase gene in Ctenopharyngodon idellus. AB - Glutamine synthetase (GS) is considered a master enzyme that catalyzes ATP dependent biosynthesis of glutamine from glutamate. In the present study, the GS gene was cloned from the intestine of grass carp (Ctenopharyngodon idellus). The full-length cDNA sequence of GS encodes a 371-amino-acid polypetide. Phylogenetic analysis of the C. idellus GS sequence reveals common carp (Cyprinus carpio) as its closest neighbor. GS mRNA was differentially expressed in different tissues, with high to low gradient expression the intestine, brain, muscle, heart, gill, liver, pituitary gland, and spleen. Additionally, GS exhibited a dynamic pattern of expression during embryonic development, reaching maximal and minimal levels in the organ and hatching stages, respectively, and constant low levels from 7 to 28days post-hatching. We also assessed dietary protein levels and feed sources in diet-regulated fish, and the results suggested that low crude protein (CP) and fish meal stimulate GS gene expression. Furthermore, intestinal GS mRNA expression was significantly increased by 0.2, 0.4, 0.6, 0.8mM concentrations of glutamine dipeptide in vitro. This study provides valuable knowledge about the regulation of GS expression in teleosts. PMID- 28636950 TI - Structural evidence of quercetin multi-target bioactivity: A reverse virtual screening strategy. AB - The ubiquitous flavonoid quercetin is broadly recognized for showing diverse biological and health-promoting effects, such as anti-cancer, anti-inflammatory and cytoprotective activities. The therapeutic potential of quercetin and similar compounds for preventing such diverse oxidative stress-related pathologies has been generally attributed to their direct antioxidant properties. Nevertheless, accumulated evidence indicates that quercetin is also able to interact with multiple cellular targets influencing the activity of diverse signaling pathways. Even though there are a number of well-established protein targets such as phosphatidylinositol 3 kinase and xanthine oxidase, there remains a lack of a comprehensive knowledge of the potential mechanisms of action of quercetin and its target space. In the present work we adopted a reverse screening strategy based on ligand similarity (SHAFTS) and target structure (idTarget, LIBRA) resulting in a set of predicted protein target candidates. Furthermore, using this method we corroborated a broad array of previously experimentally tested candidates among the predicted targets, supporting the suitability of this screening approach. Notably, all of the predicted target candidates belonged to two main protein families, protein kinases and poly [ADP-ribose] polymerases. They also included key proteins involved at different points within the same signaling pathways or within interconnected signaling pathways, supporting a pleiotropic, multilevel and potentially synergistic mechanism of action of quercetin. In this context we highlight the value of quercetin's broad target profile for its therapeutic potential in diseases like inflammation, neurodegeneration and cancer. PMID- 28636951 TI - Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV. AB - CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases. PMID- 28636952 TI - Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors. AB - Evidence is mounting that the major histocompatibility complex (MHC) molecule HLA F (human leukocyte antigen F) regulates the immune system in pregnancy, infection, and autoimmunity by signaling through NK cell receptors (NKRs). We present structural, biochemical, and evolutionary analyses demonstrating that HLA F presents peptides of unconventional length dictated by a newly arisen mutation (R62W) that has produced an open-ended groove accommodating particularly long peptides. Compared to empty HLA-F open conformers (OCs), HLA-F tetramers bound with human-derived peptides differentially stained leukocytes, suggesting peptide dependent engagement. Our in vitro studies confirm that NKRs differentiate between peptide-bound and peptide-free HLA-F. The complex structure of peptide loaded beta2m-HLA-F bound to the inhibitory LIR1 revealed similarities to high affinity recognition of the viral MHC-I mimic UL18 and a docking strategy that relies on contacts with HLA-F as well as beta2m, thus precluding binding to HLA-F OCs. These findings provide a biochemical framework to understand how HLA-F could regulate immunity via interactions with NKRs. PMID- 28636953 TI - Dicer Deficiency Differentially Impacts Microglia of the Developing and Adult Brain. AB - Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time. PMID- 28636955 TI - Inflammatory Ly6Chigh Monocytes Protect against Candidiasis through IL-15-Driven NK Cell/Neutrophil Activation. AB - Neutrophils play a crucial role in defense against systemic candidiasis, a disease associated with a high mortality rate in patients receiving immunosuppressive therapy, although the early immune mechanisms that boost the candidacidal activity of neutrophils remain to be defined in depth. Here, we used a murine model of systemic candidiasis to explore the role of inflammatory Ly6Chigh monocytes in NK cell-mediated neutrophil activation during the innate immune response against C. albicans. We found that efficient anti-Candida immunity required a collaborative response between the spleen and kidney, which relied on type I interferon-dependent IL-15 production by spleen inflammatory Ly6Chigh monocytes to drive efficient activation and GM-CSF release by spleen NK cells; this in turn was necessary to boost the Candida killing potential of kidney neutrophils. Our findings unveil a role for IL-15 as a critical mediator in defense against systemic candidiasis and hold promise for the design of IL-15 based antifungal immunotherapies. PMID- 28636957 TI - Glutathione Primes T Cell Metabolism for Inflammation. PMID- 28636956 TI - Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches. AB - The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation. PMID- 28636954 TI - Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. AB - During antibody affinity maturation, germinal center (GC) B cells cycle between affinity-driven selection in the light zone (LZ) and proliferation and somatic hypermutation in the dark zone (DZ). Although selection of GC B cells is triggered by antigen-dependent signals delivered in the LZ, DZ proliferation occurs in the absence of such signals. We show that positive selection triggered by T cell help activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes the anabolic program that supports DZ proliferation. Blocking mTORC1 prior to growth prevented clonal expansion, whereas blockade after cells reached peak size had little to no effect. Conversely, constitutively active mTORC1 led to DZ enrichment but loss of competitiveness and impaired affinity maturation. Thus, mTORC1 activation is required for fueling B cells prior to DZ proliferation rather than for allowing cell-cycle progression itself and must be regulated dynamically during cyclic re-entry to ensure efficient affinity-based selection. PMID- 28636958 TI - Protective and Pathological Immunity during Central Nervous System Infections. AB - The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted that innate pathways limit pathogen invasion of the CNS and adaptive immunity mediates control of many neural infections. As protective responses can result in bystander damage, there are regulatory mechanisms that balance protective and pathological inflammation, but these mechanisms might also allow microbial persistence. The focus of this review is to consider the host pathogen interactions that influence neurotropic infections and to highlight advances in our understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege. PMID- 28636962 TI - Reactive Astrocytes: Production, Function, and Therapeutic Potential. AB - Astrocytes constitute approximately 30% of the cells in the mammalian central nervous system (CNS). They are integral to brain and spinal-cord physiology and perform many functions important for normal neuronal development, synapse formation, and proper propagation of action potentials. We still know very little, however, about how these functions change in response to immune attack, chronic neurodegenerative disease, or acute trauma. In this review, we summarize recent studies that demonstrate that different initiating CNS injuries can elicit at least two types of "reactive" astrocytes with strikingly different properties, one type being helpful and the other harmful. We will also discuss new methods for purifying and investigating reactive-astrocyte functions and provide an overview of new markers for delineating these different states of reactive astrocytes. The discovery that astrocytes have different types of reactive states has important implications for the development of new therapies for CNS injury and diseases. PMID- 28636960 TI - Mechanisms and Therapeutic Relevance of Neuro-immune Communication. AB - Active research at the frontiers of immunology and neuroscience has identified multiple points of interaction and communication between the immune system and the nervous system. Immune cell activation stimulates neuronal circuits that regulate innate and adaptive immunity. Molecular mechanistic insights into the inflammatory reflex and other neuro-immune interactions have greatly advanced our understanding of immunity and identified new therapeutic possibilities in inflammatory and autoimmune diseases. Recent successful clinical trials using bioelectronic devices that modulate the inflammatory reflex to significantly ameliorate rheumatoid arthritis and inflammatory bowel disease provide a path for using electrons as a therapeutic modality for targeting molecular mechanisms of immunity. Here, we review mechanisms of peripheral sensory neuronal function in response to immune challenges, the neural regulation of immunity and inflammation, and the therapeutic implications of those mechanistic insights. PMID- 28636959 TI - The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut. AB - Interactions between the nervous and immune systems enable the gut to respond to the variety of dietary products that it absorbs, the broad spectrum of pathogens that it encounters, and the diverse microbiome that it harbors. The enteric nervous system (ENS) senses and reacts to the dynamic ecosystem of the gastrointestinal (GI) tract by translating chemical cues from the environment into neuronal impulses that propagate throughout the gut and into other organs in the body, including the central nervous system (CNS). This review will describe the current understanding of the anatomy and physiology of the GI tract by focusing on the ENS and the mucosal immune system. We highlight emerging literature that the ENS is essential for important aspects of microbe-induced immune responses in the gut. Although most basic and applied research in neuroscience has focused on the brain, the proximity of the ENS to the immune system and its interface with the external environment suggest that novel paradigms for nervous system function await discovery. PMID- 28636963 TI - T-bet Runs INTERFERence. AB - In this issue of Immunity, Iwata et al. (2017) report that the transcription factor T-bet acts as a selective repressor of the type I interferon (IFN) transcriptional program in response to IFN-gamma signaling. PMID- 28636964 TI - RNA Interference in Mammals: The Virus Strikes Back. AB - The importance of RNA interference (RNAi) as a mammalian antiviral defense mechanism has been controversial. Qiu et al. (2017) now present data suggesting that the difficulty of detecting RNAi in virus-infected mammalian cells reflects the expression of highly effective viral suppressors of RNAi. PMID- 28636961 TI - Myeloid Cells in the Central Nervous System. AB - The central nervous system (CNS) and its meningeal coverings accommodate a diverse myeloid compartment that includes parenchymal microglia and perivascular macrophages, as well as choroid plexus and meningeal macrophages, dendritic cells, and granulocytes. These myeloid populations enjoy an intimate relationship with the CNS, where they play an essential role in both health and disease. Although the importance of these cells is clearly recognized, their exact function in the CNS continues to be explored. Here, we review the subsets of myeloid cells that inhabit the parenchyma, meninges, and choroid plexus and discuss their roles in CNS homeostasis. We also discuss the role of these cells in various neurological pathologies, such as autoimmunity, mechanical injury, neurodegeneration, and infection. We highlight the neuroprotective nature of certain myeloid cells by emphasizing their therapeutic potential for the treatment of neurological conditions. PMID- 28636965 TI - HLA-F: A New Kid Licensed for Peptide Presentation. AB - HLA-F, a non-classical MHC molecule, is not known to present peptides. Dulberger et al. (2017) show that HLA-F contains a distinct peptide-binding groove and can present a diverse array of peptides. LIR1, however, recognized HLA-F away from bound peptide, leaving open whether peptide-HLA-F-specific T and NK receptors exist. PMID- 28636966 TI - The TORC that Gets the GC Cycling. AB - The signaling pathways regulating positive selection in germinal centers (GCs) are incompletely understood. Ersching et al. (2017) identify a critical but temporal role for the action of the kinase mechanistic target of rapamycin complex (mTORC1), which promotes key changes in GC B cells and thereby facilitates affinity maturation. PMID- 28636967 TI - A Few Good Commensals: Gut Microbes Use IFN-gamma to Fight Salmonella. AB - Whereas strong evidence supports the notion that the microbiota promotes immune system maturation in multiple tissues, the identity of the specific microbes that elicit protective immunity to different infections is less clear. In a recent issue of Cell Host & Microbe, Thiemann et al. (2017) report the identification of specific gut bacteria that protect from Salmonella infection by priming host IFN gamma responses. PMID- 28636968 TI - T-Regulating Hair Follicle Stem Cells. AB - Regulatory T (Treg) cells are well known to modulate inflammatory responses. In a recent issue of Cell, Ali et al. (2017) reveal a function for Treg cells in stem cell maintenance by showing that skin-resident Foxp3+ Treg cells preferentially localize to the hair follicle stem cell (HFSC) niche to control HFSC-mediated hair regeneration. PMID- 28636969 TI - Human Virus-Derived Small RNAs Can Confer Antiviral Immunity in Mammals. AB - RNA interference (RNAi) functions as a potent antiviral immunity in plants and invertebrates; however, whether RNAi plays antiviral roles in mammals remains unclear. Here, using human enterovirus 71 (HEV71) as a model, we showed HEV71 3A protein as an authentic viral suppressor of RNAi during viral infection. When the 3A-mediated RNAi suppression was impaired, the mutant HEV71 readily triggered the production of abundant HEV71-derived small RNAs with canonical siRNA properties in cells and mice. These virus-derived siRNAs were produced from viral dsRNA replicative intermediates in a Dicer-dependent manner and loaded into AGO, and they were fully active in degrading cognate viral RNAs. Recombinant HEV71 deficient in 3A-mediated RNAi suppression was significantly restricted in human somatic cells and mice, whereas Dicer deficiency rescued HEV71 infection independently of type I interferon response. Thus, RNAi can function as an antiviral immunity, which is induced and suppressed by a human virus, in mammals. PMID- 28636970 TI - Performance of titanium salts compared to conventional FeCl3 for the removal of algal organic matter (AOM) in synthetic seawater: Coagulation performance, organic fraction removal and floc characteristics. AB - During algal bloom periods, operation of seawater reverse osmosis (SWRO) pretreatment processes (e.g. ultrafiltration (UF)) has been hindered due to the high concentration of algal cells and algal organic matter (AOM). The present study evaluated for the first time the performance of titanium salts (i.e. titanium tetrachloride (TiCl4) and polytitanium tetrachloride (PTC)) for the removal of AOM in seawater and results were compared with the conventional FeCl3 coagulant. Previous studies already demonstrated that titanium salts not only provide a cost-effective alternative to conventional coagulants by producing a valuable by-product but also minimise the environmental impact of sludge production. Results from this study showed that both TiCl4 and PTC achieved better performance than FeCl3 in terms of turbidity, UV254 and dissolved organic carbon (DOC) removal at similar coagulant dose. Liquid chromatography - organic carbon detection (LC-OCD) was used to determine the removal of AOM compounds based on their molecular weight (MW). This investigation revealed that both humic substances and low MW organics were preferentially removed (i.e. up to 93% removal) while all three coagulants showed poorer performance for the removal of high MW biopolymers (i.e. less than 50% removal). The detailed characterization of flocs indicated that both titanium coagulants can grow faster, reach larger size and present a more compact structure, which is highly advantageous for the design of smaller and more compact mixing and sedimentation tanks. Both titanium coagulants also presented a higher ability to withstand shear force, which was related to the higher amount of DOC adsorbed with the aggregated flocs. Finally, TiCl4 had a better recovery after breakage suggesting that charge neutralization may be the dominant mechanism for this coagulant, while the lower recovery of both PTC and FeCl3 indicated that sweep flocculation is also a contributing mechanism for the coagulation of AOM. PMID- 28636971 TI - Simulated long-term effects of varying tree retention on wood production, dead wood and carbon stock changes. AB - Boreal forests are an important source of timber and pulp wood, but provide also other products and services. Utilizing a simulation program and field data from a tree retention experiment in a Scots pine forest in central Sweden, we simulated the consequences during the following 100 years of various levels of retention on production of merchantable wood, dead wood input (as a proxy for biodiversity), and carbon stock changes. At the stand level, wood production decreased with increased retention levels, while dead wood input and carbon stock increased. We also compared 12 scenarios representing a land sharing/land sparing gradient. In each scenario, a constant volume of wood was harvested with a specific level of retention in a 100-ha landscape. The area not needed to reach the defined volume was set-aside during a 100-year rotation period, leading to decreasing area of set-asides with increasing level of retention across the 12 scenarios. Dead wood input was positively affected by the level of tree retention whereas the average carbon stock decreased slightly with increasing level of tree retention. The scenarios will probably vary in how they favor species preferring different substrates. Therefore, we conclude that a larger variation of landscape-level conservation strategies, also including active creation of dead wood, may be an attractive complement to the existing management. PMID- 28636972 TI - Assessing landowners' attitudes toward wild hogs and support for control options. AB - Wild hogs (Sus scrofa) are an invasive species with destructive habits, particularly rooting and wallowing, which can directly impact agricultural crops, pasture land, and water quality. Considering wild hogs are widely dispersed across the landscape, they are extremely difficult to control. Disagreements can arise among different stakeholders over whether and how their populations should be managed. The purpose of this article was to examine Tennessee, United States landowners' attitudes toward wild hogs, to compare acceptability of control methods, and to evaluate factors significantly influencing public support for regulations to control wild hogs. Logistic regression was employed to analyze data collected from a statewide survey of rural landowners in the fall of 2015. Landowners had overwhelmingly negative attitudes towards wild hogs, and were concerned about their impact on the natural environment and rural economy. Although landowners showed support for controlling wild hogs, levels of acceptability for management options varied. Respondents favored active management and supported education and incentive-based control programs to control wild hogs. Cognitive concepts such as social and personal norms and awareness of consequences, as well as demographic characteristics, significantly predicted landowners' support for state regulations to control wild hogs in Tennessee. Findings increase our understanding of the human dimensions of wild hog management and that of other similarly invasive animals, and may guide resource managers in designing effective and socially acceptable management strategies to control wild hog populations in Tennessee and elsewhere. PMID- 28636973 TI - Amide-to-triazole switch vs. in vivo NEP-inhibition approaches to promote radiopeptide targeting of GRPR-positive tumors. AB - INTRODUCTION: Radiolabeled bombesin (BBN)-analogs have been proposed for diagnosis and therapy of gastrin-releasing peptide receptor (GRPR)-expressing tumors, such as prostate, breast and lung cancer. Metabolic stability represents a crucial factor for the success of this approach by ensuring sufficient delivery of circulating radioligand to tumor sites. The amide-to-triazole switch on the backbone of DOTA-PEG4-[Nle14]BBN(7-14) (1) was reported to improve the in vitro stability of resulting 177Lu-radioligands. On the other hand, in-situ inhibition of neutral endopeptidase (NEP) by coinjection of phosphoramidon (PA) was shown to significantly improve the in vivo stability and tumor uptake of biodegradable radiopeptides. We herein compare the impact of the two methods on the bioavailability and localization of 177Lu-DOTA-PEG4-[Nle14]BBN(7-14) analogs in GRPR-positive tumors in mice. METHODS: The 1,4-disubstituted [1-3]-triazole was used to replace one (2: Gly11-His12; 3: Ala9-Val10) or two (4: Ala9-Val10 and Gly11-His12) peptide bonds in 1 (reference) and all compounds were labeled with 177Lu. Each of [177Lu]1-[177Lu]4 was injected without (control) or with PA in healthy mice. Blood samples collected 5min post-injection (pi) were analyzed by HPLC. Biodistribution of [177Lu]1-[177Lu]4 was conducted in SCID mice bearing human prostate adenocarcinoma PC-3 xenografts at 4h pi. Groups of 4 animals were injected with radioligand, alone (controls), or with coinjection of PA, or of a mixture of PA and excess and [Tyr4]BBN to determine GRPR-specificity of uptake (Block). RESULTS: The in vivo stability of the radioligands was: [177Lu]1 (25% intact), [177Lu]2 (45% intact), [177Lu]3 (30% intact) and [177Lu]4 (40% intact). By PA-coinjection these values notably increased to 90%-93%. Moreover, treatment with PA induced an impressive and GRPR-specific uptake of all radioligands in the PC-3 xenografts at 4h pi: [177Lu]1: 4.7+/-0.4 to 24.8+/-4.9%ID/g; [177Lu]2: 8.3+/ 1.2 to 26.0+/-1.1%ID/g; [177Lu]3: 6.6+/-0.4 to 21.3+/-4.4%ID/g; and [177Lu]4: 4.8+/-1.6 to 13.7+/-3.8%ID/g. CONCLUSIONS: This study has shown that amide-to triazole substitutions in 177Lu-DOTA-PEG4-[Nle14]BBN(7-14) induced minor effects on bioavailability and tumor uptake in mice models, whereas in-situ NEP inhibition(s) by PA impressively improved in vivo profiles. PMID- 28636975 TI - Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae and Methicillin-Resistant Staphylococcus aureus in pig farms in Switzerland. AB - The presence of Methicillin-Resistant Staphylococcus aureus (MRSA) in pig farms has been widely reported, and the emergence of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) has been documented in several countries. However, data for Switzerland are very scarce. This study aimed to compare changes in the prevalence of MRSA in Swiss pig farms between 2008 and 2015 and make the first ever estimates of the presence of ESBL-E and carbapenemase producers in pigs and pig farm workers. Results showed that ESBL-E was present in both pigs and farm workers and that the proportion of farms with MRSA had increased fourfold in seven years (from 7% to 31%). Associations between antibiotic use and resistant bacteria carriage were shown. PMID- 28636974 TI - SEMA3A partially reverses VEGF effects through binding to neuropilin-1. AB - Cross-talk between hematopoietic stem cells (HSCs) and bone marrow stromal cells (BMSCs) is essential for HSCs regulation and leukemogenesis. Studying bone marrow of myelodysplasia patients, a pre-leukemic condition, we found mRNA overexpression of vascular endothelial growth factor A (VEGFA) in CD34+ HSCs and semaphorin 3A (SEMA3A) in BMSCs. To better understand the role of VEGFA and SEMA3A in leukemogenesis, we recruited 30 myelodysplastic syndrome (MDS) patients, 29 acute myeloid leukemia (6 secondary to MDS) patients and 12 controls. We found higher VEGFA expression in de novo AML patients (without prior MDS) group (p=0.0073) and higher SEMA3A expression in all BMSCs patient's samples compared to control group. We then overexpressed VEGFA in an acute myelogenous leukemia cell line, KG1 cells, and in normal CD34+ cells. This overexpression increased KG1 (p=0.045) and CD34+ cell (p=0.042) viability and KG1 (p=0.042) and CD34+ cell (p=0.047) proliferation. Moreover, KG1 and CD34+ cells overexpressing VEGFA also had increased proliferation when co-cultured with human marrow stromal HS5 cells (p=0.045 and p=0.02, respectively). However, co-culture of these transformed cells with HS5 cells overexpressing SEMA3A reduced KG1 (p=0.004) and CD34+ (p=0.009) proliferation. Co-culture of KG1 transformed cells with HS27 cells overexpressing SEMA3A reduced KG1 proliferation as well (p=0.01). To investigate whether the dominant SEMA3A effect over VEGFA could be due to competition for neuropilin1 receptor (NRP1), we performed immunoprecipitation with anti-NRP1 antibody of cell extracts of co-cultured KG1 and HS5 cells, induced or not by VEGFA and SEMA3A recombinant proteins. Results showed a preferential association of NRP1 with SEMA3A, suggesting that SEMA3A can partially reverse the effects caused by the VEGFA preventing its binding with the NRP1 receptor. Since both hematopoietic cells, leukemic and normal, showed similar behavior, we suppose that the attempt to reversion of VEGF effects by SEMA3A is a homeostatic phenomenon in the hematopoietic niche. Finally, we conclude that VEGFA overexpression confers AML cell advantages and SEMA3A may partially reverse this effect; thus, SEMA3A protein combined with VEGFA inhibitors could be beneficial for AML treatment. PMID- 28636977 TI - Long-term trend of O3 in a mega City (Shanghai), China: Characteristics, causes, and interactions with precursors. AB - In recent years, ozone (O3) is often the major pollutant during summertime in China. In order to better understand this problem, a long-term measurement of ozone (from 2006 to 2015) and its precursors (NOx and VOCs) as well as the photochemical parameter (UV radiation) in a mega city of China (Shanghai) is analyzed. The focus of this study is to investigate the trend of O3 and the causes of the O3 trend in large cities in China. In order to understand the relationship between the O3 precursors and O3 formation, two distinguished different sites of measurements are selected in the study, including an urbanization site (XJH-Xujiahui) and a remote site (DT-Dongtan). At the XJH site, there are high local emissions of ozone precursors (such as VOCs and NOx), which is suitable to study the effect of O3 precursors on O3 formation. In contrast, at the DT site, where there are low local emissions, the measured result can be used to analyze the background conditions nearby the city of Shanghai. The analysis shows that there were long-term trends of O3 and NOx concentrations at the urban site (XJH) from 2006 to 2015 (O3 increasing 67% and NOx decreasing 38%), while there were very small trends of O3 and NOx concentrations at the background site (DT). The analysis for causing the O3 trend suggests that (1) the large O3 increase at the urban area (XJH) was not due to the regional transport of O3; (2) the measurement of solar radiation had not significant trend during the period, and was not the major cause for the long-term O3 trend; (3) the measurement of VOCs had small change during the same period, suggesting that the trend in NOx concentrations at the urban site (XJH) was a major factor for causing the long term change of O3 at the urban area of Shanghai. As a result, the O3 and NOx concentrations from 2006 to 2015 at the urban area of Shanghai were strongly anti correlated, suggesting that the extremely high NOx concentration in the urban area depressed the O3 concentrations. It is interesting to note that the anti correlation between O3 and NOx was in an un-linearly relationship. Under high O3 concentration condition, the ratio of Delta[O3]/Delta[NOx] was as large as -1.5. In contrast, under low O3 concentrations, the ratio of Delta[O3]/Delta[NOx] was only -0.2. This result suggested that when O3 concentration was high, it was more sensitive to NOx concentration, while when O3 concentration was low, it was less sensitive to NOx concentration. This study provides useful insights for better understanding the causes of the long-term-trend of regional O3 pollution nearby Shanghai, and has important implication for air pollution control in large cities in China. Due to the fact that NOx and VOCs are not only precursors for O3, but also are important precursors for particular matter (PM). If reduction of NOx leads to decrease in PM, but increase in O3, the NOx emission control become a very complicated issue and need to carefully design a comprehensive control method. PMID- 28636976 TI - Improving soil nutrient availability increases carbon rhizodeposition under maize and soybean in Mollisols. AB - Rhizodeposited carbon (C) is an important source of soil organic C, and plays an important role in the C cycle in the soil-plant-atmosphere continuum. However, interactive effects of plant species and soil nutrient availability on C rhizodeposition remain unclear. This experiment examined the effect of soil nutrient availability on C rhizodeposition of C4 maize and C3 soybean with contrasting photosynthetic capacity. The soils (Mollisols) were collected from three treatments of no fertilizer (Control), inorganic fertilizer only (NPK), and NPK plus organic manure (NPKM) in a 24-year fertilization field trial. The plants were labelled with 13C at the vegetative and reproductive stages. The 13C abundance of shoots, roots and soil were quantified at 0, 7days after 13C labelling, and at maturity. Increasing soil nutrient availability enhanced the C rhizodeposition due to the greater C fixation in shoots and distribution to roots and soil. The higher amount of averaged below-ground C allocated to soil resulted in greater specific rhizodeposited C from soybean than maize. Additional organic amendment further enhanced them. As a result, higher soil nutrient availability increased total soil organic C under both maize and soybean systems though there was no significant difference between the two crop systems. All these suggested that higher soil nutrient availability favors C rhizodeposition. Mean 80, 260 and 300kgfixedCha-1 were estimated to transfer into soil in the Control, NPK and NPKM treatments, respectively, during one growing season. PMID- 28636978 TI - Psychiatric comorbidity with hypothalamic hamartoma: Systematic review for predictive clinical features. AB - OBJECTIVE: We conducted a systematic review of the English-language literature to identify clinical features associated with a higher risk of psychiatric symptoms (aggression and rage behaviors) in patients with hypothalamic hamartoma (HH) and epilepsy. METHODS: Two publicly-accessible databases (PubMed and Cochrane Library) were searched for Hypothalamic Hamartoma AND Epilepsy. We identified peer-reviewed original research publications (case reports or clinical series; N=19) in which clinical data was provided on an individual basis. Subjects were cohorted into those with (N=51) and without (N=68) behavioral aggression. Multiple clinical features were collated and subjected to univariate analysis to determine possible differences between these two cohorts. RESULTS: The presence of aggression significantly correlated with 1) male gender, 2) younger age at time of first seizure onset, 3) the presence of intellectual disability, and 4) the presence of multiple seizure types (versus gelastic seizures only). For those patients undergoing surgical treatment, aggression also correlated with younger age at the time of surgical intervention. CONCLUSION: Possible predictive clinical features for the presence of aggression and rage behaviors in patients with hypothalamic hamartoma and epilepsy are identified. These results may contribute to the complex treatment decisions that are unique to this population. PMID- 28636989 TI - SATB1 overexpression correlates with gastrointestinal neoplasms invasion and metastasis: a meta-analysis for Chinese population. AB - BACKGROUND: Gastrointestinal neoplasm (GIN) is the most common neoplasm in China. The global chromatin organizer SATB1 (special AT-rich sequence binding protein 1) is aberrantly expressed in multiple human neoplasms. We conducted this meta analysis to investigate whether the invasion and metastasis of GIN correlates with SATB1 levels in tumor tissues in Chinese patients. MATERIALS AND METHODS: Eligible studies were identified through multiple search strategies in the databases PubMed, Embase, Medline, CNKI, and WANFANG, and the relevant clinicopathological data were extracted. Data were pooled using the Mantel Haenszel fixed-effects or DerSimonian-Laid random-effects model. RESULTS: Fourteen studies consisting of 1622 patients were included. There were 3, 3, and 8 studies that evaluated esophageal, gastric, and colorectal cancers, respectively. The overall mean percentage of patients with elevated SATB1 levels was 47.84%. Among patients with GIN, SATB1 overexpression was associated with depth of invasion (T stage: RR 1.27, 95% CI 1.18-1.36, P = 0.000), regional lymph node metastasis (N stage: RR 1.51, 95% CI 1.22-1.87, P = 0.000), and distant metastasis (M stage: RR 2.54, 95% CI 1.46-4.41, P = 0.001). The tumor type most closely linked with invasion and metastasis in GIN was gastric cancer (RR for T stage: 1.64, RR for N stage: 1.68, RR for M stage: 3.15). CONCLUSIONS: Invasion and metastasis of GIN in Chinese patients correlates with SATB1 overexpression in tumor tissues, most profoundly in gastric cancer. PMID- 28636991 TI - Non-invasive detection of somatic mutations using next-generation sequencing in primary central nervous system lymphoma. AB - PURPOSE: Primary central nervous system lymphomas (PCNSL) have recurrent genomic alterations. The main objective of our study was to demonstrate that targeted sequencing of circulating cell-free DNA (cfDNA) released by PCNSL at the time of diagnosis could identify somatic mutations by next-generation sequencing (NGS). PATIENTS AND METHODS: PlasmacfDNA and matched tumor DNA (tDNA) from 25 PCNSL patients were sequenced using an Ion Torrent Personal Genome Machine (Life Technologies(r)). First, patient-specific targeted sequencing of identified somatic mutations in tDNA was performed. Then, a second sequencing targeting MYD88 c.T778C was performed and compared to plasma samples from 25 age-matched control patients suffering from other types of cancer. RESULTS: According to the patient-specific targeted sequencing, eight patients (32% [95% CI 15-54%]) had detectable somatic mutations in cfDNA. Considering MYD88 sequencing, six patients had the specific c.T778C alteration detected in plasma. Using a control group, the sensitivity was 24% [9-45%] and the specificity was 100%. Tumor volume or deep brain structure involvement did not influence the detection of somatic mutations in plasma. CONCLUSION: This pilot study provided evidence that somatic mutations can be detected by NGS in the cfDNA of a subset of patients suffering from PCNSL. PMID- 28636992 TI - Acetylsalicylic acid inhibits the growth of melanoma tumors via SOX2-dependent PAF-R-independent signaling pathway. AB - Acquired resistance to standard therapies remains a serious challenge, requiring novel therapeutic approaches that incorporate potential factors involved in tumor resistance. As cancers including melanoma express inflammatory cyclooxygenases generating prostaglandins implicated in tumor growth, we investigated mechanism of anti-inflammatory drug, acetylsalicylic acid (ASA) which has been shown to inhibit various tumor types, however, its effects against highly aggressive melanoma model are unclear. Given our reports that an activation of platelet activating factor-receptor (PAF-R) augments the growth and impede efficacies of therapeutic agents in experimental melanoma, we also sought to determine if PAF-R mediates anti-melanoma activity of ASA. The current studies using stably PAF-R positive (B16-PAFR) and negative (B16-MSCV) murine melanoma cells and PAF-R expressing and deficient mice, demonstrate that ASA inhibits the in-vitro and in vivo growth of highly aggressive B16F10 melanoma via bypassing tumoral or stromal PAF-R signaling. Similar ASA-induced effects in-vitro were seen in human melanoma and nasopharyngeal carcinoma cells positive or negative in PAF-R. Mechanistically, the ASA-induced decrease in cell survival and increase in apoptosis were significantly blocked by prostaglandin F2 alpha (PGF2alpha) agonists. Importantly, PCR array and qRT-PCR analysis of B16-tumors revealed significant downregulation of sry-related high-mobility-box-2 (SOX2) oncogene by ASA treatment. Interestingly, modulation of SOX2 expression by PGF2alpha agonists and upregulation by fibroblast growth factor 1 (FGF-1) rescued melanoma cells from ASA-induced decreased survival and increased apoptosis. Moreover, PGF2alpha receptor antagonist, AL8810 mimics ASA-induced decreased melanoma cells survival which was significantly blocked by PGF2alpha and FGF-1. These findings indicate that ASA inhibits the growth of aggressive melanoma via SOX2-dependent-PAF-R indepedent pathway. PMID- 28636993 TI - Polymorphisms and expression pattern of circular RNA circ-ITCH contributes to the carcinogenesis of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) ranks the sixth most common cancer and the third cause of cancer-related mortality worldwide. Recent studies identified that circ ITCH Suppresses mutiple cancers proliferation via inhibiting the Wnt/beta-Catenin pathway. In current study, conducted a genetic association study together with epidemiological follow-up study to delineate the role of circ-ITCH in the development and progression of HCC. we found rs10485505 (adjusted OR =1.18; 95% CI=1.06-1.31; P value =3.1*10-3) and rs4911154 (adjusted OR =1.27; 95% CI=1.14 1.43; P value =3.7*10-5) were significantly associated with increased HCC risk. The expression level of circ-ITCH was significantly lower in HCC tissues, compared with that in adjacent tissues (P value < 0.001). Cox regression analysis indicated that high expression of circ-ITCH was associated with favorable survival of HCC (HR=0.45; 95% CI=0.29-0.68; P value < 0.001). These results indicate that circ-ITCH may have an inhibitory effect on HCC, and could serve as susceptibility and prognostic biomarkers for HCC patients. PMID- 28636998 TI - Physiologically based pharmacokinetic modeling for predicting irinotecan exposure in human body. AB - Colorectal cancer is the third leading cause of cancer-related deaths in the United States. Treatment of colorectal cancer remains a challenge to clinicians as well as drug developers. Irinotecan, a Camptothecin derivative, is successfully used for the treatment of this rapidly progressing malignancy and finds its place in the first line of therapeutic agents. Irinotecan is also effective in treating SCLC, malignant glioma and pancreatic adenocarcinoma. However, its adverse effects limit its clinical application. Mainly metabolized by hepatic route, and excreted through biliary tract, this dug has been found to possess high variation in patients in its pharmacokinetic (PK) profile. Physiologically based pharmacokinetic (PBPK) models using compartmental approach have attained their position to foresee the possible PK behavior of different drugs before their administration to patients and such models have been proposed for several anticancer agents. In this work, we used WB-PBPK technology to develop a model in a population of tumor patients who used IV irinotecan therapy. This model depicted the concentration of drug and its pharmacologically active metabolite in human body over a specific period of time. Knowledge about pharmacokinetic parameters is extracted from this profile and the model is evaluated by the observed results of clinical study presented in literature. The predicted behavior of the drug by this approach is in good agreement with the observed results and can aid in further exploration of PK of irinotecan in cancer patients, especially in those concomitantly suffer from other morbidity. PMID- 28637001 TI - A novel method to generate Salmonella Typhi Ty21a ghosts exploiting the lambda phage holin-endolysin system. AB - Human typhoid fever caused by Salmonella Typhi still poses a severe global disease burden in developing countries despite the availability of commercial vaccines. In this study, we constructed a non-living S. Typhi Ty21a vaccine candidate by employing a lambda (lambda) phage-derived holin-endolysin system to efficiently construct bacterial ghosts. The lysis plasmid pJHL464 harbors an R lysis cassette that is stringently regulated by dual promoters containing cI857/lambdaPR and ParaBAD/araC components. The plasmid was introduced into an asd gene-deleted S. Typhi Ty21a strain designated JOL1675. The in vitro expression of endolysin (~17.76 kDa) in the subsequent JOL1675 vaccine construct when grown under lysis inducible conditions was validated by immunoblotting. In scanning electron microscopy analysis, surface transmembrane tunnels and a collapsed body were visualized in the ghosts. Following 48 h of lysis, no viable JOL1675 cells remained, indicating that lysis of all cells was achieved. Subcutaneous immunizations of mice with the JOL1675 ghosts produced significantly increasing titers of serum IgG and vaginal wash secretory IgA antibodies against JOL1675 outer membrane proteins during the observational period. Further, serum collected at 6 weeks post-immunization of rabbits exhibited effective bactericidal activity against wild type S. Typhi in the presence of complement. These data showed that JOL1675 ghosts are highly immunogenic and elicit humoral and mucosal responses expected to correlate with protective immunity against S. typhi. Collectively, our findings support the conclusion that incorporating a lambda phage holin-endolysin-mediated lysis construct into S. Typhi is an efficient strategy for developing a novel and safe non-living typhoid vaccine candidate. PMID- 28637006 TI - The effect of CA125 on metastasis of ovarian cancer: old marker new function. AB - CA125 has been used extensively to screen for neoplasms, especially in ovarian cancer. The serum CA125 level can be used as a better prognosis evaluation and it may dynamic monitoring the disease progression. We explored the effect of CA125 on ovarian cancer cell migration and its underlying mechanism. Transwell assays showed that exposure to 0.2 MUg/ml or 0.4 MUg/ml CA125 for 48 h increased migration of A2780 and OVCAR-3 ovarian cancer cells. This effect of CA125 was blocked addition of 200 ng/ml DKK-1, a Wnt pathway inhibitor. Conversely, addition of CA125 reversed the inhibitory effect of Wnt inhibition in A2780 cells pretreated with DKK-1. Examination of CA125 levels in serum from 97 ovarian cancer patients revealed no relationship between a patient's age or CA125 level currently used clinically for ovarian cancer diagnosis and metastasis. However, using receiver operating characteristic (ROC) curves, we identified a new cut-off value for the serum CA125 concentration (82.9 U/ml) that is predictive of metastasis. The area under the curve is 0.632. This new cut-off value has the potential to serve as a clinically useful indicator of metastasis in ovarian cancer patients. PMID- 28637003 TI - Structural recognition of tubulysin B derivatives by multidrug resistance efflux transporters in human cancer cells. AB - Multidrug resistance (MDR) is a major hindrance to curative chemotherapy of various human malignancies. Hence, novel chemotherapeutics must be evaluated for their recognition by MDR efflux transporters. Herein we explored the cytotoxic activity of synthetic tubulysin B (Tub-B, EC1009) derivatives (Tub-B hydrazide/EC0347 and Tub-B bis-ether/EC1820), and their recognition by the MDR efflux transporters P-glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP). Originally isolated from Myxobacteria, tubulysins exhibited potent cytotoxic activity via microtubule depolymerization, and evaded recognition by these MDR efflux pumps. We show that subtle modifications in the natural Tub-B structure enhance its cytotoxicity and drug efflux efficiency. Whereas increasing the lipophilicity of Tub-B drugs enhanced their diffusion into the cell and consequently decreased the IC50 values (>= 0.27 nM), increasing drug polarity enhanced their recognition by P-gp (>200 fold resistance in P-gp-overexpressing cells). Furthermore, restricting drug exposure time to the clinically relevant 4 h pulse, markedly enhanced efflux by P gp, resulting in a 1000-fold increased resistance, which was further enhanced upon increased P-gp levels (i.e. an additional 3-fold increase in P-gp levels resulted in >6,000-fold resistance). The unique ability of EC1009 to evade recognition by MDR efflux pumps warrants drug development of tubulysin B derivatives as potent antitumor agents which overcome MDR in cancer. PMID- 28637007 TI - c-Fos-dependent miR-22 targets MDC1 and regulates DNA repair in terminally differentiated cells. AB - Terminally differentiated cells have a reduced capacity to repair double-stranded breaks (DSB) in DNA, however, the underlying molecular mechanism remains unclear. Here, we show that miR-22 is upregulated during postmitotic differentiation of human breast MCF-7 cells, hematopoietic HL60 and K562 cells. Increased expression of miR-22 in differentiated cells was associated with decreased expression of MDC1, a protein that plays a key role in the response to DSBs. This downregulation of MDC1 was accompanied by reduced DSB repair, impaired recruitment of the protein to the site of DNA damage following IR. Conversely, inhibiting miR-22 enhanced MDC1 protein levels, recovered MDC1 foci, fully rescued DSB repair in terminally differentiated cells. Moreover, MDC1 levels, IR induced MDC1 foci, and the efficiency of DSB repair were fully rescued by siRNA mediated knockdown of c-Fos in differentiated cells. These findings indicate that the c-Fos/miR-22/MDC1 axis plays a relevant role in DNA repair in terminally differentiated cells, which may facilitate our understanding of molecular mechanism underlying the downregulating DNA repair in differentiated cells. PMID- 28637022 TI - CDKN2A methylation in esophageal cancer: a meta-analysis. AB - CDKN2A is a tumor suppressor gene and is frequently inactivated in human cancers by hypermethylation of its promoter. However, the role and diagnostic value of CDKN2A methylation in esophageal cancer (EC) remains controversial. Therefore, we performed a meta-analysis, including data from 42 articles (2656 ECs, 612 precancerous lesions, and 2367 controls). A significant increase in the frequency of CDKN2A methylation was identified during EC carcinogenesis: cancer vs. controls, odds ratio (OR) = 12.60 (95 % CI, 8.90-17.85); cancer vs. precancerous lesions, OR = 2.89 (95% CI, 2.20-3.79); and precancerous lesions vs. controls, OR = 7.38, 95% (CI, 4.31-12.66). CDKN2A promoter methylation was associated with EC tumor grade (OR = 1.79; 95% CI, 1.20-2.67) and clinical stage (OR = 2.56; 95% CI, 1.33-4.92). Additionally, the sensitivity, specificity, and area under the summary receiver operating characteristic curve (AUC) for diagnosis of EC based on CDKN2A methylation were 0.52 (95% CI, 0.44-0.59), 0.96 (95% CI, 0.93-0.98), and 0.83 (95% CI, 0.79-0.86), respectively. AUCs for blood and tissue sample subgroups were 0.90 and 0.82, respectively. Our findings indicate that CDKN2A methylation has a vital role in EC tumorigenesis and could be a biomarker for early diagnosis of EC. PMID- 28637010 TI - Local application of bacteria improves safety of Salmonella -mediated tumor therapy and retains advantages of systemic infection. AB - Cancer is a devastating disease and a large socio-economic burden. Novel therapeutic solutions are on the rise, although a cure remains elusive. Application of microorganisms represents an ancient therapeutic strategy, lately revoked and refined via simultaneous attenuation and amelioration of pathogenic properties. Salmonella Typhimurium has prevailed in preclinical development. Yet, using virulent strains for systemic treatment might cause severe side effects. In the present study, we highlight a modified strain based on Salmonella Typhimurium UK-1 expressing hexa-acylated Lipid A. We corroborate improved anti-tumor properties of this strain and investigate to which extent an intra-tumoral (i.t.) route of infection could help improve safety and retain advantages of systemic intravenous (i.v.) application. Our results show that i.t. infection exhibits therapeutic efficacy against CT26 and F1.A11 tumors similar to a systemic route of inoculation. Moreover, i.t. application allows extensive dose titration without compromising tumor colonization. Adverse colonization of healthy organs was generally reduced via i.t. infection and accompanied by less body weight loss of the murine host. Despite local application, adjuvanticity remained, and a CT26 specific CD8+ T cell response was effectively stimulated. Most interestingly, also secondary tumors could be targeted with this strategy, thereby extending the unique tumor targeting ability of Salmonella. The i.t. route of inoculation may reap the benefits of systemic infection and aid in safety assurance while directing potency of an oncolytic vector to where it is most needed, namely the primary tumor. PMID- 28637028 TI - Maximizing Outcome in Light Treatment: Patient Behavior as the Light Treatment Delivery System. AB - The effectiveness of light treatment depends on the treatment being properly received by the patient. Examination of the typical light treatment prescription shows that delivery of each component of the prescription consists of a behavior on the part of the patient. Light treatment delivery, and thus light treatment effectiveness, can be maximized by conceptualizing the treatment as a behavior change in the patient and by the application of well-established behavior change techniques. PMID- 28637023 TI - Cationic liquid crystalline nanoparticles for the delivery of synthetic RNAi based therapeutics. AB - RNA interference (RNAi)-based therapeutics have been used to silence the expression of targeted pathological genes. Small interfering RNA (siRNAs) and microRNA (miRNAs) inhibitor have performed this function. However, short half life, poor cellular uptake, and nonspecific distribution of small RNAs call for the development of novel delivery systems to facilitate the use of RNAi. We developed a novel cationic liquid crystalline nanoparticle (CLCN) to efficiently deliver synthetic siRNAs and miRNAs. CLCNs were prepared by using high-speed homogenization and assembled with synthetic siRNA or miRNA molecules in nuclease free water to create CLCN/siRNA or miRNA complexes. The homogeneous and stable CLCNs and CLCN-siRNA complexes were about 100 nm in diameter, with positively charged surfaces. CLCNs are nontoxic and are taken up by human cells though endocytosis. Significant inhibition of gene expression was detected in transiently transfected lung cancer H1299 cells treated with CLCNs/anti-GFP complexes 24 hours after transfection. Biodistribution analysis showed that the CLCNs and CLCNs-RNAi complexes were successfully delivered to various organs and into the subcutaneous human lung cancer H1299 tumor xenografts in mice 24 hours after systemic administration. These results suggest that CLCNs are a unique and advanced delivery system capable of protecting RNAi from degradation and of efficiently delivering RNAi in vitro and in vivo. PMID- 28637026 TI - Clinic characteristics of psoriasis in China: a nationwide survey in over 12000 patients. AB - Psoriasis is a worldwide chronic inflammatory disease, involving both skin and joints. In order to characterize psoriasis in Han Chinese population, we conducted this nationwide prospective and hospital based survey, in which 56 hospitals with departments of dermatology participated, located in 33 cities across China. A total of 12,031 outpatients with psoriasis were registered during 2009 to 2010, which the data was collected by standard questionnaires. The main data acquisition included demographics, family history, disease status and other comorbidities. Physical and dermatological examination, including body surface area (BSA) and psoriasis area severity index (PASI) were applied to evaluate the disease severity. Descriptive statistics, 2 tailed t-test and chi-square test were used appropriately for the statistical analysis. From the study, we found that the male and female ratio of the patients was 1.49:1. Mean age of onset was 30.2 +/- 14.5 years for males and 27.1 +/- 15.6 years for females (P < 0.05). Scalp was the most common onset site (52.8%), The mean PASI was 18.70 +/- 10.01, indicating that most patients presenting at the hospitals had moderate-to-severe psoriasis and the majority was psoriasis vulgaris (96.5%). Among 12,031 patients, 23.1% had a family history of psoriasis,16.1% had comorbidities, and 29.9% had nail changes. The most important aggravation factor was season change (60.2%), followed by psychological stress (34.5%), and there significant differences between genders on trigger factors. In conclusion, this study characterizing psoriasis in Han Chinese population, could be used as basic data for future study. PMID- 28637029 TI - Blue-Enriched Morning Light as a Countermeasure to Light at the Wrong Time: Effects on Cognition, Sleepiness, Sleep, and Circadian Phase. AB - Light during the day and darkness at night are crucial factors for proper entrainment of the human circadian system to the solar 24-h day. However, modern life and work styles have led to much more time spent indoors, often with lower daytime and higher evening/nighttime light intensity from electrical lighting than outdoors. Whether this has long-term consequences for human health is being currently investigated. We tested if bright blue-enriched morning light over several days could counteract the detrimental effects of inadequate daytime and evening lighting. In a seminaturalistic, within-between subject study design, 18 young participants were exposed to different lighting conditions on 3 evenings (blue-enriched, bright orange, or dim light), after exposure to 2 lighting conditions (mixed blue-enriched light and control light, for 3 days each) in the mornings. Subjective sleepiness, reaction times, salivary melatonin concentrations, and nighttime sleep were assessed. Exposure to the blue-enriched morning lighting showed acute wake-promoting effects and faster reaction times than with control lighting. Some of these effects persisted until the evening, and performance improved over several days. The magnitude of circadian phase shifts induced by combinations of 3 different evening and 2 morning lighting conditions were significantly smaller with the blue-enriched morning light. During the night, participants had longer total sleep times after orange light exposure than after blue light exposure in the evening. Our results indicate that bright blue-enriched morning light stabilizes circadian phase, and it could be an effective counterstrategy for poor lighting during the day and also light exposure at the wrong time, such as in the late evening. PMID- 28637031 TI - Association between Metabolic Syndrome and Serum Nerve Growth Factor Levels in Women with Overactive Bladder. AB - OBJECTIVE: This study aimed to determine the association between overactive bladder (OAB), metabolic syndrome (MetS) and serum nerve growth factors (NGF). STUDY DESIGN: Serum samples from a group of 90 women that included patients with OAB (group 1), patients with both OAB and MetS (group 2) and healthy women without OAB and MetS (group 3). Each group included 30 patients. Serum levels of NGF were compared among the groups. RESULTS: When the groups were compared with respect to NGF levels, group 2 was found to have significantly higher NGF levels (p = 0.001). A NGF threshold of >380 ng/mL had a sensitivity of 81.7% and a specificity of 100% to discriminate between groups 2 and 3. CONCLUSION: Our findings support the theory that possible sympathetic overactivity, proinflammatory status, oxidative stress and other pathological conditions associated with MetS and potentially involved in the development of OAB lead to increased serum NGF levels. These findings may help to shed light on the complicated pathogenesis of OAB. PMID- 28637030 TI - Patency Capsule Tolerability in School-Aged Children. AB - BACKGROUND: A patency capsule (PC) can help predict capsule endoscope (CE) retention; however, PC tolerability is unknown in children. We retrospectively evaluated PC tolerability in school-aged children. METHODS: Sixty-one patients (median age, 12.9 years; range 7.4-17.3 years) who underwent PC examination were analyzed for occurrence and determinants of ingestion difficulty and relationships between ingestion of the 2 capsules. We defined ingestion difficulty as taking 30 min or more, or failure, to ingest the PC. RESULTS: Thirty-nine patients (64%) successfully ingested the PC without ingestion difficulty. The other 22 had ingestion difficulty and were significantly younger (11.7 +/- 2.2 vs. 13.0 +/- 1.8 years; p = 0.04) and shorter (143.3 +/- 14.0 vs. 154.6 +/- 12.5 cm; p = 0.003) than those without ingestion difficulty. Multivariate analysis showed that the most significant factor for predicting PC ingestion difficulty was height (cutoff value, 152 cm). Time to ingest the CE was significantly shorter than that for PC ingestion (8 +/- 32 vs. 20 +/- 58 min; p = 0.01). All patients indicated that ingestion of the CE was easier because of its smooth surface compared with the PC. CONCLUSIONS: PC ingestion is not guaranteed in school-aged children. PC ingestion ability should be evaluated by considering the child's height and lack of experience ingesting capsules prior to PC examination. PMID- 28637032 TI - Investigation of an Immediate Effect of Bright Light on Oxygen Consumption, Heart Rate, Cortisol, and alpha-Amylase in Seasonal Affective Disorder Subjects and Healthy Controls. AB - BACKGROUND: Body (fat) mass has been shown to decrease following bright light treatment for overweight women, irrespective of their seasonal (light) dependence. It is not known if this is due to an (immediate) increase of metabolism. METHODS: Ten women with seasonal affective disorder (SAD) and 10 non SAD women matched by age, body mass index, and menopausal status participated in a laboratory study in the morning, twice within 1-5 days. During one session, bright light (4,300 lx) was presented for 30 min, and during the other session, red light (250 lx "placebo") was used. After an initial 15 min of sitting quietly in an experimental chamber, 10-min measurements were done before, at the end, and 15 min after light exposure; the subjects remained seated for 80 min in total. The measurements included 5-min oxyspirography (oxygen consumption, carbon dioxide emission, and heart rate), saliva sampling for the estimation of cortisol and alpha-amylase concentrations, and self-rating of mood, energy, and sleepiness. RESULTS: There was no light-specific effect on the measured variables, except that sleepiness was reduced more with bright light than with red light in the combined group. alpha-Amylase values were lower in the SAD patients than in the non-SAD controls. CONCLUSIONS: Morning artificial bright light, in comparison with dim red light, had no immediate effect on metabolism and resting sympathetic tone, though subjective sleepiness decreased more with bright light. SAD patients have low salivary alpha-amylase levels, indicating lower sympathetic tone. PMID- 28637035 TI - Is There a Relationship between Vegetarianism and Seasonal Affective Disorder? A Pilot Study. AB - BACKGROUND AND AIM: Seasonal patterns of food intake are found in healthy individuals and particularly in patients with seasonal affective disorder (SAD). One nutritional choice is a vegetarian diet. METHODS: In a Finnish population study, FINRISK 2012, information about diet and SAD was collected. In a Dutch outpatient clinic, SAD patients were asked if they were vegetarian. RESULTS: The percentage of SAD patients among Finnish vegetarians was 4 times higher than in the normal population. The percentage of vegetarians among the SAD patients in a Dutch outpatient clinic was 3 times higher than in the normal population. In the Dutch population, the seasonal loss of energy, in particular, is related to vegetarianism. CONCLUSION: These findings suggest a possible link between vegetarianism and SAD. PMID- 28637033 TI - Quantitative Swept-Source Optical Coherence Tomography of Early Enamel Erosion in vivo. AB - Swept-source optical coherence tomography (SS-OCT) shows potential for the in vivo quantitative evaluation of micro-structural enamel surface phenomena occurring during early erosive demineralization. This randomized controlled single-blind cross-over clinical study aimed to evaluate the use of SS-OCT for detecting optical changes in the enamel of 30 healthy volunteers subjected to orange juice rinsing (erosive challenge) in comparison to mineral water rinsing (control), according to wiped and non-wiped enamel surface states. Participants were randomly allocated to 60 min of orange juice rinsing (pH 3.8) followed by 60 min of water rinsing (pH 6.7) and vice versa, with a 2-week wash-out period. In addition, the labial surfaces of the right or left maxillary incisors were wiped prior to SS-OCT imaging. An automated ImageJ algorithm was designed to analyse the back-scattered OCT signal intensity (D) after orange juice rinsing compared to after water rinsing. D was quantified as the OCT signal scattering from the 33 um sub-surface enamel, normalised by the total OCT signal intensity entering the enamel. The back-scattered OCT signal intensity increased by 3.1% (95% CI 1.1 5.1%) in the wiped incisors and by 3.5% (95% CI 1.5-5.5%) in the unwiped incisors (p < 0.0001). Wiping reduced the back-scattered OCT signal intensity by 1.7% (95% CI -3.2 to -0.3%; p = 0.02) in comparison to the unwiped enamel surfaces for both rinsing solutions (p = 0.2). SS-OCT detected OCT signal changes in the superficial sub-surface enamel of maxillary central incisor teeth of healthy volunteers after orange juice rinsing. PMID- 28637034 TI - Recovery of Food Intake after Gastrectomy for Gastric Cancer: Based on a Large Scale Gastric Cancer Cohort. AB - BACKGROUND: This study was aimed at evaluating the food intake and nutritional status of patients who underwent gastrectomy for gastric cancer based on a large scale gastric cancer cohort. METHODS: An observational prospective cohort study for gastric cancer has been conducted since 2010. From the cohort data, we selected the data for patients who completed at least 2 days of 3-day diet diaries and who underwent subtotal gastrectomy (STG) or total gastrectomy (TG). As a control group, patients who underwent endoscopic submucosal dissection were also included. The collected diet data were converted to macro- and micronutrients using computerized software, and the nutrient intakes were compared. RESULTS: Among 6,556 patients who participated in the cohort study from 2011 to 2016, 1,289 patients who completed at least 2 days of 3-day diet diaries were included in this study. During the postoperative 3-month period, body weight was significantly decreased in the and TG groups. However, there was no difference in nutrient intake among the 3 groups except vitamin D and calcium intake. Similar results were observed during the postoperative 12 months period. CONCLUSIONS: Postoperative body weight loss and anemia might originate from altered absorptive function and metabolic change after gastrectomy rather than decreased nutrient intake. PMID- 28637036 TI - Differentiating Incident from Recurrent Stroke Using Administrative Data: The Impact of Varying Lengths of Look-Back Periods on the Risk of Misclassification. AB - BACKGROUND/AIMS: Administrative data are widely used to monitor epidemiological trends in stroke and outcomes; yet there is scant empirical guidance on how to best differentiate incident from recurrent stroke. METHODS: We identified all hospital admissions in New South Wales, Australia, with a principal stroke diagnosis from July 1, 2013 to June 30, 2014, linked to 12 years of previous admissions. We calculated the proportion of cases identified with a prior stroke to determine the number of years of look-back required to minimise misclassification of incident and recurrent strokes. RESULTS: Using the maximum available look-back period of 12 years, 1,171 out of 8,364 eligible stroke cases (14.0%) had a stroke history. A 1-year look-back period identified only 25.1% of these patients and 1 in 10 stroke cases were misclassified as incident. With a 10 year clearance period, less than 1 in 100 stroke cases were misclassified as incident. The risk of misclassification was lower in patients younger than 65 years and in those with haemorrhagic stroke. CONCLUSION: Hospital administrative data sets linked to prior admissions can be used to distinguish recurrent from incident stroke. The risk of misclassifying recurrent stroke cases as incident events is negligible with a look-back period of 10 years. PMID- 28637037 TI - Surgical Site Infection after Hepatectomy for Hepatocellular Carcinoma. AB - AIMS: To clarify the clinical impact, risk factors, and preventive methods for surgical site infection (SSI) after hepatectomy for hepatocellular carcinoma (HCC). METHODS: We included 879 consecutive patients who underwent hepatectomy for HCC between 2002 and 2011. Univariate and multivariate analyses were conducted to identify the risk factors for incisional and organ/space SSIs. ORs and 95% CIs are reported. RESULTS: The incidences of incisional and organ/space SSIs were 24 (2.7%) and 73 (8.3%), respectively. High body mass index, multiple resections, and organ/space SSI were associated with incisional SSIs, while repeat hepatectomy (OR 2.14, 95% CI 1.27-3.60), ascites (OR 2.97, 95% CI 1.55 5.48), and bile leakage (OR 4.77, 95% CI 2.77-8.11) were independent risk factors for organ/space SSI. Among the cases with bile leakage, lower rates of organ/space SSIs tended to be observed in patients with cystic duct tubes than in patients without such tubes (13.2 vs. 26.5%, p = 0.157). Retrograde drain infections increased when drain placement was prolonged for more than 4 postoperative days. CONCLUSION: Bile leakage was associated with the greatest risk of organ/space SSI after hepatectomy for HCC. Cystic duct tubes might be useful for preventing bile leakage and subsequent organ/space SSI after procedures that extensively expose Glissonean pedicles. PMID- 28637038 TI - Synergic Impact of Vascular Calcification and Low Autonomic Tone in Mortality of Hemodialysis Patients. AB - BACKGROUND: Both cardiovascular calcification and autonomic dysfunction are frequently encountered in hemodialysis patients. We aimed to investigate the relationship between cardiovascular calcification and heart rate variability (HRV) and their influence on long-term outcome. METHODS: Seventy-eight hemodialysis patients underwent echocardiogram and radiography of the pelvis and hands to identify valvular and vascular calcification. HRV was evaluated using a commercial machine. RESULTS: Based on the average, the patients were divided into higher and lower subgroups of high frequency (HF) and low frequency (LF) respectively. Patients with higher LF were younger and were found to have a lower proportion of diabetes. Their hemoglobin, albumin, and bone morphogenic protein (BMP)-7 levels were significantly higher and both high-sensitive C-reactive protein (hs-CRP) and osteoprotegerin levels were lower (all p < 0.05). In patients of the higher HF group, the proportion of diabetes was lower but they were found to have higher levels of BMP-7 and lower levels of hs-CRP, interleukin 6 (all p < 0.05). Significantly higher LF and HF were noted in patients without vascular calcification, but only hand artery (HA) calcification was negatively correlated with both LF and HF in multivariate analysis. Low LF and high hs-CRP were the independent predictors of mortality. Coexistence of low LF band and HA calcification was associated with the worse outcome. CONCLUSIONS: Abnormal autonomic nervous function was closely related to inflammation and mortality in hemodialysis patients. Calcification of HA was associated with autonomic dysfunction and patients with lower autonomic tone and HA calcification had the highest mortality rate in this population. PMID- 28637040 TI - A Possible Role of Therapeutic Drug Monitoring in Virological Breakthrough during Simeprevir and PEG-IFN Treatment in HCV-4. PMID- 28637039 TI - Different Impacts of Preoperative Radiotherapy and Chemoradiotherapy on Oncological Outcomes in Patients with Stages II and III Lower Rectal Cancer: A Propensity Score Analysis. AB - BACKGROUND/AIMS: The neoadjuvant therapy for locally advanced rectal cancer has been changed from radiotherapy (RT) to chemoradiotherapy (CRT). This study is aimed at evaluating the benefit of CRT in patients with stage II or III lower rectal cancer, with regard to the impact on recurrence. METHODS: A total of 474 patients with clinical stage II or III lower rectal cancer who received either preoperative RT (n = 221) or CRT (n = 253) followed by total mesorectal excision were identified from our institutional database. Propensity score analysis was performed to mitigate selection biases. RESULTS: Among stage II patients, the CRT group showed a significantly lower 5-year local recurrence rate than the RT group (3.0 vs. 14.8%, p = 0.002). In contrast, among stage III patients, the CRT group showed a significantly lower 5-year distant recurrence rate than the RT group (27.8 vs. 42.6%, p = 0.04) and also a better 5-year recurrence-free survival (64.2 vs. 48.3%, p = 0.03). CONCLUSIONS: Addition of concurrent chemotherapy to preoperative RT significantly enhanced the local control in stage II patients and decreased distant recurrence in stage III patients. The oncological benefit of CRT may differ between patients with stage II or III rectal cancer. PMID- 28637042 TI - Visions and the Progress of Science. PMID- 28637041 TI - The Effects of Fungicides on Human 3beta-Hydroxysteroid Dehydrogenase 1 and Aromatase in Human Placental Cell Line JEG-3. AB - Placenta secretes a large amount of progesterone and estradiol, which are critical for maintaining pregnancy. In human placenta, 3beta-hydroxysteroid dehydrogenase 1 (HSD3B1) catalyzes pregnenolone to form progesterone, and aromatase (CYP19A1) catalyzes testosterone into estradiol. Fungicides display antifungal activities and are widely used to prevent fungal infections in agricultural plants. These chemicals include azoles, such as tebuconazole (TEB), triadimefon (TRI), and vinclozolin (VCZ) or organotins, such as tributyltin (TBT) and tetrabutyltin (TTBT). Fungicides may disrupt the activities of these 2 enzymes. In the present study, we investigated the effects of these fungicides on steroid production in a human placental cell line JEG-3 and on HSD3B1 and CYP19A1 activities. Of all fungicides tested at 100 umol/L, only TBT inhibited pregnenolone-mediated progesterone production in JEG-3 cells by over 50%. Except TTBT, all other 4 fungicides inhibited testosterone-mediated estradiol production by over 50%. TBT was a moderate HSD3B1 inhibitor with a half maximal inhibitory concentration (IC50) of 45.60 +/- 0.12 umol/L. When pregnenolone was used to determine the mode of inhibition, TBT was a competitive inhibitor of HSD3B1. The IC50 values of TEB, TRI, VCZ, and TBT for CYP19A1 were 56.84 +/- 0.13, 58.73 +/- 0.14, 57.42 +/- 0.171, and 4.58 +/- 0.048 umol/L, respectively. TEB, TRI, and VCZ were noncompetitive inhibitors of CYP19A1, while TBT was a competitive inhibitor of this enzyme. Therefore, they are endocrine disruptors. PMID- 28637043 TI - Editorial. PMID- 28637044 TI - Depressed Patients Hospitalized in Southeast-Facing Rooms Are Discharged Earlier than Patients in Northwest-Facing Rooms. AB - BACKGROUND AND AIM: Improvement in patients admitted to inpatient wards with severe depression is slow, and such patients are often discharged with residual symptoms which put them at risk for relapse. New treatments that can speed up recovery are highly desired. This naturalistic follow-up study in a specialized affective disorders unit investigated the impact of daylight on the length of hospital stay and improvement of depression. METHODS: For a period of 1 year, we collected data on sociodemographics, length of stay, vitamin D, and depression severity for patients in an inpatient affective disorders unit. The ward is located with one facade that faces southeast (SE); the opposite one faces northwest (NW) and receives far less light and no direct sunlight during winter. RESULTS: SE-facing rooms received far more daylight than NW-facing rooms. The length of stay was significantly lower in the SE rooms, i.e., 29.2 (+/-26.8) versus 58.8 (+/-42.0) days in the NW rooms (p = 0.01). There was a statistically nonsignificant greater reduction of 52.2% in depression severity for the patients staying in the SE rooms compared to 42.2% in the NW rooms, which may nevertheless be clinically relevant. CONCLUSION: Due to the study design, no causality for the observed difference in length of stay can be given, but the results support findings in previous studies of the importance of architectural orientation providing natural daylight as a factor for improvement. PMID- 28637045 TI - Effects of Injection of Gamma-Aminobutyric Acid Agonists into the Nucleus Accumbens on Naloxone-Induced Morphine Withdrawal. AB - AIMS: This study was to investigate the effects of local administration of gamma aminobutyric acid (GABA) agonists into the nucleus accumbens (NAc) on naloxone induced morphine withdrawal symptoms. METHODS: Bilateral guide cannulas were stereotaxically implanted in the shell or core regions of the NAc of Sprague Dawley rats. After a recovery period, 3 morphine pellets, each consisting of 75 mg morphine base, were placed subcutaneously on the first and third days of the study with the rats under mild ether anaesthesia. The GABA agonists, baclofen hydrochloride or muscimol hydrobromide, were injected into the NAc, and morphine withdrawal was induced by naloxone on the fifth day. RESULTS: Administration of baclofen to the shell or core regions of the NAc of Sprague-Dawley rats led to statistically significant decreases in both behavioural and locomotor activity parameters during the morphine withdrawal period, compared to the control group. However, there were no statistically significant changes in locomotor activity or withdrawal behavioural parameters, with the exception of wet dog shakes, between control and muscimol-treated groups. CONCLUSION: These findings show that GABAergic conduction in the NAc is effective on the morphine withdrawal symptoms, and that both the shell and core regions of the NAc are associated with this effect. PMID- 28637047 TI - Pleural Adhesion Assessment as a Predictor for Pneumothorax after Endobronchial Valve Treatment. AB - BACKGROUND: Pneumothorax after bronchoscopic lung volume reduction using one-way endobronchial valves (EBVs) in patients with advanced emphysema occurs in approximately 20% of patients. It is not well known which factors predict the development of pneumothorax. OBJECTIVE: To assess whether pleural adhesions on pretreatment high-resolution computed tomography (HRCT) scans are associated with pneumothorax occurrence after EBV treatment. METHODS: HRCT scan analyses were performed on all patients who received EBV treatment in a randomized controlled trial. Three blinded readers scored adhesions by number and by measuring the longest axis of each pleural adhesion in the treated lung. The Pleural Adhesion Score (PAS) was calculated by adding 1 point for each small pleural lesion (<1 mm), 5 points for each medium-sized lesion (1-5 mm), and 10 points for each large lesion (>5 mm). RESULTS: The HRCT scans of 64 treated patients were assessed, of whom 14 developed pneumothorax. Patients who developed pneumothorax had a higher median number of pleural adhesions, 2.7 (IQR 1.9-4) compared to 1.7 (1-2.7) adhesions in the group without pneumothorax (p < 0.01). The PAS in the group with pneumothorax was higher compared to that in the group without: 14.3 (12.4-24.1) versus 6.7 (3.7-11.2) (p < 0.01). A threshold PAS of >=12 was associated with a higher risk of pneumothorax (OR 13.0, 95% CI 3.1-54.9). A score <12 did not rule out the occurrence of pneumothorax. CONCLUSION: A higher number of pleural adhesions on HRCT with a subsequent higher PAS in the treated lung is associated with a higher occurrence of pneumothorax after EBV treatment. PMID- 28637048 TI - Use of Light Therapy by Office-Based Physicians. AB - BACKGROUND: Light therapy (LT) is a non-pharmacological biological treatment that has been used in psychiatry since the 1980s. Previous research has investigated the usage of LT in hospitals. The aim of this study was to examine the pattern of use of LT by office-based physicians. METHODS: A questionnaire was sent by mail to 400 randomly selected doctors in Austria. We made sure that the sample was equally representative of general practitioners (GPs) and psychiatrists, public health service doctors and private doctors, physicians in cities and in the country as well as male and female doctors. Non-responders were asked by phone and e-mail to answer the questionnaire. We achieved a response rate of 27.7%. RESULTS: LT was generally recommended by 67.3% of all physicians (91.6% of the psychiatrists but only 46.6% of the GPs). The recommended location of treatment was patients' homes in 90%. Physicians were asked whether they considered LT to be an appropriate treatment for various disorders. There were affirmative answers from: 94.2% for seasonal affective disorder (SAD), 93.3% for sub-syndromal SAD, 60.6% for non-seasonal recurrent major depressive disorder, 35.6% for jet lag syndrome, 35.6% for chronobiological problems with shift work, 22.1% for insomnia, 13.5% for premenstrual dysphoric disorder, and 10.6% for behavioural problems with Alzheimer's disease. CONCLUSIONS: Our results indicate that LT is regularly recommended by office-based physicians, especially psychiatrists. However, there is potential for greater application of LT in indications other than depressive disorder. The results found here are comparable to previous findings in psychiatric hospitals. PMID- 28637046 TI - The Preoperative Composite Physiologic Index May Predict Mortality in Lung Cancer Patients with Combined Pulmonary Fibrosis and Emphysema. AB - BACKGROUND: It remains unclear whether the preoperative pulmonary function parameters and prognostic indices that are indicative of nutritional and immunological status are associated with prognosis in lung cancer patients with combined pulmonary fibrosis and emphysema (CPFE) who have undergone surgery. OBJECTIVE: The aim of this study is to identify prognostic determinants in these patients. METHODS: The medical records of all patients with lung cancer associated with CPFE who had undergone surgery at Shinshu University Hospital were retrospectively reviewed to obtain clinical data, including the results of preoperative pulmonary function tests and laboratory examinations, chest high resolution computed tomography (HRCT), and survival. RESULTS: Univariate Cox proportional hazards regression analysis showed that a high pathological stage of the lung cancer, a higher preoperative serum carcinoembryonic antigen level, and a higher preoperative composite physiologic index (CPI) were associated with a high risk of death. Multivariate analysis showed that a high pathological stage of the lung cancer (HR: 1.579; p = 0.0305) and a higher preoperative CPI (HR: 1.034; p = 0.0174) were independently associated with a high risk of death. In contrast, the severity of fibrosis or emphysema on chest HRCT, the individual pulmonary function parameters, the prognostic nutritional index, the neutrophil to-lymphocyte ratio, and the platelet-to-lymphocyte ratio were not associated with prognosis. In the Kaplan-Meier analysis, the log-rank test showed significant differences in survival between the high-CPI and the low-CPI group (p = 0.0234). CONCLUSION: The preoperative CPI may predict mortality and provide more powerful prognostic information than individual pulmonary function parameters in lung cancer patients with CPFE who have undergone surgery. PMID- 28637049 TI - Protecting Oligodendrocytes by Targeting Non-Glutamate Receptors as a New Therapeutic Strategy for Ischemic Stroke. AB - Ischemic stroke has many devastating effects within the brain. At the cellular level, excitotoxicity has been a popular pharmacological target for therapeutics. To date, many clinical trials have been performed with drugs that target excitatory neurotransmitter receptors, such as NMDA receptor agonists. The results, however, have been lackluster. Most efforts to understand the impacts of excitotoxicity on the brain have focused primarily on neurons, and to a lesser degree, on gliocytes as cellular targets. Recent evidence suggests that oligodendrocytes (OLGs), the myelin-forming cells in the central nervous system, are damaged by ischemia in a manner completely different from that in neurons. Whereas ischemia primarily damages neurons through overactivation of ionotropic glutamate receptors, the ischemia damage in OLGs occurs through overactivation of H+-gated transient receptor potential channels. Given the differential mechanisms of ischemic injury between neurons and OLGs, strategies to target non-glutamate receptors to prevent OLG damage/demyelination deserve greater attention in drug development. Such strategies, combined with neuroprotective measures, could provide an excellent therapeutic avenue for the treatment of ischemic stroke. PMID- 28637050 TI - Ultrasonography for the Diagnosis of Pneumothorax after Transbronchial Lung Cryobiopsy in Diffuse Parenchymal Lung Diseases. AB - BACKGROUND: Transbronchial lung cryobiopsy (TBLC) can be indicated in diffuse parenchymal lung diseases (DPLDs) when a confident noninvasive diagnosis cannot be made. The 2 most relevant complications of TBLC are bleeding and pneumothorax (PTX). The accuracy of chest ultrasonography (US) for the detection of PTX is higher when compared to chest X-ray (CXR) with reference to computed tomography (CT) scan as a gold standard. OBJECTIVE: We evaluated the accuracy of chest US in detecting PTX after TBLC in patients with DPLDs. METHODS: Patients underwent TBLC during rigid bronchoscopy in deep sedation. Cryobiopsy was performed with fluoroscopic guidance. Three hours later, patients underwent chest US and standard CXR. When there was no concordance between chest US and CXR, chest CT was required. RESULTS: Forty-three patients were enrolled into the study. Cryobiopsy was performed in the right lung in 36 (84%) patients. PTX was diagnosed in 10 (23%) patients by CXR. There was complete agreement between radiologists interpreting CXR (k = 1, 95% CI 1). Chest US was positive for PTX in 11 (25%) patients. There was complete agreement between pulmonologists interpreting chest US (k = 1, 95% CI 1). The prevalence of PTX diagnosed by concordance of CXR and chest US was 23% (10/43, 95% CI 11.8-38.7). The sensitivity and specificity of chest US were 90% (95% CI 55.5-99.7) and 94% (95% CI 79.8-99.3), respectively. Moreover, the positive and negative predictive values were 82% (95% CI 48-98) and 97% (95% CI 84-100), respectively. CONCLUSION: Chest US is a highly sensitive and specific diagnostic tool for the diagnosis of PTX after TBLC. PMID- 28637052 TI - Subtle eye movement metrics reveal task-relevant representations prior to visual search. AB - Visual search is thought to be guided by an active visual working memory (VWM) representation of the task-relevant features, referred to as the search template. In three experiments using a probe technique, we investigated which eye movement metrics reveal which search template is activated prior to the search, and distinguish it from future relevant or no longer relevant VWM content. Participants memorized a target color for a subsequent search task, while being instructed to keep central fixation. Before the search display appeared, we briefly presented two task-irrelevant colored probe stimuli to the left and right from fixation, one of which could match the current target template. In all three experiments, participants made both more and larger eye movements towards the probe matching the target color. The bias was predominantly expressed in microsaccades, 100-250 ms after probe onset. Experiment 2 used a retro-cue technique to show that these metrics distinguish between relevant and dropped representations. Finally, Experiment 3 used a sequential task paradigm, and showed that the same metrics also distinguish between current and prospective search templates. Taken together, we show how subtle eye movements track task relevant representations for selective attention prior to visual search. PMID- 28637051 TI - Teaching Transnasal Endoscopy to Graduate Students Without a Hospital or Simulation Laboratory: Pool Noodles and Cadavers. AB - Purpose: This study reports on a training opportunity in endoscopy in which speech-language pathology graduate students use inanimate objects and cadavers. Best practices for transnasal endoscopy in vivo require a physician to be nearby, but many graduate programs do not have this access. Method: Endoscopy was offered as a graduate elective. Students (13 women) initially learned to manipulate the endoscope through the lumen of a swimming pool noodle that was embedded with trinkets. Endoscopic examination of inanimate objects became increasingly complex, followed by endoscopic examination of a cadaver. Results: Pre- and postexamination measures and qualitative data from the 13 students revealed that students increased in confidence and in interest in this aspect of the field. All students met practical competencies for handling the endoscope, passing the endoscope on a narrow tube, and visualizing objects. Some students had the opportunity to pass the endoscope on a peer and did so successfully. Conclusion: For programs with a cadaver lab available, this protocol offers an affordable option compared with purchasing a simulator. For those with neither a cadaver lab nor a simulation lab, passing the endoscope on inanimate objects alone is beneficial to student development and learning. PMID- 28637053 TI - A new analytical method for characterizing nonlinear visual processes with stimuli of arbitrary distribution: Theory and applications. AB - Characterization of the functional relationship between sensory inputs and neuronal or observers' perceptual responses is one of the fundamental goals of systems neuroscience and psychophysics. Conventional methods, such as reverse correlation and spike-triggered data analyses are limited in their ability to resolve complex and inherently nonlinear neuronal/perceptual processes because these methods require input stimuli to be Gaussian with a zero mean. Recent studies have shown that analyses based on a generalized linear model (GLM) do not require such specific input characteristics and have advantages over conventional methods. GLM, however, relies on iterative optimization algorithms and its calculation costs become very expensive when estimating the nonlinear parameters of a large-scale system using large volumes of data. In this paper, we introduce a new analytical method for identifying a nonlinear system without relying on iterative calculations and yet also not requiring any specific stimulus distribution. We demonstrate the results of numerical simulations, showing that our noniterative method is as accurate as GLM in estimating nonlinear parameters in many cases and outperforms conventional, spike-triggered data analyses. As an example of the application of our method to actual psychophysical data, we investigated how different spatiotemporal frequency channels interact in assessments of motion direction. The nonlinear interaction estimated by our method was consistent with findings from previous vision studies and supports the validity of our method for nonlinear system identification. PMID- 28637055 TI - A Pilot Study on Professional Documentation: Do We Write From a Strengths Perspective? AB - Purpose: There is growing evidence supporting the use of strengths-based practices when serving families. The purpose of this study was to examine the use of strengths-based approaches in the context of written professional documentation. We specifically explored whether or not interdisciplinary clinicians in one university-based medical center clinic write from a strengths perspective (e.g., writing focuses on abilities rather than on deficits) when documenting child behavior in autism diagnostic clinics. Method: We gathered narrative-based writing samples (a total of 299 phrases) from 20 patient reports. Using a coding system developed by the research team (intraclass correlation coefficient = .801 on final definitions and coding system), we analyzed the extent to which interdisciplinary clinicians included strengths-based language (e.g., language that emphasizes a person's strengths rather than limitations) in their written documentation. An independent researcher coded a random sample (20% of entire sample) of the data to document reliability of the coded data (97% interrater agreement). Results: Our findings indicated that clinicians in our study used deficit-based language significantly more than neutral and strengths based language in written documentation. Conclusion: This preliminary evidence suggests a need to reflect upon our own understanding of strengths-based practices and the way professionals write about children in clinical documentation. PMID- 28637054 TI - Modeling Alphabet Skills as Instructive Feedback Within a Phonological Awareness Intervention. AB - Purpose: This study evaluated the efficacy of an instructive feedback strategy for modeling letter names and sounds during presentation of positive feedback within a small-group phonological awareness intervention for preschoolers. Method: Two experiments were conducted using multiple-baseline designs across children and behaviors. Letter name and sound identification and performance on a phonological awareness fluency measure served as the primary outcome variables. Six children completed Experiment 1. A progressive time delay was added to instructive feedback to elicit a response from the 9 children in the second experiment. Results: In the first experiment, 6 children demonstrated gains on phonological awareness but not alphabet knowledge. With the addition of progressive time delay in the second experiment, all 9 children demonstrated gains on letter name and sound identification as well as phonological awareness skills. Conclusions: Progressive time delay to prompt children's responses appears to bolster the effects of instructive feedback as an efficient strategy for modeling alphabet skills within a broader early literacy curriculum. Modeling alphabet skills did not detract from, and may have enhanced, phonological awareness instruction for preschoolers. PMID- 28637056 TI - [Urosepsis in Children]. AB - Urinary tract infections (UTI) are the most common infectious diseases in children. Urosepsis in childhood, though rare, is the most complicated possible variant. In newborns and infants, unspecific symptoms are a significant barrier to a fast and reliable diagnosis, which is crucial to successful treatment. In addition to urine and laboratory tests as well as non-invasive examinations (ultrasound), there may be an indication for invasive examinations of the kidneys (DMSA scans) in cases of a severe infection. Conservative therapy consists of targeted parenteral antibiotic treatment and paediatric sepsis management. Surgical desobstruction and urinary diversion are indicated if conservative therapy has failed. In addition to catheterised drainage of the upper and lower urinary tract, open surgery techniques are used in due consideration of the child and situation. Also, causal factors such as congenital malformations of the urinary system leading to impaired urinary drainage (vesicoureteral reflux, obstruction) have to be evaluated and treated. PMID- 28637057 TI - Primary Hyperparathyroidism and Hypercalcemia During Pregnancy. PMID- 28637058 TI - Evaluation of Cases of Abdominal Wall Endometriosis at Universidade Estadual de Campinas in a period of 10 Years. AB - Purpose To determine the clinical and epidemiological characteristics of abdominal wall endometriosis (AWE), as well as the rate and recurrence factors for the disease. Methods A retrospective study of 52 women with AWE was performed at Universidade Estadual de Campinas from 2004 to 2014. Of the 231 surgeries performed for the diagnosis of endometriosis, 52 women were found to have abdominal wall endometriosis (AWE). The frequencies, means and standard deviations of the clinical characteristics of these women were calculated, as well as the recurrence rate of AWE. To determine the risk factors for disease recurrence, Fisher's exact test was used. Results The mean age of the patients was 30.71 +/- 5.91 years. The main clinical manifestations were pain (98%) and sensation of a mass (36.5%). We observed that 94% of these women had undergone at least 1 cesarean section, and 73% had used medication for the postoperative control of endometriosis. The lesion was most commonly located in the cesarean section scar (65%). The recurrence rate of the disease was of 26.9%. All 14 women who had relapsed had surgical margins compromised in the previous surgery. There was no correlation between recurrent AWE and a previous cesarean section (p = 0.18), previous laparotomy (p = 0.11), previous laparoscopy (p = 0.12) and postoperative hormone therapy (p = 0.51). Conclusion Women with previous cesarean sections with local pain or lumps should be investigated for AWE. The recurrence of AWE is high, especially when the first surgery is not appropriate and leaves compromised surgical margins. PMID- 28637059 TI - Erratum to: Persistent Urogenital Sinus: Diagnostic Imaging for Clinical Management. What Does the Radiologist Need to Know? PMID- 28637060 TI - Comparison of Azithromycin versus Erythromycin for Prolongation of Latency in Pregnancies Complicated by Preterm Premature Rupture of Membranes. PMID- 28637061 TI - Multifetal Pregnancy Reduction of Trichorionic Triplet Gestations: What is the Benefit? PMID- 28637062 TI - Prospective Comparison of Enfamil and Similac Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants. PMID- 28637063 TI - Exploring diagnostic and therapeutic implications of endoscopic mucosal resection in EUS-staged T2 esophageal adenocarcinoma. AB - Background and study aims Treatment strategies for clinical (c)T2N0M0 esophageal adenocarcinoma (EAC) are subject to debate owing to the relative inaccuracy of tumor staging by endoscopic ultrasound (EUS), with profound implications in overstaged patients. We aimed to evaluate the final histological diagnosis of patients initially staged as having a cT2 tumor by EUS, and to assess the value of endoscopic reassessment by an interventional endoscopist, followed by an endoscopic resection when deemed feasible. Patients and methods Two distinct cohorts of patients with cT2 EAC as determined by EUS were included: a retrospective surgical cohort of patients treated by primary esophagectomy, and a prospective cohort of patients who underwent an endoscopic reassessment by an interventional endoscopist. The main outcome measure was the final pathological (p)T stage. Results We identified 134 patients with stage T2 EAC from the surgical cohort. In 72 patients treated by primary esophagectomy, 32/72 (44 %) were downstaged to a pT1 tumor. In 12/72 (17 %), the surgical resection specimen showed tumor characteristics that fulfilled the current criteria for a curative endoscopic resection. In 13 prospectively identified patients with cT2N0M0 EAC, an expert endoscopic reassessment was done. In 11/13 (85 %) the lesion appeared endoscopically resectable and a complete endoscopic resection was performed. Histology revealed a pT1 tumor in all 11 patients, with 5/13 (38 %) fulfilling current criteria for a curative endoscopic resection. Conclusions In this study, 44 % of cT2 EACs were in fact pT1 tumors. Curative treatment by endoscopic resection was achieved in more than a third of these cases. To avoid an unnecessary esophagectomy, an endoscopic reassessment by an interventional endoscopist is recommended for all patients with cT2N0M0 EAC. PMID- 28637064 TI - Safety and efficacy of glycopyrrolate as a premedication for endoscopic submucosal dissection: a randomized, double-blind, placebo-controlled study. AB - : Background and study aims Anticholinergic premedication has not been validated for endoscopic submucosal dissection (ESD). In this randomized, double-blind, placebo-controlled trial, we investigated the efficacy and safety of glycopyrrolate as a premedication for ESD. Methods A total of 196 patients undergoing ESD at a single tertiary medical center between December 2014 and February 2016 were randomly allocated to receive one of the following two premedications: glycopyrrolate (0.004 mg/kg intramuscularly [IM]) or placebo (2.0 mL normal saline solution IM). All patients received the premedication 30 minutes prior to ESD in a double-blind manner. The endoscopists reported the ease of performing the procedure and the incidence of secretion-induced hypoxemia, cough, and other procedure-related adverse events. Results Glycopyrrolate and placebo were received by 96 and 100 patients, respectively. ESD was successfully performed in all patients without any serious adverse events related to sedation or ESD. The median visual analog scale for procedure ease was higher in the glycopyrrolate group at 8 (interquartile range [IQR] 7 - 9) vs. 7 (IQR 6 - 8.25); P < 0.001. The proportions of patients with secretion-induced hypoxemia (4.4 % vs. 14.3 %; P = 0.03) and cough (16.7 % vs. 35.7 %; P = 0.005) were lower in the glycopyrrolate group. Conclusions The use of glycopyrrolate as a premedication for ESD significantly improved the ease of performing the procedure and reduced the incidence of secretion-induced hypoxemia and cough during ESD. Glycopyrrolate may be a promising premedication to ensure safe and stable ESD procedures. TRIAL REGISTRATION: Clinical Research Information Service (CRIS): KCT0001540. PMID- 28637067 TI - Erratum to: Impact of Preoperative Computed Tomography Angiogram on Abdominal Flap Breast Reconstruction Outcomes: A Systematic Review. PMID- 28637066 TI - [Surgery for Pulmonary Metastases in Patients with Advanced Soft Tissue and Osteosarcomas]. AB - Background Advanced soft tissue or osteosarcoma is often associated with lung metastases. Curative pulmonary metastasectomy is appropriate for patients with successfully resected primary cancer who show no evidence of extrapulmonary metastases, with proven functional operability and completely resectable metastases. Material and Methods Systematic literature research and qualitative analysis of studies on patients undergoing lung metastasectomy after resection of primary sarcoma published since 01.01.2010. We assessed operative findings, survival data and prognostic factors. Results Pulmonary metastasectomy results in a median postmetastasectomy survival of 8.76 to 69.9 months. Five year survival rates after metastasectomy vary between 21.7 and 56.8%. The patients' prognosis depends particularly on complete resection of all suspected metastases. Intrapulmonary recurrence could be treated by repeated resection, but this procedure requires careful decision for indication. Re-metastasectomy might result in a favourable outcome in selected cases. Conclusion Pulmonary metastasectomy should be considered as treatment of choice in selected patients with isolated lung metastases from osteosarcoma. Optimal indication might lead to an advantage in patients with metastasectomy of isolated lung metastases from soft tissue. PMID- 28637068 TI - Traumatic Suprascapular Nerve Injury at the Notch-A Reason for the Posterior Approach in Brachial Plexus Reconstruction. PMID- 28637069 TI - [Preference Changes Regarding Future Work Area and Intended Position Among German Residents after Four Years of Residency]. AB - Introduction We investigated the preferences of medical residents in Germany with regard to future working place (hospital or private practice) and position (employment/self-employment in private practice; resp. specialist/senior or chief physician in the hospital). This is analysed in a gender comparative perspective, including the influence of parenthood. Methods Annual postal surveys among graduates of seven medical faculties in Germany from their last year ("Practical Year") until after four years of postgraduate training. The return rate at baseline was 48 % and the four surveys after reached rates from 85 % up. In all samples about two thirds were women, which corresponds to the actual gender differentiation in under- and postgraduate training. Descriptive statistics and regression analyses were performed. Results Compared to private practice the hospital is clearly preferred, although the attraction of hospital jobs decreased over the years. The decision for or against the hospital is connected to the discipline. Working in private practice is seen as possibility for part time work. Men prefer self-employment whereas women prefer to work under an employment contract. In the hospital, male doctors prefer to work in leading positions. Those positions are associated with full-time work. Leadership training especially takes place in university hospitals. Discussion Three trends are recognized: Reluctance against leading positions, growing interest for part time work and rising popularity of work as an employee in private practice. Those trends can be understood as a rejection of traditional professional role models. The realization of these preferences is easily feasible because of the current labour market situation. Therefore, emerging problems have to be faced in another way. A change of gender-typical role models was rarely detected. PMID- 28637070 TI - [Complementary Therapies for Cancer]. PMID- 28637065 TI - Evaluation of an e-learning system for diagnosis of gastric lesions using magnifying narrow-band imaging: a multicenter randomized controlled study. AB - Background and study aim Magnifying narrow-band imaging (M-NBI) is useful for the accurate diagnosis of early gastric cancer (EGC). However, acquiring skill at M NBI diagnosis takes substantial effort. An Internet-based e-learning system to teach endoscopic diagnosis of EGC using M-NBI has been developed. This study evaluated its effectiveness. Participants and methods This study was designed as a multicenter randomized controlled trial. We recruited endoscopists as participants from all over Japan. After completing Test 1, which consisted of M NBI images of 40 gastric lesions, participants were randomly assigned to the e learning or non-e-learning groups. Only the e-learning group was allowed to access the e-learning system. After the e-learning period, both groups received Test 2. The analysis set was participants who scored < 80 % accuracy on Test 1. The primary end point was the difference in accuracy between Test 1 and Test 2 for the two groups. Results A total of 395 participants from 77 institutions completed Test 1 (198 in the e-learning group and 197 in the non-e-learning group). After the e-learning period, all 395 completed Test 2. The analysis sets were e-learning group: n = 184; and non-e-learning group: n = 184. The mean Test 1 score was 59.9 % for the e-learning group and 61.7 % for the non-e-learning group. The change in accuracy in Test 2 was significantly higher in the e learning group than in the non-e-learning group (7.4 points vs. 0.14 points, respectively; P < 0.001). Conclusion This study clearly demonstrated the efficacy of the e-learning system in improving practitioners' capabilities to diagnose EGC using M-NBI.Trial registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000008569). PMID- 28637071 TI - [70-year-old Woman with Hypertension Difficult to Stabilize]. PMID- 28637072 TI - [How to Classify and Evaluate Complementary and Alternative Medicines in Oncology]. AB - There are a vast number of complementary and alternative medicines (CAM) in oncology. Also patients' needs for information on these methods are growing. Helping patients to classify and evaluate CAM methods is a challenge. The Cancer Information Service at the German Cancer Research Center has developed a benefit risk-assessment based on evidence-based medicine and individual patient traits: To rate a CAM's benefit, the scientific evidence and the patient's therapeutic goals have to be taken into account. To estimate its risks, both, the method itself and the patient's status of health must be considered. PMID- 28637073 TI - [Complementary and Alternative Medicine in Oncology - What Makes Sense?] AB - The basis of any complementary therapy should be the recommendation of a healthy lifestyle (diet, nutrition, exercise, stress-reduction), and appropriate self help techniques (e. g. thermotherapy, herbal OTC-products) aimed at releasing the patients' most debilitating symptoms. For therapy-resistant or strong symptoms, more invasive interventions or medical treatments with an acceptable evidence base can be used (e. g. acupuncture for cancer pain, herbal prescriptions). The effects of any complementary intervention should be controlled for a period of six weeks after its administration. Patients should be advised not to use products or methods with possibly harmful side effects or negative interactions with conventional medications. PMID- 28637074 TI - [Nutrition in Cancer: Effective in Prevention and Treatment?] AB - Nutritional effects on cancer occurrence and on treatment outcome in cancer patients may depend on food preferences and on the quantity of foods supplied. However, it has been difficult to reliably show beneficial effects of specific dietary concepts on cancer incidence. On the other hand, obesity as a result of chronic overfeeding has been linked firmly to an increased risk of a number of cancers as well as on cancer recurrence after treatment. Metabolic consequences of obesity and other components of the metabolic syndrome may be responsible for inducing and/or promoting cancer growth and should be antagonized by regular moderate physical activity in healthy subjects and in cancer survivors. During cancer treatment and in patients with advanced disease, inadequate food intake and physical inactivity may lead to malnutrition, while recurrent and chronic systemic inflammatory reactions induce chronic catabolism with a preferential loss of muscle and cell mass, condition referred to as cachexia. PMID- 28637075 TI - [Vitamins and Minerals in Oncology]. AB - The use of vitamins and minerals to prevent cancer as well as their supportive use in oncological patients is widespread and often occurs without the knowledge of the treating physician. Beyond general recommendations with regard to a balanced and healthy diet, no evidence exists supporting the use of vitamins and minerals in the prevention of cancer. Furthermore, the diet of oncological patients should contain vitamins and minerals of the same quantity as for healthy individuals. In particular, there is currently no rationale for a high-dosage administration of antioxidants. PMID- 28637076 TI - [Clinical Course of an Early Childhood-Onset Granulomatosis with Polyangiitis]. AB - History A 26-year-old male patient presented with an eight-week history of unspecific symptoms such as weight loss and fever. Besides, he also suffered from haemoptysis, cough, and arthralgia. Since the age of twelve years, the patient has been treated for Wegner's granulomatosis. At the age of 20 years he received a kidney transplant which failed only four years later. Investigations The relapse we clinically suspected was confirmed by CT scan showing bilateral pulmonary manifestations. Moreover, we found highly positive antibodies against proteinase 3. Treatment and course After an induction therapy using Glucocorticoids and Rituximab, accompanied by plasmapheresis, the patient's clinical condition showed a marked improvement. We were able to discharge him continuing the treatment in an outpatient setting. Conclusion Childhood-onset GPA is a life-threatening disease and often characterized by recurring relapses as well as a significantly reduced quality of life for the patient. PMID- 28637077 TI - [Tracheostomy Home Care of Patients after Long Term Ventilation on the ICU - a Position Paper]. PMID- 28637078 TI - [Update: Cardiovascular Sleep Medicine]. AB - The prevalence of sleep-disordered breathing (SDB) is high in patients with cardiovascular diseases. Typical symptoms like daytime sleepiness can be absent and those patients may report unspecific, therapy-resistant symptoms related to their underlying disease. Particularly sleep-related symptoms like nocturia, nocturnal dyspnea and pectangina can be present. Based on the results of recently published studies, the treatment of central sleep apnea in patients with symptomatic, systolic heart failure by adaptive servo-ventilation is no longer recommended. Although the treatment of obstructive sleep apnea did not prevent cardiovascular events, it improved snoring, daytime sleepiness and health-related quality of life. Furthermore, studies imply that treatment of SDB should be considered as an adjunct treatment modality in patients with hypertension and atrial fibrillation. Due to the high prevalence, screening for SDB can help to identify patients at high cardiovascular risk. PMID- 28637079 TI - ? PMID- 28637080 TI - The Prognostic Importance of Bronchoalveolar Lavage Fluid CXCL9 During Minimal Acute Rejection on the Risk of Chronic Lung Allograft Dysfunction. AB - The clinical significance and treatment strategies for minimal acute rejection (grade A1), the most common form of acute rejection (AR), remain controversial. In this retrospective single-center cohort study of 441 lung transplant recipients, we formally evaluate the association between minimal AR and chronic lung allograft dysfunction (CLAD) and test a novel hypothesis using bronchoalveolar lavage (BAL) CXCL9 concentration during minimal AR as a biomarker of subsequent CLAD development. In univariable and multivariable models adjusted for all histopathologic injury patterns, minimal AR was not associated with CLAD development. However, minimal AR with elevated BAL CXCL9 concentrations markedly increased CLAD risk in a dose-response manner. Minimal AR with CXCL9 concentrations greater than the 25th, 50th, and 75th percentile had adjusted hazard ratios (HRs) for CLAD of 1.1 (95% confidence interval [CI] 0.8-1.6), 1.6 (95% CI 1.1-2.3), and 2.2 (95% CI 1.4-3.4), respectively. Thus we demonstrate the utility of BAL CXCL9 measurement as a prognostic biomarker that allows discrimination of recipients at increased risk of CLAD development after minimal AR. BAL CXCL9 measurement during transbronchial biopsies may provide clinically useful prognostic data and guide treatment decisions for this common form of AR, as a possible strategy to minimize CLAD development. PMID- 28637081 TI - Molecular characterization of gluten hydrolysing Bacillus sp. and their efficacy and biotherapeutic potential as probiotics using Caco-2 cell line. AB - AIM: To isolate and characterize indigenous gluten hydrolysing bacteria from wheat sourdough and curd samples and further evaluation of their probiotic potentiality. METHODS AND RESULTS: Indigenous gluten hydrolysing isolates GS 33, GS 143, GS 181 and GS 188 were identified as Bacillus sp. by molecular-typing methods and studied extensively for their functional and probiotic attributes. All the tested isolates could survive at pH 2 and toxicity of 0.3% bile and also exhibited cell surface hydrophobicity and autoaggregation phenotype. The isolates were adhered strongly to Caco-2 cells and coaggregated with Escherichia coli MTCC 433 and Listeria monocytogenes MTCC 1143 preventing pathogen invasion into Caco-2 cells in vitro. In addition, the minimum inhibitory concentration of selected antibiotics for all the investigated gluten hydrolysing isolates was within the breakpoint values as recommended by the European Food Safety Authority. CONCLUSION: The indigenous high intensity gluten hydrolysing bacteria exhibited high resistance to gastric and pancreatic stress and possessed antibacterial, aggregation, adhesion and pathogen exclusion properties, and as a potential probiotics, either alone or in consortium would be useful in the development of gluten-free wheat foods. SIGNIFICANCE AND IMPACT OF THE STUDY: Exploring new indigenous gluten hydrolysing bacteria from wheat sourdough and curd samples would be beneficial in developing gluten-free wheat foods using potential indigenous probiotics. PMID- 28637082 TI - Positive aspects of having had cancer: A mixed-methods analysis of responses from the American Cancer Society Study of Cancer Survivors-II (SCS-II). AB - OBJECTIVE: This study focused on understanding positive aspects of cancer among a large, national sample of survivors, 2, 5, and 10 years' postcancer diagnosis, who responded to the American Cancer Society Study of Cancer Survivors - II (SCS II) survey "Please tell us about any positive aspects of having cancer." METHODS: A sequential mixed methods approach examined (1) thematic categories of positive aspects from cancer survivors (n = 5149) and (2) variation in themes by sociodemographics, cancer type, stage of disease, and length of survivorship. RESULTS: Themes comprised 21 positive aspects within Thornton's typology of benefits that cancer survivors attribute to their illness: life perspectives, self, and relationships. New themes pertaining to gratitude and medical support during diagnosis and treatment, health-related changes, follow-up/surveillance, and helping others emerged that are not otherwise included in widely used existing benefit finding cancer scales. Gratitude and appreciation for life were the most frequently endorsed themes. Sociodemographics and stage of disease were associated with positive aspect themes. Themes were not associated with survivor cohorts. CONCLUSIONS: No differences in perceived positive aspects across survivor cohorts suggest that positive aspects of cancer may exist long after diagnosis for many survivors. However, variation across sociodemographics and clinical variables suggests cancer survivors differentially experience positive aspects from their cancer diagnosis. IMPLICATIONS FOR CANCER SURVIVORS: This analysis provides new information about cancer survivors' perceptions of positive aspects from their cancer and factors associated with benefit finding and personal growth. This information can be useful in further refining quality-of life measures and interventions for cancer survivors. PMID- 28637084 TI - Integra dermal regeneration template for neck reconstruction in a previously irradiated patient. PMID- 28637083 TI - Changes in spiritual well-being and psychological outcomes in ovarian cancer survivors. AB - OBJECTIVE: Because of the poor prognosis of ovarian cancer and concomitant distress, understanding contributors to positive well-being is critical. This study examines spiritual growth as a domain of posttraumatic growth and its contribution to longitudinal emotional outcomes in ovarian cancer. METHODS: Ovarian cancer patients (N = 241) completed measures assessing spirituality (Functional Assessment of Chronic Illness Therapy-Spiritual Well-being-12; subscales: faith, meaning, and peace), depression (Center for Epidemiologic Studies Depression Scale), cancer-specific anxiety (Impact of Event Scale), and total mood disturbance (TMD; Profile of Mood States) prior to surgery and 1-year postsurgery. Stressful life events in the year after diagnosis were measured at 1 year postsurgery. Regressions examined the association between changes in spirituality and depression, anxiety, and TMD at 1-year postsurgery. Additionally, spiritual change was examined as a moderator of the effect of recent life events on mood. RESULTS: Increases in peace were related to lower depression (beta = -.40, P < .001), anxiety (beta = -.20, P = .004), and TMD (beta = -.41, P < .001) at 1 year. Changes in meaning and faith were unrelated to all outcomes. Additionally, changes in peace moderated the effect of stressful life events on depression (beta = -.14, P = .027), anxiety (beta = -.16, P = .05), and TMD (beta = -.17, P = .01), such that those with a high number of life events paired with a decrease in peace experienced the worst psychological outcomes at 1 year. CONCLUSION: These findings suggest that the quality of peace may be the most adaptive facet of spiritual growth in cancer patients. Furthermore, changes in peace appear to moderate the effect of life events on psychological well-being. PMID- 28637085 TI - Successful delivery derived from cryopreserved rare human spermatozoa with novel cryopiece. AB - Herein, we report the clinical outcomes following intracytoplasmic sperm injection (ICSI) with cryopiece cryopreserved rare human spermatozoa from severe male factor infertility patients. We established a novel cryopiece system on the basis of previous studies. In this study, 126 spermatozoa from four patients with non-obstructiveazoospermia (NOA) or severe oligozoospermia were stored in cryopiece and then thawed on the day of the oocyte retrieval, 88 (83%) spermatozoa were recovered with a 47.5% (38 of 80) motile rate. Routine ICSI were performed in enrolled 30 MII oocytes from their spouse with their own spermatozoa, respectively. Twenty-two (73%) fertilization and 19 (86%) zygote cleavage were observed. Finally, a total of 11 embryos were achieved and each female patient received a transplantation of two fresh embryos. Four healthy babies were born at term. In conclusion, our novel cryopiece can be applied in assisted reproduction through ICSI with an effective motile spermatozoa recovery rate, high fertilization rate, and successful pregnancy result. PMID- 28637086 TI - Climate drives plant-pollinator interactions even along small-scale climate gradients: the case of the Aegean. AB - Plant-pollinator network structure is the outcome of ecological and evolutionary processes, and although the importance of environmental factors is beyond doubt, our knowledge of how abiotic factors (e.g. climate) shape plant-pollinator networks remains limited. This knowledge gap is critical, as climate change poses a major threat to ecosystems, especially in the Mediterranean. This study focuses on one of the hottest parts of the Mediterranean Basin, the Aegean Archipelago, Greece, and examines how climate affects species richness and network properties (e.g. nestedness, modularity and specialisation) - either directly or indirectly through species richness. We sampled systematically 39 local plant-pollinator networks on eight islands along a north-south climate gradient in the Aegean. All plant-pollinator material used in the analyses was collected in 2012 and identified to species level. Aspects of climate used in the models were expressed as average conditions (mean temperature and annual precipitation) or as seasonal variability (isothermality and temperature seasonality). Structural properties of plant-pollinator networks were found to be strongly associated with species richness, which was in turn affected by climate, implying that pollination network structure is driven indirectly by climate. In addition, climate had a direct effect on network structure, especially on modularity and specialisation. Different aspects of climate affected network properties in different ways. We highlight that even in a relatively narrow latitudinal gradient, such as within the Aegean Sea region, climate constitutes a significant driver of plant pollinator interactions. PMID- 28637088 TI - Latitudinal variation in the competition-colonisation trade-off reveals rate mediated mechanisms of coexistence. AB - Theories of species coexistence often describe a trade-off between colonising and competitive abilities. In sessile marine invertebrates, this trade-off can manifest as trends in species distributions relative to the size of isolated patches of substrate. Based on their abilities to find available substrate and competitively exclude neighbours, good colonisers tend to dominate smaller patches, whereas better competitors tend to monopolise larger patches. In theory, species with equivalent colonising and competitive abilities should display similar distributions across patch sizes. We used patch size to observe this manifestation of the competition-colonisation trade-off over 20 degrees of latitude. The trade-off was more readily observed at lower latitudes and was proportional to the 'ecological age' of communities (i.e. the degree of resource acquisition and likelihood of species interactions). Results suggest that ecological age may mediate the prominence of stochastic or deterministic coexistence mechanisms and will depend on the rate of ecological processes. PMID- 28637087 TI - Deleting pck improves growth and suppresses by-product formation during 1,3 propanediol fermentation by Klebsiella pneumoniae. AB - AIMS: To investigate the role of phosphoenolpyruvate (PEP) carboxylation in cell metabolism in Klebsiella pneumoniae. METHODS AND RESULTS: The effects of deleting pck, which encodes PEP carboxykinase (PCK), and/or ppc, which encodes PEP carboxylase (PPC), on growth, enzyme activity and metabolite formation of Kl. pneumoniae were investigated. A self-regulatory mechanism of PEP carboxylation was found in ppc- or pck-deficient mutants, which resulted in almost no change in succinate formation. However, almost no growth was observed in a ppc- and pck deficient mutant. Interestingly, only deleting pck affected the energy metabolism and promoted aerobic cell growth. Under micro-aerobic conditions, although there was only a small (8.1%) increase of 1,3-propanediol production by such pck deficient mutant during a 2-l fed-batch process, the by-products 2,3-butanediol and acetate significantly decreased by 73.0% and 54.8%, respectively, compared with those in the parent strain. CONCLUSIONS: PEP carboxylation could be a critical anaplerotic reaction for converting C3 to C4 metabolites in the central metabolism of Kl. pneumoniae. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first to identify the critical role of PEP carboxylation, as well as those of PPC and PCK, which are responsible for this reaction, in Kl. pneumoniae. In addition, the pck-deficient mutant was proven to be a valuable 1,3-propanediol producer. PMID- 28637089 TI - Sperm DNA damage measured by sperm chromatin structure assay in men with a history of undescended testes. AB - The aim of this study was to compare sperm DNA damage between men with a history of congenital undescended testis (UDT) and men with a history of acquired UDT. A long-term follow-up study of men with previous UDT was performed. Fifty men with congenital UDT who had undergone orchiopexy at childhood age, 49 men with acquired UDT after a 'wait-and-see'-protocol (e.g. awaiting spontaneous descent until puberty and perform an orchiopexy in case of non-decent), and 22 healthy proven fertile men were included. The DNA fragmentation index (DFI) using sperm chromatin structure assay (SCSA) was used to express the level of sperm DNA damage. Decreased fertility potential was considered if DFI was above 30%. Sperm DNA damage was not statistically different between cases of congenital and acquired UDT. DFI was significantly more often >30% in the complete group of men with congenital UDT (9/50; 18%) and in the subgroup with bilateral congenital UDT (3/7; 43%) in comparison with the controls (none) (p-value 0.049 and 0.01, respectively). Age at orchiopexy in congenital UDT had no statistical effect on DNA damage. In men with acquired UDT, DFI did not statistically differ between those having undergone orchiopexy and those experiencing spontaneous descent. This study supports the hypothesis that UDT is a spectrum representing both congenital UDT and acquired UDT. Sperm DNA damage at adult age is not influenced by age at orchiopexy in congenital UDT cases and by orchiopexy or spontaneous descent in acquired UDT cases. PMID- 28637090 TI - Early warning systems and rapid response to the deteriorating patient in hospital: A realist evaluation. AB - AIM: To test the Rapid Response Systems programme theory against actual practice components of the Rapid Response Systems implemented to identify those contexts and mechanisms which have an impact on the successful achievement of desired outcomes in practice. BACKGROUND: Rapid Response Systems allow deteriorating patients to be recognized using Early Warning Systems, referred early via escalation protocols and managed at the bedside by competent staff. DESIGN: Realist evaluation. METHODS: The research design was an embedded multiple case study approach of four wards in two hospitals in Northern Ireland which followed the principles of Realist Evaluation. We used various mixed methods including individual and focus group interviews, observation of nursing practice between June-November 2010 and document analysis of Early Warning Systems audit data between May-October 2010 and hospital acute care training records over 4.5 years from 2003-2008. Data were analysed using NiVivo8 and SPPS. RESULTS: A cross-case analysis highlighted similar patterns of factors which enabled or constrained successful recognition, referral and response to deteriorating patients in practice. Key enabling factors were the use of clinical judgement by experienced nurses and the empowerment of nurses as a result of organizational change associated with implementation of Early Warning System protocols. Key constraining factors were low staffing and inappropriate skill mix levels, rigid implementation of protocols and culturally embedded suboptimal communication processes. CONCLUSION: Successful implementation of Rapid Response Systems was dependent on adopting organizational and cultural changes that facilitated staff empowerment, flexible implementation of protocols and ongoing experiential learning. PMID- 28637091 TI - Nurse managers: Determinants and behaviours in relation to patient and visitor aggression in general hospitals. A qualitative study. AB - AIM(S): To explore nurse managers' behaviours, attitudes, perceived social norms, and behavioural control in the prevention and management of patient and visitor aggression in general hospitals. BACKGROUND: Patient and visitor aggression in general hospitals is a global problem that incurs substantial human suffering and organizational cost. Managers are key persons for creating low-aggression environments, yet their role and behaviours in reducing patient and visitor aggression remains unexplored. DESIGN: A qualitative descriptive study underpinned by the Reasoned Action Approach. METHOD(S): Between October 2015 January 2016, we conducted five focus groups and 13 individual interviews with nurse leaders in Switzerland. The semi-structured interviews and focus groups were recorded, transcribed, and analysed in a qualitative content analysis. FINDINGS: We identified three main themes: (i) Background factors: "Patient and visitor aggression is perceived through different lenses"; (ii) Determinants and intention: "Good intentions competing with harsh organizational reality"; (iii) Behaviours: "Preventing and managing aggressive behaviour and relentlessly striving to create low-aggression work environments". CONCLUSION(S): Addressing patient and visitor aggression is difficult for nurse managers due to a lack of effective communication, organizational feedback loops, protocols, and procedures that connect the situational and organizational management of aggressive incidents. Furthermore, tackling aggression at an organizational level is a major challenge for nurse managers due to scant financial resources and lack of interest. Treating patient and visitor aggression as a business case may increase organizational awareness and interest. Furthermore, clear communication of expectations, needs and resources could optimize support provision for staff. PMID- 28637092 TI - Evaluation of Strategies for Increasing Transplantation Should Be Based on a Current and Precise Assessment of the State of Organ Donation. PMID- 28637093 TI - Intra-Abdominal Cooling System Limits Ischemia-Reperfusion Injury During Robot Assisted Renal Transplantation. AB - Robot-assisted kidney transplantation is feasible; however, concerns have been raised about possible increases in warm ischemia times. We describe a novel intra abdominal cooling system to continuously cool the kidney during the procedure. Porcine kidneys were procured by standard open technique. Groups were as follows: Robotic renal transplantation with (n = 11) and without (n = 6) continuous intra abdominal cooling and conventional open technique with intermittent 4 degrees C saline cooling (n = 6). Renal cortex temperature, magnetic resonance imaging, and histology were analyzed. Robotic renal transplantation required a longer anastomosis time, either with or without the cooling system, compared to the open approach (70.4 +/- 17.7 min and 74.0 +/- 21.5 min vs. 48.7 +/- 11.2 min, p-values < 0.05). The temperature was lower in the robotic group with cooling system compared to the open approach group (6.5 +/- 3.1 degrees C vs. 22.5 +/- 6.5 degrees C; p = 0.001) or compared to the robotic group without the cooling system (28.7 +/- 3.3 degrees C; p < 0.001). Magnetic resonance imaging parenchymal heterogeneities and histologic ischemia-reperfusion lesions were more severe in the robotic group without cooling than in the cooled (open and robotic) groups. Robot-assisted kidney transplantation prolongs the warm ischemia time of the donor kidney. We developed a novel intra-abdominal cooling system that suppresses the noncontrolled rewarming of donor kidneys during the transplant procedure and prevents ischemia-reperfusion injuries. PMID- 28637094 TI - Acclimation responses to high light by Guazuma ulmifolia Lam. (Malvaceae) leaves at different stages of development. AB - The re-composition of deforested environments requires the prior acclimation of seedlings to full sun in nurseries. Seedlings can overcome excess light either through the acclimation of pre-existing fully expanded leaves or through the development of new leaves that are acclimated to the new light environment. Here, we compared the acclimation capacity of mature (MatL, fully expanded at the time of transfer) and newly expanded (NewL, expanded after the light shift) leaves of Guazuma ulmifolia Lam. (Malvaceae) seedlings to high light. The seedlings were initially grown under shade and then transferred to full sunlight. MatL and NewL were used for chlorophyll fluorescence and gas exchange analyses, pigment extraction and morpho-anatomical measurements. After the transfer of seedlings to full sun, the MatL persisted and acclimated to some extent to the new light condition, since they underwent alterations in some morpho-physiological traits and maintained a functional electron transport chain and positive net photosynthesis rate. However, long-term exposure to high light led to chronic photoinhibition in MatL, which could be related to the limited plasticity of leaf morpho-anatomical attributes. However, the NewL showed a high capacity to use the absorbed energy in photochemistry and dissipate excess energy harmlessly, attributes that were favoured by the high structural plasticity exhibited by these leaves. Both the maintenance of mature, photosynthetically active leaves and the production of new leaves with a high capacity to cope with excess energy were important for acclimation of G. ulmifolia seedlings. PMID- 28637095 TI - Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig. AB - Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+ PD-1high Tfh cells, CD95+ GL7+ germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study. PMID- 28637097 TI - Coding proforma in TNFLO clinic from a UK centre, an audit of 85 procedures. PMID- 28637096 TI - Uncovering the decision-making work of transferring dying patients home from critical care units: An integrative review. AB - AIMS: To understand how decisions are made to transfer dying patients home from critical care units. BACKGROUND: Many people prefer a home death, but a high proportion die in critical care units. Transferring dying patients home is recognized to be complex but transfer decision-making itself remains unclear. DESIGN: Integrative review. DATA SOURCES: Seven bibliographic databases (origin 2015), grey literature and reference lists were searched. REVIEW METHODS: An integrative review method was used to synthesize data from diverse sources. Papers were selected through title and abstract screening and full-text reviewing, using inclusion and exclusion criteria derived from review questions. Following quality appraisal, data were extracted and synthesized using normalization process theory as a framework. RESULTS: The number of patients transferred home ranged from 1-346, with most papers reporting on the transfer of one or two patients. Four themes regarding transfer decision-making work were generated: divergent views and practice, multiple stakeholders' involvement in decision-making, collective work and limited understanding of individuals' experiences. CONCLUSION: The practice of transferring patients home to die and its decision-making varies internationally and is usually influenced by the care system, culture or religion. It is less common to transfer patients home to die from critical care units in western societies. A better understanding of the decision-making work was obtained but mainly from the perspective of hospital based healthcare professionals. Further research is needed to develop decision making practice guidance to facilitate patients' wishes to die at home. PMID- 28637098 TI - Uncovering the contribution of epigenetics to plant phenotypic variation in Mediterranean ecosystems. AB - Epigenetic signals can affect plant phenotype and fitness and be stably inherited across multiple generations. Epigenetic regulation plays a key role in the mechanisms of plant response to the environment, without altering DNA sequence. As plants cannot adapt behaviourally or migrate instantly, such dynamic epigenetic responses may be particularly crucial for survival of plants within changing and challenging environments, such as the Mediterranean-Type Ecosystems (MTEs). These ecosystems suffer recurrent stressful events (warm and dry summers with associated fire regimes) that have selected for plants with similar phenotypic complex traits, resulting in similar vegetation growth forms. However, the potential role of epigenetics in plant adaptation to recurrent stressful environments such as the MTEs has generally been ignored. To understand the full spectrum of adaptive processes in such contexts, it is imperative to prompt study of the causes and consequences of epigenetic variation in natural populations. With this purpose, we review here current knowledge on epigenetic variation in natural populations and the genetic and epigenetic basis of some key traits for plants in the MTEs, namely those traits involved in adaptation to drought, fire and oligotrophic soils. We conclude there is still much to be learned about 'plant epigenetics in the wild' and, thus, we propose future research steps in the study of natural epigenetic variation of key traits in the MTEs at different scales. PMID- 28637099 TI - Aggregation and phosphorylation of alpha-synuclein with proteinase K resistance in focal alpha-synucleinopathy predominantly localized to the cardiac sympathetic nervous system. PMID- 28637100 TI - Women's expectations and experiences of rupture of membranes and views of the potential use of reagent pads for detecting amniotic fluid. AB - AIMS: To explore first-time mothers' expectations and experiences regarding rupture of membranes at term and their views on the potential use of reagent pads that detect amniotic fluid. BACKGROUND: There is little information available on women's experiences of spontaneous rupture of membranes, or interest in using methods to confirm rupture of membranes (e.g. reagent pads). DESIGN: Descriptive qualitative study, using focus groups and telephone interviews with women during pregnancy and after the birth of their first baby. Thematic analysis was undertaken to analyse women's responses. METHODS: Ethics committee approval was obtained. Twenty-five women participated in the study of whom 13 contributed both during pregnancy and postpartum between October 2015-March 2016. FINDINGS: Three overarching themes were identified from the data from women's expectations and experiences: uncertainty in how, when and where membranes may rupture; information which was felt to be limited and confirmation of rupture of membranes. The potential use of reagent pads met with varied responses. CONCLUSION: Women were interested in having facts and figures regarding rupture of membranes, such as characteristics of liquor; volume and probability of membranes rupturing spontaneously at term. Use of a pad as a means of confirmation was viewed as helpful, although the potential for increasing anxiety was raised. PMID- 28637101 TI - [Cardiovascular Risk in Patients with Non-alcoholic Fatty Liver Disease]. AB - Non-alcoholic fatty liver disease (NAFLD) includes a wide spectrum of diseases that range from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. In addition, the burden of NAFLD is rapidly growing. Previously, NAFLD was regarded as a hepatic manifestation of metabolic syndrome, which is a traditional cardiovascular disease (CVD) risk factor. However, there has been an increasing evidence that suggest NAFLD to be an independent risk factor of CVD. Therefore, currently, NAFLD should be reconsidered as not only a simple manifestation of metabolic syndrome, but also a systemic disease that contribute to CVD. There are some reasonable hypotheses about the relationship between NAFLD and CVD. Moreover, many studies have been performed to better understand this relationship. Nonetheless, the underlying mechanisms and pathogenesis of NAFLD that contribute to CVD have not yet been fully elucidated to date. This review focuses on the underlying mechanisms and relationship between NAFLD and CVD. PMID- 28637102 TI - [The Progression of Liver Fibrosis in Non-alcoholic Fatty Liver Disease]. AB - Understanding the pathogenesis of non-alcoholic steatohepatitis (NASH) and its fibrosis progression is still evolving. Nonetheless, current evidence suggests that mechanisms involved are very complex parallel processes with multiple metabolic factors. Lipotoxicity related with excess saturated free fatty acids, obesity, and insulin resistance acts as the central driver of cellular injury via oxidative stress. Hepatocyte apoptosis and/or senescence are also contribute to the activation of inflammasome via various intra- and inter-cellular signaling mechanisms that lead to fibrosis. Current evidence suggests that periportal components, including ductular reaction and expansion of the hepatic progenitor cell compartment, may be involved and that the T-helper 17 cell response may mediate disease progression. This review aims to provide a brief overview of the pathogenesis of NASH and fibrosis progression from inflammation to fibrosis. PMID- 28637103 TI - [The Development of Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease]. AB - Non-alcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). NAFLD-related HCCs (NAFLD-HCCs) have the following clinical features: high body mass index, deranged lipid profiles, diabetes mellitus, hypertension, and metabolic syndrome. Among them, obesity, diabetes mellitus, and high Fe contents in the liver are risk factors of developing HCC in patients with NAFLD. Inflammatory cytokines, adipokines, insulin like growth factor-I, and lipotoxicity are intermingled and may cross react with each other to develop HCC. Because there is no guideline for early detection of HCC in patients with NAFLD, NAFLD-HCCs tend to be greater in size and in advanced stages when detected compared with hepatitis virus-related HCCs. Therefore, there is an urgent need of a surveillance program for the early detection of HCC. Treatment of NAFLD-HCCs is not different from other causes related HCCs. However, patients with NAFLD-HCCs have cardiovascular disease and other metabolic problems, which may complicate treatment. PMID- 28637104 TI - [Treatment Options in Non-alcoholic Fatty Liver Disease]. AB - The prevalence of non-alcoholic fatty liver disease (NAFLD) has sharply increased over the past several decades in Korea. In most cases of NAFLD, metabolic stress and cellular apoptosis are often driven by metabolic abnormality, eventually leading to inflammation and fibrosis . Along with a dramatic surge in the obesity epidemic, 10-20% of NAFLD patients ultimately progress to non-alcoholic steatohepatitis (NASH), a precursor to cirrhosis and hepatocellular carcinoma, as well as multi-organ systemic diseases. Currently, diet and exercise are chiefly recommended to achieve significant weight loss and improve metabolic dysfunction in patients with NAFLD. However, weight loss remains to be an elusive goal for both clinical practitioners and NAFLD patients. To date, although there has not been any proven pharmacotherapy against NAFLD, numerous promising pipelines with good target engagement are under development. Moreover, given the global landmark phase 3 trials using obeticholic acid (a farnesoid X receptor agonist, REGENERATE trial) and elafibranor (a dual peroxisome proliferator-activated receptor alpha/delta agonist, RESOLVE-IT trial), the era of specific target therapies focusing on molecular and metabolic pathogenesis of NASH and fibrosis is near at hand. In this paper, we briefly cover the current and future therapeutic options in patients with NAFLD across the entire spectrum of diseases. PMID- 28637105 TI - Cytomegalovirus Gastric Ulcer Complicated with Pyloric Obstruction in a Patient with Ulcerative Colitis. AB - In patients with inflammatory bowel disease (IBD), cytomegalovirus (CMV) infections could aggravate the course of IBD but it is difficult to distinguish CMV infection from IBD exacerbation endoscopically. Usually, CMV tends to localize to the colon and other organic involvements were reported very rare in the IBD patients. Herein, we report a case that CMV gastric ulcer complicated with pyloric obstruction in a patient with ulcerative colitis during ganciclovir therapy, which was resolved by surgical gastrojejunostomy with review of literature. PMID- 28637106 TI - [A Case of Hemorrhage of an Esophageal Duplication Cyst Improved by Endoscopic Drainage]. AB - Esophageal duplication cyst is a rare congenital gastrointestinal malformation. It is the second most common duplication cyst following small bowel duplication cyst in the gastrointestinal tract. Patients with an esophageal duplication cyst are generally asymptomatic; however, some patients may present the following symptoms: dysphagia, chest pain, stridor, unproductive cough, and epigastric discomfort by compression of the surrounding structures. Surgical removal is the treatment of choice in symptomatic cases and can be considered in asymptomatic cases if they are at risk for developing complications, such as ulceration or perforation. Herein, we report a case of hemorrhage of an esophageal duplication cyst, which was improved by endoscopic drainage. PMID- 28637107 TI - Malignant Melanoma of the Anus Found during Routine Colonoscopy in Ulcerative Colitis. AB - Inflammatory bowel disease (IBD) is characterized by recurrent or chronic inflammation of the gastrointestinal tract, which results in increased risk of developing cancer. Anorectal malignant melanoma is often misdiagnosed as either hemorrhoids or benign anorectal conditions in inflammatory bowel disease. Therefore, the overall prognosis and survival of IBD are poor. To date, the best treatment strategy remains controversial. Only early diagnosis and complete excision yield survival benefit. Here, we report a 64-year-old woman with ulcerative colitis, who was found to have anal malignant melanoma on routine colonoscopy. The lesion was confined to the mucosa with no distant metastasis. She underwent complete trans-anal excision. There was no recurrence at the four year follow-up. Physicians should be aware of increased risk of cancer development in IBD patients and remember the importance of meticulous inspection of the anal canal. PMID- 28637108 TI - [Henoch-Schonlein Purpura Presenting as Intussusception]. AB - Henoch-Schonlein purpura (HSP) is systemic vasculitis disease with various clinical manifestations. Gastrointestinal symptoms in patients with HSP are usually common, with an incidence rate of 62-90%. Most of these gastrointestinal symptoms occur after typical skin purpura, which is a very important clinical evidence for making a diagnosis of HSP. It is difficult to diagnose HSP without skin rash. About 25% of patients may experience gastrointestinal symptoms as their first symptoms. Herein, we report a case of ileo-colic intussusception associated with HSP in a 5-years-old girl presented with diffuse abdominal distension. Our patient did present any symptoms of HSP, such as purpura, arthralgia or arthritis, before surgery. PMID- 28637110 TI - Guidelines for cauda equina syndrome. Red flags and white flags. Systematic review and implications for triage. AB - INTRODUCTION: Patients with cauda equina syndrome (CES) are frequently referred late when neurological damage cannot be reversed. National Guidelines for emergency referral, imaging and treatment of CES contain symptoms and/or signs that are those of late often, irreversible CES. Referral at this stage may be too late for that patient. METHODS: Seven sources were reviewed. Advice re emergency referral/imaging/treatment were reviewed. Symptoms/signs were compared with a standard classification of CES. RESULTS: 37 recommendations: 12 (32%) were symptoms/signs of bilateral radiculopathy (treatment usually leads to favourable outcomes). Thirteen recommendations (35%) were described in an imprecise way (could be interpreted as early or late CES). Twelve sets of symptoms/signs (32%) were those of late, often irreversible CES where an unfavourable outcome would be expected. CONCLUSIONS: Thirty-two percent of the so-called "red flag" symptoms and signs of CES in seven sources were definitely those of late, irreversible CES. These could be seen as "white flags" [flags of defeat and surrender]. Thirty five percent of the recommendations if interpreted pessimistically (e.g. absent perineal sensation or urinary incontinence) would also be white flags; potentially therefore two-thirds of the so-called "red flag" symptoms/signs of CES could be those of late irreversible CES. Only 32% of the symptoms/signs were true "red flags" i.e. they warn of further, avoidable damage ahead. Guidelines should be redrawn to emphasise referral of patients who are at risk of developing CES or who have early CES. It is illogical for these guidelines to emphasise the clinical features of severe, often untreatable, CES. Demand for emergency MRI will increase; MRI is part of triage and should be performed at the DGH. PMID- 28637111 TI - Spinal epidural cavernous hemangioma: case report. AB - Pure epidural cavernous hemangiomas are quite rare. In this paper, a case of lumbar epidural cavernous hemangioma presenting as a lumbar radiculopathy is presented. The magnetic resonance imaging findings, differential diagnosis and therapy options of this rare case are discussed. PMID- 28637109 TI - Closing the dura: dural hitching versus surgicel and tisseel overlay graft in craniocervicaldecompression for Chiari 1 malformation. AB - BACKGROUND: This study compares dural hitching to surgicel and tisseel overlay graft following craniocervical decompression and C1 laminectomy with simple durotomy for Chiari I malformation. Outcome measures were syrinx decompression, headache resolution and complication rates. METHODS: A retrospective analysis of case notes was conducted. Patients who had undergone craniocervical decompression (CCD) were grouped by method of dural closure. Outcomes compared were rates of syrinx decompression, headache resolution, and post-operative complications. Statistical analysis was conducted using SPSS v20. RESULTS: We identified 32 adult patients for inclusion in this study. 53.1% (n = 17) had asyrinx, and 78.1% (n = 25) had a pre-operative headache. All were treated with suboccipital craniectomy, C1 laminectomy (with or without C2 laminectomy), and durotomy. The dura was either left open by dural hitching (n = 23) or closed with surgicel and tisseel overlay graft (n = 9). We found a statistically significant association between the method of dural closure and the rate of syrinx resolution. Resolution occurred in 91.7% (n = 11) of the hitching group, compared to 20.0% (n = 1) of the overlay graft group: Chi2(1) = 5.6, p = .018. There were no statistically significant differences between the two groups in the rates of headache resolution or other complications. CONCLUSIONS: In patients with symptomatic Chiari I malformation and associated syringomyelia, syrinx resolution is more likely if the dura is hitched open rather than closed bysurgicel and tisseel overlay graft after durotomy. PMID- 28637112 TI - Schistosoma haematobium, a rare aetiology of spinal cord compression. PMID- 28637113 TI - Case report of intraventricular schwannoma. AB - We describe the case of a 52 year old male presenting with subacute headache. Cranial imaging suggested haemorrhage into a parietal, partially intraventricular, space occupying lesion. The radiology was interpreted to be most consistent with a glioblastoma. The lesion was near totally resected. The histopathology was a WHO grade 1 schwannoma. PMID- 28637114 TI - Diffuse large B-cell lymphoma: a rare complication of an abdominal CSF pseudocyst. AB - Abdominal CSF pseudocysts are an uncommon complication of ventriculo-peritoneal shunting. We report the case of a 35 year old man with a myelomenigocele, associated Chiari 2 malformation, and VP shunt developing a Diffuse Large B-Cell Lymphoma within the lining of an abdominal CSF pseuodcyst. This diagnosis should be considered in those with recurrent pseudocysts, or those associated with a swinging pyrexia and high C-Reactive protein, in the absence of infection. PMID- 28637116 TI - Neurosurgeon or spinal surgeon - who should treat cauda equina syndrome? AB - Suspected cauda equina syndrome (CES) requires urgent evaluation, investigation and treatment. Timing of cauda equina decompression is crucial, and delays in its management, leading to significant irreversible disability can be devastating for patient and surgeon alike. The standard of care in CES therefore needs to be clear and unambiguous. Todd and Dickson have written an excellent paper summarising the condition, and have outlined what they feel is the standard of care. We would ask the authors to clarify an important point. PMID- 28637115 TI - Ruptured carotid-ophthalmic aneurysm treatment: a non-inferiority meta-analysis comparing endovascular coiling and surgical clipping. AB - INTRODUCTION: Aneurysms of the carotid-ophthalmic segment are relatively rare, comprising only five percent of all intracranial aneurysms. There is no consensus regarding the optimal management for ruptured carotid-ophthalmic aneurysms, whether endovascular coiling or surgical clipping provide the most favourable patient outcome. The aim of this meta-analysis is to analyse these two treatment modalities for ruptured carotid-ophthalmic aneurysms with respect to independent clinical outcome. METHODS: We performed a systematic literature search in PubMed, Cochrane Central Registry of Controlled Trials and Clinicaltrials.gov for treatment of ruptured carotid-ophthalmic aneurysms, comparing endovascular coiling and surgical clipping. Primary outcome in the study was independent clinical patient outcome at follow up (defined as Glasgow Outcome Scale four five). Secondary outcomes were poor clinical patient outcome, mortality and total angiographic occlusion. The meta-analysis was performed using the Mantel-Haenszel method for dichotomous outcome. RESULTS: Four studies met the inclusion criteria and were included in the meta-analysis. In total, 152 patients were included. Sixty-seven of these patients were treated with endovascular coiling and 85 patients were treated with microsurgical clipping. The proportion of patients with an independent clinical outcome after coiling and clipping was comparable, OR 1.04 (95% CI: 0.40, 2.71). The proportion of patients with an independent outcome in the endovascular group was 76% and in the surgical group 71%. Mortality between the two treatment arms was equal. CONCLUSION: Clinical outcome after endovascular coiling and surgical clipping for ruptured carotid-ophthalmic aneurysms was comparable between surgical clipping and endovascular coiling. There was no proven difference in clinical outcome after endovascular coiling and surgical clipping for ruptured carotid-ophthalmic aneurysms but the evidence was based on few studies of moderate to low quality and we cannot rule out the possibility of a difference in clinical outcome between the two treatment modalities. PMID- 28637117 TI - Spontaneous cerebrospinal fluid rhinorrhoea with meningitis secondary to ecchordosis physaliphora. AB - Transclival CSF fistulae are rare. We report a 40-year-old female who presented with meningitis after a short history of CSF rhinorrhoea. The defect resulted from the rare notochordal remnant, ecchordosis physaliphora (EP), and was successfully resected and repaired endoscopically. PMID- 28637118 TI - Asymptomatic Chiari Type I malformation: should patients be advised against participation in contact sports? AB - BACKGROUND: Chiari type I malformation (CM-I) is characterised by caudal displacement of the cerebellar tonsils through the foramen magnum, crowding the craniocervical junction. It is being increasingly diagnosed in asymptomatic patients due to the widespread availability of MRI, and there are case reports of these patients suffering sudden death or neurological injury following head or neck trauma, raising the issue of whether they should be prohibited from contact sport participation, given the likelihood of frequent trauma. General neurosurgical opinion is that patients who are symptomatic and those with an associated spinal cord syrinx should be offered foramen magnum decompression, however asymptomatic patients without syringomyelia are not offered this in the majority of cases. METHODS: The authors performed a full review of the published literature, including all case reports, case series, studies and literature reviews regarding CM-I and either contact sports or trauma, excluding patients that had undergone surgical intervention and those becoming symptomatic in circumstances other than head or neck trauma. RESULTS: 21 case reports of CM-I patients deteriorating following trauma were identified, including four cases of sudden death following head or neck injury. However, studies of large samples of CM-I patients are yet to capture an incident of sudden death or acute neurological deterioration, suggesting that the risk is very low. CM-I patients may have an increased risk of concussion and post-concussion syndrome compared to the background population however. CONCLUSION: Overall, the authors feel that there should be no restriction of sports participation for CM-I patients, but a discussion to make them and their families aware of the possible increased risks is important. PMID- 28637119 TI - Disco vertebral osteomyelitis causing intradural spinal abscess with cauda equina compression. AB - Intradural extramedullary spinal infections causing cauda equina compression are uncommon. We report an Escherichia coli bacteraemia causing lumbar discitis and an intracanalicular collection compressing the cauda equina: initially thought to be an epidural empyema, however microsurgery revealed an intradural location. Decompression, drainage, antibiotics, and neuropathy treatment are essential management. PMID- 28637120 TI - Is tutobone an efficient alternative to other implants used in anterior cervical discectomy and fusion surgeries? AB - BACKGROUND: The graft site morbidity following iliac crest harvesting is significant. To overcome this, different bone substitutes like coral dowels, solvent dissolved bovine/human bone substitutes, and carbon fiber/titanium cages have been used. This study was undertaken to assess the postoperative radiological fusion rates and symptom relief in patients who had Tutobone used as an interbody spacer compared to autologous bone graft (ABG), cages, surgibone and coral dowels. METHODS: This was a retrospective, observational study. Case notes and post-operative cervical spine radiographs done at two subsequent follow-ups were reviewed. Data were derived from all Anterior Cervical Discectomy and fusion (ACDF) surgeries performed at our centre over a 10-year period for degenerative cervical spine disease. We analysed 530 patients. Exclusion criteria included incomplete notes, complex cervical surgery (both anterior and posterior fixation and vertebrectomies). Patients were divided into 3 groups, patients treated with (1) Autologous bone graft, (2) Tutobone and (3) other implants which include cages, surgibone and coral dowels. RESULTS: An analysis of 530 patients who had ACDF with either ABG (n = 328) or tutobone (n = 95) or other implants (n = 90) is presented. A significantly greater number of patients in whom autologous bone was used had more than one level surgery. The median follow-up times were 3 months and 12 months. Rates of fusion and time to fusion with bone substitutes were inferior to ABG in our series, but there was not much to choose amongst them. CONCLUSION: The use of ABG in ACDF leads to fusion in a shorter duration and greater proportion of patients, when compared to substitutes. Other implants like Tutobone (cheaper alternative), cages, etc can also be used in ACDF procedures with good efficacy with the added advantage of preventing donor site morbidity. There was no association between fusion rates and symptom relief and between use of plating and fusion. PMID- 28637121 TI - Iatrogenic syringomyelia secondary to lumboperitoneal shunt altered by the raised intra-abdominal pressure of pregnancy. AB - We report a case of a 37 year old female with syringomyelia secondary to lumboperitoneal (LP) shunt. Syrinx regression occurred with raised intra abdominal pressure due to pregnancy and subsequently redeveloped after parturition. To our knowledge a case of pregnancy associated syringomyelia regression has not been previously reported. PMID- 28637122 TI - A new cinnamic acid glycoside from roots of Heracleum dissectum. AB - From the roots of Heracleum dissectum Lebb., one new cinnamic acid glycoside derivative named dissectumoside (1), together with eight known compounds including three phenolics, three phenolic glycosides and two phenylpropanoic glycoside were isolated using various chromatographic methods. Among them compound 2-9 was isolated from the plant for the first time. Their structures were elucidated and identified on the basis of their physicochemical properties and by extensive analyses of NMR spectroscopy and high-resolution mass spectrometry. The results of triglyceride accumulation screening in 3T3-L1 cells showed that compounds 1, 5 and 9 exhibited significantly accelerating activities of adipogenesis in adipocytes. PMID- 28637123 TI - Inhibition of Swarming motility of Pseudomonas aeruginosa by Methanol extracts of Alpinia officinarum Hance. and Cinnamomum tamala T. Nees and Eberm. AB - Bacterial drug resistance is a challenge in clinical settings, especially in countries like India. Hence, discovery of novel alternative therapeutics has become a necessity in the fight against drug resistance. Compounds that inhibit bacterial virulence properties form new therapeutic alternatives. Pseudomonas aeruginosa is an opportunistic, nosocomial pathogen that infects immune compromised patients. Swarming motility is an important virulence property of Pseudomonas which aids it in reaching host cells under nutrient limiting conditions. Here, we report the screening of five plant extracts against swarming motility of P. aeruginosa and show that methanol extracts of Alpinia officinarum and Cinnamomum tamala inhibit swarming motility at 5 MUg mL-1 without inhibiting its growth. These extracts did not inhibit swimming and twitching motilities indicating a mode of action specific to swarming pathway. Preliminary experiments indicated that rhamnolipid production was not affected. This study reveals the potential of the two plants in anti-virulence drug discovery. PMID- 28637124 TI - Recovery and creative practices in people with severe mental illness: evaluating well-being and social inclusion. AB - PURPOSE: This mixed (quantitative-qualitative) study evaluates the impact of an artistic workshop on a group of people with severe mental illness (SMI). This study focuses on the impact of creative practices on well-being and social inclusion outcomes. METHOD: After participating in a creative workshop, 31 people diagnosed with a SMI completed pre/post-intervention measures, namely, the Warwick-Edinburgh Mental Well-Being Scale and the Social Inclusion questionnaire. It was applied in two-way repeated measures analysis of variance. The statistic Wilcoxon and Kruskal-Wallis were applied for non-parametric data to measure pre/post-test effects and workshop experience effects, respectively. In addition to quantitative measures, one observer participated in each workshop that ran in parallel in order to deepen and triangulate quantitative outcomes. RESULTS: The qualitative and quantitative results show that social inclusion improved in a significant way with an important size effect. Psychological wellbeing increased significantly with a low size effect. CONCLUSIONS: In accordance with these results, creative practices with people diagnosed with SMI are recommended. In order to increase the impact of these interventions, it is recommended to utilize public space away from clinical environments and to include people without SMI in creative activities together with SMI patients. Implications for Rehabilitation: Creative practices can significantly improve social inclusions and well-being in people with severe mental illness. Participating in creative workshops helps to elaborate personal meanings and promote recovery. Creative practices in mental health services can challenge professional roles and institutional practices. Participation of people with and without severe mental illness engaged together in artistic activities can decrease public stigma. PMID- 28637125 TI - Bilateral movements increase sustained extensor force in the paretic arm. AB - PURPOSE: Muscle weakness in the extensors poststroke is a common motor impairment. Unfortunately, research is unclear on whether bilateral movements increase extensor force production in the paretic arm. This study investigated sustained force production while stroke individuals maximally extended their wrist and fingers on their paretic arm. Specifically, we determined isometric force production in three conditions: (a) unilateral paretic arm, (b) unilateral nonparetic arm, and (c) bilateral (both arms executing the same movement simultaneously). METHODS: Seventeen chronic stroke patients produced isometric sustained force by executing wrist and fingers extension in unilateral and bilateral contraction conditions. Mean force, force variability (coefficient of variation), and signal-to-noise ratio were calculated for each contraction condition. RESULTS: Analysis of two-way (Arm * Type of Condition: 2 * 2; Paretic or Nonparetic Arm * Unilateral or Bilateral Conditions) within-subjects ANOVAs revealed that the bilateral condition increased sustained force in the paretic arm, but reduced sustained force in the nonparetic arm. Further, although the paretic arm exhibited more force variability and less signal-to-noise ratio than the nonparetic arm during a unilateral condition, there were no differences when participants simultaneously executed isometric contractions with both arms. CONCLUSIONS: Our unique findings indicate that bilateral contractions transiently increased extensor force in the paretic arm. Implications for Rehabilitation Bilateral movements increased isometric wrsit extensor force in paretic arms and redcued force in nonparetic arms versus unilateral movements. Both paretic and nonparetic arms produced similar force variability and signal-to-noise ratio during bilateral movements. Increased sustained force in the paretic arm during the bilateral condition indicates that rehabilitation protocols based on bilateral movements may be beneficial for functional recovery. PMID- 28637126 TI - Ecological momentary assessment for rehabilitation of chronic illness and disability. AB - PURPOSE: The main objectives of this manuscript were to provide a theoretical perspective on naturalistic delivery in rehabilitation based upon a literature review and establish a rationale for using ecological momentary assessment (EMA) for naturalistic assessment for chronic illness and disability (CID) in rehabilitation. METHOD: Existing literature on EMA use across CID cohorts was gathered and analyzed to form a theoretical overview of implementation of this method in research. This review summarizes study results and provides a comprehensive literature table for greater analysis. RESULTS: EMA has been shown to optimize clinician time and reduce costs, reach greater numbers of people with disability-related needs, and reduce the need for retrospective recall through the collection of more objective data. Mixed method approaches were most commonly seen in the literature, and sampling schedules and the outcomes assessed varied widely. CONCLUSIONS: EMA is emerging as a novel modality of assessment in rehabilitation. Scientists and clinicians should consider incorporating this assessment approach as a rehabilitation tool that may more accurately assess the complex and dynamic nature of disability over the long-term through an objective and ecologically-valid data source. Implications for rehabilitation Ecological momentary assessment (EMA) has been underutilized in the rehabilitation field and should be considered by researchers and clinicians as a novel assessment method for capturing rich, ecologically-valid data. EMA methods provide a greater capability to assess complex or difficult to measure outcomes of interest when compared with more traditional approaches conducted during finite clinic hours due to data collection occurring, with or without any input from the user, through wearable technology, and without a needed clinician presence. EMA data can be integrated with other data sources (e.g., self-report or clinician observation) to assess a more comprehensive picture of outcomes of interest, including highlighting discordance and identifying the most efficient target areas for intervention. PMID- 28637127 TI - Clinical utility of the modified trunk impairment scale for stroke survivors. AB - OBJECTIVE: The present study aimed to determine the discriminant power of the modified Trunk Impairment Scale (mTIS) in stroke survivors versus healthy adults. DESIGN: Cross-sectional. SETTING: Inpatient rehabilitation center. PARTICIPANTS: Fifty-five subjects with stroke and 29 healthy adults. METHODS: Subjects were examined using the mTIS, Berg Balance Scale, and Timed Up and Go test for balance; 5-m Walk Test and Functional Ambulation Category for gait; Fugl-Meyer Assessment for motor function; Postural Assessment Scale for Stroke-Trunk Control and Trunk Control Test for trunk control; and Modified Barthel Index for activities of daily living performance. RESULTS: The mTIS results differed significantly between stroke survivors and healthy adults (p < 0.001). In addition, mTIS scores were significantly correlated with the Berg Balance Scale (r = 0.82), Timed Up and Go test (r = -0.70), 5-m Walk Test (r = 0.73), Functional Ambulation Category (r = 0.54), Fugl-Meyer Assessment (r = 0.37-0.80), Postural Assessment Scale for Stroke-Trunk Control and Trunk Control Test (r = 0.55-0.63), and Modified Barthel Index score (r = 0.56) results (p < 0.05-0.01). The mTIS also showed 66% influence on the Berg Balance Scale, 49% on the Timed Up and Go test, 53% on the 5-m Walk Test, 28% on the Functional Ambulation Category, 12% on the Fugl-Meyer Assessment-upper extremity, 64% on the Fugl-Meyer Assessment-lower extremity, and 30% on the Modified Barthel Index. The cutoff value of the mTIS for the Modified Barthel Index classification was >10.5 points, while the area under the curve had a moderate accuracy of 73%. CONCLUSION: The mTIS can be used to examine the degree of trunk control or the level of trunk impairment, which is seen as a prerequisite for balance, gait, motor function, and activities of daily living performance in stroke survivors. Implications for Rehabilitation The modified Trunk Impairment Scale can be used as an assessment tool to classify the degree of trunk control or its level of impairment in stroke survivors. The modified Trunk Impairment Scale may have a favorable correlation with assessing physical functions such as balance, gait, motor function, and ADL in stroke survivors. PMID- 28637128 TI - Maximizing gait and balance: behaviors and decision-making processes of persons with multiple sclerosis and physical therapists. AB - PURPOSE: To describe the behavioral decisions used by persons with multiple sclerosis (MS) and physical therapists to maximize gait and balance following outpatient physical therapy. METHODS: A multi-method case series with seven matched pairs (persons with MS-physical therapists). Quota sampling maximized variability among persons with MS (disease steps score range 3-6). Three of the four physical therapists were MS or neurology certified. Persons with MS completed a phone survey, follow-up interview, and standardized questionnaires. Physical therapists completed an interview. Data were collected 2-8 weeks following discharge. Content and constant comparison analyses were used for thematic development and triangulation. RESULTS: Core themes arose exemplifying the decision-making processes and actions of persons with MS (challenging self by pushing but respecting limits) and physical therapists (finding the right fit). One overarching theme, keeping their lived world large, or participation in valued life roles, emerged integrating both perspectives driving decision-making. CONCLUSIONS: Participants have a shared goal of maximizing gait and balance so persons with MS can participate in valued life roles. Understanding the differences in the behavioral decisions and optimizing skill sets in shared decision-making and self-management may enhance the therapeutic partnership and engagement in gait- and balance-enhancing behaviors. Implications for Rehabilitation Persons with MS and physical therapists have a shared goal of maximizing gait and balance so persons with MS can participate in valued activities and life roles, or more poetically, keep their lived world large. Knowledge that persons with MS aim to challenge themselves by pushing but respecting limits can provide physical therapists with greater insight in helping persons with MS resolve uncertainty, set meaningful goals, and build the routines and resilience needed for engagement in gait- and balance-enhancing behaviors. Enriching skill sets in shared decision-making, behavior change and self management may optimize the physical therapist toolbox. PMID- 28637130 TI - Community integration and life satisfaction among individuals with spinal cord injury living in the community after receiving institutional care in Bangladesh. AB - PURPOSE: This study reports level of community integration and life satisfaction among individuals who sustained traumatic spinal cord injuries, received institutional rehabilitation care services, and went back to live in the community in Bangladesh. It examines the impact of type of injury, demographic characteristics, socio-economic profile, and secondary health conditions on community integration and life satisfaction and explores the association between these two measures. METHOD: Individuals with spinal cord injury were telephone interviewed by the Centre for the Rehabilitation of the Paralysed, Bangladesh from February to June of 2014. Data were collected from the subjects on type of injury, demographic and socio-economic profile, and secondary health conditions. The outcome measures were determined by using two validated tools - Community Integration Questionnaire and Life Satisfaction 9 Questionnaire. RESULTS: Total community integration and life satisfaction scores were 15.09 and 3.69, respectively. A significant positive relationship between community integration and life satisfaction was revealed. Type of injury, gender, and age were found to be significant predictors of both community integration and life satisfaction scores. Higher education was significantly related to community integration and life satisfaction scores. CONCLUSION: Participants scored low in total community integration and life satisfaction, suggesting there is a great need to develop interventions by governmental and non-governmental organizations to better integrate individuals with spinal cord injury in the community. Implications for Rehabilitation Government and non-government organizations should offer disability friendly public transportation facilities for individuals with spinal cord injury so that they can return to education, resume employment, and involve in social activities. Entrepreneurs and businesses should develop assistive devices featuring low technology, considering the rural structure and housing conditions in Bangladesh. Innovations being made in assistive technology should be supported by subsidies and grants. They should also plan to offer injury appropriate employment opportunities for individuals who suffer major injuries like spinal cord injury in Bangladesh. Housing facilities with accessible bathrooms, kitchens and stairs should be designed and offered for this population to improve their ability to self-care and decrease the dependence on caregivers for household tasks such as - cooking meals and taking care of children. PMID- 28637129 TI - Patient reported outcomes in GNE myopathy: incorporating a valid assessment of physical function in a rare disease. AB - BACKGROUND: The aim of this analysis was to evaluate the psychometric properties of three patient reported outcome (PRO) measures characterizing physical function in GNE myopathy: the Human Activity Profile, the Inclusion Body Myositis Functional Rating Scale, and the Activities-specific Balance Confidence scale. METHODS: This analysis used data from 35 GNE myopathy subjects participating in a natural history study. For construct validity, correlational and known-group analyses were between the PROs and physical assessments. Reliability of the PROs between baseline and 6 months was evaluated using the intra-class correlation coefficient model; internal consistency was tested with Cronbach's alpha. RESULTS: The hypothesized moderate positive correlations for construct validity were supported; the strongest correlation was between the human activity profile adjusted activity score and the adult myopathy assessment endurance subscale score (r = 0.81; p < 0.0001). The PROs were able to discriminate between known high and low functioning groups for the adult myopathy assessment tool. Internal consistency of the PROs was high (alpha > 0.8) and there was strong reliability (ICC >0.62). CONCLUSION: The PROs are valid and reliable measures of physical function in GNE myopathy and should be incorporated in investigations to better understand the impact of progressive muscle weakness on physical function in this rare disease population. Implications for Rehabilitation GNE myopathy is a rare muscle disease that results in slow progressive muscle atrophy and weakness, ultimately leading to wheelchair use and dependence on a caregiver. There is limited knowledge on the impact of this disease on the health-related quality of life, specifically physical function, of this rare disease population. Three patient reported outcomes have been shown to be valid and reliable in GNE myopathy subjects and should be incorporated in future investigations to better understand how progressive muscle weakness impacts physical functions in this rare disease population. The patient reported outcome scores of GNE myopathy patients indicate a high risk for falls and impaired physical functioning, so it is important clinicians assess and provide interventions for these subjects to maintain their functional capacity. PMID- 28637132 TI - International employee perspectives on disability management. AB - PURPOSE: To provide an international analysis of employees' views of the influence of disability management (DM) on the workplace. METHODOLOGY: An international research team with representation from Australia, Canada, China, and Switzerland collected survey data from employees in public and private companies in their respective regions. Due to lack of availability of current measures, a research team-created survey was used and a total of 1201 respondents were collected across the four countries. ANALYSIS: Multiple linear (enter) regression was also employed to predict DM's influence on job satisfaction, physical health, mental health, workplace morale and reduced sickness absence, from respondents' perceptions of whether their company provided disability prevention, stay-at-work, and return-to-work initiatives within their organization. One-way ANOVA comparisons were used to examine differences on demographic variables including company status (public versus private), union status (union versus nonunion), and gender. RESULTS: The perceived influence of DM programs was related to perceptions of job satisfaction; whereas, relationships with mental health, physical health, morale, and sickness absence were variable according to type of DM program and whether the response was related to self or others. Difference analyses (ANOVA) revealed significantly more positive perceptions for private and nonunion organizations; no gender effects were found. CONCLUSIONS: There is perceived value of DM from the perspective of employees, especially with respect to its value for coworkers. Implications for Rehabilitation Rehabilitation efforts should continue to focus attention on the value of disability management (DM). In particular, DM that is fully committed to the biopsychosocial model would be supported by this research. Employees reported the most value in the psychosocial variables addressed by DM, such that rehabilitation professionals could focus on these valued aspects to improve buy-in from employees. The interest in coworker value may provide another avenue for rehabilitation efforts to increase uptake, by highlighting the value of intervention efforts for employee coworkers. Rehabilitation professionals in union environments may need to be particularly cognizant of the need for encouraging psychosocial and coworker value potentially seen by employees in order to increase acceptance and participation for organizational DM efforts. PMID- 28637131 TI - Translation, cultural adaptation, reliability, and validity of the Turkish version of the Penn Shoulder Score. AB - PURPOSE: The purpose of this study is to translate the Penn Shoulder Score into Turkish and to establish its cultural adaptation, reliability, and validity in patients with shoulder dysfunctions. METHODS: The Penn Shoulder Score was translated and culturally adapted from English into Turkish. Subsequently, the Penn Shoulder Score, the Constant Score, the American Shoulder and Elbow Score, and the Western Ontario Rotator Cuff Index were completed by 97 patients with shoulder dysfunctions. To determine the test-retest reliability, 30 patients completed the Penn Shoulder Score again on day 3. Intraclass correlation coefficient and Cronbach alpha were calculated to assess reliability. The validity of the questionnaire was assessed in terms of convergent validity with Pearson Correlation Coefficient using the Constant Score, the American Shoulder and Elbow Score, and the Western Ontario Rotator Cuff Index. RESULTS: Internal consistency was good, with a Cronbach alpha of 0.81. The Intraclass correlation coefficient was 0.90 (95% confidence interval: 0.78, 0.90), demonstrating good test-retest reliability. Pearson correlation coefficients of the Penn Shoulder Score in relation with the Constant Score, the American Shoulder and Elbow Score, and the Western Ontario Rotator Cuff Index were 0.65, 0.78, and -0.77, respectively. CONCLUSION: The Turkish version of the Penn Shoulder Score is a reliable and valid measure for assessing patients with shoulder dysfunctions. Implications for Rehabilitation The Turkish version of the Penn shoulder score is valid and reliable outcome measure for assessing patients with shoulder dysfunctions. The Turkish version of the Penn shoulder score could be easily performed by patients and it is easy to score by clinicians. It is recommended to use in clinical settings and in research. PMID- 28637133 TI - Efficacy of the whole-body vibration for pain, fatigue and quality of life in women with fibromyalgia: a systematic review. AB - PURPOSE: To determine the quality of evidence on the use of whole-body vibration (WBV) in controlling pain, fatigue and quality of life in women with fibromyalgia. METHODS: The search involved MEDLINE/PubMed, LILACS, CINAHL, CENTRAL and PEDro, without temporal or language restriction. The terms "fibromyalgia" and "whole-body vibration" were used. Trials (randomized or quasi randomized) that compared a group of women with fibromyalgia who received WBV to a control group with no intervention were included. The quality of evidence was assessed using the GRADE system. The quantitative evaluation by meta-analysis was also used, whenever possible. RESULTS: Three studies were included. Regarding the outcome pain, it has not been possible to assess the magnitude of effect of treatment. The result of the outcome fatigue showed no difference between the groups after the proposed intervention (Mean Difference: 0.01; 95% CI: -0.11 to 0.09). The meta-analysis for the outcome quality of life showed a small difference between groups, favoring the WBV group (Standard Mean Difference: 0.4943; p = 0.05; 95% CI: 0.0045 to 0.9841). CONCLUSIONS: The results, based on very low quality of evidence, were inconclusive regarding pain, and showed no clinically important effects on the control of fatigue and improvement of quality of life. Implications for rehabilitation There is no evidence to support the use of whole-body vibration for pain treatment of women with fibromyalgia. The use of whole-body vibration in women with fibromyalgia showed no clinically important effects in the control of fatigue and improvement of quality of life. PMID- 28637134 TI - An exploratory qualitative study of the meaning and value of a running/walking program for women after a diagnosis of breast cancer. AB - PURPOSE: To generate insights into the personal meaning and value of a running/walking program for women after a diagnosis of breast cancer. METHODS: After completing a 12-week running/walking program with a 5-km training goal, eight women were interviewed and seven participated in a focus group. The interviews and focus group were audio-recorded and transcribed verbatim. Data were thematically analyzed. RESULTS: Data portrayed the personal benefits and value of the clinic. Four themes were identified: (1) receiving practical information and addressing targeted concerns, (2) pushing personal limits, (3) enabling a committed mindset, and (4) seeing benefits and challenges of running/walking with a group. CONCLUSIONS: Findings provide initial understanding of how women experience a running/walking program after a diagnosis of breast cancer and what they find to be important about their experiences. The range of positive benefits experienced by women suggests a running/walking program can help fill a gap in care for women diagnosed with breast cancer, and thus be part of cancer rehabilitation. However, because some women felt isolated at times, future research should seek to examine how running/walking programs can be modified and tailored so that all women find it socially beneficial. Implications for Rehabilitation The diagnosis and treatment of breast cancer can result in side effects and increase the risk of long-term disability. Physical activity can help women manage the side effects and lessen the risk of long-term disability. In a relatively small sample, this study shows that participation in a running/walking program can be an important part of breast cancer recovery. PMID- 28637135 TI - Cross-cultural validity of the ABILOCO questionnaire for individuals with stroke, based on Rasch analysis. AB - PURPOSE: The purpose of this study was to evaluate the cross-cultural validity of the Brazilian version of the ABILOCO questionnaire for stroke subjects. MATERIALS AND METHODS: Cross-cultural adaptation of the original English version of the ABILOCO to the Brazilian-Portuguese language followed standardized procedures. The adapted version was administered to 136 stroke subjects and its measurement properties were assessed using Rash analysis. Cross-cultural validity was based on cultural invariance analyses. RESULTS: Goodness-of-fit analysis revealed one misfitting item. The principal component analysis of the residuals showed that the first dimension explained 45% of the variance in locomotion ability; however, the eigenvalue was 1.92. The ABILOCO-Brazil divided the sample into two levels of ability and the items into about seven levels of difficulty. The item-person map showed some ceiling effect. Cultural invariance analyses revealed that although there were differences in the item calibrations between the ABILOCO-original and ABILOCO-Brazil, they did not impact the measures of locomotion ability. CONCLUSIONS: The ABILOCO-Brazil demonstrated satisfactory measurement properties to be used within both clinical and research contexts in Brazil, as well cross cultural validity to be used in international/multicentric studies. However, the presence of ceiling effect suggests that it may not be appropriate for the assessment of individuals with high levels of locomotion ability. Implications for rehabilitation Self-report measures of locomotion ability are clinically important, since they describe the abilities of the individuals within real life contexts. The ABILOCO questionnaire, specific for stroke survivors, demonstrated satisfactory measurement properties, but may not be most appropriate to assess individuals with high levels of locomotion ability The results of the cross cultural validity showed that the ABILOCO-Original and the ABILOCO-Brazil calibrations may be used interchangeable. PMID- 28637136 TI - Virtual environment navigation with look-around mode to explore new real spaces by people who are blind. AB - BACKGROUND: This paper examines the ability of people who are blind to construct a mental map and perform orientation tasks in real space by using Nintendo Wii technologies to explore virtual environments. The participant explores new spaces through haptic and auditory feedback triggered by pointing or walking in the virtual environments and later constructs a mental map, which can be used to navigate in real space. METHODS: The study included 10 participants who were congenitally or adventitiously blind, divided into experimental and control groups. The research was implemented by using virtual environments exploration and orientation tasks in real spaces, using both qualitative and quantitative methods in its methodology. RESULTS: The results show that the mode of exploration afforded to the experimental group is radically new in orientation and mobility training; as a result 60% of the experimental participants constructed mental maps that were based on map model, compared with only 30% of the control group participants. CONCLUSIONS: Using technology that enabled them to explore and to collect spatial information in a way that does not exist in real space influenced the ability of the experimental group to construct a mental map based on the map model. Implications for rehabilitation The virtual cane system for the first time enables people who are blind to explore and collect spatial information via the look-around mode in addition to the walk-around mode. People who are blind prefer to use look-around mode to explore new spaces, as opposed to the walking mode. Although the look-around mode requires users to establish a complex collecting and processing procedure for the spatial data, people who are blind using this mode are able to construct a mental map as a map model. For people who are blind (as for the sighted) construction of a mental map based on map model offers more flexibility in choosing a walking path in a real space, accounting for changes that occur in the space. PMID- 28637137 TI - Development and acceptability testing of decision trees for self-management of prosthetic socket fit in adults with lower limb amputation. AB - PURPOSE: The most common complaint lower limb prosthesis users report is inadequacy of a proper socket fit. Adjustments to the residual limb-socket interface can be made by the prosthesis user without consultation of a clinician in many scenarios through skilled self-management. Decision trees guide prosthesis wearers through the self-management process, empowering them to rectify fit issues, or referring them to a clinician when necessary. This study examines the development and acceptability testing of patient-centered decision trees for lower limb prosthesis users. METHODS: Decision trees underwent a four stage process: literature review and expert consultation, designing, two-rounds of expert panel review and revisions, and target audience testing. RESULTS: Fifteen lower limb prosthesis users (average age 61 years) reviewed the decision trees and completed an acceptability questionnaire. Participants reported agreement of 80% or above in five of the eight questions related to acceptability of the decision trees. Disagreement was related to the level of experience of the respondent. CONCLUSIONS: Decision trees were found to be easy to use, illustrate correct solutions to common issues, and have terminology consistent with that of a new prosthesis user. Some users with greater than 1.5 years of experience would not use the decision trees based on their own self-management skills. Implications for Rehabilitation Discomfort of the residual limb-prosthetic socket interface is the most common reason for clinician visits. Prosthesis users can use decision trees to guide them through the process of obtaining a proper socket fit independently. Newer users may benefit from using the decision trees more than experienced users. PMID- 28637138 TI - Psychometric properties of Persian version of the Caregiver Burden Scale in Iranian caregivers of patients with spinal cord injury. AB - PURPOSE: To investigate the psychometric properties of the Persian version of Caregiver Burden Scale (CBS) in caregivers of patients with spinal cord injury. METHODS: This is a cross-sectional study. After a forward-backward translation, the CBS was administered to 110 caregivers of patients with spinal cord injury (men = 60, women = 50). Factor structure was evaluated by confirmatory factor analysis. The Internal consistency and test-retest reliability of the CBS were examined using Cronbach's alpha and the intraclass correlation coefficient, respectively. Construct validity was assessed by examining the relationship among CBS and the World Health Organization Quality of Life, and the Beck Depression Inventory. RESULTS: The results of confirmatory factor analysis provided support for a five-factor model of CBS. All subscales of CBS revealed acceptable internal consistency (0.698-0.755), except for environment subscale (0.559). The CBS showed adequate test-retest reliability for its subscales (0.745-0.900). All subscales of CBS significantly correlated with both Beck Depression Inventory and World Health Organization Quality of Life, confirming construct validity. CONCLUSIONS: The Persian version of the CBS is a valid and reliable measure for assessing burden of care in caregivers of patients with spinal cord injury. Implications for Rehabilitation Spinal cord injury leads to depression, high levels of stress and diminished quality of life due to the high physical, emotional, and social burdens in caregivers. Persian version of the Caregiver Burden Scale is a valid and reliable tool for assessing burden in Iranian caregivers of patients with spinal cord injury. PMID- 28637139 TI - Translation, cross-cultural adaptation and validation of the Persian version of COOP/WONCA charts in Persian-speaking Iranians with multiple sclerosis. AB - PURPOSE: Translation, cross-culturally adaptation and validation of a Persian version of COOP/WONCA charts in Persian-speaking Iranians with multiple sclerosis (MS). METHOD: The Persian version of COOP/WONCA charts was developed after a standard forward translation, synthesis and backward translation. A total of 197 subjects with MS participated in this study. They were asked to complete the COOP/WONCA charts and Short-Form 36 Health Survey (SF-36). The COOP/WONCA charts were re-administered to 50 patients, 4 weeks after the first session. Expanded Disability Status Scale (EDSS) was also scored for each subject by the referring physician. Construct validity was assessed by testing linear relationship between corresponding domains of the COOP/WONCA charts, the SF-36 and the EDSS. Test retest reliability was examined using interclass correlation coefficient (ICC), standard error of measurement (SEM) and minimal detectable change (MDC) values. RESULTS: Related domains of COOP/WONCA charts and SF-36 demonstrated strong linear relationships with Spearman's coefficients ranging from -0.51 to -0.75 (p< 0.05). Physical fitness and daily activity charts also demonstrated strong relationships with the EDSS by Spearman's coefficients of 0.65 and 0.50, respectively (p< 0.05). The ICC values for most of COOP/WONCA charts domains were acceptable (>0.70) except for feelings and quality-of-life domains that were 0.50 and 0.51, respectively. CONCLUSIONS: The Persian version of the COOP/WONCA charts was shown to be psychometrically appropriate to evaluate the functional level and quality of life in Persian-speaking Iranians with MS. Implications for rehabilitation COOP/WONCA charts are now available in Persian and demonstrate good psychometric properties. COOP/WONCA charts demonstrate excellent reliability and construct validity in a Persian-speaking Iranian population with MS. Minimal detectable change in COOP/WONCA is now available in MS to guide within and between group analyses. Knowledge on a wide variety of physical, mental and emotional parameters as well as the status of patients' symptoms, daily activities and quality of life helps rehabilitation clinicians and service providers plan preventive and remedial interventions more effectively. PMID- 28637140 TI - Intimate partner violence in women with disabilities: perception of healthcare and attitudes of health professionals. AB - PURPOSE: Intimate partner violence (IPV) is a major social problem and public health issue, but we still have a relatively small amount of data about partner violence in women with disabilities. The main objective of this study was to understand the experiences of women with disabilities who are or have been abused by their partners and to explore the knowledge, views and training requirements of primary care professionals. METHOD: Qualitative study using semi-structured interviews with women with disabilities who had experienced IPV (n = 14), and focus groups with healthcare professionals (n = 16). RESULTS: Women with disabilities suffer specific forms of abuse. Because they depend on the people around them to take action, they are subordinate and this can prolong the abuse. The healthcare staff frequently mentioned that it is often difficult to notice that women with disabilities are being abused. Their lack of training about disabilities and gender-based violence makes them less sure of their ability to identify and deal with any possible cases of abuse. CONCLUSIONS: The difficulties described by the women interviewed are broadly speaking the same as those described by the healthcare professionals consulted. A number of suggestions for improvements are provided based on the results found. Implications for Rehabilitation The rehabilitation of abused disabled women implies that women perceive the health system as a resource to resolve their situation. Healthcare professionals should be trained on how to detect, treat and communicate with disabled women who experience partner violence. Is needed to establish a comprehensive system of coordination between services involved in caring for abused women and with disabilities. PMID- 28637141 TI - Misconceptions about traumatic brain injury among probation services. AB - PURPOSE: The prevalence of traumatic brain injury (TBI) among offender populations is significantly higher than among the general population. Despite this, no study has yet assessed the knowledge of members of the probation service surrounding TBI. METHOD: Knowledge was assessed among members of the Probation Board for Northern Ireland (PBNI) using a cross-sectional online version of the Common Misconceptions about TBI (CM-TBI) questionnaire. Mean total misconception scores, along with scores on four subdomains (recovery, sequelae, insight, and hidden injury) were calculated. Analysis of variance was used to explore differences in misconceptions based on the collected demographic information. RESULTS: The overall mean percentage of misconceptions for the group was 22.37%. The subdomain with the highest rate of misconceptions (38.21%) was insight into injury which covered misconceptions around offenders' self-awareness of injuries. Those who knew someone with a brain injury scored significantly higher in the CM TBI total score, F(1,63) = 6.639, p = 0.012, the recovery subdomain, F(1,63) = 10.080, p = 0.002, and the insight subdomain, F(1,63) = 5.834, p = 0.019. Additionally, significant training deficits around TBI were observed among the probation service. CONCLUSIONS: This study is the first of its kind to examine the level of understanding around TBI within probation services. The findings reflect potential barriers to identification and rehabilitation of TBI for offenders coming into contact with the criminal justice system. A lack of identification coupled with misconceptions about TBI could lead to inaccurate court reporting with a subsequent impact on sentencing. Implications for Rehabilitation Despite being one of the first points of contact for offenders entering the criminal justice system, members of the probation service reported having no formal training on traumatic brain injury (TBI). The subdomain with the highest rate of misconceptions (insight into injury) revealed an over-reliance on survivors of brain injury to identify, understand, and communicate the extent and severity of their injuries. Probation service personnel require training on TBI to improve awareness of the potential outcomes of the condition, ensuring injuries are identified and referred to the appropriate care pathways. PMID- 28637142 TI - Feasibility of a cognitive strategy training intervention for people with Parkinson's disease. AB - PURPOSE: To investigate the feasibility of a novel client-centered cognitive strategy training intervention for people with Parkinson's disease (PD). MATERIALS AND METHODS: This was a case series of seven people with PD without dementia but with subjective cognitive decline. The intervention involved >=5 treatment sessions at the participant's home. Participant acceptance and engagement were assessed by the Credibility/Expectancy Questionnaire (CEQ), Client Satisfaction Questionnaire (CSQ), enjoyment and effort ratings, and homework completion. Logistical information was tracked, and the Canadian Occupational Performance Measure (COPM) was an exploratory outcome measure. Data analysis was descriptive. RESULTS: CEQ scores were positive and increased over time. CSQ scores were high (M = 30.8, SD = 0.75), with all participants rating all items positively. Almost all (95%) effort and enjoyment ratings were >=3 (Much), and homework completion rates averaged 84% (SD = 18). Intervention duration was 6-15 weeks (M = 9.2, SD = 2.8), with treatment sessions averaging 1.7 h (SD = 0.5). Group and most individual COPM ratings improved >=2 points. CONCLUSIONS: These findings support the feasibility of the intervention for people with PD. It was acceptable, engaging, and promising in terms of its effect on self-identified functional cognitive problems. Implications for Rehabilitation People with Parkinson's disease (PD) without dementia can experience cognitive decline that negatively impacts function and quality of life. Strategy-based interventions that explicitly train for transfer may mitigate the negative functional consequences of cognitive decline in this population. We developed a client-centered cognitive strategy training intervention for people with PD. This small case series supports its feasibility, indicating that it is acceptable and engaging for people with PD and promising in terms of its effect on self identified functional cognitive problems. PMID- 28637143 TI - Validity and reliability of an activity monitor to quantify arm movements and activity in adults following distal radius fracture. AB - PURPOSE: To examine the validity and reliability of an activity monitor to estimate upper limb activity. METHODS: Thirty-two adults after distal radial fracture were recruited. 15 adults performed five upper limb activities during two testing sessions, one week apart to investigate criterion validity against the criterion reference of three-dimensional motion analysis, convergent validity, and test-retest reliability. 17 adults in two therapy groups wore monitors for three consecutive days at baseline and six weeks post-intervention. Hypothesis testing (noninferiority) assessed comparison of group differences. RESULTS: There were large, significant positive correlations between monitor counts and motion analysis for affected/unaffected wrists during the grocery shelving [r = 0.82, r = 0.73, respectively] and floor sweeping activities [r = 0.54, r = 0.59, respectively]. Large confidence intervals relative to means suggests the monitor could not accurately predict motion analysis distance or acceleration. Relative reliability was excellent in affected/unaffected wrists for crank ergometer [ICC(2,1) = 0.91, ICC(2,1) = 0.88, respectively], grocery shelving [ICC(2,1) = 0.83, ICC(2,1) = 0.89, respectively], and table dusting activities [ICC(2,1) = 0.77, ICC(2,1) = 0.83, respectively]. Correlations and reliability for typing were poor; hypothesis testing of group equivalence was not confirmed. CONCLUSIONS: There is preliminary evidence that an activity monitor is a valid and reliable tool to measure gross arm activity after distal radial fracture. Implications for Rehabilitation Distal radius fractures are one of the most common upper limb fractures that cause activity limitations and participation restrictions. After a distal radius fracture patients are often referred to therapy (physiotherapy, occupational therapy, hand therapy) for rehabilitation to return to pre-injury function and activity levels. Activity monitors may be a valid and reliable measurement tool that therapists can use with their patients to quantify gross arm activity to enable monitoring of injury recovery and rehabilitation adherence. Activity monitors may not be sufficiently reliable and valid to monitor fine movements of the wrist and hand after distal radius fracture. PMID- 28637144 TI - What information do patients need following a whiplash injury? The perspectives of patients and physiotherapists. AB - PURPOSE: The aims of the present study were to identify information that individuals with whiplash associated disorders (WAD) need to know in the early stages of recovery and to establish whether there is a difference between what physiotherapists and whiplash-injured patients perceive as important information. METHOD: Forty-one participants were recruited (20 whiplash-injured patients, 21 physiotherapists). Participants were asked to provide five statements to one open ended question about what they believe is the most important information individuals with WAD need to know in the early stages of recovery. Participants provided 182 statements which were reviewed independently and organised into themes by two of the authors. RESULTS: Six key themes emerged from the statements. These included general information about whiplash injury, treatment and recovery, reassurance, provision of poor information and patients' interaction with general practitioners, maintaining daily activities, and compensation claims and litigation. Both patients and physiotherapists agreed on the type of general whiplash information that should be provided however, major differences were found with regard to information pertaining to compensation claims and litigation and maintaining daily activities. CONCLUSIONS: The findings of this study provide some insight into the type of information that WAD individuals require in the early stages of recovery. Implications for Rehabilitation The provision of reassurance can be an effective communication tool to decrease patients concerns about their injury and help strengthen the patient-health practitioner relationship. Although clinical guidelines for the management of whiplash injuries recommend that individuals must remain physically active post-injury, statements from the patient group indicate that this information is not always provided and clearly explained to patients. Keeping in line with the patient centred care approach of being responsive to patient needs and values, it is essential for health practitioners to be attentive to patients' preferences regarding the level of participation in treatment decisions. Processes need to be developed to deliver individuals with WAD accurate information regarding compensation claims so that these factors do not distract from focusing on recovery. PMID- 28637145 TI - Amount of balance necessary for the independence of transfer and stair-climbing in stroke inpatients. AB - PURPOSE: The purpose of this study was to clarify the amount of balance necessary for the independence of transfer and stair-climbing in stroke patients. METHOD: This study included 111 stroke inpatients. Simple and multiple regression analyses were conducted to establish the association between the FIM(r) instrument scores for transfer or stair-climbing and Berg Balance Scale. Furthermore, receiver operating characteristic curves were used to elucidate the amount of balance necessary for the independence of transfer and stair-climbing. RESULT: Simple and multiple regression analyses showed that the FIM(r) instrument scores for transfer and stair-climbing were strongly associated with Berg Balance Scale. On comparison of the independent and supervision-dependent groups, Berg Balance Scale cut-off values for transfer and stair-climbing were 41/40 and 54/53 points, respectively. On comparison of the independent-supervision and dependent groups, the cut-off values for transfer and stair-climbing were 30/29 and 41/40 points, respectively. CONCLUSIONS: The calculated cut-off values indicated the amount of balance necessary for the independence of transfer and stair-climbing, with and without supervision, in stroke patients. Berg Balance Scale has a good discriminatory ability and cut-off values are clinically useful to determine the appropriate independence levels of transfer and stair-climbing in hospital wards. Implications for rehabilitation The Berg Balance Scale's (BBS) strong association with transfer and stair-climbing independence and performance indicates that establishing cut-off values is vitally important for the established use of the BBS clinically. The cut-off values calculated herein accurately demonstrate the level of balance necessary for transfer and stair-climbing independence, with and without supervision, in stroke patients. These criteria should be employed clinically for determining the level of independence for transfer and stair climbing as well as for setting balance training goals aimed at improving transfer and stair-climbing. PMID- 28637146 TI - Instilling positive beliefs about disabilities: pilot testing a novel experiential learning activity for rehabilitation students. AB - PURPOSE: To develop and test a novel impairment simulation activity to teach beginning rehabilitation students how people adapt to physical impairments. METHODS: Masters of Occupational Therapy students (n = 14) and Doctor of Physical Therapy students (n = 18) completed the study during the first month of their program. Students were randomized to the experimental or control learning activity. Experimental students learned to perform simple tasks while simulating paraplegia and hemiplegia. Control students viewed videos of others completing tasks with these impairments. Before and after the learning activities, all students estimated average self-perceived health, life satisfaction, and depression ratings among people with paraplegia and hemiplegia. RESULTS: Experimental students increased their estimates of self-perceived health, and decreased their estimates of depression rates, among people with paraplegia and hemiplegia after the learning activity. The control activity had no effect on these estimates. CONCLUSIONS: Impairment simulation can be an effective way to teach rehabilitation students about the adaptations that people make to physical impairments. Positive impairment simulations should allow students to experience success in completing activities of daily living with impairments. Impairment simulation is complementary to other pedagogical methods, such as simulated clinical encounters using standardized patients. Implication of Rehabilitation It is important for rehabilitation students to learn how people live well with disabilities. Impairment simulations can improve students' assessments of quality of life with disabilities. To be beneficial, impairment simulations must include guided exposure to effective methods for completing daily tasks with disabilities. PMID- 28637147 TI - Musculoskeletal complaints in individuals with finger or partial hand amputations in the Netherlands: a cross-sectional study. AB - PURPOSE: To compare the prevalence of musculoskeletal complaints (MSCs) in individuals with finger or partial hand amputations (FPHAs) with a control group and to explore the effect and predictors of MSCs in individuals with FPHAs. METHOD: A questionnaire-based cross-sectional study was conducted. The primary outcome measures were: prevalence of MSCs, health status, pain-related disability, physical work demands, work productivity, and hand function. RESULTS: The response rate was 61%. A comparable proportion of individuals with FPHAs (n = 99) and controls (n = 102) reported MSCs in the preceding 4 weeks (33% vs. 28%, respectively) or in the preceding year (37% vs. 33%, respectively). Individuals with FPHAs with MSCs experienced more pain than controls with MSCs. Regular occurrence of stump sensations and self-reported limited range of motion (ROM) of the wrist of the affected limb were predictors for MSCs in individuals with FPHAs. CONCLUSIONS: The prevalence of MSCs was comparable in individuals with FPHAs and controls. However, clinicians should pay special attention to the risk of developing MSCs in patients with stump sensations and limited ROM of the wrist of the affected limb. Future research should focus on the role of wrist movements and compensatory movements in the development of MSCs in individuals with FPHAs. Implications for Rehabilitation The prevalence of musculoskeletal complaints (MSCs) in individuals with finger or partial hand amputations (FPHAs) and control subjects was similar. Regular occurrence of stump sensations and limited range of motion of the wrist of the affected limb were predictors of developing MSCs in individuals with FPHAs. Clinicians should pay special attention to individuals with FPHAs with the presence of these predictors of developing MSCs. For a better understanding of the development of and treatment options for MSCs, future research focusing on the role of wrist function in the development of MSCs in individuals with FPHAs is necessary. PMID- 28637148 TI - Pure tone hearing profiles in children with otitis media with effusion. AB - INTRODUCTION: Otitis media with effusion (OME) is a common middle ear disease in children. The associated conductive hearing loss is a major concern for hearing health professionals. The aim of the present study was to describe the configuration of pure tone audiograms of children with OME and to design a statistical stratification algorithm to facilitate hearing loss profiling in children with OME. METHODS: School age children with OME were recruited. Bone and air conduction thresholds were obtained using standard procedures. Hierarchical cluster analysis was employed to determine audiometric profile groups. The Mandarin Hearing in Noise Test was used to measure sentence perception in children for cluster analysis validity assessment. RESULTS: Ninety-seven children (164 ears) aged between 72 months and 153 months were examined. Air conduction thresholds averaged for 500 Hz, 1000 Hz and 2000 Hz were in the range of 8.3-53.3 dB HL with a mean of 26.8 dB HL. Bone conduction thresholds were found to be influenced by middle ear pathology with a maximal elevation at 2000 Hz of 25 dB HL. Four audiometric profiles were identified. Cluster 1 contained 54 ears (32.9%) with normal or near normal hearing, Clusters 2 contained 37 ears (22.6%) with mild hearing loss, Cluster 3 included 48 ears (29.3%) and Cluster 4 included 25 ears (15.2%) with moderate hearing loss. Stability and validity of the four cluster profiling procedure was examined and established with satisfactory results. CONCLUSIONS: OME in children is associated with pure tone hearing thresholds ranging from normal to moderate hearing loss. The hierarchical clustering algorithm proved useful as a novel means of profiling hearing loss in children with OME and may assist in identifying affected children at greater risk of auditory disadvantage. Implications for rehabilitation A hierarchical cluster analysis method can be used to determine audiometric profiles in children with OME. This algorithm assists to identify children at greater risk of auditory disadvantage. Cluster groups with more elevated pure tone thresholds may be targeted for priority in clinical surveillance and medical/surgical intervention. PMID- 28637150 TI - Family matters: compensable injury and the effect on family. AB - PURPOSE: It is well acknowledged that involvement in injury compensation processes can have a substantial impact on the recovery of the injured person. However, little attention has been given to the social or family consequences of compensable injury. The aims of this study were to better understand both the impact of compensable injury on the family and the role that families play after an injury, throughout the compensation process, and during return to work. METHODS: Eighteen injured persons and nine family members recruited through three compensation authorities in Victoria (Australia) were interviewed. A thematic analysis was used to identify the role that family played after injury and how family members were affected during the recovery and compensation process. RESULTS: The results highlight the important role family members play following a compensable injury, in addition to factors that impact family members' daily living, health, and well-being. The study suggests that compensation processes can have an impact on family members, despite compensation systems not formally acknowledging the family in policy or procedure. CONCLUSIONS: Compensation authorities should formally consider the role of family in recovery from injury, not only as one means of addressing the overall burden of injury but as a conduit for improving health and function among injured people. Implications for Rehabilitation Family members play an important role after compensable injury that includes providing administrative, instrumental, and emotional support. The recovery and injury compensation process can also have a major impact on family members, particularly in the case of prolonged and complex injuries and illnesses Compensation authorities should formally consider the role of family in the recovery from injury, not only as one means of addressing the overall burden of injury but, as a conduit for improving health and function among injured people. PMID- 28637151 TI - Work-related experiences of head and neck cancer survivors: an exploratory and descriptive qualitative study. AB - PURPOSE: This exploratory and descriptive study contributes to the growing knowledge about the return-to-work (RTW) experience of head and neck cancer (HNC) survivors. Viewing RTW as a process, participants were asked to consider the work related experience with HNC at different phases: (1) at diagnosis/pre-treatment, (2) working during treatment (if the respondent did not take a work disability leave), and (3) post-treatment/RTW (if the respondent took a work disability leave). METHODS: Data were gathered in nine individual semi-structured in-depth interviews with patients receiving treatment at a quaternary cancer center's HNC clinic in Ontario, Canada. Using a constant comparative method of theme development, codes were identified in and derived from the data. Codes with similar characteristics were grouped, used to develop overarching themes, and were organized according to the RTW factors identified in the literature. RESULTS: Each phase has different barriers that are in turn addressed by different facilitators. As reflected in the literature, we found that RTW or the process of work continuation is complex. Many players and interactions contribute to the worker's experience. CONCLUSIONS: By recognizing that work-related experiences differ by phases, clinicians and employers can better support HNC survivors depending on the phase of the RTW process. Implications for Rehabilitation Our findings suggest that when rehabilitation specialists are working with survivors to develop interventions, the return-to-work phase and work context rather than diagnosis should be considered as a starting point. At every phase, supportive and empathetic managers are a key to successful work experiences for people who have been diagnosed and are being treated for head and neck cancer. Rehabilitation specialists should help survivors to seek supportive interactions with the environment that are essential to enable the ability to work. PMID- 28637152 TI - How physical therapists instruct patients with stroke: an observational study on attentional focus during gait rehabilitation after stroke. AB - PURPOSE: People without neurological impairments show superior motor learning when they focus on movement effects (external focus) rather than on movement execution itself (internal focus). Despite its potential for neurorehabilitation, it remains unclear to what extent external focus strategies are currently incorporated in rehabilitation post-stroke. Therefore, we observed how physical therapists use attentional focus when treating gait of rehabilitating patients with stroke. METHODS: Twenty physical therapist-patient couples from six rehabilitation centers participated. Per couple, one regular gait-training session was video-recorded. Therapists' statements were classified using a standardized scoring method to determine the relative proportion of internally and externally focused instructions/feedback. Also, we explored associations between therapists' use of external/internal focus strategies and patients' focus preference, length of stay, mobility, and cognition. RESULTS: Therapists' instructions were generally more external while feedback was more internal. Therapists used relatively more externally focused statements for patients with a longer length of stay (B = -0.239, p = 0.013) and for patients who had a stronger internal focus preference (B = -0.930, p = 0.035). CONCLUSIONS: Physical therapists used more external focus instructions, but more internally focused feedback. Also, they seem to adapt their attentional focus use to patients' focus preference and rehabilitation phase. Future research may determine how these factors influence the effectiveness of different attentional foci for motor learning post-stroke. IMPLICATIONS FOR REHABILITATION Physical therapists use a balanced mix of internal focus and external focus instructions and feedback when treating gait of stroke patients. Therapists predominantly used an external focus for patients in later rehabilitation phases, and for patients with stronger internal focus preferences, possibly in an attempt to stimulate more automatic control of movement in these patients. Future research should further explore how a patients' focus preference and rehabilitation phase influence the effectiveness of different focus strategies. Awaiting further research, we recommend that therapists use both attentional focus strategies, and explore per patient which focus works best on a trial-and-error basis. PMID- 28637149 TI - Personal meaning in relation to daily functioning of a patient in physical therapy practice: narratives of a patient, a family member, and physical therapist. AB - PURPOSE: To get insight into personal meaning of a person involved in a physical therapy intervention. METHODS: Mrs. A, a 76-year-old woman is referred to a physical therapist (PT) for assessment of functioning and training before total hip arthroplasty (THA). The patient, her daughter, and PT were asked to write a story about their daily life. Stories were analyzed according to the narrative scheme based on a method to find meaning in daily life, which consists of four phases: 1. Motivation; 2. Competences; 3. Performance; and 4. EVALUATION: RESULTS: Mrs. A was mainly motivated by her will to do enjoyable social activities and stay independent. Although she tried her best to undertake activities (performance) that made her proud (evaluation), her pain and physical limitations were anti-competences that motivated her to attend healthcare. Although the PT seemed to be aware of personal participation goals, her main motivation was to improve and evaluate functions and activities. The daughter was motivated by good relationships and did not see herself as informal caregiver. CONCLUSIONS: The narrative method was a valuable tool to clarify motivations, competences, and values in the process of creating personal meaning related to functioning. This knowledge could help caregivers in applying patient-centered goal-setting and treatment on a participation level. Implications for rehabilitation Personal meaning of people's functioning within their daily context can be clarified from daily life stories. This case report demonstrates that motivations and goals may differ between patient and therapist; the PT seems to focus on improving and evaluating functions and activities, while the patient seems to focus her motivations and personal meaning on participation. This approach may help in patient-centered goal-setting at the level of activities and participation. PMID- 28637153 TI - Dutch version of the Fear of Pain Questionnaire for adolescents with chronic pain. AB - BACKGROUND: Fear of pain is important in the development and maintenance of chronic pain. The Fear of Pain Questionnaire-Child version has been developed to assess pain related fear in children and adolescents. OBJECTIVE: Translating the original questionnaire into Dutch, and investigating internal consistency and construct validity to enable use in the Dutch pain rehabilitation setting for treatment and research. METHODS: Cross-sectional validation study: After forward and back translation of the FOPQ-C, adolescents (11-22 years old) with chronic musculoskeletal pain completed an assessment containing the Dutch Fear of Pain Questionnaire, and questionnaires about demographics, pain catastrophizing, functional disability, and pain intensity. Internal consistency and construct validity were evaluated through exploratory factor analysis (principal axis factoring with oblique rotation) and hypotheses testing using pain catastrophizing, functional disability, and pain intensity as comparative constructs. RESULTS: Eighty-six adolescents completed the assessment. Exploratory factor analysis resulted in a two-factor structure, explaining 43% of the variance. Internal consistency was strong (Cronbach's alpha = 0.92 total scale, alpha = 0.88 factor 1, and alpha = .86 factor 2). Five out of 6 hypotheses were confirmed. CONCLUSIONS: The Dutch version demonstrated good internal consistency and good construct validity in a population of adolescents with chronic musculoskeletal pain. Implications for rehabilitation The Fear of Pain Questionnaire-Child version was developed to measure fear of pain and avoidance in children and adolescents with chronic pain. Identification of fear of pain and activities that are being avoided are important during screening and assessment of the adolescent for chronic pain rehabilitation treatment. The presence of fear of pain and/or avoidance behavior is important information to shape and target multidisciplinary rehabilitation treatment. PMID- 28637154 TI - Shoulder pain after stroke - experiences, consequences in daily life and effects of interventions: a qualitative study. AB - PURPOSE: To describe experiences of shoulder pain after stroke, how pain affects daily life and perceived effects of interventions. METHOD: A qualitative interview study including 13 community-dwelling persons (six women; median age 65 years) with persistent shoulder pain after stroke. RESULTS: Three categories emerged from the content analysis. In "Multiple pain characteristics" an insidious pain onset was reported. The pain existed both day and night and could be located around the shoulder girdle but also have radiation to the arm and hand. An explanation of the pain was seldom given. In "Limitations caused by the pain" it was described how the pain negatively influenced personal care, household activities and leisure, but also could lead to emotional reactions. In "Multiple pain interventions with various effects" a variety of interventions were described. Self-management interventions with gentle movements were perceived most effective. A restraint attitude to pain medication due to side effects was reported. CONCLUSIONS: Shoulder pain after stroke can lead to a variety of pain characteristics. As the pain is complex and may affect many important areas in a person's life, multidisciplinary rehabilitation interventions are important. Implications for rehabilitation Shoulder pain after stroke can lead to a variety of pain characteristics with radiation to the arm and hand Shoulder pain often influence personal care, household activities and leisure negatively, which may lead to emotional reactions Self-management interventions with gentle movements are perceived most effective As the shoulder pain after stroke is complex, interventions by a multidisciplinary team may be needed. PMID- 28637155 TI - Reliability, validity, and norms of the 2-min walk test in children with and without neuromuscular disorders aged 6-12. AB - PURPOSE: The 2-min walk test may be more appropriate functional exercise test for young children. This study aimed to examine the 2-min walk test's reliability; validity; and minimal clinically important difference; and to establish norms for children aged 6-12. METHODS: Sixty-one healthy children were recruited to examine the 2-min walk test's reliability. Forty-six children with neuromuscular disorders (63% cerebral palsy) were recruited to test the validity. The normative study involved 716 healthy children without neuromuscular disorders (male = 51%, female = 49%). They walked at a self-selected speed for 2 min along a smooth, flat path 15 m in length. RESULTS: The mean distance covered in the 2-min walk test was 152.8 m (SD =27.5). No significant difference was found in the children's test-retest results (p > 0.05). The intra- and inter-rater reliability were high (all intra-class correlation coefficients >0.8). All children, except one with neuromuscular disorders, completed the 2-min walk test, of which the minimal clinically important difference at 95% confidence interval was 23.2 m for the entire group, 15.7 m for children walking with aids, and 16.6 m for those walking independently. CONCLUSIONS: The 2-min walk test is a feasible, reliable, and valid exercise test for children with and without neuromuscular disorders aged 6-12. The first normative references and minimal clinically important difference for children with neuromuscular disorders were established for children of this age group. Implications for rehabilitation The 2-min walk test is a feasible, safe, reliable, and valid time-based walk test for children aged 6 12 years. Normative references have been established for healthy children aged 6 12 years. Minimal clinically important difference at 95% confidence interval were calculated for children with neuromuscular disorders who walked without aids (i.e., independent and stand-by supervision) and those who walked with aids equal to 16.6 and 15.7 m, respectively. Distance covered by the healthy children in the 2 min did not correlate with age, gender, height, and weight of the children. PMID- 28637156 TI - The sink or SWIM hypothesis; a roadmap from pathology to work instability. AB - PURPOSE: Selecting the most appropriate health-related work outcome to evaluate an intervention can be fraught with difficulty. To aid clinicians in navigating this problem we have developed a model, which illustrates how pathology can affect specific measureable quantities, such as work instability. METHODS: Using a modified-Delphi procedure, a panel of experts met initially to analyze the content of 95 health-related work outcome measures and organize the identified areas of measurement into a coherent model, complemented by a narrative review of the literature. This initial model underwent two rounds of stakeholder-based feedback, the results of which were incorporated in the final expert panel meeting to produce the States-traits Work Instability Model (SWIM). RESULTS: The States-traits Work Instability Model (SWIM) illustrates how changes to an individual's physical and psychological states and traits might affect their work related performance, well-being and self-efficacy. Moreover, each concept utilized in the model was specifically selected as it represents a measurable quantity, for which there are tools available. CONCLUSION: The SWIM is arguably the first holistic model of work that is based on both the clinical realities of vocational rehabilitation, sociological research, and is born from analyzing the basis of practical measurements. Implications for Rehabilitation Work Instability * Work instability has multiple causes many of which are amenable to intervention * The model clarifies the measureable domains of vocational rehabilitation interventions, which is of particular benefit for services working with people with disability at work who are struggling to remain in work * The model conceptualizes how the potential areas for intervention may be related based on evidence available in the literature. PMID- 28637157 TI - Maximal and submaximal aerobic tests for wheelchair-dependent persons with spinal cord injury: a systematic review to summarize and identify useful applications for clinical rehabilitation. AB - PURPOSE: To summarize the available maximal and submaximal aerobic exercise tests for wheelchair-dependent persons with a spinal cord injury (SCI) and to identify useful applications for clinical rehabilitation. METHOD: The databases of PubMed, CINAHL(r), EMBASE, and PsycINFO(r) were searched for English-language studies published prior to March 2015. Two independent raters identified and examined studies that reported on laboratory-based aerobic exercise tests in persons with an SCI, according to the PRISMA statement. RESULTS: The test protocols of maximal (n = 105) and submaximal (n = 28) exercise tests, covered by 95 included studies, were assessed. A large variety in patient characteristics, test objectives, test protocols, exercise modes, and outcome parameters was reported. Few studies reported on adherence to recommendations, adverse events, and peak outcome validation. CONCLUSIONS: An incremental test protocol with small, individualized, increments per stage seems preferable for testing maximal aerobic capacity, but additional validation of the available test modes is required to draw conclusions. Submaximal testing is relevant for assessing the performance at daily life intensities and for estimating VO2peak. Consensus regarding reporting test procedures and outcomes needs to be achieved to enhance comparability of rehabilitation results. Implications for Rehabilitation Regularly testing the cardiovascular capacity during SCI rehabilitation will enable us to monitor the impact of rehabilitation interventions on an individual level. The incremental arm ergometry test with small increments per stage is most relevant for the assessment of the peak cardiovascular capacity. For the assessment of daily life functioning, the submaximal wheelchair ergometer test is preferable. Hand cycling is a promising exercise mode for both testing and training. Systematically reporting on test termination, criteria for attaining valid peak outcomes and adverse events is necessary to enhance comparability of results. PMID- 28637158 TI - A reused method for molasses-processed wastewater: Effect on silage quality and anaerobic digestion performance of Pennisetum purpereum. AB - The silage quality and anaerobic digestion performance of Pennisetum purpereum with molasses-processed wastewater addition were assessed. The silage samples with molasses-processed wastewater addition obtained higher lactic acid concentration of 15.18-23.38mg/g FM, lower pH value of 3.96-4.45 and lower NH3-N content of 0.47-0.64mg/g FM. No obvious difference was observed in the dominant phyla and genus, but the relative abundance of Lactobacillus reached up to 77.39%, increased by 84% compared to the silage samples without molasses processed wastewater addition. Combined the silage quality and bacterial community, the decreased in pH value of fresh material caused by molasses processed wastewater addition was the main reason for improving the silage quality. Meanwhile, the increased in COD concentration is beneficial for improving the specific methane yield and the maximum specific methane yield of 259+/-5.75mL/g VS was obtained with adding 20g/kg molasses-alcoholic wastewater. Molasses-processed wastewater is an alternative additive for silage. PMID- 28637159 TI - Methane production and fertilizing value of organic waste: Organic matter characterization for a better prediction of valorization pathways. AB - Organic wastes are potential sources of both energy as well as crop production fertilizers. Correlations and models, involving organic matter characterization, have been previously described by several authors although there is still a lack in knowledge on the potential of simultaneous predictions of methane and organic fertilizer quality to optimize the wastes treatments. A methodology combining chemical accessibility and fluorescence spectroscopy was used to characterize 82 different organic wastes. Characterization data were compared with the biochemical methane potential (BMP), and with the biodegradable organic carbon obtained by soil incubation (C_bio). High correlations values were observed (R2 of 0.818 for BMP and 0.845 for C_bio). Model coefficients highlighted the differences and similarities between anaerobic and aerobic soil biodegradation, suggesting that anaerobic recalcitrant molecules could enhance soil fertility. This is a first step in the development of a tool for optimising both types of valorisation according to agrosystem needs and constraints. PMID- 28637160 TI - Energy-producing electro-flocculation for harvest of Dunaliella salina. AB - In this study, an efficient electro-flocculation process for Dunaliella salina with energy production by aluminum-air battery has been successfully applied. The formed aluminum hydroxide hydrates during discharging of battery were positively charged, which have a great potential for microalgae flocculation. The precipitation of aluminum hydroxide hydrates by algae also could improve the performance of aluminum-air battery. The harvesting efficiency could reach 97% in 20mins with energy production of 0.11kWh/kg. This discharging electro flocculation (DEF) technology provides a new energy producing process to effectively harvest microalgae. PMID- 28637161 TI - Sequential batch thermophilic solid-state anaerobic digestion of lignocellulosic biomass via recirculating digestate as inoculum - Part II: Microbial diversity and succession. AB - This study aimed to investigate the effect of recirculation of digestate as inoculum on the microbial communities in thermophilic solid-state anaerobic digestion (SS-AD) of yard trimmings. The SS-AD consisted of 4 consecutive runs (30days/run), with digestate from the previous run being used as the inoculum of the subsequent run. Bacterial and archaeal communities (day 0, 4, 8, 12, 20, and 30) were examined using Illumina sequencing of 16S rRNA genes. The results revealed substantial microbial succession toward increased diversity until run 3. The proportions of Firmicutes that contained cellulolytic bacteria doubled, which might explain the concomitantly increased cellulose degradation and volatile fatty acids (VFAs). Clostridia and Thermotogae appeared to correlate with VFAs. The VFA accumulation likely induced dynamic shifts of methanogens, particularly to hydrogenotrophic Methanothermobacter, implying that non-acetoclastic oxidative pathway dominated during the steady-state thermophilic SS-AD. This study suggested that recirculating SS-AD digestate might be an effective way for inoculation. PMID- 28637162 TI - Response of antimicrobial nitrofurazone-degrading biocathode communities to different cathode potentials. AB - Bioelectrodegradation of various organic pollutants has been extensively studied. However, whether different cathode potentials could alter the antimicrobial degrading biocathode community structure and composition remain poorly understood. Here, the microbial community structure and composition of the nitrofurans nitrofurazone (NFZ) degrading biocathode in response to different cathode potentials (-0.45+/-0.01, -0.65+/-0.01 and -0.86+/-0.05V vs standard hydrogen electrode, with applied cell voltages of 0.2, 0.5 and 0.8V, respectively) were investigated. The bioelectrodegradation efficiency and degree of NFZ were highly related to different cathode potentials. The 0.2 and 0.5V performed biocathode communities were similar but significantly differed from those of the 0.8V and open circuit biofilms. The bacteria possessing functions of nitroaromatics reduction and electrons transfer (e.g. Klebsiella, Enterococcus, Citrobacter and Desulfovibrio) were selectively enriched in different biocathode communities. This study offers new insights into the ecological response of antimicrobial-degrading biocathode communities to different cathode potentials. PMID- 28637163 TI - The impacts of biomass properties on pyrolysis yields, economic and environmental performance of the pyrolysis-bioenergy-biochar platform to carbon negative energy. AB - This study evaluated the impact of biomass properties on the pyrolysis product yields, economic and environmental performance for the pyrolysis-biochar bioenergy platform. We developed and applied a fast pyrolysis, feedstock sensitive, regression-based chemical process model to 346 different feedstocks, which were grouped into five types: woody, stalk/cob/ear, grass/plant, organic residue/product and husk/shell/pit. The results show that biomass ash content of 0.3-7.7wt% increases biochar yield from 0.13 to 0.16kg/kg of biomass, and decreases biofuel yields from 87.3 to 40.7 gallons per tonne. Higher O/C ratio (0.88-1.12) in biomass decreases biochar yield and increases biofuel yields within the same ash content level. Higher ash content of biomass increases minimum fuel selling price (MFSP), while higher O/C ratio of biomass decreases MFSP within the same ash content level. The impact of ash and O/C ratio of biomass on GHG emissions are not consistent for all feedstocks. PMID- 28637165 TI - Quantification of the methane concentration using anaerobic oxidation of methane coupled to extracellular electron transfer. AB - A biofilm anode acclimated with growth media containing acetate, then acetate+methane, and finally methane alone produced electrical current in a microbial electrochemical cell (MxC) fed with methane as the sole electron donor. Geobacter was the dominant genus for the bacterial domain (93%) in the biofilm anode, while methanogens (Methanocorpusculum labreanum and Methanosaeta concilii) accounted for 82% of the total archaeal clones in the biofilm. Fluorescence in situ hybridization (FISH) imaging clearly showed a biofilm of mixed bacteria and archaea, suggesting a syntrophic interaction between them for performing anaerobic oxidation of methane (AOM) in the biofilm anode. Measured cumulative coulombs were linearly correlated to the methane-gas concentration in the range of 10-99.97% (R2>=0.99) when the measurement was sustained for at least 50min Thus, cumulative coulombs over 50min could be used to quantify the methane concentration in gas samples. PMID- 28637164 TI - Biological nutrient removal and molecular biological characteristics in an anaerobic-multistage anaerobic/oxic (A-MAO) process to treat municipal wastewater. AB - This study aimed to present an anaerobic-multistage anaerobic/oxic (A-MAO) process to treat municipal wastewater. The average COD, NH4+-N, TN, and TP removal efficiency were 91.81%, 96.26%, 83.73% and 94.49%, respectively. Temperature plunge and C/N decrease have a certain impact on the modified process. Characteristics of microbial community, function microorganism, and correlation of microbial community with environmental variables in five compartments were carried out by Illumina Miseq high-throughput sequencing. The differences of microbial community were observed and Blastocatella, Flavobacterium and Pseudomonas were the dominant genus. Nitrosomonas and Nitrospira occupied a dominant position in AOB and NOB, respectively. Rhodospirillaceae and Rhodocyclaceae owned a considerable proportion in phosphorus removal bacteria. DO and COD played significant roles on affecting the microbial components. The A-MAO process in this study demonstrated a high potential for nutrient removal from municipal wastewater. PMID- 28637166 TI - Comparison of the anaerobic digestion at the mesophilic and thermophilic temperature regime of organic wastes from the agribusiness. AB - An overall kinetic power law model has been successfully applied to study the anaerobic digestion of agricultural wastes. In this comparative kinetic study feed composition, organic load rate, residence time and process temperature have been systematically varied in an automated semi-continuous fermentation system to obtain the dependency of the rate of degradation as biogas production on the organic load rate and temperature. The results show that the overall reaction order depend only on the Chemical Oxygen Demand (COD) at values between 3.6 and 3.7. The Arrhenius approach shows a shift in the rate determining step between the mesophilic and thermophilic temperature regimes. The activation energy at the temperature insensitive mesophilic regime is very small at 8.9 (kJ/mole), while the activation energy at the temperature sensitive thermophilic regime lies around 117 (kJ/mole). PMID- 28637167 TI - Effects of dissolved oxygen concentration on photosynthetic bacteria wastewater treatment: Pollutants removal, cell growth and pigments production. AB - Dissolved oxygen (DO) is an important parameter in photosynthetic bacteria (PSB) wastewater treatment. This study set different DO levels and detected the pollutants removal, PSB growth and pigments production. Results showed that DO significantly influenced the performances of PSB wastewater treatment process. The highest COD (93%) and NH3-N removal (83%) was achieved under DO of 4-8mg/L, but DO of 2-4mg/L was recommended considering the aeration cost. PSB biomass reached 1645mg/L under DO of 4-8mg/L with satisfying co-enzyme Q10 content. The biomass yield was relatively stable at all DO levels. For bacteriochlorophyll and carotenoids, DO>1mg/L could satisfy their production. On the other hand, DO<0.5mg/L led to the highest dehydrogenase activity. According to the different purposes, the optimal treatment time was different. The most pigments production occurred at 24h; biomass reached peak at 48h; and the optimal time for pollutants removal was 72h. PMID- 28637168 TI - Sulfur balance of sulfur dioxide-ethanol-water fractionation of sugarcane straw. AB - The sulfur balance of SO2-ethanol-water (AVAP(r)) fractionation of sugarcane (SC) straw was investigated. Hydrogen sulfite and sulfite anions are nearly absent in the liquors, despite cations present in straw, whose effect is thus limited to neutralization of lignosulfonic acids decreasing the acidity. Higher degree of sulfonation was observed for dissolved straw lignin compared to wood lignin (0.8 0.9 vs. 0.25 S/C9). Sulfur dioxide amounts of 0.9-1.2, 4.1-4.3 and 44-49g per o.d.kg straw were bound to pulp, precipitated lignin and lignosulfonic acid, respectively, while the rest of SO2 was recovered by distillation from the spent fractionation suspensions. PMID- 28637169 TI - Novel molecules lncRNAs, tRFs and circRNAs deciphered from next-generation sequencing/RNA sequencing: computational databases and tools. AB - Powerful next-generation sequencing (NGS) technologies, more specifically RNA sequencing (RNA-seq), have been pivotal toward the detection and analysis and hypotheses generation of novel biomolecules, long noncoding RNAs (lncRNAs), tRNA derived fragments (tRFs) and circular RNAs (circRNAs). Experimental validation of the occurrence of these biomolecules inside the cell has been reported. Their differential expression and functionally important role in several cancers types as well as other diseases such as Alzheimer's and cardiovascular diseases have garnered interest toward further studies in this research arena. In this review, starting from a brief relevant introduction to NGS and RNA-seq and the expression and role of lncRNAs, tRFs and circRNAs in cancer, we have comprehensively analyzed the current landscape of databases developed and computational software used for analyses and visualization for this emerging and highly interesting field of these novel biomolecules. Our review will help the end users and research investigators gain information on the existing databases and tools as well as an understanding of the specific features which these offer. This will be useful for the researchers in their proper usage thereby guiding them toward novel hypotheses generation and saving time and costs involved in extensive experimental processes in these three different novel functional RNAs. PMID- 28637170 TI - Neuroprotective effect of pressure-oriented flow regulation and pH-stat management in selective antegrade brain perfusion during total aortic arch repair. AB - OBJECTIVES: The aim of this study was to assess the safety and effectiveness of our selective antegrade brain perfusion (SABP) strategy, which is characterized by moderate hypothermic and low-pressure management under pH-stat using a completely closed cardiopulmonary bypass circuit with a single centrifugal pump. METHODS: Forty-nine consecutive patients (median age, 74) underwent total aortic arch replacement using a 4-branched graft. SABP was conducted with individual cannulation in all arch vessels. The SABP flow rate was monitored, and the flow rates of each arch vessel were also measured in patients with available data. RESULTS: One patient died of cerebral infarction, and 7 had transient neurological deficits without apparent findings on postoperative imaging studies and without residual sequels at hospital discharge. The operation, cardiopulmonary bypass, cardiac arrest, circulatory arrest and SABP times were 327 min (interquartile range, 292-381), 211 (184-247), 107 (84.8-138.3), 54.0 (48 68) and 137 (114-158), respectively. The total flow of the SABP was 18.1 ml/kg/min (15.7-20.9). The flow rates of the brachiocephalic, the left carotid and the left subclavian arteries were 9.5 ml/kg/min (7.7-11.5), 4.2 (2.8-5.7) and 4.5 (3.7-5.5), respectively. Only the flow rate of the brachiocephalic artery was significantly correlated with the total SABP flow rate (Spearman rank correlation coefficient, r = 0.58, P < 0.01). CONCLUSIONS: The moderate hypothermic, high flow, low-pressure SABP strategy with pH-stat management can be applied in adult aortic surgery; however, the feasibility and effectiveness of this concept need further evaluation in a prospective controlled study. PMID- 28637171 TI - Representation of Rapid Image Sequences in V4 Networks. AB - Natural viewing often consists of sequences of brief fixations to image patches of different structure. Whether and how briefly presented sequential stimuli are encoded in a temporal-position manner is poorly understood. Here, we performed multiple-electrode recordings in the visual cortex (area V4) of nonhuman primates (Macaca mulatta) viewing a sequence of 7 briefly flashed natural images, and measured correlations between the cue-triggered population response in the presence and absence of the stimulus. Surprisingly, we found significant correlations for images occurring at the beginning and the end of a sequence, but not for those in the middle. The correlation strength increased with stimulus exposure and favored the image position in the sequence rather than image identity. These results challenge the commonly held view that images are represented in visual cortex exclusively based on their informational content, and indicate that, in the absence of sensory information, neuronal populations exhibit reactivation of stimulus-evoked responses in a way that reflects temporal position within a stimulus sequence. PMID- 28637172 TI - Identification of four type II toxin-antitoxin systems in Actinobacillus pleuropneumoniae. AB - Toxin-antitoxin (TA) systems are small genetic elements that are widely prevalent in the genomes of bacteria and archaea. These modules have been identified in various bacteria and proposed to play an important role in bacterial physiology and virulence. However, their presence in the genomes of Actinobacillus species has received no attention. In this study, we describe the identification of four type II TA systems in Actinobacillus pleuropneumoniae, the causative agent of porcine pleuropneumonia. Reverse transcription PCR analysis revealed that the genes encoding the toxin and antitoxin are co-transcribed. Overexpression of each toxin inhibited the growth of Escherichia coli, and the toxic effect could be counteracted by its cognate antitoxin. The pull-down experiments demonstrated that each toxin interacts with its cognate antitoxin in vivo. The promoter activity assays showed that each antitoxin could autoregulate either positively or negatively the TA operon transcription. In addition, the APJL_0660/0659 TA system is present in half of the detected serovars of A. pleuropneumoniae, while the others are present in all. Collectively, we identified four type II TA systems in A. pleuropneumoniae, and this study has laid the foundation for further functional study of these TA systems. PMID- 28637173 TI - Crystallographic analyses illustrate significant plasticity and efficient recoding of meganuclease target specificity. AB - The retargeting of protein-DNA specificity, outside of extremely modular DNA binding proteins such as TAL effectors, has generally proved to be quite challenging. Here, we describe structural analyses of five different extensively retargeted variants of a single homing endonuclease, that have been shown to function efficiently in ex vivo and in vivo applications. The redesigned proteins harbor mutations at up to 53 residues (18%) of their amino acid sequence, primarily distributed across the DNA binding surface, making them among the most significantly reengineered ligand-binding proteins to date. Specificity is derived from the combined contributions of DNA-contacting residues and of neighboring residues that influence local structural organization. Changes in specificity are facilitated by the ability of all those residues to readily exchange both form and function. The fidelity of recognition is not precisely correlated with the fraction or total number of residues in the protein-DNA interface that are actually involved in DNA contacts, including directional hydrogen bonds. The plasticity of the DNA-recognition surface of this protein, which allows substantial retargeting of recognition specificity without requiring significant alteration of the surrounding protein architecture, reflects the ability of the corresponding genetic elements to maintain mobility and persistence in the face of genetic drift within potential host target sites. PMID- 28637174 TI - Effect of Prenatal Exposure to Waterpipe Tobacco Smoke on Learning and Memory of Adult Offspring Rats. AB - Introduction: Waterpipe tobacco smoking has increased in prevalence worldwide, including among pregnant women. In this study, we investigated the effect of prenatal maternal waterpipe tobacco smoke (WTS) exposure during different stages of pregnancy on learning and memory of adult offspring rats. Methods: Pregnant rats received either fresh air or mainstream WTS (2 hours daily) during early, mid, late, or whole gestational period. Male offspring rats were followed through 20 weeks. Outcomes included (1) spatial learning and memory using the radial arm water maze (RAWM), (2) levels of brain derived neurotrophic factor (BDNF) in the hippocampus, and (3) oxidative stress biomarkers (superoxide dismutase, catalase, glutathione peroxidase and thiobarbituric acid reactive substances). Results: Relative to offspring whose mothers were exposed to fresh air, prenatal exposure to WTS at any stage of pregnancy resulted in short- and long-term memory impairment in adult offspring rats (p < .05). This impairment was associated with reduced levels of BDNF in hippocampus (p < .05). However, prenatal WTS did not affect the level of oxidative stress biomarkers in hippocampus. Prenatal WTS during late gestation increased the activity of catalase as compared to control. Conclusion: Prenatal maternal WTS exposure can impair the memory of adult male offspring. These results support development of interventions that target pregnant women who smoke waterpipe during pregnancy. Implications: We examined for the first time the effect of prenatal waterpipe tobacco smoke exposure on learning and memory of offspring. The results showed that in utero exposure to waterpipe tobacco smoke was associated with impaired memory and decreased brain derived neurotrophic factor in hippocampus of adult male offspring rats. PMID- 28637175 TI - Multiple Subpial Transections for Medically Refractory Epilepsy: A Disaggregated Review of Patient-Level Data. AB - BACKGROUND: Multiple subpial transections (MST) are a treatment for seizure foci in nonresectable eloquent areas. OBJECTIVE: To systematically review patient level data regarding MST. METHODS: Studies describing patient-level data for MST procedures were extracted from the Medline and PubMed databases, yielding a synthetic cohort of 212 patients from 34 studies. Data regarding seizure outcome, patient demographics, seizure type, surgery type, and complications were extracted and analyzed. RESULTS: Seizure freedom was achieved in 55.2% of patients undergoing MST combined with resection, and 23.9% of patients undergoing MST alone. Significant predictors for seizure freedom were a temporal lobe focus (odds ratio 4.9; 95% confidence interval 1.71, 14.3) and resection of portions of the focus, when feasible (odds ratio 3.88; 95% confidence interval 2.02, 7.45). Complications were frequent, with transient mono- or hemiparesis affecting 19.8% of patients, transient dysphasia 12.3%, and permanent paresis or dysphasia in 6.6% and 1.9% of patients, respectively. CONCLUSION: MST is an effective treatment for refractory epilepsy in eloquent cortex, with greater chances of seizure freedom when portions of the focus are resected in tandem with MST. The reported rates of seizure freedom with MST are higher than those of existing neuromodulatory therapies, such as vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation, though these latter therapies are supported by randomized-controlled trials, while MST is not. The reported complication rate of MST is higher than that of resection and neuromodulatory therapies. MST remains a viable option for the treatment of eloquent foci, provided a careful risk-benefit analysis is conducted. PMID- 28637177 TI - Brucellosis: myriad ways of presentation. PMID- 28637179 TI - Is delayed surgical revascularization in acute myocardial infarction useful or dangerous? New insights into an old problem. AB - OBJECTIVES: Haemodynamically stable patients admitted for coronary artery bypass grafting in acute myocardial infarction often undergo delayed surgery in order to avoid the risks of emergency surgery. However, initially stable patients undergoing delayed surgery may develop low cardiac output syndrome (LCOS) during the waiting period, which might be a major drawback of this strategy. We aim to define risk factors and clinical consequences of LCOS during the waiting period. METHODS: A total of 530 consecutive patients with acute myocardial infarction (33% non-ST-segment elevation myocardial infarction and 67% ST-segment-elevation myocardial infarction) underwent isolated coronary artery bypass grafting between 2008 and 2013. Outcomes after either immediate (<48 h after onset of symptoms) or delayed (>48 h after onset of symptoms) therapy were compared. Predictors of preoperative development of LCOS were identified using multivariate regression analysis. RESULTS: Of the 327 patients undergoing delayed therapy, 39 (12%) developed preoperative LCOS, resulting in increased mortality compared with patients who remained stable (21 vs 7.6%, P < 0.001). Immediate therapy resulted in similar mortality compared with delayed therapy (6.4 vs 7.6%; P = 0.68) and better 7-year survival (70 vs 55%; P < 0.001). Predictors of developing LCOS were reduced left ventricular function (odds ratio 4.4), renal impairment (odds ratio 3.0), acute pulmonary infection (odds ratio 3.4) and the extent of troponin elevation at admission (odds ratio 1.01 per increase by 1 ug/l). CONCLUSIONS: In patients with acute myocardial infarction undergoing delayed coronary artery bypass grafting, preoperative LCOS is a relevant and dangerous condition that can be avoided by operating immediately or by carefully selecting patients to be delayed according to the risk parameters identified preoperatively. PMID- 28637178 TI - The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice. AB - Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher risk of atherosclerosis. In this study, the AT04A anti-PCSK9 vaccine was evaluated for its therapeutic potential in ameliorating or even preventing coronary heart disease in the atherogenic APOE*3Leiden.CETP mouse model. Methods and results: Control and AT04A vaccine-treated mice were fed western-type diet for 18 weeks. Antibody titres, plasma lipids, and inflammatory markers were monitored by ELISA, FPLC, and multiplexed immunoassay, respectively. The progression of atherosclerosis was evaluated by histological analysis of serial cross-sections from the aortic sinus. The AT04A vaccine induced high and persistent antibody levels against PCSK9, causing a significant reduction in plasma total cholesterol (-53%, P < 0.001) and LDLc compared with controls. Plasma inflammatory markers such as serum amyloid A (SAA), macrophage inflammatory protein-1beta (MIP-1beta/CCL4), macrophage-derived chemokine (MDC/CCL22), cytokine stem cell factor (SCF), and vascular endothelial growth factor A (VEGF-A) were significantly diminished in AT04A-treated mice. As a consequence, treatment with the AT04A vaccine resulted in a decrease in atherosclerotic lesion area (-64%, P = 0.004) and aortic inflammation as well as in more lesion-free aortic segments (+119%, P = 0.026), compared with control. Conclusions: AT04A vaccine induces an effective immune response against PCSK9 in APOE*3Leiden.CETP mice, leading to a significant reduction of plasma lipids, systemic and vascular inflammation, and atherosclerotic lesions in the aorta. PMID- 28637176 TI - Dissociation of Striatal Dopamine and Tyrosine Hydroxylase Expression from Aging Related Motor Decline: Evidence from Calorie Restriction Intervention. AB - The escalating increase in retirees living beyond their eighth decade brings increased prevalence of aging-related impairments, including locomotor impairment (Parkinsonism) that may affect ~50% of those reaching age 80, but has no confirmed neurobiological mechanism. Lifestyle strategies that attenuate motor decline, and its allied mechanisms, must be identified. Aging studies report little to moderate loss of striatal dopamine (DA) or tyrosine hydroxylase (TH) in nigrostriatal terminals, in contrast to ~70%-80% loss associated with bradykinesia onset in Parkinson's disease. These studies evaluated the effect of ~6 months 30% calorie restriction (CR) on nigrostriatal DA regulation and aging related locomotor decline initiated at 12 months of age in Brown-Norway Fischer F1 hybrid rats. The aging-related decline in locomotor activity was prevented by CR. However, striatal DA or TH expression was decreased in the CR group, but increased in substantia nigra versus the ad libitum group or 12-month-old cohort. In a 4- to 6-month-old cohort, pharmacological TH inhibition reduced striatal DA ~30%, comparable with decreases reported in aged rats and the CR group, without affecting locomotor activity. The dissociation of moderate striatal DA reduction from locomotor activity seen in both studies suggests that aging-related decreases in striatal DA are dissociated from locomotor decline. PMID- 28637180 TI - Participatory design of probability-based decision support tools for in-hospital nurses. AB - Objective: To describe nurses' preferences for the design of a probability-based clinical decision support (PB-CDS) tool for in-hospital clinical deterioration. Methods: A convenience sample of bedside nurses, charge nurses, and rapid response nurses (n = 20) from adult and pediatric hospitals completed participatory design sessions with researchers in a simulation laboratory to elicit preferred design considerations for a PB-CDS tool. Following theme-based content analysis, we shared findings with user interface designers and created a low-fidelity prototype. Results: Three major themes and several considerations for design elements of a PB-CDS tool surfaced from end users. Themes focused on "painting a picture" of the patient condition over time, promoting empowerment, and aligning probability information with what a nurse already believes about the patient. The most notable design element consideration included visualizing a temporal trend of the predicted probability of the outcome along with user selected overlapping depictions of vital signs, laboratory values, and outcome related treatments and interventions. Participants expressed that the prototype adequately operationalized requests from the design sessions. Conclusions: Participatory design served as a valuable method in taking the first step toward developing PB-CDS tools for nurses. This information about preferred design elements of tools that support, rather than interrupt, nurses' cognitive workflows can benefit future studies in this field as well as nurses' practice. PMID- 28637182 TI - Effect of lifelong antibiotic treatment for aortic arch prosthesis infection. AB - A patient who underwent multiple aortic operations suffered persistent infection of the ascending aorta and arch prosthesis and was finally treated with lifelong antibiotics. An 8-year follow-up with positron emission computed tomography is reported. PMID- 28637184 TI - A Preliminary Naturalistic Study of Low-Dose Ketamine for Depression and Suicide Ideation in the Emergency Department. PMID- 28637181 TI - Crosstalk between histone modifications indicates that inhibition of arginine methyltransferase CARM1 activity reverses HIV latency. AB - In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription. Interestingly, H3K27 acetylation further stimulates H3R26 methylation, which subsequently abrogates the recruitment of SEC, forming a negative feedback regulatory loop. Importantly, by inhibiting methyltransferase activity of CARM1, the enzyme responsible for H3R26 methylation, HIV-1 transcription is reactivated in several HIV latency cell models, including a primary resting CD4+ T cell model. When combined with other latency disrupting compounds such as JQ1 or vorinostat/SAHA, the CARM1 inhibitor achieved synergistic effects on HIV-1 activation. This study suggests that coordinated and dynamic modifications at histone H3K27 and H3R26 orchestrate HIV-1 LTR-mediated transcription, and potentially opens a new avenue to disrupt latent HIV-1 infection by targeting specific epigenetic enzymes. PMID- 28637183 TI - NucliTrack: an integrated nuclei tracking application. AB - Summary: Live imaging studies give unparalleled insight into dynamic single cell behaviours and fate decisions. However, the challenge of reliably tracking single cells over long periods of time limits both the throughput and ease with which such studies can be performed. Here, we present NucliTrack, a cross platform solution for automatically segmenting, tracking and extracting features from fluorescently labelled nuclei. NucliTrack performs similarly to other state-of the-art cell tracking algorithms, but NucliTrack's interactive, graphical interface makes it significantly more user friendly. Availability and implementation: NucliTrack is available as a free, cross platform application and open source Python package. Installation details and documentation are at: http://nuclitrack.readthedocs.io/en/latest/ A video guide can be viewed online: https://www.youtube.com/watch?v=J6e0D9F-qSU Source code is available through Github: https://github.com/samocooper/nuclitrack. A Matlab toolbox is also available at: https://uk.mathworks.com/matlabcentral/fileexchange/61479 samocooper-nuclitrack-matlab. Contact: sam@socooper.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28637185 TI - A novel method of open reduction and internal fixation of a displaced manubrial fracture using distal clavicle locking plates. AB - A 52-year-old man sustained a sternal fracture after a blunt traumatic chest injury. He was in severe pain in the intensive care unit, which resulted in difficulty breathing and increased analgesic requirement, and a decision was made to stabilize his manubrial fracture. Orthopaedic and thoracic surgeons jointly performed open reduction and internal fixation of the displaced manubrial fracture using 2 distal clavicle locking plates. This resulted in improvement in patient's pain and helped with his subsequent recovery and discharge from the hospital. This case report describes a new, safe and effective method of treating this uncommon injury. PMID- 28637187 TI - Identification of pulmonary vein reconnection gaps with high-density mapping in redo atrial fibrillation ablation procedures. AB - Aims: Maps obtained by means of electroanatomic high-density mapping (HDM) systems have shown their use in the identification of conduction gaps in experimental atrial linear lesion models. The objective of this study was to assess the use of HDM in the recognition of reconnection gaps in pulmonary veins (PV) in redo atrial fibrillation (AF) ablation procedures. Methods and results: One hundred and eight patients were included in a non-randomized study that assessed the recognition of reconnection gaps in PV by means of HDM compared to a control group that received conventional non-fluoroscopic guidance with a circular multipolar catheter (CMC). Among the HDM group, adequate recognition of reconnection gaps was obtained in 60.99% of the reconnected PVs (86 of 141), a figure significantly higher than that achieved with analysis of CMC recorded signals (39.66%, 48 of 121; P = 0.001). The number of applications and total radiofrequency time were also significantly lower in the HDM group (12.46 +/- 6.1 vs. 15.63 +/- 7.7 and 7.61 +/- 3 vs. 9.29 +/- 5; P = 0.02, and P = 0.03, respectively). At the 6-month follow-up, no statistically significant differences were found in recurrence of AF or any other atrial tachycardia between the HDM group (8 patients, 14.8%) and the control group in (16 patients, 29.6%; P = 0.104). Conclusion: An analysis of the high-density activation maps allows greater precision in the identification of reconnection gaps in PV, which results in lower radiofrequency time for the new isolation. PMID- 28637188 TI - The influence of whole-corn feeding method during the finishing stage on the performance of overfed mule ducks. AB - The aim of this trial was to compare 2 feeding systems based on whole corn, a loose-mix and a free-choice feeding system, during the finishing stage on the performance of ducks. Five hundred sixteen day-old male mule ducks (Muscovy drake * Pekin duck) were divided into 3 groups that differed in the presentation of the diet they received between 58 and 88 d of age: a complete pelleted diet (Control (CON) group; AMEn 12.1 MJ/kg, CP 15.0%) containing 500 g of corn per kg; or whole corn (AMEn 13.9 MJ/kg, CP 7.3%) and protein-rich pellets (AMEn 10.3 MJ/kg, CP 22.7%) in equal quantities mixed in the same feeders (loose-mix feeding [LMF] group) or in 2 separate feeders (free-choice feeding [FCF] group). From 89 to 99 d, 72 birds/group were overfed with a mixture containing mainly corn and water and then slaughtered to determine the weight and commercial value of the fatty liver. Feed intake was measured daily. Body weight (BW) was measured at 58, 88, and 99 d of age. From 58 to 88 d, total feed intake of the FCF group was +7% and +9% (+558 g and +672 g) higher than in the groups CON and LMF, respectively (P = 0.005). At 88 d, the BW was higher in the CON group than in the FCF group (4,959 vs. 4,778 g, P < 0.001), the LMF group being intermediate (4,874 g). During the experimental stage, the feed conversion ratio was higher in the FCF group than in the 2 others (+32%, P = 0.024), but the energy intake was similar between the 3 groups (92.6 MJ/duck, P = 0.353).After overfeeding (99 d), the BW (6,593 g), weight (642 g), and commercial grading of fatty liver were similar (P > 0.05) in the 3 groups. The present results suggest that loose-mix feeding during the finishing stage using whole corn is a solution for reducing feed cost. PMID- 28637189 TI - Assessment of Whole-Body Vibration Exposure in Mining Earth-moving Equipment and Other Vehicles Used in Surface Mining. AB - This study characterized whole-body vibration exposures in a set of vehicles that operate in open-pit mines and compared three different daily exposure parameters based on the ISO 2631-1:1997 and ISO 2631-5:2004 standards. Full-shift, 6 to 12 hour, continuous whole-body vibration measurements were collected from 11 representative types of vehicles in terms of hours of operation and number of vehicles used. For each type of vehicle, the exposure parameters (A(8), VDV(8), and Sed(8)) were calculated for each axis (x, y, and z), and in addition, shear or horizontal (?xy) and vector sum (?xyx) whole-body vibration exposure. Findings showed that: (i) substantially higher shear and vector sum whole-body vibration exposures indicated relatively high levels of exposure on the non-predominant axis; (ii) the predominant axis of exposure varied across the different type of vehicles; (iii) there were differences in whole-body vibration exposure parameters regarding the standards-based predictions of potentially adverse health outcomes (the impulsive exposure parameters VDV(8) and Sed(8) were higher and reduced acceptable vehicle operation times by one-half to two-thirds relative to A(8) exposures); and (iv) based on the predominant exposures and the time to reach daily vibration action limits, the operation of most mining vehicles would be limited to less than 8 hours a day. Differences in whole-body vibration exposure parameters impact the prediction of potentially adverse health outcomes and may introduce some uncertainty regarding how to best characterize a vehicle operator's actual exposure. PMID- 28637186 TI - CpG and methylation-dependent DNA binding and dynamics of the methylcytosine binding domain 2 protein at the single-molecule level. AB - The methylcytosine-binding domain 2 (MBD2) protein recruits the nucleosome remodeling and deacetylase complex (NuRD) to methylated DNA to modify chromatin and regulate transcription. Importantly, MBD2 functions within CpG islands that contain 100s to 1000s of potential binding sites. Since NuRD physically rearranges nucleosomes, the dynamic mobility of this complex is directly related to function. In these studies, we use NMR and single-molecule atomic force microscopy and fluorescence imaging to study DNA binding dynamics of MBD2. Single molecule fluorescence tracking on DNA tightropes containing regions with CpG-rich and CpG-free regions reveals that MBD2 carries out unbiased 1D diffusion on CpG rich DNA but subdiffusion on CpG-free DNA. In contrast, the protein stably and statically binds to methylated CpG (mCpG) regions. The intrinsically disordered region (IDR) on MBD2 both reduces exchange between mCpG sites along the DNA as well as the dissociation from DNA, acting like an anchor that restricts the dynamic mobility of the MBD domain. Unexpectedly, MBD2 binding to methylated CpGs induces DNA bending that is augmented by the IDR region of the protein. These results suggest that MBD2 targets NuRD to unmethylated or methylated CpG islands where its distinct dynamic binding modes help maintain open or closed chromatin, respectively. PMID- 28637191 TI - Value-added strategy models to provide quality services in senior health business. AB - Objective: The rapid population aging is now a global issue. The increase in the elderly population will impact the health care industry and health enterprises; various senior needs will promote the growth of the senior health industry. Most senior health studies are focused on the demand side and scarcely on supply. Our study selected quality enterprises focused on aging health and analyzed different strategies to provide excellent quality services to senior health enterprises. Design: We selected 33 quality senior health enterprises in Taiwan and investigated their excellent quality services strategies by face-to-face semi structured in-depth interviews with CEO and managers of each enterprise in 2013. Setting: A total of 33 senior health enterprises in Taiwan. Participants: Overall, 65 CEOs and managers of 33 enterprises were interviewed individually. Intervention(s): None. Main Outcome Measure(s): Core values and vision, organization structure, quality services provided, strategies for quality services. Results: This study's results indicated four type of value-added strategy models adopted by senior enterprises to offer quality services: (i) residential care and co-residence model, (ii) home care and living in place model, (iii) community e-business experience model and (iv) virtual and physical portable device model. The common part in these four strategy models is that the services provided are elderly centered. These models offer virtual and physical integrations, and also offer total solutions for the elderly and their caregivers. Through investigation of successful strategy models for providing quality services to seniors, we identified opportunities to develop innovative service models and successful characteristics, also policy implications were summarized. Conclusions: The observations from this study will serve as a primary evidenced base for enterprises developing their senior market and, also for promoting the value co-creation possibility through dialogue between customers and those that deliver service. PMID- 28637190 TI - Evolution of the sperm methylome of primates is associated with retrotransposon insertions and genome instability. AB - Changes in gene expression resulting from epigenetic and/or genetic changes play an important role in the evolutionary divergence of phenotypes. To explore how epigenetic and genetic changes are linked during primate evolution, we have compared the genome-wide DNA methylation profiles (methylomes) of humans and chimpanzees, which have a 1.2% DNA sequence divergence, of sperm, the frontal cortices, B cells, and neutrophils. We revealed that species-specific differentially methylated regions (S-DMRs), ranging from several hundred base pairs (bp) to several kilo base pairs (kb), were frequently associated with sequence changes in transcription factor-binding sites and insertions of Alu and SVA retrotransposons. We then generated a reference macaque sperm methylome map and revealed, in sperm, that both human and chimpanzee S-DMRs arose more frequently owing to methylation loss rather than gain. Moreover, we observed that the sperm methylomes contained many more hypomethylated domains (HMDs), ranging from 20 to 500 kb, than did the somatic methylomes. Interestingly, the sperm HMDs changed rapidly during primate evolution; hundreds of sperm HMDs were specific to humans, whereas most somatic HMDs were highly conserved between humans and chimpanzees. Notably, these human-specific sperm HMDs frequently occurred in regions exhibiting copy number variations. Our findings indicate that primate evolution, particularly in the germline, is significantly impacted by reciprocal changes in the genome and epigenome. PMID- 28637192 TI - An Explorative Study Examining Augmentative and Alternative Communication Training in the Field of Music Therapy. AB - Background: Music therapists work with many people who require Augmentative and Alternative Communication (AAC). As communication goals are central to music therapy practice, many music therapists would benefit from training in AAC. Objective: The purpose of this survey study was to determine the state of AAC education for music therapists at the university level, how AAC is being used in music therapy sessions, and how practicing music therapists are trained in AAC. Methods: Music therapy faculty and credentialed music therapists in North America and Europe were invited to complete an online survey. Descriptive statistics were used to analyze survey data from each group of respondents. Results: With regard to training in AAC at the university level, results indicate that almost half of music therapy faculty (44.66%) provided some training. The primary reason given for not providing training was a lack of educator knowledge in this area. Results indicate that a majority (81.77%) of music therapy clinicians are familiar with AAC and slightly over half (55.08%) reported that they work with clients who use AAC. Sixty-two percent of music therapists reported using AAC to promote expressive language, and 49% to increase receptive language. Over 80% of clinicians stated they would benefit from additional AAC training. Conclusions: Although a majority of music therapists are familiar with ACC, results indicate that ACC competency could be enhanced through university-level instruction and continuing professional development courses. PMID- 28637193 TI - Effect of Intensive Personalized "5As+5Rs" Intervention on Smoking Cessation in Hospitalized Acute Coronary Syndrome Patients Not Ready to Quit Immediately: A Randomized Controlled Trial. AB - Introduction: The acute coronary syndrome (ACS) patients who are not ready to quit smoking immediately have an extremely low rate of cessation. This study aims to investigate the efficacy of intensive personalized '5As+5Rs'intervention (IPANR intervention) on smoking cessation in this population. Methods: A parallel group randomized controlled trial was carried out, which compared IPANR intervention with routine 5Rs (control) at Fu Xing Hospital, Capital Medical University, Bei Jing, China. Three hundred and twenty hospitalized ACS smokers who were not ready to quit were randomly distributed to IPANR intervention group comprising three individual counseling during hospitalization and 15 intensive follow-up sessions (weekly during months 1, 2, 3, and monthly thereafter until month 6) or 5Rs group in a 1:1 fashion by 8 cardiologists who were blinded to the allocation sequence. Primary end point was carbon monoxide-confirmed continuous abstinence rate (CAR) through week 9 to week 12. Secondary outcome included abstinence rate at 24 weeks. Results: Overall, 97.5% (312/320) participants completed the trial. An intention-to-treat analysis showed statistically significant advantage of IPANR compared with control group at 4 weeks CAR (27.5% vs. 17.5%, RR = 1.571, 95% CI = 1.032-2.392, p = 0.032, number needed to treat (NNT) = 10), and abstinence rate at 24 weeks (23.8% vs.15.0%, RR 1.583, 95% CI = 0.998-2.512, p = 0.048, NNT: 11.36). At 24 weeks, cigarettes smoked per day by the patients who failed to quit were significant lower in IPANR group than 5Rs group (13.21 +/- 8.23 vs. 17.45 +/- 10.71; p < 0.001). Conclusions: The IPANR initiated during hospitalization, is a feasible and effective approach for smoking cessation in ACS patients not ready to quit immediately. Implications: Smoking has a major impact on acute stages of ACS for recurrent ischemic events and long-term outcomes. However, there are few evidence-based treatments for smokers who are not ready to quit. This study described a cessation intervention initiated during hospitalization and included 15 intensive follow-up aimed at enabling ACS smokers who were not ready to quit immediately to deliver adequate motivational and behavior change counseling. Given its effectiveness demonstrated in this prospective study, this intervention in hospitalized ACS smokers might have the potential to substantially improve the cessation rate of ACS patients who are not ready to quit smoking immediately. PMID- 28637194 TI - High iron supply inhibits the synthesis of the genotoxin colibactin by pathogenic Escherichia coli through a non-canonical Fur/RyhB-mediated pathway. AB - The genotoxin colibactin is a secondary metabolite produced by a variety of pathogenic Enterobacteria, and is associated with colon cancer development and acute systemic infections. The colibactin biosynthesis requires the enzymatic activity of the phosphopantetheinyl transferase ClbA. We recently evidenced that two master regulators of bacterial iron homeostasis, i.e. the ferric uptake regulator (Fur) and the small regulatory non-coding RNA RyhB, were involved in the regulation of the clbA transcription and of the colibactin production. In this study, we investigated the impact of high iron supply on clbA transcription and colibactin production in wild type, DeltaryhB, Deltafur and DeltaryhB Deltafur strains. This revealed that high iron resulted in decreased synthesis of the genotoxin colibactin through both pathways dependent and independent of Fur/RyhB. This work highlights the complex regulatory mechanism that controls an important bacterial virulence and carcinogenesis factor by regulators of bacterial iron homeostasis. PMID- 28637195 TI - Social Disconnection in Schizophrenia and the General Community. AB - Social disability is a defining characteristic of schizophrenia and a substantial public health problem. It has several components that are difficult to disentangle. One component, social disconnection, occurs extensively in the general community among nonhelp-seeking individuals. Social disconnection is an objective, long-standing lack of social/family relationships and minimal participation in social activities. It is associated with negative health effects, including early mortality, and is distinct from subjective loneliness. These 2 topics, social disability in schizophrenia and social disconnection in the general community, have generated entirely distinct research literatures that differ in their respective knowledge gaps and emphases. Specifically, the consequences of social disability in schizophrenia are unknown but its determinants (ie, nonsocial cognition, social cognition, and social motivation) have been well-examined. Conversely, the health consequences of social disconnection in the general community are well-established, but the determinants are largely unknown. Social disconnection is a condition that presents substantial public health concerns, exists within and outside of current psychiatric diagnostic boundaries, and may be related to the schizophrenia spectrum. A comparison of these 2 literatures is mutually informative and it generates intriguing research questions that can be critically evaluated. PMID- 28637196 TI - Chronological Change of Right Ventricle by Chronic Intermittent Hypoxia in Mice. AB - Study Objective: No studies have investigated sequential changes in the heart on magnetic resonance imaging (MRI), along with observation of functional lung phenotypes and genetics, over the duration of chronic intermittent hypoxia (CIH). We investigated chronological changes in heart and lung phenotypes after CIH using a mouse model to provide new insights into the pathophysiology of sleep apnea-induced cardiovascular disease. Methods: C57BL/6J adult male mice were randomized to 4 or 8 weeks of CIH. Cardiac cine-MRI images were analyzed to assess functional parameters of right ventricle (RV). Histopathological features of myocytes and pulmonary vessels, as well as genes involved in the endothelin (ET) system, were investigated. Results: Function of the RV reduced significantly at 4 weeks and continuously decreased following another 4 weeks of CIH, although the rate of decrease was attenuated. Notably, persistence of reduced ejection fraction and end-systole RV wall thickness (WT) and increases in the ET system of the lungs and blood strongly implied the development of pulmonary hypertension after 8 weeks of CIH. Conclusions: RV dysfunction with reduced end-systole RV WT could be a late phenotype in long-standing CIH and possibly also in obstructive sleep apnea. PMID- 28637197 TI - Pontocerebellar hypoplasia with spinal muscular atrophy (PCH1): identification of SLC25A46 mutations in the original Dutch PCH1 family. PMID- 28637198 TI - Multi-target activity of Hemidesmus indicus decoction against innovative HIV-1 drug targets and characterization of Lupeol mode of action. AB - Despite the availability of several anti-retrovirals, there is still an urgent need for developing novel therapeutic strategies and finding new drugs against underexplored HIV-1 targets. Among them, there are the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H) function and the cellular alpha-glucosidase, involved in the control mechanisms of N-linked glycoproteins formation in the endoplasmic reticulum. It is known that many natural compounds, such as pentacyclic triterpenes, are a promising class of HIV-1 inhibitors. Hence, here we tested the pentacyclic triterpene Lupeol, showing that it inhibits the HIV-1 RT-associated RNase H function. We then performed combination studies of Lupeol and the active site RNase H inhibitor RDS1759, and blind docking calculations, demonstrating that Lupeol binds to an HIV-1 RT allosteric pocket. On the bases of these results and searching for potential multitarget active drug supplement, we also investigated the anti-HIV-1 activity of Hemidesmus indicus, an Ayurveda medicinal plant containing Lupeol. Results supported the potential of this plant as a valuable multitarget active drug source. In fact, by virtue of its numerous active metabolites, H. indicus was able to inhibit not only the RT associated RNase H function, but also the HIV-1 RT-associated RNA-dependent DNA polymerase activity and the cellular alpha-glucosidase. PMID- 28637199 TI - First ex vivo and preliminary sheep model results of the new TRIBIO aortic valve bioprosthesis in small aortic annuli. AB - OBJECTIVES: Small aortic annuli are challenging in aortic valve replacement. Prosthesis-patient mismatch, accompanied by high transvalvular gradients and small orifice area, is an often faced problem impairing postoperative outcome. The new TRIBIO bioprosthesis aims to enable enhanced haemodynamics, being increasingly important with decreasing annular size. This study compares ex vivo hydrodynamics of TRIBIO with 2 established bioprostheses in small annuli at different stroke volumes, simulating 'rest' and 'exercise', and evaluates haemodynamics of TRIBIO in a sheep model. METHODS: Ex vivo: Porcine aortic roots were hardened with glutaraldehyde, approaching the stiffness of decalcified roots. Each bioprosthesis (TRIBIO, TrifectaTM, Perimount(r) Magna Ease), size 19 mm, was implanted in each aortic root and inserted into a pulse duplicator, determining hydrodynamics and geometric orifice area at different stroke volumes (74, 90, 104 ml). Sheep model: Postoperative transvalvular gradients were assessed after implantation of 19 mm TRIBIO in aortic position. RESULTS: Ex vivo: Mean transvalvular gradients were lowest in TRIBIO (7.3, 8.7, 10.2 mmHg at 74, 90, 104 ml) with significant difference to Perimount(r) Magna Ease. Geometric orifice area in TRIBIO was 2.7 cm2 and significantly larger compared to Perimount(r) Magna Ease and TrifectaTM. Opening of TRIBIO was uniform and apparently complete, whereas leaflet's outward movement was restricted particularly in Perimount(r) Magna Ease. Sheep model: TRIBIO presented with low transvalvular gradients (deltapmean 4.1 +/- 2 mmHg, deltapmax 7.8 +/- 4.6 mmHg), unimpaired leaflet motion and no central or paravalvular leakage. CONCLUSIONS: Ex vivo, the TRIBIO achieved superior hydrodynamics compared to latest generation bioprostheses. These excellent data are supported by very low transvalvular gradients in a preliminary sheep model. PMID- 28637200 TI - An Emerging Theoretical Model of Music Therapy Student Development. AB - Background: Music therapy students negotiate a complex relationship with music and its use in clinical work throughout their education and training. This distinct, pervasive, and evolving relationship suggests a developmental process unique to music therapy. Objective: The purpose of this grounded theory study was to create a theoretical model of music therapy students' developmental process, beginning with a study within one large Midwestern university. Methods: Participants (N = 15) were music therapy students who completed one 60-minute intensive interview, followed by a 20-minute member check meeting. Recorded interviews were transcribed, analyzed, and coded using open and axial coding. Results: The theoretical model that emerged was a six-step sequential developmental progression that included the following themes: (a) Personal Connection, (b) Turning Point, (c) Adjusting Relationship with Music, (d) Growth and Development, (e) Evolution, and (f) Empowerment. The first three steps are linear; development continues in a cyclical process among the last three steps. As the cycle continues, music therapy students continue to grow and develop their skills, leading to increased empowerment, and more specifically, increased self efficacy and competence. Conclusions: Further exploration of the model is needed to inform educators' and other key stakeholders' understanding of student needs and concerns as they progress through music therapy degree programs. PMID- 28637201 TI - Size is the Most Important Predictor of Aneurysm Rupture Among Multiple Cerebral Aneurysms: Post Hoc Subgroup Analysis of Unruptured Cerebral Aneurysm Study Japan. AB - BACKGROUND: Multiple cerebral aneurysms are encountered in approximately 15% to 35% of patients harboring unruptured cerebral aneurysms. It would be of clinical value to determine which of them is most likely to rupture. OBJECTIVE: To characterize features of the ruptured aneurysm relative to other concomitant fellow aneurysms in patients with multiple cerebral aneurysms. METHODS: From a total of 5720 patients who were prospectively registered in the Unruptured Cerebral Aneurysm Study in Japan, a subgroup of patients with multiple cerebral aneurysms who developed subarachnoid hemorrhage was extracted for this post hoc analysis. Intrapatient comparisons of each aneurysm were carried out using aneurysm-specific factors such as size, location, and shape to identify predictors of rupture among the fellow aneurysms in a patient with multiple cerebral aneurysms. RESULTS: Twenty-five patients with 62 aneurysms were identified from the total cohort of 5720 patients. With the distinctiveness in size, which means the aneurysm was the single largest among the multiple aneurysms, the ruptured aneurysm in each case was discriminated from the other coexisting aneurysms with a sensitivity of 0.76 and specificity of 0.86. CONCLUSION: Our results suggest that the largest aneurysm is likely to rupture among coexisting aneurysms in a patient with multiple cerebral aneurysms. PMID- 28637202 TI - Adherence to Antipsychotic Medication and Criminal Recidivism in a Canadian Provincial Offender Population. AB - Preliminary evidence suggests that adherence to antipsychotic medication reduces criminal recidivism among patients diagnosed with schizophrenia. However, existing studies operationalize antipsychotic adherence as a binary variable (usually using a threshold of >=80%), which does not reflect the prevalence of suboptimal adherence in real-world settings. The purpose of the current analysis was to investigate the association between successive ordinal levels of antipsychotic adherence and criminal recidivism in a well-defined sample of offenders diagnosed with schizophrenia (n = 11462). Adherence was measured using the medication possession ratio (MPR) and analyzed as a time-dependent covariate in multivariable regression models. Data were drawn from linked, comprehensive diagnostic, pharmacy and justice system records, and individuals were followed for an average of 10 years. Adjusted rate ratios (ARR) and confidence intervals (CI) are reported. Overall mean MPR was 0.41. Increasing levels of antipsychotic adherence were not associated with progressively lower rates of offending. However, when compared to the reference group (MPR >= 80%) all lower adherence levels were significantly associated (P < .001) with increased risk of violent (ARR = 1.58; 95% CI = 1.46-1.71) and nonviolent (ARR = 1.41; 95% CI = 1.33-1.50) offenses. Significance was replicated in separate sensitivity analyses. Previously published studies reporting reductions in crime may have been influenced by antipsychotic adherence >=80%. Binary operationalization of adherence is an inaccurate predictor of recidivism. Future research addressing functional outcomes of antipsychotic adherence should conceptualize adherence as an incremental independent variable. PMID- 28637203 TI - Morphological Diversity Strongly Constrains Synaptic Connectivity and Plasticity. AB - Synaptic connectivity between neurons is naturally constrained by the anatomical overlap of neuronal arbors, the space on the axon available for synapses, and by physiological mechanisms that form synapses at a subset of potential synapse locations. What is not known is how these constraints impact emergent connectivity in a circuit with diverse morphologies. We investigated the role of morphological diversity within and across neuronal types on emergent connectivity in a model of neocortical microcircuitry. We found that the average overlap between the dendritic and axonal arbors of different types of neurons determines neuron-type specific patterns of distance-dependent connectivity, severely constraining the space of possible connectomes. However, higher order connectivity motifs depend on the diverse branching patterns of individual arbors of neurons belonging to the same type. Morphological diversity across neuronal types, therefore, imposes a specific structure on first order connectivity, and morphological diversity within neuronal types imposes a higher order structure of connectivity. We estimate that the morphological constraints resulting from diversity within and across neuron types together lead to a 10-fold reduction of the entropy of possible connectivity configurations, revealing an upper bound on the space explored by structural plasticity. PMID- 28637204 TI - Cohort Profile: The Well-being in HospitAL Employees (WHALE) study. PMID- 28637205 TI - Evolution and comparative genomics of pAQU-like conjugative plasmids in Vibrio species. AB - Objectives: To investigate a set of MDR conjugative plasmids found in Vibrio species and characterize the underlying evolution process. Methods: pAQU-type plasmids from Vibrio species were sequenced using both Illumina and PacBio platforms. Bioinformatics tools were utilized to analyse the typical MDR regions and core genes in the plasmids. Results: The nine pAQU-type plasmids ranged from ~160 to 206 kb in size and were found to harbour as many as 111 core genes encoding conjugative, replication and maintenance functions. Eight plasmids were found to carry a typical MDR region, which contained various accessory and resistance genes, including ISCR1-blaPER-1-bearing complex class 1 integrons, ISCR2-floR, ISCR2-tet(D)-tetR-ISCR2, qnrVC6, a Tn10-like structure and others associated with mobile elements. Comparison between a plasmid without resistance genes and different MDR plasmids showed that integration of different mobile elements, such as IS26, ISCR1, ISCR2, IS10 and IS6100, into the plasmid backbone was the key mechanism by which foreign resistance genes were acquired during the evolution process. Conclusions: This study identified pAQU-type plasmids as emerging MDR conjugative plasmids among important pathogens from different origins in Asia. These findings suggest that aquatic bacteria constitute a major reservoir of resistance genes, which may be transmissible to other human pathogens during food production and processing. PMID- 28637207 TI - The Use of Semitranslucent Rubber Pledgets During Microsurgical Dissection of Cerebellopontine Angle Tumors: Technical Note. AB - BACKGROUND AND IMPORTANCE: Dissection of cerebellopontine angle (CPA) tumors that abut or adhere to the brainstem or cranial nerves can be a challenging surgical endeavor. We describe the use of semitranslucent latex rubber pledgets in the tumor-brain interface as a method to improve visualization and protection of vital tissue during microsurgical dissection of CPA masses. The rubber pledgets are fashioned by cutting circular discs out of the cuff portion of talc-free, partially opaque latex gloves. These pledgets provide a semitranslucent, nonadherent membrane that can be placed between vital neural tissues and a tumor capsule to minimize trauma during dissection. The semitranslucent latex enables visualization of the underlying anatomical structures while also providing a protective surface onto which a suction device can be rested to facilitate clearance of the surgical field. CLINICAL PRESENTATION: A 56-yr-old woman with left ear tinnitus presented with a 3-cm CPA meningioma. During microsurgical dissection, rubber pledgets were used to preserve the interface between the brain stem, cranial nerves, and tumor capsule. The use of the rubber pledgets appeared to secure the interface between to tumor and the brain while at the same time protecting the cranial nerves, brainstem, and cerebellum. CONCLUSION: Semitranslucent rubber pledgets may facilitate microsurgical dissection of CPA tumors. PMID- 28637208 TI - Unit conversions between LOINC codes. AB - Logical Observation Identifiers Names and Codes (LOINC) is the most widely used controlled vocabulary to identify laboratory tests. A given laboratory test can often be reported in more than 1 unit of measure (eg, grams or moles), and LOINC defines unique codes for each unit. Consequently, an identical laboratory test performed by 2 different clinical laboratories may have different LOINC codes. The absence of unit conversions between compatible LOINC codes impedes data aggregation and analysis of laboratory results. To develop such conversions, a computational process was developed to review the LOINC standard for potential conversions, and multiple expert reviewers oversaw and finalized the conversion list. In all, 285 bidirectional conversions were identified, including conversions for routine clinical tests such as sodium, magnesium, and human immunodeficiency virus (HIV). Unit conversions were applied to the aggregation of laboratory test results to demonstrate their usefulness. Diverse informatics projects may benefit from the ability to interconvert compatible results. PMID- 28637206 TI - Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. AB - Combining anticatabolic agents with parathyroid hormone (PTH) to enhance bone mass has yielded mixed results in osteoporosis patients. Toward the goal of enhancing the efficacy of these regimens, we tested their utility in combination with loss of the transcription factor Nmp4 because disabling this gene amplifies PTH-induced increases in trabecular bone in mice by boosting osteoblast secretory activity. We addressed whether combining a sustained anabolic response with an anticatabolic results in superior bone acquisition compared with PTH monotherapy. Additionally, we inquired whether Nmp4 interferes with anticatabolic efficacy. Wild-type and Nmp4-/- mice were ovariectomized at 12 weeks of age, followed by therapy regimens, administered from 16 to 24 weeks, and included individually or combined PTH, alendronate (ALN), zoledronate (ZOL), and raloxifene (RAL). Anabolic therapeutic efficacy generally corresponded with PTH + RAL = PTH + ZOL > PTH + ALN = PTH > vehicle control. Loss of Nmp4 enhanced femoral trabecular bone increases under PTH + RAL and PTH + ZOL. RAL and ZOL promoted bone restoration, but unexpectedly, loss of Nmp4 boosted RAL-induced increases in femoral trabecular bone. The combination of PTH, RAL, and loss of Nmp4 significantly increased bone marrow osteoprogenitor number, but did not affect adipogenesis or osteoclastogenesis. RAL, but not ZOL, increased osteoprogenitors in both genotypes. Nmp4 status did not influence bone serum marker responses to treatments, but Nmp4-/- mice as a group showed elevated levels of the bone formation marker osteocalcin. We conclude that the heightened osteoanabolism of the Nmp4-/- skeleton enhances the effectiveness of diverse osteoporosis treatments, in part by increasing hyperanabolic osteoprogenitors. Nmp4 provides a promising target pathway for identifying barriers to pharmacologically induced bone formation. PMID- 28637209 TI - Purification and characterization of two new cell-bound bioactive compounds produced by wild Lactococcus lactis strain. AB - Novel compounds and innovative methods are required considering that antibiotic resistance has reached a crisis point. In the study, two cell-bound antimicrobial compounds produced by Lactococcus lactis ID1.5 were isolated and partially characterized. Following purification by cationic exchange and a solid-phase C18 column, antimicrobial activity was recovered after three runs of RPC using 60% (v/v) and 100% (v/v) of 2-propanol for elution, suggesting that more than one antimicrobial compound were produced by L. lactis ID1.5, which were in this study called compounds AI and AII. The mass spectrum of AI and AII showed major intensity ions at m/z 1070.05 and 955.9 Da, respectively. The compound AI showed a spectrum of antimicrobial activity mainly against L. lactis species, while the organisms most sensitive to compound AII were Bacillus subtilis, Listeria innocua, Streptococcus pneumoniae and Pseudomonas aeruginosa. The antimicrobial activity of both compounds was suppressed by treatment with Tween 80. Nevertheless, both compounds showed high stability to heat and proteases treatments. The isolated compounds, AI and AII, showed distinct properties from other antimicrobial substances already reported as produced by L. lactis, and have a significant inhibitory effect against two clinically important respiratory pathogens. PMID- 28637210 TI - Improvement in CRPS After Deep Dry Needling Suggests a Role in Myofascial Pain. PMID- 28637211 TI - Optimization of Pheromone Traps for Coryphodema tristis (Lepidoptera: Cossidae). AB - The Coryphodema tristis (Drury) is an important pest of Eucalyptus nitens (Deane and Maiden) plantations in South Africa. The gregarious larvae of this pest cause damage by feeding on the tree sapwood, and adults emerge in spring each year. The aim of this study was to optimize pheromone traps for operational use in management programs. This was achieved by investigating different pheromone blend combinations and trap types for efficacy under field conditions. Our results confirm that the cross vane bucket funnel trap baited with a 95:2.5:2.5 volumetric blend of Z9-14:OAc, Z9-14:OH, and 14Ac was superior to similarly baited standard bucket funnel and delta traps. We also estimated the release rate and ratios of the pheromone compounds loaded into an artificial permeation dispenser through solid-phase microextraction sampling. Results showed that the released blend of pheromone compounds mirrored the dispensed ratios relatively accurately and that release rates are affected by temperature. PMID- 28637213 TI - Vaccination to prevent atherosclerotic cardiovascular diseases. PMID- 28637212 TI - Survival and Feeding Rates of Four Aphid Species (Hemiptera: Aphididae) on Various Sucrose Concentrations in Diets. AB - Different concentrations of sucrose were used to investigate how survival and feeding was affected in four species of aphids (Hemiptera: Aphididae). Seven sucrose concentrations were evaluated in feeding chambers fitted with parafilm membranes and infested with nymphs of Aphis glycines Matsumura, Diuraphis noxia Kurdjumov, Myzus persicae Sulzer, or Schizaphis graminum Rondani at 25 degrees C and a photoperiod of 14:10 (L:D) h. Survival on each diet was recorded 1, 3, 5, 7, 9, and 11 d. Diet volumes (MUl) consumed and amounts of honeydew produced were then determined. Aphid survival differed significantly by concentration, time (d), and aphid species. Aphis glycines survival was highest (83.8%) on 30% sucrose although percent survival in the 70's occurred on concentrations ranging from 15-25%. Diuraphis noxia survival was highest on the 15 and 20% sucrose concentrations. Survival for Myzus persicae was optimal on 20% sucrose (92%) but did not differ that much (5%) on concentrations of 15-35%. Schizaphis graminum survival (93.0-93.6%) was highest on sucrose concentrations ranging from 20-30% sucrose. Myzus persicae and S. graminum, which feed on a wide-range of host plants, were overall more adapted to feeding on a wider range of sucrose concentrations than the more host-restricted aphid species, A. glycines. Diet consumption by A. glycines did not vary on the sucrose concentrations, but D. noxia and M. persicae exhibited increased consumption on diets that provided optimal survival. Results will aid in the design of short-term studies using sucrose-only diets to evaluate effects of bioactive materials on aphid survival for up to 11 d. PMID- 28637214 TI - Health and Social-Physical Environment Profiles Among Older Adults Living Alone: Associations With Depressive Symptoms. AB - Objectives: We examined differences in depressive symptoms among people 65 and older who live alone, exploring whether these differences are associated with both health and environmental contexts. Method: Data are from the 2006 wave of Health Retirement Study (N = 2,956, age range: 65-104). We used a two-step cluster analytical approach to identify subgroups of health-limitation profiles and environmental profiles. Logistic regression models determined associations between subgroups and depressive symptoms. Results: Cluster analysis identified four health-profile subgroups (sensory-cognitively impaired, physically impaired, multiply impaired, and healthy) and three different physical-social environmental profile subgroups (physically average/socially unsupported, physically unsupported/socially supported, and physically supported/socially above average). Compared to members of healthier groups, members of the multiply impaired group were the oldest and were more likely both to live in senior housing and to have depressive symptoms if they lived in a physically average/socially unsupported environment. Members of the sensory-cognitively impaired group were more likely to have depressive symptoms when they lived in a physically unsupported/socially supported environment. Discussion: Findings regarding the range of both health and social-physical environmental profiles as well as the associations between person-environment profiles combinations (fit) and depressive symptomatology have important policy and intervention implications. PMID- 28637215 TI - Managerial Ownership in Nursing Homes: Staffing, Quality, and Financial Performance. AB - Purpose of the Study: Ownership of nursing homes (NHs) has primarily focused broadly on differences between for-profit (FP), nonprofit (NFP), and government operated facilities. Yet, among FPs, the understanding of detailed ownership structures at individual NHs is rather limited. Particularly, NH administrators may hold significant equity interests in their facilities, leading to heterogeneous financial incentives and NH outcomes. Through the principal-agent theory, this article studies how managerial ownership of individual facilities affects NH outcomes. Design and Methods: We use a unique panel dataset of Ohio NHs (2005-2010) to empirically examine the relationship between managerial equity ownership and NH staffing, quality, and financial performance. We identify facility administrators as owner-managers if they have more than 5% of the equity stakes or are relatives of the owners. The statistical analysis is based on the pooled ordinary least squares and NH-fixed effect models. Results: We find that owner-managed NHs are associated with higher nursing staff levels compared to other FP NHs. Surprisingly, despite higher staffing levels, owner-managed NHs are not associated with better quality and we find no statistically significant difference in financial performance between owner-managed and nonowner-managed FP NHs. Our results do not support the principal-agent model and we offer alternative explanations for future research. Implications: Our findings provide empirical evidence that NH ownership structures are more nuanced than simply broadly categorizing facilities as FP or NFP, and our results do not fully align with the standard principal-agent model. The role of managerial ownership should be considered in future NH research and policy discussions. PMID- 28637216 TI - Qualitative Analysis and Detection of the Pyrolytic Products of JWH-018 and 11 Additional Synthetic Cannabinoids in the Presence of Common Herbal Smoking Substrates. AB - Synthetic cannabinoids have become a ubiquitous challenge in forensic toxicology and seized drug analysis. Thermal degradation products have yet to be identified and evaluated for toxicity in comparison to parent and metabolic compounds. An investigation into these pyrolytic products, as the major route of ingestion is inhalation, may produce additional insight to understand the toxicity of synthetic cannabinoids. The pyrolysis of JWH-018 and 11 additional synthetic cannabinoids and six herbal plant substrates were conducted using an in-house constructed smoking simulator. After pyrolysis of herbal material alone, the plant substrate was spiked with the drug compounds to 2-5% w/w concentrations. Samples were collected, filtered, evaporated under nitrogen gas, reconstituted in methanol, and analyzed via gas chromatograph-mass spectrometer. Pyrolysis of the plant material alone produced 10 consistently observed compounds between the six plant species. The pyrolysis of the synthetic cannabinoids produced a total of 52 pyrolytic compounds, where 32 were unique to a particular parent compound and the remaining 20 were common products between multiple cannabinoids. The thermal degradation followed three major pathways that are outlined to assist in producing a predictive model for new synthetic cannabinoids that may arise in case samples. The observed pyrolytic products are also viable options for analysis in post mortem samples and the evaluation of toxicity. PMID- 28637217 TI - Experimental Support That Natural Selection Has Shaped the Latitudinal Distribution of Mitochondrial Haplotypes in Australian Drosophila melanogaster. AB - Cellular metabolism is regulated by enzyme complexes within the mitochondrion, the function of which are sensitive to the prevailing temperature. Such thermal sensitivity, coupled with the observation that population frequencies of mitochondrial haplotypes tend to associate with latitude, altitude, or climatic regions across species distributions, led to the hypothesis that thermal selection has played a role in shaping standing variation in the mitochondrial DNA (mtDNA) sequence. This hypothesis, however, remains controversial, and requires evidence that the distribution of haplotypes observed in nature corresponds with the capacity of these haplotypes to confer differences in thermal tolerance. Specifically, haplotypes predominating in tropical climates are predicted to encode increased tolerance to heat stress, but decreased tolerance to cold stress. We present direct evidence for these predictions, using mtDNA haplotypes sampled from the Australian distribution of Drosophila melanogaster. We show that the ability of flies to tolerate extreme thermal challenges is affected by sequence variation across mtDNA haplotypes, and that the thermal performance associated with each haplotype corresponds with its latitudinal prevalence. The haplotype that predominates at low (subtropical) latitudes confers greater resilience to heat stress, but lower resilience to cold stress, than haplotypes predominating at higher (temperate) latitudes. We explore molecular mechanisms that might underlie these responses, presenting evidence that the effects are in part regulated by SNPs that do not change the protein sequence. Our findings suggest that standing variation in the mitochondrial genome can be shaped by thermal selection, and could therefore contribute to evolutionary adaptation under climatic stress. PMID- 28637219 TI - Preventing occupational injury among police officers: does motivation matter? AB - Background: Injury prevention is an important issue for police officers, but the effectiveness of prevention initiatives is dependent on officers' motivation toward, and adherence to, recommended health and safety guidelines. Aims: To understand effects of police officers' motivation to prevent occupational injury on beliefs about safety and adherence to injury prevention behaviours. Methods: Full-time police officers completed a survey comprising validated psychometric scales to assess autonomous, controlled and amotivated forms of motivation (Treatment Self-Regulation Questionnaire), behavioural adherence (Self-reported Treatment Adherence Scale) and beliefs (Safety Attitude Questionnaire) with respect to injury prevention behaviours. Results: There were 207 participants; response rate was 87%. Hierarchical multiple regression analyses demonstrated that autonomous motivation was positively related to behavioural adherence, commitment to safety and prioritizing injury prevention. Controlled motivation was a positive predictor of safety communication barriers. Amotivation was positively associated with fatalism regarding injury prevention, safety violation and worry. Conclusions: These findings are consistent with the tenets of self determination theory in that autonomous motivation was a positive predictor of adaptive safety beliefs and adherence to injury prevention behaviours. PMID- 28637218 TI - Genome-wide characterization and expression analysis enables identification of abiotic stress-responsive MYB transcription factors in cassava (Manihot esculenta). AB - The myeloblastosis (MYB) transcription factor superfamily is the largest transcription factor family in plants, playing different roles during stress response. However, abiotic stress-responsive MYB transcription factors have not been systematically studied in cassava (Manihot esculenta), an important tropical tuber root crop. In this study, we used a genome-wide transcriptome analysis to predict 299 putative MeMYB genes in the cassava genome. Under drought and cold stresses, many MeMYB genes exhibited different expression patterns in cassava leaves, indicating that these genes might play a role in abiotic stress responses. We found that several stress-responsive MeMYB genes responded to abscisic acid (ABA) in cassava leaves. We characterize four MeMYBs, namely MeMYB1, MeMYB2, MeMYB4, and MeMYB9, as R2R3-MYB transcription factors. Furthermore, RNAi-driven repression of MeMYB2 resulted in drought and cold tolerance in transgenic cassava. Gene expression assays in wild-type and MeMYB2 RNAi cassava plants revealed that MeMYB2 may affect other MeMYBs as well as MeWRKYs under drought and cold stress, suggesting crosstalk between MYB and WRKY family genes under stress conditions in cassava. PMID- 28637220 TI - Temporal changes in health within 5 years before and after disability pension-the HUNT Study. AB - Background: Health status has been reported to change before, during and after disability pension receipt. These associations might be subject to temporal changes according to changes in policy, incidence of disability pensions and other contextual factors. We compared the perceived health around time of disability retirement among persons receiving disability pension in the 1990 s and 2000 s in Norway. Methods: We linked data from two consecutive cross sectional population based Norwegian health surveys, HUNT2 (1995-97) and HUNT3 (2006-08), to national registries, identifying those who received disability pension within 5 years before or after participation in the survey (HUNT2: n = 5362, HUNT3: n = 4649). We used logistic regression to assess associations of time from receiving a disability pension with self-rated health, insomnia, depression and anxiety symptoms and subsequently estimated adjusted prevalence over time. Results: Prevalence of poor self-rated health peaked around time of receiving disability pension in both decades. For those aged 50+, prevalence the year before disability pension was slightly lower in 2006-08 (74%, 95% CI 70-79%) than in 1995-97 (83%, 95% CI 79-87%), whereas peak prevalence was similar between surveys for those younger than 50. Depression symptoms peaked more pronouncedly in 1995-97 than in 2006-08, whereas prevalence of anxiety symptoms was similar at time of receiving disability pension between surveys. Conclusions: We found no strong evidence of differences in health selection to disability pension in the 2000 s compared to the 1990 s. However, we found indication of less depression symptoms around time of disability pension in the 2000 s compared to the 1990 s. PMID- 28637222 TI - Risk Factors for the Development of Delayed TSH Elevation in Neonatal Intensive Care Unit Newborns. AB - Context: Delayed thyrotropin (TSH) elevation (dTSH) is defined as elevated TSH at the second neonatal screening (after normal TSH levels at the initial screening) in premature, low-birth-weight, and ill newborns, mostly in the neonatal intensive care unit (NICU) setting. The pathogenesis of dTSH is elusive. Objective: To identify the risk factors for dTSH development among newborns in the NICU. Design, Setting, and Patients: A retrospective medical record review of neonates with dTSH was conducted in eight university-affiliated NICUs. Two controls were selected for each patient, matched for sex and birth weight. The risk factors for dTSH were identified by univariate analysis, followed by multivariate analysis. Main Outcome Measures: Maternal variables, types of NICU treatments and procedures, syndromes, and various medical conditions were compared between dTSH patients and their matched controls. Results: We enrolled 100 dTSH patients and 200 matched controls and 46 variables were compared between the two groups. Twelve risk factors for dTSH were identified on univariate analysis: cesarean section, mechanical ventilation, patent ductus arteriosus (PDA), pneumothorax, and administration of cefotaxime, vancomycin, fluconazole, dopamine, ibuprofen, furosemide, insulin, and packed red blood cells. On multivariate analysis, four risk factors were identified: PDA and vancomycin, insulin, and furosemide administration. In 26 twin pairs, in which one twin had dTSH, all variables presented similarly in both twins. Conclusions: Although some variables had direct effects on pituitary-thyroid axis dysfunction, these variables, altogether, reflect the severity of the clinical conditions in the NICU, which is the common basis for dTSH. PMID- 28637221 TI - Digital direct detection of microRNAs using single molecule arrays. AB - MicroRNAs (miRNAs) are involved in many biological pathways, and detecting miRNAs accurately is critical for diagnosing a variety of diseases including cancer. However, most current methods for miRNA detection require lengthy sample preparation and amplification steps that can bias the results. In addition, lack of specificity and reproducibility give rise to various challenges in detection of circulating miRNAs in biological samples. In this work, we applied the Single Molecule Array (Simoa) technique to develop an ultra-sensitive sandwich assay for direct detection of multiple miRNAs without pre-amplification. We successfully detected miRNAs at femtomolar concentrations (with limits of detection [LODs] ranging from 1 to 30 fM) and high specificity (distinguishing miRNAs with a single nucleotide mismatch). This method was effective against a range of diverse target sequences, suggesting a general approach for miRNA detection. To demonstrate the practical application of this technique, we detected miRNAs in a variety of sample types including human serum and total RNA. The high sensitivity and simple workflow of the Simoa method represent excellent advantages for miRNA based diagnostics of human diseases. PMID- 28637223 TI - Millions of Years Behind: Slow Adaptation of Ruminants to Grasslands. AB - The Late Cretaceous appearance of grasses, followed by the Cenozoic advancement of grasslands as dominant biomes, has contributed to the evolution of a range of specialized herbivores adapted to new diets, as well as to increasingly open and arid habitats. Many mammals including ruminants, the most diversified ungulate suborder, evolved high-crowned (hypsodont) teeth as an adaptation to tooth wearing diets and habitats. The impact of different causes of tooth wear is still a matter of debate, and the temporal pattern of hypsodonty evolution in relation to the evolution of grasslands remains unclear. We present an improved time calibrated molecular phylogeny of Cetartiodactyla, with phylogenetic reconstruction of ancestral ruminant diets and habitats, based on characteristics of extant taxa. Using this timeline, as well as the fossil record of grasslands, we conduct phylogenetic comparative analyses showing that hypsodonty in ruminants evolved as an adaptation to both diet and habitat. Our results demonstrate a slow, perhaps constrained, evolution of hypsodonty toward estimated optimal states, excluding the possibility of immediate adaptation. This augments recent findings that slow adaptation is not uncommon on million-year time scales. PMID- 28637224 TI - Impact of a Macleaya cordata-derived alkaloid extract on necrotic enteritis in broilers. AB - Necrotic enteritis (NE) causes significant economic losses in the broiler chicken industry, especially in birds raised without in-feed antibiotics. A standardized blend of plant-derived isoquinoline alkaloids (IQA) derived from Macleaya cordata has shown to have anti-inflammatory potency and promoted animal productivity. This study investigated the effects of IQA supplementation on broiler chickens under NE challenge. A 2 * 2 factorial arrangement of treatments was employed with factors: NE challenge (no or yes), and additives (no additive or IQA at 0.15 g/kg) in starter, grower, and finisher diets. Birds were challenged with Eimeria spp. on d 9 and 108 to 109Clostridium perfringens on d 14. Each treatment had 7 replicate floor pens with 17 birds each. NE challenge negatively affected growth performance, livability, and carcass traits. Regardless of challenge, IQA increased feed intake and gain on d 24 (P < 0.05) and 35 (P < 0.01) and improved FCR (P < 0.05), flock uniformity (P < 0.01) and breast meat yield (P < 0.001) on d 35. Supplementation of IQA also reduced lesions in the duodenum (P < 0.05), jejunum (P < 0.001), and ileum (P < 0.001). This study suggests that IQA may protect broilers from NE indicating its role as a promising antibiotic alternative. PMID- 28637225 TI - Characteristics of Escherichia coli isolated from broiler chickens with colibacillosis in commercial farms from a common hatchery. AB - To investigate the epidemiologic aspects of colibacillosis in broiler chickens, 83 Escherichia coli isolates obtained from the pericarditis and perihepatitis lesions in broiler chickens from 4 commercial farms, 5 isolates recovered from 5 samples of yolk sac contents that were pooled from 25 emaciated chicks, and 4 fecal isolates obtained from a hatchery that supplied chicks to the 4 commercial farms mentioned above were genetically and bacteriologically characterized. Using pulsed-field gel electrophoresis (PFGE), a total of 92 isolates were classified into 33 pulsotypes. Identical pulsotypes were observed in isolates obtained from hatchery samples and the affected broiler chickens on multiple farms at various sampling times. Seventeen representative isolates with no common origin belonging to 6 pulsotypes and an additional 27 isolates with the other pulsotypes were used for further experiments. Isolates with identical pulsotypes exhibited common traits for virulence-associated genes, lipopolysaccharide core types, and phylogenetic groups. Nine of the isolates were serologically typed as O125 with various types of H antigens and 3 were typed as O25:H4. In the 27 isolates resistant to ceftiofur (CTF), which is a third generation cephalosporin, the blaCTX-M-2, blaCMY-2, blaCTX-M-14, blaCTX-M-65 genes were found in 15, 8, 3, and 1 isolate(s), respectively, and another isolate resistant to CTF had both the blaCTX-M-2 and the blaCMY-2 genes. In the 16 isolates with the blaCTX-M-2 gene, the chromosomal location of the gene was identified in 12 isolates. The plasmid mediated quinolone resistance genes, oqxAB and aac(6')-Ib-cr, were found in 2 and 3 isolates, respectively. Conjugation experiments revealed that the blaCTX-M-2 (4 isolates), blaCTX-M-14 (3 isolates), blaSHV-12 (1 isolate), and oqxAB (2 isolates) genes were transferred. Our data suggest that E. coli strains with identical pulsotypes had been caused the incidences of colibacillosis and that the antimicrobial resistance genes on conjugative plasmids and those integrated into the chromosome may be spread among avian pathogenic E. coli strains in multiple farms. PMID- 28637226 TI - Epidemiologic Risk Factors for In Situ and Invasive Breast Cancers Among Postmenopausal Women in the National Institutes of Health-AARP Diet and Health Study. AB - Comparing risk factor associations between invasive breast cancers and possible precursors may further our understanding of factors related to initiation versus progression. Accordingly, among 190,325 postmenopausal participants in the National Institutes of Health-AARP Diet and Health Study (1995-2011), we compared the association between risk factors and incident ductal carcinoma in situ (DCIS; n = 1,453) with that of risk factors and invasive ductal carcinomas (n = 7,525); in addition, we compared the association between risk factors and lobular carcinoma in situ (LCIS; n = 186) with that of risk factors and invasive lobular carcinomas (n = 1,191). Hazard ratios and 95% confidence intervals were estimated from multivariable Cox proportional hazards regression models. We used case-only multivariable logistic regression to test for heterogeneity in associations. Younger age at menopause was associated with a higher risk of DCIS but lower risks of LCIS and invasive ductal carcinomas (P for heterogeneity < 0.01). Prior breast biopsy was more strongly associated with the risk of LCIS than the risk of DCIS (P for heterogeneity = 0.04). Increased risks associated with use of menopausal hormone therapy were stronger for LCIS than DCIS (P for heterogeneity = 0.03) and invasive lobular carcinomas (P for heterogeneity < 0.01). Associations were similar for race, age at menarche, age at first birth, family history, alcohol consumption, and smoking status, which suggests that most risk factor associations are similar for in situ and invasive cancers and may influence early stages of tumorigenesis. The differential associations observed for various factors may provide important clues for understanding the etiology of certain breast cancers. PMID- 28637227 TI - Echocardiographic reference ranges for normal left ventricular 2D strain: results from the EACVI NORRE study. AB - Aims: To obtain the normal ranges for 2D echocardiographic (2DE) measurements of left ventricular (LV) strain from a large group of healthy volunteers accounting for age and gender. Methods and results: A total of 549 (mean age: 45.6 +/- 13.3 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. 2DE data sets have been analysed with a vendor-independent software package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire the data sets. The lowest expected values of LV strains and twist calculated as +/- 1.96 standard deviations from the mean were -16.7% in men and -17.8% in women for longitudinal strain, -22.3% and -23.6% for circumferential strain, 20.6% and 21.5% for radial strain, and 2.2 degrees and 1.9 degrees for twist, respectively. In multivariable analysis, longitudinal strain decreased with age whereas the opposite occurred with circumferential and radial strain. Male gender was associated with lower strain for longitudinal, circumferential, and radial strain. Inter-vendor differences were observed for circumferential and radial strain despite the use of vendor-independent software. Importantly, no intervendor differences were noted in longitudinal strain. Conclusion: The NORRE study provides contemporary, applicable 2D echocardiographic reference ranges for LV longitudinal, radial, and circumferential strain. Our data highlight the importance of age- and gender-specific reference values for LV strain. PMID- 28637228 TI - Application of social network analysis in the assessment of organization infrastructure for service delivery: a three district case study from post conflict northern Uganda. AB - In post-conflict settings, service coverage indices are unlikely to be sustained if health systems are built on weak and unstable inter-organization networks-here referred to as infrastructure. The objective of this study was to assess the inter-organization infrastructure that supports the provision of selected health services in the reconstruction phase after conflict in northern Uganda. Applied social network analysis was used to establish the structure, size and function among organizations supporting the provision of (1) HIV treatment, (2) maternal delivery services and (3) workforce strengthening. Overall, 87 organizations were identified from 48 respondent organizations in the three post-conflict districts in northern Uganda. A two-stage snowball approach was used starting with service provider organizations in each district. Data included a list of organizations and their key attributes related to the provision of each service for the year 2012-13. The findings show that inter-organization networks are mostly focused on HIV treatment and least for workforce strengthening. The networks for HIV treatment and maternal services were about 3-4 times denser relative to the network for workforce strengthening. The network for HIV treatment accounted for 69-81% of the aggregated network in Gulu and Kitgum districts. In contrast, the network for workforce strengthening contributed the least (6% and 10%) in these two districts. Likewise, the networks supporting a young district (Amuru) was under invested with few organizations and sparse connections. Overall, organizations exhibited a broad range of functional roles in supporting HIV treatment compared to other services in the study. Basic information about the inter-organization setup (infrastructure)-can contribute to knowledge for building organization networks in more equitable ways. More connected organizations can be leveraged for faster communication and resource flow to boost the delivery of health services. PMID- 28637229 TI - Can passage in Galleria mellonella activate virulence factors of Paracoccidioides brasiliensis as in the murine model? AB - Paracoccidioidomycosis (PCM) is a fungal disease restricted to Latin countries, and its etiologic agents derive from the Paracoccidioides genus. Attenuation or loss of virulence in Paracoccidioides spp. following successive subculturing has been described. However, virulence can be recovered by passage in mammalian host. In this study, the recovery of adhesion of P. brasiliensis through passage in mice was compared to that in the insect Galleria mellonella. Analysis of in vitro fungal-host cell interaction, gene expression of adhesins, and analysis of the survival curves revealed that Galleria mellonella is useful for the reactivation of P. brasiliensis adhesion. PMID- 28637230 TI - Perceived Stress and Its Relationship With Chronic Medical Conditions and Multimorbidity Among 229,293 Community-Dwelling Adults in 44 Low- and Middle Income Countries. AB - In this study, we assessed the association of chronic medical conditions and multimorbidity with perceived stress among community-dwelling adults in 44 low- and middle-income countries. Data from the World Health Survey (2002-2004), including 229,293 adults, were analyzed. A perceived stress score (range, 0 (lowest stress)-100 (highest stress)) was computed on the basis of 2 questions from the Perceived Stress Scale. Eleven chronic conditions were assessed. Multivariable linear regression analyses were conducted to explore the associations. All chronic conditions were associated with significantly higher mean perceived stress scores, with the exception of edentulism. The associations were particularly strong for depression (beta = 14.71, 95% confidence interval (CI): 13.68, 15.74), visual impairment (beta = 10.66, 95% CI: 8.09, 13.23), and schizophrenia (beta = 9.98, 95% CI: 7.71, 12.24). Compared with no chronic conditions, the beta coefficients for perceived stress with the presence of 1, 2, 3, and >=4 chronic conditions were 5.58 (95% CI: 4.94, 6.23), 9.58 (95% CI: 8.67, 10.49), 14.15 (95% CI: 12.63, 15.67), and 20.17 (95% CI: 18.29, 22.05), respectively. The associations with perceived stress were significantly stronger among the poorest individuals for arthritis, asthma, diabetes, edentulism, and >=4 chronic conditions. Our data suggest that a range of chronic conditions and multimorbidity are associated with greatly increased perceived stress among people in low- and middle-income countries, and that the poorest persons may be a particularly vulnerable group. PMID- 28637231 TI - Aortic valve cord mimicking fibroelastoma. PMID- 28637232 TI - PhylOligo: a package to identify contaminant or untargeted organism sequences in genome assemblies. AB - Motivation: Genome sequencing projects sometimes uncover more organisms than expected, especially for complex and/or non-model organisms. It is therefore useful to develop software to identify mix of organisms from genome sequence assemblies. Results: Here we present PhylOligo, a new package including tools to explore, identify and extract organism-specific sequences in a genome assembly using the analysis of their DNA compositional characteristics. Availability and implementation: The tools are written in Python3 and R under the GPLv3 Licence and can be found at https://github.com/itsmeludo/Phyloligo/. Contact: ludovic.mallet@inra.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28637233 TI - Identification of exosomal muscle-specific miRNAs in serum of myotonic dystrophy patients relating to muscle disease progress. AB - Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, which is characterised by progressive muscle wasting and the discovery of reliable blood-based biomarkers could be useful for the disease progress monitoring. There have been some reports showing that the presence of specific miRNAs in blood correlates with DM1. In one of these, our group identified four muscle-specific miRNAs, miR-1, miR-133a, miR-133b and miR-206, which correlated with the progression of muscle wasting observed in DM1 patients. The levels of the four muscle-specific miRNAs were elevated in the serum of DM1 patients compared to healthy participants and were also elevated in the serum of progressive muscle wasting DM1 patients compared to disease-stable DM1 patients. The aim of this work was to characterise the ontology of these four muscle specific miRNAs in the blood circulation of DM1 patients. Here we show that the four muscle-specific miRNAs are encapsulated within exosomes isolated from DM1 patients. Our results show for the first time, the presence of miRNAs encapsulated within exosomes in blood circulation of DM1 patients. More interestingly, the levels of the four exosomal muscle-specific miRNAs are associated with the progression of muscle wasting in DM1 patients. We propose that exosomal muscle-specific miRNAs may be useful molecular biomarkers for monitoring the progress of muscle wasting in DM1 patients. There has been a growing interest regarding the clinical applications of exosomes and their role in prognosis and therapy of various diseases and the above results contribute towards this way. PMID- 28637234 TI - A baseline assessment by healthcare professionals of Dutch pharmacotherapeutic care for the elderly with polypharmacy. AB - Background: Polypharmacy is common in the elderly population and is associated with an increased risk of adverse drug events. To diminish this risk, the guideline 'Polypharmacy in the Elderly' has been developed in 2012. This study examines, to what extent Dutch pharmacotherapeutic practice amongst elderly with polypharmacy mirrors the best practice described in this guideline and which barriers threaten it. Methods: An observational study was conducted in 2013/14 using a questionnaire distributed amongst Dutch healthcare professionals and elderly patients with polypharmacy. Healthcare professionals were asked about their current practice and the presence of five significant barriers, selected through a literature review and from expert opinion. These barriers are: inadequate transfer of patient records; insufficient documentation of prescribed drugs; a lack of collaboration between professionals; a failure to take a full control of the medication and insufficient involvement of the patient. The patients were asked about their experience with pharmacotherapeutic care. Results: No more than 26% of the healthcare professionals indicated that they use the guideline. The five barriers threatening the pharmacotherapeutic care were found to be present. Forty-three percent of the patients mentioned that their medication was assessed last year. Conclusion: The guideline is not used frequently by the healthcare professionals, but there is a will to improve the care by following this guideline. However, the presence of the five barriers hampers its implementation. Good management of those barriers is necessary in order to improve the collaboration between primary and secondary care and to enhance the documentation of prescribed drugs. PMID- 28637235 TI - Monotherapy with either dolutegravir or raltegravir fails to durably suppress HIV viraemia in humanized mice. AB - Objectives: To compare the effectiveness of HIV integrase inhibitor monotherapy between raltegravir and dolutegravir as an approach to simplify therapy. Methods: We evaluated and compared the efficacy of 20 week monotherapy with dolutegravir or raltegravir in humanized mice (HSC-NSG) infected with HIVBaL. Plasma HIV RNA was measured by quantitative RT-PCR (limit of detection of 150 copies/45 MUL of plasma) and drug levels by LC-MS/MS. Escape viruses were genotyped and analysed for replication capacity and drug susceptibility in tissue culture. Results: Drug untreated control mice maintained constant viraemia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC50 of <8 nM) and dolutegravir (EC50 of <1 nM). Mice treated with raltegravir or dolutegravir had plasma drug levels comparable to those in humans. Monotherapy with raltegravir initially suppressed HIV viraemia, but failed to maintain suppression in 4/4 mice. Viruses from raltegravir failing mice developed mutations G140G/S and Q148H/K, and were resistant to both raltegravir (EC50 values of >100 nM) and dolutegravir (EC50 values ranging from 8.8 to 13.3 nM). Monotherapy with dolutegravir suppressed viraemia in 5/5 of mice, but viraemia rebounded in one animal. The virus from this mouse had mutations E138K, G140S, Q148H, N155H and S230R, was highly resistant to both raltegravir (EC50 of >1000 nM) and dolutegravir (EC50 of 550 nM), and replicated to levels similar to those of control viruses in PBMCs. Conclusions: Monotherapy with either raltegravir or dolutegravir does not consistently maintain HIV suppression, suggesting that dual therapy may be required in simplification strategies. PMID- 28637237 TI - Long-Term Evolutionary Change in the Lumen of Intracranial Atherosclerotic Stenosis Following Angioplasty and Stenting. AB - BACKGROUND: Angioplasty and stenting is a recognized treatment option for patients with intracranial atherosclerosis. OBJECTIVE: To evaluate the long-term evolutionary luminal changes of intracranial atherosclerosis after angioplasty and stenting. METHODS: This was a retrospective study with patient consent. Eighty-two patients presenting with acute and minor cerebral ischemia due to stenosis >=70%, who had received medical therapy with or without stenting (Wingspan), were invited. Luminal imaging was provided using 3-dimensional rotational angiography (3-DRA) at baseline and 12 mo, and cone-beam computed tomography angiography with intravenous contrast (CBCT) was provided at follow-up (median 82.4 mo [interquartile range 61.9-96.9 mo]). RESULTS: Thirty-six patients in the stenting group and 26 patients in the medical group were recruited and completed the study. There was no statistically significant difference in demographics between the 2 patient groups. The luminal gain at 12 or 80 mo as compared to baseline in the stenting group was significantly greater than that in the medical group (12 mo: median gain 30% vs 7.2%, P < .001; 80 mo: median gain 42.9% vs 7.2%, P < .0001). Luminal loss or unchanged lumen was correlated with recurrent ischemic event. The differences in the stenosis degree assessment between CBCT and 3-DRA in the same 10 patients with or without stenting were 1.2 +/- 0.6% or 0.2 +/- 0.06%, respectively. There was a correlation between recurrent ischemic events and luminal loss. CONCLUSION: Arterial lumen after angioplasty and stenting can probably be well maintained and delayed luminal gain does occur, long-term luminal loss is associated with recurrent ischemic events, CBCT might be useful as a less-invasive means for long-term assessment. PMID- 28637236 TI - The ribosome assembly gene network is controlled by the feedback regulation of transcription elongation. AB - Ribosome assembly requires the concerted expression of hundreds of genes, which are transcribed by all three nuclear RNA polymerases. Transcription elongation involves dynamic interactions between RNA polymerases and chromatin. We performed a synthetic lethal screening in Saccharomyces cerevisiae with a conditional allele of SPT6, which encodes one of the factors that facilitates this process. Some of these synthetic mutants corresponded to factors that facilitate pre-rRNA processing and ribosome biogenesis. We found that the in vivo depletion of one of these factors, Arb1, activated transcription elongation in the set of genes involved directly in ribosome assembly. Under these depletion conditions, Spt6 was physically targeted to the up-regulated genes, where it helped maintain their chromatin integrity and the synthesis of properly stable mRNAs. The mRNA profiles of a large set of ribosome biogenesis mutants confirmed the existence of a feedback regulatory network among ribosome assembly genes. The transcriptional response in this network depended on both the specific malfunction and the role of the regulated gene. In accordance with our screening, Spt6 positively contributed to the optimal operation of this global network. On the whole, this work uncovers a feedback control of ribosome biogenesis by fine-tuning transcription elongation in ribosome assembly factor-coding genes. PMID- 28637238 TI - Chlamydia trachomatis Seroprevalence and Ultrasound-Diagnosed Uterine Fibroids in a Large Population of Young African-American Women. AB - Reproductive tract infections have long been hypothesized to increase the risk of uterine fibroids. Few studies have been conducted, even for the common infection genital Chlamydia trachomatis (gCT), and only with self-reported gCT data. Our investigation used micro-immunofluorescence serology for gCT to characterize past exposure. We used cross-sectional enrollment data from a prospective fibroid study carried out in the Detroit, Michigan, area; ultrasound examinations systematically screened for fibroids. Participants were African-American women aged 23-34 years (recruited in 2010-2012). Age- and multivariable-adjusted logistic regression models were used to estimate odds ratios. A total of 1,587 women (94% of participants) had unequivocal gCT serology results; 22% had fibroids. Those who were seropositive for gCT were less likely to have fibroids (age-adjusted odds ratio = 0.68, 95% confidence interval: 0.54, 0.87; multivariable-adjusted odds ratio = 0.80, 95% confidence interval: 0.62, 1.03). Inverse associations were similar across categories of fibroid size, number, and total volume. Participant groups likely to have had multiple or severe infections (multiple serovar groups, more sex partners, clinically diagnosed chlamydia) all showed statistically significantly reduced odds of fibroids. A protective association of gCT with fibroids was unexpected but plausible. gCT infection might increase immune surveillance and eliminate early lesions. Further investigation on the relationship between fibroid development and reproductive tract infections is needed. PMID- 28637239 TI - Misleading takotsubo-like syndrome unravelled by intracoronary imaging. PMID- 28637240 TI - TFEB activation restores migration ability to Tsc1-deficient adult neural stem/progenitor cells. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs). Therefore, reactivation of cell migration of NSPCs might be the crucial step for the treatment of patients. In order to identify potential in vitro targets activating migration, we generated Tsc1-deficient NSPCs. These cells summarize most of the biochemical and morphological characteristics of TSC neural cells, such as the mTORC1 activation, the formation of abnormally enlarged astrocytes-like cells, the reduction of autophagy flux and the impairment of cell migration. Moreover, nuclear translocation, namely activation of the transcription factor EB (TFEB) was markedly impaired. Herein, we show that compounds such as everolimus, ionomycin and curcumin, which directly or indirectly stimulate TFEB nuclear translocation, restore Tsc1-deficient NSPC migration. Our data suggest that reduction of TFEB activation, caused by mTORC1 hyperactivation, contributes to the migration deficit characterizing Tsc1 deficient NSPCs. The present work highlights TFEB as a druggable protein target for SEGAs therapy, which can be additionally or alternatively exploited for the mTORC1-directed inhibitory approach. PMID- 28637243 TI - Nanopore sequencing data analysis: state of the art, applications and challenges. AB - The nanopore sequencing process is based on the transit of a DNA molecule through a nanoscopic pore, and since the 90s is considered as one of the most promising approaches to detect polymeric molecules. In 2014, Oxford Nanopore Technologies (ONT) launched a beta-testing program that supplied the scientific community with the first prototype of a nanopore sequencer: the MinION. Thanks to this program, several research groups had the opportunity to evaluate the performance of this novel instrument and develop novel computational approaches for analyzing this new generation of data. Despite the short period of time from the release of the MinION, a large number of algorithms and tools have been developed for base calling, data handling, read mapping, de novo assembly and variant discovery. Here, we face the main computational challenges related to the analysis of nanopore data, and we carry out a comprehensive and up-to-date survey of the algorithmic solutions adopted by the bioinformatic community comparing performance and reporting limits and advantages of using this new generation of sequences for genomic analyses. Our analyses demonstrate that the use of nanopore data dramatically improves the de novo assembly of genomes and allows for the exploration of structural variants with an unprecedented accuracy and resolution. However, despite the impressive improvements reached by ONT in the past 2 years, the use of these data for small-variant calling is still challenging, and at present, it needs to be coupled with complementary short sequences for mitigating the intrinsic biases of nanopore sequencing technology. PMID- 28637241 TI - The chromatin remodeling complex Swi/Snf regulates splicing of meiotic transcripts in Saccharomyces cerevisiae. AB - Despite its relatively streamlined genome, there are important examples of regulated RNA splicing in Saccharomyces cerevisiae, such as splicing of meiotic transcripts. Like other eukaryotes, S. cerevisiae undergoes a dramatic reprogramming of gene expression during meiosis, including regulated splicing of a number of crucial meiosis-specific RNAs. Splicing of a subset of these is dependent upon the splicing activator Mer1. Here we show a crucial role for the chromatin remodeler Swi/Snf in regulation of splicing of meiotic genes and find that the complex affects meiotic splicing in two ways. First, we show that Swi/Snf regulates nutrient-dependent downregulation of ribosomal protein encoding RNAs, leading to the redistribution of spliceosomes from this abundant class of intron-containing RNAs (the ribosomal protein genes) to Mer1-regulated transcripts. We also demonstrate that Mer1 expression is dependent on Snf2, its acetylation state and histone H3 lysine 9 acetylation at the MER1 locus. Hence, Snf2 exerts systems level control of meiotic gene expression through two temporally distinct mechanisms, demonstrating that it is a key regulator of meiotic splicing in S. cerevisiae. We also reveal an evolutionarily conserved mechanism whereby the cell redirects its energy from maintaining its translational capacity to the process of meiosis. PMID- 28637242 TI - Yes-associated protein and WW-containing transcription regulator 1 regulate the expression of sex-determining genes in Sertoli cells, but their inactivation does not cause sex reversal. AB - Yes-associated protein (YAP) and WW-containing transcription regulator 1 (WWTR1) are two functionally redundant transcriptional regulators that are downstream effectors of the Hippo signaling pathway, and that act as major regulators of cell growth and differentiation. To elucidate their role in Sertoli cells, primary Sertoli cell culture from Yapflox/flox; Wwtr1flox/flox animals were infected with a Cre recombinase-expressing adenovirus. Concomitant inactivation of Yap and Wwtr1 resulted in a decrease in the mRNA levels of the male sex differentiation genes Dhh, Dmrt1, Sox9, and Wt1, whereas those of genes involved in female differentiation (Wnt4, Rspo1, and Foxl2) were induced. SOX9, FOXL2, and WNT4 proteins were regulated in the same manner as their mRNAs in response to loss of YAP and WWTR1. To further characterize the role of YAP and WWTR1 in Sertoli cells, we generated a mouse model (Yapflox/flox; Wwtr1flox/flox; Amhcre/+) in which Yap and Wwtr1 were conditionally deleted in Sertoli cells. An increase in the number of apoptotic cells was observed in the seminiferous tubules of 4 dpp mutant mice, leading to a reduction in testis weights and a decrease in the number of Sertoli cells in adult animals. Gene expression analyses of testes from 4 dpp Yapflox/flox; Wwtr1flox/flox; Amhcre/+ mice showed that Sertoli cell differentiation is initially altered, as Dhh, Dmrt1, and Sox9 mRNA levels were downregulated, whereas Wnt4 mRNA levels were increased. However, expression of these genes was not changed in older animals. Together, these results suggest a novel role of the Hippo signaling pathway in the mechanisms of sex differentiation. PMID- 28637244 TI - Elevated homocysteine increases the risk of left atrial/left atrial appendage thrombus in non-valvular atrial fibrillation with low CHA2DS2-VASc score. AB - Aims: To assess the association and the predictive value of plasma homocysteine (Hcy) levels with LA/LAA thrombus in non-valvular Atrial fibrillation (AF) patients with low CHA2DS2-VASc score. Methods and results: Eight hundred and eighty-eight consecutive patients in non-valvular AF with CHA2DS2-VASc score of 0 and 1 were enrolled. All patients routinely underwent transthoracic echocardiography and transoesophageal echocardiography. A total of thirty-two patients had LA/LAA thrombus. Compared with patients without LA/LAA thrombus, plasma Hcy levels were significantly higher in patients with LA/LAA thrombus (16.5 +/- 4.8 mmol/L vs. 13.4 +/- 4.1 mmol/L, P = 0.009). In multivariate analysis, Hcy was independently associated with LA/LAA thrombus (OR 1.048, 95% CI 1.007-1.090, P = 0.022). Hcy demonstrated a significant predictive value with area under the curve of 0.722 (95% CI 0.662-0.781, P < 0.001). The optimal cut off point for Hcy predicting LA/LAA thrombus was 13.5 mmol/L (sensitivity 67%, specificity 65%). Patients with Hcy >=13.5 mmol/L had higher prevalence of LA/LAA thrombus compared with those with Hcy <13.5 mmol/L (6.1% vs. 2.1%, P < 0.001). Elevated Hcy significantly increased the risk of LA/LAA thrombus in patients with CHA2DS2-VASc score of 0 and 1 (OR 11.789, 95% CI 1.437-96.746, P = 0.022; OR 2.256, 95% CI 1.007-5.155, P = 0.048, respectively). Conclusion: Elevated plasma Hcy increases the risk of LA/LAA thrombus in non-valvular AF patients with low CHA2DS2-VASc score, thus it should be taken into account in prediction of thromboembolism. PMID- 28637245 TI - Motor Output Variability Impairs Driving Ability in Older Adults: Reply to Stinchcombe, Dickerson, Weaver, and Bedard. PMID- 28637247 TI - Surgery for patients with 'lower grade' glioma: putting assumptions, beliefs and convictions into perspective. PMID- 28637246 TI - Effect of Psilocybin on Empathy and Moral Decision-Making. AB - Background: Impaired empathic abilities lead to severe negative social consequences and influence the development and treatment of several psychiatric disorders. Furthermore, empathy has been shown to play a crucial role in moral and prosocial behavior. Although the serotonin system has been implicated in modulating empathy and moral behavior, the relative contribution of the various serotonin receptor subtypes is still unknown. Methods: We investigated the acute effect of psilocybin (0.215 mg/kg p.o.) in healthy human subjects on different facets of empathy and hypothetical moral decision-making using the multifaceted empathy test (n=32) and the moral dilemma task (n=24). Results: Psilocybin significantly increased emotional, but not cognitive empathy compared with placebo, and the increase in implicit emotional empathy was significantly associated with psilocybin-induced changed meaning of percepts. In contrast, moral decision-making remained unaffected by psilocybin. Conclusions: These findings provide first evidence that psilocybin has distinct effects on social cognition by enhancing emotional empathy but not moral behavior. Furthermore, together with previous findings, psilocybin appears to promote emotional empathy presumably via activation of serotonin 2A/1A receptors, suggesting that targeting serotonin 2A/1A receptors has implications for potential treatment of dysfunctional social cognition. PMID- 28637248 TI - Expression and comparison of codon optimised Aspergillus tubingensis amylase variants in Saccharomyces cerevisiae. AB - The expression of codon optimised genes is a popular genetic engineering approach for the production of industrially relevant proteins. This study investigates and compares the expression of codon optimised and codon adapted amylase variants. The Aspergillus tubingensis raw starch hydrolysing alpha-amylase (amyA) and glucoamylase (glaA) encoding genes were redesigned using synonymous codons and expressed in Saccharomyces cerevisiae Y294. Codon optimisation to favour S. cerevisiae codon bias resulted in a decrease in extracellular enzyme activity of 72% (30.28 nkat ml-1) and 68% (4.08 nkat ml-1) compared to the expression of the native amyA and glaA genes, respectively, after 96 h of growth. However, a lower cultivation temperature and co-expression with the PDI1 gene increased extracellular activity levels of the codon optimised alpha-amylase and glucoamylase, respectively. Despite the identical amino acid sequence of GlaA, GlaA_Opt and GlaA_CBI, differential scanning fluorimetry revealed changes in the glucoamylase proteins' melting temperatures (>3 degrees C). Shifts in the fluorescence curves suggest changes in glucoamylase tertiary structure. Results indicate that synonymous codon changes resulting from codon optimisation of amyA and glaA genes does not guarantee increased recombinant protein production and that there is crucial translational information present within the coding sequence that controls protein folding and secretion. PMID- 28637249 TI - Bypass Surgery for Complex Intracranial Aneurysms: 15 Years of Experience at a Single Institution and Review of Pertinent Literature. AB - BACKGROUND: Bypass surgery is a treatment option for complex intracranial aneurysms. OBJECTIVE: To determine the utility of bypass surgery for the treatment of complex intracranial aneurysms and to review the literature on this topic. METHODS: Sixty-two patients were included in this retrospective study. Unruptured aneurysms were dominant (80.6%), and the internal carotid artery was the most common location of the aneurysm (56.4%), followed by the middle cerebral artery (21.0%). The mean maximal diameter of the aneurysms was 20.5 +/- 11.4 mm. The clinical and angiographic states were evaluated preoperatively, immediately after surgery (within 3 days) and at the last follow-up. The mean angiographic and clinical follow-up duration was 34.2 +/- 38.9 and 46.5 +/- 42.5 months, respectively. RESULTS: Sixty-one patients (98.3%) underwent extracranial intracranial bypass, and 1 underwent intracranial-intracranial bypass. At the last follow-up angiography, 58 aneurysms (93.5%) were completely obliterated and 4 were incompletely obliterated, with a graft patency of 90.3%. Surgical mortality was 0 and permanent morbidity was 8.1%. A good clinical outcome (Karnofsky Performance Scale >= 70 and modified Rankin Scale score <= 2) was achieved in 91.9% of patients (n = 57). CONCLUSION: With a proper selection of bypass type, bypass-associated treatment can be a good alternative for patients with complex intracranial aneurysms when conventional microsurgical clipping or endovascular intervention is not feasible. PMID- 28637251 TI - Intracoronary autologous bone marrow cell transfer after acute myocardial infarction: abort and refocus. PMID- 28637250 TI - Use of SpyTag/SpyCatcher to construct bispecific antibodies that target two epitopes of a single antigen. AB - Bispecific antibody targeting of two different antigens is promising, but when fragment-based antibodies are used, homogeneous production is difficult. To overcome this difficulty, we developed a method using the SpyTag/SpyCatcher system in which a covalent bond is formed between the two polypeptides. Using this method, we constructed a bispecific antibody that simultaneously interacted with two different epitopes of roundabout homologue 1 (ROBO1), a membrane protein associated with cancer progression. A bispecific tetravalent antibody with an additional functional moiety was also constructed by using a dimeric biotin binding protein. An interaction analysis of ROBO1-expressing cells and the recombinant antigen demonstrated the improved binding ability of the bispecific antibodies through spontaneous binding of the two antibody fragments to their respective epitopes. In addition, multivalency delayed dissociation, which is advantageous in therapy and diagnosis. PMID- 28637252 TI - Wheat seed weight and quality differ temporally in sensitivity to warm or cool conditions during seed development and maturation. AB - Background and aims: Short periods of extreme temperature may affect wheat (Triticum aestivum) seed weight, but also quality. Temporal sensitivity to extreme temperature during seed development and maturation was investigated. Methods: Plants of 'Tybalt' grown at ambient temperature were moved to growth cabinets at 29/20 degrees C or 34/20 degrees C (2010), or 15/10 degrees C or 34/20 degrees C (2011), for successive 7-d periods from 7 DAA (days after anthesis) onwards, and also 7-65 DAA in 2011. Seed samples were harvested serially and moisture content, weight, ability to germinate, subsequent longevity in air-dry storage and bread-making quality were determined. Key Results: High temperature (34/20 degrees C) reduced final seed weight, with greatest temporal sensitivity at 7-14 or 14-21 DAA. Several aspects of bread-making quality were also most sensitive to high temperature then, but whereas protein quality decreased protein and sulphur concentrations improved. Early exposure to high temperature provided earlier development of ability to germinate and tolerate desiccation, but had little effect on maximum germination capacity. All treatments at 15/10 degrees C resulted in ability to germinate declining between 58 and 65 DAA. Early exposure to high temperature hastened improvement in seed storage longevity, but the subsequent decline in late maturation preceded that in the control. Long (7-65 DAA) exposure to 15/10 degrees C disrupted the development of seed longevity, with no improvement after seed filling ended. Longevity improved during maturation drying in other treatments. Early (7-14 DAA) exposure to high temperature reduced and low temperature increased subsequent longevity at harvest maturity, whereas late (35 or 42-49 DAA) exposure to high temperature increased and low temperature reduced it. Conclusions: Temporal sensitivity to extreme temperature was detected. It varied considerably amongst the contrasting seed variables investigated. Subsequent seed longevity at harvest maturity responded negatively to temperature early in development, but positively later in development and throughout maturation. PMID- 28637253 TI - Synthesis and Secretion of Isoflavones by Field-Grown Soybean. AB - Isoflavones play important roles in rhizosphere plant-microbe interactions. Daidzein and genistein secreted by soybean roots induce the symbiotic interaction with rhizobia and may modulate rhizosphere interactions with microbes. Yet despite their important roles, little is known about the biosynthesis, secretion and fate of isoflavones in field-grown soybeans. Here, we analyzed isoflavone contents and the expression of isoflavone biosynthesis genes in field-grown soybeans. In roots, isoflavone contents and composition did not change with crop growth, but the expression of UGT4, an isoflavone-specific 7-O glucosyltransferase, and of ICHG (isoflavone conjugates hydrolyzing beta glucosidase) was decreased during the reproductive stages. Isoflavone contents were higher in rhizosphere soil than in bulk soil during both vegetative and reproductive stages, and were comparable in the rhizosphere soil between these two stages. We analyzed the degradation dynamics of daidzein and its glucosides to develop a model for predicting rhizosphere isoflavone contents from the amount of isoflavones secreted in hydroponic culture. Conjugates of daidzein were degraded much faster than daidzein, with degradation rate constants of 8.51 d-1 for malonyldaidzin and 11.6 d-1 for daidzin, vs. 9.15 * 10-2 d-1 for daidzein. The model suggested that secretion of isoflavones into the rhizosphere is higher during vegetative stages than during reproductive stages in field-grown soybean. PMID- 28637254 TI - Phylogeography of Lionfishes (Pterois) Indicate Taxonomic Over Splitting and Hybrid Origin of the Invasive Pterois volitans. AB - The lionfish is an iconic marine fish, and recently renowned for a disastrous introduction into the West Atlantic. Genetic surveys of the putative invaders (Pterois volitans and Pterois miles) in their natural Indo-Pacific range can illuminate both topics. Previous research indicated that P. volitans and P. miles are sister species that hybridize in the invasive range, but hybridization in the native range is unknown. Here, we apply mtDNA COI and 2 nuclear introns (S7 RP1 and Gpd2) from 229 lionfish including the 2 invaders and 2 closely-related taxa (44 P. miles, 91 P. volitans, 31 Pterois lunulata, and 63 Pterois russelii) from 10 locations in their native ranges. Genetic data are supplemented with key morphological characters: dorsal, anal, and pectoral fin ray counts. We observed 2 lineages (d = 4.07%, 0.89%, and 2.75% at COI, S7 RP1, and Gpd2, respectively) among the 4 putative species: an Indian Ocean lineage represented by P. miles, and a Pacific Ocean lineage represented by P. lunulata and P. russelii. All specimens of the invasive P. volitans appear to be hybrids between the Indian Ocean P. miles and a Pacific lineage encompassing P. lunulata/russelii, a conclusion supported by both genetics and morphology. The divergences between Indian and Pacific forms are within the range of species-level partitions in fishes, and we recommend retention of the names P. miles and P. russelii for Indian and Pacific forms. The hybrid origin of the Atlantic invasion invokes the possibility of heterosis as a contributing factor to invasion success. PMID- 28637256 TI - Telomeres, oxidative stress, and myocardial infarction. PMID- 28637255 TI - A biomechanical study of 4 different sternum closure techniques under different deformation modes. AB - OBJECTIVES: This study experimentally compares the efficiency of the 4 most preferred sternal closure tehniques, in 3 different deformation modes of the chest. METHODS: Polyurethane sternum models fixed by conventional wiring, steel band, ZipFix band and figure-8 wiring are tested statically under lateral distraction, longitudinal shear and torsional deformation modes. As a result, load-deformation curves are obtained. The closure efficiency of the techniques is then compared with respect to allowable load (corresponding to 2 mm displacement), rigidity, rupture load and rupture displacement. A comparison in terms of cost and ease of application has also been presented. RESULTS: The highest allowable load and rigidity values in simple tension and longitudinal shear are obtained by the steel and ZipFix band techniques, respectively. In torsion mode, the highest allowable load is provided by the ZipFix band and the highest rigidty is attained by the steel band technique. The highest rupture loads under simple tension, longitudinal shear and torsion modes are observed in ZipFix, steel band and conventional wiring, respectively. Steel band closure provides the least rupture displacement in simple tension as well as torsion, whereas ZipFix bands give the smallest rupture displacements in longitudinal shear. However, in every loading mode there were no statistically significant differences in allowable load, rigidity and rupture load values between the closure methods, and only rupture displacement values were statistically different for each method. CONCLUSIONS: Our results showed that conventional wiring is the most advantageous closing method when compared to the others. PMID- 28637257 TI - Effects of a chromosome 9 quantitative trait locus for ascites on economically important traits in broilers. AB - A quantitative trait locus on chromosome 9 was previously shown to be associated with ascites in multiple experimental and commercial populations. A study to evaluate the association of the QTL, based on variable number tandem repeat genotypes, with economically important traits was carried out on a commercial male elite line. Results indicated the highest fat and the lowest fillet mean were associated with the most resistant ascites genotype. All other traits measured for this genotype showed no trend towards positive or negatively impacting production values. The results suggest that a balanced approach could be undertaken in commercial broiler breeding operations to reduce ascites susceptibility in broiler populations without compromising overall genetic progress for traits of economic importance. PMID- 28637258 TI - 'Dysfunctional' adipose tissue in cardiovascular disease: a reprogrammable target or an innocent bystander? PMID- 28637259 TI - Caddyshack therapeutics: overcoming glioblastoma adaptation. PMID- 28637260 TI - Associations of obesity and lifestyle with the risk and mortality of bloodstream infection in a general population: a 15-year follow-up of 64 027 individuals in the HUNT Study. AB - Background: Bloodstream infections (BSI) cause considerable morbidity and mortality, and primary prevention should be a priority. Lifestyle factors are of particular interest since they represent a modifiable target. Methods: We conducted a prospective cohort study among participants in the population-based Norwegian HUNT2 Survey, where 64 027 participants were followed from 1995-97 through 2011 by linkage to prospectively recorded information on BSI at local and regional hospitals. The exposures were: baseline body mass index (BMI) measurements; and self-reported smoking habits, leisure time physical activity and alcohol intake. The outcomes were hazard ratios (HR) of BSI and BSI mortality. Results: During 810 453 person-years and median follow-up of 14.8 years, 1844 (2.9%) participants experienced at least one BSI and 396 (0.62%) died from BSI. Compared with normal weight participants (BMI 18.5-24.9 kg/m2), the age and sex-adjusted risk of a first-time BSI was 31% [95% confidence interval (CI) 14-51%] higher at BMI 30.0-34.9 kg/m2, 87% (95% CI 50-135%) higher at BMI 35.0 39.9 kg/m2 and 210% (95% CI 117-341%) higher at BMI >= 40.0 kg/m2. The risk of BSI mortality was similarly increased. Compared with never-smokers, current smokers had 51% (95% CI 34-70%) and 75% (95% CI 34-129%) higher risks of BSI and BSI mortality, respectively. Physically inactive participants had 71% (95% CI 42 107%) and 108% (95% CI 37-216%) higher risks of BSI and BSI mortality, respectively, compared with the most physically active. Conclusions: Obesity, smoking and physical inactivity carry increased risk of BSI and BSI mortality. PMID- 28637262 TI - Qualitative Exploration of a Smoking Cessation Trial for People Living With HIV in South Africa. AB - Introduction: In South Africa, people living with HIV have a high prevalence of smoking, which undermines the beneficial effects of antiretroviral therapy. However, little is known about barriers to smoking cessation and what interventions work for people living with HIV in this setting. Methods: A randomized trial comparing intensive anti-smoking counseling versus counseling and nicotine replacement therapy was recently concluded in Klerksdorp, South Africa. In a post-trial follow-up, 23 in-depth interviews with patients and one focus group discussion with counselors from the trial were conducted. A codebook was developed and codes were applied to the transcripts, which were analyzed using a thematic analysis. Results: Barriers at the economic, social/interpersonal, and individual levels induced stress, which hindered smoking cessation. Economic stressors included unemployment and poverty. Social or interpersonal stressors were lack of social support for quitting smoking and lack of social support due to having HIV. Individual stressors were traumatic life events. Alcohol was used to cope with stress and frequently co-occurred with smoking. Managing cravings was a barrier unrelated to stress. Participants proposed income and employment opportunities, group counseling, and more frequent counseling as solutions to address stressors at different levels. Nicotine replacement therapy was helpful to mitigate cravings. Conclusions: Future smoking cessation interventions need to target barriers at multiple levels. Increasing the supply and duration of nicotine replacement therapy may increase its effectiveness. Other behavioral approaches such as group counseling or peer counseling could hold promise in this setting but need to be tested for efficacy through randomized controlled trials. Implications: To our knowledge, this is the first qualitative study examining barriers to smoking cessation for people living with HIV in South Africa. Smoking is highly prevalent among people with HIV in South Africa and cessation interventions are urgently needed. A better understanding of barriers to smoking cessation that people with HIV face will lead to the development of contextually appropriate interventions. This study also provides feedback on interventions from a recently concluded smoking cessation randomized trial and will help guide the design of future smoking cessation trials. PMID- 28637263 TI - Nearly nondiffracting electron lattice beams generated by polygonal slits. AB - A method for generating electron lattice beams carrying vortices using nanofabricated polygonal slits in a transmission electron microscope is proposed. Experimental and simulation study of the intensity of the beams verified their Bessel beam-like nearly nondiffracting behavior. Phase analysis using a diffractive imaging method found arrays of quantized vortices, forming an electron beam lattice with cylindrical intensity distribution in the propagation direction. Such vortex lattice beams may be used in a variety of applications including nanofabrication, particle manipulation or a new electron imaging method. PMID- 28637261 TI - Further Simulations and Analyses Demonstrate Open Problems of Phylostratigraphy. AB - Phylostratigraphy, originally designed for gene age estimation by BLAST-based protein homology searches of sequenced genomes, has been widely used for studying patterns and inferring mechanisms of gene origination and evolution. We previously showed by computer simulation that phylostratigraphy underestimates gene age for a nonnegligible fraction of genes and that the underestimation is severer for genes with certain properties such as fast evolution and short protein sequences. Consequently, many previously reported age distributions of gene properties may have been methodological artifacts rather than biological realities. Domazet-Loso and colleagues recently argued that our simulations were flawed and that phylostratigraphic bias does not impact inferences about gene emergence and evolution. Here we discuss conceptual difficulties of phylostratigraphy, identify numerous problems in Domazet-Loso et al.'s argument, reconfirm phylostratigraphic error using simulations suggested by Domazet-Loso and colleagues, and demonstrate that a phylostratigraphic trend claimed to be robust to error disappears when genes likely to be error-resistant are analyzed. We conclude that extreme caution is needed in interpreting phylostratigraphic results because of the inherent biases of the method and that reanalysis using genes exhibiting no error in realistic simulations may help reduce spurious findings. PMID- 28637264 TI - Impact of admission serum potassium on mortality in patients with chronic kidney disease and cardiovascular disease. AB - Background: Little is known about the effect of admission potassium (K) on risk of in-hospital mortality in chronic kidney disease (CKD) and cardiovascular disease (CVD) patients. Aim: The aim of this study was to assess the relationship between admission serum K and in-hospital mortality in all hospitalized patients stratified by CKD and/or CVD status. Design and Methods: All adult hospitalized patients who had admission serum K between years 2011 and 2013 were enrolled. Admission serum K was categorized into seven groups (<3.0, 3.0-3.5, 3.5-4.0, 4.0 4.5, 4.5-5.0, 5.0-5.5 and >=5.5 mEq/L). The odds ratio (OR) of in-hospital mortality by admission serum K, using K 4.0-4.5 mEq/L as the reference group, was obtained by logistic regression analysis. Results: 73,983 patients were studied. The lowest incidence of in-hospital mortality was associated with serum K within 4.0-4.5 mEq/L. A U-shaped curve emerged demonstrating higher in-hospital mortality associated with both serum K < 4.0 and >4.5 mEq/L. After adjusting for potential confounders, both serum K < 4.0 mEq/L and >5.0 mEq/L were associated with increased in-hospital mortality with ORs of 3.26 (95% CI 2.03-4.98), 2.40 (95% CI 1.89-3.04), 1.38 (95%CI 1.15-1.66), 1.89 (95% CI 1.49-2.38) and 3.62 (95%CI 2.73-4.76) when serum K were within <3.0, 3.0-3.5, 3.5-4.0, 5.0-5.5, and >=5.5 mEq/L, respectively. In CVD patients, the highest in-hospital mortality was associated with serum K < 3.0 mEq/L (OR 1.70, 95%CI 1.31-2.18). In CKD patients, the highest in-hospital mortality was associated with serum K >= 5.5 mEq/L (OR 3.26, 95%CI 2.14-4.90). Conclusion: Admission serum K < 4.0 mEq/L and >5.0 mEq/L were associated with increased in-hospital mortality. The mortality risk among patients with various admission potassium levels was affected by CKD and/or CVD status. PMID- 28637265 TI - Importance of Carbapenemase Production Detection in Carbapenem-Resistant Enterobacteriaceae: Looking Beyond Epidemiological Purposes. PMID- 28637266 TI - Family Caregivers of Older Adults, 1999-2015: Trends in Characteristics, Circumstances, and Role-Related Appraisal. AB - Purpose of Study: To assess trends in family caregiving between 1999 and 2015. Design and Methods: We construct nationally representative profiles of community dwelling older adults receiving help with self-care or indoor mobility and their "primary" family or unpaid caregiver using the 1999 and 2004 National Long Term Care Survey, 2011 and 2015 National Health and Aging Trends Study, and linked caregiver surveys. Trends are examined. Results: Older adults receiving help were incrementally younger, more racially diverse, and better educated in 2015. Primary caregivers overwhelmingly continued to be spouses and adult children. Arrangements were increasingly 4 years or longer in duration (shifting from 44.8% in 1999 to 60.5% by 2015). On average, primary caregivers provided about or in excess of 30 hr per week at all four time points. Spouses provided fewer hours of care, were twice as likely to work, and half as likely to report substantial emotional, physical, and financial difficulty due to caregiving in 2015 than 1999. Adult children provided comparable hours of care to a more impaired population; a similar proportion reported substantial caregiving-related difficulty at each time. Use of respite care nearly doubled from 8.5% in 1999 to 15.7% in 2015. Dementia caregivers were less likely to report substantial physical and financial difficulty and more likely to use respite care in 2015 than 1999. Implications: Family caregivers' circumstances generally improved during the 16-year period. Results diverge from prevailing concerns regarding the state of family caregiving and demonstrate the importance of longitudinally monitoring trends in late-life family caregiving. PMID- 28637267 TI - Global travel patterns: an overview. PMID- 28637268 TI - Predicting structured metadata from unstructured metadata. AB - Enormous amounts of biomedical data have been and are being produced by investigators all over the world. However, one crucial and limiting factor in data reuse is accurate, structured and complete description of the data or data about the data-defined as metadata. We propose a framework to predict structured metadata terms from unstructured metadata for improving quality and quantity of metadata, using the Gene Expression Omnibus (GEO) microarray database. Our framework consists of classifiers trained using term frequency-inverse document frequency (TF-IDF) features and a second approach based on topics modeled using a Latent Dirichlet Allocation model (LDA) to reduce the dimensionality of the unstructured data. Our results on the GEO database show that structured metadata terms can be the most accurately predicted using the TF-IDF approach followed by LDA both outperforming the majority vote baseline. While some accuracy is lost by the dimensionality reduction of LDA, the difference is small for elements with few possible values, and there is a large improvement over the majority classifier baseline. Overall this is a promising approach for metadata prediction that is likely to be applicable to other datasets and has implications for researchers interested in biomedical metadata curation and metadata prediction. PMID- 28637269 TI - Announcing the Genome Atlas of Bamboo and Rattan (GABR) project: promoting research in evolution and in economically and ecologically beneficial plants. AB - Bamboo and rattan are widely grown for manufacturing, horticulture, and agroforestry. Bamboo and rattan production might help reduce poverty, boost economic growth, mitigate climate change, and protect the natural environment. Despite progress in research, sufficient molecular and genomic resources to study these species are lacking. We launched the Genome Atlas of Bamboo and Rattan (GABR) project, a comprehensive, coordinated international effort to accelerate understanding of bamboo and rattan genetics through genome analysis. GABR includes 2 core subprojects: Bamboo-T1K (Transcriptomes of 1000 Bamboos) and Rattan-G5 (Genomes of 5 Rattans), and several other subprojects. Here we describe the organization, directions, and status of GABR. PMID- 28637270 TI - In Planta Recapitulation of Isoprene Synthase Evolution from Ocimene Synthases. AB - Isoprene is the most abundant biogenic volatile hydrocarbon compound naturally emitted by plants and plays a major role in atmospheric chemistry. It has been proposed that isoprene synthases (IspS) may readily evolve from other terpene synthases, but this hypothesis has not been experimentally investigated. We isolated and functionally validated in Arabidopsis the first isoprene synthase gene, AdoIspS, from a monocotyledonous species (Arundo donax L., Poaceae). Phylogenetic reconstruction indicates that AdoIspS and dicots isoprene synthases most likely originated by parallel evolution from TPS-b monoterpene synthases. Site-directed mutagenesis demonstrated invivo the functional and evolutionary relevance of the residues considered diagnostic for IspS function. One of these positions was identified by saturating mutagenesis as a major determinant of substrate specificity in AdoIspS able to cause invivo a dramatic change in total volatile emission from hemi- to monoterpenes and supporting evolution of isoprene synthases from ocimene synthases. The mechanism responsible for IspS neofunctionalization by active site size modulation by a single amino acid mutation demonstrated in this study might be general, as the very same amino acidic position is implicated in the parallel evolution of different short-chain terpene synthases from both angiosperms and gymnosperms. Based on these results, we present a model reconciling in a unified conceptual framework the apparently contrasting patterns previously observed for isoprene synthase evolution in plants. These results indicate that parallel evolution may be driven by relatively simple biophysical constraints, and illustrate the intimate molecular evolutionary links between the structural and functional bases of traits with global relevance. PMID- 28637271 TI - Logical Issues With the Pressure Natriuresis Theory of Chronic Hypertension. AB - The term "abnormal pressure natriuresis" refers to a subnormal effect of a given level of blood pressure (BP) on sodium excretion. It is widely believed that abnormal pressure natriuresis causes an initial increase in BP to be sustained. We refer to this view as the "pressure natriuresis theory of chronic hypertension." The proponents of the theory contend that all forms of chronic hypertension are sustained by abnormal pressure natriuresis, irrespective of how hypertension is initiated. This theory would appear to follow from "the three laws of long-term arterial pressure regulation" stated by Guyton and Coleman more than 3 decades ago. These "laws" articulate the concept that for a given level of salt intake, the relationship between arterial pressure and sodium excretion determines the chronic level of BP. Here, we review and examine the recent assertion by Beard that these "laws" of long-term BP control amount to nothing more than a series of tautologies. Our analysis supports Beard's assertion, and also indicates that contemporary investigators often use tautological reasoning in support of the pressure natriuresis theory of chronic hypertension. Although the theory itself is not a tautology, it does not appear to be testable because it holds that abnormal pressure natriuresis causes salt-induced hypertension to be sustained through abnormal increases in cardiac output that are too small to be detected. PMID- 28637272 TI - Illogical Critiques of the Pressure Natriuresis Theory of Chronic Hypertension. PMID- 28637273 TI - Gingival recession in mandibular incisors and symphysis morphology-a retrospective cohort study. AB - Objective: To evaluate if the morphology of the mandibular symphysis is associated with the development of gingival recession. Materials and methods: A cohort of 177 patients was followed longitudinally for up to 5 years post treatment. Based on the width of the symphysis, participants were divided into three groups: narrow (n = 57); average (n = 63), and wide symphysis (n = 57). Morphology of the symphysis and inclination of incisors were measured on lateral cephalometric radiographs before treatment (Ts), at the end of treatment (T0) and 5 years after treatment (T5). Gingival recession and the change of clinical crown heights in mandibular incisors were measured on plaster models made at TS, T0, and T5. Results: From TS to T5 the change in inclination was comparable in the narrow, average, and wide groups. At T5, gingival labial recession was present in 19.3 per cent of patients with narrow symphysis, 20.6 per cent with average symphysis, and 14 per cent of patients with wide symphysis. The difference was not significant. The mean change of clinical crown height was <1 mm (TS - T5). The regression model showed some evidence that incisor inclination at Ts might have been associated with the change of mean clinical crown height (-2.51, 95% CI: -4.6 to -0.4, P = 0.02). The logistic regression model demonstrated that H1 (Height 1) might be associated with the development of gingival recession (OR = 0.75, 95% CI: 0.58 to 0.96, P = 0.03). Conclusion: Within the limitations of this study, there is no evidence that the overall morphology of the mandibular symphysis is associated with gingival recession development. PMID- 28637274 TI - Association of Bariatric Surgery With Risk of Infectious Diseases: A Self Controlled Case Series Analysis. AB - Background: Although emerging data demonstrate that obesity is a risk factor for infectious diseases, no study has investigated the relationship of bariatric surgery with the risk of infectious diseases among obese adults. Methods: We conducted a self-controlled case series analysis using data from the State Emergency Department Database and State Inpatient Database of 3 US states (California, Florida, and Nebraska) from 2005 through 2011. We included obese adults who underwent bariatric surgery as an instrument of weight reduction. Primary outcomes were emergency department (ED) visit or hospitalization for skin and soft-tissue infection (SSTI), respiratory infection, intra-abdominal infection, or urinary tract infection (UTI). Results: Among 56277 obese adults who underwent bariatric surgery, compared to presurgery months 13-24 as the reference period, the risk of ED visit or hospitalization in the 0- to 12-month postsurgery period decreased significantly for SSTI (aOR, 0.85 [95% confidence interval {CI}, .76-.95]) and respiratory infection (aOR, 0.82 [95% CI, .75-.90]) and remained significantly low in the 13- to 24-month postsurgery period (aORs, 0.77 [95% CI, .68-.86] and 0.75 [95% CI, .68-.82], respectively). By contrast, the risk increased significantly in the 0- to 12-month postsurgery period for intra-abdominal infection (aOR, 2.09 [95% CI, 1.78-2.46]) and UTI (aOR, 1.93 [95% CI, 1.74-2.15]) and remained high in the 13- to 24-month postsurgery period (aORs, 1.29 [95% CI, 1.09-1.54] and 1.31 [95% CI, 1.17-1.47], respectively). Conclusions: We found a divergent risk pattern in the risk of 4 common infectious diseases after bariatric surgery. The risk of SSTI and respiratory infection decreased after bariatric surgery whereas that of intra-abdominal infection and UTI increased. PMID- 28637275 TI - 16GT: a fast and sensitive variant caller using a 16-genotype probabilistic model. AB - 16GT is a variant caller for Illumina whole-genome and whole-exome sequencing data. It uses a new 16-genotype probabilistic model to unify single nucleotide polymorphism and insertion and deletion calling in a single variant calling algorithm. In benchmark comparisons with 5 other widely used variant callers on a modern 36-core server, 16GT demonstrated improved sensitivity in calling single nucleotide polymorphisms, and it provided comparable sensitivity and accuracy for calling insertions and deletions as compared to the GATK HaplotypeCaller. 16GT is available at https://github.com/aquaskyline/16GT. PMID- 28637277 TI - Measuring CO2 and HCO3- permeabilities of isolated chloroplasts using a MIMS-18O approach. AB - To support photosynthetic CO2 fixation by Rubisco, the chloroplast must be fed with inorganic carbon in the form of CO2 or bicarbonate. However, the mechanisms allowing the rapid passage of this gas and this charged molecule through the bounding membranes of the chloroplast envelope are not yet completely elucidated. We describe here a method allowing us to measure the permeability of these two molecules through the chloroplast envelope using a membrane inlet mass spectrometer and 18O-labelled inorganic carbon. We established that the internal stromal carbonic anhydrase activity is not limiting for this technique, and precisely measured the chloroplast surface area and permeability values for CO2 and bicarbonate. This was performed on chloroplasts from several plant species, with values ranging from 2.3 * 10-4 m s-1 to 8 * 10-4 m s-1 permeability for CO2 and 1 * 10-8 m s-1 for bicarbonate. We were able to apply our method to chloroplasts from an Arabidopsis aquaporin mutant, and this showed that CO2 permeability was reduced 50% in the mutant compared with the wild-type reference. PMID- 28637276 TI - Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. AB - Significant transcriptome alterations are detected in the brain of patients with amyotrophic lateral sclerosis (ALS), including carriers of the C9orf72 repeat expansion and C9orf72-negative sporadic cases. Recently, the expression of repetitive element transcripts has been associated with toxicity and, while increased repetitive element expression has been observed in several neurodegenerative diseases, little is known about their contribution to ALS. To assess whether aberrant expression of repetitive element sequences are observed in ALS, we analysed RNA sequencing data from C9orf72-positive and sporadic ALS cases, as well as healthy controls. Transcripts from multiple classes and subclasses of repetitive elements (LINEs, endogenous retroviruses, DNA transposons, simple repeats, etc.) were significantly increased in the frontal cortex of C9orf72 ALS patients. A large collection of patient samples, representing both C9orf72 positive and negative ALS, ALS/FTLD, and FTLD cases, was used to validate the levels of several repetitive element transcripts. These analyses confirmed that repetitive element expression was significantly increased in C9orf72-positive compared to C9orf72-negative or control cases. While previous studies suggest an important link between TDP-43 and repetitive element biology, our data indicate that TDP-43 pathology alone is insufficient to account for the observed changes in repetitive elements in ALS/FTLD. Instead, we found that repetitive element expression positively correlated with RNA polymerase II activity in postmortem brain, and pharmacologic modulation of RNA polymerase II activity altered repetitive element expression in vitro. We conclude that increased RNA polymerase II activity in ALS/FTLD may lead to increased repetitive element transcript expression, a novel pathological feature of ALS/FTLD. PMID- 28637279 TI - High-dimensional multivariate mediation with application to neuroimaging data. AB - Mediation analysis is an important tool in the behavioral sciences for investigating the role of intermediate variables that lie in the path between a treatment and an outcome variable. The influence of the intermediate variable on the outcome is often explored using a linear structural equation model (LSEM), with model coefficients interpreted as possible effects. While there has been significant research on the topic, little work has been done when the intermediate variable (mediator) is a high-dimensional vector. In this work, we introduce a novel method for identifying potential mediators in this setting called the directions of mediation (DMs). DMs linearly combine potential mediators into a smaller number of orthogonal components, with components ranked based on the proportion of the LSEM likelihood each accounts for. This method is well suited for cases when many potential mediators are measured. Examples of high-dimensional potential mediators are brain images composed of hundreds of thousands of voxels, genetic variation measured at millions of single nucleotide polymorphisms (SNPs), or vectors of thousands of variables in large-scale epidemiological studies. We demonstrate the method using a functional magnetic resonance imaging study of thermal pain where we are interested in determining which brain locations mediate the relationship between the application of a thermal stimulus and self-reported pain. PMID- 28637280 TI - Editorial: Networking and collaboration: a stronghold of the yeast research community. PMID- 28637281 TI - Pulmonary sarcomatoid carcinoma-a new hope. PMID- 28637278 TI - Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast. AB - Trypanosoma brucei, the causative agent of sleeping sickness (Human African Trypanosomiasis, HAT), contains a kinetoplast with the mitochondrial DNA (kDNA), comprising of >70% AT base pairs. This has prompted studies of drugs interacting with AT-rich DNA, such as the N-phenylbenzamide bis(2-aminoimidazoline) derivatives 1 [4-((4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((4,5-dihydro-1H imidazol-2-yl)amino)phenyl)benzamide dihydrochloride] and 2 [N-(3-chloro-4-((4,5 dihydro-1H-imidazol-2-yl)amino)phenyl)-4-((4,5-dihydro-1H-imidazol-2 yl)amino)benzamide] as potential drugs for HAT. Both compounds show in vitro effects against T. brucei and in vivo curative activity in a mouse model of HAT. The main objective was to identify their cellular target inside the parasite. We were able to demonstrate that the compounds have a clear effect on the S-phase of T. brucei cell cycle by inflicting specific damage on the kinetoplast. Surface plasmon resonance (SPR)-biosensor experiments show that the drug can displace HMG box-containing proteins essential for kDNA function from their kDNA binding sites. The crystal structure of the complex of the oligonucleotide d[AAATTT]2 with compound 1 solved at 1.25 A (PDB-ID: 5LIT) shows that the drug covers the minor groove of DNA, displaces bound water and interacts with neighbouring DNA molecules as a cross-linking agent. We conclude that 1 and 2 are powerful trypanocides that act directly on the kinetoplast, a structure unique to the order Kinetoplastida. PMID- 28637282 TI - The effect of predisposing atheroembolic risk factors on renal functional recovery between laparoscopy and open technique in patients with T1-stage renal cell carcinoma who underwent partial nephrectomy: a retrospective comparison study. AB - Objective: The present study aimed to determine the effect of an increasing number of predisposing atheroembolic risk factors on the development of chronic kidney disease (CKD) after partial nephrectomy (PN) in patients with T1-stage renal cell carcinoma (RCC). Methods: The study included 147 patients with T1 stage RCC with a normal contralateral kidney and without preoperative CKD, who underwent open (OPN, N = 83, 56.5%) or laparoscopic PN (LPN, N = 64, 43.5%) between 2003 and 2014. Postoperative CKD was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2. The predictive factors for CKD between OPN and LPN were statistically assessed among various known clinicopathological factors associated with renal function in PN with a significance of two-sided P value <0.05. Results: During a median follow-up of 42 months, the recurrence rate was 0.7% (n = 1), and the rate of postoperative CKD was 11.6% (n = 17). Significant differences in CKD-free survival were observed among patients with atheroembolic risks 5-7, 3-4 and 1-2 (P = 0.027). Regarding the predictive factors for the postoperative development of CKD between OPN and LPN, a predisposing atheroembolic risk >=3 was significant among other clinicopathological factors in multivariate analysis (hazard ratio, 3.007, P = 0.031). Conclusion: Patients with T1-staged RCC with >=3 predisposing atheroembolic risk factors have a significantly higher risk of developing CKD after PN. Patients who underwent LPN had a lesser incidence of CKD development than patients who underwent OPN with >=3 predisposing atheroembolic risk factors. PMID- 28637284 TI - Descriptive texture analyses of cooked patties made of chicken breast with the woody breast condition. AB - The woody breast (WB) condition negatively influences the texture characteristics and quality of intact broiler breast fillets (Pectoralis major). But the impact of WB on ground meat is unknown. The objective of this study was to evaluate the effects of WB on the texture and cook loss of ground meat made of broiler breast fillets. Broiler breasts (deboned 3 h postmortem) were collected on 3 separate trial d from the commercial deboning line and classified into normal and severe WB fillet categories. Individual fillets were either ground and formed into patties or left intact prior to being stored for 7 d at -20 degrees C. Samples were then cooked directly from the frozen state to an endpoint temperature of 76 degrees C for cook loss, instrumental (patties: Allo-Kramer shear; fillets: Warner-Bratzler shear), and descriptive sensory analysis of texture. Cook loss was greater (P < 0.05) in intact WB fillets compared to that in intact normal fillets, but there was no difference (P > 0.05) between WB and normal patties. There was no difference (P > 0.05) in shear force between normal and WB samples regardless of meat type. Sensory analysis showed that average scores of springiness and hardness of intact WB fillets were greater than those of normal fillets (P < 0.05). However, there were no significant differences (P > 0.05) in average scores for sensory attributes cohesiveness, hardness, juiciness, fibrous, and rate of breakdown between WB and normal patties. WB patties exhibited lower springiness and chewiness scores (P < 0.05) than normal patties. Data suggest that undesirable differences in sensory texture characteristics between cooked intact WB and normal breast meat can be minimized in a ground product. PMID- 28637283 TI - An Essential Physiological Role for MCT8 in Bone in Male Mice. AB - T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance. PMID- 28637285 TI - A qualitative study of the impact of endometriosis on male partners. AB - STUDY QUESTION: What is the impact of endometriosis on male partners of women with the condition? SUMMARY ANSWER: Endometriosis significantly impacts men across several life domains and can negatively impact emotional well-being. WHAT IS KNOWN ALREADY: Endometriosis has been shown to negatively impact women's quality of life and may strain intimate relationships. Little is known about the impact on male partners. STUDY DESIGN, SIZE, DURATION: The ENDOPART study was a cross-sectional, qualitative study of 22 women with endometriosis and their male partners (n = 44) in the UK (2012-2013). PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria: laparoscopic diagnosis of endometriosis; the presence of symptoms for at least a year; partners living together. Data were collected via face to face, semi structured interviews with partners interviewed separately. Data were analysed thematically, assisted by NVivo 10. MAIN RESULTS AND THE ROLE OF CHANCE: Men reported that endometriosis affected many life domains including sex and intimacy, planning for and having children, working lives and household income. It also required them to take on additional support tasks and roles. Endometriosis also had an impact on men's emotions, with responses including helplessness, frustration, worry and anger. The absence of professional or wider societal recognition of the impact on male partners, and a lack of support available to men, results in male partners having a marginalized status in endometriosis care. LIMITATIONS REASONS FOR CAUTION: Self-selection of participants may have resulted in a sample representing those with more severe symptoms. Couples included are in effect 'survivors' in relationship terms, therefore, findings may underestimate the contribution of endometriosis to relationship breakdown. WIDER IMPLICATIONS OF THE FINDINGS: The study extends knowledge about the impact of endometriosis on relationships, which thus far has been drawn largely from studies with women, by providing new insights about how this condition affects male partners. Healthcare practitioners need to take a more couple-centred, biopsychosocial approach toward the treatment of endometriosis, inclusive of partners and relationship issues. The findings demonstrate a need for information and support resources aimed at partners and couples. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Economic and Social Research Council (reference ES/J003662/1). The authors have no conflicts of interest. PMID- 28637288 TI - Validation of a risk assessment instrument for pulmonary arterial hypertension. PMID- 28637286 TI - Structure-seq2: sensitive and accurate genome-wide profiling of RNA structure in vivo. AB - RNA serves many functions in biology such as splicing, temperature sensing, and innate immunity. These functions are often determined by the structure of RNA. There is thus a pressing need to understand RNA structure and how it changes during diverse biological processes both in vivo and genome-wide. Here, we present Structure-seq2, which provides nucleotide-resolution RNA structural information in vivo and genome-wide. This optimized version of our original Structure-seq method increases sensitivity by at least 4-fold and improves data quality by minimizing formation of a deleterious by-product, reducing ligation bias, and improving read coverage. We also present a variation of Structure-seq2 in which a biotinylated nucleotide is incorporated during reverse transcription, which greatly facilitates the protocol by eliminating two PAGE purification steps. We benchmark Structure-seq2 on both mRNA and rRNA structure in rice (Oryza sativa). We demonstrate that Structure-seq2 can lead to new biological insights. Our Structure-seq2 datasets uncover hidden breaks in chloroplast rRNA and identify a previously unreported N1-methyladenosine (m1A) in a nuclear-encoded Oryza sativa rRNA. Overall, Structure-seq2 is a rapid, sensitive, and unbiased method to probe RNA in vivo and genome-wide that facilitates new insights into RNA biology. PMID- 28637287 TI - Pooled analysis of two randomized, double-blind trials comparing proposed biosimilar LA-EP2006 with reference pegfilgrastim in breast cancer. AB - Background: Following the functional and physicochemical characterization of a proposed biosimilar, comparative clinical studies help to confirm biosimilarity by demonstrating similar safety and efficacy to the reference product in a sensitive patient population. Patients and methods: LA-EP2006 is a proposed biosimilar that has been developed for pegfilgrastim, a long-acting form of granulocyte colony-stimulating factor for the prevention of neutropenia. The current analysis reports data pooled from two independent, multinational, prospective, randomized, controlled, double-blind phase III studies of similar design comparing the safety and efficacy of reference pegfilgrastim with LA EP2006 in patients with breast cancer receiving myelotoxic (neo)adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy and requiring granulocyte colony-stimulating factor. Results: A total of 624 patients were randomized in the PROTECT-1 and PROTECT-2 studies (NCT01735175; NCT01516736) (LA EP2006: n = 314; reference: n = 310). Baseline characteristics of patients were well balanced across treatment groups. The primary end point, mean duration of severe neutropenia in the first chemotherapy cycle was similar in both the LA EP2006 and reference groups (1.05 +/- 1.055 days versus 1.01 +/- 0.958 days), with a treatment difference of - 0.04 days [95% confidence interval (CI): -0.19 to 0.11] that met the equivalence criteria (the 95% CI were within the defined margin of +/-1 day). Secondary end points, such as the nadir of absolute neutrophil count and the incidence of febrile neutropenia, were also similar between LA-EP2006 and reference pegfilgrastim. The safety and tolerability profile of LA-EP2006 was similar to that observed with reference pegfilgrastim, and there were no reports of neutralizing antibodies. Conclusions: This pooled analysis confirms, as a part of totality of evidence approach, that the proposed biosimilar pegfilgrastim LA-EP2006 has a comparable efficacy and safety profile to reference pegfilgrastim in patients with breast cancer receiving TAC chemotherapy. Clinical trial numbers: NCT01735175 and NCT01516736. PMID- 28637289 TI - The Importance of Knowing When You Don't Remember: Neural Signaling of Retrieval Failure Predicts Memory Improvement Over Time. AB - Just as the ability to remember prior events is critical for guiding our decision making, so too is the ability to recognize the limitations of our memory. Indeed, we hypothesize that neural signaling of retrieval failure promotes more accurate memory judgments over time. To test this hypothesis, we collected longitudinal functional magnetic resonance imaging data from 8 to 9 years olds, 10 to 12 years olds, and adults, with two time points spaced approximately 1.4 years apart (198 scan sessions in total). Participants performed an episodic memory retrieval task in which they could either select a response or report uncertainty about the target memory detail. Children who engaged anterior insula more strongly during inaccurate or uncertain responses exhibited greater longitudinal increases in anterior prefrontal cortex activation for decisions to report uncertainty; both of these neural variables predicted improvements in episodic memory. Together, the results suggest that the brain processes supporting effective cognitive control and decision-making continue to develop in middle childhood and play an important role for memory development. PMID- 28637290 TI - A Bright Side to the Work-Family Interface: Husbands' Support as a Resource in Double-and-Triple-Duty Caregiving Wives' Work Lives. AB - Purpose of the Study: This study examined how women who combine long-term care employment with unpaid, informal caregiving roles for children (double-duty-child caregivers), older adults (double-duty-elder caregivers), and both children and older adults (triple-duty caregivers) differed from their workplace-only caregiving counterparts on workplace factors related to job retention (i.e., job satisfaction and turnover intentions) and performance (i.e., perceived obligation to work while sick and emotional exhaustion). The moderating effects of perceived spouse support were also examined. Design and Methods: Regression analyses were conducted on survey data from 546 married, heterosexual women employed in U.S. based nursing homes. Results: Compared to workplace-only caregivers, double-duty elder and triple-duty caregivers reported more emotional exhaustion. Double-duty child caregivers reported lower turnover intentions and both double-and-triple duty caregivers felt less obligated to work while sick when perceiving greater support from husbands. Implications: Results indicate that double-and-triple-duty caregiving women's job retention and obligation to work while sick may depend on perceived spouse support, highlighting the important role husbands play in their wives' professional lives. Findings also lend support to the emerging literature on marriage-to-work positive spillover, and suggest that long-term care organizations should target marital relationships in family-friendly initiatives to retain and engage double-and-triple-duty caregiving employees. PMID- 28637291 TI - Pediatric to Adult Care Transition: Perspectives of Young Adults With Sickle Cell Disease. AB - Objectives: The aim of this study was to explore perspectives of transition and transition readiness of young adult patients (YAs) with sickle cell disease (SCD) who have transitioned to adult health care. Methods: In all, 19 YAs with SCD (ages 18-30 years) participated in one of three focus groups and completed a brief questionnaire about transition topics. Transcripts were coded and emergent themes were examined using the social-ecological model of adolescent and young adult readiness for transition (SMART). Results: Themes were consistent with most SMART components. Adult provider relationships and negative medical experiences emerged as salient factors. YAs ranked choosing an adult provider, seeking emergency care, understanding medications/medication adherence, knowing SCD complications, and being aware of the impact of health behaviors as the most important topics to include in transition programming. Conclusions: The unique perspectives of YAs can inform the development and evaluation of SCD transition programming by incorporating the identified themes. PMID- 28637292 TI - Ten-year real-life effectiveness of coronary artery bypass using radial artery or great saphenous vein grafts in a single centre Chinese hospital. AB - OBJECTIVES: Long-term effectiveness of coronary artery bypass grafting using radial artery (RA) or great saphenous vein (SVG) grafts as a second conduit was compared. METHODS: Patients received simple elective off-pump coronary artery bypass involving both the left internal thoracic artery (LITA) and the left anterior descending artery between January 1999 and December 2005 at Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China. RA graft patients (n = 147 LITA + RA and n = 61 LITA + RA + SVG) were matched with SVG graft patients (n = 208 LITA + SVG). Mean follow-up was 86.5 months. RESULTS: Baseline characteristics were comparable before and after surgery. Intraoperative hospital mortality was not significantly different. In all, 378 (90.9%) patients completed postoperative follow-up (197 in the RA and 181 in SVG). Overall survival was significantly better in the RA group (Log-rank, P = 0.017) with 88% 10-year survival in the RA group and 81% in the SVG group. All-cause mortality was significantly lower in the RA group (hazard ratio 0.42, 95% confidence interval 0.20-0.88, P = 0.020). Major adverse cardiovascular event-free survival was significantly better in the RA group than in the SVG group (Log-rank, P = 0.019). No significant difference in the length of postoperative angina relief was found. CONCLUSIONS: Using the RA as the secondary graft for coronary artery bypass grafting improved long-term postoperative survival and reduced the incidence of postoperative major adverse cardiovascular events. PMID- 28637294 TI - Over-Time Impacts of Pictorial Health Warning Labels and their Differences across Smoker Subgroups: Results from Adult Smokers in Canada and Australia. AB - Introduction: This study examines patterns of change in different smoker subgroups' responses to new pictorial health warning labels (HWLs) over the initial, two year post-implementation period in Canada, where HWLs include package inserts with cessation messages, and Australia, where "plain" packaging (i.e., prohibition of brand imagery) was also implemented. Methods: Data were collected from online consumer panels in Canada (nsmokers = 3153; nobservations = 5826) and Australia (nsmokers = 2699; nobservations = 5818) from September 2012 to September 2014, with approximately 1000 adult smokers surveyed in each country every four months, using replenishment to maintain sample size. Data were analyzed using generalized estimating equation models where main effects and interactions among time, country, and socio-demographic factors on HWL responses (i.e., attention to HWLs; cognitive and behavioral responses to HWLs) were examined. Results: Over time, attention to HWLs declined but cognitive and forgoing responses to HWLs increased, in both Canada and Australia. In both countries, compared to smokers with low income and/or education, smokers with high income and/or education showed an increase over time in attention and cognitive responses to HWLs (p < .05). In Australia only, compared to older smokers, younger smokers showed less decline over time in attention and greater increase in cognitive and forgoing responses to HWLs (p < .001). Conclusions: Novel HWL policies in Canada and Australia appear effective in staving off "wear out" over the first 2 years after implementation, particularly amongst smokers who are from higher SES groups and, in Australia, who are younger. Implications: Previous research shows that the effects of health warning label (HWL) on smokers decline over time, but no studies to date have evaluated whether trends differ across socio-demographic groups. This study suggests that innovative policy configurations that combine prominent pictorial HWLs with inserts (Canada) and with "plain" packaging (Australia) may delay wear out over the first 2 years after implementation. While this study found evidence for wear out in attention to HWLs, other HWL responses (cognitive responses, forgoing cigarettes) actually increased over time, with greater increases amongst smokers with higher income and/or education. PMID- 28637293 TI - Conserved Nonexonic Elements: A Novel Class of Marker for Phylogenomics. AB - Noncoding markers have a particular appeal as tools for phylogenomic analysis because, at least in vertebrates, they appear less subject to strong variation in GC content among lineages. Thus far, ultraconserved elements (UCEs) and introns have been the most widely used noncoding markers. Here we analyze and study the evolutionary properties of a new type of noncoding marker, conserved nonexonic elements (CNEEs), which consists of noncoding elements that are estimated to evolve slower than the neutral rate across a set of species. Although they often include UCEs, CNEEs are distinct from UCEs because they are not ultraconserved, and, most importantly, the core region alone is analyzed, rather than both the core and its flanking regions. Using a data set of 16 birds plus an alligator outgroup, and ~3600-~3800 loci per marker type, we found that although CNEEs were less variable than bioinformatically derived UCEs or introns and in some cases exhibited a slower approach to branch resolution as determined by phylogenomic subsampling, the quality of CNEE alignments was superior to those of the other markers, with fewer gaps and missing species. Phylogenetic resolution using coalescent approaches was comparable among the three marker types, with most nodes being fully and congruently resolved. Comparison of phylogenetic results across the three marker types indicated that one branch, the sister group to the passerine + falcon clade, was resolved differently and with moderate (>70%) bootstrap support between CNEEs and UCEs or introns. Overall, CNEEs appear to be promising as phylogenomic markers, yielding phylogenetic resolution as high as for UCEs and introns but with fewer gaps, less ambiguity in alignments and with patterns of nucleotide substitution more consistent with the assumptions of commonly used methods of phylogenetic analysis. PMID- 28637295 TI - Inhibition of polyamine synthesis causes entry of the mouse blastocyst into embryonic diapause. AB - Embryonic diapause is a common reproductive strategy amongst mammals, requiring an intimate cross-talk between the endometrium and the blastocyst. To date, the precise molecular signals responsible are unknown in the mouse or any other mammal. Previous studies in the mink implicate polyamines as major regulators of the control of diapause. In the mouse, inhibiting the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC1) during early pregnancy largely prevents implantation, but the fate of the nonimplanted embryos is unknown. To determine whether polyamines control mouse embryonic diapause, we treated pregnant mice with an ODC1 inhibitor from d3.5 to d6.5 postcoitum. At d7.5, 72% of females had no signs of implantation whilst the remaining females exhibited disrupted placental formation and degenerate embryos. In the females with no implantation, we obtained viable blastocysts that had attenuated cell proliferation, indicating a state of diapause. When cultured in vitro, these exhibited trophoblast outgrowth, indicative of reactivation of embryogenesis. In contrast, direct culture of d3.5 blastocysts with an ODC1 inhibitor failed to cause entry into diapause. Examination of the polyamine pathway enzymes and a number of implantation factors indicated inhibition of ODC1 resulted in a uterine phenotype that resembled diapause, with some compensatory increases in crucial genes. Thus, we conclude that an absence or paucity of polyamines induces the uterine quiescence that causes entry of the blastocyst into embryonic diapause. PMID- 28637296 TI - omiXcore: a web server for prediction of protein interactions with large RNA. AB - Summary: Here we introduce omiXcore, a server for calculations of protein binding to large RNAs (> 500 nucleotides). Our webserver allows (i) use of both protein and RNA sequences without size restriction, (ii) pre-compiled library for exploration of human long intergenic RNAs interactions and (iii) prediction of binding sites. Results: omiXcore was trained and tested on enhanced UV Cross Linking and ImmunoPrecipitation data. The method discriminates interacting and non-interacting protein-RNA pairs and identifies RNA binding sites with Areas under the ROC curve > 0.80, which suggests that the tool is particularly useful to prioritize candidates for further experimental validation. Availability and implementation: omiXcore is freely accessed on the web at http://service.tartaglialab.com/grant_submission/omixcore. Contact: gian.tartaglia@crg.es. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28637298 TI - Presyncopal episodes after implantation of dual-chamber pacemaker programmed in SafeR pacing mode. PMID- 28637299 TI - Serological investigation of Mycoplasma synoviae infection in China from 2010 to 2015. AB - Mycoplasma synoviae can cause worldwide respiratory diseases, synovitis, or subclinical symptoms in poultry. M. synoviae infection occurs throughout the yr and causes significant economic losses, including increased mortality, condemnations, medication, and live production cost. In the present study, the seroprevalence of M. synoviae among 44,395 non-vaccinated chickens from 21 provinces in China from 2010 to 2015 was estimated using ELISA. The overall seroprevalence was 41.19%. Seropositive rates in different yr ranged between 24.70 and 57.20%; the highest seropositive rate was observed in 2010, and the lowest was observed in 2013. The prevalence rates varied greatly in different provinces from 5.10 to 100%. Of the 463 commercial flocks tested, 375 (80.99%) were positive for M. synoviae by ELISA. The seasonal distribution ranged between 26.83% (in October) and 53.98% (in July). An investigation of chickens according to age further showed that M. synoviae can infect chickens at any age. Our findings indicate that M. synoviae infection is very common in China and should prompt further research into its prevalence to develop effective control and prevention strategies. PMID- 28637297 TI - A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas. AB - Context: Despite progesterone's key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood. Objective: The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas. Design: Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro. Methods: Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein-protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines. Results: Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma. Conclusions: Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone's ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis. PMID- 28637302 TI - RE: "RISK PREDICTION FOR EPITHELIAL OVARIAN CANCER IN 11 UNITED STATES-BASED CASE CONTROL STUDIES: INCORPORATION OF EPIDEMIOLOGIC RISK FACTORS AND 17 CONFIRMED GENETIC LOCI". PMID- 28637301 TI - EDEN: evolutionary dynamics within environments. AB - Summary: Metagenomics revolutionized the field of microbial ecology, giving access to Gb-sized datasets of microbial communities under natural conditions. This enables fine-grained analyses of the functions of community members, studies of their association with phenotypes and environments, as well as of their microevolution and adaptation to changing environmental conditions. However, phylogenetic methods for studying adaptation and evolutionary dynamics are not able to cope with big data. EDEN is the first software for the rapid detection of protein families and regions under positive selection, as well as their associated biological processes, from meta- and pangenome data. It provides an interactive result visualization for detailed comparative analyses. Availability and implementation: EDEN is available as a Docker installation under the GPL 3.0 license, allowing its use on common operating systems, at http://www.github.com/hzi-bifo/eden. Contact: alice.mchardy@helmholtz-hzi.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28637300 TI - Commercial rodent diets differentially regulate autoimmune glomerulonephritis, epigenetics and microbiota in MRL/lpr mice. AB - The course and severity of lupus in spontaneous murine lupus models varies among laboratories, which may be due to variations in diet, housing and/or local environmental conditions. In this study, we investigated the influence of common rodent diets while keeping other factors constant. Female lupus-prone MRL/lpr (MRL/MpJ-Faslpr/J) mice were subjected to the same housing conditions and given one of the three diets: Teklad 7013 containing isoflavone-rich soy and alfalfa, Harlan 2018 isoflavone-rich soy-based diet or Research Diets Inc. D11112226 (RD) purified-ingredients diet containing casein and no phytoestrogens. While the total caloric intake was similar among all three treatment groups, mice fed on the 2018 diet developed higher levels of proteinuria and mice fed on either 7013 or 2018 developed higher levels of glomerular immune complex deposition. Remarkably, mice fed the RD diet had markedly decreased proteinuria with diminished C3, total IgG, IgG1 and IgG3 immune complex deposition, along with reduced CD11b+ cellular infiltration into the glomeruli. The type of diet intake also influenced cytokine production, fecal microbiota (increased Lachnospiraceae in mice fed on 2018), altered microRNAs (miRNAs; higher levels of lupus associated miR-148a and miR-183 in mice fed on 7013 and/or 2018) and altered DNA methylation. This is the first study to comprehensively compare the cellular, molecular and epigenetic effects of these commercial diets in murine lupus. PMID- 28637303 TI - Management of Acute Unilateral Nondisplaced Subaxial Cervical Facet Fractures. AB - BACKGROUND: Few studies have focused on the management of patients with nondisplaced cervical facet fractures. OBJECTIVE: To determine the rate of successful nonoperative management and risk factors for instability in patients with acute traumatic, unilateral, nondisplaced cervical facet fractures. METHODS: We reviewed patients with single or multilevel unilateral nondisplaced or minimally displaced subaxial cervical facet fractures between 2008 and 2014. Facet fractures were classified as type A1 fractures: superior facet fracture of caudal vertebra; type A2: inferior facet fracture of rostral vertebral; and type A3: floating lateral mass (fracture of pedicle and vertical laminar fracture). All patients were given a trial of nonoperative management with external immobilization using a hard cervical collar. Follow-up clinical data and cervical spine radiographs were analyzed to determine factors associated with instability. RESULTS: Thirty-five patients (34 males, mean age 40.2 +/- 2.4 yr) were reviewed. The mean follow-up duration was 2.7 +/- 0.4 mo. The distribution of fracture types was type A1 (n = 15), type A2 (n = 4), type A3 (n = 5), type A1 and A2 fractures (n = 10), and type A1 and A3 fractures (n = 1). Nonoperative management was successful in 29 patients (82.9%), and 6 patients developed instability requiring surgery. All patients who failed nonoperative management had associated injuries suggesting a more severe mechanism of injury. No significant association was found between the type of facet fracture and outcome (Fisher's exact test, P = .18). CONCLUSION: In our series, more than 80% of the patients with unilateral, nondisplaced cervical facet fractures underwent successful nonoperative management in the short term. PMID- 28637304 TI - Effects of alternative electron acceptors on the activity and community structure of methane-producing and consuming microbes in the sediments of two shallow boreal lakes. AB - The role of anaerobic CH4 oxidation in controlling lake sediment CH4 emissions remains unclear. Therefore, we tested how relevant EAs (SO42-, NO3-, Fe3+, Mn4+, O2) affect CH4 production and oxidation in the sediments of two shallow boreal lakes. The changes induced to microbial communities by the addition of Fe3+ and Mn4+ were studied using next-generation sequencing targeting the 16S rRNA and methyl-coenzyme M reductase (mcrA) genes and mcrA transcripts. Putative anaerobic CH4-oxidizing archaea (ANME-2D) and bacteria (NC 10) were scarce (up to 3.4% and 0.5% of archaeal and bacterial 16S rRNA genes, respectively), likely due to the low environmental stability associated with shallow depths. Consequently, the potential anaerobic CH4 oxidation (0-2.1 nmol g-1dry weight (DW)d-1) was not enhanced by the addition of EAs, nor important in consuming the produced CH4 (0.6 82.5 nmol g-1DWd-1). Instead, the increased EA availability suppressed CH4 production via the outcompetition of methanogens by anaerobically respiring bacteria and via the increased protection of organic matter from microbial degradation induced by Fe3+ and Mn4+. Future studies could particularly assess whether anaerobic CH4 oxidation has any ecological relevance in reducing CH4 emissions from the numerous CH4-emitting shallow lakes in boreal and tundra landscapes. PMID- 28637306 TI - Introduction of a much needed physical function-focused medication review tool. PMID- 28637305 TI - Left atrial structure and function in cardiac amyloidosis. AB - Aims: Although cardiac amyloidosis (CA) is characterized by significant left atrial (LA) dilatation, the characteristics of LA function remain to be fully investigated. Methods and results: We assessed LA function by speckle-tracking echocardiography in 124 patients with CA and sinus rhythm: 68 with light chain (AL), 29 with mutant (ATTRm), 27 with wild-type (ATTRwt) transthyretin amyloidosis. Conventional and strain-derived parameters, including LA peak longitudinal strain (LS) and strain rate (peak LSR: reservoir function; early LSR: conduit function; late LSR: active function), were assessed compared between CA patients and 20 healthy controls of similar age and gender. All LA function phases, including LA longitudinal strain, peak LSR, early and late LSR were significantly impaired in CA compared to healthy controls after adjusting for LA size, LV ejection fraction and LV filling pressures (E/E') (all P < 0.05). Peak LA LS was moderately correlated with LV global LS (R = -0.60, P < 0.001); late LSR was correlated with A wave at the level of LV inflow (R = -0.69, P < 0.001). Among the different CA subtypes, peak LS and LA active emptying fraction were worse in ATTRwt than AL and ATTRm [P < 0.05 after adjustment for age, sex, body mass index, systolic blood pressure, heart rate, LA volume index, severity of mitral regurgitation, left ejection fraction, and left ventricular end-diastolic pressure (E/E')]. Conclusion: In CA, LA function was severely impaired and highly correlated with LV deformation. Differences in LA function between amyloid subtypes suggest that amyloid aetiology plays a role in the pathophysiology of cardiac dysfunction in CA. PMID- 28637307 TI - Sparing carbapenem usage. AB - Background: Carbapenem resistance in Gram-negative bacteria is increasing in many countries and use of carbapenems and antibiotics to which resistance is linked should be reduced to slow its emergence. There are no directly equivalent antibiotics and the alternatives are less well supported by clinical trials. The few new agents are expensive. Objectives: To provide guidance on strategies to reduce carbapenem usage. Methods: A literature review was performed as described in the BSAC/HIS/BIA/IPS Joint Working Party on Multiresistant Gram-negative Infection Report. Results: Older agents remain active against some of the pathogens, although expectations of broad-spectrum cover for empirical treatment have risen. Education, expert advice on treatment and antimicrobial stewardship can produce significant reductions in use. Conclusions: More agents may need to be introduced onto the antibiotic formulary of the hospital, despite the poor quality of scientific studies in some cases. PMID- 28637308 TI - Three-dimensional right-ventricular regional deformation and survival in pulmonary hypertension. AB - Aims: Survival in pulmonary hypertension (PH) relates to right ventricular (RV) function. However, the RV unique anatomy and structure limit 2D analysis and its regional 3D function has not been studied yet. The aim of this study was to assess the implications of global and regional 3D RV deformation on clinical condition and survival in adults with PH and healthy controls. Methods and results: We collected a prospective longitudinal cohort of 104 consecutive PH patients and 34 healthy controls between September 2014 and December 2015. Acquired 3D transthoracic RV echocardiographic sequences were analysed by semi automatic software (TomTec 4D RV-Function 2.0). Output meshes were post-processed to extract regional motion and deformation. Global and regional statistics provided deformation patterns for each subgroup of subjects. RV lateral and inferior regions showed the highest deformation. In PH patients, RV global and regional motion and deformation [both circumferential, longitudinal, and area strain (AS)] were affected in all segments (P < 0.001 against healthy controls). Deformation patterns gradually worsened with the clinical condition. Over 6.7 [5.8-7.2] months follow-up, 16 (15.4%) patients died from cardio-pulmonary causes. Right atrial pressure, global RV AS, tricuspid annular plane systolic excursion, 3D RV ejection fraction, and end-diastolic volume were independent predictors of survival. Global RV AS > -18% was the most powerful RV function parameter, identifying patients with a 48%-increased risk of death (AUC 0.83 [0.74-0.90], P < 0.001). Conclusion: Right ventricular strain patterns gradually worsen in PH patients and provide independent prognostic information in this population. PMID- 28637309 TI - Anterior Cervical Pseudarthrosis Treated with Bilateral Posterior Cervical Cages. AB - BACKGROUND: Pseudarthrosis after anterior cervical discectomy and fusion (ACDF) causes persistent pain and related disability. Posterior revision surgery results in higher healing rates, but is more extensive compared to anterior surgery. OBJECTIVE: To evaluate minimally disruptive, tissue sparing posterior fusion via bilateral placement of posterior cages between the facet joints as an alternative treatment option. METHODS: A retrospective, multicenter, medical chart review was performed and included 25 patients with symptomatic pseudarthrosis after ACDF treated with posterior cervical cages, and in select cases, anterior revision. Visual analog scale (VAS) for neck and arm pain, Neck Disability Index (NDI), and perioperative metrics were collected. Fusion at 1 yr was determined via assessment of computed tomography (CT) scan and x-rays. RESULTS: Mean follow-up was 18 mo. VAS neck and arm scores at last follow-up improved significantly from 7.9 +/- 1.5 to 3.8 +/- 2.3 and 7.24 +/- 2.2 to 3.12 +/- 2.5, respectively. NDI scores decreased from 65.1 +/- 20.3 to 29.1 +/- 17.9 at 18 mo. Fusion at 1 yr was confirmed by CT in all 17 patients with available scans and by x-ray in all 25 patients. CONCLUSION: Revision of cervical pseudarthrosis after ACDF using a tissue sparing posterior approach to place cages bilaterally between the facet joints is an effective surgical strategy in select cases. Along with positive clinical and radiological outcomes, the procedure is associated with less blood loss, shorter operating times, and briefer hospital stays compared to revision with lateral mass fixation or interspinous wiring. PMID- 28637311 TI - Whole Woman's Health v. Hellerstedt: The Empirical Case Against Trap Laws. AB - This commentary examines the US Supreme Court case Whole Woman's Health v Hellerstedt.1 This comment synthesizes the case, focusing primarily on its legislative and appellate history as well as the Supreme Court's analysis. The comment finds that while Whole Woman's Health represented a judicial victory for those who seek to safeguard and preserve abortion rights, it nevertheless further rooted the primacy of the Supreme Court's flawed framework in Planned Parenthood v Casey2, which rests on perpetuating the notion of abortion as a threat against women's physical and mental health. PMID- 28637310 TI - The metagenomic data life-cycle: standards and best practices. AB - Metagenomics data analyses from independent studies can only be compared if the analysis workflows are described in a harmonized way. In this overview, we have mapped the landscape of data standards available for the description of essential steps in metagenomics: (i) material sampling, (ii) material sequencing, (iii) data analysis, and (iv) data archiving and publishing. Taking examples from marine research, we summarize essential variables used to describe material sampling processes and sequencing procedures in a metagenomics experiment. These aspects of metagenomics dataset generation have been to some extent addressed by the scientific community, but greater awareness and adoption is still needed. We emphasize the lack of standards relating to reporting how metagenomics datasets are analysed and how the metagenomics data analysis outputs should be archived and published. We propose best practice as a foundation for a community standard to enable reproducibility and better sharing of metagenomics datasets, leading ultimately to greater metagenomics data reuse and repurposing. PMID- 28637312 TI - The Provision of Healthcare to Young and Dependent Children: The Principles, Concepts, and Utility of the Children Act 1989. AB - This article undertakes a thorough analysis of the case law concerned with the provision of healthcare to young and dependent children. It demonstrates how, despite the procedural changes introduced by the Children Act 1989 at an early stage in this body of case law, cases have continued to be brought to court by way of applications for the court to exercise its inherent jurisdiction or in wardship rather than using the orders introduced by the Act. In determining these cases, the court is focused upon its protective duty to the vulnerable but proceedings appear to be adversarial contests between the claims of adults to know what is best for the child in which the medical view normally prevails. Through consideration of the principles and concepts of the Children Act of parental responsibility, working together, the welfare principle and placing the child at the centre of care, this article demonstrates their utility, as yet to be fully realised, in relation to the responsibilities of parents, professionals, public authorities, and the courts concerned with the provision of healthcare to young and dependent children. PMID- 28637314 TI - DNA methylation signatures and coagulation factors in the peripheral blood leucocytes of epithelial ovarian cancer. AB - Solid tumors are increasingly recognized as a systemic disease that is manifested by changes in DNA, RNA, proteins and metabolites in the blood. Whereas many studies have reported gene mutation events in the circulation, few studies have focused on epigenetic DNA methylation markers. To identify DNA methylation biomarkers in peripheral blood for ovarian cancer, we performed a two-stage epigenome-wide association study. In the discovery stage, we measured genome wide DNA methylation for 485 000 CpG sites in peripheral blood in 24 epithelial ovarian cancer (EOC) cases and 24 age-matched healthy controls. We selected 96 significantly differentially methylated CpG sites for validation using Illumina's Custom VeraCode methylation assay in 206 EOC cases and 205 controls and 46 CpG sites validated in the independent replication samples. A set of 6 of these 46 CpG sites was found by the receiver operating characteristic analysis to have a prediction accuracy of 77.3% for all EOC (95% confidence interval: 72.9-81.8%). Pathway analysis of the genes associated with the 46 CpG sites revealed an enrichment of immune system process genes, including LYST (cg16962115, FDR = 1.24E-04), CADM1 (cg21933078, FDR = 1.22E-02) and NFATC1 (cg06784563, FDR = 1.46E 02). Furthermore, DNA methylation status in peripheral blood was correlated with platelet parameters/coagulation factor levels. This study discovered a panel of epigenetic liquid biopsy markers closely associated with overall immunologic conditions and platelet parameters/coagulation systems of the patients for detection of all stages and subtypes of EOC. PMID- 28637313 TI - Trajectories of Alcohol Use Disorders and Their Differential Impact: A Population Based Cohort Study in Goa, India. AB - Aims: The aim of this study was to examine trajectories of Alcohol Use Disorders (AUD) over a 6 year period and compare the bio-psycho-social correlates between these trajectories. Methods: Community-based cohort of 1899 adult men were interviewed in 2006-2008 and 2012-2014. AUD were assessed using the Alcohol Use Disorder Identification Test, and potential correlates including psycho-social problems, morbidity and physiological parameters were measured at follow-up. Logistic regression was conducted to estimate odds ratios (ORs) for the association of persistent and incident AUD, respectively, with the potential correlates. Analyses were weighted to account for sampling design, number of adults aged 18-49 years in the household and non-response. Results: Compared with men who had recovered from AUD, there was strong evidence (P < 0.001) that men with persistent AUD were more likely to have marital problems, tobacco use, and raised Gamma Glutamyl Transferase (GGT) and strong evidence (0.001 < P < 0.01) that they were more likely to have workplace problems, social problems, increased healthcare contact and raised Mean Corpuscular Volume (MCV). Compared with men who did not have AUD at baseline and follow-up, there was strong evidence (P < 0.001) that men with incident AUD were more likely to have workplace problems, social problems, marital problems, tobacco use, and raised GGT and strong evidence (0.001 < P < 0.01) that they were more likely to have hypertension, accident and injuries and Common Mental Disorders (CMD). Conclusion: This community-based longitudinal study of AUD, the first from a low and middle income country, clearly demonstrates significant health and social consequences of AUD in men and highlights the need for interventions for their treatment and prevention. Short Summary: Compared to persistent AUD, recovery from AUD has several benefits in health and social domains. Compared to developing new AUD, not having AUD has several benefits in health and social domains. Sustaining the state of not having AUD or recovery can lead to accumulation of health and social capital over time. PMID- 28637316 TI - Incorporating comparative genomics into the design-test-learn cycle of microbial strain engineering. AB - Engineering microbes with new properties is an important goal in industrial engineering, to establish biological factories for production of biofuels, commodity chemicals and pharmaceutics. But engineering microbes to produce new compounds with high yield remains a major challenge toward economically viable production. Incorporating several modern approaches, including synthetic and systems biology, metabolic modeling and regulatory rewiring, has proven to significantly advance industrial strain engineering. This review highlights how comparative genomics can also facilitate strain engineering, by identifying novel genes and pathways, regulatory mechanisms and genetic background effects for engineering. We discuss how incorporating comparative genomics into the design test-learn cycle of strain engineering can provide novel information that complements other engineering strategies. PMID- 28637315 TI - Attenuated Effects of Bile Acids on Glucose Metabolism and Insulin Sensitivity in a Male Mouse Model of Prenatal Undernutrition. AB - Prenatal undernutrition and low birth weight are associated with risk of type 2 diabetes and obesity. Prenatal caloric restriction results in low birth weight, glucose intolerance, obesity, and reduced plasma bile acids (BAs) in offspring mice. Because BAs can regulate systemic metabolism and glucose homeostasis, we hypothesized that BA supplementation could prevent diet-induced obesity and glucose intolerance in this model of developmental programming. Pregnant dams were food restricted by 50% from gestational days 12.5 to 18.5. Offspring of both undernourished (UN) and control (C) dams given unrestricted diets were weaned to high-fat diets with or without supplementation with 0.25% w/w ursodeoxycholic acid (UDCA), yielding four experimental groups: C, UN, C + UDCA, and UN + UDCA. Glucose homeostasis, BA composition, liver and intestinal gene expression, and microbiota composition were analyzed in the four groups. Although UDCA supplementation ameliorated diet-induced obesity in C mice, there was no effect in UN mice. UDCA similarly lowered fasting insulin, and improved glucose tolerance, pyruvate tolerance, and liver steatosis in C, but not UN, animals. BA composition differed significantly, and liver and ileal expression of genes involved in BA metabolism (Cyp7b1, Shp) were differentially induced by UDCA in C vs UN animals. Bacterial taxa in fecal microbiota correlated with treatment groups and metabolic parameters. In conclusion, prenatal undernutrition alters responsiveness to the metabolic benefits of BA supplementation, with resistance to the weight-lowering and insulin-sensitizing effects of UDCA supplementation. Our findings suggest that BA metabolism may be a previously unrecognized contributor to developmentally programmed diabetes risk. PMID- 28637317 TI - Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA. PMID- 28637318 TI - Experience-Dependent Regulation of Cajal-Retzius Cell Networks in the Developing and Adult Mouse Hippocampus. AB - In contrast to their near-disappearance in the adult neocortex, Cajal-Retzius cells have been suggested to persist longer in the hippocampus. A distinctive feature of the mature hippocampus, not maintained by other cortical areas, is its ability to sustain adult neurogenesis. Here, we have investigated whether environmental manipulations affecting hippocampal postnatal neurogenesis have a parallel impact on Cajal-Retzius cells. We used multiple mouse reporter lines to unequivocally identify Cajal-Retzius cells and quantify their densities during postnatal development. We found that exposure to an enriched environment increased the persistence of Cajal-Retzius cells in the hippocampus, but not in adjacent cortical regions. We did not observe a similar effect for parvalbumin expressing interneurons, which suggested the occurrence of a cell type-specific process. In addition, we did not detect obvious changes either in Cajal-Retzius cell electrophysiological or morphological features, when compared with what previously reported in animals not exposed to enriched conditions. However, optogenetically triggered synaptic output of Cajal-Retzius cells onto local interneurons was enhanced, consistent with our observation of higher Cajal Retzius cell densities. In conclusion, our data reveal a novel form of hippocampal, cell type-specific, experience-dependent network plasticity. We propose that this phenomenon may be involved in the regulation of enrichment dependent enhanced hippocampal postnatal neurogenesis. PMID- 28637320 TI - Biological functions based on protein interplays. PMID- 28637322 TI - Predicting Perceived Isolation Among Midlife and Older LGBT Adults: The Role of Welcoming Aging Service Providers. AB - Background and Objectives: Older lesbian, gay, bisexual, and transgender (LGBT) adults are more likely to live alone and less likely to have children compared with their heterosexual counterparts. The lack of immediate family system can render older LGBT adults particularly vulnerable to social isolation and its consequences. The current study utilizes social exclusion theory, which asserts that not only material resources but also engagement with and inclusion into the society are necessary for marginalized people to be integrated into the mainstream. The study examines whether aging service providers (e.g., senior centers, adult day care, transportation, employment services) who are perceived by older LGBT adults as welcoming to LGBT people may reduce this population's perceived isolation. Research Design and Methods: Data were collected through a needs assessment survey designed for the aging LGBT community in North Carolina. Adults aged 45 and over who self-identified as LGBT were recruited at several formal and informal groups. The survey yielded 222 valid responses. The outcome variable was perceived isolation. Key independent variables included having experienced welcoming aging service providers and living alone. Results: After controlling for potential confounders and demographics, logistic regression results showed that having experienced welcoming aging service providers was a protective factor against perceived isolation and it also buffered the negative impact of living alone. Discussion and Implications: The findings provided preliminary evidence for a new direction of intervention research-targeting LGBT cultural competence training for medical and social service providers. PMID- 28637319 TI - Matrix metalloproteinases: their functional role in lung cancer. AB - Lung malignancy is the foremost cause of cancer-related deaths globally and is frequently related to long-term tobacco smoking. Recent studies reveal that the expression of matrix metalloproteinases (MMPs) is extremely high in lung tumors compared with non-malignant lung tissue. MMPs are zinc-dependent proteases and are involved in the degradation of extracellular matrix (ECM). Several investigations have shown that MMPs manipulate the activity of non-ECM molecules, including cytokines, growth factors and receptors that control the tumor microenvironment. In this review, we have summarized and critically reviewed the published works on the role of MMPs in non-small-cell lung cancer. We have also explored the structure of MMPs, their various types and roles in lung cancer metastasis including invasion, migration and angiogenesis. PMID- 28637321 TI - Amino acid substrates impose polyamine, eIF5A, or hypusine requirement for peptide synthesis. AB - Whereas ribosomes efficiently catalyze peptide bond synthesis by most amino acids, the imino acid proline is a poor substrate for protein synthesis. Previous studies have shown that the translation factor eIF5A and its bacterial ortholog EF-P bind in the E site of the ribosome where they contact the peptidyl-tRNA in the P site and play a critical role in promoting the synthesis of polyproline peptides. Using misacylated Pro-tRNAPhe and Phe-tRNAPro, we show that the imino acid proline and not tRNAPro imposes the primary eIF5A requirement for polyproline synthesis. Though most proline analogs require eIF5A for efficient peptide synthesis, azetidine-2-caboxylic acid, a more flexible four-membered ring derivative of proline, shows relaxed eIF5A dependency, indicating that the structural rigidity of proline might contribute to the requirement for eIF5A. Finally, we examine the interplay between eIF5A and polyamines in promoting translation elongation. We show that eIF5A can obviate the polyamine requirement for general translation elongation, and that this activity is independent of the conserved hypusine modification on eIF5A. Thus, we propose that the body of eIF5A functionally substitutes for polyamines to promote general protein synthesis and that the hypusine modification on eIF5A is critically important for poor substrates like proline. PMID- 28637323 TI - Evolution of Transcription Activator-Like Effectors in Xanthomonas oryzae. AB - Transcription activator-like effectors (TALEs) are secreted by plant-pathogenic Xanthomonas bacteria into plant cells where they act as transcriptional activators and, hence, are major drivers in reprogramming the plant for the benefit of the pathogen. TALEs possess a highly repetitive DNA-binding domain of typically 34 amino acid (AA) tandem repeats, where AA 12 and 13, termed repeat variable di-residue (RVD), determine target specificity. Different Xanthomonas strains possess different repertoires of TALEs. Here, we study the evolution of TALEs from the level of RVDs determining target specificity down to the level of DNA sequence with focus on rice-pathogenic Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc) strains. We observe that codon pairs coding for individual RVDs are conserved to a similar degree as the flanking repeat sequence. We find strong indications that TALEs may evolve 1) by base substitutions in codon pairs coding for RVDs, 2) by recombination of N-terminal or C-terminal regions of existing TALEs, or 3) by deletion of individual TALE repeats, and we propose possible mechanisms. We find indications that the reassortment of TALE genes in clusters is mediated by an integron-like mechanism in Xoc. We finally study the effect of the presence/absence and evolutionary modifications of TALEs on transcriptional activation of putative target genes in rice, and find that even single RVD swaps may lead to considerable differences in activation. This correlation allowed a refined prediction of TALE targets, which is the crucial step to decipher their virulence activity. PMID- 28637324 TI - The effects of phytosterols on the sexual behavior and reproductive function in the Japanese quail (Coturnix coturnix japonica). AB - Phytosterols (PS) are plant origin sterols naturally found in many foods and added as food additives. Since 1950, PS have attracted considerable attention due to their ability to lower serum cholesterol and inhibit cardiovascular disease (CVD). However, recent studies have found that PS act as endocrine-disrupting chemicals in laboratory animals. Therefore, this study was aimed at finding the mechanism(s) for PS effects on the sexual behaviors and reproductive functions in male Japanese quails (Coturnix coturnix japonica). At 15 d of age, 30 male Japanese quails were randomly assigned to 3 groups for the chronic in-vivo experiment. Animals were gavaged daily with single dose of PS suspension (PS dissolved in medium chain triglyceride [MCT]) into the crop sac from 15-100 d of age. Following maturation, a sexual behavior test, semen collection, and test of fertilization ability were performed. Blood was collected by cervical dislocation at 100 day of age for hormones analysis. To observe the direct effects of PS on the testis, interstitial cells of the normal testes were cultured for 24 h. Ovine LH (O-LH) was used for half of each group to stimulate interstitial cells for testosterone production. The results showed that chronic doses of PS reduced (P < 0.01) mount and copulation behavior in male quails (primarily in the group receiving 800 mg/kg BW). Both acute in vitro and chronic in vivo experiments revealed a reduction in testosterone (P < 0.05) after PS treatments; concomitantly, Leydig cell numbers were also low (P < 0.05) at a dose of 800 mg/kg BW. Real-time PCR results showed lower expression of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) at the same dose. The results suggested that feeding large amounts of PS reduced testosterone levels and sexual behavior by affecting Leydig cell proliferation, and cholesterol trafficking, 17beta-HSD expression in the testes of male Japanese quail. PMID- 28637325 TI - The Leading Edge of the Geographic Distribution of Ixodes scapularis (Acari: Ixodidae). PMID- 28637326 TI - Treatment of Pertussis-2017. PMID- 28637328 TI - Diesel Engine Exhaust: Basis for Occupational Exposure Limit Value. AB - Diesel engines are widely used in transport and power supply, making occupational exposure to diesel exhaust common. Both human and animal studies associate exposure to diesel exhaust with inflammatory lung effects, cardiovascular effects, and an increased risk of lung cancer. The International Agency for Research on Cancer has evaluated diesel exhaust as carcinogenic to humans. Yet national or regional limit values for controlling occupational exposure to diesel exhaust are rare. In recent decades, stricter emission regulations have led to diesel technologies evolving significantly, resulting in changes in exhaust emissions and composition. These changes are also expected to influence the health effects of diesel exhaust. This review provides an overview of the current knowledge on the health effects of diesel exhaust and the influence of new diesel technologies on the health risk. It discusses the relevant exposure indicators and perspectives for setting occupational exposure limit values for diesel exhaust, and outlines directions for future research. The review is based on a collaborative evaluation report by the Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals and the Dutch Expert Committee on Occupational Safety. PMID- 28637329 TI - Health Benefits Associated With Three Helping Behaviors: Evidence for Incident Cardiovascular Disease. AB - Objective: The purpose of this study was to investigate the association between three helping behaviors and incident cardiovascular disease (CVD; heart attack, stroke; fatal and nonfatal), with an exploration of gender differences. The study is framed within the caregiving system model. Helping others is argued to be an evolved characteristic of humans that yields beneficial health effects. Methods: Data were taken from the 2004-2014 waves of the Health and Retirement Study. The three forms of helping others considered were formal volunteering, informal helping, and caregiving for a parent or spouse. Cox proportional hazards models were estimated for gender-stratified samples. Results: Women who volunteered showed a lower risk of incident CVD compared to women who did not volunteer. Men who informally helped others in the community exhibited a lower risk of incident CVD compared to men who did not provide this form of help. Caregiving status was generally not associated with incident CVD for women or men. Discussion: The results demonstrated that specific types of prosocial behavior may be beneficial for women and men. However, tests for effect differences showed that gender did not moderate the relationships between these helping behaviors and CVD risk. PMID- 28637330 TI - Occurrence of aminoglycoside-modifying enzymes among isolates of Escherichia coli exhibiting high levels of aminoglycoside resistance isolated from Korean cattle farms. AB - This study investigated 247 Escherichia coli isolates collected from four cattle farms to characterize aminoglycoside-modifying enzyme (AME) genes, their plasmid replicons and transferability. Out of 247 isolates a high number of isolates (total 202; 81.78%) were found to be resistant to various antibiotics by disc diffusion. Of the 247 strains, 139 (56.3%) were resistant to streptomycin, and other antibiotic resistances followed as tetracycline (12.15%), ampicillin (7%), chloramphenicol (5.7%) and trimethoprim-sulfamethoxazole (0.8%). Among 247 isolates B1 was the predominant phylogenetic group identified comprising 151 isolates (61.1%), followed by groups A (27.9%), D (7%) and B2 (4%). Out of 139 isolates investigated for AME, 130 (93.5%) isolates carried at least one AME gene. aph3"-1a and aph3"-1b (46%) were the principal genes detected, followed by aac3-IVa (34.5%). ant2"-1a was the least detected gene (2.2%). Nine (6.5%) strains carried no AME genes. Twelve (63.2%) among 19 isolates transferred an AME gene to a recipient and aph3?-1a was the dominant transferred gene. Transferability mainly occurred via the IncFIB replicon type (52.6%). Pulsed field gel electrophoresis typing demonstrated a higher degree of diversity with 14 distinct cluster types. This result suggests that commensal microflora from food-producing animals has a tremendous ability to harbor and transfer AME genes, and poses a potential risk by dissemination of resistance to humans through the food chain. PMID- 28637331 TI - Antioxidants as stabilizers for His6-OPH: is this an unusual or regular role for them with enzymes? AB - The effect of 14 different antioxidants on the activity of a hexahistidine-tagged organophosphorus hydrolase (His6-OPH) has been studied in vitro. It has been found that antioxidants can have a positive, neutral or negative effect on the activity of His6-OPH in a native form or in the form of an enzyme-polyelectrolyte complex, while the enzyme itself does not affect their antioxidant activity. A significant stabilizing effect of a number of antioxidants on His6-OPH has been shown against its inhibiting with organic solvents (DMSO and isopropyl alcohol). The kinetics of the process has been studied. Based on molecular docking of all tested antioxidants to the surface of His6-OPH dimer, options of their localization have been identified. These data were used to explain the revealed stabilizing effect of the antioxidants on the enzyme as well as their negative influence on His6-OPH activity. PMID- 28637327 TI - Effect of simvastatin on baboon endometriosis. AB - Endometriosis, a common disorder affecting women of reproductive age, is characterized by ectopic growth of the endometrial tissues, altered steroid hormone response, and inflammation. Previous studies revealed that statins, selective inhibitors of the key step of mevalonate pathway, inhibit growth of endometrial stromal cells in vitro and reduce endometriotic lesions in murine models of endometriosis. This study evaluated the effects of simvastatin on the development of endometriosis in a baboon model of this disease. Sixteen baboons were randomly assigned to the treatment group (simvastatin, 20 mg daily) or to the control group. Endometriotic lesions were evaluated by laparoscopy after 3 months. The volume of red, orange-red, and white endometriotic lesions was significantly reduced by 78% in animals treated with simvastatin. The expression of a marker of proliferation, proliferating cell nuclear antigen (PCNA), was significantly reduced in animals receiving simvastatin in red lesions, white lesions, black lesions, and in adhesions. Simvastatin was also associated with an increase in the expression of estrogen receptor alpha in red lesions, and a decrease in the expression of estrogen receptor beta in black lesions, in adhesions, and in eutopic endometrium. Furthermore, simvastatin significantly reduced the expression of neopterin, a marker of inflammation, oxidative stress, and immune system activation. Collectively, the present findings indicate that the inhibition of the mevalonate pathway by simvastatin reduces the risk of developing endometriosis in the primate model of this disease by decreasing the growth of endometrial lesions, by modulating the expression of genes encoding for estrogen receptors, and by reducing inflammation. PMID- 28637332 TI - Coarse particle inclusion and lignocellulose-rich fiber addition in feed benefit performance and health of broiler chickens. AB - Measures to improve gut health and nutrient digestibility have been sought due to in-feed antibiotics being phased out in poultry. The appropriate physical structure of feed ingredients and addition of dietary fiber may be beneficial in enhancing gut health in poultry. In this study, the effect of a lignocellulose rich fiber source and corn particle size on broiler performance, gizzard development, nutrient digestibility, cecal microflora, and litter quality was evaluated. A total of 684 day-old male Ross 308 chicks were randomly allocated to 6 treatments with 6 replicate pens, each housing 19 birds. A 2 * 3 factorial arrangement of treatments was applied with the factors of: corn particle size (coarse: 2,982 MUm or fine: 941 MUm geometric mean diameter), and 3 levels of lignocellulose (0%, 1% or 2%). Significant particle size * fiber interaction was observed for feed conversion ratio (FCR) at d 10 (P < 0.05). The birds fed coarsely ground corn (CGC) had lower FCR than those fed finely ground corn (FGC) only at 2% of lignocellulose but not at 1% or no lignocellulose addition. Birds fed FGC were heavier (P < 0.001) at d 10. In contrast, at d 24 and 35, birds fed CGC had lower FCR than those fed FGC (P < 0.05). Ileal gross energy and protein digestibility increased in birds fed CGC compared with those fed FGC at d 24 (P < 0.05). Relative gizzard weight was higher (P < 0.05) on d 24 and 35 in birds fed CGC as compared to those fed FGC. Birds consumed 2% dietary lignocellulose had decreased counts of cecal Clostridium spp. compared to those with 1% lignocellulose (P < 0.05) at d 24. On d 35, both levels of lignocellulose had significantly decreased (P < 0.05) litter moisture content compared to the control. In conclusion, birds fed pelleted diets containing CGC exhibited improved FCR, and increased nutrient digestibility, which may have been caused by larger gizzards. Furthermore, dietary lignocellulose addition is beneficial to litter quality. PMID- 28637333 TI - Infections in Early Life and Development of Celiac Disease. AB - It has been suggested that early infections are associated with increased risk for later celiac disease (CD). We analyzed prospective claims data of infants from Bavaria, Germany, born between 2005 and 2007 (n = 295,420), containing information on medically attended infectious diseases according to International Classification of Diseases, Tenth Revision, codes in quarterly intervals. We calculated hazard ratios and 95% confidence intervals for time to CD diagnosis by infection exposure, adjusting for sex, calendar month of birth, and number of previous healthcare visits. CD risk was higher among children who had had a gastrointestinal infection during the first year of life (hazard ratio = 1.32, 95% confidence interval: 1.12, 1.55) and, to a lesser extent, among children who had had a respiratory infection during the first year of life (hazard ratio = 1.22, 95% confidence interval: 1.04, 1.43). Repeated gastrointestinal infections during the first year of life were associated with particularly increased risk of CD in later life. These findings indicate that early gastrointestinal infections may be relevant for CD development. PMID- 28637334 TI - New predictor of aortic enlargement in uncomplicated type B aortic dissection based on elliptic Fourier analysis. AB - OBJECTIVES: This study aimed to re-examine the conventional predictive factors for dissected aortic enlargement, such as the aortic and false lumen diameter and to consider whether the morphological elements of the dissected aorta could be predictors by quantifying the 'shape' of the true lumen based on elliptic Fourier analysis. METHODS: A total of 80 patients with uncomplicated type B aortic dissection were included. The patients were divided into 'Enlargement group' and 'No Change group.' Between the 2 groups, the mean systolic blood pressure during follow-up, aortic and false lumen maximum diameters, and analysed morphological data were compared using each statistical method. RESULTS: The maximum aortic and false lumen diameters were significantly larger in the Enlargement group than in the No Change group (39.3 vs 35.9 mm; P = 0.0058) (23.5 vs 18.2 mm; P = 0.000095). The principal component 1, which is the data calculated by elliptic Fourier analysis, was significantly lower in the Enlargement group than in the No Change group (0.020 vs - 0.072; P = 0.000049). The mean systolic blood pressure >=130 mmHg, aortic diameter, false lumen diameter and principal component 1 were included in the Cox proportional hazard model as covariates to determine the significant predictive variable. Principal component 1 demonstrated the only significance with aortic enlargement on multivariate analysis (odds ratio = 0.32; P = 0.048). CONCLUSIONS: The analysed and calculated morphological data of the shape of the true lumen can be more effective predictive factors of aortic enlargement of type B dissection than the conventional factors. PMID- 28637335 TI - Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by the loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology. We had previously found that glial derived neurotrophic factor (GDNF) is reduced in SMA astrocytes. However, reduced GDNF expression does not play a major role in SMA pathology as viral-mediated GDNF re-expression did not improve astrocyte function or motor neuron loss. In contrast, we found that SMA astrocytes increased microRNA (miR) production and secretion compared to control astrocytes, suggesting potential toxic gain-of-function properties. Specifically, we found that miR-146a was significantly upregulated in SMA induced pluripotent stem cell (iPSC)-derived astrocytes and SMNDelta7 mouse spinal cord. Moreover, increased miR-146a was sufficient to induce motor neuron loss in vitro, whereas miR-146a inhibition prevented SMA astrocyte-induced motor neuron loss. Together, these data indicate that altered astrocyte production of miR-146a may be a contributing factor in astrocyte-mediated SMA pathology. PMID- 28637337 TI - Matrix completion with side information and its applications in predicting the antigenicity of influenza viruses. AB - Motivation: Low-rank matrix completion has been demonstrated to be powerful in predicting antigenic distances among influenza viruses and vaccines from partially revealed hemagglutination inhibition table. Meanwhile, influenza hemagglutinin (HA) protein sequences are also effective in inferring antigenic distances. Thus, it is natural to integrate HA protein sequence information into low-rank matrix completion model to help infer influenza antigenicity, which is critical to influenza vaccine development. Results: We have proposed a novel algorithm called biological matrix completion with side information (BMCSI), which first measures HA protein sequence similarities among influenza viruses (especially on epitopes) and then integrates the similarity information into a low-rank matrix completion model to predict influenza antigenicity. This algorithm exploits both the correlations among viruses and vaccines in serological tests and the power of HA sequence in predicting influenza antigenicity. We applied this model into H3N2 seasonal influenza virus data. Comparing to previous methods, we significantly reduced the prediction root-mean square error in a 10-fold cross validation analysis. Based on the cartographies constructed from imputed data, we showed that the antigenic evolution of H3N2 seasonal influenza is generally S-shaped while the genetic evolution is half circle shaped. We also showed that the Spearman correlation between genetic and antigenic distances (among antigenic clusters) is 0.83, demonstrating a globally high correspondence and some local discrepancies between influenza genetic and antigenic evolution. Finally, we showed that 4.4%+/-1.2% genetic variance (corresponding to 3.11 +/- 1.08 antigenic distances) caused an antigenic drift event for H3N2 influenza viruses historically. Availability and implementation: The software and data for this study are available at http://bi.sky.zstu.edu.cn/BMCSI/. Contact: jialiang.yang@mssm.edu or pinganhe@zstu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28637336 TI - Identification of Arabidopsis thaliana upstream open reading frames encoding peptide sequences that cause ribosomal arrest. AB - Specific sequences of certain nascent peptides cause programmed ribosomal arrest during mRNA translation to control gene expression. In eukaryotes, most known regulatory arrest peptides are encoded by upstream open reading frames (uORFs) present in the 5'-untranslated region of mRNAs. However, to date, a limited number of eukaryotic uORFs encoding arrest peptides have been reported. Here, we searched for arrest peptide-encoding uORFs among Arabidopsis thaliana uORFs with evolutionarily conserved peptide sequences. Analysis of in vitro translation products of 22 conserved uORFs identified three novel uORFs causing ribosomal arrest in a peptide sequence-dependent manner. Stop codon-scanning mutagenesis, in which the effect of changing the uORF stop codon position on the ribosomal arrest was examined, and toeprint analysis revealed that two of the three uORFs cause ribosomal arrest during translation elongation, whereas the other one causes ribosomal arrest during translation termination. Transient expression assays showed that the newly identified arrest-causing uORFs exerted a strong sequence-dependent repressive effect on the expression of the downstream reporter gene in A. thaliana protoplasts. These results suggest that the peptide sequences of the three uORFs identified in this study cause ribosomal arrest in the uORFs, thereby repressing the expression of proteins encoded by the main ORFs. PMID- 28637338 TI - Complex interactions between potentially pathogenic, opportunistic, and resident bacteria emerge during infection on a reef-building coral. AB - Increased bacterial diversity on diseased corals can obscure disease etiology and complicate our understanding of pathogenesis. To untangle microbes that may cause white band disease signs from microbes responding to disease, we inoculated healthy Acropora cervicornis corals with an infectious dose from visibly diseased corals. We sampled these dosed corals and healthy controls over time for sequencing of the bacterial 16S region. Endozoicomonas were associated with healthy fragments from 4/10 colonies, dominating microbiomes before dosing and decreasing over time only in corals that displayed disease signs, suggesting a role in disease resistance. We grouped disease-associated bacteria by when they increased in abundance (primary vs secondary) and whether they originated in the dose (colonizers) or the previously healthy corals (responders). We found that all primary responders increased in all dosed corals regardless of final disease state and are therefore unlikely to cause disease signs. In contrast, primary colonizers in the families Pasteurellaceae and Francisellaceae increased solely in dosed corals that ultimately displayed disease signs, and may be infectious foreign bacteria involved in the development of disease signs. Moving away from a static comparison of diseased and healthy bacterial communities, we provide a framework to identify key players in other coral diseases. PMID- 28637340 TI - An Analysis of the Use of Multichannel Microelectrode Recording During Deep Brain Stimulation Surgeries at a Single Center. AB - BACKGROUND: Microelectrode recording (MER) can be used to map out the target nucleus and identify ideal lead placement. OBJECTIVE: To assess the use of multichannel MER to increase the efficiency of lead placement without compromising patient safety. METHODS: Analysis of a single center's technique for utilizing multichannel MER with 3 consistent anterior-to-posterior simultaneous passes that include an evaluation of the location of final lead placement, patient diagnosis, target nuclei, and additional work involved for refinement of targeting. Lead revision rates and rate of hemorrhage are also assessed. RESULTS: There were a total of 237 lead placements in 123 patients over a 4-yr period. In 4.2% of lead placements, additional planning was required, while only 2.5% required additional MER. The lead placement matched 51.3% of the time in bilateral placements and was consistent regardless of target nuclei. In 84.8% of cases, the final lead placement was within the initial 3 MER passes. An additional 11.3% could be placed without the need for an additional pass. There were 2 lead revisions and no hemorrhage or stroke complications. CONCLUSION: This series demonstrates that our technique of multichannel MER leads to accurate and efficient lead placement maintaining its safety profile. PMID- 28637339 TI - Emergence of ceftazidime/avibactam non-susceptibility in an MDR Klebsiella pneumoniae isolate. AB - Background: Avibactam is a novel broad-range beta-lactamase inhibitor active against Ambler class A (including ESBL and KPC) and some Ambler class C and D (e.g. OXA-48) enzymes. We here report on the emergence of ceftazidime/avibactam resistance in clinical, multiresistant, OXA-48 and CTX-M-14-producing Klebsiella pneumoniae isolate DT12 during ceftazidime/avibactam treatment. Methods and results: Comparative whole-genome sequence analysis identified two SNPs in the CTX-M-14-encoding gene leading to two amino acid changes (P170S and T264I). Compared with WT CTX-M-14, expression of the CTX-M-14Delta170Delta264 isoform in Escherichia coli led to a >64- and 16-fold increase in ceftazidime and ceftazidime/avibactam MICs, respectively, functionally linking the observed SNPs and elevated MICs. The mutated CTX-M-14 isoform exhibited augmented ceftazidime hydrolytic activity, which was a reasonable cause for impaired susceptibility to avibactam inhibition. The P170S exchange in CTX-M-14 was found in association with elevated ceftazidime/avibactam MICs for independent K. pneumoniae isolates, but was not sufficient for full resistance. Apparently, additional CTX-M independent mechanisms contribute to ceftazidime/avibactam resistance in K. pneumoniae DT12. Conclusions: This study on the molecular basis of ceftazidime/avibactam resistance in clinical K. pneumoniae emerging in vivo underscores the need for continuous monitoring of ceftazidime/avibactam susceptibility during therapy. Despite sustained inhibition of OXA-48, rapid development of CTX-M-14 isoforms exhibiting augmented ceftazidime hydrolytic activity may limit the usefulness of ceftazidime/avibactam monotherapies in infections caused by isolates carrying blaCTX-M-14 and blaOXA-48. PMID- 28637341 TI - Assessment of Workers' Exposure to Grain Dust and Bioaerosols During the Loading of Vessels' Hold: An Example at a Port in the Province of Quebec. AB - Longshoremen are exposed to large amounts of grain dust while loading of grain into the holds of vessels. Grain dust inhalation has been linked to respiratory diseases such as chronic bronchitis, hypersensitivity, pneumonitis, and toxic pneumonitis. Our objective was to characterize the exposure of longshoremen to inhalable and total dust, endotoxins, and cultivable bacteria and fungi during the loading of grain in a vessel's hold at the Port of Montreal in order to assess the potential health risks. Sampling campaigns were conducted during the loading of two different types of grain (wheat and corn). Environmental samples of microorganisms (bacteria, fungus, and actinomycetes) were taken near the top opening of the ship's holds while personal breathing zone measurements of dust and endotoxins were sampled during the worker's 5-hour shifts. Our study show that all measurements are above the recommendations with concentration going up to 390 mg m-3 of total dust, 89 mg m-3 of inhalable fraction, 550 000 EU m-3 of endotoxins, 20 000 CFU m-3 of bacteria, 61 000 CFU m-3 of fungus and 2500 CFU m-3 of actinomycetes. In conclusion, longshoremen are exposed to very high levels of dust and of microorganisms and their components during grain loading work. Protective equipment needs to be enforced for all workers during such tasks in order to reduce their exposure. PMID- 28637342 TI - Genetic heterogeneity of atrial fibrillation susceptibility loci across racial or ethnic groups. PMID- 28637343 TI - Health and Demographic Surveillance System (HDSS) in Matlab, Bangladesh. PMID- 28637344 TI - Nicotine Delivery to the Aerosol of a Heat-Not-Burn Tobacco Product: Comparison With a Tobacco Cigarette and E-Cigarettes. AB - Introduction: The purpose was to measure nicotine levels to the tobacco and levels emitted to the aerosol of a heat-not-burn product (HnB, IQOS) compared to e-cigarettes (ECs) and a tobacco cigarette. Methods: The HnB device and regular and menthol sticks were purchased from Italy. Three types of ECs (ciga-like, eGo style, and variable wattage) and a commercially-available tobacco cigarette were also tested. A custom-made liquid containing 2% nicotine was used with ECs. Products were tested using Health Canada Intense puffing regime while HnB and ECs were additionally tested using a 4-second puff duration regime while maintaining the same puff volume. Results: Nicotine content in HnB regular and menthol tobacco sticks was 15.2 +/- 1.1 mg/g and 15.6 +/- 1.7 mg/g tobacco respectively. The levels of nicotine to the aerosol were similar for regular and menthol HnB products (1.40 +/- 0.16 and 1.38 +/- 0.11 mg/12 puffs respectively) and did not change significantly with prolonged puff duration. The tobacco cigarette delivered the highest level of nicotine (1.99 +/- 0.20 mg/cigarette), with levels being higher than HnB and ECs under Health Canada Intense regime but similar to eGo-style and variable wattage ECs at prolonged puff duration regime. Conclusions: The HnB product delivers nicotine to the aerosol at levels higher than ECs but lower than a tobacco cigarette when tested using Health Canada Intense puffing regime. No change in HnB nicotine delivery was observed at prolonged puff duration with the same puff volume, unlike ECs which deliver more nicotine with longer puff duration. Implications: Nicotine delivery to the smoker is expected to play an important role in the ability of any harm-reduction product to successfully substitute smoking. This study evaluated the content and nicotine delivery to the aerosol of a heat-not-burn tobacco product (IQOS) in comparison with e-cigarettes and a tobacco cigarette. The main findings were that the heat-not-burn tobacco sticks contained similar nicotine concentration to tobacco cigarettes, and that the levels of nicotine delivered to the aerosol of the heat-not-burn products were lower than tobacco cigarette, higher than e cigarettes at low puff duration but lower than high-power e-cigarettes at longer puff duration. PMID- 28637345 TI - "He Wouldn't Turn Me Loose". PMID- 28637347 TI - Mechanisms underlying the long-term survival of the monocot Dracaena marginata under drought conditions. AB - Efficient water management is essential for the survival of vascular plants under drought stress. While interrelations among drought stress, plant anatomy and physiological functions have been described in woody dicots, similar research is very limited for non-palm arborescent and shrubby monocots despite their generally high drought tolerance. In this study, potted transplants of Dracaena marginata Lam. in primary growth stage were exposed to several short- and long term drought periods. Continuous measurements of sap flow and stem diameter, the evaluation of capacitance and leaf conductance, the quantification of non structural carbohydrates (NSC), and organ-specific anatomical analyses were performed to reveal the mechanisms promoting plant resistance to limited soil moisture. The plants showed sensitive stomata regulation in the face of drying soil, but only intermediate resistance to water loss through cuticular transpiration. The water losses were compensated by water release from stem characterized by densely interconnected, parenchyma-rich ground tissue and considerable hydraulic capacitance. Our results suggest that the high concentration of osmotically active NSC in aboveground organs combined with the production of root pressures supported water uptake and the restoration of depleted reserves after watering. The described anatomical features and physiological mechanisms impart D. marginata with high resistance to irregular watering and long-term water scarcity. These findings should help to improve predictions with respect to the impacts of droughts on this plant group. PMID- 28637346 TI - An ion beam-induced Arabidopsis mutant with marked chromosomal rearrangement. AB - Ion beams have been used as an effective tool in mutation breeding for the creation of crops with novel characteristics. Recent analyses have revealed that ion beams induce large chromosomal alterations, in addition to small mutations comprising base changes or frameshifts. In an effort to understand the potential capability of ion beams, we analyzed an Arabidopsis mutant possessing an abnormal genetic trait. The Arabidopsis mutant uvh3-2 is hypersensitive to UVB radiation when photoreactivation is unavailable. uvh3-2 plants grow normally and produce seeds by self-pollination. SSLP and CAPS analyses of F2 plants showed abnormal recombination frequency on chromosomes 2 and 3. PCR-based analysis and sequencing revealed that one-third of chromosome 3 was translocated to chromosome 2 in uvh3 2. FISH analysis using a 180 bp centromeric repeat and 45S ribosomal DNA (rDNA) as probes showed that the 45S rDNA signal was positioned away from that of the 180 bp centromeric repeat in uvh3-2, suggesting the insertion of a large chromosome fragment into the chromosome with 45S rDNA clusters. F1 plants derived from a cross between uvh3-2 and wild-type showed reduced fertility. PCR-based analysis of F2 plants suggested that reproductive cells carrying normal chromosome 2 and uvh3-2-derived chromosome 3 are unable to survive and therefore produce zygote. These results showed that ion beams could induce marked genomic alterations, and could possibly lead to the generation of novel plant species and crop strains. PMID- 28637348 TI - Hydrogen Peroxide Sensing Based on Inner Surfaces Modification of Solid-State Nanopore. AB - There are many techniques for the detection of molecules. But detection of molecules through solid-state nanopore in a solution is one of the promising, high-throughput, and low-cost technology used these days. In the present investigation, a solid-state nanopore platform was fabricated for the detection of hydrogen peroxide (H2O2), which is not only a label free product but also a significant participant in the redox reaction. We have successfully fabricated silicon nitride (Si3N4) nanopores with diameters of ~50 nm by using a focused Ga ion beam, the inner surface of the nanopore has been modified with horseradish peroxidase (HRP) by employing carbodiimide coupling chemistry. The immobilized HRP enzymes have ability to induce redox reactions in a single nanopore channel. Moreover, a real-time single aggregated ABTS*+ molecular translocation events were monitored and investigated. The designed solid-state nanopore biosensor is reversible and can be applied to detect H2O2 multiple times. PMID- 28637349 TI - The Antibacterial Polyamide 6-ZnO Hierarchical Nanofibers Fabricated by Atomic Layer Deposition and Hydrothermal Growth. AB - In this paper, we report the combination of atomic layer deposition (ALD) with hydrothermal techniques to deposit ZnO on electrospun polyamide 6 (PA 6) nanofiber (NF) surface in the purpose of antibacterial application. The micro- and nanostructures of the hierarchical fibers are characterized by field emission scanning electron microscopy (FE-SEM), high-resolution transmission electron microscopy (HRTEM), and scanning transmission electron microscopy (STEM). We find that NFs can grow into "water lily"- and "caterpillar"-like shapes, which depend on the number of ALD cycles and the hydrothermal reaction period. It is believed that the thickness of ZnO seed layer by ALD process and the period in hydrothermal reaction have the same importance in crystalline growth and hierarchical fiber formation. The tests of antibacterial activity demonstrate that the ZnO/PA 6 core-shell composite fabricated by the combination of ALD with hydrothermal are markedly efficient in suppressing bacteria survivorship. PMID- 28637350 TI - Structural Peculiarities of Ion-Conductive Organic-Inorganic Polymer Composites Based on Aliphatic Epoxy Resin and Salt of Lithium Perchlorate. AB - The article is concerned with hybrid amorphous polymers synthesized basing on epoxy oligomer of diglycide aliphatic ester of polyethylene glycol that was cured by polyethylene polyamine and lithium perchlorate salt. Structural peculiarities of organic-inorganic polymer composites were studied by differential scanning calorimetry, wide-angle X-ray spectra, infrared spectroscopic, scanning electron microscopy, elemental analysis, and transmission and reflective optical microscopy. On the one hand, the results showed that the introduction of LiClO4 salt into epoxy polymer leads to formation of the coordinative metal-polymer complexes of donor-acceptor type between central Li+ ion and ligand. On the other hand, the appearance of amorphous microinclusions, probably of inorganic nature, was also found. PMID- 28637351 TI - Tuning Surface Chemistry of Polyetheretherketone by Gold Coating and Plasma Treatment. AB - Polyetheretherketone (PEEK) has good chemical and biomechanical properties that are excellent for biomedical applications. However, PEEK exhibits hydrophobic and other surface characteristics which cause limited cell adhesion. We have investigated the potential of Ar plasma treatment for the formation of a nanostructured PEEK surface in order to enhance cell adhesion. The specific aim of this study was to reveal the effect of the interface of plasma-treated and gold-coated PEEK matrices on adhesion and spreading of mouse embryonic fibroblasts. The surface characteristics (polarity, surface chemistry, and structure) before and after treatment were evaluated by various experimental techniques (gravimetry, goniometry, X-ray photoelectron spectroscopy (XPS), and electrokinetic analysis). Further, atomic force microscopy (AFM) was employed to examine PEEK surface morphology and roughness. The biological response of cells towards nanostructured PEEK was evaluated in terms of cell adhesion, spreading, and proliferation. Detailed cell morphology was evaluated by scanning electron microscopy (SEM). Compared to plasma treatment, gold coating improved PEEK wettability. The XPS method showed a decrease in the carbon concentration with increasing time of plasma treatment. Cell adhesion determined on the interface between plasma-treated and gold-coated PEEK matrices was directly proportional to the thickness of a gold layer on a sample. Our results suggest that plasma treatment in a combination with gold coating could be used in biomedical applications requiring enhanced cell adhesion. PMID- 28637352 TI - Absence of conformational change in complement factor 3 and factor XII adsorbed to acrylate polymers is related to a high degree of polymer backbone flexibility. AB - In previous investigations, the authors have examined the adsorption of albumin, immunoglobulin, and fibrinogen to a series of acrylate polymers with different backbone and side-group flexibility. The authors showed that protein adsorption to acrylates with high flexibility, such as poly(lauryl methacrylate) (PLMA), tends to preserve native conformation. In the present study, the authors have continued this work by examining the conformational changes that occur during the binding of complement factor 3 (C3) and coagulation factor XII (FXII). Native C3 adsorbed readily to all solid surfaces tested, including a series of acrylate surfaces of varying backbone flexibility. However, a monoclonal antibody recognizing a "hidden" epitope of C3 (only exposed during C3 activation or denaturation) bound to the C3 on the rigid acrylate surfaces or on polystyrene (also rigid), but not to C3 on the flexible PLMA, indicating that varying degrees of conformational change had occurred with binding to different surfaces. Similarly, FXII was activated only on the rigid poly(butyl methacrylate) surface, as assessed by the formation of FXIIa-antithrombin (AT) complexes; in contrast, it remained in its native form on the flexible PLMA surface. The authors also found that water wettability hysteresis, defined as the difference between the advancing and receding contact angles, was highest for the PLMA surface, indicating that a dynamic change in the interface polymer structure may help protect the adsorbed protein from conformational changes and denaturation. PMID- 28637355 TI - Evaluation of employment-support services for adults with autism spectrum disorder. AB - The employment rate among persons with autism spectrum disorder has been noted as unacceptably low. Employment-support services are increasingly linked to the potential for favorable job outcomes, yet little is known about employment support practices and the outcome of these interventions. This mixed-methods study examined employment-support resources for persons with autism spectrum disorder. An online survey was completed by 137 senior clinicians or administrators in employment-support programs in Canada. Additionally, 122 follow up interviews were conducted with individuals with autism spectrum disorder (n = 71) and their parents/caregivers (n = 51). Findings indicate that the quality and beneficial impact of employment-support services for adults with autism spectrum disorder may be more favorably perceived by employment-support personnel than by individuals with autism spectrum disorder and their families. Furthermore, employment-support personnel were more disparaging about autism spectrum disorder vocational support capacity within their community, compared to their own programs. Individuals with autism spectrum disorder and their families seek services that support both accessing and retaining employment. Capacity-building in employment support for youth and adults with autism spectrum disorder is recommended, based on a reported insufficiency of, and a lack of evidence guiding, existing services. Program recommendations and an emerging model for integrated vocational support in autism spectrum disorder are offered. PMID- 28637356 TI - A New Mobile Application for Standardizing Diabetic Foot Images. AB - BACKGROUND: We describe the development of a new mobile app called "FootSnap," to standardize photographs of diabetic feet and test its reliability on different occasions and between different operators. METHODS: FootSnap was developed by a multidisciplinary team for use with the iPad. The plantar surface of 30 diabetic feet and 30 nondiabetic control feet were imaged using FootSnap on two separate occasions by two different operators. Reproducibility of foot images was determined using the Jaccard similarity index (JSI). RESULTS: High intra- and interoperator reliability was demonstrated with JSI values of 0.89-0.91 for diabetic feet and 0.93-0.94 for control feet. CONCLUSIONS: Similarly high reliability between groups indicates FootSnap is appropriate for longitudinal follow-ups in diabetic feet, with potential for monitoring pathology. PMID- 28637357 TI - Behavioral intention to take up different types of HIV testing among men who have sex with men who were never-testers in Hong Kong. AB - Human immunodeficiency virus (HIV) testing is an important global prevention strategy but underutilized by local men who have sex with men (MSM). This study investigated the prevalence of behavioral intention to take up HIV testing (specific or any type), in the next six months among MSM who had not been tested for HIV in the last three years (never-testers) in Hong Kong. The data was based on 141 never-testers of 430 MSM who completed the anonymous baseline telephone survey of an ongoing randomized controlled trial from January 2015 to August 2015. Only 17.7% of them showed strong intention to take up any type of HIV testing in the next six months. Adjusted analysis showed that perceived benefit of HIV testing (adjusted odds ratio [AOR]: 1.29, 95% confidence interval [CI]: 1.01, 1.66), perceived psychological barriers of HIV testing (AOR: 0.85, 95%CI: 0.73, 1.00), and perceived self-efficacy in taking up HIV testing (AOR: 1.28, 95%CI: 1.07, 1.52) were significantly associated with behavioral intention to take up any HIV testing. Perceived cue to action from non-governmental organization staff was positively associated with a marginal p-value of 0.077 (AOR: 2.37, 95%CI: 0.97, 5.77). It is warranted to strengthen perceived benefit, remove psychological barriers, and increase perceived self-efficacy related to HIV testing. Innovative and effective health promotions are greatly needed to increase HIV testing coverage among never-testers. PMID- 28637354 TI - Essential Dietary Bioactive Lipids in Neuroinflammatory Diseases. AB - SIGNIFICANCE: Under physiological conditions, neurons and glia are in a healthy, redox-balanced environment; when injury perturbs this equilibrium, a neuroinflammatory state is established by activated microglia that triggers pro inflammatory responses and alters the oxidant/antioxidant balance, thus leading to neuronal loss and neurodegeneration. In neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, amyothrophic lateral sclerosis, and multiple sclerosis), the brain is in a constitutively self-sustaining cycle of inflammation and oxidative stress that prompts and amplifies brain damage. Recent Advances: Recently, an increasing amount of scientific data highlight the ability of specific nutrients to cross the blood-brain barrier, and to modulate inflammatory and oxidative pathways. Therefore, nutritional approaches may contribute to restore the lost equilibrium among factors accounting for neurodegeneration. CRITICAL ISSUES: Herein, we critically examine how essential lipids (including fatty acids, liposoluble vitamins and phytosterols) might contribute to accelerate or prevent the onset and progression of such pathologies. In particular, we highlight that experimental and clinical findings, although promising, are still inadequate to draw definitive conclusions. FUTURE DIRECTIONS: More research is warranted in order to establish the real impact of lipid intake on brain health, especially when redox balance and inflammatory responses have been already compromised. In the future, it would be hoped to gain a detailed knowledge of chemical modifications and dynamic properties of such nutrients, before planning to exploit them as potential therapeutics. Antioxid. Redox Signal. 29, 37-60. PMID- 28637358 TI - Comparative Simulation Study of Glucose Control Methods Designed for Use in the Intensive Care Unit Setting via a Novel Controller Scoring Metric. AB - BACKGROUND: Effective glucose control in the intensive care unit (ICU) setting has the potential to decrease morbidity and mortality rates and thereby decrease health care expenditures. To evaluate what constitutes effective glucose control, typically several metrics are reported, including time in range, time in mild and severe hypoglycemia, coefficient of variation, and others. To date, there is no one metric that combines all of these individual metrics to give a number indicative of overall performance. We proposed a composite metric that combines 5 commonly reported metrics, and we used this composite metric to compare 6 glucose controllers. METHODS: We evaluated the following controllers: Ideal Medical Technologies (IMT) artificial-intelligence-based controller, Yale protocol, Glucommander, Wintergerst et al PID controller, GRIP, and NICE-SUGAR. We evaluated each controller across 80 simulated patients, 4 clinically relevant exogenous dextrose infusions, and one nonclinical infusion as a test of the controller's ability to handle difficult situations. This gave a total of 2400 5 day simulations, and 585 604 individual glucose values for analysis. We used a random walk sensor error model that gave a 10% MARD. For each controller, we calculated severe hypoglycemia (<40 mg/dL), mild hypoglycemia (40-69 mg/dL), normoglycemia (70-140 mg/dL), hyperglycemia (>140 mg/dL), and coefficient of variation (CV), as well as our novel controller metric. RESULTS: For the controllers tested, we achieved the following median values for our novel controller scoring metric: IMT: 88.1, YALE: 46.7, GLUC: 47.2, PID: 50, GRIP: 48.2, NICE: 46.4. CONCLUSION: The novel scoring metric employed in this study shows promise as a means for evaluating new and existing ICU-based glucose controllers, and it could be used in the future to compare results of glucose control studies in critical care. The IMT AI-based glucose controller demonstrated the most consistent performance results based on this new metric. PMID- 28637359 TI - Decreased paraoxonase 2 enzymatic activity in monocyte/macrophages cells. A comparative in vivo and in vitro study for diabetes. AB - AIM: To investigate peripheral blood monocytes/macrophages (Mo/M?) paraoxonase 2 (PON2) in diabetes and the factors modulating its activity. METHODS: One hundred and eighteen patients with newly diagnosed uncomplicated type 2 diabetes mellitus were compared regarding clinical, biochemical and oxidative stress parameters with 80 healthy subjects. The capacity of the peripheral blood mononuclear cells (PBMNC) to release pro-oxidants and to neutralise them was determined by measuring the respiratory burst (RB) and the intracellular antioxidant enzyme PON2. In vitro experiments were conducted on a differentiated monocytes cell line (dU937) that was exposed to serum deprivation followed by addition of isolated lipoproteins (VLDL or LDL). RESULTS: Paraoxonase 2 activity in Mo/M? was significantly lower in type 2 diabetes patients (0.042 +/- 0.044 vs 0.165 +/- 0.133U lactonase activity/mg protein in controls, p < .0005) and decreased in the obese in all groups. It was inversely correlated to parameters of adiposity (BMI and Waist Circumference), of glucose control (blood glucose, fructosamine and HbA1c) and insulin resistance (HOMA-IR). In multivariate regression models, 15 34% of the PON2 variance was explained by diabetes. The in vitro addition of VLDL normalised the RB of serum deprived dU937 cells, S- (to 82 +/- 18% of the cells incubated with serum, S+) and PON2 activity (from 0.524 +/- 0.061 in S - to 0.298 +/- 0.048 U/mg protein). In contrast, when LDL was added, the RB remained lower (61 +/- 12% of S+, p = .03) and PON2 higher (0.580 +/- 0.030 U/mg protein, p = .003). CONCLUSIONS: The decrease in monocyte/macrophage PON2 enzymatic activity observed in type 2 diabetes cannot be totally explained by abdominal obesity and insulin resistance. The underlying molecular mechanisms need to be identified. PMID- 28637360 TI - Who or what has agency in the discussion of antimicrobial resistance in UK news media (2010-2015)? A transitivity analysis. AB - The increase in infections resistant to the existing antimicrobial medicines has become a topic of concern for health professionals, policy makers and publics across the globe; however, among the public there is a sense that this is an issue beyond their control. Research has shown that the news media can have a significant role to play in the public's understanding of science and medicine. In this article, we respond to a call by research councils in the United Kingdom to study antibiotic or antimicrobial resistance as a social phenomenon by providing a linguistic analysis of reporting on this issue in the UK press. We combine transitivity analysis with a social representations framework to determine who and what the social actors are in discussions of antimicrobial resistance in the UK press (2010-2015), as well as which of those social actors are characterised as having agency in the processes around antimicrobial resistance. Findings show that antibiotics and the infections they are designed to treat are instilled with agency, that there is a tension between allocating responsibility to either doctors-as-prescribers or patients-as-users and collectivisation of the general public as an unspecified 'we': marginalising livestock farming and pharmaceutical industry responsibilities. PMID- 28637363 TI - "Think positively": Parkinson's disease, biomedicine, and hope in contemporary Germany. AB - Narratives of hope shape contemporary engagements with Parkinson's disease. On the one hand, a "biomedical narrative of hope" promises that biomedical research will help to transform this treatable but incurable disease into a curable one in the future. On the other hand, a more individual "illness narrative of hope" encourages patients to influence the course of Parkinson's disease by practicing self-care and positive thinking. This article asks how these two narratives of hope interact. It bases its argument on an analysis of data from 13 focus groups conducted in Germany in 2012 and 2014 with patients with Parkinson's disease and their relatives. Participants were asked to have their say on clinical trials for advanced therapies for Parkinson's disease and, while doing so, envisioned their biosocial selves in the present and the future. Three "modes of being" for patients were drawn from this body of data: a "users on stand-by" mode, an "unengaged" mode, and an "experimental pioneers" mode. Both narratives of hope were important to all three modes, yet they were mobilized at different frequencies and also had different statuses. While the biomedical narrative of hope was deemed an important "dream of the future" that participants passively supported without having to make it their own, the illness narrative of hope was a truth discourse that took an imperative form: having Parkinson's disease implied the need to maintain a positive attitude. PMID- 28637361 TI - Antioxidant activity of phenolic compounds from extracts of Eucalyptus globulus and Melaleuca styphelioides and their protective role on D-glucose-induced hyperglycemic stress and oxalate stress in NRK-49Fcells. AB - Phytochemicals serve as potential therapeutic agents for the prevention and treatment of diseases. In this study, we elucidate the renoprotective activity of compounds isolated from Eucalyptus globulus and Melaleuca styphelioides extracts in glucose- and oxalate-challenged NRK-49F cell model. The antioxidant potential of isolated compounds was evaluated based on their effect on antioxidant enzyme activities and lipid peroxidation levels. The results demonstrated that exposure of NRK-49F cells to glucose and oxalate stress augmented cell damage and attenuated antioxidant enzyme activities. The phytochemicals 2,2,8-trimethyl-6 formyl-chrom-3-ene-7-O-beta-D-glucopyranoside, Cornusiin B and tellimagrandin I treatment restored antioxidant enzyme activity, significantly lowered lipid peroxidation levels and effectively protected cells from glucose and oxalate stress equivalent to the known antioxidant, N-acetyl cysteine. Pterocarinin A significantly reversed cellular damage owing to glucose stress. In conclusion, the compounds isolated from E. globulus and M. styphelioides showed potential cytoprotective and anti-oxidative property against glucose- and oxalate-induced oxidative stress in NRK-49F cells. PMID- 28637362 TI - Spindle Cell Mucoepidermoid Carcinoma of the Palatine Tonsil With CRTC1-MAML2 Fusion Transcript: Report of a Rare Case in a 17-Year-Old Boy and a Review of the Literature. AB - Mucoepidermoid carcinoma (MEC) with a predominant spindle cell composition occurring in the palatine tonsil is exceedingly rare. We present a case of a 17 year-old boy with an uncommon spindle cell variant of MEC arising in the palatine tonsil. Histologically, the tumor showed a solid, noncystic architecture and was composed of a predominant population of bland spindle to fusiform cells arranged in organoid nests with interspersed goblet cells and focal areas of ductular structures. Reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization (FISH) revealed the presence of a t(11;19) CRTC1-MAML2 gene fusion in this rare variant of MEC. This is the first case report of a spindle cell MEC of the palatine tonsil, with molecular genetic confirmation. It illustrates the importance of awareness and recognition of this uncommon histological variant of MEC, which will help establish appropriate treatment and prognostication. PMID- 28637353 TI - Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming. AB - SIGNIFICANCE: The molecular events that promote the development of pulmonary hypertension (PH) are complex and incompletely understood. The complex interplay between the pulmonary vasculature and its immediate microenvironment involving cells of immune system (i.e., macrophages) promotes a persistent inflammatory state, pathological angiogenesis, and fibrosis that are driven by metabolic reprogramming of mesenchymal and immune cells. Recent Advancements: Consistent with previous findings in the field of cancer metabolism, increased glycolytic rates, incomplete glucose and glutamine oxidation to support anabolism and anaplerosis, altered lipid synthesis/oxidation ratios, increased one-carbon metabolism, and activation of the pentose phosphate pathway to support nucleoside synthesis are but some of the key metabolic signatures of vascular cells in PH. In addition, metabolic reprogramming of macrophages is observed in PH and is characterized by distinct features, such as the induction of specific activation or polarization states that enable their participation in the vascular remodeling process. CRITICAL ISSUES: Accumulation of reducing equivalents, such as NAD(P)H in PH cells, also contributes to their altered phenotype both directly and indirectly by regulating the activity of the transcriptional co-repressor C terminal-binding protein 1 to control the proliferative/inflammatory gene expression in resident and immune cells. Further, similar to the role of anomalous metabolism in mitochondria in cancer, in PH short-term hypoxia dependent and long-term hypoxia-independent alterations of mitochondrial activity, in the absence of genetic mutation of key mitochondrial enzymes, have been observed and explored as potential therapeutic targets. FUTURE DIRECTIONS: For the foreseeable future, short- and long-term metabolic reprogramming will become a candidate druggable target in the treatment of PH. Antioxid. Redox Signal. 28, 230-250. PMID- 28637365 TI - Insight into the C-F bond mechanism of molecular analogs for antibacterial drug design. AB - The activities of biological molecules usually rely on both of intra-molecular and intermolecular interactions between their function groups. These interactions include interonic attraction theory, Van der Waal's forces and the function of geometry on the individual molecules, whether they are naturally or synthetic. The purpose of this study was to evaluate the antibacterial activity of C-F bond compound using combination of experiments verification and theoretical calculation. We target on the insect natural products from the maggots of Chrysomyis megacephala Fabricius. Based on density functional theory(DFT) and B3LYP method, a theoretical study of the C-F bond on fluoride was designed to explore compounds 2 and 4 antibacterial structure-activity relationship. With the progress in DFT, first-principle calculation based on DFT has gradually become a routine method for drug design, quantum chemistry and other science fields. PMID- 28637364 TI - Comparison of Perioperative Outcomes Between Holmium Laser Enucleation of the Prostate and Robot-Assisted Simple Prostatectomy. AB - OBJECTIVES: To compare perioperative outcomes for patients undergoing holmium laser enucleation of the prostate (HoLEP) and robotic-assisted simple prostatectomy (RSP) for benign prostatic hypertrophy (BPH). METHODS: Patient demographics and perioperative outcomes were compared between 600 patients undergoing HoLEP and 32 patients undergoing RSP at two separate academic institutions between 2008 and 2015. RESULTS: Patients undergoing HoLEP and RSP had comparable ages (71 vs 71, p = 0.96) and baseline American Urological Association Symptom Scores (20 vs 24, p = 0.21). There was no difference in mean specimen weight (96 g vs 110 g, p = 0.15). Mean operative time was reduced in the HoLEP cohort (103 minutes vs 274 minutes, p < 0.001). Patients undergoing HoLEP had lesser decreases in hemoglobin, decreased transfusions rates, shorter hospital stays, and decreased mean duration of catheterization. There was no difference in the rate of complications Clavien grade 3 or greater (p = 0.33). CONCLUSIONS: HoLEP and RSP are both efficacious treatments for large gland BPH. In expert hands, HoLEP appears to have a favorable perioperative profile. Further studies are necessary to compare long-term efficacy, cost, and learning curve influences, especially as minimally invasive approaches become more widespread. PMID- 28637366 TI - HPLC-ESI-MS/MS analysis of phenolics and in vitro antioxidant activity of Epilobium angustifolium L. AB - The aerial parts of Epilobium plants are widely used as folk medicine and food around the world. The present study was aimed to investigate the antioxidant activities and active chemical constituents from Epilobium angustifolium L. The results revealed that the EtOAc extract, rich in phenolic compounds and flavonoids (16.81 +/- 0.67 g GAE/100 g extract and 4.95 +/- 0.21 g QE/100 g extract, respectively), possessed significantly antioxidant activities in reducing power, DPPH radical scavenging activity, ABTS radical scavenging activity and highly in inhibiting lipid peroxidation activity. Simultaneously, active fractions F to H from EtOAc extracts showing potent in vitro antioxidant activities also contained high content of total phenolic and flavonoid. Twenty eight compounds were identified as phenolic compounds and flavonoids by LC-MS/MS. The results illustrate that the E. angustifolium L., which is rich in phenolics, could be used as a natural resource of antioxidant ingredient. PMID- 28637367 TI - Parental perceptions of hypothermia treatment for neonatal hypoxic-ischaemic encephalopathy. AB - AIMS: Hypothermia Treatment (HT) is now the standard care for neonatal hypoxic ischaemic encephalopathy (HIE). We conducted a survey to explore parental perceptions of HT as there is little information about this in the current literature. METHODS: Postal questionnaire survey included families (n = 51) whose babies received HT at Princess Anne Hospital, Southampton, UK, with 23 questions covering communication, clinical management, follow-up, and care in general. Statistical analysis of descriptive and analytical tests were done using Minitab 16. RESULTS: The response rate was 60.8%. All parents had concerns amongst which perceptions of pain and distress were described by 41%. Temporary concerns about bonding were common (83.8%), more so in babies transferred from other hospitals (p = .04). Only 61.3% felt they had a good understanding of HT. The need for improvements in the quality (71%) and frequency of communication (48.3%) were also highlighted. CONCLUSIONS: Parents were worried about pain and distress, bonding and about outcomes after HT. Consistency in communication, regular updates, involvement of parents in decision making, strong support mechanisms and balanced discussions about long term outcomes at an early stage are of high importance to families whose babies undergo HT. PMID- 28637369 TI - Segmental resection of the uterine wall for placenta previa percreta: some clarifications. PMID- 28637368 TI - Emergency Ureteral Stone Treatment Score Predicts Outcomes of Ureteroscopic Intervention in Acute Obstructive Uropathy Secondary to Urolithiasis. AB - INTRODUCTION: Immediate ureteroscopic treatment for patients presenting to the emergency room with symptomatic ureterolithiasis is more commonly being utilized. Recent reports demonstrate good efficacy for emergency ureteroscopy (URS); however, preoperative predictors of treatment success have not been described. In this study, we report our multicenter experience with emergency URS and identify predictors of successful treatment. We also describe the Emergency Ureteral Stone Treatment (EUST) score, which integrates these predictors and stratifies patients into those that are likely and unlikely to have successful treatment. MATERIALS AND METHODS: Laboratory and radiographic data for all patients who underwent emergency URS for acute symptomatic ureterolithiasis from 2010 to 2015 were reviewed. Statistical difference among parameters for patients who were stone free (SF) and not SF was assessed with the Student's t-test. Cutoff values for significant predictors were determined using sensitivity and specificity analysis. The EUST score was determined based on the number of cutoffs a patient was below. RESULTS: Two hundred two of 247 patients (81.8%) were SF. Two complications (ureteral perforation) occurred. Stone size, duration of symptoms before presentation, and serum white blood count at presentation did not affect SF rates. 95.5% of the treatment failures were attributed to a tight ureter preventing stone access. Patients who received alpha blockers before treatment were more likely to be SF (98.0% vs 55.5%, p < 0.01). Periureteral density (PUD) was lower in SF patients (2.8 HU vs 19.6 HU, p < 0.01), whereas the increase in serum creatinine from baseline (DeltaCr) was greater in non-SF patients (0.44 mg/dL vs 0.20 mg/dL, p < 0.01). EUST score of 0, 1, and 2 correlated with SF rates of 20.6%, 81.9%, and 99.2%, respectively. CONCLUSIONS: Combined consideration of PUD and DeltaCr with the EUST score can assist in selecting optimal candidates for immediate ureteroscopic management. Administration of alpha blockers before surgery may improve success rates by providing preoperative ureteral dilation. PMID- 28637370 TI - A case of indolent AML with five-year survival without treatment. PMID- 28637371 TI - Association between dietary patterns and serum adiponectin: a cross-sectional study in a Japanese population. AB - The aim of this study was to evaluate the associations between dietary pattern, adiponectin and insulin resistance. The study population consisted of 612 men and women aged 35-69 years old who had participated in the baseline survey of Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima Prefecture. Diets and lifestyle related variables were assessed by questionnaires. Multiple regression analyses were used to analyse the relations between dietary patterns and high molecular weight (HMW) adiponectin. For further analysis, path analysis was used to test the hypothesised model of association between dietary pattern, serum adiponectin and insulin resistance. The result showed that higher score of bread and dairy pattern was directly associated with increased serum level of adiponectin in women, which was inversely related to homeostasis model assessment of insulin resistance (HOMA-IR). In conclusion, higher consumption of bread and dairy products, and low intake of rice may be associated with increased serum adiponectin in women. PMID- 28637372 TI - Recent migration and sample representativeness in a Danish genetic study. PMID- 28637373 TI - Efficacy, pharmacokinetic and pharmacodynamic evaluation of apaziquone in the treatment of non-muscle invasive bladder cancer. AB - INTRODUCTION: Apaziquone (also known as EO9 and QapzolaTM) is a prodrug that is activated to DNA damaging species by oxidoreductases (particularly NQO1) and has the ability to kill aerobic and/or hypoxic cancer cells. Areas covered: Whilst its poor pharmacokinetic properties contributed to its failure in phase II clinical trials when administered intravenously, these properties were ideal for loco-regional therapies. Apaziquone demonstrated good anti-cancer activity against non-muscle invasive bladder cancer (NMIBC) when administered intravesically to marker lesions and was well tolerated with no systemic side effects. However, phase III clinical trials did not reach statistical significance for the primary endpoint of 2-year recurrence in apaziquone over placebo although improvements were observed. Post-hoc analysis of the combined study data did indicate a significant benefit for patients treated with apaziquone, especially when the instillation of apaziquone was given 30 min or more after surgery. A further phase III study is ongoing to test the hypotheses generated in the unsuccessful phase III studies conducted to date. Expert opinion: Because of its specific pharmacological properties, Apaziquone is excellently suited for local therapy such as NMIBC. Future studies should include proper biomarkers. PMID- 28637374 TI - Facial emotion recognition in Parkinson's disease: Association with age and olfaction. AB - OBJECTIVE: The ability to recognize facial emotion expressions has been reported to be impaired in Parkinson's disease (PD), yet previous studies showed inconsistent findings. The aim of this study was to further investigate facial emotion recognition (FER) in PD patients and its association with demographic and clinical parameters (including motor and nonmotor symptoms). METHOD: Thirty-four nondemented PD patients and 24 age- and sex-matched healthy controls (HC) underwent clinical neurological and neuropsychological assessment, standardized olfactory testing with Sniffin' Sticks, and the Ekman 60 Faces Emotion Recognition Test. RESULTS: PD patients had a significantly lower score on the total FER task than HC (p = .006), even after controlling for the potential confounding factors depression and apathy. The PD group had a specific impairment in the recognition of surprise (p = .007). The recognition of anger approached statistical significance (p = .07). Increasing chronological age and age at disease onset were associated with worse performance on the FER task in PD patients. Olfactory function along with PD diagnosis predicted worse FER performance within all study participants. CONCLUSION: Facial emotion recognition and especially the recognition of surprise are significantly impaired in PD patients compared with age- and sex-matched HC. The association of FER with age and olfactory function is endorsed by common structures that undergo neurodegeneration in PD. The relevance of FER in social interaction stresses the clinical relevance and the need for further investigation in this field. Future studies should also determine whether impaired FER is already present in premotor stages of PD. PMID- 28637375 TI - Anticoagulant therapy for recurrent in-stent thrombosis following carotid artery stenting: A case report. AB - We report a case in which strict anticoagulant therapy management was useful for a recurrent in-stent thrombosis after carotid artery stenting (CAS). An 84-year old man presented with cognitive decline that progressed rapidly over two months. Head magnetic resonance imaging showed an acute-stage infarct occurring frequently in the right cerebral hemisphere, and he underwent hospitalization and treatment. On neck magnetic resonance angiography (MRA), severe stenosis was found at the origin of the right internal carotid artery. Since he took aspirin, clopidogrel, and a statin after placement of an indwelling coronary stent, we treated him by adding argatroban and edaravone drip therapy to his existing medication. CAS was performed on day 15 of the hospitalization. A small in-stent thrombosis with plaque protrusion was observed on a carotid sonogram performed at the second day after CAS, and re-examination at the seventh day confirmed enlargement of the lesion and an increase in peak systolic velocity; thus, a second CAS procedure was performed on the same day. After the second CAS, oral cilostazol was added for triple antiplatelet therapy (TAPT), but as the in-stent thrombosis increased further, we started a continuous infusion of heparin with the goal of an activated partial thromboplastin time (APTT) of 50 to 65 seconds. After starting heparin, the lesion did not progress; after 14 days of continuous heparin infusion, the patient was switched to TAPT, and regression of the plaque was confirmed. This case demonstrated to us that controlled anticoagulation therapy can be an effective treatment for cases in which a thrombus recurs within a stent after CAS. PMID- 28637376 TI - Cystometrogram: the low-cost method for rural areas and its benefits. AB - Cystometrography (CMG) is a means of studying bladder pressure. It is a very useful diagnostic tool in patients with lower urinary tract symptoms for which a simple cystoscopy will not offer sufficient information to form a diagnosis. Of the 8893 patients who underwent screening for urological conditions in rural northeast India during 2010-2014, 280 with lower urinary tract symptoms were investigated with a combination of cystoscopy and CMG. By corresponding CMG diagnosis and treatment, we could examine patients' overall satisfaction with both the procedure and the treatment. We describe a low-cost method of CMG and our results using this method in rural areas of India. PMID- 28637378 TI - Surveillance to Inform Control of Emerging Plant Diseases: An Epidemiological Perspective. AB - The rise in emerging pathogens and strains has led to increased calls for more effective surveillance in plant health. We show how epidemiological insights about the dynamics of disease spread can improve the targeting of when and where to sample. We outline some relatively simple but powerful statistical approaches to inform surveillance and describe how they can be adapted to include epidemiological information. This enables us to address questions such as: Following the first report of an invading pathogen, what is the likely incidence of disease? If no cases of disease have been found, how certain can we be that the disease was not simply missed by chance? We illustrate the use of spatially explicit stochastic models to optimize targeting of surveillance and control resources. Finally, we discuss how modern detection and diagnostic technologies as well as information from passive surveillance networks (e.g., citizen science) can be integrated into surveillance strategies. PMID- 28637377 TI - The Candidatus Liberibacter-Host Interface: Insights into Pathogenesis Mechanisms and Disease Control. AB - "Candidatus Liberibacter" species are associated with economically devastating diseases of citrus, potato, and many other crops. The importance of these diseases as well as the proliferation of new diseases on a wider host range is likely to increase as the insects vectoring the "Ca. Liberibacter" species expand their territories worldwide. Here, we review the progress on understanding pathogenesis mechanisms of "Ca. Liberibacter" species and the control approaches for diseases they cause. We discuss the Liberibacter virulence traits, including secretion systems, putative effectors, and lipopolysaccharides (LPSs), as well as other important traits likely to contribute to disease development, e.g., flagella, prophages, and salicylic acid hydroxylase. The pathogenesis mechanisms of Liberibacters are discussed. Liberibacters secrete Sec-dependent effectors (SDEs) or other virulence factors into the phloem elements or companion cells to interfere with host targets (e.g., proteins or genes), which cause cell death, necrosis, or other phenotypes of phloem elements or companion cells, leading to localized cell responses and systemic malfunction of phloem. Receptors on the remaining organelles in the phloem, such as plastid, vacuole, mitochondrion, or endoplasmic reticulum, interact with secreted SDEs and/or other virulence factors secreted or located on the Liberibacter outer membrane to trigger cell responses. Some of the host genes or proteins targeted by SDEs or other virulence factors of Liberibacters serve as susceptibility genes that facilitate compatibility (e.g., promoting pathogen growth or suppressing immune responses) or disease development. In addition, Liberibacters trigger plant immunity response via pathogen-associated molecular patterns (PAMPs, such as lipopolysaccharides), which leads to premature cell death, callose deposition, or phloem protein accumulation, causing a localized response and/or systemic effect on phloem transportation. Physical presence of Liberibacters and their metabolic activities may disturb the function of phloem, via disrupting osmotic gradients, or the integrity of phloem conductivity. We also review disease management strategies, including promising new technologies. Citrus production in the presence of Huanglongbing is possible if the most promising management approaches are integrated. HLB management is discussed in the context of local, area-wide, and regional Huanglongbing/Asian Citrus Psyllid epidemiological zones. For zebra chip disease control, aggressive psyllid management enables potato production, although insecticide resistance is becoming an issue. Meanwhile, new technologies such as clustered regularly interspaced short palindromic repeat (CRISPR)-derived genome editing provide an unprecedented opportunity to provide long-term solutions. PMID- 28637379 TI - Neuropsychological outcomes of pediatric demyelinating diseases: a review. AB - Immune-mediated central nervous system (CNS) demyelinating diseases impact various areas of the brain, optic nerves, and/or spinal cord and can result in a wide range of neurologic symptoms including adverse cognitive outcomes. Neuropsychological outcomes in adult multiple sclerosis (MS) are well documented, while literature on such outcomes in pediatric cohorts is more limited. Furthermore, literature on neuropsychological outcomes in pediatric acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and transverse myelitis (TM) is even more limited. This paper is the first to review what is known about neuropsychological outcomes associated with immune-mediated CNS demyelinating diseases, with a focus on pediatric MS, ADEM, NMO, and TM. Additionally, this review illuminates the need to clarify differences in neuropsychological sequelae between conditions, characterize longitudinal cognitive outcomes, and investigate neuropsychological outcomes in relation to clinical variables (e.g., age of onset, disease duration, number of relapses) and psychosocial variables (e.g., fatigue, emotional problems, behavioral functioning) to better understand neuropsychological outcomes associated with these conditions. PMID- 28637381 TI - Role of Caspase-3-Mediated Apoptosis in Chronic Caspase-3-Cleaved Tau Accumulation and Blood-Brain Barrier Damage in the Corpus Callosum after Traumatic Brain Injury in Rats. AB - Traumatic brain injury (TBI) may be a significant risk factor for development of neurodegenerative disorders such as chronic traumatic encephalopathy (CTE), post traumatic epilepsy (PTE), and Alzheimer's (AD) and Parkinson's (PD) diseases. Chronic TBI is associated with several pathological features that are also characteristic of neurodegenerative diseases, including tau pathologies, caspase 3-mediated apoptosis, neuroinflammation, and microvascular alterations. The goal of this study was to evaluate changes following TBI in cleaved-caspase-3 and caspase-3-cleaved tau truncated at Asp421, and their relationships to cellular markers potentially associated with inflammation and blood-brain (BBB) barrier damage. We studied astrocytes (glial fibrillary acidic protein [GFAP]), microglia (ionized calcium-binding adapter molecule 1 [Iba1]), BBB (endothelial barrier antigen [EBA]), and activated microglia/macrophages (cluster of differentiation 68 [CD68]). We employed immunohistochemistry at different time points from 24 h to 3 months after controlled cortical impact (CCI) injury in rats, with particular interest in white matter. The study demonstrated that CCI caused chronic upregulation of cleaved-caspase-3 in the white matter of the corpus callosum. Increases in cleaved-caspase-3 in the corpus callosum were accompanied by accumulation of caspase-3-cleaved tau, with increasing perivascular aggregation 3 months after CCI. Immunofluorescence experiments further showed cellular co-localization of cleaved-caspase-3 with GFAP and CD68 and its adjacent localization with EBA, suggesting involvement of apoptosis and neuroinflammation in mechanisms of delayed BBB and microvascular damage that could contribute to white matter changes. This study also provides the first evidence that evolving upregulation of cleaved-caspase-3 is associated with accumulation of caspase-3 cleaved tau following experimental TBI, thus providing new insights into potential common mechanisms mediated by caspase-3 and underlying chronic TBI pathologies and neurodegenerative diseases. PMID- 28637380 TI - Diabetes-related weight change in a Canadian First Nation cohort. AB - The Canadian First Nations population is disproportionately burdened by diabetes and diabetes complications. Body weight management is purported to be important in the prevention and management of diabetes. In this study, we sought to describe weight change in a First Nation cohort according to diabetes status and management. Study data were from two diabetes screening studies in Sandy Bay First Nation in Manitoba, Canada, collected in 2002/2003 (baseline) and 2011/2012 (follow-up). The cohort was composed of respondents to both screening studies (n=171). Fasting blood samples, anthropometric, health and demographic data were collected. At baseline, 24.8% (n=41) of the cohort members had diabetes. At follow-up, an additional 20.6% (n=34) developed diabetes. Among all participants with diabetes (long-term and incident cases), 66.6% lost weight between the two study periods. Among only participants with long-term diabetes (>8 years), 31.7% lost >10 kg. HbA1c at baseline, positive change in HbA1c over time, and use of metformin were significantly associated with weight loss >=5%, independent of age, sex, and BMI at baseline. Further research is needed to better understand if and how diabetes-related weight loss contributes to morbidity and mortality in this First Nation population. PMID- 28637382 TI - Rates and Correlates of Binge Drinking Among College Students With Disabilities, United States, 2013. AB - OBJECTIVE: Our objective was to provide the first comprehensive picture of alcohol use and binge drinking by US college students with disabilities (SWDs), who represent at least 11% (1.6 million) of the US college student population. METHODS: In fall 2013, we used a stratified random sampling technique to identify and recruit 2440 SWDs from 122 US colleges and universities. A total of 1285 (53%) SWDs from 61 (50%) colleges and universities completed a survey of alcohol and other drug use and the use of substances by student peers. We conducted 4 multiple logistic regression analyses to compare binge-drinking and non-binge drinking SWDs by potential correlates of such use and a final model that included only significant variables. RESULTS: SWDs aged <21 vs >=21 (odds ratio [OR] = 0.90; 95% confidence interval [CI], 0.82-0.99) who spent more time vs less time socializing (OR = 1.24; 95% CI, 1.11-1.38), who spent less time vs more time studying (OR = -0.89; 95% CI, -0.80 to -0.99), and who used vs did not use marijuana (OR = 1.44; 95% CI, 1.18-1.75) or amphetamines (OR = 1.82; 95% CI, 1.15 2.89) were significantly more likely to binge drink. SWDs who reported using barbiturates were less likely to binge drink than were those who did not use barbiturates (OR = -0.36; 95% CI, -0.21 to -0.61). In the final model, use of amphetamines (OR = 1.74; 95% CI, 1.15-2.65) or marijuana (OR = 1.60; 95% CI, 1.32 1.94) was the highest predictor of binge drinking. CONCLUSION: SWDs' reported rates of binge drinking, although high, were not as high as those of nondisabled college students. Nevertheless, prevention efforts should be targeted toward college SWDs. PMID- 28637383 TI - Inflammation-Induced Osteogenesis in a Rabbit Tibia Model. AB - Pathologic conditions associated with bone formation can serve as models to identify bone-promoting mediators. The inflammatory response to bacterial infections generally leads to osteolysis and impaired bone healing, but paradoxically, it can also have pro-osteogenic effects. As a potential model to investigate pro-osteogenic stimuli, this study characterizes the bone formation in an established rabbit tibia model of periprosthetic infection. Our hypothesis was that the infection with Staphylococcus aureus (S. aureus) correlates with bone formation as a response to local inflammation. Fluorochromes showed excessive subperiosteal bone formation in infected tibiae, starting the first week and continuing throughout the study period. Despite the observed cortical lysis on micro-CT after 28 days, infection resulted in a twofold higher bone volume in the proximal tibiae compared to uninfected controls. The ipsilateral fibulae, nor the contralateral fibulae or tibiae were affected by infection. Next, we sought to confine the cause of stimulated bone formation to the isolated S. aureus cell wall. In absence of virulent bacterial infection, the S. aureus cell wall extract induced bone in a more favorable way without cortical lysis. This suggests that the sterile inflammatory reaction to bacterial antigens may be harnessed for bone regenerative purposes. Future investigations in this rabbit tibia model can lead to further identification of effective stimuli for clinical application. PMID- 28637384 TI - Long-Term Effects of High-Protein Diets on Renal Function. AB - Chronic kidney disease (CKD) has a prevalence of approximately 13% and is most frequently caused by diabetes and hypertension. In population studies, CKD etiology is often uncertain. Some experimental and observational human studies have suggested that high-protein intake may increase CKD progression and even cause CKD in healthy people. The protein source may be important. Daily red meat consumption over years may increase CKD risk, whereas white meat and dairy proteins appear to have no such effect, and fruit and vegetable proteins may be renal protective. Few randomized trials exist with an observation time greater than 6 months, and most of these were conducted in patients with preexisting diseases that dispose to CKD. Results conflict and do not allow any conclusion about kidney-damaging effects of long-term, high-protein intake. Until additional data become available, present knowledge seems to substantiate a concern. Screening for CKD should be considered before and during long-term, high-protein intake. PMID- 28637385 TI - Applying cognitive restructuring in therapy: The clinical reality in Spain. AB - : Cognitive restructuring is one of the most widely used techniques among psychologists of different orientations. However, there is a lack of clarity in what concerns its precise definition, functioning, effectiveness, and components. OBJECTIVE: To obtain precise information on how psychotherapists use cognitive restructuring in their clinical practice in Spain. METHOD: A survey study was conducted following a descriptive quantitative methodology, with a cross sectional design and a non-random sampling method. Three hundred and twenty psychotherapists responded to a questionnaire, created ad hoc, on cognitive restructuring. RESULTS: Cognitive restructuring is widely used by therapists with different levels of experience, training, and following different psychotherapeutic approaches. Furthermore, it is applied to address a wide variety of psychological problems. There exist relevant differences in the use of the technique depending on the therapists' level of experience. CONCLUSIONS: This study has shown, for the first time, how cognitive restructuring is applied in daily clinical practice. The main implications of these results are discussed, and new lines of inquiry are proposed. PMID- 28637387 TI - Immunopathology of Chikungunya Virus Infection: Lessons Learned from Patients and Animal Models. AB - Chikungunya virus (CHIKV) is an arthropod-borne alphavirus that causes acute and chronic arthritis. The virus reemerged in the Indian Ocean islands in 2005-2006 and is responsible for outbreaks in the Caribbean islands and the Americas since late 2013. Despite the wealth of research over the past 10 years, there are no commercially available antiviral drugs or vaccines. Treatment usually involves analgesics, anti-inflammatory drugs, and supportive care. Most studies have been focused on understanding the pathogenesis of CHIKV infection through clinical observation and with animal models. In this review, the clinical manifestations of CHIKV that define the disease and the use of relevant animal models, from mice to nonhuman primates, are discussed. Understanding key cellular factors in CHIKV infection and the interplay with the immune system will aid in the development of preventive and therapeutic approaches to combat this painful viral disease in humans. PMID- 28637386 TI - Enzymes and Enzyme Activity Encoded by Nonenveloped Viruses. AB - Viruses are obligate intracellular parasites that rely on host cell machineries for their replication and survival. Although viruses tend to make optimal use of the host cell protein repertoire, they need to encode essential enzymatic or effector functions that may not be available or accessible in the host cellular milieu. The enzymes encoded by nonenveloped viruses-a group of viruses that lack any lipid coating or envelope-play vital roles in all the stages of the viral life cycle. This review summarizes the structural, biochemical, and mechanistic information available for several classes of enzymes and autocatalytic activity encoded by nonenveloped viruses. Advances in research and development of antiviral inhibitors targeting specific viral enzymes are also highlighted. PMID- 28637388 TI - Progressive Multifocal Leukoencephalopathy: Endemic Viruses and Lethal Brain Disease. AB - In 1971, the first human polyomavirus was isolated from the brain of a patient who died from a rapidly progressing demyelinating disease known as progressive multifocal leukoencephalopathy. The virus was named JC virus after the initials of the patient. In that same year a second human polyomavirus was discovered in the urine of a kidney transplant patient and named BK virus. In the intervening years it became clear that both viruses were widespread in the human population but only rarely caused disease. The past decade has witnessed the discovery of eleven new human polyomaviruses, two of which cause unusual and rare cancers. We present an overview of the history of these viruses and the evolution of JC polyomavirus-induced progressive multifocal leukoencephalopathy over three different epochs. We review what is currently known about JC polyomavirus, what is suspected, and what remains to be done to understand the biology of how this mostly harmless endemic virus gives rise to lethal disease. PMID- 28637389 TI - Occurrence of polycyclic aromatic hydrocarbons in various types of raw oilseeds from different regions of China. AB - Ninety-five samples of 18 types of oilseeds used for edible oil production were collected from different origins of China. The occurrence of polycyclic aromatic hydrocarbons (PAHs) in these oilseeds was presented after the analysis by using a simplified gas chromatography-mass spectrometry method. The results indicated that some of these oilseeds were not found of indeno[1,2,3-cd]pyrene, dibenz[a,h]anthracene, and benzo[ghi]perylene. Naphthalene and phenanthrene had higher concentration than other individual PAH in the same sample. The range of BaP, PAH4, and PAH16 concentration in these 95 samples was 0.1-14.1, 1.1-74.6, and 81.8-466.8 ug/kg, respectively. LPAH accounted for 87.1-99.5% of the total concentration of PAHs in all of studied oilseeds. The average concentrations of PAH16 in different types of oilseed were different. Meanwhile, the samples collected from different origins of China presented various levels of PAH16. The differences between herbaceous plant oilseeds and woody plant oilseeds in terms of PAH levels were not observed. PMID- 28637390 TI - Isolation, structural elucidation and antiplasmodial activity of fucosterol compound from brown seaweed, Sargassum linearifolium against malarial parasite Plasmodium falciparum. AB - The brown seaweed, Sargassum linearifolium (Turner) C. Agardh, 1820 is commonly available along the south-east coast of India. Its compound fucosterol was isolated and confirmed through spectral characterisation and chemical transformation methods. The antiplasmodial effect of the isolated fucosterol was investigated against the 3D7 chloroquine sensitive Plasmodium falciparum strain, parasitaemia percentage was determined at 48 h and morphological change was studied through microscopic examination after Giemsa staining. A perceptible antiplasmodial effect was produced by fucosterol compound against the P. falciparum and positive control, chloroquine with the IC50 values (MUg/mL) of 7.48 and 12.81, respectively. Fucosterol showed higher antiplasmodial activity as compared to chloroquine. It is inferred that both the fucosterol and chloroquine could have inhibited the schizont stage of the parasite during the intra erythrocyte asexual development. The findings underline the usefulness of the seaweed-based fucosterol and further studies are warranted. PMID- 28637391 TI - A study of burden of care and its correlates among family members supporting relatives and loved ones with traumatic spinal cord injuries. AB - OBJECTIVE: To understand and describe in a sample of caregivers of persons with spinal cord injury, their burden of care, resilience and life satisfaction and to explore the relationship between these variables. DESIGN: Cross-sectional design. SETTING: One Spinal Cord Injury Acute Inpatient Unit from a general hospital. SUBJECTS: Seventy-five relatives of persons with spinal cord injuries (84% women) with a mean age of 48.55 ( SD = 12.55) years. INTERVENTIONS: None. MEASURES: Demographics (neurological loss and severity according to the American Spinal Injury Association criteria), the Zarit Burden Interview, the Resilience Scale and the Life Satisfaction Checklist. RESULTS: All caregivers experienced feelings of different intensities of burden (52% mild-to-moderate, 43% moderate-to-severe and 5% severe), and none of them expressed little or no burden at the assessment moment. Caregivers' main worries were "dependence" and "the future of the injured." Resilience was medium-to-high (mean = 141.93, SD = 23.44) for the whole sample with just a minority of them revealing low (15%) or very low resilience (7%). The highest scores were obtained in relation to "caregivers' independence" and "meaning of their lives." Life satisfaction scores were medium-to-high (mean = 36.6, SD = 6). These scores were not related to demographics or the severity of the injury. Zarit Burden Interview scores were negatively correlated to Resilience Scale ( r = -.370, P = .001) and Life Satisfaction Checklist scores ( r = -.412, P < .001). CONCLUSION: More resilient and satisfied caregivers experienced lower burden. Burden is moderate-to-high and mainly related to uncertainty about the future, caregivers' insecurity with caregiving and dependence of the injured. PMID- 28637392 TI - Thoughts on human geriatric rehabilitation from a geriatric greyhound: lessons learned from the rehabilitation given to an aged dog. PMID- 28637393 TI - Introductory paragraph. PMID- 28637394 TI - Comparison of bone healing, as assessed by computed tomography, following tibial tuberosity advancement in dogs with and without autogenous cancellous bone grafts. AB - AIMS: To objectively compare measures of bone healing, using computed tomography (CT) in dogs following bilateral tibial tuberosity advancement (TTA), between tibiae treated with and without autogenous cancellous bone grafts. METHODS: Ten dogs with bilateral cranial cruciate ligament disease requiring surgical stabilisation were prospectively recruited to undergo single-session bilateral TTA, with only one, randomly assigned, tibia receiving bone graft in the osteotomy deficit. Bone healing at the osteotomy site was assessed using CT performed 38-70 days post-operatively. CT images were evaluated using both objective measurements of osseous bridging and subjective evaluation by six radiologists. Repeated measures ANOVA was used to compare the objective outcomes between the grafted and non-grafted tibiae. RESULTS: The mean percentage of the osteotomy deficit bridged at the lateral cortex was greater in grafted (77.6, SD 35.2%) compared to non-grafted (63.0, SD 36.5%) tibiae (p=0.001), but did not differ at the medial cortex (p=0.1). The mean minimum callus width was greater in grafted (7.2, SD 3.3 mm) compared to non-grafted (3.6, SD 2.9 mm) tibiae (p<0.001). There was no difference in mean attenuation (measured in Hounsfield units) of the callus between grafted and non-grafted tibiae (p=0.5). The grafted tibia was deemed to have superior bone healing in 50/60 subjective assessments made by radiologists. CONCLUSIONS: Superior osseous bridging was detected by CT analysis following TTA using autogenous cancellous bone grafts compared with no graft. This was shown by greater bridging percentage at the lateral cortex and formation of a broader callus. Qualitative assessments made by six radiologists also supported the conclusion that bone healing was improved by use of autogenous cancellous bone graft. CT was a useful method for assessing evidence of bone healing following TTA. CLINICAL RELEVANCE: These findings justify the application of autogenous cancellous bone graft to augment healing following TTA in dogs. PMID- 28637397 TI - Ursolic acid derivatives for pharmaceutical use: a patent review (2012-2016). AB - INTRODUCTION: Ursolic acid (UA), belongs to a group of pentacyclic triterpenoids and is known to possess some very interesting biological properties. Protocols have been developed in order to synthesize bioactive UA analogs which have resulted in numerous ursolic acid analogs being synthesized during the period 2012-2016. Ursolic acid and its analogues can be employed to treat various cancers, inflammatory diseases, diabetes, Parkinson's disease, Alzheimer's disease, hepatitis B, hepatitis C and AIDS to mention but a few. Areas covered: This review covers patents on therapeutic activities of ursolic acid (UA) and its synthetic derivatives published during the four year period 2012-2016. A discussion about structure-activity relationships (SAR) of these analogs is also included. Expert opinion: Ursolic acid and its synthetic derivatives demonstrated excellent anticancer, antidiabetic, antiarrhythmic, anti-hyperlipidemic, antimicrobial, anti-hypercholesterolemic, and anti-cardiovascular properties. Additionally, various ursolic acid analogues have been synthesized through modification at positions C2-OH, C3-OH and C17-CO2H. It is noteworthy that the C 17 amide and amino analogs of UA possessed better anticancer activity compared to the parent compound (UA). Most importantly, UA has the potential to conjugate with other anticancer drugs or be transformed into its halo derivatives since this will greatly facilitate scientists to get lead compounds in cancer drug discovery. PMID- 28637398 TI - What Do We Know About NOD-Like Receptors in Plant Immunity? AB - The first plant disease resistance (R) genes were identified and cloned more than two decades ago. Since then, many more R genes have been identified and characterized in numerous plant pathosystems. Most of these encode members of the large family of intracellular NLRs (NOD-like receptors), which also includes animal immune receptors. New discoveries in this expanding field of research provide new elements for our understanding of plant NLR function. But what do we know about plant NLR function today? Genetic, structural, and functional analyses have uncovered a number of commonalities and differences in pathogen recognition strategies as well as how NLRs are regulated and activate defense signaling, but many unknowns remain. This review gives an update on the latest discoveries and breakthroughs in this field, with an emphasis on structural findings and some comparison to animal NLRs, which can provide additional insights and paradigms in plant NLR function. PMID- 28637396 TI - Modulation of miR29a improves impaired post-ischemic angiogenesis in hyperglycemia. AB - Individuals with diabetes mellitus suffer from impaired angiogenesis and this contributes to poorer peripheral arterial disease outcomes. In experimental peripheral arterial disease, angiogenesis and perfusion recovery are impaired in mice with diabetes. We recently showed that a disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) is upregulated in ischemic endothelial cells and plays a key role in post-ischemic angiogenesis and perfusion recovery following experimental peripheral arterial disease. Here we investigated the role of miR29a in the regulation of endothelial cell ADAM12 expression in ischemia and how hyperglycemia negatively affects this regulation. We also explored whether modulating miR29a can improve impaired post-ischemic angiogenesis associated with hyperglycemia. Additionally, we tested whether miR29a modulation could improve post ischemic angiogenesis in the setting of impaired vascular endothelial growth factor signaling. We forced miR29a expression in ischemic endothelial cells and assessed ADAM12 expression. We also evaluated whether hyperglycemia in vivo and in vitro impair ischemia-induced ADAM12 upregulation and miR29a downregulation. Lastly, we determined whether modulating endothelial cell miR29a expression in ischemia and hyperglycemia could improve impaired endothelial cell functions. We found under ischemic conditions where ADAM12 is upregulated in endothelial cells, miR29a is downregulated. Forced expression of miR29a in ischemic endothelial cell prevented ADAM12 upregulation . In ischemic hind limbs of mice with type 1 diabetes and in endothelial cells exposed to simulated ischemia plus hyperglycemia, ADAM12 upregulation and miR29a downregulation were blunted while angiogenesis was impaired. Knocking down miR29a with an miR29a inhibitor was sufficient to improve ADAM12 upregulation and angiogenesis in simulated ischemia plus hyperglycemia. It was also sufficient to improve perfusion recovery in type 1 diabetes mellitus mice in vivo and angiogenesis in vitro even when vascular endothelial growth factor signaling was impaired with blocking antibodies. In conclusion, MiR29a regulates endothelial cell ADAM12 upregulation in ischemia and this is impaired in hyperglycemia. Modulating miR29a improves impaired post ischemic angiogenesis associated with hyperglycemia. Impact statement Individuals with diabetes are more likely to develop peripheral arterial disease (PAD), and when PAD is present, in those with diabetes, it is more severe and there is currently no effective medical treatment for impaired blood flow which occurs in diabetics with PAD. The current work advances the field by providing an understanding of a molecular mechanism involved in impaired post ischemic angiogenesis in diabetes. It shows for the first time that failure to downregulate miR29a in ischemic diabetic tissues is a major contributing factor to poor perfusion recovery in experimental PAD, and miR29a is elevated in skeletal muscle samples from human diabetics compared with levels in those without diabetes. Knocking down the elevated miR29a in ischemic diabetic mouse hind limbs improved perfusion recovery following experimental PAD. This shows miR29a modulation as a novel therapeutic target for improving blood flow in diabetics with PAD. PMID- 28637399 TI - * Biomineralized Recombinant Collagen-Based Scaffold Mimicking Native Bone Enhances Mesenchymal Stem Cell Interaction and Differentiation. AB - The need of synthetic bone grafts that recreate from macro- to nanoscale level the biochemical and biophysical cues of bone extracellular matrix has been a major driving force for the development of new generation of biomaterials. In this study, synthetic bone substitutes have been synthesized via biomimetic mineralization of a recombinant collagen type I-derived peptide (RCP), enriched in tri-amino acid sequence arginine-glycine-aspartate (RGD). Three-dimensional (3D) isotropic porous scaffolds of three different compositions are developed by freeze-drying: non-mineralized (RCP, as a control), mineralized (Ap/RCP), and mineralized scaffolds in the presence of magnesium (MgAp/RCP) that closely imitate bone composition. The effect of mineral phase on scaffold pore size, porosity, and permeability, as well as on their in vitro kinetic degradation, is evaluated. The ultimate goal is to investigate how chemical (i.e., surface chemistry and ion release from scaffold) together with physical signals (i.e., surface nanotopography) conferred via biomimetic mineralization can persuade and guide mesenchymal stem cell (MSC) interaction and fate. The three scaffold compositions showed optimum pore size and porosity for osteoconduction, without significant differences between them. The degradation tests confirmed that MgAp/RCP scaffolds presented higher reactivity under physiological condition compared to Ap/RCP ones. The in vitro study revealed an enhanced cell growth and proliferation on MgAp/RCP scaffolds at day 7, 14, and 21. Furthermore, MgAp/RCP scaffolds potentially promoted cell migration through the inner areas reaching the bottom of the scaffold after 14 days. MSCs cultured on MgAp/RCP scaffolds displayed higher gene and protein expressions of osteogenic markers when comparing them with the results of those MSCs grown on RCP or Ap/RCP scaffolds. This work highlights that mineralization of recombinant collagen mimicking bone mineral composition and morphology is a versatile approach to design smart scaffold interface in a 3D model guiding MSC fate. PMID- 28637400 TI - Impulse Oscillometry System and Anthropometric Variables of Preschoolers, Children and Adolescents Systematic Review. AB - BACKGROUND: To identify the anthropometric variables in equations/reference values of impulse oscillometry system (IOS) parameters in preschoolers, children and adolescents. METHOD: Systematic search on the databases MEDLINE/Ovid, SCOPUS and SciELO using the key words "preschool, child and adolescent", "impulse oscillometry", "reference values" and its variations. RESULTS: This review considered a total of 13 articles. The studies presented height, weight, sex and age as the variables correlated to oscillometric parameters. Most studies do not present the correlation values of analyzed variables, and only a few presented the results considering gender differences. The coefficients of determination of the equations were low, specially for the samples including preschoolers. Height was identified as the most influent predictive variable to IOS parameters in the studied age group. CONCLUSION: Anthropometric variables, especially height, plays an important role determining reference values/equations for oscillometric parameters, however, the data acquisition method should be standardized. PMID- 28637401 TI - Ambulatory Arterial Stiffness Index (AASI) is Unable to Estimate Arterial Stiffness of Hypertensive Subjects: Role of Nocturnal Dipping of Blood Pressure. AB - BACKGROUND: Ambulatory Arterial Stiffness Index (AASI) has been proposed as an indirect and simpler method to estimate the Arterial Stiffness (AS). AASI, calculated from a set of data collected during a 24-hours ambulatory blood pressure monitoring (ABPM), is defined as 1 minus the regression slope of diastolic on systolic blood pressure (BP) values. For a given increase in diastolic BP, the increase in systolic BP is smaller in a compliant compared to a stiff artery; the stiffer the arterial tree, the closer AASI is to 1. AASI was demonstrated to predict cardiovascular mortality, cerebrovascular events and to be associated with target organ damage. Taking into account the almost complete absence of data regarding the ability of AASI to predict the different degree of AS when hypertensives are divided into four classes of dipping in relation to the extent of the nocturnal reduction of BP (extreme dippers, dippers, mild dippers and reverse dippers) aim to clarify the ability of AASI to estimate the different degree of AS of hypertensive subjects with different nocturnal BP profile and resulting in different extent of organ damage. MATERIALS AND METHODS: We enrolled 816 subjects (403 men and 413 women) with essential hypertension, referred to the U.O.C of Medicina Interna e Cardioangiologia of the University of Palermo; 173 subjects (71 men and 102 women, mean age 44.4 +/- 14.6 years) without a history of hypertension were enrolled as controls. RESULTS: The analysis of data was performed by dividing the population into four categories in relation to the extent of the nocturnal decline of BP: 124 extreme dipper (mean age 54,8 +/- 12,4 years, men 46.8 %); 287 dipper (mean age 55,9 +/- 14,2 years, men 54,0 %); 271 mild dipper (mean age 61,5 +/- 14,7 years, men 52,0 %); 134 reverse dipper (mean age 61,5 +/- 14,7 years, men 33.6 %). The mean value of AASI was significantly higher for mild and reverse dippers versus control patients and versus the other categories of dipping. The multiple regression analysis with AASI as the dependent variable confirmed the significant association between AASI and nocturnal dip (p: 0.015). The Multinomial Logistic Regression Analysis, in which AASI values were adjusted for the main confounders (age, sex, Body Mass Index, 24h SBP, 24h DBP) showed that the association between AASI and dipping is maintained only for dipper and extreme dipper hypertensives, missing the significance for mild and reverse subjects. CONCLUSION: 1) AASI levels are associated with night-to-day BP ratio; 2) Lower levels of AASI are significantly associated to extreme dipper and dipper BP nocturnal profile when compared to healthy controls. 3) After correction for the major confounding factors, the association between AASI and the high-damaged class of hypertensive subjects with lower or no nocturnal fall of BP is lost. Our findings support the hypothesis that AASI is unable to estimate AS of older hypertensive subjects with a high burden of organ and vascular damage and several comorbidities, probably because the nocturnal reduction of BP is the main determinant of AASI, being more powerful than AS itself. PMID- 28637402 TI - Antioxidant SkQ1 Alleviates Signs of Alzheimer's Disease-like Pathology in Old OXYS Rats by Reversing Mitochondrial Deterioration. AB - BACKGROUND: Mitochondrial dysfunction is called the missing link between brain aging and Alzheimer's disease (AD), the most common type of age-related dementia worldwide. Among the most advanced and promising of approaches to prevention or slowing of AD are therapeutic strategies targeting mitochondria. OBJECTIVE: Mitochondria-targeted antioxidant SkQ1 can suppress the development of AD signs, but its therapeutic potential in AD at clinical stages is currently unknown. METHOD: Using OXYS rats that simulate key characteristics of sporadic AD, we evaluated effects of SkQ1 treatment from the age of 19 to 24 months on the locomotor and exploratory activities, signs of neurodegeneration detectable by magnetic resonance imaging (MRI), amyloid-beta (Abeta) protein levels in the hippocampus and serum, and structure of the mitochondrial apparatus in hippocampal neurons. RESULTS: Treatment with SkQ1 increased behavioral activity in OXYS and Wistar (control) rats. According to MRI, SkQ1 decreased the percentage of animals with demyelination only among Wistar rats. At the same time, the antioxidant reduced hippocampal Abeta1-40 and Abeta1-42 protein levels in both rat strains and did not affect serum Abeta levels. The number of mitochondria was significantly lower in OXYS rats; SkQ1 had no effect on this parameter but significantly reduced the destructive changes in mitochondria of both rat strains. As a result, in OXYS rats, the proportion of severely damaged mitochondria decreased, whereas in Wistar rats, the proportion of intact mitochondria increased. CONCLUSION: According to our past and present results, the repair of the mitochondrial apparatus by SkQ1 is a promising strategy against AD. PMID- 28637403 TI - Experiences with 99mTc-HMPAO in a Diagnostic Pathway for Violent Patients with Schizophrenic Spectrum Disorders. AB - BACKGROUND AND OBJECTIVE: In a security ward we assessed the diagnostic contribution of single photon scintigraphy [SPECT] in our diagnostic pathway for patients with serious mental disease and a history of violence. METHODS: Twenty patients were examined between 2012 and 2015 and the findings compared to those in nine patients with the same diagnosis, but no history of violence. RESULTS: All violent patients had areas with reduced accumulation of 99mTc-HMPAO frontally and in the temporal lobe, in the non-violent group only two patients demonstrated these findings. CONCLUSION: Traditionally, low accumulation of the tracer in SPECT is related to reduced perfusion of brain tissue. We discuss our findings in the light of other possible pathophysiological mechanisms. PMID- 28637404 TI - Role of DNA and RNA N6-Adenine Methylation in Regulating Stem Cell Fate. AB - BACKGROUND: Epigenetic modifications have been evidenced to participate in eukaryotic stem cell fate decision. Among the most studied, 5-methylcytosine (m5C) and its derivatives are wellestablished epigenetic codes that play important roles in stem cell pluripotency and differentiation. Based on improved detection techniques, recent studies have succeeded in defining N6-adenine methylation (m6A) in eukaryotic DNA and RNA. The abundant m6A methylation in RNA was shown to be involved in multiple cellular metabolisms while the presence and functional potential of DNA m6A methylation in different species advanced our knowledge in the m6A-mediated biological processes. CONCLUSION: m6A modification has been observed during embryogenesis and has been proposed to fine-tune stem cell regulation. The m6A methyltransferases and demethylases work together to control the dynamic state of m6A marks in genomic DNA and RNA to ensure proper cell fate transition and determination, which are vital to the development and survival of eukaryotes. PMID- 28637406 TI - Socioeconomic Status: The Missing Link Between Obesity and Diabetes Mellitus? AB - BACKGROUND: Currently, there is an epidemic expansion of obesity rates worldwide. The increasing number of obese individuals associated with the aging of population leads to increasing number of individuals with type 2 diabetes mellitus (T2DM) at the same rate. The traditional factors that link obesity to T2DM are related to genetics, hypercaloric diet, sedentary lifestyle, and stress. Individuals from lower Socioeconomic Status (SES) have restricted autonomy and opportunities that could lead to more stress and consequently increase in stress hormones, such as cortisol, catecholamines, glucagon, and growth hormone, which might ultimately change fat deposition, increasing visceral fat and increasing the risk of T2DM development. METHODS: We conducted a review of the literature on the effects of low SES and the risk of developing T2DM in obese persons. RESULTS: 191 studies were found. The obesity of lower SES individuals is more central than that for individuals from higher socioeconomic position. It is also proposed that the quality of food seems to be lower, with more intake of fat and simple carbohydrates and less of fruits, vegetables and whole wheat bread, in the more disadvantaged social classes. The lower income neighborhoods, without exercise facilities and unsafety are also associated with higher indices of physical inactivity. Cross sectional and prospective studies confirm the relationship between lower socioeconomic status and obesity and diabetes. The lower SES is associated to metabolic implications that are linked to insulin resistance and possibly may also interfere with the ability of beta cell to secrete insulin and change the gut microbiota, increasing even more the future risk of developing diabetes. PMID- 28637405 TI - Molecular Dynamics Simulations, Challenges and Opportunities: A Biologist's Prospective. AB - Molecular dynamics (MD) is a computational technique which is used to study biomolecules in virtual environment. Each of the constituent atoms represents a particle and hence the biomolecule embodies a multi-particle mechanical system analyzed within a simulation box during MD analysis. The potential energies of the atoms are explained by a mathematical expression consisting of different forces and space parameters. There are various software and force fields that have been developed for MD studies of the biomolecules. MD analysis has unravelled the various biological mechanisms (protein folding/unfolding, protein small molecule interactions, protein-protein interactions, DNA/RNA-protein interactions, proteins embedded in membrane, lipid-lipid interactions, drug transport etc.) operating at the atomic and molecular levels. However, there are still some parameters including torsions in amino acids, carbohydrates (whose structure is extended and not well defined like that of proteins) and single stranded nucleic acids for which the force fields need further improvement, although there are several workers putting in constant efforts in these directions. The existing force fields are not efficient for studying the crowded environment inside the cells, since these interactions involve multiple factors in real time. Therefore, the improved force fields may provide the opportunities for their wider applications on the complex biosystems in diverse cellular conditions. In conclusion, the intervention of MD in the basic sciences involving interdisciplinary approaches will be helpful for understanding many fundamental biological and physiological processes at the molecular levels that may be further applied in various fields including biotechnology, fisheries, sustainable agriculture and biomedical research. PMID- 28637407 TI - Oral Insulin: Myth or Reality. AB - BACKGROUND: Diabetes Mellitus (DM) is a disorder of glucose metabolism marked by hyperglycemia, glycosuria, hyperlipidemia, negative nitrogen balance and ketonaemia. DM is a major healthcare problems today and its treatment costs billions of dollars worldwide annually. The cases of diabetes have increased rapidly in recent years throughout the world. Currently, for the management of Type-1 Diabetes Mellitus (TIDM), Multiple Daily Insulin (MDI) injections is the most popular treatment. Oral administration of insulin is the most suitable and attractive as compared to subcutaneous route but unfortunately cannot be utilized for the administration of peptides and proteins due to poor epithelial permeability and enzymatic degradation within the gastrointestinal tract. Since many years, extensive research has been carried out to explore the potential ways of insulin administration based on novel methods such as liposome, microsphere, nanoparticle, mouth dissolving strips, sprays exploiting oral and pulmonary route. These next generation efficient therapies for T1DM may help to improve the quality of life of diabetic patients especially in Insulin Dependent Diabetes Mellitus (IDDM). CONCLUSION: This review emphasizes on the most recent progress made in the development of oral insulin delivery formulations, and focuses on key lessons and implications from studies undertaken till date with the oral insulin formulations. Further, this review analyzes effectiveness of the advancements, applications and limitations of the technologies in delivering insulin to the targeted site through oral administration. PMID- 28637408 TI - Lifestyle Modifications in Non-Alcoholic Fatty Liver Disease and Non- Alcoholic Steatohepatitis. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases worldwide, affecting more than 30% of general population. High-fat diets, physical inactivity and obesity, all prevalent in the western societies, are strongly associated with the development and progression of NAFLD. Current drug therapies have not consistently shown substantial beneficial effects. Thus, lifestyle modification appears to be the optimal intervention in combating the disease. Accordingly, several studies have concluded that weight loss, via increase in physical activity, and dietary interventions could potential ameliorate biochemical, histological, and structural abnormalities of non alcoholic fatty liver disease. The aim of this review is to summarize the findings of these lifestyle intervention studies and discuss the implementation of each intervention, and its effectiveness in the management of the disease in everyday clinical practice. PMID- 28637409 TI - Fertility Drugs and Ovarian Cancer. AB - The aetiology of ovarian cancer is multifactorial with both endogenous and exogenous risk factors playing an important role. The exact pathogenesis of ovarian cancer is still not well understood, despite the number of hypotheses published. Due to an increase in the number of women using fertility drugs, much attention has been focused on the long-term health effects of such drugs. Although fertility drugs facilitate the ovulation process, it is however associated with a significant increase in hormone concentrations, placing exposed women at increased risk of gynaecological cancer. Many clinical and epidemiological studies have examined the association between fertility drugs and ovarian cancer risk. Results from these studies have been contradictory, as some studies have reported an increased risk of ovarian cancer while others reported no increased risk. Nevertheless, recent studies have shown that women who used fertility drugs and did not conceive had a higher risk of developing ovarian cancer, compared to women who used fertility drugs and conceived and delivered successfully. This review discusses the effect of fertility drugs on the risk of developing ovarian cancer, providing details on four possible scenarios associated with fertility treatment. In addition, the limitations of previous studies and their impact on our understanding of the association between fertility drugs and ovarian cancer have also been highlighted. PMID- 28637410 TI - New Research for Quinazoline-2,4-diones as HPPD Inhibitors Based on 2D-MLR and 3D QSAR Models. AB - AIM AND OBJECTIVE: 4-Hydroxyphenylpyruvate dioxygenase (HPPD), converting phydroxyphenylpyruvate (HPPA) to homogentisate (HGA), is an important target for treating type I tyrosinemia and synthesizing novel herbicides due to its significant role in tyrosine catabolism. Hence, it is imperative to design novel HPPD inhibitors that can block HPPA-HGA conversion, which leads to the deficiency in isoprenoid redox cofactors such as plastoquinone and tocopherol, and finally caused growth inhibition. This study was undertaken to investigate structural requirements for their HPPD inhibition with better biological activity. MATERIALS AND METHODS: Based on the structure-activity relationships, a series of quinolinone-2,4- diones derivatives were studied using combined of 2D multiple linear regression (2D-MLR) and 3D quantitative structure-activity relationship (3D-QSAR). Firstly, genetic algorithm (GA) was applied and descriptors generated in DRAGON 5.5 software were used for building 2D-MLR models in the QSARINGS. Then CoMFA and CoMSIA models were performed by using alignment of the common framework and the pharmacophore model. The obtained models were validated through internal and external validation to verify predictive abilities. Especially, the CoMFA and CoMSIA contour maps were used to show vital structural characteristics related to HPPD inhibitors activities. RESULTS: The 2D-MLR liner equation and corresponding parameters were listed as follows:pKi = -38.2034Me+22.4078GATS2m-1.4265EEig15r 2.1849Hy+32.9158ntr=28, npred=6, R2=0.863, Q2LOO=0.787, Q2LMO=0.607, Q2F1=0.780, Q2F2=0.780, Q2F3=0.860,CCCpred=0.920. RMSEtr=0.253, RMSEpred=0.555, F=36.289The steric contours graph indicated that small and negative electrostatic substitutions at R1 and R2regions were favorable for the better activity, and hydrogen-bond donors at this region would alsoincrease the activity. Positive electrostatic and bulky substitutions in the R3 position would enhancethe activity. The analysis of these models suggested that the steric factor of R4 position was crucialfor activity of quinazoline-2,4-diones HPPD inhibitors, bulky substitutions might improve thebioactivity of these inhibitors greatly, meanwhile, hydrogen-bond acceptor groups in this positionwere required for higher activity. CONCLUSION: In this study, a combined 2D-MLR, CoMFA and CoMSIA models demonstrated satisfying results through internal and external validation, especially good predictive abilities and the CoMFA and CoMSIA contour maps showed vital structural characteristics related to HPPD inhibitors activities. PMID- 28637411 TI - Venom Peptides and Toxins - A Prospective Spearhead in Cancer Treatment. AB - BACKGROUND & AIM: Cancer is a condition of genetically or environmentally mutated, uncontrollable cell growth that directly affects human morbidity and mortality. Many treatments have been adopted to reduce cancer cell proliferation; however, new mutated developments of some cancer cells have started to show resistance towards current therapies and treatments that cause some drugs to lose their efficacy. Additionally, deleterious side-effects of some hard application methods like radiation therapy, chemotherapy, and surgery are less favorable. Accumulative research effort has revealed that peptides and toxins identified from underutilized natural sources including venomous reptiles, amphibians, insects, arachnids, marine organisms and plants are increasingly being employed in cancer treatment. This demands more peptides / toxins to be identified from underutilized natural sources as an alternative therapeutic approach. METHOD & RESULTS: Accumulative research effort has revealed that peptides and toxins identified from underutilized natural sources including venomous reptiles, amphibians, insects, arachnids, marine organisms and plants are increasingly being employed in cancer treatment. Secondary structures / pharmacophore modifications have proven to be an important criterion for raising the efficacy level and anticancer effects. Structure specificity and structural-related cytotoxicity have successfully allowed these peptides to target and cause sufficient damage to malignant cells with minimal cytotoxicity effects towards healthy cells. On top of that, some these pure peptides had adopted multiple anticancer mechanisms and demonstrated collective anticancer effects within a single application. CONCLUSION: Our review exclusively selected peptides and toxins found identified from various natural sources in combating malignant cells, their selectivity towards specific anticancer mechanisms, and the prospective of conjugated peptide as a single entity for a new therapeutic strategy. PMID- 28637412 TI - Vascular Lesion Thickness in the Lenticulostriate Artery Region Serves as a Biomarker for Early Neurological Deterioration. AB - BACKGROUND: Early neurological deterioration (END) was common in single small subcortical infarction (SSSI). Distal type of SSSI (dSSSI) was reported to have a lower risk of END than proximal type of SSSI (pSSSI) in lenticulostriate artery(LSA) territory. However, dSSSIs with different lesion thickness might have different risks of END. OBJECTIVE: In this prospective cohort study, we aimed to investigate whether dSSSIs visible on >=3 serial axial diffusion weighted imaging (DWI) slices were also imaging markers for END. METHODS: Patients of SSSIs in the LSA territory admitted within 72 hours from the onset were selected in a prospective stroke database. Clinical characteristics including the occurrence of END after admission were recorded. The lowest slice (LS), total number of slices (TNS) involved and the maximum axial diameter were evaluated for lesion location and size on axial plane of DWI images. Lesion patterns were categorized according to LS and TNS. Multivariate logistic analysis was performed to determine the imaging pattern that associated with END. RESULTS: A total of 201 out of 1,158 patients were analyzed. END occurred in 32(15.9%) patients after admission. SSSI was categorized to pSSSI (LS<=2), distal and large SSSI (dl-SSSI, LS>2, TNS>=3), distal and small SSSI (ds-SSSI, LS>2, TNS<3) respectively. Multivariate logistic analysis showed that ds-SSSI patients had a significantly lower rate of END(OR 0.20, 95% CI 0.06-0.71, P=0.013) comparing to dl-SSSI patients; pSSSI patients, however, had a similar rate of END (OR 1.27, 95% CI 0.50-3.21, P=0.611) to dl SSSI patients. CONCLUSION: Except for pSSSI, dl-SSSI was also an imaging marker for END in the territory of LSA. PMID- 28637413 TI - Early-phase 18F-AV-45 PET Imaging can Detect Crossed Cerebellar Diaschisis Following Carotid Artery Stenosis and Cerebral Hypoperfusion. AB - BACKGROUND: Carotid artery stenosis (CAS) may induce cerebral hypoperfusion. Early-phase 18F-Florbetapir (AV-45/Amyvid, 18F-AV-45) positron emission tomography (PET) imaging can provide perfusion-like property (pAV-45) for the estimation of cerebral blood flow (CBF). Supra-tentorial lesions may cause decreased blood flow and metabolism in the contralateral cerebellum known as crossed cerebellar diaschisis (CCD). OBJECTIVE: The aim was to study the occurrence of CCD after CAS using pAV-45 PET. METHODS: Eleven healthy controls and 21 patients with unilateral CAS were studied. All subjects underwent 18F-AV 45 PET imaging and arterial spin labeling (ASL) CBF magnetic resonance perfusion imaging. The pAV-45 and ASL CBF values were first correlated. Then, cerebral and cerebellar hypoperfusion volume was analyzed. The cerebral and cerebellar perfusion asymmetry indices (AIs) were calculated from the pAV-45 standard uptake value ratios (SUVRs) of bilateral cerebral and cerebellar cortices, respectively. RESULTS: We found that pAV-45 SUVR was significantly correlated to ASL CBF (p<0.0001, r=0.5731). The AI of cerebellar perfusion was negatively correlated to that of cerebral perfusion (p<0.0001, r=-0.8751). Multiple linear regression showed the cerebral AI (p<0.0001) and hypoperfusion volume (p=0.02) but not the infarction severity and CAS degree significantly correlated to cerebellar AI. If the lower limit of 95% confidence interval of cerebellar AI in healthy controls was set as cut-off for positive CCD, the occurrence of CCD correlated to infarction severity in CAS patients (p=0.03). CONCLUSION: Our results suggest pAV 45 is reliable to study CBF change. Under unilateral CAS, cerebral AI and hypoperfusion severity may determine the occurrence of CCD. PMID- 28637415 TI - Study on Adsorption and Sustained Release of Eucommia ulmoides Oliv. Leaf Extracts on Activated Carbon. AB - BACKGROUND: Due to its excellent adsorption capability, activated carbon(AC) has also been employed as a drug carrier. However, applications of the AC carrier in traditional Chinese medicine (TCM) have been rare. We selected the Eucommia ulmoides leaf extract as the drug of choice and AC as its carrier, to investigate the adsorption and sustained release behavior of the Eucommia ulmoides leaf extract on the AC. METHODS: AC was employed in this study as the sustained release carrier and its capability for adsorption and sustained release of Eucommia ulmoides leaf extracts was systematically investigated. Acid or alkali modified AC was assessed for its ability to absorb and sustain release of Eucommia ulmoides leaf extracts according to a variety of adsorption/release rate and composition. RESULTS: Results demonstrated that the adsorption rate for the differently modified AC reached above 80 %, whereas the adsorption of Eucommia ulmoides leaf extracts on the AC was selective. The composition of the sustained release liquid, which was treated by the acid modified AC, was almost similar to the original extract. The acid modified AC was therefore taken as an optimal carrier that can be used for Eucommia ulmoides leaf extracts sustained release. CONCLUSION: The synchronous release and absorption of different ingredients in the active ingredient release process ensures the global and cooperative effect with sustained and less toxic advantages. The ideal synchronous release is that the absorbed component proportion is consistent with its release. The acid modified AC was therefore taken as the optimal carrier that can be used for Eucommia ulmoides leaf extracts sustained release. PMID- 28637414 TI - Hyperfibrinogenemia is Significantly Associated with an Increased Risk of In hospital Mortality in Acute Ischemic Stroke Patients. AB - BACKGROUND: The impact of hyperfibrinogenemia on short-term outcomes after acute ischemic stroke (AIS) is still not well understood. OBJECTIVE: We investigated the association between hyperfibrinogenemia upon hospital admission and the short term prognosis of AIS patients. METHODS: A total of 3,212 AIS patients enrolled from December 2013 to May 2014 across 22 hospitals in Suzhou city were included in the present study. Hyperfibrinogenemia was defined as having a serum fibrinogen>4.0g/L. Cox proportional hazard and logistic regression models were used to estimate the effect of hyperfibrinogenemia on all-cause in-hospital mortality and poor discharge outcome (modified Rankin Scale score>=3) in AIS patients. RESULTS: During hospitalization, 106 patients (3.3%) died from all cause and 1226 (38.2%) patients experienced poor functional outcome at discharge. Multivariable model adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, white blood cell count and other covariates, showed that hyperfibrinogenemia was associated with a 1.76-fold increase in the risk of in hospital mortality (hazard ratio [HR] 1.76; 95% confidence interval [CI], 1.10 2.81; P-value=0.019). However, there was no significant association between hyperfibrinogenemia and poor outcome at discharge (adjusted odds ratios[OR]1.15; 95% CI 0.86-1.53; P-value=0.338). Sensitivity and subgroup analyses also confirmed a significant association between hyperfibrinogenemia and in-hospital mortality. CONCLUSION: In patients with AIS, hyperfibrinogenemia at the time of admission was independently associated with increased in-hospital mortality. PMID- 28637416 TI - Mixed Micelles as Nano Polymer Therapeutics of Docetaxel: Increased In vitro Cytotoxicity and Decreased In vivo Toxicity. AB - BACKGROUND: Docetaxel (DTX) has been used to treat several types of cancers, but it has provided pharmaceutical challenges due to its poor water solubility and toxicities associated with the co-solvents (tween-80 and ethanol). Nanopolymer therapeutics can be engineered to deliver anticancer agent specifically to cancer cells, thereby leaving normal healthy cells unaffected by toxic drugs such as DTX. The objective of the present study was to synthesize the polyacrylic acid (PAA)-DTX conjugate (PAADC) and preparation of nanopolymer therapeutics such as PAADC/DSPE-mPEG2000 mixed micelles (PAADC-DP MMs). METHODS: The prepared PAADC-DP MMs were characterized for mean particle size and zeta potential, in vitro release profile using dialysis technique, hemolytic behavior against human blood, and cytotoxicity against human cancer cell line (A549) using MTT assay. In vivo acute toxicity of PAADC-DP MMs was determined in albino mice at intravenous single dose of 40 mg/kg. RESULTS: PAADC-DP MMs showed mean particle size of 443+/ 9nm. PAADC-DP MMs showed maximum DTX loading (DTX equivalent; 90.5+/-2.7%) with minimum DSPE-mPEG2000 molecules (1:1 ratio), while to load 77.9+/-2.2% of plain DTX, more DSPE-mPEG2000 is required(1:10 ratio). The developed PAADC-DP MMs system showed significantly lower CMC (5 ng/mL), sustained release profile (28.6+/-1.9% after 48 h of study), lower hemolytic behavior (13.7+/-1.3% of hemolysis ratio at 40 ug/mL concentration and after 1 h incubation), higher in vitro cytotoxicity (IC50 of 0.0064+/-0.001 nM after 48 h study) and remarkably reduced in vivo toxicity (9.9+/-2.1% body weight loss) in mice when compared to marketed Taxotere(r). CONCLUSION: The obtained results clearly demonstrated that the developed PAADC-DP MMs system is a promising approach for cancer chemotherapy with reduced toxicity. PMID- 28637417 TI - Effect of Heteropterys aphrodisiaca on Anxiety and Male Exposure of Female Mice with Advanced Age. AB - BACKGROUND: Effect of Heteropterys aphrodisiaca (dog-node) on anxiety and function of adult female wistar mice. The project is an experiment with the use of H. aphrodisiac root extract, in order to observe the frequency of sexual exposure of females exposed to the extract, quantify the effect of the extract on the concentration of total testosterone and observe the anxiety levels of the animals exposed. Results will be measured with the laboratory testosterone test and LCE and CA tests. METHODS: In preparation of the extract, the root was oven dried at 40 degrees C and diluted in alcohol extract (100g of root for 1 liter of alcohol) and lyophilized. 40 adult female mice were enrolled, separated in control group (placebo) and treatment group (50 mg/kg/day) for 15, 30, 45 and 60 days. At each period, hormonal testosterone and anxiety levels by the Elevated Cross Labyrinth (ECL) tests and Open Camp (CA) were measured in 10 animals that were later euthanized (SBNeC). RESULTS: The results showed an improvement in the decrease of anxiety, as shown in the variables of number of open arm entries, time on the same side of the field, less avoidance and leakage. However, it appears that the time of exposure to the extract does not result in increased benefit, with possible decline of effect after 45 days of use. CONCLUSION: With this performed experiment with the "no-de-cachorro" extract, it was possible to understand a little more how this root can act in relation to anxiety, as predicted by the pharmacology that validates the animal models; anxiolytic components decrease anxiety-related behaviors, as shown in the variables of entry numbers in the open arm, time on the same side of the field, less avoidance and escape. However, it seems that the time of exposure to the extract does not modify the performance in the tests, observing until an apparent exhaustion of the anxiolytic action, which evidences the need for more specific studies on the possible effects of the extract. PMID- 28637418 TI - Anti-Inflammatory Effect of Crocus sativus on Serum Cytokine Levels in Subjects with Metabolic Syndrome: A Randomized, Double-Blind, Placebo- Controlled Trial. AB - BACKGROUND/AIMS: A growing body of evidence supports an important role of inflammatory cytokines in the development and progression of the Metabolic Syndrome (MetS), which explains, at least in part, its relationship with an increased cardiovascular-risk. Several studies have reported the therapeutic impact of crocus-sativus in a preclinical/clinical setting. Here we have explored the effects of crocus-sativus, on the serum concentrations of twelve serum cytokines in subjects with MetS in a randomized control trial. METHODS: Forty four adult volunteers, who met the diagnostic-criteria of MetS, were enrolled and randomly divided into 2 groups, to receive 100 mg/day crocus-sativus for 12 weeks. 12 cytokines, including IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL 10, TNF-alpha, MCP-1, IFN-gamma, EGF, and VEGF were measured using sandwich chemi luminescence assays before/after therapy. RESULTS: Individuals with MetS who received crocus-sativus had significantly (P<0.05) lower levels of total cholesterol, low density-lipoprotein-cholesterol and triglyceride (TG), fasting blood-sugar and hsCRP, however the serum concentration of high density lipoprotein-cholesterol markedly enhanced after therapy (e.g., TG level reduced from 148.86+/-71.49 to 101.90+/-38.19 after therapy, P= 0.003). Moreover, we observed that treatment with Crocus-sativus affected the serumconcentrations of some pro-/anti-inflamatory cytokines. In particular, the level of VEGF was increased from 12.64 pg/mL (95% CI: 9.60-17.67) to 16.59 (95% CI: 11.33-35.98, P= 0.033. Similar results were detected for IL-6 and EGF. CONCLUSION: Our findings provide a novel insight into the therapeutic effects of this therapy in MetS patients via perturbation of serum cytokines and reducing the levels of triglyceride and LDL/TC, but further studies are required in larger populations. PMID- 28637419 TI - Pharmacological Inhibitors of NAD Biosynthesis as Potential An ticancer Agents. AB - BACKGROUND: Alteration of cellular metabolism is a hallmark of cancer, which underlies exciting opportunities to develop effective, anti-cancer therapeutics through inhibition of cancer metabolism. Nicotinamide Adenine Dinucleotide (NAD+), an essential coenzyme of energy metabolism and a signaling molecule linking cellular energy status to a spectrum of molecular regulation, has been shown to be in high demand in a variety of cancer cells. Depletion of NAD+ by inhibition of its key biosynthetic enzymes has become an attractive strategy to target cancer. OBJECTIVE AND METHOD: The main objective of this article is to review the recent patents which develop and implicate the chemical inhibitors of the key NAD+ biosynthetic enzymes for cancer treatment. We first discuss the biological principles of NAD+ metabolism in normal and malignant cells, with a focus on the feasibility of selectively targeting cancer cells by pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT) and indoleamine/tryptophan 2,3-dioxygenases (IDO/TDO), the rate-limiting salvage and de novo NAD+ biosynthetic enzymes, respectively. We then analyze a series of recent patents on development and optimization of chemical scaffolds for inhibiting NAMPT or IDO/TDO enzymes as potential anticancer drugs. Conclusion and Results: We have reviewed 16 relevant patents published since 2015, and summarized the chemical properties, mechanisms of action and proposed applications of the patented compounds. Without a better understanding of the properties of these compounds, their utility for further optimization and clinical use is unknown. For the compounds that have been tested using cell and mouse models of cancer, results look promising and clinical trials are currently ongoing to see if these results translate to improved cancer treatments. PMID- 28637420 TI - Bioinformatic Insights on Target Receptors of Amiodarone in Human and Acanthamoeba castellanii. AB - BACKGROUND: Amiodarone is prescribed for certain cardiac arrhythmias in current medical practice. The drug targets and inhibits voltage dependent sodium (Na+ v), calcium (Ca+2 v), potassium (K+ v) channels, enzymes like cytochrome P450 and oxidosqualene cyclase. Past studies have shown that amiodarone exerts antiparasitic effects against Trypanosoma cruzi and Acanthamoeba castellanii. OBJECTIVES: The presence of aforementioned targets and the type of cell death induced by amiodarone in pathogenic eukaryotes like Acanthamoeba castellanii remains to be established. We inferred the presence of homologous targets of amiodarone in A. castellanii compared with humans. METHODS: This study used bioinformatics exploration for amino acid sequence homology, ligand binding attribute predictions, 3D structural model development, and experimental assays that highlight similarity between certain target proteins in Acanthamoeba as compared to humans. RESULTS: The sequence identity scores for amino acids and 3D models show that A. castellanii expresses similar types of targets of amiodarone like Na+ v - K+1 v channels, cytochrome P450 3A4, and lanosterol synthase (oxidosqualene cyclase). We show that even though human like L-type and two pore Ca+2 channels are present in A. castellanii, there was no evidence of the expression of T-type voltage dependent Ca+2 channels. Growth assays showed amoebicidal and amoebistatic effects at doses of 40-80MUg/ml. CONCLUSION: The existing bioinformatics tools, ligand binding attribute prediction, and model building offer a specific method to establish homology of proteins, discover drug targets, and facilitate the investigation of the evolution of several types of cardinal ion channels from unicellular eukaryotes to multicellular species as humans. PMID- 28637421 TI - A novel pathway-based distance score enhances assessment of disease heterogeneity in gene expression. AB - BACKGROUND: Distance based unsupervised clustering of gene expression data is commonly used to identify heterogeneity in biologic samples. However, high noise levels in gene expression data and relatively high correlation between genes are often encountered, so traditional distances such as Euclidean distance may not be effective at discriminating the biological differences between samples. An alternative method to examine disease phenotypes is to use pre-defined biological pathways. These pathways have been shown to be perturbed in different ways in different subjects who have similar clinical features. We hypothesize that differences in the expressions of genes in a given pathway are more predictive of differences in biological differences compared to standard approaches and if integrated into clustering analysis will enhance the robustness and accuracy of the clustering method. To examine this hypothesis, we developed a novel computational method to assess the biological differences between samples using gene expression data by assuming that ontologically defined biological pathways in biologically similar samples have similar behavior. RESULTS: Pre-defined biological pathways were downloaded and genes in each pathway were used to cluster samples using the Gaussian mixture model. The clustering results across different pathways were then summarized to calculate the pathway-based distance score between samples. This method was applied to both simulated and real data sets and compared to the traditional Euclidean distance and another pathway-based clustering method, Pathifier. The results show that the pathway-based distance score performs significantly better than the Euclidean distance, especially when the heterogeneity is low and genes in the same pathways are correlated. Compared to Pathifier, we demonstrated that our approach achieves higher accuracy and robustness for small pathways. When the pathway size is large, by downsampling the pathways into smaller pathways, our approach was able to achieve comparable performance. CONCLUSIONS: We have developed a novel distance score that represents the biological differences between samples using gene expression data and pre-defined biological pathway information. Application of this distance score results in more accurate, robust, and biologically meaningful clustering results in both simulated data and real data when compared to traditional methods. It also has comparable or better performance compared to Pathifier. PMID- 28637422 TI - Optimal alpha reduces error rates in gene expression studies: a meta-analysis approach. AB - BACKGROUND: Transcriptomic approaches (microarray and RNA-seq) have been a tremendous advance for molecular science in all disciplines, but they have made interpretation of hypothesis testing more difficult because of the large number of comparisons that are done within an experiment. The result has been a proliferation of techniques aimed at solving the multiple comparisons problem, techniques that have focused primarily on minimizing Type I error with little or no concern about concomitant increases in Type II errors. We have previously proposed a novel approach for setting statistical thresholds with applications for high throughput omics-data, optimal alpha, which minimizes the probability of making either error (i.e. Type I or II) and eliminates the need for post-hoc adjustments. RESULTS: A meta-analysis of 242 microarray studies extracted from the peer-reviewed literature found that current practices for setting statistical thresholds led to very high Type II error rates. Further, we demonstrate that applying the optimal alpha approach results in error rates as low or lower than error rates obtained when using (i) no post-hoc adjustment, (ii) a Bonferroni adjustment and (iii) a false discovery rate (FDR) adjustment which is widely used in transcriptome studies. CONCLUSIONS: We conclude that optimal alpha can reduce error rates associated with transcripts in both microarray and RNA-seq experiments, but point out that improved statistical techniques alone cannot solve the problems associated with high throughput datasets - these approaches need to be coupled with improved experimental design that considers larger sample sizes and/or greater study replication. PMID- 28637423 TI - The relation between DNA methylation patterns and serum cytokine levels in community-dwelling adults: a preliminary study. AB - BACKGROUND: The levels of circulating cytokines fluctuate with age, acute illness, and chronic disease, and are predictive of mortality; this is also true for patterns of DNA (CpG) methylation. Given that immune cells are particularly sensitive to changes in the concentration of cytokines in their microenvironment, we hypothesized that serum levels of TNF, IL-6, IL-8 and IL-10 would correlate with genome-wide alterations in the DNA methylation levels of blood leukocytes. To test this, we evaluated community-dwelling adults (n = 14; 48-78 years old) recruited to a pilot study for the Canadian Longitudinal Study on Aging (CLSA), examining DNA methylation patterns in peripheral blood mononuclear cells using the Illumina HumanMethylation 450 K BeadChip. RESULTS: We show that, apart from age, serum IL-10 levels exhibited the most substantial association to DNA methylation patterns, followed by TNF, IL-6 and IL-8. Furthermore, while the levels of these cytokines were higher in elderly adults, no associations with epigenetic accelerated aging, derived using the epigenetic clock, were observed. CONCLUSIONS: As a preliminary study with a small sample size, the conclusions drawn from this work must be viewed with caution; however, our observations are encouraging and certainly warrant more suitably powered studies of this relationship. PMID- 28637424 TI - Gabapentin in procedure-specific postoperative pain management - preplanned subgroup analyses from a systematic review with meta-analyses and trial sequential analyses. AB - BACKGROUND: It has been argued that postoperative pain treatment should be "procedure-specific", since different analgesics may have specific effects dependent on the surgical procedure. The aim of the present subgroup analysis was to compare the beneficial and harmful effects of perioperative gabapentin treatment in different surgical procedures. METHODS: Relevant databases were searched for randomized clinical trials (RCTs) comparing gabapentin versus placebo. Two authors independently screened titles and abstracts, extracted data and assessed risk of bias. The primary outcomes were differences in 24-h morphine consumption, and serious adverse events (SAE) between surgical procedures. These subgroup analyses were predefined in a PRISMA compliant systematic review registered at PROSPERO (ID: CRD42013006538). It was predefined that conclusions should primarily be based on trials classified as overall low risk of bias. RESULTS: Seventy-four RCTs with 5645 patients were included, assessing benefit and harm in cholecystectomy, hysterectomy, mastectomy, and arthroplasty surgery, spinal surgery, and thoracic surgery. Only eight of 74 trials were classified as overall low risk of bias limiting our ability to conclude on the estimates in most meta-analyses. The differences between surgical procedures in these trials were not statistically significant when tested for subgroup differences. Fifteen trials with 1377 patients reported a total of 59 SAEs, most of which were observed in the thoracic surgery group. CONCLUSION: Both beneficial and harmful effects in these subgroup analyses were influenced by bias and insufficient data, limiting conclusions. With these limitations, we could not adequately test for differences in beneficial or harmful outcomes between six surgical subgroups undergoing perioperative gabapentin treatment. PMID- 28637425 TI - The colonization and divergence patterns of Brandt's vole (Lasiopodomys brandtii) populations reveal evidence of genetic surfing. AB - BACKGROUND: The colonial habit of Brandt's vole (Lasiopodomys brandtii) differs from that of most other species of the genus Microtus. The demographic history of this species and the patterns shaping its current genetic structure remain unknown. Here, we explored patterns of genetic differentiation and infered the demographic history of Brandt's vole populations through analyses of nuclear microsatellite and D-loop sequences. RESULTS: Phylogenetic analyses divided the sampled populations into three main clusters, which represent the southeastern, northeastern and western parts of the total range in Mongolia and China. Molecular data revealed an ancestral area located in the southeast of the extant range, in the Xilinguole District, Inner Mongolia, China, from where Brandt's vole populations began expanding. A gene flow analysis suggested that the most likely colonization route was from the ancestral area and was followed by subsequent northeastward and westward range expansions. We identified decreases in genetic diversity with increasing distance from the founder population within the newly occupied regions (northeastern and western regions), clinal patterns in the allele frequencies, alleles that were rare in the original area that have become common in the newly occupied regions, and higher genetic differentiation in the expanded range compared with the original one. CONCLUSION: Our results indicate that L. brandtii most likely originated from the southeastern part of its current geographic range, and subsequently colonized into the northeastern and western parts by expansion. The genetic patterns among the derived populations and with respect to the original population are consistent with that expected under genetic surfing models, which indicated that genetic drift, rather than gene flow, is the predominant factor underlying the genetic structure of expanding Brandt's vole populations. PMID- 28637426 TI - Bioinformatics: indispensable, yet hidden in plain sight? AB - BACKGROUND: Bioinformatics has multitudinous identities, organisational alignments and disciplinary links. This variety allows bioinformaticians and bioinformatic work to contribute to much (if not most) of life science research in profound ways. The multitude of bioinformatic work also translates into a multitude of credit-distribution arrangements, apparently dismissing that work. RESULTS: We report on the epistemic and social arrangements that characterise the relationship between bioinformatics and life science. We describe, in sociological terms, the character, power and future of bioinformatic work. The character of bioinformatic work is such that its cultural, institutional and technical structures allow for it to be black-boxed easily. The result is that bioinformatic expertise and contributions travel easily and quickly, yet remain largely uncredited. The power of bioinformatic work is shaped by its dependency on life science work, which combined with the black-boxed character of bioinformatic expertise further contributes to situating bioinformatics on the periphery of the life sciences. Finally, the imagined futures of bioinformatic work suggest that bioinformatics will become ever more indispensable without necessarily becoming more visible, forcing bioinformaticians into difficult professional and career choices. CONCLUSIONS: Bioinformatic expertise and labour is epistemically central but often institutionally peripheral. In part, this is a result of the ways in which the character, power distribution and potential futures of bioinformatics are constituted. However, alternative paths can be imagined. PMID- 28637427 TI - Aging and obesity are associated with undiagnosed hypertension in a cohort of males in the Central Province of Sri Lanka: a cross-sectional descriptive study. AB - BACKGROUND: Lifestyle factors associated with hypertension (HT) in South Asian populations are relatively unknown. The objective of the current study was to investigate the prevalence rates of undiagnosed HT and factors associated with it in a cohort of males from the Central Province of Sri Lanka. METHODS: The study group consisted of 2462 males (mean age 31 years, range: 16-72 years) who underwent a routine medical examination at the National Transport Medical Institute, Kandy, Sri Lanka. Participants with previously diagnosed heart disease, diabetes, hypertension or other chronic illnesses were excluded from this study. Dietary and other lifestyle factors were studied using validated self administered questionnaires. Body Mass Index (BMI) cut-off values for Asians were used to categorize the subjects according to weight status. The association of individual dietary and lifestyle patterns with HT was assessed by fitting into binary logistic regression models. RESULTS: The mean systolic (SBP) and diastolic blood pressures (DBP) of the individuals were 125.9 mmHg and 80.5 mmHg, respectively. The prevalence rate of undiagnosed HT was 31.7%. Both SBP and DBP showed significant positive correlations with age, weight, BMI and waist circumference. After adjusting for potential confounders, HT was associated with older age (p = 0.001) and increased weight status (p < 0.001) with trends of association for level of education (p = 0.058). Level of income, alcohol consumption, sleeping hours, smoking, physical activity level, ethnic difference, consumption of fruits, fish, meat, dairy, sweets or fried snacks were not significantly associated with HT. Obese males were 92.1% [odds ratio: 1.9 (1.4 2.7)] more likely to be hypertensive compared to normal weight males. CONCLUSIONS: Undiagnosed HT is prevalent at an alarming rate among adult males in the Central Province of Sri Lanka. Its association with age and BMI (weight status) highlights the importance of routine screening for HT as well as interventions targeted at reducing obesity to curb the rise of this modifiable cardiovascular disease risk factor. PMID- 28637428 TI - Quality of care provided in two Scottish rural community maternity units: a retrospective case review. AB - BACKGROUND: Women in Scotland with uncomplicated pregnancies are encouraged by professional bodies and national guidelines to access community based models of midwife-led care for their labour and birth. The evidence base for these guidelines relates to comparisons of predominantly urban birth settings in England. There appears to be little evidence available about the quality of the care during the antenatal, birth and post birth periods available for women within the Scottish Community Maternity Unit (CMU) model. The research aim was to explore the safety and effectiveness of the maternity services provided at two rural Community Maternity Units in Scotland, both 40 miles by main road access from a tertiary obstetric unit. METHODS: Following appropriate NHS and University ethical approval, an anonymous retrospective review of consecutive maternity records for all women who accessed care at the CMUs over a 12 month period (June 2011 to May 2012) was undertaken in 2013 -14. Data was extracted using variables chosen to provide a description of the socio-demographics of the cohort and the process and outcomes of the care provided. Data were analysed using descriptive statistics. RESULTS: Regarding effectiveness, the correct care pathway was allocated to 97.5% of women, early access to antenatal care achieved by 95.7% of women, 94.8% of women at one CMU received continuity of carer and 78.6% of those clinically eligible accessed care in labour. 11.9% were appropriately transferred to obstetrician-led care antenatally and 16.9% were transferred in labour. All women received one-to one care in labour and 67.1% of babies born at the CMUs were breastfed at birth. Regarding safety, severe morbidity for women was rare, perineal trauma of 3rd degree tear occurred for 0.3% of women and 1.0% experienced an episiotomy. Severe post partum haemorrhage occurred for 0.3% of women. Babies admitted to the Neonatal unit were discharged within 48 hrs. CONCLUSION: These findings support the recommendations of professional bodies and national guidelines. Maternity service provision at rural CMUs achieved a consistently high standard of safety and effectiveness when measured against national standards and international evidence. PMID- 28637429 TI - Effects of selection for fast growth on survival rate during grow-out phase in giant freshwater prawn (Macrobrachium rosenbergii). AB - BACKGROUND: Correlated genetic response in survival to selection for high growth has not been reported in giant freshwater prawn (GFP) (Macrobrachium rosenbergii). The main aim of this study was to measure genetic changes and estimate heritability for this character (survival rate) and its genetic associations with body traits in a GFP population selected over eight generations from 2008 to 2015. Statistical analyses were conducted on 106,696 data records, using threshold logistic mixed model. RESULTS: The estimated heritability for survival was 0.14 +/- 0.04 and significant. Genetic associations of survival with body traits (weight, length and width) were weak, with the estimates of genetic correlations between the traits close to zero. Realised genetic changes in survival, calculated as the difference in estimated breeding values between the selection line and control group within the same generation, was in positive direction but the estimates were not significantly different from zero regardless of the expression unit used either in actual unit of measurement or genetic standard deviation unit. On the other hand, communal testing of stocks in the latest generation, namely G7 (2015), showed that the selection line had 18% higher survival rate than progeny of the wild prawns originated from Mekong river. This result suggests that inadvertent changes in survival occurred during domestication-selection. CONCLUSIONS: It is concluded that selection for high growth had no significant effect on survival in the present population of M. rosenbergii. PMID- 28637430 TI - Malaria control by commodities without practical malariology. AB - Malaria remains a serious clinical and public health problem, the object of an ongoing technological and humanitarian struggle to abate the very substantial harm done. The manner by which humanity approached malaria control changed abruptly and profoundly after 1945 with the advent of the insecticide DDT. Malariologists in the first half of the twentieth century conceived precise modifications to natural or man-made environments aimed at making those less hospitable to specific anopheline mosquito vector species. This practical malariology achieved very significant reductions in burdens of morbidity and mortality, but the revolutionary insecticide eliminated the need for its specialized knowledge and diverse practices. By 1970 mosquito resistance to DDT and perceived environmental concerns precipitated the collapse of what had been a vigorous global campaign to eradicate malaria. Humanity did not then revitalize practical malariology but turned to another commodity as the foundation of control strategy, the war-spurred suite of synthetic antimalarial drugs developed in the 1940s and 1950s. When those drugs became lost to parasite resistance in the latter twentieth century, malaria resurged globally. Since 2005, tens of billions of dollars mobilized new commodities to control malaria: point-of-care diagnostics, effective artemisinin-based treatments, and longer-lasting insecticide treated bed nets. The know-how of practical malariology is not part of that ongoing commodities-based strategy. This article examines contemporary malaria control in the broad strokes of a strategy mitigating the consequences of infection contrasted to that of the abandoned practical malariology strategy of prevention. The inherent risks and limitations of over-reliance upon commodities in striving to control malaria may prompt consideration of a strategic posture inclusive of the proven methods of practical malariology. PMID- 28637431 TI - Continuous long-term cytotoxicity monitoring in 3D spheroids of beetle luciferase expressing hepatocytes by nondestructive bioluminescence measurement. AB - BACKGROUND: Three-dimensional (3D) spheroids are frequently used in toxicological study because their morphology and function closely resemble those of tissue. As these properties are maintained over a long term, repeated treatment of the spheroids with a test object is possible. Generally, in the repeated treatment test to assess cytotoxicity in the spheroids, ATP assay, colorimetric measurement using pigments or high-content imaging analysis is performed. However, continuous assessment of cytotoxicity in the same spheroids using the above assays or analysis is impossible because the spheroids must be disrupted or killed. To overcome this technical limitation, we constructed a simple monitoring system in which cytotoxicity in the spheroids can be continuously monitored by nondestructive bioluminescence measurement. RESULTS: Mouse primary hepatocytes were isolated from transchromosomic (Tc) mice harboring a mouse artificial chromosome (MAC) vector expressing beetle luciferase Emerald Luc (ELuc) under the control of cytomegalovirus immediate early enhancer/chicken beta-actin promoter/rabbit beta-globin intron II (CAG) promoter, and used in 3D cultures. We confirmed that both luminescence and albumin secretion from the spheroids seeded in the 96-well format Cell-ableTM were maintained for approximately 1 month. Finally, we repetitively treated the luminescent 3D spheroids with representative hepatotoxicants for approximately 1 month, and continuously and nondestructively measured bioluminescence every day. We successfully obtained daily changes of the dose-response bioluminescence curves for the respective toxicants. CONCLUSIONS: In this study, we constructed a monitoring system in which cytotoxicity in the same 3D spheroids was continuously and sensitively monitored over a long term. Because this system can be easily applied to other cells, such as human primary cells or stem cells, it is expected to serve as the preferred platform for simple and cost-effective long-term monitoring of cellular events, including cytotoxicity. PMID- 28637432 TI - Current guidelines for BRCA testing of breast cancer patients are insufficient to detect all mutation carriers. AB - BACKGROUND: Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in South-Eastern Norway. METHODS: 1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated. RESULTS: A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%. CONCLUSIONS: Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family. PMID- 28637434 TI - Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis. AB - BACKGROUND: To evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC). METHODS: The genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed. RESULTS: In the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395-3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138-30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946-11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136-4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001). CONCLUSION: Results still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea. PMID- 28637433 TI - Postoperative alignment of TKA in patients with severe preoperative varus or valgus deformity: is there a difference between surgical techniques? AB - BACKGROUND: There have been conflicting studies published regarding the ability of various total knee arthroplasty (TKA) techniques to correct preoperative deformity. The purpose of this study was to compare the postoperative radiographic alignment in patients with severe preoperative coronal deformity (>=10 degrees varus/valgus) who underwent three different TKA techniques; manual instrumentation (MAN), computer navigated instrumentation (NAV) and patient specific instrumentation (PSI). METHODS: Patients, who received a TKA with a preoperative coronal deformity of >=10 degrees with available radiographs were included in this retrospective study. The groups were: MAN; n = 54, NAV; n = 52 and PSI; n = 53. The mechanical axis (varus / valgus) and the posterior tibial slope were measured and analysed using standing long leg- and lateral radiographs. RESULTS: The overall mean postoperative varus / valgus deformity was 2.8 degrees (range, 0 to 9.9; SD 2.3) and 2.5 degrees (range, 0 to 14.7; SD 2.3), respectively. The overall outliers (>3 degrees ) represented 30.2% (48 /159) of cases and were distributed as followed: MAN group: 31.5%, NAV group: 34.6%, PSI group: 24.4%. No significant statistical differences were found between these groups. The distribution of the severe outliers (>5 degrees ) was 14.8% in the MAN group, 23% in the NAV group and 5.6% in the PSI group. The PSI group had significantly (p = 0.0108) fewer severe outliers compared to the NAV group while all other pairs were not statistically significant. CONCLUSIONS: In severe varus / valgus deformity the three surgical techniques demonstrated similar postoperative radiographic alignment. However, in reducing severe outliers (> 5 degrees ) and in achieving the planned posterior tibial slope the PSI technique for TKA may be superior to computer navigation and the conventional technique. Further prospective studies are needed to determine which technique is the best regarding reducing outliers in patients with severe preoperative coronal deformity. PMID- 28637437 TI - Curative resection by splenectomy for solitary splenic metastasis from early gastric cancer: a case report and literature review. AB - BACKGROUND: Solitary metastasis of a malignancy to the spleen is rare, particularly for gastric cancer. Only a few case reports have documented isolated splenic metastasis from early gastric cancer. We describe a case of splenic metastasis from early gastric cancer. CASE PRESENTATION: A 60-year-old man underwent a distal gastrectomy for early gastric cancer. It infiltrated the submucosa with pathological nodal involvement (pT1bN2M0, stage IIB). One year after the gastrectomy, an abdominal computed tomography scan showed a low-density lesion, 17 mm in diameter, at the upper pole of the spleen. Positron emission tomography/computed tomography showed focal accumulation of fluorine-18 fluorodeoxyglucose in the spleen without extrasplenic tumor dissemination or metastasis. We diagnosed splenic metastasis of gastric cancer, and performed a splenectomy. Histological examination confirmed moderately differentiated tubular adenocarcinoma and poorly differentiated adenocarcinoma (solid type) that was consistent with the features of the primary gastric cancer. The splenic tumor was pathologically and immunohistochemically diagnosed as a metastasis from the gastric carcinoma. More than 18 months after the splenectomy, the patient has had no evidence of recurrent gastric cancer. CONCLUSION: When solitary metastasis to the spleen is suspected during the postoperative follow-up of a patient with gastric cancer, a splenectomy is a potentially effective treatment. PMID- 28637435 TI - Association between polymorphism rs11200638 in the HTRA1 gene and the response to anti-VEGF treatment of exudative AMD: a meta-analysis. AB - BACKGROUND: Anti-angiogenesis treatments are the most commonly used treatments for the vision loss caused by exudative age-related macular degeneration (AMD), in which the anti-vascular endothelial growth factor (VEGF) drugs with ranibizumab and bevacizumab are current standard treatments. However, the outcome of anti-VEGF therapeutics is not uniform in all patients. METHODS: We performed a literature-based meta-analysis including, five published studies relevant to HTRA1 and response to anti-VEGF treatment (bevacizumab or ranibizumab). Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Sensitivity analysis and meta-regression were also performed. Q-statistic test and Egger's test was used to evaluate heterogeneity and publication bias respectively. RESULTS: Overall, no association between the rs11200638 polymorphism in HTRA1 gene and the anti-VEGF treatment response was found in the genotype GG versus AA (OR = 1.06; 95% CI: 0.77 to 1.48; P = 0.98), genotype GA versus AA (OR = 1.11; 95% CI: 0.83 to 1.47; P = 0.93), genotype GG + GA versus AA (OR = 1.22; 95% CI: 0.94 to 1.57; P = 0.09), and allele G versus A (OR = 0.92; 95% CI: 0.78 to 1.08; P = 0.14). In the subgroup analysis by ethnicity Caucasian population, and a significant association was still not observed in all genetic models. Sensitivity analysis indicated the robustness of our findings, and no publication bias was observed in our meta-analysis. CONCLUSIONS: This study shows that there was no association between the polymorphism rs11200638 in HTRA1 gene and response to anti-VEGF treatment of exudative AMD. However, more studies are needed to further prove the conclusion of present study, especially well-designed and high quality randomised controlled trials or intervention studies. PMID- 28637436 TI - Management of early gastric cancer that meet the indication for radical lymph node dissection following endoscopic resection: a retrospective cohort analysis. AB - BACKGROUND: Endoscopic resection (ER) has been widely accepted as the standard treatment for early gastric cancer (EGC). However, in patients considered to have undergone non-curative ER due to their potential risk of lymph node metastasis (LNM), additional gastrectomy is recommended. The aim of the present study was to identify EGC patients after non-curative ER at high risk of LNM. METHODS: A total of 150 patients who had undergone ER for EGC were diagnosed as non-curative ER due to their potential risk of LNM. Clinicopathological data and clinical outcomes were examined retrospectively. RESULTS: Additional gastrectomy with lymph node dissection was performed in 73 patients, and the remaining 77 patients were followed-up without additional gastrectomy. In patients who underwent additional gastrectomy, 8 patients had local residual tumor, and 8 patients had LNM, which were limited in the peritumoral nodes. Only lymphatic invasion (p = 0.012) was a statistically significant factor for LNM. The 5-year overall survival and recurrence-free survival were not significantly different between patients with and without additional gastrectomy. CONCLUSION: Additional gastrectomy with lymph node dissection is recommended for patients who were diagnosed as non-curative ER with lymphatic invasion, and minimizing the extent of lymph node dissection may be allowed for these patients. PMID- 28637438 TI - The efficacy and safety of tranexamic acid in revision total knee arthroplasty: a meta-analysis. AB - BACKGROUND: There is no consistent conclusion regarding the efficacy and safety of the intravenous administration of tranexamic acid (TXA) for reducing blood loss in revision total knee arthroplasty (TKA). We performed a meta-analysis of comparative trials to evaluate the efficacy and safety of TXA in revision TKA. METHODS: We conducted a search of PubMed, EMBASE, The Cochrane Library and Web of Science for randomized controlled trials (RCTs) and non-RCTs. Two authors selected the studies, extracted the data, and assessed the risk of bias independently. A pooled meta-analysis was performed using RevMan 5.3 software. RESULTS: Four non-RCTs met the inclusion criteria. The meta-analysis indicated that the use of TXA was related to significantly less transfusion requirements (RD = -0.25; 95% CI: -0.43 to -0.08; P = 0.005), drainage volume (MD = -321.07; 95% CI: -445.13 to -197.01, P = 0.005), hemoglobin reduction (MD = -0.52; 95% CI: -0.79 to -0.25, P = 0.0001), and length of hospital stay (MD = -2.36; 95% CI: 4.00 to -0.71, P = 0.005). No significant differences in the incidence of deep venous thrombosis (DVT) or pulmonary embolism (PE) were noted. CONCLUSIONS: The use of TXA for patients undergoing revision TKA may reduce blood loss and transfusion requirements without increasing the risk of postoperative venous thromboembolism. Due to the limited quality of the currently available evidence, more high-quality RCTs are required. PMID- 28637439 TI - A qualitative analysis of smokers' perceptions about lung cancer screening. AB - BACKGROUND: In 2013, the US Preventive Services Task Force (USPSTF) began recommending lung cancer screening for high risk smokers aged 55-80 years using low-dose computed tomography (CT) scan. In light of these updated recommendations, there is a need to understand smokers' knowledge of and experiences with lung cancer screening in order to inform the design of patient education and tobacco cessation programs. The purpose of this study is to describe results of a qualitative study examining smokers' perceptions around lung cancer screening tests. METHODS: In 2009, prior to the release of the updated USPSTF recommendations, we conducted 12 120-min, gender-specific focus groups with 105 current smokers in Charlotte, North Carolina and Cincinnati, Ohio. Focus group facilitators asked participants about their experience with three lung cancer screening tests, including CT scan, chest x-ray, and sputum cytology. Focus group transcripts were transcribed and qualitatively analyzed using constant comparative methods. RESULTS: Participants were 41-67 years-old, with a mean smoking history of 38.9 pack-years. Overall, 34.3% would meet the USPSTF's current eligibility criteria for screening. Most participants were unaware of all three lung cancer screening tests. The few participants who had been screened recalled limited information about the test. Nevertheless, many participants expressed a strong desire to pursue lung cancer screening. Using the social ecological model for health promotion, we identified potential barriers to lung cancer screening at the 1) health care system level (cost of procedure, confusion around results), 2) cultural level (fatalistic beliefs, distrust of medical system), and 3) individual level (lack of knowledge, denial of risk, concerns about the procedure). Although this study was conducted prior to the updated USPSTF recommendations, these findings provide a baseline for future studies examining smokers' perceptions of lung cancer screening. CONCLUSION: We recommend clear and patient-friendly educational tools to improve patient understanding of screening risks and benefits and the use of best practices to help smokers quit. Further qualitative studies are needed to assess changes in smokers' perceptions as lung cancer screening with CT scan becomes more widely used in community practice. PMID- 28637440 TI - Acute airway compromise due to parathyroid tumour apoplexy: an exceptionally rare and potentially life-threatening presentation. AB - BACKGROUND: Spontaneous haemorrhage into a parathyroid adenoma is a rare and potentially life-threatening presentation. CASE PRESENTATION: We report the case of a 45 year old female recently diagnosed with primary hyperparathyroidism who presented with chest discomfort and acute airway compromise due to spontaneous extracapsular haemorrhage into a parathyroid adenoma. Computed tomography (CT) imaging showed a hypopharyngeal haematoma extending 10 cm into the superior mediastinum. Surgical decompression of the cyst followed by enbloc resection of the parathyroid tumour was performed after elective intubation. Calcium and parathyroid hormone (PTH) levels had fallen prior to surgery and remain normal post-operatively. CONCLUSION: Spontaneous parathyroid haemorrhage should be considered in any patient with unexplained spontaneous cervical haemorrhage, particularly if there is a history of hyperparathyroidism. Initial evaluation of such patients should include serum calcium and PTH as well as imaging. PMID- 28637441 TI - Impact of tobacco industry and other corporations in the defeat of the 1994 Clinton health care plan. AB - BACKGROUND: The primary reason cited by many scholars for the defeat of the Clinton Administration's 1994 health care reform bill has long been identified as Health Insurance Association of America and National Federation of Independent Businesses opposition to the bill. Given this predominant consensus combined with sizeable proposed funding for the bill by a large tobacco product tax, this manuscript examined what the tobacco industry's role was in whole or part in defeating the Clinton health care bill. METHODS: This research occurred through crosschecking internal tobacco industry documents and Clinton White House documents. RESULTS: Prior to the passage of the bill, the tobacco industry accepted a compromise of 45 cents per pack increase phased in over five years. Due to this compromise, the industry or third party allies had no role in the ultimate defeat in the bill. CONCLUSIONS: The primary reason for the bill's ultimate defeat was general business (but not tobacco industry and third party ally) opposition, the bill running out of time, and conflicting bills. Secondary reasons for the bill's defeat included issues with: employer mandates, high taxes on insurance plans, impacts on medical research and education, Congressional attention to other issues, election year politics, and possible future excise tax possibilities. PMID- 28637442 TI - Membranous nephropathy: a retrospective observational study of membranous nephropathy in north east and central London. AB - BACKGROUND: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. MN is a clinically heterogeneous disease and it is difficult to accurately predict outcomes (including end stage renal failure) at presentation and whom to treat with potentially toxic therapies. We aimed to identify factors predicting outcome in MN in our cohort from two large tertiary London units by undertaking a retrospective data analysis of 148 biopsy-proven MN patients from North East and Central London between 1995 and 2015. METHODS: Review of clinical and biochemistry databases. RESULTS: Surprisingly, patients that reached end stage renal failure (ESRF) had a less severe nephrosis compared to those that did not develop ESRF; serum albumin 33 g/L (3.3 g/dL) versus 24 g/L (2.4 g/dL), p = 0.002 and urinary protein creatinine ratio (uPCR) 550 mg/mmol (5500 mg/g) versus 902 mg/mmol (9020 mg/g), p = 0.0124. The correlation with ESRF was strongest with the presenting creatinine; 215 MUmol/L (2.43 mg/dL) compared to 81 MUmol/L (0.92 mg/dL), p < 0.0001. Patients presenting with creatinine of >120 MUmol/L (1.36 mg/dL; corresponding to an eGFR of <=60 ml/min in non-Black males) had an increased rate of ESRF and a faster decline. Other traditional risk factors for progression were not significantly associated with ESRF. Black patients presented with higher serum creatinine but no statistically significant difference in the estimated glomerular filtration rate, a higher rate of progression to ESRF and had a poorer response to treatment. CONCLUSIONS: This ethnically diverse cohort does not demonstrate the traditional risk profile associated with development of ESRF. Thus, careful consideration of therapeutic options is crucial, as current risk modelling cannot accurately predict the risk of ESRF. Further studies are required to elucidate the role of antibodies and risk genes. PMID- 28637443 TI - Trichoderma virens beta-glucosidase I (BGLI) gene; expression in Saccharomyces cerevisiae including docking and molecular dynamics studies. AB - BACKGROUND: Cellulose, a linear polymer of beta 1-4, linked glucose, is the most abundant renewable fraction of plant biomass (lignocellulose). It is synergistically converted to glucose by endoglucanase (EG) cellobiohydrolase (CBH) and beta-glucosidase (BGL) of the cellulase complex. BGL plays a major role in the conversion of randomly cleaved cellooligosaccharides into glucose. As it is well known, Saccharomyces cerevisiae can efficiently convert glucose into ethanol under anaerobic conditions. Therefore, S.cerevisiae was genetically modified with the objective of heterologous extracellular expression of the BGLI gene of Trichoderma virens making it capable of utilizing cellobiose to produce ethanol. RESULTS: The cDNA and a genomic sequence of the BGLI gene of Trichoderma virens was cloned in the yeast expression vector pGAPZalpha and separately transformed to Saccharomyces cerevisiae. The size of the BGLI cDNA clone was 1363 bp and the genomic DNA clone contained an additional 76 bp single intron following the first exon. The gene was 90% similar to the DNA sequence and 99% similar to the deduced amino acid sequence of 1,4-beta-D-glucosidase of T. atroviride (AC237343.1). The BGLI activity expressed by the recombinant genomic clone was 3.4 times greater (1.7 x 10-3 IU ml-1) than that observed for the cDNA clone (5 x 10-4 IU ml-1). Furthermore, the activity was similar to the activity of locally isolated Trichoderma virens (1.5 x 10-3 IU ml-1). The estimated size of the protein was 52 kDA. In fermentation studies, the maximum ethanol production by the genomic and the cDNA clones were 0.36 g and 0.06 g /g of cellobiose respectively. Molecular docking results indicated that the bare protein and cellobiose-protein complex behave in a similar manner with considerable stability in aqueous medium. The deduced binding site and the binding affinity of the constructed homology model appeared to be reasonable. Moreover, it was identified that the five hydrogen bonds formed between the amino acid residues of BGLI and cellobiose are mainly involved in the integrity of enzyme-substrate association. CONCLUSIONS: The BGLI activity was remarkably higher in the genomic DNA clone compared to the cDNA clone. Cellobiose was successfully fermented into ethanol by the recombinant S.cerevisiae genomic DNA clone. It has the potential to be used in the industrial production of ethanol as it is capable of simultaneous saccharification and fermentation of cellobiose. Homology modeling, docking studies and molecular dynamics simulation studies will provide a realistic model for further studies in the modification of active site residues which could be followed by mutation studies to improve the catalytic action of BGLI. PMID- 28637444 TI - A comparison of nutritional intake and daily physical activity of girls aged 8-11 years old in Makkah, Saudi Arabia according to weight status. AB - BACKGROUND: Obesity rates in Saudi Arabia are amongst the highest in the world. It is known that teenage girls are less active than teenage boys, but less is known about the diet and activity patterns in younger girls. Therefore this study sought to investigate dietary intake and daily physical activity in girls aged 8 11 years old in Saudi Arabia. METHODS: This was a cross- sectional observational study conducted in seven schools across the city of Makkah. A total of 266 girls had anthropometric measurements taken including height, weight, waist circumference and body fat estimations. Dietary assessment using a 4 day unweighed diet diary was undertaken in 136 of these participants, and 134 agreed to monitor their physical activity for the 4 days using an accelerometer. After exclusion for under-reporting, 109 remained in the dietary analysis and 78 in the physical activity analyses. Differences in means between BMI groups were determined using one-way ANOVA with post hoc Tukey test. Multivariable linear regression analysis was performed to look at the effect of multiple variables on body weight. RESULTS: A total of 30% of participants were classified obese or overweight. There was a significant difference in the mean daily energy intake between the BMI groups with the obese group having the highest energy, fat, carbohydrate and protein intake (obese group: 2677 +/- 804 kcal/d; healthy weight group: 1806 +/- 403 kcal/d, p < 0.001), but the percentage contribution of the macronutrients to energy intake remained the same across the BMI groups. There were no differences in number of steps taken per day or time spent in moderate to vigorous intensity exercise according to BMI category. Most of the girls did not meet daily physical activity guidelines (5969 to 6773 steps per day and 18.5 - 22.5 mins per day of moderate to vigorous activity). Multiple linear regression showed that energy intake positively predicted body weight (Beta = 0.279, p =0 .001), whereas, total energy expenditure per kg of body weight and family income had a significant negative influence on body weight (Beta = -0.661, p < 0.001; 0.131, p = 0.028 respectively). CONCLUSIONS: The results of this cross sectional analysis suggest that obesity in girls aged 8-11 years is linked to excessive energy intake from all macronutrients and the majority of girls in all weight categories are inactive. Research should be conducted to further investigate causal relationships in longitudinal studies and develop interventions to promote dietary change and activity that is culturally acceptable for girls in Saudi Arabia. PMID- 28637446 TI - miR-363-5p as potential prognostic marker for hepatocellular carcinoma indicated by weighted co-expression network analysis of miRNAs and mRNA. AB - BACKGROUND: This study aimed to investigate potential miRNAs and genes associated with the prognosis of hepatocellular carcinoma (HCC). METHODS: Weighted co expression network analysis was utilized to analyze the mRNA and miRNA sequencing data of HCC from TCGA (The Cancer Genome Atlas) database. Significant network modules were identified, and then functions of genes in the gene network modules and target genes of miRNAs in the miRNA network modules were explored. Additionally, correlations between network modules and prognostic factors of HCC were analyzed. RESULTS: In total, 10 mRNA network modules were identified, three of which were significantly related to tumor stage, NAFLD (non-alcoholic fatty liver disease) and patient age. Four miRNA network modules were identified, of which one was associated with tumor stage. Targets of hsa-miR-363-5p were found distributed in the gene network modules, such as RGPD5, RGPD6, ZNF445 and ZNF780B. Kaplan-Meier test revealed that low expression of hsa-miR-363-5p was associated with better overall survival of HCC patients. CONCLUSION: hsa-miR-363 5p may be a potential prognostic marker for HCC. PMID- 28637445 TI - Cerebellar mutism syndrome in children with brain tumours of the posterior fossa. AB - BACKGROUND: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. METHODS: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. DISCUSSION: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014. PMID- 28637447 TI - Differential gene expression at different stages of mesocarp development in high- and low-yielding oil palm. AB - BACKGROUND: The oil yield trait of oil palm is expected to involve multiple genes, environmental influences and interactions. Many of the underlying mechanisms that contribute to oil yield are still poorly understood. In this study, we used a microarray approach to study the gene expression profiles of mesocarp tissue at different developmental stages, comparing genetically related high- and low- oil yielding palms to identify genes that contributed to the higher oil-yielding palm and might contribute to the wider genetic improvement of oil palm breeding populations. RESULTS: A total of 3412 (2001 annotated) gene candidates were found to be significantly differentially expressed between high- and low-yielding palms at at least one of the different stages of mesocarp development evaluated. Gene Ontologies (GO) enrichment analysis identified 28 significantly enriched GO terms, including regulation of transcription, fatty acid biosynthesis and metabolic processes. These differentially expressed genes comprise several transcription factors, such as, bHLH, Dof zinc finger proteins and MADS box proteins. Several genes involved in glycolysis, TCA, and fatty acid biosynthesis pathways were also found up-regulated in high-yielding oil palm, among them; pyruvate dehydrogenase E1 component Subunit Beta (PDH), ATP-citrate lyase, beta- ketoacyl-ACP synthases I (KAS I), beta- ketoacyl-ACP synthases III (KAS III) and ketoacyl-ACP reductase (KAR). Sucrose metabolism-related genes such as Invertase, Sucrose Synthase 2 and Sucrose Phosphatase 2 were found to be down regulated in high-yielding oil palms, compared to the lower yield palms. CONCLUSIONS: Our findings indicate that a higher carbon flux (channeled through down-regulation of the Sucrose Synthase 2 pathway) was being utilized by up regulated genes involved in glycolysis, TCA and fatty acid biosynthesis leading to enhanced oil production in the high-yielding oil palm. These findings are an important stepping stone to understand the processes that lead to production of high-yielding oil palms and have implications for breeding to maximize oil production. PMID- 28637448 TI - Vitamin D levels and deficiency with different occupations: a systematic review. AB - BACKGROUND: Vitamin D deficiency is prevalent worldwide, but some groups are at greater risk. We aim to evaluate vitamin D levels in different occupations and identify groups vulnerable to vitamin D deficiency. METHODS: An electronic search conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and CINAHL Plus with Full Text generated 2505 hits; 71 peer-reviewed articles fulfilled the inclusion criteria. Occupations investigated included outdoor and indoor workers, shiftworkers, lead/smelter workers, coalminers, and healthcare professionals. We calculated the pooled average metabolite level as mean +/- SD; deficiency/insufficiency status was described as % of the total number of subjects in a given category. RESULTS: Compared to outdoor workers, indoor workers had lower 25-hydroxyvitamin D (25-(OH)D) levels (40.6 +/- 13.3 vs. 66.7 +/- 16.7 nmol/L; p < 0.0001). Mean 25-(OH)D levels (in nmol/L) in shiftworkers, lead/smelter workers and coalminers were 33.8 +/- 10.0, 77.8 +/- 5.4 and 56.6 +/- 28.4, respectively. Vitamin D deficiency (25-(OH)D < 50 nmol/L), was high in shiftworkers (80%) and indoor workers (78%) compared to outdoor workers (48%). Among healthcare professionals, medical residents and healthcare students had the lowest levels of mean 25-(OH)D, 44.0 +/- 8.3 nmol/L and 45.2 +/- 5.5 nmol/L, respectively. The mean 25-(OH)D level of practising physicians, 55.0 +/- 5.8 nmol/L, was significantly different from both medical residents (p < 0.0001) and healthcare students (p < 0.0001). Nurses and other healthcare employees had 25 (OH)D levels of 63.4 +/- 4.2 nmol/L and 63.0 +/- 11.0 nmol/L, respectively, which differed significantly compared to practising physicians (p = 0.01), medical residents (p < 0.0001) and healthcare students (p < 0.0001). Rates of vitamin D deficiency among healthcare professionals were: healthcare students 72%, medical residents 65%, practising physicians 46%, other healthcare employees 44%, and nurses 43%. Combined rates of vitamin D deficiency or insufficiency (25-(OH)D < 75 nmol/L) were very high in all investigated groups. Potential confounders such as gender and body composition were not consistently reported in the primary studies and were therefore not analyzed. Furthermore, the descriptions of occupational characteristics may be incomplete. These are limitations of our systematic review. CONCLUSIONS: Our review demonstrates that shiftworkers, healthcare workers and indoor workers are at high risk to develop vitamin D deficiency, which may reflect key lifestyle differences (e.g. sunlight exposure). This may help target health promotion and preventive efforts. PMID- 28637449 TI - Task shifting interpersonal counseling for depression: a pragmatic randomized controlled trial in primary care. AB - BACKGROUND: Task shifting approaches (rational redistribution of tasks among health workforce teams) to train lay professionals to assist with integrating mental health treatment in primary care has been recommended to close the mental health treatment gap for depression in low- and middle-income countries. This study aims to examine the a new model for depression care in a low-resource environment compared to enhanced treatment at usual (E-TAU). METHODS: We trained non-specialist community health workers (local lay employees of the public health system) to provide Interpersonal Counseling (IPC) to treat depressive symptoms in the Brazilian, Sao Paulo city, family health strategy (FHS). We conducted a randomized controlled trial involving 86 patients with a current major depressive disorder or dysthymia (based on DSM-IV) recruited from an FHS clinic. Participants were randomized to IPC intervention (n = 43) or E-TAU (n = 43). Participants allocated to IPC received 3-4 sessions provided by community health workers; research psychologists followed the E-TAU participants to facilitate their referral to specialized mental health care within the public system. Reduction of depressive symptoms was assessed using the Hamilton Rating Scale (HDRS-17) and the Patient Health Questionnaire (PHQ-9); minor psychiatric symptomatology (including depression, anxiety and somatoform symptoms) were measured using the Self Reporting Questionnaire (SRQ); and functioning was measured by the Clinical Global Impression Scale over a 2-month period. RESULTS: Intention-to-treat analysis showed significant improvement on symptoms for both groups over 2 months, without significant differences between them. Per-protocol analysis showed significant better HDRS-17 outcomes for the IPC group. CONCLUSIONS: Training non-specialist community health workers in low- and middle income countries to provide IPC could be a successful strategy in reducing the burden of depression and also potentially a low-cost and effective alternative to specialist-led services that might not be possible in low income settings. TRIAL REGISTRATION: Brazilian Clinical Trials, number RBR-5qhmb5 (trial url: http://www.ensaiosclinicos.gov.br/rg/RBR-5qhmb5/) , retrospectively registered after May 1, 2013. PMID- 28637450 TI - Health care use and costs at the end of life: a comparison of elderly Australian decedents with and without a cancer history. AB - BACKGROUND: There is limited population-level research on end-of-life care in Australia that considers health care use and costs across hospital and community sectors. The aim of this study was to quantify health care use and costs in the last 6 months of life in a cohort of elderly Australian decedents and to examine the factors associated with end-of-life resource use and costs. METHODS: A retrospective cohort study using routinely collected health data from Australian Government Department of Veterans' Affairs clients. The study included two cohorts of elderly Australians who died between 2005 and 2009; one cohort with a recorded cancer diagnosis and a comparison cohort with no evidence of a cancer history. We examined hospitalisations, emergency department (ED) visits, prescription drugs, clinician visits, pathology, and procedures and associated costs in the last 6 months of life. We used negative binominal regression to explore factors associated with health service use and costs. RESULTS: The cancer cohort had significantly higher rates of health service use and 27% higher total health care costs than the comparison cohort; in both cohorts, costs were driven primarily by hospitalisations. Older age was associated with lower costs and those who died in residential aged care incurred half the costs of those who died in hospital. CONCLUSIONS: The results suggest differences in end-of-life care pathways dependent on patient factors, with younger, community-dwelling patients and those with a history of cancer incurring significantly greater costs. There is a need to examine whether the investment in end-of-life care meets patient and societal needs. PMID- 28637451 TI - Performance of cone beam computed tomography and conventional intraoral radiographs in detecting interproximal alveolar bone lesions: a study in pig mandibles. AB - BACKGROUND: Cone beam computed tomography (CBCT) has been largely used in dentistry. Nevertheless, there is lack of evidence regarding CBCT accuracy in the diagnosis of early periodontal lesions as well as the correlation between accuracy and lesion size. The aim of this study was to evaluate accuracy of CBCT and conventional intraoral radiographs in detecting different-sized interproximal bone lesions created in pig mandibles. The hypothesis was that CBCT accuracy would be superior to radiographs in detecting incipient bone lesions. METHODS: Twenty swine dry mandibles were used, totalizing 80 experimental sites. Four groups were created according to exposure time to perchloric acid 70-72%: controls (no exposure), 2-hour exposure, 4-hour exposure, and 6-hour exposure. Standardized CBCT and conventional intraoral radiographs were taken and analyzed by two trained radiologists. The presence of lesions in the dry mandible was considered the gold standard. Sensitivity, specificity, and accuracy in detecting different-sized bone lesions were calculated for CBCT and intraoral radiographs. RESULTS: Accuracy of CBCT ranged from 0.762 to 0.825 and accuracy of periapical radiography ranged from 0.700 to 0.813, according to examiner and time of acid exposure. Inter-examiner agreement varied from slight to fair, whereas intra examiner agreement varied from moderate to substantial. CONCLUSIONS: CBCT performance was not superior to that provided by conventional intraoral radiographs in the detection of interproximal bone loss. PMID- 28637452 TI - Downregulation of Talin-1 expression associates with increased proliferation and migration of vascular smooth muscle cells in aortic dissection. AB - BACKGROUND: This study aimed to assessed whether Talin-1 is involved in the pathogenesis of aortic dissection via regulating vascular smooth muscle cell (VSMC) biological function. METHODS: Human aortic samples were obtained from organ donors who died from nonvascular diseases as normal controls and from patients undergoing surgical repair of thoracic aortic dissection. The expression level and distribution of Talin-1 were detected using westernblot analysis and immunohistochemistry in each sample. We inhibited the expression of Talin-1 via RNA interference in VSMCs. VSMC proliferation was detected by Cell-counting Kit-8 analyses. Scratch test and flow cytometry were used to identify the migration and apoptosis ability. Antibody microarray analysis and qRT-PCR were used to detect some protein and mRNA changes which were induced by Talin-1 downregulation. RESULTS: Talin-1 was significantly downregulated in the media of aortic dissection samples compared with controls (P < 0.05). Talin-1 knockdown significantly induced VSMC proliferation and migration in vitro. Proteins which involved in cell cycle can be regulated by downregulating Talin-1. Down regulation of Talin-1 can significanly increased the expression of anaphase promoting complex subunit 2 (APC2) and decreased p19 alternative reading frame (p19ARF), Cullin-3, and beta actin's expression. CONCLUSIONS: Talin-1 induces VSMCs proliferation and migration. It downregulated in aortic dissection, which might play a potential role in the development of aortic dissection. PMID- 28637453 TI - Electroacupuncture at LI11 promotes jejunal motility via the parasympathetic pathway. AB - BACKGROUND: Gastrointestinal motility disorder has been demonstrated to be regulated by acupuncture treatment. The mechanisms underlying the effects of acupuncture stimulation of abdominal and lower limb acupoints on gastrointestinal motility have been thoroughly studied; however, the physiology underlying the effects of acupuncture on the forelimbs to mediate gastrointestinal motility requires further exploration. The aim of this study was to determine whether electroacupuncture (EA) at LI11 promotes jejunal motility, whether the parasympathetic pathway participates in this effect, and if so, which somatic afferent nerve fibres are involved. METHODS: A manometric balloon was used to observe jejunal motility. The effects and mechanisms of EA at LI11 were explored in male Sprague-Dawley rats with or without drug administration (propranolol, clenbuterol, acetylcholine, and atropine) and with or without vagotomy. Three types of male mice (beta1beta2 receptor-knockout [beta1beta2-/-] mice, M2M3 receptor-knockout [M2M3-/-] mice and wild-type [WT] mice) were also studied by using different EA intensities (1, 2, 4, 6, and 8 mA). A total of 72 rats and 56 mice were included in the study. RESULTS: EA at LI11 increased the contractile amplitude of jejunal motility in the majority of both rats and mice. However, EA at LI11 did not enhance jejunal motility in rats administered atropine, rats that underwent vagotomy, and M2M3-??/- mice (at all intensities). In WT mice, EA at LI11 significantly increased jejunal motility at all intensities except 1 mA, and a plateau was reached at intensities greater than 4 mA. CONCLUSION: Our results suggest that EA at LI11 promotes jejunal motility primarily by exciting the parasympathetic pathway, and that Adelta-fibres and C-fibres may play important roles in the process. PMID- 28637454 TI - Relationships of work characteristics to job satisfaction, turnover intention, and burnout among doctors in the district public-private mixed health system of Bangladesh. AB - BACKGROUND: Work design integrates work characteristics having organizational, social and job components which influence employees' welfare and also organizational goals. We investigated the effects of work characteristics and other predictors to job satisfaction, turnover intention, and burnout in doctors of the public primary, public secondary and private facilities of the district health system of Bangladesh. METHODS: A quantitative study using a self administered questionnaire containing mostly structured items was conducted among the public and private doctors with a sample size of 384 from 29 out of a total 64 districts of Bangladesh during October and November 2015. All variables including work characteristics and outcomes of interest were based on literature and measured on 5-point Likert scale. Multivariate analysis of variance, bivariate correlation, and multiple regression were the models operated through SPSS version-21. RESULTS: A total of 354 doctors responded. No significant differences were found between public primary and secondary level doctors on combined work characteristics and outcomes variables, which however differed significantly between the public and private doctors. Organizational support was the strongest predictor adversely affecting job satisfaction, turnover intention and burnout of both the public and private doctors; private doctors' experienced more support. The effects of health-professional politics on the public doctors were alarming. CONCLUSION: Work design of the Bangladesh's health system is in need of ample development. Doing so, improvement in organizational supports is crucial; however, other work characteristics components are also important for enhancing doctors' welfare and health system productivity. PMID- 28637455 TI - Mental disorders and the use of primary health care services among homeless shelter users in the Helsinki metropolitan area, Finland. AB - BACKGROUND: Homelessness is associated with increased morbidity, mortality and health care use. The aim of this study was to examine the role of mental disorders in relation to the use of 1) daytime primary health care services and 2) after hours primary health care emergency room (PHER) services among homeless shelter users in the Helsinki Metropolitan Area, Finland. METHODS: The study cohort consists of all 158 homeless persons using the four shelters operating in the study area during two selected nights. The health records were analyzed over a period of 3 years prior to the sample nights and data on morbidity and primary health care visits were gathered. We used negative binomial regression to estimate the association between mental disorders and daytime visits to primary health care and after hours visits to PHERs. RESULTS: During the 3 years the 158 homeless persons in the cohort made 1410 visits to a physician in primary health care. The cohort exhibited high rates of mental disorders, including substance use disorders (SUDs); i.e. 141 persons (89%) had a mental disorder. We found dual diagnosis, defined as SUD concurring with other mental disorder, to be strongly associated with daytime primary health care utilization (IRR 11.0, 95% CI 5.9 20.6) when compared with those without any mental disorder diagnosis. The association was somewhat weaker for those with only SUDs (IRR 4.9, 95% CI 2.5 9.9) or with only other mental disorders (IRR 5.0, 95% CI 2.4-10.8). When focusing upon the after hours visits to PHERs we observed that both dual diagnosis (IRR 14.1, 95% CI 6.3-31.2) and SUDs (11.5, 95% CI 5.7-23.3) were strongly associated with utilization of PHERs compared to those without any mental disorder. In spite of a high numbers of visits, we found undertreatment of chronic conditions such as hypertension and diabetes. CONCLUSIONS: Dual diagnosis is particularly strongly associated with primary health care daytime visits among homeless persons staying in shelters, while after hours visits to primary health care level emergency rooms are strongly associated with both dual diagnosis and SUDs. Active treatment for SUDs could reduce the amount of emergency visits made by homeless shelter users. PMID- 28637456 TI - The modified Yi qi decoction protects cardiac ischemia-reperfusion induced injury in rats. AB - BACKGROUND: To investigate the effects and involved mechanisms of the modified Yi Qi decoction (MYQ) in cardiac ischemia-reperfusion (IR) induced injury. METHODS: Male Sprague-Dawley rats were subjected to a 30-min coronary arterial occlusion followed by reperfusion, low or high dose decoction of MYQ was administrated orally for 1 week or 1 month. RESULTS: Both in 1 week and 1 month IR rat groups, cardiac function indexes were significantly impaired compared with sham group rats, accompanied with higher ratio of infarct size to risk size, decreased expressions of sodium calcium exchanger (NCX1) and sarcoplasmic reticulum Ca2+ ATPase (Serca2a), and different expressions of autophagic proteins, Beclin-1 and LC3. Treatment with MYQ (low or high dose) for 1 week showed no marked beneficial effects on cardiac function and cardiac injury (ratio of infarct size to risk size), although expressions of anti-apoptotic protein, Bcl-2, NCX1 and Serca2a were increased. Treatment with MYQ (low or high dose) for 1 month showed significantly improved effects on cardiac function and cardiac injury (ratio of infarct size to risk size), accompanied with increase of Bcl-2, NCX1 and Serca2a expressions, and decrease of Bax (a pro-apoptotic protein) and Beclin-1 expressions. CONCLUSIONS: The results show that MYQ have potential therapeutic effects on IR-induced cardiac injury, which may be through regulation of apoptotic proteins, cytosolic Ca2+ handling proteins and autophagic proteins signal pathways. PMID- 28637457 TI - Descriptive and network analyses of the equine contact network at an equestrian show in Ontario, Canada and implications for disease spread. AB - BACKGROUND: Identifying the contact structure within a population of horses attending a competition is an important element towards understanding the potential for the spread of equine pathogens as the horses subsequently travel from location to location. However, there is limited information in Ontario, Canada to quantify contact patterns of horses. The objective of this study was to describe the network of potential contacts associated with an equestrian show to determine how this network structure may influence potential disease transmission. RESULTS: This was a descriptive study of horses attending an equestrian show in southern Ontario, Canada on July 6 and 7, 2014. Horse show participants completed a questionnaire about their horse, travel patterns, and infection control practices. Questionnaire responses were received from horse owners of 79.7% (55/69) of the horses attending the show. Owners reported that horses attending the show were vaccinated for diseases such as rabies, equine influenza, and equine herpesvirus. Owners demonstrated high compliance with most infection control practices by reporting reduced opportunities for direct and indirect contact while away from home. The two-mode undirected network consisted of 820 nodes (41 locations and 779 horses). Eight percent of nodes in the network represented horses attending the show, 87% of nodes represented horses not attending the show, but boarded at individual home facilities, and 5% represented locations. The median degree of a horse in the network was 33 (range: 1-105). CONCLUSIONS: Developing disease management strategies without the explicit consideration of horses boarded at individual home facilities would underestimate the connectivity of horses in the population. The results of this study provides information that can be used by equestrian show organizers to configure event management in such a way that can limit the extent of potential disease spread. PMID- 28637458 TI - Exposure of hospitalised pregnant women to plasticizers contained in medical devices. AB - BACKGROUND: Medical devices (MDs) in polyvinyl chloride (PVC) are not a well known source of exposure to plasticizers, in particular during pregnancy. Because of its toxicity, the di-(2-ethylhexyl) phthalate (DEHP) has been replaced by other plasticizers such as di (isononyl)-cyclohexane-1,2-dicarboxilic acid (DINCH), tri-octyltrimellitate (TOTM) and di-(isononyl) phthalate (DiNP). Our study aimed to quantify the plasticizers (DEHP and alternative plasticizers) contained in PVC medical devices used for hospitalised pregnant women and to describe which these MDs had been used (type, number, duration of exposure). METHODS: The plasticizers contained in the MDs used for daily care in the Obstetrics Department of a French University Hospital were extracted from PVC (after contact with a chloroform solution), identified and quantified by gas chromatography-mass-spectrometry analysis. A total of 168 pregnant women hospitalised in the Obstetrics Department with at least one catheter were included in the observational study. The median number of MDs containing plasticizers used and the daily duration of exposure to the MDs were compared in three groups of pregnant women: "Pathology group" (women hospitalised for an obstetric disorder who did not give birth during this hospitalisation; n = 52), "Pathology and delivery group" (hospitalised for an obstetric disorder and who gave birth during this stay; n = 23) and "Delivery group" (admitted for planned or spontaneous delivery without obstetric disorder; n = 93). RESULTS: DiNP, TOTM and DINCH were the predominant plasticizers contained in the MDs at an amount of 29 to 36 g per 100 g of PVC. Women in the "Pathology group" (preterm labour or other pathology) were exposed to a median number of two MDs containing TOTM and one MD containing DiNP, fewer than those in the "Pathology and delivery group" (p < 0.05). Women in the "Pathology group" had a median exposure of 3.4 h/day to MDs containing DiNP and 8.2 h/day to MDs containing TOTM, longer than those in the "Delivery group" (p < 0.01). CONCLUSIONS: Our study shows that the medical management of pregnant women in a hospital setting entails exposure to MDs containing alternative plasticizers (DiNP, TOTM and DINCH). PMID- 28637459 TI - The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. AB - The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays critical roles in orchestrating of immune system, especially cytokine receptors and they can modulate the polarization of T helper cells. This pathway is regulated by an array of regulator proteins, including Suppressors of Cytokine Signaling (SOCS), Protein Inhibitors of Activated STATs (PIAS) and Protein Tyrosine Phosphatases (PTPs) determining the initiation, duration and termination of the signaling cascades. Dysregulation of the JAK-STAT pathway in T helper cells may result in various immune disorders. In this review, we represent how the JAK-STAT pathway is generally regulated and then in Th cell subsets in more detail. Finally, we introduce novel targeted strategies as promising therapeutic approaches in the treatment of immune disorders. Studies are ongoing for identifying the other regulators of the JAK-STAT pathway and designing innovative therapeutic strategies. Therefore, further investigation is needed. PMID- 28637460 TI - Healthcare utilization and costs for patients initiating Dabigatran or Warfarin. AB - BACKGROUND: Novel oral anticoagulants (NOAC) such as dabigatran, when compared to warfarin, have been shown to potentially reduce the risk of stroke in patients with non-valvular atrial fibrillation (NVAF) together with lower healthcare resource utilization (HCRU) and similar total costs. This study expands on previous work by comparing HCRU and costs for patients newly diagnosed with NVAF and newly initiated on dabigatran or warfarin, and is the first study specifically in a Medicare population. METHODS: A retrospective matched-cohort study was conducted using data from administrative health care claims during the study period 01/01/2010-12/31/2012. Cox regression analyses were used to compare all-cause risk of first hospitalizations and emergency room (ER) visits. Medical, pharmacy, and total costs per-patient-per-month (PPPM) were compared between dabigatran and warfarin users. RESULTS: A total of 1110 patients initiated on dabigatran were propensity score-matched with corresponding patients initiated on warfarin. The mean number of hospitalizations (0.92 vs. 1.13, P = 0.012), ER visits (1.32 vs. 1.56, P < 0.01), office visits (21.43 vs. 29.41; P < 0.01), and outpatient visits (10.86 vs. 22.02; P < 0.01) were lower among dabigatran compared to warfarin users. Patients initiated on dabigatran had significantly lower risk of first all-cause ER visits [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.73-0.98] compared to those initiated on warfarin. Adjusted mean pharmacy costs PPPM were significantly greater for dabigatran users ($510 vs. $250, P < 0.001); however, mean medical costs PPPM ($1912 vs. $1956, P = 0.55) and mean total costs PPPM ($2381 vs. $2183, P = 0.10) were not significantly different compared to warfarin users. CONCLUSIONS: Dabigatran users had significantly lower HCRU compared to warfarin users. In addition, dabigatran users had lower risk of all-cause ER visits. Despite higher pharmacy costs, the two cohorts did not differ significantly in medical or total all-cause costs. PMID- 28637461 TI - Prenatal exposure to antifungal medication may change anogenital distance in male offspring: a preliminary study. AB - BACKGROUND: Vaginal candidiasis is frequent among pregnant women and it is treated with anti-fungal medication (conazoles). Conazoles have anti-androgenic properties and prenatal exposure in rodents is associated with a shorter (less masculine) anogenital distance (AGD) in male offspring. To our knowledge this has never been studied in humans. METHOD: In the Odense Child Cohort pregnant women residing in Odense municipality, Denmark, were recruited at gestational age 8-16 weeks between 2010 and 2012. Of the eligible 2421 mother-child pairs, 812 mother son pairs were included. Questionnaire data on medicine use were collected in first and third trimester and physical examination at age 3 month was performed. Ano-scrotal distance; measured from the centre of anus to the posterior base of scrotum (AGDas). Ano-cephalad distance; measured from the centre of anus to the cephalad insertion of the penis (AGDap) and penile width; measured at the base of the penis. RESULTS: Eighty seven women had used antifungal medicine during pregnancy. Maternal use of oral fluconazole (n = 4) was associated with a 6.4 mm shorter AGDas (95% CI: -11.9;-0.9) in the male offspring. Use of antifungal vaginal tablets (n = 21), was associated with a non-significantly shorter AGDas ( 1.9 mm; 95% CI: -4.3; 0.5) whereas exposure to vaginal cream (n = 23) was not associated to AGDas. Use of antifungal medicine in the window of genital development between 8 and 14 weeks of gestation was associated with a larger reduction in AGDas than exposure outside this window. Antifungal medicine intake was not associated with AGDap and penil width. CONCLUSION: Our preliminary findings prompted us to hypothesize that maternal use of conazole antifungal medication during pregnancy may affect the masculinization of male offspring. If confirmed, pregnant women should be advised to use antifungal medicine with caution. PMID- 28637462 TI - Outbreak tracking of Aleutian mink disease virus (AMDV) using partial NS1 gene sequencing. AB - BACKGROUND: Aleutian Mink Disease (AMD) is an infectious disease of mink (Neovison vison) and globally a major cause of economic losses in mink farming. The disease is caused by Aleutian Mink Disease Virus (AMDV) that belongs to the genus Amdoparvovirus within the Parvoviridae family. Several strains have been described with varying virulence and the severity of infection also depends on the host's genotype and immune status. Clinical signs include respiratory distress in kits and unthriftiness and low quality of the pelts. The infection can also be subclinical. Systematic control of AMDV in Danish mink farms was voluntarily initiated in 1976. Over recent decades the disease was mainly restricted to the very northern part of the country (Northern Jutland), with only sporadic outbreaks outside this region. Most of the viruses from this region have remained very closely related at the nucleotide level for decades. However, in 2015, several outbreaks of AMDV occurred at mink farms throughout Denmark, and the sources of these outbreaks were not known. METHODS: Partial NS1 gene sequencing, phylogenetic analyses data were utilized along with epidemiological to determine the origin of the outbreaks. RESULTS: The phylogenetic analyses of partial NS1 gene sequences revealed that the outbreaks were caused by two different clusters of viruses that were clearly different from the strains found in Northern Jutland. These clusters had restricted geographical distribution, and the variation within the clusters was remarkably low. The outbreaks on Zealand were epidemiologically linked and a close sequence match was found to two virus sequences from Sweden. The other cluster of outbreaks restricted to Jutland and Funen were linked to three feed producers (FP) but secondary transmissions between farms in the same geographical area could not be excluded. CONCLUSION: This study confirmed that partial NS1 sequencing can be used in outbreak tracking to determine major viral clusters of AMDV. Using this method, two new distinct AMDV clusters with low intra-cluster sequence diversity were identified, and epidemiological data helped to reveal possible ways of viral introduction into the affected herds. PMID- 28637463 TI - Health and safety matters! Associations between organizational practices and personal support workers' life and work stress in Ontario, Canada. AB - BACKGROUND: The home and community care sector is one of the fastest growing sectors globally and most prominently in mature industrialized countries. Personal support workers (PSWs) are the largest occupational group in the sector. This paper focuses on the emotional health of PSWs working in the home and community care sector in Ontario, Canada. The purpose of this paper is to present evidence on the associations between PSWs' life and work stress and organizational practices of full-time and guaranteed hours, and PSWs' perceptions of support at work and preference for hours. METHODS: Data come from our 2015 survey of 1543 PSWs. Dependent variables are life and work stress. Independent variables are: objective organizational practices of full-time and guaranteed hours, and subjective organizational practices of perceived support at work, and preferred hours of work. Descriptive statistics, correlations and ordinary least square regression analyses with collinearity tests are conducted. RESULTS: Organizational practices of employing PSWs in full-time or guaranteed hours are not associated with their life and work stress. However, those who perceive support from their organizations are also the ones reporting lower life and work stress. In addition, those PSWs perceiving support from their supervisor report lower work stress. PSWs would like to work in their preferred hours, and those who prefer to work more hours report lower life and work stress, and conversely, those who prefer to work less hours report life and work stress. CONCLUSION: For PSWs in home and community care, perceived support from their organizations and supervisors, and employment in preferred hours are important factors related to their life and work stress. PMID- 28637464 TI - Kaiso differentially regulates components of the Notch signaling pathway in intestinal cells. AB - BACKGROUND: In mammalian intestines, Notch signaling plays a critical role in mediating cell fate decisions; it promotes the absorptive (or enterocyte) cell fate, while concomitantly inhibiting the secretory cell fate (i.e. goblet, Paneth and enteroendocrine cells). We recently reported that intestinal-specific Kaiso overexpressing mice (Kaiso Tg ) exhibited chronic intestinal inflammation and had increased numbers of all three secretory cell types, hinting that Kaiso might regulate Notch signaling in the gut. However, Kaiso's precise role in Notch signaling and whether the Kaiso Tg secretory cell fate phenotype was linked to Kaiso-induced inflammation had yet to be elucidated. METHODS: Intestines from 3 month old Non-transgenic and Kaiso Tg mice were "Swiss" rolled and analysed for the expression of Notch1, Dll-1, Jagged-1, and secretory cell markers by immunohistochemistry and immunofluorescence. To evaluate inflammation, morphological analyses and myeloperoxidase assays were performed on intestines from 3-month old Kaiso Tg and control mice. Notch1, Dll-1 and Jagged-1 expression were also assessed in stable Kaiso-depleted colon cancer cells and isolated intestinal epithelial cells using real time PCR and western blotting. To assess Kaiso binding to the DLL1, JAG1 and NOTCH1 promoter regions, chromatin immunoprecipitation was performed on three colon cancer cell lines. RESULTS: Here we demonstrate that Kaiso promotes secretory cell hyperplasia independently of Kaiso-induced inflammation. Moreover, Kaiso regulates several components of the Notch signaling pathway in intestinal cells, namely, Dll-1, Jagged-1 and Notch1. Notably, we found that in Kaiso Tg mice intestines, Notch1 and Dll-1 expression are significantly reduced while Jagged-1 expression is increased. Chromatin immunoprecipitation experiments revealed that Kaiso associates with the DLL1 and JAG1 promoter regions in a methylation-dependent manner in colon carcinoma cell lines, suggesting that these Notch ligands are putative Kaiso target genes. CONCLUSION: Here, we provide evidence that Kaiso's effects on intestinal secretory cell fates precede the development of intestinal inflammation in Kaiso Tg mice. We also demonstrate that Kaiso inhibits the expression of Dll-1, which likely contributes to the secretory cell phenotype observed in our transgenic mice. In contrast, Kaiso promotes Jagged-1 expression, which may have implications in Notch-mediated colon cancer progression. PMID- 28637465 TI - Early pulmonary response is critical for extra-pulmonary carbon nanoparticle mediated effects: comparison of inhalation versus intra-arterial infusion exposures in mice. AB - BACKGROUND: The death toll associated with inhaled ambient particulate matter (PM) is attributed mainly to cardio-vascular rather than pulmonary effects. However, it is unclear whether the key event for cardiovascular impairment is particle translocation from lung to circulation (direct effect) or indirect effects due to pulmonary particle-cell interactions. In this work, we addressed this issue by exposing healthy mice via inhalation and intra-arterial infusion (IAI) to carbon nanoparticles (CNP) as surrogate for soot, a major constituent of (ultrafine) urban PM. METHODS: Equivalent surface area CNP doses in the blood (30mm2 per animal) were applied by IAI or inhalation (lung-deposited dose 10,000mm2; accounting for 0.3% of lung-to-blood CNP translocation). Mice were analyzed for changes in hematology and molecular markers of endothelial/epithelial dysfunction, pro-inflammatory reactions, oxidative stress, and coagulation in lungs and extra-pulmonary organs after CNP inhalation (4 h and 24 h) and CNP infusion (4 h). For methodological reasons, we used two different CNP types (spark-discharge and Printex90), with very similar physicochemical properties [>=98 and >=95% elemental carbon; 10 and 14 nm primary particle diameter; and 800 and 300 m2/g specific surface area] for inhalation and IAI respectively. RESULTS: Mild pulmonary inflammatory responses and significant systemic effects were observed following 4 h and 24 h CNP inhalation. Increased retention of activated leukocytes, secondary thrombocytosis, and pro-inflammatory responses in secondary organs were detected following 4 h and 24 h of CNP inhalation only. Interestingly, among the investigated extra-pulmonary tissues (i.e. aorta, heart, and liver); aorta revealed as the most susceptible extra pulmonary target following inhalation exposure. Bypassing the lungs by IAI however did not induce any extra-pulmonary effects at 4 h as compared to inhalation. CONCLUSIONS: Our findings indicate that extra-pulmonary effects due to CNP inhalation are dominated by indirect effects (particle-cell interactions in the lung) rather than direct effects (translocated CNPs) within the first hours after exposure. Hence, CNP translocation may not be the key event inducing early cardiovascular impairment following air pollution episodes. The considerable response detected in the aorta after CNP inhalation warrants more emphasis on this tissue in future studies. PMID- 28637467 TI - Imported Plasmodium falciparum and locally transmitted Plasmodium vivax: cross border malaria transmission scenario in northwestern Thailand. AB - BACKGROUND: Cross-border malaria transmission is an important problem for national malaria control programmes. The epidemiology of cross-border malaria is further complicated in areas where Plasmodium falciparum and Plasmodium vivax are both endemic. By combining passive case detection data with entomological data, a transmission scenario on the northwestern Thai-Myanmar border where P. falciparum is likely driven by importation was described, whereas P. vivax is also locally transmitted. This study highlights the differences in the level of control required to eliminate P. falciparum and P. vivax from the same region. METHODS: Malaria case data were collected from malaria clinics in Suan Oi village, Tak Province, Thailand between 2011 and 2014. Infections were diagnosed by light microscopy. Demographic data, including migrant status, were correlated with concomitantly collected entomology data from 1330 mosquito trap nights using logistic regression. Malaria infection in the captured mosquitoes was detected by ELISA. RESULTS: Recent migrants were almost four times more likely to be infected with P. falciparum compared with Thai patients (OR 3.84, p < 0.001) and cases were significantly associated with seasonal migration. However, P. falciparum infection was not associated with the Anopheles mosquito capture rates, suggesting predominantly imported infections. In contrast, recent migrants were equally likely to present with P. vivax as mid-term migrants. Both migrant groups were twice as likely to be infected with P. vivax in comparison to the resident Thai population (OR 1.96, p < 0.001 and OR 1.94, p < 0.001, respectively). Plasmodium vivax cases were strongly correlated with age and local capture rates of two major vector species Anopheles minimus and Anopheles maculatus (OR 1.23, p = 0.020 and OR 1.33, p = 0.046, respectively), suggesting that a high level of local transmission might be causing these infections. CONCLUSIONS: On the Thai Myanmar border, P. falciparum infections occur mostly in the recent migrant population with a seasonality reflecting that of agricultural activity, rather than that of the local mosquito population. This suggests that P. falciparum was mostly imported. In contrast, P. vivax cases were significantly associated with mosquito capture rates and less with migrant status, indicating local transmission. This highlights the different timelines and requirements for P. falciparum and P. vivax elimination in the same region and underlines the importance of multinational, cross-border malaria control. PMID- 28637468 TI - Chorioallantoic membranes of embryonated chicken eggs as an alternative system for isolation of equine influenza virus. AB - BACKGROUND: Influenza virus isolation in embryonated chicken eggs (ECEs) is not applicable for rapid diagnosis, however it allows the recovery and propagation of the viable virus. A low number of infectious virus particles in the swabs, poor quality of samples or individual strain properties can lead to difficulties during the virus isolation process. We propose to utilize chorioallantoic membranes (CAM) of ECEs with the assistance of real-time RT PCR to facilitate equine influenza virus isolation. METHODS: Real-time RT PCR was used to detect influenza virus genetic material in amniotic/allantoic fluids (AF) and CAM of ECEs. Haemagglutination assay was used for AF. We used highly diluted virus as a substitute of clinical specimen for ECEs inoculation. RESULTS: Our study demonstrated that real-time RT PCR testing of CAM homogenates was more useful than testing of AF for EIV detection in ECEs. Positive results from CAM allowed to select the embryos from those with haemagglutination assay (HA) - and real time RT PCR-negative AF for further passages. Using homogenates of CAM for subsequent passages, we finally obtained HA-positive AF, which confirmed virus replication. CONCLUSION: We postulate that real-time RT PCR testing of CAM homogenates and their subsequent passages may facilitate the isolation of equine influenza viruses. PMID- 28637466 TI - The KT Jeang Retrovirology prize 2017: Michael Emerman. PMID- 28637469 TI - Impact of phthalate and BPA exposure during in utero windows of susceptibility on reproductive hormones and sexual maturation in peripubertal males. AB - BACKGROUND: Phthalates and BPA are endocrine disrupting chemicals (EDCs) widely used in consumer products. Evidence suggests that phthalate and BPA exposure alters steroid hormone levels in adults, while in utero exposure has been associated with altered fetal reproductive development in boys. However, the impact of exposure during distinct critical windows of in utero development on hormone concentrations and sexual maturation during the pubertal transition has not been examined. The objective of this study was to assess trimester-specific in utero phthalate and BPA exposure in relation to measures of reproductive development among peripubertal boys in a Mexico City birth cohort. METHODS: We measured maternal urinary phthalate metabolites and BPA during the first, second, and third trimesters of pregnancy. We measured serum levels of testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone binding globulin (SHBG), and assessed sexual maturation (Tanner staging and testicular volume) among male children at age 8-14 years (n = 109). Linear and logistic regression were used to investigate trimester-specific in utero exposure as predictors of peripubertal hormone levels and sexual maturation, respectively. In sensitivity analyses we evaluated estimated exposure at 7 weeks gestation and rates of change in exposure across pregnancy in relation to outcomes. RESULTS: Exposure to phthalates during the third trimester was associated with reduced odds of having a Tanner stage >1 for pubic hair development (e.g. MBzP OR = 0.18 per interquartile range (IQR) increase; 95% CI:0.03-0.97) and higher peripubertal SHBG levels (e.g. MBzP 15.2%/IQR; 95% CI:3.2-28%), while first and second trimester phthalates were not. In contrast, exposure to DEHP during the first trimester was associated with higher estradiol (11%/IQR; 95% CI:1.5-22%), while second or third trimester DEHP exposure was not. Sensitivity analyses yielded similar findings. CONCLUSIONS: Associations between in utero phthalate and BPA exposure and peripubertal measures of male reproductive development are dependent on the timing of that exposure during gestation. These findings suggest that future epidemiological studies relating in utero EDC exposure to pubertal outcomes should consider windows of susceptibility. PMID- 28637470 TI - Promoting physical activity among adolescent girls: the Girls in Sport group randomized trial. AB - BACKGROUND: Slowing the decline in participation in physical activity among adolescent girls is a public health priority. This study reports the outcomes from a multi-component school-based intervention (Girls in Sport), focused on promoting physical activity among adolescent girls. METHODS: Group randomized controlled trial in 24 secondary schools (12 intervention and 12 control). Assessments were conducted at baseline (2009) and at 18 months post-baseline (2010). The setting was secondary schools in urban, regional and rural areas of New South Wales, Australia. All girls in Grade 8 in 2009 who attended these schools were invited to participate in the study (N = 1769). Using a Health Promoting Schools and Action Learning Frameworks, each school formed a committee and developed an action plan for promoting physical activity among Grade 8 girls. The action plan incorporated strategies in three main areas - i) the formal curriculum, ii) school environment, and iii) home/school/community links - based on the results of formative data from target girls and staff and on individual needs of the school. A member of the research team supported each school throughout the intervention. The main outcome measure was accelerometer-derived total physical activity (TPA) spent in physical activity. Data were analyzed from December 2011 to March 2012. RESULTS: 1518 girls (mean age 13.6y +/-0.02) were assessed at baseline. There was a significant decline in TPA from baseline to 18 month follow-up with no differences between girls in the intervention and control schools. Only one-third of schools (4/12) implemented the intervention as per their action plan. Per-protocol analyses on these schools revealed a smaller decline in percentage of time spent in MVPA among girls in the intervention group (adjusted difference 0.5%, 95% CI = -0.01, 0.99, P = 0.05). CONCLUSIONS: The Girls in Sport intervention was not effective in reducing the decline in physical activity among adolescent girls. Lack of implementation by most intervention schools was the main reason for a null effect. Identifying strategies to enhance implementation levels is critical to determining the true potential of this intervention approach. TRIAL REGISTRATION: This study was retrospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12610001077055 . Date of registration: 7 December 2010. PMID- 28637471 TI - Enhanced humoural and cellular immune responses to influenza H7N9 antigen HA1-2 fused with flagellin in chickens. AB - BACKGROUND: Sudden increases in the number of human A (H7N9) cases reported during December and January have been observed in previous years. Most reported infection cases are due to prior exposure to live poultry or potentially contaminated environments. Low pathogenicity of influenza A (H7N9) virus in avian species complicates timely discovery of infected birds. Therefore, there is a pressing need to develop safe and effective anti-H7N9 vaccines for poultry to reduce the risk of human infection and prevent the emergence of novel mutated strains. In addition to a good antigen, an effective vaccine also requires an appropriate adjuvant to enhance its immunogenicity. Previously, we generated an H7N9 influenza recombinant subunit vaccine (HA1-2-fliC), in which haemagglutinin globular head domain (HA1-2) was fused with flagellin (fliC), a potent TLR5 ligand, and demonstrated that HA1-2-fliC elicited effective HA1-2-specific immune responses in mice. RESULTS: In this study, we determined flagellin-induced expression profiles of cytokines and chemokines in different types of avian immune cells in vitro and ex vivo. We found that flagellin significantly increased the expression levels of CXCL inflammatory chemokines (CXCLi1 and CXCLi2) and CCL chemokines (MIP-1beta and MCP-3) in avian macrophage HD11 cells. In addition, HA1-2-fliC induced significant upregulation of cytokines (IL-1beta, IL-6, IL-18 and IFN-gamma) and chemokines (CXCLi1, CXCLi2 and MIP-1beta) in ex vivo splenic lymphocytes and peripheral blood mononuclear cells (PBMCs), suggesting that flagellin promoted immune responses of avian cells in vitro. We also evaluated specific humoural and cellular immune responses induced by HA1-2 fliC and found that chickens immunised intramuscularly with HA1-2-fliC showed significantly higher HA1-2-specific immunoglobulin (Ig)G titers in serum. Furthermore, HA1-2-fliC potentiated cellular immune responses, as reflected by an increase in CD4+ and CD8+ T cells and proliferation of PBMCs. Significantly higher levels of IFN-gamma and IL-4 in PBMCs from chickens vaccinated with HA1-2 fliC further indicated that HA1-2-fliC promoted a balanced Th1/Th2 immune response. CONCLUSIONS: We demonstrated that the use of the flagellin as an adjuvant potentiated immunogenicity of influenza subunit vaccine HA1-2 in vitro and in vivo. These findings provide a basis for the development of H7N9 influenza HA1-2 subunit vaccines for chickens. PMID- 28637472 TI - Variability in P1 gene redefines phylogenetic relationships among cassava brown streak viruses. AB - BACKGROUND: Cassava brown streak disease is emerging as the most important viral disease of cassava in Africa, and is consequently a threat to food security. Two distinct species of the genus Ipomovirus (family Potyviridae) cause the disease: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV). To understand the evolutionary relationships among the viruses, 64 nucleotide sequences from the variable P1 gene from major cassava producing areas of east and central-southern Africa were determined. METHODS: We sequenced an amplicon of the P1 region of 31 isolates from Malawi and Tanzania. In addition to these, 33 previously reported sequences of virus isolates from Uganda, Kenya, Tanzania, Malawi and Mozambique were added to the analysis. RESULTS: Phylogenetic analyses revealed three major P1 clades of Cassava brown streak viruses (CBSVs): in addition to a clade of most CBSV and a clade containing all UCBSV, a novel, intermediate clade of CBSV isolates which has been tentatively called CBSV Tanzania (CBSV-TZ). Virus isolates of the distinctive CBSV-TZ had nucleotide identities as low as 63.2 and 63.7% with other members of CBSV and UCBSV respectively. CONCLUSIONS: Grouping of P1 gene sequences indicated for distinct sub-populations of CBSV, but not UCBSV. Representatives of all three clades were found in both Tanzania and Malawi. PMID- 28637473 TI - Sustainability in Health care by Allocating Resources Effectively (SHARE) 7: supporting staff in evidence-based decision-making, implementation and evaluation in a local healthcare setting. AB - BACKGROUND: This is the seventh in a series of papers reporting Sustainability in Health care by Allocating Resources Effectively (SHARE) in a local healthcare setting. The SHARE Program was a systematic, integrated, evidence-based program for resource allocation within a large Australian health service. It aimed to facilitate proactive use of evidence from research and local data; evidence-based decision-making for resource allocation including disinvestment; and development, implementation and evaluation of disinvestment projects. From the literature and responses of local stakeholders it was clear that provision of expertise and education, training and support of health service staff would be required to achieve these aims. Four support services were proposed. This paper is a detailed case report of the development, implementation and evaluation of a Data Service, Capacity Building Service and Project Support Service. An Evidence Service is reported separately. METHODS: Literature reviews, surveys, interviews, consultation and workshops were used to capture and process the relevant information. Existing theoretical frameworks were adapted for evaluation and explication of processes and outcomes. RESULTS: Surveys and interviews identified current practice in use of evidence in decision-making, implementation and evaluation; staff needs for evidence-based practice; nature, type and availability of local health service data; and preferred formats for education and training. The Capacity Building and Project Support Services were successful in achieving short term objectives; but long term outcomes were not evaluated due to reduced funding. The Data Service was not implemented at all. Factors influencing the processes and outcomes are discussed. CONCLUSION: Health service staff need access to education, training, expertise and support to enable evidence-based decision-making and to implement and evaluate the changes arising from those decisions. Three support services were proposed based on research evidence and local findings. Local factors, some unanticipated and some unavoidable, were the main barriers to successful implementation. All three proposed support services hold promise as facilitators of EBP in the local healthcare setting. The findings from this study will inform further exploration. PMID- 28637474 TI - Arsenic trioxide inhibits EBV reactivation and promotes cell death in EBV positive lymphoma cells. AB - BACKGROUND: Epstein-Barr Virus (EBV) is associated with hematopoietic malignancies, such as Burkitt's lymphoma, post-transplantation lymphoproliferative disorder, and diffuse large B-cell lymphoma. The current approach for EBV-associated lymphoma involves chemotherapy to eradicate cancer cells, however, normal cells may be injured and organ dysfunction may occur with currently employed regimens. This research is focused on employing arsenic trioxide (ATO) as EBV-specific cancer therapy takes advantage of the fact the EBV resides within the malignant cells. METHODS AND RESULTS: Our research reveals that low ATO inhibits EBV gene expression and genome replication. EBV spontaneous reactivation starts as early as 6 h after re-suspending EBV-positive Mutu cells in RPMI media in the absence of ATO, however this does not occur in Mutu cells cultured with ATO. ATO's inhibition of EBV spontaneous reactivation is dose dependent. The expression of the EBV immediate early gene Zta and early gene BMRF1 is blocked with low concentrations of ATO (0.5 nM - 2 nM) in EBV latency type I cells and EBV-infected PBMC cells. The combination of ATO and ganciclovir further diminishes EBV gene expression. ATO-mediated reduction of EBV gene expression can be rescued by co-treatment with the proteasome inhibitor MG132, indicating that ATO promotes ubiquitin conjugation and proteasomal degradation of EBV genes. Co-immunoprecipitation assays with antibodies against Zta pulls down more ubiquitin in ATO treated cell lysates. Furthermore, MG132 reverses the inhibitory effect of ATO on anti-IgM-, PMA- and TGF-beta-mediated EBV reactivation. Thus, mechanistically ATO's inhibition of EBV gene expression occurs via the ubiquitin pathway. Moreover, ATO treatment results in increased cell death in EBV-positive cells compared to EBV-negative cells, as demonstrated by both MTT and trypan blue assays. ATO-induced cell death in EBV-positive cells is dose dependent. ATO and ganciclovir in combination further enhances cell death specifically in EBV-positive cells. CONCLUSION: ATO-mediated inhibition of EBV lytic gene expression results in cell death selectively in EBV-positive lymphocytes, suggesting that ATO may potentially serve as a drug to treat EBV related lymphomas in the clinical setting. PMID- 28637476 TI - Eliminating acetate formation improves citramalate production by metabolically engineered Escherichia coli. AB - BACKGROUND: Citramalate, a chemical precursor to the industrially important methacrylic acid (MAA), can be synthesized using Escherichia coli overexpressing citramalate synthase (cimA gene). Deletion of gltA encoding citrate synthase and leuC encoding 3-isopropylmalate dehydratase were critical to achieving high citramalate yields. Acetate is an undesirable by-product potentially formed from pyruvate and acetyl-CoA, the precursors of citramalate during aerobic growth of E. coli. This study investigated strategies to minimize acetate and maximize citramalate production in E. coli mutants expressing the cimA gene. RESULTS: Key knockouts that minimized acetate formation included acetate kinase (ackA), phosphotransacetylase (pta), and in particular pyruvate oxidase (poxB). Deletion of glucose 6-phosphate dehydrogenase (zwf) and ATP synthase (atpFH) aimed at improving glycolytic flux negatively impacted cell growth and citramalate accumulation in shake flasks. In a repetitive fed-batch process, E. coli gltA leuC ackA-pta poxB overexpressing cimA generated 54.1 g/L citramalate with a yield of 0.64 g/g glucose (78% of theoretical maximum yield), and only 1.4 g/L acetate in 87 h. CONCLUSIONS: This study identified the gene deletions critical to reducing acetate accumulation during aerobic growth and citramalate production in metabolically engineered E. coli strains. The citramalate yield and final titer relative to acetate at the end of the fed-batch process are the highest reported to date (a mass ratio of citramalate to acetate of nearly 40) without being detrimental to citramalate productivity, significantly improving a potential process for the production of this five-carbon chemical. PMID- 28637477 TI - Determinants of intra-household food allocation between adults in South Asia - a systematic review. AB - BACKGROUND: Nutrition interventions, often delivered at the household level, could increase their efficiency by channelling resources towards pregnant or lactating women, instead of leaving resources to be disproportionately allocated to traditionally favoured men. However, understanding of how to design targeted nutrition programs is limited by a lack of understanding of the factors affecting the intra-household allocation of food. METHODS: We systematically reviewed literature on the factors affecting the allocation of food to adults in South Asian households (in Afghanistan, Bangladesh, Bhutan, India, Islamic Republic of Iran, Maldives, Nepal, Pakistan, Sri Lanka) and developed a framework of food allocation determinants. Two reviewers independently searched and filtered results from PubMed, Web of Knowledge and Scopus databases by using pre-defined search terms and hand-searching the references from selected papers. Determinants were extracted, categorised into a framework, and narratively described. We used adapted Downs and Black and Critical Appraisal Skills Programme checklists to assess the quality of evidence. RESULTS: Out of 6928 retrieved studies we found 60 relevant results. Recent, high quality evidence was limited and mainly from Bangladesh, India and Nepal. There were no results from Iran, Afghanistan, Maldives, or Bhutan. At the intra-household level, food allocation was determined by relative differences in household members' income, bargaining power, food behaviours, social status, tastes and preferences, and interpersonal relationships. Household-level determinants included wealth, food security, occupation, land ownership, household size, religion / ethnicity / caste, education, and nutrition knowledge. In general, the highest inequity occurred in households experiencing severe or unexpected food insecurity, and also in better off, high caste households, whereas poorer, low caste but not severely food insecure households were more equitable. Food allocation also varied regionally and seasonally. CONCLUSION: Program benefits may be differentially distributed within households of different socioeconomic status, and targeting of nutrition programs might be improved by influencing determinants that are amenable to change, such as food security, women's employment, or nutrition knowledge. Longitudinal studies in different settings could unravel causal effects. Conclusions are not generalizable to the whole South Asian region, and research is needed in many countries. PMID- 28637475 TI - Uptake of label-free graphene oxide by Caco-2 cells is dependent on the cell differentiation status. AB - BACKGROUND: Understanding the interaction of graphene-related materials (GRM) with human cells is a key to the assessment of their potential risks for human health. There is a knowledge gap regarding the potential uptake of GRM by human intestinal cells after unintended ingestion. Therefore the aim of our study was to investigate the interaction of label-free graphene oxide (GO) with the intestinal cell line Caco-2 in vitro and to shed light on the influence of the cell phenotype given by the differentiation status on cellular uptake behaviour. RESULTS: Internalisation of two label-free GOs with different lateral size and thickness by undifferentiated and differentiated Caco-2 cells was analysed by scanning electron microscopy and transmission electron microscopy. Semi quantification of cells associated with GRM was performed by flow cytometry. Undifferentiated Caco-2 cells showed significant amounts of cell-associated GRM, whereas differentiated Caco-2 cells exhibited low adhesion of GO sheets. Transmission electron microscopy analysis revealed internalisation of both applied GO (small and large) by undifferentiated Caco-2 cells. Even large GO sheets with lateral dimensions up to 10 um, were found internalised by undifferentiated cells, presumably by macropinocytosis. In contrast, no GO uptake could be found for differentiated Caco-2 cells exhibiting an enterocyte-like morphology with apical brush border. CONCLUSIONS: Our results show that the internalisation of GO is highly dependent on the cell differentiation status of human intestinal cells. During differentiation Caco-2 cells undergo intense phenotypic changes which lead to a dramatic decrease in GRM internalisation. The results support the hypothesis that the cell surface topography of differentiated Caco-2 cells given by the brush border leads to low adhesion of GO sheets and sterical hindrance for material uptake. In addition, the mechanical properties of GRM, especially flexibility of the sheets, seem to be an important factor for internalisation of large GO sheets by epithelial cells. Our results highlight the importance of the choice of the in vitro model to enable better in vitro-in vivo translation. PMID- 28637478 TI - Out of Africa: the mite community (Arachnida: Acariformes) of the common waxbill, Estrilda astrild (Linnaeus, 1758) (Passeriformes: Estrildidae) in Brazil. AB - BACKGROUND: The common waxbill, Estrilda astrild (L., 1758) (Passeriformes: Estrildidae) is a small passerine bird native to Sub-Saharan Africa that has been introduced into several regions of the world. RESULTS: In the present paper, eight mite species (Acariformes) are reported from this host from Brazil, including three species new to science: Montesauria caravela n. sp., M. conquistador n. sp. (Proctophyllodidae), Trouessartia transatlantica n. sp., T. minuscula Gaud & Mouchet, 1958, T. estrildae Gaud & Mouchet, 1958 (Trouessartiidae), Onychalges pachyspathus Gaud, 1968 (Pyroglyphidae), Paddacoptes paddae (Fain, 1964) (Dermationidae) and Neocheyletiella megaphallos (Lawrence, 1959) (Cheyletidae). Comparative material from Africa was also studied. CONCLUSIONS: These mites represent at least three morpho-ecological groups regarding their microhabitats occupied on the bird: (i) vane mites (Montesauria and Trouessartia on the large wing and tail feathers); (ii) down mites (Onychalges); and (iii) skin mites (Paddacoptes and Neocheyletiella). On one bird individual we found representatives of all eight mite species. Although the common waxbill was introduced to the Neotropical region almost two centuries ago, we demonstrate that it still retains its Old World acarofauna and has not yet acquired any representatives of typical Neotropical mite taxa. PMID- 28637480 TI - Institutional analysis of stereotactic body radiotherapy (SBRT) for oligometastatic lymph node metastases. AB - BACKGROUND: In limited metastatic burden of disease, stereotactic body radiotherapy (SBRT) has been shown to achieve high local control rates. It has been hypothesized that SBRT may translate to a better quality of life by delaying the need for systemic chemotherapy and possibly increasing survival. There is limited published literature on the efficacy of SBRT in limited nodal metastases. The primary aim is to review institutional outcomes of patients with solitary or oligometastatic lymph nodes treated with SBRT. METHODS: A retrospective study of patients treated with SBRT to metastatic lymph nodes (March 2010-June 2015) was conducted. Endpoints of this study were local control (LC), chemotherapy-free survival (CFS) following SBRT, toxicities, progression free survival (PFS), and overall survival (OS). RESULTS: Eighteen patients with a mean age of 65 years underwent SBRT to metastatic lymph nodes. Median follow-up was 33.6 months. There were four hepatocellular carcinoma, seven colorectal, four pancreatic, one esophageal, one gallbladder and one lung primary. Eleven (61%) patients had lymph node metastases at initial presentation of metastatic disease. Seven patients (39%) had systemic therapy prior to SBRT, with five patients receiving two lines of chemotherapy. Eight patients had solitary metastatic disease at the time of radiotherapy. All patients had <5 metastases. Median size of lymph node metastases was 1.95 cm (range: 0.8-6.2 cm). RT doses were 31 to 60 Gy in four to ten fractions, with 44% of patients receiving 35 Gy in 5 fractions. At 1 year, LC was 94% and CFS from SBRT was 60%. One-year PFS and OS were 39% and 89% respectively. There were no grade 3 or higher toxicities. CONCLUSIONS: In this single institution study, SBRT to oligometastatic lymph nodes provided excellent LC and a moderate chemotherapy-free interval with minimal toxicities. Disease progression remains prominent in these patients and larger studies are warranted to identify those who benefit most from SBRT. PMID- 28637479 TI - Pediatric eMental healthcare technologies: a systematic review of implementation foci in research studies, and government and organizational documents. AB - BACKGROUND: Researchers, healthcare planners, and policymakers convey a sense of urgency in using eMental healthcare technologies to improve pediatric mental healthcare availability and access. Yet, different stakeholders may focus on different aspects of implementation. We conducted a systematic review to identify implementation foci in research studies and government/organizational documents for eMental healthcare technologies for pediatric mental healthcare. METHODS: A search of eleven electronic databases and grey literature was conducted. We included research studies and documents from organization and government websites if the focus included eMental healthcare technology for children/adolescents (0 18 years), and implementation was studied and reported (research studies) or goals/recommendations regarding implementation were made (documents). We assessed study quality using the Mixed Methods Appraisal Tool and document quality using the Appraisal of Guidelines for Research & Evaluation II. Implementation information was grouped according to Proctor and colleagues' implementation outcomes-acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, and sustainability-and grouped separately for studies and documents. RESULTS: Twenty research studies and nine government/organizational documents met eligibility criteria. These articles represented implementation of eMental healthcare technologies in the USA (14 studies), United Kingdom (2 documents, 3 studies), Canada (2 documents, 1 study), Australia (4 documents, 1 study), New Zealand (1 study), and the Netherlands (1 document). The quality of research studies was excellent (n = 11), good (n = 6), and poor (n = 1). These eMental health studies focused on the acceptability (70%, n = 14) and appropriateness (50%, n = 10) of eMental healthcare technologies to users and mental healthcare professionals. The quality of government and organizational documents was high (n = 2), medium (n = 6), and low (n = 1). These documents focused on cost (100%, n = 9), penetration (89%, n = 8), feasibility (78%, n = 7), and sustainability (67%, n = 6) of implementing eMental healthcare technology. CONCLUSION: To date, research studies have largely focused on acceptability and appropriateness, while government/organizational documents state goals and recommendations regarding costs, feasibility, and sustainability of eMental healthcare technologies. These differences suggest that the research evidence available for pediatric eMental healthcare technologies does not reflect the focus of governments and organizations. Partnerships between researchers, healthcare planners, and policymakers may help to align implementation research with policy development, decision-making, and funding foci. PMID- 28637481 TI - Arthroscopic treatment of focal osteochondral lesions of the first metatarsophalangeal joint. AB - BACKGROUND: Although arthroscopic surgical treatment of the first metatarsophalangeal (MTP) joint involves painful sesamoid excision, synovectomy, debridement, and partial cheilectomy, no gold standard treatment technique has been defined in the literature for hallux rigidus and focal osteochondral lesions. This study aimed to assess the arthroscopic treatment for early-grade focal osteochondral lesions of the first MTP joint and to determine the impact of arthroscopic microhole drill surgery on foot function and activities of daily living in a group of patients who failed conservative treatment. METHODS: This prospective study included 14 patients with hallux rigidus and focal osteochondral lesions of the first MTP joint who underwent surgery in 2014 and were followed on a regular basis thereafter. RESULTS: The patients had mean preoperative VPS (visual pain scale) and AOFAS (American Orthopedic Foot and Ankle Society)-Hallux scores of 8.14 +/- 0.86 SD and 48.64 +/- 4.27, respectively; the corresponding postoperative values of both scores were 1.86 +/- 0.66 SD and 87.00 +/- 3.70, respectively. Both VPS and AOFAS-Hallux scores changed significantly. DISCUSSION: In this prospective study, we explored the impact of arthroscopic microhole drill surgery on foot function and activities of daily living in patients with focal osteochondral lesions of the first MTP joint. Our results showed significant improvements in VPS and AOFAS scores with this treatment. CONCLUSIONS: An arthroscopic microhole drill technique can be used with impressive functional scores and without any complications in patients who failed conservative therapy for hallux rigidus with focal chondral injury. PMID- 28637483 TI - Analyzing human decisions in IGRT of head-and-neck cancer patients to teach image registration algorithms what experts know. AB - BACKGROUND: In IGRT of deformable head-and-neck anatomy, patient setup corrections are derived by rigid registration methods. In practice, experienced radiation therapists often correct the resulting vectors, thus indicating a different prioritization of alignment of local structures. Purpose of this study is to transfer the knowledge experts apply when correcting the automatically generated result (pre-match) to automated registration. METHODS: Datasets of 25 head-and-neck-cancer patients with daily CBCTs and corresponding approved setup correction vectors were analyzed. Local similarity measures were evaluated to identify the criteria for human corrections with regard to alignment quality, analogous to the radiomics approach. Clustering of similarity improvement patterns is applied to reveal priorities in the alignment quality. RESULTS: The radiation therapists prioritized to align the spinal cord closest to the high dose area. Both target volumes followed with second and third highest priority. The bony pre-match influenced the human correction along the crania-caudal axis. Based on the extracted priorities, a new rigid registration procedure is constructed which is capable of reproducing the corrections of experts. CONCLUSIONS: The proposed approach extracts knowledge of experts performing IGRT corrections to enable new rigid registration methods that are capable of mimicking human decisions. In the future, the deduction of knowledge-based corrections for different cohorts can be established automating such supervised learning approaches. PMID- 28637482 TI - MicroRNA-200c and microRNA- 141 are regulated by a FOXP3-KAT2B axis and associated with tumor metastasis in breast cancer. AB - BACKGROUND: Members of the microRNA (miR)-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive. METHODS: We investigated FOXP3-inducible breast cancer cells, Foxp3 heterozygous Scurfy mutant (Foxp3 sf/+ ) female mice, and patients with breast cancer for characterization of the formation and regulation of the miR-200 family in breast cancer cells and circulation. Participants (259), including patients with breast cancer or benign breast tumors, members of breast cancer families, and healthy controls, were assessed for tumor and circulating levels of the miR-200 family. RESULTS: First, we identified a FOXP3-KAT2B-miR-200c/141 axis in breast cancer cells. Second, aging Foxp3 sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and miR-141 were lower in Foxp3 sf/+ tumor cells than in normal breast epithelial cells, but plasma levels of miR-200c and miR-141 in the Foxp3 sf/+ mice increased during tumor progression and metastasis. Third, in patients with breast cancer, the levels of miR-200c and 141 were lower in FOXP3 low relative to those with FOXP3 high breast cancer cells, especially in late-stage and metastatic cancer cells. The levels of miR-200c and miR-141 were higher in plasma from patients with metastatic breast cancer than in plasma from those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or from healthy controls. Finally, in Foxp3 sf/+ mice, plasma miR-200c and miR-141 appeared to be released from tumor cells. CONCLUSIONS: miR-200c and miR-141 are regulated by a FOXP3-KAT2B axis in breast cancer cells, and circulating levels of miR-200c and miR-141 are potential biomarkers for early detection of breast cancer metastases. PMID- 28637484 TI - Seasonal and geographical distribution of bacillary dysentery (shigellosis) and associated climate risk factors in Kon Tam Province in Vietnam from 1999 to 2013. AB - BACKGROUND: Bacillary dysentery (BD) is an acute bacterial infection of the intestine caused by Shigella spp., with clinical symptoms ranging from fever to bloody diarrhoea to abdominal cramps to tenesmus. In Vietnam, enteric bacterial pathogens are an important cause of diarrhoea and most cases in children under 5 years of age are due to Shigella strains. The serogroups S. flexneri and S. sonnei are considered to be the most common. The main objective of this study was to, for the first time, assess the seasonal patterns and geographic distribution of BD in Vietnam, and to determine the climate risk factors associated with the incidence of BD in Kon Tum Province, where the highest rate of bacillary dysentery was observed from 1999 to 2013. METHODS: The seasonal patterns and geographic distribution of BD was assessed in Vietnam using a seasonal-trend decomposition procedure based on loess. In addition, negative binomial regression models were used to determine the climate risk factors associated with the incidence of BD in Kon Tum Province, from 1999 to 2013. RESULTS: Overall, incidence rates of BD have slightly decreased over time (except for an extremely high incidence in 2012 in the north of Vietnam). The central regions (north/south central coast and central highlands) had relatively high incidence rates, whereas the northwest/east and Red River Delta regions had low incidence rates. Overall, seasonal plots showed a high peak in the mid-rainy reason and a second smaller peak in the early or late rainy season. The incidence rates significantly increased between May and October ("wet season") across the country. In Kon Tum Province, temperature, humidity, and precipitation were found to be positively associated with the incidence of BD. CONCLUSIONS: Our findings provide insights into the seasonal patterns and geographic distribution of BD in Vietnam and its associated climate risk factors in Kon Tum Province. This study may help clinicians and the general public to better understand the timings of outbreaks and therefore equip them with the knowledge to plan better interventions (such as improving water, sanitation, and hygiene conditions) during peak seasons. This can, in turn, prevent or reduce outbreaks and onwards transmission during an outbreak. PMID- 28637485 TI - The development of lower respiratory tract microbiome in mice. AB - BACKGROUND: Although culture-independent methods have paved the way for characterization of the lung microbiome, the dynamic changes in the lung microbiome from neonatal stage to adult age have not been investigated. RESULTS: In this study, we tracked changes in composition and diversity of the lung microbiome in C57BL/6N mice, starting from 1-week-old neonates to 8-week-old mice. Towards this, the lungs were sterilely excised from mice of different ages from 1 to 8 weeks. High-throughput DNA sequencing of the 16S rRNA gene followed by composition and diversity analysis was utilized to decipher the microbiome in these samples. Microbiome analysis suggests that the changes in the lung microbiome correlated with age. The lung microbiome was primarily dominated by phyla Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria in all the stages from week 1 to week 8 after birth. Although Defluvibacter was the predominant genus in 1-week-old neonatal mice, Streptococcus became the dominant genus at the age of 2 weeks. Lactobacillus, Defluvibacter, Streptococcus, and Achromobacter were the dominant genera in 3-week-old mice, while Lactobacillus and Achromobacter were the most abundant genera in 4-week-old mice. Interestingly, relatively greater diversity (at the genus level) during the age of 5 to 6 weeks was observed as compared to the earlier weeks. The diversity of the lung microbiome remained stable between 6 and 8 weeks of age. CONCLUSIONS: In summary, we have tracked the development of the lung microbiome in mice from an early age of 1 week to adulthood. The lung microbiome is dominated by the phyla Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria. However, dynamic changes were observed at the genus level. Relatively higher richness in the microbial diversity was achieved by age of 6 weeks and then maintained at later ages. We believe that this study improves our understanding of the development of the mice lung microbiome and will facilitate further analyses of the role of the lung microbiome in chronic lung diseases. PMID- 28637486 TI - A guide to using the Theoretical Domains Framework of behaviour change to investigate implementation problems. AB - BACKGROUND: Implementing new practices requires changes in the behaviour of relevant actors, and this is facilitated by understanding of the determinants of current and desired behaviours. The Theoretical Domains Framework (TDF) was developed by a collaboration of behavioural scientists and implementation researchers who identified theories relevant to implementation and grouped constructs from these theories into domains. The collaboration aimed to provide a comprehensive, theory-informed approach to identify determinants of behaviour. The first version was published in 2005, and a subsequent version following a validation exercise was published in 2012. This guide offers practical guidance for those who wish to apply the TDF to assess implementation problems and support intervention design. It presents a brief rationale for using a theoretical approach to investigate and address implementation problems, summarises the TDF and its development, and describes how to apply the TDF to achieve implementation objectives. Examples from the implementation research literature are presented to illustrate relevant methods and practical considerations. METHODS: Researchers from Canada, the UK and Australia attended a 3-day meeting in December 2012 to build an international collaboration among researchers and decision-makers interested in the advancing use of the TDF. The participants were experienced in using the TDF to assess implementation problems, design interventions, and/or understand change processes. This guide is an output of the meeting and also draws on the authors' collective experience. Examples from the implementation research literature judged by authors to be representative of specific applications of the TDF are included in this guide. RESULTS: We explain and illustrate methods, with a focus on qualitative approaches, for selecting and specifying target behaviours key to implementation, selecting the study design, deciding the sampling strategy, developing study materials, collecting and analysing data, and reporting findings of TDF-based studies. Areas for development include methods for triangulating data, e.g. from interviews, questionnaires and observation and methods for designing interventions based on TDF-based problem analysis. CONCLUSIONS: We offer this guide to the implementation community to assist in the application of the TDF to achieve implementation objectives. Benefits of using the TDF include the provision of a theoretical basis for implementation studies, good coverage of potential reasons for slow diffusion of evidence into practice and a method for progressing from theory-based investigation to intervention. PMID- 28637488 TI - A high-throughput colorimetric assay for detection of Schistosoma mansoni viability based on the tetrazolium salt XTT. AB - BACKGROUND: Schistosoma mansoni is a trematode parasite that causes schistosomiasis, one of the most prevalent neglected tropical diseases, leading to the loss of 2.6 million disability-adjusted life years. Praziquantel is the only drug available, and new drugs are required. The most common strategy in schistosomiasis drug discovery is the use of the schistosomula larval-stage for a pre-screen in drug sensitivity assays. However, assessing schistosomula viability by microscopy has always been a limitation to the throughput of such assays. Hence, the development of validated, robust high-throughput in vitro assays for Schistosoma with simple readouts is needed. Here, we present a simple and affordable alternative to assess schistosomula viability. The method employed is based on the hydrosoluble tetrazolium salt XTT which has been widely used in other organisms but has never been used to drug screen in schistosomes. RESULTS: We showed that schistosomula reduce XTT salt to a coloured formazan product and that absorbance levels reflected the viability and parasites number. This XTT viability assay was validated for high throughput screening of compounds in schistosomula, and dose-response curves of compounds could be reproduced. CONCLUSIONS: We conclude that the XTT viability assay could be applied for the screening of large compounds collections in S. mansoni and accelerate the identification of novel antischistosomal compounds. PMID- 28637487 TI - The NF1 somatic mutational landscape in sporadic human cancers. AB - BACKGROUND: Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and cafe-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1. MAIN BODY: Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context. CONCLUSION: As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1. PMID- 28637490 TI - Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency. AB - BACKGROUND: Lipoid congenital adrenal hyperplasia (CAH) (OMIM n. 201710) is the most severe form of congenital adrenal hyperplasia. It is characterized by severe adrenal and gonadal steroidogenesis impairment due to a defect in the conversion of cholesterol to pregnenolone. Affected infants experience salt loss, but glucocorticoid and mineralocorticoid replacement therapy enables long-term survival. Classic lipoid congenital adrenal hyperplasia is relatively common in Japan and Korea but extremely rare in Caucasian populations. CASE PRESENTATION: A female infant of Italian origin came to our attention in late infancy with a clinical picture of acute adrenal insufficiency. The study of the STAR gene revealed two genomic variants c.562C > T and c.577C > T in compound heterozygosity. At the protein level, the two mutations determine the p.Arg188Cys variant (rs104894090) and the p.Arg193Ter variant (rs387907235), respectively. Sanger sequencing was used to confirm the identified variants and to perform familial study. The mother carried the p.Arg188Cys variant, while the father carried the p.Arg193Ter variant. CONCLUSION: To our knowledge this is the second case of classic lipoid congenital adrenal hyperplasia reported in the Italian population. STAR mutations resulting in lipoid congenital adrenal hyperplasia should be considered all over the world in the differential diagnosis of newborn babies and infants with primary adrenal insufficiency. PMID- 28637489 TI - Synaptoimmunology - roles in health and disease. AB - Mounting evidence suggests that the nervous and immune systems are intricately linked. Many proteins first identified in the immune system have since been detected at synapses, playing different roles in normal and pathological situations. In addition, novel immunological functions are emerging for proteins typically expressed at synapses. Under normal conditions, release of inflammatory mediators generally represents an adaptive and regulated response of the brain to immune signals. On the other hand, when immune challenge becomes prolonged and/or uncontrolled, the consequent inflammatory response leads to maladaptive synaptic plasticity and brain disorders. In this review, we will first provide a summary of the cell signaling pathways in neurons and immune cells. We will then examine how immunological mechanisms might influence synaptic function, and in particular synaptic plasticity, in the healthy and pathological CNS. A better understanding of neuro-immune system interactions in brain circuitries relevant to neuropsychiatric and neurological disorders should provide specific biomarkers to measure the status of the neuroimmunological response and help design novel neuroimmune-targeted therapeutics. PMID- 28637491 TI - Stable centromere positioning in diverse sequence contexts of complex and satellite centromeres of maize and wild relatives. AB - BACKGROUND: Paradoxically, centromeres are known both for their characteristic repeat sequences (satellite DNA) and for being epigenetically defined. Maize (Zea mays mays) is an attractive model for studying centromere positioning because many of its large (~2 Mb) centromeres are not dominated by satellite DNA. These centromeres, which we call complex centromeres, allow for both assembly into reference genomes and for mapping short reads from ChIP-seq with antibodies to centromeric histone H3 (cenH3). RESULTS: We found frequent complex centromeres in maize and its wild relatives Z. mays parviglumis, Z. mays mexicana, and particularly Z. mays huehuetenangensis. Analysis of individual plants reveals minor variation in the positions of complex centromeres among siblings. However, such positional shifts are stochastic and not heritable, consistent with prior findings that centromere positioning is stable at the population level. Centromeres are also stable in multiple F1 hybrid contexts. Analysis of repeats in Z. mays and other species (Zea diploperennis, Zea luxurians, and Tripsacum dactyloides) reveals tenfold differences in abundance of the major satellite CentC, but similar high levels of sequence polymorphism in individual CentC copies. Deviation from the CentC consensus has little or no effect on binding of cenH3. CONCLUSIONS: These data indicate that complex centromeres are neither a peculiarity of cultivation nor inbreeding in Z. mays. While extensive arrays of CentC may be the norm for other Zea and Tripsacum species, these data also reveal that a wide diversity of DNA sequences and multiple types of genetic elements in and near centromeres support centromere function and constrain centromere positions. PMID- 28637492 TI - Expression patterns of FSHD-causing DUX4 and myogenic transcription factors PAX3 and PAX7 are spatially distinct in differentiating human stem cell cultures. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is most commonly inherited in an autosomal dominant pattern and caused by the abnormal expression of DUX4 in skeletal muscle. The DUX4 transcription factor has DNA binding domains similar to several paired class homeotic transcription factors, but only myogenic factors PAX3 and PAX7 rescue cell viability when co-expressed with DUX4 in mouse myoblasts. This observation suggests competition for DNA binding sites in satellite cells might limit muscle repair and may be one aspect of DUX4 associated myotoxicity. The competition hypothesis requires that DUX4 and PAX3/7 be expressed in the same cells at some point during development or in adult tissues. We modeled myogenesis using human isogenic iPS and ES cells and examined expression patterns of DUX4, PAX3, and PAX7 to determine if conditions that promote PAX3 and PAX7 expression in cell culture also promote DUX4 expression in the same cells. METHODS: Isogenic iPSCs were generated from human fibroblasts of two FSHD-affected individuals with somatic mosaicism. Clones containing the shortened FSHD-causing D4Z4 array or the long non-pathogenic array were isolated from the same individuals. We also examined myogenesis in commercially available hES cell lines derived from FSHD-affected and non-affected embryos. DUX4, PAX3, and PAX7 messenger RNAs (mRNAs) were quantified during a 40-day differentiation protocol, and antibodies were used to identify cell types in different stages of differentiation to determine if DUX4 and PAX3 or PAX7 are present in the same cells. RESULTS: Human iPS and ES cells differentiated into skeletal myocytes as evidenced by Titin positive multinucleated fibers appearing toward the end of a 40-day differentiation protocol. PAX3 and PAX7 were expressed at similar times during differentiation, and DUX4 positive nuclei were seen at terminal stages of differentiation in cells containing the short D4Z4 arrays. Nuclei that expressed both DUX4 and PAX3, or DUX4 and PAX7 were not observed after examining immunostained nuclei at five different time points during myogenic differentiation of pluripotent cells. CONCLUSIONS: We conclude that DUX4, PAX3, and PAX7 have distinct expression patterns during myogenic differentiation of stem cells. Our findings are consistent with the hypothesis that muscle damage in FSHD is due to DUX4-mediated toxicity causing destruction of terminally differentiated myofibers. While these studies examine DUX4, PAX3, and PAX7 expression patterns during stem cell myogenesis, they should not be generalized to tissue repair in adult muscle tissue. PMID- 28637493 TI - The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma. AB - BACKGROUND: 5-Fluorouracil (5-FU) is a widely used drug for the therapy of cancer. However, the chemoresistance of tumor cells to 5-FU usually limits its clinical effectiveness. In this study, we explored the role of NLRP3 inflammasome in 5-FU resistance of oral squamous cell carcinoma (OSCC). METHODS: The mRNA and protein expression levels of NLRP3, Caspase1 and IL-1beta in resected OSCC specimens or cell lines were measured respectively by quantitative real time-PCR (qRT-PCR) and western blot. NLRP3 and Ki-67 expression in paraffin-embedded OSCC tissues was determined by immunohistochemistry. The correlation between 5-FU treatment and the expression and activation of NLRP3 inflammasome was further examined by evaluating NLRP3 and IL-1beta expression in OSCC cell lines without or with NLRP3 knocked down. Cell viabilities of OSCC cells were determined by the MTT assay. Apoptosis and intracellular reactive oxygen species (ROS) of OSCC cells induced by 5-FU were measured by the flow cytometer. The carcinogen-induced tongue squamous carcinoma mice model was established by continuous oral administration of 4-nitroquinoline 1-oxide in wild-type BALB/c, Nlrp3 -/- and Caspase1 -/- mice. Tumor incidence were observed and tumor area were evaluated. RESULTS: In the clinical analysis, expression and activation of NLRP3 inflammasome was clearly increased in OSCC tissues of patients who received 5-FU based chemotherapy. Multivariate Cox regression analysis revealed that this high expression was significantly correlated with tumor stage and differentiation, and was associated with poor prognosis. Moreover, 5-FU treatment increased expression and activation of NLRP3 inflammasome in OSCC cells in a cell culture system and xenograft mouse model. Silencing of NLRP3 expression significantly inhibited OSCC cell proliferation and enhanced 5-FU-induced apoptosis of OSCC cells. Further investigation showed that intracellular ROS induced by 5-FU promoted the expression and activation of NLRP3 inflammasome and increased the production of interleukin (IL)-1beta, which then mediated the chemoresistance. With the carcinogen-induced OSCC model, we found less and later tumor incidence in Nlrp3 /- and Caspase1 -/- mice than wild-type mice. And greater decrease of tumor area was observed in the gene deficient mice treated with 5-FU. CONCLUSIONS: Our findings suggest that NLRP3 inflammasome promoted 5-FU resistance of OSCC both in vitro and in vivo, and targeting the ROS/NLRP3 inflammasome/IL-1beta signaling pathway may help 5-FU-based adjuvant chemotherapy of OSCC. PMID- 28637495 TI - Diurnal variation in the core interthreshold zone and its relation to cutaneous sensation threshold zone. AB - BACKGROUND: The core interthreshold zone (CIZ) is defined as the range between temperatures at the onset of shivering and sweating. Its circadian or diurnal variation has not been extensively studied. The present study examined whether the CIZ is subject to a diurnal rhythm. In addition, according to the previous finding that the CIZ was proportionally correlated with peripheral interthreshold zone (PIZ), it was also examined whether cutaneous sensation threshold zone (CSZ), a determinant of the PIZ, is correlated with the CIZ. METHODS: The CIZ and the CSZ were measured in ten Japanese men who underwent three experiments in a single day on the morning, afternoon, and evening in the 2014 experiment (so called single-day experiment) and six Japanese men underwent the same experiments on the morning of day 1, the afternoon of day 2, and the evening of day 3 in the 2015 experiment (so-called multiple-day experiment). Air temperature was controlled at 20-24 degrees C. Each subject wore a suit perfused with 25 degrees C water at a rate of 600 cm3/min and exercised on an ergometer at 50% of their maximum work rate for 10-15 min until their rate of sweating increased. They then remained seated without exercising until their oxygen uptake increased. Rectal temperature, skin temperatures at seven sites, the sweating rate at the forehead, and oxygen uptake were continuously monitored throughout experiment. Cutaneous warm and cold sensation thresholds at three sites were measured using 1 and 2-cm2 probes. RESULTS: The results from the single-day experiment demonstrated a small change in the CIZ and core temperature prior to exercise (T c-init) whereas those from the multiple-day experiment demonstrated continuous increase in the CIZ and T c-init. The CSZ measured with a 1-cm2 probe was inversely proportional to the average skin temperature at three sites prior to measurement (T sk-av). CONCLUSION: The results suggested that the CIZ may be not dependent on time of a day but Tc-init per se and may not be associated with the CSZ. PMID- 28637494 TI - Euiiyin-tang in the treatment of obesity: study protocol for a randomised controlled trial. AB - BACKGROUND: Obesity is a public health concern in many countries due to its increasing prevalence. Euiiyin-tang is an herbal medicine formula often used as a clinical treatment for obesity. It acts to eliminate humidity and purify the blood, the causes of obesity identified by the theoretical framework of Korean medicine. The purpose of this study is to evaluate the efficacy and safety of Euiiyin-tang in treating obesity. METHODS/DESIGN: This study is a randomised, double-blinded and placebo-controlled, multicentre trial. It has two parallel arms: the Euiiyin-tang group and the placebo group. A total of 160 obese adult women will be enrolled in the trial. The participants will be randomly divided at a 1:1 ratio at visit 2 (baseline). The participants will be administered Euiiyin tang or placebo for 12 weeks. The primary endpoint is the change in weight occurring between baseline and post-treatment. The secondary outcomes include average weight reduction, changes in body fat, waist and hip circumferences, body mass index, and lipid profile, and the results of questionnaires such as the Korean version of Obesity-related Quality of Life, the Korean version of Eating Attitudes Test, the Social Readjustment Rating Scale, and the Stress Reaction Inventory. DISCUSSION: The present study will provide research methodologies for evaluating the efficacy and safety of Euiiyin-tang in patients with obesity. In addition, it will provide evidence of correlation between obesity and Sasang constitutional medicine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01724099 . Registered on 2 November 2012. PMID- 28637496 TI - MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells. AB - BACKGROUND: MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear. METHODS: MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model. RESULTS: Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21 overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis. CONCLUSIONS: As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL mediated interaction of Treg cells with endothelial cells. PMID- 28637497 TI - Influence of low-flow time on survival after extracorporeal cardiopulmonary resuscitation (eCPR). AB - BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) support under extracorporeal cardiopulmonary resuscitation (eCPR) is the last option and may be offered to selected patients. Several factors predict outcome in these patients, including initial heart rhythm, comorbidities, and bystander cardiopulmonary resuscitation (CPR). We evaluated outcomes of all VA-ECMO patients treated within the last 5 years at our center in respect to low-flow duration during CPR. METHODS: We report retrospective registry data on all patients with eCPR treated at a university hospital between October 2010 and May 2016. RESULTS: A total of 133 patients (mean age 58.7 +/- 2.6 years, Simplified Acute Physiology Score II score at admission 48.1 +/- 3.4) were included in the analysis. The indication for eCPR was either in-hospital or out-of-hospital cardiac arrest without return of spontaneous circulation (n = 74 and 59, respectively). There was a significant difference in survival rates between groups (eCPR in-hospital cardiac arrest [IHCA] 18.9%, eCPR out-of-hospital cardiac arrest [OHCA] 8.5%; p < 0.042). Mean low-flow duration (i.e., duration of mechanical CPR until VA-ECMO support) was 59.6 +/- 5.0 minutes in all patients and significantly shorter in IHCA patients than in OHCA patients (49.6 +/- 5.9 vs. 72.2 +/- 7.4 minutes, p = 0.001). Low-flow time strongly correlated with survival (p < 0.001) and was an independent predictor of mortality. CONCLUSIONS: Time to full support is an important and alterable predictor of patient survival in eCPR, suggesting that VA-ECMO therapy should be established as fast as possible in the selected patients destined for eCPR. PMID- 28637499 TI - Diagnostic relevance of urinary steroid profiles on ovarian granulosa cell tumors: two case reports. AB - BACKGROUND: Granulosa cell tumor of the ovary is the most frequent sex cord stromal tumor and represents 2 to 5% of all primary ovarian cancers. Ovarian granulosa cell tumor is a malignant tumor with slow progression and in some cases this tumor is hormonally active. The recurrence of granulosa cell tumor often happens after 5 years. CASE PRESENTATION: We describe two cases of postmenopausal women with adult-type granulosa cell tumors of the ovary. Patient 1 is a 49-year old European woman with a recurrent tumor; patient 2 is a 55-year-old European woman without recurrence of tumor. Urinary steroid profiles of patient 1 were monitored during a 5-year period starting from before an operation (13 samples). In patient 2, the urinary steroid profiles were monitored during a 3-year period starting from after an operation (six samples). The 24-hour urinary samples were examined and the urinary concentration of 20 androgen, progesterone, and corticoid metabolites was quantitatively determined by gas chromatography-mass spectrometry with selected ion-monitoring mode. CONCLUSIONS: Based on these cases a correlation could be observed between increased levels of the urinary steroids and the recurrence of ovarian granulosa cell tumor; therefore, we concluded that a urinary steroid profile could be a more effective method to follow-up such patients compared to the traditional serum hormones determinations supplemented with conventional tumor markers. PMID- 28637498 TI - Incidence of thyroid dysfunction in an Iranian adult population: the predictor role of thyroid autoantibodies: results from a prospective population-based cohort study. AB - BACKGROUND: The prevalence of thyroid dysfunction is high in Isfahan, an area of iodine sufficient in Iran. The aim of this study is to investigate the incidence of thyroid dysfunctions in adults of metropolitan Isfahan and to determine the role of thyroid autoantibodies. METHODS: In a population-based cohort study in 2006-2011, we measured TSH, T4, T3, thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) in 618 out of 2254 people who were euthyroid in 2006. The incidence rates per 1000 person-year (pr) were calculated. The odds ratio (OR), relative risk (RR), and 95% confidence interval (95% CI) were calculated based on logistic regression to quantify the potential predictors of thyroid dysfunction. The receiver-operator characteristic (ROC) analysis along with area under the curve (AUC) was used to determine the optimal cutoff values for baseline TPOAb and TgAb as predictors of thyroid dysfunction. RESULTS: Within a 6-year follow-up, the incidence rate of hypothyroidism was 3.3 in women and 2.1 in men while the incidence rate of hyperthyroidism was 3.8 in women and none in men per 1000 (person-year). A cutoff value of TPOAb at 38 IU/mL was obtained to differentiate the patients with hypothyroidism and hyperthyroidism, with specificity of 0.75 and sensitivity of 0.76, and AUC (CI 95%) of 0.882 (0.743 1.02), P = 0.01 and 0.817 (0.600-1.035) P = 0.033, respectively. There is a statistically significant association of hypothyroidism and hyperthyroidism with positive TPOAb [RR (CI 95%): 1.99 (1.27-3.13) and 2.20 (1.23-3.95), respectively]. CONCLUSIONS: The incidence rate of thyroid dysfunction is high in Isfahan, and higher TPOAb concentration is its strong predictor. PMID- 28637500 TI - Association of antenatal care and place of delivery with newborn care practices: evidence from a cross-sectional survey in rural Uttar Pradesh, India. AB - BACKGROUND: Appropriate immediate newborn care is vital for neonatal survival. Antenatal period is a crucial time to impart knowledge and awareness to mothers regarding newborn care, either during facility visits or during home visits by community health workers (CHWs) especially in the rural context. In this paper, we report newborn care practices in rural Uttar Pradesh (UP) and have explored association between newborn care practices with antenatal care, contact with community health workers during pregnancy and place of childbirth. METHODS: We use cross-sectional baseline data (which is part of a larger intervention project) collected from 129 gram panchayats (GPs) from 15 administrative blocks spread over five districts of UP in 2013. From currently married women (n = 2208) of 15-49 years, who delivered 15 months prior to the survey, we collected information on women's demographic and socio-economic characteristics, knowledge and practice of reproductive, maternal, newborn, child health and nutrition behaviours. Association of newborn practices with antenatal care, contacts by community health worker during pregnancy and place of childbirth were tested using random intercept logistic regression, adjusting for socio-economic and demographic factors and accounting for clustering at the GP and block levels. RESULTS: Eighty-three percent of 2208 mothers received ANC, but only half of the respondents received a minimum of three ANC visits. More than two thirds of respondents delivered at a health facility. Practice of newborn care was poor: merely one fourth of women practised clean cord care, one third of women followed good breastfeeding practices (initiation with an hour of birth, fed colostrum and did not give pre-lacteal feeds) and one third provided adequate thermal care (kept baby warm and delayed bathing). Only 5% followed all above practices with evidence of clustering of newborn care practices at the block and GP levels. While facility-based childbirth was strongly associated with appropriate newborn care practices, ANC visits and contacts with CHWs was not associated with all newborn care practices. CONCLUSION: The quality of ANC care provided needs to be improved to have an impact on newborn care practices. Our finding emphasizes the importance of facility-based birthing. There is a need for training CHWs to strengthen their counselling skills on newborn care. Variation of newborn care practices between communities should be taken into consideration while implementing any intervention to optimize benefits. PMID- 28637502 TI - Clinicopathologic characteristics and prognosis of gastroenteropancreatic neuroendocrine neoplasms: a multicenter study in South China. AB - BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of rare tumors. Many issues in terms of epidemiologic features, pathogenesis, and treatment of GEP-NENs are still under discussion. Our study aimed to analyze the clinicopathologic characteristics and prognosis of Chinese patients with GEP-NENs. METHODS: Complete clinicopathologic data and survival information of 1183 patients with GEP-NENs treated between 2005 and 2015 were collected from five medical centers in Guangdong Province, China. Patient survival was estimated using the Kaplan-Meier method and analyzed using the log rank test; prognostic factors were analyzed using the Cox proportional hazards model. RESULTS: The most common tumor location was the rectum (37.4%), followed by the pancreas (28.1%), stomach (20.7%), small intestine (7.2%), appendix (3.4%), and colon (3.3%). After initial definitive diagnosis, 1016 (85.9%) patients underwent surgery. The 1-, 3-, and 5-year overall survival (OS) rates for the entire cohort were 87.9%, 78.5%, and 72.8%, respectively. The 3-year OS rates of patients with G1, G2, and G3 tumors were 93.1%, 82.7%, and 43.1%, respectively (P < 0.001). The 3-year OS rates of patients with stage I, II, III, and IV tumors were 96.0%, 87.3%, 64.0%, and 46.8%, respectively (P < 0.001). Patients with distant metastasis who underwent palliative surgery had a longer survival than those who did not (P = 0.003). Similar survival benefits of palliative surgery were observed in patients with neuroendocrine tumor (P = 0.031) or neuroendocrine carcinoma (P = 0.046). In multivariate analysis, age, grade, N category, M category, and surgery were found to be independent prognostic factors. CONCLUSIONS: Patients with GEP-NENs who are women, younger than 50 years old, have smaller tumor size, have lower tumor grade, have lower T/N/M category, and who undergo surgery can have potentially longer survival time. Our data showed that surgery can improve the prognosis of GEP-NEN patients with distant metastasis. However, randomized controlled trials need to be conducted to establish the optimal criteria for selecting patients to undergo surgery. PMID- 28637501 TI - S100A8 inhibits PDGF-induced proliferation of airway smooth muscle cells dependent on the receptor for advanced glycation end-products. AB - BACKGROUND: Airway remodeling is a key feature of asthma, characterized by increased proliferation of airway smooth muscle cells (ASMCs). S100A8 is a calcium-binding protein with a potential to regulate cell proliferation. Here, the effect of exogenous S100A8 protein on the proliferation of ASMCs induced by platelet-derived growth factor (PDGF) and the underlying molecular mechanism was investigated. METHODS: Rat ASMCs were cultured with or without a neutralizing antibody to the receptor for advanced glycation end-products (RAGE), a potential receptor for S100A8 protein. Purified recombinant rat S100A8 protein was then added into the cultured cells, and the proliferation of ASMCs induced by PDGF was detected by colorimetric-based WST-8 assay and ampedance-based xCELLigence proliferation assay. The expression levels of RAGE in ASMCs were analyzed using western blotting assay. RESULTS: Results showed that exogenous S100A8 inhibited the PDGF-induced proliferation of rat ASMCs in a dose-dependent manner with the maximal effect at 1 MUg/ml in vitro. Furthermore, when ASMCs was pre-treated with anti-RAGE neutralizing antibody, the inhibitory effect of S100A8 on PDGF-induced proliferation was significantly suppressed. In addition, neither the treatment with S100A8 or PDGF alone nor the pre-treatment with rS100A8 followed by PDGF stimulation affected the expression levels of RAGE. CONCLUSIONS: Our study demonstrated that S100A8 inhibits PDGF-induced ASMCs proliferation in a manner dependent on membrane receptor RAGE. PMID- 28637504 TI - Impact of free delivery policy on utilization of maternal health services in county referral hospitals in Kenya. AB - BACKGROUND: Kenya has a high maternal mortality rate. Provision of skilled delivery plays a major role in reducing maternal mortality. Cost is a hindrance to the utilization of skilled delivery. The Government of Kenya introduced a policy of free delivery services in government facilities beginning June 2013. We sought to determine the impact of this intervention on facility based deliveries in Kenya. METHODS: We compared deliveries and antenatal attendance in 47 county referral hospitals and 30 low cost private hospitals not participating in the free delivery policy for 2013 and 2014 respectively. The data was extracted from the Kenya Health Information System. Multiple regression was done to assess factors influencing increase in number of deliveries among the county referral hospitals. RESULTS: The number of deliveries and antenatal attendance increased by 26.8% and 16.2% in county referral hospitals and decreased by 11.9% and 5.4% respectively in low cost private hospitals. Increase in deliveries among county referral hospitals was influenced by population size of county and type of county referral hospital. Counties with level 5 hospitals recorded more deliveries compared to those with level 4 hospitals. CONCLUSION: This intervention increased the number of facility based deliveries. Policy makers may consider incorporating low cost private hospitals so as to increase the coverage of this intervention. PMID- 28637503 TI - Expression of endogenous mouse APP modulates beta-amyloid deposition in hAPP transgenic mice. AB - Amyloid-beta (Abeta) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer's disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Abeta and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches.Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Abeta deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAbeta were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAbeta together with endogenous mAbeta. Furthermore, the cellular response to Abeta deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research. PMID- 28637505 TI - Human lung and monocyte-derived macrophages differ with regard to the effects of beta2-adrenoceptor agonists on cytokine release. AB - BACKGROUND: beta2-adrenoceptor agonists have been shown to reduce the lipopolysaccharide (LPS)-induced cytokine release by human monocyte-derived macrophages (MDMs). We compare the expression of beta2-adrenoceptors and the inhibitory effect of formoterol and salmeterol on the LPS-induced release of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and a range of chemokines (CCL2, 3, 4, and IL-8) by human lung macrophages (LMs) and MDMs. METHODS: LMs were isolated from patients undergoing resection and MDMs were obtained from blood monocytes in the presence of GM-CSF. LMs and MDMs were incubated in the absence or presence of formoterol or salmeterol prior to stimulation with LPS. The effects of formoterol were also assessed in the presence of the phosphodiesterase inhibitor roflumilast. RESULTS: LPS-induced cytokine production was higher in LMs than in MDMs. Salmeterol and formoterol exerted an inhibitory effect on the LPS-induced production of TNF-alpha, IL-6, CCL2, CCL3, and CCL4 in MDMs. In contrast, the beta2-adrenoceptor agonists were devoid of any effect on LMs - even in the presence of roflumilast. The expression of beta2-adrenergic receptors was detected on Western blots in MDMs but not in LMs. CONCLUSIONS: Concentrations of beta2-adrenoceptor agonists that cause relaxation of the human bronchus can inhibit cytokine production by LPS stimulated MDMs but not by LMs. PMID- 28637506 TI - Improved gamma-linolenic acid production in Mucor circinelloides by homologous overexpressing of delta-12 and delta-6 desaturases. AB - BACKGROUND: gamma-Linolenic acid (GLA) is important because of its nutritional value and medicinal applications. Although the biosynthetic pathways of some plant and microbial GLA have been deciphered, current understanding of the correlation between desaturases and GLA synthesis in oleaginous fungi is incomplete. In previous work, we found that a large amount of oleic acid (OA) had not been converted to linoleic acid (LA) or GLA in Mucor circinelloides CBS 277.49, which may be due to inadequate activities of the delta-12 or delta-6 desaturases, and thus leading to the accumulation of OA and LA. Thus, it is necessary to explore the main contributing factor during the process of GLA biosynthesis in M. circinelloides. RESULTS: To enhance GLA production in M. circinelloides, homologous overexpression of delta-12 and two delta-6 desaturases (named delta-6-1 and delta-6-2, respectively) were analyzed. When delta-6 desaturase were overexpressed in M. circinelloides, up to 43% GLA was produced in the total fatty acids, and the yield of GLA reached 180 mg/l, which were, respectively, 38 and 33% higher than the control strain. CONCLUSION: These findings revealed that delta-6 desaturase (especially for delta-6-1 desaturase) plays an important role in GLA synthesis by M. circinelloides. The strain overexpressing delta-6-1 desaturase may have potential application in microbial GLA production. PMID- 28637508 TI - Hyperpolarized 13C urea myocardial first-pass perfusion imaging using velocity selective excitation. AB - BACKGROUND: A velocity-selective binomial excitation scheme for myocardial first pass perfusion measurements with hyperpolarized 13C substrates, which preserves bolus magnetization inside the blood pool, is presented. The proposed method is evaluated against gadolinium-enhanced 1H measurements in-vivo. METHODS: The proposed excitation with an echo-planar imaging readout was implemented on a clinical CMR system. Dynamic myocardial stress perfusion images were acquired in six healthy pigs after bolus injection of hyperpolarized 13C urea with the velocity-selective vs. conventional excitation, as well as standard 1H gadolinium enhanced images. Signal-to-noise, contrast-to-noise (CNR) and homogeneity of semi quantitative perfusion measures were compared between methods based on first-pass signal-intensity time curves extracted from a mid-ventricular slice. Diagnostic feasibility is demonstrated in a case of septal infarction. RESULTS: Velocity selective excitation provides over three-fold reduction in blood pool signal with a two-fold increase in myocardial CNR. Extracted first-pass perfusion curves reveal a significantly reduced variability of semi-quantitative first-pass perfusion measures (12-20%) for velocity-selective excitation compared to conventional excitation (28-93%), comparable to that of reference 1H gadolinium data (9-15%). Overall image quality appears comparable between the velocity selective hyperpolarized and gadolinium-enhanced imaging. CONCLUSION: The feasibility of hyperpolarized 13C first-pass perfusion CMR has been demonstrated in swine. Comparison with reference 1H gadolinium data revealed sufficient data quality and indicates the potential of hyperpolarized perfusion imaging for human applications. PMID- 28637507 TI - Dysregulated expression of long noncoding RNAs in gynecologic cancers. AB - Cancers of the female reproductive system include ovarian, uterine, vaginal, cervical and vulvar cancers, which are termed gynecologic cancer. The emergence of long noncoding RNAs (lncRNAs), which are believed to play a crucial role in several different biological processes, has made the regulation of gene expression more complex. Although the function of lncRNAs is still rather elusive, their broad involvement in the initiation and progression of various cancers is clear. They are also involved in the pathogenesis of cancers of the female reproductive system. LncRNAs play a critical physiological role in apoptosis, metastasis, invasion, migration and cell proliferation in these cancers. Different expression profiles of lncRNAs have been observed in various types of tumors compared with normal tissues and between malignant and benign tumors. These differential expression patterns may lead to the promotion or suppression of cancer development and tumorigenesis. In the current review, we present the lncRNAs that show a differential expression between cancerous and normal tissues in ovarian, cervical and endometrial cancers, and highlight the associations between lncRNAs and some of the molecular pathways involved in these cancers. PMID- 28637509 TI - Genetic effects of rs3740199 polymorphism in ADAM12 gene on knee osteoarthritis: a meta-analysis. AB - BACKGROUND: Knee osteoarthritis (OA) is a complex arthritic condition in which genetic factors play an important role. ADAM12 gene is one of the recognized candidate genes although the results are conflicting. To derive a more precise estimation of the association between rs3740199 polymorphism in ADAM12 gene and risk of knee OA, we performed a meta-analysis based on six related studies, including a total of 2185 cases and 3716 controls. METHODS: A comprehensive search was performed to identify related studies up to April 14, 2017. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Different genetic models were used to assess the pooled and stratified data. RESULTS: Overall, no significant association was found in all genetic models (C vs. G, OR = 0.983, 95% CI = 0.910-1.061; CC vs. GG, OR = 1.033, 95% CI = 0.851-1.255; CG vs. GG, OR = 1.030, 95% CI = 0.877-1.209; CC/CG vs. GG, OR = 1.031, 95% CI = 0.886-1.201; CC vs. CG/GG, OR = 1.017, 95% CI = 0.868 1.190). When stratified by ethnicity, no significant association was found. CONCLUSIONS: This meta-analysis suggested that the rs3740199 polymorphism does not contribute to the development of knee OA. Additional well-designed large studies are required to confirm these findings in different populations. PMID- 28637510 TI - A new monoclonal antibody detects downregulation of protein tyrosine phosphatase receptor type gamma in chronic myeloid leukemia patients. AB - BACKGROUND: Protein tyrosine phosphatase receptor gamma (PTPRG) is a ubiquitously expressed member of the protein tyrosine phosphatase family known to act as a tumor suppressor gene in many different neoplasms with mechanisms of inactivation including mutations and methylation of CpG islands in the promoter region. Although a critical role in human hematopoiesis and an oncosuppressor role in chronic myeloid leukemia (CML) have been reported, only one polyclonal antibody (named chPTPRG) has been described as capable of recognizing the native antigen of this phosphatase by flow cytometry. Protein biomarkers of CML have not yet found applications in the clinic, and in this study, we have analyzed a group of newly diagnosed CML patients before and after treatment. The aim of this work was to characterize and exploit a newly developed murine monoclonal antibody specific for the PTPRG extracellular domain (named TPgamma B9-2) to better define PTPRG protein downregulation in CML patients. METHODS: TPgamma B9-2 specifically recognizes PTPRG (both human and murine) by flow cytometry, western blotting, immunoprecipitation, and immunohistochemistry. RESULTS: Co-localization experiments performed with both anti-PTPRG antibodies identified the presence of isoforms and confirmed protein downregulation at diagnosis in the Philadelphia positive myeloid lineage (including CD34+/CD38bright/dim cells). After effective tyrosine kinase inhibitor (TKI) treatment, its expression recovered in tandem with the return of Philadelphia-negative hematopoiesis. Of note, PTPRG mRNA levels remain unchanged in tyrosine kinase inhibitors (TKI) non-responder patients, confirming that downregulation selectively occurs in primary CML cells. CONCLUSIONS: The availability of this unique antibody permits its evaluation for clinical application including the support for diagnosis and follow-up of these disorders. Evaluation of PTPRG as a potential therapeutic target is also facilitated by the availability of a specific reagent capable to specifically detect its target in various experimental conditions. PMID- 28637511 TI - The emergence of mesencephalic trigeminal neurons. AB - BACKGROUND: The cells of the mesencephalic trigeminal nucleus (MTN) are the proprioceptive sensory neurons that innervate the jaw closing muscles. These cells differentiate close to the two key signalling centres that influence the dorsal midbrain, the isthmus, which mediates its effects via FGF and WNT signalling and the roof plate, which is a major source of BMP signalling as well as WNT signalling. METHODS: In this study, we have set out to analyse the importance of FGF, WNT and BMP signalling for the development of the MTN. We have employed pharmacological inhibitors of these pathways in explant cultures as well as utilising the electroporation of inhibitory constructs in vivo in the chick embryo. RESULTS: We find that interfering with either FGF or WNT signalling has pronounced effects on MTN development whilst abrogation of BMP signalling has no effect. We show that treatment of explants with either FGF or WNT antagonists results in the generation of fewer MTN neurons and affects MTN axon extension and that inhibition of both these pathways has an additive effect. To complement these studies, we have used in vivo electroporation to inhibit BMP, FGF and WNT signalling within dorsal midbrain cells prior to, and during, their differentiation as MTN neurons. Again, we find that inhibition of BMP signalling has no effect on the development of MTN neurons. We additionally find that cells electroporated with inhibitory constructs for either FGF or WNT signalling can differentiate as MTN neurons suggesting that these pathways are not required cell intrinsically for the emergence of these neurons. Indeed, we also show that explants of dorsal mesencephalon lacking both the isthmus and roof plate can generate MTN neurons. However, we did find that inhibiting FGF or WNT signalling had consequences for MTN differentiation. CONCLUSIONS: Our results suggest that the emergence of MTN neurons is an intrinsic property of the dorsal mesencephalon of gnathostomes, and that this population undergoes expansion, and maturation, along with the rest of the dorsal midbrain under the influence of FGF and WNT signalling. PMID- 28637513 TI - Sinonasal teratocarcinosarcoma: a case report. AB - BACKGROUND: Sinonasal teratocarcinosarcoma is a rare and aggressive malignancy with histological features of both carcinosarcoma and teratoma. The optimal management of this malignancy is unclear, with most patients being managed by a combination of surgery and radiotherapy. CASE PRESENTATION: We describe an 83 year-old white woman with sinonasal teratocarcinosarcoma of her left nasal cavity treated with surgical debulking initially with radiological evidence of residual disease which was treated with radiotherapy (60 Gy in 30 fractions). A follow-up examination at 2 years showed no evidence of recurrence. CONCLUSIONS: In cases of sinonasal teratocarcinosarcoma with residual disease post-surgery, radiotherapy alone can be an effective option. PMID- 28637514 TI - Performance of point-of-care international normalized ratio measurement to diagnose trauma-induced coagulopathy. AB - BACKGROUND: Trauma-induced coagulopathy (TIC) is a common feature after severe trauma. Detection of TIC is based upon classic coagulation tests including international normalized ratio (INR) value. Point-of-care (POC) devices have been developed to rapidly measure INR at the bedside on whole blood. The aim of the study was to test the precision of the Coagucheck(r) XS Pro device for INR measurement at hospital admission after severe trauma. METHODS: We conducted a prospective observational study in a French level I trauma center. From January 2015 to May 2016, 98 patients with a suspicion of a post-traumatic acute hemorrhage had POC-INR measurement on whole blood concomitantly to classic laboratory INR determination (lab-INR) on plasma at hospital admission. The agreement between the two methods in sorting three predefined categories of INR (normal coagulation, moderate TIC and severe TIC) was evaluated using the Cohen's kappa test with a quadratic weighting. The correlation between POC-INR and lab INR was measured using the Pearson's coefficient. We also performed a Bland and Altman analysis. RESULTS: The agreement between the lab-INR and the POC-INR was moderate (Kappa = 0.45 [95% CI 0.36-0.50]) and the correlation between the two measurements was also weak (Pearson's coefficient = 0.44 [95% CI 0.27-0.59]). Using a Bland and Altman analysis, the mean difference (bias) for INR was 0.22 [95% CI 0.02-0.42], and the standard deviation (precision) of the difference was 1.01. DISCUSSION/CONCLUSION: POC Coagucheck(r) XS Pro device is not reliable to measure bedside INR. Its moderate agreement with lab-INR weakens the usefulness of such device after severe trauma. TRIAL REGISTRATION: NCT02869737 . Registered 9 August 2016. PMID- 28637512 TI - Single- or double-unit UCBT following RIC in adults with AL: a report from Eurocord, the ALWP and the CTIWP of the EBMT. AB - BACKGROUND: The feasibility of cord blood transplantation (CBT) in adults is limited by the relatively low number of hematopoietic stem/progenitor cells contained in one single CB unit. The infusion of two CB units from different partially HLA-matched donors (double CBT) is frequently performed in patients who lack a sufficiently rich single CB unit. METHODS: We compared CBT outcomes in patients given single or double CBT following reduced-intensity conditioning (RIC) in a retrospective multicenter registry-based study. Inclusion criteria included adult (>=18 years) patients, acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), complete remission (CR) at the time of transplantation, first single (with a cryopreserved TNC >= 2.5 * 107/kg) or double CBT between 2004 and 2014, and RIC conditioning. RESULTS: Data from 534 patients with AML (n = 408) or ALL (n = 126) receiving a first single (n = 172) or double (n = 362) CBT were included in the analyses. In univariate analysis, in comparison to patients transplanted with a single CB, double CB recipients had a similar incidence of neutrophil engraftment but a suggestion for a higher incidence of grade II-IV acute GVHD (36 versus 28%, P = 0.08). In multivariate analyses, in comparison to single CBT recipients, double CBT patients had a comparable incidence of relapse (HR = 0.9, P = 0.5) and of nonrelapse mortality (HR = 0.8, P = 0.3), as well as comparable overall (HR = 0.8, P = 0.17), leukemia free (HR = 0.8, P = 0.2) and GVHD-free, relapse-free (HR = 1.0, P = 0.3) survival. CONCLUSIONS: These data failed to demonstrate better transplantation outcomes in adult patients receiving double CBT in comparison to those receiving single CBT with adequate TNC after RIC. PMID- 28637517 TI - Priorities for African youth for engaging in DOHaD. AB - A challenge for implementing DOHaD-defined health promotion is how to engage the at-risk population. The WHO Health Promoting School (HPS) model has proven success engaging youth and improving health behaviors. Hence, we introduced DOHaD concepts to 151 pupils aged 12-15 years in three HPS programs in rural Uganda, inquired what factors would make DOHaD-related health promotion resonate with them, and discussed how they recommended making learning about DOHaD acceptable to youth. Economic factors were judged the most compelling; with nutrition and responsive care elements next in importance. Suggested approaches included: teach how good health is beneficial, what works and why, and give tools to use to achieve it, and make information positive rather than linked to later harm. Involve youth in making DOHaD learning happen, make being a parent sound interesting, and include issues meaningful to boys. These are the first data from youth charged with addressing their engagement in the DOHaD agenda. PMID- 28637516 TI - Feeding heat-oxidized oil to dairy cows affects milk fat nutritional quality. AB - Heating oil and oilseeds results in oxidation products that affect ruminal biohydrogenation of polyunsaturated fatty acids, altering milk fatty acids profile, and could be transferred to milk. An experiment was conducted to investigate the effects of oil heating on rumen and milk fatty acids profile and the transfer of oxidation products to milk. Sunflower oil was heated at 150 degrees C for 15 h and given to lactating dairy cows in a 2*2 arrangement: two groups of two cows, equipped with a ruminal cannula and receiving two diets (containing either heated or unheated oil) during two experimental periods. Oil heating generated hydroperoxides and/or hydroxyacids and aldehydes, in particular trans-2,trans-4-decadienal. In milk, heated oil only significantly decreased trans-11-C18:1 and cis-9,trans-11-CLA percentage compared to non-heated oil, and slightly increased cis-9,cis-12-C18:2 percentage, which was probably linked to an inhibition of the ruminal Delta12 isomerase by oxidative products in the rumen. However, feeding highly oxidized oil did not result in the appearance of hydroperoxides or hydroxyacids in milk and did not increase milk aldehydes content. PMID- 28637515 TI - Current globalization of drug interventional clinical trials: characteristics and associated factors, 2011-2013. AB - BACKGROUND: Clinical trial globalization is a major trend for industry-sponsored clinical trials. There has been a shift in clinical trial sites towards emerging regions of Eastern Europe, Latin America, Asia, the Middle East, and Africa. Our study objectives were to evaluate the current characteristics of clinical trials and to find out the associated multiple factors which could explain clinical trial globalization and its implications for clinical trial globalization in 2011 2013. METHODS: The data elements of "phase," "recruitment status," "type of sponsor," "age groups," and "design of trial" from 30 countries were extracted from the ClinicalTrials.gov website. Ten continental representative countries including the USA were selected and the design elements were compared to those of the USA. Factors associated with trial site distribution were chosen for a multilinear regression analysis. RESULTS: The USA, Germany, France, Canada, and United Kingdom were the "top five" countries which frequently held clinical trials. The design elements from nine continental representative countries were quite different from those of the USA; phase 1 trials were more prevalent in India (OR 1.517, p < 0.001) while phase 3 trials were much more prevalent in all nine representative countries than in the USA. A larger number of "child" age group trials was performed in Poland (OR 1.852, p < 0.001), Israel (OR 1.546, p = 0.005), and South Africa (OR 1.963, p < 0.001) than in the USA. Multivariate analysis showed that health care expenditure per capita, Economic Freedom Index, Human Capital Index, and Intellectual Property Rights Index could explain the variance of regional distribution of clinical trials by 63.6%. CONCLUSIONS: The globalization of clinical trials in the emerging regions of Asia, South Africa, and Eastern Europe developed in parallel with the factors of economic drive, population for recruitment, and regulatory constraints. PMID- 28637518 TI - Non-Digital Game Playing by Older Adults. AB - Research on video games' effect on cognition and behaviour has been extensive, yet little research has explored non-digital forms of game playing, especially among older adults. As part of a larger survey on game playing, 886 respondents (>= age 55) filled out questionnaires about non-digital game play. The study aims were to determine perceived benefits of non-digital game play and to determine socio-demographic factors that might predict perceived benefits. Survey results indicate that non-digital game playing is social in nature and common (73% of respondents) among older adults. Older adults play for fun, but also to help maintain their cognition. Regression analyses indicated various socio-demographic factors - age, education, gender, and race - were independently associated with perceived benefits from game playing. The results thus emphasize the importance of non-digital game playing in this population and suggest that efforts to facilitate game playing may improve social interactions and quality of life. PMID- 28637519 TI - Gender associated developmental trajectories of SDQ-dysregulation profile and its predictors in children. AB - BACKGROUND: Severe mood dysregulation is common in childhood and can be highly impairing. The Dysregulation Profile (DP) can be considered as a broader phenotype of emotional dysregulation, including affect, cognition and behaviour. Since mood dysregulation may persist, but differently in boys and girls, the gender associated course needs to be considered longitudinally to gain a better insight in order to support the children more adequately. This study is focusing on gender associated subgroup trajectories of the Strengths and Difficulties Questionnaire-Dysregulation Profile (SDQ-DP) in middle childhood (9-13 years of age) and includes the potential impact of clinical and psychosocial characteristics. METHOD: The data set was available from the BELLA study on mental health and well-being in children and adolescents, which is the mental health module of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). A representative epidemiological sample of 564 children living in Germany was examined at three assessment points over 2 years (data collection 2003-2006). The SDQ-DP of children aged 9-13 years was evaluated using Latent Class Growth Analysis (LCGA). RESULTS: For both genders three trajectories with low (girls 67.0% and boys 59.5%), moderate (girls 28.0% and boys 31.7%) and high SDQ-DP (girls 5.0% and boys 8.8%) scores were detected. The courses of low and moderate subgroups were stable, while in the high SDQ-DP subgroup boys showed a decreasing and girls an increasing trend in symptom severity on a descriptive level. The results of the multinomial logistic regression analyses revealed a significant influence of mainly externalising but also internalising problems both increasing the risk of moderate and high SDQ-DP in both genders. Good quality of life was a protective factor for the SDQ-DP course in all subgroups. CONCLUSION: In addition to the known clinical and scientific value of the SDQ-DP, three distinguishable trajectories of SDQ-DP in boys and girls could be found. High externalising problems at the beginning of the trajectory were associated with an undesirable course of SDQ-DP. These findings might be helpful for better psychoeducation, counselling and monitoring in clinical cases and public health. PMID- 28637520 TI - Citrulline decreases hepatic endotoxin-induced injury in fructose-induced non alcoholic liver disease: an ex vivo study in the isolated perfused rat liver. AB - Steatosis can sensitise the liver to various challenges and favour the development of non-alcoholic fatty liver disease (NAFLD). In this context, fructose feeding promotes endotoxin translocation from the gut, contributing to disease progression via an inflammatory process. Citrulline is protective against fructose-induced NAFLD; we hypothesised that this property might be related to its anti-inflammatory and antioxidative action against endotoxin-induced hepatic injuries. This hypothesis was evaluated in a model of perfused liver isolated from NAFLD rats. Male Sprague-Dawley rats (n 30) were fed either a standard rodent chow or a 60 % fructose diet alone, or supplemented with citrulline (1 g/kg per d) for 4 weeks. After an evaluation of their metabolic status, fasted rats received an intraperitoneal injection of lipopolysaccharide (LPS) (2.5 mg/kg). After 1 h, the livers were isolated and perfused for 1 h to study liver function and metabolism, inflammation and oxidative status. In vivo, citrulline significantly decreased dyslipidaemia induced by a high-fructose diet and insulin resistance. In the isolated perfused rat livers, endotoxaemia resulted in higher cytolysis (alanine aminotransferase release) and higher inflammation (Toll-like receptor 4) in livers of fructose-fed rats, and it was prevented by citrulline supplementation. Oxidative stress and antioxidative defences were similar in all three groups. Amino acid exchanges and metabolism (ammonia and urea release) were only slightly different between the three groups. In this context of mild steatosis, our results suggest that fructose-induced NAFLD leads to an increased hepatic sensitivity to LPS-induced inflammation. Citrulline-induced restriction of the inflammatory process may thus contribute to the prevention of NAFLD. PMID- 28637521 TI - Rapid improvement in beliefs, mood, and performance following an experimental success experience in an analogue test of recovery-oriented cognitive therapy. AB - BACKGROUND: Negative symptoms significantly contribute to disability and lack of community participation for low functioning individuals with schizophrenia. Cognitive therapy has been shown to improve negative symptoms and functional outcome in this population. Elucidation of the mechanisms of the therapy would lead to a better understanding of negative symptoms and the development of more effective interventions to promote recovery. The objective of this study was to determine (1) whether guided success at a card-sorting task will produce improvement in defeatist beliefs, positive beliefs about the self, mood, and card sorting performance, and (2) whether these changes in beliefs and mood predict improvements in unguided card-sorting. METHODS: Individuals with schizophrenia having prominent negative symptoms and impaired neurocognitive performance (N = 35) were randomized to guided success (n = 19) or a control (n = 16) condition. RESULTS: Controlling for baseline performance, the experimental group performed significantly better, endorsed defeatist beliefs to a lesser degree, reported greater positive self-concept, and reported better mood than the control condition immediately after the experimental session. A composite index of change in defeatist beliefs, self-concept, and mood was significantly correlated with improvements in card-sorting. CONCLUSIONS: This analogue study supports the rationale of cognitive therapy and provides a general therapeutic model in which experiential interventions that produce success have a significant immediate effect on a behavioral task, mediated by changes in beliefs and mood. The rapid improvement is a promising indicator of the responsiveness of this population, often regarded as recalcitrant, to cognitively-targeted behavioral interventions. PMID- 28637522 TI - Evaluation of urinary resveratrol as a biomarker of dietary resveratrol intake in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. AB - In vitro studies have shown several beneficial properties of resveratrol. Epidemiological evidence is still scarce, probably because of the difficulty in estimating resveratrol exposure accurately. The current study aimed to assess the relationships between acute and habitual dietary resveratrol and wine intake and urinary resveratrol excretion in a European population. A stratified random subsample of 475 men and women from four countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cross-sectional study, who had provided 24-h urine samples and completed a 24-h dietary recall (24-HDR) on the same day, were included. Acute and habitual dietary data were collected using standardised 24-HDR software and a validated country-specific dietary questionnaire, respectively. Phenol-Explorer was used to estimate the intake of resveratrol and other stilbenes. Urinary resveratrol was analysed using tandem MS. Spearman's correlation coefficients between estimated dietary intakes of resveratrol and other stilbenes and consumption of wine, their main food source, were very high (r>0.9) when measured using dietary questionnaires and were slightly lower with 24-HDR (r>0.8). Partial Spearman's correlations between urinary resveratrol excretion and intake of resveratrol, total stilbenes or wine were found to be higher when using the 24-HDR (R 2 partial approximately 0.6) than when using the dietary questionnaires (R 2 partial approximately 0.5). Moderate to high correlations between dietary resveratrol, total stilbenes and wine, and urinary resveratrol concentrations were observed. These support the earlier findings that 24-h urinary resveratrol is an effective biomarker of both resveratrol and wine intakes. These correlations also support the validity of the estimation of resveratrol intake using the dietary questionnaire and Phenol Explorer. PMID- 28637523 TI - Ureaplasma urealyticum and U. parvum in sexually active women attending public health clinics in Brazil. AB - Ureaplasma urealyticum and U. parvum have been associated with genital infections. The purpose of this study was to detect the presence of ureaplasmas and other sexually transmitted infections in sexually active women from Brazil and relate these data to demographic and sexual health, and cytokines IL-6 and IL 1beta. Samples of cervical swab of 302 women were examined at the Family Health Units in Vitoria da Conquista. The frequency of detection by conventional PCR was 76.2% for Mollicutes. In qPCR, the frequency found was 16.6% for U. urealyticum and 60.6% U. parvum and the bacterial load of these microorganisms was not significantly associated with signs and symptoms of genital infection. The frequency found for Trichomonas vaginalis, Neisseria gonorrhoeae, Gardnerella vaginalis and Chlamydia trachomatis was 3.0%, 21.5%, 42.4% and 1.7%, respectively. Higher levels of IL-1beta were associated with control women colonized by U. urealyticum and U. parvum. Increased levels of IL-6 were associated with women who exhibited U. parvum. Sexually active women, with more than one sexual partner in the last 3 months, living in a rural area were associated with increased odds of certain U. parvum serovar infection. PMID- 28637524 TI - A new look at the supposed risks of early institutional rearing. AB - The main focus is on the assessment of the effects of early institutional care and compares three longitudinal studies from Romania, Greece and Hong Kong/China. The findings have been strikingly contrasting. The review asks if the risks are dependent on whether or not the institutional rearing is accompanied by gross pervasive deprivation (as it was in Romania) and investigates the methodological issues to explore the causal influence of the outcomes. Evidence is considered on changing institutional practices and the benefits of doing so. Comparison is made between institutions with major deprivation and those without global deprivation. A small number of studies are discussed that look at direct comparisons between institutional and community care. The empirical and conceptual implications of the findings are discussed. PMID- 28637525 TI - Eye-Tracking Evidence of a Maintenance Bias in Social Anxiety. AB - BACKGROUND: The mechanisms and triggers of the attentional bias in social anxiety are not yet fully determined, and the modulating role of personality traits is being increasingly acknowledged. AIMS: Our main purpose was to test whether social anxiety is associated with mechanisms of hypervigilance, avoidance (static biases), vigilance-avoidance or the maintenance of attention (dynamic biases). Our secondary goal was to explore the role of personality structure in shaping the attention bias. METHOD: Participants with high vs low social anxiety and different personality structures viewed pairs of faces (free-viewing eye-tracking task) representing different emotions (anger, happiness and neutrality). Their eye movements were registered and analysed for both whole-trial (static) and time dependent (dynamic) measures. RESULTS: Comparisons between participants with high and low social anxiety levels did not yield evidence of differences in eye tracking measures for the whole trial (latency of first fixation, first fixation direction, total dwell time), but the two groups differed in the time course of overt attention during the trial (dwell time across three successive time segments): participants with high social anxiety were slower in disengaging their attention from happy faces. Similar results were obtained using a full-sample, regression-based analysis. CONCLUSION: Our results speak in favour of a maintenance bias in social anxiety. Preliminary results indicated that personality structure may not affect the maintenance (dynamic) bias of socially anxious individuals, although depressive personality structures may favour manifestations of a (static) hypervigilance bias. PMID- 28637526 TI - Hiding in the swamp: new capillariid nematode parasitizing New Zealand brown mudfish. AB - The extent of New Zealand's freshwater fish-parasite diversity has yet to be fully revealed, with host-parasite relationships still to be described from nearly half the known fish community. While advances in the number of fish species examined and parasite taxa described are being made, some parasite groups, such as nematodes, remain poorly understood. In the present study we combined morphological and molecular analyses to characterize a capillariid nematode found infecting the swim bladder of the brown mudfish Neochanna apoda, an endemic New Zealand fish from peat-swamp-forests. Morphologically, the studied nematodes are distinct from other Capillariinae taxa by the features of the male posterior end, namely the shape of the bursa lobes, and shape of spicule distal end. Male specimens were classified into three different types according to differences in the shape of the bursa lobes at the posterior end, but only one was successfully characterized molecularly. Molecular analysis indicated that the studied capillariid is distinct from other genera. However, inferences about the phylogenetic position of the capillariid reported here will remain uncertain, due to the limited number of Capillariinae taxa characterized molecularly. The discovery of this new capillariid, which atypically infects the swim bladder of its host, which itself inhabits a very unique ecosystem, underlines the very interesting evolutionary history of this parasite, which for now will remain unresolved. PMID- 28637527 TI - Rodents, goats and dogs - their potential roles in the transmission of schistosomiasis in China. AB - Schistosomiasis in China has been substantially reduced due to an effective control programme employing various measures including bovine and human chemotherapy, and the removal of bovines from endemic areas. To fulfil elimination targets, it will be necessary to identify other possible reservoir hosts for Schistosoma japonicum and include them in future control efforts. This study determined the infection prevalence of S. japonicum in rodents (0-9.21%), dogs (0-18.37%) and goats (6.9-46.4%) from the Dongting Lake area of Hunan province, using a combination of traditional coproparasitological techniques (miracidial hatching technique and Kato-Katz thick smear technique) and molecular methods [quantitative real-time PCR (qPCR) and droplet digital PCR (ddPCR)]. We found a much higher prevalence in goats than previously recorded in this setting. Cattle and water buffalo were also examined using the same procedures and all were found to be infected, emphasising the occurrence of active transmission. qPCR and ddPCR were much more sensitive than the coproparasitological procedures with both KK and MHT considerably underestimating the true prevalence in all animals surveyed. The high level of S. japonicum prevalence in goats indicates that they are likely important reservoirs in schistosomiasis transmission, necessitating their inclusion as targets of control, if the goal of elimination is to be achieved in China. PMID- 28637528 TI - Maternal verbal responsiveness and directiveness: consistency, stability, and relations to child early linguistic development. AB - Maternal responsive and directive speech to children at ages 0;10 and 2;0 was investigated by applying a procedure first introduced by Flynn and Masur (2007) to a new language community (Finnish). The issues examined were consistency and stability over time, and also the role of responsiveness and directiveness in child linguistic development at 1;0 and 2;6. The measures of maternal speech from each age were used to predict the results of the subsequent linguistic assessment. Negative correlations between responsive and directive utterances were found at both ages. The frequencies of responsive utterances and supportive directives increased over time. Responsiveness was positively, and intrusive directiveness negatively, related to child early comprehensive skills and the use of symbolic actions and communicative gestures. By contrast, no relations were found between responsiveness and directiveness and children's later linguistic capacities. PMID- 28637529 TI - Predictors of adults' body mass index and the association with index child's infant birth weight, in the Lifeways Cross-Generation Cohort Study of a thousand families in the Republic of Ireland. AB - The Lifeways study is novel in having information on three generations of the same families. It is well established that infant birth weight (IBW) predicts individuals' risk of adult chronic disease and more recently studies report cross generation transmission of risk patterns. The aims of this analysis were to examine whether adults' birth weights were associated with measures of own health status or social position and to relate adults' birth weights to that of the index child's IBW. Finally, we assessed whether birth weight of either adults or children was associated with adult body mass index (BMI) of parents and grandparents. We included 1075 children whose IBW was recorded at recruitment from hospital records and 2546 adult cohort members followed from 2001 until 2014. At baseline, a sub-group of 920 adults had reported own birth weight (RBW). Results showed male adults' RBW were significantly higher than females' (P=0.001). Mothers' RBW was significantly correlated with IBW (r=0.178, P<0.001). In mixed effects linear models with BMI as the outcome variable, of all adults, and in sub-groups of adults with RBW and of mothers only, the IBW was associated with adult BMI adjusting for other predictors. Adults' BMI was positively associated with age (P=0.013), index child's IBW (P=0.001), gender (P<0.001) but not own RBW, adjusting for family identification number. When mothers were removed from the adult models however, IBW ceased to be associated with BMI, a final model showed RBW being associated with adult BMI (P=0.04). There are cross generational associations in the Lifeways cohort, the maternal association being stronger. PMID- 28637530 TI - Characterization of the complete mitochondrial genome of Ortleppascaris sinensis (Nematoda: Heterocheilidae) and comparative mitogenomic analysis of eighteen Ascaridida nematodes. AB - Ortleppascaris sinensis (Nematoda: Ascaridida) is a dominant intestinal nematode of the captive Chinese alligator. However, the epidemiology, molecular ecology and population genetics of this parasite remain largely unexplored. In this study, the complete mitochondrial (mt) genome sequence of O. sinensis was first determined using a polymerase chain reaction (PCR)-based primer-walking strategy, and this is also the first sequencing of the complete mitochondrial genome of a member of the genus Ortleppascaris. The circular mitochondrial genome (13,828 bp) of O. sinensis contained 12 protein-coding, 22 transfer RNA and 2 ribosomal RNA genes, but lacked the ATP synthetase subunit 8 gene. Finally, phylogenetic analysis of mtDNAs indicated that the genus Ortleppascaris should be attributed to the family Heterocheilidae. It is necessary to sequence more mtNDAs of Ortleppascaris nematodes in the future to test and confirm our conclusion. The complete mitochondrial genome sequence of O. sinensis reported here should contribute to molecular diagnosis, epidemiological investigations and ecological studies of O. sinensis and other related Ascaridida nematodes. PMID- 28637531 TI - Minimising generation of acid whey during Greek yoghurt manufacturing. AB - Greek yoghurt, a popular dairy product, generates large amounts of acid whey as a by-product during manufacturing. Post-processing treatment of this stream presents one of the main concerns for the industry. The objective of this study was to manipulate initial milk total solids content (15, 20 or 23 g/100 g) by addition of milk protein concentrate, thus reducing whey expulsion. Such an adjustment was investigated from the technological standpoint including starter culture performance, chemical and physical properties of manufactured Greek yoghurt and generated acid whey. A comparison was made to commercially available products. Increasing protein content in regular yoghurt reduced the amount of acid whey during whey draining. This protein fortification also enhanced the Lb. bulgaricus growth rate and proteolytic activity. Best structural properties including higher gel strength and lower syneresis were observed in the Greek yoghurt produced with 20 g/100 g initial milk total solid compared to manufactured or commercially available products, while acid whey generation was lowered due to lower drainage requirement. PMID- 28637532 TI - Estimating the economic impact of subclinical ketosis in dairy cattle using a dynamic stochastic simulation model. AB - The objective of this study was to estimate the economic impact of subclinical ketosis (SCK) in dairy cows. This metabolic disorder occurs in the period around calving and is associated with an increased risk of other diseases. Therefore, SCK affects farm productivity and profitability. Estimating the economic impact of SCK may make farmers more aware of this problem, and can improve their decision-making regarding interventions to reduce SCK. We developed a dynamic stochastic simulation model that enables estimating the economic impact of SCK and related diseases (i.e. mastitis, metritis, displaced abomasum, lameness and clinical ketosis) occurring during the first 30 days after calving. This model, which was applied to a typical Dutch dairy herd, groups cows according to their parity (1 to 5+), and simulates the dynamics of SCK and related diseases, and milk production per cow during one lactation. The economic impact of SCK and related diseases resulted from a reduced milk production, discarded milk, treatment costs, costs from a prolonged calving interval and removal (culling or dying) of cows. The total costs of SCK were ?130 per case per year, with a range between ?39 and ?348 (5 to 95 percentiles). The total costs of SCK per case per year, moreover, increased from ?83 per year in parity 1 to ?175 in parity 3. Most cows with SCK, however, had SCK only (61%), and costs were ?58 per case per year. Total costs of SCK per case per year resulted for 36% from a prolonged calving interval, 24% from reduced milk production, 19% from treatment, 14% from discarded milk and 6% from removal. Results of the sensitivity analysis showed that the disease incidence, removal risk, relations of SCK with other diseases and prices of milk resulted in a high variation of costs of SCK. The costs of SCK, therefore, might differ per farm because of farm-specific circumstances. Improving data collection on the incidence of SCK and related diseases, and on consequences of diseases can further improve economic estimations. PMID- 28637535 TI - Routine hospital management of self-harm and risk of further self-harm: propensity score analysis using record-based cohort data. AB - BACKGROUND: The care received by people presenting to hospital following self harm varies and it is unclear how different types of treatment affect risk of further self-harm. METHOD: Observational cohort data from the Manchester Self Harm Project, UK, included 16 456 individuals presenting to an Emergency Department with self-harm between 2003 and 2011. Individuals were followed up for 12 months. We also used data from a smaller cohort of individuals presenting to 31 hospitals in England during a 3-month period in 2010/2011, followed up for 6 months. Propensity score (PS) methods were used to address observed confounding. Missing data were imputed using multiple imputation. RESULTS: Following PS stratification, those who received a psychosocial assessment had a lower risk of repeat hospital attendance for self-harm than those who were not assessed [RR 0.87, 95% confidence interval (CI) 0.80-0.95]. The risk was reduced most among people less likely to be assessed. Following PS matching, we found no associations between risks of repeat self-harm and admission to a medical bed, referral to outpatient psychiatry or admission to a psychiatric bed. We did not find a relationship between psychosocial assessment and repeat self-harm in the 31 centre cohort. CONCLUSIONS: This study shows the potential value of using novel statistical techniques in large mental health datasets to estimate treatment effects. We found that specialist psychosocial assessment may reduce the risk of repeat self-harm. This type of routine care should be provided for all individuals who present to hospital after self-harm, regardless of perceived risk. PMID- 28637536 TI - Mental health morbidity among people subject to immigration detention in the UK: a feasibility study. AB - AIMS: The UK has one of the largest systems of immigration detention in Europe.. Those detained include asylum-seekers and foreign national prisoners, groups with a higher prevalence of mental health vulnerabilities compared with the general population. In light of little published research on the mental health status of detainees in immigration removal centres (IRCs), the primary aim of this study was to explore whether it was feasible to conduct psychiatric research in such a setting. A secondary aim was to compare the mental health of those seeking asylum with the rest of the detainees. METHODS: Cross-sectional study with simple random sampling followed by opportunistic sampling. Exclusion criteria included inadequate knowledge of English and European Union nationality. Six validated tools were used to screen for mental health disorders including developmental disorders like Personality Disorder, Attention Deficit Hyperactivity Disorder (ADHD), Autistic Spectrum Disorder (ASD) and Intellectual Disability, as well as for needs assessment. These were the MINI v6, SAPAS, AQ-10, ASRS, LDSQ and CANFOR. Demographic data were obtained using a participant demographic sheet. Researchers were trained in the use of the screening battery and inter-rater reliability assessed by joint ratings. RESULTS: A total of 101 subjects were interviewed. Overall response rate was 39%. The most prevalent screened mental disorder was depression (52.5%), followed by personality disorder (34.7%) and post-traumatic stress disorder (20.8%). 21.8% were at moderate to high suicidal risk. 14.9 and 13.9% screened positive for ASD and ADHD, respectively. The greatest unmet needs were in the areas of intimate relationships (76.2%), psychological distress (72.3%) and sexual expression (71.3%). Overall presence of mental disorder was comparable with levels found in prisons. The numbers in each group were too small to carry out any further analysis. CONCLUSION: It is feasible to undertake a psychiatric morbidity survey in an IRC. Limitations of the study include potential selection bias, use of screening tools, use of single site study, high refusal rates, the lack of interpreters and lack of women and children in study sample. Future studies should involve the in-reach team to recruit participants and should be run by a steering group consisting of clinicians from the IRC as well as academics. PMID- 28637534 TI - Depression and pain: primary data and meta-analysis among 237 952 people across 47 low- and middle-income countries. AB - BACKGROUND: Depression and pain are leading causes of global disability. However, there is a paucity of multinational population data assessing the association between depression and pain, particularly among low- and middle-income countries (LMICs) where both are common. Therefore, we investigated this association across 47 LMICs. METHODS: Community-based data on 273 952 individuals from 47 LMICs were analysed. Multivariable logistic and linear regression analyses were performed to assess the association between the International Classification of Diseases, 10th Revision depression/depression subtypes (over the past 12 months) and pain in the previous 30 days based on self-reported data. Country-wide meta-analysis adjusting for age and sex was also conducted. RESULTS: The prevalence of severe pain was 8.0, 28.2, 20.2, and 34.0% for no depression, subsyndromal depression, brief depressive episode, and depressive episode, respectively. Logistic regression adjusted for socio-demographic variables, anxiety and chronic medical conditions (arthritis, diabetes, angina, asthma) demonstrated that compared with no depression, subsyndromal depression, brief depressive episode, and depressive episode were associated with a 2.16 [95% confidence interval (CI) 1.83-2.55], 1.45 (95% CI 1.22-1.73), and 2.11 (95% CI 1.87-2.39) increase in odds of severe pain, respectively. Similar results were obtained when a continuous pain scale was used as the outcome. Depression was significantly associated with severe pain in 44/47 countries with a pooled odds ratio of 3.93 (95% CI 3.54-4.37). CONCLUSION: Depression and severe pain are highly comorbid across LMICs, independent of anxiety and chronic medical conditions. Whether depression treatment or pain management in patients with comorbid pain and depression leads to better clinical outcome is an area for future research. PMID- 28637537 TI - Occult HIV infection in a large sample of health-care users in Lombardy, Italy in 2014-2015: implications for control strategies. AB - We estimated the number of people unaware of their human immunodeficiency virus (HIV) infection in our province, Pavia (population 540 000) in Lombardy, Italy, by means of anonymous unlinked testing of 10 044 serum/plasma samples residual from clinical analyses at the outpatient clinic of Policlinico San Matteo in 2014 and 2015. Ethical and legal approval was obtained prior to study start. Samples were irreversibly anonymised, only retaining gender and 5-year age class. Five sample pools were tested for HIV using LIAISON(r) XL MUREX HIV Ab/Ag (DiaSorin, Saluggia, Italy). If the pool tested positive, individual samples underwent confirmatory tests, Innotest HIV Antigen mAb (Fujirebio Europe, Gent, Belgium) and HIV BLOT 2.2 (MP Diagnostics, Singapore). Among the 10 044 samples processed, eight were confirmed positive (0.08%, 95% confidence interval 0.03-0.16%), all were males and age was >50 in 3 (37.5%). If projected to the entire population of the Pavia province, this would result in approximately 1000 people unaware of their HIV infection, with age older than expected. In Italy, HIV testing is voluntary, universally free-of-charge and (upon request) anonymous. Nevertheless, this study demonstrates that it is suboptimally employed, and that new strategies and population-level actions will be needed to achieve better implementation of HIV testing and HIV control in our province. PMID- 28637533 TI - Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis. AB - Sphingolipids (SLs) are an integral part of all eukaryotic cellular membranes. In addition, they have indispensable functions as signalling molecules controlling a myriad of cellular events. Disruption of either the de novo synthesis or the degradation pathways has been shown to have detrimental effects. The earlier identification of selective inhibitors of fungal SL biosynthesis promised potent broad-spectrum anti-fungal agents, which later encouraged testing some of those agents against protozoan parasites. In this review we focus on the key enzymes of the SL de novo biosynthetic pathway in protozoan parasites of the Apicomplexa and Kinetoplastidae, outlining the divergence and interconnection between host and pathogen metabolism. The druggability of the SL biosynthesis is considered, alongside recent technology advances that will enable the dissection and analyses of this pathway in the parasitic protozoa. The future impact of these advances for the development of new therapeutics for both globally threatening and neglected infectious diseases is potentially profound. PMID- 28637538 TI - Chief Resident Dictation of Operative Cases and Its Relationship to American Board of Surgery Examination Performance. PMID- 28637539 TI - Laparoscopic Excision of Remnant Gallbladder after Subtotal Cholecystectomy. PMID- 28637540 TI - Biliary Cystadenoma and Cystadenocarcinoma of the Gallbladder: A Clinical Review. PMID- 28637541 TI - Lap-Belt-Induced Pediatric Blunt Traumatic Abdominal Wall Hernia. PMID- 28637542 TI - Pericarditis as a Result of Pneumomediastinum after Uncomplicated Laparoscopic Totally Extraperitoneal Inguinal Hernia Repair. PMID- 28637543 TI - Gracilis Flap for Perineal Closures in Minimally Invasive Abdominoperineal Resection. PMID- 28637545 TI - A Strangulated Cecal Volvulus through the Foramen of Winslow, a Rare Presentation of Internal Herniation. PMID- 28637544 TI - Evaluation of Blood Flow with Indocyanine Green-Guided Imaging to Determine Optimal Site for Gastric Conduit Anastomosis to Prevent Anastomotic Leak after Esophagectomy. PMID- 28637546 TI - Impact of Preinjury Anticoagulation with Warfarin on Outcomes of Adult Trauma Patients: Experience of a Level 1 Trauma Center. PMID- 28637547 TI - End-Stage Pancreatic Adenocarcinoma Presenting as a Sister Mary Joseph's Nodule. PMID- 28637548 TI - Pancreatic Pseudocyst-Induced Gastric Varices: A Rare Case of Extrahepatic Portal Hypertension? PMID- 28637549 TI - Segmental Resection versus Local Excision for Colonic Endometriosis. PMID- 28637550 TI - Esophageal Hematoma following Acute Esophageal Barotrauma. PMID- 28637551 TI - Outcomes of Geriatric Trauma Patients on Preinjury Anticoagulation: A Multicenter Study. AB - Outpatient anticoagulation in the geriatric trauma patient is a challenging clinical problem. The aim of this study is to determine clinical outcomes associated with class of preinjury anticoagulants (PA) used by this population. This is a multicenter retrospective cohort study among four Level II trauma centers. A total of 1642 patients were evaluated; 684 patients were on anticoagulation and 958 patients were not. Patients on PA were compared with those who were not. Drug classes were divided into thromboxane A2 inhibitors, vitamin K factor-dependent inhibitors, antithrombin III activation, platelet P2Y12 inhibitors, and thrombin inhibitors. Multivariate regression was used to adjust for age, gender, race, mechanism of injury, and Injury Severity Score. No single or combination of anticoagulation agents had a significant association with mortality; however, there were positive trends toward increased mortality were noted for all antiplatelet groups involving thromboxane A2 inhibitors and platelet P2Y12 inhibitors classes. The likelihood of complications was significantly higher with platelet P2Y12 inhibitors adjusted odds ratio (aOR) 2.39 [95% confidence interval (CI) 1.32, 4.3]. The likelihood of blood transfusion was increased with vitamin K inhibitors aOR 2.89 (95% CI 1.3, 6.5), P2Y12 inhibitors aOR 2.76 (95% CI 1.12, 6.76), and combined thromboxane A2 and P2Y12 inhibitors aOR 2.89 (95% CI 1.13, 7.46). P2Y12 inhibitors were also more likely associated with traumatic brain injury aOR 2.16 (95% CI 1.01, 4.6). All classes of PA were associated with solid organ injury. There were no significant differences in the use of antiplatelet agents between patients with major indications for PA and those without major indications. Geriatric trauma patients on outpatient anticoagulants have a higher likelihood of developing complications, packed red blood cell transfusions, traumatic brain injury, and solid organ injury. Attention should be paid to patients on platelet P2Y12 inhibitors, vitamin K inhibitors, and thromboxane A2 inhibitor agents combined with platelet P2Y12 inhibitors. Opportunities exist to address the use of antiplatelet agents among patients without major indications to improve patient outcomes. PMID- 28637552 TI - Standardized, Interdepartmental, Simulation-Based Central Line Insertion Course Closes an Educational Gap and Improves Intern Comfort with the Procedure. AB - Central line placement is a common procedure, routinely performed by junior residents in medical and surgical departments. Before this project, no standardized instructional course on the insertion of central lines existed at our institution, and few interns had received formal ultrasound training. Interns from five departments participated in a simulation-based central line insertion course. Intern familiarity with the procedure and with ultrasound, as well as their prior experience with line placement and their level of comfort, was assessed. Of the 99 interns in participating departments, 45 per cent had been trained as of October 2015. Forty-one per cent were female. The majority (59.5%) had no prior formal ultrasound training, and 46.0 per cent had never placed a line as primary operator. Scores increased significantly, from a precourse score mean of 13.7 to a postcourse score mean of 16.1, P < 0.001. All three of the self reported measures of comfort with ultrasound also improved significantly. All interns reported the course was "very much" helpful, and 100 per cent reported they felt "somewhat" or "much" more comfortable with the procedure after attendance. To our knowledge, this is the first hospital-wide, standardized, simulation-based central line insertion course in the United States. Preliminary results indicate overwhelming satisfaction with the course, better ultrasound preparedness, and improved comfort with central line insertion. PMID- 28637553 TI - More Helmets Fewer Deaths: Motorcycle Helmet Legislation Impacts Traumatic Brain Injury-Related Mortality in Young Adults. AB - The aim of our study was to assess the impact of helmet legislations on the incidence and the mortality rate of motorcycle collision (MCC)-related traumatic brain injury (TBI) in young adult trauma patients. A 1-year (2011) retrospective analysis was performed of all patients under 21 years old with trauma-related hospitalization using the Nationwide Inpatient Sample database (representing 20% of all in-patient admissions). Patients with MCC were identified using E-codes. States were classified into three groups based on helmet legislations: universal age helmet legislation, <18 years helmet legislation, and <21 years helmet legislation. Outcome measures were the rates of TBI and mortality. Linear regression analysis was used to assess outcomes among the states. A total of 1,165,150 patients with trauma-related hospitalizations across 29 states were reviewed of which, 587 patients with MCC were included. Ten states had universal age legislation; 13 states had age <18 years legislation, and 6 states had age <21 years legislation. There was a lower incidence in the rate of TBI (P = 0.03) in states with universal helmet legislations compared with states with age restricted helmet legislation. Universal helmet legislations lowered the rate of MCC-related TBI injures by a factor of 2.15 (beta coefficient: 2.15; 95% confidence interval: 0.91-10.18; P = 0.04). States with age-restricted helmet legislations have a higher rate of traumatic brain injury and mortality compared with states with universal helmet legislations. Establishing universal helmet legislations across the states may provide a potential preventive strategy against traumatic brain injury. PMID- 28637554 TI - The G60 Trauma Center: A Future Consideration? AB - With a considerably increasing elderly population, we sought to determine whether the volume of elderly trauma patients treated impacted outcomes at two different Level I trauma centers. This is a retrospective review of all elderly patients (>60 years) at two state-verified Level I trauma centers over the past five years. The elderly trauma center (ETC) saw a greater proportion (52%) of elderly patients than the reference trauma center (30%, TC). Demographic and clinical characteristics were abstracted and stratified into ETC and TC groups for comparison. Primary outcomes were overall postinjury complication and mortality rates, as well as death after major complication (failure to rescue). ETC patients were older (78.6 vs 70.5), more likely to be admitted with severe head injuries (head abbreviated injury score >= 3, 50.0% vs 32%), had a greater overall injury burden (injury severity score > 16 41.4% vs 21.1%), and required intensive care unit admission (81.3% vs 64%) than the TC group. Need for operative intervention, mechanism of injury, and comorbidities were similar between the two groups. Overall complications were higher in trauma patients admitted to the TC (21.9% vs 14.3%), as well as failure to rescue (4.0% vs 1.8%). Adjusting for confounding factors, ETC had significantly lower chance of developing a postinjury complication (adjusted odds ratios [AOR] = 0.4, 95% confidence interval [CI] = [0.3, 0.5]), failure to rescue (AOR = 0.3, 95% CI = [0.1, 0.5]), and overall mortality (AOR = 0.3, 95% CI = [0.2, 0.4]). Improved outcomes were demonstrated in the Level I center treating a higher proportion of elderly patients. Exact etiology of these benefits should be determined for quality improvement in care of the injured geriatric patient. PMID- 28637555 TI - Overview of Nonoperative Blunt Splenic Injury Management with Associated Splenic Artery Pseudoaneurysm. AB - The delayed development of splenic artery pseudoaneurysm (SAP) can complicate the nonoperative management of splenic injuries. We sought to determine the utility of repeat imaging in diagnosing SAP in patients managed nonoperatively without angioembolization. We hypothesized that a significant rate of SAPs would be found in this population on repeat imaging. Patients undergoing nonoperative splenic injury management from January 2011 to June 2015 were queried from the trauma registry. Rates of repeat imaging, angioembolization, readmission, and SAP development were analyzed. Further, subanalyses investigating the incidence of SAP in patients managed nonoperatively without angioembolization were conducted. A total of 133 patients met inclusion criteria. Repeat imaging rate was 40 per cent, angioembolization rate was 26 per cent, and readmission rate was 6 per cent. Within the study population, nine SAPs were found (8/9 in patients with splenic injury grade >=III). Of these nine SAPs, three (33%) were identified on initial scans and embolized, whereas six (67%) were found on repeat imaging in patients not initially receiving angioembolization. Splenic injuries are typically managed nonoperatively without serious complications. Our results suggest patients with splenic injuries grade >=III managed nonoperatively without angioembolization should have repeat imaging within 48 hours to rule out the possibility of SAP. PMID- 28637556 TI - Pretrauma Functional Independence Measure Score Predicts Survival in Geriatric Trauma. AB - The Functional Independence Measure (FIM) is used by rehabilitation professionals to access disability. The FIM score combines both motor and cognitive parameters to assess a patient's level of required assistance in performing activities of daily living (ADL). The geriatric trauma patient is becoming an increasingly important cohort for trauma services. FIM has been shown to predict discharge outcomes and those at high risk for falls. We hypothesized pretrauma FIM scores may predict survival in the geriatric trauma population. This was a retrospective study of patients 65 years and older that were admitted to our Level I trauma center from July 1, 2006 to July 1, 2012. A total 941 patients underwent stepwise regression to identify those factors predicting survival. Age, Injury Severity Score, revised trauma score, body mass index, and pretrauma FIM scores (12-point scale) were studied. The primary outcome was survival. Statistical significance reached at P value <0.05. Multiple logistic regression analysis was then performed. A total of 1315 patients were identified and complete data were available on 941 patients. Mean age was 78 (SD +/- 8.2), mean Injury Severity Score was 13(SD +/- 8.7), and mean body mass index was 26. Overall mortality was 11 per cent. The odds ratio of survival was 3.532 (95% confidence interval = 2.191-5.718) times greater for every 1-point increase in the preadmission FIM expression score. Glasgow Coma Scale, revised trauma score, gender, and pretrauma FIM expression scores were predictive of survival in the geriatric trauma patient. Pretrauma FIM expression can be used to predict survival in the elderly trauma victim. Further study is needed to establish the role of FIM as part of trauma scoring systems. PMID- 28637557 TI - Nomogram-Derived Prediction of Postoperative Ileus after Colectomy: An Assessment from Nationwide Procedure-Targeted Cohort. AB - Postoperative ileus (POI) is a clinical burden to health-care system. This study aims to evaluate the incidence and predictors of POI in patients undergoing colectomy and create a nomogram by using recently released procedure-targeted nationwide database. Patients who underwent elective colectomy in 2012 and 2013 were identified from American College of Surgeons National Surgical Quality Improvement Program using the new procedure-targeted database. Demographics, comorbidities, and 30-day postoperative outcomes were evaluated. Variables in the final stepwise multiple logistic regression model for each outcome were selected in a stepwise fashion using Akaike's information criterion. A nomogram was created to aid in the calculation of POI risk for individual patients. A total of 29,201 patients met the inclusion criteria; 3834 (13.1%) developed POI with a male predominance (55.9%). Patients who developed ileus had longer length of hospital stay (11 vs 5 days; P < 0.001) and operative time (200 vs 174 minutes; P < 0.001). In the stepwise logistic regression model, the following variables were found to be independent risk factors for POI: older age (P < 0.001), male gender (P < 0.001), American Society of Anesthesiologists class III/IV (P < 0.001), open approach (P < 0.001), preoperative septic conditions (P < 0.001), omission of oral antibiotic before surgery (P < 0.001), right colectomy or total colectomy vs other procedures (P < 0.001), smoking (P = 0.001), decreased preoperative serum albumin level (P < 0.001), and prolonged operating time (P < 0.001). All postoperative complications were more frequently occurred in patients with POI. The nomogram accurately predicted POI with a concordant index for this model of 0.69. The use of minimal invasive techniques, control of preoperative septic conditions, oral antibiotic bowel preparation and shorter operative time are associated with a decreased rate of POI. External validation is essential for the confirmation and further evaluation of our logistic regression model and nomogram. PMID- 28637558 TI - Travel Time Influences Readmission Risk: Geospatial Mapping of Surgical Readmissions. AB - The University of Virginia (UVA) has recently become an Accountable Care Organization (ACO), intensifying efforts to provide better care for individuals. UVA's ACO population resides across the entire Commonwealth, with a large percentage of patients living in rural areas. To provide better health for this population, the central tenet of the ACO mission, we identified geographic risk factors influencing hospital readmission. We analyzed the relationship between the distance of patients' residence to the nearest hospital and 30-day readmission in general surgery patients. A retrospective chart review using January 1, 2011 through October 31, 2013 American College of Surgeons National Surgical Quality Improvement Program data for general surgery procedures was conducted. ArcGIS mapped street addresses provided graphical representation of distance between surgical population and the nearest hospital. We analyzed the impact on readmission, of time traveled, insurance status, and median household income. Each increase of 10 minutes in travel time from the patient's residence to the nearest hospital, not just UVA, was associated with a 9 per cent increase in the probability of readmission after adjusting for patient characteristics, preoperative comorbidities, laboratory values, and postoperative complications before or after discharge (odds ratio = 1.09; 95% confidence interval = 1.01 1.17; P = 0.019). Unlike urban hospitals, those serving rural populations may be at particular risk of postsurgical readmissions. Patients living furthest from a hospital facility are most at risk for readmission after a general surgery procedure. This vulnerable population may benefit most from comprehensive discharge planning. PMID- 28637559 TI - Complex Abdominal Wall Hernia Repair in Contaminated Surgical Fields: Factors Affecting the Choice of Prosthesis. AB - To compare patients with complex abdominal wall hernias undergoing surgical repair using synthetic nonabsorbable or biologic meshes in contaminated fields. Retrospective review of 62 patients with complex abdominal wall hernia with surgical repair in an elective setting and in the context of a clean-contaminated or contaminated fields (January 2009-April 2015). Two groups according to the prosthesis (synthetic nonabsorbable, n = 48 or biologic, n = 14). Mean follow-up was 24.6 (15.8) months. Clean-contaminated wounds were significantly more frequent in the synthetic group. Contaminated wounds were significantly more frequent in the biologic group. Enterocutaneous fistula, recurrent hernia, and removal of chronic infected mesh were significantly more frequently in the biologic group. Differences in postoperative complications and surgical site infections were not found. Recurrence was higher in the biologic group (35.7% vs 8.3%, P = 0.03). In the elective repair of complex hernia, the level of contamination, a recurrent hernia, an enterocutaneous fistula or removal of chronic infected mesh were the factors affecting the choice of prosthesis. In the clean-contaminated setting, the use of a synthetic nonabsorbable mesh versus a biologic mesh did not increase the rate of postoperative infections. Recurrences are significantly higher with biologic meshes. PMID- 28637560 TI - Despite Trauma Center Closures, Trauma System Regionalization Reduces Mortality and Time to Definitive Care in Severely Injured Patients. AB - The Northern Ohio Trauma System (NOTS), consisting of multiple hospital systems, was established in 2010 to improve trauma outcomes. This study assessed its impact on mortality and time to definitive care, focusing especially on the severely injured patients. NOTS trauma registry was queried for all trauma activations from 2008 to 2013. The years between 2008-2009 and 2011-2013 were designated as pre- and post-NOTS, respectively. Data from 2010 was excluded as a transitional year. Two trauma centers (TCs) closed in 2010. Predetermined patient subgroups were analyzed. A total of 27,843 patients were examined. Mean age was 46 and 64 per cent were male. Median Injury Severity Score (ISS) was five, and 87 per cent sustained blunt injuries. Of these, 10,641 patients were pre-NOTS and 17,202 were post-NOTS. Comparing the two groups, mortality decreased from 5 to 4 per cent post-NOTS (P < 0.001); median time to definitive care increased by 12 minutes post-NOTS. Multivariate logistic regression showed that NOTS implementation was an independent predictor for survival (P = 0.008), whereas time to definitive care was not. Subgroup analyses demonstrated mortality reductions post-NOTS for all subgroups except patients with penetrating injuries, where mortality remained the same despite an increase in ISS. Patients with ISS >=15 had a 23 per cent relative reduction in mortality, and their median time to definitive care decreased by 12 minutes. Implementation of a collaborative, regional trauma system was associated with mortality reduction and shortened time to definitive care in the severely injured patients. These findings highlight the importance of collaboration in the future development of regional trauma systems. PMID- 28637561 TI - Considering Postoperative Functional Hypoaldosteronism after Unilateral Adrenalectomy. AB - Conn's Syndrome is an uncommon condition. Patients who have undergone adrenalectomy in the early postoperative period can demonstrate biochemical hypoaldosteronism. Given the rare nature of this phenomenon we investigated its incidence and whether it translated to clinical findings. A single-institution retrospective review of all patients with biochemically proven hyperaldosteronism from 2005 to 2014 that underwent unilateral adrenalectomy. A total of 29 patients fit the inclusion criteria. Functional hypoaldosteronism had appreciated in 18/29 (62%) patients, whereas 11 patients (38%) had normal postoperative aldosterone. No significant differences between diagnostic groups were found in terms of clinical outcomes (length of stay, postoperative symptomatology, and readmissions P = 0.669, 0.154, and 0.268, respectively). Two (7%) patients required medical therapy. Biochemical evidence of functional hypoaldosteronism was identified in two-thirds of patients undergoing unilateral adrenalectomy. Although contralateral aldosterone suppression can be anticipated, the phenotypic response varied and the outcomes were similar to patients with normal aldosterone levels. Current guidelines make no formal recommendations for assessment of hypoaldosteronism after adrenalectomy, resulting in varying practice paradigms. Surgeons should consider the risk of postoperative hypoaldosteronism in these patients and counsel patients accordingly. Prospective investigations should be performed to assist in development of an outcomes-based care delivery model for these patients. PMID- 28637562 TI - IBD: A Growing and Vulnerable Cohort of Hospitalized Patients with Clostridium difficile Infection. AB - The most recent nationwide data show a rising incidence of Clostridium difficile infection in hospitalized patients with ulcerative colitis (UC). We describe recent national trends with regard to incidence, mortality, and the rate of total colectomy. The Nationwide Inpatient Sample database identified patients admitted to hospitals in the United States with diagnoses of C. difficile and inflammatory bowel disease (IBD) during the study years 2007 to 2013. We analyzed incidence of C. difficile, mortality, and colectomy rates. From 2007 to 2013, incidence of patients with IBD admitted with the primary diagnosis of C. difficile rose faster than the non-IBD population (1.24% to 2.14% vs 0.26% to 0.30%, P < 0.0001) and specifically in the UC population rose from 2.36 to 3.48 per cent (P < 0.001). The mortality of non-IBD patients with C. difficile decreased 47 per cent (3.76% to 1.99%, P = 0.003), whereas mortality of IBD patients with C. difficile decreased 54 per cent (6.08% to 2.79%, P = 0.003). For UC patients with primary diagnosis C. difficile, the percentage undergoing total colectomy decreased by 38 per cent (2.47% vs 1.51%, P = 0.049). The incidence of C. difficile continues to rise in the both the IBD and non-IBD population. Our study shows decreasing mortality for IBD and non-IBD patients with C. difficile but a greater decrease in mortality for IBD patients. PMID- 28637563 TI - Postoperative Neutrophil-to-Lymphocyte Ratio as a Predictor of Long-Term Prognosis after Pancreatectomy for Pancreatic Carcinoma: A Retrospective Analysis. AB - To clarify the prognostic value of the postoperative blood neutrophil-to lymphocyte ratio (NLR) in patients undergoing pancreatectomy for pancreatic carcinoma (PAC). A high preoperative NLR has been reported to be a predictor of poor survival in patients with various cancers including PAC. However, it has not been extensively examined in postoperative NLR after pancreatectomy for PAC. This retrospective study enrolled 86 patients who underwent pancreatectomy without preoperative therapy for PAC from 2005 to 2013. Clinicopathological parameters, including postoperative NLR, were evaluated to identify predictors of the overall and recurrence-free survival of patients after pancreatectomy. Univariate and multivariate analyses were performed, using the Cox proportional hazards model. Univariate and multivariate analyses showed that postoperative NLR at one month was an independent prognostic factor in the overall and recurrence-free survival of patients. The 3-year survival rate after pancreatectomy was as follows: 33.9 per cent in patients with a postoperative NLR of less than 3.0 at one month; and 7.3 per cent in those with a postoperative NLR of 3.0 or more at one month (P < 0.001). The overall survival rate after pancreatectomy in the NLR at one month >=3.0 group was significantly lower than in the NLR at one month <3.0 group: one year, 42.6 versus 81.9 per cent; three year, 7.3 versus 33.9 per cent (P < 0.001). The results of the study suggest that the postoperative NLR at one month is an independent predictor of survival after pancreatectomy in patients with PAC. PMID- 28637565 TI - Is Percutaneous Cholecystostomy a Good Alternative Treatment for Acute Cholecystitis in High-Risk Patients? AB - Cholecystectomy is the treatment of choice for acute cholecystitis but the management of high-risk surgical patients is a difficult dilemma. Percutaneous cholecystostomy (PC) could represent a safer and less invasive option. The aim of the study was to assess the outcomes of PC in high-risk patients. This is a retrospective single-center study; data were collected from our hospital electronic record system. From February 2009 to March 2014, there were 753 patients admitted with acute cholecystitis. Of these 39 were considered high risk for surgery and underwent PC during their hospital stay. The radiological approach was transperitoneal in 29 patients and transhepatic in 10 patients. Median follow-up was 19 months. There were 27 males (69.2%) and 12 females (30.8%) with a mean age of 72 years (range 41-90 years). Twenty-seven patients had PC as definitive treatment (group A) and 12 patients as a bridge to cholecystectomy (group B). There were no postprocedure complications. Five patients in group A were readmitted once with another episode of cholecystitis after PC (18.5%), one patient in group B was readmitted with cholecystitis after two years before proceeding to cholecystectomy, and two patients were readmitted after cholecystectomy (16.6%) for intra-abdominal collections treated with percutaneous radiological drainage. Seven patients died (17.9%) as a result of severe biliary sepsis during their index hospital admission. PC is a safe approach in high-risk patients with acute cholecystitis and can provide satisfactory long-term results when cholecystectomy is not a viable option. PMID- 28637564 TI - Do Iodine-Impregnated Adhesive Surgical Drapes Reduce Surgical Site Infections during Open Ventral Hernia Repair? A Comparative Analysis. AB - This study evaluated the role of iodine-impregnated adhesive drapes to reduce surgical site infections and occurrences in open ventral hernia repairs. All patients undergoing open ventral hernia repair of clean wounds with a retromuscular repair using synthetic mesh by a single surgeon were prospectively evaluated from the American Hernia Society Quality Collaborative. Patients were divided into those that had an Ioban drape and those that did not. The primary endpoints of this study were postoperative surgical site occurrence and infections. One hundred and four patients met inclusion criteria and were analyzed. There were 56 patients that received a 3MTM IobanTM drape and 48 patients did not. The two groups were similar based on baseline demographics, risk factors, and operative details. There were four (7%) surgical site occurrences in the Ioban group (one wound cellulitis, one superficial surgical site infection, one allergic reaction to the Ioban, and one sterile seroma). There was one (2%) surgical site occurrence in the non-Ioban group (one superficial wound dehiscence). For patients undergoing clean ventral hernia repair with synthetic mesh placed in the retrorectus plane, the use of an iodine impregnated drape does not result in a reduction in surgical site occurrences or superficial surgical site infections. PMID- 28637566 TI - Evolving Role of Hepatic Resection for Metastatic Urologic Malignancies. AB - Liver resection for noncolorectal, nonneuroendocrine metastases remains controversial. Here, we evaluate a single institutional experience with hepatic resection for metastatic urologic malignancies. A single-institution review of patients who underwent hepatic resection for metastatic urologic tumors between the years of 2000 and 2013 was performed. Patient charts were analyzed for pathologic data and perioperative outcomes including short- and long-term morbidity, mortality, and overall and disease-free survival. Eleven patients were identified who underwent hepatic resection for metastatic urologic malignancy. The mean age was 63.5 years. All patients had an R0 resection. There were three major complications. Mean length of stay was 6.5 days and there was no 90-day mortality. Three patients have died of recurrent disease at an average of 11.2 months from resection to death. The remaining patients are still alive during a mean follow-up of 31.5 months. Five-year overall and disease-free survival was 50 and 21 months, respectively. Hepatic resection for metastatic urologic tumors is safe with low morbidity and mortality and durable long-term survival can be achieved. Liver resection for isolated hepatic disease should be considered for this rare metastatic disease to the liver. PMID- 28637568 TI - Disparities in the Age-Related Rates of Colorectal Cancer in the United States. AB - The incidence of colorectal cancer (CRC) among Americans under the age of 50 years is increasing. The purpose of this study was to identify racial and socioeconomic disparities associated with this trend. The National Cancer Data Base was used to identify patients with CRC from 1998 to 2011. Patients were stratified by age (<50 versus >60 years), with ages 50 to 60 years omitted from the analysis to minimize overlapping trends between the two age groups. Relative frequencies (RFs) by year were plotted against demographic variables. Changes in RF over time and intervals from diagnosis to treatment (including surgery and chemotherapy) were compared. A total of 1,213,192 patients were studied; 885,510 patients with colon cancer and 327,682 with rectal or rectosigmoid cancer. Patients <50 years had higher RF for stage III/IV CRC compared with >60 years, with the highest rate of increase in stage III colon cancer (0.198% per year). Patients <50 years had higher RF for CRC if they were African-American or Hispanic. Hispanic patients <50 years had the highest rates of increase for both colon (RF = 0.300% per year) and rectal cancer (RF = 0.248% per year). Compared with race, other variables including education and income were not found to have as strong an association on age-related rates of CRC. No clinically significant differences were observed for time from diagnosis to treatment in either age group. Important racial disparities are associated with differences in age related CRC rates, warranting further investigation to develop improved strategies for the earlier detection of CRC in these populations. PMID- 28637567 TI - The Impact of Early Recurrence on Quality of Life after Cytoreduction with HIPEC. AB - Improved oncological outcomes after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in highly selected patients have been well documented. The extensive nature of the procedure adversely affects quality of life (QoL). The aim of this study is to longitudinally evaluate QoL following CRS/HIPEC. This is a retrospective review of a prospectively maintained database of patients with peritoneal malignancies undergoing CRS/HIPEC. Clinicopathological data, oncologic outcomes, and QoL were analyzed preoperatively and postoperatively at 2 weeks, and 1, 3, 6, and 12 months. The Functional Assessment of Cancer Therapy-Colorectal instrument was used to determine changes in QoL after CRS/HIPEC and the impact of early recurrence (<12 months) on QoL. Thirty-six patients underwent CRS/HIPEC over 36 months. The median peritoneal cancer index score was 18 and the completeness of cytoreduction 0/1 rate was 97.2 per cent. Postoperative major morbidity was 16.7 per cent with one perioperative death. Disease-free survival was 12.6 months in patients with high-grade tumors versus 31.0 months in those with low-grade tumors (P = 0.03). QoL decreased postoperatively and improved to baseline in six months. Patients with early recurrence had a decrease in global QoL compared with preoperative QoL at 6 (P < 0.03) and 12 months (P < 0.05). This correlation was not found in patients who had not recurred. Patients who undergo CRS/HIPEC have a decrease in QoL that plateaus in 3 to 6 months. Early recurrence adversely impacts QoL at 6 and 12 months. This study emphasizes the importance of patient selection for CRS/HIPEC. The expected QoL trajectory in patients at risk for early recurrence must be carefully weighed against the potential oncological benefit of CRS/HIPEC. PMID- 28637569 TI - Assessing Field Triage Decisions and the International Classification Injury Severity Score (ICISS) at Predicting Outcomes of Trauma Patients. AB - Florida considers the International Classification Injury Severity Score (ICISS) from hospital discharges within a geographic region in the apportionment of trauma centers (TCs). Patients with an ICISS <0.85 are considered to require triage to a TC, yet many are triaged to an emergency department (ED). We assess outcomes of those with an ICISS <0.85 by the actual triage decision of emergency medical services (EMS). From October 2011 to October 2013, 39,021 consecutive admissions with injury ICD-9 codes were analyzed. ICISS was calculated from the product of the survival risk ratios for a patient's three worst injuries. Outcomes were compared between patients with ICISS <0.85 either triaged to the ED or its separate, neighboring, free-standing TC at a large urban hospital. A total of 32,191 (83%) patients were triaged to the ED by EMS and 6,827 (17%) were triaged to the TC. Of these, 2544 had an ICISS <0.85, with 2145 (84%) being triaged to the TC and 399 (16%) to the ED. In these patients, those taken to the TC more often required admission, and those taken to the ED had better outcomes. When the confounders influencing triage to an ED or a TC are eliminated, those triaged by EMS to the ED rather than the TC had better overall outcomes. EMS providers better identified patients at risk for mortality than did the retrospective application of ICISS. ICISS <0.85 does not identify the absolute need for TC as EMS providers were able to appropriately triage a large portion of this population to the ED. PMID- 28637570 TI - Risk Factors that Predict Recurrent Clostridium difficile Infections in Surgical Patients. AB - Clostridium difficile (C. difficile) infection (CDI) is a serious problem mostly studied during patients' index infections. The aim of this study is to define the incidence of primary and recurrent postoperative (postop) CDI in a single institution's entire surgical population and to identify risk factors that influence disease recurrence. Using electronic medical records from 2002 to 2012, charts were reviewed from all patients with laboratory-proven (enzyme-linked immunosorbent assay or polymerase chain reaction methods) C. difficile-positive stool samples. Index postop CDI was defined as a positive C. difficile assay (CDA) within 30 days of surgery and recurrence was defined as a positive CDA within 30 days of any surgery in a patient with a previously documented positive CDA. Patient demographics, surgical diagnoses, and laboratory data were recorded. Approximately 342,000 surgeries were performed in the study period with a 0.6 per cent (2188 patients) incidence of index postop CDI. Patients undergoing musculoskeletal surgery had the highest recurrent CDI rate [odds ratio (OR) 3.09 (1.47-6.49), P = 0.003]. Use of any steroid (OR 2.45 [1.43-4.20], P = 0.002) or other immunosuppressant (OR 2.64 [1.09-6.38], P = 0.011) within six months of surgery was associated with an increased risk of the development of a recurrent CDI. Across surgical specialties at our institution, postop index CDI is low and patients have about a 5-fold increased risk for developing recurrent CDI. Patients undergoing musculoskeletal surgery are at greater risk for CDI recurrence and younger age, use of steroids and immune modulators, and surgery by organ system are independent risk factors for a recurrent CDI. PMID- 28637571 TI - Workforce Issues in Pediatric Surgery. AB - High salaries indicate a demand for pediatric surgeons in excess of the supply, despite only a slight growth in the pediatric-age population and a sharp increase in numbers of trainees. Top-level neonatal intensive care units require 24-hour-7 day pediatric surgical availability, so hospitals are willing to pay surgeons a premium and engage high-priced locum tenens surgeons to fill vacancies in coverage. With increased supply comes an erosion of the numbers of cases performed by trainees and surgeons in practice. Caseloads may be inadequate to gain expertise and maintain skills. A quality initiative sponsored by the American College of Surgeons and the American Pediatric Surgical Association will discourage underresourced community facilities and surgeons without specialty training from performing operations on children, mostly common conditions such as appendicitis. This will further increase demand for specialty-trained practitioners. Receiving less attention are considerations of value, the ratio of quality per dollar cost. Cost concerns, paramount among buyers of health care (businesses, insurance companies, and governmental health agencies), will prefer community hospitals that have lower cost structures than specialty children's facilities. Less recognized are the costs to families, who for a myriad of reasons would prefer closer alternatives. Cost considerations support providing pediatric surgical services in local facilities. Quality considerations may be addressed by a tiered system where top centers would care for conditions that require technical expertise and advanced modalities. Evidence indicates that pediatric surgeons already direct such cases to more specialized centers. PMID- 28637572 TI - Investigating Cyclooxygenase Inhibition in a Rat Pulmonary Contusion Model: A Laboratory Study Finding No Improvement with Ibuprofen. AB - Minimal advances have been made in the management of pulmonary contusions (PCs). The purpose of this study was to evaluate the impact of cyclooxygenase inhibition on outcomes following PC in a rat model. PC was induced in anesthetized adult rats. Ibuprofen was given to the treatment group (TG) and water was given to the control group (CG). Lung injury was assessed with pulse oximetry, arterial blood gases, CT, and histopathologic examination. Inflammation was measured with both serum and bronchoalveolar lavage (BAL) levels of tumor necrosis factor alpha and interleukin-6. Rats in the TG did not differ from rats in the CG with respect to oxygenation. Pathologic examination demonstrated a trend toward more inflammatory infiltrate in the CG, yet the sizes of the contusions were larger in the TG. The CG trended toward decreased levels of interleukin-6 in the serum and BAL at both three and seven days. While BAL levels of tumor necrosis factor alpha were increased in the TG at three days compared to the CG, they trended toward a reduced amount at seven days. Our data do not support cyclooxygenase inhibition for treatment to decrease the respiratory compromise associated with PC in this model of rat PCs. PMID- 28637573 TI - Laparoscopic Appendectomy Protocol Expedites Management of Uncomplicated Acute Appendicitis. AB - Bed availability remains a constant struggle for tertiary care centers resulting in the use of management protocols to streamline patient care and reduce length of stay (LOS). A standardized perioperative management protocol for uncomplicated acute appendicitis (UA) was implemented in April 2014 to decrease both CT scan usage and LOS. Patients who underwent laparoscopic appendectomy for UA from April 2012 to May 2013 (PRE group) and April 2014 to May 2015 (POST group) were compared retrospectively. There were no differences in patient demographics or clinical findings between the groups. All patients in the PRE group had a CT scan for the diagnosis of appendicitis, whereas there was a 14 per cent decrease in the POST group (P = 0.002). There was a significant decrease in median LOS between the groups [PRE 1.3 vs POST 0.9 days; (P < 0.001)]. There was no difference in subsequent emergency department visits for complications [3 (4%) vs 4 (4%); P = 1.0] or 30-day readmission rate [1 (1%) vs 5 (5%); P = 0.22] between the groups. A standardized perioperative management protocol for UA patients significantly decreased CT scan utilization and LOS without compromising patient care. PMID- 28637575 TI - Credentialing and Privileging of Pharmacists: A Resource Paper from the Council on Credentialing in Pharmacy. AB - This Resource Paper has been made available elsewhere in the American Journal of Health-Systems Pharmacy Volume 71(21), pp.1891-1900 (November 2014) and has an original DOI of 10.2146/ajhp140420. PMID- 28637574 TI - Perforated Colonic Diverticula Presenting as Periorbital and Cervical Subcutaneous Emphysema. PMID- 28637576 TI - Antimicrobial Use and Resistance in Australia (AURA) surveillance system: coordinating national data on antimicrobial use and resistance for Australia. AB - Objective The aim of the present study was to describe the process of establishment and coordination of the national Antimicrobial Use and Resistance in Australia (AURA) surveillance system. Methods Existing surveillance programs conducted by health organisations at state or multi-jurisdictional levels were reviewed, and gaps and opportunities identified for the development of a national system. In view of the time frame available as part of the Australian Government Department of Health funding agreement, the strategy used by the Australian Commission on Safety and Quality in Health Care was to commence work with existing surveillance programs, expanding and enhancing them and developing new systems where gaps were identified. Using the specifications of the AURA national system, the data from each of these elements were then analysed and reported. The system provides coverage for the acute and community sectors for antimicrobial use and antimicrobial resistance. Results The AURA surveillance system integrates eight streams of surveillance activities, including passive and targeted surveillance of antimicrobial use and resistance from hospitals (public and private) and the community (general practitioners and aged care homes). A gap was identified in timely surveillance of critical antimicrobial resistances (CARs), which resulted in the development of the national CARAlert system. The first comprehensive analyses of data across the surveillance programs was published in June 2016, providing baseline data for future reports to build on. Conclusion The AURA surveillance system has established the framework and foundation systems for an integrated and comprehensive picture of both antimicrobial use and resistance in Australia over time. National coordination and support will improve data collection, standardisation and analysis, and will facilitate collaboration across the states and territories, the Australian Government and the private sector. AURA publications will inform policy development and clinical decision making and improve consumer awareness of antimicrobial use and resistance. The system will continue to develop as a comprehensive system, with additional data over time, and appropriate clinical and epidemiological review. What is known about this topic? Surveillance of antimicrobial use and resistance is critical to inform effective policy development and public health responses to the growing problem of antimicrobial resistance. Until now, surveillance of antimicrobial use and resistance in Australia has been fragmented, with state and territory and professional group differences in data collection, analysis and reporting. What does this paper add? This paper profiles the development of the AURA surveillance system, the first nationally coordinated surveillance system for antimicrobial use and resistance, and its use of a partnership approach with contributing programs in order to promote participation and to obtain data to inform strategies to prevent and contain antimicrobial resistance. This paper highlights the establishment phase, noting that the system continues to be improved with growing participation from all sectors. What are the implications for practitioners? National surveillance data from the AURA surveillance system provides evidence for action to guide improvements in infection control, antimicrobial prescribing and the prevention and control of antimicrobial resistance across all healthcare sectors. It will also enable trends to be identified and reported on, and have the capability of determining the effect of interventions to improve and rationalise antimicrobial prescribing. PMID- 28637577 TI - Physiotherapists' perceptions of workplace competency: a mixed-methods observational study. AB - Objectives Workplace-based competency is increasingly considered fundamental to patient safety and quality healthcare. The aim of the present study was to identify and describe physiotherapists' perceptions of workplace competency.Methods The present study was a mixed-methods cross-sectional observational study. Thematic and descriptive analysis of qualitative and survey data were undertaken. Forty-six physiotherapists employed at a metropolitan acute public hospital participated in interviews or focus groups; a subgroup of 31 participants also completed an online survey.Results Five main themes were identified: (1) despite the availability of workplace learning opportunities and supports, less-experienced staff reported limited confidence; (2) assessment and feedback around workplace competency was limited, predominantly informal and unstructured, with less than half of the cohort (42%) agreeing feedback received was useful for improving their workplace skills; (3) practicing within individual scope is an important aspect of workplace competency as a physiotherapist; (4) most (81%) agreed it was important for them to self-determine their learning and development goals, and they relied primarily on informal discussion to achieve these goals; and, (5) physiotherapists felt motivated regarding workplace learning, with 97% interested in developing their workplace skills however, nearly half (45%) did not feel they had sufficient time to do so.Conclusions The perceptions of physiotherapists working in a metropolitan acute public hospital are reflected in five themes. These themes elucidate how workplace competency is supported, maintained and developed among physiotherapists in this setting. These themes also highlight key challenges of workplace learning faced by this cohort of physiotherapists and allude to methods that may assist with improving feedback mechanisms and knowledge acquisition.What is known about this topic? Studies investigating employee perceptions around workplace competency, knowledge, skills and learning are found across a range of industries. Workplace-based competency is increasingly considered fundamental to patient safety and quality health care. There is little known about physiotherapists' perceptions of workplace competency.What does this paper add? This study has identified and described themes around physiotherapists' perceptions of their workplace knowledge and skills.What are the implications for practitioners? The themes identified provide support for the development, implementation and evaluation of a workplace-based competency framework for physiotherapists. PMID- 28637578 TI - Clinical activity profile of preregistration physiotherapy students during clinical placements. AB - Objective The aim of the present study was to determine the clinical activity profile of preregistration physiotherapy students during clinical placements and their clinical activity contribution to health service delivery.Methods Clinical activity data for 2014 were obtained from five Queensland public sector hospitals providing preregistration physiotherapy students clinical education in three key clinical areas (cardiorespiratory, musculoskeletal and neurological) over four 5 week placement blocks. Data regarding the number of student occasions of service (OOS) and the length of the OOS (LOOS) were collected to determine the average OOS and LOOS per student in each clinical area.Results Twenty weeks of student data were collected from each hospital in each clinical area, representing 29.1% of cardiorespiratory, musculoskeletal and neurorehabilitation student placements. Students completed 19051 OOS. The average OOS per student per block for cardiorespiratory, musculoskeletal and neurorehabilitation placements was 98.3, 74.0 and 72.4 respectively. Two-way ANOVA revealed a main effect of weeks (F=402.1, P<0.001) and clinical area (F =1331.5, P<0.001) for LOOS.In addition, an interaction was found between clinical placement week and clinical area for LOOS (F=8.4, P<0.001).Conclusions Student clinical activity data are useful for understanding the student contribution to health services. Student contribution appears to increase throughout the clinical placement and consideration should be given to the clinical educator:student ratio to enhance overall student contribution.What is known about the topic? Quantitative data describing physiotherapy student clinical care activity during placements are limited.What does this paper add? This paper profiles physiotherapy student clinical care activity and the changes occurring over 5-week placements.What are the implications for practitioners? Physiotherapy students provide clinical activity for health services that changes over their 5-week placement. Student clinical activity should be considered when responding to placement demand and planning service delivery. PMID- 28637579 TI - Abortion: findings from women and men participating in the Understanding Fertility Management in contemporary Australia national survey. AB - : Background There are few reliable Australian abortion data. The aim was to investigate prevalence, sexual experiences and socioeconomic characteristics of women and men who report having had or being a partner in an abortion. METHODS: A cross-sectional survey of women and men aged 18-50 years randomly selected from the Australian Electoral Roll was used. Weighted multivariable analyses were conducted. RESULTS: Data from 2235 returned (of 15480) mailed surveys were analysed. One in six women and one in 10 men had experienced or been a partner in an abortion. In adjusted analyses, for women, experience of sexual coercion [adjusted odds ratio (AOR) 2.18, 95% confidence interval (CI) 1.46, 3.24] was associated with significantly increased odds of abortion, and socioeconomic advantage (AOR=0.57; 95% CI 0.39, 0.84), being comfortable negotiating contraceptive use (AOR 0.26; 95% CI 0.09, 0.73) and importance of religion in fertility choices (AOR=0.55; 95% CI 0.35, 0.87) were associated with significantly reduced odds. For men, sexual coercion (AOR=3.05; 95% CI 1.51, 6.18) and metropolitan residence (AOR=1.70; 95% CI 1.06, 2.75) significantly increased the odds of reporting being a partner in an abortion. CONCLUSIONS: The findings contribute to scarce information about abortion in Australia. The high prevalence of abortion suggests that effective contraceptive counselling and accessible contraception services are not sufficient, and that there is a continuing need for universal pregnancy advice and abortion services. The association between sexual coercion and abortion warrants further investigation. PMID- 28637580 TI - Association between sexually transmissible infection testing, numbers of partners and talking to partners and friends about sexual health: survey of young adults. AB - : Background Young adults, aged 18-30 years, comprise the largest proportion of sexually transmissible infection (STI) notifications in Australia compared with other age groups. Understanding the influence of partner and friendship networks on their STI testing practices may enhance health promotion efforts to increase testing for this group. METHOD: Participants aged 21-30 years, living in Australia for >=3 years, were recruited within nightlife precincts in Melbourne, Australia. They completed a survey on demographic items, sexual health attitudes, sexual health knowledge and STI testing experiences and perceptions. Responses to items related to talking to partners and friends about STI testing were allocated partner and friend communication scores. Analyses included chi2 tests of independence and independent sample t-tests. RESULTS: Overall, 36.5% (61/167) of participants had tested for STIs in the previous 12 months. Of those who had tested for STIs, most had significantly higher numbers of sexual partners in the same period (P<0.05), and were significantly more likely to have felt at risk of STI acquisition (P<0.05). Significantly greater mean partner and friend communication scores were associated with higher numbers of sexual partners, feeling at risk of STIs, and testing for STIs in the previous 12 months (all P<0.05). There were no significant differences when participants were stratified by gender or age. CONCLUSION: Talking to partners and friends about STI testing is associated with testing rates for young adults. Feeling at risk and increased numbers of sexual partners may be associated with the promotion of STI testing among friends and partners. PMID- 28637581 TI - How partnership type and HIV seroconcordance affect HIV transmission risk in regular sexual partnerships: a cross-sectional survey of Australian gay and bisexual men. AB - : Background Regular sexual partnerships among gay and bisexual men (GBM) who practice condomless anal intercourse (CLAI) have not been well characterised in terms of partnership type, HIV seroconcordance and risk of HIV transmission. Primarily sexual regular partnerships, although commonly reported by gay men, have largely been ignored in research and HIV prevention. Among regular partners reporting CLAI with each other, we determined factors differentiating romantic or committed relationships from partnerships organised primarily around sex ('fuckbuddies') and estimated the proportion of CLAI presenting risk for HIV transmission. METHODS: An online, cross-sectional survey of Australian GBM was conducted. Univariate and multivariate generalised estimating equations were used to determine statistical associations. RESULTS: Men reported on 2250 regular sexual partnerships. Over half the partnerships were romantic or committed relationships. Over half the partnerships were HIV-negative seroconcordant (54.9%), 3.1% were HIV-positive seroconcordant, 5.2% were serodiscordant and 36.8% were of unknown seroconcordance. Potential risks presented by CLAI were sometimes mitigated by protective factors, such as having a clear spoken agreement about sex with outside partners, having fewer outside partners, openly discussing HIV risk and having an agreement to reduce risk from outside partners. These protective factors were more often found in romantic or committed relationships than among primarily sexual partnerships, and were less often found in partnerships of unknown seroconcordance. CONCLUSION: CLAI is more common among regular sexual partnerships considered to be of a romantic, committed nature. However, factors associated with such romantic or committed partnerships can also protect against HIV transmission risk. Unknown seroconcordance, particularly lack of communication about HIV status among primarily sexual partnerships, is a key risk factor that needs to be addressed by HIV education. PMID- 28637582 TI - Principles of capacity management, applied in the mental health context. AB - Objective The aim of the paper was to describe a suite of capacity management principles that have been applied in the mental health setting that resulted in a significant reduction in time spent in two emergency departments (ED) and improved throughput.Methods The project consisted of a multifocal change approach over three phases that included: (1) the implementation of a suite of fundamental capacity management activities led by the service and clinical director; (2) a targeted Winter Demand Plan supported by McKinsey and Co.; and (3) a sustainability of change phase. Descriptive statistics was used to analyse the performance data that was collected through-out the project.Results This capacity management project has resulted in sustained patient flow improvement. There was a reduction in the average length of stay (LOS) in the ED for consumers with mental health presentations to the ED. At the commencement of the project, in July 2014, the average LOS was 20.5h compared with 8.5h in December 2015 post the sustainability phase. In July 2014, the percentage of consumers staying longer than 24h was 26% (n=112); in November and December 2015, this had reduced to 6% and 7 5% respectively (less than one consumer per day).Conclusion Improving patient flow is multifactorial. Increased attendances in public EDs by people with mental health problems and the lengthening boarding in the ED affect the overall ED throughput. Key strategies to improve mental health consumer flow need to focus on engagement, leadership, embedding fundamentals, managing and target setting.What is known about the topic? Improving patient flow in the acute sector is an emerging topic in the health literature in response to increasing pressures of access block in EDs.What does this paper add? This paper describes the application of a suite of patient flow improvement principles that were applied in the mental health setting that significantly reduced the waiting time for consumers in two EDs.What are the implications for practitioners? No single improvement will reduce access block in the ED for mental health consumers. Reductions in waiting times require a concerted, multifocal approach across all components of the acute mental health journey. PMID- 28637583 TI - The Revised Trauma Score plus serum albumin level improves the prediction of mortality in trauma patients. AB - INTRODUCTION: The Revised Trauma Score (RTS) is used worldwide in prehospital practice and in the emergency department (ED) settings to triage trauma patients. The main purpose of this study was to evaluate the value of the RTS plus serum albumin (RTS-A) and to compare it with other existing trauma scores as well as to compare the predictive performance of the Trauma and Injury Severity Score with the RTS-A (TRISS-A) with the original TRISS. METHODS: This was a single center, trauma registry based observational cohort study. Data were collected from consecutive patients with blunt or penetrating injuries who presented to the emergency department of a tertiary referral hospital, between January 2012 and June 2016. 3145 and 2447 patients were assigned to the derivation group and validation group, respectively. Main outcome was in-hospital mortality. RESULTS: Among patients in the derivation group, the median [interquartile range] age was 59 [43-73] years, and 66.7% were male. The area under the receiver operating characteristic curves (AUC) of the RTS-A (0.948; 95% CI: 0.939-0.955) was higher than that of the RTS (0.919; 95% CI: 0.909-0.929). In patients with blunt trauma, the AUC of the TRISS-A (0.960; 95% CI: 0.952-0.967) was significantly higher than that of the original TRISS (0.949; 95% CI: 0.941-0.957). CONCLUSION: The value of the RTS-A predicts the in-hospital mortality of trauma patients better than the RTS, and the TRISS-A is a better mortality predictor compared to the original TRISS in patients with blunt trauma. PMID- 28637584 TI - Decreased TIM-3 expression of peripheral blood natural killer cells in patients with severe aplastic anemia. AB - Severe aplastic anemia (SAA) is an autoimmune disease characterized by severe pancytopenia and bone marrow failure. In our previous studies, we found natural killer (NK) cells were aberrant in SAA patients. T cell immunoglobulin mucin-3 (TIM-3), an important regulator of immunity, is widely detected on NK cells and may contribute as a marker of activation and maturation of NK cells. In this study, we found that SAA untreated patients had lower TIM-3 expression on NK cells and CD56dim NK subsets compared with normal controls, and were correlated with the severity of pancytopenia of SAA. After immunosuppressive therapy (IST), TIM-3 expression recovered to normal level. Moreover, the TIM-3 mRNA levels in NK cells significantly increased in SAA remission patients after IST. We inferred that low expression of TIM-3 on NK cells might lead to NK cells dysfunction and involve in the progress of bone marrow failure in SAA. PMID- 28637585 TI - Effects of periodontal endoscopy on the treatment of periodontitis: A systematic review and meta-analysis. AB - BACKGROUND: For this systematic review, the authors evaluated and synthesized the available scientific evidence related to the effects of periodontal endoscopy on the treatment of periodontitis. METHODS: The authors searched PubMed, Embase, Cochrane Library, Chinese Scientific Journals database, China National Knowledge Infrastructure, and Chinese Medicine Premier's Wanfang database for articles about periodontal endoscopy that were published through January 2017. The authors considered the percentage of residual calculus, average treatment time, bleeding on probing (BOP), gingival inflammation (GI), and probing depth (PD) as outcome measures. The authors extracted data and performed meta-analyses for groups of articles for which it was appropriate. RESULTS: The authors identified 8 articles as being suitable for this systematic review. The investigators of 3 studies reported results related to BOP and GI that revealed some advantages of periodontal endoscopy over traditional scaling and root planing (SRP). The investigators of 4 studies explored PD and found no difference between periodontal endoscopy and traditional SRP. The authors could not perform meta analyses on the study results related to BOP, GI, or PD. The percentage of residual calculus after periodontal endoscope-aided debridement was significantly less than the percentage of residual calculus after traditional SRP (mean difference, -3.18; 95% confidence interval, -4.86 to -1.49; P = .002; heterogeneity I2 = 74%). The authors found that periodontal endoscopy took significantly more time than traditional SRP (mean difference, 6.01 minutes; 95% confidence interval, 4.23 to 7.8; P < .00001; heterogeneity I2 = 0%). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Periodontal endoscopy may provide additional benefits for calculus removal compared with traditional SRP, although it could take more time to perform. With respect to BOP, GI, and PD, the authors found no sufficient evidence to support the difference between the use of periodontal endoscopy and traditional SRP. The authors concluded that additional scientific research is required to assess the effects of periodontal endoscopy on the treatment of periodontitis. PMID- 28637586 TI - Soluble LR11 associates with aortic root calcification in asymptomatic treated male patients with familial hypercholesterolemia. AB - BACKGROUND AND AIMS: Despite statin treatment, a high prevalence of severe vascular calcification is found in patients with familial hypercholesterolemia (FH). We assessed the relation between the circulating soluble form of low density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11), a risk factor for cardiovascular disease, and vascular calcification in asymptomatic statin-treated heterozygous FH patients. METHODS: In 123 asymptomatic heterozygous FH patients (age 40-69 years), aortic root (ARC), aortic valve (AVC) and coronary artery calcification (CAC) were determined with CT-based calcium scoring expressed in Agatston units. Plasma sLR11 levels were measured by sandwich ELISA. RESULTS: Seventy-three patients displayed ARC, 48 had AVC and 96 CAC. Plasma sLR11 levels were positively correlated with the presence of ARC (r = 0.2, p = 0.03), but not with AVC or CAC. The correlation between sLR11 levels and ARC was restricted to male FH patients (r = 0.31, p = 0.006). Multivariate logistic analyses showed that the association of plasma sLR11 with the presence of ARC was independent of other determinants (Adjusted Odds Ratio, 2.01 (95% CI = 1.28-3.16) p = 0.002). CONCLUSIONS: Plasma sLR11 is associated with ARC in male FH patients and may be mechanistically involved in the differential distribution of atherosclerotic lesions in the vasculature. PMID- 28637587 TI - Comparative study on secretome and transmembranome of immature and mature metacestodes of Echinococcus multilocularis. AB - Alveolar echinococcosis (AE) is a worldwide zoonosis caused by E. multilocularis. Humans become infected through oral ingestion of the eggs. Host of E. multilocularis produces immune responses that help to either reject and/or limit the growth of this parasite, and in response the parasite produces molecules against this immune attack. This study identifies candidate key molecules in the early infection phase and the chronic stage of the parasite infestation, through comparison of gene expression of 4- and 16-week metacestodes. First, RNA was isolated from 4- and 16-weeks metacestodes of E. multilocularis (Nemuro strain). Thereafter, clean reads with lengths of 50bp or longer were compared against a reference genome using TopHat. Functional annotation of transcripts of E. multilocularis were investigated using multi-step bioinformatics tools. At the gene ontology (GO) level, 356 and 1774 transmembrane (TM) predicted proteins of the E. multilocularis were mapped to an enhanced 'hydrolase activity' and increased 'transmembrane transporter activity', respectively. In addition, comparison of gene expression level between 4- and 16-week metacestode revealed 168 different expression (DE) genes. This study has demonstrated that, the expression levels of predicted ES and TM proteins in E. multilocularis change in the transformation from one stage to another. Genes that are highly expressed in immature or mature metacestode could be explored as novel candidates for diagnostic antigens and vaccine targets. PMID- 28637588 TI - Is artificial neural network an ideal modelling technique? PMID- 28637589 TI - Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy. AB - IgA nephropathy (IgAN), a frequent cause of chronic kidney disease worldwide, is characterized by mesangial deposition of galactose-deficient IgA1-containing immune complexes. Complement involvement in IgAN pathogenesis is suggested by the glomerular deposition of complement components and the strong protection from IgAN development conferred by the deletion of the CFHR3 and CFHR1 genes (DeltaCFHR3-CFHR1). Here we searched for correlations between clinical progression and levels of factor H (FH) and FH-related protein 1 (FHR-1) using well-characterized patient cohorts consisting of 112 patients with IgAN, 46 with non-complement-related autosomal dominant polycystic kidney disease (ADPKD), and 76 control individuals. Patients with either IgAN or ADPKD presented normal FH but abnormally elevated FHR-1 levels and FHR-1/FH ratios compared to control individuals. Highest FHR-1 levels and FHR-1/FH ratios are found in patients with IgAN with disease progression and in patients with ADPKD who have reached chronic kidney disease, suggesting that renal function impairment elevates the FHR-1/FH ratio, which may increase FHR-1/FH competition for activated C3 fragments. Interestingly, DeltaCFHR3-CFHR1 homozygotes are protected from IgAN, but not from ADPKD, and we found five IgAN patients with low FH carrying CFH or CFI pathogenic variants. These data support a decreased FH activity in IgAN due to increased FHR 1/FH competition or pathogenic CFH variants. They also suggest that alternative pathway complement activation in patients with IgAN, initially triggered by galactose-deficient IgA1-containing immune complexes, may exacerbate in a vicious circle as renal function deterioration increase FHR-1 levels. Thus, a role of FHR 1 in IgAN pathogenesis is to compete with complement regulation by FH. PMID- 28637590 TI - Evaluation of readmissions due to surgical site infections: A potential target for quality improvement. AB - INTRODUCTION: Readmissions have become a focus of pay-for-performance programs. Surgical site infections (SSI) are the reason for most readmissions. Readmissions for SSI could be a unique target for quality improvement. METHODS: Readmission risk for SSI were evaluated for patients undergoing colectomies from 2013 to 2014. Hazard models were developed to examine factors associated with and hospital-level variation in risk-adjusted rates of readmission for SSI. RESULTS: Among 59,088 patients at 525 hospitals, the rate of readmissions for SSI ranged from 1.45% to 6.34%. Characteristics associated with a greater likelihood of SSI readmissions include male gender, smoking, open surgery and hospitals with increased socioeconomically-disadvantaged patients. After risk adjustment, there was little correlation between hospital performance with SSI readmission rate and performance with overall SSI or total readmission rate (r2 = 0.29, r2 = 0.14). CONCLUSIONS: Readmission for SSI represents a unique aspect of quality beyond that offered by measuring only SSI or readmission rates alone, and may provide actionable quality improvement. PMID- 28637591 TI - Salicylate-induced frequency-map reorganization in four subfields of the mouse auditory cortex. AB - Salicylate is the active ingredient in aspirin, and in high-doses it is used as an experimental tool to induce transient hearing loss, tinnitus, and hyperacusis. These salicylate-induced perceptual disturbances are associated with tonotopic map reorganization and neural activity modulation, and such neural correlates have been examined in the central auditory pathway, including the auditory cortex (AC). Although previous studies have reported that salicylate induces increases in noise-burst-evoked neural responses and reorganization of tonotopic maps in the primary AC, little is known about the effects of salicylate on other frequency-organized AC subfields such as the anterior auditory, secondary auditory, and dorsomedial fields. Therefore, to examine salicylate-induced spatiotemporal effects on AC subfields, we measured sound-evoked neural activity in mice before and after the administration of sodium salicylate (SS, 200 mg/kg), using flavoprotein auto-fluorescence imaging. SS-treatment gradually reduced responses driven by tone-bursts with lower (<=8 kHz) and higher (>=25 kHz) frequencies over 3 h, whereas evoked responses to tone-bursts within middle-range frequencies (e.g., 12 and 16 kHz) were sustained and unchanged in the four subfields. Additionally, in each of the four subfields, SS-treatment induced similar reorganization of tonotopic maps, and the response areas selectively driven by the middle-range frequencies were profoundly expanded. Our results indicate that the SS-induced tonotopic map reorganizations in each of the four AC subfields were similar, and only the extent of the activated areas responsive to tone-bursts with specific frequencies was subfield-dependent. Thus, we expect that examining cortical reorganization induced by SS may open the possibility of new treatments aimed at altering cortical reorganization into the normative functional organization. PMID- 28637592 TI - Personalized modeling for real-time pressure ulcer prevention in sitting posture. AB - Ischial pressure ulcer is an important risk for every paraplegic person and a major public health issue. Pressure ulcers appear following excessive compression of buttock's soft tissues by bony structures, and particularly in ischial and sacral bones. Current prevention techniques are mainly based on daily skin inspection to spot red patches or injuries. Nevertheless, most pressure ulcers occur internally and are difficult to detect early. Estimating internal strains within soft tissues could help to evaluate the risk of pressure ulcer. A subject specific biomechanical model could be used to assess internal strains from measured skin surface pressures. However, a realistic 3D non-linear Finite Element buttock model, with different layers of tissue materials for skin, fat and muscles, requires somewhere between minutes and hours to compute, therefore forbidding its use in a real-time daily prevention context. In this article, we propose to optimize these computations by using a reduced order modeling technique (ROM) based on proper orthogonal decompositions of the pressure and strain fields coupled with a machine learning method. ROM allows strains to be evaluated inside the model interactively (i.e. in less than a second) for any pressure field measured below the buttocks. In our case, with only 19 modes of variation of pressure patterns, an error divergence of one percent is observed compared to the full scale simulation for evaluating the strain field. This reduced model could therefore be the first step towards interactive pressure ulcer prevention in a daily set-up. PMID- 28637593 TI - Remote ischemic preconditioning of transplant recipients to reduce graft ischemia and reperfusion injuries: A systematic review. AB - BACKGROUND: Solid organ transplantation is an accepted treatment for end-stage solid organ diseases. During the procedure, ischemia and reperfusion injury may affect graft and patient outcomes. Remote ischemic preconditioning (rIC) has been shown to reduce ischemia and reperfusion injury and can be performed safely. Thus, rIC may potentially improve outcomes after solid organ transplantation. Traditionally, the focus of rIC has been on the donor. However, preconditioning the recipient may be a more suitable approach in transplant settings. The current review analyzed previously published studies where rIC was performed on transplant recipients. METHODS: PubMed and EMBASE databases were searched for eligible clinical and animal studies evaluating rIC of recipients. Articles were analyzed and compared qualitatively. Risk of bias was assessed using the Cochrane Collaboration's tool for interventional clinical studies and SYRCLEs risk of bias tool for animal studies. RESULTS: A total of 12 studies were included. Overall, these studies were heterogeneous due to differences in populations and intervention set-up. Some of the studies suggested improvement of graft function, while other studies did not show any effect. The quality of the 12 included studies was predominantly low. CONCLUSION: Due to the heterogeneity and quality of the included studies the result, that rIC may be beneficial in transplantation of some organs, should be interpreted with caution. The result must be confirmed by further clinical studies. PMID- 28637594 TI - Association of plasma dipeptidyl peptidase-4 activity with non-alcoholic fatty liver disease in nondiabetic Chinese population. AB - OBJECTIVE: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is attributed to a "multi-hits hypothesis" involving insulin resistance, oxidative stress and inflammation. Dipeptidyl peptidase-4 (DPP4) was identified as a novel adipokine capable of enhancing the"multi-hits". Hence, we investigated the association between plasma DPP4 activity and NAFLD in nondiabetic Chinese population. DESIGN AND METHODS: We performed a cross-sectional study using data from 1105 subjects (36-79years) in Guilin between 2015 and 2016. Plasma DPP4 activity, homeostatic model assessment of insulin resistance (HOMA-IR), oxidative stress parameters, and inflammatory markers were measured in all participants. NAFLD and its severity were diagnosed by ultrasound after the exclusion of alcohol abuse and other liver diseases. RESULTS: Participants in the highest quartile of DPP4 activity had higher HOMA-IR, nitrotyrosine, 8-iso-PGF2a, interleukin-6, CRP, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase compared with those in the lowest quartile (all P<0.05). Plasma DPP4 activity gradually increased across the groups according to the ultrasonographic severity of steatosis (P<0.001 for the trend). In the highest DPP4 quartile, NAFLD risk was higher (odds ratio 1.88; 95% CI 1.04-3.37) than in the lowest quartile after adjustment for confounders. The risk for NAFLD increased more with higher levels of DPP4 activity, HOMA-IR, nitrotyrosine, 8-iso PGF2a, interleukin-6 and CRP. CONCLUSIONS: Plasma DPP4 activity is significantly associated with NAFLD. The underlying mechanisms may be partly attributed to the interactions between insulin resistance, oxidative stress, inflammation, and DPP4. PMID- 28637595 TI - A one-year mortality clinical prediction rule for patients with heart failure. AB - AIMS: To create and validate a clinical prediction rule which is easy to manage, reproducible and that allows classifying patients admitted for heart failure according to their one-year mortality risk. METHODS: A prospective cohort study carried out with 2565 consecutive patients admitted with heart failure in 13 hospitals in Spain. The derivation cohort was made up of 1283 patients and 1282 formed the validation cohort. In the derivation cohort, we carried out a multivariate logistic model to predict one-year mortality. The performance of the derived predictive risk score was externally validated in the validation cohort, and internally validated by K-fold cross-validation. The risk score was categorized into four risk levels. RESULTS: The mean age was 77.2years, 49.7% were female and there were 611 (23.8%) deaths in the follow-up period. The variables included in the predictive model were: age>=75, systolic blood pressure<135, New York Heart Association class III-IV, heart valve disease, dementia, prior hospitalization, haemoglobin<13, sodium<136, urea>=86, length of stay>=14 and Physical dimension of Minnesota Living with Heart Failure questionnaire. The AUC for the risk score were 0.73 and 0.70 in the derivation and validation cohorts, respectively, and 0.73 in the K-fold cross-validation. The percentage of mortality ranged from 8.08% in the low-risk to 58.20% in the high-risk groups (p<0.0001; AUC, 0.72). CONCLUSIONS: This model based on routinely available data, for admitted patients and with a follow-up at one year is a simple and easy-to-use tool for improving management of patients with heart failure. PMID- 28637596 TI - Y balance test has no correlation with the Stability Index of the Biodex Balance System. AB - STUDY DESIGN: A cross-sectional study design. BACKGROUND: The Stability Index of the Biodex Balance System (SI-BBS) and Y Balance Test (YBT) has been used in studies assessing postural stability but no studies have verified the association of the YBT with the SI-BBS. OBJECTIVE: To analyze the association of the Y Balance Test (YBT) with the Stability Index of the Biodex Balance System (SI-BBS) to evaluate postural stability. METHODS: Forty participants who engaged in recreational physical activities, 12 of whom had a history of injury to the lower limbs. Was used the SI-BBS and the anterior, posterolateral, posteromedial, and composite measures of the YBT. The order of execution of the tests and of the lower limbs evaluated was randomized and blind tested by two evaluators. RESULTS: Pearson's correlation coefficient was used to check the strength of the relationship between the distances achieved on the YBT and the SI-BBS. The YBT showed excellent reliability in the anterior, posteromedial, and posterolateral directions. However, the YBT showed no statistically significant correlation with any variables in the SI-BBS, indicating poor validity between YBT and SI-BBS assessments of postural stability in people with and without history of lower limb injuries. CONCLUSIONS: The results of this study showed the YBT is not correlated with the SI-BBS as an assessment of postural stability. This finding has implications for researchers and clinicians using YBT results as the only measure of postural stability. PMID- 28637598 TI - The use and perceived usefulness of a patient-specific measurement instrument in physiotherapy goal setting. A qualitative study. AB - OBJECTIVES: Physiotherapists are encouraged to set goals together with their patients to deliver client-centred care. In practice however, this goal-setting process is poorly specified, with limited patient involvement. The Patient Specific Complaints instrument (PSC) can support the goal-setting process. Despite its being frequently used by Dutch physiotherapists, its actual role in goal setting is unknown. The objective was to examine physiotherapy goal-setting and the use of the PSC within this process, as well as the physiotherapists' perception of the usefulness of the PSC. METHODS: Consultations between physiotherapists and patients were observed and physiotherapists were interviewed. Data were analysed by directed content analysis, using a goal setting framework as the coding scheme whose phases include: goal negotiation, goal setting, planning, and appraisal and feedback. RESULTS: The patients' problems were comprehensively explored, with the PSC focussing on activity problems. Goal-setting and planning phases were poorly specified and mainly physiotherapist-led. The physiotherapists appreciated the PSC for patient involvement during goal negotiation and evaluation. Its perceived usefulness for goal setting and planning ranged from useful for tailoring goals to the patient's needs to not useful at all. One major reason to use it was meeting external audit obligations. CONCLUSIONS: There are some discrepancies between how physiotherapists use the PSC and how they perceived its usefulness. Physiotherapists did use the PSC in a goal-setting process, though often as a standalone tool without integration in the whole physiotherapy process, and with limited patient involvement. In this way, its full potential for goal setting is not utilized. PMID- 28637597 TI - Effects of lower body quadrant neural mobilization in healthy and low back pain populations: A systematic review and meta-analysis. AB - BACKGROUND: Neural mobilization (NM) is widely used to assess and treat several neuromuscular disorders. However, information regarding the NM effects targeting the lower body quadrant is scarce. OBJECTIVES: To determine the effects of NM techniques targeting the lower body quadrant in healthy and low back pain (LBP) populations. DESIGN: Systematic review with meta-analysis. METHOD: Randomized controlled trials were included if any form of NM was applied to the lower body quadrant. Pain, disability, and lower limb flexibility were the main outcomes. PEDro scale was used to assess methodological quality. RESULTS: Forty-five studies were selected for full-text analysis, and ten were included in the meta analysis, involving 502 participants. Overall, studies presented fair to good quality, with a mean PEDro score of 6.3 (from 4 to 8). Five studies used healthy participants, and five targeted people with LBP. A moderate effect size (g = 0.73, 95% CI: 0.48-0.98) was determined, favoring the use of NM to increase flexibility in healthy adults. Larger effect sizes were found for the effect of NM in pain reduction (g = 0.82, 95% CI 0.56-1.08) and disability improvement (g = 1.59, 95% CI: 1.14-2.03), in people with LBP. CONCLUSION: Evidence suggests that there are positive effects from the application of NM to the lower body quadrant. Specifically, NM shows moderate effects on flexibility in healthy participants, and large effects on pain and disability in people with LBP. Nevertheless, more studies with high methodological quality are necessary to support these conclusions. PMID- 28637599 TI - Isokinetic clinical assessment of rotator cuff strength in subacromial shoulder impingement. AB - BACKGROUND: Current conservative management of subacromial shoulder impingement (SSI) includes generic strengthening exercises, especially for internal (IR) and external (ER) shoulder rotators. However, there is no evidence that the strength or the ratio of strength between these muscle groups is different between those with SSI (cases) and an asymptomatic population (controls). OBJECTIVE: To identify if isokinetic rotator cuff strength or the ratio of strength is significantly different between cases and controls. STUDY DESIGN: Case Control Study. METHOD: Fifty one cases with SSI and 51 asymptomatic controls matched for age, gender, hand dominance and physical activity level completed isokinetic peak torque glenohumeral IR and ER testing. Within the SSI group, 31 dominant limbs were symptomatic and 20 non-dominant limbs were symptomatic. IR and ER were measured separately using continuous reciprocal concentric (con) and eccentric (ecc) contraction cycles at a speed of 60 degrees per second and again at 120 degrees per second. Values of peak torque (PT), relative peak torque (RPT) and ratios were compared using independent t-tests between the SSI and asymptomatic groups. RESULTS: Significant strength differences between the two groups were present only when the symptomatic SSI shoulder was the dominant shoulder (con ER PT at 60 degrees /second, ecc ER PT at 120 degrees /second, ecc ER RPT at 120 degrees /second and ecc IR PT at 60 degrees /second and 120 degrees /second). CONCLUSIONS: Changes in rotator cuff strength in SSI may be related to limb dominance, which may have implications for strengthening regimes. LEVEL OF EVIDENCE: Level 3a. PMID- 28637601 TI - Clinical assessment of subacromial shoulder impingement - Which factors differ from the asymptomatic population? AB - BACKGROUND: To date, the significance of factors purported to be associated with subacromial shoulder impingement (SSI) and what differences, if any, are present in those with SSI compared to a matched asymptomatic population has not been identified. Gaining information about differences between people with SSI and asymptomatic people may direct clinicians towards treatments that impact upon these differences. OBJECTIVE: Compare the assessment findings of factors suggested to be associated with SSI; passive posterior shoulder range, passive internal rotation range, resting cervical and thoracic postures, active thoracic range in standing and scapula positioning between cases experiencing SSI and a matched asymptomatic group (controls). STUDY DESIGN: Case Control Study. METHOD: Fifty one SSI cases and 51 asymptomatic controls were matched for age, gender, hand dominance and physical activity level. The suggested associated factors were measured bilaterally. Independent t-tests were used to compare each of these measurements between the groups. Any variables for which a significant difference was identified, were then included in a conditional logistic regression analysis to identify independent predictors of SSI. RESULTS: The SSI group had significantly increased resting thoracic flexion and forward head posture, as well as significantly reduced upper thoracic active motion, passive internal rotation range and posterior shoulder range than the matched asymptomatic group. No independent predictors of SSI were identified in conditional logistic regression analysis. CONCLUSION: Thoracic posture, passive internal rotation range and posterior shoulder range were significantly different between cases experiencing SSI and a matched asymptomatic group. LEVEL OF EVIDENCE: Level 3a. PMID- 28637602 TI - Perceived task complexity of trunk stability exercises. AB - BACKGROUND: Perceived task complexity can impact participation in an exercise programme and the level of skill acquisition resulting from participation. Although trunk stability exercises are commonly included in the management of people with low back pain, potential differences in perceived task complexity between those exercises have not been investigated previously. OBJECTIVE: To investigate the perceived task complexity following first time instruction of two common stability exercises: the abdominal brace and abdominal hollow. DESIGN: Cross-sectional. METHODS: Twenty-four naive healthy participants received instruction in the performance of an abdominal brace and an abdominal hollow with feedback. Participants rated their perceived task complexity (mental, physical, and temporal demand, performance, effort, frustration) for each exercise on the NASA-Task Load Index. RESULTS: The abdominal hollow was associated with higher perceived mental demand than the abdominal brace (p = 0.01), and required more time to learn (p < 0.01). The abdominal brace was associated with greater mental demand and frustration when performed after the abdominal hollow than before. CONCLUSIONS: This study has provided the first evidence for differences in perceived task complexity between two commonly used trunk stability exercises. Those differences in perceived task complexity may influence the selection of exercises intended to enhance the robustness of spinal stability. PMID- 28637604 TI - Cervical flexion-rotation test and physiological range of motion - A comparative study of patients with myogenic temporomandibular disorder versus healthy subjects. AB - BACKGROUND: Temporomandibular Disorders (TMD) refer to several common clinical disorders which involve the masticatory muscles, the temporomandibular joint (TMJ) and the adjacent structures. Although neck signs and symptoms are found with higher prevalence in TMD patients compared to the overall population, whether limitation of cervical mobility is an additional positive finding in this cohort is still an open question. OBJECTIVE: To compare the physiological cervical range of motion (CROM) and the extent of rotation during cervical flexion (flexion-rotation test, FRT) in people with TMD (muscular origin) and healthy control subjects. METHOD: The range of motion of the neck and FRT was measured in 20 women with myogenic TMD and 20 age matched healthy controls. RESULTS: Women with myogenic TMD had significantly lower FRT scores compared to their matched healthy women. No difference was found between groups in CROM in any of the planes of movement. The FRT was positive (less than 32 degrees ) in 90% of the TMD participants versus 5% in the healthy control but the findings were not correlated with TMD severity. CONCLUSION: The results point out a potential involvement of the upper cervical joints (c1-c2) in women with myogenic TMD. PMID- 28637600 TI - Distinguishing between nociceptive and neuropathic components in chronic low back pain using behavioural evaluation and sensory examination. AB - BACKGROUND: Diagnosis of chronic low back pain (CLBP) is traditionally predicated on identifying underlying pathological or anatomical causes, with treatment outcomes modest at best. Alternately, it is suggested that identification of underlying pain mechanisms with treatments targeted towards specific pain phenotypes may yield more success. Differentiation between nociceptive and neuropathic components of CLBP is problematic; evidence suggests that clinicians fail to identify a significant neuropathic component in many CLBP patients. The painDETECT questionnaire (PDQ) was specifically developed to identify occult but significant neuropathic components in individuals thought to have predominantly nociceptive pain. METHODS: Using the PDQ, we classified 50 CLBP patients into two distinct groups; those with predominantly nociceptive pain (Group 1) and those with a significant neuropathic component (Group 2). We characterised these two distinct CLBP sub-groups using a) questionnaire-based behavioural evaluation measuring pain-related function and quality of life, pain intensity and psychological well-being and b) sensory examination, using two-point and tactile threshold discrimination. OBJECTIVE: We sought to determine if differences in the pain phenotype of each CLBP sub-group would be reflected in sensory and behavioural group profiles. RESULTS: We report that Group 1 and Group 2 sub groups demonstrate unique clinical profiles with significant differences in sensory tactile discrimination thresholds and in a wide range of behavioural domains measuring pain intensity, disability and psychological well-being. CONCLUSION: We have demonstrated distinct clinical profiles for CLBP patient sub groups classified by PDQ. Our results give diagnostic confidence in using the PDQ to characterise two distinct pain phenotypes in a heterogeneous CLBP population. PMID- 28637603 TI - Reliability and validity of two multidimensional self-reported physical activity questionnaires in people with chronic low back pain. AB - BACKGROUND: Although there is some evidence for reliability and validity of self report physical activity (PA) questionnaires in the general adult population, it is unclear whether we can assume similar measurement properties in people with chronic low back pain (LBP). OBJECTIVE: To determine the test-retest reliability of the International Physical Activity Questionnaire (IPAQ) long-version and the Baecke Physical Activity Questionnaire (BPAQ) and their criterion-related validity against data derived from accelerometers in patients with chronic LBP. DESIGN: Cross-sectional study. METHODS: Patients with non-specific chronic LBP were recruited. Each participant attended the clinic twice (one week interval) and completed self-report PA. Accelerometer measures >7 days included time spent in moderate-and-vigorous physical activity, steps/day, counts/minute, and vector magnitude counts/minute. Intraclass Correlation Coefficients (ICC) and Bland and Altman method were used to determine reliability and spearman rho correlation were used for criterion-related validity. RESULTS: A total of 73 patients were included in our analyses. The reliability analyses revealed that the BPAQ and its subscales have moderate to excellent reliability (ICC2,1: 0.61 to 0.81), whereas IPAQ and most IPAQ domains (except walking) showed poor reliability (ICC2,1: 0.20 to 0.40). The Bland and Altman method revealed larger discrepancies for the IPAQ. For the validity analysis, questionnaire and accelerometer measures showed at best fair correlation (rho < 0.37). CONCLUSIONS: Although the BPAQ showed better reliability than the IPAQ long-version, both questionnaires did not demonstrate acceptable validity against accelerometer data. These findings suggest that questionnaire and accelerometer PA measures should not be used interchangeably in this population. PMID- 28637605 TI - 'I need to do another course' - Italian physiotherapists' knowledge and beliefs when assessing psychosocial factors in patients presenting with chronic low back pain. AB - OBJECTIVES: Psychosocial factors play an important role in the development and subsequent recovery of individuals suffering from chronic low back pain (CLBP). The study explored physiotherapists' personal beliefs and knowledge about the biopsychosocial model and the different ways they assess and manage psychosocial factors in patients presenting with CLBP. METHODS: Qualitative research design using semi-structured interviews and a constructivist grounded theory approach to data collection and analysis. A purposive sample of eight physiotherapists practicing in Italy and having experience with patients presenting chronic musculoskeletal problems were recruited from private clinics. RESULTS: Three main categories were constructed: 1) conceptions of the biopsychosocial model and its role in CLBP; 2) evaluation and management of PS factors; 3) barriers in the assessment and treatment. CONCLUSIONS: Physiotherapists showed a basic knowledge of the biopsychosocial model and partially recognised social, emotional, cognitive and psychological factors in chronic low back pain patients, and their contribution in the individual patient's pain and disability. Physiotherapists highlighted the presence of barriers in the evaluation and treatment of people with CLBP, and some participants displayed a lack of skills to overcome these barriers. Physiotherapists perceived limited education and training to successfully address psychosocial factors in the management of patients with chronic low back pain, indicating the need to incorporate the biopsychosocial model in the daily practice and improve the training and education of the psychosocial assessment and management. PMID- 28637606 TI - Inter-examiner classification reliability of Mechanical Diagnosis and Therapy for extremity problems - Systematic review. AB - BACKGROUND: Mechanical Diagnosis and Therapy (MDT) is used in the treatment of extremity problems. Classifying clinical problems is one method of providing effective treatment to a target population. Classification reliability is a key factor to determine the precise clinical problem and to direct an appropriate intervention. OBJECTIVES: To explore inter-examiner reliability of the MDT classification for extremity problems in three reliability designs: 1) vignette reliability using surveys with patient vignettes, 2) concurrent reliability, where multiple assessors decide a classification by observing someone's assessment, 3) successive reliability, where multiple assessors independently assess the same patient at different times. DESIGN: Systematic review with data synthesis in a quantitative format. METHOD: Agreement of MDT subgroups was examined using the Kappa value, with the operational definition of acceptable reliability set at >= 0.6. The level of evidence was determined considering the methodological quality of the studies. RESULTS/FINDINGS: Six studies were included and all studies met the criteria for high quality. Kappa values for the vignette reliability design (five studies) were >= 0.7. There was data from two cohorts in one study for the concurrent reliability design and the Kappa values ranged from 0.45 to 1.0. Kappa values for the successive reliability design (data from three cohorts in one study) were < 0.6. CONCLUSION: The current review found strong evidence of acceptable inter-examiner reliability of MDT classification for extremity problems in the vignette reliability design, limited evidence of acceptable reliability in the concurrent reliability design and unacceptable reliability in the successive reliability design. PMID- 28637607 TI - Response to letter to the Editor 'Altered breathing pattern valuation relative to dyspnea assessment and treatment for low back pain: Effects of clinical practice'. PMID- 28637608 TI - Regarding 'Classification characteristics of a chronic low back pain population using a combined McKenzie and patho-anatomical assessment' authored by Flavell C et al., manual therapy 26 (2016), 201-207. PMID- 28637609 TI - Reply to the letter to the editor regarding 'Classification characteristics of a chronic low back pain population using a combined McKenzie and patho-anatomical assessment'. PMID- 28637611 TI - Emotional communication in support groups for siblings of children with disabilities. AB - OBJECTIVE: Support groups are often arranged for siblings of children with disabilities to prevent psychological maladjustment. This study describes how children express emotions in support groups and how group leaders and other children respond. METHOD: Conversations in 17 group sessions for siblings aged 11 to 16 were coded with VR-CoDES to report frequency of emotional expressions and responses. RESULTS: Children expressed negative emotion during group sessions (n=235), 59% as cues and 41%concerns. The immediate response was in 98% of the instances from the group leader. 38% of the responses focused on emotion, cognition or behavior. CONCLUSION: Children express emotions, but seldom respond immediately to others' emotional expressions in support groups. Group leaders should attend to emotion, cognition and behavior more frequently. PRACTICE IMPLICATIONS: Group leaders may better fulfill the support potential of support groups through explicitly stating the role of participants, and by exploring emotional aspects. PMID- 28637610 TI - An exploration of how positive emotions are expressed by older people and nurse assistants in homecare visits. AB - OBJECTIVE: We don't know how positive emotions are being expressed by patients and health care providers in consultations. The aim of this study is to identify positive emotions expressed by older people and nurse assistants to discuss the function of these in the visits. METHOD: This paper presents secondary analysis of consultations in the COMHOME project. In this pilot study, six transcribed consultations between nurse assistants and older people in home health care were analysed using a coding system for positive emotions with seven categories capturing both content and emotional intensity of positive affect. RESULTS: We found 114 expressions of positive emotions, 63% from nurse assistants and 37% from patients. Patients mostly expressed gratitude, indicating that patients are grateful for being helped. Nurse assistants mostly expressed Praise or Support, indicating that they gave their patients positive affirmation. CONCLUSION: The praise and support given by nurse assistants to older people in home health care seemed effective in fostering relationships and maintaining patient resilience. Thus, we claim that emotional talk in communication also should include positive emotions. PRACTICE IMPLICATION: Teaching health care providers about the importance of expressions of positive emotions should be integrated in communication skills training. PMID- 28637612 TI - Eliciting patient preferences in shared decision-making (SDM): Comparing conversation analysis and SDM measurements. AB - OBJECTIVE: To explore how physicians bring up patient preferences, and how it aligns with assessments of shared decision-making. METHODS: Qualitative conversation analysis of physicians formulating hypotheses about the patient's treatment preference was compared with quantitative scores on SDM and 'patient preferences' using OPTION(5) and MAPPIN'SDM. RESULTS: Physicians occasionally formulate hypotheses about patients' preferences and then present a treatment option on the basis of that ("if you think X+we can do Y"). This practice may promote SDM in that the decisions are treated as contingent on patient preferences. However, the way these hypotheses are formulated, simultaneously constrains the patient's freedom of choice and exerts a pressure to accept the physician's recommendation. These opposing effects may in part explain cases where different assessment instruments yield large variations in SDM measures. CONCLUSION: Eliciting patient preferences is a complex phenomenon that can be difficult to reduce into an accurate number. Detailed analysis can shed light on how patient preferences are elicited, and its consequences for patient involvement. Comparing CA and SDM measurements can contribute to specifying communicative actions that SDM scores are based on. PRACTICE IMPLICATIONS: Our findings have implications for SDM communication skills training and further development of SDM measurements. PMID- 28637613 TI - The inseparability of emotional and instrumental care in cancer: Towards a more powerful science of clinical communication. AB - OBJECTIVE: Clinical communication literature currently distinguishes clinicians' emotional care of patients from instrumental aspects of clinical care, and regards clinicians' explicit emotional engagement with patients as the key to emotional care. Here we critically appraise this view. METHODS: We draw on empirical evidence and recent reviews and critiques focusing on cancer care. RESULTS: Patients and families do not generally seek explicit emotional engagement from their practitioners; nor does such engagement consistently improve patient outcomes. Instead some evidence indicates that anxious patients and families can be comforted by clinicians' focus on instrumental care. CONCLUSIONS: Such findings can be interpreted according to the view that clinical relationships evoke attachment processes. In the context of mortal illness, patients are comforted by being able to trust clinicians whom they regard as having the expertize to look after them. From this perspective, instrumental and emotional care are inseparable. Clinicians' clinical authority and expertize are the basis for the emotional comfort they can provide. PRACTICE IMPLICATIONS: For researchers and educators, a consequence of appreciating the inseparability of emotional and instrumental care will be greater emphasis on learning from, and collaborating with, clinicians. Clinicians, in turn, can benefit by communication scientists developing new approaches to supporting their communication. These approaches will need to recognize that clinicians' emphasis on their authority and clinical expertize in communicating with patients can be central to providing emotional comfort, and not necessarily a way to avoid doing so. PMID- 28637614 TI - Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia. AB - The inherited marrow failure syndromes (IBMFS) are a heterogeneous group of diseases characterized by failure in the production of one or more blood lineage. The clinical manifestations of the IBMFS vary according to the type and number of blood cell lines involved, including different combinations of anemia, leukopenia, and thrombocytopenia. In some IBMFS, systemic non-hematologic manifestations, including congenital malformations, mucocutaneous abnormalities, developmental delay, and other medical complications, may be present. Fanconi anemia (FA), caused by germline pathogenic variants in the DNA repair genes comprising the FA/BRCA pathway is associated with congenital anomalies, bone marrow failure, and increased risk of myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and solid tumors. Dyskeratosis congenita (DC) is a telomere biology disorder (TBD) caused by aberrations in key telomere biology genes. In addition to mucocutaneous manifestations, patients with DC are at increased risk of marrow failure, MDS, AML, pulmonary fibrosis, and other complications. Ribosomal biology defects are the primary causes of Diamond Blackfan anemia (DBA) and Shwachman Diamond syndrome (SDS). In addition to pure red blood cell aplasia, DBA is associated with elevated risk of solid tumors, AML, and MDS. Patients with SDS have pancreatic insufficiency, neutropenia, as well as MDS and AML risks. Patients with severe congenital neutropenia (SCN), caused by pathogenic variants in genes essential in myeloid development, have profound neutropenia and high risk of MDS and AML. Herein we review the genetic causes, clinical features, diagnostic modalities, predisposition to malignancies with focus on leukemogenic markers whenever available, and approaches to treatments of the classical IBMFS: FA, DC, SDS, DBA, and SCN. PMID- 28637615 TI - Cancer predisposition syndromes associated with myeloid malignancy. AB - The majority of myeloid malignancies are caused by sporadic somatic events rather than cancer predisposition. Nonetheless, the identification of hereditary cancer predisposition syndromes is critical when caring for patients with myeloid malignancies since detection may direct decisions related to cancer treatment and surveillance. A positive genetic test result also has important implications for other family members who can use this information to undergo their own testing to determine their cancer risk. We review the demographics, genetic mechanisms of disease, diagnostic approach, malignancy risk, and management for the following five cancer predisposition syndromes associated with myeloid malignancies: Li Fraumeni, constitutional mismatch repair deficiency, Werner, Bloom, and Nijmegen breakage. PMID- 28637616 TI - Down syndrome, RASopathies, and other rare syndromes. AB - In this article we discuss the occurrence of myeloid neoplasms in patients with a range of syndromes that are due to germline defects of the RAS signaling pathway and in patients with trisomy 21. Both RAS mutations and trisomy 21 are common somatic events contributing to leukemogenis. Thus, the increased leukemia risk observed in children affected by these conditions is biologically highly plausible. Children with myeloid neoplasms in the context of these syndromes require different treatments than children with sporadic myeloid neoplasms and provide an opportunity to study the role of trisomy 21 and RAS signaling during leukemogenesis and development. PMID- 28637617 TI - Introduction: Genetic syndromes predisposing to myeloid neoplasia. PMID- 28637618 TI - Recognition of familial myeloid neoplasia in adults. AB - Hereditary hematologic malignancy (HM) syndromes are increasingly recognized as causative of adult hematopoietic cancers, and the advent of next-generation sequencing has accelerated the discovery of new syndromes based on dense clustering of these diseases in particular families. Updated classifications schemes for myeloid malignancies will now include recommendations for taking a family history on all patients diagnosed with hematopoietic malignancies and for genetic counseling and testing of appropriate individuals and families. Therefore, now more than ever, clinicians and pathologists will need to have a high index of suspicion and be familiar with the aspects of a patient's personal or family history that should raise suspicion regarding these syndromes as well as the options for clinical testing. Whenever possible, individuals should be tested with certified, clinical platforms that can detect both point mutations and genomic rearrangements that disrupt gene function so that results are immediately actionable. Individuals and families who test negative for mutations in the known germline predisposition genes serve as important sources of discovery for new inherited susceptibility syndromes. PMID- 28637619 TI - Practical considerations for diagnosis and management of patients and carriers. AB - Newly diagnosed children and adults with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) need to be screened for presence of a genetic predisposition syndrome because the information on the genetic status is likely to influence clinical care and management of the patient and the family. Scenarios in which genetic counseling is advised include presence of a mutation on somatic screen that can be associated with a germline predisposition, hematologic or cytogenetic characteristics suggestive of an underlying susceptibility syndrome, non-hematological phenotype suspicious for a familial condition, history of previous malignancy, or a family history of cancer, cytopenia, autoimmunity, or organ-system manifestation fitting a predisposition syndrome. With increasing complexity on phenotypes, genetics, and leukemia risk of the recently recognized predisposition syndromes, specialized clinics for hereditary hematologic malignancies have been initiated to guide genetic testing and support hematologists integrating genetic data into therapeutic strategies and clinical care. Recommendations for surveillance of carriers are currently based on expert opinion and subject to future modification when a more complete picture for the distinct genetic entities will arise. PMID- 28637620 TI - RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM). AB - In this review, we discuss disease-causing alterations of RUNT-related transcription factor 1 (RUNX1), a master regulator of hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) typically presents with (1) mild to moderate thrombocytopenia with normal-sized platelets; (2) functional platelets defects leading to prolonged bleeding; and (3) an increased risk to develop myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or T-cell acute lymphoblastic leukemia (T-ALL). Hematological neoplasms in carriers of a germline RUNX1 mutation need additional secondary mutations or chromosome aberrations to develop. If a disease-causing mutation is known in the family, it is important to prevent hematopoietic stem cell transplantation from a sibling or other relative carrying the familial mutation. First experiments introducing a wild-type copy of RUNX1 into induce pluripotent stem cells (iPSC) lines from patients with FPDMM appear to demonstrate that by gene correction reversal of the phenotype may be possible. PMID- 28637622 TI - Familial CEBPA-mutated acute myeloid leukemia. AB - Familial CEBPA-mutated acute myeloid leukemia (AML) represents a recognized leukemia predisposition syndrome, with several families described in the literature since the initial report in 2004. The pathological features and long term survival of individuals with familial CEBPA-mutated AML are reminiscent of sporadic CEBPAdm AML. Germline mutations predominantly localize to the N terminal and are associated with near complete penetrance, with age of AML onset from 2-50 years, frequently accompanied by the acquisition of a second CEBPA mutation in C-terminal domain. Patients appear to have a significant risk of late AML recurrence and these typically represent independent leukemic episodes, characterized by a unique molecular profile that is distinct from that of the preceding tumor. While these patients respond well to salvage therapies, allogeneic hematopoietic stem cell transplantation (HSCT) should be considered for patients with high-risk features at presentation or recurrent disease, with the aim of eradicating the germline mutation and improving long-term survival. In contrast, inherited C-terminal CEBPA mutations occur less frequently and appear to demonstrate reduced penetrance, impeding clinical detection and surveillance. PMID- 28637621 TI - GATA2 deficiency and related myeloid neoplasms. AB - The GATA2 gene codes for a hematopoietic transcription factor that through its two zinc fingers (ZF) can occupy GATA-DNA motifs in a countless number of genes. It is crucial for the proliferation and maintenance of hematopoietic stem cells. During the past 5 years, germline heterozygous mutations in GATA2 were reported in several hundred patients with various phenotypes ranging from mild cytopenia to severe immunodeficiency involving B cells, natural killer cells, CD4+ cells, monocytes and dendritic cells (MonoMAC/DCML), and myeloid neoplasia. Some patients additionally show syndromic features such as congenital deafness and lymphedema (originally defining the Emberger syndrome) or pulmonary disease and vascular problems. The common clinical denominator in all reported cohorts is the propensity for myeloid neoplasia (myelodysplastic syndrome [MDS], myeloproliferative neoplasms [MPN], chronic myelomonocytic leukemia [CMML], acute myeloid leukemia [AML]) with an overall prevalence of approximately 75% and a median age of onset of roughly 20 years. Three major mutational types are encountered in GATA2-deficient patients: truncating mutations prior to ZF2, missense mutations within ZF2, and noncoding variants in the +9.5kb regulatory region of GATA2. Recurrent somatic lesions comprise monosomy 7 and trisomy 8 karyotypes and mutations in SETBP1 and ASXL1 genes. The high risk for progression to advanced myeloid neoplasia and life-threatening infectious complications guide decision-making towards timely stem cell transplantation. PMID- 28637623 TI - DDX41-related myeloid neoplasia. AB - While early presentation of familial leukemia syndromes is typical, long disease anticipation may mask cases of familial traits in seemingly spontaneous disease. Germline mutations in DDX41 gene have been discovered in several leukemia families, as well as in mostly adult patients with seemingly spontaneous disease but having strong family histories of myeloid neoplasia. As with other familial genes, DDX41 mutation carriers can develop neoplasia through acquisition of another somatic mutation, thereby affecting both DDX41 alleles. In other patients, somatic mutations of different driver genes can substitute for acquired missense DDX41 during progression. Conversely, non-familial cases with heterozygous somatic DDX41 mutations point towards other mutations that can substitute for the germ line founder DDX41 lesions. In either circumstance, total inactivation of DDX41 appears to be cell-lethal, explaining why frameshift germline lesions have not been found to be accompanied by deletions of the DDX41 locus on 5q. The precise function of the DDX41 protein is unknown; considerable evidence suggests its involvement in RNA splicing. Thus DDX41 can be included in the now large group of mutated spliceosomal genes affected in myeloid neoplasia. However, it appears that DDX4 is so far the only example of a germline spliceosomal mutation in leukemia. Clinically, recognition of DDX41 mutated cases may have implications for surveillance, assessment of prognosis, and, perhaps, for design of targeted therapies. PMID- 28637625 TI - Counterfeit drugs: A plot worthy of John le Carre. PMID- 28637624 TI - ETV6 in hematopoiesis and leukemia predisposition. AB - The ETV6 (also known as TEL) gene encodes a transcriptional repressor that plays a critical role in hematopoiesis and in embryonic development. While somatic ETV6 translocations and missense mutations are frequently observed in human cancers, the role of ETV6 in malignant transformation was unclear. Recently, autosomal dominant germline ETV6 mutations were discovered in families with inherited thrombocytopenia and a propensity to develop hematological malignancy, unequivocally demonstrating a role for ETV6 in leukemogenesis. Studies of germline ETV6 mutations also uncovered an important function of ETV6 in megakaryocyte development. Here we discuss our current understanding of the role of ETV6 in malignancy and in hematopoiesis. PMID- 28637626 TI - Chromosome 4q25 variants and recurrence after second-generation cryoballoon ablation in patients with paroxysmal atrial fibrillation. AB - BACKGROUND: Chromosome 4q25 single-nucleotide polymorphisms (SNPs) are associated with atrial fibrillation (AF) recurrence after radiofrequency catheter ablation, however the underlying mechanism is unknown. Pulmonary vein (PV) reconnections are common post-radiofrequency ablation. We explored the pre-procedural parameters, including AF susceptibility SNPs, predicting the response to PV isolation (PVI) using second-generation cryoballoons. METHODS: One hundred fifty seven paroxysmal AF patients undergoing PVI using second-generation cryoballoons and genetic testing were enrolled. The top 6 AF-associated Japanese ancestry SNPs were evaluated. Fourteen-day consecutive monitoring was performed to detect AF recurrences. RESULTS: Early recurrence of AF (ERAF) was detected in 74(47.1%) patients, and the AF-free survival at 12-months after single procedures was 72.1%. Cox's proportional models determined that higher pro-BNP values (hazard ratio [HR]=1.001; 95% confidence interval [CI]=1.000-1.001; p=0.003) and the rs1906617 risk allele (HR=2.440; 95% CI=1.062-5.605; p=0.035) were independently associated with ERAFs, and the rs1906617 risk allele (HR=4.339; 95% CI=1.044 18.028; p=0.043) was the sole factor significantly associated with AF recurrence. Second procedures were performed in 41 patients a median of 6.0[5.0-9.5] months later, and 42/162(25.9%) PVs were reconnected. Reconnections were similarly observed in rs1906617 risk allele carriers and wild-type patients. Risk allele carriers at rs1906617 were more likely to have non-PV foci, but did not reach statistical significance (10/35 vs. 0/6, p=0.132). CONCLUSIONS: AF risk alleles on chromosome 4q25 modulated the risk of AF recurrence after PVI using second generation cryoballoons in patients with paroxysmal AF. Our study results suggested that non-PV foci might be the more likely mechanism of a high AF recurrence in chromosome 4q25 variant carriers. PMID- 28637628 TI - Dietary Habits and Psychosocial Outcomes in Women with Fibromyalgia. PMID- 28637627 TI - Pulmonary arterial resistance and compliance in preterm infants. AB - BACKGROUND: Preterm birth is known to be associated with an increased risk of pulmonary arterial hypertension, although how preterm birth influences pulmonary hemodynamics has not been fully understood. Pulmonary arterial resistance (Rp) and compliance (Cp) are important factors to assess the pulmonary circulation. The purpose of this study is to clarify the relationship between Rp and Cp in preterm infants. METHODS: We performed cardiac catheterization in 96 infants (50 males) with ventricular septal defect, and compared pulmonary hemodynamic parameters including Rp and Cp between preterm and full-term infants. RESULTS: Thirteen infants were preterm. There were no significant differences in sex, age, preoperative pulmonary arterial pressure, preoperative pulmonary-to-systemic flow ratio, and preoperative Rp between the 2 groups. However, preoperative Cp and resistor-capacitor (RC) time in preterm infants were significantly lower than those in full-term infants (2.1 vs 2.8mL/mmHg/m2 and 0.31 vs 0.36s, respectively; p<0.05 and p<0.01, respectively). Postoperative systolic and mean pulmonary arterial pressures were higher in preterm infants than those in full-term infants (29 vs 25mmHg and 18 vs 14mmHg, respectively; both p<0.01). It was also observed that postoperative Cp was lower in preterm infants, although postoperative Rp remained unchanged. CONCLUSIONS: We demonstrated that preterm infants with pulmonary arterial hypertension had lower Cp than full-term infants, causing a modest increase in pulmonary arterial pressure. It is important to consider the unique pulmonary vasculature characterized by lower Cp, when managing preterm infants with congenital heart disease. PMID- 28637629 TI - Culturally Responsive Teaching: A Framework for Consideration in Dietetics Education. PMID- 28637630 TI - Author's Response. PMID- 28637631 TI - Validity of a Digital Diet Estimation Method for Use with Preschool Children. AB - BACKGROUND: The validity of using the Remote Food Photography Method (RFPM) for measuring food intake of minority preschool children's intake is not well documented. OBJECTIVE: Our aim was to determine the validity of intake estimations made by human raters using the RFPM compared with those obtained by weighing all foods and beverages consumed by 3- to 5-year-old children (weighed method). DESIGN: We conducted a cross-sectional observational study. PARTICIPANTS/SETTINGS: A convenience sample of 54 3- to 5-year-old Hispanic and African-American children were observed during a 12-hour period at Baylor Metabolic Research Unit between June 2013 and January 2014. MAIN OUTCOME MEASURES: All foods/beverages consumed by the children were provided by Baylor research coordinators who took and wirelessly transmitted before-and-after pictures of the trays to trained human raters at the Pennington Biomedical Research Center who estimated grams consumed. Energy and macronutrients were calculated using the Food and Nutrient Database for Dietary Studies or food facts data provided by manufacturers. STATISTICAL ANALYSES: Paired t test, mean differences, and Bland-Altman limits of agreement were performed. RESULTS: Compared to the weighed method, the rater method significantly overestimated total intake by 34+/-71 g (P<0.0001), with a mean percent error of 2.9% (root mean square error=7.1%), and total energy intake by 75+/-102 kcal (P<0.0001), with a mean percent error of 7.5% (root mean square error=12.3%). The standard error for the macronutrient intakes ranged from 11.0% to 20.2%. The Bland-Altman approach demonstrated a positive slope for the rater method relative to the weighed method for total intake in grams (P=0.006), carbohydrate (P=0.01), and protein (P=0.01) (ie, magnitude of the bias increased with increasing intakes). CONCLUSIONS: The rater method overestimated total intake in grams and energy in kilocalories in minority preschool children in a well-controlled condition and needs to be further tested in a free-living environment. PMID- 28637632 TI - 'De-pathologising' the psychological responses to injury and pain. PMID- 28637633 TI - Physical activity correlates among people with psychosis: Data from 47 low- and middle-income countries. AB - BACKGROUND: People with schizophrenia engage in low levels of physical activity (PA). However, few large-scale studies have investigated the factors that may influence PA participation in individuals with psychosis and data from low- and middle-income countries (LMICs) is especially scarce. Thus, we investigated PA correlates in a large sample of people with a psychosis diagnosis across 47 LMICs. METHODS: Cross-sectional data from the World Health Survey, restricting to those with a self-reported lifetime diagnosis of schizophrenia/psychotic disorder, was analyzed. PA was assessed by the International Physical Activity Questionnaire (IPAQ) and participants were dichotomized into those that do and do not (low PA) meet the minimum recommended PA weekly targets (>=150min). A range of socio-demographic, health behavior, and mental and physical health variables were examined using random effects logistic regression. RESULTS: Overall 2407 people (mean 42.0years, 41.5% males) with schizophrenia/psychosis were included. The prevalence of low PA was 39.2% (95%CI=37.0%-41.2%). Male sex (odds ratio (OR)=1.33), increasing age, unemployment (vs. employed OR=2.50), urban setting (vs. rural OR=1.75), inadequate fruit consumption (vs. adequate fruit intake OR=3.03), depression (OR=1.33), sleep/energy disturbance, and mobility limitations were significantly associated with low PA. Marital status, education, wealth, smoking, vegetable and alcohol consumption, anxiety, cognition, pain, and chronic medical conditions were not significant correlates. CONCLUSION: PA is influenced by a range of factors among people with psychosis. These correlates should be considered in interventions aiming to facilitate PA in psychotic individuals living in LMICs. PMID- 28637634 TI - Optimization of food waste compost with the use of biochar. AB - This paper aims to examine the influence of biochar produced from lawn waste in accelerating the degradation and mineralization rates of food waste compost. Biochar produced at two different temperatures (350 and 450 degrees C) was applied at the rates 10 and 15% (w/w) of the total waste to an in-vessel compost bioreactor for evaluating its effects on food waste compost. The quality of compost was assessed against stabilization indices such as moisture contents (MC), electrical conductivity (EC), organic matters (OM) degradation, change in total carbon (TC) and mineral nitrogen contents such as ammonium (NH4+) and nitrate (NO3-). The use of biochar significantly improved the composting process and physiochemical properties of the final compost. Results showed that in comparison to control trial, biochar amended compost mixtures rapidly achieved the thermophilic temperature, increased the OM degradation by 14.4-15.3%, concentration of NH4+ by 37.8-45.6% and NO3- by 50-62%. The most prominent effects in term of achieving rapid thermophilic temperature and a higher concentration of NH4+ and NO3- were observed at 15% (w/w) biochar. According to compost quality standard of United States (US), California, Germany, and Austria, the compost stability as a result of biochar addition was achieved in 50-60 days. Nonetheless, the biochar produced at 450 degrees C had similar effects as to biochar produced at 350 degrees C for most of the compost parameters. Therefore, it is recommended to produce biochar at 350 degrees C to reduce the energy requirements for resource recovery of biomass and should be added at a concentration of 15% (w/w) to the compost bioreactor for achieving a stable compost. PMID- 28637636 TI - Epilepsy after cerebral infection: review of the literature and the potential for surgery. AB - The risk of unprovoked seizures in population-based cohorts of cerebral infection survivors is 7-8% in developed countries, rising to considerably higher rates in resource-poor countries. The main risk factors for epilepsy after cerebral infection, besides acute seizures, are infection-associated brain lesions and status epilepticus during the acute phase. Despite the high prevalence of pharmacoresistant epilepsies after cerebral infections, especially in patients with MRI-identifiable lesions, only a small minority undergoes epilepsy surgery. However, excellent surgical candidates are particularly those with a history of meningitis or encephalitis in early childhood, hippocampal sclerosis on MRI, as well as a history, seizure semiology, and EEG-findings compatible with the diagnosis of a mesial temporal lobe epilepsy syndrome. More challenging are patients with neocortical/extratemporal lobe epilepsies post cerebral infection. Finally, patients with a severe hemispheric injury with contralateral hemiparesis are candidates for hemispherectomy/hemispherotomy. This review attempts to shed some light on this frequent cause of symptomatic focal epilepsy, with an emphasis on the chances offered by epilepsy surgery. PMID- 28637635 TI - Stereotactic bilateral transfrontal minimal radiofrequency thermocoagulation of the amygdalohippocampal complex for bilateral medial temporal lobe epilepsy: a retrospective study of 12 patients. AB - Some patients with temporal lobe epilepsy have bilateral discharges and a few have bilateral medial temporal sclerosis. Stereotactic bilateral radiofrequency thermocoagulation (RFTC) of the amygdalohippocampal complex can terminate seizures or reduce seizure severity in patients with bilateral medial temporal lobe epilepsy (BMTLE). To explore the safety and efficacy of bilateral transfrontal minimal RFTC of the amygdalohippocampal complex for the treatment of BMTLE. A total of 12 BMTLE patients were treated with bilateral transfrontal minimal RFTC of the amygdalohippocampal complex under limited coagulations. The volumes of coagulated lesions were less than 0.6 cm3 Clinical outcomes were evaluated using Engel's classification, the Liverpool Seizure Severity Scale (LSSS) 2.0, Wechsler Adult Intelligence Scale-Revised (WAIS-R), and Wechsler Memory Scale-Revised (WMS-R). Quality of life (QOL) was evaluated using the 36 item Short Form Health Survey (SF-36). Of the 12 patients, five (42%) were assessed as Engel Class I during 12-62 months of follow-up. LSSS scores declined sharply compared with the baseline of patients not in the seizure-free category. Functions of memory and intelligence declined transiently without statistical significance (p>0.05) immediately after surgery, but improved significantly (p<0.05) six months later. The qualities of life improved except vitality. Bilateral transfrontal minimal RFTC of the amygdalohippocampal complex may terminate seizures or reduce seizure severity in patients with BMTLE. Under limited coagulations, neuropsychological function was not affected but improved along with seizure control. PMID- 28637637 TI - Alternating hemiplegia of childhood and a pathogenic variant of ATP1A3: a case report and pathophysiological considerations. AB - We describe a case of a child suffering from alternating hemiplegia with a heterozygous p. E815K pathogenic variant of ATP1A3. The patient started to present abnormal eye movements in the first days of life, followed by the appearance at 2 months of dystonic episodes, and later on, by recurrent episodes of alternating hemiplegia more often on the right side. A severe epilepsy started at the age of 2 years with episodes of status epilepticus since the onset which frequently recurred, requiring admission to the intensive care unit. MRI showed bilateral mesial temporal sclerosis and a left-sided ischaemic lesion. Interictal EEG showed bilateral abnormalities, whereas postictal EEG after status epilepticus showed overt slowing on the left side, suggesting a predominant involvement of ictal activity of the left hemisphere. We hypothesize that in our patient, the left hemisphere might have been more prominently affected by the pathogenetic abnormalities underlying alternating hemiplegia of childhood, rendering it more prone to early ischaemic lesions and recurrent unilateral status epilepticus. We speculate whether alternating hemiplegia of childhood shares some common pathophysiological mechanisms with familial hemiplegic migraine that may be associated with a pathogenic variant of ATP1A2. PMID- 28637638 TI - The Gap in Medical Informatics and Continuing Education Between the United States and China: A Comparison of Conferences in 2016. AB - BACKGROUND: China launched its second health reform in 2010 with considerable investments in medical informatics (MI). However, to the best of our knowledge, research on the outcomes of this ambitious undertaking has been limited. OBJECTIVE: Our aim was to understand the development of MI and the state of continuing education in China and the United States from the perspective of conferences. METHODS: We conducted a quantitative and qualitative analysis of four MI conferences in China and two in the United States: China Medical Information Association Annual Symposium (CMIAAS), China Hospital Information Network Annual Conference (CHINC), China Health Information Technology Exchange Annual Conference (CHITEC), China Annual Proceeding of Medical Informatics (CPMI) versus the American Medical Informatics Association (AMIA) and Healthcare Information and Management Systems Society (HIMSS). The scale, composition, and regional distribution of attendees, topics, and research fields for each conference were summarized and compared. RESULTS: CMIAAS and CPMI are mainstream academic conferences, while CHINC and CHITEC are industry conferences in China. Compared to HIMSS 2016, the meeting duration of CHITEC was 3 versus 5 days, the number of conference sessions was 132 versus 950+, the number of attendees was 5000 versus 40,000+, the number of vendors was 152 versus 1400+, the number of subforums was 12 versus 230, the number of preconference education symposiums and workshops was 0 versus 12, and the duration of preconference educational symposiums and workshops was 0 versus 1 day. Compared to AMIA, the meeting duration of Chinese CMIAAS was 2 versus 5 days, the number of conference sessions was 42 versus 110, the number of attendees was 200 versus 2500+, the number of vendors was 5 versus 75+, and the number of subforums was 4 versus 10. The number of preconference tutorials and working groups was 0 versus 29, and the duration of tutorials and working group was 0 versus 1.5 days. CONCLUSIONS: Given the size of the Chinese economy and the substantial investment in MI, the output in terms of conferences remains low. The impact of conferences on continuing education to professionals is not significant. Chinese researchers and professionals should approach MI with greater rigor, including validated research methods, formal training, and effective continuing education, in order to utilize knowledge gained by other countries and to expand collaboration. PMID- 28637639 TI - Wendy Burn: On Ilkley Moor with cats. PMID- 28637640 TI - Six members quit US presidential AIDS council as Trump "simply does not care". PMID- 28637641 TI - Five minutes with . . . Debbie Robson. PMID- 28637642 TI - Emergency department attendance following 4-component meningococcal B vaccination in infants. AB - INTRODUCTION: In September 2015, the UK became the first country in the world to introduce the 4-component meningococcal B vaccine(4CMenB) into the routine vaccine schedule for infants. 4CMenB is known to cause fever in infants. Infants presenting with fever, particularly those under 3 months, have a significant risk of serious bacterial infection(SBI). METHOD: Between September 2015 and January 2016, we performed a prospective audit of management of infants between 30 and 180 days attending the regional paediatric emergency department(ED) in Northern Ireland, within 4 days of receiving 4CMenB. RESULTS: 35 ED attendances in infants aged 30-180 days were due to symptoms occurring after primary vaccinations including 4CMenB, representing an estimated 0.8% of the vaccinated population in the catchment area. 86% of infants presented after the first vaccine and parents reported giving paracetamol to 94% of infants. 80% of infants presented with fever. Blood tests were performed in 62% of infants and leucocytosis was present in 73%. All cultures taken were negative and 51% were admitted to hospital. 100% of final diagnoses were vaccine related (diagnosis made by exclusion). DISCUSSION: In this study, an estimated 0.8% of the vaccinated population in the catchment area attended ED with symptoms occurring after primary vaccinations including 4CMenB. Infants with fever have a higher risk of SBI, but infants with fever in the post-vaccination period may not have the same risk. Further data are essential to inform national guidelines on investigation and management of fever in infants following vaccination with 4CMenB, possibly incorporating a less invasive approach. PMID- 28637643 TI - Cancer and the limits of longevity. PMID- 28637645 TI - Doctors can act as advocates on health effects of poverty, says BMA. PMID- 28637644 TI - Does attendance at a specialist antenatal clinic improve clinical outcomes in women with class III obesity compared with standard care? A retrospective case note analysis. AB - OBJECTIVES: To determine whether attendance at a specialised multidisciplinary antenatal clinic for women with class III obesity (BMI >40 kg/m2) is associated with improved clinical outcomes compared with standard antenatal care. DESIGN: Retrospective cohort study using routinely collected data from electronic patient record. SETTING: Community and hospital based antenatal care. PARTICIPANTS: Women with a singleton pregnancy with class III obesity booked for antenatal care and delivered in one of two hospitals in NHS Lothian, Scotland, UK between 2008 and 2014. Maternal and offspring outcomes were compared in women who attended a specialised obesity clinic (n=511) compared with standard antenatal care (n=502). MAIN OUTCOME MEASURES: Included stillbirth, low birth weight, gestational diabetes, induction of labour and caesarean section. RESULTS: Compared with standard care, women receiving specialist care were less likely to have a stillbirth (OR 0.12, 95% CI 0.06 to 0.97) and a low birthweight baby (OR 0.57, 95% CI 0.33 to 0.99) and more likely to be screened for (100% vs 73.6%; p<0.001) and diagnosed with (26.0% vs 12.5%; p<0.001) gestational diabetes, to require induction of labour (38.4% vs 29.9%; p=0.009), an elective (20.3% vs 17.7%; p<0.001) and emergency (23.9% vs 20.3%; p<0.001) caesarean section and attend antenatal triage one or more times during pregnancy (77.7% vs 53.1%; p<0.001). Women attending the specialist clinic had a higher BMI (44.5 kg/m2 (4.3) vs 43.2 kg/m2 (3.1); p<0.001) and were more likely to be nulliparous (46.0% vs 24.9%; p<0.001). There were no other differences in maternal demographic or maternal and offspring outcomes between groups. CONCLUSIONS: Attendance at a specialised antenatal clinic for obesity is associated with reduced rates of stillbirth and low birth weight and improved detection of gestational diabetes. The improvement in clinical outcomes is associated with an increase in healthcare attendance to obstetric triage and clinical interventions including induction of labour and caesarean section. PMID- 28637646 TI - Author's reply to Dean. PMID- 28637647 TI - Chronic purulent nasal discharge. PMID- 28637648 TI - Are final year medical students ready to save lives in Italy? Not yet. PMID- 28637649 TI - Measuring the distribution of adolescent births among 15-19-year-olds in Chile: an ecological study. AB - BACKGROUND: Although within Latin America Chile has one of the lowest birth rates among adolescents, it has a high rate in comparison to other developed nations. AIM: To explore trends in birth rates among adolescents by selected demographics in Chile. METHODS: The national trend in birth rates was examined for women aged 15-19 years between 1992 and 2012. The birth rates for regions and communes were calculated using birth and census data and were analysed to determine its relationship to the regional or communal poverty rate, which were obtained from the Casen Survey. Differences in educational attainment were explored among adolescents with first-order and second-order or higher births using the Chi square test. RESULTS: The birth rate among adolescents has experienced a 25% decline in the past 20 years. Cross-regional variance in birth rates could not be explained by poverty rates. Within the Metropolitan Region, there is a positive correlation between poverty and adolescent birth rates. Among adolescents giving birth, 67% had completed 10-12 years of school at birth, but there is a significant difference in educational attainment between girls with a first-order and those with a higher-order birth. CONCLUSIONS: In Chile, the adolescent birth rate varies greatly among regions and communes. This study found that urban and wealthy areas had lower birth rates than poor and rural ones, and that girls with a first-order birth had completed more years of school than girls with higher order births. PMID- 28637650 TI - Achalasia leading to diagnosis of adenocarcinoma of the oesophagus. AB - A 50-year-old male with a 7 month history of progressive dysphagia to solids then subsequently to liquids. He underwent a diagnostic gastroscopy which was normal. A further barium swallow suggested achalasia. He was referred to a tertiary centre, where he underwent pH and manometry studies which confirmed a diagnosis of achalasia. He was referred for a laparoscopic cardiomyotomy, and at surgery there was a suspected tumour at the gastro-oesophageal junction. A follow-up endoscopy with biopsies was normal. Following this, a positron emission tomography scan showed T3 distal oesophageal cancer with no nodal involvement or distal metastasis. An attempt at oesophagectomy was performed, but at operation there was locally advanced carcinoma infiltrating the coeliac axis. He is currently undergoing palliative chemotherapy. PMID- 28637651 TI - Pivotal Role of O-GlcNAc Modification in Cold-Induced Thermogenesis by Brown Adipose Tissue Through Mitochondrial Biogenesis. AB - Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. O-linked N-acetylglucosamine (O-GlcNAc) modification is characterized by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of O-GlcNAc modification in adipose tissues. Here, we report the critical role of O-GlcNAc modification in cold-induced thermogenesis. Deletion of Ogt in WAT and BAT using adiponectin promoter-driven Cre recombinase resulted in severe cold intolerance with decreased uncoupling protein 1 (Ucp1) expression. Furthermore, Ogt deletion led to decreased mitochondrial protein expression in conjunction with decreased peroxisome proliferator-activated receptor gamma coactivator 1-alpha protein expression. This phenotype was further confirmed by deletion of Ogt in BAT using Ucp1 promoter-driven Cre recombinase, suggesting that O-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a fatty acid-rich ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, O-GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses. PMID- 28637652 TI - GM-CSF- and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures. AB - M1 and M2 activated macrophages (Mphis) have different roles in inflammation. Because pathogens may first encounter resting cells, we investigated lipid mediator profiles prior to full activation. Human monocytes were differentiated with granulocyte Mphi colony-stimulating factor (GM-CSF) or Mphi colony stimulating factor (M-CSF), which are known to prime toward M1 or M2 phenotypes, respectively. Lipid mediators released during resting conditions and produced in response to bacterial stimuli (LPS/N-formylmethionyl-leucyl-phenylalanine or peptidoglycan) were quantified by liquid chromatography-mass spectrometry. In resting conditions, both Mphi phenotypes released primarily proresolving lipid mediators (prostaglandin E2 metabolite, lipoxin A4, and 18 hydroxyeicosapentaenoic acid). A striking shift toward proinflammatory eicosanoids was observed when the same cells were exposed (30 min) to bacterial stimuli: M-CSF Mphis produced considerably more 5-lipoxygenase products, particularly leukotriene C4, potentially linked to M2 functions in asthma. Prostaglandins were formed by both Mphi types. In the M-CSF cells, there was also an enhanced release of arachidonic acid and activation of cytosolic phospholipase A2 However, GM-CSF cells expressed higher levels of 5-lipoxygenase and 5 lipoxygenase-activating protein, and in ionophore incubations these cells also produced the highest levels of 5-hydroxyeicosatetraenoic acid. In summary, GM-CSF and M-CSF Mphis displayed similar proresolving lipid mediator formation in resting conditions but shifted toward different proinflammatory eicosanoids upon bacterial stimuli. This demonstrates that preference for specific eicosanoid pathways is primed by CSFs before full M1/M2 activation.-Lukic, A., Larssen, P., Fauland, A., Samuelsson, B., Wheelock, C. E., Gabrielsson, S., Radmark, O. GM-CSF and M-CSF-primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures. PMID- 28637654 TI - Implementation of Instrument-Based Vision Screening for Preschool-Age Children in Primary Care. AB - BACKGROUND: Vision screening is an essential element of well-child care for young children. Recently, several professional groups have recommended the use of instrument-based screening; however, studies demonstrating the effectiveness of this technique in pediatric primary care settings are lacking. METHODS: We designed a cluster randomized quality improvement project to test the implementation of instrument-based vision screening for 3- to 5-year-old children within a pediatric primary care network. The program consisted of 12 pediatric practices randomized into phase 1 and phase 2 groups. We evaluated the effect of the intervention on completed vision screening at well-child visits, family satisfaction, and referrals to eye care specialists. RESULTS: Instrument-based vision screening increased completed screening among 3- to 5-year-old children from 54% to 89% in the phase 1 group and from 65% to 92% in the phase 2 group. Improvement was most marked among 3-year-old children, with completed screening increasing from 39% with chart-based screening to 87% with instrument screening. Family satisfaction was higher with instrument screening. In addition, instrument screening was associated with a 15% reduction in referrals to eye care specialists. CONCLUSIONS: Instrument-based vision screening for preschool-aged children can be effectively implemented into primary care practice, results in substantially improved rates of completed vision screening at well-child visits, and may result in a reduction in unnecessary referrals to eye care specialists. Additional research is needed regarding how best to overcome barriers to the widespread use of this technology in pediatric primary care settings, as well as its longer-term effect on referrals and the prevalence of amblyopia. PMID- 28637653 TI - The Prognostic Value of Fasting Plasma Glucose, Two-Hour Postload Glucose, and HbA1c in Patients With Coronary Artery Disease: A Report From EUROASPIRE IV: A Survey From the European Society of Cardiology. AB - OBJECTIVE: Three tests are recommended for identifying dysglycemia: fasting glucose (FPG), 2-h postload glucose (2h-PG) from an oral glucose tolerance test (OGTT), and glycated hemoglobin A1c (HbA1c). This study explored the prognostic value of these screening tests in patients with coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: FPG, 2h-PG, and HbA1c were used to screen 4,004 CAD patients without a history of diabetes (age 18-80 years) for dysglycemia. The prognostic value of these tests was studied after 2 years of follow-up. The primary end point included cardiovascular mortality, nonfatal myocardial infarction, stroke, or hospitalization for heart failure and a secondary end point of incident diabetes. RESULTS: Complete information including all three glycemic parameters was available in 3,775 patients (94.3%), of whom 246 (6.5%) experienced the primary end point. Neither FPG nor HbA1c predicted the primary outcome, whereas the 2h-PG, dichotomized as <7.8 vs. >=7.8 mmol/L, was a significant predictor (hazard ratio 1.38, 95% CI 1.07-1.78; P = 0.01). During follow-up, diabetes developed in 78 of the 2,609 patients (3.0%) without diabetes at baseline. An FPG between 6.1 and 6.9 mmol/L did not predict incident diabetes, whereas HbA1c 5.7-6.5% and 2h-PG 7.8-11.0 mmol/L were both significant independent predictors. CONCLUSIONS: The 2h-PG, in contrast to FPG and HbA1c, provides significant prognostic information regarding cardiovascular events in patients with CAD. Furthermore, elevated 2h-PG and HbA1c are significant prognostic indicators of an increased risk of incident diabetes. PMID- 28637655 TI - Elimination Communication: Diaper-Free in America. PMID- 28637656 TI - Benchmarking life expectancy and cancer mortality: global comparison with cardiovascular disease 1981-2010. AB - Objective To quantify the impact of cancer (all cancers combined and major sites) compared with cardiovascular disease (CVD) on longevity worldwide during 1981 2010.Design Retrospective demographic analysis using aggregated data.Setting National civil registration systems in member states of the World Health Organization.Participants 52 populations with moderate to high quality data on cause specific mortality.Main outcome measures Disease specific contributions to changes in life expectancy in ages 40-84 (LE40-84) over time in populations grouped by two levels of Human Development Index (HDI) values.Results Declining CVD mortality rates during 1981-2010 contributed to, on average, over half of the gains in LE40-84; the corresponding gains were 2.3 (men) and 1.7 (women) years, and 0.5 (men) and 0.8 (women) years in very high and medium and high HDI populations, respectively. Declines in cancer mortality rates contributed to, on average, 20% of the gains in LE40-84, or 0.8 (men) and 0.5 (women) years in very high HDI populations, and to over 10% or 0.2 years (both sexes) in medium and high HDI populations. Declining lung cancer mortality rates brought about the largest LE40-84 gain in men in very high HDI populations (up to 0.7 years in the Netherlands), whereas in medium and high HDI populations its contribution was smaller yet still positive. Among women, declines in breast cancer mortality rates were largely responsible for the improvement in longevity, particularly among very high HDI populations (up to 0.3 years in the United Kingdom). In contrast, losses in LE40-84 were observed in many medium and high HDI populations as a result of increasing breast cancer mortality rates.Conclusions The control of CVD has led to substantial gains in LE40-84 worldwide. The inequality in improvement in longevity attributed to declining cancer mortality rates reflects inequities in implementation of cancer control, particularly in less resourced populations and in women. Global actions are needed to revitalize efforts for cancer control, with a specific focus on less resourced countries. PMID- 28637657 TI - Seasonal factors influence quantal transmitter release and calcium dependence at amphibian neuromuscular junctions. AB - Amphibian neuromuscular junctions (NMJs) are composed of hundreds of neurotransmitter release sites that exhibit nonuniform transmitter release probabilities and demonstrated seasonal modulation. We examined whether recruitment of release sites is variable when the extracellular calcium concentration ([Ca2+]o) is increased in the wet and dry seasons. The amount of transmitter released from the entire nerve terminal increases by approximately the fourth power as [Ca2+]o is increased. Toad (Bufo marinus) NMJs were visualized using 3,3'-diethyloxardicarbocyanine iodide [DiOC2(5)] fluorescence, and focal loose patch extracellular recordings were used to record the end-plate currents (EPCs) from small groups of release sites. Quantal content (me ), average probability of quantal release (pe ), and the number of active release sites (ne ) were determined for different [Ca2+]o Our results indicated that the recruitment of quantal release sites with increasing [Ca2+]o differs spatially (between different groups of release sites) and also temporally (in different seasons). These differences were reflected by the nonuniform alterations in pe and ne Most release site groups demonstrated an increase in both pe and ne when [Ca2+]o increased. In ~30% of release site groups examined, pe decreased while ne increased only during the active period (wet season). Although the dry season induced parallel right shift in the quantal release versus extracellular calcium concentration when compared with the wet season, the dependence of quantal content on [Ca2+]o was not changed. These results demonstrate the flexibility, reserve, and adaptive capacity of neuromuscular junctions in maintaining appropriate levels of neurotransmission. PMID- 28637658 TI - Decreased myoblast differentiation in chronic binge alcohol-administered simian immunodeficiency virus-infected male macaques: role of decreased miR-206. AB - Skeletal muscle stem cells play a critical role in regeneration of myofibers. We previously demonstrated that chronic binge alcohol (CBA) markedly attenuates myoblast differentiation potential and myogenic gene expression. Muscle-specific microRNAs (miRs) are implicated in regulation of myogenic genes. The aim of this study was to determine whether myoblasts isolated from asymptomatic CBA administered simian immunodeficiency virus (SIV)-infected macaques treated with antiretroviral therapy (ART) showed similar impairments and, if so, to elucidate potential underlying mechanisms. Myoblasts were isolated from muscle at 11 mo after SIV infection from CBA/SIV macaques and from time-matched sucrose (SUC) treated SIV-infected (SUC/SIV) animals and age-matched controls. Myoblast differentiation and myogenic gene expression were significantly decreased in myoblasts from SUC/SIV and CBA/SIV animals compared with controls. SIV and CBA decreased muscle-specific miR-206 in plasma and muscle and SIV decreased miR-206 expression in myoblasts, with no statistically significant changes in other muscle-specific miRs. These findings were associated with a significant increase in histone deacetylase 4 (HDAC4) and decrease in myogenic enhancer factor 2C (MEF2C) expression in CBA/SIV muscle. Transfection with miR-206 inhibitor decreased myotube differentiation, increased expression of HDAC4, and decreased MEF2C, suggesting a critical role of miR-206 in myogenesis. Moreover, HDAC4 was confirmed to be a direct miR-206 target. These results support a mechanistic role for decreased miR-206 in suppression of myoblast differentiation resulting from chronic alcohol and SIV infection. The parallel changes in skeletal muscle and circulating levels of miR-206 warrant studies to establish the possible use of plasma miR-206 as an indicator of impaired muscle function. PMID- 28637659 TI - Enduring effects of perinatal nicotine exposure on murine sleep in adulthood. AB - The long-term consequences of early life nicotine exposure are poorly defined. Approximately 8-10% of women report smoking during pregnancy, and this may promote aberrant development in the offspring. To this end, we investigated potential enduring effects of perinatal nicotine exposure on murine sleep and affective behaviors in adulthood (~13-15 wk of age) in C57Bl6j mice. Mothers received a water bottle containing 200 ug/ml nicotine bitartrate dihydrate in 2% wt/vol saccharin or pH-matched 2% saccharin with 0.2% (vol/vol) tartaric acid throughout pregnancy and before weaning. Upon reaching adulthood, offspring were tested in the open field and elevated plus maze, as well as the forced swim and sucrose anhedonia tests. Nicotine-exposed male (but not female) mice had reduced mobility in the open field, but no differences were observed in anxiety-like or depressive-like responses. Upon observing this male-specific phenotype, we further assessed sleep-wake states via wireless EEG/EMG telemetry. Following baseline recording, we assessed whether mice exposed to nicotine altered their homeostatic response to 5 h of total sleep deprivation and whether nicotine influenced responses to a powerful somnogen [i.e., lipopolysaccharides (LPS)]. Males exposed to perinatal nicotine decreased the percent time spent awake and increased time in non-rapid eye movement (NREM) sleep, without changes to REM sleep. Nicotine-exposed males also displayed exaggerated responses (increased time asleep and NREM spectral power) to sleep deprivation. Nicotine-exposed animals additionally had blunted EEG slow-wave responses to LPS administration. Together, our data suggest that perinatal nicotine exposure has long-lasting effects on normal sleep and homeostatic sleep processes into adulthood. PMID- 28637660 TI - Interleukin-33 induces growth-regulated oncogene-alpha expression and secretion in human umbilical vein endothelial cells. AB - Although interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays proinflammatory roles in immune cells as an "alarmin," little is known regarding the biological actions of IL-33 on vascular endothelial cells. To investigate the effects of IL-33 on vascular endothelial cells, we first screened the IL-33 regulated proteins in human umbilical vein endothelial cells (HUVECs) using a dot blot array and observed that IL-33 markedly increased growth-regulated oncogene alpha (GRO-alpha), a chemokine that is also known as chemokine (C-X-C motif) ligand 1 (CXCL1). Real-time reverse transcription PCR and ELISA demonstrated that IL-33 induced GRO-alpha expression and secretion in HUVECs in a dose- and a time dependent manner. Western immunoblot assay revealed that IL-33 activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK). In addition, translocation of nuclear factor-kappaB (NF-kappaB) p65 to the nucleus of HUVECs was observed by IL-33 stimulation. Furthermore, treatment with pharmacological inhibitors against ERK1/2 (PD98059), JNK (SP600125), or NF-kappaB (BAY11-7085) significantly suppressed IL-33-induced GRO-alpha gene expression and secretion from HUVECs. Moreover, immunohistochemical staining demonstrated that IL-33 and GRO-alpha coexpressed in the endothelium of human carotid atherosclerotic plaque. Taken together, the present study indicates that IL-33 localized in the human atherosclerotic plaque increases GRO-alpha mRNA expression and protein secretion via activation of ERK1/2, JNK, and NF-kappaB in HUVECs, suggesting that IL-33 plays an important role in the pathophysiology and development of atherosclerosis. PMID- 28637661 TI - The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment. AB - Chromosome rearrangements involving the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPCs) expressing MLL AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development. Cells expressing MLL-AF9 efficiently developed AML in NSGS mice. In contrast, MLL-Af4 cells, which were fully oncogenic under lymphoid conditions present in NSG mice, displayed compromised transformation capacity in a myeloid microenvironment. MLL-Af4 activated a self-renewal program in a lineage-dependent manner, showing the leukemogenic activity of MLL-Af4 was interlinked with lymphoid lineage commitment. The C-terminal homology domain (CHD) of Af4 was sufficient to confer this linkage. Although the MLL-CHD fusion protein failed to immortalize HSPCs in myeloid conditions in vitro, it could successfully induce ALL in NSG mice. Our data suggest that defective self-renewal ability and leukemogenesis of MLL-Af4 myeloid cells could contribute to the strong B-cell ALL association of MLL-AF4 leukemia observed in the clinic. PMID- 28637663 TI - NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease. AB - Transfer of T-cell receptors (TCRs) specific for tumor-associated antigens is a promising approach for cancer immunotherapy. We developed the TCR gene editing technology that is based on the knockout of the endogenous TCR alpha and beta genes, followed by the introduction of tumor-specific TCR genes, and that proved safer and more effective than conventional TCR gene transfer. Although successful, complete editing requires extensive cell manipulation and 4 transduction procedures. Here we propose a novel and clinically feasible TCR "single editing" (SE) approach, based on the disruption of the endogenous TCR alpha chain only, followed by the transfer of genes encoding for a tumor-specific TCR. We validated SE with the clinical grade HLA-A2 restricted NY-ESO-1157-165 specific TCR. SE allowed the rapid production of high numbers of tumor-specific T cells, with optimal TCR expression and preferential stem memory and central memory phenotype. Similarly to unedited T cells redirected by TCR gene transfer (TCR transferred [TR]), SE T cells efficiently killed NY-ESO-1pos targets; however, although TR cells proved highly alloreactive, SE cells showed a favorable safety profile. Accordingly, when infused in NSG mice previously engrafted with myeloma, SE cells mediated tumor rejection without inducing xenogeneic graft-versus-host disease, thus resulting in significantly higher survival than that observed in mice treated with TR cells. Overall, single TCR gene editing represents a clinically feasible approach that is able to increase the safety and efficacy of cancer adoptive immunotherapy. PMID- 28637662 TI - Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. AB - Daratumumab plus pomalidomide and dexamethasone (pom-dex) was evaluated in patients with relapsed/refractory multiple myeloma with >=2 prior lines of therapy who were refractory to their last treatment. Patients received daratumumab 16 mg/kg at the recommended dosing schedule, pomalidomide 4 mg daily for 21 days of each 28-day cycle, and dexamethasone 40 mg weekly. Safety was the primary end point. Overall response rate (ORR) and minimal residual disease (MRD) by next-generation sequencing were secondary end points. Patients (N = 103) received a median (range) of 4 (1-13) prior therapies; 76% received >=3 prior therapies. The safety profile of daratumumab plus pom-dex was similar to that of pom-dex alone, with the exception of daratumumab-specific infusion-related reactions (50%) and a higher incidence of neutropenia, although without an increase in infection rate. Common grade >=3 adverse events were neutropenia (78%), anemia (28%), and leukopenia (24%). ORR was 60% and was generally consistent across subgroups (58% in double-refractory patients). Among patients with a complete response or better, 29% were MRD negative at a threshold of 10-5 Among the 62 responders, median duration of response was not estimable (NE; 95% confidence interval [CI], 13.6-NE). At a median follow-up of 13.1 months, the median progression-free survival was 8.8 (95% CI, 4.6-15.4) months and median overall survival was 17.5 (95% CI, 13.3-NE) months. The estimated 12-month survival rate was 66% (95% CI, 55.6-74.8). Aside from increased neutropenia, the safety profile of daratumumab plus pom-dex was consistent with that of the individual therapies. Deep, durable responses were observed in heavily treated patients. The study was registered at www.clinicaltrials.gov as #NCT01998971. PMID- 28637665 TI - Hmga2 promotes the development of myelofibrosis in Jak2V617F knockin mice by enhancing TGF-beta1 and Cxcl12 pathways. AB - Myelofibrosis (MF) is a devastating blood disorder. The JAK2V617F mutation has been detected in ~50% cases of MF. Elevated expression of high-mobility group AT hook 2 (HMGA2) has also been frequently observed in patients with MF. Interestingly, upregulation of HMGA2 expression has been found in association with the JAK2V617F mutation in significant cases of MF. However, the contribution of HMGA2 in the pathogenesis of MF remains elusive. To determine the effects of concurrent expression of HMGA2 and JAK2V617F mutation in hematopoiesis, we transduced bone marrow cells from Jak2V617F knockin mice with lentivirus expressing Hmga2 and performed bone marrow transplantation. Expression of Hmga2 enhanced megakaryopoiesis, increased extramedullary hematopoiesis, and accelerated the development of MF in mice expressing Jak2V617F Mechanistically, the data show that expression of Hmga2 enhances the activation of transforming growth factor-beta1 (TGF-beta1) and Cxcl12 pathways in mice expressing Jak2V617F In addition, expression of Hmga2 causes upregulation of Fzd2, Ifi27l2a, and TGF beta receptor 2. Forced expression of Cxcl12, Fzd2, or Ifi27l2a increases megakaryocytic differentiation and proliferation in the bone marrow of Jak2V617F mice, whereas TGF-beta1 or Cxcl12 stimulation induces collagen deposition in the bone marrow mesenchymal stromal cells. Together, these findings demonstrate that expression of Hmga2 cooperates with Jak2V617F in the pathogenesis of MF. PMID- 28637664 TI - Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding. AB - Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out alphaIIbbeta3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring >=1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation. PMID- 28637667 TI - Thrombocytopenia in pregnancy. AB - Thrombocytopenia develops in 5% to 10% of women during pregnancy or in the immediate postpartum period. A low platelet count is often an incidental feature, but it might also provide a biomarker of a coexisting systemic or gestational disorder and a potential reason for a maternal intervention or treatment that might pose harm to the fetus. This chapter reflects our approach to these issues with an emphasis on advances made over the past 5 to 10 years in understanding and managing the more common causes of thrombocytopenia in pregnancy. Recent trends in the management of immune thrombocytopenia translate into more women contemplating pregnancy while on treatment with thrombopoietin receptor agonists, rituximab, or mycophenylate, which pose known or unknown risks to the fetus. New criteria to diagnose preeclampsia, judicious reliance on measurement of ADAMTS13 to make management decisions in suspected thrombotic thrombocytopenic purpura, new evidence supporting the efficacy and safety of anticomplement therapy for atypical hemolytic uremic syndrome during pregnancy, and implications of thrombotic microangiopathies for subsequent pregnancies are evolving rapidly. The goals of the chapter are to help the hematology consultant work through the differential diagnosis of thrombocytopenia in pregnancy based on trimester of presentation, severity of thrombocytopenia, and coincident clinical and laboratory manifestations, and to provide guidance for dealing with some of the more common and difficult diagnostic and management decisions. PMID- 28637666 TI - NR4A orphan nuclear receptor family members, NR4A2 and NR4A3, regulate neutrophil number and survival. AB - The lifespan of neutrophils is plastic and highly responsive to factors that regulate cellular survival. Defects in neutrophil number and survival are common to both hematologic disorders and chronic inflammatory diseases. At sites of inflammation, neutrophils respond to multiple signals that activate protein kinase A (PKA) signaling, which positively regulates neutrophil survival. The aim of this study was to define transcriptional responses to PKA activation and to delineate the roles of these factors in neutrophil function and survival. In human neutrophil gene array studies, we show that PKA activation upregulates a significant number of apoptosis-related genes, the most highly regulated of these being NR4A2 and NR4A3 Direct PKA activation by the site-selective PKA agonist pair N6/8-AHA (8-AHA-cAMP and N6-MB-cAMP) and treatment with endogenous activators of PKA, including adenosine and prostaglandin E2, results in a profound delay of neutrophil apoptosis and concomitant upregulation of NR4A2/3 in a PKA-dependent manner. NR4A3 expression is also increased at sites of neutrophilic inflammation in a human model of intradermal inflammation. PKA activation also promotes survival of murine neutrophil progenitor cells, and small interfering RNA to NR4A2 decreases neutrophil production in this model. Antisense knockdown of NR4A2 and NR4A3 homologs in zebrafish larvae significantly reduces the absolute neutrophil number without affecting cellular migration. In summary, we show that NR4A2 and NR4A3 are components of a downstream transcriptional response to PKA activation in the neutrophil, and that they positively regulate neutrophil survival and homeostasis. PMID- 28637669 TI - High rise living after Grenfell. PMID- 28637668 TI - Approaches to assessing shoulder pain. PMID- 28637671 TI - Are new hepatitis C drugs all they're cracked up to be? PMID- 28637670 TI - A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis. AB - OBJECTIVES: The aim of this report is to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence as well as similar efficacy, safety and immunogenicity between GP2013, a biosimilar rituximab, and innovator rituximab (RTX) in patients with rheumatoid arthritis (RA) with inadequate response or intolerance to tumour necrosis factor inhibitor (TNFi) treatment. METHODS: In this multinational, randomised, double-blind, parallel-group study, 312 patients with active disease despite prior TNFi therapy were randomised to receive GP2013 or either the EU (RTX-EU) or the US (RTX-US) reference product, along with methotrexate (MTX) and folic acid. The primary endpoint was the area under the serum concentration-time curve from study drug infusion to infinity (AUC0-inf). Additional PK and PD parameters, along with efficacy, immunogenicity and safety outcomes were also assessed up to week 24. RESULTS: The 90% CI of the geometric mean ratio of the AUCs were within the bioequivalence limits of 80% to 125% for all three comparisons; GP2013 versus RTX-EU: 1.106 (90% CI 1.010 to 1.210); GP2013 versus RTX-US: 1.012 (90% CI 0.925 to 1.108); and RTX-EU versus RTX-US: 1.093 (90% CI 0.989 to 1.208). Three-way PD equivalence of B cell depletion was also demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. CONCLUSIONS: Three-way PK/PD equivalence of GP2013, RTX EU and RTX-US was demonstrated. Efficacy, safety and immunogenicity profiles were similar between GP2013 and RTX. TRIAL REGISTRATION NUMBER: NCT01274182; Results. PMID- 28637673 TI - Lipopolysaccharide downregulates macrophage-derived IL-22 to modulate alcohol induced hepatocyte cell death. AB - Interleukin-22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS, and effects on alcohol-induced hepatocyte cell death are unexplored and were examined in this study. Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5-fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration-dependent manner with a maximum reduction of 5-fold. LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacological inhibitor of c-Jun NH2-terminal kinase (JNK) and by JNK knockdown. Next, we explored whether macrophage-derived IL-22 regulated ethanol-induced hepatocyte death. Conditioned media from IL-10-stimulated macrophages attenuated ethanol-induced hepatocyte caspase-3/7 activity, and apoptosis as assessed by fluorometric assay and TdT-mediated dUTP nick-end labeling (TUNEL) staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy-drinking controls, implying a state of IL-22 resistance in human AH. Macrophage-derived IL-22 protects hepatocytes from ethanol-induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH. PMID- 28637676 TI - S-nitrosylation/denitrosylation regulates myoblast proliferation. Focus on "Balance between S-nitrosylation and denitrosylation modulates myoblast proliferation independently of soluble guanylyl cyclase activation". PMID- 28637675 TI - Structure/functional aspects of the human riboflavin transporter-3 (SLC52A3): role of the predicted glycosylation and substrate-interacting sites. AB - The human riboflavin (RF) transporter-3 (hRFVT-3; product of the SLC52A3 gene) plays an essential role in the intestinal RF absorption process and is expressed exclusively at the apical membrane domain of polarized enterocytes. Previous studies have characterized different physiological/biological aspects of this transporter, but nothing is known about the glycosylation status of the hRFVT-3 protein and role of this modification in its physiology/biology. Additionally, little is known about the residues in the hRFVT-3 protein that interact with the ligand, RF. We addressed these issues using appropriate biochemical/molecular approaches, a protein-docking model, and established intestinal/renal epithelial cells. Our results showed that the hRFVT-3 protein is glycosylated and that glycosylation is important for its function. Mutating the predicted N glycosylation sites at Asn94 and Asn168 led to a significant decrease in RF uptake; it also led to a marked intracellular (in the endoplasmic reticulum, ER) retention of the mutated proteins as shown by live-cell confocal imaging studies. The protein-docking model used in this study has identified a number of putative substrate-interacting sites: Ser16, Ile20, Trp24, Phe142, Thr314, and Asn315 Mutating these potential interacting sites was indeed found to lead to a significant inhibition in RF uptake and to intracellular (ER) retention of the mutated proteins (except for the Phe142 mutant). These results demonstrate that the hRFVT-3 protein is glycosylated and this glycosylation is important for its function and cell surface expression. This study also identified a number of residues in the hRFVT-3 polypeptide that are important for its function/cell surface expression. PMID- 28637677 TI - Is FoxO1 the culprit, partner in crime, or a protector in systemic inflammation? PMID- 28637674 TI - Oxidative stress destabilizes protein arginine methyltransferase 4 via glycogen synthase kinase 3beta to impede lung epithelial cell migration. AB - Oxidative stress impacts normal cellular function leading to the pathogenesis of various diseases including pulmonary illnesses. Protein arginine methyltransferase 4 (PRMT4) is critical for normal lung alveolar epithelial cell development; however, the regulation of PRMT4 within such pulmonary diseases has yet to be elucidated. Using biochemical approaches, we uncovered that peroxide (H2O2) treatment decreases PRMT4 protein stability in murine lung epithelial (MLE12) cells to impede cell migration. Protein kinase glycogen synthase kinase 3beta (GSK-3beta) interacts with PRMT4 and catalyzes PRMT4 T132 phosphorylation that protects PRMT4 from ubiquitin proteasomal degradation. H2O2 downregulates GSK-3beta to reduce PRMT4 at protein level. PRMT4 promotes cell migration and H2O2 degrades PRMT4 to inhibit lung epithelial cell migration. These observations demonstrate that oxidative stress destabilizes PRMT4 via GSK-3beta signaling to impede lung epithelial cell migration that may hinder the lung repair and regeneration process. PMID- 28637678 TI - Regulation of the unfolded protein response by noncoding RNA. AB - Cells are exposed to various intrinsic and extrinsic stresses in both physiological and pathological conditions. To adapt to those conditions, cells have evolved various mechanisms to cope with the disturbances in protein demand, largely through the unfolded protein response (UPR) in the endoplasmic reticulum (ER), but also through the integrated stress response (ISR). Both responses initiate downstream signaling to transcription factors that, in turn, trigger adaptive programs and/or in the case of prolonged stress, cell death mechanisms. Recently, noncoding RNAs, including microRNA and long noncoding RNA, have emerged as key players in the stress responses. These noncoding RNAs act as both regulators and effectors of the UPR and fine-tune the output of the stress signaling pathways. Although much is known about the UPR and the cross talk that exists between pathways, the contribution of small noncoding RNA has not been fully assessed. Herein we bring together and review the current known functions of noncoding RNA in regulating adaptive pathways in both physiological and pathophysiological conditions, illustrating how they operate within the known UPR functions and contribute to diverse cellular outcomes. PMID- 28637680 TI - Myoendothelial gap junctions mediate regulation of angiopoietin-2-induced vascular hyporeactivity after hypoxia through connexin 43-gated cAMP transfer. AB - Angiopoietin-2 (Ang-2) contributes to vascular hyporeactivity after hemorrhagic shock and hypoxia through upregulation of inducible nitric oxide synthase (iNOS) in a vascular endothelial cell (VEC)-specific and Ang-2/Tie2 receptor-dependent manner. While iNOS is primarily expressed in vascular smooth muscle cells (VSMCs), the mechanisms of signal transfer from VECs to VSMCs are unknown. A double-sided coculture model with VECs and VSMCs from Sprague-Dawley rats was used to investigate the role of myoendothelial gap junctions (MEGJs), the connexin (Cx) isoforms involved, and other relevant mechanisms. After hypoxia, VSMCs treated with exogenous Ang-2 showed increased iNOS expression and hyporeactivity, as well as MEGJ formation and communication. These Ang-2 effects were suppressed by the MEGJ inhibitor 18alpha-glycyrrhetic acid (18-GA), Tie2 siRNA, or Cx43 siRNA. Reagents antagonizing cAMP or protein kinase A (PKA) in VECs inhibited Cx43 expression in MEGJs, decreasing MEGJ formation and associated communication, after hypoxia following Ang-2 treatment. The increased cAMP levels in VSMCs and transfer of Alexa Fluor 488-labeled cAMP from VECs to VSMCs, after hypoxia following Ang-2 treatment, was antagonized by Cx43 siRNA. A cAMP antagonist added to VECs or VSMCs inhibited both increased iNOS expression and hyporeactivity in VSMCs subjected to hypoxia following Ang-2 treatment. Based on these findings, we propose that Cx43 was the Cx isoform involved in MEGJ-mediated VEC-dependent regulation of Ang-2, which induces iNOS protein expression and vascular hyporeactivity after hypoxia. Cx43 was upregulated by cAMP and PKA, permitting cAMP transfer between cells. PMID- 28637679 TI - Characterization of ectonucleotidase expression in the rat carotid body: regulation by chronic hypoxia. AB - The carotid body (CB) chemoreflex maintains blood Po2 and Pco2/H+ homeostasis and displays sensory plasticity during exposure to chronic hypoxia. Purinergic signaling via P1 and P2 receptors plays a pivotal role in shaping the afferent discharge at the sensory synapse containing catecholaminergic chemoreceptor (type I) cells, glial-like type II cells, and sensory (petrosal) nerve endings. However, little is known about the family of ectonucleotidases that control synaptic nucleotide levels. Using quantitative PCR (qPCR), we first compared expression levels of ectonucleoside triphosphate diphosphohydrolases (NTPDases1,2,3,5,6) and ecto-5'-nucleotidase (E5'Nt/CD73) mRNAs in juvenile rat CB vs. brain, petrosal ganglia, sympathetic (superior cervical) ganglia, and a sympathoadrenal chromaffin (MAH) cell line. In whole CB extracts, qPCR revealed a high relative expression of surface-located members NTPDase1,2 and E5'Nt/CD73, compared with low NTPDase3 expression. Immunofluorescence staining of CB sections or dissociated CB cultures localized NTPDase2,3 and E5'Nt/CD73 protein to the periphery of type I clusters, and in association with sensory nerve fibers and/or isolated type II cells. Interestingly, in CBs obtained from rats reared under chronic hypobaric hypoxia (~60 kPa, equivalent to 4,300 m) for 5-7 days, in addition to the expected upregulation of tyrosine hydroxylase and VEGF mRNAs, there was a significant upregulation of NTPDase3 and E5'Nt/CD73 mRNA, but a downregulation of NTPDase1 and NTPDase2 relative to normoxic controls. We conclude that NTPDase1,2,3 and E5'Nt/CD73 are the predominant surface-located ectonucleotidases in the rat CB and suggest that their differential regulation during chronic hypoxia may contribute to CB plasticity via control of synaptic ATP, ADP, and adenosine pools. PMID- 28637681 TI - Two Tales of Cytauxzoon felis Infections in Domestic Cats. AB - Cytauxzoonosis is an emerging infectious disease that affects wild felids as well as the domestic cat; it is caused by the apicomplexan protozoan parasites belonging to the genus Cytauxzoon. Cytauxzoonfelis is the species of major concern, whose transmission occurs via the bite of an infected tick. Cytauxzoonosis of the domestic cat has historically been considered uniformly fatal, with a short course of illness, and most domestic cats die within 9 to 15 days postinfection. However, increasing evidence of domestic cats surviving C. felis infection suggests the existence of different strains with various levels of pathogenicity. Although wild felids are considered natural reservoirs for this parasite, a number of studies suggest that domestic cats that have survived nonlethal infections may serve as an additional reservoir. The current article comprehensively reviews the parasite and its life cycle, geographic distribution, genetic variability, and pathogenesis, as well as host immunology and the diagnosis, treatment, and prevention of infection in the domestic cat. This information should provide a basis for better understanding the parasite as well as the pathogenesis of the disease. PMID- 28637683 TI - An environmental scan of quality indicators in critical care. AB - BACKGROUND: We performed a directed environmental scan to identify and categorize quality indicators unique to critical care that are reported by key stakeholder organizations. METHODS: We convened a panel of experts (n = 9) to identify key organizations that are focused on quality improvement or critical care, and reviewed their online publications and website content for quality indicators. We identified quality indicators specific to the care of critically ill adult patients and then categorized them according to the Donabedian and the Institute of Medicine frameworks. We also noted the organizations' rationale for selecting these indicators and their reported evidence base. RESULTS: From 28 targeted organizations, we identified 222 quality indicators, 127 of which were unique. Of the 127 indicators, 63 (32.5%) were safety indicators and 61 (31.4%) were effectiveness indicators. The rationale for selecting quality indicators was supported by consensus for 58 (26.1%) of the 222 indicators and by published research evidence for 45 (20.3%); for 119 indicators (53.6%), the rationale was not reported or the reader was referred to other organizations' reports. Of the 127 unique quality indicators, 27 (21.2%) were accompanied by a formal grading of evidence, whereas for 52 (40.9%), no reference to evidence was provided. INTERPRETATION: There are many quality indicators related to critical care that are available in the public domain. However, owing to a paucity of rationale for selection, supporting evidence and results of implementation, it is not clear which indicators should be adopted for use. PMID- 28637682 TI - Cellular mechanism of fibril formation from serum amyloid A1 protein. AB - Serum amyloid A1 (SAA1) is an apolipoprotein that binds to the high-density lipoprotein (HDL) fraction of the serum and constitutes the fibril precursor protein in systemic AA amyloidosis. We here show that HDL binding blocks fibril formation from soluble SAA1 protein, whereas internalization into mononuclear phagocytes leads to the formation of amyloid. SAA1 aggregation in the cell model disturbs the integrity of vesicular membranes and leads to lysosomal leakage and apoptotic death. The formed amyloid becomes deposited outside the cell where it can seed the fibrillation of extracellular SAA1. Our data imply that cells are transiently required in the amyloidogenic cascade and promote the initial nucleation of the deposits. This mechanism reconciles previous evidence for the extracellular location of deposits and amyloid precursor protein with observations the cells are crucial for the formation of amyloid. PMID- 28637684 TI - Placebo might be superior to antipsychotics in management of delirium in the palliative care setting. PMID- 28637685 TI - Milk Oligosaccharides Inhibit Human Rotavirus Infectivity in MA104 Cells. AB - Background: Oligosaccharides in milk act as soluble decoy receptors and prevent pathogen adhesion to the infant gut. Milk oligosaccharides reduce infectivity of a porcine rotavirus strain; however, the effects on human rotaviruses are less well understood.Objective: In this study, we determined the effect of specific and abundant milk oligosaccharides on the infectivity of 2 globally dominant human rotavirus strains.Methods: Four milk oligosaccharides-2'-fucosyllactose (2'FL), 3'-sialyllactose (3'SL), 6'-sialyllactose (6'SL), and galacto oligosaccharides-were tested for their effects on the infectivity of human rotaviruses G1P[8] and G2P[4] through fluorescent focus assays on African green monkey kidney epithelial cells (MA104 cells). Oligosaccharides were added at different time points in the infectivity assays. Infections in the absence of oligosaccharides served as controls.Results: When compared with infections in the absence of glycans, all oligosaccharides substantially reduced the infectivity of both human rotavirus strains in vitro; however, virus strain-specific differences in effects were observed. Compared with control infections, the maximum reduction in G1P[8] infectivity was seen with 2'FL when added after the onset of infection (62% reduction, P < 0.01), whereas the maximum reduction in G2P[4] infectivity was seen with the mixture of 3'SL + 6'SL when added during infection (73% reduction, P < 0.01). The mixture of 3'SL + 6'SL at the same ratio as is present in breast milk was more potent in reducing G2P[4] infectivity (73% reduction, P < 0.01) than when compared with 3'SL (47% reduction) or 6'SL (40% reduction) individually. For all oligosaccharides the reduction in infectivity was mediated by an effect on the virus and not on the cells.Conclusions: Milk oligosaccharides reduce the infectivity of human rotaviruses in MA104 cells, primarily through an effect on the virus. Although breastfed infants are directly protected, the addition of specific oligosaccharides to infant formula may confer these benefits to formula-fed infants. PMID- 28637686 TI - High Serum Phospholipid Dihomo-gamma-Linoleic Acid Concentration and Low Delta5 Desaturase Activity Are Associated with Increased Risk of Type 2 Diabetes among Japanese Adults in the Hitachi Health Study. AB - Background: The association between the circulating fatty acid (FA) composition and type 2 diabetes (T2D) has been reported in Western populations, but evidence is scarce among Asian populations, including Japanese, who consume large amounts of fish.Objective: The objective of the present study was to prospectively examine the association between circulating concentrations of individual FAs and T2D incidence among Japanese adults.Methods: We conducted a nested case-control study in a cohort of 4754 employees, aged 34-69 y, who attended a comprehensive health checkup in 2008-2009 and donated blood samples for the Hitachi Health Study. During 5 y of follow-up, diabetes was identified on the basis of plasma glucose, glycated hemoglobin, and self-report. Two controls matched to each case by sex, age, and date of checkup were randomly chosen by using density sampling, resulting in 336 cases and 678 controls with FA measurements. GC was used to measure the FA composition in serum phospholipids. Cox proportional hazards regression was used to estimate the HRs and 95% CIs after adjusting for potential confounders. We examined the association of T2D risk with 25 different individual and combinations of FAs.Results: T2D risk was positively associated with serum dihomo-gamma-linoleic acid concentration (highest compared with the lowest quartile-HR: 1.49; 95% CI: 1.04, 2.11; P-trend = 0.02) and inversely associated with Delta5-desaturase activity (highest compared with the lowest quartile-HR: 0.72; 95% CI: 0.52, 0.99; P-trend = 0.02), independent of body mass index (BMI). There were also inverse associations between T2D risk with serum total n-6 (omega 6) polyunsaturated fatty acids (PUFAs), linoleic acid, and cis-vaccenic acid, but these were attenuated and became nonsignificant after adjustment for BMI. Serum n 3 (omega-3) PUFAs and saturated fatty acids (SFAs) were not associated with T2D risk.Conclusions: T2D risk was associated with circulating concentrations of the n-6 PUFA dihomo-gamma-linoleic acid and Delta5-desaturase activity but not with n 3 PUFA or SFA concentrations in Japanese adults. PMID- 28637687 TI - Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models. AB - Purpose: Bioinformatics analysis followed by in vivo studies in patient-derived xenograft (PDX) models were used to identify and validate CDK 4/6 inhibition as an effective therapeutic strategy for medulloblastoma, particularly group 3 MYC amplified tumors that have the worst clinical prognosis.Experimental Design: A protein interaction network derived from a Sleeping Beauty mutagenesis model of medulloblastoma was used to identify potential novel therapeutic targets. The top hit from this analysis was validated in vivo using PDX models of medulloblastoma implanted subcutaneously in the flank and orthotopically in the cerebellum of mice.Results: Informatics analysis identified the CDK4/6/CYCLIN D/RB pathway as a novel "druggable" pathway for multiple subgroups of medulloblastoma. Palbociclib, a highly specific inhibitor of CDK4/6, was found to inhibit RB phosphorylation and cause G1 arrest in PDX models of medulloblastoma. The drug caused rapid regression of Sonic hedgehog (SHH) and MYC-amplified group 3 medulloblastoma subcutaneous tumors and provided a highly significant survival advantage to mice bearing MYC-amplified intracranial tumors.Conclusions: Inhibition of CDK4/6 is potentially a highly effective strategy for the treatment of SHH and MYC amplified group 3 medulloblastoma. Clin Cancer Res; 23(19); 5802-13. (c)2017 AACR. PMID- 28637688 TI - FUS-DDIT3 Fusion Protein-Driven IGF-IR Signaling is a Therapeutic Target in Myxoid Liposarcoma. AB - Purpose: Myxoid liposarcoma is an aggressive disease with particular propensity to develop hematogenic metastases. Over 90% of myxoid liposarcoma are characterized by a reciprocal t(12;16)(q13;p11) translocation. The resulting chimeric FUS-DDIT3 fusion protein plays a crucial role in myxoid liposarcoma pathogenesis; however, its specific impact on oncogenic signaling pathways remains to be substantiated. We here investigate the functional role of FUS-DDIT3 in IGF-IR/PI3K/Akt signaling driving myxoid liposarcoma pathogenesis.Experimental Design: Immunohistochemical evaluation of key effectors of the IGF-IR/PI3K/Akt signaling axis was performed in a comprehensive cohort of myxoid liposarcoma specimens. FUS-DDIT3 dependency and biological function of the IGF-IR/PI3K/Akt signaling cascade were analyzed using a HT1080 fibrosarcoma-based myxoid liposarcoma tumor model and multiple tumor-derived myxoid liposarcoma cell lines. An established myxoid liposarcoma avian chorioallantoic membrane model was used for in vivo confirmation of the preclinical in vitro results.Results: A comprehensive subset of myxoid liposarcoma specimens showed elevated expression and phosphorylation levels of various IGF-IR/PI3K/Akt signaling effectors. In HT1080 fibrosarcoma cells, overexpression of FUS-DDIT3 induced aberrant IGF IR/PI3K/Akt pathway activity, which was dependent on transcriptional induction of the IGF2 gene. Conversely, RNAi-mediated FUS-DDIT3 knockdown in myxoid liposarcoma cells led to an inactivation of IGF-IR/PI3K/Akt signaling associated with diminished IGF2 mRNA expression. Treatment of myxoid liposarcoma cell lines with several IGF-IR inhibitors resulted in significant growth inhibition in vitro and in vivoConclusions: Our preclinical study substantiates the fundamental role of the IGF-IR/PI3K/Akt signaling pathway in myxoid liposarcoma pathogenesis and provides a mechanism-based rationale for molecular- targeted approaches in myxoid liposarcoma cancer therapy. Clin Cancer Res; 23(20); 6227-38. (c)2017 AACR. PMID- 28637690 TI - p53: master of life, death, and the epigenome. AB - Long understood as a bona fide tumor suppressor that safeguards the integrity of the genome via regulating numerous cellular outcomes, p53 may also exert its decisive and versatile functions by controlling DNA methylation. In this issue of Genes & Development, Tovy and colleagues (pp. 959-972) report that, in naive mouse embryonic stem cells (ESCs), p53 controls DNA methylation homeostasis by regulating the expression of key counteracting components of the DNA methylation machinery. Their findings indicate that p53 may exert its "guardian of genome" duties at least in part via safeguarding the epigenome of ESCs. PMID- 28637689 TI - Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer. AB - Purpose: The TP53 tumor-suppressor gene is mutated in >95% of high-grade serous ovarian cancers. Detecting an autologous antibody response to TP53 that might improve early detection.Experimental Design: An immunoassay was developed to measure TP53 autoantibody in sera from 378 cases of invasive epithelial ovarian cancer and 944 age-matched healthy controls from the United States, Australia, and the United Kingdom. Serial preclinical samples from cases and controls were also assayed from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).Results: Using a cutoff value of 78 U/mL to achieve a specificity of 97.4%, TP53 autoantibody was elevated in 30% of 50 cases from MD Anderson, 21.3% of 108 cases from the Australian Ovarian Cancer Study, and 21% of 220 cases from the UKCTOCS. Among 164 cases with rising CA125 detected with the UKCTOCS risk of ovarian cancer algorithm (ROCA), 20.7% had elevated TP53 autoantibody. In cases missed by the ROCA, 16% of cases had elevated TP53 autoantibody. Of the 34 ovarian cancer cases detected with the ROCA, TP53 autoantibody titers were elevated 11.0 months before CA125. In the 9 cases missed by the ROCA, TP53 autoantibody was elevated 22.9 months before cancer diagnosis. Similar sensitivity was obtained using assays with specific mutant and wild-type TP53.Conclusions: TP53 autoantibody levels provide a biomarker with clinically significant lead time over elevation of CA125 or an elevated ROCA value. Quantitative assessment of autoantibodies in combination with CA125 holds promise for earlier detection of invasive epithelial ovarian cancer. Clin Cancer Res; 23(19); 5912-22. (c)2017 AACR. PMID- 28637691 TI - Settling the m6A debate: methylation of mature mRNA is not dynamic but accelerates turnover. AB - Post-transcriptional modification of RNA nucleosides has been implicated as a pivotal regulator of mRNA biology. In this issue of Genes & Development, Ke and colleagues (pp. 990-1006) provide insights into the temporal and spatial distribution of N6-methyladenosine (m6A) in RNA transcripts by analyzing different subcellular fractions. Using a recently developed biochemical approach for detecting m6A, the researchers show that m6A methylations are enriched in exons and are added to transcripts prior to splicing. Although m6A addition is widely thought to be readily reversible, they demonstrate in HeLa cells that once RNA is released from chromatin, the modifications are surprisingly static. This study integrates data from previous publications to clarify conflicting conclusions regarding the role of m6A in mRNA biogenesis and function. Ke and colleagues found that m6A methylation levels negatively correlate with transcript half-life but are not required for most pre-mRNA splicing events. PMID- 28637692 TI - m6A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. AB - Understanding the biologic role of N6-methyladenosine (m6A) RNA modifications in mRNA requires an understanding of when and where in the life of a pre-mRNA transcript the modifications are made. We found that HeLa cell chromatin associated nascent pre-mRNA (CA-RNA) contains many unspliced introns and m6A in exons but very rarely in introns. The m6A methylation is essentially completed upon the release of mRNA into the nucleoplasm. Furthermore, the content and location of each m6A modification in steady-state cytoplasmic mRNA are largely indistinguishable from those in the newly synthesized CA-RNA or nucleoplasmic mRNA. This result suggests that quantitatively little methylation or demethylation occurs in cytoplasmic mRNA. In addition, only ~10% of m6As in CA RNA are within 50 nucleotides of 5' or 3' splice sites, and the vast majority of exons harboring m6A in wild-type mouse stem cells is spliced the same in cells lacking the major m6A methyltransferase Mettl3. Both HeLa and mouse embryonic stem cell mRNAs harboring m6As have shorter half-lives, and thousands of these mRNAs have increased half-lives (twofold or more) in Mettl3 knockout cells compared with wild type. In summary, m6A is added to exons before or soon after exon definition in nascent pre-mRNA, and while m6A is not required for most splicing, its addition in the nascent transcript is a determinant of cytoplasmic mRNA stability. PMID- 28637695 TI - Corrigendum: Dicer loss and recovery induce an oncogenic switch driven by transcriptional activation of the oncofetal Imp1-3 family. PMID- 28637693 TI - Neuroblast differentiation during development and in neuroblastoma requires KIF1Bbeta-mediated transport of TRKA. AB - We recently identified pathogenic KIF1Bbeta mutations in sympathetic nervous system malignancies that are defective in developmental apoptosis. Here we deleted KIF1Bbeta in the mouse sympathetic nervous system and observed impaired sympathetic nervous function and misexpression of genes required for sympathoadrenal lineage differentiation. We discovered that KIF1Bbeta is required for nerve growth factor (NGF)-dependent neuronal differentiation through anterograde transport of the NGF receptor TRKA. Moreover, pathogenic KIF1Bbeta mutations identified in neuroblastoma impair TRKA transport. Expression of neuronal differentiation markers is ablated in both KIF1Bbeta-deficient mouse neuroblasts and human neuroblastomas that lack KIF1Bbeta. Transcriptomic analyses show that unfavorable neuroblastomas resemble mouse sympathetic neuroblasts lacking KIF1Bbeta independent of MYCN amplification and the loss of genes neighboring KIF1B on chromosome 1p36. Thus, defective precursor cell differentiation, a common trait of aggressive childhood malignancies, is a pathogenic effect of KIF1Bbeta loss in neuroblastomas. Furthermore, neuropathy associated KIF1Bbeta mutations impede cargo transport, providing a direct link between neuroblastomas and neurodegeneration. PMID- 28637696 TI - A Game of Unknowns. PMID- 28637694 TI - Dendritic Eph organizes dendrodendritic segregation in discrete olfactory map formation in Drosophila. AB - Proper function of the neural network results from the precise connections between axons and dendrites of presynaptic and postsynaptic neurons, respectively. In the Drosophila olfactory system, the dendrites of projection neurons (PNs) stereotypically target one of ~50 glomeruli in the antennal lobe (AL), the primary olfactory center in the brain, and form synapses with the axons of olfactory receptor neurons (ORNs). Here, we show that Eph and Ephrin, the well known axon guidance molecules, instruct the dendrodendritic segregation during the discrete olfactory map formation. The Eph receptor tyrosine kinase is highly expressed and localized in the glomeruli related to reproductive behavior in the developing AL. In one of the pheromone-sensing glomeruli (DA1), the Eph cell autonomously regulates its dendrites to reside in a single glomerulus by interacting with Ephrins expressed in adjacent PN dendrites. Our data demonstrate that the trans interaction between dendritic Eph and Ephrin is essential for the PN dendritic boundary formation in the DA1 olfactory circuit, potentially enabling strict segregation of odor detection between pheromones and the other odors. PMID- 28637697 TI - GAS6: Pouring GASoline Into the Inflammatory Inferno of Venous Thrombosis. PMID- 28637699 TI - ATVB Named Lecture Review-Insight Into Author: Jeffrey M. Hoeg. PMID- 28637698 TI - Charming the Snake: Venom-Derived Peptides Show Surprising Efficacy as Glycoprotein VI-Targeting Antithrombotic Agents. PMID- 28637700 TI - ATVB Named Lecture Review-Insight Into Author: John H. Griffin. PMID- 28637702 TI - Cell Death in the Vessel Wall: The Good, the Bad, the Ugly. PMID- 28637705 TI - Light exercise heart rate on-kinetics: a comparison of data fitted with sigmoidal and exponential functions and the impact of fitness and exercise intensity. AB - This study examined the suitability of sigmoidal (SIG) and exponential (EXP) functions for modeling HR kinetics at the onset of a 5-min low-intensity cycling ergometer exercise test (5MT). The effects of training status, absolute and relative workloads, and high versus low workloads on the accuracy and reliability of these functions were also examined. Untrained participants (UTabs; n = 13) performed 5MTs at 100W. One group of trained participants (n = 10) also performed 5MTs at 100W (ETabs). Another group of trained participants (n = 9) performed 5MTs at 45% and 60% VO2 max (ET45 and ET60, respectively). SIG and EXP functions were fitted to HR data from 5MTs. A 30-s lead-in time was included when fitting SIG functions. Functions were compared using the standard error of the regression (SER), and test-retest reliability of curve parameters. SER for EXP functions was significantly lower than for SIG functions across all groups. When residuals from the 30-s lead-in time were omitted, EXP functions only outperformed SIG functions in ET60 (EXP, 2.7 +/- 1.2 beats.min-1; SIG, 3.1 +/- 1.1 beats.min-1: P < 0.05). Goodness of fit and test-retest reliability of curve parameters were best in ET60 and comparatively poor in UTabs Overall, goodness of fit and test-retest reliability of curve parameters favored functions fitted to 5MTs performed by trained participants at a high and relative workload, while functions fitted to data from untrained participants exercising at a low and absolute workload were less accurate and reliable. PMID- 28637704 TI - The Structure-function remodeling in rabbit hearts of myocardial infarction. AB - Animal models are of importance to investigate basic mechanisms for ischemic heart failure (HF). The objective of the study was to create a rabbit model through multiple coronary artery ligations to investigate the postoperative structure-function remodeling of the left ventricle (LV) and coronary arterial trees. Here, we hypothesize that the interplay of the degenerated coronary vasculature and increased ventricle wall stress relevant to cardiac fibrosis in vicinity of myocardial infarction (MI) precipitates the incidence and progression of ischemic HF Echocardiographic measurements showed an approximately monotonic drop of fractional shortening and ejection fraction from 40% and 73% down to 28% and 58% as well as persistent enlargement of LV cavity and slight mitral regurgitation at postoperative 12 weeks. Micro-CT and histological measurements showed that coronary vascular rarefaction and cardiac fibrosis relevant to inflammation occurred concurrently in vicinity of MI at postoperative 12 weeks albeit there was compensatory vascular growth at postoperative 6 weeks. These findings validate the proposed rabbit model and prove the hypothesis. The post-MI rabbit model can serve as a reference to test various drugs for treatment of ischemic HF. PMID- 28637706 TI - Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation. AB - Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM-1). Recently, we reported that ICAM-1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC-MR-/ ) and wild-type littermate controls (EC-MR+/+). MR was specifically deleted in heart EC, and in EC-containing tissues, but not in leukocytes of TAC EC-MR-/- mice. While EC-MR-/- TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNFalpha and the endothelin receptors in the LV as compared to EC-MR+/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM-1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC-MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload. PMID- 28637707 TI - Daily rhythms of cloacal temperature in broiler chickens of different age groups administered with zinc gluconate and probiotic during the hot-dry season. AB - The aim of the experiment was to evaluate effects of zinc gluconate (ZnGlu) and probiotic administration on the daily rhythm of cloacal temperature (tcloacal) in broiler chickens of different age groups during the hot-dry season. One-day-old broiler chicks (n = 60) were divided into groups I-IV of 15 chicks per group, and treated for 35 days: Group I (control) was given deionized water; Group II, ZnGlu (50 mg/kg); Group III, probiotic (4.125 * 106 cfu/100 mL), and Group IV, ZnGlu (50 mg/kg) + probiotic (4.125 * 106 cfu/100 mL). Air dry-bulb temperature (tdb), relative humidity (RH), and temperature-humidity index (THI) inside the pen, and tcloacal of each broiler chick were obtained bihourly over a 24-h period; on days 21, 28, and 35 of the study. Values of tdb (32.10 +/- 0.49 degrees C), RH (49.94 +/- 1.91%), and THI (38.85 +/- 0.42) obtained were outside the thermoneutral zone for broiler chickens, and suggested that the birds were subjected to heat stress. Application of the periodic model showed disruption of daily rhythm of tcloacal in broilers on day 21, which was synchronized by probiotic administration. The administration of probiotics or ZnGlu + probiotics to a greater extent decreased the mesor and amplitude, delayed the acrophases of tcloacal in broilers, especially at day 35, as compared to the controls. Overall, the tcloacal values in broiler chickens administered with probiotic alone (41.25 +/- 0.05 degrees C) and ZnGlu + probiotic (41.52 +/- 0.05 degrees C) were lower (P < 0.001) than that of the controls (41.94 +/- 0.06 degrees C). In conclusion, probiotic alone synchronized tcloacal of the birds at day 21, and, in addition, decreased tcloacal response most, followed by its coadministration with ZnGlu, the antioxidants may be beneficial in modulating daily rhythmicity of tcloacal and alleviating adverse effects of heat stress on broiler chickens during the hot-dry season. PMID- 28637708 TI - Hypohydration impairs endurance performance: a blinded study. AB - The general scientific consensus is that starting exercise with hypohydration >2% body mass impairs endurance performance/capacity, but most previous studies might be confounded by a lack of subject blinding. This study examined the effect of hypohydration in a single blind manner using combined oral and intragastric rehydration to manipulate hydration status. After familiarization, seven active males (mean +/- SD: age 25 +/- 2 years, height 1.79 +/- 0.07, body mass 78.6 +/- 6.2, VO2peak 48 +/- 7 mL.kg.min-1) completed two randomized trials at 34 degrees C. Trials involved an intermittent exercise preload (8 * 15 min exercise/5 min rest), followed by a 15-min all-out performance test on a cycle ergometer. During the preload, water was ingested orally every 10 min (0.2 mL.kg body mass-1). Additional water was infused into the stomach via a gastric feeding tube to replace sweat loss (EU) or induce hypohydration of ~2.5% body mass (HYP). Blood samples were drawn and thirst sensation rated before, during, and after exercise. Body mass loss during the preload was greater (2.4 +/- 0.2% vs. 0.1 +/- 0.1%; P < 0.001), while work completed during the performance test was lower (152 +/- 24 kJ vs. 165 +/- 22 kJ; P < 0.05) during HYP At the end of the preload, heart rate, RPE, serum osmolality, and thirst were greater and plasma volume lower during HYP (P < 0.05). These results provide novel data demonstrating that exercise performance in the heat is impaired by hypohydration, even when subjects are blinded to the intervention. PMID- 28637709 TI - Genome-Wide Association Analyses Based on Broadly Different Specifications for Prior Distributions, Genomic Windows, and Estimation Methods. AB - A currently popular strategy (EMMAX) for genome-wide association (GWA) analysis infers association for the specific marker of interest by treating its effect as fixed while treating all other marker effects as classical Gaussian random effects. It may be more statistically coherent to specify all markers as sharing the same prior distribution, whether that distribution is Gaussian, heavy-tailed (BayesA), or has variable selection specifications based on a mixture of, say, two Gaussian distributions [stochastic search and variable selection (SSVS)]. Furthermore, all such GWA inference should be formally based on posterior probabilities or test statistics as we present here, rather than merely being based on point estimates. We compared these three broad categories of priors within a simulation study to investigate the effects of different degrees of skewness for quantitative trait loci (QTL) effects and numbers of QTL using 43,266 SNP marker genotypes from 922 Duroc-Pietrain F2-cross pigs. Genomic regions were based either on single SNP associations, on nonoverlapping windows of various fixed sizes (0.5-3 Mb), or on adaptively determined windows that cluster the genome into blocks based on linkage disequilibrium. We found that SSVS and BayesA lead to the best receiver operating curve properties in almost all cases. We also evaluated approximate maximum a posteriori (MAP) approaches to BayesA and SSVS as potential computationally feasible alternatives; however, MAP inferences were not promising, particularly due to their sensitivity to starting values. We determined that it is advantageous to use variable selection specifications based on adaptively constructed genomic window lengths for GWA studies. PMID- 28637711 TI - The Exon Junction Complex and Srp54 Contribute to Hedgehog Signaling via ci RNA Splicing in Drosophila melanogaster. AB - Hedgehog (Hh) regulates the Cubitus interruptus (Ci) transcription factor in Drosophila melanogaster by activating full-length Ci-155 and blocking processing to the Ci-75 repressor. However, the interplay between the regulation of Ci-155 levels and activity, as well as processing-independent mechanisms that affect Ci 155 levels, have not been explored extensively. Here, we identified Mago Nashi (Mago) and Y14 core Exon Junction Complex (EJC) proteins, as well as the Srp54 splicing factor, as modifiers of Hh pathway activity under sensitized conditions. Mago inhibition reduced Hh pathway activity by altering the splicing pattern of ci to reduce Ci-155 levels. Srp54 inhibition also affected pathway activity by reducing ci RNA levels but additionally altered Ci-155 levels and activity independently of ci splicing. Further tests using ci transgenes and ci mutations confirmed evidence from studying the effects of Mago and Srp54 that relatively small changes in the level of Ci-155 primary translation product alter Hh pathway activity under a variety of sensitized conditions. We additionally used ci transgenes lacking intron sequences or the presumed translation initiation codon for an alternatively spliced ci RNA to provide further evidence that Mago acts principally by modulating the levels of the major ci RNA encoding Ci-155, and to show that ci introns are necessary to support the production of sufficient Ci-155 for robust Hh signaling and may also be important mediators of regulatory inputs. PMID- 28637710 TI - The Combined Action of Duplicated Boron Transporters Is Required for Maize Growth in Boron-Deficient Conditions. AB - The micronutrient boron is essential in maintaining the structure of plant cell walls and is critical for high yields in crop species. Boron can move into plants by diffusion or by active and facilitated transport mechanisms. We recently showed that mutations in the maize boron efflux transporter ROTTEN EAR (RTE) cause severe developmental defects and sterility. RTE is part of a small gene family containing five additional members (RTE2-RTE6) that show tissue-specific expression. The close paralogous gene RTE2 encodes a protein with 95% amino acid identity with RTE and is similarly expressed in shoot and root cells surrounding the vasculature. Despite sharing a similar function with RTE, mutations in the RTE2 gene do not cause growth defects in the shoot, even in boron-deficient conditions. However, rte2 mutants strongly enhance the rte phenotype in soils with low boron content, producing shorter plants that fail to form all reproductive structures. The joint action of RTE and RTE2 is also required in root development. These defects can be fully complemented by supplying boric acid, suggesting that diffusion or additional transport mechanisms overcome active boron transport deficiencies in the presence of an excess of boron. Overall, these results suggest that RTE2 and RTE function are essential for maize shoot and root growth in boron-deficient conditions. PMID- 28637713 TI - A pilot study of interprofessional palliative care education of medical students in the UK and USA. AB - BACKGROUND: Educating medical students to care for patients at the end-of-life is increasingly recognised as an essential component of training. Traditionally, medical student programmes are run by doctors, but patient care is delivered by an interprofessional team. Our programmes in the UK and USA independently developed a teaching experience led by an interprofessional team of palliative care health professionals. OBJECTIVES: This study explores the palliative care health professionals' perceptions, regarding their unique role in medical student palliative care education. METHODS: This is the first study to ascertain views of an interprofessional team delivering palliative care education to medical students. Focus groups enable interaction between members of the group as well as the generation of consensus of comments among group members. RESULTS: Two major themes were identified: perceived benefits and value of the experience, and the challenges and lessons learnt from the experiences. CONCLUSIONS: Despite different structures and settings, this experiential learning in palliative care provided a rewarding interprofessional experience that has historically been difficult to achieve. PMID- 28637714 TI - Advance care planning in Medicare: an early look at the impact of new reimbursement on billing and clinical practice. AB - OBJECTIVE: In this study, we examined the US Medicare programme's (government funded social insurance for the elderly or disabled) new reimbursement for advance care planning (ACP) that began on 1 January 2016. This single-centre study addressed whether clinicians who have ACP conversations with patients will use the new reimbursement code and if the new reimbursement is successful at motivating clinicians to have more ACP conversations with patients. METHODS: This is a multimethod study. To gain a general sense of ACP practice and code visibility, we first surveyed 493 clinicians in a large academic medical centre (20% response rate). Then, for more in-depth answers and to illuminate the reasons behind survey findings, we conducted semistructured interviews with 28 physicians. RESULTS: We found that while clinicians are open to using the reimbursement codes, organisational barriers such as low visibility and documentation make it difficult for clinicians to bill for ACP. Moreover, structural and professional factors have rendered Medicare's ACP reimbursement largely ineffective at motivating healthcare providers to perform more ACP conversations during the first 3 months of this policy. CONCLUSIONS: It does not appear that Medicare's reimbursement of ACP has made a significant, direct impact on ACP billing or practice during the policy's first 90 days. However, there is a symbolic role that this change can serve, and the policy could have more impact as its existence becomes more widely known. Barriers to ACP that we identify should be addressed directly to expand the use of ACP. PMID- 28637712 TI - Shrinking Daughters: Rlm1-Dependent G1/S Checkpoint Maintains Saccharomyces cerevisiae Daughter Cell Size and Viability. AB - The Rlm1 transcription factor is a target of the cell wall integrity pathway. We report that an rlm1Delta mutant grown on a nonfermentable carbon source at low osmolarity forms cell groups in which a mother cell is surrounded by smaller "satellite-daughter" cells. Mother cells in these groups progressed through repeated rounds of cell division with normal rates of bud growth and genetic stability; however, these cells underwent precocious START relative to wild-type mothers. Thus, once activated, Rlm1 delays the transition from G1 to S, a mechanism we term the cell wall/START (CW/START) checkpoint. The rlm1Delta satellite-cell phenotype is suppressed by deletion of either SLT2, which encodes the kinase that activates Rlm1, or SWI4, which is also activated by Slt2; suggesting that Slt2 can have opposing roles in regulating the START transition. Consistent with an Rlm1-dependent CW/START checkpoint, rlm1Delta satellite daughters were unable to grow or divide further even after transfer to rich medium, but UV irradiation in G1 could partially rescue rlm1Delta satellite daughters in the next division. Indeed, after cytokinesis, these satellite daughters shrank rapidly, displayed amorphous actin staining, and became more permeable. As a working hypothesis, we propose that duplication of an "actin organizing center" in late G1 may be required both to progress through START and to reestablish the actin cytoskeleton in daughter cells. PMID- 28637715 TI - Tyrosine Kinase Inhibitors Protect the Salivary Gland from Radiation Damage by Inhibiting Activation of Protein Kinase C-delta. AB - In patients undergoing irradiation (IR) therapy, injury to nontumor tissues can result in debilitating, and sometimes permanent, side effects. We have defined protein kinase C-delta (PKCdelta) as a regulator of DNA damage-induced apoptosis and have shown that phosphorylation of PKCdelta by c-Abl and c-Src activates its proapoptotic function. Here, we have explored the use of tyrosine kinase inhibitors (TKI) of c-Src and c-Abl to block activation of PKCdelta for radioprotection of the salivary gland. Dasatinib, imatinib, and bosutinib all suppressed tyrosine phosphorylation of PKCdelta and inhibited IR-induced apoptosis in vitro To determine whether TKIs can provide radioprotection of salivary gland function in vivo, mice were treated with TKIs and a single or fractionated doses of irradiation. Delivery of dasatinib or imatinib within 3 hours of a single or fractionated dose of irradiation resulted in >75% protection of salivary gland function at 60 days. Continuous dosing with dasatinib extended protection to at least 5 months and correlated with histologic evidence of salivary gland acinar cell regeneration. Pretreatment with TKIs had no impact on clonogenic survival of head and neck squamous cell carcinoma (HNSCC) cells, and in mice harboring HNSCC cell-derived xenografts, combining dasatinib or imatinib with fractionated irradiation did not enhance tumor growth. Our studies indicate that TKIs may be useful clinically to protect nontumor tissue in HNC patients undergoing radiotherapy, without negatively impacting cancer treatment. Mol Cancer Ther; 16(9); 1989-98. (c)2017 AACR. PMID- 28637716 TI - Modulation of Plasma Metabolite Biomarkers of the MAPK Pathway with MEK Inhibitor RO4987655: Pharmacodynamic and Predictive Potential in Metastatic Melanoma. AB - MAPK pathway activation is frequently observed in human malignancies, including melanoma, and is associated with sensitivity to MEK inhibition and changes in cellular metabolism. Using quantitative mass spectrometry-based metabolomics, we identified in preclinical models 21 plasma metabolites including amino acids, propionylcarnitine, phosphatidylcholines, and sphingomyelins that were significantly altered in two B-RAF-mutant melanoma xenografts and that were reversed following a single dose of the potent and selective MEK inhibitor RO4987655. Treatment of non-tumor-bearing animals and mice bearing the PTEN-null U87MG human glioblastoma xenograft elicited plasma changes only in amino acids and propionylcarnitine. In patients with advanced melanoma treated with RO4987655, on-treatment changes of amino acids were observed in patients with disease progression and not in responders. In contrast, changes in phosphatidylcholines and sphingomyelins were observed in responders. Furthermore, pretreatment levels of seven lipids identified in the preclinical screen were statistically significantly able to predict objective responses to RO4987655. The RO4987655 treatment-related changes were greater than baseline physiological variability in nontreated individuals. This study provides evidence of a translational exo-metabolomic plasma readout predictive of clinical efficacy together with pharmacodynamic utility following treatment with a signal transduction inhibitor. Mol Cancer Ther; 16(10); 2315-23. (c)2017 AACR. PMID- 28637721 TI - Red blood cell distribution width as a risk factor for inhospital mortality in obstetric patients admitted to an intensive care unit: a single centre retrospective cohort study. AB - BACKGROUND: Red blood cell distribution width (RDW) has been shown to predict mortality in critically ill patients. To our knowledge, whether or not RDW is associated with clinical outcomes of obstetric patients requiring critical care has not been evaluated. METHODS: This was a single centre, retrospective, observational study of obstetric patients admitted to the intensive care unit (ICU). Patients were excluded from the analysis if they had known haematological diseases or recently underwent blood transfusion. Patients who died or were discharged from the ICU within 24 hours of admission were also excluded. Patient clinical characteristics at ICU admission were retrieved from the medical charts. Multiple logistic regression was used to estimate OR and 95% CI for inhospital mortality associated with RDW. The receiver operating characteristic curve was used to examine the performance of RDW, alone or in combination with the Acute Physiology and Chronic Health Evaluation II score (APACHE II), in predicting inhospital mortality. RESULTS: A total of 376 patients were included in the study. The hospital mortality rate was 5.32%. A significant association was found between baseline RDW levels and hospital mortality (OR per per cent increase in RDW, 1.31; 95% CI 1.15 to 1.49). Further adjustment for haematocrit and other potential confounders did not appreciably alter the result (p<0.001). The area under the curve (AUC) for inhospital mortality based on RDW was similar to that based on the APACHE II score (0.752 vs 0.766). A combination of these two factors resulted in substantial improvement in risk prediction, with an AUC value of 0.872 (p<0.001). CONCLUSIONS: The study suggests that RDW is an independent predictor for inhospital mortality among ICU admitted obstetric patients. Combining RDW and APACHE II score could significantly improve inhospital prognostic prediction among these critically ill obstetric patients. PMID- 28637720 TI - Notch1 maintains dormancy of olfactory horizontal basal cells, a reserve neural stem cell. AB - The remarkable capacity of the adult olfactory epithelium (OE) to regenerate fully both neurosensory and nonneuronal cell types after severe epithelial injury depends on life-long persistence of two stem cell populations: the horizontal basal cells (HBCs), which are quiescent and held in reserve, and mitotically active globose basal cells. It has recently been demonstrated that down regulation of the DeltaN form of the transcription factor p63 is both necessary and sufficient to release HBCs from dormancy. However, the mechanisms by which p63 is down-regulated after acute OE injury remain unknown. To identify the cellular source of potential signaling mechanisms, we assessed HBC activation after neuron-only and sustentacular cell death. We found that ablation of sustentacular cells is sufficient for HBC activation to multipotency. By expression analysis, next-generation sequencing, and immunohistochemical examination, down-regulation of Notch pathway signaling is coincident with HBC activation. Therefore, using HBC-specific conditional knockout of Notch receptors and overexpression of N1ICD, we show that Notch signaling maintains p63 levels and HBC dormancy, in contrast to its suppression of p63 expression in other tissues. Additionally, Notch1, but not Notch2, is required to maintain HBC dormancy after selective neuronal degeneration. Taken together, our data indicate that the activation of HBCs observed after tissue injury or sustentacular cell ablation is caused by the reduction/elimination of Notch signaling on HBCs; elimination of Jagged1 expressed by sustentacular cells may be the ligand responsible. PMID- 28637722 TI - Cross-sectional surveillance study to phenotype lorry drivers' sedentary behaviours, physical activity and cardio-metabolic health. AB - OBJECTIVES: Elevated risk factors for a number of chronic diseases have been identified in lorry drivers. Unhealthy lifestyle behaviours such as a lack of physical activity (PA) and high levels of sedentary behaviour (sitting) likely contribute to this elevated risk. This study behaviourally phenotyped UK lorry drivers' sedentary and non-sedentary behaviours during workdays and non-workdays and examined markers of drivers cardio-metabolic health. SETTING: A transport company from the East Midlands, UK. PARTICIPANTS: A sample of 159 male heavy goods vehicle drivers (91% white European; (median (range)) age: 50 (24, 67) years) completed the health assessments. 87 (age: 50.0 (25.0, 65.0); body mass index (BMI): 27.7 (19.6, 43.4) kg/m2) provided objective information on sedentary and non-sedentary time. OUTCOMES: Participants self-reported their sociodemographic information. Primary outcomes: sedentary behaviour and PA, assessed over 7 days using an activPAL3 inclinometer. Cardio-metabolic markers included: blood pressure (BP), heart rate, waist circumference (WC), hip circumference, body composition and fasted capillary blood glucose, triglycerides, high-density lipopreotein cholesterol, low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels. These cardio-metabolic markers were treated as secondary outcomes. RESULTS: Lorry drivers presented an unhealthy cardio-metabolic health profile (median (IQR) systolic BP: 129 (108.5, 164) mm Hg; diastolic BP: 81 (63, 104) mm Hg; BMI: 29 (20, 47) kg/m2; WC: 102 (77.5, 146.5) cm; LDL-C: 3 (1, 6) mmol/L; TC: 4.9 (3, 7.5) mmol/L). 84% were overweight or obese, 43% had type 2 diabetes or prediabetes and 34% had the metabolic syndrome. The subsample of lorry drivers with objective postural data (n=87) accumulated 13 hours/day and 8 hours/day of sedentary behaviour on workdays and non-workdays (p<0.001), respectively. On average, drivers accrued 12 min/day on workdays and 6 min/day on non-workdays of moderate-to-vigorous PA (MVPA). CONCLUSION: Lorry drivers demonstrate a high-risk cardio-metabolic profile and are highly sedentary and physically inactive. Interventions to reduce sitting and increase MVPA during breaks and leisure time to improve cardio metabolic health are urgently needed. Educational programmes to raise awareness about diet and exercise are recommended. PMID- 28637723 TI - Impact of consumer copayments for subsidised medicines on health services use and outcomes: a protocol using linked administrative data from Western Australia. AB - INTRODUCTION: Across the world, health systems are adopting approaches to manage rising healthcare costs. One common strategy is a medication copayments scheme where consumers make a contribution (copayment) towards the cost of their dispensed medicines, with remaining costs subsidised by the health insurance service, which in Australia is the Federal Government.In Australia, copayments have tended to increase in proportion to inflation, but in January 2005, the copayment increased substantially more than inflation. Results from aggregated dispensing data showed that this increase led to a significant decrease in the use of several medicines. The aim of this study is to determine the demographic and clinical characteristics of individuals ceasing or reducing statin medication use following the January 2005 Pharmaceutical Benefit Scheme (PBS) copayment increase and the effects on their health outcomes. METHODS AND ANALYSIS: This whole-of-population study comprises a series of retrospective, observational investigations using linked administrative health data on a cohort of West Australians (WA) who had at least one statin dispensed between 1 May 2002 and 30 June 2010. Individual-level data on the use of pharmaceuticals, general practitioner (GP) visits, hospitalisations and death are used.This study will identify patients who were stable users of statin medication in 2004 with follow up commencing from 2005 onwards. Subgroups determined by change in adherence levels of statin medication from 2004 to 2005 will be classified as continuation, reduction or cessation of statin therapy and explored for differences in health outcomes and health service utilisation after the 2005 copayment change. ETHICS AND DISSEMINATION: Ethics approvals have been obtained from the Western Australian Department of Health (#2007/33), University of Western Australia (RA/4/1/1775) and University of Notre Dame (0 14 167F). Outputs from the findings will be published in peer reviewed journals designed for a policy audience and presented at state, national and international conferences. PMID- 28637724 TI - Cross-sectional association between ZIP code-level gentrification and homelessness among a large community-based sample of people who inject drugs in 19 US cities. AB - BACKGROUND: Housing instability has been associated with poor health outcomes among people who inject drugs (PWID). This study investigates the associations of local-level housing and economic conditions with homelessness among a large sample of PWID, which is an underexplored topic to date. METHODS: PWID in this cross-sectional study were recruited from 19 large cities in the USA as part of National HIV Behavioral Surveillance. PWID provided self-reported information on demographics, behaviours and life events. Homelessness was defined as residing on the street, in a shelter, in a single room occupancy hotel, or in a car or temporarily residing with friends or relatives any time in the past year. Data on county-level rental housing unaffordability and demand for assisted housing units, and ZIP code-level gentrification (eg, index of percent increases in non Hispanic white residents, household income, gross rent from 1990 to 2009) and economic deprivation were collected from the US Census Bureau and Department of Housing and Urban Development. Multilevel models evaluated the associations of local economic and housing characteristics with homelessness. RESULTS: Sixty percent (5394/8992) of the participants reported homelessness in the past year. The multivariable model demonstrated that PWID living in ZIP codes with higher levels of gentrification had higher odds of homelessness in the past year (gentrification: adjusted OR=1.11, 95% CI=1.04 to 1.17). CONCLUSIONS: Additional research is needed to determine the mechanisms through which gentrification increases homelessness among PWID to develop appropriate community-level interventions. PMID- 28637725 TI - Filling the gaps in SARDs research: collection and linkage of administrative health data and self-reported survey data for a general population-based cohort of individuals with and without diagnoses of systemic autoimmune rheumatic disease (SARDs) from British Columbia, Canada. AB - PURPOSE: Systemic autoimmune rheumatic diseases (SARDs) are a group of debilitating autoimmune diseases, including systemic lupus erythematosus and related disorders. Assessing the healthcare and economic burden of SARDs has been challenging: while administrative databases can be used to determine healthcare utilisation and costs with minimal selection and recall bias, other health, sociodemographic and economic data have typically been sourced from highly selected, clinic-based cohorts. To address these gaps, we are collecting self reported survey data from a general population-based cohort of individuals with and without SARDs and linking it to their longitudinal administrative health data. PARTICIPANTS: Using administrative data from the province of British Columbia (BC), Canada, we established a population-based cohort of all BC adults receiving care for SARDs during 1996-2010 (n=20 729) and non-SARD individuals randomly selected from the general population. BC Ministry of Health granted us contact information for 12 000 SARD and non-SARD individuals, who were recruited to complete the surveys by mail or online. FINDINGS TO DATE: Four hundred individuals were initially invited to participate, with 135 (34%) consenting and 127 (94%) submitting the first survey (72% completed online). Sixty-three (49.6%) reported >=1 SARD diagnosis. The non-SARDs group (n=64) was 92% female with mean age 57.0+/-11.6 years. The SARDs group (n=63) was 94% female with mean age 56.5+/ 13.1 years. Forty-eight per cent of those with SARDs were current-or-former smokers (mean 10.6+/-16.2 pack-years), and 33% were overweight or obese (mean body mass index of 24.4+/-5.3). FUTURE PLANS: Health and productivity data collected from the surveys will be linked to participants' administrative health data from the years 1990-2013, allowing us to determine the healthcare and lost productivity costs of SARDs, and assess the impact of patient-reported variables on utilisation, costs, disability and clinical outcomes. Findings will be disseminated through scientific conferences and peer-reviewed journals. PMID- 28637726 TI - Interventions for preventing mother-to-child HIV transmission: protocol of an overview of systematic reviews. AB - INTRODUCTION: Various interventions to prevent mother-to-child-transmission (MTCT) of HIV have been investigated and implemented. A number of systematic reviews assessing the efficacy of interventions for the prevention of MTCT of HIV reported antiretroviral prophylaxis, caesarean section before labour and before ruptured membranes, and complete avoidance of breastfeeding were efficacious for preventing MTCT of HIV. Recent WHO guidelines recommend lifelong antiretroviral therapy for all pregnant women for treatment of the woman's own HIV infection and for prevention of MTCT of HIV. Therefore, the objective of this overview is to evaluate the currently available systematic reviews of interventions for preventing MTCT of HIV, and to identify the current best evidence-based interventions for reducing the risk of MTCT of HIV. METHODS AND ANALYSIS: We will include only peer-reviewed systematic reviews of randomised or quasi-randomised controlled trials assessing the effects of interventions for preventing MTCT of HIV that target both HIV-infected women and children aged 2 years and younger born to HIV-infected women. We will search the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effectiveness, Ovid MEDLINE and EMBASE. We will assess review eligibility, the methodological quality of included systematic reviews using A Measurement Tool to Assess The Systematic Reviews and will extract data, comparing our results and resolving discrepancies by consensus. Finally, we will independently assess the certainty of the evidence using Grades of Recommendation, Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: Ethics approval is not required. We will publish the results in a peer-reviewed journal and present at conferences, which will inform future research and will be useful for healthcare managers, administrators and policymakers to guide resource allocation decisions and optimisation of interventions to prevent the MTCT of HIV. PMID- 28637727 TI - A protocol for prospective studies of 25-hydroxyvitamin D, leptin and body mass index in relation to cutaneous melanoma incidence and survival. AB - INTRODUCTION: The incidence and mortality rates of cutaneous melanoma (CM) are increasing among fair-skinned populations worldwide. Ultraviolet radiation (UVR) is the principal risk factor for CM, but is also the main source of 25 hydroxyvitamin D (25(OH)D), which has been associated with reduced risk and better prognosis of some cancer types. However, both low and high 25(OH)D levels have been associated with increased risk of CM. Obesity as measured by body mass index (BMI) is associated with risk of several cancers and has also been suggested as a risk factor for CM, and may also be related to insufficient 25(OH)D and/or high leptin levels. Moreover, contracting a CM diagnosis has been associated with increased risk of developing second cancer. We aim to study whether low prediagnostic serum levels of 25(OH)D, high prediagnostic levels of BMI and high serum leptin levels influence CM incidence, Breslow thickness and CM mortality, and risk of second cancer and survival after a CM diagnosis. METHODS AND ANALYSIS: Cohort and nested case-control studies will be carried out using the population-based Janus Serum Bank Cohort (archival prediagnostic sera, BMI, smoking and physical activity), with follow-up from 1972 to 2014. Additional data will be received from the Cancer Registry of Norway, the national Cause of Death Registry, Statistics Norway (education and occupation) and exposure matrices of UVR. Time-to-event regression models will be used to analyse the cohort data, while the nested case-control studies will be analysed by conditional logistic regression. A multilevel approach will be applied when incorporating group-level data. ETHICS AND DISSEMINATION: The project is approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer-reviewed journals, at scientific conferences and in the news media. PMID- 28637728 TI - Efficacy of long-acting release octreotide for preventing chemotherapy-induced diarrhoea: protocol for a systematic review. AB - INTRODUCTION: Diarrhoea is a common adverse effect induced by chemotherapy that can reduce the dose of chemotherapeutic drugs or interrupt the chemotherapy schedule. The current treatment strategies have various limitations. It has been shown that long-acting release octreotide (octreotide LAR) can decrease the occurrence and severity of diarrhoea, yet the efficacy of octreotide LAR in preventing chemotherapy-induced diarrhoea (CID) remains to be assessed. The main objective of this paper was to draw up a protocol for systematic review to evaluate the protective effects of octreotide LAR on CID. METHODS AND ANALYSIS: We searched Medline, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Data and the VIP Database without language restrictions from inception until 1 September 2016. The references of relevant studies were also manually searched. Two investigators independently accessed the selected studies, extracted data and assessed the reliability of the studies. Any discrepancies were resolved by a third investigator. The effect size of the selected studies was assessed by different measures based on the type of data. The selected studies were descriptively analysed. We then chose a fixed-effect model or a random-effect model based on statistical homogeneity, and pooled data from the studies for meta-analysis, if possible. The primary outcome was the incidence of diarrhoea. The secondary outcomes were the duration of diarrhoea, incidence of diarrhoea-associated symptoms, physical function and quality of life. All statistical analyses were performed by Review Manager V.5.3. ETHICS AND DISSEMINATION: This systematic review did not require ethics approval, because it included aggregated published data, and not individual patient data. The review was published in a peer-reviewed journal. TRIAL REGISTRATION: This systematic review protocol was registered with PROSPERO (registration number: CRD 42016048573). PMID- 28637729 TI - Incidence of diabetes-related complications in Chinese patients with type 1 diabetes: a population-based longitudinal cohort study in Taiwan. AB - OBJECTIVE: To estimate the incidence densities and cumulative incidence of diabetes-related complications in patients with type 1 diabetes for a maximum of 15-year follow-up. The estimations were further stratified by gender and age at diagnosis (ie, early onset: 0-12 years, late onset:>=13 years). DESIGN: A population-based retrospective longitudinal cohort study. SETTING: Taiwan's National Health Insurance medical claims. PARTICIPANTS: 4007 patients newly diagnosed with type 1 diabetes were identified during 1999-2012. OUTCOME MEASURES: Acute complications included diabetic ketoacidosis (DKA) and hypoglycaemia. Chronic complications were cardiovascular diseases (CVD), retinopathy, neuropathy and nephropathy. RESULTS: The incidence density of retinopathy was greatest (97.74 per 1000 person-years), followed by those of nephropathy (31.36), neuropathy (23.93) and CVD (4.39). Among acute complications, the incidence density of DKA was greatest (121.11 per 1000 person years). The cumulative incidences of acute complications after 12 years following diagnosis were estimated to be 52.1%, 36.1% and 4.1% for DKA, outpatient hypoglycaemia and hospitalised hypoglycaemia, respectively. For chronic complications, the cumulative incidence of retinopathy after 12 years following diagnosis was greatest (65.2%), followed by those of nephropathy (30.2%), neuropathy (23.7%) and CVD (4.1%). Females with late-onset diabetes were greatly affected by advanced retinopathy (ie, sight-threatening diabetic retinopathy) and hospitalised hypoglycaemia, whereas those with early-onset diabetes were more vulnerable to DKA. Chronic complications were more commonly seen in late-onset diabetes, whereas early-onset diabetes were most affected by acute complications. CONCLUSIONS: Ethnic Chinese patients with type 1 diabetes were greatly affected by DKA and retinopathy. The incidence of diabetes-related complications differed by age at diagnosis and sex. PMID- 28637730 TI - The relationship between physician burnout and quality of healthcare in terms of safety and acceptability: a systematic review. AB - OBJECTIVES: This study reviews the current state of the published peer-reviewed literature related to physician burnout and two quality of care dimensions. The purpose of this systematic literature review is to address the question, 'How does physician burnout affect the quality of healthcare related to the dimensions of acceptability and safety?' DESIGN: Using a multiphase screening process, this systematic literature review is based on publically available peer-reviewed studies published between 2002 and 2017. Six electronic databases were searched: (1) MEDLINE Current, (2) MEDLINE In-process, (3) MEDLINE Epub Ahead of Print, (4) PsycINFO, (5) Embase and (6) Web of Science. SETTING: Physicians practicing in civilian settings. PARTICIPANTS: Practicing physicians who have completed training. PRIMARY AND SECONDARY OUTCOME MEASURES: Quality of healthcare related to acceptability (ie, patient satisfaction, physician communication and physician attitudes) and safety (ie, minimising risks or harm to patients). RESULTS: 4114 unique citations were identified. Of these, 12 articles were included in the review. Two studies were rated as having high risk of bias and 10 as having moderate risk. Four studies were conducted in North America, four in Europe, one in the Middle East and three in East Asia. Results of this systematic literature review suggest there is moderate evidence that burnout is associated with safety related quality of care. Because of the variability in the way patient acceptability-related quality of care was measured and the inconsistency in study findings, the evidence supporting the relationship between burnout and patient acceptability-related quality of care is less strong. CONCLUSIONS: The focus on direct care-related quality highlights additional ways that physician burnout affects the healthcare system. These studies can help to inform decisions about how to improve patient care by addressing physician burnout. Continued work looking at the relationship between dimensions of acceptability-related quality of care measures and burnout is needed to advance the field. PMID- 28637731 TI - The impact of the asylum process on mental health: a longitudinal study of unaccompanied refugee minors in Norway. AB - OBJECTIVES: To examine the mental health of unaccompanied refugee minors prospectively during the asylum-seeking process, with a focus on specific stages in the asylum process, such as age assessment, placement in a supportive or non supportive facility and final decision on the asylum applications. DESIGN: This was a21/2 year follow-up study of unaccompanied minors (UM) seeking asylum in Norway. Data were collected within three weeks (n=138) and at 4 months (n=101), 15 months (n=84) and 26 months (n=69) after arrival. SETTING: Initially in an observation and orientation centre for unaccompanied asylum-seeking adolescents, and subsequently wherever the UM were located in other refugee facilities in Norway. PARTICIPANTS: Male UM from Afghanistan, Somalia, Algeria and Iran. MAIN OUTCOME MEASURES: Mental health symptoms assessed by Hopkins Symptom Checklist-25 and Harvard Trauma Questionnaire. RESULTS: At the group level, the young asylum seekers reported high levels of psychological distress on arrival and symptom levels that stayed relatively unchanged over time. According to age-assessment procedures, 56% of the population were not recognised as minors. Subsequent placement in a low-support facility was associated with higher levels of psychological distress in the follow-up period. Those who were placed in a reception centre for adults had higher levels of psychological distress symptoms both after 15 months and 26 months compared with the remaining participants who were placed in reception centres for youth. Refusal of asylum was highly associated with higher levels of psychological distress. CONCLUSION: Mental health trajectory of young asylum seekers appears to be negatively affected by low support and refusal of asylum. PMID- 28637733 TI - Integration of sexually transmitted infection (STI) services into HIV care and treatment services for women living with HIV: a systematic review. AB - OBJECTIVE: To review and critically appraise the existing evidence on integration of sexually transmitted infection (STI) services into HIV care and treatment services for women living with HIV. DESIGN: Systematic review. DATA SOURCES: Four electronic databases were searched through 16February 2017 using keywords for HIV, STIs and integration. Reference lists of included articles and other reviews were also screened. REVIEW METHODS: We included studies that compared women living with HIV who received STI services integrated into HIV care and treatment services with those who received HIV care and treatment services without integrated STI services or standard of care. RESULTS: Of 170 articles identified, 3 studies reported in 4 articles were included. Two studies evaluated comprehensive care for people living with HIV in the UK; in both cases, quality and uptake of STI services seemed to improve following integration. The third study conducted a comparative case study across different models of care in Swaziland: two clinics integrated with sexual and reproductive health services (including STI services), and two stand-alone HIV clinics (without STI services). Coverage for Pap smears among women living with HIV was higher at the fully integrated site, but there was no significant difference in the prevalence of sexual health screening or advice on sexual health. Reported client satisfaction was generally higher at the stand-alone HIV clinic, and a diverse range of factors related to implementation of different care models challenged the notion that integrated services are always superior or desired. CONCLUSION: While there is a limited evidence base for integrating STI services into HIV care and treatment services, existing studies indicate that integration is feasible and has the potential for positive outcomes. However, diverse population needs and health system factors must be considered when designing models of care to provide STI services to women living with HIV. PMID- 28637732 TI - Outpatient percutaneous native renal biopsy: safety profile in a large monocentric cohort. AB - OBJECTIVES: We aim to evaluate the safety of performing percutaneous native kidney biopsy (PKB) as an outpatient procedure (implying an observation period of 6 hours) compared with the traditional inpatient policy. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Group I, in whom PKB was performed in the outpatient department (2012-2016) and followed by 6 hours' observation period and then by regular outpatient visits and group II, in whom PKB was performed and followed by at least 1 day hospital admission. Group II included retrospectively retrieved patients who underwent PKB in our Institution between January 2000 and November 2012 as an inpatient procedure. All biopsies were performed by a single nephrologist following a structured protocol. RESULTS: 462 biopsies were reviewed, 210 (45.5%) of patients were women and the mean age was 54.7+/-17.9 years. One hundred and twenty-nine (27.9%) of these biopsies were performed in outpatients. A total of 36 (7.8%) of patients developed a complication, and of those, 9 (1.9%) suffered for a major complication (arteriovenous fistula (six cases, 1.2%), ischaemic stroke (2; 0.4%), thromboembolic pulmonary embolism (1; 0.2%)) and 27 (5.8%) for minor(macroscopic haematuria (12 cases, 2.6%), haematomas on sonography not requiring intervention (15 cases, 3.2%)). When comparing the complication rate between groups I and II, no statical difference was observed. When analysing together both groups, after multivariate analysis, serum creatinine >3 mg/dL (OR 2.03, 95% CI 1.18 to 6.81) and known severe hypertension (OR 2.01, 95% CI 1.2 to 4.7) were found to be independent risk factors for minor and major complications, respectively. Conversely, we found no association of risk with the number of biopsy passes, gender, age, diagnosis, presence of haematuria before the kidney biopsy nor the degree of proteinuria. CONCLUSIONS: Outpatient biopsy could be a valuable, safe and perhaps cost effective method of obtaining diagnostic renal tissue in the majority of patients. PMID- 28637734 TI - Pregnancy-specific stress, fetoplacental haemodynamics, and neonatal outcomes in women with small for gestational age pregnancies: a secondary analysis of the multicentre Prospective Observational Trial to Optimise Paediatric Health in Intrauterine Growth Restriction. AB - OBJECTIVES: To examine associations between maternal pregnancy-specific stress and umbilical (UA PI) and middle cerebral artery pulsatility indices (MCA PI), cerebroplacental ratio, absent end diastolic flow (AEDF), birthweight, prematurity, neonatal intensive care unit admission and adverse obstetric outcomes in women with small for gestational age pregnancies. It was hypothesised that maternal pregnancy-specific stress would be associated with fetoplacental haemodynamics and neonatal outcomes. DESIGN: This is a secondary analysis of data collected for a large-scale prospective observational study. SETTING: This study was conducted in the seven major obstetric hospitals in Ireland and Northern Ireland. PARTICIPANTS: Participants included 331 women who participated in the Prospective Observational Trial to Optimise Paediatric Health in Intrauterine Growth Restriction. Women with singleton pregnancies between 24 and 36 weeks gestation, estimated fetal weight <10th percentile and no major structural or chromosomal abnormalities were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Serial Doppler ultrasound examinations of the umbilical and middle cerebral arteries between 20 and 42 weeks gestation, Pregnancy Distress Questionnaire (PDQ) scores between 23 and 40 weeks gestation and neonatal outcomes. RESULTS: Concerns about physical symptoms and body image at 35-40 weeks were associated with lower odds of abnormal UAPI (OR 0.826, 95% CI 0.696 to 0.979, p=0.028). PDQ score (OR 1.073, 95% CI 1.012 to 1.137, p=0.017), concerns about birth and the baby (OR 1.143, 95% CI 1.037 to 1.260, p=0.007) and concerns about physical symptoms and body image (OR 1.283, 95% CI 1.070 to 1.538, p=0.007) at 29-34 weeks were associated with higher odds of abnormal MCA PI. Concerns about birth and the baby at 29-34 weeks (OR 1.202, 95% CI 1.018 to 1.421, p=0.030) were associated with higher odds of AEDF. Concerns about physical symptoms and body image at 35 40 weeks were associated with decreased odds of neonatal intensive care unit admission (OR 0.635, 95% CI 0.435 to 0.927, p=0.019). CONCLUSIONS: These findings suggest that fetoplacental haemodynamics may be a mechanistic link between maternal prenatal stress and fetal and neonatal well-being, but additional research is required. PMID- 28637735 TI - Development of the Tailored Rett Intervention and Assessment Longitudinal (TRIAL) database and the Rett Evaluation of Symptoms and Treatments (REST) Questionnaire. AB - INTRODUCTION: Rett syndrome (RTT) is a pervasive neurodevelopmental disorder that presents with deficits in brain functioning leading to language and learning regression, characteristic hand stereotypies and developmental delay. Different mutations in the gene implicated in RTT-methyl-CpG-binding protein 2 (MECP2) establishes RTT as a disorder with divergent symptomatology ranging from individuals with severe to milder phenotypes. A reliable and single multidimensional questionnaire is needed that can embrace all symptoms, and the relationships between them, and can map clinically meaningful data to symptomatology across the lifespan in patients with RTT. As part of the HealthTracker-based Tailored Rett Intervention and Assessment Longitudinal (TRIAL) database, the Rett Evaluation of Symptoms and Treatments (REST) Questionnaire will be able to marry with the physiological aspects of the disease obtained using wearable sensor technology, along with genetic and psychosocial data to stratify patients. Taken together, the web-based TRIAL database will empower clinicians and researchers with the confidence to delineate between different aspects of disorder symptomatology to streamline care pathways for individuals or for those patients entering clinical trials. This protocol describes the anticipated development of the REST questionnaire and the TRIAL database which links with the outcomes of the wearable sensor technology, and will serve as a barometer for longitudinal patient monitoring in patients with RTT. METHODS AND ANALYSIS: The US Food and Drug Administration Guidance for Patient-Reported Outcome Measures will be used as a template to inform the methodology of the study. It will follow an iterative framework that will include item/concept identification, item/concept elicitation in parent/carer-mediated focus groups, expert clinician feedback, web-based presentation of questionnaires, initial scale development, instrument refinement and instrument validation. ETHICS AND DISSEMINATION: The study has received favourable opinion from the National Health Service (NHS) Research Ethics Committee (REC): NHS Research Ethics Committee (REC)-London, Bromley Research Ethics Committee (reference: 15/LO/1772). PMID- 28637736 TI - Transcatheter closure, mini-invasive closure and open-heart surgical repair for treatment of perimembranous ventricular septal defects in children: a protocol for a network meta-analysis. AB - INTRODUCTION: Both transcatheter device closure and surgical repair are effective treatments with excellent midterm outcomes for perimembranous ventricular septal defects (pmVSDs) in children. The mini-invasive periventricular device occlusion technique has become prevalent in research and application, but evidence is limited for the assessment of transcatheter closure, mini-invasive closure and open-heart surgical repair. This study comprehensively compares the efficacy, safety and costs of transcatheter closure, mini-invasive closure and open-heart surgical repair for treatment of pmVSDs in children using Bayesian network meta analysis. METHODS AND ANALYSIS: A systematic search will be performed using Chinese Biomedical Literature Database, China National Knowledge Infrastructure, PubMed, EMBASE.com and the Cochrane Central Register of Controlled Trials to include random controlled trials, prospective or retrospective cohort studies comparing the efficacy, safety and costs of transcatheter closure, mini-invasive closure and open-heart surgical repair. The risk of bias for the included prospective or retrospective cohort studies will be evaluated according to the risk of bias in non-randomised studies of interventions (ROBINS-I). For random controlled trials, we will use risk of bias tool from Cochrane Handbook version 5.1.0. A Bayesian network meta-analysis will be conducted using R-3.3.2 software. ETHICS AND DISSEMINATION: Ethical approval and patient consent are not required since this study is a network meta-analysis based on published trials. The results of this network meta-analysis will be submitted to a peer-reviewed journal for publication. PROTOCOL REGISTRATION NUMBER: CRD42016053352. PMID- 28637737 TI - Management of shoulder pain by UK general practitioners (GPs): a national survey. AB - OBJECTIVES: Studies in Canada, the USA and Australia suggested low confidence among general practitioners (GPs) in diagnosing and managing shoulder pain, with frequent use of investigations. There are no comparable studies in the UK; our objective was to describe the diagnosis and management of shoulder pain by GPs in the UK. METHODS: A national survey of a random sample of 5000 UK GPs collected data on shoulder pain diagnosis and management using two clinical vignettes that described primary care presentations with rotator cuff tendinopathy (RCT) and adhesive capsulitis (AdhC). RESULTS: Seven hundred and fourteen (14.7%) responses were received. 56% and 83% of GPs were confident in their diagnosis of RCT and AdhC, respectively, and a wide range of investigations and management options were reported. For the RCT presentation, plain radiographs of the shoulder were most common (60%), followed by blood tests (42%) and ultrasound scans (USS) (38%). 19% of those who recommended a radiograph and 76% of those who recommended a USS did so 'to confirm the diagnosis'. For the AdhC presentation, the most common investigations were blood tests (60%), plain shoulder radiographs (58%) and USS (31%). More than two-thirds of those recommending a USS did so 'to confirm the diagnosis'. The most commonly recommended treatment for both presentations was physiotherapy (RCT 77%, AdhC 71%) followed by non-steroidal anti-inflammatory drugs (RCT 58%, AdhC 74%). 17% opted to refer the RCT to secondary care (most often musculoskeletal interface service), compared with 31% for the AdhC. CONCLUSIONS: This survey of GPs in the UK highlights reliance on radiographs and blood tests in the management of common shoulder pain presentations. GPs report referring more than 7 out of 10 patients with RCT and AdhC to physiotherapists. These findings need to be viewed in the context of low response to the survey and, therefore, potential non-response bias. PMID- 28637739 TI - Intrathecal baclofen therapy in paediatrics: a study protocol for an Australian multicentre, 10-year prospective audit. AB - INTRODUCTION: Increasing clinical use of Intrathecal baclofen (ITB) in Australian tertiary paediatric hospitals, along with the need for standardised assessment and reporting of adverse events, saw the formation of the Australian Paediatric ITB Research Group (APIRG). APIRG developed a National ITB Audit tool designed to capture clinical outcomes and adverse events data for all Australian children and adolescents receiving ITB therapy. METHODS AND ANALYSIS: The Australian ITB Audit is a 10 year, longitudinal, prospective, clinical audit collecting all adverse events and assessment data across body functions and structure, participation and activity level domains of the ICF. Data will be collected at baseline, 6 and 12 months with ongoing capture of all adverse event data. This is the first Australian study that aims to capture clinical and adverse event data from a complete population of children with neurological impairment receiving a specific intervention between 2011 and 2021. This multi-centre study will inform ITB clinical practice in children and adolescents, direct patient selection, record and aid decision making regarding adverse events and investigate the impact of ITB therapy on family and patient quality of life. ETHICS AND DISSEMINATION: This project was approved by the individual Human Research Ethics committees at the six Australian tertiary hospitals involved in the study. Results will be published in various peer reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN 12610000323022; Pre results. PMID- 28637740 TI - Tablet computers versus optical aids to support education and learning in children and young people with low vision: protocol for a pilot randomised controlled trial, CREATE (Children Reading with Electronic Assistance To Educate). AB - INTRODUCTION: Low vision and blindness adversely affect education and independence of children and young people. New 'assistive' technologies such as tablet computers can display text in enlarged font, read text out to the user, allow speech input and conversion into typed text, offer document and spreadsheet processing and give access to wide sources of information such as the internet. Research on these devices in low vision has been limited to case series. METHODS AND ANALYSIS: We will carry out a pilot randomised controlled trial (RCT) to assess the feasibility of a full RCT of assistive technologies for children/young people with low vision. We will recruit 40 students age 10-18 years in India and the UK, whom we will randomise 1:1 into two parallel groups. The active intervention will be Apple iPads; the control arm will be the local standard low vision aid care. Primary outcomes will be acceptance/usage, accessibility of the device and trial feasibility measures (time to recruit children, lost to follow up). Exploratory outcomes will be validated measures of vision-related quality of life for children/young people as well as validated measures of reading and educational outcomes. In addition, we will carry out semistructured interviews with the participants and their teachers. ETHICS AND DISSEMINATION: NRES reference 15/NS/0068; dissemination is planned via healthcare and education sector conferences and publications, as well as via patient support organisations. TRIAL REGISTRATION NUMBER: NCT02798848; IRAS ID 179658, UCL reference 15/0570. PMID- 28637738 TI - The REAnimation Low Immune Status Markers (REALISM) project: a protocol for broad characterisation and follow-up of injury-induced immunosuppression in intensive care unit (ICU) critically ill patients. AB - INTRODUCTION: The host response to septic shock is dynamic and complex. A sepsis induced immunosuppression phase has recently been acknowledged and linked to bad outcomes and increased healthcare costs. Moreover, a marked suppression of the immune response has also been partially described in patients hospitalized in intensive care unit (ICU) for severe trauma or burns. It has been hypothesized that immune monitoring could enable identification of patients who might most benefit from novel, adjunctive immune-stimulating therapies. However, there is currently neither a clear definition for such injury-induced immunosuppression nor a stratification biomarker compatible with clinical constraints. METHODS AND ANALYSIS: We set up a prospective, longitudinal single-centre clinical study to determine the incidence, severity and persistency of innate and adaptive immune alterations in ICU patients. We optimized a workflow to describe and follow the immunoinflammatory status of 550 patients (septic shock, severe trauma/burn and major surgery) during the first 2 months after their initial injury. On each time point, two immune functional tests will be performed to determine whole-blood TNF alpha production in response to ex vivo lipopolysaccharide stimulation and the T lymphocyte proliferation in response to phytohaemagglutinin. In addition, a complete immunophenotyping using flow cytometry including monocyte HLA-DR expression and lymphocyte subsets will be obtained. New markers (ie, levels of expression of host mRNA and viral reactivation) will be also evaluated. Reference intervals will be determined from a cohort of 150 age-matched healthy volunteers. This clinical study will provide, for the first time, data describing the immune status of severe ICU patients over time. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the institutional review board (no 69HCL15_0379) and the French National Security agency for drugs and health-related products. Results will be disseminated through presentations at scientific meetings and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Registration number: NCT02638779. Pre-results. PMID- 28637741 TI - The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial. AB - INTRODUCTION: Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. METHODS AND ANALYSIS: The CLOSED study is a multicentre, double blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. ETHICS: Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION: EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results. PMID- 28637742 TI - Primary prevention implantable cardioverter defibrillator in patients with non ischaemic cardiomyopathy: a meta-analysis of randomised controlled trials. AB - OBJECTIVES: The objective of this meta-analysis of randomised controlled trials (RCTs) is to evaluate the role of primary prevention implantable cardioverter defibrillator (ICD) in patients with non-ischaemic cardiomyopathy (NICM). SETTING: A meta-analysis of RCTs performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. DATA SOURCES: The PubMed, MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases were searched for relevant articles. PARTICIPANTS: A total of 5 RCTs with 2573 patients with NICM were included. INTERVENTION: Primary prevention ICD, compared with medical therapy alone. PRIMARY AND SECONDARY OUTCOME MEASURES: All cause mortality (primary outcome) and sudden cardiac death (SCD, secondary outcome). DATA ANALYSIS: Summary estimate HR were constructed using the random effect DerSimonian and Laird's model. Multiple study-level subgroup analyses were performed, and interaction was tested using random-effect analysis. RESULTS: Compared with medical therapy alone, ICD placement was associated with lower risk of all-cause mortality (HR 0.79; 95% CI 0.64 to 0.93; p<0.001; I2=0%) at a mean follow-up of 4.2 years. The risk of SCD was also lower with ICD placement (RR 0.47; 95% CI 0.30 to 0.73; p=0.001; I2=0%) compared with control. On subgroup analyses, there was a suggestion of possible effect modification by age, in which benefit was observed in age group <60 years (HR 0.64; 95% CI 0.47 to 0.89), but not with age >=60 years (HR 0.82; 95% CI 0.65 to 1.03) (Pinteraction=0.058), but not with other study-level variables. CONCLUSIONS: Compared with medical therapy alone, primary prevention ICD therapy in patients with NICM is associated with a significant reduction in all-cause mortality, especially in younger patients. Future dedicated studies are needed to investigate the role of primary prevention ICD in the elderly population. PROSPEROREGISTRATIONNUMBER: PROSPERO CRD42016052010. PMID- 28637743 TI - Knowledge, attitude and practice of healthcare professionals towards infliximab and insulin glargine biosimilars: result of a UK web-based survey. AB - OBJECTIVE: To investigate healthcare professionals' knowledge and attitudes towards infliximab and insulin glargine biosimilars and the factors influencing their prescribing. Then, to compare healthcare professionals' attitudes with the utilisation of these biosimilars in UK hospitals. DESIGN: Self-administered, one time web-based survey and drug utilisation analysis. SETTING AND DATA SOURCES: Professional associations and societies in the field of dermatology, diabetology, gastroenterology and rheumatology in the UK, between 8 August 2016 and 8 January 2017. The volume of utilisation of branded and biosimilar infliximab and insulin glargine in UK hospitals was derived from the DEFINE database, between 2015 and 2016. OUTCOMES: Participants' knowledge and awareness of biosimilars and factors influencing their use and corresponding usage of infliximab and insulin glargine biosimilars. RESULTS: Responses were obtained from 234 healthcare professionals across dermatology, diabetology, gastroenterology and rheumatology specialties. 75% of respondents were aware that biosimilars were available on their local formulary. 77% of respondents considered biosimilars extremely or very important to save costs for the NHS. Gastroenterologists had the highest utilisation of infliximab biosimilars (14%) in 2015 rising to (62%) in 2016. Healthcare professionals had greater concerns about safety and efficacy when switching patients to biosimilars than when starting biosimilars in biological naive patients. Guidance from National Institute for Health and Care Excellence and robust pharmacovigilance studies on biosimilars were both considered important factors in increasing biosimilars use. CONCLUSION: British healthcare professionals are well informed about biosimilars with high level of awareness. Safety and efficacy concerns were higher in switching than in initiating biosimilars among some prescribers. It is probable that personal experience of biologics as well as discipline-specific guidance influenced prescribers' responses. PMID- 28637745 TI - Corrections: Cost-effectiveness of therapist-guided internet-delivered cognitive behaviour therapy for paediatric obsessive-compulsive disorder: results from a randomised controlled trial. PMID- 28637744 TI - Group clinics for young adults with diabetes in an ethnically diverse, socioeconomically deprived setting (TOGETHER study): protocol for a realist review, co-design and mixed methods, participatory evaluation of a new care model. AB - INTRODUCTION: Young adults with diabetes often report dissatisfaction with care and have poor diabetes-related health outcomes. As diabetes prevalence continues to rise, group-based care could provide a sustainable alternative to traditional one-to-one consultations, by engaging young people through life stage-, context- and culturally-sensitive approaches. In this study, we will co-design and evaluate a group-based care model for young adults with diabetes and complex health and social needs in socioeconomically deprived areas. METHODS AND ANALYSIS: This participatory study will include three phases. In phase 1, we will carry out a realist review to synthesise the literature on group-based care for young adults with diabetes. This theory-driven understanding will provide the basis for phase 2, where we will draw on experience-based co-design methodologies to develop a new, group-based care model for young adults (aged <25 years, under the care of adult diabetes services). In phase 3, we will use a researcher-in residence approach to implement and evaluate the co-designed group clinic model and compare with traditional care. We will employ qualitative (observations in clinics, patient and staff interviews and document analysis) and quantitative methods (eg, biological markers, patient enablement instrument and diabetes distress scale), including a cost analysis. ETHICS AND DISSEMINATION: National Health Service ethics approval has been granted (reference 17/NI/0019). The project will directly inform service redesign to better meet the needs of young adults with diabetes in socioeconomically deprived areas and may guide a possible cluster-randomised trial, powered to clinical and cost-effectiveness outcomes. Findings from this study may be transferable to other long-term conditions and/or age groups. Project outputs will include briefing statements, summaries and academic papers, tailored for different audiences, including people living with diabetes, clinicians, policy makers and strategic decision makers. REGISTRATION DETAILS: PROSPERO (CRD42017058726). PMID- 28637747 TI - F-actin prevents interaction between sperm DNA and the oocyte meiotic spindle in C. elegans. AB - Fertilization occurs during female meiosis in most animals, which raises the question of what prevents the sperm DNA from interacting with the meiotic spindle. In this study, we find that Caenorhabditis elegans sperm DNA stays in a fixed position at the opposite end of the embryo from the meiotic spindle while yolk granules are transported throughout the embryo by kinesin-1. In the absence of F-actin, the sperm DNA, centrioles, and organelles were transported as a unit with the yolk granules, resulting in sperm DNA within 2 um of the meiotic spindle. F-actin imaging revealed a cytoplasmic meshwork that might restrict transport in a size-dependent manner. However, increasing yolk granule size did not slow their velocity, and the F-actin moved with the yolk granules. Instead, sperm contents connect to the cortical F-actin to prevent interaction with the meiotic spindle. PMID- 28637746 TI - Early protection to stress mediated by CDK-dependent PI3,5P2 signaling from the vacuole/lysosome. AB - Adaptation to environmental stress is critical for cell survival. Adaptation generally occurs via changes in transcription and translation. However, there is a time lag before changes in gene expression, which suggests that more rapid mechanisms likely exist. In this study, we show that in yeast, the cyclin dependent kinase Pho85/CDK5 provides protection against hyperosmotic stress and acts before long-term adaptation provided by Hog1. This protection requires the vacuolar/endolysosomal signaling lipid PI3,5P2 We show that Pho85/CDK5 directly phosphorylates and positively regulates the PI3P-5 kinase Fab1/PIKfyve complex and provide evidence that this regulation is conserved in mammalian cells. Moreover, this regulation is particularly crucial in yeast for the stress-induced transient elevation of PI3,5P2 Our study reveals a rapid protection mechanism regulated by Pho85/CDK5 via signaling from the vacuole/lysosome, which is distinct temporally and spatially from the previously discovered long-term adaptation Hog1 pathway, which signals from the nucleus. PMID- 28637749 TI - Cell cycle-dependent spatial segregation of telomerase from sites of DNA damage. AB - Telomerase can generate a novel telomere at DNA double-strand breaks (DSBs), an event called de novo telomere addition. How this activity is suppressed remains unclear. Combining single-molecule imaging and deep sequencing, we show that the budding yeast telomerase RNA (TLC1 RNA) is spatially segregated to the nucleolus and excluded from sites of DNA repair in a cell cycle-dependent manner. Although TLC1 RNA accumulates in the nucleoplasm in G1/S, Pif1 activity promotes TLC1 RNA localization in the nucleolus in G2/M. In the presence of DSBs, TLC1 RNA remains nucleolar in most G2/M cells but accumulates in the nucleoplasm and colocalizes with DSBs in rad52Delta cells, leading to de novo telomere additions. Nucleoplasmic accumulation of TLC1 RNA depends on Cdc13 localization at DSBs and on the SUMO ligase Siz1, which is required for de novo telomere addition in rad52Delta cells. This study reveals novel roles for Pif1, Rad52, and Siz1 dependent sumoylation in the spatial exclusion of telomerase from sites of DNA repair. PMID- 28637750 TI - Interplay of PA-X and NS1 Proteins in Replication and Pathogenesis of a Temperature-Sensitive 2009 Pandemic H1N1 Influenza A Virus. AB - Influenza A viruses (IAVs) cause seasonal epidemics and occasional pandemics, representing a serious public health concern. It has been described that one mechanism used by some IAV strains to escape the host innate immune responses and modulate virus pathogenicity involves the ability of the PA-X and NS1 proteins to inhibit the host protein synthesis in infected cells. It was reported that for the 2009 pandemic H1N1 IAV (pH1N1) only the PA-X protein had this inhibiting capability, while the NS1 protein did not. In this work, we have evaluated, for the first time, the combined effect of PA-X- and NS1-mediated inhibition of general gene expression on virus pathogenesis, using a temperature-sensitive, live-attenuated 2009 pandemic H1N1 IAV (pH1N1 LAIV). We found that viruses containing PA-X and NS1 proteins that simultaneously have (PAWT+/NS1MUT+) or do not have (PAMUT-/NS1WT-) the ability to block host gene expression showed reduced pathogenicity in vivo However, a virus where the ability to inhibit host protein expression was switched between PA-X and NS1 (PAMUT-/NS1MUT+) presented pathogenicity similar to that of a virus containing both wild-type proteins (PAWT+/NS1WT-). Our findings suggest that inhibition of host protein expression is subject to a strict balance, which can determine the successful progression of IAV infection. Importantly, knowledge obtained from our studies could be used for the development of new and more effective vaccine approaches against IAV.IMPORTANCE Influenza A viruses (IAVs) are one of the most common causes of respiratory infections in humans, resulting in thousands of deaths annually. Furthermore, IAVs can cause unpredictable pandemics of great consequence when viruses not previously circulating in humans are introduced into humans. The defense machinery provided by the host innate immune system limits IAV replication; however, to counteract host antiviral activities, IAVs have developed different inhibition mechanisms, including prevention of host gene expression mediated by the viral PA-X and NS1 proteins. Here, we provide evidence demonstrating that optimal control of host protein synthesis by IAV PA-X and/or NS1 proteins is required for efficient IAV replication in the host. Moreover, we demonstrate the feasibility of genetically controlling the ability of IAV PA-X and NS1 proteins to inhibit host immune responses, providing an approach to develop more effective vaccines to combat disease caused by this important respiratory pathogen. PMID- 28637748 TI - Impaired spliceosomal UsnRNP assembly leads to Sm mRNA down-regulation and Sm protein degradation. AB - Specialized assembly factors facilitate the formation of many macromolecular complexes in vivo. The formation of Sm core structures of spliceosomal U-rich small nuclear ribonucleoprotein particles (UsnRNPs) requires assembly factors united in protein arginine methyltransferase 5 (PRMT5) and survival motor neuron (SMN) complexes. We demonstrate that perturbations of this assembly machinery trigger complex cellular responses that prevent aggregation of unassembled Sm proteins. Inactivation of the SMN complex results in the initial tailback of Sm proteins on the PRMT5 complex, followed by down-regulation of their encoding mRNAs. In contrast, reduction of pICln, a PRMT5 complex subunit, leads to the retention of newly synthesized Sm proteins on ribosomes and their subsequent lysosomal degradation. Overexpression of Sm proteins under these conditions results in a surplus of Sm proteins over pICln, promoting their aggregation. Our studies identify an elaborate safeguarding system that prevents individual Sm proteins from aggregating, contributing to cellular UsnRNP homeostasis. PMID- 28637752 TI - Identification of Intermediate in Hepatitis B Virus CCC DNA Formation and Sensitive and Selective CCC DNA Detection. AB - The hepatitis B virus (HBV) covalently closed circular (CCC) DNA functions as the only viral template capable of coding for all the viral RNA species and is thus essential to initiate and sustain viral replication. CCC DNA is converted, in a multi-step and ill-understood process, from a relaxed circular (RC) DNA, in which neither of the two DNA strands is covalently closed. To detect putative intermediates during RC to CCC DNA conversion, two 3' exonucleases Exo I and Exo III, in combination were used to degrade all DNA strands with a free 3' end, which would nevertheless preserve closed circular DNA, either single-stranded (SS) or double-stranded (DS). Indeed, a RC DNA species with a covalently closed minus strand but an open plus strand (closed minus-strand RC DNA or cM-RC DNA) was detected by this approach. Further analyses indicated that at least some of the plus strands in such a putative intermediate likely still retained the RNA primer that is attached to the 5' end of the plus strand in RC DNA, suggesting that minus strand closing can occur before plus strand processing. Furthermore, the same nuclease treatment proved to be useful for sensitive and specific detection of CCC DNA by removing all DNA species other than closed circular DNA. Application of these and similar approaches may allow the identification of additional intermediates during CCC DNA formation and facilitate specific and sensitive detection of CCC DNA, which should help elucidate the pathways of CCC DNA formation and factors involved.IMPORTANCE The hepatitis B virus (HBV) covalently closed circular (CCC) DNA is the molecular basis of viral persistence, by serving as the viral transcriptional template. CCC DNA is converted, in a multi-step and ill-understood process, from a relaxed circular (RC) DNA. Little is currently understood about the pathways or factors involved in CCC DNA formation. We have now detected a likely intermediate during the conversion of RC to CCC DNA, thus providing important clues to the pathways of CCC DNA formation. Furthermore, the same experimental approach that led to the detection of the intermediate could also facilitate specific and sensitive detection of CCC DNA, which has remained challenging. This and similar approaches will help identify additional intermediates during CCC DNA formation and elucidate the pathways and factors involved. PMID- 28637751 TI - Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity. AB - Understanding the interactions between rabies virus (RABV) and individual host cell proteins is critical for the development of targeted therapies. Here we report that interferon-induced protein with tetratricopeptide repeats 2 (Ifit2), an interferon-stimulated gene (ISG) with possible RNA-binding capacity, is an important restriction factor for rabies virus. When Ifit2 was depleted, RABV grew more quickly in mouse neuroblastoma cells in vitro This effect was replicated in vivo, where Ifit2 knockout mice displayed a dramatically more severe disease phenotype than wild-type mice after intranasal inoculation of RABV. This increase in pathogenicity correlated to an increase in RABV mRNA and live viral load in the brain, as well as to an accelerated spread to brain regions normally affected by this RABV model. These results suggest that Ifit2 exerts its antiviral effect mainly at the level of viral replication, as opposed to functioning as a mechanism that restricts viral entry/egress or transports RABV particles through axons.IMPORTANCE Rabies is a fatal zoonotic disease with a nearly 100% case fatality rate. Although there are effective vaccines for rabies, this disease still takes the lives of about 50,000 people each year. Victims tend to be children living in regions without comprehensive medical infrastructure who present to health care workers too late for postexposure prophylaxis. The protein discussed in our report, Ifit2, is found to be an important restriction factor for rabies virus, acting directly or indirectly against viral replication. A more nuanced understanding of this interaction may reveal a step of a pathway or site at which the system could be exploited for the development of a targeted therapy. PMID- 28637753 TI - Structural mimicry of the dengue virus envelope glycoprotein revealed by the crystallographic study of an idiotype-anti-idiotype Fab complex. AB - A detailed understanding of the fine specificity of serotype-specific human antibodies is vital for the development and evaluation of new vaccines for pathogenic Flaviviruses such as Dengue virus (DENV) and Zika virus. In this study, we thoroughly characterize the structural footprint of an anti-idiotype antibody (E1) specific for a potent, fully human DENV serotype 1-specific antibody termed HM14c10, derived from a recovered patient. The crystal structure at a resolution of 2.5 A of a complex between the Fab fragments of E1 and HM14c10 provides the first detailed molecular comparison of an anti-idiotype paratope specific for a human antibody with its analogous epitope- a discontinuous quaternary structure located at the surface of the viral particle that spans adjacent envelope (E) proteins. This comparison reveals that the footprints left by E1 and E on HM14c10 largely overlap, explaining why formation of the binary complexes are mutually exclusive. Structural mimicry of the DENV E epitope by the E1 combining site is achieved via the formation of numerous interactions with heavy chain CDRs of HM14c10, while fewer interactions are observed with its light chain, compared to the E protein. We show that E1 can be utilized to detect HM14c10-like antibodies in sera from patients recovered from a DENV-1 infection suggesting that this is a public (common) idiotype. These data demonstrate the utility of employing an anti-idiotype antibody to monitor a patient's specific immune responses and suggest routes for improvement of E 'mimicry' by E1 through increasing its recognition of the FabHM14c10 light chain CDRs.IMPORTANCE A chimeric yellow fever/dengue live-attenuated tetravalent vaccine is now marketed. Dengue remains a significant public health problem, because protection conferred by this vaccine is uneven against the four circulating serotypes. Reliable tools must be developed to measure the immune response of individuals exposed to DENV, either via viral infection or through vaccination. Anti-idiotypic antibodies provide precision tools for analyzing the pharmacokinetics of antibodies in an immune response and also for measuring the amount of circulating anti-infective therapeutic antibodies. Here, we characterize how an anti-idiotypic antibody (E1) binds the antibody HM14c10, which potently neutralizes DENV serotype 1. We report the crystal structure at a resolution of 2.5 A of a complex between the Fab fragments of E1 and HM14c10 and provide the first detailed molecular comparison between the anti-idiotype surface and its analogous epitope located at the surface of the Dengue viral particle. PMID- 28637755 TI - Seasonal H3N2 and 2009 Pandemic H1N1 Influenza A Viruses Reassort Efficiently but Produce Attenuated Progeny. AB - Reassortment of gene segments between coinfecting influenza A viruses (IAVs) facilitates viral diversification and has a significant epidemiological impact on seasonal and pandemic influenza. Since 1977, human IAVs of H1N1 and H3N2 subtypes have cocirculated with relatively few documented cases of reassortment. We evaluated the potential for viruses of the 2009 pandemic H1N1 (pH1N1) and seasonal H3N2 lineages to reassort under experimental conditions. Results of heterologous coinfections with pH1N1 and H3N2 viruses were compared to those obtained following coinfection with homologous, genetically tagged, pH1N1 viruses as a control. High genotype diversity was observed among progeny of both coinfections; however, diversity was more limited following heterologous coinfection. Pairwise analysis of genotype patterns revealed that homologous reassortment was random while heterologous reassortment was characterized by specific biases. pH1N1/H3N2 reassortant genotypes produced under single-cycle coinfection conditions showed a strong preference for homologous PB2-PA combinations and general preferences for the H3N2 NA, pH1N1 M, and H3N2 PB2 except when paired with the pH1N1 PA or NP. Multicycle coinfection results corroborated these findings and revealed an additional preference for the H3N2 HA. Segment compatibility was further investigated by measuring chimeric polymerase activity and growth of selected reassortants in human tracheobronchial epithelial cells. In guinea pigs inoculated with a mixture of viruses, parental H3N2 viruses dominated but reassortants also infected and transmitted to cage mates. Taken together, our results indicate that strong intrinsic barriers to reassortment between seasonal H3N2 and pH1N1 viruses are few but that the reassortants formed are attenuated relative to parental strains.IMPORTANCE The genome of IAV is relatively simple, comprising eight RNA segments, each of which typically encodes one or two proteins. Each viral protein carries out multiple functions in coordination with other viral components and the machinery of the cell. When two IAVs coinfect a cell, they can exchange genes through reassortment. The resultant progeny viruses often suffer fitness defects due to suboptimal interactions among divergent viral components. The genetic diversity generated through reassortment can facilitate the emergence of novel outbreak strains. Thus, it is important to understand the efficiency of reassortment and the factors that limit its potential. The research described here offers new tools for studying reassortment between two strains of interest and applies those tools to viruses of the 2009 pandemic H1N1 and seasonal H3N2 lineages, which currently cocirculate in humans and therefore have the potential to give rise to novel epidemic strains. PMID- 28637754 TI - Functional Evolution of Influenza Virus NS1 Protein in Currently Circulating Human 2009 Pandemic H1N1 Viruses. AB - In 2009, a novel H1N1 influenza virus emerged in humans, causing a global pandemic. It was previously shown that the NS1 protein from this human 2009 pandemic H1N1 (pH1N1) virus was an effective interferon (IFN) antagonist but could not inhibit general host gene expression, unlike other NS1 proteins from seasonal human H1N1 and H3N2 viruses. Here we show that the NS1 protein from currently circulating pH1N1 viruses has evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) with respect to the original protein. Notably, these 6 residue changes restore the ability of pH1N1 NS1 to inhibit general host gene expression, mainly by their ability to restore binding to the cellular factor CPSF30. This is the first report describing the ability of the pH1N1 NS1 protein to naturally acquire mutations that restore this function. Importantly, a recombinant pH1N1 virus containing these 6 amino acid changes in the NS1 protein (pH1N1/NSs-6mut) inhibited host IFN and proinflammatory responses to a greater extent than that with the parental virus (pH1N1/NS1-wt), yet virus titers were not significantly increased in cell cultures or in mouse lungs, and the disease was partially attenuated. The pH1N1/NSs-6mut virus grew similarly to pH1N1/NSs-wt in mouse lungs, but infection with pH1N1/NSs-6mut induced lower levels of proinflammatory cytokines, likely due to a general inhibition of gene expression mediated by the mutated NS1 protein. This lower level of inflammation induced by the pH1N1/NSs-6mut virus likely accounts for the attenuated disease phenotype and may represent a host-virus adaptation affecting influenza virus pathogenesis.IMPORTANCE Seasonal influenza A viruses (IAVs) are among the most common causes of respiratory infections in humans. In addition, occasional pandemics are caused when IAVs circulating in other species emerge in the human population. In 2009, a swine-origin H1N1 IAV (pH1N1) was transmitted to humans, infecting people then and up to the present. It was previously shown that the NS1 protein from the 2009 pandemic H1N1 (pH1N1) virus is not able to inhibit general gene expression. However, currently circulating pH1N1 viruses have evolved to encode 6 amino acid changes (E55K, L90I, I123V, E125D, K131E, and N205S) that allow the NS1 protein of contemporary pH1N1 strains to inhibit host gene expression, which correlates with its ability to interact with CPSF30. Infection with a recombinant pH1N1 virus encoding these 6 amino acid changes (pH1N1/NSs 6mut) induced lower levels of proinflammatory cytokines, resulting in viral attenuation in vivo This might represent an adaptation of pH1N1 virus to humans. PMID- 28637757 TI - Going against the Tide: Selective Cellular Protein Synthesis during Virally Induced Host Shutoff. AB - Many viral infections cause host shutoff, a state in which host protein synthesis is globally inhibited. Emerging evidence from vaccinia and influenza A virus infections indicates that subsets of cellular proteins are resistant to host shutoff and continue to be synthesized. Remarkably, the proteins of oxidative phosphorylation, the cellular-energy-generating machinery, are selectively synthesized in both cases. Identifying mechanisms that drive selective protein synthesis should facilitate understanding both viral replication and fundamental cell biology. PMID- 28637756 TI - High-Resolution Metatranscriptomics Reveals the Ecological Dynamics of Mosquito Associated RNA Viruses in Western Australia. AB - Mosquitoes harbor a high diversity of RNA viruses, including many that impact human health. Despite a growing effort to describe the extent and nature of the mosquito virome, little is known about how these viruses persist, spread, and interact with both their hosts and other microbes. To address this issue we performed a metatranscriptomics analysis of 12 Western Australian mosquito populations structured by species and geographic location. Our results identified the complete genomes of 24 species of RNA viruses from a diverse range of viral families and orders, among which 19 are newly described. Comparisons of viromes revealed a striking difference between the two mosquito genera, with viromes of mosquitoes of the Aedes genus exhibiting substantially less diversity and lower abundances than those of mosquitoes of the Culex genus, within which the viral abundance reached 16.87% of the total non-rRNA. In addition, there was little overlap in viral diversity between the two genera, although the viromes were very similar among the three Culex species studied, suggesting that the host taxon plays a major role in structuring virus diversity. In contrast, we found no evidence that geographic location played a major role in shaping RNA virus diversity, and several viruses discovered here exhibited high similarity (95 to 98% nucleotide identity) to those from Indonesia and China. Finally, using abundance-level and phylogenetic relationships, we were able to distinguish potential mosquito viruses from those present in coinfecting bacteria, fungi, and protists. In sum, our metatranscriptomics approach provides important insights into the ecology of mosquito RNA viruses.IMPORTANCE Studies of virus ecology have generally focused on individual viral species. However, recent advances in bulk RNA sequencing make it possible to utilize metatranscriptomic approaches to reveal both complete virus diversity and the relative abundance of these viruses. We used such a metatranscriptomic approach to determine key aspects of the ecology of mosquito viruses in Western Australia. Our results show that RNA viruses are some of the most important components of the mosquito transcriptome, and we identified 19 new virus species from a diverse set of virus families. A key result was that host genetic background plays a more important role in shaping virus diversity than sampling location, with Culex species harboring more viruses at higher abundance than those from Aedes mosquitoes. PMID- 28637758 TI - Genome-Wide Analysis of 18 Epstein-Barr Viruses Isolated from Primary Nasopharyngeal Carcinoma Biopsy Specimens. AB - Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that is highly prevalent in almost all human populations and is associated with many human cancers, such as nasopharyngeal carcinoma (NPC), Hodgkin's disease, and gastric carcinoma. However, in these EBV-associated cancers, only NPC exhibits remarkable ethnic and geographic distribution. We hypothesized that EBV genomic variations might contribute to the pathogenesis of different human cancers in different geographic areas. In this study, we collected 18 NPC biopsy specimens from the Hunan Province in southern China and de novo assembled 18 NPC biopsy specimen derived EBV (NPC-EBV) genomes, designated HN1 to HN18. This was achieved through target enrichment of EBV DNA by hybridization, followed by next-generation sequencing, to reveal sequence diversity. These EBV genomes harbored 20,570 variations totally, including 20,328 substitutions, 88 insertions, and 154 deletions, compared to the EBV reference genome. Phylogenetic analysis revealed that all NPC-EBV genomes were distinct from other EBV genomes. Furthermore, HN1 to HN18 had some nonsynonymous variations in EBV genes including genes encoding latent, early lytic, and tegument proteins, such as substitutions within transmembrane domains 1 and 3 of LMP1, FoP_duplication, and zf-AD domains of ENBA1, in addition to aberrations in noncoding regions, especially in BamHI A rightward transcript microRNAs. These variations might have potential biological significance. In conclusion, we reported a genome-wide view of sequence variation in EBV isolated from primary NPC biopsy specimens obtained from the Hunan Province. This might contribute to further understanding of how genomic variations contribute to carcinogenesis, which would impact the treatment of EBV associated cancer.IMPORTANCE Nasopharyngeal carcinoma (NPC) is highly associated with Epstein-Barr virus (EBV) infection and exhibits remarkable ethnic and geographic distribution. Hunan Province in southern China has a high incidence rate of NPCs. Here, we report 18 novel EBV genome sequences from viruses isolated from primary NPC biopsy specimens in this region, revealing whole-genome sequence diversity. PMID- 28637759 TI - Role of the JNK Pathway in Varicella-Zoster Virus Lytic Infection and Reactivation. AB - Mechanisms of neuronal infection by varicella-zoster virus (VZV) have been challenging to study due to the relatively strict human tropism of the virus and the paucity of tractable experimental models. Cellular mitogen-activated protein kinases (MAPKs) have been shown to play a role in VZV infection of nonneuronal cells, with distinct consequences for infectivity in different cell types. Here, we utilize several human neuronal culture systems to investigate the role of one such MAPK, the c-Jun N-terminal kinase (JNK), in VZV lytic infection and reactivation. We find that the JNK pathway is specifically activated following infection of human embryonic stem cell-derived neurons and that this activation of JNK is essential for efficient viral protein expression and replication. Inhibition of the JNK pathway blocked viral replication in a manner distinct from that of acyclovir, and an acyclovir-resistant VZV isolate was as sensitive to the effects of JNK inhibition as an acyclovir-sensitive VZV isolate in neurons. Moreover, in a microfluidic-based human neuronal model of viral latency and reactivation, we found that inhibition of the JNK pathway resulted in a marked reduction in reactivation of VZV. Finally, we utilized a novel technique to efficiently generate cells expressing markers of human sensory neurons from neural crest cells and established a critical role for the JNK pathway in infection of these cells. In summary, the JNK pathway plays an important role in lytic infection and reactivation of VZV in physiologically relevant cell types and may provide an alternative target for antiviral therapy.IMPORTANCE Varicella zoster virus (VZV) has infected over 90% of people worldwide. While primary infection leads to the typically self-limiting condition of chickenpox, the virus can remain dormant in the nervous system and may reactivate later in life, leading to shingles or inflammatory diseases of the nervous system and eye with potentially severe consequences. Here, we take advantage of newer stem cell-based technologies to study the mechanisms by which VZV infects human neurons. We find that the c-Jun N-terminal kinase (JNK) pathway is activated by VZV infection and that blockade of this pathway limits lytic replication (as occurs during primary infection). In addition, JNK inhibition limits viral reactivation, exhibiting parallels with herpes simplex virus reactivation. The identification of the role of the JNK pathway in VZV infection of neurons reveals potential avenues for the development of alternate antiviral drugs. PMID- 28637760 TI - Discovery of a highly divergent coronavirus in the Asian house shrew from China illuminates the origin of the alphacoronaviruses. AB - Although shrews are one of the largest groups of mammals little is known about their role in the evolution and transmission of viral pathogens including coronaviruses. We captured 266 Asian house shrews (Suncus murinus) in Jiangxi and Zhejiang provinces, China, during 2013-2015. Coronavirus (CoV) RNA was detected in 24 Asian house shrews, with an overall prevalence of 9.02%. Complete viral genome sequences were successfully recovered from the RNA positive samples. The newly discovered shrew CoV fell into four lineages reflecting their geographic origins, indicative of largely allopatric evolution. Notably, these viruses were most closely related to alphacoronaviruses, but sufficiently divergent that they should be considered a novel member of the genus Alphacoronavirus, which we denote Wencheng shrew virus (WESV). Phylogenetic analysis revealed that WESV was a highly divergent member of the alphacoronaviruses and, more dramatically, that the S gene of WESV fell in a cluster that was genetically distinct from that of known coronaviruses. The divergent position of WESV suggests that coronaviruses have a long association with Asian house shrews. In addition, the genome of WESV contains a distinct NS7 gene that exhibits no sequence similarity to any known viruses. Together, these data suggest that shrews are natural reservoirs for coronaviruses and may have played an important and long-term role in CoV evolution.IMPORTANCE The subfamily Coronavirinae contains several notorious human and animal pathogens, including severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and porcine epidemic diarrhea virus. Because of their genetic diversity and phylogenetic relationships it has been proposed that the alphacoronaviruses likely have their ultimate ancestry in those viruses residing in bats. Here, we described a novel alphacoronavirus (Wencheng shrew virus, WESV) that was sampled from Asian house shrews in China. Notably, WESV is a highly divergent member of the alphacoronaviruses and possesses an S gene that is genetically distinct from that of all known coronaviruses. In addition, the genome of WESV contains a distinct NS7 gene that exhibits no sequence similarity to any known viruses. Together, these data suggest that shrews are important and long-standing hosts for coronaviruses that merit additional research and surveillance. PMID- 28637761 TI - Mother-to-Child HIV Transmission Bottleneck Selects for Consensus Virus with Lower Gag-Protease-Driven Replication Capacity. AB - In the large majority of cases, HIV infection is established by a single variant, and understanding the characteristics of successfully transmitted variants is relevant to prevention strategies. Few studies have investigated the viral determinants of mother-to-child transmission. To determine the impact of Gag protease-driven viral replication capacity on mother-to-child transmission, the replication capacities of 148 recombinant viruses encoding plasma-derived Gag protease from 53 nontransmitter mothers, 48 transmitter mothers, and 47 infected infants were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. All study participants were infected with HIV-1 subtype C. There was no significant difference in replication capacities between the nontransmitter (n = 53) and transmitter (n = 44) mothers (P = 0.48). Infant-derived Gag-protease NL4-3 recombinant viruses (n = 41) were found to have a significantly lower Gag protease-driven replication capacity than that of viruses derived from the mothers (P < 0.0001 by a paired t test). High percent similarities to consensus subtype C Gag, p17, p24, and protease sequences were also found in the infants (n = 28) in comparison to their mothers (P = 0.07, P = 0.002, P = 0.03, and P = 0.02, respectively, as determined by a paired t test). These data suggest that of the viral quasispecies found in mothers, the HIV mother-to-child transmission bottleneck favors the transmission of consensus-like viruses with lower viral replication capacities.IMPORTANCE Understanding the characteristics of successfully transmitted HIV variants has important implications for preventative interventions. Little is known about the viral determinants of HIV mother-to child transmission (MTCT). We addressed the role of viral replication capacity driven by Gag, a major structural protein that is a significant determinant of overall viral replicative ability and an important target of the host immune response, in the MTCT bottleneck. This study advances our understanding of the genetic bottleneck in MTCT by revealing that viruses transmitted to infants have a lower replicative ability as well as a higher similarity to the population consensus (in this case HIV subtype C) than those of their mothers. Furthermore, the observation that "consensus-like" virus sequences correspond to lower in vitro replication abilities yet appear to be preferentially transmitted suggests that viral characteristics favoring transmission are decoupled from those that enhance replicative capacity. PMID- 28637762 TI - Differential Requirement of Human Cytomegalovirus UL112-113 Protein Isoforms for Viral Replication. AB - The UL112-113 gene is one of the few alternatively spliced genes of human cytomegalovirus (HCMV). It codes for four phosphoproteins, p34, p43, p50, and p84, all of which are expressed with early kinetics and accumulate at sites of viral DNA replication within the host cell nucleus. Although these proteins are known to play important, possibly essential, roles in the viral replication cycle, little is known about the contribution of individual UL112-113 protein products. Here we used splice site mutagenesis, intron deletion and substitution, and nonsense mutagenesis to prevent the individual expression of each UL112-113 protein isoform and to investigate the importance of each isoform for viral replication. We show that HCMV mutants lacking p34 or p50 expression replicated to high titers in human fibroblasts and endothelial cells, indicating that these proteins are nonessential for viral replication, while mutant viruses carrying a stop mutation within the p84 coding sequence were severely growth impaired. Viral replication could not be detected upon the inactivation of p43 expression, indicating that this UL112-113 protein is essential for viral replication. We also analyzed the ability of UL112-113 proteins to recruit other viral proteins to intranuclear prereplication compartments. While UL112-113 expression was sufficient to recruit the UL44-encoded viral DNA polymerase processivity factor, it was not sufficient for the recruitment of the viral UL84 and UL117 proteins. Remarkably, both the p43 and p84 isoforms were required for the efficient recruitment of pUL44, which is consistent with their critical role in the viral life cycle.IMPORTANCE Human cytomegalovirus requires gene products from 11 genetic loci for the lytic replication of its genome. One of these loci, UL112 113, encodes four proteins with common N termini by alternative splicing. In this study, we inactivated the expression of each of the four UL112-113 proteins individually and determined their requirement for HCMV replication. We found that two of the UL112-113 gene products were dispensable for viral replication in human fibroblasts and endothelial cells. In contrast, viral replication was severely reduced or absent when one of the other two gene products was inactivated, indicating that they are of crucial importance for the viral replication cycle. We further showed that the latter two gene products are involved in the recruitment of pUL44, an essential cofactor of the viral DNA polymerase, to specific sites within the cell nucleus that are thought to serve as starting points for viral DNA replication. PMID- 28637764 TI - Roth's spot in megaloblastic anaemia. PMID- 28637763 TI - Analysis of Herpes Simplex Virus Reactivation in Explant Reveals a Method Dependent Difference in Measured Timing of Reactivation. AB - Herpes simplex virus (HSV) infection is widespread in the human population. Following orofacial infection, HSV establishes latency in innervating sensory neurons, primarily located in the trigeminal ganglia. A central feature of HSV pathogenesis is the ability to periodically reactivate in those neurons and be transported back to the body surface. Both transmission and disease, such as keratitis, encephalitis, and neurodegeneration, have been linked to reactivation. Despite invaluable insights obtained from model systems, interactions between viral and host functions that regulate reactivation are still incompletely understood. Various assays are used for measuring reactivation in animal models, but there have been limited comparisons between methods and the accuracy of detecting the timing of reactivation and the corresponding amount of infectious virus produced in the ganglia per reactivation event. Here, we directly compare two approaches for measuring reactivation in latently infected explanted ganglia by sampling media from the explanted cultures or by homogenization of the ganglia and compare the results to viral protein expression in the whole ganglia. We show that infectious virus detection by direct homogenization of explanted ganglia correlates with viral protein expression, but detection of infectious virus in medium samples from explanted cultures does not occur until extensive spread of virus is observed in the ganglia. The medium-sampling method is therefore not reflective of the initial timing of reactivation, and the additional variables influencing spread of virus in the ganglia should be considered when interpreting results obtained using this method.IMPORTANCE The development of treatments to prevent and/or treat HSV infection rely upon understanding viral and host factors that influence reactivation. Progress is dependent on experimental methods that accurately measure the frequency and timing of reactivation in latently infected neurons. In this study, two methods for detecting reactivation using the explant model are compared. We show through direct tissue homogenization that reactivation occurs much earlier than can be detected by the indirect method of sampling media from explanted cultures. Thus, the sampling method does not detect the initial timing of reactivation, and results obtained using this method are subject to additional variables with the potential to obscure reactivation outcomes. PMID- 28637766 TI - Emery-Dreifuss muscular dystrophy-linked genes and centronuclear myopathy-linked genes regulate myonuclear movement by distinct mechanisms. AB - Muscle cells are a syncytium in which the many nuclei are positioned to maximize the distance between adjacent nuclei. Although mispositioned nuclei are correlated with many muscle disorders, it is not known whether this common phenotype is the result of a common mechanism. To answer this question, we disrupted the expression of genes linked to Emery-Dreifuss muscular dystrophy (EDMD) and centronuclear myopathy (CNM) in Drosophila and evaluated the position of the nuclei. We found that the genes linked to EDMD and CNM were each necessary to properly position nuclei. However, the specific phenotypes were different. EDMD-linked genes were necessary for the initial separation of nuclei into distinct clusters, suggesting that these factors relieve interactions between nuclei. CNM-linked genes were necessary to maintain the nuclei within clusters as they moved toward the muscle ends, suggesting that these factors were necessary to maintain interactions between nuclei. Together these data suggest that nuclear position is disrupted by distinct mechanisms in EDMD and CNM. PMID- 28637765 TI - Electrostatic interaction between polyglutamylated tubulin and the nexin-dynein regulatory complex regulates flagellar motility. AB - Tubulins undergo various posttranslational modifications. Among them, polyglutamylation is involved in the motility of eukaryotic flagella and the stability of the axonemal microtubules. However, it remains unclear where polyglutamylated tubulin localizes precisely within the axoneme and how tubulin polyglutamylation affects flagellar motility. In this study, we identified the three-dimensional localization of the polyglutamylated tubulin in Chlamydomonas flagella using antibody labeling and cryo-electron tomography. Polyglutamylated tubulins specifically located in close proximity to a microtubule-cross-bridging structure called the nexin-dynein regulatory complex (N-DRC). Because N-DRC is positively charged, we hypothesized that there is an electrostatic interaction between the polyglutamylated tubulin and the N-DRC, and therefore we mutated the amino acid sequences of DRC4 to modify the charge of the N-DRC. We found that both augmentation and reduction of the positive charge on DRC4 resulted in reduced flagellar motility. Moreover, reduced motility in a mutant with a structurally defective N-DRC was partially restored by increasing the positive charge on DRC4. These results clearly indicate that beating motion of flagella is maintained by the electrostatic cross-bridge formed between the negatively charged polyglutamylated tubulins and the positively charged N-DRC. PMID- 28637767 TI - A short region upstream of the yeast vacuolar Qa-SNARE heptad-repeats promotes membrane fusion through enhanced SNARE complex assembly. AB - Whereas SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein receptor) heptad-repeats are well studied, SNAREs also have upstream N-domains of indeterminate function. The assembly of yeast vacuolar SNAREs into complexes for fusion can be studied in chemically defined reactions. Complementary proteoliposomes bearing a Rab:GTP and either the vacuolar R-SNARE or one of the three integrally anchored Q-SNAREs were incubated with the tethering/SM protein complex HOPS and the two other soluble SNAREs (lacking a transmembrane anchor) or their SNARE heptad-repeat domains. Fusion required a transmembrane-anchored R SNARE on one membrane and an anchored Q-SNARE on the other. The N-domain of the Qb-SNARE was completely dispensable for fusion. Whereas fusion can be promoted by very high concentrations of the Qa-SNARE heptad-repeat domain alone, at physiological concentrations the Qa-SNARE heptad-repeat domain alone has almost no fusion activity. The 181-198 region of Qa, immediately upstream of the SNARE heptad-repeat domain, is required for normal fusion activity with HOPS. This region is needed for normal SNARE complex assembly. PMID- 28637770 TI - Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice. AB - BACKGROUND: The use of opioids to alleviate pain is complicated by the risk of severe adverse events and the large variability in dose requirements. Pharmacogenetics (PGx) could possibly be used to tailor pain medication based on an individual's genetic background. Many potential genetic markers have been described, and the importance of genetic predisposition in opioid efficacy and toxicity has been demonstrated in knockout mouse models and human twin studies. Such predictors are especially of value for neonates and young children, in whom the assessment of efficacy or side effects is complicated by the inability of the patient to communicate this properly. The current problem is determining which of the many potential candidates to focus on for clinical implementation. CONTENT: We systematically searched publications on PGx for opioids in 5 databases, aiming to identify PGx markers with sufficient robust data and high enough occurrence for potential clinical application. The initial search yielded 4257 unique citations, eventually resulting in 852 relevant articles covering 24 genes. From these genes, we evaluated the evidence and selected the most promising 10 markers: cytochrome P450 family 2 subfamily D member 6 (CYP2D6), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 3 subfamily A member 5 (CYP3A5), UDP glucuronosyltransferase family 2 member B7 (UGT2B7), ATP binding cassette subfamily B member 1 (ABCB1), ATP binding cassette subfamily C member 3 (ABCC3), solute carrier family 22 member 1 (SLC22A1), opioid receptor kappa 1 (OPRM1), catechol-O-methyltransferase (COMT), and potassium voltage-gated channel subfamily J member 6 (KCNJ6). Treatment guidelines based on genotype are already available only for CYP2D6. SUMMARY: The application of PGx in the management of pain with opioids has the potential to improve therapy. We provide a shortlist of 10 genes that are the most promising markers for clinical use in this context. PMID- 28637768 TI - VRK2A is an A-type lamin-dependent nuclear envelope kinase that phosphorylates BAF. AB - The nuclear envelope (NE) is critical for numerous fundamental cellular functions, and mutations in several NE constituents can lead to a heterogeneous spectrum of diseases. We used proximity biotinylation to uncover new constituents of the inner nuclear membrane (INM) by comparative BioID analysis of lamin A, Sun2 and a minimal INM-targeting motif. These studies identify vaccinia-related kinase-2 (VRK2) as a candidate constituent of the INM. The transmembrane VRK2A isoform is retained at the NE by association with A-type lamins. Furthermore, VRK2A physically interacts with A-type, but not B-type, lamins. Finally, we show that VRK2 phosphorylates barrier to autointegration factor (BAF), a small and highly dynamic chromatin-binding protein, which has roles including NE reassembly, cell cycle, and chromatin organization in cells, and subtly alters its nuclear mobility. Together these findings support the value of using BioID to identify unrecognized constituents of distinct subcellular compartments refractory to biochemical isolation and reveal VRK2A as a transmembrane kinase in the NE that regulates BAF. PMID- 28637769 TI - Potential contribution of tandem circadian enhancers to nonlinear oscillations in clock gene expression. AB - Limit-cycle oscillations require the presence of nonlinear processes. Although mathematical studies have long suggested that multiple nonlinear processes are required for autonomous circadian oscillation in clock gene expression, the underlying mechanism remains controversial. Here we show experimentally that cell autonomous circadian transcription of a mammalian clock gene requires a functionally interdependent tandem E-box motif; the lack of either of the two E boxes results in arrhythmic transcription. Although previous studies indicated the role of the tandem motifs in increasing circadian amplitude, enhancing amplitude does not explain the mechanism for limit-cycle oscillations in transcription. In this study, mathematical analysis suggests that the interdependent behavior of enhancer elements including not only E-boxes but also ROR response elements might contribute to limit-cycle oscillations by increasing transcriptional nonlinearity. As expected, introduction of the interdependence of circadian enhancer elements into mathematical models resulted in autonomous transcriptional oscillation with low Hill coefficients. Together these findings suggest that interdependent tandem enhancer motifs on multiple clock genes might cooperatively enhance nonlinearity in the whole circadian feedback system, which would lead to limit-cycle oscillations in clock gene expression. PMID- 28637771 TI - Medicare Advantage Associated With More Racial Disparity Than Traditional Medicare For Hospital Readmissions. AB - We compared racial disparities in thirty-day readmissions between traditional Medicare and Medicare Advantage beneficiaries who underwent one of six major surgeries in New York State in 2013. We found that Medicare Advantage was associated with greater racial disparity, compared to traditional Medicare. After controlling for patient, hospital, and geographic characteristics in a propensity score based approach, we found that in traditional Medicare, black patients were 33 percent more likely than white patients to be readmitted, whereas in Medicare Advantage, black patients were 64 percent more likely than white patients to be readmitted. Our findings suggest that the risk-reduction strategies adopted by Medicare Advantage plans have not been successful in lowering the markedly higher rate of readmission among black patients, compared to white patients. PMID- 28637773 TI - Follow-up of a randomized trial on postdischarge nutrition in preterm-born children at age 8 y. AB - Background: Early nutritional interventions may modulate health risks in preterm born infants. Previously, we showed that preterm-born infants fed an isocaloric protein- and mineral-enriched postdischarge formula (PDF) from term age to 6-mo corrected age (CA) gained more lean mass than did those fed term formula (TF). Long-term follow-up of randomized nutritional trials is important to test the hypothesis that short-term positive effects on health are sustainable.Objective: The aim of this follow-up study was to compare body size, body composition, and metabolic health at age 8 y in preterm-born children who were randomly assigned to receive either PDF or TF from term age until 6-mo CA.Design: A total of 79 of 152 children (52%) from the original randomized controlled trial were enrolled for follow-up at age 8 y. Weight, height, and head circumference were measured by using standard methods. Body composition, including fat mass, lean mass, bone mineral content, and bone mineral density, was determined by dual-energy X-ray absorptiometry. Blood pressure was measured in the supine position by using an automatic device. Metabolic variables, including glucose, insulin, insulin-like growth factor I, triglycerides, cholesterol, cortisol, and leptin, were measured after an overnight fast. Nutritional habits at age 8 y were assessed by using a 3 d nutritional diary.Results: At age 8 y, no differences were found in body size, body composition, bone variables, and metabolic health variables when comparing children fed PDF with those fed TF. Adjustment for known and possible confounders did not change these results.Conclusions: In this follow-up study in preterm-born children, we showed that the favorable effects of PDF at 6-mo CA either were not maintained or could not be confirmed because of attrition at the age of 8 y. We suggest that future research should focus on nutritional interventions in the pre and postdischarge period as a continuum rather than as separate entities. This trial was registered at www.trialregister.nl as NTR 2972 (follow-up study [STEP-2 (Study Towards the Effects of Post-discharge Nutrition 2)]) and NTR 55 [original randomized controlled trial (STEP)]. PMID- 28637772 TI - Tolerance to increased supplemented dietary intakes of methionine in healthy older adults. AB - Background: l-Methionine (Met) is an essential amino acid for humans and is important for protein synthesis and the formation of polyamines and is involved in the synthesis of many metabolites, including homocysteine. Free-Met supplements have been claimed to have multiple positive effects; however, it remains unclear what the exact tolerance level is. With aging, Met metabolism changes, and increased plasma homocysteine is more apparent. High plasma concentrations of homocysteine are assumed to be associated with a high risk of developing atherosclerosis.Objective: We estimated the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level (LOAEL) of supplemented, oral, free Met in healthy older adults by examining the increase in plasma homocysteine as the primary determinant.Design: We provided capsules with free Met to 15 healthy older adult subjects for 4 wk at climbing dosages of, on average, 9.2, 22.5, 46.3 and 91 mg . kg body weight-1 . d-1 with washout periods of 2 wk between each intake. Before, at 2 and 4 wk during, and 2 wk after each dosage, we studied a complete panel of biochemical blood variables to detect possible intolerance to increased Met intake. Plasma homocysteine and body composition were measured, and tolerance, quality of life, and cognitive function were assessed via questionnaires.Results: Plasma homocysteine was elevated with the highest dose of supplemented Met. The estimated NOAEL of supplemented Met was set at 46.3 mg . kg body weight-1 . d-1, and the estimated LOAEL of supplemented Met was set at 91 mg . kg body weight-1 . d-1 (on the basis of the actual intakes) in subjects independent of sex. No signs of intolerance were observed via questionnaires or other blood variables at the LOAEL. There were no meaningful changes in body composition.Conclusions: On the basis of plasma homocysteine, the NOAEL of supplemented Met intake is 46.3 and the LOAEL is 91 mg . kg body weight-1 . d-1 in healthy older adults. Both the NOAEL and LOAEL are not associated with meaningful effects on health and wellbeing. This trial was registered at clinicaltrials.gov as NCT02566434. PMID- 28637774 TI - Most deaths of babies and brain injuries in childbirth are avoidable, says college. PMID- 28637775 TI - Increased Proximal Aortic Diameter is Associated With Risk of Cardiovascular Events and All-Cause Mortality in Blacks The Jackson Heart Study. AB - BACKGROUND: Enlargement of the proximal aorta is associated with aortic wall tissue remodeling, including fragmentation of the elastin fibers, increased synthesis of collagen, and calcification, all of which are associated with aortic wall stiffening. We hypothesized that the proximal aortic diameter (AoD) is associated with cardiovascular events in a community-based cohort of blacks. METHODS AND RESULTS: We investigated the associations between AoD and cardiovascular events among 3018 black participants (mean age, 55.9 years; 69% women) without past history of cardiovascular disease in the Jackson Heart Study. AoD was measured using echocardiography at the level of the sinuses of Valsalva at end diastole. Cardiovascular event was defined as incident myocardial infarction, fatal coronary artery disease, stroke, or heart failure hospitalization. Cox proportional hazards regression models were used to evaluate the association between baseline AoD and cardiovascular events. Over a median follow-up of 8.3 years, there were 258 cardiovascular events (incident rate, 10.5 per 1000 person-years). After adjustment for traditional risk factors, increased AoD was significantly associated with cardiovascular events (hazard ratio per 1 cm increase, 1.72; 95% CI, 1.10-2.69; P<0.05). Participants in the top AoD quintile had a higher incidence of cardiovascular events compared to those not in the top quintile (hazard ratio, 1.47; 95% CI, 1.11-1.94; P<0.005) after adjustment for risk factors. CONCLUSIONS: Greater AoD was associated with an increased risk of cardiovascular events in a community-based cohort of blacks. AoD may be useful as a predictor of incident cardiovascular events and further investigation is warranted. PMID- 28637776 TI - Targeting of Extracellular RNA Reduces Edema Formation and Infarct Size and Improves Survival After Myocardial Infarction in Mice. AB - BACKGROUND: Following myocardial infarction (MI), peri-infarct myocardial edema formation further impairs cardiac function. Extracellular RNA (eRNA) released from injured cells strongly increases vascular permeability. This study aimed to assess the role of eRNA in MI-induced cardiac edema formation, infarct size, cardiac function, and survival after acute MI and to evaluate the therapeutic potential of ribonuclease 1 (RNase-1) treatment as an eRNA-degrading intervention. METHODS AND RESULTS: C57BL/6J mice were subjected to MI by permanent ligation of the left anterior descending coronary artery. Plasma eRNA levels were significantly increased compared with those in controls starting from 30 minutes after ligation. Systemic application of RNase-1, but not DNase, significantly reduced myocardial edema formation 24 hours after ligation compared with controls. Consequently, eRNA degradation by RNase-1 significantly improved the perfusion of collateral arteries in the border zone of the infarcted myocardium 24 hours after ligation of the left anterior descending coronary artery, as detected by micro-computed tomography imaging. Although there was no significant difference in the area at risk, the area of vital myocardium was markedly larger in mice treated with RNase-1 compared with controls, as detected by Evans blue and 2,3,5-triphenyltetrazolium chloride staining. The increase in viable myocardium was associated with significantly preserved left ventricular function, as assessed by echocardiography. Moreover, RNase-1 significantly improved 8-week survival following MI. CONCLUSIONS: eRNA is an unrecognized permeability factor in vivo, associated with myocardial edema formation after acute MI. RNase-1 counteracts eRNA-induced edema formation and preserves perfusion of the infarction border zone, reducing infarct size and protecting cardiac function after MI. PMID- 28637777 TI - The American Heart Association Ideal Cardiovascular Health and Incident Type 2 Diabetes Mellitus Among Blacks: The Jackson Heart Study. AB - BACKGROUND: The concept of ideal cardiovascular health (CVH), defined by the American Heart Association primarily for coronary heart disease and stroke prevention, may apply to diabetes mellitus prevention among blacks. METHODS AND RESULTS: Our sample included 2668 adults in the Jackson Heart Study with complete baseline data on 6 of 7 American Heart Association CVH metrics (body mass index, healthy diet, smoking, total cholesterol, blood pressure, and physical activity). Incident diabetes mellitus was defined as fasting glucose >=126 mg/dL, physician diagnosis, use of diabetes mellitus drugs, or glycosylated hemoglobin >=6.5%. A summary CVH score from 0 to 6, based on presence/absence of ideal CVH metrics, was derived for each participant. Cox regression was used to estimate adjusted hazard ratios. Mean age was 55 years (65% women) with 492 incident diabetes mellitus events over 7.6 years (24.6 cases/1000 person-years). Three quarters of participants had only 1 or 2 ideal CVH metrics; no participant had all 6. After adjustment for demographic factors (age, sex, education, and income) and high sensitivity C-reactive protein, each additional ideal CVH metric was associated with a 17% diabetes mellitus risk reduction (hazard ratio, 0.83; 95% CI, 0.74 0.93). The association was attenuated with further adjustment for homeostasis model assessment for insulin resistance (hazard ratio, 0.89; 95% CI, 0.79-1.00). Compared with participants with 1 or no ideal CVH metric, diabetes mellitus risk was 15% and 37% lower in those with 2 and >=3 ideal CVH metrics, respectively. CONCLUSIONS: The AHA concept of ideal CVH is applicable to diabetes mellitus prevention among blacks. These associations were largely explained by insulin resistance. PMID- 28637778 TI - Breastfeeding and the Risk of Maternal Cardiovascular Disease: A Prospective Study of 300 000 Chinese Women. AB - BACKGROUND: Breastfeeding confers substantial benefits to child health and has also been associated with lower risk of maternal cardiovascular diseases (CVDs) in later life. However, the evidence on the effects of CVD is still inconsistent, especially in East Asians, in whom the frequency and duration of breastfeeding significantly differ from those in the West. METHODS AND RESULTS: In 2004-2008, the nationwide China Kadoorie Biobank recruited 0.5 million individuals aged 30 to 79 years from 10 diverse regions across China. During 8 years of follow-up, 16 671 incident cases of coronary heart disease and 23 983 cases of stroke were recorded among 289 573 women without prior CVD at baseline. Cox regression yielded adjusted hazard ratios (HRs) and 95% CIs for incident CVD by breastfeeding. Overall, ~99% of women had given birth, among whom 97% reported a history of breastfeeding, with a median duration of 12 months per child. Compared with parous women who had never breastfed, ever breastfeeding was associated with a significantly lower risk of CVD, with adjusted HRs of 0.91 (95% CI, 0.84-0.99) for coronary heart disease and 0.92 (95% CI, 0.85-0.99) for stroke. Women who had breastfed for >=24 months had an 18% (HR, 0.82; 0.77-0.87) lower risk of coronary heart disease and a 17% (HR, 0.83; 0.79-0.87) lower risk of stroke compared with women who had never breastfed. Among women who ever breastfed, each additional 6 months of breastfeeding per child was associated with an adjusted HR of 0.96 (95% CI, 0.94-0.98) for coronary heart disease and 0.97 (95% CI, 0.96-0.98) for stroke. CONCLUSIONS: Among Chinese women, a history of breastfeeding was associated with an ~10% lower risk of CVD in later life and the magnitude of the inverse association was stronger among those with a longer duration of breastfeeding. PMID- 28637779 TI - Racial Differences in Arterial Stiffness are Mainly Determined by Blood Pressure Levels: Results From the ELSA-Brasil Study. AB - BACKGROUND: Black people have a higher risk of developing hypertension and presenting higher vascular stiffening. Our aim was to investigate whether the association between race and aortic stiffness could be explained by differences in the primary risk factors. METHODS AND RESULTS: We analyzed data from 11 472 adults (mean age, 51.9+/-8.9; 53.8% female) self-reported as white (n=6173), brown (n=3364), or black (n=1935). Their carotid-to-femoral pulse wave velocity (cf-PWV) as well as clinical and anthropometric parameters were measured. cf-PWV was higher in blacks than in whites or browns (men: white, 9.63+/-1.81; brown, 9.63+/-1.88; black, 9.98+/-1.99; women: white, 8.84+/-1.64; brown, 9.02+/-1.68; black, 9.34+/-1.91; P<0.05). However, this difference disappeared after adjustments for age, mean arterial pressure, heart rate, waist circumference, fasting glucose, and glomerular filtration rate (men: white, 9.68+/-1.54; brown, 9.68+/-1.50; black, 9.73+/-1.52; women: white, 8.93+/-1.32; brown, 8.98+/-1.29; black, 9.02+/-1.32; P>0.05). The association between race and arterial stiffness was significant for brown and black women in the highest cf-PWV quartile, even after controlling for covariates. There were no differences in the age-related increase in cf-PWV among the racial groups after adjustment, confirming the strong effect of age and mean arterial pressure on cf-PWV revealed by the multiple linear regression. CONCLUSIONS: Racial differences in cf-PWV were mainly attributed to differences in mean arterial pressure and age, although they cannot fully explain the association between race and cf-PWV in women in the highest cf PWV values. This suggests that therapeutic approaches to overcome the effects of aging on the vascular system should focus on blood pressure control, especially in the black population. PMID- 28637781 TI - Detecting optic nerve head swelling on ultrasound and optical coherence tomography in children and young people: an observational study. AB - BACKGROUND: Following high-profile cases, referrals for evaluation of 'suspicious optic discs' to eye clinics in the UK have sharply increased, asking ophthalmologists to reliably distinguish between true and pseudopapilloedema. Optic nerve sheath dilatation (ONSD) on ocular ultrasound (US) is considered a reliable sign of true papilloedema, but this test is not widely available. Recently, anterior bowing of Bruch's membrane (BM) and increased retinal nerve fibre layer thickness on optical coherence tomography (OCT) have emerged as indicators of intracranial hypertension, and OCT is widely available. We aimed to evaluate safety and efficacy of the diagnostic workup in our service, with particular emphasis of diagnostic reliability of US and OCT. METHODS: Retrospective service evaluation/cohort study of children and young people younger than 16 years investigated for 'suspicious discs' over a 7-month period in 2016 at a single eye care provider in London, UK. 61 children and young people underwent clinical assessment, US scan and OCT. RESULTS: Of 61 cases, 3 had intracranial pathology. At presentation, only one had ONSD on US and anterior bowing of BM on OCT. Increased nerve fibre layer thickness in at least one of three relevant sectors was observed in two cases. All three cases of intracranial pathology, however, had significant points in their presenting or medical history. CONCLUSION: Ophthalmologists and optometrists must not rely on funduscopy and ocular imaging when assessing a child for possible intracranial disease; history and basic neurological assessment are critical in the diagnostic workup. PMID- 28637780 TI - Sex-Based Differences in the Performance of the HEART Score in Patients Presenting to the Emergency Department With Acute Chest Pain. AB - BACKGROUND: Sex-based differences in clinical presentation, pathophysiology, and outcomes of patients with acute chest pain are increasingly being recognized, but are not implemented in guidelines and clinical prediction tools. We evaluated the performance of the HEART score in women versus men, because sex-based differences may exist among the algorithm's components: history, electrocardiogram, age, risk factors, and admission troponin level. METHODS AND RESULTS: The HEART score was retrospectively assessed in 831 women and 1084 men presenting to the emergency department with acute chest pain, assigning patients to the low-, intermediate-, or high-risk category for the occurrence of major adverse cardiac events (MACE) within 6 weeks. MACE, consisting of myocardial infarction, coronary revascularization, and all-cause death, also included events during index visit. Six-week MACE rates were 2 times lower in women than men (10.0% versus 20.8%; P<0.01). Despite similar discriminatory accuracy of the HEART score among women and men (c-statistic, 0.80 [0.75-0.84] versus 0.77 [0.74-0.81]; P=0.43), 6-week MACE rates were significantly lower in women than men across all HEART risk categories: 2.1% versus 6.5% (P<0.01) in the low-risk category, 12.7% versus 21.3% (P<0.01) in intermediate-risk category, and 53.1% versus 77.0% (P=0.02) in the high-risk category. The HEART score-adjusted risk ratio for men was 1.6 (1.3 2.0; P<0.01). CONCLUSIONS: The markedly higher 6-week MACE risk in men across all HEART risk categories should be taken into account when using the HEART score to guide clinical decision making; early discharge with a low-risk HEART score appears less safe for men than women with acute chest pain. PMID- 28637782 TI - The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity. AB - RATIONALE: Genome-wide association studies previously identified an association of rs9388451 at chromosome 6q22.3 (near HEY2) with Brugada syndrome. The causal gene and underlying mechanism remain unresolved. OBJECTIVE: We used an integrative approach entailing transcriptomic studies in human hearts and electrophysiological studies in Hey2+/- (Hey2 heterozygous knockout) mice to dissect the underpinnings of the 6q22.31 association with Brugada syndrome. METHODS AND RESULTS: We queried expression quantitative trait locus data acquired in 190 human left ventricular samples from the genotype-tissue expression consortium for cis-expression quantitative trait locus effects of rs9388451, which revealed an association between Brugada syndrome risk allele dosage and HEY2 expression (beta=+0.159; P=0.0036). In the same transcriptomic data, we conducted genome-wide coexpression analysis for HEY2, which uncovered KCNIP2, encoding the beta-subunit of the channel underlying the transient outward current (Ito), as the transcript most robustly correlating with HEY2 expression (beta=+1.47; P=2*10-34). Transcript abundance of Hey2 and the Ito subunits Kcnip2 and Kcnd2, assessed by quantitative reverse transcription-polymerase chain reaction, was higher in subepicardium versus subendocardium in both left and right ventricles, with lower levels in Hey2+/- mice compared with wild type. Surface ECG measurements showed less prominent J waves in Hey2+/- mice compared with wild-type. In wild-type mice, patch-clamp electrophysiological studies on cardiomyocytes from right ventricle demonstrated a shorter action potential duration and a lower Vmax in subepicardium compared with subendocardium cardiomyocytes, which was paralleled by a higher Ito and a lower sodium current (INa) density in subepicardium versus subendocardium. These transmural differences were diminished in Hey2+/- mice because of changes in subepicardial cardiomyocytes. CONCLUSIONS: This study uncovers a role of HEY2 in the normal transmural electrophysiological gradient in the ventricle and provides compelling evidence that genetic variation at 6q22.31 (rs9388451) is associated with Brugada syndrome through a HEY2-dependent alteration of ion channel expression across the cardiac ventricular wall. PMID- 28637783 TI - Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a. AB - RATIONALE: Inflammation is a key contributor to atherosclerosis. MicroRNA-146a (miR-146a) has been identified as a critical brake on proinflammatory nuclear factor kappa light chain enhancer of activated B cells signaling in several cell types, including endothelial cells and bone marrow (BM)-derived cells. Importantly, miR-146a expression is elevated in human atherosclerotic plaques, and polymorphisms in the miR-146a precursor have been associated with risk of coronary artery disease. OBJECTIVE: To define the role of endogenous miR-146a during atherogenesis. METHODS AND RESULTS: Paradoxically, Ldlr-/- (low-density lipoprotein receptor null) mice deficient in miR-146a develop less atherosclerosis, despite having highly elevated levels of circulating proinflammatory cytokines. In contrast, cytokine levels are normalized in Ldlr-/ ;miR-146a-/- mice receiving wild-type BM transplantation, and these mice have enhanced endothelial cell activation and elevated atherosclerotic plaque burden compared with Ldlr-/- mice receiving wild-type BM, demonstrating the atheroprotective role of miR-146a in the endothelium. We find that deficiency of miR-146a in BM-derived cells precipitates defects in hematopoietic stem cell function, contributing to extramedullary hematopoiesis, splenomegaly, BM failure, and decreased levels of circulating proatherogenic cells in mice fed an atherogenic diet. These hematopoietic phenotypes seem to be driven by unrestrained inflammatory signaling that leads to the expansion and eventual exhaustion of hematopoietic cells, and this occurs in the face of lower levels of circulating low-density lipoprotein cholesterol in mice lacking miR-146a in BM derived cells. Furthermore, we identify sortilin-1(Sort1), a known regulator of circulating low-density lipoprotein levels in humans, as a novel target of miR 146a. CONCLUSIONS: Our study reveals that miR-146a regulates cholesterol metabolism and tempers chronic inflammatory responses to atherogenic diet by restraining proinflammatory signaling in endothelial cells and BM-derived cells. PMID- 28637785 TI - Surgical emergency: rupture of infected brachial artery pseudoaneurysm. PMID- 28637787 TI - Biophysics and biofluid dynamics of primary cilia: evidence for and against the flow-sensing function. AB - Primary cilia have been called "the forgotten organelle" for over 20 yr. As cilia now have their own journal and several books devoted to their study, perhaps it is time to reconsider the moniker "forgotten organelle." In fact, during the drafting of this review, 12 relevant publications have been issued; we therefore apologize in advance for any relevant work we inadvertently omitted. What purpose is yet another ciliary review? The primary goal of this review is to specifically examine the evidence for and against the hypothesized flow-sensing function of primary cilia expressed by differentiated epithelia within a kidney tubule, bringing together differing disciplines and their respective conceptual and experimental approaches. We will show that understanding the biophysics/biomechanics of primary cilia provides essential information for understanding any potential role of ciliary function in disease. We will summarize experimental and mathematical models used to characterize renal fluid flow and incident force on primary cilia and to characterize the mechanical response of cilia to an externally applied force and discuss possible ciliary mediated cell signaling pathways triggered by flow. Throughout, we stress the importance of separating the effects of fluid shear and stretch from the action of hydrodynamic drag. PMID- 28637786 TI - The role of capsaicin-sensitive C-fiber afferent pathways in the control of micturition in spinal-intact and spinal cord-injured mice. AB - We examined bladder and urethral sphincter activity in mice with or without spinal cord injury (SCI) after C-fiber afferent desensitization induced by capsaicin pretreatment and changes in electrophysiological properties of mouse bladder afferent neurons 4 wk after SCI. Female C57BL/6N mice were divided into four groups: 1) spinal intact (SI)-control, 2) SI-capsaicin pretreatment (Cap), 3) SCI-control, and 4) SCI-Cap groups. Continuous cystometry and external urethral sphincter (EUS)-electromyogram (EMG) were conducted under an awake condition. In the Cap groups, capsaicin (25, 50, or 100 mg/kg) was injected subcutaneously 4 days before the experiments. In the SI-Cap group, 100 mg/kg capsaicin pretreatment significantly increased bladder capacity and decreased the silent period duration of EUS/EMG compared with the SI-control group. In the SCI Cap group, 50 and 100 mg/kg capsaicin pretreatment decreased the number of nonvoiding contractions (NVCs) and the duration of reduced EUS activity during voiding, respectively, compared with the SCI-control group. In SCI mice, hexamethonium, a ganglionic blocker, almost completely blocked NVCs, suggesting that they are of neurogenic origin. Patch-clamp recordings in capsaicin-sensitive bladder afferent neurons from SCI mice showed hyperexcitability, which was evidenced by decreased spike thresholds and increased firing rate compared with SI mice. These results indicate that capsaicin-sensitive C-fiber afferent pathways, which become hyperexcitable after SCI, can modulate bladder and urethral sphincter activity in awake SI and SCI mice. Detrusor overactivity as shown by NVCs in SCI mice is significantly but partially dependent on capsaicin sensitive C-fiber afferents, whereas the EUS relaxation during voiding is enhanced by capsaicin-sensitive C-fiber bladder afferents in SI and SCI mice. PMID- 28637784 TI - TNFR2 Stimulation Promotes Mitochondrial Fusion via Stat3- and NF-kB-Dependent Activation of OPA1 Expression. AB - RATIONALE: Mitochondria are important cellular organelles and play essential roles in maintaining cell structure and function. Emerging evidence indicates that in addition to having proinflammatory and proapoptotic effects, TNFalpha (tumor necrosis factor alpha) can, under certain circumstances, promote improvements in mitochondrial integrity and function, phenomena that can be ascribed to the existence of TNFR2 (TNFalpha receptor 2). OBJECTIVE: The present study aimed to investigate whether and how TNFR2 activation mediates the effects of TNFalpha on mitochondria. METHODS AND RESULTS: Freshly isolated neonatal mouse cardiac myocytes treated with shRNA targeting TNFR1 were used to study the effects of TNFR2 activation on mitochondrial function. Neonatal mouse cardiac myocytes exhibited increases in mitochondrial fusion, a change that was associated with increases in mitochondrial membrane potential, intracellular ATP levels, and oxygen consumption capacity. Importantly, TNFR2 activation-induced increases in OPA1 (optic atrophy 1) protein expression were responsible for the above enhancements, and these changes could be attenuated using siRNA targeting OPA1. Moreover, both Stat3 and RelA bound to the promoter region of OPA1 and their interactions synergistically upregulated OPA1 expression at the transcriptional level. Stat3 acetylation at lysine 370 or lysine 383 played a key role in the ability of Stat3 to form a supercomplex with RelA. Meanwhile, p300 modulated Stat3 acetylation in HEK293T (human embryonic kidney 293T) cells, and p300-mediated Stat3/RelA interactions played an indispensable role in OPA1 upregulation. Finally, TNFR2 activation exerted beneficial effects on OPA1 expression in an in vivo transverse aortic constriction model, whereby TNFR1 knockout mice exhibited better outcomes than in mice with both TNFR1 and TNFR2 knocked out. CONCLUSIONS: TNFR2 activation protects cardiac myocytes against stress by upregulating OPA1 expression. This process was facilitated by p300 mediated Stat3 acetylation and Stat3/RelA interactions, leading to improvements in mitochondrial morphology and function. PMID- 28637789 TI - Harnessing basic and clinic tools to evaluate SGLT2 inhibitor nephrotoxicity. AB - Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of medications that target the transporter that reabsorbs ~90% of glucose in the S1 segment of the proximal convoluted tubule. As a result, SGLT2 inhibition increases urinary glucose excretion, effectively lowering plasma glucose levels. In addition to reducing hemoglobin A1c levels, these drugs also lower body weight, blood pressure, and uric acid levels in Type 2 diabetes mellitus (T2DM) patients. Importantly, empagliflozin has been observed to slow progression of kidney disease and reduce dialysis requirements in T2DM patients. However, the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) has collected over 100 cases of acute kidney injury (AKI) for canagloflozin and dapagliflozin since their approval. Of the 101 patients, 96 required hospitalization, 22 required intensive care unit admission, and 15 underwent hemodialysis. The FDA now requires that AKI be listed as a potential side effect of the SGLT2 inhibitors along with cautious prescription of these drugs with other medications, such as renin-angiotensin-system antagonists, diuretics, and NSAIDs. It is unclear, however, whether this FAERS reported "AKI" actually represents structural kidney injury, as randomized, controlled trials of these drugs do not describe AKI as an adverse event despite coprescription with RAS blockers and diuretics. As a result of this FDA warning, diabetic patients with early-stage CKD may not be prescribed an SGLT2 inhibitor for fear of AKI. Thus, it is imperative to ascertain whether the reported AKI represents true structural kidney injury or a functional decline in glomerular filtration rate. We propose using readily available clinical tools with experimental biomarkers of kidney injury and kidney-on-a-chip technology to resolve this question and provide solid evidence about the AKI risk of these drugs for healthcare providers. PMID- 28637788 TI - The effects of neuromodulation in a novel obese-prone rat model of detrusor underactivity. AB - Obesity is a global epidemic associated with an increased risk for lower urinary tract dysfunction. Inefficient voiding and urinary retention may arise in late stage obesity when the expulsive force of the detrusor smooth muscle cannot overcome outlet resistance. Detrusor underactivity (DUA) and impaired contractility may contribute to the pathogenesis of nonobstructive urinary retention. We used cystometry and electrical stimulation of peripheral nerves (pudendal and pelvic nerves) to characterize and improve bladder function in urethane-anesthetized obese-prone (OP) and obese-resistant (OR) rats following diet-induced obesity (DIO). OP rats exhibited urinary retention and impaired detrusor contractility following DIO, reflected as increased volume threshold, decreased peak micturition pressure, and decreased voiding efficiency (VE) compared with OR rats. Electrical stimulation of the sensory branch of the pudendal nerve did not increase VE, whereas patterned bursting stimulation of the motor branch of the pudendal nerve increased VE twofold in OP rats. OP rats required increased amplitude of electrical stimulation of the pelvic nerve to elicit bladder contractions, and maximum evoked bladder contraction amplitudes were decreased relative to OR rats. Collectively, these studies characterize a novel animal model of DUA that can be used to determine pathophysiology and suggest that neuromodulation is a potential management option for DUA. PMID- 28637790 TI - Protection of kidneys by magnesium in cisplatin chemotherapy: a fight between two metals. PMID- 28637791 TI - Store-operated calcium entry suppressed the TGF-beta1/Smad3 signaling pathway in glomerular mesangial cells. AB - Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca2+ entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-beta1 (TGF-beta1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-beta1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 uM), a classical activator of store operated Ca2+ channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-beta1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La3+; 5 uM) and GSK-7975A (10 uM), both of which are selective blockers of store-operated Ca2+ channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca2+ channels, significantly augmented TGF-beta1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF beta1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-beta1/Smad3 signaling pathway. PMID- 28637792 TI - Reactive sulfur species inactivate Ca2+/calmodulin-dependent protein kinase IV via S-polysulfidation of its active-site cysteine residue. AB - Reactive sulfur species (RSS) modulate protein functions via S-polysulfidation of reactive Cys residues. Here, we report that Ca2+/calmodulin (CaM)-dependent protein kinase IV (CaMKIV) was reversibly inactivated by RSS via polysulfidation of the active-site Cys residue. CaMKIV is phosphorylated at Thr196 by its upstream CaMK kinase (CaMKK), resulting in the induction of its full activity. In vitro incubation of CaMKIV with the exogenous RSS donors Na2S n (n = 2-4) resulted in dose-dependent inhibition of the CaMKK-induced phospho-Thr196 and consequent inactivation of the enzyme activity. Conversely, mutated CaMKIV (C198V) was refractory to the Na2S n -induced enzyme inhibition. A biotin polyethylene glycol-conjugated maleimide capture assay revealed that Cys198 in CaMKIV represents a target for S-polysulfidation. Furthermore, phosho-Thr196 and CaMKIV activity were inhibited by incubation with cysteine hydropersulfide, a newly identified RSS that is generated from cystine by cystathionine-gamma-lyase. In transfected cells expressing CaMKIV, ionomycin-induced CaMKIV phosphorylation at Thr196 was decreased upon treatment with either Na2S4 or the endoplasmic reticulum (ER) stress inducer thapsigargin, whereas cells expressing mutant CaMKIV (C198V) were resistant to this treatment. In addition, the ionomycin induced phospho-Thr196 of endogenous CaMKIV was also inhibited by treatment either with Na2S4 or thapsigargin in Jurkat T lymphocytes. Taken together, these data define a novel signaling function for intracellular RSS in inhibiting CaMKIV activity via S-polysulfidation of its Cys198 during the response to ER stress. PMID- 28637793 TI - Endothelial cell metabolism in health and disease: impact of hypoxia. AB - In contrast to the general belief, endothelial cell (EC) metabolism has recently been identified as a driver rather than a bystander effect of angiogenesis in health and disease. Indeed, different EC subtypes present with distinct metabolic properties, which determine their function in angiogenesis upon growth factor stimulation. One of the main stimulators of angiogenesis is hypoxia, frequently observed in disease settings such as cancer and atherosclerosis. It has long been established that hypoxic signalling and metabolism changes are highly interlinked. In this review, we will provide an overview of the literature and recent findings on hypoxia-driven EC function and metabolism in health and disease. We summarize evidence on metabolic crosstalk between different hypoxic cell types with ECs and suggest new metabolic targets. PMID- 28637794 TI - A TRPV1-to-secretagogin regulatory axis controls pancreatic beta-cell survival by modulating protein turnover. AB - Ca2+-sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single-cell RNA-seq reveals retained expression of the TRP family members in beta-cells from diabetic donors. Amongst these, pharmacological probing identifies Ca2+-permeable transient receptor potential vanilloid type 1 channels (TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV1s fails to rescue insulin release from pancreatic islets of glucose intolerant secretagogin knock-out(-/-) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin-/- mice is due to beta-cell loss, which is underpinned by the collapse of protein folding and deregulation of secretagogin dependent USP9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV1s in diabetic pancreata, a TRPV1-to-secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of beta-cells. PMID- 28637795 TI - Genome-Wide Association Studies of Cancer in Diverse Populations. AB - Genome-wide association studies (GWAS) of cancer have identified more than 700 risk loci, of which approximately 80% were first discovered in European ancestry populations, approximately 15% in East Asians, 3% in multiethnic scans, and less than 1% in African and Latin American populations. These percentages closely mirror the distribution of samples included in the discovery phase of cancer GWAS to date (84% European, 11% East Asian, 4% African, and 1% Latin American ancestry). GWAS in non-European ancestry populations have provided insight into ancestry-specific variation in cancer and have pointed to regions of susceptibility that are of particular importance in certain populations. Uncovering and characterizing cancer risk loci in diverse populations is critical for understanding underlying biological mechanisms and developing future genetic risk prediction models in non-European ancestry populations. New GWAS and continued collaborations will be required to eliminate population inequalities in the number of studies, sample sizes, and variant content on GWAS arrays, and to better align genetic research in cancer to the global distribution of race/ethnicity Cancer Epidemiol Biomarkers Prev; 27(4); 405-17. (c)2018 AACRSee all articles in this CEBP Focus section, "Genome-Wide Association Studies in Cancer." PMID- 28637799 TI - 68Ga-PSMA PET/CT and Volumetric Morphology of PET-Positive Lymph Nodes Stratified by Tumor Differentiation of Prostate Cancer. AB - 68Ga-prostate-specific membrane antigen (PSMA) PET/CT is a new method to detect early nodal metastases in patients with biochemical relapse of prostate cancer. In this retrospective investigation, the dimensions, volume, localization, and SUVmax of nodes identified by 68Ga-PSMA were correlated to their Gleason score (GS) at diagnosis. Methods: All PET/CT images were acquired 60 +/- 10 min after intravenous injection of 68Ga-PSMA (mean dose, 176 MBq). In 147 prostate cancer patients (mean age, 68 y; range, 44-87 y) with prostate-specific antigen relapse (mean prostate-specific antigen level, 5 ng/mL; range, 0.25-294 ng/mL), 362 68Ga PSMA PET-positive lymph nodes (LNs) were identified. These patients were classified on the basis of their histopathology at primary diagnosis into either low- (GS <= 6, well differentiated), intermediate- (GS = 7, moderately differentiated), or high-GS cohorts (GS >= 8, poorly differentiated prostate cancer). Using semiautomated LN segmentation software (Fraunhofer MEVIS), we measured node volume and short-axis dimensions (SADs) and long-axis dimensions based on CT and compared with the SUVmax Nodes demonstrating uptake of 68Ga-PSMA with an SUVmax of 2.0 or more were considered PSMA-positive, and nodes with an SAD of 8 mm or more were considered positive by morphologic criteria. Results: Mean SUVmax was 13.5 (95% confidence interval [CI], 10.9-16.1), 12.4 (95% CI, 9.9 14.9), and 17.8 (95% CI, 15.4-20.3) within the low-, intermediate-, and high-GS groups, respectively. The morphologic assessment of the 68Ga-PSMA-positive LN demonstrated that the low-GS cohort presented with smaller 68Ga-PSMA-positive LNs (mean SAD, 7.7 mm; n = 113), followed by intermediate- (mean SAD, 9.4 mm; n = 122) and high-GS cohorts (mean SAD, 9.5 mm; n = 127). On the basis of the CT morphology criteria, only 34% of low-GS patients, 56% of intermediate-GS patients, and 53% of high-GS patients were considered CT positive. Overall, 68Ga PSMA imaging led to a reclassification of stage in 90 patients (61%) from cN0 to cN1 over CT. Conclusion:68Ga-PSMA PET is a promising modality in biochemical recurrent prostate cancer patients for N staging. Conventional imaging underestimates LN involvement compared with PSMA molecular staging score in each GS cohort. The sensitivity of 68Ga-PSMA PET/CT enables earlier detection of subcentimeter LN metastases in the biochemical recurrence setting. PMID- 28637801 TI - Accuracy in the Eye of the Beholder: Can We Improve Agreement in Prostate Cancer Diagnostics with PSMA PET/CT? PMID- 28637796 TI - Quantifying the Genetic Correlation between Multiple Cancer Types. AB - Background: Many cancers share specific genetic risk factors, including both rare high-penetrance mutations and common SNPs identified through genome-wide association studies (GWAS). However, little is known about the overall shared heritability across cancers. Quantifying the extent to which two distinct cancers share genetic origin will give insights to shared biological mechanisms underlying cancer and inform design for future genetic association studies.Methods: In this study, we estimated the pair-wise genetic correlation between six cancer types (breast, colorectal, lung, ovarian, pancreatic, and prostate) using cancer-specific GWAS summary statistics data based on 66,958 case and 70,665 control subjects of European ancestry. We also estimated genetic correlations between cancers and 14 noncancer diseases and traits.Results: After adjusting for 15 pair-wise genetic correlation tests between cancers, we found significant (P < 0.003) genetic correlations between pancreatic and colorectal cancer (rg = 0.55, P = 0.003), lung and colorectal cancer (rg = 0.31, P = 0.001). We also found suggestive genetic correlations between lung and breast cancer (rg = 0.27, P = 0.009), and colorectal and breast cancer (rg = 0.22, P = 0.01). In contrast, we found no evidence that prostate cancer shared an appreciable proportion of heritability with other cancers. After adjusting for 84 tests studying genetic correlations between cancer types and other traits (Bonferroni corrected P value: 0.0006), only the genetic correlation between lung cancer and smoking remained significant (rg = 0.41, P = 1.03 * 10-6). We also observed nominally significant genetic correlations between body mass index and all cancers except ovarian cancer.Conclusions: Our results highlight novel genetic correlations and lend support to previous observational studies that have observed links between cancers and risk factors.Impact: This study demonstrates modest genetic correlations between cancers; in particular, breast, colorectal, and lung cancer share some degree of genetic basis. Cancer Epidemiol Biomarkers Prev; 26(9); 1427-35. (c)2017 AACR. PMID- 28637800 TI - Pharmacokinetics, Biodistribution, and Radiation Dosimetry for 89Zr-Trastuzumab in Patients with Esophagogastric Cancer. AB - Trastuzumab with chemotherapy improves clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)-positive esophagogastric adenocarcinoma (EGA). Despite the therapeutic benefit, responses are rarely complete, and most patients develop progression. To our knowledge, this is the first report evaluating 89Zr-trastuzumab in HER2-positive EGA; here, we evaluate the safety, pharmacokinetics, biodistribution, and dosimetry 89Zr-trastuzumab. Methods: Trastuzumab was conjugated with deferoxamine and radiolabeled with 89Zr. A mean activity of 184 MBq was administered to 10 patients with metastatic HER2-positive EGA. PET imaging, whole-body probe counts, and blood draws were performed to assess pharmacokinetics, biodistribution, and dosimetry. Results: No clinically significant toxicities were observed. At the end of infusion, the estimated 89Zr trastuzumab in plasma volume was a median 102% (range, 78%-113%) of the injected dose. The median biologic half-life T1/2beta was 111 h (range, 78-193 h). The median biologic whole-body retention half-life was 370 h (range, 257-578 h). PET images showed optimal tumor visualization at 5-8 d after injection. The maximum tumor SUV ranged from no to minimal uptake in 3 patients to a median of 6.8 (range, 2.9-22.7) for 20 lesions in 7 patients. Dosimetry estimates from OLINDA showed that the organs receiving the highest absorbed doses were the liver and heart wall, with median values of 1.37 and 1.12 mGy/MBq, respectively. Conclusion:89Zr-trastuzumab imaging tracer is safe and provides high-quality images in patients with HER2-positive EGA, with an optimal imaging time of 5-8 d after injection. PMID- 28637802 TI - Tumor Uptake of 64Cu-DOTA-Trastuzumab in Patients with Metastatic Breast Cancer. AB - The goal of this study was to characterize the relationship between tumor uptake of 64Cu-DOTA-trastuzumab as measured by PET/CT and standard, immunohistochemistry (IHC)-based, histopathologic classification of human epidermal growth factor receptor 2 (HER2) status in women with metastatic breast cancer (MBC). Methods: Women with biopsy-confirmed MBC and not given trastuzumab for 2 mo or more underwent complete staging, including 18F-FDG PET/CT. Patients were classified as HER2-positive (HER2+) or -negative (HER2-) based on fluorescence in situ hybridization (FISH)-supplemented immunohistochemistry of biopsied tumor tissue. Eighteen patients underwent 64Cu-DOTA-trastuzumab injection, preceded in 16 cases by trastuzumab infusion (45 mg). PET/CT was performed 21-25 (day 1) and 47-49 (day 2) h after 64Cu-DOTA-trastuzumab injection. Radiolabel uptake in prominent lesions was measured as SUVmax Average intrapatient SUVmax (pt) was compared between HER2+ and HER2- patients. Results: Eleven women were HER2+ (8 immunohistochemistry 3+; 3 immunohistochemistry 2+/FISH amplified), whereas 7 were HER2- (3 immunohistochemistry 2+/FISH nonamplified; 4 immunohistochemistry 1+). Median pt for day 1 and day 2 was 6.6 and 6.8 g/mL for HER 2+ and 3.7 and 4.3 g/mL for HER2- patients (P < 0.005 either day). The distributions of pt overlapped between the 2 groups, and interpatient variability was greater for HER2+ than HER2- disease (P < 0.005 and 0.001, respectively, on days 1 and 2). Conclusion: By 1 d after injection, uptake of 64Cu-DOTA-trastuzumab in MBC is strongly associated with patient HER2 status and is indicative of binding to HER2. The variability within and among HER2+ patients, as well as the overlap between the HER2+ and HER2- groups, suggests a role for 64Cu-DOTA-trastuzumab PET/CT in optimizing treatments that include trastuzumab. PMID- 28637803 TI - Protein Malnutrition Alters Tryptophan and Angiotensin-Converting Enzyme 2 Homeostasis and Adaptive Immune Responses in Human Rotavirus-Infected Gnotobiotic Pigs with Human Infant Fecal Microbiota Transplant. AB - Malnutrition leads to increased morbidity and is evident in almost half of all deaths in children under the age of 5 years. Mortality due to rotavirus diarrhea is common in developing countries where malnutrition is prevalent; however, the relationship between malnutrition and rotavirus infection remains unclear. In this study, gnotobiotic pigs transplanted with the fecal microbiota of a healthy 2-month-old infant were fed protein-sufficient or -deficient diets and infected with virulent human rotavirus (HRV). After human rotavirus infection, protein deficient pigs had decreased human rotavirus antibody titers and total IgA concentrations, systemic T helper (CD3+ CD4+) and cytotoxic T (CD3+ CD8+) lymphocyte frequencies, and serum tryptophan and angiotensin I-converting enzyme 2. Additionally, deficient-diet pigs had impaired tryptophan catabolism postinfection compared with sufficient-diet pigs. Tryptophan supplementation was tested as an intervention in additional groups of fecal microbiota-transplanted, rotavirus-infected, sufficient- and deficient-diet pigs. Tryptophan supplementation increased the frequencies of regulatory (CD4+ or CD8+ CD25+ FoxP3+) T cells in pigs on both the sufficient and the deficient diets. These results suggest that a protein-deficient diet impairs activation of the adaptive immune response following HRV infection and alters tryptophan homeostasis. PMID- 28637804 TI - Bioactive Immune Components of Anti-Diarrheagenic Enterotoxigenic Escherichia coli Hyperimmune Bovine Colostrum Products. AB - Diarrhea is a common illness among travelers to resource-limited countries, the most prevalent attributable agent being enterotoxigenic Escherichia coli (ETEC). At this time, there are no vaccines licensed specifically for the prevention of ETEC-induced traveler's diarrhea (TD), and this has propelled investigation of alternative preventive methods. Colostrum, the first milk expressed after birthing, is rich in immunoglobulins and innate immune components for protection of newborns against infectious agents. Hyperimmune bovine colostrum (HBC) produced by immunization of cows during gestation (and containing high levels of specific antibodies) is a practical and effective prophylactic tool against gastrointestinal illnesses. A commercial HBC product, Travelan, is available for prevention of ETEC-induced diarrhea. Despite its demonstrated clinical efficacy, the underlying immune components and antimicrobial activity that contribute to protection remain undefined. We investigated innate and adaptive immune components of several commercial HBC products formulated to reduce the risk of ETEC-induced diarrhea, including Travelan and IMM-124E, a newer product that has broader gastrointestinal health benefits. The immune components measured included total and ETEC-specific IgG, total IgA, cytokines, growth factors, and lactoferrin. HBC products contained high levels of IgG specific for multiple ETEC antigens, including O-polysaccharide 78 and colonization factor antigen I (CFA/I) present in the administered vaccines. Antimicrobial activity was measured in vitro using novel functional assays. HBC greatly reduced ETEC motility in soft agar and exhibited bactericidal activity in the presence of complement. We have identified immune components and antimicrobial activity potentially involved in the prevention of ETEC infection by HBC in vivo. PMID- 28637805 TI - Conjugation of PspA4Pro with Capsular Streptococcus pneumoniae Polysaccharide Serotype 14 Does Not Reduce the Induction of Cross-Reactive Antibodies. AB - Current pneumococcal vaccines are composed of bacterial polysaccharides as antigens, plain or conjugated to carrier proteins. While efficacious against vaccine serotypes, epidemiologic data show an increasing incidence of infections caused by nonvaccine serotypes of Streptococcus pneumoniae The use of pneumococcal surface protein A (PspA) as a carrier protein in a conjugate vaccine could help prevent serotype replacement by increasing vaccine coverage and reducing selective pressure of S. pneumoniae serotypes. PspA is present in all pneumococcal strains, is highly immunogenic, and is known to induce protective antibodies. Based on its sequence, PspA has been classified into three families and six clades. A PspA fragment derived from family 2, clade 4 (PspA4Pro), was shown to generate antibodies with a broad range of cross-reactivity, across clades and families. Here, PspA4Pro was modified and conjugated to capsular polysaccharide serotype 14 (PS14). We investigated the impact of conjugation on the immune response induced to PspA4Pro and PS14. Mice immunized with the PS14 mPspA4Pro conjugate produced higher titers of anti-PS14 antibodies than the animals that received coadministered antigens. The conjugate induced antibodies with opsonophagocytic activity against PS14-carrying strains, as well as against a panel of strains bearing PspAs from five clades (encompassing families 1 and 2) bearing a non-PS14 serotype. Furthermore, mice immunized with PS14-mPspA4Pro were protected against nasal colonization with a nonrelated S. pneumoniae strain bearing PspA from clade 1, serotype 6B. These results demonstrate that the cross reactivity mediated by PspA4Pro is retained following conjugation, supporting the use of PspA4 as a carrier protein in order to enhance pneumococcal vaccine coverage and encourage its further investigation as a candidate in future vaccine designs. PMID- 28637806 TI - The Pneumococcal Serotype 15C Capsule Is Partially O-Acetylated and Allows for Limited Evasion of 23-Valent Pneumococcal Polysaccharide Vaccine-Elicited Anti Serotype 15B Antibodies. AB - As a species, Streptococcus pneumoniae (the pneumococcus) utilizes a diverse array of capsular polysaccharides to evade the host. In contrast to large variations in sugar composition and linkage formation, O-acetylation is a subtle capsular modification that nonetheless has a large impact on capsular shielding and recognition of the capsule by vaccine-elicited antibodies. Serotype 15B, which is included in the 23-valent pneumococcal polysaccharide vaccine (PPV23), carries the putative O-acetyltransferase gene wciZ The coding sequence of wciZ contains eight consecutive TA repeats [(TA)8]. Replication slippage is thought to result in the addition or loss of TA repeats, subsequently causing frameshift and truncation of WciZ to yield a nonacetylated serotype, 15C. Using sensitive serological tools, we show that serotype 15C isolates whose wciZ contains seven or nine TA repeats retain partial O-acetylation, while serotype 15C isolates whose wciZ contains six TA repeats have barely detectable O-acetylation. We confirmed by inhibition enzyme-linked immunosorbent assay that (TA)7 serotype 15C is ~0.1% as acetylated as serotype 15B, while serotype 15X is nonacetylated. To eliminate the impact of genetic background, we created isogenic serotype 15B, (TA)7 serotype 15C, and 15BDeltawciZ (15X) strains and found that reduction or absence of WciZ-mediated O-acetylation did not affect capsular shielding from phagocytes, biofilm formation, adhesion to nasopharyngeal cells, desiccation tolerance, or murine colonization. Sera from PPV23-immunized persons opsonized serotype 15B significantly but only slightly better than serotypes 15C and 15X; thus, PPV23 may not result in expansion of serotype 15C. PMID- 28637808 TI - DMT efficiently inhibits hepatic gluconeogenesis by regulating the Galphaq signaling pathway. AB - Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease with complicated pathogenesis and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. G protein-coupled receptors (GPCRs) are classified as distinct families by heterotrimeric G proteins, primarily including Galphas, Galphai and Galphaq. Galphas-coupled GPCRs function potently in the regulation of hepatic gluconeogenesis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and Galphai-coupled GPCRs exhibit inhibitory effect on adenylyl cyclase and reduce intracellular cAMP level. However, little is known about the regulation of Galphaq-coupled GPCRs in hepatic gluconeogenesis. Here, small-molecule 2-(2,4-dimethoxy-3-methylphenyl)-7 (thiophen-2-yl)-9-(trifluoromethyl)-2,3-dihydropyrido[3',2':4,5]thieno[3,2 d]pyrimidin-4(1H)-one (DMT) was determined to suppress hepatic glucose production and reduce mRNA levels of gluconeogenic genes. Treatment of DMT in db/db mice decreased fasting blood glucose and hemoglobin A1C (HbA1c) levels, while improved glucose tolerance and pyruvate tolerance. Mechanism study demonstrated that DMT inhibited gluconeogenesis by regulating the Galphaq/phospholipase C (PLC)/inositol-1,4,5-triphosphate receptor (IP3R)-mediated calcium (Ca2+)/calmodulin (CaM)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O1 (FOXO1) signaling pathway. To our knowledge, DMT might be the first reported small molecule able to suppress hepatic gluconeogenesis by regulating Galphaq signaling, and our current work has also highlighted the potential of DMT in the treatment of T2DM. PMID- 28637807 TI - Sudden Cardiac Death Substrate Imaged by Magnetic Resonance Imaging: From Investigational Tool to Clinical Applications. AB - Sudden cardiac death (SCD) is a devastating event afflicting 350 000 Americans annually despite the availability of life-saving preventive therapy, the implantable cardioverter defibrillator. SCD prevention strategies are hampered by over-reliance on global left ventricular ejection fraction <35% as the most important criterion to determine implantable cardioverter defibrillator candidacy. Annually in the United States alone, this results in ~130 000 implantable cardioverter defibrillator placements at a cost of >$3 billion but only a 5% incidence per year of appropriate firings. This approach further fails to identify individuals who experience the majority, as many as 80%, of SCD events, which occur in the setting of more preserved left ventricular ejection fraction. Better risk stratification is needed to improve care and should be guided by direct pathophysiologic markers of arrhythmic substrate, such as specific left ventricular structural abnormalities. There is an increasing body of literature to support the prognostic value of cardiac magnetic resonance imaging with late gadolinium enhancement in phenotyping the left ventricular to identify those at highest risk for SCD. Cardiac magnetic resonance has unparalleled tissue characterization ability and provides exquisite detail about myocardial structure and composition, abnormalities of which form the direct, pathophysiologic substrate for SCD. Here, we review the evolution and the current state of cardiac magnetic resonance for imaging the arrhythmic substrate, both as a research tool and for clinical applications. PMID- 28637809 TI - rRNA Pseudogenes in Filamentous Ascomycetes as Revealed by Genome Data. AB - The nuclear ribosomal DNA (rDNA) is considered as a paradigm of concerted evolution. Components of the rDNA tandem repeats (45S) are widely used in phylogenetic studies of different organisms and the internal transcribed spacer (ITS) region was recently selected as a fungal DNA bar code. However, rRNA pseudogenes, as one kind of escape from concerted evolution, were reported in a wide range of organisms, especially in plants and animals. Moreover, large numbers of 5S rRNA pseudogenes were identified in several filamentous ascomycetes. To study whether rDNA evolves in a strict concerted manner and test whether rRNA pseudogenes exist in more species of ascomycetes, intragenomic rDNA polymorphisms were analyzed using whole genome sequences. Divergent rDNA paralogs were found to coexist within a single genome in seven filamentous ascomycetes examined. A great number of paralogs were identified as pseudogenes according to the mutation and secondary structure analyses. Phylogenetic analyses of the three rRNA coding regions of the 45S rDNA repeats, i.e., 18S, 5.8S, and 28S, revealed an interspecies clustering pattern of those different rDNA paralogs. The identified rRNA pseudogenic sequences were validated using specific primers designed. Mutation analyses revealed that the repeat-induced point (RIP) mutation was probably responsible for the formation of those rRNA pseudogenes. PMID- 28637810 TI - McClintock: An Integrated Pipeline for Detecting Transposable Element Insertions in Whole-Genome Shotgun Sequencing Data. AB - Transposable element (TE) insertions are among the most challenging types of variants to detect in genomic data because of their repetitive nature and complex mechanisms of replication . Nevertheless, the recent availability of large resequencing data sets has spurred the development of many new methods to detect TE insertions in whole-genome shotgun sequences. Here we report an integrated bioinformatics pipeline for the detection of TE insertions in whole-genome shotgun data, called McClintock (https://github.com/bergmanlab/mcclintock), which automatically runs and standardizes output for multiple TE detection methods. We demonstrate the utility of McClintock by evaluating six TE detection methods using simulated and real genome data from the model microbial eukaryote, Saccharomyces cerevisiae We find substantial variation among McClintock component methods in their ability to detect nonreference TEs in the yeast genome, but show that nonreference TEs at nearly all biologically realistic locations can be detected in simulated data by combining multiple methods that use split-read and read-pair evidence. In general, our results reveal that split-read methods detect fewer nonreference TE insertions than read-pair methods, but generally have much higher positional accuracy. Analysis of a large sample of real yeast genomes reveals that most McClintock component methods can recover known aspects of TE biology in yeast such as the transpositional activity status of families, target preferences, and target site duplication structure, albeit with varying levels of accuracy. Our work provides a general framework for integrating and analyzing results from multiple TE detection methods, as well as useful guidance for researchers studying TEs in yeast resequencing data. PMID- 28637811 TI - Bayesian Networks Illustrate Genomic and Residual Trait Connections in Maize (Zea mays L.). AB - Relationships among traits were investigated on the genomic and residual levels using novel methodology. This included inference on these relationships via Bayesian networks and an assessment of the networks with structural equation models. The methodology employed three steps. First, a Bayesian multiple-trait Gaussian model was fitted to the data to decompose phenotypic values into their genomic and residual components. Second, genomic and residual network structures among traits were learned from estimates of these two components. Network learning was performed using six different algorithmic settings for comparison, of which two were score-based and four were constraint-based approaches. Third, structural equation model analyses ranked the networks in terms of goodness of fit and predictive ability, and compared them with the standard multiple-trait fully recursive network. The methodology was applied to experimental data representing the European heterotic maize pools Dent and Flint (Zea mays L.). Inferences on genomic and residual trait connections were depicted separately as directed acyclic graphs. These graphs provide information beyond mere pairwise genetic or residual associations between traits, illustrating for example conditional independencies and hinting at potential causal links among traits. Network analysis suggested some genetic correlations as potentially spurious. Genomic and residual networks were compared between Dent and Flint. PMID- 28637812 TI - Sensitivity of neurons in the middle temporal area of marmoset monkeys to random dot motion. AB - Neurons in the middle temporal area (MT) of the primate cerebral cortex respond to moving visual stimuli. The sensitivity of MT neurons to motion signals can be characterized by using random-dot stimuli, in which the strength of the motion signal is manipulated by adding different levels of noise (elements that move in random directions). In macaques, this has allowed the calculation of "neurometric" thresholds. We characterized the responses of MT neurons in sufentanil/nitrous oxide-anesthetized marmoset monkeys, a species that has attracted considerable recent interest as an animal model for vision research. We found that MT neurons show a wide range of neurometric thresholds and that the responses of the most sensitive neurons could account for the behavioral performance of macaques and humans. We also investigated factors that contributed to the wide range of observed thresholds. The difference in firing rate between responses to motion in the preferred and null directions was the most effective predictor of neurometric threshold, whereas the direction tuning bandwidth had no correlation with the threshold. We also showed that it is possible to obtain reliable estimates of neurometric thresholds using stimuli that were not highly optimized for each neuron, as is often necessary when recording from large populations of neurons with different receptive field concurrently, as was the case in this study. These results demonstrate that marmoset MT shows an essential physiological similarity to macaque MT and suggest that its neurons are capable of representing motion signals that allow for comparable motion-in-noise judgments.NEW & NOTEWORTHY We report the activity of neurons in marmoset MT in response to random-dot motion stimuli of varying coherence. The information carried by individual MT neurons was comparable to that of the macaque, and the maximum firing rates were a strong predictor of sensitivity. Our study provides key information regarding the neural basis of motion perception in the marmoset, a small primate species that is becoming increasingly popular as an experimental model. PMID- 28637814 TI - Effective assessments of electroencephalography during stroke recovery: contemporary approaches and considerations. AB - Stroke is one of the leading causes of permanent disability worldwide, relying conventionally on extended periods of physiotherapy to recover functional ability. While neuroimaging techniques and emerging neurorehabilitation paradigms have advanced our understanding of pathophysiological mechanisms underlying stroke, recent evidence has renewed focus on quantifying features of cortical activity present in electroencephalography recordings to greatly enhance our understanding of stroke treatment and recovery. This Neuro Forum article reviews these key advances and discusses the importance of quantifying electroencephalography in future assessments of stroke survivors. PMID- 28637813 TI - Contribution of blood oxygen and carbon dioxide sensing to the energetic optimization of human walking. AB - People can adapt their gait to minimize energetic cost, indicating that walking's neural control has access to ongoing measurements of the body's energy use. In this study we tested the hypothesis that an important source of energetic cost measurements arises from blood gas receptors that are sensitive to O2 and CO2 concentrations. These receptors are known to play a role in regulating other physiological processes related to energy consumption, such as ventilation rate. Given the role of O2 and CO2 in oxidative metabolism, sensing their levels can provide an accurate estimate of the body's total energy use. To test our hypothesis, we simulated an added energetic cost for blood gas receptors that depended on a subject's step frequency and determined if subjects changed their behavior in response to this simulated cost. These energetic costs were simulated by controlling inspired gas concentrations to decrease the circulating levels of O2 and increase CO2 We found this blood gas control to be effective at shifting the step frequency that minimized the ventilation rate and perceived exertion away from the normally preferred frequency, indicating that these receptors provide the nervous system with strong physiological and psychological signals. However, rather than adapt their preferred step frequency toward these lower simulated costs, subjects persevered at their normally preferred frequency even after extensive experience with the new simulated costs. These results suggest that blood gas receptors play a negligible role in sensing energetic cost for the purpose of optimizing gait.NEW & NOTEWORTHY Human gait adaptation implies that the nervous system senses energetic cost, yet this signal is unknown. We tested the hypothesis that the blood gas receptors sense cost for gait optimization by controlling blood O2 and CO2 with step frequency as people walked. At the simulated energetic minimum, ventilation and perceived exertion were lowest, yet subjects preferred walking at their original frequency. This suggests that blood gas receptors are not critical for sensing cost during gait. PMID- 28637815 TI - The proinflammatory cytokine tumor necrosis factor-alpha excites subfornical organ neurons. AB - Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine implicated in cardiovascular and autonomic regulation via actions in the central nervous system. TNF-alpha-/- mice do not develop angiotensin II (ANG II)-induced hypertension, and administration of TNF-alpha into the bloodstream of rats increases blood pressure and sympathetic tone. Recent studies have shown that lesion of the subfornical organ (SFO) attenuates the hypertensive and autonomic effects of TNF-alpha, while direct administration of TNF-alpha into the SFO increases blood pressure, suggesting the SFO to be a key site for the actions of TNF-alpha. Therefore, we used patch-clamp techniques to examine both acute and long-term effects of TNF-alpha on the excitability of Sprague-Dawley rat SFO neurons. It was observed that acute bath application of TNF-alpha depolarized SFO neurons and subsequently increased action potential firing rate. Furthermore, the magnitude of depolarization and the proportion of depolarized SFO neurons were concentration dependent. Interestingly, following 24-h incubation with TNF-alpha, the basal firing rate of the SFO neurons was increased and the rheobase was decreased, suggesting that TNF-alpha elevates SFO neuron excitability. This effect was likely mediated by the transient sodium current, as TNF-alpha increased the magnitude of the current and lowered its threshold of activation. In contrast, TNF-alpha did not appear to modulate either the delayed rectifier potassium current or the transient potassium current. These data suggest that acute and long-term TNF-alpha exposure elevates SFO neuron activity, providing a basis for TNF-alpha hypertensive and sympathetic effects.NEW & NOTEWORTHY Considerable recent evidence has suggested important links between inflammation and the pathological mechanisms underlying hypertension. The present study describes cellular mechanisms through which acute and long-term exposure of tumor necrosis factor-alpha (TNF-alpha) influences the activity of subfornical organ neurons by modulating the voltage-gated transient Na+ current. This provides critical new information regarding the specific pathological mechanisms through which inflammation and TNF-alpha in particular may result in the development of hypertension. PMID- 28637816 TI - Timing during transitions in Bengalese finch song: implications for motor sequencing. AB - To investigate mechanisms of action sequencing, we examined the relationship between timing and sequencing of syllables in Bengalese finch song. An individual's song comprises acoustically distinct syllables organized into probabilistic sequences: a given syllable potentially can transition to several different syllables (divergence points), and several different syllables can transition to a given syllable (convergence points). In agreement with previous studies, we found that more probable transitions at divergence points occur with shorter intersyllable gaps. One intuition for this relationship is that selection between syllables reflects a competitive branching process, in which stronger links to one syllable lead to both higher probabilities and shorter latencies for transitions to that syllable vs. competing alternatives. However, we found that simulations of competitive race models result in overlapping winning-time distributions for competing outcomes and fail to replicate the strong negative correlation between probability and gap duration found in song data. Further investigation of song structure revealed strong positive correlation between gap durations for transitions that share a common convergent point. Such transitions are not related by a common competitive process, but instead reflect a common terminal syllable. In contrast to gap durations, transition probabilities were not correlated at convergence points. Together, our data suggest that syllable selection happens early during the gap, with gap timing determined chiefly by the latency to syllable initiation. This may result from a process in which probabilistic sequencing is first stabilized, followed by a shortening of the latency to syllables that are sung more often.NEW & NOTEWORTHY Bengalese finch songs consist of probabilistic sequences of syllables. Previous studies revealed a strong negative correlation between transition probability and the duration of intersyllable gaps. We show here that the negative correlation is inconsistent with previous suggestions that timing at syllable transitions is governed by a race between competing alternatives. Rather, the data suggest that syllable selection happens early during the gap, with gap timing determined chiefly by the latency to syllable initiation. PMID- 28637817 TI - The neural mechanisms able to predict future emotion regulation decisions. AB - Emotion regulation is crucial in maintaining healthy psychological well-being, and its dysregulation is often linked to a range of neuropsychiatric disorders including depression. The neurobiological underpinnings of cognitive reappraisal, an emotion regulation strategy, have been shown to include the amygdala and regions of the prefrontal cortex. A novel study by Dore, Weber, and Ochsner (J Neurosci 37: 2580-2588, 2017) has demonstrated that neural activity in these regions during uninstructed visualization of affective stimuli can successfully predict which individuals are more likely to subsequently employ emotion regulation, and under what circumstances. PMID- 28637818 TI - The cerebellum does more than sensory prediction error-based learning in sensorimotor adaptation tasks. AB - Individuals with damage to the cerebellum perform poorly in sensorimotor adaptation paradigms. This deficit has been attributed to impairment in sensory prediction error-based updating of an internal forward model, a form of implicit learning. These individuals can, however, successfully counter a perturbation when instructed with an explicit aiming strategy. This successful use of an instructed aiming strategy presents a paradox: In adaptation tasks, why do individuals with cerebellar damage not come up with an aiming solution on their own to compensate for their implicit learning deficit? To explore this question, we employed a variant of a visuomotor rotation task in which, before executing a movement on each trial, the participants verbally reported their intended aiming location. Compared with healthy control participants, participants with spinocerebellar ataxia displayed impairments in both implicit learning and aiming. This was observed when the visuomotor rotation was introduced abruptly (experiment 1) or gradually (experiment 2). This dual deficit does not appear to be related to the increased movement variance associated with ataxia: Healthy undergraduates showed little change in implicit learning or aiming when their movement feedback was artificially manipulated to produce similar levels of variability (experiment 3). Taken together the results indicate that a consequence of cerebellar dysfunction is not only impaired sensory prediction error-based learning but also a difficulty in developing and/or maintaining an aiming solution in response to a visuomotor perturbation. We suggest that this dual deficit can be explained by the cerebellum forming part of a network that learns and maintains action-outcome associations across trials.NEW & NOTEWORTHY Individuals with cerebellar pathology are impaired in sensorimotor adaptation. This deficit has been attributed to an impairment in error-based learning, specifically, from a deficit in using sensory prediction errors to update an internal model. Here we show that these individuals also have difficulty in discovering an aiming solution to overcome their adaptation deficit, suggesting a new role for the cerebellum in sensorimotor adaptation tasks. PMID- 28637819 TI - Long-interval intracortical inhibition is asymmetric in young but not older adults. AB - Aging is typically accompanied by a decline in manual dexterity and handedness; the dominant hand executes tasks of manual dexterity more quickly and accurately than the nondominant hand in younger adults, but this advantage typically declines with age. Age-related changes in intracortical inhibitory processes might play a role in the age-related decline in manual dexterity. Long-interval intracortical inhibition (LICI) is asymmetric in young adults, with more sensitive and more powerful LICI circuits in the dominant hemisphere than in the nondominant hemisphere. Here we investigated whether the hemispheric asymmetry in LICI in younger adults persists in healthy older adults. Paired-pulse transcranial magnetic stimulation was used to measure LICI in the dominant and nondominant hemispheres of younger and older adults; LICI stimulus-response curves were obtained by varying conditioning stimulus intensity at two different interstimulus intervals [100 ms (LICI100) and 150 ms]. We have replicated the finding that LICI100 circuits are more sensitive and more powerful in the dominant than the nondominant hemisphere of young adults and extend this finding to show that the hemispheric asymmetry in LICI100 is lost with age. In the context of behavioral observations showing that dominant hand movements in younger adults are more fluent than nondominant hand movements in younger adults and dominant hand movements in older adults, we speculate a role of LICI100 in the age-related decline in manual dexterity.NEW & NOTEWORTHY In younger adults, more sensitive and more powerful long-interval intracortical inhibitory circuits are evident in the hemisphere controlling the more dexterous hand; this is not the case in older adults, for whom long-interval intracortical inhibitory circuits are symmetric and more variable than in younger adults. We speculate that the highly sensitive and powerful long-interval intracortical inhibition circuits in the dominant hemisphere play a role in manual dexterity. PMID- 28637820 TI - Dynamic mechanisms of visually guided 3D motion tracking. AB - The continuous perception of motion-through-depth is critical for both navigation and interacting with objects in a dynamic three-dimensional (3D) world. Here we used 3D tracking to simultaneously assess the perception of motion in all directions, facilitating comparisons of responses to motion-through-depth to frontoparallel motion. Observers manually tracked a stereoscopic target as it moved in a 3D Brownian random walk. We found that continuous tracking of motion through-depth was selectively impaired, showing different spatiotemporal properties compared with frontoparallel motion tracking. Two separate factors were found to contribute to this selective impairment. The first is the geometric constraint that motion-through-depth yields much smaller retinal projections than frontoparallel motion, given the same object speed in the 3D environment. The second factor is the sluggish nature of disparity processing, which is present even for frontoparallel motion tracking of a disparity-defined stimulus. Thus, despite the ecological importance of reacting to approaching objects, both the geometry of 3D vision and the nature of disparity processing result in considerable impairments for tracking motion-through-depth using binocular cues.NEW & NOTEWORTHY We characterize motion perception continuously in all directions using an ecologically relevant, manual target tracking paradigm we recently developed. This approach reveals a selective impairment to the perception of motion-through-depth. Geometric considerations demonstrate that this impairment is not consistent with previously observed spatial deficits (e.g., stereomotion suppression). However, results from an examination of disparity processing are consistent with the longer latencies observed in discrete, trial-based measurements of the perception of motion-through-depth. PMID- 28637821 TI - Endovascular management of aneurysms associated with spinal arteriovenous malformations. AB - BACKGROUND: Spinal aneurysms are rare among spinal arteriovenous malformations (SAVMs). There are few reports of endovascular management of spinal aneurysms associated with SAVM. OBJECTIVE: To present endovascular management of aneurysms associated with SAVM. METHODS: Of 91 patients with SAVMs,eight (9%) presented with aneurysms. Of these, three were male and five were female with a median age of 18 years (range 11-38). We evaluated the presenting pattern, lesion level, type of the target aneurysm related to the presenting pattern and AVM nidus, and the result obtained after embolization or open surgery. Clinical status was evaluated by Aminoff-Logue (ALS) gait and micturition scale scores. RESULTS: The presenting patterns were subarachnoid hemorrhage (SAH, n=3) or mass effect caused by extrinsic (n=4) or intrinsic (n=1) cord compression. Aneurysms were located in four cervical, two thoracic, and two lumbar enlargement areas. There were two prenidal (arterial), three nidal, and three postnidal (venous) aneurysms. The mean diameter of the aneurysms was 9 mm (range 3-27). Glue embolization (n=6), open surgery (n=1), and combined surgery and embolization (n=1) was performed to obliterate the aneurysms. Obliteration of the target aneurysms resulted in improvement of symptoms and clinical stabilization of SAVMs in all patients during a mean of 55 months (range 7-228) of follow-up. CONCLUSIONS: Identification of a symptomatic aneurysm should be associated with clinical presentation pattern. Targeted obliteration of the aneurysm by embolization and/or surgery resulted in improvement of symptoms and stabilization of SAVM. PMID- 28637822 TI - Pattern of pressure gradient alterations after venous sinus stenting for idiopathic intracranial hypertension predicts stent-adjacent stenosis: a proposed classification system. AB - OBJECTIVE: Venous sinus stenting (VSS) is a safe and effective treatment for idiopathic intracranial hypertension (IIH) with angiographic venous sinus stenosis. However, predictors of stent-adjacent stenosis (SAS) remain poorly defined. METHODS: We performed a retrospective review of 47 patients with IIH and intracranial venous stenosis who underwent VSS with pre- and post-stent venography. Patient characteristics, treatments and outcomes were reviewed. Changes in pressure gradient after VSS were classified according to pattern of gradient resolution into types I-III. RESULTS: Type I gradient resolution, in which mean venous pressure (MVP) in the transverse sinus (TS) decreases towards MVP in the sigmoid sinus (SS), occurred in 18 patients (38.3%). Type II gradient resolution pattern, in which SS MVP increases towards that in the TS, occurred in 7patients (14.9%). Type III pattern, in which MVP equilibrates to a middle value, occurred in 22patients (46.8%). SAS occurred in 0%, 28.6%, and 22.7% of patients in types I, II and III, respectively. Compared with patients with type I gradient resolution, SAS was more common in those with type II (p=0.0181) and type III (p=0.0306) patterns. CONCLUSIONS: The pattern of change in the trans-stenosis venous pressure gradient may be predictive of SAS and is a useful tool for classifying the response of the venous obstruction to stenting. A type I pattern appears to represent the ideal response to VSS. Some patients with type II and III changes, particularly if they have other predictors of recurrent stenosis, may benefit from longer initial stent constructs. PMID- 28637824 TI - In This Issue of Diabetes. PMID- 28637823 TI - Titin force enhancement following active stretch of skinned skeletal muscle fibres. AB - In actively stretched skeletal muscle sarcomeres, titin-based force is enhanced, increasing the stiffness of active sarcomeres. Titin force enhancement in sarcomeres is vastly reduced in mdm, a genetic mutation with a deletion in titin. Whether loss of titin force enhancement is associated with compensatory mechanisms at higher structural levels of organization, such as single fibres or entire muscles, is unclear. The aim of this study was to determine whether mechanical deficiencies in titin force enhancement are also observed at the fibre level, and whether mechanisms compensate for the loss of titin force enhancement. Single skinned fibres from control and mutant mice were stretched actively and passively beyond filament overlap to observe titin-based force. Mutant fibres generated lower contractile stress (force divided by cross-sectional area) than control fibres. Titin force enhancement was observed in control fibres stretched beyond filament overlap, but was overshadowed in mutant fibres by an abundance of collagen and high variability in mechanics. However, titin force enhancement could be measured in all control fibres and most mutant fibres following short stretches, accounting for ~25% of the total stress following active stretch. Our results show that the partial loss of titin force enhancement in myofibrils is not preserved in all mutant fibres and this mutation likely affects fibres differentially within a muscle. An increase in collagen helps to reestablish total force at long sarcomere lengths with the loss in titin force enhancement in some mutant fibres, increasing the overall strength of mutant fibres. PMID- 28637825 TI - We Know More Than We Can Tell About Diabetes and Vascular Disease: The 2016 Edwin Bierman Award Lecture. AB - The Edwin Bierman Award Lecture is presented in honor of the memory of Edwin L. Bierman, MD, an exemplary scientist, mentor, and leader in the field of diabetes, obesity, hyperlipidemia, and atherosclerosis. The award and lecture recognizes a leading scientist in the field of macrovascular complications and contributing risk factors in diabetes. Clay F. Semenkovich, MD, the Irene E. and Michael M. Karl Professor and Chief of the Division of Endocrinology, Metabolism and Lipid Research at Washington University School of Medicine in St. Louis, St. Louis, MO, received the prestigious award at the American Diabetes Association's 76th Scientific Sessions, 10-14 June 2016, in New Orleans, LA. He presented the Edwin Bierman Award Lecture, "We Know More Than We Can Tell About Diabetes and Vascular Disease," on Sunday, 12 June 2016.Diabetes is a disorder of abnormal lipid metabolism, a notion strongly supported by the work of Edwin Bierman, for whom this eponymous lecture is named. This abnormal lipid environment continues to be associated with devastating vascular complications in diabetes despite current therapies, suggesting that our understanding of the pathophysiology of blood vessel disease in diabetes is limited. In this review, potential new insights into the nature of diabetic vasculopathy will be discussed. Recent observations suggest that while the concept of distinct macrovascular and microvascular complications of diabetes has been useful, vascular diseases in diabetes may be more interrelated than previously appreciated. Moreover, the intermediary metabolic pathway of de novo lipogenesis, which synthesizes lipids from simple precursors, is robustly sensitive to insulin and may contribute to these complications. De novo lipogenesis requires fatty acid synthase, and recent studies of this enzyme suggest that endogenously produced lipids are channeled to specific intracellular sites to affect physiology. These findings raise the possibility that novel approaches to treating diabetes and its complications could be based on altering the intracellular lipid milieu. PMID- 28637826 TI - Indirect Regulation of Endogenous Glucose Production by Insulin: The Single Gateway Hypothesis Revisited. AB - On the basis of studies that investigated the intraportal versus systemic insulin infusion and transendothelial transport of insulin, we proposed the "single gateway hypothesis," which supposes an indirect regulation of hepatic glucose production by insulin; the rate-limiting transport of insulin across the adipose tissue capillaries is responsible for the slow suppression of free fatty acids (FFAs), which in turn is responsible for delayed suppression of hepatic endogenous glucose production (EGP) during insulin infusion. Preventing the fall in plasma FFAs during insulin infusion either by administering intralipids or by inhibiting adipose tissue lipolysis led to failure in EGP suppression, thus supporting our hypothesis. More recently, mice lacking hepatic Foxo1 in addition to Akt1 and Akt2 (L-AktFoxo1TKO), all required for insulin signaling, surprisingly showed normal glycemia. Inhibiting the fall of plasma FFAs in these mice prevented the suppression of EGP during a clamp, reaffirming that the site of insulin action to control EGP is extrahepatic. Measuring whole-body turnover rates of glucose and FFAs in L-AktFoxo1TKO mice also confirmed that hepatic EGP was regulated by insulin-mediated control of FFAs. The knockout mouse model in combination with sophisticated molecular techniques confirmed our physiological findings and the single gateway hypothesis. PMID- 28637827 TI - Islet Encapsulation: Physiological Possibilities and Limitations. AB - A logical cure for type 1 diabetes (T1D) involves replacing the lost insulin producing cells with new ones, preferably cells from a well-characterized and unlimited source of human insulin-producing cells. This straightforward and simple solution to provide a cure for T1D is immensely attractive but entails at least two inherent and thus far unresolved hurdles: 1) provision of an unlimited source of functional human insulin-producing cells and 2) prevention of rejection without the side effects of systemic immunosuppression. Generation of transplantable insulin-producing cells from human embryonic stem cells or induced pluripotent stem cells is at present close to reality, and we are currently awaiting the first clinical studies. Focus is now directed to foster development of novel means to control the immune system to enable large-scale clinical application. Encapsulation introduces a physical barrier that prevents access of immune cells to the transplanted cells but also hinders blood vessel ingrowth. Therefore, oxygen, nutrient, and hormonal passage over the encapsulation membrane is solely dependent on diffusion over the immune barrier, contributing to delays in glucose sensing and insulin secretion kinetics. This Perspective focuses on the physiological possibilities and limitations of an encapsulation strategy to establish near-normoglycemia in subjects with T1D, assuming that glucose responsive insulin-producing cells are available for transplantation. PMID- 28637828 TI - Ambient Air Pollution and Type 2 Diabetes: Do the Metabolic Effects of Air Pollution Start Early in Life? PMID- 28637830 TI - A Light Harvesting Complex-Like Protein in Maintenance of Photosynthetic Components in Chlamydomonas. AB - Using a genetic approach, we have identified and characterized a novel protein, named Msf1 (Maintenance factor for photosystem I), that is required for the maintenance of specific components of the photosynthetic apparatus in the green alga Chlamydomonas reinhardtii Msf1 belongs to the superfamily of light harvesting complex proteins with three transmembrane domains and consensus chlorophyll-binding sites. Loss of Msf1 leads to reduced accumulation of photosystem I and chlorophyll-binding proteins/complexes. Msf1is a component of a thylakoid complex containing key enzymes of the tetrapyrrole biosynthetic pathway, thus revealing a possible link between Msf1 and chlorophyll biosynthesis. Protein interaction assays and greening experiments demonstrate that Msf1 interacts with Copper target homolog1 (CHL27B) and accumulates concomitantly with chlorophyll in Chlamydomonas, implying that chlorophyll stabilizes Msf1. Contrary to other light-harvesting complex-like genes, the expression of Msf1 is not stimulated by high-light stress, but its protein level increases significantly under heat shock, iron and copper limitation, as well as in stationary cells. Based on these results, we propose that Msf1 is required for the maintenance of photosystem I and specific protein-chlorophyll complexes especially under certain stress conditions. PMID- 28637831 TI - OsHAD1, a Haloacid Dehalogenase-Like APase, Enhances Phosphate Accumulation. AB - Phosphorus (P) deficiency limits plant growth and yield. Since plants can absorb only the inorganic form of P (Pi), a large portion of soil P (organic and inorganic P complexes) remains unused. Here, we identified and characterized a PHR2-regulated, novel low-Pi-responsive haloacid dehalogenase (HAD)-like hydrolase, OsHAD1 While OsHAD1 is a functional HAD protein having both acid phosphatase and phytase activities, it showed little homology with other known low-Pi-responsive HAD superfamily members. Recombinant OsHAD1 is active at acidic pH and dephosphorylates a broad range of organic and inorganic P-containing substrates, including phosphorylated serine and sodium phytate. Exogenous application of recombinant OsHAD1 protein in growth medium supplemented with phytate led to marked increases in growth and total P content of Pi-deficient wild-type rice (Oryza sativa) seedlings. Furthermore, overexpression of OsHAD1 in rice resulted in enhanced phosphatase activity, biomass, and total and soluble P contents in Pi-deficient transgenic seedlings treated with phytate as a restricted Pi source. Gene expression and metabolite profiling revealed enhanced Pi starvation responses, such as up-regulation of multiple genes involved in Pi uptake and solubilization, accumulation of organic acids, enhanced secretory phosphatase activity, and depletion of ATP in overexpression lines as compared with the wild type. To elucidate the underlying regulatory mechanisms of OsHAD1, we performed in vitro pull-down assays, which revealed the association of OsHAD1 with protein kinases such as OsNDPKs. We conclude that, besides dephosphorylation of cellular organic P, OsHAD1 in coordination with kinases may regulate the phosphorylation status of downstream targets to accomplish Pi homeostasis under limited Pi supply. PMID- 28637833 TI - Management of neuropathy musculoskeletal deficits is much more than general global exercises: physiotherapy-based programs for diabetes long-term complications. PMID- 28637832 TI - Autophosphorylation Affects Substrate-Binding Affinity of Tobacco Ca2+-Dependent Protein Kinase1. AB - Protein kinases regulate diverse physiological processes. Because many kinases preserve inherent autophosphorylation capability, autophosphorylation appears to be one of the most important mechanisms for cellular signaling. However, physiological functions of autophosphorylation are still largely unknown, other than the self-activation by phosphorylation of activation loop in the catalytic domain. REPRESSION OF SHOOT GROWTH (RSG) is the transcription factor involved in gibberellin (GA) feedback regulation. The tobacco (Nicotiana tabacum) Ca2+ dependent protein kinase, NtCDPK1, phosphorylates RSG, resulting in the negative regulation of RSG. NtCDPK1 was previously shown to be autophosphorylated in a Ca2+-dependent manner. Here, we investigated the functional importance of autophosphorylation in NtCDPK1. Ser-6 and Thr-21 were identified as autophosphorylation sites of NtCDPK1. Autophosphorylation not only reduced the binding affinity of NtCDPK1 for RSG, but also inhibited the homodimerization of NtCDPK1. Furthermore, autophosphorylation decreased the phosphorylation efficiency of RSG yet increased that of myelin basic protein. Ser-6 and Thr-21 of NtCDPK1 were phosphorylated in response to GAs in plants. The substitution of these autophosphorylation sites with Ala enhanced the NtCDPK1 overexpression induced sensitization of seeds to a GA biosynthetic inhibitor during germination. These results suggest new functions of autophosphorylation in CDPKs, namely, autophosphorylation can prevent the excessive phosphorylation of substrates and alter the substrate preference of CDPKs. PMID- 28637834 TI - Reply to Drs. Sacco et al. PMID- 28637837 TI - Physiological thermal limits predict differential responses of bees to urban heat island effects. AB - Changes in community composition are an important, but hard to predict, effect of climate change. Here, we use a wild-bee study system to test the ability of critical thermal maxima (CTmax, a measure of heat tolerance) to predict community responses to urban heat-island effects in Raleigh, NC, USA. Among 15 focal species, CTmax ranged from 44.6 to 51.3 degrees C, and was strongly predictive of population responses to urban warming across 18 study sites (r2 = 0.44). Species with low CTmax declined the most. After phylogenetic correction, solitary species and cavity-nesting species (bumblebees) had the lowest CTmax, suggesting that these groups may be most sensitive to climate change. Community responses to urban and global warming will likely retain strong physiological signal, even after decades of warming during which time lags and interspecific interactions could modulate direct effects of temperature. PMID- 28637835 TI - Do COPD subtypes really exist? COPD heterogeneity and clustering in 10 independent cohorts. AB - BACKGROUND: COPD is a heterogeneous disease, but there is little consensus on specific definitions for COPD subtypes. Unsupervised clustering offers the promise of 'unbiased' data-driven assessment of COPD heterogeneity. Multiple groups have identified COPD subtypes using cluster analysis, but there has been no systematic assessment of the reproducibility of these subtypes. OBJECTIVE: We performed clustering analyses across 10 cohorts in North America and Europe in order to assess the reproducibility of (1) correlation patterns of key COPD related clinical characteristics and (2) clustering results. METHODS: We studied 17 146 individuals with COPD using identical methods and common COPD-related characteristics across cohorts (FEV1, FEV1/FVC, FVC, body mass index, Modified Medical Research Council score, asthma and cardiovascular comorbid disease). Correlation patterns between these clinical characteristics were assessed by principal components analysis (PCA). Cluster analysis was performed using k medoids and hierarchical clustering, and concordance of clustering solutions was quantified with normalised mutual information (NMI), a metric that ranges from 0 to 1 with higher values indicating greater concordance. RESULTS: The reproducibility of COPD clustering subtypes across studies was modest (median NMI range 0.17-0.43). For methods that excluded individuals that did not clearly belong to any cluster, agreement was better but still suboptimal (median NMI range 0.32-0.60). Continuous representations of COPD clinical characteristics derived from PCA were much more consistent across studies. CONCLUSIONS: Identical clustering analyses across multiple COPD cohorts showed modest reproducibility. COPD heterogeneity is better characterised by continuous disease traits coexisting in varying degrees within the same individual, rather than by mutually exclusive COPD subtypes. PMID- 28637839 TI - Correction to 'A hypervariable mitochondrial protein coding sequence associated with geographical origin in a cosmopolitan bloom-forming alga, Heterosigma akashiwo'. PMID- 28637836 TI - Bacterial Cellulose Shifts Transcriptome and Proteome of Cultured Endothelial Cells Towards Native Differentiation. AB - Preserving the native phenotype of primary cells in vitro is a complex challenge. Recently, hydrogel-based cellular matrices have evolved as alternatives to conventional cell culture techniques. We developed a bacterial cellulose-based aqueous gel-like biomaterial, dubbed Xellulin, which mimics a cellular microenvironment and seems to maintain the native phenotype of cultured and primary cells. When applied to human umbilical vein endothelial cells (HUVEC), it allowed the continuous cultivation of cell monolayers for more than one year without degradation or dedifferentiation. To investigate the impact of Xellulin on the endothelial cell phenotype in detail, we applied quantitative transcriptomics and proteomics and compared the molecular makeup of native HUVEC, HUVEC on collagen-coated Xellulin and collagen-coated cell culture plastic (polystyrene).Statistical analysis of 12,475 transcripts and 7831 proteins unveiled massive quantitative differences of the compared transcriptomes and proteomes. K-means clustering followed by network analysis showed that HUVEC on plastic upregulate transcripts and proteins controlling proliferation, cell cycle and protein biosynthesis. In contrast, HUVEC on Xellulin maintained, by and large, the expression levels of genes supporting their native biological functions and signaling networks such as integrin, receptor tyrosine kinase MAP/ERK and PI3K signaling pathways, while decreasing the expression of proliferation associated proteins. Moreover, CD34-an endothelial cell differentiation marker usually lost early during cell culture - was re-expressed within 2 weeks on Xellulin but not on plastic. And HUVEC on Xellulin showed a significantly stronger functional responsiveness to a prototypic pro-inflammatory stimulus than HUVEC on plastic.Taken together, this is one of the most comprehensive transcriptomic and proteomic studies of native and propagated HUVEC, which underscores the importance of the morphology of the cellular microenvironment to regulate cellular differentiation, and demonstrates, for the first time, the potential of Xellulin as versatile tool promoting an in vivo-like phenotype in primary and propagated cell culture. PMID- 28637838 TI - Experimental species removals impact the architecture of pollination networks. AB - Mutualistic networks are key for the creation and maintenance of biodiversity, yet are threatened by global environmental change. Most simulation models assume that network structure remains static after species losses, despite theoretical and empirical reasons to expect dynamic responses. We assessed the effects of experimental single bumblebee species removals on the structure of entire flower visitation networks. We hypothesized that network structure would change following processes linking interspecific competition with dietary niche breadth. We found that single pollinator species losses impact pollination network structure: resource complementarity decreased, while resource overlap increased. Despite marginally increased connectance, fewer plant species were visited after species removals. These changes may have negative functional impacts, as complementarity is important for maintaining biodiversity-ecological functioning relationships and visitation of rare plant species is critical for maintaining diverse plant communities. PMID- 28637840 TI - Promoting Sleep Oscillations and Their Functional Coupling by Transcranial Stimulation Enhances Memory Consolidation in Mild Cognitive Impairment. AB - Alzheimer's disease (AD) not only involves loss of memory functions, but also prominent deterioration of sleep physiology, which is already evident at the stage of mild cognitive impairment (MCI). Cortical slow oscillations (SO; 0.5-1 Hz) and thalamocortical spindle activity (12-15 Hz) during sleep, and their temporal coordination, are considered critical for memory formation. We investigated the potential of slow oscillatory transcranial direct current stimulation (so-tDCS), applied during a daytime nap in a sleep-state-dependent manner, to modulate these activity patterns and sleep-related memory consolidation in nine male and seven female human patients with MCI. Stimulation significantly increased overall SO and spindle power, amplified spindle power during SO up-phases, and led to stronger synchronization between SO and spindle power fluctuations in EEG recordings. Moreover, visual declarative memory was improved by so-tDCS compared with sham stimulation and was associated with stronger synchronization. These findings indicate a well-tolerated therapeutic approach for disordered sleep physiology and memory deficits in MCI patients and advance our understanding of offline memory consolidation.SIGNIFICANCE STATEMENT In the light of increasing evidence that sleep disruption is crucially involved in the progression of Alzheimer's disease (AD), sleep appears as a promising treatment target in this pathology, particularly to counteract memory decline. This study demonstrates the potential of a noninvasive brain stimulation method during sleep in patients with mild cognitive impairment (MCI), a precursor of AD, and advances our understanding of its mechanism. We provide first time evidence that slow oscillatory transcranial stimulation amplifies the functional cross frequency coupling between memory-relevant brain oscillations and improves visual memory consolidation in patients with MCI. PMID- 28637843 TI - POEMS syndrome: a rare cause of exudative ascites and chronic peripheral neuropathy. AB - POEMS syndrome (Peripheral neuropathy, Organomegaly, Endocrinopathy, M protein, Skin changes) is a rare plasma cell disorder with multisystem involvementA 40 year-old man with a chronic history of unexplained peripheral neuropathy , presented with exudative ascites.He was found to have an incidental osteolytic lesion of the sacrum proven to be a plasmacytoma. Immunoelectrophoresis for monoclonal protein was negative.In addition, the patient was found to have hepatosplenomegaly, erectile dysfunction, hyperprolactinaemia and hypothyroidism.The patient, was given steroid along with lenalidomide, and showed a good clinical response. PMID- 28637842 TI - Thromboembolism in active ulcerative colitis. AB - Inflammatory bowel disease (IBD) has a range of both intestinal and extraintestinal manifestations. Thromboembolism involving the arterial and/or venous systems is rare. Early recognition and treatment of thrombosis in patients with IBD may prevent progression and minimise complications. However, clear guidelines on the duration of treatment and indications for primary prophylaxis need to be established. We report a case of a young patient with ulcerative colitis, who developed multiple site arterial and venous thrombosis, all occurring within short intervals of each other. PMID- 28637844 TI - A dirty cause of vancomycin-mediated Henoch-Schonlein purpura: oxygen tubing is not a foley. AB - A 59-year-old male presented with methicillin-resistantStaphylococcus aureus bacteraemia from a prostatic abscess and was treated with vancomycin. Two weeks into his treatment course, he developed severe joint pains, abdominal pain with bloody, mucinous stools and a diffuse palpable purpuric rash on his extremities. Biopsy of the rash showed IgA immune-complex deposition consistent with Henoch SchA nlein purpura. After treatment with glucocorticoids, his symptoms resolved completely. Vancomycin is an extremely commonly used antibiotic with certain well known adverse effects. Henoch-SchA nlein purpura, a vasculitis involving abdominal pain, arthralgias and palpable purpura, is a much less common side effect, as seen in this patient. Given that vancomycin is widely used internationally, clinicians should be aware of the risks entailed by its use. PMID- 28637841 TI - Protein Tyrosine Phosphatase delta Mediates the Sema3A-Induced Cortical Basal Dendritic Arborization through the Activation of Fyn Tyrosine Kinase. AB - Leukocyte common antigen-related (LAR) class protein tyrosine phosphatases (PTPs) are critical for axonal guidance; however, their relation to specific guidance cues is poorly defined. We here show that PTP-3, a LAR homolog in Caenorhabditis elegans, is involved in axon guidance regulated by Semaphorin-2A-signaling. PTPdelta, one of the vertebrate LAR class PTPs, participates in the Semaphorin-3A (Sema3A)-induced growth cone collapse response of primary cultured dorsal root ganglion neurons from Mus musculus embryos. In vivo, however, the contribution of PTPdelta in Sema3A-regualted axon guidance was minimal. Instead, PTPdelta played a major role in Sema3A-dependent cortical dendritic growth. Ptpdelta-/- and Sema3a-/- mutant mice exhibited poor arborization of basal dendrites of cortical layer V neurons. This phenotype was observed in both male and female mutants. The double-heterozygous mutants, Ptpdelta+/-; Sema3a+/-, also showed a similar phenotype, indicating the genetic interaction. In Ptpdelta-/- brains, Fyn and Src kinases were hyperphosphorylated at their C-terminal Tyr527 residues. Sema3A stimulation induced dephosphorylation of Tyr527 in the dendrites of wild-type cortical neurons but not of Ptpdelta-/- Arborization of cortical basal dendrites was reduced in Fyn-/- as well as in Ptpdelta+/-; Fyn+/- double-heterozygous mutants. Collectively, PTPdelta mediates Sema3A-signaling through the activation of Fyn by C-terminal dephosphorylation.SIGNIFICANCE STATEMENT The relation of leukocyte common antigen-related (LAR) class protein tyrosine phosphatases (PTPs) and specific axon guidance cues is poorly defined. We show that PTP-3, a LAR homolog in Caenorhabditis elegans, participates in Sema2A-regulated axon guidance. PTPdelta, a member of vertebrate LAR class PTPs, is involved in Sema3A regulated cortical dendritic growth. In Sema3A signaling, PTPdelta activates Fyn and Src kinases by dephosphorylating their C-terminal Tyr residues. This is the first evidence showing that LAR class PTPs participate in Semaphorin signaling in vivo. PMID- 28637846 TI - Superior mesenteric artery syndrome in a healthy adolescent. PMID- 28637845 TI - Successful conservative management of a permanent pacemaker pocket infection: a less invasive approach. AB - We present a successful conservative management strategy for a frail elderly patient with a cardiac resynchronisation pacemaker who presented with evidence of an Enterobacter cloacae pacemaker pocket infection. A device washout and debridement procedure was performed, with reburial of the device in a new prepectoral pocket and creation of a closed-loop continuous antibiotic infusion into the infected pacemaker pocket. This was followed by a 6-week course of ambulatory intravenous antibiotic therapy. This conservative management strategy avoided the need for a more invasive and high-risk full device extraction, which the patient clearly stated he did not wish to have. Up-to-date consensus management guidelines recommend extraction of the entire implanted system in this situation; however, in this case we demonstrate an alternative conservative management option, which may be suitable for frail elderly and comorbid patients or for patients who decline device extraction. PMID- 28637847 TI - Asymmetric competition impacts evolutionary rescue in a changing environment. AB - Interspecific competition can strongly influence the evolutionary response of a species to a changing environment, impacting the chance that the species survives or goes extinct. Previous work has shown that when two species compete for a temporally shifting resource distribution, the species lagging behind the resource peak is the first to go extinct due to competitive exclusion. However, this work assumed symmetrically distributed resources and competition. Asymmetries can generate differences between species in population sizes, genetic variation and trait means. We show that asymmetric resource availability or competition can facilitate coexistence and even occasionally cause the leading species to go extinct first. Surprisingly, we also find cases where traits evolve in the opposite direction to the changing environment because of a 'vacuum of competitive release' created when the lagging species declines in number. Thus, the species exhibiting the slowest rate of trait evolution is not always the most likely to go extinct in a changing environment. Our results demonstrate that the extent to which species appear to be tracking environmental change and the extent to which they are preadapted to that change may not necessarily determine which species will be the winners and which will be the losers in a rapidly changing world. PMID- 28637848 TI - Using Captain Scott's Discovery specimens to unlock the past: has Antarctic cyanobacterial diversity changed over the last 100 years? AB - Evidence of climate-driven environmental change is increasing in Antarctica, and with it comes concern that this will propagate to impacts on biological communities. Recognition and prediction of change needs to incorporate the extent and timescales over which communities vary under extant conditions. However, few observations of Antarctic microbial communities, which dominate inland habitats, allow this. We therefore carried out the first molecular comparison of Cyanobacteria in historic herbarium microbial mats from freshwater ecosystems on Ross Island and the McMurdo Ice Shelf, collected by Captain R.F. Scott's 'Discovery' Expedition (1902-1903), with modern samples from those areas. Using 16S rRNA gene surveys, we found that modern and historic cyanobacteria assemblages showed some variation in community structure but were dominated by the same genotypes. Modern communities had a higher richness, including genotypes not found in historic samples, but they had the highest similarity to other cyanobacteria sequences from Antarctica. The results imply slow cyanobacterial 16S rRNA gene genotype turnover and considerable community stability within Antarctic microbial mats. We suggest that this relates to Antarctic freshwater 'organisms requiring a capacity to withstand diverse stresses, and that this could also provide a degree of resistance and resilience to future climatic driven environmental change in Antarctica. PMID- 28637849 TI - Breaking out of the comfort zone: El Nino-Southern Oscillation as a driver of trophic flows in a benthic consumer of the Humboldt Current ecosystem. AB - The trophic flow of a species is considered a characteristic trait reflecting its trophic position and function in the ecosystem and its interaction with the environment. However, climate patterns are changing and we ignore how patterns of trophic flow are being affected. In the Humboldt Current ecosystem, arguably one of the most productive marine systems, El Nino-Southern Oscillation is the main source of interannual and longer-term variability. To assess the effect of this variability on trophic flow we built a 16-year series of mass-specific somatic production rate (P/B) of the Peruvian scallop (Argopecten purpuratus), a species belonging to a former tropical fauna that thrived in this cold ecosystem. A strong increase of the P/B ratio of this species was observed during nutrient poor, warmer water conditions typical of El Nino, owing to the massive recruitment of fast-growing juvenile scallops. Trophic ecology theory predicts that when primary production is nutrient limited, the trophic flow of organisms occupying low trophic levels should be constrained (bottom-up control). For former tropical fauna thriving in cold, productive upwelling coastal zones, a short time of low food conditions but warm waters during El Nino could be sufficient to waken their ancestral biological features and display massive proliferations. PMID- 28637850 TI - Hierarchical complexity and the size limits of life. AB - Over the past 3.8 billion years, the maximum size of life has increased by approximately 18 orders of magnitude. Much of this increase is associated with two major evolutionary innovations: the evolution of eukaryotes from prokaryotic cells approximately 1.9 billion years ago (Ga), and multicellular life diversifying from unicellular ancestors approximately 0.6 Ga. However, the quantitative relationship between organismal size and structural complexity remains poorly documented. We assessed this relationship using a comprehensive dataset that includes organismal size and level of biological complexity for 11 172 extant genera. We find that the distributions of sizes within complexity levels are unimodal, whereas the aggregate distribution is multimodal. Moreover, both the mean size and the range of size occupied increases with each additional level of complexity. Increases in size range are non-symmetric: the maximum organismal size increases more than the minimum. The majority of the observed increase in organismal size over the history of life on the Earth is accounted for by two discrete jumps in complexity rather than evolutionary trends within levels of complexity. Our results provide quantitative support for an evolutionary expansion away from a minimal size constraint and suggest a fundamental rescaling of the constraints on minimal and maximal size as biological complexity increases. PMID- 28637851 TI - Island Rule, quantitative genetics and brain-body size evolution in Homo floresiensis. AB - Colonization of islands often activate a complex chain of adaptive events that, over a relatively short evolutionary time, may drive strong shifts in body size, a pattern known as the Island Rule. It is arguably difficult to perform a direct analysis of the natural selection forces behind such a change in body size. Here, we used quantitative evolutionary genetic models, coupled with simulations and pattern-oriented modelling, to analyse the evolution of brain and body size in Homo floresiensis, a diminutive hominin species that appeared around 700 kya and survived up to relatively recent times (60-90 kya) on Flores Island, Indonesia. The hypothesis of neutral evolution was rejected in 97% of the simulations, and estimated selection gradients are within the range found in living natural populations. We showed that insularity may have triggered slightly different evolutionary trajectories for body and brain size, which means explaining the exceedingly small cranial volume of H. floresiensis requires additional selective forces acting on brain size alone. Our analyses also support previous conclusions that H. floresiensis may be most likely derived from an early Indonesian H. erectus, which is coherent with currently accepted biogeographical scenario for Homo expansion out of Africa. PMID- 28637852 TI - Testing the molecular clock using mechanistic models of fossil preservation and molecular evolution. AB - Molecular sequence data provide information about relative times only, and fossil based age constraints are the ultimate source of information about absolute times in molecular clock dating analyses. Thus, fossil calibrations are critical to molecular clock dating, but competing methods are difficult to evaluate empirically because the true evolutionary time scale is never known. Here, we combine mechanistic models of fossil preservation and sequence evolution in simulations to evaluate different approaches to constructing fossil calibrations and their impact on Bayesian molecular clock dating, and the relative impact of fossil versus molecular sampling. We show that divergence time estimation is impacted by the model of fossil preservation, sampling intensity and tree shape. The addition of sequence data may improve molecular clock estimates, but accuracy and precision is dominated by the quality of the fossil calibrations. Posterior means and medians are poor representatives of true divergence times; posterior intervals provide a much more accurate estimate of divergence times, though they may be wide and often do not have high coverage probability. Our results highlight the importance of increased fossil sampling and improved statistical approaches to generating calibrations, which should incorporate the non-uniform nature of ecological and temporal fossil species distributions. PMID- 28637853 TI - Trophic state changes can affect the importance of methane-derived carbon in aquatic food webs. AB - Methane-derived carbon, incorporated by methane-oxidizing bacteria, has been identified as a significant source of carbon in food webs of many lakes. By measuring the stable carbon isotopic composition (delta13C values) of particulate organic matter, Chironomidae and Daphnia spp. and their resting eggs (ephippia), we show that methane-derived carbon presently plays a relevant role in the food web of hypertrophic Lake De Waay, The Netherlands. Sediment geochemistry, diatom analyses and delta13C measurements of chironomid and Daphnia remains in the lake sediments indicate that oligotrophication and re-eutrophication of the lake during the twentieth century had a strong impact on in-lake oxygen availability. This, in turn, influenced the relevance of methane-derived carbon in the diet of aquatic invertebrates. Our results show that, contrary to expectations, methane derived relative to photosynthetically produced organic carbon became more relevant for at least some invertebrates during periods with higher nutrient availability for algal growth, indicating a proportionally higher use of methane derived carbon in the lake's food web during peak eutrophication phases. Contributions of methane-derived carbon to the diet of the investigated invertebrates are estimated to have ranged from 0-11% during the phase with the lowest nutrient availability to 13-20% during the peak eutrophication phase. PMID- 28637854 TI - Fish prey change strategy with the direction of a threat. AB - Predation is a fundamental interaction between species, yet it is unclear what escape strategies are effective for prey survival. Classical theory proposes that prey should either escape in a direction that conforms to a performance optimum or that is random and therefore unpredictable. Here, we show that larval zebrafish (Danio rerio) instead use a mixed strategy that may be either random or directed. This was determined by testing classic theory with measurements of the escape direction in response to a predator robot. We found that prey consistently escaped in a direction contralateral to the robot when approached from the side of the prey's body. At such an orientation, the predator appeared in the prey's central visual field and the contralateral response was consistent with a model of strategy that maximizes the distance from the predator. By contrast, when the robot approached the rostral or caudal ends of the body, and appeared in the prey's peripheral vision, the escape showed an equal probability of a contralateral or ipsilateral direction. At this orientation, a contralateral response offered little strategic advantage. Therefore, zebrafish larvae adopt an escape strategy that maximizes distance from the threat when strategically beneficial and that is otherwise random. This sensory-mediated mixed strategy may be employed by a diversity of animals and offers a new paradigm for understanding the factors that govern prey survival. PMID- 28637855 TI - Fear of the human 'super predator' reduces feeding time in large carnivores. AB - Large carnivores' fear of the human 'super predator' has the potential to alter their feeding behaviour and result in human-induced trophic cascades. However, it has yet to be experimentally tested if large carnivores perceive humans as predators and react strongly enough to have cascading effects on their prey. We conducted a predator playback experiment exposing pumas to predator (human) and non-predator control (frog) sounds at puma feeding sites to measure immediate fear responses to humans and the subsequent impacts on feeding. We found that pumas fled more frequently, took longer to return, and reduced their overall feeding time by more than half in response to hearing the human 'super predator'. Combined with our previous work showing higher kill rates of deer in more urbanized landscapes, this study reveals that fear is the mechanism driving an ecological cascade from humans to increased puma predation on deer. By demonstrating that the fear of humans can cause a strong reduction in feeding by pumas, our results support that non-consumptive forms of human disturbance may alter the ecological role of large carnivores. PMID- 28637857 TI - Acute peaks of testosterone suppress paternal care: evidence from individual hormonal reaction norms. AB - A long-standing tenet of evolutionary endocrinology states that testosterone mediates the life-history trade-off between mating and paternal care. However, the support for a role of testosterone in suppressing paternal care is mixed: implantation studies in birds suggest that high-level testosterone implants suppress paternal care, but circulating levels of testosterone and paternal care are typically not correlated. Because any trade-off in real life must be realized with hormone levels that are within an individual's reaction norm, it is crucial to show that natural changes in the hormone can modulate behaviour. Here, we used GnRH-injections to alter testosterone levels of free-living male black redstarts within each individual's hormonal reaction norm: individuals experiencing a short term peak in testosterone resumed feeding their offspring later and showed a stronger suppression of offspring-feeding behaviour than control males. For the first time, this study demonstrated that short-term peaks in testosterone within the hormonal reaction norm of individuals can suppress paternal behaviour. Our findings reconcile previous seemingly contradictive effects that testosterone implants had on paternal care and the absence of correlations between circulating testosterone levels and paternal care, and demonstrate that the differential production of testosterone within the hormonal reaction norm of single individuals can indeed function as a mechanism to mediate a potential trade-off between mating and parenting. On a broader note, our results suggest that natural and short peaks in testosterone can elicit adaptive behavioural changes. PMID- 28637856 TI - How to get the most bang for your buck: the evolution and physiology of nutrition dependent resource allocation strategies. AB - All organisms use resources to grow, survive and reproduce. The supply of these resources varies widely across landscapes and time, imposing ultimate constraints on the maximal trait values for allocation-related traits. In this review, we address three key questions fundamental to our understanding of the evolution of allocation strategies and their underlying mechanisms. First, we ask: how diverse are flexible resource allocation strategies among different organisms? We find there are many, varied, examples of flexible strategies that depend on nutrition. However, this diversity is often ignored in some of the best-known cases of resource allocation shifts, such as the commonly observed pattern of lifespan extension under nutrient limitation. A greater appreciation of the wide variety of flexible allocation strategies leads directly to our second major question: what conditions select for different plastic allocation strategies? Here, we highlight the need for additional models that explicitly consider the evolution of phenotypically plastic allocation strategies and empirical tests of the predictions of those models in natural populations. Finally, we consider the question: what are the underlying mechanisms determining resource allocation strategies? Although evolutionary biologists assume differential allocation of resources is a major factor limiting trait evolution, few proximate mechanisms are known that specifically support the model. We argue that an integrated framework can reconcile evolutionary models with proximate mechanisms that appear at first glance to be in conflict with these models. Overall, we encourage future studies to: (i) mimic ecological conditions in which those patterns evolve, and (ii) take advantage of the 'omic' opportunities to produce multi-level data and analytical models that effectively integrate across physiological and evolutionary theory. PMID- 28637858 TI - Maternal and nourishment factors interact to influence offspring developmental trajectories in social wasps. AB - The social and nutritional environments during early development have the potential to affect offspring traits, but the mechanisms and molecular underpinnings of these effects remain elusive. We used Polistes fuscatus paper wasps to dissect how maternally controlled factors (vibrational signals and nourishment) interact to induce different caste developmental trajectories in female offspring, leading to worker or reproductive (gyne) traits. We established a set of caste phenotype biomarkers in P. fuscatus females, finding that gyne destined individuals had high expression of three caste-related genes hypothesized to have roles in diapause and mitochondrial metabolism. We then experimentally manipulated maternal vibrational signals (via artificial 'antennal drumming') and nourishment levels (via restricted foraging). We found that these caste-related biomarker genes were responsive to drumming, nourishment level or their interaction. Our results provide a striking example of the potent influence of maternal and nutritional effects in influencing transcriptional activity and developmental outcomes in offspring. PMID- 28637859 TI - Seeds integrate biological information about conspecific and allospecific neighbours. AB - Numerous organisms integrate information from multiple sources and express adaptive behaviours, but how they do so at different developmental stages remains to be identified. Seeds, which are the embryonic stage of plants, need to make decisions about the timing of emergence in response to environmental cues related to survival. We investigated the timing of emergence of Plantago asiatica (Plantaginaceae) seed while manipulating the presence of Trifolium repens seed and the relatedness of neighbouring P. asiatica seed. The relatedness of neighbouring P. asiatica seed and the presence of seeds of T. repens did not on their own influence the timing of P. asiatica emergence. However, when encountering a T. repens seed, a P. asiatica seed emerged faster in the presence of a sibling seed than in the presence of a non-sibling seed. Water extracts of seeds gave the same result. We show that P. asiatica seeds integrate information about the relatedness of neighbouring P. asiatica seeds and the presence of seeds of a different species via water-soluble chemicals and adjust their emergence behaviour in response. These findings suggest the presence of kin-dependent interspecific interactions. PMID- 28637860 TI - Higher-order neural processing tunes motion neurons to visual ecology in three species of hawkmoths. AB - To sample information optimally, sensory systems must adapt to the ecological demands of each animal species. These adaptations can occur peripherally, in the anatomical structures of sensory organs and their receptors; and centrally, as higher-order neural processing in the brain. While a rich body of investigations has focused on peripheral adaptations, our understanding is sparse when it comes to central mechanisms. We quantified how peripheral adaptations in the eyes, and central adaptations in the wide-field motion vision system, set the trade-off between resolution and sensitivity in three species of hawkmoths active at very different light levels: nocturnal Deilephila elpenor, crepuscular Manduca sexta, and diurnal Macroglossum stellatarum. Using optical measurements and physiological recordings from the photoreceptors and wide-field motion neurons in the lobula complex, we demonstrate that all three species use spatial and temporal summation to improve visual performance in dim light. The diurnal Macroglossum relies least on summation, but can only see at brighter intensities. Manduca, with large sensitive eyes, relies less on neural summation than the smaller eyed Deilephila, but both species attain similar visual performance at nocturnal light levels. Our results reveal how the visual systems of these three hawkmoth species are intimately matched to their visual ecologies. PMID- 28637861 TI - Epidemic and endemic pathogen dynamics correspond to distinct host population microbiomes at a landscape scale. AB - Infectious diseases have serious impacts on human and wildlife populations, but the effects of a disease can vary, even among individuals or populations of the same host species. Identifying the reasons for this variation is key to understanding disease dynamics and mitigating infectious disease impacts, but disentangling cause and correlation during natural outbreaks is extremely challenging. This study aims to understand associations between symbiotic bacterial communities and an infectious disease, and examines multiple host populations before or after pathogen invasion to infer likely causal links. The results show that symbiotic bacteria are linked to fundamentally different outcomes of pathogen infection: host-pathogen coexistence (endemic infection) or host population extirpation (epidemic infection). Diversity and composition of skin-associated bacteria differed between populations of the frog, Rana sierrae, that coexist with or were extirpated by the fungal pathogen, Batrachochytrium dendrobatidis (Bd). Data from multiple populations sampled before or after pathogen invasion were used to infer cause and effect in the relationship between the fungal pathogen and symbiotic bacteria. Among host populations, variation in the composition of the skin microbiome was most strongly predicted by pathogen infection severity, even in analyses where the outcome of infection did not vary. This result suggests that pathogen infection shapes variation in the skin microbiome across host populations that coexist with or are driven to extirpation by the pathogen. By contrast, microbiome richness was largely unaffected by pathogen infection intensity, but was strongly predicted by geographical region of the host population, indicating the importance of environmental or host genetic factors in shaping microbiome richness. Thus, while both richness and composition of the microbiome differed between endemic and epidemic host populations, the underlying causes are most likely different: pathogen infection appears to shape microbiome composition, while microbiome richness was less sensitive to pathogen-induced disturbance. Because higher richness was correlated with host persistence in the presence of Bd, and richness appeared relatively stable to Bd infection, microbiome richness may contribute to disease resistance, although the latter remains to be directly tested. PMID- 28637862 TI - Multicenter Registry Analysis of Center Characteristics Associated with Technique Failure in Patients on Incident Peritoneal Dialysis. AB - BACKGROUND AND OBJECTIVES: Technique failure is a major limitation of peritoneal dialysis. Our study aimed to identify center- and patient-level predictors of peritoneal dialysis technique failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients on incident peritoneal dialysis in Australia from 2004 to 2014 were included in the study using data from the Australia and New Zealand Dialysis and Transplant Registry. Center- and patient-level characteristics associated with technique failure were evaluated using Cox shared frailty models. Death-censored technique failure and cause-specific technique failure were analyzed as secondary outcomes. RESULTS: The study included 9362 patients from 51 centers in Australia. The technique failure rate was 0.35 (95% confidence interval, 0.34 to 0.36) episodes per patient-year, with a sevenfold variation across centers that was mainly associated with center-level characteristics. Technique failure was significantly less likely in centers with larger proportions of patients treated with peritoneal dialysis (>29%; adjusted hazard ratio, 0.83; 95% confidence interval, 0.73 to 0.94) and more likely in smaller centers (<16 new patients per year; adjusted hazard ratio, 1.10; 95% confidence interval, 1.00 to 1.21) and centers with lower proportions of patients achieving target baseline serum phosphate levels (<40%; adjusted hazard ratio, 1.15; 95% confidence interval, 1.03 to 1.29). Similar results were observed for death censored technique failure, except that center target phosphate achievement was not significantly associated. Technique failure due to infection, social reasons, mechanical causes, or death was variably associated with center size, proportion of patients on peritoneal dialysis, and/or target phosphate achievement, automated peritoneal dialysis exposure, icodextrin use, and antifungal use. The variation of hazards of technique failure across centers was reduced by 28% after adjusting for patient-specific factors and an additional 53% after adding center specific factors. CONCLUSIONS: Technique failure varies widely across centers in Australia. A significant proportion of this variation is related to potentially modifiable center characteristics, including peritoneal dialysis center size, proportion of patients on peritoneal dialysis, and proportion of patients on peritoneal dialysis achieving target phosphate level. PMID- 28637863 TI - Managing Issues in Dialysis for the Patient with AKI. PMID- 28637864 TI - Are Peritoneal Dialysis Center Characteristics a Modifiable Risk Factor to Improve Peritoneal Dialysis Outcomes? PMID- 28637866 TI - Endoplasmic reticulum-mitochondria junction is required for iron homeostasis. AB - The endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) is a protein complex that physically tethers the two organelles to each other and creates the physical basis for communication between them. ERMES functions in lipid exchange between the ER and mitochondria, protein import into mitochondria, and maintenance of mitochondrial morphology and genome. Here, we report that ERMES is also required for iron homeostasis. Loss of ERMES components activates an Aft1-dependent iron deficiency response even in iron-replete conditions, leading to accumulation of excess iron inside the cell. This function is independent of known ERMES roles in calcium regulation, phospholipid biosynthesis, or effects on mitochondrial morphology. A mutation in the vacuolar protein sorting 13 (VPS13) gene that rescues the glycolytic phenotype of ERMES mutants suppresses the iron deficiency response and iron accumulation. Our findings reveal that proper communication between the ER and mitochondria is required for appropriate maintenance of cellular iron levels. PMID- 28637865 TI - An evolutionarily distinct family of polysaccharide lyases removes rhamnose capping of complex arabinogalactan proteins. AB - The human gut microbiota utilizes complex carbohydrates as major nutrients. The requirement for efficient glycan degrading systems exerts a major selection pressure on this microbial community. Thus, we propose that this microbial ecosystem represents a substantial resource for discovering novel carbohydrate active enzymes. To test this hypothesis we screened the potential enzymatic functions of hypothetical proteins encoded by genes of Bacteroides thetaiotaomicron that were up-regulated by arabinogalactan proteins or AGPs. Although AGPs are ubiquitous in plants, there is a paucity of information on their detailed structure, the function of these glycans in planta, and the mechanisms by which they are depolymerized in microbial ecosystems. Here we have discovered a new polysaccharide lyase family that is specific for the l-rhamnose alpha1,4-d-glucuronic acid linkage that caps the side chains of complex AGPs. The reaction product generated by the lyase, Delta4,5-unsaturated uronic acid, is removed from AGP by a glycoside hydrolase located in family GH105, producing the final product 4-deoxy-beta-l-threo-hex-4-enepyranosyl-uronic acid. The crystal structure of a member of the novel lyase family revealed a catalytic domain that displays an (alpha/alpha)6 barrel-fold. In the center of the barrel is a deep pocket, which, based on mutagenesis data and amino acid conservation, comprises the active site of the lyase. A tyrosine is the proposed catalytic base in the beta-elimination reaction. This study illustrates how highly complex glycans can be used as a scaffold to discover new enzyme families within microbial ecosystems where carbohydrate metabolism is a major evolutionary driver. PMID- 28637867 TI - Full-length cellular beta-secretase has a trimeric subunit stoichiometry, and its sulfur-rich transmembrane interaction site modulates cytosolic copper compartmentalization. AB - The beta-secretase (BACE1) initiates processing of the amyloid precursor protein (APP) into Abeta peptides, which have been implicated as central players in the pathology of Alzheimer disease. BACE1 has been described as a copper-binding protein and its oligomeric state as being monomeric, dimeric, and/or multimeric, but the native cellular stoichiometry has remained elusive. Here, by using single molecule fluorescence and in vitro cross-linking experiments with photo activatable unnatural amino acids, we show that full-length BACE1, independently of its subcellular localization, exists as trimers in human cells. We found that trimerization requires the BACE1 transmembrane sequences (TMSs) and cytoplasmic domains, with residues Ala463 and Cys466 buried within the trimer interface of the sulfur-rich core of the TMSs. Our 3D model predicts that the sulfur-rich core of the trimeric BACE1 TMS is accessible to metal ions, but copper ions did not trigger trimerization. The results of functional assays of endogenous BACE1 suggest that it has a role in intracellular copper compartmentalization by transferring cytosolic copper to intracellular compartments, while leaving the overall cellular copper concentration unaltered. Adding to existing physiological models, our results provide novel insight into the atypical interactions between copper and BACE1 and into its non-enzymatic activities. In conclusion, therapeutic Alzheimer disease prevention strategies aimed at decreasing BACE1 protein levels should be regarded with caution, because adverse effects in copper homeostasis may occur. PMID- 28637868 TI - Post-transcriptional regulation of ERBB2 by miR26a/b and HuR confers resistance to tamoxifen in estrogen receptor-positive breast cancer cells. AB - Tamoxifen-resistant (TAMR) estrogen receptor-positive (ER+) breast cancer is characterized by elevated Erb-B2 receptor tyrosine kinase 2 (ERBB2) expression. However, the underlying mechanisms responsible for the increased ERBB2 expression in the TAMR cells remain poorly understood. Herein, we reported that the ERBB2 expression is regulated at the post-transcriptional level by miR26a/b and the RNA binding protein human antigen R (HuR), both of which associate with the 3'-UTR of the ERBB2 transcripts. We demonstrated that miR26a/b inhibits the translation of ERBB2 mRNA, whereas HuR enhances the stability of the ERBB2 mRNA. In TAMR ER+ breast cancer cells with elevated ERBB2 expression, we observed a decrease in the level of miR26a/b and an increase in the level of HuR. The forced expression of miR26a/b or the depletion of HuR decreased ERBB2 expression in the TAMR cells, resulting in the reversal of tamoxifen resistance. In contrast, the inactivation of miR26a/b or forced expression of HuR decreased tamoxifen responsiveness of the parental ER+ breast cancer cells. We further showed that the increase in HuR expression in the TAMR ER+ breast cancer cells is attributable to an increase in the HuR mRNA isoform with shortened 3'-UTR, which exhibits increased translational activity. This shortening of the HuR mRNA 3'-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells. Taken together, we have characterized a model in which the interplay between miR26a/b and HuR post-transcriptionally up-regulates ERBB2 expression in TAMR ER+ breast cancer cells. PMID- 28637870 TI - Cardiac myocyte p38alpha kinase regulates angiogenesis via myocyte-endothelial cell cross-talk during stress-induced remodeling in the heart. AB - Stress-induced p38 mitogen-activated protein kinase (MAPK) activity is implicated in pathological remodeling in the heart. For example, constitutive p38 MAPK activation in cardiomyocytes induces pathological features, including myocyte hypertrophy, apoptosis, contractile dysfunction, and fetal gene expression. However, the physiological function of cardiomyocyte p38 MAPK activity in beneficial compensatory vascular remodeling is unclear. This report investigated the functional role and the underlying mechanisms of cardiomyocyte p38 MAPK activity in cardiac remodeling induced by chronic stress. Using both in vitro and in vivo model systems, we found that p38 MAPK activity is required for hypoxia induced pro-angiogenic activity from cardiomyocytes and that p38 MAPK activation in cardiomyocyte is sufficient to promote paracrine signaling-mediated, pro angiogenic activity. We further demonstrate that VEGF is a paracrine factor responsible for the p38 MAPK-mediated pro-angiogenic activity from cardiomyocytes and that p38 MAPK pathway activation is sufficient for inducing VEGF secretion from cardiomyocytes in an Sp1-dependent manner. More significantly, cardiomyocyte specific inactivation of p38alpha in mouse heart impaired compensatory angiogenesis after pressure overload and promoted early onset of heart failure. In summary, p38alphaMAPK has a critical role in the cross-talk between cardiomyocytes and vasculature by regulating stress-induced VEGF expression and secretion in cardiomyocytes. We conclude that as part of a stress-induced signaling pathway, p38 MAPK activity significantly contributes to both pathological and compensatory remodeling in the heart. PMID- 28637869 TI - Heat shock proteins stimulate APOBEC-3-mediated cytidine deamination in the hepatitis B virus. AB - Apolipoprotein B mRNA-editing enzyme catalytic subunit 3 (APOBEC-3) enzymes are cytidine deaminases that are broadly and constitutively expressed. They are often up-regulated during carcinogenesis and candidate genes for causing the major single-base substitution in cancer-associated DNA mutations. Moreover, APOBEC-3s are involved in host innate immunity against many viruses. However, how APOBEC-3 mutational activity is regulated in normal and pathological conditions remains largely unknown. Heat shock protein levels are often elevated in both carcinogenesis and viral infection and are associated with DNA mutations. Here, using mutational analyses of hepatitis B virus (HBV), we found that Hsp90 stimulates deamination activity of APOBEC-3G (A3G), A3B, and A3C during co expression in human liver HepG2 cells. Hsp90 directly stimulated A3G deamination activity when the purified proteins were used in in vitro reactions. Hsp40, -60, and -70 also had variable stimulatory effects in the cellular assay, but not in vitro Sequencing analyses further demonstrated that Hsp90 increased both A3G cytosine mutation efficiency on HBV DNA and total HBV mutation frequency. In addition, Hsp90 shifted A3G's cytosine region selection in HBV DNA and increased A3G's 5' nucleoside preference for deoxycytidine (5'-CC). Furthermore, the Hsp90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin dose dependently inhibited A3G and A3B mutational activity on HBV viral DNA. Hsp90 knockdown by siRNA or by Hsp90 active-site mutation also decreased A3G activity. These results indicate that heat shock proteins, in particular Hsp90, stimulate APOBEC-3-mediated DNA deamination activity, suggesting a potential physiological role in carcinogenesis and viral innate immunity. PMID- 28637871 TI - Phosphorylation at serine 31 targets tyrosine hydroxylase to vesicles for transport along microtubules. AB - Tyrosine hydroxylase (TH) catalyzes the conversion of l-tyrosine into l-DOPA, which is the rate-limiting step in the synthesis of catecholamines, such as dopamine, in dopaminergergic neurons. Low dopamine levels and death of the dopaminergic neurons are hallmarks of Parkinson's disease (PD), where alpha synuclein is also a key player. TH is highly regulated, notably by phosphorylation of several Ser/Thr residues in the N-terminal tail. However, the functional role of TH phosphorylation at the Ser-31 site (THSer(P)-31) remains unclear. Here, we report that THSer(P)-31 co-distributes with the Golgi complex and synaptic-like vesicles in rat and human dopaminergic cells. We also found that the TH microsomal fraction content decreases after inhibition of cyclin dependent kinase 5 (Cdk5) and ERK1/2. The cellular distribution of an overexpressed phospho-null mutant, TH1-S31A, was restricted to the soma of neuroblastoma cells, with decreased association with the microsomal fraction, whereas a phospho-mimic mutant, TH1-S31E, was distributed throughout the soma and neurites. TH1-S31E associated with vesicular monoamine transporter 2 (VMAT2) and alpha-synuclein in neuroblastoma cells, and endogenous THSer(P)-31 was detected in VMAT2- and alpha-synuclein-immunoprecipitated mouse brain samples. Microtubule disruption or co-transfection with alpha-synuclein A53T, a PD-associated mutation, caused TH1-S31E accumulation in the cell soma. Our results indicate that Ser-31 phosphorylation may regulate TH subcellular localization by enabling its transport along microtubules, notably toward the projection terminals. These findings disclose a new mechanism of TH regulation by phosphorylation and reveal its interaction with key players in PD, opening up new research avenues for better understanding dopamine synthesis in physiological and pathological states. PMID- 28637872 TI - Hydrogen sulfide modulates eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation status in the integrated stress-response pathway. AB - Hydrogen sulfide (H2S) regulates various physiological processes, including neuronal activity, vascular tone, inflammation, and energy metabolism. Moreover, H2S elicits cytoprotective effects against stressors in various cellular models of injury. However, the mechanism of the signaling pathways mediating the cytoprotective functions of H2S is not well understood. We previously uncovered a heme-dependent metabolic switch for transient induction of H2S production in the trans-sulfuration pathway. Here, we demonstrate that increased endogenous H2S production or its exogenous administration modulates major components of the integrated stress response promoting a metabolic state primed for stress response. We show that H2S transiently increases phosphorylation of eukaryotic translation initiation factor 2 (eIF2alpha) resulting in inhibition of general protein synthesis. The H2S-induced increase in eIF2alpha phosphorylation was mediated at least in part by inhibition of protein phosphatase-1 (PP1c) via persulfidation at Cys-127. Overexpression of a PP1c cysteine mutant (C127S-PP1c) abrogated the H2S effect on eIF2alpha phosphorylation. Our data support a model in which H2S exerts its cytoprotective effect on ISR signaling by inducing a transient adaptive reprogramming of global mRNA translation. Although a transient increase in endogenous H2S production provides cytoprotection, its chronic increase such as in cystathionine beta-synthase deficiency may pose a problem. PMID- 28637873 TI - Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface-selective regulation of complement activation. AB - Spontaneous activation enables the complement system to respond very rapidly to diverse threats. This activation is efficiently suppressed by complement factor H (CFH) on self-surfaces but not on foreign surfaces. The surface selectivity of CFH, a soluble protein containing 20 complement-control protein modules (CCPs 1 20), may be compromised by disease-linked mutations. However, which of the several functions of CFH drives this self-surface selectivity remains unknown. To address this, we expressed human CFH mutants in Pichia pastoris We found that recombinant I62-CFH (protective against age-related macular degeneration) and V62 CFH functioned equivalently, matching or outperforming plasma-derived CFH, whereas R53H-CFH, linked to atypical hemolytic uremic syndrome (aHUS), was defective in C3bBb decay-accelerating activity (DAA) and factor I cofactor activity (CA). The aHUS-linked CCP 19 mutant D1119G-CFH had virtually no CA on (self-like) sheep erythrocytes (ES) but retained DAA. The aHUS-linked CCP 20 mutant S1191L/V1197A-CFH (LA-CFH) had dramatically reduced CA on ES but was less compromised in DAA. D1119G-CFH and LA-CFH both performed poorly at preventing complement-mediated hemolysis of ES PspCN, a CFH-binding Streptococcus pneumoniae protein domain, binds CFH tightly and increases accessibility of CCPs 19 and 20. PspCN did not improve the DAA of any CFH variant on ES Conversely, PspCN boosted the CA, on ES, of I62-CFH, R53H-CFH, and LA-CFH and also enhanced hemolysis protection by I62-CFH and LA-CFH. We conclude that CCPs 19 and 20 are critical for efficient CA on self-surfaces but less important for DAA. Exposing CCPs 19 and 20 with PspCN and thus enhancing CA on self-surfaces may reverse deficiencies of some CFH variants. PMID- 28637875 TI - Coupled feedback loops control the stimulus-dependent dynamics of the yeast transcription factor Msn2. AB - Information about environmental stimuli often can be encoded by the dynamics of signaling molecules or transcription factors. In the yeast Saccharomyces cerevisiae, different types of stresses induce distinct nuclear translocation dynamics of the general stress-responsive transcription factor Msn2, but the underlying mechanisms remain unclear. Using deterministic and stochastic modeling, we reproduced in silico the different dynamic responses of Msn2 to glucose limitation and osmotic stress observed in vivo and found that a positive feedback loop on protein kinase A mediated by the AMP-activated protein kinase Snf1 is coupled with a negative feedback loop to generate the characteristic pulsatile dynamics of Msn2. The model predicted that the stimulus-specific positive feedback loop could be responsible for the difference between Msn2 dynamics induced by glucose limitation and osmotic stress. This prediction was further verified experimentally by time-lapse microscopic examinations of the snf1Delta strain. In this mutant lacking the Snf1-mediated positive feedback loop, Msn2 responds similarly to glucose limitation and osmotic stress, and its pulsatile translocation is largely abrogated. Our combined computational and experimental analysis reveals a regulatory mechanism by which cells can encode information about environmental cues into distinct signaling dynamics through stimulus-specific network architectures. PMID- 28637874 TI - Direct demonstration of a neonatal Fc receptor (FcRn)-driven endosomal sorting pathway for cellular recycling of albumin. AB - Albumin is the most abundant plasma protein involved in the transport of many compounds, such as fatty acids, bilirubin, and heme. The endothelial cellular neonatal Fc receptor (FcRn) has been suggested to play a central role in maintaining high albumin plasma levels through a cellular recycling pathway. However, direct mapping of this process is still lacking. This work presents the use of wild-type and engineered recombinant albumins with either decreased or increased FcRn affinity in combination with a low or high FcRn-expressing endothelium cell line to clearly define the FcRn involvement, intracellular pathway, and kinetics of albumin trafficking by flow cytometry, quantitative confocal microscopy, and an albumin-recycling assay. We found that cellular albumin internalization was proportional to FcRn expression and albumin-binding affinity. Albumin accumulation in early endosomes was independent of FcRn-binding affinity, but differences in FcRn-binding affinities significantly affected the albumin distribution between late endosomes and lysosomes. Unlike albumin with low FcRn-binding affinity, albumin with high FcRn-binding affinity was directed less to the lysosomes, suggestive of FcRn-directed albumin salvage from lysosomal degradation. Furthermore, the amount of recycled albumin in cell culture media corresponded to FcRn-binding affinity, with a ~3.3-fold increase after 1 h for the high FcRn-binding albumin variant compared with wild-type albumin. Together, these findings uncover an FcRn-dependent endosomal cellular-sorting pathway that has great importance in describing fundamental mechanisms of intracellular albumin recycling and the possibility to tune albumin-based therapeutic effects by FcRn-binding affinity. PMID- 28637876 TI - Monocyte-Derived Dendritic Cells with Silenced PD-1 Ligands and Transpresenting Interleukin-15 Stimulate Strong Tumor-Reactive T-cell Expansion. AB - Although allogeneic stem cell transplantation (allo-SCT) can elicit graft-versus tumor (GVT) immunity, patients often relapse due to residual tumor cells. As essential orchestrators of the immune system, vaccination with dendritic cells (DC) is an appealing strategy to boost the GVT response. Nevertheless, durable clinical responses after DC vaccination are still limited, stressing the need to improve current DC vaccines. Aiming to empower DC potency, we engineered monocyte derived DCs to deprive them of ligands for the immune checkpoint regulated by programmed death 1 (PD-1). We also equipped them with interleukin (IL)-15 "transpresentation" skills. Transfection with short interfering (si)RNA targeting the PD-1 ligands PD-L1 and PD-L2, in combination with IL15 and IL15Ralpha mRNA, preserved their mature DC profile and rendered the DCs superior in inducing T cell proliferation and IFNgamma and TNFalpha production. Translated into an ex vivo hematological disease setting, DCs deprived of PD-1 ligands (PD-L), equipped with IL15/IL15Ralpha expression, or most effectively, both, induced superior expansion of minor histocompatibility antigen-specific CD8+ T cells from transplanted cancer patients. These data support the combinatorial approach of in situ suppression of the PD-L inhibitory checkpoints with DC-mediated IL15 transpresentation to promote antigen-specific T-cell responses and, ultimately, contribute to GVT immunity. Cancer Immunol Res; 5(8); 710-5. (c)2017 AACR. PMID- 28637877 TI - Ex Vivo Expanded Adaptive NK Cells Effectively Kill Primary Acute Lymphoblastic Leukemia Cells. AB - Manipulation of human natural killer (NK) cell repertoires promises more effective strategies for NK cell-based cancer immunotherapy. A subset of highly differentiated NK cells, termed adaptive NK cells, expands naturally in vivo in response to human cytomegalovirus (HCMV) infection, carries unique repertoires of inhibitory killer cell immunoglobulin-like receptors (KIR), and displays strong cytotoxicity against tumor cells. Here, we established a robust and scalable protocol for ex vivo generation and expansion of adaptive NK cells for cell therapy against pediatric acute lymphoblastic leukemia (ALL). Culture of polyclonal NK cells together with feeder cells expressing HLA-E, the ligand for the activating NKG2C receptor, led to selective expansion of adaptive NK cells with enhanced alloreactivity against HLA-mismatched targets. The ex vivo expanded adaptive NK cells gradually obtained a more differentiated phenotype and were specific and highly efficient killers of allogeneic pediatric T- and precursor B cell acute lymphoblastic leukemia (ALL) blasts, previously shown to be refractory to killing by autologous NK cells and the NK-cell line NK92 currently in clinical testing. Selective expansion of NK cells that express one single inhibitory KIR for self-HLA class I would allow exploitation of the full potential of NK-cell alloreactivity in cancer immunotherapy. In summary, our data suggest that adaptive NK cells may hold utility for therapy of refractory ALL, either as a bridge to transplant or for patients that lack stem cell donors. Cancer Immunol Res; 5(8); 654-65. (c)2017 AACR. PMID- 28637878 TI - CD4+ T Cell and NK Cell Interplay Key to Regression of MHC Class Ilow Tumors upon TLR7/8 Agonist Therapy. AB - One of the next challenges in cancer immunotherapy is the resistance of tumors to T-cell-based treatments through loss of MHC class I. Here, we show that under these circumstances, the Toll-like receptor (TLR)-7/8 ligand imiquimod, but not the TLR3 ligand poly I:C or TLR9 ligand CpG, mediated an effective antitumor response. The rejection of these immune-escaped cancers was mediated by NK cells and CD4+ T cells, whereas activated CD8+ T cells were dispensable. Application of the innate immune stimulator at a distant site activated NK cells and thereby elicited tumor-specific T-cell responses in tumor-bearing mice. Mechanistically, imiquimod activated NK cells to kill tumor cells, resulting in release of tumor antigens and induction of tumor-specific CD4+ T cells. These T helper cells provoked a strong induction of CXCL9 and CXCL10 in the tumor environment. Simultaneously, imiquimod induced the expression of the cognate chemokine receptor CXCR3 on peripheral lymphocytes. This ignited intratumoral CD4+ T-cell infiltration and accumulation, which was critical for tumor rejection; CXCR3 blocking antibodies mitigated the clinical response. In the effector phase, NK cell recruitment to tumors and their activation depended on CD4+ T cells. Together, we have uncovered a potent immune axis of tumor-specific CD4+ T cells and NK cells that eliminates escaped MHC-Ilow tumors. Cancer Immunol Res; 5(8); 642-53. (c)2017 AACR. PMID- 28637879 TI - Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus. AB - BACKGROUND: Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. METHODS: We measured P2Y12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-kappaB pathway in regulating P2Y12 receptor expression in megakaryocytes. RESULTS: Platelet P2Y12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y12 expression correlates with ADP induced platelet aggregation (r=0.89, P<0.01). P2Y12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36+/-3% versus 49+/-5%, respectively, P<0.05). Using a FeCl3-injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9+/-0.3 mg versus 8.3+/-0.4 mg, respectively, P<0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-kappaB increases platelet P2Y12 receptor expression in diabetes mellitus. CONCLUSIONS: Platelet P2Y12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus. PMID- 28637880 TI - Study Comparing Vein Integrity and Clinical Outcomes in Open Vein Harvesting and 2 Types of Endoscopic Vein Harvesting for Coronary Artery Bypass Grafting: The VICO Randomized Clinical Trial (Vein Integrity and Clinical Outcomes). AB - BACKGROUND: Current consensus statements maintain that endoscopic vein harvesting (EVH) should be standard care in coronary artery bypass graft surgery, but vein quality and clinical outcomes have been questioned. The VICO trial (Vein Integrity and Clinical Outcomes) was designed to assess the impact of different vein harvesting methods on vessel damage and whether this contributes to clinical outcomes after coronary artery bypass grafting. METHODS: In this single-center, randomized clinical trial, patients undergoing coronary artery bypass grafting with an internal mammary artery and with 1 to 4 vein grafts were recruited. All veins were harvested by a single experienced practitioner. We randomly allocated 300 patients into closed tunnel CO2 EVH (n=100), open tunnel CO2 EVH (n=100), and traditional open vein harvesting (n=100) groups. The primary end point was endothelial integrity and muscular damage of the harvested vein. Secondary end points included clinical outcomes (major adverse cardiac events), use of healthcare resources, and impact on health status (quality-adjusted life-years). RESULTS: The open vein harvesting group demonstrated marginally better endothelial integrity in random samples (85% versus 88% versus 93% for closed tunnel EVH, open tunnel EVH, and open vein harvesting; P<0.001). Closed tunnel EVH displayed the lowest longitudinal hypertrophy (1% versus 13.5% versus 3%; P=0.001). However, no differences in endothelial stretching were observed between groups (37% versus 37% versus 31%; P=0.62). Secondary clinical outcomes demonstrated no significant differences in composite major adverse cardiac event scores at each time point up to 48 months. The quality-adjusted life-year gain per patient was 0.11 (P<0.001) for closed tunnel EVH and 0.07 (P=0.003) for open tunnel EVH compared with open vein harvesting. The likelihood of being cost effective, at a predefined threshold of L20 000 per quality-adjusted life-year gained, was 75% for closed tunnel EVH, 19% for open tunnel EVH, and 6% for open vein harvesting. CONCLUSIONS: Our study demonstrates that harvesting techniques affect the integrity of different vein layers, albeit only slightly. Secondary outcomes suggest that histological findings do not directly contribute to major adverse cardiac event outcomes. Gains in health status were observed, and cost effectiveness was better with closed tunnel EVH. High-level experience with endoscopic harvesting performed by a dedicated specialist practitioner gives optimal results comparable to those of open vein harvesting. CLINICAL TRIAL REGISTRATION: URL: https://www.isrctn.com. International Standard Randomised Controlled Trial Registry Number: 91485426. PMID- 28637881 TI - Physical Activity and Prognosis in the TOPCAT Trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist). AB - BACKGROUND: Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with preserved ejection fraction is less well characterized. METHODS: The baseline self-reported PA of 1751 subjects enrolled in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) was categorized as poor, intermediate, or ideal PA with American Heart Association criteria. PA was related to the primary composite outcome (HF hospitalization, cardiovascular mortality, or aborted cardiac arrest), its components, and all-cause mortality with the use of multivariable Cox models. RESULTS: The mean age at enrollment was 68.6+/-9.6 years. Few patients met American Heart Association criteria for ideal activity (11% ideal, 14% intermediate, 75% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients (397 HF hospitalizations, 222 cardiovascular deaths, and 6 aborted cardiac arrests). Compared with those with ideal baseline PA, poor and intermediate baseline PA was associated with a greater risk of the primary outcome (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.28-3.28; HR, 1.95; 95% CI, 1.15-3.33, respectively), HF hospitalization (HR, 1.93; 95% CI, 1.16-3.22; HR, 1.84; 95% CI, 1.02-3.31), cardiovascular mortality (HR, 4.36; 95% CI, 1.37-13.83; HR, 4.05; 95% CI, 1.17-14.04), and all-cause mortality (HR, 2.95; 95% CI, 1.44-6.02; HR, 2.05; 95% CI, 0.90-4.67) after multivariable adjustment for potential confounders. CONCLUSIONS: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302. PMID- 28637882 TI - FLT3 dancing on the stem cell. AB - Whether or not FLT3 mutations are present and expressed within a leukemic hematopoietic stem cell has engendered some controversy. New evidence has now been presented on this issue that could change the way we manage the disease in the future. PMID- 28637885 TI - In This Issue of Diabetes Care. PMID- 28637883 TI - Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3 ITD-induced myeloproliferation. AB - Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD-driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology. PMID- 28637884 TI - Vaccination establishes clonal relatives of germinal center T cells in the blood of humans. AB - Germinal center T follicular helper cells (GCTfh) in lymphatic tissue are critical for B cell differentiation and protective antibody induction, but whether GCTfh establish clonal derivatives as circulating memory T cells is less understood. Here, we used markers expressed on GCTfh, CXCR5, PD1, and ICOS, to identify potential circulating CXCR5+CD4+ Tfh-like cells (cTfh) in humans, and investigated their functional phenotypes, diversity, and ontogeny in paired donor blood and tonsils, and in blood after vaccination. Based on T cell receptor repertoire analysis, we found that PD-1-expressing cTfh and tonsillar GCTfh cells were clonally related. Furthermore, an activated, antigen-specific PD1+ICOS+ cTfh subset clonally expanded after booster immunization whose frequencies correlated with vaccine-specific serum IgG; these phenotypically resembled GCTfh, and were clonally related to a resting PD1+ICOS- CD4+ memory T cell subset. Thus, we postulate that vaccination establishes clonal relatives of GCTfh within the circulating memory CD4+CXCR5+PD1+ T cell pool that expand upon reencounter of their cognate antigen. PMID- 28637886 TI - Cardiovascular Disease and Type 2 Diabetes: Has the Dawn of a New Era Arrived? AB - Hyperglycemia is the major risk factor for microvascular complications in patients with type 2 diabetes (T2D). However, cardiovascular disease (CVD) is the principal cause of death, and lowering HbA1c has only a modest effect on reducing CVD risk and mortality. The recently published LEADER and SUSTAIN-6 trials demonstrate that, in T2D patients with high CVD risk, the glucagon-like peptide 1 receptor agonists liraglutide and semaglutide reduce the primary major adverse cardiac events (MACE) end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) by 13% and 24%, respectively. The EMPA-REG OUTCOME, IRIS (subjects without diabetes), and PROactive (second principal end point) studies also demonstrated a significant reduction in cardiovascular events in T2D patients treated with empagliflozin and pioglitazone. However, the benefit of these four antidiabetes agents (liraglutide, semaglutide, empagliflozin, and pioglitazone) on the three individual MACE end points differed, suggesting that different underlying mechanisms were responsible for the reduction in cardiovascular events. Since liraglutide, semaglutide, pioglitazone, and empagliflozin similarly lower the plasma glucose concentration but appear to reduce CVD risk by different mechanisms, there emerges the intriguing possibility that, if used in combination, the effects of these antidiabetes agents may be additive or even multiplicative with regard to cardiovascular benefit. PMID- 28637887 TI - Mitigating Cardiovascular Risk in Type 2 Diabetes With Antidiabetes Drugs: A Review of Principal Cardiovascular Outcome Results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 Trials. AB - The U.S. Food and Drug Administration (FDA) issued a diabetes guidance in 2008 mandating that all new antidiabetes drugs rule out excess cardiovascular (CV) risk, defined as an upper bound of the two-sided 95% CI for major adverse CV events (MACE) of less than 1.80 preapproval and 1.30 postapproval. Over 25 large, prospective, randomized, controlled clinical trials involving nearly 195,000 subjects thus far have been completed or are ongoing in accordance with this guidance. The results of seven trials have been presented so far-three with dipeptidyl peptidase 4 inhibitors, one with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and three with glucagon-like peptide 1 receptor agonists (GLP 1 RA). While all seven trials showed noninferiority in the rate of MACE with the use of these agents compared with placebo, three of them revealed CV benefits. Treatment with empagliflozin (an SGLT2 inhibitor) and treatment with liraglutide (a GLP-1 RA) both significantly reduced the risk of MACE, mortality from CV causes, and mortality from any cause when compared with placebo. Treatment with semaglutide, another GLP-1 RA, showed a significantly lower rate of MACE but not mortality from CV or any cause compared with placebo. In all of the trials, the effects of treatment on outcomes were out of proportion to the small differences in glycemic control levels, suggesting that the effects observed were likely unrelated to differences in the glucose-lowering efficacy. Overall, the results of these trials yield a favorable benefit-risk balance for these therapies in mitigating CV risk in patients with type 2 diabetes. More research is needed to elucidate the underlying mechanisms and confirm whether the CV benefits are a class effect or whether the benefits persist in patients without established CV disease or are evident even in patients without diabetes. PMID- 28637888 TI - Maternal BMI and Glycemia Impact the Fetal Metabolome. AB - OBJECTIVE: We used targeted metabolomics to determine associations of maternal BMI and glucose levels with cord blood metabolites and associations of cord blood metabolites with newborn birth weight and adiposity in mother-offspring dyads. RESEARCH DESIGN AND METHODS: Targeted metabolomic assays were performed on cord blood serum samples from European ancestry, Afro-Caribbean, Thai, and Mexican American newborns (400 from each ancestry group) whose mothers participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and who had anthropometric measurements at birth. RESULTS: Meta-analysis across the four cohorts demonstrated significant correlation of all cord blood metabolites analyzed with maternal fasting levels of the same metabolites at ~28 weeks' gestation except for triglycerides, asparagine/aspartate, arginine, and the acylcarnitine C14-OH/C12-DC. Meta-analyses also demonstrated that maternal BMI with or without adjustment for maternal glucose was associated with cord blood metabolites including the branched-chain amino acids and their metabolites as well as phenylalanine. One-hour but not fasting glucose was associated with cord blood 3-hydroxybutyrate and its carnitine ester, a medium-chain acylcarnitine, and glycerol. A number of cord blood metabolites were associated with newborn birth weight and sum of skinfolds, including a negative association of triglycerides and positive association of 3-hydroxybutyrate, its carnitine ester, and serine with both newborn outcomes. CONCLUSIONS: Maternal BMI and glycemia are associated with different components of the newborn metabolome, consistent with their independent effects on newborn size at birth. Maternal BMI is associated with a newborn metabolic signature characteristic of insulin resistance and risk of type 2 diabetes in adults. PMID- 28637889 TI - Targeted Metabolomics Demonstrates Distinct and Overlapping Maternal Metabolites Associated With BMI, Glucose, and Insulin Sensitivity During Pregnancy Across Four Ancestry Groups. AB - OBJECTIVE: We used targeted metabolomics in pregnant mothers to compare maternal metabolite associations with maternal BMI, glycemia, and insulin sensitivity. RESEARCH DESIGN AND METHODS: Targeted metabolomic assays of clinical metabolites, amino acids, and acylcarnitines were performed on fasting and 1-h postglucose serum samples from European ancestry, Afro-Caribbean, Thai, and Mexican American mothers (400 from each ancestry group) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and underwent an oral glucose tolerance test at ~28 weeks gestation. RESULTS: K-means clustering, which identified patterns of metabolite levels across ancestry groups, demonstrated that, at both fasting and 1-h, levels of the majority of metabolites were similar across ancestry groups. Meta-analyses demonstrated association of a broad array of fasting and 1-h metabolites, including lipids and amino acids and their metabolites, with maternal BMI, glucose levels, and insulin sensitivity before and after adjustment for the different phenotypes. At fasting and 1 h, a mix of metabolites was identified that were common across phenotypes or associated with only one or two phenotypes. Partial correlation estimates, which allowed comparison of the strength of association of different metabolites with maternal phenotypes, demonstrated that metabolites most strongly associated with different phenotypes included some that were common across as well as unique to each phenotype. CONCLUSIONS: Maternal BMI and glycemia have metabolic signatures that are both shared and unique to each phenotype. These signatures largely remain consistent across different ancestry groups and may contribute to the common and independent effects of these two phenotypes on adverse pregnancy outcomes. PMID- 28637891 TI - Comment on Rubino et al. Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations. Diabetes Care 2016;39:861-877. PMID- 28637892 TI - Comment on American Diabetes Association. Standards of Medical Care in Diabetes 2017. Diabetes Care 2017;40(Suppl. 1):S1-S135. PMID- 28637893 TI - Response to Comment on American Diabetes Association. Standards of Medical Care in Diabetes-2017. Diabetes Care 2017;40(Suppl. 1):S1-S135. PMID- 28637894 TI - Deep insight into neutrophil trafficking in various organs. AB - Neutrophils are professional phagocytes that constitute the first line of defense in humans. The primary function of neutrophils is to eliminate invading pathogens through oxidative and nonoxidative mechanisms. Because neutrophils rapidly migrate into inflammatory foci via diapedesis and chemotaxis, neutrophil recruitment has long been considered a hallmark of inflammation. Recent advances in intravital microscopic technologies using animal model systems have enabled researchers to directly visualize neutrophil trafficking. Consequently, the specific mechanisms of neutrophil transmigration have been identified, and even the reverse migration of neutrophils can be verified visually. Moreover, the detailed phenomena of neutrophil infiltration into various organs, such as the liver, lymphoid organs, and CNS have been identified. This progress in the study of neutrophil migration from the blood vessels to organs results in a deeper understanding of these immune cells' motility and morphology, which are closely related to the spatiotemporal regulation of the overall immune response. In this review, we discuss our current understanding of neutrophil trafficking in various organs. PMID- 28637895 TI - CD4+CD8beta+ double-positive T cells in skin-draining lymph nodes respond to inflammatory signals from the skin. AB - CD4+CD8+ double-positive (DP), mature, peripheral T cells are readily detectable in a variety of species and tissues. Despite a common association with autoimmune and malignant skin disorders, however, little is understood about their role or function. Herein, we show that DP T cells are readily detectable in the blood, spleen, and peripheral lymph nodes of naive C57BL/6 mice. DP T cells were also present in Jalpha18-/- and CD1d-/- mice, indicating that these cells are not NK-T cells. After skin administration of CASAC adjuvant, but not Quil A adjuvant, both total DP T cells and skin-infiltrating DP T cells increased in number. We explored the possibility that DP T cells could represent aggregates between CD4+ and CD8+ single-positive T cells and found strong evidence that a large proportion of apparent DP T cells were indeed aggregates. However, the existence of true CD4+CD8+ DP T cells was confirmed by Amnis ImageStream (Millipore Sigma, Billerica, MA, USA) imaging. Multiple rounds of FACS sorting separated true DP cells from aggregates and indicated that conventional analyses may lead to ~10 fold overestimation of DP T cell numbers. The high degree of aggregate contamination and overestimation of DP abundance using conventional analysis techniques may explain discrepancies reported in the literature for DP T cell origin, phenotype, and function. PMID- 28637896 TI - Technical Advance: New in vitro method for assaying the migration of primary B cells using an endothelial monolayer as substrate. AB - Migration of B cells supports their development and recruitment into functional niches. Therefore, defining factors that control B cell migration will lead to a better understanding of adaptive immunity. In vitro cell migration assays with B cells have been limited by poor adhesion of cells to glass coated with adhesion molecules. We have developed a technique using monolayers of endothelial cells as the substrate for B cell migration and used this technique to establish a robust in vitro assay for B cell migration. We use TNF-alpha to up-regulate surface expression of the adhesion molecule VCAM-1 on endothelial cells. The ligand VLA-4 is expressed on B cells, allowing them to interact with the endothelial monolayer and migrate on its surface. We tested our new method by examining the role of L plastin (LPL), an F-actin-bundling protein, in B cell migration. LPL-deficient (LPL-/-) B cells displayed decreased speed and increased arrest coefficient compared with wild-type (WT) B cells, following chemokine stimulation. However, the confinement ratios for WT and LPL-/- B cells were similar. Thus, we demonstrate how the use of endothelial monolayers as a substrate will support future interrogation of molecular pathways essential to B cell migration. PMID- 28637897 TI - Heritability of resting heart rate and association with mortality in middle-aged and elderly twins. AB - OBJECTIVE: Resting heart rate (RHR) possibly has a hereditary component and is associated with longevity. We used the classical biometric twin study design to investigate the heritability of RHR in a population of middle-aged and elderly twins and, furthermore, studied the association between RHR and mortality. METHODS: In total, 4282 twins without cardiovascular disease were included from the Danish Twin Registry, hereof 1233 twin pairs and 1816 'single twins' (twins with a non-participating co-twin); mean age 61.7 (SD 11.1) years; 1334 (31.2%) twins died during median 16.3 (IQR 13.8-16.5) years of follow-up assessed through Danish national registers. RHR was assessed by palpating radial pulse. RESULTS: Within pair correlations for RHR adjusted for sex and age were 0.23 (95% CI 0.14 to 0.32) and 0.10 (0.03 to 0.17) for RHR in monozygotic (MZ) and dizygotic (DZ) twin pairs, respectively. Overall, heritability estimates were 0.23 (95% CI 0.15 to 0.30); 0.27 (0.15 to 0.38) for males and 0.17 (0.06 to 0.28) for females. In multivariable models adjusting for age, gender, body mass index, diabetes, hypertension, pulmonary function, smoking, physical activity and zygosity, RHR was significantly associated with mortality (eg, RHR >90 vs 61-70 beats per min: all-cause HR 1.56 (95% CI 1.21 to 2.03); cardiovascular 2.19 (1.30 to 3.67). Intrapair twin comparison revealed that the twin with the higher RHR was significantly more likely to die first and the probability increased with increase in intrapair difference in RHR. CONCLUSIONS: RHR is a trait with a genetic influence in middle-aged and elderly twins free of cardiovascular disease. RHR is independently associated with longevity even when familial factors are controlled for in a twin design. PMID- 28637898 TI - Activation of Complement by Pigment Epithelium-Derived Factor in Rheumatoid Arthritis. AB - The aim of this study was to identify molecules that trigger complement activation in rheumatic joints. C4d, the final cleavage product of C4 activation, is found in the diseased joint and can bind covalently to complement-activating molecules. By using a highly specific Ab against a cleavage neoepitope in C4d, several molecules that were specifically bound to C4d were identified from pooled synovial fluid (SF) from four rheumatoid arthritis (RA) patients. One of these molecules, pigment epithelium-derived factor (PEDF), is a broadly expressed multifunctional member of the serine proteinase inhibitor family. Using ELISA, we confirmed the presence of various amounts of complexes between PEDF and C4d in the SF from 30 RA patients, whereas none were detected in SF from control subjects. Correlation analyses suggested that, in arthritis patients, C4d-PEDF complexes found in sera arise from the joints, as well as from other tissues, and levels of the complexes did not differ in sera of RA patients and healthy controls. When immobilized, recombinant PEDF expressed in eukaryotic cells activated the classical complement pathway but not the alternative or lectin pathways. C1q protein was demonstrated to bind immobilized PEDF, and PEDF was shown to bind to immobilized C1q, in particular its head regions, which are known to interact with other activators of the classical pathway. Our results call for further investigation into the role of PEDF in inflammatory processes in the joint, which, in combination with classical complement activation, appears to be part of a (patho-)physiologic response. PMID- 28637900 TI - Activation of Mouse Tcrb: Uncoupling RUNX1 Function from Its Cooperative Binding with ETS1. AB - T lineage commitment requires the coordination of key transcription factors (TFs) in multipotent progenitors that transition them away from other lineages and cement T cell identity. Two important TFs for the multipotent progenitors to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the TCR beta (Tcrb) locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Ebeta, which harbors two RUNX-ETS composite sites. An outstanding issue in understanding T cell gene expression programs is whether RUNX1 and ETS1 have independent functions in enhancer activation that can be dissected from cooperative binding. We now show that RUNX1 is sufficient to activate the endogenous mouse Ebeta element and its neighboring 25 kb region by independently tethering this TF without coincidental ETS1 binding. Moreover, RUNX1 is sufficient for long-range promoter-Ebeta looping, nucleosome clearance, and robust transcription throughout the Tcrb recombination center, spanning both DbetaJbeta clusters. We also find that a RUNX1 domain, termed the negative regulatory domain for DNA binding, can compensate for the loss of ETS1 binding at adjacent sites. Thus, we have defined independent roles for RUNX1 in the activation of a T cell developmental enhancer, as well as its ability to mediate specific changes in chromatin landscapes that accompany long-range induction of recombination center promoters. PMID- 28637899 TI - Dietary Salt Exacerbates Experimental Colitis. AB - The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10 deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10-deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD. PMID- 28637901 TI - Caveolin-1 Influences LFA-1 Redistribution upon TCR Stimulation in CD8 T Cells. AB - TCR stimulation by peptide-MHC complexes on APCs requires precise reorganization of molecules into the area of cellular contact to form an immunological synapse from where T cell signaling is initiated. Caveolin (Cav)1, a widely expressed transmembrane protein, is involved in the regulation of membrane composition, cellular polarity and trafficking, and the organization of signal transduction pathways. The presence of Cav1 protein in T cells was identified only recently, and its function in this context is not well understood. We show that Cav1 knockout CD8 T cells have a reduction in membrane cholesterol and sphingomyelin, and upon TCR triggering they exhibit altered morphology and polarity, with reduced effector function compared with Cav1 wild-type CD8 T cells. In particular, redistribution of the beta2 integrin LFA-1 to the immunological synapse is compromised in Cav1-knockout T cells, as is the ability of LFA-1 to form high-avidity interactions with ICAM-1. Our results identify a role for Cav1 in membrane organization and beta2 integrin function in primary CD8 T cells. PMID- 28637902 TI - TGF-beta1 Suppresses IL-33-Induced Mast Cell Function. AB - TGF-beta1 is involved in many pathological conditions, including autoimmune disorders, cancer, and cardiovascular and allergic diseases. We have previously found that TGF-beta1 can suppress IgE-mediated mast cell activation of human and mouse mast cells. IL-33 is a member of the IL-1 family capable of inducing mast cell responses and enhancing IgE-mediated activation. In this study, we investigated the effects of TGF-beta on IL-33-mediated mast cell activation. Bone marrow-derived mast cells cultured in TGF-beta1, beta2, or beta3 showed reduced IL-33-mediated production of TNF, IL-6, IL-13, and MCP-1 in a concentration dependent manner. TGF-beta1 inhibited IL-33-mediated Akt and ERK phosphorylation as well as NF-kappaB- and AP-1-mediated transcription. These effects were functionally important, as TGF-beta1 injection suppressed IL-33-induced systemic cytokines in vivo and inhibited IL-33-mediated cytokine release from human mast cells. TGF-beta1 also suppressed the combined effects of IL-33 and IgE-mediated activation on mouse and human mast cells. The role of IL-33 in the pathogenesis of allergic diseases is incompletely understood. These findings, consistent with our previously reported effects of TGF-beta1 on IgE-mediated activation, demonstrate that TGF-beta1 can provide broad inhibitory signals to activated mast cells. PMID- 28637904 TI - IFN-gamma-Expressing Th17 Cells Are Required for Development of Severe Ocular Surface Autoimmunity. AB - Th17 cells are critical effectors mediating the ocular surface autoimmunity in dry eye disease (DED). Increased IFN-gamma has also been implicated in DED; however, it remains unclear to what extent Th1 cells contribute to DED pathogenesis. In this study, we investigated the cellular source of IFN-gamma and assessed its contribution to corneal epitheliopathy in DED mice. We discovered a significant IL-17A+IFN-gamma+ (Th17/1) population and determined that these cells are derived from Th17 precursors. Adoptive transfer of Th17/1, but not Th1, cells confers the disease to naive recipients as effectively as do Th17 cells alone. DED-induced IL-12 and IL-23 are required for in vivo transition of pathogenic Th17 cells to IFN-gamma producers. Furthermore, using IFN-gamma-deficient Th17 cells, we demonstrate the disease-amplifying role of Th17-derived IFN-gamma in DED pathogenesis. These results clearly demonstrate that Th17 cells mediate ocular surface autoimmunity through both IL-17A and IFN-gamma. PMID- 28637903 TI - Involvement of NK Cells in IL-28B-Mediated Immunity against Influenza Virus Infection. AB - IL-28B is a member of the newly discovered type III IFN family and exhibits unique antiviral properties compared with other family members. NK cells play a critical role in defending against viruses; however, little is known about the role of IL-28B in NK cell function. In a mouse model of influenza A virus (mouse adapted influenza A/PR/8/34 strain) infection, long-term overexpression of IL-28B induced by hepatocyte-specific gene delivery exerted a strong antiviral effect in the presence of NK cells. In IL-28B-overexpressing wild-type mice, the percentages and absolute numbers of NK cells in the spleen, liver, and lung were markedly increased, with higher proliferation and accelerated NK cell maturation based on phenotypes staining with CD11b and CD27 or CD11b and KLRG1. Furthermore, the effect of IL-28B on NK cells was macrophage dependent, as confirmed in an in vitro coculture assay and in in vivo macrophage- or alveolar macrophage-depletion experiments. Transwell studies demonstrated that CFSE-labeled NK cell proliferation was driven, in a dose-dependent manner, by unknown soluble factor(s) secreted by IL-28B-stimulated alveolar macrophages, without requiring direct cell-cell contact. An understanding of the NK cell-promoting features of IL-28B will facilitate future clinical application of this cytokine. PMID- 28637905 TI - p120-Catenin Downregulation and PIK3CA Mutations Cooperate to Induce Invasion through MMP1 in HNSCC. AB - Despite recent improvements in treatment for head and neck squamous cell carcinoma (HNSCC), half of all patients with a regional or advanced disease will die within 5 years from diagnosis. Therefore, identification of mechanisms driving the aggressive behavior of HNSCC is of utmost importance. Because p120 catenin (CTNND1/P120CTN) downregulation and PIK3CA mutations are commonly found in HNSCC, the objective of this study was to identify their impact on fundamental processes of metastasis, specifically, migration and invasion. Furthermore, this study aimed to identify the key effector proteins regulated by P120CTN downregulation and PIK3CA mutations. Studies using oral keratinocytes demonstrated that P120CTN downregulation and PIK3CA mutations increased migration and invasion. In addition, P120CTN downregulation and PIK3CA mutations resulted in elevated matrix metallopeptidase 1 (MMP1) levels. Inhibition of MMP1 resulted in decreased invasion, suggesting that MMP1 plays a critical role in HNSCC invasion. Moreover, analysis of HNSCC patient specimens from The Cancer Genome Atlas confirmed these findings. Tumors with low P120CTN and PI3K pathway mutations have higher levels of MMP1 compared to tumors with high P120CTN and no PI3K pathway mutations. In conclusion, this study demonstrates that P120CTN downregulation and PIK3CA mutations promote MMP1-driven invasion, providing a potential novel target for limiting metastasis in HNSCC.Implications: Because of its role in invasion, MMP1 represents a novel, potential target for limiting metastasis in a subset of HNSCCs with P120CTN downregulation and PIK3CA mutations. Mol Cancer Res; 15(10); 1398-409. (c)2017 AACR. PMID- 28637906 TI - Anogenital warts and other HPV-associated anogenital lesions in the HIV-positive patient: a systematic review and meta-analysis of the efficacy and safety of interventions assessed in controlled clinical trials. AB - OBJECTIVES: Anogenital warts (AGW, condylomata acuminata) and intraepithelial neoplasia (IEN) do not only impact health and social well-being, they are also associated with considerable costs for the healthcare systems. Immunocompromised and HIV-positive patients carry the highest epidemiological burden of human papillomavirus (HPV) infection and comprise a population specifically susceptible to treatment failures and recurrences. This systematic review aimed at identifying and appraising the available evidence from controlled studies of interventions for the treatment of AGW and IEN in immunocompromised patients. METHODS: We conducted a comprehensive literature search. The Cochrane Collaboration's tool was used to assess risk of bias in included studies. Our confidence in the (pooled) effect-estimates was evaluated according to the Grading of Recommendations Assessment, Development and Evaluation approach. All evaluations were based on data independently extracted by two review authors. RESULTS: Nine randomised controlled trials and two controlled studies were eligible, investigating external AGW, intra-anal and/or vaginal warts, and intra anal and/or perianal IEN. The identified studies assessed imiquimod, cidofovir, fluorouracil, electrocautery, systemic interferon-alpha and interferon-beta, and the combination of intralesional interferon-alpha and podophyllin. Four studies combined an ablational intervention with either imiquimod, cidofovir, intralesional or systemic interferon-alpha. One study investigated an experimental therapeutic vaccination (HPV 16 E7) at different concentrations. CONCLUSIONS: The quality of the evidence ranged from 'very low' to 'moderate' and was limited by the often small samples. Evidence was available for the efficacy of electrocautery for intra-anal IEN, and imiquimod cream for external AGW. Some further interventions should be subjected to investigations in larger samples. No data on some interventions established for the treatment of AGW in immunocompetent patients such as podophyllotoxin, sinecatechins, laser ablation or trichloroacetate were available. Future trials should address these gaps and include relevant patient-reported outcomes such as health-related quality of life. PMID- 28637907 TI - Validation of a New Web Application for Identification of Fungi by Use of Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. AB - Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry has emerged as a reliable technique to identify molds involved in human diseases, including dermatophytes, provided that exhaustive reference databases are available. This study assessed an online identification application based on original algorithms and an extensive in-house reference database comprising 11,851 spectra (938 fungal species and 246 fungal genera). Validation criteria were established using an initial panel of 422 molds, including dermatophytes, previously identified via DNA sequencing (126 species). The application was further assessed using a separate panel of 501 cultured clinical isolates (88 mold taxa including dermatophytes) derived from five hospital laboratories. A total of 438 (87.35%) isolates were correctly identified at the species level, while 26 (5.22%) were assigned to the correct genus but the wrong species and 37 (7.43%) were not identified, since the defined threshold of 20 was not reached. The use of the Bruker Daltonics database included in the MALDI Biotyper software resulted in a much higher rate of unidentified isolates (39.76 and 74.30% using the score thresholds 1.7 and 2.0, respectively). Moreover, the identification delay of the online application remained compatible with real-time online queries (0.15 s per spectrum), and the application was faster than identifications using the MALDI Biotyper software. This is the first study to assess an online identification system based on MALDI-TOF spectrum analysis. We have successfully applied this approach to identify molds, including dermatophytes, for which diversity is insufficiently represented in commercial databases. This free-access application is available to medical mycologists to improve fungal identification. PMID- 28637908 TI - Rapid Filter-Based Detection and Culture of Burkholderia pseudomallei from Small Volumes of Urine. AB - Clinical outcomes of melioidosis patients improve when the infecting agent, Burkholderia pseudomallei, is rapidly detected and identified by laboratory testing. Detection of B. pseudomallei DNA or recovery of the pathogen by culture from urine can support a diagnosis of melioidosis and guide patient care. Two new methods, designated filter-capture DNA isolation (FCDI) and filter cellular recovery (FCR), were developed to increase the sensitivity of detection and recovery of viable B. pseudomallei cells from small volumes (0.45 ml) of urine. DNA from eight strains of B. pseudomallei that were spiked into synthetic urine at low concentrations (1 * 102 CFU/ml) was detected in FCDI cell lysates using real-time PCR with greater consistency than with preparations from a QIAamp DNA Blood minikit. The FCR method showed greater B. pseudomallei detection sensitivity than conventional urine culture methods and resulted in typical colony growth at 24 h from as few as 1 * 102 CFU/ml. In addition, the FCR method does not rely on precipitation of a urine pellet by centrifugation and requires a smaller volume of urine. The FCDI and FCR methods described here could improve time-to-results and decrease the number of negative B. pseudomallei reports that are currently observed from urine culture as a consequence of samples containing low or variable bacterial cell concentrations. PMID- 28637909 TI - Rapid Differentiation of Haemophilus influenzae and Haemophilus haemolyticus by Use of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry with ClinProTools Mass Spectrum Analysis. AB - Haemophilus influenzae is associated with severe invasive disease, while Haemophilus haemolyticus is considered part of the commensal flora in the human respiratory tract. Although the addition of a custom mass spectrum library into the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system could improve identification of these two species, the establishment of such a custom database is technically complicated and requires a large amount of resources, which most clinical laboratories cannot afford. In this study, we developed a mass spectrum analysis model with 7 mass peak biomarkers for the identification of H. influenzae and H. haemolyticus using the ClinProTools software. We evaluated the diagnostic performance of this model using 408 H. influenzae and H. haemolyticus isolates from clinical respiratory specimens from 363 hospitalized patients and compared the identification results with those obtained with the Bruker IVD MALDI Biotyper. The IVD MALDI Biotyper identified only 86.9% of H. influenzae (311/358) and 98.0% of H. haemolyticus (49/50) clinical isolates to the species level. In comparison, the ClinProTools mass spectrum model could identify 100% of H. influenzae (358/358) and H. haemolyticus (50/50) clinical strains to the species level and significantly improved the species identification rate (McNemar's test, P < 0.0001). In conclusion, the use of ClinProTools demonstrated an alternative way for users lacking special expertise in mass spectrometry to handle closely related bacterial species when the proprietary spectrum library failed. This approach should be useful for the differentiation of other closely related bacterial species. PMID- 28637910 TI - Excellent Diagnostic Characteristics for Ultrafast Gene Profiling of DEFA1-IL1B LTF in Detection of Prosthetic Joint Infections. AB - The timely and exact diagnosis of prosthetic joint infection (PJI) is crucial for surgical decision-making. Intraoperatively, delivery of the result within an hour is required. Alpha-defensin lateral immunoassay of joint fluid (JF) is precise for the intraoperative exclusion of PJI; however, for patients with a limited amount of JF and/or in cases where the JF is bloody, this test is unhelpful. Important information is hidden in periprosthetic tissues that may much better reflect the current status of implant pathology. We therefore investigated the utility of the gene expression patterns of 12 candidate genes (TLR1, -2, -4, -6, and 10, DEFA1, LTF, IL1B, BPI, CRP, IFNG, and DEFB4A) previously associated with infection for detection of PJI in periprosthetic tissues of patients with total joint arthroplasty (TJA) (n = 76) reoperated for PJI (n = 38) or aseptic failure (n = 38), using the ultrafast quantitative reverse transcription-PCR (RT-PCR) Xxpress system (BJS Biotechnologies Ltd.). Advanced data-mining algorithms were applied for data analysis. For PJI, we detected elevated mRNA expression levels of DEFA1 (P < 0.0001), IL1B (P < 0.0001), LTF (P < 0.0001), TLR1 (P = 0.02), and BPI (P = 0.01) in comparison to those in tissues from aseptic cases. A feature selection algorithm revealed that the DEFA1-IL1B-LTF pattern was the most appropriate for detection/exclusion of PJI, achieving 94.5% sensitivity and 95.7% specificity, with likelihood ratios (LRs) for positive and negative results of 16.3 and 0.06, respectively. Taken together, the results show that DEFA1-IL1B-LTF gene expression detection by use of ultrafast qRT-PCR linked to an electronic calculator allows detection of patients with a high probability of PJI within 45 min after sampling. Further testing on a larger cohort of patients is needed. PMID- 28637911 TI - Discovery of Specific Antigens That Can Predict Microfilarial Intensity in Loa loa Infection. AB - Antigen-based immunoassays are currently needed for point-of-care quantification of Loa loa microfilariae (mf). Coupling transcriptomic approaches with bioinformatic analysis, we have identified 11 specific putative proteins (coding mRNAs) with potential utility as biomarkers of patent (mf + ) L. loa infection. We successfully developed antigen capture immunoassays to quantify 2 (LOAG_14221 and LOAG_15846) of these proteins in individual plasma/serum samples. Of the 2 quantifiable circulating biomarkers, LOAG_14221 showed the highest degree of specificity, particularly with a monoclonal antibody-based immunoassay. Moreover, the levels of LOAG_14221 in L. loa mf + patients were positively correlated to the mf densities in the corresponding blood samples (r = 0.53 and P = 0.008 for polyclonal assay; r = 0.54 and P = 0.004 for monoclonal assay). Thus, LOAG_14221 is a very promising biomarker that will be exploited in a quantitative point-of care immunoassay for determination of L. loa mf densities. PMID- 28637912 TI - Parallel Evaluation of the MALDI Sepsityper and Verigene BC-GN Assays for Rapid Identification of Gram-Negative Bacilli from Positive Blood Cultures. AB - Rapid identification of microorganisms from positive blood cultures has improved clinical management and antimicrobial stewardship. The advent of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has reduced the time to identification of cultured isolates and is now often the definitive method used in the clinical microbiology laboratory. The commercial in vitro diagnostic MALDI Sepsityper (Sepsityper) kit has the potential for standardization and clinical routine use for the rapid identification of a broad range of bacteria from positive blood cultures. In this study, we performed a parallel evaluation of the Sepsityper (Bruker Daltonics, Billerica, MA) and the Verigene BC-GN (BC-GN) assays (Nanosphere, Inc., Northfield, IL) for the identification of Gram-negative bacilli. A total of 210 Bactec bottles demonstrating Gram-negative bacilli were prospectively enrolled for this study. Among these, 200 monomicrobial cultures were included in the comparative analysis. For monomicrobial cultures, the BC-GN detected 85% (170/200) compared to that detected by routine culture while the Sepsityper detected 94% (188/200) and 91% (181/200) to the genus and species levels, respectively. Comparable positive percentage agreement and negative percentage agreement were observed between the Sepsityper (96.5% and 98.8%, respectively) and the BC-GN (99.4% and 99.8%, respectively) when only (n = 170, 85%) organisms targeted by the latter test were included in the analysis. In conclusion, the two methods evaluated in this study showed excellent performance characteristics for the identification of Gram-negative bacilli commonly isolated from blood cultures. The Sepsityper showed a broader identification range capability that may further improve clinical management and antimicrobial stewardship in patients with less frequent Gram-negative bacilli bloodstream infections. PMID- 28637913 TI - Predicting green: really radical (plant) predictive processing. AB - In this article we account for the way plants respond to salient features of their environment under the free-energy principle for biological systems. Biological self-organization amounts to the minimization of surprise over time. We posit that any self-organizing system must embody a generative model whose predictions ensure that (expected) free energy is minimized through action. Plants respond in a fast, and yet coordinated manner, to environmental contingencies. They pro-actively sample their local environment to elicit information with an adaptive value. Our main thesis is that plant behaviour takes place by way of a process (active inference) that predicts the environmental sources of sensory stimulation. This principle, we argue, endows plants with a form of perception that underwrites purposeful, anticipatory behaviour. The aim of the article is to assess the prospects of a radical predictive processing story that would follow naturally from the free-energy principle for biological systems; an approach that may ultimately bear upon our understanding of life and cognition more broadly. PMID- 28637914 TI - Soiled adhesive pads shear clean by slipping: a robust self-cleaning mechanism in climbing beetles. AB - Animals using adhesive pads to climb smooth surfaces face the problem of keeping their pads clean and functional. Here, a self-cleaning mechanism is proposed whereby soiled feet would slip on the surface due to a lack of adhesion but shed particles in return. Our study offers an in situ quantification of self-cleaning performance in fibrillar adhesives, using the dock beetle as a model organism. After beetles soiled their pads by stepping into patches of spherical beads, we found that their gait was significantly affected. Specifically, soiled pads slipped 10 times further than clean pads, with more particles deposited for longer slips. Like previous studies, we found that particle size affected cleaning performance. Large (45 MUm) beads were removed most effectively, followed by medium (10 MUm) and small (1 MUm). Consistent with our results from climbing beetles, force measurements on freshly severed legs revealed larger detachment forces of medium particles from adhesive pads compared to a flat surface, possibly due to interlocking between fibres. By contrast, dock leaves showed an overall larger affinity to the beads and thus reduced the need for cleaning. Self-cleaning through slippage provides a mechanism robust to particle size and may inspire solutions for artificial adhesives. PMID- 28637916 TI - Model-based analysis of an outbreak of bubonic plague in Cairo in 1801. AB - Bubonic plague has caused three deadly pandemics in human history: from the mid sixth to mid-eighth century, from the mid-fourteenth to the mid-eighteenth century and from the end of the nineteenth until the mid-twentieth century. Between the second and the third pandemics, plague was causing sporadic outbreaks in only a few countries in the Middle East, including Egypt. Little is known about this historical phase of plague, even though it represents the temporal, geographical and phylogenetic transition between the second and third pandemics. Here we analysed in detail an outbreak of plague that took place in Cairo in 1801, and for which epidemiological data are uniquely available thanks to the presence of medical officers accompanying the Napoleonic expedition into Egypt at that time. We propose a new stochastic model describing how bubonic plague outbreaks unfold in both rat and human populations, and perform Bayesian inference under this model using a particle Markov chain Monte Carlo. Rat carcasses were estimated to be infectious for approximately 4 days after death, which is in good agreement with local observations on the survival of infectious rat fleas. The estimated transmission rate between rats implies a basic reproduction number R0 of approximately 3, causing the collapse of the rat population in approximately 100 days. Simultaneously, the force of infection exerted by each infected rat carcass onto the human population increases progressively by more than an order of magnitude. We also considered human-to human transmission via pneumonic plague or human specific vectors, but found this route to account for only a small fraction of cases and to be significantly below the threshold required to sustain an outbreak. PMID- 28637917 TI - Degree heterogeneity and stability of ecological networks. AB - A classic measure of ecological stability describes the tendency of a community to return to equilibrium after small perturbations. While many advances show how the network architecture of these communities severely constrains such tendencies, one of the most fundamental properties of network structure, i.e. degree heterogeneity-the variability of the number of links associated with each species, deserves further study. Here we show that the effects of degree heterogeneity on stability vary with different types of interspecific interactions. Degree heterogeneity consistently destabilizes ecological networks with both competitive and mutualistic interactions, while its effects on networks of predator-prey interactions such as food webs depend on prey contiguity, i.e. the extent to which the species consume an unbroken sequence of prey in community niche space. Increasing degree heterogeneity tends to stabilize food webs except those with the highest prey contiguity. These findings help explain why food webs are highly but not completely interval and, more broadly, deepen our understanding of the stability of complex ecological networks. PMID- 28637918 TI - Direct enzymatic bioelectrocatalysis: differentiating between myth and reality. AB - Enzymatic bioelectrocatalysis is being increasingly exploited to better understand oxidoreductase enzymes, to develop minimalistic yet specific biosensor platforms, and to develop alternative energy conversion devices and bioelectrosynthetic devices for the production of energy and/or important chemical commodities. In some cases, these enzymes are able to electronically communicate with an appropriately designed electrode surface without the requirement of an electron mediator to shuttle electrons between the enzyme and electrode. This phenomenon has been termed direct electron transfer or direct bioelectrocatalysis. While many thorough studies have extensively investigated this fascinating feat, it is sometimes difficult to differentiate desirable enzymatic bioelectrocatalysis from electrocatalysis deriving from inactivated enzyme that may have also released its catalytic cofactor. This article will review direct bioelectrocatalysis of several oxidoreductases, with an emphasis on experiments that provide support for direct bioelectrocatalysis versus denatured enzyme or dissociated cofactor. Finally, this review will conclude with a series of proposed control experiments that could be adopted to discern successful direct electronic communication of an enzyme from its denatured counterpart. PMID- 28637915 TI - Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment. AB - Cancer remains one of the leading causes of death, albeit enormous efforts to cure the disease. To overcome the major challenges in cancer therapy, we need to have a better understanding of the tumour microenvironment (TME), as well as a more effective means to screen anti-cancer drug leads; both can be achieved using advanced technologies, including the emerging tumour-on-a-chip technology. Here, we review the recent development of the tumour-on-a-chip technology, which integrates microfluidics, microfabrication, tissue engineering and biomaterials research, and offers new opportunities for building and applying functional three dimensional in vitro human tumour models for oncology research, immunotherapy studies and drug screening. In particular, tumour-on-a-chip microdevices allow well-controlled microscopic studies of the interaction among tumour cells, immune cells and cells in the TME, of which simple tissue cultures and animal models are not amenable to do. The challenges in developing the next-generation tumour-on-a chip technology are also discussed. PMID- 28637919 TI - The morphological heterogeneity of cricket flow-sensing hairs conveys the complex flow signature of predator attacks. AB - Arthropod flow-sensing hair length ranges over more than an order of magnitude, from 0.1 to 5 mm. Previous studies repeatedly identified the longest hairs as the most sensitive, but recent studies identified the shortest hairs as the most responsive. We resolved this apparent conflict by proposing a new model, taking into account both the initial and long-term aspects of the flow pattern produced by a lunging predator. After the estimation of the mechanical parameters of hairs, we measured the flow produced by predator mimics and compared the predicted and observed values of hair displacements in this flow. Short and long hairs respond over different time scales during the course of an attack. By harbouring a canopy of hairs of different lengths, forming a continuum, the insect can fractionize these moments. Short hairs are more agile, but are less able to harvest energy from the air. This may result in longer hairs firing their neurons earlier, despite their slower deflection. The complex interplay between hair agility and sensitivity is also modulated by the predator distance and the attack speed, characteristics defining flow properties. We conclude that the morphological heterogeneity of the hair canopy mirrors the flow complexity of an entire attack, from launch to grasp. PMID- 28637920 TI - Hippocampal Activity Patterns Reflect the Topology of Spaces: Evidence from Narrative Coding. PMID- 28637922 TI - Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. AB - Geographic atrophy is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are no approved treatments. Genetic studies in AMD patients have implicated dysregulation of the alternative complement pathway in the pathogenesis of geographic atrophy. Lampalizumab is a potential therapeutic that targets complement factor D, a pivotal activator of the alternative complement pathway. The MAHALO phase 2 clinical trial was a multicenter, randomized, controlled study that evaluated lampalizumab administered by intravitreal injection monthly (n = 42) and every other month (n = 41) versus sham control (n = 40) in patients with geographic atrophy secondary to AMD. The primary endpoint was the mean change in lesion area from baseline to month 18 as measured by fundus autofluorescence. Specific AMD-associated genetic polymorphisms were also analyzed. The MAHALO study met its primary efficacy endpoint with an acceptable safety profile; monthly lampalizumab treatment demonstrated a 20% reduction in lesion area progression versus sham control [80% confidence interval (CI), 4 to 37%]. A more substantial monthly treatment benefit of 44% reduction in geographic atrophy area progression versus sham control (95% CI, 15 to 73%) was observed in a subgroup of complement factor I (CFI) risk allele carriers (57% of the patients analyzed were CFI risk-allele carriers). The MAHALO study shows a potential treatment effect in patients with geographic atrophy and supports therapeutic targeting of the alternative complement pathway for treating AMD pathogenesis. PMID- 28637923 TI - Infectivity of Plasmodium falciparum sporozoites determines emerging parasitemia in infected volunteers. AB - Malaria sporozoites must first undergo intrahepatic development before a pathogenic blood-stage infection is established. The success of infection depends on host and parasite factors. In healthy human volunteers undergoing controlled human malaria infection (CHMI), we directly compared three clinical Plasmodium falciparum isolates for their ability to infect primary human hepatocytes in vitro and to drive the production of blood-stage parasites in vivo. Our data show a correlation between the efficiency of strain-specific sporozoite invasion of human hepatocytes and the dynamics of patent parasitemia in study subjects, highlighting intrinsic differences in infectivity among P. falciparum isolates from distinct geographical locales. The observed heterogeneity in infectivity among strains underscores the value of assessing the protective efficacy of candidate malaria vaccines against heterologous strains in the CHMI model. PMID- 28637925 TI - Flipping the kill switch. AB - Alveolar macrophages display an impairment in delayed bacterial killing in chronic obstructive pulmonary disease (COPD) that may contribute to an increased susceptibility to bacterial infection. PMID- 28637926 TI - When they go low, we go high. AB - High-frequency electrical interference can be used to drive activity deep in the brain. PMID- 28637924 TI - VP4- and VP7-specific antibodies mediate heterotypic immunity to rotavirus in humans. AB - Human rotaviruses (RVs) are the leading cause of severe diarrhea in young children worldwide. The molecular mechanisms underlying the rapid induction of heterotypic protective immunity to RV, which provides the basis for the efficacy of licensed monovalent RV vaccines, have remained unknown for more than 30 years. We used RV-specific single cell-sorted intestinal B cells from human adults, barcode-based deep sequencing of antibody repertoires, monoclonal antibody expression, and serologic and functional characterization to demonstrate that infection-induced heterotypic immunoglobulins (Igs) primarily directed to VP5*, the stalk region of the RV attachment protein, VP4, are able to mediate heterotypic protective immunity. Heterotypic protective Igs against VP7, the capsid glycoprotein, and VP8*, the cell-binding region of VP4, are also generated after infection; however, our data suggest that homotypic anti-VP7 and non neutralizing VP8* responses occur more commonly in people. These results indicate that humans can circumvent the extensive serotypic diversity of circulating RV strains by generating frequent heterotypic neutralizing antibody responses to VP7, VP8*, and most often, to VP5* after natural infection. These findings further suggest that recombinant VP5* may represent a useful target for the development of an improved, third-generation, broadly effective RV vaccine and warrants more direct examination. PMID- 28637927 TI - "AMP"(K)ed up recovery from ischemia-reperfusion injury. AB - Aging decreases tolerance to ischemia-reperfusion injury, which is mitigated by sestrin2-driven substrate metabolism. PMID- 28637929 TI - Systematic Prediction of the Impacts of Mutations in MicroRNA Seed Sequences. AB - MicroRNAs are a class of small non-coding RNAs that are involved in many important biological processes and the dysfunction of microRNA has been associated with many diseases. The seed region of a microRNA is of crucial importance to its target recognition. Mutations in microRNA seed regions may disrupt the binding of microRNAs to their original target genes and make them bind to new target genes. Here we use a knowledge-based computational method to systematically predict the functional effects of all the possible single nucleotide mutations in human microRNA seed regions. The result provides a comprehensive reference for the functional assessment of the impacts of possible natural and artificial single nucleotide mutations in microRNA seed regions. PMID- 28637930 TI - Towards a Consistent, Quantitative Evaluation of MicroRNA Evolution. AB - The miRBase currently reports more than 25,000 microRNAs in several hundred genomes that belong to more than 1000 families of homologous sequences. Quantitative investigations of miRNA gene evolution requires the construction of data sets that are consistent in their coverage and include those genomes that are of interest in a given study. Given the size and structure of data, this can be achieved only with the help of a fully automatic pipeline that improves the available seed alignments, extends the set of available sequences by homology search, and reliably identifies true positive homology search results. Here we describe the current progress towards such a system, emphasizing the task of improving and completing the initial seed alignment. PMID- 28637931 TI - Comparative miRomics of Salt-Tolerant and Salt-Sensitive Rice. AB - Increase in soil salt causes osmotic and ionic stress to plants, which inhibits their growth and productivity. Rice production is also hampered by salinity and the effect of salt is most severe at the seedling and reproductive stages. Salainity tolerance is a quantitative property controlled by multiple genes coding for signaling molecules, ion transporters, metabolic enzymes and transcription regulators. MicroRNAs are key modulators of gene-expression that act at the post-transcriptional level by translation repression or transcript cleavage. They also play an important role in regulating plant's response to salt stress. In this work we adopted the approach of comparative and integrated data mining to understand the miRNA-mediated regulation of salt-stress in rice. We profiled and compared the miRNA regulations using natural varieties and transgenic lines with contrasting behaviors in response to salt-stress. The information obtained from sRNAseq, RNAseq and degradome datasets was integrated to identify the salt-deregulated miRNAs, their targets and the associated metabolic pathways. The analysis revealed the modulation of many biological pathways, which are involved in salt-tolerance and play an important role in plant phenotype and physiology. The end modifications of the miRNAs were also studied in our analysis and isomiRs having a dynamic role in salt-tolerance mechanism were identified. PMID- 28637928 TI - The long noncoding RNA Wisper controls cardiac fibrosis and remodeling. AB - Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified Wisper (Wisp2 super-enhancer-associated RNA) as a cardiac fibroblast enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis. Loss-of-function approaches in vitro using modified antisense oligonucleotides (ASOs) demonstrated that Wisper is a specific regulator of cardiac fibroblast proliferation, migration, and survival. Accordingly, ASO mediated silencing of Wisper in vivo attenuated MI-induced fibrosis and cardiac dysfunction. Functionally, Wisper regulates cardiac fibroblast gene expression programs critical for cell identity, extracellular matrix deposition, proliferation, and survival. In addition, its association with TIA1-related protein allows it to control the expression of a profibrotic form of lysyl hydroxylase 2, implicated in collagen cross-linking and stabilization of the matrix. Together, our findings identify Wisper as a cardiac fibroblast-enriched super-enhancer-associated lncRNA that represents an attractive therapeutic target to reduce the pathological development of cardiac fibrosis in response to MI and prevent adverse remodeling in the damaged heart. PMID- 28637932 TI - Synergistic immunotoxin-paclitaxel combination against lymphoma. PMID- 28637933 TI - Rhabdomyolysis in MELAS may be multifactorial. PMID- 28637934 TI - A case of rhabdomyolysis after status epilepticus without stroke-like episodes in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. PMID- 28637935 TI - A case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) with the largest lesion in the temporal lobe. AB - Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system with a predilection for the hindbrain. Generally, lesions decrease in size with increasing distance from the hindbrain. We herein describe a case of CLIPPERS in a patient showing the largest lesions in the temporal lobe. A 49-year-old man consulted to our hospital with a 22-day history of a high fever and an abnormal visual field involving the left eye. Brain MRI showed a FLAIR hyperintense lesion in the right temporal lobe with punctate gadolinium enhancement. Several days later, lesions showing similar enhancement extended to the pons, medulla oblongata, and cerebellar hemispheres. Biopsy of the right temporal lobe lesion revealed perivascular lymphocytic infiltrates without any findings of demyelination, lymphoma, or glioma. He was diagnosed with CLIPPERS based on clinical, radiological, and histopathological findings. Clinical and radiological findings improved quickly after steroid therapy. CLIPPERS could represent larger lesions distant from the hindbrain showing punctate enhancement. PMID- 28637936 TI - A case of Bickerstaff brainstem encephalitis with transient reflex myoclonus. AB - A 33-year-old woman was admitted due to disturbance of consciousness, dysarthria, dysphagia, sensory disturbances and weakness of the left upper limb after mycoplasma infection. She was treated with intravenous immunoglobulin and intravenous high-dose methylprednisolone as Bickerstaff brainstem encephalitis (BBE). On the 15th hospital day, reflex myoclonus appeared on her face, neck, body and limbs induced by techniques of jaw jerk reflex and patellar tendon reflex. The myoclonus was disappeared after two weeks in accordance with improvement of BBE. The transient reflex myoclonus may be originated from brainstem lesion which was affected by BBE. Reflex myoclonus is thought to be rare symptom in patient with BBE. PMID- 28637937 TI - Herpes simplex encephalitis presenting as stroke-like symptoms with atypical MRI findings and lacking cerebrospinal fluid pleocytosis. AB - A 73-year-old woman presented with sudden onset of right hemiparesis and was diagnosed as having cerebral infarction on the basis of diffusion-weighted brain MRI, which demonstrated lesions in the left parietal cortex. On the 3rd day, the patient developed right upper limb myoclonus, aphasia, and disturbance of consciousness with high fever. On the 6th day, she was transferred to our hospital with suspected viral encephalitis, and treatment with acyclovir was started. By the 6th day, the lesions detected by MRI had expanded to the gyrus cinguli, insula and thalamus, but not to the temporal lobe. At that time, the CSF cell count was 8/MUl, and this later increased to 17/MUl by the 13th day. Although herpes simplex virus DNA was detected in the CSF on the 6th day, there was no evidence of CSF pleocytosis or temporal lobe abnormalities demonstrable by brain MRI throughout the whole follow-up period. This was very atypical case of herpes simplex encephalitis characterized by a stroke-like episode, atypical MRI findings, and absence of cerebrospinal fluid pleocytosis. It is important to be mindful that herpes simplex encephalitis (HSE) can have an atypical presentation, and that sufficient acyclovir treatment should be initiated until HSE can be ruled out. PMID- 28637938 TI - Questionnaire survey on the process of specialty training in neurology in Japan. AB - Documentation of the current status of specialty training to become a neurologist in Japan would represent an important basis for constructing better neurology training program in the planned reform of the specialty training system in Japan. The committee for future neurology specialty system of Japanese Society of Neurology (JSN) conducted a questionnaire survey on the process of specialty training of each trainee for neurology in board-certified educational facilities and semi-educational facilities throughout Japan. The response rate was 46.2% in all facilities and 87.5% in medical universities. The training process of 905 trainees over 5 grades was clarified, which was estimated to be about 80% of all the relevant subjects. Specialty training dedicated to neurology was started at the 3rd year of residency in 87.8% of subjects. During the 3 years following junior residency, 51.3% of subjects ran the rotation training between university and city hospital, whereas 36.5% was trained within the same institution throughout the 3 years of training period. PMID- 28637939 TI - Surgery of Thymic Tumor with Persistent Left Superior Vena Cava. AB - Because a persistent left superior vena cava (PLSVC) is a rare congenital malformation in the thoracic venous system, surgery of the thymus in such patients has rarely been reported. We herein present a case involving a 68-year old woman who was treated for a thymic tumor adhering to a PLSVC. She underwent complete resection of the thymic tumor through median sternotomy with left-sided video-assisted thoracic surgery. Although the tumor was close to the left phrenic nerve, this nerve was safely preserved. The pathological diagnosis was mucosa associated lymphoid tissue (MALT) lymphoma of the thymus. Thoracoscopy combined with median sternotomy enabled us to perform a safe surgical procedure for this patient. PMID- 28637940 TI - Thoracoscopic Thymectomy with Tangential Partial Resection of the Innominate Vein. AB - We herein report a case in which thoracoscopic thymectomy with partial resection of the brachiocephalic vein was performed using a subxiphoid approach. We suggest the usefulness of the subxiphoid approach in thymectomy. We could extend the indications of thoracoscopic thymectomy for invasive tumors. Thoracoscopic thymectomy with the combined resection of part of the brachiocephalic vein was possible. The pathological diagnosis of the tumor was diffuse large cell B-cell lymphoma. Since the postoperative complications were minimal, postoperative adjuvant chemotherapy could be initiated without delay. This operation might be unnecessary. However, we could decrease the invasiveness of surgery using our procedures without sternotomy. Thoracoscopic thymectomy using subxiphid approach seems to be an ideal procedure for the surgical treatment of invasive lesions. PMID- 28637942 TI - Clinical Characteristics and Psychotropic Prescribing Patterns Associated with impaired Concentration in Asians with Depressive Disorders: The REAP-AD Study. AB - The Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) study aimed to survey and review antidepressant prescribing patterns in different clinical settings in Asian countries/areas. The REAP-AD study collected comprehensive data for psychiatric patients prescribed antidepressants in 10 Asian countries/areas during the period from March to June 2013. Depressive disorders have been an important issue closely associated with ill-health and disability in the realm of mental health. Impaired concentration was found to be a consistent symptom in depressive disorders regardless of clinical course, and a predictor of poor treatment outcome. In this work we aimed to identify clinical characteristics independently associated with impaired concentration in patients with depressive disorders, using data from the REAP-AD study. A total of 336 depressive disorder patients with impaired concentration and 786 depressive disorder patients without impaired concentration were recruited from 40 centers in 10 Asian countries/areas. A binary logistic regression model was fitted to identify the independent correlates of impaired concentration in patients with depressive disorders. After adjusting the effects of covariates, the binary logistic model showed that impaired concentration was independently associated with higher rates of loss of interest (P < 0.0001), fatigue (P < 0.0001), low self-confidence (P < 0.0001) and appetite disturbance (P < 0.0001) and with a lower rate of adjunctive antipsychotic prescription (P = 0.007). Our findings suggest that impaired concentration and its associated depressive symptom profiles constitute a unitary depressive symptom cluster that is also an intervening variable for poor social function. PMID- 28637941 TI - A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1alpha/Nrf2/HO-1 Pathway. AB - In this study, we investigated the cardioprotective mechanisms of action of DT 010, a novel danshensu-tetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (.O2-), hydroxyl radical (.OH) and peroxynitrite anion (ONOO-) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury. PMID- 28637943 TI - Stereoelectroencephalography: Indication and Efficacy. AB - Stereoelectroencephalography (SEEG) is a method for invasive study of patients with refractory epilepsy. Localization of the epileptogenic zone in SEEG relied on the hypothesis of anatomo-electro-clinical analysis limited by X-ray, analog electroencephalography (EEG), and seizure semiology in the 1950s. Modern neuroimaging studies and digital video-EEG have developed the hypothesis aiming at more precise localization of the epileptic network. Certain clinical scenarios favor SEEG over subdural EEG (SDEEG). SEEG can cover extensive areas of bilateral hemispheres with highly accurate sampling from sulcal areas and deep brain structures. A hybrid technique of SEEG and subdural strip electrode placement has been reported to overcome the SEEG limitations of poor functional mapping. Technological advances including acquisition of three-dimensional angiography and magnetic resonance image (MRI) in frameless conditions, advanced multimodal planning, and robot-assisted implantation have contributed to the accuracy and safety of electrode implantation in a simplified fashion. A recent meta-analysis of the safety of SEEG concluded the low value of the pooled prevalence for all complications. The complications of SEEG were significantly less than those of SDEEG. The removal of electrodes for SEEG was much simpler than for SDEEG and allowed sufficient time for data analysis, discussion, and consensus for both patients and physicians before the proceeding treatment. Furthermore, SEEG is applicable as a therapeutic alternative for deep-seated lesions, e.g., nodular heterotopia, in nonoperative epilepsies using SEEG-guided radiofrequency thermocoagulation. We review the SEEG method with technological advances for planning and implantation of electrodes. We highlight the indication and efficacy, advantages and disadvantages of SEEG compared with SDEEG. PMID- 28637944 TI - Service and sales workers, are they vulnerable to smoking cessation? AB - The aim of the present study was to evaluate the association between failed smoking cessation and occupation by age stratification among Korean males and provide quantitative evidence of factors associated with failed smoking cessation. The study comprised 3,127 male workers who had attempted smoking cessation during their life time. Data were obtained from the Korea National Health and Nutrition Examination Survey from 2010 to 2012. Participants were stratified by age into two subgroups comprising a younger group (19-40 yr) and an older group (41-60 yr). Multiple logistic regression analyses were used to estimate odds ratios (ORs) for failed smoking cessation. In the younger group, failed smoking cessation was related to the occupational fields "service and sales" and "manual work" compared to "office work" (OR: 2.10, 95% confidence interval (CI): 1.34-3.29; and OR: 1.47, 95% CI: 1.02-2.12, respectively). In the older group, the ORs of failed smoking cessation occupational categories "service and sales" and "manual work" [ref: office workers] were 0.58 (0.40-0.85) and 0.90 (0.66-1.24), respectively. Failed smoking cessation is associated with occupational categories and age stratification. Policy makers need to create tailored anti-smoking policy considering the occupation and the age of the subjects. PMID- 28637945 TI - Multiplex PCR assay for the simultaneous detection and differentiation of clonal lineages of Erysipelothrix rhusiopathiae serovar 1a strains currently circulating in Japan. AB - The species Erysipelothrixrhusiopathiae displays genetic heterogeneity; however, E. rhusiopathiae serovar 1a strains currently circulating in Japan exhibit remarkably low levels of genetic diversity and group into clonal sublineages of Lineage IVb (IVb-1 and IVb-2). In the present study, based on whole genome sequencing data, we designed primers for a multiplex PCR assay to simultaneously detect and differentiate the sublineages of E. rhusiopathiae strains. Among the one hundred and twenty-seven isolates of various serovar strains, including isolates from a wide range of hosts and geographic origins, the PCR assay could successfully detect and differentiate the serovar 1a strains belonging to the sublineages. PMID- 28637946 TI - Basal cell adenocarcinoma in the gland of the third eyelid of a brown bear (Ursus arctos). AB - The right third eyelid of an adult female brown bear (Ursus arctos) was swollen and removed. Histopathology revealed a tumor exhibiting proliferation with mild infiltration, consisting of multi-stratified glandular structures of the innermost laminal neoplastic cells and the basaloid neoplastic cells, and with eosinophilic thick basal lamina material around the glandular structures. Both types of neoplastic cells exhibited moderate anisokaryosis, and mitotic figures were observed in the basaloid neoplastic cells. The laminal neoplastic cells were cytokeratin (CK) 8/18-positive. In contrast, the basaloid neoplastic cells were CK14- and p63-positive, but alpha-smooth muscle actin- and calponin-negative. The case described herein is the first report of basal cell adenocarcinoma in the gland of the third eyelid of a bear. PMID- 28637947 TI - Neurosurgical Virtual Reality Simulation for Brain Tumor Using High-definition Computer Graphics: A Review of the Literature. AB - Simulation and planning of surgery using a virtual reality model is becoming common with advances in computer technology. In this study, we conducted a literature search to find trends in virtual simulation of surgery for brain tumors. A MEDLINE search for "neurosurgery AND (simulation OR virtual reality)" retrieved a total of 1,298 articles published in the past 10 years. After eliminating studies designed solely for education and training purposes, 28 articles about the clinical application remained. The finding that the vast majority of the articles were about education and training rather than clinical applications suggests that several issues need be addressed for clinical application of surgical simulation. In addition, 10 of the 28 articles were from Japanese groups. In general, the 28 articles demonstrated clinical benefits of virtual surgical simulation. Simulation was particularly useful in better understanding complicated spatial relations of anatomical landmarks and in examining surgical approaches. In some studies, Virtual reality models were used on either surgical navigation system or augmented reality technology, which projects virtual reality images onto the operating field. Reported problems were difficulties in standardized, objective evaluation of surgical simulation systems; inability to respond to tissue deformation caused by surgical maneuvers; absence of the system functionality to reflect features of tissue (e.g., hardness and adhesion); and many problems with image processing. The amount of description about image processing tended to be insufficient, indicating that the level of evidence, risk of bias, precision, and reproducibility need to be addressed for further advances and ultimately for full clinical application. PMID- 28637948 TI - In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing's syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry. AB - The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushing's syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (rho = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels <=2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5 mg loading for the diagnosis of adrenal SCS. PMID- 28637949 TI - Comparative analysis of allyl isothiocyanate (AITC)-induced carbohydrate oxidation changes via TRPV1 between mice and chickens. AB - Postprandial hyperglycemia is a risk factor for cardiovascular diseases. It has been reported that intragastric administration of allyl isothiocyanate (AITC), which is one of the pungent ingredients of wasabi and horseradish but it is not included in hot chili pepper, increased carbohydrate oxidation and reduced postprandial increase of blood glucose via transient receptor potential vanilloid 1 (TRPV1)in mice. However, the action site of AITC on TRPV1 for increasing carbohydrate oxidation is unclear. Both mammalian and chicken TRPV1 (cTRPV1) are activated by heat and acid, but unlike its mammalian counterpart, cTRPV1 is only faintly activated by capsaicin. This difference is due to the 8 chicken-specific amino acid residues around transmembrane 3, which is the main site of capsaicin binding in rat TRPV1. Moreover, AITC-induced activation of mouse TRPV1 (mTRPV1) is largely dependent on S513, a residue that is involved in capsaicin-binding. Thus, we hypothesized that the increase of carbohydrate oxidation by AITC in mammals is induced by the binding of AITC to the capsaicin-binding site of TRPV1. In this study, we performed a comparative study using chickens and mice, since chickens are thought to partly lack the capsaicin-binding site of TRPV1. We examined the effects of AITC on the respiratory quotient (RQ), the index of carbohydrate oxidation and fat oxidation, in chickens and mice. Respiratory gas analysis revealed that AITC does not increase the RQ in chickens, and Ca2+ imaging methods and a whole cell-patch clamp analysis showed that AITC does not activate cTRPV1. These results implied that the capsaicin-binding site is an important region for increasing carbohydrate oxidation by AITC administration in animals. PMID- 28637950 TI - ADAM17 regulates TNF-alpha expression upon lipopolysaccharide stimulation in oral keratinocytes. AB - A disintegrin and metalloprotease 17 (ADAM17) is a tumor necrosis factor (TNF) converting enzyme and was first identified as the enzyme that cleaves the prodomain of TNF-alpha, a proinflammatory cytokine that plays a central role in immune regulation and a variety of inflammatory responses in destructive periodontal disease. The aim of the present study was to verify the presence of ADAM17 in the gingival epithelium and elucidate its involvement in the release of TNF-alphain oral keratinocytes. Immunohistochemical analyses of ADAM17 were performed in gingival tissues obtained from patients and in human oral keratinocytes (HOKs). Additionally, levels of TNF-alpha and ADAM17 in HOKs exposed to lipopolysaccharide (LPS) were assessed using enzyme-linked immunosorbent assays. Moreover, the effects of ADAM17 inhibitor, matrix metalloproteinase (MMP) inhibitor, and ADAM17 siRNA on TNF-alpha concentration were assessed. Strong immunoreactivity for ADAM17 was observed in the epithelium of the inflamed gingival tissues and in HOKs. Furthermore, treatment with either ADAM17 inhibitor or ADAM17 siRNA inhibited the generation of TNF-alpha induced by LPS in HOKs. The present study demonstrates that ADAM17 is strongly expressed in the epithelium of gingival tissues and suggests that ADAM17 may be a key enzyme that regulates the generation of TNF-alpha in oral keratinocytes. PMID- 28637951 TI - Porphyromonas gingivalis-induced IL-33 down-regulates hCAP-18/LL-37 production in human gingival epithelial cells. AB - hCAP-18/LL-37 is an antimicrobial peptide that is mainly expressed in epithelial cells. Gingival epithelial cells play pivotal roles in antimicrobial defense by expressing hCAP-18/LL-37. Porphyromonas gingivalis is a primary pathogen for chronic periodontitis and produces cysteine proteinase gingipains, which induce proinflammatory cytokines production, leading to enhance inflammatory responses. In contrast, gingipains attenuate immune responses, leading to induce anti inflammatory responses. In this study, we investigated the ability of gingipains to attenuate P. gingivalis-induced hCAP-18/LL-37 production by human gingival epithelial Ca9-22 cells. The expression of LL-37 mRNA was increased by the infection of Ca9-22 cells with a P. gingivalis gingipains-null mutant KDP136 compared with P. gingivalis wild-type strain ATCC 33277. Interleukin (IL)-33 is involved in the development of chronic inflammatory diseases, and P. gingivalis infection increases IL-33 production by human gingival epithelial cells. P. gingivalis-induced LL-37 mRNA expression was augmented in IL-33 small interfering RNA-transfected Ca9-22 cells. Maxacalcitol (22-oxacalcitriol: OCT) is a biologically active metabolite of vitamin D3 analog, and OCT increases hCAP-18/LL 37 production by human gingival epithelial cells. The increasing expression of LL 37 mRNA by OCT was down-regulated by infection of the cells with P. gingivalis ATCC 33277 in Ca9-22 cells. Furthermore, P. gingivalis infection induced IL-33 mRNA expression in Ca9-22 cells; therefore, P. gingivalis-induced endogenous IL 33 down-regulated hCAP-18/LL-37 production by the bacterium. These findings suggested that endogenous IL-33 down-regulates the induction of hCAP-18/LL-37 production in human gingival epithelial cells. PMID- 28637952 TI - Heat-shock protein 72 promotes platelet aggregation induced by various platelet activators in rats. AB - Increase of thrombus in the coronary arteries is positively correlated with the level of heat-shock protein 72 (HSP72) in the blood of patients with acute myocardial infarction (AMI). Platelet aggregation participates in thrombus formation on ruptured plaque in AMI. In this study, we aimed to clarify the role of HSP72 in thrombus formation by evaluating the effects of HSP72 on platelet aggregation. Platelet aggregation activities were measured in platelet-rich plasma obtained from male Sprague-Dawley rats with or without the platelet activators, such as adenosine diphosphate (ADP), collagen, thrombin receptor activating peptide-6 (TRAP-6), ristocetin, and arachidonic acid. Changes in aggregation were estimated by the co-addition of recombinant HSP72 and anti-HSP72 antibodies. Our results showed that addition of HSP72 increased platelet aggregation in the presence of low concentrations of ADP, collagen, TRAP-6, ristocetin, and arachidonic acid. Increased platelet aggregation stimulated by ADP and HSP72 was reduced by the co-addition of anti-HSP72 antibodies. Thus, these findings suggested that HSP72 was released extracellularly in response to stress, promoting thrombus formation and AMI. Additionally, treatment with anti HSP72 antibodies may control platelet aggregation induced by extracellular HSP72. PMID- 28637953 TI - Synapse-specific effects of IL-1beta on long-term potentiation in the mouse hippocampus. AB - Interleukin-1beta (IL-1beta) is a key molecule in the inflammatory responses elicited during infection and injury. It exerts local effects on synaptic plasticity by binding to IL-1 receptors that are expressed at high levels in the hippocampus. We examined the effects of IL-1beta on synaptic plasticity in different hippocampal regions in acute mouse brain slices by measuring long-term potentiation (LTP). IL-1beta (1 ng/mL) was applied for 30 min before LTP was induced with high-frequency stimulation (HFS). LTP was significantly impaired by either IL-1beta application to the Schaffer collateral-CA1 synapses or the associational/commissural (A/C) fiber-CA3 synapses, which are both dependent on N methyl-D-aspartate (NMDA) receptor activation. However, mossy fiber-CA3 LTP, which is expressed presynaptically in an NMDA-independent manner, was not impaired by IL-1beta. Our results demonstrate that IL-1beta exerts variable effects on LTP at different kinds of synapses, indicating that IL-1beta has synapse-specific effects on hippocampal synaptic plasticity. PMID- 28637954 TI - Increases in IL-33 production by fimbriae and lipopeptide from Porphyromonas gingivalis in mouse bone marrow-derived dendritic cells via Toll-like receptor 2. AB - Interleukin-33 (IL-33) is an IL-1 cytokine family member that is involved in the development of chronic inflammatory diseases and the initiation of allergic inflammation in response to pathogens. Porphyromonas gingivalis is a primary pathogen that is involved in chronic periodontitis and its bacterial components induce inflammatory responses. Dendritic cells (DCs) recognize pathogen- associated molecular patterns by expression of pattern-recognition receptors, such as Toll-like receptors (TLRs). DCs play an essential role in resistance to infection and maintenance of mucosal immune system. In this study, we investigated whether P. gingivalis increases the expression of IL-33 in mouse bone marrow-derived DCs (BMDCs). BMDCs exhibited an increased expression of IL-33 mRNA upon stimulation with P. gingivalis whole cells. Furthermore, fimbriae and lipopeptide derived from P. gingivalis exhibited higher IL-33 mRNA expression than P. gingivalis whole cells. In contrast, lipopolysaccharide derived from P. gingivalis did not induce IL-33 mRNA expression in BMDCs. The IL-33 mRNA expression after stimulation with fimbriae or lipopeptide was up-regulated in BMDCs from wild-type mice but not from TLR2-deficient (TLR2-/-) mice. IL-33 production induced by fimbriae and lipopeptide accumulated in the cytoplasm of BMDCs from wild-type mice, but not from TLR2-/- mice. These findings suggested that IL-33 production induced by P. gingivalis fimbriae and lipopeptide is recognized by TLR2 and may modulate DC function in periodontal diseases. PMID- 28637955 TI - Fine structure of human thoracic duct as revealed by light and scanning electron microscopy. AB - Little information has been available regarding microanatomy of human thoracic duct in spite of the importance for an understanding of pathophysiology in clinical medicine. The present study demonstrated a fine structure of human thoracic duct system by light and scanning electron microscopy. A number of longitudinal or spiral ridges and grooves were formed on luminal surfaces of the lymphangia and lymph sac, it likely facilitating fluent lymph flow. The endothelial cells displayed various cell shapes in compliance with their distributed regions. The lymph sac joining large vein composed a peculiar multiple valve structure presumably ensuring lymph storage and prevention of lymph backflow. The longitudinal muscle sheet in the tunica intima and circular muscle bundles in the tunica media constructed an integrated power unit probably eliciting spontaneous lymph propulsion. Furthermore, the thoracic duct was richly supplied with blood vessels not only in the tunica externa, but also just beneath the endothelium. The present findings provide a morphological basis for investigation of human thoracic duct in basic and clinical medicine. PMID- 28637956 TI - CD36 involvement in the olfactory perception of oleic aldehyde, an odour-active volatile compound, in mice. AB - Cluster of differentiation 36 (CD36) is a broadly expressed transmembrane receptor that has multiple ligands. It has been found to occur abundantly on the surface of the olfactory epithelium in mice and postulated to play a role in mammalian olfaction. However, there have been no ethological analyses of the mammalian behaviour showing CD36 involvement in the olfactory perception of a distinct odour-active volatile compound. In this study, we aimed to assess whether mammals perceive oleic aldehyde, an odour-active volatile that serves as a potential CD36 ligand, and if so, whether CD36 is involved in the sensing by following measurements using CD36-knockout mice and their wild-type littermates. In a two-bottle choice test, wild-type mice, but not CD36-knockout mice, discriminated a sucrose solution containing oleic aldehyde from the sucrose solution alone. To assess the importance of the olfactory system in the oleic aldehyde perception, we conducted an exploration test where the animals could rely primarily on the odour of test volatiles for recognition. We found that the wild-type, but not CD36-knockout mice, were aware of the compound. Our results provide behavioural evidence that CD36 plays a role in the perception of specific odour-active volatile compounds in the nasal cavity. PMID- 28637959 TI - Examination of Dose Reduction Using Image Noise Reduction Technology in Cardiovascular X-ray Systems. AB - The aim of this study is to establish radiation exposure dose reduction protocols during cardiac intervention by decreasing the entrance dose at flat panel detector (FPD) with image quality evaluations. For measuring entrance surface dose (ESD), we have used a Radical 9015 dosimeter (6 cc ion chamber) placed under 20 cm thick acrylic plates at the patient's entrance reference point. We performed an image quality assessment based on quantitative as well as visual evaluation of the images obtained via current and dose reduction protocols. The visual evaluation was performed by measuring the signal to noise ratio and contrast using a cine/digital angiography cardiac phantom. The quantitative evaluation was performed by cardiologists and radiological technologists using the five-point scale method. For the dose reduction protocol, we used an image noise reduction technique to prevent the deterioration of image quality. The ESDs for the fluoroscopy and digital cine in the dose reduction protocol were 18.0 mGy/min and 0.18 mGy/frame, respectively, which corresponded to 81% and 49% of the ESD in the current protocol. Our results reveal that the ESD for fluoroscopy was lower than the diagnostic reference level (20 mGy/min) for interventional radiology. We recommend a lower dose setting and the maintenance of image quality using noise reduction techniques. This will ensure use of a lower FPD entrance dose compared to the initial dose setting currently recommended by manufacturers. PMID- 28637957 TI - Gm7325 is MyoD-dependently expressed in activated muscle satellite cells. AB - The Gm7325 gene, bioinformatically identified in the mouse genome, encodes a small protein but has not been characterized until recently. Our gene expression analysis revealed that Gm7325 transcription is remarkably upregulated in injured skeletal muscle tissues. Activated satellite cells and immature myotubes were densely decorated with positive signals for Gm7325 mRNA in in situ hybridization analysis, while no obvious signals were observed in quiescent satellite cells and mature myofibers. In the 5'-flanking regions of mouse Gm7325 and its human homologue, conserved E-box motifs for helix-loop-helix transcription factors are repeatedly arranged around the putative promoter regions. Reporter gene assays suggested that MyoD, a master transcription factor for myogenesis, binds to the conserved E-box motifs to activate Gm7325 expression. Therefore, Gm7325, as a novel MyoD-target gene, is specifically induced in activated satellite cells, and may have an important role in skeletal myogenesis. PMID- 28637958 TI - Validation of Cross-calibration Schemes for Quantitative Bone SPECT/CT Using Different Sources under Various Geometric Conditions. AB - PURPOSE: Several cross-calibration schemes have been proposed to produce quantitative values in bone SPECT imaging. Differences in the radionuclide sources and geometric conditions can decrease the accuracy of cross-calibration factor (CCF). The present study aimed to validate the effects of calibration schemes using different sources under various geometric conditions. METHODS: Temporal variations as well as variations in acquisition counts and the shapes of 57Co standard and 99mTc point sources and a 99mTc disk source were determined. The effects of the geometric conditions of the source-to-camera distance (SCD) and lateral distance on the CCF were investigated by moving the camera or source away from the origin. The system planar sensitivity of NEMA incorporated into a Symbia Intevo SPECT/CT device (Siemens(r)) was defined as reference values. RESULTS: The temporal variation in CCF using the 57Co source was relatively stable within the range of 0.7% to 2.3%, whereas the 99mTc source ranged from 2.7% to 7.3%. In terms of source shape, the 57Co standard point source was the most stable. Both SCD and lateral distance decreased as a function of distance from the origin. Errors in the geometric condition were higher for the 57Co standard point source than the 99mTc disk source. CONCLUSIONS: Different calibration schemes influenced the reliability of quantitative values. The 57Co standard point source was stable over a long period, and this helped to maintain the quality of quantitative SPECT/CT imaging data. The CCF accuracy of the 99mTc source decreased depending on the preparative method. The method of calibration for quantitative SPECT should be immediately standardized to eliminate uncertainty. PMID- 28637961 TI - 2. Current Status of DRLs in the World. PMID- 28637960 TI - Pacemaker-induced Metallic Artifacts in Coronary Computed Tomography Angiography: Clinical Feasibility of Single Energy Metal Artifact Reduction Technique. AB - BACKGROUND: Coronary computed tomography angiography (CCTA) in patients with pacemaker suffers from metallic lead-induced artifacts, which often interfere with accurate assessment of coronary luminal stenosis. The purpose of this study was to assess a frequency of the lead-induced artifacts and artifact-suppression effect by the single energy metal artifact reduction (SEMAR) technique. METHODS: Forty-one patients with a dual-chamber pacemaker were evaluated using a 320 multi detector row CT (MDCT). Among them, 22 patients with motion-free full data reconstruction images were the final candidates. Images with and without the SMEAR technique were subjectively compared, and the degree of metallic artifacts was compared. RESULTS: On images without SEMAR, severe metallic artifacts were often observed in the right coronary artery (#1, #2, #3) and distal anterior descending branch (#8). These artifacts were effectively suppressed by SEMAR, and the luminal accessibility was significantly improved in #3 and #8. CONCLUSION: While pacemaker leads often cause metallic-induced artifacts, SEMAR technique reduced the artifacts and significantly improved the accessibility of coronary lumen in #3 and #8. PMID- 28637962 TI - 3. Diagnostic Imaging for Prostate Cancer. PMID- 28637963 TI - Welcome to Imaging Section for Coloring Your Research Life. PMID- 28637964 TI - How to Utilize the Nuclear Medicine Division. PMID- 28637965 TI - Introduction of the Radiotherapy Division of the JSRT. PMID- 28637966 TI - Participation/Dispatch Reports on International Conferences in 2017. PMID- 28637967 TI - Activity Report of Medical Imaging System Division and JIRA VISION 2020. PMID- 28637968 TI - Transmit. PMID- 28637970 TI - Impact of Door-to-Balloon Time in Patients With ST-Elevation Myocardial Infarction Who Arrived by Self-Transport - Acute Myocardial Infarction-Kyoto Multi-Center Risk Study Group. AB - BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) who arrive at a hospital via self-transport reportedly have a delayed door-to-balloon time (DBT). However, the clinical impacts of delayed DBT on in-hospital mortality among such patients are not well known.Methods and Results:In total, 1,172 STEMI patients who underwent primary percutaneous coronary intervention between January 2009 and December 2013 from the Acute Myocardial Infarction (AMI) Kyoto Registry were analyzed. Compared with the emergency medical service (EMS) group (n=804), the self-transport group (n=368) was younger and had a significantly longer DBT (115 min vs. 90 min, P<0.01), with fewer patients having a Killip classification of 2 or higher. The in-hospital mortality rate was lower in the self-transport group than in the EMS group (3.3% vs. 7.1%, P<0.01). A DBT >90 min was an independent predictor of in-hospital mortality in EMS patients (odds ratio (OR)=2.43, P=0.01) but not in self-transport patients (OR=0.89, P=0.87). CONCLUSIONS: The present study demonstrated that there was no relationship between in-hospital prognosis and DBT <=90 min in STEMI patients using self transport. The prognosis of these patients cannot be improved by focusing only on DBT. Treatment strategies based on means of transport should also be considered. PMID- 28637973 TI - Neural mechanisms of nociception during orthodontic treatment. AB - Orthodontic tooth movement is accompanied by inflammatory responses in the periodontal ligament. Chemical mediators such as interleukin-1beta have key roles in nociception around teeth. Such nociceptive inputs to the periodontal ligament continue for several days and potentially induce plastic changes in higher brain regions, including the cerebral cortex. This review summarizes research on orthodontic treatment-induced modulation of neural activities in the central nervous system. Furthermore, we describe our recent findings on the spatiotemporal effects of orthodontic treatment in the somatosensory and insular cortices. PMID- 28637972 TI - Preface. PMID- 28637969 TI - Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of SCN5A-D1275N-Related Cardiac Sodium Channelopathy. AB - BACKGROUND: TheSCN5Agene encodes the alpha subunit of the cardiac voltage-gated sodium channel, NaV1.5. The missense mutation, D1275N, has been associated with a range of unusual phenotypes associated with reduced NaV1.5 function, including cardiac conduction disease and dilated cardiomyopathy. Curiously, the reported biophysical properties ofSCN5A-D1275N channels vary with experimental system.Methods and Results:First, using a human embryonic kidney (HEK) 293 cell based heterologous expression system, theSCN5A-D1275N channels showed similar maximum sodium conductance but a significantly depolarizing shift of activation gate (+10 mV) compared to wild type. Second, we generated human-induced pluripotent stem cells (hiPSCs) from a 24-year-old female who carried heterozygousSCN5A-D1275N and analyzed the differentiated cardiomyocytes (CMs). AlthoughSCN5Atranscript levels were equivalent between D1275N and control hiPSC CMs, both the total amount of NaV1.5 and the membrane fractions were reduced approximately half in the D1275N cells, which were rescued by the proteasome inhibitor MG132 treatment. Electrophysiological assays revealed that maximum sodium conductance was reduced to approximately half of that in control hiPSC-CMs in the D1275N cells, and maximum upstroke velocity of action potential was lower in D1275N, which was consistent with the reduced protein level of NaV1.5. CONCLUSIONS: This study successfully demonstrated diminished sodium currents resulting from lower NaV1.5 protein levels, which is dependent on proteasomal degradation, using a hiPSC-based model forSCN5A-D1275N-related sodium channelopathy. PMID- 28637977 TI - The oral mucosal membrane and transient receptor potential channels. AB - The oral cavity is the first line of defense, sensation, and secretion of the alimentary canal. Oral perception contributes to the enjoyment of food and beverages and to avoiding consumption of poisonous or harmful substances. Oral sensation is served by somatosensory nervous systems distributed to the oral membrane. Recent studies reported that oral epithelial cells may transduce temperature and touch through membranous sensors, which comprise ion channels with multimodal properties, and nerves. Here, we describe the possible role of oral epithelial cells in oral perception. PMID- 28637974 TI - Neuron-glia interaction is a key mechanism underlying persistent orofacial pain. AB - Excitability of neurons in the trigeminal ganglion (TG), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (C1-C2) is greatly enhanced after orofacial inflammation and trigeminal nerve injury, and TG, Vc, and C1-C2 neurons remain sensitized long after such episodes. Sensitized neurons generate various molecules, which are released from nociceptive neurons in these areas and are involved in modulating the excitability of TG, Vc, and C1-C2 nociceptive neurons. Hyperexcitable nociceptive neurons also activate satellite glial cells in the TG and microglial cells and astrocytes in the Vc and C1-C2. Glial cell activation spreads throughout the TG, Vc, and C1-C2 and triggers the release of various molecules involved in modulating nociceptive neurons in TG, Vc, and C1-C2 neurons. These findings suggest that functional interaction between neurons and glial cells is critical in persistent orofacial pain associated with orofacial inflammation and trigeminal nerve injury. PMID- 28637975 TI - Projection and synaptic connectivity of trigeminal mesencephalic nucleus neurons controlling jaw reflexes. AB - Neurons in the trigeminal mesencephalic nucleus (Vmes) receive deep sensation (proprioception) from jaw-closing muscle spindles and periodontal ligaments and project primarily to the jaw-closing motoneuron pool (jaw-closing nucleus) of the trigeminal motor nucleus and to the supratrigeminal nucleus. Numerous articles have described the morphology and physiology of the central projections of Vmes afferents originating from the muscle spindles and periodontal ligaments. However, no report has provided a detailed description of projection and synaptic connectivity, especially of single afferents, and their functional implications. In this review, we reanalyze data obtained by single intra-axonal recording and labeling of functionally identified Vmes muscle spindle afferents and periodontal ligament afferents and by electron microscopic observation of their projection features and synaptic organization of boutons, to compare the data for the jaw closing nucleus and supratrigeminal nucleus. Our analysis shows that each Vmes afferent type has characteristic projection pattern and synaptic feature that may be important in jaw-reflex control. PMID- 28637978 TI - Mechanisms underlying delta- and MU-opioid receptor agonist-induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats. AB - The nucleus accumbens is a terminal area of the mesolimbic dopaminergic system that arises in the ventral tegmental area. Opioids are thought to enhance dopaminergic activity in the nucleus accumbens by activating delta- and MU-opioid receptors in the ventral tegmental area. However, delta- and MU-opioid receptor agonists increase extracellular levels of accumbal dopamine when infused directly into the nucleus accumbens of rats. Therefore, the roles of delta- and MU-opioid receptors in regulation of accumbal dopaminergic neural activity have been analyzed by using delta- and MU-opioid receptor ligands. This review describes the mechanisms underlying the stimulatory effects on accumbal dopamine efflux, which are induced by local administration of delta- and MU-opioid receptor agonists into the nucleus accumbens of freely moving rats. The focus of this article is neurochemical studies that use in vivo microdialysis techniques. Taken together, the in vivo neurochemical evidence from these studies indicates that delta- and MU-opioid receptor agonists increase accumbal dopamine efflux by activating naloxone-sensitive opioid receptors, and by mechanisms independent of naloxone-sensitive opioid receptors, in the nucleus accumbens. PMID- 28637976 TI - Coordinated control of the tongue during suckling-like activity and respiration. AB - The tongue can move freely and is important in oral motor functions. Tongue movement must be coordinated with movement of the hyoid, mandible, and pharyngeal wall, to which it is attached. Our previous study using isolated brainstem-spinal cord preparations showed that application of N-methyl-D-aspartate induces rhythmic activity in the hypoglossal nerve that is coincident with rhythmic activity in the ipsilateral trigeminal motor nerve. Partial or complete midline transection of the preparation only abolishes activity in the trigeminal motor nerve; therefore, the neuronal network contributing to coordinated activity of the jaw/tongue muscles is located on both sides of the preparation and sends motor commands to contralateral trigeminal motoneurons. Arterially perfused decerebrate rat preparations exhibit stable inspiratory activity in the phrenic nerve, with efferent nerves innervating the upper airway muscles (the hypoglossal nerve, a branch of the cervical spinal nerve, the external branch of the superior laryngeal nerve, and the recurrent laryngeal nerve) under normocapnic conditions (5% CO2). During hypercapnia (8% CO2), pre-inspiratory discharges appear in all nerves innervating upper airway muscles. Such coordinated activity in the pre inspiratory phase contributes to dilation of the upper airway and improves hypercapnia. PMID- 28637971 TI - Esculentoside A ameliorates cecal ligation and puncture-induced acute kidney injury in rats. AB - Esculentoside A (EsA), a saponin isolated from Phytolacca esculenta, can attenuate acute liver and lung injury. However, whether EsA has a protective effect against sepsis-induced acute kidney injury (AKI) has not been reported. In this study, EsA (2.5, 5, or 10 mg/kg) was given to rats with sepsis induced by cecal ligation and puncture (CLP). We found that EsA improved the survival of septic rats in a dose-dependent manner. In addition, EsA lowered the kidney tubular damage score and decreased blood urea nitrogen and creatinine. Moreover, EsA inhibited excessive generation of pro-inflammatory tumor necrosis factor alpha, IL-1beta, and IL-6 in the serum and downregulated cyclooxygenase-2 and inducible nitric oxide synthase in the renal tissues of septic rats. EsA also suppressed the production of malonaldehyde and the activity of myeloperoxidase in the septic kidney and enhanced the activity of superoxide dismutase and glutathione. The anti-inflammatory and antioxidative effects of a high dose of EsA were comparable to those of dexamethasone. Mechanically, EsA inhibited CLP induced increases in high-mobility group box 1, Toll-like receptor-4, and myeloid differentiation primary response 88 and nuclear accumulation of nuclear factor kappa B p65 in renal tissues. In vitro, lipopolysaccharide-induced alteration of AKI-related factors in HK-2 cells, which had been evaluated in vivo, was inhibited after EsA administration. Taken together, our study suggests that EsA effectively protects rats against septic AKI caused by CLP. PMID- 28637979 TI - The oral microbiome and human health. AB - In this brief review, we discuss our previous research on the relationship between the bacterial composition of salivary microbiota and periodontal disease. Analysis using a terminal restriction fragment length polymorphism method and an international comparison suggest that the predominance of the genera Prevotella and Veillonella in the salivary microbiota is attributable to periodontal disease conditions, and that the predominance of the genus Neisseria indicates healthy periodontal conditions. Furthermore, we recently used next-generation sequencing technology to perform a detailed large-scale analysis of the salivary microbiota. An important finding of that study was that high bacterial richness in the salivary microbiota was significantly associated with poor oral health, as indicated by decayed teeth, periodontitis, and poor oral hygiene. Another important result was that relative abundance of predominant bacteria in saliva was significantly associated with oral health-related conditions. Of the two different cohabiting groups of bacteria found in the salivary microbiota, a greater relative abundance of group I bacteria, which include Prevotella and Veillonella species, was associated with poor oral health, high body mass index, and old age. These findings suggest that the salivary microbiota reflects oral and systemic conditions. PMID- 28637980 TI - Satisfaction with dietary life affects oral health-related quality of life and subjective well-being in very elderly people. AB - Age-related deterioration in physical and oral health reduces healthy life expectancy and is thus an important problem for very elderly people. We investigated the effects of satisfaction with dietary life (SDL) in everyday life on oral health-related quality of life (OHRQoL) and subjective well-being and examined associations between these factors. We evaluated 426 elders aged 85 years or older. All participants completed a questionnaire that inquired about age, gender, drinking status, body mass index, cognitive function, disability, and comorbidities, among other covariates. Oral, physical, and mental health conditions were also examined. Associations of questionnaire results for SDL with items on subjective well-being (Philadelphia Geriatric Center Morale Scale [PGC] and World Health Organization-5 [WHO-5]) and OHRQoL (Geriatric Oral Health Assessment Index [GOHAI]) were confirmed with multiple logistic regression analysis. In a multivariate model adjusted for various confounders, participants with self-reported "enjoyable" SDL had significantly lower risks for having the lowest scores on the GOHAI, PGC, and WHO-5 (odds ratio [OR] = 0.460, 95% confidence interval [CI] = 0.277-0.762; OR = 0.589, 95% CI = 0.348-0.996; and OR = 0.452, 95% CI = 0.263-0.775, respectively). These associations remained after further adjustment for number of teeth. PMID- 28637981 TI - Effects of vascular endothelial growth factor on osteoblasts around dental implants in vitro and in vivo. AB - Vasculogenesis is a pivotal procedure during dental implant osseointegration and bone repair process. Vascular endothelial growth factor (VEGF), regarded as one of the most important vasculogenesis factor, also plays a central role in bone repair, but its role around dental implants is still unknown. In the present study, rat primary osteoblasts seeded on titanium discs were tested using proliferation, enzyme-linked immunosorbent assay, Real-time PCR, and alkaline phosphatase (ALP) expression. Chicken embryo chorioallantoic membrane (CAM) was used to test the vasculogenesis property. In vivo VEGF-coated implants assay was used to test the osteocalcin (OCN)- and CD31-positive cells around an implant. VEGF could significantly promote osteoblasts seeded on titanium surfaces proliferation and secretion of VEGF protein (P < 0.05); increasing of VEGF, VEGFR1, VEGFR2, NRP-1, ALP and Runx2 mRNA expression (P < 0.05); up-regulating ALP expression on days 7 and 11 (P < 0.01). Supernatant of VEGF-induced osteoblasts could promote CAM vasculogenesis (P < 0.05). In vivo, VEGF-coated implants could promote OCN- and CD31-positive cells around bone lacunas. The present study shows that VEGF could induce primary rat osteoblasts proliferation, VEGF protein secretion, ALP expression, and VEGF-related mRNA expression in vitro. Osteoblasts co-cultured with VEGF could promote neovascularization in chicken embryos. In the in vivo experiments, coating the implant with VEGF could promote osteoblasts and endothelial cell expression. PMID- 28637982 TI - In vivo evaluation of chitosan-glycerol gel scaffolds seeded with stem cells for full-thickness mandibular bone regeneration. AB - The aim of this study was to evaluate in vivo bone regeneration, mediated by adipose-derived stem cells (ADSCs), induced to differentiate into osteoblasts and carried by a scaffold gel. In the test group, bone regeneration was mediated by ADSCs, induced to differentiate into osteoblasts, and carried by a scaffold gel. In the control group a scaffold without cells was used. The scaffold, consisting of chitosan and glycerol phosphate, was maintained in situ by a cross-linked resorbable membrane. The osteogenic potential of ADSCs was confirmed by osteocalcin assay and Von Kossa staining performed before implantation. Histological assays detected an initial increase in bone formation in the test group compared with the control group. Microcomputed tomography analysis did not show significant differences between the two groups. Both histological and microcomputed tomography analysis were performed on the ex vivo specimens after a follow-up period of 8 weeks. We observed that differentiated ADSCs could increase bone regeneration and that the scaffold used here can be a suitable carrier to entrap and maintain the cells in situ. On the contrary, the membrane used was not functional in isolating the site of the defect from surrounding soft tissues and caused a significant inflammatory reaction. PMID- 28637983 TI - Repeatability of measurements of surface electromyographic variables during maximum voluntary contraction of temporalis and masseter muscles in normal adults. AB - This study evaluated the intraexaminer repeatability of measurements of surface electromyography (EMG) variables and functional indices of the myoelectric signals from the masseter and temporalis muscles bilaterally in 15 healthy men. The test was repeated on two different days without templates. The resting muscle activity was recorded once, and two kinds of maximum voluntary contraction (MVC) tasks were performed and recorded three times. The two MVC tasks involved clenching the teeth and biting down on two cotton rolls bilaterally with the posterior teeth. The intraclass correlation coefficient (ICC) of amplitude was >88% and that of frequency was >95% during the two MVC tasks but not under resting conditions. The ICC of the asymmetry and activity indices during the two MVC tasks was >76%. A Bland-Altman analysis revealed no significant difference in amplitude or frequency or in the two indices between the two days during the MVC tasks. In conclusion, the measurements of surface EMG variables and the indices obtained according to the study protocol were highly repeatable in healthy men. Additional studies using templates and intraexaminer measurement errors are warranted in both men and women for complete validation of these findings. PMID- 28637984 TI - Anti-inflammatory effect of rosuvastatin decreases alveolar bone loss in experimental periodontitis. AB - The effects of systemically administered rosuvastatin on alveolar bone loss (ABL), cytokine levels and oxidative status were investigated in rats with ligature-induced periodontitis. Rats were divided randomly into four groups: a non-ligated group (C); a non-ligated+rosuvastatin group (R); a ligated group (P); and a ligated+rosuvastatin group (PR). Ligatures were placed at the maxillary second molars, and rosuvastatin was administered for 14 days. After the rats had been euthanatized, histomorphometric and histological analyses were performed, and the serum levels of interleukin (IL)-1beta, IL-10 and oxidant and antioxidant parameters (malondialdehyde [MDA], superoxide dismutase, glutathione, and glutathione peroxidase) were evaluted by enzyme-linked immunosorbent assay. Rosuvastatin significantly decreased the extent of ABL, inflammatory infiltration and osteoclasts in periodontitis, but increased the numbers of osteoblasts. Although rosuvastatin reduced the levels of IL-1beta, they did not differ significantly between the PR and P groups. In the PR group, not only were IL-10 levels significantly higher but also the ratio of IL-1beta to IL-10 was lower than in the P group. Although MDA levels were significantly increased in the P group relative to the C group, they did not differ significantly between the PR and C groups. The present data suggest that rosuvastatin decreases ABL in ligature-induced periodontitis, and that its anti-inflammatory effect is more remarkable than its antioxidant effect. PMID- 28637985 TI - Three-dimensional evaluation of the location of the mandibular canal using cone beam computed tomography for orthodontic anchorage devices. AB - This study investigated guidelines for placement of monocortical screws in the mandible, particularly the mandibular canal. In this study of 35 patients, we used cone-beam computed tomography to determine the distance from the alveolar crest to the superior border of the mandibular canal (DMC) and the shortest distance from the buccal and lingual cortex to the mandibular canal (attaining distance) in the areas between premolars (premolar area), between the second premolar and first molar (middle area), and between the first and second molars (molar area). The DMC values for these areas were 16.55, 18.94, and 16.58 mm, respectively, and were similar in adults and adolescents. When the attaining distance was 8 mm, the heights on the buccal and lingual sides of the areas were 9 and 16.6 mm, 13.7 and 14.7 mm, and 15.3 and 12 mm, respectively. Risk of proximity to the mandibular canal should be considered at above heights or greater when an orthodontic anchorage device (OAD) 8 mm in length is placed. Careful attention is needed for placements on lingual side in adolescents. By reducing the OAD length to 6 mm, placement safety increases in all areas except the premolar area, especially on the buccal side. PMID- 28637986 TI - The logic behind the use of fissure sealant retention as a proxy outcome measure for dental caries prevention. AB - Fissure sealant retention is traditionally considered as a proxy measure for caries prevention. This study investigated the logic behind this proposition, and its validity. A logical framework of the proposition was established. The mechanism of caries development was transferred into a Directed acyclic graph, and this was used to investigate the logical framework. The sensitivity and specificity of full sealant retention in the prediction of dental carious lesion development and the number of false positive/false negative prediction rates were computed. The sensitivity/specificity was statistically compared to that of random values. A contradiction in the logical framework was identified. The mean sensitivity/specificity was 37.9% (SD = 27.8%) and 67.6% (SD = 28.4%), respectively. When these values were compared against random values (30.5%, SD = 25.7% and 58.7%, SD = 31.6%), a non-significant sensitivity (P = 0.06) and a borderline higher specificity (P = 0.04) were observed. The overall false prediction rate was 33.7%, with 16.9% and 16.8% false negative and false positive predictions, respectively. The sensitivity/specificity was too low and the false prediction rate was too high to consider retention a valid proxy for caries prevention. The logic behind the investigated proposition is flawed, contradicted by the current empirical evidence, and thus invalid. PMID- 28637987 TI - Three-dimensional finite element analysis of the effects of implant diameter and photofunctionalization on peri-implant stress. AB - Previous finite element analyses of peri-implant stress assumed a bone-implant contact (BIC) ratio of 100%, even though the BIC ratio is known to be approximately 50% or less. However, the recent development of ultraviolet treatment of titanium immediately before use, known as photofunctionalization, significantly increased the BIC ratio, to 98.2%. We used a unique finite element analysis model that enabled us to examine the effects of different BIC ratios on peri-implant stress. A three-dimensional model was constructed under conditions of vertical or oblique loading, an implant diameter of 3.3, 3.75, or 5.0 mm, and a BIC ratio of 53.0% or 98.2%. Photofunctionalization and larger implant diameters were associated with reduced stress on surrounding tissues. Under vertical loading, photofunctionalization had a greater effect than increased implant diameter on stress reduction. Under oblique loading, increased implant diameter had a greater effect than photofunctionalization on stress reduction. PMID- 28637988 TI - Comparison of gene expression profiles of gingival carcinoma Ca9-22 cells and colorectal adenocarcinoma HT-29 cells to identify potentially important mediators of SLPI-induced cell migration. AB - Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor whose expression level is positively correlated with tumor aggressiveness and metastatic potential. However, the mechanism underlying SLPI-induced enhancement of malignant phenotype is not completely understood. The malignancy of cancer cells is highly dependent on cell migration activity. Our previous study revealed that gingival carcinoma Ca9-22 cells, but not colorectal adenocarcinoma HT-29 cells, expressed SLPI. Therefore, we investigated the migration activity of these two cell types to understand the nature of SLPI-mediated tumor aggressiveness and metastatic potential. In vitro wound healing assay indicated that HT-29 cells and SLPI-deleted Ca9-22 cells showed lower migration activity than wild-type Ca9-22 cells, suggesting that SLPI-induced cell migration plays an important role in tumor aggressiveness and metastatic potential. In addition, our gene expression profiling study based on microarray data for the three cell types identified a number of candidates, including LCP1 and GLI, that could be key molecules in the mechanism of SLPI-induced cell migration. PMID- 28637989 TI - HLA-A*26-A*30 and HLA-DRB1*10 could be predictors of nasopharyngeal carcinoma risk in high-risk Tunisian families. AB - We investigated human leukocyte antigen (HLA) profiles for Tunisians with nasopharyngeal carcinoma (NPC), their families, and a sample of unrelated healthy Tunisians in order to identify HLA specificities associated with familial NPC. HLA-A, -B, and -DRB1 typing was successful for 36 NPC patients, 72 unaffected family members, and 130 community controls, and the chi square or Fisher exact test was used to compare allele frequencies between cases and controls. We observed a consistent protective effect of HLA-DRB1*10 on NPC development. However, none of the NPC patients or their family members had a positive result for this HLA marker (0% vs 9.2% in controls, P = 0.047). In addition, HLA-A*26 was probably an induction marker, as its allelic frequency was significantly higher among NPC patients than among controls (P = 0.003) and among NPC patients than among at-risk family members (P = 0.067). Logistic regression analysis of the joint effect of selected HLA specificities showed that HLA-A*26 and HLA-A*30 were co-associated and have an important effect on NPC risk. Despite the small size of our cohort, we showed that HLA-A*26-A*30 and HLA-DRB1*10 might be predictive markers for NPC screening of Tunisian families with a high risk of NPC. PMID- 28637990 TI - Effect of the leukotriene receptor antagonist montelukast on orthodontic tooth movement. AB - Asthma is a chronic inflammatory disease, and its prevalence is relatively high among children. Optimal management of asthma often requires long-term pharmacotherapy; however, the effects of these medications on orthodontic treatment is uncertain. We evaluated the effects of the leukotriene LTD4 receptor antagonist montelukast on orthodontic tooth movement in an animal model. Eight mongrel dogs were given montelukast for periods up to 4 weeks. An orthodontic force of 150-200 g was applied to move the second and fourth premolars toward the site of the extracted third premolar. The distance between premolars was measured at baseline and at weeks 1, 2, and 4. Histological examination with hematoxylin eosin staining was used to evaluate osteoclast activity. A slight delay in orthodontic movement and decreased osteoclast activity were observed in the montelukast-treated group, as compared with untreated controls. However, the differences were not statistically significant (P > 0.05). Our findings suggest that montelukast use will not interfere with orthodontic treatment of asthma patients. However, these findings require confirmation in clinical studies. PMID- 28637992 TI - Ten-year clinical observation of a porcelain laminate veneer seated with biological tissue adaptation (BTA) technique. AB - This clinical report describes the use of biological tissue adaptation technique for placement of a porcelain laminate veneer in a 50-year-old woman. The author developed this prosthetic technique to facilitate alignment of gingival levels for esthetic purposes. The laminate veneer was seated on the maxillary central incisor with an adhesive system. Although the margin of the restoration overhangs, no gingival inflammation or recession has been observed during a follow-up period of 10 years and 9 months. PMID- 28637991 TI - Low-intensity pulsed ultrasound inhibits lipopolysaccharide-induced IL-6 and RANKL expression in osteoblasts. AB - Periodontal disease is caused by inflammation induced by Porphyromonas gingivalis (P.g.) lipopolysaccharide (LPS) and involves expression of proinflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha, and receptor activator of nuclear factor kappa B ligand (RANKL), which are implicated in bone resorption. Low-intensity pulsed ultrasound (LIPUS) is commonly used in the treatment of bone fracture. However, the mechanisms by which LIPUS inhibits LPS-induced inflammatory cytokines are poorly understood. Therefore, we investigated the effects of LIPUS on LPS-induced expression of the proinflammatory cytokines IL-6 and RANKL. MC3T3-E1 cells were incubated in the presence or absence of P.g. LPS and then stimulated with LIPUS for 30 min/day for a maximum of 14 days. LPS increased mRNA and protein expressions of IL-6 and RANKL on day 14. In addition, mRNA expression of COX-2 LPS was higher after 3 and 7 days of LIPUS treatment. PGE2 was induced by LPS after 7 and 14 days of culture. LIPUS suppressed all stimulatory effects of LPS. These results suggest that LIPUS inhibits LPS-induced expression of inflammation cytokines by suppressing PGE2 production and might thus have potential applications in the treatment of periodontitis. PMID- 28637993 TI - Association between Excessive Alcohol Use and Alcohol-Related Injuries in College Students: A Multi-Center Cross-Sectional Study in Japan. AB - Alcohol-related injuries in college students are a major public health problem worldwide. We clarified the association between excessive drinking and alcohol related injuries in Japanese college students. This was a cross-sectional study with a self-administered questionnaire. From January to March 2013, we sampled all college students and graduate students aged 20 years or older during annual health examinations at three colleges in Mie Prefecture in Japan. The questionnaire assessed the frequency of alcohol drinking, amount of alcohol consumed per day, binge drinking during the past year, alcohol-related injuries during the past year, and demographic data. Logistic regression analysis was conducted on the association between excessive alcohol use and alcohol-related injuries. A total of 2,842 students underwent health examinations, of whom 2,177 (76.6%) completed the questionnaire. Subjects included 1,219 men (56.0%) and 958 women (44.0%). Eighty-eight men (7.2%) and 93 women (9.7%) were classified as excessive weekly drinkers, while 693 men (56.8%) and 458 women (47.8%) were determined to be binge drinkers. Eighty-one men (6.6%) and 26 women (2.7%) had experienced alcohol-related injuries during the past year. In the logistic regression analysis, binge drinkers (odds ratio 25.6 [8.05-81.4]) and excessive weekly drinkers (odds ratio 3.83 [2.41-6.09]) had a history of significantly more alcohol-related injuries, even after adjusting for age and sex. In conclusion, alcohol-related injuries in college students in Japan were strongly associated with excessive drinking. As a strategy for preventing such injuries in this population, an interventional study is required to identify effective methods for reducing excessive alcohol use. PMID- 28637994 TI - Anti-diabetic activities of traditional Chinese herbal medicine in streptozotocin induced diabetic rats. AB - Zhen Qi Hypoglycemic Capsules (ZQHC) is a traditional Chinese herbal medicine containing medical activities by ougi (Astragalus membranaceus) and ousei (Polygonatum rhizome). Although ZQHC has been traditionally utilized as an anti diabetic medicine in China, there is no evidence. Therefore, this study investigated the beneficial effects of ZQHC against diabetes using streptozotocin (STZ)-induced diabetic rats by biochemical and morphological methods. Eight-week old male Fisher strain rats were intraperitoneally injected with STZ (50 mg/kg of B.W.) to induce diabetes and were fed ad lib feeding with normal diet containing 4% ZQHC for 30 days. Blood and urine samples were collected for biochemical analysis, and liver and pancreas samples were prepared for morphological analysis. Values of blood glucose, AST and ALT of ZQHC oral administrated diabetic rats were lower than those of diabetic rats without administration. Morphological analysis revealed that ZQHC induced sustainment of insulin secreted beta cells survival and suppression of hepatocellular fat droplet accumulation. These results suggested that oral administration of ZQHC has anti-diabetic activities those were mainly associated with improvement of liver metabolism. PMID- 28637995 TI - Intracranial Bony Canal of the Middle Meningeal Artery - Morphological and Histological Analysis. AB - : The middle meningeal artery (MMA) can play an important role in the surgical revascularization. However, the MMA can be easily injured if it passes through a bony canal. We investigated the morphological and histological features of the bony canal to improve surgical results. MATERIALS AND METHODS: Fifty adult dry skulls were investigated. The length of the bony canal and the distance from the orbital rim to the bony canal were measured. Additionally, 28 cadaveric heads were examined histologically. RESULTS: Sixty-three bony canals were found in 43 skulls. The mean length of bony canals was 9.2 mm, and the mean distance from the orbital rim was 24.0 mm. The bony canal ran mainly from the sphenoid bone (69.8%) to the parietal bone (73.0%). Histologically, both sides of the meningeal grooves gradually closed the distance, and formed the bony canal. The MMA inside the bony canal was enveloped with collagen tissues, divided into branches, and was accompanied by the vein. CONCLUSIONS: The bony canal is located around the pterion and is formed during bone growth. The MMA is covered with collagen tissues inside the bony canal. It is possible to safely expose and preserve the MMA during craniotomy with careful drilling. PMID- 28637996 TI - The localization of calcitonin gene-related peptide in the human trigeminal ganglion and masseter muscle. AB - The localization of calcitonin gene-related peptide (CGRP) is similar to that of a neurotransmitter which indicates masticatory muscle pain in the area of the masseter fascia. CGRP is released from the trigeminal ganglion (TG). The aim of this study was to analyze the distribution of CGRP in the fascia of the masseter muscle (FMM) and TG in a morphometric manner, with respect to the location and density of CGRP-immunopositive reaction fiber (CGRP-IRF). A higher number of the CGRP-IRF were mainly found located around elongated blood vessels and small nerves on the origin side of the middle zone FMM in the O group (presented with occlusion). In the sectional histochemical analysis of the O group, the CGRP-IRF were clearly detected in oval vessels, large elongated vessels and large nerves in contrast with that of the Non-O group (presented with no occlusion) samples. The number of CGRP-immunopositive ganglion cells (CGRP-IPGCs) in the O group mandibular nerve division was higher than that of other divisions. A reduction of the CGRP-IRF numbers were found in the no-loading groups. The characterization of these locations of CGRP-IPGCs can also provide useful data for the understanding of myofascial pain syndrome of the masseter muscle (MM). PMID- 28637998 TI - Reinvestigation of the Morphological Characteristics of the Lateral Ulnar Collateral Ligament in Humans. AB - To clarify the cause of posterolateral rotatory instability after damage to the lateral ulnar collateral ligament (LUCL), the morphological characteristics of the LUCL were reinvestigated and three-dimensional (3D) image of the ligament was reconstructed using 35 human elbows. The results were as follows: 1) the insertion point of the LUCL on the humerus was almost at the center of the capitellum, and its width was 2.61 +/- 1.02 mm. The insertion point of the LUCL on the ulna was located from the lesser sigmoid notch to the supinator crest and had a width of 9.0 +/- 2.8 mm. The proximal insertion of the LUCL on the ulna was 7.0 +/- 3.0 mm, and the distal part was on the articular surface of the radial head. 2) Three-dimensional imaging of the LUCL revealed an anterior curved shape that covered the radial head. Based on these results, it was clear that both the supinator crest and the lesser sigmoid notch could be useful as osseous landmarks. We think that these anatomical results are useful for surgeons performing LUCL reconstruction. PMID- 28637997 TI - Positional relationships of abdominal aortic branches for contrast radiography of the inferior mesenteric artery using the coeliac trunk and superior mesenteric artery as landmarks. AB - PURPOSE: To establish a method by which angiography of the inferior mesenteric artery (IMA) can be performed smoothly, we investigated the relative locations of the coeliac trunk (CT), superior mesenteric artery (SMA), IMA, and left renal artery (LtRA). METHODS: From a total of 60 cadavers, 32 cadavers with few arteriosclerotic lesions and little vascular tortuosity were selected for the study. The abdominal aorta (Ao) were removed and incised on both lateral side, along the vertical axis and transected into the ventral and dorsal sides. The intravascular lumen on the ventral side of the Ao was photographed using a digital camera, and the horizontal and vertical diameters of the sites of confluence of the CT, SMA, and IMA, were measured on the computer screen. We also calculated the distances between the branches, including the CT, SMA, IMA, LtRA, and the common iliac artery (CoI). RESULTS: Although the SMA-IMA distance did not correlate with the CT-SMA distance, the ratio of the SMA-IMA to CT-CoI distance was four times greater than the ratio of the CT-SMA to CT-CoI distance. CONCLUSIONS: The site of branching of the IMA can be inferred to some extent from the CT and SMA distance. PMID- 28637999 TI - A morphological study of the foramina of the mandible in the Japanese macaque by cone-beam computed tomography. AB - The mandibular canal (MC) contains vessels and nerves in the mandible of the Japanese macaque (JM). The inferior alveolar nerves and vessels of the mandible insert from the mandibular foramen and then run through the MC, the mental foramen and spinal foramen to the outside of the mandible. However, the detailed morphological properties of multiple canals, such as the accessory canal (AC) of the mandible, are unknown in JMs. The purpose of this study was to describe the multiple canals of JMs and to determine the location and analyse the measurements of the JM mandible. In this study, we also showed the course of the lingual foramen in 17 JMs (male: n = 8; female: n = 9) using cone-beam computed tomography (CBCT). In our results, we classified multiple mental foramina and multiple lingual foramina found on the mandibular body at the premolar or molar region. However, there was no significance between the formation of mandibular properties and the lingual foramen. These multiple foramina contain nerves and blood vessels have a few branched canals; these branches run downward and connect with the inferior mandibular nerve and artery. These morphological features may provide useful information about surgical treatment of the alveolus in a human model. PMID- 28638000 TI - Effectiveness of workplace exercise supervised by a physical therapist among nurses conducting shift work: A randomized controlled trial. AB - OBJECTIVES: This study aimed to evaluate the effectiveness of supervised exercise among nurses conducting shift work for health promotion. METHODS: A total of 30 healthy female nurses conducting shift work participated in this study and they were randomly assigned to one of the following 2 groups: The supervised exercise group (SG; participants exercised under the supervision of a physical therapist (PT)) and the voluntary exercise group (VG; participants exercised without supervision). The study participants were asked to exercise twice/week for 12 weeks for 24 sessions. The primary outcome was aerobic fitness, and the secondary outcomes were muscle strength, anthropometric data, biochemical parameters, and mental health. We compared all the outcomes before and after the intervention within each group and between both groups at follow-up. RESULTS: Aerobic fitness increased in the SG whereas it decreased in the VG, but these changes were not statistically significant (p=0.053 and 0.073, respectively). However, the between group difference was significant in the intervention effect (p=0.010). Muscle strength, high-density lipoprotein cholesterol and metabolic profile (high molecular weight adiponectin), and depressive symptom significantly improved in the SG over time, even though the SG exercised less as compared with the VG. Moreover, significant differences in muscle strength, and low-density lipoprotein cholesterol and reactive oxygen metabolite levels were observed between both groups, and these parameters were better in the SG than in the VG. CONCLUSIONS: Our data-suggest the effectiveness of exercise supervised by a PT at the workplace of nurses conducting shift work for health promotion. PMID- 28638001 TI - Comparison between Glioblastoma and Primary Central Nervous System Lymphoma Using MR Image-based Texture Analysis. AB - PURPOSE: To elucidate differences between glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL) with MR image-based texture features. METHODS: This was an Institutional Review Board (IRB)-approved retrospective study. Consecutive, pathologically proven, initially treated 44 patients with GBM and 16 patients with PCNSL were enrolled. We calculated a total of 67 image texture features on the largest contrast-enhancing lesion in each patient on post contrast T1-weighted images. Texture analyses included first-order features (histogram) and second-order features calculated with gray level co-occurrence matrix, gray level run length matrix (GLRLM), gray level size zone matrix, and multiple gray level size zone matrix. All texture features were measured by two neuroradiologists independently and the intraclass correlation coefficients were calculated. Reproducible features with the intraclass correlation coefficients of greater than 0.7 were used for hierarchical clustering between the cases and the features along with unpaired t statistics-based comparisons under the control of false discovery rate (FDR) < 0.05. Principal component analysis (PCA) was performed to find the predominant features in evaluating the differences between GBM and PCNSL. RESULTS: Twenty-one out of the 67 features satisfied the acceptable intraclass correlation coefficient and the FDR constraints. PCA suggested first-order entropy, median, GLRLM-based run length non-uniformity, and run percentage as the distinguished features. Compared with PCNSL, run percentage and median were significantly lower, and entropy and run length non-uniformity were significantly higher in GBM. CONCLUSIONS: Among MR image-based textures, first-order entropy, median, GLRLM-based run length non-uniformity, and run percentage are considered to enhance differences between GBM and PCNSL. PMID- 28638002 TI - Predictors of International Normalized Ratio Variability in Patients With Atrial Fibrillation Under Warfarin Therapy. AB - BACKGROUND: Variability in the international normalized ratio (INR) of prothrombin time has been suggested to be related to outcome in patients with atrial fibrillation (AF) under warfarin therapy, but its determinants remain unclear.Methods and Results:The study population consisted of 626 AF patients under warfarin therapy in the Shinken Database (n=22,230). INR variability was calculated by Fihn's method. Determinants of high log INR variability (defined as over mean+standard deviation) were determined by logistic regression analyses. Symptomatic heart failure (odds ratio [OR] 3.974, 95% confidence interval [CI] 2.510-6.292), older age (>=75 years old; OR 2.984, 95% CI 1.844-4.826) and severe renal dysfunction (eGFR <30 mL/min/1.73 m2; OR 3.918, 95% CI 1.742-8.813) were identified as independent predictors of high INR variability on multivariate logistic regression analysis. CONCLUSIONS: The determinants of INR variability in AF patients under warfarin therapy could assist Japanese clinicians in identifying patients likely to show unstable warfarin control irrespective of the definition of the target INR range. PMID- 28638003 TI - Molecular and cellular events during blastocyst implantation in the receptive uterus: clues from mouse models. AB - The success of implantation is an interactive process between the blastocyst and the uterus. Synchronized development of embryos with uterine differentiation to a receptive state is necessary to complete pregnancy. The period of uterine receptivity for implantation is limited and referred to as the "implantation window", which is regulated by ovarian steroid hormones. Implantation process is complicated due to the many signaling molecules in the hierarchical mechanisms with the embryo-uterine dialogue. The mouse is widely used in animal research, and is uniquely suited for reproductive studies, i.e., having a large litter size and brief estrous cycles. This review first describes why the mouse is the preferred model for implantation studies, focusing on uterine morphology and physiological traits, and then highlights the knowledge on uterine receptivity and the hormonal regulation of blastocyst implantation in mice. Our recent study revealed that selective proteolysis in the activated blastocyst is associated with the completion of blastocyst implantation after embryo transfer. Furthermore, in the context of blastocyst implantation in the mouse, this review discusses the window of uterine receptivity, hormonal regulation, uterine vascular permeability and angiogenesis, the delayed-implantation mouse model, morphogens, adhesion molecules, crosslinker proteins, extracellular matrix, and matricellular proteins. A better understanding of uterine and blastocyst biology during the peri-implantation period should facilitate further development of reproductive technology. PMID- 28638004 TI - Modification of the HCMV-specific IFN-gamma release test (QuantiFERON-CMV) and a novel proposal for its application. AB - Human cytomegalovirus (HCMV) is universally distributed among humans without any adverse effects; however, it induces severe diseases in immunocompromised patients such as organ transplant recipients and AIDS patients. To manage these immunocompromised patients, an easy clinical examination for the monitoring of disease risk is required. In this study, we modified the interferon-gamma (IFN gamma) release test (QuantiFERON(r)-CMV) using HCMV immediate early-1 (IE-1) or pp65 whole proteins, or UV-inactivated HCMV particles as an antigen. The response of heparinized peripheral blood from healthy volunteers to the pp65 protein showed an obvious dose-dependent sigmoid curve, although no correlation was observed between results of this assay and an ELISPOT assay. The addition of pp65 to the blood samples at a final concentration of 1*103 to 1*105 pg/ml was found to be optimum. Using this assay, we observed a significant enhancement in cellular immunity in volunteers after the daily ingestion of yogurt for 8 weeks, which suggested a novel application of the assay in addition to monitoring HCMV infection risk. IFN-gamma secretion from peripheral blood cells on HCMV-antigen stimulation differed significantly between individuals; therefore, the assay could not be normalized. Nevertheless, it was found to be particularly useful for observing fluctuations in cellular immune activity on an individual level. PMID- 28638005 TI - Sclerosing Mesenteritis Causing Chylous Ascites and Small Bowel Perforation. AB - BACKGROUND Sclerosing mesenteritis (SM) is a rare idiopathic inflammation and fibrosis of the mesentery. Its etiology and pathogenesis remain unclear. It has been linked to abdominal trauma related to peritoneal dialysis, recent abdominal surgery, idiopathic inflammatory disorder, paraneoplastic syndrome, ischemia/infection, and autoimmunity. Abdominal CT is the most sensitive imaging modality, and diagnosis is usually confirmed by surgical biopsy. Patients most often present with abdominal pain, nausea, vomiting, diarrhea, and weight loss, and less commonly with chylous ascites and small bowel obstruction. Treatment is usually supportive; surgical intervention may be attempted for life-threatening complications such as bowel obstruction or perforation. CASE REPORT This report describes an 80-year-old man with hypertension and end-stage renal disease (ESRD) presenting with increasing abdominal pain and tenderness over the past 5 months. Abdominal enhanced computed tomography (CT) revealed a fat-ring sign and peritoneal calcifications along the serosa surface of small bowel consistent with sclerosing mesenteritis. His hospital course was complicated by increasing ascites requiring multiple ultrasound-guided paracentesis, worsening leukocytosis, and persistent hypotension after dialysis, requiring pressor support. Ascitic fluid analysis was consistent with chylous ascites. The patient subsequently developed small bowel obstruction causing focal perforation, leading to the death of our patient. In this report, we review the clinical presentation, radiographic findings, treatment, and outcome in our patient and review the relevant literature. CONCLUSIONS Diagnosis of sclerosing mesenteritis is challenging due to its nonspecific clinical features. Sclerosing mesenteritis is a debilitating albeit self-limiting disorder that can rarely become fulminant, largely due to its complications. PMID- 28638006 TI - Effect of Probiotics on Glucose and Lipid Metabolism in Type 2 Diabetes Mellitus: A Meta-Analysis of 12 Randomized Controlled Trials. AB - BACKGROUND It has been unclear whether supplemental probiotics therapy improves clinical outcomes in type 2 diabetic patients. This meta-analysis aimed to summarize the effect of probiotics on glucose and lipid metabolism and C-reactive protein (CRP) from 12 randomized controlled trials (RCTs). MATERIAL AND METHODS An up-to-date search was performed for all relevant RCTs up to April 2016 from PubMed, Embase, and Cochrane Library. Standardized mean difference (SMD) and weighted mean difference (WMD) were calculated for a fixed-effect and random effect meta-analysis to assess the impact of supplemental probiotics on fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile, and CRP level. RESULTS A total of 12 studies (684 patients) were entered into the final analysis. The effect of probiotics was significant on reducing HbA1c level (standardized mean difference [SMD], -0.38; confidence interval [CI], -0.62 to 0.14, P=0.002; I2=0%, P=0.72 for heterogeneity), fasting insulin level (SMD, 0.38; CI -0.59 to -0.18, P=0.0003; I2=0%, P=0.81 for heterogeneity), and HOMA-IR (SMD, -0.99; CI -1.52 to -0.47, P=0.0002; I2=86%, P<0.00001 for heterogeneity). Pooled results on effects of probiotics on FPG, CRP, or lipid profile were either non-significant or highly heterogeneous. CONCLUSIONS This meta-analysis demonstrated that probiotics supplementation was associated with significant improvement in HbA1c and fasting insulin in type 2 diabetes patients. More randomized placebo-controlled trials with large sample sizes are warranted to confirm our conclusions. PMID- 28638007 TI - [Re-operations in patients with heart wounds]. AB - AIM: To define the risk factors of complications which are followed by re operations in patients with cardiac and pericardial wounds and to prevent these complications. MATERIAL AND METHODS: Retrospective and prospective analysis of 1072 victims with cardiac and pericardial injuries for 35 years was performed. Overall mortality was 17.2%. 98 patients died during surgery. Postoperative bleeding was observed in 38 (3.9%) cases. RESULTS: In 28 cases re-operations were performed for bleeding-related complications. Indications for re-thoracotomy were one-time drainage from pleural cavity over 500 ml or bleeding rate over 100 ml per hour for 4 hours. Prevention of postoperative bleeding in case of cardiac and pericardial wounds was developed on basis of analysis of these observations. CONCLUSION: Risk factors of complications requiring re-operation are cardiomyopathy of different etiology, technical and tactical errors during primary intervention and hypocoagulation with massive blood loss. Prevention of these complications includes careful heart wound closure, comprehensive intraoperative control, correction of hemostatic system. PMID- 28638008 TI - [The results of pulmonary veins isolation to prevent postoperative atrial fibrillation]. AB - AIM: To compare an efficacy of primary surgical (epicardial bipolar pulmonary veins isolation) and pharmacological (amiodarone) prevention of postoperative atrial fibrillation. MATERIAL AND METHODS: The study included 117 patients with coronary artery disease without previous paroxysms of atrial fibrillation who were randomized into 3 groups. The first (I) group (n=39) included patients who underwent coronary artery bypass grafting without radiofrequency ablation of pulmonary veins and prophylactic amiodarone administration. The second (II) group (n=38) consisted of patients who received amiodarone as a prevention of postoperative atrial fibrillation. In the third (III) group (n=40) simultaneous CABG and pulmonary veins isolation were made. RESULTS: The incidence of atrial fibrillation in early postoperative period was significantly lower in the 3rd group compared with control group (90% vs 69.2%, p=0.021). 1-year freedom from atrial fibrillation was 97.5% in group III vs. 84.2% in group II (p=0.004). In group I the incidence of early postoperative atrial fibrillation was 30.8% with following decrease to 17.9% in 12 months. CONCLUSION: Simultaneous preventive pulmonary veins isolation during CABG is safe and effective, significantly reduces duration of hospital-stay and incidence of postoperative atrial fibrillation. PMID- 28638009 TI - [Videolaparoscopy in diagnosis and treatment of diseases simulating acute appendicitis]. AB - AIM: To analyze videolaparoscopic diagnosis and treatment of abdominal pathology simulating acute appendicitis (AA). MATERIAL AND METHODS: For the period 2008 2015 at Sklifosovsky Research Institute of Emergency Care 2784 patients with suspected AA underwent clinical, laboratory and ultrasonic examination. Depending on survey results patients were divided into 2 groups. Group I included 1352 (48.6%) patients with AA, group II - 1432 (51.4%) patients with suspected AA. All of them underwent videolaparoscopy. RESULTS AND DISCUSSION: Videolaparoscopy confirmed AA in 1308 (96.7%) patients of group I and 856 (59,8%) patients of group II. In the 1st group 36 (2.7%) patients had pathology simulating AA and 8 (0.6%) patients had not organic changes; in the 2nd group these values were 462 (32.3%) and 114 (7.9%) respectively. Absence of organic changes was explained by functional bowel disorders. In 95 (3.4%) out of 498 (17.9%) patients of both groups with simulating diseases videolaparoscopy was made and in 49 (1.8%) cases indications for laparotomy were established. In 354 (12.7%) patients with simulating diseases and 122 (4.4%) patients without organic changes operations were not carried out. CONCLUSION: Videolaparoscopy in patients scheduled for appendectomy or with unclear clinical picture allows to diagnose various forms of AA, simulating diseases and to perform necessary surgery. PMID- 28638011 TI - [Collagen types ratio in prediction of postoperative ventral hernias]. AB - AIM: To analyze collagen types ratio in skin and aponeurosis in order to predict postoperative ventral hernias. MATERIAL AND METHODS: The trial included 141 patients for the period 2012-2015. Group I (n=65) of patients without ventral hernias was divided into subgroup AI (primary operation, n=41) and BI (re operation, n=24). Group II consisted of 76 patients with ventral hernias. We performed histological examination of skin and aponeurosis to define the collagen structure of connective tissue. RESULTS: There were significant differences between collagen type I/III ratio in skin (2.81+/-0.52 in group I vs. 1.13+/-0.48 in group II) and aponeurosis (2.69+/-0.41 vs. 1.09+/-0.21, respectively, p<=0.05). We revealed strong direct correlation (r=+0.92) between aponeurosis and skin specimens in one group. Collagen type I level was 73.81+/-2.74% in subgroup AI and 72.03+/-2.47% in subgroup BI. Collagen type I was predominant (p<=0.05). CONCLUSION: In patients with ventral hernias collagen type I/III ratio in skin is 2.54 times lower than in patients without hernias. Significant correlation of collagen types in skin and aponeurosis (r= +0.92) allows to predict the risk of postoperative ventral hernias on basis of skin fragment. PMID- 28638012 TI - [Comparative analysis of laparotomy closure techniques]. AB - AIM: To assess experimentally different laparotomy closure techniques. MATERIAL AND METHODS: Experimental research on laboratory animals was performed. Laboratory animals underwent laparotomy followed by aponeurosis suturing by using of interrupted, continuous suture and continuous suture with an arrangement of stitches at different levels. Tensometric and histological examination of tissue specimens together with sutures was made in 7, 14, 60 days after surgery. RESULTS: Correlation of laparotomy closure technique with values of durability, elasticity and wound process course was obtained. CONCLUSION: Continuous suture after laparotomy promotes the formation of more mature granulation tissue and more solid scar with low elasticity compared with interrupted sutures. PMID- 28638010 TI - [Evaluating an effectiveness of surgical treatment of gastroesophageal reflux disease combined with hiatal hernia]. AB - AIM: To assess an effectiveness of surgical treatment of gastroesophageal reflux disease (GERD) combined with hiatal hernia (HH). MATERIAL AND METHODS: The trial included 96 patients with GERD and HH who were divided into 2 groups. The principal difference between groups was the use of surgery in the main group and therapeutic treatment in the comparison group. RESULTS: The effectiveness of surgical treatment is superior to therapeutic treatment of GERD by more than 2.5 times. CONCLUSION: HH combined with GERD is an indication for surgical treatment. Fundoplication cuff should not lead to angular and rotational esophageal deformation. Nissen procedure in Donahue modification (Short Floppy Nissen) simulates optimally the geometry of esophago-gastric junction and His angle. PMID- 28638014 TI - [Sliding ingvinal haernias in children]. AB - AIM: To study the features of diagnosis and treatment of children with sliding inguinal hernias. MATERIAL AND METHODS: 30-year experience of treatment of 19 boys with sliding inguinal hernia and 1 boy with bilateral sliding femoral hernia was analyzed. RESULTS: 14 out of all children with inguinal and femoral hernia admitted with the diagnosis of incarcerated inguinal hernia. Accurate diagnosis was established during the operation as a rule. Surgical treatment of sliding hernias in children presents some difficulties. Intraoperative injury of bladder was observed in 2 children with sliding inguinal hernia. All children with sliding hernias have recovered after surgery. CONCLUSION: Sliding inguinal hernia in children are rare, sliding femoral hernia is even rarer. In most cases children with sliding inguinal hernias are diagnosed with incarcerated inguinal hernia. Colon and bladder as the elements of sliding inguinal hernias remain viable after infringement. PMID- 28638013 TI - [Surgical treatment of diabetic neuroosteoarthropathy (DNOAP) and its long-term results]. AB - AIM: To develop pathogenetically justified surgical treatment of diabetic neuroosteoarthropathy (DNOAP). MATERIAL AND METHODS: 52 patients were operated and long-term results were studied in 36 of them. 2 groups were assessed depending on completeness of surgical treatment including changed synovial structures removal. Tarso-metatarsal arthrodesis was created after synovectomy in median foot to restore longitudinal arch. Cruro-calcaneal neoarthrosis was performed after elimination of posterior focus of DNOAP. Excision of large, deep plantar ulcer (or osteomyelitic fistula) was completed by tissues tension with needles for primary wound healing. RESULTS: DNOAP patients are tolerant against surgical infection that is decreased in patients with neuropathic form of diabetic foot syndrome. Skin plasty is followed by rejection in DNOAP that was cured with prednisolone. Deep suppurations complicating foot skeleton fragmentation have subacute course and do not lead to sepsis. Infected wounds heal by primary intention in 98% after closure with primary suture. It was empirically found that synovectomy and osteochondral detritus removal discontinue DNOAP course. Reconstructive surgical stage is aimed to restoring the shape and function of the foot. Analysis of long-term outcomes showed absence of DNOAP signs in 76.2+/-9.2% of cases after radical surgery and positive results of treatment in 97.2+/-2.7% of patients. CONCLUSION: Our data conceptually assume the possibility of autoimmune mechanism in DNOAP pathogenesis. On this basis pathogenetically reasonable surgical procedures are established to interrupt pathological process. These interventions differ by technological aspects only depending on middle or rear foot destruction. PMID- 28638015 TI - [Microelemental homeostasis correction of and oxidative stress in patients with acute intestinal obstruction]. AB - AIM: To improve the results of treatment of patients with acute small bowel obstruction. MATERIAL AND METHODS: The research is based on the results of a comprehensive survey 202 people with acute small bowel obstruction. Reamberin was used in 102 patients treatment. RESULTS: It was established that metalloenzymes take an active part in the formation of endotoxemia in people with acute small bowel obstruction. Also, in patients as a result of an imbalance between oxidant and antioxidant systems, accumulated a significant amount of lipid peroxidation products, along with it a decrease activity of enzymes of antioxidant system. reamberin application in complex treatment of acute small bowel obstruction provided the reduction in the time correction of oxidative stress by preventing the growth and activity of lipid peroxidation products with simultaneous stimulation of the antioxidant system and contributed to the normalization of microelement homeostasis. PMID- 28638016 TI - [Atrioventricular junction reconstruction in severe calcification of mitral fibrous annulus]. PMID- 28638017 TI - [Intraoperative disinfection, sterilization and repeated use of infected titanium implant in treatment of scalp radial ulcer with recurrent meningioma]. PMID- 28638018 TI - [Results of treatment of gastric cancer and metachromic metastases in liver and lungs]. PMID- 28638019 TI - [Extracorporeal circulation in cardiac surgery: state of the problem]. PMID- 28638020 TI - [Anatomico-morphological justification of nerve-sparing lymphodissection for breast cancer]. PMID- 28638021 TI - [Right ventricular dysfunction after tetralogy of Fallot repair: are all questions resolved?] PMID- 28638022 TI - [Resolution of National Surgical Congress. April 8, 2017, Moscow]. PMID- 28638023 TI - [The development of ideas about the organization of the speech system]. AB - This work represents an insight into a problem of studying one of the higher mental functions of humans - speech, its primary role in the development of man as a biosocial being. Various concepts of speech and the problem of the dominance of cerebral hemispheres in language function are analyzed. It touched upon the ontogenesis of hemispheric asymmetry. The problem of 'codominance' of right and left hemispheres depending on the nature of the task solving by the subject and the functional level of information processing is discussed. The authors highlight that the problem has an interdisciplinary nature, it is marked at the junction of neurophysiology, neuropsychology, neurology and defectology. PMID- 28638025 TI - [Music therapy as an effective method of neurorehabilitation]. AB - AIM: To assess the role of music therapy in the recovery of motor, speech and autonomic functions in patients with ischemic stroke (II). MATERIAL AND METHODS: Forty-five patients with II in the middle cerebral artery were examined. The patients were randomized into three groups (main, comparison and control) of 15 individuals each. With patients of the first and the second groups on the 3rd, 5th, 7th and 9th days of the rehabilitation period the special set of exercises with music and without that respectively was fulfilled. The third group received a basic set of physical exercises (a control group).The third group was control. Dynamics of patients' state was estimated by the NIHSS, the Rivermead Mobility Index, the Action Research Arm Test and the modified scale for speech evaluation on the 2nd, 4th, 6th, 8th and 10th day of disease. A study of cardiorespiratory synchronization was conducted since the 6th day of stroke. RESULTS AND CONCLUSION: The statistically significant efficacy of music therapy was shown for all parameters. The authors suggest that neuroplasticity may underlie the mechanisms of the programs used in the study. PMID- 28638024 TI - [Diagnosis and treatment of cognitive impairment in adults with attention deficit hyperactivity disorder]. AB - AIM: To qualify cognitive impairment in adults with attention deficit hyperactivity disorder (ADHD) and evaluate the efficacy of memoplant in the treatment of this pathology. MATERIAL AND METHODS: The authors present the results of the clinical, psychological and electroencephalographic examination of 40 patients with ADHD, aged from 18 to 45 years. All patients received memoplant in dose of 240 mg a day for 8 weeks. RESULTS AND CONCLUSION: Adult patients with ADHD were characterized by both subjective and objective disorders of memory and attention. The results of the electroencephalographic study suggested the dysfunction of the frontal-thalamic regulatory system and the lack of non specific activation of the reticular formation. After treatment, clinical improvement was observed in 24 patients (60.0%). Repeated psychological and neuropsychological examinations showed a reduction of inattention and improvement of memory performance. PMID- 28638026 TI - [Analysis of the efficacy of reflexology in the complex treatment of chronic migraine]. AB - AIM: To evaluate the effect of different reflexology techniques on main clinical indices of patients with chronic migraine, the number of analgesics used and dynamics of chronic migraine comorbid disorders. MATERIAL AND METHODS: The study included 84 patients (60 women (71.5%) and 24 men (28.5%)), aged from 18 to 63 years, with a diagnosis of chronic migraine. Patients were randomized in 4 groups - Su Jok (n=22), acupuncture (n=22), electroacupuncture (n=20), control (n=20). Topiramate was administered in all groups in dose of 100 mg daily. Patients were evaluated before treatment, after 4 and 16 weeks from randomization. RESULTS: There was a marked regression in frequency of headache in reflexological groups in comparison with the control. The number of days with headache was 19+/-1.12 at baseline and 6.57+/-1.3 days after treatment in the Su Jok group; 21.6+/-1.688 and 7+/-1.786 days in the acupuncture group; 20.25+/-1.97 and 5.75+/-0.633 days in the electroacupuncture group. Each of the methods had an impact on various clinical aspects of chronic migraine and comorbid disorders: Su Jok was most effective in treatment of autonomic disorders, the use of acupuncture resulted in the significant reduction of headache intensity and regression of anxiety disorders. The electroacupuncture group showed a significant increase in pain threshold and the least number of days with headache per month. CONCLUSION: Reflexotherapy is a method of choice in the complex treatment of patients with chronic migraine. Taking into account complex diagnosis, the individually oriented approach in prescribing of different reflexology techniques for successful treatment and subsequent rehabilitation of patients with chronic migraine is required. PMID- 28638027 TI - [The drug-drug interactions in a psychiatric hospital]. AB - An analysis of 132 drugs used in a psychiatric hospital for the estimation of the possibility of drug-drug interactions has been carried out. It has been established that one in five potential combination has a drug-drug interaction with clinically significant interactions being more frequent. Psychotropic drugs occupy a leading position in the number of such interactions. This analysis is able to improve the safety of the combined pharmacotherapies by choosing an alternative drug, correction of dose or active monitoring of the clinical condition of the patient, including laboratory and instrumental data. PMID- 28638028 TI - [Main directions of differential diagnosis optimization and rational treatment of an acute vertigo attack]. AB - AIM: To develop and assess the validity of the clinical algorithm VERTIGO for the differential diagnosis of central and peripheral vertigo and optimization of treatment of patients with vertigo. MATERIAL AND METHODS: Sixty-five patients with an acute attack of vertigo, aged from 18 to 75 years (53+/-6.7 years), were studied. All patients underwent standard neurological examination. In case of signs of central vertigo, patients underwent neuroimaging. Diagnostic accuracy, sensitivity and specificity of the VERTIGO algorithm as well as its positive and negative prognostic values were calculated. RESULTS: The sensitivity of VERTIGO for the diagnosis of central vertigo was 100% (95% CI: 78.2-100%), specificity 94.0% (95% CI: 83.5-98.8%), positive prognostic value 83.3% (95% CI: 58.6-96.4%); negative prognostic value 100% (95% CI: 92.5-100%). Cohen's kappa estimated by the results of final diagnosis was 0.88. CONCLUSION: Differential treatment of patients with acute vertigo should be performed according to the current recommendations and include multimodal pharmacological medications, e.g. cavinton forte, to restore the vestibular control by the stimulation of neuroplasticity. The VERTIGO algorithm allows the increase of the efficacy of clinical differential diagnosis of central and peripheral vertigo. PMID- 28638029 TI - [Pharmacotherapy of attention deficit hyperactivity disorder in children: the results of a multicenter double-blind placebo-controlled study of hopantenic acid]. AB - AIM: To assess the efficacy and safety of hopantenic acid (pantogam) compared to placebo in the treatment of attention deficit hyperactivity disorder (ADHD) in children, aged from 6 to 12 years, during 4 month in the prospective multicenter comparative double-blind placebo-controlled study in parallel groups. MATERIAL AND METHODS: One hundred patients enrolled in the safety assessment population were stratified into two equal pantogam and placebo groups. Eighty-nine patients who completed the study in according to the protocol were included in the efficacy assessment group: 45 in the pantogam group and 44 in the placebo group. Pantogam was administered in tablets (250 mg) in the therapeutic dose 30 mg/kg of body mass, divided into 2 doses, during 4 month. Patient's state was assessed by the total score on ADHD-DSM-IV, CGI-S WFIRS-P and results of the Toulouse-Pieron test for sustained attention. RESULTS AND CONCLUSION: There was a trend towards an increase in the percentage of patients with positive changes (a decrease in the total ADHD-DSM-IV by >=25%) in the end of the 3rd and 4th month in the pantogam group (treatment response was 66.7 and 68.9%, respectively) compared to the placebo group (treatment response was 52.3 and 61.4%, respectively). A significant decrease in disease severity assessed by the CGI-S was noted in the pantogam group compared to the placebo group. After 4 month of treatment with pantogam, the severity of functional disturbances was reduced by 4 out of 6 WFIRS P domains: Family, School and learning, Child's self-concept and Risky activities. Pantogam improved the measures of sustained attention (accuracy and speed) in the Toulouse-Pieron test. The drug used in mean daily dose 30 mg/kg during 4 month had a favorable safety profile which did not differ from that of placebo. PMID- 28638030 TI - [Characteristics of cerebral glucose metabolism in patients with cognitive impairment in Parkinson's disease]. AB - AIM: To study the relationship between early cognitive impairment symptoms and cerebral glucose metabolism in different brain regions (according to the positron emission tomography (PET) data) in Parkinson's disease (PD) in order to increase the diagnostic and treatment efficacy. MATERIAL AND METHODS: Two groups of patients with PD (stage I-III), including 11 patients without cognitive disorders and 13 with mild cognitive impairment (MCI), were examined. The control group included 10 age-matched people with normal cognition. To evaluate cognitive state, the Mini mental state examination (MMSE), the Frontal assessment battery (FAB) and the 'clock drawing test' were used. The regional cerebral glucose metabolism rate (CMRglu) was assessed using PET with 18F-fluorodeoxyglucose (FDG). RESULTS AND CONCLUSION: In PD patients, CMRglu were decreased in the frontal (Brodmann areas (BA) 9, 10, 11, 46, 47), occipital (BA 19) and parietal (BA 39), temporal (BA 20, 37), and cingulate cortex (BA 32) compared to the control group. Cerebral glucose metabolism was decreased in the frontal (BA 8, 9, 10, 45, 46, 47), parietal (BA 7, 39, 40) and cingulate cortex (BA 23, 24, 31, 32) in the group of PD patients with MCI compared to PD patients with normal cognition. Hypometabolism in BA 7, 8, 23, 24, 31, 40 was revealed only in comparison of PD and PD-MCI groups, and did not appear in case of comparison of cognitively normal PD patients with the control group. It is possible to suggest that the mentioned above brain areas were associated with cognitive impairment. The revealed glucose hypometabolism pattern possibly has the diagnostic value for the early and preclinical diagnosis of MCI in PD and control of treatment efficacy. PMID- 28638031 TI - [Anxiolytic and antidepressant effects of emoxipine, reamberin and mexidol in experimental diabetes mellitus]. AB - AIM: To perform a comparative study of anxiolytic and antidepressant effects of derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) in experimental diabetes mellitus. MATERIAL AND METHODS: An effect of emoxipine, reamberin and mexidol on manifestations of anxiety in 'elevated plus maze' (EPM) and duration of 'desperate behavior' (DB) in Porsolt test in rats with alloxan diabetes during medication course was studied. Alpha-lipoic (thioctic) acid (alpha-LA) was used as a reference drug. In additional experimental series, an effect of emoxipine, reamberin, mexidol and alpha-LA on the intensity of hyperglycemia in experimental DM was investigated. RESULTS AND CONCLUSION: All studied medications used in doses equivalent to therapeutic range in humans and administered for 14 days significantly reduced manifestations of anxiety and depression in rats with alloxan diabetes. The most pronounced anxiolytic potential was demonstrated for emoxipine that emerged as the only medication in the study that reduced manifestations of anxiety not only in comparison with 'alloxan diabetes-control' groups but also in comparison to 'intact control'. The intensity of tranquilizing activity of derivatives of 3-oxypyridine and succinic acid was similar to that of alpha-LA while the thymoanaleptic activity, when the drugs were administered in maximal doses to rats with experimental DM, was higher. Both emoxipine and mexidol as well as alpha-LA in all studied doses significantly decreased hyperglycemia in alloxan diabetes. Reamberin demonstrated only insignificant tendencies of the same trend. PMID- 28638032 TI - [Association of polymorphic variants of PIP5K2A and HTR2C genes with response to antidepressant therapy of patients with a current depressive episode]. AB - AIM: To study the association between polymorphisms of PIP5K2A and HTR2C genes and response to antidepressant therapy in patients with a current depressive episode. MATERIAL AND METHODS: The study included 222 patients (168 women and 54 men) with a current depressive episode. The assessment of the severity of the current depressive episode and the efficacy of treatment was performed using the Hamilton depression scale (HDRS-17) and the Clinical global impression scale (CGI S, CGI-I). The association of treatment efficacy with PIP5K2A polymorphisms rs10430590, rs10828317 and HTR2C polymorphisms rs6318, rs569959, rs3813929, rs12858300 was studied. RESULTS AND CONCLUSION: Polymorphisms rs10828317 and rs10430590 in the PIP5K2A gene were associated with the CGI-S total score at day 28 of therapy. Polymorphism rs6318 in the HTR2C gene was associated with response to antidepressant therapy followed by clinical improvement of patients with current depressive episode on the 28th day of antidepressant therapy. PMID- 28638033 TI - [The biomarkers of cerebral ischemia as a new method for the validation of the efficacy of cytoprotective therapy]. AB - AIM: To study blood plasma concentrations of NR2-peptide in patients with ischemic stroke (IS) to assess its diagnostic value as a biomarker of cerebral ischemia and determine the dynamics of the biomarker during treatment with cortexin. MATERIAL AND METHODS: One hundred and twenty patients, aged from 18 to 70 years, including 36 with transient ischemic attack (TIA) and 84 with IS in the carotid territory (n=70) and vertebral/basilar territory with the Wallenberg Zakharchenko syndrome (n=14), were enrolled. The National Institute of Health Stroke scale (NIHSS) was used to assess neurological status. Blood plasma concentration of NR2-peptide was measured in all patients at admission and after treatment. All laboratory results were compared with neuroimaging (MRI, CT) data. RESULTS: Concentrations of NR2-peptide detected in all patients were higher than in controls (>1.5 ng/ml), p<0.0001. The direct correlation between NR2-peptide (from 3.38 ng/ml to 15.6 ng/ml) and ischemic lesion (from few to 80 mm) was observed. A decrease in NR2-peptide concentration (from 8.5 to 5,.9 ng/ml, p<0.0001) was noted in patients treated with cortexin after 10-day treatment course. CONCLUSION: NR2-peptide blood assay is a reliable hemotest of brain ischemia. Cortexin has a sufficient therapeutic efficacy. PMID- 28638034 TI - [Post-graduated education and medical pedagogics: a new approach based on the competence-oriented educational program for neurologists in the field of children epileptology]. AB - The highly qualified performance of jobs according to professional standards due to the reformed system of additional professional education is one of the objectives of practical health care. The development of the educational program 'Children epileptology. Clinical, diagnostic and treatment issues' for increasing the qualification of neurologists was based on the competent approach that orients the content and process of education on the formation of competence in work performance. Work performance, in its turn, allowed the determination of professional tasks by neurologists. Module principles used in the development of the Program provided its structuration in accordance to step by step formation of physician competencies aimed to solve professional tasks. In its turn, professional tasks determined a choice of didactic conditions of each educational module (form, methods and means of education) that leads to the achievement of planned results. PMID- 28638035 TI - [The abnomal personalities in the conception of H. Gruhle]. AB - Understanding of psychopathic personality in the conception of H. Gruhle, a famous German psychiatrist, is analyzed. The issue that the psychopathic personality is accidentally combined with mental illness, psychosis is contradictory to the conception of 'general degenerative constitution'; psychopathology can be isolated and transient. There is absence of age criteria in the diagnosis of psychopathy as well. The initial attempt of H. Gruhle to systematically consider all types of psychopathy was not well substantiated, therefore the author returned to Kraepelin's systematics of psychopathic personality according to prominent traid. PMID- 28638036 TI - [Seronegative nonparaneoplastic Lambert-Eaton myasthenic syndrome]. AB - The authors studied two patients with Lambert-Eaton myasthenic syndrome (LEMS) in whom the repeated examination did not find specific of LEMS P/Q type voltage gates calcium channel autoantibodies. The results of clinical testing and electrophysiological examination showed the typical character of movement disorders with the absence of tendon reflexes and signs of disautonomia as well as a decrease in M-response amplitude and phenomena of decrement with low frequency- and increment with high frequency stimulation. Both patients revealed no signs of paraneoplastic process. Autoimmune character of the damage was confirmed by the effectiveness of treatment with glucocorticoid hormones. PMID- 28638037 TI - [Melatonin in therapy of sleep disorders age-related estrogen deficiency]. AB - AIM: To assess quantitative characteristics of sleep in perimenopausal women treated with melatonin in a dose of 3 mg during 3 month. MATERIAL AND METHODS: A study included 21 perimenopausal women with sleep disorders. Seventeen women completed the study. Insomnia Severity Index (ISI), anamnestic and gynecological examinations, polysomnographic monitoring (PSM) were used. All patients received melatonin (melaxen) 30 min before going to bed in a dose of 3 mg daily during 3 month. RESULTS: Insomnia was confirmed by PSM. The dynamics of PSM demonstrated the improvement of the latency to sleep onset, total sleep efficiency and increase in percentage of REM-sleep. A significant number of EEG activation responses showed a decrease in sleep fragmentation and improvement of the structure of sleep segments. CONCLUSION: The use of melatonin drugs, including melaxen in a dose of 3 mg during 3 month, is one of the main methods of treatment of sleep disorders in age-related estrogen deficiency. The main clinical effect was due to the elimination of pre- and intrasomnic disorders. PMID- 28638038 TI - [A current view on the history of atypical antipsychotics]. AB - Based on the analysis of the original literature, the author for the first time systemizes the data on the story of atypical antipsychotic drugs. The history of introduction of the first atypical neuroleptics - clozapine and sulpiride, which launched the dichotomic development of psychopharmacology of atypical antipsychotics, is described. Historical facts on the introduction into practice of different sulpiride- and clozapine-like neuroleptics as well as the relationship of their history with the elaboration of dopamine and serotonin hypotheses of mechanisms of action of antipsychotics are presented. The author analyzes the efficacy and tolerability of treatment with different atypical neuroleptics. An importance of evidence-based medicine principles in the history of atypical antipsychotics is described. A significance of the history of some atypical and typical (pericyazine) neuroleptics in the evolution of conceptions on the validity of evidence-based medicine in psychiatry is evaluated. Main stages in the history of typical and atypical antipsychotics are determined. PMID- 28638039 TI - [Headache immunology]. AB - The overview is dedicated to the neuroimmunological mechanisms of headache development and chronification. Based on the analyzed data, the authors determined the relationship between immunological parameters and duration, intensity and other characteristics of this disease. These findings confirm that immunocompetent cells can be used as headache biomarkers and predictors of treatment efficacy. Questions about the role of separate parts of the immune system in the development and maintenance of a headache require further research. Studies of humoral immunity appeared to be very promising. PMID- 28638040 TI - [Complex application 2-ethyl-6-methyl-3-hydroxypyridine-succinate and vinpocetine in cerebrovascular disorder.] AB - Developing brain ischemia due to cerebral vascularization leads to disruption of brain metabolism. Chronic cerebral hypoperfusion leads to irreversible brain damage and plays an important role in the development of some types of dementia. Early use of antioxidants such as ethyl ether apovincamine acid (vinpocetine) and 2-ethyl-6-methyl-3-hydroxypyridine-succinate in the treatment of this pathology is seen as a real pathogenetically based method of correction of cerebral metabolism with cerebral vascular disorders, demonstrating the increase in cerebral blood flow and also neuroprotective effects. Clinical studies and studies on biological models show that the main mechanisms of action of vinpocetine and 2-ethyl-6-methyl-3-hydroxypyridine-succinate, although have a similar focus, but implementing neuroprotective and nootropic effects via various links in the pathogenesis of ischemic brain damage. PMID- 28638041 TI - [The presumption of mental health: is it really proved?] AB - The article is devoted to one of the most complicated and peculiar problems of modern psychiatry - the presumption of mental health. Its originality is seen in the fact that practically all speaking and writing about it noted the importance of this principle for the protection of rights and legal interests of citizens, failing into the field of psychiatry. However, expressing this opinion, doctors and lawyers offer very few arguments in support of this view. Traditional arguments in favor of the presumption of mental health, scattered and unsystematic, prove to be absolutely insolvent. It was also found out that the similarity of the presumption of mental health with the presumption of innocence is capable to entail negative consequences. The noted similarity strengthens stigmatizing effect of psychiatric diagnosis, making it extremely undesirable for the patient, and the basis of the relationship between the patient and the doctor laid counterproductive antagonistic model as the model of mutual relations of the accused with the prosecutor. The main conclusion of authors is that the supporters of the presumption of mental health have yet to prove its right to exist, to work out its content and try to neutralize some of the negative consequences of its possible implementation in practice. Without compliance with the listed conditions to bring the presumption of mental health to the level of one of the fundamental principles of Russian psychiatry would be premature. PMID- 28638042 TI - [About the measures taken to improve the mental health service in the Republic of Uzbekistan for 2013-2016]. PMID- 28638043 TI - [The resolution of Expert Board meeting 'Advanced stage of Parkinson's disease. Possibilities of the transition to non-invasive methods of treatment'. Moscow. Dec16 2016]. PMID- 28638044 TI - [A.A. Mikhailenko, A.N. Kuznetsov, N.S. Il'insky 'Science, art and ill nerves' M. RANS, 2014. 216 p. 2nd Ed. 2016, 290 p.] PMID- 28638045 TI - Treatment of sarcopenia and glucose intolerance through mitochondrial activation by 5-aminolevulinic acid. AB - Recently, sarcopenia has attracted attention as therapeutic target because it constitutes a risk factor for metabolic and cardiovascular diseases. We focused 5 aminolevulinic acid (ALA) which act as electron carriers in the mitochondrial electron transport system. The mice that received ALA for 8 weeks gained muscle strength and endurance, and exhibited increased muscle mass and mitochondrial amount. Administration of ALA to sarcopenia mice aged 100 weeks and chronic kidney disease (CKD) model mice also increased muscle mass and improved physical performance. Metabolome analysis revealed increased branched-chain amino acids (BCAAs) levels in the skeletal muscle of ALA-treated mice. Quantitative PCR analysis revealed decreased expression levels in branched-chain amino acid transaminases (BCATs) that degrade BCAAs and other muscle-degrading factors, and increased levels of mitochondria-activating factors. We also studied in cultured myocytes and obtained compatible results. ALA-treated mice tended to increase body weight, but reduced blood glucose level. These suggested that ALA treatment not only activated muscle mitochondria but also enhanced muscle mass through an increase in BCAAs contents, as to improve muscle strength, endurance and glucose tolerance in mice. In these ways, muscle mitochondrial activation with ALA is suggested to be useful for the treatment of sarcopenia and glucose intolerance. PMID- 28638046 TI - A note on the stationary distribution of stochastic SEIR epidemic model with saturated incidence rate. AB - The stochastic SEIR infectious diseases model with saturated incidence rate is studied in this paper. By constructing appropriate Lyapunov functions, we show that there is a stationary distribution for the system and the ergodicity holds provided [Formula: see text] > 1. In particular, we improve the results obtained by previous studies greatly, condition in our Theorem is more concise and elegant. PMID- 28638047 TI - Semi-rational engineering of a thermostable aldo-keto reductase from Thermotoga maritima for synthesis of enantiopure ethyl-2-hydroxy-4-phenylbutyrate (EHPB). AB - A novel aldo-keto reductase Tm1743 characterized from Thermotoga maritima was explored as an effective biocatalyst in chiral alcohol production. Natural Tm1743 catalyzes asymmetric reduction of ethyl 2-oxo-4-phenylbutyrate (EOPB) at high efficiency, but the production of, ethyl (S)-2-hydroxy-4-phenylbutyrate ((S) EHPB), which is less desirable, is preferred with an enantiomeric excess (ee) value of 76.5%. Thus, altering the enantioselectivity of Tm1743 to obtain the more valuable product (R)-EHPB for angiotensin drug synthesis is highly desired. In this work, we determined the crystal structure of Tm1743 in complex with its cofactor NADP+ at 2.0 A resolution, and investigated the enantioselectivity of Tm1743 through semi-rational enzyme design. Molecular simulations based on the crystal structure obtained two binding models representing the pro-S and pro-R conformations of EOPB. Saturation mutagenesis studies revealed that Trp21 and Trp86 play important roles in determining the enantioselectivity of Tm1743. The best (R)- and (S)-EHPB preferring Tm1743 mutants, denoted as W21S/W86E and W21L/W118H, were identified; their ee values are 99.4% and 99.6% and the catalytic efficiencies are 0.81 and 0.12 mM-1s-1, respectively. Our work presents an efficient strategy to improve the enantioselectivity of a natural biocatalyst, which will serve as a guide for further exploration of new green catalysts for asymmetric reactions. PMID- 28638048 TI - Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice. AB - Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino acid transporter activity and causes fetal growth restriction. Folate deficient mice had lower serum folate (-60%). In late pregnancy, fetal weight in the folate deficient group was decreased (-17%, p < 0.05), whereas placental weight, litter size and crown rump length were unaltered. Maternal folate deficiency inhibited placental mTORC1 and mTORC2 signaling and decreased trophoblast plasma membrane System A and L amino acid transporter activities and transporter isoform expression. Folate deficiency also caused a decrease in phosphorylation of specific functional readouts of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues. We have identified a novel specific molecular link between maternal folate availability and fetal growth, involving regulation of placental mTOR signaling by folate, resulting in changes in placental nutrient transport. mTOR folate sensing may have broad biological significance because of the critical role of folate in normal cell function and the wide range of disorders, including cancer, that have been linked to folate availability. PMID- 28638049 TI - Immunomodulatory Effects of Nanoparticles on Skin Allergy. AB - In recent years there has been considerable effort to understand the interaction of nanomaterials with the skin. In this study we use an in vivo mouse model of allergic contact dermatitis to investigate how nanoparticles (NPs) may alter allergic responses in skin. We investigate a variety of NPs that vary in size, charge and composition. Results show that small (<200 nm) negative and neutral charged NPs exhibit an immunosuppressive effect but that positively charged NPs do not. Confocal imaging suggests positively charged NPs may penetrate skin to a lesser extent and thereby are less able interact with and alter the local immune responses. Interestingly, negatively charged silica (20 nm) NPs suppress allergic response to two chemically distinct sensitizers; 1-fluoro-2, 4-dinitrobenzene and 2-deoxyurushiol. Skin wiping and NP application time studies suggest that the immunomodulatory mechanism is not due solely to the blocking of sensitizer adduct formation in skin. Results suggest that NPs modulate early immune events that impact mast cell degranulation. Our study shows for the first time the potential to modulate the elicitation phase of the allergic response which depends on the NP charge and composition. These finding can be used to inform the design topical therapeutics to mitigate allergic responses in skin. PMID- 28638050 TI - De novo yeast genome assemblies from MinION, PacBio and MiSeq platforms. AB - Long-read sequencing technologies such as Pacific Biosciences and Oxford Nanopore MinION are capable of producing long sequencing reads with average fragment lengths of over 10,000 base-pairs and maximum lengths reaching 100,000 base- pairs. Compared with short reads, the assemblies obtained from long-read sequencing platforms have much higher contig continuity and genome completeness as long fragments are able to extend paths into problematic or repetitive regions. Many successful assembly applications of the Pacific Biosciences technology have been reported ranging from small bacterial genomes to large plant and animal genomes. Recently, genome assemblies using Oxford Nanopore MinION data have attracted much attention due to the portability and low cost of this novel sequencing instrument. In this paper, we re-sequenced a well characterized genome, the Saccharomyces cerevisiae S288C strain using three different platforms: MinION, PacBio and MiSeq. We present a comprehensive metric comparison of assemblies generated by various pipelines and discuss how the platform associated data characteristics affect the assembly quality. With a given read depth of 31X, the assemblies from both Pacific Biosciences and Oxford Nanopore MinION show excellent continuity and completeness for the 16 nuclear chromosomes, but not for the mitochondrial genome, whose reconstruction still represents a significant challenge. PMID- 28638051 TI - Experimental evidence for reciprocity in allogrooming among wild-type Norway rats. AB - If individuals help more those who have previously helped them, stable cooperation may ensue through alternation of roles between donors and recipients. Allogrooming, which is costly to donors and beneficial to recipients, is often exchanged between social partners. Arguably, allogrooming and allopreening are the most frequently exchanged social services and have been used as a standard model of reciprocal cooperation. However, evidence for the application of reciprocity rules among social partners allogrooming each other hitherto is merely correlational. Here, we tested whether female Norway rats (Rattus norvegicus) apply the decision rule characterising direct reciprocity: help someone who has helped you before, by experimentally manipulating both the need for allogrooming and the behavioural response. Furthermore, we checked whether trading of grooming services is influenced by the rank of the social partner. We show that rats groom social partners reciprocally and prefer to do so up the hierarchy, i.e. they groom dominant partners more often than subordinates, while reciprocating with both. This provides experimental evidence that animals render a costly social service by applying reciprocity decision rules when showing a natural hygienic behaviour. The fact that allogrooming is more readily shown up the hierarchy may suggest an appeasing function. PMID- 28638052 TI - Determination of Crucial Immunogenic Epitopes in Major Peanut Allergy Protein, Ara h2, via Novel Nanoallergen Platform. AB - Current methods for detection and diagnosis of allergies do not provide epitope specific immunogenic information and hence lack critical information that could aid in the prediction of clinical responses. To address this issue, we developed a nanoparticle based platform, called nanoallergens that enable multivalent display of potential allergy epitopes for determining the immunogenicity of each IgE binding epitope. By synthesizing nanoallergens that present various epitopes from the major peanut allergen, Ara h2, we directly determined the immunogenicity of each epitope, alone and in combination with other epitopes, using patient sera. This information provided insights on which epitopes are most critical for physiological responses to Ara h2 and revealed the importance of both high and low affinity epitopes for allergic responses. We anticipate the nanoallergen platform to be used to provide information regarding allergic reactions and therefore potentially aid in more accurate diagnosis and design of personalized treatment options. PMID- 28638053 TI - Hard X-rays as pump and probe of atomic motion in oxide glasses. AB - Nowadays powerful X-ray sources like synchrotrons and free-electron lasers are considered as ultimate tools for probing microscopic properties in materials. However, the correct interpretation of such experiments requires a good understanding on how the beam affects the properties of the sample, knowledge that is currently lacking for intense X-rays. Here we use X-ray photon correlation spectroscopy to probe static and dynamic properties of oxide and metallic glasses. We find that although the structure does not depend on the flux, strong fluxes do induce a non-trivial microscopic motion in oxide glasses, whereas no such dependence is found for metallic glasses. These results show that high fluxes can alter dynamical properties in hard materials, an effect that needs to be considered in the analysis of X-ray data but which also gives novel possibilities to study materials properties since the beam can not only be used to probe the dynamics but also to pump it. PMID- 28638055 TI - Pupil response hazard rates predict perceived gaze durations. AB - We investigated the mechanisms for evaluating perceived gaze-shift duration. Timing relies on the accumulation of endogenous physiological signals. Here we focused on arousal, measured through pupil dilation, as a candidate timing signal. Participants timed gaze-shifts performed by face stimuli in a Standard/Probe comparison task. Pupil responses were binned according to "Longer/Shorter" judgements in trials where Standard and Probe were identical. This ensured that pupil responses reflected endogenous arousal fluctuations opposed to differences in stimulus content. We found that pupil hazard rates predicted the classification of sub-second intervals (steeper dilation = "Longer" classifications). This shows that the accumulation of endogenous arousal signals informs gaze-shift timing judgements. We also found that participants relied exclusively on the 2nd stimulus to perform the classification, providing insights into timing strategies under conditions of maximum uncertainty. We observed no dissociation in pupil responses when timing equivalent neutral spatial displacements, indicating that a stimulus-dependent timer exploits arousal to time gaze-shifts. PMID- 28638056 TI - Trap Modulated Charge Carrier Transport in Polyethylene/Graphene Nanocomposites. AB - The role of trap characteristics in modulating charge transport properties is attracting much attentions in electrical and electronic engineering, which has an important effect on the electrical properties of dielectrics. This paper focuses on the electrical properties of Low-density Polyethylene (LDPE)/graphene nanocomposites (NCs), as well as the corresponding trap level characteristics. The dc conductivity, breakdown strength and space charge behaviors of NCs with the filler content of 0 wt%, 0.005 wt%, 0.01 wt%, 0.1 wt% and 0.5 wt% are studied, and their trap level distributions are characterized by isothermal discharge current (IDC) tests. The experimental results show that the 0.005 wt% LDPE/graphene NCs have a lower dc conductivity, a higher breakdown strength and a much smaller amount of space charge accumulation than the neat LDPE. It is indicated that the graphene addition with a filler content of 0.005 wt% introduces large quantities of deep carrier traps that reduce charge carrier mobility and result in the homocharge accumulation near the electrodes. The deep trap modulated charge carrier transport attributes to reduce the dc conductivity, suppress the injection of space charges into polymer bulks and enhance the breakdown strength, which is of great significance in improving electrical properties of polymer dielectrics. PMID- 28638054 TI - Drug-Repositioning Screening for Keap1-Nrf2 Binding Inhibitors using Fluorescence Correlation Spectroscopy. AB - The Kelch-like ECH-associating protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. The Cul3/Keap1 E3 ubiquitin ligase complex interacts with Nrf2, leading to Nrf2 ubiquitination and degradation. In this study, we focused on the disruption of the Keap1-Nrf2 interaction to upregulate Nrf2 expression and the transcription of ARE-controlled cytoprotective oxidative stress response enzymes, such as HO-1. We completed a drug-repositioning screening for inhibitors of Keap1 Nrf2 protein-protein interactions using a newly established fluorescence correlation spectroscopy (FCS) screening system. The binding reaction between Nrf2 and Keap1 was successfully detected with a KD of 2.6 MUM using our FCS system. The initial screening of 1,633 drugs resulted in 12 candidate drugs. Among them, 2 drugs significantly increased Nrf2 protein levels in HepG2 cells. These two promising drugs also upregulated ARE gene promoter activity and increased HO-1 mRNA expression, which confirms their ability to dissociate Nrf2 and Keap1. Thus, drug-repositioning screening for Keap1-Nrf2 binding inhibitors using FCS enabled us to find two promising known drugs that can induce the activation of the Nrf2-ARE pathway. PMID- 28638058 TI - Theoretical analyses on orbital angular momentum modes in conventional graded index multimode fibre. AB - Orbital angular momentum (OAM) modes are another mode basis to represent spatial modes. There have been increasing interests in exploiting OAM modes in specialty fibres. In this paper, we present a comprehensive characterisation of OAM modes in conventional graded-index multimode fibre (MMF). 1) We synthesise the circularly polarized OAM modes by properly combining two fold degenerate cylindrical vector modes (eigenmodes) and analyse the total angular momentum, i.e. spin angular momentum and orbital angular momentum. 2) We divide all the OAM modes of the conventional graded-index MMF into 10 OAM mode groups with effective refractive index differences between different mode groups above 10-4 enabling low-level inter-group crosstalk. 3) We study the chromatic dispersion, differential group delay, effective mode area, and nonlinearity for each OAM mode group over a wide wavelength ranging from 1520 to 1630 nm covering the whole C band and L band. 4) We discuss the performance tolerance to fibre ellipticity and bending. 5) We further address the robustness of performance against fibre perturbations including the core size, index contrast and the imperfect index profile of the practically fabricated MMFs. The obtained results may provide theoretical basis for further space-division multiplexing applications employing OAM modes in conventional graded-index MMF. PMID- 28638057 TI - The Variation in the Rhizosphere Microbiome of Cotton with Soil Type, Genotype and Developmental Stage. AB - Plant roots and soil microorganisms interact with each other mainly in the rhizosphere. Changes in the community structure of the rhizosphere microbiome are influenced by many factors. In this study, we determined the community structure of rhizosphere bacteria in cotton, and studied the variation of rhizosphere bacterial community structure in different soil types and developmental stages using TM-1, an upland cotton cultivar (Gossypium hirsutum L.) and Hai 7124, a sea island cotton cultivar (G. barbadense L.) by high-throughput sequencing technology. Six bacterial phyla were found dominantly in cotton rhizosphere bacterial community including Acidobacteria, Actinobacteria, Bacteroidetes, Planctomycetes, Proteobacteria, and Verrucomicrobia. The abundance of Acidobacteria, Cyanobacteria, Firmicutes, Planctomycetes and Proteobacteria were largely influenced by cotton root. Bacterial alpha-diversity in rhizosphere was lower than that of bulk soil in nutrient-rich soil, but higher in cotton continuous cropping field soil. The beta-diversity in nutrient-rich soil was greater than that in continuous cropping field soil. The community structure of the rhizosphere bacteria varied significantly during different developmental stages. Our results provided insights into the dynamics of cotton rhizosphere bacterial community and would facilitate to improve cotton growth and development through adjusting soil bacterial community structure artificially. PMID- 28638059 TI - Cis-regulatory evolution in prokaryotes revealed by interspecific archaeal hybrids. AB - The study of allele-specific expression (ASE) in interspecific hybrids has played a central role in our understanding of a wide range of phenomena, including genomic imprinting, X-chromosome inactivation, and cis-regulatory evolution. However across the hundreds of studies of hybrid ASE, all have been restricted to sexually reproducing eukaryotes, leaving a major gap in our understanding of the genomic patterns of cis-regulatory evolution in prokaryotes. Here we introduce a method to generate stable hybrids between two species of halophilic archaea, and measure genome-wide ASE in these hybrids with RNA-seq. We found that over half of all genes have significant ASE, and that genes encoding kinases show evidence of lineage-specific selection on their cis-regulation. This pattern of polygenic selection suggested species-specific adaptation to low phosphate conditions, which we confirmed with growth experiments. Altogether, our work extends the study of ASE to archaea, and suggests that cis-regulation can evolve under polygenic lineage-specific selection in prokaryotes. PMID- 28638061 TI - A new study on the growth behavior of austenite grains during heating processes. AB - In this paper, the effects of the heating temperature and holding time on the austenite grain growth of SCM435 steel were studied and analyzed in terms of the average, macro-axis and minor-axis size of the grains. The results indicated that the classical Sellars model was highly consistent for describing the growth stage of the new austenite but poorly described the initial nucleation-growth stage and stability stage of the austenite. A new model that expresses the average austenite grain growth of SCM435 steel was developed, and the values calculated based on this model were highly consistent with the actual measured values. The standard deviation and expected grain-size expressions increased as the heating temperature and holding time increased. The macro-axis and minor-axis size of the grains were linearly correlated with the average size, and the ratio of the macro axis to the minor-axis size remained generally constant during grain growth. Furthermore, this paper provides a new way of thinking about heredity in materials science from the perspective of mathematical characteristics. PMID- 28638060 TI - Epidural Dexmedetomidine Reduces the Requirement of Propofol during Total Intravenous Anaesthesia and Improves Analgesia after Surgery in Patients undergoing Open Thoracic Surgery. AB - The aim of this study was to assess the systemic and analgesic effects of epidural dexmedetomidine in thoracic epidural anaesthesia (TEA) combined with total intravenous anaesthesia during thoracic surgery. Seventy-one patients undergoing open thoracotomy were included in this study and randomly divided into three groups: Control group (Group C): patients received TEA with levobupivacaine alone and were intravenously infused with saline; Epidural group (Group E): patients received TEA with levobupivacaine and dexmedetomidine, and were intravenously infused with saline; Intravenous group (group V): patients received TEA with levobupivacaine alone and were intravenously infused with dexmedetomidine. The doses of propofol used in the induction and maintenance of general anaesthesia, cardiovascular response, dose and first time of postoperative analgesia and verbal rating scale were recorded. The induction and maintenance were significantly lower in the Groups E and V. Verbal rating scale and postoperative analgesic requirements were significantly lower in Group E than in Groups C and V. Patients in Group C had more severe cardiovascular responses, as compared with Groups E and V. Epidural administration of dexmedetomidine reduced the induction and maintenance of propofol, and inhibited the cardiovascular response after intubation and extubation. Moreover, epidural dexmedetomidine provided better analgesia after open thoracotomy. PMID- 28638063 TI - Crystallisation of the amorphous ices in the intermediate pressure regime. AB - The crystallisation behaviour of very high-density amorphous ice (VHDA) and unannealed high-density amorphous ice (uHDA) has been studied in situ by volumetry and ex situ by powder x-ray diffraction in the intermediate pressure range 0.7-1.8 GPa employing different heating rates (0.5, 5 and 30 K min-1). This study shows that at pressures >1 GPa the crystallisation behaviour of VHDA and uHDA is basically the same for all heating rates. That is, parallel crystallisation is almost entirely suppressed with mainly ice XII forming. This contrasts former results reporting parallel crystallisation to approximately levelled phase mixtures of ice IV and ice XII even at higher pressures for uHDA. We speculate this to be due to formation of microcracks upon decompression in earlier works, but not in the present one. Crystallisation temperatures T x are up to 16 K higher than previously reported, raising the low-temperature border to no man's land and opening a considerably larger window for future studies on non crystalline water. The results indicate uHDA to contain heterogeneities on the nanoscale, but VHDA to be rather homogeneous with nano-crystallites being largely absent. Upon transforming uHDA to VHDA, the nano-scale heterogeneities disappear for >1 GPa whereas microcracks do not. PMID- 28638062 TI - CH2 Linkage Effects on the Reactivity of Bis(aminophosphine)-Ruthenium Complexes for Selective Hydrogenation of Esters into Alcohols. AB - A novel ruthenium complex binding to two subtly different aminophosphine ligands, (o-PPh2C6H4CH2NH2)(o-PPh2C6H4NH2)RuCl2, was successfully isolated. This bis(aminophosphine)-ruthenium complex shows efficient activity in both dimethyl oxalate (DMO) and methyl benzoate (MB) hydrogenation. On the contrast, similar complexes (o-PPh2C6H4NH2)2RuCl2 and (o-PPh2C6H4CH2NH2)2RuCl2, can only effectively catalyze the hydrogenation of DMO and MB, respectively. Our experimental studies in combination of theoretical calculations reveal that the remarkable substrate selectivity in the hydrogenation of esters arises from the nonbonding interactions operated by the CH2 linkage of the ligand. PMID- 28638065 TI - Colorimetric detection of magnesium (II) ions using tryptophan functionalized gold nanoparticles. AB - The functional nanoparticles with specific molecular probe appear to be a promising approach for developing colorimetric nanosensor. In this work, we have synthesized tryptophan capped gold nanoparticles (AuNPs) and used to establish colorimetric detection of magnesium (Mg2+). The colorimetric response of the AuNPs toward Mg2+ was noticed with naked eyes, and spectral changes were monitored by using UV-Vis spectrophotometer. The detection response was rapid (less than 1 min), with a detection limit (LOD) about 0.2 umol L-1. The proposed nanoprobe shows characteristic red-shift of the AuNPs at 620 nm and high selectivity for Mg2+ due to the binding affinity of the tryptophan with Mg2+. The real-time response of the UV-Vis spectrum was monitored at three different concentrations of Mg2+ (0.45, 0.50, and 0.55 umol L-1). The AuNPs probe was suitable to provide a molecular platform for selective coordination with Mg2+ over Ca2+ ions, thus it could be facile to establish a practically viable sensing system. Furthermore, experimental results were confirmed to exhibit excellent linear curve for urine and serum samples spiked with Mg2+. Thus, this nanosensor is practically useful for the detection of Mg2+, without using expensive instruments, enzymes and/or DNA molecules. PMID- 28638066 TI - Mummified Oligocene fruits of Schima (Theaceae) and their systematic and biogeographic implications. AB - The genus Schima includes about 20 species and is distributed only in southern China and adjacent areas of Asia. The previous molecular phylogenetic analysis suggested Schima is in the tribe Gordoniae, along with Gordonia and Franklinia. However, because few fossils have been reported, the biogeographic origin of Schima is still poorly known. In this paper mummified fossil fruits of Schima are described from the upper Oligocene Yongning Formation of the Nanning Basin, Guangxi, South China. In gross morphology, the new fossil species, Schima kwangsiensis, is similar to the extant S. superba by its pentacarpellate, loculicidally dehiscent capsules, 5 imbricate sepals, pedicels with bracteoles and marginally winged seeds. Due to its excellent preservation, the new species may provide sufficient details for understanding the early evolutionary and phytogeographic history of the genus. Morphological clustering analysis shows that the new fossil species is closely related to two extant species (S. wallichii and S. superba) in the genus, implying that they may belong to an ancient taxon that occurs earlier than the others. More importantly, this discovery represents the earliest record of this genus in Asia and it explicitly moves the fossil record back to the late Oligocene in this region. PMID- 28638064 TI - Quantitative Phosphoproteomics Reveals a Role for Collapsin Response Mediator Protein 2 in PDGF-Induced Cell Migration. AB - The Platelet Derived Growth Factor (PDGF) family of ligands have well established functions in the induction of cell proliferation and migration during development, tissue homeostasis and interactions between tumours and stroma. However, the mechanisms by which these actions are executed are incompletely understood. Here we report a differential phosphoproteomics study, using a SILAC approach, of PDGF-stimulated mouse embryonic fibroblasts (MEFs). 116 phospho sites were identified as up-regulated and 45 down-regulated in response to PDGF stimulation. These encompass proteins involved in cell adhesion, cytoskeleton regulation and vesicle-mediated transport, significantly expanding the range of proteins implicated in PDGF signalling pathways. Included in the down-regulated class was the microtubule bundling protein Collapsin Response Mediator Protein 2 (CRMP2). In response to stimulation with PDGF, CRMP2 was dephosphorylated on Thr514, an event known to increase CRMP2 activity. This was reversed in the presence of micromolar concentrations of the protein phosphatase inhibitor okadaic acid, implicating PDGF-induced activation of protein phosphatase 1 (PP1) in CRMP2 regulation. Depletion of CRMP2 resulted in impairment of PDGF-mediated cell migration in an in vitro wound healing assay. These results show that CRMP2 is required for PDGF-directed cell migration in vitro. PMID- 28638067 TI - Highly-efficient photocatalytic degradation of methylene blue by PoPD-modified TiO 2 nanocomposites due to photosensitization-synergetic effect of TiO2 with PoPD. AB - Poly-o-phenylenediamine modified TiO2 nanocomposites were successfully synthesized via an 'in situ' oxidative polymerization method. The modified nanocomposites were characterized by BET, XRD, TEM, FT-IR, TGA, XPS, EA and UV Vis DRS. The photocatalytic degradation of methylene blue was chosen as a model reaction to evaluate the photocatalytic activities of TiO2 and PoPD/TiO2. The results indicated that PoPD/TiO2 nanocomposites exhibited good photocatalytic activity and stability. The photocatalytic activity of PoPD/TiO2 increased as the initial pH increased because of electrostatic adsorption between the photocatalyst and MB as well as the generation of .OH, whereas it exhibited an earlier increasing and later decreasing trend as the concentration of the photocatalyst increased owing to the absorption of visible light. The photocatalytic stability of the PoPD/TiO2 nanocomposite was dependent on the stability of its structure. Based on radical trapping experiments and ESR measurements, the origin of oxidizing ability of PoPD/TiO2 nanocomposites on photocatalytic degradation of MB was proposed, which taking into account of .OH and .O2- were the first and second important ROS, respectively. The possible photocatalytic mechanism and photocatalytic activity enhanced mechanism has been proposed, taking into account the photosensitization effect and synergetic effect of TiO2 with PoPD. PMID- 28638068 TI - Microbiota-derived butyrate suppresses group 3 innate lymphoid cells in terminal ileal Peyer's patches. AB - The regional specialization of intestinal immune cells is affected by the longitudinal heterogeneity of environmental factors. Although the distribution of group 3 innate lymphoid cells (ILC3s) is well characterized in the lamina propria, it is poorly defined in Peyer's patches (PPs) along the intestine. Given that PP ILC3s are closely associated with mucosal immune regulation, it is important to characterize the regulatory mechanism of ILC3s. Here, we found that terminal ileal PPs of specific pathogen-free (SPF) mice have fewer NKp46+ ILC3s than jejunal PPs, while there was no difference in NKp46+ ILC3 numbers between terminal ileal and jejunal PPs in antibiotics (ABX)-treated mice. We also found that butyrate levels in the terminal ileal PPs of SPF mice were higher than those in the jejunal PPs of SPF mice and terminal ileal PPs of ABX-treated mice. The reduced number of NKp46+ ILC3s in terminal ileal PPs resulted in a decrease in Csf2 expression and, in turn, resulted in reduced regulatory T cells and enhanced antigen-specific T-cell proliferation. Thus, we suggest that NKp46+ ILC3s are negatively regulated by microbiota-derived butyrate in terminal ileal PPs and the reduced ILC3 frequency is closely associated with antigen-specific immune induction in terminal ileal PPs. PMID- 28638069 TI - Global profiling of phytohormone dynamics during combined drought and pathogen stress in Arabidopsis thaliana reveals ABA and JA as major regulators. AB - Global transcriptome studies demonstrated the existence of unique plant responses under combined stress which are otherwise not seen during individual stresses. In order to combat combined stress plants use signaling pathways and 'cross talk' mediated by hormones involved in stress and growth related processes. However, interactions among hormones' pathways in combined stressed plants are not yet known. Here we studied dynamics of different hormones under individual and combined drought and pathogen infection in Arabidopsis thaliana by liquid chromatography-mass spectrometry (LC-MS) based profiling. Our results revealed abscisic acid (ABA) and salicylic acid (SA) as key regulators under individual drought and pathogen stress respectively. Under combined drought and host pathogen stress (DH) we observed non-induced levels of ABA with an upsurge in SA and jasmonic acid (JA) concentrations, underscoring their role in basal tolerance against host pathogen. Under a non-host pathogen interaction with drought (DNH) stressed plants, ABA, SA and JA profiles were similar to those under DH or non host pathogen alone. We propose that plants use SA/JA dependent signaling during DH stress which antagonize ABA biosynthesis and signaling pathways during early stage of stress. The study provides insights into hormone modulation at different time points during combined stress. PMID- 28638071 TI - Emergent stochastic oscillations and signal detection in tree networks of excitable elements. AB - We study the stochastic dynamics of strongly-coupled excitable elements on a tree network. The peripheral nodes receive independent random inputs which may induce large spiking events propagating through the branches of the tree and leading to global coherent oscillations in the network. This scenario may be relevant to action potential generation in certain sensory neurons, which possess myelinated distal dendritic tree-like arbors with excitable nodes of Ranvier at peripheral and branching nodes and exhibit noisy periodic sequences of action potentials. We focus on the spiking statistics of the central node, which fires in response to a noisy input at peripheral nodes. We show that, in the strong coupling regime, relevant to myelinated dendritic trees, the spike train statistics can be predicted from an isolated excitable element with rescaled parameters according to the network topology. Furthermore, we show that by varying the network topology the spike train statistics of the central node can be tuned to have a certain firing rate and variability, or to allow for an optimal discrimination of inputs applied at the peripheral nodes. PMID- 28638070 TI - Thioesterase YbgC affects motility by modulating c-di-GMP levels in Shewanella oneidensis. AB - Because of ubiquity of thioesters, thioesterases play a critical role in metabolism, membrane biosynthesis, signal transduction, and gene regulation. In many bacteria, YbgC is such an enzyme, whose coding gene mostly resides in the tol-pal cluster. Although all other proteins encoded in the tol-pal cluster are clearly involved in maintaining cell envelope integrity and cell division, little is known about the physiological role of YbgC. In this study, we identify in Shewanella oneidensis, a gamma-proteobacterium used as a research model for environmental microbes, YbgC as a motility regulator. The loss of YbgC results in enhanced motility, which is likely due to the increased rotation rate of the flagellum. The regulatory function of YbgC requires its thioesterase activity but could not be replaced by YbgC homologues of other bacteria. We further show that the regulation of YbgC is mediated by the second message c-di-GMP. PMID- 28638073 TI - Plasmon-induced selective carbon dioxide conversion on earth-abundant aluminum cuprous oxide antenna-reactor nanoparticles. AB - The rational combination of plasmonic nanoantennas with active transition metal based catalysts, known as 'antenna-reactor' nanostructures, holds promise to expand the scope of chemical reactions possible with plasmonic photocatalysis. Here, we report earth-abundant embedded aluminum in cuprous oxide antenna-reactor heterostructures that operate more effectively and selectively for the reverse water-gas shift reaction under milder illumination than in conventional thermal conditions. Through rigorous comparison of the spatial temperature profile, optical absorption, and integrated electric field enhancement of the catalyst, we have been able to distinguish between competing photothermal and hot-carrier driven mechanistic pathways. The antenna-reactor geometry efficiently harnesses the plasmon resonance of aluminum to supply energetic hot-carriers and increases optical absorption in cuprous oxide for selective carbon dioxide conversion to carbon monoxide with visible light. The transition from noble metals to aluminum based antenna-reactor heterostructures in plasmonic photocatalysis provides a sustainable route to high-value chemicals and reaffirms the practical potential of plasmon-mediated chemical transformations.Plasmon-enhanced photocatalysis holds promise for the control of chemical reactions. Here the authors report an Al@Cu2O heterostructure based on earth abundant materials to transform CO2 into CO at significantly milder conditions. PMID- 28638072 TI - Diet-induced reconstruction of mucosal microbiota associated with alterations of epithelium lectin expression and regulation in the maintenance of rumen homeostasis. AB - It is unknown whether lectins of the rumen epithelium contribute to the recognition of mucosal microbes and activation of tolerogenic cytokines in ruminant animals. We applied an integrated method of RNA-seq and 16S rRNA gene sequencing to investigate alterations of epithelial lectin expression and regulation with a diet-induced reconstruction of the mucosal microbiota in the goat rumen. Our results showed that the diversity and richness of the rumen mucosal microbiota were promoted by the dietary concentrate. Meantime, in the rumen epithelium, five lectin genes, namely, sialic acid-binding Ig-like lectin 14 (LOC102180073), C-type lectin domain family 4, member E (CLEC4E), C-type lectin domain family 7, member A (CLEC7A), C-type lectin domain family 16, member A (CLEC16A), and lectin, mannose-binding 2 (LMAN2), were indicated to promote the expression of 8 tolerogenic cytokines, transforming growth factor beta 1 (TGFB1) and 4 enzyme genes involved in retinoic acid biosynthesis via 6 signaling pathways. Analysis of the combined data showed that 9 microbial genera (Clostridium_IV, Desulfobulbus, Eubacterium, Ochrobactrum, Propionibacterium, Pseudomonas, Slackia, Staphylococcus and Subdivision5_genera_IS) were highly related to the expression of functional lectins. These findings provide new insights into the interactions between the rumen epithelium and mucosal microbiota in the maintenance of rumen homeostasis. PMID- 28638074 TI - Geochemical constraints on the Hadean environment from mineral fingerprints of prokaryotes. AB - The environmental conditions on the Earth before 4 billion years ago are highly uncertain, largely because of the lack of a substantial rock record from this period. During this time interval, known as the Hadean, the young planet transformed from an uninhabited world to the one capable of supporting, and inhabited by the first living cells. These cells formed in a fluid environment they could not at first control, with homeostatic mechanisms developing only later. It is therefore possible that present-day organisms retain some record of the primordial fluid in which the first cells formed. Here we present new data on the elemental compositions and mineral fingerprints of both Bacteria and Archaea, using these data to constrain the environment in which life formed. The cradle solution that produced this elemental signature was saturated in barite, sphene, chalcedony, apatite, and clay minerals. The presence of these minerals, as well as other chemical features, suggests that the cradle environment of life may have been a weathering fluid interacting with dry-land silicate rocks. The specific mineral assemblage provides evidence for a moderate Hadean climate with dry and wet seasons and a lower atmospheric abundance of CO2 than is present today. PMID- 28638075 TI - Mycobacterial heat shock protein 65 mediated metabolic shift in decidualization of human endometrial stromal cells. AB - Successful implantation is dependent on the appropriate decidualization of endometrial stromal cells for the establishment of pregnancy in women. Mycobacterial heat shock protein 65 (HSP65) is involved in pathogenesis of the genital tuberculosis (GTB), one of the common causes of infertility in emerging countries. Though implantation failure appears to be the major cause, understanding the status of decidualizaiton process in women diagnosed with GTB has not been thoroughly addressed. We, therefore, explored the effect of HSP65 protein on the endometrial cell metabolism during in vitro decidualization. In order to identify the cellular metabolism of decidual cells with and without HSP65 treatment, proton NMR based characterization of metabolites extracted from cells and culture media were performed. In presence of HSP65, significant reduction in the decidual phenotype of endometrial stromal cells and prolactin expression is suggestive of impairment in decidualization. The intracellular and extracellular metabolic changes in HSP65 treated endometrial stromal cells produced a distinct pattern, reflecting the interaction between the protein and cellular metabolism. HSP65 mediated dysregulation in cellular metabolism is associated with poor decidualization. Besides enriching the present knowledge on metabolic changes underlying stromal cells decidualization, these findings assist in identifying potential molecular causes for decidualization failure in GTB women. PMID- 28638077 TI - Vapour-Induced Liquid Crystallinity and Self-Recovery Mechanochromism of Helical Block Copolymer. AB - New molecular design of conjugated polymer that possess high sensitivity to vapour and self-recovering property against pressure is proposed. We synthesised a rod-rod diblock copolymer, poly(3-((3S)-3,7-dimethyl-octyl)-thiophene)-block poly(4-octyl phenylisocyanide) (PTh- b -PPI), composed of a pi-conjugated polymer and a rod-type helical coiled polymer. Introduction of PPI block in the block copolymer architecture enabled PTh- b -PPI film to exhibit solid-to-liquid crystal phase transition by exposure to chloroform vapour, accompanied with colour change (purple-to-yellow), which is the first report on a new phenomenon of "vapour-induced liquid crystallinity". In addition, PTh- b -PPI film showed colour change (purple-to-vermillion) during mechanical shearing, and spontaneously recovered under ambient conditions. We concluded that rod-type helical coiled polymer PPI block performs crucial roles as intrinsically vapour induced liquid crystallinity and self-reassembling property in the architecture of PTh- b -PPI. PMID- 28638076 TI - Single-molecule analysis reveals that DNA replication dynamics vary across the course of schizogony in the malaria parasite Plasmodium falciparum. AB - The mechanics of DNA replication and cell cycling are well-characterized in model organisms, but less is known about these basic aspects of cell biology in early diverging Apicomplexan parasites, which do not divide by canonical binary fission but undergo unconventional cycles. Schizogony in the malaria parasite, Plasmodium, generates ~16-24 new nuclei via independent, asynchronous rounds of genome replication prior to cytokinesis and little is known about the control of DNA replication that facilitates this. We have characterised replication dynamics in P. falciparum throughout schizogony, using DNA fibre labelling and combing to visualise replication forks at a single-molecule level. We show that origins are very closely spaced in Plasmodium compared to most model systems, and that replication dynamics vary across the course of schizogony, from faster synthesis rates and more widely-spaced origins through to slower synthesis rates and closer spaced origins. This is the opposite of the pattern usually seen across S-phase in human cells, when a single genome is replicated. Replication forks also appear to stall at an unusually high rate throughout schizogony. Our work explores Plasmodium DNA replication in unprecedented detail and opens up tremendous scope for analysing cell cycle dynamics and developing interventions targetting this unique aspect of malaria biology. PMID- 28638080 TI - Thermoelectric performance of n-type Mg2Ge. AB - Magnesium-based thermoelectric materials (Mg2X, X = Si, Ge, Sn) have received considerable attention due to their availability, low toxicity, and reasonably good thermoelectric performance. The synthesis of these materials with high purity is challenging, however, due to the reactive nature and high vapour pressure of magnesium. In the current study, high purity single phase n-type Mg2Ge has been fabricated through a one-step reaction of MgH2 and elemental Ge, using spark plasma sintering (SPS) to reduce the formation of magnesium oxides due to the liberation of hydrogen. We have found that Bi has a very limited solubility in Mg2Ge and results in the precipitation of Mg2Bi3. Bismuth doping increases the electrical conductivity of Mg2Ge up to its solubility limit, beyond which the variation is minimal. The main improvement in the thermoelectric performance is originated from the significant phonon scattering achieved by the Mg2Bi3 precipitates located mainly at grain boundaries. This reduces the lattice thermal conductivity by ~50% and increases the maximum zT for n-type Mg2Ge to 0.32, compared to previously reported maximum value of 0.2 for Sb-doped Mg2Ge. PMID- 28638079 TI - Transcriptome changes between compatible and incompatible graft combination of Litchi chinensis by digital gene expression profile. AB - Plant grafting has been practiced widely in horticulture and proved as a useful tool in science. However, the mechanisms of graft healing or graft incompatibility remain poorly understood. In this study, Litchi chinensis cv. 'Jingganghongnuo' homograft ('J/J') and 'Jingganghongnuo'/'zhuangyuanhong' heterograft ('J/Z') as compatible and incompatible combination, respectively, was used to study transcriptional changes between incompatible and compatible graft during graft union formation. Anatomical observation indicated that three stages (2 h, 14 d and 21 d after grafting) were critical for graft union formation and selected for high-throughput sequencing. Results indicated 6060 DEGs were differentially expressed in the compatible combination and 5267 DEGs exhibiting in the incompatible one. KEGG pathway enrichment analysis revealed that DEGs were involved in metabolism, wound response, phenylpropanoid biosynthesis and plant hormone signal transduction. The expression of 9 DEGs annotated in auxin pathway was up-regulated in compatible combination than that in incompatible combination. The IAA concentration confirmed that the IAA might promote the graft compatibility. In addition, 13 DEGs related to lignin biosynthesis were differentially expressed during graft healing process. Overall, our results provide abundant sequence resources for studying mechanisms underlying graft compatibility and establish a platform for further studies of litchi and other evergreen fruit trees. PMID- 28638078 TI - The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington's disease. AB - Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington's disease (HD), Parkinson's disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown. Using drug screening in C. elegans nematodes with neuronal expression of human exon-1 huntingtin (128Q), we found that 3beta-Methoxy Pregnenolone (MAP4343), 17beta-oestradiol (17betaE2) and 12 flavonoids including isoquercitrin promote neuronal function in 128Q nematodes. MAP4343, 17betaE2 and isoquercitrin also promote stress resistance in mutant Htt striatal cells derived from knock-in HD mice. Interestingly, daf-16/FOXO is required for MAP4343, 17betaE2 and isoquercitrin to sustain neuronal function in 128Q nematodes. This similarly applies to the GSK3 inhibitor lithium chloride (LiCl) and, as previously described, to resveratrol and the AMPK activator metformin. Daf 16/FOXO and the targets engaged by these compounds define a sub-network enriched for stress-response and neuronally-active pathways. Collectively, these data highlights the dependence on a daf-16/FOXO-interaction network as a common feature of several compound families for prolonging neuronal function in HD. PMID- 28638081 TI - Development of lysosome-mimicking vesicles to study the effect of abnormal accumulation of sphingosine on membrane properties. AB - Synthetic systems are widely used to unveil the molecular mechanisms of complex cellular events. Artificial membranes are key examples of models employed to address lipid-lipid and lipid-protein interactions. In this work, we developed a new synthetic system that more closely resembles the lysosome - the lysosome mimicking vesicles (LMVs) - displaying stable acid-to-neutral pH gradient across the membrane. To evaluate the advantages of this synthetic system, we assessed the distinct effects of sphingosine (Sph) accumulation in membrane structure and biophysical properties of standard liposomes (no pH gradient) and in LMVs with lipid composition tuned to mimic physiological- or NPC1-like lysosomes. Ternary 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/Sphingomyelin (SM)/Cholesterol (Chol) mixtures with, respectively, low and high Chol/SM levels were prepared. The effect of Sph on membrane permeability and biophysical properties was evaluated by fluorescence spectroscopy, electrophoretic and dynamic light scattering. The results showed that overall Sph has the ability to cause a shift in vesicle surface charge, increase membrane order and promote a rapid increase in membrane permeability. These effects are enhanced in NPC1- LMVs. The results suggest that lysosomal accumulation of these lipids, as observed under pathological conditions, might significantly affect lysosomal membrane structure and integrity, and therefore contribute to the impairment of cell function. PMID- 28638082 TI - Tandem malonate-based glucosides (TMGs) for membrane protein structural studies. AB - High-resolution membrane protein structures are essential for understanding the molecular basis of diverse biological events and important in drug development. Detergents are usually used to extract these bio-macromolecules from the membranes and maintain them in a soluble and stable state in aqueous solutions for downstream characterization. However, many eukaryotic membrane proteins solubilized in conventional detergents tend to undergo structural degradation, necessitating the development of new amphiphilic agents with enhanced properties. In this study, we designed and synthesized a novel class of glucoside amphiphiles, designated tandem malonate-based glucosides (TMGs). A few TMG agents proved effective at both stabilizing a range of membrane proteins and extracting proteins from the membrane environment. These favourable characteristics, along with synthetic convenience, indicate that these agents have potential in membrane protein research. PMID- 28638083 TI - Multiple thermal spin transport performances of graphene nanoribbon heterojuction co-doped with Nitrogen and Boron. AB - Graphene nanoribbon is a popular material in spintronics owing to its unique electronic properties. Here, we propose a novel spin caloritronics device based on zigzag graphene nanoribbon (ZGNR), which is a heterojunction consisting of a pure single-hydrogen-terminated ZGNR and one doped with nitrogen and boron. Using the density functional theory combined with the non-equilibrium Green's function, we investigate the thermal spin transport properties of the heterojunction under different magnetic configurations only by a temperature gradient without an external gate or bias voltage. Our results indicate that thermally-induced spin polarized currents can be tuned by switching the magnetic configurations, resulting in a perfect thermal colossal magnetoresistance effect. The heterojunctions with different magnetic configurations exhibit a variety of excellent transport characteristics, including the spin-Seebeck effect, the spin filtering effect, the temperature switching effect, the negative differential thermal resistance effect and the spin-Seebeck diode feature, which makes the heterojunction a promising candidate for high-efficiently multifunctional spin caloritronic applications. PMID- 28638084 TI - Identification and expression analysis of chemosensory receptor genes in an aphid endoparasitoid Aphidius gifuensis. AB - Olfaction and gustation play critical roles during the host-location search process of insects. Several chemosensory receptor genes are thought to be involved in providing specificity to the olfactory sensory neuron responses. The aphid endoparasitoid, Aphidius gifuensis, has been used as a biological control agent against a variety of aphid species; this parasitoid is able to detect its target host(s) effectively during the parasitic process. To understand the mechanism of host detection in A. gifuensis, we assembled specific antennal transcriptomes of each sex through next generation sequencing technology to identify the major chemosensory receptor genes. Using a bioinformatics screen, we identified 100 olfactory receptors candidates (62 odorant receptors, 15 gustatory receptors, and 23 ionotropic receptors) from the sex-specific antennal transcriptome. In addition, combining with the demonstrated functions of chemosensory genes in other insects, the sex-, tissue-, and host-specific expression profile of chemosensory genes potentially revealed the candidate physiological functions. The identification and expression profile of chemosensory receptor genes in A. gifuensis provide valuable information for understanding and investigating the intraspecific or interspecific chemical communications in the solitary parasitic wasps. PMID- 28638086 TI - Wnt2b attenuates HSCs activation and liver fibrosis through negative regulating TLR4 signaling. AB - The Wingless-type MMTV integration site family member 2b (Wnt2b) has been found to be a principal mediator of liver development and regeneration. However, the significance of Wnt2b in the pathogenesis of fibrosis-related liver diseases remains undefined. Here, we report that Wnt2b was highly expressed in the fibrotic liver tissues, exhibiting protective effects against activation of hepatic stellate cells (HSCs) and fibrosis progression. We identified a negative regulation of Wnt2b on the toll-like receptor 4 (TLR4) activation-mediated pro fibrogenic effects. Wnt2b was shown not only to directly suppress LPS-induced HSCs activation, but also to inhibit TLR4-enhanced the sensitivity of HSCs to transforming growth factor beta (TGF-beta). Mechanistic study showed that Wnt2b suppresses TLR4 signaling through inhibiting the expression of TLR4 as well as the activation of NF-kappaB and MAPKs. These findings provided new insights into the pathophysiology of liver fibrosis by characterizing Wnt2b as a novel endogenous suppressor of TLR4 signaling, maintaining tissue homeostasis during the early stage of hepatic fibrosis-associated liver diseases. PMID- 28638085 TI - Differential regulations of vestibulo-ocular reflex and optokinetic response by beta- and alpha2-adrenergic receptors in the cerebellar flocculus. AB - Norepinephrine modulates synaptic plasticity in various brain regions and is implicated in memory formation, consolidation and retrieval. The cerebellum is involved in motor learning, and adaptations of the vestibulo-ocular reflex (VOR) and optokinetic response (OKR) have been studied as models of cerebellum dependent motor learning. Previous studies showed the involvement of adrenergic systems in the regulation of VOR, OKR and cerebellar synaptic functions. Here, we show differential contributions of beta- and alpha2-adrenergic receptors in the mouse cerebellar flocculus to VOR and OKR control. Effects of application of beta or alpha2-adrenergic agonist or antagonist into the flocculus suggest that the beta-adrenergic receptor activity maintains the VOR gain at high levels and contributes to adaptation of OKR, and that alpha2-adrenergic receptor counteracts the beta-receptor activity in VOR and OKR control. We also examined effects of norepinephrine application, and the results suggest that norepinephrine regulates VOR and OKR through beta-adrenergic receptor at low concentrations and through alpha2-receptor at high concentrations. PMID- 28638087 TI - Mesoscopic Multimodal Imaging Provides New Insight to Tumor Tissue Evaluation: An Example of Macrophage Imaging of Hepatic Tumor using Organosilica Nanoparticles. AB - Multimodal imaging using novel multifunctional nanoparticles provides new approach to biomedical field. Thiol-organosilica nanoparticles containing iron oxide magnetic nanoparticles (MNPs) and rhodamine B (thiol OS-MNP/Rho) were applied to multimodal imaging of hepatic tumor of Long-Evans Cinnamon (LEC) rat. The magnetic resonance imaging (MRI) of LEC rats revealed tumors in the liver clearly and semi-quantitatively due to a labeling of macrophages in liver. The fluorescent imaging (FI) showed abnormal fluorescent patterns of the liver at the mesoscopic level that was between macroscopic and microscopic level. We performed correlation analysis between optical imaging including FI and MRI. We found that the labeled macrophages located specific area in the tumor tissue and influenced the tumor size on MRI. In addition histological observation showed the labeled macrophages related specific tissue in the pathological region. We demonstrated a new approach to evaluate tumor tissue at the macroscopic and microscopic level as well as mesoscopic level using multimodal imaging. PMID- 28638089 TI - A screen for inhibitory peptides of hepatitis C virus identifies a novel entry inhibitor targeting E1 and E2. AB - Hepatitis C virus (HCV) entry into hepatocytes is a multistep process that represents a promising target for antiviral intervention. The viral envelope protein E1E2 plays a critical role in HCV entry. In this study, we sought to identify peptide inhibitors of HCV by screening a library of overlapping peptides covering E1E2. Screening the peptide library identified several novel anti-HCV peptides. Four peptides from glycoprotein E2 were selected for further investigation. The 50% effective dose (ED50) was approximately 5 nM for each peptide. Our data indicated that these peptides inhibited HCV entry at the post attachment step. Moreover, these peptides blocked cell-to-cell transmission of HCVcc and had broad-spectrum antiviral effects on HCVcc. These peptides exhibited combination inhibitory effects on HCVcc infection when combined with IFN-alpha2b or anti-CD81 antibody. Interestingly, we observed that E2-42 associated with E1 and E2. Our results indicate that E2-42 inhibits HCV entry via E1 and E2. These findings suggest a new avenue for HCV therapeutic development. PMID- 28638088 TI - Chemokine receptor CXCR4 regulates CaMKII/CREB pathway in spinal neurons that underlies cancer-induced bone pain. AB - We previously demonstrated that the chemokine receptor CXCR4 plays an important role in cancer-induced bone pain by activating spinal neurons and glial cells. However, the specific neuronal mechanism of CXCR4 signaling is not clear. We further report that CXCR4 contributes to the activation of the neuronal CaMKII/CREB pathway in cancer-induced bone pain. We used a tumor cell implantation (TCI) model and observed that CXCR4, p-CaMKII and p-CREB were persistently up-regulated in spinal neurons. CXCR4 also co-expressed with p CaMKII and p-CREB, and mediated p-CaMKII and p-CREB expression after TCI. Intrathecal delivery of CXCR4 siRNA or CaMKII inhibitor AIP2 abrogated TCI induced pain hypersensitivity and TCI-induced increase in p-CaMKII and p-CREB expression. Intrathecal injection of the principal ligand for CXCR4, SDF-1, promoted p-CaMKII and p-CREB expression in naive rats, which was prevented by post-administration of CXCR4 inhibitor Plerixafor or PLC inhibitor U73122. Plerixafor, U73122, or AIP2 also alleviated SDF-1-elicited pain behaviors. Intrathecal injection of CXCR4 siRNA significantly suppressed TCI-induced up regulation of NMDAR1 mRNA and protein, which is a known gene target of CREB. Collectively, these results suggest that the CaMKII/CREB pathway in spinal neurons mediates CXCR4-facilitated pain hypersensitivity in cancer rats. PMID- 28638090 TI - A change in the aggregation pathway of bovine serum albumin in the presence of arginine and its derivatives. AB - Chemical chaperones including arginine and its derivatives are widely used by biochemists working on the design of agents, which are able to efficiently suppress protein aggregation. To elucidate the mechanisms of anti-aggregation activity of chemical chaperones, methods based on registration of the increment in light scattering intensity must be supplemented with methods for direct detection of the portion of aggregated protein (gammaagg). For this purpose asymmetric flow field-flow fractionation was used in the present work. It was shown that heat-induced aggregation of bovine serum albumin (BSA) followed the kinetics of the reaction of the second order (0.1 M sodium phosphate buffer, pH 7.0, 70 degrees C). It was proposed to use R h vs gammaagg plots to characterize the aggregation pathway (R h is the hydrodynamic radius of the protein aggregates, which was calculated from the dynamic light scattering data). The changes in the shape of R h vs gammaagg plots in the presence of arginine, arginine amide and arginine ethyl ester are indicative of the changes in the aggregation pathway of BSA aggregation. A conclusion has been made that larger aggregates are formed in the presence of arginine hydrochloride and its derivatives. PMID- 28638092 TI - From shifting cultivation to teak plantation: effect on overland flow and sediment yield in a montane tropical catchment. AB - Soil erosion supplies large quantities of sediments to rivers of Southeastern Asia. It reduces soil fertility of agro-ecosystems located on hillslopes, and it degrades, downstream, water resource quality and leads to the siltation of reservoirs. An increase in the surface area covered with commercial perennial monocultures such as teak plantations is currently observed at the expanse of traditional slash-and-burn cultivation systems in steep montane environments of these regions. The impacts of land-use change on the hydrological response and sediment yields have been investigated in a representative catchment of Laos monitored for 13 years. After the gradual conversion of rice-based shifting cultivation to teak plantation-based systems, overland flow contribution to stream flow increased from 16 to 31% and sediment yield raised from 98 to 609 Mg km-2. This result is explained by the higher kinetic energy of raindrops falling from the canopy, the virtual absence of understorey vegetation cover to dissipate drop energy and the formation of an impermeable surface crust accelerating the formation and concentration of overland flow. The 25-to-50% lower 137Cs activities measured in soils collected under mature teak plantations compared to soils under other land uses illustrate the severity of soil erosion processes occurring in teak plantations. PMID- 28638091 TI - The cannabinoid ligand LH-21 reduces anxiety and improves glucose handling in diet-induced obese pre-diabetic mice. AB - LH-21 is a triazol derivative that has been described as a low-permeant neutral CB1 antagonist, though its pharmacology is still unclear. It has been associated with anti-obesity actions in obese rats. However, its role in preventing type 2 diabetes (T2D) onset have not been studied yet. Given CB1 receptors remain as potential pharmacological targets to fight against obesity and T2D, we wanted to explore the metabolic impact of this compound in an animal model of obesity and pre-diabetes as well as the lack of relevant actions in related central processes such as anxiety. C57BL/6J mice were rendered obese and pre-diabetic by feeding a high-fat diet for 15 weeks and then treated with LH-21 or vehicle for two weeks. Food intake, body weight and glucose handling were assessed, together with other relevant parameters. Behavioural performance was evaluated by the open field test and the elevated plus maze. LH-21 did not affect food intake nor body weight but it improved glucose handling, displaying tissue-specific beneficial actions. Unexpectedly, LH-21 induced anxiolysis and reverted obesity-induced anxiety, apparently through GPR55 receptor. These results suggest that LH-21 can be a new candidate to fight against diabetes onset. Indeed, this compound shows potential in counteracting obesity-related anxiety. PMID- 28638093 TI - Fatty acid composition and phospholipid types used in infant formulas modifies the establishment of human gut bacteria in germ-free mice. AB - Human milk fat contains high concentrations of medium-chained fatty acids (MCFA) and triacylglycerols emulsified by a sphingomyelin-rich phospholipid membrane (milk phospholipids, MPL). Infant formula comprises mainly long-chained fatty acids (LCFA) emulsified with dairy proteins and soy lecithin (SL) lacking sphingomyelin. Sphingomyelin content and saturation level of phospholipids affect the gut lipase activity, which alters the concentrations of lipid hydrolysis products in ileum and colon, and hereby putatively affects the competitive advantage of specific gut bacteria. Thus, differences in phospholipid and FA composition may modulate the establishment of the gut microbiota. We investigated effects of fatty acid (FA) composition and emulsification (MPL vs SL) ingested during establishment of human gut microbiota in germ-free mice, and found that cecal microbiotas from mice given MCFA-rich emulsions were characterized by high relative abundances of Bacteroidaceae and Desulfovibrionaceae, while LCFA-rich emulsions caused higher abundances of Enterobacteriaceae, Erysipelotrichaceae, Coriobacteriaceae and Enterococcaceae. Consumption of SL-emulsified lipids skewed the community towards more Enterococcaceae and Enterobacteriaceae, while MPL increased Bacteroidaceae, Desulfovibrionaceae, Rikkenellaceae and Porphyromonadaceae. Intake of SL increased cecal concentrations of iso-valeric and iso-butyric acids. This suggests that fat-type and emulsifiers applied in infant formula may have distinct effects on the establishment of the gut microbiota in formula-fed infants. PMID- 28638094 TI - Microsaccades are sensitive to word structure: A novel approach to study language processing. AB - Microsaccades are miniature eye movements that occur involuntarily during fixation. They are typically inhibited following stimulus onset and are released from inhibition about 300 ms post-stimulus. Microsaccade-inhibition is modulated by low level features of visual stimuli, but it is currently unknown whether they are sensitive to higher level, abstract linguistic properties. To address this question, we measured the timing of microsaccades while subjects were presented with written Hebrew words and pronounceable nonwords (pseudowords). We manipulated the underlying structure of pseudowords such that half of them contained real roots while the other half contained invented roots. Importantly, orthographic similarity to real words was equated between the two conditions. Microsaccade onset was significantly slower following real-root compared to invented-root stimuli. Similar results were obtained when considering post stimulus delay of eye blinks. Moreover, microsaccade-delay was positively and significantly correlated with measures of real-word similarity. These findings demonstrate, for the first time, sensitivity of microsaccades to linguistic structure. Because microsaccades are involuntary and can be measured in the absence of overt response, our results provide initial evidence that they can be used as a novel physiological measure in the study of language processes in healthy and clinical populations. PMID- 28638096 TI - Identification of a flavonoid isolated from plum (Prunus domestica) as a potent inhibitor of Hepatitis C virus entry. AB - Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases that often requires liver transplantation. The standard therapies are limited by severe side effects, resistance development, high expense and in a substantial proportion of cases, fail to clear the infection which bespeak the need for development of well-tolerated antivirals. Since most of the drug development strategies target the replication stage of viral lifecycle, the identification of entry inhibitors might be crucial especially in case of liver-transplant recipients. In the present study we have evaluated fruits which are known for their hepatoprotective effects in order to screen for entry inhibitors. We report the identification of a flavonoid, rutin, isolated from Prunus domestica as a new HCV entry inhibitor. Characterization and confirmation of the chemical structure was done by LC-ESI-MS, NMR and IR spectral analyses. Rutin significantly inhibited HCV-LP binding to hepatoma cells and inhibited cell-culture derived HCV (HCVcc) entry into hepatoma cells. Importantly, rutin was found to be non-toxic to hepatoma cells. Furthermore, rutin inhibits the early entry stage of HCV lifecycle possibly by directly acting on the viral particle. In conclusion, rutin is a promising candidate for development of anti-HCV therapeutics in the management of HCV infection. PMID- 28638097 TI - Linking the rotation of a rigid body to the Schrodinger equation: The quantum tennis racket effect and beyond. AB - The design of efficient and robust pulse sequences is a fundamental requirement in quantum control. Numerical methods can be used for this purpose, but with relatively little insight into the control mechanism. Here, we show that the free rotation of a classical rigid body plays a fundamental role in the control of two level quantum systems by means of external electromagnetic pulses. For a state to state transfer, we derive a family of control fields depending upon two free parameters, which allow us to adjust the efficiency, the time and the robustness of the control process. As an illustrative example, we consider the quantum analog of the tennis racket effect, which is a geometric property of any classical rigid body. This effect is demonstrated experimentally for the control of a spin 1/2 particle by using techniques of Nuclear Magnetic Resonance. We also show that the dynamics of a rigid body can be used to implement one-qubit quantum gates. In particular, non-adiabatic geometric quantum phase gates can be realized based on the Montgomery phase of a rigid body. The robustness issue of the gates is discussed. PMID- 28638095 TI - Mitochondria localization induced self-assembly of peptide amphiphiles for cellular dysfunction. AB - Achieving spatiotemporal control of molecular self-assembly associated with actuation of biological functions inside living cells remains a challenge owing to the complexity of the cellular environments and the lack of characterization tools. We present, for the first time, the organelle-localized self-assembly of a peptide amphiphile as a powerful strategy for controlling cellular fate. A phenylalanine dipeptide (FF) with a mitochondria-targeting moiety, triphenyl phosphonium (Mito-FF), preferentially accumulates inside mitochondria and reaches the critical aggregation concentration to form a fibrous nanostructure, which is monitored by confocal laser scanning microscopy and transmission electron microscopy. The Mito-FF fibrils induce mitochondrial dysfunction via membrane disruption to cause apoptosis. The organelle-specific supramolecular system provides a new opportunity for therapeutics and in-depth investigations of cellular functions.Spatiotemporal control of intracellular molecular self assembly holds promise for therapeutic applications. Here the authors develop a peptide consisting of a phenylalanine dipeptide with a mitochondrial targeting moiety to form self-assembling fibrous nanostructures within mitochondria, leading to apoptosis. PMID- 28638098 TI - Bounds for coherence of quantum superpositions in high dimension. AB - Quantum coherence plays a major role in the promotion for quantum information processing and designing quantum technology. Since coherence is rooted in superposition principle, it is vital to understand the coherence change with respect to superpositions. Here we study the bounds for coherence of quantum superpositions in high dimension. We consider three most frequently used measures of coherence, i.e. the relative entropy of coherence, l 1 norm of coherence and robustness of coherence. For a quantum state (an arbitrary dimension) and its arbitrary decomposition, we give the upper and lower bounds for coherence of the superposition state in terms of the coherence of the states being superposed. PMID- 28638099 TI - Brilliant X-rays using a Two-Stage Plasma Insertion Device. AB - Particle accelerators have made an enormous impact in all fields of natural sciences, from elementary particle physics, to the imaging of proteins and the development of new pharmaceuticals. Modern light sources have advanced many fields by providing extraordinarily bright, short X-ray pulses. Here we present a novel numerical study, demonstrating that existing third generation light sources can significantly enhance the brightness and photon energy of their X-ray pulses by undulating their beams within plasma wakefields. This study shows that a three order of magnitude increase in X-ray brightness and over an order of magnitude increase in X-ray photon energy is achieved by passing a 3 GeV electron beam through a two-stage plasma insertion device. The production mechanism micro bunches the electron beam and ensures the pulses are radially polarised on creation. We also demonstrate that the micro-bunched electron beam is itself an effective wakefield driver that can potentially accelerate a witness electron beam up to 6 GeV. PMID- 28638100 TI - Camphor-Engine-Driven Micro-Boat Guides Evolution of Chemical Gardens. AB - A micro-boat self-propelled by a camphor engine, carrying seed crystals of FeCl3, promoted the evolution of chemical gardens when placed on the surface of aqueous solutions of potassium hexacyanoferrate. Inverse chemical gardens (growing from the top downward) were observed. The growth of the "inverse" chemical gardens was slowed down with an increase in the concentration of the potassium hexacyanoferrate. Heliciform precipitates were formed under the self-propulsion of the micro-boat. A phenomenological model, satisfactorily describing the self locomotion of the camphor-driven micro-boat, is introduced and checked. PMID- 28638101 TI - Naked singularity, firewall, and Hawking radiation. AB - Spacetime singularity has always been of interest since the proof of the Penrose Hawking singularity theorem. Naked singularity naturally emerges from reasonable initial conditions in the collapsing process. A recent interesting approach in black hole information problem implies that we need a firewall to break the surplus entanglements among the Hawking photons. Classically, the firewall becomes a naked singularity. We find some vacuum analytical solutions in R n gravity of the firewall-type and use these solutions as concrete models to study the naked singularities. By using standard quantum theory, we investigate the Hawking radiation emitted from the black holes with naked singularities. Here we show that the singularity itself does not destroy information. A unitary quantum theory works well around a firewall-type singularity. We discuss the validity of our result in general relativity. Further our result demonstrates that the temperature of the Hawking radiation still can be expressed in the form of the surface gravity divided by 2pi. This indicates that a naked singularity may not compromise the Hakwing evaporation process. PMID- 28638102 TI - miR-509-5p and miR-1243 increase the sensitivity to gemcitabine by inhibiting epithelial-mesenchymal transition in pancreatic cancer. AB - The epithelial-mesenchymal transition (EMT) contributes to various processes in cancer progression, such as metastasis and drug resistance. Since we have already established a cell-based reporter system for identifying EMT-suppressive microRNAs (miRNAs) in the pancreatic cancer cell line Panc1, we performed a function-based screening assay by combining this reporter system and a miRNA library composed of 1,090 miRNAs. As a result, we identified miR-509-5p and miR 1243 as EMT-suppressive miRNAs, although the mechanisms for EMT-suppression induced by these miRNAs have yet to be clarified. Herein, we demonstrated that overexpression of miR-509-5p and miR-1243 increased the expression of E-cadherin through the suppression of EMT-related gene expression and that drug sensitivity increased with a combination of each of these miRNAs and gemcitabine. Moreover, miR-509-5p was associated with worse overall survival in patients with pancreatic cancer and was identified as an independently selected predictor of mortality. Our findings suggest that miR-509-5p and miR-1243 might be novel chemotherapeutic targets and serve as biomarkers in pancreatic cancer. PMID- 28638103 TI - The application of ultrasound in detecting lymph nodal recurrence in the treated neck of head and neck cancer patients. AB - Early detection of neck lymph node (LN) recurrence is paramount in improving the prognosis of treated head and neck cancer patients. Ultrasound (US) with US guided fine needle aspiration (FNA) and core needle biopsy (CNB) have been shown to have great accuracy for LN diagnoses in the untreated neck. However, in the treated neck with fibrosis, their roles are not clarified. Here, we retrospectively review 153 treated head and neck cancer patients who had received US and US-guided FNA/CNB. In multivariate logistic regression analyses, size (short-axis diameter >0.8 cm) (odds ratio (OR) 4.19, P = 0.007), round shape (short/long axis ratio >0.5) (OR 3.44, P = 0.03), heterogeneous internal echo (OR 3.92, P = 0.009) and irregular margin (OR 7.32, P < 0.001) are effective US features in predicting recurrent LNs in the treated neck. However, hypoechogenicity (OR 2.38, P = 0.289) and chaotic/absent vascular pattern (OR 3.04, P = 0.33) are ineffective. US-guided FNA (sensitivity/specificity: 95.24%/97.92%) is effective in the treated neck, though with high non-diagnostic rate (29.69%). US-guided CNB (sensitivity/specificity: 84.62%/100%) is also effective, though with low negative predictive value (62.5%). Overall, US with US guided FNA/CNB are still effective diagnostic tools for neck nodal recurrence surveillance. PMID- 28638104 TI - Anti-proliferative therapy for HIV cure: a compound interest approach. AB - In the era of antiretroviral therapy (ART), HIV-1 infection is no longer tantamount to early death. Yet the benefits of treatment are available only to those who can access, afford, and tolerate taking daily pills. True cure is challenged by HIV latency, the ability of chromosomally integrated virus to persist within memory CD4+ T cells in a non-replicative state and activate when ART is discontinued. Using a mathematical model of HIV dynamics, we demonstrate that treatment strategies offering modest but continual enhancement of reservoir clearance rates result in faster cure than abrupt, one-time reductions in reservoir size. We frame this concept in terms of compounding interest: small changes in interest rate drastically improve returns over time. On ART, latent cell proliferation rates are orders of magnitude larger than activation and new infection rates. Contingent on subtypes of cells that may make up the reservoir and their respective proliferation rates, our model predicts that coupling clinically available, anti-proliferative therapies with ART could result in functional cure within 2-10 years rather than several decades on ART alone. PMID- 28638105 TI - High efficacy in vitro selection procedure for generating transgenic parasites of Plasmodium berghei using an antibiotic toxic to rodent hosts. AB - The malaria parasite Plasmodium berghei is one of the main rodent malaria models. A shortcoming of this model parasite is its low flexibility in genetic manipulation. As this parasite cannot be continuously propagated in cell cultures, in vivo drug selection procedures are necessary to isolate genetic mutants. Drugs harmful to rodents therefore cannot be used for drug selection, which restricts the range of genetic manipulation. In this study, we addressed this problem by establishing a novel in vitro culture drug selection method, which we used in combination with other established methods to successfully isolate genetically manipulated parasites. The target mutants were enriched to the desired level within two weeks. We show that our system can also be used for sequential genetic manipulation of parasites carrying the traditionally used selection markers, demonstrate the procedure's versatility, and show its use in isolating specific genetically manipulated parasites. This novel in vitro selection method increases the number of available selection markers, allowing more extensive genetic manipulation in malaria parasite research. PMID- 28638106 TI - Protective Efficacy of the Trivalent Pseudomonas aeruginosa Vaccine Candidate PcrV-OprI-Hcp1 in Murine Pneumonia and Burn Models. AB - Pseudomonas aeruginosa is a formidable pathogen that is responsible for a diverse spectrum of human infectious diseases, resulting in considerable annual mortality rates. Because of biofilm formation and its ability of rapidly acquires of resistance to many antibiotics, P. aeruginosa related infections are difficult to treat, and therefore, developing an effective vaccine is the most promising method for combating infection. In the present study, we designed a novel trivalent vaccine, PcrV28-294-OprI25-83-Hcp11-162 (POH), and evaluated its protective efficacy in murine pneumonia and burn models. POH existed as a dimer in solution, it induced better protection efficacy in P. aeruginosa lethal pneumonia and murine burn models than single components alone when formulated with Al(OH)3 adjuvant, and it showed broad immune protection against several clinical isolates of P. aeruginosa. Immunization with POH induced strong immune responses and resulted in reduced bacterial loads, decreased pathology, inflammatory cytokine expression and inflammatory cell infiltration. Furthermore, in vitro opsonophagocytic killing assay and passive immunization studies indicated that the protective efficacy mediated by POH vaccination was largely attributed to POH-specific antibodies. Taken together, these data provided evidence that POH is a potentially promising vaccine candidate for combating P. aeruginosa infection in pneumonia and burn infections. PMID- 28638107 TI - Tracking protein function with sodium multi quantum spectroscopy in a 3D-tissue culture based on microcavity arrays. AB - The aim of this study was to observe the effects of strophanthin induced inhibition of the Na-/K-ATPase in liver cells using a magnetic resonance (MR) compatible bioreactor. A microcavity array with a high density three-dimensional cell culture served as a functional magnetic resonance imaging (MRI) phantom for sodium multi quantum (MQ) spectroscopy. Direct contrast enhanced (DCE) MRI revealed the homogenous distribution of biochemical substances inside the bioreactor. NMR experiments using advanced bioreactors have advantages with respect to having full control over a variety of physiological parameters such as temperature, gas composition and fluid flow. Simultaneous detection of single quantum (SQ) and triple quantum (TQ) MR signals improves accuracy and was achieved by application of a pulse sequence with a time proportional phase increment (TQTPPI). The time course of the Na-/K-ATPase inhibition in the cell culture was demonstrated by the corresponding alterations of sodium TQ/SQ MR signals. PMID- 28638108 TI - Pregnancy outcomes in nulliparous women after ultrasound ablation of uterine fibroids: A single-central retrospective study. AB - To explore the impact of high-intensity focused ultrasound (HIFU) ablation of uterine fibroids in nulliparous women on subsequent pregnancy and delivery. A retrospective analysis was conducted of nulliparous women who received HIFU treatment at Chongqing Medical University, Chongqing,China, from January 1, 2010, to January 1, 2015. A total of 189 cases were enrolled, the median follow-up time was three years. Among them,there were 131 cases pregnancy with a total of 133 times,the pregnancy rate was 69.3% (131/189),and the spontaneous conception rate was 95.4% (125/131). Of 131 pregnant women, 19 were on-going pregnancy, terminated pregnancy 114 times,which include 93 times successfully delivery with a 76.3% (87/114) full-term birth rate,and the cesarean section rate was 72.0% (67/93). Of 94 newborns,the average birth weight was (3.3 +/- 0.4)kg (range:1.5 4.8 kg), and a pair of them were identical twins. The incidence of complications during pregnancy and delivery were 10.8% (10/93) and 7.5% (7/93),respectively,except one woman failed on-going pregnancy and one woman suffered hysterectomy due to the complications,others all successful pregnant and delivered. Multiple-factor regression analysis found that age and infertility history were the important factors that may affect pregnancy after HIFU (P < 0.01). Nulliparous women who undergo HIFU treatment for uterine fibroids can subsequently have successful pregnancy and delivery safely. PMID- 28638109 TI - Voxel-based morphometric brain comparison between healthy subjects and major depressive disorder patients in Japanese with the s/s genotype of 5-HTTLPR. AB - Individuals with s/s genotype of serotonin transporter gene-linked promotor region (5-HTTLPR), which appear with a high frequency in Japanese, exhibit more diagnosable depression in relation to stressful life events than those with the s/l or l/l genotype. We prospectively investigated the brain volume changes in first-episode and medication naive major depression disorder patients (MDD) with the s/s genotype in Japanese. We assessed the differences between 27 MDD with the s/s genotype and 44 healthy subjects (HS) with the same genotype using a whole brain voxel-by-voxel statistical analysis of MRI. Gray matter volume in a brain region with significant clusters obtained via voxel-based morphometry analysis were measured and, as an exploratory analysis, evaluated for relationships to the subcategory scores (core, sleep, activity, psychic, somatic anxiety, delusion) of the Hamilton Depression Rating Scale (HAM-D) and the Social Readjustment Rating Scale (SRRS). The brain volume in the left insula lobe was significantly smaller in the MDD than in the HS. The left insula lobe volume correlated negatively with the "psychic" score of HAM-D and the SRRS. In a Japanese population with the s/s genotype, we found an atrophy of the insula in the MDD, which might be associated with "psychic" symptom and stress events. PMID- 28638110 TI - A novel and effective method to generate human porcine-specific regulatory T cells with high expression of IL-10, TGF-beta1 and IL-35. AB - Organ transplantation remains the most effective treatment for patients with late stage organ failure. Transgenic pigs provide an alternative organ donor source to the limited availability of human organs. However, cellular rejection still remains to be the obstacle for xenotransplantation. Superior to other methods, antigen-specific regulatory T cells (Treg) alleviate cellular rejection with fewer side effects. Here we demonstrate the use of a fast method to provide tolerogenic dendritic cells (tolDC) that can be used to generate effective porcine-specific Treg cells (PSTreg). TolDC were produced within three days from human monocytes in medium supplemented with anti-inflammatory cytokines. Treg were generated from naive CD4+ T cells and induced to become PSTreg by cocultivation with porcine-antigen-loaded tolDC. Results showed that PSTreg exhibited the expected phenotype, CD4+CD25+CD127low/- Foxp3+, and a more activated phenotype. The specificity of PSTreg was demonstrated by suppression of effector T cell (Teff) activation markers of different stages and inhibition of Teff cell proliferation. TolDC and PSTreg exhibited high expression of IL-10 and TGF-beta1 at both protein and RNA levels, and PSTreg also highly expressed IL-35 at RNA levels. Upon restimulation, PSTreg retained the activated phenotype and specificity. Taken together, the newly developed procedure allows efficient generation of highly suppressive PSTreg. PMID- 28638111 TI - Transcriptome analyses of taste organoids reveal multiple pathways involved in taste cell generation. AB - Taste cells undergo constant turnover throughout life; however, the molecular mechanisms governing taste cell generation are not well understood. Using RNA Seq, we systematically surveyed the transcriptome landscape of taste organoids at different stages of growth. Our data show the staged expression of a variety of genes and identify multiple signaling pathways underlying taste cell differentiation and taste stem/progenitor cell proliferation. For example, transcripts of taste receptors appear only or predominantly in late-stage organoids. Prior to that, transcription factors and other signaling elements are upregulated. RNA-Seq identified a number of well-characterized signaling pathways in taste organoid cultures, such as those involving Wnt, bone morphogenetic proteins (BMPs), Notch, and Hedgehog (Hh). By pharmacological manipulation, we demonstrate that Wnt, BMPs, Notch, and Hh signaling pathways are necessary for taste cell proliferation, differentiation and cell fate determination. The temporal expression profiles displayed by taste organoids may also lead to the identification of currently unknown transducer elements underlying sour, salt, and other taste qualities, given the staged expression of taste receptor genes and taste transduction elements in cultured organoids. PMID- 28638112 TI - The structure-function relationship of disulfide bonds in etanercept. AB - Etanercept is a TNFalpha receptor Fc fusion protein used for the treatment of rheumatic disease and psoriasis. Physicochemical and functional investigation of process fractions during development of the etanercept biosimilar GP2015 (Erelzi(r)) revealed a correlation between reduced potency and incorrect disulfide bridging between specific cysteines in the receptor domain. This novel structure-function relationship was found to be the molecular basis for reduced potency in recent Enbrel(r) batches, which exhibit higher levels of incorrect disulfide bridging. Interestingly, incorrect disulfide bridging was found to be reversible under serum-like redox conditions, restoring potency to normal levels. This redox dependent reversibility suggests that these variants are likely not relevant for clinical efficacy once the drug enters the bloodstream. Nonetheless, incorrect disulfide bridging in etanercept represents a new quality attribute that is critical for biopharmaceutical functionality and should thus be carefully monitored and controlled to guarantee patient safety. PMID- 28638113 TI - Clinical Significance and Next-Generation Sequencing of Chinese Pulmonary Sarcomatoid Carcinoma. AB - Pulmonary Sarcomatoid Carcinoma (PSC) constitutes a heterogeneous group of non small-cell lung carcinomas (NSCLCs) with a poor prognosis. In this study, a group of 7 patients with PSC was studied. Microscope analysis of all 7 cases revealed a pleomorphic carcinoma subtype. Moreover, 5 cases (71.4%) were composed entirely of malignant sarcomatoid-like elements, and 2 cases (28.6%) were composed of malignant sarcomatoid-like elements and at least 10% adenocarcinoma-like elements. Immunohistochemically, the PSC components of all 7 cases were positive for vimentin and cytokeratins, including cytokeratin (CK) and cytokeratin 7 (CK7). Next-Generation Sequencing (NGS) was performed, and a total of 136 putative somatic variants and one gene fusion were identified, of which 16 variants were considered hot spot mutations, including the genes EGFR, EML4-ALK, MET, BRAF, PIK3CA, and TP53. Of these hot spot mutations, one sample expressing an EML4-ALK fusion was further confirmed by Ventana IHC, and one sample containing an EGFR exon 19 deletion was also confirmed. The NGS results imply that TP53 mutations occur often in PSCs and that EML4-ALK fusion events and EGFR exon deletions also occur in these rare tumors. Molecular targeted therapy may be a useful treatment strategy for these rare lung tumors. PMID- 28638114 TI - Key driving forces of desertification in the Mu Us Desert, China. AB - The temporal trends and key driving forces of desertification in the Mu Us Desert are representatives of most arid regions of Asia with a high risk of desertification. We analyzed the significance of Aeolian transport on desertification in the Mu Us Desert by field investigations, sampling, wind tunnel experiments, particle size and nutrient measurements, and statistics on aeolian transport potentials. The results showed that high intensities of aeolian processes may result in low differences in aeolian transport despite differences in the underlying sediments. When high desertification occurred in the 1970s, the annual losses of the ammonium N, nitrate N, available K, and available P were approximately 116, 312, 46,436, and 1,251 kg km-2, respectively. After 2010, the losses were only 8, 20, 3,208, and 84 kg km-2, which were generally only 6.7% of those in the 1970s. The results showed that although human activity may trigger desertification, the dramatic decline of aeolian transport and low nutrient loss may be the key driving forces for the occurrence of rehabilitation in this region. PMID- 28638115 TI - Effect of impurity resonant states on optical and thermoelectric properties on the surface of a topological insulator. AB - We investigate the thermoelectric effect on a topological insulator surface with particular interest in impurity-induced resonant states. To clarify the role of the resonant states, we calculate the dc and ac conductivities and the thermoelectric coefficients along the longitudinal direction within the full Born approximation. It is found that at low temperatures, the impurity resonant state with strong energy de-pendence can lead to a zero-energy peak in the dc conductivity, whose height is sensitively dependent on the strength of scattering potential, and even can reverse the sign of the thermopower, implying the switching from n- to p-type carriers. Also, we exhibit the thermoelectric signatures for the filling process of a magnetic band gap by the resonant state. We further study the impurity effect on the dynamic optical conductivity, and find that the resonant state also generates an optical conductivity peak at the absorption edge for the interband transition. These results provide new perspectives for understanding the doping effect on topological insulator materials. PMID- 28638116 TI - Laser-ultrasonic delivery of agents into articular cartilage. AB - Research is ongoing to develop drug therapies to manage osteoarthritis (OA) and articular cartilage (AC) injuries. However, means to deliver drug to localized AC lesions are highly limited and not clinically available. This study investigates the capability of laser ultrasound (laser-induced plasma sound source) to deliver agents (methylene blue, MB, in PBS) into bovine AC. Treatment samples (n = 10) were immersed in MB solution simultaneously with LU exposure, while adjacent control 1 tissue (n = 10) was pre-treated with LU followed by immersion in MB and adjacent control 2 tissue (n = 10) was only immersed in MB. AC exposed (n = 22) or not exposed (n = 27) to LU were characterized for anomalies in structure, composition, viability or RNA expression. Optically detected MB content was significantly (p < 0.01) higher in treatment samples up to a depth of 500 um from AC surface as compared to controls. No major unwanted short-term effects on AC structure, proteoglycan or collagen contents, chondrocyte viability or RNA expression levels were detected. In conclusion, LU can deliver agents into AC without major short-term concerns on safety. LU could reveal new strategies for the development of localized drug therapies in AC. PMID- 28638117 TI - Disrupted functional connectivity between the periaqueductal gray and other brain regions in a rat model of recurrent headache. AB - Functional connectivity (FC) has been used to investigate the pathophysiology of migraine. We aimed to identify atypical FC between the periaqueductal gray (PAG) and other brain areas in rats induced by repeated meningeal nociception. The rat model was established by infusing an inflammatory soup (IS) through supradural catheters in conscious rats. Quiescent and face-grooming behaviors were observed to assess nociceptive behavior. FC analysis seeded on the PAG was performed on rats 21 days after IS infusion. The rats exhibited nociceptive behavior correlates of human behaviors associated with migraine after IS infusion. The PAG showed increased FC with the prefrontal cortex, cingulate gyrus, and motor cortex but decreased FC with the basal ganglia, dorsal lateral thalamus, internal capsule and prelimbic cortex in the rat model. The atypical FC of the PAG with brain regions in the rat model that are involved in nociception, somatosensory processing, emotional processing, and pain modulation are consistent with the clinical data from migraineurs, indicate that resting-state FC changes in migraine patients may be a consequence of headache attacks, and further validate this rat model of chronic migraine. PMID- 28638118 TI - Conformational plasticity and evolutionary analysis of the myotilin tandem Ig domains. AB - Myotilin is a component of the sarcomere where it plays an important role in organisation and maintenance of Z-disk integrity. This involves direct binding to F-actin and filamin C, a function mediated by its Ig domain pair. While the structures of these two individual domains are known, information about their relative orientation and flexibility remains limited. We set on to characterise the Ig domain pair of myotilin with emphasis on its molecular structure, dynamics and phylogeny. First, sequence conservation analysis of myotilin shed light on the molecular basis of myotilinopathies and revealed several motifs in Ig domains found also in I-band proteins. In particular, a highly conserved Glu344 mapping to Ig domain linker, was identified as a critical component of the inter-domain hinge mechanism. Next, SAXS and molecular dynamics revealed that Ig domain pair exists as a multi-conformation species with dynamic exchange between extended and compact orientations. Mutation of AKE motif to AAA further confirmed its impact on inter-domain flexibility. We hypothesise that the conformational plasticity of the Ig domain pair in its unbound form is part of the binding partner recognition mechanism. PMID- 28638121 TI - Neural coding: Face values. PMID- 28638120 TI - Neural circuits underlying thirst and fluid homeostasis. AB - Thirst motivates animals to find and consume water. More than 40 years ago, a set of interconnected brain structures known as the lamina terminalis was shown to govern thirst. However, owing to the anatomical complexity of these brain regions, the structure and dynamics of their underlying neural circuitry have remained obscure. Recently, the emergence of new tools for neural recording and manipulation has reinvigorated the study of this circuit and prompted re examination of longstanding questions about the neural origins of thirst. Here, we review these advances, discuss what they teach us about the control of drinking behaviour and outline the key questions that remain unanswered. PMID- 28638119 TI - Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. AB - The study of sex differences in the brain is a topic of neuroscientific study that has broad reaching implications for culture, society and biomedical science. Recent research in rodent models has led to dramatic shifts in our views of the mechanisms underlying the sexual differentiation of the brain. These include the surprising discoveries of a role for immune cells and inflammatory mediators in brain masculinization and a role for epigenetic suppression in brain feminization. How and to what degree these findings will translate to human brain development will be questions of central importance in future research in this field. PMID- 28638122 TI - Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines. AB - Overexpression of HER2 has been reported in around 25% of human breast cancers. Despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments, the mechanisms for which are poorly understood. Here, we investigated the sensitivity of a panel of breast cancer cell lines to treatment with various types of HER-family inhibitors alone or in combination with other tyrosine kinase inhibitors or chemotherapeutic agents. We found that treatment with the second-generation irreversible HER family inhibitors, particularly afatinib and neratinib, were more effective than treatment with the first-generation reversible inhibitors in inhibiting growth, migration and downstream cell signalling in breast cancer cells. Of the three HER2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors, while MDA-MB-453 was comparatively resistant. Combinations of HER-family inhibitors with NVP-AEW541, dasatinib or crizotinib (inhibitors of IGF-1R, Src and c-Met/ALK, respectively) led to synergistic effects in some of the cell lines examined. In particular, treatment with a combination of Src and HER-family member inhibitors resulted in synergistic growth inhibition of MDA-MB453 cells, implicating Src as a mediator of resistance to HER2-targeting agents. Our results suggest that combining HER family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation. PMID- 28638123 TI - Transient cell assembly networks encode stable spatial memories. AB - One of the mysteries of memory is that it can last despite changes in the underlying synaptic architecture. How can we, for example, maintain an internal spatial map of an environment over months or years when the underlying network is full of transient connections? In the following, we propose a computational model for describing the emergence of the hippocampal cognitive map in a network of transient place cell assemblies and demonstrate, using methods of algebraic topology, how such a network can maintain spatial memory over time. PMID- 28638127 TI - The Relevance of Arieti's Work in the Age of Medication. AB - This paper looks at the relevance of psychoanalysis as a treatment option for psychotic individuals at a time when psychosis is invariably considered to be a biologically-based brain disease, for which the preferred course of treatment is psychotropic medication. In recent years, the use of psychoanalysis has declined noticeably in favor of evidenced-based biomedical approaches, which rely heavily upon statistical probabilities for ameliorating specific psychotic symptoms. Well publicized biological approaches have proliferated, often to the detriment of the psychotic individual's general health, emotional recovery, and long-term rehabilitation. Sadly, these approaches may also be a significant factor affecting mortality rates in those suffering with psychosis, known to be about 25 years shorter, on average, than the general population. PMID- 28638124 TI - Expression of the Human Herpesvirus 6A Latency-Associated Transcript U94A Disrupts Human Oligodendrocyte Progenitor Migration. AB - Progression of demyelinating diseases is caused by an imbalance of two opposing processes: persistent destruction of myelin and myelin repair by differentiating oligodendrocyte progenitor cells (OPCs). Repair that cannot keep pace with destruction results in progressive loss of myelin. Viral infections have long been suspected to be involved in these processes but their specific role remains elusive. Here we describe a novel mechanism by which HHV-6A, a member of the human herpesvirus family, may contribute to inadequate myelin repair after injury. PMID- 28638131 TI - The Flexible Function of the Modern Kleinian Psychoanalytic Approach: Interpreting Through the Unbearable Security of Paranoid and Depressive Phantasies. AB - Working to establish analytic contact (Waska, 2007) with a patient involves the verbal act of interpretation. But, how one interprets and what we try to hold in words is not the same with each patient. Each patient requires, invites, provokes and responds to a unique mixture of interpretive elements or approaches. The projective identification process that is so often the bedrock of the transference, and therefore the catalyst of the counter-transference, forms the psychological climate between patient and analyst. Case material is used to explore a Modern Kleinian interpretive approach with both a very entrenched depressive position (Klein, 1935, 1940) patient and a very primitive paranoid schizoid (Klein, 1946) patient. Both these individuals desired relief from their symptoms of anxiety, anger, emptiness, and guilt. But, their unbearable unconscious phantasies offered pathological security that they were familiar with and therefore they preferred the known internal trauma and chaos to facing the unknown and undefined reality of self and other that change, grief, and growth would bring. PMID- 28638132 TI - Troubled Journeys: Some Motivations of Young Muslim Men to Join the Islamic State. AB - Large numbers of young people have joined jihadists groups in the Syrian/Iraqi conflict. Why would these young people decide to become jihadist fighters? What are the representations of the West they hold and how do these representations shape their decision? Drawing on the psychotherapeutic work with Syrian and Iraqi asylum seekers, this paper seeks to explain the most intimate reasons of young Muslim would-be fighters to join the Islamic State militias. PMID- 28638133 TI - The agenetic body: prosthetics or the new Promethean ideal. AB - In our rapidly changing world, we are often encouraged to treat our bodies as objects of constant improvement by means of various facilities and innovations. As part of this "Promethean tendency," the present-day alliance between medicine and technology has opened up a new perspective on the ill and disabled body, by providing access to sophisticated prosthetics that are increasingly seen as ideal remedies. These devices allow patients to benefit from previously unimaginable treatments and inestimable scientific advances, yet they also create new forms of dependency that go beyond simply forming a habit. They are part of a complex process which results in the construction of a body full of paradoxes and whose effects go beyond the subject's image construction. Based on the case of Mathilde, a little girl with a partial arm agenesis, the author traces some elements of the psychic process of constructing a body: from a congenital malformation towards a body "supplemented" by a prosthesis. PMID- 28638134 TI - Melancholia, Narcissism and Depression. AB - This paper discusses ideas about depression as a paradigmatic symptom of contemporaneous psychological suffering and makes a comparison between depression and melancholia. The ideas we describe were stimulated by two comparative studies that were conducted based on an analysis of how depressed subjects relate to the concept of desire, their feelings of shame and their self-image in today's age. PMID- 28638136 TI - Ternary Resistance Switching Memory Behavior Based on Graphene Oxide Embedded in a Polystyrene Polymer Layer. AB - Nonvolatile ternary memory devices were fabricated using the composite of polystyrene (PS) and graphene oxide(GO) as active layers, which have an reliable intermediate state. The current-voltage (I-V) curves of the indium tin oxide (ITO)/PS+GO/Al device under the external applied voltages exhibited current tri stability with three conductivity states, which clearly revealed ternary memory performance. Under the stimulus of the external voltage, a stable intermediate conductivity state was observed. In the write-read-erase-read test, the ITO/PS+GO/Al device exhibited rewritable, nonvolatile, ternary memory properties. The resistance as functions of the time indicated that three conductivity states held for 2 * 105 s, suggesting that the good stability of the ITO/PS+GO/Al devices. HRTEM and XPS observation indicated that the Al top electrode reacted with oxygen within in GO. PMID- 28638135 TI - Temperature dependence of protein-water interactions in a gated yeast aquaporin. AB - Regulation of aquaporins is a key process of living organisms to counteract sudden osmotic changes. Aqy1, which is a water transporting aquaporin of the yeast Pichia pastoris, is suggested to be gated by chemo-mechanical stimuli as a protective regulatory-response against rapid freezing. Here, we tested the influence of temperature by determining the X-ray structure of Aqy1 at room temperature (RT) at 1.3 A resolution, and by exploring the structural dynamics of Aqy1 during freezing through molecular dynamics simulations. At ambient temperature and in a lipid bilayer, Aqy1 adopts a closed conformation that is globally better described by the RT than by the low-temperature (LT) crystal structure. Locally, for the blocking-residue Tyr31 and the water molecules inside the pore, both LT and RT data sets are consistent with the positions observed in the simulations at room-temperature. Moreover, as the temperature was lowered, Tyr31 adopted a conformation that more effectively blocked the channel, and its motion was accompanied by a temperature-driven rearrangement of the water molecules inside the channel. We therefore speculate that temperature drives Aqy1 from a loosely- to a tightly-blocked state. This analysis provides high resolution structural evidence of the influence of temperature on membrane transport channels. PMID- 28638137 TI - Optimized microwave illusion device. AB - We report the design, fabrication and experimental verification of an illusion device working at microwave frequencies. A two dimensional topology optimization procedure is employed to find the binary layout of a dielectric coating that, when wrapped around a metallic cylinder, mimics the scattering from a predefined, arbitrarily-shaped dielectric object. Fabrication is carried out with 3D-printing and spatially resolved near field measurements in a waveguide configuration were performed, allowing us to map the illusion effect. Our work provides general guidelines for engineering electromagnetic illusions but can be extended to shape the near and far-field radiations using low index isotropic materials. PMID- 28638138 TI - Immune regulation by oral tolerance induces alternate activation of macrophages and reduces markers of plaque destabilization in Apobtm2Sgy/Ldlrtm1Her/J mice. AB - Atherosclerosis is the leading cause for cardiovascular mortality. We determined the effect of multi-antigenic construct expressing three peptides AHC (ApoB100, HSP60 and outer membrane protein of chlamydia pneumonia) in stabilizing advanced atherosclerosis in Apobtm2Sgy/Ldlrtm1Her/J mice. Atherosclerosis was induced by feeding high fat diet (HFD) to mice for 10 weeks, followed by five oral dosing with purified AHC or ovalbumin on alternate days and continued on HFD for another 10 weeks. Tolerance was associated with significantly higher numbers of regulatory T cells both in aortic sinus and spleen with higher mRNA expression of CTLA4 (3 fold), Foxp3 (1.4 folds) and TGF-beta (1.62) in aorta. Tregs cells were found to induce alternate activation of macrophages to M2 phenotype, with a reduction in plaque inflammation. AHC treatment showed evidence of plaque stabilization as observed by reduction in plaque necrosis in aortic sinus (35.8%) and in brachiocephalic artery (26%), with reduced expression of Tissue factor and MMP9. Macrophage apoptosis was reduced and collagen content was enhanced by treatment. Our results suggest that tolerance to atherogenic peptides increases regulatory T cells which activate M2 macrophages, prevent T cell proliferation and reduce plaque destabilization and inflammatory markers thus providing evidences for plaque stabilization in mice with advanced atherosclerosis. PMID- 28638139 TI - Platelet releasates promote the proliferation of hepatocellular carcinoma cells by suppressing the expression of KLF6. AB - Platelets in the primary tumor microenvironment play crucial roles in the regulation of tumor progression, but the mechanisms underlying are poorly understood. Here, we report that platelet releasates exerted a proliferative effect on hepatocellular carcinoma (HCC) cells both in vitro and in vivo. This effect depended on a reduction of KLF6 expression in HCC cells. After incubation with either platelets or platelet granule contents, SMMC.7721 and HepG2 cells exhibited significant increases in proliferation and decreases in apoptosis. However, no effect was observed when incubating cancer cells with resuspended activated platelet pellet which exhausted of releasates. Platelet releasates also increased the population of HCC cells in the S and G2/M phases of the cell cycle and reduced the cell population in the G0/G1 phase. Moreover, knocking down KLF6 expression significantly diminished the platelet-mediated enhancement of HCC growth. In addition, blocking TGF-beta signaling with the TGF-beta receptor inhibitor SB431542 counteracted the effect of platelets on KLF6 expression and proliferation of HCC cells. Based on these findings, we conclude that platelet releasates, especially TGF-beta, promote the proliferation of SMMC.7721 and HepG2 cells by decreasing expression of KLF6. This discovery identifies a potential new therapeutic target for the prevention and treatment of hepatocellular carcinoma. PMID- 28638141 TI - al mena: a comprehensive resource of human genetic variants integrating genomes and exomes from Arab, Middle Eastern and North African populations. AB - Middle East and North Africa (MENA) encompass very unique populations, with a rich history and encompasses characteristic ethnic, linguistic and genetic diversity. The genetic diversity of MENA region has been largely unknown. The recent availability of whole-exome and whole-genome sequences from the region has made it possible to collect population-specific allele frequencies. The integration of data sets from this region would provide insights into the landscape of genetic variants in this region. We integrated genetic variants from multiple data sets systematically, available from this region to create a compendium of over 26 million genetic variations. The variants were systematically annotated and their allele frequencies in the data sets were computed and available as a web interface which enables quick query. As a proof of principle for application of the compendium for genetic epidemiology, we analyzed the allele frequencies for variants in transglutaminase 1 (TGM1) gene, associated with autosomal recessive lamellar ichthyosis. Our analysis revealed that the carrier frequency of selected variants differed widely with significant interethnic differences. To the best of our knowledge, al mena is the first and most comprehensive repertoire of genetic variations from the Arab, Middle Eastern and North African region. We hope al mena would accelerate Precision Medicine in the region. PMID- 28638140 TI - Imaging dynamic fingerprints of competing E2 and SN2 reactions. AB - The competition between bimolecular nucleophilic substitution and base-induced elimination is of fundamental importance for the synthesis of pure samples in organic chemistry. Many factors that influence this competition have been identified over the years, but the underlying atomistic dynamics have remained difficult to observe. We present product velocity distributions for a series of reactive collisions of the type X- + RY with X and Y denoting the halogen atoms fluorine, chlorine and iodine. By increasing the size of the residue R from methyl to tert-butyl in several steps, we find that the dynamics drastically change from backward to dominant forward scattering of the leaving ion relative to the reactant RY velocity. This characteristic fingerprint is also confirmed by direct dynamics simulations for ethyl as residue and attributed to the dynamics of elimination reactions. This work opens the door to a detailed atomistic understanding of transformation reactions in even larger systems.The competition between chemical reactions critically affects our natural environment and the synthesis of new materials. Here, the authors present an approach to directly image distinct fingerprints of essential organic reactions and monitor their competition as a function of steric substitution. PMID- 28638142 TI - Inter-generational instability of inserted repeats during transmission in spinocerebellar ataxia type 31. AB - The causative mutation for spinocerebellar ataxia type 31 (SCA31) is an intronic insertion containing pathogenic pentanucleotide repeats, (TGGAA)n. We examined to what degree the inserted repeats were unstable during transmission. In 14 parent child pairs, the average change of onset age was -6.4+/-7.3 years (mean+/-s.d.) in the child generation when compared with the parent generation. Of the 11 pairs analyzed, six showed expansion of inserted repeat length during transmission, and five showed contraction. On average, the inserted repeats expanded by 12.2+/-32.7 bp during transmission, but their mean length (with a 95% confidence interval) was not significantly different between parent and child generations. We consider that the length of the inserted repeats in SCA31 is changeable during transmission, but inter-generational instability is not marked, as far as the current sizing method can determine. PMID- 28638143 TI - Siblings with optic neuropathy and RTN4IP1 mutation. AB - Inherited optic neuropathies (IONs) are neurodegenerative disorders affecting the optic nerve and the nervous system. Dominant and recessive IONs are known. Many of the dominant IONs are caused by mutations of OPA1. Autosomal-recessive IONs are rare. OPA10 is an autosomal-recessive ION due to mutations in RTN4IP1. Patients with RTN4IP1 mutations show extraocular manifestations. We report brothers with optic neuropathy who had novel mutations in the RTN4IP1 gene. This is the first report of Japanese patients with OPA10. They showed extraocular manifestations resembling mitochondrial encephalopathy. PMID- 28638144 TI - On the interaction of toxic Heavy Metals (Cd, Hg, Pb) with graphene quantum dots and infinite graphene. AB - The promise of graphene and its derivatives as next generation sensors for real time detection of toxic heavy metals (HM) requires a clear understanding of behavior of these metals on the graphene surface and response of the graphene to adsorption events. Our calculations herein were focused on the investigation of the interaction between three HMs, namely Cd, Hg and Pb, with graphene quantum dots (GQDs). We determine binding energies and heights of both neutral and charged HM ions on these GQDs. The results show that the adsorption energy of donor-like physisorbed neutral Pb atoms is larger than that of either Cd or Hg. In contrast to the donor-like behavior of elemental HMs, the chemisorbed charged HM species act as typical acceptors. The energy barriers to migration of the neutral adatoms on GQDs are also estimated. In addition, we show how the substitution of a carbon atom by a HM adatom changes the geometric structure of GQDs and hence their electronic and vibrational properties. UV-visible absorption spectra of HM-adsorbed GQDs vary with the size and shape of the GQD. Based on our results, we suggest a route towards the development of a graphene-based sensing platform for the optical detection of toxic HMs. PMID- 28638145 TI - A sacrificial layer strategy for photolithography on highly hydrophobic surface and its application for electrowetting devices. AB - Patterning micro-structures on highly hydrophobic surface by photolithography is usually inevitable for fabricating devices based on electrowetting effects. The key challenges for such photolithography processes are how to coat photoresist uniformly and maintain the hydrophobicity of the highly hydrophobic surface, which are usually two contradict aspects. Moreover, the patterned microstructure must adhere to the highly hydrophobic surface excellently, which is critical for device application. However, a simple and robust fabrication process that fulfills all the above requirements was seldom reported. In this paper, we developed a sacrificial layer photolithography strategy on highly hydrophobic surface. Photoresist is easily coated uniformly all over the substrate by introducing a sacrificial layer between the photoresist and the highly hydrophobic surface. The hydrophobicity of the exposed hydrophobic surface was maintained and the adhesion of the microstructures to the substrate is excellent. An electrowetting display sample was demonstrated by this fabrication strategy, which showed dynamic image displaying with response time less than 40 ms. The strategy is applicable to both rigid and flexible substrate and manufacturing compatible. We believe our developed photolithography process is important for research and development of devices based on electrowetting effect. PMID- 28638146 TI - Outstanding compressive creep strength in Cr/Ir-codoped (Mo0.85Nb0.15)Si2 crystals with the unique cross-lamellar microstructure. AB - A (Mo0.85Nb0.15)Si2 crystal with an oriented, lamellar, C40/C11b two-phase microstructure is a promising ultrahigh-temperature (UHT) structural material, but its low room-temperature fracture toughness and low high-temperature strength prevent its practical application. As a possibility to overcome these problems, we first found a development of unique "cross-lamellar microstructure", by the cooping of Cr and Ir. The cross-lamellar microstructure consists of a rod-like C11b-phase grains that extend along a direction perpendicular to the lamellar interface in addition to the C40/C11b fine lamellae. In this study, the effectiveness of the cross-lamellar microstructure for improving the high temperature creep deformation property, being the most essential for UHT materials, was examined by using the oriented crystals. The creep rate significantly reduced along a loading orientation parallel to the lamellar interface. Furthermore, the degradation in creep strength for other loading orientation that is not parallel to the lamellar interface, which has been a serious problem up to now, was also suppressed. The results demonstrated that the simultaneous improvement of high-temperature creep strength and room temperature fracture toughness can be first accomplished by the development of unique cross lamellar microstructure, which opens a potential avenue for the development of novel UHT materials as alternatives to existing Ni-based superalloys. PMID- 28638148 TI - Full-time response of starch subjected to microwave heating. AB - The effect of non-ionizing microwave radiation on starch is due to a gelatinization temperature range that changes starch structure and properties. However, the changes in starch upon microwave heating are observable throughout the heating process. We compared the effects on starch heating by microwaves to the effects by rapid and regular conventional heating. Our results show that microwave heating promotes the rapid rearrangement of starch molecules at low temperatures; starch showed a stable dielectric response and a high dielectric constant. Microwave heating changed the Cole-Cole curve and the polarization of starch suspension at low temperatures. A marked transition at 2.45 GHz resulted in a double-polarization phenomenon. At temperatures below gelatinization, microwave-induced dielectric rearrangement and changes in the polarization characteristics of starch suspensions reduced the absorption properties; at temperatures above gelatinization, these characteristics became consistent with conventional heating. Throughout the heating process, microwaves change the electrical response and polarization characteristics of the starch at low temperatures, but on the macro level, there is no enhancement of the material's microwave absorption properties. In contrast, with the warming process, the starch exhibited a "blocking effect", and the absorption properties of the starch quickly returned to the level observed in conductive heating after gelatinization. PMID- 28638147 TI - Sensitivity of human pluripotent stem cells to insulin precipitation induced by peristaltic pump-based medium circulation: considerations on process development. AB - Controlled large-scale production of human pluripotent stem cells (hPSCs) is indispensable for their envisioned clinical translation. Aiming at advanced process development in suspension culture, the sensitivity of hPSC media to continuous peristaltic pump-based circulation, a well-established technology extensively used in hydraulically-driven bioreactors, was investigated. Unexpectedly, conditioning of low protein media (i.e. E8 and TeSR-E8) in a peristaltic pump circuit induced severe viability loss of hPSCs cultured as aggregates in suspension. Optical, biochemical, and cytological analyses of the media revealed that the applied circulation mode resulted in the reduction of the growth hormone insulin by precipitation of micro-sized particles. Notably, in contrast to insulin depletion, individual withdrawal of other medium protein components (i.e. bFGF, TGFbeta1 or transferrin) provoked minor reduction of hPSC viability, if any. Supplementation of the surfactant glycerol or the use of the insulin analogue Aspart did not overcome the issue of insulin precipitation. In contrast, the presence of bovine or human serum albumin (BSA or HSA, respectively) stabilized insulin rescuing its content, possibly by acting as molecular chaperone-like protein, ultimately supporting hPSC maintenance. This study highlights the potential and the requirement of media optimization for automated hPSC processing and has broad implications on media development and bioreactor-based technologies. PMID- 28638149 TI - Hsp90 inhibitor induces nuclear translocation of HSF1 predominantly in hippocampal CA1 region. PMID- 28638150 TI - Strain-balanced type-II superlattices for efficient multi-junction solar cells. AB - Multi-junction solar cells made by assembling semiconductor materials with different bandgap energies have hold the record conversion efficiencies for many years and are currently approaching 50%. Theoretical efficiency limits make use of optimum designs with the right lattice constant-bandgap energy combination, which requires a 1.0-1.15 eV material lattice-matched to GaAs/Ge. Nevertheless, the lack of suitable semiconductor materials is hindering the achievement of the predicted efficiencies, since the only candidates were up to now complex quaternary and quinary alloys with inherent epitaxial growth problems that degrade carrier dynamics. Here we show how the use of strain-balanced GaAsSb/GaAsN superlattices might solve this problem. We demonstrate that the spatial separation of Sb and N atoms avoids the ubiquitous growth problems and improves crystal quality. Moreover, these new structures allow for additional control of the effective bandgap through the period thickness and provide a type II band alignment with long carrier lifetimes. All this leads to a strong enhancement of the external quantum efficiency under photovoltaic conditions with respect to bulk layers of equivalent thickness. Our results show that GaAsSb/GaAsN superlattices with short periods are the ideal (pseudo)material to be integrated in new GaAs/Ge-based multi-junction solar cells that could approach the theoretical efficiency limit. PMID- 28638151 TI - The crystal structure of human Rogdi provides insight into the causes of Kohlschutter-Tonz Syndrome. AB - Kohlschutter-Tonz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta. Rogdi, an essential protein, is highly conserved across metazoans, and mutations in Rogdi are linked to KTS. However, how certain mutations in Rogdi abolish its physiological functions and cause KTS is not known. In this study, we determined the crystal structure of human Rogdi protein at atomic resolution. Rogdi forms a novel elongated curved structure comprising the alpha domain, a leucine-zipper-like four-helix bundle, and a characteristic beta-sheet domain. Within the alpha domain, the N-terminal H1 helix (residues 19-45) pairs with the C-terminal H6 helix (residues 252-287) in an antiparallel manner, indicating that the integrity of the four-helix bundle requires both N- and C-terminal residues. The crystal structure, in conjunction with biochemical data, indicates that the alpha domain might undergo a conformational change and provide a structural platform for protein-protein interactions. Disruption of the four-helix bundle by mutation results in significant destabilization of the structure. This study provides structural insights into how certain mutations in Rogdi affect its structure and cause KTS, which has important implications for the development of pharmaceutical agents against this debilitating neurological disease. PMID- 28638154 TI - [Assessment of predictive dermal exposure to chemicals in the work environment]. AB - Assessment of dermal exposure to chemicals in the work environment is problematic, mainly as a result of the lack of measurement data on occupational exposure to chemicals. Due to common prevalence of occupational skin exposure and its health consequences it is necessary to look for efficient solutions allowing for reliable exposure assessment. The aim of the study is to present predictive models used to assess non-measured dermal exposure, as well as to acquaint Polish users with the principles of the selected model functioning. This paper presents examples of models to assist the employer in the the assessment of occupational exposure associated with the skin contact with chemicals, developed in European Union (EU) countries, as well as in countries outside the EU. Based on the literature data dermal exposure models EASE (Estimation and Assessment of Substance Exposure), COSHH Essentials (Control of Substances Hazardous to Health Regulations), DREAM (Dermal Exposure Assessment Method), Stoffenmanager , ECETOC TRA (European Centre for Ecotoxicology and Toxicology of Chemicals Targeted Risk Assessment), MEASE (Metal's EASE), PHED (Pesticide Handlers Exposure Database), DERM (Dermal Exposure Ranking Method) and RISKOFDERM (Risk Assessment of Occupational Dermal Exposure to Chemicals) were briefly described. Moreover the characteristics of RISKOFDERM, guidelines for its use, information on input and output data were further detailed. Problem of full work shift dermal exposure assessment is described. An example of exposure assessment using RISKOFDERM and effectiveness evaluation to date were also presented. When no measurements are available, RISKOFDERM allows dermal exposure assessment and thus can improve the risk assessment quality and effectiveness of dermal risk management. Med Pr 2017;68(4):557-569. PMID- 28638155 TI - From the Editor. PMID- 28638152 TI - Combination of a high-fat diet with sweetened condensed milk exacerbates inflammation and insulin resistance induced by each separately in mice. AB - Obesogenic diets increase body weight and cause insulin resistance (IR), however, the association of these changes with the main macronutrient in the diet remains to be elucidated. Male C57BL/6 mice were fed with: control (CD), CD and sweetened condensed milk (HS), high-fat (HF), and HF and condensed milk (HSHF). After 2 months, increased body weight, glucose intolerance, adipocyte size and cholesterol levels were observed. As compared with CD, HS ingested the same amount of calories whereas HF and HSHF ingested less. HS had increased plasma AST activity and liver type I collagen. HF caused mild liver steatosis and hepatocellular damage. HF and HSHF increased LDL-cholesterol, hepatocyte and adipocyte hypertrophy, TNF-alpha by macrophages and decreased lipogenesis and adiponectin in adipose tissue (AT). HSHF exacerbated these effects, increasing IR, lipolysis, mRNA expression of F4/80 and leptin in AT, Tlr-4 in soleus muscle and IL-6, IL-1beta, VCAM-1, and ICAM-1 protein in AT. The three obesogenic diets induced obesity and metabolic dysfunction. HS was more proinflammatory than the HF and induced hepatic fibrosis. The HF was more detrimental in terms of insulin sensitivity, and it caused liver steatosis. The combination HSHF exacerbated the effects of each separately on insulin resistance and AT inflammatory state. PMID- 28638156 TI - Goal-Directed Perfusion Methodology for Determining Oxygenator Performance during Clinical Cardiopulmonary Bypass. AB - New generation oxygenators incorporate arterial line filtration either sequential to, or directly in, the gas exchange module. This unique design may affect gas exchange performance by altering the operational characteristics of the device. The present study was designed to evaluate three oxygenators in a clinical setting using a goal-directed perfusion algorithm during cardiopulmonary bypass (CPB). After institutional review board approval, 60 adult patients undergoing cardiac surgery for acquired heart disease were matched for disease state and body size into three groups based on oxygenator type: Terumo SX18TM (n = 20), Terumo FX15TM (n = 20), and LivaNova Inspire6FTM 6 Dual (n = 20). An external arterial line filter was used with the FX15, whereas the SX18 and Inspire6F had integrated arterial filters. All perfusion, anesthetic and postoperative care management was standardized using institutional goal-directed patient management processes. Data were collected and stored according to quality improvement guidelines. There were no differences in demographics or type of surgical procedure performed among groups. The Inspire6F patients required lower fraction of inspired oxygen values as compared to the SX18 (67.9% +/- 6.2% vs. 75.4% +/- 6.5%, p < .005) and FX15 (79.1% +/- 8.4%, p < .0001) groups. Arterial oxygen content and oxygen delivery were slightly higher in the FX15 group as compared to SX18 (13.1 +/- 1.4 mL O2/dL vs. 12.4 +/- 1.1 mL O2/dL, 611.1 +/- 150.4 mL O2 vs. 528.2 +/- 102.3 mL O2, p < .05). The FX15 patients had significantly higher CPB hematocrits compared to SX18 patients (30.3% +/- 3.9% vs. 27.7% +/- 2.6%, p < .05), but were not different when compared to the Inspire6F group (28.8% +/- 3.5%, p < .50). There were no differences in intraoperative transfusion rates, but a higher percent of patients received postoperative transfusions in the SX18 group as compared to either FX15 or Inspire6F groups (p < .039). There were no differences in postoperative morbidity or complications in any group. In conclusion, the use of the SX18 was comparable to newer generation oxygenators in regard to gas exchange performance and the degree of hemodilution. PMID- 28638157 TI - Complex Cardiac Surgery on Patients with a Body Weight of Less Than 5 kg without Donor Blood Transfusion. AB - Performing safe cardiac surgery in neonates or infants whose parents are Jehovah's Witnesses is only possible in a coordinated team approach. An unconditional prerequisite is a cardiopulmonary bypass (CPB) circuit with a very low priming volume to minimize hemodilution. In the past decade, we have developed a functional blood-sparing approach at our institution. The extracorporeal circuit was miniaturized. This had to be recently adapted, faced with a challenge associated with the switch to high-volume crystalloid cardioplegia. A filtration circuit was added. Here, we report an open heart surgery on three consecutive children of Jehovah's Witness parents with a body weight of 2.7, 4.5, and 4.8 kg, respectively. Procedures consisted of one arterial switch operation and two repairs of complete atrioventricular septal defects. Our static priming volume of less than 90 mL resulted in a nadir hematocrit during CPB of 27.7% (Hb 8.9 g/dL) in a patient which happened to have the lowest body weight of 2.7 kg. The two other patients had their lowest hematocrit at 31.4% (Hb 10.2 g/dL). The three children could be treated without any kind of transfusion of blood which had left the circulation or its extensions, in accordance with the parents' wishes, and enjoy favorable outcomes without transfusion of blood products during their entire hospital stay. PMID- 28638158 TI - Cardiac Surgery in Developing Countries. AB - This literature review summarizes recommendations and challenges encountered when establishing cardiac surgery centers in developing countries and common heart diseases encountered abroad. Cardiac surgery is not widely available in most developing countries, and most patients have no choice but to live in morbid conditions. The ideal continuous treatment for these patients would be provided by a local, sustainable cardiac surgery center. A collaborative effort from international volunteers, nongovernmental organizations, local governments, and private benefactors is necessary to facilitate adequate cardiac care in developing countries. PMID- 28638159 TI - In Vitro Evaluation of the Fresenius Kabi CATSmart Autotransfusion System. AB - Use of autotransfusion systems to collect, wash, and concentrate shed blood during surgical procedures is a widely used method for reducing postoperative anemia and the need for blood transfusions. The aim of this study was to evaluate the CATSmart Continuous Autotransfusion System wash program performance with small (200 or 700 mL) and large volumes (1,000 mL) of shed blood and to determine non-inferiority of the CATSmart to the C.A.T.S plus system. Human whole blood was collected in citrate phosphate dextrose, diluted, and divided into two aliquots to be processed as a pair using the C.A.T.S plus and CATSmart systems with their corresponding wash programs: low-volume, high quality/smart, or emergency wash. Final packed red cell product was analyzed for red blood cell (RBC), white blood cell, and platelet counts; hemoglobin; hemolysis; RBC recovery rates; and elimination of albumin, total protein, and potassium. The mean hematocrit (HCT) after processing with CATSmart and C.A.T.S plus systems were 59.63% and 57.71%, respectively. The calculated overall RBC recovery rates on the CATSmart and C.A.T.S plus systems were 85.41% and 84.99%, respectively. Elimination of albumin (97.5%, 98.0%), total proteins (97.1%, 97.5%), and potassium (92.1%, 91.9%) were also calculated for the CATSmart and C.A.T.S plus systems. The CATSmart and C.A.T.S plus systems both provided a high-quality product in terms of HCT, protein elimination, and hemolysis rates across the range of tested shed blood volumes and all wash programs. The study was able to confirm the CATSmart is non inferior to the C.A.T.S plus system. PMID- 28638160 TI - Low-Flow Extracorporeal Carbon Dioxide Removal Using the Hemolung Respiratory Dialysis System(r) to Facilitate Lung-Protective Mechanical Ventilation in Acute Respiratory Distress Syndrome. AB - Extracorporeal carbon dioxide removal (ECCO2R) permits reductions in alveolar ventilation requirements that the lungs would otherwise have to provide. This concept was applied to a case of hypercapnia refractory to high-level invasive mechanical ventilator support. We present a case of an 18-year-old man who developed post-pneumonectomy acute respiratory distress syndrome (ARDS) after resection of a mediastinal germ cell tumor involving the left lung hilum. Hypercapnia and hypoxemia persisted despite ventilator support even at traumatic levels. ECCO2R using a miniaturized system was instituted and provided effective carbon dioxide elimination. This facilitated establishment of lung-protective ventilator settings and lung function recovery. Extracorporeal lung support increasingly is being applied to treat ARDS. However, conventional extracorporeal membrane oxygenation (ECMO) generally involves using large cannulae capable of carrying high flow rates. A subset of patients with ARDS has mixed hypercapnia and hypoxemia despite high-level ventilator support. In the absence of profound hypoxemia, ECCO2R may be used to reduce ventilator support requirements to lung protective levels, while avoiding risks associated with conventional ECMO. PMID- 28638162 TI - The Goal Directed Therapy Symposium: Goal Directed Therapy in Perfusion - The New Take on Adequacy of Perfusion. PMID- 28638161 TI - Argatroban for Heparin-Induced Thrombocytopenia during Venovenous Extracorporeal Membrane Oxygenation with Continuous Venovenous Hemofiltration. AB - Patients receiving extracorporeal membrane oxygenation (ECMO) are at risk of circuit thrombosis due to constant contact between blood and the extracorporeal components. Unfractionated heparin has traditionally been used in this setting as a systemic form of anticoagulation to prevent thrombosis of the circuit. However, if a patient develops heparin-induced thrombocytopenia (HIT), an alternative anticoagulant would be required while the patient is maintained on ECMO. Unfortunately, the pharmacokinetic changes induced by ECMO and critical illness may potentially affect optimal drug dosing. In addition, other modalities, such as continuous renal replacement therapy, may further complicate dosing strategies. We report the case of a 27-year-old man with severe acute respiratory distress syndrome who developed HIT while on venovenous ECMO with continuous venovenous hemofiltration. We describe the successful use of an argatroban infusion in this setting at much higher doses than what has previously been reported in the adult literature. PMID- 28638163 TI - Variation in Measurement and Reporting of Goal Directed Perfusion Parameters. PMID- 28638164 TI - Is it Time for Goal-Directed Therapy in Perfusion. PMID- 28638165 TI - Is Timing Everything? PMID- 28638166 TI - Will Real-Time Monitoring Technology be a Game Changer for Perfusion Safety? PMID- 28638167 TI - Computational Fluid Dynamics Analysis of the Venturi Dustiness Tester. AB - Dustiness quantifies the propensity of a finely divided solid to be aerosolized by a prescribed mechanical stimulus. Dustiness is relevant wherever powders are mixed, transferred or handled, and is important in the control of hazardous exposures and the prevention of dust explosions and product loss. Limited quantities of active pharmaceutical powders available for testing led to the development (at University of North Carolina) of a Venturi-driven dustiness tester. The powder is turbulently injected at high speed (Re ~ 2 * 104) into a glass chamber; the aerosol is then gently sampled (Re ~ 2 * 103) through two filters located at the top of the chamber; the dustiness index is the ratio of sampled to injected mass of powder. Injection is activated by suction at an Extraction Port at the top of the chamber; loss of powder during injection compromises the sampled dustiness. The present work analyzes the flow inside the Venturi Dustiness Tester, using an Unsteady Reynolds-Averaged Navier-Stokes formulation with the k-omega Shear Stress Transport turbulence model. The simulation considers single-phase flow, valid for small particles (Stokes number Stk <1). Results show that ~ 24% of fluid-tracers escape the tester before the Sampling Phase begins. Dispersion of the powder during the Injection Phase results in a uniform aerosol inside the tester, even for inhomogeneous injections, satisfying a necessary condition for the accurate evaluation of dustiness. Simulations are also performed under the conditions of reduced Extraction-Port flow; results confirm the importance of high Extraction-Port flow rate (standard operation) for uniform distribution of fluid tracers. Simulations are also performed under the conditions of delayed powder injection; results show that a uniform aerosol is still achieved provided 0.5 s elapses between powder injection and sampling. PMID- 28638168 TI - PTSD and Cannabis-Related Coping Among Recent Veterans in New York City. AB - This article presents interview and focus group data from veterans of recent conflicts in Iraq and Afghanistan about their use of cannabis as a coping tool for dealing with posttraumatic stress disorder. Veterans' comparisons of cannabis, alcohol, and psychopharmaceuticals tended to highlight advantages to cannabis use as more effective and less complicated by side effects. Some participants suggested that cannabis can be part of an approach-based coping strategy that aids with introspection and direct confrontation of the sources of personal trauma. Others, however, held that cannabis use was part of a less productive, avoidant coping strategy. Some self-reports suggested the need for more nuanced theorizations of coping behaviors, as they indicated motivations for use that were grounded in symptom alleviation rather than any direct confrontation with (or avoidance of) sources of trauma. PMID- 28638169 TI - Organ and effective dose reduction for region-of-interest (ROI) CBCT and fluoroscopy. AB - In some medical-imaging procedures using CBCT and fluoroscopy, it may be needed to visualize only the center of the field-of-view with optimal quality. To reduce the dose to the patient as well as enable increased contrast in the region of interest (ROI) during CBCT and fluoroscopy procedures, a 0.7 mm thick Cu ROI attenuator with a circular aperture 12% of the FOV was used. The aim of this study was to quantify the dose-reduction benefit of ROI imaging during a typical CBCT and interventional fluoroscopy procedures in the head and torso. The Toshiba Infinix C-Arm System was modeled in BEAMnrc/EGSnrc with and without the ROI attenuator. Patient organ and effective doses were calculated in DOSXYZnrc/EGSnrc Monte-Carlo software for CBCT and interventional procedures. We first compared the entrance dose with and without the ROI attenuator on a 20 cm thick solid water block. Then we simulated a CBCT scan and an interventional fluoroscopy procedure on the head and torso with and without an ROI attenuator. The results showed that the entrance-surface dose reduction in the solid water is about 85.7% outside the ROI opening and 10.5% in the ROI opening. The results showed a reduction in most organ doses of 45%-70% and in effective dose of 46%-66% compared to the dose in a CBCT scan and in an interventional procedure without the ROI attenuator. This work provides evidence of substantial reduction of organ and effective doses when using an ROI attenuator during CBCT and fluoroscopic procedures. PMID- 28638170 TI - Atlas-based automatic measurements of the morphology of the tibiofemoral joint. AB - PURPOSE: Anatomical metrics of the tibiofemoral joint support assessment of joint stability and surgical planning. We propose an automated, atlas-based algorithm to streamline the measurements in 3D images of the joint and reduce user dependence of the metrics arising from manual identification of the anatomical landmarks. METHODS: The method is initialized with coarse registrations of a set of atlas images to the fixed input image. The initial registrations are then refined separately for the tibia and femur and the best matching atlas is selected. Finally, the anatomical landmarks of the best matching atlas are transformed onto the input image by deforming a surface model of the atlas to fit the shape of the tibial plateau in the input image (a mesh-to-volume registration). We apply the method to weight-bearing volumetric images of the knee obtained from 23 subjects using an extremity cone-beam CT system. Results of the automated algorithm were compared to an expert radiologist for measurements of Static Alignment (SA), Medial Tibial Slope (MTS) and Lateral Tibial Slope (LTS). RESULTS: Intra-reader variability as high as ~10% for LTS and 7% for MTS (ratio of standard deviation to the mean in repeated measurements) was found for expert radiologist, illustrating the potential benefits of an automated approach in improving the precision of the metrics. The proposed method achieved excellent registration of the atlas mesh to the input volumes. The resulting automated measurements yielded high correlations with expert radiologist, as indicated by correlation coefficients of 0.72 for MTS, 0.8 for LTS, and 0.89 for SA. CONCLUSIONS: The automated method for measurement of anatomical metrics of the tibiofemoral joint achieves high correlation with expert radiologist without the need for time consuming and error prone manual selection of landmarks. PMID- 28638171 TI - 3D Printed Abdominal Aortic Aneurysm Phantom for Image Guided Surgical Planning with a Patient Specific Fenestrated Endovascular Graft System. AB - : Following new trends in precision medicine, Juxatarenal Abdominal Aortic Aneurysm (JAAA) treatment has been enabled by using patient-specific fenestrated endovascular grafts. The X-ray guided procedure requires precise orientation of multiple modular endografts within the arteries confirmed via radiopaque markers. Patient-specific 3D printed phantoms could familiarize physicians with complex procedures and new devices in a risk-free simulation environment to avoid periprocedural complications and improve training. Using the Vascular Modeling Toolkit (VMTK), 3D Data from a CTA imaging of a patient scheduled for Fenestrated EndoVascular Aortic Repair (FEVAR) was segmented to isolate the aortic lumen, thrombus, and calcifications. A stereolithographic mesh (STL) was generated and then modified in Autodesk MeshMixer for fabrication via a Stratasys Eden 260 printer in a flexible photopolymer to simulate arterial compliance. Fluoroscopic guided simulation of the patient-specific FEVAR procedure was performed by interventionists using all demonstration endografts and accessory devices. Analysis compared treatment strategy between the planned procedure, the simulation procedure, and the patient procedure using a derived scoring scheme. RESULTS: With training on the patient-specific 3D printed AAA phantom, the clinical team optimized their procedural strategy. Anatomical landmarks and all devices were visible under x-ray during the simulation mimicking the clinical environment. The actual patient procedure went without complications. CONCLUSIONS: With advances in 3D printing, fabrication of patient specific AAA phantoms is possible. Simulation with 3D printed phantoms shows potential to inform clinical interventional procedures in addition to CTA diagnostic imaging. PMID- 28638172 TI - Investigation of Noise and Contrast Sensitivity of an Electron Multiplying Charge Coupled Device (EMCCD) based Cone Beam Micro-CT System. AB - A small animal micro-CT system was built using an EMCCD detectors having complex pre-digitization amplification technology, high-resolution, high-sensitivity and low-noise. Noise in CBCT reconstructed images when using pre-digitization amplification behaves differently than commonly used detectors and warrants a detailed investigation. In this study, noise power and contrast sensitivity were estimated for the newly built system. Noise analysis was performed by scanning a water phantom. Tube voltage was lowered to minimum delivered by the tube (20 kVp and 0.5 mA) and detector gain was varied. Contrast sensitivity was analyzed by using a phantom containing different iodine contrast solutions (20% to 70%) filled in six different tubes. First, we scanned the phantom using various x-ray exposures at 40 kVp while changing the gain to maintain the background air value of the projection images constant. Next, the exposure was varied while the detector gain was maintained constant. Radial NPS plots show that noise power level increases as gain increases. Contrast sensitivity was analyzed by calculating ratio of signal-to-noise ratios (SNR) for increased gain with those of low constant gain at each exposure. The SNR value at low constant gain was always lower than SNR of high detector gain at all x-ray settings and iodine contrast. The largest increase of SNR approached 1.3 for low contrast feature for an iodine concentration of 20%. Despite an increase in noise level as gain increases, the SNR improvement shows that signal level also increases because of the unique on-chip gain of the detector. PMID- 28638173 TI - Lens of the eye dose calculation for neuro-interventional procedures and CBCT scans of the head. AB - The aim of this work is to develop a method to calculate lens dose for fluoroscopically-guided neuro-interventional procedures and for CBCT scans of the head. EGSnrc Monte Carlo software is used to determine the dose to the lens of the eye for the projection geometry and exposure parameters used in these procedures. This information is provided by a digital CAN bus on the Toshiba Infinix C-Arm system which is saved in a log file by the real-time skin-dose tracking system (DTS) we previously developed. The x-ray beam spectra on this machine were simulated using BEAMnrc. These spectra were compared to those determined by SpekCalc and validated through measured percent-depth-dose (PDD) curves and half-value-layer (HVL) measurements. We simulated CBCT procedures in DOSXYZnrc for a CTDI head phantom and compared the surface dose distribution with that measured with Gafchromic film, and also for an SK150 head phantom and compared the lens dose with that measured with an ionization chamber. Both methods demonstrated good agreement. Organ dose calculated for a simulated neuro interventional-procedure using DOSXYZnrc with the Zubal CT voxel phantom agreed within 10% with that calculated by PCXMC code for most organs. To calculate the lens dose in a neuro-interventional procedure, we developed a library of normalized lens dose values for different projection angles and kVp's. The total lens dose is then calculated by summing the values over all beam projections and can be included on the DTS report at the end of the procedure. PMID- 28638174 TI - Near-Real Time Measurement of Carbonaceous Aerosol Using Microplasma Spectroscopy: Application to Measurement of Carbon Nanomaterials. AB - A sensitive, field-portable microplasma spectroscopy method has been developed for real-time measurement of carbon nanomaterials. The method involves microconcentration of aerosol on a microelectrode tip for subsequent analysis for atomic carbon using laser-induced breakdown spectroscopy (LIBS) or spark emission spectroscopy (SES). The spark-induced microplasma was characterized by measuring the excitation temperature (15,000 - 35,000 K), electron density (1.0 * 1017 - 2.2 * 1017 cm-3), and spectral responses as functions of time and interelectrode distance. The system was calibrated and detection limits were determined for total atomic carbon (TAC) using a carbon emission line at 247.856 nm (C I) for various carbonaceous materials including sucrose, EDTA, caffeine, sodium carbonate, carbon black, and carbon nanotubes. The limit of detection for total atomic carbon was 1.61 ng, equivalent to 238 ng m-3 when sampling at 1.5 L min-1 for 5 min. To improve the selectivity for carbon nanomaterials, which consist of elemental carbon (EC), the cathode was heated to 300 degrees C to reduce the contribution of organic carbon to the total atomic carbon. Measurements of carbon nanotube aerosol at elevated electrode temperature showed improved selectivity to elemental carbon and compared well with the measurements from thermal optical method (NIOSH Method 5040). The study shows that the SES method to be an excellent candidate for development as a low-cost, hand-portable, real-time instrument for measurement of carbonaceous aerosols and nanomaterials. PMID- 28638175 TI - Lessons from LOCHI. PMID- 28638176 TI - Gallbladder Carcinoma in the United States: A Population Based Clinical Outcomes Study Involving 22,343 Patients from the Surveillance, Epidemiology, and End Result Database (1973-2013). AB - INTRODUCTION: Gallbladder carcinoma (GBC) is the most common malignancy of the biliary tract and the third most common gastrointestinal tract malignancy. This study examines a large cohort of GBC patients in the United States in an effort to define demographics, clinical, and pathologic features impacting clinical outcomes. METHODS: Demographic and clinical data on 22,343 GBC patients was abstracted from the SEER database (1973-2013). RESULTS: GBC was presented most often among Caucasian (63.9%) females (70.7%) as poorly or moderately differentiated (42.5% and 38.2%) tumors, with lymph node involvement (88.2%). Surgery alone was the most common treatment modality for GBC patients (55.0%). Combination surgery and radiation (10.6%) achieved significantly longer survival rates compared to surgery alone (4.0 +/- 0.2 versus 3.7 +/- 0.1 years, p = 0.004). Overall mortality was 87.0% and cancer-specific mortality was 75.4%. CONCLUSIONS: GBC is an uncommon malignancy that presents most often among females in their 8th decade of life, with over a third of cases presenting with distant metastasis. The incidence of GBC has doubled in the last decade concurrent with increases in cholecystectomy rates attributable in part to improved histopathological detection, as well as laparoscopic advances and enhanced endoscopic techniques. Surgical resection confers significant survival benefit in GBC patients. PMID- 28638177 TI - Highly Luminescent Water-Dispersible NIR-Emitting Wurtzite CuInS2/ZnS Core/Shell Colloidal Quantum Dots. AB - Copper indium sulfide (CIS) quantum dots (QDs) are attractive as labels for biomedical imaging, since they have large absorption coefficients across a broad spectral range, size- and composition-tunable photoluminescence from the visible to the near-infrared, and low toxicity. However, the application of NIR-emitting CIS QDs is still hindered by large size and shape dispersions and low photoluminescence quantum yields (PLQYs). In this work, we develop an efficient pathway to synthesize highly luminescent NIR-emitting wurtzite CIS/ZnS QDs, starting from template Cu2-x S nanocrystals (NCs), which are converted by topotactic partial Cu+ for In3+ exchange into CIS NCs. These NCs are subsequently used as cores for the overgrowth of ZnS shells (<=1 nm thick). The CIS/ZnS core/shell QDs exhibit PL tunability from the first to the second NIR window (750 1100 nm), with PLQYs ranging from 75% (at 820 nm) to 25% (at 1050 nm), and can be readily transferred to water upon exchange of the native ligands for mercaptoundecanoic acid. The resulting water-dispersible CIS/ZnS QDs possess good colloidal stability over at least 6 months and PLQYs ranging from 39% (at 820 nm) to 6% (at 1050 nm). These PLQYs are superior to those of commonly available water soluble NIR-fluorophores (dyes and QDs), making the hydrophilic CIS/ZnS QDs developed in this work promising candidates for further application as NIR emitters in bioimaging. The hydrophobic CIS/ZnS QDs obtained immediately after the ZnS shelling are also attractive as fluorophores in luminescent solar concentrators. PMID- 28638178 TI - Determining Safety Inspection Thresholds for Employee Incentives Programs on Construction Sites. AB - The goal of this project was to evaluate approaches of determining the numerical value of a safety inspection score that would activate a reward in an employee safety incentive program. Safety inspections are a reflection of the physical working conditions at a construction site and provide a safety score that can be used in incentive programs to reward workers. Yet it is unclear what level of safety should be used when implementing this kind of program. This study explored five ways of grouping safety inspection data collected during 19 months at Harvard University-owned construction projects. Each approach grouped the data by one of the following: owner, general contractor, project, trade, or subcontractor. The median value for each grouping provided the threshold score. These five approaches were then applied to data from a completed project in order to calculate the frequency and distribution of rewards in a monthly safety incentive program. The application of each approach was evaluated qualitatively for consistency, competitiveness, attainability, and fairness. The owner-specific approach resulted in a threshold score of 96.3% and met all of the qualitative evaluation goals. It had the most competitive reward distribution (only 1/3 of the project duration) yet it was also attainable. By treating all workers equally and maintaining the same value throughout the project duration, this approach was fair and consistent. The owner-based approach for threshold determination can be used by owners or general contractors when creating leading indicator incentives programs and by researchers in future studies on incentive program effectiveness. PMID- 28638181 TI - The Clinical Value, Principle, and Basic Practical Technique of Mindfulness Intervention. AB - Mindfulness intervention is a psychotherapy based on the Buddhist practice of meditation, combining the theories and methodology of contemporary psychology. The empirical research in recent years has indicated that mindfulness intervention yields favorable results including reduction of depression relapse, alleviation of the symptoms of depression and anxiety, reduction of substance abuse, relief of pain, blood pressure management, enhancement of immunity, and improvement of sleep. Currently, mindfulness therapy has become the mainstream of psychotherapy in the realm of European and American psychotherapy. The fields of psychology and psychotherapy in China have also begun to introduce mindfulness intervention in recent years. However, there is a lack of relevant practice and research in the field of clinical mental health. This article will briefly introduce the concept of mindfulness, the basic mechanism of the intervention, and the basic skills and guidelines in clinical practice. PMID- 28638179 TI - Danhong Huayu Koufuye Prevents Diabetic Retinopathy in Streptozotocin-Induced Diabetic Rats via Antioxidation and Anti-Inflammation. AB - Danhong Huayu Koufuye (DHK), a traditional Chinese prescription, is used to treat central retinal vein occlusion clinically. We previously reported that DHK prevented diabetic retinopathy (DR) in rats. Moreover, we found that it protected endothelial cells from hyperglycemia-induced apoptosis through antioxidation and anti-inflammation. Here, we investigated whether antioxidative and anti inflammatory activities of DHK contributed to its therapeutic effect on DR in streptozotocin- (STZ-) induced diabetic rats. DHK significantly blocked the breakdown of the blood-retinal barrier (BRB) and increased the thickness of the inner nuclear layer (INL), as well as suppressed the swelling of the ganglion cell layer (GCL) in diabetic retinas. DHK remarkably increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in plasma, and decreased serum level of nitric oxide (NO). Moreover, DHK markedly reduced the serum levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1). Furthermore, DHK significantly downregulated protein expressions of VEGF and inducible NO synthase (iNOS) and mRNA expression of ICAM-1 in retinas. These results suggest that the antioxidative and anti inflammatory activities of DHK may be important mechanisms involved in the protective effect of DHK on DR in STZ-induced diabetic rats. PMID- 28638180 TI - In Situ Cytokine Expression and Morphometric Evaluation of Total Collagen and Collagens Type I and Type III in Keloid Scars. AB - Keloids are characterized by excessive collagen deposition and growth beyond the edges of the initial injury, and cytokines may be related to their formation. The objective of this study was to evaluate the collagen fibers, analyze in situ expression of cytokines in keloid lesions, and compare to the control group. Results showed that there was a predominance of women and nonwhite and direct black ancestry. Keloid showed a significant increase in total and type III collagen. Significantly, the expression of mRNA for TGF-beta in keloid was increased, the expressions of IFN-gamma, IFN-gammaR1, and IL-10 were lower, and IFN-gammaR1 and TNF-alpha had no statistical difference. Correlations between collagen type III and TGF-beta mRNA expression were positive and significant, IFN gamma, IFN-gammaR1, and IL-10 were negative and significant, and TNF-alpha showed no statistical difference. We conclude that there was a significant increase of total collagen in keloid and predominance of collagen type III compared to the controls, showing keloid as an immature lesion. There is a significant increase in TGF-beta mRNA in keloid lesions, and a significant decrease in IFN-gamma and IL-10, suggesting that these cytokines are related to keloid lesions. PMID- 28638182 TI - Sleep Quality in University Students with Premenstrual Dysphoric Disorder. AB - BACKGROUND: Up to 8% of women in their reproductive years are affected by Premenstral Dysphoric Disorder (PMDD). Sleep disturbances such as insomnia or hypersomnia are one of the DSM-IV-TR's defining criteria for the diagnosis of PMDD and are found in about 70% of women with the disorder. However, studies are lacking that specifically address the effects of PMDD on quality of sleep. AIM: This study was designed to evaluate the prevalence of Premenstrual DysphoricDisorder (PMDD) and its impact on sleep quality in female university students. METHODS: We developed an 18-item PMDD scale based on The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) to diagnose PMDD in female university studentswho ranged in age from 18 to 30 years and had regular menstrual cycles.Participants were categorized into a PMDD group or a No/PMDD group and sleep quality was compared between the two groups. The evaluation tool used to measure sleep quality was the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The prevalence of PMDD in female universitystudents was 25.5%. Analysis of the PSQI demonstrated that 80.5% of those in PMDD group had a PSQI that scored >5; however, only 56.4% in the No/PMDD grouphad a PSQI that scored >5 (chi2 =12.459, p<0.001). The mean PSQI score was 8.2(3.4) in the PMDD group and was 6.5(3.1) in the No/PMDD group (t=3.648, p<0.001). CONCLUSIONS: Female university students who experience PMDD are deeply affected by sleep problems. Lower sleep quality, daytime dysfunction, and sleep disturbance are common sleep problems among female university students with PMDD. PMID- 28638183 TI - Psychometric Properties of the Chinese Version of the Arabic Scale of Death Anxiety. AB - BACKGROUND: Death anxiety is regarded as a risk and maintaining factor of psychopathology. While the Arabic Scale of Death Anxiety (ASDA) is a brief, commonly used assessment, such a tool is lacking in Chinese clinical practice. AIM: The current study was conducted to develop a Chinese version of the ASDA, i.e., the ASDA(C), using a multistage back-translation technique, and examine the psychometric properties of the scale. METHODS: A total of 1372 participants from hospitals and universities located in three geographic areas of China were recruited for this study. To calculate the criterion-related validity of the ASDA(C) compared to the Chinese version of the longer-form Multidimensional Orientation toward Dying and Death Inventory (MODDI-F/chin), 49 undergraduates were randomly assigned to complete both questionnaires. Of the total participants, 56 were randomly assigned to retake the ASDA(C) in order to estimate the one-week, test-retest reliability of the ASDA(C). RESULTS: The overall Cronbach's alpha was 0.91 for the whole scale. The one-week, test-retest reliability was 0.96. Exploratory Factor Analysis (EFA) revealed three factors, "fear of dead people and tombs," "fear of lethal disease," and "fear of postmortem events," accounted for 57.09% of the total variance. Factor structure for the three-factor model was sound. The correlation between the total scores on the ASDA(C) and the MODDI-F/chin was 0.54, indicating acceptable concurrent validity. CONCLUSIONS: ASDA(C) has adequate psychometrics and properties that make it a reliable and valid scale to assess death anxiety in Mandarin-speaking Chinese. PMID- 28638184 TI - An analysis of factors influencing drinking relapse among patients with alcohol induced psychiatric and behavioral disorders. AB - BACKGROUND: Patients with alcohol-induced psychiatric and behavioral disorders have higher drinking relapse rates after treatment when compared to those without these disorders. AIM: To investigate factors influencing drinking relapse among patients with alcohol-induced psychiatric and behavioral disorders and provide guidance for rehabilitative intervention for those being treated for substance use disorders. METHODS: Patients were randomly assigned into either the study group or the control group. We used Chi-square test to analyze their general demographics, drinking history, and hospitalizations. Factors influencing the relapse were analyzed by logistic regression analyses. RESULTS: The univariate analysis showed that factors included ethnicity, level of education, occupation, marital status, duration of psychiatric symptoms and deception about alcohol use; multivariate analysis showed that marital status, duration of psychiatric symptoms, and deception about alcohol use were correlated with relapse among patients with psychiatric and behavioral disorders. CONCLUSIONS: For patients who were single, psychiatric symptoms were more likely to occur between the first and fifth year of alcohol consumption, and those who were deceptive about their alcohol use were more likely to have a relapse than those who were not. PMID- 28638185 TI - Literature Searches in the Conduct of Systematic Reviews and Evaluations. AB - Performing a literature search is an important part of performing a systematic review or a meta-analysis of biomedical literature, which have now become the gold standards for determining what qualifies as 'evidence-based' medicine. Combining searches of English-language databases and the large Chinese-language databases can identify new, potentially important, sources of data that are not include in the traditional English-only reviews. Selection of a restricted subset of databases for conducting the literature search or using inappropriate methods to identify appropriate articles within each database can lead to biased results and incorrect conclusions. This article introduces common English and Chinese databases, describes the search engines available for conducting searches, discusses the basic methods and common pitfalls of conducting searches, and provides an example of a search to highlight these issues. PMID- 28638186 TI - Current Problems in the Research and Development of more Effective Antidepressants. AB - This commentary was stimulated by discussions held at the First China Antidepressants Research and Development Summit held in Beijing in October 2015. Hosted by the Chinese Psychiatrist Psychopharmacology Commission and including leading clinicians, neuroscientists, and representatives of the pharmaceutical industry, the summit focused on the major problems that are limiting the development of more effective antidepressant medications. In the absence of clear biomarkers of depression, clinicians must base treatment decisions on clinical phenomenology; the lack of clear biological targets results in currently available antidepressants that take a long time to be effective, have low rates of full remission, and high rates of relapse. Basic research on depression by neuroscientists in China is internationally recognized, but the vast proportion of candidate chemical compounds Chinese researchers propose as potential treatments for depression fail when tested clinically. This high failure rate of proposed agents has rapidly increased the cost of bringing new drugs to market, so pharmaceutical firms prefer to 'tweak' currently approved medications rather than take the financial risk of supporting the development of novel antidepressants. Thus, the development of new, more effective treatments for depression is at a stalemate. Given the huge impact of depression on the economic development of China and other countries, it is essential to actively solicit the support of governments and communities in the efforts of clinicians, researchers, and the pharmaceutical industry to overcome this stalemate. PMID- 28638187 TI - Atypical Features and Bipolar Disorder. AB - Bipolar Disorder (BD) features with various of clinical symptoms, leading to the misdiagnosis of major depressive disorder (MDD). The atypical features (ATFs) are regarded as one of valuable index to identify BD from depressed patients. The ATFs should be helpful to the differential diagnose of the two diseases. In this forum, we discussed the issue of the relation between the ATFs and BD. PMID- 28638188 TI - Case Report of Cushing's Syndrome with an Acute Psychotic Presentation. AB - A 36-year-old Chinese woman was brought to the emergency department of a general hospital with a 3-day history of mania, persecutory delusions, and suicidal ideation; she also had a 6-month history of disrupted sleep, hypervigilance, and somatic symptoms. Her physical exam on admission to the psychosomatic ward identified a moon-shaped face, exophthalmos, and purple striae on her legs, so acute psychiatric symptoms secondary to Cushing's syndrome was suspected. Elevated plasma cortisol and adrenocorticotropic hormone (ACTH) and identification of a mass on her left adrenal gland on the computed tomography (CT) scan of her abdomen confirmed the diagnosis. Low dose quetiapine (75-125 mg/d) and alprazolam (0.4 mg/qn) were prescribed to control the psychotic symptoms and improve her sleep. After surgical removal of a benign ACTH independent adrenal tumor, her cortisol and ACTH levels returned to normal and her psychiatric symptoms gradually diminished over a one-month period, at which point she was discharged. Low-dose quetiapine was continued for 2 months after discharge and then discontinued; by this time her psychiatric symptoms had completely disappeared. In this case the patient had pathognomonic symptoms of CS, so it was relatively easy to make the diagnosis; but acute psychotic symptoms in CS can be life-threatening and may not be associated with the typical physical symptoms of CS (if there is only modest hypercortisolemia), so psychiatric clinicians should always consider CS among the possible differential diagnoses for unexplained acute psychosis. PMID- 28638190 TI - Primary Question and Hypothesis Testing in Randomized Controlled Clinical Trials. AB - We briefly reviewed and provided cautions about some of the fundamental concepts used in the design of medical and public studies, especially primary question, hypothesis testing and sample size in this short note. We also talked about some of the extensions and development in the recent years. PMID- 28638189 TI - Sphenoid Wing Meningioma Presenting as Cognitive Impairment. AB - Frontal meningioma may present solely withpsychological symptoms that resemble dementia. We present the case of a 42-year-old man who initially was thought to have dementia, but he was eventually diagnosed with dementia caused by a sphenoid wing meningioma. Diagnosis of this illness is often delayed due to the insidious nature of the symptoms, which may be mistaken as symptoms of dementia. As cognitive impairment is complex and easily overlooked, it is important to accurately assess neuropsychological function in patients with large brain tumors. PMID- 28638191 TI - Tai Chi for Schizophrenia: A Systematic Review. AB - BACKGROUND: Tai Chi as a form of moderate aerobic exercise originating in China, could promote balance and healing of the mind-body. Furthermore, Tai Chi has been used as an adjunctive treatment for patients with schizophrenia. However, no meta analysis or systematic review on adjunctive Tai Chi for patients with schizophrenia has yet been reported. AIM: A systematic review and meta-analysis was conducted to examine the efficacy of Tai Chi as an adjunctive treatment for schizophrenia using randomized controlled trial (RCT) data. METHOD: Two evaluators independently and systematically searched both English- and Chinese language databases for RCTs of Tai Chi for schizophrenia patients, selected studies, extracted data, conducted quality assessment and data synthesis. Statistical analyses were performed using the Review Manager (version 5.3). The Cochrane Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to assess the strength of the evidence. RESULTS: In 6 RCTs conducted in mainland China and Hong Kong, there were 483 participants including 215 subjects in the intervention group and 268 subjects in the control group. The trials lasted 16.0 (6.2) weeks. Compared to control group, we found significant differences regarding improvement of negative symptoms assessed by the Positive and Negative Syndrome Scale (PANSS) negative symptom sub-score (2 trials) and Scale for the Assessment of Negative Symptoms (SANS) (3 trials) over the study period in the intervention group (5 trials with 6 treatment arms, n=451, SMD: 0.87 (95%CI: -1.51, -0.24), p=0.007; I2=90%). Furthermore, there is no significant difference regarding improvement of positive symptoms assessed by the PANSS positive symptom sub-score (2 trials) and Scale for the Assessment of Positive Symptoms (SAPS) (2 trials) over the study period (4 trials with 5 treatment arms, n=391, SMD: -0.09 (95%CI: -0.44, 0.26), p=0.60; I2=65%). All included RCTs did not report side effects. Based on the GRADE, the strength of the evidence for primary outcome was 'very low'. CONCLUSIONS: The data available on the effectiveness of adjunctive Tai Chi in patients with schizophrenia who are receiving antipsychotic is insufficient to arrive at a definitive conclusion about its efficacy. Furthermore, follow-up time in the available studies was relatively short, and all studies did not use blinded assessment of outcome measures. High-quality randomized trials are needed to inform clinical recommendations. PMID- 28638192 TI - Treatment Effect of Antipsychotics in Combination with Horticultural Therapy on Patients with Schizophrenia: A Randomized, Double-blind, Placebo-controlled Study. AB - BACKGROUND: As a newly developed treatment method for schizophrenia, horticultural therapy is gaining more attention. However, there is as of now little research investigating this topic as well as a general lack of studies adopting into standard treatment plans. AIMS: Investigate treatment effect of horticultural therapy on patients with schizophrenia and its possibility of standardized application in psychiatric hospitals. METHODS: 110 patients with schizophrenia who met the inclusion criteria and provided informed consent were selected from the rehabilitation ward of the Minhang District Mental Health Center from September 2015 to December 2015. We used random-number methods to classify patients into either the intervention group or the control group. While the two groups both received normal medications, the intervention group also attended horticultural therapy. Patients in the intervention group were led by a rehabilitation therapist who had obtained the level II psychological counselor qualification (the standard qualification for counselors in China). The treatment period lasted for 12 weeks. Treatment was held 3 times every week and each session lasted for 90 minutes. The specific contents included ridging, planting, watering, fertilizing and pruning of flowers; plowing, sowing, watering, fertilizing, weeding and catching pests for gardens; appreciating, collecting vegetables, cooking and tasting for flowers and grasses. During the final 10 minutes of every session, patients mutually expressed their thoughts and experiences and the rehabilitation therapist concluded the session. The two groups were measured by the Positive and Negative Syndrome Scale (PANSS) at baseline, the end of the 4th week and the end of the 12th week. RESULTS: There was no statistically significant difference in gender, age, course of disease, marital status, mean dosage of antipsychotic medications and PANSS score before the intervention among two groups. The PANSS score in the intervention group was statistically significant lower than in the control group both at the end of the 4th week (t=-4.03, p<0.001) and at the end of the 12th week (t=-5.57, p<0.001). There were statistically significant differences before and after intervention in the intervention group (F=253.03, p<0.001); there was statistically significant differences before and after intervention in the control group (F=67.66, p<0.001). There was statistically significant difference in the positive scale score among the two groups both at the end of the 4th week (t=-3.69, p<0.001) and the end of the 12th week (t=-3.55, p<0.001); there was a statistically significant difference in the general psychopathology scale score among the two groups both at the end of the 4th week (t=-3.67, p<0.001) and the end of the 12th week (t=-3.34, p<0.001). Likewise, there were statistically significant differences in the positive scale scores at baseline, end of the 4th week and the end of the 12th week both among the intervention group (F=13.76, p<0.001) and the control group (F=5.12, p=0.02); there were statistically significant differences in the general psychopathology scale scores at the baseline, the end of the 4th weekand the end of the 12th week both among the intervention group (F=156.40, p<0.001) and the control group (F=56.72, p<0.001). There was statistically significant differences in the negative scale score at the end of the 12th week among the two groups (t=-2.76, p<0.001). There were statistically significant differences in the positive scale scores at the baseline, the end of the 4th week and the end of the 12th week both among the intervention group (F=103.94, p<0.001) and the control group (F=34.03, p<0.001). CONCLUSIONS: Although antipsychotic medications can alleviate the psychiatric symptoms of patients with schizophrenia, the treatment effect for both positive and negative symptoms would be even more effective if it is combined with horticultural therapy. PMID- 28638193 TI - A Comparison Study of Quetiapine and Risperidone's Effectiveness and Safety on Treating Alcohol-induced Mental Disorder. AB - BACKGROUND: Compared with Risperidone, Quetiapine's effectiveness and safety on treating alcohol-induced mental disorder is still unclear. OBJECTIVE: To investigate the clinical effectiveness and safety of Quetiapine on treating alcohol-induced mental disorder. METHODS: One hundred and forty-eight patients with alcohol-induced mental disorder were divided into the experimental group (75 patients) and the control group (73 patients) by the treatments they received. The patients in the experimental group were treated with Quetiapine by taking it three times per day orally. The mean (sd) maintenance dose was 151.2(27.3) mg/d, and the treatment cycle was 6 weeks. Patients in the control group received Risperidone once per day orally with a mean (sd) maintenance dose being 2.3(0.9) mg/d, and the treatment cycle was 6 weeks as well. The PANSS scale was used to assess patients' before and after treatment. The researchers also observed any adverse reactions in both treatment strategies and evaluated the effectiveness and safety of both treatment strategies. RESULTS: The mean (sd) PANSS scale score of the experimental group after two weeks of treatment was 71.9 (10.2), which was clearly better than the mean (sd) score before treatment (82.6 [11.4]), and was significantly better than the control group's mean (sd) score after two weeks (76.5[12.8]). Also, the experimental group's scores after 4 weeks of treatment and 6 weeks of treatment were significantly better than the control group. The experimental group's efficacy rate (94.7%) was higher than the control group's (90.4%); the cure rate of the experimental group (33.3%) was higher than that of the control group (24.7%), and the difference was statistically significant. The rates of adverse reactions in the experimental and control groups were 13.3% and 19.2% respectively, and they were significantly different from each other. CONCLUSION: Treating alcohol-induced mental disorder with Quetiapine is more effective than treating it with Risperidone. Quetiapine can improve patients' symptoms quickly, and lower the chance of adverse reactions. It is effective and safe. PMID- 28638194 TI - A Case Report of Psychoactive Drugs Aggravating and Alleviating Meige Syndrome. AB - The present case report described a 61-year-old female patient who was diagnosed as Meige syndrome with double eyelid spasm, anxiety and insomnia. After she was treated with psychoactive drugs, it was found that clonazepam tablets in the benzodiazepine class and dopamine antagonist olanzapine tablets aggravated double eyelid spasm; while eszopiclone tablets as a specificity gamma-aminobutyric acid receptor binding drug alleviated this condition. The present case suggests that psychoactive drugs have both positive and negative effects on treating Meige syndrome. As for the patients who also have emotion disorder, their conditions should be observed carefully when choosing which psychoactive drug to use. The specificity gamma-aminobutyric acid receptor binding drugs should be the prime choice, such as eszopiclone. PMID- 28638195 TI - Malignant Syndrome or Withdrawal Reaction? AB - We report on a case of a female patient who had serious side effects from treatment with clozapine and chlorpromazine and the appeared to have a withdrawal reaction from cessation of clozapine. During the treatment process she was misdiagnosed as having malignant syndrome. This case highlights the importance of clinicians being able to distinguish malignant syndrome from withdrawal reactions, and to be familiar with treatment and prevention methods for both. PMID- 28638196 TI - Primary Delusion and the Sociopolitical Milieu in India - A Case Report & Short Review. AB - Delusion has always been a central topic for psychiatric research with regard to its etiology, pathogenesis, diagnosis, treatment, and forensic relevance. Among these, primary delusion seems to be the interest of many psychiatrists. Content of delusion has always been the area of interest of cultural psychiatry. We have tried to discuss the various aspects of primary delusion and also tried to explain how cultural and sociopolitical environment in a country like India can shape the formation of primary delusion and influence its psychopathology. PMID- 28638197 TI - Does More Data Mean Higher Efficiency? An Experience from Pre- and Post-treatment Study with Missing Data. AB - In this paper we compare two moment-based methods which have been widely used to test the hypothesis of no treatment effect in pre- and post-treatment studies with data missing completely at random. Our theoretical derivation and simulation results show that the method based on all available data is not necessarily more efficient than the method that uses only complete data pairs. We propose an optimal linear combination of these two methods which turns to be more powerful in all cases. PMID- 28638199 TI - Factors Associated with Significant Anxiety and Depressive Symptoms in Pregnant Women with a History of Complications. AB - BACKGROUND: The occurrence of complications during the gestation period is higher among pregnant women with a history of complications than among pregnant women without previous complications. High-risk pregnancy can cause negative emotional symptoms such as anxiety and depression in pregnant women. Current research on anxiety and depression symptoms in pregnant women is sparse. AIMS: To examine the incidence of anxiety and depression symptoms in pregnant women with a history of previous complications or high risk pregnancy and related risk factors. METHODS: Women with a history of previous complications in pregnancy or current 'high risk' pregnancy (e.g. test tube fertilization, etc.) were classified as 'high risk'. 197 of these 'high risk' women who were in their second trimester (16 to 20 weeks) underwent a monthly comprehensive assessment using the Hospital Anxiety and Depression Scale (HAD) in the last 4 months of the gestation period. The Edinburgh Postnatal Depression Scale (EPDS) was used for assessment and risk factor investigation 3 to 7 days, 42 days, and 3 months after childbirth. RESULTS: The mean (sd) HAD anxiety score among 'high-risk'women at the time of enrollment was 3.69 (2.76) and depression score was 3.42 (2.53). Significant anxiety symptoms and depression symptoms were found in 14 cases (7.18 %) and 10 cases (5.13%), respectively. Multivariate analysis showed a correlation between anxiety symptoms and history of miscarriage (OR: 8.162, 95%CI: 1.213 to 54.914)and testing positive for hepatitis (OR: 8.912, 95%CI: 1.052 to 75.498). Depressive symptoms were correlated with glucose positive urine (OR: 30.529, 95%CI: 1.312 to 710.610) and history of hemorrhaging (OR: 7.122, 95%CI: 1.015 to 49.984). General factors associated with anxiety and depression symptoms include patients' health status in the recent 3 months, concerns about fetal health, quality of marital relationship, and relationship with in-laws. CONCLUSIONS: Anxiety and depression symptoms are commonly seen in pregnant women with a history of previous complications or current 'high risk' pregnancy. Patients' recent health status, relationship with in-laws, marital quality and concerns about fetal health are associated with anxiety and depression symptoms during pregnancy. PMID- 28638200 TI - Brain Gamma-Aminobutyric Acid (GABA) Concentration of the Prefrontal Lobe in Unmedicated Patients with Obsessive-Compulsive Disorder: A Research of Magnetic Resonance Spectroscopy. AB - BACKGROUND: In recent years, a large number of neuroimaging studies found that the Cortico-Striato- Thalamo-Cortical circuit (CSTC), including the prefrontal lobe, a significant part of CSTC, has disturbance metabolically in patients with Obsessive-Compulsive Disorder (OCD). AIM: Explore the correlation between the neuro-metabolic features and clinical characteristics of OCD patients using magnetic resonance spectroscopy technology. METHODS: 88 patients with OCD who were not received medication and outpatient treatment for 8 weeks and 76 health controls were enrolled, there was no significant difference in gender, age or education level between the two groups. SIEMENS 3.0T MRI scanner was used to measure the spectral wave of Orbito Frontal Cortex (OFC) and Anterior Cingulate Cortex (ACC) of participants, setting mega-press sequences. Meanwhile, the concentrations of gamma-aminobutyric acid (GABA), glutamine/glutamate complex (Glx) and N-Acetyl Aspartate (NAA) were measured relative to concentration of water, on the ACC and OFC of participants, for statistical analysis via LC model version 6.3 software. The concentration of metabolic substances of the OCD group compared to the healthy control group was analyzed using two sample t-test. The correlation between substance concentration and scores on the scales, including Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Anxiety scale (HAMA) and Hamilton Depression scale (HAMD) was carried out using the Pearson correlation method. RESULTS: Compared with healthy controls, the GABA/W and NAA/W concentration in individuals with OCD are significantly decreased (p=0.031, t=2.193, p=0.002, t=3.223). Also, the concentration of GABA/W had a trend of decrease in the ACC. The GABA/W of the OFC had a negative correlation with Y-BOCS O, Y-BOCS-C and Y-BOCS-T scores (p=0.037, r=0.221; p=0.007, r=0.283; p=0.014, r=0.259). CONCLUSIONS: These results support that GABA concentration in the OFC area of patients with OCD is significantly decreased and the concentration in the ACC has a trend of decreasing. All of these indicate that there is a relationship between the GABA concentration and the psychopathology of OCD. PMID- 28638201 TI - A Pilot Longitudinal Study on Cerebrospinal Fluid (CSF) Tau Protein in Alzheimer's Disease and Vascular Dementia. AB - BACKGROUND: Alzheimer's disease (AD) has high a prevalence rate, high medical costs, and care difficulties, and has become a serious social and economic problem in our aging society. So far, there has not been a reliable and objective diagnostic criteria for AD found. In recent years, there have been many domestic and foreign studies on the biological markers of cerebrospinal fluid in the patients with AD, and high levels of the T-tau, P-tau found in cerebrospinal fluid (CSF) is at this point an indisputable fact. However, the relationship between these markers and the severity of dementia, as well as the development of the disease, should be further studied. OBJECTIVE: Compare the CSF level of total tau (T-tau) and phosphorylated tau at threonine 231 (P-tau231) between patients with moderate to severe Alzheimer's disease (AD) and those with vascular dementia (VD) at baseline, and 6 month follow-up. Observe the differences between patients with AD and control group, as well as the changes as the disease develops. METHODS: There were 11 patients with moderate AD (10 <= MMSE <= 20), 10 patients with severe AD (MMSE <= 9), and 7 age-matched patients with severe VD at baseline, among which 7 AD patients and 6 VD patients completed the 6 months follow-up. CSF levels of T-tau, P-tau231 were measured with sandwich ELISA. RESULT: At baseline, the concentrations of the CSF level of T-tau were 470.08 (263.58) pg/mL in the AD group and 208.76 (42.24) pg/mL in the VD group. This difference was statistically significant (Z= -3.369, p <0.001). The concentrations of CSF level of P-tau231 were 90.94 (49.86) pg/mL in the AD group and 42.96 (13.10) pg/mL in the VD group. This difference was also statistically significant (Z = -3.237, p <0.001). Compared to patients with severe VD, the concentration of CSF T-tau in patients with severe AD was significantly higher (Z= -2.830, p = 0.005), as well as the concentration of CSF P-tau231 (Z = -2.392, p = 0.017). The concentration of CSF P-tau231 in the patients with moderate AD was significantly higher than that in the patients with severe VD (Z = -2.605, p = 0.009). At the 6 months follow-up, there were no statistically significant differences in the changes of CSF T-tau and CSF P-tau231 concentrations between the AD group and VD group. CONCLUSION: The CSF level of T-tau and P-tau231 in the AD patients was significantly higher than that in the VD patients. The concentration of CSF P-tau231 in the moderate AD patients was significantly higher than that in the patients with severe AD. During the 6 months follow-up, the changes of the CSF concentrations of T-tau and P-tau231 between AD group and VD group were not statistically significant. PMID- 28638202 TI - Characteristics of Aggressive Behavior among Male Inpatients with Schizophrenia. AB - BACKGROUND: The incidence of the aggressive behavior is higher among the patients with severe mental disorder such as schizophrenia than the general population. The study of factors related to aggressive behavior has great meaning in designing prevention and intervention methods with this population of patients. AIMS: To understand the characteristics of assaultive behavior of male patients with schizophrenia who have been hospitalized. METHODS: Using a continuous sampling method, data from 75 male inpatients with a diagnosis of schizophrenia was collected at the psychiatric unit of Central South University Second Xiangya Hospital (Changsha, China) from August 2015 to February 2016.On the third day after hospitalization participants were given a general questionnaire as well as being assessed using the modified overt aggression scale (MOAS), historical clinical risk management-20 (HCR-20) questionnaire, hare psychopathic checklist revised (PCL-R), and positive and negative syndrome scale (PANSS).Based on results of the MOAS participants were group into an 'aggressive behavior' group (39 cases) and 'non-aggressive behavior' group (36 cases). The differences in socio-demographic characteristics and scores on the other evaluation tools were then compared between these two groups. RESULTS: Participants in the 'aggressive behavior' group had significantly different scores in the HCR-20 in the H1 (past violence events), H2 (violent events when young), H10 (disobedience in the past), and C4 (impulsiveness) sections; as well in the anti-social section of PCL-R; and significantly higher PANSS scores in the positive symptom, depressive symptoms and paranoid symptom sections than those in the 'non-aggressive behavior' group. CONCLUSIONS: A combination of adverse and traumatic life events such as a history of violence, vulnerabilities in ones personality (e.g. impulsive or antisocial tendencies) and psychopathology of current illness (e.g. significant anxiety and depressive symptoms) contribute to aggressive behavior in male inpatients with schizophrenia. Our results contribute to the literature that will hopefully aid in ensuring patient and staff safety, as well as providing more information in working with this vulnerable population. PMID- 28638198 TI - Efficacy of Atypical Antipsychotics in the Management of Acute Agitation and Aggression in Hospitalized Patients with Schizophrenia or Bipolar Disorder: Results from a Systematic Review. AB - Acute agitation and aggression are common symptoms in patients with bipolar disorder and schizophrenia. In this review, we discuss the prevalence, clinical assessment strategies, treatment options, and current Western and Chinese guidelines for the management of acute agitation and aggression in patients with bipolar disorder or schizophrenia. Among available approaches, we discuss in detail recent evidence supporting the use of intramuscular (IM) antipsychotics and some recently approved oral atypical antipsychotics for the management of acute aggression and agitation in hospitalized patients with bipolar disorder or schizophrenia presenting with acute agitation or aggression, highlighting some differences between individual antipsychotic agents. PMID- 28638203 TI - The History, Diagnosis and Treatment of Disruptive Mood Dysregulation Disorder. AB - Disruptive mood dysregulation disorder was newly included as a diagnostic category in Diagnostic and statistical manual of mental disorders fifth edition (DSM-5), but the knowledge about it in the clinical practice field is still limited. Therefore, the aim of the present article is to introduce this diagnostic category's history, key points of diagnosis, treatment and its impact on clinical practice for clinical reference. PMID- 28638204 TI - Modern methods for longitudinal data analysis, capabilities, caveats and cautions. AB - Longitudinal studies are used in mental health research and services studies. The dominant approaches for longitudinal data analysis are the generalized linear mixed-effects models (GLMM) and the weighted generalized estimating equations (WGEE). Although both classes of models have been extensively published and widely applied, differences between and limitations about these methods are not clearly delineated and well documented. Unfortunately, some of the differences and limitations carry significant implications for reporting, comparing and interpreting research findings. In this report, we review both major approaches for longitudinal data analysis and highlight their similarities and major differences. We focus on comparison of the two classes of models in terms of model assumptions, model parameter interpretation, applicability and limitations, using both real and simulated data. We discuss caveats and cautions when applying the two different approaches to real study data. PMID- 28638205 TI - Effects of Transcranial Direct Current Stimulation (tDCS) for Auditory Hallucinations: A Systematic Review. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasion brain stimulation, which has been suggested as a safe and promising treatment for auditory hallucinations, however, no systematic review has been conducted to evaluate the effects of tDCS on auditory hallucinations (AH). OBJECTIVE: To investigate the efficacy and safety of tDCS for auditory hallucinations among patients with schizophrenia. METHODS: We searched relevant randomized controlled trials (RCTs) from PubMed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure, Chongqing VIP database for Chinese Technical Periodicals, WANFANG DATA, Chinese Biological Medical Literature Database, and Taiwan Electronic Periodical Services (TEPS) before February 13, 2016. Studies were selected based on pre-defined inclusion and exclusion criteria. The quality of each included study was assessed by the risk of bias table. The levels of evidence of primary outcomes were evaluated using GRADE criteria. Data synthesis was conducted using RevMan 5.3. RESULTS: 304 papers were screened. Finally, three studies with a combined sample size of 87 patients were included in the meta analysis. Two studies were classified as having 'low risk of bias', one study was classified as having 'unclear'. Inconsistent results and the overall level of evidence of primary outcome was graded as 'low'. CONCLUSIONS: The sample sizes of the published studies were small and the results were inconsistent. We could not draw any strong conclusions from these trials. Further high quality RCTs with large sample sizes are needed to assess the efficacy of tDCS for auditory hallucinations in patients with schizophrenia. PMID- 28638206 TI - Effect of Repetitive Transcranial Magnetic Stimulation on Cigarette Smoking in Patients with Schizophrenia. AB - BACKGROUND: The high smoking rate among patients with schizophrenia is an important public health problem, and researchers have been studying how to change the status quo. OBJECTIVE: We investigated the effects of high frequency (10Hz) repetitive transcranial magnetic stimulation on the amount of cigarette smoking in patients with schizophrenia. METHOD: This study enrolled 37 male patients with schizophrenia who were at a stable stage of treatment. Patients were randomly divided into a treatment group (n=19) and a control group (n=18). The treatment group received repetitive transcranial magnetic stimulation (rTMS) on the left prefrontal dorsolateral cortex (DLPFC), and the control group received placebo treatment. The number of cigarettes smoked were recorded at 7 days before treatment, during the course of treatment (i.e. for 21 days), and 3 weeks after treatment had ended. Assessments using the Positive and Negative Syndrome Scale (PANSS), Wisconsin Card Sorting Test (WCST), and Montgomery Asberg Depression Rating Scale (MADRS) were applied before and after treatment. RESULT: Compared to the control group, the number of cigarettes smoked in the treatment group showed a statistically significant reduction in the first week after treatment. However, there was no significant correlation between the scores on PANSS, WCST and MADRS and the number of cigarettes smoked before and after treatment in both groups. DISCUSSION: High frequency (10Hz) repetitive transcranial magnetic stimulation on the left prefrontal cortex can reduce the number of cigarettes smoked in patients with schizophrenia. PMID- 28638207 TI - Effect of Clonazepam Co-Administered with Clozapine on the Serum Clozapine and Norclozapine Concentration of Patients with Schizophrenia: A Retrospective Survey. AB - BACKGROUND: For patients with schizophrenia clozapine (CLZ) is sometimes co prescribed with clonazepam (CLNAZ). However, the impact of administration of CLZ along with CLNAZ on the serum concentration of CLZ and its major metabolite N-CLZ in schizophrenia is not well understood. AIM: To investigate the effects of CLNAZ co-medication, patient gender, age and CLZ dosage on serum concentration of CLZ and norclozapine (N-CLZ) in individuals with schizophrenia. METHODS: Serum CLZ and N-CLZ concentrations and demographic data were retrospectively analyzed for 341 patients with schizophrenia. We used SPSS 21.0 to perform stepwise regression to analyze the concentration data and demographics. Variables included in the analysis were: serum concentration of CLZ, N-CLZ, and CLZ dosage, gender, age and CLNAZ co-medication. RESULTS: (1) CLNAZ co-medication significantly affects serum CLZ and N-CLZ concentration in schizophrenics (p=0.010, p=0.020); (2) CLNAZ co medication, gender and CLZ dosage significantly affect serum CLZ concentration in patients with schizophrenia (p=0.010, p=0.009, p<0.001). Serum CLZ concentration is negatively correlated with CLNAZ co-medication, and is positively correlated with being female and CLZ dosage; (3) CLNAZ co-medication and CLZ dosage were significantly related to serum N-CLZ concentration in participants (p=0.020, p<0.001). Serum N-CLZ concentration was negatively correlated with CLNAZ comedication, and positively correlated with CLZ dosage. CONCLUSION: CLNAZ co medication is associated with changes in serum CLZ and N-CLZ concentration. It is indicated that gender and/or CLZ dosage are also related to serum CLZ and N-CLZ concentration. Therapeutic drug monitoring and dosage regulation of CLZ should be performed for patients with schizophrenia who are also taking CLNAZ to maintain a safe and effective serum concentration of CLZ and N-CLZ. PMID- 28638208 TI - Eye Movement Indices in the Study of Depressive Disorder. AB - BACKGROUND: Impaired cognition is one of the most common core symptoms of depressive disorder. Eye movement testing mainly reflects patients' cognitive functions, such as cognition, memory, attention, recognition, and recall. This type of testing has great potential to improve theories related to cognitive functioning in depressive episodes as well as potential in its clinical application. AIMS: This study investigated whether eye movement indices of patients with unmedicated depressive disorder were abnormal or not, as well as the relationship between these indices and mental symptoms. METHODS: Sixty patients with depressive disorder and sixty healthy controls (who were matched by gender, age and years of education) were recruited, and completed eye movement tests including three tasks: fixation task, saccade task and free-view task. The EyeLink desktop eye tracking system was employed to collect eye movement information, and analyze the eye movement indices of the three tasks between the two groups. RESULTS: (1) In the fixation task, compared to healthy controls, patients with depressive disorder showed more fixations, shorter fixation durations, more saccades and longer saccadic lengths; (2) In the saccade task, patients with depressive disorder showed longer anti-saccade latencies and smaller anti-saccade peak velocities; (3) In the free-view task, patients with depressive disorder showed fewer saccades and longer mean fixation durations; (4) Correlation analysis showed that there was a negative correlation between the pro saccade amplitude and anxiety symptoms, and a positive correlation between the anti-saccade latency and anxiety symptoms. The depression symptoms were negatively correlated with fixation times, saccades, and saccadic paths respectively in the free-view task; while the mean fixation duration and depression symptoms showed a positive correlation. CONCLUSION: Compared to healthy controls, patients with depressive disorder showed significantly abnormal eye movement indices. In addition patients' anxiety and depression symptoms and eye movement indices were correlated. The pathological meaning of these phenomena deserve further exploration. PMID- 28638209 TI - Comparative Analysis of Results from a Cognitive Emotion Regulation Questionnaire Between International Students from West Asia and Xinjiang College Students in China. AB - BACKGROUND: The Cognitive Emotion Regulation Questionnaire (CERQ) is a cognitive and emotional tool measuring how individuals deal with stressful life events. However differences exist in the results of CERQ among individuals. OBJECTIVE: This study was conducted to investigate the CERQ results and depressive symptoms of students at our university (both local and international students) in order to provide further guidance for psychological interventions. METHODS: 255 sophomore and junior international students (171 male and 84 female) and 262 sophomore and junior Chinese students (124 male and 138 female) were investigated using CERQ, ASLEC and SDS questionnaires. Results were analyzed using SPSS 16.0. RESULT: Compared to Chinese students, international students more often used cognitive adjustment methods such as "positive refocusing","re-focus on planning" and "catastrophizing". In regression equations where depression symptoms were used as the dependent variable, "self-blaming" and "catastrophizing"positively contributed to depression symptoms in international students, while"acceptance" was negatively correlated with depression symptoms.In Chinese students, "life events score" and "catastrophizing"were positively correlated withdepression symptoms, while "positive re-evaluating" was negatively correlated with depression symptoms. CONCLUSION: Among students of different races, positive coping methods were negatively correlated with depression symptoms and could possibly prevent the occurrence of depression, while negative coping methods were positively correlated with depression.Encouraging students to use adaptive coping methods during psychological intervention is an effective way to adjust cognitions and behavior for depression prevention. PMID- 28638210 TI - Why is Diagnosing MDD Challenging? AB - Depression is highly prevalent and one of the major contributors to disability worldwide. However, one of the findings from the DSM-5 field trials was that inter-rater reliability for diagnosing major depressive disorder was very poor. Why is diagnosing MDD so challenging? This article attempts to explain why undefined pathogenesis and complicated phenotypes complicate the diagnosis of MDD. However, further biomarker and translational research is still necessary to help clinicians screen and diagnose depression in the future rather than relying solely on current subjective diagnostic criteria. PMID- 28638211 TI - Psychogenic Blepharospasm: A Diagnostic Dilemma. AB - Blepharospasm is an uncontrolled spasmodic contraction of the orbicularis muscles of the eye resulting in an abnormal tic or twitch of eyes. It usually lasts for seconds to minutes but in severe cases eyes may be closed for hours. It may be essentially benign or secondary due to a lesion in basal ganglia, pyramidal tract, and trauma, local pathology in the eyes or drug induced. Here we are presenting a case of psychogenic blepharospasm. A 65 year old woman presented with a history of episodic inability of opening her eyes for the past 6 months. She had repeated abrupt closure of eyes which would persist for 1 hour. It made her socially and interpersonally disabled. Systemic and neurological causes were ruled out by detailed physical examinations and investigations including neuroimaging. Following poor response to oral medications she was injected with 7 units of Botox only in the muscles of the right eye. But within seconds she received relief in both eyes. During the next session she received a needle prick in one eye with no medication and immediately both of her eyes opened from a tightly closed position. In this case the patient reported stress due to increased workload around the house. From our case it depicts that a true movement disorder is often difficult to distinguish from functional disorder. So evaluation and management of patient's external and internal stress will be of immense help before conducting any invasive treatment. PMID- 28638212 TI - Choking Phobia : An Uncommon Phobic Disorder, Treated with Behavior Therapy : A Case Report and Review of the Literature. AB - Choking phobia is a relatively uncommon phobic disorder which is often encountered by otorhinolaryngologists and referred to psychiatrists as a cause of psychogenic dysphagia. If not diagnosed early and treated appropriately, it can have severe detrimental effects on the physical and psychological health of an individual. We present a case of a 20 year old female who presented with choking phobia and was treated with behavior therapy. Additionally, we discuss the differential diagnosis and treatment strategies of this rare anxiety disorder. PMID- 28638213 TI - Comment on "Disability, Psychiatric Symptoms, and Quality of Life in Infertile Women: A Cross-Sectional Study In Turkey". AB - The aim of this work is to comment on the study about disability, psychiatric symptoms and quality of life in infertile women of Turkey that was published in this Journal. We suggest that future studies use larger samples, consider the influence of factors such as cause of infertility and assisted reproductive techniques (ARTs) and, last but not least, exclude other comorbidities which may influence the data analysis. PMID- 28638214 TI - Two Paradoxes in Linear Regression Analysis. AB - Regression is one of the favorite tools in applied statistics. However, misuse and misinterpretation of results from regression analysis are common in biomedical research. In this paper we use statistical theory and simulation studies to clarify some paradoxes around this popular statistical method. In particular, we show that a widely used model selection procedure employed in many publications in top medical journals is wrong. Formal procedures based on solid statistical theory should be used in model selection. PMID- 28638215 TI - Endoscopic shielding technique, a new method in therapeutic endoscopy. AB - Prevention of late complications after large endoscopic resection is inefficient with current methods. Endoscopic shielding, as a simple and safe technique, has been proposed to improve the incidence of these events. Different methods, sheets or hydrogels, have showed proven efficacy in the prevention of late bleeding and perforation, as well as the improvement of tissue repair, in experimental models and in clinical practice. PMID- 28638216 TI - Role of surgery in pancreatic cancer. AB - Treatment of pancreatic cancer is multimodal and surgery is an essential part, mandatory for curative potential. Also chemotherapy is essential, and serious postoperative complications or rapid disease progression may preclude completion of multimodal treatment. The sequence of treatment interventions has therefore become an important concern, and numerous ongoing randomized controlled trials compare clinical outcome after upfront surgery and neoadjuvant treatment with subsequent resection. In previous years, borderline resectable and locally advanced pancreatic cancer was most often considered unresectable. More effective chemotherapy together with the latest improvements in surgical expertise has resulted in extended operations, pushing the borders of resectability. Multivisceral resections with or without resection of major mesenteric vessels are now performed in numerous patients, resulting in better outcome, recorded as overall survival and/or patient reported outcome. But postoperative morbidity increases concurrently, and clinical benefit must be carefully evaluated against risk of potential harm, associated with new comprehensive multimodal treatment sequences. Even though cost/utility analyses are deficient, extended surgery has resulted in significantly longer and better life for many patients with no other treatment alternative. Improved selection of patients to surgery and/or chemotherapy will in the near future be possible, based on better tumor biology insight. Clinically available biomarkers enabling personalized treatment are forthcoming, but these options are still limited. The importance of surgical resection for each patient's prognosis is presently increasing, justifying sustained expansion of the surgical treatment modality. PMID- 28638217 TI - Diet in irritable bowel syndrome: What to recommend, not what to forbid to patients! AB - A substantial proportion of patients with irritable bowel syndrome (IBS) associate their symptoms with the ingestion of specific foods. Therefore, in recent years, scientific research has increasingly focused on the role of diet in IBS and dietary management is now considered an important tool in IBS treatment. This article reviews the main dietary approaches in IBS emphasizing evidence from experimental and observational studies and summarizing the main diet and lifestyle recommendations provided by dietary guidelines and scientific literature. Despite the limited evidence for a beneficial role, general advice on healthy eating and lifestyle is recommended as the first-line approach in the dietary management of IBS. Standard recommendations include adhering to a regular meal pattern, reducing intake of insoluble fibers, alcohol, caffeine, spicy foods, and fat, as well as performing regular physical activity and ensuring a good hydration. Second-line dietary approach should be considered where IBS symptoms persist and recommendations include following a low FODMAP diet, to be delivered only by a healthcare professional with expertise in dietary management. The efficacy of this diet is supported by a growing body of evidence. In contrast, the role of lactose or gluten dietary restriction in the treatment of IBS remains subject to ongoing research with a lack of high-quality evidence. Likewise, further clinical trials are needed to conclude the efficacy of probiotics on IBS symptoms. PMID- 28638218 TI - New endoscopes and add-on devices to improve colonoscopy performance. AB - Colonoscopy is the gold standard for colorectal cancer prevention; however, it is still an imperfect modality. Precancerous lesions can be lost during screening examinations, thus increasing the risk of interval cancer. A variety of factors either patient-, or endoscopist dependent or even the procedure itself may contribute to loss of lesions. Sophisticated modalities including advanced technology endoscopes and add-on devices have been developed in an effort to eliminate colonoscopy's drawbacks and maximize its ability to detect potentially culprit polyps. Novel colonoscopes aim to widen the field of view. They incorporate more than one cameras enabling simultaneous image transmission. In that way the field of view can expand up to 330 degrees . On the other hand a plethora of add-on devices attachable on the standard colonoscope promise to detect lesions in the proximal aspect of colonic folds either by offering a retrograde view of the lumen or by straightening the haustral folds during withdrawal. In this minireview we discuss how these recent advances affect colonoscopy performance by improving its quality indicators (cecal intubation rate, adenoma detection rate) and other metrics (polyp detection rate, adenomas per colonoscopy, polyp/adenoma miss rate) associated with examination's outcomes. PMID- 28638219 TI - Spontaneous regression of hepatocellular carcinoma: A mini-review. AB - Spontaneous tumor regression is an extremely rare phenomenon in the oncology field. However, there are several case reports resulted in the regression of hepatocellular carcinoma (HCC) and the accumulation of clinical information and analyses of the mechanism can contribute to the development of a novel therapy. For this purpose, we have carefully reviewed 23 cases of spontaneously regressed HCC published in recent 5 years and our case. The information regarding the tumor size, tumor marker, treatments, etc., have been summarized. The mechanism of spontaneous regression has been discussed to date and presumed to be due to many factors, including hypoxia and immunological reactions. In this careful review of the 24 cases based on the clinical information, hypoxia, systemic inflammation, and both upon spontaneous regression were seen in 3, 8, and 4 cases, respectively among the 15 cases for which the information regarding the proposed mechanisms are available. Recent development of immunotherapeutic approaches in oncology shows promising results, therefore, accumulation of additional cases and analysis of mechanisms underlying the spontaneous regression of HCC are essential and could lead to the development of a new generation of immunotherapies including antibodies directed against immune reactions. PMID- 28638220 TI - Green tea polyphenols ameliorate non-alcoholic fatty liver disease through upregulating AMPK activation in high fat fed Zucker fatty rats. AB - AIM: To investigate protective effects and molecular mechanisms of green tea polyphenols (GTP) on non-alcoholic fatty liver disease (NAFLD) in Zucker fatty (ZF) rats. METHODS: Male ZF rats were fed a high-fat diet (HFD) for 2 wk then treated with GTP (200 mg/kg) or saline (5 mL/kg) for 8 wk, with Zucker lean rat as their control. At the end of experiment, serum and liver tissue were collected for measurement of metabolic parameters, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), inflammatory cytokines and hepatic triglyceride and liver histology. Immunoblotting was used to detect phosphorylation of AMP activated protein kinase (AMPK) acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein 1c (SREBP1c). RESULTS: Genetically obese ZF rats on a HFD presented with metabolic features of hepatic pathological changes comparable to human with NAFLD. GTP intervention decreased weight gain (10.1%, P = 0.052) and significantly lowered visceral fat (31.0%, P < 0.01). Compared with ZF-controls, GTP treatment significantly reduced fasting serum insulin, glucose and lipids levels. Reduction in serum ALT and AST levels (both P < 0.01) were observed in GTP-treated ZF rats. GTP treatment also attenuated the elevated TNFalpha and IL-6 in the circulation. The increased hepatic TG accumulation and cytoplasmic lipid droplet were attenuated by GTP treatment, associated with significantly increased expression of AMPK-Thr172 (P < 0.05) and phosphorylated ACC and SREBP1c (both P < 0.05), indicating diminished hepatic lipogenesis and triglycerides out flux from liver in GTP treated rats. CONCLUSION: The protective effects of GTP against HFD-induced NAFLD in genetically obese ZF rats are positively correlated to reduction in hepatic lipogenesis through upregulating the AMPK pathway. PMID- 28638221 TI - Prevalence of IFNL3 rs4803217 single nucleotide polymorphism and clinical course of chronic hepatitis C. AB - AIM: To evaluate the association of IFNL3 (IL28B) SNP rs4803217 with severity of disease and treatment outcome in chronic hepatitis C (CHC). METHODS: The study enrolled 196 CHC Polish patients (82 women and 114 men in age 20-64) infected with hepatitis C virus (HCV) genotype 1. They were treatment naive and qualified to pegylated interferon alpha (PEG-IFN-alpha) and ribavirin (RBV) therapy. The analyzed baseline parameters included: degree of inflammation, stage of fibrosis, viral load as well as alanine aminotransferase (ALT), asparagine aminotransferase (AST) and total bilirubin (TBIL). The analysis of response to therapy included: sustained virological response (SVR), defined as undetectable serum HCV RNA level six month after completion of 48-wk therapy, and relapse, defined as achieving undetectable viral load at the end of treatment but not SVR. HCV genotyping and HCV RNA quantification were performed using commercially available tests. DNA was isolated from peripheral blood mononuclear cells or from buccal cell swabs. In addition to rs4803217, also single nucleotide polymorphisms (SNPs) (rs12979860, rs8099917 and rs12980275) of known significance in predicting of HCV clearance were analyzed. SNPs were determined by high resolution melt analysis and confirmed by sequencing of amplicons. RESULTS: Frequency of rs4803217 genotypes in studied group was as follows: 27.55%; 54.59% and 17.86% for CC, CA and AA, respectively. The rs4803217 SNP, similar to other analyzed SNPs, was not associated with severity of CHC (grade of inflammation, stage of fibrosis, baseline viral load as well as biochemical parameters: ALT, AST, TBIL). It was demonstrated that the rs4803217C allele is associated with SVR (C vs A: P < 0.0001; dose of C allele: P = 0.0002) and non-relapse (C vs A: P = 0.001; dose of C allele: P = 0.002). Moreover, it was found that patients with CC genotype have significantly higher response rates as compared with CA/AA patients (P < 0.0001), whereas patients carrying A allele are significantly predisposed to relapse after treatment (P = 0.0007). Moreover, the association of rs4803217 with SVR was comparable to that of rs12979860 and stronger as observed for rs12980275 and rs8099917. Association of rs4803217 with relapse, was the strongest as compared with the other SNPs. The analysis of combined rs4803217 and rs8099917 genotypes demonstrated that additional genotyping of rs8099917 had no significant impact on the prediction of SVR. Multivariate analysis revealed that among analyzed SNPs only rs4803217 is an independent predictor of SVR (P = 0.016) and relapse (P = 0.024). CONCLUSION: The rs4803217 SNP is a strong, independent and superior predictor of SVR and relapse in HCV genotype 1 infected CHC patients treated with PEG-IFN-alpha and RBV. PMID- 28638222 TI - Corticotropin-releasing factor stimulates colonic motility via muscarinic receptors in the rat. AB - AIM: To measure exogenous corticotropin-releasing factor (CRF)-induced motility of the isolated rat colon and to demonstrate the effect of pharmacologic inhibition on CRF-induced motility. METHODS: The isolated vascularly-perfused rat colon was used. Luminal pressure was monitored via microtip catheter pressure transducers in the proximal and distal colon. At first, exogenous CRF was administered in a stepwise manner and the concentration of CRF yielding maximal colonic motility was selected. After recording basal colonic motility, hexamethonium, phentolamine, propranolol, atropine and tetrodotoxin were infused into the isolated colon. Initially, only the test drug was infused; then, CRF was added. The motility index was expressed as percentage change over basal level. RESULTS: Administration of 1.4, 14.4, 144 and 288 pmol/L CRF progressively increased colonic motility in the proximal and distal colon. Infusion of atropine or tetrodotoxin reduced CRF-induced motility of both the proximal and distal colon, whereas hexamethonium, phentolamine and propranolol had no effect. CONCLUSION: CRF-induced colonic motility appears to be mediated by local cholinergic signaling via muscarinic receptors. Muscarinic receptors are potential targets for counteracting CRF-induced colonic hypermotility. PMID- 28638223 TI - Clinical significance of changes in the Th17/Treg ratio in autoimmune liver disease. AB - AIM: To investigate the levels, ratios, and clinical significance of T helper 17 (Th17) cells and regulatory T (Treg) cells in the peripheral blood of patients with autoimmune liver disease (AILD). METHODS: Forty-two AILD patients were included in the experimental group (group E), and 11 healthy subjects were recruited as the control group (group C). Flow cytometry was performed to determine the percentages of Th17 and Treg cells in peripheral blood lymphocytes. Furthermore, a range of biochemical indices was measured simultaneously in the blood of group E patients. RESULTS: The percentage of Th17 cells and the Th17/Treg ratio were higher in group E than in group C (P < 0.01), whereas the percentage of Tregs was lower in the group E patients (P < 0.05). Patients in group E who were admitted with AILD in the active stage showed significantly higher Th17 percentages and Th17/Treg ratios than those measured in patients with AILD in remission (P < 0.05). In addition, among patients with AILD in the active stage, individuals that remained unhealed after hospitalization showed significantly higher baseline values of the Th17 percentage and the Th17/Treg ratio than those detected in patients who improved after treatment (P < 0.05). The results suggested that imbalance in the Th17/Treg ratio plays an important role in the pathogenesis and development of AILD. CONCLUSION: A high Th17/Treg ratio appears to predict poor short-term prognosis in patients with AILD in the active stage. PMID- 28638224 TI - Inhibitory effect of oxymatrine on hepatocyte apoptosis via TLR4/PI3K/Akt/GSK 3beta signaling pathway. AB - AIM: To evaluate the effect of oxymatrine (OMT) on hepatocyte apoptosis in rats with lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver failure (ALF). METHODS: LPS/D-GalN was used to establish a model of ALF in rats. To evaluate the effect of OMT, we assessed apoptosis by transmission electron microscopy, and the pathological changes in the liver by light microscopy with hematoxylin and eosin staining. An automated biochemical analyzer was used to measure serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Enzyme-linked immunosorbent assay was used to determine the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Western blotting was used to detect protein levels in liver tissues. Streptavidin peroxidase immunohistochemistry was used to observe expression of Toll-like receptor (TLR)4, active caspase-3, Bax and Bcl-2. RESULTS: All rats in the normal control and OMT pretreated groups survived. The mortality rate in the model group was 30%. OMT preconditioning down-regulated apoptosis of hepatocytes and ameliorated pathological changes in liver tissue. The levels of AST, ALT, TNF-alpha and IL 1beta in the model group increased significantly, and were significantly reduced by OMT pretreatment. OMT pretreatment down-regulated expression of TLR4 and active caspase-3 and the Bax/Bcl-2 ratio, and up-regulated expression of P AktSer473 (Akt phosphorylated at serine 473) and P-GSK3betaSer9 (glycogen synthase kinase 3beta phosphorylated at serine 9) induced by LPS/D-GalN. CONCLUSION: OMT inhibits hepatocyte apoptosis by suppressing the TLR4/PI3K/Akt/GSK-3beta signaling pathway, which suggests that OMT is an effective candidate for ameliorating acute liver failure. PMID- 28638227 TI - Relationship between serum adenosine deaminase levels and liver histology in autoimmune hepatitis. AB - AIM: To evaluate the relationship between serum adenosine deaminase (ADA) levels and histological features in patients with autoimmune hepatitis (AIH). METHODS: A total of 80 subjects (52 AIH cases and 28 healthy controls) were included in the study. Patients were diagnosed according to the simplified criteria suggested by the International Autoimmune Hepatitis Group. All of the cases had been diagnosed with AIH between 2010-2015 at Hacettepe University, Department of Gastroenterology. Serum blood samples were collected and stored at -80 degrees C until the biochemical estimation of ADA activity. The diagnosis of patients was confirmed by liver biopsy. Serum ADA > 20 U/L was considered to be high level. RESULTS: Mean serum ADA levels were significantly higher in AIH patients than those in healthy controls (25.4 +/- 9.6 U/L vs 12.8 +/- 2.2 U/L, P < 0.001). Serum ADA levels > 20 U/L were found in 63.5% AIH patients and in 0% healthy controls (P < 0.001). Mean serum ADA levels were significantly increased in each stage of histological activity: 15.2 +/- 3.5 U/L for patients with mild interface hepatitis, 23.1 +/- 10.0 U/L for patients with moderate interface hepatitis and 30.9 +/- 7.0 U/L for patients with severe interface hepatitis (P < 0.001). Correlation analysis showed that there was a positive association between serum ADA levels and histological activity (r = 0.71, P < 0.001). Receiver operating characteristic analysis suggested that 24.5 U/L was the optimum cut-off point of ADA level for severe interface hepatitis (sensitivity 88%, specificity 85.2%, area under the curve: 0.88). CONCLUSION: Because of the positive correlation with inflammatory activity, serum ADA level may be a potential biomarker for predicting or monitoring histological activity in patients with AIH. PMID- 28638226 TI - Validation of a serum microRNA panel as biomarkers for early diagnosis of hepatocellular carcinoma post-hepatitis C infection in Egyptian patients. AB - AIM: To investigate the prospective importance of serum micro (mi)RNAs (miR-125b, miR-138b, miR-1269, miR-214-5p, miR-494, miR375 and miR-145) as early biomarkers for the diagnosis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS: Two-hundred and fifty HCV4a patients, 224 HCV4a-HCC patients, and 84 healthy controls were enrolled in the study. Expression levels of miR214-5p, miR-125b, miR-1269 and miR-375 were quantified using quantitative real-time PCR. RESULTS: Expression of the selected miRNAs in serum was significantly lower in HCC patients than in the healthy controls, except for miR-1269 and miR-494. There was a significant difference between HCC and HCV patients, in particular for HCC and late stage fibrosis, rather than HCV patients and early fibrosis. It is obvious that miR-1269 was significantly upregulated in HCC cases compared to hepatic fibrosis cases. Each miRNA can show HCC progression. Multivariate logistic regression analysis indicated that the tested panel of miRNAs (miR214 5p, miR-125b, miR-1269 and miR-375) represent accurate and specific indictors of HCC development. CONCLUSION: This study presents a panel of miRNAs with strong power as putative diagnostic and prognostic biomarkers for HCV-induced HCC. Moreover, miR-214-5p and miR-1269 could be considered as early biomarkers for tracking the progress of liver fibrosis to HCC. PMID- 28638228 TI - Clinical significance of the neutrophil-lymphocyte ratio as an early predictive marker for adverse outcomes in patients with acute pancreatitis. AB - AIM: To investigated the prognostic value of the neutrophil-lymphocyte ratio (NLR) in patients with acute pancreatitis and determined an optimal cut-off value for the prediction of adverse outcomes in these patients. METHODS: We retrospectively analyzed 490 patients with acute pancreatitis diagnosed between March 2007 and December 2012. NLRs were calculated at admission and 24, 48, and 72 h after admission. Patients were grouped according to acute pancreatitis severity and organ failure occurrence, and a comparative analysis was performed to compare the NLR between groups. RESULTS: Among the 490 patients, 70 had severe acute pancreatitis with 31 experiencing organ failure. The severe acute pancreatitis group had a significantly higher NLR than the mild acute pancreatitis group on all 4 d (median, 6.14, 6.71, 5.70, and 4.00 vs 4.74, 4.47, 3.20, and 3.30, respectively, P < 0.05). The organ failure group had a significantly higher NLR than the group without organ failure on all 4 d (median, 7.09, 6.72, 6.27, and 6.24 vs 4.85, 4.49, 3.35, and 2.34, respectively, P < 0.05). The optimal cut-off value for baseline NLR was 4.76 in predicting severity and 4.88 in predicting organ failure in acute pancreatitis. CONCLUSION: Elevated baseline NLR correlates with severe acute pancreatitis and organ failure. PMID- 28638225 TI - Sodium selenite ameliorates dextran sulfate sodium-induced chronic colitis in mice by decreasing Th1, Th17, and gammadeltaT and increasing CD4(+)CD25(+) regulatory T-cell responses. AB - AIM: To assess the effect of sodium selenite on the severity of dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. METHODS: Mice were randomly divided into four groups (n = 10/group): normal group, selenium (Se) group, chronic colitis group, and Se + chronic colitis group. The mice were sacrificed on day 26. Survival rates, clinical symptoms, colon length, and histological changes were determined. The percentages and absolute numbers of immune system cells in the lamina propria lymphocytes (LPL) of the colon, the expression of mRNA in colon tissue, and the concentrations of Th1, Th17, and Treg cytokines in LPL from the large intestine, were measured. RESULTS: Se significantly ameliorated the symptoms of colitis and histological injury (P < 0.05 each), increasing the proportions of neutrophils and CD4+ CD25+ T cells (P < 0.05 each) and decreasing the proportions of gammadeltaT cells, CD4+, CD4+CD44+, and CD4+ CD69+ T cells in LPL (P < 0.05 each). Moreover, Se reduced the expression of IL-6, IFN-gamma, IL 17A, IL-21, T-bet, and RORgammat (P < 0.05 each), but enhanced the expression of IL-10 and Foxp3 (P < 0.05 each). CONCLUSION: These results suggest that Se protects against DSS-induced chronic colitis perhaps by increasing the number of CD4(+)CD25(+) Tregs that suppress the secretion of proinflammatory cytokines and populations of Th1, Th17, and gammadeltaT cells. PMID- 28638229 TI - Dietary and metabolomic determinants of relapse in ulcerative colitis patients: A pilot prospective cohort study. AB - AIM: To identify demographic, clinical, metabolomic, and lifestyle related predictors of relapse in adult ulcerative colitis (UC) patients. METHODS: In this prospective pilot study, UC patients in clinical remission were recruited and followed-up at 12 mo to assess a clinical relapse, or not. At baseline information on demographic and clinical parameters was collected. Serum and urine samples were collected for analysis of metabolomic assays using a combined direct infusion/liquid chromatography tandem mass spectrometry and nuclear magnetic resolution spectroscopy. Stool samples were also collected to measure fecal calprotectin (FCP). Dietary assessment was performed using a validated self administered food frequency questionnaire. RESULTS: Twenty patients were included (mean age: 42.7 +/- 14.8 years, females: 55%). Seven patients (35%) experienced a clinical relapse during the follow-up period. While 6 patients (66.7%) with normal body weight developed a clinical relapse, 1 UC patient (9.1%) who was overweight/obese relapsed during the follow-up (P = 0.02). At baseline, poultry intake was significantly higher in patients who were still in remission during follow-up (0.9 oz vs 0.2 oz, P = 0.002). Five patients (71.4%) with FCP > 150 MUg/g and 2 patients (15.4%) with normal FCP (<= 150 MUg/g) at baseline relapsed during the follow-up (P = 0.02). Interestingly, baseline urinary and serum metabolomic profiling of UC patients with or without clinical relapse within 12 mo showed a significant difference. The most important metabolites that were responsible for this discrimination were trans-aconitate, cystine and acetamide in urine, and 3-hydroxybutyrate, acetoacetate and acetone in serum. CONCLUSION: A combination of baseline dietary intake, fecal calprotectin, and metabolomic factors are associated with risk of UC clinical relapse within 12 mo. PMID- 28638230 TI - Role of three-dimensional endoanal ultrasound in assessing the anal sphincter morphology of female patients with chronic proctalgia. AB - AIM: To assess the role of three-dimensional endoanal ultrasound (3D-EAUS) for morphological assessment of the anal sphincter of female patients with chronic proctalgia (CP). METHODS: In this unmatched case control study, 30 consecutive female patients with CP and 25 normal women (control group) were enrolled. 3D EAUS was performed in all subjects. Thickness and length of internal anal sphincter (IAS), thickness of puborectalis muscle (PR), length of the external anal sphincter (EAS) plus PR, and puborectalis angle were measured and compared between the two groups. RESULTS: Patients with CP had significantly shorter IAS length and greater PR thickness, as compared to those in normal individuals (26.28 +/- 3.59 mm vs 28.87 +/- 4.84 mm, P < 0.05 and 9.67 +/- 1.57 mm vs 8.85 +/ 0.97 mm, P < 0.05, respectively). No significant between-group differences were observed with respect to IAS thickness and the EAS plus PR length (P > 0.05). Puborectalis angle in the CP group was significantly decreased, both in resting (88.23 degrees +/- 1.81 degrees vs 89.94 degrees +/- 2.07 degrees in control group, P < 0.05) and straining (88.47 degrees +/- 3.32 degrees vs 90.72 degrees +/- 1.87 degrees in control group, P < 0.05) phases, which suggest the presence of paradoxical contraction of PR in patients with CP. In the CP group, no significant difference in puborectalis angle was observed between the resting and straining phases (88.23 degrees +/- 1.81 degrees vs 88.47 degrees +/- 3.32 degrees respectively, P > 0.05). CONCLUSION: The association of greater PR thickness and paradoxical contraction of PR with CP suggest their potential value as markers of CP. PMID- 28638231 TI - Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer. AB - AIM: To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). METHODS: An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. RESULTS: The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI (P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites (P = 0.009), liver metastasis (P = 0.035), and decreased survival time (P = 0.022). N-syndecan expression was significantly associated with tumor size (P = 0.025), but not with survival time (P = 0.539). CONCLUSION: High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer. PMID- 28638232 TI - Epidemiology of functional gastrointestinal disorders in children and adolescents: A systematic review. AB - AIM: To assess the prevalence of functional gastrointestinal disorders (FGIDs) in children and adolescents. METHODS: PubMed, EMBASE, and Scopus databases were searched for original articles from inception to September 2016. The literature search was made in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. For inclusion, each study had to report epidemiological data on FGIDs in children between 4 and 18 years old and contain standardized outcome based on Rome II, III or IV criteria. The overall quality of included epidemiological studies was evaluated in accordance with Loney's proposal for prevalence studies of health literature. Two reviewers assessed each study for data inclusion and extraction. Discrepancies were reconciled through discussion with seniors. RESULTS: A total of 659 articles were identified from the databases and 16 through manual search. A total of 43 articles fulfilled the eligibility criteria for full-text reading, with 26 remaining to be included in the final analysis. All studies were written in English and published between 2005 and 2016. Eight (30.8%) articles were performed in North America, five (19.2%) in Latin America, five (19.2%) in Europe, seven (27%) in Asia, and one (3.8%) in Africa. Sample size varied between 114 and 99416 subjects, totaling 132600 individuals. Fourteen (53.9%) studies recruited their target samples from schools, 11 (42.3%) from healthcare settings and the remaining one (3.8%) from online panel community. The overall FGID prevalence rates for student samples ranged from 9.9% to 29% to as high as 87% in clinical samples. Cyclic vomiting, irritable bowel syndrome and functional constipation were the most researched conditions, with a prevalence ranging from 0.2% to 6.2%, 0% to 45.1% and 0.5% to 86.9%, respectively. The qualitative appraisal revealed that most of the studies showed average or below average generalizability. CONCLUSION: The heterogeneity of the studies on FGIDs must be improved in order to allow comparison. Improvements should include appropriate sampling of representative population, comparable study setting, and consistent data collection. PMID- 28638233 TI - Esophageal carcinoma originating in the surface epithelium with immunohistochemically proven esophageal gland duct differentiation: A case report. AB - A case of esophageal carcinoma exclusively composed of adenocarcinoma simulating an esophageal gland duct in a 61-year-old man is presented. The tumor arose as a slightly elevated lesion in the middle intrathoracic esophagus. It was almost completely overlaid with non-neoplastic stratified squamous epithelial cells. Beneath the overlying surface epithelium, an adenocarcinoma that was bilayered in structure diffusely invaded both the mucosal and submucosal layers. Although the tumor consisted exclusively of adenocarcinomatous cells, a keratinizing squamous cell carcinoma component was focally observed. The invasive carcinoma was focally continuous with the small area of the surface squamous epithelial layer, which was confirmed to be neoplastic by immunohistochemistry. Morphological and immunohistochemical examinations suggested that the adenocarcinomatous component arose from the esophageal surface epithelium and clearly differentiated into an esophageal gland duct. It is important to consider the possibility of this type of adenocarcinoma when diagnosing a ductal or glandular lesion of the esophagus in small biopsy specimens. PMID- 28638235 TI - Managing health and safety risks: Implications for tailoring health and safety management system practices. AB - As national and international health and safety management system (HSMS) standards are voluntarily accepted or regulated into practice, organizations are making an effort to modify and integrate strategic elements of a connected management system into their daily risk management practices. In high-risk industries such as mining, that effort takes on added importance. The mining industry has long recognized the importance of a more integrated approach to recognizing and responding to site-specific risks, encouraging the adoption of a risk-based management framework. Recently, the U.S. National Mining Association led the development of an industry-specific HSMS built on the strategic frameworks of ANSI: Z10, OHSAS 18001, The American Chemistry Council's Responsible Care, and ILO-OSH 2001. All of these standards provide strategic guidance and focus on how to incorporate a plan-do-check-act cycle into the identification, management and evaluation of worksite risks. This paper details an exploratory study into whether practices associated with executing a risk based management framework are visible through the actions of an organization's site-level management of health and safety risks. The results of this study show ways that site-level leaders manage day-to-day risk at their operations that can be characterized according to practices associated with a risk-based management framework. Having tangible operational examples of day-to-day risk management can serve as a starting point for evaluating field-level risk assessment efforts and their alignment to overall company efforts at effective risk mitigation through a HSMS or other processes. PMID- 28638236 TI - Public Transit Equity Analysis at Metropolitan and Local Scales: A Focus on Nine Large Cities in the US. AB - Recent studies on transit service through an equity lens have captured broad trends from the literature and national-level data or analyzed disaggregate data at the local level. This study integrates these methods by employing a geostatistical analysis of new transit access and income data compilations from the Environmental Protection Agency. By using a national data set, this study demonstrates a method for income-based transit equity analysis and provides results spanning nine large auto-oriented cities in the US. Results demonstrate variability among cities' transit services to low-income populations, with differing results when viewed at the regional and local levels. Regional-level analysis of transit service hides significant variation through spatial averaging, whereas the new data employed in this study demonstrates a block-group scale equity analysis that can be used on a national-scale data set. The methods used can be adapted for evaluation of transit and other modes' transportation service in areas to evaluate equity at the regional level and at the neighborhood scale while controlling for spatial autocorrelation. Transit service equity planning can be enhanced by employing local Moran's I to improve local analysis. PMID- 28638234 TI - Ischemic or toxic injury: A challenging diagnosis and treatment of drug-induced stenosis of the sigmoid colon. AB - A 48-year-old woman was admitted with 15-mo history of abdominal pain, diarrhea and hematochezia, and 5-mo history of defecation difficulty. She had been successively admitted to nine hospitals, with an initial diagnosis of inflammatory bowel disease with stenotic sigmoid colon. Findings from computed tomography virtual colonoscopy, radiography with meglumine diatrizoate, endoscopic balloon dilatation, metallic stent implantation and later overall colonoscopy, coupled with the newfound knowledge of compound Qingdai pill-taking, led to a subsequent diagnosis of ischemic or toxic bowel disease with sigmoid colon stenosis. The patient was successfully treated by laparoscopic sigmoid colectomy, and postoperative pathological examination revealed ischemic or toxic injury of the sigmoid colon, providing a final diagnosis of drug-induced sigmoid colon stenosis. This case highlights that adequate awareness of drug-induced colon stenosis has a decisive role in avoiding misdiagnosis and mistreatment. The diagnostic and therapeutic experiences learnt from this case suggest that endoscopic balloon expansion and colonic metallic stent implantation as bridge treatments were demonstrated as crucial for the differential diagnosis of benign colonic stenosis. Skillful surgical technique and appropriate perioperative management helped to ensure the safety of our patient in subsequent surgery after long-term use of glucocorticoids. PMID- 28638237 TI - Friendships Lost: The Social Consequences of Violent Victimization. AB - Few studies have examined the impact of violent victimization on friendship networks. This study used two waves of data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to examine the effects of violent victimization on number peer- and self-reported friendships. Guided by stigma theory (Goffman, 1963), fixed-effect regression models controlling for depression, delinquency, substance use, and school engagement were completed to predict changes in number of friends following victimization. Consistent with the theory, results indicate that experiencing violent victimization (e.g., jumped, stabbed, shot at) was associated with a decrease in number of friends. These effects were magnified for females and for individuals with a greater number of depressive symptoms. These results were consistent even when models were run separately for each individual type of victimization. Treatment and prevention implications are discussed. PMID- 28638238 TI - A Computational Methodology to Overcome the Challenges Associated With the Search for Specific Enzyme Targets to Develop Drugs Against Leishmania major. AB - We present an approach for detecting enzymes that are specific of Leishmania major compared with Homo sapiens and provide targets that may assist research in drug development. This approach is based on traditional techniques of sequence homology comparison by similarity search and Markov modeling; it integrates the characterization of enzymatic functionality, secondary and tertiary protein structures, protein domain architecture, and metabolic environment. From 67 enzymes represented by 42 enzymatic activities classified by AnEnPi (Analogous Enzymes Pipeline) as specific for L major compared with H sapiens, only 40 (23 Enzyme Commission [EC] numbers) could actually be considered as strictly specific of L major and 27 enzymes (19 EC numbers) were disregarded for having ambiguous homologies or analogies with H sapiens. Among the 40 strictly specific enzymes, we identified sterol 24-C-methyltransferase, pyruvate phosphate dikinase, trypanothione synthetase, and RNA-editing ligase as 4 essential enzymes for L major that may serve as targets for drug development. PMID- 28638239 TI - Using Transfer Learning for Improved Mortality Prediction in a Data-Scarce Hospital Setting. AB - Algorithm-based clinical decision support (CDS) systems associate patient-derived health data with outcomes of interest, such as in-hospital mortality. However, the quality of such associations often depends on the availability of site specific training data. Without sufficient quantities of data, the underlying statistical apparatus cannot differentiate useful patterns from noise and, as a result, may underperform. This initial training data burden limits the widespread, out-of-the-box, use of machine learning-based risk scoring systems. In this study, we implement a statistical transfer learning technique, which uses a large "source" data set to drastically reduce the amount of data needed to perform well on a "target" site for which training data are scarce. We test this transfer technique with AutoTriage, a mortality prediction algorithm, on patient charts from the Beth Israel Deaconess Medical Center (the source) and a population of 48 249 adult inpatients from University of California San Francisco Medical Center (the target institution). We find that the amount of training data required to surpass 0.80 area under the receiver operating characteristic (AUROC) on the target set decreases from more than 4000 patients to fewer than 220. This performance is superior to the Modified Early Warning Score (AUROC: 0.76) and corresponds to a decrease in clinical data collection time from approximately 6 months to less than 10 days. Our results highlight the usefulness of transfer learning in the specialization of CDS systems to new hospital sites, without requiring expensive and time-consuming data collection efforts. PMID- 28638241 TI - Oral Anaerobic Bacteria in the Etiology of Ankylosing Spondylitis. AB - Ankylosing spondylitis (AS) is associated with periodontitis. Anti-Porphyromonas gingivalis and anti-Prevotella intermedia antibody titers were higher in patients with spondyloarthritis than in healthy people. Sulfasalazine is an effective antibiotic treatment for AS. Moxifloxacin and rifamycin were also found to be significantly effective. The etiology hypothesis suggests that oral anaerobic bacteria such as Porphyromonas spp and Prevotella spp contribute to the disease. These bacteria have been identified in AS, and we will discuss their pathogenic properties with respect to our knowledge of the disease. Periodontal pathogens are likely to be responsible for the development of AS in genetically susceptible individuals. This finding should guide the development of more comprehensive and efficacious treatment strategies for AS. PMID- 28638240 TI - Perioperative Management of Neurological Conditions. AB - Perioperative care of the patients with neurological diseases can be challenging. Most important consideration is the management and understanding of pathophysiology of these disorders and evaluation of new neurological changes that occur perioperatively. Perioperative generally refers to 3 phases of surgery: preoperative, intraoperative, and postoperative. We have tried to address few commonly encountered neurological conditions in clinical practice, such as delirium, stroke, epilepsy, myasthenia gravis, and Parkinson disease. In this article, we emphasize on early diagnosis and management strategies of neurological disorders in the perioperative period to minimize morbidity and mortality of patients. PMID- 28638242 TI - Cost-Utility of a Single-Injection Combined Corticosteroid-Hyaluronic Acid Formulation vs a 2-Injection Regimen of Sequential Corticosteroid and Hyaluronic Acid Injections. AB - Research has shown early and sustained relief with a combination therapy of a corticosteroid (CS) and hyaluronic acid (HA) in knee osteoarthritis (OA) patients. This can be administered via a single injection containing both products or as separate injections. The former may be more expensive when considering only product cost, but the latter incurs the additional costs and time of a second procedure. The purpose of this study was to compare the cost utility of the single injection with the 2-injection regimen. The results of this analysis revealed that the single-injection formulation of a CS and HA may be cost-effective, assuming a willingness-to-pay of $50 000 per quality-adjusted life year gained, for symptomatic relief of OA symptoms. This treatment may also be more desirable to patients who find injections to be inconvenient or unpleasant. PMID- 28638243 TI - Subacromial Anesthetics Increase Proprioceptive Deficit in the Shoulder and Elbow in Patients With Subacromial Impingement Syndrome. AB - Shoulder proprioception gives information regarding arm joint position and movement direction. Several studies have investigated shoulder proprioceptive acuity in patients with subacromial impingement syndrome (SIS); however, differences in protocols and between-subjects designs have limited scientific inferences regarding proprioception and SIS. We aimed to determine within-subject differences in shoulder and elbow proprioceptive acuity in 17 patients with stage 2 SIS following treatment of a local anesthetic injection. In addition, we used 17 healthy, age-, sex-, and arm dominance-matched controls to determine the magnitude of differences after treatment. Joint position sense (JPS) was measured before and after treatment in both groups in the sagittal plane for the shoulder and elbow. Our results indicate that patients with SIS have less sensitivity to angular position and tended to overshoot their targets with greater variability during angle-matching tasks for the shoulder (1.8 degrees difference, P = .042) and elbow (5.6 degrees difference, P = .001) than controls. The disparities in JPS found in patients with SIS were not resolved following subacromial injection; in fact, the magnitude of the errors increased after treatment where postinjection errors were significantly greater (P = .046) than controls, with an average difference of 2.4 degrees . These findings suggest that patients with SIS have decrements in either the signaling or processing of proprioceptive information and may use pain to reduce these inequalities. PMID- 28638244 TI - Cardiac Rehabilitation for Patients With Coronary Artery Disease: A Practical Guide to Enhance Patient Outcomes Through Continuity of Care. AB - Coronary artery disease (CAD) is a leading cause of disease burden worldwide. Referral to cardiac rehabilitation (CR) is a class I recommendation for all patients with CAD based on findings that participation can reduce cardiovascular and all-cause mortality, as well as improve functional capacity and quality of life. However, programme uptake remains low, systematic progression through the traditional CR phases is often lacking, and communication between health care providers is frequently suboptimal, resulting in fragmented care. Only 30% to 50% of eligible patients are typically referred to outpatient CR and fewer still complete the programme. In contemporary models of CR, patients are no longer treated by a single practitioner, but rather by an array of health professionals, across multiples specialities and health care settings. The risk of fragmented care in CR may be great, and a concerted approach is required to achieve continuity and optimise patient outcomes. 'Continuity of care' has been described as the delivery of services in a coherent, logical, and timely fashion and which entails 3 specific domains: informational, management, and relational continuity. This is examined in the context of CR. PMID- 28638245 TI - Optical Coherence Tomography Technology and Quality Improvement Methods for Optical Coherence Tomography Images of Skin: A Short Review. AB - Optical coherence tomography (OCT) delivers 3-dimensional images of tissue microstructures. Although OCT imaging offers a promising high-resolution method, OCT images experience some artifacts that lead to misapprehension of tissue structures. Speckle, intensity decay, and blurring are 3 major artifacts in OCT images. Speckle is due to the low coherent light source used in the configuration of OCT. Intensity decay is a deterioration of light with respect to depth, and blurring is the consequence of deficiencies of optical components. In this short review, we summarize some of the image enhancement algorithms for OCT images which address the abovementioned artifacts. PMID- 28638246 TI - Prevalence of Painful Temporomandibular Disorders and Correlation to Lifestyle Factors among Adolescents in Norway. AB - AIM: To estimate the prevalence of painful temporomandibular disorders (TMD-P) among adolescents and to investigate correlations with health, environment, and lifestyle factors. METHODS: For this cross-sectional case-control study, 562 patients were consecutively recruited at their yearly revision control from four dental clinics in Rogaland County, Norway. Patients completed a questionnaire on general health, socioeconomics, demographics, and lifestyle factors. Responses to two screening questions identified patients with TMD-P, who then underwent clinical examination to verify the TMD diagnosis. Pain intensity was assessed on a visual analogue scale. Patients without TMD-P constituted the control group and were not clinically examined. RESULTS: 7% experienced TMD-P. The female-to-male ratio is 3:1; median age is 17 years. Patients at urban clinics had higher prevalence compared with those at rural clinics. TMD-P patients had headache and severe menstrual pain compared to controls. They were more likely to live with divorced/single parents and less likely to have regular physical activity. Myalgia was present in 21 patients with TMD-P, arthralgia in nine, and myalgia and arthralgia in nine. Females had higher pain intensity than males. CONCLUSIONS: A low prevalence of TMD-P was shown but was comparable to other studies. Sex, health, lifestyle, and environment factors were associated with TMD P. PMID- 28638247 TI - Is Sutureless Pancreaticogastrostomy More Effective than Single-Layer Duct-to Mucosa Pancreaticojejunostomy in Pancreaticoduodenectomy? AB - OBJECTIVE: The present study aimed to assess the safety of pancreatic anastomosis after pancreaticoduodenectomy (PD) and to compare the results of sutureless pancreatogastrostomy (PG) with those of single-layer duct-to-mucosa pancreatojejunostomy (PJ) after PD in patients with malignant disease of the pancreatic head and of the periampullary region. MATERIALS AND METHODS: The study included 173 consecutive patients undergoing PD from May 2009 to December 2015 at a single surgical center. Single-layer duct-to-mucosa PJ was performed in 52 patients and sutureless PG in the remaining 123. The primary endpoint was the safety of the procedures, which was assessed as the occurrence of complications during hospitalization. Postoperative pancreatic fistula (POPF) was classified as grade A, B, or C according to the International Study Group of Pancreatic Fistula classification. RESULTS: We found that the incidence of POPF was 11.52%. With regard to POPF, the present study showed no significant difference in the two groups (p=0.043). The incidence of Grade C POPF was significantly higher in the PJ group than in the PG group (p=0.001), which was been reflected in the form of a higher rate of postoperative hemorrhage (p=0.001), intra-abdominal abscess (p=0.012), and septic shock (p=0.012) events in the PJ group. CONCLUSION: The evaluation of short-term outcomes demonstrates that suturelessPG is a feasible and safe technique, associated with lower life-threatening complications than single-layer duct-to-mucosa PJ. If long-term functional outcomes confirm similar results, sutureless PG could become a valid alternative for pancreatic anastomosis after PD in patients with soft pancreas and high morbidity. PMID- 28638248 TI - Evaluation of Microorganisms Causing Ventilator-Associated Pneumonia in a Pediatric Intensive Care Unit. AB - OBJECTIVE: The aim of this study was to identify microorganisms causing ventilator-associated pneumonia (VAP) and also study the antibiotic resistance/susceptibility. MATERIALS AND METHODS: We retrospectively assessed microorganisms isolated from patients diagnosed with VAP in a pediatric intensive care unit between January 1, 2014, and June 30, 2016. RESULTS: We included 44 patients diagnosed with VAP. The prevalence thereof was 8.6 patients per 1,000 ventilator days. Mechanical ventilation was required for 56.5% of patients. Thirty-three patients (75%) died. An underlying chronic disease was detected in 75% of patients (n=33). Fifty microorganisms were isolated from 44 patients. Single microorganisms were isolated from 86.4% (n=38) and two from 13.6% (n=6) of patients. Of all the isolated bacteria, 96% (n=48) were gram-negative; the most common was Pseudomonas aeruginosa (32%), followed by Klebsiella pneumoniae (24%) and Acinetobacter baumannii (22%). The isolates were most susceptible to colistin (92.6%), followed by piperacillin-tazobactam (71.4%), amikacin (65.2%), and gentamicin (52.2%). No enterobacterium or Acinetobacter strain was resistant to colistin; however, 13% of P. aeruginosa isolates were resistant. CONCLUSION: In VAP, it is essential to catalog antibiotic resistance patterns of bacteria present in the unit to ensure that empirical antibiotic therapy is effective. PMID- 28638249 TI - Circulatory Levels of C-X-C Motif Chemokine Ligands 1, 9, and 10 Are Elevated in Patients with Ischemic Stroke. AB - OBJECTIVE: Inflammation plays a significant role in the development of ischemic stroke. CXC chemokines play pleiotropic roles in prolonged leukocyte locomotion, astrocyte migration/activation, and neural attachment/sprouting in response to focal stroke. In this study, we aimed to explore the changes in serum levels of three chemokines, C-X-C motif chemokine ligand 1 (CXCL1), C-X-C motif chemokine ligand 9 (CXCL9), and C-X-C motif chemokine ligand 10 (CXCL10), in ischemic stroke patients at the time of admission and before discharge from the hospital ward. MATERIALS AND METHODS: In this study, we recruited 43 unrelated ischemic stroke patients using an easy convenience method or accidental sampling which is a type of non-probability sampling that involves the sample being drawn from that part of the population that is close to hand. We also enrolled 50 genetically unrelated healthy controls showing no history of neurologic, cardiovascular, or inflammatory diseases. Serum levels of the considered chemokines were measured by enzyme-linked immunosorbent assay (ELISA) in patients and healthy controls. RESULTS: No significant difference was observed in ischemic stroke patients following hospitalization and prior discharging from the hospital; however, there was a significant difference in serum levels of CXCL9 and CXCL10 between patients and healthy controls. We also found that the level of the chemokine was not related to gender or medical therapy. It appears that CXCL9 and CXCL10 are more predisposing factors and play a direct role in stroke considering that they were higher in patients than in healthy controls. CONCLUSION: We believe that this study might be used as a basis for further studies on more effective medication regimens to prevent the onset and subsequent complications of stroke. However, these mediators are useful diagnostic and prognostic tools rather than therapeutic tools. PMID- 28638250 TI - Phacoemulsification and Core Vitrectomy in Fuchs' Heterochromic Uveitis. AB - OBJECTIVE: To evaluate the efficacy of phacoemulsification combined with posterior capsulorhexis, core vitrectomy and ciliary sulcus intraocular lens (IOL) implantation in patients with Fuchs' heterochromic uveitis (FHU). MATERIALS AND METHODS: A total of 18 eyes of 18 patients with FHU underwent cataract surgery were included in the study. 18 eyes with FHU underwent posterior capsulorhexis, core vitrectomy and poly (methyl methacrylate) (PMMA) IOL implantation in the ciliary sulcus. Subjects were chosen for this procedure based on an intraoperative vitreous haziness assessment, performed by indirect ophthalmoscopy. Patients with +2 or more vitreous haziness qualified for this procedure. RESULTS: Of the 83 eyes with FHU that underwent cataract surgery, 18 eyes (21.6%) of 18 patients were employed in the study. There were 11 (61.1%) men and 7 (38.9%) women in the study; ages ranged from 23 to 47, with a mean of 32.06 years. Follow-up ranged from 8 months to 49 months. There were no intraoperative complications except for peripheral iris bleeding in 7 eyes. There was no severe intraocular inflammation in any patient postoperatively. All patients had 0.05 or better logMAR visual acuity after corneal suture removal. Glaucoma developed in 2 patients. For the short term period, the main vision threatening problem was suture-induced astigmatism. CONCLUSION: Cataract surgery combined with posterior capsulorhexis, core vitrectomy and IOL implantation in the ciliary sulcus is safe and leads to good visual outcome due to the removal of the hazy vitreous in patients with FHU. PMID- 28638251 TI - What is the Importance of Body Composition in Obesity-related Depression? AB - OBJECTIVE: It is known that depression is common in obese individuals. Besides the effects of obesity, pathogenic effects of increase in visceral and abdominal fat mass on depression are also being investigated. Our study aimed to show the relationship between visceral fat percentage detected with practical methods and the presence and severity of depression. MATERIALS AND METHODS: Our study included 104 obese patients and 50 healthy controls. In all individuals, the severity of depression was assessed using the Beck Depression Inventory (BDI). Anthropometric measurements, visceral fat percentage, and body fat percentage were measured using the bioelectric impedance method. RESULTS: The mean age was 51.5+/-12.3 years, and 65 participants (62.5%) were women. BDI scores were statistically higher in the obese group than in the control group (23.1+/-10.9 and 12.1+/-9.4, p<0.001). In the obese group, 63.5% of patients were depressed, and in the control group, this was 24%. Women were more depressed in the obese group, but there was no significant difference between men and women in the control group. Body fat percentage was the highest correlating parameter with depression severity. Positive correlation was found between depression severity and body mass index, waist circumference, hip circumference, and visceral fat percentage. In the logistic regression analysis, obesity was found as an independent risk factor for depression (OR: 4.84, 2.1-10.7, p<0.001). CONCLUSION: According to the results of our study, obesity is a significant and independent risk factor for depression. Obesity type and body composition are important factors that determine the severity of depression. PMID- 28638252 TI - Evaluation of the Ki-67 Proliferation Index and Urocortin Expression in Women with Ovarian Endometriomas. AB - OBJECTIVE: The reasons why endometriosis is more aggressive and invasive in some patients are unknown. Despite the importance of population-based clinically defined risk factors in the prediction of recurrence, biochemical markers obtained from the patient are more valuable for prediction on an individual basis. Therefore, the discovery of significant potential biomarkers could be useful to clinicians for shedding light on the pathogenesis of endometriosis and in the monitoring recurrence. MATERIALS AND METHODS: This study included 50 patients who underwent surgery for ovarian cysts that were diagnosed as endometrioma. The age of the patients, stage of the endometriosis, diameter and localization of endometriomas, type of surgery, and pre- and postoperative cancer antigen 125 (CA125) levels were compared between patients with and without recurrence. The archived pathology slides were stained with Ki-67 and anti urocortin antibodies for reevaluation. By comparing the pathology parameters of the patients with and without recurrence, the association between these parameters and recurrence was investigated. RESULTS: The median Ki-67 proliferation index of the patients with recurrence (7.5+/-6.5) was statistically significant compared with that of the patients without recurrence (1+/-4) (p=0.003). The urocortin epithelial staining intensity and percentage were not found to be statistically significant in comparison. A statistically significant difference was determined between postoperative CA125 median levels of patients without recurrence (10+/-17.6) and those of patients with recurrence (29.9+/ 18.1) (p=0.003). CONCLUSION: The Ki-67 proliferation index may be useful for predicting prognosis and recurrence risk. PMID- 28638253 TI - Effects of Vitamin D Therapy on Quality of Life in Patients with Fibromyalgia. AB - OBJECTIVE: The role of vitamin D in the etiopathogenesis of fibromyalgia and non specific musculoskeletal pain is controversial. In our study, we aimed to investigate the effect of vitamin D therapy on quality of life in patients with fibromyalgia. MATERIALS AND METHODS: Seventy patients diagnosed with fibromyalgia and 65 age- and sex-matched controls were included in the study. Patients were grouped as deficient (<20 ng/mL), inadequate (20-30 ng/mL), and sufficient (>30 ng/mL) according to the levels of vitamin D. Vitamin D replacement was performed for patients with deficiencies and inadequacies. Before and after vitamin D therapy, patients filled in the assessment tools, fibromyalgia impact questionnaire (FIQ), Arizona sexual experience scale (ASEX), Beck depression inventory (BDI), visual analog scale (VAS), and short form-36 (SF-36). RESULTS: Vitamin D deficiencies and inadequacies were observed in 60% of the patients (n=42). Among patients with low and normal levels of vitamin D, no statistically significant difference was observed in their values. In scales examined after vitamin D replacement therapy, statistically significant differences were observed in the FIQ, BDI, VAS, and SF-36 compared with pre-treatment. CONCLUSION: Vitamin D deficiency seems to be linked to the pathogenesis of fibromyalgia. Vitamin D supplementation may improve the quality of life in patients with fibromyalgia. PMID- 28638254 TI - Inflammation and Oxidation Biomarkers in Patients with Cystic Fibrosis: The Influence of Azithromycin. AB - OBJECTIVE: In addition to their antibiotic effect, macrolides appear to modulate the inflammatory response in cystic fibrosis (CF) and could influence oxidative stress. The objective of this study was to assess oxidation biomarkers and levels of inflammation and to determine whether there is an association between these parameters and the intake of macrolides. MATERIALS AND METHODS: The subjects included in this cross-sectional study were, on the one hand, clinically stable patients with CF and, on the other, healthy controls. The following serum and plasma inflammatory and oxidative stress biomarkers were measured: interleukin-6 (IL-6), reactive C protein (RCP), tumor necrosis alpha (TNF-alpha), glutathione peroxidase (GPx), total antioxidant capacity (TAC), catalase (CAT), and superoxide dismutase (SOD), together with markers of lipid peroxidation (8 isoprostanes and thiobarbituric acid reactive substances [TBARS]). Clinical, anthropometric, lung function, radiological, and analytical variables (albumin, prealbumin, vitamins, and zinc) were also recorded. RESULTS: We studied 36 adults with CF and 41 controls. No differences were observed in age, gender, or anthropometric variables. The patients had significantly higher levels of IL-6, TNF-alpha, RCP, TBARS, and isoprostanes, and lower levels of SOD than the controls. Twenty-three of the patients were treated with azithromycin, and they had more severe clinical and radiological parameters than those who were not but nevertheless presented significantly lower levels of TNF-alpha. No differences were observed in the markers of oxidation. CONCLUSION: Inflammation and oxidation biomarkers were increased in patients with CF compared with controls. The use of azithromycin was associated with reduced TNF-alpha levels and did not influence oxidation parameters. PMID- 28638255 TI - Sleep Quality and its Association with Disease Severity in Psoriasis. AB - OBJECTIVE: The main purpose of this research was to crosscheck sleep quality in patients with psoriasis with that in healthy individuals and to evaluate a possible relationship between sleep quality and disease severity in these patients. MATERIALS AND METHODS: Fifty-eight patients with plaque psoriasis and 58 age- and gender-matched healthy individuals were included. The Psoriasis Area and Severity Index (PASI) scoring method was used to assess the disease severity in patients with psoriasis. The sleep quality of the participants was evaluated by the Pittsburgh Sleep Quality Index (PSQI). The sleep quality scores of the patients with psoriasis were compared to those of healthy controls. Pearson's correlation test and independent samples t-test and were used to interpret the data. RESULTS: The mean disease duration was 11.1+/-7.4 years (mean+/-standard deviation), and the mean PASI was 14.1+/-5.3. In total, 60% of the patients with psoriasis (n=35) experienced poor sleep quality, and this frequency was considerably higher in the patients with psoriasis than in the healthy controls (p<0.000). Further, the mean PSQI in the patients with psoriasis (7.01+/-41.4) was higher than that in the healthy controls (4.18+/-2.76, p=0.000). The scores of daytime dysfunction, habitual sleep efficiency, and subjective sleep quality, which are the three components of sleep quality, were considerably higher in the patients with psoriasis than in the healthy controls (p=0.007, p=0.032, and p=0.034, respectively). CONCLUSION: Our results showing impaired sleep quality and its association with disease severity in patients with psoriasis may contribute to the management of psoriasis. PMID- 28638256 TI - Comparison of Ultrasonography and Low-Dose Computed Tomography for the Diagnosis of Pediatric Urolithiasis in the Emergency Department. AB - OBJECTIVE: This study aimed to compare ultrasonography (US) and low-dose computed tomography (LDCT) for diagnosing pediatric urolithiasis in the emergency department. MATERIALS AND METHODS: This retrospective study was approved by our institutional ethics committee, and informed consent was waived. From March 2016 to March 2017, 100 consecutive patients met the selection criteria and were enrolled in the study. Patients were randomly selected in a 1:1 ratio and were allocated to one of the following two imaging groups: US or abdominal LDCT. LDCT examinations were performed using a 320-detector row CT. Radiation dose analysis was performed using Radimetrics. US examinations were performed using the Aplio 500 ultrasound system. The presence of urolithiasis, anatomical location of urolithiasis, and measurements of renal stones were evaluated and recorded. RESULTS: There were statistically significant differences between US and standard dose CT (SDCT) with respect to the diagnosis of urolithiasis, anatomical location of urolithiasis, and measurements of renal stones (p<0.001, p=0.005, and p=0.03, respectively). The mean effective radiation dose of LDCT was 1.44+/-0.34 mSv and that of SDCT was calculated to be 4.36+/-1.33 mSv. There was no statistically significant difference between LDCT and SDCT with regard to the diagnosis of urolithiasis, anatomical location of urolithiasis and measurements of renal stones (p=1 for all). The diagnostic accuracy of US and LDCT was 0.68 and 1.0, respectively. CONCLUSION: Low-dose computed tomography had 1/3 SDCT radiation dose, and LDCT and SDCT accurately diagnosed pediatric urolithiasis in the emergency department. US had a lower accuracy than SDCT and LDCT for diagnosing pediatric urolithiasis in the emergency department. LDCT can be an alternative for SDCT for diagnosing pediatric urolithiasis. PMID- 28638257 TI - XRCC1 Gene Polymorphisms and miR-21 Expression in Patients with Colorectal Carcinoma. AB - OBJECTIVE: The objectives of this study were to evaluate the impact of two X-ray repair cross complementing 1 (XRCC1) gene polymorphisms (Arg194Trp and Arg399Gln) on the risk of development of colorectal cancer (CRC) and to assess the expression levels of microRNA-21 (miR-21) in CRC patients. MATERIALS AND METHODS: A case-control cross sectional study was conducted on 50 CRC patients and 50 cancer-free subjects. DNA and miR-21 were extracted from whole blood samples. The expression levels of the XRCC1 polymorphisms and miR-21 were assessed by real time PCR in all subjects of the study. RESULTS: Genotype analysis revealed a significant association between CRC risk and both the Arg194Trp genotype (OR=11.407, 95% CI=4.039-32.221, p<0.001) and the Arg399Gln genotype (OR=3.778, 95% CI= 1.6-8.919, p=0.002). The expression levels of circulating miR-21 were able to detect CRC cases significantly (p=0.022) with a sensitivity of 82% and a specificity of 56% (Area under the curve (AUC)=0.633) but were unable to distinguish between early and late cases (AJCC classification) (p=0.194). CONCLUSION: The XRCC1 Arg194Trp and Arg399Gln polymorphisms both confer high susceptibility for the development of CRC. Circulating miR-21 expression levels are a potentially diagnostic non-invasive genetic marker of CRC. PMID- 28638258 TI - Evacuation of Hospitals during Disaster, Establishment of a Field Hospital, and Communication. AB - The buildings, working personnel, and patients and their relatives may directly or indirectly be affected by the disasters. Here we will discuss evacuation, establishing a field hospital, communication, the role of the media in disasters, and defending against sabotage. The affected individuals should be evacuated and transferred to secure zones safely and rapidly. How the decision for evacuation should be made and how the evacuation triage should be performed are important issues. Field hospitals should be established within the bounds of possibility for continuation of the treatments of evacuated people. The standards for the field hospitals and its sections that may be created according to the needs will be explained. Undoubtedly, since one of the most important subjects in disasters is communication, the types of communication in disasters and their significance will be mentioned. How the relationships with the media should be an aspect of communication and how they can be beneficially used will also be mentioned. As in all organizations and institutions, sabotage attempts may also be present concerning health facilities. For this reason, during the preparation of the hospital disaster plan, defending against sabotage will be discussed, and what should be done at that stage will be mentioned. PMID- 28638259 TI - Global Alert: Zika Virus-an Emerging Arbovirus. AB - Zika virus (ZIKV) is an arbovirus of the Flavivirus genus, and it has an envelope and a single RNA molecule. In early 2016, the World Health Organization declared ZIKV infection to be an emerging global health threat. The major transmission route of the virus to humans is Aedes mosquitoes. ZIKV can be transmitted between humans by transplacental, perinatal, and sexual routes and via blood and body fluids. ZIKV infection usually results in a mild and self-limiting disease with low-grade fever, conjunctivitis, and periorbital edema. Neurological complications such as Guillain-Barre syndrome, meningoencephalitis, acute disseminated encephalomyelitis, acute myelitis, and transverse myelitis have been reported during ZIKV infection. Intrauterine and congenital ZIKV infections have strong teratogenic effects on the fetus. Intrauterine or congenital ZIKV infection can lead to microcephaly, ocular anomalies (such as macular atrophy, pigment mottling, and optic nerve anomalies), and cardiac anomalies (such as atrial or ventricular septal defect). Calcification in the brain between the cortical and subcortical areas, ventriculomegaly, cerebellar hypoplasia, corpus callosum hypoplasia, cortical/subcortical atrophy, delayed myelination, enlarged cisterna magna, and craniofacial disproportion have been reported as brain development defects. ZIKV infection usually results in a mild disease, and it does not require specific therapy. However, complications of infection during the early period of life are serious. Thus, many drugs have been investigated, and vaccine development studies have been conducted to prevent ZIKV infection. Vector control and personal protection from mosquito-borne transmission are important for decreasing the prevalence of ZIKV infection. In particular, pregnant residents or travelers to endemic areas should be carefully protected against mosquito-borne transmission. PMID- 28638261 TI - Coincidence of Polysplenia, Kartagener Syndrome, Dorsal Pancreas Agenesis, and Polycystic Kidney Disease in an Adult. AB - Here we present the case of an adult male patient with the anomalies of polysplenia, Kartagener syndrome, dorsal pancreas agenesis, and adult polycystic kidney disease. Familiarity with this extremely rare coincidence may improve diagnostic accuracy and patient management. PMID- 28638260 TI - Infantile Nephropathic Cystinosis: A Novel CTNS Mutation. AB - Cystinosis is a rare autosomal recessive metabolic disorder characterized by the accumulation of cystine in lysosomes, which results from defects in the carrier mediated transport protein encoded by the CTNS gene. Infantile nephropathic cystinosis (INC) is one of the major complications of cystinosis. It is characterized by findings of Fanconi's syndrome within the first year of life. Here we report two patients with INC presenting with signs of Fanconi's syndrome and describe a novel CTNS mutation. PMID- 28638262 TI - Free-Floating Pigmented Vitreous Cyst. PMID- 28638263 TI - Cutaneous Presentation of Diffuse Large B-Cell Lymphoma. PMID- 28638264 TI - A Severely Encrusted Forgotten Double J Ureteral Catheter. PMID- 28638265 TI - "Steinstrasse" in the Biliary Tract. PMID- 28638266 TI - Nuclear Expression of GS28 Protein: A Novel Biomarker that Predicts Prognosis in Colorectal Cancers. AB - Aims: GS28 (Golgi SNARE protein, 28 kDa), a member of the soluble N ethylmaleimide-sensitive factor attachment protein receptors (SNARE) protein family, plays a critical role in mammalian endoplasmic reticulum (ER)-Golgi or intra-Golgi vesicle transport. To date, few researches on the GS28 protein in human cancer tissues have been reported. In this study, we assessed the prognostic value of GS28 in patients with colorectal cancer (CRC). Methods and results: We screened for GS28 expression using immunohistochemistry in 230 surgical CRC specimens. The CRCs were right-sided and left-sided in 28.3% (65/230) and 71.3% (164/230) of patients, respectively. GS28 staining results were available in 214 cases. Among these, there were 26 nuclear predominant cases and 188 non-nuclear predominant cases. Stromal GS28 expression was noted in 152 cases of CRC. GS28 nuclear predominant immunoreactivity was significantly associated with advanced tumour stage (p = 0.045) and marginally associated with perineural invasion (p = 0.064). Decreased GS28 expression in the stromal cells was significantly associated with lymph node metastasis (N stage; p = 0.036). GS28 expression was not associated with epidermal growth factor receptor (EGFR) immunohistochemical positivity or KRAS mutation status. Investigation of the prognostic value of GS28 with Kaplan-Meier analysis revealed a correlation with overall survival (p = 0.004). Cases with GS28 nuclear predominant expression had significantly poorer overall survival than those with a non-nuclear predominant pattern. Conclusions: Taken together, these results indicate that GS28 nuclear predominant expression could serve as a prognostic marker for CRC and may help in identifying aggressive forms of CRC. PMID- 28638267 TI - Synergistic Antitumor Effect of Sorafenib in Combination with ATM Inhibitor in Hepatocellular Carcinoma Cells. AB - Background: Currently, sorafenib is the only systemic chemotherapy drug for advanced stage Hepatocellular carcinoma (HCC). However, emerging data from some clinical HCC patients indicate that sorafenib alone has only moderate antitumor efficacy, and could not inhibit disease metastasis and progression. KU-55933 is a specific ATM inhibitor, which has pro-apoptotic effect on tumor cells. In this study, we analyzed the synergistic effect of sorafenib and KU-55933 on the proliferation of HCC cell lines. Methods: Three HCC cell lines were treated with sorafenib and KU-55933 alone or combination in vitro to investigate inhibitory effect by MTT and wound healing assay. Epithelial to mesenchymal transition (EMT) phenotype change was investigated after sorafenib and KU-55933 treatment by microscopy. Akt signaling pathway proteins including p-Akt, p-mTOR and p-p70S6K were examined by western blot. In addition, cleaved PARP and autophage-related proteins LC3A/B were detected by western blot. Results: KU-55933 can enhance the effect of sorafenib in inhibiting cell proliferation and migration, overcoming EMT, inducing cell apoptosis via inactivating Akt signaling pathway and inducing autophage. The combination treatment with sorafenib and KU-55933 resulted in a strong synergistic effect in vitro. Conclusion: Our results demonstrate that sorafenib combined with KU-55933 treatment does effectively inhibit proliferation of HCC cell lines synergistically. These data suggests that KU-55933 may be a promising chemosensitizer to sorafenib in the treatment of HCC. PMID- 28638268 TI - KLF6 inhibited oral cancer migration and invasion via downregulation of mesenchymal markers and inhibition of MMP-9 activities. AB - Kruppel-like factors can bind to specific DNA motifs and regulate various cellular functions, such as metabolism, cell proliferation, and differentiation. Kruppel-like factor 6 (KLF6), a member of this family, is downregulated in human cancers. Oral cancer is a highly prevalent type in Taiwan. Although KLF6 overexpression in human cancer cells inhibits cell proliferation, induces apoptosis, and attenuates cell migration, the effects of KLF6 on oral cancer remains poorly elucidated. This study investigated the role of KLF6 in oral cancer tumorigenesis. Immunohistochemical staining revealed that nuclear KLF6 level was significantly and inversely associated with tumor size and stages. KLF6 overexpression attenuated the migration and invasion of oral cancer SAS cells. Zymography assay demonstrated that KLF6 inhibited the activities of matrix metalloproteinase 9 (MMP-9) and weakened the expression of mesenchymal markers, such as snail, slug, and vimentin. Our study is the first to provide demonstrate that KLF6 functions as a tumor suppressor gene and prevents the metastasis of oral cancer cells. PMID- 28638269 TI - Clinical insomnia and associated factors in failed back surgery syndrome: a retrospective cross-sectional study. AB - Background Insomnia frequently occurs to patients with persistent back pain. By worsening pain, mood, and physical functioning, insomnia could lead to the negative clinical consequences of patients with failed back surgery syndrome (FBSS). This retrospective and cross-sectional study aims to identify the risk factors associated with clinical insomnia in FBSS patients. Methods A total of 194 patients with FBSS, who met the study inclusion criteria, were included in this analysis. The Insomnia Severity Index (ISI) was utilized to ascertain the presence of clinical insomnia (ISI score >= 15). Logistic regression analysis evaluates patient demographic factors, clinical factors including prior surgical factors, and psychological factors to identify the risk factors of clinical insomnia in FBSS patients. Results After the persistent pain following lumbar spine surgery worsened, 63.4% of patients reported a change from mild to severe insomnia. In addition, 26.2% of patients met the criteria for clinically significant insomnia. In a multivariate logistic regression analysis, high pain intensity (odds ratio (OR) =2.742, 95% confidence interval (CI): 1.022 - 7.353, P=0.045), high pain catastrophizing (OR=4.185, 95% CI: 1.697 - 10.324, P=0.002), greater level of depression (OR =3.330, 95% CI: 1.127 - 9.837, P=0.030) were significantly associated with clinical insomnia. However, patient demographic factors and clinical factors including prior surgical factors were not significantly associated with clinical insomnia. Conclusions Insomnia should be addressed as a critical part of pain management in FBSS patients with these risk factors, especially in patients with high pain catastrophizing. PMID- 28638270 TI - Existence of a Strong Correlation of Biomarkers and miRNA in Females with Metabolic Syndrome and Obesity in a Population of West Virginia. AB - Objectives: Metabolic syndrome causes complications like cardiovascular disease and type 2 diabetes mellitus (T2DM). As metabolic syndrome develops, altered levels of cytokines and microRNAs (miRNA) are measurable in the circulation. We aimed to construct a panel detecting abnormal levels of cytokines and miRNAs in patients at risk for metabolic syndrome. Methods: Participants included 54 patients from a Family Medicine Clinic at Marshall University School of Medicine, in groups of: Control, Obese, and Metabolic Syndrome (MetS). Results: Serum levels of leptin, adiponectin, leptin: adiponectin ratio, IL-6, six miRNAs (320a, 197-3p, 23-3p, 221-3p, 27a-3p, and 130a-3p), were measured. Among the three groups, leptin, and leptin: adiponectin ratio, and IL-6 levels were highest in MetS, and levels in Obese were greater than Control (p>0.05). Adiponectin levels were lower in Obese compared to Control, but lowest in MetS (p<0.05). MiRNAs levels were lowest in MetS, and levels in Obese were lower than Control (p>0.05). Conclusion: Our results support the clinical application of biomarkers in diagnosing early stage MetS, which will enable attenuation of disease progression before onset of irreversible complications. Since West Virginians are high-risk for developing MetS, our biomarker panel could reduce the disease burden on our population. PMID- 28638272 TI - Bioactivities of ethanol extract from the Antarctic freshwater microalga, Chloromonas sp. AB - Cancer is the principal cause of human death and occurs through highly complex processes that involve the multiple coordinated mechanisms of tumorigenesis. A number of studies have indicated that the microalgae extracts showed anticancer activity in a variety of human cancer cells and can provide a new insight in the development of novel anti-cancer therapy. Here, in order to investigate molecular mechanisms of anticancer activity in the Antarctic freshwater microalga, Chloromonas sp., we prepared ethanol extract of Chloromonas sp. (ETCH) and performed several in vitro assays using human normal keratinocyte (HaCaT) and different types of cancer cells including cervical, melanoma, and breast cancer cells (HeLa, A375 and Hs578T, respectively). We revealed that ETCH had the antioxidant capacity, and caused significant cell growth inhibition and apoptosis of cancer cells in a dose-dependent manner, whereas it showed no anti proliferation to normal cells. In addition, ETCH had a significant inhibitory effect on cell invasion without the cytotoxic effect. Furthermore, ETCH-induced apoptosis was mediated by increase in pro-apoptotic proteins including cleaved caspase-3 and p53, and by decrease in anti-apoptotic protein, Bcl-2 in ETCH treated cancer cells. Taken together, this work firstly explored the antioxidant and anticancer activities of an Antarctic freshwater microalga, and ETCH could be a potential therapeutic candidate in the treatment of human cancer. PMID- 28638271 TI - ProEx C as Diagnostic Marker for Detection of Urothelial Carcinoma in Urinary Samples: A Review. AB - The gold standard for the detection of urothelial carcinoma is represented by urethro-cystoscopy and biopsy. Both procedures are invasive and expensive and therefore cytology is often used as first approach to investigate on a possible neoplasia, being a safe and cost-effective diagnostic modality of evaluation. Because cytology alone is not highly sensitive for detection of low grade urothelial carcinoma and recurrence of the disease, several adjunct markers and urine based tests for urothelial carcinoma have been developed, which can help in the final diagnosis. In particular, ProEx C is an immunohistochemical cocktail containing antibodies direct against topoisomerase IIalpha (TOP2A) and minichromosome maintenance 2 (MCM2) proteins. It proved to be a valid biomarker especially in detecting squamous intraepithelial lesions in cervical liquid-based samples and in discerning these lesions from their mimickers, as well as in ovarian, endometrial, vulvar, primary and metastatic melanomas, breast, pancreatic and renal cell carcinomas. This brief review covers the effective utility of ProEx C as adjunct tool in assessing the urothelial lesions in urine cytology, also providing prognostic and therapeutic information to help in clinical decisions. PMID- 28638273 TI - The Effect of Nefopam Infusion during Laparascopic Cholecystectomy on Postoperative Pain. AB - Background: While recovery from remifentanil is fast due to its rapid metabolism, it can induce hyperalgesia by activation of N-methyl-D-aspartic acid (NMDA) receptors. Therefore, administration of NMDA receptor antagonists such as ketamine is effective in relieving hyperalgesia caused by remifentanil. A previous study showed that nefopam administration before anesthesia combined with low-dose remifentanil reduced pain and analgesic consumption during the immediate postoperative period. We hypothesized that intraoperative infusion of nefopam during laparoscopic cholecystectomy would be as effective as ketamine in controlling pain during the acute postoperative period after sevoflurane and remifentanil based anesthesia. Methods: Sixty patients scheduled to undergo laparoscopic cholecystectomy were randomly divided into three groups. General anesthesia was maintained with sevoflurane and effect-site target concentration of remifentanil (4 ng/ml) in all patients. An intravenous bolus of nefopam (0.3 mg/kg) was given, followed by continuous infusion (65 ug/kg/h) in Group N (n=20). An intravenous bolus of ketamine (0.3 mg/kg) was administered, followed by continuous infusion (180 ug/kg/h) in Group K (n=20), and Group C received a bolus and subsequent infusion of normal saline equal to the infusion received by Group K (n=20). We compared postoperative Visual Analogue Scale (VAS) scores and analgesic requirements over the first 8 postoperative hours between groups. Results: The pain scores (VAS) and fentanyl requirements for 1 h after surgery were significantly lower in the nefopam and ketamine groups compared with the control group (p<0.05). There were no differences between the nefopam and ketamine groups. The three groups showed no differences in VAS scores and number of analgesic injections from 1 to 8 h after surgery. Conclusion: Intraoperative nefopam infusion during laparoscopic cholecystectomy reduced opioid requirements and pain scores (VAS) during the early postoperative period after remifentanil based anesthesia. PMID- 28638274 TI - Hypoxia-regulated MicroRNA-210 Overexpression is Associated with Tumor Development and Progression in Upper Tract Urothelial Carcinoma. AB - BACKGROUND: Hypoxia has been shown to facilitate tumor progression. Hypoxia regulated microRNA-210 (miR-210) may play an important role in carcinogenesis and tumor progression. In this study, we evaluated the clinical significance of miR 210 expression in upper tract urothelial carcinoma (UTUC). METHODS: Eighty-three UTUC patients participated in this study. All of them provided cancer tissue samples and 50 of them provided non-cancerous urothelium samples. Clinicopathologic data were collected by reviewing medical records. The expression of miR-210 and hypoxia-inducible factor-1alpha (HIF-1alpha) was determined by quantitative real-time polymerase chain reaction. The relationship between clinicopathologic variables and the expression of miR-210 and HIF-1alpha was analyzed statistically. RESULTS: MiR-210 is overexpressed in UTUC compared to non-cancerous urothelium (p < 0.001); it is also upregulated in high-stage and high-grade tumors (p = 0.020 and 0.049, respectively). HIF-1alpha is overexpressed in UTUC and correlates positively with miR-210 expression (r = 0.442, p = 0.001). CONCLUSION: Both miR-210 and HIF-1alpha are involved in promoting UTUC carcinogenesis. MiR-210 is also correlated with tumor progression. Further studies are needed to clarify the underlying mechanism. PMID- 28638275 TI - The Application of Dehydroepiandrosterone on Improving Mitochondrial Function and Reducing Apoptosis of Cumulus Cells in Poor Ovarian Responders. AB - Poor ovarian responders (PORs) pose a great challenge for in vitro fertilization (IVF). Previous studies have suggested that dehydroepiandrosterone (DHEA) may improve IVF outcomes in PORs. The current study attempted to investigate the clinical benefits of DHEA in PORs and the possible mechanisms of DHEA on cumulus cells (CCs). This was a prospective study performed at one tertiary center from January 2015 to March 2016. A total of 131 women who underwent IVF treatment participated, including 59 normal ovarian responders (NORs) and 72 PORs. PORs were assigned to receive DHEA supplementation or not before the IVF cycle. For all patients, CCs were obtained after oocyte retrieval. In the CCs, mRNA expression of apoptosis-related genes and mitochondrial transcription factor A (TFAM) gene, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, mitochondrial dehydrogenase activity and mitochondrial mass were measured. The results indicated that PORs with DHEA supplementation produces a great number of top-quality embryos at day 3 and increased the number of transferred embryos and fertilization rate compared with those without DHEA supplementation. Additionally, supplementation with DHEA in PORs decreased DNA damage and apoptosis in CCs while enhancing the mitochondrial mass, mitochondrial dehydrogenase activity and TFAM expression in CCs. In conclusion, our results showed that the benefits of DHEA supplementation on IVF outcomes in PORs were significant, and the effects may be partially mediated by improving mitochondrial function and reducing apoptosis in CCs. PMID- 28638276 TI - Gastric Juice-Based Real-Time PCR for Tailored Helicobacter Pylori Treatment: A Practical Approach. AB - A gastric juice-based real-time polymerase chain reaction (PCR) assay was established to identify Helicobacter pylori infection, clarithromycin susceptibility and human CYP2C19 genotypes and to guide the choice of proton pump inhibitor (PPI), clarithromycin and amoxicillin treatment for tailored H. pylori eradication therapy. From January 2013 to November 2014, 178 consecutive dyspeptic patients were enrolled for collection of gastric biopsy samples and gastric juice by endoscopy at the Peking University Third Hospital; 105 and 73 H. pylori-positive and -negative patients, respectively, were included in this study. H. pylori infection was defined as samples with both a strongly positive rapid urease test (RUT) and positive H. pylori histology. A series of primers and probes were distributed into four reactions for identifying the H. pylori cagH gene coupled with an internal control (Rnase P gene), A2142G and A2143G mutants of the H. pylori 23S rRNA gene, and single-nucleotide polymorphisms (SNPs) G681A of CYP2C19*2 and G636A of CYP2C19*3. The E-test and DNA sequencing were used to evaluate the H. pylori clarithromycin susceptibility phenotype and genotype. The SNPs CYP2C19*2 and CYP2C19*3 were also evaluated by nucleotide sequencing. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of this gastric juice-based real-time PCR assay were evaluated by comparing with the same measures obtained through gastric biopsy based PCR and culture. The H. pylori diagnostic sensitivities of the culture, PCR, and gastric biopsy- and gastric juice-based real-time PCR assays were 90.48% (95/105), 92.38% (97/105), 97.14% (102/105) and 100% (105/105), respectively; the specificities of the above methods were all 100%. Higher false-negative rates were found among the gastric biopsy samples assessed by culture (10.48%, 11/105), PCR (7.62%, 8/105) and real-time PCR (2.86%, 3/105) than in gastric juice by real time PCR. Regarding clarithromycin susceptibility, a concordance of 82.98% (78/94) and discordance of 17.02% (16/94) were observed among the different methods, discrepancies that mainly represent differences between the H. pylori clarithromycin susceptibility phenotype and genotype. Three coinfections of susceptible and resistant strains were detected, with resistant-to-susceptible ratios of 1.16, 3.44, and 8.26. The CYP2C19 genotyping results from gastric juice by real-time PCR were completely in accordance with those obtained from biopsy samples by conventional PCR. This gastric juice-based real-time PCR assay is a more accurate method for detecting H. pylori infection, clarithromycin susceptibility and CYP2C19 polymorphisms. The method may be employed to inform the choice of proton pump inhibitor (PPI), clarithromycin and amoxicillin treatment for tailored H. pylori eradication therapy. PMID- 28638277 TI - Titanium Dioxide Nanoparticles as Radiosensitisers: An In vitro and Phantom-Based Study. AB - Objective: Radiosensitisation caused by titanium dioxide nanoparticles (TiO2-NPs) is investigated using phantoms (PRESAGE(r) dosimeters) and in vitro using two types of cell lines, cultured human keratinocyte (HaCaT) and prostate cancer (DU145) cells. Methods: Anatase TiO2-NPs were synthesised, characterised and functionalised to allow dispersion in culture-medium for in vitro studies and halocarbons (PRESAGE(r) chemical compositions). PRESAGE(r) dosimeters were scanned with spectrophotometer to determine the radiation dose enhancement. Clonogenic and cell viability assays were employed to determine cells survival curves from which the dose enhancement levels "radiosensitisation" are deduced. Results: Comparable levels of radiosensitisation were observed in both phantoms and cells at kilovoltage ranges of x-ray energies (slightly higher in vitro). Significant radiosensitisation (~67 %) of control was also noted in cells at megavoltage energies (commonly used in radiotherapy), compared to negligible levels detected by phantoms. This difference is attributed to biochemical effects, specifically the generation of reactive oxygen species (ROS) such as hydroxyl radicals (*OH), which are only manifested in aqueous environments of cells and are non-existent in case of phantoms. Conclusions: This research shows that TiO2-NPs improve the efficiency of dose delivery, which has implications for future radiotherapy treatments. Literature shows that Ti2O3-NPs can be used as imaging agents hence with these findings renders these NPs as theranostic agents. PMID- 28638278 TI - Lifespan and associated factors of peripheral intravenous Cannula among infants admitted in public hospitals of Mekelle City, Tigray, Ethiopia, 2016. AB - BACKGROUND: Peripheral Intravenous cannula (IV) is the most common vascular access device used to administer medications with the exception of medication or fluid with high or low PH or hyperosmolarity which may cause severe damage to small veins. The insertion of a peripheral intravenous cannula in newborn infants can be difficult. Appropriate veins with sufficient capacity to insert a cannula become less available throughout the hospital stay. Once a peripheral intravenous cannula is inserted, it is desirable that its patency can be maintained as long as possible. This study was aimed to assess the lifespan and associated factors of peripheral intravenous cannula among infants admitted in public hospitals of Mekelle city, Tigray, Ethiopia, 2016. METHODS: The method used was a prospective cohort study. 178 study subjects were recruited using systematic random sampling technique. The data was collected by structured questionairre and observational checklist. RESULTS: More than half of infants (94) had a short cannula lifespan (below 30 h). Multivariable logistic regression analysis showed that Pediatric intensive care unit (PICU) [AOR = 6.93; 95% CI (1.56,30.71)], clinical experience (3-5 years) [AOR = 0.168; 95% CI (0.060-0.469)], insertion site (arm) [AOR = 0.126;95% CI (0.046-0.349)], reason for removal (dislodgement and complication) [AOR = 8.15; 95% CI (2.49,26.63) [AOR = 10.48;95% CI (3.08,35.65)], medication [AOR = 0.17;95% CI (0.37,0.784)], corticosteroids [0.164; 95% CI (0.034,0.793)] and blood transfusion [AOR = 0.12; 95% CI (0.028-0.509)] were the statistically significant variables associated with the lifespan of a peripheral intravenous cannula. CONCLUSIONS: Untimely removal of peripheral intravenous cannulas was higher in infants and demographic. Cannulation and health care factors had significant effects on the lifespan of a peripheral intravenous cannula. PMID- 28638281 TI - From the Editor's Desk: Sailing Into Summer 2017. PMID- 28638280 TI - Anticonvulsant hypersensitivity syndrome after phenytoin administration in an adolescent patient: a case report and review of literature. AB - BACKGROUND: Hypersensitivity is a rare adverse drug reaction (ADR) associated with anti-epileptic medications. Phenytoin is one of the commonly used drugs for treatment of epilepsy that encounters a hypersensitivity reaction. This reaction can be ranged from mild cutaneous rash to anticonvulsant hypersensitivity syndrome (AHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) that includes fever, rash, eosinophilia and involvement of multiple internal organs. CASE PRESENTATION: A 15 year old middle eastern female patient from Gaza strip with free past medical and allergic history. She presented to An-Najah National University Hospital (NNUH) in Nablus with intermittent high grade fever, jaundice, rash and skin peeling. On examination, she had axillary and inguinal lymphadenopathy, moderate splenomegaly and diffuse maculopapular rash. The patient was on phenytoin which started 1 month prior to her presentation as a seizure prophylaxis due to previous head injury. Eventually, the patient was diagnosed with AHS/DRESS. CONCLUSIONS: AHS is a diagnosis of exclusion and it is significantly underreported that requires a high index of suspicion. We liked to share this case and shed the light in more details on AHS/DRESS. Our goal was to help making AHS more reported in the literature in adolescent patients, as well as to make physicians more alert of this condition's seriousness when they prescribe antiepileptic medications in particular. In this report, we included the first case of AHS which was reported in an adolescent patient in Palestine. Moreover, we reviewed the available literature for a better understanding of the pathophysiology and management of AHS. We still believe that the full understanding of the pathogenesis of AHS is lacking, and also we are lacking a clinical tool or scoring system to determine the severity of AHS/DRESS. PMID- 28638282 TI - Transfusion Service Observations: Red Blood Cell Surname-Antibody Pairings. PMID- 28638279 TI - Preventive actions of allergen immunotherapy: the facts and the effects in search of evidence. AB - Allergen immunotherapy (AIT) is the only treatment that works on the causes of allergy. Available AIT nowadays are subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) for allergic rhinitis and asthma, while for allergy to Hymenoptera venom only subcutaneous route is recommended. A bulk of trials and meta-analyses demonstrated that efficacy and safety of AIT in decreasing allergic clinical symptoms and use of rescue medications, while its preventive capacity is yet under investigation. The most important of these effects is the prevention of potentially fatal anaphylactic reactions to Hymenoptera stings by venom immunotherapy (VIT). A certain number of studies thus far available showed that AIT, in both forms, is able to prevent the progress of allergic rhinitis into asthma and the development of new sensitizations. These effects should be related to the mechanisms of action of AIT. In fact, it has been demonstrated that both SCIT and SLIT are able to modify the allergen presentation by dendritic cells, with result in modification of the phenotype of allergen-specific T cells, switching from the typical of allergic inflammation Th2-type response to a Th1-type one. Also allergen-specific T regulatory (Treg) cells play a pivotal role by producing suppressive cytokines, such as IL-10 and TGF-beta. However, the only plain evidence of a preventive effect concerns VIT, while the other outcomes need to be furtherly investigated. PMID- 28638283 TI - Relapsing Pleural Effusion in a Patient on Automated Peritoneal Dialysis. PMID- 28638284 TI - How Much Negative Pressure Are We Generating During Thoracentesis? PMID- 28638285 TI - Clinical Images: Left Atrial Air Embolism Following Computed Tomography-Guided Lung Biopsy. PMID- 28638286 TI - Bioethics in Practice: Ethical Issues in the Care of Transgender Patients. PMID- 28638287 TI - Use of Sodium Hyaluronate/Carboxymethylcellulose Bioresorbable Membrane in Loop Ileostomy Construction Facilitates Stoma Closure. AB - BACKGROUND: Loop ileostomy is a common adjunct to surgical procedures for low rectal cancers and inflammatory bowel disease. Ileostomy closure through a limited incision can be technically challenging. We hypothesized that placing a sodium hyaluronate/carboxymethylcellulose (SH/CMC) bioresorbable membrane at loop ileostomy creation would decrease stoma closure time without increasing morbidity. METHODS: In a retrospective review at a single institution with 6 board-certified colorectal surgeons, patients with loop ileostomy creation and closure between September 1999 and December 2011 were grouped based on SH/CMC placement at ileostomy creation. Data were abstracted for age, sex, body mass index (BMI), primary diagnosis, length of surgery, staff surgeon, interval between surgeries, and postoperative morbidity. The primary endpoint was the length of the surgery for ileostomy closure. Secondary outcome measures were length of stay, wound infection rate, and other complications. RESULTS: A total of 293 patients were identified. Group 1 (with SH/CMC) included 146 patients, and Group 2 (without SH/CMC) included 147 patients. The groups were matched according to age, sex, BMI, interval between creation and closure, and indication for surgery. The average surgical time for closure was significantly shorter in Group 1 (46.4 minutes +/- 2.7) compared to Group 2 (60 minutes +/- 2.3) (P=0.0001). We found no difference between the groups in length of stay, wound infection rate, or complication rate. CONCLUSION: The use of SH/CMC in loop ileostomy creation significantly decreases the operative time required for stoma closure with no increase in the complication rate. PMID- 28638288 TI - Effects of Immunomodulators and Biologic Agents on Sexual Health in Patients With Inflammatory Bowel Disease. AB - BACKGROUND: Although much knowledge has been gained regarding the medical and surgical management of inflammatory bowel disease (IBD), a paucity of information is available on the psychosexual issues related to IBD. The aim of this study was to evaluate the sexual health of patients with IBD who were taking immunomodulators and/or biologic agents vs patients with IBD who were not on that medication regimen. METHODS: All study participants completed a validated sexual health questionnaire, the Female Sexual Function Index or the International Index of Erectile Function, to assess their subjective perception of the effect of IBD on the different domains of sexual function during the prior 1-month time period. RESULTS: No statistically significant differences in any baseline demographic variables were found for either sex between the group taking immunomodulators/biologic agents and the nontreatment group. Among females and males, individual question responses, domain scores, and total scores showed no statistically significant differences between the 2 treatment groups. CONCLUSION: Our data suggest that the use of immunomodulators or biologic agents does not affect female or male sexual health. However, treatment of patients with IBD must be individualized based on the aggressive nature of the disease, treatment goals, and the tolerability of various medications. PMID- 28638289 TI - Diagnosis and Treatment of Hereditary Hemorrhagic Telangiectasia. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disorder known for its debilitating symptoms. More than 90% of patients with HHT experience epistaxis, and they average up to 18 bleeds per month. We review the current literature on the pathophysiology, clinical presentation, and management of HHT. METHODS: We searched MEDLINE, EMBASE, and PubMed and identified 19 articles published since 2000 with current information on HHT. RESULTS: HHT is a disease more commonly associated with significant morbidity rather than mortality. The morbidity of the disease and decreased quality of life are the result of the recurrent and potentially severe epistaxis that the majority of patients with HHT experience. During active epistaxis, the effective emergency techniques of locally applied pressure, nasal packing anteriorly and/or posteriorly, and cauterization are effective. Medical treatment with antiestrogen therapy has shown promising results, but further research is needed to determine the long-term side effects and the limitations of lifelong therapy. Research directed toward bleeding reduction and prevention has yet to have a breakthrough. Although initial reports suggest that intranasal bevacizumab is an effective agent, further research is required. CONCLUSION: Interventional treatments in life-threatening and/or severe circumstances will continue to be used because of their effectiveness. Research into the pathophysiology of HHT has led to the development of potential therapies that prevent and decrease the severity of epistaxis, but the current evidence is insufficient to ascertain best practice. At present, appropriate management of acute epistaxis coupled with early diagnosis and referral to an ear, nose, and throat specialist should be the mainstay of treatment. PMID- 28638292 TI - Combined Oral Contraceptive Pill Initiation in a Patient With Major Depressive Disorder, Premenstrual Dysphoric Disorder, Social Anxiety, Panic Disorder, and Histrionic Personality Disorder. AB - BACKGROUND: Comorbid psychiatric conditions present an added layer of challenge in managing patients, as each condition and associated set of symptoms exacerbate the complexity of the overall presentation. Premenopausal women may be at particular risk for inadequate care, as their comorbid conditions may present overlapping symptoms and mask independent premenstrual symptoms. The prevalence of premenstrual dysphoric disorder and associated conditions can be as high as 8% in women of reproductive age. Recognizing and assessing premenstrual symptoms that are comorbid with other psychiatric conditions can help contribute to a comprehensive treatment strategy and potentially improve the treatment response for the comorbid conditions. Combined oral contraceptive pills (COCPs) have been approved for premenstrual conditions and should be considered by the psychiatrist as an available treatment option. CASE REPORT: A 34-year-old Caucasian female patient with comorbid major depressive disorder, premenstrual dysphoric disorder, social anxiety, panic disorder, and histrionic personality disorder, with persistent suicidal ideation and distress intolerance, was treated with norgestimate-ethinyl estradiol with improvement in mood, anxiety, and menstrual cramping and with associated diminished suicidal ideation and improved distress tolerance. CONCLUSION: In this case, Beck Depression Inventory and Beck Anxiety Inventory scores, as well as self- and peer-reported functionality, all suggested improvement in symptoms following the introduction of COCPs. The neurohormonal contribution to psychiatric conditions continues to be studied and is becoming increasingly important. An understanding of the presence and etiology of premenstrual symptoms should be part of a comprehensive psychiatric assessment of female patients, and consideration of COCPs in the treatment plan adds a potentially potent option for symptom mitigation and remission. PMID- 28638290 TI - Medication-Induced Tardive Dyskinesia: A Review and Update. AB - BACKGROUND: Tardive dyskinesia (TD) is a movement disorder that causes involuntary, repetitive body movements and is commonly seen in patients who are on long-term treatment with antipsychotic medications. However, several other classes of medications with different mechanisms are also associated with TD. METHODS: We conducted a PubMed search using keywords and combined word searches that involved medication-induced TD, as well as agents that are associated with causing or are used to treat medication-induced TD. We attempted to include as many recent (publication date of 2015 and later) articles as possible. RESULTS: The reported incidence of TD seems to be reduced with the use of atypical antipsychotic drugs, yet the risk of developing TD remains with these medications. Furthermore, several other medication classes have a high prevalence of TD and yet are not commonly considered to be TD-inducing. This review highlights the need for a prevention-based focus of TD treatment that starts with a clinical consideration of pharmacologic choices related to each individual patient's history. CONCLUSION: This review offers the information current as of 2016 on the pathophysiology, etiology, and epidemiology of TD, as well as the medications associated with TD, mechanisms of medication-induced TD, and treatments for medication-induced TD. PMID- 28638291 TI - Pain and Psychology-A Reciprocal Relationship. AB - BACKGROUND: Depression typically affects 5% of the general population, but among patients with chronic pain, 30%-45% experience depression. Studies have shown that the relationship between depression and pain is bidirectional: depression is a positive predictor of the development of chronic pain, and chronic pain increases the risk of developing depression. METHODS: This literature review focuses on the relationship between psychology and pain, covering studies that have investigated the association between depression, pain sensitivity, opioid abuse, and gender differences in pain perception. We conducted a PubMed search pairing the word pain with depression, opioid use, and gender differences. RESULTS: The relationship between depression and pain is complex, as suggested by numerous studies that propose depression to be a moderator of the relationship between pain severity, physical functioning, and opioid use. Neuroimaging also suggests an anatomic overlap in the pathway of chronic pain and depression. Positive psychological factors, namely hope, pain acceptance, and optimism, affect the adjustment to persistent pain. CONCLUSION: The intricate relationship between pain and psychology is evidenced by the clinical overlap in their presentations and the overlap between the anatomic regions in the brain associated with the emotional and sensory features of pain and the areas affected by depression. Studies are beginning to improve our understanding of these two systems, but more studies are needed to elucidate the relationship. PMID- 28638294 TI - Persistent Sciatic Artery: A Favorable Anatomic Variant in a Setting of Trauma. AB - BACKGROUND: Persistent sciatic artery (PSA) is a rare congenital anomaly of the circulation of the lower limb that results from the persistence of an artery that normally regresses early in embryonic development. PSA is usually an incidental finding and is exceedingly rare to find bilaterally. CASE REPORT: We present the case of a rare presentation of PSA that resulted in a favorable outcome for a patient who sustained a gunshot wound to his midthigh and discuss the history, embryology, anatomy, classification schema, imaging evaluation, complications, diagnosis, and management of PSA. CONCLUSION: PSAs are of doubtful clinical significance when found incidentally at imaging; however, individual patient symptoms, unique arterial anatomy, and the PSA classification best determine the appropriate treatment options. PMID- 28638293 TI - Septic Embolic Stroke Resulting From Staphylococcus lugdunensis Endocarditis. AB - BACKGROUND: Staphylococcus lugdunensis, a member of the coagulase-negative staphylococci (CoNS), has been recognized as a causal organism for infective endocarditis since the 1980s. Although most CoNS have an insidious and chronic nature, they are involved in a variety of systemic infections. S lugdunensis infective endocarditis is a rare entity but is as catastrophic as Staphylococcus aureus infective endocarditis and requires aggressive antibiotic therapy and, typically, valve replacement. S lugdunensis infective endocarditis-induced septic embolic cerebrovascular accident has rarely been reported in the literature. CASE REPORT: We present the case of a 63-year-old African American man who presented with sudden-onset aphasia and right-sided hemiplegia and was admitted for the management of cerebrovascular accident. Afterwards, he developed a fever and was found to have S lugdunensis bacteremia, with subsequent imaging revealing vegetations of the mitral valve. Despite being treated with culture-appropriate antibiotics, he remained persistently bacteremic and required surgical mitral valve replacement. CONCLUSION: S lugdunensis infective endocarditis is rare but can have a malignant course and requires early surgical intervention in most cases. PMID- 28638295 TI - Eagle Syndrome Secondary to Osteoradionecrosis of the Styloid Process. AB - BACKGROUND: Eagle syndrome is a rare condition caused by elongation of the styloid process or ossification of the stylohyoid ligament. The symptomatology can be vague but may include dysphagia, odynophagia, otalgia, foreign body sensation, facial pain, trismus, headache, tinnitus, increased salivation, and/or voice changes. CASE REPORT: We present the case of a 58-year-old male believed to have acquired Eagle syndrome secondary to osteoradionecrosis of the styloid process following radiation therapy used as adjuvant treatment for a surgically resected pT2N1M0 squamous cell carcinoma of the right tonsil. CONCLUSION: Radiation is a common component of treatment for head and neck cancers. The diagnosis of Eagle syndrome secondary to osteoradionecrosis of the styloid process is an elusive, but important, diagnosis to consider because the condition can be treated successfully. PMID- 28638297 TI - Pediatric Nasal Tip Amputation Successfully Treated with Nonmicrovascular Replantation and Hyperbaric Oxygen Therapy. AB - BACKGROUND: Nasal tip amputation is a rare but difficult problem to manage. Nonmicrovascular nasal tip replantation is a valid and relatively simple repair option for moderate nasal defects, but tissue ischemia and graft failure occur frequently. CASE REPORT: We present the case of a pediatric nasal tip amputation from a dog bite treated with replantation within 5 hours. The 2.5-cm avulsed tip contained skin, cartilage, and mucosa and was replanted as a 3-layer composite graft. Hyperbaric oxygen (HBO) therapy was initiated for 2 weeks postoperatively. The outcome was functionally adequate, and the majority of the native nasal tissue was salvaged. CONCLUSION: HBO therapy can be used after nonmicrovascular nasal tip replantation to improve graft survival and potentially decrease the need for revision surgery. PMID- 28638296 TI - Ultrasound-Guided Percutaneous Cervical and Upper Thoracic Sympathetic Chain Neuromodulation for Upper Extremity Complex Regional Pain Syndrome. AB - BACKGROUND: Complex regional pain syndrome (CRPS) comprises a group of conditions characterized by severe, debilitating pain that is disproportionate to any inciting event and is not distributed in a specific nerve distribution or dermatome. CASE REPORT: A 42-year-old female with a 2-year history of right upper extremity CRPS type I refractory to conventional management underwent an ultrasound-guided and fluoroscopy confirmed percutaneous peripheral nerve stimulation trial with a lead extending from the C6 to the T3 level to cover the cervical and upper thoracic sympathetic chain. The patient subsequently received a permanent ultrasound-guided lead and implantable pulse generator. At 1-month follow-up, the patient's pain intensity had declined from a weekly average of 8/10 to 1/10 on the verbal pain scale with marked improvement in function. The patient continues to be pain-free or experiences only minimal discomfort 7 years after the implant. She experienced no complications and has discontinued all her pain medications since the implant. CONCLUSION: The placement of a peripheral nerve-stimulating electrode resulted in sustained suppression of intractable pain secondary to CRPS. Ultrasonography guidance enabled the nonsurgical minimally invasive percutaneous approach. Use of ultrasonography may improve the safety of the procedure by permitting direct visualization of the related anatomic structures, thereby reducing the risk of injury to the inferior thyroid artery, vertebral artery, esophagus, intervertebral disc, and pleura. PMID- 28638298 TI - Uncertainty of Myocardial Perfusion Imaging in Chest Pain Risk Stratification. AB - BACKGROUND: Chest pain is a common presenting symptom in the emergency department (ED). Although the diagnostic workup for chest pain is well established, the best time to perform invasive cardiac catheterization in patients with low to moderate risk of coronary artery disease is still unclear, particularly if noninvasive tests such as the electrocardiogram (ECG) and nuclear myocardial perfusion scan show nonsignificant findings. CASE REPORT: We present the case of a 52-year-old female who presented to the ED with acute-onset chest pain that had started early in the morning while she was sleeping. She had presented to the ED 2 weeks prior with chest pain, but her ECG and transthoracic echocardiogram were normal, and her myocardial perfusion scan revealed no significant perfusion defect, so she was discharged. During her second ED visit, the patient developed an arrhythmia, diagnosed as supraventricular tachycardia, that was rapidly converted to sinus rhythm with one dose of intravenous adenosine. Because of her persistent chest pain and the arrhythmia, she underwent cardiac catheterization that revealed coronary artery disease with 80% middle left anterior descending artery stenosis. Percutaneous coronary intervention was performed, and the patient's symptoms resolved. CONCLUSION: Chest pain evaluation is challenging for ED physicians, hospitalists, and cardiologists. Although the nuclear myocardial perfusion scan has excellent sensitivity and specificity in ischemic detection, the clinical examination remains the primary determinant of further management. PMID- 28638299 TI - Cannabinoids in Pediatrics. AB - Despite its controversial nature, the use of medical marijuana and cannabis derived medicinal products grows more popular with each passing year. As of November 2016, over 40 states have passed legislation regarding the use of either medical marijuana or cannabidiol products. Many providers have started encountering patients experimenting with cannabis products for a wide range of conditions. While the debate continues regarding these agents for both medicinal and recreational use in the general population, special consideration needs to be made for pediatric use. This review will deliver the history of marijuana use and legislation in the United States in addition to the currently available medical literature to equip pediatric health care providers with resources to provide patients and their parents the best recommendation for safe and appropriate use of cannabis-containing compounds. PMID- 28638300 TI - Characteristics of Pediatric Clinical Interventions Documented by a School of Pharmacy. AB - OBJECTIVES: Documentation of interventions by pharmacists has become a standard of practice in clinical practice sites. Pharmacists' interventions in pediatric practice settings for short periods of time have been reported in the literature. A single study has described faculty and student interventions in the pediatric setting. The objective of this study was to characterize 4 years of interventions by faculty and students of a school of pharmacy that occurred at various pediatric practice sites throughout a state. METHODS: Pharmacy practice faculty and fourth year student pharmacists are required to document clinical interventions during advanced pharmacy practice experiences. Interventions are documented in a single, commercially available, Web-based system. Reports of interventions with cost avoidance at pediatric inpatient and outpatient practice sites throughout a state from 2011 to 2014 were collected and analyzed. Data were sorted based on year, practice site, type, and number of activities and interventions, and estimated cost avoidance. RESULTS: Two full-time faculty members practiced in pediatrics and, on average, 25 students entered interventions at pediatric sites each year. A total of 12,784 interventions were documented by faculty and students over the 4-year period, with students entering 81.8% of the interventions and 69% occurring in the inpatient setting. Total cost avoidance for all 4 years was $1,684,609. The most frequent interventions were patient medication history, patient counseling, allergy information clarified, drug therapy adjusted, and drug information. CONCLUSIONS: Pharmacy faculty and students documented various types of clinical interventions in the inpatient and outpatient pediatric settings and demonstrated a positive impact at pediatric practice sites throughout a state, as well as cost avoidance in the associated healthcare systems. PMID- 28638301 TI - Toxic and Essential Trace Element Content of Commonly Administered Pediatric Oral Medications. AB - OBJECTIVES: The aim of this study was to test the hypothesis that commonly administered pediatric oral medications are a significant source of toxic elements. The concentrations of 16 elements were determined in 14 frequently used pediatric oral medications. METHODS: Samples were prepared for analysis by dilution or nitric acid microwave-assisted digestion and analyzed by inductively coupled plasma mass spectrometry. The intake of each element from administration for 1 week of the medication's maximum recommended daily dose to 6-month-olds was calculated and compared to an exposure guideline for that element. Exposure guidelines used for adverse effects were minimal risk levels, oral reference dose, permissible or permitted daily exposure, provisional tolerable weekly intake, and tolerable upper intake concentrations. Exposure guidelines utilized for desired effect were adequate intake and recommended dietary allowance. RESULTS: Intake of the maximum recommended daily dose by 6-month-olds for 1 week would not deliver more than the exposure guideline of any of the elements, with the exceptions of chromium in several medications and zinc in the pediatric electrolyte solution, if it was consumed for 1 week. CONCLUSIONS: Consumed alone, these frequently administered pediatric oral medications would not deliver amounts of toxic elements that exceed established exposure guidelines for adverse effects, nor would most significantly contribute to adequate intake of essential elements. PMID- 28638302 TI - Extended Stability and Sterility of Antihemophilic Factor Human. AB - OBJECTIVES: Antihemophilic factor human is a factor VIII product used to supplement those with hemophilia. Recent data show treatment benefit and cost saving opportunities if factor products are administered as a continuous infusion rather than conventional bolus dose. This method has not been widely used given the lack of evidence for safe and effective use beyond 3 hours from preparation. The objectives of this study were to determine the physical and chemical stability and sterility of antihemophilic factor human over a 7-day period. METHODS: Antihemophilic factor human was obtained from the manufacturer. Baseline stability and sterility were determined by factor activity levels along with bacterial and fungal cultures. These tests were also evaluated over a span of 7 days at room temperature and under refrigeration. RESULTS: Each sample was inspected at the time of delivery and showed no visible signs of physical changes. Factor activity levels were maintained between 88% and 102% of baseline measurements. No growth was observed for bacterial or fungal cultures in any sample after 4 weeks of incubation. CONCLUSIONS: Antihemophilic factor human maintained physical stability and chemical stability and remained sterile for the 7-day period, allowing extended stability and continuous infusions to be considered. PMID- 28638303 TI - The Use of Gabapentin for Pain and Agitation in Neonates and Infants in a Neonatal ICU. AB - OBJECTIVES: Limited data support how to safely and effectively treat refractory pain and agitation in neonates and infants. Gabapentin has been used in this patient population and has shown promising results, yet there is still a paucity of data about its clinical efficacy. There is a need for a larger evaluation to determine its effectiveness. This study describes one institution's experience with gabapentin for the treatment of refractory pain and agitation in the neonatal intensive care unit (NICU). METHODS: This was a retrospective, observational evaluation of patients who received gabapentin in the level IV NICU at the Cleveland Clinic Children's Hospital. Changes in neonatal pain, agitation, and sedation scale (N-PASS) scores and analgesic and sedative medication requirements were analyzed, as were gabapentin dose requirements and adverse reactions. RESULTS: Between January 2012 and November 2015, 22 patients received gabapentin and were included in this study. The average gabapentin starting dose was 10.2 mg/kg/day, with maximum doses up to 25.5 mg/kg/day. The median N-PASS score at gabapentin therapy initiation was 3.1 and after gabapentin initiation the last N-PASS score documented was 0 in all but 5 patients. Gabapentin use reduced the need for analgesic or sedative medications. The drug was well tolerated, and only 1 patient experienced an adverse reaction to gabapentin (i.e., nystagmus). CONCLUSIONS: Gabapentin was well tolerated and associated with decreases in pain scores. It's use resulted in decreased requirements for analgesic and sedative medications. Gabapentin therapy appears to be an effective option for neonates and infants with refractory pain and agitation. PMID- 28638304 TI - Extended Infusion of Piperacillin/Tazobactam in Children. AB - OBJECTIVES: Extended-infusion piperacillin/tazobactam (TZP) has been associated with positive clinical outcomes in adults, but similar data in children are lacking. The objective of this study was to describe efficacy outcomes with pediatric patients receiving extended-infusion TZP. METHODS: This was a retrospective case series of children aged 1 month to 17 years who had documented Gram-negative infection and received extended-infusion TZP between April 2011 and March 2012. The primary outcome was 21-day clinical cure defined as negative follow-up cultures, where available, and infection resolution. RESULTS: Fifty children with a median (interquartile range [IQR]) age of 5 (2-9) years were included in the study. Patients received a median (IQR) TZP dose of 111.4 (100 112.5) mg/kg administered every 8 hours over 4 hours. Clinical and microbiologic cure were observed in 74% and 100% of patients, respectively. Patients not meeting criterial for 21-day clinical cure were younger (1 vs 7 years, p = 0.087) and had a longer length of hospital stay (23 vs 11 days, p = 0.037). CONCLUSIONS: The majority of children in this cohort achieved 21-day clinical cure with extended-interval TZP. Those without clinical cure tended to be younger and critically ill. Additional comparative studies evaluating traditional and extended-infusion TZP in children are needed. PMID- 28638305 TI - Predictors of Adverse Outcomes in Children With Staphylococcus aureus Bacteremia. AB - OBJECTIVES: Staphylococcus aureus bacteremia is a common infection, associated with significant morbidity and mortality in children. Factors associated with adverse treatment outcomes are poorly understood in the pediatric population. METHODS: Our study compared clinical and microbiologic characteristics of children admitted during a 5-year period (2007-2012) to a large university-based hospital and found to have S aureus bacteremia with outcome measures, in order to identify risk factors associated with treatment failure (defined as 30-day mortality, delayed microbiologic resolution, or recurrence of S aureus bacteremia within 60 days of completing effective antibiotic therapy). RESULTS: In all, 71 patients were found to have S aureus bacteremia, and of these, 17 patients (24%) experienced treatment failure. Based on the logistic regression model, only high vancomycin minimum inhibitory concentration in combination with a high-risk source of infection (i.e., infected graft or device, intra-abdominal infection, or respiratory tract infection) was significantly associated with risk of treatment failure. CONCLUSIONS: Infection associated with a high-risk source may increase the chance of treatment failure in pediatric patients with S aureus bacteremia. Vancomycin minimum inhibitory concentration alone was not found to be a predictor of treatment outcomes. PMID- 28638306 TI - Effect of Maternal Obesity on Maternal-Fetal Transfer of Preoperative Cefazolin at Cesarean Section. AB - OBJECTIVES: American Congress of Obstetricians and Gynecologists recommends a single dose of antibiotic prophylaxis before all cesarean sections (C/S). This recommendation is based on pharmacokinetic studies that include only non-obese patients. We sought to evaluate 1) cefazolin plasma concentrations among obese and non-obese patients after administration of a 2-g cefazolin dose for prevention of surgical wound infections, and 2) whether cefazolin concentration in fetal circulation may be protective against pathogens that cause early onset neonatal sepsis. METHODS: Maternal and fetal cefazolin plasma concentrations were compared between obese (body mass index [BMI] >= 30 kg/m2) and non-obese (BMI < 25 kg/m2) healthy, term pregnant women undergoing scheduled C/S. Liquid chromatographic-tandem mass spectrometric (LC-MS/MS) methods were used for quantification of total and free cefazolin concentrations in maternal blood (MB) and umbilical cord blood (UCB). RESULTS: Eight women were screened and consented. There was no difference between groups in MB total and free cefazolin concentrations. All MB samples had total and free cefazolin concentrations greater than the minimum inhibitory concentration 90 (MIC90) for Group B Streptococcus (GBS), Staphylococcus aureus, and Escherichia coli. All UCB samples had total and free cefazolin concentrations greater than MIC90 for GBS and S aureus, even when administered as briefly as 18 minutes before delivery. A lower concentration of total cefazolin was detected in UCB of neonates of obese women compared to non-obese women (p > 0.05). CONCLUSIONS: Administration of 2 g of cefazolin to women undergoing scheduled C/S might be an adequate prophylactic dose for surgical wound infection in both non-obese and obese patients; and cefazolin concentration in fetal circulation may be protective against GBS and S aureus. PMID- 28638307 TI - Rectal Metyrapone for Treatment of Hypercortisolism in an Infant with McCune Albright Syndrome. AB - Infantile Cushing syndrome is an infrequent yet potentially fatal manifestation of McCune-Albright syndrome, for which there are few safe treatments available. Ketoconazole is limited by potential hepatotoxicity in this population. Metyrapone may be an effective treatment, but it may not be tolerated when given orally. An infant with McCune-Albright syndrome presented with severe Cushing syndrome. Oral metyrapone resulted in feeding refusal, and ketoconazole caused an increase in liver enzymes; however, she was successfully treated with metyrapone given rectally. The patient avoided a feeding tube, and her serum cortisol concentration was lowered to a safe level. Metyrapone given per rectum may be a safe and effective alternative to oral metyrapone in treating young children with Cushing syndrome. PMID- 28638308 TI - Pediatric News. PMID- 28638309 TI - Editor's Introduction to This Issue (G&I 15:2, 2017). PMID- 28638310 TI - Analysis of Gene Expression in Human Dermal Fibroblasts Treated with Senescence Modulating COX Inhibitors. AB - We have previously reported that NS-398, a cyclooxygenase-2 (COX-2)-selective inhibitor, inhibited replicative cellular senescence in human dermal fibroblasts and skin aging in hairless mice. In contrast, celecoxib, another COX-2-selective inhibitor, and aspirin, a non-selective COX inhibitor, accelerated the senescence and aging. To figure out causal factors for the senescence-modulating effect of the inhibitors, we here performed cDNA microarray experiment and subsequent Gene Set Enrichment Analysis. The data showed that several senescence-related gene sets were regulated by the inhibitor treatment. NS-398 up-regulated gene sets involved in the tumor necrosis factor beta receptor pathway and the fructose and mannose metabolism, whereas it down-regulated a gene set involved in protein secretion. Celecoxib up-regulated gene sets involved in G2M checkpoint and E2F targets. Aspirin up-regulated the gene set involved in protein secretion, and down-regulated gene sets involved in RNA transcription. These results suggest that COX inhibitors modulate cellular senescence by different mechanisms and will provide useful information to understand senescence-modulating mechanisms of COX inhibitors. PMID- 28638311 TI - A Variant in RUNX3 Is Associated with the Risk of Ankylosing Spondylitis in Koreans. AB - Ankylosing spondylitis (AS) is a chronic autoinflammatory disease that affects the spine and sacroiliac joints. Regarding its etiology, although HLA-B27 is known to be the strongest genetic factor of AS, much evidence suggests the potential contribution of non-MHC genes to the susceptibility to AS. Most of these non-MHC genes have been discovered in non-Asian populations; however, just some of them have been validated in Koreans. In this study, we aimed to identify additional AS-associated single-nucleotide polymorphism (SNP) candidates by replicating the candidate SNPs in Korean AS patients and healthy controls. For this, we selected three SNPs (rs11249215 in RUNX3, rs6556416 in IL12B, and rs8070463 in TBKBP1), which were previously reported as risk factors of AS but have not been studied in Koreans, and performed genotyping assays using a total of 1138 Korean samples (572 AS patients and 566 healthy controls). Of the three SNP candidates, one SNP in RUNX3 (rs11249215) was significantly associated with the risk of AS (odds ratio, 1.31; 95% confidence interval, 1.02 to 1.68, p = 0.03). These results will be helpful in elucidating the pathogenesis of AS and may be useful for developing AS risk prediction models in Koreans. PMID- 28638312 TI - In Silico Signature Prediction Modeling in Cytolethal Distending Toxin-Producing Escherichia coli Strains. AB - In this study, cytolethal distending toxin (CDT) producer isolates genome were compared with genome of pathogenic and commensal Escherichia coli strains. Conserved genomic signatures among different types of CDT producer E. coli strains were assessed. It was shown that they could be used as biomarkers for research purposes and clinical diagnosis by polymerase chain reaction, or in vaccine development. cdt genes and several other genetic biomarkers were identified as signature sequences in CDT producer strains. The identified signatures include several individual phage proteins (holins, nucleases, and terminases, and transferases) and multiple members of different protein families (the lambda family, phage-integrase family, phage-tail tape protein family, putative membrane proteins, regulatory proteins, restriction-modification system proteins, tail fiber-assembly proteins, base plate-assembly proteins, and other prophage tail-related proteins). In this study, a sporadic phylogenic pattern was demonstrated in the CDT-producing strains. In conclusion, conserved signature proteins in a wide range of pathogenic bacterial strains can potentially be used in modern vaccine-design strategies. PMID- 28638313 TI - Real life pharmaceutical treatment patterns for adult patients with focal epilepsy in Germany: a longitudinal and cross-sectional analysis of recently approved anti-epileptic drugs. AB - Objectives: The aim of this study was to investigate the antiepileptic drug (AED) treatment of adults suffering from focal epilepsies (FE) in Germany. Of special interest was the number and percentage of the patients 16 years and older receiving no treatment with an AED, treatment with one AED (monotherapy), treatment with more than one AED, and treatment with a novel AED. The definition for "novel" was newly approved at the time of market entry since 2006 (last 10 years): eslicarbazepine (ESL), lacosamide (LCM), perampanel (PER), and retigabine (RTG). Methods: The analysis was based on a claims data set covering the years 2007 to 2014, provided by AOK PLUS, a German statutory health insurance. Two patient samples were defined: (1) prevalent patients suffering from FE (at least one in- or outpatient diagnosis of FE and at least one prescription of an AED), and (2) incident FE patients (first in- or outpatient diagnosis of FE without any previous diagnoses/AED prescriptions in the preceding 6 months). Patient observation started at date of first observed inpatient or outpatient focal epilepsy diagnosis within the analyzed period. Each patient was classified as a "no AED therapy", "AED monotherapy" or "more than one AED therapy". Patients were analyzed by number and type of concomitantly prescribed AEDs in yearly tranches (no, one, two, three, four, more than four AEDs; novel versus non-novel AEDs). Results: A total of 34,422 patients diagnosed with FE aged 16 year or older (mean age 59.6 years, 48.7% female) were identified. The mean follow-up period was 1,891 days (5.2 years) since first confirmed diagnosis. The percentage of prevalent patients diagnosed with FE who received one AED (monotherapy) was stable overall and ranged between a minimum of 66.2% (2007) and a maximum of 68.9% (2010). The percentage of patients who received two AEDs ranged from 23.6% (2012) to 25.8% (2007). The remaining patients received therapies with three (6.0% in 2010 to 6.7% in 2007), four (1.0% in 2010 to 1.2% in 2009) or more than four AEDs (0.1% in 2014 to 0.3% in 2013). Between 8.1%-16.6% (2007; 2014) of the patients received no AED therapy in the observed period. In the first year after the diagnosis of FE (incident patients), 9.7% of patients didn't receive any AED therapy. Of those treated with at least one AED, 80.0% received one AED (monotherapy) only, 17.0% received therapy with two AEDs, 2.6% with three AEDs, 0.3% with four AEDs, and 0.1% with >4 AEDs during the respective observation time window and remained stable throughout the four-year follow-up period. Of prevalent patients with a diagnosis of FE, 1,889 (5.5%) received at least one prescription of a novel AED during the observation period; 98.6% of these patients received the novel AED in combination with at least one other AED. Of those patients, 269 (14.2%) received >1 novel AED. The analysis of the patients receiving novel AEDs by the time from the first confirmed diagnosis of FE until the prescription of a novel AED resulted in a mean duration of 4.0 years (SD 2.0) for ESL, 3.6 years (SD 2.2) for LCM, 5.7 years (SD 1.2) for PER, and 4.6 years (SD 0.8 years) for RTG. The mean number of AEDs prescribed before the novel AEDs were 3.2 for ESL, 2.4 for LCM, 5.0 for PER and 5.2 for RTG. Conclusions: Most patients aged 16 years or older, suffering from focal seizures, received AED monotherapy. Novel AEDs were prescribed in a small proportion of patients (<6%) and relatively late in the treatment course. These results are consistent with the recommendations of the German Society for Epileptology (Deutsche Gesellschaft fur Epileptologie, DGfE) which suggests a number of monotherapy options - these options do not include the novel AEDs described in this study. PMID- 28638314 TI - In-person retail marketing claims in tobacco and E-cigarette shops in Southern California. AB - BACKGROUND: E-cigarette use has been increasing in the United States, though knowledge of potential risks and harms associated with e-cigarette use is low. Marketing of e-cigarettes may serve as a source of information to shape beliefs and attitudes toward e-cigarettes. The purpose of this study was to identify the most common marketing claims made within "vape" and tobacco shops in sales interactions with customers in demographically diverse cities. METHODS: Vape and tobacco shops from three diverse cities in Southern California were selected for inclusion in the study. From May 2015 to July 2015, simulated customers asked salespeople in vape and tobacco shops how e-cigarettes compare to conventional cigarettes, and then recorded the resulting claims that were made using a standardized form designed for this purpose. Data were analyzed from January to March 2016. RESULTS: The most frequent claims made by sales staff were that: smoking e-cigarettes helps one quit smoking (57% of the simulated shopping interactions), e-cigarettes come in multiple flavors (54%), and e-cigarettes are healthier than conventional cigarettes (50%). Simulated customer interactions that took place in vape shops included more positive marketing claims than those that occurred in tobacco shops; this relationship approached statistical significance (p = .087). There was a significant relationship between city and the average number of positive e-cigarette claims made (p < .001). CONCLUSIONS: A wide range of marketing claims are made about e-cigarettes in retail settings. These may vary by geographic location, community demographics, and type of retail outlet. PMID- 28638315 TI - Acute Abdomen: A Rare Case of Ruptured Hepatocellular Carcinoma. AB - Spontaneous ruptures of hepatocellular carcinoma (HCC) are rare. Nevertheless they may lead to difficult decisions in the emergency situation. The acute therapies include conservative treatment, transarterial embolization and surgery. Curative treatment of HCC can be achieved by liver resection solely. The decision making depends on prognostic patient's factors, such as hepatic viral infection status, Child-Pugh grade, liver cirrhosis and number of tumors. In this case transarterial embolization was preferable as a bridging therapy prior to further diagnostics and therapy, to lower the perioperative morbidity and mortality. The therapy of these cases needs an interdisciplinary approach to choose the best possible procedure in each case. PMID- 28638316 TI - A New Generation of Brain-Computer Interfaces Driven by Discovery of Latent EEG fMRI Linkages Using Tensor Decomposition. AB - A Brain-Computer Interface (BCI) is a setup permitting the control of external devices by decoding brain activity. Electroencephalography (EEG) has been extensively used for decoding brain activity since it is non-invasive, cheap, portable, and has high temporal resolution to allow real-time operation. Due to its poor spatial specificity, BCIs based on EEG can require extensive training and multiple trials to decode brain activity (consequently slowing down the operation of the BCI). On the other hand, BCIs based on functional magnetic resonance imaging (fMRI) are more accurate owing to its superior spatial resolution and sensitivity to underlying neuronal processes which are functionally localized. However, due to its relatively low temporal resolution, high cost, and lack of portability, fMRI is unlikely to be used for routine BCI. We propose a new approach for transferring the capabilities of fMRI to EEG, which includes simultaneous EEG/fMRI sessions for finding a mapping from EEG to fMRI, followed by a BCI run from only EEG data, but driven by fMRI-like features obtained from the mapping identified previously. Our novel data-driven method is likely to discover latent linkages between electrical and hemodynamic signatures of neural activity hitherto unexplored using model-driven methods, and is likely to serve as a template for a novel multi-modal strategy wherein cross-modal EEG fMRI interactions are exploited for the operation of a unimodal EEG system, leading to a new generation of EEG-based BCIs. PMID- 28638317 TI - Emergence Time and Skin Melanin Spot Patterns Do Not Correlate with Growth Performance, Social Competitive Ability or Stress Response in Farmed Rainbow Trout. AB - In wild salmonid fish, specific individual behavioral traits have been correlated with the timing of fry emergence from their gravel spawning nests; Early emerging fish display more aggressive behavior and have a higher probability of becoming socially dominant, compared to fish that emerge at a later stage. Apart from aggression and dominance, other behavioral and metabolic traits, such as boldness, metabolic rate, or growth, have also been linked to emergence time. Altogether, the traits of early- and late-emerging fish resemble those of the proactive and reactive stress-coping style, respectively. As proactive fish are considered more resilient to stress, it may be desirable to select these for aquaculture production. However, it is currently unclear to what extent the link between emergence time and stress-coping styles is maintained in the selective breeding of farmed fish. In the present study, eyed eggs from a commercial supplier were hatched, and larvae fractionated according to their emergence time. Later on, juvenile fish from different emergence fractions were subjected to a stress challenge and also tested to evaluate their competitive ability for food. Beyond some slight dissimilarities in the acute stress responses, emergence fraction displayed no correlation with growth rates, or the ability to compete for feed. Within the whole group of fish utilized in the experiments, no relationship between skin melanin spot pattern and growth performance, stress response intensity, or competitive ability was found. Altogether, the differences in physiological traits related to emergence time were not as strong as those found in earlier studies. It is hypothesized, that the origin and degree of domestication of the fish might be partly responsible for this. The predictive value of skin spots or emergence time to infer the fish stress coping style in farmed fish is also discussed. PMID- 28638318 TI - Maturation, Behavioral Activation, and Connectivity of Adult-Born Medium Spiny Neurons in a Striatal Song Nucleus. AB - Neurogenesis continues in the adult songbird brain. Many telencephalic song control regions incorporate new neurons into their existing circuits in adulthood. One song nucleus that receives many new neurons is Area X. Because this striatal region is crucial for song learning and song maintenance the recruitment of new neurons into Area X could influence these processes. As an entry point into addressing this possibility, we investigated the maturation and connectivity within the song circuit and behavioral activation of newly generated Area X neurons. Using BrdU birth dating and virally mediated GFP expression we followed adult-generated neurons from their place of birth in the ventricle to their place of incorporation into Area X. We show that newborn neurons receive glutamatergic input from pallial/cortical song nuclei. Additionally, backfills revealed that the new neurons connect to pallidal-like projection neurons that innervate the thalamus. Using in situ hybridization, we found that new neurons express the mRNA for D1- and D2-type dopamine receptors. Employing DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) and EGR-1 (early growth response protein 1) as markers for neural maturation and activation, we established that at 42 days after labeling approximately 80% of new neurons were mature medium spiny neurons (MSNs) and could be activated by singing behavior. Finally, we compared the MSN density in Area X of birds up to seven years of age and found a significant increase with age, indicating that new neurons are constantly added to the nucleus. In summary, we provide evidence that newborn MSNs in Area X constantly functionally integrate into the circuit and are thus likely to play a role in the maintenance and regulation of adult song. PMID- 28638319 TI - Dynamiceuticals: The Next Stage in Personalized Medicine. AB - The surge in the interest in personalized medicine necessitates a corresponding rational approach for implementing such individualized therapies. Dynamiceuticals represents a natural extension of the Pharmaceutical and Electroceutical fields, where the precise determination of the dynamical regimes of the pathophysiology will guide to devise therapies that ameliorate the pathology in a well-controlled manner, thus being precisely tailored toward the implementation of individualized medicine. This approach foretells to lessen side-effects and achieve superior efficacy as compared with current trial-and-error or open-loop strategies. But does the current state of knowledge and technology allow this scheme to offer what it claims? PMID- 28638320 TI - Membrane Fusion Involved in Neurotransmission: Glimpse from Electron Microscope and Molecular Simulation. AB - Membrane fusion is one of the most fundamental physiological processes in eukaryotes for triggering the fusion of lipid and content, as well as the neurotransmission. However, the architecture features of neurotransmitter release machinery and interdependent mechanism of synaptic membrane fusion have not been extensively studied. This review article expounds the neuronal membrane fusion processes, discusses the fundamental steps in all fusion reactions (membrane aggregation, membrane association, lipid rearrangement and lipid and content mixing) and the probable mechanism coupling to the delivery of neurotransmitters. Subsequently, this work summarizes the research on the fusion process in synaptic transmission, using electron microscopy (EM) and molecular simulation approaches. Finally, we propose the future outlook for more exciting applications of membrane fusion involved in synaptic transmission, with the aid of stochastic optical reconstruction microscopy (STORM), cryo-EM (cryo-EM), and molecular simulations. PMID- 28638321 TI - Membrane Guanylate Cyclase catalytic Subdomain: Structure and Linkage with Calcium Sensors and Bicarbonate. AB - Membrane guanylate cyclase (MGC) is a ubiquitous multi-switching cyclic GMP generating signaling machine linked with countless physiological processes. In mammals it is encoded by seven distinct homologous genes. It is a single transmembrane spanning multi-modular protein; composed of integrated blocks and existing in homo-dimeric form. Its core catalytic domain (CCD) module is a common transduction center where all incoming signals are translated into the production of cyclic GMP, a cellular signal second messenger. Crystal structure of the MGC's CCD does not exist and its precise identity is ill-defined. Here, we define it at a sub-molecular level for the phototransduction-linked MGC, the rod outer segment guanylate cyclase type 1, ROS-GC1. (1) The CCD is a conserved 145-residue structural unit, represented by the segment V820-P964. (2) It exists as a homo dimer and contains seven conserved catalytic elements (CEs) wedged into seven conserved motifs. (3) It also contains a conserved 21-residue neurocalcin delta modulated structural domain, V836-L857. (4) Site-directed mutagenesis documents that each of the seven CEs governs the cyclase's catalytic activity. (5) In contrast to the soluble and the bacterium MGC which use Mn2+-GTP substrate for catalysis, MGC CCD uses the natural Mg2+-GTP substrate. (6) Strikingly, the MGC CCD requires anchoring by the Transmembrane Domain (TMD) to exhibit its major (~92%) catalytic activity; in isolated form the activity is only marginal. This feature is not linked with any unique sequence of the TMD; there is minimal conservation in TMD. Finally, (7) the seven CEs control each of four phototransduction pathways- -two Ca2+-sensor GCAPs-, one Ca2+-sensor, S100B-, and one bicarbonate-modulated. The findings disclose that the CCD of ROS-GC1 has built-in regulatory elements that control its signal translational activity. Due to conservation of these regulatory elements, it is proposed that these elements also control the physiological activity of other members of MGC family. PMID- 28638322 TI - Neural Signals Related to Outcome Evaluation Are Stronger in CA1 than CA3. AB - We have shown previously that CA1 conveys significant neural signals necessary to update value of the chosen target, namely chosen value and reward signals. To better understand hippocampal neural processes related to valuation, we compared chosen value- and reward-related neural activity between the CA3 and CA1 regions. Single units were recorded with tetrodes from the dorsal CA3 and CA1 regions of rats performing a dynamic foraging task, and chosen value- and reward-related neural activity was estimated using a reinforcement learning model and multiple regression analyses. Neural signals for chosen value and reward converged in both CA3 and CA1 when a trial outcome was revealed. However, these neural signals were stronger in CA1 than CA3. Consequently, neural signals for reward prediction error and updated chosen value were stronger in CA1 than CA3. Together with our previous finding that CA1 conveys stronger value signals than the subiculum, our results raise the possibility that CA1 might play a particularly important role among hippocampal subregions in evaluating experienced events. PMID- 28638324 TI - Stochastic Signatures of Involuntary Head Micro-movements Can Be Used to Classify Females of ABIDE into Different Subtypes of Neurodevelopmental Disorders. AB - Background: The approximate 5:1 male to female ratio in clinical detection of Autism Spectrum Disorder (ASD) prevents research from characterizing the female phenotype. Current open access repositories [such as those in the Autism Brain Imaging Data Exchange (ABIDE I-II)] contain large numbers of females to help begin providing a new characterization of females on the autistic spectrum. Here we introduce new methods to integrate data in a scale-free manner from continuous biophysical rhythms of the nervous systems and discrete (ordinal) observational scores. Methods: New data-types derived from image-based involuntary head motions and personalized statistical platform were combined with a data-driven approach to unveil sub-groups within the female cohort. Further, to help refine the clinical DSM-based ASD vs. Asperger's Syndrome (AS) criteria, distributional analyses of ordinal score data from Autism Diagnostic Observation Schedule (ADOS) based criteria were used on both the female and male phenotypes. Results: Separate clusters were automatically uncovered in the female cohort corresponding to differential levels of severity. Specifically, the AS-subgroup emerged as the most severely affected with an excess level of noise and randomness in the involuntary head micro-movements. Extending the methods to characterize males of ABIDE revealed ASD-males to be more affected than AS-males. A thorough study of ADOS-2 and ADOS-G scores provided confounding results regarding the ASD vs. AS male comparison, whereby the ADOS-2 rendered the AS-phenotype worse off than the ASD-phenotype, while ADOS-G flipped the results. Females with AS scored higher on severity than ASD-females in all ADOS test versions and their scores provided evidence for significantly higher severity than males. However, the statistical landscapes underlying female and male scores appeared disparate. As such, further interpretation of the ADOS data seems problematic, rather suggesting the critical need to develop an entirely new metric to measure social behavior in females. Conclusions: According to the outcome of objective, data-driven analyses and subjective clinical observation, these results support the proposition that the female phenotype is different. Consequently the "social behavioral male ruler" will continue to mask the female autistic phenotype. It is our proposition that new observational behavioral tests ought to contain normative scales, be statistically sound and combined with objective data-driven approaches to better characterize the females across the human lifespan. PMID- 28638323 TI - Sortilin Fragments Deposit at Senile Plaques in Human Cerebrum. AB - Genetic variations in the vacuolar protein sorting 10 protein (Vps10p) family have been linked to Alzheimer's disease (AD). Here we demonstrate deposition of fragments from the Vps10p member sortilin at senile plaques (SPs) in aged and AD human cerebrum. Sortilin changes were characterized in postmortem brains with antibodies against the extracellular and intracellular C-terminal domains. The two antibodies exhibited identical labeling in normal human cerebrum, occurring in the somata and dendrites of cortical and hippocampal neurons. The C-terminal antibody also marked extracellular lesions in some aged and all AD cases, appearing as isolated fibrils, mini-plaques, dense-packing or circular mature looking plaques. Sortilin and beta-amyloid (Abeta) deposition were correlated overtly in a region/lamina- and case-dependent manner as analyzed in the temporal lobe structures, with co-localized immunofluorescence seen at individual SPs. However, sortilin deposition rarely occurred around the pia, at vascular wall or in areas with typical diffuse Abeta deposition, with the labeling not enhanced by section pretreatment with heating or formic acid. Levels of a major sortilin fragment ~15 kDa, predicted to derive from the C-terminal region, were dramatically elevated in AD relative to control cortical lysates. Thus, sortilin fragments are a prominent constituent of the extracellularly deposited protein products at SPs in human cerebrum. PMID- 28638325 TI - Dopamine, Noradrenaline and Differences in Sexual Behavior between Roman High and Low Avoidance Male Rats: A Microdialysis Study in the Medial Prefrontal Cortex. AB - Roman High- (RHA) and Low-Avoidance (RLA) outbred rats, which differ for a respectively rapid vs. poor acquisition of the active avoidance response in the shuttle-box, display differences in sexual activity when put in the presence of a sexually receptive female rat. Indeed RHA rats show higher levels of sexual motivation and copulatory performance than RLA rats, which persist also after repeated sexual activity. These differences have been correlated to a higher tone of the mesolimbic dopaminergic system of RHA rats vs. RLA rats, revealed by the higher increase of dopamine found in the dialysate obtained from the nucleus accumbens of RHA than RLA rats during sexual activity. This work shows that extracellular dopamine and noradrenaline (NA) also, increase in the dialysate from the medial prefrontal cortex (mPFC) of male RHA and RLA rats put in the presence of an inaccessible female rat and more markedly during direct sexual interaction. Such increases in dopamine (and its main metabolite 3,4 dihydroxyphenylacetic acid, DOPAC) and NA were found in both sexually naive and experienced animals, but they were higher: (i) in RHA than in RLA rats; and (ii) in sexually experienced RHA and RLA rats than in their naive counterparts. Finally, the differences in dopamine and NA in the mPFC occurred concomitantly to those in sexual activity, as RHA rats displayed higher levels of sexual motivation and copulatory performance than RLA rats in both the sexually naive and experienced conditions. These results suggest that a higher dopaminergic tone also occurs in the mPFC, together with an increased noradrenergic tone, which may be involved in the different copulatory patterns found in RHA and RLA rats, as suggested for the mesolimbic dopaminergic system. PMID- 28638326 TI - Commentary: Decoding the Charitable Brain: Empathy, Perspective Taking, and Attention Shifts Differentially Predict Altruistic Giving. PMID- 28638327 TI - Noninvasive Brain Stimulation and Personal Identity: Ethical Considerations. AB - As noninvasive brain stimulation (NIBS) technology advances, these methods may become increasingly capable of influencing complex networks of mental functioning. We suggest that these might include cognitive and affective processes underlying personality and belief systems, which would raise important questions concerning personal identity and autonomy. We give particular attention to the relationship between personal identity and belief, emphasizing the importance of respecting users' personal values. We posit that research participants and patients should be encouraged to take an active approach to considering the personal implications of altering their own cognition, particularly in cases of neurocognitive "enhancement." We suggest that efforts to encourage careful consideration through the informed consent process would contribute usefully to studies and treatments that use NIBS. PMID- 28638328 TI - Protocol for the Reconstructing Consciousness and Cognition (ReCCognition) Study. AB - Important scientific and clinical questions persist about general anesthesia despite the ubiquitous clinical use of anesthetic drugs in humans since their discovery. For example, it is not known how the brain reconstitutes consciousness and cognition after the profound functional perturbation of the anesthetized state, nor has a specific pattern of functional recovery been characterized. To date, there has been a lack of detailed investigation into rates of recovery and the potential orderly return of attention, sensorimotor function, memory, reasoning and logic, abstract thinking, and processing speed. Moreover, whether such neurobehavioral functions display an invariant sequence of return across individuals is similarly unknown. To address these questions, we designed a study of healthy volunteers undergoing general anesthesia with electroencephalography and serial testing of cognitive functions (NCT01911195). The aims of this study are to characterize the temporal patterns of neurobehavioral recovery over the first several hours following termination of a deep inhaled isoflurane general anesthetic and to identify common patterns of cognitive function recovery. Additionally, we will conduct spectral analysis and reconstruct functional networks from electroencephalographic data to identify any neural correlates (e.g., connectivity patterns, graph-theoretical variables) of cognitive recovery after the perturbation of general anesthesia. To accomplish these objectives, we will enroll a total of 60 consenting adults aged 20-40 across the three participating sites. Half of the study subjects will receive general anesthesia slowly titrated to loss of consciousness (LOC) with an intravenous infusion of propofol and thereafter be maintained for 3 h with 1.3 age adjusted minimum alveolar concentration of isoflurane, while the other half of subjects serves as awake controls to gauge effects of repeated neurobehavioral testing, spontaneous fatigue and endogenous rest-activity patterns. PMID- 28638329 TI - The Contribution of Cognitive Factors to Individual Differences in Understanding Noise-Vocoded Speech in Young and Older Adults. AB - Noise-vocoded speech is commonly used to simulate the sensation after cochlear implantation as it consists of spectrally degraded speech. High individual variability exists in learning to understand both noise-vocoded speech and speech perceived through a cochlear implant (CI). This variability is partly ascribed to differing cognitive abilities like working memory, verbal skills or attention. Although clinically highly relevant, up to now, no consensus has been achieved about which cognitive factors exactly predict the intelligibility of speech in noise-vocoded situations in healthy subjects or in patients after cochlear implantation. We aimed to establish a test battery that can be used to predict speech understanding in patients prior to receiving a CI. Young and old healthy listeners completed a noise-vocoded speech test in addition to cognitive tests tapping on verbal memory, working memory, lexicon and retrieval skills as well as cognitive flexibility and attention. Partial-least-squares analysis revealed that six variables were important to significantly predict vocoded-speech performance. These were the ability to perceive visually degraded speech tested by the Text Reception Threshold, vocabulary size assessed with the Multiple Choice Word Test, working memory gauged with the Operation Span Test, verbal learning and recall of the Verbal Learning and Retention Test and task switching abilities tested by the Comprehensive Trail-Making Test. Thus, these cognitive abilities explain individual differences in noise-vocoded speech understanding and should be considered when aiming to predict hearing-aid outcome. PMID- 28638330 TI - Flat vs. Expressive Storytelling: Young Children's Learning and Retention of a Social Robot's Narrative. AB - Prior research with preschool children has established that dialogic or active book reading is an effective method for expanding young children's vocabulary. In this exploratory study, we asked whether similar benefits are observed when a robot engages in dialogic reading with preschoolers. Given the established effectiveness of active reading, we also asked whether this effectiveness was critically dependent on the expressive characteristics of the robot. For approximately half the children, the robot's active reading was expressive; the robot's voice included a wide range of intonation and emotion (Expressive). For the remaining children, the robot read and conversed with a flat voice, which sounded similar to a classic text-to-speech engine and had little dynamic range (Flat). The robot's movements were kept constant across conditions. We performed a verification study using Amazon Mechanical Turk (AMT) to confirm that the Expressive robot was viewed as significantly more expressive, more emotional, and less passive than the Flat robot. We invited 45 preschoolers with an average age of 5 years who were either English Language Learners (ELL), bilingual, or native English speakers to engage in the reading task with the robot. The robot narrated a story from a picture book, using active reading techniques and including a set of target vocabulary words in the narration. Children were post-tested on the vocabulary words and were also asked to retell the story to a puppet. A subset of 34 children performed a second story retelling 4-6 weeks later. Children reported liking and learning from the robot a similar amount in the Expressive and Flat conditions. However, as compared to children in the Flat condition, children in the Expressive condition were more concentrated and engaged as indexed by their facial expressions; they emulated the robot's story more in their story retells; and they told longer stories during their delayed retelling. Furthermore, children who responded to the robot's active reading questions were more likely to correctly identify the target vocabulary words in the Expressive condition than in the Flat condition. Taken together, these results suggest that children may benefit more from the expressive robot than from the flat robot. PMID- 28638331 TI - Monosynaptic Stretch Reflex Fails to Explain the Initial Postural Response to Sudden Lateral Perturbations. AB - Postural reflexes are essential for locomotion and postural stability, and may play an important role in the etiology of chronic back pain. It has recently been theoretically predicted, and with the help of unilateral perturbations of the trunk experimentally confirmed that the sensorimotor control must lower the reflex amplitude for increasing reflex delays to maintain spinal stability. The underlying neuromuscular mechanism for the compensation of postural perturbations, however, is not yet fully understood. In this study, we applied unilateral and bilateral sudden external perturbations to the trunk of healthy subjects and measured the muscular activity and the movement onset of the trunk. We found that the onset of the trunk muscle activity is prior to, or coincident with, the onset of the trunk movement. Additionally, the results of our experiments imply that the muscular response mechanism integrates distant sensory information from both sides of the body. These findings rule out a simple monosynaptic stretch reflex in favor of a more complex polysynaptic postural reflex mechanism to compensate postural perturbations. Moreover, the previously predicted negative correlation between reflex delay and reflex gain was also confirmed for bilateral perturbations. PMID- 28638332 TI - Commentary: Skilled Bimanual Training Drives Motor Cortex Plasticity in Children With Unilateral Cerebral Palsy. PMID- 28638333 TI - Switching Adaptability in Human-Inspired Sidesteps: A Minimal Model. AB - Humans can adapt to abruptly changing situations by coordinating redundant components, even in bipedality. Conventional adaptability has been reproduced by various computational approaches, such as optimal control, neural oscillator, and reinforcement learning; however, the adaptability in bipedal locomotion necessary for biological and social activities, such as unpredicted direction change in chase-and-escape, is unknown due to the dynamically unstable multi-link closed loop system. Here we propose a switching adaptation model for performing bipedal locomotion by improving autonomous distributed control, where autonomous actuators interact without central control and switch the roles for propulsion, balancing, and leg swing. Our switching mobility model achieved direction change at any time using only three actuators, although it showed higher motor costs than comparable models without direction change. Our method of evaluating such adaptation at any time should be utilized as a prerequisite for understanding universal motor control. The proposed algorithm may simply explain and predict the adaptation mechanism in human bipedality to coordinate the actuator functions within and between limbs. PMID- 28638334 TI - Frontal Theta Dynamics during Response Conflict in Long-Term Mindfulness Meditators. AB - Mindfulness meditators often show greater efficiency in resolving response conflicts than non-meditators. However, the neural mechanisms underlying the improved behavioral efficiency are unclear. Here, we investigated frontal theta dynamics-a neural mechanism involved in cognitive control processes-in long-term mindfulness meditators. The dynamics of EEG theta oscillations (4-8 Hz) recorded over the medial frontal cortex (MFC) were examined in terms of their power (MFC theta power) and their functional connectivity with other brain areas (the MFC centered theta network). Using a flanker-type paradigm, EEG data were obtained from 22 long-term mindfulness meditators and compared to those from 23 matched controls without meditation experience. Meditators showed more efficient cognitive control after conflicts, evidenced by fewer error responses irrespective of response timing. Furthermore, meditators exhibited enhanced conflict modulations of the MFC-centered theta network shortly before the response, in particular for the functional connection between the MFC and the motor cortex. In contrast, MFC theta power was comparable between groups. These results suggest that the higher behavioral efficiency after conflicts in mindfulness meditators could be a function of increased engagement to control the motor system in association with the MFC-centered theta network. PMID- 28638335 TI - Quantification of Head Movement Predictability and Implications for Suppression of Vestibular Input during Locomotion. AB - Achieved motor movement can be estimated using both sensory and motor signals. The value of motor signals for estimating movement should depend critically on the stereotypy or predictability of the resulting actions. As predictability increases, motor signals become more reliable indicators of achieved movement, so weight attributed to sensory signals should decrease accordingly. Here we describe a method to quantify this predictability for head movement during human locomotion by measuring head motion with an inertial measurement unit (IMU), and calculating the variance explained by the mean movement over one stride, i.e., a metric similar to the coefficient of determination. Predictability exhibits differences across activities, being most predictable during running, and changes over the course of a stride, being least predictable around the time of heel strike and toe-off. In addition to quantifying predictability, we relate this metric to sensory-motor weighting via a statistically optimal model based on two key assumptions: (1) average head movement provides a conservative estimate of the efference copy prediction, and (2) noise on sensory signals scales with signal magnitude. The model suggests that differences in predictability should lead to changes in the weight attributed to vestibular sensory signals for estimating head movement. In agreement with the model, prior research reports that vestibular perturbations have greatest impact at the time points and during activities where high vestibular weight is predicted. Thus, we propose a unified explanation for time-and activity-dependent modulation of vestibular effects that was lacking previously. Furthermore, the proposed predictability metric constitutes a convenient general method for quantifying any kind of kinematic variability. The probabilistic model is also general; it applies to any situation in which achieved movement is estimated from both motor signals and zero-mean sensory signals with signal-dependent noise. PMID- 28638336 TI - Emphysematous Pyelonephritis and Cystitis: Unusual Adverse Events during Concurrent Chemoradiotherapy for Lung Cancer. AB - Various adverse events can occur during antineoplastic therapy. A 67-year-old diabetic woman developed an emphysematous urinary tract infection (UTI) associated with chemoradiotherapy for lung cancer. She had received weekly carboplatin plus paclitaxel with thoracic radiotherapy and developed a fever on day 19. Computed tomography showed a large quantity of gas within the urinary tract. She was therefore diagnosed with emphysematous UTI. Poor diabetes control due to the weekly administration of dexamethasone, an existing urinary tract obstruction, and bone marrow suppression were involved in her serious infection. The potential development of emphysematous UTI during chemoradiotherapy should be considered in at-risk patients. PMID- 28638337 TI - Intravitreal Anti-Vascular Endothelial Growth Factor for Macular Edema due to Complex Retinal Arterial Macroaneurysms. AB - INTRODUCTION: Complex retinal arterial macroaneurysms (RAM) are often accompanied by hemorrhage and/or affect the macula. We evaluated the effect of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy using ranibizumab or aflibercept with or without laser photocoagulation in the treatment of macular edema due to RAM. METHODS: A case report of two patients with secondary macular edema caused by RAM is presented. The first case was a 76-year-old female treated with two 0.5-mg injections of ranibizumab and additional focal laser photocoagulation. This patient presented a solely intraretinal exudation. The second patient was a 96-year-old female, who received one 2.0-mg injection of aflibercept. She showed sub- and intraretinal edema. We documented the clinical courses of these patients based on fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography. Patients were followed-up for 12 months. RESULTS: Patients were treated successfully using anti-VEGF therapy (ranibizumab or aflibercept) with or without laser photocoagulation. In both cases, we observed a complete regression of the macular edema and an increase in visual acuity. CONCLUSION: RAM can manifest with heterogeneous findings. Intravitreal anti-VEGF therapy with or without laser photocoagulation may be an effective treatment option in cases of macular edema due to RAM. Aflibercept and ranibizumab seem to be a potent anti-VEGF therapy for RAM. Individualized patient care is needed. PMID- 28638338 TI - Physical Exercise with Music Reduces Gray and White Matter Loss in the Frontal Cortex of Elderly People: The Mihama-Kiho Scan Project. AB - Findings from previous studies suggest that physical exercise combined with cognitive training produces more positive effects on cognitive function in elderly people than physical exercise alone. However, the brain plasticity associated with these proposed benefits of combined therapy has not yet been investigated in elderly subjects. We hypothesized that the dual task group would experience greater benefits than the physical exercise alone and non-exercise control groups with regard to both cognitive function and brain plasticity. This study investigated the effect of physical exercise with musical accompaniment on structural brain changes in healthy elderly people. Fifty-one participants performed physical exercise (once a week for an hour with professional trainers) with musical accompaniment (ExM), 61 participants performed the same exercise without music (Ex), and 32 participants made up the non-exercise group (Cont). After the 1-year intervention, visuospatial functioning of the ExM but not the Ex group was significantly better than that of the Cont group. Voxel-based morphometry analyses revealed that the ExM group showed greater right superior frontal gyrus volume and preserved volumes of the right anterior cingulate gyrus, left superior temporal gyrus, and insula. These results indicate that compared with exercise alone, physical exercise with music induces greater positive effects on cognitive function and leads to subtle neuroanatomical changes in the brains of elderly people. Therefore, physical exercise with music may be a beneficial intervention to delay age-related cognitive decline. PMID- 28638340 TI - Neurologically Potent Molecules from Crataegus oxyacantha; Isolation, Anticholinesterase Inhibition, and Molecular Docking. AB - Crataegus oxyacantha is an important herbal supplement and famous for its antioxidant potential. The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer's disease. The compounds isolated from C. oxyacantha were evaluated for cholinesterases inhibitory activity using Ellman's assay with Galantamine as standard drug. Total of nine (1-9) compounds were isolated. Compounds 1 and 2 were isolated for the first time from natural source. Important natural products like beta-Sitosterol-3-O-beta-D-Glucopyranoside (3), lupeol (4), beta-sitosterol (5), betulin (6), betulinic acid (7), oleanolic acid (8), and chrysin (9) have also been isolated from C. oxyacantha. Overall, all the compounds exhibited an overwhelming acetylcholinesterase (AChE) inhibition potential in the range 5.22 44.47 MUM. The compound 3 was prominent AChE inhibitor with IC50 value of 5.22 MUM. Likewise, all the compounds were also potent in butyrylcholinesterase (BChE) inhibitions with IC50s of up to 0.55-15.36 MUM. All the compounds, except 3, were selective toward BChE. Mechanism of the inhibition of both the enzymes were further studied by docking procedures using Genetic Optimization for Ligand Docking suit v5.4.1. Furthermore, computational blood brain barrier prediction of the isolated compounds suggest that these are BBB+. PMID- 28638341 TI - Herbal Medicine AC591 Prevents Oxaliplatin-Induced Peripheral Neuropathy in Animal Model and Cancer Patients. AB - Oxaliplatin is clinically compelling because of severe peripheral neuropathy. The side effect can result in dosage reductions or even cessation of chemotherapy, and no effective treatments are available. AC591 is a standardized extract of Huangqi Guizhi Wuwu decoction, an herbal formula recorded in "Synopsis of the Golden Chamber" for improving limb numbness and pain. In this study, we investigated whether AC591 could protect against oxaliplatin-induced peripheral neuropathy. To clarify it, a rat model of oxaliplatin-induced peripheral neuropathy was established, and neuroprotective effect of AC591 was studied. Our results showed that pretreatment with AC591 reduced oxaliplatin-induced cold hyperalgesia, mechanical allodynia as well as morphological damage of dorsal root ganglion. Microarray analysis indicated the neuroprotective action of AC591 depended on the modulation of multiple molecular targets and pathways involved in the downregulation of inflammation and immune response. Moreover, AC591 enhanced the antitumor activity of oxaliplatin to some extent in Balb/c mice bearing CT-26 carcinoma cells. The efficacy of AC591 is also investigated in 72 colorectal cancer patients. After four cycles of treatment, the percentage of grades 1-2 neurotoxicity in AC591-treated group (n = 36) was 25%, whereas in the control group the incidence was 55.55% (P < 0.01) (n = 36). No significant differences in the tumor response rate between the two groups were found. These evidences suggested that AC591 can prevent oxaliplatin-induced neuropathy without reducing its antitumor activity, and may be a promising adjuvant to alleviate sensory symptoms in clinical practice. PMID- 28638339 TI - Nutritional and Pharmacological Strategies to Regulate Microglial Polarization in Cognitive Aging and Alzheimer's Disease. AB - The study of microglia, the immune cells of the brain, has experienced a renaissance after the discovery of microglia polarization. In fact, the concept that activated microglia can shift into the M1 pro-inflammatory or M2 neuroprotective phenotypes, depending on brain microenvironment, has completely changed the understanding of microglia in brain aging and neurodegenerative diseases. Microglia polarization is particularly important in aging since an increased inflammatory status of body compartments, including the brain, has been reported in elderly people. In addition, inflammatory markers, mainly derived from activated microglia, are widely present in neurodegenerative diseases. Microglial inflammatory dysfunction, also linked to microglial senescence, has been extensively demonstrated and associated with cognitive impairment in neuropathological conditions related to aging. In fact, microglia polarization is known to influence cognitive function and has therefore become a main player in neurodegenerative diseases leading to dementia. As the life span of human beings increases, so does the prevalence of cognitive dysfunction. Thus, therapeutic strategies aimed to modify microglia polarization are currently being developed. Pharmacological approaches able to shift microglia from M1 pro-inflammatory to M2 neuroprotective phenotype are actually being studied, by acting on many different molecular targets, such as glycogen synthase kinase-3 (GSK3) beta, AMP-activated protein kinase (AMPK), histone deacetylases (HDACs), etc. Furthermore, nutritional approaches can also modify microglia polarization and, consequently, impact cognitive function. Several bioactive compounds normally present in foods, such as polyphenols, can have anti-inflammatory effects on microglia. Both pharmacological and nutritional approaches seem to be promising, but still need further development. Here we review recent data on these approaches and propose that their combination could have a synergistic effect to counteract cognitive aging impairment and Alzheimer's disease (AD) through immunomodulation of microglia polarization, i.e., by driving the shift of activated microglia from the pro-inflammatory M1 to the neuroprotective M2 phenotype. PMID- 28638343 TI - Editorial: Biomarkers in Drug Hypersensitivity. PMID- 28638344 TI - The Beneficial Effects of Bisphosphonate-enoxacin on Cortical Bone Mass and Strength in Ovariectomized Rats. AB - Osteoporosis is a major age-related bone disease characterized by low bone mineral density and a high risk of fractures. Bisphosphonates are considered as effective agents treating osteoporosis. However, long-term use of bisphosphonates is associated with some serious side effects, which limits the widespread clinical use of bisphosphonates. Here, we demonstrate a novel type of bone targeting anti-resorptive agent, bisphosphonate-enoxacin (BE). In this study, ovariectomized rat model was established and treated with PBS, zoledronate (50 MUg/kg) and different dose of BE (5 mg/kg and 10 mg/kg), respectively. The rats subjected to sham-operation and PBS treatment were considered as control group. Then, micro-computed tomography scanning, biomechanical tests, nano-indentation test and Raman analysis were used to compare the effects of zoledronate and BE on cortical bone mass, strength, and composition in ovariectomized rats. We found that both zoledronate and BE were beneficial to cortical bone strength. Three point bending and nano-indentation tests showed that zoledronate- and BE-treated groups had superior general and local biomechanical properties compared to the ovariectomized groups. Interestingly, it seemed that BE-treated group got a better biomechanical property than the zoledronate-treated group. Also, BE treated group showed significantly increased proteoglycan content compared with the zoledronate-treated group. We hypothesized that the increased bone strength and biomechanical properties was due to altered bone composition after treatment with BE. BE, a new bone-targeting agent, may be considered a more suitable anti resorptive agent to treat osteoporosis and other bone diseases associated with decreased bone mass. PMID- 28638342 TI - Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study. AB - Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET(r) Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269 965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics. PMID- 28638345 TI - Heterogeneity and Developmental Connections between Cell Types Inhabiting Teeth. AB - Every tissue is composed of multiple cell types that are developmentally, evolutionary and functionally integrated into the unit we call an organ. Teeth, our organs for biting and mastication, are complex and made of many different cell types connected or disconnected in terms of their ontogeny. In general, epithelial and mesenchymal compartments represent the major framework of tooth formation. Thus, they give rise to the two most important matrix-producing populations: ameloblasts generating enamel and odontoblasts producing dentin. However, the real picture is far from this quite simplified view. Diverse pulp cells, the immune system, the vascular system, the innervation and cells organizing the dental follicle all interact, and jointly participate in transforming lifeless matrix into a functional organ that can sense and protect itself. Here we outline the heterogeneity of cell types that inhabit the tooth, and also provide a life history of the major populations. The mouse model system has been indispensable not only for the studies of cell lineages and heterogeneity, but also for the investigation of dental stem cells and tooth patterning during development. Finally, we briefly discuss the evolutionary aspects of cell type diversity and dental tissue integration. PMID- 28638347 TI - Bile Acids Do Not Contribute to the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis. AB - Previously, we have found that intracellular calcium homeostasis is altered in platelets from an experimental model of liver cirrhosis, the bile-duct ligated (BDL) rat; these alterations are compatible with the existence of a hypercoagulable state and related to an enhanced intracellular calcium release evoked by thrombin and an increased amount of calcium stored in the intracellular organelles. In the present study we have investigated the role of bile acids in those alterations of the BDL cirrhotic model. Cholic acid (CA) or deoxycholic acid (DCA) did not change P-selectin expression or platelet aggregation in any group but elevated baseline platelet calcium levels. Incubation with both bile acids reduced calcium release after stimulation with thrombin in the absence of extracellular calcium. Pretreatment with CA but not with DCA reduced significantly thrombin-induced calcium entry in all three experimental groups. The capacitative calcium entry was also significantly lower in platelets pretreated with both bile acids. The simultaneous addition of thapsigargin and ionomycin to estimate the total amount of calcium in platelet internal stores was decreased by pretreatment with both CA and DCA, although these changes were significantly different in the control rats only with CA and in the BDL platelets with DCA. These results indicate that CA and DCA reduce calcium movements in platelets of control and BDL animals, thus suggesting that bile acids do not participate in the alterations observed in the BDL cirrotic model. PMID- 28638348 TI - The Redox Balance in Erythrocytes, Plasma, and Periosteum of Patients with Titanium Fixation of the Jaw. AB - Titanium miniplates and screws are commonly used for fixation of jaw fractured or osteotomies. Despite the opinion of their biocompatibility, in clinical practice symptoms of chronic inflammation around the fixation develop in some patients, even many years after the application of miniplates and screws. The cause of these complications is still an unanswered question. Taking into account that oxidative stress is one of the toxic action of titanium, we have evaluated the antioxidant barrier as well as oxidative stress in the erythrocytes, plasma and periosteum covering the titanium fixation of the jaw. The study group was composed of 32 patients aged 20-30 with inserted miniplates and screws. The antioxidant defense: catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase-1 (SOD1), uric acid (UA), total antioxidant capacity (TAC), as well as oxidative damage products: advanced oxidation protein products (AOPP), advanced glycation end products (AGE), dityrosine, kynurenine, N-formylkynurenine, tryptophan, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), total oxidant status (TOS), and oxidative status index (OSI) were evaluated. SOD1 activity (?37%), and tryptophan levels (?34%) showed a significant decrease while AOPP (?25%), TOS (?80%) and OSI (?101%) were significantly elevated in maxillary periosteum of patients who underwent bimaxillary osteotomies as compared to the control group. SOD-1 (?55%), TAC (?58.6%), AGE (?60%) and N-formylkynurenine (?34%) was statistically reduced while AOPP (?38%), MDA (?29%), 4-HNE (?114%), TOS (?99%), and OSI (?381%) were significantly higher in the mandibular periosteum covering miniplates/screw compared with the control tissues. There were no correlations between antioxidants and oxidative stress markers in the periosteum of all patients and the blood. As exposure to the Ti6Al4V titanium alloy leads to disturbances of redox balance in the periosteum surrounding titanium implants of the maxilla and the mandible so antioxidant supplementation should be recommended to the patients undergoing treatment of dentofacial deformities with the use of titanium implants. The results we obtained may also indicate a need to improve the quality of titanium jaw fixations through increase of TiO2 passivation layer thickness or to develop new, the most highly biodegradable materials for their production. PMID- 28638349 TI - Cardiorespiratory Coordination in Repeated Maximal Exercise. AB - Increases in cardiorespiratory coordination (CRC) after training with no differences in performance and physiological variables have recently been reported using a principal component analysis approach. However, no research has yet evaluated the short-term effects of exercise on CRC. The aim of this study was to delineate the behavior of CRC under different physiological initial conditions produced by repeated maximal exercises. Fifteen participants performed 2 consecutive graded and maximal cycling tests. Test 1 was performed without any previous exercise, and Test 2 6 min after Test 1. Both tests started at 0 W and the workload was increased by 25 W/min in males and 20 W/min in females, until they were not able to maintain the prescribed cycling frequency of 70 rpm for more than 5 consecutive seconds. A principal component (PC) analysis of selected cardiovascular and cardiorespiratory variables (expired fraction of O2, expired fraction of CO2, ventilation, systolic blood pressure, diastolic blood pressure, and heart rate) was performed to evaluate the CRC defined by the number of PCs in both tests. In order to quantify the degree of coordination, the information entropy was calculated and the eigenvalues of the first PC (PC1) were compared between tests. Although no significant differences were found between the tests with respect to the performed maximal workload (Wmax), maximal oxygen consumption (VO2 max), or ventilatory threshold (VT), an increase in the number of PCs and/or a decrease of eigenvalues of PC1 (t = 2.95; p = 0.01; d = 1.08) was found in Test 2 compared to Test 1. Moreover, entropy was significantly higher (Z = 2.33; p = 0.02; d = 1.43) in the last test. In conclusion, despite the fact that no significant differences were observed in the conventionally explored maximal performance and physiological variables (Wmax, VO2 max, and VT) between tests, a reduction of CRC was observed in Test 2. These results emphasize the interest of CRC evaluation in the assessment and interpretation of cardiorespiratory exercise testing. PMID- 28638346 TI - MicroRNAs in Muscle: Characterizing the Powerlifter Phenotype. AB - Powerlifters are the epitome of muscular adaptation and are able to generate extreme forces. The molecular mechanisms underpinning the significant capacity for force generation and hypertrophy are not fully elucidated. MicroRNAs (miRs) are short non-coding RNA sequences that control gene expression via promotion of transcript breakdown and/or translational inhibition. Differences in basal miR expression may partially account for phenotypic differences in muscle mass and function between powerlifters and untrained age-matched controls. Muscle biopsies were obtained from m. vastus lateralis of 15 national level powerlifters (25.1 +/ 5.8 years) and 13 untrained controls (24.1 +/- 2.0 years). The powerlifters were stronger than the controls (isokinetic knee extension at 60 degrees /s: 307.8 +/- 51.6 Nm vs. 211.9 +/- 41.9 Nm, respectively P < 0.001), and also had larger muscle fibers (type I CSA 9,122 +/- 1,238 vs. 4,511 +/- 798 MUm2p < 0.001 and type II CSA 11,100 +/- 1,656 vs. 5,468 +/- 1,477 MUm2p < 0.001). Of the 17 miRs species analyzed, 12 were differently expressed (p < 0.05) between groups with 7 being more abundant in powerlifters and five having lower expression. Established transcriptionally regulated miR downstream gene targets involved in muscle mass regulation, including myostatin and MyoD, were also differentially expressed between groups. Correlation analysis demonstrates the abundance of eight miRs was correlated to phenotype including peak strength, fiber size, satellite cell abundance, and fiber type regardless of grouping. The unique miR expression profiles between groups allow for categorization of individuals as either powerlifter or healthy controls based on a five miR signature (miR-126, -23b, 16, -23a, -15a) with considerable accuracy (100%). Thus, this unique miR expression may be important to the characterization of the powerlifter phenotype. PMID- 28638350 TI - Branched-Chain Amino Acid Ingestion Stimulates Muscle Myofibrillar Protein Synthesis following Resistance Exercise in Humans. AB - The ingestion of intact protein or essential amino acids (EAA) stimulates mechanistic target of rapamycin complex-1 (mTORC1) signaling and muscle protein synthesis (MPS) following resistance exercise. The purpose of this study was to investigate the response of myofibrillar-MPS to ingestion of branched-chain amino acids (BCAAs) only (i.e., without concurrent ingestion of other EAA, intact protein, or other macronutrients) following resistance exercise in humans. Ten young (20.1 +/- 1.3 years), resistance-trained men completed two trials, ingesting either 5.6 g BCAA or a placebo (PLA) drink immediately after resistance exercise. Myofibrillar-MPS was measured during exercise recovery with a primed, constant infusion of L-[ring13C6] phenylalanine and collection of muscle biopsies pre and 4 h-post drink ingestion. Blood samples were collected at time-points before and after drink ingestion. Western blotting was used to measure the phosphorylation status of mTORC1 signaling proteins in biopsies collected pre, 1 , and 4 h-post drink. The percentage increase from baseline in plasma leucine (300 +/- 96%), isoleucine (300 +/- 88%), and valine (144 +/- 59%) concentrations peaked 0.5 h-post drink in BCAA. A greater phosphorylation status of S6K1Thr389 (P = 0.017) and PRAS40 (P = 0.037) was observed in BCAA than PLA at 1 h-post drink ingestion. Myofibrillar-MPS was 22% higher (P = 0.012) in BCAA (0.110 +/- 0.009%/h) than PLA (0.090 +/- 0.006%/h). Phenylalanine Ra was ~6% lower in BCAA (18.00 +/- 4.31 MUmol.kgBM-1) than PLA (21.75 +/- 4.89 MUmol.kgBM-1; P = 0.028) after drink ingestion. We conclude that ingesting BCAAs alone increases the post exercise stimulation of myofibrillar-MPS and phosphorylation status mTORC1 signaling. PMID- 28638351 TI - Transcranial Direct Current Stimulation: Considerations for Research in Adolescent Depression. AB - Adolescent depression is a prevalent disorder with substantial morbidity and mortality. Current treatment interventions do not target relevant pathophysiology and are frequently ineffective, thereby leading to a substantial burden for individuals, families, and society. During adolescence, the prefrontal cortex undergoes extensive structural and functional changes. Recent work suggests that frontolimbic development in depressed adolescents is delayed or aberrant. The judicious application of non-invasive brain stimulation techniques to the prefrontal cortex may present a promising opportunity for durable interventions in adolescent depression. Transcranial direct current stimulation (tDCS) applies a low-intensity, continuous current that alters cortical excitability. While this modality does not elicit action potentials, it is thought to manipulate neuronal activity and neuroplasticity. Specifically, tDCS may modulate N-methyl-d aspartate receptors and L-type voltage-gated calcium channels and effect changes through long-term potentiation or long-term depression-like mechanisms. This mini review considers the neurobiological rationale for developing tDCS protocols in adolescent depression, reviews existing work in adult mood disorders, surveys the existing tDCS literature in adolescent populations, reviews safety studies, and discusses distinct ethical considerations in work with adolescents. PMID- 28638352 TI - Why Psychiatric Research Must Abandon Traditional Diagnostic Classification and Adopt a Fully Dimensional Scope: Two Solutions to a Persistent Problem. PMID- 28638354 TI - Investigating Team Coordination in Baseball Using a Novel Joint Decision Making Paradigm. AB - A novel joint decision making paradigm for assessing team coordination was developed and tested using baseball infielders. Balls launched onto an infield at different trajectories were filmed using four video cameras that were each placed at one of the typical positions of the four infielders. Each participant viewed temporally occluded videos for one of the four positions and were asked to say either "ball" if they would attempt to field it or the name of the bag that they would cover. The evaluation of two experienced coaches was used to assign a group coordination score for each trajectory and group decision times were calculated. Thirty groups of 4 current college baseball players were: (i) teammates (players from same team/view from own position), (ii) non-teammates (players from different teams/view from own position), or (iii) scrambled teammates (players from same team/view not from own position). Teammates performed significantly better (i.e., faster and more coordinated decisions) than the other two groups, whereas scrambled teammates performed significantly better than non-teammates. These findings suggest that team coordination is achieved through both experience with one's teammates' responses to particular events (e.g., a ball hit up the middle) and one's own general action capabilities (e.g., running speed). The sensitivity of our joint decision making paradigm to group makeup provides support for its use as a method for studying team coordination. PMID- 28638353 TI - The Effects of Spatial Endogenous Pre-cueing across Eccentricities. AB - Frequently, we use expectations about likely locations of a target to guide the allocation of our attention. Despite the importance of this attentional process in everyday tasks, examination of pre-cueing effects on attention, particularly endogenous pre-cueing effects, has been relatively little explored outside an eccentricity of 20 degrees . Given the visual field has functional subdivisions that attentional processes can differ significantly among the foveal, perifoveal, and more peripheral areas, how endogenous pre-cues that carry spatial information of targets influence our allocation of attention across a large visual field (especially in the more peripheral areas) remains unclear. We present two experiments examining how the expectation of the location of the target shapes the distribution of attention across eccentricities in the visual field. We measured participants' ability to pick out a target among distractors in the visual field after the presentation of a highly valid cue indicating the size of the area in which the target was likely to occur, or the likely direction of the target (left or right side of the display). Our first experiment showed that participants had a higher target detection rate with faster responses, particularly at eccentricities of 20 degrees and 30 degrees . There was also a marginal advantage of pre-cueing effects when trials of the same size cue were blocked compared to when trials were mixed. Experiment 2 demonstrated a higher target detection rate when the target occurred at the cued direction. This pre cueing effect was greater at larger eccentricities and with a longer cue-target interval. Our findings on the endogenous pre-cueing effects across a large visual area were summarized using a simple model to assist in conceptualizing the modifications of the distribution of attention over the visual field. We discuss our finding in light of cognitive penetration of perception, and highlight the importance of examining attentional process across a large area of the visual field. PMID- 28638355 TI - Motion Event Similarity Judgments in One or Two Languages: An Exploration of Monolingual Speakers of English and Chinese vs. L2 Learners of English. AB - Languages differ systematically in how to encode a motion event. English characteristically expresses manner in verb root and path in verb particle; in Chinese, varied aspects of motion, such as manner, path and cause, can be simultaneously encoded in a verb compound. This study investigates whether typological differences, as such, influence how first and second language learners conceptualize motion events, as suggested by behavioral evidences. Specifically, the performance of Chinese learners of English, at three proficiencies, was compared to that of two groups of monolingual speakers in a triads matching task. The first set of analyses regarding categorisation preferences indicates that participants across groups preferred the path-matched (rather than manner-matched) screens. However, the second set of analyses regarding reaction time suggests, firstly, that English monolingual speakers reacted significantly more quickly in selecting the manner-matched scenes compared with monolingual speakers of Chinese, who tended to use an approximately equal amount of time in making manner- and path-matched decisions, a finding that can arguably be mapped onto the typological difference between the two languages. Secondly, the pattern of response latency in low-level L2 learners looked more like that of monolingual speakers of Chinese. Only at intermediate and advanced levels of acquisition did the behavioral pattern of L2 learners become target like, thus suggesting language-specific constraints from the L1 at an early stage of acquisition. Overall, our results suggest that motion event cognition may be linked to, among other things, the linguistic structure of motion description in particular languages. PMID- 28638356 TI - How Can Smoking Cessation Be Induced Before Surgery? A Systematic Review and Meta Analysis of Behavior Change Techniques and Other Intervention Characteristics. AB - Background: Smokers who continue to smoke up to the point of surgery are at increased risk of a range of complications during and following surgery. Objective: To identify whether behavioral and/or pharmacological interventions increase the likelihood that smokers quit prior to elective surgery and which intervention components are associated with larger effects. Design: Systematic review with meta-analysis. Data sources: MEDLINE, Embase, and Embase Classic, CINAHL, CENTRAL. Study selection: Studies testing the effect of smoking reduction interventions delivered at least 24 h before elective surgery were included. Study appraisal and synthesis: Potential studies were independently screened by two people. Data relating to study characteristics and risk of bias were extracted. The effects of the interventions on pre-operative smoking abstinence were estimated using random effects meta-analyses. The association between specific intervention components (behavior change techniques; mode; duration; number of sessions; interventionist) and smoking cessation effect sizes were estimated using meta-regressions. Results: Twenty-two studies comprising 2,992 smokers were included and 19 studies were meta-analyzed. Interventions increased the proportion of smokers who were abstinent or reduced smoking by surgery relative to control: g = 0.56, 95% CI 0.32-0.80, with rates nearly double in the intervention (46.2%) relative to the control (24.5%). Interventions that comprised more sessions, delivered face-to-face and by nurses, as well as specific behavior change techniques (providing information on consequence of smoking/cessation; providing information on withdrawal symptoms; goal setting; review of goals; regular monitoring by others; and giving options for additional or later support) were associated with larger effects. Conclusion: Rates of smoking can be halved prior to surgery and a number of intervention characteristics can increase these effects. There was, however, some indication of publication bias meaning the benefits of such interventions may be smaller than estimated. Registration: Prospero 2015: CRD42015024733. PMID- 28638357 TI - Leaders' Behaviors Matter: The Role of Delegation in Promoting Employees' Feedback-Seeking Behavior. AB - Feedback helps employees to evaluate and improve their performance, but there have been relatively few empirical investigations into how leaders can encourage employees to seek feedback. To fill this gap we examined the relationship among delegation, psychological empowerment, and feedback-seeking behavior. We hypothesized that delegation promotes feedback-seeking behavior by psychologically empowering subordinates. In addition, power distance moderates the relationship between delegation and feedback-seeking behavior. Analysis of data from a sample of 248 full-time employees of a hotel group in northern China indicated that delegation predicts subordinates' feedback seeking for individuals with moderate and high power distance orientation, but not for those with low power distance orientation. The mediation hypothesis was also supported. PMID- 28638358 TI - Learning to Detect Triggers of Airway Symptoms: The Role of Illness Beliefs, Conceptual Categories and Actual Experience with Allergic Symptoms. AB - Background: In asthma and allergic rhinitis, beliefs about what triggers allergic reactions often do not match objective allergy tests. This may be due to insensitivity for expectancy violations as a result of holding trigger beliefs based on conceptual relationships among triggers. In this laboratory experiment, we aimed to investigate how pre-existing beliefs and conceptual relationships among triggers interact with actual experience when learning differential symptom expectations. Methods: Healthy participants (N = 48) received information that allergic reactions were a result of specific sensitivities versus general allergic vulnerability. Next, they performed a trigger learning task using a differential conditioning paradigm: brief inhalation of CO2 enriched air was used to induce symptoms, while participants were led to believe that the symptoms came about as a result of inhaled allergens (conditioned stimuli, CS's; CS+ followed by symptoms, CS- not followed by symptoms). CS+ and CS- stimuli either shared (e.g., birds-mammals) or did not share (e.g. birds-fungi) category membership. During Acquisition, participants reported symptom expectancy and symptom intensity for all triggers. During a Test 1 day later, participants rated symptom expectancies for old CS+/CS- triggers, for novel triggers within categories, and for exemplars of novel trigger categories. Data were analyzed using multilevel models. Findings: Only a subgroup of participants (n = 22) showed differences between CO2 and room air symptoms. In this group of responders, analysis of symptom expectancies during acquisition did not result in significant differential symptom CS+/CS- acquisition. A retention test 1 day later showed differential CS+/CS- symptom expectancies: When CS categories did not share category membership, specific sensitivity beliefs improved retention of CS+/CS- differentiation. However, when CS categories shared category membership, general vulnerability beliefs improved retention of CS+/CS- differentiation. Furthermore, participants showed some selectivity in generalization of symptom expectancies to novel categories, as symptom expectancies did not generalize to novel categories that were unrelated to CS+ or CS- categories. Generalization to novel categories was not affected by information about general vulnerability or specific sensitivities. Discussion: Pre-existing vulnerability beliefs and conceptual relationships between trigger categories influence differential symptom expectancies to allergic triggers. PMID- 28638360 TI - Sequential Effects in Essay Ratings: Evidence of Assimilation Effects Using Cross Classified Models. AB - Writing assessments are an indispensable part of most language competency tests. In our research, we used cross-classified models to study rater effects in the real essay rating process of a large-scale, high-stakes educational examination administered in China in 2011. Generally, four cross-classified models are suggested for investigation of rater effects: (1) the existence of sequential effects, (2) the direction of the sequential effects, and (3) differences in raters by their individual characteristics. We applied these models to the data to account for possible cluster effects caused by the application of multiple rating strategies. The results of our research showed that raters demonstrated sequential effects during the rating process. In contrast to many other studies on rater effects, our study found that raters exhibited assimilation effects. The more experienced, lenient, and qualified raters were less susceptible to assimilation effects. In addition, our research demonstrated the feasibility and appropriateness of using cross-classified models in assessing rater effects for such data structures. This paper also discusses the implications for educators and practitioners who are interested in reducing sequential effects in the rating process, and suggests directions for future research. PMID- 28638359 TI - Neural Correlates of Outcome of the Psychotherapy Compared to Antidepressant Therapy in Anxiety and Depression Disorders: A Meta-Analysis. AB - The most prevalent mental disorders, anxiety and depression, are commonly associated with structural and functional changes in the fronto-limbic brain areas. The clinical trials investigating patients with affective disorders showed different outcome to different treatments such as psychotherapy or pharmacotherapy. It is, however, still unexplored how these interventions approach affect the functional brain. This meta-analysis aims to compare the effects of psychotherapy compared to antidepressant therapy on functional brain activity in anxiety and depression disorders. Twenty-one samples with psychotherapy and seventeen samples with antidepressant therapy were included. The main finding showed an inverse effect of the two treatments on the right paracingulate activity. The patients undergoing psychotherapy showed an increase in the right paracingulate activity while pharmacological treatment led to a decrease of activation of this area. This finding seems to support the recent studies that hypothesize how psychotherapy, through the self-knowledge and the meaning processing, involves a top-down emotional regulation. PMID- 28638361 TI - Bilingual Language Switching: Production vs. Recognition. AB - This study aims at assessing how bilinguals select words in the appropriate language in production and recognition while minimizing interference from the non appropriate language. Two prominent models are considered which assume that when one language is in use, the other is suppressed. The Inhibitory Control (IC) model suggests that, in both production and recognition, the amount of inhibition on the non-target language is greater for the stronger compared to the weaker language. In contrast, the Bilingual Interactive Activation (BIA) model proposes that, in language recognition, the amount of inhibition on the weaker language is stronger than otherwise. To investigate whether bilingual language production and recognition can be accounted for by a single model of bilingual processing, we tested a group of native speakers of Dutch (L1), advanced speakers of English (L2) in a bilingual recognition and production task. Specifically, language switching costs were measured while participants performed a lexical decision (recognition) and a picture naming (production) task involving language switching. Results suggest that while in language recognition the amount of inhibition applied to the non-appropriate language increases along with its dominance as predicted by the IC model, in production the amount of inhibition applied to the non-relevant language is not related to language dominance, but rather it may be modulated by speakers' unconscious strategies to foster the weaker language. This difference indicates that bilingual language recognition and production might rely on different processing mechanisms and cannot be accounted within one of the existing models of bilingual language processing. PMID- 28638362 TI - Basic Psychological Needs Satisfaction Mediates the Association between Self Control Skills and Subjective Well-Being. AB - Although studies have shown that self-control skills (SCSs) are positively linked to both personal and interpersonal outcomes in adolescent students, studies on the putative mechanisms underlying this relationship are scarce. Drawing on Self Determination Theory and previous studies, we theorized that the association between students' SCSs and their subjective well-being (SWB) in school may be mediated by students' perceived satisfaction of their basic psychological needs for competence, relatedness, and autonomy. The sample consisted of 1576 Israeli adolescent students (54% girls) in grades 10-12 (mean age 16) enrolled in 20 schools. A mediation model was tested with structural equation modeling and a robust bootstrap method for testing indirect effects, controlling for school level variance. The findings supported the hypothesized model and a post hoc multi-group comparison analysis yielded gender invariance in the model. The findings suggest that both girls and boys with high SCSs may perceive themselves as having greater needs satisfaction in school and consequently higher school related SWB. Implications for policy and practice are discussed. PMID- 28638363 TI - Toddlers Selectively Help Fair Agents. AB - : Previous research showed that infants and toddlers are inclined to help prosocial agents and assign a positive valence to fair distributions. Also, they expect that positive and negative actions directed toward distributors will conform to reciprocity principles. This study investigates whether toddlers are selective in helping others, as a function of others' previous distributive actions. Toddlers were presented with real-life events in which two actresses distributed resources either equally or unequally between two puppets. Then, they played together with a ball that accidentally fell to the ground and asked participants to help them to retrieve it. Participants preferred to help the actress who performed equal distributions. This finding suggests that by the second year children's prosocial actions are modulated by their emerging sense of fairness. HIGHLIGHTS: Toddlers (mean age = 25 months) are selective in helping distributors. Toddlers prefer helping a fair rather than an unfair distributor. Toddlers' selective helping provides evidence for an early sense of fairness. PMID- 28638364 TI - Impact of Neuronal Membrane Damage on the Local Field Potential in a Large-Scale Simulation of Cerebral Cortex. AB - Within multiscale brain dynamics, the structure-function relationship between cellular changes at a lower scale and coordinated oscillations at a higher scale is not well understood. This relationship may be particularly relevant for understanding functional impairments after a mild traumatic brain injury (mTBI) when current neuroimaging methods do not reveal morphological changes to the brain common in moderate to severe TBI such as diffuse axonal injury or gray matter lesions. Here, we created a physiology-based model of cerebral cortex using a publicly released modeling framework (GEneral NEural SImulation System) to explore the possibility that performance deficits characteristic of blast induced mTBI may reflect dysfunctional, local network activity influenced by microscale neuronal damage at the cellular level. We operationalized microscale damage to neurons as the formation of pores on the neuronal membrane based on research using blast paradigms, and in our model, pores were simulated by a change in membrane conductance. We then tracked changes in simulated electrical activity. Our model contained 585 simulated neurons, comprised of 14 types of cortical and thalamic neurons each with its own compartmental morphology and electrophysiological properties. Comparing the functional activity of neurons before and after simulated damage, we found that simulated pores in the membrane reduced both action potential generation and local field potential (LFP) power in the 1-40 Hz range of the power spectrum. Furthermore, the location of damage modulated the strength of these effects: pore formation on simulated axons reduced LFP power more strongly than did pore formation on the soma and the dendrites. These results indicate that even small amounts of cellular damage can negatively impact functional activity of larger scale oscillations, and our findings suggest that multiscale modeling provides a promising avenue to elucidate these relationships. PMID- 28638365 TI - Motor Impairments in Transient Ischemic Attack Increase the Odds of a Subsequent Stroke: A Meta-Analysis. AB - BACKGROUND AND PURPOSE: Transient ischemic attack (TIA) increases the risk for a subsequent stroke. Typical symptoms include motor weakness, gait disturbance, and loss of coordination. The association between the presence of motor impairments during a TIA and the chances of a subsequent stroke has not been examined. In the current meta-analysis, we examine whether the odds of a stroke are greater in TIA individuals who experience motor impairments as compared with those who do not experience motor impairments. METHODS: We conducted a systematic search of electronic databases as well as manual searches of the reference lists of retrieved articles. The meta-analysis included studies that reported an odds ratio relating motor impairments to a subsequent stroke, or the number of individuals with or without motor impairments who experienced a subsequent stroke. We examined these studies using rigorous meta-analysis techniques including random effects model, forest and funnel plots, I2, publication bias, and fail-safe analysis. RESULTS: Twenty-four studies with 15,129 participants from North America, Australia, Asia, and Europe qualified for inclusion. An odds ratio of 2.11 (95% CI, 1.67-2.65, p = 0.000) suggested that the chances of a subsequent stroke are increased by twofolds in individuals who experience motor impairments during a TIA compared with those individuals who have no motor impairments. CONCLUSION: The presence of motor impairments during TIA is a significantly high-risk clinical characteristic for a subsequent stroke. The current evidence for motor impairments following TIA relies exclusively on the clinical reports of unilateral motor weakness. A comprehensive examination of motor impairments in TIA will enhance TIA prognosis and restoration of residual motor impairments. PMID- 28638366 TI - Gonadotropin-Releasing Hormone and Its Role in the Enteric Nervous System. AB - Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone, and luteinizing hormone orchestrate the reproduction cycle and regulate the sex steroid secretion from the gonads. In mammals, GnRH1 is secreted as a hormone from the hypothalamus, whereas both GnRH1 and GnRH2 are present as neurotransmitters/peptides in various tissues, where the peptides exert many different effects. mRNA coding for GnRH1 and GnRH2 have been described in the human gastrointestinal tract, and GnRH has been found in both submucosal and myenteric neurons. mRNA coding for GnRH and the fully expressed peptide have been found in rat enteric neurons by some researchers but not by others. mRNA coding for GnRH receptors, but not the fully expressed receptor, has been found in one rat study. GnRH influences gastrointestinal motility and secretion. GnRH analogs are clinically used in the treatment of sex hormone-dependent diseases, i.e., endometriosis and malignancies, and as pretreatment for in vitro fertilization. Reduced numbers of enteric neurons and IgM antibodies against GnRH and progonadoliberin-2 (precursor of GnRH2) have been observed after such treatment, with the clinical picture of gastrointestinal dysmotility. Similarly, a rat model of enteric neurodegeneration has been developed after administration of the GnRH analog buserelin. Serum IgM antibodies against GnRH1, progonadoliberin-2, and GnRH receptors have been described in patients with signs and symptoms of gastrointestinal dysmotility and/or autonomic dysfunction, such as irritable bowel syndrome, enteric dysmotility, diabetes mellitus, and primary Sjogren's syndrome. Thus, apart from regulation of reproduction and sex hormone secretion, GnRH also constitutes a part of enteric nervous system (ENS) and its functions during physiological and pathological conditions. This review aimed to describe the role of GnRH in the ENS. PMID- 28638367 TI - GnRH Agonist Trigger and LH Activity Luteal Phase Support versus hCG Trigger and Conventional Luteal Phase Support in Fresh Embryo Transfer IVF/ICSI Cycles-A Systematic PRISMA Review and Meta-analysis. AB - INTRODUCTION: The use of GnRH agonist (GnRHa) for final oocyte maturation trigger in oocyte donation and elective frozen embryo transfer cycles is well established due to lower ovarian hyperstimulation syndrome (OHSS) rates as compared to hCG trigger. A recent Cochrane meta-analysis concluded that GnRHa trigger was associated with reduced live birth rates (LBRs) in fresh autologous IVF cycles compared to hCG trigger. However, the evidence is not unequivocal, and recent trials have found encouraging reproductive outcomes among couples undergoing GnRHa trigger and individualized luteal LH activity support. Thus, the aim was to compare GnRHa trigger followed by luteal LH activity support with hCG trigger in IVF patients undergoing fresh embryo transfer. MATERIAL AND METHODS: We conducted a systematic review and meta-analysis of randomized trials published until December 14, 2016. The population was infertile patients submitted to IVF/ICSI cycles with GnRH antagonist cotreatment who underwent fresh embryo transfer. The intervention was GnRHa trigger followed by LH activity luteal phase support (LPS). The comparator was hCG trigger followed by a standard LPS. The critical outcome measures were LBR and OHSS rate. The secondary outcome measures were number of oocytes retrieved, clinical and ongoing pregnancy rates, and miscarriage rates. RESULTS: A total of five studies met the selection criteria comprising a total of 859 patients. The LBR was not significantly different between the GnRHa and hCG trigger groups (OR 0.84, 95% CI 0.62, 1.14). OHSS was reported in a total of 4/413 cases in the GnRHa group compared to 7/413 in the hCG group (OR 0.48, 95% CI 0.15, 1.60). We observed a slight, but non-significant increase in miscarriage rate in the GnRHa triggered group compared to the hCG group (OR 1.85; 95% CI 0.97, 3.54). CONCLUSION: GnRHa trigger with LH activity LPS resulted in comparable LBRs compared to hCG trigger. The most recent trials reported LBRs close to unity indicating that individualization of the LH activity LPS improved the luteal phase deficiency reported in the first GnRHa trigger studies. However, LPS optimization is needed to further limit OHSS in the subgroup of normoresponder patients (<14 follicles >= 11 mm). PROSPERO REGISTRATION NUMBER: CRD42016051091. PMID- 28638368 TI - Impact of Ferrous Iron on Microbial Community of the Biofilm in Microbial Fuel Cells. AB - The performance of microbial electrochemical cells depends upon microbial community structure and metabolic activity of the electrode biofilms. Iron as a signal affects biofilm development and enrichment of exoelectrogenic bacteria. In this study, the effect of ferrous iron on microbial communities of the electrode biofilms in microbial fuel cells (MFCs) was investigated. Voltage production showed that ferrous iron of 100 MUM facilitated MFC start-up compared to 150 MUM, 200 MUM, and without supplement of ferrous iron. However, higher concentration of ferrous iron had an inhibitive influence on current generation after 30 days of operation. Illumina Hiseq sequencing of 16S rRNA gene amplicons indicated that ferrous iron substantially changed microbial community structures of both anode and cathode biofilms. Principal component analysis showed that the response of microbial communities of the anode biofilms to higher concentration of ferrous iron was more sensitive. The majority of predominant populations of the anode biofilms in MFCs belonged to Geobacter, which was different from the populations of the cathode biofilms. An obvious shift of community structures of the cathode biofilms occurred after ferrous iron addition. This study implied that ferrous iron influenced the power output and microbial community of MFCs. PMID- 28638369 TI - Diversity and Activity of Diazotrophs in Great Barrier Reef Surface Waters. AB - Discrepancies between bioavailable nitrogen (N) concentrations and phytoplankton growth rates in the oligotrophic waters of the Great Barrier Reef (GBR) suggest that undetermined N sources must play a significant role in supporting primary productivity. One such source could be biological dinitrogen (N2) fixation through the activity of "diazotrophic" bacterioplankton. Here, we investigated N2 fixation and diazotroph community composition over 10 degrees S of latitude within GBR surface waters. Qualitative N2 fixation rates were found to be variable across the GBR but were relatively high in coastal, inner and outer GBR waters, reaching 68 nmol L-1 d-1. Diazotroph assemblages, identified by amplicon sequencing of the nifH gene, were dominated by the cyanobacterium Trichodesmium erythraeum, gamma-proteobacteria from the Gamma A clade, and delta proteobacterial phylotypes related to sulfate-reducing genera. However, diazotroph communities exhibited significant spatial heterogeneity, correlated with shifts in dissolved inorganic nutrient concentrations. Specifically, heterotrophic diazotrophs generally increased in relative abundance with increasing concentrations of phosphate and N, while Trichodesmium was proportionally more abundant when concentrations of these nutrients were low. This study provides the first in-depth characterization of diazotroph community composition and N2 fixation dynamics within the oligotrophic, N-limited surface waters of the GBR. Our observations highlight the need to re-evaluate N cycling dynamics within oligotrophic coral reef systems, to include diverse N2 fixing assemblages as a potentially significant source of dissolved N within the water column. PMID- 28638370 TI - Removal of Foodborne Pathogen Biofilms by Acidic Electrolyzed Water. AB - Biofilms, which are complex microbial communities embedded in the protective extracellular polymeric substances (EPS), are difficult to remove in food production facilities. In this study, the use of acidic electrolyzed water (AEW) to remove foodborne pathogen biofilms was evaluated. We used a green fluorescent protein-tagged Escherichia coli for monitoring the efficiency of AEW for removing biofilms, where under the optimal treatment conditions, the fluorescent signal of cells in the biofilm disappeared rapidly and the population of biofilm cells was reduced by more than 67%. Additionally, AEW triggered EPS disruption, as indicated by the deformation of the carbohydrate C-O-C bond and deformation of the aromatic rings in the amino acids tyrosine and phenylalanine. These deformations were identified by EPS chemical analysis and Raman spectroscopic analysis. Scanning electron microscopy (SEM) images confirmed that the breakup and detachment of biofilm were enhanced after AEW treatment. Further, AEW also eradicated biofilms formed by both Gram-negative bacteria (Vibrio parahaemolyticus) and Gram-positive bacteria (Listeria monocytogenes) and was observed to inactivate the detached cells which are a potential source of secondary pollution. This study demonstrates that AEW could be a reliable foodborne pathogen biofilm disrupter and an eco-friendly alternative to sanitizers traditionally used in the food industry. PMID- 28638371 TI - The Anticancer Peptide TAT-RasGAP317-326 Exerts Broad Antimicrobial Activity. AB - Antibiotic resistance has become a major health issue. Nosocomial infections and the prevalence of resistant pathogenic bacterial strains are rising steadily. Therefore, there is an urgent need to develop new classes of antibiotics effective on multi-resistant nosocomial pathogenic bacteria. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP), called TAT-RasGAP317-326, induces cancer cell death, inhibits metastatic progression, and sensitizes tumor cells to various anti-cancer treatments in vitro and in vivo. We here report that TAT-RasGAP317-326 also possesses antimicrobial activity. In vitro, TAT-RasGAP317-326, but not mutated or truncated forms of the peptide, efficiently killed a series of bacteria including Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa. In vivo experiments revealed that TAT-RasGAP317-326 protects mice from lethal E. coli-induced peritonitis if administrated locally at the onset of infection. However, the protective effect was lost when treatment was delayed, likely due to rapid clearance and inadequate biodistribution of the peptide. Peptide modifications might overcome these shortcomings to increase the in vivo efficacy of the compound in the context of the currently limited antimicrobial options. PMID- 28638373 TI - Interactions between Food Additive Silica Nanoparticles and Food Matrices. AB - Nanoparticles (NPs) have been widely utilized in the food industry as additives with their beneficial characteristics, such as improving sensory property and processing suitability, enhancing functional and nutritional values, and extending shelf-life of foods. Silica is used as an anti-caking agent to improve flow property of powered ingredients and as a carrier for flavors or active compounds in food. Along with the rapid development of nanotechnology, the sizes of silica fall into nanoscale, thereby raising concerns about the potential toxicity of nano-sized silica materials. There have been a number of studies carried out to investigate possible adverse effects of NPs on the gastrointestinal tract. The interactions between NPs and surrounding food matrices should be also taken into account since the interactions can affect their bioavailability, efficacy, and toxicity. In the present study, we investigated the interactions between food additive silica NPs and food matrices, such as saccharides, proteins, lipids, and minerals. Quantitative analysis was performed to determine food component-NP corona using HPLC, fluorescence quenching, GC-MS, and ICP-AES. The results demonstrate that zeta potential and hydrodynamic radius of silica NPs changed in the presence of all food matrices, but their solubility was not affected. However, quantitative analysis on the interactions revealed that a small portion of food matrices interacted with silica NPs and the interactions were highly dependent on the type of food component. Moreover, minor nutrients could also affect the interactions, as evidenced by higher NP interaction with honey rather than with a simple sugar mixture containing an equivalent amount of fructose, glucose, sucrose, and maltose. These findings provide fundamental information to extend our understanding about the interactions between silica NPs and food components and to predict the interaction effect on the safety aspects of food-grade NPs. PMID- 28638372 TI - Diversity and Composition of Sulfate-Reducing Microbial Communities Based on Genomic DNA and RNA Transcription in Production Water of High Temperature and Corrosive Oil Reservoir. AB - Deep subsurface petroleum reservoir ecosystems harbor a high diversity of microorganisms, and microbial influenced corrosion is a major problem for the petroleum industry. Here, we used high-throughput sequencing to explore the microbial communities based on genomic 16S rDNA and metabolically active 16S rRNA analyses of production water samples with different extents of corrosion from a high-temperature oil reservoir. Results showed that Desulfotignum and Roseovarius were the most abundant genera in both genomic and active bacterial communities of all the samples. Both genomic and active archaeal communities were mainly composed of Archaeoglobus and Methanolobus. Within both bacteria and archaea, the active and genomic communities were compositionally distinct from one another across the different oil wells (bacteria p = 0.002; archaea p = 0.01). In addition, the sulfate-reducing microorganisms (SRMs) were specifically assessed by Sanger sequencing of functional genes aprA and dsrA encoding the enzymes adenosine-5'-phosphosulfate reductase and dissimilatory sulfite reductase, respectively. Functional gene analysis indicated that potentially active Archaeoglobus, Desulfotignum, Desulfovibrio, and Thermodesulforhabdus were frequently detected, with Archaeoglobus as the most abundant and active sulfate reducing group. Canonical correspondence analysis revealed that the SRM communities in petroleum reservoir system were closely related to pH of the production water and sulfate concentration. This study highlights the importance of distinguishing the metabolically active microorganisms from the genomic community and extends our knowledge on the active SRM communities in corrosive petroleum reservoirs. PMID- 28638374 TI - Azole Resistance in Aspergillus fumigatus: A Consequence of Antifungal Use in Agriculture? AB - Agricultural industry uses pesticides to optimize food production for the growing human population. A major issue for crops is fungal phytopathogens, which are treated mainly with azole fungicides. Azoles are also the main medical treatment in the management of Aspergillus diseases caused by ubiquitous fungi, such as Aspergillus fumigatus. However, epidemiological research demonstrated an increasing prevalence of azole-resistant strains in A. fumigatus. The main resistance mechanism is a combination of alterations in the gene cyp51A (TR34/L98H). Surprisingly, this mutation is not only found in patients receiving long-term azole therapy for chronic aspergillosis but also in azole naive patients. This suggests an environmental route of resistance through the exposure of azole fungicides in agriculture. In this review, we report data from several studies that strongly suggest that agricultural azoles are responsible for medical treatment failure in azole-naive patients in clinical settings. PMID- 28638375 TI - Valorization of Spent Escherichia coli Media Using Green Microalgae Chlamydomonas reinhardtii and Feedstock Production. AB - The coupling of Chlamydomonas reinhardtii biomass production for nutrients removal of Escherichia coli anaerobic broth (EAB) is thought to be an economically feasible option for the cultivation of microalgae. The feasibility of growing microalgae in using EAB high in nutrients for the production of more biomass was examined. EAB comprised of nutrient-abundant effluents, which can be used to produce microalgae biomass and remove environment pollutant simultaneously. In this study, C. reinhardtii 21gr (cc1690) was cultivated in different diluted E. coli anaerobic broth supplemented with trace elements under mixotrophic and heterotrophic conditions. The results showed that C. reinhardtii grown in 1*, 1/2*, 1/5* and 1/10*E. coli anaerobic broth under mixotrophic conditions exhibited specific growth rates of 2.71, 2.68, 1.45, and 1.13 day-1, and biomass production of 201.9, 184.2, 175.5, and 163.8 mg L-1, respectively. Under heterotrophic conditions, the specific growth rates were 1.80, 1.86, 1.75, and 1.02 day-1, and biomass production were 45.6, 29.4, 15.8, and 12.1 mg L-1, respectively. The removal efficiency of chemical oxygen demand, total-nitrogen and total-phosphorus from 1*E. coli anaerobic broth was 21.51, 22.41, and 15.53%. Moreover, the dry biomass had relatively high carbohydrate (44.3%) and lipid content (18.7%). Therefore, this study provides an environmentally sustainable as well economical method for biomass production in promising model microalgae and subsequently paves the way for industrial use. PMID- 28638376 TI - First Molecular Detection of Piroplasm Infection in Pet Dogs from Gansu, China. AB - Babesiosis, the hemolytic disease caused by Babesia, which is a tick-transmitted obligate intraerythrocytic protozoan parasite. This disease is responsible for significant mortality and morbidity rates and enormous economic losses to the livestock industry in tropical and subtropical regions worldwide. In this study, blood samples were collected from 141 pet dogs from Gansu, China, and analyzed for Babesia or Theileria spp. infection using specific PCR and sequencing based on 18S rRNA gene fragments. The results indicated that 18S rRNA gene sequences from 11 samples were similar to the 18S rRNA gene sequences in Babesia canis vogeli (2) and Theileria sinensis (9). The total infected rates of B. canis vogeli and T. sinensis were 1.4% (2/141) and 6.4% (9/141), respectively. This represents the first molecular report of T. sinensis in dogs worldwide and of B. canis vogeli in dogs from Gansu province of China. Furthermore, the finding of T. sinensis in dogs may represent the common infection of this parasite occurring in Gansu. PMID- 28638378 TI - Corrigendum: Long-Term Enrichment of Stress-Tolerant Cellulolytic Soil Populations following Timber Harvesting Evidenced by Multi-Omic Stable Isotope Probing. AB - [This corrects the article on p. 537 in vol. 8, PMID: 28443069.]. PMID- 28638377 TI - A Novel Bromodomain Inhibitor Reverses HIV-1 Latency through Specific Binding with BRD4 to Promote Tat and P-TEFb Association. AB - While combinatory antiretroviral therapy (cART) can effectively reduce HIV-1 viremia, it cannot eliminate HIV-1 infection. In the presence of cART, viral reservoirs remain latent, impeding the cure of HIV-1/AIDS. Recently, latency reversing agents (LRAs) have been developed with the intent of purging latent HIV 1, providing an intriguing strategy for the eradication of the residual viral reservoirs. Our earlier studies show that the first-generation, methyl-triazolo bromodomain, and extra-terminal domain inhibitor (BETi), JQ1, facilitates the reversal of HIV-1 latency. BETis have emerged as a new class of compounds that are promising for this HIV-1 "shock and kill" eradication approach. However, when used as a single drug, JQ1 only modestly reverses HIV-1 latency, which complicates studying the underlining mechanisms. Meanwhile, it has been widely discussed that the induction of latent proviruses is stochastic (Ho et al., 2013). Thus, new BETis are currently under active development with focus on improving potency, ease of synthesis and structural diversity. Using fluorous tagged multicomponent reactions, we developed a novel second-generation, 3,5 dimethylisoxazole BETi based on an imidazo[1,2-a] pyrazine scaffold, UMB-32. Furthermore, we screened 37 UMB-32 derivatives and identified that one, UMB-136, reactivates HIV-1 in multiple cell models of HIV-1 latency with better efficiency than either JQ1 or UMB-32. UMB-136 enhances HIV-1 transcription and increases viral production through the release of P-TEFb. Importantly, UMB-136 enhances the latency-reversing effects of PKC agonists (prostratin, bryostatin-1) in CD8 depleted PBMCs containing latent viral reservoirs. Our results illustrate that structurally improved BETis, such as UMB-136, may be useful as promising LRAs for HIV-1 eradication. PMID- 28638380 TI - Candida albicans Yeast, Pseudohyphal, and Hyphal Morphogenesis Differentially Affects Immune Recognition. AB - Candida albicans is a human opportunist pathogen that can grow as yeast, pseudohyphae, or true hyphae in vitro and in vivo, depending on environmental conditions. Reversible cellular morphogenesis is an important virulence factor that facilitates invasion of host tissues, escape from phagocytes, and dissemination in the blood stream. The innate immune system is the first line of defense against C. albicans infections and is influenced by recognition of wall components that vary in composition in different morphological forms. However, the relationship between cellular morphogenesis and immune recognition of this fungus is not fully understood. We therefore studied various vegetative cell types of C. albicans, singly and in combination, to assess the consequences of cellular morphogenesis on selected immune cytokine outputs from human monocytes. Hyphae stimulated proportionally lower levels of certain cytokines from monocytes per unit of cell surface area than yeast cells, but did not suppress cytokine response when copresented with yeast cells. Pseudohyphal cells induced intermediate cytokine responses. Yeast monomorphic mutants had elevated cytokine responses under conditions that otherwise supported filamentous growth and mutants of yeast and hyphal cells that were defective in cell wall mannosylation or lacking certain hypha-specific cell wall proteins could variably unmask or deplete the surface of immunostimulatory ligands. These observations underline the critical importance of C. albicans morphology and morphology-associated changes in the cell wall composition that affect both immune recognition and pathogenesis. PMID- 28638379 TI - Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia. AB - The success of hematopoietic stem cell transplantation (HSCT) lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL), caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter. PMID- 28638381 TI - Anti-Bovine Programmed Death-1 Rat-Bovine Chimeric Antibody for Immunotherapy of Bovine Leukemia Virus Infection in Cattle. AB - Blockade of immunoinhibitory molecules, such as programmed death-1 (PD-1)/PD ligand 1 (PD-L1), is a promising strategy for reinvigorating exhausted T cells and preventing disease progression in a variety of chronic infections. Application of this therapeutic strategy to cattle requires bovinized chimeric antibody targeting immunoinhibitory molecules. In this study, anti-bovine PD-1 rat-bovine chimeric monoclonal antibody 5D2 (Boch5D2) was constructed with mammalian expression systems, and its biochemical function and antiviral effect were characterized in vitro and in vivo using cattle infected with bovine leukemia virus (BLV). Purified Boch5D2 was capable of detecting bovine PD-1 molecules expressed on cell membranes in flow cytometric analysis. In particular, Biacore analysis determined that the binding affinity of Boch5D2 to bovine PD-1 protein was similar to that of the original anti-bovine PD-1 rat monoclonal antibody 5D2. Boch5D2 was also capable of blocking PD-1/PD-L1 binding at the same level as 5D2. The immunomodulatory and therapeutic effects of Boch5D2 were evaluated by in vivo administration of the antibody to a BLV-infected calf. Inoculated Boch5D2 was sustained in the serum for a longer period. Boch5D2 inoculation resulted in activation of the proliferation of BLV-specific CD4+ T cells and decrease in the proviral load of BLV in the peripheral blood. This study demonstrates that Boch5D2 retains an equivalent biochemical function to that of the original antibody 5D2 and is a candidate therapeutic agent for regulating antiviral immune response in vivo. Clinical efficacy of PD-1/PD-L1 blockade awaits further experimentation with a large number of animals. PMID- 28638383 TI - Non-canonical Glucocorticoid Receptor Transactivation of gilz by Alcohol Suppresses Cell Inflammatory Response. AB - Acute alcohol exposure suppresses cell inflammatory response. The underlying mechanism has not been fully defined. Here we report that alcohol was able to activate glucocorticoid receptor (GR) signaling in the absence of glucocorticoids (GCs) and upregulated glucocorticoid-induced leucine zipper (gilz), a prominent GC-responsive gene. Such a non-canonical activation of GR was not blocked by mifepristone, a potent GC competitor. The proximal promoter of gilz, encompassing five GC-responsive elements (GREs), was incorporated and tested in a luciferase reporter system. Deletion and/or mutation of the GREs abrogated the promoter responsiveness to alcohol. Thus, the GR-GRE interaction transduced the alcohol action on gilz. Alcohol induced GR nuclear translocation, which was enhanced by the alcohol dehydrogenase inhibitor fomepizole, suggesting that it was alcohol, not its metabolites, that engendered the effect. Gel mobility shift assay showed that unliganded GR was able to bind GREs and such interaction withstood clinically relevant levels of alcohol. GR knockout via CRISPR/Cas9 gene targeting or GILZ depletion via small RNA interference diminished alcohol suppression of cell inflammatory response to LPS. Thus, a previously unrecognized, non-canonical GR activation of gilz is involved in alcohol modulation of cell immune response. PMID- 28638384 TI - Induced Regulatory T Cells Superimpose Their Suppressive Capacity with Effector T Cells in Lymph Nodes via Antigen-Specific S1p1-Dependent Egress Blockage. AB - Regulatory T cells (Tregs) restrict overexuberant lymphocyte activation. While close proximity between Tregs and their suppression targets is important for optimal inhibition, and literature indicates that draining lymph nodes (LNs) may serve as a prime location for the suppression, signaling details orchestrating this event are not fully characterized. Using a protocol to enable peripheral generation of inducible antigen-specific Tregs (asTregs) to control allergen induced asthma, we have identified an antigen-specific mechanism that locks asTregs within hilar LNs which in turn suppresses airway inflammation. The suppressive asTregs, upon antigen stimulation in the LN, downregulate sphingosine 1-phosphate receptor 1 egress receptor expression. These asTregs in turn mediate the downregulation of the same receptor on incoming effector T cells. Therefore, asTregs and effector T cells are locked in these draining LNs for prolonged interactions. Disruption of individual steps of this retention sequence abolishes the inflammation controlled by asTregs. Collectively, this study identifies a new requirement of spatial congregation with their suppression targets essential for asTreg functions and suggests therapeutic programs via Treg traffic control. PMID- 28638382 TI - Expanding Role of T Cells in Human Autoimmune Diseases of the Central Nervous System. AB - It is being increasingly recognized that a dysregulation of the immune system plays a vital role in neurological disorders and shapes the treatment of the disease. Aberrant T cell responses, in particular, are key in driving autoimmunity and have been traditionally associated with multiple sclerosis. Yet, it is evident that there are other neurological diseases in which autoreactive T cells have an active role in pathogenesis. In this review, we report on the recent progress in profiling and assessing the functionality of autoreactive T cells in central nervous system (CNS) autoimmune disorders that are currently postulated to be primarily T cell driven. We also explore the autoreactive T cell response in a recently emerging group of syndromes characterized by autoantibodies against neuronal cell-surface proteins. Common methodology implemented in T cell biology is further considered as it is an important determinant in their detection and characterization. An improved understanding of the contribution of autoreactive T cells expands our knowledge of the autoimmune response in CNS disorders and can offer novel methods of therapeutic intervention. PMID- 28638387 TI - Predicting Flowering Behavior and Exploring Its Genetic Determinism in an Apple Multi-family Population Based on Statistical Indices and Simplified Phenotyping. AB - Irregular flowering over years is commonly observed in fruit trees. The early prediction of tree behavior is highly desirable in breeding programmes. This study aims at performing such predictions, combining simplified phenotyping and statistics methods. Sequences of vegetative vs. floral annual shoots (AS) were observed along axes in trees belonging to five apple related full-sib families. Sequences were analyzed using Markovian and linear mixed models including year and site effects. Indices of flowering irregularity, periodicity and synchronicity were estimated, at tree and axis scales. They were used to predict tree behavior and detect QTL with a Bayesian pedigree-based analysis, using an integrated genetic map containing 6,849 SNPs. The combination of a Biennial Bearing Index (BBI) with an autoregressive coefficient (gamma g ) efficiently predicted and classified the genotype behaviors, despite few misclassifications. Four QTLs common to BBIs and gamma g and one for synchronicity were highlighted and revealed the complex genetic architecture of the traits. Irregularity resulted from high AS synchronism, whereas regularity resulted from either asynchronous locally alternating or continual regular AS flowering. A relevant and time-saving method, based on a posteriori sampling of axes and statistical indices is proposed, which is efficient to evaluate the tree breeding values for flowering regularity and could be transferred to other species. PMID- 28638386 TI - Weighted Gene Co-expression Network Analysis of the Dioscin Rich Medicinal Plant Dioscorea nipponica. AB - Dioscorea contains critically important species which can be used as staple foods or sources of bioactive substances, including Dioscorea nipponica, which has been used to develop highly successful drugs to treat cardiovascular disease. Its major active ingredients are thought to be sterol compounds such as diosgenin, which has been called "medicinal gold" because of its valuable properties. However, reliance on naturally growing plants as a production system limits the potential use of D. nipponica, raising interest in engineering metabolic pathways to enhance the production of secondary metabolites. However, the biosynthetic pathway of diosgenin is still poorly understood, and D. nipponica is poorly characterized at a molecular level, hindering in-depth investigation. In the present work, the RNAs from five organs and seven methyl jasmonate treated D. nipponica rhizomes were sequenced using the Illumina high-throughput sequencing platform, yielding 52 gigabases of data, which were pooled and assembled into a reference transcriptome. Four hundred and eighty two genes were found to be highly expressed in the rhizomes, and these genes are mainly involved in stress response and transcriptional regulation. Based on their expression patterns, 36 genes were selected for further investigation as candidate genes involved in dioscin biosynthesis. Constructing co-expression networks based on significant changes in gene expression revealed 15 gene modules. Of these, four modules with properties correlating to dioscin regulation and biosynthesis, consisting of 4,665 genes in total, were selected for further functional investigation. These results improve our understanding of dioscin biosynthesis in this important medicinal plant and will help guide more intensive investigations. PMID- 28638385 TI - Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities. AB - Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy. PMID- 28638388 TI - Using In Situ Symbiotic Seed Germination to Restore Over-collected Medicinal Orchids in Southwest China. AB - Due to increasing demand for medicinal and horticultural uses, the Orchidaceae is in urgent need of innovative and novel propagation techniques that address both market demand and conservation. Traditionally, restoration techniques have been centered on ex situ asymbiotic or symbiotic seed germination techniques that are not cost-effective, have limited genetic potential and often result in low survival rates in the field. Here, we propose a novel in situ advanced restoration-friendly program for the endangered epiphytic orchid species Dendrobium devonianum, in which a series of in situ symbiotic seed germination trials base on conspecific fungal isolates were conducted at two sites in Yunnan Province, China. We found that percentage germination varied among treatments and locations; control treatments (no inoculum) did not germinate at both sites. We found that the optimal treatment, having the highest in situ seed germination rate (0.94-1.44%) with no significant variation among sites, supported a warm, moist and fixed site that allowed for light penetration. When accounting for seed density, percentage germination was highest (2.78-2.35%) at low densities and did not vary among locations for the treatment that supported optimal conditions. Similarly for the same treatment, seed germination ranged from 0.24 to 5.87% among seasons but also did vary among sites. This study reports on the cultivation and restoration of an endangered epiphytic orchid species by in situ symbiotic seed germination and is likely to have broad application to the horticulture and conservation of the Orchidaceae. PMID- 28638389 TI - Recognition of Orobanche cumana Below-Ground Parasitism Through Physiological and Hyper Spectral Measurements in Sunflower (Helianthus annuus L.). AB - Broomrape (Orobanche and Phelipanche spp.) parasitism is a severe problem in many crops worldwide, including in the Mediterranean basin. Most of the damage occurs during the sub-soil developmental stage of the parasite, by the time the parasite emerges from the ground, damage to the crop has already been done. One feasible method for sensing early, below-ground parasitism is through physiological measurements, which provide preliminary indications of slight changes in plant vitality and productivity. However, a complete physiological field survey is slow, costly and requires skilled manpower. In recent decades, visible to shortwave infrared (VIS-SWIR) hyperspectral tools have exhibited great potential for faster, cheaper, simpler and non-destructive tracking of physiological changes. The advantage of VIS-SWIR is even greater when narrow-band signatures are analyzed with an advanced statistical technique, like a partial least squares regression (PLS-R). The technique can pinpoint the most physiologically sensitive wavebands across an entire spectrum, even in the presence of high levels of noise and collinearity. The current study evaluated a method for early detection of Orobanche cumana parasitism in sunflower that combines plant physiology, hyperspectral readings and PLS-R. Seeds of susceptible and resistant O. cumana sunflower varieties were planted in infested (15 mg kg-1 seeds) and non-infested soil. The plants were examined weekly to detect any physiological or structural changes; the examinations were accompanied by hyperspectral readings. During the early stage of the parasitism, significant differences between infected and non infected sunflower plants were found in the reflectance of near and shortwave infrared areas. Physiological measurements revealed no differences between treatments until O. cumana inflorescences emerged. However, levels of several macro- and microelements tended to decrease during the early stage of O. cumana parasitism. Analysis of leaf cross-sections revealed differences in range and in mesophyll structure as a result of different levels of nutrients in sunflower plants, manifesting the presence of O. cumana infections. The findings of an advanced PLS-R analysis emphasized the correlation between specific reflectance changes in the SWIR range and levels of various nutrients in sunflower plants. This work demonstrates potential for the early detection of O. cumana parasitism on sunflower roots using hyperspectral tools. PMID- 28638391 TI - Glomus mosseae Inoculation Improves the Root System Architecture, Photosynthetic Efficiency and Flavonoids Accumulation of Liquorice under Nutrient Stress. AB - The poor quality and low productivity of cultivated liquorice (Glycyrrhiza uralensis) continues to put pressure on wild plant populations. As arbuscular mycorrhizal fungi are known to support plant growth and in some cases even to enhance the accumulation of valuable molecules in the plant, the effect of Glomus mosseae on the growth and active ingredient contents was evaluated in liquorice plants grown under nutrient deficiency. We created a nutrient-deficient environment by mixing paddy soil, washed river sand, and pumice at a ratio of 1:5:1. Our results showed that the inoculation of pot-grown liquorice plants with G. mosseae significantly increased the shoot and root biomass (by 25- and 17 folds, respectively) and the contents of glycyrrhizic acid, liquiritin, isoliquiritin, and isoliquiritigenin in the main root (by 1.6-, 4.8-, 6.5-, and 4.4-folds, respectively). Both isoliquiritin and isoliquiritigenin were detectable in the lateral roots of the plants inoculated with G. mosseae, but not in plants without G. mosseae inoculation. G. mosseae inoculation improved the features of the root system and increased photosynthetic efficiency of liquorice. The uptake of P and K by liquorice increased when G. mosseae was inoculated, leading to the depletion of these macronutrients in the soil; G. mosseae also improved the availability of Mg, Cu, Zn, and Mn. Based on these results, we concluded that the inoculation of liquorice plants with G. mosseae is beneficial, particularly for those grown in nutrient-deficient soil, and such positive effect is related to the improvement of the root system and an increased photosynthetic efficiency. PMID- 28638390 TI - Characterization, Genomic Organization, Abundance, and Chromosomal Distribution of Ty1-copia Retrotransposons in Erianthus arundinaceus. AB - Erianthus arundinaceus is an important wild species of the genus Saccharum with many valuable traits. However, the composition and structure of its genome are largely unknown, which have hindered its utilization in sugarcane breeding and evolutionary research. Retrotransposons constitute an appreciable fraction of plant genomes and may have played a significant role in the evolution and sequence organization of genomes. In the current study, we investigate the phylogenetic diversity and genomic abundance of Ty1-copia retrotransposons for the first time and inspect their chromosomal distribution patterns in E. arundinaceus. In total, 70 Ty1-copia reverse transcriptase (RT) sequences with significant levels of heterogeneity were obtained. The phylogenetic analysis revealed these Ty1-copia retrotransposons were classified into four distinct evolutionary lineages (Tork/TAR, Tork/Angela, Retrofit/Ale, and Sire/Maximus). Dot-blot analysis showed estimated the total copy number of Ty1-copia retrotransposons to be about 4.5 * 103 in the E. arundinaceus genome, indicating they were a significant component. Fluorescence in situ hybridization revealed that Ty1-copia retrotransposons from the four lineages had strikingly similar patterns of chromosomal enrichment, being exclusively enriched in the subterminal heterochromatic regions of most E. arundinaceus chromosomes. This is the first clear evidence of the presence of Ty1-copia retrotransposons in the subterminal heterochromatin of E. arundinaceus. Altogether, these results promote the understanding of the diversification of Ty1-copia retrotransposons and shed light on their chromosomal distribution patterns in E. arundinaceus. PMID- 28638392 TI - Evaluation of Borage Extracts As Potential Biostimulant Using a Phenomic, Agronomic, Physiological, and Biochemical Approach. AB - Biostimulants are substances able to improve water and nutrient use efficiency and counteract stress factors by enhancing primary and secondary metabolism. Premise of the work was to exploit raw extracts from leaves (LE) or flowers (FE) of Borago officinalis L., to enhance yield and quality of Lactuca sativa 'Longifolia,' and to set up a protocol to assess their effects. To this aim, an integrated study on agronomic, physiological and biochemical aspects, including also a phenomic approach, has been adopted. Extracts were diluted to 1 or 10 mL L 1, sprayed onto lettuce plants at the middle of the growing cycle and 1 day before harvest. Control plants were treated with water. Non-destructive analyses were conducted to assess the effect of extracts on biomass with an innovative imaging technique, and on leaf photosynthetic efficiency (chlorophyll a fluorescence and leaf gas exchanges). At harvest, the levels of ethylene, photosynthetic pigments, nitrate, and primary (sucrose and total sugars) and secondary (total phenols and flavonoids) metabolites, including the activity and levels of phenylalanine ammonia lyase (PAL) were assessed. Moreover, a preliminary study of the effects during postharvest was performed. Borage extracts enhanced the primary metabolism by increasing leaf pigments and photosynthetic activity. Plant fresh weight increased upon treatments with 10 mL L-1 doses, as correctly estimated by multi-view angles images. Chlorophyll a fluorescence data showed that FEs were able to increase the number of active reaction centers per cross section; a similar trend was observed for the performance index. Ethylene was three-fold lower in FEs treatments. Nitrate and sugar levels did not change in response to the different treatments. Total flavonoids and phenols, as well as the total protein levels, the in vitro PAL specific activity, and the levels of PAL-like polypeptides were increased by all borage extracts, with particular regard to FEs. FEs also proved efficient in preventing degradation and inducing an increase in photosynthetic pigments during storage. In conclusion, borage extracts, with particular regard to the flower ones, appear to indeed exert biostimulant effects on lettuce; future work will be required to further investigate on their efficacy in different conditions and/or species. PMID- 28638393 TI - Non-chemical Control of Root Parasitic Weeds with Biochar. AB - This study tested whether soil-applied biochar can impact the seed germination and attachment of root parasitic weeds. Three hypotheses were evaluated: (i) biochar adsorbs host-exuded signaling molecules; (ii) biochar activates plants' innate system-wide defenses against invasion by the parasite; and (iii) biochar has a systemic influence on the amount of seed germination stimulant produced or released by the host plant. Three types of experiments were performed: (I) pot trials with tomato (Solanum lycopersicum) infested with Phelipanche aegyptiaca PERS. (Egyptian broomrape) and three different types of biochar at concentrations ranging from 0 to 1.5% weight, wherein tomato plant biomass, P. aegyptiaca biomass, and number of P. aegyptiaca-tomato root attachments were quantified; (II) split-root biochar/no-biochar experiments under hydroponic growing conditions performed in polyethylene bags with tomato plant rootings, wherein P. aegyptiaca seed germination percentage and radicle attachment numbers were quantified; and (III) germination trials, wherein the effect of biochar adsorption of GR-24 (artificial germination stimulant) on P. aegyptiaca seed germination was quantified. Addition of biochar to the pot soil (Experiment I) resulted in lower levels of P. aegyptiaca infection in the tomato plants, mainly through a decrease in the number of P. aegyptiaca attachments. This led to improved tomato plant growth. In Experiment II, P. aegyptiaca seed germination percentage decreased in the biochar-treated root zone as compared with the no biochar control root zone; P. aegyptiaca radicle attachment numbers decreased accordingly. This experiment showed that biochar did not induce a systemic change in the activity of the stimulant molecules exuded by the tomato roots, toxicity to the radicles, or a change in the ability of the radicles to penetrate the tomato roots. The major cause for the decrease in germination percentage was physical adsorption of the stimulant molecule by the biochar (Experiment III). Adding biochar to soil to reduce infections by root parasitic weeds is an innovative means of control with the potential to become an important strategy both for non-chemical treatment of this family of pests, and for enhancing the economic feasibility of the pyrolysis/biochar platform. This platform is often viewed as one of a handful of credible strategies for helping to mitigate climate change. PMID- 28638394 TI - A Comparative Study of Selected Physical and Biochemical Traits of Wild-Type and Transgenic Sorghum to Reveal Differences Relevant to Grain Quality. AB - Transgenic sorghum featuring RNAi suppression of certain kafirins was developed recently, to address the problem of poor protein digestibility in the grain. However, it was not firmly established if other important quality parameters were adversely affected by this genetic intervention. In the present study several quality parameters were investigated by surveying several important physical and biochemical grain traits. Important differences in grain weight, density and endosperm texture were found that serve to differentiate the transgenic grains from their wild-type counterpart. In addition, ultrastructural analysis of the protein bodies revealed a changed morphology that is indicative of the effect of suppressed kafirins. Importantly, lysine was found to be significantly increased in one of the transgenic lines in comparison to wild-type; while no significant changes in anti-nutritional factors could be detected. The results have been insightful for demonstrating some of the corollary changes in transgenic sorghum grain, that emerge from imposed kafirin suppression. PMID- 28638395 TI - Modulation of Antioxidant Defense System Is Associated with Combined Drought and Heat Stress Tolerance in Citrus. AB - Drought and high temperatures are two major abiotic stress factors that often occur simultaneously in nature, affecting negatively crop performance and yield. Moreover, these environmental challenges induce oxidative stress in plants through the production of reactive oxygen species (ROS). Carrizo citrange and Cleopatra mandarin are two citrus genotypes with contrasting ability to cope with the combination of drought and heat stress. In this work, a direct relationship between an increased antioxidant activity and stress tolerance is reported. According to our results, the ability of Carrizo plants to efficiently coordinate superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), and glutathione reductase (GR) activities involved in ROS detoxification along with the maintenance of a favorable GSH/GSSG ratio could be related to their relative tolerance to this stress combination. On the other hand, the increment of SOD activity and the inefficient GR activation along with the lack of CAT and APX activities in Cleopatra plants in response to the combination of drought and heat stress, could contribute to an increased oxidative stress and the higher sensibility of this citrus genotype to this stress combination. PMID- 28638396 TI - Defoliating Insect Mass Outbreak Affects Soil N Fluxes and Tree N Nutrition in Scots Pine Forests. AB - Biotic stress by mass outbreaks of defoliating pest insects does not only affect tree performance by reducing its photosynthetic capacity, but also changes N cycling in the soil of forest ecosystems. However, how insect induced defoliation affects soil N fluxes and, in turn, tree N nutrition is not well-studied. In the present study, we quantified N input and output fluxes via dry matter input, throughfall, and soil leachates. Furthermore, we investigated the effects of mass insect herbivory on tree N acquisition (i.e., organic and inorganic 15N net uptake capacity of fine roots) as well as N pools in fine roots and needles in a Scots pine (Pinus sylvestris L.) forest over an entire vegetation period. Plots were either infested by the nun moth (Lymantria monacha L.) or served as controls. Our results show an increased N input by insect feces, litter, and throughfall at the infested plots compared to controls, as well as increased leaching of nitrate. However, the additional N input into the soil did not increase, but reduce inorganic and organic net N uptake capacity of Scots pine roots. N pools in the fine roots and needles of infested trees showed an accumulation of total N, amino acid-N, protein-N, and structural N in the roots and the remaining needles as a compensatory response triggered by defoliation. Thus, although soil N availability was increased via surplus N input, trees did not respond with an increased N acquisition, but rather invested resources into defense by accumulation of amino acid-N and protein-N as a survival strategy. PMID- 28638397 TI - Generation, Annotation, and Analysis of a Large-Scale Expressed Sequence Tag Library from Arabidopsis pumila to Explore Salt-Responsive Genes. AB - Arabidopsis pumila is an ephemeral plant, and a close relative of the model plant Arabidopsis thaliana, but it possesses higher photosynthetic efficiency, higher propagation rate, and higher salinity tolerance compared to those A. thaliana, thus providing a candidate plant system for gene mining for environmental adaption and salt tolerance. However, A. pumila is an under-explored resource for understanding the genetic mechanisms underlying abiotic stress adaptation. To improve our understanding of the molecular and genetic mechanisms of salt stress adaptation, more than 19,900 clones randomly selected from a cDNA library constructed previously from leaf tissue exposed to high-salinity shock were sequenced. A total of 16,014 high-quality expressed sequence tags (ESTs) were generated, which have been deposited in the dbEST GenBank under accession numbers JZ932319 to JZ948332. Clustering and assembly of these ESTs resulted in the identification of 8,835 unique sequences, consisting of 2,469 contigs and 6,366 singletons. The blastx results revealed 8,011 unigenes with significant similarity to known genes, while only 425 unigenes remained uncharacterized. Functional classification demonstrated an abundance of unigenes involved in binding, catalytic, structural or transporter activities, and in pathways of energy, carbohydrate, amino acid, or lipid metabolism. At least seven main classes of genes were related to salt-tolerance among the 8,835 unigenes. Many previously reported salt tolerance genes were also manifested in this library, for example VP1, H+-ATPase, NHX1, SOS2, SOS3, NAC, MYB, ERF, LEA, P5CS1. In addition, 251 transcription factors were identified from the library, classified into 42 families. Lastly, changes in expression of the 12 most abundant unigenes, 12 transcription factor genes, and 19 stress-related genes in the first 24 h of exposure to high-salinity stress conditions were monitored by qRT-PCR. The large scale EST library obtained in this study provides first-hand information on gene sequences expressed in young leaves of A. pumila exposed to salt shock. The rapid discovery of known or unknown genes related to salinity stress response in A. pumila will facilitate the understanding of complex adaptive mechanisms for ephemerals. PMID- 28638398 TI - Discovery of Putative Herbicide Resistance Genes and Its Regulatory Network in Chickpea Using Transcriptome Sequencing. AB - Background: Chickpea (Cicer arietinum L.) contributes 75% of total pulse production. Being cheaper than animal protein, makes it important in dietary requirement of developing countries. Weed not only competes with chickpea resulting into drastic yield reduction but also creates problem of harboring fungi, bacterial diseases and insect pests. Chemical approach having new herbicide discovery has constraint of limited lead molecule options, statutory regulations and environmental clearance. Through genetic approach, transgenic herbicide tolerant crop has given successful result but led to serious concern over ecological safety thus non-transgenic approach like marker assisted selection is desirable. Since large variability in tolerance limit of herbicide already exists in chickpea varieties, thus the genes offering herbicide tolerance can be introgressed in variety improvement programme. Transcriptome studies can discover such associated key genes with herbicide tolerance in chickpea. Results: This is first transcriptomic studies of chickpea or even any legume crop using two herbicide susceptible and tolerant genotypes exposed to imidazoline (Imazethapyr). Approximately 90 million paired-end reads generated from four samples were processed and assembled into 30,803 contigs using reference based assembly. We report 6,310 differentially expressed genes (DEGs), of which 3,037 were regulated by 980 miRNAs, 1,528 transcription factors associated with 897 DEGs, 47 Hub proteins, 3,540 putative Simple Sequence Repeat-Functional Domain Marker (SSR-FDM), 13,778 genic Single Nucleotide Polymorphism (SNP) putative markers and 1,174 Indels. Randomly selected 20 DEGs were validated using qPCR. Pathway analysis suggested that xenobiotic degradation related gene, glutathione S-transferase (GST) were only up-regulated in presence of herbicide. Down regulation of DNA replication genes and up-regulation of abscisic acid pathway genes were observed. Study further reveals the role of cytochrome P450, xyloglucan endotransglucosylase/hydrolase, glutamate dehydrogenase, methyl crotonoyl carboxylase and of thaumatin-like genes in herbicide resistance. Conclusion: Reported DEGs can be used as genomic resource for future discovery of candidate genes associated with herbicide tolerance. Reported markers can be used for future association studies in order to develop marker assisted selection (MAS) for refinement. In endeavor of chickpea variety development programme, these findings can be of immense use in improving productivity of chickpea germplasm. PMID- 28638399 TI - Recent Genetic Gains in Nitrogen Use Efficiency in Oilseed Rape. AB - Nitrogen is essential for plant growth, and N fertilization allows farmers to obtain high yields and produce sufficient agricultural commodities. On the other hand, nitrogen losses potentially cause adverse effects to ecosystems and to human health. Increasing nitrogen use efficiency (NUE) is vital to solve the conflict between productivity, to secure the demand of a growing world population, and the protection of the environment. To ensure this, genetic improvement is considered to be a paramount aspect toward ecofriendly crop production. Winter oilseed rape (Brassica napus L.) is the second most important oilseed crop in the world and is cultivated in many regions across the temperate zones. To our knowledge, this study reports the most comprehensive field-based data generated to date for an empirical evaluation of genetic improvement in winter oilseed rape varieties under two divergent nitrogen fertilization levels (NFLs). A collection of 30 elite varieties registered between 1989 and 2014, including hybrids and open pollinated varieties, was tested in a 2-year experiment in 10 environments across Germany for changes in seed yield and seed quality traits. Furthermore, NUE was calculated. We observed a highly significant genetics-driven increase in seed yield per-se and, thus, increased NUE at both NFLs. On average, seed yield from modern open-pollinated varieties and modern hybrids was higher than from old open-pollinated varieties and old hybrids. The annual yield progress across all tested varieties was ~35 kg ha-1 year-1 at low nitrogen and 45 kg ha-1 year-1 under high nitrogen fertilization. Furthermore, in modern varieties an increased oil concentration and decreased protein concentration was observed. Despite, the significant effects of nitrogen fertilization, a surprisingly low average seed yield gap of 180 kg N ha-1 was noted between high and low nitrogen fertilization. Due to contrary effects of N fertilization on seed yield per-se and seed oil concentration an oil yield of 2.04 t ha-1 was measured at both N levels. Collectively, the data reveal that genetic improvement through modern breeding techniques in conjunction with reduced N fertilizer inputs has a tremendous potential to increase NUE of oilseed rape. PMID- 28638400 TI - Integration of Cadmium Accumulation, Subcellular Distribution, and Physiological Responses to Understand Cadmium Tolerance in Apple Rootstocks. AB - Cadmium (Cd) is a nonessential and highly toxic element causing agricultural problems. However, little information is available about the variation in Cd tolerance among apple rootstocks and its underlying physiological regulation mechanisms. This study investigated Cd accumulation, subcellular distribution, and chemical forms as well as physiological changes among four apple rootstocks exposed to either 0 or 300 MUM CdCl2. The results showed that variations in Cd tolerance existed among these rootstocks. Cd exposure caused decline in photosynthesis, chlorophyll and biomass in four apple rootstocks, which was less pronounced in M. baccata, indicating its higher Cd tolerance. This finding was corroborated with higher Cd tolerance indexes (TIs) of the whole plant in M. baccata than those in the other three apple rootstocks. Among the four apple rootstocks, M. baccata displayed the lowest Cd concentrations in roots, wood, and leaves, the smallest total Cd amounts as well as the lowest BCF. In apple rootstocks, it was found that to immobilize Cd in cell wall and soluble fraction (most likely in vacuole) and to convert it into pectate- or protein- integrated forms and undissolved Cd phosphate forms may be the primary strategies to reduce Cd mobility and toxicity. The physiological changes including ROS, carbohydrates and antioxidants were in line with the variations of Cd tolerance among four apple rootstocks. In comparison with the other three apple rootstocks, M. baccata had lower concentrations of ROS in roots and bark, H2O2 in roots and leaves and MDA in roots, wood and bark, but higher concentrations of soluble sugars in bark and starch in roots and leaves, and enhanced antioxidants. These results indicate that M. baccata are more tolerant to Cd stress than the other three apple rootstocks under the current experiment conditions, which is probably related to Cd accumulation, subcellular partitioning and chemical forms of Cd and well coordinated antioxidant defense mechanisms. PMID- 28638401 TI - Development of Elite BPH-Resistant Wide-Spectrum Restorer Lines for Three and Two Line Hybrid Rice. AB - Hybrid rice has contributed significantly to the world food security. Breeding of elite high-yield, strong-resistant broad-spectrum restorer line is an important strategy for hybrid rice in commercial breeding programs. Here, we developed three elite brown planthopper (BPH)-resistant wide-spectrum restorer lines by pyramiding big-panicle gene Gn8.1, BPH-resistant genes Bph6 and Bph9, fertility restorer genes Rf3, Rf4, Rf5, and Rf6 through molecular marker assisted selection. Resistance analysis revealed that the newly developed restorer lines showed stronger BPH-resistance than any of the single-gene donor parent Luoyang-6 and Luoyang-9. Moreover, the three new restorer lines had broad spectrum recovery capabilities for Honglian CMS, Wild abortive CMS and two-line GMS sterile lines, and higher grain yields than that of the recurrent parent 9,311 under nature field conditions. Importantly, the hybrid crosses also showed good performance for grain yield and BPH-resistance. Thus, the development of elite BPH-resistant wide-spectrum restorer lines has a promising future for breeding of broad spectrum BPH-resistant high-yield varieties. PMID- 28638402 TI - DNA Methylation, Nuclear Organization, and Cancer. AB - The dramatic re-organization of the cancer cell nucleus creates telltale morphological features critical for pathological staging of tumors. In addition, the changes to the mutational and epigenetic landscape in cancer cells alter the structure and stability of the genome and directly contribute to malignancy. DNA methylation is one of the best studied epigenetic changes in cancer, as nearly every type of cancer studied shows a loss of DNA methylation spread across most of the genome. This global hypomethylation is accompanied by hypermethylation at distinct loci, and much of the work on DNA methylation in cancer has focused on how local changes contribute to gene expression. However, the emerging picture is that the changes to DNA methylation in cancer cells has little direct effect on gene expression but instead impacts the organization of the genome in the nucleus. Several recent studies that take a broad view of the cancer epigenome find that the most profound changes to the cancer methylome are spread across large segments of the genome, and that the focal changes are reflective of a whole reorganization of epigenome. Hallmarks of nuclear reorganization in cancer are found in the long regions of chromatin marked by histone methylation (LOCKs) and nuclear lamina interactions (LADs). In this review, we focus on a novel perspective that DNA methylation changes in cancer impact the global structure of heterochromatin, LADs and LOCKs, and how these global changes, in turn, contribute to gene expression changes and genomic stability. PMID- 28638403 TI - Jaburetox: update on a urease-derived peptide. AB - Urease from Canavalia ensiformis seeds was the first enzyme ever to be crystallized, in 1926. These proteins, found in plants, bacteria and fungi, present different biological properties including catalytic hydrolysis of urea, and also enzyme-independent activities, such as induction of exocytosis, pro inflammatory effects, neurotoxicity, antifungal and insecticidal properties. Urease is toxic to insects and fungi per se but part of this toxicity relies on an internal peptide (~11 kDa), which is released upon digestion of the protein by insect enzymes. A recombinant form of this peptide, called jaburetox (JBTX), was constructed using jbureII gene as a template. The peptide exhibits liposome disruption properties, and insecticidal and fungicidal activities. Here we review the known biological properties activities of JBTX, and comment on new ones not yet fully characterized. JBTX was able to cause mortality of Aedes aegypti larvae in a feeding assay whereas in a dose as low as of 0.1 MUg it provoked death of Triatoma infestans bugs. JBTX (10-5-10-6 M) inhibits the growth of E. coli, P. aeruginosa and B. cereus after 24 h incubation. Multilamellar liposomes interacting with JBTX undergo reorganization of the membrane's lipids as detected by small angle X-ray scattering (SAXS) studies. Encapsulating JBTX into lipid nanoparticles led to an increase of the peptide's antifungal activity. Transgenic tobacco and sugarcane plants expressing the insecticidal peptide JBTX, showed increased resistance to attack of the insect pests Spodoptera frugiperda, Diatraea saccharalis and Telchin licus licus. Many questions remain unanswered; however, so far, JBTX has shown to be a versatile peptide that can be used against various insect and fungus species, and in new bacterial control strategies. PMID- 28638405 TI - A Combined One-Class SVM and Template-Matching Approach for User-Aided Human Fall Detection by Means of Floor Acoustic Features. AB - The primary cause of injury-related death for the elders is represented by falls. The scientific community devoted them particular attention, since injuries can be limited by an early detection of the event. The solution proposed in this paper is based on a combined One-Class SVM (OCSVM) and template-matching classifier that discriminate human falls from nonfalls in a semisupervised framework. Acoustic signals are captured by means of a Floor Acoustic Sensor; then Mel Frequency Cepstral Coefficients and Gaussian Mean Supervectors (GMSs) are extracted for the fall/nonfall discrimination. Here we propose a single-sensor two-stage user-aided approach: in the first stage, the OCSVM detects abnormal acoustic events. In the second, the template-matching classifier produces the final decision exploiting a set of template GMSs related to the events marked as false positives by the user. The performance of the algorithm has been evaluated on a corpus containing human falls and nonfall sounds. Compared to the OCSVM only approach, the proposed algorithm improves the performance by 10.14% in clean conditions and 4.84% in noisy conditions. Compared to Popescu and Mahnot (2009) the performance improvement is 19.96% in clean conditions and 8.08% in noisy conditions. PMID- 28638406 TI - An HTML5-Based Pure Website Solution for Rapidly Viewing and Processing Large Scale 3D Medical Volume Reconstruction on Mobile Internet. AB - This study aimed to propose a pure web-based solution to serve users to access large-scale 3D medical volume anywhere with good user experience and complete details. A novel solution of the Master-Slave interaction mode was proposed, which absorbed advantages of remote volume rendering and surface rendering. On server side, we designed a message-responding mechanism to listen to interactive requests from clients (Slave model) and to guide Master volume rendering. On client side, we used HTML5 to normalize user-interactive behaviors on Slave model and enhance the accuracy of behavior request and user-friendly experience. The results showed that more than four independent tasks (each with a data size of 249.4 MB) could be simultaneously carried out with a 100-KBps client bandwidth (extreme test); the first loading time was <12 s, and the response time of each behavior request for final high quality image remained at approximately 1 s, while the peak value of bandwidth was <50-KBps. Meanwhile, the FPS value for each client was >=40. This solution could serve the users by rapidly accessing the application via one URL hyperlink without special software and hardware requirement in a diversified network environment and could be easily integrated into other telemedical systems seamlessly. PMID- 28638404 TI - Puerarin Protects against Cardiac Fibrosis Associated with the Inhibition of TGF beta1/Smad2-Mediated Endothelial-to-Mesenchymal Transition. AB - BACKGROUND: Puerarin is a kind of flavonoids and is extracted from Chinese herb Kudzu root. Puerarin is widely used as an adjuvant therapy in Chinese clinics. But little is known about its effects on regulating cardiac fibrosis. METHODS: Mice were subjected to transverse aorta constriction (TAC) for 8 weeks; meanwhile puerarin was given 1 week after TAC. Cardiac fibrosis was assessed by pathological staining. The mRNA and protein changes of CD31 and vimentin in both animal and human umbilical vein endothelial cells (HUVECs) models were detected. Immunofluorescence colocalization of CD31 and vimentin and scratch test were carried out to examine TGF-beta1-induced changes in HUVECs. The agonist and antagonist of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) were used to explore the underlying mechanism. RESULTS: Puerarin mitigated TAC-induced cardiac fibrosis, accompanied with suppressed endothelial-to-mesenchymal transition (EndMT). The consistent results were achieved in HUVECs model. TGF beta1/Smad2 signaling pathway was blunted and PPAR-gamma expression was upregulated in puerarin-treated mice and HUVECs. Pioglitazone could reproduce the protective effect in HUVECs, while GW9662 reversed this effect imposed by puerarin. CONCLUSION: Puerarin protected against TAC-induced cardiac fibrosis, and this protective effect may be attributed to the upregulation of PPAR-gamma and the inhibition of TGF-beta1/Smad2-mediated EndMT. PMID- 28638407 TI - The Proline 7 Substitution in the Preproneuropeptide Y Is Associated with Higher Hepatic Lipase Activity In Vivo. AB - Hepatic lipase (HL) functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Plasma HL activity is known to be regulated by hormonal and metabolic factors, but HL responsiveness to insulin as well as its role in modulating atherosclerotic risk is still controversial. We investigated on the influence of a known polymorphism in the neurotransmitter neuropeptide Y (NPY) on HL activity in two different cohorts consisting of diabetic and nondiabetic patients. HL activity was 24% and 34% higher on nondiabetic and diabetic subjects in the presence of the 7Pro allele in NPY, respectively. The presence of the 7Pro allele was an independent predictor of HL activity in multivariate analyses in both cohorts. These data suggest a regulatory effect of NPY on HL activity. Among carriers of the 7Pro allele, we also found a statistically significant lower absolute number of infarctions compared to noncarriers (p < 0.05) and a nonsignificant trend towards less myocardial infarction in the 7Pro allele diabetic carriers (p = 0.085). In conclusion, the common 7Pro allele in NPY was associated with higher HL activity in nondiabetic and diabetic subjects and its presence seems to coincide with a lower frequency of certain cardiovascular events. PMID- 28638408 TI - Reanalysis and External Validation of a Decision Tree Model for Detecting Unrecognized Diabetes in Rural Chinese Individuals. AB - We reanalyzed previous data to develop a more simplified decision tree model as a screening tool for unrecognized diabetes, using basic information in Beijing community health records. Then, the model was validated in another rural town. Only three non-laboratory-based risk factors (age, BMI, and presence of hypertension) with fewer branches were used in the new model. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve (AUC) for detecting diabetes were calculated. The AUC values in internal and external validation groups were 0.708 and 0.629, respectively. Subjects with high risk of diabetes had significantly higher HOMA-IR, but no significant difference in HOMA-B was observed. This simple tool will help general practitioners and residents assess the risk of diabetes quickly and easily. This study also validates the strong associations of insulin resistance and early stage of diabetes, suggesting that more attention should be paid to the current model in rural Chinese adult populations. PMID- 28638410 TI - Low Survival Rates of Oral and Oropharyngeal Squamous Cell Carcinoma. AB - AIM: To assess the epidemiological and clinical factors that influence the prognosis of oral and oropharyngeal squamous cell carcinoma (SCC). METHODS: One hundred and twenty-one cases of oral and oropharyngeal SCC were selected. The survival curves for each variable were estimated using the Kaplan-Meier method. The Cox regression model was applied to assess the effect of the variables on survival. RESULTS: Cancers at an advanced stage were observed in 103 patients (85.1%). Cancers on the tongue were more frequent (23.1%). The survival analysis was 59.9% in one year, 40.7% in two years, and 27.8% in 5 years. There was a significant low survival rate linked to alcohol intake (p = 0.038), advanced cancer staging (p = 0.003), and procedures without surgery (p < 0.001). When these variables were included in the Cox regression model only surgery procedures (p = 0.005) demonstrated a significant effect on survival. CONCLUSION: The findings suggest that patients who underwent surgery had a greater survival rate compared with those that did not. The low survival rates and the high percentage of patients diagnosed at advanced stages demonstrate that oral and oropharyngeal cancer patients should receive more attention. PMID- 28638409 TI - Differential Fasting Plasma Glucose and Ketone Body Levels in GHRKO versus 3xTg AD Mice: A Potential Contributor to Aging-Related Cognitive Status? AB - Cognitive function declines with age and appears to correlate with decreased cerebral metabolic rate (CMR). Caloric restriction, an antiaging manipulation that extends life-span and can preserve cognitive function, is associated with decreased glucose uptake, decreased lactate levels, and increased ketone body (KB) levels in the brain. Since the majority of brain nutrients come from the periphery, this study examined whether the capacity to regulate peripheral glucose levels and KB production differs in animals with successful cognitive aging (growth hormone receptor knockouts, GHRKOs) versus unsuccessful cognitive aging (the 3xTg-AD mouse model of Alzheimer's disease). Animals were fasted for 5 hours with their plasma glucose and KB levels subsequently measured. Intriguingly, in GHRKO mice, compared to those in controls, fasting plasma glucose levels were significantly decreased while their KB levels were significantly increased. Conversely, 3xTg-AD mice, compared to controls, exhibited significantly elevated plasma glucose levels and significantly reduced plasma KB levels. Taken together, these results suggest that the capacity to provide the brain with KBs versus glucose throughout an animal's life could somehow help preserve cognitive function with age, potentially through minimizing overall brain exposure to reactive oxygen species and advanced glycation end products and improving mitochondrial function. PMID- 28638411 TI - Regular Dental Visits: Influence on Health-Related Quality of Life in 1,607 Patients with Oral Squamous Cell Carcinoma. AB - BACKGROUND: The incidence of oral squamous cell carcinoma (OSCC) is in the top 10 of all cancer entities. Regular oral examinations by dentists play an important role in oral cancer prevention. METHODS: Patients with OSCC (n = 1,607) and physicians (n = 1,489) completed questionnaires during the DOSAK Rehab Study. The psychosocial and functional factors collected in these questionnaires were assessed in the present study. We compared patients who visited their dentist at least once a year (group A) with those who visited their dentist less than once a year (group B). RESULTS: Patients in group A had significantly better health related quality of life after tumor treatment than patients in group B. Patients in group A also had a smaller tumor size and less lymph node metastasis and lost fewer teeth during the treatment. This resulted in better prosthetic rehabilitation and better psychological status after tumor treatment. CONCLUSIONS: Dentists play an important role in the early recognition of oral cancer. This study should encourage dentists to take a more active role in oral cancer prevention. PMID- 28638412 TI - Molecular Identification of Aminoglycoside-Modifying Enzymes and Plasmid-Mediated Quinolone Resistance Genes among Klebsiella pneumoniae Clinical Isolates Recovered from Egyptian Patients. AB - Inappropriate use of antibiotics in clinical settings is thought to have led to the global emergence and spread of multidrug-resistant pathogens. The goal of this study was to investigate the prevalence of genes encoding aminoglycoside resistance and plasmid-mediated quinolone resistance among clinical isolates of Klebsiella pneumoniae. All K. pneumoniae isolates were phenotypically identified using API 20E and then confirmed genotypically through amplification of the specific K. pneumoniae phoE gene. All isolates were genotyped by the enterobacterial repetitive intergenic consensus polymerase chain reaction technique (ERIC-PCR). Antibiotic susceptibility testing was done by a modified Kirby-Bauer method and broth microdilution. All resistant or intermediate resistant isolates to either gentamicin or amikacin were screened for 7 different genes encoding aminoglycoside-modifying enzymes (AMEs). In addition, all resistant or intermediate-resistant isolates to either ciprofloxacin or levofloxacin were screened for 5 genes encoding the quinolone resistance protein (Qnr), 1 gene encoding quinolone-modifying enzyme, and 3 genes encoding quinolone efflux pumps. Biotyping using API 20E revealed 13 different biotypes. Genotyping demonstrated that all isolates were related to 2 main phylogenetic groups. Susceptibility testing revealed that carbapenems and tigecycline were the most effective agents. Investigation of genes encoding AMEs revealed that acc(6')-Ib was the most prevalent, followed by acc(3')-II, aph(3')-IV, and ant(3'')-I. Examination of genes encoding Qnr proteins demonstrated that qnrB was the most prevalent, followed by qnrS, qnrD, and qnrC. It was found that 61%, 26%, and 12% of quinolone-resistant K. pneumoniae isolates harbored acc(6')-Ib-cr, oqxAB, and qebA, respectively. The current study demonstrated a high prevalence of aminoglycoside and quinolone resistance genes among clinical isolates of K. pneumoniae. PMID- 28638413 TI - Uterine Cavity Abnormalities in Patients with Endometriosis in Alexandria: A Diagnostic Test Accuracy Study. AB - Endometriosis is strongly associated with infertility. Endometrial polyps are prevalent in infertile women and they have similar pathological characteristics to endometriosis, suggesting a possible association. Uterine malformations as uterine septum and hypoplastic uterus are also linked to endometriosis. Hysterosalpingogram and transvaginal ultrasonography are used to diagnose endometrial lesions. Hysteroscopy can detect small lesions that might be missed. Recently, 4D ultrasonography is being used, but which is superior has not been established yet. We aim to compare 4D ultrasonography to office hysteroscopy in evaluating uterine cavity in cases with endometriosis; also we aim at correlating these findings with the stage of endometriosis. 50 cases of endometriosis diagnosed by laparoscopy were randomly selected from El Shatby fertility clinic, Alexandria University, Egypt, with exclusion of cases with any previous intrauterine surgery or any hormonal treatment. Transvaginal 4D ultrasonography and office hysteroscopy were done. 4D ultrasonography agreed with office hysteroscopy in diagnosing abnormal uterine findings in 14 cases and four additional cases were diagnosed by hysteroscopy alone. Conclusion. Endometrial polyps, septate uterus, and hypoplastic uterus are more prevalent among infertile women who happen to have endometriosis. 4D ultrasonography and office hysteroscopy are equally successful in assessing the uterine cavity. PMID- 28638415 TI - Corrigendum to "Physiologic Conditions Affect Toxicity of Ingested Industrial Fluoride". AB - [This corrects the article DOI: 10.1155/2013/439490.]. PMID- 28638414 TI - An Examination of the Role of Transcriptional and Posttranscriptional Regulation in Rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is an aggressive family of soft tissue tumors that most commonly manifests in children. RMS variants express several skeletal muscle markers, suggesting myogenic stem or progenitor cell origin of RMS. In this review, the roles of both recently identified and well-established microRNAs in RMS are discussed and summarized in a succinct, tabulated format. Additionally, the subtypes of RMS are reviewed along with the involvement of basic helix-loop helix (bHLH) proteins, Pax proteins, and microRNAs in normal and pathologic myogenesis. Finally, the current and potential future treatment options for RMS are outlined. PMID- 28638416 TI - Corrigendum to "Detection of Gastrointestinal Pathogens from Stool Samples on Hemoccult Cards by Multiplex PCR". AB - [This corrects the article DOI: 10.1155/2017/3472537.]. PMID- 28638417 TI - Development and Validation of a Decision-Making Stratification Algorithm to Optimize the Use of Rapid Diagnostic Testing for Patients with Staphylococcus Bacteremia. AB - PURPOSE: To evaluate whether introducing rapid diagnostic testing in conjunction with implementing a stratification algorithm for testing eligibility would be an appropriate clinical and cost saving approach. METHOD: An internal concurrent 4 month observational study was performed. Positive blood cultures continued to be worked up in accordance with standard of care. An additional call to the infectious disease (ID) pharmacy service occurred for all positive blood cultures with Gram-positive cocci in clusters (GPCC). The ID pharmacy service investigated each case using a prespecified stratification algorithm to minimize unnecessary use of rapid identification testing. RESULTS: 43 patients with GPCC were screened. Only nine patients met inclusion criteria for QuickFISHTM testing. The average expected time avoided to optimize antibiotic therapy is 35 +/- 16 hours. If the QuickFISH test had been indiscriminately implemented for all cases, the cost for performing this test would have been $5,590. However, using the prespecified algorithm, only 9 patients were tested for a projected cost of $1,170. CONCLUSION: Introducing rapid diagnostic testing in conjunction with implementing patient stratification algorithm for rapid identification of GPCC from blood cultures in addition to the ID pharmacy intervention will provide a positive impact on the clinical and economic outcomes in our health care setting. PMID- 28638419 TI - Diagnostic Yield of a Direct Quantitative Smear of Lower Respiratory Tract Secretions in Patients with Suspected Pneumonia Compared to a Semi-quantitative Culture. AB - BACKGROUND: Microorganism isolation from respiratory tract specimens is the standard of care in patients with suspected nosocomial and ventilator associated pneumonia. However, these methods are time-consuming and are influenced by several factors. A direct quantitative smear (DQS) with proper staining may be an easy, cost-effective, rapid method. We evaluated the diagnostic yield of direct smears compared to semi-quantitative culture methods. MATERIALS AND METHODS: Hospitalized, intubated patients with clinically suspected pneumonia and patients who underwent diagnostic bronchoscopic alveolar lavage (BAL) and trans endotracheal aspiration (TEA) were enrolled in a prospective study. The obtained specimens were Gram stained and microorganisms were computed per 10 high-power fields (HPFs) of light microscopy. All samples were cultured by a standard semi quantitative method. Colony-forming units (CFU) >104/mL and >105 CFU/mL were reported as culture-positive for BAL and TEA, respectively. RESULTS: A total of 331 respiratory specimens were analyzed. Based on culture results, the best cut off point was 35 microorganisms in 10 HPFs of microscopy and provided 90.4% sensitivity and 90.8% specificity. The best cut-off point for 25 microorganisms in 10 fields of light microscopy provided 95.2% sensitivity and 85.7% specificity. CONCLUSION: A DQS obtained by BAL and TEA may be a reliable and rapid method to diagnose pneumonia and anticipate semi-quantitative culture results. The sensitivity and specificity of a direct smear have adequate diagnostic yield to recommend it as an adjunct to microorganism-isolation methods. PMID- 28638418 TI - The Expression of STAT3 and STAT5A Genes in Severe Refractory Asthma. AB - BACKGROUND: Despite being a high burden disorder, the pathogenesis of severe refractory asthma (SRA) is poorly understood. There are some evidences for the involvement of members of the signal transducer and activator of transcription (STAT) family, including STAT3 and STAT5a. Our study aimed to evaluate the gene expression of STAT3 and STAT5a in asthma and SRA to establish if there is an association. MATERIALS AND METHODS: Using quantitative real-time polymerase chain reactions (qRT-PCR), the transcript levels of STAT3 and STAT5a were evaluated in peripheral blood mononuclear lymphocytes (PBML) isolated from 13 patients with SRA, 14 with mild asthma, and 30 healthy volunteers. RESULTS: There were no significant differences in STAT3 transcript levels between study groups. There was however a significant difference in STAT5a transcript levels between cases and controls (p-value=0.03). In comparison to healthy controls, the levels of STAT5a were notably lower in patients with mild asthma and significantly least in those with SRA. CONCLUSION: Our study found no appreciable association between STAT3 gene expression and either mild asthma or SRA. However, the STAT5a down regulation in asthmatics and especially SRA is a notable finding which denotes on association between STAT5a and different level of asthma. PMID- 28638420 TI - Treatment Delay and Total Delay among Pulmonary Tuberculosis Patients in the North of Iran: Application Survival Data Analysis. AB - BACKGROUND: Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. Identifying the factors associated with the treatment delay and total delay would be helpful in the prevention of tuberculosis and in reducing the burden on the health care system. The objective of this study was to assess the treatment delay and total delay in TB patients and investigate the factors causing these delays. MATERIALS AND METHODS: This was a longitudinal study conducted in 2009-2015. Our study consisted of 1694 TB patients registered in the TB center of Mazandaran province. Data regarding the patients' demographic characteristics and clinical factors associated with treatment delay and total delay were analyzed. Kaplan Meier plots and log rank tests were used to assess the survival pattern. Cox proportional hazards model for multivariable analysis was discussed. We used mean values and median (Q2) [first quartile (Q1)-third quartile (Q3)] to describe delays. RESULTS: The median treatment delay and total delay were 35 (ranged 23-80) and 36 (ranged 24-82) days, respectively. The mean age of TB patients was 47.40+/-20.3. No significant association was found between the location of residence, nationality, gender, and type of pulmonary TB patients with treatment delay and total delay. Additionally, age, prison status of patients, HIV test, and contact history had a significant relationship with the treatment delay and total delay (p-value <0.05). It was shown that the median total delay in men patients in the <=14 year-old age group, imprisoner patients, rural patients, patients who have not received an HIV test, smear negative patients, those who are Iranian, and TB patients whose contact history was unknown was lower than that of others. The highest median treatment delay and total delay was in the >60 age groups, and were 41 and 44 days, respectively. Treatment delay was the same as the total delay except in the place of residence variable; median treatment delay among urban patients was less than that of rural patients. CONCLUSION: According to this study age, prison status of patients, HIV test and contact history had a significant relationship with the treatment delay and total delay (P-value<0.05). Understanding the factors that are closely associated with these delays is essential to effectively control TB and could be helpful in reducing these delays. PMID- 28638422 TI - Cognitive Impairment among Patients with Chronic Obstructive Pulmonary Disease Compared to Normal Individuals. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the most important causes of morbidity and mortality worldwide. The complications of COPD are numerous, and cognitive impairment is one of the most common complications that relates to mortality and morbidity directly. The present study was conducted with the aim of evaluating the prevalence of cognitive impairment in patients with COPD in comparison to normal individuals. MATERIALS AND METHODS: In this case-control study, 87 patients with COPD, whose diagnoses were confirmed by a pulmonologist based on the spirometry test findings, were included. The mini mental state examination (MMSE) questionnaire was administered for assessing the cognitive impairment. Arterial oxygen saturation was measured. The MMSE questionnaires were administered to 60 healthy, age-and-sex-matched individuals without a history of myocardial infarction or cerebrovascular infarction, and their arterial oxygen saturations were measured. The data were analyzed using the SPSS (version 20) software. RESULTS: In the case group, 42 patients (48.27%) had no cognitive impairment, 39 (44.82%) had mild, and 6 (6.89%) had moderate cognitive impairment. In the control group, 38 (63.33%) had no cognitive impairment, 20 (33.33%) mild and 2 (3.33 %) moderate cognitive impairment. There were significant relationships between the cognitive impairment and arterial oxygen saturation, severity of COPD, and higher age. The prevalence of cognitive impairment was 51.71% in the case group and 36.66% in the control group. CONCLUSION: According the results of the present study, COPD increased the risk of cognitive impairment significantly and is related to the severity of COPD, arterial oxygen saturation, and higher age. PMID- 28638421 TI - Item Selection and Content Validity of the Risk Factors of Post-Intubation Tracheal Stenosis Observation Questionnaire for ICU-Admitted Patients. AB - BACKGROUND: Laryngotracheal stenosis as a late complication of prolonged endotracheal intubation is a life-threatening event. In order to determine the related risk factors for this complication, which may vary among different countries, designing a valid questionnaire is necessary. The aim of this study was to select the items and evaluate the face and content validities of a questionnaire developed for assessment of risk factors of post-intubation tracheal stenosis (PITS) in patients admitted in the intensive care unit. MATERIALS AND METHODS: A mixed method study design was used in four steps in 2015, i.e., 1) a literature review, 2) focus groups with five experts in the field, 3) consultations with intensive care unit (ICU) specialists and thoracic surgeons, and 4) evaluation of content and face validity with 15 experts in a scientific panel using two self-administered questionnaires. Content validity index (CVI) was computed for individual items as well as the overall scale. RESULTS: We extracted the items from different sources of information. An initial version of the 52-item questionnaire was developed and classified into four domains including patient characteristics, intubation features, equipment-drugs, and complications. The items with an excellent modified kappa were included in the questionnaire. Five questions received more criticism instead of support and were removed (Item-CVI<0.55, fair modified kappa). The ones with an Item-CVI > 0.60 and a good modified kappa were revised, merged, or retained. The new 43-item questionnaire found a scale-level CVI, averaging (Scale-CVI/Ave) of 0.91. CONCLUSION: The PITS risk factors questionnaire was developed and validated through item selection, expert opinions, and content validity index. PMID- 28638424 TI - Application of Fuzzy Delphi in the Selection of COPD Risk Factors among Steel Industry Workers. AB - BACKGROUND: The Delphi method has been widely applied in many study areas to systematically gather experts' input on particular topic. Recently, it has become increasingly well known in health related research. This paper applied the Fuzzy Delphi method to enhance the validation of a questionnaire pertaining chronic obstructive pulmonary disease (COPD) risk factors among metal industry workers. MATERIALS AND METHODS: A detailed, predefined list of possible risk factors for COPD among metal industry workers was created through a comprehensive and exhaustive review of literature from 1995 to 2015. The COPD questionnaire were distributed among people identified as occupational, environmental, and hygiene experts. Linguistic variable using Likert scale was used by the expert to indicate their expert judgment of each item. Subsequently, the linguistic variable was converted into a triangular fuzzy number. The average score of the fuzzy number will be used to determine whether the item will be removed or retained. RESULTS: Ten experts were involved in evaluating 26 items. The experts were in agreement with most of the items, with an average fuzzy number range between 0.429 and 0.800. Two items were removed and three items were added, leaving a total 26 items selected for the COPD risk factors questionnaire. The experts were in disagreement with each other for items F10 and F11 where most of the experts claimed that the question is too subjective and based on self perception only. CONCLUSION: The fuzzy Delphi method enhanced the accuracy of the questionnaire pertaining to COPD risk factors, and decreased the length of the established tools. PMID- 28638423 TI - Relationship between Plasma Levels of Zinc and Clinical Course of Pneumonia. AB - BACKGROUND: Pneumonia is a common disease and is more prevalent among children and the elderly. Zinc (Zn) is an essential substance for the human body and plays an important role in regulating the immune system. Studies have shown a possible relation between the Zn plasma levels and pneumonia. MATERIALS AND METHODS: In a cross-sectional study, 100 patients with pneumonia, who were referred to the Educational-Medical Centers of Tabriz University of Medical Sciences, were included in the study. The plasma levels of Zn of all patients were measured. The patients were divided into two groups of normal and low plasma levels of Zn. The severity and clinical course of pneumonia, including the durations of fever, tachycardia, and tachypnea were evaluated and compared between the two groups. RESULTS: The plasma levels of Zn were normal in 56 patients and low in 44 patients. The mean duration of fever, tachycardia, and tachypnea in the group with normal plasma levels of Zn were 1.58+/-0.68, 2.04+/-0.81, and 2.78+/-0.84 days, respectively; and those in the group with decreased Zn plasma levels were 1.72+/-0.70, 2.18+/-0.90, and 2.97+/-0.91 days, respectively. There were no statistically significant differences between the two groups (P>0.05). However, the incidence of severe pneumonia was significantly less in the group with normal Zn plasma levels (P=0.001). CONCLUSION: Based on the findings of the present study, there was no statistically significant relationship between the plasma levels of Zn and the clinical course of pneumonia. However, Zn lowered the incidence of severe pneumonia. PMID- 28638425 TI - The Effect of Wood Aerosols and Bioaerosols on the Respiratory Systems of Wood Manufacturing Industry Workers in Golestan Province. AB - BACKGROUND: Occupational exposure to dust leads to acute and chronic respiratory diseases, occupational asthma, and depressed lung function. In the light of a lack of comprehensive studies on the exposure of Iranian workers to wood dusts, the objective of this study was to monitor the occupational exposure to wood dust and bioaerosol, and their correlation with the lung function parameters in chipboard manufacturing industry workers. MATERIALS AND METHODS: A cross sectional study was conducted on chipboard workers in Golestan Province; a total of 150 men (100 exposed cases and 50 controls) were assessed. Workers were monitored for inhalable wood dust and lung function parameters, i.e., FVC, FEV1, FEV1/FVC, and FEF25-75%. The workers' exposure to bioaerosols was measured using a bacterial sampler; a total of 68 area samples were collected. The analysis was performed using the Mann-Whitney, Kruskal-Wallis, and regression statistical tests. RESULTS: The geometric mean value and geometric standard deviation of inhalable wood dust for the exposed and control groups were 19 +/- 2.00 mg/m3 and 0.008 +/- 0.001 mg/m3, respectively. A statistically significant correlation was observed between the lung parameters and cumulative exposure to inhalable wood dust, whereas a statistically significant correlation was not observed between the lung parameters and bioaerosol exposure. However, the exposure of Iranian workers to bioaerosols was higher, compared to their foreign coworkers. CONCLUSION: Considering the high level of exposure among workers in this study along with their lung function results, long-term exposure to wood dust may be detrimental to the workers' health and steps to limit their exposure should be considered seriously. PMID- 28638426 TI - Pulmonary Functions and Health-Related Quality of Life among Silica-Exposed Workers. AB - BACKGROUND: This study aimed to investigate the pulmonary functions of silica exposed workers and their health-related quality of life in an insulator manufacturing industry. MATERIALS AND METHODS: In this cross-sectional study, participants selected from the manufacturing unit (n = 127) constituted the exposed group and those from the administrative department (n = 30) constituted the unexposed group. All subjects were evaluated using personal air sampling of crystalline silica, pulmonary function tests, and a quality of life questionnaire (36-item short form health survey [SF-36]). RESULTS: The mean (SD) concentrations of crystalline silica were 0.507 (0.23) mg/m3 and 0.0116 (0.008) mg/m3 for the exposed and unexposed groups, respectively. All the pulmonary function indices and all the physical and mental health domains of the workers were significantly lower than those of the administrative clerks (p < 0.05). The silica concentration did not significantly correlate with the quality of life components and all the pulmonary function indices (p > 0.05), except for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) (p < 0.05). CONCLUSION: In conclusion, the workers exposed to higher levels of crystalline silica had lower values of pulmonary function indices and lower health-related quality of life; however, further follow-up studies are needed to confirm these findings. PMID- 28638427 TI - Colopharyngoplasty in Patients with Severe Pharyngoesophageal Corrosive Injury: A Complicated but Worthwhile Procedure to Restore GI Tract Continuity, A Case Series. AB - BACKGROUND: Pharyngoesophageal strictures (PES) after corrosive injury impose a problematic condition for both physicians and patients in terms of their management and patients' quality of life. Colopharyngoplasty is a complex procedure, which is used to restore swallowing in these severely disabled patients. We describe our experience in treating nine patients with severe PES after corrosive injuries in a referral center. MATERIALS AND METHODS: A retrospective analysis of our database from 2009 to 2014 showed nine patients (seven men; age range: 18 to 47 years) with severe PES who underwent colopharyngoplasty ~6 months (range: 4-10) after caustic material ingestion. All patients had a feeding jejunostomy tube before reconstruction. Esophagectomy with or without gastrectomy was performed in all patients, except for one; thereafter, an isoperistaltic segment of the left colon was pulled up, and a pharyngocolic anastomosis was performed. Eight patients had a tracheostomy created either before reconstruction due to respiratory symptoms or at the time of definitive surgery to prevent aspiration in the early post-operative period. RESULTS: Almost all survivors had a satisfactory swallowing at the end of the follow-up (range: 4 60 months). The jejunostomy tube could be removed in all of the patients after a median of 5 months. One patient died of sepsis due to graft necrosis in the immediate post-operative period. Another patient died 5 months after the first surgery following a revision surgery for intractable dysphagia. At the end of the follow-up, only one patient tolerated tracheostomy tube decannulation. Two patients required laryngotracheal dissociation because of massive aspiration and recurrent episodes of pneumonia. Five patients still had a tracheostomy because of an severely destroyed larynx (two patients) and aspiration (three patients). CONCLUSION: Colopharyngoplasty is considered a complicated but trustworthy procedure to restore gastrointestinal tract continuity after severe corrosive injury. Undeniably, laryngeal involvement adversely affects the functional outcome. The post-operative course is frequently protracted, accompanied with several problems. Aspiration is nearly the most problematic event in the early post-operative period, which mandates a multidisciplinary approach to manage it. PMID- 28638428 TI - Acute Respiratory Failure as the First Manifestation of Antisynthetase Syndrome. AB - We report the case of a 40-year-old man with acute respiratory failure syndrome that later proved to be an initial manifestation of antisynthetase syndrome. The diagnosis of this rare combination of a connective tissue disease and an acute respiratory failure is difficult in a previously asymptomatic patient. Early diagnosis and immunosuppressive therapy started precociously prevented the disease progression and resulted in a good outcome. PMID- 28638429 TI - Adalimumab-Responsive Refractory Sarcoidosis Following Multiple Eyebrow Tattoos: A Case Report. AB - Sarcoidosis is a granulomatous disease that can involve multiple organs including the lungs, eyes, nerves, and skin. Cosmetic tattooing can be a predisposing factor for sarcoidosis, and its incidence is likely to increase along with its popularity. A 47-year-old woman with symptoms of fever and polyarthritis along with erythema nodosum lesions on the legs, swollen eyebrows, and a history of multiple eyebrow tattooing was referred to our center. Since the signs and symptoms were positive for Lofgren's syndrome triad including erythema nodosum, bilateral hilar lymphadenopathy, and polyarthritis, a diagnosis of acute sarcoidosis was made, and treatment was started accordingly. The patient was unresponsive to routine therapeutic agents used for sarcoidosis; however, she successfully responded to adalimumab. Our case indicates that systemic sarcoidosis could develop as a reaction to cosmetic tattooing, which might be refractory to conventional therapeutic agents including corticosteroids and non biologic disease-modifying anti-rheumatic drugs, while tumor necrosis factor antagonists such as adalimumab, could lead to disease remission. PMID- 28638430 TI - Treatment of Esophageal Perforation with Primary Closure and Reinforcement Using TachoSil. AB - Two patients with iatrogenic esophageal perforation following rigid esophagoscopy for foreign body removal were successfully treated with primary repair and reinforcement using a collagen patch coated with human fibrinogen and thrombin (TachoSil, Nycomed, Austria, Vienna). The clinical implication of this report is that TachoSil can be used to bolster the repair site of esophageal perforation. PMID- 28638432 TI - Mechanical Stimulation of the HT7 Acupuncture Point to Reduce Ethanol Self Administration in Rats. AB - BACKGROUND: Alcoholism, which is a disabling addiction disorder, is a major public health problem worldwide. The present study was designed to determine whether the application of acupuncture at the Shenmen (HT7) point suppresses voluntary alcohol consumption in addicted rats and whether this suppressive effect is potentiated by the administration of naltrexone. METHODS: Rats were initially trained to self-administer a sucrose solution by operating a lever. A mechanical acupuncture instrument (MAI) for objective mechanical stimulation was used on rats whose baseline response had been determined. In addition, the effect of HT7 acupuncture on beta-endorphin concentration and ethanol intake via naltrexone were investigated in different groups. RESULTS: We found that ethanol intake and beta-endorphin level in rats being treated with the MAI at the HT7 point reduced significantly. The treatment of naltrexone at high doses reduced the ethanol intake and low-dose injection of naltrexone in conjunction with the MAI also suppressed ethanol intake. CONCLUSIONS: The results of the current study indicate that using the MAI at the HT7 point effectively reduces ethanol consumption in rats. Furthermore, the coadministration of the MAI and a low dose of naltrexone can produce some more potent reducing effect of ethanol intake than can acupuncture alone. PMID- 28638431 TI - Erzhi Pill(r) Repairs Experimental Liver Injury via TSC/mTOR Signaling Pathway Inhibiting Excessive Apoptosis. AB - The present study aimed to investigate the mechanism of hepatoprotective effect of Erzhi Pill (EZP) on the liver injury via observing TSC/mTOR signaling pathway activation. The experimental liver injury was induced by 2-acetylaminofluorene (2 AAF) treatment combined with partial hepatectomy (PH). EZP treated 2-AAF/PH induced liver injury by the therapeutic and prophylactic administration. After the administration of EZP, the activities of aspartic transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AKP), and gamma-glutamyl transpeptidase (gamma-GT) were decreased, followed by the decreased levels of hepatocyte apoptosis and caspase-3 expression. However, the secretion of albumin, liver weight, and index of liver weight were elevated. Microscopic examination showed that EZP restored pathological liver injury. Meanwhile, Rheb and mammalian target of rapamycin (mTOR) activation were suppressed, and tuberous sclerosis complex (TSC) expression was elevated in liver tissues induced by 2-AAF/PHx and accompanied with lower-expression of Bax, Notch1, p70S6K, and 4E-EIF and upregulated levels of Bcl-2 and Cyclin D. Hepatoprotective effect of EZP was possibly realized via inhibiting TSC/mTOR signaling pathway to suppress excessive apoptosis of hepatocyte. PMID- 28638433 TI - Shenqiwan Ameliorates Renal Fibrosis in Rats by Inhibiting TGF-beta1/Smads Signaling Pathway. AB - Epithelial-mesenchymal transition (EMT) refers to the transition of epithelial cells into mesenchymal cells. Emerging evidence suggests that EMT is a key point in renal interstitial fibrosis (RIF). Traditional Chinese Medicine Shenqiwan (SQW) is widely used in clinical treatment of chronic kidney disease, but the underlying mechanism remains unclear. The purpose of this study is to investigate the effect of SQW on renal fibrosis and its association with TGF-beta1/Smads signaling pathway. A rat model of adenine (150 mg/kg) was established and intragastrically treated with various concentrations of SQW at dose of 1.5 g/kg, 3 g/kg, and 6 g/kg. Control group and model group were given the same volume of saline. Meanwhile, the positive control group was treated with Enalapril (4 mg/kg). Animals were sacrificed on 21st day after administration. The results showed that SQW could significantly relieve renal pathological damage caused by adenine, increase gene and protein expression of E-cadherin, and decrease the expression of Vimentin in kidney samples. In addition, SQW efficiently inhibited the mRNA and protein expression of p-Smad2/3 by upregulating Smad7. These results suggest that SQW could slow down the progression of renal fibrosis, possibly by inhibiting TGF-beta1/Smads signaling pathway. PMID- 28638434 TI - An evaluation of the protective role of vitamin C in reactive oxygen species induced hepatotoxicity due to hexavalent chromium in vitro and in vivo. AB - BACKGROUD: Drinking water contamination with hexavalent chromium [Cr (VI)] has become one of the most serious public health problems, thus the investigation of Cr (VI)-induced hepatotoxicity has attracted much attention in recent years. METHODS: In the present study, by determining the indices of hepatotoxicity induced by Cr (VI), the source of accumulated reactive oxygen species (ROS), and the protective effect of the antioxidant Vitamin C (Vit C), we explored the mechanisms involved in Cr (VI)-induced hepatotoxicity in vitro and in vivo. RESULTS: We found Cr (VI) caused hepatotoxicity characterized by the alterations of several enzymatic and cytokine markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukine-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha), etc. ROS production after Cr (VI) exposure was origins from the inhibition of electron transfer chain (ETC) and antioxidant system. Vit C inhibited ROS accumulation thus protected against Cr (VI)-induced hepatotoxicity in L-02 hepatocytes and in the rat model. CONCLUSIONS: We concluded that ROS played a role in Cr (VI)-induced hepatotoxicity and Vit C exhibited protective effect. Our current data provides important clues for studying the mechanisms involved in Cr (VI)-induced liver injury, and may be of great help to develop therapeutic strategies for prevention and treatment of liver diseases involving ROS accumulation for occupational exposure population. PMID- 28638435 TI - Exclusive breastfeeding and mothers' employment status in Gondar town, Northwest Ethiopia: a comparative cross-sectional study. AB - BACKGROUND: Exclusive breastfeeding is defined as feeding an infant breast milk only, for the first six months. In Ethiopia, more than half of infants do not receive exclusive breastfeeding. Workplace barriers contribute to these low rates of exclusive breastfeeding practices. Understanding the sociodemographic, health related, behavioral and economic factors is crucial to promote the practice of exclusive breastfeeding in Ethiopia. Therefore, the aim of this study was to assess the extent of exclusive breastfeeding practice and associated factors among employed and unemployed mothers with children of age 7-12 months in Gondar town, northwest Ethiopia, 2015. METHODS: A community based comparative cross sectional study was conducted in October 2015. Simple random sampling technique was used to select 649 eligible mothers with children age 7-12 months during the study period. A structured and pretested interviewer administered questionnaire was used to collect the data. Three logistic regression models: whole sample, employed and not employed, were fitted. RESULTS: A total of 649 (333 unemployed and 316 employed) mothers were interviewed. The mean duration of mothers to exclusively breastfeed was 4.77 months (+/- 1.36 Standard Deviation [SD]). Exclusive breastfeeding was higher among unemployed 48.0% with 95% Confidence Interval (CI) (42.0%, 54.0%) than employed (20.9%) with 95% CI (16.0%, 25.0%). Parity of three children and above (Adjusted Odds Ratio [AOR] = 3.48), and having social support (AOR = 3.45) were positively associated with exclusive breastfeeding while poor knowledge (AOR = 0.30), wealth index of the medium level (AOR = 0.38) were negatively associated among employed mothers. In the case of unemployed mothers, vaginal delivery (AOR = 2.60) and having social support (AOR = 3.03) were positively associated with exclusive breastfeeding while, poor knowledge (AOR = 0.28), and not having antenatal care (AOR = 0.56) were negatively associated. CONCLUSIONS: The overall exclusive breastfeeding practice of mothers was low. However, unemployed mothers breastfeed more than employed mothers. Providing a special support for employed mothers and revising either the legislation of the two month postpartum maternity leave or applying different alternatives is recommended. PMID- 28638436 TI - In vivo label-free mapping of the effect of a photosystem II inhibiting herbicide in plants using chlorophyll fluorescence lifetime. AB - BACKGROUND: In order to better understand and improve the mode of action of agrochemicals, it is useful to be able to visualize their uptake and distribution in vivo, non-invasively and, ideally, in the field. Here we explore the potential of plant autofluorescence (specifically chlorophyll fluorescence) to provide a readout of herbicide action across the scales utilising multiphoton-excited fluorescence lifetime imaging, wide-field single-photon excited fluorescence lifetime imaging and single point fluorescence lifetime measurements via a fibre optic probe. RESULTS: Our studies indicate that changes in chlorophyll fluorescence lifetime can be utilised as an indirect readout of a photosystem II inhibiting herbicide activity in living plant leaves at three different scales: cellular (~MUm), single point (~1 mm2) and macroscopic (~8 * 6 mm2 of a leaf). Multiphoton excited fluorescence lifetime imaging of Triticum aestivum leaves indicated that there is an increase in the spatially averaged chlorophyll fluorescence lifetime of leaves treated with Flagon EC-a photosystem II inhibiting herbicide. The untreated leaf exhibited an average lifetime of 560 +/- 30 ps while the leaf imaged 2 h post treatment exhibited an increased lifetime of 2000 +/- 440 ps in different fields of view. The results from in vivo wide-field single-photon excited fluorescence lifetime imaging excited at 440 nm indicated an increase in chlorophyll fluorescence lifetime from 521 ps in an untreated leaf to 1000 ps, just 3 min after treating the same leaf with Flagon EC, and to 2150 ps after 27 min. In vivo single point fluorescence lifetime measurements demonstrated a similar increase in chlorophyll fluorescence lifetime. Untreated leaf presented a fluorescence lifetime of 435 ps in the 440 nm excited chlorophyll channel, CH4 (620-710 nm). In the first 5 min after treatment, mean fluorescence lifetime is observed to have increased to 1 ns and then to 1.3 ns after 60 min. For all these in vivo plant autofluorescence lifetime measurements, the plants were not dark-adapted. CONCLUSIONS: We demonstrate that the local impact of a photosystem II herbicide on living plant leaves can be conveniently mapped in space and time via changes in autofluorescence lifetime, which we attribute to changes in chlorophyll fluorescence. Using portable fibre-optic probe instrumentation originally designed for label-free biomedical applications, this capability could be deployed outside the laboratory for monitoring the distribution of herbicides in growing plants. PMID- 28638437 TI - A multiplex PCR for rapid identification of Brassica species in the triangle of U. AB - BACKGROUND: Within the Brassicaceae, six species from the genus Brassica are widely cultivated throughout the world as oilseed, condiment, fodder or vegetable crops. The genetic relationships among the six Brassica species are described by U's triangle model. Extensive shared traits and diverse morphotypes among Brassica species make identification and classification based on phenotypic data alone challenging and unreliable, especially when dealing with large germplasm collections. Consequently, a major issue for genebank collections is ensuring the correct identification of species. Molecular genotyping based on simple sequence repeat (SSR) marker sequencing or the Illumina Infinium Brassica napus 60K single nucleotide polymorphism (SNP) array has been used to identify species and assess genetic diversity of Brassica collections. However, these methods are technically challenging, expensive and time-consuming, making them unsuitable for routine or rapid screening of Brassica accessions for germplasm management. A cheaper, faster and simpler method for Brassica species identification is described here. RESULTS: A multiplex polymerase chain reaction (MPCR) consisting of new and existing primers specific to the Brassica A, B and C genomes was able to reliably distinguish all six Brassica species in the triangle of U with 16 control samples of known species identity. Further validation against 120 Brassica accessions previously genotyped showed that the MPCR is highly accurate and comparable to more advanced techniques such as SSR marker sequencing or the Illumina Infinium B. napus 60K SNP array. In addition, the MPCR was sensitive enough to detect seed contaminations in pooled seed samples of Brassica accessions. CONCLUSION: A cheap and fast multiplex PCR assay for identification of Brassica species in the triangle of U was developed and validated in this study. The MPCR assay can be readily implemented in any basic molecular laboratory and should prove useful for the management of Brassica germplasm collections in genebanks. PMID- 28638439 TI - Non-invasive absolute measurement of leaf water content using terahertz quantum cascade lasers. AB - BACKGROUND: Plant water resource management is one of the main future challenges to fight recent climatic changes. The knowledge of the plant water content could be indispensable for water saving strategies. Terahertz spectroscopic techniques are particularly promising as a non-invasive tool for measuring leaf water content, thanks to the high predominance of the water contribution to the total leaf absorption. Terahertz quantum cascade lasers (THz QCL) are one of the most successful sources of THz radiation. RESULTS: Here we present a new method which improves the precision of THz techniques by combining a transmission measurement performed using a THz QCL source, with simple pictures of leaves taken by an optical camera. As a proof of principle, we performed transmission measurements on six plants of Vitis vinifera L. (cv "Colorino"). We found a linear law which relates the leaf water mass to the product between the leaf optical depth in the THz and the projected area. Results are in optimal agreement with the proposed law, which reproduces the experimental data with 95% accuracy. CONCLUSIONS: This method may overcome the issues related to intra-variety heterogeneities and retrieve the leaf water mass in a fast, simple, and non-invasive way. In the future this technique could highlight different behaviours in preserving the water status during drought stress. PMID- 28638438 TI - Real-time monitoring of PtaHMGB activity in poplar transactivation assays. AB - BACKGROUND: Precise control of gene expression is essential to synchronize plant development with the environment. In perennial plants, transcriptional regulation remains poorly understood, mainly due to the long time required to perform functional studies. Transcriptional reporters based on luciferase have been useful to study circadian and diurnal regulation of gene expression, both by transcription factors and chromatin remodelers. The high mobility group proteins are considered transcriptional chaperones that also modify the chromatin architecture. They have been found in several species, presenting in some cases a circadian expression of their mRNA or protein. RESULTS: Transactivation experiments have been shown as a powerful and fast method to obtain information about the potential role of transcription factors upon a certain reporter. We designed and validated a luciferase transcriptional reporter using the 5' sequence upstream ATG of Populus tremula * alba LHY2 gene. We showed the robustness of this reporter line under long day and continuous light conditions. Moreover, we confirmed that pPtaLHY2::LUC activity reproduces the accumulation of PtaLHY2 mRNA. We performed transactivation studies by transient expression, using the reporter line as a genetic background, unraveling a new function of a high mobility group protein in poplar, which can activate the PtaLHY2 promoter in a gate-dependent manner. We also showed PtaHMGB2/3 needs darkness to produce that activation and exhibits an active degradation after dawn, mediated by the 26S proteasome. CONCLUSIONS: We generated a stable luciferase reporter poplar line based on the circadian clock gene PtaLHY2, which can be used to investigate transcriptional regulation and signal transduction pathway. Using this reporter line as a genetic background, we established a methodology to rapidly assess potential regulators of diurnal and circadian rhythms. This tool allowed us to demonstrate that PtaHMGB2/3 promotes the transcriptional activation of our reporter in a gate-dependent manner. Moreover, we added new information about the PtaHMGB2/3 protein regulation along the day. This methodology can be easily adapted to other transcription factors and reporters. PMID- 28638440 TI - Finding Solvable Units of Variables in Nonlinear ODEs of ECM Degradation Pathway Network. AB - We consider ordinary differential equation (ODE) model for a pathway network that arises in extracellular matrix (ECM) degradation. For solving the ODEs, we propose applying the mass conservation law (MCL), together with a stoichiometry called doubling rule, to them. Then it leads to extracting new units of variables in the ODEs that can be solved explicitly, at least in principle. The simulation results for the ODE solutions show that the numerical solutions are indeed in good accord with theoretical solutions and satisfy the MALs. PMID- 28638441 TI - Efficient dehydration and recovery of ionic liquid after lignocellulosic processing using pervaporation. AB - BACKGROUND: Biomass pretreatment using certain ionic liquids (ILs) is very efficient, generally producing a substrate that is amenable to saccharification with fermentable sugar yields approaching theoretical limits. Although promising, several challenges must be addressed before an IL pretreatment technology can become commercially viable. One of the most significant challenges is the affordable and scalable recovery and recycle of the IL itself. Pervaporation (PV) is a highly selective and scalable membrane separation process for quantitatively recovering volatile solutes or solvents directly from non-volatile solvents that could prove more versatile for IL dehydration. RESULTS: We evaluated a commercially available PV system for IL dehydration and recycling as part of an integrated IL pretreatment process using 1-ethyl-3-methylimidazolium acetate ([C2C1Im][OAc]) that has been proven to be very effective as a biomass pretreatment solvent. Separation factors as high as 1500 were observed. We demonstrate that >99.9 wt% [C2C1Im][OAc] can be recovered from aqueous solution (<=20 wt% IL) and recycled five times. A preliminary technoeconomic analysis validated the promising role of PV in improving overall biorefinery process economics, especially in the case where other IL recovery technologies might lead to significant losses. CONCLUSIONS: These findings establish the foundation for further development of PV as an effective method of recovering and recycling ILs using a commercially viable process technology. PMID- 28638444 TI - Understanding the barriers and improving care in type 2 diabetes: Brazilian perspective in time to do more in diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a complex disease, particularly in a continental country like Brazil. We attempted to understand and evaluate the perceptions and routines of Brazilians with T2DM and physicians, compared with other countries. METHODS: We compared the results from a 20-min online survey in Brazil with simultaneously collated data from India, Japan, Spain, UK and USA. RESULTS: In total, 652 adults with T2DM and 337 treating physicians were enrolled, of whom 100 patients and 55 physicians were from Brazil. The numbers of primary care physicians from the five countries were 221 versus 43 in Brazil, diabetes specialists were 61 versus 12. There was disconnect between the opinions of physicians and people with diabetes globally. Further, there were differences between clinical practices in Brazil versus the rest of the world, in many areas Brazilians were performing better. CONCLUSIONS: Communication between patients and physicians should be clearer. There is an urgent need to identify the deficits in education, in order to address the clinical inertia within the diabetes management team. There is a necessity to understand the specific requirements of the Brazilian population in order to contextualise international guidelines and implement local changes in practice. PMID- 28638443 TI - Dosage compensation and sex-specific epigenetic landscape of the X chromosome in the pea aphid. AB - BACKGROUND: Heterogametic species display a differential number of sex chromosomes resulting in imbalanced transcription levels for these chromosomes between males and females. To correct this disequilibrium, dosage compensation mechanisms involving gene expression and chromatin accessibility regulations have emerged throughout evolution. In insects, these mechanisms have been extensively characterized only in Drosophila but not in insects of agronomical importance. Aphids are indeed major pests of a wide range of crops. Their remarkable ability to switch from asexual to sexual reproduction during their life cycle largely explains the economic losses they can cause. As heterogametic insects, male aphids are X0, while females (asexual and sexual) are XX. RESULTS: Here, we analyzed transcriptomic and open chromatin data obtained from whole male and female individuals to evaluate the putative existence of a dosage compensation mechanism involving differential chromatin accessibility of the pea aphid's X chromosome. Transcriptomic analyses first showed X/AA and XX/AA expression ratios for expressed genes close to 1 in males and females, respectively, suggesting dosage compensation in the pea aphid. Analyses of open chromatin data obtained by Formaldehyde-Assisted Isolation of Regulatory Elements (FAIRE-seq) revealed a X chromosome chromatin accessibility globally and significantly higher in males than in females, while autosomes' chromatin accessibility is similar between sexes. Moreover, chromatin environment of X-linked genes displaying similar expression levels in males and females-and thus likely to be compensated-is significantly more accessible in males. CONCLUSIONS: Our results suggest the existence of an underlying epigenetic mechanism enhancing the X chromosome chromatin accessibility in males to allow X-linked gene dose correction between sexes in the pea aphid, similar to Drosophila. Our study gives new evidence into the comprehension of dosage compensation in link with chromatin biology in insects and newly in a major crop pest, taking benefits from both transcriptomic and open chromatin data. PMID- 28638442 TI - Computational dynamic approaches for temporal omics data with applications to systems medicine. AB - Modeling and predicting biological dynamic systems and simultaneously estimating the kinetic structural and functional parameters are extremely important in systems and computational biology. This is key for understanding the complexity of the human health, drug response, disease susceptibility and pathogenesis for systems medicine. Temporal omics data used to measure the dynamic biological systems are essentials to discover complex biological interactions and clinical mechanism and causations. However, the delineation of the possible associations and causalities of genes, proteins, metabolites, cells and other biological entities from high throughput time course omics data is challenging for which conventional experimental techniques are not suited in the big omics era. In this paper, we present various recently developed dynamic trajectory and causal network approaches for temporal omics data, which are extremely useful for those researchers who want to start working in this challenging research area. Moreover, applications to various biological systems, health conditions and disease status, and examples that summarize the state-of-the art performances depending on different specific mining tasks are presented. We critically discuss the merits, drawbacks and limitations of the approaches, and the associated main challenges for the years ahead. The most recent computing tools and software to analyze specific problem type, associated platform resources, and other potentials for the dynamic trajectory and interaction methods are also presented and discussed in detail. PMID- 28638445 TI - Association of MAGE A1-6 Expression with Lung Cancer Progression. AB - The melanoma-associated antigen (MAGE) genes are known to be expressed in various kinds of tumors including lung cancer. Although they are studied as targets for immunotherapy and tools for early detection of lung cancer, the correlation between MAGE expression and the prognosis in lung cancer has not been clarified. In this study, we evaluated the relationship between MAGE A1-6 gene expression and the clinical prognosis in lung cancer. Bone marrow aspirations were performed in 60 patients who were diagnosed as lung cancer and underwent lung cancer surgery between 2007 and 2008. Each bone marrow was examined using nested reverse transcription- polymerase chain reaction (RT-PCR) with the MAGE common primer to detect MAGE A1-6. Overall survival rate, disease-free survival rate, recurrence, and distant metastasis were reviewed retrospectively. Survival periods were analyzed using SPSS ver. 20.0. Of the total 60 lung cancer patients, 9 patients (15%) had MAGE A1-6. MAGE A1-6-positive patients showed poor overall survival and overall disease-free survival rates (43.8 +/- 26.1, 43.2 +/- 26.9 months, respectively) compared with MAGE A1-6-negative patients (54.4 +/- 17.2, 44.8 +/- 22.1 months, respectively). No significant difference was shown in either survival rates. In conclusion, MAGE A1-6 expression of bone marrow in lung cancer patients correlated with poor survival rates. We suggest that MAGE A1-6 may be considered as a novel prognostic factor for lung cancer which leads to effective follow-up and treatment. PMID- 28638446 TI - Overexpression of Transcobalamin 1 is an Independent Negative Prognosticator in Rectal Cancers Receiving Concurrent Chemoradiotherapy. AB - Objective: Neoadjuvant concurrent chemoradiotherapy (CCRT) is an increasingly common therapeutic strategy for locally advanced rectal cancer, but stratification of risk and final outcomes remain a major challenge. Transcobalamin 1 (TCN1), a vitamin B12 (cobalamin)-binding protein, regulates cobalamin homeostasis. High expression of TCN1 have been reported in neoplasms such as breast cancer and hepatocellular carcinoma. However, little is known about the relevance of TCN1 to rectal cancer receiving CCRT. This study examined the predictive and prognostic impact of TCN1 expression in patients with rectal cancer following neoadjuvant CCRT. Methods: Through data mining from a published transcriptome of rectal cancers (GSE35452), we identified upregulation of TCN1 gene as the most significantly predicted poor response to CCRT among ion transport-related genes (GO:0006811). We evaluated TCN1 immunohistochemistry and performed an H-score analysis on endoscopic biopsy specimens from 172 rectal cancer patients receiving neoadjuvant CCRT followed by curative surgery. Expression levels of TCN1 were further correlated with clinicopathologic features, therapeutic response, tumor regression grade (TRG) and survivals including metastasis-free survival (MeFS), disease-specific survival (DSS) and recurrent-free survival (LRFS). Results: TCN1 overexpression was significantly related to advanced post-treatment tumor (T3, T4; p<0.001) and nodal status (N1, N2; p<0.001), vascular invasion (p=0.003) and inferior tumor regression grade (p < 0.001). In survival analyses, TCN1 overexpression was significantly associated with shorter DSS (p<0.0001), MeFS (p=0.0002) and LRFS (p=0.0001). Furthermore, it remained an independent prognosticator of worse DSS (p=0.002, hazard ratio=3.344), MeFS (p=0.021, hazard ratio=3.015) and LRFS (p=0.037, hazard ratio=3.037) in the multivariate comparison. Conclusion: Overexpression of TCN1 is associated with poor therapeutic response and adverse outcomes in rectal cancer patients receiving CCRT, justifying the potential prognostic value of TCN1 in rectal cancer receiving CCRT. PMID- 28638447 TI - Serum IgG4:IgG Ratio Predicts Recurrence of Patients with Hepatocellular Carcinoma after Curative Resection. AB - Aim: IgG4 is associated with a Th1-to-Th2 switch, which plays a vital role in metastasis, in patients with malignances; thus, we aimed to investigate its clinical significance in predicting hepatocellular carcinoma (HCC) recurrence in the present study. Methods: The correlation between serum IgG4:IgG ratio and recurrence was analyzed in a cohort of 195 patients undergoing curative resection in 2012. Another 100 patients were analyzed in a prospective independent cohort during 2012-2013 to validate the value of serum IgG4. Serum IgG4 and total IgG concentrations were measured with an automatic immune analyzer and the optimal cutoff value for serum IgG4 levels was determined by X-tile software. Results: Our data revealed that serum IgG4:IgG were significantly elevated in patients with tumor recurrence (P<0.05). A cutoff IgG:IgG4 ratio of 0.08 was set to stratify HCC patients into high (>0.08) and low (<=0.08) groups. High serum IgG4:IgG ratio correlated with significantly shorter time-to-recurrence (median 11.85 months vs. 39.20, P=0.005). Univariate and multivariate analyses demonstrated that serum IgG4:IgG ratio is an independent indicator of tumor recurrence and this retained its clinical significance even in conventional low recurrence-risk subgroups, including patients with low alpha-fetoprotein and early-stage diseases. Conclusion: Our results demonstrated that elevated serum IgG4:IgG ratio is associated with poor clinical outcomes in HCC patients and therefore, and can serve as a novel prognostic predictor for HCC patients undergoing resection. Analyzing serum IgG4 would be useful to tailor individualized therapies for patients. PMID- 28638448 TI - Ratio of Autoantibodies of Tumor Suppressor AIMP2 and Its Oncogenic Variant Is Associated with Clinical Outcome in Lung Cancer. AB - Aminoacyl-tRNA synthetase-interacting multi-functional protein 2 (AIMP2) works as potent tumor suppressor, while its splicing variant lacking exon 2 (AIMP2-DX2) competes with AIMP2 for binding to target proteins and compromises its anti-tumor activity. Assuming that AIMP2 and its variant AIMP2-DX2 could be released out to human sera in pathological condition, we investigated the diagnostic and prognostic usefulness of autoantibodies against AIMP2 and AIMP2-DX2 by measuring their serum levels in 80 normal and lung cancer samples that were matched in age, gender and smoking status. The area under the curve of AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 autoantibody ratio was low (0.416, 0.579, and 0.357, respectively), suggesting limited diagnostic value. A total of 165 lung cancer patients were classified into low and high AIMP2-DX2, AIMP2, and AIMP2-DX2/AIMP2 based on the median expression of each parameter. The high AIMP2-DX2 group was older and had larger tumors (>3 cm) than the low AIMP2-DX2 group. The high AIMP2 DX2/AIMP2 group had higher CYFRA-21 levels and significantly shorter overall survival than the low AIMP2-DX2/AIMP2 group (18.6 vs. 48.9 months, P = 0.021, Log Rank Test). Taken together, autoantibodies against AIMP2-DX2 and AIMP2 are detectable in the human blood and the increased ratio of AIMP2-DX2/AIMP2 is related to poor clinical outcome of lung cancer. PMID- 28638449 TI - Plasma Mesothelin as a Novel Diagnostic and Prognostic Biomarker in Colorectal Cancer. AB - Objective Mesothelin is a cell surface protein and overexpressed in many cancers. However, the potential value of mesothelin as plasma biomarker in colorectal cancer has not been explored. The purpose of this study was to identify whether plasma mesothelin is a suitable diagnostic and prognostic biomarker for colorectal cancer. Methods We performed a two-stage case-control study to evaluate plasma mesothelin levels in colorectal cancer using enzyme-linked immunosorbent assay (ELISA). Preoperative and postoperative plasma were collected to examine the level changes influenced by surgery. Receiver operating characteristic (ROC) curves were applied to identify the diagnostic value of plasma mesothelin. We also conducted univariate Kaplan-Meier survival analysis and Cox regression analysis of patients with survival information. Results We found that the plasma mesothelin levels in colorectal cancer patients were significantly higher than that in the controls (P < 0.001) with an AUC value of 0.690 (95% CI = 0.625 to 0.752). Individuals with lower mesothelin level had a longer survival time (adjusted HR = 4.43, 95% CI = 1.93-10.15, P < 0.001). Furthermore, Patients had slightly decreased mesothelin levels in postoperative plasma than preoperative plasma, although the alteration was not statistically significant (P = 0.052). Conclusion Our findings highlight the correlative relationship between plasma mesothelin levels and the presence and progression of colorectal cancer. Plasma mesothelin may be a potential diagnostic and, or prognostic biomarker for colorectal cancer. PMID- 28638450 TI - Osteopontin is Critical for Hyperactive mTOR-Induced Tumorigenesis in Oral Squamous Cell Carcinoma. AB - Mechanistic target of rapamycin (mTOR) plays a critical role in the development of oral squamous cell carcinoma (OSCC), but the underlying mechanisms remain poorly understood. Here we have demonstrated that the expression of osteopontin (OPN) was dramatically up-regulated in OSCC tissues and cell lines. Moreover, reduction of OPN suppressed cell proliferation, colony formation, and in vivo tumorigenic ability of OSCC cell lines Tca8113. In addition, there was a strong positive correlation between mTORC1 activity and OPN expression in OSCC tissues and cell lines. Furthermore, mTOR complex 1 (mTORC1) enhanced OPN expression through up-regulation of ERRalpha. Therefore, OPN is a downstream target of mTORC1 and is crucial for OSCC development. mTORC1, ERRalpha, and OPN may be potential targets for treatment of OSCC with aberrant mTORC1 signaling. PMID- 28638451 TI - Antiemetic Effectiveness and Cost-Saving of Aprepitant plus Granisetron Is Superior to Palonosetron in Gastrointestinal Cancer Patients Who Received Moderately Emetogenic Chemotherapy. AB - Purpose The therapeutic benefit of a three-drug combination of antiemetics has not been established in moderately emetogenic chemotherapy (MEC). The aim of this study was to compare the antiemetic effectiveness and cost-saving of palonosetron plus dexamethasone (control group) with aprepitant, granisetron, and dexamethasone (study group) in cancer patients who received MEC. Methods We switched the standard antiemetic treatment from the control group to the study group in gastrointestinal cancer patients who received MEC after October 2015. The antiemetics in both groups were modified using salvage antiemetic therapy at the clinicians' discretion, according to the severity of chemotherapy-induced nausea and vomiting. We retrospectively reviewed the electronic medical records from patients, before and after switching groups, from between April 2014 and March 2016. Results We evaluated 443 treatment courses in 83 patients. The proportion of courses that included salvage antiemetic therapy in the control group and the study group was 34.8 % (116/333) and 8.2 % (9/110), respectively, and was statistically significant (p < 0.001). The mean integrated costs of antiemetics per course in the control group and the study group were 193 +/- 55 USD and 143 +/- 38 USD, respectively. Multivariate logistic regression analysis revealed that the study group was significantly associated with a reduced risk of requiring salvage antiemetic therapy (p = 0.038). Conclusions These results suggest that the antiemetic effectiveness and cost-saving of a three-drug combination of aprepitant, generic granisetron, and dexamethasone was superior to a two-drug combination of palonosetron plus dexamethasone in gastrointestinal cancer patients who received MEC. PMID- 28638452 TI - Targeting TPX2 Suppresses the Tumorigenesis of Hepatocellular Carcinoma Cells Resulting in Arrested Mitotic Phase Progression and Increased Genomic Instability. AB - Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. Therefore, a better knowledge of molecular hepatocarcinogenesis will provide opportunities for designing targeted therapies. TPX2 (targeting protein for Xklp2) is overexpressed as a consequence of oncogenic alterations and is likely to alter the proper regulation of chromosome segregation in cancer cells. Disrupting the machinery which is responsible for mitosis and chromosome instability in cancer cells can be one of the most successful strategies for cancer therapy. Therefore, we consider the targeting TPX2 could provide novel therapeutic strategies for cancer. In this study, increased TPX2 protein expression was present in 16 (42%) of 38 primary HCCs and was associated with advanced stage, distant metastatic HCCs and poor prognosis. Knockdown of TPX2 inhibited cancer cell growth and downregulation of cyclin A, cyclin E and CDK2 proteins. However, over-expressed EGFP-TPX2 protein enhanced the in vitro tumor spheroid formation and rescued the TPX2 depleted cell growth. Targeting TPX2 caused a rising impaired chromosomal instability resulting in multinuclearity, cell cycle progression arrest, apotosis, senescence and an increased polyploidy in cells. An image-cytometry analysis revealed cell cycle progression arrest after TPX2 inhibition. A correlation was observed between the downregulation of the protein levels of genes related to chromosomal segregation and spindle assembly checkpoint (securin, seprase, Aurora A, Aurora B, Cyclin B1, Cyclin B2, MPS1, BUB1, BUB3, MAD1 and MAD2) and increased cell ploidy, indicating mitotic progression failure and the loss of the balance of genomic instability. In vitro tumor spheroid assay and in vivo xenografts mouse model showed a therapeutic opportunity. Our findings indicate that targeting TPX2 lead to suppress tumorigenicity in liver cancer cells, suggesting that TPX2 is a potential target for anticancer therapy in HCC. PMID- 28638453 TI - The Clinical Impact of c-MET Over-Expression in Advanced Biliary Tract Cancer (BTC). AB - Background: c-MET is a proto-oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Activation of HGF-c-MET signaling involves cell invasiveness and evokes metastasis through direct involvement of tumor angiogenesis. However, the value of c-MET overexpression is still unknown in metastatic biliary tract cancer (BTC). Methods: We analyzed the incidence and clinicopathologic characteristics of c-MET overexpression in advanced BTC. Moreover, we investigated the value of c-MET overexpression in predicting response to gemicitabine plus cisplatin (GC), a first line standard regimen, and as a prognostic marker in metastatic BTC. Results: The BTC subtype distribution (N=44) was as follows: intrahepatic cholangiocarcinoma (IHCC, n=7), extrahepatic cholangiocarcinoma (EHCC, n=25) and gallbladder cancer (GBC, n=12). Liver (52.3%) was the predominant metastatic site, followed by lymph nodes (36.4%) and bone (15.9%). Among the 44 patients analyzed for c-MET expression, 15 (34.1%) exhibited c-MET overexpression in tumor tissues. There was no significant difference in the prevalence of c-MET overexpression among primary sites in EHCC (7/25, 28.0%), IHCC (3/7, 42.9%), and GBC (5/12, 41.7%). There was also no significant correlation between specific clinicopathologic variables and c-MET expression. Comparing the tumor-response to GC according to c-MET expression (overexpression vs. non-overexpression), there was no significant difference in either RR or DCR (p=0.394 and p >0.999, respectively). The median PFS for all 44 patients was 9.00 months (95% CI, 7.5-10.5 months) and there was no significant difference for PFS between patients with c-MET overexpression and those without (p=0.917). The median OS was 14.4 months (95% CI, 11.9-16.9 months). There was no significant difference in OS between patients with c-MET overexpression compared to those without (13.7 vs. 14.4 months, respectively; p=0.708). Conclusions: c MET overexpression was detected in 34.1% of advanced BTC patients irrespective of tumor location. c-MET overexpression did not predict response to GC or survival. Further studies are needed to fully elucidate the value of c-MET overexpression as a novel biomarker in these patients. PMID- 28638454 TI - Downregulation of Mitochondrial Single Stranded DNA Binding Protein (SSBP1) Induces Mitochondrial Dysfunction and Increases the Radiosensitivity in Non-Small Cell Lung Cancer Cells. AB - Radiotherapy is one of the major therapeutic strategies for human non-small cell lung cancer (NSCLC), but intrinsic radioresistance of cancer cells makes a further improvement of radiotherapy for NSCLC challenging. Mitochondrial function is frequently dysregulated in cancer cells for adaptation to the changes of tumor microenvironment after exposure to radiation. Therefore, targeting mitochondrial biogenesis and bioenergetics is an attractive strategy to sensitize cancer cells to radiation therapy. In this study, we found that downregulation of single strand DNA-binding protein 1 (SSBP1) in H1299 cells was associated with inducing mitochondrial dysfunction and increasing radiosensitivity to ionizing radiation. Mechanistically, SSBP1 loss induced mitochondrial dysfunction via decreasing mitochondrial DNA copy number and ATP generation, enhancing the mitochondrial derived ROS accumulation and downregulating key glycolytic enzymes expression. SSBP1 knockdown increased the radiosensitivity of H1299 cells by inducing increased apoptosis, prolonged G2/M phase arrest and defective homologous recombination repair of DNA double-strand breaks. Our findings identified SSBP1 as a radioresistance-related protein, providing potential novel mitochondrial target for sensitizing NSCLC to radiotherapy. PMID- 28638455 TI - The Prognostic and Predictive Value of Carbohydrate Antigen 19-9 in Metastatic Colorectal Cancer Patients with First Line Bevacizumab Containing Chemotherapy. AB - Objective: We had previously demonstrated that the carbohydrate antigen 19-9 (CA19-9), lactate dehydrogenase (LDH), neutrophil lymphocyte ratio (NLR) are prognostic factors for patients with metastatic colorectal cancer (mCRC). In this study, we try to analysis the association of these blood-based biomarkers with bevacizumab efficacy in the first line setting. Methods: A total of 284 eligible consecutive mCRC patients who received first-line chemotherapy with or without bevacizumab were studied from 2007 to 2014 at Sun Yat-Sen University Cancer Center. The endpoints were overall survival (OS), progression free survival (PFS). Results: Among all the patients, the initial elevated CA19-9, high LDH, and NLR > 2.47 were confirmed as independent unfavorable prognostic factors. The CA19-9 and LDH levels were significantly associated with PFS. In the high CA19-9 subgroup, patients had favorable OS from bevacizumab administration in the first line therapy (32.1 vs. 20.1 months, P = 0.03), but without PFS benefit. In terms of different levels of LDH, and NLR, there were no survival benefit from bevacizumab treatment. Conclusions: Our results suggest that the initial CA19-9, LDH, and NLR levels could be independent prognostic biomarkers in mCRC patients. And among all these factors, the initial high CA19-9 level could be a predictor for bevacizumab effect. PMID- 28638456 TI - Temozolomide and Bevacizumab Induction before Chemoradiotherapy in Patients with Bulky Glioblastoma and/or with Severe Neurological Impairment. AB - Background. New approaches are needed for patients newly diagnosed with bulky glioblastoma (GB) and/or with severe neurological impairment that cannot benefit from first line temozolomide (TMZ)-based chemoradiotherapy. Bevacizumab (BEV), an antiangiogenic anti-VEGF-R monoclonal antibody, has a rapid impact on tumor related brain edema in recurrent GB. The present study reports the feasibility and efficacy of an induction treatment with TMZ and BEV to alleviate the initial neurological impairment and/or to reduce the tumor volume before a delayed chemoradiotherapy. Methods. We retrospectively analyzed tumor and target volumes and clinical neurological status in 39 patients with bulky GB and/or with severe neurological impairment after an induction treatment combining TMZ and BEV. Neurological and radiological responses were assessed according to RANO criteria. Calculating gross tumor and clinical target volumes (GTV and CTV) was done at diagnosis and before radiotherapy. Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan Meier methods. Safety was reported according to NCTCAE. Results. A cohort of 39 patients was analyzed between December 2010 and April 2014. Upfront standard TMZ-based chemoradiotherapy was recused due either to tumor volume or impairment of neurological status and/or performance status. After TMZ/BEV induction (median time of 3 months), 6 (15%) patients achieved a partial response (PR), and 17 (44%) had a stable disease. 24 patients (62%) received a radical-intent chemoradiotherapy. TMZ-BEV induced median reduction of the clinical target volume (CTV) was 25.9% [-84.4%; - 4.8%]. The median PFS and OS were 8.4 months [95% CI: (6.6 - 9.9)] and 11.0 months [95% CI: (9.3 - 13.7)], respectively in the whole cohort and 10.8 [95% CI: (9.3 - 12.9)] and 15.0 [95% CI: (13.2 - 17.8)] for irradiated patients. Induction treatment led to corticosteroid dose reduction or cessation in 21 patients (54%). KPS improvement was observed in 38% of patients. Toxicity was mild with only 7/39 (18%) grade III-IV toxicity, including 1 digestive bleeding and 1 epistaxis. Conclusion. TMZ-BEV induction led to CTV reduction allowing for optimal chemoradiotherapy in a majority (62%) of patients for which radiotherapy was initially recused. A clinical benefit was obtained with improved KPS and a decrease in steroid dose. PMID- 28638457 TI - Upregulation of Coxsackie Adenovirus Receptor Sensitizes Cisplatin-Resistant Lung Cancer Cells to CRAd-Induced Inhibition. AB - Objective. Conditionally replicating adenoviruses (CRAds) have been proven potent oncolytic viruses in previous studies. They selectively replicate in the tumor cells because of incorporated survivin promoter and ultimately lead to their killing with minimal side effects on normal tissue. Chemotherapy with cisplatin is commonly employed for treating tumors, but its cytotoxic effects and development of resistance remained major concerns to be dealt with. The aim of this study was to explore the anticancer potential of survivin regulated CRAd alone or in combination with cisplatin in the A549 lung cancer cell line and cisplatin-resistant lung cancer cell line, A549-DDPR. Methods. CRAd was genetically engineered in our laboratory by removing its E1B region and adding survivin promoter to control its replication. A549, H292, and H661 lung cancer cell lines were procured from the CAS-China. The anti-tumor effectiveness of combined treatment (cisplatin plus CRAd) was evaluated in vitro through MTS assays and in vivo through mouse model experimentation. RT- PCR was used to assess MDR gene and mRNA expression of coxsackie adenoviral receptor (CAR). Results. Results of in vitro studies established that A549 lung cancer cells were highly sensitive to cisplatin showing dose-dependent inhibition. The resistant cells of A549-DDPR exhibited very less sensitivity to cisplatin but were infected with CRAd more efficiently as compared to A549. A549-DDPR cells exhibited higher expression of MDR gene and CAR in the RT-PCR analysis. The nearly similar rise in the CAR expression was seen when lung cancer cell lines received cisplatin in combined treatment (cisplatin plus CRAd). Combined anti-cancer therapy (cisplatin plus oncolytic virus) proved more efficient than monotherapy in the killing of cancer cells. Results of in vivo experiments recapitulated nearly similar tumor inhibition activities. Conclusion. This study highlighted the significant role of survivin in gene therapy as it has the potential to render CRAd more tumor specific. It also establishes that higher CAR expression plays a vital role in the success of adenovirus-based therapies. Furthermore, a careful combination of chemotherapy drugs and oncolytic viruses can culminate in significant therapeutic achievements against cancer. PMID- 28638458 TI - Anti-Metastatic Effect of Semi-Purified Nuphar Lutea Leaf Extracts. AB - Nuphar lutea L. SM., leaf and rhizome extracts (NUP), contain nupharidines as active components. Nupharidines belong to the sesquiterpene lactones class of a naturally occurring plant terpenoids. This family of compounds has gained considerable interest for treating infection, inflammation and cancer. NF-kappaB is a central, downstream regulator of inflammation, cell proliferation and apoptosis. In our previous work we demonstrated strong inhibition of NF-kappaB activity and induction of apoptosis by NUP. In addition, NUP exhibited anti inflammatory properties and partial protection from LPS-induced septic shock by modulating ERK pathway and cytokine secretion in macrophages. In the present study, we examined the effect of NUP in a B16 melanoma experimental murine lung metastasis model and its ability to affect the ERK and NF-kappaB pathways in variety of cell lines. We showed that NUP and cisplatin combined treatment was synergistic and reduced the lung metastatic load. In addition NUP treatment inhibited TNFalpha-induced IkappaBalpha degradation and NF- kappaB nuclear translocation. We also observed that NUP induced ERK activation. Furthermore, ERK inhibition prevented NF-kappaB inactivation by NUP. Overall, our work implies that co-administration of NF-kappaB inhibitors such as NUP, with standard anti cancer drugs, may act as "sensitizers" for more effective chemotherapy. PMID- 28638459 TI - Towards Prognostic Profiling of Non-Small Cell Lung Cancer: New Perspectives on the Relevance of Polo-Like Kinase 1 Expression, the TP53 Mutation Status and Hypoxia. AB - Background: Currently, prognosis of non-small cell lung cancer (NSCLC) patients is based on clinicopathological factors, including TNM stage. However, there are considerable differences in patient outcome within a similar staging group, even when patients received identical treatments. In order to improve prognostic predictions and to guide treatment options, additional parameters influencing outcome are required. Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division and the DNA damage response, is considered as a new potential biomarker in this research area. While several studies reported Plk1 overexpression in a broad range of human malignancies, inconsistent results were published regarding the clinical significance hereof. A prognostic panel, consisting of Plk1 and additional biomarkers that are related to the Plk1 pathway, might further improve prediction of patient prognosis. Methods: In this study, we evaluated for the first time the prognostic value of Plk1 mRNA and protein expression in combination with the TP53 mutation status (next generation sequencing), induction of apoptotic cell death (immunohistochemistry for cleaved caspase 3) and hypoxia (immunohistochemistry for carbonic anhydrase IX (CA IX)) in 98 NSCLC adenocarcinoma patients. Results: Both Plk1 mRNA and protein expression and CA IX protein levels were upregulated in the majority of tumor samples. Plk1 mRNA and protein expression levels were higher in TP53 mutant samples, suggesting that Plk1 overexpression is, at least partially, the result of loss of functional p53 (<0.05). Interestingly, the outcome of patients with both Plk1 mRNA and CA IX protein overexpression, who also harbored a TP53 mutation, was much worse than that of patients with aberrant expression of only one of the three markers (p=0.001). Conclusion: The combined evaluation of Plk1 mRNA expression, CA IX protein expression and TP53 mutations shows promise as a prognostic panel in NSCLC patients. Moreover, these results pave the way for new combination strategies with Plk1 inhibitors. PMID- 28638461 TI - Current Status of Immune Checkpoint Inhibitors in Gastrointestinal Cancers. AB - The expansion of our understanding of tumor immunity and the recent success of new cancer immunotherapy has reignited the hope that we can treat cancer effectively with immunotherapeutic approaches. Immune checkpoint inhibitors have shown significant efficacy in the treatment of some solid and hematologic malignancies. Encouraged by recent success in some other types of malignancies, many clinical trials are ongoing to evaluate the efficacy of immune checkpoint inhibitors in gastrointestinal (GI) malignancies. In this review, we briefly discuss theoretical background and current status of immune checkpoint inhibitors in GI cancers. We summarize the key studies and present the ongoing clinical trials involving immune checkpoint inhibitors in GI cancers. PMID- 28638460 TI - ZEB1 Mediates Drug Resistance and EMT in p300-Deficient CRC. AB - We discuss the hypothesis that ZEB1-Wnt-p300 signaling integrates epithelial to mesenchymal transition (EMT) and resistance to histone deacetylase inhibitors (HDACis) in colorectal cancer (CRC) cells. The HDACi butyrate, derived from dietary fiber, has been linked to CRC prevention, and other HDACis have been proposed as therapeutic agents against CRC. We have previously discussed that resistance to butyrate likely contributes to colonic carcinogenesis, and we have demonstrated that butyrate resistance leads to cross-resistance to cancer therapeutic HDACis. Deregulated Wnt signaling is the major initiating event in most CRC cases. One mechanism whereby butyrate and other HDACis exert their anti CRC effects is via Wnt signaling hyperactivation, which promotes CRC cell apoptosis. The histone acetylases (HATs) CBP and p300 are mediators of Wnt transcriptional activity, and play divergent roles in the downstream consequences of Wnt signaling. CBP-mediated Wnt signaling is associated with cell proliferation and stem cell maintenance; whereas, p300-mediated Wnt activity is associated with differentiation. We have found that CBP and p300 differentially affect the ability of butyrate to influence Wnt signaling, apoptosis, and proliferation. ZEB1 is a Wnt signaling-targeted gene, whose product is a transcription factor expressed at the invasive front of carcinomas where it promotes malignant progression and EMT. ZEB1 is typically a transcriptional repressor; however, when associated with p300, ZEB1 enhances transcription. These changes in ZEB1 activity likely affect the cancer cell phenotype. ZEB1 has been shown to promote resistance to chemotherapeutic agents, and expression of ZEB1 is upregulated in butyrate-resistant CRC cells that lack p300 expression. Since the expression of ZEB1 correlates with poor outcomes in cancer, ZEB represents a relevant therapeutic target. Here we propose that targeting the signaling network established by ZEB1, Wnt signaling, and p300 signaling can reverse HDACi resistance and inhibit EMT. PMID- 28638462 TI - Reorganized Collagen in the Tumor Microenvironment of Gastric Cancer and Its Association with Prognosis. AB - Collagen components in the tumor microenvironment substantially influence cancer pathogenesis and progression. Nevertheless, in gastric cancer, collagen status and its prognostic role remain unclear. Using picrosirius red staining and immunohistochemistry, we found that collagen deposition was significantly increased in gastric cancer when compared with non-neoplastic tissues, and in cancer stroma, more immature collagen components were present, suggesting a qualitative change. Furthermore, the morphology of collagen fibers could be weakly, moderately or strongly changed in gastric cancer; when weakly or moderately changed, they appeared similar to normal collagen fibers, except for a higher linearization and density; when strongly changed, they were thicker and less eosinophilic, sharply differently from their normal counterparts. In addition, we found abundant myofibroblasts and elevated expression of lysyl oxidase-like 2 (the enzyme that mediates crosslinking of collagen molecules) in cancer stroma, which might contribute to the increased collagen deposition and crosslinking. Last, five collagen architectural parameters (alignment, density, width, length and straightness) were analyzed with second harmonic generation imaging, a highly specific technology for detection of collagen fibers, and our data indicated that all the parameters were significantly increased in the tumor microenvironment. Of the five parameters, collagen width was the most powerful parameter in predicting 5-year overall survival, and increased collagen width was associated with reduced survival. The prognostic value of collagen width was superior to traditional clinicopathological parameters, and this was validated in two unrelated gastric cancer cohorts that contained 225 and 151 patients. Collectively, the collagen status (content, maturity, morphology and architecture) was profoundly reorganized in the tumor microenvironment of gastric cancer, and collagen width could serve as a valuable prognostic indicator. PMID- 28638463 TI - Deficiency of hMLH1 and hMSH2 expression is a poor prognostic factor in Early Gastric Cancer (EGC). AB - Purpose: The aim of the study was to investigate the effect of deficiency of hMLH1 and hMSH2 expression on the prognosis of early gastric cancer (EGC) in Chinese populations. Methods: A total of 160 EGC patients who underwent curative gastrectomy with lymphadenectomy from January 2011 to July 2014 at Xinhua Hospital were evaluated. The expression rates of hMLH1 and hMSH2 were examined using tissues preserved in paraffin blocks by immunohistochemical staining. The clinicopathological characteristics and prognosis of EGC with deficient hMLH1 and hMSH2 were analyzed. Results: On immunohistochemical staining, the loss expression of hMLH1 and hMSH2 were observed in 89 (55.6%) and 45 (28.1%), respectively. The hMLH1 deficiency was associated with the middle third of tumor location (P = 0.041). According to Kaplan-Meier survival analysis and Log-Rank test, the loss expression of hMLH1 and hMSH2 were associated with worse survival than positive hMLH1 (HR = 0.247, 95% CI = 0.078-0.781, P = 0.017) and hMSH2 (HR = 0.174, 95% CI = 0.051-0.601, P = 0.006) in EGC. Conclusion: The main conclusions were as follows: The hMLH1 deficiency was preferred to the middle third of EGC. Lymph node metastasis (LNM) was a prognostic factor of EGC. And the prognosis of EGC patients with deficient mismatch repair (dMMR, mainly including deficient hMLH1 and hMSH2) was obviously worse than proficient mismatch repair (pMMR). PMID- 28638464 TI - Overexpression of PAK1 Correlates with Aberrant Expression of EMT Markers and Poor Prognosis in Non-Small Cell Lung Cancer. AB - Objective: p21-activated kinases (PAKs) are serine/threonine protein kinases. PAK1 and epithelial-mesenchymal transition (EMT) are key therapeutic targets in cancer. The clinical significance of PAK1 and its potential association with EMT phenotype in non-small cell lung cancer (NSCLC) was investigated. Methods: Immunohistochemistry was used to detect the expression of PAK1, and mesenchymal and epithelial markers (vimentin, N-cadherin, and E-cadherin) in 186 cases of NSCLC tissues and 50 cases of tumor-adjacent normal tissues. The correlation of PAK1 with the clinicopathological characteristics, prognosis, and mesenchymal and epithelial markers in NSCLC were analyzed. Results: Compared with the non-tumor tissues, PAK1, vimentin, and N-cadherin levels were markedly elevated in NSCLC tissues, whereas the E-cadherin levels were significantly decreased (P<0.05). The aberrant expression of PAK1 was significantly associated with TNM stage and metastasis (P<0.001). Patients who displayed high expression of PAK1 may achieve a poorer progression-free survival (PFS) and overall survival (OS), compared to those with low expression of PAK1 (P=0.001 and P<0.001). Univariate and multivariate analysis showed that high expression of PAK1 was an independent predictor of poor prognosis [hazard ratio (HR) =2.121, P<0.001, HR=1.928, P=0.001, respectively]. In addition, significant correlations were observed between the EMT markers and OS or PFS (P<0.01). Interestingly, PAK1 expression was positively correlated with vimentin and N-cadherin levels (r=0.473, P<0.001; r=0.526, P<0.001, respectively) and negatively correlated with E-cadherin levels (r=-0.463, P<0.001) in NSCLC tissues. Conclusion: PAK1 may promote NSCLC progression and metastasis through EMT, thereby exhibiting the potential of an efficient prognostic predictor in NSCLC patients. PMID- 28638465 TI - Prediction of Lymph Node Metastases in Gastric Cancer by Serum APE1 Expression. AB - Aims: To investigate the functional role of serum Human apurinic/apyrimidinic endonuclease 1 (APE1) in prediction of lymph node metastasis in gastric cancer patients. Materials and methods: Serum samples were pre-operational collected from 86 patients with gastric cancer from Tianjin Medical University Cancer Institute and Hospital from March 2016 to August 2016. The serum of APE1 was measured by ELISA development kit and other CA242, CA724, CA199 and CEA levels by electrochemiluminescence assay. Results: The total of 86 patients with gastric cancer was classified into two groups (lymph node positive and negative groups). Using ELISA assay, we found out that the concentration of serum APE1 was higher in lymph node positive group than that of lymph node negative group. The receiver operating characteristic (ROC) curve was performed to analyze, indicating that area under the ROC curve of serum APE1 were better than those of each regular markers (CEA+CA199+CA242+CA724) or combination of these markers. Additionally, the APE1 overexpression was uncovered in tissue of gastric cancer patients with lymph nodes metastases, which is correlation with results of serum APE1. Conclusion: Serum APE1 was identified as a valuable marker for prediction of lymph node metastases in patients with gastric cancer. PMID- 28638466 TI - Long Noncoding RNA CCAT2 as a Potential Novel Biomarker to Predict the Clinical Outcome of Cancer Patients: A Meta-Analysis. AB - Background: Colon Cancer-Associated Transcript 2 (CCAT2) has been demonstrated associated with clinical outcomes in various tumors. However, the results from each study were unfortunately insufficient and not completely consistent. Therefore, we conduct a systematic meta-analysis to evaluate the value for a feasible biomarker for metastasis and prognosis. Methods: A meta-analysis was performed using data obtained through a systematic search of PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Wanfang database and VIP database. The pooled odds ratio (OR) and hazard ratio (HR) with 95% Confidence interval (CI ) using random-effect were used to identify the relationship of CCAT2 with clinical outcome of cancer patients. Subgroup analysis and sensitivity analysis were performed. Results: A total of 867 patients from eight studies were finally included. Patients with high CCAT2 expression underwent an increased risk of lymph node metastasis (LNM) (OR=3.09, 95% CI: 1.53 6.26) and distant metastasis (DM) (OR=7.70, 95% CI: 3.26-18.17). CCAT2 was also significantly correlated with overall survival (OS) (HR=2.19, 95%CI: 1.70-2.82) and progression-free survival (PFS) (HR=2.59, 95% CI: 1.78-3.76). Moderate heterogeneity was observed in meta-analysis for LNM. However, the results remained robust in multiple sensitivity analyses. Conclusions: High expression of CCAT2 was linked with poor clinical outcome. CCAT2 can serve as a potential molecular marker for prognosis in different types of cancers. PMID- 28638467 TI - Dual-Responsive Molecular Probe for Tumor Targeted Imaging and Photodynamic Therapy. AB - The precision oncology significantly relies on the development of multifunctional agents to integrate tumor targeting, imaging and therapeutics. In this study, a first small-molecule theranostic probe, RhoSSCy is constructed by conjugating 5' carboxyrhodamines (Rho) and heptamethine cyanine IR765 (Cy) using a reducible disulfide linker and pH tunable amino-group to realize thiols/pH dual sensing. In vitro experiments verify that RhoSSCy is highly sensitive for quantitative analysis and imaging intracellular pH gradient and biothiols. Furthermore, RhoSSCy shows superb tumor targeted dual-modal imaging via near-infrared fluorescence (NIRF) and photoacoustic (PA). Importantly, RhoSSCy also induces strongly reactive oxygen species for tumor photodynamic therapy (PDT) with robust antitumor activity both in vitro and in vivo. Such versatile small-molecule theranostic probe may be promising for tumor targeted imaging and precision therapy. PMID- 28638468 TI - Current and emerging techniques for antibiotic susceptibility tests. AB - Infectious diseases caused by bacterial pathogens are a worldwide burden. Serious bacterial infection-related complications, such as sepsis, affect over a million people every year with mortality rates ranging from 30% to 50%. Crucial clinical microbiology laboratory responsibilities associated with patient management and treatment include isolating and identifying the causative bacterium and performing antibiotic susceptibility tests (ASTs), which are labor-intensive, complex, imprecise, and slow (taking days, depending on the growth rate of the pathogen). Considering the life-threatening condition of a septic patient and the increasing prevalence of antibiotic-resistant bacteria in hospitals, rapid and automated diagnostic tools are needed. This review summarizes the existing commercial AST methods and discusses some of the promising emerging AST tools that will empower humans to win the evolutionary war between microbial genes and human wits. PMID- 28638469 TI - Dual-pH Sensitive Charge-reversal Nanocomplex for Tumor-targeted Drug Delivery with Enhanced Anticancer Activity. AB - Poly(beta-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor targeted drug delivery with enhanced anticancer activity. PMID- 28638470 TI - Bright Polymer Dots Tracking Stem Cell Engraftment and Migration to Injured Mouse Liver. AB - Stem cell therapy holds promise for treatment of intractable diseases and injured organs. For clinical translation, it is pivotal to understand the homing, engraftment, and differentiation processes of stem cells in a living body. Here we report near-infrared (NIR) fluorescent semiconductor polymer dots (Pdots) for bright labeling and tracking of human mesenchymal stem cells (MSCs). The Pdots exhibit narrow-band emission at 775 nm with a quantum yield of 22%, among the highest value for various NIR probes. The Pdots together with a cell penetrating peptide are able to track stem cells over two weeks without disturbing their multipotent properties, as confirmed by the analyses on cell proliferation, differentiation, stem-cell markers, and immunophenotyping. The in vivo cell tracking was demonstrated in a liver-resection mouse model, which indicated that the Pdot-labeled MSCs after tail-vein transplantation were initially trapped in lung, gradually migrated to the injured liver, and then proliferated into cell clusters. Liver-function analysis and histological examination revealed that the inflammation induced by liver resection was apparently decreased after stem cell transplantation. With the bright labeling, superior biocompatibility, and long term tracking performance, the Pdot probes are promising for stem cell research and regenerative medicine. PMID- 28638471 TI - Rapid Detection of Avian Influenza Virus by Fluorescent Diagnostic Assay using an Epitope-Derived Peptide. AB - Currently, the point of care testing (POCT) is not fully developed for subtype specific avian influenza virus detection. In this study, an H5N1 hemaglutinin 1 (HA1) epitope (P0: KPNDAINF) and three modified peptides (P1: KPNTAINF, P2: KPNGAINF, P3: KPNDAINDAINF) were evaluated as POCT elements for rapid detection of avian influenza virus. Based on modeling predictions by Autodock Vina, binding affinity varied depending on alteration of one amino acid in these peptides. The binding energy of P2 indicated its potential for a strong interaction with HA. Fluorescence-linked immunosorbent assay experimentally demonstrated the interaction between these peptides and virus. The four peptides interacted with HA1 of H5N3 with different binding affinities with P2 showing the strongest binding affinity. When P0 and P2 peptides were used in rapid fluorescent immunochromatographic test (FICT) as detection elements, the inter-assay coefficients of variation (CV) indicated that P2-linked FICT was more acceptable than the P0-linked FICT in the presence of human specimens. Antibody pair-linked FICT was influenced by clinical samples more than the P2-linked FICT assay, which showed a 4-fold improvement in the detection limit of H5N3 and maintained H5 subtype-specificity. Compared to the rapid diagnostic test (RDT) which is not specific for influenza subtypes, P2-linked FICT could increase virus detection. In conclusion, results of this study suggest that HA epitope-derived peptides can be used as alternatives to antibodies for a rapid fluorescent diagnostic assay to detect avian influenza virus. PMID- 28638473 TI - Rapid fluorescence imaging of spinal cord following epidural administration of a nerve-highlighting fluorophore. AB - Iatrogenic spinal cord injury (SCI) is the most devastating complication of spine surgery, which usually results in permanent and serious disabilities of patients. Improvement of the visualization and discrimination of the spinal cord is critical for accuracy and safety during surgery; however, to date, there is no suitable technology to fulfill this clinical need. Here, we first show an efficient and rapid fluorescence imaging of the spinal cord in rabbit by epidural administration of a nerve-highlighting fluorophore, i.e. (E, E)-1,4-bis(p aminostryl)-2-methoxy benzene (BMB). The BMB is firstly encapsulated into polymeric micelles to form a BMB-micelle (BMB-m) formulation with well-dispersion in normal saline solution. After epidural administration of BMB-m, BMB is transported by the flow of cerebrospinal fluid (CSF) and binds to the peripheral region of the white matter thus facilitating rapid staining of the spinal cord. Furthermore, this BMB imaging technology also holds great potential for visually monitoring the integrity of the spinal cord in real time and promptly identifying acute SCI during spine surgery. PMID- 28638472 TI - Advances in the detection of telomerase activity using isothermal amplification. AB - Telomerase plays a significantly important role in keeping the telomere length of a chromosome. Telomerase overexpresses in nearly all tumor cells, suggesting that telomerase could be not only a promising biomarker but also a potential therapeutic target for cancers. Therefore, numerous efforts focusing on the detection of telomerase activity have been reported from polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assays to PCR free assays such as isothermal amplification in recent decade. In this review, we highlight the strategies for the detection of telomerase activity using isothermal amplification and discuss some of the challenges in designing future telomerase assays as well. PMID- 28638474 TI - Self-Assembly of Gold Nanoparticles Shows Microenvironment-Mediated Dynamic Switching and Enhanced Brain Tumor Targeting. AB - Inorganic nanoparticles with unique physical properties have been explored as nanomedicines for brain tumor treatment. However, the clinical applications of the inorganic formulations are often hindered by the biological barriers and failure to be bioeliminated. The size of the nanoparticle is an essential design parameter which plays a significant role to affect the tumor targeting and biodistribution. Here, we report a feasible approach for the assembly of gold nanoparticles into ~80 nm nanospheres as a drug delivery platform for enhanced retention in brain tumors with the ability to be dynamically switched into the single formulation for excretion. These nanoassemblies can target epidermal growth factor receptors on cancer cells and are responsive to tumor microenvironmental characteristics, including high vascular permeability and acidic and redox conditions. Anticancer drug release was controlled by a pH responsive mechanism. Intracellular L-glutathione (GSH) triggered the complete breakdown of nanoassemblies to single gold nanoparticles. Furthermore, in vivo studies have shown that nanospheres display enhanced tumor-targeting efficiency and therapeutic effects relative to single-nanoparticle formulations. Hence, gold nanoassemblies present an effective targeting strategy for brain tumor treatment. PMID- 28638475 TI - Tamoxifen activates Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia. AB - Long-term application of Tamoxifen (TAM) is usually recommended for hormone receptor positive breast cancer patients. Unfortunately, TAM will inevitably increase the incidence of endometrial hyperplasia even endometrial cancer. Despite of substantial investigations, no effective approaches to prevent TAM induced endometrial carcinogenesis have been acknowledged. In this study, we found that inhibition of Nrf2 could be valuable to prevent TAM-induced endometrial hyperplasia. Upon TAM treatment, the mRNA and protein expression of autophagy adaptor SQSTM1 was specifically increased in endometrial cells but not breast cancer cells. Knocking-down of SQSTM1 expression retarded TAM-promoted growth of endometrial cancer cells. TAM stimulated SQSTM1 transcription specifically in endometrial cells by enhancing phosphorylation and nuclear translocation of Nrf2. Indeed, the expression of Nrf2 and SQSTM1 were positively correlated in primary endometrial tissues. In rats with TAM-induced endometrial hyperplasia, both Nrf2 and SQSTM1 expression were increased. Nrf2 inhibitor brusatol effectively attenuated TAM-induced SQSTM1 upregulation and endometrial hyperplasia. The kinase of Nrf2, PRKCD, was activated by TAM. Once PRKCD was depleted, TAM failed to promote Nrf2 phosphorylation and SQSTM1 expression. In summary, TAM stimulated Nrf2-dependent SQSTM1 transcription to promote endometrial hyperplasia by activating PRKCD. Therefore, blocking PRKCD-Nrf2 SQSTM1 signaling could be useful to prevent TAM-induced endometrial hyperplasia. PMID- 28638476 TI - Therapeutic Inhibition of miR-4260 Suppresses Colorectal Cancer via Targeting MCC and SMAD4. AB - Dysregulation of microRNAs (miRNAs, miRs) and their putative target genes have been increasingly reported to contribute to colorectal cancer. However, miRNAs that directly target the mutated in colorectal cancer (MCC) gene, a tumor suppressor which is downregulated or inactivated in colorectal cancer, remain largely unknown. By using an array-based miRNA analysis, we identified a group of miRNAs that were dysregulated in human metastatic versus non-metastatic colorectal cancer tissues. One of these miRNAs, miR-4260, was predicted to target MCC in the miRDB database. Results using human HCT116 and HT29 colorectal cancer cell lines showed that miR-4260 mimic enhanced cell proliferation and migration and reduced apoptosis induced by the chemotherapeutic agent 5-fluorouracil while miR-4260 inhibitor had inverse effects. Furthermore, miR-4260 negatively regulated MCC as well as SMAD4 by directly binding to the 3'untranslational region (3'UTR). Using siRNAs targeting MCC or SMAD4, we showed that upregulation of MCC and SMAD4 was essential to mediate the functional roles of miR-4260 inhibitor in colorectal cancer cells. Our in vivo experiments indicated that inhibition of miR-4260 reduced colorectal tumor growth in nude mice subcutaneously implanted with HCT116 cells. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4, strongly suggesting the clinical relevance of targeting miR-4260 in the treatment of colorectal cancer. In summary, we identified miR-4260 as a novel oncomiR for colorectal cancer that targets MCC and SMAD4. Inhibition of miR-4260 can, therefore, be a potential therapeutic strategy for colorectal cancer. PMID- 28638477 TI - Triptolide Inhibits the AR Signaling Pathway to Suppress the Proliferation of Enzalutamide Resistant Prostate Cancer Cells. AB - Enzalutamide is a second-generation androgen receptor (AR) antagonist for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Unfortunately, AR dysfunction means that resistance to enzalutamide will eventually develop. Thus, novel agents are urgently needed to treat this devastating disease. Triptolide (TPL), a key active compound extracted from the Chinese herb Thunder God Vine (Tripterygium wilfordii Hook F.), possesses anti cancer activity in human prostate cancer cells. However, the effects of TPL against CRPC cells and the underlying mechanism of any such effect are unknown. In this study, we found that TPL at low dose inhibits the transactivation activity of both full-length and truncated AR without changing their protein levels. Interestingly, TPL inhibits phosphorylation of AR and its CRPC-associated variant AR-V7 at Ser515 through XPB/CDK7. As a result, TPL suppresses the binding of AR to promoter regions in AR target genes along with reduced TFIIH and RNA Pol II recruitment. Moreover, TPL at low dose reduces the viability of prostate cancer cells expressing AR or AR-Vs. Low-dose TPL also shows a synergistic effect with enzalutamide to inhibit CRPC cell survival in vitro, and enhances the anti cancer effect of enzalutamide on CRPC xenografts with minimal side effects. Taken together, our data demonstrate that TPL targets the transactivation activity of both full-length and truncated ARs. Our results also suggest that TPL is a potential drug for CRPC, and can be used in combination with enzalutamide to treat CRPC. PMID- 28638479 TI - Should Low Molecular Weight PSMA Targeted Ligands Get Bigger and Use Albumin Ligands for PSMA Targeting? AB - Prostate Specific Membrane Antigen (PSMA) is strongly expressed in prostate cancer. Recently a number of low-molecular-weight inhibitors have demonstrated excellent PSMA targeting activity for both imaging as well as Lutecium-177 radiotherapy in human trials. The paper by Choy et al raises the question of whether we can further increase the effectiveness of PSMA targeted therapy by adding an albumin-binding entity to low-molecular-weight agents. PMID- 28638478 TI - 177Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice. AB - Prostate-specific membrane antigen (PSMA) continues to be an active biomarker for small-molecule PSMA-targeted imaging and therapeutic agents for prostate cancer and various non-prostatic tumors that are characterized by PSMA expression on their neovasculature. One of the challenges for small-molecule PSMA inhibitors with respect to delivering therapeutic payloads is their rapid renal clearance. In order to overcome this pharmacokinetic challenge, we outfitted a 177Lu-labeled phosphoramidate-based PSMA inhibitor (CTT1298) with an albumin-binding motif (CTT1403) and compared its in vivo performance with that of an analogous compound lacking the albumin-binding motif (CTT1401). The radiolabeling of CTT1401 and CTT1403 was achieved using click chemistry to connect 177Lu-DOTA-N3 to the dibenzocyclooctyne (DBCO)-bearing CTT1298 inhibitor cores. A direct comparison in vitro and in vivo performance was made for CTT1401 and CTT1403; the specificity and efficacy by means of cellular uptake and internalization, biodistribution, and therapeutic efficacy were determined for both compounds. While both compounds displayed excellent uptake and rapid internalization in PSMA+ PC3-PIP cells, the albumin binding moiety in CTT1403 conferred clear advantages to the PSMA inhibitor scaffold including increased circulating half-life and prostate tumor uptake that continued to increase up to 168 h post-injection. This increased tumor uptake translated into superior therapeutic efficacy of CTT1403 in PSMA+ PC3-PIP human xenograft tumors. PMID- 28638480 TI - Mouse IP-10 Gene Delivered by Folate-modified Chitosan Nanoparticles and Dendritic/tumor Cells Fusion Vaccine Effectively Inhibit the Growth of Hepatocellular Carcinoma in Mice. AB - Dendritic cells (DC) and tumor cell fusion vaccine (DC/tumor cell fusion vaccine) is considered an effective approach in cancer biotherapy. However, its therapeutic effects in early clinical trials have been suboptimal partially due to the immunosuppressive tumor environment. In this study, we used nanoparticles of folate (FA)-modified chitosan, a non-viral vector capable of targeting tumor cells with high expression of FA receptors. FA-chitosan nanoparticles were used as biological carriers for the expression plasmid of the mouse interferon-induced protein-10 (mIP-10) gene, a potent chemoattractant for cytotoxic T cells. The combination of FA-chitosan/mIP-10 and DC/tumor cell fusion vaccine against hepatocellular carcinoma (HCC) effectively inhibited the growth of implanted HCC tumors and prolonged the survival of mice. The combination therapy significantly reduced myeloid-derived suppressor cells (MDSC) in mouse spleen, local tumor, and bone marrow while increasing tumor-specific IFN-gamma responses. Furthermore, the combination therapy significantly inhibited tumor cell proliferation while promoting their apoptosis. Taken together, our data illustrate that the mIP-10 enhances the anti-tumor effect of DC/tumor cell fusion vaccine by alleviating the immunosuppressive tumor environment. PMID- 28638481 TI - Neonatal Heart-Enriched miR-708 Promotes Proliferation and Stress Resistance of Cardiomyocytes in Rodents. AB - Adult heart has limited potential for regeneration after pathological injury due to the limited cell proliferation of cardiomyocytes and the quiescent status of progenitor cells. As such, induction of cell-cycle reentry of cardiomyocytes is one of the key strategies for regeneration of damaged heart. In this study, a subset of miRNAs including miR-708 were identified to be much more abundant in the embryonic and neonatal cardiomyocytes than that in adult rodents. Overexpression of miR-708 promoted cellular proliferation of H9C2 cells or primary cardiomyocytes from neonatal rats or mice in vitro. Lipid nanoparticle delivery of miR-708 promoted myocardial regeneration and heart function recovery in vivo. In addition, miR-708 protected cardiomyocytes against stress-induced apoptosis under hypoxia or isoproterenol treatments. miR-708 inhibited the expression of MAPK14, which has been demonstrated arresting the cell cycle in cardiomyocytes. The cell proliferation-promoting function of miR-708 was dependent at least partly on the expression of MAPK14. These findings strengthen the potential of applying miRNAs to reconstitute lost cardiomyocytes in injured hearts, and may provide a novel miRNA candidate for promoting heart regeneration. PMID- 28638482 TI - Implantable and Biodegradable Macroporous Iron Oxide Frameworks for Efficient Regeneration and Repair of Infracted Heart. AB - The construction, characterization and surgical application of a multilayered iron oxide-based macroporous composite framework were reported in this study. The framework consisted of a highly porous iron oxide core, a gelatin-based hydrogel intermediary layer and a matrigel outer cover, which conferred a multitude of desirable properties including excellent biocompatibility, improved mechanical strength and controlled biodegradability. The large pore sizes and high extent of pore interconnectivity of the framework stimulated robust neovascularization and resulted in substantially better cell viability and proliferation as a result of improved transport efficiency for oxygen and nutrients. In addition, rat models with myocardial infraction showed sustained heart tissue regeneration over the infract region and significant improvement of cardiac functions following the surgical implantation of the framework. These results demonstrated that the current framework might hold great potential for cardiac repair in patients with myocardial infraction. PMID- 28638483 TI - Thermoacoustic Imaging and Therapy Guidance based on Ultra-short Pulsed Microwave Pumped Thermoelastic Effect Induced with Superparamagnetic Iron Oxide Nanoparticles. AB - Multifunctional nanoparticle-mediated imaging and therapeutic techniques are promising modalities for accurate localization and targeted treatment of cancer in clinical settings. Thermoacoustic (TA) imaging is highly sensitive to detect the distribution of water, ions or specific nanoprobes and provides excellent resolution, good contrast and superior tissue penetrability. TA therapy is a potential non-invasive approach for the treatment of deep-seated tumors. In this study, human serum albumin (HSA)-functionalized superparamagnetic iron oxide nanoparticle (HSA-SPIO) is used as a multifunctional nanoprobe with clinical application potential for MRI, TA imaging and treatment of tumor. In addition to be a MRI contrast agent for tumor localization, HSA-SPIO can absorb pulsed microwave energy and transform it into shockwave via the thermoelastic effect. Thereby, the reconstructed TA image by detecting TA signal is expected to be a sensitive and accurate representation of the HSA-SPIO accumulation in tumor. More importantly, owing to the selective retention of HSA-SPIO in tumor tissues and strong TA shockwave at the cellular level, HSA-SPIO induced TA effect under microwave-pulse radiation can be used to highly-efficiently kill cancer cells and inhibit tumor growth. Furthermore, ultra-short pulsed microwave with high excitation efficiency and deep penetrability in biological tissues makes TA therapy a highly-efficient anti-tumor modality on the versatile platform. Overall, HSA-SPIO mediated MRI and TA imaging would offer more comprehensive diagnostic information and enable dynamic visualization of nanoagents in the tumorous tissue thereby tumor-targeted therapy. PMID- 28638485 TI - PSMA-PET for Lymph Node Detection in Recurrent Prostate Cancer: How do we use the Magic Bullet? PMID- 28638484 TI - Surface De-PEGylation Controls Nanoparticle-Mediated siRNA Delivery In Vitro and In Vivo. AB - The present work proposes a unique de-PEGylation strategy for controllable delivery of small interfering RNA (siRNA) using a robust lipid-polymer hybrid nanoparticle (NP) platform. The self-assembled hybrid NPs are composed of a lipid poly(ethylene glycol) (lipid-PEG) shell and a polymer/cationic lipid solid core, wherein the lipid-PEG molecules can gradually dissociate from NP surface in the presence of serum albumin. The de-PEGylation kinetics of a series of different lipid-PEGs is measured with their respective NPs, and the NP performance is comprehensively investigated in vitro and in vivo. This systematic study reveals that the lipophilic tails of lipid-PEG dictate its dissociation rate from NP surface, determining the uptake by tumor cells and macrophages, pharmacokinetics, biodistribution, and gene silencing efficacy of these hybrid siRNA NPs. Based on our observations, we here propose that lipid-PEGs with long and saturated lipophilic tails might be required for effective siRNA delivery to tumor cells and gene silencing of the lipid-polymer hybrid NPs after systemic administration. PMID- 28638486 TI - In Molecular Pursuit of Bone Metastasis by Fluciclovine PET. AB - Diagnosing bone metastases with traditional anatomic modalities, such as MRI and CT, is limited by sensitivity, and conventional bone radiotracers are only indirect markers of cancer activity. Fortunately, molecular imaging is uniquely capable of providing radiotracers such as fluciclovine and radiolabeled choline, that actually target tumors in the bone. The merits of research in imaging osseous metastases in animal models using these radiotracers and the implications for future clinical translation are discussed. PMID- 28638488 TI - A Look Inside of the Complex Pathogenesis of B-RAF(V600E)-Driven Cancer. AB - Cancer is a very complex disease, where cell alterations (i.e. gene mutations, dysregulated signaling pathway(s) and epigenetic modifications) contribute to its development and progression. Elucidating the connections among these cell modifications is a critical challenge, in order to understand the mechanisms which are activated from cancer cells to survive and proliferate. Interesting, Prof. Peng Hou and colleagues, at the First Affiliated Hospital of Xi'an Jiaotong University in China, identified unknown epigenetic mechanisms and their involvement in the tumorigenesis of B-RAF(V600E)-driven cancer. PMID- 28638487 TI - Current Strategies and Challenges for Purification of Cardiomyocytes Derived from Human Pluripotent Stem Cells. AB - Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) are considered a most promising option for cell-based cardiac repair. Hence, various protocols have been developed for differentiating hPSCs into CMs. Despite remarkable improvement in the generation of hPSC-CMs, without purification, these protocols can only generate mixed cell populations including undifferentiated hPSCs or non-CMs, which may elicit adverse outcomes. Therefore, one of the major challenges for clinical use of hPSC-CMs is the development of efficient isolation techniques that allow enrichment of hPSC-CMs. In this review, we will discuss diverse strategies that have been developed to enrich hPSC-CMs. We will describe major characteristics of individual hPSC-CM purification methods including their scientific principles, advantages, limitations, and needed improvements. Development of a comprehensive system which can enrich hPSC-CMs will be ultimately useful for cell therapy for diseased hearts, human cardiac disease modeling, cardiac toxicity screening, and cardiac tissue engineering. PMID- 28638489 TI - Harnessing Integrative Omics to Facilitate Molecular Imaging of the Human Epidermal Growth Factor Receptor Family for Precision Medicine. AB - Cancer is a growing problem worldwide. The cause of death in cancer patients is often due to treatment-resistant metastatic disease. Many molecularly targeted anticancer drugs have been developed against 'oncogenic driver' pathways. However, these treatments are usually only effective in properly selected patients. Resistance to molecularly targeted drugs through selective pressure on acquired mutations or molecular rewiring can hinder their effectiveness. This review summarizes how molecular imaging techniques can potentially facilitate the optimal implementation of targeted agents. Using the human epidermal growth factor receptor (HER) family as a model in (pre)clinical studies, we illustrate how molecular imaging may be employed to characterize whole body target expression as well as monitor drug effectiveness and the emergence of tumor resistance. We further discuss how an integrative omics discovery platform could guide the selection of 'effect sensors' - new molecular imaging targets - which are dynamic markers that indicate treatment effectiveness or resistance. PMID- 28638491 TI - O-GlcNAc-ylation in the Nuclear Pore Complex. AB - O-GlcNAc-ylation is the post-translational addition of an O-linked beta-N acetylglucosamine to the serine and threonine residues of thousands of proteins in eukaryotic cells. Specifically, half of the thirty different types of protein components in the nuclear pore complex (NPC) are modified by O-GlcNAc, of which the majority are intrinsically disordered nucleoporins (Nups) containing multiple phenylalanine-glycine (FG) repeats. Moreover, these FG-Nups form a strict selectivity barrier with a high density of O-GlcNAc in the NPC to mediate bidirectional trafficking between the cytoplasm and nucleus. However, the roles that O-GlcNAc plays in the structure and function of the NPC remain obscure. In this review paper, we will discuss the current knowledge of O-GlcNAc-ylated Nups, highlight some new techniques used to probe O-GlcNAc's roles in the nuclear pore, and finally propose a new model for the effect of O-GlcNAc on the NPC's permeability. PMID- 28638492 TI - Importance of Radiological Evaluation of Global Spinal Balance Together with Lower Limb Alignment in Planning Lumbar Spine Deformity Surgery - Illustrative Case Presentation. AB - BACKGROUND: The presented case illustrates the critical role of a detailed preoperative radiological evaluation in complex spine surgery. CASE REPORT: A 49 year-old patient was admitted for a revision surgery after L3-L5 fusion. Preoperative assessment showed preserved sagittal balance, coronal imbalance and valgus knee deformity. The patient reported pain of 8-10 in VAS (Visual Analogue Scale) and had an ODI (Oswestry Disability Index) of 60%. The first step of the surgery was L2-S1 fusion with decompression and spine deformity correction. The second step involved anti-valgus osteotomy of the right tibial bone. CONCLUSIONS: The assessment of global spinal balance together with lower extremity alignment should be strongly recommended. PMID- 28638493 TI - Tibialis Anterior Muscle Hernia: A Case of Chronic, Dull Pain and Swelling in Leg Diagnosed by Dynamic Ultrasonography. AB - BACKGROUND: Symptomatic muscle hernias are not uncommon in the lower extremities and are a rare cause of chronic leg pain. They are most commonly seen in the tibialis anterior muscle, occurring through fascial defects, usually after trauma. There are about 200 cases of muscle hernias described in the literature. The diagnosis is challenging as most of the patients present with non-specific chronic leg pain. Dynamic muscle ultrasonography at rest and at stress is often used for the diagnosis. CASE REPORT: We describe a case of tibialis anterior muscle hernia presenting with persistent dull pain and swelling along the anterior aspect of the leg on straining the leg muscles. Dynamic ultrasonography was performed, which showed a defect in the fascial sheath of the muscle through which the tibialis anterior muscle herniated and produced a focal bulge along the anterior aspect of the leg. Based upon physical examination and dynamic ultrasonographic findings, a diagnosis of tibialis anterior muscle hernia was made. CONCLUSIONS: Tibialis anterior muscle hernia is a rare diagnosis and should be included in the differential diagnosis in a patient with chronic leg pain and swelling. Dynamic ultrasound is crucial in confirming the diagnosis and should be done on straining the muscles of the affected limb. PMID- 28638490 TI - Obesity and microbiota: an example of an intricate relationship. AB - It is widely accepted that metabolic disorders, such as obesity, are closely linked to lifestyle and diet. Recently, the central role played by the intestinal microbiota in human metabolism and in progression of metabolic disorders has become evident. In this context, animal studies and human trials have demonstrated that alterations of the intestinal microbiota towards enhanced energy harvest is a characteristic of the obese phenotype. Many publications, involving both animal studies and clinical trials, have reported on the successful exploitation of probiotics and prebiotics to treat obesity. However, the molecular mechanisms underlying these observed anti-obesity effects of probiotics and prebiotic therapies are still obscure. The aim of this mini-review is to discuss the intricate relationship of various factors, including diet, gut microbiota, and host genetics, that are believed to impact on the development of obesity, and to understand how modulation of the gut microbiota with dietary intervention may alleviate obesity-associated symptoms. PMID- 28638494 TI - An Unusual Case of Live Caesarean Scar Ectopic Pregnancy: A Common Entity in an Uncommon Location. AB - BACKGROUND: Scar pregnancy is an extremely rare type of ectopic pregnancy, where there is implantation of the gestational sac onto the anterior wall of the uterus at the site of previous LSCS scar in a multipara female. Due to a poor vascular supply to the lower uterine segment, caesarean scars may heal improperly predisposing it to be a site of improper implantation of the gestational sac. RESULTS: The characteristic features are empty uterus and cervix, gestational sac in the anterior part of lower uterine segment with a history of painless vaginal bleeding. It carries a high risk of morbidity related to uterine rupture and extensive haemorrhage. CONCLUSIONS: In case of a previous LSCS delivery in a female with a viable gestational sac in the lower uterine segment and elevated B Hcg levels, the possibility of scar ectopic pregnancy should be considered. KCl or methotrexate can be injected directly into the foetal pole under transvaginal ultrasound guidance in order to stop the cardiac activity in the foetus. The knowledge of the specific ultrasound features of uncommon locations of ectopic pregnancies such as an ectopic scar is crucial for a correct diagnosis and early management in order to prevent complications. PMID- 28638495 TI - An Atypical Presentation of Congenital Pulmonary Airway Malformation (CPAM): A Rare Case with Antenatal Ultrasound Findings and Review of Literature. AB - BACKGROUND: Congenital pulmonary airway malformation (CPAM) is a relatively rare congenital anomaly with a wide spectrum of ultrasound features depending on the specific variety of CPAM. Antenatal ultrasound is a valuable, safe, nonionizing, cost-effective, widely available and easily reproducible imaging tool and is indispensable in the diagnosis of CPAM. In this paper, we aimed to report an atypical imaging presentation of CPAM type II in the second trimester, extensively involving all lobes of the left lung. CASE REPORT: A 25-year-old G1P0A0 woman with a gestational age of around 22 weeks was referred for an anomaly scan. The antenatal ultrasound scan showed a single, live, intrauterine foetus corresponding to a gestational age of around 22 weeks and 4 days. There were multiple, anechoic structures noted within the pulmonary tissue in the left hemithorax, each measuring around 3 to 4 mm in diameter. The lesion was extending from the left lower lobe up to the apical (apicoposterior) segment of the left upper lobe. The ultrasound diagnosis of congenital pulmonary airway malformation type II was made. After explaining the condition and the poor prognosis to the patient, an informed consent was obtained after she opted for medical termination of pregnancy. CONCLUSIONS: Congenital pulmonary airway malformation (CPAM) is an uncommon foetal anomaly with a very wide range of ultrasound appearances depending on the specific type of CPAM. CPAM also has a wide spectrum of differential diagnoses and a variable prognosis. Antenatal ultrasound should always be the primary mode of diagnosis in CPAM. PMID- 28638496 TI - Effect of Early Follow-Up After Hospital Discharge on Outcomes in Patients With Heart Failure or Chronic Obstructive Pulmonary Disease: A Systematic Review. AB - BACKGROUND: Transitions in care can increase patients' vulnerability to adverse events. In particular, patients admitted for heart failure or chronic obstructive pulmonary disorder (COPD) have high rates of readmission and return emergency department visits. Heart failure patients have the highest 30-day readmission rates in Canada, and COPD patients comprise the highest volume of readmissions. Combined, these two conditions account for the largest number of emergency department returns. Prompt follow-up of discharged patients has been linked with reduced rates of readmission, emergency department use, and death. This systematic review evaluated the clinical effectiveness of early follow-up, within either 7 days or 30 days after hospital discharge, compared with usual care or a different time to follow-up, in reducing readmissions, emergency department visits, and mortality in patients with heart failure or COPD. METHODS: We performed a literature search to identify studies published in English up to May 25, 2016, on early follow-up after discharge from hospital in patients with heart failure or COPD. A single reviewer screened the titles and abstracts and obtained full-text articles for studies meeting the eligibility criteria. The risk of bias in the studies was evaluated according to ROBINS-I and EPOC criteria, and the quality of the body of evidence for each outcome was examined according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. RESULTS: From a total of 3,228 unique citations, we identified 10 eligible studies: one randomized controlled trial, two nonrandomized controlled trials, and seven observational studies. Four studies were specifically on 7-day follow-up and 30-day health outcomes. The other six studies were on 30-day follow-up and more variable time to health outcomes. Follow-up was conducted by general and specialist physicians, nurses, and pharmacists in clinics, by telephone, and by home visit. Risk of bias was moderate for most of the studies. Having follow-up within either 7 days or 30 days after hospitalization for heart failure or COPD was associated with lower all-cause readmissions, emergency department visits, and mortality, even after accounting for confounders such as age, sex, socioeconomic status, and disease severity (GRADE: Very low to low). However, the evidence was inconsistent. We did not find a difference in effectiveness between studies using a 7-day versus a 30 day follow-up. CONCLUSIONS: Based on low- and very low-quality evidence, follow up within 7 days and within 30 days of discharge from hospitalization for heart failure or COPD-compared with usual care or no follow-up-were both associated with a reduced risk of all-cause readmission, emergency department visits, and mortality. Overall, there is a lack of large, methodologically robust studies specifically focusing on the effectiveness of 7-day follow-up after discharge in improving patient outcomes. PMID- 28638497 TI - FIBER DIRECTION ESTIMATION, SMOOTHING AND TRACKING IN DIFFUSION MRI. AB - Diffusion magnetic resonance imaging is an imaging technology designed to probe anatomical architectures of biological samples in an in vivo and noninvasive manner through measuring water diffusion. The contribution of this paper is threefold. First, it proposes a new method to identify and estimate multiple diffusion directions within a voxel through a new and identifiable parametrization of the widely used multi-tensor model. Unlike many existing methods, this method focuses on the estimation of diffusion directions rather than the diffusion tensors. Second, this paper proposes a novel direction smoothing method which greatly improves direction estimation in regions with crossing fibers. This smoothing method is shown to have excellent theoretical and empirical properties. Last, this paper develops a fiber tracking algorithm that can handle multiple directions within a voxel. The overall methodology is illustrated with simulated data and a data set collected for the study of Alzheimer's disease by the Alzheimer's Disease Neuroimaging Initiative (ADNI). PMID- 28638499 TI - Avascular Necrosis of the Capitate. PMID- 28638498 TI - Estimation of High-Dimensional Graphical Models Using Regularized Score Matching. AB - Graphical models are widely used to model stochastic dependences among large collections of variables. We introduce a new method of estimating undirected conditional independence graphs based on the score matching loss, introduced by Hyvarinen (2005), and subsequently extended in Hyvarinen (2007). The regularized score matching method we propose applies to settings with continuous observations and allows for computationally efficient treatment of possibly non-Gaussian exponential family models. In the well-explored Gaussian setting, regularized score matching avoids issues of asymmetry that arise when applying the technique of neighborhood selection, and compared to existing methods that directly yield symmetric estimates, the score matching approach has the advantage that the considered loss is quadratic and gives piecewise linear solution paths under l1 regularization. Under suitable irrepresentability conditions, we show that l1 regularized score matching is consistent for graph estimation in sparse high dimensional settings. Through numerical experiments and an application to RNAseq data, we confirm that regularized score matching achieves state-of-the-art performance in the Gaussian case and provides a valuable tool for computationally efficient estimation in non-Gaussian graphical models. PMID- 28638500 TI - A Pilot Study Exploring the Quadratic Nature of the Relationship of Strength to Performance among Shot Putters. AB - The purpose of this pilot study was to examine the quadratic nature of the relationship between the strength and throwing distance in the shot put. A survey was sent to throws coaches with Master Coach or USA Track and Field Level III distinction to examine fifty-three collegiate and elite throwers (24 male, 29 female). The coaches reported the thrower's personal best shot put distance and preseason weight room 1RM for bench press, power clean, and squat exercises. Relationship between distance and 1RM was determined via general linear model polynomial contrast analysis and regression. Data analysis showed significant linear and quadratic trends for distance and 1RM power clean for both male (linear: p<=0.001, quadratic: p<=0.003) and female (linear: p<=0.001, quadratic: p=0.001) elite and collegiate shot put athletes. Analysis also provided a quadratic equation to compare personal best distance and 1RM power clean. The power clean was found to be more closely related to shot put distance as compared with squat and also with bench press, which is the least related. Based on the results of this investigation, in addition to strength exercises such as the squat and bench press, power exercises such as the power clean should also be incorporated into strength and conditioning programs of shot put athletes for optimal performance. PMID- 28638501 TI - The Growing Health Literacy Gap and Graduate Medical Education. PMID- 28638502 TI - Immigration, Graduate Medical Education, and Ethical Dilemmas. PMID- 28638503 TI - Rural Medical Education Programs: A Proposed Nomenclature. PMID- 28638504 TI - Solving One of Graduate Medical Education's Problems: A Loss of Thoroughness. PMID- 28638505 TI - Remediation Strategies for Systems-Based Practice and Practice-Based Learning and Improvement Milestones. PMID- 28638506 TI - Efficacy of Interventions to Reduce Resident Physician Burnout: A Systematic Review. AB - BACKGROUND: Studies report high burnout prevalence among resident physicians, with little consensus on methods to effectively reduce it. OBJECTIVE: This systematic literature review explores the efficacy of interventions in reducing resident burnout. METHODS: PubMed, Embase, and Web of Science were searched using these key words: burnout and resident, intern, or residency. We excluded review articles, editorials, letters, and non-English-language articles. We abstracted data on study characteristics, population, interventions, and outcomes. When appropriate, data were pooled using random effects meta-analysis to account for between-study heterogeneity. Study quality was assessed using Newcastle-Ottawa Scale (cohort studies) and Jadad scale (randomized control trials [RCTs]). RESULTS: Of 1294 retrieved articles, 19 (6 RCTs, 13 cohort studies) enrolling 2030 residents and examining 12 interventions met criteria, with 9 studying the 2003 and 2011 Accreditation Council for Graduate Medical Education (ACGME) duty hour restrictions. Work hour reductions were associated with score decrease (mean difference, -2.73; 95% confidence interval (CI) -4.12 to -1.34; P < .001) and lower odds ratio (OR) for residents reporting emotional exhaustion (42%; OR = 0.58; 95% CI 0.43-0.77; P < .001); a small, significant decrease in depersonalization score (-1.73; 95% CI -3.00 to -0.46; P = .008); and no effect on mean personal accomplishment score (0.93; 95% CI -0.19-2.06; P = .10) or for residents with high levels of personal accomplishment (OR = 1.01; 95% CI 0.67 1.54; P = .95). Among interventions, self-care workshops showed decreases in depersonalization scores, and a meditation intervention reduced emotional exhaustion. CONCLUSIONS: The ACGME work hour limits were associated with improvement in emotional exhaustion and burnout. PMID- 28638508 TI - Are Milestones Really Measuring Development? PMID- 28638507 TI - The Impact of Using Mean Versus Mode When Assessing Resident Competency. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education Milestone Project was implemented in 2014 to standardize assessments and progression of residents. While it is recommended that milestones not be used as tools for direct assessments of resident competency, many programs have used or adapted milestone tools for this purpose. OBJECTIVE: We sought to explore use of the most frequent milestone level at which a resident was evaluated (ie, the mode), and compared this to the standard practice of using the arithmetic mean for summarizing performance. METHODS: We reviewed all Family Medicine Milestone evaluations from 1 program for the first 2 academic years of milestone implementation. Mean and mode scores were calculated across 24 unique residents, 841 evaluation forms, and 5897 measurements. The proportion of overestimation errors (where the mean is at least 0.5 larger than the mode) and underestimation errors (where the mean is at least 0.5 less than the mode) were then compared across resident training year and subcompetency. RESULTS: For the 24 residents, an estimation error occurred in 175 of 792 of the comparisons (22%). Of these errors, 118 (67%) were overestimation errors. First-year residents accounted for 55% (96 of 175) of all estimation errors. All subcompetencies had some estimation errors, with 6 having greater than 5%. CONCLUSIONS: If the trend for using the milestones as stand-alone assessment tools is to continue, aggregating data by using frequency distributions and mode would be a more stable and appropriate approach given their nominal or, at best, ordinal nature. PMID- 28638509 TI - Resident Experiences With Implementation of the I-PASS Handoff Bundle. AB - BACKGROUND: The I-PASS Handoff Study found that introduction of a handoff bundle (handoff and teamwork training for residents, a mnemonic, a handoff tool, a faculty development program, and a sustainability campaign) at 9 pediatrics residency programs was associated with improved communication and patient safety. OBJECTIVE: This parallel qualitative study aimed to understand resident experiences with I-PASS and to inform future implementation and sustainability strategies. METHODS: Resident experiences with I-PASS were explored in focus groups (N = 50 residents) at 8 hospitals throughout 2012-2013. A content analysis of transcripts was conducted following the principles of grounded theory. RESULTS: Residents generally accepted I-PASS as an ideal format for handoffs, and valued learning a structured approach. Across all sites, residents reported full adherence to I-PASS when observed, but selective adherence in usual practice. Residents adhered more closely when patients were complex, teams were unfamiliar, and during evening handoff. Residents reported using elements of the I-PASS mnemonic variably, with Illness Severity and Action Items most consistently used, but Synthesis by Receiver least used, except when observed. Most residents were receptive to the electronic handoff tool, but perceptions about usability varied across sites. Experiences with observation and feedback were mixed. Concern about efficiency commonly influenced attitudes about I-PASS. CONCLUSIONS: Residents generally supported I-PASS implementation, but adherence was influenced by patient type, context, and individual and team factors. Our findings could inform future implementation, particularly around the areas of resident engagement in change, sensitivity to resident level, perceived efficiency, and faculty observation. PMID- 28638510 TI - Viewing Resident Experience With I-PASS Implementation Through Different Implementation, Diffusion, and Sustainability Frameworks. PMID- 28638511 TI - Passing a Technical Skills Examination in the First Year of Surgical Residency Can Predict Future Performance. AB - BACKGROUND: The ability of an assessment to predict performance would be of major benefit to residency programs, allowing for early identification of residents at risk. OBJECTIVE: We sought to establish whether passing the Objective Structured Assessment of Technical Skills (OSATS) examination in postgraduate year 1 (PGY-1) predicts future performance. METHODS: Between 2002 and 2012, 133 PGY-1 surgery residents at the University of Toronto (Toronto, Ontario, Canada) completed an 8 station, simulated OSATS examination as a component of training. With recently set passing scores, residents were assigned a pass/fail status using 3 standards setting methods (contrasting groups, borderline group, and borderline regression). Future in-training performance was compared between residents who had passed and those who failed the OSATS, using in-training evaluation reports from resident files. A Mann-Whitney U test compared performance among groups at PGY-2 and PGY-4 levels. RESULTS: Residents who passed the OSATS examination outperformed those who failed, when compared during PGY-2 across all 3 standard setting methodologies (P < .05). During PGY-4, only the contrasting groups method showed a significant difference (P < .05). CONCLUSIONS: We found that PGY-1 surgical resident pass/fail status on a technical skills examination was associated with future performance on in-training evaluation reports in later years. This provides validity evidence for the current PGY-1 pass/fail score, and suggests that this technical skills examination may be used to predict performance and to identify residents who require remediation. PMID- 28638512 TI - An Early Assessment of the ACGME CLER Program: A National Survey of Designated Institutional Officials. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) Clinical Learning Environment Review (CLER) is an innovative element of the ACGME's new accreditation system. To date, little information has been collected regarding the value of CLER. OBJECTIVE: The purpose of this study is to collect information on designated institutional officials' (DIOs') perspectives about the initial CLER visits conducted at their institutions. METHODS: The authors created and distributed a survey to DIOs about their initial CLER visits. Demographic data were compared across survey responses with Spearman's rank correlation and the Kruskal-Wallis test. RESULTS: The authors received responses from 63% of DIOs (186 of 297) at institutions that participated in the initial CLER visits, with 88% (164 of 186) having served as DIO during the visit. Seventy-two percent (114 of 158) reported institutional changes to address CLER focus areas prior to the visit, yet only 32% (51 of 157) reported that additional resources were allocated to these areas after the site visit. Sixty-five percent (102 of 156) reported institutional executive leadership was positive about participating in CLER; 85% (134 of 158) reported that ACGME conducted the visits efficiently; 84% (133 of 158) reported that the site visit accurately assessed the institution's performance in the CLER focus areas; and 60% (93 of 156) reported CLER provided high-value information. CONCLUSION: Survey results from DIOs suggest that CLER is an effective mechanism to improve the learning environment. Common concerns included limited advance notice for the site visit and disruptions of clinical practice. PMID- 28638513 TI - The Continuous Quality Improvement of CLER. PMID- 28638515 TI - Use of Fellow as Clinical Teacher (FACT) Curriculum for Teaching During Consultation: Effect on Subspecialty Fellow Teaching Skills. AB - BACKGROUND: Subspecialty consultation in inpatient care is increasing. Teaching by subspecialty fellows in a consultation setting may be an important source of work-based learning for students and residents. However, teaching and evaluation of learners in this context may be challenging due to personal and systems-based barriers. OBJECTIVE: We developed and evaluated a framework designed to overcome barriers to teaching and to improve fellow teaching skills during inpatient consultation. METHODS: The PARTNER (Partner with resident, Assess the learner, Reinforce positives, Teaching objectives, New knowledge, Execute recommendations, Review) framework was delivered to rheumatology and pulmonary and critical care medicine fellows at 3 academic medical centers as part of a 2-session Fellow as Clinical Teacher (FACT) curriculum. Fellows' teaching skills were evaluated using an objective structured teaching exercise (OSTE) pre- and postcurriculum, and at the end of the academic year. Self-assessment surveys were used to evaluate fellows' self-perception of teaching skills. RESULTS: Twelve of 16 eligible fellows (75%) participated in the program and completed 73 OSTE cases. Teaching skills measured by OSTEs and self-assessment surveys improved after administration of the FACT curriculum. There was no significant skill decay at the end-of-year evaluation. The curriculum was rated highly, and 73% (8 of 11) of fellows stated they would teach more frequently as a result of the intervention. CONCLUSIONS: The FACT curriculum was practical and feasible, and significantly improved fellows' teaching skills teaching during inpatient consultation. PMID- 28638514 TI - Internal Medicine Residents' Ambulatory Management of Core Geriatric Conditions. AB - BACKGROUND: Adults aged 65 years and older account for more than 33% of annual visits to internal medicine (IM) generalists and specialists. Geriatrics experiences are not standardized for IM residents. Data are lacking on IM residents' continuity experiences with older adults and competencies relevant to their care. OBJECTIVE: To explore patient demographics and the prevalence of common geriatric conditions in IM residents' continuity clinics. METHODS: We collected data on age and sex for all IM residents' active clinic patients during 2011-2012. Academic site continuity panels for 351 IM residents were drawn from 4 academic medical center sites. Common geriatric conditions, defined by Assessing Care of Vulnerable Elders measures and the American Geriatrics Society IM geriatrics competencies, were identified through International Classification of Disease, ninth edition, coded electronic problem lists for residents' patients aged 65 years and older and cross-checked by audit of 20% of patients' charts across 1 year. RESULTS: Patient panels for 351 IM residents (of a possible 411, 85%) were reviewed. Older adults made up 21% of patients in IM residents' panels (range, 14%-28%); patients >= 75 (8%) or 85 (2%) years old were relatively rare. Concordance between electronic problem lists and chart audit was poor for most core geriatric conditions. On chart audit, active management of core geriatric conditions was variable: for example, memory loss (10%-25%), falls/gait abnormality (26%-42%), and osteoporosis (11%-35%). CONCLUSIONS: The IM residents' exposure to core geriatric conditions and management of older adults was variable across 4 academic medical center sites and often lower than anticipated in community practice. PMID- 28638516 TI - A Professionalism Curricular Model to Promote Transformative Learning Among Residents. AB - BACKGROUND: Using the frameworks of transformational learning and situated learning theory, we developed a technology-enhanced professionalism curricular model to build a learning community aimed at promoting residents' self-reflection and self-awareness. The RAPR model had 4 components: (1) Recognize: elicit awareness; (2) Appreciate: question assumptions and take multiple perspectives; (3) Practice: try new/changed perspectives; and (4) Reflect: articulate implications of transformed views on future actions. OBJECTIVE: The authors explored the acceptability and practicality of the RAPR model in teaching professionalism in a residency setting, including how residents and faculty perceive the model, how well residents carry out the curricular activities, and whether these activities support transformational learning. METHODS: A convenience sample of 52 postgraduate years 1 through 3 internal medicine residents participated in the 10-hour curriculum over 4 weeks. A constructivist approach guided the thematic analysis of residents' written reflections, which were a required curricular task. RESULTS: A total of 94% (49 of 52) of residents participated in 2 implementation periods (January and March 2015). Findings suggested that RAPR has the potential to foster professionalism transformation in 3 domains: (1) attitudinal, with participants reporting they viewed professionalism in a more positive light and felt more empathetic toward patients; (2) behavioral, with residents indicating their ability to listen to patients increased; and (3) cognitive, with residents indicating the discussions improved their ability to reflect, and this helped them create meaning from experiences. CONCLUSIONS: Our findings suggest that RAPR offers an acceptable and practical strategy to teach professionalism to residents. PMID- 28638517 TI - Writing Well: The Long-Term Effect on Empathy, Observation, and Physician Writing Through a Residency Writers' Workshop. AB - BACKGROUND: Writing narratives during medical training can provide a way to derive meaning from challenging experiences, enhance reflection, and combat burnout. The Yale Internal Medicine Residency Writers' Workshop, an annual 2-day intensive workshop followed by faculty-guided writing revision and publication, has been training resident physicians in the craft of writing since 2003. OBJECTIVE: The study aimed to assess the long-term effects of a craft-focused writers' workshop for residents on empathy, observation skills, and future writing. METHODS: A survey of closed and open-ended questions was sent to former workshop participants (2003-2013), who rated and described the workshop's influence on their observation skills, empathy, improvement in writing, and continued informal and formal writing. A total of 89 of 130 participants (68%) completed the online survey. We identified key themes in written responses and collected quantitative ratings on a 5-point Likert scale of self-reported influence on these factors. Simple statistics and narrative analysis were used to derive results. RESULTS: Most participants agreed or strongly agreed that the workshop influenced their ability for careful observation (72 of 85, 85%); ability to be empathic with patients or colleagues (51 of 77, 66%); quality of writing (69 of 77, 90%); and continued formal or informal writing (52 of 77 [68%] and 41 of 77 [53%], respectively). Participants felt the workshop improved their attention to detail, provided a deeper understanding of others' experiences, and improved their writing. CONCLUSIONS: Participants in a residency writers' workshop experienced lasting effects on observation, empathy, and writing skills. PMID- 28638518 TI - Automated Reporting of Trainee Metrics Using Electronic Clinical Systems. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education has called for increased emphasis on reporting objective performance measures to trainees and programs. However, reporting of objective measures, including clinical volume, is largely omitted from training programs. OBJECTIVE: To use automated electronic medical systems at a tertiary pediatric care hospital to create a dashboard that reports objective trainee and program metrics, including clinical volume and diagnoses in a pediatrics residency. METHODS: We queried an enterprise data warehouse that aggregates data daily from multiple hospital systems to identify patient encounters during which senior pediatrics residents at Boston Children's Hospital had entered documentation over a 9-month period. From this query, we created a filterable dashboard to display clinical volume and diagnosis data by individual resident and in aggregate. RESULTS: A total of 44 of 45 senior residents (98%) in the program were included in analysis. We identified 12 198 patient encounters during which a senior pediatrics resident had entered documentation; these included a median of 332 inpatient encounters per resident, 122 emergency department encounters, and 84 outpatient encounters. The most common diagnoses stratified by clinical site were: inpatient - dehydration (median = 61); emergency department - long-term/current drug therapy (median = 16); and outpatient - encounter for immunization (median = 48). CONCLUSIONS: We used electronic health record systems to generate performance dashboards for trainees in a pediatrics residency across different sites of care with reported volume by diagnosis. Our dashboards provide feedback to program leadership regarding individual and aggregate trainee experience and allow individual trainees to compare their clinical exposure to peers. PMID- 28638520 TI - The Consultant Chat: A Novel Didactic Method for Specialist Presentations to Emergency Medicine Residents. PMID- 28638519 TI - The View From Over Here: A Framework for Multi-Source Feedback. PMID- 28638521 TI - A Mathematical Formula for Institutional GME Program Support. PMID- 28638522 TI - Institutional Review Board Checklist for Trainee Quality Improvement Project Approvals. PMID- 28638523 TI - Enhancing Resident Scholarly Productivity by Facilitating Web-Based Access to Publicly Accessible Datasets. PMID- 28638524 TI - Changing Spaces and Learning Environments to Improve Inpatient Interprofessional Education for Internal Medicine Residents. PMID- 28638525 TI - Teaching Nutrition in Graduate Medical Education: An Interactive Workshop. PMID- 28638526 TI - Revamping Journal Club for the Millennial Learner. PMID- 28638527 TI - Taking SGIM's Teaching Educators Across the Continuum of Health Care on the Road A Local, Interprofessional Faculty Development Innovation. PMID- 28638528 TI - Meeting the Primary Care Needs of Transgender Patients Through Simulation. PMID- 28638529 TI - Creating Provider-Level Quality Reports for Residents to Improve the Clinical Learning Environment. PMID- 28638530 TI - A Simulation-Based Resident as Surgical Teacher (RAST) Program. PMID- 28638531 TI - An Interprofessional Multimodal Patient Experience-Focused Curriculum. PMID- 28638532 TI - Using a Poverty Simulation in Graduate Medical Education as a Mechanism to Introduce Social Determinants of Health and Cultural Competency. PMID- 28638533 TI - Podcasting in Medical Education: How Long Should an Educational Podcast Be? PMID- 28638534 TI - Social Support Network Outreach: A No-Cost Intervention to Improve Resident Well Being. PMID- 28638535 TI - Flipping Out: Does the Flipped Classroom Learning Model Work for GME? PMID- 28638536 TI - Science Fiction in Medical Education: The Case of Learning Styles. PMID- 28638538 TI - Resident First Author Publications. PMID- 28638537 TI - Education Versus Service in Residency: A False Dichotomy? PMID- 28638539 TI - The Electronic Health Record: A Blessing for Patient Safety but a Curse for Medical Education? PMID- 28638541 TI - Entrustment Versus Competency-Continued Confusion. PMID- 28638540 TI - The Importance of Grit in Medical Training. PMID- 28638542 TI - A Call for Collegiality in Residency. PMID- 28638544 TI - Presentation Pet Peeves. PMID- 28638543 TI - Life as a Resident in the Inaugural Class of a New Residency Program. PMID- 28638545 TI - Program Performance in the Next Accreditation System (NAS): Results of the 2015 2016 Annual Data Review. PMID- 28638546 TI - Comparing the effect of diode laser against acyclovir cream for the treatment of herpes labialis. AB - BACKGROUND: Recently alternative therapies such as the use of diode laser therapy have been introduced for recurrent herpes labial infection. The aim of this study was to evaluate the effectiveness of diode laser for treatment of recurrent herpes labialis. MATERIAL AND METHODS: This was single-blind randomized clinical trial to evaluate the efficacy of diode laser for the treatment of recurrent herpes labial. In total, 60 patients whit recurrent herpes simplex labialis were selected and randomly divided in to three groups. 20 patients received treatment whit diode laser (at a wavelength of 870 nm, energy density 4.5 j/cm2), 20 patients were treated with acyclovir cream 5%, 20 patients received treatment with laser-off (placebo). The end point was lesions crusting. Data analyzed by Tukey HSD Test and One-way ANOVA (at a significance level of 0.05) in SPSS-20 software. RESULTS: The mean length of recovery time (day) in the laser, off laser, and acyclovir groups was 2.20+/-0.41, 4.30+/-1.03, and 3.4+/-1.142, respectively. There is a significant difference between three groups in this regard (P<0.0001). The mean duration of pain (day) was 1.35+/-0.74, 2.65+/-1.27, and 2.30+/-0.92 for laser, off laser, and acyclovir groups, respectively (P<0.0001). CONCLUSIONS: Treatment with diode laser reduced the length of recovery time and pain severity faster than treatment with acyclovir cream. Key words:Recurrent herpes labial, Acyclovir, Low level laser therapy. PMID- 28638547 TI - Push-out bond strength of different endodontic obturation material at three different sites - In-vitro study. AB - BACKGROUND: The key to success of any root canal therapy is adequate obturation of the prepared root canal space. Root canal sealers are not dimensionally stable and might dissolve partially over a period of time. The objective of this in vitro study is to evaluate the push-out bond strength to intraradicular dentin of two endodontic obturation materials. MATERIAL AND METHODS: Forty extracted single rooted permanent teeth were used. Canals orifice was explored, teeth were instrumented. The samples were divided into two groups each containing twenty specimens obturated with different obturation material (Group1 Epiphany/Resilon and Group 2 Gutta Percha/AH Plus).The obturation systems used in this study was Element Obturation unit (Sybron Endo). Each tooth root was horizontally sectioned in approximately 2-mm thick slices from the coronal 1/3rd, middle 1/3rd and apical 1/3rd. The push-out bond strength of each specimen was calculated using Universal Testing Machine. The statistical analysis was done using two way analysis of variance (ANOVA) and tukey's test. RESULTS: There was significant difference between push out bond strength of Resilon/Epiphany and AH Plus/Gutta Percha. Gutta percha group was superior with push out bond strength of 2.22 (+/- 0.16) Mpa in comparison to Resilon/Epiphany group with 1.61 (+/-0.14) Mpa (p<0.001). CONCLUSIONS: The interfacial bond strength achieved with Resilon/Epiphany self-etch (SE) to intraradicular dentine was not superior to that of AH Plus/Gutta Percha. Key words:AH Plus, Apical leakage, Epiphany, Gutta percha, Push-out test Resilon. PMID- 28638548 TI - Dentin bonding agent with improved bond strength to dentin through incorporation of sepiolite nanoparticles. AB - BACKGROUND: The study aims to investigate the effect of incorporation of sepiolite nanoparticles on the microtensile bond strength of an experimental dentin bonding to the human dentin. MATERIAL AND METHODS: The sepiolite nanoparticles were incorporated into an experimental methacrylate-based dentin bonding system in concentrations of 0.0, 0.2, 1.0, 2.0, and 5.0 weight percents. The specimens were then ultrasonicated to finely disperse the nanoparticles in the adhesive matrix. The coronal enamel of 30 intact human premolars was cut to expose dentin. Having etched, rinsed, and blot dried the experimental bonding agents were applied to dentin surface. Adper Single Bond was used as control group according to the manufactor's instruction. Then all the teeth were built up by composite and sectioned in stick form for microtensile test. The fracture surface was observed using SEM. The data were analyzed by ANOVA and Tukey's post Hoc test. RESULTS: The results indicated that the incorporation of the nanofiller, improved the bond strength to dentin with the highest values obtained at 1 w% sepiolite nanoparticle content. CONCLUSIONS: Sepiolite nanoparticles can be considered as novel fillers to improve the mechanical properties of dentin bonding agents. Key words:Dentin bonding agent, nanoparticles, bond strength, sepiolite, microtensile test. PMID- 28638549 TI - Antibacterial activity of different root canal sealers against Enterococcus faecalis. AB - BACKGROUND: The aim of the present study was to compare in vitro the antimicrobial activity of different root canal sealers against Enterococcus faecalis, prior and subsequent to setting. MATERIAL AND METHODS: Agar diffusion test (ADT) was used for evaluating the antibacterial activity of non-set sealer while the direct contact test (DCT) was used for after setting. RESULTS: ADT: Except for TotalFill BC Sealer all the others sealers tested showed antibacterial activity. BioRootTMRCS, MTA Fillapex and Sealapex Root Canal Sealer showed the lowest antibacterial activity, a significant increase in antibacterial effect for both Pulp Canal SealerTM and AH plus sealers were found. Significantly higher were the mean diameters of the bacterial inhibition zone by both EasySeal or N2 sealers. DCT: AH plus and Sealapex Root Canal Sealer doesn't show any bactericidal effect after 6 min of contact. After 15 and 60 min of contact a significant increment for AH plus and for Sealapex Root Canal Sealer of the bactericidal effect was found. Significantly much higher was the antibacterial effect of Sealapex Root Canal Sealer compare to that observed for AH plus. BioRootTMRCS, MTA Fillapex, Pulp Canal SealerTM and N2 showed at least means of the number of colonies formed in milliliter after 6 min of contact. Except for N2, a significant increase in bactericidal effect after 15 and 60 min for the other compared sealers (BioRootTMRCS, MTA Fillapex and Pulp Canal SealerTM). CONCLUSIONS: For every contact times considered, both TotalFill BC Sealer and EasySeal were bactericidal against E. faecalis and killed all bacteria. Key words:Agar diffusion test, antibacterial activity, direct contact test, Enterococcus faecalis, root canal sealer. PMID- 28638550 TI - Shear bond strength of orthodontic metal brackets to aged composite using three primers. AB - BACKGROUND: This study aimed to assess the effect of surface preparation with sandblasting and diamond bur along with the use of three primers on shear bond strength (SBS) of metal brackets to aged composite. MATERIAL AND METHODS: In this in vitro, experimental study, 60 Filtek Z250 composite discs were fabricated (10*2mm), immersed in distilled water for 24 hours and subjected to 5000 thermal cycles. They were randomly divided into two groups (n=30) of sandblasting with aluminum oxide particles for 10 seconds and surface roughening with bur. Each group was randomly divided into three subgroups (n=10) for use of Transbond XT, Assure Plus and Composite Primer. Metal brackets were bonded and the samples were stored in distilled water for 24 hours followed by 2000 thermal cycles. The SBS of brackets was measured and the adhesive remnant index (ARI) score was calculated. The data were analyzed by one-way ANOVA, t-test and Chi square test. RESULTS: The difference in the mean SBS was not significant among the six subgroups. CONCLUSIONS: All combinations of primers and surface preparation methods provided adequately high SBS between brackets and aged composite surfaces. Considering the ARI scores, surface roughening by bur is superior to sandblasting. Key words:Shear strength, composite resins, orthodontic brackets, aged composite, surface preparation. PMID- 28638551 TI - Effectiveness of flossing loops in the control of the gingival health. AB - BACKGROUND: One of the key factor in the good condition of periodontal tissues is their daily hygiene. Oral hygiene techniques such brushing and a good interdental hygiene by correct flossing are very important. The aim of this study is to compare the use of dental floss in a loop vs traditional floss in the control of Loe-Silness Gingival Index (IG), Turesky's Plaque Index (IPT), Gingival Bleeding Index (IS) and the values of interleukin 6 (IL-6) and interleukin 8 (IL-8). MATERIAL AND METHODS: A comparative study of 40 patients in which each patient was his own control, using during 45 days each one of the devices (new loop floss and conventional floss) of interdental hygiene analysed. Data for Loe-Silness Gingival Index (IG), Turesky's Plaque Index (IPT), Gingival Bleeding Index (IS) and the values of interleukin 6 (IL-6) and interleukin 8 (IL-8)were collected and measured in every visit for every type of interdental hygiene device. RESULTS: Our data indicates that the rate of Turesky's Plaque Index presented statistically significant differences between groups (loop: 1.66 +/- 0.8; traditional: 1.12 +/- 0.8; p<0.0001). The rest of the indices studied showed no statistically significant differences. CONCLUSIONS: The creation of new dental floss designs try to make their use easier and more sensitive, and plaque removal more effective. The loop design can facilitate interdental hygiene, reaching similar effectiveness than traditional floss, improving some indicators, such as Turesky's Plaque Index. Key words:Dental floss, bacterial plaque, loop floss, plaque index, periodontal diseases. PMID- 28638552 TI - Efficacy of three methods for inserting calcium hydroxide-based paste in root canals. AB - BACKGROUND: To compare the quality of calcium hydroxide paste fillings performed by three different techniques. MATERIAL AND METHODS: Sixty extracted maxillary central incisors, with previous root canal treatment, were decoronated and the gutta-percha was completely removed from the root canals. Subsequently, the canals were filled with a calcium hydroxide-based paste composed of calcium hydroxide, bismuth carbonate, and glycerin. The study samples were divided into the following three groups on the basis of three insertion techniques (n = 20, each): conventional technique using a hand instrument (MAN), rotary Lentulo spiral (LEN) technique, and a combined technique combining conventional hand files with sonic activation through the EndoActivator device (EA). The quality of fillings was evaluated radiographically by two examiners on the basis of the amount of voids and the apical limit. RESULTS: The canals filled with LEN or MAN had less void volume compared to the EA technique (P >0.01), with no significant differences between them. Considering the apical limits, the three tested techniques showed comparable results (P >0.05). CONCLUSIONS: A combined approach utilizing hand files with sonic activation showed no enhancements over the LEN or MAN techniques on the quality of intracanal placement of calcium hydroxide paste. Key words:Calcium hydroxide placement, EndoActivator, Lentulo spirals, intracanal medication, root canal treatment. PMID- 28638553 TI - A review of 640 Oral squamous cell carcinoma cases in Nigeria. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most prevalent malignant neoplasm in the oral cavity and accounts for 70% to 90% of all oral malignant neoplasms. The aim of this study was to examine the demographic distribution of OSCC in five Tertiary Health centres in Nigeria. MATERIAL AND METHODS: All cases diagnosed as OSCC during the period from 1970 -2014 were retrieved from the records of five teaching hospitals in Nigeria. Hematoxylin and eosin stained histological slides of all cases that had a diagnosis of OSCC were reviewed for confirmation and inclusion. Data from all the centers was collated at the University College Hospital, Ibadan by 2 researchers. The data was entered into and analyzed with the SPSS for Windows (version 20.0; SPSS Inc. Chicago, IL). Simple descriptive and comparative analyses were done, with the test of statistical significance set at p <= 0.05. RESULTS: A total of 640 cases of OSCC were seen out of 1560 oral malignant neoplasms representing 41% of all the oral malignancies seen. The mean age of occurence of OSCC was 55.5 (+/-17.0) years and a peak age incidence in the sixth and seventh decades of life. OSCC occurred more in males (60.9%) than females (39.1%) with a male: female ratio of 1.6:1. The well differentiated OSCC with 309 (48.3%) cases, was the most common grade, while the moderately differentiated and poorly differentiated OSCC accounted for 232 (36.2%) and 92 (14.4%) cases respectively. CONCLUSIONS: This study showed that OSCC is more common in males, most commonly seen in the 60-69 age group and the commonest site of occurrence was the mandibular mucosa. The well differentiated OSCC was the most common histology sub-type. Key words:Oral squamous cell carcinoma, tongue, palate, mandible. PMID- 28638555 TI - A comparative evaluation: Oral leukoplakia surgical management using diode laser, CO2 laser, and cryosurgery. AB - BACKGROUND: The comparatively evaluate the three surgical treatment modalities namely cryosurgery, diode and CO2 laser surgery in terms of healing outcomes on the day of surgery, first and second week post operatively and recurrence at the end of 18 months was assessed. MATERIAL AND METHODS: Thirty selected patients were divided randomly into three groups. Each group comprising of ten patients were subjected to one of the three modalities of treatment namely cryosurgery, diode laser or CO2 laser surgery for ablation of OL. Obtained data was analyzed using mainly using Chi-square and Anova tests. RESULTS: Study showed statistical significant differences (p > 0.05) for evaluation parameters like pain, edema and scar. The parameters like infection, recurrence, bleeding showed no statistical significance. Pain was significantly higher in CO2 laser surgery group as compared with diode laser group. There was no recurrence observed at the end of the 6 months follow up period in all the three study groups. CONCLUSIONS: Observations from the study highlights that all three surgical modalities used in this study were effective for treatment of OL, and the overall summation of the results of the study showed that laser therapy (CO2 and Diode) seems to offer better clinically significant results than cryotherapy. Key words:Oral premalignant lesion, leukoplakia, cryosurgery, CO2 laser surgery, diode laser surgery. PMID- 28638554 TI - Effect of professional dental prophylaxis on the surface gloss and roughness of CAD/CAM restorative materials. AB - BACKGROUND: This study aimed to evaluate the effect of dental prophylaxis on the surface gloss and roughness of different indirect restorative materials for computer-aided design/computer-aided manufacturing (CAD/CAM): two types of CAD/CAM composite resin blocks (Shofu Block HC and Estelite Block) and two types of CAD/CAM ceramic blocks (IPS Empress CAD and Celtra DUO). MATERIAL AND METHODS: After polishing the CAD/CAM blocks and applying prophylaxis pastes, professional dental prophylaxis was performed using four different experimental protocols (n = 5 each): mechanical cleaning with Merssage Regular for 10 s four times (Group 1); four cycles of mechanical cleaning with Merssage Regular for 10 s and Merssage Fine for 10 s (Group 2); four cycles of mechanical cleaning with Merssage Regular for 10 s and Merssage Fine for 30 s (Group 3); and mechanical cleaning with Merssage Fine for 10 s four times (Group 4). A glossmeter was used to measure surface gloss before and after mechanical cleaning, and a contact stylus profilometer was used to measure surface roughness (Ra). RESULTS: Polishing with prophylactic paste led to a significant reduction in surface gloss and increase in surface roughness among resin composite blocks, whereas the polishing-related change in surface gloss or roughness was smaller in Celtra DUO, a zirconia reinforced lithium silicate block. CONCLUSIONS: Changes in surface gloss and roughness due to polishing with a prophylactic paste containing large particles were not improved by subsequent polishing with a prophylactic paste containing fine particles. Key words:CAD/CAM, professional dental prophylaxis, prophylactic paste, surface gloss, surface roughness. PMID- 28638556 TI - Effects of Different Powder to liquid Ratios on the Push out Bond Strength of CEM Cement on Simulated Perforations in the Furcal Area. AB - BACKGROUND: Proper bond strength to dentin is one of the properties of biomaterials used for therapeutic purposes such as repair of furcal perforations. The aim of the present study to evaluate the effects of different powder to liquid ratios of Calcium-enriched mixture (CEM) on the push-out bond strengths in simulated perforations in the furcal area and compare it with Mineral trioxide aggregate (MTA). MATERIAL AND METHODS: Furcal perforations, measuring 1.3 mm in diameter and 2 mm in height, were prepared in 120 mandibular first molars. Then the samples were randomly assigned to two groups (n=60). MTA and CEM cement were used for the repair of perforations in groups 1 and 2, respectively. Each group was divided into 3 subgroups based on the powder to liquid rations as follows: subgroup 1 (W/P) , 1:2; subgroup 2, 1:3; and subgroup 3, 1:4. After mixing and placing the materials in the perforation area, the samples were placed in closed containers at 37 degrees C and 100% relative humidity for one week. A universal testing machine was used to determine the bond strength values. After recording the standard deviations, data were analyzed with two-way ANOVA. Statistical significance was set at P<0.05. RESULTS: In the MTA and CEM groups the highest push-out bond strength values were recorded in the third (W/P: 1:4) and first (W/P: 1:2) subgroups, respectively. There were significant differences in both groups between the ratios mentioned above and the other ratios (P<0.05). CONCLUSIONS: Under the limitations of the present study, an increase in the powder-to-liquid ratio in CEM cement resulted in a decrease in bond strength, contrary to MTA. Key words:CEM, Perforation, Powder-to-liquid ratio, push-out bond strength, MTA. PMID- 28638557 TI - Continuous Apical Negative-Pressure Ultrasonic Irrigation (CANUI): A new concept for activating irrigants. AB - BACKGROUND: Irrigation of the root canal system is an essential step in the endodontic treatment. The aim of this article is to introduce continuous apical negative-pressure ultrasonic irrigation (CANUI), a new irrigation concept, and compare the characteristics of this new technique with current devices for activating the irrigant. MATERIAL AND METHODS: CANUI is designed for cleaning and disinfecting the root canal system. The device consists of a tube inside another tube that allows the continuous ultrasonic exchange of fresh irrigant, as the irrigant is simultaneously aspirated apically. The coronal and apical tubes are 0.75 and 0.3 mm in diameter, respectively. It is composed of a nickel-titanium microcannula suitable for the working length of curved canals. RESULTS: The CANUI technique has the advantages of apical negative pressure (to avoid apical extrusion of the irrigant) and continuous ultrasonic irrigation (continuous refreshment of the irrigant and forced introduction into the canal ramifications). CONCLUSIONS: The CANUI technique could improve the irrigation technique of dentists to reach more disinfection in endodontic treatments. Key words:Apical negative pressure, continuous ultrasonic irrigation, irrigation in curved canals, irrigation systems. PMID- 28638558 TI - Impacted lower third molars and distal caries in the mandibular second molar. Is prophylactic removal of lower third molars justified? AB - BACKGROUND: The objective of this study was to evaluate the association between the presence of mandibular third molars and the occurrence of carious lesions in the distal aspect of the mandibular second molar. MATERIAL AND METHODS: A retrospective cohort study comprising 327 lower third molars extracted in the Oral Surgery and Implantology Master's Degree program of the School of Dentistry of the University of Barcelona (Barcelona, Spain) was carried out. A descriptive and bivariate analysis was made. The diagnosis of caries in the second molar and the position of the mandibular third molar were evaluated through panoramic radiographies. RESULTS: The sample included 203 patients, 94 males (46.3%) and 109 females (53.7%), with a mean age of 26,8 years and 327 lower third molars. The prevalence of second molar distal caries was 25.4% (95% CI= 20.6% to 30.2%). This pathology was significantly more frequent when the third molar was in a horizontal position (27.7%), when the contact point was at (45,8%) or below (47.0%) the cementoenamel junction (CEJ), and when the distal CEJ of the mandibular second molar and the mesial CEJ of the third molar was 7 to 12 mm apart. CONCLUSIONS: Horizontal lower third molars with contact points at or below the CEJ are more likely to produce distal caries in the mandibular second molars. Due to the high prevalence of this pathology (20.6% to 30.2%), a prophylactic removal of lower third molars with the above-mentioned features might be advisable. Key words:Second molar, caries, third molar, prophylactic removal. PMID- 28638559 TI - Comparative Evaluation of Anti Microbial effects of Triple Antibiotic Paste and Amox and its derivatives against E. Faecalis: An in vitro study. AB - BACKGROUND: Enterococcus faecalis is a microorganism commonly detected in asymptomatic, persistent endodontic infections. Triple antibiotic paste has stood the test of time as a proven antibiotic combination against E. Faecalis. However, problems with this include staining of teeth and standardization of the preparation. Thus, the search for better alternatives and better preparation techniques is still on. AIM: To observe the potential of combinations [(Amoxicillin+ Metronidazole, Amoxicillin Clavulanic Acid + Metronidazole; Amoxicillin and Cloxacillin + Metronidazole)] over Triple Antibiotic Paste. MATERIAL AND METHODS: Fifty single rooted teeth free from dental caries were selected for the study. Teeth were cut at equal distance from root apex (13mm from apex) with sterile diamond disk and straight hand piece for standardization of root length. The opening of root canal was enlarged with engine driven pro taper files. To remove the organic and inorganic debris, canal was cleaned with 17% EDTA followed by 2.5% NaOCl for 5min. Distilled water irrigation was done for 5 min to remove any traces of used chemical and then sterilized in autoclave at 1200c for 15 min. at 15 lbs pressure. Bacteria cultured on blood agar plate and at the same time fresh antibiotic combinations were made and placed in the root canals, then incubated in the incubator, under sterile conditions and observed at 24hrs, 48hr and 72hrs. RESULTS: The largest inhibition zones were observed for the Triple Antibiotic Paste, followed by Amoxicillin and Clavulanic acid + Metronidazole group however, the clearest zones were achieved with Amoxicillin and Clavlunic acid + Metronidazole group and the smallest for Amoxicillin and Metronidazole group. CONCLUSIONS: The results suggest that though Triple antibiotic showed the maximum inhibition, Amoxicillin and Clavulanic acid combination along with Metronidazole gave the most reliable results. Further studies using the different combinations and different concentrations along with different methods of increasing the shelf life of such medications can be undertaken. Key words:Enterococcus faecalis, Triple Antibiotic Paste, Amoxcillin, Clavulanic acid. PMID- 28638560 TI - Effects of Different Percentages of Microhydroxyapatite on Microhardness of Resin modified Glass-ionomer and Zirconomer. AB - BACKGROUND: Hydroxyapatite (HA) is the main mineral component of the tooth structure, which exhibits considerable biological behavior and its incorporation might improve microhardness of dental materials. Microhardness of restorative materials, like glass-ionomer, is critical for the clinical longevity of restorations. The aim of this study was to evaluate the microhardness of two glass-ionomers types by incorporating different percentages of microhydroxyapatite. MATERIAL AND METHODS: In this study, 80 disc-shaped experimental specimens (6 mm in diameter, 2 mm in height) were prepared in 8 groups, including resin-modified glass-ionomer (RMGI, GC, Gold Label, Japan), zirconia-reinforced glass-ionomer (Zirconomer, Shofu, Kyoto, Japan), and their mixture with 0, 5, 15 and 25 wt% of microhydroxyapatite (Sigma-Aldrich, Germany). All the specimens were stored in deionized water at 37oC for 24 hours. Then Vickers microhardness test was carried out on the both sides of specimens and data were analyzed using two-way ANOVA and paired t-test (P<0.05). RESULTS: Microhardness of Zirconomer and RMGI increased significantly due to adding 5 and 15 wt% of micrhydrox-yapatite (P<0.001). The highest Vickers hardness number (VHN) was recorded in the RMGI group with 5 wt% of microhydroxyapatite. In addition, in all the study groups RMGI exhibited higher microhardness values than Zirconomer (P<0.001). However, microhardness values decreased significantly after adding 25 wt% of microhydroxyapatite to Zirconomer (P<0.001). Similarly, VHN decreased in RMGI groups containing 25 wt% of HA compared to control groups (without HA) (P<0.001). CONCLUSIONS: Incorporation of 5 and 15 wt% of microhydroxyapatite to RMGI and Zirconomer improved microhardness, while adding 25 wt% of HA decreased hardness with both experimental materials compared to the control groups (without HA). Key words:Microhardness, Resin-modified glass ionomer, Zirconia-reinforced glass ionomer, Microhydroxyapatite. PMID- 28638562 TI - A rare case of oral multisystem Langerhans cell histiocytosis. AB - Langerhans cell histiocytosis (LCH) is a rare disorder characterized by high proliferation of Langerhans dendritic cells. LCH is a solitary or multifocal disease that primarily involves bone tissue and often affects children and young men. A 29 years-old Caucasian man was referred to the Oral Surgery Unit of George Eastman Hospital - Umberto I teaching hospital, with third degree mobility of teeth belonging to second, third and fourth quadrant. Panoramic radiograph showed multiple radiolucent areas with well demarcated borders on the right and left site of the mandible and on the left site of the maxilla. Extractions of compromised teeth and biopsy of the osteolytic tissue were performed. The final diagnosis of multisystem Langerhans cell histiocytosis of the soft and hard tissues of the oral cavity was made. The patient was sent to the Hematology department of Umberto I Teaching Hospital of "Sapienza" - University of Rome for the proper treatment. The present case of rare multisystem LCH involving oral hard and soft tissues shows the strong importance of better investigate, with appropriate additional exams, initial shifty symptoms that could lead to a misdiagnosis. Key words:Differential diagnosis, microscopic diagnosis, Langerhans cell histiocytosis. PMID- 28638561 TI - Importance and methodologies of endodontic microleakage studies: A systematic review. AB - INTRODUCTION: It is very important to obtain a tight seal in obturated root canal, making it necessary to conduct clinical or laboratory studies on the sealability of endodontic materials. Different methodologies have been historically used to assess microleakage of different endodontic materials. The aim of the present study was to comprehensively review different material testing methods used in microleakage studies, their interpretation and importance in endodontic literature. MATERIAL AND METHODS: A systematic search was conducted in Medline, Cochrane, and Web of Science databases. In addition, the reference lists of review articles on the topic were searched. No language restriction was applied. Two independent reviewers screened the article. RESULTS: Microleakage is considered the single most important risk factor responsible for apical periodontitis. Dye penetration, dye diffusion, bacterial and endototoxin infiltration, fluid filtration, glucose, caffeine and protein infiltration, radioisotope penetration, animal studies, and electrochemical or 3D evaluation are different methodologies used to assess dental leakage. 91 out of 177 articles in the primary search were included in the study. These methods are very divergent in their viewpoints; that is why their results cannot be easily compared. It is necessary to standardize microleakage detection methods in order to more correctly evaluate the phenomena that are found between the root canal wall and the root canal filling materials. CONCLUSIONS: All the methods are useful if studies are performed strictly with large sample sizes and proper control groups and if the technique can be standardized. Furthermore, more evaluations of the reliability of the methods are strongly recommended. Key words:Dental leakage, review, root canal, material testing methods, data interpretation. PMID- 28638563 TI - Extraskeletal myxoid chondrosarcoma of the masticator space in a pediatric patient. AB - Extraskeletal myxoid chondrosarcoma (EMC) is a malignant soft-tissue neoplasm rarely described in the head and neck region of children and adolescents. We describe a case of EMC affecting the masticator space and a literature review. A 13-year-old boy who presented a large painless, diffuse mass causing progressive midfacial asymmetry of 6 months duration. Histopathological evaluation revealed a multinodular lesion, containing scattered round vacuolated tumor cells dispersed in an abundant myxoid stroma, separated by fibrous septae. Immunohistochemical analysis revealed positivity for vimentin, neuron-specific enolase, and chromogranin. The Ki-67 labelling index was 42%. The patient was treated surgically with tumor resection followed by adjuvant local radiotherapy. The patient died 1 year after initial diagnosis due to locoregional tumor dissemination. EMC should be considered in the differential diagnosis of myxoid neoplasms in the head and neck region. Key words:Extraskeletal myxoid chondrosarcoma, masticator space, parapharyngeal space, immunohistochemistry, children. PMID- 28638564 TI - Glandular odontogenic cyst associated with ameloblastoma: Case report and review of the literature. AB - Glandular odontogenic cyst (GOC) associated with ameloblastoma is an exceedingly rare histologic presentation with no known clinical significance or treatment applications. Four cases have been reported, three in the mandible and one in the maxilla. The age range is 14-65 and with male predilection. All four presented with swellings and two with pain. We add one more case to the literature of a 58 year old male presenting with an expansile multilocular radiolucency between teeth #19-23. The ameloblastomatous changes in this case are consistent with those of a unicystic ameloblastoma-mural subtype. Although the histologic changes are those of a unicystic ameloblastoma, the clinical and radiographic findings are not. This case therefore presents a clinical challenge with regards to treatment planning for recurrence and prognosis. We conclude that treatment for GOC therefore be based on individual clinical presentation. Key words:Glandular odontogenic cyst, GOC, ameloblastoma, unicystic ameloblastoma, mural unicystic ameloblastoma. PMID- 28638566 TI - Necessity is the mother of invention: an innovative hospitalist-resident initiative for improving quality and reducing readmissions from skilled nursing facilities. AB - Background: Hospital readmissions have been a major challenge to the US health system. Medicare data shows that approximately 25% of Medicare skilled nursing facility (SNF) residents are readmitted back to the hospital within 30 days. Some of the major reasons for high readmission rates include fragmented information exchange during transitions of care and limited access to physicians round-the clock in SNFs. These represent safety, quality, and health outcome concerns. Aim: The goal of the project was to reduce hospital readmission rates from SNFs by improving transition of care and increasing physician availability in SNFs (five to seven days a week physical presence with 24/7 accessibility by phone). Methods: We proposed a model whereby a hospitalist-led team, including the resident on the geriatrics rotation, followed patients discharged from the hospital to one SNF. Readmission rates pre- and post-implementation were compared. Study results: The period between January 2014 and June 2014 served as the baseline and showed readmission rate of 32.32% from the SNF back to the hospital. After we implemented the new hospitalist SNF model in June 2014, readmission rates decreased to 23.96% between July 2014 and December 2014. From January 2015 to June 2015, the overall readmission rate from the SNF reduced further to 16.06%. Statistical analysis revealed a post-intervention odds ratio of 0.403 (p < 0.001). Conclusion: The government is piloting several care models that incentivize value- based behavior. Our study strongly suggests that the hospitalist-resident continuity model of following patients to the SNFs can significantly decrease 30-days hospital readmission rates. PMID- 28638567 TI - Nephrology key information for internists. AB - Hospitalists and primary care physicians encounter renal disease daily. Although most cases of acute kidney injury (AKI) are secondary to dehydration and resolve by giving fluids, many cases of AKI are due to not uncommon but unfamiliar causes needing nephrology evaluation. Common indications to consult a nephrologist on an emergency basis include hyperkalemia or volume overload in end stage renal disease patients (ESRD). Other causes of immediate consultation are cresenteric glomerulonephritis / rapidly progressive glomerulonephritis in which renal prognosis of the patient depends on timely intervention. The following evidence based key information could improve patient care and outcomes. Abbreviations: AKI: Acute kidney injury ESRD: End stage renal disease patients. PMID- 28638568 TI - Dizziness in a community hospital: central neurological causes, clinical predictors, and diagnostic yield and cost of neuroimaging studies. AB - Objectives: Neuroimaging is contributing to the rising costs of dizziness evaluation. This study examined the rate of central neurological causes of dizziness, relevant clinical predictors, and the costs and diagnostic yields of neuroimaging in dizziness assessment. Methods: We retrospectively reviewed the records of 521 adult patients who visited the hospital during a 12-month period with dizziness as the chief complaint. Clinical findings were analyzed using Fisher's exact test to determine how they correlated with central neurological causes of dizziness identified by neuroimaging. Costs and diagnostic yields of neuroimaging were calculated. Results: Of the 521 patients, 1.5% had dizziness produced by central neurological causes. Gait abnormalities, limb ataxia, diabetes mellitus, and the existence of multiple neurological findings predicted central causes. Cases were associated with gait abnormalities, limb ataxia, diabetes mellitus, and the existence of multiple neurological findings . Brain computed tomography (CT) and magnetic resonance imaging (MRI) were performed in 42% and 9.5% of the examined cases, respectively, with diagnostic yields of 3.6% and 12%, respectively. Nine cases of dizziness were diagnosed from 269 brain scans, costing $607 914. Conclusion: Clinical evaluation can predict the presence of central neurological causes of dizziness, whereas neuroimaging is a costly and low-yield approach. Guidelines are needed for physicians, regarding the appropriateness of ordering neuroimaging studies. Abbreviations: OR: odds ratio; CI: confidence interval; ED: emergency department; CT: computed tomography; MRI: magnetic resonance imaging; HINTS: Head impulse, Nystagmus, Test of skew. PMID- 28638569 TI - Quality improvement for HIV screening in a primary care resident clinic. AB - : Primary care physicians are responsible for the initiation of the preventive health screening tests and examinations for their patients. Resident physicians may be uncomfortable obtaining a sexual history from their patient. A performance improvement project was carried out in the resident clinic to see if we could improve HIV screening of our patients. With a cohesive effort between the faculty preceptors and residents, we were able to improve screening rates for HIV and improve some aspects, but not all, of sexual history taking for our population of patients. We identified two patients who screened positive for a rate of 1.4%. ABBREVIATIONS: CDC. PMID- 28638570 TI - Barriers in accessing care services for physically disabled in a hospital setting in Riyadh, Saudi Arabia, cross-sectional study. AB - Objective: The aim of this study was to identify the significant difficulties in access to health care services experienced by patients with physical disabilities. Method: A cross-sectional study at King Abdul Aziz Medical City, Riyadh, Saudi Arabia on 235 persons with physical disability, from 1 January to 30 June 2014. Results: A total of 88% of the people with disability reported having the need for someone to accompany them. Over 52% were unsatisfied with parking, 49.8% with the waiting area, 51.3% with wheel-chair services, and nearly 45% were unsatisfied with toilet facilities for the physically disabled. Those who were wheel-chair bound had statistically significant lower mean score for satisfaction with services and facilities related to parking area, reception, and appointment, elevator, and physiotherapy.The majority were satisfied with the attitude of the clinical staff. Conclusion: The majority of patients with physical disability require assistance and cannot move around independently in the healthcare facilities. Nearly half of these patients face several challenges in accessing health care services and are unsatisfied with the services received. Patients with physical disability who are wheel-chair bound have a lesser degree of satisfaction than those who are not wheel-chair bound. PMID- 28638572 TI - Hypersensitivity pneumonitis: an overlooked cause of cough and dyspnea. AB - Hypersensitivity pneumonitis (HP) is an immune-mediated pulmonary disorder involving inflammation of the lung interstitium, terminal bronchioles, and alveoli caused by the immune response to the inhalation of an offending environmental airborne agent. It can manifest as exertional dyspnea, fatigue, weight loss, and progressive respiratory failure if left untreated. Because of its protean features, it can be misdiagnosed as other common obstructive lung conditions such as asthma. If triggers are not avoided, it can progress to irreversible pulmonary fibrosis. In this article, we present the case of a 51 year-old male who presented to our hospital with recurrent bouts of dyspnea and cough, initially diagnosed as an asthma exacerbation. He received a final diagnosis of HP after investigation of his workplace revealed airborne spores and surface molds from multiple fungal species, serology revealed eosinophilia, and computed tomography showed bronchiectasis. Avoidance of occupational exposure resulted in significant improvement of his respiratory symptoms after two months. Abbreviations: HP: Hypersensitivity pneumonitis. PMID- 28638573 TI - Acute intermittent porphyria: a test of clinical acumen. AB - Acute intermittent porphyria (AIP) is a rare autosomal dominant hepatic porphyria due to deficiency of hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase leading to accumulation of porphyrin precursors. However, gene defect alone is usually not sufficient to cause an acute attack, and many extrinsic factors play a role. Diagnostic tests are defined, but clinical suspicion is often delayed as symptoms mimic other common conditions. We report a case of a 18-year-old male with severe, persistent, and generalized abdominal pain along with marked hyponatremia, with subsequent development of altered mentation needing intensive care. He improved after infusion of intravenous dextrose. AIP can mimic many common surgical and medical conditions such as appendicitis, cholecystitis, pancreatitis, etc., and may lead to extensive diagnostics or surgical intervention if missed. Diagnosis of AIP requires high clinical suspicion. It should be considered in a patient with recurrent abdominal symptoms, intractable hyponatremia, along with neurological manifestations. Early diagnosis and treatment can prevent recurrent episodes and can potentially be lifesaving. Abbreviations: AIP: Acute intermittent porphyria; ALA: Aminolevulinic acid; PBG: Porphobilinogen. PMID- 28638571 TI - Prevalence of QT prolongation and associated LVEF changes in diabetic patients over a four-year retrospective time period. AB - Aim: To evaluate the prevalence and longitudinal changes of prolonged QTc in DM patients admitted to our community hospital, and to determine, if any, its correlation with changes of left ventricular ejection fraction (LVEF). Methods: A retrospective chart review of patients with Type 1 (T1DM) and Type 2 (T2DM) with at least two admissions during a four-year period was performed to identify QTc interval, and LVEF, as measured on transthoracic echocardiogram. Changes in QTc and LVEF between patient hospital admissions were compared. Results: A prolonged QTc interval was found in 66.7% (n = 24) of type 1 and 51.3% (n = 154) type 2 diabetic patients. The QTc interval is progressively increased in both type 1 and type 2 diabetes during follow-up, although it did not reach statistical significance. A total of 62% patients (23 out 37 patients) had a reduction of LVEF during follow-up. Conclusion and Discussion: High prevalence of QTc prolongation was confirmed in hospitalized patients with in both T1DM and T2DM. Significant reduction of LVEF correlated with QTc prolongation over a mean of 17.3 months in T2DM patients, and may have implications for interventions. Abbreviations CHF: Congestive heart failure LVEF: Left ventricular ejection fraction. PMID- 28638574 TI - Thyrotoxic periodic paralysis: a case study and review of the literature. AB - Acute hypokalemic paralysis is a rare cause of acute weakness. Morbidity and mortality associated with unrecognized disease can occur and include respiratory failure and possibly death. Common causes of hypokalemic paralysis include thyrotoxic periodic paralysis (TPP) which is a disorder most frequently seen in Asian males. TPP is characterized by sudden onset of hypokalemia and paralysis that primarily affects the lower extremities. Treatment of TPP includes replacing potassium rapidly, using nonselective beta-blockade and correcting the underlying hyperthyroidism as soon as possible. TPP is curable once euthyroid state is achieved. It is vital for physicians to be able to differentiate TPP from familial hypokalemic periodic paralysis, a more common cause of periodic paralysis in Caucasians and western countries. We describe a 19-year-old Caucasian man who presented with acute onset lower extremity paralysis secondary to acute hypokalemia and was found to have new onset Graves' disease. Abbreviations: TPP: Thyrotoxic periodic paralysis. PMID- 28638575 TI - Danon disease for the cardiologist: case report and review of the literature. AB - Danon disease is a rare, X-linked dominant genetic disorder that is caused by defects in the lysosome-associated membrane protein 2 (LAMP2) gene. It manifests predominantly in young males with a classic triad of cardiomyopathy, skeletal myopathy, and intellectual disability. Death from cardiac disease is the ultimate cause of demise in many patients if left untreated. Given the rarity of the condition, the natural history is poorly understood. Here, we present a case report on a 14-year-old Hispanic boy with Danon disease, highlighting major clinical events and diagnostic study findings over a six-year period from age of symptom onset to age of death. He had significant hypertrophic cardiomyopathy (ventricular septal thickness 65 mm) and experienced various arrhythmias during his clinical course including Wolf-Parkinson-White syndrome, non-sustained ventricular tachycardia, and pre-excited atrial fibrillation with a fasciculoventricular anomalous accessory pathway. He had sudden cardiac death from ventricular fibrillation at age 14 and his heart had a weight of 1425 grams at autopsy. We also provide a review of the cardiac Danon disease literature related to diagnostic and management approaches to aid cardiologists in evaluating and treating cardiac manifestations in Danon disease patients. PMID- 28638576 TI - A classic case of arrhythmogenic right ventricular cardiomyopathy (ARVC) and literature review. AB - Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a relatively under recognized hereditary cardiomyopathy. It is characterized pathologically by fibro fatty infiltration of right ventricular (RV) myocardium and clinically by consequences of RV electrical instability. Timely intervention with device therapy and pharmacotherapy may help reduce the risk of arrhythmic events or sudden cardiac death. Here, we describe a classic case of a young adult with ARVC and a brief literature review. The patient presented with exertional palpitations and ARVC was suspected after his routine electrocardiogram (EKG) revealed symmetric T wave inversions and possible epsilon waves in right precordial leads. Subsequent work up showed fatty infiltration of RV myocardium on cardiac magnetic resonance imaging and inducible ventricular tachycardia from the right ventricle during electrophysiologic study. Those findings confirmed the diagnosis of ARVC and warranted treatment with implantable cardioverter defibrillator. It is always exciting to encounter rare pathological entities with classic clinical findings, especially when they present as a diagnostic challenge.We were able to provide correct diagnosis and management, thereby preventing the potentially lethal consequences. Therefore, it is important to recognize the possible EKG findings of ARVC and to know when to pursue further investigations and to implement therapies. PMID- 28638577 TI - A rare case of apical hypertrophic cardiomyopathy (AHCM). AB - Apical hypertrophic cardiomyopathy is a rare form of hypertrophic cardiomyopathy that involves thickening of the distal portion of the left ventricular wall. Most commonly seen in the Japan, with a prevalence rate of about 15% of all HCM patient, its incidence in the USA is approximately 3% of HCM cases. We report a case of a 46-year-old woman with history of hypertension who presented to emergency department with worsening dyspnea and orthopnea with features of left ventricular hypertrophy (LVH) and diffuse large T-wave inversions in the lateral leads on a 12-lead ECG. Further work up revealed severe concentric LVH, with near obliteration of the LV cavity. Ventriculogram showed severe symmetric hypertrophy of the mid to lower septum, extending to the apex of left ventricle with significant pressure gradient of at least 160 mmHg across the apex to mid septal cavity, with no significant gradient across the left ventricular outflow tract. These findings were consistent with apical hypertrophic cardiomyopathy. She was treated with verapamil and metoprolol and has remained asymptomatic over last 2.5 years of follow-up. Although the clinical presentation of AHCM can be variable and nonspecific; however, hallmark findings on ECG and echo can be extremely important in its diagnosis. Abbreviations: AHCM: Apical hypertrophic cardiomyopathy; ECG: Electrocardiogram; LVH: Left ventricular hypertrophy; LVOT: Left ventricular outflow tract. PMID- 28638578 TI - A rare case of aerococcus urinae infective endocarditis. AB - Introduction:Aerococcus urinae is a rare cause of infective endocarditis. Aerococcus is a gram positive cocci that is easily misidentified as Staphylococci or Streptococci. The true incidence rate of this pathogen is likely underestimated. Recent advances in laboratory diagnostic methods with matrix associated laser desorption ionization time-of-flight mass spectrometry (MALDI TOF-MS) have lead to increased recognition of this pathogen in the clinical microbiology lab, and awareness as a cause of infective endocarditis in the infectious disease community. Case reports: Aerococcus usually affects males with underlying urinary tract conditions. Herein, we report a case of prosthetic aortic valve endocarditis caused by Aerococcus urinae. Discussion: Our patient was considered high risk for cardiac surgery and was treated successfully with intravenous antibiotics alone for six weeks. Conclusion: Infective endocarditis should be considered in all cases of Aerococcus bacteremia and appropriate diagnostic evaluations pursued. Abbreviations: AV: Aortic valve; IE: Infective endocarditis. PMID- 28638579 TI - Non-ST elevation myocardial infarction secondary to carbon monoxide intoxication. AB - Carbon monoxide poisoning has been documented in literature to cause severe neurological and tissue toxicity within the body. However, cardiotoxicity is often overlooked, but not uncommon. Previous research studies and case reports have revealed a significant relationship between carbon monoxide intoxication and myocardial ischemic events. We report a case of a 48-year-old male, who was exposed to severe smoke inhalation due to a house fire and subsequently developed a non-ST elevation myocardial infarction. Ischemic changes were evident on electrocardiogram, which demonstrated T-wave inversion in lead III and ST-segment depression in leads V4-V6. Elevated cardiac enzymes were also present. After standard treatment for an acute cardiac event, the patient fully recovered. This case demonstrates that myocardial ischemic changes due to carbon monoxide poisoning may be reversible if recognized in early stages and treated appropriately, thus reminding physicians that a proper cardiovascular examination and diagnostic testing should be performed on all patients with carbon monoxide poisoning. Abbreviations: NSTEMI: Non-ST elevation myocardial infarction. PMID- 28638580 TI - There may be more than meets the eye with Clostridium perfringens bacteremia. AB - We present the case of an 89-year-old man with a 1 month history of fevers and fatigue. Blood cultures were positive for Clostridium perfringens. The patient had worsening abdominal distension in which an abdominal computed tomography scan uncovered a colonic mass, and further work-up revealed poorly differentiated adenocarcinoma. The patient was treated with antibiotics, but unfortunately, given his age and the new malignancy, he was discharged to hospice care. The association between clostridial bacteremia and colon cancer has been well described in the literature and is further discussed in this article. This case highlights the importance of recognizing possible occult malignancy in the right clinical setting in patients found to have clostridial bacteremia. PMID- 28638581 TI - Images in clinical medicine: Tophi. AB - Tophi (plural of tophus, Latin for "stone") are stone-like deposits of monosodium urate in the soft tissues, synovial tissues, or in bones near the joints. They are pathognomonic for gout, the most common inflammatory arthritis in the United States, with an estimated lifetime prevalence of 4%. It is usually the end result of loss of the balance between uric acid production and excretion. It can be found anywhere in the body especially in areas of friction or trauma. It is usually painless and rarely to present as the initial manifestation of gout. It is diagnosed mainly clinically. Imaging is mainly used to assess the complication like bony erosions. The American College of Rheumatology (ACR) guidelines currently indicate that urate-lowering therapy should be initiated in patients with the presence of tophi visible on examination or imaging (ACR Evidence A). First-line therapy for urate lowering remains the xanthine oxidase inhibitor allopurinol. The ACR currently recommends colchicine, 0.6 mg (or 0.5 mg) once or twice daily, or low dose NSAIDs should be continued to reduce gout flare incidence for six months after resolution of the tophus. Daily prednisone <=10 mg has been endorsed as an acceptable second-line prophylactic agent. Abbreviations: ACR: American College of Rheumatology; NSAID: non-steroidal anti-inflammatory drug. PMID- 28638583 TI - comparison of the Serum Levels of Trace Elements in Areas with High or Low Rate of Esophageal Cancer. AB - BACKGROUND There is a critical role for trace elements in cancer prevention. Since northeast Iran is known as a high risk area for esophageal cancer, this study was designed to compare the serum levels of some trace elements in high and low rate areas of Golestan province. METHODS We used 240 fasting serum samples obtained in 2011 from eastern and western parts of Golestan province during the non-communicable diseases' screening program. To carry out laboratory examinations, the samples were firstly deproteinated and then the concentrations of the intended elements were measured by an atomic absorption spectrometer. A total of 227 samples were used in the present study and the remaining 13 samples were excluded due to inappropriate conditions. RESULTS The mean serum level of zinc in the high-risk region was significantly lower than that in the low-risk region. But no significant difference was detected in serum levels of copper, magnesium, and manganese in the low-risk and high-risk regions. CONCLUSION As this study was an ecological study with no comparison between patients with cancer and healthy population, its results cannot be used for the general population. Therefore, complementary studies including case-control studies are suggested for further evaluation of the relationship between these elements and the incidence of esophageal cancer. PMID- 28638582 TI - An Overview of Inflammatory Bowel Disease: General Consideration and Genetic Screening Approach in Diagnosis of Early Onset Subsets. AB - Inflammatory bowel disease (IBD) is the consequence of an aberrant hemostasis of the immune cells at the gut mucosal border. Based on clinical manifestation, laboratory tests, radiological studies, endoscopic and histological features, this disease is divided into three main types including Crohn's disease (CD), Ulcerative colitis (UC), and IBDunclassified (IBD-U). IBD is frequently presented in adults, but about 20% of IBD cases are diagnosed during childhood called pediatric IBD (PIBD). Some patients in the latter group emerge the first symptoms during infancy or under 5 years of age named infantile and very early onset IBD (VEO-IBD), respectively. These subtypes make a small fraction of PIBD, but they have exclusive phenotypic and genetic characteristics such that they are accompanied by severe disease course and resistance to conventional therapy. In this context, understanding the underlying molecular pathology opens a promising field for individualized and effective treatment. Here, we describe current hypotheses on IBD pathophysiology then explain the new idea about genetic screening technology as a good potential approach to identify the causal variants early in the disease manifestation, which is especially important for the fast and accurate treatment of VEO-IBD. PMID- 28638585 TI - Clinicopathological Study of Seronegative Celiac Disease in Adults in Pakistan: A Pilot Study. AB - BACKGROUND Celiac disease (CD) is usually missed, if the serology is negative. We aimed to evaluate the clinicopathological characteristics of seronegative CD (SNCD) and its response to gluten-free diet (GFD) in adult patients. METHODS This observational study was carried out at the Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan from 2009 to 2015. All consecutive adult patients (>=17 years) with features of marked villous atrophy (Marsh class>=III) on duodenal biopsy, negative tissue transglutaminase IgA and IgG antibodies (anti-tTg IgA and IgG) and human leukocyte antigen (HLA) DQ2 or DQ8 serotypes were studied. Clinical characteristics, laboratory parameters, and response to GFD were analyzed by SPSS software version 20. Median and interquartile range (IQR) were used for summarizing quantitative data. Frequency (percentages) was used for qualitative data. RESULTS A total of 12 patients with median age of 31.5 years (IQR: 19.75-46.75 years), of whom five (41.6%) were men were studied. The presenting complaints were: weight loss in 11 (91.6%) and abdominal pain in 9 (75%) patients. Anemia was observed in 10 (83.3%) patients with median hemoglobin of 9.5 g/dL (IQR: 6.3-13.25 g/dL). Median alanine transaminase (ALT) was 21 U/L (IQR: 13-27 U/L) and median albumin was 3 g/dL (IQR: 2.4-3.6 g/dL). Anti-tTg IgA and IgG were negative in all patients. HLA DQ serotyping showed homozygous DQ2 and DQ8 in four and one patients, respectively; while heterozygous DQ2 and DQ8 in five and two patients, respectively. All patients were advised to receive GFD. Nine (75%) patients showed complete clinical response. Two patients were non-compliant and one with non-alcoholic fatty liver disease (NAFLD)-related cirrhosis had partial clinical response. Out of the nine responders, two patients showed response within 6 months while the remaining showed improvement over a year period. CONCLUSION The diagnosis of SNCD is rewarding as it responds favorably to GFD in most patients. HLA serology provides an important tool for diagnosis of this entity. PMID- 28638584 TI - The Prevalence of Non-alcoholic Fatty Liver Disease and Diabetes Mellitus in an Iranian Population. AB - BACKGROUND Type II diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are important causes of morbidity and mortality worldwide. We aimed to estimate the prevalence of DM in the context of NAFLD. METHODS In this cross sectional study, we studied 5052 participants, aged 18 years and older, of a baseline population-based cohort in northern Iran (N=6143). The prevalence of DM was estimated in individuals with and without NAFLD. The association between NAFLD and T2DM was evaluated using logistic regression with the adjustment of confounding effects of age, sex, body mass index, lipid profiles, and fasting insulin. RESULTS In men, the prevalence (95% confidence interval) of T2DM was 5.34% (4.35%-6.34%) and 15.06% (13.12%-17.00%) in individuals without and with NAFLD, respectively (p <0.001). In women without NAFLD, the prevalence was 8.27% (6.83%-9.71%) while in the presence of NAFLD, the prevalence was 27.21% (24.59% 29.83%), (p <0.001). In univariate analysis, the chance of having T2DM was 3.700 (3.130-4.380) times more in patients with NAFLD compared with subjects without NAFLD (p<0.001). This chance was reduced (Odds Ratio=1.976, 95% CI: 1.593-2.451, p <0.001) after removing the effects of other variables. CONCLUSION The prevalence of T2DM is increased in the context of NAFLD. This condition may be considered as an independent predictor of T2DM. PMID- 28638586 TI - Clarithromycin versus Gemifloxacin in Quadruple Therapeutic Regimens for Helicobacter Pylori Infection Eradication. AB - BACKGROUND Helicobacter pylori (H. pylori) infection is a major casual factor in any peptic diseases. Clarithromycin as one of the drugs recommended for the infection eradication regimen has shown different levels of resistance. The present study is comparing the effectiveness of clarithromycin- and gemifloxacin based quadruple regimens in H. pylori eradication. METHODS This was a prospective double blind randomized clinical trial on patients with clear indication of H. pylori eradication. The patients were randomly divided into two groups: "BPAC group" treated with bismuth subcitrate (240 mg), pantoprazole (20 mg), amoxicillin (1 gr), and clarithromycin (500 mg), all twice daily, and the "BPAG group" treated with bismuth subcitrate, pantoprazole, and amoxicillin with same doses as "BPAC group" and gemifloxacin (320 mg daily) all for 10 days. Three months after the end of therapy, 14C-Urea breath test was performed to confirm the eradication. All the patients were assessed for compliance and drug side effects. Based on per-protocol (PP) and intention-to-treat (ITT) methods, data were analyzed and a P value<0.05 was considered as statistically significant. This project has been registered in the Iranian registry of clinical trials (IRCT). RESULTS Three patients were excluded from the survey and finally, 179 patients (89 patients in BPAC group and 90 patients in BPAG group) including 71(39.66%) men with the mean age of 46.4+/-12.3 years completed the treatment period. The incidence of side effects between the two study groups did not differ significantly. The success rate of BPAC regimen eradication was remarkably greater than BPAG regimen (ITT analysis; 89% vs 77%, respectively; CI 95%: 1.072 5.507, P<0.015 and PP analysis; 91% vs 77.8% respectively; CI 95%: P<0.015). There was no significant relationship between the demographic features and the eradication results. CONCLUSION The results showed that gemifloxacin is not a good alternative for clarithromycin in H. pylori eradication regimens in our region. PMID- 28638587 TI - Association between Helicobacter Pylori Infection and Alopecia Areata: A Study in Iranian Population. AB - BACKGROUND Alopecia areata is an immune mediated inflammatory hair loss, which occurs in all ethnic and age groups, and both sexes. However no significant etiology has been known for this disease. Helicobacter pylori (H. pylori) , is an organism colonized in gastric mucosa. This bacterium has been associated with certain extra-digestive dermatological conditions. The causal relationship between alopecia areata and H. pylori infection has been discussed in literature. Therefore, we conducted this study to evaluate the prevalence of H. pylori infection in patients with alopecia areata and assess the risk of this infection in patients with this disease in order to determine its potential roles in the physiopathology of this disease. METHODS Between 2014 and 2015, we prospectively studied 81 patients with alopecia areata and 81 healthy volunteers with similar age and sex. Patients without any history of H. pylori infection were included in the study and underwent urease breath test. All results were analyzed using SPSS software (version 21.0) and p value<0.05 was considered as statistically significant. RESULTS 81 patients and 81 controls with the mean age of 34.9+/-11.6 and 38.2+/-13.4 years were studied (p=0.097). 48 (59.3%) and 45 (55.6%) individuals were male, in cases and control groups respectively (p =0.634). The result of urea breath test (UBT) was positive in 43 (53.1%) patients in cases and 27 (33.3%) individuals in control group, which was significantly different (p =0.011). The risk of H. pylori infection in alopecia areata was 2.263 (95% CI: 1.199-4.273). CONCLUSION The results of our study showed significant difference between H. pylori infection in individuals with and without alopecia areata, which shows that H. pylori contamination may be effective in physiopathology of alopecia areata. Therefore these results should be tested in large multivariable cohorts and controlled trials to reach more accurate evidence in the future and to generalize this idea to larger population. PMID- 28638588 TI - Synovial Sarcoma of the Esophagus: A Case Report and Review of Literature. AB - Synovial sarcoma is an uncommon soft tissue tumor occurring mainly in the periarticular region of the extremities in young adults. It happens less frequently in the head and neck, mediastinum, lungs, heart, and digestive tract. A 28-year-old man two months after total esophagectomy with final diagnosis of esophageal synovial sarcoma was referred to our Positron Emission Tomography (PET CT) department for the evaluation of treatment response and further treatment planning. To our knowledge this case is the 11th case of esophageal synovial sarcoma, being reported in the literature. We presented the 11th case of esophageal synovial sarcoma. Synovial sarcomas are very rare tumor entities, particularly in the gastrointestinal tract and are likely to be mistaken with other more common tumors such as gastrointestinal stromal tumors. PMID- 28638589 TI - Gastrocolic Fistula Presented as an Early Complication of Gastric Surgery in a 42 year-old Man. AB - Currently, surgery is less needed for the treatment of refractory peptic ulcer disease (PUD) or its complications. So, the complications of PUD surgery have been clearly declined. Here in, we present a 42-year-old man with chronic watery diarrhea and significant weight loss during 2 years after gastrojejunostomy for the treatment of obstructive PUD. Small bowel gastrointestinal series showed rapid transit without passage of contrast in the parts of small bowel. The patient was scheduled for exploratory laparotomy. During the surgery a large fistula was detected between the stomach and transverse colon, which was repaired. At the follow-up 6 months after the surgery, the patient did not have any history of recurrence of diarrhea and had 10 kg weight gain. Gastrocolic fistula is a very rare complication of surgical management of PUD. Barium enema is the most helpful imaging procedure for the diagnosis of gastrocolic fistula and surgery after correction of nutritional status is suggested especially for malnourished patients. PMID- 28638590 TI - A Rare Cause of Hemoperitoneum in a Patient with Cirrhosis and Portal Hypertension. PMID- 28638592 TI - Evaluating the quality of peer interactions in children and adolescents with autism with the Penn Interactive Peer Play Scale (PIPPS). AB - BACKGROUND: A core difficulty for individuals with autism is making friends and successfully engaging and interacting with peers. The majority of measures to assess peer interactions are observations in a school setting or self-report. The present study examined the convergent validity of using a teacher rating scale, the Penn Interactive Peer Play Scale (PIPPS), for collecting information about the quality of peer interactions at school. METHODS: Teachers completed the PIPPS for 107 children with ASD when the child was 9 and 13 years of age. Clinicians completed diagnostic and cognitive assessments and caregivers completed the Autism Diagnostic Interview-Revised (ADI-R) when the child was 9. RESULTS: Parent report of reciprocal friendships from the ADI-R was associated with teacher report about how socially connected the child was at school on the PIPPS, indicating strong convergence between teachers and parents. Children with more severe restricted and repetitive behaviors and lower verbal abilities were less connected with peers. Children with access to typical peers had more connections with peers compared to those who were in a special education classroom. CONCLUSIONS: The findings suggest that teacher ratings from the PIPPS can accurately capture the quality of peer interactions in children and adolescents with ASD and may be useful for clinicians and researchers to evaluate peer engagement in the classroom. PMID- 28638591 TI - Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism. AB - BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery. PMID- 28638593 TI - A potential nanobiotechnology platform based on infectious bursal disease subviral particles. AB - We describe a novel nanobiotechnology platform based on subviral particles derived from infectious bursal disease virus (IBD-SVPs). The major virus coat protein VP2 assembles into spherical, 23 nm SVPs when expressed as a heterologous protein in the yeast Pichia pastoris. We recovered up to 38 mg of IBD-SVPs at > 95% purity from 1 L of recombinant yeast culture. The purified particles were able to tolerate organic solvents up to 20% concentration (ethanol or dimethylsulfoxide), they resisted temperatures up to 65 degrees C and remained stable over a wide pH range (2.5-9.0). We achieved bioconjugation to the amine groups of lysine residues and to the carboxyl groups of aspartic and glutamic acid residues, allowing the functionalization of IBD-SVPs with biotin. The accessibility of surface amine groups was measured using Alexa Fluor 488 N hydroxysuccinimide (NHS) ester, an amine-selective fluorescent dye, revealing that approximately 60 dye molecules were attached to the surface of each particle. IBD-SVPs can therefore be exploited as a robust and versatile nanoscaffold to display diverse functional ligands. PMID- 28638594 TI - High burden of antimicrobial resistance among gram negative bacteria causing healthcare associated infections in a critical care unit of Nepal. AB - BACKGROUND: Healthcare associated infections (HCAI) and antimicrobial resistance are principal threats to the patients of intensive care units and are the major determining factors for patient outcome. They are associated with increased morbidity, mortality, excess hospitalization and financial costs. The present study is an attempt to investigate the spectrum and antimicrobial resistance of bacterial isolates involved in healthcare associated infections (HCAI) in the patients of a critical care unit at a tertiary care university hospital in Kathmandu, Nepal. METHODS: A laboratory based study was conducted over the period of 15 months (January 2014 to March 2015) among the patients of intensive care unit of Tribhuvan University Teaching Hospital, Kathmandu, Nepal. Clinical specimens from patients with suspected healthcare-associated infection were processed and bacterial isolates were identified with standard microbiological methods. Antimicrobial susceptibilities of the isolated strains were determined according to the CLSI guidelines and beta-lactamases (ESBL, AmpC, MBL and KPC) were detected by various phenotypic tests. RESULTS: One hundred and forty nine clinical specimens received from 135 patients suspected of HCAI (out of 491 patients) were found with significant bacterial growth. Specimens were from patients suspected of hospital-acquired pneumonia (16%, 79/491), bloodstream infections (5.7%, 28/491), surgical site infections (4.7%, 23/491), and urinary tract infections (3.9%, 19/491). Acinetobacter spp., Klebsiella spp., Escherichia coli and Burkholderia cepacia were the leading bacterial pathogens. Extremely high level of drug resistance (95.8%) along with the production of beta lactamases (ESBL; 43.7%, AmpC; 27.5%), MBL; 50.2% and KPC; 4.2%) was observed among Gram negative bacterial isolates. CONCLUSION: Healthcare associated infections are very common in our ICU. Gram negative bacterial pathogens are major culprits associated with these infections and there is alarming state of drug resistance among these isolates. Continuous surveillance and establishment of preventive and control measures of healthcare associated infections are urgently needed in our setting. PMID- 28638595 TI - Use of 90% ethanol to decontaminate stethoscopes in resource limited settings. AB - BACKGROUND: In developing countries like Nepal, 90% ethanol is cheap and is available in most hospitals. The unavailability of isopropyl alcohol (IPA) in these settings led us to compare the efficacy between 90% ethanol and isopropyl alcohol pads in reducing the bacterial contamination of diaphragm of stethoscope. METHODS: A randomized blinded experimental study was carried out to determine the difference between cleaning stethoscopes with 90% ethanol and IPA. Cultures of diaphragm were taken before and after cleaning with one of the cleaning agent. Colony forming units (CFU) count and organism identification was done by a blinded investigator. CFU before and after cleaning were compared using Wilcoxon signed-rank test. Mann Whitney U test was used to compare the decrease in CFU count between the cleaning agents. RESULTS: About 30% of the stethoscopes harbored potential pathogens. Significant reduction in CFU was observed with both IPA (Wilcoxon signed-rank test, P value <0.001) and 90% ethanol (Wilcoxon signed rank test, P value <0.001). Comparing median decrease in CFU between cleaning with IPA and with 90% ethanol, no significant difference was found (Mann Whitney U test; U = 1357, P value >0.05). CONCLUSIONS: Both 90% ethanol and IPA are equally effective in decontaminating the diaphragm of stethoscope. Selection of agent should be done on the basis of cost and availability. PMID- 28638597 TI - Rest tremor revisited: Parkinson's disease and other disorders. AB - Tremor is the most common movement disorder characterized by a rhythmical, involuntary oscillatory movement of a body part. Since distinct diseases can cause similar tremor manifestations and vice-versa, it is challenging to make an accurate diagnosis. This applies particularly for tremor at rest. This entity was only rarely studied in the past, although a multitude of clinical studies on prevalence and clinical features of tremor in Parkinson's disease (PD), essential tremor and dystonia, have been carried out. Monosymptomatic rest tremor has been further separated from tremor-dominated PD. Rest tremor is also found in dystonic tremor, essential tremor with a rest component, Holmes tremor and a few even rarer conditions. Dopamine transporter imaging and several electrophysiological methods provide additional clues for tremor differential diagnosis. New evidence from neuroimaging and electrophysiological studies has broadened our knowledge on the pathophysiology of Parkinsonian and non-Parkinsonian tremor. Large cohort studies are warranted in future to explore the nature course and biological basis of tremor in common tremor related disorders. PMID- 28638596 TI - Environmental insults: critical triggers for amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons. As a complex disease, the ageing process and complicated gene-environment interactions are involved in the majority of cases. MAIN BODY: Significant advances have been made in unravelling the genetic susceptibility to ALS with massively parallel sequencing technologies, while environmental insults remain a suspected but largely unexplored source of risk. Several studies applying the strategy of Mendelian randomisation have strengthened the link between environmental insults and ALS, but none so far has proved conclusive. We propose a new ALS model which links the current knowledge of genetic factors, ageing and environmental insults. This model provides a mechanism as to how ALS is initiated, with environmental insults playing a critical role. CONCLUSION: The available evidence has suggested that inherited defect(s) could cause mitochondrial dysfunction, which would establish the primary susceptibility to ALS. Further study of the underlying mechanism may shed light on ALS pathogenesis. Environmental insults are a critical trigger for ALS, particularly in the aged individuals with other toxicant susceptible genes. The identification of ALS triggers could lead to preventive strategies for those individuals at risk. PMID- 28638599 TI - Obesity and kidney disease: hidden consequences of the epidemic. AB - Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risk of diabetes, cardiovascular disease and also for chronic kidney disease (CKD). A high body mass index is one of the strongest risk factors for new-onset CKD. In individuals affected by obesity, a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight. The increase in intraglomerular pressure can damage the kidneys and raise the risk of developing CKD in the long term. The incidence of obesity-related glomerulopathy has increased 10-fold in recent years. Obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. This year World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyles and health policy measures that make preventive behaviors an affordable option. PMID- 28638601 TI - The efficacy of rituximab in adult frequently relapsing minimal change disease. AB - BACKGROUND: Corticosteroids are the basis of treatment for nephrotic syndrome due to minimal change disease (MCD), but 25% of patients have frequently relapsing nephrotic syndrome (FRNS) and 30% become steroid dependent. Prolonged use of conventional immunosuppressants causes significant toxicity. Rituximab (RTX) is now included in guidelines for childhood MCD. Evidence for use in adult MCD is limited. We describe a single-centre experience of RTX use in adult MCD. METHODS: Outcomes of all adult MCD patients treated with RTX for FRNS between 2008 and 2015 were retrospectively analysed. RESULTS: Thirteen patients received RTX; 11/13 had childhood-onset MCD. All had FRNS and 10 were steroid dependent. Eleven patients experienced one or more major treatment side effect from conventional therapy. At the time of RTX treatment, six patients were relapsing. All entered remission after RTX. The median length of follow-up after the first RTX treatment was 20 months (range 6-85). After RTX, the rate of relapse was reduced from 4 to 0.4/year (Wilcoxon signed rank P <= 0.05). Seven patients relapsed after RTX after a median of 10 months (range 1-11). All seven relapsing patients were successfully re-treated with RTX and none developed RTX-resistant nephrosis. The median number of courses of RTX per patient was 1 (range 1-5). The number of additional immunosuppressants, steroid dependency and antihypertensive agents were also reduced. At the last follow-up, two patients remained on low-dose steroids. No RTX-related adverse events were observed. CONCLUSION: RTX is safe and effective in adults with FRNS due to MCD. The median rate of relapse is significantly reduced following RTX treatment and additional immunosuppressant exposure is minimized. PMID- 28638598 TI - Caregiver burden is increased in Parkinson's disease with mild cognitive impairment (PD-MCI). AB - BACKGROUND: There is limited evidence on caregiver outcomes associated with mild cognitive impairment in patients with Parkinson's disease (PD-MCI) and the coping strategies used by these caregivers. METHODS: To investigate this relationship, we examined levels of burden, depression, anxiety, coping strategies and positive aspects of caregiving in the informal caregivers of 96 PD patients. The PD patients were classified using MDS-Task Force Level II criteria as showing either normal cognition (PD-N; n = 51), PD-MCI (n = 30) or with dementia (PDD; n = 15). RESULTS: Mean Zarit Burden Interview (ZBI) score increased significantly between carers of PD-N (M = 13.39, SD = 12.22) compared to those of PD-MCI patients (M = 22.00, SD = 10.8), and between carers of PD-MCI and PDD patients (M = 29.33, SD = 9.59). Moreover, the proportion of carers showing clinically significant levels of burden (ZBI score >= 21) also increased as the patients' cognitive status declined (18% for PD-N; 60% for PD-MCI; and 80% for PDD) and was mirrored by an increasing amount of time spent providing care by the caregivers. Caregiver ZBI score was independent of patient neuropsychiatric symptoms, motor function, disease duration and time that caregivers spent caregiving. Caregiver use of different coping strategies increased with worsening cognition. However, we found only equivocal evidence that the use of problem-focused, emotion-focused and dysfunctional coping mediated the association between patient cognitive status and caregiver burden, because the inverse models that used caregiver burden as the mediator were also significant. CONCLUSIONS: The study highlights the impact of Parkinson's disease on those providing care when the patient's cognition is poor, including those with MCI. Caregiver well-being has important implications for caregiver support, nursing home placement and disease course. PMID- 28638600 TI - Quantification of bleeding volume using computed tomography and clinical complications after percutaneous renal biopsy. AB - Background: The aim of this study was to investigate specific bleeding volume after percutaneous renal biopsy (PRB) and the correlation between bleeding volume and clinical parameters. Methods: A retrospective study of 252 consecutive patients (153 male patients and 99 female patients) who underwent PRB at the Department of Nephrology, Japanese Red Cross Ishinomaki Hospital, between July 2013 and January 2016 was conducted. PRB was performed under ultrasound guidance using an automated spring-loaded biopsy device and a 16-cm, 16-gauge needle. Patients underwent computed tomography (CT) the day after PRB. Bleeding volume after PRB was evaluated using reconstructed CT data. Results: The median bleeding volume after PRB was 38 mL (25th-75th percentile, 18-85 mL), with >=4 punctures identified as a risk factor for massive bleeding. The incidence rates of macrohematuria, transient hypotension and bladder obstruction were 14.3, 8.7 and 4.7%, respectively. Post-PRB blood transfusion and intervention were required in 4.7 and 0.8% of patients, respectively. Conclusion: Although it is difficult to assess the risk for massive bleeding prior to PRB, we do provide evidence of a specific increased risk with >=4 puncture attempts, and recommend careful follow up of these patients. PMID- 28638602 TI - B cell-depleting therapy with rituximab or ofatumumab in immunoglobulin A nephropathy or vasculitis with nephritis. AB - BACKGROUND: Approximately 30% of adult patients with immunoglobulin A (IgA) nephropathy (IgAN) or IgA vasculitis with nephritis (IgAVN) develop end-stage renal disease during long-term follow-up. In particular, patients with nephritic nephrotic syndrome have an increased risk of rapid progression. Conventional immunosuppressive therapy with corticosteroids (CSs) may be insufficient for disease control and is associated with a number of side effects. Rituximab (RTX) has been shown to be well tolerated and effective in a range of glomerular diseases, but there is little information on its therapeutic potential in IgAN. The humanized anti-CD20 monoclonal antibody ofatumumab (OFAB) may be an alternative drug for patients intolerant or unresponsive to RTX, but so far there is no report on its use in IgAVN or IgAN. METHODS: We describe clinical outcomes after 17-22 months in four adult patients with biopsy-confirmed IgAVN or IgAN treated with RTX or OFAB as well as CS soon after diagnosis. All presented with nephritic-nephrotic syndrome and one had crescentic IgAN. Rebiopsy was performed in two cases. RESULTS: RTX and OFAB were well tolerated. Albuminuria was <250 mg/day in three patients at last evaluation and two regained normal renal function. In all cases, renal function improved after therapy. In one patient with severe IgA vasculitis, rebiopsy showed disappearance of subendothelial but not mesangial immune complexes. In the case with crescentic IgAN, rebiopsy after 9 months showed no active necrotic lesions. CONCLUSIONS: B cell-depleting therapy may be an alternative treatment for patients with IgAN or IgAVN and nephritic nephrotic syndrome. A possible CS-sparing effect should be further evaluated in randomized controlled clinical trials. PMID- 28638604 TI - Impact of poverty and race on pre-end-stage renal disease care among dialysis patients in the United States. AB - BACKGROUND: Access to nephrology care prior to end-stage renal disease (ESRD) is significantly associated with lower rates of morbidity and mortality. We assessed the association of area-level and individual-level indicators of poverty and race/ethnicity on pre-ESRD care provided by nephrologists. METHODS: In this retrospective cohort study using the US Renal Data System database, we identified 739 537 patients initiated on maintenance dialysis from 1 January 2007 through 31 December 2012. We assessed the Medicare-Medicaid dual eligibility status as an indicator of individual-level poverty and ZIP code-level median household income (MHI) data obtained from the 2010 US census. We conducted multivariable logistic regression of pre-ESRD nephrology care as the outcome variable. RESULTS: Among patients in the lowest area-level MHI quintile, 61.28% received pre-ESRD nephrology care versus 67.68% among those in higher quintiles (P < 0.001). Similarly, the proportions of dual-eligible and nondual-eligible patients who had pre-ESRD nephrology care were 61.49 and 69.84%, respectively (P < 0.001). Patients in the lowest area-level MHI quintile were associated with significantly lower likelihood of pre-ESRD nephrology care (adjusted odds ratio [aOR] 0.86 [95% confidence interval (CI) 0.85-0.87]) compared with those in higher quintiles. Both African American (AA) and Hispanic patients were significantly less likely to have received pre-ESRD nephrology care [aOR 0.85 (95% CI 0.84-0.86) and aOR 0.72 (95% CI 0.71-0.74), respectively]. CONCLUSIONS: Individual- and area-level measures of poverty, AA race and Hispanic ethnicity were independently associated with a lower likelihood of pre-ESRD nephrology care. Efforts to improve pre-ESRD nephrology care may require focusing on the poor and minority groups. PMID- 28638603 TI - Serum osteoprotegerin and renal function in the general population: the Tromso Study. AB - BACKGROUND: Serum osteoprotegerin (OPG) is elevated in patients with chronic kidney disease (CKD) and increases with decreasing renal function. However, there are limited data regarding the association between OPG and renal function in the general population. The aim of the present study was to explore the relation between serum OPG and renal function in subjects recruited from the general population. METHODS: We conducted a cross-sectional study with 6689 participants recruited from the general population in Tromso, Norway. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equations. OPG was modelled both as a continuous and categorical variable. General linear models and linear regression with adjustment for possible confounders were used to study the association between OPG and eGFR. Analyses were stratified by the median age, as serum OPG and age displayed a significant interaction on eGFR. RESULTS: In participants <=62.2 years with normal renal function (eGFR >=90 mL/min/1.73 m2) eGFR increased by 0.35 mL/min/1.73 m2 (95% CI 0.13-0.56) per 1 standard deviation (SD) increase in serum OPG after multiple adjustment. In participants older than the median age with impaired renal function (eGFR <90 mL/min/1.73 m2), eGFR decreased by 1.54 (95% CI -2.06 to -1.01) per 1 SD increase in serum OPG. CONCLUSIONS: OPG was associated with an increased eGFR in younger subjects with normal renal function and with a decreased eGFR in older subjects with reduced renal function. Our findings imply that the association between OPG and eGFR varies with age and renal function. PMID- 28638605 TI - Effect of ethnicity and socioeconomic status on vascular access provision and performance in an urban NHS hospital. AB - BACKGROUND: The aim of this study was to examine the effect of ethnicity, socioeconomic group (SEG) and comorbidities on provision of vascular access for haemodialysis (HD). METHODS: This was a retrospective review of two databases of HD sessions and access operations from 2003-11. Access modality of first HD session and details of transplanted patients were derived from the renal database. Follow-up was until 1 January 2015. Primary failure (PF) was defined as an arteriovenous fistula (AVF) used for fewer than six consecutive dialysis sessions. AVF survival was defined as being until the date the AVF was abandoned. Ethnicity was coded from hospital records. SEG was calculated from postcodes and 2011 census data from the Office of National Statistics. Comorbidities were calculated with the Charlson Comorbidity Index. RESULTS: Five hundred incident patients started chronic HD in the study period. Mode of starting HD was not associated with ethnicity (P = 0.27) or SEG (P = 0.45). Patients from ethnic minorities were younger when starting dialysis (P < 0.0001). Some 928 AVF patients' first AVF operations were analysed: 68% Caucasian, 26% Asian and 6% Afro-Caribbean. Half were in the most deprived SEG and 11% in the least deprived SEG. PF did not differ by ethnicity (P = 0.29), SEG (P = 0.75) or comorbidities (P = 0.54). AVF survival was not different according to ethnicity (P = 0.13) or SEG (P = 0.87). AVF survival was better for patients with a low comorbidity score (P = 0.04). The distribution of transplant recipients by ethnic group and SEG was similar to the distributions of all HD starters. CONCLUSION: Ethnicity and socioeconomic group had no effect on mode of starting HD, primary AVF failure rate or AVF survival. Ethnic minorities were younger at start of dialysis and at their first AVF operation. PMID- 28638606 TI - Palliative care for patients with end-stage renal disease: approach to treatment that aims to improve quality of life and relieve suffering for patients (and families) with chronic illnesses. AB - Providing end-of-life care to patients suffering from chronic kidney disease (CKD) and/or end-stage renal disease often presents ethical challenges to families and health care providers. However, as the conditions these patients present with are multifaceted in nature, so should be the approach when determining prognosis and treatment strategies for this patient population. Having an interdisciplinary palliative team in place to address any concerns that may arise during conversations related to end-of-life care encourages effective communication between the patient, the family and the medical team. Through the use of a case study, the authors demonstrate how an interdisciplinary palliative team can be used to make decisions that satisfy the patient's and the medical team's desires for end-of-life care. PMID- 28638607 TI - Course of chronic kidney disease in French patients. AB - BACKGROUND: In 1998, a French survey showed that the referral of patients with chronic kidney disease to a nephrologist was delayed, resulting in many emergency initiations of dialysis. In 2009, the ORACLE study aimed to describe the renal course of dialysis patients from their first nephrology visit to their first dialysis session. METHODS: The ORACLE study was a multicentre retrospective study of all patients who started chronic dialysis. Data were collected at the first nephrology visit and at the first dialysis session. RESULTS: In total, 720 patients were included (69 centres). At the first nephrology visit, the mean Cockcroft-Gault (CG) indicator was 31.8 mL/min (22.7 in 1998) and 52.4% of patients (73% in 1998) had a CG <30. The mean time between the first nephrology visit and the first dialysis session was 48 months (35 months in 1998). CONCLUSION: In 2009, most patients were referred a long time before dialysis initiation, which likely allowed them to benefit from the impact of nephrology care on early outcomes when on dialysis. However, 34.2% of the dialysis sessions were still initiated under emergency conditions. PMID- 28638608 TI - The role of psychological factors in fatigue among end-stage kidney disease patients: a critical review. AB - Fatigue is a common and debilitating symptom, affecting 42-89% of end-stage kidney disease patients, persisting even in pre-dialysis care and stable kidney transplantation, with huge repercussions on functioning, quality of life and patient outcomes. This paper presents a critical review of current evidence for the role of psychological factors in renal fatigue. To date, research has concentrated primarily on the contribution of depression, anxiety and subjective sleep quality to the experience of fatigue. These factors display consistent and strong associations with fatigue, above and beyond the role of demographic and clinical factors. Considerably less research is available on other psychological factors, such as social support, stress, self-efficacy, illness and fatigue specific beliefs and behaviours, and among transplant recipients and patients in pre-dialysis care. Promising evidence is available on the contribution of illness beliefs and behaviours to the experience of fatigue and there is some indication that these factors may vary according to treatment modality, reflecting the differential burdens and coping necessities associated with each treatment modality. However, the use of generic fatigue scales casts doubt on what specifically is being measured among dialysis patients, illness-related fatigue or post-dialysis-specific fatigue. Therefore, it is important to corroborate the available evidence and further explore, qualitatively and quantitatively, the differences in fatigues and fatigue-specific beliefs and behaviours according to renal replacement therapy, to ensure that any model and subsequent intervention is relevant and grounded in the experiences of patients. PMID- 28638609 TI - Cognitive function and advanced kidney disease: longitudinal trends and impact on decision-making. AB - Background: Cognitive impairment commonly affects renal patients. But little is known about the influence of dialysis modality on cognitive trends or the influence of cognitive impairment on decision-making in renal patients. This study evaluated cognitive trends amongst chronic kidney disease (CKD), haemodialysis (HD) and peritoneal dialysis (PD) patients. The relationship between cognitive impairment and decision-making capacity (DMC) was also assessed. Methods: Patients were recruited from three outpatient clinics. Cognitive function was assessed 4-monthly for up to 2 years, using the Montreal Cognitive Assessment (MoCA) tool. Cognitive trends were assessed using mixed model analysis. DMC was assessed using the Macarthur Competency Assessment tool (MacCAT-T). MacCAT-T scores were compared between patients with cognitive impairment (MoCA <26) and those without. Results: In total, 102 (41 HD, 25 PD and 36 CKD) patients were recruited into the prospective study. After multivariate analysis, the total MoCA scores declined faster in dialysis compared with CKD patients [coefficient = -0.03, 95% confidence interval (95% CI) = -0.056 to - 0.004; P = 0.025]. The MoCA executive scores declined faster in the HD compared with PD patients (coefficient = -0.12, 95% CI = -0.233 to - 0.007; P = 0.037). DMC was assessed in 10 patients. Those with cognitive impairment had lower MacCAT T compared with those without [median (interquartile range) 19 (17.9-19.6) versus 17.4 (16.3-18.4); P = 0.049]. Conclusions: Cognition declines faster in dialysis patients compared with CKD patients and in HD patients compared with PD patients. Cognitive impairment affects DMC in patients with advanced kidney disease. PMID- 28638610 TI - Looking for the needle in the kidney transplantation haystack. AB - The diagnosis of acute rejection still relies on renal allograft biopsy. In fact, histological features including C4d staining can be useful to differentiate cellular and antibody-mediated acute rejection. However, the pathogenic mechanism to define the type of rejection is usually assessed by anti-HLA donor specific antibodies (DSA) monitoring. Suspicion of acute rejection is usually based on renal function deterioration. This method has low sensitivity. Moreover, creatinine increase follows graft injury and therefore the diagnosis is performed when there is an ongoing acute rejection. One strategy to overcome the limitation of serum creatinine as predictor of acute rejection is to perform surveillance protocol biopsies. However, the low incidence of subclinical acute rejection among patients treated with tacrolimus-based immunosuppression makes this procedure questionable in terms of cost-effectiveness. In this scenario new biomarkers predicting acute rejection are urgently needed. Ideally, such biomarkers should anticipate acute rejection, thus allowing preventive actions such as maintenance immunosupression intensification and/or modification. Alternatively, these new biomarkers should at least improve the predictive value of serum creatinine monitoring. Although many of the new biomarkers are promising, none have been translated to the clinic to date because of a lack of validation studies and the existence of major methodological concerns. PMID- 28638611 TI - Does size matter? Kidney transplant donor size determines kidney function among living donors. AB - BACKGROUND: Kidney donor outcomes are gaining attention, particularly as donor eligibility criteria continue to expand. Kidney size, a useful predictor of recipient kidney function, also likely correlates with donor outcomes. Although donor evaluation includes donor kidney size measurements, the association between kidney size and outcomes are poorly defined. METHODS: We examined the relationship between kidney size (body surface area-adjusted total volume, cortical volume and length) and renal outcomes (post-operative recovery and longer-term kidney function) among 85 kidney donors using general linear models and time-to-chronic kidney disease data. RESULTS: Donors with the largest adjusted cortical volume were more likely to achieve an estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m2 over a median 24-month follow-up than those with smaller cortical volumes (P <0.001), had a shorter duration of renal recovery (1.3-2.2 versus 32.5 days) and started with a higher eGFR at pre donation (107-110 versus 91 mL/min/1.73 m2) and immediately post-nephrectomy (~63 versus 50-51 mL/min/1.73 m2). Similar findings were seen with adjusted total volume and length. CONCLUSIONS: Larger kidney donors were more likely to achieve an eGFR >=60 mL/min/1.73 m2 with renal recovery over a shorter duration due to higher pre-donation and initial post-nephrectomy eGFRs. PMID- 28638612 TI - Assessment of physical performance and quality of life in kidney-transplanted patients: a cross-sectional study. AB - BACKGROUND: Information on physical and mental wellness in renal transplantation is limited. Therefore, we performed a cross-sectional study to evaluate and describe the different components of physical performance and quality of life (QoL) in a cohort of kidney-transplanted patients. METHODS: Physical performance and QoL were determined through the administration of validated tests and questionnaires [muscle strength, dynamometer handgrip, tactile sensitivity, visual analogue scale (VAS) for pain, Timed Up and Go (TUG) test, Fatigue Severity Scale (FSS) and the 36-item Short Form Health Survey]. The patients were divided into three groups based on time elapsed since transplantation: early (in the first 6 months), middle (from 7 to 60 months) and late (>60 months). RESULTS: Of 132 enrolled patients, 11 patients (8.3%) presented a severe reduction of muscle strength, 63 patients (47%) had significant bilateral impaired handgrip and tactile sensitivity was altered in 23 patients (17.4%). TUG assessment showed significant mobility limitation in 29 patients (21.9%). The FSS presented a pathological value in 50 patients (37.3%), while the mean VAS was 1.8 +/- 2.7. There were no significant differences in physical performance parameters among the three patient groups. There were inverse correlations among different components of physical performance and age, comorbidity and dialysis vintage, and there was a direct correlation with renal function. During the first months after transplantation there were limitations in physical, social and emotional activities. Overall, the self-perceived physical performance was significantly lower in transplanted patients with respect to the normal reference level. CONCLUSION: Kidney-transplanted patients may present different degrees of impairment in physical performance and quality of life. Systematic functional assessment is essential to identify patients needing intensive and personalized rehabilitation programmes. PMID- 28638613 TI - Cuff extrusion in peritoneal dialysis: single-centre experience with the cuff shaving procedure in five patients over a 4-year period. AB - Catheter-related infections in peritoneal dialysis (PD) remain a significant complication, and some patients with recurrent exit-site (ESI) and/or tunnel infections may experience external cuff extrusion. In these cases, cuff-shaving has been described as a possible course of treatment. During a 4-year period, there were 44 patients with PD at our department; all received double-cuffed Tenckhoff catheters. Six (13%) never started on PD. Five (13%) of the 38 active PD patients experienced cuff extrusion. Causes of end-stage renal disease (ESRD) were diabetic nephropathy (n = 1), toxic nephropathy (n = 1), hypertensive nephrosclerosis (n = 1), systemic disease (n = 1) and one with unknown cause. PD catheters were inserted by the Department of Surgery and our patients waited a mean of 3.71 weeks (0.57-7.86) from catheter insertion to PD start. Patients were followed up by monthly and even fortnightly during infections. Our cohort experienced two (1-5) ESIs per patient prior to cuff extrusion. Cultures showed growth of Staphylococcus aureus and the patients received dicloxacillin orally 500 mg qid for 3-4 weeks. Of the 38 active PD patients, 5 (13%) developed cuff extrusion with an incidence of 0.20 episodes/patient/year, manifesting on average at 32 weeks (17.3-40.6), due to repeated ESI in four patients and substantial weight loss in one patient. All five underwent cuff-shaving and the ESIs resolved completely in 80% of the cases assisted by supplemental treatment with mupirocin and/or dicloxacillin. There were no complications to the cuff-shaving procedure itself. None of the five patients experienced new ESIs after cuff-shaving had been performed. Cuff-shaving reduces the rate of recurring ESIs. The procedure is safe, if performed correctly, and poses no risk to the patient or the catheter. PMID- 28638614 TI - Loss of kAE1 expression in collecting ducts of end-stage kidneys from a family with SLC4A1 G609R-associated distal renal tubular acidosis. AB - Distal renal tubular acidosis caused by missense mutations in kidney isoform of anion exchanger 1 (kAE1/SLC4A1), the basolateral membrane Cl-/HCO3- exchanger of renal alpha-intercalated cells, has been extensively investigated in heterologous expression systems but rarely in human kidneys. The preferential apical localization of distal renal tubular acidosis (dRTA)-associated kAE1 mutants R901X, G609R and M909T in cultured epithelial monolayers has not been examined in human kidney. Here, we present kidney tissues from dRTA-affected siblings heterozygous for kAE1 G609R, characterized by predominant absence rather than mistargeting of kAE1 in intercalated cells. Thus, studies of heterologous recombinant expression of mutant proteins should be, whenever possible, interpreted in comparison to affected patient tissues. PMID- 28638615 TI - Erratum: Morbidity, mortality and quality of life in the ageing haemodialysis population: results from the ELDERLY study. AB - [This corrects the article DOI: 10.1093/ckj/sfw087.]. PMID- 28638616 TI - Vitamin D deficiency among newly diagnosed tuberculosis patients and their household contacts: a comparative cross-sectional study. AB - BACKGROUND: Recent studies suggest that the incidence and severity of tuberculosis is associated with low levels of vitamin D. Even though individuals living in Ethiopia have a high exposure to sunlight which is a source of vitamin D, tuberculosis is still one of the major causes of morbidity and mortality in the country. Therefore, this study aimed to determine the prevalence and associated factors of vitamin D deficiency in newly diagnosed tuberculosis patients, household contacts and community controls in Gondar, Ethiopia. METHODS: A comparative cross-sectional study design was conducted. Blood samples were collected from newly diagnosed smear positive pulmonary TB patients, their household contacts and community controls. Serum 25(OH)-vitamin D3 was determined by an Enzyme Linked Immunosorbent Assay. A serum level of 25(OH)-vitamin D3 below < 50 nmol/L was defined as vitamin D deficiency and <25 nmol/L as severe vitamin D deficiency. RESULTS: A total of 126 newly diagnosed smear positive TB patients, 57 house hold contacts and 70 apparently community controls were included in the study. The mean +/- SD age (years) of TB patients, house hold contacts and community controls was 29.8 +/- 11.9, 24.3 +/- 14.7 and 27.3 +/- 7.6 respectively. Ninety out of 126 (71.4%) TB patients were underweight with a BMI of < 18.5 kg/m2. The mean 25(OH)-vitamin D3 level of TB patients (30.1 +/- 19.3 nmol/L) was significantly lower than community controls (38.5 +/- 20.9 nmol/L, P = 0.005 and household contacts (37.7 +/- 12.8 nmol/L, P =0.031).). The prevalence of vitamin D deficiency was higher in TB patients (83.3%) than in community controls (67.1%, P = 0.009). The prevalence of vitamin D deficiency was also found higher in household contacts (80.7%). Severe vitamin D deficiency was observed in 53%(67/126), 30% (21/70), 19.3%(11/57) of TB patients, community controls and household contacts respectively. Low BMI (AOR = 2.13; 95%CI: 1.02, 3.28) and being positive for tuberculosis (AOR = 1.93; 95%CI: 1.06, 2.86) were significant predictors of severe vitamin D deficiency. CONCLUSION: High prevalence of vitamin D deficiency was found among newly diagnosed TB patients and in their household contacts. The present study warrants further studies to determine the role of vitamin D supplementation in the prevention and treatment of tuberculosis in Ethiopia. PMID- 28638617 TI - Clinical pharmacists in primary care: Provider satisfaction and perceived impact on quality of care provided. AB - PURPOSE: The purpose of this study is to evaluate primary care provider satisfaction and perceived impact of clinical pharmacy services on the disease state management in primary care. METHODS: A cross-sectional survey with 24 items and 4 domains was distributed anonymously to pharmacy residency program directors across the United States who were requested to forward the survey to their primary care provider colleagues. Primary care providers were asked to complete the survey. RESULTS: A total of 144 primary care providers responded to the survey, with 130 reporting a clinical pharmacist within their primary care practice and 114 completing the entire survey. Primary care providers report pharmacists positively impact quality of care (mean = 5.5 on Likert scale of 1-6; standard deviation = 0.72), high satisfaction with pharmacy services provided (5.5; standard deviation = 0.79), and no increase in workload as a result of clinical pharmacists (5.5; standard deviation = 0.77). Primary care providers would recommend clinical pharmacists to other primary care practices (5.7; standard deviation = 0.59). Primary care providers perceived specific types of pharmacy services to have the greatest impact on patient care: medication therapy management (38.6%), disease-focused management (29.82%), and medication reconciliation (11.4%). Primary care providers indicated the most valuable disease-focused pharmacy services as diabetes (58.78%), hypertension (9.65%), and pain (11.4%). CONCLUSION: Primary care providers report high satisfaction with and perceived benefit of clinical pharmacy services in primary care and viewed medication therapy management and disease-focused management of diabetes, hypertension, and pain as the most valuable clinical pharmacy services. These results can be used to inform development or expansion of clinical pharmacy services in primary care. PMID- 28638618 TI - Swyer-James-MacLeod syndrome-a rare diagnosis presented through two adult patients. AB - Swyer-James-MacLeod syndrome (SJMS) is a rare syndrome of acute obliterative bronchiolitis following an early childhood infective insult to the lungs. This causes arrest of alveolarization, affecting lung development with hypoplasia of the ipsilateral pulmonary artery and results in a characteristic radiological pattern, such as a unilateral hyperlucent lung with expiratory air-trapping and pruned-tree appearance on pulmonary angiogram. The clinical presentation is either recurrent chest infections, exertional dyspnoea or it may be an incidental finding. Management involves early prevention of infection, airway clearance, and regular vaccinations. We describe two adult patients with SJMS: A 51-year-old female of Indian ethnicity presenting with recurrent haemoptysis and a 40-year old Indigenous male presenting acutely with sepsis and background history of recurrent chest infections. These cases highlight the importance of being aware of and accurately recognizing this rare condition, to be able to manage patients appropriately and avoid incorrect and unnecessary treatment. PMID- 28638619 TI - Propionibacterium acnes pleural empyema following medical thoracoscopy. AB - Propionibacterium acnes (P. acnes) is a Gram-positive anaerobic rod and a common skin commensal that colonizes sebaceous glands. It has infrequently been associated with invasive opportunistic infections and can cause implant associated infections through a biofilm mode of growth. Medical thoracoscopy is a common procedure for diagnosis and treatment of exudative pleural effusions; empyema is a recognized complication. We present a rare case of P. acnes pleural empyema 3 weeks following medical thoracoscopy and subsequent intercostal drain insertion for 3 days in a 75-year-old man. We postulate that pathogenesis may be associated with inoculation at the time of thoracoscopy or via biofilm formation on the intercostal drain. This case highlights the potential for this pathogen to cause clinically significant disease following thoracoscopy and pleural drainage. PMID- 28638620 TI - Chest pain and recurrent chylothorax: an unusual presentation of malignant pleural mesothelioma. AB - Malignant mesothelioma presenting with recurrent chylous effusion is rare. We describe the case of a 34-year-old female Macedonian immigrant who presented with central chest pain and subsequently a left-sided chylous pleural effusion. The diagnosis was made on pleural biopsy via video-assisted thoracoscopic surgery (VATS). Our case demonstrates the utility of thoracic magnetic resonance imaging (MRI) and the difficulties associated with pleural cytology and cervical lymph node biopsy in the establishment of a diagnosis of mesothelioma. It is a reminder that mesothelioma can metastasize to mediastinal and cervical lymph nodes, can occur in young people, and may present as a chylothorax. PMID- 28638621 TI - The role of DSM-5 borderline personality symptomatology and traits in the link between childhood trauma and suicidal risk in psychiatric patients. AB - BACKGROUND: Childhood traumas appear to be linked to suicidal behavior. However, the factors that mediate between these two phenomena are not sufficiently understood. Recent findings suggest that borderline personality disorder (BPD) may explain some of the association. METHOD: The present study investigated the potential mediating role of BPD symptomatology and traits between reported childhood trauma and suicidal risk in adult psychiatric outpatients (N = 124). BPD symptomatology was measured with DSM-5 Section II criterion-counts (SCID-II; Structured Clinical Interview for DSM-IV Axis II), whereas BPD traits were measured with specified DSM-5 Section III traits (PID-5; Personality Inventory for DSM-5). Childhood traumas were self-reported (CTQ; Childhood Trauma Questionnaire), whereas level of suicidal risk was measured with a structured interview (MINI Suicidality Module; Mini International Neuropsychiatric Interview). Mediation effects were tested by bias-corrected (10.000 boot-strapped samples) confidence intervals. RESULTS: BPD features account for a considerable part of the cross-sectional association between childhood trauma and level of suicidal risk, even when controlling for the influence of gender, age, and educational level. This finding remained stable when testing the model without the suicidality-related BPD criterion and PID-5 items. DSM-5 Section II BPD criterion-counts explained 67% of the total effect, whereas DSM-5 Section III BPD traits accounted for 82% of the total effect. The specific DSM-5 Section III trait facets of "Depressivity" (52%) and "Perceptual Dysregulation" (37%) accounted for most of this effect. CONCLUSIONS: The findings provide preliminary support for the proposed mediation model indicating that BPD features may help explain relations between childhood trauma and elevated suicidal risk in adult life, in particular for DSM-5 Section III personality traits of depressivity (e.g., pessimism, guilt, and shame) and perceptual dysregulation (e.g., dissociation). To reduce the suicidal risk among those with a history of childhood trauma, BPD features (including "Depressivity" and "Perceptual Dysregulation") might be an important target of assessment, risk management, and treatment. However, other factors are likely to be involved, and a longitudinal and more large-scale design is warranted for a conclusive test of mediation. PMID- 28638622 TI - The synergistic use of plant and isolated bacteria to clean up polycyclic aromatic hydrocarbons from contaminated soil. AB - BACKGROUND: Biological methods of polycyclic aromatic hydrocarbons (PAH) contamination elimination typically involve the transformation of contaminants to non-toxic materials by microorganisms and plants and appear to be the most effective methods available. METHODS: In this study, Bacillus licheniformis and Bacillus mojavensis isolated from oil-contaminated soils were inoculated onto Festuca arundinacea seeds before planting in the pot and 3 weeks after planting by syringe injection into the rhizospheric zone in order to study the elimination of PAHs from Festuca's rhizosphere in the greenhouse. Some physical and chemical properties of the soil, PAH concentrations, seeds germination percentage, root and shoot biomasses of the treated samples were examined. RESULTS: The results showed that the treated samples inoculated with both bacteria had a significantly higher percentage of seed germination and root and shoot biomass compared to other treatments. The concentration of some PAHs reduced significantly (Pvalue < 0.05) in the rhizosphere of the treated samples inoculated with both bacteria compared to in contaminated soils. Concentrations of some PAHs (eg. Naphthalene, Phenanthrene, Benzo[a]anthracene and Dibenzo[a,h]anthracene) even reached below the detection limit of the method. The PAHs concentrations in the treated samples inoculated with bacteria was decreased significantly (Pvalue < 0.05). Therefore, the results showed the high efficiency of the Festuca and bacterial inoculation in eliminating PAHs from the soil. CONCLUSION: According to the results, the partnership of Festuca with B. licheniformis and B. mojavensis isolates displayed positive effect on PAHs dissipation and can be effective cleanup technology with high performance. PMID- 28638623 TI - The genetic architecture of growth traits in Salix matsudana under salt stress. AB - Willow (Salix) is one of the most important ornamental tree species in landscape plants. One species, Salix matsudana, is widely used as a shade tree and border tree because of its soft branches and plump crown. Some varieties of S. matsudana were salt tolerant and could grow normally in coastal regions. However, the molecular mechanisms of salt tolerance for S. matsudana have been less clear. Here, we addressed this issue by performing a mapping experiment containing 195 intraspecific F1 progeny of S. matsudana, derived from salt-sensitive 'yanjiang' and salt-tolerant '9901', grown by cuttings in a 100 mM NaCl solution. Growth performance of these progeny under salt stress was investigated, displaying marked genotypic variability with the coefficients of variance of 28.64-86.11% in shoot and root growth traits. We further mapped specific QTLs contributing to these differences to the Salix genome. Of the 204 QTLs identified, a few were detected to explain a remarkably larger portion of the phenotypic variation than many others. Many detected QTLs were found to reside in the region of candidate genes of known biological function. The discovery of growth QTLs expressed under salt stress provides important information for marker-assisted breeding of salt tolerant Salix varieties and founds the basis for the application of S. matsudana in coastal afforestation. PMID- 28638624 TI - Kikuchi-Fujimoto disease: a case report of a multi-drug resistant, grueling disease. AB - Histiocytic necrotizing lymphadenitis or Kikuchi-Fujimoto disease (KFD) is characterized by its rare occurrence. Mostly prevalent among Asian women, KFD manifests with lymphadenopathy-affecting mostly cervical and rarely generalized or retroperitoneal regions-in addition to fever. It is a self-limited disease that resolves within 1-4 months, responding remarkably to glucocorticosteroids or hydroxychloroquine. However, some rare cases prove to be unresponsive to the previously mentioned therapies. Here is a description of a case of KFD affecting a 67-year-old Syrian woman with a history of hypothyroidism due to iodine deficiency. The patient's initial clinical picture was malaise, fever, pericarditis and generalized lymphadenopathy. As treatment, she was given glucocorticosteroids with no significant response, while hydroxychloroquine proved to be partially effective. Until the date of this report, she has been receiving hydroxychloroquine with only slight clinical improvement. This case is proving to be resistant unlike most KFD cases that generally respond very well to treatment. PMID- 28638625 TI - Early eculizumab use in atypical haemolytic uraemic syndrome in a Jehovah's Witness refusing blood products. AB - Thrombotic microangiopathy (TMA) is characterized by microscopic angiopathic haemolytic anaemia, thrombocytopenia and organ injury. Supportive therapies include the use of blood products. Recently the terminal complement inhibitor eculizumab has been approved in atypical haemolytic uraemic syndrome (aHUS) in some countries. We report the case of a 23-year-old female Jehovah's Witness presenting with vaginal haemorrhage from thrombocytopaenia, severe anaemia (nadir Hb 28 g/L) and anuric acute kidney injury with TMA secondary to aHUS. Despite a life threatening illness, the patient declined the use of blood components and plasma exchange. Eculizumab was administered early with subsequent improvement and resolution of haemolysis, return to baseline renal function whilst avoiding use of blood products. This case demonstrates the effective use of eculizumab for life saving therapy in a patient refusing blood products. It highlights the importance of accessibility for high cost therapies, but the disparity in access between healthcare systems. PMID- 28638626 TI - Effects of liposomal-curcumin on five opportunistic bacterial strains found in the equine hindgut - preliminary study. AB - BACKGROUND: The horse intestinal tract is sensitive and contains a highly complex microbial population. A shift in the microbial population can lead to various issues such as inflammation and colic. The use of nutraceuticals in the equine industry is on the rise and curcumin is thought to possess antimicrobial properties that may help to minimize the proliferation of opportunistic bacteria. METHODS: Four cecally-cannulated horses were utilized to determine the optimal dose of liposomal-curcumin (LIPC) on reducing Streptococcus bovis/equinus complex (SBEC), Escherichia coli K-12, Escherichia coli general, Clostridium difficile, and Clostridium perfringens in the equine hindgut without adversely affecting cecal characteristics. In the first study cecal fluid was collected from each horse and composited for an in vitro, 24 h batch culture to examine LIPC at four different dosages (15, 20, 25, and 30 g) in a completely randomized design. A subsequent in vivo 4 * 4 Latin square design study was conducted to evaluate no LIPC (control, CON) or LIPC dosed at 15, 25, and 35 g per day (dosages determined from in vitro results) for 9 days on the efficacy of LIPC on selected bacterial strains, pH, and volatile fatty acids. Each period was 14 days with 9 d for acclimation and 5 d withdrawal period. RESULTS: In the in vitro study dosage had no effect (P >= 0.42) on Clostridium strains, but as the dose increased SBEC concentrations increased (P = 0.001). Concentrations of the E. coli strain varied with dose. In vivo, LIPC's antimicrobial properties, at 15 g, significantly decreased (P = 0.02) SBEC when compared to 25 and 35 g dosages. C. perfringens decreased linearly (P = 0.03) as LIPC dose increased. Butyrate decreased linearly (P = 0.01) as LIPC dose increased. CONCLUSION: Further studies should be conducted with a longer dosing period to examine the antimicrobial properties of curcumin without adversely affecting cecal characteristics. PMID- 28638628 TI - Multiple sclerosis epidemiology in Latin America: An updated survey. AB - : Novel epidemiological data have appeared in recent years in Latin America (LATAM). The objective of this study was to perform an updated systematic review of the epidemiology of the disease reported in LATAM. METHODS: We conducted a systematic review of published epidemiological articles from January 1995 to December 2016. RESULTS: Incidence data were found in four studies and ranged from 0.3 to 3 annual cases per 100,000 person-years. Prevalence was reported in 13 studies and ranged from 0.83 to 38.2 cases per 100,000 inhabitants. Two studies showed an increase in prevalence and incidence in the last five years in specific regions. CONCLUSION: The study provides updated information on epidemiological features of MS in the region. The frequency reported is lower compared with some European and North American countries; however, due to recent observations, studies including follow-up assessment of prevalence and incidence should be conducted in the region. PMID- 28638627 TI - Environmental factors influencing multiple sclerosis in Latin America. AB - It is generally accepted that autoimmune diseases like multiple sclerosis (MS) arise from complex interactions between genetic susceptibility and environmental factors. Genetic variants confer predisposition to develop MS, but cannot be therapeutically modified. On the other hand, several studies have shown that different lifestyle and environmental factors influence disease development, as well as activity levels and progression. Unlike genetic risk factors, these can be modified, with potential for prevention, particularly in high-risk populations. Most studies identifying particular lifestyle and environmental factors have been carried out in Caucasian patients with MS. Little or no data is available on the behavior of these factors in Latin American populations. Ethnic and geographic differences between Latin America and other world regions suggest potential regional variations in MS, at least with respect to some of these factors. Furthermore, particular environmental characteristics observed more frequently in Latin America could explain regional differences in MS prevalence. Site-specific studies exploring influences of local environmental factors are warranted. PMID- 28638629 TI - Pathophysiology of copeptin in kidney disease and hypertension. AB - Copeptin is derived from the cleavage of the precursor of arginine vasopressin (AVP), produced in an equimolar ratio in hypothalamus and processed during axonal transport AVP is an unstable peptide and has a short half-life of 5-20 min. Unlike AVP, copeptin is a stable molecule and can easily be measured. Recent evidence suggest that increased copeptin levels have been associated with worse outcomes in various clinical conditions including chronic kidney disease (CKD) and hypertension. In this review, the data regarding copeptin with kidney function (evaluated as glomerular filtration rate, increased albumin/protein excretion or both) and hypertension with regard to performed studies, prognosis and pathogenesis was summarised. PMID- 28638630 TI - Crystal structure of a pyrazine-2,3-dicarboxamide ligand and of its silver(I) nitrate complex, a three-dimensional coordination polymer. AB - The title ligand, C18H16N6O2.2H2O (L1) [N2,N3-bis-(pyridin-4-ylmeth-yl)pyrazine 2,3-dicarboxamide], crystallized as a dihydrate. The mol-ecule is U-shaped with the carboxamide groups being cis to one another, making a dihedral angle of 81.6 (5) degrees . The terminal pyridine rings are inclined to one another by 58.5 (4) degrees . There is an intra-molecular N-H?Npyrazine hydrogen bond present, forming an S(5) ring motif. In the crystal, adjacent mol-ecules are linked by N H?Ocarboxamide hydrogen bonds, forming a chain along [001]. A chain of hydrogen bonded water mol-ecules is linked to the chain of (L1) mol-ecules by O-H?N hydrogen bonds, forming columns propagating along the c axis. The columns are linked by C-H?O and C-H?N hydrogen bonds, forming a three-dimensional supra molecular structure. The reaction of ligand (L1) with silver(I) nitrate led to the formation of a new three-dimensional coordination polymer, {[Ag(C18H16N6O2)]NO3} n , poly[[[MU4-N2,N3-bis-(pyridin-4-ylmeth-yl)pyrazine-2,3 dicarboxamide]-silver(I)] nitrate] (I). The asymmetric unit is composed of half of one silver ion, located on a twofold rotation axis, half a ligand mol-ecule and half a positionally disordered nitrate anion located about a twofold rotation axis. The full mol-ecule of the ligand is generated by twofold rotational symmetry, with this twofold axis bis-ecting the Car-Car bonds of the pyrazine ring and the Ag-Ag bond. The carboxamide groups are now trans to one another, making a dihedral angle of 65.8 (4) degrees . The two terminal pyridine rings are inclined to one another by 6.6 (3) degrees . Two ligands wrap around an Ag-Ag bond of 3.1638 (11) A, forming a figure-of-eight-shaped complex mol-ecule. Each silver ion is coordinated by two pyridine N atoms and by two carboxamide O atoms of neighbouring mol-ecules, hence forming a three-dimensional framework. The nitrate anion is linked to the framework by N-H?O and C-H?O hydrogen bonds. PMID- 28638631 TI - Crystal structures of three N-(3-acetyl-phen-yl)quinoline-2-carboxamides. AB - In the title compounds, N-(5-acetyl-2-methyl-phen-yl)quinoline-2-carboxamide [C19H16N2O2, (I)], N-(5-acetyl-2-bromo-phen-yl)quinoline-2-carboxamide [C18H13BrN2O2, (II)] and N-(5-acetyl-2-ethynylphen-yl)quinoline-2-carboxamide [C20H14N2O2, (III)], the quinoline ring system is essentially planar and forms a dihedral angles of 3.68 (5) (I), 5.59 (7) (II) and 1.87 (6) degrees (III) with the acetyl-substituted ring. The mol-ecular structures of (I) and (III) each feature an intra-molecular N-H?N hydrogen bond, forming an S(5) ring, while in (II) an intra-molecular bifurcated N-H?(N,Br) hydrogen bond forms two S(5) rings. In the crystals, weak C-H?O hydrogen bonds link mol-ecules of (I) into C(7) chains long [010], mol-ecules of (II) into chains of R22(8) rings along [110] and mol-ecules of (III) into C(8) chains along [010]. In (I), there are no significant pi-pi stacking inter-actions under 4 A, but in both (II) and (III), pi-pi inter-actions link the weak hydrogen-bonded chains into layers parallel to (001) [centroid-centroid disttances of 3.748 (1) A in (II) and 3.577 (1), 3.784 (1) and 3.780 (1) A in (III)]. PMID- 28638632 TI - Crystal structure of di-MU-chlorido-bis-(chlorido-{N1,N1-diethyl-N4-[(pyridin-2 yl-kappaN)methyl-idene]benzene-1,4-di-amine-kappaN4}mercury(II)). AB - The title dinuclear mercury(II) complex, [Hg2Cl4(C16H19N3)2], synthesized from the pyridine-derived Schiff base (E)-N1,N1-diethyl-N4-[(pyridin-2-yl)methyl idene]benzene-1,4-di-amine (DPMBD), has inversion symmetry. The five-coordinated HgII atoms have distorted square-pyramidal stereochemistry comprising two N-atom donors from bidentate chelate BPMBD ligands and three Cl-atom donors, two bridging and one monodentate. The dihedral angle between the benzene and the pyridine rings in the BPMBD ligand is 7.55 (4) degrees . In the crystal, the dinuclear mol-ecules are linked by weak C-H?Cl hydrogen bonds, forming zigzag ribbons lying parallel to [001]. Also present in the structure are pi-pi inter actions between benzene and pyridine rings [minimum ring-centroid separation = 3.698 (8) A]. PMID- 28638633 TI - 1,3-Bis{(E)-[4-(di-methyl-amino)-benzyl-idene]amino}-propan-2-ol: chain structure formation via an O-H?N hydrogen bond. AB - The asymmetric unit of the title compound, C21H28N4O, consists of two unique mol ecules linked by an O-H?N hydrogen bond. The conformation of both C=N bonds is E and the azomethine functional groups lie close to the plane of their associated benzene rings in each of the independent mol-ecules. The dihedral angles between the two benzene rings are 83.14 (4) and 75.45 (4) degrees . The plane of the one of the N(CH3)2 units is twisted away from the benzene ring by 18.8 (2) degrees , indicating loss of conjugation between the lone electron pair and the benzene ring. In the crystal structure, O-H?N hydrogen bonds together with C-H?O hydrogen bonds link neighbouring supra-molecular dimers into a three-dimensional network. PMID- 28638634 TI - Synthesis and crystal structure of a new magnesium phosphate Na3RbMg7(PO4)6. AB - A new magnesium phosphate, Na3RbMg7(PO4)6 [tris-odium rubidium hepta-magnesium hexakis(ortho-phosphate)], has been synthesized as single crystals by the flux method and exhibits a new structure type. Its original structure is built up from MgO x (x = 5 and 6) polyhedra linked directly to each other through common corners or edges and reinforced by corner-sharing with PO4 tetra-hedra. The resulting anionic three-dimensional framework leads to the formation of channels along the [010] direction, in which the Na+ cations are located, while the Rb+ cations are located in large inter-stitial cavities. PMID- 28638635 TI - Crystal structure of an apremilast ethanol hemisolvate hemihydrate solvatomorph. AB - The title compound, C22H24N2O7S.0.5C2H5OH.0.5H2O {systematic name: (S)-4 acetamido-2-[1-(3-eth-oxy-4-meth-oxy-phen-yl)-2-(methyl-sulfon-yl)eth-yl]iso-indo line-1,3-dione ethanol hemisolvate hemihydrate}, is a novel solvatomorph of apremilast (AP), which is an inhibitor of phosphodiesterase 4 (PDE4) and is indicated for the treatment of adult patients with active psoriatic arthritis. The asymmetric unit contains one mol-ecule of AP and disordered mol-ecules of ethanol and water, both with half occupancy. The dihedral angle between the planes of the phenyl ring and the iso-indole ring is 67.9 (2) degrees . Extensive intra- and inter-molecular hydrogen bonds help to stabilize the mol-ecular conformation and sustain the crystal packing. PMID- 28638636 TI - Crystal structure and electrochemical properties of [Ni(bztmpen)(CH3CN)](BF4)2 {bztmpen is N-benzyl-N,N',N'-tris-[(6-methyl-pyridin-2-yl)meth-yl]ethane-1,2-di amine}. AB - The mononuclear nickel title complex (acetonitrile-kappaN){N-benzyl-N,N',N'-tris [(6-methyl-pyridin-2-yl)meth-yl]ethane-1,2-di-amine}-nickel(II) bis-(tetra-fluor ido-borate), [Ni(C30H35N5)(CH3CN)](BF4)2, was prepared from the reaction of Ni(BF4)2.6H2O with N-benzyl-N,N',N'-tris-[(6-methyl-pyridin-2-yl)meth-yl]ethane 1,2-di-amine (bztmpen) in aceto-nitrile at room temperature. With an open site occupied by the aceto-nitrile mol-ecule, the nickel(II) atom is chelated by five N-atom sites from the ligand and one N atom from the ligand, showing an overall octa-hedral coordination environment. Compared with analogues where the 6-methyl substituent is absent, the bond length around the Ni2+ cation are evidently longer. Upon reductive dissociation of the acetro-nitrile mol-ecule, the title complex has an open site for a catalytic reaction. The title complex has two redox couples at -1.50 and -1.80 V (versus Fc+/0) based on nickel. The F atoms of the two BF4- counter-anions are split into two groups and the occupancy ratios refined to 0.611 (18):0.389 (18) and 0.71 (2):0.29 (2). PMID- 28638637 TI - Crystal structure of chlorido-[1-(4-nitro-phen-yl)thio-urea-kappaS]bis-(tri phenyl-phosphane-kappaP)silver(I). AB - In the title compound, [AgCl(C7H7N3O2S)(C18H15P)2], the AgI ion is in a distorted tetra-hedral coordination environment formed by P atoms from two tri-phenyl phosphane ligands, one terminal S atom from the 1-(4-nitro-phen-yl)thio-urea ligand and a chloride ion. In the crystal, bifurcated (N-H)2?Cl hydrogen bonds [with graph-set motif R21(6)] connect complex mol-ecules, forming zigzag chains along [001]. These chains are linked via weak C-H?O hydrogen bonds, forming a two dimensional network parallel to (100). An intra-molecular N-H?Cl hydrogen bond forming an S(6) ring is also observed. PMID- 28638638 TI - Crystal structure of 2,2'-(ethane-1,2-di-yl)bis-(2,3-di-hydro-1H-naphtho-[1,2 e][1,3]oxazine): a prospective raw material for polybenzoxazines. AB - In the title compound, C26H24N2O2, the oxazine moiety is fused to a naphthalene ring system. The asymmetric unit consists of one half of the mol-ecule, which lies about an inversion centre. The C atoms of the ethyl-ene spacer group adopt an anti-periplanar arrangement. The oxazine ring adopts a half-chair conformation. In the crystal, supra-molecular chains running along the b axis are formed via short C-H?pi contacts. The crystal studied was a non-merohedral twin with a fractional contribution of 0.168 (2) of the minor twin component. PMID- 28638639 TI - Crystal structure of a heterometallic coordination polymer: poly[di-aqua-bis-(MU7 benzene-1,3,5-tri-carboxyl-ato)dicalcium(II)copper(II)]. AB - In the title complex, [Ca2Cu(C9H3O6)2(H2O)2] n , the CaII and CuII cations are bridged by the benzene-1,3,5-tri-carboxyl-ate anions (BTC3-) to form the coordination polymer, in which each BTC3- anion bridges two CuII and five CaII cations with a MU7 coordination mode. The CuII cation, located at an inversion centre, is in a nearly square-planar geometry defined by four O atoms from four bridging BTC3- anions, while the CaII cation is in a distorted octa-hedral geometry defined by five O atoms from bridging BTC3- anions and one water mol ecule. O-H?O hydrogen bonds between coordinating water mol-ecules and carboxyl groups further stabilize the structure; pi-pi stacking is also observed between parallel benzene rings, the centroid-to-centroid distance being 3.357 (2) A. PMID- 28638640 TI - Crystal structure of N,N'-di-decyl-pyromellitic di-imide. AB - The title compound, C30H44N2O4 [systematic name: 2,6-di-decyl-pyrrolo-[3,4-f]iso indole-1,3,5,7(2H,6H)-tetra-one], consists of a central pyromellitic di-imide moiety with terminal decyl groups at the N-atom positions. The centre of the mol ecule lies on a crystallographic inversion centre so the asymmetric unit contains one half-mol-ecule. The mol-ecule exhibits a rod-shaped conformation, like other similar compounds of this type, the distance between the ends of terminal decyl groups being 32.45 A. The packing is dominated by a lamellar arrangement of the mol-ecules, which is reinforced by C-H?O hydrogen bonds and C-O?pi inter-actions, forming a classic herringbone structure. The mol-ecular structure is consistent with the theoretical calculations performed by density functional theory (DFT). PMID- 28638641 TI - Secondary bonding in di-methyl-bis-(morpholine-4-carbodi-thio-ato kappa2S,S')tin(IV): crystal structure and Hirshfeld surface analysis. AB - The title compound, [Sn(CH3)2(C5H8NOS2)2], has the SnIV atom bound by two methyl groups which lie over the weaker Sn-S bonds formed by two asymmetrically chelating di-thio-carbamate ligands so that the coordination geometry is skew trapezoidal bipyramidal. The most prominent feature of the mol-ecular packing are secondary Sn?S inter-actions [Sn?S = 3.5654 (7) A] that lead to centrosymmetric dimers. These are connected into a three-dimensional architecture via methyl-ene C-H?S and methyl-C-H?O(morpholino) inter-actions. The Sn?S inter-actions are clearly evident in the Hirshfeld surface analysis of the title compound along with a number of other inter-molecular contacts. PMID- 28638642 TI - Crystal structure of phenyl N-(3,5-di-methyl-phenyl)carbamate. AB - The asymmetric unit of the title compound, C15H15NO2, contains two independent mol-ecules (A and B). The di-methyl-phenyl ring, the phenyl ring and the central carbamate N-C(=O)-O group are not coplanar. In mol-ecule A, the di-methyl-phenyl and phenyl rings are inclined to the carbamate group mean plane by 27.71 (13) and 71.70 (4) degrees , respectively, and to one another by 84.53 (13) degrees . The corresponding dihedral angles in mol-ecule B are 34.33 (11), 66.32 (13) and 85.48 (12) degrees , respectively. In the crystal, the A and B mol-ecules are arranged alternately linked through N-H?O(carbon-yl) hydrogen bonds, forming -A-B-A-B- chains, which extend along [100]. Within the chains and linking neighbouring chains there are C-H?pi inter-actions present, forming columns along the a-axis direction. The columns are linked by offset pi-pi stacking inter-actions, forming a three-dimensional network [shortest centroid-centroid distance = 3.606 (1) A]. PMID- 28638643 TI - Crystal structure of dilead(II) oxochromate(VI) oxotellurate(IV). AB - Reaction of chromium(III) precursors with TeO2 in PbF2/PbO melts in air led to oxidation of chromium(III) to chromium(VI), whereas tellurium remained its oxidation state of IV. In the resulting title compound, Pb2(CrO4)(TeO3), the two types of anions are isolated from each other, hence a double salt is formed. The two independent Pb2+ cations exhibit coordination number nine under formation of very distorted coordination polyhedra [bond-length range = 2.363 (6)-3.276 (7) A]. The oxochromate(VI) and oxotellurate(IV) anions have tetra-hedral and trigonal-pyramidal configurations, respectively. In the crystal structure, (001) layers of metal cations alternate with layers of TeO32- and CrO42- anions along [001], forming a three-dimensional framework structure. Pb2(CrO4)(TeO3) is isotypic with its sulfate analogue Pb2(SO4)(TeO3) and is comparatively discussed. PMID- 28638644 TI - Crystal structure of 3-amino-pyridinium 1'-carb-oxy-ferrocene-1-carboxyl-ate. AB - The structure of the title salt, (C5H7N2)[Fe(C6H4O2)(C6H5O2)], consists of 3 amino-pyridinium cations and 1'-carb-oxy-ferrocene-1-carboxyl-ate monoanions. The ferrocenyl moiety of the anion adopts a typical sandwich structure, with Fe-C distances in the range 2.0270 (15)-2.0568 (17) A. The anion possesses an eclipsed conformation, with the torsion angle phi (Csubst-Cpcent-Cpcent- Csubst) equal to 66.0 degrees . The conformations of other 1'-carb-oxy-ferrocene-1-carboxyl-ate monoanions are compared and analyzed on the basis of literature data. PMID- 28638645 TI - A new example of intra-molecular C-H?Ni anagostic inter-actions: synthesis, crystal structure and Hirshfeld analysis of cis-bis-[4-methyl-2-(1,2,3,4-tetra hydro-naphthalen-1-yl-idene)hydrazinecarbo-thio-amidato-kappa2N1,S]nickel(II) di methyl-formamide monosolvate. AB - The reaction of NiII acetate tetra-hydrate with 4-methyl-2-(1,2,3,4-tetra-hydro naphthalen-1-yl-idene)hydrazinecarbo-thio-amide in a 2:1 molar ratio and recrystallization from di-methyl-formamide yielded the title compound, [Ni(C12H14N3S)2].C3H7NO. The ligands act as monoanionic kappa2N1,S-donors, forming five-membered metallarings. The NiII ion is fourfold coordinated in a distorted square-planar cis-configuration, which is rather uncommon for mono-thio semicarbazone complexes. Intra-molecular H?Ni trans-inter-actions are observed [H?Ni distances are 2.50 and 2.57 A] and thus anagostic inter-actions can be suggested. The Hirshfeld surface analysis indicates that the major contributions for the crystal packing are H?H (66.6%), H?S (12.3%) and H?C (10.9%) inter actions. In the crystal, the complex mol-ecules are linked by di-methyl-formamide solvent mol-ecules through N-H?O inter-actions into one-dimensional hydrogen bonded polymers along [010]. PMID- 28638646 TI - Crystal structure of 4,4'-bis-[3-(piperidin-1-yl)prop-1-yn-1-yl]-1,1'-biphen-yl. AB - The title compound, C28H32N2, (I), is one of a second generation of compounds designed and synthesized based on a very potent and selective alpha9alpha10 nicotinic acetyl-choline receptor antagonist ZZ161C {1,1'-[[1,1'-biphen-yl]-4,4' diylbis(prop-2-yne-3,1-di-yl)]bis-(3,4-di-methyl-pyridin-1-ium) bromide}, which has shown analgesic effects in a chemotherapy-induced neuropathy animal model. Compound (I) was synthesized by the reaction of 4,4'-bis-(3-bromo-prop-1-yn-1-yl) 1,1'-biphenyl with piperidine at room temperature in aceto-nitrile. The single crystal used for X-ray analysis was obtained by dissolving (I) in a mixture of di chloro-methane and methanol, followed by slow evaporation of the solvent. In the crystal of (I), the biphenyl moiety has a twisted conformation, with a dihedral angle of 25.93 (4) degrees between the benzene rings. Both piperidine head groups in (I) are in the chair conformation and are oriented so that the N-atom lone pairs of each piperidine group point away from the central biphenyl moiety. PMID- 28638647 TI - Crystal structure of (3S*,4R*)-4-fluoro-3-(4-meth-oxy-phen-yl)-1-oxo-2-phenyl 1,2,3,4-tetra-hydro-iso-quinoline-4-carb-oxy-lic acid. AB - The title compound, C23H18FNO4, crystallized as a racemate. It exhibits a cis conformation with respect to the F atom and the methine H atom. The piperidine ring has a screw-boat conformation. The meth-oxy-phenyl ring and the phenyl ring are inclined to the mean plane of the iso-quinoline ring system by 89.85 (4) and 46.62 (5) degrees , respectively, and by 78.15 (5) degrees to one another. In the crystal, mol-ecules are linked by an O-H?O hydrogen bond forming chains propagating along the a-axis direction. The chains are linked by C-H?F hydrogen bonds, forming layers lying parallel to the ab plane. PMID- 28638648 TI - An infinite two-dimensional hybrid water-chloride network in a 4'-(furan-2-yl) 2,2':6',2''-terpyridine nickel(II) matrix. AB - A new complex, namely bis-[4'-(furan-2-yl)-2,2':6',2''-terpyridine]-nickel(II) dichloride deca-hydrate, [Ni(C19H13N3O)2]Cl2.10H2O, has been crystallized by solvent evaporation and characterized by single-crystal X-ray diffraction. The coordination environment of the NiII cation is distorted octa-hedral with slight deviations from an idealized geometry. The most intriguing structural feature is an infinite two-dimensional hybrid water-chloride network parallel to (011) constructed by O-H?O and O-H?Cl hydrogen bonds involving two independent chloride ions and ten independent solvent water mol-ecules with an l-shaped pattern. One of the furyl rings is disordered with a refined occupancy ratio of 0.786 (13):0.214 (13). PMID- 28638649 TI - Crystal structure of 5-chloro-N1-(5-phenyl-1H-pyrazol-3-yl)benzene-1,2-di-amine. AB - The title compound, C15H13ClN4, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit, which are far from planar as a result of steric repulsion between the rings. The benzene and phenyl rings are inclined to the central pyrazole ring by 46.64 (10) and 17.87 (10) degrees in mol-ecule A, and by 40.02 (10) and 14.18 (10) degrees in mol-ecule B. The aromatic rings are inclined to one another by 58.77 (9) degrees in mol-ecule A, and 36.95 (8) degrees in mol-ecule B. In the crystal, the A and B mol-ecules are linked by two pairs of N-H?N hydrogen bonds forming A-B dimers. These are further linked by a fifth N-H?N hydrogen bond, forming tetra-mer-like units that stack along the a axis direction, forming columns, which are in turn linked by C-H?pi inter actions, forming layers parallel to the ac plane. PMID- 28638651 TI - A metastable polymorphic form of the anti-fungal anilino-pyrimidine active pyrimethanil. AB - A second metastable form of the title compound, C12H13N3 (systematic name: 4,6 dimethyl-N-phenyl-pyrimidin-2-amine), was isolated from an attempted co crystallization experiment with meso-erythriol in dimethyl sulfoxide (DMSO). The crystals of form 2 at 120 K are monoclinic, space group P21/n with Z' = 4 compared to the previously reported triclinic form with Z' = 2 [Sun et al. (2011 ?). Acta Chim. Sin.69, 1909-1914]. The four independent mol-ecules in the asymmetric unit form two discrete dimeric units through a concerted pair of N-H?N hydrogen bonds with a graph-set notation of R22(8). The origin of the polymorphic behaviour is revealed in that the conformation of each dimer present in the asymmetric unit of the structure is unique and determined by the rotation of the second mol-ecule in the dimer with respect to the first. PMID- 28638650 TI - Synthesis and crystal structures of three new benzotriazolylpropanamides. AB - The base-catalyzed Michael addition of 2-methyl-acryl-amide to benzotriazole afforded 3-(1H-benzotriazol-1-yl)-2-methyl-propanamide, C10H12N4O (1), in 32% yield in addition to small amounts of isomeric 3-(2H-benzotriazol-2-yl)-2-methyl propanamide, C10H12N4O (2). In a similar manner, 3-(1H-benzotriazol-1-yl)-N,N-di methyl-propanamide, C11H14N4O (3), was prepared from benzotriazole and N,N-di methyl-acryl-amide. All three products have been structurally characterized by single-crystal X-ray diffraction. The crystal structures of 1 and 2 comprise infinite arrays formed by N-H?O and N-H?N bridges, as well as pi-pi inter actions, while the mol-ecules of 3 are aggregated to simple pi-dimers in the crystal. PMID- 28638652 TI - Crystal structure of a silver-, cobalt- and iron-based phosphate with an alluaudite-like structure: Ag1.655Co1.64Fe1.36(PO4)3. AB - The new silver-, cobalt- and iron-based phosphate, silver cobalt iron tris(ortho phosphate), Ag1.655Co1.64Fe1.36(PO4)3, was synthesized by solid-state reactions. Its structure is isotypic to that of Na2Co2Fe(PO4)3, and belongs to the alluaudite family, with a partial cationic disorder, the AgI atoms being located on an inversion centre and twofold rotation axis sites (Wyckoff positions 4a and 4e), with partial occupancies of 0.885 (2) and 0.7688 (19), respectively. One of the two P atoms in the asymmetric unit completely fills one 4e site while the Co and Fe atoms fill another 4e site, with partial occupancies of 0.86 (5) and 0.14 (5), respectively. The remaining Co2+ and Fe3+ cations are distributed on a general position, 8f, in a 0.39 (4):0.61 (4) ratio. All O atoms and the other P atoms are in general positions. The structure is built up from zigzag chains of edge-sharing [MO6] (M = Fe/Co) octa-hedra stacked parallel to [101]. These chains are linked together through PO4 tetra-hedra, forming polyhedral sheets perpendicular to [010]. The resulting framework displays two types of channels running along [001], in which the AgI atoms (coordination number eight) are located. PMID- 28638653 TI - Crystal structure of calcium dinickel(II) iron(III) tris-(orthophosphate): CaNi2Fe(PO4)3. AB - The title compound, CaNi2Fe(PO4)3, was synthesized by solid-state reactions. Its structure is closely related to that of alpha-CrPO4 in the space group Imma. Except for two O atoms in general positions, all atoms are located in special positions. The three-dimensional framework is built up from two types of sheets extending parallel to (100). The first sheet is made up from two edge-sharing [NiO6] octa-hedra, leading to the formation of [Ni2O10] double octa-hedra that are connected to two PO4 tetra-hedra through a common edge and corners. The second sheet results from rows of corner-sharing [FeO6] octa-hedra and PO4 tetra hedra forming an infinite linear chain. These layers are linked together through common corners of PO4 tetra-hedra and [FeO6] octa-hedra, resulting in an open three-dimensional framework that delimits two types of channels parallel to [100] and [010] in which the eightfold-coordinated CaII cations are located. PMID- 28638654 TI - Three closely related (2E,2'E)-3,3'-(1,4-phenyl-ene)bis-[1-(meth-oxy-phen-yl)prop 2-en-1-ones]: supra-molecular assemblies in one dimension mediated by hydrogen bonding and C-H?pi inter-actions. AB - In the title compounds, (2E,2'E)-3,3'-(1,4-phenyl-ene)bis-[1-(2-meth-oxy-phen yl)prop-2-en-1-one], C26H22O4 (I), (2E,2'E)-3,3'-(1,4-phenyl-ene)bis-[1-(3-meth oxy-phen-yl)prop-2-en-1-one], C26H22O4 (II) and (2E,2'E)-3,3'-(1,4-phenyl-ene)bis [1-(3,4-di-meth-oxy-phen-yl)prop-2-en-1-one], C28H26O6 (III), the asymmetric unit consists of a half-mol-ecule, completed by crystallographic inversion symmetry. The dihedral angles between the central and terminal benzene rings are 56.98 (8), 7.74 (7) and 7.73 (7) degrees for (I), (II) and (III), respectively. In the crystal of (I), mol-ecules are linked by pairs of C-H?pi inter-actions into chains running parallel to [101]. The packing for (II) and (III), features inversion dimers linked by pairs of C-H?O hydrogen bonds, forming R22(16) and R22(14) ring motifs, respectively, as parts of [201] and [101] chains, respectively. PMID- 28638655 TI - Crystal structure of N-(4-oxo-2-sulfanyl-idene-1,3-thia-zolidin-3-yl)-2-(thio phen-3-yl)acetamide. AB - The title compound, C9H8N2O2S3, crystallizes with two mol-ecules (A and B) in the asymmetric unit. Both have similar conformations (overlay r.m.s. deviation = 0.209 A) and are linked by an N-H?O hydrogen bond. In both mol-ecules, the thio phene rings show orientational disorder, with occupancy factors of 0.6727 (17) and 0.3273 (17) for mol-ecule A, and 0.7916 (19) and 0.2084 (19) for mol-ecule B. The five-membered rings make an angle of 79.7 (2) degrees in mol-ecule A and an angle of 66.8 (2) degrees in mol-ecule B. In the crystal, chains of mol-ecules running along the a-axis direction are linked by N-H?O hydrogen bonds. The inter action of adjacent chains through N-H?O hydrogen bonds leads to two types of ring structures containing four mol-ecules and described by the graph-set motifs R44(18) and R42(14). PMID- 28638656 TI - Crystal structure of 2-azido-1,3-bis-(2,6-diiso-propyl-phen-yl)-1,3,2-di-aza phospho-lidine. AB - The title compound, C26H38N5P, was synthesized by reacting 2-chloro-1,3-bis-(2,6 diiso-propyl-phen-yl)-1,3,2-di-aza-phospho-lidine with sodium azide and a catalytic amount of lithium chloride in tetra-hydro-furan. The title compound is the first structurally characterized 2-azido-1,3,2-di-aza-phospho-lidine and exhibits a P atom in a trigonal pyramidal geometry. The azide P-N bond length of 1.8547 (16) A is significantly longer than the P-N separations for the chelating di-amine [P-N = 1.6680 (15) and 1.6684 (14) A]. The sterically hindered 2,6-diiso propyl-phenyl groups twist away from the central heterocycle, with dihedral angles between the central heteocyclic ring and benzene rings of 76.17 (10) and 79.74 (9) degrees . In the crystal, a weak C-H?N link to the terminal N atom of the azide group leads to [100] chains. PMID- 28638657 TI - 6-Chloro-1-phenyl-indoline-2,3-dione: absolute structure, non-linear optical and charge-transport properties. AB - In the title compound, C14H8ClNO2, the dihedral angle between the isatin moiety (r.m.s. deviation = 0.014 A) and the phenyl ring is 51.8 (1) degrees . All mol ecules have the same 'frozen chiral' conformation in the non-centrosymmetric P212121 space group. A polycrystalline sample of the title compound exhibits a considerable second-order non-linear optical effect (frequency doubling of 1064 nm light to output 532 nm light). In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, generating chains along the [100] direction. Based on a DFT calculation, [100] proves to be the most favourable direction for charge transport and the title crystal could be used as a hole-transport material because of its high hole mobility. PMID- 28638658 TI - Different intra- and inter-molecular hydrogen-bonding patterns in (3S,4aS,8aS)-2 [(2R,3S)-3-(2,5-X2-benzamido)-2-(2,5-X2-benzo-yloxy)-4-phenyl-butyl]-N-tert butyldeca-hydro-iso-quinoline-3-carboxamides (X = H or Cl): compounds with moderate aspartyl protease inhibition activity. AB - The crystal structures of (3S,4aS,8aS)-2-[(2R,3S)-3-benzamido-2-benzo-yloxy-4 phenyl-but-yl]-N-tert-butyldeca-hydro-iso-quinoline-3-carboxamide, C38H47N3O4, (I), and (3S,4aS,8aS)-2-[(2R,3S)-3-(2,5-di-chloro-benzamido)-2-(2,5-di-chloro benzo-yloxy)-4-phenyl-but-yl]-N-tert-butyldeca-hydro-iso-quinoline-3-carboxamide, C38H43Cl4N3O4, (II), are described. Despite their chemical similarity, they adopt different conformations in the solid state: (I) features a bifurcated intra molecular N-H?(N,O) hydrogen bond from the tert-butylamide NH group to the piperidine N atom and the benzoate O atom, whereas (II) has an intra-molecular N H?O link from the benzamide NH group to the tert-butyl-amide O atom. In the crystal of (I), mol-ecules are linked by C(4) amide N-H?O hydrogen bonds into chains propagating in the [010] direction, with both donor and acceptor parts of the benzamide group. In the extended structure of (II), C(11) N-H?O chains propagating in the [010] direction arise, with the donor being the tert butylamide NH group and the acceptor being the O atom of the benzamide group. PMID- 28638659 TI - 2-[(4-Chloro-phen-yl)selan-yl]-3,4-di-hydro-2H-benzo[h]chromene-5,6-dione: crystal structure and Hirshfeld analysis. AB - The title organoselenium compound, C19H13ClO3Se {systematic name: 2-[(4-chloro phen-yl)selan-yl]-2H,3H,4H,5H,6H-naphtho-[1,2-b]pyran-5,6-dione}, has the substituted 2-pyranyl ring in a half-chair conformation with the methyl-ene-C atom bound to the methine-C atom being the flap atom. The dihedral angle between the two aromatic regions of the mol-ecule is 9.96 (9) degrees and indicates a step-like conformation. An intra-molecular Se?O inter-action of 2.8122 (13) A is noted. In the crystal, pi-pi contacts between naphthyl rings [inter-centroid distance = 3.7213 (12) A] and between naphthyl and chloro-benzene rings [inter centroid distance = 3.7715 (13) A], along with C-Cl?pi(chloro-benzene) contacts, lead to supra-molecular layers parallel to the ab plane, which are connected into a three-dimensional architecture via methyl-ene-C-H?O(carbon-yl) inter-actions. The contributions of these and other weak contacts to the Hirshfeld surface is described. PMID- 28638660 TI - Analysis of Clinical Characteristics of Immune-Related Dry Eye. AB - AIM: To discuss the clinical characteristics of immune-related dry eye. METHODS: Simple dry eye (SDE) group: we selected 224 patients of simple dry eye with no systemic lesions. Immune-related dry eye (IRDE) group: we selected 207 patients of dry eye complicated with immune system diseases, including 70 cases of Sjogren's syndrome (SS), 72 cases of systemic lupus erythematosus (SLE), and 65 cases of rheumatoid arthritis (RA). The classification of all patients was performed. The difference between the two groups was compared, including age, gender, ocular surface fluorescein staining and inflammatory reaction, tear breakup time (TBUT), Shirmer I test, confocal microscopy scan, and dry eye grading. RESULTS: Compared with the SDE group, the patients of IRDE group were younger (P < 0.05). The female patients were significantly more than the male ones (P < 0.05). Corneal staining counts and ocular surface inflammation were significantly increased (P < 0.05). TBUT and Shirmer I test shortened significantly (P < 0.05). Corneal nerve fibers were less, and the number of local lymphocyte was significant increased. The number of dry eye patients in the moderate or above IRDE group was significantly increased (P < 0.05). CONCLUSIONS: The dry eye symptom and sign and ocular surface inflammation of IRDE were significantly more severe than those of the SDE. PMID- 28638661 TI - Efficacy and Tolerability of Tenofovir Disoproxil Fumarate Based Regimen as Compared to Zidovudine Based Regimens: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Although tenofovir (TDF)/emtricitabine (FTC)/efavirenz (EFV) and zidovudine (ZDV)/lamivudine (3TC)/efavirenz (EFV) are used as preferred first line regimen, their head-to-head comparison in terms of their efficacy and tolerability was limited. This review aimed to synthesize the best available evidence on the comparative efficacy and tolerability of the two regimens. METHODS: Seven sites and databases in addition to Google search until August 20, 2016, were searched. Only randomized clinical trials conducted on adult population were included in this study. Our primary outcome was viral load suppression while secondary outcomes were death and tolerability. Undetectable viral load is defined as <50 Human Immunodeficiency Virus (HIV) ribonucleic acid (RNA) copies/ml. Joanna Briggs institute meta-analysis of statistics assessment and review instrument (JBI-MAStARI) and critical appraisal and data extraction tool were applied for critical assessment and data extraction, respectively. We performed a random effect meta-analysis to pool the relative risk (RR) for viral load suppression (<50 HIV RNA copies/ml and <400 HIV RNA copies/ml), tolerability, and death. RESULT: Data was extracted from four articles, which included a total of 2381 participants. We found superior viral load suppression among tenofovir (TDF) arm compared to zidovudine (ZDV) arm. Tenofovir arm achieves viral load <50 HIV RNA copies/ml (RR = 1.12, 95% confidence interval (CI) [1.04, 1.21], I2 = 0%) higher than zidovudine arm. Similarly TDF arm is superior in viral load suppression to <400 HIV RNA copies/ml (RR = 1.19, 95% CI [1.11, 1.27], I2 = 0%). Moreover, TDF based regimens were more likely to be tolerated than ZDV based regimens (4 trials, 2381 participants (RR = 1.06, 95% CI [1.02, 1.10], I2 = 51%)). However, forest plot of death shows that it was not significant (RR = 0.91, 95% CI [0.51, 1.62]). CONCLUSION: The use of TDF/FTC/EFV as first line regimen for naive HIV-1 infected adult patient showed superior viral load suppression and tolerability as compared to ZDV/3TC/EFV. In order to compare the death outcome of both ZDV/3TC/EFV and TDF/FTC/EFV further research is needed. PMID- 28638662 TI - Comparison of DNA Extraction Protocols and Molecular Targets to Diagnose Tuberculous Meningitis. AB - Tuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis. The aims of this study were to evaluate in-house molecular diagnostic protocols of DNA extraction directly from CSF samples and the targets amplified by qPCR as an accurate and fast diagnosis of TBM. One hundred CSF samples from 68 patients suspected of TBM were studied. Four DNA extraction techniques (phenol-chloroform thiocyanate guanidine, silica thiocyanate guanidine, resin, and resin with ethanol) were compared and CSF samples were used to determine the best target (IS6110, MPB64, and hsp65 KDa) by qPCR. The extraction protocol using the phenol chloroform-thiocyanate guanidine showed the best results in terms of quantification and sensitivity of PCR amplification, presenting up to 10 times more DNA than the second best protocol, the silica guanidine thiocyanate. The target that showed the best result for TBM diagnosis was the IS6110. This target showed 91% sensitivity and 97% specificity when we analyzed the results by sample and showed 100% sensitivity and 98% specificity when we analyzed the results by patient. The DNA extraction with phenol-chloroform-thiocyanate guanidine followed by IS6110 target amplification has been shown to be suitable for diagnosis of TBM in our clinical setting. PMID- 28638663 TI - Acute Abdominal Compartment Syndrome following Extraperitoneal Bladder Perforation. AB - Extraperitoneal bladder perforation is a known complication of a commonly performed rigid cystoscopy. If unrecognized, this complication can lead to continuous intra-abdominal fluid leakage with consequent organ function impairment and symptoms. This is the first case report in literature of a transurethral bladder perforation causing an acute abdominal compartment syndrome, which was subsequently managed conservatively with supportive management only. Case Presentation. We describe a clinical course of a 73-year old Caucasian female whose initial acute presentation involved urinary symptoms. Surgery and general anaesthesia during rigid cystoscopy were complicated by an initially unrecognized extraperitoneal bladder perforation, resulting in fluid extravasation. This extravasation resulted in transurethral bladder resection syndrome with acute intra-abdominal free fluid accumulation. This complication caused acute abdominal compartment syndrome resulting in respiratory end-organ compromise and immediate postextubation respiratory failure. Patient required an emergency reintubation. During the management, diagnosis was considered through the use of the point of care abdominal ultrasound. Postoperatively, patient was managed conservatively in intensive care. Postoperative course included an approximate nine liters of urinary diuresis and supportive ventilation for four days. Conclusion. There is equipoise in the clinical management of abdominal compartment syndrome with regard to supportive medical management alone or invasive surgical treatment. PMID- 28638664 TI - Torsade de Pointes Induced by Hypokalemia from Imipenem and Piperacillin. AB - Imipenem-cilastatin and piperacillin-tazobactam are two antibiotics with broad antimicrobial coverage. Besides the many well established adverse effects of these drugs, there have been few case reports of hypokalemia. Here we present an interesting case of resistant hypokalemia caused by these drugs leading to Torsades de Pointes which has never been reported in the past. Hypokalemia resolved with discontinuation of piperacillin. PMID- 28638665 TI - A Rare Case of Septic Shock Secondary to Emphysematous Hepatitis. AB - OBJECTIVE: To describe a case of emphysematous hepatitis which is a rare clinical entity, characterized by a fatal, rapidly progressive infection of the liver with a radiological appearance simulating emphysematous pyelonephritis and to help provide more data about the causative organisms and precipitating factors of this pathology. DATA SOURCES AND SYNTHESIS: Relevant literature was reviewed and, to the best of our knowledge, there is limited data regarding the pathogenesis, causative organisms, and management of this condition. CONCLUSION: Emphysematous hepatitis is a rapidly progressive infection that can be fatal in the absence of appropriate therapeutic intervention. Initial clinical manifestations are usually subtle and thus high clinical suspicion is required for early diagnosis and management of this condition to help decrease the mortality rates. PMID- 28638667 TI - The Semantics of Priapism and the First Sign of Chronic Myeloid Leukemia. AB - Priapism is defined as an erection that persists beyond four hours, lasting beyond or unrelated to sexual stimulation (Salonia et al., 2014). Because the risk of ischemic damage and impotence is high with priapism (35%), management guidelines are directed towards rapid treatment of this condition (Salonia et al., 2014). This report describes the rare case of an 18-year-old male who presented to the Emergency Department (ED) three times with recurrent and worsening episodes of sustained penile erections. On the patient's third visit, he presented with priapism of greater than six-hour duration that was found to be the result of chronic myeloid leukemia. Clinician awareness of the diagnostic semantics and differential diagnosis surrounding priapism is pivotal in its urgent management. PMID- 28638666 TI - Osteoma Cutis of the Face in CBCT Images. AB - Osteoma cutis (OC) is a rare benign disorder where osseous nodules form in the reticular layer of normal skin. These nodules are formed by the deposition of lamellar bone and are characterized by osteocytes in the core and osteoclasts around the periphery. Interpretation of osteoma cutis cases has always been challenging especially using conventional two-dimensional (2D) radiographs, owing to difficulty in localization. Cone beam CT (CBCT), with its three-dimensional (3D) capabilities, offers a great tool to help detect and diagnose these calcific entities. We report a case of miliary type OC incidentally detected in the maxillofacial region using CBCT imaging. PMID- 28638668 TI - Severe Short Stature in an Adolescent Male with Prader-Willi Syndrome and Congenital Adrenal Hyperplasia: A Therapeutic Conundrum. AB - Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in excess androgen production which can lead to early epiphyseal fusion and short stature. Prader-Willi syndrome (PWS) is a genetic disorder resulting from a defect on chromosome 15 due to paternal deletion, maternal uniparental disomy, or imprinting defect. Ninety percent of patients with PWS have short stature. In this article we report a patient with simple-virilizing CAH and PWS who was overtreated with glucocorticoids for CAH and not supplemented with growth hormone for PWS, resulting in a significantly short adult height. PMID- 28638669 TI - External Beam Radiation and Brachytherapy for Prostate Cancer: Is It a Possible Trigger of Large Cell Neuroendocrine Carcinoma of the Urinary Bladder? AB - Neuroendocrine tumors commonly involve the respiratory and gastrointestinal systems. Primary genitourinary neuroendocrine tumors are rare, accounting for less than 1% of all bladder carcinomas. Four histopathologic subtypes have been described. Among those, large cell neuroendocrine carcinoma (LCNEC) is the least common, is more aggressive, and generally presents in an advanced stage with poor prognosis compared to transitional cell bladder carcinoma. There is no standardized treatment regimen because of the rarity of the disease. Herein, we present a case of 72-year-old male patient with previously treated prostate cancer, who received external beam radiation therapy and high dose brachytherapy, presenting with intermittent hematuria. Cystoscopy and transurethral resection of bladder tumor (TURBT) were performed. The histopathology and immunohistochemistry were consistent with large cell neuroendocrine carcinoma (LCNEC). Further studies are required to proof the higher risk of neuroendocrine carcinoma of the bladder in patients treated with external beam radiation therapy and brachytherapy for prostate cancer. PMID- 28638670 TI - Arthroscopic Treatment of 2 Consecutive Cases of Dysplasia Epiphysealis Hemimelica of the Ankle: A 5-Year Follow-Up Report. AB - The dysplasia epiphysealis hemimelica (DEH) is a rare disease of unknown etiology consisting in an abnormal osteocartilaginous growth at the epiphysis, usually hemimelic with histological findings similar to benign osteochondroma. In this case series, we described the results of the arthroscopic treatment of 2 consecutive cases of intra-articular ankle localization of DEH in 2 patients aged 9 and 10 years. The good result obtained, persistent at the 5-year follow-up, leads us to consider the arthroscopic approach as a reliable treatment in patient affected by intra-articular ankle DEH. PMID- 28638671 TI - Prenatal Diagnosis of Atrioventricular Block and QT Interval Prolongation by Fetal Magnetocardiography in a Fetus with Trisomy 18 and SCN5A R1193Q Variant. AB - We report a case of fetal trisomy 18 with SCN5A R1193Q variant that presented with sinus bradycardia, 2 : 1 atrioventricular block (AVB), and QT interval prolongation. These complex arrhythmias were diagnosed by fetal magnetocardiography combined with ultrasound findings. Advanced AVB and ventricular arrhythmias were confirmed after birth. Genetic testing of the baby revealed a SCN5A R1193Q variant, which we considered could account for the various arrhythmias in this case. PMID- 28638672 TI - Response to: Comment on "Failure of the Pipeline Embolization Device in Posterior Communicating Artery Aneurysms Associated with a Fetal Posterior Cerebral Artery". PMID- 28638673 TI - Monitoring of Cellular Changes in the Bone Marrow following PTH(1-34) Treatment of OVX Rats Using a Portable Stray-Field NMR Scanner. AB - Osteoporosis is characterized by reduction in trabecular bone in conjunction with increased marrow cell adiposity. While these changes occur within weeks, monitoring of treatment efficacy as performed by DEXA is sensitive only to long term changes. MRI is sensitive to bone marrow changes but is less affordable. In a recent study, we have shown that a stray-field NMR can monitor bone marrow cellular changes that are related to osteoporosis. Objectives. To demonstrate sensitivity of a low-field tabletop NMR scanner to bone marrow dynamics following hormonal treatment in rats. Methods. Two-month-old female rats (n = 36) were ovariectomized (OVX) and dosed for the ensuing 3 or 5 weeks with 20 mg/kg of PTH(1-34). Hind limbs femurs and tibiae were isolated and underwent ex vivo microradiography and histology and NMR relaxometry at 6 weeks (preventive experiment) and 11 weeks (therapeutic treatment experiment) after OVX. Results. OVX rats developed osteoporotic changes including adipogenic marrow compared to Sham and PTH treated rats. T2 and ADC NMR relaxation coefficients were found to correlate with marrow composition. Conclusions. This study suggests that stray field NMR, an affordable method that is sensitive to the rapid cellular changes in bone marrow, may have a clinical value in monitoring hormonal treatment for osteoporosis. PMID- 28638674 TI - Role of Personality in Behavioral Responses to New Environments in Captive Asiatic Lions (Panthera leo persica). AB - Studying personality in captive animals may enable the development of individual based management decisions, which may improve animal welfare. Asiatic lions at London Zoo represent an opportunity to research an understudied species' response to new environments since they have experienced social and physical changes, such as new enclosures and increased social interaction with humans. This project aimed to investigate the role of personality in behavioral responses to these changes. Lion personality questionnaires completed by keepers and direct focal animal observations were used to create personality profiles. Time budgets and enclosure use were determined and compared between control nights and event nights and between the lions' previous enclosure and their new one. The results showed a lack of difference in time budget and enclosure use between control and social event nights, and the spread of participation index values revealed that the lions use their enclosures unevenly. Personality profiles identified various traits that could assist with individual-based management decisions. As the first study to assess Asiatic lions personality, this research contributes to the creation of consistent and valid methodology for evaluating captive animal personality that may improve husbandry and welfare protocols for individual lions, leading to the improved health and success of the species. PMID- 28638675 TI - Petroleum Hydrocarbon Fingerprints of Water and Sediment Samples of Buffalo River Estuary in the Eastern Cape Province, South Africa. AB - Petroleum hydrocarbon status of the Buffalo River Estuary in East London, South Africa, was evaluated from January to May, 2016. Surface water and sediment samples were collected from five points in the estuary and extracted using standard methods. The extracts were subsequently analyzed by gas chromatography flame ionization detection. Results showed that total petroleum hydrocarbon (TPH) varied from 7.65 to 477 MUg/L in the water and 12.59 to 1,100 mg/kg in the sediments, with mean values of 146.50 +/- 27.96 MUg/L and 209.81 +/- 63.82 mg/kg, respectively. Concentrations of TPH in the sediments correlated significantly with organic carbon (OC) in both seasons. TPH and OC levels were slightly lower in summer than in autumn in the two environmental matrices, and the average amount of TPH in the water samples collected from all the sampling stations was generally lower than the EU standard limit of 300 MUg/L. However, the levels in the sediments exceeded the EGASPIN target value (50 mg/kg) for mineral oil but were below the intervention value (5,000 mg/kg), indicating a serious impact of industrial growth and urbanization on the area, although the n-alkane ratios and indexes used for source tracking revealed excessive flow from both natural and anthropogenic sources. PMID- 28638676 TI - Utilization of longitudinal ultrasound to quantify joint soft-tissue changes in a mouse model of posttraumatic osteoarthritis. AB - To assess the utility of longitudinal ultrasound (US) to quantify volumetric changes in joint soft tissues during the progression of posttraumatic osteoarthritis (PTOA) in mice, and validate the US results with histological findings. A longitudinal cohort of 3-month-old wild-type C57BL/6 male mice received the Hulth-Telhag surgical procedure on right knee to induce PTOA, and sham surgery on their left knee as control. US scans were performed on both knees before, 2, 4, 6, and 8 weeks post-surgery. Joint space volume and Power-Doppler (PD) volume were obtained from US images via Amira software. A parallel cross sectional cohort of mice was killed at each US time point, and knee joints were subjected to histological analysis to obtain synovial soft-tissue area and OARSI scores. The correlation between US joint space volume and histological synovial soft-tissue area or OARSI score was assessed via linear regression analysis. US images indicated increased joint space volume in PTOA joints over time, which was associated with synovial inflammation and cartilage damage by histology. These changes started from 2 weeks post-surgery and gradually became more severe. No change was detected in sham joints. Increased joint space volume was significantly correlated with increased synovial soft-tissue area and the OARSI score (P<0.001). PD signal was detected in the joint space of PTOA joints at 6 weeks post-surgery, which was consistent with the location of blood vessels that stained positively for CD31 and alpha-smooth muscle actin in the synovium. This study indicates that US is a cost-effective longitudinal outcome measure of volumetric and vascular changes in joint soft tissues during PTOA progression in mice, which positively correlates with synovial inflammation and cartilage damage. PMID- 28638677 TI - Changes in sirtuin 2 and sirtuin 3 mRNA expressions in rheumatoid arthritis. AB - OBJECTIVE: Sirtuins (SIRTs) play a prominent role in metabolism, apoptosis, aging, inflammation, and epigenetics. Inflammation, apoptosis, and epigenetics are pathogenic issues in rheumatoid arthritis (RA). This study aimed to evaluate SIRT2 and SIRT3 mRNA expressions in patients with RA. MATERIAL AND METHODS: Fifty four patients with RA and 26 healthy controls were enrolled. Disease activity was determined using the disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) (score of >2.6 was considered to be active). SIRT2 and SIRT3 mRNA expressions in the extracellular plasma were investigated by real-time PCR. RESULTS: SIRT3 mRNA expression was higher in the RA group than in the healthy control group (4.64 fold, p<0.001), whereas SIRT2 mRNA expression was relatively lower in the RA group than in the healthy control group (0.55 fold, p=0.109). However, SIRT2 (1.73 fold, p=0.065) and SIRT3 (3.58 fold, p=0.051) mRNA expressions were relatively higher in patients with active RA than in those with inactive RA. CONCLUSION: In RA, SIRT3 mRNA expression is increased, whereas SIRT2 mRNA expression is decreased. Conversely, SIRT2 and SIRT3 mRNA expressions increase in active RA. Therefore, the fate of each SIRT may differ in RA. PMID- 28638678 TI - Detailed features of hematological involvement and medication-induced cytopenia in systemic lupus erythematosus patients: single center results of 221 patients. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) may affect a number of systems, with the hematological system being one of the most common. Our aim is to determine the existence of cytopenia at diagnosis or during follow-up of our SLE patients as well as the associated factors. MATERIAL AND METHODS: A cohort of SLE patients that had been followed-up in the Department of Rheumotology from 1998 to 2015 was retrospectively assessed. Clinical and laboratory findings about the patients were recorded. RESULTS: Out of 221 patients composing the cohort, cytopenia was already present in 83.3% (n=184) at the time of diagnosis. Anemia was detected in 56.1% (n=124), leukopenia in 28.9% (n=64), lymphopenia in 76% (n=168), neutropenia in 4.5% (n=10), and thrombocytopenia in 17.2% (n=38) of patients. The proportion of patients with cumulative cytopenia was 90% (n=199). Cumulative cytopenia was disease-related in 83.4% (n=166) and medication-related in 16.6% (n=33) of the patients. In cases of drug-induced cytopenia, azathioprine was the most frequently prescribed drug. In patients with cytopenia at the time of diagnosis, erythrocyte sedimentation rates (ESR) were higher, C3 and C4 hypocomplementemia was more prevalent, and they were positive for anti-ds-DNA at a greater proportion (p<0.001, p=0.015, p=0.028, and p=0.019, respectively). Moreover, photosensitivity, renal involvement, and antiphospholipid syndrome (APS) were detected more frequently in patients with cytopenia at the time of diagnosis. There was no difference between the two patient sets in terms of other organ involvement (p>0.05). CONCLUSION: The most common hematological disorders in SLE patients are lymphopenia and anemia, and patients must be further examined for APS and renal involvement if they suffer cytopenia. PMID- 28638679 TI - Decrease of serum biomarker of type II Collagen degradation (Coll2-1) by intra articular injection of an autologous plasma-rich-platelet in patients with unilateral primary knee osteoarthritis. AB - OBJECTIVE: This study aimed to evaluate the effect of one dose of intra-articular injection of (PRP) in the knee joint on a specific osteoarthritis (OA) serum biomarker of cartilage degeneration, Collagen 2-1 (Coll2-1), over a short period of 3 months. The aim extended to clarify the effect of PRP on the functional status of the osteoarthritic knee joint. MATERIAL AND METHODS: Sixty patients with primary unilateral knee OA were enrolled in this study. They were subdivided according to Kellgren-Lawrence grading scale (KL) into (Group I): including patients with KL grade < 3 and (Group II): including patients with KL grade >=3. Patients were asked to complete the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Score. PRP was prepared and injected immediately into the affected knee. Serum Coll2-1 (S.Coll2-1) concentration was measured by enzyme linked immunosorbent assay (ELISA) kit pre and 3 months after PRP injection. RESULTS: Significant reduction in S.Coll2-1 concentration in primary knee OA patients; (p<0.001) and (p<0.05) in group I and group II respectively as well as significant improvements in WOMAC total and WOMAC sub-scores values were noted after single intra-articular PRP injection with maximal functional improvements were achieved after 3 months (p<0.001). Mild cases experienced favorable results with no remarkable adverse reactions were observed. CONCLUSION: Reduction in specific OA biomarker S.Coll2-1 following intra-articular PRP injection emphasize that PRP could be a promising safe and tolerable effective therapeutic option which improves function from basal states in primary knee OA patients. PMID- 28638680 TI - Genetic influence of growth and differentiation factor 5 gene polymorphism (+104T/C) on the development of knee osteoarthritis and its association with disease severity. AB - OBJECTIVE: The growth and differentiation factor 5 (GDF5) gene is recognized for its role in the development, repair, and maintenance of cartilage and bone. The present case-control study was conducted to detect the genetic association between GDF5 (+104T/C) single-nucleotide polymorphism (SNP) and primary knee osteoarthritis (KOA), as well as the possible association of SNP with the severity of KOA. MATERIAL AND METHODS: The study included 50 patients with primary KOA and 50 healthy control subjects. The severity of the disease was assessed by using the Kellgren-Laurence (K-L) grading system and aided by the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) score, visual analog scale (VAS) score, and tenderness score. The genetic association of the SNP with primary KOA was assessed by means of the TaqMan(r) allelic discrimination technique. RESULTS: The radiological assessment of patients according to the K-L grading system revealed a statistically significant association between the wild-type (TT) genotype and disease severity in both the right and left knees (p=0.049). The frequency distribution of patients with VAS score <=6 was significantly higher in patients carrying the TT genotype (p=0.005) as compared to the CT and CC genotypes. The mean WOMAC score was significantly higher in patients carrying the TT genotype as compared to patients carrying the CC and CT genotypes (p=0.017). No statistically significant association was detected on comparing the frequency distribution of allele and genotype frequencies of the SNP in patients and healthy controls. CONCLUSION: The results of the current study revealed a possible genetic association between GDF5 (+104T/C) SNP and the severity of KOA, which might be of benefit for the detection of patients with a high risk for disease progression. The present study did not detect an association between the SNP and development of KOA. PMID- 28638681 TI - Efficacy of extracorporeal shockwave therapy and low-intensity pulsed ultrasound in a rat knee osteoarthritis model: A randomized controlled trial. AB - OBJECTIVE: This study aims to assess the efficacy of extracorporeal shockwave therapy (ESWT) and low-intensity pulsed ultrasound (LIPUS) on osteoarthritic rat knees. MATERIAL AND METHODS: Twenty-four rats were divided into 3 groups: group 1 control (n=8), group 2-LIPUS (n=8) and group 3-ESWT (n=8). Cartilage degeneration was provided using mono-iodo-asetate (MIA). One milligram of MIA was delivered to the right knees in group 1 and both knees in group 2 and 3. A 0.09% saline solution was delivered to the left knees in group 1 for control. Twenty-four hours after the delivery, ESWT was applied once on the right knees in the group 2 rats to the medial tibia plateu with a 1 Hz frequency and 800 impulses. LIPUS was applied to the right knees in the group 2 rats to the medial tibia plateu with a 3 mHz frequency and 40 mW/cm2 intensity for 20 minutes over a period of 15 days. Pain scores were measured with a knee bend test. Bone mineral density measurements and scintigraphic bone scans were performed. Histopathological examination was done using a modified Mankin scale. RESULTS: There was no difference among the right knee subchondral bone osteoblastic activities (p>0.05). The left knee osteoblastic activities in the LIPUS and extracorporeal shockwave therapy (ESWT) groups were higher than those in the control group (p<0.05), but there was no difference between the LIPUS and ESWT groups. There was no difference among the groups for both knee subchondral bone BMD values (p>0.05). The modified Mankin scores of both the right and left knees of the ESWT and LIPUS groups were lower than those of the control group (p<0.05), but there was no difference between the ESWT and LIPUS groups. The pain scores of both knees of the ESWT and LIPUS groups at day 7 were higher than those of the control group (p<0.05), but there was no difference between the ESWT and LIPUS groups. There was no difference among the pain scores of the right knees at day 14 (p<0.05). CONCLUSION: ESWT and LIPUS have systemic proliferative and regenerative effects on cartilage and tissue. PMID- 28638682 TI - Oral ulcer activity in Behcet's disease: Poor medication adherence is an underestimated risk factor. AB - OBJECTIVE: The aim of this study was to evaluate the relationship between oral ulcer activity and medication adherence according to gender in Behcet's disease (BD) patients. MATERIAL AND METHODS: The study group included 330 BD patients (F/M: 167/163, mean age: 38.5+/-10.5 years). Oral ulcer activity and medication adherence were evaluated in the previous month. Medication adherence was evaluated using the 8-item Morisky Medication Adherence Scale (MMAS-8) having a score range of "0" to "8" with high scores indicating better adherence. Low adherence was defined as <6 points on MMAS-8. RESULTS: Over half of the group had active oral ulcers (n=219, 66.4%) within the month preceding the visit. The number of oral ulcers was significantly higher in female patients with low medication adherence (2.39+/-3.24) than in the rest of the female group (1.28+/ 2.05; p=0.023). Although a similar trend was also observed in male patients (2.14+/-3.3 vs. 1.81+/-2.31), a significant relationship was not observed (p=0.89). The frequency of medication intake per day was lower in patients with high medication adherence than in the rest of the study group (p=0.04). CONCLUSION: Low medication adherence is a hidden risk factor in the management of BD. Poor adherence was associated with oral ulcer activity in female BD patients. PMID- 28638683 TI - Low prevalence of obesity in Behcet's disease is associated with high obestatin level. AB - OBJECTIVE: Chronic inflammatory diseases are associated with altered body composition. Ghrelin has anti-inflammatory effects, and its level is altered in obesity and inflammatory diseases. The aim of the study was to evaluate the prevalence of obesity and ghrelin and obestatin levels in patients with Behcet's disease (BD). MATERIAL AND METHODS: One hundred and forty-three (143) patients with BD and 112 healthy controls (HC) were enrolled. Participants were subdivided according to the body mass index (BMI) as lean (<18.5 kg/m2), normal weight (18.5 24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (>=30 kg/m2). In addition to the routine evaluations (fasting blood glucose, lipid profile, and kidney and liver function tests), serum acylated-ghrelin (AG), unacylated-ghrelin (UAG), total ghrelin (TG) and obestatin levels were analyzed. Student's t-test and chi square test were used for statistical analysis. RESULTS: The prevalence of obesity was relatively lower in the BD group than in the HC group (12.6% vs. 20.5%, p=0.089). Serum ghrelin levels were similar in the BD and HC groups (p>0.05 for all) although the obestatin level was higher in the BD group compared to the HC group (p<0.001). Serum UAG, TG and obestatin levels were lower in obese BD patients (n=18) than non-obese BD patients (p=0.027, p=0.014 and p=0.001, respectively). CONCLUSION: The obestatin level was high and the prevalence of obesity was low in the BD group. Moreover, obese BD patients had low obestatin levels. These results suggest that obestatin may protect BD patients from obesity. PMID- 28638684 TI - The new ACR/EULAR criteria for rheumatoid arthritis can identify patients with same disease activity but less damage by ultrasound. AB - OBJECTIVE: We aimed to compare the ultrasound findings of patients fulfilling the 1987 ACR [OLD-rheumatoid arthritis (RA)] and the new ACR/EULAR (NEW-RA) classification criteria to examine the impact of the new criteria on disease characteristics, particularly disease duration. MATERIAL AND METHODS: A total of 2730 hands, wrists, elbows, knees, ankles, and foot joints of 105 consecutive patients with inflammatory arthritis, i.e., 82 patients fulfilling the RA criteria (60 patients, OLD-RA; 22 patients, NEW-RA alone) and 23 patients with undifferentiated arthritis, were scanned using ultrasound. Synovitis, erosions, and power Doppler (PD) findings were scored using a scale of 0-3 and scores form each joint were added up to calculate synovitis, PD and erosion scores for each patient. RESULTS: OLD-RA and NEW-RA patients had similar swollen joint count, tender joint count, acute-phase response, patient global, and disease activity assessment 28 scores. The disease duration was longer in OLD-RA patients [30 (3 179) months] than in NEW-RA patients [16 (0-45) months; p=0.009]. Both the groups had similar synovitis and PD scores, whereas erosion scores were higher in OLD-RA patients than in NEW-RA patients (p=0.009). Patients with undifferentiated arthritis were older than those with RA and had fewer swollen joints than NEW-RA patients [0 (0-4) vs. 2 (0-9); p=0.017]. All other disease activity parameters were similar in both NEW-RA and OLD-RA patients. Both the synovitis (p=0.006) and erosion (p=0.007) scores were lower in patients with undifferentiated arthritis than in OLD-RA patients, despite the scores being similar to those in NEW-RA patients. CONCLUSION: The new ACR/EULAR RA criteria enabled the classification of patients with similar disease activity (by clinical assessment and ultrasound) but with less damage. A similar disease activity should ensure suitability for an intervention, and a shorter duration and less damage should improve the outcome with patient benefit. PMID- 28638686 TI - Rheumatoid Arthritis: Are psychological factors effective in disease flare? AB - OBJECTIVE: Rheumatoid arthritis (RA) is clinically an undulant disease, and reasons for flare or remission vary. We aimed to identify factors potentially associated with disease flare and remission. MATERIAL AND METHODS: Two hundred and seventy-four patients with RA who were admitted to our center between January 2010 and January 2016 were included. Disease activity was evaluated using disease activity score 28 (DAS 28); functional status was evaluated using the modified Health Assessment Questionnaire (m-HAQ), a questionnaire that comprises flare or remission domains such as psychological stress and mood status, physical trauma, nutrition regimen, infection, antibiotic use, and seasonal weather changes. Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were used to identify if patients had a mood disorder. Four subscales of Arthritis Impact Measurement Scale-2 (AIMS-2) (level of tension, mood, general perception of health, and satisfaction with health) were used to determine patient quality of life. RESULTS: Of the 274 patients, 261 were female (95.3%) and 13 were male (4.7%); the mean age was 52.10+/-9.41 years. According to patients' perception, the most frequent reasons for joint symptoms were psychological stress/mood disorder (86.1%), followed by infection (49.6%) and trauma (46.4%). The most frequent factors for remission of symptoms were antibiotic use (42.7%), cold weather (34.3%), and hot weather (19%). CONCLUSION: Psychological stress and mood status are independent factors for relapse periods in patients with RA. These should be considered particularly in patients who are resistant to different treatment regimens and in whom any other reason for disease flare is not obvious. PMID- 28638685 TI - Carotid artery stiffness in Behcet's disease. AB - OBJECTIVE: Increased carotid arterial stiffness (CAS) is a predictor of subclinical early atherosclerosis as well as carotid intima-media thickness (cIMT). We aimed to determine CAS and cIMT in Behcet's disease (BD). MATERIAL AND METHODS: BD (n=49) and rheumatoid arthritis (RA) (n=64) patients and healthy controls (HC) (n=40) were included in the study. cIMT was measured. CAS indices, including arterial compliance (AC), arterial distensibility (AD), Young's elastic modulus (YEM), Peterson's elastic modulus (Ep), and beta stiffness index (betaSI) were measured based on the diameter-pressure relationship. RESULTS: When compared to the HC group, the mean cIMT was significantly higher in the RA group (p=0.033), but it was not higher in the BD group. The CAS indices, including AD, AC, Ep, and betaSI were not significantly different among the study groups. Moreover, the cIMT and CAS indices were not significantly different between active (n=20) and inactive BD patients, and these indices were not correlated with the scores of disease activity. AD, AC and Ep were significantly lower in the BD patients with a positive pathergy reaction than in those with a negative reaction. CONCLUSION: These results suggest that BD does not directly lead to arterial stiffness or to an increase in cIMT. PMID- 28638687 TI - Aneurysm of the ascending aorta in systemic lupus erythematosus: Case report and review of the literature. AB - Cardiovascular manifestations in patients with systemic lupus erythematosus (SLE) are common, but aortic aneurysm formation is rare. We present a 63-year-old male SLE patient with a two-year history of skin lesions, leucopenia, pericarditis, mitral valve vegetations consistent with Liebman-Sacks endocarditis, and an aneurysm of the ascending aorta, which was successfully repaired surgically. Histologic examination of the aneurysm showed medial cystic degeneration, smooth muscle necrosis, and mild adventitial perivascular lymphocytic aggregates. This histology is typical of thoracic aneurysms that carry a high risk for aortic dissection and patient death. The case highlights the importance of early detection and treatment of thoracic aortic aneurysms in patients with SLE. PMID- 28638689 TI - Visceral Leishmaniasis in a patient with rheumatoid arthritis undergoing treatment with methotrexate: Case report and review of the literature. AB - There is growing concern regarding the emergence of visceral leishmaniasis (VL), a disseminated parasitic disease caused by protozoa of the genus Leishmania, as an opportunistic infection in immunocompromised patients. This association has been principally studied in the context of human immunodeficiency virus infection, but VL has also been reported in patients undergoing treatment with immunosuppressive medication for various indications. Here a case of VL in a patient with rheumatoid arthritis undergoing treatment with methotrexate and corticosteroid is presented. Despite the rarity of such incidents, physicians should include VL in the differential diagnosis because this infection, if left untreated, is characterized by significant mortality. PMID- 28638688 TI - Spontaneous regression of Epstein-Barr virus-associated lymphoproliferative disorder in a juvenile idiopathic arthritis patient after the discontinuation of methotrexate and etanercept. AB - A case of a 16-year-old female with polyarticular juvenile idiopathic arthritis (JIA) since the age of 4 years is reported here. This patient also suffered from multiple congenital anomalies. On long-term treatment with oral methotrexate (MTX) and etanercept, multiple subcutaneous nodules were detected, which were accompanied by increased lactate dehydrogenase and uric acid levels. A biopsy of the largest nodule revealed Epstein-Barr (EB) virus-positive diffuse large B-cell lymphoma (DLBCL). The patient was classified as clinical stage IIIA due to a mediastinal lesion. Immunosuppressive treatment was discontinued immediately, which led to regression of the remaining nodules and normalization of the lactate dehydrogenase levels. The patient was considered to have an iatrogenic lymphoproliferative disorder classified as "other iatrogenic immunodeficiency associated lymphoproliferative disorders" by the World health organization (WHO). To our knowledge, this is the first case report of a JIA patient with EBV positive DLBCL following the administration of etanercept and methotrexate and spontaneous regression of lymphoproliferation after the discontinuation of antirheumatic treatment. PMID- 28638690 TI - An unusual case of diffuse pigmented villonodular synovitis of the shoulder: A multidisciplinary approach with arthroscopic synovectomy and adjuvant radiotherapy. AB - Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder of the synovial membrane. This condition is usually monoarticular, can be locally destructive, and involves muscles, tendons, bursae, bones, and skin. The most commonly affected joints are the knee and hip, followed by the ankle and shoulder. Patients often present with pain, swelling, and joint effusion; however, the duration of symptoms varies. Total synovectomy is the preferred treatment for PVNS. Subtotal synovectomy is a factor of recurrence, and in diffuse PVNS, total excision is very difficult to achieve. Radiotherapy may have an adjunctive role, particularly in incomplete resection or as a treatment of salvation in recurrent cases. This treatment modality has low toxicity levels and enables satisfactory joint function. This is a case report of a rare case of diffuse PVNS of the shoulder that was treated with partial arthroscopic synovectomy and adjuvant radiotherapy. A 74-year-old male patient presented with gradual onset pain, hemarthrosis, and functional impairment of the right shoulder without previous trauma history. Magnetic resonance imaging of the shoulder demonstrated a diffuse synovial thickening that was compatible with PVNS and rotator cuff destruction. The lesion was partially excised by arthroscopy. The patient underwent adjuvant radiation therapy with a total dose of 40 Gy/20 fractions/4 weeks. At the final follow-up, i.e., 1 month after treatment, the patient had increased shoulder mobility and no pain, with a mild change in cutaneous pigmentation. Radiation therapy is safe and effective in treating and preventing recurrence of diffuse PVNS, particularly after incomplete synovectomy. PMID- 28638691 TI - Catastrophic antiphospholipid syndrome treated with rituximab: A case report. AB - Catastrophic antiphospholipid syndrome (CAPS) is a rare and fatal condition that is characterized by diffuse venous and/or arterial thromboembolism within a short period of time and histopathological confirmation of small-vessel occlusion in at least one organ or tissue in the presence of positive antiphospholipid antibodies. Here we report the case of a 19-year-old woman with CAPS. During the first week of her hospitalization, she was diagnosed with CAPS on the basis of skin necrosis, pulmonary artery thrombosis, cerebral venous sinus thrombosis, and positive lupus anticoagulant. She was treated with corticosteroids, intravenous immunoglobulins, plasmapheresis, and anticoagulants. Forty days after the onset of CAPS, cutaneous lesions were recurred during skin surgery. She required a high dose of corticosteroids, intravenous immunoglobulins, and rituximab. No further thrombotic events occurred. Rituximab may be an effective treatment option for patients with CAPS. PMID- 28638692 TI - A report of three cases with lupus myelitis. AB - Lupus myelitis (LM) is a rare but serious complication of systemic lupus erythematosus (SLE). In 2009, Birnbaum et al. suggested that LM could be classified into two subtypes, namely gray and white matter myelitis, based on neurological examination findings. Here we describe three cases of this disorder, one with signs of white matter dysfunction and two with signs of gray matter dysfunction. We discuss the potential role of autoantibodies in the development of LM. PMID- 28638693 TI - Management of the temporomandibular joint in inflammatory arthritis: Involvement of surgical procedures. AB - Many conditions may affect the temporomandibular joint (TMJ), but its incidence in individual joint diseases is low. However, inflammatory arthropathies, particularly rheumatoid and psoriatic arthritis and ankylosing spondylitis, appear to have a propensity for affecting the joint. Symptoms include pain, restriction in mouth opening, locking, and noises, which together can lead to significant impairment. Jaw rest, a soft diet, a bite splint, and medical therapy, including disease-modifying antirheumatic drugs (DMARDs) and simple analgesia, are the bedrock of initial treatment and will improve most symptoms in most patients. Symptom deterioration does not necessarily follow disease progression, but when it does, TMJ arthroscopy and arthrocentesis can help modulate pain, increase mouth opening, and relieve locking. These minimally invasive procedures have few complications and can be repeated. Operations to repair or remove a damaged intra-articular disc or to refine joint anatomy are used in select cases. Total TMJ replacement is reserved for patients where joint collapse or fusion has occurred or in whom other treatments have failed to provide adequate symptomatic control. It yields excellent outcomes and is approved by the National Institute of Health and Care Excellence (NICE), UK. Knowledge of the assessment and treatment of the TMJ, which differs from other joints affected by inflammatory arthritis due to its unique anatomy and function, is not widespread outside of the field of oral and maxillofacial surgery. The aim of this article is to highlight the peculiarities of TMJ disease secondary to rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis and how to best manage these ailments, which should help guide when referral to a specialist TMJ surgeon is appropriate. PMID- 28638694 TI - Giant cell arteritis, polymyalgia rheumatica, and late-onset rheumatoid arthritis: Can they be components of a single disease process in elderly patients? AB - OBJECTIVE: To report two patients with giant cell arteritis (GCA) who developed rheumatoid arthritis (RA) and to review the literature in terms of coexistence of RA, GCA, and polymyalgia rheumatica (PMR). METHODS: We conducted a comprehensive review of the English literature from 1980 to 2015 to analyze data on the coexistence of GCA and RA. The PubMed, Web of Science, Proquest, and Ovid databases were searched for articles using the term RA combined with temporal arteritis, GCA, and PMR. RESULTS: We identified 17 other cases of coexistent GCA and RA reported in the English literature, together with our 2 cases (19 cases). They included 14 females and 5 males, with a mean age of 74.3 years (range: 57 84) at the time of GCA. The mean age at the time of RA diagnosis was 69.6 years (range 24-83). The average time elapsed between the onset of GCA and the development of RA was 6.7 years (range: 3 month-34 years). RA and GCA were reported as the first disease in 10 cases and 4 cases, respectively. The development of these 2 diseases in a narrow period of time appeared in 4 cases (3 months-19 months). PMR was the first disease in 1 case. CONCLUSION: RA, GCA, and PMR may appear simultaneously or consecutively; therefore, we suggest that physicians should be alert about such a fact so that a proper diagnosis and treatment could be tailored accordingly. PMID- 28638695 TI - Pre-rheumatoid arthritis and its prevention. AB - Pre-rheumatoid arthritis (pre-RA) is the preclinical period of the disease that precedes the onset of clinically apparent RA. It includes the interaction between genetic and environmental risk factors and development of disease-related autoantibodies and joint symptoms and signs, which may be considered nonspecific or unclassified for RA. A better understanding of the pre-RA stage will be useful in developing screening programs for early detection of RA. Identifying and modifying risk factors such as smoking, periodontitis, obesity, viral infections, and hormonal or dietary factors will be useful in preventing RA in susceptible population. PMID- 28638697 TI - Breast calcinosis in a patient with Dermatomyositis. PMID- 28638696 TI - Basic radiological assessment of synovial diseases: a pictorial essay. AB - The synovium is a specialized tissue lining the synovial joints, bursae, and tendon sheaths of the body. It is affected by various localized or systemic disorders. Synovial diseases can be classified as inflammatory, infectious, degenerative, traumatic, hemorrhagic, and neoplastic. Damage in other intraarticular structures, particularly cartilages, generally occurs as a part of pathologic processes involving the synovium, leading to irreversible joint destruction. Imaging has an essential role in the early detection of synovial diseases prior to irreversible joint damage. Obtaining and understanding characteristic imaging findings of synovial diseases enables a proper diagnosis for early treatment. This article focuses on the recent literature that is related with the role of imaging in synovial disease. PMID- 28638698 TI - Atypical antipsychotic therapy in Parkinson's disease psychosis: A retrospective study. AB - OBJECTIVE: Parkinson's disease psychosis (PDP) is a frequent complication of idiopathic Parkinson's disease (iPD) with significant impact on quality of life and association with poorer outcomes. Atypical antipsychotic drugs (APDs) are often used for the treatment of PDP; however, their use is often complicated by adverse drug reactions (ADRs). In this study, we present patients with PDP who were treated with the most commonly used atypical antipsychotic agents and review their respective ADRs. METHODS: A retrospective study was carried out to include a total of 45 patients with iPD who visited a movement disorders clinic between 2006 and 2015. All PDP patients treated with atypical APDs were included in the analysis for their specific ADRs. RESULTS: Forty-five iPD patients (mean age of onset: 62.67 +/- 9.86 years) were included, of those 10 patients had psychosis (mean age of onset: 76.80 +/- 4.61 years). Of the 45 patients, 22.2% were found to have psychotic symptoms, of whom 70% had hallucinations, 20% had delusions, and 10% illusions. Seventy percent of psychotic symptoms occurred after ten or more years from diagnosis of iPD. PDP patients were treated with quetiapine, olanzapine, and risperidone separately or in combination, all of which were found to have certain ADRs. LIMITATIONS: This study was limited by its retrospective study design and small sample size and with likely selection bias. CONCLUSIONS: The prevalence of PDP is relatively high in older patients with iPD. The uses of the currently available atypical APDs in this patient population are often complicated by ADRs. The selective 5-HT 2A inverse agonist, pimavanserin, could be a better alternative in the treatment of PDP. PMID- 28638699 TI - Plantar Exteroceptive Inefficiency causes an asynergic use of plantar and visual afferents for postural control: Best means of remediation. AB - INTRODUCTION: Some subjects have difficulty to integrate both visual and plantar inputs, showing at the same time a "postural blindness" and a Plantar Exteroceptive Inefficiency (PEI). The former corresponds to a better stability eyes closed (EC) than eyes open (EO), while the latter is defined as a better stability on foam than on firm ground. Clinical studies reported that a manipulation of either plantar or visual input could affect the weight of both cues in postural control, suggesting interdependence in their use. The purpose of the experiment is to characterize the PEI phenomenon better and see if such synergy can be objectified. METHODS: We recruited 48 subjects (25 +/- 3.3 years) and assessed their balance with a force platform, EO, EC, at 40 or 200 cm, on firm ground, Depron(r) foam, Dynachoc(r) foam, or on a 3 mm-thick Anterior Bar AB(r). We assessed their sensorial preferences through their PQ and RQ. RESULTS: The main results are that there normally exists a synergy in the use of plantar and visual afferents, but only at 40 cm and in the absence of PEI. CONCLUSIONS: Plantar Exteroceptive Inefficiency interferes with the role of vision in postural control, its effects are distance specific, are better revealed by Depron(r) foam and the AB(r) improves posture but does not solve visual-podal asynergy. These results also have clinical interests as they indicate the best way in terms of distance and choice of foam to diagnostic PEI. Finally, they suggest restricting the use of the AB(r), commonly employed. These findings can be useful for clinicians concerned with foot, eye, and posture. PMID- 28638700 TI - Vowel decoding from single-trial speech-evoked electrophysiological responses: A feature-based machine learning approach. AB - INTRODUCTION: Scalp-recorded electrophysiological responses to complex, periodic auditory signals reflect phase-locked activity from neural ensembles within the auditory system. These responses, referred to as frequency-following responses (FFRs), have been widely utilized to index typical and atypical representation of speech signals in the auditory system. One of the major limitations in FFR is the low signal-to-noise ratio at the level of single trials. For this reason, the analysis relies on averaging across thousands of trials. The ability to examine the quality of single-trial FFRs will allow investigation of trial-by-trial dynamics of the FFR, which has been impossible due to the averaging approach. METHODS: In a novel, data-driven approach, we used machine learning principles to decode information related to the speech signal from single trial FFRs. FFRs were collected from participants while they listened to two vowels produced by two speakers. Scalp-recorded electrophysiological responses were projected onto a low dimensional spectral feature space independently derived from the same two vowels produced by 40 speakers, which were not presented to the participants. A novel supervised machine learning classifier was trained to discriminate vowel tokens on a subset of FFRs from each participant, and tested on the remaining subset. RESULTS: We demonstrate reliable decoding of speech signals at the level of single-trials by decomposing the raw FFR based on information-bearing spectral features in the speech signal that were independently derived. CONCLUSIONS: Taken together, the ability to extract interpretable features at the level of single trials in a data-driven manner offers unchartered possibilities in the noninvasive assessment of human auditory function. PMID- 28638701 TI - Reinnervation of denervated muscle by implantation of nerve-muscle-endplate band graft to the native motor zone of the target muscle. AB - INTRODUCTION: Motor endplate reinnervation is critical for restoring motor function of the denervated muscle. We developed a novel surgical technique called nerve-muscle-endplate band grafting (NMEG) for muscle reinnervation. METHODS: Experimentally denervated sternomastoid muscle in the rat was reinnervated by transferring a NMEG from the ipsilateral sternohyoid muscle to the native motor zone (NMZ) of the target muscle. A NMEG pedicle contained a block of muscle (~ 6 * 6 * 3 mm), a nerve branch with axon terminals, and a motor endplate band with numerous neuromuscular junctions. At 3 months after surgery, maximal tetanic muscle force measurement, muscle mass and myofiber morphology, motoneurons, regenerated axons, and axon-endplate connections of the muscles were analyzed. RESULTS: The mean force of the reinnervated muscles was 82% of the contralateral controls. The average weight of the treated muscles was 89% of the controls. The reinnervated muscles exhibited extensive axonal regeneration. Specifically, the mean count of the regenerated axons in the reinnervated muscles reached up to 76.8% of the controls. The majority (80%) of the denervated endplates in the target muscle regained motor innervation. CONCLUSIONS: The NMZ of the denervated muscle is an ideal site for NMEG implantation and for the development of new microsurgical and therapeutic strategies to achieve sufficient axonal regeneration, rapid endplate reinnervation, and optimal functional recovery. NMEG NMZ technique may become a useful tool in the treatment of muscle paralysis caused by peripheral nerve injuries in certain clinical situations. PMID- 28638702 TI - Cerebral blood flow evaluation of intensive rosuvastatin therapy in stroke/transient ischemic attack patients with intracranial arterial atherosclerotic stenosis study: Rationale and design. AB - INTRODUCTION: The risk of recurrent stroke is high in patients with intracranial atherosclerotic stenosis (ICAS). Statin use has been demonstrated to decrease the incidence of stroke by reducing atherosclerotic plaque burden. However, its effect on the hemodynamic situation and cerebral perfusion status has not yet been validated. With the use of computed tomography perfusion (CTP), we aim to evaluate the impact of Rosuvastatin on cerebral hemodynamic changes, as well as the downstream perfusion. METHOD: Cerebral bood flow evaluation of intensive rosuvastatin therapy in patients with intracranial arterial atherosclerotic stenosis (CEIRIS) is a single-center, prospective, randomized, parallel-group, and open-label trial, and it will include 50 participants as estimated. Patients with moderate to severe (50%-99%) ICAS are randomized 1:1 to 10 mg/day or 20 mg/day Rosuvastatin and followed every 13 weeks until 52 weeks. The primary outcome for the trial is the change in the relative regional cerebral blood flow evaluated by CTP after 52 weeks of Rosuvastatin treatment. The secondary outcomes are cerebral blood volume, change in the degree of stenosis of the target vessel and lipid parameters. CONCLUSION: The CEIRIS trial about the effects of statin on the temporal hemodynamic progression of ICAS may extend our understanding of the basic pathophysiology and mechanisms of stroke in ICAS patients. PMID- 28638703 TI - Childhood trauma and negative memory bias as shared risk factors for psychopathology and comorbidity in a naturalistic psychiatric patient sample. AB - BACKGROUND: Both childhood trauma and negative memory bias are associated with the onset and severity level of several psychiatric disorders, such as depression and anxiety disorders. Studies on these risk factors, however, generally use homogeneous noncomorbid samples. Hence, studies in naturalistic psychiatric samples are lacking. Moreover, we know little about the quantitative relationship between the frequency of traumatic childhood events, strength of memory bias and number of comorbid psychiatric disorders; the latter being an index of severity. The current study examined the association of childhood trauma and negative memory bias with psychopathology in a large naturalistic psychiatric patient sample. METHODS: Frequency of traumatic childhood events (emotional neglect, psychological-, physical- and sexual abuse) was assessed using a questionnaire in a sample of 252 adult psychiatric patients with no psychotic or bipolar-I disorder and no cognitive disorder as main diagnosis. Patients were diagnosed for DSM-IV Axis-I and Axis-II disorders using a structured clinical interview. This allowed for the assessment of comorbidity between disorders. Negative memory bias for verbal stimuli was measured using a computer task. RESULTS: Linear regression models revealed that the frequency of childhood trauma as well as negative memory bias was positively associated with psychiatric comorbidity, separately and above and beyond each other (all p < .01). CONCLUSIONS: The results indicate that childhood trauma and negative memory bias may be of importance for a broader spectrum of psychiatric diagnoses, besides the frequently studied affective disorders. Importantly, frequently experiencing traumatic events during childhood increases the risk of comorbid psychiatric disorders. PMID- 28638704 TI - Lipid and hyperglycemia factors in first-ever penetrating artery infarction, a comparison between different subtypes. AB - BACKGROUND: The pathogenesis and progression of branch atheromatous disease (BAD), which differs from lipohyalinotic degeneration (LD), remains controversial. Few studies have investigated the lipid indices and glycometabolism status factors for BAD in first-ever penetrating artery infarction (PAI). METHODS: We retrospectively examined acute stroke patients with PAI admitted within 3 days after stroke. All patients underwent diffusion weight magnetic resonance imaging (DWI) and magnetic resonance angiography (MRA) and/or computed tomography angiography (CTA). Progression was defined as an increase by 2 point or higher in the National Institutes of Health Stroke Scale score. The characteristics, clinical data were statistically analyzed. RESULTS: BAD and LD were diagnosed in 142 (57%) and 107 (43%) patients, respectively. Patients with BAD had higher low-density lipoprotein cholesterol (LDL-C) compared with those with LD (p = .013). Elevated LDL-C was related to early neurological deterioration in patients with BAD (p = .045). The percentage of lenticulostriate arterial (LSA) infarction was greater than that of the pontine penetrating arterial (PPA) infarction in acute PAI (75.1% vs. 24.9%; p < .001). PPA infarction was more prevalent in the BAD group compared with the LD group (34.5% vs. 12.1%, p < .001). The PPA infarction had older age at onset and higher HbA1c concentrations than those with the LSA infarction (p = .014, p = .036 respectively) in the BAD and LD patients, respectively. CONCLUSION: LDL-C may be associated with both the pathogenesis and progression of intracranial BAD. The LSA infarction was the most frequently subtypes in PAI. Age at onset and HbA1c seem to be closely associated with the PPA infarction of first-ever PAI. PMID- 28638705 TI - The innovative development in interferon beta treatments of relapsing-remitting multiple sclerosis. AB - The introduction of interferon beta therapies more than 20 years ago marked a milestone in the treatment of relapsing-remitting multiple sclerosis (RRMS) with a significant impact on the approach to modern multiple sclerosis (MS) care. Key learnings and perspectives from the early days of disease modifying therapies in MS have improved the knowledge base of MS, need for treatment, and patient care. The continuous development of interferons over the past two decades outlines a journey with increased understanding of the pharmacodynamics and pharmacokinetic mechanisms of interferons, leading to innovative formulations with an improved benefit/risk profile. PMID- 28638706 TI - Cardiac troponin and cerebral herniation in acute intracerebral hemorrhage. AB - OBJECTIVES: To explore the association, if any, between the relationship between cardiac troponin and cerebral herniation after intracerebral hemorrhage (ICH). METHODS: Six hundred and eighty-seven consecutive ICH patients admitted to West China Hospital from May 1, 2014 to September 1, 2015 were retrospectively reviewed. Data on demographics, etiology, laboratory examinations at admission including serum cardiac troponin, computed tomography (CT) scans at admission and follow-up, and clinical outcomes were obtained. Using multiple logistic regression to identify the relationship of troponin and herniation. The association between troponin and hematoma volume was assessed using bivariate correlation and linear regression. RESULTS: Among 188 (27.4%) patients who underwent the test of serum cardiac troponin at admission, 16 (8.5%) demonstrated cerebral herniation. The median time from symptom onset to CT at admission and follow-up was 4 and 30.25 hr, respectively. In multivariate analysis, elevated troponin was independently associated with cerebral herniation (adjusted odds ratio [OR] 5.19; 95% confidence interval [CI], 1.08-24.93). And those with elevated troponin had larger hematoma volume at follow-up in bivariate correlation (correlation coefficient, .375, p = .003) and linear regression (beta, .370, 95% CI, 0.062-0.320, p = .005), higher National Institutes of Health Stroke Scale score (adjusted OR 2.06; 95% CI, 1.06-4.01, p = .033) and lower Glasgow Coma Scale score (adjusted OR 2.34; 95% CI, 1.17-4.68, p = .016) than those without. CONCLUSIONS: Elevated cardiac troponin was associated with an almost five-fold increased risk of cerebral herniation, but not in-hospital mortality. The possibility of cerebral herniation should be considered when ICH patients with large hematoma volume and elevated troponin. PMID- 28638707 TI - Sexual dysfunction in female patients with relapsing-remitting multiple sclerosis. AB - INTRODUCTION: Sexual dysfunction (SD) is one of the common symptoms of multiple sclerosis (MS) and is often underdiagnosed, especially in women. Relapsing remitting multiple sclerosis (RRMS) is the most widespread form of the disease, but the data on SD occurrence in this particular group of patients is limited. The aim of the study was to analyze the associations between demographic factors, symptoms and signs of MS, psychiatric comorbidities and SD in female patients with RRMS. MATERIAL & METHODS: A subgroup of 86 sexually active women with RRMS out of 218 total MS respondents was analyzed. Exclusion criteria included active relapse, EDSS score equal or higher than 6.5, and current pregnancy. All patients completed questionnaires including demographic data, questions about symptoms and signs of MS, Female Sexual Function Index (FSFI) for sexual performance, Patient Health Questionnaire 9 (PHQ-9) for depression, and Fatigue Severity Scale (FSS) for fatigue evaluation. RESULTS: According to FSFI, SD occurred in 21 (27.27%) of the respondents. SD occurrence was associated with depression (p < .05) and speech disturbances (p < .04). A negative effect on sexual performance was associated with depression intensity (p < .003), fatigue intensity (p < .05), more advanced age at diagnosis (p < .02), lower education level (p < .05), and smaller area of residence (p < .002). CONCLUSIONS: SD in women with RRMS is mostly associated with psychosocial parameters. Patients who are more depressed, presenting speech problems, less educated, and from smaller towns, should be considered high-risk for sexual dysfunction. PMID- 28638708 TI - Citation classics in central nervous system inflammatory demyelinating disease. AB - OBJECTIVES: To identify and analyze the characteristics of the most influential articles about central nervous system (CNS) inflammatory demyelinating disease. MATERIALS AND METHODS: The Institute for Scientific Information (ISI) Web of Science database and the 2014 Journal Citation Reports Science Edition were used to retrieve the top 100 cited articles on CNS inflammatory demyelinating disease. The citation numbers, journals, years of publication, authorships, article types, subjects and main issues were analyzed. For neuromyelitis optica (NMO), articles that were cited more than 100 times were regarded as a citation classic and described separately. RESULTS: The top 100 cited articles were published between 1972 and 2011 in 13 journals. The highest number of articles (n = 24) was published in Brain, followed by The New England Journal of Medicine (n = 21). The average number of citations was 664 (range 330-3,897), and 64% of the articles were from the United States and the United Kingdom. The majority of the top 100 cited articles were related to multiple sclerosis (n = 87), and only a few articles reported on other topics such as NMO (n = 9), acute disseminated encephalomyelitis (n = 2) and optic neuritis (n = 2). Among the top 100 cited articles, 77% were original articles. Forty-one citation classics were found for NMO. CONCLUSIONS: Our study provides a historical perspective on the research progress on CNS inflammatory demyelinating disease and may serve as a guide for important advances and trends in the field for associated researchers. PMID- 28638709 TI - "Cure" for multiple sclerosis (MS)-Evolving views of therapy goals in patients on different stages of the disease: A pilot study in a cohort of Polish MS patients. AB - INTRODUCTION: New aggressive treatments promise improvement of results in the treatment of multiple sclerosis (MS), however, with high risk of serious complications. In this study, we analyzed patients' acceptance for risks connected with the MS treatment. METHODS: The study was designed as a prospective nonanonymous online questionnaire. Responders were asked about the definition of the "cure" for MS and crucial goals in the treatment. RESULTS: One hundred and eighty patients filled in the questionnaire (129 women and 51 men), and the mean age was 33 years (SD = 10.29). The MS forms were as follows: relapsing-remitting (65%), secondary progressive (14%), primary progressive (10%), and other (11%), with mean EDSS score of 3 points (SD = 2.6). For 50% of the patients, relief of symptoms such as fatigue (72%), paresis (66%), and balance disorders (65%) was synonymous with "cure." The patients with faster progression of the disease were likely to accept risky "curative" treatments-with average 68% accepted mortality risk (p = .003). Over 81% of patients accepted mortality rates over 1% for the treatment that achieves self-defined cure. CONCLUSION: The study shows that the MS patients are likely to accept even very risky treatments as long as they promise patient-defined "cure." PMID- 28638710 TI - Nicotine-prevented learning and memory impairment in REM sleep-deprived rat is modulated by DREAM protein in the hippocampus. AB - INTRODUCTION: REM sleep deprivation is associated with impairment in learning and memory, and nicotine treatment has been shown to attenuate this effect. Recent studies have demonstrated the importance of DREAM protein in learning and memory processes. This study investigates the association of DREAM protein in REM sleep deprived rats hippocampus upon nicotine treatment. METHODS: Male Sprague Dawley rats were subjected to normal condition, REM sleep deprivation and control wide platform condition for 72 hr. During this procedure, saline or nicotine (1 mg/kg) was given subcutaneously twice a day. Then, Morris water maze (MWM) test was used to assess learning and memory performance of the rats. The rats were sacrificed and the brain was harvested for immunohistochemistry and Western blot analysis. RESULTS: MWM test found that REM sleep deprivation significantly impaired learning and memory performance without defect in locomotor function associated with a significant increase in hippocampus DREAM protein expression in CA1, CA2, CA3, and DG regions and the mean relative level of DREAM protein compared to other experimental groups. Treatment with acute nicotine significantly prevented these effects and decreased expression of DREAM protein in all the hippocampus regions but only slightly reduce the mean relative level of DREAM protein. CONCLUSION: This study suggests that changes in DREAM protein expression in CA1, CA2, CA3, and DG regions of rat's hippocampus and mean relative level of DREAM protein may involve in the mechanism of nicotine treatment-prevented REM sleep deprivation-induced learning and memory impairment in rats. PMID- 28638711 TI - Decrease in brain-derived neurotrophic factor at plasma level but not in serum concentrations in suicide behavior: A systematic review and meta-analysis. AB - INTRODUCTION: Suicide is known as a major health concern worldwide. There is evidence for the role of brain-derived neurotrophic factor (BDNF) in suicide behavior. Therefore, this factor has been proposed as a biomarker for suicide behavior. Clinical studies have measured BDNF concentrations at central and peripheral levels. As a consequence, the aim of this study was to assess BDNF levels in blood plasma and serum to see whether there is a difference in concentrations in patients with suicide behavior when compared to those in controls, using a meta-analysis approach. METHODS: We conducted a systematic review and meta-analysis. The search strategy was performed using three databases: PubMed, EBSCO and ScienceDirect. The meta-analysis included a total of nine case-control studies, six measured the BDNF level in serum and three in plasma in suicide behavior. RESULTS: A decrease in BDNF levels in plasma was observed (d = -0.73, 95% CI -1.42 to -0.03 pg/ml). In the case of serum concentrations, no BDNF differences were encountered between cases and controls (d = 0.09, 95% CI -0.31 to 0.13 ng/ml, p(Q) = .92). CONCLUSIONS: According to the results found in the present meta-analysis, the plasma BDNF level could be suggest as a potential biomarker in suicide behavior. However, since the number of studies included in the analysis is limited, a larger number is necessary to determine conclusively the role of BDNF as a biomarker in suicide behavior. PMID- 28638712 TI - Frontal assessment battery and frontal atrophy in amyotrophic lateral sclerosis. AB - OBJECTIVES: To determine the potential utility of the frontal assessment battery (FAB) in assessing cognitive impairments in amyotrophic lateral sclerosis (ALS), we investigated the association between the FAB score and regional gray matter volume, and ascertained whether the regional brain alterations related to cognitive impairments occur in relatively mild stage of ALS. MATERIALS AND METHODS: Twenty-four ALS patients with a Mini-Mental State Examination score of >23, a normal score on the Self-Rating Depression Scale, little or no disturbance in speech and handling utensils on the ALS Functional Rating Scale (ALSFRS), and normal measures on respiratory tests (respiratory function test and arterial blood gas analysis), and two age-matched normal control groups (one for FAB assessment and the other for brain morphometry) underwent FAB testing and structural magnetic resonance imaging. We applied voxel-based morphometry to investigate the relationship between the FAB score and regional brain alteration, and assessed the relationship between the altered regional brain volume and ALSFRS or respiratory tests. RESULTS: Frontal assessment battery scores were significantly lower in ALS patients than in normal controls. Volume reduction in the right orbitofrontal gyrus in ALS was correlated with a lower FAB score. There was no correlation between the right orbitofrontal gyrus volume and ALSFRS or respiratory tests. CONCLUSIONS: The results suggest that the FAB is an adequate tool for detecting cognitive impairments related to frontal lobe pathology in the relatively mild stage of ALS, independent of physical dysfunctions. PMID- 28638713 TI - The behavioral and physiological effects of high-fat diet and alcohol consumption: Sex differences in C57BL6/J mice. AB - BACKGROUND AND OBJECTIVE: Animal studies can be a great tool to investigate sex differences in a variety of different ways, including behavioral and physiological responses to drug treatments and different "lifestyle variables" such as diets. Consumption of both high-fat diets and alcohol is known to affect anxiety behaviors and overall health. This project investigated how high-fat diet and alcohol access and its combination affected the behavior and physiology of male and female C57BL/6J mice. METHOD: Mice were separated into three food groups: high-fat diet, 10% fat diet, and regular chow, and each group was paired with either water or 10% alcohol. Behavioral assays included diet and alcohol preference, light-dark box, open field, and feeding and drinking measurements. Physiological measures included glucose tolerance tests and measurement of brain derived neurotrophic factor, insulin, and leptin levels. RESULTS: Females and males differed in the open field, as male mice decreased activity, while females increased activity when consuming high-fat diet. While females consumed more ethanol than males, alcohol consumption was able to improve glucose tolerance and increase anxiety in both sexes. Lastly, females were more resistant to the physiological changes caused by high-fat diet than males, as females consuming high-fat diet exhibited decreased insulin secretion, less change to brain-derived neurotrophic factor levels, and better glucose tolerance than males consuming high-fat diet. CONCLUSION: These results suggest that the response to high-fat diet and alcohol consumption is sex dependent and that males are more affected both behaviorally and physiologically by high-fat diet compared to females. PMID- 28638714 TI - Swallowing safety in Parkinson's disease after zona incerta deep brain stimulation. AB - OBJECTIVES: The objective of this study was to examine swallowing function in patients with Parkinson's disease before and after caudal zona incerta deep brain (cZI DBS) surgery. The aims were to examine the effect of cZI DBS on swallowing safety regarding liquid and solid food, as well as to identify the effect of cZI DBS on body mass index (BMI) and specific items from part II of the Unified Parkinson's Disease Rating Scale (UPDRS). MATERIALS AND METHODS: The median age of the 14 patients was 57 years (range 46-71), with a median disease duration of 6 years (range 2-13). The present sample is an extension of a previous report, into which six additional patients have been added. Fiber endoscopic examinations of swallowing function, measures of BMI, and evaluation of UPDRS part II items were made before and 12 months after surgery, with and without activated DBS. RESULTS: There were no significant changes due to cZI DBS regarding penetration/aspiration, pharyngeal residue or premature spillage (p > .05). Median BMI increased by +1.1 kg/m2 12 months after surgery (p = .01, r = .50). All reported specific symptoms from the UPDRS part II were slight or mild. A significant improvement regarding handling of utensils was seen 12 months postoperatively (p = .03, r = -.42). CONCLUSIONS: Caudal zona incerta DBS was found not to have a negative impact on swallowing safety. A significant increase in postoperative weight was observed, and speech seemed to be slightly negatively affected, whereas handling of utensils was improved with cZI DBS. PMID- 28638717 TI - Validation of the Parkinson Fatigue Scale in Chinese Parkinson's disease patients. AB - OBJECTIVE: Fatigue is a common nonmotor symptom in Parkinson's disease (PD); however, the Parkinson's disease fatigue scale (PFS), which is designed to measure fatigue in PD, has not been validated in China. The aim of this study was to determine the validity and reliability of the Chinese version of the PFS in PD patients. METHODS: A total of 115 PD patients were evaluated at baseline and after 7 days. Assessments included the PFS, the Fatigue Severity Scale (FSS), and scales assessing motor, cognition, depression, and anxiety. Acceptability was assessed in terms of the rate of missing data and floor and ceiling effects. Cronbach's alpha was calculated to determine internal consistency. Test-retest reliability was assessed using the intraclass correlation coefficient (ICC). Spearman's rank correlation coefficients were used to calculate convergent and divergent validity between PFS scores and scales assessing clinical characteristics. RESULTS: No data were missing for the PFS. Compared with the original scoring method, the binary scoring method had relatively large floor effects (5.21% vs. 17.39%) and ceiling effects (0.90% vs. 4.31%). The internal consistency and test-retest reliability of the PFS were satisfactory (original scoring method: Cronbach's alpha = 0.97, ICC = 0.94; binary scoring method: Cronbach's alpha = 0.94, ICC = 0.94). The PFS score exhibited strong convergent validity with FSS score (correlation coefficient = 0.87). PFS score was weakly to moderately correlated with disease duration and with measures of disease stage, motor function, depression, and anxiety (range of correlation coefficients: 0.25 0.48). There was no significant correlation between PFS score and either onset age or MoCA score (range of correlation coefficients: -0.05 to 0.12). CONCLUSION: The Chinese version of the PFS is a valid measure for assessing fatigue in PD. PMID- 28638716 TI - Long noncoding RNA expression in peripheral blood mononuclear cells and suicide risk in Chinese patients with major depressive disorder. AB - BACKGROUND: WHO stated that nearly one million people commit suicide every year worldly, and 40% of the suicide completer suffered from depression. The primary aim of this study was to explore the association between long noncoding RNAs (lncRNAs) expression in peripheral blood mononuclear cells (PBMCs) and suicide risk of patients with major depressive disorder (MDD). METHODS: Using Human LncRNA 3.0 microarray profiling which includes 30,586 human lncRNAs and RT-PCR, six down-regulated lncRNAs were identified differentially expressed in MDD patients. According to suicidal ideation and suicidal attempt, the suicide risk of MDD patients was classified into suicidal ideation versus no suicidal ideation groups, and past attempt versus no past attempt groups, respectively. The expression of six lncRNAs in MDD patients and controls were examined by RT-PCR. RESULTS: The expression of six lncRNAs had significant differences between no suicidal ideation, suicidal ideation, and controls; corresponding lncRNAs associated with suicidal attempt had remarkable differences between no past attempt, past attempt, and controls. Additionally, only the expression of lncRNAs in suicidal ideation group and past attempt group markedly declined compared with controls. CONCLUSIONS: This study indicated that the expression of six down regulated lncRNAs had a negative association with suicide risk in MDD patients, and the expression of lncRNAs in PBMCs could have the potential to help clinician judge the suicide risk of MDD patients to provide timely treatment and prevent suicide. PMID- 28638715 TI - Rat intersubjective decisions are encoded by frequency-specific oscillatory contexts. AB - INTRODUCTION: It is unknown how the brain coordinates decisions to withstand personal costs in order to prevent other individuals' distress. Here we test whether local field potential (LFP) oscillations between brain regions create "neural contexts" that select specific brain functions and encode the outcomes of these types of intersubjective decisions. METHODS: Rats participated in an "Intersubjective Avoidance Test" (IAT) that tested rats' willingness to enter an innately aversive chamber to prevent another rat from getting shocked. c-Fos immunoreactivity was used to screen for brain regions involved in IAT performance. Multi-site local field potential (LFP) recordings were collected simultaneously and bilaterally from five brain regions implicated in the c-Fos studies while rats made decisions in the IAT. Local field potential recordings were analyzed using an elastic net penalized regression framework. RESULTS: Rats voluntarily entered an innately aversive chamber to prevent another rat from getting shocked, and c-Fos immunoreactivity in brain regions known to be involved in human empathy-including the anterior cingulate, insula, orbital frontal cortex, and amygdala-correlated with the magnitude of "intersubjective avoidance" each rat displayed. Local field potential recordings revealed that optimal accounts of rats' performance in the task require specific frequencies of LFP oscillations between brain regions in addition to specific frequencies of LFP oscillations within brain regions. Alpha and low gamma coherence between spatially distributed brain regions predicts more intersubjective avoidance, while theta and high gamma coherence between a separate subset of brain regions predicts less intersubjective avoidance. Phase relationship analyses indicated that choice-relevant coherence in the alpha range reflects information passed from the amygdala to cortical structures, while coherence in the theta range reflects information passed in the reverse direction. CONCLUSION: These results indicate that the frequency-specific "neural context" surrounding brain regions involved in social cognition encodes outcomes of decisions that affect others, above and beyond signals from any set of brain regions in isolation. PMID- 28638718 TI - Substance P NK1 receptor in the rat corpus callosum during postnatal development. AB - INTRODUCTION: The expression of substance P (SP) receptor (neurokinin 1, NK1) was studied in the rat corpus callosum (cc) from postnatal day 0 (the first 24 hr from birth, P0) to P30. METHODS: We used immunocytochemistry to study the presence of intracallosal NK1-immunopositive neurons (NK1IP-n) during cc development. RESULTS: NK1IP-n first appeared on P5. Their number increased significantly between P5 and P10, it remained almost constant between P10 and P15, then declined slightly until P30. The size of intracallosal NK1IP-n increased constantly from P5 (102.3 MUm2) to P30 (262.07 MUm2). From P5 onward, their distribution pattern was adult-like, that is, they were more numerous in the lateral and intermediate parts of the cc, and declined to few or none approaching the midline. At P5, intracallosal NK1IP-n had a predominantly round cell bodies with primary dendrites of different thickness from which originated thinner secondary branches. Between P10 and P15, dendrites were longer and more thickly branched, and displayed several varicosities as well as short, thin appendages. Between P20 and P30, NK1IP-n were qualitatively indistinguishable from those of adult animals and could be classified as bipolar (fusiform and rectangular), round-polygonal, and pyramidal (triangular-pyriform). CONCLUSIONS: Number of NK1IP-n increase between P5 and P10, then declines, but unlike other intracallosal neurons, NK1IP-n make up a significant population in the adult cc. These findings suggest that NK1IP-n may be involved in the myelination of callosal axons, could play an important role in their pathfinding. Since they are also found in adult rat cc, it is likely that their role changes during lifetime. PMID- 28638719 TI - Abnormal amplitude of low-frequency fluctuations and functional connectivity of resting-state functional magnetic resonance imaging in patients with leukoaraiosis. AB - INTRODUCTION: This study aimed to investigate the cerebral function deficits in patients with leukoaraiosis (LA) and the correlation with white matter hyperintensity (WMH) using functional MRI (fMRI) technology. MATERIALS AND METHODS: Twenty-eight patients with LA and 30 volunteers were enrolled in this study. All patients underwent structural MRI and resting-state functional MRI (rs fMRI) scanning. The amplitude of low-frequency fluctuations (ALFF) of rs-fMRI signals for the two groups was compared using two-sample t tests. A one-sample t test was performed on the individual z-value maps to identify the functional connectivity of each group. The z values were compared between the two groups using a two-sample t test. Partial correlations between ALFF values and functional connectivity of the brain regions that showed group differences and Fazekas scores of the WMH were analyzed. RESULTS: Compared with the control group, the LA group showed a significant decrease in the ALFF in the left parahippocampal gyrus (PHG) and an increased ALFF in the left inferior semi-lunar lobule and right superior orbital frontal gyrus (SOFG). The patients with LA showed an increased functional connectivity between the right insular region and the right SOFG and between the right calcarine cortex and the left PHG. After the effects of age, gender, and years of education were corrected as covariates, the functional connectivity strength of the right insular and the right SOFG showed close correlations with the Fazekas scores. CONCLUSION: Our results enhance the understanding of the pathomechanism of LA. Leukoaraiosis is associated with widespread cerebral function deficits, which show a close correlation with WMH and can be measured by rs-fMRI. PMID- 28638720 TI - Negative emotion evoked by viewing snakes has a motivating effect on cognitive processing in human children with or without intellectual disability. AB - BACKGROUND: It is well known that prioritization of the processing of threatening stimuli generally induces deleterious effects on task performance. However, a study recently reported that emotion (possibly fear) evoked by viewing images of snakes exerts a facilitating effect upon making judgments of the images' color in neurotypical adults and schoolchildren. Here, the author has attempted to confirm the relevance of this notion in children with and without intellectual disability. METHODS: The author here compared the reaction time required to name the colors of snake and flower images between children with Down syndrome (DS) and mental age matched, typically-developing (TD) children. RESULTS: Snake images were responded to faster than flower images in both the groups, while the children with DS tended to respond more slowly overall. CONCLUSIONS: As in TD children, negative emotion can have a motivating effect on cognitive processing in children with DS. Some implications of the findings are pointed out with respect to the lower-level task persistence as a characteristic motivational orientation in children with DS. PMID- 28638721 TI - Long-term cost of spouses' informal support for dependent midlife stroke survivors. AB - OBJECTIVES: Stroke is a major global disease that requires extensive care and support from society and relatives. The aim of this study was to identify and quantify the long-term informal support and to estimate the annual cost of informal support provided by spouses to their stroke surviving partner. METHOD: Data were based on the 7-year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke. One-third of the spouses stated that they provided support to their stroke surviving partner. The magnitude of the support was assessed with a study-specific time-diary and was estimated for independent and dependent stroke survivors based on the scores of the modified Rankin Scale. To deal with skewed data, a two-part econometric model was used to estimate the annual cost of informal support. RESULT: Cohabitant dyads of 221 stroke survivors aged <70 at stroke onset were included in the study. Spouses of independent stroke survivors (n = 188) provided on average 0.15 hr/day of practical support and 0.48 hr/day of being available. Corresponding figures for spouses of dependent stroke survivors (n = 33) were 5.00 regarding practical support and 9.51 regarding being available. The mean annual cost of informal support provided for independent stroke survivors was estimated at ?991 and ?25,127 for dependent stroke survivor. CONCLUSION: The opportunity cost of informal support provided to dependent midlife stroke survivors is of a major magnitude many years after stroke onset and should be considered in economic evaluations of health care. PMID- 28638723 TI - Low-dose methotrexate in sickle-cell disease: a pilot study with rationale borrowed from rheumatoid arthritis. AB - BACKGROUND: Inflammation is a major feature of sickle cell disease (SCD). Low dose methotrexate (MTX) has long been used in chronic inflammatory diseases. This pilot study examined the MTX effect on acute vaso-occlusive pain crises (VOC) in SCD patients. METHODS: Fourteen adults on hydroxyurea with severe and refractory VOC received one intramuscular injection of 10 mg of MTX per week for 12 weeks. A single weekly dose of 5 mg of leucovorin was administered orally 48 h after each MTX injection. The primary outcome was reduction in number/intensity of acute pain episodes. The secondary outcomes were improvement of quality of life (QOL) and reduction of the inflammatory status. RESULTS: MTX did not significantly change the median VOC frequency (12 before vs 10.5 during treatment, P = 0.6240) or the median McGill pain index (45 at week 0 vs 39.5 at week 12, P = 0.9311). However, there was a decrease of >=50% in chronic pain resulting from avascular osteonecrosis (AVN) in 5 out of 7 patients with radiologic evidence of AVN, with the perception of longer pain-free periods. There was a 44.4% median gain in physical function in the SF-36 QOL questionnaire (P = 0.0198). MTX treatment up regulated two C-X-C motif chemokines (CXCL), CXCL10 (P = 0.0463) and CXCL12 (P < 0.0001), without significant effect on 14 additional plasma inflammatory markers. Adverse events: One individual had fever of unknown origin. Respiratory tract infections were recorded in five patients. Among the latter, one also had dengue fever and another had a central venous line infection and died of pneumonia and septic shock. Three patients with previous history of hydroxyurea-induced hematological toxicity developed low blood platelet counts while receiving simultaneously MTX and hydroxyurea. CONCLUSIONS: Although MTX did not reduce acute VOC frequency/intensity, it decreased chronic pain and led to QOL improvement. Trial registration http://www.who.int/ictrp/en/ and http://www.ensaiosclinicos.gov.br, RBR-2s9xvn, 19 December 2016, retrospectively registered. PMID- 28638722 TI - Associations between cognitive impairment and motor dysfunction in Parkinson's disease. AB - INTRODUCTION: Numerous studies have been carried out to explore the potential association between neurologic deficits and variable clinical manifestations of Parkinson's disease (PD). The aim of our study was to investigate the association between cognitive performance and motor dysfunction in Chinese patients with PD. METHODS: Data from 96 patients with PD were obtained from the Parkinson's disease patient cohort database of Huashan Hospital. All participants underwent a comprehensive neuropsychological evaluation to assess cognitive status, that included scoring on the Mini-mental state examination (MMSE), followed by more detailed cognitive assessment on five main cognitive domains (verbal memory, nonverbal memory, visuospatial function, language and attention/executive function). Correlations between cognitive and motor scores were investigated after controlling for age, disease duration, education, and gender. RESULTS: We report a significant correlation between subdomains of cognitive impairment and motor dysfunction using analyses of the multiple linear regression. Notably, executive function and attention was significantly associated with bradykinesia and rigidity, while visuospatial function was associated with bradykinesia and tremor. CONCLUSIONS: The association between motor dysfunction and cognitive decline in PD might highlight deficits represented by a shared neurochemical pathway. PMID- 28638724 TI - Calcium electroporation induces tumor eradication, long-lasting immunity and cytokine responses in the CT26 colon cancer mouse model. AB - Electroporation is used in cancer treatment because of its ability to increase local cytotoxicity of e.g. bleomycin (electrochemotherapy) and calcium (calcium electroporation). Calcium electroporation is a novel anticancer treatment that selectively kills cancer cells by necrosis, a cell death pathway that stimulates the immune system due to high release of antigens and "danger signals." In this exploratory study, we aimed to investigate whether calcium electroporation could initiate an anticancer immune response similar to electrochemotherapy. To this end, we treated immunocompetent balb/c mice with CT26 colon tumors with calcium electroporation, electrochemotherapy, or ultrasound-based delivery of calcium or bleomycin. High treatment efficiency was observed with 100% complete remission in all four groups (12/12 with complete remission in each treatment group). In addition, none of the surviving mice from these groups formed new tumors when re challenged with CT26 cancer cells 100-d post treatment, whereas mice challenged with different cancer cells (4T1 breast cancer) all developed tumors. Treatment of immunodeficient mice with calcium electroporation and electrochemotherapy showed no long-lasting tumor response. Calcium electroporation and electrochemotherapy was associated with a release of High Mobility Group Box 1 protein (HMGB1) in vitro (p = 0.029) and a significant increase of the overall systemic level of pro-inflammatory cytokines in serum from the treated mice (p < 0.003). These findings indicate that calcium electroporation as well as electrochemotherapy could have a role as immune stimulators in future treatments. PMID- 28638725 TI - Administration of a vasoactive intestinal peptide antagonist enhances the autologous anti-leukemia T cell response in murine models of acute leukemia. AB - Vasoactive intestinal peptide (VIP) is a neuroendocrine peptide hormone that has potent anti-inflammatory activities. VIP signaling through its receptor VPAC1 on T cells leads to reduced proliferation and a reduction in pro-inflammatory cytokine secretion. We report here that inhibition of the VIP pathway with a peptide antagonist significantly enhances a T-cell-dependent, autologous anti leukemia response in murine models of acute myeloid leukemia and T lymphoblastic leukemia. Subcutaneous administration of the VIP antagonist, VIPhyb, resulted in reduced tumor burden and significantly enhanced survival (30-50% survival) over vehicle-treated controls (0-20% survival). The T cells in mice treated with VIPhyb expressed lower levels of the co-inhibitory PD-1 and secreted higher levels of IFNgamma. Furthermore, T cells from VIPhyb-treated survivors were protective against C1498 following adoptive transfer. These data highlight the potential for the VIP pathway as a novel target for immunomodulation in settings of hematological malignancies. PMID- 28638727 TI - Identification of an immunogenic neo-epitope encoded by mouse sarcoma using CXCR3 ligand mRNAs as sensors. AB - The CXCR3 ligands CXCL9, 10, and 11 play critical roles in the amplification of immune responses by recruiting CXCR3+ immune effector cells to the tumor site. Taking advantage of this property of CXCR3 ligands, we aimed to establish a novel approach to identify immunogenic mutated-antigens. We examined the feasibility of using CXCR3 ligand mRNAs as sensors for detection of specific immune responses in human and murine systems. We further investigated whether this approach is applicable for the identification of immunogenic mutated-antigens by using murine sarcoma lines. Rapid synthesis of CXCR3 ligand mRNAs occurred shortly after specific immune responses in both human and murine immune systems. Particularly, in CMS5 tumor-bearing mice, we detected specific immune responses to mutated mitogen-activated protein kinase 2 (ERK2), which has previously been identified as an immunogenic mutated-antigen. Furthermore, by combining this approach with whole-exome and transcriptome sequencing analyses, we identified an immunogenic neo-epitope derived from mutated staphylococcal nuclease domain-containing protein 1 (Snd1) in CMS7 tumor-bearing mice. Most importantly, we successfully detected the specific immune response to this neo-epitope even without co administration of anti-cytotoxic T-lymphocyte protein-4 (CTLA-4), anti-programmed cell death-1 (PD-1) and anti-glucocorticoid-induced TNFR-related protein (GITR) antibodies, which vigorously augmented the immune response and consequently enabled us to detect the specific immune response to this neo-epitope by conventional IFNgamma intracellular staining method. Our data indicate the potential usefulness of this strategy for the identification of immunogenic mutated-antigens. We propose that this approach would be of great help for the development of personalized cancer vaccine therapies in future. PMID- 28638726 TI - Downregulation of antigen presentation-associated pathway proteins is linked to poor outcome in triple-negative breast cancer patient tumors. AB - Triple-negative breast cancer (TNBC) is a heterogeneous subtype with varying disease outcomes. Tumor-infiltrating lymphocytes (TILs) are frequent in TNBC and have been shown to correlate with outcome, suggesting an immunogenic component in this subtype. However, other factors intrinsic to the cancer cells may also influence outcome. To identify proteins and molecular pathways associated with recurrence in TNBC, 34 formalin-fixed paraffin-embedded (FFPE) primary TNBC tumors were investigated by global proteomic profiling using mass spectrometry. Approximately, half of the patients were lymph node-negative and remained free of local or distant metastasis within 10 y follow-up, while the other half developed distant metastasis. Proteomic profiling identified >4,000 proteins, of which 63 exhibited altered expression in primary tumors of recurrence versus recurrence free patients. Importantly, downregulation of proteins in the major histocompatibility complex (MHC) class I antigen presentation pathways were enriched, including TAP1, TAP2, CALR, HLA-A, ERAP1 and TAPBP, and were associated with significantly shorter recurrence-free and overall survival. In addition, proteins involved in cancer cell proliferation and growth, including GBP1, RAD23B, WARS and STAT1, also exhibited altered expression in primary tumors of recurrence versus recurrence-free patients. The association between the antigen presentation pathway and outcome were validated in a second sample set of 10 primary TNBC tumors and corresponding metastases using proteomics and in a large public gene expression database of 249 TNBC and 580 basal-like breast cancer cases. Our study demonstrates that downregulation of antigen presentation is a key mechanism for TNBC cells to avoid immune surveillance, allowing continued growth and spread. PMID- 28638728 TI - Gene expression analysis in Cutaneous T-Cell Lymphomas (CTCL) highlights disease heterogeneity and potential diagnostic and prognostic indicators. AB - Cutaneous T-Cell Lymphomas (CTCL) are rare, but potentially devastating malignancies, whose pathogenesis remains poorly elucidated. Unfortunately, currently it is not possible to predict based on the available criteria in which patients the cancer will progress and which patients will experience an indolent disease course. Furthermore, at early stages this malignancy often masquerades as psoriasis, chronic eczema or other benign inflammatory dermatoses. As a result, it takes on average 6 y to diagnose this lymphoma since its initial presentation. In this study, we performed transcription expression profiling using TruSeq targeted RNA gene expression on 181 fresh and formalin-fixed and paraffin embedded (FFPE) skin samples from CTCL patients and patients affected by benign inflammatory dermatoses that often mimic CTCL clinically and on histology (e.g., psoriasis, chronic eczema, etc.) We also analyzed multiple longitudinal biopsies that were obtained from the same patients over time. Our results underscore significant molecular heterogeneity with respect to gene expression between different patients and even within the same patients over time. Our study also confirmed TOX, FYB, LEF1, CCR4, ITK, EED, POU2AF, IL26, STAT5, BLK, GTSF1 and PSORS1C2 genes as being differentially expressed between CTCL and benign skin biopsies. In addition, we found that differential expression for a subset of these markers (e.g., TOX, FYB, GTSF1 and CCR4) may be useful in prognosticating this disease. This research, combined with other molecular analyses, prepares the foundation for the development of personalized molecular approach toward diagnosis and management of CTCL. PMID- 28638729 TI - Cellular immunotherapies for cancer. AB - Lessons learned over decades on the use of gene and cell therapies have found clinical applicability in the field of cancer immunotherapy. On December 16th, 2016 a symposium was held in Pamplona (Spain) to analyze and discuss the critical points for the clinical success of adoptive cell transfer strategies in cancer immunotherapy. Cellular immunotherapy is being currently exploited for the development of new cancer vaccines using ex vivo manipulated dendritic cells or to enhance the number of effector cells, transferring reinvigorated NK cells or T cells. In this meeting report, we summarize the main topics covered and provide an overview of the field of cellular immunotherapy. PMID- 28638730 TI - Blockade of only TGF-beta 1 and 2 is sufficient to enhance the efficacy of vaccine and PD-1 checkpoint blockade immunotherapy. AB - Checkpoint inhibition has established immunotherapy as a major modality of cancer treatment. However, the success of cancer immunotherapy is still limited as immune regulation of tumor immunity is very complicated and mechanisms involved may also differ among cancer types. Beside checkpoints, other good candidates for immunotherapy are immunosuppressive cytokines. TGF-beta is a very potent immunosuppressive cytokine involved in suppression of tumor immunity and also necessary for the function of some regulatory cells. TGF-beta has three isoforms, TGF-beta 1, 2 and 3. It has been demonstrated in multiple mouse tumor models that inhibition of all three isoforms of TGF-beta facilitates natural tumor immunosurveillance and tumor vaccine efficacy. However, individual isoforms of TGF-beta are not well studied yet. Here, by using monoclonal antibodies (mAbs) specific for TGF-beta isoforms, we asked whether it is necessary to inhibit TGF beta3 to enhance tumor immunity. We found that blockade of TGF-beta1 and 2 and of all isoforms provided similar effects on tumor natural immunosurveillance and therapeutic vaccine-induced tumor immunity. The protection was CD8+ T cell dependent. Blockade of TGF-beta increased vaccine-induced Th1-type response measured by IFNgamma production or T-bet expression in both tumor draining lymph nodes and tumors, although it did not increase tumor antigen-specific CD8+ T cell numbers. Therefore, protection correlated with qualitative rather than quantitative changes in T cells. Furthermore, when combined with PD-1 blockade, blockade of TGF-beta1 and 2 further increased vaccine efficacy. In conclusion, blocking TGF-beta1 and 2 is sufficient to enhance tumor immunity, and it can be further enhanced with PD-1 blockade. PMID- 28638731 TI - Novel anti-myeloma immunotherapies targeting the SLAM family of receptors. AB - Treatment for multiple myeloma (MM) has significantly advanced in the last decade with the introduction of proteasome inhibitors and immunomodulatory therapies. Unfortunately, MM continues to cause significant morbidity and most patients eventually succumb to the disease. As in other areas of cancer, immunotherapy in MM has also evolved and holds promise to deliver long-lasting remissions or even cure. The signaling lymphocyte activation molecules (SLAM) family of surface proteins represents a group of potential targets for immunotherapy in MM as some of the family members are expressed consistently on plasma cells and also on myeloma propagating pre-plasma cells. Here, we review the SLAM family members in detail, describe their tissue distribution, biologic pathways, as well as relevant pre-clinical studies and clinical trials in MM. Our review demonstrates the value of SLAM family receptors as potential targets for anti-myeloma immunotherapies and outlines how immunotherapeutic approaches can be developed. PMID- 28638732 TI - Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer. AB - Up to now, the efficacy of programmed death protein 1/programmed death ligand 1 (PD-1/PD-L1) blockade in pancreatic cancer (PC) remains uncertain. Serum levels of soluble PD-1 and PD-L1 (sPD-1/sPD-L1) have been reported to be independent prognostic factors in solid tumors susceptible to checkpoint blockade. Provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer are poorly understood. To the best of our knowledge, sPD-1 and sPD-L1 have not been measured conjointly in any cancer type yet. In contrast to other tumor entities, sPD-1/sPD-L1 levels did not indicate an adverse outcome in a cohort of 41 patients with advanced PC. We observed a close positive correlation of sPD-L1 levels with sPD-1 in patients with advanced PC, suggesting a common provenience and regulation of sPD-1 and sPD-L1 in cancer patients. Higher sPD-L1 levels were present in patients with elevated C-reactive protein or strong tumoral T cell infiltration, while no correlation of sPD-L1 levels with tumoral PD-L1 expression was found. Our findings indicate that sPD-1 and sPD-L1 are markers of systemic inflammation in (pancreatic) cancer. In a subset of PC patients, elevation in sPD L1 levels might be caused by an inflammatory tumor type - independent of tumoral PD-L1 expression. PMID- 28638733 TI - Identification of autoantibodies to ECH1 and HNRNPA2B1 as potential biomarkers in the early detection of lung cancer. AB - Identification of biomarkers for early detection of lung cancer (LC) is important, in turn leading to more effective treatment and reduction of mortality. Serological proteome analysis (SERPA) was used to identify proteins around 34 kD as ECH1 and HNRNPA2B1, which had been recognized by serum autoantibody from 25 LC patients. In the validation study, including 90 sera from LC patients and 89 sera from normal individuals, autoantibody to ECH1 achieved an area under the curve (AUC) of 0.799 with sensitivity of 62.2% and specificity of 95.5% in discriminating LC from normal individuals, and showed negative correlation with tumor size (rs = -0.256, p = 0.023). Autoantibody to HNRNPA2B1 performed an AUC of 0.874 with sensitivity of 72.2% and specificity of 95.5%, and showed negative correlation with lymph node metastasis (rs = -0.279, p = 0.012). By using longitudinal preclinical samples, autoantibody to ECH1 showed an AUC of 0.763 with sensitivity of 60.0% and specificity of 89.3% in distinguishing early stage LC from matched normal controls, and elevated autoantibody levels could be detected greater than 2 y before LC diagnosis. ECH1 and HNRNPA2B1 are autoantigens that elicit autoimmune responses in LC and their autoantibody can be the potential biomarkers for the early detection of LC. PMID- 28638734 TI - Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells. AB - The mechanisms of immunogenicity underlying mild heat-shock (mHS) treatment < 42 degrees C of tumor cells are largely attributed to the action of heat-shock proteins; however, little is known about the immunogenicity of tumor cells undergoing severe cytotoxic heat-shock treatment (sHS > 43 degrees C). Here, we found that sHS, but not mHS (42 degrees C), induces immunogenic cell death in human cancer cell lines as defined by the induction of ER stress response and ROS generation, cell surface exposure of calreticulin, HSP70 and HSP90, decrease of cell surface CD47, release of ATP and HMGB1. Only sHS-treated tumor cells were efficiently killed and phagocytosed by dendritic cells (DCs), which was partially dependent on cell surface calreticulin. DCs loaded with mHS or sHS-treated tumor cells displayed similar level of maturation and stimulated IFNgamma-producing CD8+ T cells without any additional adjuvants in vitro. However, only DCs loaded with sHS-treated tumor cells stimulated antigen-specific CD4+ T cells and induced higher CD8+ T-cell activation and proliferation. sHS-treated murine cells also exposed calreticulin, HSP70 and HSP90 and activated higher DC maturation than mHS treated cells. Vaccination with sHS-treated tumor cells elicited protective immunity in mice. In this study, we defined specific conditions for the sHS treatment of human lung and ovarian tumor cells to arrive at optimal ratio between effective cell death, immunogenicity and content of tumor antigens for immunotherapeutic vaccine generation. PMID- 28638735 TI - Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant. AB - Among reported advantages of umbilical cord blood (CB) in transplantation is lower leukemia relapse probability. Underlying cellular mechanisms of graft-vs. leukemia (GVL) are thought to include a prominent role for T cells. Cells of the CB's mother, maternal microchimerism (MMc), were recently strongly, but indirectly, implicated in this GVL benefit. We assayed MMc directly and hypothesized benefit accrues from CB maternal T cells. MMc was quantified in 51 CBs and, within memory T, naive T, B, NK cells, and monocytes in 27 CBs. Polymorphism-specific quantitative-PCR assays targeted maternal genotypes non shared with CBs. Overall MMc was common and often at substantial levels. It was present in 52.9% of CB and in 33.3-55.6% of tested subsets. Remarkably, MMc quantities were greater in memory T cells than other subsets (p < 0.001). Expressed as genome equivalents (gEq) per 105 total gEq tested (gEq/105), memory T cell MMc averaged 850.2 gEq/105, while other subset mean quantities were 13.8 30.1 gEq/105. After adjustment for proportionality in CB, MMc remained 6-17 times greater in memory T, and 3-9 times greater in naive T, vs. non-T-cell subsets. Further, CB-origin MMc was detected in vivo in a patient up to 6 mo post transplantation, including among T cells. Overall, results revealed levels and phenotypes of CB MMc with potential relevance to CB transplantation and, more broadly, to offspring health. PMID- 28638736 TI - Transcriptional factor EB regulates macrophage polarization in the tumor microenvironment. AB - Tumor microenvironment (TME) contains a variety of infiltrating immune cells. Among them, tumor-associated macrophages (TAMs) and their alternative activation contribute greatly to the progression of tumors. The mechanisms governing macrophage polarization in the TME are unclear. Here, we show that in TAMs or macrophages under tumor-conditioned medium treatment, the expression of transcription factor EB (TFEB) is reduced and more of the TFEB protein is in an inactive cytosolic form. Transforming growth factor (TGF)-beta is identified as a main driving force for the reduced TFEB expression and activity in TAMs via activating ERK signaling. TFEB interference in macrophages significantly enhanced their alternative activation, with reduced expression of MHC-II and co stimulatory molecule CD80, decreased ability to activate T cells, and increased ability to attract tumor cells. When co-inoculated with tumor cells, macrophages with TFEB knockdown significantly enhanced tumor growth with increased infiltration of M2-like macrophages, reduced infiltration of CD8+ T cells, and enhanced angiogenesis in the tumors. Mechanistic studies revealed that TFEB downregulation resulted in macrophage M2 polarization through reducing SOCS3 production and enhancing STAT3 activation. We further demonstrate that the activation of TFEB by hydroxypropyl-beta-cyclodextrin in macrophages suppressed their M2 polarization and tumor-promoting capacity, and that macrophage-specific TFEB overexpression inhibited breast tumor growth in mice. Therefore, our data suggest that TFEB plays critical roles in macrophage polarization, and the downregulation of TFEB expression and activation is an integral part of tumor induced immune editing in the TME. This study provides a rationale for a new cancer treatment strategy by modulating macrophage polarization through activating TFEB. PMID- 28638737 TI - Selective activation of anti-CD73 mechanisms in control of primary tumors and metastases. AB - The emerging role for CD73 in driving cancer growth and metastasis has presented opportunities to develop anti-CD73 monoclonal antibodies (mAbs) in the treatment of human cancers. Blockade of CD73 by antagonistic CD73 mAbs ameliorates tumor growth and metastasis via the inhibition of enzymatic and non-enzymatic CD73 pathways. In this study, we investigated whether Fc-receptor cross-linking represented a non-redundant mechanism by which anti-CD73 mAbs exert potent suppression of solid tumors and metastases. We engineered four anti-CD73 mAbs, each different in their ability to modulate CD73 enzymatic function and bind Fc receptors. mAbs recognizing a similar epitope of CD73 (CD73-04, TY/23 and 2C5) displayed the greatest antitumor activity. Importantly, we observed that the optimal control of metastasis by anti-CD73 mAbs involved primarily Fc receptor engagement, while suppression of solid tumors required both, enzyme inhibition and activation of Fc receptors. Engagement of Fc-receptors was also essential for optimal anti-metastatic effect in combination with either A2AR inhibitor or anti PD-1 mAb treatment. The control of experimental metastases relied on the activation of host NK cells and IFNgamma, while NK cells, CD8+ T cells and IFNgamma were needed for effective antitumor effect in the spontaneous metastases model. These observations advance our understanding of the enzymatic and non enzymatic functions of anti-CD73 mAbs in solid tumors and metastases. Altogether, these findings will greatly assist in the design of anti-CD73 mAbs to be used as either single agents or in combination with other immunotherapeutic molecules or targeted therapies. PMID- 28638738 TI - Activation of the FcgammaReceptorIIIa on human natural killer cells leads to increased expression of functional interleukin-21 receptor. AB - Natural killer (NK) cells are innate immune effector cells that play a crucial role in immune surveillance and the destruction of cancer cells. NK cells express a low-affinity receptor for the Fc or constant region of immunoglobulin G (FcgammaRIIIa) and multiple cytokine receptors that respond to antibody-coated targets and cytokines in the tumor microenvironment. In the present work, microarray gene expression analysis revealed that the IL-21 receptor (IL-21R) was strongly upregulated following FcR stimulation. The IL-21R was found to be upregulated on FcR-stimulated NK cells at the transcript level as determined by reverse transcription polymerase chain reaction (RT-PCR). Immunoblot analysis revealed that protein expression of the IL-21R peaked at 8 h post-stimulation of the FcR. Inhibition of the mitogen-activated protein kinase (MAPK) pathway downstream of the FcR blocked the induction of IL-21R expression. Increased expression of the IL-21R sensitized NK cells to IL-21 stimulation, as treatment of FcR-stimulated NK cells led to significantly increased phosphorylation of STAT1 and STAT3, as measured by intracellular flow cytometry and immunoblot analysis. Following FcR-stimulation, IL-21-activated NK cells were better able to mediate the lysis of trastuzumab-coated human epidermal growth factor receptor 2 (HER2+) SK-BR-3 tumor cells as compared to control-treated cells. Likewise, IL-21 induced NK cell secretion of IFNgamma following exposure to antibody-coated tumor cells was enhanced following FcR-stimulation. The analysis of NK cells from patients receiving trastuzumab therapy for HER2+ cancer exhibited increased levels of the IL-21R following the administration of antibody suggesting that the presence of monoclonal antibody-coated tumor cells in vivo can stimulate the increased expression of IL-21R on NK cells. PMID- 28638739 TI - Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01 specific allorestricted T cell receptor transgenic T cells. AB - Background: Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A*02:01/CHM1 specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8+) T cells against ES. Patients and Methods: Three refractory HLA-A2+ ES patients were treated with HLA-A*02:01/peptide-specific allorepertoire-derived (i.e., allorestricted) CD8+ T cells. Patient #1 received up to 4.8 * 105/kg body weight HLA-A*02:01- allorestricted donor-derived wild-type CD8+ T cells. Patient #2 received up to 8.2 * 106/kg HLA-A*02:01- donor-derived and patient #3 up to 6 * 106/kg autologous allorestricted TCR transgenic CD8+ T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1 peptide 319 (CHM1319). Results: HLA-A*02:01/CHM1319-specific allorestricted CD8+ T cells showed specific in vitro lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GvHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1319 TCR transgenic T cells could be tracked in his BM for weeks. Conclusions: CHM1319-TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A*02:01/antigen specific allorestricted T cells proliferate in vivo without causing GvHD. PMID- 28638740 TI - Tumor cells PD-L1 expression as a favorable prognosis factor in nasopharyngeal carcinoma patients with pre-existing intratumor-infiltrating lymphocytes. AB - Programmed death ligand 1 (PD-L1) expression represents a mechanism of immune escape by inhibiting T cell immunity. This study systematically evaluated the expression of PD-L1, spatial distribution of CD3+ immune cells and the relationship of both factors to survival in nasopharyngeal carcinoma (NPC) patients. A total of 209 NPC patients treated between 1991 and 2000 were included. Pairs of TMAs were immunohistochemically stained with PD-L1 and CD3. Survival analysis was evaluated according to PD-L1 status and the spatial distribution of CD3+ immune cells in the primary lesion microenvironment. PD-L1 staining was observed on tumor cells and tumor-infiltrating immune cells (TILs); however, PD-L1-positive immune cells were more common (98/209) than PD-L1 positive tumor cells (68/209). Limited numbers of intra-tumoral CD3+ T cells (median number: 20) were detected. Patients with higher CD3+ T cell infiltration, both intratumorally and peritumorally, had higher PD-L1 expression on tumor cells (both p < 0.001) and immune cells (p = 0.002 and p < 0.001, respectively). Increasing intratumoral CD3 infiltration was correlated with increased overall survival (OS) (p = 0.008) and disease-free survival (DFS) (p = 0.003). Nevertheless, patients with low levels of peritumoral TILs showed superior OS (p = 0.557) and DFS to those with higher levels of peritumoral TILs (p = 0.671). Moreover, type classification based on intratumoral CD3 infiltration and tumor cell PD-L1 expression was an independent prognostic factor for NPC patients. PD L1 expression on tumor cells is a favorable prognosis factor in NPC patients with pre-existing intratumor-infiltrating lymphocytes. PMID- 28638741 TI - Innate gammadeltaT17 cells play a protective role in DSS-induced colitis via recruitment of Gr-1+CD11b+ myeloid suppressor cells. AB - Innate gammadelta T cells play critical roles in mucosal immunity such as regulating intestinal epithelial homeostasis. In addition, gammadelta T cells are significantly increased in the inflamed mucosa of patients with ulcerative colitis. However, gammadelta T cells are a heterogeneous population. IL-17 producing versus IFNgamma-producing gammadelta T cells play differential roles in different disease settings. Therefore, dissecting the exact role of different subsets of gammadelta T cells in colitis is essential for understanding colitis immunopathogenesis. In the current study, we found that TCR delta-deficient mice had a more severe dextran sodium sulfate (DSS)-induced colitis that was reduced upon reconstitution of gammadeltaT17 cells but not IFNgamma-producing gammadelta T cells. Immunophenotyping of the cellular infiltrate upon DSS-induced colitis showed a reduced infiltration of Gr-1+CD11b+ myeloid cells into the sites of inflammation in mice lacking gammadeltaT17 cells. Further experiments demonstrated that IL-17, IL-18, and chemokine CXCL5 were critical in Gr-1+CD11b+ myeloid cell recruitment. In vitro T cell suppressive assay indicated that this Gr-1+CD11b+ population was immunosuppressive. Depletion of Gr-1+CD11b+ myeloid cells resulted in an increase severity of DSS-induced colitis. Our study elucidates a new immune pathway involving gammadeltaT17-dependent recruitment of Gr-1+CD11b+ myeloid cells to the site of colitis inflammation important in the protection of colitis initiation and progression. PMID- 28638742 TI - An epigenetic modifier triggers therapeutic immune responses against breast cancer. PMID- 28638743 TI - Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications. AB - If there is a great new hope in the treatment of cancer, the immune system is it. Innate and adaptive immunity either promote or attenuate tumorigenesis and so can have opposing effects on the therapeutic outcome. Originally described as potent antivirals, Type-I interferons (IFNs) were quickly recognized as central coordinators of tumor-immune system interactions. Type-I-IFNs are produced by, and act on, both tumor and immune cells being either host-protecting or tumor promoting. Here, we discuss Type-I-IFNs in infectious and cancer diseases highlighting their dichotomous role and raising the importance to deeply understand the underlying mechanisms so to reshape the way we can exploit Type-I IFNs therapeutically. PMID- 28638744 TI - Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects. AB - The demethylating agent 5-azacytidine (AZA) has proven its efficacy in the treatment of myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Treg). Here, we investigated the impact of AZA on xenogeneic graft-vs.-host disease (xGVHD) and graft-vs.-leukemia effects in a humanized murine model of transplantation (human PBMCs-infused NSG mice), and described the impact of the drug on human T cells in vivo. We observed that AZA improved both survival and xGVHD scores. Further, AZA significantly decreased human T-cell proliferation as well as IFNgamma and TNF-alpha serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA significantly increased Treg frequency through hypomethylation of FOXP3i1 as well as increased Treg proliferation. The latter was subsequent to higher STAT5 signaling in Treg from AZA-treated mice, which resulted from higher IL-2 secretion by conventional T cells from AZA-treated mice itself secondary to demethylation of the IL-2 gene promoter by AZA. Importantly, Tregs harvested from AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Finally, graft-vs.-leukemia effects (assessed by growth inhibition of THP-1 cells, transfected to express the luciferase gene) were not abrogated by AZA. In summary, our data demonstrate that AZA prevents xGVHD without abrogating graft-vs.-leukemia effects. These findings could serve as basis for further studies of GVHD prevention by AZA in acute myeloid leukemia patients offered an allogeneic transplantation. PMID- 28638746 TI - A Quantitative Study on Anonymity and Professionalism within an Online Free Open Access Medical Education Community. AB - The increasing use of social media to share knowledge in medical education has led to concerns about the professionalism of online medical learners and physicians. However, there is a lack of research on the behavior of professionals within open online discussions. In 2013, the Academic Life in Emergency Medicine website (ALiEM.com) launched a series of moderated online case discussions that provided an opportunity to explore the relationship between anonymity and professionalism. Comments from 12 case discussions conducted over a one-year period were analyzed using modified scales of anonymity and professionalism derived by Kilner and Hoadley. Descriptive statistics and Spearman calculations were conducted for the professionalism score, anonymity score, and level of participation. No correlation was found between professionalism and anonymity scores (rho = -0.004, p = 0.97). However, the number of comments (rho = 0.35, p < 0.01) and number of cases contributed to (rho = 0.26, p < 0.05) correlated positively with clear identification. Our results differed from previous literature, the majority of which found anonymity associated with unprofessionalism. We believe that this may be a result of the fostering of a professional environment through the use of a website with a positive reputation, the modelling of respectful behaviour by the moderators, the norms of the broader online community, and the pre-specified objectives for each discussion. PMID- 28638745 TI - Obesity, Cardiovascular Disease and Sleep Disorders: Insights into the Rising Epidemic. AB - Cardiovascular disease (CVD) is the main cause of death among adult men and women in the USA and impacts millions around the globe. Traditional risk factors for CVD include obesity, diabetes, hypertension and dyslipidemia. The modern-day epidemic of obesity not only increased the rate of CVD but also ushered in an additional CVD risk factor to be added to the list; that is obstructive sleep apnea (OSA). In this review, we discuss the growing epidemic of obesity and OSA, highlighting the common pathogenic hypotheses linking these risk factors to CVD. We will also highlight the therapeutic rationale of OSA as a way to reduce CVD risk. PMID- 28638747 TI - Health Care Disparities Among Lesbian, Gay, Bisexual, and Transgender Youth: A Literature Review. AB - About 3.5% Americans identify themselves as lesbian, gay, or bisexual while 0.3% identify themselves as transgender. The LGBT (lesbian, gay, bisexual, and transgender) community belongs to almost every race, ethnicity, religion, age, and socioeconomic group. The LGBT youth are at a higher risk for substance use, sexually transmitted diseases (STDs), cancers, cardiovascular diseases, obesity, bullying, isolation, rejection, anxiety, depression, and suicide as compared to the general population. LGBT youth receive poor quality of care due to stigma, lack of healthcare providers' awareness, and insensitivity to the unique needs of this community. The main objective of this literature review is to highlight the challenges faced by the LGBT youth and to enhance the awareness among physicians about the existing disparities in order to provide a more comprehensive, evidence based, and humane medical care to this community. PMID- 28638748 TI - Policy Address. PMID- 28638750 TI - Lecture by Sir Michael Marmot, President of the World Medical Association-Asking for the engagement of doctors in "Social Determinations of Health". PMID- 28638749 TI - JMA President Dr. Yokokura Was Elected to the WMA Presidency. PMID- 28638751 TI - The 2nd World Veterinary Association-World Medical Association Global Conference on One Health. PMID- 28638752 TI - Japan Medical Association's Efforts in Dealing with Dementia. PMID- 28638753 TI - Healthcare Delivery to a Repopulated Village after the Fukushima Nuclear Disaster: A Case of Kawauchi Village, Fukushima, Japan. PMID- 28638754 TI - Report on the World Medical Association General Assembly and the Junior Doctors Network Meetings, Taipei, 2016. PMID- 28638755 TI - From a Far Eastern Study Room. PMID- 28638756 TI - From the Editor's Desk. PMID- 28638757 TI - (BEDT-TTF)2Cu2(HCOO)5: An Organic-Inorganic Hybrid Conducting Magnet. AB - This month's cover picture results from Professor Bin Zhang's collaborative work between Chinese Academy of Sciences and Peking University (China). Since the discovery of high-temperature superconductors for hole doping on parent antiferromagnetic compound La2CuO4, the antiferromagnetic molecular crystal with a (4,4) grid copper-formate framework Cu(HCOO)2(H2O)4 and its deuterated compound (Cu(DCOO)2(D2O)4) have been studied extensively for supposed dual-functional molecular crystals. The cover picture shows the ideal situation by replacing intercalated H2O with an organic donor. The organic-inorganic hybrid (BEDT TTF)2Cu2(HCOO)5 is obtained through the electrochemical oxidation of neutral BEDT TTF in the presence of an ammonium salt of the 1D copper-formate framework [(C2H5)3NH]2Cu2(HCOO)5 in a C6H5Cl-C2H5OH solution. For more details, read the full text of the Communication at 10.1002/open.201700041. PMID- 28638758 TI - Virtual Issue: Advances in Electrochemistry. AB - Advances in Electrochemistry! This Virtual Issue on Advances in Electrochemistry highlights the rich diversity in the exciting and dynamic field of electrochemistry. PMID- 28638759 TI - Synthetic Approaches toward Monocyclic 3-Amino-beta-lactams. AB - Due to the emerging resistance against classical beta-lactam-based antibiotics, a growing number of bacterial infections has become harder to treat. This alarming tendency necessitates continued research on novel antibacterial agents. Many classes of beta-lactam antibiotics are characterized by the presence of the 3 aminoazetidin-2-one core, which resembles the natural substrate of the target penicillin-binding proteins. In that respect, this Review summarizes the different synthetic pathways toward this key structure for the development of new antibacterial agents. The most extensively applied methods for 3-amino-beta lactam ring formation are discussed, in addition to a few less common strategies. Moreover, approaches to introduce the 3-amino substituent after ring formation are also covered. PMID- 28638760 TI - (BEDT-TTF)2Cu2(HCOO)5: An Organic-Inorganic Hybrid Conducting Magnet. AB - A dual-functional organic-inorganic hybrid (BEDT-TTF)2Cu2(HCOO)5 (1) (BEDT TTF=bis(ethylenedithio)tetrathiafulvalene) was obtained through the electrochemical oxidation of neutral BEDT-TTF in the presence of an ammonium salt of the one-dimensional copper-formate framework [(C2H5)3NH]2Cu2(HCOO)5 in a C6H5Cl-C2H5OH solution. Compound 1 was composed of organic donor BEDT-TTF+0?5 in a theta-phase arrangement and Jahn-Teller distorted (4,4) grid anion sheets [Cu2(HCOO)5-] n with S=1/2. We identified the material as a semiconductor with values of sigma300K=10-1 S cm-1. The anion sheet is a coordination isomer of [Cu2(HCOO)5-] n and, compared with the starting material, shows antiferromagnetic behavior as the well-known inorganic Cu-O, Co-O square layers for creating inorganic conducting magnets. Long-range antiferromagnetic ordering was observed at 8.0 K. PMID- 28638761 TI - Peroxidase Activity of a c-Type Cytochrome b5 in the Non-Native State is Comparable to that of Native Peroxidases. AB - The design of artificial metalloenzymes has achieved tremendous progress, although few designs can achieve catalytic performances comparable to that of native enzymes. Moreover, the structure and function of artificial metalloenzymes in non-native states has rarely been explored. Herein, we found that a c-type cytochrome b5 (Cyt b5), N57C/S71C Cyt b5, with heme covalently attached to the protein matrix through two Cys-heme linkages, adopts a non-native state with an open heme site after guanidine hydrochloride (Gdn?HCl)-induced unfolding, which facilitates H2O2 activation and substrate binding. Stopped-flow kinetic studies further revealed that c-type Cyt b5 in the non-native state exhibited impressive peroxidase activity comparable to that of native peroxidases, such as the most efficient horseradish peroxidase. This study presents an alternative approach to the design of functional artificial metalloenzymes by exploring enzymatic functions in non-native states. PMID- 28638763 TI - The Hidden Face of Wine Polyphenol Polymerization Highlighted by High-Resolution Mass Spectrometry. AB - Polyphenols, including tannins and red anthocyanin pigments, are responsible for the color, taste, and beneficial health properties of plant-derived foods and beverages, especially in red wines. Known compounds represent only the emerged part of the "wine polyphenol iceberg". It is believed that the immersed part results from complex cascades of reactions involving grape polyphenols and yeast metabolites. We used a non-targeted strategy based on high-resolution mass spectrometry and Kendrick mass defect plots to explore this hypothesis. Reactions of acetaldehyde, epicatechin, and malvidin-3-O-glucoside, representing yeast metabolites, tannins, and anthocyanins, respectively, were selected for a proof of-concept experiment. A series of compounds including expected and so-far unknown structures were detected. Random polymerization involving both the original substrates and intermediate products resulting from cascade reactions was demonstrated. PMID- 28638762 TI - Reductive Deamination by Benzyne for Deoxy Sugar Synthesis Through a Domino Reaction. AB - Benzyne was developed as a reducing agent in the key step of converting amino sugars and ketoses into deoxy sugars, which occur widely in natural products. Many deoxy sugars exhibit antibiotic and anticancer activities, and furthermore, they play essential biological roles. By treatment with CS2 and then Ac2O, amino sugars and ketoses were converted into the corresponding 1,3-thiazolidine-2 thiones. In the key step, these intermediates were treated with 2 trimethylsilylphenyl triflate (2.0 equiv.) and CsF (3.0 equiv.) in MeCN at 25 degrees C to produce acyclic enol acetates in 60-63 % yields. Saponification of the enol acetates with NaOMe/MeOH followed by intramolecular cyclization afforded the target 2-deoxy sugars. The key step of the reductive deamination involved a domino 1,2-elimination/[3+2]-cycloaddition/retro [3+2]-ring-opening sequence. The generality of this new method was proven by the use of various substrates, including pentoses, hexoses, monosaccharides, disaccharides, aldoses, and ketoses. PMID- 28638764 TI - Small-Molecule Dengue Virus Co-imprinting and Its Application as an Electrochemical Sensor. AB - Polymers can be synthesized to recognize small molecules. This is achieved by introducing the target molecule during monomer self-assembly, where they can be incorporated during cross-linking polymerization. Following additional pre processing, the material obtained can then be applied as a sensing layer for these molecules in many applications. The sensitivity of the polymers depends on the "active sites" imprinted on the surface. Increasing the number of active sites on the polymers surface can be achieved by using nanoparticles as a platform to support and concentrate the molecules for imprinting. In this work, we report the first use of dengue virus as a supporting nanoparticle to make for a more effective polymer composite sensor for the detection of bisphenol A (BPA), which is an environmental contaminant. The dengue virus has a nanoparticle size of around 100 nm and its surface provides regions where lipids and hydrophobic compounds can bind, making it an ideal support. The mixing of BPA with dengue prior to monomer self-assembly led to imprinted polymer surfaces with much higher density BPA binding sites and a limit of detection of 0.1 pm. We demonstrate that a BPA-dengue co-imprinting polymer composite sensor shows a very high sensitivity for BPA, but with lower production costs and technical requirements than other comparable methods. PMID- 28638765 TI - Convenient and General Zinc-Catalyzed Borylation of Aryl Diazonium Salts and Aryltriazenes under Mild Conditions. AB - A convenient and general zinc-catalyzed borylation of aryl diazonium salts and aryltriazenes has been developed. With bis- (pinacolato)diboron as the borylation reagent, aryldiazonium tetrafluoroborate salts and aryltriazenes were transformed into the corresponding arylboronates in moderate to excellent yields under mild conditions. As a convenient and practical methodology, no additional ligands, base, or any other additives are required here. PMID- 28638766 TI - Metalate-Mediated Functionalization of P4 by Trapping Anionic [Cp*Fe(CO)2(eta1 P4)]- with Lewis Acids. AB - The development of selective functionalization strategies of white phosphorus (P4) is important to avoid the current chlorinated intermediates. The use of transition metals (TMs) could lead to catalytic procedures, but these are severely hampered by the high reactivity and unpredictable nature of the tetrahedron. Herein, we report selective first steps by reacting P4 with a metal anion [Cp*Fe(CO)2]- (Cp*=C5(CH3)5), which, in the presence of bulky Lewis acids (LA; B(C6F5)3 or BPh3), leads to unique TM-substituted LA-stabilized bicyclo[1.1.0]tetraphosphabutanide anions [Cp*Fe(CO)2(eta1-P4?LA)]-. Their P nucleophilic site can be subsequently protonated to afford the transient LA-free neutral butterflies exo,endo- and exo,exo-Cp*Fe- (CO)2(eta1-P4H), allowing controllable stepwise metalate-mediated functionalization of P4. PMID- 28638767 TI - Novel 5-(Benzo[b]thiophen-3-yl)pyridine-3-carbaldehyde (BTPA) Functionalization Framework For Modulating Fullerene Electronics. AB - Through a cycloaddition reaction, fullerene (C60) was derivatized with a novel organic compound 5-(benzo[b]thiophen-3-yl)pyridine-3-carbaldehyde to form the processable and stable 3-(benzo[b]thiophene-3yl)-5-fullero-1 methylpyrrolidinepyridine (BTFP) compound. BTFP exhibits close similarities to phenyl-C61-butyric-acid-methyl-ester (PCBM) in terms of first reduction potential values (-0.62 and -0.61 V vs. Ag/AgCl, for BTFP and PCBM, respectively) and lowest occupied molecular orbital (LUMO) energy level values (3.93 eV in both cases). In chloroform, BTFP exhibits a bathochromic shift in the lambdamax of BTFP (lambdamax,BTFP=290 nm and lambdamax,PCBM=260 nm), owing to the grafted benzo[b]thiophene-3-yl)pyridine moiety. Despite the similarity in LUMO (3.93 eV) energy values, BTFP and PCBM differ in their luminescence-quenching ability. The bathochromic shift in the lambdamax of BTFP (relative to PCMB) is likely to contribute to improved light absorption of a suitable donor for photovoltaic applications. PMID- 28638768 TI - Spin-Forbidden Branching in the Mechanism of the Intrinsic Haber-Weiss Reaction. AB - The mechanism of the O2?- and H2O2 reaction (Haber-Weiss) under solvent-free conditions has been characterized at the DFT and CCSD(T) level of theory to account for the ease of this reaction in the gas phase and the formation of two different set of products (Blanksby et al., Angew. Chem. Int. Ed. 2007, 46, 4948). The reaction is shown to proceed through an electron-transfer process from the superoxide anion to hydrogen peroxide, along two pathways. While the O3?- + H2O products are formed from a spin-allowed reaction (on the doublet surface), the preferred products, O?-(H2O)+3O2, are formed through a spin-forbidden reaction as a result of a favorable crossing point between the doublet and quartet surface. Plausible reasons for the preference toward the latter set are given in terms of the characteristics of the minimum energy crossing point (MECP) and the stability of an intermediate formed (after the MECP) in the quartet surface. These unique results show that these two pathways are associated with a bifurcation, yielding spin-dependent products. PMID- 28638769 TI - Deeper Insight into the Six-Step Domino Reaction of Aldehydes with Malononitrile and Evaluation of Antiviral and Antimalarial Activities of the Obtained Bicyclic Products. AB - The straightforward and efficient synthesis of complex aza- and carbobicyclic compounds, which are of importance for medicinal chemistry, is a challenge for modern chemical methodology. An unprecedented metal-free six-step domino reaction of aldehydes with malononitrile was presented in our previous study to provide, in a single operation, these bicyclic nitrogen-containing molecules. Presented here is a deeper investigation of this atom-economical domino process by extending the scope of aldehydes, performing post-modifications of domino products, applying bifunctional organocatalysts and comprehensive NMR studies of selected domino products. The thermodynamic aspects of the overall reaction are also demonstrated using DFT methods in conjunction with a semi-empirical treatment of van der Waals interactions. Furthermore, biological studies of seven highly functionalized and artemisinin-containing domino products against human cytomegalovirus (HCMV) and Plasmodium falciparum 3D7 are presented. Remarkably, in vitro tests against HCMV revealed five domino products to be highly active compounds (EC50 0.071-1.8 MUm), outperforming the clinical reference drug ganciclovir (EC50 2.6 MUm). Against P. falciparum 3D7, three of the investigated artemisinin-derived domino products (EC50 0.72-1.8 nm) were more potent than the clinical drug chloroquine (EC50 9.1 nm). PMID- 28638770 TI - Sequential Uncaging with Green Light can be Achieved by Fine-Tuning the Structure of a Dicyanocoumarin Chromophore. AB - We report the synthesis and photochemical properties of a series of dicyanocoumarinylmethyl (DEAdcCM)- and dicyanocoumarinylethyl (DEAdcCE)-based photocages of carboxylic acids and amines with absorption maximum around 500 nm. Photolysis studies with green light have demonstrated that the structure of the coumarin chromophore as well as the nature of the leaving group and the type of bond to be photocleaved (ester or carbamate) have a strong influence on the rate and efficiency of the uncaging process. These experimental observations were also supported by DFT calculations. Such differences in deprotection kinetics have been exploited to sequentially photolyze two dicyanocoumarin-caged model compounds (e.g., benzoic acid and ethylamine), and open the way to increasing the number of functional levels that can be addressed with light in a single system, particularly when combining dicyanocoumarin caging groups with other photocleavable protecting groups, which remain intact under green light irradiation. PMID- 28638771 TI - Electronic pi-to-pi* Excitations of Rhodamine Dyes Exhibit a Time-Dependent Kohn Sham Theory "Cyanine Problem". AB - The longest-wavelength pi-to-pi* electronic excitations of rhodamine-like dyes (RDs) with different group 16 heteroatoms (O, S, Se, Te) have been investigated. Time-dependent Kohn-Sham theory (TDKST) calculations were compared with coupled cluster (CC) and equations-of-motion (EOM) CC results for pi-to-pi* singlet and triplet excitations. The RDs exhibit characteristics in the TDKST calculations that are very similar to previously investigated cyanine dyes, in the sense that the singlet energies obtained with nonhybrid functionals are too high compared with the CC results at the SD(T) level. The errors became increasingly larger for functionals with increasing amounts of exact exchange. TDKST with all tested functionals led to severe underestimations of the corresponding triplet excitations and overestimations of the singlet-triplet gaps. Long-range-corrected range-separated exchange and "optimal tuning" of the range separation parameter did not significantly improve the TDKST results. A detailed analysis suggests that the problem is differential electron correlation between the ground and excited states, which is not treated sufficiently by the relatively small integrals over the exchange-correlation response kernel that enter the excitation energy expression. Numerical criteria are suggested that may help identify "cyanine-like" problems in TDKST calculations of excitation spectra. PMID- 28638772 TI - Tin, Bismuth, and Tin-Bismuth Alloy Electrodeposition from Chlorometalate Salts in Deep Eutectic Solvents. AB - The electrodeposition of tin, bismuth, and tin-bismuth alloys from SnII and BiIII chlorometalate salts in the choline chloride/ethylene glycol (1:2 molar ratio) deep eutectic solvent was studied on glassy carbon and gold by cyclic voltammetry, rotating disc voltammetry, and chronoamperometry. The SnII containing electrolyte showed one voltammetric redox process corresponding to SnII/Sn0. The diffusion coefficient of [SnCl3]-, detected as the dominating species by Raman spectroscopy, was determined from Levich and Cottrell analyses. The BiIII-containing electrolyte showed two voltammetric reduction processes, both attributed to BiIII/Bi0. Dimensionless current/time transients revealed that the electrodeposition of both Sn and Bi on glassy carbon proceeded by 3D progressive nucleation at a low overpotential and changed to instantaneous at higher overpotentials. The nucleation rate of Bi on glassy carbon was considerably smaller than that of Sn. Elemental Sn and Bi were electrodeposited on Au-coated glass slides from their respective salt solutions, as were Sn-Bi alloys from a 2:1 SnII/BiIII solution. The biphasic Sn-Bi alloys changed from a Bi-rich composition to a Sn-rich composition by making the deposition potential more negative. PMID- 28638773 TI - beta-Octabromo- and beta-Octakis(trifluoromethyl)isocorroles: New Sterically Constrained Macrocyclic Ligands. AB - Presented herein is a study of the acid-induced demetalation of two sterically hindered copper corroles, Cu beta-octabromo-meso-triphenylcorrole (Cu[Br8TPC]) and beta-octakis(trifluoromethyl)-meso-tris(p-methoxyphenyl)corrole (Cu[(CF3)8TpOMePC]). Unlike reductive demetalation, which affords the free-base beta-octabromocorrole, demetalation of Cu[Br8TPC] under non- reductive conditions (CHCl3/H2SO4) resulted in moderate yields of free-base 5- and 10-hydroxy isocorroles. The isomeric free bases could be complexed to CoII and NiII, affording stable complexes. Only reductive demetalation was found to work for Cu[(CF3)8TpOMePC], affording a highly saddled, hydrated corrole, H3[5-OH,10-H (CF3)8TpOMePC], where the elements of water had added across C5 and C10. Interaction of this novel free base with CoII resulted in Co[iso-10-H [CF3)8TpOMePC], a CoII 10-hydro isocorrole. The new metal complexes were all characterized by single-crystal X-ray diffraction analysis and, despite their sterically hindered nature, were found to exhibit almost perfectly planar isocorrole cores. PMID- 28638774 TI - Nature of the Ru-NO Coordination Bond: Kohn-Sham Molecular Orbital and Energy Decomposition Analysis. AB - We have analyzed structure, stability, and Ru-NO bonding of the trans [RuCl(NO)(NH3)4]2+ complex by using relativistic density functional theory. First, we focus on the bond dissociation energies associated with the three canonical dissociation modes leading to [RuCl(NH3)4]++NO+, [RuCl(NH3)4]2++NO, and [RuCl(NH3)4]3++NO-. The main objective is to understand the Ru-NO+ bonding mechanism in the conceptual framework of Kohn-Sham molecular orbital theory in combination with a quantitative energy decomposition analysis. In our analyses, we have addressed the importance of the synergism between Ru-NO+ sigma-donation and pi-backdonation as well as the so-called negative trans influence of the Cl- ligand on the Ru-NO bond. For completeness, the Ru-NO+ bonding mechanism is compared with that of the corresponding Ru-CO bond. PMID- 28638775 TI - Host-Guest Complexes of C-Ethyl-2-methylresorcinarene and Aromatic N,N'-Dioxides. AB - The C-ethyl-2-methylresorcinarene (1) forms 1:1 in-cavity complexes with aromatic N,N'-dioxides, only if each of the aromatic rings has an N-O group. The structurally different C-shaped 2,2'-bipyridine N,N'-dioxide (2,2'-BiPyNO) and the linear rod-shaped 4,4'-bipyridine N,N'-dioxide (4,4'-BiPyNO) both form 1:1 in cavity complexes with the host resorcinarene in C4v crown and C2v conformations, respectively. In the solid state, the host-guest interactions between the 1,3 bis(4-pyridyl)propane N,N'-dioxide (BiPyPNO) and the host 1 stabilize the unfavorable anti-gauche conformation. Contrary to the N,N'-dioxide guests, the mono-N-oxide guest, 4-phenylpyridine N-oxide (4PhPyNO), does not form an in cavity complex in the solid state. The host-guest complexation and the relative guest affinities were studied through 1H NMR competition experiments in methanol. Single-crystal X-ray crystallography of the 1:1 complexes supports the proposed solution-state structures, also revealing strong hydrogen bonds between the host and the guests, not observed in solution owing to hydrogen/deuterium (H/D) exchange processes in methanol. PMID- 28638776 TI - Synthetic Approaches for the Preparation of Phosphoramidate Prodrugs of 2' Deoxypseudoisocytidine. AB - A synthetic procedure for the preparation of phosphoramidate prodrugs of C nucleosides is reported. Different phosphorochloridates were reacted with 3'-O protected N-acetyl-2'-deoxypseudoisocytidine or 3'-O-protected 2' deoxypseudoisocytidine, followed by acidic hydrolysis of the protecting group. In the presence of the N-acetyl moiety, the enolisable keto group of the nucleobase was able to react (like the 5'-OH) with the phosphorochloridates to give bisphosphorylated derivatives. Epimerisation (beta to alpha) occurred if the amino group of the nucleobase was unprotected. These side reactions demonstrate the peculiar behaviour of C-nucleosides compared to their nucleoside analogues. It was demonstrated that the first enzymatic activation step for this new class of prodrugs can be mediated by carboxypeptidase and that it follows the same pathway and rate reported for ProTides of more conventional nucleoside analogues. These new phosphoramidate derivatives deserve further investigation for their therapeutic potential as anti-cancer agents. PMID- 28638777 TI - Heterobifunctional Dyes: Highly Fluorescent Linkers Based on Cyanine Dyes. AB - Herein, we present a new synthetic route to cyanine-based heterobifunctional dyes and their application as fluorescent linkers between polymers and biomolecules. The synthesized compounds, designed in the visible spectral range, are equipped with two different reactive groups for highly selective conjugation under physiological conditions. By applying indolenine precursors with functionalized benzenes, we achieved water-soluble asymmetric cyanine dyes bearing maleimido and N-hydroxysuccinimidyl functionalities in a three-step synthesis. Spectroscopic characterization revealed good molar absorption coefficients and moderate fluorescence quantum yields. Further reaction with polyethylene glycol yielded dye-polymer conjugates that were subsequently coupled to the antibody cetuximab, often applied in cancer therapy. Successful coupling was confirmed by mass shifts detected by gel electrophoresis. Receptor-binding studies and live-cell imaging revealed that labeling did not alter the biological function. In sum, we provided a successful synthetic pathway to rigid heterobifunctional cyanine dyes that are applicable as fluorescent linkers, for example, for connecting antibodies with macromolecules. Our approach contributes to the field of bioconjugation chemistry, such as antibody-drug conjugates by combining diagnostic and therapeutic approaches. PMID- 28638778 TI - Synthesis and Detonation Properties of 5-Amino-2,4,6-trinitro-1,3-dihydroxy benzene. AB - 5-Amino-4,6-dinitro-1,3-dihydroxy-benzene (6) was synthesized through the ring opening reaction of macrocyclic compound 4 with the aid of VNS (vicarious nucleophilic substitution of hydrogen) reaction conditions. The mechanism of ring opening of macrocyclic compound 4 was studied. 5-Amino-2,4,6-trinitro-1,3 dihydroxy-benzene (8) was obtained after the nitration of 6 in KNO3 and concentrated sulfuric acid. The thermal stability, sensitivity, and other detonation performances of 6 or 8 were compared to commercially used 1,3,5 triamino-2,4,6-trinitrobenzene (TATB) or 1,3,5-trinitrotriazacyclohexane (RDX), respectively. All target compounds were characterized by using single-crystal X ray diffraction, NMR spectroscopy, elemental analysis, and differential scanning calorimetry. The sensitivities were determined by using BAM methods (drop-hammer and friction tests). Performance parameters, including heats of formation and detonation properties, were calculated by using Gaussian 03 and EXPLO5 v6.01 programs, respectively. It is worth pointing out that compound 8 has a remarkable measured density of 2.078 g cm-3 at 298 K. In addition, compound 8 is more insensitive than RDX (compound 8: IS=11 J; RDX: IS=7 J; IS is the impact sensitivity). PMID- 28638779 TI - Emerging Trends in Phosphorene Fabrication towards Next Generation Devices. AB - The challenge of science and technology is to design and make materials that will dominate the future of our society. In this context, black phosphorus has emerged as a new, intriguing two-dimensional (2D) material, together with its monolayer, which is referred to as phosphorene. The exploration of this new 2D material demands various fabrication methods to achieve potential applications- this demand motivated this review. This article is aimed at supplementing the concrete understanding of existing phosphorene fabrication techniques, which forms the foundation for a variety of applications. Here, the major issue of the degradation encountered in realizing devices based on few-layered black phosphorus and phosphorene is reviewed. The prospects of phosphorene in future research are also described by discussing its significance and explaining ways to advance state-of-art of phosphorene-based devices. In addition, a detailed presentation on the demand for future studies to promote well-systemized fabrication methods towards large-area, high-yield and perfectly protected phosphorene for the development of reliable devices in optoelectronic applications and other areas is offered. PMID- 28638781 TI - Bioinspired Mechano-Sensitive Macroporous Ceramic Sponge for Logical Drug and Cell Delivery. AB - On-demand, ultrahigh precision delivery of molecules and cells assisted by scaffold is a pivotal theme in the field of controlled release, but it remains extremely challenging for ceramic-based macroporous scaffolds that are prevalently used in regenerative medicine. Sea sponges (Phylum Porifera), whose bodies possess hierarchical pores or channels and organic/inorganic composite structures, can delicately control water intake/circulation and therefore achieve high precision mass transportation of food, oxygen, and wastes. Inspired by leuconoid sponge, in this study, the authors design and fabricate a biomimetic macroporous ceramic composite sponge (CCS) for high precision logic delivery of molecules and cells regulated by mechanical stimulus. The CCS reveals unique on demand AND logic release behaviors in response to dual-gates of moisture and pressure (or strain) and, more importantly, 1 cm3 volume of CCS achieves unprecedentedly delivery precision of ~100 ng per cycle for hydrophobic or hydrophilic molecules and ~1400 cells per cycle for fibroblasts, respectively. PMID- 28638782 TI - Hot Hole Enhanced Synergistic Catalytic Oxidation on Pt-Cu Alloy Clusters. AB - Hot holes in Pt-Cu alloy clusters can act as catalyst to accelerate the intrinsic aerobic oxidation reactions. It is described that under visible light irradiation the synergistic alcohol catalytic oxidation on Pt-Cu alloy clusters (~1.1 nm)/TiO2 nanobelts could be significant promoted by interband-excitation generated long-lifetime hot holes in the clusters. PMID- 28638784 TI - Coordination of Surface-Induced Reaction and Intercalation: Toward a High Performance Carbon Anode for Sodium-Ion Batteries. AB - Oxygen-rich carbon material is successfully fabricated from a porous carbon and evaluated as anode for sodium-ion battery. With the strategy of optimal combination of fast surface redox reaction and reversible intercalation, the oxygen-rich carbon anode exhibits a large reversible capacity (447 mAh g-1 at 0.2 A g-1), high rate capability (172 mAh g-1 at 20 A g-1), and excellent cycling stability. PMID- 28638783 TI - Recent Advances of Activatable Molecular Probes Based on Semiconducting Polymer Nanoparticles in Sensing and Imaging. AB - Molecular probes that change their signals in response to the target of interest have a critical role in fundamental biology and medicine. Semiconducting polymer nanoparticles (SPNs) have recently emerged as a new generation of purely organic photonic nanoagents with desirable properties for biological applications. In particular, tunable optical properties of SPNs allow them to be developed into photoluminescence, chemiluminescence, and photoacoustic probes, wherein SPNs usually serve as the energy donor and internal reference for luminescence and photoacoustic probes, respectively. Moreover, facile surface modification and intraparticle engineering provide the versatility to make them responsive to various biologically and pathologically important substances and indexes including small-molecule mediators, proteins, pH and temperature. This article focuses on recent advances in the development of SPN-based activatable molecular probes for sensing and imaging. The designs and applications of these probes are discussed in details, and the present challenges to further advance them into life science are also analyzed. PMID- 28638785 TI - Hydrophilic Sponges for Leaf-Inspired Continuous Pumping of Liquids. AB - A bio-inspired, leaf-like pumping strategy by mimicking the transpiration process through leaves is developed for autonomous and continuous liquid transport enabled by durable hydrophilic sponges. Without any external power sources, flows are continuously generated ascribed to the combination of capillary wicking and evaporation of water. To validate this method, durable hydrophilic polydimethylsiloxane sponges modified with polyvinyl alcohol via a "dip-coat-dry" method have been fabricated, which maintains hydrophilicity more than 2 months. The as-made sponges are further applied to achieve stable laminar flow patterns, chemical gradients, and "stop-flow" manipulation of the flow in microfluidic devices. More importantly, the ease-of-operation and excellent pumping capacity have also been verified with over 24 h's pumping and quasi-stable high flow rates up to 15 uL min-1. The present strategy can be easily integrated to other miniaturized systems requiring pressure-driven flow and should have potential applications, such as cell culture, micromixing, and continuous flow reaction. PMID- 28638780 TI - Materials Design and System Construction for Conventional and New-Concept Supercapacitors. AB - With the development of renewable energy and electrified transportation, electrochemical energy storage will be more urgent in the future. Supercapacitors have received extensive attention due to their high power density, fast charge and discharge rates, and long-term cycling stability. During past five years, supercapacitors have been boomed benefited from the development of nanostructured materials synthesis and the promoted innovation of devices construction. In this review, we have summarized the current state-of-the-art development on the fabrication of high-performance supercapacitors. From the electrode material perspective, a variety of materials have been explored for advanced electrode materials with smart material-design strategies such as carbonaceous materials, metal compounds and conducting polymers. Proper nanostructures are engineered to provide sufficient electroactive sites and enhance the kinetics of ion and electron transport. Besides, new-concept supercapacitors have been developed for practical application. Microsupercapacitors and fiber supercapacitors have been explored for portable and compact electronic devices. Subsequently, we have introduced Li-/Na-ion supercapacitors composed of battery-type electrodes and capacitor-type electrode. Integrated energy devices are also explored by incorporating supercapacitors with energy conversion systems for sustainable energy storage. In brief, this review provides a comprehensive summary of recent progress on electrode materials design and burgeoning devices constructions for high-performance supercapacitors. PMID- 28638786 TI - Polyelectrolyte-Enrobed Cancer Cells in View of Personalized Immune-Therapy. AB - Targeting the immune system with a personalized vaccine containing cues derived from the patient's malignancy might be a promising approach in the fight against cancer. It includes neo-antigens as well as nonmutated tumor antigens, preferentially leading to an immune response that is directed to a broader range of epitopes compared to strategies involving a single antigen. Here, this paper reports on an elegant method to encapsulate whole cancer cells into polyelectrolyte particles. Porous and nonaggregated microparticles containing dead cancer cells are obtained by admixing mannitol and live cancer cells with oppositely charged polyelectrolytes, dextran sulfate (anionic polysaccharide), and poly-l-arginine (cationic polypeptide) prior to atomization into a hot air stream. It shows that the polyelectrolyte-enrobed cancer cells, upon redispersion in phosphate buffered saline buffer, are stable and do not release cell proteins in the supernatant. In vitro experiments reveal that the particles are nontoxic and strongly increase uptake of cell lysate by dendritic cells. In vitro assessment of antigen presentation by dendritic cells reveal the potential of the polyelectrolyte-enrobed cancer cells as promotors of antigen cross-presentation. Finally, it is demonstrated that the immunogenicity can be enhanced by surface adsorption of a polymer-substituted TLR7-agonist. PMID- 28638787 TI - Bioadhesive Bacterial Microswimmers for Targeted Drug Delivery in the Urinary and Gastrointestinal Tracts. AB - Bacteria-driven biohybrid microswimmers (bacteriabots), which integrate motile bacterial cells and functional synthetic cargo parts (e.g., microparticles encapsulating drug), are recently studied for targeted drug delivery. However, adhesion of such bacteriabots to the tissues on the site of a disease (which can increase the drug delivery efficiency) is not studied yet. Here, this paper proposes an approach to attach bacteriabots to certain types of epithelial cells (expressing mannose on the membrane), based on the affinity between lectin molecules on the tip of bacterial type I pili and mannose molecules on the epithelial cells. It is shown that the bacteria can anchor their cargo particles to mannose-functionalized surfaces and mannose-expressing cells (ATCC HTB-9) using the lectin-mannose bond. The attachment mechanism is confirmed by comparing the adhesion of bacteriabots fabricated from bacterial strains with or without type I pili to mannose-covered surfaces and cells. The proposed bioadhesive motile system can be further improved by expressing more specific adhesion moieties on the membrane of the bacteria. PMID- 28638788 TI - Histone deacetylases, microRNA and leptin crosstalk in pancreatic cancer. AB - Because pancreatic cancer (PC) historically has had poor prognosis and five year survival rates, it has been intensely investigated. Analysis of PC incidence and biology has shown a link between different risk factors such as smoking, alcoholism, and obesity and disease progression. Important factors affecting PC include the epigenomic changes driven by DNA methylation and histone acetylation, and actions of microRNA inducing oncogenic or tumor suppressor effects. Studies have identified markers whose dysregulation seem to play important roles in PC progression. PC markers involve classical histone deacetylases (HDAC), PC stem cell (PCSC), and leptin. In this review, we discuss the role of several PC biomarkers, and the potential crosstalk between HDAC, microRNA, and leptin in PC progression. Dysregulated expression of these molecules can increase proliferation, survival, PCSC, resistance to chemotherapy and tumor angiogenesis. The potential relationships between these molecules are further analyzed using data from The Cancer Genome Atlas and crosstalk pathways generated by the Pathway Studio Platform (Ariadne Genomics, Inc.). Oncogenic miRNA21 and tumor suppressor miRNA200 have been previously linked to leptin signaling. Preliminary analysis of PC biopsies and signaling crosstalk suggests that the main adipokine leptin could affect the expression of microRNA and HDAC in PC. Data analysis suggests that HDAC-microRNA-leptin signaling crosstalk may be a new target for PC therapy. PMID- 28638789 TI - Multidisciplinary approach of colorectal cancer liver metastases. AB - Large bowel cancer is a worldwide public health challenge. More than one third of patients present an advanced stage of disease at diagnosis and the liver is the most common site of metastases. Selection criteria for early diagnosis, chemotherapy and surgery have been recently expanded. The definition of resectability remains unclear. The presence of metastases is the most significant prognostic factor. For this reason the surgical resection of hepatic metastases is the leading treatment. The most appropriate resection approach remains to be defined. The two step and simultaneous resection processes of both primary and metastases have comparable survival long-term outcomes. The advent of targeted biological chemotherapeutic agents and the development of loco-regional therapies (chemoembolization, thermal ablation, arterial infusion chemotherapy) contribute to extend favorable results. Standardized evidence-based protocols are missing, hence optimal management of hepatic metastases should be single patient tailored and decided by a multidisciplinary team. This article reviews the outcomes of resection, systemic and loco-regional therapies of liver metastases originating from large bowel cancer. PMID- 28638790 TI - Evolving role of Sorafenib in the management of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant diseases worldwide and comes third in cancer-related mortality. Although there is a broad spectrum of treatment options to choose from, only a few patients are eligible candidates to receive a curative therapy according to their stage of disease, and thus palliative treatment is implemented in the majority of the patients suffering from liver cancer. Sorafenib, a multikinase inhibitor, is the only currently approved agent for systemic therapy in patients with advanced stage HCC and early stage liver disease. It has been shown to improve the overall survival, but with various side effects, while its cost is not negligible. Sorafenib has been in the market for a decade and has set the stage for personalized targeted therapy. Its role during this time has ranged from monotherapy to neoadjuvant and adjuvant treatment with surgical resection, liver transplantation and chemoembolization or even in combination with other chemotherapeutic agents. In this review our aim is to highlight in depth the current position of Sorafenib in the armamentarium against HCC and how that has evolved over time in its use either as a single agent or in combination with other therapies. PMID- 28638791 TI - Magnetic resonance imaging for diagnosis and neoadjuvant treatment evaluation in locally advanced rectal cancer: A pictorial review. AB - High-resolution pelvic magnetic resonance imaging (MRI) is the primary method for staging rectal cancer. MRI is highly accurate in the primary staging of rectal cancer; however, it has not proven to be effective in re-staging, especially in complete response evaluation after neoadjuvant therapy. Neoadjuvant chemoradiotherapy produces many changes in rectal tumors and on adjacent area, as a result, local tumor extent may not be accurately determined. However, adding diffusion-weighted sequences to the standard approach can improve diagnostic accuracy. In this pictorial review, an overview of the situation of MRI in the staging and re-staging of rectal cancer is exhibited as a pictorial assay. An experience- and literature-based discussion of limitations and difficulties in interpretation are also presented. PMID- 28638792 TI - Immunotherapy in pancreatic cancer: Unleash its potential through novel combinations. AB - Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States, with poor response to current standard of care, short progression-free and overall survival. Immunotherapies that target cytotoxic T lymphocyte antigen-4, programmed cell death protein-1, and programmed death ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma, renal cell carcinoma, and non-small cell lung cancer due to high numbers of somatic mutations, combined with cytotoxic T-cell responses. However, single checkpoint blockade was ineffective in pancreatic cancer, highlighting the challenges including the poor antigenicity, a dense desmoplastic stroma, and a largely immunosuppressive microenvironment. In this review, we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy, radiotherapy, and targeted therapy. These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses. PMID- 28638793 TI - Current state and controversies in fertility preservation in women with breast cancer. AB - On average, over 25000 women are diagnosed with breast cancer under the age of 45 annually in the United States. Because an increasing number of young women delay childbearing to later life for various reasons, a growing population of women experience breast cancer before completing childbearing. In this context, preservation of fertility potential of breast cancer survivors has become an essential concept in modern cancer care. In this review, we will outline the currently available fertility preservation options for women with breast cancer of reproductive age, discuss the controversy behind hormonal suppression for gonadal protection against chemotherapy and highlight the importance of timely referral by cancer care providers. PMID- 28638794 TI - Biological mesh reconstruction of the pelvic floor following abdominoperineal excision for cancer: A review. AB - Extralevator abdominoperineal excision and pelvic exenteration are mutilating operations that leave wide perineal wounds. Such large wounds are prone to infection and perineal herniation, and their closure is a major concern to most surgeons. Different approaches to the perineal repair exist, varying from primary or mesh closure to myocutaneous flaps. Each technique has its own associated advantages and potential complications and the ideal approach is still debated. In the present study, we reviewed the current literature and our own local data regarding the use of biological mesh for perineal wound closure. Current evidence suggests that the use of biological mesh carries an acceptable risk of wound complications compared to primary closure and is similar to flap reconstruction. In addition, the rate of perineal hernia is lower in early follow-up, while long term hernia occurrence appears to be similar between the different techniques. Finally, it is an easy and quick reconstruction method. Although more expensive than primary closure, the cost associated with the use of a biological mesh is at least equal, if not less, than flap reconstruction. PMID- 28638795 TI - Potential prognostic biomarkers in pancreatic juice of resectable pancreatic ductal adenocarcinoma. AB - Despite potentially curative surgery pancreatic cancer has a dismal prognosis. Serum cancer antigen 19-9 (CA 19-9) correlates with tumor burden, resectability and survival in patients with pancreatic ductal adenocarcinoma. Identification of novel biomarkers may facilitate early diagnosis of pancreatic cancer and improve survival. Pancreatic juice is a rich source of cancer-specific proteins rendering it a promising tool for identifying biomarkers. Recent proteomic and microRNA expression analyses have identified several biomarkers of potential diagnostic and prognostic value. Tumor markers CA 19-9 and carcinoembryonic antigen (CEA) are widely used in the characterization of premalignant and malignant lesions of the pancreas. Elevated level of CEA in bile is a marker for malignancy and a predictor of hepatic recurrence. The potential value of CA 19-9, CEA and lactate dehydrogenase as prognostic biomarkers in pancreatic juice and bile is unknown. Specimens of pancreatic juice and bile can be readily collected during surgical resection of the tumor. Profiling of pancreatic juice and bile to identify novel prognostic biomarkers may improve selection of patients for adjuvant therapy with a favorable impact on overall survival in patients diagnosed with pancreatic cancer. PMID- 28638796 TI - Levels of neutrophil gelatinase-assosciated lipocalin in patients with head and neck squamous cell carcinoma in Indian population from Haryana state. AB - AIM: To study the levels of neutrophil gelatinase associated lipocalin (NGAL) in head and neck squamous cell carcinoma (HNSCC). METHODS: This was a non randomized case control study conducted at Department of Biochemistry, in collaboration with Regional Cancer Center over a period of one year. The study population included 50 adult newly diagnosed HNSCC patients reporting in outpatient department at Regional Cancer Center and compared with 50 healthy controls. NGAL was estimated by ELISA technique. Student t test and chi2 test were applied for comparison of means of study groups. Correlations between groups were analyzed using Pearson correlation coefficient (r) formula. RESULTS: Patients with HNSCC exhibited significantly increased levels of NGAL (P < 0.05) as compared to healthy controls (978.88 +/- 261.39 ng/mL vs 34.83 +/- 7.59 ng/mL). Out of 50, 26 patients (52%) were in stage IV, 21 (42%) in stage III, 1 (2%) patient in stage II and 2 (4%) patients were in stage I. Metastasis was absent in 98% patients and mean NGAL levels were highest in these patients but P value was not significant. Mean NGAL levels were highest in stage IV [1041.54 +/- 222.15 ng/mL (stage IV) vs 1040 +/- 0.00 ng/mL (stage I); 900 +/- 0.00 ng/mL (stage II) and 1031.90 +/- 202.55 ng/mL (stage III)] and chi2 test was highly significant (P < 0.001). Thirty-six patients (72%) were having moderately differentiated HNSCC and mean NGAL levels were maximum in patients with well differentiated HNSCC (1164 +/- 315.64 ng/mL vs 1013.33 +/- 161.19 ng/mL in moderately differentiated and 890 +/- 11.55 ng/mL in poorly differentiated) and the results were also highly significant (P < 0.001, chi2 test). CONCLUSION: The present work demonstrates a potential role of NGAL as cancer biomarker and its use in monitoring the HNSCC progression. PMID- 28638797 TI - Recurrence-free survival as a putative surrogate for overall survival in phase III trials of curative-intent treatment of colorectal liver metastases: Systematic review. AB - AIM: To verify whether recurrence-free survival (RFS) surrogates overall survival (OS) in phase III trials for resectable colorectal liver metastases (CRLM). METHODS: MEDLINE, EMBASE, and Scopus databases were consulted. Eligible studies were phase III trials testing any type of systemic therapy (neoadjuvant, adjuvant or perioperative) added to surgery in patients with resectable CRLM. A linear regression model based on hazard ratios (HR) of OS and RFS was performed. RESULTS: Of 3059 studies, 5 phase III trials (1162 patients) were included for analyses. A linear regression weighted by each trial was used to estimate the association between each HR and RFS. The originated formula was: OS HR = (0.93 * RFS HR) + 0.14; with RFS 95%CI (0.48-1.38), with P = 0.007. CONCLUSION: This association suggests that RFS could work as a putative surrogate endpoint of OS in this population, avoiding bigger, longer and more resource-consuming trials. The OS could be assumed based on RFS and our model could be useful to better estimate sample size calculations of phase III trials of CRLM aiming for OS. PMID- 28638798 TI - Robot-assisted laparoscopic vs open gastrectomy for gastric cancer: Systematic review and meta-analysis. AB - AIM: To evaluate the potential effectiveness of robot-assisted gastrectomy (RAG) in comparison to open gastrectomy (OG) for gastric cancer patients. METHODS: A comprehensive systematic literature search using PubMed, EMBASE, and the Cochrane Library was carried out to identify studies comparing RAG and OG in gastric cancer. Participants of any age and sex were considered for inclusion in comparative studies of the two techniques independently from type of gastrectomy. A meta-analysis of short-term perioperative outcomes was performed to evaluate whether RAG is equivalent to OG. The primary outcome measures were set for estimated blood loss, operative time, conversion rate, morbidity, and hospital stay. Secondary among postoperative complications, wound infection, bleeding and anastomotic leakage were also analysed. RESULTS: A total of 6 articles, 5 retrospective and 1 randomized controlled study, involving 6123 patients overall, with 689 (11.3%) cases submitted to RAG and 5434 (88.7%) to OG, satisfied the eligibility criteria and were included in the meta-analysis. RAG was associated with longer operation time than OG (weighted mean difference 72.20 min; P < 0.001), but with reduction in blood loss and shorter hospital stay (weighted mean difference -166.83 mL and -1.97 d respectively; P < 0.001). No differences were found with respect to overall postoperative complications (P = 0.65), wound infection (P = 0.35), bleeding (P = 0.65), and anastomotic leakage (P = 0.06). The postoperative mortality rates were similar between the two groups. With respect to oncological outcomes, no statistical differences among the number of harvested lymph nodes were found (weighted mean difference -1.12; P = 0.10). CONCLUSION: RAG seems to be a technically valid alternative to OG for performing radical gastrectomy in gastric cancer resulting in safe complications. PMID- 28638799 TI - Bilateral diffuse grade 5 radiation pneumonitis after intensity modulated radiation therapy for localized lung cancer. AB - We are reporting a case of fatal radiation pneumonitis that developed six months following chemoradiation for limited stage small cell lung cancer. The patient was a 67-year-old man with a past medical history of Hashimoto's thyroiditis and remote suspicion for CREST, neither of which were active in the years leading up to treatment. He received 6600 cGy delivered in 200 cGy daily fractions via intensity modulated radiation therapy with concurrent cisplatin/etoposide followed by additional chemotherapy with dose-reduced cisplatin/etoposide and carboplatin/etoposide and then received prophylactic cranial irradiation. The subsequent months were notable for progressively worsening episodes of respiratory compromise despite administration of prolonged steroids and he ultimately expired. Imaging demonstrated bilateral interstitial and airspace opacities. Autopsy findings were consistent with pneumonitis secondary to chemoradiation as well as lymphangitic spread of small cell carcinoma. The process was diffuse bilaterally although his radiation was delivered focally to the right lung and mediastinum. PMID- 28638800 TI - Prostatic adenocarcinoma oncocytic variant: Case report and literature review. AB - The oncocytic variant of prostatic adenocarcinoma is exceptionally rare with only 4 cases reported in the English literature. Little is known about the clinical behavior of this variant of prostatic adenocarcinoma, because of the exceptionally low number of reported cases. The 2016 World Health Organization Classification of Tumors of Prostate does not recognize the oncocytic variant, again likely related to the exceptional paucity of reported cases. Here, we report the fifth case of the oncocytic variant of acinar type prostatic adenocarcinoma in an asymptomatic 64-year-old Caucasian American male with elevated serum prostate specific antigen (7.33 ng/mL; normal range 0-4.00 ng/mL) during routine blood screening for diabetes mellitus. At subsequent transrectal prostate biopsy, the right side of prostate was infiltrated by adenocarcinoma with tumor cells forming variably differentiated glands, including some poorly differentiated. Tumor cell nuclear:cytoplasmic ratio was low, with small to intermediate sized vesicular nuclei and only rare discernable small nucleoli. Cellular cytoplasm was characteristically granular pink with sharply defined cell membranes. Positive AMACR (P504S) epithelial immunohistochemical staining and absence of staining for prostatic basal cells confirmed the tumor to be primary prostatic adenocarcinoma. AMACR immunohistochemical staining was also helpful with accurate grading of the tumor due to the difficulty of differentiating tumor cells from residual prostate myocytes at routine hematoxylin and eosin (HE) staining. This new case adds to the exceptionally small number of previously reported cases of the oncocytic variant of primary prostatic adenocarcinoma. It also highlights the difficulty associated with Gleason scoring of the oncocytic variant by routine HE evaluation and the usefulness of AMACR (P504S) immunostaining for accurate grading of prostatic adenocarcinoma in the oncocytic variant. PMID- 28638801 TI - Pancreatic neuroendocrine tumor Grade 1 patients followed up without surgery: Case series. AB - Among the three grades of neuroendocrine tumors (NETs), the prognosis for Grade 1 (G1) with surgery is very good. Therefore, we evaluated the prognoses of pancreatic NET (PNET) G1 patients without surgery. A total of 8 patients who were diagnosed with NET G1, with an observation period of more than 6 mo until surgery or without surgery, were recruited. The patients who underwent surgery were ultimately diagnosed using specimens obtained during the surgery, whereas the patients who did not undergo surgery were diagnosed using specimens obtained by endoscopic ultrasonography-guided fine needle aspiration. Overall, we mainly evaluated the observation period and tumor growth. The observation period for the five cases with surgery ranged from 6-80 mo, and tumor growth was observed in one case. In contrast, the observation period for the three cases without surgery ranged from 17-54 mo, and tumor growth was not observed. Therefore, although the first-choice treatment for NETs is surgery, our experience includes certain NET G1 patients who were followed up without surgery. PMID- 28638802 TI - Target migration from re-inflation of adjacent atelectasis during lung stereotactic body radiotherapy. AB - Stereotactic body radiotherapy (SBRT) is a widely accepted option for the treatment of medically inoperable early-stage non-small cell lung cancer (NSCLC). Herein, we highlight the importance of interfraction image guidance during SBRT. We describe a case of early-stage NSCLC associated with segmental atelectasis that translocated 15 mm anteroinferiorly due to re-expansion of the adjacent segmental atelectasis following the first fraction. The case exemplifies the importance of cross-sectional image-guided radiotherapy that shows the intended target, as opposed to aligning based on rigid anatomy alone, especially in cases associated with potentially "volatile" anatomic areas. PMID- 28638803 TI - Peptide Nucleic Acid Knockdown and Intra-host Cell Complementation of Ehrlichia Type IV Secretion System Effector. AB - Survival of Ehrlichia chaffeensis depends on obligatory intracellular infection. One of the barriers to E. chaffeensis research progress has been the inability, using conventional techniques, to generate knock-out mutants for genes essential for intracellular infection. This study examined the use of Peptide Nucleic Acids (PNAs) technology to interrupt type IV secretion system (T4SS) effector protein expression in E. chaffeensis followed by intracellular complementation of the effector to determine its requirement for infection. Successful E. chaffeensis infection depends on the E. chaffeensis-specific T4SS protein effector, ehrlichial translocated factor-1 (Etf-1), which induces Rab5-regulated autophagy to provide host cytosolic nutrients required for E. chaffeensis proliferation. Etf-1 is also imported by host cell mitochondria where it inhibits host cell apoptosis to prolong its infection. We designed a PNA specific to Etf-1 and showed that the PNA bound to the target region of single-stranded Etf-1 RNA using a competitive binding assay. Electroporation of E. chaffeensis with this PNA significantly reduced Etf-1 mRNA and protein, and the bacteria's ability to induce host cell autophagy and infect host cells. Etf-1 PNA-mediated inhibition of ehrlichial Etf-1 expression and E. chaffeensis infection could be intracellularly trans-complemented by ectopic expression of Etf-1-GFP in host cells. These data affirmed the critical role of bacterial T4SS effector in host cell autophagy and E. chaffeensis infection, and demonstrated the use of PNA to analyze the gene functions of obligate intracellular bacteria. PMID- 28638804 TI - PKC-eta-MARCKS Signaling Promotes Intracellular Survival of Unopsonized Burkholderia thailandensis. AB - Pathogenic Burkholderia rely on host factors for efficient intracellular replication and are highly refractory to antibiotic treatment. To identify host genes that are required by Burkholderia spp. during infection, we performed a RNA interference (RNAi) screen of the human kinome and identified 35 host kinases that facilitated Burkholderia thailandensis intracellular survival in human monocytic THP-1 cells. We validated a selection of host kinases using imaging flow cytometry to assess efficiency of B. thailandensis survival in the host upon siRNA-mediated knockdown. We focused on the role of the novel protein kinase C isoform, PKC-eta, in Burkholderia infection and characterized PKC-eta/MARCKS signaling as a key event that promotes the survival of unopsonized B. thailandensis CDC2721121 within host cells. While infection of lung epithelial cells with unopsonized Gram-negative bacteria stimulated phosphorylation of Ser175/160 in the MARCKS effector domain, siRNA-mediated knockdown of PKC-eta expression reduced the levels of phosphorylated MARCKS by >3-fold in response to infection with Bt CDC2721121. We compared the effect of the conventional PKC alpha and novel PKC-eta isoforms on the growth of B. thailandensis CDC2721121 within monocytic THP-1 cells and found that >=75% knock-down of PRKCH transcript levels reduced intracellular bacterial load 100% more efficiently when compared to growth in cells siRNA-depleted of the classical PKC-alpha, suggesting that the PKC-eta isoform can specifically mediate Burkholderia intracellular survival. Based on imaging studies of intracellular B. thailandensis, we found that PKC-eta function stimulates phagocytic pathways that promote B. thailandensis escape into the cytoplasm leading to activation of autophagosome flux. Identification of host kinases that are targeted by Burkholderia during infection provides valuable molecular insights in understanding Burkholderia pathogenesis, and ultimately, in designing effective host-targeted therapies against infectious disease caused by intracellular pathogens. PMID- 28638805 TI - Increased Zinc Availability Enhances Initial Aggregation and Biofilm Formation of Streptococcus pneumoniae. AB - Bacteria growing within biofilms are protected from antibiotics and the immune system. Within these structures, horizontal transfer of genes encoding virulence factors, and promoting antibiotic resistance occurs, making biofilms an extremely important aspect of pneumococcal colonization and persistence. Identifying environmental cues that contribute to the formation of biofilms is critical to understanding pneumococcal colonization and infection. Iron has been shown to be essential for the formation of pneumococcal biofilms; however, the role of other physiologically important metals such as copper, zinc, and manganese has been largely neglected. In this study, we investigated the effect of metals on pneumococcal aggregation and early biofilm formation. Our results show that biofilms increase as zinc concentrations increase. The effect was found to be zinc-specific, as altering copper and manganese concentrations did not affect biofilm formation. Scanning electron microscopy analysis revealed structural differences between biofilms grown in varying concentrations of zinc. Analysis of biofilm formation in a mutant strain lacking the peroxide-generating enzyme pyruvate oxidase, SpxB, revealed that zinc does not protect against pneumococcal H2O2. Further, analysis of a mutant strain lacking the major autolysin, LytA, indicated the role of zinc as a negative regulator of LytA-dependent autolysis, which could affect biofilm formation. Additionally, analysis of cell-cell aggregation via plating and microscopy revealed that high concentrations of zinc contribute to intercellular interaction of pneumococci. The findings from this study demonstrate that metal availability contributes to the ability of pneumococci to form aggregates and subsequently, biofilms. PMID- 28638808 TI - Introductory editorial to 30th anniversary edition. PMID- 28638806 TI - In vitro Increased Respiratory Activity of Selected Oral Bacteria May Explain Competitive and Collaborative Interactions in the Oral Microbiome. AB - Understanding the driving forces behind the shifts in the ecological balance of the oral microbiota will become essential for the future management and treatment of periodontitis. As the use of competitive approaches for modulating bacterial outgrowth is unexplored in the oral ecosystem, our study aimed to investigate both the associations among groups of functional compounds and the impact of individual substrates on selected members of the oral microbiome. We employed the Phenotype Microarray high-throughput technology to analyse the microbial cellular phenotypes of 15 oral bacteria. Multivariate statistical analysis was used to detect respiratory activity triggers and to assess similar metabolic activities. Carbon and nitrogen were relevant for the respiration of health-associated bacteria, explaining competitive interactions when grown in biofilms. Carbon, nitrogen, and peptides tended to decrease the respiratory activity of all pathobionts, but not significantly. None of the evaluated compounds significantly increased activity of pathobionts at both 24 and 48 h. Additionally, metabolite requirements of pathobionts were dissimilar, suggesting that collective modulation of their respiratory activity may be challenging. Flow cytometry indicated that the metabolic activity detected in the Biolog plates may not be a direct result of the number of bacterial cells. In addition, damage to the cell membrane may not influence overall respiratory activity. Our methodology confirmed previously reported competitive and collaborative interactions among bacterial groups, which could be used either as marker of health status or as targets for modulation of the oral environment. PMID- 28638809 TI - Dual peer mentoring program for undergraduate medical students: exploring the perceptions of mentors and mentees. AB - Background: Despite the advantages of dual peer mentoring, there are a few reports of implementing and evaluating such programs for medical students. This study aimed at exploring the perceptions of mentors and mentees about the dual peer mentoring program for the first year undergraduate medical students of Tehran University of Medical Sciences. Methods: This qualitative study was conducted at the end of the first year of implementing the mentoring program. All mentees and mentors were invited to participate in focus group discussions. Data were analyzed using a qualitative content analysis. Results: All mentors (n= 12) and a group of mentees (n= 21) participated in focus group discussion sessions. We provided a variety of supports for the mentees including academic and psychosocial support and positive relationship; as a result, some developments occurred to the mentors We also explored participants' views on some unique aspects of the program such as student-authorized, dual mentoring, and role model sessions. Conclusion: Our participants found the mentoring program beneficial in various academic achievements and psychosocial supports for both the mentors and the mentees. Dual peer mentoring program can be an alternative to school administered programs. PMID- 28638811 TI - Cost-effectiveness of Eplerenone in treatment of cardiovascular diseases: a systematic review. AB - Background: No clear evidence is available on the cost-effectiveness of eplerenone in treatment of cardiovascular diseases. Thus, the present study aimed at systematically reviewing studies that have investigated this issue. Methods: This systematic review study was conducted in 2016. The required information were collected using key Mesh words from the following databases: Google scholar, PubMed, Science Direct, MagIran, SID, Scopus, and handsearching journals and the references of the selected articles. The quality of the selected articles was assessed by the Drummond's checklist. Results: Nine articles were included from 296 articles found in the literature review. The selected studies have been conducted in 8 countries (The United States, Britain, Australia, Switzerland, France, Spain, the Netherlands, and Canada). In general, the costeffectiveness of eplerenone was investigated in 31 757 patients with cardiovascular diseases. The average of quality-adjusted life years (QALY) in studies with nonmodeling approach was equal to 0.0908 in Framingham approach, 0.0595 in Saskatchewan approach, and 0.1309 in Worcester approach. The overall average cost of treating cardiovascular diseases with eplerenone was equal to US$6694 in 1 year. Cost per additional (QALY) was estimated to be US$9478. Incremental cost-effectiveness ratio was high in the United States compared to European countries. The Average quality of articles was estimated to be 7.4 from 10. Conclusions: Based on the results of the studies reviewed in the present study, it seems that eplerenone has acceptable costeffectiveness compared with current treatments, placebo, and similar drugs. PMID- 28638810 TI - Common malignant cutaneous conditions among albinos in Kenya. AB - Background: Albinos in Africa are at constant risk of developing skin cancer due to the damage caused by ultra-violet exposure. This study identifies the common skin conditions among albinos in Kenya as a country located along the equator. Methods: In this descriptive study on albino patients who were admitted to Mbagathi District Hospital in Nairobi, Kenya the census method was used for sampling and a total of 151 albinos were registered. All necessary data including age, gender, type, site and the number of skin lesions were recorded. Suspected patients with malignant and premalignant lesions were studied individually through skin biopsy and histopathological investigation. Finally, the collected data were analyzed using SPSS software. Results: Albinos with serious skin lesions were 121(80%) patients. Females were 64 (52.9%). The frequency of the following premalignant and malignant skin lesions including actinic-cheilitis, solar elastosis, actinic keratosis (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were 17.88%, 11.92%, 37.08%, 7.94% and 5.29%, respectively. Hands (20.52%), face (19.20%), head (18.18%), shoulder (14.56%) and neck (7.94%) were the most affected areas by malignant and premalignant lesions. Conclusions: BCC was the most common type of cutaneous malignancy on the face and shoulders while AK was the most common cutaneous pre-malignancy on the hands and face in albinos in Kenya. Therefore, appropriate physical protection, avoiding any trauma when carrying sharp, heavy or rough instruments by the shoulder and hands, and finally urgent and quality treatment for any lesion even a small erosion and ulcer, especially on exposed areas in albinos, are recommended. PMID- 28638812 TI - How canola and sunflower oils affect lipid profile and anthropometric parameters of participants with dyslipidemia. AB - Background: Restricted intakes of saturated and trans-fatty acids and replacement with poly or monounsaturated fatty acids are emphasized in healthy diets. This study evaluates the effects of a six-month consumption of canola oil compared to sunflower oil on lipid profile and anthropometric parameters of people affected by dyslipidemia. Methods: This randomized controlled trial was conducted on 96 patients with dyslipidemia, who were randomly assigned into canola oil or the sunflower oil groups. The participants were instructed to record the contents of their daily meals, beverages, fruits, and snacks a day before treatment, at the second clinic visit, in the third month, and at the end of study (i.e., six months). Lipid profile and anthropometric parameters were compared between the two groups. Student t-test or Mann Whitney U test was used for statistical comparisons of variables between groups. Multivariate analysis was performed to adjust the confounding factor effects. Results: Of the enrolled participants, 44 (45.8%) were on sunflower oil diet and 52 (54.2%) on canola oil diet. We observed no change in anthropometric parameters and thus no significant difference between the two groups (p>0.05). Significant reductions in LDL-C (p<0.001), total cholesterol (p<0.001) and triglyceride levels (p<0.001), and significant elevation in HDL-C (p=0.008) were observed in canola oil group, as well as those who used sunflower oil. Conclusion: Dietary fats in the form of canola oil or sunflower oil effectively lower the serum cholesterol, LDL-C and triglyceride concentrations. They also result in an increase in serum concentration of HDL-C. These oils, however, did not modify general anthropometric parameters. PMID- 28638807 TI - Translational Rodent Models for Research on Parasitic Protozoa-A Review of Confounders and Possibilities. AB - Rodents, in particular Mus musculus, have a long and invaluable history as models for human diseases in biomedical research, although their translational value has been challenged in a number of cases. We provide some examples in which rodents have been suboptimal as models for human biology and discuss confounders which influence experiments and may explain some of the misleading results. Infections of rodents with protozoan parasites are no exception in requiring close consideration upon model choice. We focus on the significant differences between inbred, outbred and wild animals, and the importance of factors such as microbiota, which are gaining attention as crucial variables in infection experiments. Frequently, mouse or rat models are chosen for convenience, e.g., availability in the institution rather than on an unbiased evaluation of whether they provide the answer to a given question. Apart from a general discussion on translational success or failure, we provide examples where infections with single-celled parasites in a chosen lab rodent gave contradictory or misleading results, and when possible discuss the reason for this. We present emerging alternatives to traditional rodent models, such as humanized mice and organoid primary cell cultures. So-called recombinant inbred strains such as the Collaborative Cross collection are also a potential solution for certain challenges. In addition, we emphasize the advantages of using wild rodents for certain immunological, ecological, and/or behavioral questions. The experimental challenges (e.g., availability of species-specific reagents) that come with the use of such non-model systems are also discussed. Our intention is to foster critical judgment of both traditional and newly available translational rodent models for research on parasitic protozoa that can complement the existing mouse and rat models. PMID- 28638813 TI - Impractical CME programs: Influential parameters in Iran. AB - Background: Traditional approaches in Continuing Medical Education (CME) appear to be ineffective in any improvement of the patients' care, reducing the medical errors, and/or altering physicians' behaviors. However, they are still executed by the CME providers, and are popular among the majority of the physicians. In this study, we aimed to explore the parameters involved in the degree of effectiveness of CME program in Iran. Methods: In this study, 31 participants, consisting of general practitioners, CME experts and providers were recruited to participate in in-depth interviews and field observations concerning experiences with CME. Application was made of the qualitative paradigm along with the qualitative content analysis, using grounded theory data analysis methodology (constant comparative analysis). Results: Based on the participants' experiences, the insufficient consistency between the training program contents and the demands of GPs, in addition to the non-beneficiary programs for the physicians and the non-comprehensive educational designs, created a negative attitude to the continuing education among physicians. This could be defined by an unrealistic continuing education program, which is the main theme here. Conclusion: Impracticable continuing education has created a negative attitude toward the CME programs among physicians so much that they consider these programs less important, resulting in attending the said programs without any specific aim: they dodge absenteeism just to get the credit points. Evidently, promoting CME programs to improve the performance of the physicians requires factual needs assessment over and above adaptation of the contents to the physicians' performance. PMID- 28638814 TI - Congenital urogenital abnormalities in children with congenital hypothyroidism. AB - Background: Congenital hypothyroidism (CH), as one of the most common congenital endocrine disorders, may be significantly associated with congenital malformations. This study investigates urogenital abnormalities in children with primary CH (PCH). Methods: This case-control study was conducted on 200 children aged three months to 1 year, referred to Amir-Kabir Hospital, Arak, Iran. One hundred children with PCH, as the case group, and 100 healthy children, as the control group, were selected using convenient sampling. For all children, demographic data checklists were filled, and physical examination, abdomen and pelvic ultrasound and other diagnostic measures (if necessary) were performed to evaluate the congenital urogenital abnormalities including anomalies of the penis and urethra, and disorders and anomalies of the scrotal contents. Results: Among 92 (100%) urogenital anomalies diagnosed, highest frequencies with 37 (40.2%), 26(28.2%) and 9 (9.7%) cases including hypospadias, Cryptorchidism, and hydrocele, respectively. The frequency of urogenital abnormalities among 32 children with PCH, with 52 cases (56.5%) was significantly higher than the frequency of abnormalities among the 21 children in the control group, with 40 cases (43.4%). (OR=2.04; 95%CI: 1.1-3.6; p=0.014). Conclusion: Our study demonstrated that PCH is significantly associated with the congenital urogenital abnormalities. However, due to the lack of evidence in this area, further studies are recommended to determine the necessity of conducting screening programs for abnormalities of the urogenital system in children with CH at birth. PMID- 28638815 TI - Diabetic foot workshop: Improving technical and educational skills for nurses. AB - Diabetes mellitus as one of the most common metabolic disorders has some complications, one of the main ones is diabetic foot (DF). Appropriate care and education prevents 85% of diabetic foot amputations. An ideal management to prevent and treat diabetic foot necessitates a close collaboration between the health team members and the diabetic patient. Therefore, improving nurses' knowledge about DF care and advancement in the quality of care provided by the nurses could significantly improve diabetic foot prevention and management. Therefore, the aim of DF workshop was to improve technical and educational skills of the nurses to prevent and manage diabetic foot. Considering the vital role of the nurses in providing DF care, EMRI decided to conduct Diabetic foot workshop for them. The following five steps were designed for the 14 coordinating sessions in the workshop: Goals definition, deciding about attendees, location selection, creating agenda, and developing a follow-up plan. "Diabetic Foot Workshop for Nurses" provides appropriate training to DF nurses at the national level; and combining theory and practice in this workshop not only increases nurses' knowledge, but also improves their skills in the field of the diabetic foot. Providing education and care to patients by DF nurse specialists instead of general nurses could be an important output of this workshop, which may lead to DF prevention and amputation decrease in the long term. PMID- 28638817 TI - A Challenging Case of Hepatoblastoma Concomitant with Autosomal Recessive Polycystic Kidney Disease and Caroli Syndrome-Review of the Literature. AB - We report a rare case of an 18-month-old female with autosomal recessive polycystic kidney disease, Caroli syndrome, and pure fetal type hepatoblastoma. The liver tumor was surgically resected with no chemotherapy given. Now 9 years post resection she demonstrates no local or distant recurrence and stable renal function. PMID- 28638816 TI - Prevalence of asthma among Middle Eastern children: A systematic review. AB - Background: The prevalence of asthma and allergy has increased during the last decades, especially in children. However, little is known about it in the Middle East region. This systematic review is aimed to estimate the prevalence of asthma among the Middle Eastern children. Methods: Local and international scientific databases including SID, Iranmedex, Medline and Science Direct were systematically searched for relevant keywords including; asthma, prevalence, children, International Study of Asthma and Allergies in Childhood (ISACC) and the names of Middle Eastern countries for the period of 1996-2011. Papers in Persian and English which met the defined criteria were included into the study. Bibliographies of the extracted articles were also searched. After extraction of data, heterogeneity between studies and publication bias were measured using Egger's-test. Effect size was pooled by the random-effect model. Since significant heterogeneity was found between studies, univariate meta-regression analyses were done to assess the association of variables with the overall results. Results: Fifty studies in the Middle East examined the prevalence of asthma and allergy in children under the age of 18 years according to the ISAAC criteria and were included. A total number of 289,717 children were examined in the included studies and the prevalence varied from 0.7 % in Isfahan to 22.3 % in Bagdad. The total prevalence of diagnosed asthma was calculated 7.53 % (95% Cl: 6.38-8.75). Prevalence of asthma in the 13-14 years age group was 7.57% (95% Cl: 5.78-9.29) and in 6-7 years age group was 7.43% (95% Cl: 5.75-9.10). The prevalence of asthma among girls, based on random effect model, was 6.30% (95% Cl: 4.97-7.61) and among boys, it was 8.91% (95% Cl: 6.80-11.04). Conclusion: The prevalence of asthma in the Middle East is lower than most developed countries. However, there is not enough longitudinal data to estimate the trend over time. In order to have more accurate estimates and to provide evidence for proper planning, standard epidemiologic studies should be conducted in countries of the region. PMID- 28638818 TI - Effects of Anakinra on Health-Related Quality of Life in a Patient with 1129G>A/928G>A Mutations in MVK Gene and Heterozygosity for the Mutation 2107C>A in CIAS1 Gene. AB - Mevalonate kinase deficiency impairs several aspects of the patient's quality of life, thus early diagnosis and treatment are required to improve health-related quality of life (HRQOL). A 15-year-old patient with double heterozygosity for the mutations 1129G>A and 928G>A in MVK gene, heterozygosity for the mutation 2107C>A in CIAS1 gene and hyper-IgD syndrome phenotype, has been treated with anakinra with a reduction of 50% in the number of fever episodes per month, a reduction of 33% in the days of fever for each attack and normal blood tests in the intercritical phase. The RAND 36-Item Health Survey has been used for the assessment of HRQOL before and after the treatment with anakinra. The patient's quality of life showed an overall improvement of 27%; results showed a better improvement in role limitations due to physical health (50%). PMID- 28638819 TI - Testosterone Modifies Alterations to Detrusor Muscle after Partial Bladder Outlet Obstruction in Juvenile Mice. AB - Lower urinary tract symptoms secondary to posterior urethral valves (PUV) arise in boys during adolescence. The reasons for this have previously been attributed to increased urine output as boys experience increased growth. Additionally, there are few choices for clinicians to effectively treat these complications. We formed the new hypothesis that increased androgen levels at this time of childhood development could play a role at the cellular level in obstructed bladders. To test this hypothesis, we investigated the role of testosterone on bladder detrusor muscle following injury from partial bladder outlet obstruction (PO) in mice. A PO model was surgically created in juvenile male mice. A group of mice were castrated by bilateral orchiectomy at time of obstruction (CPO). Testosterone cypionate was administered to a group of castrated, obstructed mice (CPOT). Bladder function was assessed by voiding stain on paper (VSOP). Bladders were analyzed at 7 and 28 days by weight and histology. Detrusor collagen to smooth muscle ratio (Col/SM) was calculated using Masson's trichrome stain. All obstructed groups had lower max voided volumes (MVV) than sham mice at 1 day. Hormonally intact mice (PO) continued to have lower MVV at 7 and 28 days while CPO mice improved to sham levels at both time points. In accordance, PO mice had higher bladder-to-body weight ratios than CPO and sham mice demonstrating greater bladder hypertrophy. Histologically, Col/SM was lower in sham and CPO mice. When testosterone was restored in CPOT mice, MVV remained low at 7 and 28 days compared to CPO and bladder-to-body weight ratios were also greater than CPO. Histologic changes were also seen in CPOT mice with higher Col/SM than sham and CPO mice. In conclusion, our findings support a role for testosterone in the fibrotic changes that occur after obstruction in male mice. This suggests that while other changes may occur in adolescent boys that cause complication in boys with PUV, the bladder itself responds to testosterone at the cellular level. This opens the door to a new understanding of pathways that influence bladder fibrosis and could lead to novel approaches to treat boys with PUV. PMID- 28638820 TI - Dementia Literacy among Community-Dwelling Older Adults in Urban China: A Cross sectional Study. AB - OBJECTIVE: Delay in seeking diagnosis of dementia is common in China. Misinformation and poor knowledge about dementia may contribute to it. The study was designed to explore the nationwide dementia literacy among older adults in urban China and to investigate the factors associated with overall dementia literacy. METHODS: In a cross-sectional study, a convenience sample of 3,439 community-dwelling old adults aged 60 and over was recruited from 34 cities in 20 provinces between June 20 and August 20, 2014. All participants were administered the face-to-face mental health literacy questionnaire, which included the prevalence, symptoms, intention, and options for treatment of dementia. Stepwise multivariate regression analysis was used to explore factors associated with overall dementia literacy. RESULTS: The response rate was 87.4%. The overall dementia literacy was 55.5% (SD = 20.9%) among all respondents. The correct response rate was higher for questions on symptoms (58.7-89.6%), but lower for questions on the prevalence (22.2%) and choosing appropriate professional care personnel (22.2%). Being male [OR = 1.256, 95% CI (1.022-1.543)], having lower per capita annual income [OR = 1.314, 95% CI (1.064-1.623)], lower education [OR = 1.462, 95% CI (1.162-1.839)], and suspected depression [OR = 1.248, 95% CI (1.009-1.543)] were negatively associated with overall dementia literacy. CONCLUSION: Dementia literacy among community-dwelling older adults in urban China remains very low, in particular about the impact of dementia and appropriate treatment personnel. Community educational programs aiming to close this knowledge gap are encouraged to focus on those in the population at highest risk of low dementia literacy. PMID- 28638821 TI - The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth. AB - Cell size is amenable by genetic and environmental factors. The highly conserved nutrient-responsive Target of Rapamycin (TOR) signaling pathway regulates cellular metabolic status and growth in response to numerous inputs. Timing and duration of TOR pathway activity is pivotal for both cell mass built up as well as cell cycle progression and is controlled and fine-tuned by the abundance and quality of nutrients, hormonal signals, growth factors, stress, and oxygen. TOR kinases function within two functionally and structurally discrete multiprotein complexes, TORC1 and TORC2, that are implicated in temporal and spatial control of cell size and growth respectively; however, recent data indicate that such functional distinctions are much more complex. Here, we briefly review roles of the two complexes in cellular growth and cytoarchitecture in various experimental model systems. PMID- 28638823 TI - Comparing the Effect of Animal-Rearing Education in Japan with Conventional Animal-Assisted Education. AB - An increasing number of teachers are introducing animals into their class so that pupils foster cognitive, physiological, and social skills through their interaction with animals. Along with such an educational style termed animal assisted education (AAE), Japanese formal education has also utilized animals for education. Japanese animal-rearing education is unique regarding the following two points: (1) it takes the form of "education through assisting animals" rather than "animals assisting education" and (2) animal rearing is embedded in formal education. While conventional AAE expects the benefit from the social support of animals, Japanese animal-rearing education expects benefit from nurturing and caring for animals. The present study aims to identify effective methods for using animals for education by highlighting the benefits of Japanese animal rearing education. An overview of Japanese animal-rearing education is followed by a critical review of empirical studies of conventional AAE and Japanese animal rearing education. Despite the differences in the educational styles, it was found that both systems commonly help children adapt to school. Additionally, conventional AAE were effective in enhancing cognitive and athletic ability of students and foster social skills, while Japanese animal-rearing education enhanced academic knowledge and skills and cultivated sympathy for animals and other people. Furthermore, it was demonstrated that the experience of raising animals affects children's development for a long time even after children stop raising animals. In order to determine the effect of animal presence at school, however, more empirical studies with various viewpoints are necessary for both styles of education. Concerning Japanese animal-rearing education, the effects of the differences such as the amount of exposure to animals, developmental stage or character of individual children, the types of animals need to be controlled for a more sophisticated examination. Empirical studies show that preadolescence is one of the periods in which animal rearing has the greatest impact on children's development. It is suggested that through the program of raising school animals, conventional AAE obtains more a variety of effects in their interaction with animals. PMID- 28638824 TI - Dual Epidemics of Club Drug Use and Sexually Transmitted Infections among Chinese Female Sex Workers: New Challenges to STI Prevention. AB - OBJECTIVES: To evaluate club drug use and its potential association with STI among female sex workers (FSWs) in China. METHODS: From November 2008 to January 2009, participants were recruited at sex work venues in five cities for a questionnaire survey. Free testing for syphilis, Chlamydia trachomatis (CT), and Neisseria gonorrhoeae (NG) was provided. Logistic regression models were used to assess factors associated with club drug use and its association with STI. RESULTS: A total of 1604 eligible FSWs were included. The overall prevalence of any STI infection and club drug use in the past 12 months was 22.6% and 7.4%, respectively. STI prevalence was significantly higher among club drug users (33.1%) than among nonusers (21.7%, P < 0.05). Multivariable logistic regression found that club drug use was associated with younger age (AOR 2.4, 95% CI 1.0, 6.0), higher education, having injected drugs (AOR 24.4, 95% CI 6.2, 96.8), and having had STI symptoms (AOR 2.2, 95% CI 1.4, 3.4). CONCLUSIONS: Club drug use and STI were highly prevalent among FSWs in China, especially among young FSWs. Club drug users had more risk behaviors and higher STI rates. A coordinated risk reduction framework is urgently needed to address the dual epidemic of drug use and STI. PMID- 28638825 TI - Thyroid Dysfunction in Non-Interferon Treated Hepatitis C Patients Residing in Hepatitis Endemic Area. AB - BACKGROUND: Association of thyroid dysfunction (TD) with interferon treatment of HCV is well known to clinicians. However, a few studies have highlighted the role of hepatitis C virus per se in the development of TD. The aim of this study was to know the prevalence of TD in non-interferon treated HCV infected patients referred for thyroid function testing. PATIENTS AND METHODS: Among 557 ELISA positive HCV patients 446 (341 females, 105 males) were selected for this study. Serums FT4, FT3, and TSH were determined by radioimmunoassay method. RESULTS: TD was detected in 15.2% of patients: 9.0% hypothyroidism and 6.3% hyperthyroidism. In increasing order subclinical hypothyroidism, overt hypothyroidism, overt hyperthyroidism, and subclinical hyperthyroidism were found in 4.7%, 4.3%, 3.6%, and 2.7% patients, respectively. Overall TD was more common in female than in male HCV patients but the difference was not significant (16.1% versus 12.4%; p = 0.648). Hyperthyroidism and subclinical hypothyroidism were slightly more common in female and overall hypothyroidism and overt hypothyroidism in male patients but the difference was not statistically significant (p > 0.05). The incidence of TD was relatively high in patients above 36 years (median age) but the difference was not statistically significant either collectively or in gender base groups (p > 0.05). CONCLUSION: Prior to interferon treatment, HCV infection itself causes biochemical thyroid dysfunction in 15.2% of local HCV patients. PMID- 28638826 TI - Anxiolytics, Sedatives, and Hypnotics Prescribed by Dentists in Brazil in 2010. AB - OBJECTIVE: To describe dental prescriptions for anxiolytics, sedatives, and hypnotics for Brazilian outpatients in 2010. METHODS: A cross-sectional study was conducted using data on the use of anxiolytics, sedatives, and hypnotics from the Brazilian Health Surveillance Agency, Brazil, 2010. For each prescription, prescribed drugs and the prescribed amount were identified. Prescribed medications were classified according to Anatomical Therapeutic Chemical code. We calculated the number of Defined Daily Doses (DDD) for anxiolytics, sedatives, and hypnotics by code, their mean DDD, and DDD per inhabitant per year. RESULTS: There were 16,436 prescriptions dispensed, including anxiolytics, sedatives, and hypnotics. These prescriptions corresponded to 3,555,780.50 mg, distributed as 2,286,200.50 mg (64.30%) of anxiolytics and 1,269,580.00 mg (35.70%) of sedatives and hypnotics. This amount allowed treating approximately 474,106 individuals (number of DDD). The anxiolytics most frequently dispensed were bromazepam (25.30%), alprazolam (19.19%), and diazepam (15.60%). Sedatives and hypnotics mostly prescribed were zolpidem (9.55%), midazolam (6.99%), and flunitrazepam (2.14%). The per capita rates (100,000 inhabitants) of anxiolytics and sedatives/hypnotics were 6.83 and 1.78, respectively. CONCLUSIONS: Benzodiazepines and derivatives were the most frequently prescribed drugs. There was a low rate of dental prescriptions for anxiolytics, sedatives, and hypnotics, although excessive doses were concentrated in the same prescription. PMID- 28638822 TI - Extracellular Vesicles in Renal Pathophysiology. AB - Extracellular vesicles are a heterogeneous population of microparticles released by virtually all living cells which have been recently widely investigated in different biological fields. They are typically composed of two primary types (exosomes and microvesicles) and are recently commanding increasing attention as mediators of cellular signaling. Indeed, these vesicles can affect recipient cells by carrying and delivering complex cargos of biomolecules (including proteins, lipids and nucleic acids), protected from enzymatic degradation in the environment. Their importance has been demonstrated in the pathophysiology of several organs, in particular in kidney, where different cell types secrete extracellular vesicles that mediate their communication with downstream urinary tract cells. Over the past few years, evidence has been shown that vesicles participate in kidney development and normal physiology. Moreover, EVs are widely demonstrated to be implicated in cellular signaling during renal regenerative and pathological processes. Although many EV mechanisms are still poorly understood, in particular in kidney, the discovery of their role could help to shed light on renal biological processes which are so far elusive. Lastly, extracellular vesicles secreted by renal cells gather in urine, thus becoming a great resource for disease or recovery markers and a promising non-invasive diagnostic instrument for renal disease. In the present review, we discuss the most recent findings on the role of extracellular vesicles in renal physiopathology and their potential implication in diagnosis and therapy. PMID- 28638827 TI - Cardiovascular Autonomic Neuropathy Is an Independent Risk Factor for Left Ventricular Diastolic Dysfunction in Patients with Type 2 Diabetes. AB - AIM: This study aimed to evaluate the association between cardiovascular autonomic neuropathy (CAN) and left ventricular diastolic dysfunction (LVDD) in type 2 diabetes patients. METHODS: 315 type 2 diabetes patients from inpatients of Drum Tower Hospital were included and classified into no CAN (NCAN), possible CAN (PCAN), and definite CAN (DCAN) based on cardiovascular autonomic reflex tests. The left ventricular diastolic function was assessed by tissue Doppler imaging echocardiography. RESULTS: The distribution of NCAN, PCAN, and DCAN was 11.4%, 51.1%, and 37.5%, respectively. The proportion of LVDD increased among the groups of NCAN, PCAN, and DCAN (39.4%, 45.3%, and 68.0%, P = 0.001). Patients with DCAN had higher filling pressure (E/e' ratio) (10.9 +/- 2.7 versus 9.4 +/- 2.8, P = 0.013) and impaired diastolic performance (e') (6.8 +/- 1.7 versus 8.6 +/- 2.4, P = 0.004) compared with NCAN. CAN was found to be an independent risk factor for LVDD from the multivariate regression analysis (OR = 1.628, P = 0.009, 95% CI 1.131-2.344). CONCLUSIONS: Our results indicated that CAN was an independent risk marker for the presence of LVDD in patients with diabetes. Early diagnosis and treatment of CAN are advocated for preventing LVDD in type 2 diabetes. PMID- 28638828 TI - Surveillance Program for Diagnosis of HCC in Liver Cirrhosis: Role of Ultrasound Echo Patterns. AB - International guidelines suggest ultrasound surveillance for hepatocellular carcinoma (HCC) early diagnosis in liver cirrhosis (LC) patients, but 40% of nodules <2 cm escape detection. We investigated the existence of an ultrasound pattern indicating a higher risk of developing HCC in patients under surveillance. 359 patients with LC (Child-Pugh A-B8) underwent ultrasound screening (median follow-up 54 months, range 12-90 months), liver function tests, alpha-fetoprotein assay, and portal hypertension evaluation. Echo patterns were homogeneous, bright liver, coarse, coarse small nodular pattern, and coarse large nodular pattern. During follow-up 13.9% developed HCC. At multivariate analysis using Cox's model alpha-fetoprotein, coarse large nodular pattern, portal hypertension, and age were independent predictors of HCC development. Kaplan Meier estimates of HCC cumulative risk in relation to the baseline echo patterns showed risk of 75% in coarse large nodular pattern patients, 23% coarse small nodular pattern, 21% coarse pattern, 0% homogeneous, and bright liver echo patterns (log-rank test = 23.6, P < 0.001). Coarse large nodular pattern indicates a major risk factor for HCC as 40.7% of patients with this pattern developed HCC. Homogeneous and bright liver echo patterns and the absence of portal hypertension were not related to HCC. This observation could raise the question of possibly modifying the follow-up timing in this subset of patients. PMID- 28638830 TI - Abdominal Hernias, Giant Colon Diverticulum, GIST, Intestinal Pneumatosis, Colon Ischemia, Cold Intussusception, Gallstone Ileus, and Foreign Bodies: Our Experience and Literature Review of Incidental Gastrointestinal MDCT Findings. AB - Incidental gastrointestinal findings are commonly detected on MDCT exams performed for various medical indications. This review describes the radiological MDCT spectrum of appearances already present in the past literature and in today's experience of several gastrointestinal acute conditions such as abdominal hernia, giant colon diverticulum, GIST, intestinal pneumatosis, colon ischemia, cold intussusception, gallstone ileus, and foreign bodies which can require medical and surgical intervention or clinical follow-up. The clinical presentation of this illness is frequently nonspecific: abdominal pain, distension, nausea, fever, rectal bleeding, vomiting, constipation, or a palpable mass, depending on the disease. A proper differential diagnosis is essential in the assessment of treatment and in this case MDCT exam plays a central rule. We wish that this article will familiarize the radiologist in the diagnosis of this kind of incidental MDCT findings for better orientation of the therapy. PMID- 28638831 TI - Corrigendum to "Differences in Brain Metabolic Impairment between Chronic Mild/Moderate TBI Patients with and without Visible Brain Lesions Based on MRI". AB - [This corrects the article DOI: 10.1155/2016/3794029.]. PMID- 28638829 TI - Mitochondrial-Targeted Molecular Imaging in Cardiac Disease. AB - The present study aimed to discuss the role of mitochondrion in cardiac function and disease. The mitochondrion plays a fundamental role in cellular processes ranging from metabolism to apoptosis. The mitochondrial-targeted molecular imaging could potentially illustrate changes in global and regional cardiac dysfunction. The collective changes that occur in mitochondrial-targeted molecular imaging probes have been widely explored and developed. As probes currently used in the preclinical setting still have a lot of shortcomings, the development of myocardial metabolic activity, viability, perfusion, and blood flow molecular imaging probes holds great potential for accurately evaluating the myocardial viability and functional reserve. The advantages of molecular imaging provide a perspective on investigating the mitochondrial function of the myocardium in vivo noninvasively and quantitatively. The molecular imaging tracers of single-photon emission computed tomography and positron emission tomography could give more detailed information on myocardial metabolism and restoration. In this study, series mitochondrial-targeted 99mTc-, 123I-, and 18F labeled tracers displayed broad applications because they could provide a direct link between mitochondrial dysfunction and cardiac disease. PMID- 28638832 TI - The Response of Macro- and Micronutrient Nutrient Status and Biochemical Processes in Rats Fed on a Diet with Selenium-Enriched Defatted Rapeseed and/or Vitamin E Supplementation. AB - The response of nutrient status and biochemical processes in (i) Wistar and (ii) spontaneously hypertensive (SHR) rats upon dietary intake of selenium- (Se-) enriched defatted rapeseed (DRS) and/or vitamin E fortification was examined to assess the health benefit of DRS in animal nutrition. Twenty-four individuals of each type of rat were used: The control group was fed with an untreated diet (Diet A). In Diets B and C, soybean meal was replaced with defatted DRS, which comprised 14% of the total diet. The selenized DRS application resulted in ~3 fold increase of Se content in the diet. Diet C was also fortified with the addition of vitamin E, increasing the natural content by 30%. The Se content of the blood and kidneys tended to increase in the DRS groups, where the changes were significant (P < 0.05) only in the case of SHR rats. The iodine (I) content and the proportion of iodide in rat livers indicated a lower transformation rate of iodide into organoiodine compounds compared to the control. Slight and ambiguous alterations in the antioxidative response of the rat were observed in the DRS groups, but the addition of vitamin E to the diet helped to moderate these effects. PMID- 28638834 TI - Personalized Consent Flow in Contemporary Data Sharing for Medical Research: A Viewpoint. AB - BACKGROUND: Health data personally collected by individuals with wearable devices and smartphones is becoming an important data source for healthcare, but also for medical research. OBJECTIVE: To describe a new consent model that allows people to control their personally collected health data and determine to what extent they want to share these for research purposes. METHODS: We developed, in close collaboration with patients, researchers, healthcare professionals, privacy experts, and an accredited Medical Ethical Review Committee, an innovative concept called "personalized consent flow" within a research platform connected to a personal health record. The development was an iterative process with informal meetings, semistructured interviews, and surveys. The final concept of the personalized consent flow was reviewed by patients and improved and approved by the same patients in a focus group. RESULTS: This concept could result in optimal control for individual users, since they will answer questions about how they will share data. Furthermore, it enables users to collect data for specific studies and add expiration dates to their data. This work facilitates further discussion about dynamic and personalized consent. A pilot study with the personalized consent model is currently being carried out. PMID- 28638833 TI - Isolation and Abiotic Stress Resistance Analyses of a Catalase Gene from Ipomoea batatas (L.) Lam. AB - As an indicator of the antioxidant capability of plants, catalase can detoxify reactive oxygen species (ROS) generated by environmental stresses. Sweet potato is one of the top six most important crops in the world. However, its catalases remain largely unknown. In this study, a catalase encoding gene, IbCAT2 (accession number: KY615708), was identified and cloned from sweet potato cv. Xushu 18. It contained a 1479 nucleotides' open reading frame (ORF). S-R-L, Q-K L, and a putative calmodulin binding domain were located at the C-terminus of IbCAT2, which suggests that IbCAT2 could be a peroxisomal catalase. Next generation sequencing (NGS) based quantitative analyses showed that IbCAT2 was mainly expressed in young leaves and expanding tuberous roots under normal conditions. When exposed to 10% PEG6000 or 200 mmol/L NaCl solutions, IbCAT2 was upregulated rapidly in the first 11 days and then downregulated, although different tissues showed different degree of change. Overexpression of IbCAT2 conferred salt and drought tolerance in Escherichia coli and Saccharomyces cerevisiae. The positive response of IbCAT2 to abiotic stresses suggested that IbCAT2 might play an important role in stress responses. PMID- 28638835 TI - Quality Improvement Interventions for Nutritional Assessment among Pregnant Mothers in Northeastern Uganda. AB - INTRODUCTION: Assessment of pregnant mothers for nutritional status is a neglected intervention. In Kaabong Hospital, nutritional status of pregnant mothers was not assessed during antenatal care (ANC) visits. A quality improvement (QI) project was initiated to increase nutritional assessment using midupper arm circumference (MUAC) among pregnant mothers during ANC visits from 0 to 90% between April and September 2015. METHOD: Baylor-Uganda formed ANC Work Improvement Team (WIT) that reviewed ANC register, identified gaps in quality of care, analyzed root causes using cause-effect diagram, developed solutions, and tested and implemented the solution using Plan-Do-Study-Act cycles. Planned and tested changes included the provision of anthropometric tools, integrated ANC register, and data use. RESULT: In April 2015 (baseline), none (0/235) of the pregnant women were assessed for nutritional status using MUAC. Following QI interventions, nutritional assessment improved to 79% (200/252) in May 2015 and to 100% (241/241) in June 2015. The 100% performance was sustained until August 2016. Overall, 39 cases of malnutrition-1 (2.6%) severe (MUAC < 19.0 cm) and 38 (97.4%) moderate acute malnutrition (MUAC 19-22.0 cm)-were identified and linked to nutritional rehabilitation program. CONCLUSION: QI interventions are critical in achieving high rates of nutritional status assessment and identifying malnourished pregnant women during ANC visits. PMID- 28638836 TI - Detecting the Candidate Gender Determinants by Bioinformatic Prediction of miRNAs and Their Targets from Transcriptome Sequences of the Male and Female Flowers in Salix suchowensis. AB - MicroRNAs (miRNAs) belong to a class of small, noncoding, and endogenous single stranded RNAs that negatively regulate gene expression at the posttranscriptional level. Potential miRNAs can be identified based on sequence homology since miRNAs are highly conserved in plants. In this study, we aligned the expressed sequence tags derived from flower buds of male and female S. suchowensis to miRNAs in the miRBase, which enable us to identify 34 potential miRNAs from flower buds of the alternate sexes. Among them, 11 were from the female and 23 were from the male. Analyzing sequence complementarity led to identification of 124 and 55 miRNA targets in the male and female flower buds, respectively. By mapping the target genes of the predicted miRNAs to the sequence assemblies of S. suchowensis, a miR156 mediated gene was detected at the gender locus of willow, which was a transcription factor involved in flower development. It is noteworthy that this target is not expressed in male flower, while it is expressed fairly highly in female flower based on the transcriptome data derived from the alternate sexes of willows. This study provides new bioinformatic clue for further exploring the genetic mechanism underlying gender determination in willows. PMID- 28638838 TI - Kaposi Sarcoma Mimicking Acute Flare of Ulcerative Colitis. AB - Besides an AIDS-defining illness, Kaposi sarcoma (KS) is also seen in individuals on long-term immunosuppressant therapy. We report KS in a 70-year-old immunocompetent man, which initially mimicked acute flare of ulcerative colitis (UC). He was hospitalized multiple times for complaints of watery diarrhea and tenesmus. Despite treatment with mesalamine, short courses of methylprednisolone, and one dose of infliximab, his symptoms improved only partially. He underwent colonoscopy, which revealed mild active colitis and a mass in the ascending colon. After treatment of acute flare with methylprednisone and mesalamine, he underwent total colectomy with end ileostomy. The histopathology confirmed stage I adenocarcinoma of colon. He continued to experience watery diarrhea, which was attributed to intractable UC, and he underwent protectomy several weeks later. The histopathology of rectum revealed KS. After surgery, watery diarrhea resolved completely. Review of literature suggests KS has been rarely reported in immunocompetent individuals with inflammatory bowel disease. PMID- 28638837 TI - Validation of a Novel Immunoline Assay for Patient Stratification according to Virulence of the Infecting Helicobacter pylori Strain and Eradication Status. AB - Helicobacter pylori infection shows a worldwide prevalence of around 50%. However, only a minority of infected individuals develop clinical symptoms or diseases. The presence of H. pylori virulence factors, such as CagA and VacA, has been associated with disease development, but assessment of virulence factor presence requires gastric biopsies. Here, we evaluate the H. pylori recomLine test for risk stratification of infected patients by comparing the test score and immune recognition of type I or type II strains defined by the virulence factors CagA, VacA, GroEL, UreA, HcpC, and gGT with patient's disease status according to histology. Moreover, the immune responses of eradicated individuals from two different populations were analysed. Their immune response frequencies and intensities against all antigens except CagA declined below the detection limit. CagA was particularly long lasting in both independent populations. An isolated CagA band often represents past eradication with a likelihood of 88.7%. In addition, a high recomLine score was significantly associated with high-grade gastritis, atrophy, intestinal metaplasia, and gastric cancer. Thus, the recomLine is a sensitive and specific noninvasive test for detecting serum responses against H. pylori in actively infected and eradicated individuals. Moreover, it allows stratifying patients according to their disease state. PMID- 28638839 TI - Broken Heart Syndrome in a Patient on Maintenance Hemodialysis. AB - Context:Broken heart syndrome or Takotsubo cardiomyopathy (TC) is a disorder characterized by transient left ventricular apical ballooning that almost invariably precedes emotional or physical stress. Although the patients with chronic kidney disease on hemodialysis have shown to exhibit sustained activity of sympathetic nervous system, the presentation of TC in these patients is a rare entity with few case reports in the literature. Case Report: A 75-year-old female with past medical history of end-stage renal disease presented with chest pressure and heaviness that started during her maintenance hemodialysis session. Electrocardiogram showed ST elevation and T wave inversion in V3-V6 leads. Emergent left heart catheterization was done that showed normal coronaries and akinesis of apical left ventricle wall consistent with TC. She was started on maximal medical management and underwent hemodialysis the next day without recurrence of the symptoms. Conclusion: TC may an underdiagnosed entity in patients on hemodialysis. However, it should be considered in the differential diagnosis in hemodialysis patients, particularly who presents with chest pain and/or symptoms. PMID- 28638840 TI - Epidemiology of Injuries in Stand-Up Paddle Boarding. AB - BACKGROUND: Stand-up paddle boarding (SUP) is a recreational activity and sport that has grown exponentially, with participation increasing from 1.1 million in 2010 to 2.8 million in 2014 in the United States alone. Despite this growth in participation, SUP remains underresearched with regard to injury epidemiology. PURPOSE: To investigate injury epidemiology (severity, location, type, mechanism) in SUP. STUDY DESIGN: Descriptive epidemiology study. METHODS: An open-source online survey was administered to active SUP participants internationally. The survey captured information relevant to demographics, participation, and injury history over the past 12 months. RESULTS: Of 240 participants included in the data analysis, 67.1% were males, and 54.6% were involved in competition. Participants spent a mean 192.6 +/- 179.5 hours participating in SUP per year, most commonly for fun and fitness (43.3%) at the beach or bay (63.0%). A total of 95 participants had sustained at least 1 injury. A total of 161 injuries were recorded, resulting in an injury rate of 3.63 (95% CI, 3.04-4.16) per 1000 hours of SUP. The shoulder/upper arm was the most frequently injured body location, accounting for 32.9% of all injuries, followed by the lower back (14.3%) and the elbow/forearm (11.8%). The most common injury types were to muscle/tendon (50.4%), joint/ligament (22.6%), and skin (14.2%). Endurance paddling was the most frequently reported mechanism of injury (34.5%), followed by contact with a paddler's own board (20.1%) and sprint paddling (9.3%). Key risk factors for sustaining an injury were age >46 years, competitive status, and participating for >4.8 hours/week, as well as using SUP for racing. CONCLUSION: This is the first study to report injury epidemiology for SUP. It is evident that both sexes participate in SUP for fun, fitness, and competition. With regard to injuries, the shoulder, lower back, and elbow are the most injury prone; older age, competitive status, and longer hours of participation all influenced the chance of injury. Findings from this study provide the foundation for injury prevention strategies. PMID- 28638841 TI - Economic Barriers in the Treatment of Clostridium difficile Infection With Oral Vancomycin. AB - Vancomycin is an increasingly important option for the treatment of Clostridium difficile infection, but economic barriers to its use remain significant in the outpatient setting. Generic vancomycin capsules are still inexplicably expensive and not universally covered by insurers. This report highlights the potential adverse consequences of cost-related nonadherence to vancomycin therapy and the challenges that clinicians face when prescribing oral vancomycin. PMID- 28638842 TI - Choosing Wisely Overnight? Residents' Approach to Fever. AB - We surveyed internal medicine residents regarding how they approach febrile patients in cross-cover settings. Residents frequently use the term "full fever work-up," and rely on this for sign-out. Despite this, residents felt fever work ups were not evidenced-based, and definitions of when and how to respond to a fever varied. PMID- 28638843 TI - Susceptibility to Cryptococcal Meningoencephalitis Associated With Idiopathic CD4+ Lymphopenia and Secondary Germline or Acquired Defects. AB - Idiopathic CD4+ lymphopenia (ICL) predisposes to opportunistic infections (OIs) but can often remain asymptomatic and does not have a strong association with monogenic mutations. Likewise, cryptococcal meningoencephalitis, the most common OI in ICL, is not strongly associated with monogenic mutations. In this study, we describe 2 patients with ICL plus an additional immune defect: one from an E57K genetic mutation in the nuclear factor-kappabeta essential modulator, and the other with acquired autoantibodies to granulocyte-macrophage colony-stimulating factor. Thus, these cases may exemplify a "multi-hit model" in patients with ICL who acquire OIs. PMID- 28638844 TI - Predictors of Unplanned Hospitalization in Patients Receiving Outpatient Parenteral Antimicrobial Therapy Across a Large Integrated Healthcare Network. AB - BACKGROUND: Outpatient parenteral antimicrobial therapy (OPAT) prescribing has increased along with the trend toward early discharge of hospitalized patients who have infections. There is limited literature that assesses unplanned hospitalizations during OPAT. This study aims to elucidate the predictors of unplanned hospitalization in OPAT patients after discharge from acute-care facilities within Carolinas HealthCare System (CHS). Understanding these predictors may inform future interventions to improve treatment efficacy and patient outcomes. METHODS: The study cohort included hospitalized patients aged >19 years who initiated OPAT in an acute-care facility within CHS in 2014-2015. Patients who had OPAT prescribed at an ambulatory-care facility were excluded. The primary outcome was unplanned hospitalization anytime during the at-risk time from discharge through 90 days. RESULTS: The unplanned hospitalization rate for the cohort was 18.5%. In adjusted analysis, having OPAT delivered at a skilled nursing facility was associated with a 46% (incident risk ratio = 1.46; 95% confidence interval = 1.04-2.06) increased risk of an unplanned hospitalization compared with patients receiving OPAT at home after adjustment for demographics, comorbidities, indication, treatment duration, and antimicrobial prescribed. Infusion, dialysis, and rehabilitation centers had the lowest rates of unplanned hospitalizations. CONCLUSIONS: These results suggest that the location of OPAT delivery is associated with unplanned hospitalizations and that older patients need additional support during OPAT. PMID- 28638846 TI - The Pandemic H30 Subclone of Sequence Type 131 (ST131) as the Leading Cause of Multidrug-Resistant Escherichia coli Infections in the United States (2011-2012). AB - BACKGROUND: Extraintestinal Escherichia coli infections are increasingly challenging due to emerging antimicrobial resistance, including resistance to extended-spectrum beta-lactams and fluoroquinolones. Sequence type 131 (ST131) is a leading contributor. METHODS: Three hundred sixty E. coli clinical isolates from across the United States (2011-2012), selected randomly from the SENTRY collection within 3 resistance categories (extended-spectrum cephalosporin [ECS] reduced susceptibility [RS]; fluoroquinolone-resistant, ESC-susceptible; and fluoroquinolone-susceptible, ESC-susceptible) were typed for phylogroup, sequence type complex (STc), subsets thereof, virulence genotype, O type, and beta lactamase genes. Molecular results were compared with susceptibility profile, specimen type, age, and sex. RESULTS: Phylogroup B2 accounted for most isolates, especially fluoroquinolone-resistant isolates (83%). Group B2-derived ST131 and its H30 subclone (divided between H30Rx and H30R1) predominated, especially among ESC-RS and fluoroquinolone-resistant isolates. In contrast, among fluoroquinolone susceptible isolates, group B2-derived STc73 and STc95 predominated. Within each resistance category, ST131 isolates exhibited more extensive resistance and/or virulence profiles than non-ST131 isolates. ST131-H30 was distributed broadly by geographical region, age, and specimen type and exhibited distinctive beta lactamase genes. Back-calculations indicated that within the source population ST131 accounted for 26.4% of isolates overall (vs 17% in 2007), including 19.8% ST131-H30, 13.2% ST131-H30R1, and 6.6% each ST131-H30Rx and non-H30 ST131. CONCLUSIONS: ST131-H30, with its ESC resistance-associated H30Rx subset, caused most antimicrobial-resistant E. coli infections across the United States in 2011 2012 and, since 2007, increased in relative prevalence by >50%. Focused attention to this strain could help combat the current E. coli resistance epidemic. PMID- 28638845 TI - Detection of the Northeastern African Rift Valley Fever Virus Lineage During the 2015 Outbreak in Mauritania. AB - BACKGROUND: Rift Valley fever (RVF) is an acute viral anthropozoonosis that causes epizootics and epidemics among livestock population and humans. Multiple emergences and reemergences of the virus have occurred in Mauritania over the last decade. This article describes the outbreak that occurred in 2015 in Mauritania and reports the results of serological and molecular investigations of blood samples collected from suspected RVF patients. METHODS: An RVF outbreak was reported from 14 September to 26 November 2015 in Mauritania. Overall, 184 suspected cases from different localities were identified by 26 health facilities. Blood samples were collected and tested by enzyme-linked immunosorbent assay (ELISA) and real-time reverse-transcription polymerase chain reaction (RT-PCR) at the Institut Pasteur de Dakar (IPD). Sequencing of partial genomes and phylogenetic analyses were performed on RT-PCR-positive samples. As part of routine surveillance at IPD, samples were also screened for dengue, yellow fever, West Nile, Crimean Congo hemorrhagic fever, Zika, and Chikungunya viruses by ELISA and RT-PCR. RESULTS: Of the 184 suspected cases, there were 57 confirmed cases and 12 deaths. Phylogenetic analysis of the sequences indicated an emergence of a virus that originated from Northeastern Africa. Our results show co-circulation of other arboviruses in Mauritania-dengue, Crimean Congo hemorrhagic fever, and West Nile viruses. CONCLUSION: The Northeastern Africa lineage of RVF was responsible for the outbreak in Mauritania in 2015. Co circulation of multiples arboviruses was detected. This calls for systematic differential diagnosis and highlights the need to strengthen arbovirus surveillance in Africa. PMID- 28638847 TI - Spontaneous Clearance of Hepatitis C Virus Infection Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men. AB - We assessed spontaneous clearance in 27 human immunodeficiency virus-infected men who have sex with men (MSM) who seroconverted for hepatitis C virus (HCV). In contrast with a recent estimate of 45.8%, we found a spontaneous clearance rate of 11.1% (95% confidence interval = 2.4-29.2). This finding suggests that treatment deferral to await spontaneous clearance might not be justified for MSM with sexually acquired HCV. PMID- 28638848 TI - Cytomegalovirus Infection With Retinitis After Brentuximab Vedotin Treatment for CD30+ Lymphoma. AB - Brentuximab vedotin is an antibody-conjugated chemotherapy targeting CD30 indicated in treatment of several lymphomas. We report the first 3 cases of cytomegalovirus severe infections with retinitis following this treatment. Evolution was favorable, but relapse occurred after treatment rechallenge. We suggest vigilance about cytomegalovirus in patients treated with brentuximab vedotin. PMID- 28638849 TI - Refractory T-Cell Anergy and Rapidly Fatal Progressive Multifocal Leukoencephalopathy After Prolonged CTLA4 Therapy. AB - Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to central nervous system replication of the human polyomavirus JC virus (JCV) in immunosuppressed patients. The only effective therapeutic approach is to restore anti-JCV T-cell responses. In this study, we describe a case of rapidly fatal PML with JCV T-cell anergy in a renal transplant patient treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). T-cell anergy could not be reversed despite several therapeutic approaches. Progressive multifocal leukoencephalopathy secondary to biotherapy induced T-cell anergy may thus represent a subset of PML with major resistance to anti-JCV immune recovery. PMID- 28638850 TI - Probiotic Lactobacillus Species Strengthen Intestinal Barrier Function and Tight Junction Integrity in Experimental Necrotizing Enterocolitis. AB - Necrotizing enterocolitis (NEC) is a serious intestinal disease that occurs in newborn infants. It is associated with major morbidity and affects 5% of all infants admitted to neonatal intensive care units. Probiotics have variable efficacy in preventing necrotizing enterocolitis. Tight junctions (TJ) are protein complexes that maintain epithelial barrier integrity. We hypothesized that the probiotics Lactobacillus rhamnosus and Lactobacillus plantarum strengthen intestinal barrier function, promote TJ integrity, and protect against experimental NEC. Both an in vitro and an in vivo experimental model of NEC were studied. Cultured human intestinal Caco-2 cells were pretreated with L. rhamnosus and L. plantarum probiotics. TJ were then disrupted by EGTA calcium switch or LPS to mimic NEC in vitro. Trans-epithelial resistance (TER) and flux of fluorescein isothiocynate dextran was measured. TJ structure was evaluated by ZO-1 immunofluorescence. In vivo effects of ingested probiotics on intestinal injury and ZO-1 expression were assessed in a rat model of NEC infected with Cronobacter sakazakii (CS). Caco-2 cells treated with individual probiotics demonstrated higher TER and lower permeability compared to untreated cells (p<0.0001). ZO-1 immunofluorescence confirmed TJ stability in treated cells. Rat pups fed probiotics alone had more intestinal injury compared with controls (p=0.0106). Probiotics were protective against injury when given in combination with CS, with no difference in intestinal injury compared to controls (p=0.21). Increased permeability was observed in the probiotic and CS groups (p=0.03, p=0.05), but not in the probiotic plus CS group (p=0.79). Lactobacillus sp. strengthened intestinal barrier function and preserved TJ integrity in an in vitro experimental model of NEC. In vivo, probiotic bacteria were not beneficial when given alone, but were protective in the presence of CS in a rat model of NEC. PMID- 28638852 TI - Olfactory dysfunction in patients with primary progressive MS. AB - OBJECTIVE: We tested the hypothesis that olfactory function is more impaired in patients with primary progressive MS (PPMS) than that in relapsing-remitting MS (RRMS). METHODS: Standardized olfactory testing was performed in 32 patients with PPMS, 32 patients with RRMS, and 32 healthy controls (HCs). Patients with olfactory dysfunction due to an alternative primary etiology were excluded. The validated olfactory testing method yielded individual scores for olfactory threshold, odor discrimination, and odor identification, along with a composite Threshold Discrimination Identification (TDI) score. RESULTS: Olfactory dysfunction was identified in 27 (84%) patients with PPMS, 10 (31%) patients with RRMS, and 1 (3%) HC. While age and sex were similar between PPMS and HCs, the TDI score and all olfactory subscores were significantly worse in patients with PPMS compared with HCs (all p < 0.001). After adjustment for differences in age, sex, Expanded Disability Status Scale (EDSS), and disease duration, odor discrimination, odor identification, and the composite TDI score were worse in patients with PPMS vs RRMS (p = 0.03, 0.04, and 0.02, respectively). Neither age, sex, EDSS, nor disease duration was significantly associated with the composite TDI score. CONCLUSIONS: Olfactory dysfunction was more frequent and severe in PPMS compared with RRMS, independent of disease duration and overall disability status. Further research on cellular level differences in olfactory neural pathways may lead to new insights about disease pathogenesis in MS. PMID- 28638851 TI - Mucosal biopsy shows immunologic changes of the colon in patients with early MS. AB - OBJECTIVE: To investigate immune cells of the colonic mucosa and fecal short chain fatty acids (SCFAs) in treatment-naive patients with a clinically isolated syndrome (CIS) or early relapsing MS. METHODS: In this cross-sectional proof-of concept study, we obtained mucosal specimens during ileocolonoscopy from 15 untreated patients with CIS/MS and 10 controls. Mucosal immune cells were analyzed by FACS, and gas chromatography-mass spectrometry measurements of stool samples served to determine SCFA. RESULTS: The number of total dendritic cells (DCs), CD103+ tolerogenic DCs, and CD4+25+127-regulatory T cells (Tregs) was significantly reduced in the distal colon of patients with CIS/MS compared with controls, whereas we found no differences in the proximal colon. The patients' fecal samples also showed a substantially lower content of SCFA and especially lower levels of butyrate and acetate. CONCLUSIONS: Our findings indicate a disturbed homeostasis of colonic DCs and Tregs in patients with MS which could be associated with colonic SCFA depletion. Although not implying causality, these findings confirm parallel abnormalities of the gut in MS and warrant further research if modulation of the colonic SCFA profile or the colonic Treg pool can serve to modify the course of MS. PMID- 28638853 TI - An unusual case of miliary PML-IRIS in an HIV+ patient. PMID- 28638854 TI - Autoimmune episodic ataxia in patients with anti-CASPR2 antibody-associated encephalitis. AB - OBJECTIVE: To report paroxysmal episodes of cerebellar ataxia in a patient with anti-contactin-associated protein-like 2 (CASPR2) antibody-related autoimmune encephalitis and to search for similar paroxysmal ataxia in a cohort of patients with anti-CASPR2 antibody-associated autoimmune encephalitis. METHODS: We report a patient with paroxysmal episodes of cerebellar ataxia observed during autoimmune encephalitis with anti-CASPR2 antibodies. In addition, clinical analysis was performed in a retrospective cohort of 37 patients with anti-CASPR2 antibodies to search for transient episodes of ataxia. Paroxysmal symptoms were further specified from the referral physicians, the patients, or their relatives. RESULTS: A 61-year-old man with limbic encephalitis and anti-CASPR2 antibodies developed stereotyped paroxysmal episodes of cerebellar ataxia, including gait imbalance, dysarthria, and dysmetria, 1 month after the onset of the encephalitis. The ataxic episodes were specifically triggered by orthostatism and emotions. Both limbic symptoms and transient ataxic episodes resolved after treatment with steroids and IV cyclophosphamide. Among 37 other patients with anti-CASPR2 antibodies, we identified 5 additional cases with similar paroxysmal ataxic episodes that included gait imbalance (5 cases), slurred speech (3 cases), limb dysmetria (3 cases), and nystagmus (1 case). All had concomitant limbic encephalitis. Paroxysmal ataxia was not observed in patients with neuromyotonia or Morvan syndrome. Triggering factors (orthostatism or anger) were reported in 4 patients. Episodes resolved with immunomodulatory treatments in 4 patients and spontaneously in 1 case. CONCLUSIONS: Paroxysmal cerebellar ataxia must be added to the spectrum of the anti-CASPR2 antibody syndrome. PMID- 28638856 TI - Devising a Composite Index to Analyze and Model Loneliness and Related Health Risks in the United Kingdom. AB - Objective:This research presents a framework through which a spatial composite index is devised to determine areas of potential loneliness and associated health risks. The research is evidenced on the London borough of Southwark in the United Kingdom but is designed such that it could be applied more widely. Method: The work adopts a quantitative approach through the combination of census and accessibility variables at a small area level. The output is a scoring system whereby each area is assigned a value indicating the likely presence of loneliness and potentially corresponding health risks. Results: Findings imply that loneliness is quantifiable and that this correlates with socioeconomic and accessibility measures. A strong clustering is evident in Southwark. Discussion: This research builds on previous attempts to locate and quantify loneliness with favorable results. The outcome provides a replicable solution to assist the public service with the targeting of areas deemed most at risk from loneliness and resultant mental and physical health conditions at a time when such issues are high on the political agenda. PMID- 28638855 TI - End of Life Care and Do Not Resuscitate Orders: How Much Does Age Influence Decision Making? A Systematic Review and Meta-Analysis. AB - With population aging, "do not resuscitate" (DNAR) decisions, pertaining to the appropriateness of attempting resuscitation following a cardiac arrest, are becoming commoner. It is unclear from the literature whether using age to make these decisions represents "ageism." We undertook a systematic review of the literature using CINAHL, Medline, and the Cochrane database to investigate the relationship between age and DNAR. All 10 studies fulfilling our inclusion criteria found that "do not attempt resuscitation" orders were more prevalent in older patients; eight demonstrated that this was independent of other mediating factors such as illness severity and likely outcome. In studies comparing age groups, the adjusted odds of having a DNAR order were greater in patients aged 75 to 84 and >=85 years (adjusted odds ratio [AOR] 1.70, 95% confidence interval [CI] = [1.25, 2.33] and 2.96, 95% CI = [2.34, 3.74], respectively), compared with those <65 years. In studies treating age as a continuous variable, there was no significant increase in the use of DNAR with age (AOR 0.98, 95% CI = [0.84, 1.15]). In conclusion, age increases the use of "do not resuscitate" orders, but more research is needed to determine whether this represents "ageism." PMID- 28638857 TI - Development of the FDA Tobacco Credibility Scale (FDA-TCS). AB - OBJECTIVES: Messages from organizations with high, compared to low, credibility may be more persuasive. Whereas the tobacco industry has long recognized the importance of credibility in promoting its messages and public image, the source credibility of key tobacco control organizations has gone largely unmeasured. To assess credibility of a key tobacco regulator, we developed a scale of the US Food and Drug Administration (FDA) tobacco-related credibility. METHODS: We developed and tested 30 items reflective of the dimensions of source credibility (trust, expertise, and public interest) and FDA's tobacco regulatory roles in a sample of 1353 US adults and assessed reliability and validity. RESULTS: Factor analysis identified 3 dimensions of the FDA Tobacco Credibility Scale (FDA-TCS): public interest, trust, and expertise. The 3 subscales showed evidence of reliability and convergent validity; all subscales were correlated with general FDA credibility and trust in government. Those who knew that the FDA regulates tobacco scored higher on the trust and expertise subscales. The subscales were also associated with support for potential regulations, suggesting criterion related validity. CONCLUSIONS: The FDA-TCS allows for an understanding of the impact of credibility on responses to the FDA's tobacco control communications and regulatory efforts. PMID- 28638858 TI - Endocannabinoid metabolism in neurodegenerative diseases. PMID- 28638860 TI - Collaboration, workshops, and symposia. PMID- 28638859 TI - A Review of the Aetiopathogenesis and Clinical and Histopathological Features of Oral Mucosal Melanoma. AB - Oral mucosal melanoma is an uncommon, usually heavily melanin-pigmented, but occasionally amelanotic aggressive tumour with a poor prognosis. Despite radical surgery, radiotherapy, or chemotherapy, local recurrence and distant metastasis are frequent. Microscopical examination is essential for diagnosis, and routine histological staining must be supplemented by immunohistochemical studies. The aetiology is unknown, the pathogenesis is poorly understood, and the 5-year survival rate rarely exceeds 30%. In most cases, oral mucosal melanoma arises from epithelial melanocytes in the basal layer of the epithelium and less frequently from immature melanocytes arrested in the lamina propria. In both cases the melanocytes undergo malignant transformation, invade deeper tissues, and metastasize to regional lymph nodes and to distant sites. Very rarely metastasis from skin melanoma may give rise to oral mucosal melanoma that may be mistaken for primary oral mucosal melanoma. The pathogenesis of oral mucosal melanoma is complex involving multiple interactions between cytogenetic factors including dysregulation of the cKit signalling pathways, cell cycle, apoptosis, and cell-to-cell interactions on the one hand and melanin itself, melanin intermediates, and local microenvironmental agents regulating melanogenesis on the other hand. The detailed mechanisms that initiate the malignant transformation of oral melanocytes and thereafter sustain and promote the process of melanomagenesis are unknown. PMID- 28638861 TI - RANDOMIZED ANTICANCER AND CYTOTOXICITY ACTIVITIES OF GUIBOURTIA COLEOSPERMA AND DIOSPYROS CHAMAETHAMNUS. AB - BACKGROUND: Plants have consistently proven to be a reliable and yet not fully explored source of medicines. In light of this, there is a constant demand for new treatment regimens for cancer. Namibia has a rich diversity of plant species of over 4300 with 17 % of them being endemic to Namibia. Plants growing in Namibia's diverse climatic zones produce many secondary metabolites as part of adaptation to their environment. This article focused on the screening of such phytochemicals and their cytotoxic and anticancer properties in vitro. Two Namibian plants Diospyros chamaethamnus and Guibourtia coleosperma were randomly selected for this purpose. MATERIALS AND METHODS: The plants were screened for the presence of coumarins, alkaloids, flavonoids, anthraquinones, steroids and terpenoids using thin layer chromatography. Anticancer screening was performed on a panel of three cancer cell lines, while cytotoxicity was determined using a human fibroblast cell line, both using the SRB method. RESULTS: Alkaloids, anthraquinones, flavonoids and steroids were detected in both organic and aqueous extracts of the two plants. The organic plant extracts had a greater anti proliferative effect on the cancer cell lines than the aqueous extracts; the D. chamaethamnus organic root extract was the most potent with an IC50 of 16.08, 29.12 and 24.67 ug/mL against TK10, UACC62 and MCF7 cells, respectively. Furthermore, cytotoxicity analysis revealed the non-toxic nature of the extracts, except for the organic root extract of D. chamaethamnus that showed significant cytotoxicity (IC50 13.03 ug/mL). CONCLUSION: D. chamaethamnus is a potential candidate for the development of a plant based cancer treatment. The study showed the value of random screening in drug discovery from plants for pharmacological activity that is unrelated to their ethnomedicinal uses. PMID- 28638862 TI - RAW REHMANNIA RADIX POLYSACCHARIDE CAN EFFECTIVELY RELEASE PEROXIDATIVE INJURY INDUCED BY DUCK HEPATITIS A VIRUS. AB - BACKGROUND: Duck viral hepatitis (DVH), caused by duck hepatitis A virus (DHAV), is a fatal contagious infectious disease which spreads rapidly with high morbidity and high mortality, and there is no effective clinical drug against DVH. MATERIALS AND METHODS: Raw Rehmannia Radix Polysaccharide (RRRP), Lycii Fructus polysaccharides and Astragalus Radix polysaccharides were experimented in vitro and in vivo. Mortality rate, livers change, liver lesion scoring, peroxidative injury evaluation indexes in vitro and in vivo, and hepatic injury evaluation indexes of optimal one were detected and observed in this experiment. RESULTS: RRRP could reduce mortality with the protection rate about 20.0% compared with that of the viral control (VC) group, finding that RRRP was the most effective against DHAV. The average liver scoring of the VC, blank control (BC), RRRP groups were 3.5, 0, 2.1. Significant difference (P<0.05) appeared between any two groups, demonstrating that it can alleviate liver pathological change. RRRP could make the hepatic injury evaluation indexes similar to BC group while the levels of the VC group were higher than other two groups in general. The levels of SOD, GSH-Px, CAT of RRRP group showed significant higher than that of VC group while the levels of NOS and MDA showed the opposite tendency, thus, RRRP could release peroxidative injury. CONCLUSION: RRRP was the most effective against duck hepatitis A virus (DHAV). RRRP could reduce mortality, alleviate liver pathological change, down-regulate liver lesion score, release peroxidative injury and hepatic injury. The antiviral and peroxidative injury releasing activity of RRRP for DHAV provided a platform to test novel drug strategies for hepatitis A virus in human beings. PMID- 28638863 TI - NEUROPROTECTIVE EFFECT OF TERMINALIA CHEBULA EXTRACTS AND ELLAGIC ACID IN PC12 CELLS. AB - BACKGROUND: Alzheimer's disease (AD) is one of the common neurodegenerative disorders among elderly. The purpose of this study was to determine the neuroprotective effect and mechanisms of action underlying the Terminalia chebula extracts and ellagic acid by using beta-amyloid25-35 (Abeta25-35)-induced cell toxicity in an undifferentiated pheochromocytoma (PC12) cell line. MATERIALS AND METHODS: The T. chebula extracts were prepared using the methanol, water, and 95% ethanol. Specifically, the ellagic acid was obtained in our laboratory. Assays including cell toxicity and changes in intracellular reactive oxygen species (ROS) and calcium level were evaluated to examine the neuroprotective effects and mechanisms of the T. chebula extracts and ellagic acid. RESULTS: The methanolic and water extracts of T. chebula and ellagic acid exhibited the strongest neuroprotective activity against Abeta25-35-induced PC12 cell damages at 0.5-5.0 MUg/ml. The ellagic acid also exhibited partial neuroprotective activity against H2O2-induced PC12 cell damages at 0.5-5.0 MUg/ml. The methanolic and water extracts of T. chebula and ellagic acid protected PC12 cells from Abeta25-35 mediated cell damages and enhanced cell viability thorough two key mechanisms by: (1) inhibiting ROS production and (2) reducing calcium ion influx. CONCLUSION: The T. chebula represents a promising plant-source as medicine in the application for the treatment of AD. Further investigation focusing on the active component of T. chebula extracts e.g., ellagic acid is crucial to verify the neuroprotective efficacy and mechanisms in vivo. PMID- 28638865 TI - SOME ENGINEERING PROPERTIES OF SHELLED AND KERNEL TEA (Camellia sinensis) SEEDS. AB - BACKGROUND: Camellia sinensis is the source of tea leaves and it is an economic crop now grown around the World. Tea seed oil has been used for cooking in China and other Asian countries for more than a thousand years. Tea is the most widely consumed beverages after water in the world. It is mainly produced in Asia, central Africa, and exported throughout the World. Some engineering properties (size dimensions, sphericity, volume, bulk and true densities, friction coefficient, colour characteristics and mechanical behaviour as rupture force of shelled and kernel tea (Camellia sinensis) seeds were determined in this study. MATERIALS AND METHODS: This research was carried out for shelled and kernel tea seeds. The shelled tea seeds used in this study were obtained from East-Black Sea Tea Cooperative Institution in Rize city of Turkey. Shelled and kernel tea seeds were characterized as large and small sizes. RESULTS: The average geometric mean diameter and seed mass of the shelled tea seeds were 15.8 mm, 10.7 mm (large size); 1.47 g, 0.49 g (small size); while the average geometric mean diameter and seed mass of the kernel tea seeds were 11.8 mm, 8 mm for large size; 0.97 g, 0.31 g for small size, respectively. The sphericity, surface area and volume values were found to be higher in a larger size than small size for the shelled and kernel tea samples. The shelled tea seed's colour intensity (Chroma) were found between 59.31 and 64.22 for large size, while the kernel tea seed's chroma values were found between 56.04 68.34 for large size, respectively. The rupture force values of kernel tea seeds were higher than shelled tea seeds for the large size along X axis; whereas, the rupture force values of along X axis were higher than Y axis for large size of shelled tea seeds. The static coefficients of friction of shelled and kernel tea seeds for the large and small sizes higher values for rubber than the other friction surfaces. CONCLUSION: Some engineering properties, such as geometric mean diameter, sphericity, volume, bulk and true densities, the coefficient of friction, L*, a*, b* colour characteristics and rupture force of shelled and kernel tea (Camellia sinensis) seeds will serve to design the equipment used in postharvest treatments. PMID- 28638864 TI - PROTECTIVE EFFECT OF VANILLIC ACID ON OVARIECTOMY-INDUCED OSTEOPOROSIS IN RATS. AB - BACKGROUND: The need for an anti-osteoporotic agent is in high demand since osteoporosis contributes to high rates of disability or impairment (high osteoporotic fracture), morbidity and mortality. Hence, the present study is designed to evaluate the protective effects of vanillic acid (VA) against bilateral ovariectomy-induced osteoporosis in female Sprague-Dawley (SD) rats. MATERIALS AND METHODS: Forty healthy female adult SD rats were separated in to four groups with sham-operated control with bilateral laprotomy (Sham; n = 10), bilateral overiectomy (OVX; n = 10) group, OVX rats were orallay administrated with 50 mg/kg b.wt of VA (OVX + 50 VA; n = 10) or 100 mg/kg b.wt of VA (OVX + 100 VA; n = 10) for 12 weeks (post-treatment) after 4 weeks of OVX. RESULTS: A significant change in the body weight gain was noted in OVX group, while treatment with VA substantially reverted to normalcy. Meanwhile, the bone mineral density and content (BMD and BMC) were substantially improved on supplementation with VA. Also, the bone turnover markers like calcium (Ca), phosphorous (P), osteocalcin (OC), alkaline phosphatase (ALP) and deoxypyridinoline (DPD) and inflammatory markers (IL-1beta, IL-6, and TNF-alpha) levels were markedly attenuated in VA-treated rats. Moreover, the biomechanical stability was greatly ameliorated with VA administration. Both the dose of VA showed potent anti osteoporotic activity, but VA 100 mg showed highest protective effects as compared with 50 mg of VA. CONCLUSION: Based on the outcome, we concluded that VA 100 showed better anti-osteoporotic activity by improving BMD and BMC as well as biomechanical stability and therefore used as an alternative therapy for treating postmenopausal osteoporosis. PMID- 28638866 TI - KINETICS OF MODULATORY ROLE OF Cyperus esculentus L. ON THE SPECIFIC ACTIVITY OF KEY CARBOHYDRATE METABOLIZING ENZYMES. AB - BACKGROUND: The continuous search for new lead compounds as viable inhibitors of specific enzymes linked to carbohydrate metabolism has intensified. Cyperus esculentus L. is one of the therapeutically implicated botanicals against several degenerative diseases including diabetes mellitus. MATERIALS AND METHODS: This study evaluated the antioxidant and mechanism(s) of inhibitory potential of aqueous extract of C. esculentus on alpha-amylase and alpha-glucosidase in vitro. The extract was investigated for its radical scavenging and hypoglycaemic potentials using standard experimental procedures. Lineweaver-Burke plot was used to predict the manner in which the enzymes were inhibited. RESULTS: The data obtained revealed that the extract moderately and potently inhibited the specific activities of alpha-amylase and alpha-glucosidase, respectively. The inhibition was concentration-related with respective IC50 values of 5.19 and 0.78 mg/mL relative to that of the control (3.72 and 3.55 mg/mL). The extract also significantly scavenged free radicals and the effects elicited could be ascribed to its phytoconstituents. CONCLUSION: The respective competitive and non competitive mode of action of the extract is due to its inhibitory potentials on the activities of alpha-amylase and alpha-glucosidase. Going forward, in addition to completely characterize the exact compound(s) responsible for the elicited activity in this study, pertinent attention will be given to the in vivo evaluation of the identified constituents. PMID- 28638867 TI - ANTITUMOR EFFECTS OF CHRYSANTHEMIN IN PC-3 HUMAN PROSTATE CANCER CELLS ARE MEDIATED VIA APOPTOSIS INDUCTION, CASPASE SIGNALLING PATHWAY AND LOSS OF MITOCHONDRIAL MEMBRANE POTENTIAL. AB - BACKGROUND: The main objective of the current research work was to investigate the antitumor and apoptotic effects of chrysanthemin in PC-3 human prostate cancer cells. MATERIALS AND METHODS: MTT assay was used to evaluate the effects of chrysanthemin on cell viability whereas flow cytometry along with fluorescence microscopy were used to study apoptotic induction in these cells. Effects on caspase activation were detected through western blot assay. RESULTS: Results showed that chrysanthemin inhibited cancer cell growth in PC-3 cancer cells in a time-dependent as well as concentration-dependent manner. Chrysanthemin-treated cells at 10, 50 and 150 uM doses led to 34.2%, 56.7% and 69.1% apoptosis in these cells respectively. The percentage of cells with depolarized mitochondria increased from 5.3% in untreated control cells to 27.2%, 57.6% and 86.9% in cells treated with 10, 50 and 150 uM dose of chrysanthemin respectively. Chrysanthemin also enhanced the activity of all three caspases viz., caspase-3, 8 and 9 in a dose-dependent fashion. CONCLUSIONS: The study concluded that chrysanthemin ledanticancer effects in PC-3 prostate cancer cells by inducing apoptosis, activating caspasesignaling pathway and loss of mitochondrial membrane potential. PMID- 28638868 TI - IN VIVO EFFECT OF RUTA CHALEPENSIS EXTRACT ON HEPATIC CYTOCHROME 3A1 IN RATS. AB - BACKGROUND: Since the time when drugs began to be used, it became evident that they could produce a therapeutic effect, but also a clinical condition of toxicity or no effect at all on humans, despite using the same doses in different patients. Such untoward effects were termed "drug idiosyncrasy" and also "idiosyncratic drug effects", but the factors producing such diverse responses were never taken into account. MATERIALS AND METHODS: Ruta chalepensis L. (fringed rue) is an herbaceous plant of the Rutaceae family used in traditional medicine due to its properties, such as its analgesic and antipyretic effects. This study used 25 male rats divided into five groups. Plant extract was administered to Groups 1 and 2 at doses of 100 and 30 mg/kg/day, respectively, for three days; Group 3 was administered 100 mg/kg/day of dexamethasone (DEX), as well as 100 mg/kg/day of Ruta chalepensis extract; Group 4 was administered 100 mg/kg/day of DEX and treated as positive control; Group 5 was treated as negative control and was administered a physiological solution. Twenty-four hours after the the last dose, the animals were sacrificed and their livers were extracted. RESULTS: The aqueous extract of Ruta chalepensis, intraperitoneally administered, was able to induce cytochrome 3A1 in doses of 30 mg/kg/day, and a greater inducing effect occurs when the plant is co-administered in doses of 100 mg/kg/day with dexamethasone. CONCLUSION: This study suggests that aqueous extract of Ruta chalepensis can induce cytochrome 3a1. This study helps provide a better understanding of CYP3a regulation. Future in vitro work is needed to determine the compounds that produce the cytochrome modulation. PMID- 28638870 TI - APOPTOSIS INDUCTION OF EPIFRIEDELINOL ON HUMAN CERVICAL CANCER CELL LINE. AB - BACKGROUND: Present investigation evaluates the antitumor activity of epifriedelinol for the management of cervical cancer by inducing process of apoptosis. METHODS: Human Cervical Cancer Cell Line, C33A and HeLa were selected for study and treated with epifriedelinol at a concentration of (50-1000 ug/ml). Cytotoxicity of epifriedelinol was estimated by MTT assay and induction of apoptosis was assessed by estimating the activity of caspase 3, 8 and 9 enzyme, apoptosis assay and translocation of cytochrome c. Moreover an expression of several proteins that plays role in the apoptosis process was estimated by western blot method. RESULTS: Result of the study suggested that treatment with epifriedelinol significantly decrease the viability count of cancerous cell in a dose perndent manner and also enhances the formation of oligonucleosome in both the cell lines. However activity of caspase enzymes and translocation of cytochrome c were enhanced after treatment with epifriedelinol. It was also observed that epifriedelinol treatment alters the ratio of pro-apoptotic to anti apoptotic proteins and enhances the expressions of inhibitor of apoptosis proteins (IAP). CONCLUSION: Result of our study proves the anticancer activity of epifriedelinol in cervical cancer by inducing apoptosis as treatment with it enhances the production of oligonucleosomes, translocation of cytochrome c and activity caspase enzymes. PMID- 28638869 TI - REDUCING TOXICITY AND INCREASING EFFICIENCY: ACONITINE WITH LIQUIRITIN AND GLYCYRRHETINIC ACID REGULATE CALCIUM REGULATORY PROTEINS IN RAT MYOCARDIAL CELL. AB - BACKGROUND: Compatibility of Radix Aconiti Carmichaeli and Liquorice is known to treat heart diseases such as heart failure and cardiac arrhythmias. This work answers the question that whether the active components (Aconitine, Liquiritin and Glycyrrhetinic Acid) of Radix Aconiti Carmichaeli and Liquorice could result in regulating intracellular calcium homeostasis and calcium cycling, and thereby verifies the therapeutic material basis. MATERIALS AND METHODS: The myocardial cells were divided into twelve groups randomly as control group, Aconitine group, nine different dose groups that orthogonal combined with Aconitine, Liquiritin and Glycyrrhetinic Acid, and Verapamil group. The myocardial cellular survival rate and morphology were assessed. The expression of calcium regulation protein(RyR2, NCX1, DHPR-a1) in the myocardial cell by Western-blotting. RESULTS: The results exhibited that Aconitine (120 uM) significantly damaged on myocardial cell, decreased the survival rate and expression of Na+/Ca2+ exchangers (NCX1) and dihydropteridine reducta-alpha1 (DHPR-a1), and increased the expression of ryanodine receptor type2 (RyR2) obviously. The compatibility groups (Aconitine, Liquiritin and Glycyrrhetinic Acid) all could against the damage on the myocardial cell by Aconitine at different levels. CONCLUSION: Aconitine with Liquiritin and Glycyrrhetinic Acid may regulate the expression of calcium regulated proteins to protect myocardial cells from damage. PMID- 28638871 TI - EFFECT OF YISHENJIANPI RECIPE ON SEMEN QUALITY AND SPERM MITOCHONDRIA IN MICE WITH OLIGOASTHENOZOOSPERMIA INDUCED BY TRIPTERYGIUM GLYCOSIDES. AB - BACKGROUND: Kidney tonifying - spleen strengthening method being one of the modalities for treatment of astheno-oligozoospermia is currently commonly used in the clinical setting. To investigate the mechanism of YiShenJianPi (YSJP) Recipe, used in Traditional Chinese Medicine to benefit "the kidney" and strengthen "the spleen". MATERIALS AND METHODS: Oligoasthenozoospermia, male BALB/c mice were randomly divided into normal control, disease model, positive control, low-dosage and high-dosage groups. Oligoasthenozoospermia was induced by tripterygium glucosides intragastric administration before treatment started. Through using computer-aided sperm analysis to test the changes in sperm quality, utilizing flow cytometry to test the percentage of sperm with normal mitochondrial transmembrane potential (JC-1 + %), utilizing X-ray microscopy to observe epididymal sperm ultra-microstructure placing special emphasis and photographing the differences in mitochondria of the flagellum region. RESULTS: Compared with DM, sperm quality of the treated mice was significantly better (P<0.05, respectively). Compared with PC, the LD group had significantly better quality sperms, while the parameters in the HD group were numerically better. Compared with NC, all other groups had significantly lower percentage of sperms with normal mitochondrial membrane potential. In PC, LD and HD groups, the percentage of sperms with normal mitochondrial membrane potential was significantly higher than that of D. The 9+9+2 mitochondrial sheath structure was complete in NC but damaged in DM. In the treatment groups, this structure was fairly clear. CONCLUSION: YSJP improved semen quality with oligoasthenozoospermia by improving sperm mitochondrial membrane potential and restoring sperm mitochondrial ultrastructure. PMID- 28638872 TI - HEMORHEOLOGY INDEX CHANGES IN A RAT ACUTE BLOOD STASIS MODEL: A SYSTEMATIC REVIEW AND META-ANALYSIS. AB - BACKGROUND: Blood stasis has received increasing attention in research related to traditional Chinese medicine (TCM) and integrative Chinese and Western medicine. More than 90% of research studies use hemorheology indexes to evaluate the establishment of animal blood stasis models rather than pathological methods, as hemorheology index evaluations of blood stasis were short of the consolidated standard. The aim of this study was to evaluate the accuracy of hemorheology indexes in rat models of acute blood stasis (ABS) based on studies in which the ABS model had been confirmed by pathological methods. MATERIALS AND METHODS: We searched the Chinese National Knowledge Infrastructure database (CNKI), Chinese Medical Journal Database (CMJD), Chinese Biology Medicine disc (CBM), Wanfang database, and PubMed for studies of rat blood stasis models; the search identified 18 studies of rat ABS models induced by subcutaneous injection of epinephrine combined with an ice bath. Each included study received a modified Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) score list and methodological quality assessment, then data related to whole blood viscosity, plasma viscosity, platelet aggregation rate, erythrocyte aggregation index, and fibrinogen concentration were extracted. Extracted data were analyzed using Revman 5.3; heterogeneity was tested using Egger's test. RESULTS: A total of 343 studies of rat blood stasis were reviewed. Eighteen studies were included in this meta analysis; the mean CAMARADES score was 3.5. The rat ABS model revealed a significant increase in whole blood viscosity (medium shear rate), whole blood viscosity (high shear rate), plasma viscosity, platelet aggregation rate, erythrocyte aggregation index, and fibrinogen concentration compared to controls, with weighted mean differences (WMD) of 2.42 mPa/s (95% confidence interval (CI) = 1.73 - 3.10); 1.76 mPa/s (95% CI = 1.28 - 2.24); 0.39 mPa/s (95% CI = 0.24 - 0.55); 13.66% (95% CI = 9.78 - 17.55); 0.84 (95% CI = 0.53 - 1.16); and 1.22 g/L (95% CI = 0.76 - 1.67), respectively. Subgroup analysis showed that whole blood viscosity, plasma viscosity, and the platelet aggregation rate test methods were more sensitive when measured at 0-24 h than at 24-72 h after induction of blood stasis. CONCLUSIONS: Rat blood stasis studies have incomplete experimental design and quality controls, and thus need an integrated improvement. Meta-analysis of included studies indicated that the unified hemorheology index of whole blood viscosity (medium and high shear rate), platelet aggregation rate, erythrocyte aggregation rate, and fibrinogen concentration might be used for assessment of rat ABS models independent of pathology methods. PMID- 28638873 TI - PROTECTIVE EFFECT OF CAMEL MILK AS ANTI-DIABETIC SUPPLEMENT: BIOCHEMICAL, MOLECULAR AND IMMUNOHISTOCHEMICAL STUDY. AB - BACKGROUND: Diabetes is a serious disease affects human health. Diabetes in advanced stages is accompanied by general weakness and alteration in fats and carbohydrates metabolism. Recently there are some scientific trends about the usage of camel milk (CM) in the treatment of diabetes and its associated alterations. CM contains vital active particles with insulin like action that cure diabetes and its complications but how these effects occur, still unclear. MATERIALS AND METHODS: Seventy-five adult male rats of the albino type divided into five equal groups. Group 1 served as a negative control (C). Group 2 was supplemented with camel milk (CM). Diabetes was induced in the remaining groups (3, 4 and 5). Group 3 served as positive diabetic control (D). Group 4 served as diabetic and administered metformin (D+MET). Group 5 served as diabetes and supplemented with camel milk (D+CM). Camel milk was supplemented for two consecutive months. Serum glucose, leptin, insulin, liver, kidney, antioxidants, MDA and lipid profiles were assayed. Tissues from liver and adipose tissues were examined using RT-PCR analysis for the changes in mRNA expression of genes of carbohydrates and lipid metabolism. Pancreas and liver were used for immunohistochemical examination using specific antibodies. RESULTS: Camel milk supplementation ameliorated serum biochemical measurements that altered after diabetes induction. CM supplementation up-regulated mRNA expression of IRS-2, PK, and FASN genes, while down-regulated the expression of CPT-1 to control mRNA expression level. CM did not affect the expression of PEPCK gene. On the other hand, metformin failed to reduce the expression of CPT-1 compared to camel milk administered rats. Immunohistochemical findings revealed that CM administration restored the immunostaining reactivity of insulin and GLUT-4 in the pancreas of diabetic rats. CONCLUSION: CM administration is of medical importance and helps physicians in the treatment of diabetes mellitus. PMID- 28638875 TI - WHOLE BODY VIBRATION IMPROVES ATTENTION AND MOTOR PERFORMANCE IN MICE DEPENDING ON THE DURATION OF THE WHOLE-BODY VIBRATION SESSION. AB - BACKGROUND: Whole body vibration (WBV) is a form of physical stimulation via mechanical vibrations transmitted to a subject. It is assumed that WBV induces sensory stimulation in cortical brain regions through the activation of skin and muscle receptors responding to the vibration. The effects of WBV on muscle strength are well described. However, little is known about the impact of WBV on the brain. Recently, it was shown in humans that WBV improves attention in an acute WBV protocol. Preclinical research is needed to unravel the underlying brain mechanism. As a first step, we examined whether chronic WBV improves attention in mice. MATERIAL AND METHODS: A custom made vibrating platform for mice with low intensity vibrations was used. Male CD1 mice (3 months of age) received five weeks WBV (30 Hz; 1.9 G), five days a week with sessions of five (n=12) or 30 (n=10) minutes. Control mice (pseudo-WBV; n=12 and 10 for the five and 30 minute sessions, respectively) were treated in a similar way, but did not receive the actual vibration. Object recognition tasks were used as an attention test (novel and spatial object recognition - the primary outcome measure). A Balance beam was used for motor performance, serving as a secondary outcome measure. RESULTS: WBV sessions of five (but not WBV sessions of 30 minutes) improved balance beam performance (mice gained 28% in time needed to cross the beam) and novel object recognition (mice paid significantly more attention to the novel object) as compared to pseudo WBV, but no change was found for spatial object performance (mice did not notice the relocation). Although 30 minutes WBV sessions were not beneficial, it did not impair either attention or motor performance. CONCLUSION: These results show that brief sessions of WBV improve, next to motor performance, attention for object recognition, but not spatial cues of the objects. The selective improvement of attention in mice opens the avenue to unravel the underlying brain mechanisms. PMID- 28638874 TI - THE USE OF PLANTS TO PROTECT PLANTS AND FOOD AGAINST FUNGAL PATHOGENS: A REVIEW. AB - BACKGROUND: Plant fungal pathogens play a crucial role in the profitability, quality and quantity of plant production. These phytopathogens are persistent in avoiding plant defences causing diseases and quality losses around the world that amount to billions of US dollars annually. To control the scourge of plant fungal diseases, farmers have used fungicides to manage the damage of plant pathogenic fungi. Drawbacks such as development of resistance and environmental toxicity associated with these chemicals have motivated researchers and cultivators to investigate other possibilities. MATERIALS AND METHODS: Several databases were accessed to determine work done on protecting plants against plant fungal pathogens with plant extracts using search terms "plant fungal pathogen", "plant extracts" and "phytopathogens". Proposals are made on the best extractants and bioassay techniques to be used. RESULTS: In addition to chemical fungicides, biological agents have been used to deal with plant fungal diseases. There are many examples where plant extracts or plant derived compounds have been used as commercial deterrents of fungi on a large scale in agricultural and horticultural setups. One advantage of this approach is that plant extracts usually contain more than one antifungal compound. Consequently the development of resistance of pathogens may be lower if the different compounds affect a different metabolic process. Plants cultivated using plants extracts may also be marketed as organically produced. Many papers have been published on effective antimicrobial compounds present in plant extracts focusing on applications in human health. More research is required to develop suitable, sustainable, effective, cheaper botanical products that can be used to help overcome the scourge of plant fungal diseases. CONCLUSIONS: Scientists who have worked only on using plants to control human and animal fungal pathogens should consider the advantages of focusing on plant fungal pathogens. This approach could not only potentially increase food security for rural farmers, lead to commercial rewards, but it is also much easier to test the efficacy in greenhouse or field experiments. Even if extracts are toxic it may still be useful in the floriculture industry. PMID- 28638876 TI - PHYTOCHEMICAL SCREENING, ANTIMICROBIAL AND CYTOTOXICITY STUDIES OF ETHANOL LEAF EXTRACT OF APHANIASENEGALENSIS (SAPINDACEAE). AB - BACKGROUND: Aphania senegalensis (Sapindaceae) is commonly used in Senegalese traditional medicine to treat pain, inflammation, asthenia, bacterial and fungal infections. The aim of this study was to determine the type of phytochemical constituents present in the ethanol leaf extract and its antimicrobial activity against selected bacterial and fungal pathogens. MATERIALS AND METHODS: The ethanol leaf extract of A. senegalensis was evaluated for its cytotoxic effect in the MTT assay against Vero cells. Flavonoids and tannins were the main constituents of the ethanol leaf extract. RESULTS: The extract inhibited the growth of the three fungal strains used in this study moderately with the lowest MIC obtained for Candidaalbicans (0.16 mg/mL). The extract also inhibited the growth of Aspergillus fumigatus and Cryptococcus neoformans with an MIC of 0.62 mg/mL. For bacterial pathogens, strong inhibition was obtained against Enterococcusfaecalis (ATTC 29212) (MIC 0.08 mg/mL), while moderate inhibition was obtained for Escherichia coli (ATTC 25922) (MIC 0.16 mg/mL) and Staphylococcus aureus (ATTC 29213) (MIC 0.31mg/mL). The extract however did not inhibit the growth of Pseudomonasaeruginosa (ATTC 27853) at the highest concentration (2.5 mg/ml) tested. The ethanol leaf extract of A. senegalensis had a higher cytotoxicity than berberine used as the positive control (LC502.67+/-0.04 ug/mL and 9.99+/-0.54 ug/mL respectively). The best selectivity index values was obtained for Enterococcus faecalis (SI = 1.24), followed by Escherichia coli (SI = 0.62) for bacterial pathogens and C. albicans (SI = 0.62) for fungal pathogens. CONCLUSION: The findings of this study suggest that the extracts may not be safe for use in animals infected by some pathogens. PMID- 28638877 TI - PROTECTIVE EFFECT OF IRIS GERMANICA L. IN Beta-AMYLOID-INDUCED ANIMAL MODEL OF ALZHEIMER'S DISEASE. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia that is an irretrievable chronic neurodegenerative disease. In the current study, we have examined the therapeutic effects of Iris germanica extract on Amyloid beta (Abeta) induced memory impairment. MATERIALS AND METHODS: Wistar rats were divided into five groups of 8 per each. Groups were as followed: control group which were normal rats without induction of AD, Abeta group which received Abeta (50 ng/side), iris 100 group which received Abeta + Iris (100 mg/kg), iris 200 group which received Abeta + Iris (200 mg/kg), and iris 400 group which received Abeta + Iris (400 mg/kg). AD was established by intrahippocampal injection of 50 ng/MUl/side Abeta1-42. The day after surgery, animals in treatment groups received different doses of the aqueous extract of Iris by gavage for 30 days. Morris water maze test (MWM) was performed to assess the effects of I. germanica on learning and memory of rats with Abeta induced AD. RESULTS: Data from MWM tests, including escape latency and traveled distance, demonstrated that I. germanica extract could markedly improve spatial memory in comparison to control. Moreover, the plant had a significantly better effect on the performance of AD rats in the probe test. CONCLUSION: I. germanica extract can successfully reverse spatial learning dysfunction in an experimental model of AD. Further neuro psyco pharmacological studies are mandatory to reveal the mechanism of action of this natural remedy in the management of AD symptoms. PMID- 28638879 TI - TRADITIONAL KNOWLEDGE OF MEDICINAL PLANTS IN TRIBES OF TRIPURA IN NORTHEAST, INDIA. AB - BACKGROUND: The present study was carried out in Mandwi area and its outskirts of Tripura district of tribal areas Autonomous district council to document the available ethno-medicinal plants and their traditional application among Mandwi tribes. METHODOLOGY: Field explorations were carried out during the months of March-June 2013. The ethno-medicinal survey was conducted particularly with Tripuri tribe in Mandai area, with the help of local medicine men, locally known as bhoidho (Tripuri). Data were collected through structure questionnaires and observations during the field visits. RESULTS: In the present study the local population used a total of 51 plant species belonging to 32 families to cure a variety of diseases. Of the 51 plants, 21 were herbs, followed by trees (17) and shrubs (8). Climbers and ferns had reported 2 species for each one grass species was found. Fabaceae was the dominant family with the highest number of species (6) followed by Asteracae (4 species) and Lamiaceae (5 species). Seven other families had 2 species each and 22 families were represented by a single species. In case single diseases, the highest number of plants (7 species) was used for dysentery, followed by body pain (6 species), cough (6 species) and toothache (6 species). CONCLUSION: The present study concluded that, the Tripuri tribes of the study area possess rich knowledge on the medicinal plants and their utilization. Thus the present study focuses on the documentation of the traditional knowledge of these valuable plants, which could enhance the potential of these medicinal plants to other communities as well and by understanding the importance, other communities can also be helpful for conservation of these resources for further use. PMID- 28638878 TI - EFFECT OF FUCOIDAN ON B16 MURINE MELANOMA CELL MELANIN FORMATION AND APOPTOSIS. AB - BACKGROUND: Fucoidan is a complex sulfated polysaccharide extracted from brown seaweed and has a wide variety of biological activities. It not only inhibits cancer cell growth but also inhibits tyrosinase in vitro. Therefore, it is of interest to investigate the effect of fucoidan on B16 murine melanoma cells as the findings may provide new insights into the underlying mechanism regarding the inhibition of melanin formation by fucoidan. In the present study, we aimed to investigate the anti-melanogenic effect of fucoidan and its inhibitory effect on B16 cells. MATERIALS AND METHODS: The influence of fucoidan on B16 melanoma cells and cellular tyrosinase was examined. Cell viability was examined by the cell counting kit-8 assay. Cellular tyrosinase activity and melanin content were determined using spectrophotometric methods and protein expression was analyzed by immunoblotting. Morphological changes in B16 melanoma cells were examined by phase contrast microscopy and apoptosis was analyzed by flow cytometry. RESULTS: In vitro studies were performed using cell viability analysis and showed that fucoidan significantly decreased viable cell number in a dose-response manner with an IC50 of 550 +/-4.3 ug/mL. Cell morphology was altered and significant apoptosis was induced when cells were exposed to 550 ug/mL fucoidan for 48 h. CONCLUSION: This study provides substantial evidence to show that fucoidan inhibits B16 melanoma cell proliferation and cellular tyrosinase activity. Fucoidan may be useful in the treatment of hyperpigmentation and as a skin whitening agent in the cosmetics industry. PMID- 28638880 TI - EFFICIENCY OF BORAGE SEEDS OIL AGAINST GAMMA IRRADIATION-INDUCED HEPATOTOXICITY IN MALE RATS: POSSIBLE ANTIOXIDANT ACTIVITY. AB - BACKGROUND: Borage (Borago officinal L.) is an annual herbaceous plant of great interest because its oil contains a high percentage of gamma-linolenic acid (GLA). The present work was carried out to detect fatty acids composition of the oil extracted from borage seeds (BO) and its potential effectiveness against gamma-irradiation- induced hepatotoxicity in male rats. MATERIALS AND METHODS: GC MS analysis of fatty acids methyl esters of BO was performed to identify fatty acids composition. Sixty rats were divided into five groups (12 rats each): Control, irradiated; rats were exposed to (6.5 Gy) of whole body gamma-radiation, BO (50 mg/kg b.wt), irradiated BO post-treated and irradiated BO prepost-treated. Six rats from each group were sacrificed at two time intervals 7 and 15 days post irradiation. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) levels, lipids profile, as well as serum and hepatic reduced glutathione (GSH) and lipid peroxide (malondialdehyde) (MDA) levels were assessed. Histopathological examination of liver sections were also carried out. RESULTS: The results showed that the high contents of BO extracted by cold pressing, were linoleic acid (34.23%) and GLA (24.79%). Also, oral administration of BO significantly improved serum levels of liver enzymes, lipids profile, as well as serum and hepatic GSH and MDA levels (p<0.001) as compared with irradiated rats after 15 days post irradiation. Moreover, it exerted marked amelioration against irradiation-induced histopathological changes in liver tissues. The improvement was more pronounced in irradiated BO prepost-treated group than irradiated BO post-treated. CONCLUSION: BO has a beneficial role in reducing hepatotoxicity and oxidative stress induced by radiation exposure. Therefore, BO may be used as a beneficial supplement for patients during radiotherapy treatment. PMID- 28638881 TI - ARISTOLOCHIA BRACTEOLATE RETZ. ATTENUATES HYPERURICEMIA IN A METABOLIC ARTHRITIS RAT MODEL. AB - BACKGROUND: The leaves of Aristolochia bracteolata Retz. has been documented in the folk medicine literature for its anti-arthritic activity. The target of the research envisaged was to elucidate the activity of A. bracteolata extract on hyperuricemic condition in arthritis rat model. MATERIALS AND METHODS: Dried and powdered plant leaves were extracted using ether and chloroform. Potassium oxonate was injected intra-articularly to produce arthritis. The hyperuricemic effect, of A. bracteolate was analyzed by studying levels of uric acid in serum as well as in urine of arthritis induced rats. Effects of plant extracts were also studied on BUN (blood urea nitrogen) levels and fraction of uric acid excreted. RESULTS: Results indicate that administration of A. bracteolata presented substantial change in uric acid concentration, augmented by potassium oxonate administration in rats. The reduction in levels of uric acid levels was nearly same as allopurinol. The investigation also revealed that the primary plant extract has nephroprotective effect by enhancing the production of Prostaglandin E2 and Interleukin-1. Histological studies of rat kidney slices indicated the safety of the present plant extract. CONCLUSION: The crude extract of A. bracteolate can be used to reduce hyperuricemia in metabolic arthritis produced in rat model, without inducing any potential damaging effects. PMID- 28638882 TI - POSSIBLE HYPOCHOLESTEROLEMIC EFFECT OF GINGER AND ROSEMARY OILS IN RATS. AB - BACKGROUND: Hypercholesterolemia is a major risk factor for development of atherosclerosis. The present study was conducted to evaluate the potential effect of ginger oil alone or combined with rosemary oil as hypocholesterolemic agent in rats fed high fat diet. MATERIALS AND METHODS: Healthy female albino rats (n=80) weighting about (150-180 g) were included in this study divided into two equal groups; Group (I): were fed on the basal diet. Group (I) were divided into 4 subgroups each 10: Group (Ia): negative control. Group (Ib): Rats received i.p 2.5 g/Kg b.w of ginger oil. Group (Ic): rats received i.p 2.5 g/Kg b.w of rosemary oil. Group (Id): Rats received i.p 5 g/Kg b.w mixture of ginger oil and rosemary oil (1:1). The second main groups; Group (II): high fat diet (HFD) were fed on the basal diet plus cholesterol (1%), bile salt (0.25%) and animal fat (15%) to induce hypercholesterolemia for six weeks. Group (II) was divided into 4subgroups: Group (IIa): HFD. Group (IIb): HFD were treated with i.p 2.5 g/Kg b.w ginger oil. Group (IIc): (n=10) HFD were treated with i.p 2.5 g/Kg b.w rosemary oil. Group (IId): (n=10) HFD were treated with i.p 5 g/Kg b.w mixture of oils. RESULTS: It was found that HFD rats showed a significant elevation in glucose, total cholesterol, triglyceride, GOT, GPT, alkaline phosphatase and a reduction in serum HDL-c compared with negative control. Treatment with ginger oil, rosemary oil and their mixture modulated the elevation of these parameters. Histopathological examination of the liver tissue of HFD rats showed a lipid deposition and macrophage infiltration and stenosis of hepatic vein. Treatment with mixture oils preserves normal structure of liver. CONCLUSION: It was concluded that, hypocholesterolemic effect was related to the active oil content as Rosemary oil contain - alpha-pinene, Camphor, cineole, borneol and Ginger oil contain Linalool, Terpineol, Borneol, Eucalyptol. PMID- 28638883 TI - ANTIOXIDANT AND ANTI-INFLAMMATORY EFFECTS OF RHAMNAZIN ON LIPOPOLYSACCHARIDE INDUCED ACUTE LUNG INJURY AND INFLAMMATION IN RATS. AB - BACKGROUND: Acute Lung Injury (ALI) results into severe inflammation and oxidative stress to the pulmonary tissue. Rhamnazin is a natural flavonoid and known for its antioxidant and anti-inflammatory properties. MATERIALS AND METHODS: The antioxidative and anti-inflammatory properties rhamnazin were tested for protection against the acute lung injury. We investigated whether rhamnazin improves the lipopolysaccharide (LPS)-induced ALI in an animal model (rat). We also studied the probable molecular mechanism of action of rhamnazin. Rhamnazin was injected intraperitoneally (i.p.) (5, 10 and 20 mg/kg) two days before intratracheal LPS challenge (5mg/kg). The changes in lung wet-to-dry weight ratio, LDH activity, pulmonary histopathology, BALF protein concentration, MPO activity, oxidative stress, cytokine production were estimated. RESULTS: The results showed a significant attenuation of all the inflammatory parameters and a marked improvement in the pulmonary histopathology in the animal groups pretreated with rhamnazin. The rhamnazin pretreated group also showed activation of Nrf2 pathway and attenuation of ROS such as H2O2, MDA and hydroxyl ion. These results indicated that rhamnazin could attenuate the symptoms of ALI in rats due to its strong antioxidant and anti-inflammatory properties. CONCLUSION: The results strongly demonstrated that rhamnazin provides protection against LPS induced ALI. The underlying mechanisms of its anti-inflammatory action may include inhibition of Nrf2 mediated antioxidative pathway. PMID- 28638884 TI - ANTICANCER ACTIVITY OF 5, 7-DIMETHOXYFLAVONE AGAINST LIVER CANCER CELL LINE HEPG2 INVOLVES APOPTOSIS, ROS GENERATION AND CELL CYCLE ARREST. AB - BACKGROUND: Flavonoids are considered potential anticancer agents owing to their properties to interact with a diversity of cellular entities. Among flavonoids, methylated flavones are more efficient anticancer agents due to their higher stability in vivo. The purpose of the present study was, therefore, to evaluate the anticancer effect of methylated natural flavonoid 5, 7-dimethoxyflavone (5, 7 DMF). MATERIALS AND METHODS: MTT assay was used to determine the anticancer activity and IC50 of 5, -DMF). Cell viability, cell cycle distribution, reactive oxygen species (ROS) and mitochondrial membrane potential (DeltaPsim) were carried out by flow cytometry. Apoptosis was studied by DAPI staining. RESULTS: MTT assay revealed that the molecule reduced the cell viability of HepG2 cancer cells. The IC50 of 5, 7-DMF was found to be 25 uM. Our result indicated that 5, 7 DMF triggered production of ROS and significantly reduced DeltaPsim . It also leads to arrest of HepG2 cells in Sub-G1 stage of cell cycle, and ultimately induced apoptosis in a concentration-dependent manner, as indicated by DAPI staging. Additionally, 5, 7-DMF also reduced the colony forming potential of the HepG2 cells concentration dependently. CONCLUSION: Taken together, we conclude that 5, 7-DMF induces cell death via ROS generation, cell cycle arrest and apoptosis, and, therefore, may prove beneficial in the treatment of liver cancer. PMID- 28638886 TI - MECHANISMS OF COIX SEED COMPOSITIONS IN THE TREATMENT OF SPLEEN DEFICIENCY AND WET DAMPNESS ZHENG. AB - BACKGROUND: Coix seed has the functions of fortifying the spleen and inhibiting the dampness. However, it remains unclear which Coix seed compositions is responsible for these functions. Previous investigations have revealed that the main compositions of Coix seed are proteins, polysaccharides, oils and starches. The objectives of this study are to explore which is the most effective compositions in fortifying the spleen and examine how Coix seed works in regulating the water transport on the spleen deficiency and wet dampness (SDWD) rat model. MATERIALS AND METHODS: The rats used were divided into (i) control group, (ii) model group, (iii) decoction group, (iv) protein group, (v) polysaccharide group, (vi) oil group and (vii) starch group. The urine volume, the drinking volume and the water loading index in each group were calculated. Agilent 8*60K array was used for microarray-based gene expression analysis. The differential mRNAs related to the transport activity were screened. qRT-PCR was used to validate the mRNA microarray. RESULTS: The results demonstrated that all treatment groups could decrease the dampness of SDWD rats. mRNA microarray had significant effect on the protein group and the polysaccharide group in regulating the water transport, among which the most significant mRNA was Fabp6, Slc51a, Slc51b, Slc11a2, Slc4a10 and AQP3 respectively. CONCLUSION: The compositions of proteins and polysaccharides had the most significant effect in regulating the water transport of SDWD rat model. The contributing mRNA focused on Fabp, Slc and AQP family. PMID- 28638885 TI - ANTI-ULCEROGENIC EFFICACY AND MECHANISMS OF EDIBLE AND NATURAL INGREDIENTS IN NSAID-INDUCED ANIMAL MODELS. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of the most commonly used medicines and proven to be effective for certain disorders. Some people use NSAIDs on daily basis for preventive purpose. But a variety of severe side effects can be induced by NSAIDs. Studies have shown that edible natural ingredients exhibit preventive benefit of gastric ulcer. This paper reviews the efficacy and safety of edible natural ingredients in preventing the development of gastric ulcer induced by NSAIDs in animal models. METHODS: A systematic literature search was conducted on PubMed, using the terms "herbal medicines" and "gastric ulcer", "herbal medicines" and "peptic ulcer", "food" and "peptic ulcer", "food" and "gastric ulcer", "natural ingredient" and "peptic ulcer", "natural ingredient" and "gastric ulcer", "alternative medicine" and "peptic ulcer", "alternative medicine" and "gastric ulcer", "complementary medicine" and "peptic ulcer", "complementary medicine" and "gastric ulcer" in papers published in English between January 1, 1960 and January 31, 2016, resulting in a total of 6146 articles containing these terms. After exclusion of studies not related prevention, not in NSAID model or using non-edible natural ingredients, 54 articles were included in this review. RESULTS: Numerous studies have demonstrated that edible natural ingredients exhibit antiulcerogenic benefit in NSAID-induced animal models. The mechanisms by which edible, ingredient-induced anti-ulcerogenic effects include stimulation of mucous cell proliferation, antioxidation, inhibition of gastric acid secretion, as well as inhibition of H (+), K (+)- ATPase activities. Utilization of edible, natural ingredients could be a safe, valuable alternative to prevent the development of NSAID-induced gastric ulcer, particularly for the subjects who are long-term users of NSAIDs. PMID- 28638887 TI - A MOUSE MODEL OF MAMMARY HYPERPLASIA INDUCED BY ORAL HORMONE ADMINISTRATION. AB - BACKGROUND: Mammary hyperplasia is one of the most common benign breast disorders. Although traditional Chinese medicine has a vast experience in the treatment of mammary hyperplasia, it is not accepted widely due to its unclear mechanism. METHODS AND MATERIALS: To address the mechanism, we developed a mouse model of mammary hyperplasia. We gave mice estradiol valerate tablets and progesterone capsules sequentially for one month by intragastric administration. RESULTS: Mice treated by this method had a series of pathological changes which are similar to those detected in women with mammary hyperplasia, including ectopic level of estradiol and progesterone in serum, hyperplasia of mammary glands and increased expression of ERalpha and PR. CONCLUSION: This model will facilitate the mechanical study of traditional medicine on mammary hyperplasia. PMID- 28638889 TI - REDUCTION OF INTRA-ARTICULAR ADHESION BY TOPICAL APPLICATION OF DAIDZEIN FOLLOWING KNEE SURGERY IN RABBITS. AB - BACKGROUND: Intra-articular adhesion is the commonest complication that is faced by orthopedic surgeons after knee surgery. Thus, the present investigation evaluates the effect of daidzein on intra-articular adhesion in rabbits. MATERIAL AND METHODS: All the rabbits were separated in to four different groups each group carries ten rabbits. Cancellous bone was exposed in each rabbit by removing cortical bone from both side of the femoral condyle. Following daidzein (2.5, 5 and 10 mg/ml) was topically applied for the duration of 10 min to the decorticated areas. Thereafter for the period of 4 week surgical limb was fixed. Effect of daidzein on intra articular adhesion was estimated by visual score through macroscopic examination, histopathology study, hydroxyproline content, fibroblast and collage density. RESULTS: Data obtained in the study suggest that topical application of daidzein (5 and 10 mg/ml) loose the collagen and significantly decreases the adhesion at the decorticated areas. Moreover there were significant reduction in the fibroblast density, hydroxyproline content and optical density of collagen tissue in daidzein (5 and 10 mg/ml) treated group than control. CONCLUSION: Thus present study concludes that topical application of daidzein reduces intra-articular adhesion around the knee. PMID- 28638888 TI - MODULATION OF KEY BIOCHEMICAL MARKERS RELEVANT TO STROKE BY ANTIARIS AFRICANA LEAF EXTRACT FOLLOWING CEREBRAL ISCHEMIA/REPERFUSION INJURY. AB - BACKGROUND: Oxidative stress plays a significant role in stroke pathogenesis. Hence, plants rich in antioxidant phytochemicals have been suggested as effective remedies for prevention and treatment of stroke and other neurological diseases. Antiaris africana Engl. (Moraceae) is traditionally used for the management of brain-related problems but there is paucity of data on its anti-stroke potential. MATERIALS AND METHODS: Ischemia/reperfusion injury was induced by a 30 min bilateral common carotid artery occlusion/ 2 h reperfusion (BCCAO/R) in the brain of male Wistar rats. A sham-operated group which was not subjected to BCCAO/R and a group subjected to BCCAO/R without treatment with MEA served as controls. The ameliorative effect of 14 days of pretreatment with 50 mg/kg or 100 mg/kg A. africana methanol leaf extract (MEA) on BCCAO/R-mediated alterations to key markers of oxidative stress (malondialdehyde, reduced glutathione, xanthine oxidase, superoxide dismutase, catalase and glutathione peroxidase) and neurochemical disturbances and excitotoxicity (myeloperoxidase, glutamine synthetase, Na+/K+ ATPase, acetylcholinesterase and tyrosine hydroxylase), was evaluated and compared with the effect produced by treatment with 20 mg/kg quercetin as a reference standard. RESULTS: Results show that pretreatment with MEA significantly mitigated or reversed BCCAO/R-induced changes in the level or activity of the evaluated biochemical markers of oxidative stress, neurochemical dysfunction and excitotoxicity compared with the BCCAO/R untreated control group (p < 0.05). The effect produced by 100 mg/kg MEA was similar to that of the reference standard, quercetin. CONCLUSION: These results revealed the neuroprotective potential of A. africana in stroke and other ischemia-related pathologies. PMID- 28638890 TI - INHIBITORY EFFECT OF CHITOSAN OLIGOSACCHARIDE ON HUMAN HEPATOMA CELLS IN VITRO. AB - BACKGROUND: Chitosan oligosaccharide, the degradation products of chitin, was reported to have a wide range of physiological functions and biological activities. In this study, we explored the inhibitory effect of Chitosan oligosaccharide on human hepatoma cells. MATERIALS AND METHODS: MTT assay was applied to detect cell viability of the human hepatoma cells treated with Chitosan oligosaccharide. Flow cytometric analysis was used to investigate the apoptosis of the human hepatoma cells treated with Chitosan oligosaccharide. We employed western blot to investigate the underlying mechanisms involved in the apoptosis. RESULTS: Our data indicated that chitosan oligosaccharide dose dependently inhibited the growth of hepatoma cells and induced apoptosis. On the molecular level, chitosan oligosaccharide decreased Bcl-2 and increased Caspase-3 expression which may be related to the apoptosis of hepatoma cells. CONCLUSION: Our results provide an experimental basis for the clinical development of Chitosan oligosaccharide as a novel anti-hepatoma drug. PMID- 28638891 TI - EFFECT OF ASTRAGALOSIDE ON VITAMIN D-RECEPTOR EXPRESSION AFTER ENDOTHELIN-1 INDUCED CARDIOMYOCYTE INJURY. AB - BACKGROUND: Astragaloside, which is one of the main components of Astragalus membranaceus, has been widely used in the treatment of congestive heart failure in China, and it can protect cardiomyocytes. Its mechanism of action remains unclear. Therefore, the present study was carried out to investigate the influence of astragaloside on rat cardiomyocytes stimulated with endothelin-1 (ET 1), and explored the underlying mechanism. MATERIALS AND METHODS: ET-1 was used to stimulate primary rat cardiomyocytes and establish a cardiomyocyte hypertrophy model. Different astragaloside doses were administered in combination with ET-1. Cardiomyocyte hypertrophy and apoptosis were examined using transmission electron microscopy (TEM) and flow cytometry, respectively. The molecular mechanism was explored by analyzing the mRNA of the vitamin D receptor (VDR), cytochrome P450 family 27 subfamily B member 1(CYP27B), cytochrome P450 family 24 subfamily A member 1(CYP24A) and renin mRNA levels by quantificational real-time polymerase chain reaction(qRT-PCR). RESULTS: Rat cardiomyocyte hypertrophy model was established successfully. Astragaloside administration significantly affected cell apoptosis and significantly inhibited ET-1-induced cardiomyocyte hypertrophy in a dose-dependent manner. Astragaloside treatment affected the expression of signaling molecules in the vitamin D axis. CONCLUSION: Astragaloside inhibits ET 1-induced cardiomyocyte hypertrophy. This effect can be reversed by regulating the levels of the relevant factors in the vitamin D axis. PMID- 28638892 TI - IN VIVO EFFECT OF GUIDING-HERB RADIX PLATYCODONIS AND RADIX CYATHULAE ON PAEONIFLORIN PHARMACOKINETICS OF XUEFU ZHUYU TANG IN RATS. AB - BACKGROUND: Xuefu Zhuyu Tang (XFZYT), first recorded in Correction of Errors in Medical Works by Qing-ren Wang, has been proven reliable and effective for curing various diseases such as atherosclerosis, hypertension, hyperlipidemia, and angina pectoris. It consists of 11 herbs and two of them, Radix platycodonis and Radix cyathulae, have been traditionally considered as guiding herbs and deeply valued by tens of millions of Chinese medicine practitioners. Do Radix platycodonis and Radix cyathulae affect the pharmacokinetics of the effective constituent-paeoniflorin of XFZYT? If yes, in what way? This study aims to answer these questions. MATERIALS AND METHODS: The medicinal solutions of XFZYT, XFZYT without Radix platycodonis (XFZYT-JG), XFZYT without Radix cyathulae (XFZYT-NX), and XFZYT without Radix platycodonis and Radix cyathulae (XFZYT-JG-NX) were prepared and administrated to rats in the normal group and the blood-stasis model group by gavage, respectively. The blood samples of rats in the normal group were obtained 5, 10, 15, 20, 30, 45, 60, 120, and 240 minutes after gavage; whereas the blood samples of rats in the blood-stasis model group were obtained 10, 15, 20, 30, 45, 90, 150, and 240 minutes after gavage. Biological samples were processed; the assays of specificity, precision, linearity, intra-day and inter day precisions, recovery and stability were conducted; high performance liquid chromatography was performed to detect paeoniflorin content; and DAS software was adopted to generate pharmacokinetic parameters. Mobile phase was composed of acetonitrile and water (16:84), detection wavelength was 230 nm, and riboflavin was set as internal standard substance. RESULTS: The pharmacokinetic parameters of the rats in the normal group after oral gavage of XFZYT, XFZYT-JG, XFZYT-NX, and XFZYT-JG-NX were Cmax = (0.363+/-0.248, 0.065+/-0.020, 0.099+/-0.033, 0.099+/ 0.020) mg/L, Tmax = (0.276+/-0.084, 0.583+/-0.342, 0.555+/-0.228, 0.317+/ 0.033)h, t1/2 = (0.501+/-0.241, 1.021+/-0.522, 0.853+/-0.377, 1.227+/-0.402) h; and AUC0-infinity = (0.381+/-0.415, 0.13+/-0.085, 0.166+/-0.066, 0.185+/-0.059) mg/L.h.; whereas the pharmacokinetic parameters for the rats in the blood-stasis model group after oral gavage of XFZYT, XFZYT-JG, XFZYT-NX, and XFZYT-JG-NX were Cmax = (0.315+/-0.153, 0.215+/-0.044, 0.228+/-0.056, 0.248+/-0.09) mg/L, Tmax = (0.5+/-0, 0.667+/-0.129, 0.5+/-0, 0.542+/-0.102) h, t1/2 = (0.408+/-0.146, 0.813+/-0.135, 0.708+/-0.383, 0.741+/-0.173) h, and AUC0-infinity = (0.306+/ 0.157, 0.408+/-0.136, 0.368+/-0.159, 0.381+/-0.246) mg/L.h. CONCLUSION: The guiding herbs, Radix platycodonis and Radix cyathulae, significantly increased the absorption amount and rate of paeoniflorin in XFZYT, and accelerated its elimination from the blood. PMID- 28638893 TI - CHINESE HERBAL DECOCTION AS A COMPLEMENTARY THERAPY FOR ATROPHIC GASTRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS. AB - BACKGROUND: Chinese herbal decoction (CHD) has been extensively used in the treatment of atrophic gastritis (AG) in China and other Far Eastern countries. We conducted a systematic review and meta-analysis to estimate the efficacy and safety of CHD in AG. MATERIALS AND METHODS: Pubmed, Embase, Cochrane central register of controlled trials (central), VIP, China National Knowledge Infrastructure, Sinomed, Wanfang data were searched (up to December 2015). Randomized controlled trials recruiting patients with AG comparing CHD (alone or with western medicine (WM)) with WM were eligible. Dichotomous data were pooled to obtain relative risk (RR), with a 95% confidence interval (CI). RESULTS: Forty two articles including 3,874 patients were identified. CHD, used alone or with WM, had beneficial effect over WM in the improvement of clinical manifestations (RR=1.28; 95% CI 1.22-1.34) and pathological change (RR=1.42; 95% CI 1.30-1.54) for AG patients. However, the H. pylori eradication effect of CHD was not supported by the existing clinical evidence, because of the significant study heterogeneity (I2>50%) and inconsistency between the primary results and sensitivity analysis. CONCLUSIONS: CHD, if prescribed as a complementary therapy to WM, may improve the clinical manifestations and pathological change for AG patients. But its monotherapy for H. pylori eradication is not supported by enough clinical evidence. PMID- 28638894 TI - Hepatitis B Vaccination Rate in Patients with Diabetes: Assessment of Racial and Socioeconomic Disparity. AB - INTRODUCTION: Less hygienic use of blood glucose monitoring equipment such as blood glucose meters, lancets, finger stick devices or other diabetes-care equipment such as syringes or insulin pens by self-administration often exposes the diabetic patient to Hepatitis B infection. This study evaluates hepatitis B vaccination among individuals with diabetes. METHODS: The study used data from the 2000-2013 National Health Interview Survey (NHIS). Vaccination rates among adult individuals with diabetes of various ethnic backgrounds was accessed and compared using chis-square tests. Multivariable logistic regression model was used to compare factors affecting hepatitis B vaccination among individuals with diabetes. RESULTS: The crude rate of diabetes in this population was 5.4%. The rate of vaccination among individuals with diabetes differed across racial groups (Asians 31.8% vs. blacks 30.7%; and whites 26.5%; p<0.01). After multivariate regression, the leading factors affecting hepatitis B vaccination included Age (40-60 years) (OR=0.51, 95% CI=0.47-0.57, p<0.01), lack of college education (OR=0.71,95% CI=0.64-0.79, p<0.01), foreign birth (OR=0.83, 95% CI=0.72-0.95, p<0.01), and Hispanic ethnicity (OR=0.88, 95% CI=0.78-1.00, P<0.05). CONCLUSION: Social and economic factors-education, insurance status, age, poverty level, and place of birth affect rates of vaccination among individuals with diabetes. PMID- 28638896 TI - A Scalable Cyberinfrastructure for Interactive Visualization of Terascale Microscopy Data. AB - The goal of the recently emerged field of connectomics is to generate a wiring diagram of the brain at different scales. To identify brain circuitry, neuroscientists use specialized microscopes to perform multichannel imaging of labeled neurons at a very high resolution. CLARITY tissue clearing allows imaging labeled circuits through entire tissue blocks, without the need for tissue sectioning and section-to-section alignment. Imaging the large and complex non human primate brain with sufficient resolution to identify and disambiguate between axons, in particular, produces massive data, creating great computational challenges to the study of neural circuits. Researchers require novel software capabilities for compiling, stitching, and visualizing large imagery. In this work, we detail the image acquisition process and a hierarchical streaming platform, ViSUS, that enables interactive visualization of these massive multi volume datasets using a standard desktop computer. The ViSUS visualization framework has previously been shown to be suitable for 3D combustion simulation, climate simulation and visualization of large scale panoramic images. The platform is organized around a hierarchical cache oblivious data layout, called the IDX file format, which enables interactive visualization and exploration in ViSUS, scaling to the largest 3D images. In this paper we showcase the VISUS framework used in an interactive setting with the microscopy data. PMID- 28638897 TI - Adaptive liquid flow behavior in 3D nanopores. AB - Liquid flow speed in 2D nanochannel models has previously been characterized, whereas liquid flow behavior in 3D nanostructured materials remains unknown. To fill this gap, we have developed a novel liquid nanofoam (LN) system composed of nanoporous silica gel particles and a non-wettable liquid phase. We demonstrated that the dynamic behavior of the LN sample was strain rate insensitive by impacting it with a drop weight at various incident speeds. Using this experimental setup, we measured the effective liquid flow speed in 3D nanopores and showed that it was 5 orders of magnitude higher than that of quasi-static loading. Importantly, the liquid infiltration speed as well as the energy absorption efficiency of the LN was found to be adaptive to the incident speed and energy level. This provides a mechanistic explanation for the high energy absorption efficiency of LNs at high blast impact levels and strain rates, and demonstrates the importance of experimentally investigating the liquid flow behavior in 3D instead of the traditional 2D nanopores. PMID- 28638898 TI - Laser photolysis studies of omega-bond dissociation in aromatic carbonyls with a C-C triple bond stimulated by triplet sensitization. AB - We have prepared three types of carbonyl compounds, benzoylethynylmethyl phenyl sulfide (2@SPh), (p-benzoyl)phenylethynylmethyl phenyl sulfide (3@SPh) and p (benzoylethynyl)benzyl phenyl sulfide (4@SPh) with benzoyl and phenylthiylmethyl groups, which are interconnected with a C-C triple bond and a phenyl ring. Laser flash photolysis of 3@SPh and 4@SPh in acetonitrile provided the transient absorption spectra of the corresponding triplet states where no chemical reactions were recognized. Upon laser flash photolysis of 2@SPh, the absorption band due to the phenylthiyl radical (PTR) was obtained, indicating that the C-S bond cleaved in the excited state. Triplet sensitization of these carbonyl compounds using acetone and xanthone was conducted using laser photolysis techniques. The formation of triplet 3@SPh was seen in the transient absorption, whereas the PTR formation was observed for 2@SPh and 4@SPh, indicating that the triplet states were reactive for the C-S bond dissociation. The C-S bond dissociation mechanism for 4@SPh upon triplet sensitization is discussed in comparison with those for 2@SPh and 3@SPh. PMID- 28638899 TI - Surface cleaning of artworks: structure and dynamics of nanostructured fluids confined in polymeric hydrogel networks. AB - Nanosystems and confinement tools for the controlled release of a cleaning agent, e.g., hydrogels and microemulsions, have been used for several years for the treatment of delicate surfaces in art restoration interventions. However, notwithstanding the unprecedented achievements from an application point of view, a fundamental comprehension of their interaction mechanism is still lacking. In this study PVA hydrogels, obtained via freeze-thaw processes, are prepared as scaffolds for water-based nanostructured fluids for application in the cleaning of artworks: rheological, thermal, microscopic and scattering techniques showed that, depending on the number of freeze-thaw cycles, the hydrogels exhibit different physicochemical and viscoelastic properties, making them suitable for application in a broad range of cleaning issues. The gels have been loaded with an oil-in-water microemulsion and the diffusion of the microemulsion droplets inside the polymeric network has been investigated through Fluorescence Correlation Spectroscopy (FCS), demonstrating that the microemulsion is permanently kept inside the matrix and can freely diffuse in the network. In addition, we show that when the gel-microemulsion system is put in contact with a layer of hydrophobic grime, a dynamic interaction between the microemulsion droplets and the underlying layer is established, leading to the solubilization of the hydrophobic molecules inside the droplets in the gel matrix. Thus, for the first time, through FCS, insights into the removal mechanism of hydrophobic grime upon interaction with a cleaning agent embedded in the polymeric matrix are obtained. PMID- 28638895 TI - Chronic Orofacial Pain: Burning Mouth Syndrome and Other Neuropathic Disorders. AB - Chronic orofacial pain is a symptom associated with a wide range of neuropathic, neurovascular, idiopathic, and myofascial conditions that affect a significant proportion of the population. While the collective impact of the subset of the orofacial pain disorders involving neurogenic and idiopathic mechanisms is substantial, some of these are relatively uncommon. Hence, patients with these disorders can be vulnerable to misdiagnosis, sometimes for years, increasing the symptom burden and delaying effective treatment. This manuscript first reviews the decision tree to be followed in diagnosing any neuropathic pain condition, as well as the levels of evidence needed to make a diagnosis with each of several levels of confidence: definite, probable, or possible. It then examines the clinical literature related to the idiopathic and neurogenic conditions that can occasion chronic orofacial pain, including burning mouth syndrome, trigeminal neuralgia, glossopharyngeal neuralgia, post-herpetic neuralgia, and atypical odontalgia. Temporomandibular disorders also are examined as are other headache conditions, even though they are not neurologic conditions, because they are common and can mimic symptoms of the latter disorders. For each of these conditions, the paper reviews literature regarding incidence and prevalence, physiologic and other contributing factors, diagnostic signs and symptoms, and empirical evidence regarding treatments. Finally, in order to improve the quality and accuracy of clinical diagnosis, as well as the efficiency with which effective treatment is initiated and delivered, criteria are offered that can be instrumental in making a differential diagnosis. PMID- 28638900 TI - Ordering of ferromagnetic nanoparticles in nematic liquid crystals. AB - Dispersions of magnetic nanoparticles in a nematic liquid crystal were investigated as magnetic fields were applied in three different boundary condition geometries: (i) planar substrates and B?n, (ii) planar substrates and B||n, and (iii) homeotropic substrates and B?n. Particle chaining is observed when a magnetic field is applied, with a periodicity perpendicular to the chains. Furthermore, linear chains are observed for the magnetic field applied perpendicular to the director, while zigzag chains are formed when the magnetic field direction is parallel to the director field. This is attributed to a change from a dipolar defect configuration around dispersed nanoparticles, to a quadrupolar one, i.e. the change from satellite to Saturn-ring defects. This effect is largely independent of the sample thickness. The dynamic development of the chain length, as well as their two-dimensional order parameter was studied in all cases. Chain lengths increased rapidly until saturation at approximately l = 30 MUm after a time of about t = 10 s. Similarly, the chain order parameters increased until saturation between S = 0.8-0.9, independent of sample geometry. PMID- 28638901 TI - An innovative scheme for sub-50 nm patterning via electrohydrodynamic lithography. AB - The fabrication of large-area and well-ordered nanostructures using lithographic techniques is challenging. We have developed novel approaches for sub-50 nm nanopatterning using an electrohydrodynamic lithography (EHL) technique by tailoring experimental parameters such as applied voltage, stamp features, filling ratio, and choice of resist film. We obtain a sub-50 nm pattern replica from a master stamp that contains an array of line patterns having 50 nm widths. Moreover, we show that a far-smaller pattern replication than the original pattern size can be readily obtained by carefully adjusting the experimental conditions. Perfect- and much smaller-pattern replicas have been realized from the master stamp with an array of hole patterns having a 400 nm hole size by tuning the filling ratio. We also demonstrate that an array of 30 nm graphene nanoribbons can be easily fabricated by exploring a hierarchical core-shell template structure employing a bilayer resist film via an EHL technique. The proposed minimal-contact patterning method is simple, versatile, and inexpensive and has potential to become a powerful technique for realizing feasible ultrafine nanostructures on a wafer scale. PMID- 28638903 TI - Adsorption versus aggregation of NIPAM nanogels: new insight into their behaviour at the air/water interface as a function of concentration. AB - We have used neutron reflectivity (NR) measurements in combination with dynamic light scattering (DLS), surface tension and ellipsometry, to study the adsorption behaviour at the air/water interface of N-isopropylacrylamide-based nanogels as a function of concentration. The data provide clear evidence that the nanogels are adsorbed at the interface in a strongly deformed shape and forming a multi-layer where the thickness increases with nanogel concentration in the bulk. The combination of surface characterisation techniques and bulk studies indicate that interfacial film formation is preferred over bulk aggregation. This observation at the air/water interface supports the Derjaguin prediction, that a sphere's interaction with a plane (the thick adsorbed nanogel layer at interface) is much larger than nanogel-nanogel (sphere-sphere) association in the bulk. These findings, in particular the changes in conformations and the thick layer adsorption at the interface as a function of concentration, impact significantly on a number of applications for which nanogels are currently being investigated. These results contribute to the understanding of the behaviour of soft colloids at the interfaces. PMID- 28638904 TI - Dissolution behaviour and activation of selenium in phosphonium based ionic liquids. AB - The dissolution behaviour of grey selenium in phosphonium based ionic liquids (ILs) has been investigated for the first time by 31P and 77Se nuclear magnetic resonance (NMR) experiments. The investigations evidence the formation of trialkylphosphane selenides which can serve as a selenium reservoir in the subsequent formation of metal selenides. PMID- 28638905 TI - Thermal stability and thermal conductivity of phosphorene in phosphorene/graphene van der Waals heterostructures. AB - Phosphorene, a new two-dimensional (2D) semiconducting material, has attracted tremendous attention recently. However, its structural instability under ambient conditions poses a great challenge to its practical applications. A possible solution for this problem is to encapsulate phosphorene with more stable 2D materials, such as graphene, forming van der Waals heterostructures. In this study, using molecular dynamics simulations, we show that the thermal stability of phosphorene in phosphorene/graphene heterostructures can be enhanced significantly. By sandwiching phosphorene between two graphene sheets, its thermally stable temperature is increased by 150 K. We further study the thermal transport properties of phosphorene and find surprisingly that the in-plane thermal conductivity of phosphorene in phosphorene/graphene heterostructures is much higher than that of the free-standing one, with a net increase of 20-60%. This surprising increase in thermal conductivity arises from the increase in phonon group velocity and the extremely strong phonon coupling between phosphorene and the graphene substrate. Our findings have an important meaning for the practical applications of phosphorene in nanodevices. PMID- 28638906 TI - Controlled defect creation and removal in graphene and MoS2 monolayers. AB - It is known that defects strongly influence the properties of two-dimensional (2D) materials. The controlled creation and removal of defects can be utilized to tailor the optical and electronic responses of these 2D materials for optoelectronic and nanoelectronic applications. In this study, we developed an efficient approach to reversibly control the defect states in mechanically exfoliated graphene and molybdenum disulfide (MoS2) monolayers. The defects were created by aluminium oxide (Al2O3) plasmas and removed by moderate thermal annealing at up to 300 degrees C. We employed Raman and photoluminescence (PL) as well as electrical characterization to monitor the variation of the defect level in graphene and MoS2. For graphene, Raman spectra indicate that the Al2O3 plasma induced sp3-type defects with a controlled concentration, which have been substantially removed after thermal annealing. A similar trend was also observed in monolayer MoS2, as revealed by the defect-related emission peak (Xb) in the PL spectra. We further showed that the defects induced by the Al2O3 plasma in both 2D materials can be restored to any intended level via annealing under well controlled conditions. Our work presents a new route to the functional design of the optical and electronic properties of graphene and MoS2-based devices through defect engineering. PMID- 28638907 TI - Ruthenium(ii) p-cymene complexes of a benzimidazole-based ligand capable of VEGFR2 inhibition: hydrolysis, reactivity and cytotoxicity studies. AB - The design of Ru or other metal-based anticancer agents may achieve better and faster optimization if the ligands used are also designed to have standalone functions. In this scenario, even after dissociation from the metal complex under adverse conditions, the ligand would have anti-cancer properties. In our work, we have generated a bispyrazole-containing benzimidazole ligand with potency against vascular endothelial growth factor receptor 2 (VEGFR2), which is known to have roles in vasculogenesis/angiogenesis. This ligand was used to obtain ternary Ru(ii) p-cymene complexes with the formulations [(eta6-p-cymene)Ru(HL)(Cl)](Cl) (1), [(eta6-p-cymene)Ru(HL)(Br)](Br) (2) and [(eta6-p-cymene)Ru(HL)(I)](I) (3). 1H NMR data supports that hydrolysis of the complex is governed by halide substitution, and the extent of hydrolysis followed the trend 3 > 1 > 2. All the complexes have low affinity towards DNA bases (average Kb ~ 103 M-1 for CT DNA); however, all the complexes are cytotoxic in nature, with IC50 values less than 15 MUM. The presence of excess glutathione (GSH) liberates HL from the complexes in solution. The ability of the Ru complex to impair mitochondrial function and reduce the cellular GSH pool is thought to be the reason that it retains activity in the presence of GSH despite the ability of GSH to degrade the complexes. The chloride analogue 1 shows the best in vitro cytotoxicity against a prostate cancer cell line (LNCaP), with an IC50 of 6.4 MUM. The complexes show anti proliferative activity by the mitochondria-mediated intrinsic apoptotic pathway. Docking studies showed that HL has high affinity towards vascular endothelial growth factor receptor 2 (VEGFR2). The complexes show anti-metastatic activity (in vitro) at almost non-toxic dosages, and the effect is sustained even 48 h after removal of the complexes from the culture media. PMID- 28638910 TI - Dark plasmonic mode based perfect absorption and refractive index sensing. AB - Dark plasmonic resonances in metallic nanostructures are essential for many potential applications such as refractive index sensing, single molecule detection, nanolasers etc. However, it is difficult to excite the dark modes in optical experiments and thus the practical applications are severely limited. Herein, we demonstrate a simple method to experimentally excite the quadrupolar and higher-order plasmonic modes with normal incident light. By directionally depositing silver films onto the sidewalls of metal-covered one-dimensional grating, we have experimentally observed a series of asymmetrical resonances at the plasmonic ranges of silver gratings. Interestingly, both of the reflection and transmission coefficients of high-order plasmonic modes are reduced to around zero, demonstrating the perfect absorption very well. The corresponding numerical simulations show that these resonances are the well-known dark modes. Different from the conventional dark modes in plasmonic dimers, here the dark modes are the electric oscillations (as standing waves) within the silver sidewalls that are excited by charge accumulation via the bright plasmonic resonance of the top silver strips. In addition to the simple realization of perfect absorption, the dark modes are found to be quite sensitive to the environmental changes. The experimentally measured reflective index sensitivity is around 458 nm per RIU (refractive index unit), which is much higher than the sensitivity of the metal covered grating without silver sidewalls. This research shall pave new routes to practical applications of dark surface plasmons. PMID- 28638911 TI - Synthesis and characterization of catalytically active thiazolium gold(i) carbenes. AB - Thiamin analogs were used to synthesize mono gold(i)-carbene derivatives in a single step under aqueous conditions. The resulting thiazolium gold(i)-carbenes catalyze 5-endo-dig carbocyclization of an acetylenic dicarbonyl compound in organic solvents and hydroalkoxylation of an allene in aqueous buffer. PMID- 28638915 TI - [Optogenetic activation of dorsal hippocampal astrocytic Rac1 blocks the learning of associative memory]. AB - Rac1 belongs to the family of Rho GTPases, and plays important roles in the brain function. It affects the cell migration and axon guidance via regulating the cytoskeleton and cellular morphology. However, the effect of its dynamic activation in regulating physiological function remains unclear. Recently, a photoactivatable analogue of Rac1 (PA-Rac1) has been developed, allowing the activation of Rac1 by the specific wavelength of light in living cells. Thus, we constructed recombinant adeno-associated virus (AAV) of PA-Rac1 and its light insensitive mutant PA-Rac1-C450A under the control of the mouse glial fibrillary acidic protein (mGFAP) promoter to manipulate Rac1 activity in astrocytes by optical stimulation. Primary culture of hippocampal astrocytes was infected with the recombinant AAV-PA-Rac1 or AAV-PA-Rac1-C450A. Real-time fluorescence imaging showed that the cell membrane of the astrocyte expressing PA-Rac1 protruded near the light spot, while the astrocyte expressing PA-Rac1-C450A did not. We injected AAV-PA-Rac1 and AAV-PA-Rac1-C450A into dorsal hippocampus to investigate the role of the activation of Rac1 in regulating the associative learning. With optical stimulation, the PA-Rac1 group, rather than the PA-Rac1-C450A group, showed slower learning curve during the fear conditioning compared with the control group, indicating that activating astrocytic Rac1 blocks the formation of contextual memory. Our data suggest that the activation of Rac1 in dorsal hippocampal astrocyte plays an important role in the associative learning. PMID- 28638916 TI - [Different subtypes of estrogen receptor alpha and related signal molecules in the hippocampus are associated with spatial cognitive impairment of diabetic mice]. AB - To study the correlation between the spatial cognitive impairment and different subtypes of estrogen receptor alpha (ERalpha) of hippocampus in diabetic mice, we used alloxan (intraperitoneal injection) to induce type 1 diabetes in male Kunming mice and compared the spatial cognitive ability of the model mice with that of control mice through Morris water maze test. Meanwhile, using Western blot, we detected the protein expressions of ER-alpha36, ER-alpha66, caveolin-1, PKCalpha, cAMP-response element binding protein 2 (CREB2), and synaptophysin (Syn) in the hippocampus of the mice. The results showed that on the 3rd and 5th days of training, the ability of spatial learning and memory in the diabetic mice was significantly inferior to that of the control mice (P < 0.05). In the diabetic mice, the protein expressions of caveolin-1 and PKCalpha were decreased (P < 0.05), but ER-alpha66 expression was unaffected, while ER-alpha36 and CREB2 expressions were significantly increased (P < 0.05) compared with those of the control mice. The results suggest that abnormal expression of ER-alpha36 and related signal molecules may be important factors for diabetes-induced spatial cognitive impairment. PMID- 28638918 TI - [Generation of tnnt2a knock-out zebrafish via CRISPR/Cas9 and phenotypic analysis]. AB - Cardiac troponin T (cTnT) serves as a structural protein of myocardial fiber, and participates in heart excitation-contraction coupling process. Here, we generated tnnt2a (cTnT-coding gene) deletion mutant zebrafish via CRISPR/Cas9 technique, and performed phenotypic analysis of the identified tnnt2a mutants. We observed that there was no significant difference between heterozygous mutant and wild type zebrafish, and the homozygous mutants displayed significant malformations in heart, including cardiac arrest, atrium and ventricle enlargement, pericardium effusion, and the individuals usually died before 7 day post fertilization (dpf). We further analyzed the expression alternations of heart sarcomere genes (tnnt2a, actc1a, tpm4a, myl7, vmhc) at transcriptional level in tnnt2a-/-(Delta2) zebrafish by performing real time RT-PCR, and found that the RNA expression level of tnnt2a in tnnt2a-/- zebrafish decreased constantly at each time point of developmental stages, and actc1a, tpm4a, myl7 and vmhc all showed higher expressions at early developmental stages and lower expressions at late developmental stages, in comparison with those of wild type zebrafish. Lastly, electron microscopy on cardiac tissues suggested that there were significant changes of the thick or thin filament structures in tnnt2a-/-(Delta2) zebrafish, which was further confirmed by F-actin and Tpm4 immunofluorescence staining. The tnnt2a-/- zebrafish generated by CRISPR/Cas9 bears the most common symptoms of patients with dilated cardiomyopathy, and therefore can be used as a tool to study TNNT2-deficiency related cardiomyopathy. PMID- 28638917 TI - Influence of sodium nitroprusside on expressions of FBXL5 and IRP2 in SH-SY5Y cells. AB - Iron accumulation in the brain is associated with the pathogenesis of Parkinson's disease (PD). Misexpression of some iron transport and storage proteins is related to iron dyshomeostasis. Iron regulatory proteins (IRPs) including IRP1 and IRP2 are cytosolic proteins that play important roles in maintaining cellular iron homeostasis. F-box and leucine-rich repeat protein 5 (FBXL5) is involved in the regulation of iron metabolism by degrading IRP2 through the ubiquitin proteasome system. Nitric oxide (NO) enhances the binding activity of IRP1, but its effect on IRP2 is ambiguous. Therefore, in the present study, we aim to determine whether sodium nitroprusside (SNP), a NO donor, regulates FBXL5 and IRP2 expression in cultured SH-SY5Y cells. MTT assay revealed that treatment of SNP attenuated the cell viability in a dose-dependent manner. Flow cytometry test showed that 100 and 300 MUmol/L SNP administration significantly reduced the mitochondrial membrane potential by 45% and 60%, respectively. Moreover, Western blotting analysis demonstrated that 300 MUmol/L SNP significantly increased FBXL5 expression by about 39%, whereas the expression of IRP2 was decreased by 46%, correspondingly. These findings provide evidence that SNP could induce mitochondrial dysfunction, enhance FBXL5 expression and decrease IRP2 expression in SH-SY5Y cells. PMID- 28638919 TI - [Analyses of exercise-induced muscle damage-specific microRNA expression and molecular target of sarcolemmal damage in rats]. AB - In the present study, we were to screen the specific microRNA (miRNA) of exercise induced muscle damage (EIMD) and assess the EIMD-specific miRNAs-regulated target of sarcolemmal damage in rats. Twenty-four male Sprague-Dawley (SD) rats were randomly divided into 3 groups, which included sedentary (C), 24 h post-exercise (E24) and 48 h post-exercise (E48) groups. Rat EIMD model was established by an acute eccentric exercise, i.e., a downhill running treatment at -16o gradient. EIMD characteristics were verified by Evans blue dye staining, differentially expressed miRNAs were detected by microarray assay, EIMD-specific miRNAs expressions were further validated by real-time quantitative RT-PCR (RT-qPCR), and targets of the miRNAs were predicted based on mRNA expressions of associated proteins and related pathway core molecules of sarcolemmal damage. Two EIMD specific expressed miRNAs, including miR-206-3p and miR-139-3p, were found in the study. There was a significantly negative correlation (P < 0.05) between miR-206 3p expression and dystrophin (r = -0.68), utrophin (r = -0.64), JNK (r = -0.62) or ERK1 (r = -0.68) respectively, but no correlation was found between miR-139-3p and these biomolecules. The results suggest that: i) the expression profile of miRNAs in rat is significantly affected by EIMD, ii) miR-206-3p and miR-139-3p are the EIMD-specific miRNAs, and iii) miR-206-3p may control sarcolemmal damage by regulating dystrophin, utrophin, JNK and ERK1. PMID- 28638920 TI - [A study on toxic effects of sodium salicylate on rat cochlear spiral ganglion neurons: dopamine receptors mediate expressions of NMDA and GABAA receptors]. AB - The aim of the present study was to observe whether dopamine receptor (DR) was involved in the effects of sodium salicylate (SS) on the expressions of N-methyl D-aspartic acid (NMDA) and gamma-aminobutyric acid (GABA) receptors in rat cochlear spiral ganglion neurons (SGNs). Forty-eight hours after primary culture of rat SGNs, immunofluorescence technique was applied to detect expressions of DR1 and DR2, the two subtypes of dopamine receptors. Western blot was performed to assess NMDA receptor NR1 subunit and GABAA receptor subunit alpha2 (GABRalpha2) protein expressions in the SGNs after the treatments of SS alone or in combination with DR antagonists. The results demonstrated that: (1) The DR1 and DR2 were expressed in the bodies and axons of the SGN; (2) After the treatment with SS, the surface protein expressions of GABRalpha2 and NR1 were decreased by 44.69% and 21.57%, respectively, while the total protein expressions showed no significant changes; (3) Neither SS + SCH23390 (DR1 antagonist) group nor SS + Eticlopride (DR2 antagonist) group showed significant differences in GABRalpha2 and NR1 surface protein expressions compared with the control group. These results suggest that SS regulates the surface GABAA and NMDA receptors trafficking on SGN, and the mechanism may involve DR mediation. PMID- 28638921 TI - [Protective effect of synthetic salidroside on acute lung injury in rats]. AB - To study the protective effect and mechanism of synthetic salidroside on acute lung injury (ALI) induced by lipopolysaccharide (LPS), male Sprague-Dawley (SD) rats were randomly divided into saline control group, 3 mg/kg LPS model group, different doses of salidroside groups (5, 20 and 80 mg/kg), and 5 mg/kg dexamethasone group. Intratracheal LPS instillation was used to establish the ALI model 0.5 h after intraperitoneal injection of salidroside or dexamethasone, and the rats were sacrificed 6 h later. Lung wet/dry weight ratio (W/D) was calculated. Lung tissue pathology and lung injury score (LIS) were observed and evaluated through hematoxylin and eosin (HE) staining. The centrifugal sediment of bronchoalveolar lavage fluid (BALF) was used to count the polymorphonuclear leukocyte (PMN) number by Wright's staining, and the centrifugal supernatant of BALF was used to determine the contents of protein and inflammatory factors (TNF alpha, IL-1beta and IL-6). The contents of myeloperoxidase (MPO) and malondialdehyde (MDA) in lung tissue were determined. Western blot was used to detect the expression levels of phosphorylated and total nuclear factor kappa B (NF-kappaB)/p65 protein in lung tissue. The results showed that, compared with LPS group, the intervention of synthetic salidroside alleviated the pathological damage in lung tissue, decreased the LIS and lung W/D ratio (P < 0.05), reduced the PMN number, the contents of protein and inflammatory factors in BALF (P < 0.05), reduced the contents of MPO and MDA in lung tissue (P < 0.05), and inhibited the expression of p-NF-kappaB in lung tissue (P < 0.05). The results suggest that synthetic salidroside has a protective effect on ALI induced by LPS, and its mechanism is related to inhibiting the phosphorylation of NF-kappaB and reducing the aggregation of PMN in the lung. PMID- 28638922 TI - [Palmitoylation of heat shock protein 90 in mouse sperm]. AB - Protein palmitoylation, one of post-translation modifications, refers to the addition of saturated 16-carbon palmitic acid to cysteine residues via the thioester bond. It plays key roles in various functional activities, such as the interaction, stability and location of proteins. Heat shock protein 90 (Hsp90), an important molecular chaperone, has been reported to be involved in sperm capacitation. However, it remains unclear whether protein palmitoylation exists in sperm and whether Hsp90 in sperm is palmitoylated under different physiological conditions. In this study, we examined whether the protein palmitoylation is present in mouse cauda epididymis sperm using acyl-biotin exchange method, predicted the potential palmitoylated sites of Hsp90 by the software CSS-Palm 4.0 and detected the palmitoylated Hsp90 in the mouse sperm from caput epididymis and cauda epididymis by immunoprecipitation. We found that some proteins, approximately 50, 65, 72, 85 and 130 kDa, were palmitoylated in mouse cauda epididymis sperm. Five sites in two Hsp90 isoforms were predicted to be palmitoylated. The results also showed that Hsp90 in mouse sperm was palmitoylated and its palmitoylation level was involved in different physiological conditions: the palmitoylation level of cauda epididymis sperm was higher than that of caput epididymis sperm; and the palmitoylation level after capacitation was much higher than that before capacitation. In conclusion, this study reveals that protein palmitoylation is present in mouse sperm and the palmitoylated Hsp90 is associated with different physiological conditions in sperm. PMID- 28638923 TI - [Reconstitution of large conductance calcium-activated potassium channels into artificial planar lipid bilayers]. AB - This study was aimed to establish a method to create a stable planar lipid bilayer membranes (PLBMs), in which large conductance calcium-activated potassium channels (BKCa) were reconstituted. Using spreading method, PLBMs were prepared by decane lipid fluid consisting of N2-weathered mixture of phosphatidylcholine and cholesterol at 3:1 ratio. After successful incorporation of BKCa channel into PLBMs, single channel characteristics of BKCa were studied by patch clamp method. The results showed that i) the single channel conductance of BKCa was (206.8 +/- 16.9) pS; ii) the activities of BKCa channel were voltage dependent; iii) in the bath solution without Ca2+, there was almost no BKCa channel activities regardless of under hyperpolarization or repolarization conditions; iv) under the condition of +40 mV membrane potential, BKCa channels were activated in a Ca2+ concentration dependent manner; v) when [Ca2+] was increased from 1 MUmol/L to 100 MUmol/L, both the channel open probability and the average open time were increased, and the average close time was decreased from (32.2 +/- 2.8) ms to (2.1 +/- 1.8) ms; vi) the reverse potential of the reconstituted BKCa was -30 mV when [K+] was at 40/140 mmol/L (Cis/Trans). These results suggest that the spreading method could serve as a new method for preparing PLBMs and the reconstituted BKCa into PLBMs showed similar electrophysiological characteristics to natural BKCa channels, so the PLBMs with incorporated BKCa can be used in the studies of pharmacology and dynamics of BKCa channel. PMID- 28638924 TI - [Measurement of kinetic parameters of skeletal muscle protein synthesis in rats by deuterated water]. AB - The aim of the present study was to measure the kinetic parameters of skeletal muscle protein synthesis in rats by deuterated water (2H2O). Twenty Sprague Dawley (SD) rats were labeled by 2H2O through intraperitoneal injection and drinking. At the each end of the 1st, 3rd, 5th, 6th and 10th week after the first 2H2O labeling, four rats were sacrificed by cardiac puncture for blood plasma and quadriceps femoris sampling. Skeletal muscle protein and free amino acids in plasma were purified, hydrolyzed by hydrochloric acid and derived. The deuterium enrichments of 2H-labeled alanyl in skeletal muscle protein and plasma protein bound 2H-labeled alanine were determined by gas chromatography-mass spectrometry (GC-MS). The fractional synthesis rate of skeletal muscle protein and synthetic dynamic equation were calculated. The fractional synthetic rate of skeletal muscle protein was 12.8%/week, and synthetic dynamic equation was ft = 0.158 * (1 - e-0.128t). The results suggest that the kinetic parameters of skeletal muscle protein synthesis can be measured by 2H2O labeling, and the method can be applied in long-term labeling experiment. PMID- 28638925 TI - [Autophagy and hypoxic ischemic brain injuries]. AB - Autophagy is a highly evolutionarily conserved physiological mechanism of organism, including several stages such as autophagosomes formation, the fusion of lysosomes and autophagosomes, and autophagosomes degradation. In physiological conditions, autophagy is responsible for clearing the spoiled organelles and long lived proteins to maintain the homeostasis of cells and organism. Meanwhile, autophagy is also involved in the formation and development of diseases, but the mechanism has not been confirmed yet. The relationship between autophagy and hypoxic ischemic brain injuries represented by stroke is a research hotpot in recent years, but there is no clear conclusion about autophagy's role and mechanism in hypoxic ischemic brain injuries. We reviewed the activation, function and mechanism of autophagy in hypoxic ischemic brain injuries, in order to provide some perspectives on these researches. PMID- 28638926 TI - [Mechanisms and applications of transcutaneous electrical nerve stimulation in analgesia]. AB - Transcutaneous electrical nerve stimulation (TENS), as a non-pharmacological and non-invasive analgesic therapy with low-cost, has been widely used to relieve pain in various clinical applications, by delivering current pulses to the skin area to activate the peripheral nerve fibers. Nevertheless, analgesia induced by TENS varied in the clinical practice, which could be caused by the fact that TENS with different stimulus parameters has different biological mechanisms in relieving pain. Therefore, to advance our understanding of TENS in various basic and clinical studies, we discussed (1) neurophysiological and biochemical mechanisms of TENS-induced analgesia; (2) relevant factors that may influence analgesic effects of TENS from the perspectives of stimulus parameters, including stimulated position, pulse parameters (current intensity, frequency, and pulse width), stimulus duration and used times in each day; and (3) applications of TENS in relieving clinical pain, including post-operative pain, chronic low back pain and labor pain. Finally, we propose that TENS may involve multiple and complex psychological neurophysiological mechanisms, and suggest that different analgesic effects of TENS with different stimulus parameters should be taken into consideration in clinical applications. In addition, to optimize analgesic effect, we recommend that individual-based TENS stimulation parameters should be designed by considering individual differences among patients, e.g., adaptively adjusting the stimulation parameters based on the dynamic ratings of patients' pain. PMID- 28638927 TI - [Involvement of aquaporin-4 in synaptic plasticity, learning and memory]. AB - Aquaporin-4 (AQP-4) is the predominant water channel in the central nervous system (CNS) and primarily expressed in astrocytes. Astrocytes have been generally believed to play important roles in regulating synaptic plasticity and information processing. However, the role of AQP-4 in regulating synaptic plasticity, learning and memory, cognitive function is only beginning to be investigated. It is well known that synaptic plasticity is the prime candidate for mediating of learning and memory. Long term potentiation (LTP) and long term depression (LTD) are two forms of synaptic plasticity, and they share some but not all the properties and mechanisms. Hippocampus is a part of limbic system that is particularly important in regulation of learning and memory. This article is to review some research progresses of the function of AQP-4 in synaptic plasticity, learning and memory, and propose the possible role of AQP-4 as a new target in the treatment of cognitive dysfunction. PMID- 28638928 TI - [Fat deposition in skeletal muscle and its regulation]. AB - Under normal condition, there are a few lipid droplets in skeletal muscle. But in skeletal muscle acute injury, muscular dystrophy, muscle atrophy, obesity, diabetes and other pathological conditions, the fat deposition in skeletal muscle increases, which implicate that the fat deposition may play an important role in the pathogenesis of these diseases. However, the mechanisms of development and regulation of fat deposition in skeletal muscle are not clear. Clarifying the key signaling pathways and regulatory factors that affect fat deposition in skeletal muscle, and exploring new ways to improve the fat deposition in skeletal muscle will not only help to deepen our understanding of the pathogenesis of these diseases, but also provide new ideas for the treatment of these diseases. This paper reviews the research progresses and main mechanisms of fat deposition in skeletal muscle. PMID- 28638929 TI - [Research progress of neuregulin 4 biological function]. AB - Neuregulin 4 (NRG4) is a kind of protein containing epidermal growth factor (EGF) like domains, mainly expressed and secreted by brown adipocytes. It specifically activates EGF receptor ErbB4 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4) to stimulate cell proliferation, inhibit apoptosis and improve energy metabolism of cells. Increasing evidence has shown that NRG4 plays an important role in epithelial cell-related diseases, cardiovascular diseases, tumors and glycolipid metabolic diseases, and therefore it could be a potential therapeutic target of some diseases. PMID- 28638930 TI - [Different adipose tissue depots and metabolic syndrome in human]. AB - Obesity is characterized by abnormal and excessive adipose tissue accumulated in the body. Compared with peripheral obesity (the accumulation of subcutaneous adipose tissue), abdominal obesity (the accumulation of visceral adipose tissue) is associated with increased risk of the metabolic syndrome, such as diabetes, hypertension, atherosclerosis, and dyslipidemia. Adipose tissue is a highly heterogeneous endocrine organ. Adipose tissue depots differ significantly in anatomy, cell biology, glucose and lipid metabolism as well as in endocrine regulation. Visceral adipose tissue has a stronger metabolic activity and secrets a larger amount of free fat acids, adipocytokines, hormones and inflammatory factors, which flux into the liver directly via the hepatic portal vein. These characteristics indicate that visceral adiposity may lead to the metabolic syndrome and thus visceral adipose tissue might be the clinical target for the prevention and treatment of obesity. PMID- 28638931 TI - [Operative techniques and results of tibial pilon fractures]. AB - BACKGROUND: The anatomical reconstruction of tibial pilon fractures is a major challenge with respect to preoperative planning, time management and the intraoperative procedure. OBJECTIVE: Presentation of the various surgical procedures available and the clinical outcome. MATERIAL AND METHODS: The established open reduction and internal plate fixation procedures form the basis for new minimally invasive treatment concepts. The current results of comparative studies and basic literature are discussed. RESULTS: The treatment result depends on the severity of the initial fracture and accompanying soft tissue damage. Essential is an anatomical reduction with an articular displacement of less than 2 mm. Overall, only approximately half of all patients return to work within 1 year. The fixation procedure used is not relevant for this purpose. Both plate fixation and the combination of external fixator plus minimally invasive articular reconstruction with and without arthroscopy achieve equivalent results. CONCLUSION: Good clinical results can be achieved by an accurate preoperative planning with respect to the surgical procedure, time of surgery and the surgical steps. In cases of disregarding these points and inadequate surgical expertise, loss of function and reduced quality of life are impending. PMID- 28638932 TI - [Treatment of recurrent laryngeal nerve paralysis]. AB - Whereas static vocal fold medialization or lateralization are currently the standard procedures, new dynamic treatment methods such as reinnervation and laryngeal pacing focus on better toning and remobilization of the paralyzed vocal folds. End-to-end or jump anastomoses of the recurrent laryngeal nerve can preserve muscle mass and avoid atrophy, thus enabling subsequent dynamic therapeutic options. Prognostic evaluation and the time point of therapeutic intervention are important issues in the management of patients with recurrent laryngeal nerve paralysis. Irreversible interventions should be avoided at early time points or during childhood in order to allow for spontaneous remission and dynamic therapeutic options. PMID- 28638933 TI - [Implementation status of Regulation EU 536/2014 in the member states]. AB - The upcoming Regulation EU 536/2014 for clinical trials of medicinal products for human use requires multinational cooperation in the assessment of clinical trial applications by the member states concerned as well as one single decision per member state concerned, supported by the new EU Portal and database system. The implementation makes national reorganisation of the processes necessary, especially coordination and cooperation between the national competent authorities and the ethics committees, necessary.A brief overview of implementation status with regard to national law adaptations, (re-) organisation, information technology systems as well as national or multinational pilot projects in 7 of 28 member states is given.Within these member states some national laws have been adapted already, while others will be soon. The national reorganisation covers mostly administrative organisation and coordination especially within the ethics committees. Overall, it is foreseen that a reduced number of ethics committees will be involved in the approval of clinical trials on medicinal products within the member states.Most of the seven member states expect that in addition to the new EU Portal/database system a national IT system for national cooperation and interaction will be necessary. Therefore, an interface within the EU system for national systems is essential.In order to test the new processes some member states are running national pilot projects or are planning them. In addition, almost all participate in the voluntary multinational assessment of clinical trials on medicinal products, which had existed since 2009, a few also in cooperation with their ethics committees.The member states are confident that all national processes will be in place when the EU regulation becomes applicable. PMID- 28638934 TI - [The impact of the EU Regulation 536/2014 on the tasks and functioning of ethics committees in Germany]. AB - The EU Clinical Trial Regulation 536/2014 (CTR) and its implementation in Germany led to substantial changes of the established, well-accepted and effective system of reviewing clinical trial applications by ethics committees (ECs), which impair their independence. For the first time, the German federal legislator specified in detail the composition, functioning, tasks and responsibilities of ECs. ECs have to be registered with the federal drug authority BfArM and if an EC does not perform properly the registration can be withdrawn. In addition, the drug authorities may override the negative opinion expressed by an EC. The ECs will also lose their financial autonomy as the fees will be fixed by the federal government. The tasks and responsibilities of the ECs remain almost entirely unchanged, however. The ECs remain involved in the assessment of both parts of the application dossier. Part I is assessed together with the drug authorities, the drug authorities having the lead. The assessment of part II remains the sole responsibility of the EC. As the deadlines for the assessment became rather short, in particular for multinational trials, and the communication with the sponsor will be in writing only, the established procedures of ECs have to be modified. Up to now it was common to verbally discuss problematic issues with the sponsor. The CTR is focused on written communication with the sponsor via the EU portal. ECs, their office staff and chairpersons will need considerable professionalism and respective training. The future workflow requires substantial IT support. The ECs and the Association of Medical Ethics Committees in Germany will do their utmost to protect efficiently the research subjects and to promote Germany as a major destination for clinical research. PMID- 28638935 TI - JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1. AB - Long-range anterograde axonal transport of TrkB is important for neurons to exert appropriate BDNF responses. TrkB anterograde axonal delivery is mediated by kinesin-1, which associates with TrkB via the adaptor protein JIP3 or the Slp1/Rab27B/CRMP-2 protein complex. However, little is known about the activation mechanisms of TrkB-loaded kinesin-1. Here, we show that JIP1 mediates TrkB anterograde axonal transport using JIP1 knockout mice, sciatic nerve ligation analysis and live imaging. Next, we proved that JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport. Finally, microtubule-binding and microfluidic chamber assays revealed that JIP1 and JIP3 cooperate to relieve kinesin-1 autoinhibition, which depends on the binding of JIP1 to kinesin-1 heavy chain (KHC) and light chain (KLC) and the binding of JIP3 to KLC and is essential for TrkB anterograde axonal transport and BDNF-induced TrkB retrograde signal. These findings could deepen our understanding of the regulation mechanism underlying TrkB anterograde axonal transport and provide a novel kinesin-1 autoinhibition-relieving model. PMID- 28638938 TI - [Geriatric case management at the kitchen table : Patient outcome of the pilot project for a regional geriatric care concept in the District of Lippe]. AB - BACKGROUND: The interdisciplinary healthcare treatment of the elderly needs to consider their complex needs. There is a need for new structures of care to be tested, as in the model project regional geriatric care (RVG) concept. The aim is to qualitatively improve the treatment of elderly, multimorbid people by the implementation of case management and therefore to promote living in their own home and avoidance of the necessity for care. OBJECTIVE: How can the quality of care of a geriatric care concept be measured and the benefits for the target group be evaluated? MATERIALS AND METHODS: The explorative evaluation study reports patient outcomes for n = 380 participants who underwent geriatric assessment at the beginning of the intervention and again 12 months later. Descriptive and bivariate data analyses are reported. RESULTS: Participants of the RVG often had a greater need of support because of functional limitations. They rated their physical abilities, limitations and health mostly as being stable. The subjective mental well-being was significantly improved and satisfaction and acceptance by participants and their family members was high. CONCLUSION: The RVG care model enables a qualitatively improved geriatric care in the District of Lippe and considers the high potential for prevention. For organizing care and supporting independent living at home, it is more important to focus on the functional limitations of the elderly than on individual diseases. The tested concept for evaluation has limitations but serves as a basis for future clinical studies. PMID- 28638937 TI - Anti-GITR Antibody Treatment Increases TCR Repertoire Diversity of Regulatory but not Effector T Cells Engaged in the Immune Response Against B16 Melanoma. AB - Crosslinking of glucocorticoid-induced TNF family-related receptor (GITR) with agonist antibodies restores cancer immunity by enhancing effector T cell (Teff) responses while interfering with intra-tumor regulatory T cell (Treg) stability and/or accumulation. However, how anti-GITR antibody infusion changes T cell receptor (TCR) repertoire of Teffs and Tregs engaged in anti-tumor immune response is unclear. Here, we used a transgenic mouse model (TCRmini) where T cells express naturally generated but limited TCR repertoire to trace the fate of individual T cells recognizing B16 melanoma in tumor-bearing mice, treated or non treated with an anti-GITR monoclonal antibody DTA-1. Analysis of TCRs of CD4+ T cells from these mice revealed that the TCR repertoire of dominant tumor-reactive Teff clones remained rather similar in treated and non-treated mice. In contrast, both tumor-associated and peripheral TCR repertoire of Tregs, which were mostly distinct from that of Teffs, underwent DTA-1 mediated remodeling characterized by depletion of dominant clones and an emergence of more diverse, low-frequency clones bearing increased numbers of TCRs shared with Teffs. We conclude that the DTA-1 infusion eliminates activated Tregs engaged in the initial maintenance of tolerogenic niche for tumor growth, but over time, it favors tumor replenishment by Tregs expressing an array of TCRs able to compete with Teffs for recognition of the same tumor antigens which may prevent its complete eradication. PMID- 28638939 TI - [Consequences of autopsies for the living : Causes of death in the clinical diagnosis "septic and toxic shock"]. AB - BACKGROUND: There is reason to believe that the diagnosis of septic and toxic shock, as indicated on the death certificate, cannot be confirmed as the cause of death without autopsy and subsequent histological analysis. The external examination of the corpse can therefore not represent the sole basis for a reliable statement about the infection status of a corpse, e. g. as a prerequisite for embalming. MATERIAL AND METHODS: The validity of autopsy in determining septic and toxic shock as the cause of death is demonstrated in 7 exemplary cases. RESULTS: Decades of experience in a university pathology institute have shown that an external examination of the corpse alone is not suitable for certifying the cause of death if an infectious disease is suspected. Consequently, only autopsy with subsequent histological analysis provides reliable statements on the etiopathogenesis of the underlying process. Possible problems and discrepancies between clinical and pathological diagnoses are discussed on the basis of several cases with or without autoptic confirmation of the septic shock. The case of a missionary from Africa infected with Lassa virus serves to point out the seriousness of the threat an undiagnosed infection may represent to the attending staff. CONCLUSION: During the treatment of patients suspected to have an infectious cause of fever of unknown origin, compliance with the usual safety regulations, including adequate disinfecting measures, is essential. In cases with fatal outcome, not infrequently under the clinical picture of a septic and toxic shock, autopsy should be regularly performed to confirm the type of infection and the infectious cause of death. Rapid and open communication between the professional groups involved plays a crucial role in this process. PMID- 28638940 TI - Laparoscopic vesico-ureteral reimplantation with Lich-Gregoir approach in children: medium term results of 159 renal units in 117 children. AB - PURPOSE: Vesico-ureteral reflux (VUR) represents one of the most significant risk factors for acute pyelonephritis in children. Surgery is an important part of its management. Laparoscopic ureteric reimplantation using the Lich-Gregoir technique is an option for VUR. The aim of this study is to assess short- and medium-term outcomes of this approach. MATERIALS AND METHODS: This is a retrospective study including all children with VUR treated by laparoscopic extravesical ureteral reimplantation with the Lich-Gregoir technique in University Hospital of Saint Etienne from August 2007 to May 2016. Surgery was performed after the age of 12 months in cases with repeated urinary tract infection (UTI) and a deterioration of renal function. All patients were followed-up post operatively. RESULTS: 117 children (92 girls, 25 boys) representing 159 renal units were included. The mean age at surgery was 47.1 months (+/-32.7 months). The mean follow-up was 59.3 months (+/-31 months). The resolution rate for VUR in terms of no febrile urinary UTIs was 98.3%. The mean operative time was 96 min (+/-37.7 min) for unilateral procedures and 128 min (+/-46.1 min) for bilateral procedures. The mean hospital stay was 25.3 h (+/-6.3 h). There was no difference between males and females regarding age, weight, renal function or follow-up duration. CONCLUSIONS: Laparoscopic reimplantation with Lich-Gregoir technique is an efficient, quick and safe technique for the management of VUR. The success rate is comparable to open techniques with the advantages of laparoscopic approach; this can potentially be performed as a Day Case procedure. PMID- 28638941 TI - Subcutaneous endoscopically assisted ligation of spermatic vessels (SEAL-SV) using an epidural-&-spinal needle: a novel technique to repair adolescent varicocele. AB - We describe a novel technique of subcutaneous endoscopically assisted ligation of spermatic vessels (SEAL-SV) using a modified epidural-&-spinal needle. This technique achieves very cosmetic and minimally invasive outcomes. We have successfully performed SEAL-SV for five consecutive boys and considered it a simple, safe, and effective procedure for adolescent varicoceles. PMID- 28638942 TI - Morel-Lavallee lesion in pediatric trauma. AB - Morel-Lavallee lesions (MLL) are closed degloving injuries that have been rarely described in the pediatric literature. These internal degloving injuries can have serious complications and long-term morbidity. Early diagnosis and intervention is imperative. We present the case of a 20-month-old with MLL of the thigh. PMID- 28638943 TI - Elevated serum heat shock protein 70 and liver stiffness reflect hepatic dysfunction and severity in postoperative biliary atresia. AB - BACKGROUND: Biliary atresia (BA) is a severe chronic liver disease characterized by progressive obstructive cholangiopathy of biliary tract. Heat shock protein 70 (HSP70) is involved in protecting cells against a wide variety of stress and plays a protective role in tissue damage. The purpose of this study was to investigate serum HSP70 and liver stiffness in BA and determine the association of serum HSP70, liver stiffness, and outcome parameters in post-Kasai BA patients. METHODS: One hundred post-Kasai BA patients and 40 controls were enrolled. Serum HSP70 levels were analyzed using enzyme-linked immunosorbent assay. Liver stiffness values were assessed by transient elastography. RESULTS: BA patients had significantly higher serum HSP70 and liver stiffness values than controls. Serum HSP70 and liver stiffness values were markedly elevated in BA patients with jaundice compared to those without jaundice (P < 0.001). Furthermore, serum HSP70 was more elevated in BA children with portal hypertension than those without portal hypertension (35.1 +/- 2.1 vs. 27.9 +/- 2.5 ng/mL, P < 0.001). Moreover, serum HSP70 was positively correlated with serum aspartate aminotransferase (r = 0.491, P < 0.001), alanine aminotransferase (r = 0.448, P < 0.001), total bilirubin (r = 0.303, P = 0.002), alkaline phosphatase (r = 0.414, P < 0.001), and liver stiffness values (r = 0.455, P < 0.001). There was a negative correlation between serum HSP70 and serum albumin (r = -0.434, P = 0.001). CONCLUSION: Serum HSP70 and liver stiffness values were higher in BA patients than controls. The increased serum HSP70 was correlated with hepatic dysfunction in BA. Consequently, serum HSP70 and liver stiffness could serve as non-invasive parameters reflecting the severity in post-Kasai BA. PMID- 28638944 TI - The effect of fight cost structure on fighting behaviour involving simultaneous decisions and variable investment levels. AB - In the "producer-scrounger" model, a producer discovers a resource and is in turn discovered by a second individual, the scrounger, who attempts to steal it. This resource can be food or a territory, and in some situations, potentially divisible. In a previous paper we considered a producer and scrounger competing for an indivisible resource, where each individual could choose the level of energy that they would invest in the contest. The higher the investment, the higher the probability of success, but also the higher the costs incurred in the contest. In that paper decisions were sequential with the scrounger choosing their strategy before the producer. In this paper we consider a version of the game where decisions are made simultaneously. For the same cost functions as before, we analyse this case in detail, and then make comparisons between the two cases. Finally we discuss some real examples with potentially variable and asymmetric energetic investments, including intraspecific contests amongst spiders and amongst parasitoid wasps. In the case of the spiders, detailed estimates of energetic expenditure are available which demonstrate the asymmetric values assumed in our models. For the wasps the value of the resource can affect the probabilities of success of the defender and attacker, and differential energetic investment can be inferred. In general for real populations energy usage varies markedly depending upon crucial parameters extrinsic to the individual such as resource value and intrinsic ones such as age, and is thus an important factor to consider when modelling. PMID- 28638936 TI - Nuclear receptors in neural stem/progenitor cell homeostasis. AB - In the central nervous system, embryonic and adult neural stem/progenitor cells (NSCs) generate the enormous variety and huge numbers of neuronal and glial cells that provide structural and functional support in the brain and spinal cord. Over the last decades, nuclear receptors and their natural ligands have emerged as critical regulators of NSC homeostasis during embryonic development and adult life. Furthermore, substantial progress has been achieved towards elucidating the molecular mechanisms of nuclear receptors action in proliferative and differentiation capacities of NSCs. Aberrant expression or function of nuclear receptors in NSCs also contributes to the pathogenesis of various nervous system diseases. Here, we review recent advances in our understanding of the regulatory roles of steroid, non-steroid, and orphan nuclear receptors in NSC fate decisions. These studies establish nuclear receptors as key therapeutic targets in brain diseases. PMID- 28638946 TI - Nerve atrophy in trigeminal neuralgia due to neurovascular compression and its association with surgical outcomes after microvascular decompression. AB - BACKGROUND: Idiopathic trigeminal neuralgia (TN) is caused by neurovascular compression and is often related to morphological changes in the trigeminal nerve. The aim of this study was to quantitatively measure atrophic changes of trigeminal nerves in patients with TN, and to further investigate whether nerve atrophy affected the efficacy of microvascular decompression (MVD). METHODS: We conducted a prospective case-control study of 60 consecutive patients with TN and 30 sex- and age-matched healthy controls. All subjects underwent high-resolution three-dimensional MRI. The volume of the cisternal segment of trigeminal nerves was measured and compared using 3D Slicer software. Patients with TN underwent primary MVD and regular follow-up for at least 2 years. Associations of nerve atrophy with patient characteristics and operative outcomes were analyzed. RESULTS: The mean volume of the affected trigeminal nerve was significantly reduced in comparison to that of the nonaffected side (65.8 +/- 21.1 versus 77.9 +/- 19.3 mm3, P = 0.001) and controls (65.8 +/- 21.1 versus 74.7 +/- 16.5 mm3, P = 0.003). Fifty-two patients (86.7%) achieved complete pain relief without medication immediately after surgery, and 77.6% of patients were complete pain relief at the 2-year follow-up. The Spearman correlation test showed that there was a positive correlation (r = 0.46, P = 0.018) between the degree of trigeminal nerve indentation and nerve atrophy. In multivariate logistic regression analysis, two factors, indentation on nerve root (OR = 2.968, P = 0.022) and degree of nerve atrophy (OR = 1.18, P = 0.035), were associated with the long term outcome. CONCLUSIONS: TN is associated with atrophy on the affected nerve. Furthermore, greater nerve atrophy is associated with more severe trigeminal nerve indentation and better long-term outcome following MVD. PMID- 28638945 TI - Surgical treatment of unruptured distal basilar artery aneurysm: durability and risk factors for neurological worsening. AB - BACKGROUND: Distal basilar artery aneurysms (DBAs) consist of basilar apex and basilar artery-superior cerebellar artery bifurcation (BA-SCA) aneurysms. The authors aimed to investigate clinical and radiological differences between two locations and to evaluate the 12-month surgical outcome in unruptured DBAs. METHODS: Fifty-six consecutive patients who underwent surgical treatment (37 basilar apex and 19 BA-SCA aneurysms) between April 2012 and February 2016 were retrospectively evaluated. In patients with a preoperative modified Rankin Scale score (mRS) of more than 1, neurological worsening (NW) was defined as an increase in one or more mRS. In patients without symptoms, NW was defined as mRS >=2. RESULTS: The mean age of the patient population was 64 +/- 9.6 years, and 48 (86%) were female. Mean follow-up period was 2.6 +/- 0.94 years. An excellent (mRS 0 to 1) outcome was archived in 31 (55%), 45 (82%), and 48 (87%) patients at 30 days, 6 months, and 12 months, respectively. Clinical and radiological characteristics showed no differences between two locations. One early death (1.8%) and one severe morbidity (1.8%) due to rupture were observed. The postoperative annual rupture rate was 1.4% overall (145 patient-years). After adjustment for age and location, large or giant DBA was related to 30-day and 12 month NW [n = 22 (39%) and n = 6 (11%); p = 0.009 and 0.002, respectively], aneurysm localization in the interpeduncular cistern (LIC) and perforator territory infarction were related to 30-day NW (p = 0.002 and 0.002), and DBA that needed bypass surgery and previously treated recurrent DBA were related to NW at 12 months (p = 0.017 and 0.001). Multivariate analysis showed that LIC was significantly related to perforator territory infarction (p = 0.003). CONCLUSIONS: Clinical and radiological characteristics were not different between basilar apex and BA-SCA aneurysms; therefore, they should not be discussed separately. To avoid neurological worsening, results of surgical treatment for unruptured DBAs should be improved. PMID- 28638948 TI - Does socioeconomic status influence the epidemiology and outcome of distal radial fractures in adults? AB - PURPOSE: The aim of this study in adult patients with a distal radial fracture was to determine whether socioeconomic status influenced the epidemiology, mechanism of injury, fracture severity, or the outcome according to function, radiographic assessment, and rate of associated complications. METHODS: We identified 3983 distal radial fractures over a 7-year period. Socioeconomic status was assigned using the Carstairs score, and the population was divided into quintiles depending on deprivation. Patient demographics, mechanism of injury, fracture severity, and radiographic assessment at time of injury were assessed for epidemiological differences according to social quintile. Functional outcome was assessed using grip strength, Moberg pickup test, return to normal use of the hand, and range of movement. Radiographs were assessed at 1 week, 6 weeks, and 1 year. Complications were defined as malunion, carpal tunnel syndrome, complex regional pain syndrome (CRPS), persistent pain, and subjective cosmetic deformity of the wrist. RESULTS: Socioeconomically deprived patients were significantly younger (p < 0.001) and more likely to be male (p = 0.017); after adjusting for confounding factors, deprived patients were 3.1 (95% CI 1.4 4.7) years younger than the most affluent patients (p < 0.001). Deprived patients were more likely to sustain their fracture by a high-energy mechanism (p = 0.004). There were no significant differences between quintiles in outcome. There was a significantly greater prevalence of CRPS in more affluent patients (p = 0.004). CONCLUSIONS: Socioeconomically deprived patients sustaining a distal radial fracture are more likely to be younger and male. Outcome is not influenced by socioeconomic status, but the prevalence of CRPS is greater in more affluent patients. PMID- 28638947 TI - Genetic and environmental influences on conduct and antisocial personality problems in childhood, adolescence, and adulthood. AB - Conduct problems in children and adolescents can predict antisocial personality disorder and related problems, such as crime and conviction. We sought an explanation for such predictions by performing a genetic longitudinal analysis. We estimated the effects of genetic, shared environmental, and unique environmental factors on variation in conduct problems measured at childhood and adolescence and antisocial personality problems measured at adulthood and on the covariation across ages. We also tested whether these estimates differed by sex. Longitudinal data were collected in the Netherlands Twin Register over a period of 27 years. Age appropriate and comparable measures of conduct and antisocial personality problems, assessed with the Achenbach System of Empirically Based Assessment, were available for 9783 9-10-year-old, 6839 13-18-year-old, and 7909 19-65-year-old twin pairs, respectively; 5114 twins have two or more assessments. At all ages, men scored higher than women. There were no sex differences in the estimates of the genetic and environmental influences. During childhood, genetic and environmental factors shared by children in families explained 43 and 44% of the variance of conduct problems, with the remaining variance due to unique environment. During adolescence and adulthood, genetic and unique environmental factors equally explained the variation. Longitudinal correlations across age varied between 0.20 and 0.38 and were mainly due to stable genetic factors. We conclude that shared environment is mainly of importance during childhood, while genetic factors contribute to variation in conduct and antisocial personality problems at all ages, and also underlie its stability over age. PMID- 28638949 TI - A career in orthopaedics. PMID- 28638952 TI - Assessing the Impact and Effectiveness of Hearing Voices Network Self-Help Groups. AB - The Hearing Voices Network (HVN) is an influential service-user led organisation that promotes self-help as an important aspect of recovery. This study presents the first systematic assessment of the impact and effectiveness of HVN self-help groups. A customized 45-item questionnaire, the Hearing Voices Groups Survey, was sent to 62 groups affiliated with the English HVN. 101 responses were received. Group attendance was credited with a range of positive emotional, social and clinical outcomes. Aspects that were particularly valued included: opportunities to meet other voice hearers, provision of support that was unavailable elsewhere, and the group being a safe and confidential place to discuss difficult issues. Participants perceived HVN groups to facilitate recovery processes and to be an important resource for helping them cope with their experiences. Mental health professionals can use their expertise to support the successful running of these groups. PMID- 28638950 TI - Surgical treatment for metastases of the cervical spine. AB - BACKGROUND: There are limited information and inconclusive results for the management of patients with cervical spine metastases. Therefore, we performed this study to evaluate the survival and outcome of these patients, and the surgical risk and complications. MATERIALS AND METHODS: We retrospectively studied 24 patients [14 men and 10 women; mean age, 71 years (range 54-89 years)], with cervical spine metastases, who underwent palliative surgical treatment, from December 2010 to December 2016. Mean follow-up was 14 months (range 1-42 months). We evaluated the survival and the outcome of the patients with respect to pain relief and neurological status, and the surgical risk and complications. RESULTS: At the last follow-up, three patients were alive with disease, and 21 patients were dead with disease. Overall median survival was 14.8 months (range 1-47 months). A posterior approach was performed in 15 patients, an anterior approach with corpectomy and fusion in eight patients, and a two-stage combined approach in one patient. Overall, 21 patients experienced complete or almost complete, two patients mild, and one patient no pain relief; seven patients experienced complete neurological improvement, two patients moderate, while four patients remained stable. Overall, five patients experienced six complications including residual pain, sagittal malalignment with instability, and wound dehiscence; in five complications, a reoperation was necessary. CONCLUSIONS: Palliative surgical treatment is usually performed in patients with metastatic bone disease of the cervical spine. Appropriate selection of the surgical technique is mandatory. However, the survival of the patients is dismal, and complications should be expected. PMID- 28638953 TI - [Chronic leg ulcers]. AB - Chronic wounds often manifest as ulcers on the lower legs. The main causes of chronic leg ulcers are chronic venous insufficiency and/or peripheral arterial occlusive disease in approximately 80% of all patients. However, there are also numerous other potentially relevant factors which can cause or almost impede the healing of chronic leg ulcers. Therefore, disease such as vasculitis, livedo vasculopathy, pyoderma gangrenosum, necrobiosis lipoidica, Martorell hypertensive leg ulcer, calciphylaxis, infectious diseases, neoplasms, drugs, cutaneous artefacts and genetic defects are exemplarily presented. The successful therapy of patients with chronic leg ulcers is only possible on the basis of an adequate diagnosis. Therapeutic options include conservative, surgical and interventional treatment options. In particular the consequent implementation of compression therapy is of very great importance in the therapy of most patients with chronic leg ulcers and edema. However, a permanent effective treatment always requires a causally oriented therapy, which usually needs an interdisciplinary and interprofessional approach. PMID- 28638951 TI - Isoflurane and ketamine:xylazine differentially affect intraocular pressure associated scotopic threshold responses in Sprague-Dawley rats. AB - PURPOSE: Amplitudes of electroretinograms (ERG) are enhanced during acute, moderate elevation of intraocular pressure (IOP) in rats anaesthetised with isoflurane. As anaesthetics alone are known to affect ERG amplitudes, the present study compares the effects of inhalant isoflurane and injected ketamine:xylazine on the scotopic threshold response (STR) in rats with moderate IOP elevation. METHODS: Isoflurane-anaesthetised (n = 9) and ketamine:xylazine-anaesthetised (n = 6) rats underwent acute unilateral IOP elevation using a vascular loop anterior to the equator of the right eye. STRs to a luminance series (subthreshold to 3.04 log scotopic cd s/m2) were recorded from each eye of Sprague-Dawley rats before, during, and after IOP elevation. RESULTS: Positive STR (pSTR) amplitudes for all conditions were significantly smaller (p = 0.0001) for isoflurane- than for ketamine:xylazine-anaesthetised rats. In addition, ketamine:xylazine was associated with a progressive increase in pSTR amplitudes over time (p = 0.0028). IOP elevation was associated with an increase in pSTR amplitude (both anaesthetics p < 0.0001). The absolute interocular differences in IOP-associated enhancement of pSTR amplitudes for ketamine:xylazine and isoflurane were similar (66.3 +/- 35.5 vs. 54.2 +/- 24.1 uV, respectively). However, the fold increase in amplitude during IOP elevation was significantly higher in the isoflurane- than in the ketamine:xylazine-anaesthetised rats (16.8 +/- 29.7x vs. 2.1 +/- 2.7x, respectively, p = 0.0004). CONCLUSIONS: The anaesthetics differentially affect the STRs in the rat model with markedly reduced amplitudes with isoflurane compared to ketamine:xylazine. However, the IOP-associated enhancement is of similar absolute magnitude for the two anaesthetics, suggesting that IOP stress and anaesthetic effects operate on separate retinal mechanisms. PMID- 28638954 TI - Palliative home care for patients with advanced haematological malignancies-a multicenter survey. AB - Patients with advanced haematological malignancies in non-curative settings suffer from complex physical symptoms and psychosocial distress, comparable to patients with solid tumour entities. Nevertheless, numerous problems at the interface between haematology and palliative home care have been described. From January 2011 until October 2014, we performed a retrospective, multicenter analysis of all patients with haematological malignancies (ICD 10: C81-C95) being treated by the respective specialized palliative home care (SAPV) team. Three SAPV teams were surveyed. Disease entity, physical symptoms, psychosocial distress, number of hospital admissions, therapeutic interventions and other items were analysed descriptively. Of 3,955 SAPV patients, 1.8% (n = 73) suffered from haematological malignancies. Main problems were deterioration of general condition, pain or psychological problems. Thirty-seven percent developed new symptoms during SAPV, mainly pain, psychological distress or deterioration of general status. In 33%, patients were referred to hospital, mainly due to deterioration of general condition or pain. Seventy percent died within 3 months after beginning SAPV care; 83% died at home or in a nursing home. Patients suffering from advanced haematological malignancies were statistically underrepresented in SAPV, and SAPV was installed rather at the very last days of life. By far, more patients were able to die outside a hospital as compared to reference cohorts of haematological patients not being treated in SAPV. The spectrum of documented problems is comparable to other patient cohorts being treated in SAPV; therefore, the options and benefits of palliative home care should be incorporated in palliative haematological treatment concepts more vigorously and consequently. PMID- 28638955 TI - Lipopolysaccharide-induced CCN1 production enhances interleukin-6 secretion in bronchial epithelial cells. AB - Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a clinical complication caused by primary or secondary lung injury, as well as by systemic inflammation. Researches regarding molecular pathophysiology of ALI/ARDS are immerging with an ultimate aim towards developing prognostic molecular biomarkers and molecule-based therapy. However, the molecular mechanisms concerning ALI/ARDS are still not completely understood. The purpose of the present study was to identify a crucial role of CCN1 in inflammatory microenvironment during ALI/ARDS and focus on a potential communication between CCN1 and interleukin-6 (IL-6) in the airway epithelial cells. Our data illustrated that the expression levels of CCN1 and IL-6 in bronchoalveolar lavage fluid (BALF) in a lipopolysaccharide (LPS)-induced ALI mouse model were significantly elevated and the pulmonary expression of CCN1 was restricted to bronchial epithelial cells. Interestingly, both endogenous and exogenous CCN1 stimulated IL-6 production in vitro. Furthermore, LPS-induced IL-6 production in a bronchial epithelial cell line was blocked by CCN siRNA whereas CCN1 induced by LPS was sensitive to PI3K inhibition. Together, our data indicate a linear signal pathway, LPS-CCN1-IL-6, existing in bronchial epithelial cells after LPS exposure. This finding may represent an additional mechanism and a novel target for development of therapy and biomarker on ALI/ARDS. PMID- 28638956 TI - Dynamic phenotypes: illustrating a single-cell odyssey. PMID- 28638959 TI - [Psychotraumatology : Differentiation, extension and public discourse]. AB - The first description of posttraumatic stress disorder (PTSD) in the 1980s marked the origin of psychotraumatology. Based on the variety of developments in the meantime and being relevant for basic research and clinical application, a differentiation of diagnoses according to the new International Classification of Diseases (ICD-11) are presented including PTSD, complex PTSD, prolonged grief disorder and adjustment disorder. In addition, extension towards traumatic and adverse childhood experiences and their significance for lifetime mental and somatic morbidity are described. Concerning these childhood traumata and adversities, distinct biological and epigenetic factors have been extensively investigated. Also, research groups have postulated that important psychological disorders should be differentiated according to those with and those without reference to pathogenetic trauma. Lastly, regarding relevant public discourses, societal dimensions of victimhood and compensation are discussed as well as a global perspective with respect to continuous and historical traumatization. PMID- 28638962 TI - Sensitivity of the Endogeic Tropical Earthworm Pontoscolex corethrurus to the Presence of Heavy Crude Oil. AB - Contamination of soil with petroleum is common in oil-producing areas across the tropical regions of the world. There is limited knowledge on the sensitivity of endogeic tropical earthworms to the contamination of soil with total petroleum hydrocarbons (TPH) present in crude oil. Pontoscolex corethrurus is a dominant species in tropical agroecosystems around oil-processing facilities. The sensitivity of P. corethrurus to soil artificially contaminated with "Maya" Mexican heavy crude oil was investigated through avoidance and acute ecotoxicity tests, using the following measured concentrations: 0 (reference soil), 551, 969, 4845, 9991 and 14,869 mg/kg. The avoidance test showed that P. corethrurus displayed a significant avoidance behavior to heavy crude oil at a concentration of 9991 mg/kg or higher. In contrast, acute toxicity tests indicate that the median lethal concentration (LC50) was 3067.32 mg/kg; however, growth (weight loss) was more sensitive than mortality. Our study revealed that P. corethrurus is sensitive to TPH, thus highlighting the importance of P. corethrurus for petroleum ecotoxicological tests. PMID- 28638961 TI - Evaluation of systolic and diastolic properties of hypertensive heart failure using speckle-tracking echocardiography with high volume rates. AB - Left ventricular (LV) properties in hypertension (HTN) could be deteriorated by pressure overload, especially in endocardium, resulting in hypertensive heart failure (HHF). We sought to noninvasively examine LV systolic and diastolic functions at three myocardial layers in HTN and elucidate features of HHF by speckle-tracking echocardiography (STE) with high volume rates. We examined normotensive controls (n = 54), HTN patients without LV hypertrophy (LVH) (n = 50), and HTN patients with LVH (n = 40) and HHF patients (n = 45). The HHF group was divided into two subgroups based on their LVEF (20 heart failure with preserved ejection fraction: HFpEF and 25 heart failure with reduced ejection fraction: HFrEF). LV layer systolic function was assessed by strain rate during systole. Pulmonary capillary wedge pressure (PCWP) was estimated (ePCWP) using kinetics-tracking index (KT index) that we previously reported. HTN patients with LVH had a significant deterioration of systolic and diastolic properties compared with normotensive controls in the absence of a significant reduction in LVEF. Patients with HHF had further deterioration of systolic and diastolic properties compared with HTN patients with LVH. LV strain at entire myocardium and ePCWP in HFrEF was deteriorated compared with those in HFpEF. Deterioration of LV layer SR was more typical during systole, isovolumic relaxation, and early diastole compared with control. LV dilation was independently associated with LVEF (r = 0.48, p < 0.001) and ePCWP (r = 0.47, p < 0.001), and LVH (LV mass index) was independently associated with E/e' (r = 0.37, p = 0.025), LVEF (r = -0.44, p < 0.001), and ePCWP (r = 0.67, p < 0.001). LV layer analysis by STE could detect subtle impairments in systolic function before the deterioration of LVEF in patients with HTN. The ePCWP that was estimated using KT index was the independent factor associated with HHF. The ePCWP may be useful to noninvasively detect the early stage of HHF. PMID- 28638960 TI - Comparative diagnostic evaluation of OMP31 gene based TaqMan(r) real-time PCR assay with visual LAMP assay and indirect ELISA for caprine brucellosis. AB - Brucellosis is one of the leading causes of abortion in domestic animals that imposes costs on both economy and society. The disease is highly zoonotic and poses risk to animal handlers due to its zoonotic nature. It causes stillbirth, loss of kids and abortion in last term of pregnancy. Reproductive damage includes infertility in does and orchitis and epididymitis in breeding bucks, which result in high financial losses to farmers and the agriculture industry as a whole. It requires highly sensitive and specific assays to diagnose the disease at field level. In the current study, a visual loop-mediated isothermal amplification (LAMP) assay and the TaqMan(r) real-time PCR were developed with high sensitivity and specificity. For the TaqMan(r) probe, real-time PCR primers were developed using Omp31 gene as target and primers were designed using discontiguous conserved sequences of Omp31 gene. The Omp31 probes were designed by attaching 6 FAM reporter dye at the 5' end and BHQ-1 quencher at the 3' end. Published primers were used for visual LAMP assay targeting the Omp25 gene. Sensitivity of the standardized visual LAMP assay and TaqMan(r) real-time PCR assay was determined by serial dilution of positive Brucella melitensis DNA (102 to 10-4 ng) obtained from standard culture. The TaqMan(r) probe real-time assay can detect as low as 100 fg of B. melitensis DNA, whereas culture from vaginal swab washings has a limit of detection (LOD) of only 1 cfu/ml. Similarly, the visual LAMP assay can detect as low as 10 fg of B. melitensis DNA as compared to an LOD of 30 cfu/ml from culture of vaginal swab washings. Both assays were compared with serological tests (serum tube agglutination test (STAT) and indirect enzyme linked immunosorbent assay (iELISA)) for diagnostic sensitivity and specificity. Diagnostic sensitivities and specificities for TaqMan(r) real-time PCR vs. LAMP assays were 98 and 100% vs. 100 and 97.8%, respectively. Results of visual LAMP assay indicated that LAMP is a fast, specific, sensitive, inexpensive and suitable method for diagnosis of B. melitensis infection under field conditions. On the other hand, Omp31 TaqMan(r) probe real-time assay can be used in conjunction with the other field-based diagnostic tests due to its high specificity. PMID- 28638963 TI - Attenuation of the Atmospheric Migration Ability of Polychlorinated Naphthalenes (PCN-2) Based on Three-dimensional QSAR Models with Full Factor Experimental Design. AB - Based on the experimental subcooled liquid vapor pressures (P L) of 17 polychlorinated naphthalene (PCN) congeners, one type of three-dimensional quantitative structure-activity relationship (3D-QSAR) models, comparative molecular similarity indices analysis (CoMSIA), was constructed with Sybyl software. Full factor experimental design was used to obtain the final regulation scheme for PCN, and then carry out modification of PCN-2 to significantly lower its P L. The contour maps of CoMSIA model showed that the migration ability of PCN decreases when the Cl atoms at the 2-, 3-, 4-, 5-, 6-, 7- and 8-positions of PCNs are replaced by electropositive groups. After modification of PCN-2, 12 types of new modified PCN-2 compounds were obtained with lnP L values two orders of magnitude lower than that of PCN-2. In addition, there are significant differences between the calculated total energies and energy gaps of the new modified compounds and those of PCN-2. PMID- 28638964 TI - Ships' Ballast Water Treatment by Chlorination Can Generate Toxic Trihalomethanes. AB - The International Maritime Organization (IMO) will enforce a new abundance-based performance standard for ballast water in September, 2017. Strong oxidants, like chlorine, have been proposed as a method for achieving this standard. However chlorine treatment of ballast water can produce hazardous trihalomethanes. We assessed maximum trihalomethane production from one chlorine dose for three types of ballast water (fresh, brackish and marine) and three levels of total organic carbon (TOC) concentration (natural, filtered, enhanced). While the current standard test considers a 5 day voyage, there is a high possibility of shorter trips and sudden change of plans that will release treated waters in the environment. Water source and TOC significantly affected trihalomethane production, with the highest amounts generated in brackish waters and enhanced TOC concentration. The concentration of brominated trihalomethanes increased from background levels and was highest in brackish water, followed by marine and fresh water. PMID- 28638965 TI - Internalizing and externalizing problems in childhood and adolescence as predictors of work incapacity in young adulthood. AB - BACKGROUND: There is limited information regarding the association between youth mental health problems and work incapacity in adulthood. We investigated whether internalizing (depressive, anxious, somatic complaints) and externalizing (aggressive, rule-breaking) behavior problems in childhood and adolescence were associated with sickness absence (SA) and disability pension (DP) in young adulthood. METHODS: Data were used from the population-based and prospective Twin Study of Child and Adolescent Development (TCHAD) which includes all Swedish twins born in 1985-1986 (N = 2570). Internalizing and externalizing behavior problems were assessed with the Child Behavior Checklist at ages of 8-9, 13-14, 16-17, and 19-20 years. Individuals participating in TCHAD were followed regarding SA and DP during 2001-2013 using nationwide registers. Cox regression models were applied to assess hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Each one-unit increase of rule-breaking behavior implied a significant higher risk for SA in early adulthood, despite of age at assessment, with the highest HR of 1.12 (95% CI 1.05-1.19) at age of 8-9 years. Higher levels of anxious and depressive symptoms in childhood and adolescence were associated with DP in early adulthood despite age at assessment, with the highest risk at age 19-20 years [HR 1.31 (95% CI 1.12-1.53)]. The associations attenuated slightly when familial factors were taken into account. CONCLUSIONS: Internalizing and externalizing behavior problems identified at an early age (8-9 years) increased risk for SA and DP in young adulthood. These findings indicate that early prevention and intervention efforts to reduce behavior problems may promote a successful start in working life. PMID- 28638966 TI - Measuring everyday functional competence using the Rasch assessment of everyday activity limitations (REAL) item bank. AB - OBJECTIVE: Traditional patient-reported physical function instruments often poorly differentiate patients with mild-to-moderate disability. We describe the development and psychometric evaluation of a generic item bank for measuring everyday activity limitations in outpatient populations. STUDY DESIGN AND SETTING: Seventy-two items generated from patient interviews and mapped to the International Classification of Functioning, Disability and Health (ICF) domestic life chapter were administered to 1128 adults representative of the Dutch population. The partial credit model was fitted to the item responses and evaluated with respect to its assumptions, model fit, and differential item functioning (DIF). Measurement performance of a computerized adaptive testing (CAT) algorithm was compared with the SF-36 physical functioning scale (PF-10). RESULTS: A final bank of 41 items was developed. All items demonstrated acceptable fit to the partial credit model and measurement invariance across age, sex, and educational level. Five- and ten-item CAT simulations were shown to have high measurement precision, which exceeded that of SF-36 physical functioning scale across the physical function continuum. Floor effects were absent for a 10 item empirical CAT simulation, and ceiling effects were low (13.5%) compared with SF-36 physical functioning (38.1%). CAT also discriminated better than SF-36 physical functioning between age groups, number of chronic conditions, and respondents with or without rheumatic conditions. CONCLUSION: The Rasch assessment of everyday activity limitations (REAL) item bank will hopefully prove a useful instrument for assessing everyday activity limitations. T-scores obtained using derived measures can be used to benchmark physical function outcomes against the general Dutch adult population. PMID- 28638967 TI - Socio-demographic, clinical characteristics and utilization of mental health care services associated with SF-6D utility scores in patients with mental disorders: contributions of the quantile regression. AB - PURPOSE: Health-related quality of life (HRQoL) is a widely used concept in the assessment of health care. Some generic HRQoL instruments, based on specific algorithms, can generate utility scores which reflect the preferences of the general population for the different health states described by the instrument. This study aimed to investigate the relationships between utility scores and potentially associated factors in patients with mental disorders followed in inpatient and/or outpatient care settings using two statistical methods. METHODS: Patients were recruited in four psychiatric sectors in France. Patient responses to the SF-36 generic HRQoL instrument were used to calculate SF-6D utility scores. The relationships between utility scores and patient socio-demographic, clinical characteristics, and mental health care utilization, considered as potentially associated factors, were studied using OLS and quantile regressions. RESULTS: One hundred and seventy six patients were included. Women, severely ill patients and those hospitalized full-time tended to report lower utility scores, whereas psychotic disorders (as opposed to mood disorders) and part-time care were associated with higher scores. The quantile regression highlighted that the size of the associations between the utility scores and some patient characteristics varied along with the utility score distribution, and provided more accurate estimated values than OLS regression. CONCLUSIONS: The quantile regression may constitute a relevant complement for the analysis of factors associated with utility scores. For policy decision-making, the association of full-time hospitalization with lower utility scores while part-time care was associated with higher scores supports the further development of alternatives to full-time hospitalizations. PMID- 28638968 TI - [Large vessel vasculitis : Giant cell arteritis and Takayasu arteritis]. AB - According to the Chapel Hill Classification, large vessel vasculitides encompass giant cell arteritis (GCA) and the histologically related Takakaysu arteritis (TAK). The two diseases lack autoantibodies and present with a systemic inflammatory response. GCA typically shows a sudden onset with profound sickness, loss of appetite and of body weight, and temporal headache. Due to the substantial risk of sudden blindness, diagnostic work-up has to be performed immediately and treatment started without delay. A close association between polymyalgia rheumatica (PMR) and GCA is well established. Takayasu arteritis very often begins in adolescence. In contrast to GCA, the general symptoms are much less pronounced and aside from occasional carotidodynia there is a lack of diagnostic symptoms. TAK is often diagnosed in late stages due to exercise induced claudication. PMID- 28638969 TI - Introduction: Childhood and Disability. AB - From growth attenuation therapy for severely developmentally disabled children to the post-natal management of infants with trisomy 13 and 18, pediatric treatment decisions regularly involve assessments of the probability and severity of a child's disability. Because these decisions are almost always made by surrogate decision-makers (parents and caregivers) and because these decision-makers must often make decisions based on both prognostic guesses and potentially biased quality of life judgments, they are among the most ethically complex in pediatric care. As the introduction to HEC Forum's special thematic issue on Childhood and Disability, this article orients the reader to the history of bioethics' relationship to both pediatric ethics and disability studies and introduces the issue's five manuscripts. As clinicians, disability scholars, philosophers and clinical ethicists writing on various aspects of pediatric disability, the articles' authors all invite readers to dig beneath an overly-simplified version of what disability might mean to children and families and instead embrace a posture of genuine humility, recognizing both the limits and harms of traditional medical and bioethical responses (or indifferences) to the disabled child. PMID- 28638970 TI - Ramp lesions associated with ACL injuries are more likely to be present in contact injuries and complete ACL tears. AB - PURPOSE: The purpose of this study was to analyse patient and injury characteristics as well as arthroscopic findings in a prospective cohort of ACL injured patients with or without an associated ramp lesion. METHODS: Two hundred and twenty-four patients undergoing a primary (n = 196) or revision (n = 28) ACL reconstruction were included. The presence of a ramp lesion was determined by a systematic arthroscopic inspection of the posteromedial compartment. Chi-square tests were used to compare the population of ACL-injured patients with and without a ramp lesion regarding sex, age, body mass index, previous ACL injuries, sport before injury, and injury characteristics. Significance was set at p < 0.05. RESULTS: Fifty-three out of 224 patients had a ramp lesion (24%). The presence of the latter was not related to any of the analysed patient characteristics. The prevalence of the lesion was higher in contact injuries (n = 19; 41%) compared with non-contact injures (n = 34; 19%; p < 0.001). It was higher in patients with complete ACL ruptures (n = 49; 27%) as opposed to partial ruptures (n = 1; 4%; p = 0.01). A patient was 2.98 [95% CI 1.49-5.98] times more likely to have a ramp lesion if the ACL injury was declared to have been caused by direct contact and 8.71 [95% CI 1.15-66.12] times more likely if the ACL tear was complete. CONCLUSION: Ramp lesions may be anticipated in almost one out of four patients undergoing ACL reconstruction, especially if a patient sustained a contact injury and in the presence of a complete ACL tear. LEVEL OF EVIDENCE: III. PMID- 28638971 TI - Longer duration of operative time enhances healing metabolites and improves patient outcome after Achilles tendon rupture surgery. AB - PURPOSE: The relationship between the duration of operative time (DOT), healing response and patient outcome has not been previously investigated. An enhanced healing response related to DOT may potentiate repair processes, especially in hypovascular and sparsely metabolized musculoskeletal tissues such as tendons. This study aimed to investigate the association between DOT and the metabolic healing response, patient-reported outcome and the rate of post-operative complications after acute Achilles tendon injury. METHODS: Observational cohort, cross-sectional study with observers blinded to patient grouping. A total of two hundred and fifty-six prospectively randomized patients (210 men, 46 women; mean age 41 years) with an acute total Achilles tendon rupture all operated on with uniform anaesthetic and surgical technique were retrospectively assessed. At 2 weeks post-operatively, six metabolites were quantified using microdialysis. At 3, 6 and 12 months, patient-reported pain, walking ability and physical activity were examined using self-reported questionnaires, Achilles tendon total rupture score, foot and ankle outcome score and physical activity scale. At 12 months, functional outcome was assessed using the heel-rise test. Complications, such as deep venous thrombosis, infections and re-operations, were recorded throughout the study. RESULTS: Patients who underwent longer DOT exhibited higher levels of glutamate (p = 0.026) and glycerol (p = 0.023) at 2 weeks. At the 1-year follow up, longer DOT was associated with significantly less loss in physical activity (p = 0.003), less pain (p = 0.009), less walking limitations (p = 0.022) and better functional outcome (p = 0.014). DOT did not significantly correlate with the rate of adverse events, such as deep venous thrombosis, infections or re ruptures. Higher glutamate levels were associated with less loss in physical activity (p = 0.017). All correlations were confirmed by multiple linear regressions taking confounding factors into consideration. CONCLUSION: The results from this study suggest a previously unknown mechanism, increased metabolic response associated with longer DOT, which may improve patient outcome after Achilles tendon rupture surgery. Allowing for a higher amount of traumatized tissue, as reflected by up-regulation of glycerol in patients with longer DOT, may prove to be an important surgical tip for stimulation of repair of hypometabolic soft tissue injuries, such as Achilles tendon ruptures. LEVEL OF EVIDENCE: II. PMID- 28638972 TI - Isolation of two new retrotransposon sequences and development of molecular and cytological markers for Dasypyrum villosum (L.). AB - Dasypyrum villosum is a valuable genetic resource for wheat improvement. With the aim to efficiently monitor the D. villosum chromatin introduced into common wheat, two novel retrotransposon sequences were isolated by RAPD, and were successfully converted to D. villosum-specific SCAR markers. In addition, we constructed a chromosomal karyotype of D. villosum. Our results revealed that different accessions of D. villosum showed slightly different signal patterns, indicating that distribution of repeats did not diverge significantly among D. villosum accessions. The two SCAR markers and FISH karyotype of D. villosum could be used for efficient and precise identification of D. villosum chromatin in wheat breeding. PMID- 28638973 TI - A retrospective observational cohort study investigating the association between acute kidney injury and all-cause mortality among patients undergoing endovascular repair of abdominal aortic aneurysms. AB - BACKGROUND: Acute kidney injury (AKI) has been found to be associated with short- and long-term mortality and morbidity in various clinical settings. However, it is unknown whether AKI after endovascular repair of abdominal aortic aneurysms (EVAR) is associated with postoperative mortality. METHODS: This observational study analyzed patients who underwent EVAR. The primary outcome was all-cause mortality. The outcomes of patients with and without postoperative AKI were compared using the Kaplan-Meier method and log-rank test. Factors with P < 0.05 on the univariate analysis were entered into the multivariate Cox regression model. Predictors of AKI were also determined using Cox univariate and multivariate analysis. The identified predictors of AKI were excluded from multivariate analysis for all-cause mortality because these factors could intermediate outcome. RESULTS: There were 490 eligible patients. After a follow up of 28.3 (16.8) months [mean (standard deviation)], 62 patients (12.7%) died. AKI occurred in 59 patients (12.0%). AKI was found by the log-rank test to be associated with a significant increase of all-cause mortality (P < 0.001). Preoperative estimated glomerular filtration rate, preoperative peripheral vascular disease, and emergency surgery were found to be independent predictors of AKI and these variables were excluded from the main analysis. Multivariate analysis showed AKI [hazard ratio (HR) = 1.19, 95% confidence interval (CI) 1.01 3.60, P = 0.045] and transfusion (HR = 1.05, 95% CI 1.01-1.09, P = 0.011) were independent predictors of mortality. CONCLUSIONS: In the present study, AKI and transfusion were associated with significant increases in all-cause mortality after EVAR. PMID- 28638974 TI - Categorical templates are more useful when features are consistent: Evidence from eye movements during search for societally important vehicles. AB - Unlike in laboratory visual search tasks-wherein participants are typically presented with a pictorial representation of the item they are asked to seek out in real-world searches, the observer rarely has veridical knowledge of the visual features that define their target. During categorical search, observers look for any instance of a categorically defined target (e.g., helping a family member look for their mobile phone). In these circumstances, people may not have information about noncritical features (e.g., the phone's color), and must instead create a broad mental representation using the features that define (or are typical of) the category of objects they are seeking out (e.g., modern phones are typically rectangular and thin). In the current investigation (Experiment 1), using a categorical visual search task, we add to the body of evidence suggesting that categorical templates are effective enough to conduct efficient visual searches. When color information was available (Experiment 1a), attentional guidance, attention restriction, and object identification were enhanced when participants looked for categories with consistent features (e.g., ambulances) relative to categories with more variable features (e.g., sedans). When color information was removed (Experiment 1b), attention benefits disappeared, but object recognition was still better for feature-consistent target categories. In Experiment 2, we empirically validated the relative homogeneity of our societally important vehicle stimuli. Taken together, our results are in line with a category-consistent view of categorical target templates (Yu, Maxfield, & Zelinsky in, Psychological Science, 2016. doi: 10.1177/0956797616640237 ), and suggest that when features of a category are consistent and predictable, searchers can create mental representations that allow for the efficient guidance and restriction of attention as well as swift object identification. PMID- 28638975 TI - Does grasping capacity influence object size estimates? It depends on the context. AB - Linkenauger, Witt, and Proffitt (Journal of Experimental Psychology: Human Perception and Performance, 37(5), 1432-1441, 2011, Experiment 2) reported that right-handers estimated objects as smaller if they intended to grasp them in their right rather than their left hand. Based on the action-specific account, they argued that this scaling effect occurred because participants believed their right hand could grasp larger objects. However, Collier and Lawson (Journal of Experimental Psychology: Human Perception and Performance, 43(4), 749-769, 2017) failed to replicate this effect. Here, we investigated whether this discrepancy in results arose from demand characteristics. We investigated two forms of demand characteristics: altering responses following conscious hypothesis guessing (Experiments 1 and 2), and subtle influences of the experimental context (Experiment 3). We found no scaling effects when participants were given instructions which implied the expected outcome of the experiment (Experiment 1), but they were obtained when we used unrealistically explicit instructions which gave the exact prediction made by the action-specific account (Experiment 2). Scaling effects were also found using a context in which grasping capacity could seem relevant for size estimation (by asking participants about the perceived graspability of an object immediately before asking about its size on every trial, as was done in Linkenauger et al., 2011; Experiment 2). These results suggest that demand characteristics due to context effects could explain the scaling effects reported in Experiment 2 of Linkenauger et al. (2011), rather than either hypothesis guessing, or, as proposed by the action-specific account, a change in the perceived size of objects. PMID- 28638977 TI - SPECT/CT and PET/CT molecular imaging in medullary thyroid carcinoma. Are we running in the right direction? PMID- 28638976 TI - LILRB receptor-mediated regulation of myeloid cell maturation and function. AB - The leukocyte immunoglobulin-like receptor (LILR) family comprises a set of paired immunomodulatory receptors expressed among human myeloid and lymphocyte cell populations. While six members of LILR subfamily A (LILRA) associate with membrane adaptors to signal via immunoreceptor tyrosine-based activating motifs (ITAM), LILR subfamily B (LILRB) members signal via multiple cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). Ligand specificity of some LILR family members has been studied in detail, but new perspective into the immunoregulatory aspects of this receptor family in human myeloid cells has been limited. LILRB receptors and the murine ortholog, paired immunoglobulin-like receptor B (PIRB), have been shown to negatively regulate maturation pathways in myeloid cells including mast cells, neutrophils, dendritic cells, as well as B cells. Our laboratory further demonstrated in mouse models that PIRB regulated functional development of myeloid-derived suppressor cell and the formation of a tumor-permissive microenvironment. Based on observations from the literature and our own studies, our laboratory is focusing on how LILRs modulate immune homeostasis of human myeloid cells and how these pathways may be targeted in disease states. Integrity of this pathway in tumor microenvironments, for example, permits a myeloid phenotype that suppresses antitumor adaptive immunity. This review presents the evidence supporting a role of LILRs as myeloid cell regulators and ongoing efforts to understand the functional immunology surrounding this family. PMID- 28638978 TI - Screening score for early detection of cardio-metabolic risk in Indian adults. AB - OBJECTIVES: To develop and to evaluate efficacy of screening score for early detection of cardio-metabolic risk (CMR) in adults. METHODS: Cross-sectional data on anthropometry, lipids, sugar levels, diet, and physical activity were collected on 720 adults (361 men, 35-50 year) using standardized techniques. Screening score was developed using regression analysis-cluster of risk conditions (blood pressure, lipids, and sugar levels) was dependent variable against age, sex, waist, diet, and physical activity as independent variables. Odd ratios were added to obtain final score and receiver-operating characteristic (ROC) curves were constructed to identify cut-off value of CMR score. RESULTS: Mean age and BMI were 42.7 +/- 9.4 years and 25.7 +/- 5.0 kg/m2. Analysis showed age, male sex, waist, lack of fruits, green leafy vegetables, and lack of physical activity were independent predictors for increased CMR (p < 0.05). Total score ranged from 0 to 20. Area under the curve for ROC was 0.728 [95% (CI) 0.67 0.78]. Criterion value >8 had sensitivity (76%) and specificity (56%) for screening cases with CMR. CONCLUSIONS: Screening score is a pragmatic way of identifying individuals with CMR without performing biochemical tests. Cost effective community screening programs may be planned. PMID- 28638980 TI - First report of typical Brazilian Toxoplasma gondii genotypes from isolates of free-range chickens (Gallus gallus domesticus) circulating in the state of Paraiba, Northeast Brazil. AB - This study evaluated, for the first time, the genetic diversity of Toxoplasma gondii isolates from free-range chickens from the state of Paraiba, Northeast Brazil. Tissue samples from 33 chickens from properties in five municipalities of Paraiba (Esperanca, Olho d'Agua, Malta, Monteiro, and Patos) were bioassayed in mice. The brains of mice infected with T. gondii cysts were used for DNA extraction and genotyping. Genotyping was performed using 11 PCR-RFLP markers and 15 microsatellite (MS) markers. Complete genotyping results were obtained for 29 isolates, with nine genotypes detected by RFLP and 15 genotypes identified by MS. Three genotypes (#273, #274, and #277) have only been recently identified from pigs in the region. Brazilian clonal types BrII and BrIII were identified from one isolate each. Clonal types I, II, and III were not detected by RFLP. Genotype #13 (Caribbean 1), detected in 48.3% (14/29) of isolates from four of the five municipalities investigated, was the most prevalent genotype in the state of Paraiba. However, the MS analysis showed that of these 14 isolates, only four were unique genotypes, and considering the distance between the municipalities from where they were collected, it is possible that only seven are independent isolates while the others are clones. The other genotypes were restricted to different microregions. The results indicate that the Caribbean 1 lineage of T. gondii is circulating widely in Northeast Brazil. The genotypic diversity of T. gondii in the state of Paraiba is high, and microsatellite analysis revealed this diversity with higher resolution than PCR-RFLP. PMID- 28638979 TI - Endocytosis is required for exocytosis and priming of respiratory burst activity in human neutrophils. AB - OBJECTIVE AND DESIGN: Neutrophil generation of reactive oxygen species (ROS) is enhanced by exposure to pro-inflammatory agents in a process termed priming. Priming is depending on exocytosis of neutrophil granules and p47phox phosphorylation-dependent translocation of cytosolic NADPH oxidase components. Clathrin-mediated endocytosis was recently reported to be necessary for priming, but the mechanism linking endocytosis to priming was not identified. The present study examined the hypothesis that endocytosis regulates neutrophil priming by controlling granule exocytosis. MATERIALS AND METHODS: Clathrin-mediated endocytosis by isolated human neutrophils was inhibited by chlorpromazine, monodansylcadaverine, and sucrose. Exocytosis of granule subsets was measured as release of granule components by ELISA or chemiluminescence. ROS generation was measured as extracellular release of superoxide as reduction of ferrocytochrome c. p38 MAPK activation and p47phox phosphorylation were measured by immunoblot analysis. Statistical analysis was performed using a one-way ANOVA with the Tukey Kramer multiple-comparison test. RESULTS: Inhibition of endocytosis prevented priming of superoxide release by TNFalpha and inhibited TNFalpha stimulation and priming of exocytosis of all four granule subsets. Inhibition of endocytosis did not reduce TNFalpha-stimulated p38 MAPK activation or p47phox phosphorylation. Inhibition of NADPH oxidase activity blocked TNFalpha stimulation of secretory vesicle and gelatinase granule exocytosis. CONCLUSIONS: Endocytosis is linked to priming of respiratory burst activity through ROS-mediated control of granule exocytosis. PMID- 28638981 TI - Use of systemic glucocorticoids and the risk of major osteoporotic fractures in patients with sarcoidosis. AB - : This study revealed the risk of major osteoporotic fracture in patients with sarcoidosis exposed to glucocorticoids. Current use of glucocorticoids was associated with a risk of fracture, with no difference between patients with and without sarcoidosis. Sarcoidosis per se was not associated with an increased fracture risk. INTRODUCTION: Sarcoidosis is a multi-organ, chronic inflammatory, granulomatous disorder that most frequently affects the lungs, lymph nodes, skin, eyes, and liver, but may occur in any organ, including the bones. While oral glucocorticoids (GCs) are commonly used as initial treatment, little is known about the risk of major osteoporotic fractures in patients with sarcoidosis exposed to GCs. METHODS: A case-control study was conducted using the Danish National Hospital Discharge Registry (NHDR) between January 1995 and December 2011. Conditional logistics regression models were used to derive adjusted odds ratios (OR) of major osteoporotic fractures in subjects with and without sarcoidosis stratified by average daily and cumulative dose exposures. RESULTS: A total of 376,858 subjects with a major osteoporotic fracture and the same number of subjects without this event were identified (mean age 64.2 +/- 19.5 years, 69% female). In patients with sarcoidosis (n = 124), current use of GC was associated with an increased risk of major osteoporotic fracture (adjusted (adj.) OR 1.74; 95% CI 1.17-2.58), which dropped to baseline levels after discontinuation. In subjects without sarcoidosis, this risk was comparable (adj. OR 1.36; 95% CI 1.32 1.40). In sarcoidosis patients, cumulative dose 1.0-4.9 g and >10 g prednisolone equivalents were associated with increased risk of major osteoporotic fracture (adj. OR 2.75; 95% CI 1.06-7.14 and 2.22; 95% CI 1.17-4.22, respectively), whereas a cumulative dose of <1.0 g and 5.0-9.9 g was not associated with major osteoporotic fracture risk. CONCLUSION: Both in subjects with and without sarcoidosis, current expose to GC is associated with increased risk of major osteoporotic fractures, with no between-group difference. Sarcoidosis per se was not associated with increased fracture risk. Having sarcoidosis per se, i.e., if not treated with GC, is not a risk factor for fracture, and such patients may only need risk assessment when they commence GC therapy. PMID- 28638982 TI - Image quality at synthetic brain magnetic resonance imaging in children. AB - BACKGROUND: The clinical application of the multi-echo, multi-delay technique of synthetic magnetic resonance imaging (MRI) generates multiple sequences in a single acquisition but has mainly been used in adults. OBJECTIVE: To evaluate the image quality of synthetic brain MR in children compared with that of conventional images. MATERIALS AND METHODS: Twenty-nine children (median age: 6 years, range: 0-16 years) underwent synthetic and conventional imaging. Synthetic (T2-weighted, T1-weighted and fluid-attenuated inversion recovery [FLAIR]) images with settings matching those of the conventional images were generated. The overall image quality, gray/white matter differentiation, lesion conspicuity and image degradations were rated on a 5-point scale. The relative contrasts were assessed quantitatively and acquisition times for the two imaging techniques were compared. RESULTS: Synthetic images were inferior due to more pronounced image degradations; however, there were no significant differences for T1- and T2 weighted images in children <2 years old. The quality of T1- and T2-weighted images were within the diagnostically acceptable range. FLAIR images showed greatly reduced quality. Gray/white matter differentiation was comparable or better in synthetic T1- and T2-weighted images, but poorer in FLAIR images. There was no effect on lesion conspicuity. Synthetic images had equal or greater relative contrast. Acquisition time was approximately two-thirds of that for conventional sequences. CONCLUSION: Synthetic T1- and T2-weighted images were diagnostically acceptable, but synthetic FLAIR images were not. Lesion conspicuity and gray/white matter differentiation were comparable to conventional MRI. PMID- 28638983 TI - Treatment of benign thyroid nodules by high intensity focused ultrasound (HIFU) at different acoustic powers: a study on in-silico phantom. AB - BACKGROUND: The non-surgical therapies of benign thyroid nodules are gaining momentum due to the possibility to reduce the nodule's volume and avoid surgery. As the last technique introduced, high intensity focused ultrasound allows the thermal tissue treatment by directing energy inside the targeted nodule with no invasive instruments. In the present study we applied the Food and Drug Administration high intensity focused ultrasound simulator to in-silico phantom to evaluate the effects obtained by different acoustic powers. METHODS: The simulated layers were water and thyroid tissue. The source was a spherically curved circular transducer with radius r = 2.3 cm generating a continuous wave beam at a frequency of 3 MHz. The focal distance was 6.5 cm. The sequence included a pulse (8 s) with acoustic power at different value from 5 to 50 W, and a cooling-off interval (32 s). RESULTS: The use of acoustic power of 5 W allowed to achieve the threshold of temperature for coagulative necrosis (55 degrees C) at 1 s. The simulation with 50 W showed that temperature was significantly higher (above 300 degrees C) at 1 s and is maintained at high levels for a long interval. CONCLUSION: Since 2016, we treated patients according to the present experience, and a significant reduction of nodule's volume was observed with good patent's comfort and no complications (unpublished data). Also, no anesthesia was practiced. We feel that the present data could contribute to develop a high intensity focused ultrasound therapy of benign thyroid nodules free from potential complications. PMID- 28638984 TI - Associations of aldosterone and renin concentrations with inflammation-the Study of Health in Pomerania and the German Conn's Registry. AB - PURPOSE: Chronic inflammation is an age-independent and body mass index independent contributor to the development of multi-morbidity. Alterations of the renin-angiotensin-aldosterone system are observed within the context of proinflammatory states. We assessed circulating aldosterone, renin, and inflammatory biomarker concentrations in healthy, normotensive subjects and patients with primary aldosteronism. METHODS: We included 1177 normotensive individuals from the population-based Study of Health in Pomerania (first follow up, Study of Health in Pomerania-1) and 103 primary aldosteronism patients from the German Conn's Registry. A 1:1 matching for sex, age, body mass index, smoking status, diabetes mellitus, and the estimated glomerular filtration rate was performed to determine whether primary aldosteronism patients exhibit higher inflammatory biomarker concentrations than normotensive controls. The associations of plasma aldosterone concentration or plasma renin concentration with circulating fibrinogen concentrations, white blood cell count, and high sensitive C-reactive protein concentrations in the normotensive sample were determined with multivariable linear and logistic regression analyses. RESULTS: 1:1 matched primary aldosteronism patients demonstrated significantly (p < 0.01) higher plasma aldosterone concentration (198 vs. 47 ng/l), lower plasma renin concentration (3.1 vs. 7.7 ng/l) and higher high sensitive C-reactive protein concentrations (1.5 vs. 1.0 mg/l) than normotensive controls. Within the normotensive cohort, plasma renin concentration but not plasma aldosterone concentration was positively associated with fibrinogen concentrations and white blood cell count. Further, a J-shaped association between plasma renin concentration and high sensitive C-reactive protein concentrations was detected. CONCLUSIONS: High plasma aldosterone concentration in a primary aldosteronism cohort and high plasma renin concentration in normotensive subjects are associated with increased concentrations of inflammatory biomarkers. This suggests a link between the renin-angiotensin-aldosterone system and inflammatory processes in patients with primary aldosteronism and even in normotensive subjects. PMID- 28638985 TI - Glucuronidation of deoxynivalenol (DON) by different animal species: identification of iso-DON glucuronides and iso-deepoxy-DON glucuronides as novel DON metabolites in pigs, rats, mice, and cows. AB - The Fusarium mycotoxin deoxynivalenol (DON) is a frequent contaminant of cereal based food and feed. Mammals metabolize DON by conjugation to glucuronic acid (GlcAc), the extent and regioselectivity of which is species-dependent. So far, only DON-3-glucuronide (DON-3-GlcAc) and DON-15-GlcAc have been unequivocally identified as mammalian DON glucuronides, and DON-7-GlcAc has been proposed as further DON metabolite. In the present work, qualitative HPLC-MS/MS analysis of urine samples of animals treated with DON (rats: 2 mg/kg bw, single bolus, gavage; mice: 1 mg/kg bw, single i.p. injection; pigs: 74 ug/kg bw, single bolus, gavage; cows: 5.2 mg DON/kg dry mass, oral for 13 weeks) revealed additional DON and deepoxy-DON (DOM) glucuronides. To elucidate their structures, DON and DOM were incubated with human (HLM) and rat liver microsomes (RLM). Besides the expected DON/DOM-3- and 15-GlcAc, minor amounts of four DON- and four DOM glucuronides were formed. Isolation and enzymatic hydrolysis of four of these compounds yielded iso-DON and iso-DOM, the identities of which were eventually confirmed by NMR. Incubation of iso-DON and iso-DOM with RLM and HLM yielded two main glucuronides for each parent compound, which were isolated and identified as iso-DON/DOM-3-GlcAc and iso-DON/DOM-8-GlcAc by NMR. Iso-DON-3-GlcAc, most likely misidentified as DON-7-GlcAc in the literature, proved to be a major DON metabolite in rats and a minor metabolite in pigs. In addition, iso-DON-8-GlcAc turned out to be one of the major DON metabolites in mice. DOM-3-GlcAc was the dominant DON metabolite in urine of cows and an important DON metabolite in rat urine. Iso-DOM-3-GlcAc was detected in urine of DON-treated rats and cows. Finally, DON-8,15-hemiketal-8-glucuronide, a previously described by-product of DON-3-GlcAc production by RLM, was identified in urine of DON-exposed mice and rats. The discovery of several novel DON-derived glucuronides in animal urine requires adaptation of the currently used methods for DON-biomarker analysis. PMID- 28638986 TI - Effect of electrode potentials on the microbial community of photo bioelectrochemical systems. AB - Increasing attention is being paid to the adoption of photoautotrophic microbes in bioelectrochemical systems (BESs) because of the advantages of self sustainability. Biased potential on the anode was capable of adjusting the performance of non-photo BESs, and the microbial community structure was also changed; however, few studies have been conducted to investigate the effects of potential on microbial community structure in photo-BESs. In this work, the response of microbial community structure to different potentials (i.e., 0, 0.2, 0.4 and 0.6 V vs. Ag/AgCl) was characterized with 454 pyrosequencing. Four samples were collected and they generated 42865 16S rDNA sequencing reads with an average length of 429 bp. The potential at 0.2 V resulted in the highest current density (378.8 mA m-2) and showed a strong selection for gamma-proteobacteria (30.8% of the sequences). alpha-Diversity analysis showed that microbial diversity increased with increased potential. Rhodopseudomonas palustris was dominant among known exoelectrogens in the biofilm biased at 0.4 V. The results provided an insight into the mechanism of potential regulation on the performance of photo-BESs and changes in microbial community structure. PMID- 28638988 TI - Same-day genomic and epigenomic diagnosis of brain tumors using real-time nanopore sequencing. AB - Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis, and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous system tumors, the current World Health Organization classification explicitly demands molecular testing, e.g., for 1p/19q-codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making. Here, we explored the potential of a pocket-size nanopore sequencing device for multimodal and rapid molecular diagnostics of cancer. Low pass whole genome sequencing was used to simultaneously generate copy number (CN) and methylation profiles from native tumor DNA in the same sequencing run. Single nucleotide variants in IDH1, IDH2, TP53, H3F3A, and the TERT promoter region were identified using deep amplicon sequencing. Nanopore sequencing yielded ~0.1X genome coverage within 6 h and resulting CN and epigenetic profiles correlated well with matched microarray data. Diagnostically relevant alterations, such as 1p/19q codeletion, and focal amplifications could be recapitulated. Using ad hoc random forests, we could perform supervised pan-cancer classification to distinguish gliomas, medulloblastomas, and brain metastases of different primary sites. Single nucleotide variants in IDH1, IDH2, and H3F3A were identified using deep amplicon sequencing within minutes of sequencing. Detection of TP53 and TERT promoter mutations shows that sequencing of entire genes and GC-rich regions is feasible. Nanopore sequencing allows same-day detection of structural variants, point mutations, and methylation profiling using a single device with negligible capital cost. It outperforms hybridization-based and current sequencing technologies with respect to time to diagnosis and required laboratory equipment and expertise, aiming to make precision medicine possible for every cancer patient, even in resource-restricted settings. PMID- 28638989 TI - Parietal white matter lesions in Alzheimer's disease are associated with cortical neurodegenerative pathology, but not with small vessel disease. AB - Cerebral white matter lesions (WML) encompass axonal loss and demyelination, and the pathogenesis is assumed to be small vessel disease (SVD)-related ischemia. However, WML may also result from the activation of Wallerian degeneration as a consequence of cortical Alzheimer's disease (AD) pathology, i.e. hyperphosphorylated tau (HPtau) and amyloid-beta (Abeta) deposition. WML seen in AD have a posterior predominance compared to non-demented individuals but it is unclear whether the pathological and molecular signatures of WML differ between these two groups. We investigated differences in the composition and aetiology of parietal WML from AD and non-demented controls. Parietal WML tissue from 55 human post-mortem brains (AD, n = 27; non-demented controls, n = 28) were quantitatively assessed for axonal loss and demyelination, as well as for cortical HPtau and Abeta burden and SVD. Biochemical assessment included Wallerian degeneration protease calpain and the myelin-associated glycoprotein (MAG) to proteolipid protein (PLP) ratio (MAG:PLP) as a measure of hypoperfusion. WML severity was associated with both axonal loss and demyelination in AD, but only with demyelination in controls. Calpain was significantly increased in WML tissue in AD, whereas MAG:PLP was significantly reduced in controls. Calpain levels were associated with increasing amounts of cortical AD-pathology but not SVD. We conclude that parietal WML seen in AD differ in their pathological composition and aetiology compared to WML seen in aged controls: WML seen in AD may be associated with Wallerian degeneration that is triggered by cortical AD pathology, whereas WML in aged controls are due to ischaemia. Hence, parietal WML as seen on MRI should not invariably be interpreted as a surrogate biomarker for SVD as they may be indicative of cortical AD-pathology, and therefore, AD should also be considered as the main underlying cause for cognitive impairment in cases with parietal WML. PMID- 28638987 TI - Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. AB - Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies. PMID- 28638990 TI - Pharmacological intervention of MKL/SRF signaling by CCG-1423 impedes endothelial cell migration and angiogenesis. AB - De novo synthesis of cytoskeleton-regulatory proteins triggered by the megakaryoblastic leukemia (MKL)/serum response factor (SRF) transcriptional system in response to pro-angiogenic growth factors lies at the heart of endothelial cell (EC) migration (a critical element of angiogenesis) and neovascularization. This study explores whether pharmacological intervention of MKL/SRF signaling axis by CCG-1423 is able to suppress angiogenesis. Our studies show that CCG-1423 inhibits migration and cord morphogenesis of EC in vitro and sprouting angiogenesis ex vivo and in vivo, suggesting CCG-1423 could be a novel anti-angiogenic agent. Kymography analyses of membrane dynamics of EC revealed that CCG-1423 treatment causes a major defect in membrane protrusion. CCG-1423 treatment led to attenuated expression of several actin-binding proteins that are important for driving membrane protrusion including ArpC2, VASP, and profilin1 (Pfn1) with the most drastic effect seen on the expression of Pfn1. Finally, depletion of Pfn1 alone is also sufficient for a dramatic decrease in sprouting angiogenesis of EC in vitro and ex vivo, further suggesting that Pfn1 depletion may be one of the mechanisms of the anti-angiogenic action of CCG-1423. PMID- 28638992 TI - A QM/MM study on the enzymatic inactivation of cefotaxime. AB - The reaction between the antibiotic cefotaxime and the CTX-M-14 class A serine hydrolase is addressed from a theoretical point of view, by means of hybrid quantum mechanics/molecular mechanical (QM/MM) calculations, adopting a new approach that postulates that the residue Ser70 itself should play the role of the acid-base species required for the cefotaxime acylation. The proposed mechanism differs from earlier proposals existing in literature for other class A beta-lactamases. The results confirm the hypothesis, and show that the reaction should occur via a concerted mechanism in which the acylation of the lactam carbonyl carbon, protonation of the N7 lactam atom, and opening of the beta lactam ring occurs simultaneously. Exploration of the potential energy surface shows three critical points, associated with reactants, transition state and product. The transition state is characterized by frequency, intrinsic reaction coordinate, atomic charge, and bond orders calculations. The calculated activation barrier is 20 kcal mol-1, and the reaction appears to be slightly endothermic by about 12 kcal mol-1. We conclude that this approach is feasible, and should be considered as an alternative mechanism or may exist in competition with others already published in the literature. This information should be useful for the design of novel antibiotics and beta-lactamase inhibitors. Graphical abstract Three-dimensional view of the potential energy surface of cefotaxime. PMID- 28638991 TI - Integrating Tinbergen's inquiries: Mimicry and play in humans and other social mammals. AB - Visual signals convey emotions and intentions between individuals. Darwin underlined that human facial expressions represent a shared heritage between our species and many other social mammals. Social play is a fertile field to examine the role and the potential communicative function of facial expressions. The relaxed open-mouth (or play face) is a context-specific playful expression, which is widespread in human and non-human mammals. Here, we focus on playful communication by applying Tinbergen's four areas of inquiry: proximate causation, ontogeny, function, and evolution. First of all we explore mimicry by focusing on its neural substrates and factors of modulation within playful and non-playful context (proximate causation). Play face is one of the earliest facial expressions to appear and be mimicked in neonates. The motor resonance between infants and their caregivers is essential later in life when individuals begin to engage in increasingly complex social interactions, including play (ontogeny). The success of a playful session can be evaluated by its duration in time. Mirroring facial expressions prolongs the session by favoring individuals to fine tune their own motor sequences accordingly (function). Finally, through a comparative approach we also demonstrate that the elements constituting play communication and mimicry are sensitive to the quality of interindividual relationships of a species, thus reflecting the nature of its social network and style (evolution). In conclusion, our goal is to integrate Tinbergen's four areas of ethological inquiry to provide a broader framework regarding the importance of communication and mimicry in the play domain of humans and other social mammals. PMID- 28638993 TI - Discrepancy in socioeconomic status does not fully explain the variation in diet quality between consumers of different coffee types. AB - PURPOSE: Habitual consumers of different coffee types may vary in socioeconomic status (SES), which is an important determinant of diet quality. Nonetheless, research on diet quality among coffee consumers was scarce. We aimed to compare the diet quality of coffee consumers with different preferences towards coffee type and additive usage. METHODS: In this cross-sectional analysis, intake data of food, coffee, and additive usage from the adult respondents of the 2011-2012 Australian Health Survey were used. Participants were grouped according to the type of coffee (espresso and ground coffee, E&G; coffee made from coffee mixes and instant coffee, M&I; non-consumers, NC) and additives (milk, sugar, and intense sweetener) consumed. Adjusted food group intake was compared between consumption groups using general linear model. RESULTS: E&G drinkers had better SES than M&I and NC. After adjusting for covariates, the mean dairy intake of E&G drinkers was 22.2% higher than M&I drinkers (p < 0.001) and 33.1% higher than NC (p < 0.001). Mean discretionary food intake of E&G drinkers was 12.1% lower than M&I (p = 0.003) and 12.3% lower than NC (p = 0.001). In terms of additive usage, non-users of coffee additive had the lowest dairy food intake and the highest discretionary food intake. CONCLUSIONS: Coffee consumers' different preferences towards coffee type and additive usages reflected significant variations in their diet quality, even after adjustment of SES. Therefore, future epidemiological studies should consider separating coffee drinkers according to their habitual consumption of different types of coffee. PMID- 28638994 TI - Adherence to Mediterranean diet in relation to bone mineral density and risk of fracture: a systematic review and meta-analysis of observational studies. AB - PURPOSE: We aimed to systematically review available data on the association between adherence to MD and BMD as well as risk of fractures and to summarize this information through a meta-analysis. METHODS: Previous studies in the field of adherence to MD in relation to BMD and risk of fracture were selected through searching PubMed, Scopus, ISI Web of Science and Google Scholar databases prior to June, 2016 using Mesh and non-Mesh relevant keywords. RESULTS: In the meta analysis of four effect sizes, obtained from three studies, we found that adherence to MD was associated with a 21% reduced risk of hip fracture (overall RR 0.79; 95% CIs 0.72-0.87). Adherence to MD was positively associated with lumber spine's (mean difference of BMD comparing highest and lowest categories of MD score 0.12; 95% CI 0.06-0.19 g/cm2), femoral neck (0.10; 0.06-0.15 g/cm2) and total hip (0.11; 0.09-0.14 g/cm2) BMD. Meta-regression of included observational studies revealed a significant inverse linear association between Mediterranean diet score and risk of hip fracture, such that one unit increase in the score of Mediterranean diet was associated with a reduction in the risk of hip fracture (RR 0.95, 95% CI 0.92-0.98 p = 0.01). CONCLUSION: Adherence to MD was associated with a reduced risk of fracture as well as with a higher mean BMD. PMID- 28638995 TI - Transport of long-chain polyunsaturated fatty acids in preterm infant plasma is dominated by phosphatidylcholine. AB - BACKGROUND: Docosahexaenoic (C22:6) and arachidonic (C20:4) acids are long-chain polyunsaturated fatty acids (LC-PUFA) essential to neonatal development, being present in the glycerophospholipids of all organs, particularly the brain. In plasma, LC-PUFAs are mainly present in lipoprotein lipids, which are neutral lipids (triglycerides and cholesterol esters) and glycerophospholipids, like choline containing phosphatidylcholine (PC). PURPOSE: To guide future supplementation strategies of C22:6 and C20:4 in combination with choline, we determined the distribution of C20:4 and C22:6 between PC and neutral lipid. METHODS: Preterm infant plasma (N = 59, postmenstrual age [PMA] 33.9 wk (32.4 36.0)) and cord plasma (N = 34, PMA 34.0 wk (30.86-38.4)) were investigated. PC and neutral lipids were extracted and analyzed using tandem mass spectrometry and gas chromatography, respectively. Data are reported as medians and 25th/75th percentiles. RESULTS: In cord blood, C20:4-PC and C22:6-PC comprised 36.1% (34.2 38.6) and 10.2% (8.8-12.8) of total PC, respectively. In preterm infant plasma, values were only 20.8% (19.2-23.1) and 5.7% (5.2-6.0), respectively (p < 0.001 each). Nevertheless, in preterm infant plasma, 80.6% (77.6-83.0) of C20:4 and 86.0% (83.0-88.9) of C22:6 were found in PC. These values exceeded the proportions of C20:4 and C22:6 in PC of cord plasma [71.3% (67.8-72.9) and 79.2% (75.2-85.4), respectively] (p < 0.0001 each). CONCLUSION: Irrespective of the low proportions of C20:4-PC and C22:6-PC in preterm infant plasma lipids, PC is the major transporter for C20:4 and C22:6. Our data support the hypotheses that choline deficiency may impair end-organ availability of these LC-PUFA in preterm infants. Therefore, supplementation of C20:4 and C22:6 might better be accompanied by choline supplementation. PMID- 28638996 TI - Smooth at one end and rough at the other: influence of object texture on grasping behaviour. AB - When picking up objects using a pinch grip, there are usually numerous places at which one could place the thumb and index finger. Yet, people seem to consistently place them at or close to the centre of mass (COM), presumably to minimize torque and therefore the required grip force. People also prefer to grasp objects by parallel surfaces and ones with higher friction coefficients (rough surfaces), to prevent the object from slipping when they lift it. Here, we examine the trade-off between friction and COM. Participants were asked to grasp and lift aluminium bars of which one end was polished and therefore smooth and the other was rough. Their finger positions were recorded to determine how they grasped the objects. The bars were oriented horizontally in the frontal plane, with the centre aligned with the participants' body midline. The bars varied in the horizontal offset between the COM and the edge of the rough region. The offset could be 0, 1 or 2 cm. We expected participants to grasp closer to the rough area than the centre of the bar. Completely rough bars and completely smooth bars served as control conditions. The slipperiness of the surface that was grasped affected the height of the grasping points, indicating that participants adjusted their grasping behaviour to the slipperiness of the surface. However, the tendency to grasp closer to the rough area was minimal. This shows that the judged COM largely determines how an object is grasped. Friction has very limited influence. PMID- 28638997 TI - Follistatin treatment suppresses SERCA1b levels independently of other players of calcium homeostasis in C2C12 myotubes. AB - Follistatin (FS) is a high affinity activin-binding protein, neutralizing the effects of the Transforming Growth Factor-beta (TGF-beta) superfamily members, as myostatin (MSTN). Since MSTN emerged as a negative regulator, FS has been considered as a stimulator of skeletal muscle growth and differentiation. Here, we studied the effect of FS administration on the Ca2+-homeostasis of differentiating C2C12 skeletal muscle cells. FS-treatment increased the fusion index, the size of terminally differentiated myotubes, and transiently elevated the expression of the calcium-dependent protein phosphatase, calcineurin, at the beginning of differentiation. Functional experiments did not detect any alterations in the Ca2+ transients following the stimulation by KCl or caffeine in myotubes. On the other hand, decreased Ca2+-uptake capability was determined by calculating the maximal pump rate (332 +/- 17 vs. 279 +/- 11 uM/s, in control and FS-treated myotubes, respectively; p < 0.05). In the same way, the expression and ATPase activity of the neonatal sarcoplasmic/endoplasmic reticulum Ca2+ATPase (SERCA1b) were decreased (0.59 +/- 0.01 vs. 0.19 +/- 0.01 mM ATP/min, in control and FS-treated myotubes, respectively; p < 0.05). However, the expression level of other proteins involved in Ca2+-homeostasis and differentiation (calsequestrin, STIM1, MyoD) were not affected. Our results suggest that the FS controlled myotube growth is paralleled with the tight regulation of cytosolic calcium concentration, and the decline of SERCA1b appears to be one of the key components in this process. PMID- 28638998 TI - Italian normative data and validation of two neuropsychological tests of face recognition: Benton Facial Recognition Test and Cambridge Face Memory Test. AB - The Benton Facial Recognition Test (BFRT) and Cambridge Face Memory Test (CFMT) are two of the most common tests used to assess face discrimination and recognition abilities and to identify individuals with prosopagnosia. However, recent studies highlighted that participant-stimulus match ethnicity, as much as gender, has to be taken into account in interpreting results from these tests. Here, in order to obtain more appropriate normative data for an Italian sample, the CFMT and BFRT were administered to a large cohort of young adults. We found that scores from the BFRT are not affected by participants' gender and are only slightly affected by participant-stimulus ethnicity match, whereas both these factors seem to influence the scores of the CFMT. Moreover, the inclusion of a sample of individuals with suspected face recognition impairment allowed us to show that the use of more appropriate normative data can increase the BFRT efficacy in identifying individuals with face discrimination impairments; by contrast, the efficacy of the CFMT in classifying individuals with a face recognition deficit was confirmed. Finally, our data show that the lack of inversion effect (the difference between the total score of the upright and inverted versions of the CFMT) could be used as further index to assess congenital prosopagnosia. Overall, our results confirm the importance of having norms derived from controls with a similar experience of faces as the "potential" prosopagnosic individuals when assessing face recognition abilities. PMID- 28638999 TI - Osteopontin and clusterin levels in type 2 diabetes mellitus: differential association with peripheral autonomic nerve function. AB - Osteopontin (OPN) and clusterin are secreted glycoproteins potentially associated with nerve function. Sudomotor dysfunction is associated with the development of foot ulcerations. The purpose of this study was to investigate the potential relationship of OPN and clusterin with sudomotor function (i.e., autonomic nerves that control sweating) in participants with type 2 diabetes mellitus (T2DM). Sudomotor function was assessed using SUDOSCAN(r) which measures electrochemical skin conductance (ESC) of the hands and feet. Demographics (e.g., age, gender, race, body mass index (BMI)), HbA1c, 25-hydroxyvitamin D, creatinine, OPN, and clusterin were also determined for the participants. Fifty individuals with T2DM (age = 59+/-11 years; 23/27 male/female; 13 African Americans) participated in this study. Lower ESC for the hands and feet were observed in African Americans versus Caucasians/Asians (p < 0.05). No significant ESC differences were observed for good [HbA1c <7%] versus poor [HbA1c >=7%] glycemic control. With regard to gender, ESC values were lower for the hands for females (p < 0.05). In linear regression with ESC for the hands or feet as the dependent variable, increased OPN levels, but not clusterin, were independently associated with reduced sudomotor function while adjusting for age, gender, race, BMI, and glycemic control (ESC hands model R 2 = 0.504, p < 0.001; ESC feet model R 2 = 0.534, p < 0.001). The association between OPN and reduced sudomotor function found in our study warrants further investigation to delineate the underlying mechanisms and determine if OPN is neuroprotective, involved in the pathogenesis of sudomotor dysfunction, or simply a bystander. PMID- 28639000 TI - Infections in Neurocritical Care. AB - Neurointensive care (NICU) patients experience complex infectious disease challenges. Central nervous system (CNS) infections are difficult to diagnose and treat, and post-neurosurgical patients are vulnerable to a unique set of healthcare-acquired infections (HAI) in addition to those typical of critically ill patients. The purpose of this review is to summarize the approach to suspected infection in the NICU and discuss management of several infectious syndromes in the NICU setting. PMID- 28639001 TI - SANGUINATETM (PEGylated Carboxyhemoglobin Bovine) Improves Cerebral Blood Flow to Vulnerable Brain Regions at Risk of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage. AB - BACKGROUND: Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been linked to focal reductions in cerebral blood flow (CBF) and microvascular impairments in oxygen delivery. Effective therapies that restore flow and oxygen transport to vulnerable brain regions are currently lacking. SANGUINATE is a dual-action carbon monoxide-releasing and hemoglobin-based oxygen transfer agent with efficacy in animal models of focal brain ischemia and tolerability in patients with sickle cell disease. METHODS: We performed a safety and proof-of-principle study in 12 SAH patients at risk of DCI across three escalating doses (160, 240, and 320 mg/kg). We used 15O-PET (performed at baseline, after SANGUINATE and at 24 h) to evaluate efficacy for improving CBF and restoring flow-metabolism balance (assessed by oxygen extraction fraction [OEF]) to vulnerable regions (defined as baseline OEF >= 0.50). RESULTS: SANGUINATE resulted in a transient rise in mean arterial pressure (116 +/- 15-127 +/- 13 mm Hg, p = 0.001) that normalized by 24 h and allowed three patients with DCI to be weaned off vasopressors. No adverse events were noted during infusion. Global CBF did not rise (43 +/- 8-46 +/- 9 ml/100 g/min) although a trend was seen at the highest dose (45 +/- 7-51 +/- 9, p = 0.044). However, a significant 16% rise in regional CBF associated with reduction in OEF was seen in vulnerable regions, but did not persist at 24 h. CONCLUSIONS: We demonstrated that this novel agent can improve regional CBF and may improve oxygen supply-demand balance. Clinical studies (likely with repeat dosing) are required to evaluate whether this effect can prevent DCI or cerebral infarction. PMID- 28639002 TI - Risk factors of flare in rheumatoid arthritis patients with both clinical and ultrasonographic remission: a retrospective study from China. AB - Ultrasonographic remission in addition to clinical remission is probably becoming a new target in the treatment of rheumatoid arthritis. The current study aimed to investigate the risk factors of flare in RA patients who achieved both clinical and ultrasonographic remission. RA patients fulfilled both clinical remission and ultrasonographic remissions were retrospectively enrolled in this study. Baseline clinical, laboratory, and ultrasonographic data were collected. Durations of clinical remission before enrollment and medication strategy during follow-up were recorded. Differences between the flare and the non-flare group were analyzed. Risk factors of flare were assessed with univariate and multivariate Cox proportional hazards models. One hundred and twenty-one RA patients were included. Forty-eight patients relapsed during a median follow-up period of 12.3 months. The flare group had higher percentage of females, shorter duration of clinical remission before enrollment, higher baseline ESR and DAS28 (ESR), and lower baseline gray scale score. Univariate Cox regression revealed female, short duration of remission, high DAS28 (ESR), and failure to achieve 2010 ACR/EULAR remission criteria were risk factors of flare. Furthermore, multivariate analysis showed short duration of remission was the only independent risk factor of flare (HR 0.93, 95% CI 0.88-0.98, P = 0.007). One more month in duration of remission led to a reduction in flare of 7.3%. Short duration of remission at baseline could be an independent risk factor of flare in RA patients who achieved both clinical and ultrasonographic remission, which implicates the significance of sustained remission in the prognosis of RA patients. PMID- 28639003 TI - The crucial role of activin A/ALK4 pathway in the pathogenesis of Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation. AB - Atrial fibrosis, the hallmark of structural remodeling associated with atrial fibrillation (AF), is characterized by abnormal proliferation of atrial fibroblasts and excessive deposition of extracellular matrix. Transforming growth factor-beta1 (TGF-beta1)/activin receptor-like kinase 5 (ALK5)/Smad2/3/4 pathway has been reported to be involved in the process. Recent studies have implicated both activin A and its specific downstream component activin receptor-like kinase 4 (ALK4) in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 haplodeficiency attenuated the pressure overload- and myocardial infarction induced ventricular fibrosis. However, the role of activin A/ALK4 in the pathogenesis of atrial fibrosis and vulnerability to AF remains unknown. Our study provided experimental and clinical evidence for the involvement of activin A and ALK4 in the pathophysiology of atrial fibrosis and AF. Patients with AF had higher activin A and ALK4 expression in atriums as compared to individuals devoid of AF. After angiotensin-II (Ang-II) stimulation which mimicked atrial fibrosis progression, ALK4-deficient mice showed lower expression of ALK4 in atriums, reduced activation of atrial fibroblasts, blunted atrial enlargement and atrial fibrosis, and further reduced AF vulnerability upon right atrial electrophysiological studies as compared to wild-type littermates. Moreover, we found that apart from the well-known TGF-beta1/ALK5 pathway, the activation of activin A/ALK4/smad2/3 pathway played an important role in the pathogenesis of Ang-II-mediated atrial fibrosis and inducibility of AF, suggesting that targeting ALK4 might be a potential therapy for atrial fibrosis and AF. PMID- 28639004 TI - The Hair in the Sinus: Sharp-Ended Rootless Head Hair Fragments can be Found in Large Amounts in Pilonidal Sinus Nests. AB - PURPOSE: Hair has been identified as the causative agent of Pilonidal Sinus Disease (PSD). Stiffer, dark hair as well as hairiness has been postulated as causative factors. Astonishingly, despite the early clinical significance of this condition (Hodges in Boston Med Surg J 2:485-486, 1880), macroscopic and microscopic examinations of hair inside pilonidal sinus cavities have been scarce. The purpose of this study was to study the morphological aspects of the hair found in PSD in order to determine the origin of the hair. METHODS: Hair from inside pilonidal sinus cavities was collected intraoperatively from 20 PSD patients. Additionally, occipital, lumbar and intergluteal hair was harvested from the same patients and compared to the hair of volunteer-matched pair patients admitted to the hospital at the same time for non-PSD surgery. Intra- and intergroup variations of hair length were characterized with analysis of variance. Numbers and lengths of pilonidal sinus nest hair were recorded. Hair was examined clinically and with light and scanning electron microscopy using surface enhancing gold and carbon dust coating techniques. RESULTS: Analysis of 624 pilonidal sinus nest hair samples from 20 independent sinus cavities revealed that hair within pilonidal sinus nests is rootless in 74%. Shorter hair was found inside the pilonidal sinus compared to other sites (length 0.9 +/- 0.7 cm p < 0.0001). Furthermore, hair found inside of the sinus was significantly shorter than hair protruding from pores (p < 0.000). Hair samples show razor sharp but no broken or split ends. On electron microscopy, these spiky hair ends resemble cut hair ends. Pilonidal hair nests contained between 1 and over 400 hair fragments. CONCLUSION: Short hair fragments with rootless sharp cut ends were found within pilonidal sinus cavities. Morphologically, these fragments resemble short cut rather than intact body hair. Since short cut hair, e.g., derived from the head potentially enters the pilonidal cavity more easily than longer hair, the source of these cut hair fragments needs to be eliminated when aiming to prevent Pilonidal Sinus Disease. PMID- 28639005 TI - Central Hepatectomy Still Plays an Important Role in Treatment of Early-Stage Centrally Located Hepatocellular Carcinoma. AB - BACKGROUND: Surgical management of centrally located hepatocellular carcinoma (CL HCC) poses a great challenge. Major hepatectomy (MH) might compromise future remnant liver volume (FRLV), while the long-term benefits of central hepatectomy (CH) had not been well demonstrated. METHODS: Consecutive patients with early stage CL-HCC who underwent liver resection were enrolled. Fifteen patients underwent CH, while thirty-three were subjected to MH. All relevant clinicopathological variables were analyzed. Disease-free survival (DFS) and overall survival (OS) of both groups were compared. RESULTS: There were no differences between CH and MH in terms of predisposing liver disease, tumor size, blood loss, complication rate and vascular invasion. Mean FRLV increased from 40.9 to 69.2% by using CH resection lines. The parenchymal transection time is longer in CH. There were no differences of DFS between two groups. The 5-year OS rates of CH and MH were 93.3 and 62.6%, respectively. MH was a poor prognostic factor. CONCLUSIONS: CH is a relatively time-consuming and technique-demanding procedure, but excellent long-term survival could be achieved. CH could increase liver volume preservation without compromising intra-hepatic recurrence. In an endemic area of hepatitis and cirrhosis, CH should still play an important role in surgical treatment of CL-HCC. PMID- 28639007 TI - Is electroconvulsive therapy an evidence-based treatment for catatonia? A systematic review and meta-analysis. AB - We aimed to review and discuss the evidence-based arguments for the efficacy of electroconvulsive therapy (ECT) in the treatment of catatonia. Randomized controlled trials (RCTs) and observational studies focusing on the response to ECT in catatonia were selected in PubMed, the Cochrane Library, Embase, ClinicalTrials.gov and Current Controlled Trials through October 2016 and qualitatively described. Trials assessing pre-post differences using a catatonia or clinical improvement rating scale were pooled together using a random effect model. Secondary outcomes were adverse effects of anesthesia and seizure. 564 patients from 28 studies were included. RCTs were of low quality and were heterogeneous; therefore, it was not possible to combine their efficacy results. An improvement of catatonic symptoms after ECT treatment was evidenced in ten studies (SMD = -3.14, 95% CI [-3.95; -2.34]). The adverse effects that were reported in seven studies included mental confusion, memory loss, headache, or adverse effects associated with anesthesia. ECT protocols were heterogeneous. The literature consistently describes improvement in catatonic symptoms after ECT. However, the published studies fail to demonstrate efficacy and effectiveness. It is now crucial to design and perform a quality RCT to robustly validate the use of ECT in catatonia.Prospero registration information: PROSPERO 2016: CRD42016041660. PMID- 28639008 TI - Evaluation of running knotless barbed suture for capsular closure in primary total knee arthroplasty for osteoarthritis-a prospective randomized study. AB - AIMS: This study was conducted to compare the barbed vs. traditional suture technique in capsular closure of total knee arthroplasty in terms of closure time, cost, needle prick injury, post-operative complication, blood loss and post operative function. PATIENTS AND METHODS: Eighty patients in a barbed suture group and 90 in a traditional group were enrolled in this prospective randomized study. RESULTS: Barbed suture was associated with 4.1 minutes (P < 0.001) faster closure. It was found to be cheaper in terms of direct material cost [30.4%]. Needle prick injury was found in 6.7% (P = 0.020) of cases in the traditional group. Blood loss, post-operative complication and post-operative function were comparable in both groups. CONCLUSION: Barbed suture use in capsular closure of knee arthroplasty is an efficient and cost effective method, and recommended for use in the future. PMID- 28639009 TI - Chipping and lengthening over nailing technique for femoral shaft nonunion with shortening. AB - PURPOSE: Chipping and lengthening over nailing (CLON) technique was developed to treat femoral shaft nonunion with shortening more than 10 mm. The purpose of the current retrospective case series was to clarify the effectiveness of the CLON technique on the femoral shaft nonunion following intramedullary nailing. METHODS: Clinical and radiological outcomes in the patients receiving operative treatment for femoral shaft nonunion between August 2012 and December 2016 were retrospectively reviewed using the Refractory Fracture Data Registry at the authors' institution. The CLON technique was indicated for patients with the femoral shaft nonunion with shortening more than 10 mm. RESULTS: Five patients with median follow-up of 32 months (range, 14 to 50 months) were included in this study. All patients achieved bone union at the median of 8 months after the CLON technique. The median limb length discrepancy was 2.0 mm at the most recent follow-up. CONCLUSIONS: The present study demonstrated that the CLON technique for femoral shaft nonunion may be the first choice as operative treatment for femoral shaft nonunion with shortening more than 10 mm. PMID- 28639010 TI - Modulation of calcium carbonate precipitation by exopolysaccharide in Bacillus sp. JH7. AB - Extracellular polymeric substance (EPS) is proposed to facilitate calcium ion supersaturation through its nucleation effect during the microbially induced calcium carbonate precipitation (MICP) process. However, the supersaturation effect of Ca2+ via EPS in MICP has not been clearly demonstrated. Enhanced exopolysaccharide production of the alkali- and halotolerant MICP-capable bacteria, Bacillus sp. JH7, was achieved through glycerol addition. This was demonstrated by measuring cellular precipitation and Congo red binding. Interestingly, field emission scanning electron microscopy and energy-dispersive X-ray spectrometry analysis demonstrated that there was no MICP under glycerol amended conditions. Although glycerol promoted exopolysaccharide capture of Ca2+ ions, Ca2+ embedded onto EPS did not participate in MICP formation. The pH was reduced in glycerol-added media, which led us to analyze high acetate production under our test conditions. Purified glycerol-induced exopolysaccharide showed a higher capacity of Ca2+ capture than the control. Quantitative RT-PCR analysis showed that three genes involved in exopolysaccharide production were highly upregulated by glycerol. The amounts of three detected monosaccharides (arabinose, glucose, and mannose) were altered by glycerol. Cell hydrophobicity measurements indicated that glycerol could confer more hydrophilic characteristics to cells, which might enhance Ca2+ binding onto EPS. Unexpectedly, our data demonstrated, for the first time, that glycerol could promote exopolysaccharide and acetate production under our test condition, which could inhibit MICP by reducing the availability of free Ca2+. PMID- 28639006 TI - Angiogenic growth factors in myocardial infarction: a critical appraisal. AB - In the recent past, substantial advances have been made in the treatment of myocardial infarction (MI). Despite the impact of these positive developments, MI remains to be a leading cause of morbidity as well as mortality. An interesting hypothesis is that the development of new blood vessels (angiogenesis) or the remodeling of preexisting collaterals may form natural bypasses that could compensate for the occlusion of an epicardial coronary artery. A number of angiogenic factors are proven to be elicited during MI. Exogenous supplementation of these growth factors either in the form of recombinant protein or gene would enhance the collateral vessel formation and thereby improve the outcome after MI. The aim of this review is to describe the nature and potentials of different angiogenic factors, their expression, their efficacy in animal studies, and clinical trials pertaining to MI. PMID- 28639011 TI - Guselkumab for the Treatment of Psoriasis: A Review of Phase III Trials. AB - INTRODUCTION: Interleukin (IL)-23 inhibitors are a new class of biologics currently undergoing clinical trials for the treatment of moderate-to-severe psoriasis. Phase III studies of guselkumab, an IL-23 receptor monoclonal antibody, are currently underway. METHODS: We summarize the available phase III results to date, establishing the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis. RESULTS: Currently, there are available data of up to 48 weeks from two Phase III, multicenter, randomized, double-blind, placebo- and comparator-controlled clinical trials, VOYAGE 1 and VOYAGE 2. At week 16, the proportion of patients attaining at least a 90% improvement from baseline in the Psoriasis Area and Severity Index (PASI 90) was 73.3% in VOYAGE 1 and 70.0% in VOYAGE 2. Guselkumab remained efficacious through 48 weeks of treatment. Guselkumab maintained a satisfactory safety profile with the most frequently reported adverse events being nasopharyngitis, headache, and upper respiratory tract infection. CONCLUSION: Phase III trials of Guselkumab suggest a favorable efficacy and safety profile of this novel drug. Although further studies are needed to assess long-term safety and efficacy, based on the results to date, guselkumab appears to be a promising therapeutic option for moderate-to severe plaque-type psoriasis. PMID- 28639012 TI - The effect of social learning on avoidance of aposematic prey in juvenile great tits (Parus major). AB - Social learning plays an important role in acquiring new foraging skills and food preferences in many bird species but its potential role in learning to avoid aposematic prey has never been studied. We tested the effect of social learning on the acquisition of avoidance of aposematic insect prey (firebug Pyrrhocoris apterus; Heteroptera) in juvenile, hand-reared great tits (Parus major). Behaviour towards aposematic prey was compared between two groups of birds: (1) the observers that were, prior to encounter with firebugs, allowed to watch the experienced conspecific demonstrator repeatedly refuse to attack the prey, and (2) the control birds that lacked this opportunity. Observing an experienced demonstrator was not sufficient for learning complete avoidance, because birds from both groups attacked at least the first firebug they had encountered in avoidance training. However, the opportunity to observe the avoidance behaviour of another bird significantly increased the rate of subsequent individual learning of observers in comparison with control birds. Social learning also decreased mortality of firebugs killed by the birds during the avoidance learning. Socially enhanced learning to avoid aposematic prey might be a mechanism important especially for naive juvenile birds learning from their parents, but it could also enhance learning in adults from their more experienced flock mates. Because social learning of avoidance may also lead to decreased mortality of aposematic prey, its effect should be taken into account in scenarios considering evolution and maintenance of prey warning signals. PMID- 28639013 TI - Revisiting the environmental Kuznets curve and pollution haven hypotheses: MIKTA sample. AB - This study aims to examine the validity of the environmental Kuznets curve (EKC) and pollution haven hypotheses in Mexico, Indonesia, South Korea, Turkey, and Australia (MIKTA) countries from 1982 to 2011 by using a panel vector auto regressive (PVAR) model. Empirical findings imply that the EKC hypothesis is rejected by the MIKTA sample. However, PVAR estimations reveal Granger causality from income level, foreign direct investment (FDI) inward, and energy consumption to CO2 emissions. Orthogonalized impulse-response functions are derived from PVAR estimations. According to the analysis results, the response of CO2 emissions to a shock on FDI is positive. These results assert that FDI has a detrimental effect on environmental quality in MIKTA countries which means the pollution haven hypothesis is confirmed by the MIKTA sample. Therefore, MIKTA countries should revise their current economic growth plans to provide sustainable development and also re-organize their legal infrastructure to induce usage of renewable energy sources. PMID- 28639014 TI - Sediments as a sink for UV filters and benzotriazoles: the case study of Upper Iguacu watershed, Curitiba (Brazil). AB - Ingredients in home and personal care products, including UV filters and benzotriazoles, are high production volume chemicals extensively used in our daily life, despite several studies revealed their potential eco-toxicity and endocrine-disrupting capacity. Due to some features, such as high lipophilicity, low degradability, and persistence of many of these compounds, sediments can be considered a sink for them in the aquatic environment. In the present study, nine organic UV filters and three benzotriazoles were investigated for the first time in sediments from four urban rivers in Brazil. The contaminants were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results revealed that octocrylene (OC), etylhexyl-methoxycinnamate (EHMC), benzophenone-3 (oxybenzone, BP3), and benzotriazole (BZT) were the predominant compounds adsorbed on the sediments, with concentrations ranging from 5.6 to 322.2 ng g-1 dry weight. The results reported in this work constitute the first data on the accumulation of polar benzotriazoles and lipophilic organic UV filters in sediments from Brazil. PMID- 28639015 TI - Phytoextraction of Pb, Cr, Ni, and Zn using the aquatic plant Limnobium laevigatum and its potential use in the treatment of wastewater. AB - In order to study the bioaccumulation of Pb, Cr, Ni, and Zn and the stress response, the floating aquatic plant Limnobium laevigatum was exposed to increasing concentrations of a mixture of these metals for 28 days, and its potential use in the treatment of wastewater was evaluated. The metal concentrations of the treatment 1 (T1) were Pb 1 MUg L-1, Cr 4 MUg L-1, Ni 25 MUg L-1, and Zn 30 MUg L-1; of treatment 2 (T2) were Pb 70 MUg L-1, Cr 70 MUg L-1, Ni 70 MUg L-1, and Zn 70 MUg L-1; and of treatment 3 (T3) were Pb 1000 MUg L-1, Cr 1000 MUg L-1, Ni 500 MUg L-1, and Zn 100 MUg L-1, and there was also a control group (without added metal). The accumulation of Pb, Cr, Ni, and Zn in roots was higher than in leaves of L. laevigatum, and the bioconcentration factor revealed that the concentrations of Ni and Zn in the leaf and root exceeded by over a thousand times the concentrations of those in the culture medium (2000 in leaf and 6800 in root for Ni; 3300 in leaf and 11,500 in root for Zn). Thus, this species can be considered as a hyperaccumulator of these metals. In general, the changes observed in the morphological and physiological parameters and the formation of products of lipid peroxidation of membranes during the exposure to moderate concentrations (T2) of the mixture of metals did not cause harmful effects to the survival of the species within the first 14 days of exposure. Taking into account the accumulation capacity and tolerance to heavy metals, L. laevigatum is suitable for phytoremediation in aquatic environments contaminated with moderated concentrations of Cr, Ni, Pb, and Zn in the early stages of exposure. PMID- 28639016 TI - Accumulation properties of polychlorinated biphenyl congeners in Yusho patients and prediction of their cytochrome P450-dependent metabolism by in silico analysis. AB - In what has become known as the Yusho incident, thousands of people in western Japan were poisoned by the accidental ingestion of rice bran oil contaminated with polychlorinated biphenyls (PCBs) and various dioxins and dioxin-like compounds. In this study, we investigated the accumulation patterns of 69 PCB congeners in the blood of Yusho patients in comparison with those of non-exposed controls. The blood samples were collected at medical check-ups in 2004 and 2005. To compare the patterns of PCB congeners, we calculated the concentration ratio of each congener relative to the 2,2',4,4',5,5'-hexaCB (CB153) concentration. The concentration ratios of tetra- and penta-chlorinated congeners in the blood of Yusho patients were significantly lower than those of controls. To examine the cytochrome P450 (CYP)-dependent metabolic potential of the 2,3',4,4'5-pentaCB (CB118), CB153, and 2,3,3',4,4'5-hexaCB (CB156) congeners, we conducted PCB-CYP (CYP1A1, CYP1A2, CYP2A6, and CYP2B6) docking simulation by in silico analysis. The docking models showed that human CYP1A1, CYP2A6, and CYP2B6 isozymes have the potential to metabolize CB118 and CB153. On the other hand, it was inferred that CB156 is difficult to be metabolized by these four CYP isozymes. These results indicate that CYP1 and CYP2 isozymes may be involved in the characteristic accumulation patterns of PCB congeners in the blood of Yusho patients. PMID- 28639017 TI - Removal of polyvinylamine sulfonate anthrapyridone dye by application of heterogeneous electro-Fenton process. AB - Diversity and rapidly multiplication of the pollutants incite as to improve the conventional treatments wastewater methods. One of the bottlenecks often faced is the presence into wastewater of organic pollutants with complex structures that requests the design of efficient processes. Thus, this work investigates the removal of polyvinylamine sulfonate anthrapyridone (PSA) dye which complex structure makes difficult its degradation by conventional technologies. For that, a heterogeneous oxidative process using pyrite as sustainable catalyst was designed. Initially, the performance of the system BBD-carbon felt as anode and cathode, respectively for the production of H2O2 was determined in comparison with system boron-doped diamond nickel foam. The carbon felt electrode provided the highest oxidant production, and it was selected for the treatment of the polymeric dye. Several oxidative processes were evaluated, and the best degradation levels were obtained by application of electro-Fenton-pyrite process. In addition, it was determined that dye removal followed a kinetic model of pseudo-first-order achieving the highest efficiency by operation at optimum dosage of pyrite 2 g/L and 200 mA of current intensity. Depending on the optimal experimental conditions, these values lead to a nearly complete mineralization (total organic carbon removal of 95%) after 6 h. Furthermore, the reusability of pyrite was evaluated, by removal of PSA in four cycles. PMID- 28639018 TI - Test of aerobic TCE degradation by willows (Salix viminalis) and willows inoculated with TCE-cometabolizing strains of Burkholderia cepacia. AB - Trichloroethylene (TCE) is a widespread soil and groundwater pollutant and clean up is often problematic and expensive. Phytoremediation may be a cost-effective solution at some sites. This study investigates TCE degradation by willows (S. viminalis) and willows inoculated with three strains of B. cepacia (301C, PR1-31 and VM1330-pTOM), using chloride formation as an indicator of dehalogenation. Willows were grown in non-sterile, hydroponic conditions for 3 weeks in chloride free nutrient solution spiked with TCE. TCE was added weekly due to rapid loss by volatilization. Chloride and TCE in solution were measured every 2-3 days and chloride and metabolite concentrations in plants were measured at test termination. Based on transpiration, no tree toxicity of TCE exposure was observed. However, trees grown in chloride-free solution showed severely inhibited transpiration. No or very little chloride was formed during the test, and levels of chloride in TCE-exposed trees were not elevated. Chloride concentrations in chloride containing TCE-free nutrient solution doubled within 23 days, indicating active exclusion of chloride by root cell membranes. Only traces of TCE-metabolites were detected in plant tissue. We conclude that TCE is not, or to a limited extent (less than 3%), aerobically degraded by the willow trees. The three strains of B. cepacia did not enhance TCE mineralization. Future successful application of rhizo- and phytodegradation of TCE requires measures to be taken to improve the degradation rates. PMID- 28639019 TI - Cultivation of freshwater microalgae in biodiesel wash water. AB - Biodiesel wash water is a contaminating industrial effluent that must be treated prior to disposal. The use of this effluent as a low-cost alternative cultivation medium for microalgae could represent a viable supplementary treatment. We cultivated 11 microalgae species with potential use for biodiesel production to assess their growth capacities in biodiesel industrial washing waters. Only Monoraphidium contortum, Ankistrodesmus sp., Chlorococcum sp., and one unidentified Chlorophyceae species grew effectively in that effluent. M. contortum showed the highest growth capacity and had the second highest fatty acid content (267.9 mg g-1 of DW), predominantly producing palmitic (20.9%), 7,10,13-hexadecatrienoic (14%), oleic (16.2%), linoleic (10.5%), and linolenic acids (23.2%). In the second phase of the experiment, the microalgae were cultivated in biodiesel wash water at 75% of its initial concentration as well as in WC (control) medium. After 21 days of cultivation, 25.8 and 7.2% of the effluent nitrate and phosphate were removed, respectively, and the chemical oxygen demand was diminished by 31.2%. These results suggest the possibility of cultivating biodiesel producing microalgae in industrial wash water effluents. PMID- 28639020 TI - Investigation of the removal mechanism of Cr(VI) in groundwater using activated carbon and cast iron combined system. AB - Zero-valent iron (Fe0) has been widely used for Cr(VI) removal; however, the removal mechanisms of Cr(VI) from aqueous solution under complex hydrogeochemical conditions were poorly understood. In this research, the mixed materials containing cast iron and activated carbon were packed in columns for the treatment of aqueous Cr(VI)-Cr(III) in groundwater with high concentration of Ca2+, Mg2+, HCO3-, NO3-, and SO42-. We investigate the influences of those ions on Cr(VI) removal, especially emphasizing on the reaction mechanisms and associated precipitations which may lead to porosity loss by using X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) techniques. The results show that the precipitations accumulated on the material surface were (Fe/Cr) (oxy)hydroxide, mixed Fe(III)-Cr(III) (oxy)hydroxides, Fe2O3, CaCO3, and MgCO3. During these reactions, the Cr(VI) was reduced to Cr(III) coupled with the oxidated Fe0 to Fe(II) through the galvanic corrosion formed by the Fe0-C and/or the direct electron transfer between Fe0 and Cr(VI). In addition, Cr(VI) could be reduced by aqueous Fe(II), which dominated the whole removal efficiency. The primary aqueous Cr(III) was completely removed together with Cr(III) reduced from Cr(VI) even when Cr(VI) was detected in the effluent, which meant that the aqueous Cr(III) could occupy the adsorption sites. In general, the combined system was useful for the Cr(VI)-Cr(III) treatment based on galvanic corrosion, and the hardness ions had a negative effect on Cr(VI) removal by forming the carbonates which might promote the passivation of materials and decrease the removal capacity of the system. PMID- 28639021 TI - Evapotranspiration versus oxygen intrusion: which is the main force in alleviating bioclogging of vertical-flow constructed wetlands during a resting operation? AB - Clogging is the most significant challenge limiting the application of constructed wetlands. Application of a forced resting period is a practical way to relieve clogging, particularly bioclogging. To reveal the alleviation mechanisms behind such a resting operation, evapotranspiration and oxygen flux were studied during a resting period in a laboratory vertical-flow constructed wetland model through physical simulation and numerical model analysis. In addition, the optimum theoretical resting duration was determined based on the time required for oxygen to completely fill the pores, i.e., formation of a sufficiently thick and completely dry layer. The results indicated that (1) evapotranspiration was not the key factor, but was a driving force in the alleviation of bioclogging; (2) the rate of oxygen diffusion into the pores was sufficient to oxidize and disperse the flocculant biofilm, which was essential to alleviate bioclogging. This study provides important insights into understanding how clogging/bioclogging can be alleviated in vertical-flow constructed wetlands. Graphical abstract Evapotranspiration versus oxygen intrusion in alleviating bioclogging in vertical flow constructed wetlands. PMID- 28639022 TI - Citrus stand ages regulate the fraction alteration of soil organic carbon under a citrus/Stropharua rugodo-annulata intercropping system in the Three Gorges Reservoir area, China. AB - Soil carbon fractionation is a valuable indicator in assessing stabilization of soil organic matter and soil quality. However, limited studies have addressed how different vegetation stand ages under intercropping agroforestry systems, could affect organic carbon (OC) accumulation in bulk soil and its physical fractions. A field study thus investigated the impact of citrus plantation age (15-, 25-, and 45-year citrus) on the bulk soil organic carbon (SOC) and SOC fractions and yields of Stropharia rugoso-annulata (SRA) in the Three Gorges Reservoir area, Chongqing, China. Results indicated that the intercropping practice of SRA with citrus significantly increased the SOC by 57.4-61.6% in topsoil (0-10 cm) and by 24.8-39.9% in subsoil (10-30 cm). With a significantly higher enhancement under the 25-year citrus stand than the other two stands, all these citrus stands of three ages also resulted in a significant increase of free particulate OC (fPOC, 60.1-62.4% in topsoil and 34.8-46.7% in subsoil), intra-micro aggregate particulate OC (iPOC, 167.6-206.0% in topsoil and 2.77-61.09% in subsoil), and mineral-associated OC (MOC, 43.6-46.5% in topsoil and 26.0-51.5% in subsoil). However, there were no significant differences in yields of SRA under three citrus stands. Our results demonstrated that citrus stand ages did play an important role in soil carbon sequestration and fractionation under a citrus/SRA intercropping system, which could therefore provide a sustainable agroforestry system to enhance concurrently the SOC accumulation while mitigating farmland CO2 emission. PMID- 28639023 TI - Uncertainties in vegetated buffer strip function in controlling phosphorus export from agricultural land in the Canadian prairies. AB - Vegetated buffer strips (VBSs) are widely encouraged as a cost-effective strategy to address phosphorus (P) pollution associated with agricultural production. However, there is a lack of evidence in the effectiveness of these measures for tackling diffuse P pollution in cold-climate regions under concentrated runoff flow conditions. This research aimed to investigate the effects of VBSs on reducing P concentrations in surface runoff at three different watersheds in Manitoba, Canada. Surface runoff samples were collected in four sub-catchments from each watershed by installing paired weirs at 0.5-m and at 5-m into the VBSs along the expected runoff flow path. In addition, P concentrations were measured in soil samples collected within and outside of the runoff flow path to gain further insight into P dynamics within VBSs at each study site. The results indicate that VBSs had little or no significant effect on reducing the concentration of P forms in surface runoff in the majority of situations, resulting in reduced runoff losses of total, dissolved and particulate P concentrations in only 23, 12 and 12% of the situations, respectively. In addition, Olsen extractable P concentrations in VBS soils were not significantly different from field soils both within and outside of the flow path. The ineffective P retention by VBSs in this region is likely associated with the fact that the majority of the runoff flow is concentrated through small portions of VBSs and occurs during snowmelt when biogeochemical processes responsible for P retention in VBSs are limited. Further research is needed to develop alternative management practices that enhance P retention during concentrated snowmelt runoff events in such cold-climate regions. PMID- 28639024 TI - Nematicidal potential of hydrolates from the semi industrial vapor-pressure extraction of Spanish aromatic plants. AB - The nematicidal activity of hydrolate by-products from the semi industrial vapor pressure essential oil extraction of selected aromatic plant species (commercial: Lavandula * intermedia Emeric ex Loisel. var. super, Thymus vulgaris L., T. zygis Loefl ex L. and experimentally pre-domesticated: L. luisieri (Rozeira) Rivas Martinez) was investigated against the root-knot nematode Meloidogyne javanica by in vitro and in vivo bioassays. Liquid-liquid extraction of hydrolates yielded the corresponding aqueous and organic fractions which were biological and chemically studied. Hydrolates from L. * intermedia var. super, L. luisieri, T. vulgaris, and T. zygis showed strong in vitro nematicidal effects against M. javanica (J2 mortality and suppression of egg hatching). In the case of the Thymus species, the active components were found in the organic fraction, characterized by thymol as major component. Conversely, the nematicidal activity of L. * intermedia var. super and L. luisieri remained in the corresponding aqueous fractions. In vivo tests on tomato seedlings at sublethal doses of the hydrolates/organic fractions induced a significant reduction of nematode infectivity. In pot experiments, all hydrolates tested on tomato plants significantly affect the infection frequency and reproduction rate of the nematode population. This study demonstrates that L. * intermedia var. super, L. luisieri, T. vulgaris, and T. zygis hydrolates could be an exploitable source of potential waste protection products on root-knot nematodes. PMID- 28639025 TI - Characteristics of volatile compound emission and odor pollution from municipal solid waste treating/disposal facilities of a city in Eastern China. AB - Transfer station, incineration plant, and landfill site made up the major parts of municipal solid waste disposal system of S city in Eastern China. Characteristics of volatile compounds (VCs) and odor pollution of each facility were investigated from a systematic perspective. Also major index related to odor pollution, i.e., species and concentration of VCs, olfactory odor concentration, and theoretic odor concentration, was quantified. Oxygenated compounds and hydrocarbons were the most abundant VCs in the three facilities. Different chemical species were quantified, and the following average concentrations were obtained: transfer station, 54 VCs, 2472.47 MUg/m3; incineration plant, 75 VCs, 33,129.25 MUg/m3; and landfill site, 71 VCs, 1694.33 MUg/m3. Furthermore, the average olfactory odor concentrations were 20,388.80; 50,677.50; and 4951.17, respectively. The highest odor nuisance was detected in the waste tipping port of the incineration plant. A positive correlation between the olfactory and chemical odor concentrations was found with R 2 = 0.918 (n = 15, P < 0.01). The result shows odor pollution risk transfer from landfill to incineration plant when adopting thermal technology to deal with the non-source-separated waste. Strong attention thus needs to be paid on the enclosed systems in incineration plant to avoid any accidental odor emission. PMID- 28639026 TI - Regulation of engineered nanomaterials: current challenges, insights and future directions. AB - Substantial production and wide applications of engineered nanomaterials (ENMs) have raised concerns over their potential influences on the environment and humans. However, regulations of products containing ENMs are scarce, even in countries with the greatest volume of ENMs produced, such as the United States and China. After a comprehensive review of life cycles of ENMs, five major challenges to regulators posed by ENMs are proposed in this review: (a) ENMs exhibit variable physicochemical characteristics, which makes them difficult for regulators to establish regulatory definition; (b) Due to diverse sources and transport pathways for ENMs, it is difficult to monitor or predict their fates in the environment; (c) There is a lack of reliable techniques for quantifying exposures to ENMs; (d) Because of diverse intrinsic properties of ENMs and dynamic environmental conditions, it is difficult to predict bioavailability of ENMs on wildlife and the environment; and (e) There are knowledge gaps in toxicity and toxic mechanisms of ENMs from which to predict their hazards. These challenges are all related to issues in conventional assessments of risks that regulators rely on. To address the fast-growing nanotechnology market with limited resources, four ENMs (nanoparticles of Ag, TiO2, ZnO and Fe2O3) have been prioritized for research. Compulsory reporting schemes (registration and labelling) for commercial products containing ENMs should be adopted. Moreover, to accommodate their potential risks in time, an integrative use of quantitative structure-activity relationship and adverse outcome pathway (QSAR-AOP), together with qualitative alternatives to conventional risk assessment are proposed as tools for decision making of regulators. PMID- 28639028 TI - Erratum to: Breast cancer risk models: a comprehensive overview of existing models, validation, and clinical applications. PMID- 28639027 TI - First detection of enteric adenoviruses genotype 41 in recreation spring areas of Taiwan. AB - Human adenoviruses (HAdVs) are DNA viruses found in recreational water, such as water parks and swimming pools. Human adenovirus 41 (HAdV-41) is the most common serotype detected and is a leading cause of acute diarrheal disease. The focus of this study is to determine the prevalence of HAdVs in hot springs. Of 57 samples collected from four different geological sites, 16 samples have shown evidence of HAdVs (28.1%). HAdV-41 and porcine adenovirus 5 (PAdV-5) were the two types isolated, with a greater frequency of HAdV-41, which in other settings has been associated with acute diarrhea. The highest occurrence was found in private hot tubs/Yuya (37.5%), followed by an outlet of hot springs (30.8%); public pools and foot pools shared the same detection rate of 21.4% (3/14). However, there was no evidence supporting a link between water quality indicators and HAdV detection rate. From a phylogenic analysis and BLAST against the NCBI database, it was concluded that HAdV-41 obtained from hot spring areas are closely related to global environmental genotypes. PMID- 28639029 TI - COX2 induction: a mechanism of endocrine breast cancer resistance? AB - PURPOSE: Urine prostaglandin E2 (PGE2) levels have shown to be a risk factor of breast cancer, and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is known to be beneficial in preventing breast cancer risk and/or recurrence with or without aromatase inhibitors. We hypothesized that the use of an aromatase inhibitor triggers the activation of the inflammatory pathway via release of PGE2. METHODS: A single oral 25 mg dose of an aromatase inhibitor (exemestane) was given to 14 healthy postmenopausal female volunteers. Blood and urine samples were collected between 0 and 72 h post-dosing for pharmacokinetic and pharmacodynamic analysis. RESULTS: Our findings showed that urine PGE2 levels were markedly increased 72 h after exemestane administration (average pre-dosing PGE2 levels, 4061.1 pg/mL vs. post-dosing average PGE2 levels, 10732.5 pg/mL, P = 0.001, Wilcoxon Rank Test). Out of 14 subjects enrolled in the study, one subject showed no change in PGE2; another showed a 23-fold decreased in PGE2; and the remaining 12 showed an average of 8.4-fold increase in PGE2 levels (range 1.3 30.5, standard deviation 9.2) after exemestane administration. We found no statistically significant correlations between fold increase in urine PGE2 levels and the pharmacokinetics of either exemestane or 17-hydroexemestane (major in vivo metabolite of exemestane). CONCLUSION: Our results indicate that one of the pharmacological effects to aromatase inhibitors (e.g., exemestane) involves the activation of the inflammatory pathway via release of PGE2. Further in vitro mechanistic and in vivo translational studies designed to elucidate the role of this newly discovered effect are now warranted. PMID- 28639030 TI - Utilization of hypofractionated whole-breast radiation therapy in patients receiving chemotherapy: a National Cancer Database analysis. AB - PURPOSE: Results from four major hypofractionated whole-breast radiotherapy (HF WBRT) trials have demonstrated equivalence in select patients with early-stage breast cancer when compared with conventionally fractionated WBRT (CF-WBRT). Because relatively little data were available on patients receiving neoadjuvant or adjuvant chemotherapy, consensus guidelines published in 2011 did not endorse the use of HF-WBRT in this population. Our goal is to evaluate trends in utilization of HF-WBRT in patients receiving chemotherapy. METHODS AND MATERIALS: We retrospectively analyzed data from 2004 to 2013 in the National Cancer DataBase on breast cancer patients treated with HF-WBRT who met the clinical criteria proposed by consensus guidelines (i.e., age >0 years, T1-2N0, and breast conserving surgery), regardless of receipt of chemotherapy. We employed logistic regression to delineate and compare clinical and demographic factors associated with utilization of HF-WBRT and CF-WBRT. RESULTS: A total of 56,836 women were treated with chemotherapy and WBRT (without regional nodal irradiation) from 2004 to 2013; 9.0% (n = 5093) were treated with HF-WBRT. Utilization of HF-WBRT increased from 4.6% in 2004 to 18.2% in 2013 (odds ratio [OR] 1.21/year; P < 0.001). Among patients receiving chemotherapy, factors most dramatically associated with increased odds of receiving HF-WBRT on multivariate analysis were academic facilities (OR 2.07; P < 0.001), age >80 (OR 2.58; P < 0.001), west region (OR 1.91; P < 0.001), and distance >50 miles from cancer reporting facility (OR 1.43; P < 0.001). Factors associated with decreased odds of receiving HF-WBRT included white race, income <$48,000, lack of private insurance, T2 versus T1, and higher grade (all P < 0.02). CONCLUSIONS: Despite the absence of consensus guideline recommendations, the use of HF-WBRT in patients receiving chemotherapy has increased fourfold (absolute = 13.6%) over the last decade. Increased utilization of HF-WBRT should result in institutional reports verifying its safety and efficacy. PMID- 28639031 TI - Opioid use among female breast cancer patients using different adjuvant endocrine therapy regimens. AB - PURPOSE: To explore differences in opioid use across different adjuvant endocrine therapy (AET) regimens, factors associated with opioid use, and the impact of opioid use on overall survival in female breast cancer patients treated with AET. METHODS: This retrospective study analyzed 2006-2012 SEER-Medicare datasets, following patients for at least two years from the index date, defined as the first date they filled an AET prescription. The study included adult women with incident, primary, hormone-receptor-positive, stage I-III breast cancer. They were also first-time AET users, and fee-for-service Medicare enrollees continuously enrolled in Medicare Parts A, B, and D. The main independent variable was the AET regimen. We measured whether patients used opioids after the initiation of AET. RESULTS: After the adjustment of inverse probability treatment weights and unbalanced covariates, the average treatment effect probabilities of opioid use were similar between those who used aromatase inhibitors (AI) only and those used tamoxifen (TAM) only (56.2 vs. 55.3%, respectively). Opioid use probabilities for those who switched from AI to TAM were higher than those for the TAM-only and AI-only groups. Opioid use was also significantly associated with AET non-adherence. Opioid users had a significantly higher risk of death (adjusted hazard ratio [HR] = 1.59, p < 0.001). CONCLUSIONS: Switching from AI to TAM was associated with a high likelihood of opioid use. Opioid use was significantly associated with AET non-adherence and higher risk of mortality in female Medicare beneficiaries with breast cancer even after adjusting for adherence. PMID- 28639032 TI - Case Study: Microbial Ecology and Forensics of Chinese Drywall-Elemental Sulfur Disproportionation as Primary Generator of Hydrogen Sulfide. AB - Drywall manufactured in China released foul odors attributed to volatile sulfur compounds. These included hydrogen sulfide, methyl mercaptan, and sulfur dioxide. Given that calcium sulfate is the main component of drywall, one would suspect bacterial reduction of sulfate to sulfide as the primary culprit. However, when the forensics, i.e., the microbial and chemical signatures left in the drywall, are studied, the evidence suggests that, rather than dissimilatory sulfate reduction, disproportionation of elemental sulfur to hydrogen sulfide and sulfate was actually the primary cause of the malodors. Forensic evidence suggests that the transformation of elemental sulfur went through several abiological and microbial stages: (1) partial volatilization of elemental sulfur during the manufacture of plaster of Paris, (2) partial abiotic disproportionation of elemental sulfur to sulfide and thiosulfate during the manufacture of drywall, (3) microbial disproportionation of elemental sulfur to sulfide and sulfate resulting in neutralization of all alkalinity, and acidification below pH 4, (4) acidophilic microbial disproportionation of elemental sulfur to sulfide and sulfuric acid, and (5) hydrogen sulfide volatilization, coating of copper fixtures resulting in corrosion, and oxidation to sulfur dioxide. PMID- 28639034 TI - Ageing, health status and coverage rate effects on community prescription costs in Ireland. AB - AIMS AND OBJECTIVES: This paper aims to explore how GMS drug costs depend on age, gender, income, health status, community drug scheme coverage rates and whether they display significant differences across regions of Ireland. We also aim to find out whether the GMS drug costs of high and low income cohorts respond similarly to changes in their health status. The paper projects GMS drug costs in 2026 and examines the separate cost of population ageing and population growth over the period. We also aim to simulate the estimated model to show how much giving free prescription drugs to all persons aged 'under 5' would add to 2026 GMS drug costs, and also how much giving universal GMS coverage to all persons in 2026 would add to 2026 GMS drug costs. METHODS: We construct a multivariate logistic regression model of GMS community drug costs in Ireland. We progress the methodology used in earlier studies by explicitly modelling how regional incomes and regional health status interact in determining GMS drug costs in Ireland. An age cohort and region breakdown of the simulated GMS drug costs, of both projected demographic trends and public policy measures that have been adopted or are under consideration, are also investigated. FINDINGS: We find that GMS drug costs depend on age-but not gender-on income, health status, community drug scheme coverage rates, and they are significantly lower for all age cohorts in Donegal and the North West region. The GMS drug costs of high income cohorts tend to increase as their health status improves, whereas they tend to decrease as the health status of low income cohorts improves. A uniform 1% gain in health status has little impact on total GMS prescribing costs. Similarly, if the health status of all Irish regions improved to match that of the East region in 2010 it would only have reduced public prescription costs by around 32 ? million of the 1.8 ? billion GMS drugs bill. We find that giving free prescription drugs to all persons aged 'under 5' in 2010 would have only a minor impact on 2010 GMS drug costs, whereas giving universal GMS coverage to all persons would have doubled public prescription costs from 1.8 ? billion to circa 3.6 ? billion. PMID- 28639033 TI - Functional restoration of CD56bright NK cells facilitates immune control via IL 15 and NKG2D in patients under antiviral treatment for chronic hepatitis B. AB - BACKGROUND AND AIMS: Hepatitis B virus (HBV) is intrinsically immunogenic, with long-lasting immune control in many patients. However, the mechanisms and key cell types underlying effective immune control are incompletely understood. METHODS: We studied the restoration of natural killer (NK) cell numbers and function post antiviral treatment in 52 hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who received telbivudine (LdT) for 48 weeks. Blood samples were collected at week 0, 12, 24, 36, and 48 and tested for HBV DNA, hepatitis B surface antigen (HBsAg), HBeAg, liver enzymes, and NK cell parameters. RESULTS: Compared with baseline, the number of peripheral CD3 CD56bright NK cells increased significantly from week 24 to 48, especially in patients with baseline alanine transaminase (ALT) two- to fivefold the upper line of normal (ULN) or HBV DNA <9 log10 copies/ml. Expression (number and density) of activating receptors NKG2D and NKp46 on CD3-CD56bright NK cells was enhanced, while inhibitory receptor NKG2A decreased. Notably, numbers of CD3-CD56bright or NKG2D+CD3-CD56bright NK cells were significantly better restored in patients with HBeAg seroconversion. NK cell activating serum interleukin 15 (IL-15) was significantly increased during LdT treatment, especially in HBeAg seroconverters. LdT significantly enhanced expression of NKG2D and IL-15 in cultures of purified peripheral NK cells from treatment-naive HBeAg-positive CHB patients. CONCLUSIONS: Functional restoration of CD56bright NK cells via upregulation of IL 15 and NKG2D is a novel activity of LdT and likely other antivirals, independent of its effect on HBV replication. This also demonstrates the importance of host immune restoration in controlling chronic HBV infection. PMID- 28639035 TI - Mitigation of pedestrian heat stress using parasols in a humid subtropical region. AB - Concerns over heat illness have been an increasing social problem in humid subtropical regions. One measure for avoiding excessive heat stress in hot outdoor environments is the use of parasols or umbrellas. The advantage of parasols is that they are a mobile and inexpensive way to provide personal shade outdoors. The objectives of this study were to compare the wet-bulb globe temperature (WBGT) under parasols and at an unshaded point as a reference, and to quantify the reduction in WBGT from the use of parasols in a humid subtropical region. Measurements using three parasols of different colors and materials were conducted at the athletics field at Daido University, Nagoya, Japan, between 9:00 and 15:00 Japan Standard Time in August 2015. The WBGT was obtained at heights of 0.1 m (ankles), 1.1 m (abdomen), and 1.7 m (head) above ground, according to the measurement procedure described in ISO 7243. On a sunny and partly cloudy day, the use of a parasol lowered the average globe temperature by up to 6.2 degrees C, through blocking direct solar radiation. The average reduction in WBGT by the parasol was found to be 1.8 degrees C at head level in sunny conditions with solar radiation of over 800 W/m2. The reduction in WBGT at head level by the use of parasols in sunny conditions was greater than that in cloudy conditions. However, although parasols can reduce WBGT at the head level of the user regardless of solar radiation, they cannot reduce it at the level of the abdomen or ankles. PMID- 28639036 TI - Customization of laparoscopic gastric devascularization and splenectomy for gastric varices based on CT vascular anatomy. AB - BACKGROUND: Laparoscopic gastric devascularization(Lap GDS) and splenectomy (SPL) for gastric varices is technically challenging because of highly developed collateral vessels and bleeding tendency. We investigated the feasibility of customization of Lap GDS and SPL based on CT vascular anatomy. METHODS: We analyzed 61 cirrhotic patients with gastric varices who underwent Lap GDS and SPL between 2006 and 2014. Lap GDS was customized according to the afferent feeding veins (left gastric vein (LGV) and/or posterior gastric vein (PGV)/short gastric vein (SGV)) and efferent drainage veins (gastrorenal shunt and/or gastrophrenic shunt, or numerous retroperitoneal veins) based on CT imaging. RESULTS: Thirty four patients with efferent drainage veins suitable for balloon-occluded retrograde transvenous obliteration (B-RTO) underwent B-RTO instead of surgical GDS, with subsequent Lap SPL. Among 27 patients with gastric varices unsuitable for B-RTO, 15 patients with PGV/SGV underwent Lap GDS of the greater curvature and SPL, and 12 patients with LGV or LGV/PGV/SGV underwent Lap GDS of the greater and lesser curvature and SPL. The mean operation time was 294 min and mean blood loss was 198 g. There was no mortality or severe morbidity. Gastric varices were eradicated in all 61 patients, with no bleeding or recurrence during a mean follow-up of 55.9 months. The cumulative 3-, 5-, and 7-year survival rates were 92, 82, and 64%, respectively. CONCLUSIONS: Lap GDS and SPL customized based on CT vascular anatomy is a safe and effective procedure for treating gastric varices. PMID- 28639038 TI - Characteristics predicting laparoscopic skill in medical students: nine years' experience in a single center. AB - INTRODUCTION: We introduced laparoscopic simulator training for medical students in 2007. This study was designed to identify factors that predict the laparoscopic skill of medical students, to identify intergenerational differences in abilities, and to estimate the variability of results in each training group. Our ultimate goal was to determine the optimal educational program for teaching laparoscopic surgery to medical students. METHODS: Between 2007 and 2015, a total of 270 fifth-year medical students were enrolled in this observational study. Before training, the participants were asked questions about their interest in laparoscopic surgery, experience with playing video games, confidence about driving, and manual dexterity. After the training, aspects of their competence (execution time, instrument path length, and economy of instrument movement) were assessed. RESULTS: Multiple regression analysis identified significant effects of manual dexterity, gender, and confidence about driving on the results of the training. The training results have significantly improved over recent years. The variability among the results in each training group was relatively small. CONCLUSIONS: We identified the characteristics of medical students with excellent laparoscopic skills. We observed educational benefits from interactions between medical students within each training group. Our study suggests that selection and grouping are important to the success of modern programs designed to train medical students in laparoscopic surgery. PMID- 28639037 TI - Long-term oncological outcomes of submucosal manipulation during non-curative endoscopic submucosal dissection for submucosal invasive gastric cancer: a multicenter retrospective study in Japan. AB - BACKGROUND: Sufficient information is not available on the extent to which lymph node metastasis (LNM) and prognosis are affected by submucosal manipulation during endoscopic submucosal dissection (ESD) for submucosal invasive gastric cancer (SMGC). We aimed to identify the effects of submucosal manipulation during ESD on LNM and prognosis in patients with SMGC. METHODS: From 19 institutions in Japan, 2526 patients who failed to meet the current curative criteria for ESD between 2000 and 2011 were recruited. After exclusion, 1969 patients were remained. Based on the treatment strategy after ESD, 1064 patients underwent additional radical surgery. A total of 890 of 1064 patients with SMGC, LNM and cancer recurrence, and prognosis were retrospectively reviewed. RESULTS: The median follow-up duration was 67 months. A total of 214 patients had SM1 (depth of tumor invasion from the muscularis mucosae <500 MUm) invasive cancer and 676 patients had SM2 (depth of tumor invasion from the muscularis mucosae >=500 MUm) invasive cancer. LNM was found in 84 patients (9.4%), and 14 patients (1.6%) developed cancer recurrence. The 3-year and 5-year overall survival rates were 96.1 and 91.7%, respectively. The 3-year and 5-year disease-specific survival rates were 99.3 and 98.5%, respectively. CONCLUSIONS: The rates of LNM and cancer recurrence, and prognosis of patients who underwent additional radical surgery after non-curative ESD for SMGC were excellent. Submucosal manipulation during ESD for SMGC does not seem to enhance the risk for LNM or worsen the prognosis compared to surgical series. PMID- 28639039 TI - A novel endoscopic surgery for dysphagia after stroke. AB - BACKGROUND: Dysphagia is a common complication in stroke patients, which severely affects quality of life. This study aimed to evaluate the effectiveness and safety of temperature-controlled plasma radiofrequency (coblation)-assisted endoscopic cricopharyngeal myotomy (CAECPM) for the treatment sustained (>6 months) dysphagia in stroke patients. METHODS: This retrospective case-control study included a total of 24 stroke patients with sustained dysphagia, who were either treated with transcervical cricopharyngeal myotomy (CPM) (n = 16) or CAECPM (n = 12). The patients' swallowing function was evaluated by the Chinese version of the swallow quality-of-life questionnaire (CSWAL-QOL), and dysphagia and aspiration was evaluated using the videofluoroscopic swallowing study (VFSS) swallowing (VFSS-SWAL) score and VSSF aspiration (VFSS-ASPI) score. In each patient, esophageal pressure and complications were also recorded. RESULTS: The CSWAL-QOL score was increased and the VFSS-SWAL and VFSS-ASPI scores were reduced after CAECPM treatment. The upper esophageal sphincter pressure was significantly reduced after CAECPM. Only 1 of 12 (8.3%) patients had subcutaneous and mediastinal emphysema, and 2 patients had gastric regurgitation. CONCLUSION: This exploratory study demonstrates that CAECPM is worth further investigation for dysphagia after stroke. CAECPM may be an effective and safe treatment for sustained dysphagia in stroke patients. Larges and prospective studies are required to validate these results. PMID- 28639040 TI - Mobile gastrointestinal and endoscopic surgery in rural Ecuador: 20 years' experience of Cinterandes. AB - INTRODUCTION: Five billion people worldwide do not have timely access to surgical care. Cinterandes is one of the only mobile surgical units in low- and middle income countries. This paper examines the methodology that Cinterandes uses to deliver mobile surgery. METHODS: Founding and core staff were interviewed, four missions were participated in, and internal documents and records were analysed between 1 May and 1 July 2014. RESULTS: Cinterandes performed 7641 operations over the last 20 years (60% gastrointestinal/laparoscopic), travelling 300,000 km to remote areas of Ecuador. The mobile surgery programme was initiated by a local Ecuadorian surgeon in 1980. Funding was acquired from businesses, private hospitals, and individuals, to fund a low-cost surgical truck, simple equipment, and running costs. The mobile surgical unit is a 24-foot modified Isuzu truck containing a preparation room with general equipment storage and running water, together with an operating room including the operating table, anaesthetic and surgical equipment. Mission structure includes: patient identification by a network of local medical personnel in remote regions; pre-operative assessment at 1 week by core team via teleconsultations; four-day surgical missions; post operative recovery in tents or a local clinic; post-operative follow-up care by local personnel and remote teleconsultations. The permanent core team includes seven members; lead surgeon, lead anaesthetist, operating-room technician, medical coordinator, driver, general coordinator, and receptionist. Additional support members include seven regular surgeons, residents, medical students, and volunteers. CONCLUSION: Surgery is a very effective way to gain the trust of the community, due to immediate results. Trust opens doors to other programmes (e.g. family medicine). Surgery can be incorporated with all other aspects of health care, which can in turn be incorporated with all other aspects of human development, education, food production and nutrition, housing, work and productivity, communication, and recreation. PMID- 28639041 TI - Long-term outcomes and quality of life after surgical or conservative treatment of benign simple liver cysts. AB - BACKGROUND: Benign liver cysts are common and are often detected incidentally. Most patients do not require intervention. Occasionally, large dominant or multifocal small cysts cause symptoms as a result of rapid growth, secondary infection, intra-cystic bleeding or compression of adjacent organs. AIM: To compare presenting symptoms and outcomes of a consecutive series of patients with benign liver cysts treated either conservatively or by surgical intervention. Long-term quality of life (QoL) was also assessed. METHODS: Retrospective analysis of prospectively collected data was conducted. Long-term general and disease-specific quality of life was also documented. RESULTS: Ninety-five patients were included in the study (46 treated operatively, 49 treated conservatively). 80% were female, and the mean age of the cohort was 58 years. Those who had surgical intervention were older (62 vs 55 years, p = 0.004), were more likely to have shortness of breath at presentation (11 vs 5%, p = 0.018) and had larger cysts (12 vs 4 cm, p < 0.001) compared with those offered conservative treatment. Laparoscopic stapled excision was the most common operative procedure (70%) and the overall complication rate was 20%. At a median follow-up of 64 months, 17% (8/46) of the surgically treated patients had radiological evidence of cyst recurrence but only 9% (4/46) were symptomatic. At median follow-up of 71 months, 37% (14/38) of conservatively treated patients had unchanged or new symptoms compared to the first presentation. Furthermore, 10% (4/38) of this group had additional radiological or surgical intervention for persistent symptoms during the follow-up period. Overall, there was no difference in long term QoL between the two groups. CONCLUSION: Surgical intervention for selected patients with symptomatic benign liver cysts results in low long-term recurrence rates and excellent patient-reported outcomes and quality of life. Laparoscopic stapled excision can be done safely and reliably in carefully selected patients. PMID- 28639042 TI - Comparative study between endoscopic submucosal dissection and surgery in patients with early gastric cancer. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is accepted as a standard treatment in patients with early gastric cancer (EGC) who have a negligible risk of lymph node metastasis. The aim of this study was to compare the short-term and long-term outcomes between ESD and surgery in patients with EGC that fulfilled the expanded indication of ESD on their final pathologic report. METHODS: We reviewed the clinical data of patients who underwent gastric ESD and surgery between January 2007 and December 2012. Patients with pathologically confirmed EGC that fulfilled the expanded indication of ESD on their final pathologic report were analyzed. RESULTS: Among 2023 patients, 817 (40.4%) underwent ESD and 1206 (59.6%) underwent surgery. The proportion of cases meeting the absolute indication was significantly higher in the ESD group than in the surgery group (66.0 vs. 26.2%). Lesions on the middle third, >3 cm in size, flat or depressed, and of undifferentiated histology were significantly more common in the surgery group than in the ESD group. The ESD group showed lower acute complication rates [8.1% (66 of 817) vs. 18.1% (218 of 1206), P <= 0.001] and procedure-related mortality [0 vs. 0.3% (4 of 1206), P = 0.153] than the surgical group. The annual incidence of recurrent gastric cancer was 2.18% in the ESD group and 0.19% in the surgery group. The 5-year overall and disease-specific survival rates were not significantly different between the ESD group and the surgery group (overall survival: 96.4 vs. 97.2%, P = 0.423; disease-specific survival: 99.6 vs. 99.2%, P = 0.203). CONCLUSIONS: Although EGC lesions had poorer features in the surgery group than in the ESD group, ESD was comparable to surgery for EGCs that fulfilled the expanded indication of ESD, with lower rates of acute complication and comparable overall survival. PMID- 28639043 TI - Ultrasonographic optic nerve sheath diameter for predicting elevated intracranial pressure during laparoscopic surgery: a systematic review and meta-analysis. AB - BACKGROUND: Laparoscopic surgery involves the creation of a carbon dioxide (CO2) pneumoperitoneum to facilitate a clear surgical view, which may result in an elevated intracranial pressure (ICP). Depending on the surgical area, steep Trendelenburg positioning may be used as well, further increasing the ICP. The objective of this study was to assess the effects of laparoscopic surgery on changes in ICP assessed by ultrasonographic measurement of optic nerve sheath diameter (ONSD), which is a generally accepted simple, reliable, and non-invasive ICP measurement technique. METHODS: A computerized literature search was performed in August 2016 to identity prospective studies that measured ONSD to assess ICP changes during laparoscopic surgery. The primary outcome was the change in ONSD during the early (0-30 min) and late (30-120 min) periods after initiating pneumoperitoneum, compared with baseline values measured after anesthesia induction. Mean differences (MDs) with 95% confidence intervals [CIs] were calculated. RESULTS: Nine observational studies and one randomized controlled trial, with a total of 460 subjects, were analyzed. Compared to the baseline value after anesthesia induction, significant increases in ONSD were observed in both the early period (MD 0.46, 95% CI 0.31-0.61, P < 0.001, I 2 = 97.3%) and late period (MD 0.67, 95% CI 0.20-1.14, P = 0.005, I 2 = 99.2%). Comparing the ONSD during the early and late periods revealed no significant differences over time. CONCLUSIONS: The current meta-analysis revealed that ICP elevation during laparoscopy could be anticipated through a significant increase in the ONSD in the early (0-30 min) and late (30-120 min) periods during CO2 pneumoperitoneum. PMID- 28639045 TI - Passing the fundamentals of endoscopic surgery (FES) exam: linking specialty choice and attitudes about endoscopic surgery to success. AB - INTRODUCTION: Previous work has shown that up to 30% of graduating surgery residents fail the fundamentals of endoscopic surgery (FES) exam. This study investigated the extent to which FES pass rates differ in a specific sample of individuals who have chosen a career in GI surgery and to examine the relationships between FES performance and confidence in performing flexible endoscopy. METHODS: Fellows attending the 2016 SAGES Flexible Endoscopy Course were invited to complete the FES manual skills examination. Participants also provided survey responses examining demographics, fellowship type, endoscopy curricula in residency, previous endoscopic case volume, confidence in performing endoscopy, and future practice plans. RESULTS: Twenty-nine (age: 32.24 +/- 3.24; 72% men) fellows completed the FES skills examination. Reported fellowships were MIS/Bariatric (41.4%), MIS (24.1%), bariatric (13.8%), flexible endoscopy (6.9%), Advanced GI (6.9%), and MIS/bariatric/flexible endoscopy (6.9%). Almost half (41.4%) had previously participated in a simulation curricula, with 20.7% completing a didactic endoscopy curriculum. Fellows reported performing an average of 110 +/- 109.48 EGDs and 77.44 +/- 58.80 colonoscopies. The majority (96.4%) indicated that they will perform endoscopy at least occasionally in practice. Overall pass rate was 60%. Previous endoscopy experience did not correlate with overall FES examination scores. However, confidence performing EGDs (r = 0.57, p < 0.01), colonoscopies (r = 0.45, p < 0.05), polypectomy (r = 0.52, p < 0.01), and PEGs (r = 0.46, p < 0.05) did. CONCLUSIONS: These data support existing research suggesting that current flexible endoscopy training in residency may be insufficient for trainees to pass the FES examination, and that failure rates hold true even for this select group of trainees who have chosen a profession in GI surgery and intend to use endoscopy in practice. PMID- 28639044 TI - Short-term surgical outcomes of minimally invasive repeat hepatectomy for recurrent liver cancer. AB - BACKGROUND: Repeat liver resection is an effective treatment, with long-term surgical outcomes for recurrent hepatocellular carcinoma and colorectal liver metastasis. However, the efficacy of a minimally invasive surgical approach for recurrent liver cancer is not yet confirmed. The purpose of this study is to examine the efficacy of minimally invasive repeat liver resection (MISRLR) compared with open repeat liver resection (ORLR) for primary and metastatic liver cancer. Here, we retrospectively analyzed the clinicopathological features and short-term surgical outcomes of patients undergoing MISRLR and ORLR. METHODS: From 2005 to 2016, 97 patients with liver cancer underwent repeat hepatectomy. Of these patients, 68 patients receiving macroscopically curative resection and only hepatectomy, without other additional operations, were selected. Twenty patients underwent MISRLR and 48 patients underwent ORLR. We compared the clinicopathological and surgical parameters in the MISRLR group with those in the ORLR group. RESULTS: There were no statistically significant differences in patients' gender, age, viral infection status, Child-Pugh classification, tumor size, tumor number, tumor location, or the presence of liver cirrhosis in the two groups. The operative times were similar, but blood loss was significantly lower in MISRLR group (159 vs. 502 ml, P = 0.0035). The length of the postoperative hospital stay was significantly shorter in the MISRLR group (14.2 vs. 19.2 days, P = 0.0275). Postoperative complications were observed only in the ORLR group, with a complication rate of 19%. CONCLUSIONS: We demonstrate that MISRLR for primary and metastatic liver cancer reduces blood loss and postoperative complications compared with ORLR. MISRLR might be a feasible and effective procedure for the selected patients. PMID- 28639046 TI - Is multidetector CT-based bone mineral density and quantitative bone microstructure assessment at the spine still feasible using ultra-low tube current and sparse sampling? AB - OBJECTIVE: Osteoporosis diagnosis using multidetector CT (MDCT) is limited to relatively high radiation exposure. We investigated the effect of simulated ultra low-dose protocols on in-vivo bone mineral density (BMD) and quantitative trabecular bone assessment. MATERIALS AND METHODS: Institutional review board approval was obtained. Twelve subjects with osteoporotic vertebral fractures and 12 age- and gender-matched controls undergoing routine thoracic and abdominal MDCT were included (average effective dose: 10 mSv). Ultra-low radiation examinations were achieved by simulating lower tube currents and sparse samplings at 50%, 25% and 10% of the original dose. BMD and trabecular bone parameters were extracted in T10-L5. RESULTS: Except for BMD measurements in sparse sampling data, absolute values of all parameters derived from ultra-low-dose data were significantly different from those derived from original dose images (p<0.05). BMD, apparent bone fraction and trabecular thickness were still consistently lower in subjects with than in those without fractures (p<0.05). CONCLUSION: In ultra-low-dose scans, BMD and microstructure parameters were able to differentiate subjects with and without vertebral fractures, suggesting osteoporosis diagnosis is feasible. However, absolute values differed from original values. BMD from sparse sampling appeared to be more robust. This dose dependency of parameters should be considered for future clinical use. KEY POINTS: * BMD and quantitative bone parameters are assessable in ultra-low-dose in vivo MDCT scans. * Bone mineral density does not change significantly when sparse sampling is applied. * Quantitative trabecular bone microstructure measurements are sensitive to dose reduction. * Osteoporosis subjects could be differentiated even at 10% of original dose. * Radiation exposure should be considered when comparing quantitative bone parameters. PMID- 28639047 TI - Apparent diffusion coefficient maps obtained from high b value diffusion-weighted imaging in the preoperative evaluation of gliomas at 3T: comparison with standard b value diffusion-weighted imaging. AB - OBJECTIVE: To assess whether ADC maps obtained from high b value DWI were more valuable in preoperatively evaluating the grade, Ki-67 index and outcome of gliomas. METHODS: Sixty-three patients with gliomas, who underwent preoperative multi b value DWI at 3 T, were enrolled. The ADC1000, ADC2000 and ADC3000 maps were generated. Receiver operating characteristic analyses were conducted to determine the area under the curve (AUC) in differentiating high-grade gliomas (HGG) from low-grade gliomas (LGG). Pearson correlation coefficients (R value) were calculated to investigate the correlation between parameters with the Ki-67 proliferation index. Survival analysis was conducted by using Cox regression. RESULTS: The AUC of the mean ADC1000 value (0.820) was lower than that of the mean ADC2000 value (0.847) and mean ADC3000 value (0.875) in differentiating HGG from LGG. The R value of the mean ADC1000 value (-0.499) was less negative than that of the mean ADC2000 value (-0.530) and mean ADC3000 value (-0.567). The mean ADC3000 value was an independent prognosis factor for gliomas (p = 0.008), while the mean ADC1000 and ADC2000 values were not. CONCLUSION: ADC maps obtained from high b value DWI might be a better imaging biomarker in the preoperative evaluation of gliomas. KEY POINTS: * ADC 3000 maps could improve the differentiation between HGG and LGG. * The mean ADC 3000 value had a closer correlation with the Ki-67 index. * The mean ADC 3000 value was an independent prognosis factor for gliomas. PMID- 28639048 TI - Evaluating anorexia-related brain atrophy using MP2RAGE-based morphometry. AB - AIM: To evaluate brain atrophy in anorexic patients by automated cerebral segmentation with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) MRI sequence. MATERIAL AND METHODS: Twenty patients (female; mean age, 27.9 years), presenting consecutively for brain MRI between August 2014-December 2016 with clinical suspicion of anorexia nervosa and BMI<18.5 kg/m2 were included. Controls were ten healthy females (mean age, 26.5 years). Automated brain morphometry was performed based on MP2RAGE. Means of morphometric results in the two groups were compared and correlation with BMI was analysed. RESULTS: Significantly lower volumes of total brain, grey matter (GM), white matter (WM), cerebellum and insula were found in anorexic patients. Anorexics had higher volumes of CSF, ventricles, lateral ventricles and third ventricle. When adjusted means for weight and height were compared, the volume of WM and cerebellum were not significantly different. However, volume of WM was significantly affected by weight and positively correlated with BMI. Significant positive correlations were found between BMI and volumes of total brain, GM, cortical GM and WM. BMI was negatively correlated with volumes of CSF and third ventricle. CONCLUSION: Brain atrophy was demonstrated in anorexic patients with MP2RAGE-based automated segmentation, which seems to reliably estimate brain volume. KEY POINTS: * Automated brain segmentation based on 3-D MRI seems to reliably estimate brain volume. * This technique detected brain atrophy in patients suffering from anorexia nervosa. * Brain changes in anorexia nervosa can be quantitatively and qualitatively followed-up by MRI. PMID- 28639049 TI - Multiparametric voxel-based analyses of standardized uptake values and apparent diffusion coefficients of soft-tissue tumours with a positron emission tomography/magnetic resonance system: Preliminary results. AB - OBJECTIVES: To investigate the usefulness of voxel-based analysis of standardized uptake values (SUVs) and apparent diffusion coefficients (ADCs) for evaluating soft-tissue tumour malignancy with a PET/MR system. METHODS: Thirty-five subjects with either ten low/intermediate-grade tumours or 25 high-grade tumours were prospectively enrolled. Zoomed diffusion-weighted and fluorodeoxyglucose (18FDG) PET images were acquired along with fat-suppressed T2-weighted images (FST2WIs). Regions of interest (ROIs) were drawn on FST2WIs including the tumour in all slices. ROIs were pasted onto PET and ADC-maps to measure SUVs and ADCs within tumour ROIs. Tumour volume, SUVmax, ADCminimum, the heterogeneity and the correlation coefficients of SUV and ADC were recorded. The parameters of high- and low/intermediate-grade groups were compared, and receiver operating characteristic (ROC) analysis was also performed. RESULTS: The mean correlation coefficient for SUV and ADC in high-grade sarcomas was lower than that of low/intermediate-grade tumours (-0.41 +/- 0.25 vs. -0.08 +/- 0.34, P < 0.01). Other parameters did not differ significantly. ROC analysis demonstrated that correlation coefficient showed the best diagnostic performance for differentiating the two groups (AUC 0.79, sensitivity 96.0%, specificity 60%, accuracy 85.7%). CONCLUSIONS: SUV and ADC determined via PET/MR may be useful for differentiating between high-grade and low/intermediate-grade soft tissue tumours. KEY POINTS: * PET/MR allows voxel-based comparison of SUVs and ADCs in soft-tissue tumours. * A comprehensive assessment of internal heterogeneity was performed with scatter plots. * SUVmax or ADCminimum could not differentiate high grade sarcoma from low/intermediate-grade tumours. * Only the correlation coefficient between SUV and ADC differentiated the two groups. * The correlation coefficient showed the best diagnostic performance by ROC analysis. PMID- 28639050 TI - Paeoniflorin Suppressed High Glucose-Induced Retinal Microglia MMP-9 Expression and Inflammatory Response via Inhibition of TLR4/NF-kappaB Pathway Through Upregulation of SOCS3 in Diabetic Retinopathy. AB - Diabetic retinopathy (DR) is a serious-threatening complication of diabetes and urgently needed to be treated. Evidence has accumulated indicating that microglia inflammation within the retina plays a critical role in DR. Microglial matrix metalloproteinase 9 (MMP-9) has an important role in the destruction of the integrity of the blood-retinal barrier (BRB) associated with the development of DR. MMP-9 was also considered important for regulating inflammatory responses. Paeoniflorin, a monoterpene glucoside, has a potent immunomodulatory effect on microglia. We hypothesized that paeoniflorin could significantly suppress microglial MMP-9 activation induced by high glucose and further relieve DR. BV2 cells were used to investigate the effects and mechanism of paeoniflorin. The activation of MMP-9 was measured by gelatin zymography. Cell signaling was measured by western blot assay and immunofluorescence assay. High glucose increased the activation of MMP-9 in BV2 cells, which was abolished by HMGB1, TLR4, p38 MAPK, and NF-kappaB inhibition. Phosphorylation of p38 MAPK induced by high glucose was decreased by TLR4 inhibition in BV2 cells. Paeoniflorin induced suppressor of cytokine signaling 3 (SOCS3) expression and reduced MMP-9 activation in BV2 cells. The effect of paeoniflorin on SOCS3 was abolished by the TLR4 inhibitor. In streptozotocin (STZ)-induced diabetes mice, paeoniflorin induced SOCS3 expression and reduced MMP-9 activation. Paeoniflorin suppressed STZ-induced IBA-1 and IL-1beta expression and decreased STZ-induced high blood glucose level. In conclusion, paeoniflorin suppressed high glucose-induced retinal microglia MMP-9 expression and inflammatory response via inhibition of the TLR4/NF-kappaB pathway through upregulation of SOCS3 in diabetic retinopathy. PMID- 28639051 TI - Adjuvant treatment for pancreatic ductal carcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a very poor prognosis. Most of the patients are diagnosed in advanced stages of the disease, and 5-year survival rates in these patients remains <10%. Surgery still remains the only radical treatment option, although only 15-20% of patients are candidates for surgical resection at the time of the diagnosis. Patients who undergo radical surgery still have a limited survival rate, being the average of 23 months. Three clinical trials have shown that adjuvant chemotherapy therapy after surgery may improve survival: CONKO-1, ESPAC-3, and ESPAC-4. Adjuvant therapy is recommended in patients with R0/R1, T1-4/N1-0 tumors and with ECOG 0-1. In patients with ECOG 2, the decision needs to be individualized. Treatment schemes that have demonstrated efficacy include gemcitabine alone, 5-fluorouracil, or the combination of gemcitabine and capecitabine for six months. Prior to adjuvant treatment, the following test are recommended: Complete blood tests, including CA19.9 biomarker; imaging studies to rule out early disease relapse (preferable thorax-abdomen-pelvic CT). Studies that have evaluated the efficacy of radiation therapy in the adjuvant setting have presented conflicting results. Its use should be considered in patients with R1 or R2 tumors or in those with lymph nodes involved. PMID- 28639052 TI - Gentamicin-Loaded Polysaccharide Membranes for Prevention and Treatment of Post operative Wound Infections in the Skeletal System. AB - PURPOSE: To develop polysaccharide-based membranes that allow controlled and localized delivery of gentamicin for the treatment of post-operative bone infections. METHODS: Membranes made of gellan gum (GUM), sodium alginate (ALG), GUM and ALG crosslinked with calcium ions (GUM + Ca and ALG + Ca, respectively) as well as reference collagen (COL) were produced by freeze-drying. Mechanical properties, drug release, antimicrobial activity and cytocompatibility of the membranes were assessed. RESULTS: The most appropriate handling and mechanical properties (Young's modulus, E = 92 +/- 4 MPa and breaking force, F MAX = 2.6 +/ 0.1 N) had GUM + Ca membrane. In contrast, COL membrane showed F MAX = 0.14 +/- 0.02 N, E = 1.0 +/- 0.3 MPa and was deemed to be unsuitable for antibiotic delivery. The pharmacokinetic data demonstrated a uniform and sustainable delivery of gentamicin from GUM + Ca (44.4 +/- 1.3% within 3 weeks), while for COL, ALG and ALG + Ca membranes the most of the drug was released within 24 h (55.3 +/- 1.9%, 52.5 +/- 1.5% and 37.5 +/- 1.8%, respectively). Antimicrobial activity against S. aureus and S. epidermidis was confirmed for all the membranes. GUM + Ca and COL membranes supported osteoblasts growth, whereas on ALG and ALG + Ca membranes cell growth was reduced. CONCLUSIONS: GUM + Ca membrane holds promise for effective treatment of bone infections thanks to favorable pharmacokinetics, bactericidal activity, cytocompatibility and good mechanical properties. PMID- 28639053 TI - Managing the genomic revolution in cancer diagnostics. AB - Molecular tumor profiling is now a routine part of patient care, revealing targetable genomic alterations and molecularly distinct tumor subtypes with therapeutic and prognostic implications. The widespread adoption of next generation sequencing technologies has greatly facilitated clinical implementation of genomic data and opened the door for high-throughput multigene targeted sequencing. Herein, we discuss the variability of cancer genetic profiling currently offered by clinical laboratories, the challenges of applying rapidly evolving medical knowledge to individual patients, and the need for more standardized population-based molecular profiling. PMID- 28639054 TI - A Strong Relationship Between Oral Squamous Cell Carcinoma and DNA Repair Genes. AB - Single nucleotide polymorphisms of DNA repair genes alter protein function and modulate DNA repair efficiency in various cancers. The X-ray repair cross complementing group (XRCC) is responsible for the repair of DNA base damage and single-strand breaks. The aim of our study was to investigate the association of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms with the susceptibility to develop oral squamous cell carcinoma (OSCC) in Turkish subjects. One hundred eleven patients with OSCC and 148 healthy controls were recruited for the study. Genetic analysis was performed using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). We found that the XRCC1 Arg399Gln Gln/Gln genotype and Gln allele were risk factors for OSCC. Also, Arg/Arg genotype and Arg allele had protective effects against OSCC. Relative to XRCC3 Thr241Met polymorphism, carrying homozygote variants (Thr/Thr and Met/Met) was related with elevated OSCC risk. However, the heterozygote genotype and Thr allele variants were shown to be protective against OSCC. We suggest that XRCC1 Arg399Gln Gln/Gln genotype, Gln allele, and homozygote variants of XRCC3 Thr241Met polymorphism may be a risk factor for predisposition of OSCC in Turkish. In addition, XRCC3 Thr241Met genotype could be associated with tumor size and level of daily smoking. PMID- 28639055 TI - Effects of Kaolin (M-99-099) Application on Antioxidant and Phenolic Compounds in Tea Leaves (Camellia sinensis L.O. Kuntze). AB - In this study, the effects of kaolin (M-99-099) applications on the total phenolic and antioxidant contents of tea leaves (Camellia sinensis (L.) O. Kuntze) harvested in three different periods were investigated. For this purpose, four different strategies including standard fertilizer application (T), 3% kaolin+standard fertilizer application (Ka1), 6% kaolin+standard fertilizer application (Ka2), and control (C) (nothing applied) were used to compare the effects of these strategies on total phenolic content, FRAP values, and DPPH radical scavenging capacities of tea leaves. It has been proven that the kaolin applications, Ka1 and Ka2, increase the phenolic content and antioxidant contents of tea samples. While the kaolin applications have higher values at 1st harvest than those of T and C, they have the lowest values at 3rd harvest. PMID- 28639056 TI - Relevance of the Clinical and Psychophysiological Variables in the Dyssynergic Defecation: A Comparative Study in Elderly Subjects. AB - The relevance of several clinical and psychophysiological variables in the dyssynergic defecation in elderly subjects was investigated in this study. To accomplish this, 30 elderly subjects (10 without anorectal disorders, 10 with chronic constipation and 10 with dyssynergic defecation) were repeatedly assessed once per week for 4 weeks, with the following measures being collected at each session: EMG-activity (uV) of the external anal sphincter (at rest, during squeezing, and during straining to defecate), stool frequency, difficulty defecation level, pain grade during defecation, and satisfaction level after evacuation. A 3 (group) * 4 (sessions) mixed-measures MANOVA revealed a significant main effect for group (Wilks's lambda = 0.006; F = 28.45; p < 0.01), but not for sessions (Wilks's lambda = 0.874; F = 0.94; p > 0.05) or for the group x sessions interaction (Wilks's lambda = 0.811; F = 1.45; p > 0.05). One way ANOVA and Scheffe's posthoc tests were used to isolate the differences between the groups with respect to the seven different measures. These analysis showed significant differences between the groups on all four clinical variables but only for one psychophysiological variable, EMG-activity during straining to defecate. Significant differences were evidenced between all pairs examined for the difficulty defecation level and pain grade. The complete results of these analysis are presented and the conclusions drawn from them are discussed. PMID- 28639057 TI - Factors controlling the reactivity of divalent metal ions towards pheophytin a. AB - In this study, we evaluate the factors which determine the reactivity of divalent metal ions in the spontaneous formation of metallochlorophylls, using experimental and computational approaches. Kinetic studies were carried out using pheophytin a in reactions with various divalent metal ions combined with non- or weakly-coordinative counter ions in a series of organic solvents. To obtain detailed insights into the solvent effect, the metalations with the whole set of cations were investigated in three solvents and with Zn2+ in seven solvents. The reactions were monitored using electronic absorption spectroscopy and the stopped flow technique. DFT calculations were employed to shed light on the role of solvent in activating the metal ions towards porphyrinoids. This experimental and computational analysis gives detailed information regarding how the solvent and the counter ion assist/hinder the metalation reaction as activators/inhibitors. The metalation course is dictated to a large extent by the reaction medium, via either the activation or deactivation of the incoming metal ion. The solvent may affect the metalation in several ways, mainly via H-bonding with pyrrolenine nitrogens and the activation/deactivation of the incoming cation. It also seems to affect the activation enthalpy by causing slight conformational changes in the macrocyclic ligand. These new mechanistic insights contribute to a better understanding of the "metal-counterion-solvent" interplay in the metalation of porphyrinoids. In addition, they are highly relevant to the mechanisms of metalation reactions catalyzed by chelatases and explain the differences between the insertion of Mg2+ and other divalent cations. PMID- 28639058 TI - Geospatial Analysis of Drug Poisoning Deaths Involving Heroin in the USA, 2000 2014. AB - We investigate the geographic patterns of drug poisoning deaths involving heroin by county for the USA from 2000 to 2014. The county-level patterns of mortality are examined with respect to age-adjusted rates of death for different classes of urbanization and racial and ethnic groups, while rates based on raw counts of drug poisoning deaths involving heroin are estimated for different age groups and by gender. To account for possible underestimations in these rates due to small areas or small numbers, spatial empirical Baye's estimation techniques have been used to smooth the rates of death and alleviate underestimation when analyzing spatial patterns for these different groups. The geographic pattern of poisoning deaths involving heroin has shifted from the west coast of the USA in the year 2000 to New England, the Mid-Atlantic region, and the Great Lakes and central Ohio Valley by 2014. The evolution over space and time of clusters of drug poisoning deaths involving heroin is confirmed through the SaTScan analysis. For this period, White males were found to be the most impacted population group overall; however, Blacks and Hispanics are highly impacted in counties where significant populations of these two groups reside. Our results show that while 35-54-year-olds were the most highly impacted age group by county from 2000 to 2010, by 2014, the trend had changed with an increasing number of counties experiencing higher death rates for individuals 25-34 years. The percentage of counties across the USA classified as large metro with deaths involving heroin is estimated to have decreased from approximately 73% in 2010 to just fewer than 56% in 2014, with a shift to small metro and non-metro counties. Understanding the geographic variations in impact on different population groups in the USA has become particularly necessary in light of the extreme increase in the use and misuse of street drugs including heroin and the subsequent rise in opioid-related deaths in the USA. PMID- 28639059 TI - Safety of flexible endoscopic biopsy of the pharynx and larynx under topical anesthesia. AB - Recent advancements in transnasal endoscopy enable a shift in diagnostic workup of lesions in the pharynx and larynx, from an examination with biopsy under general anesthesia to an office-based examination with flexible endoscopic biopsy under topical anesthesia. Procedural complications were evaluated to assess the safety of office-based flexible endoscopic biopsy in patients with benign and malignant laryngopharyngeal lesions. Patients who underwent flexible endoscopic biopsy from 2012 to 2016 were evaluated retrospectively. Complications were classified using the Clavien-Dindo classification of surgical complications. A total of 201 flexible endoscopic biopsies were performed in 187 patients. Two Clavien-Dindo grade I (laryngospasm and anterior epistaxis), one grade II (laryngeal bleeding), and one grade IIIb (laryngeal edema) complication were observed. The first complication was self-limiting and the other three required an intervention. All patients fully recovered without sequelae. Flexible endoscopic biopsy appears to be a safe office-based procedure for the diagnosis of benign and malignant laryngopharyngeal lesions. PMID- 28639060 TI - Surgical options in benign parotid tumors: a proposal for classification. AB - Different surgical options are currently available for treating benign tumors of the parotid gland, and the discussion on optimal treatment continues despite several meta-analyses. These options include more limited resections (extracapsular dissection, partial lateral parotidectomy) versus more extensive and traditional options (lateral parotid lobectomy, total parotidectomy). Different schools favor one option or another based on their experience, skills and tradition. This review provides a critical analysis of the literature regarding these options. The main limitation of all the studies is the bias of selection for different surgical approaches. For this reason, we propose a staging system that could facilitate clinical decision making and the comparison of results. We propose four categories based on the size of the tumor and its location within the parotid gland. Category I includes tumors up to 3 cm, which are mobile, close to the outer surface and close to the parotid borders. Category II includes deeper tumors up to 3 cm. Category III comprises tumors greater than 3 cm involving two levels of the parotid gland, and category IV tumors are greater than 3 cm and involve more than 2 levels. For each category and for the various pathologic types, a guideline of surgical extent is proposed. The objective of this classification is to facilitate prospective multicentric studies on surgical techniques in the treatment of benign parotid tumors and to enable the comparison of results of different clinical studies. PMID- 28639062 TI - Rheumatoid arthritis: from basic findings and clinical manifestations to future therapies. PMID- 28639063 TI - Erratum to: Screen Time, Other Sedentary Behaviours, and Obesity Risk in Adults: a Review of Reviews. PMID- 28639061 TI - Oral and oropharyngeal papillomas are not associated with high-risk human papillomavirus infection. AB - The role of different types of human papillomavirus (HPV) in the development of oral and oropharyngeal papillomas remains unclear. High-risk HPV (HR-HPV) was shown to be involved in the pathogenesis of significant proportion of squamous cell carcinomas of the oropharynx. In this study, we hypothesized that in some oropharyngeal papillomas, low-risk HPV (LR-HPV) and HR-HPV infection could co exist, similar to what is observed in genital warts, and thus contribute to the elevated risk of malignancy. To test this hypothesis, we used real-time PCR to assess the presence of HPV DNA of 16 types (2 LR-HPV and 14 HR-HPV), in 75 formalin-fixed and paraffin-embedded histopathological samples of oral and oropharyngeal papillomas and in 57 squamous cell carcinomas from the same regions. We investigated the biological activity of HPV by demonstrating accumulation of P16(INK4A) protein in the viral-infected tissue samples. The presence of the LR-HPV genome from the HPV6 or HPV11 types was confirmed in 42 (56%) papillomas and in no carcinomas. HPV6/HPV11 co-infection was detected in 17 (22.7%) of the papillomas. HR-HPV DNA presence and HR-HPV activity hallmarks were not observed in any of the investigated papillomas. Thus, a causative role for HR HPV or its contribution to LR/HR-HPV co-infection in the pathogenesis of oral or oropharyngeal papillomas is unlikely. Additionally, HR-HPV and LR-HPV infections seem to be mutually exclusive in papillomas and squamous cell carcinomas of the oral cavity and oropharynx. PMID- 28639064 TI - Whole lipid profile and not only HDL cholesterol is impaired in children with coexisting type 1 diabetes and untreated celiac disease. AB - AIMS: Low HDL cholesterol (HDL-C) levels have been described in patients with coexisting type 1 diabetes mellitus (T1DM) and celiac disease (CD). Data on other possible lipid abnormalities that could further increase cardiovascular risk in these patients are scarce and incomplete. Aim of this retrospective multicenter study was to evaluate whole lipid profiles, besides HDL-C, in children with T1DM associated with biopsy-proven CD, and to investigate the influence of age and degree of adherence to gluten-free diet (GFD) on lipid changes. METHODS: A total of 261 children with both T1DM and CD were enrolled. Serum lipid profiles at CD diagnosis were compared with those after 1 year of GFD and with those of 224 matched children with T1DM alone. The adherence to GFD was judged by means of CD related antibodies. RESULTS: At CD diagnosis, children with T1DM + CD showed higher LDL cholesterol (LDL-C) compared to children with T1DM alone. Gluten withdrawal failed to normalize LDL-C levels, not even in completely adherent individuals. HbA1c values were not influenced by GFD. The youngest children were characterized at diagnosis by lower levels of total cholesterol and on treatment by a greater decrease in triglycerides levels. CONCLUSIONS: An unfavorable lipid profile, characterized not only by low HDL-C levels but also by high LDL-C values, may increase the risk of cardiovascular disease in children with T1DM and untreated CD. Therefore, a strict gluten-free diet is mandatory in these children, especially the youngest. PMID- 28639065 TI - Nosocomial Rhinocerebral Mucormycosis: Two Cases with a Temporal Relationship. AB - Mucormycosis is an unusual fungal infection that usually affects immunosuppressed patients. Small outbreaks of mucormycosis have been previously reported. We present two clinical cases of fatal rhinocerebral mucormycosis with a close temporal relationship between them and a possible nosocomial transmission: case 1 was a 75-year-old male with diabetes and COPD, treated with antibiotics and systemic corticosteroids, who developed rhinocerebral mucormycosis. Case 2 was an 88-year-old woman who was treated with systemic antibiotics and corticosteroids and developed the same infection after insertion of a nasogastric tube. Both patients concurred at the same time in our hospital, and healthcare staff was common to both of them. These cases, along with previously reported cases, highlight that, although infrequent, transmission of the fungus in the hospital environment is a real possibility that should be taken into account in order to initiate contact and air isolation precautions that could avoid nosocomial transmission of this infection. PMID- 28639067 TI - Discussion: The Characteristics and Short-Term Surgical Outcomes of Adolescent Gynecomastia by B.S. Choi et al. PMID- 28639068 TI - What About the Rheological Properties of PRP/Microfat Mixtures in Fat Grafting Procedure? AB - BACKGROUND: Fat grafting has emerged as a reference procedure in daily plastic surgery practice. Unpredictable fat resorption is the main clinical problem. For this purpose, the addition of PRP to enhance fat revascularization is now an easy and popular procedure. However, no consensus exists regarding the respective volume of fat and PRP used to obtain the ideal mixture. This study investigated the rheological properties of microfat mixed with different proportions of PRP. Results obtained were compared with commercialized hyaluronic acid fillers. METHODS: Microfat and PRP preparations were performed using standardized techniques. Lipoaspirate residue and blood were obtained from six patients undergoing aesthetic facial microlipofilling. Elastic modulus G' and tan delta (proportion of elasticity versus fluidity) were obtained for the following conditions: microfat alone and microfat mixed with 10, 30 or 50% of PRP. RESULTS: An expected decrease in elastic modulus was observed by adding increase volumes of PRP. Two groups of products with different rheological properties were considered based on statistical differences highlighted regarding the value of G'. Mean tan delta varied from 0.20 +/- 0.04 (microfat alone) to 0.28 +/- 0.08 (50% microfat/50% PRP). Microfat mixed with 10% of PRP presents consistency comparable to stiffer fillers, whereas microfat mixed with 30 or 50% corresponds to softer fillers. CONCLUSION: Rheological differences were highlighted given the proportion of PRP added to the microfat. Further studies assessing the impact of increased doses of platelets in microfat/PRP mixtures on clinical outcomes should also be investigated. Our findings will help clinicians to choose a mixture that meets their specific needs for a given indication. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 28639066 TI - Enzymatic Mechanisms Involved in Evasion of Fungi to the Oxidative Stress: Focus on Scedosporium apiospermum. AB - The airways of patients with cystic fibrosis (CF) are frequently colonized by various filamentous fungi, mainly Aspergillus fumigatus and Scedosporium species. To establish within the respiratory tract and cause an infection, these opportunistic fungi express pathogenic factors allowing adherence to the host tissues, uptake of extracellular iron, or evasion to the host immune response. During the colonization process, inhaled conidia and the subsequent hyphae are exposed to reactive oxygen species (ROS) and reactive nitrogen species (RNS) released by phagocytic cells, which cause in the fungal cells an oxidative stress and a nitrosative stress, respectively. To cope with these constraints, fungal pathogens have developed various mechanisms that protect the fungus against ROS and RNS, including enzymatic antioxidant systems. In this review, we summarize the different works performed on ROS- and RNS-detoxifying enzymes in fungi commonly encountered in the airways of CF patients and highlight their role in pathogenesis of the airway colonization or respiratory infections. The potential of these enzymes as serodiagnostic tools is also emphasized. In addition, taking advantage of the recent availability of the whole genome sequence of S. apiospermum, we identified the various genes encoding ROS- and RNS-detoxifying enzymes, which pave the way for future investigations on the role of these enzymes in pathogenesis of these emerging species since they may constitute new therapeutics targets. PMID- 28639070 TI - Osseous-Cartilaginous Spreader Graft and Nasal Framework Reconstruction. AB - Revision rhinoplasties and saddle nose deformities usually require grafting for reconstruction. Between January 1, 2000, and January 1, 2017, autologous rib grafts were used in 127 secondary and tertiary rhinoplasty patients [(57/127 females) and (70/127 males)]. Osseous-cartilaginous rib grafts (OCRGs) were divided into three parts (i.e., 1/3 upper peripheral, 1/3 central, and 1/3 lower peripheral). The harvested OCRGs were also shaped as vertical strips using a number 11 scalpel blade. These OCRGs were shaped to form the L-strut cartilaginous graft (LSCGs), osseous-cartilaginous spreader grafts (OCSGs), osseous-cartilaginous onlay grafts, nasal valve grafts (NVGs), and lower lateral cartilaginous grafts (LLCGs). The upper peripheral portion of the rib was usually used as an onlay graft for dorsal reshaping. The shape of this part was minimally convex after being cut from the main graft, and the convex shape was very appropriate for use as an onlay graft. The middle portion of the graft that consisted of the osseous and cartilaginous structure was used for the OCSGs. The middle portion of the graft that contained only cartilage was used for the LSCGs, NVGs, and LLCGs. OCRGs were used for the dorsal, alar, septal, upper lateral, and columellar struts for all patients. OCSGs were used for all of the septal grafts to provide further stability. In the nasal valve failure patients, the rib cartilage was fixed onto the lower lateral and upper lateral cartilage and was sutured using polyglactin to improve nasal valve function. One edge of the graft was sutured over the septum, and the other edge was positioned against the maxillary crest to allow for air flow at the nasal valve. After an OCSG was sutured to the septum, a flat and smooth dorsum was shaped before the dorsal onlay graft was placed and fixed. The bone fragments of the grafts that consisted of spreader and onlay grafts were tied to the radix nasi bone without any space. After 6 months of follow-up, a minimally warping defect was apparent in 8 patients but none of these patients requested another surgery. The analysis of the questionnaire responses revealed that >90% of the patients were satisfied with the outcome of the procedure. Level of evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28639069 TI - The Application of 3D Printing Technology for Simultaneous Orthognathic Surgery and Mandibular Contour Osteoplasty in the Treatment of Craniofacial Deformities. AB - BACKGROUND: Because of the limitation of specific preoperative design and surgical templates, orthognathic surgery and mandibular contour osteoplasty are generally performed in two stages. Three-dimensional printing technology has improved the accuracy of the surgery and results in good surgical predictability easily. This study aims to confirm the effectiveness, feasibility and precision of simultaneous mandibular contour osteoplasty and orthognathic surgery with the assistance of 3D printing technology. METHODS: Ten patients, who were diagnosed with mandibular hypertrophy and bimaxillary deformities, were included in the study. In addition to conventional orthognathic surgery, mandibular angle ostectomy, mandibular outer cortex grinding or mandibular border ostectomy was designed for mandibular hypertrophy. Optimal osteotomy lines and simulated surgeries were designed according the 3D printing model of the mandible. Then, surgical templates were made on the 3D printing model. No muscle excision was performed in any patient. Preoperative, predicted and postoperative measurements were taken, including the gonial angle (Ar-Go-Me) and the mandibular width (Go Go). RESULTS: All the patients had a reposeful postoperative recovery, with no indication of obvious infection, facial paralysis, osteonecrosis or bone displacement. The gonial angle was improved from 110.3 degrees +/- 11.1 to 121.3 degrees +/- 2.9, and the mandibular width was improved from 117.5 mm +/- 6.8 to 111.9 mm +/- 4.2. The discrepancies between simulation and postoperation of the left gonial angle, the right gonial angle and the mandibular width were 0.56 degrees +/- 0.22, 0.65 degrees +/- 0.3 and 0.49 mm +/- 0.43, respectively. CONCLUSIONS: The results of our study illustrated the predictability, feasibility and reliability of simultaneous mandibular contour osteoplasty and orthognathic surgery with the assistance of 3D printing technology. Our technique could achieve functional improvement and an aesthetic profile at the same time. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28639071 TI - Synthesis of substituted 2H-chromenes by a three-component reaction as potential antioxidants. AB - A series of alkoxy-substituted 2H-chromenes were synthesized by a one-pot three component reaction using salicylaldehydes, acetyl acetone and alcohol as reactant and medium with tetra-n-butylammonium fluoride (TBAF) as catalyst. Simple reaction conditions, short reaction time and overall good yield of products make this synthetic strategy an efficient one to synthesize 2H-chromene molecules. All the synthesized compounds were evaluated for antioxidant activities. Among all the new compounds, 5j and 5k showed good inhibition [Formula: see text] and [Formula: see text]) at 100 [Formula: see text] concentrations. PMID- 28639072 TI - A synthesis of functionalized arylthio-acrylates, benzo[b][1,4]thiazines and benzo[4,5]thiazolo[3,2-a]azepines from 2-methylbenzothiazole and acetylenic esters in aqueous media. AB - Alkyl (Z)-3-((2-(N-((E)-3-methoxy-3-oxoprop-1-en-1 yl)acetamido)phenyl)thio)acrylates are obtained from the reaction between 2 methylbenzothiazole and alkyl propiolates in 70% aqueous alcohol, in moderate yields. When dialkyl acetylenedicarboxylates were used under similar conditions, tetra-alkyl 9,10-dihydrobenzo[4,5]thiazolo[3,2-a]azepine-7,8,9,10 tetracarboxylates, together with dialkyl 4-acetyl-3,4-dihydro-2H benzo[b][1,4]thiazine-2,3-dicarboxylates were obtained in about 4:1 ratios. The stereochemistry of these products has been confirmed by X-ray diffraction. PMID- 28639074 TI - Worsening trends in analgesics recommended for spinal pain in primary care. AB - PURPOSE: Limited evidence exists on secular trends of analgesics for spinal pain. We investigated general practitioner's (GP) recommendations of analgesic medicines for spinal pain and investigated characteristics associated with their recommendation. METHODS: We accessed data on spinal pain consultations from the Bettering the Evaluation and Care of Health (BEACH) database, a nationally representative database on GP activity in Australia. Data extracted included consultation details and management provided. Medicines recommended were grouped as simple analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics or neuropathic pain medicines. Multivariate logistic regression determined if patient characteristics and GP characteristics were associated with medication recommendations. RESULTS: We analysed BEACH data for 9100 GPs who managed 39,303 patients with spinal pain between 2004 and 2014. Over the decade, analgesic recommendations increased. After accounting for patient and GP characteristics, there was a significant increase in the rate single-ingredient opioid analgesics [annual relative increase of 6% (RR 1.06 (95% CI 1.05-1.07), P < 0.001)] and neuropathic pain medicines [annual relative increase of 19% (RR 1.19 (95% CI 1.16-1.22), P < 0.001)] were recommended; and a significant decrease in the rate NSAIDs were recommended [annual relative decrease of 4% (RR 0.96 (95% CI 0.95-0.97), P < 0.001)]. Logistic regression identified several patient and GP characteristics associated with medicine recommendations, e.g. stronger opioids were less likely recommended for Indigenous patients [odds ratio 0.15 (95% CI 0.04-0.56)]. CONCLUSIONS: GP's analgesic recommendations for spinal pain have become increasingly divergent from guideline recommendations over time. PMID- 28639073 TI - Prognostic factors affecting outcomes in fistulating perianal Crohn's disease: a systematic review. AB - BACKGROUND: One in three patients with Crohn's disease will develop a perianal fistulae, and one third of these will achieve long-term healing or closure. A barrier to conducting well-designed clinical trials for these patients is a lack of understanding of prognostic factors. This systematic review sets out to identify factors associated with prognosis of perianal Crohn's fistulae. METHODS: This review was registered on the PROSPERO database (CRD42016050316) and conducted in line with PRISMA guidelines along a predefined protocol. English language studies assessing baseline factors related to outcomes of fistulae treatment in adult patients were included. Searches were performed on MEDLINE and Embase databases. Screening of abstracts and full texts for eligibility was performed prior to extraction of data into predesigned forms. Bias was assessed using the QUIPS tool. RESULTS: Searches identified 997 papers. Following removal of duplicates and secondary searches, 923 were screened for inclusion. Forty seven papers were reviewed at full-text level and 13, 2 of which were randomised trials, were included in the final qualitative review. Two studies reported distribution of Crohn's disease as a prognostic factor for healing. Two studies found that CARD15 mutations decreased response of fistulae to antibiotics. Complexity of fistulae anatomy was implicated in prognosis by 4 studies. CONCLUSIONS: This systematic review has identified potential prognostic markers, including genetic factors and disease behaviour. We cannot, however, draw robust conclusions from this heterogeneous group of studies; therefore, we recommend that a prospective cohort study of well-characterised patients with Crohn's perianal fistulae is undertaken. PMID- 28639076 TI - Conservative treatment for lumbar compartment syndrome shows efficacy over 2-year follow-up: a case report and literature review. AB - BACKGROUND: Since in all studies of conservative treatment of lumbar compartment syndrome the follow-up duration was less than 6 months, it is difficult to draw firm conclusions. PURPOSE: To report a patient with lumbar paraspinal compartment syndrome who was treated conservatively over a follow-up period of 2 years. STUDY DESIGN: This is a case report of a 23-year-old male college student with lumbar paraspinal compartment syndrome who was treated conservatively. METHODS: We report a case of a 23-year-old male college student with lumbar paraspinal compartment syndrome who was treated conservatively. We repeatedly checked his physical examination, laboratory tests, lumbar compartment pressures, and magnetic resonance imaging, and surgical teams were readily prepared to operate should the patient's condition worsen. To prevent complications of rhabdomyolysis, hydration and alkalization were performed. We followed him up to 2 years after discharge. RESULT: Although the temporal changes on MRI up to the 1 year point, the patient continued to have no symptoms. CONCLUSIONS: Conservative therapy can be recommended if rhabdomyolysis is under control. PMID- 28639075 TI - Does clavicular shortening after nonoperative treatment of midshaft fractures affect shoulder function? A systematic review. AB - INTRODUCTION: Clavicular shortening due to non-anatomical healing of displaced clavicular fractures is believed to have a negative effect on shoulder function after recovery. The evidence for this, however, is equivocal. This review aimed to systematically evaluate the available literature to determine whether the current beliefs about clavicular shortening can be substantiated. MATERIALS AND METHODS: This systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. PubMed, EMBASE, Web of Science and the Clinical Trial Registry were searched to identify all studies published in English that evaluated the association between clavicular shortening and shoulder function in patients aged >=16 years with a nonoperatively treated, displaced midshaft clavicular fracture. Relevant data from the selected studies was extracted and summarized. Risk of bias of the included studies was assessed using the MINORS instrument. RESULTS: Six studies, of which five were retrospective, were included in this review analyzing a total of 379 patients. Due to heterogeneity in methods and reporting across studies, a pooled analysis of the results was not feasible. No clear associations were found between shortening and shoulder function scores (DASH and Constant score) or arm strength in each of the included studies. CONCLUSION: The existing evidence to date does not allow for a valid conclusion regarding the influence of shortening on shoulder function after union of nonoperatively treated midshaft clavicular fractures. Shortening alone is currently not an evidence-based indication to operate for the goal of functional improvement. Well-powered prospective comparative studies are needed to draw firm conclusions. PMID- 28639077 TI - Microbial compositions and metabolic interactions in one- and two-phase partitioning airlift bioreactors treating a complex VOC mixture. AB - Engineered microbial ecosystems in bioscrubbers for the treatment of volatile organic compounds (VOCs) have been complicated by complex VOC mixtures from various industrial emissions. Microbial associations with VOC removal performance of the bioscrubbers are still not definitive. Here, one- and two-phase partitioning airlift bioreactors were used for the treatment of a complex VOC mixture. Microbial characteristics in both bioreactors were uncovered by high throughput metagenomics sequencing. Results showed that dominant species with specialized VOC biodegradability were mainly responsible for high removal efficiency of relative individual VOC. Competitive enzyme inhibitions among the VOC mixture were closely related to the deterioration of removal performance for individual VOC. Relative to the mass transfer resistance, the specialized biodegrading functions of microbial inoculations and enzymatic interactions among individual VOC biodegradation also must be carefully evaluated to optimize the treatment of complex VOC mixtures in bioreactors. PMID- 28639078 TI - A Genome-wide Expression Association Analysis Identifies Genes and Pathways Associated with Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with strong genetic components. To identity novel risk variants for ALS, utilizing the latest genome-wide association studies (GWAS) and eQTL study data, we conducted a genome wide expression association analysis by summary data-based Mendelian randomization (SMR) method. Summary data were derived from a large-scale GWAS of ALS, involving 12577 cases and 23475 controls. The eQTL annotation dataset included 923,021 cis-eQTL for 14,329 genes and 4732 trans-eQTL for 2612 genes. Genome-wide single gene expression association analysis was conducted by SMR software. To identify ALS-associated biological pathways, the SMR analysis results were further subjected to gene set enrichment analysis (GSEA). SMR single gene analysis identified one significant and four suggestive genes associated with ALS, including C9ORF72 (P value = 7.08 * 10-6), NT5C3L (P value = 1.33 * 10 5), GGNBP2 (P value = 1.81 * 10-5), ZNHIT3(P value = 2.94 * 10-5), and KIAA1600(P value = 9.97 * 10-5). GSEA identified 7 significant biological pathways, such as PEROXISOME (empirical P value = 0.006), GLYCOLYSIS_GLUCONEOGENESIS (empirical P value = 0.043), and ARACHIDONIC_ACID_ METABOLISM (empirical P value = 0.040). Our study provides novel clues for the genetic mechanism studies of ALS. PMID- 28639079 TI - Autonomic Nervous System Response to Stressors in Newly Diagnosed Patients with Multiple Sclerosis. AB - Autonomic dysfunction is commonly detected in patients with multiple sclerosis (MS). However, data evaluating autonomic nervous system function in early MS are limited. Present study investigates response to two different stressors in newly diagnosed MS patients, looking for the signs of autonomic dysfunction at the beginning of the disease. We examined 19 MS patients and 19 age, sex, and body mass index matched healthy controls. MS patients were newly diagnosed, untreated, and with low expanded disability status scale (EDSS) values [median 1.0 (interquartile range 1.0-1.5)]. Two stressors were used to evaluate the response of autonomic nervous system: Stroop word-color interference mental stress test and orthostasis. Plasma levels of epinephrine and norepinephrine, blood pressure (BP), and heart rate variability (HRV) parameters were evaluated. At the end of Stroop test MS patients had lower systolic BP (121 +/- 15 vs. 132 +/- 17 mmHg, p = 0.044), lower heart rate (79 +/- 9 vs. 88 +/- 16 1/min, p = 0.041), and lower epinephrine increment (10 +/- 22 vs. 30 +/- 38 pg/ml; p = 0.049) compared to healthy controls. Norepinephrine response was unaffected in MS, however, with lower norepinephrine levels during the test (p = 0.036). HRV parameters were similar in both groups. No differences in BP, heart rate, catecholamines, and HRV parameters between groups during orthostatic testing were found. We found slightly diminished sympathetic response to mental stress test, but unchanged response to orthostasis, in newly diagnosed untreated MS patients. The results suggest that autonomic dysfunction in MS is connected with more developed disease. PMID- 28639080 TI - The Use of Statins and Risk of Community-Acquired Pneumonia. AB - PURPOSE OF THE REVIEW: Community-acquired pneumonia (CAP) is still associated with a large burden and causes significant morbidity and mortality. Besides universal vaccination and antibiotic treatment, statins as adjunctive therapy may also have a beneficial role in the prevention and treatment of CAP. Our goal from this review is to discuss the epidemiology of CAP, and role of statins as adjunctive therapy in the development of CAP. RECENT FINDINGS: Statins are lipid lowering medications characterized by their ability to control hypercholesterolemia in addition to other pleiotropic effects that could explain their role in the pathogenesis of CAP. While most observational studies have shown that statins reduce risk of pneumonia in the general population, patients with diabetes, and recently in patients with myocardial infarction, no randomized controlled trial (RCT) to date has been conducted to assess the efficacy of statins to prevent development of CAP. Given the paucity of robust randomized evidence to assess statin use and the development of CAP, and considering conflicting results of the observational studies, we are not in favor of initiation of statins for either the prevention or treatment of CAP. PMID- 28639081 TI - Clinical Impact of Non-Congenital Zika Virus Infection in Infants and Children. AB - PURPOSE OF REVIEW: While the Zika virus (ZIKV) has been noted for its distinct neurotropism and identified as a significant cause for a congenital infection syndrome, there has been increased recognition of the importance to better understand the clinical impact of non-congenital ZIKV infection in infants and children. This article reviews reports of perinatal and breast milk transmission of ZIKV and summarizes current clinical outcome data of pediatric non-congenital ZIKV infection. RECENT FINDINGS: Perinatal transmission and presence of infective ZIKV particles in breast milk have been reported. Most symptomatic non-congenital ZIKV infection in infants and children is mild and self-limited, but long-term follow-up studies are lacking. The mechanism and impact of perinatal and breast milk transmission is unclear. The current WHO infant feeding guidelines in areas of ZIKV transmission support breastfeeding. Unless any scientific data raise concern regarding transmission via breastfeeding, the current guidelines should continue to be followed. Prospective population-based cohort studies to investigate maternal, perinatal, infant, and child outcomes are needed. PMID- 28639082 TI - Socio-economic factors associated with the 1-year prevalence of severe pain and pain-related sickness absence in the Austrian population. AB - BACKGROUND: The aim of this study was to (1) investigate the relation of socio economic status (SES), measured as education, occupation, and income, with the 12 month prevalence of severe pain and with pain-related sickness absence, and (2) analyse to what extent sociodemographic and medical factors influence these associations. METHODS: The study population comprised 8084 subjects aged between 15 and 65 years from the Austrian Health Interview Survey in 2006/07. Associations of SES with the 1-year prevalence of severe pain and sickness absence due to pain in those with severe pain was assessed with logistic regression analysis and adjusted for socio-demographic and chronic medical conditions. RESULTS: The 1-year prevalence of severe pain was 33.7%. Among those with severe pain, 32.9% were on sickness absence due to pain. SES was significantly associated with the prevalence of severe pain and even more strongly with sickness absence due to pain. Stepwise adjustment for socio demographics and medical factors had only marginal effects on these associations. Multivariate odds ratios (ORs) for severe pain were 1.14; 1.18 and 1.32 for low income, blue-collar workers, and low education, respectively. Related ORs for sickness absence due to pain were 1.52; 1.14 and 2.05. CONCLUSIONS: There was an association between SES, particularly measured as educational level, and the prevalence of severe pain, which was even stronger with sickness absence due to pain. PMID- 28639083 TI - Tumor vascularization and clinicopathologic parameters as prognostic factors in merkel cell carcinoma. AB - PURPOSE: Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine tumor of the skin with an increasing incidence. The clinical course is variable and reliable prognostic factors are scarce. Tumor angiogenesis has been shown to have prognostic impact in different types of cancer. The aim of our study was to determine potential prognostic factors, including tumor vascularization, for clinical outcome of MCC. METHODS: The medical records of 46 patients with MCC diagnosed between 1997 and 2010 were analyzed retrospectively. Tissue samples were immune-stained for the lymphatic endothelial vessel marker podoplanin/D2-40 and the panvascular marker CD31. These immunostained sections were analyzed using computer-assisted morphometric image analyses. Aside from the parameters of tumor vascularization, clinicopathologic features were investigated, and progression free survival (PFS) and tumor-specific survival (TSS) were assessed. Univariate and multivariate analyses were performed to determine prognostic factors. RESULTS: Male sex of the MCC patients and a high cross-sectional whole vessel area (WVA) in relation to the entire tumor area as determined on CD31-stained tumor sections were found to be negative prognostic factors for PFS in a univariate and multivariate regression analysis. Ulceration of the primary tumor was significantly associated with both impaired PFS and TSS. CONCLUSIONS: Our results indicate a high prognostic impact of tumor vascularization on the clinical outcome of MCC patients. Male sex and ulceration of the primary MCC were identified as independent unfavorable prognostic markers for the clinical outcome. As an outlook, MCC patients with increased angiogenesis might be identified and subjected to a targeted anti-angiogenic treatment. PMID- 28639084 TI - Early Palliative Care for Patients with Hematologic Malignancies: Is It Really so Difficult to Achieve? AB - Evidence points to many benefits of "early palliative care," the provision of specialist palliative care services upstream from the end of life, to improve patients' quality of life while living with a serious illness. Yet most trials of early palliative care have not included patients with hematologic malignancies. Unfortunately, patients with hematologic malignancies are also known to have substantial illness burden, poor quality of life, and aggressive care at the end of life, including a greater likelihood of dying in the hospital, receiving chemotherapy at the end of life, and low hospice utilization, compared to patients with solid tumors. Given these unmet needs, one must wonder, why is palliative care so underutilized in this population? In this article, we discuss barriers to palliative care integration in hematology, highlight several reports of successful integration, and suggest specific indications for involving palliative care in the management of hematologic malignancy patients. PMID- 28639085 TI - Nonsteroid anti-inflammatory therapy suppresses the development of proliferative vitreoretinopathy more effectively than a steroid one. AB - PURPOSE: This study proves the possibility of targeted use of the nonsteroidal anti-inflammatory drug lornoxicam to prevent the development of proliferative vitreoretinopathy (PVR). Triamcinolone acetonide (TA) was selected as a reference substance. METHODS: Wistar rats (N = 400) were used. PVR was modeled by intravitreal injection of dispase or concanavalin A. Lornoxicam or TA intravitreal administration was performed 20 min later. On the second and the third day, drugs were administrated systemic. Enucleation was performed on the first, third, seventh and 42nd or 56th day of the experiment. RESULTS: Pro inflammatory substances led to the development of sub- and epiretinal membranes. Lornoxicam decreased the incidence of membrane formation by 43 and 31% in dispase and concanavalin models, respectively. Membranes, formed during its use, were smaller and contained less fibrotic components. At the end of the experiment, the thickness of retinal and choroidal layers among the animals which had received the therapy was the same as the thickness of the retina and choroid of intact rats. Lornoxicam administration normalized the cyclooxygenases (COXs) expression in the retina and the choroid at the early stages of the experiment. TA application was less effective in both models. CONCLUSIONS: COXs blocking during the development of PVR, overwhelming inflammation in the eye and reducing its consequences, is proved to be a much more effective and safe influence than the suppression of the entire cascade of arachidonic acid metabolism. Lornoxicam did not only improve the condition of the retina and the choroid but also significantly reduced the frequency of membrane formation. PMID- 28639086 TI - How accurate is an LCD screen version of the Pelli-Robson test? AB - PURPOSE: To evaluate the accuracy and repeatability of a computer-generated Pelli Robson test displayed on liquid crystal display (LCD) systems compared to a standard Pelli-Robson chart. METHODS: Two different randomized crossover experiments were carried out for two different LCD systems for 32 subjects: 6 females and 10 males (40.5 +/- 13.0 years) and 9 females and 7 males (27.8 +/- 12.2 years), respectively, in the first and second experiment. Two repeated measurements were taken with the printed Pelli-Robson test and with the LCDs at 1 and 3 m. To test LCD reliability, measurements were repeated after 1 week. RESULTS: In Experiment 1, contrast sensitivity (CS) measured with LCD1 resulted significantly higher than Pelli-Robson both at 1 and at 3 m of about 0.20 log 1/C in both eyes (p < 0.01). Bland-Altman plots showed a proportional bias for LCD1 measures. LCD1 measurements showed reasonable repeatability: ICC was 0.83 and 0.65 at 1 and 3 m, respectively. In Experiment 2, CS measured with LCD2 resulted significantly lower than Pelli-Robson both at 1 and at 3 m of about 0.10 log 1/C in both eyes (p < 0.01). Bland-Altman plots did not show any proportional bias for LCD2 measures. LCD2 measurements showed sufficient repeatability: ICC resulted 0.51 and 0.65 at 1 and 3 m, respectively. CONCLUSIONS: Computer generated versions of Pelli-Robson test, displayed on LCD systems, do not provide accurate results compared to classic Pelli-Robson printed version. Clinicians should consider that Pelli-Robson computer-generated versions could be non interchangeable to the printed version. PMID- 28639087 TI - Haigis and SRKT formulae accuracy for intentional myopic overcorrection. AB - PURPOSE: To investigate the influence of preoperative biometric parameters on the accuracy of Haigis and SRKT formulae in predicting postoperative target refraction. METHODS: Retrospective analysis of 108 eyes (70 patients) underwent uneventful phacoemulsification surgery with implant of Alcon-SN60WF intraocular lens (IOL). Forty-five eyes were intentionally targeted to myopia (-0.75 to -1.25 dpt), while the others targeted between 0 and -0.75 dpt. Preoperative axial length and keratometry (K) were measured with optical biometry (LENSTAR-Haag Streit). Postoperative spherical equivalent was assessed 3 +/- 2 months after surgery. RESULTS: There is a significant correlation between the mean keratometry (K) and the Haigis-SRKT prediction differences (P < 0.001; r = 0.749). Linear regression indicates that a decrease of 1 diopter (D) on K implies an increase of 0.23 D on the difference between formulae prediction. K alone does not influence the prediction error for both formulas. The difference between the two formulae is dependent on K (r = -0.75; P < 0.01). Moreover, eyes with K <43.75 targeted at myopia (n = 23) showed a significant myopic shift of -0.26 +/- 0.09 dpt (P < 0.05) with Haigis, but a hyperopic shift of 0.24 +/- 0.09 dpt (P < 0.05) with SRKT. CONCLUSION: Divergences between Haigis and SRKT formulae cause uncertainty in choosing the IOL. Our results indicate that, in eyes with lower preoperative K, an IOL targeted at myopia might result in a small, but significant myopic shift with the Haigis formula, while a hyperopic shift with the SRKT formula. PMID- 28639088 TI - Comparison of visual acuity measurements via three different methods in preschool children: Lea symbols, crowded Lea symbols, Snellen E chart. AB - PURPOSE: The aim of this study was to compare three different methods to measure visual acuity (VA) in healthy and amblyopic preschool children: a Snellen E chart (SE), a single Lea symbols (SLS), and a crowded Lea symbols (CLS). METHODS: Seventy-eight eyes of 54 patients (28 females, 26 males) were included in this cross-sectional, comparative study. The control group consisted of 30 healthy cases, and the amblyopic group consisted of 24 patients with amblyopia. Best corrected VA (BCVA) measurements with SLS, CLS, and SE were compared in control eyes (CE), amblyopic eyes (AE), and fellow eyes (FE) separately. RESULTS: The mean age of the cohort was 5.7 +/- 0.7 years (range 5-7 years). The mean refractive error was +1.02 +/- 0.36 D (diopter, spherical equivalent) in CE, +5.59 +/- 2.45 D in AE, and +3.96 +/- 2.38 D in FE. The median BCVA (logMAR) was (in order of SLS, CLS, and SE) 0.00 [interquartile range (IQR) 0.10], 0.10 (IQR 0.10), 0.00 (IQR 0.10) in CE, 0.25 (IQR 0.33), 0.35 (IQR 0.30), 0.25 (IQR 0.38) in AE, and 0.10 (IQR 0.08), 0.10 (IQR 0.00), 0.10 (IQR 0.10) in FE. There was no statistically significant difference between the three methods in terms of the CE or FE (p > 0.05). In contrast, there was a statistically significant difference in AE (p < 0.05). The mean VA measurement with SLS was higher compared with CLS in AE. A positive and strong correlation between the three charts was found in all of the groups (p < 0.001). CONCLUSION: We found SLS, CLS, and SE to be consistent: all three methods can be used to obtain measurements of VA in healthy and amblyopic preschool children. PMID- 28639089 TI - Crossover clinical trial of pain relief in cataract surgery. AB - PURPOSE: To determine the effects of intra-operative Korean traditional music on pain experienced by Korean patients undergoing sequential bilateral cataract surgery. METHODS: This was a two-sequence, two-period, and two-treatment crossover study. Fifty-two patients with cataracts were divided into two groups by block randomization, and bilateral cataract surgery was performed. In group 1, patients listened to Korean traditional music (KTM) during their first but not second cataract surgery. This sequence was reversed for patients in group 2. After each surgery, patients scored their pain intensity (PI) using a visual analog scale (VAS) ranging from 0 to 10, where 0 was 'no pain' and 10 was 'unbearable pain.' RESULT: There was a statistically significant reduction in the mean VAS score with KTM (3.1 +/- 2.0) compared to that without KTM (4.1 +/- 2.2; p = 0.013). However, there were no statistically significant differences in blood pressure or pulse rates. CONCLUSION: KTM had a significant effect on reducing pain experienced by patients during cataract surgery. This may be useful in the context of other surgical procedures to reduce pain in Korean patients. PMID- 28639090 TI - Mitochondria and FOXO3 in stem cell homeostasis, a window into hematopoietic stem cell fate determination. AB - The production of all blood cells from hematopoietic stem cells (HSC) is highly sensitive to reactive oxygen species (ROS). Cumulating evidence suggests that mitochondria are critical for HSC fate determination. FOXO are known regulators of anti-oxidant response and key to the maintenance of HSC. Recent works indicate that FOXO3 is implicated in the control of mitochondrial function beyond regulating levels of ROS in HSC. Here we review these findings and discuss implications for homeostatic blood formation and stem cell fate determination. PMID- 28639091 TI - Improved Outcomes with an Outpatient Multidisciplinary Intensive Feeding Therapy Program Compared with Weekly Feeding Therapy to Reduce Enteral Tube Feeding Dependence in Medically Complex Young Children. AB - PURPOSE OF REVIEW: The prevalence of feeding disorders in medically complex children is estimated to be as high as 80%. Enteral tube nutrition (ETN) is commonly used for nutritional support in children with feeding disorders. Adverse consequences of ETN include medical complications, psychosocial problems, and higher healthcare costs. We used a retrospective cohort controlled study design to compare outcomes of our outpatient multidisciplinary intensive feeding therapy (IFT) program to our traditional therapy (TT) of single-discipline, once weekly feeding therapy to reduce ETN dependence in medically complex young children. RECENT FINDINGS: Children in the IFT cohort experienced a median reduction in ETN dependence of 49% (34.5-58.5%) compared with a median reduction of 0% (0-25%) for TT (p > 0.0001). Almost half of the IFT cohort no longer required ETN by the conclusion of the 5-week program. Medically complex young children (median age 26 months) successfully reduce or eliminate ETN in an outpatient multidisciplinary intensive feeding program. PMID- 28639093 TI - Rediscovery of Chonopeltis meridionalis Fryer, 1964 (Crustacea: Branchiura) from Labeo rosae Steindachner in the River Olifants, Mpumalanga, and the taxonomic status of C. victori Avenant-Oldewage, 1991 and C. koki Van As, 1992. AB - Chonopeltis Thiele, 1900 presently comprises 14 species, it is endemic to Africa and its species show a high degree of host-specificity towards fish families and in some cases, individual fish species. Chonopeltis meridionalis Fryer, 1964 was originally described from Labeo rosae Steindachner collected in the River Nuanetsi in Rhodesia, now Zimbabwe, Limpopo River System. At the time of description C. meridionalis was the most southerly species of the genus. Chonopeltis victori Avenant-Oldewage, 1991 was described from the River Olifants, Mpumalanga, South Africa, which also forms part of the Limpopo River System. The host fish was Labeo rosae and Labeobarbus marequensis (A. Smith), whilst C. koki Van As, 1992 was described from Labeo cylindricus Peters, collected in the River Zambezi, Eastern Caprivi, Namibia. During surveys conducted in 2012, additional material of a species of Chonopeltis was collected from Labeo rosae in the River Olifants. Upon closer examination, the new material was identified as C. meridionalis. Further investigation revealed that C. victori and C. koki share a number of characteristics with C. meridionalis. This paper provides the first scanning electron microscopy of C. meridionalis, includes additional information on fully-mature as well as sub-adult males and females. Finally, it was concluded that C. victori and C. koki are junior synonyms of C. meridionalis. PMID- 28639095 TI - Knowledge, Awareness, and Prevention of Hepatitis B Virus Infection Among Korean American Parents. AB - Hepatitis B (HB) affects 240 million people around the world, and children and young adults make up a large proportion of the infected population. Approximately 1 million people die from HB each year. Despite the seriousness of HB and its complications, many are poorly linked to clinical care. A lack of health literacy may be a critical barrier hindering access to HB care for adults as well as children in these populations. We, therefore, performed a survey to assess the level of knowledge of HB among Korean American parents. The survey was conducted on 521 Korean American adults who attended community-based HB awareness campaigns held at various locations throughout the metropolitan New York area between January 2015 and November 2016. Of these, 296 parents, who had children between ages 1 and 30, were identified. All participants were asked a series of questions regarding various aspects of HB and were evaluated on the basis of their awareness on each subject. A separate questionnaire was also employed to obtain demographic characteristics of the participants. The study revealed a significant deficit of knowledge of HB in most aspects the survey evaluated. Although the majority of the participants knew that HB is a liver disease, and many of them had been screened for HB, they had a poor understanding of vaccination, screening, their own HB status, modes of HBV transmission, and the consequences and treatment of HB. The participants also had a low level of awareness of their own children's HB status. This study demonstrates a low level of knowledge of HB among Korean American parents electing to attend a hepatitis education program. In addition, many parents are not aware of their children's screening and immune (or non-immune) status. The lack of health literacy may contribute to poor health access in HB care, not only in adults but also in children. This suggests an urgent need for education on HB in Korean American parents as well as in young children. PMID- 28639094 TI - New molecular and morphological data for opecoelid digeneans in two Mediterranean sparid fishes with descriptions of Macvicaria gibsoni n. sp. and M. crassigula (Linton, 1910) (sensu stricto). AB - Molecular and morphological data were gathered for specimens of species of Macvicaria Gibson & Bray, 1982 and Pseudopycnadena Saad-Fares & Maillard, 1986 (Digenea: Opecoelidae) collected from two sparid fishes, Diplodus vulgaris (Geoffroy Saint-Hilaire) and Sparus aurata L., off the Algerian coast of the Western Mediterranean. Phylogenetic analyses based on ITS1-5.8S-ITS2 and partial 28S rDNA sequences provided evidence for the distinct species status of eight Mediterranean species of Macvicaria. Novel molecular data are provided for four species, M. gibsoni n. sp. and M. crassigula (Linton, 1910) (sensu stricto) based on specimens from D. vulgaris, and M. mormyri (Stossich, 1885) and M. maamouriae Antar, Georgieva, Gargouri & Kostadinova, 2015 based on specimens from S. aurata; descriptions of the molecular voucher material of the former three species are provided. Two species were delineated within the "crassigula" species complex of Macvicaria, M. gibsoni n. sp. and M. crassigula (s. str.), the distinctive differentiating features being the distribution of the dorsal vitelline fields in the forebody, confluent in M. gibsoni n. sp. and non-confluent in M. crassigula (s. str.), and the molecular data for both markers. Sequences associated with morphological description are also provided for the type-species of Pseudopycnadena, P. fischthali Saad-Fares & Maillard, 1986, based on material from D. vulgaris. PMID- 28639096 TI - 'We're completely back to normal, but I'd say it's a new normal': a qualitative exploration of adaptive functioning in rural families following a parental cancer diagnosis. AB - PURPOSE: The purpose of this study was to explore rural families' functioning following a parental cancer diagnosis. METHOD: Ten families in which a parent of dependent children had received a cancer diagnosis were purposively sampled using two questionnaires based upon the Resiliency Model of Family Adjustment and Adaptation (RMFAA): the Family Crisis Oriented Personal Evaluation Scales (F COPES) and the Family Attachment Changeability Index 8 (FACI8). The total participant number was 34, which comprised the involvement of 17 parents and 17 children. The use of questionnaires ensured representation from both high and low functioning families. Qualitative data were gathered via semi-structured family interviews, and thematic analysis was used. RESULTS: Families identified three key challenges that are not accounted for by the RMFAA and may be unique to the rural cancer patient experience: frequent travel, increased work/financial demands and family separation. Families also described a number of protective factors that enabled them to cope with the demands of the cancer diagnosis, some of which were specific to rural families, while others may apply to Australian families more broadly. Many of these protective factors aligned with the RMFAA framework. CONCLUSION: The findings suggest that rural families' ability and willingness to access external resources, including informal community support and formal support services, are influenced by the strength of their internal protective factors. This result has practical implications for the development of interventions that accommodate the specific supportive care needs of rural families affected by cancer. PMID- 28639097 TI - Effect of an Internet-based telehealth system on functional capacity and cognition in breast cancer survivors: a secondary analysis of a randomized controlled trial. AB - PURPOSE: This trial determines the effect of an Internet-based tailored exercise program compared to usual care control for improving functional capacity and cognition among breast cancer survivors. METHODS: A two-arm, assessor-blinded, parallel, randomized controlled efficacy trial was conducted. Participants were recruited from the Oncology and Breast unit at the Virgen de las Nieves Hospital (Granada, Spain) between March 2012 to November 2013 and randomized to either the experimental group (an 8-week Internet-based tailored exercise program) or control group (usual care). The outcome measures were the 6-min walk test, Auditory Consonant Trigrams, and Trail Making Test. All were assessed at baseline, post-intervention, and 6-month follow-up. RESULTS: After intervention, the telerehabilitation group had significantly improved distances (d = 0.92, P < 0.001) as well as percentage of predicted of the 6-min walk test (d = 0.93, P < 0.001) compared with the control group. Significant improvement was also observed favoring the telerehabilitation group for the number of consonants recalled in total compared with the control group (d = 0.47, P = 0.04). These findings were maintained after 6-month follow-up (d = 0.80, P = 0.001; d = 0.76, P = 0.002; and d = 0.57, P = 0.02, respectively). Analysis was based on intention-to-treat principle. CONCLUSIONS: These findings support the effectiveness of a telehealth system based on an 8-week physical exercise to achieve improvements and maintain them after 6-month follow-up in terms of functional and cognitive performance in breast cancer survivors. This broad-reach modality could help the growing number of cancer survivors to face their disabling side effects. PMID- 28639098 TI - A head to head comparison of XINSORB bioresorbable sirolimus-eluting scaffold versus metallic sirolimus-eluting stent: 180 days follow-up in a porcine model. AB - We aimed to investigate the safety and efficacy of XINSORB bioresorbable sirolimus-eluting scaffold in porcine model. XINSORB scaffolds and metallic Firebird2TM stents were randomly implanted into minipigs' coronary arteries. Angiography, optical coherent tomography (OCT) and histopathological analyses were performed at post-procedure and 14-, 28-, 90-, 180-day follow-up. Thirty-two minipigs were enrolled. Eight XINSORB scaffolds and 8 Firebird2 stents were examined at each time point. Quantitative coronary angiography showed that in scaffold late luminal loss (LLL) of XINSORB scaffold was 0.26 +/- 0.13, 0.50 +/- 0.16, 0.88 +/- 0.29 and 0.43 +/- 0.24 mm at 14-, 28, 90-, and 180-day follow-up respectively, and the corresponding diameter stenosis (DS) was 7.3 +/- 4.7, 12.0 +/- 9.5, 22.1 +/- 8.0, and 16.0 +/- 9.5%. Neither in-scaffold LLL nor DS of XINSORB scaffold was significantly different in comparison with Firebird2 stent. No difference of luminal area, device area, neointimal hyperplasia, and area stenosis was detected between two devices under OCT. Scaffold area of XINSORB remained steady through the observation. Histopathology revealed the similar findings. The greatest late recoil of XINSORB scaffold was about 4.12% at 90-day follow-up, which was comparable to Firebird2 stent. Both devices showed low injury or inflammation of vessel wall. XINSORB scaffold showed early neointimal coverage on struts within 28 days under scanning electron microscopy. XINSORB scaffold suppressed neointimal hyperplasia as effectively as Firebird2 did without obvious late device recoil during the 180 days follow-up. It is feasible to carry out clinical trial to investigate the safety and efficacy of XINSORB scaffold for patients with coronary artery diseases. PMID- 28639099 TI - Erratum to: Intravascular ultrasound elastography analysis of the elastic mechanical properties of atherosclerotic plaque. PMID- 28639100 TI - STING-mediated DNA sensing in cancer immunotherapy. AB - While STING (STimulator of INterferon Genes) has been shown to be essential for cytosolic DNA-triggered innate immune activation, accumulated evidence obtained from various studies suggested that an intrinsic relevance of STING-associated signaling in tumorigenesis can be observed. Also, several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for STING, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. However, cases have also been reported where the involvement of STING shows a protective role in tumor growth. Here we summarize recent findings that have pointed towards the STING pathway as an innate immune sensing mechanism driving type I interferon production in the tumor context. Better understanding of this pathway can guide further development of novel immunotherapeutic strategies in the treatment of cancer. PMID- 28639101 TI - Prevention and treatment of cancer targeting chronic inflammation: research progress, potential agents, clinical studies and mechanisms. AB - Numerous experimental and clinical studies indicate that chronic inflammation is closely related to the initiation, progression, and spread of cancer, in which proinflammatory cytokines, such as interleukin (IL)-6, IL-1beta, and tumor necrosis factor-alpha (TNF-alpha), and transcription factors, such as nuclear factor-kappaB (NF-kappaB), and signal transducer and activator of transcription 3 (STAT3), play pivotal roles. Stimulated by proinflammatory cytokines, NF-kappaB and STAT3 can modulate the expression of target genes, most of which are oncogenic ones, and promote the survival, proliferation, invasion, and metastasis of cancer cells. Now it is generally accepted that inflammation-related molecules and pathways are useful targets for the prevention and treatment of cancer. In this review, we summarize the relationship between chronic inflammation and cancer and describe some potentially useful agents including aspirin, meformin, statins, and some natural products (green tea catechins, andrographolide, curcumin) for their cancer prevention and treatment activities targeting chronic inflammation. The results of typical clinical studies are included, and the influences of these agents on the proinflammatory cytokines and inflammation related pathways are discussed. Data from the present review support that agents targeting chronic inflammation may have a broad application prospect for the prevention and treatment of cancer in the future. PMID- 28639102 TI - The clinical and genetic characteristics in children with mitochondrial disease in China. AB - Mitochondrial disease was a clinically and genetically heterogeneous group of diseases, thus the diagnosis was very difficult to clinicians. Our objective was to analyze clinical and genetic characteristics of children with mitochondrial disease in China. We tested 141 candidate patients who have been suspected of mitochondrial disorders by using targeted next-generation sequencing (NGS), and summarized the clinical and genetic data of gene confirmed cases from Neurology Department, Beijing Children's Hospital, Capital Medical University from October 2012 to January 2015. In our study, 40 cases of gene confirmed mitochondrial disease including eight kinds of mitochondrial disease, among which Leigh syndrome was identified to be the most common type, followed by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). The age-of onset varies among mitochondrial disease, but early onset was common. All of 40 cases were gene confirmed, among which 25 cases (62.5%) with mitochondrial DNA (mtDNA) mutation, and 15 cases (37.5%) with nuclear DNA (nDNA) mutation. M.3243A>G (n=7) accounts for a large proportion of mtDNA mutation. The nDNA mutations include SURF1 (n=7), PDHA1 (n=2), and NDUFV1, NDUFAF6, SUCLA2, SUCLG1, RRM2B, and C12orf65, respectively. PMID- 28639103 TI - Analysis of diagnosis and treatment of lipoblastomatosis. PMID- 28639104 TI - Gene mutations and clinical phenotypes in Chinese children with Blau syndrome. AB - The mutations of CARD15 gene and clinical features of Chinese patients with Blau syndrome were analyzed. We identified 10 missense mutations, out of which five were new: R334L, E383D, R471C, C495R and D512F. The rest of them, R334W, R334Q, G481D, M513T and R587C, have been reported previously. Among all the mutations, R334W, R334Q and C495R had the highest frequency. Blau syndrome was found at early age after birth. It began with lepidic rash and symmetric polyarthritis and was phenotypically characterized by typical rash, arthritis, iridocyclitis and arteritis. Cardiac involvement was also found in Blau syndrome. In addition to nerve deafness, renal involvement, osteochondroma and central nervous system involvement were also found in our patients. Therefore, Chinese children with Blau syndrome have unique gene mutations and complicated clinical phenotypes. Pathologic examination and CARD15 mutation testing should be considered for diagnosis as early as possible for suspected patients. PMID- 28639105 TI - Towards efficiency in rare disease research: what is distinctive and important? AB - Characterized by their low prevalence, rare diseases are often chronically debilitating or life threatening. Despite their low prevalence, the aggregate number of individuals suffering from a rare disease is estimated to be nearly 400 million worldwide. Over the past decades, efforts from researchers, clinicians, and pharmaceutical industries have been focused on both the diagnosis and therapy of rare diseases. However, because of the lack of data and medical records for individual rare diseases and the high cost of orphan drug development, only limited progress has been achieved. In recent years, the rapid development of next-generation sequencing (NGS)-based technologies, as well as the popularity of precision medicine has facilitated a better understanding of rare diseases and their molecular etiology. As a result, molecular subclassification can be identified within each disease more clearly, significantly improving diagnostic accuracy. However, providing appropriate care for patients with rare diseases is still an enormous challenge. In this review, we provide a brief introduction to the challenges of rare disease research and make suggestions on where and how our efforts should be focused. PMID- 28639106 TI - Time to selected quit date and subsequent rates of sustained smoking abstinence. AB - In efforts to combat tobacco dependence, most smoking cessation programs offer individuals who smoke the choice of a target quit date. However, it is uncertain whether the time to the selected quit date is associated with participants' chances of achieving sustained abstinence. In a pre-specified secondary analysis of a randomized clinical trial of four financial-incentive programs or usual care to encourage smoking cessation (Halpern et al. in N Engl J Med 372(22):2108-2117, doi: 10.1056/NEJMoa1414293 , 2015), study participants were instructed to select a quit date between 0 and 90 days from enrollment. Among those who selected a quit date and provided complete baseline data (n = 1848), we used multivariable logistic regression to evaluate the association of the time to the selected quit date with 6- and 12-month biochemically-confirmed abstinence rates. In the fully adjusted model, the probability of being abstinent at 6 months if the participant selected a quit date in weeks 1, 5, 10, and 13 were 39.6, 22.6, 10.9, and 4.3%, respectively. PMID- 28639108 TI - Fructose-1,6-bisphosphate reverts iron-induced phenotype of hepatic stellate cells by chelating ferrous ions. AB - Hepatic fibrosis is an extracellular matrix deposition by hepatic stellate cells (HSC). Fibrosis can be caused by iron, which will lead to hydroxyl radical production and cell damage. Fructose-1,6-bisphosphate (FBP) has been shown to deliver therapeutic effects in many pathological situations. In this work, we aimed to test the effects of FBP in HSC cell line, GRX, exposed to an excess of iron (Fe). The Fe-treatment increased cell proliferation and FBP reversed this effect, which was not due to increased necrosis, apoptosis or changes in cell cycle. Oil Red-O staining showed that FBP successfully increased lipid content and lead GRX cells to present characteristics of quiescent HSC. Fe-treatment decreased PPAR-gamma expression and increased Col-1 expression. Both effects were reversed by FBP which also decreased TGF-beta1 levels in comparison to both control and Fe groups. FBP, also, did not present scavenger activity in the DPPH assay. The treatment with FBP resulted in decreased proliferation rate, Col-1 expression and TGF-beta1 release by HSC cells. Furthermore, activated PPAR-gamma and increased lipid droplets induce cells to become quiescent, which is a key event to reversion of hepatic fibrosis. FBP also chelates iron showing potential to improve Cell redox state. PMID- 28639107 TI - Depressive symptoms in patients with obstructive sleep apnea: biological mechanistic pathways. AB - This study examined the association between depressive symptoms, as well as depressive symptom dimensions, and three candidate biological pathways linking them to Obstructive sleep apnea (OSA): (1) inflammation; (2) circulating leptin; and (3) intermittent hypoxemia. Participants included 181 obese adults with moderate-to-severe OSA enrolled in the Cardiovascular Consequences of Sleep Apnea (COSA) trial. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II). We assessed inflammation using C-reactive protein levels (CRP), circulating leptin by radioimmunoassay using a double antibody/PEG assay, and intermittent hypoxemia by the percentage of sleep time each patient had below 90% oxyhemoglobin saturation. We found no significant associations between BDI-II total or cognitive scores and CRP, leptin, or percentage of sleep time below 90% oxyhemoglobin saturation after controlling for relevant confounding factors. Somatic symptoms, however, were positively associated with percentage of sleep time below 90% saturation (beta = 0.202, P = 0.032), but not with CRP or circulating leptin in adjusted models. Another significant predictor of depressive symptoms included sleep efficiency (betaBDI Total = -0.230, P = 0.003; betacognitive = -0.173, P = 0.030 (betasomatic = -0.255, P = 0.001). In patients with moderate-to-severe OSA, intermittent hypoxia may play a role in somatic rather than cognitive or total depressive symptoms. PMID- 28639109 TI - Occurrence of naproxen, ibuprofen, and diclofenac residues in wastewater and river water of KwaZulu-Natal Province in South Africa. AB - The present paper reports a detailed study that is based on the monitoring of naproxen, ibuprofen, and diclofenac in Mbokodweni River and wastewater treatment plants (WWTPs) located around the city of Durban in KwaZulu-Natal Province of South Africa. Target compounds were extracted from water samples using a multi template molecularly imprinted solid-phase extraction prior to separation and quantification on a high-performance liquid chromatography equipped with photo diode array detector. The analytical method yielded the detection limits of 0.15, 1.00, and 0.63 MUg/L for naproxen, ibuprofen, and diclofenac, respectively. Solid phase extraction method was evaluated for its performance using deionized water samples that were spiked with 5 and 50 MUg/L of target compounds. Recoveries were greater than 80% for all target compounds with RSD values in the range of 4.1 to 10%. Target compounds were detected in most wastewater and river water samples with ibuprofen being the most frequently detected pharmaceutical. Maximum concentrations detected in river water for naproxen, ibuprofen, and diclofenac were 6.84, 19.2, and 9.69 MUg/L, respectively. The concentrations of target compounds found in effluent and river water samples compared well with some studies. The analytical method employed in this work is fast, selective, sensitive, and affordable; therefore, it can be used routinely to evaluate the occurrence of acidic pharmaceuticals in South African water resources. PMID- 28639110 TI - Neointimal hyperplasia covering the intraluminal neo-metal carina 12 years after the simultaneous kissing stenting technique was performed: insight from optical frequency domain imaging findings. PMID- 28639111 TI - A Lifetime's Adventure in Extracellular K+ Regulation: The Scottish Connection. AB - In a career that has spanned 45 years and shows no signs of slowing down, Dr Bruce Ransom has devoted considerable time and energy to studying regulation of interstitial K+. When Bruce commenced his studies in 1969 virtually nothing was known of the functions of glial cells, but Bruce's research contributed to the physiological assignation of function to mammalian astrocytes, namely interstitial K+ buffering. The experiments that I describe in this review concern the response of the membrane potential (Em) of in vivo cat cortical astrocytes to changes in [K+]o, an experimental manoeuvre that was achieved in two different ways. The first involved recording the Em of an astrocyte while the initial aCSF was switched to one with different K+, whereas in the second series of experiments the cortex was stimulated and the response of the astrocyte Em to the K+ released from neighbouring neurons was recorded. The astrocytes responded in a qualitatively predictable manner, but quantitatively the changes were not as predicted by the Nernst equation. Elevations in interstitial K+ are not sustained and K+ returns to baseline rapidly due to the buffering capacity of astrocytes, a phenomenon studied by Bruce, and his son Chris, published 27 years after Bruce's initial publications. Thus, a lifetime spent investigating K+ buffering has seen enormous advances in glial research, from the time cells were identified as 'presumed' glial cells or 'silent cells', to the present day, where glial cells are recognised as contributing to every important physiological brain function. PMID- 28639113 TI - Ergonomic strategies to improve radiographers' posture during mammography activities. AB - OBJECTIVES: To identify alternatives for radiographers' postures while performing mammography that can contribute to reduce the risk of work-related musculoskeletal disorders (WRMSDs). METHODS: Radiographers' postures to positioning craniocaudal (CC) and mediolateral oblique (MLO) views were simulated without any intervention for three scenarios: radiographer/patient with similar statures, radiographer smaller than patient and radiographer taller than patient. Actions were taken to modify the postures: seated radiographer; patient on a step; seated patient; radiographer on a step. All the postures were analysed using kinovea 0.8.15 software and the angles were measured twice and classified according to European standard EN1005-4: 2005. RESULTS: The non-acceptable angles were measured mainly during MLO positioning when radiographer was taller than the patient: 139 degrees and 120 degrees for arm-flexion and abduction, 72 degrees for trunk and -24 degrees for head/neck-flexion. The introduction of alternative postures (radiographer seated), allowed improvements in posture (60 degrees and 99 degrees for arm flexion and abduction, 14 degrees for trunk and 0 degrees for head/neck flexion), being classified as acceptable. CONCLUSIONS: The alternative postures simulated have the potential to reduce the risk of developing WRMSDs when radiographers and patients have different statures. MAIN MESSAGES: * Radiographers' postures in mammography can contribute to work-related musculoskeletal disorders * Non-acceptable posture was identified for MLO breast positioning (radiographer taller than patient) * Adapting posture to patient biotype reduces the WRMSD risk for radiographers. PMID- 28639112 TI - Kuguacin J isolated from bitter melon leaves modulates paclitaxel sensitivity in drug-resistant human ovarian cancer cells. AB - We previously reported the multidrug resistance-reversing ability of kuguacin J (KJ) in cervical cancer cells via the inhibition of P-glycoprotein (P-gp) function. This study investigated whether KJ could promote cisplatin- and paclitaxel (PTX)-induced cancer cell death in drug-resistance human ovarian cancer cells (SKOV3). Cytotoxicity testing showed that SKOV3 was more resistant to cisplatin and PTX compared to drug-sensitive human ovarian cancer cells (A2780). The cytotoxicity of PTX was significantly increased in SKOV3 cells when co-treated with KJ. We found that enhancement of PTX toxicity in the cells was not related to P-gp inhibition. To elucidate the mechanism by which KJ increases PTX sensitivity, the expression of cell death involving proteins was analyzed by Western blot analysis. The results showed that PTX treatment increased the level of an anti-apoptotic protein, survivin, which may be involved in drug resistance in SKOV3. The co-treatment with PTX and KJ dramatically decreased the level of survivin and markedly induced cleavage of PARP and caspase-3, which are apoptotic induced molecules. These findings may support the use of KJ as an effective chemosensitizer in combination with conventional chemotherapy to promote PTX sensitization in ovarian cancer patients. PMID- 28639114 TI - Imaging-guided chest biopsies: techniques and clinical results. AB - BACKGROUND: This article aims to comprehensively describe indications, contraindications, technical aspects, diagnostic accuracy and complications of percutaneous lung biopsy. METHODS: Imaging-guided biopsy currently represents one of the predominant methods for obtaining tissue specimens in patients with lung nodules; in many cases treatment protocols are based on histological information; thus, biopsy is frequently performed, when technically feasible, or in case other techniques (such as bronchoscopy with lavage) are inconclusive. RESULTS: Although a coaxial system is suitable in any case, two categories of needles can be used: fine-needle aspiration biopsy (FNAB) and core-needle biopsy (CNB), with the latter demonstrated to have a slightly higher overall sensitivity, specificity and accuracy. CONCLUSION: Percutaneous lung biopsy is a safe procedure even though a few complications are possible: pneumothorax, pulmonary haemorrhage and haemoptysis are common complications, while air embolism and seeding are rare, but potentially fatal complications. TEACHING POINTS: * Imaging-guided biopsy is one of the main methods to obtain lung nodule specimens. * CT has the highest accuracy for diagnosis as an imaging guide. * Compared to FNAB, CNB has a higher accuracy for diagnosis. * Pneumothorax and parenchymal pulmonary haemorrhage care the most frequent complications. * Several clinical and technical variables can affect diagnostic accuracy and patient safety. PMID- 28639115 TI - Chemical Composition of Selected Commercial Herbal Remedies in Relation to Geographical Origin and Inter-Species Diversity. AB - Infusions prepared from medicinal herbs that are rich in flavonoids are very popular herbal remedies in societies of Eastern Europe. Therefore, the content of essential elements together with total flavonoids was analyzed in 65 commercially available samples of herbal drugs originating from Ukraine, Romania, and Belarus. The results showed that metallic elements (in mg kg-1 d.w.) have occurred in the following order: Fe > Mn > Zn > Cu, both for total and water-extractable species. Total flavonoids were determined in the range from 10.0 to 191.8 mg g-1 d.w. Several significant correlations have been found between the analytes, especially among water-extractable Fe with other metals, and total flavonoids and Fe, Zn, and Mn. Analysis of variance has revealed significant differences among studied samples due to their origin from different countries, especially between Belarussian samples and others. Differences owing to belonging to various plant species were also found, as it was noticed in the case of Polygoni aviculare herba in comparison with other botanical plant species. Moreover, multivariate statistical techniques, such as cluster analysis (CA) and principal component analysis (PCA) were used to gather herbal drugs based on similarity of chemical composition. CA grouped the samples into clusters with similar level of elements and total flavonoid contents, and PCA has indicated Hyperici herba, Tiliae flores, and Crataegi fructus as herbal remedies with close concentration of studied elements and flavonoids. PMID- 28639117 TI - Tubeless outpatient robotic upper urinary tract reconstruction in the pediatric population: short-term assessment of safety. AB - Robotic upper urinary tract reconstruction (UUTR) has been widely utilized for surgical management of congenital obstruction. To further reduce morbidity and simplify postoperative care, outpatient robotic pyeloplasty (RP) and robotic ureteroureterostomy (RUU) were performed without ureteral stents, drains, or urethral catheters. The aim of the study was to assess the safety of performing tubeless robotic UUTR as an outpatient procedure. A retrospective review was performed for patients who underwent outpatient tubeless RP and RUU between July 2015 and January 2017. All procedures were primary interventions. No ureteral stents, drains, or urethral catheters were utilized. No regional blocks were utilized. Patients were discharged from the post anesthesia care unit as a scheduled outpatient procedure without an extended stay. Primary outcomes included 30-day complications, emergency room (ER) visits, and readmissions. A total of 19 patients (14 male, 5 female) were identified (RP = 17, RUU = 3), including one patient who underwent staged bilateral RP. Median age was 21.5 months (range 3-220). Median weight was 11.5 kg (range 6-89). Median operative time was 167 min (range 108-249), defined as skin incision to closure. No 30-day complications, ER visits, or readmissions were observed for any patient. The study concludes that pediatric tubeless outpatient robotic UUTR is safe. Further evaluation is needed to assess this approach on a larger scale, as well as assessing the long-term outcomes of tubeless reconstruction. PMID- 28639116 TI - Integration of transcriptomic and metabolic data reveals hub transcription factors involved in drought stress response in sunflower (Helianthus annuus L.). AB - KEY MESSAGE: By integration of transcriptional and metabolic profiles we identified pathways and hubs transcription factors regulated during drought conditions in sunflower, useful for applications in molecular and/or biotechnological breeding. Drought is one of the most important environmental stresses that effects crop productivity in many agricultural regions. Sunflower is tolerant to drought conditions but the mechanisms involved in this tolerance remain unclear at the molecular level. The aim of this study was to characterize and integrate transcriptional and metabolic pathways related to drought stress in sunflower plants, by using a system biology approach. Our results showed a delay in plant senescence with an increase in the expression level of photosynthesis related genes as well as higher levels of sugars, osmoprotectant amino acids and ionic nutrients under drought conditions. In addition, we identified transcription factors that were upregulated during drought conditions and that may act as hubs in the transcriptional network. Many of these transcription factors belong to families implicated in the drought response in model species. The integration of transcriptomic and metabolomic data in this study, together with physiological measurements, has improved our understanding of the biological responses during droughts and contributes to elucidate the molecular mechanisms involved under this environmental condition. These findings will provide useful biotechnological tools to improve stress tolerance while maintaining crop yield under restricted water availability. PMID- 28639118 TI - Pharmacokinetics and immunogenicity of T0001, a newly developed anti-TNFalpha fusion protein, in healthy volunteers. AB - PURPOSE: T0001 was the first mutant of recombinant fusion protein of human tumor necrosis factor receptor and Fc fragment (rhTNFR:Fc) based on etanercept on a global scale. This study was carried out to investigate the pharmacokinetics (PK) and immunogenicity of T0001 in healthy Chinese volunteers. METHODS: This study was randomized, with a single ascending dose, and the first-in-human clinical trial of T0001. Healthy Chinese volunteers (n = 56; male: female = 1:1) were randomly assigned to receive a single subcutaneous (sc) injection of 10, 20, 35, 50, 65 or 75 mg of T0001. Blood samples were collected at designated time points after sc injection to assess immunogenicity and pharmacokinetics of T0001. RESULTS: During the study, no serious adverse events were observed. T0001 was slowly absorbed with a median Tmax of 84 h and slowly eliminated with a T1/2Z of 42.1-58.2 h. In the dose-exposure proportionality analysis, the estimated points for AUC0-infinity and Cmax were 0.87 with a 90% CI of 0.76-0.98 and 0.86 with a 90% CI of 0.74-0.97 respectively. The plasma concentration of free (unbound T0001) plasma TNFalpha and total (bound and unbound T0001) TNFalpha both increased significantly after the injection of T0001. Ten out of 56 volunteers (17.9%) tested positive for anti-drug antibodies (ADAs) at a low level. CONCLUSIONS: T0001 was safe and well-tolerated at doses up to 75 mg. Cmax and AUC0-infinity had an increasing tendency with dose levels, but we could not conclude that T0001 has linear PK properties in this study. PMID- 28639119 TI - A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. AB - PURPOSE: In vitro data showed that selexipag and its active metabolite (ACT 333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration (C max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. METHODS: This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5 mg midazolam alone (treatment A) or on top of steady-state selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600 MUg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis. RESULTS: The C max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1 hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1 hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, selexipag, and the combination was safe and well tolerated. CONCLUSION: Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with selexipag. PMID- 28639120 TI - Duloxetine and gingival bleeding: a case-report and reviews of the French and World PharmacoVigilance Databases and literature. PMID- 28639121 TI - Montelukast use-a 19-year nationwide drug utilisation study. AB - PURPOSE: Montelukast is a leukotriene receptor antagonist used in asthma and rhinitis treatment. Despite being marketed nearly two decades ago, little is known about its utilisation pattern. METHODS: Using the Danish National Prescription Registry, we identified subjects filling a montelukast prescription between 1998 and 2017. Using descriptive statistics, we reported the development in incidence, and prevalence, as well as a measure of treatment duration, and concomitant use of asthma- or anti-allergic therapy. RESULTS: We identified 147,247 individuals filling 1,327,489 montelukast prescriptions. A total of 54,349 users (37%) filled only one montelukast prescription. The prevalence increased from 0.9/1000 persons in 1998 to 3.3/1000 persons in 2016. The rate of new users reached its maximum of 2.1/1000 person-years in 2009. Among new montelukast users, 28% were still users after 1 year. Among all montelukast initiators, 60% filled at least one prescription of short-acting beta-2-agonists (SABA) up to a year prior to montelukast initiation, and 49% filled a prescription of inhaled corticosteroids (ICS). Only 0.8% (n = 1148) of all individuals initiated montelukast without a redeemed prescription of short- or long-term inhalation therapy, systemic antihistamines, or nasal topical anti allergic treatment. CONCLUSIONS: The usage of montelukast has increased over threefold since its market entry in 1998, mainly driven by an increased number of prevalent users. The majority of individuals who initiated montelukast filled a prescription of SABA up to a year prior to montelukast initiation, whereas almost half filled a prescription of ICS. PMID- 28639122 TI - Targeting Prostate-Specific Membrane Antigen (PSMA) with F-18-Labeled Compounds: the Influence of Prosthetic Groups on Tumor Uptake and Clearance Profile. AB - PURPOSE: Prostate-specific membrane antigen (PSMA) is an important biomarker expressed in the majority of prostate cancers. The favorable positron emission tomography (PET) imaging profile of the PSMA imaging agent 2-(3-(1-carboxy-5-[(6 [18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentane-dioic acid [18F]DCFPyL in preclinical prostate cancer models and in prostate cancer patients stimulated the development and validation of other fluorine-containing PSMA inhibitors to further enhance pharmacokinetics and simplify production methods. Here, we describe the synthesis and radiopharmacological evaluation of various F 18-labeled PSMA inhibitors which were prepared through different prosthetic group chemistry strategies. PROCEDURES: Prosthetic groups N-succinimidyl-4 [18F]fluorobenzoate ([18F]SFB), 4-[18F]fluorobenzaldehyde, and 2-deoxy-2 [18F]fluoro-D-glucose ([18F]FDG) were used for bioconjugation reactions to PSMA binding lysine-urea-glutamate scaffold via acylation and oxime formation. All fluorine-containing PSMA inhibitors were tested for their PSMA inhibitory potency in an in vitro competitive binding assay in comparison to an established reference compound [125I]TAAG-PSMA. Tumor uptake and clearance profiles of three F-18-labeled PSMA inhibitors ([18F]4, [18F]7, and [18F]8) were studied with dynamic PET imaging using LNCaP tumor-bearing mice. RESULTS: F-18-labeled PSMA inhibitors were synthesized in 32-69 % radiochemical yields using (1) acylation reaction at the primary amino group of the lysine residue with [18F]SFB and (2) oxime formation with 4-[18F]fluorobenzaldehyde and [18F]FDG using the respective aminooxy-functionalized lysine residue. Compound 7 displayed an IC50 value of 6 nM reflecting very high affinity for PSMA. Compounds 4 and 8 showed IC50 values of 13 and 62 nM, respectively. The IC50 value of reference compound DCFPyL was 13 nM. Dynamic PET imaging revealed the following SUV60min for radiotracer uptake in PSMA(+) LNCaP tumors: 0.98 ([18F]DCFPyL), 2.11 ([18F]7), 0.40 ([18F]4), and 0.19 ([18F]8). CONCLUSION: The observed tumor uptake and clearance profiles demonstrate the importance of the selected prosthetic group on the pharmacokinetic profile of analyzed PSMA-targeting radiotracers. Radiotracer [18F]7 displayed the highest uptake and retention in LNCaP tumors, which exceeded uptake values of reference compound [18F]DCFPyL by more than 100 %. Despite the higher kidney and liver uptake and retention of compound [18F]7, the simple radiosynthesis and the exceptionally high tumor uptake (SUV60min 2.11) and retention make radiotracer [18F]7 an interesting alternative to radiotracer [18F]DCFPyL for PET imaging of PSMA in prostate cancer. PMID- 28639123 TI - A Multispecies Approach to Co-Sleeping : Integrating Human-Animal Co-Sleeping Practices into Our Understanding of Human Sleep. AB - Human sleeping arrangements have evolved over time and differ across cultures. The majority of adults share their bed at one time or another with a partner or child, and many also sleep with pets. In fact, around half of dog and cat owners report sharing a bed or bedroom with their pet(s). However, interspecies co sleeping has been trivialized in the literature relative to interpersonal or human-human co-sleeping, receiving little attention from an interdisciplinary psychological perspective. In this paper, we provide a historical outline of the "civilizing process" that has led to current sociocultural conceptions of sleep as an individual, private function crucial for the functioning of society and the health of individuals. We identify similar historical processes at work in the formation of contemporary constructions of socially normative sleeping arrangements for humans and animals. Importantly, since previous examinations of co-sleeping practices have anthropocentrically framed this topic, the result is an incomplete understanding of co-sleeping practices. By using dogs as an exemplar of human-animal co-sleeping, and comparing human-canine sleeping with adult-child co-sleeping, we determine that both forms of co-sleeping share common factors for establishment and maintenance, and often result in similar benefits and drawbacks. We propose that human-animal and adult-child co-sleeping should be approached as legitimate and socially relevant forms of co-sleeping, and we recommend that co-sleeping be approached broadly as a social practice involving relations with humans and other animals. Because our proposition is speculative and derived from canine-centric data, we recommend ongoing theoretical refinement grounded in empirical research addressing co-sleeping between humans and multiple animal species. PMID- 28639124 TI - Low-Grade Papillary Schneiderian Carcinoma: A Case Report. AB - The nasal cavity and paranasal sinuses are covered with ciliated respiratory mucosa of ectodermal origin, known as Schneiderian epithelium, which can give rise to different types of sinonasal carcinomas. A 42-year-old woman with a history of nasal polypectomy 3 years previously presented with nasal obstruction and rhinorrhea. She was found to have a papillary mass involving the left nasal cavity, and the left maxillary and ethmoidal sinuses by radiologic examination. She underwent endonasal resection under the diagnosis of oncocytic papilloma. The resected specimen showed exuberant invasive growth of papillary or inverted architectures of epithelial cells. The neoplastic cells were very bland, showing a round to polygonal shape, low nuclear-to-cytoplasmic ratio, abundant oncocytic cytoplasm, uniform nuclei, indistinct nucleoli, and scarce mitosis. The overall features were identical to those of a recent report of a low-grade papillary Schneiderian carcinoma. The main differential diagnosis is Schneiderian papilloma, and awareness of this novel entity is important for its proper treatment. PMID- 28639125 TI - DLSanalysis.org: a web interface for analysis of dynamic light scattering data. AB - A web interface ( www.DLSanalysis.org ) for indirect Laplace transformation of dynamic light scattering data is presented. When experimental data are uploaded to the server they are processed in a few seconds, and the result is displayed on the screen in the form of a size distribution together with the experimental data and the fit to the data. No other user input than the experimental data is necessary, but various options for the analysis may be selected. No local installation of software or registration is necessary. The result of the analysis can be downloaded. PMID- 28639126 TI - A comparison of five partial volume correction methods for Tau and Amyloid PET imaging with [18F]THK5351 and [11C]PIB. AB - PURPOSE: To suppress partial volume effect (PVE) in brain PET, there have been many algorithms proposed. However, each methodology has different property due to its assumption and algorithms. Our aim of this study was to investigate the difference among partial volume correction (PVC) method for tau and amyloid PET study. METHODS: We investigated two of the most commonly used PVC methods, Muller Gartner (MG) and geometric transfer matrix (GTM) and also other three methods for clinical tau and amyloid PET imaging. One healthy control (HC) and one Alzheimer's disease (AD) PET studies of both [18F]THK5351 and [11C]PIB were performed using a Eminence STARGATE scanner (Shimadzu Inc., Kyoto, Japan). All PET images were corrected for PVE by MG, GTM, Labbe (LABBE), Regional voxel-based (RBV), and Iterative Yang (IY) methods, with segmented or parcellated anatomical information processed by FreeSurfer, derived from individual MR images. PVC results of 5 algorithms were compared with the uncorrected data. RESULTS: In regions of high uptake of [18F]THK5351 and [11C]PIB, different PVCs demonstrated different SUVRs. The degree of difference between PVE uncorrected and corrected depends on not only PVC algorithm but also type of tracer and subject condition. CONCLUSION: Presented PVC methods are straight-forward to implement but the corrected images require careful interpretation as different methods result in different levels of recovery. PMID- 28639127 TI - Obesity, Metabolic Syndrome, and Cardiac Risk Factors: Going Gluten-Free, for Better or Worse? PMID- 28639128 TI - Comparison of 4-L Polyethylene Glycol and 2-L Polyethylene Glycol Plus Ascorbic Acid in Patients with Inactive Ulcerative Colitis. AB - BACKGROUND: Although colonoscopy preparation may cause symptom flares in patients with ulcerative colitis (UC), little is known about the standard preparation regimen in this population. AIM: We aimed to compare 4L polyethylene glycol (4L PEG) with 2L polyethylene glycol plus ascorbic acid (2L-PEG-Asc) in quiescent UC patients. METHODS: Patients with inactive UC undergoing colonoscopy for surveillance or checkup of mucosal healing were prospectively enrolled at 5 tertiary hospitals. They were randomly assigned to 4L-PEG and 2L-PEG-Asc groups. The Boston Bowel Preparation Scale (BBPS) was used for the preparation quality. Symptoms were assessed using the Simple Clinical Colitis Activity Index (SCCAI) before colonoscopy, at 1 and 4 weeks after the procedure. RESULTS: Overall, 109 patients were included in the study (4L-PEG group 53, 2L-PEG-Asc group 56, the mean age at diagnosis 42.25 years, male 77). The quality of preparation was comparable between the groups (BBPS >= 6, 96.2 vs. 92.9%, p = 0.679). Although 26 patients (23.8%) had increased SCCAI scores within 4 weeks after colonoscopy, resulting in a medication dose-up or add-on in 3 patients (2.7%), the rise in scores was not different between the groups. No serious adverse events during preparation were observed in either group. However, the 2L-PEG-Asc group was more likely to be willing to repeat the preparation with the same agent than the 4L PEG group (82.1 vs. 64.2%, respectively, p = 0.034). CONCLUSION: PEG-based regimens with different volumes are equally effective and safe in inactive UC patients. 2L-PEG-Asc is more acceptable in this population as indicated by the willingness for further usage. PMID- 28639129 TI - The Inhibition of Indoleamine 2,3-Dioxygenase Accelerates Early Liver Regeneration in Mice After Partial Hepatectomy. AB - BACKGROUND AND AIM: The inflammatory response accelerates early liver regeneration after liver injury and resection. Recent studies have demonstrated that indoleamine 2,3-dioxygenase-1 (IDO1) suppresses the activation of inflammatory cells and induces immune tolerance. In this study, we examined the role of IDO1 in liver regeneration after partial hepatectomy (PHx). METHODS: WT or IDO1-knockout (IDO1-KO) mice received 70% PHx. The liver-body weight ratio after PHx was measured and hepatocyte growth was assessed by immunostaining. The expression of cell cycle genes and pro-inflammatory cytokines in the liver was analyzed by quantitative RT-PCR. In addition, 1-methyl-DL-tryptophan (1-MT), which is an IDO1 inhibitory agent, was given to WT mice and the liver-body weight ratio was measured after PHx. RESULTS: The liver-body weight ratio was significantly increased in IDO1-KO mice compared with that in WT mice after PHx. More Ki-67-positive cells were present in IDO1-KO mice than in WT mice after PHx. The expression of cell cycle genes (cyclin D1, cyclin E) and pro-inflammatory cytokines (IL-1beta, TNF-alpha and IL-6) was up-regulated in the remnant liver of IDO1-KO mice compared with WT mice. Moreover, treatment with 1-MT promoted liver regeneration. CONCLUSION: IDO1 deficiency promoted early liver regeneration after PHx, indicating that IDO1 suppresses the production of inflammatory cytokines and subsequently inhibits hepatocyte proliferation during liver regeneration. PMID- 28639130 TI - Vitamin C Improves Gastroparesis in Diabetic Rats: Effects on Gastric Contractile Responses and Oxidative Stress. AB - BACKGROUND: Diabetic gastroparesis is a common complication of diabetes mellitus, which mainly affects women. Previous studies have demonstrated that oxidative stress is involved in its onset and development. AIMS: This study evaluated the role of vitamin C on diabetes-associated gastric dysmotility. METHODS: Female rats with streptozotocin-induced diabetes were treated with vehicle (water, 1 mL/kg, p.o.), vitamin C (300 mg/kg/day, p.o.), or insulin (6 IU/day, s.c.). Gastric emptying, in vitro gastric contractility, and biochemistry parameters were analyzed at the end of the treatment (i.e. 8 weeks after the diabetes induction). RESULTS: Vitamin C reversed the delayed gastric emptying of diabetic rats to normal levels, and avoided the changes in the contractile responses to acetylcholine (0.1 nM-1 uM), but not to 5-hydroxytryptamine (0.1 nM-1 uM), in the pylorus and fundus from diabetic rats. Moreover, the contraction evoked by KCl (40 mM) in the fundus, but not in the pylorus, was intensely increased in diabetic rats treated with vitamin C. Notably, the vitamin C reestablished the reduced glutathione levels by 77% and decreased the reactive oxygen species content by 60% in the gastric tissue from diabetic rats. Despite the effects on gastric motility, vitamin C treatment did not change the fasting glycaemia or the glycated hemoglobin of diabetic rats. Unsurprisingly, insulin treatment normalized all parameters evaluated. CONCLUSIONS: Vitamin C exhibited a remarkable beneficial effect on gastric emptying dysfunction in diabetic rats, which was mediated by attenuation of oxidative stress and maintenance of the cholinergic contractile responses in fundus and pylorus. PMID- 28639132 TI - Identifying the neural substrates of intrinsic motivation during task performance. AB - Intrinsic motivation is the inherent tendency to seek out novelty and challenge, to explore and investigate, and to stretch and extend one's capacities. When people imagine performing intrinsically motivating tasks, they show heightened anterior insular cortex (AIC) activity. To fully explain the neural system of intrinsic motivation, however, requires assessing neural activity while people actually perform intrinsically motivating tasks (i.e., while answering curiosity inducing questions or solving competence-enabling anagrams). Using event-related functional magnetic resonance imaging, we found that the neural system of intrinsic motivation involves not only AIC activity, but also striatum activity and, further, AIC-striatum functional interactions. These findings suggest that subjective feelings of intrinsic satisfaction (associated with AIC activations), reward processing (associated with striatum activations), and their interactions underlie the actual experience of intrinsic motivation. These neural findings are consistent with the conceptualization of intrinsic motivation as the pursuit and satisfaction of subjective feelings (interest and enjoyment) as intrinsic rewards. PMID- 28639133 TI - Stereotactic biopsy in elderly patients: risk assessment and impact on treatment decision. AB - To evaluate risk profile, diagnostic yield and impact on treatment decision of stereotactic biopsy (SB) in elderly patients with unclear cerebral lesions. In this single center retrospective analysis we identified all patients aged >=70 years receiving SB between January 2005 and December 2015. Demographic data, Karnofsky Performance Status (KPS), histology, comorbidity (by CHA2DS2-VASc Score) and use of anticoagulation were retrieved. We scrutinized diagnostic yield, procedural complications (mortality, transient and permanent morbidity), hospitalization time and therapeutic consequence. For correlation analysis Chi Square, Mann-Whitney rank sum test and binary regression were used. Two hundred and thirty patients were included. In 229 patients SB was technically successful. Median age was 74 (70-87) years, 56.1% of patients were male and median preoperative KPS was 80% (30-100). Median CHA2DS2-VASc Score was 4 (1-9), with 29.6% receiving anticoagulation. Median hospital stay was 8 (2-29) days. Pathological diagnosis was conclusive in 97% revealing neoplastic lesions in 91.7% (high-grade glioma 62.6%, lymphoma 18.3%, metastasis 4.8%, low-grade glioma 3.0% and other tumors 3.0%) and non-neoplastic lesions in 5.3% of cases. Procedure-related mortality was 0.4%, transient and permanent morbidity occurred in 19 patients (8.3%) and eight patients (3.5%). Complication rate was not associated with any of the above-mentioned parameters. Adjuvant therapy was initiated in 171 (74.3%) patients. Decision against disease-specific therapy was only influenced by preoperative KPS (p < 0.001). SB in elderly patients is characterized by a favorable risk profile and high diagnostic yield, allowing tissue based therapeutic consequences even in patients with high comorbidity and anticoagulant medication. PMID- 28639134 TI - KIFC1 and myosin Va: two motors for acrosomal biogenesis and nuclear shaping during spermiogenesis of Portunus trituberculatus. AB - To investigate the molecular mechanisms underlying the spermiogenesis of the swimming crab Portunus trituberculatus, full lengths of motor proteins KIFC1 and myosin Va were cloned by rapid-amplification of cDNA ends from P. trituberculatus testes cDNA, and their respective probes and specific antibodies were used to track their localization during sperm maturation. Antisense probes were designed from the gene sequences and used to detect the mRNA levels of each gene. According to the results of fluorescence in situ hybridization (FISH), the transcription of kifc1 and myosin Va began at the mid-stage of spermatids, with the kifc1 mRNA being most active at the location where the acrosome cap was formed and the myosin Va was more concentrated in the acrosome complex. Immunofluorescence results showed that KIFC1 and myosin Va were highly expressed in each stage of spermigenesis. In the early spermatids, they were randomly dispersed in the cytoplasm together with cytoskeletons. At the mid-stage, the motors were gathered above one side of the nucleus where the acrosome would later form. In the late spermatids and mature sperm, the KIFC1 was closely distributed in the perinuclear region, indicating its role in nucleus deformation. Myosin Va was distributed in the acrosome complex until sperm maturity. This suggests myosin Va's potential role in material transportation during acrosome formation and maturation. The above results provide a preliminary illustration of the essential roles of KIFC1 and myosin Va in the spermiogenesis of the swimming crab P. trituberculatus. PMID- 28639131 TI - miRNA Signature of Hepatocellular Carcinoma Vascularization: How the Controls Can Influence the Signature. AB - BACKGROUND: miRNA deregulation and vascular modifications constitute promising predictors in the study of hepatocellular carcinoma (HCC). In the literature, the relative miRNA abundance in HCC is usually determined using as control non matched tumoral tissue, healthy liver, or cirrhotic liver. However, a common standard RNA control for the normalization toward the tissue gene expression was not settled yet. AIM: To assess the differences existing in the quantitative miRNA gene expression in HCC on tissue according to two different liver controls. METHODS: A wide array of miRNAs was analyzed on 22 HCCs arisen in cirrhotic and non-cirrhotic livers by means of microfluidic cards. Control samples included total RNA extracted from healthy and cirrhotic livers. Immunohistochemistry for CD34 and Nestin was performed to assess the pattern of intratumoral vascular modifications. RESULTS: Six miRNAs were deregulated in HCCs using either controls: miR-532, miR-34a, miR-93, miR-149#, miR-7f-2#, and miR-30a-5p. Notably, the miRNA expression changed significantly between HCCs arisen in cirrhotic and non-cirrhotic livers, according to the control used for normalization. Different miRNA profiles were found also in HCCs with different vascular patterns, according to the control used for normalization. CONCLUSIONS: Our data confirm that the choice of the methodology, and particularly the control used for normalization, represents the main concern in miRNA evaluation, particularly in a heterogeneous model such as liver pathology. Still we observed the deregulation of some common miRNAs as promising in HCC cancerogenesis and progression. A standardized control will be a crucial achievement to compare miRNA expression among different laboratories. PMID- 28639135 TI - Histological verification of the usefulness of magnifying endoscopy with narrow band imaging for horizontal margin diagnosis of differentiated-type early gastric cancers. AB - BACKGROUND: Although magnifying endoscopy with narrow-band imaging (ME-NBI) can help identify the horizontal margin (HM) of early gastric cancer (EGC), little is known about the factors that can clarify the HM by using ME-NBI. We aimed to characterize the pathological features of lesions in which the HM was identified using ME-NBI. METHODS: The HMs of 639 differentiated-type EGCs treated with endoscopic submucosal dissection or surgery were analyzed using conventional endoscopy and ME-NBI. The number and width of the intervening parts (IP) and the number, width, and depth of the subepithelial capillaries (SEC) in cancerous and noncancerous areas were measured. RESULTS: In 13 lesions (2.0%), more than 90% of the HM was not recognized with conventional endoscopy, but 11 of these lesions were detectable with ME-NBI (NBI group). The HMs of the other 626 lesions were mostly recognized using conventional endoscopy (WLI/CE group). In the NBI group, the IP width, standard deviation (SD), and number of IPs did not significantly differ between the cancerous and noncancerous areas. However, the SEC number was significantly larger and the depth was shallower in cancerous areas. In the WLI/CE group, the IP width and SD were significantly larger, but the IP number was significantly smaller in cancerous areas. The SEC depth was significantly shallower in cancerous areas. CONCLUSIONS: Differences of IP width, SD, and IP number may be factors for identifying HMs with conventional endoscopy. Because NBI can better visualize vessel structures, the increased SEC number and shallow SECs may clarify the HM. PMID- 28639136 TI - Long-term oncologic outcomes of robotic gastrectomy for gastric cancer compared with laparoscopic gastrectomy. AB - BACKGROUND: Initial experiences with robotic gastrectomy (RG) for gastric cancer have demonstrated favorable short-term outcomes, suggesting that RG is an effective alternative to laparoscopic gastrectomy (LG). However, data on long term survival and recurrence after RG for gastric cancer have yet to be reported. The objective of this study was to assess long-term outcomes after RG compared with LG. METHODS: We retrospectively evaluated 313 and 524 patients who underwent RG or LG, respectively, for gastric cancer between July 2005 and December 2009. We compared long-term outcomes using the entire and a propensity-score matched cohort. RESULTS: The entire cohort analysis revealed no statistically significant differences in 5-year overall survival(OS) or relapse-free survival(RFS) (p = 0.4112 and p = 0.8733, respectively): 93.3% [95% confidence interval (CI) 89.9 95.6] and 90.7% (95% CI, 86.9-93.5) after RG and 91.6% (95% CI 88.9-93.7) and 90.5% (95% CI 87.6-92.7) after LG, respectively; hazard ratios for death and recurrence in the robotic group were 0.828 (95% CI, 0.528-1.299; p = 0.4119) and 0.968 (95% CI, 0.649-1.445; p = 0.8741), respectively. The propensity-matched cohort analysis demonstrated no statistically significant differences for 5-year OS or RFS (p = 0.5207 and p = 0.2293, respectively): 93.2% and 90.7% after RG and 94.2% and 92.6% after LG, respectively; hazard ratios for death and recurrence in the robotic group were 1.194 (95% CI, 0.695-2.062; p = 0.5214) and 1.343 (95% CI, 0.830-2.192; p = 0.2321), respectively. CONCLUSION: The potential technical superiority of robotic system over laparoscopy did not improve oncological outcomes after gastrectomy. Long-term oncological outcomes were not different between RG and LG. Nevertheless, robotic applications in minimally invasive gastric cancer surgery may be an oncologically safe alternative. PMID- 28639137 TI - The Frank-Starling Law: a jigsaw of titin proportions. AB - The Frank-Starling Law dictates that the heart is able to match ejection to the dynamic changes occurring during cardiac filling, hence efficiently regulating isovolumetric contraction and shortening. In the last four decades, efforts have been made to identify a common fundamental basis for the Frank-Starling heart that can explain the direct relationship between muscle lengthening and its increased sensitization to Ca2+. The term 'myofilament length-dependent activation' describes the length-dependent properties of the myofilaments, but what is(are) the underlying molecular mechanism(s) is a matter of ongoing debate. Length-dependent activation increases formation of thick-filament strongly-bound cross-bridges on actin and imposes structural-mechanical alterations on the thin filament with greater than normal bound Ca2+. Stretch-induced effects, rather than changes in filament spacing, appear to be primarily involved in the regulation of length-dependent activation. Here, evidence is provided to support the notion that stretch-mediated effects induced by titin govern alterations of thick-filament force-producing cross-bridges and thin-filament Ca2+-cooperative responses. PMID- 28639139 TI - Ex vivo permeation of erythropoietin through porcine conjunctiva, cornea, and sclera. AB - The aim of this study is to test the permeation of human recombinant erythropoietin (rHuEPO) across conjunctiva, cornea, and sclera in an ex vivo model. Thirty fresh pig eyes were collected from a slaughterhouse. Conjunctivas (n = 10), corneas (n = 10), and scleras (n = 10) were surgically dissected from surrounding tissues. Ocular membranes were placed into Franz diffusion cells and rHuEPO was administered into the donor phase of each cell, except for control samples. Samples were collected from the receptor phase at seven time points, from 30 min to 6 h of incubation. Erythropoietin (EPO) was quantified by enzyme linked immunosorbent assay (ELISA) technique. Ocular membranes immunohistochemistry was also performed at the end of the study. EPO was detected in all test samples. After 6 h of incubation, conjunctiva was the most permeable membrane to rHuEPO (509.3 +/- 89.8 mIU/cm2, corresponding to 0.52% of the total rHuEPO administered on the donor phase), followed by sclera (359.1 +/- 123.7 mIU/cm2, corresponding to 0.35%) and finally cornea (71.0 +/- 31.8 mIU/cm2, corresponding to 0.07%). Differences between ocular membranes' permeation were statistically significant (p < 0.001). EPO immunostaining signal was positive for the three ocular membranes. We have demonstrated in an ex vivo model that porcine conjunctiva, cornea, and sclera are permeable to rHuEPO protein. These are promising results concerning ocular EPO administration. PMID- 28639138 TI - Veterinary vaccine nanotechnology: pulmonary and nasal delivery in livestock animals. AB - Veterinary vaccine development has several similarities with human vaccine development to improve the overall health and well-being of species. However, veterinary goals lean more toward feasible large-scale administration methods and low cost to high benefit immunization. Since the respiratory mucosa is easily accessible and most infectious agents begin their infection cycle at the mucosa, immunization through the respiratory route has been a highly attractive vaccine delivery strategy against infectious diseases. Additionally, vaccines administered via the respiratory mucosa could lower costs by removing the need of trained medical personnel, and lowering doses yet achieving similar or increased immune stimulation. The respiratory route often brings challenges in antigen delivery efficiency with enough potency to induce immunity. Nanoparticle (NP) technology has been shown to enhance immune activation by producing higher antibody titers and protection. Although specific mechanisms between NPs and biological membranes are still under investigation, physical parameters such as particle size and shape, as well as biological tissue distribution including mucociliary clearance influence the protection and delivery of antigens to the site of action and uptake by target cells. For respiratory delivery, various biomaterials such as mucoadhesive polymers, lipids, and polysaccharides have shown enhanced antibody production or protection in comparison to antigen alone. This review presents promising NPs administered via the nasal or pulmonary routes for veterinary applications specifically focusing on livestock animals including poultry. PMID- 28639140 TI - Determination of the thermal and epithermal neutron sensitivities of an LBO chamber. AB - An LBO (Li2B4O7) walled ionization chamber was designed to monitor the epithermal neutron fluence in boron neutron capture therapy clinical irradiation. The thermal and epithermal neutron sensitivities of the device were evaluated using accelerator neutrons from the 9Be(d, n) reaction at a deuteron energy of 4 MeV (4 MeV d-Be neutrons). The response of the chamber in terms of the electric charge induced in the LBO chamber was compared with the thermal and epithermal neutron fluences measured using the gold-foil activation method. The thermal and epithermal neutron sensitivities obtained were expressed in units of pC cm2, i.e., from the chamber response divided by neutron fluence (cm-2). The measured LBO chamber sensitivities were 2.23 * 10-7 +/- 0.34 * 10-7 (pC cm2) for thermal neutrons and 2.00 * 10-5 +/- 0.12 * 10-5 (pC cm2) for epithermal neutrons. This shows that the LBO chamber is sufficiently sensitive to epithermal neutrons to be useful for epithermal neutron monitoring in BNCT irradiation. PMID- 28639141 TI - Survival of an AIDS patient after infection with Acanthamoeba sp. of the central nervous system. AB - CASE DESCRIPTION: A 38-year-old man presented with headaches and generalized weakness. He was found to have AIDS; a ring-enhancing central nervous system lesion was found on brain imaging and he had elevated serum Toxoplasma gondii IgG levels. A diagnosis of presumptive toxoplasma encephalitis was made and he received antiretrovirals and antitoxoplasma therapy for 4 years. Intermittent headaches and evidence of disease progression on neuroimaging warranted further evaluation and cerebrospinal fluid analysis revealed amebic forms on hematoxylin and eosin staining and positive polymerase chain reaction testing for Acanthamoeba spp. He was placed on miltefosine, fluconazole, trimethoprim sulfamethoxazole and flucytosine for 7 months. Five months after therapy discontinuation he remains asymptomatic and is taking only antiretroviral therapy. CONCLUSION: This is the first report of a patient with AIDS and granulomatous amebic encephalitis who survived with medical therapy only. PMID- 28639142 TI - Serrated Polyps of Colon and Rectum: a Clinicopathologic Review. AB - BACKGROUND: In the past decade, there have been significant changes in the classification and nomenclature of colorectal polyps. Previously, only two groups of lesions were widely recognized, the adenoma and the hyperplastic polyp. Adenomas were considered the only precursor of colorectal cancer, and hyperplastic polyps were considered innocent with no malignant potential. However, recent discoveries about molecular pathways of colorectal cancers have significantly changed our understanding of these neoplasms. Serrated polyps previously uniformly called hyperplastic polyps-are now known to comprise a heterogeneous family of neoplasms united by their characteristic saw tooth morphology but differing in many important ways, including their malignant potential and molecular profile. This group of neoplasms includes both hyperplastic polyps and the more recently recognized serrated adenomas. Serrated adenomas can be subdivided into the traditional serrated adenoma and the sessile serrated adenoma/polyp. Both of these lesions show characteristic molecular changes, which differ from traditional colorectal adenomatous polyps. OBJECTIVES: In this review, we will discuss the morphologic features of serrated colorectal lesions, the molecular alterations that characterize them, and their role in colorectal cancer development. MATERIAL AND METHODS: The English literature regarding the new nomenclature will be reviewed and the key diagnostic points will be recorded. RESULTS AND DISCUSSION: This large group of polyps has recently been better classified which needs specific attention by pathologists, gastroenterologists and even surgeons. PMID- 28639143 TI - Quality of life after carotid endarterectomy: a review of the literature. AB - Strokes are one of the leading causes of death, morbidity, and disability worldwide, mainly among elderly people. It is also the third most common cause of years of life being lost, indicating a high risk of premature mortality. Revascularisation with endarterectomy (CEA) is effective in reducing the risk of death and strokes in patients with carotid artery stenosis, but the effect of invasive treatment on quality of life (QoL) still needs attention. To shed more light on the patients' perspective on this health condition, we carried out a review of the literature which aimed to analyze the level of health-related QoL among stroke survivors, with special attention to patients who had been treated with CEA. Strokes significantly reduce the level of QoL, which may subsequently be improved in the course of treatment with CEA. Patients experience a reduced level of QoL in the early postoperative period, but at 1 year following CEA, the level of QoL remains stable and is similar to that of chronically ill patients. The domains of QoL which are most affected are physical and emotional functioning, which also serve as markers for decreased QoL in the long term. Older age and comorbidities are predictors of worse QoL. Stroke survivors require proper care both immediately after a stroke happens and during the long-term rehabilitation. Measurement of QoL and of the determining factors that contribute to a reduced level of QoL, as well as focusing on determinants of QoL in stroke survivors may help to reduce patients' disability and improve their daily functioning in society as well as reducing the cost of health care. PMID- 28639144 TI - Rural versus urban compliance in the management of cryptorchidism: is there a difference? AB - : The authors compared the age and referral patterns of pediatric patients undergoing surgical intervention for cryptorchidism at a rural, West Virginia University, versus urban, Johns Hopkins University, tertiary center. A retrospective review of patients undergoing surgical evaluation for cryptorchidism was performed. Patients treated for reasons unrelated to cryptorchidism or referred for multiple urologic diagnoses were excluded. The patients at each institution were then divided into four groups based on their corrected gestational age at time of surgery. Referral times and provider specialties were also obtained. A total of 131 cases at the urban center and 100 cases at the rural center were identified. At the rural center, the average age of referral and surgery were 48.3 and 53.8 months, respectively, compared to 59.6 and 65.2 months at the urban center. Only 40% of patients at the rural site and 29% at the urban institution underwent intervention at less than 18 months of age. There was no significant difference in time of referral to surgery between the institutions. The majority of referrals were made by private practice pediatricians. CONCLUSION: In this study, a pattern of delayed referral and intervention was observed at both institutions despite differing geographic regions and heterogeneous patient populations. It is important that referring providers realize that scrotal U/S does not change management of UDT and should not delay prompt referral. What is known: * Significant referral delay is a challenging issue in the management of cryptorchidism. * Ultrasound is not a valid method for the detection of cryptorchidism. What is new: * The rural and urban management of cryptorchidism is not that different. * More emphasis should be put on the detection management of cryptorchidism. PMID- 28639145 TI - In vitro and In vivo Activity of Theaflavin-Epicatechin Combinations versus Multidrug-Resistant Acinetobacter baumannii. AB - INTRODUCTION: Acinetobacter baumannii is an important human nosocomial pathogen; most clinical isolates are multidrug-resistant (MDR). Infections caused by A. baumannii often lead to high morbidity and mortality, with limited treatment options. Owing to the small number of anti-Gram-negative antibiotics in the development pipeline, researchers are looking to other natural compounds. The aim of this study was to determine the in vitro kill kinetics, in vivo efficacy and toxicity of theaflavin-epicatechin combinations against MDR A. baumannii. METHODS: Kill-kinetic assays were performed in Mueller-Hinton 2 broth over 24 h. Toxicity of the compound in the insect model, Galleria mellonella was investigated. The effect of theaflavin-epicatechin combinations on mortality and morbidity were assessed in Acinetobacter baumannii-infected G. mellonella. Larvae were scored for morbidity (melanisation: scale; 0-4) and mortality over 96 h. RESULTS: Kill-kinetic assays revealed that monotherapy had bacteriostatic activity over 24 h, whereas theaflavin-epicatechin combinations were bactericidal (a >3 log reduction in bacterial numbers at 24 h compared with the starting inoculum). Both polyphenols were non-toxic to G. mellonella at concentrations of up to 1000 mg/kg. In vivo treatment assays showed that the combination significantly increased (t test; p <= 0.05) larval survival at 96 h to 86% [+/-17 standard deviation percentage points (pp)] compared to monotherapy with theaflavin (52% +/- 14 pp), epicatechin (44% +/- 25 pp) or PBS (31% +/- 13 pp). Morbidity was also lower in larvae treated with the combination, compared with monotherapy. CONCLUSION: Polyphenol combinations produce effective antibacterial action against A. baumannii and show great potential for the treatment of infections caused by MDR A. baumannii. PMID- 28639146 TI - In vivo Visualisation and Quantification of Bone Resorption and Bone Formation from Time-Lapse Imaging. AB - PURPOSE OF REVIEW: Mechanoregulation of bone cells was proposed over a century ago, but only now can we visualise and quantify bone resorption and bone formation and its mechanoregulation. In this review, we show how the newest advances in imaging and computational methods paved the way for this breakthrough. RECENT FINDINGS: Non-invasive in vivo assessment of bone resorption and bone formation was demonstrated by time-lapse micro-computed tomography in animals, and by high-resolution peripheral quantitative computed tomography in humans. Coupled with micro-finite element analysis, the relationships between sites of bone resorption and bone formation and low and high tissue loading, respectively, were shown. Time-lapse in vivo imaging and computational methods enabled visualising and quantifying bone resorption and bone formation as well as its mechanoregulation. Future research includes visualising and quantifying mechanoregulation of bone resorption and bone formation from molecular to organ scales, and translating the findings into medicine using personalised bone health prognosis. PMID- 28639147 TI - Rethinking cell-cycle-dependent gene expression in Schizosaccharomyces pombe. AB - Three studies of gene expression during the division cycle of Schizosaccharomyces pombe led to the proposal that a large number of genes are expressed at particular times during the S. pombe cell cycle. Yet only a small fraction of genes proposed to be expressed in a cell-cycle-dependent manner are reproducible in all three published studies. In addition to reproducibility problems, questions about expression amplitudes, cell-cycle timing of expression, synchronization artifacts, and the problem with methods for synchronizing cells must be considered. These problems and complications prompt the idea that caution should be used before accepting the conclusion that there are a large number of genes expressed in a cell-cycle-dependent manner in S. pombe. PMID- 28639149 TI - Safety, Feasibility, Results, and Economic Impact of Common Interventional Procedures in a Low-Volume Region of the United States. AB - The aim of the study was to evaluate the safety, feasibility, and economic benefit of a high-volume operator performing common interventional procedures in a rural region of the United States (U.S.). Rural areas of the U.S., even with well-equipped cardiac catheterization laboratories, may not have a full-time pediatric interventional cardiologist (PIC); this requires patients to travel out of state even for simple interventions. Since 2005, we have adopted a policy of performing cardiac catheterizations and common interventional procedures with a visiting PIC. We reviewed data of all patients who underwent cardiac catheterizations from May 2005 through March 2015 at our center. Variables analyzed were type of procedure, results, and follow-up six months after procedure. 197 catheterizations were performed, of which 80 were for single atrial septal defect (ASD), 29 for fenestrated ASD, 49 for patent ductus arteriosus (PDA), and 39 for other procedures. Device closure of single ASD was successful in 75 of 79 attempts and in 27 of 28 attempts for fenestrated ASD. PDA closure was successful in 45 of 46 attempts. Follow-up data of 6 months or more were available for 127 patients. All but two patients had no cardiovascular symptoms at 6 months. There were four minor complications and no major complications. With a technical success rate of 94.9% for single ASD closure, 97.8% for PDA closure, and results comparable to those of multi-institutional registries, cardiac catheterization and interventions can be performed safely with excellent results. Performing procedures in such an arrangement is safe, feasible, and economically beneficial. PMID- 28639150 TI - How Should We Diagnose Persistence of the Artery of the Fifth Pharyngeal Arch? PMID- 28639151 TI - Central Arterial Function Measured by Non-invasive Pulse Wave Analysis is Abnormal in Patients with Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutation of dystrophin. Cardiovascular involvement includes dilated cardiomyopathy. Non-invasive assessment of vascular function has not been evaluated in DMD. We hypothesize arterial wave reflection is abnormal in patients with DMD. Pulse wave analysis was performed on DMD patients with a SphygmoCor SCOR-PVx System to determine central blood pressure and augmentation index (AIx) as an assessment of arterial wave reflection. Results were compared to a control group. A total of 43 patients with DMD were enrolled, and compared to 43 normal controls. Central systolic blood pressure was lower, while both AIx-75 (7.8 +/- 9.6% vs. 2.1 +/- 10.4%, p 0.01, DMD vs. normal) and AIx-not corrected (16.8 +/- 10.1% vs. -3.6 +/- 10.9, p < 0.001, DMD vs. normal) were higher in the DMD compared to control. Using multivariable linear regression model, the variables found to have a significant effect on AIx-not corrected included diagnosis of DMD, height, and heart rate (r 2 = 0.257). The current data suggest that, despite lower central systolic blood pressure, patients with DMD have higher wave reflection when compared to normal controls, which may represent increased arterial stiffness. Overall there appears to be no effect on ventricular systolic function, however the long-term consequence in this group is unknown. Further study is required to determine the mechanism of these differences, which may be related to the effects of systemic steroids or the role of dystrophin in vascular function. PMID- 28639152 TI - Influence of muscle groups' activation on proximal femoral growth tendency. AB - Muscle and joint contact force influence stresses at the proximal growth plate of the femur and thus bone growth, affecting the neck shaft angle (NSA) and femoral anteversion (FA). This study aims to illustrate how different muscle groups' activation during gait affects NSA and FA development in able-bodied children. Subject-specific femur models were developed for three able-bodied children (ages 6, 7, and 11 years) using magnetic resonance images. Contributions of different muscle groups-hip flexors, hip extensors, hip adductors, hip abductors, and knee extensors-to overall hip contact force were computed. Specific growth rate for the growth plate was computed, and the growth was simulated in the principal stress direction at each element in the growth front. The predicted growth indicated decreased NSA and FA (of about [Formula: see text] over a four-month period) for able-bodied children. Hip abductors contributed the most, and hip adductors, the least, to growth rate. All muscles groups contributed to a decrease in predicted NSA ([Formula: see text]0.01[Formula: see text] 0.04[Formula: see text] and FA ([Formula: see text]0.004[Formula: see text] [Formula: see text]), except hip extensors and hip adductors, which showed a tendency to increase the FA ([Formula: see text]0.004[Formula: see text] [Formula: see text]). Understanding influences of different muscle groups on long bone growth tendency can help in treatment planning for growing children with affected gait. PMID- 28639153 TI - Genomics of Lithium Action and Response. AB - Lithium is the most successful mood stabilizer treatment for bipolar disorder. However, unlike conventional drugs that are designed to interact with a specific molecular target, the actions of lithium are distributed across many biological processes and pathways. Treatment response is subject to genetic variation between individuals and similar genetic variation may dictate susceptibility to side effects. Transcriptomic, genomic, and cell-model research strategies have all been deployed in the search for the genetic factors and biological systems that mediate the interaction between genetics and the therapeutic actions of lithium. In this review, recent findings from genome-wide studies and patient cell lines will be summarized and discussed from a standpoint that genuine progress is being made to define clinically useful mechanisms of this treatment, to place it in the context of bipolar disorder pathology, and to move towards a time when the prescription of lithium is targeted to those individuals who will derive the greatest benefit. PMID- 28639154 TI - Inflammatory myofibroblastic tumor of the gallbladder: a case report and literature review. AB - A 50-year-old man had undergone chemotherapy and radiotherapy for malignant lymphoma 1 year earlier. Follow-up computed tomography revealed a gallbladder polyp. Transabdominal ultrasound demonstrated a 20-mm hypoechoic sessile polyp with basal waist in the gallbladder fundus; the surface was covered with a hyperechoic layer of non-uniform thickness. On contrast-enhanced computed tomography, the polyp showed an early uniform and sustained staining pattern. Magnetic resonance imaging revealed that the polyp had low and slightly high signal intensities on T1- and T2-weighted imaging, respectively. Gallbladder bed resection was performed with the diagnosis of special tumor. Histologically, the polyp comprised a proliferation of myofibroblast-like spindle cells with inflammatory cell infiltration, without muscularis propria or vascular invasion. Most of the polyp surface was covered with necrotic exudate, and part of the normal epithelium remained. Consequently, a diagnosis of inflammatory myofibroblastic tumor was made. The sessile shape with basal waist, epithelium shedding, and surface necrotic exudative matter may represent intraluminal expansive growth such as a subepithelial tumor. A surface with a hyperechoic layer of non-uniform thickness on gallbladder polyp can help in the diagnosis of a tumor with expansive growth directly under the epithelium with stretching/rupture of the epithelium. PMID- 28639155 TI - Giant Caudate Lobe Hemangioma. AB - Liver hemangiomas are the most common benign liver mass and typically asymptomatic and incidentally found. Giant liver hemangiomas are defined as having an overall diameter of >5 cm and more likely to be symptomatic. We present a case of a dominant caudate lobe hemangioma presented with weight loss and abdominal pain. PMID- 28639156 TI - Retinal thickness in parafoveal subfields and visual acuity after vitrectomy for macula-off rhegmatogenous retinal detachment repair. AB - PURPOSE: To investigate retinal thickness in the central and parafoveal subfields, including segmented analysis of the inner and outer retinal layers, after vitrectomy for macula-off rhegmatogenous retinal detachment (RRD) repair. METHODS: Twenty-four eyes of 24 patients who underwent primary vitrectomy for macula-off RRD repair were enrolled in this study. Spectral-domain optical coherence tomography examination and best-corrected visual acuity (BCVA) measurements were performed at 1, 3, and 6 months after vitrectomy. RESULTS: At 1, 3, and 6 months after vitrectomy, retinal thickness in the temporal parafoveal subfield was more significantly (P = 0.004, 0.001, and 0.003, respectively) correlated with BCVA than the central subfield (P = 0.014, 0.001, and 0.022, respectively). Segmented analysis showed significant correlations between the retinal thickness of both the outer layer (P = 0.018, 0.030, and 0.018, respectively) and the inner layer (P = 0.003, 0.002, and 0.001, respectively) in the temporal parafoveal subfield and BCVA at every time point after vitrectomy. CONCLUSIONS: These results suggest that retinal thickness in the temporal parafoveal subfield may most closely reflect postoperative BCVA after macula-off RRD repair. PMID- 28639157 TI - Exercise for improving bone health in women treated for stages I-III breast cancer: a systematic review and meta-analyses. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of exercise, either alone or in combination with other interventions, compared to a control, for the preservation of bone mineral density (BMD) in early breast cancer (BC) patients. METHODS: A systematic search was conducted to identify randomized or quasi-randomized trials which met inclusion criteria including prescribed exercise for >=12 months. Ten publications from seven randomized controlled trials (RCTs), involving 1199 participants, were identified. Data on primary and secondary outcome measures related to BMD at the lumbar spine, total hip, femoral neck and greater trochanter were analysed. Meta-analyses were limited to subgroups by menopausal status as other data could not be pooled. RESULTS: Based on mean differences or mean percentage differences between groups at 1 year, exercise did not preserve BMD or bone mineral content at any site in post menopausal women. In contrast, evidence from one RCT (n = 498) found that exercise reduced bone loss in pre-menopausal women at the femoral neck [% MD = 1.20 (95% CI 0.22-2.18); P = 0.02] but not at the lumbar spine. CONCLUSIONS: Although this review indicated that exercise may result in a clinically important preservation of bone health among pre-menopausal but not post-menopausal women, further studies are needed to confirm whether or not exercise is important in preservation of bone health in women diagnosed with early BC. IMPLICATIONS FOR CANCER SURVIVORS: Exercise alone may not be sufficient to prevent bone loss in post-menopausal women at high risk of osteoporosis. Further evidence is required to determine if it provides any benefit to pharmacological therapy. PMID- 28639158 TI - Development of a survivorship needs assessment planning tool for head and neck cancer survivors and their caregivers: a preliminary study. AB - PURPOSE: The purpose of this study was to characterize primary end-of-treatment challenges in head and neck cancer (HNC) to drive the development of a survivorship needs assessment planning (SNAP) tool and evaluate its acceptability and feasibility. METHODS: Using qualitative methods (focus groups, interviews), we identified physical, emotional, and social post-treatment challenges from the perspectives of survivors (N = 17), caregivers (N = 14), and healthcare providers (N = 14) and pretested the SNAP tool. After Advisory Board ratings and consensus, the tool was finalized. RESULTS: Survivors, caregivers and clinicians consistently highlighted the importance of assessing symptoms and functional abilities (e.g., dry mouth, speech/swallowing difficulties, weight loss), health behaviors (e.g., smoking, alcohol), emotional concerns (e.g., depression, isolation, nutritional distress), and social challenges (e.g., support, finances). Caregivers were overwhelmed and intensely focused on survivors' nutrition and trach/feeding tube care while clinicians emphasized financial and access concerns. Most participants were enthusiastic about the tool and directed a flexible care plan design due to variability in dyad needs. Over 75% reported high comfort using and navigating questions on a tablet and were in strong agreement that the care plan would help families practically and emotionally. Coordination of survivorship visits with follow-up care was critical to address travel and time barriers. While survivors and clinicians recommended waiting 1-6 months after treatment, caregivers preferred earlier survivorship visits. CONCLUSIONS: Results pinpointed optimal end-of-treatment domains for routine assessment and support the feasibility of implementing a SNAP tool in the clinic. IMPLICATIONS FOR CANCER SURVIVORS: Capitalizing on technology to direct HNC survivorship care is promising. PMID- 28639159 TI - A systematic review of patient perspectives on surveillance after colorectal cancer treatment. AB - PURPOSE: Surveillance after colorectal cancer (CRC) treatment is routine, but intensive follow-up may offer little-to-no overall survival benefit. Given the growing population of CRC survivors, we aimed to systematically evaluate the literature for the patient perspective on two questions: (1) How do CRC patients perceive routine surveillance following curative treatment and what do they expect to gain from their surveillance testing or visits? (2) Which providers (specialists, nursing, primary care) are preferred by CRC survivors to guide post treatment surveillance? METHODS: Systematic searches of PubMed MEDLINE, Embase, the CENTRAL Register of Controlled Trials, CINAHL, and PsycINFO were conducted. Studies were screened for inclusion by two reviewers, with discrepancies adjudicated by a third reviewer. Data were abstracted and evaluated utilizing validated reporting tools (CONSORT, STROBE, CASP) appropriate to study design. RESULTS: Citations (3691) were screened, 91 full-text articles reviewed, and 23 studies included in the final review: 15 quantitative and 8 qualitative. Overall, 12 studies indicated CRC patients perceive routine surveillance positively, expecting to gain reassurance of continued disease suppression. Negative perceptions described in six studies included anxiety and dissatisfaction related to quality of life or psychosocial issues during follow-up. Although 5 studies supported specialist-led care, 9 studies indicated patient willingness to have follow-up with non-specialist providers (primary care or nursing). CONCLUSIONS: Patients' perceptions of follow-up after CRC are predominantly positive, although unmet needs included psychosocial support and quality of life. IMPLICATIONS FOR CANCER SURVIVORS: Survivors perceived follow-up as reassuring, however, surveillance care should be more informative and focused on survivor-specific needs. PMID- 28639160 TI - Expression and Activity Analysis of Fructosyltransferase from Aspergillus oryzae. AB - The fructosyltransferase gene was isolated and cloned from Aspergillus oryzae. The gene was 1368 bp, which encoded a protein of 455 amino acids. To analyze the activity of the expressed fructosyltransferase, the pET32a-fructosyltransferase recombined plasmid was transformed into Escherichia coli BL21. The fructosyltransferase gene was successfully expressed by Isopropyl-beta-d thiogalactoside (IPTG) induction. The molecular weight of the expression protein was about 45 kDa. The optimal conditions of protein expression were 25 degrees C, 0.1 mM IPTG, and 8 h of inducing time. The optimal concentration of urea dealing with inclusion body was 2.5 M. The expressed protein exhibited a strong fructosyl transfer activity. These results showed that the expressed fructosyltransferas owned transferase activity, and could catalyze the synthesis of sucrose-6-acetate. PMID- 28639161 TI - Moral distress and its contribution to the development of burnout syndrome among critical care providers. AB - BACKGROUND: Burnout appears to be common among critical care providers. It is characterized by three components: emotional exhaustion, depersonalization and personal accomplishment. Moral distress is the inability of a moral agent to act according to his or her core values and perceived obligations due to internal and external constraints. We aimed to estimate the correlation between moral distress and burnout among all intensive care unit (ICU) and the step-down unit (SDU) providers (physicians, nurses, nurse technicians and respiratory therapists). METHODS: A survey was conducted from August to September 2015. For data collection, a self-administered questionnaire for each critical care provider was used including basic demographic data, the Maslach Burnout Inventory (MBI) and the Moral Distress Scale-Revised (MDS-R). Correlation analysis between MBI domains and moral distress score and regression analysis to assess independent variables associated with burnout were performed. RESULTS: A total of 283 out of 389 (72.7%) critical care providers agreed to participate. The same team of physicians attended both ICU and SDU, and severe burnout was identified in 18.2% of them. Considering all others critical care providers of both units, we identified that overall 23.1% (95% CI 18.0-28.8%) presented severe burnout, and it did not differ between professional categories. The mean MDS-R rate for all ICU and SDU respondents was 111.5 and 104.5, respectively, p = 0.446. Many questions from MDS-R questionnaire were significantly associated with burnout, and those respondents with high MDS-R score (>100 points) were more likely to suffer from burnout (28.9 vs 14.4%, p = 0.010). After regression analysis, moral distress was independently associated with burnout (OR 2.4, CI 1.19-4.82, p = 0.014). CONCLUSIONS: Moral distress, resulting from therapeutic obstinacy and the provision of futile care, is an important issue among critical care providers' team, and it was significantly associated with severe burnout. PMID- 28639163 TI - agr functionality affects clinical outcomes in patients with persistent methicillin-resistant Staphylococcus aureus bacteraemia. AB - Methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) often persists despite appropriate antibiotic therapy. It is unclear what microbiological factors contribute to poor clinical outcomes in persistent MRSAB (pMRSAB). We aimed to identify clinical and microbiological risk factors for in-hospital mortality in pMRSAB. We analysed MRSAB cases prospectively collected between 2009 and 2016 at 11 hospitals in Korea, defining cases of pMRSAB as MRSAB lasting >=5 days despite administration of effective antibiotics. The first blood isolates from the pMRSAB cases were tested for staphylococcal cassette chromosome mec type, staphylococcal protein A type, accessary gene regulator (agr) type, genes for Panton-Valentine leukocidin and phenol-soluble modulin-mec, vancomycin minimum inhibitory concentration, vancomycin heteroresistance, and agr functionality. We also collected clinical information for each case. Of 960 MRSAB cases, 152 pMRSAB were finally eligible. Univariable analysis revealed that in hospital mortality was significantly associated with Charlson's comorbidity weighted index (CCWI) score, Pitt bacteremia score, sequential organ failure assessment score, presentation with septic shock, pneumonia, agr dysfunction, and vancomycin heteroresistance. Bone and joint infections were negatively associated with in-hospital mortality. Multivariable analysis revealed the following independent risk factors for in-hospital mortality: CCWI score [adjusted odds ratio (aOR), per one point, 1.25; 95% confidence interval (CI), 1.08-1.44; P = 0.003), Pitt bacteremia score (aOR, per one point, 1.33; 95% CI, 1.09-1.62; P = 0.005), non-eradicated foci of infection (aOR, 3.12; 95% CI, 1.18-8.27; P = 0.022), and agr dysfunction (aOR, 2.48; 95% CI, 1.12-5.47; P = 0.025). agr dysfunction is an independent risk factor for in-hospital mortality in pMRSAB. PMID- 28639164 TI - Lipid peroxidation in Gram-negative bacteremia modulates the risk for septic shock and infections by resistant Klebsiella pneumoniae. AB - Controversies in outcomes with the parenteral administration of antioxidants as adjuvant therapies led to the measurement of malondialdehyde (MDA), a product of lipid peroxidation, in serum collected from 120 patients with primary Gram negative bacteremia during the first 24 h from sepsis onset. MDA was measured by the thiobarbiturate assay, followed by high-performance liquid chromatography (HPLC) analysis. After receiver operator characteristic (ROC) curve analysis, patients were divided into those with high levels of MDA and low levels of MDA. The primary endpoint was the association of the level of MDA with septic shock. The level of MDA as an index of neutrophil function and associations with outcome and with infections by carbapenem-resistant Klebsiella pneumoniae were the secondary endpoints. In total, 63 patients had high and 57 had low MDA levels; 27% and 49.1%, respectively, had septic shock (p = 0.015). The rate of the concentration of MDA to the total neutrophil count was used as an expression of neutrophil function; this was lower among patients with septic shock. The odds ratio (OR) for death among patients without septic shock and low level of MDA was 4.00; this was 0.48 for patients with septic shock (p = 0.020 between the two ORs). The OR for resistance to carbapenems among patients with bacteremia by K. pneumoniae and low level of MDA was 7.50 (p = 0.011 compared to patients with bacteremia by other pathogens). Low level of circulating MDA is associated with susceptibility to septic shock and infections by carbapenem-resistant K. pneumoniae. PMID- 28639162 TI - Bacterial genome sequencing in clinical microbiology: a pathogen-oriented review. AB - In recent years, whole-genome sequencing (WGS) has been perceived as a technology with the potential to revolutionise clinical microbiology. Herein, we reviewed the literature on the use of WGS for the most commonly encountered pathogens in clinical microbiology laboratories: Escherichia coli and other Enterobacteriaceae, Staphylococcus aureus and coagulase-negative staphylococci, streptococci and enterococci, mycobacteria and Chlamydia trachomatis. For each pathogen group, we focused on five different aspects: the genome characteristics, the most common genomic approaches and the clinical uses of WGS for (i) typing and outbreak analysis, (ii) virulence investigation and (iii) in silico antimicrobial susceptibility testing. Of all the clinical usages, the most frequent and straightforward usage was to type bacteria and to trace outbreaks back. A next step toward standardisation was made thanks to the development of several new genome-wide multi-locus sequence typing systems based on WGS data. Although virulence characterisation could help in various particular clinical settings, it was done mainly to describe outbreak strains. An increasing number of studies compared genotypic to phenotypic antibiotic susceptibility testing, with mostly promising results. However, routine implementation will preferentially be done in the workflow of particular pathogens, such as mycobacteria, rather than as a broadly applicable generic tool. Overall, concrete uses of WGS in routine clinical microbiology or infection control laboratories were done, but the next big challenges will be the standardisation and validation of the procedures and bioinformatics pipelines in order to reach clinical standards. PMID- 28639166 TI - IFNgamma Block, Treosulfan Conditioning and alphabeta T Cell Deplete PBSCT for XIAP-Deficient HLH. PMID- 28639165 TI - Molecular characterization of intestinal carriage of carbapenem-resistant Enterobacteriaceae among inpatients at two Iranian university hospitals: first report of co-production of bla NDM-7 and bla OXA-48. AB - Gastrointestinal colonization of carbapenem-resistant Enterobacteriaceae (CRE) could serve as a reservoir for the transmission of these pathogens in the clinical setting. The aim of this study was to investigate the intestinal carriage of CRE and to analyze risk factors for CRE carriage. Rectal swabs were collected from 95 patients at two Iranian university hospitals. CRE screening was performed using selective media (CHROMagar and MacConkey agar). Polymerase chain reaction (PCR) was used to detect carbapenemase-encoding genes. Clonal relatedness was investigated by pulsed-field gel electrophoresis (PFGE). The rate of carriage of CRE in hospitalized patients was 37.9%. Overall, 54 CRE isolates were identified, of which 47 were carbapenemase-producers. All of the 54 CRE were detected using CHROMagar compared with 52 CRE detected using MacConkey agar. Fifteen patients were colonized by multiple CRE isolates. Three significant risk factors for CRE carriage were detected: intensive care unit (ICU) hospitalization, antibiotic exposure, and mechanical ventilation. bla OXA-48 was the most frequent carbapenemase detected, followed by bla NDM-1 and bla NDM-7. Eleven carbapenemase-producing Enterobacteriaceae (CPE) isolates co-harbored bla NDM-1 and bla OXA-48. Also, six CPE isolates co-harbored bla NDM-7 and bla OXA 48. We did not detect bla KPC, bla GES, bla IMP, or bla VIM. PFGE analysis showed that Escherichia coli clones were diverse, while Klebsiella pneumoniae isolates were divided into four clusters. Cluster I was the major clone carrying bla OXA 48 and bla CTX-M-15 genes. In our study, the carriage rate of CRE was high and the emergence of CPE isolates among patients is alarming. The implementation of adequate preventive measures such as active surveillance is urgently needed to control the spread of CPE in the healthcare setting. PMID- 28639167 TI - Azathioprine-Associated Complete NK Cell Deficiency. PMID- 28639168 TI - Sensitivity of Chaos Measures in Detecting Stress in the Focusing Control Mechanism of the Short-Sighted Eye. AB - When fixating on a stationary object, the power of the eye's lens fluctuates. Studies have suggested that changes in these so-called microfluctuations in accommodation may be a factor in the onset and progression of short-sightedness. Like many physiological signals, the fluctuations in the power of the lens exhibit chaotic behaviour. A breakdown or reduction in chaos in physiological systems indicates stress to the system or pathology. The purpose of this study was to determine whether the chaos in fluctuations of the power of the lens changes with refractive error, i.e. how short-sighted a subject is, and/or accommodative demand, i.e. the effective distance of the object that is being viewed. Six emmetropes (EMMs, non-short-sighted), six early-onset myopes (EOMs, onset of short-sightedness before the age of 15), and six late-onset myopes (LOMs, onset of short-sightedness after the age of 15) took part in the study. Accommodative microfluctuations were measured at 22 Hz using an SRW-5000 autorefractor at accommodative demands of 1 D (dioptres), 2 D, and 3 D. Chaos theory analysis was used to determine the embedding lag, embedding dimension, limit of predictability, and Lyapunov exponent. Topological transitivity was also tested for. For comparison, the power spectrum and standard deviation were calculated for each time record. The EMMs had a statistically significant higher Lyapunov exponent than the LOMs ([Formula: see text] vs. [Formula: see text]) and a lower embedding dimension than the LOMs ([Formula: see text] vs. [Formula: see text]). There was insufficient evidence (non-significant p value) of a difference between EOMs and EMMs or EOMs and LOMs. The majority of time records were topologically transitive. There was insufficient evidence of accommodative demand having an effect. Power spectrum analysis and assessment of the standard deviation of the fluctuations failed to discern differences based on refractive error. Chaos differences in accommodation microfluctuations indicate that the control system for LOMs is under stress in comparison to EMMs. Chaos theory analysis is a more sensitive marker of changes in accommodation microfluctuations than traditional analysis methods. PMID- 28639169 TI - The Effects of Predator Evolution and Genetic Variation on Predator-Prey Population-Level Dynamics. AB - This paper explores how predator evolution and the magnitude of predator genetic variation alter the population-level dynamics of predator-prey systems. We do this by analyzing a general eco-evolutionary predator-prey model using four methods: Method 1 identifies how eco-evolutionary feedbacks alter system stability in the fast and slow evolution limits; Method 2 identifies how the amount of standing predator genetic variation alters system stability; Method 3 identifies how the phase lags in predator-prey cycles depend on the amount of genetic variation; and Method 4 determines conditions for different cycle shapes in the fast and slow evolution limits using geometric singular perturbation theory. With these four methods, we identify the conditions under which predator evolution alters system stability and shapes of predator-prey cycles, and how those effect depend on the amount of genetic variation in the predator population. We discuss the advantages and disadvantages of each method and the relations between the four methods. This work shows how the four methods can be used in tandem to make general predictions about eco-evolutionary dynamics and feedbacks. PMID- 28639170 TI - Bistability and Asynchrony in a Boolean Model of the L-arabinose Operon in Escherichia coli. AB - The lactose operon in Escherichia coli was the first known gene regulatory network, and it is frequently used as a prototype for new modeling paradigms. Historically, many of these modeling frameworks use differential equations. More recently, Stigler and Veliz-Cuba proposed a Boolean model that captures the bistability of the system and all of the biological steady states. In this paper, we model the well-known arabinose operon in E. coli with a Boolean network. This has several complex features not found in the lac operon, such as a protein that is both an activator and repressor, a DNA looping mechanism for gene repression, and the lack of inducer exclusion by glucose. For 11 out of 12 choices of initial conditions, we use computational algebra and Sage to verify that the state space contains a single fixed point that correctly matches the biology. The final initial condition, medium levels of arabinose and no glucose, successfully predicts the system's bistability. Finally, we compare the state space under synchronous and asynchronous update and see that the former has several artificial cycles that go away under a general asynchronous update. PMID- 28639171 TI - Subject-Specific Axes of Rotation Based on Talar Morphology Do Not Improve Predictions of Tibiotalar and Subtalar Joint Kinematics. AB - Use of subject-specific axes of rotation may improve predictions generated by kinematic models, especially for joints with complex anatomy, such as the tibiotalar and subtalar joints of the ankle. The objective of this study was twofold. First, we compared the axes of rotation between generic and subject specific ankle models for ten control subjects. Second, we quantified the accuracy of generic and subject-specific models for predicting tibiotalar and subtalar joint motion during level walking using inverse kinematics. Here, tibiotalar and subtalar joint kinematics measured in vivo by dual-fluoroscopy served as the reference standard. The generic model was based on a cadaver study, while the subject-specific models were derived from each subject's talus reconstructed from computed tomography images. The subject-specific and generic axes of rotation were significantly different. The average angle between the modeled axes was 12.9 degrees +/- 4.3 degrees and 24.4 degrees +/- 5.9 degrees at the tibiotalar and subtalar joints, respectively. However, predictions from both models did not agree well with dynamic dual-fluoroscopy data, where errors ranged from 1.0 degrees to 8.9 degrees and 0.6 degrees to 7.6 degrees for the generic and subject-specific models, respectively. Our results suggest that methods that rely on talar morphology to define subject-specific axes may be inadequate for accurately predicting tibiotalar and subtalar joint kinematics. PMID- 28639172 TI - Influence of Cannulation Site on Carotid Perfusion During Extracorporeal Membrane Oxygenation in a Compliant Human Aortic Model. AB - Blood oxygenized by veno-arterial extracorporeal membrane oxygenation (ECMO) can be returned to the aorta (central cannulation) or to peripheral arteries (axillar, femoral). Hemodynamic effects of these cannulation types were analyzed in a mock loop with an aortic model representative of normal anatomy and compliance under physiological pressures and flow rates. Pressures, flow rates, and contribution of ECMO flow to total flow as a measure of oxygen supply were monitored in the carotids. Steady or pulsatile ECMO flow, residual or no cardiac output, and intraaortic balloon pump counterpulsation were tested as independent factors. With residual heart function, central cannulation provided the best oxygenated flow and pressure to the carotid arteries (CA). Axillar cannulation preferentially perfused the right CA at the expense of the left CA. Femoral cannulation provided only lower amounts of oxygenated blood to both CA. Pulsation increased the surplus hemodynamic energy. Counterpulsation reduced flow with femoral cannulation but improved flow and pressure with axillar cannulation. Femoral cannulation failed to provide oxygenated blood to coronary and supraaortic arteries with residual heart function. Central cannulation provided the best hemodynamics and oxygen supply to the brain. With a resting heart but not with an ejecting heart, pulsatile ECMO flow enhanced CA hemodynamics. PMID- 28639173 TI - Numerical Modelling of Femur Fracture and Experimental Validation Using Bone Simulant. AB - Bone fracture pattern prediction is still a challenge and an active field of research. The main goal of this article is to present a combined methodology (experimental and numerical) for femur fracture onset analysis. Experimental work includes the characterization of the mechanical properties and fracture testing on a bone simulant. The numerical work focuses on the development of a model whose material properties are provided by the characterization tests. The fracture location and the early stages of the crack propagation are modelled using the extended finite element method and the model is validated by fracture tests developed in the experimental work. It is shown that the accuracy of the numerical results strongly depends on a proper bone behaviour characterization. PMID- 28639174 TI - Profiling Perceptual Learning Styles of Chinese as a Second Language Learners in University Settings. AB - This study revisited Reid's (1987) perceptual learning style preference questionnaire (PLSPQ) in an attempt to answer whether the PLSPQ fits in the Chinese-as-a-second-language (CSL) context. If not, what are CSL learners' learning styles drawing on the PLSPQ? The PLSPQ was first re-examined through reliability analysis and confirmatory factor analysis (CFA) with 224 CSL learners. The results showed that Reid's six-factor PLSPQ could not satisfactorily explain the CSL learners' learning styles. Exploratory factor analyses were, therefore, performed to explore the dimensionality of the PLSPQ in the CSL context. A four-factor PLSPQ was successfully constructed including auditory/visual, kinaesthetic/tactile, group, and individual styles. Such a measurement model was cross-validated through CFAs with 118 CSL learners. The study not only lends evidence to the literature that Reid's PLSPQ lacks construct validity, but also provides CSL teachers and learners with insightful and practical guidance concerning learning styles. Implications and limitations of the present study are discussed. PMID- 28639175 TI - Valence and Origin of Emotional Words Influence on Subsequent Perception of Ambiguous Stimuli in Terms of Competence Versus Warmth. AB - The aim of this study was to examine whether the valence and origin of emotional words can alter perception of ambiguous objects in terms of warmth versus competence, fundamental dimensions of social cognition. 60 individuals were invited into the study focusing on the limits of intuition. They were asked to try to guess the meaning of Japanese pictorial signs in terms of their warmth versus competence connotations. Before each trial a subsequent memory load task was applied. Participants were supposed to read and remember words creating a factorial manipulation of valence (three levels) and origins (three levels: automatic, neutral and reflective) of affective connotations presenting to them for 500 ms. For positively valenced words, automatic originated ones resulted in perception of ambiguous signs more in terms of warmth, while reflective originated words resulted in perception of signs more in terms of competence. This study shows that social perception of warmth versus competence is susceptible to emotional influence of unrelated stimulation, and thus can be primed by objects in the environment. Warmth may be treated as linked with automatic mind processes, while competence may be treated as associated with the controlled part of the mind. In a broader context, this experiment results support claim that distinct dualities identified in dual-processes theories of mind are related to one another, and in fact they may be emanations of two more general systems of mind. PMID- 28639176 TI - Combined or Individual Effects of Dietary Probiotic Pedicoccus acidilactici and Nucleotide on Growth Performance, Intestinal Microbiota, Hemato-biochemical Parameters, and Innate Immune Response in Goldfish (Carassius auratus). AB - This study investigated the effect of dietary supplementation of probiotic Pedicoccus acidilactici and nucleotide (separately or combined) on growth performance, intestinal microbiota, hemato-immunological parameters, and immunity response in goldfish (Carassius auratus). Fish (average weight 5-6 g) were acclimatized and divided into eight experimental diets supplemented with P. acidilactici of different concentrations (0.1, 0.2, and 0.3% diet) and nucleotides (0 and 0.5% diet) for 6 months. Fish fed with experimental diets showed significant differences in terms of final weight, weight gain, feed conversion ratio, daily growth rate, and condition factor when compared to control diet (P < 0.05). Fish fed with probiotic (0.3%) separately and combined with nucleotide (0.5%) had highest RBC and WBC when compared to other diets (P < 0.05), while the highest values for Hb and Hct as well as total protein, glucose, albumin, and globulin were observed in probiotic (0.2%) and nucleotide (0.5%) combined diet. Serum lysozyme and anti-protease activities were significantly higher in probiotic (0.1 and 0.2%) and nucleotide (0.5%) combined diets. Similarly, these two diets combined showed the highest colonization of P. acidilactici when compared to other diets. In conclusion, combined dietary probiotic and nucleotide improve the growth performance, hemato-biochemical parameters, and intestine growth in C. auratus. PMID- 28639177 TI - Feasibility of Focused Beam Reflectance Measurement (FBRM) for Analysis of Pharmaceutical Suspensions in Preclinical Development. AB - This study examined the use of focused beam reflectance measurement (FBRM) for qualitative and quantitative analysis of pharmaceutical suspensions with particular application to toxicology supply preparations for use in preclinical studies. Aqueous suspensions of ibuprofen were used as prototype formulations. Initial experiments were conducted to examine the effects of operational conditions including FBRM probe angle, probe location, and mixing (method and rate of mixing) on the FBRM analysis. Once experimental conditions were optimized, the homogeneity and sedimentation-redispersion of particles in the suspensions were assessed. Ibuprofen suspension under continuous agitation was monitored using FBRM for 60 h to study particle size change over time. Another study was performed to determine if particle count rates obtained by FBRM could be correlated to suspension concentration. The location and the angle of the FBRM probe relative to the beaker contents, and the rate and the method of mixing the suspension were found to be sensitive parameters during FBRM analysis. FBRM was able to monitor the process of particle sedimentation in the suspension. The attrition of ibuprofen particles was detectable by FBRM during prolonged stirring with an increase in the number of smaller particles and decrease in the number of larger particles. A strong correlation was observed between particle count rate by FBRM and ibuprofen concentration in the suspension. Also, change in content uniformity in the suspension at different locations of the beaker was represented by FBRM particle count. Overall, FBRM has potential to be a useful tool for qualitative and quantitative analysis of pharmaceutical suspensions. PMID- 28639178 TI - Effective Skin Cancer Treatment by Topical Co-delivery of Curcumin and STAT3 siRNA Using Cationic Liposomes. AB - The aim of the present study was to evaluate the effectiveness of iontophoretic co-delivery of curcumin and anti-STAT3 siRNA using cationic liposomes against skin cancer. Curcumin was encapsulated in DOTAP-based cationic liposomes and then complexed with STAT3 siRNA. This nanocomplex was characterized for the average particle size, zeta-potential, and encapsulation efficiency. The cell viability studies in B16F10 mouse melanoma cells have shown that the co-delivery of curcumin and STAT3 siRNA significantly (p < 0.05) inhibited the cancer cell growth compared with either liposomal curcumin or STAT3 siRNA alone. The curcumin loaded liposomes were able to penetrate up to a depth of 160 MUm inside the skin after iontophoretic (0.47 mA/cm2) application. The in vivo efficacy studies were performed in the mouse model of melanoma skin cancer. Co-administration of the curcumin and STAT3 siRNA using liposomes significantly (p < 0.05) inhibited the tumor progression as measured by tumor volume and tumor weight compared with either liposomal curcumin or STAT3 siRNA alone. Furthermore, the iontophoretic administration of curcumin-loaded liposome-siRNA complex showed similar effectiveness in inhibiting tumor progression and STAT3 protein suppression compared with intratumoral administration. Taken together, cationic liposomes can be utilized for topical iontophoretic co-delivery of small molecule and siRNA for effective treatment of skin diseases. PMID- 28639181 TI - The benefits of dual and double ovulatory triggers in assisted reproduction. PMID- 28639180 TI - Initial maternal serum human chorionic gonadotropin levels in pregnancies achieved after assisted reproductive technology are higher after preimplantation genetic screening and after frozen embryo transfer: a retrospective cohort. AB - PURPOSE: Few published articles have compared initial hCG values across all different types of ART cycles, including cycles with fresh or frozen embryo transfer. No articles have compared initial hCG values in cycles utilizing preimplantation genetic screening (PGS). The purpose of this study is to compare initial hCG values after fresh embryo transfer, frozen embryo transfer, and after PGS. METHODS: This was a single-center retrospective cohort study at an academically affiliated private IVF center. All fresh and frozen embryo transfers between January 2013 and December 31, 2015 were included. We compared mean initial serum hCG values 14 days after oocyte retrieval for fresh cycles and 9 days after frozen embryo transfer. We examined cycles of single embryo transfer (SET) and double embryo transfer (DET). RESULTS: Two hundred elven IVF (fresh embryo transfer), 128 FET (frozen embryo transfer cycles, no PGS), and 111 PGS cycles (ovarian stimulation with embryo cryopreservation, PGS, and frozen transfer in a subsequent estrogen-primed cycle) with initial positive hCG values were analyzed. In patients achieving a positive hCG after SET, initial hCG values were higher after PGS compared to FET (182.4 versus 124.0 mIU/mL, p = 0.02) and IVF (182.4 versus 87.1 mIU/mL, p < 0.001) as well as FET compared to IVF (124.0 versus 87.1 mIU/mL, p < 0.01). After DET, initial hCG values were higher after PGS (222.8 mIU/mL) compared to FET (182.1 mIU/mL, p = 0.02) and IVF (131.1 mIU/mL, p = 0.001). CONCLUSIONS: Our study suggests that initial serum hCG values are higher after using PGS and higher after the transfer of a frozen embryo compared to a fresh embryo. This suggests that initial hCG values relate to the chromosomal status of embryos. Initial hCG values may help determine intervention and monitoring later in pregnancy. PMID- 28639182 TI - Differential Interaction of Myoglobin with Select Fatty Acids of Carbon Chain Lengths C8 to C16. AB - Previous studies have shown that palmitic acid (PAM) and oleic acid (OLE) can bind myoglobin (Mb). How fatty acids (FA) with different carbon chain lengths and sulfate substitution interact with Mb remains uncertain. Indeed, C8:0 and C10:0 fatty acids do not perturb the intensities of the 1H-NMR MbCN signal intensity at FA:Mb ratios below 2:1. Starting with C12:0, C12:0-C16:0, FA induce a noticeable spectral change. C12:0 and C14:0 FA affect both the 5- and 8-heme methyl signals, whereas the C16:0 FA perturbs only the 8-heme methyl signal. All C12:0-C16:0 saturated FA induce upfield shifts in the -CH2 peak of different FA in the presence of Mb. Increasing the apparent solubility with a sulfate group substitution enhances the FA interaction of lauric sulfate (LAU 1-SO4) but not palmitate sulfate acid (PAM 1-SO4). The detergent (DET) property of FA has no significant contribution. Common positive, neutral, and negative DET at DET:Mb ratio of 1:1 induce no perturbation of the MbCN spectra. The experiment observations establish a basis to investigate the molecular mechanism underlying the FA interaction with Mb. PMID- 28639183 TI - Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data. AB - OPINION STATEMENT: Atherosclerotic cardiovascular disease (ASCVD) remains the number one killer in the western world. Low-density lipoprotein cholesterol (LDL C) reduction with statins and ezetimibe has been shown to reduce the risk of cardiovascular events. Now, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mabs) are available for high-risk individuals with ASCVD or familial hypercholesterolemia on maximally tolerated statin therapy but requiring greater LDL-C reduction. PCSK9 mab outcome trial results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk (FOURIER) study, which was presented at the American College of Cardiology in March 2017, which demonstrated a decrease of 15% in primary and 20% secondary end points over a 2-year period [1**]. These results firmly demonstrated additional benefit beyond maximally tolerated statin therapy in high risk individuals. Thus, management of LDL-C will soon become more complex, as a new class of medication is added to our standard armamentarium. This review explores the discovery of PCSK9, its biology and physiology, and the development of the PCSK9 mabs. PMID- 28639184 TI - Building a Successful Superficial Venous Program. AB - OPINION STATEMENT: As the treatment of superficial venous insufficiency transitioned from the hospital to the office setting, a remarkable increase in provider interest developed. However, the novelty of the disease process and procedural opportunities are tempered by the challenges associated with knowledge acquisition, skill development, strategic planning, and program development. Only a unique recipe of clinical growth, technical acumen, management skill, operational efficiency, and financial sense lead to program success. Despite the variety of skills required, treating superficial venous insufficiency is obtainable for both the formally and non-formally trained physicians with sufficient commitment, education, and resources. PMID- 28639185 TI - The Use of Mobile Apps by Radiology Journals. PMID- 28639187 TI - Radiology Toolbox Pro App Review. PMID- 28639186 TI - Computerized Prediction of Radiological Observations Based on Quantitative Feature Analysis: Initial Experience in Liver Lesions. AB - We propose a computerized framework that, given a region of interest (ROI) circumscribing a lesion, not only predicts radiological observations related to the lesion characteristics with 83.2% average prediction accuracy but also derives explicit association between low-level imaging features and high-level semantic terms by exploiting their statistical correlation. Such direct association between semantic concepts and low-level imaging features can be leveraged to build a powerful annotation system for radiological images that not only allows the computer to infer the semantics from diverse medical images and run automatic reasoning for making diagnostic decision but also provides "human interpretable explanation" of the system output to facilitate better end user understanding of computer-based diagnostic decisions. The core component of our framework is a radiological observation detection algorithm that maximizes the low-level imaging feature relevancy for each high-level semantic term. On a liver lesion CT dataset, we have implemented our framework by incorporating a large set of state-of-the-art low-level imaging features. Additionally, we included a novel feature that quantifies lesion(s) present within the liver that have a similar appearance as the primary lesion identified by the radiologist. Our framework achieved a high prediction accuracy (83.2%), and the derived association between semantic concepts and imaging features closely correlates with human expectation. The framework has been only tested on liver lesion CT images, but it is capable of being applied to other imaging domains. PMID- 28639188 TI - Small RNA-Guided Transcriptional Gene Activation (RNAa) in Mammalian Cells. AB - Small RNA partnering with Argonaute (Ago) proteins plays important roles in diverse biological processes mainly by suppressing the expression of cognate target sequences. Mounting evidence reveals that the small RNA-Ago pathway can also positively regulate gene expression, a phenomenon termed as RNA activation (RNAa), which is evolutionarily conserved from Caenorhabditis elegans to human. In this chapter, I provide a general overview of mammalian RNAa phenomena and their basic characteristics and discuss recent advances toward understanding the nature of the molecular machinery responsible for RNAa and the development of RNAa-based research tools and therapeutics. PMID- 28639189 TI - Enhancing Neuronogenesis and Counteracting Neuropathogenic Gene Haploinsufficiencies by RNA Gene Activation. AB - Small activating RNAs (saRNAs), targeting endogenous genes and stimulating their transcription, are a promising tool for implementing a variety of neurotherapeutic strategies. Among these there is the stimulation of select histogenetic subroutines for purposes of cell-based brain repair, as well as the therapeutic treatment of gene expression deficits underlying severe neurological disorders.We employed RNA activation (RNAa) to transactivate the Emx2 transcription factor gene in embryonic cortico-cerebral precursor cells. This led to enhanced self-renewal, delayed differentiation, and reduced death of neuronally committed precursors, resulting in a remarkable expansion of the neuronogenic precursors pool. These results are of paramount interest for purposes of gene-promoted brain repair. As such, RNAa makes therapeutic stimulation of neuronogenesis via Emx2 overexpression a feasible goal, preventing the drawbacks of exogenous gene copies introduction.Moreover, we employed RNAa to achieve a gentle transactivation of the Foxg1 transcription factor gene, specifically in cortico-cerebral cells. This manipulation led to an appreciable biological outcome, while complying with endogenous gene tuning linked to early central nervous system regionalization and late activity of neocortical projection neurons. Foxg1-activating miRNAs stimulated RNApolII recruitment, possibly via Ago1. One of them worked promisingly in vivo. As such, RNAa can be a valuable approach for therapeutic treatment of the FOXG1-haploinsufficiency linked variant of the Rett syndrome. Remarkably, hemizygosity for specific genes and polygenic chromosomal segments underlies a huge number of neuropathological entities for which no cure is presently available. Based on the results reported above, RNAa might be a simple and scalable approach for fixing this class of problems. PMID- 28639190 TI - Target-Recognition Mechanism and Specificity of RNA Activation. AB - Small activating RNA (saRNA)-mediated gene activation has opened a new avenue for upregulating the expression of target genes by promoting endogenous transcription, a phenomenon known as RNA activation (RNAa). RNAa is distinct from the established RNAi mechanistic framework, although AGO2 is required by both. The precise mechanism of RNAa is currently disputable and has become a bottleneck in the development of this new technology. saRNA may achieve activation of target genes by directly binding to DNA targets in promoter, or interacting with antisense transcripts transcribed from overlapping promoter sequences, or by silencing other genes. In this chapter, we focused on recent development in our understanding of the target-recognition mechanism in RNAa. Conflicting results on saRNA targets are also discussed. Despite that the target mechanism of RNAa is more complex than expected and not completely understood so far, independent lines of evidence have suggested that saRNAs work by an "on-site" mechanism by binding to target genomic DNA in a "seed-region"-dependent manner. Finally, "off target" effects of saRNA are observed and should be carefully controlled in designing experiments for and interpreting results from RNAa-related studies. PMID- 28639191 TI - Promoter-Targeted Small Activating RNAs Alter Nucleosome Positioning. AB - Epigenetic modification of target promoters has been identified as a mechanism underlying RNA activation (RNAa) induced by promoter-targeting small activating RNAs (saRNAs), but it is unclear how the chromosomal environment influences gene expression. In a study of the activation of the OCT4, SOX2, and NANOG genes by saRNAs, we found that saRNA targeting induced nucleosome-depleted region (NDRs) and the accumulation of RNA polymerase II (RNAPII) near or at the saRNA target sites. Additionally, promoters containing certain cis-regulatory elements such as the TATA box and CpG islands (CGIs) appeared to be more susceptible to RNAa. These results provide novel insight into the mechanism underlying RNAa in that saRNAs induce NDRs in the target promoter to remove nucleosome barriers between RNAPII-binding sites and the transcription start site (TSS), resulting in rapid assembly of transcription preinitiation complex (PIC) and subsequent activation of transcription. PMID- 28639192 TI - Endogenous miRNAa: miRNA-Mediated Gene Upregulation. AB - The phenomenon of RNA activation (RNAa) was initially discovered by Li and colleagues about a decade ago. Subsequently, gene activation by exogenously expressed small activating RNA has been demonstrated in different cellular contexts by a number of laboratories. Conceivably, endogenously expressed microRNAs may also utilize RNA activation as a cellular mechanism for gene regulation, which may be dysregulated in disease states such as cancer. RNA activation can be applied to gain-of-function studies and holds great promise for disease intervention. This chapter will discuss examples of promoter-targeting microRNAs discovered in recent years and their pathophysiological relevance. I will also briefly touch upon other novel classes of microRNAs with positive gene regulatory roles, including TATA-box-activating microRNAs and enhancer-associated microRNAs. PMID- 28639193 TI - miRNA-Mediated RNA Activation in Mammalian Cells. AB - MicroRNA (miRNA or miR) is a small noncoding RNA molecule ~22 nucleotides in size, which is found in plants, animals, and some viruses. miRNAs are thought to primarily down regulate gene expression by binding to 3' untranslated regions of target transcripts, thereby triggering mRNA cleavage or repression of translation. Recently, evidence has emerged that miRNAs can interact with the promoter and activate gene expression. This mechanism, called RNA activation (RNAa), is a process of transcriptional activation where the direct interaction of miRNA on the promoter triggers the recruitment of transcription factors and RNA-Polymerase-II on the promoter to activate gene transcription. To date, very little is known about the mechanism by which miRNA regulates RNA activation (RNAa) and their role in tumor progression. This is an emerging field in RNA biology. In this chapter, we describe the mechanisms utilized by miRNAs to activate transcription. PMID- 28639194 TI - RNAa Induced by TATA Box-Targeting MicroRNAs. AB - Recent studies reveal that some nuclear microRNAs (miRNA) and synthesized siRNAs target gene promoters to activate gene transcription (RNAa). Interestingly, our group identified a novel HIV-1-encoded miRNA, miR-H3, which targets specifically the core promoter TATA box of HIV-1 and activates viral gene expression. Depletion of miR-H3 significantly impaired the replication of HIV-1. miR-H3 mimics could activate viruses from CD4+ T cells isolated from patients receiving suppressive highly active antiretroviral therapy, which is very intriguing for reducing HIV-1 latent reservoir. Further study revealed that many cellular miRNAs also function like miR-H3. For instance, let-7i targets the TATA box of the interleukin-2 (IL-2) promoter and upregulates IL-2 expression in T-lymphocytes. In RNAa induced by TATA box-targeting miRNAs, Argonaute (AGO) proteins are needed, but there is no evidence for the involvement of promoter-associated transcripts or epigenetic modifications. We propose that the binding of small RNA AGO complex to TATA box could facilitate the assembly of RNA Polymerase II transcription preinitiation complex. In addition, synthesized small RNAs targeting TATA box can also efficiently activate transcription of interested genes, such as insulin, IL-2, and c-Myc. The discovery of RNAa induced by TATA box-targeting miRNA provides an easy-to-use tool for activating gene expression. PMID- 28639195 TI - miRNA-Mediated RNAa by Targeting Enhancers. AB - MicroRNAs (miRNAs) are small noncoding RNAs that act as negative regulators of gene expression in the cytoplasm. Yet, emerging evidence has shown that miRNAs are also distributed in the nucleus, with its function largely undetermined. At the same time, while miRNAs and enhancers show obvious tissue specificity, the interaction between miRNAs and enhancers in gene regulation remains unknown. By screening miRNA databases, we have identified a subset of miRNAs, called nuclear activating miRNAs (NamiRNAs). As enhancer regulators, NamiRNAs are able to activate gene expression at the transcriptional level. In addition, we found that the regulation of enhancers mediated by NamiRNAs depends on the presence of intact enhancers and AGO2 protein. More interesting is that NamiRNAs promote global gene transcription through the binding and activation of their targeted enhancers. Our results demonstrate a novel role for miRNA as an enhancer trigger for transcriptional gene activation. Further study of the function and molecular mechanism for NamiRNAs in tumorigenesis and development is of great significance. PMID- 28639196 TI - Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Frames. AB - A number of diseases are caused by low levels of key proteins; therefore, increasing the amount of specific proteins in human bodies is of therapeutic interest. Protein expression is downregulated by some structural or sequence elements present in the 5' UTR of mRNAs, such as upstream open reading frames (uORF). Translation initiation from uORF(s) reduces translation from the downstream primary ORF encoding the main protein product in the same mRNA, leading to a less efficient protein expression. Therefore, it is possible to use antisense oligonucleotides (ASOs) to specifically inhibit translation of the uORF by base-pairing with the uAUG region of the mRNA, redirecting translation machinery to initiate from the primary AUG site. Here we review the recent findings that translation of specific mRNAs can be enhanced using ASOs targeting uORF regions. Appropriately designed and optimized ASOs are highly specific, and they act in a sequence- and position-dependent manner, with very minor off-target effects. Protein levels can be increased using this approach in different types of human and mouse cells, and, importantly, also in mice. Since uORFs are present in around half of human mRNAs, the uORF-targeting ASOs may thus have valuable potential as research tools and as therapeutics to increase the levels of proteins for a variety of genes. PMID- 28639197 TI - Repurposing CRISPR System for Transcriptional Activation. AB - In recent years, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has become the most popular one for genome editing. When the nuclease domains of Cas9 protein are mutated into deactivated form (dCas9), CRISPR/dCas9 still retains the ability to bind the targeted DNA sequence, but loses the endonuclease cleavage activity. Taking advantage of the characteristics of this engineered nuclease inactive Cas9, the CRISPR/dCas system has been repurposed into versatile RNA-guided, DNA-targeting platforms, such as genome imaging, gene regulation, and epigenetic modification. Specifically, fusion of dCas9 with activation domains allows specific and efficient transcriptional activation on a genome-wide scale among diverse organisms. The purpose of this chapter is to review most important the recently published literature on CRISPR/dCas9-based transcriptional activation systems. Compared with the conventional approaches for enhancement of the expression of specific genes of interest, CRISPR/Cas9-based system has emerged as a promising technology for genome regulation, allowing specificity, convenience, robustness, and scalability for endogenous gene activation. PMID- 28639198 TI - RNA-Mediated Gene Activation: Identifying a Candidate RNA for Preclinical Development. AB - The ability to activate gene expression would provide new opportunities for drug development for diseases caused by inadequate or nonexistent expression of a therapeutic protein. Duplex RNAs that target gene promoters are one strategy for enhancing the expression of target genes. This chapter summarizes our understanding of mechanism behind gene activation by small RNAs that bind noncoding transcripts at gene promoters. We describe a path for choosing candidate genes for therapeutic development. PMID- 28639199 TI - Treatment of Pancreatic Cancer by Aptamer Conjugated C/EBPalpha-saRNA. AB - Pancreatic cancer is estimated to become the second-leading cause of cancer related mortality by 2020. While the death rates of most other cancers continue to decline recently, the death rates of pancreatic cancer are still increasing, with less than 5% of patients achieving 5-year survival. Despite great efforts to improve treatment with combinational therapies in pancreatic cancer patients, limited progress has been made. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) has been depicted as a therapeutic target in pancreatic cancer for many years. However, the clinical outcome of KRAS-directed therapies has not been successful, suggesting that KRAS is an undruggable target. For the new druggable target, epigenetically silenced transcriptional factor C/EBPalpha (CCAAT/enhancer binding protein alpha), upregulator of a strong inhibitor of cell proliferation (p21), is upregulated by small activating RNA (saRNA) in pancreatic cancer. For the cell type-specific delivery, pancreatic cancer-specific 2'-Fluoropyrimidine RNA-aptamers (2'F-RNAs) are conjugated with C/EBPalpha-saRNA via sticky bridge sequences. The conjugates of aptamer-C/EBPalpha-saRNA upregulate the expression of C/EBPalpha in vitro and inhibit the tumor growth in vivo. It suggests that aptamer-mediated targeted delivery of therapeutic C/EBPalpha-saRNA might be the effective therapeutics under the current therapeutic modality failure in pancreatic cancer. PMID- 28639201 TI - Enhancing Angiogenesis in Mice by VEGF-Targeting Small Activating RNAs. AB - The prevalence of cardiovascular diseases is steadily increasing, and it is the leading cause of death worldwide. Therefore, new treatments, such as gene therapy are needed. During the last decade, the role of small noncoding RNAs (ncRNAs) in the regulation of gene expression at the transcriptional level has been shown. Promoter-targeted small RNAs recruit histone-modifying enzymes and can either repress or induce target gene expression. As an example, we have targeted mouse VEGF-A promoter with small hairpin RNAs (shRNAs) and identified two shRNAs which either repressed or induced VEGF-A expression on messenger RNA and protein level in vitro, depending on the targeted location. The changes in expression levels correlate with changes in the levels of epigenetic markers, such as histone modifications associated with repressed or active state of chromatin. In ischemic mouse hindlimbs, upregulation of VEGF-A expression increased vascularity and blood flow. When VEGF-A was upregulated in mouse myocardial infarction model, the blood vessel formation in the risk zone was observed and infarct size was significantly decreased already 2 weeks after treatment. We suggest that epigenetic upregulation of VEGF-A by ncRNAs can be transferred to clinical use for the treatment of ischemic diseases in the near future. PMID- 28639200 TI - Treatment of Liver Cancer by C/EBPA saRNA. AB - The prognosis for hepatocellular carcinoma (HCC) remains poor and has not improved in over two decades. Most patients with advanced HCC who are not eligible for surgery have limited treatment options due to poor liver function or large, unresectable tumors. Although sorafenib is the standard-of-care treatment for these patients, only a small number respond. For the remaining, the outlook remains bleak. A better approach to target "undruggable" molecular pathways that reverse HCC is therefore urgently needed. Small activating RNAs (saRNAs) may provide a novel strategy to activate expression of genes that become dysregulated in chronic disease. The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha), a critical regulator of hepatocyte function, is suppressed in many advanced liver diseases. By using an saRNA to activate C/EBPalpha, we can exploit the cell's own transcription machinery to enhance gene expression without relying on exogenous vectors that have been the backbone of gene therapy. saRNAs do not integrate into the host genome and can be modified to avoid immune stimulation. In preclinical models of liver disease, treatment with C/EBPalpha saRNA has shown reduction in tumor volume and improvement in serum markers of essential liver function such as albumin, bilirubin, aspartate aminotransferase (AST), and alanine transaminase (ALT). This saRNA that activates C/EBPalpha for advanced HCC is the first saRNA therapy to have entered a human clinical trial. The hope is that this new tool will help break the dismal 20-year trend and provide a more positive prognosis for patients with severe liver disease. PMID- 28639202 TI - Suppression of Prostate Cancer Metastasis by DPYSL3-Targeted saRNA. AB - Metastasis is the sole cause of cancer death and there is no curable means in clinic. Cellular protein CRMP4 (DPYSL3 gene) was previously defined as a metastasis suppressor in human prostate cancers since its expression is dramatically reduced in lymphatic metastatic diseases and DPYSL3 overexpression in prostate cancer cells significantly suppressed cancer cell migration and invasion. To develop a CRMP4-based antimetastasis therapeutic approach, the small activating RNA (saRNA) technique was utilized to enhance CRMP4 expression in prostate cancer cells. A total of 14 saRNAs were synthesized and screened in multiple prostate cancer cell lines. Two saRNAs targeting the isoform-2 promoter region were determined to have significant activating effect on DPYSL3 gene expression at the mRNA and protein levels. These saRNA also largely reduced prostate cancer cell migration and invasion in vitro and in vivo. Most significantly, PSMA aptamer-mediated prostate cancer cell homing of these saRNAs blocked distal metastasis in an orthotopic nude mouse model. In conclusion, our data demonstrated that saRNA-based DPYSL3 gene enhancement is capable of suppressing tumor metastasis in prostate cancer, which provides a potential therapeutic approach for cancer management. PMID- 28639203 TI - Development of Therapeutic dsP21-322 for Cancer Treatment. AB - Small activating RNAs (saRNAs) are a class of artificially designed short duplex RNAs targeted at the promoter of a particular gene to upregulate its expression via a mechanism known as RNA activation (RNAa) and hold great promise for treating a wide variety of diseases including those undruggable by conventional therapies. The therapeutic benefits of saRNAs have been demonstrated in a number of preclinical studies carried out in different disease models including cancer. With many tumor suppressor genes (TSGs) downregulated due to either epigenetic mechanisms or haploinsufficiency resulting from deletion/mutation, cancer is an ideal disease space for saRNA therapeutics which can restore the expression of TSGs via epigenetic reprogramming. The p21WAF1/CIP gene is a TSG frequently downregulated in cancer and an saRNA for p21WAF1/CIP known as dsP21-322 has been identified to be a sequence-specific p21WAF1/CIP activator in a number of cancer types. In this chapter, we review preclinical development of medicinal dsP21-322 for cancer, especially prostate cancer and bladder cancer, and highlight its potential for further clinical development. PMID- 28639204 TI - A Cross-National Comparison of Risk Factors for Teen Dating Violence in Mexico and the United States. AB - Involvement in dating violence has been linked with negative health outcomes including depressive symptomology, substance use, and later expressions of aggressing and victimizing behaviors. Less is known about the prevalence and mental health correlates of teen dating violence in countries like Mexico where adult partner violence is high. Additional research on teen dating violence is also needed, as it may be an important precursor to adult partner violence and linked to other mental health problems. The current study used self-report ratings to assess the similarities and differences in risk factors associated with dating violence among middle school students in Mexico and the United States. The US sample (Nus = 15,099; Mus = 12.8; 49.5% female) included non Hispanic Caucasian (24.9%), Hispanic American (20.3%), and African American (24.2%) adolescents. The Mexican sample (NMexico = 2211; MMexico = 13.67; 51% female) included 93.1% adolescents of Hispanic or Latin descent. Logistic regressions showed that dating violence victimization was reported at similar rates in the cross-national samples, though exposure to risk factors like deviant peers and substance use differed significantly by country. Our analyses indicated that, although the country of residence was not significantly associated with dating violence victimization, the strength of the association between some known risk factors and dating violence victimization varied as a function of nationality, such that there was a significant interaction between country of residence, Mexico or the US, and experiencing internalizing symptoms on experiencing physical dating violence victimization. This study contributes to the growing body of literature on dating violence, both inside and outside the US. PMID- 28639206 TI - Are Associations Between "Sexist" Video Games and Decreased Empathy Toward Women Robust? A Reanalysis of Gabbiadini et al. 2016. AB - Gabbiadini, A., Riva, P., Andrighetto, L., Volpato, C., & Bushman, B, (PloS ONE, 2016) provided evidence for a connection between "sexist" video games and decreased empathy toward girls using an experimental paradigm. These claims are based on a moderated mediation model. They reported a three-way interaction between game condition, gender, and avatar identification when predicting masculine ideology in their original study. Masculine ideology was associated, in turn, with decreased empathy. However, there were no main experimental effects for video game condition on empathy. The current analysis considers the strength of the evidence for claims made in the original study on a sample of 153 adolescents (M age = 16.812, SD = 1.241; 44.2% male). We confirmed that there was little evidence for an overall effect of game condition on empathy toward girls or women. We tested the robustness of the original reported moderated mediation models against other, theoretically derived alternatives, and found that effects differed based on how variables were measured (using alternatives in their public data file) and the statistical model used. The experimental groups differed significantly and substantially in terms of age suggesting that there might have been issues with the procedures used to randomly assign participants to conditions. These results highlight the need for preregistration of experimental protocols in video game research and raise some concerns about how moderated mediation models are used to support causal inferences. These results call into question whether use of "sexist" video games is a causal factor in the development of reduced empathy toward girls and women among adolescents. PMID- 28639208 TI - San Benedetto teaching two monks. PMID- 28639207 TI - The cell biology of the thyroid-disrupting mechanism of dichlorodiphenyltrichloroethane (DDT). AB - OBJECTIVE: Dichlorodiphenyltrichloroethane (DDT) is an organochlorine known for its pesticide properties and for its negative effects on human health. It was banned in most countries for its toxicity to the endocrine system, but due to its persistence at clinically relevant concentrations in both soil and animal tissues, DDT is still linked to several health and social problems. METHODS: We have previously shown that DDT exposure is causally related to the extracellular release of vesicular organelles such as microvesicles and/or exosomes by using immunocytochemistry with gold-tagged antibodies and various fluorescent membrane markers. RESULTS: It is now well recognized that microvesicles and/or exosomes organelles are implicated in cell-to-cell communication, and that they are fundamental elements for transferring proteins, RNA, DNA, lipids and transcriptional factors among cells. In this short review, we discussed the role of extracellular vesicle formation in the thyroid-disrupting mechanism of DDT. In particular, we described how DDT, by dislodging the thyrotropin hormone (TSH) receptor from the raft containing compartments of the cells, prevents its activation and internalization. CONCLUSION: Based on our earlier finding and on the large body of evidence here reviewed, we propose that DDT-induced formation of extracellular vesicles containing the TSH receptor could be directly involved in the development of autoimmune responses against the TSH receptor and that, therefore, their release could lead to the development of the Graves' disease. PMID- 28639209 TI - Substance use and misuse among children and youth with mental illness : A pilot study. AB - OBJECTIVE: The aim of this study was to examine prevalence, patterns and predictors of substance use among a sample of adolescent psychiatric inpatients. METHODS: Participants included 25 minors aged 12-17 years admitted to an Austrian department of child and adolescent psychiatry. Lifetime use, initiation, frequency and quantity of substance use, sociodemographic, family and school related data were collected by self-report measures. Substance use disorders were detected using CAGE (a screening instrument for problem drinking) and FTND (Fagerstrom Test For Nicotine Dependence). Clinical characteristics were extracted from medical records. RESULTS: Lifetime prevalence of any substance use (76%) and regular use (32%) were common. Prevalence was high for alcohol (76%), nicotine (44%) and illicit drug use (36%). Older age was associated with tobacco (p = 0.023), drug (p = 0.021) and cannabis use (p = 0.015) and regular use of psychotropic substances (p = 0.027). Family dysfunction predicted regular (p = 0.035) and cannabis use (p = 0.02). History of trauma prognosticated regular (p = 0.047) and tobacco use (p = 0.011). Use of any substance (p < 0.001) as well as regular use (p = 0.026) were significantly associated with peer substance use. Consuming adolescents were more likely to show academic failure, school absenteeism and behavioral problems. Alcohol (p = 0.02), drug (p = 0.017) and regular substance use (p = 0.007) were linked to suicidal ideation. A remarkable relationship between affective as well as externalizing disorders and alcohol, nicotine and drug use was found. CONCLUSIONS: Substance use is highly prevalent among youth with mental illnesses and associated with psychosocial consequences. These data highlight the need to carefully explore this population at high risk. PMID- 28639210 TI - [Oxytocin and the mechanisms of alcohol dependence]. AB - One of the crucial purposes of treating alcohol-dependent patients is to enhance their ability to stay abstinent after detoxification therapy. Anxiety and stress vulnerability are the main factors provoking alcohol craving and relapse. In the first months of abstinence, alcohol-dependent patients frequently show sleep disturbances, irritability and depression, indicating chronic activation of stress pathways. In addition, the loss of confidence in interpersonal interactions results in social withdrawal and reduced willingness to participate in therapeutic programs.Current research shows that the peptide hormone oxytocin exerts substantial anxiolytic effects and facilitates prosocial behavior. Oxytocin can be safely applied as intranasal preparation. Oxytocin acts by inhibiting the effects of the corticotropin-releasing factor on GABAergic interneurons in the amygdala and paraventricular nucleus of hypothalamus.Recent research strongly suggests that application of oxytocin may beneficially influence the mechanisms of relapse and craving by reduction of anxiety, stress vulnerability and social withdrawal in abstinent alcohol-dependent patients.This article reviews neurobiological mechanisms of oxytocin effects on stress-related pathways and discusses the potential use of oxytocin in the treatment of alcohol addiction. PMID- 28639211 TI - Selective venous sampling for primary hyperparathyroidism: how to perform an examination and interpret the results with reference to thyroid vein anatomy. AB - Primary hyperparathyroidism (pHPT) causes hypercalcemia. The treatment for pHPT is surgical dissection of the hyperfunctioning parathyroid gland. Lower rates of hypocalcemia and recurrent laryngeal nerve injury imply that minimally invasive parathyroidectomy (MIP) is safer than bilateral neck resection. Current trends in MIP use can be inferred only by reference to preoperative localization studies. Noninvasive imaging studies (typically preoperative localization studies) show good detection rates of hyperfunctioning glands; however, there have also been cases of nonlocalization or discordant results. Selective venous sampling (SVS) is an invasive localization method for detecting elevated intact parathyroid hormone in the thyroid and/or internal jugular and brachiocephalic veins. SVS was developed mainly for postoperative patients with persistent or recurrent pHPT; however, SVS could also be useful before initial operations due to its high sensitivity to pHPT. Currently, SVS is generally indicated for recurrent HPT, and for cases with negative imaging study results for HPT or discordant results. Multi-detector row helical CT is useful for imaging the anatomy of the jugular and thyroid veins. Knowledge of the thyroid vein anatomy enables the creation of sampling points in the internal jugular and brachiocephalic veins for catheterization of the thyroid veins and venous anastomoses. PMID- 28639212 TI - Surveillance of Noroviruses in Rio De Janeiro, Brazil: Occurrence of New GIV Genotype in Clinical and Wastewater Samples. AB - Genogroup (G) IV norovirus (NoV) has been described in the literature as infectious agents in humans, although there are few reports regarding the frequency and spread of this virus, resulting in insufficient epidemiological data. The aim of this study was to investigate the occurrence of GIV norovirus in the State of Rio de Janeiro, Brazil in order to evaluate frequency, concentration, and genetic diversity using clinical and environmental approaches. For this purpose, 316 stool samples were collected from acute gastroenteritis cases reported over a period of three years. Wastewater samples were also obtained from the main wastewater treatment plant (WWTP) located in Rio de Janeiro throughout one year, totalizing 156 samples. All samples were submitted to quantitative analysis by TaqManTM real-time PCR for GIV norovirus. Three out of 316 clinical samples were positive (0.9%) for GIV, with viral load ranging from 104 to 106 genome copies (CG) per gram. Regarding wastewater samples, GIV were detected in 52% of raw sewage, with viral load ranging from 104 to 106 CG per liter. Phylogenetic analysis revealed the circulation of a new GIV genotype in both clinical and environmental samples. To our knowledge, this is the first description of GIV norovirus in clinical samples in Brazil. These results demonstrate the importance of performing laboratory surveillance of clinical and environmental samples, assisting the comprehension of the epidemiology pattern of viruses with neglected diagnosis and indefinite impact in the population. PMID- 28639213 TI - Study on Photophysical Properties of N-Arylphthalamic Acid Derivative Containing 1, 2, 4-Triazole Scaffold. AB - A novel N-arylphthalamic acid derivative, 2-({4-[(1H-1,2,4-triazol-1 yl)methyl]phenyl}carbamoyl)benzoic acid (TMPCB) was synthesized and their absorption and emission spectra were recorded in fifteen different solvents of varying polarities at room temperature. Ground state dipole moment of the derivative was calculated experimentally by Guggenheim method and solvatochromic approach proposed by Bilot-Kawski. The singlet excited state dipole moment of TMPCB were calculated experimentally based on different approaches of solvent polarity function proposed by Lippert-Mataga, Bakhshiev, Kawskii-Chamma-Viallet, Reichardt and Bilot-Kawski. Singlet excited state dipole moment was greater than ground state dipole moment in all the approaches which could be attributed to considerable pi- electron density redistribution. Multiple Linear Regression (MLR) analysis based on Kamlet-Abboud-Taft and Catalan parameters were also studied to correlate solvatochromism and influence of solvents with absorbance and emission spectra. Ground and singlet excited state optimizations of the molecule were also performed using Gaussian 09 W software. HOMO-LUMO energies of the phthalamic acid derivative have been obtained using TD-DFT/PCM (B3LYP/6-31G (d, p)) computations and experimentally by using cyclic voltammetry. Mulliken charges and molecular electrostatic potential plot have also been generated from DFT calculations to identify nucleophilic and electrophilic sites of TMPCB. PMID- 28639214 TI - Acyclovir resistance in herpes simplex virus type I encephalitis: a case report. PMID- 28639215 TI - Regulation of T-type Ca2+ channel expression by herpes simplex virus-1 infection in sensory-like ND7 cells. AB - Infection of sensory neurons by herpes simplex virus (HSV)-1 disrupts electrical excitability, altering pain sensory transmission. Because of their low threshold for activation, functional expression of T-type Ca2+ channels regulates various cell functions, including neuronal excitability and neuronal communication. In this study, we have tested the effect of HSV-1 infection on the functional expression of T-type Ca2+ channels in differentiated ND7-23 sensory-like neurons. Voltage-gated Ca2+ currents were measured using whole cell patch clamp recordings in differentiated ND7-23 neurons under various culture conditions. Differentiation of ND7-23 cells evokes a significant increase in T-type Ca2+ current densities. Increased T-type Ca2+ channel expression promotes the morphological differentiation of ND7-23 cells and triggers a rebound depolarization. HSV-1 infection of differentiated ND7-23 cells causes a significant loss of T-type Ca2+ channels from the membrane. HSV-1 evoked reduction in the functional expression of T-type Ca2+ channels is mediated by several factors, including decreased expression of Cav3.2 T-type Ca2+ channel subunits and disruption of endocytic transport. Decreased functional expression of T-type Ca2+ channels by HSV-1 infection requires protein synthesis and viral replication, but occurs independently of Egr-1 expression. These findings suggest that infection of neuron-like cells by HSV-1 causes a significant disruption in the expression of T-type Ca2+ channels, which can results in morphological and functional changes in electrical excitability. PMID- 28639217 TI - Erratum to: Endocarps of menispermaceous plants in Taiwan. PMID- 28639216 TI - Biocomparison Study of Adult and Paediatric Dose Strengths of the Prostacyclin Receptor Agonist Selexipag. AB - BACKGROUND AND OBJECTIVES: Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 ug selexipag (Treatment A) vs. 4 paediatric tablets of 50 ug (Treatment B) in healthy adult male subjects. METHODS: This was an open-label, randomized, two-treatment, two-period, crossover biocomparison study. Bioequivalence criteria were explored and safety variables (vital signs, electrocardiogram, and laboratory parameters) were assessed. RESULTS: The exploratory analysis showed that the 90% confidence intervals of geometric mean ratio (Treatment B/Treatment A) for maximum plasma concentration (C max), area under the plasma concentration-time curve from zero to infinity (AUC0-infinity) of ACT-333679, as well as AUC0-infinity of selexipag, were within the bioequivalence interval (0.80, 1.25). In addition, no relevant difference in C max for selexipag between the two treatments can be concluded. Single oral dose administration of 200 ug selexipag as one tablet of 200 ug or four tablets of 50 ug was well tolerated. CONCLUSIONS: Pharmacokinetic characteristics of selexipag and its metabolite ACT-333679 following administration of one adult tablet of 200 ug selexipag and four paediatric tablets of 50 ug selexipag were comparable. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02745860. PMID- 28639218 TI - Ecogeographic variability and genetic diversity associated with seed albumins, globulins and prolamins patterns in Vicia taxa from Algeria. AB - Genetic variability was studied in 78 populations of locally collected Vicia L. taxa for seed albumins, globulins and prolamins patterns by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) along with an ecogeographic characterization of sites investigated. 131, 119 and 98 bands were respectively used for albumin, globulin and prolamin cluster analysis. Dendrograms based on the Jaccard index and the UPGMA method were generated and the degree of genetic diversity between and within taxa was evaluated. Five clusters were generated from albumins, six from globulins and four from prolamins patterns. The results reflect the great diversity of storage proteins and a high correlation was obtained between the three studied fractions. Several accessions present specific bands which could be used as a discriminatory marker both on intra and interspecific levels. No clear relationships were seen between the groups according to their geographical origin. Data obtained from ecogeographic investigation can be used for future collecting missions. PMID- 28639219 TI - Signature pattern analysis for the full-length env gene of the earliest Korean subclade B of HIV-1: outbreak among Korean hemophiliacs. AB - The epidemiological link in the hypervariable env gene between viruses infecting HIV-positive hemophiliacs (HPs) and plasma donors was not studied. We determined full-length env gene sequences in 20 HPs, 3 plasma donors whose plasma was used for domestic clotting factor (DCF) production, and 54 local controls (LCs). Env genes from viruses in frozen stored sera obtained 1-3 years after diagnosis and from samples collected several years after infection were amplified via RT-PCR and subjected to direct sequencing. Phylogenetic analysis indicated that all sequences were subtype B, including 133 sequences from 77 cases (20 HPs, 3 plasma donors, and 54 LCs) belonging to the Korean subclade B (KSB) and 6 sequences from 5 cases that did not belong to the KSB. Env gene sequences from donors O and P and those of the 20 HPs comprised 2 subclusters within the KSB, although phylogenetic analysis did not support significant bootstrap values. In contrast, signature pattern analysis indicated signature nucleotides at 43 positions between the HPs and LCs (P < 0.05). In particular, specific signature nucleotides at 4 positions were fully conserved in the HPs, but not in the LCs (P < 0.0001). Furthermore, there were 26 signature residues within the KSB and were distinct from the worldwide consensus for subtype B. In conclusion, signature pattern analysis for the hypervariable env gene revealed an epidemiological link that the 20 HPs in this study had been infected with viruses from the DCF used for treatment, consistent with our previous finding. PMID- 28639220 TI - Emergence of rabbit haemorrhagic disease virus 2 in the archipelago of Madeira, Portugal (2016-2017). AB - We report the detection of rabbit haemorrhagic disease virus 2 (RHDV2) in the Madeira archipelago, Portugal. Viral circulation was confirmed by RT-qPCR and vp60 sequencing. Epidemiological data revealed the outbreak initiated in October 2016 in Porto Santo affecting wild and domestic rabbits. It was then detected three months later on the island of Madeira. Five haplotypes were identified and a genetic overall similarity of 99.54 to 99.89% was observed between the two viral populations. Unique single nucleotide polymorphisms were recognised in the Madeira archipelago strains, two of which resulting in amino acid substitutions at positions 480 and 570 in the VP60 protein. Phylogenetic investigation by Maximum Likelihood showed all the vp60 sequences from the Madeira archipelago group together with high bootstraps. The analysis also showed that the Madeira archipelago strains are closely related to the strains detected in the south of mainland Portugal in 2016, suggesting a possible introduction from the mainland. The epidemiological data and high genetic similarity indicate a common source for the Porto Santo and Madeira RHDV2 outbreaks. Human activity related to hunting was most probably at the origin of the Madeira outbreak. PMID- 28639222 TI - Molecular and biological characterization of a new Tomato mild yellow leaf curl Aragua virus strain producing severe symptoms in tomato. AB - Tomato mild yellow leaf curl Aragua virus (ToMYLCV) is a begomovirus first reported infecting tomato (Solanum lycopersicum) and milkweed (Euphorbia heterophylla) in Venezuela. In this study, a ToMYLCV isolate (Zulia-219) was completely sequenced and its host range was evaluated. The DNA-A and DNA-B components of isolate Zulia-219 showed 93 and 85% nucleotide sequence identity with the respective counterparts of the ToMYLCV type strain. According to current demarcation criteria for begomovirus species, Zulia-219 is a new strain of ToMYLCV. Interestingly, tomato plants inoculated with ToMYLCV Zulia-219 displayed severe symptoms, including severe chlorotic leaf curling, in contrast to mild symptoms associated with the type strain of this begomovirus. These results indicate potential risks associated with this new ToMYLCV strain for tomato production in Venezuela. PMID- 28639221 TI - HBV X Protein induces overexpression of HERV-W env through NF-kappaB in HepG2 cells. AB - Human endogenous retrovirus W family (HERV-W) envelope (env) at chromosome 7 is highly expressed in the placenta and possesses fusogenic activity in trophoblast development. HERV-W env has been found to be overexpressed in some cancers and immune diseases. Viral transactivators can induce the overexpression of HERV-W env in human cell lines. Hepatitis B virus X protein (HBx) is believed to be a multifunctional oncogenic protein. Here, we reported that HBx could increase the promoter activity of HERV-W env and upregulate the mRNA levels of non-spliced and spliced HERV-W env and also its protein in human hepatoma HepG2 cells. Interestingly, we found that the inhibition of nuclear factor kappaB (NF-kappaB) using shRNA targeting NF-kappaB/p65 or PDTC (an inhibitor of NF-kappaB) could attenuate the upregulation of HERV-W env induced by HBx. These suggested that HBx might upregulate the expression of HERV-W env through NF-kappaB in HepG2 cells. This study might provide a new insight in HBV-associated liver diseases including HCC. PMID- 28639224 TI - Tackling Students' Attitudes Towards Substance Use Disorders. PMID- 28639223 TI - Imaging of Left Ventricular Hypertrophy: a Practical Utility for Differential Diagnosis and Assessment of Disease Severity. AB - PURPOSE OF REVIEW: Left ventricular hypertrophy (LVH) is often encountered in clinical practice, and it is a risk factor for cardiac mortality and morbidity. Determination of the etiology and disease severity is important for the management of patients with LVH. The aim of this review is to show the remarkable progress in cardiac imaging and its importance in clinical practice. RECENT FINDINGS: This review focuses on clinical features and characteristic cardiac imaging in LVH caused by various diseases including hypertension, aortic valve stenosis, hypertrophic cardiomyopathy, and secondary cardiomyopathies. The usefulness of echocardiography as a tool of general versatility including hemodynamic evaluation and the usefulness of cardiac magnetic resonance imaging for assessment of cardiac morphology and myocardial tissue characteristics of relevance for LVH are described. Imaging modalities now have central roles in the differentiation and prognostic assessment of LVH. PMID- 28639225 TI - The Development and Implementation of a Patient Continuity Conference in a Psychiatry Residency Program. AB - OBJECTIVE: A resident-led patient continuity case conference was initiated with the goals of improving communication among providers and increasing cohesion among residents. METHODS: A monthly case conference focusing on patient continuity of care was held over the course of the academic year. Residents were surveyed for feedback about the role of the conference in both improving their competency in navigating transitions of care and building cohesion among residents. RESULTS: The conference improved resident knowledge of care transitions and communication during transitions in care in addition to increasing comfort, cohesion, and exchange of knowledge between residents. CONCLUSIONS: Implementing a resident-led patient continuity case conference can improve resident competency during care transitions while improving cohesion among residents. PMID- 28639226 TI - Standardizing Training in Mindfulness-Based Interventions in Canadian Psychiatry Postgraduate Programs: A Competency-Based Framework. PMID- 28639227 TI - Association Study Between Coronary Artery Disease and rs1333049 Polymorphism at 9p21.3 Locus in Italian Population. AB - In this study, we verify the association between the rs1333049 single nucleotide polymorphism (9p21.3) within CDKN2A-CDKN2B and coronary artery disease (CAD) in an Italian population. We replicated rs1333049_G allele association with a significantly reduced risk of CAD (OR = 0.816; 95% confidence interval [0.705 0.945]; p = 0.0065) in 711 CAD patients and 755 normal healthy individuals. This effect is maintained even stratifying patients by gender and by risk factors. A significant association was found with age of CAD onset. Interestingly, we found a protective trend of association between the rs1333049_G allele and peripheral artery disease, a progressive atherosclerotic condition in which plaque builds up in the arteries that carry blood to the head, organs, and limbs (OR = 0.724; 95% CI [0.520-1.007]; p = 0.054). No genotype-phenotype association was found with more severe CAD clinical parameters. If certain genetic factors predispose individuals to adverse outcomes, the knowledge of a patient's genotype may influence clinical management. PMID- 28639228 TI - Role of 20-Hydroxyeicosatetraenoic Acid (20-HETE) in Androgen-Mediated Cell Viability in Prostate Cancer Cells. AB - 20-Hydroxyeicosatetraenoic acid (20-HETE) is generated intracellularly through the omega-hydroxylation of arachidonic acid by the cytochrome P450 (in humans, CYP4A11 and CYP4F2). 20-HETE induces mitogenic responses in different cancer cells. The aim of this study was to analyze how 20-HETE impacts cell survival, proliferation, and apoptosis in prostate cancer cells. Incubation of the human androgen-sensitive cells (LNCaP) with 1-10 MUM HET0016 (a selective inhibitor of 20-HETE synthesis) reduced cell viability by 49*-64%* (*p < 0.05 vs. control). This was explained by a reduction in cell proliferation (vehicle, 46 +/- 3%; 1 MUM, 23 +/- 3%*; 10 MUM, 28 +/- 3%*) and by an increase in apoptosis (vehicle, 2.1 +/- 0%; 1 MUM, 16 +/- 4%*; 10 MUM, 31 +/- 3%*). Furthermore, the increase in LNCaP cell viability induced by dihydrotestosterone (DHT, 0.1 nM) was abrogated by 30*-42%* by 1-10 MUM HET0016. Incubation with 20-HETE (5-1000 nM) increased LNCaP cell viability up to 50%*, together with a 70%* reduction in apoptosis. PC 3 (androgen-insensitive) cell viability was not affected by either HET0016 or 20 HETE. In LNCaP cells, HET0016 (10 MUM) diminished the expression of androgen receptors (AR): messenger RNA (mRNA) (40%*) and protein (50%*). DHT (10 nM) augmented CYP4F2 protein expression (1.9-fold*) and 20-HETE levels (50%*). Oppositely, enzalutamide (AR antagonist) reduced CYP4F2 mRNA and protein expressions by 30 and 25%, respectively. Thus, intracellular availability of 20 HETE is necessary to sustain LNCaP cell viability. 20-HETE may act as a signaling molecule in the pathways involved in LNCaP cell viability upon stimulation of the AR. This effect may be partially attributed to its role on securing normal AR expression levels that in turn contribute to maintain intracellular levels of 20 HETE. PMID- 28639229 TI - Pharmacokinetics of MHAA4549A, an Anti-Influenza A Monoclonal Antibody, in Healthy Subjects Challenged with Influenza A Virus in a Phase IIa Randomized Trial. AB - BACKGROUND AND OBJECTIVES: MHAA4549A, a human anti-influenza immunoglobulin (Ig) G1 monoclonal antibody, is being developed to treat patients hospitalized for influenza A infection. This study examined the pharmacokinetics (PKs) of MHAA4549A in a phase IIa, randomized, double-blind, dose-ranging trial in healthy volunteers challenged with influenza A virus. METHODS: Serum PK data were collected from 60 subjects in three single-dose groups (400, 1200, or 3600 mg) who received MHAA4549A intravenously 24-36 h after inoculation with the influenza A virus. Nasopharyngeal swab MHAA4549A concentration data were collected on days 1-8, and all subjects, including the placebo group, received 75 mg oseltamivir twice daily from days 7 to 11. Plasma samples were collected 4 h postdose on day 8 for oseltamivir and its active metabolite oseltamivir carboxylate (OC) (all subjects, n = 100), including subjects treated with oseltamivir alone and placebo. Noncompartmental analysis was performed for both nasal and serum PKs. RESULTS: MHAA4549A showed dose-proportional serum PKs with a long terminal half life (approximately 21.9-24.6 days) and slow clearance (approximately 152-240 mL/day); however, nasopharyngeal swab PKs were not dose proportional. No differences in mean plasma concentrations of oseltamivir and OC at 4 h postdose on day 8 were observed between the MHAA4549A treatment and placebo groups. No subjects who received MHAA4549A developed anti-drug antibodies. CONCLUSION: MHAA4549A serum PKs were consistent with that of a human IgG1antibody without known endogenous targets. MHAA4549A showed nonlinear PKs in nasopharyngeal swab samples, which will guide future dose selection to achieve the high drug concentrations needed at the site of action for efficacy. These data demonstrate no PK interactions between MHAA4549A and oseltamivir, and support flat dosing. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01980966. PMID- 28639230 TI - Intracellular Pharmacokinetics of Antibacterials and Their Clinical Implications. AB - The intracellular pharmacokinetics of the different classes of antimicrobials into surrogate markers of tissue accumulation (alveolar macrophages and/or total alveolar cells collected by means of bronchoalveolar lavage or peripheral white blood cells) was reviewed. The aim of this review was to discuss the clinical implications of the intracellular pharmacokinetics of antibacterials, either from the therapeutic or toxicological perspective. The different pharmacokinetic behaviour of antimicrobials within cells is mainly related to their physicochemical properties (hydrophilicity and lipophilicity), and may have several clinical implications. Therapeutic efficacy against intracellular pathogens has been correlated mainly with the intracellular concentrations achieved by the different antimicrobial agents. This is relevant especially for macrolides, tetracyclines, fluoroquinolones and rifampicin in the treatment of bacterial infections such as Legionella pneumophila pneumonia, Mycoplasma pneumoniae pneumonia, non-gonococcal urethritis and chronic staphylococcal infections. Additionally, intracellular accumulation of antibacterials was correlated with the possibility of causing organ-specific toxicity, as in the case of aminoglycosides in regard to the risk of nephrotoxicity. Finally, it should be kept in mind that intracellular accumulation may also represent a drug reservoir in the case of lipophilic antimicrobials. This may become extremely relevant from the clinical standpoint when treating critically ill patients with sepsis with antibacterials. The pathophysiology of sepsis may explain why it is necessary to start therapy with an increased loading dose of hydrophilic antimicrobials to promptly achieve therapeutically effective concentrations. PMID- 28639231 TI - What Is New in the World Health Organization 2017 Histopathology Classification? PMID- 28639232 TI - [Electroencephalography in delirium superimposed on dementia]. AB - Recognizing delirium superimposed on pre-existing cognitive impairment or dementia, 'delirium superimposed on dementia' (DSD), is challenging because signs of delirium might be interpreted as symptoms of pre-existing cognitive dysfunction.In this paper, we review the literature on the role of electrencephalography (EEG) in the differential diagnosis of delirium, dementia and DSD.Conventional EEG, applying twenty to thirty electrodes, taking thirty minutes registration, is not feasible in psychogeriatric patients. Recent studies suggest that it is possible to reliably detect delirium using only a limited number of EEG electrodes for a short period of time.With this, use of EEG in the detection of delirium in patients with cognitive impairment or clinically manifest dementia could be possible. PMID- 28639233 TI - [Physical and mental dimensions of quality of life of frail older people]. AB - Frail older people have an increased risk of limitations in performing activities of daily living, hospitalization, nursing home admission, and premature death. In this study we determined the difference in experiencing quality of life between frail and non-frail older people. We also investigated the associations between physical, psychological and social components of frailty and the physical and mental dimensions of quality of life. 374 people of 75 years and older filled in a questionnaire, the Senioren Barometer. This questionnaire contained the Tilburg Frailty Indicator (TFI) to assess frailty and the SF-12 for assessing quality of life. The study showed that frail older people on average experience a lower quality of life than non-frail older people. A considerable part of the variance of the physical and mental dimensions of quality of life could be explained by the fifteen components of frailty, after controlling for the background characteristics of the respondents, 33.2% and 36.5%, respectively. The frailty components physical inactivity, physical tiredness, and depressive symptoms were associated with the physical dimension as well as the mental dimension of quality of life. The results confirm the importance of multidimensional assessment of frailty. In addition, they provide a direction to healthcare and welfare professionals in performing interventions with the aim of increasing the quality of life of older people. PMID- 28639236 TI - The effects of intranasal dexmedetomidine premedication in children: a systematic review and meta-analysis. AB - PURPOSE: Intranasal dexmedetomidine premedication is a newly introduced method for reducing stress and anxiety before general anesthesia in children. We performed a meta-analysis to identify the effects of intranasal dexmedetomidine premedication in children. SOURCE: We conducted a systematic review to find published randomized-controlled trials using intranasal dexmedetomidine as premedication. We searched databases in EMBASETM, MEDLINE(r), and the Cochrane Controlled Trials Register using the Ovid platform. This study was conducted based on the Cochrane Review Methods. PRINCIPAL FINDINGS: This review included 1,168 participants in 13 studies. Intranasal dexmedetomidine premedication provided more satisfactory sedation at parent separation (relative risk [RR], 1.45; 95% confidence interval [CI], 1.19 to 1.76; P = 0.0002; I2 = 80%) than other premedication regimes. In addition, it reduced the need for rescue analgesics (RR, 0.58; 95% CI, 0.40 to 0.83; P = 0.003; I2 = 0%). Nevertheless, there were no differences in sedation at mask induction (RR, 1.25; 95% CI, 0.98 to 1.59; P = 0.08; I2 =71%) or in the incidence of emergence delirium (RR, 0.52; 95% CI, 0.24 to 1.13; P = 0.10; I2 = 67%). Intranasal dexmedetomidine was associated with a significantly lower incidence of nasal irritation (RR, 0.05; 95% CI, 0.01 to 0.36; P = 0.003; I2 = 0%) and postoperative nausea and vomiting (RR, 0.63; 95% CI, 0.40 to 0.99; P = 0.04; I2 = 0%) than other premedication treatments. It also showed significantly lower systolic blood pressure (weighted mean difference [WMD], -6.7 mmHg; 95% CI, -10.5 to -2.9; P = 0.0006; I2 = 96%) and heart rate (WMD, -6.8 beats.min-1; 95% CI, -11.3 to -2.6; P = 0.002; I2 = 98%). CONCLUSIONS: Intranasal dexmedetomidine provided more satisfactory sedation at parent separation and reduced the need for rescue analgesics and the incidence of nasal irritation and postoperative nausea and vomiting when compared with other premedication treatments. PMID- 28639235 TI - Biofluid lipidome: a source for potential diagnostic biomarkers. AB - Lipidomics is the identification and quantitation of changes in the lipidome of a cell, tissue, organ or biofluid in health and disease using high resolution mass spectrometry. Lipidome of a particular organism has relevance to the disease manifestation as it reflects the metabolic changes which can be a consequence of the disease. Hence these changes in the molecules can be considered as potential markers for screening and early detection of the disease. Biological fluids as blood/serum/plasma, urine, saliva, tear and cerebrospinal fluid, due to their accessibility, offer ease of collection with minimal or no discomfort to the patient and provide a ready footprint of the metabolic changes occurring during disease. This review provides a brief introduction to lipidomics and its role in understanding the metabolic changes in health and disease followed by discussion on the chemical diversity of the lipid species and their biological role, mammalian lipids and their metabolism and role of lipids in pathogens and the immune response before dwelling further into importance of studying lipidome in various biological fluids. The challenges in performing a lipidomic analysis at the experimental and data analysis stages are discussed. PMID- 28639234 TI - Novel Biomarkers of Subclinical Cardiac Dysfunction in the General Population. AB - PURPOSE OF REVIEW: Recognition of subclinical myocardial dysfunction offers clinicians and patients an opportunity for early intervention and prevention of symptomatic cardiovascular disease. We review the data on novel biomarkers in subclinical heart disease in the general population with a focus on pathophysiology, recent observational or trial data, and potential applicability and pitfalls for clinical use. RECENT FINDINGS: High-sensitivity cardiac troponin and natriuretic peptide assays are powerful markers of subclinical cardiac disease. Elevated levels of these biomarkers signify subclinical cardiac injury and hemodynamic stress and portend an adverse prognosis. Novel biomarkers of myocardial inflammation, fibrosis, and abnormal contraction are gaining momentum as predictors for incident heart failure, providing new insight into pathophysiologic mechanisms of cardiac disease. There has been exciting growth in both traditional and novel biomarkers of subclinical cardiac injury in recent years. Many biomarkers have demonstrated associations with relevant cardiovascular outcomes and may enhance the diagnostic and prognostic power of more conventional biomarkers. However, their use in "prime time" to identify patients with or at risk for subclinical cardiac dysfunction in the general population remains an open question. Strategic investigation into their clinical applicability in the context of clinical trials remains an area of ongoing investigation. PMID- 28639237 TI - Work-Home Interference, Perceived Total Workload, and the Risk of Future Sickness Absence Due to Stress-Related Mental Diagnoses Among Women and Men: a Prospective Twin Study. AB - PURPOSE: Work-home interference has been proposed as an important explanation for sickness absence (SA). Previous studies show mixed results, have not accounted for familial factors (genetics and shared everyday environment), or investigated diagnosis specific SA. The aim was to study whether work-home interference and perceived total workload predict SA due to stress-related mental diagnoses, or SA due to other mental diagnoses, among women and men, when adjusting for various confounders and familial factors. METHODS: This study included 11,916 twins, 19 47 years (49% women). Data on work-to-home and home-to-work conflicts, perceived total workload, and relevant confounders were derived from a 2005 survey, and national register data on SA spells until 2013 were obtained. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Discordant twin pair design was applied to adjust for familial factors. RESULTS: Each one unit increase in work-to-home and home-to-work conflicts, and perceived total workload was associated with higher odds for SA due to stress-related mental diagnoses and to SA due to other mental diagnoses among women, when adjusting for sociodemographic factors (ORs 1.15-1.31). Including health or familial factors, no associations remained. For men, each one unit increase in work-to-home conflicts was associated with higher odds for SA due to stress-related diagnoses (ORs 1.23 1.35), independently of confounders. CONCLUSION: Work-to-home conflict was independently associated with future SA due to stress-related diagnoses among men only. Health- and work-related factors seem to be important confounders when researching work-home interference, perceived total workload, and SA. Not including such confounders involves risking drawing incorrect conclusions. Further studies are needed to confirm sex differences and whether genetic factors are important for the associations studied. PMID- 28639238 TI - Multiple Sclerosis in Latin Americans: Genetic Aspects. AB - Latin Americans (LA) are a heterogeneous, multiethnic group of individuals who inhabit the continental countries in Latin America (LATAM), Caribbean islands and constitute the largest ethnic minority in the USA. Commonly used terminology and ethno racial classifications to define these groups may not be accurate. Risk for multiple sclerosis (MS) among LA is generally low to medium but frequencies are increasing in the American hemisphere. Genome-Wide Association Studies (GWAS) in LA show diverse variants and genetic proportions among Mestizos, the most representative ethnic population, who themselves are the product of centuries of interracial mixing between Native Americans (or Amerindians), White Caucasian Europeans, and Black Africans. Genetic distribution diversity appears to be related to migratory and historical and socio-political factors in LATAM. Epidemiologic studies show an extremely low prevalence of MS among non-mixed Amerindians; this has been attributed to protective ancestral Asian genetics and possibly, environmental factors. Mestizos and biracial LA of African ancestry have more susceptibility to MS apparently due to the historical introduction of the European HLA-DRB1*1501 gene. Contribution from HLA typing, GWAS, and ancestry informative markers (AIMs) has been determinant in the current LA genetic understanding but more regional studies are needed. The relationship between genetics and disease regional distribution is emphasized. PMID- 28639239 TI - Significant Improvement in Detecting BRAF, KRAS, and EGFR Mutations Using Next Generation Sequencing as Compared with FDA-Cleared Kits. AB - INTRODUCTION: We compared mutations detected in EGFR, KRAS, and BRAF genes using next-generation sequencing (NGS) and confirmed by Sanger sequencing with mutations that could be detected by FDA-cleared testing kits. METHODS: Paraffin embedded tissue from 822 patients was tested for mutations in EGFR, KRAS, and BRAF by NGS. Sanger sequencing of hot spots was used with locked nucleic acid to increase sensitivity for specific hot-spot mutations. This included 442 (54%) lung cancers, 168 (20%) colorectal cancers, 29 (4%) brain tumors, 33 (4%) melanomas, 14 (2%) thyroid cancers, and 16% others (pancreas, head and neck, and cancer of unknown origin). Results were compared with the approved list of detectable mutations in FDA kits for EGFR, KRAS, and BRAF. RESULTS: Of the 101 patients with EGFR abnormalities as detected by NGS, only 58 (57%) were detectable by cobas v2 and only 35 (35%) by therascreen. Therefore, 42 and 65%, respectively, more mutations were detected by NGS, including two patients with EGFR amplification. Of the 117 patients with BRAF mutation detected by NGS, 62 (53%) mutations were within codon 600, detectable by commercial kits, but 55 (47%) of the mutations were outside codon V600, detected by NGS only. Of the 321 patients with mutations in KRAS detected by NGS, 284 (88.5%) had mutations detectable by therascreen and 300 (93.5%) had mutations detectable by cobas. Therefore, 11.5 and 6.5% additional KRAS mutations were detected by NGS, respectively. CONCLUSION: NGS provides significantly more comprehensive testing for mutations as compared with FDA-cleared kits currently available commercially. PMID- 28639240 TI - Approach to thyroid carcinoma in pregnancy. AB - Thyroid carcinoma is the first cancer found in general population and the second diagnosed during pregnancy following the breast one. Diagnostic and therapeutic approaches to thyroid malignancy in pregnant women pose several and serious issues to the physicians. Even if there is no consensus about the surgical treatment of thyroid carcinomas during pregnancy, a large number of women undergo surgery over the world. The best surgical and anesthesiological treatment should be chosen after reaching a consensus between surgeons, anesthesiologists, obstetrics, and the patients. From 2000 to 2016, 18 pregnant patients underwent thyroidectomy under local anesthesia (cervical plexus block) combined with conscious sedation using benzodiazepines and opiates with ultrashort duration of action. Our 15-year experience on the thyroidectomies performed using the cervical plexus block combined with conscious sedation confirms that this combined technique offers a safe chance to defeat cancer also during pregnancy. Application of hypnosis could be an interesting alternative approach to pharmacological sedation in patients who would avoid intravenous drugs. PMID- 28639244 TI - Veterinary Public Health in Italy: From Healthy Animals to Healthy Food, Contribution to Improve Economy in Developing Countries. AB - The role of the veterinarian as a public health officer is intrinsic to the history and the culture of veterinary organization in Italy. The Veterinary service being part of the Health administration since the birth of the Italian State in the XIX Century. In the second half of the last century the birth of the Italian National Health Service confirmed that the function of the Italian veterinary service was to analyze and reduce the risks for the human population connected to the relationship man-animal-environment, animal health, food safety and security. The Italian Veterinary Medicine School curricula, reflected this "model" of veterinarian as well. In the majority of countries in the world, Veterinary Services are organized within the Agriculture Administration with the main function to assure animal health and wellbeing. After the so-called "Mad-cow crisis" the awareness of the direct and essential role of veterinary services in the prevention of human illness has been officially recognized and in the third millennium the old concept of "one health" and "human-animal interface" has gained popularity worldwide.The concept of Veterinary Public Health, has evolved at International level and has incorporated the more than a century old vision of the Italian Veterinary medicine and it is defined as "the sum of the contributions to the physical, mental and social development of people through the knowledge and application of veterinary science" (WHO, Future trends in veterinary public health. Gruppo di lavoro OMS: TE, Italy, 1999, Available from: http://www.who.int/zoonoses/vph/en/ . Last visited 16 Feb 2016, 1999).On the subject of Cooperation, Sustainability and Public Health, the EXPO 2015 event and the activities of international organizations WHO, FAO and World Organization for Animal Health are refocusing at present their worldwide mandate to protect human health and the economy of both the poorest Countries and the developed countries, according to the "new" concept of Veterinary Public Health.Focus of Italian Veterinary Services activity is connected to research, diagnosis and epidemiological analysis of infectious diseases, including zoonosis, food safety as well as food security. PMID- 28639242 TI - Accuracy of Fine Needle Cytology in Histological Prediction of Papillary Thyroid Carcinoma Variants: a Prospective Study. AB - Fine needle cytology (FNC) is a crucial procedure in the preoperative diagnosis of thyroid tumors. Papillary thyroid carcinoma (PTC), in its classic variant (cPTC), is the most common malignant neoplasm of the thyroid. Several histological variants of PTC have been described, each one with its own characteristics and prognosis. The ability of FNC to identify the variants represents a challenge even for a skilled pathologist. The aim of this study was to evaluate the diagnostic cytological accuracy of FNC in PTC and to look for specific features that could predict the different variants. This was a single center prospective study on 128 patients who received a diagnosis of PTC on FNC. The smears were blindly reviewed by two cytopathologists to create a frequency score (0, 1, 2, 3) of the features for each variant. The cytological parameters were divided into three groups: architectural, nucleo-cytoplasmic, and background features. Univariate analysis was performed by chi-square test with Yates correction and Fisher exact test as appropriate. Multiple regression analysis was performed among the variables correlated at the linear correlation. The correlation study between cytology and histology showed an accuracy of FNC in classic, follicular, and oncocytic PTC variants of 63.5, 87.5, and 87% respectively. Familiarity with cytological features may allow an early diagnosis of a given PTC variant on FNC samples. This is fundamental in a preoperative evaluation for the best surgical approach and subsequent treatment. PMID- 28639243 TI - Right atrial myocardial deformation by two-dimensional speckle tracking echocardiography predicts recurrence in paroxysmal atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is a bi-atrial disease yet little attention has been given to right heart function in AF. We propose that the assessment of right atrial (RA) and right ventricular function (RV) using two-dimensional speckle tracking echocardiography (2D-STE) could be valuable in predicting AF recurrence in patients with paroxysmal AF (PAF). METHODS: Thirty patients with PAF were prospectively recruited from a dedicated AF clinic. Right atrial size, volume, and area and RV dimensions were analyzed along with RA and RV strain derived from 2D-STE at baseline and at 3 and 12 months. RESULTS: Higher RA booster strain independently predicted sinus rhythm (SR) maintenance for up to 1 year (P = 0.001). RV strain was impaired in patients with recurrent AF compared to those in SR (P < 0.05) but did not predict AF recurrence. Two-dimensional STE for RA and RV function was simple to perform with excellent reproducibility (adjusted R 2 0.92-0.99). CONCLUSIONS: Two-dimensional STE is useful and highly reproducible in assessing right heart function in AF patients. RA booster strain function was predictive of sinus rhythm maintenance for up to 1 year. PMID- 28639245 TI - Biofilm-Forming Ability and Clonality in Acinetobacter baumannii Strains Isolated from Urine Samples and Urinary Catheters in Different European Hospitals. AB - OBJECTIVE: Biofilm formation has been associated with the persistence of Acinetobacter baumannii in hospital settings and its propensity to cause infection. We investigated the adhesion ability and clonality of 128 A. baumannii isolates recovered from urine and urinary catheters of patients admitted to 5 European hospitals during 1991-2013. METHODS: Isolates identification was confirmed by rpoB sequencing and by the presence of blaOXA-51. The presence of carbapenemases was detected by PCR. Clonality was determined by Sequence Group (SG) identification, Pulsed field gel electrophoresis (PFGE) and Multilocus sequence typing. Adhesion ability was defined by quantitative biofilm production assay and biofilms were characterized by Confocal Laser Microscopy and Scanning Electron Microscopy. RESULTS: The 128 isolates, either resistant (85.9%) or susceptible (14.1%) to carbapenems, and belonging to 50 different PFGE types and 24 different STs, were distributed among SG1 (67.2%), SG2 (10.2%) and other allelic profiles (22.7%). ST218 was the most frequent ST, corresponding to 54,5% of the isolates collected between 2011 and 2013. Among the 109 isolates showing resistance to at least 1 carbapenem, 55% revealed the presence of an acquired carbapenem-hydrolyzing class D - lactamases (CHDL): blaOXA-23 were the most frequent gene detected from 2008 onwards (75%). Among all the clinical isolates, 42.2% were strong biofilm producers, with the older isolates having the highest adhesion ability. Most isolates recovered later, belonging to ST218 and harbouring blaOXA-23, were homogeneously less adhesive. CONCLUSIONS: An evolution towards a decrease in adhesion ability and a CHDL content change was observed along the years in several European countries. PMID- 28639246 TI - ATP-Gated P2X3 Receptors Are Specialised Sensors of the Extracellular Environment. AB - P2X3 receptors are ion channels expressed by autonomic and sensory nerves and specialised in transducing extracellular ATP signals. Structural data, together with functional and biochemical studies, suggest that conformational changes of P2X3 receptors upon agonist binding influence downstream intracellular molecular mechanisms relevant for neuronal responses. Activity of P2X3 receptors is implicated in pain, itch, asthma, cardiovascular dysfunction and other pathologies. The study of these receptors has therefore a large potential in the field of drug development and interdisciplinary efforts could clarify molecular mechanisms controlling P2X3 receptor function in different physiological or pathological contexts. PMID- 28639241 TI - Huntington's Disease and Mitochondria. AB - Huntington's disease (HD) as an inherited neurodegenerative disorder leads to neuronal loss in striatum. Progressive motor dysfunction, cognitive decline, and psychiatric disturbance are the main clinical symptoms of the HD. This disease is caused by expansion of the CAG repeats in exon 1 of the huntingtin which encodes Huntingtin protein (Htt). Various cellular and molecular events play role in the pathology of HD. Mitochondria as important organelles play crucial roles in the most of neurodegenerative disorders like HD. Critical roles of the mitochondria in neurons are ATP generation, Ca2+ buffering, ROS generation, and antioxidant activity. Neurons as high-demand energy cells closely related to function, maintenance, and dynamic of mitochondria. In the most neurological disorders, mitochondrial activities and dynamic are disrupted which associate with high ROS level, low ATP generation, and apoptosis. Accumulation of mutant huntingtin (mHtt) during this disease may evoke mitochondrial dysfunction. Here, we review recent findings to support this hypothesis that mHtt could cause mitochondrial defects. In addition, by focusing normal huntingtin functions in neurons, we purpose mitochondria and Huntingtin association in normal condition. Moreover, mHtt affects various cellular signaling which ends up to mitochondrial biogenesis. So, it could be a potential candidate to decline ATP level in HD. We conclude how mitochondrial biogenesis plays a central role in the neuronal survival and activity and how mHtt affects mitochondrial trafficking, maintenance, integrity, function, dynamics, and hemostasis and makes neurons vulnerable to degeneration in HD. PMID- 28639247 TI - P2Y1 Receptors - Properties and Functional Activities. AB - In this chapter we try to show a comprehensive image of current knowledge of structure, activity and physiological role of the P2Y1 purinergic receptor. The structure, distribution and changes in the expression of this receptor are summarized, as well as the mechanism of its signaling activity by the intracellular calcium mobilization. We try to show the connection between the components of its G protein activation and cellular or physiological effects, starting from changes in protein phosphorylation patterns and ending with such remote effects as receptor-mediated apoptosis. The special emphasis is put on the role of the P2Y1 receptor in cancer cells and neuronal plasticity. We concentrate on the P2Y1 receptor, it is though impossible to completely abstract from other aspects of nucleotide signaling and cross-talk with other nucleotide receptors is here discussed. Especially, the balance between P2Y1 and P2Y12 receptors, sharing the same ligand but signaling through different pathways, is presented. PMID- 28639248 TI - P2X Receptor Activation. AB - Extracellular ATP-gated P2X receptors are trimeric non-selective cation channels important for many physiological events including immune response and neural transmission. These receptors belong to a unique class of ligand-gated ion channels composed of only six transmembrane helices and a relatively small extracellular domain that harbors three ATP-binding pockets. The crystal structures of P2X receptors, including the recent P2X3 structures representing three different stages of the gating cycle, have provided a compelling structural foundation for understanding how this class of ligand-gated ion channels function. These structures, in combination with numerous functional studies ranging from classic mutagenesis and electrophysiology to modern optogenetic pharmacology, have uncovered unique molecular mechanisms of P2X receptor function. This review article summarizes the current knowledge in P2X receptor activation, especially focusing on the mechanisms underlying ATP-binding, conformational changes in the extracellular domain, and channel gating and desensitization. PMID- 28639249 TI - Histone Post-Translational Modifications and Nucleosome Organisation in Transcriptional Regulation: Some Open Questions. AB - The organisation of chromatin is first discussed to conclude that nucleosomes play both structural and transcription-regulatory roles. The presence of nucleosomes makes difficult the access of transcriptional factors to their target sequences and the action of RNA polymerases. The histone post-translational modifications and nucleosome remodelling are first discussed, from a historical point of view, as mechanisms to remove the obstacles imposed by chromatin structure to transcription. Instead of reviewing the state of the art of the whole field, this review is centred on some open questions. First, some "non classical" histone modifications, such as short-chain acylations other than acetylation, are considered to conclude that their relationship with the concentration of metabolic intermediaries might make of them a sensor of the physiological state of the cells. Then attention is paid to the interest of studying chromatin organisation and epigenetic marks at a single nucleosome level as a complement to genome-wide approaches. Finally, as a consequence of the above questions, the review focuses on the presence of multiple histone post translational modifications on a single nucleosome. The methods to detect them and their meaning, with special emphasis on bivalent marks, are discussed. PMID- 28639250 TI - Regulation of Nephrin Phosphorylation in Diabetes and Chronic Kidney Injury. AB - Diabetes is the leading cause of microalbuminuria and end-stage renal failure in industrial countries. Disruption of the filtration barrier, seen in almost all nephrotic diseases and diabetes, is the result of the loss or effacement of the podocyte foot process, notably damage of proteins within the slit diaphragm such as nephrin. For many years, nephrin has been viewed as a structural component of the slit diaphragm. It is now well recognized that nephrin contains several tyrosine residues in its cytoplasmic domain, which influences the development of glomerular injury. In this review, we propose an overview of nephrin signaling pathways in kidney injury. PMID- 28639251 TI - Regulation of the Extracellular SERPINA5 (Protein C Inhibitor) Penetration Through Cellular Membranes. AB - It is generally accepted that the phospholipid bilayer of the cell membrane is impermeable for proteins and peptides and that these molecules require special mechanisms for their transport from the extra- to the intracellular space. Recently there is increasing evidence that certain proteins/peptides can also directly cross the phospholipid membrane. SERPINA5 (protein C inhibitor) is a secreted protease inhibitor with broad protease reactivity and wide tissue distribution. It binds glycosaminoglycans and certain phospoholipids, which can modulate its inhibitory activity. SERPINA5 has been shown to be internalized by platelets, granulocytes, HL-60 promyelocytic leukemia cells, and by Jurkat lymphoma cells. Once inside the cell it can translocate to the nucleus. There are several indications that SERPINA5 can directly cross the phospholipid bilayer of the cell membrane. In this review we will describe what is known so far about the conditions, as well as the cellular and molecular requirements for SERPINA5 translocation through the cell membrane and for its penetration of pure phospholipid vesicles. PMID- 28639252 TI - Ethnic Variations in Serum 25(OH)D Levels and Bone Ultrasound Attenuation Measurements in Blacks and Whites. AB - Vitamin D deficiency is more common in Blacks, yet Blacks have lower prevalence of bone fragility fractures or osteoporosis than Whites. Broadband ultrasound attenuation (BUA) has been used to explore the association between serum 25(OH)D levels and bone quality in White and non-white populations. We investigated serum 25(OH)D status with corresponding BUA measurements assessed cross sectionally in a cohort of 232 Blacks and 260 Whites, aged 30-95 years who were part of the calibration study of the large Adventist Health Study-2 (AHS-2). At the calibration clinics, calcaneal BUA was measured and blood drawn for serum 25(OH)D assessment. In multivariable analyses, BUA was negatively associated with age (beta-coefficient = -0.38; p < 0.0001) and positively associated with body mass index (BMI) (p (trend) < 0.0001) and positively, but non-significantly, associated with serum 25(OH)D levels. Also, as expected, females had lower BUA (beta-coefficient = -5.19; p < 0.05) and Blacks had higher BUA (beta-coefficient = 4.26; p < 0.05). Gender and race modified the relationship of serum 25(OH)D on BUA with a positive association in males (p (trend) <= 0.05), but no significant association in females after also controlling for menopausal status and hormone therapy. After also controlling for serum 25(OH)D levels, Black males had higher BUA than White men, but such differences were not found among the females. When stratifying on race, a positive association between serum 25(OH)D levels and BUA (p (trend) <= 0.05) was found in Blacks, but not among Whites. Further studies are needed to understand how racial/ethnic differences in serum 25(OH)D levels influence bone health. PMID- 28639253 TI - Ultrasonography in trauma: a nation-wide cross-sectional investigation. AB - BACKGROUND: The Focused Assessment with Sonography in Trauma (FAST) protocol is considered beneficial in emergent evaluation of trauma patients with blunt or penetrating injury and has become integrated into the Advanced Trauma Life Support (ATLS) protocol. No guidelines exist as to the use of ultrasonography in trauma in Denmark. We aimed to determine the current use of ultrasonography for assessing trauma patients in Denmark. METHODS: We conducted a nation-wide cross sectional investigation of ultrasonography usage in trauma care. The first phase consisted of an Internet-based investigation of existing guidelines, and the second phase was a series of structured interviews of orthopedic surgeons, anesthesiologists, and radiologists on call in all hospitals receiving traumatized patients in Denmark. RESULTS: Guidelines were obtained from all 22 hospitals receiving traumatized patients in Denmark. Twenty-one (95.5%) of the guidelines included and recommended FAST as part of trauma assessment. The recommended person to perform the examination was the radiologist in n = 11 (50.0%), the surgeon in n = 6 (27.3%), the anesthesiologist in n = 1 (4.5%), and unspecified in n = 3 (13.6%) facilities. FAST indications varied between circulatory instability n = 8 (36.4%), team leader's discretion n = 6 (27.3%), abdominal trauma n = 3 (13.6%), and not specified n = 6 (27.3%). Telephone interviews revealed that exams were always n = 8 (36.4%) or often n = 4 (18.2%) registered in the patients' charts. The remaining n = 10 (45.5%) facilities either never registered n = 2 (9.1%), it was not possible to register n = 1 (4.5%), or unknown by the trauma leaders n = 7 (31.8%). Images were often stored in n = 1 (4.5%), never stored in n = 10 (45.5%), not possible to store in n = 2 (9.1%), and unknown in n = 9 (40.9%) facilities. CONCLUSION: Ultrasonography was used in a non-uniform fashion by multiple specialties in Danish trauma facilities. Very few images from FAST examinations were stored and documentation was scanty. National guidelines on application and documentation of ultrasonography in trauma are called for. PMID- 28639255 TI - Necessity and feasibility of improving mental health services in China: A systematic qualitative review. AB - It has been nearly 40 years since the reform and opening up of Mainland China. The mental health services system has developed rapidly as a part of the profound socioeconomic changes that ensued. However, its development has not been as substantial as other areas of medical care. For the current qualitative systematic review, we searched databases, including China Biology Medicine disc, Weipu, China National Knowledge Infrastructure, Wanfang digital periodical full text data, China's important newspaper full text database, China Statistical Yearbook database, etc. The content of primary research, literature, and policy papers about the evolution and development of Chinese mental health services was systemically reviewed and analysed by using thematic analysis. Two main themes relative to the necessity and feasibility of reforming the current mental health services system emerged. We discuss 5 corresponding subthemes under the umbrella of the necessity of improving the current treatment, rehabilitation, prevention, and service systems and 7 requirements for the feasibility of reforming the current system. We conclude that as the development of the Chinese economy and the spirit of humanistic care continue, the improvement and reformation of the mental health services system are both necessary and feasible. PMID- 28639254 TI - Use of a digital phantom developed by QIBA for harmonizing SUVs obtained from the state-of-the-art SPECT/CT systems: a multicenter study. AB - BACKGROUND: Although quantitative analysis using standardized uptake value (SUV) becomes realistic in clinical single-photon emission computed tomography/computed tomography (SPECT/CT) imaging, reconstruction parameter settings can deliver different quantitative results among different SPECT/CT systems. This study aims to propose a use of the digital reference object (DRO), which is a National Electrical Manufacturers Association (NEMA) phantom-like object developed by the Quantitative Imaging Biomarker Alliance (QIBA) fluorodeoxyglucose-positron emission tomography technical committee, for the purpose of harmonizing SUVs in Tc-99m SPECT/CT imaging. METHODS: The NEMA body phantom with determined Tc-99m concentration was scanned with the four state-of-the-art SPECT/CT systems. SPECT data were reconstructed using different numbers of the product of subset and iteration numbers (SI) and the width of 3D Gaussian filter (3DGF). The mean (SUVmean), maximal (SUVmax), and peak (SUVpeak) SUVs for six hot spheres (10, 13, 17, 22, 28, and 37 mm) were measured after converting SPECT count into SUV using Becquerel calibration factor. DRO smoothed by 3DGF with a FWHM of 17 mm (DRO17 mm) was generated, and the corresponding SUVs were measured. The reconstruction condition to yield the lowest root mean square error (RMSE) of SUVmeans for all the spheres between DRO17 mm and actual phantom images was determined as the harmonized condition for each SPECT/CT scanner. Then, inter-scanner variability in all quantitative metrics was measured before (i.e., according to the manufacturers' recommendation or the policies of their own departments) and after harmonization. RESULTS: RMSE was lowest in the following reconstruction conditions: SI of 100 and 3DGF of 13 mm for Brightview XCT, SI of 160 and 3DGF of 3 pixels for Discovery NM/CT, SI of 60 and 3DGF of 2 pixels for Infinia, and SI of 140 and 3DGF of 15 mm for Symbia. In pre-harmonized conditions, coefficient of variations (COVs) among the SPECT/CT systems were greater than 10% for all quantitative metrics in three of the spheres, SUVmax and SUVmean, in one of the spheres. In contrast, all metrics except SUVmax in the 17-mm sphere yielded less than 10% of COVs after harmonization. CONCLUSIONS: Our proposed method clearly reduced inter-scanner variability in SUVs. A digital phantom developed by QIBA would be useful for harmonizing SUVs in multicenter trials using SPECT/CT. PMID- 28639256 TI - Response and survival benefit with chemoimmunotherapy in Epstein-Barr virus positive diffuse large B-cell lymphoma. AB - Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a haematologic malignancy with poor prognosis when treated with chemotherapy. We evaluated response and survival benefits of chemoimmunotherapy in EBV-positive DLBCL patients. A total of 117 DLBCL patients were included in our retrospective analysis; 33 were EBV-positive (17 treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] and 16 with CHOP), and 84 were EBV-negative (all treated with R-CHOP). The outcomes of interest were complete response (CR) and overall survival (OS) in EBV-positive DLBCL patients (R-CHOP versus CHOP) and in DLBCL patients treated with R-CHOP (EBV-positive vs EBV negative). There were no differences in the clinical characteristics between EBV positive and EBV-negative DLBCL patients. Among EBV-positive DLBCL patients, R CHOP was associated with higher odds of CR (OR 3.14, 95% CI 0.75-13.2; P = .10) and better OS (hazard ratio 0.30, 95% confidence interval [CI] 0.09-0.94; P = .04). There were no differences in CR rate (OR 0.52, 95% CI 0.18-1.56; P = .25) or OS (hazard ratio 0.93, 95% CI 0.32-2.67; P = .89) between EBV-positive and EBV negative DLBCL patients treated with R-CHOP. Based on our study, the addition of rituximab to CHOP is associated with improved response and survival in EBV positive DLBCL patients. Epstein-Barr virus status does not seem to affect response or survival in DLBCL patients treated with R-CHOP. PMID- 28639257 TI - Large-scale genome-wide screening of circulating microRNAs in clear cell renal cell carcinoma reveals specific signatures in late-stage disease. AB - Circulating miRNAs have shown great promises as noninvasive diagnostic and predictive biomarkers in several solid tumors. While the miRNA profiles of renal tumors have been extensively explored, knowledge of their circulating counterparts is limited. Our study aimed to provide a large-scale genome-wide profiling of plasma circulating miRNA in clear-cell renal cell carcinoma (ccRCC). Plasma samples from 94 ccRCC cases and 100 controls were screened for 754 circulating micro-RNAs (miRNA) by TaqMan arrays. Analyses including known risk factors for renal cancer-namely, age, sex, hypertension, obesity, diabetes, tobacco smoking and alcohol consumption-highlighted that circulating miRNA profiles were tightly correlated with the stage of the disease. Advanced tumors, characterized as stage III and IV, were associated with specific miRNA signatures that significantly differ from both controls and earlier stage ccRCC cases. Molecular pathway enrichment analyses of their gene targets showed high similarities with alterations observed in renal tumors. Plasma circulating levels of miR-150 were significantly associated with RCC-specific survival and could marginally improve the predictive accuracy of clinical parameters in our series, including age at diagnosis, sex and conventional staging. In summary, our results suggest that circulating miRNAs may provide insights into renal cell carcinoma progression. PMID- 28639258 TI - Tandem In Situ Monitoring for Quantitative Assessment of Mechanochemical Reactions Involving Structurally Unknown Phases. AB - We report herein quantitative in situ monitoring by simultaneous PXRD and Raman spectroscopy of the mechanochemical reaction between benzoic acid and nicotinamide, affording a rich polymorphic system with four new cocrystal polymorphs, multiple phase transformations, and a variety of reaction pathways. After observing polymorphs by in situ monitoring, we were able to isolate and characterize three of the four polymorphs, most of which are not accessible from solution. Relative stabilities among the isolated polymorphs at ambient conditions were established by slurry experiments. Using two complementary methods for in situ monitoring enabled quantitative assessment and kinetic analysis of each studied mechanochemical reaction, even when involving unknown crystal structures, and short-lived intermediates. In situ Raman monitoring was introduced here also as a standalone laboratory technique for quantitative assessment of mechanochemical reactions and understanding of mechanochemical reactivity. Our results provide an important step toward a complete and high throughput quantitative approach to mechanochemical reaction kinetics and mechanisms, necessary for the development of the mechanistic framework of milling reactions. PMID- 28639259 TI - The cost-effectiveness of three interventions for providing preventive services to low-income children. AB - OBJECTIVE: We evaluated the impact of loan repayment programmes, revising Medicaid fee-for-service rates, and changing dental hygienist supervision requirements on access to preventive dental care for children in Georgia. METHODS: We estimated cost savings from the three interventions of preventive care for young children after netting out the intervention cost. We used a regression model to evaluate the impact of changing the Medicaid reimbursement rates. The impact of supervision was evaluated by comparing general and direct supervision in school-based dental sealant programmes. RESULTS: Federal loan repayments to dentists and school-based sealant programmes (SBSPs) had lower intervention costs (with higher potential cost savings) than raising the Medicaid reimbursement rate. General supervision had costs 56% lower than direct supervision of dental hygienists for implementing a SBSP. Raising the Medicaid reimbursement rate by 10 percentage points would improve utilization by <1% and cost over $38 million. Given one parameter set, SBSPs could serve over 27 000 children with an intervention cost between $500 000 and $1.3 million with a potential cost saving of $1.1 million. Loan repayment could serve almost 13 000 children for a cost of $400 000 and a potential cost saving of $176 000. CONCLUSIONS: The three interventions all improved met need for preventive dental care. Raising the reimbursement rate alone would marginally affect utilization of Medicaid services but would not substantially increase acceptance of Medicaid by providers. Both loan repayment programmes and amending supervision requirements are potentially cost-saving interventions. Loan repayment programmes provide complete care to targeted areas, while amending supervision requirements of dental hygienists could provide preventive care across the state. PMID- 28639260 TI - Improving thermostability of (R)-selective amine transaminase from Aspergillus terreus through introduction of disulfide bonds. AB - To improve the thermostability of (R)-selective amine transaminase from Aspergillus terreus (AT-ATA), we used computer software Disulfide by Design and Modelling of Disulfide Bonds in Proteins to identify mutation sites where the disulfide bonds were most likely to form. We obtained three stabilized mutants (N25C-A28C, R131C-D134C, M150C-M280C) from seven candidates by site-directed mutagenesis. Compared to the wild type, the best two mutants N25C-A28C and M150C M280C showed improved thermal stability with a 3.1- and 3.6-fold increase in half life (t1/2 ) at 40 degrees C and a 4.6 and 5.1 degrees C increase in T5010 . In addition, the combination of mutant R131C-D134C and M150C-M280C displayed the largest shift in thermostability with a 4.6-fold increase in t1/2 at 40 degrees C and a 5.5 degrees C increase in T5010 . Molecular dynamics simulation indicated that mutations of N25C-A28C and M150C-M280C lowered the overall root mean square deviation for the overall residues at elevated temperature and consequently increased the protein rigidity. The stabilized mutation of R131C D134C was in the region of high mobility and on the protein surface, and the disulfide bond constraints the flexibility of loop 121-136. PMID- 28639261 TI - The effects of ethanol on diverse components of choice in the rat: reward discrimination, preference and relative valuation. AB - Alcohol consumption impairs judgment and choice. How alcohol alters these crucial processes is primarily unknown. Choice can be fractionated into different components including reward discrimination, preference and relative valuation that can function together or in isolation depending upon diverse factors including choice context. We examined the diverse components and contextual effects by analyzing the effects of alcohol drinking on choice behavior in a task with a reduced level of temporal and spatial constraints. Rats were trained to drink 10% ethanol during 6 weeks of behavior testing using a combined sucrose fade and two-bottle free-choice procedure. Two different sucrose pellet outcomes (e.g., constant vs. variable) were presented each week to examine the impact of voluntary drinking on reward-based decision-making. Behavioral contexts of single option, free choice and extinction were examined for each outcome set. Comparisons were made between alcohol and control groups and within the alcohol group over time to inspect choice profiles. Between-group results showed alcohol drinking animals expressed altered place preference and modified sucrose reward approach latencies. The within-group profile showed that alcohol drinking animals can express adequate reward discrimination, preference and incentive contrast during free choice. All of these components were significantly reduced during the context of extinction. Control animals were also impacted by extinction but not as severely. The findings point to a need for a greater focus on the context and the diverse components of choice when examining external and internal factors influencing decision-making during alcohol or other substance of abuse exposure. PMID- 28639262 TI - Interprofessional collaboration to improve professional practice and healthcare outcomes. AB - BACKGROUND: Poor interprofessional collaboration (IPC) can adversely affect the delivery of health services and patient care. Interventions that address IPC problems have the potential to improve professional practice and healthcare outcomes. OBJECTIVES: To assess the impact of practice-based interventions designed to improve interprofessional collaboration (IPC) amongst health and social care professionals, compared to usual care or to an alternative intervention, on at least one of the following primary outcomes: patient health outcomes, clinical process or efficiency outcomes or secondary outcomes (collaborative behaviour). SEARCH METHODS: We searched CENTRAL (2015, issue 11), MEDLINE, CINAHL, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform to November 2015. We handsearched relevant interprofessional journals to November 2015, and reviewed the reference lists of the included studies. SELECTION CRITERIA: We included randomised trials of practice-based IPC interventions involving health and social care professionals compared to usual care or to an alternative intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of each potentially relevant study. We extracted data from the included studies and assessed the risk of bias of each study. We were unable to perform a meta-analysis of study outcomes, given the small number of included studies and their heterogeneity in clinical settings, interventions and outcomes. Consequently, we summarised the study data and presented the results in a narrative format to report study methods, outcomes, impact and certainty of the evidence. MAIN RESULTS: We included nine studies in total (6540 participants); six cluster-randomised trials and three individual randomised trials (1 study randomised clinicians, 1 randomised patients, and 1 randomised clinicians and patients). All studies were conducted in high-income countries (Australia, Belgium, Sweden, UK and USA) across primary, secondary, tertiary and community care settings and had a follow-up of up to 12 months. Eight studies compared an IPC intervention with usual care and evaluated the effects of different practice-based IPC interventions: externally facilitated interprofessional activities (e.g. team action planning; 4 studies), interprofessional rounds (2 studies), interprofessional meetings (1 study), and interprofessional checklists (1 study). One study compared one type of interprofessional meeting with another type of interprofessional meeting. We assessed four studies to be at high risk of attrition bias and an equal number of studies to be at high risk of detection bias.For studies comparing an IPC intervention with usual care, functional status in stroke patients may be slightly improved by externally facilitated interprofessional activities (1 study, 464 participants, low-certainty evidence). We are uncertain whether patient-assessed quality of care (1 study, 1185 participants), continuity of care (1 study, 464 participants) or collaborative working (4 studies, 1936 participants) are improved by externally facilitated interprofessional activities, as we graded the evidence as very low-certainty for these outcomes. Healthcare professionals' adherence to recommended practices may be slightly improved with externally facilitated interprofessional activities or interprofessional meetings (3 studies, 2576 participants, low certainty evidence). The use of healthcare resources may be slightly improved by externally facilitated interprofessional activities, interprofessional checklists and rounds (4 studies, 1679 participants, low-certainty evidence). None of the included studies reported on patient mortality, morbidity or complication rates.Compared to multidisciplinary audio conferencing, multidisciplinary video conferencing may reduce the average length of treatment and may reduce the number of multidisciplinary conferences needed per patient and the patient length of stay. There was little or no difference between these interventions in the number of communications between health professionals (1 study, 100 participants; low certainty evidence). AUTHORS' CONCLUSIONS: Given that the certainty of evidence from the included studies was judged to be low to very low, there is not sufficient evidence to draw clear conclusions on the effects of IPC interventions. Neverthess, due to the difficulties health professionals encounter when collaborating in clinical practice, it is encouraging that research on the number of interventions to improve IPC has increased since this review was last updated. While this field is developing, further rigorous, mixed-method studies are required. Future studies should focus on longer acclimatisation periods before evaluating newly implemented IPC interventions, and use longer follow-up to generate a more informed understanding of the effects of IPC on clinical practice. PMID- 28639264 TI - Magnetic resonance spin-spin relaxation time estimation in a rat model of fatty liver disease. AB - PURPOSE: To compare mono- and bi-exponential relaxation model equations to discriminate between normal and fatty liver disease. MATERIALS AND METHODS: Six rats on a choline deficient amino acid modified (CDAA) diet and six on normal chow were studied. Multiple spin echo images with increasing echo times (TEs) were collected at 9.4T. Pixel-wise T2 maps were generated using mono-exponential decay function to calculate T2M , and a bi-exponential to calculate, short T2 component (T2S ), long T2 component (T2L ), and fractions of these components (rhoS , rhoL ), respectively. Statistical F-tests and Akaike's information criterion (AIC) were used to assess the relative performance of the two models. RESULTS: F-test and AIC showed that in the CDAA group, T2 bi-exponential model described the signal of T2 weighted imaging of the liver better than the mono exponential model. Controls were best described by the mono-exponential model. Mean values for T2M , T2L , T2S , rhoS , rhoL were 31.2 +/- 0.7 ms, 72.8 +/- 3.3 ms, 8.2 +/- 0.6 ms,71.2 +/- 2.1%, 30.4 +/- 1.3%, respectively, in CDAA rats, compared with 18.8 +/- 0.5 ms, 32.3 +/- 0.7 ms, 9.2 +/- 1.8 ms, 79 +/- 2%, 21.0 +/- 1.1% in controls. CONCLUSION: In the fatty liver of CDAA rats we have shown that T2 weighted images fit the bi-exponential model better than mono-exponential decays thus providing a better description of the data. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:468-476. PMID- 28639263 TI - Subthalamic beta dynamics mirror Parkinsonian bradykinesia months after neurostimulator implantation. AB - BACKGROUND: Exaggerated oscillatory activity in the beta frequency band in the subthalamic nucleus has been suggested to be related to bradykinesia in Parkinson's disease (PD). However, studies seeking correlations between such activity in the local field potential and motor performance have been limited to the immediate postoperative period, which may be confounded by a stun effect that leads to the temporary alleviation of PD deficits. METHODS: Local field potentials were recorded simultaneously with motor performance in PD patients several months after neurostimulator implantation. This was enabled by the chronic implantation of a pulse generator with the capacity to record and transmit local field potentials from deep brain stimulation electrodes. Specifically, we investigated oscillatory beta power dynamics and objective measures of bradykinesia during an upper limb alternating pronation and supination task in 9 patients. RESULTS: Although beta power was suppressed during continuously repeated movements, this suppression progressively diminished over time in tandem with a progressive decrement in the frequency and amplitude of movements. The relationship between changes within local field potentials and movement parameters was significant across patients, and not present for theta/alpha frequencies (5-12 Hz). Change in movement frequency furthermore related to beta power dynamics within patients. CONCLUSIONS: Changes in beta power are linked to changes in movement performance and the sequence effect of bradykinesia months after neurostimulator implantation. These findings provide further evidence that beta power may serve as a biomarker for bradykinesia and provide a suitable substrate for feedback control in chronic adaptive deep brain stimulation. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28639265 TI - Cutaneous squamous cell carcinoma with multiple metastases in a patient with chronic gluteal pyoderma. PMID- 28639267 TI - Hepatobiliary and Pancreatic: Hepatogastric fistula. PMID- 28639266 TI - Bakuchiol Contributes to the Hepatotoxicity of Psoralea corylifolia in Rats. AB - Psoralea corylifolia L. (Fructus Psoraleae) is widely used in Asia, but there are concerns about hepatotoxicity caused by constituents such as psoralens and bakukiol. Bakuchiol (BAK) has antiinflammatory, antipyretic, antibacterial antiviral, anticancer, and estrogenic activity but appears to be hepatotoxic in in vitro tests. This study investigated the hepatotoxicity in vivo in rats. Using intragastrically administered bakuchiol at doses of 52.5 and 262.5 mg/kg for 6 weeks. Bodyweight, relative liver weight, biochemical indicators, histopathology, mRNA expression of CYP7A1, HMG-CoA reductase, BSEP, PPARalpha, SREBP-2, and MRP3 were measured. Many abnormalities were observed in the bakuchiol-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, and increased weight of liver. The mRNA expression of CYP7A1, HMG-CoA reductase, PPARalpha, and SREBP-2 decreased in bakuchiol-treated group, the expression of BSEP increased in bakuchiol-treated low dosage, and the expression of BSEP decreased in bakuchiol-treated high dosage. In conclusion, we provide evidence for the first time that bakuchiol can induce cholestatic hepatotoxicity, suggesting potential hepatotoxicity. The mechanism may be related to effects on liver lipid metabolism, but further investigation is necessary. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28639268 TI - Gastrointestinal: Strangulated transomental hernia. PMID- 28639269 TI - Hepatobiliary and Pancreatic: Giant hepatomegaly from hepatic hemagiomatosis. PMID- 28639270 TI - Gastrointestinal: Mycotic aneurysm: An unexpected cause of severe odynophagia. PMID- 28639271 TI - Gastrointestinal: Zollinger-Ellison Syndrome: A rare cause of chronic diarrhea and abdominal pain. PMID- 28639272 TI - Contemporary Issues in Women's Health. PMID- 28639273 TI - A single-center retrospective study of pregnancy outcomes after emergency cerclage for cervical insufficiency. AB - OBJECTIVE: To compare maternal and perinatal outcomes after emergency cerclage with those after elective cerclage. METHODS: In a retrospective review, data were assessed from women with a viable singleton pregnancy who underwent elective or emergency cerclage for cervical insufficiency at the Tongji Hospital, Wuhan, China, between January 2010 and July 2015. Subgroup analyses based on cervical length (CL; <=15, 15-25, and 25-30 mm) were also conducted among women undergoing emergency cerclage. RESULTS: In total, 68 women underwent elective cerclage and 53 underwent emergency cerclage. The suture-to-delivery interval was significantly longer in the elective group (19.17 +/- 5.86 weeks) than in the emergency group (11.29 +/- 7.27 weeks; P<0.001). There was no difference between the elective and emergency groups in mean pregnancy length at delivery, frequency of Apgar score below 7 at 5 minutes (live births only), or birth weight (live births only). An inverse trend in the degree of CL shortening with pregnancy outcomes was observed; women with a CL of 25-30 mm had the best outcomes. CONCLUSION: Pregnancy outcomes were similar after emergency and elective cerclage. There was an inverse trend in the degree of CL shortening with pregnancy outcomes in the emergency cerclage group, with better outcomes observed for women with longer CL. PMID- 28639274 TI - Functional traits explain ecosystem function through opposing mechanisms. AB - The ability to explain why multispecies assemblages produce greater biomass compared to monocultures, has been a central goal in the quest to understand biodiversity effects on ecosystem function. Species contributions to ecosystem function can be driven by two processes: niche complementarity and a selection effect that is influenced by fitness (competitive) differences, and both can be approximated with measures of species' traits. It has been hypothesised that fitness differences are associated with few, singular traits while complementarity requires multidimensional trait measures. Here, using experimental data from plant assemblages, I show that the selection effect was strongest when trait dissimilarity was low, while complementarity was greatest with high trait dissimilarity. Selection effects were best explained by a single trait, plant height. Complementarity was correlated with dissimilarity across multiple traits, representing above and below ground processes. By identifying the relevant traits linked to ecosystem function, we obtain the ability to predict combinations of species that will maximise ecosystem function. PMID- 28639276 TI - Construction of meaningful identities in the context of rheumatoid arthritis, motherhood and paid work: A meta-ethnography. AB - AIMS AND OBJECTIVES: To derive new conceptual understanding about how women with rheumatoid arthritis manage their illness, motherhood and paid work, based on a comprehensive overview of existing knowledge, gained from qualitative studies. BACKGROUND: Rheumatoid arthritis affects several social aspects of life; however, little is known about how women with rheumatoid arthritis simultaneously manage their illness, motherhood and paid work. DESIGN: Qualitative metasynthesis. METHODS: A qualitative metasynthesis informed by Noblit and Hare's meta ethnography was carried out, based on studies identified by a systematic search in nine databases. RESULTS: Six studies were included. Social interactions in the performance of three interdependent subidentities emerged as an overarching category, with three subcategories: subidentities associated with (1) paid work, (2) motherhood and (3) rheumatoid arthritis. Pressure in managing one of the subidentities could restrict the fulfilment of the others. The subidentities were interpreted as being flexible, situational, contextual and competing. The women strove to construct meaningful subidentities by taking into account feedback obtained in social interactions. CONCLUSIONS: The subidentities associated with paid work and motherhood are competing subidentities. Paid work is given the highest priority, followed by motherhood and illness is the least attractive subidentity. Because of the fluctuating nature of the illness, the women constantly reconstruct the three interdependent subidentities. RELEVANCE TO CLINICAL PRACTICE: When healthcare professionals meet a woman with rheumatoid arthritis, they should consider that she might not accept the subidentity as an ill person. Health professionals should not expect that women will prioritise their illness in their everyday life. This could be included in clinical conversation with the women. PMID- 28639275 TI - Statin regulated ERK5 stimulates tight junction formation and reduces permeability in human cardiac endothelial cells. AB - The MEKK3/MEK5/ERK5 signaling axis is required for cardiovascular development in vivo. We analyzed the physiological role of ERK5 in cardiac endothelial cells and the consequence of activation of this kinase by the statin class of HMG Co-A reductase inhibitor drugs. We utilized human cardiac microvascular endothelial cells (HCMECs) and altered ERK5 expression using siRNA mediated gene silencing or overexpression of constitutively active MEK5 and ERK5 to reveal a role for ERK5 in regulating endothelial tight junction formation and cell permeability. Statin treatment of HCMECs stimulated activation of ERK5 and translocation to the plasma membrane resulting in co-localization with the tight junction protein ZO-1 and a concomitant reduction in endothelial cell permeability. Statin mediated activation of ERK5 was a consequence of reduced isoprenoid synthesis following HMG Co-A reductase inhibition. Statin pretreatment could overcome the effect of doxorubicin in reducing endothelial tight junction formation and prevent increased permeability. Our data provide the first evidence for the role of ERK5 in regulating endothelial tight junction formation and endothelial cell permeability. Statin mediated ERK5 activation and the resulting decrease in cardiac endothelial cell permeability may contribute to the cardioprotective effects of statins in reducing doxorubicin-induced cardiotoxicity. PMID- 28639277 TI - Serum Derived Transfer Factor Stimulates the Innate Immune System to Improve Survival Traits in High Risk Pathogen Scenarios. AB - Preclinical Research Transfer Factors (TFs) are low molecular weight (<5,000 daltons) biological response mediators. In the present study, a serum derived TF improved the ability of the recipient animal to survive high-risk infectious challenges (salmonellosis and canine parvoviral enteritis (CPV)) by altering the host's cytokine response profile. Mice mortally challenged with 5,000 colony forming units of Salmonella experienced a group mortality of 73% while mice treated with a single 5 mg dose of the TF demonstrated a significant decrease in morbidity (7%, p <= 0.01). The splenic bacterial load in untreated mice was over 10,000 times higher than that in the TF treated mice. Twenty-four hours post administration, the treated murine population expressed a rapid temporal increase in serum IL-6 (26-fold) and INF-gamma (77-fold) concentrations. IL-6 can act as a critical signal regulating action against bacterial pathogens. A comparative double-blind study performed using dogs confirmed to be undergoing a canine parvovirus challenge showed that when conventional supportive therapy was supplemented with a single 5 mg TF dose there was a reduction (p <= 0.01) in group mortality (68% of the TF treated group survived versus 32% of the placebo group), an observation consistent with the observed increase in INF-gamma, a cytokine associated with promoting antiviral activity. Drug Dev Res 78 : 189-195, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28639278 TI - Gate-Tunable Resonant Raman Spectroscopy of Bilayer MoS2. AB - The gate-tunable phonon properties in bilayer MoS2 are shown to be dependent on excitation energy. Raman intensity, Raman shift, and linewidth are affected by resonant excitation, while a nonresonant laser does not influence the intensity significantly. The gate-dependent Raman shift of A1g mode (either blue-, red-, or no-shift) is a result of the combined effect of antibonding electron and resonant related decoupling effect. Although the decoupling effect cannot be directly measured due to the resonant background, it can be indirectly and qualitatively probed by observing A1g mode. This study on gate-tunable resonant Raman spectroscopy has clarified the influence of carrier doping on phonon properties and demonstrates a new degree of freedom in manipulating phonons in 2D material systems. PMID- 28639279 TI - Densification of Silica Spheres: A New Pathway to Nano-Dimensioned Zeolite-Based Catalysts. AB - Nanosized materials are expected to play a unique role in the development of future catalytic processes. Herein, pre-prepared and geometrically well-defined amorphous silica spheres are densified into silica-rich zeolites with nanosized dimensions. After the densification, the obtained nanosized zeolites exhibit the same spherical morphology like the starting precursor but characterized by a drastically reduced size, higher density, and high crystallinity. The phase transformation into crystalline zeolite material and the densification effect are achieved through a well-controlled steam-assisted treatment of the larger precursor particles so that the transformation process proceeds always towards the center of the spheres, just like a shrinking process. Furthermore, this procedure is applicable also to commercially available silica particles, as well as aluminum-containing systems (precursors) leading to acidic nano-catalysts with improved catalytic performance. PMID- 28639280 TI - Mutational profiles of Brenner tumors show distinctive features uncoupling urothelial carcinomas and ovarian carcinoma with transitional cell histology. AB - Brenner tumors (BT) are rare ovarian tumors encompassing benign, borderline, and malignant variants. While the histopathology of BTs and their clinical course is well described, little is known about the underlying genetic defects. We employed targeted next generation sequencing to analyze the mutational landscape in a cohort of 23 BT cases (17 benign, 2 borderline, and 4 malignant) and 3 ovarian carcinomas with transitional cell histology (TCC). Copy number variations (CNV) were validated by fluorescence in-situ hybridization (FISH) and quantitative PCR based copy number assays. Additionally, we analyzed the TERT promotor region by conventional Sanger sequencing. We identified 25 different point mutations in 23 of the analyzed genes in BTs and 10 mutations in 8 genes in TCCs. About 57% percent of mutations occurred in genes involved in cell cycle control, DNA repair, and epigenetic regulation processes. All TCC cases harbored TP53 mutations whereas all BTs were negative and none of the mutations observed in BTs were present in TCCs. CNV analysis revealed recurrent MDM2 amplifications in 3 out of 4 of the malignant BT cases with one case harboring a concomitant amplification of CCND1. No mutations were observed in the TERT promoter region in BTs and TCCs, which is mutated in about 50%-75% of urothelial carcinoma and in 16% of ovarian clear-cell carcinomas. In conclusion, our study highlights distinct genetic features of BTs, and detection of the triplet phenotype MDM2 amplification/TP53 wt/TERT wt may aid diagnosis of malignant BT in difficult cases. Moreover, selected genetic lesions may be clinically exploitable in a metastatic setting. PMID- 28639281 TI - Resolving relationships between several Neolithic and Mesolithic populations in Northern Eurasia using geometric morphometrics. AB - OBJECTIVES: Remains from several Eastern European and Siberian Mesolithic and Neolithic sites are analysed to clarify their biological relationships. We assume that groups' geographical distances correlate with genetic and, therefore, morphological distances between them. MATERIALS AND METHODS: Material includes complete male crania from several Mesolithic and Neolithic burial sites across Northern Eurasia and from several modern populations. Geometric morphometrics and multivariate statistical techniques are applied to explore morphological trends, group distances, and correlations with their geographical position, climate, and the time of origin. RESULTS: Despite an overlap in the morphology among the modern and archeological groups, some of them show significant morphological distances. Geographical parameters account for only a small proportion of cranial variation in the sample, with larger variance explained by geography and age together. Expectations of isolation by distance are met in some but not in all cases. Climate accounts for a large proportion of autocorrelation with geography. Nearest-neighbor joining trees demonstrate group relationships predicted by the regression on geography and on climate. DISCUSSION: The obtained results are discussed in application to relationships between particular groups. Unlike the Ukrainian Mesolithic, the Yuzhny Oleni Ostrov Mesolithic displays a high morphological affinity with several groups from Northern Eurasia of both European and Asian origin. A possibility of a common substrate for the Yuzhny Oleni Ostrov Mesolithic and Siberian Neolithic groups is reviewed. The Siberian Neolithic is shown to have morphological connection with both modern Siberian groups and the Native North Americans. PMID- 28639282 TI - Adipokines played a limited role in predicting temporary growth differences between very low birthweight infants with and without bronchopulmonary dysplasia. AB - AIMS: This study explored whether growth was poorer among very low birthweight (VLBW) infants with bronchopulmonary dysplasia (BPD) and assessed adipokine levels as predictors of early growth. METHODS: We studied 53 VLBW infants born in Tampere University Hospital up to 12 months of corrected age (CA). The median gestational age of the 21 infants with BPD and 32 infants without BPD was 29 weeks, and the median birthweights were 930 (635-1470) and 1185 (650-1470) grams. Growth parameters, macronutrients intake and plasma levels of adipokines were measured. RESULTS: Bronchopulmonary dysplasia infants were lighter than controls until 36 weeks of CA, with catch-up growth achieved by three months of CA. Adipsin levels were lower in BPD infants at 28 days of postnatal age. High leptin levels seemed protective for low weight for height at nine months of CA. The duration of ventilator therapy predicted low weight for height, length for age and body mass index and BPD predicted low length for age at 12 months of CA. CONCLUSIONS: Catch-up growth in VLBW infants with BPD was achieved by three months of CA, but adipokines played a limited role in predicting growth. Shortening ventilator therapy could help growth in VLBW infants. PMID- 28639283 TI - High-Field NMR Spectroscopy Reveals Aromaticity-Modulated Hydrogen Bonding in Heterocycles. AB - From DNA base pairs to drug-receptor binding, hydrogen (H-)bonding and aromaticity are common features of heterocycles. Herein, the interplay of these bonding aspects is explored. H-bond strength modulation due to enhancement or disruption of aromaticity of heterocycles is experimentally revealed by comparing homodimer H-bond energies of aromatic heterocycles with analogs that have the same H-bonding moieties but lack cyclic pi-conjugation. NMR studies of dimerization in C6 D6 find aromaticity-modulated H-bonding (AMHB) energy effects of approximately +/-30 %, depending on whether they enhance or weaken aromatic delocalization. The attendant ring current perturbations expected from such modulation are confirmed by chemical shift changes in both observed ring C-H and calculated nucleus-independent sites. In silico modeling confirms that AMHB effects outweigh those of hybridization or dipole-dipole interaction. PMID- 28639284 TI - Soft tissue angiofibroma: Clinicopathologic, immunohistochemical and molecular analysis of 14 cases. AB - Soft tissue angiofibroma is rare and has characteristic histomorphological and genetic features. For diagnostic purposes, there are no specific antibodies available. Fourteen lesions (6 females, 8 males; age range 7-67 years) of the lower extremities (12) and trunk (2) were investigated by immunohistochemistry, including for the first time NCOA2. NCOA2 was also tested in a control group of other spindle cell lesions. The known fusion-genes (AHRR-NCOA2 and GTF2I-NCOA2) were examined using RT-PCR in order to evaluate their diagnostic value. Cases in which no fusion gene was detected were additionally analysed by RNA sequencing. All cases tested showed nuclear expression of NCOA2. However, this was not specific since other spindle cell neoplasms also expressed this marker in a high percentage of cases. Other variably positive markers were EMA, SMA, desmin and CD34. STAT6 was negative in the cases tested. By RT-PCR for the most frequently observed fusions, an AHRR-NCOA2 fusion transcript was found in 9/14 cases. GTF2I NCOA2 was not detected in the remaining cases (n = 3). RNA sequencing revealed three additional positive cases; two harbored a AHRR-NCOA2 fusion and one case a novel GAB1-ABL1 fusion. Two cases failed molecular analysis due to poor RNA quality. In conclusion, the AHRR-NCOA2 fusion is a frequent finding in soft tissue angiofibroma, while GTF2I-NCOA2 seems to be a rare genetic event. For the first time, we report a GAB1-ABL1 fusion in a soft tissue angiofibroma of a child. Nuclear expression of NCOA2 is not discriminating when compared with other spindle cell neoplasms. PMID- 28639286 TI - Provision and perceived quality of mental health services for older care home residents in England: a national survey. AB - OBJECTIVE: This study examined the nature, extent and perceived quality of the support provided by community mental health teams for older people (CMHTsOP) to care home residents. METHODS: A postal survey was sent to all CMHTsOP in England. Information was collected about teams' staffing and their involvement in case finding, assessment, medication reviews, care planning and training as well as team managers' rating of the perceived quality of the service they provided for care home residents. Data were analysed using chi-squared tests of association and ordinal regression. RESULTS: Responses were received from 225 (54%) CMHTsOP. Only 18 per cent of these teams contained staff with allocated time for care home work. Services for care home residents varied considerably between teams. Two fifths of teams provided formal training to care home staff. Team managers were more likely to perceive the quality of their service to care homes as good if they had a systematic process in place for reviewing antipsychotic drugs or routine mental health reviews, including contact with a GP. CONCLUSION: The findings suggested that more evidence is needed on the best approach for supporting care home residents with mental health needs. Areas to consider are the potential benefits of training to care home staff and regular mental health reviews, utilising links between GPs and CMHTsOP. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28639285 TI - Porphyrin modified trastuzumab improves efficacy of HER2 targeted photodynamic therapy of gastric cancer. AB - Gastric cancer (GC) is the 3rd deadliest cancer worldwide, due to limited treatment options and late diagnosis. Human epidermal growth factor receptor-2 (HER2) is overexpressed in ~20% of GC cases and anti-HER2 antibody trastuzumab in combination with conventional chemotherapy, is recognized as standard therapy for HER2-positive metastatic GC. This strategy improves GC patients' survival by 2-3 months, however its optimal results in breast cancer indicate that GC survival may be improved. A new photoimmunoconjugate was developed by conjugating a porphyrin with trastuzumab (Trast:Porph) for targeted photodynamic therapy in HER2-positive GC. Using mass spectrometry analysis, the lysine residues in the trastuzumab structure most prone for porphyrin conjugation were mapped. The in vitro data demonstrates that Trast:Porph specifically binds to HER2-positive cells, accumulates intracellularly, co-localizes with lysosomal marker LAMP1, and induces massive HER2-positive cell death upon cellular irradiation. The high selectivity and cytotoxicity of Trast:Porph based photoimmunotherapy is confirmed in vivo in comparison with trastuzumab alone, using nude mice xenografted with a HER2-positive GC cell line. In the setting of human disease, these data suggest that repetitive cycles of Trast:Porph photoimmunotherapy may be used as an improved treatment strategy in HER2-positive GC patients. PMID- 28639287 TI - Exploration of conformational changes in lactose permease upon sugar binding and proton transfer through coarse-grained simulations. AB - Escherichia coli lactose permease (LacY) actively transports lactose and other galactosides across cell membranes through lactose/H+ symport process. Lactose/H+ symport is a highly complex process that involves sugar translocation, H+ transfer, and large-scale protein conformational changes. The complete picture of lactose/H+ symport is largely unclear due to the complexity and multiscale nature of the process. In this work, we develop the force field for sugar molecules compatible with PACE, a hybrid and coarse-grained force field that couples the united-atom protein models with the coarse-grained MARTINI water/lipid. After validation, we implement the new force field to investigate the binding of a beta d-galactopyranosyl-1-thio- beta-d-galactopyranoside (TDG) molecule to a wild-type LacY. Results show that the local interactions between TDG and LacY at the binding pocket are consistent with the X-ray experiment. Transitions from inward facing to outward-facing conformations upon TDG binding and protonation of Glu269 have been achieved from ~5.5 us simulations. Both the opening of the periplasmic side and closure of the cytoplasmic side of LacY are consistent with double electron-electron resonance and thiol cross-linking experiments. Our analysis suggests that the conformational changes of LacY are a cumulative consequence of interdomain H-bonds breaking at the periplasmic side, interdomain salt-bridge formation at the cytoplasmic side, and the TDG orientational changes during the transition. PMID- 28639288 TI - The Economics and Politics of the American Health Care Act. PMID- 28639289 TI - Planar Polyolefin Nanostripes: Perhydrogenated Graphene. AB - Graphene hydrogenation gives an opportunity to introduce a band gap into the graphene electronic structure. Complete hydrogenation may lead to the graphane, a fully hydrogenated counterpart of graphene. However, pure graphane has not been successfully prepared to this day. Here, we show that hydrogenation of single walled carbon nanotubes by means of Birch reduction leads to graphene-based carbon nanostripes with uniform dimensions. Such a material exhibits interesting electrocatalytic and magnetic properties as well huge potential for hydrogen storage since the weight concentration of hydrogen is 8.78 wt.% corresponding to the composition of C1 H1.22 O0.05 and thus exceeding the theoretical concentration in pure graphane (7.74 wt.%). The obtained concentration of hydrogen is the highest value ever reported for any graphene-based material and significantly exceeds the ultimate goal of the U.S. Department of Energy for a hydrogen storage material of 7.5 wt.%. PMID- 28639290 TI - Comparison between anti-VEGF therapy and corticosteroid or laser therapy for macular oedema secondary to retinal vein occlusion: A meta-analysis. AB - WHAT IS KNOWN AND OBJECTIVE: Therapeutic effects of anti-VEGF agents, corticosteroids and laser therapy have been previously examined for treating macular oedema secondary to branch and central retinal vein occlusion (BRVO and CRVO). However, anti-VEGF efficacy has not been previously compared to corticosteroid or laser therapy efficacy. We performed a meta-analysis to compare these treatments. METHODS: Pertinent publications were identified through comprehensive literature searches. Therapeutic effects were estimated using best corrected visual acuity (BCVA), central retinal thickness (CRT) and intraocular pressure (IOP). The Review Manager (version 5.3.5) was used to perform searches. RESULTS AND DISCUSSION: Eleven randomized, controlled trials that included 1045 RVO patients were identified. For eyes with BRVO, anti-VEGF therapy improved BCVA significantly more than corticosteroid/laser therapy at 3 (P=.0002), 6 (P<.00001) and 12 months (P<.00001). For eyes with CRVO, this difference was only significant at 6 months (P=.002). The same was true when efficacy was examined using CRT at 3 and 6 months (BRVO: both P<.00001, CRVO 6 months: P=.02). Long term efficacy of anti-VEGF agents was limited in eyes with BRVO and CRVO. Improvements in BCVA were similar at 1 and 3 months (P=.74), but BCVA decreased between 3 and 6 months (P=.03). In contrast, BCVA progressively decreased 1 and 6 months following corticosteroid/laser therapy (both P<.00001). Lastly, eyes that had been treated with anti-VEGF agents had significantly lower IOP changes than eyes treated with corticosteroids/laser 3 and 6 months after initiating therapy (both P<.00001). WHAT IS NEW AND CONCLUSION: Anti-VEGF agents improve BCVA and reduce CRT more effectively and longer than corticosteroid/laser in eyes with RVO. Anti-VEGF agents also have a lower risk of elevating IOP. Additionally, anti VEGF agents are more effective for treating BRVO than CRVO. PMID- 28639292 TI - Answer to: "Biomarkers in allergic asthma: Which matrix should we use?" PMID- 28639293 TI - 'Although we're isolated, we're not really isolated': The value of information and communication technology for older people in rural Australia. AB - OBJECTIVE: Drawing from a larger study that identified the supports and services that facilitate wellness among older people from rural communities, this study examined the specific contribution made by information and communication technology (ICT). METHODS: Qualitative interviews were undertaken with 60 older adults from six Australian rural areas. A preliminary thematic analysis was conducted, followed by a higher-order inductive analysis. RESULTS: Information and communication technology use was discussed in terms of individual enrichment, and in terms of enabling connections between the individual and their social networks, community and wider service environments. CONCLUSION: Information and communication technologies may facilitate wellness for rural older people by compensating for geographical and social isolation. In the changing world of health and aged care service delivery, ICTs will be more important than ever for rural older people in building their capacity to access the services, socialisation and support that they need, regardless of location. PMID- 28639291 TI - Perfusion of isolated rat kidney with Mesenchymal Stromal Cells/Extracellular Vesicles prevents ischaemic injury. AB - Kidney donation after circulatory death (DCD) is a less than ideal option to meet organ shortages. Hypothermic machine perfusion (HMP) with Belzer solution (BS) improves the viability of DCD kidneys, although the graft clinical course remains critical. Mesenchymal stromal cells (MSC) promote tissue repair by releasing extracellular vesicles (EV). We evaluated whether delivering MSC-/MSC-derived EV during HMP protects rat DCD kidneys from ischaemic injury and investigated the underlying pathogenic mechanisms. Warm ischaemic isolated kidneys were cold perfused (4 hrs) with BS, BS supplemented with MSC or EV. Renal damage was evaluated by histology and renal gene expression by microarray analysis, RT-PCR. Malondialdehyde, lactate, LDH, glucose and pyruvate were measured in the effluent fluid. MSC-/EV-treated kidneys showed significantly less global ischaemic damage. In the MSC/EV groups, there was up-regulation of three genes encoding enzymes known to improve cell energy metabolism and three genes encoding proteins involved in ion membrane transport. In the effluent fluid, lactate, LDH, MDA and glucose were significantly lower and pyruvate higher in MSC/EV kidneys as compared with BS, suggesting the larger use of energy substrates by MSC/EV kidneys. The addition of MSC/EV to BS during HMP protects the kidney from ischaemic injury by preserving the enzymatic machinery essential for cell viability and protects the kidney from reperfusion damage. PMID- 28639294 TI - beta-Hydroxy-tetrahydroquinolines from Quinolines Using Chloroborane: Synthesis of the Peptidomimetic FISLE-412. AB - A new synthetic protocol provides a simple and direct method to generate functionalized beta-hydroxy-tetrahydroquinolines (THQs). Hydroboration of quinolines using chloroboranes followed by oxidation with NaBO3 ?H2 O led to the formation of functionalized beta-hydroxy THQs. High regio- and diastereoselectivities were observed in alpha and gamma substituted quinolines and the trans diastereomer of the beta-hydroxy-THQ was the major isostere. This new protocol was utilized to build the novel antibody-targeted lupus peptidomimetic, FISLE-412. PMID- 28639295 TI - Out-of-Plane Strain Induced in a Moire Superstructure of Monolayer MoS2 and MoSe2 on Au(111). AB - Making contact of transition metal dichalcogenides (TMDCs) with a metal surface is essential for fabricating and designing electronic devices and catalytic systems. It also generates strain in the TMDCs that plays significant role in both electronic and phonon structures. Therefore, detailed understanding of mechanism of the strain generation is important to fully comprehend the modulation effect for the electronic and phonon properties. Here, MoS2 and MoSe2 monolayers are grown on Au surface by chemical vapor deposition and it is demonstrated that the contact with a crystalline Au(111) surface gives rise to only out-of-plane strain in both MoS2 and MoSe2 layers, whereas no strain generation is observed on polycrystalline Au or SiO2 /Si surfaces. Scanning tunneling microscopy analysis provides information regarding consequent specific adsorption sites between lower S (Se) atoms in the S?Mo?S (Se?Mo?Se) structure and Au atoms via unique moire superstructure formation for MoS2 and MoSe2 layers on Au(111). This observation indicates that the specific adsorption sites give rise to out-of-plane strain in the TMDC layers. Furthermore, it also leads to effective modulation of the electronic structure of the MoS2 or MoSe2 layer. PMID- 28639296 TI - Pathways to professionalism? Quality improvement, care pathways, and the interplay of standardisation and clinical autonomy. AB - Care pathways are a prominent feature of efforts to improve healthcare quality, outcomes and accountability, but sociological studies of pathways often find professional resistance to standardisation. This qualitative study examined the adoption and adaptation of a novel pathway as part of a randomised controlled trial in an unusually complex, non-linear field - emergency general surgery - by teams of surgeons and physicians in six theoretically sampled sites in the UK. We find near-universal receptivity to the concept of a pathway as a means of improving peri-operative processes and outcomes, but concern about the impact on appropriate professional judgement. However, this concern translated not into resistance and implementation failure, but into a nuancing of the pathways-as realised in each site, and their use as a means of enhancing professional decision-making and inter-professional collaboration. We discuss our findings in the context of recent literature on the interplay between managerialism and professionalism in healthcare, and highlight practical and theoretical implications. PMID- 28639297 TI - Autophagy activation, not peroxisome proliferator-activated receptor gamma coactivator 1alpha, may mediate exercise-induced improvements in glucose handling during diet-induced obesity. AB - NEW FINDINGS: What is the central question of this study? What are the individual and combined effects of muscle-specific peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) overexpression and physical activity during high-fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle-specific PGC 1alpha overexpression provides no protection against lipid-overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC-1alpha content, protects against high-fat diet-induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise-induced protection from lipid overload. The prevalence of glucose intolerance is alarmingly high. Efforts to promote mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) to mitigate glucose intolerance have been controversial. However, physical activity remains a primary means to alleviate the condition. The aim of this study was to determine the combined effects of muscle-specific overexpression of PGC-1alpha and physical activity on glucose handling during diet-induced obesity. Wild-type (WT, ~20) and PGC-1alpha muscle transgenic (MCK-PGC-1alpha, ~20) mice were given a Western diet (WD) at 8 weeks age and allowed to consume food ab libitum throughout the study. At 12 weeks of age, all animals were divided into sedentary (SED) or voluntary wheel running (VWR) interventions. At 7, 11 and 15 weeks of age, animals underwent glucose tolerance tests (GTT) and graded exercise tests (GXT). At 16 weeks of age, tissues were collected. At 11 weeks, the MCK-PGC-1alpha animals had 50% greater glucose tolerance integrated area under the curve compared with WT. However, at 15 weeks, SED animals also had greater GTT integrated area under the curve compared with VWR, regardless of genotype; furthermore, SED animals demonstrated reduced exercise capacity compared with earlier time points, which was not seen in VWR animals. Voluntary distance run per day was correlated with GTT in VWR-WT, but not VWR-MCK-PGC-1alpha mice. Voluntary wheel running and genotype independently resulted in a greater LC3II/LC3I ratio, suggesting enhanced autophagosome formation, which was correlated with exercise-induced improvements in GTT. In conclusion, artificially increasing mitochondrial content does not protect from lipid-induced pathologies nor does it augment exercise adaptations. Physical activity ameliorates the effects of lipid overload-induced glucose intolerance, an effect that appears to be related to enhanced activation of autophagy. PMID- 28639298 TI - Prevalence, patterns and factors associated with psychotropic use in older adults with intellectual disabilities in Ireland. AB - BACKGROUND: People with intellectual disability (ID) are at increased risk of exposure to psychotropic drugs and psychotropic polypharmacy because of the higher prevalence of mental health conditions present and more controversially, the use of these agents to treat challenging behaviours. Despite the fact that many adults with ID are exposed to psychotropic polypharmacy, few studies to date have focused on the patterns of use of multiple psychotropics, or factors associated with psychotropic polypharmacy, particularly in the older population. This study aims to examine the prevalence, patterns and factors associated with psychotropic use in general and psychotropic polypharmacy in particular in a representative sample of ageing people with ID. METHODS: This was an observational cross-sectional study from Wave 1 of Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing; a nationally representative sample of 753 persons with ID aged between 41 and 90 years. Participants/proxy reported medicines (prescription and over the counter) taken on a regular basis; medication data were available for 736 participants (98%). Participants were divided into those with no psychotropic exposure, exposure to 1 psychotropic and psychotropic polypharmacy (2+ psychotropics). Patterns of psychotropic use were analysed. A multinomial logistic regression model identified factors associated with use of 1 psychotropic and psychotropic polypharmacy. RESULTS: Overall, 59.1% (436) of the sample was exposed to any psychotropic; of these, 66.2% reported psychotropic polypharmacy. Antipsychotics were the most frequently reported psychotropic class by 43% of the sample. Living in a residential institution and having a history of reporting a mental health condition or sleep problems were associated with psychotropic polypharmacy after adjusting for confounders, while those with epilepsy were less likely to experience exposure to polypharmacy, but age, gender had no significant effect. CONCLUSIONS: Psychotropic use and polypharmacy were commonplace for older adults with ID. Psychotropic use, particularly the use of psychotropic combinations, needs to be regularly reviewed for safety, efficacy and adverse effects, and rationale for use of multiple agents needs to be clear and documented. PMID- 28639299 TI - Understanding Suicide Across the Lifespan: A United States Perspective of Suicide Risk Factors, Assessment & Management. AB - Suicide is a troubling, preventable phenomenon. Prior to attempts, individuals often seek help, prompting practitioners to perform risk assessments that ideally use evidence-based risk management strategies. A literature review was performed using Harvard Countway Library of Medicine, Google Scholar, PubMed. Key words used were "Forensic Science," "Suicide Risk Management," "Pediatric Suicide Risk Factors," "Adult Suicide Risk Factors," "Geriatric Suicide Risk Factors," "Suicide Risk Assessment." Parameters limited articles to studies/reviews completed in the past twenty years in the United States. Results indicated predictors of suicide in juveniles were insomnia, burdensomeness, and recent conflicts with family or a romantic partner. Adults had greater risk if male, substance abusing, with marital/job loss. Elderly individuals with multiple medical comorbidities, hopelessness, and isolation were at higher risk. Everyone evaluated should be screened for access to firearms. Management of suicide risk involves providing the least restrictive form of treatment which maintains an individual's safety. PMID- 28639300 TI - Multiparametric MRI of the breast: A review. AB - : During their development, cancers acquire several functional capabilities, which are defined as the hallmarks of cancer. For a deeper understanding of the hallmarks of cancer, and, consequently, improved personalized patient care, diagnostic tests must be multilayered and complex to identify the relevant underlying processes of cancer development and progression. In this context, magnetic resonance imaging (MRI) has emerged as an exceptionally powerful, versatile, and precise imaging technique. MRI of the breast is an essential tool in breast imaging, with multiple indications. Dynamic contrast-enhanced MRI (CE MRI) is the most sensitive test for breast cancer detection, with a good specificity. CE-MRI provides mainly morphological, and, to some extent, functional information about tumor perfusion and vascularity. Recently, several functional imaging techniques in MRI, such as diffusion-weighted imaging and spectroscopy, have been assessed for breast imaging and this combined application is defined as multiparametric imaging. Furthermore, the application of higher field strengths (>=3T) has demonstrated improved sensitivity and specificity of breast cancer detection. Multiparametric imaging with different functional MRI parameters (mpMRI) visualizes and quantifies the functional processes of cancer development and progression at multiple levels, and provides specific information about the hallmarks of cancer. MpMRI of the breast improves diagnostic accuracy in breast cancer, obviates unnecessary breast biopsies, and enables an improved assessment and prediction of response to neoadjuvant therapy. This review will provide a comprehensive overview of the current possibilities and emerging techniques for mpMRI of the breast. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:301-315. PMID- 28639302 TI - Prospective validation of pathologic complete response models in rectal cancer: Transferability and reproducibility. AB - PURPOSE: Multiple models have been developed to predict pathologic complete response (pCR) in locally advanced rectal cancer patients. Unfortunately, validation of these models normally omit the implications of cohort differences on prediction model performance. In this work, we will perform a prospective validation of three pCR models, including information whether this validation will target transferability or reproducibility (cohort differences) of the given models. METHODS: We applied a novel methodology, the cohort differences model, to predict whether a patient belongs to the training or to the validation cohort. If the cohort differences model performs well, it would suggest a large difference in cohort characteristics meaning we would validate the transferability of the model rather than reproducibility. We tested our method in a prospective validation of three existing models for pCR prediction in 154 patients. RESULTS: Our results showed a large difference between training and validation cohort for one of the three tested models [Area under the Receiver Operating Curve (AUC) cohort differences model: 0.85], signaling the validation leans towards transferability. Two out of three models had a lower AUC for validation (0.66 and 0.58), one model showed a higher AUC in the validation cohort (0.70). DISCUSSION: We have successfully applied a new methodology in the validation of three prediction models, which allows us to indicate if a validation targeted transferability (large differences between training/validation cohort) or reproducibility (small cohort differences). PMID- 28639303 TI - An Addressable 2D Heterogeneous Nanoreactor to Study the Enzyme-Catalyzed Reaction at the Interface. AB - Membrane plays significant role in cellular enzymatic reactions. To better understand its function on membrane integral or bound enzymes, DNA origami and frame-guided assembly strategy are combined to construct a given-size, addressable enzyme-containing nanomembrane as a heterogeneous reactor to explore the enzymatic catalyst reaction on the membrane. The enzymes in the membrane are located precisely. This new kind of membrane can enrich hydrophobic substrate molecules in aqueous solution to the embedded enzymes. Otherwise, this nanomembrane shows the capability of substrate selectivity, which plays important role in the highly efficient and specific properties of enzymes in vivo. PMID- 28639304 TI - Mucinous Naevus: A case of suboptimal response to laser treatment. PMID- 28639301 TI - Improving the detection sensitivity of pH-weighted amide proton transfer MRI in acute stroke patients using extrapolated semisolid magnetization transfer reference signals. AB - PURPOSE: To quantify amide protein transfer (APT) effects in acidic ischemic lesions and assess the spatial-temporal relationship among diffusion, perfusion, and pH deficits in acute stroke patients. METHODS: Thirty acute stroke patients were scanned at 3 T. Quantitative APT (APT# ) effects in acidic ischemic lesions were measured using an extrapolated semisolid magnetization transfer reference signal technique and compared with commonly used MTRasym (3.5ppm) or APT-weighted parameters. RESULTS: The APT# images showed clear pH deficits in the ischemic lesion, whereas the MTRasym (3.5ppm) signals were slightly hypointense. The APT# contrast between acidic ischemic lesions and normal tissue in acute stroke patients was more than three times larger than MTRasym (3.5ppm) contrast (-1.45 +/- 0.40% for APT# versus -0.39 +/- 0.52% for MTRasym (3.5ppm), P < 4.6 * 10-4 ). Hypoperfused and acidic areas without an apparent diffusion coefficient abnormality were observed and assigned to an ischemic acidosis penumbra. Hypoperfused areas at normal pH were also observed and assigned to benign oligemia. Hyperintense APT signals were observed in a hemorrhage area in one case. CONCLUSIONS: The quantitative APT study using the extrapolated semisolid magnetization transfer reference signal approach enhances APT MRI sensitivity to pH compared with conventional APT-weighted MRI, allowing more reliable delineation of an ischemic acidosis in the penumbra. Magn Reson Med 78:871-880, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28639305 TI - Standard laboratory tests are recommended as supplements to the Braden scale for pressure ulcer risk. PMID- 28639306 TI - A randomized trial of a barrier lipid replacement strategy for the prevention of atopic dermatitis and allergic sensitization: the PEBBLES pilot study. PMID- 28639307 TI - Anti-D in a mother, hemizygous for the variant RHD*DNB gene, associated with hemolytic disease of the fetus and newborn. AB - BACKGROUND: Individuals with the partial D phenotype when exposed to D+ red blood cells (RBCs) carrying the epitopes they lack may develop anti-D specific for the missing epitopes. DNB is the most common partial D in Caucasians and the clinical significance for anti-D in these individuals is unknown. STUDY DESIGN AND METHODS: This article describes the serologic genotyping results and clinical manifestations in two group D+ babies of a mother presenting as group O, D+ with alloanti-D. RESULTS: The mother was hemizygous for RHD*DNB gene and sequencing confirmed a single-nucleotide change at c.1063G>A. One baby (group A, D+) displayed bilirubinemia at birth with a normal hemoglobin level. Anti-A and anti D were eluted from the RBCs. For the next ongoing pregnancy, the anti-D titer increased from 32 to 256. On delivery the baby typed group O and anti-D was eluted from the RBCs. This baby at birth exhibited anemia, reticulocytosis, and hyperbilirubinemia requiring intensive phototherapy treatment from Day 0 to Day 9 after birth and was discharged on Day 13. Intravenous immunoglobulin was also administered. Both babies were heterozygous for RHD and RHD*DNB. CONCLUSION: The anti-D produced by this woman with partial D DNB resulted in a case of hemolytic disease of the fetus and newborn (HDFN) requiring intensive treatment in the perinatal period. Anti-D formed by women with the partial D DNB phenotype has the potential to cause HDFN where the fetus is D+. Women carrying RHD*DNB should be offered appropriate prophylactic anti-D and be transfused with D- RBCs if not already alloimmunized. PMID- 28639308 TI - Discovery of wt RET and V804M RET Inhibitors: From Hit to Lead. AB - Oncogenic activation of RET kinase has been found in several neoplastic diseases, like medullary thyroid carcinoma, multiple endocrine neoplasia, papillary thyroid carcinoma, and non-small-cell lung cancer. Currently approved RET inhibitors were not originally designed to be RET inhibitors, and their potency against RET kinase has not been optimized. Hence, novel compounds able to inhibit both wild type RET (wt RET) and its mutants (e.g., V804M RET) are needed. Herein we present the development and the preliminary evaluation of a new sub-micromolar wt RET/V804M RET inhibitor, N-(2-fluoro-5-trifluoromethylphenyl)-N'-{4'-[(2'' benzamido)pyridin-4''-ylamino]phenyl}urea (69), endowed with a 4-anilinopyridine structure, starting from our previously identified 4-anilinopyrimidine hit compound. Profiling against a panel of kinases indicated 69 as a multi cKIT/wt RET/V804M RET inhibitor. PMID- 28639309 TI - Improved enzymatic performance of graphene-immobilized beta-glucosidase A in the presence of glucose-6-phosphate. AB - Optimization of cellulose enzymatic hydrolysis is crucial for cost-effective bioethanol production from lignocellulosic biomass. Enzyme immobilization in solid support allows enzyme recycling for reuse, lowering hydrolysis costs. Graphene is a nanomaterial isolated in 2004, which possesses exceptional properties for biomolecule immobilization. This study evaluates the potential for beta-glucosidase recycling by immobilization on graphene nanosheets. Data reported here demonstrated that graphene-immobilized beta-glucosidase can be recycled for at least eight cycles. Immobilization did not change the optimal temperature of catalysis and improved enzymatic stability upon storage. The role of glucose-6-phosphate on immobilized enzyme was also investigated, demonstrating that glucose-6-phosphate acts as a mixed-type activator and improves storage stability of immobilized enzyme. Complete cellulose hydrolysis using graphene immobilized beta-glucosidase in the presence of glucose-6-phosphate resulted in greatly improved hydrolysis rates, demonstrating the potential of this strategy for biomass hydrolysis. PMID- 28639310 TI - High-resolution 31 P echo-planar spectroscopic imaging in vivo at 7T. AB - PURPOSE: Conventional 31 P chemical shift imaging is time-consuming and yields only limited spatial resolution. The purpose of this study was to demonstrate feasibility of 31 P echo-planar spectroscopic imaging (EPSI) in vivo at 7T. METHODS: A 3D 31 P EPSI sequence with trapezoidal-shaped gradient pulses was implemented on a 7T MR scanner. To increase spectral width with reduced demand on gradient performance, a multishot approach was chosen. Acquisition weighting and 31 P-{1 H} double resonance for nuclear Overhauser signal enhancement were applied to increase sensitivity. RESULTS: 3D 31 P-{1 H} EPSI data from model solution and from human calf muscle and brain were obtained from voxels with effective sizes of 4.1 to 16.2 cm3 in measurement times of approximately 10 min. Individual spectra showed well-resolved resonances of endogenous 31 P-metabolites without artifacts. Volumetric high-resolution 31 P-metabolite maps in vivo showed metabolic heterogeneity of different tissues. CONCLUSION: In vivo 31 P EPSI at 7T yields high-quality metabolic images. The proposed multishot EPSI technique reduces the measurement times for acquisition of volumetric high-resolution maps of 31 P-metabolites or intracellular pH in human studies. Magn Reson Med 79:1251 1259, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28639311 TI - Increasing the pipeline and diversity of doctorally prepared nurses: Description and preliminary evaluation of a health disparities summer research program. AB - Despite calls to increase the number and diversity of doctorally prepared nurses, recent data indicate a severe shortage of PhD-prepared nurses, especially those of racial/ethnic minority backgrounds. This is concerning, given that evidence indicates that racial/ethnic minority PhD-prepared nurses are well-positioned to address health disparities, by attending to the needs/concerns of medically underrepresented groups. The purpose of this article is to describe and provide a preliminary evaluation of a summer research program for minority nursing students. Online surveys were administered to assess for student satisfaction, knowledge gains, attitudes toward research, and intentions to pursue a PhD among minority undergraduate nursing students (N = 6) participating in the 10-week program. Favorable trends were observed related to satisfaction, knowledge gains, and attitudes toward research. Fifty percent of the sample intended to pursue a PhD immediately after the program, compared to none before the program, and this result was maintained at 1-year post-program. The summer research program appears to be a promising strategy for increasing the number/diversity of PhD-prepared nurses. More research on the implementation of programs exposing minority nursing students to health disparities research is needed to strengthen evidence that similar programs can serve to increase the pipeline of diverse doctorally prepared nurses. PMID- 28639312 TI - Quantification of transmission risk in a male patient with a FLNB mosaic mutation causing Larsen syndrome: Implications for genetic counseling in postzygotic mosaicism cases. AB - We report the case of a male patient with Larsen syndrome found to be mosaic for a novel point mutation in FLNB in whom it was possible to provide evidence-based personalized counseling on transmission risk to future offspring. Using dideoxy sequencing, a low-level FLNB c.698A>G, encoding p.(Tyr233Cys) mutation was detected in buccal mucosa and fibroblast DNA. Mutation quantification was performed by deep next-generation sequencing (NGS) of DNA extracted from three somatic tissues (blood, fibroblasts, saliva) and a sperm sample. The mutation was detectable in all tissues tested, at levels ranging from 7% to 10% (mutation present in ~20% of diploid somatic cells and 7% of haploid sperm), demonstrating the involvement of both somatic and gonadal lineages in this patient. This report illustrates the clinical utility of performing targeted NGS analysis on sperm from males with a mosaic condition in order to provide personalized transmission risk and offer evidence-based counseling on reproductive safety. PMID- 28639313 TI - Change in attachment states of mind of women with binge-eating disorder. AB - Insecure and unresolved/disorganized attachment states of mind may impact affect regulation and interpersonal functioning that contribute to binge eating in women with binge-eating disorder (BED). Group psychological treatment may facilitate changes from insecure to secure and from unresolved-disorganized to non unresolved/disorganized attachment states of mind. This study used attachment theory to understand better the psychopathology of BED and co-morbid overweight status and to understand better the treatment response of patients with BED who receive group psychotherapy. Women with BED attended group psychodynamic interpersonal psychotherapy and completed the Adult Attachment Interview pretreatment and 6 months posttreatment. Matched samples of overweight women without BED and normal-weight women without BED completed the Adult Attachment Interview at 1 time point. Women with BED had significantly higher rates of preoccupied and unresolved/disorganized attachment states of mind compared to normal-weight women without BED and had similar rates of insecure and unresolved/disorganized attachment states of mind compared to overweight women without BED. Of the women with BED who had an insecure and/or unresolved/disorganized attachment states of mind at pretreatment, about 60% demonstrated clinically relevant changes to secure and to non unresolved/disorganized states of mind at 6 months post group psychodynamic interpersonal psychotherapy. Results indicated that some women with BED may benefit from interventions that help them regulate hyperactivated affect and create coherent narratives. Both women with BED and overweight women without BED may benefit from treatments that help them develop more adaptive affect regulation strategies related to unresolved/disorganized attachment states of mind. PMID- 28639314 TI - Determinants of red blood cell alloantibody detection duration: analysis of multiply alloimmunized patients supports peritransfusion factors. AB - BACKGROUND: Alloimmunization to red blood cells (RBCs) can cause serious transfusion reactions and complicate the search for compatible blood products. Alloantibodies can be detected for periods ranging from a few days to several years, yet the mechanisms controlling the duration of detectability remain unknown. We studied the detection durations in patients forming multiple antibodies to investigate whether the duration is more strongly determined by conditions present at the time of each transfusion (peritransfusion factors) or by more stable patient-specific factors likely to persist across transfusions. STUDY DESIGN AND METHODS: We studied retrospective medical records for alloimmunized patients at Massachusetts General Hospital and Brigham and Women's Hospital (1461 patients; 2187 antibodies). RESULTS: Antibodies discovered simultaneously in a patient shared similar fates: 76% persisted through the last screen or first became undetectable during the same screen. Simultaneously identified antibodies were also more persistent than sequentially identified antibodies (mean, 9.2 months vs. 4.9 months; p < 10-3 ). Within a patient, antibodies discovered simultaneously tended to be detected for similar periods of time (mean difference, 25 days), compared to the detection period for sequentially discovered antibodies (107 days, p < 10-3 ). CONCLUSIONS: The similarity in detection duration of simultaneously identified antibodies suggests that peritransfusion factors are important determinants of alloantibody detectability and duration. We also find some evidence that detection durations for sequentially identified antibodies are also more highly correlated than those for randomly selected antibodies across all patients, suggesting that patient specific factors also play a role in determining alloantibody persistence. PMID- 28639315 TI - MYC protein dysregulation is driven by BCR-PI3K signalling in diffuse large B cell lymphoma. AB - AIMS: MYC overexpression is a common feature of diffuse large B-cell lymphoma (DLBCL) and is associated with poor prognosis in patients with this neoplasm. We aimed to investigate the underlying mechanisms of MYC dysregulation, as they have not been fully determined. METHODS AND RESULTS: We immunohistochemically evaluated the correlation between B-cell receptor (BCR)-phosphoinositide 3-kinase (PI3K) pathway activity and MYC level in 108 cases of de-novo DLBCL, 25 of which featured loss of BCR, and investigated the effects of BCR-PI3K signalling on MYC level and phosphorylation in DLBCL cell lines. The expression levels of phospho SYK and phospho-AKT correlated with MYC expression in BCR-positive DLBCL. MYC expression was significantly lower in BCR-negative tumour tissues than in BCR positive tumour tissues. Upon BCR stimulation, the BCR-positive cell lines showed active BCR-PI3K signalling and decreased MYC phosphorylation at T58, leading to an increased overall level of MYC. Conversely, inhibition of BCR-PI3K signalling increased MYC phosphorylation and thus resulted in a decreased overall level of MYC. No effects were observed in the BCR-negative cell lines. CONCLUSIONS: Overexpression of MYC in DLBCL can be driven by the BCR-PI3K signalling pathway via dephosphorylation at T58, and BCR inhibitors may exert their functions by down-regulation of MYC. PMID- 28639317 TI - Factors Influencing CO2 and Energy Penalties of CO2 Mineralization Processes. AB - Carbon mineralization is one of the carbon capture utilization, and storage (CCUS) technologies that can be used to capture large quantities of CO2 and convert it into stable carbonate products that can be stored easily. Several CO2 mineralization processes have been proposed; however, there are no commercial scale projects because there are still significant issues that need to be improved before commercialization can take place. In this work, we evaluate the CO2 and energy penalties related to the most well-known types of mineralization processes developed to date, in which the mineralization reaction takes place directly under aqueous conditions, high pressures and temperatures, and compared these with newer T-P swing processes and ball-mill reactor processes, which are under development. The data used in the evaluation are taken from published literature. By comparing the three processes, we identify important variables that contribute to high CO2 and energy penalties so that future research can focus on optimization of these variables. It is observed that slurry concentration (heating) and particle size (grinding) are critical factors, with mineral calcination and operating pressure constituting other important factors. PMID- 28639316 TI - Synergism between Naproxen and Rutin in a Mouse Model of Visceral Pain. AB - Preclinical Research The aim of the present study was to evaluate the antinociceptive interaction between naproxen and the glycoside flavonoid, rutin in the acetic acid-induced writhing test in mice. Naproxen (5, 20, 50, and 100 mg/kg p.o.) or rutin (10, 25, 50, and 100mg/kg p.o.) were administered 60 min before the intraperitoneal administration with acetic acid. The dose-response curve of each individual compound and the experimental effective dose 50 (ED50 ) value were obtained to determinate different proportions of the combinations between the two compounds (naproxen-rutin 1:1, 3:1, and 3:1) in the writhing test. The results indicated a synergistic antinociceptive interaction between two drugs with different mechanism of action, naproxen and rutin in all the combinations. Drug Dev Res 78 : 184-188, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28639318 TI - Epitaxial Lift-Off of Centimeter-Scaled Spinel Ferrite Oxide Thin Films for Flexible Electronics. AB - Mechanical flexibility of electronic devices has attracted much attention from research due to the great demand in practical applications and rich commercial value. Integration of functional oxide materials in flexible polymer materials has proven an effective way to achieve flexibility of functional electronic devices. However, the chemical and mechanical incompatibilities at the interfaces of dissimilar materials make it still a big challenge to synthesize high-quality single-crystalline oxide thin film directly on flexible polymer substrates. This study reports an improved method that is employed to successfully transfer a centimeter-scaled single-crystalline LiFe5 O8 thin film on polyimide substrate. Structural characterizations show that the transferred films have essentially no difference in comparison with the as-grown films with respect to the microstructure. In particular, the transferred LiFe5 O8 films exhibit excellent magnetic properties under various mechanical bending statuses and show excellent fatigue properties during the bending cycle tests. These results demonstrate that the improved transfer method provides an effective way to compose single crystalline functional oxide thin films onto flexible substrates for applications in flexible and wearable electronics. PMID- 28639319 TI - Diet, physical activity and behavioural interventions for the treatment of overweight or obese children from the age of 6 to 11 years. AB - BACKGROUND: Child and adolescent overweight and obesity has increased globally, and can be associated with significant short- and long-term health consequences. This is an update of a Cochrane review published first in 2003, and updated previously in 2009. However, the update has now been split into six reviews addressing different childhood obesity treatments at different ages. OBJECTIVES: To assess the effects of diet, physical activity and behavioural interventions (behaviour-changing interventions) for the treatment of overweight or obese children aged 6 to 11 years. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS as well as trial registers ClinicalTrials.gov and ICTRP Search Portal. We checked references of studies and systematic reviews. We did not apply any language restrictions. The date of the last search was July 2016 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity, and behavioural interventions (behaviour-changing interventions) for treating overweight or obese children aged 6 to 11 years, with a minimum of six months' follow-up. We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or included participants with a secondary or syndromic cause of obesity. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references, extracted data, assessed risk of bias, and evaluated the quality of the evidence using the GRADE instrument. We contacted study authors for additional information. We carried out meta-analyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We included 70 RCTs with a total of 8461 participants randomised to either the intervention or control groups. The number of participants per trial ranged from 16 to 686. Fifty-five trials compared a behaviour-changing intervention with no treatment/usual care control and 15 evaluated the effectiveness of adding an additional component to a behaviour-changing intervention. Sixty-four trials were parallel RCTs, and four were cluster RCTs. Sixty-four trials were multicomponent, two were diet only and four were physical activity only interventions. Ten trials had more than two arms. The overall quality of the evidence was low or very low and 62 trials had a high risk of bias for at least one criterion. Total duration of trials ranged from six months to three years. The median age of participants was 10 years old and the median BMI z score was 2.2.Primary analyses demonstrated that behaviour-changing interventions compared to no treatment/usual care control at longest follow-up reduced BMI, BMI z score and weight. Mean difference (MD) in BMI was -0.53 kg/m2 (95% confidence interval (CI) -0.82 to -0.24); P < 0.00001; 24 trials; 2785 participants; low quality evidence. MD in BMI z score was -0.06 units (95% CI -0.10 to -0.02); P = 0.001; 37 trials; 4019 participants; low-quality evidence and MD in weight was 1.45 kg (95% CI -1.88 to -1.02); P < 0.00001; 17 trials; 1774 participants; low quality evidence.Thirty-one trials reported on serious adverse events, with 29 trials reporting zero occurrences RR 0.57 (95% CI 0.17 to 1.93); P = 0.37; 4/2105 participants in the behaviour-changing intervention groups compared with 7/1991 participants in the comparator groups). Few trials reported health-related quality of life or behaviour change outcomes, and none of the analyses demonstrated a substantial difference in these outcomes between intervention and control. In two trials reporting on minutes per day of TV viewing, a small reduction of 6.6 minutes per day (95% CI -12.88 to -0.31), P = 0.04; 2 trials; 55 participants) was found in favour of the intervention. No trials reported on all cause mortality, morbidity or socioeconomic effects, and few trials reported on participant views; none of which could be meta-analysed.As the meta-analyses revealed substantial heterogeneity, we conducted subgroup analyses to examine the impact of type of comparator, type of intervention, risk of attrition bias, setting, duration of post-intervention follow-up period, parental involvement and baseline BMI z score. No subgroup effects were shown for any of the subgroups on any of the outcomes. Some data indicated that a reduction in BMI immediately post intervention was no longer evident at follow-up at less than six months, which has to be investigated in further trials. AUTHORS' CONCLUSIONS: Multi-component behaviour-changing interventions that incorporate diet, physical activity and behaviour change may be beneficial in achieving small, short-term reductions in BMI, BMI z score and weight in children aged 6 to 11 years. The evidence suggests a very low occurrence of adverse events. The quality of the evidence was low or very low. The heterogeneity observed across all outcomes was not explained by subgrouping. Further research is required of behaviour-changing interventions in lower income countries and in children from different ethnic groups; also on the impact of behaviour-changing interventions on health-related quality of life and comorbidities. The sustainability of reduction in BMI/BMI z score and weight is a key consideration and there is a need for longer-term follow-up and further research on the most appropriate forms of post-intervention maintenance in order to ensure intervention benefits are sustained over the longer term. PMID- 28639320 TI - Diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. AB - BACKGROUND: Adolescent overweight and obesity has increased globally, and can be associated with short- and long-term health consequences. Modifying known dietary and behavioural risk factors through behaviour changing interventions (BCI) may help to reduce childhood overweight and obesity. This is an update of a review published in 2009. OBJECTIVES: To assess the effects of diet, physical activity and behavioural interventions for the treatment of overweight or obese adolescents aged 12 to 17 years. SEARCH METHODS: We performed a systematic literature search in: CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, and the trial registers ClinicalTrials.gov and ICTRP Search Portal. We checked references of identified studies and systematic reviews. There were no language restrictions. The date of the last search was July 2016 for all databases. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of diet, physical activity and behavioural interventions for treating overweight or obesity in adolescents aged 12 to 17 years. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using the GRADE instrument and extracted data following the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. MAIN RESULTS: We included 44 completed RCTs (4781 participants) and 50 ongoing studies. The number of participants in each trial varied (10 to 521) as did the length of follow-up (6 to 24 months). Participants ages ranged from 12 to 17.5 years in all trials that reported mean age at baseline. Most of the trials used a multidisciplinary intervention with a combination of diet, physical activity and behavioural components. The content and duration of the intervention, its delivery and the comparators varied across trials. The studies contributing most information to outcomes of weight and body mass index (BMI) were from studies at a low risk of bias, but studies with a high risk of bias provided data on adverse events and quality of life.The mean difference (MD) of the change in BMI at the longest follow-up period in favour of BCI was -1.18 kg/m2 (95% confidence interval (CI) 1.67 to -0.69); 2774 participants; 28 trials; low quality evidence. BCI lowered the change in BMI z score by -0.13 units (95% CI -0.21 to -0.05); 2399 participants; 20 trials; low quality evidence. BCI lowered body weight by -3.67 kg (95% CI -5.21 to -2.13); 1993 participants; 20 trials; moderate quality evidence. The effect on weight measures persisted in trials with 18 to 24 months' follow-up for both BMI (MD -1.49 kg/m2 (95% CI -2.56 to -0.41); 760 participants; 6 trials and BMI z score MD -0.34 (95% CI -0.66 to -0.02); 602 participants; 5 trials).There were subgroup differences showing larger effects for both BMI and BMI z score in studies comparing interventions with no intervention/wait list control or usual care, compared with those testing concomitant interventions delivered to both the intervention and control group. There were no subgroup differences between interventions with and without parental involvement or by intervention type or setting (health care, community, school) or mode of delivery (individual versus group).The rate of adverse events in intervention and control groups was unclear with only five trials reporting harms, and of these, details were provided in only one (low quality evidence). None of the included studies reported on all-cause mortality, morbidity or socioeconomic effects.BCIs at the longest follow-up moderately improved adolescent's health-related quality of life (standardised mean difference 0.44 ((95% CI 0.09 to 0.79); P = 0.01; 972 participants; 7 trials; 8 comparisons; low quality of evidence) but not self esteem.Trials were inconsistent in how they measured dietary intake, dietary behaviours, physical activity and behaviour. AUTHORS' CONCLUSIONS: We found low quality evidence that multidisciplinary interventions involving a combination of diet, physical activity and behavioural components reduce measures of BMI and moderate quality evidence that they reduce weight in overweight or obese adolescents, mainly when compared with no treatment or waiting list controls. Inconsistent results, risk of bias or indirectness of outcome measures used mean that the evidence should be interpreted with caution. We have identified a large number of ongoing trials (50) which we will include in future updates of this review. PMID- 28639321 TI - Association of the 5-HT2A receptor gene promoter polymorphism-1438G/A with anorexia nervosa and psychopathological traits in the Chinese Han population: A preliminary study. AB - OBJECTIVE: The aim of the study was to explore the possible role of the 5-HT2A 1438G/A polymorphism in the susceptibility to anorexia nervosa (AN) in the Chinese Han population. METHODS: The -1438G/A polymorphism of 249 female AN patients, 228 matched healthy controls, and 198 trios was genotyped using SNaP shot assay. Psychopathological traits of eating-disordered behaviors in AN subjects were examined using the Chinese version of the Eating Disorder Examination Questionnaire. RESULTS: Neither the case-control analysis nor the transmission disequilibrium test revealed significant associations between the 1438G/A polymorphism and AN (P > .05). However, AA homozygote patients with AN had lower weight and shape concern scores of the EDE-Q6.0 than those of GA heterozygotes (P < .05). DISCUSSION: Our findings suggested that female AN patients with 5-HT2A -1438AA genotype may be characterized by less severe eating disordered psychopathological traits in the Chinese Han population. PMID- 28639322 TI - TNF-alpha-Induced NOD2 and RIP2 Contribute to the Up-Regulation of Cytokines Induced by MDP in Monocytic THP-1 Cells. AB - Nucleotide-binding oligomerization domain containing 2 (NOD2)-induced signal transduction and cytokine production is regulated by a number of factors. However, the feedback effect of the pro-inflammatory TNF-alpha on NOD2-induced inflammation is not fully understood. In this study, we found unexpectedly that TNF-alpha up-regulated NOD2 ligand MDP-induced production of the CXC chemokines, including CXCL1, 2, and 8, and the pro-inflammatory cytokines, including IL 1beta, IL-6, and TNF-alpha, in a dose-dependent manner at both mRNA and protein levels in monocytic THP-1 cells. Though TNF-alpha induced the up-regulation of ubiquitin-editing enzyme A20, an important negative regulator for Toll-like receptor- and NOD2-induced inflammatory responses, the over-expression of A20 by gene transfer did not reversed MDP-induced production of cytokines, suggested that A20 did not regulate the functions of NOD2 in THP-1 cells. Meanwhile, we found that TNF-alpha up-regulated NOD2 and its down-stream adaptor protein RIP2 at both mRNA and protein levels. MDP induced the activation of ERK, JNK, p38 and NF-kappaB, and TNF-alpha pre-treatment augmented this activation. The results from pharmacological inhibition assay showed that cytokine production was dependent on MAPK signaling. In addition, we found that the pre-treatment of THP 1 cells with MDP down-regulated the mRNA levels of cytokine induced by MDP re treatment. MDP pre-treatment up-regulated NOD2, but down-regulated RIP2, and down regulated NOD2 signal transduction induced by MDP re-stimulation. Taking together, these results suggested that TNF-alpha is a positive regulator for NOD2 functions via up-regulation of NOD2 and its signal adaptor RIP2, and TNF-alpha induced A20 does not regulate MDP-induced inflammatory responses in THP-1 cells. J. Cell. Biochem. 119: 5072-5081, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28639323 TI - Molecular interactions of dioxins and DLCs with the xenosensors (PXR and CAR): An in silico risk assessment approach. AB - Dioxins and dioxin-like compounds (DLCs) are known to cause endocrine disruption in humans and animals. Being lipophilic xenobiotic chemicals, they can be easily absorbed into the biological system from the surrounding environments, thereby causing various health dysfunctions. In the present study, a total of 100 dioxins and DLCs were taken, and their binding pattern was assessed with the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in comparison with the corresponding known inhibitors and a well-studied endocrine disrupting xenobiotic, bisphenol A (BPA). The nuclear receptors CAR and PXR are known to play a significant role in handling potential toxins by coordinating cellular transport and metabolic functions of the same. Among different endocrine disrupting chemicals used in the present study, DLCs (PCDFs and PCBs) elicited better interactions in comparison with the parent dioxin (polychlorinated dibenzodioxins) compounds. On comparing D scores of all the compounds against both the receptors, PCDF 8-hydroxy-3,4-dichlorodibenzofuran (8-OH-DCDF) and PCB tetrachlorobenzyltoluene (TCBT) exhibited significant molecular interactions against PXR (-7.633 kcal mol-1 ) and CAR (-8.389 kcal mol-1 ), respectively. Predominant interactions were found to be H-bonding, pi-pi stacking, hydrophobic, polar, and van der Waals. By contrast, BPA and some natural ligands tested in this study showed lower binding affinities with these receptors than certain DLCs reported herein, ie, certain DLCs might be more toxic than the proven toxic agent, BPA. Such studies play a pivotal role in the risk assessment of exposure to dioxins and DLCs on human health. PMID- 28639324 TI - A Retina-Like Dual Band Organic Photosensor Array for Filter-Free Near-Infrared to-Memory Operations. AB - Human eyes use retina photoreceptor cells to absorb and distinguish photons from different wavelengths to construct an image. Mimicry of such a process and extension of its spectral response into the near-infrared (NIR) is indispensable for night surveillance, retinal prosthetics, and medical imaging applications. Currently, NIR organic photosensors demand optical filters to reduce visible interference, thus making filter-free and anti-visible NIR imaging a challenging task. To solve this limitation, a filter-free and conformal, retina-inspired NIR organic photosensor is presented. Featuring an integration of photosensing and floating-gate memory modules, the device possesses an acute color distinguishing capability. In general, the retina-like photosensor transduces NIR (850 nm) into nonvolatile memory and acts as a dynamic photoswitch under green light (550 nm). In doing this, a filter-free but color-distinguishing photosensor is demonstrated that selectively converts NIR optical signals into nonvolatile memory. PMID- 28639325 TI - Generalized Synthesis of Metal Oxide Nanosheets and Their Application as Li-Ion Battery Anodes. AB - Metal oxide nanosheets have attracted great attention in various fields, such as energy storage, catalysis, and sensors. Current synthesis methods of metal oxide nanosheets are laborious and not scalable. Herein, a facile and scalable method for the synthesis of metal oxide nanosheets is presented, which requires neither hydro-/solvothermal conditions nor postsynthesis template removal. The synthesis is versatile, as evidenced by the wide variety of metal oxide nanosheets derived. Nanosheet properties such as crystallinity, crystallite size, and carbon content can be controlled by tuning the synthesis conditions. The metal oxide nanosheets demonstrate promising performance as Li-ion battery anodes. PMID- 28639327 TI - Acute leukemic transformation of myelodysplastic syndrome: Is cytochemistry still relevant? PMID- 28639326 TI - Bone marrow hematons: An access point to the human hematopoietic niche. AB - To understand the complex interactions between hematopoietic stem cells and the bone marrow niche, a human experimental model is needed. Our hypothesis is that hematons are an appropriate ex vivo model of human bone marrow. We analyzed the hierarchical hematopoietic cell content and the tissue organization of single hematons from healthy donors. Most (>90%) hematons contained precursors of all cell lineages, myeloid progenitors, and LTC-ICs without preferential commitment. Approximately, half of the hematons could generate significant levels of lympho myeloid hematopoiesis after transplantation in an NSG mouse model, despite the low absolute numbers of transplanted CD34+ cells. Mesenchymal STRO-1+ and/or CD271+ cells formed a critical network that preserved hematon cohesion, and STRO 1+ cells colocalized with most hematopoietic CD34+ cells (68%). We observed an influence of age and gender. These structures represent a particularly attractive model for studying the homeostasis of the bone marrow niche and pathological changes that occur during diseases. PMID- 28639328 TI - Immunogenicity of protein aggregates of a monoclonal antibody generated by forced shaking stress with siliconized and nonsiliconized syringes in BALB/c mice. AB - OBJECTIVE: In this study, we aimed to investigate the immunogenicity of protein aggregates of monoclonal antibodies (mAbs), generated by forced shaking stress with siliconized and nonsiliconized syringes in a mouse model. METHODS: Samples were filled in siliconized and nonsiliconized syringes with shaking and headspace air. Characterization studies were performed using high-performance size exclusion chromatography, nanoparticle tracking analysis, flow cytometry, micro flow imaging and resonant mass measurement. The samples (10 or 100 MUg) were subcutaneously injected into BALB/c mice for 21 days, and the anti-drug antibody (ADA) concentrations were monitored. KEY FINDINGS: In samples shaken with siliconized syringes [SO (+)], large amounts of submicron and subvisible protein aggregates were formed by interactions with silicone oil droplets. The characteristics of protein aggregates differed between the mAb solution and shaken samples, which strongly indicates that silicone oil accelerates protein aggregation. When administered at low doses, the ADA concentration in all samples increased with repeated injections, and SO (+) induced the highest immunogenicity. However, when administered at high doses, ADA concentration decreased following prolonged repeated administration for tolerance. CONCLUSIONS: These results indicated that mAb protein aggregation induced immunogenicity in mice, and SO (+) induced higher immunogenicity than samples shaken with nonsiliconized syringe. PMID- 28639329 TI - Estimating abundance without recaptures of marked pallid sturgeon in the Mississippi River. AB - Abundance estimates are essential for assessing the viability of populations and the risks posed by alternative management actions. An effort to estimate abundance via a repeated mark-recapture experiment may fail to recapture marked individuals. We devised a method for obtaining lower bounds on abundance in the absence of recaptures for both panmictic and spatially structured populations. The method assumes few enough recaptures were expected to be missed by random chance. The upper Bayesian credible limit on expected recaptures allows probabilistic statements about the minimum number of individuals present in the population. We applied this method to data from a 12-year survey of pallid sturgeon (Scaphirhynchus albus) in the lower and middle Mississippi River (U.S.A.). None of the 241 individuals marked was recaptured in the survey. After accounting for survival and movement, our model-averaged estimate of the total abundance of pallid sturgeon >=3 years old in the study area had a 1%, 5%, or 25% chance of being <4,600, 7,000, or 15,000, respectively. When we assumed fish were distributed in proportion to survey catch per unit effort, the farthest downstream reach in the survey hosted at least 4.5-15 fish per river kilometer (rkm), whereas the remainder of the reaches in the lower and middle Mississippi River hosted at least 2.6-8.5 fish/rkm for all model variations examined. The lower Mississippi River had an average density of pallid sturgeon >=3 years old of at least 3.0-9.8 fish/rkm. The choice of Bayesian prior was the largest source of uncertainty we considered but did not alter the order of magnitude of lower bounds. Nil-recapture estimates of abundance are highly uncertain and require careful communication but can deliver insights from experiments that might otherwise be considered a failure. PMID- 28639330 TI - Listening for commissioning: A participatory study exploring young people's experiences, views and preferences of school-based sexual health and school nursing. AB - AIMS AND OBJECTIVES: To explore the experiences, views and preferences of young people aged 11-19 years regarding school-based sexual health and school nursing to inform commissioning and delivery for one local authority area in England during 2015. BACKGROUND: Promoting sexual health for young people remains a challenging, even controversial, but important public health issue. Concerns regarding accessibility, acceptability and efficacy in school-based sexual health and school nursing are evident in the literature. Additionally, a complex public health policy context now governs the funding, provision and delivery of sexual health and school nursing, which potentially presents further challenges. DESIGN: A qualitative, participatory design was used to explore sexual health and school nursing. Data were generated from 15 focus groups (n = 74), with young people aged 11-19 years, in educational-based settings in one local authority area in England. RESULTS: The resultant themes of visibility in relation to sexual health education and school nursing revealed both the complex tensions in designing and delivering acceptable and appropriate sexual health services for young people and the significance of participatory approaches. CONCLUSION: Our study shows the importance of participatory approaches in working with young people to clearly identify what they want and need in relation to sexual health. The findings also confirm the ways in which school-based sexual health remains challenging but requires a theoretical and conceptual shift. This we argue must be underpinned by participatory approaches. RELEVANCE TO CLINICAL PRACTICE: School nurses have always had a significant role to play in promoting positive sexual health for young people and they are exceptionally well placed to challenge the risk-based cultures that frequently dominate school-based sexual health. A shift of debates and practices towards the promotion of positive sexual health cultures though previously argued for now requires the active engagement and involvement of young people. PMID- 28639331 TI - Top-Down Integration of Molybdenum Disulfide Transistors with Wafer-Scale Uniformity and Layer Controllability. AB - The lack of stable and efficient techniques to synthesize high-quality large-area thin films is one of the major bottlenecks for the real-world application of the 2D transition metal dichalcogenides. In this work, the growth of molybdenum disulfide (MoS2 ) on sapphire substrates by sulfurizing the MoO3 film deposited by atomic layer deposition (ALD) is reported. The advantages of the ALD method can be well inherited, and the synthesized MoS2 films exhibit excellent layer controllability, wafer-scale uniformity, and homogeneity. MoS2 films with desired thickness can be obtained by varying MoO3 ALD cycles. The atomic force microscope and Raman measurements demonstrate that the ALD-based MoS2 has good uniformity. Clear Raman shift as a function of the film thickness is observed. Field-effect transistor devices are fabricated through a transfer-free and top-down process. High On/Off current ratio (~104 ) and medium-level electron mobilities (~0.76 cm2 V-1 s-1 for monolayer, and 5.9 cm2 V-1 s-1 for four-layer) are obtained. The work opens up an attractive approach to realize the application of wafer-scale 2D materials in integrated circuits and systems. PMID- 28639332 TI - The natural history of fetal diagnosed isolated ventricular septal defect. AB - OBJECTIVE: This study was undertaken to clarify the natural course of ventricular septal defect, and to find an index that would help in prenatal counseling. METHODS: Between January 2010 and December 2014, 18 188 fetuses underwent echocardiographic examinations. Of these, 228 isolated ventricular septal defect cases were retrospectively reviewed. RESULTS: In this retrospective study, the incidence of isolated ventricular septal defect was 1.25% (228/18 188). There were 146 patients who underwent echocardiography after delivery in order to confirm the natural course of patients with isolated ventricular septal defect. Of the 146 cases, 64 cases (43.84%) had the ventricular septal defect naturally closed in the fetal period. Of the 82 patients with ventricular septal defect at birth, 25 patients showed natural closure during follow-up. However, four patients (2.74%) required surgical treatment for ventricular septal defect. In case of perimembranous defects, natural closure is more frequent in the fetal period than in the postnatal period. CONCLUSION: Our results indicate that 60.96% (89/146) of isolated ventricular septal defects diagnosed during the fetal life are closed naturally. Perimembranous type defect, small defect (<2 mm) and maternal age less than 35 years are the good prognostic factors for the natural closure during fetal life. (c) 2017 John Wiley & Sons, Ltd. PMID- 28639333 TI - Amorphous Metallic NiFeP: A Conductive Bulk Material Achieving High Activity for Oxygen Evolution Reaction in Both Alkaline and Acidic Media. AB - The intrinsic catalytic activity at 10 mA cm-2 for oxygen evolution reaction (OER) is currently working out at overpotentials higher than 320 mV. A highly efficient electrocatalyst should possess both active sites and high conductivity; however, the loading of powder catalysts on electrodes may often suffer from the large resistance between catalysts and current collectors. This work reports a class of bulk amorphous NiFeP materials with metallic bonds from the viewpoint of electrode design. The materials reported here perfectly combine high macroscopic conductivity with surface active sites, and can be directly used as the electrodes with active sites toward high OER activity in both alkaline and acidic electrolytes. Specifically, a low overpotential of 219 mV is achieved at the geometric current density 10 mA cm-2 in an alkaline electrolyte, with the Tafel slope of 32 mV dec-1 and intrinsic overpotential of 280 mV. Meanwhile, an overpotential of 540 mV at 10 mA cm-2 is attained in an acidic electrolyte and stable for over 30 h, which is the best OER performance in both alkaline and acidic media. This work provides a different angle for the design of high performance OER electrocatalysts and facilitates the device applications of electrocatalysts. PMID- 28639334 TI - Uterine natural killer cells in patients with idiopathic recurrent miscarriage. AB - PROBLEM: Uterine natural killer (uNK) cells are major players during implantation and early pregnancy. The aim of our study was to analyze uNK cell concentration in the endometrium of idiopathic recurrent miscarriage (iRM) patients and fertile controls. METHOD OF STUDY: Out of n=130 couples with >=3 consecutive, clinical RM screened according to a standardized diagnostic protocol, n=58 patients with iRM were identified. Endometrial biopsies were investigated in patients and n=17 fertile women (controls) via immunohistochemistry. RESULTS: Compared to controls, the concentration of uNK cells was significantly higher in iRM patients (257+/ 212 vs. 148+/-73 uNK cells/mm2, P=.04). IRM patients showed a higher prevalence of >300 uNK cells/mm2 than controls (34.5% vs. 5.9%, P=.02). In 88% of controls and 62% of iRM patients, uNK cells were detected within the range of 40-300/mm2. CONCLUSION: Idiopathic recurrent miscarriage patients showed higher uNK cell levels than controls supporting the possible impact of uNK cells in the pathophysiology of miscarriage. Our cutoff levels might help to select RM patients which may benefit from immunomodulatory treatment. PMID- 28639335 TI - A systematic review on identifying risk factors associated with early sexual debut and coerced sex among adolescents and young people in communities. AB - AIMS AND OBJECTIVES: To review literature on identifying the risk factors associated with early sexual coerced debut with the aim to facilitate the healthcare workers' planning of relevant health services to improve intervention strategies for delaying of early coerced sexual debut or forced sexual debut (CSD/FSD) in the communities. BACKGROUND: Identifying the risk factors associated with coercion at first sex is crucial for developing appropriate sexual and reproductive health information and health promotion in response. However, current knowledge about the risk factors associated with coercion, sexual debut (SD) and delayed SD among young people is limited. Health information programmes are important during adolescence, when young people are developing their values and beliefs about sexual activity and sexual norms. However, little is known about those risk factors on initiation of early sexual debut to plan relevant interventions that can delay SD and prevent CSD/FSD in this population. DESIGN: A systematic review. METHODS: An extensive literature search using MEDLINE (PubMed), Nursing Journals (PubMed), Web of Science, PsychINFO and CINAHL. RESULTS: The search generated 39 published studies that met our inclusion and exclusion criteria. Thirty-two articles passed the quality appraisal and were selected. This review identified six domains of risk factors, categorised as: (1) the individual domain, (2) the family domain, (3) the partner/peer domain, (4) the school domain, (5) the community domain and (6) the cultural domain. These factors highlight the influences on sexual decision-making among adolescents and young people and the timing of their first sexual intercourse. CONCLUSION: It is important to use the outcome of this review's categorisation of identified risk factors to facilitate the healthcare workers and plan relevant sexual and reproductive health programmes more accessible to adolescents, especially young females and their parents. There is a need to evaluate the impact of these programmes that can delay SD and prevent CSD/FSD in this population. RELEVANCE TO CLINICAL PRACTICE: The results of this study could provide guidance on the planning of effective interventions for delaying of early CSD/FSD in the communities. PMID- 28639337 TI - Partially Acetylated or Benzoylated Arabinose Derivatives as Structurally Simple Organogelators: Effect of the Ester Protecting Group on Gel Properties. AB - Sugar-based low-molecular-weight gelators (LMWGs) have been used for various applications for a long time. Herein, structurally simple, ester-protected arabinosides are reported as low-molecular-weight organogelators (LMOGs) that are able to gel aromatic solvents, as well as petrol and diesel. Studies on the mechanical strength of the gels, through detailed rheological experiments, indicate that gels from the 1,2-dibenzoylated arabinose gelator possess better mechanical properties than those from the 1,2-diacetylated gelator. These results are interpreted in terms of the tendency of the former to form fibers with comparatively lower diameter than those of the latter, based on detailed field emission SEM and AFM studies. Investigations of the interactions responsible for the self-assembly of gelators through IR spectroscopy and wide-angle X-ray scattering reveal that the primary interactions responsible are hydrogen bonds between the hydroxyl groups and ester C=O, which is absent in the solid state of the gelators. In addition, pi interactions present in the 1,2-dibenzoylated derivative result in a more regular arrangement, which, in turn, leads to better mechanical properties of the gels compared with those of the 1,2-diacetylated gelator. PMID- 28639336 TI - Classification of pancreaticobiliary maljunction and clinical features in children. AB - BACKGROUND: In 2015, the Committee on Diagnostic Criteria of the Japanese Study Group on Pancreaticobiliary Maljunction (PBM) proposed a classification of PBM into four types: (A) stenotic type, (B) non-stenotic type, (C) dilated channel type, and (D) complex type. To validate this classification and clarify the clinical features of the four types of PBM, a retrospective multicenter study was conducted. METHODS: The study group of 317 children with PBM was divided into the four types of PBM. Clinical features, preoperative complications, operations, and postoperative pancreatic complications were evaluated. RESULTS: All patients underwent excision of the extrahepatic bile duct. In type A, the age was younger and there was a higher incidence of cystic dilatation. Non-dilatation of the common bile duct was frequently seen in type B. Abdominal pain with hyperamylasemia was frequently seen in types B and C. In particular, the incidence of protein plugs and biliary perforation was high in type C (56.1% and 14.3%, respectively). The overall incidence of acute pancreatitis was 7.3%. Pancreatitis after excisional surgery was rare in the children in this study. Two patients with type D (0.6%) developed chronic pancreatitis postoperatively. CONCLUSIONS: This proposed classification is simple and correlates well with clinical features. PMID- 28639338 TI - Registration strategies for multi-modal whole-body MRI mosaicing. AB - PURPOSE: To test and compare different registration approaches for performing whole-body diffusion-weighted (wbDWI) image station mosaicing, and its alignment to corresponding anatomical T1 whole-body image. METHODS: Four different registration strategies aiming at mosaicing of diffusion-weighted image stations, and their alignment to the corresponding whole-body anatomical image, were proposed and evaluated. These included two-step approaches, where diffusion weighted stations are first combined in a pairwise (Strategy 1) or groupwise (Strategy 2) manner and later non-rigidly aligned to the anatomical image; a direct pairwise mapping of DWI stations onto the anatomical image (Strategy 3); and simultaneous mosaicing of DWI and alignment to the anatomical image (Strategy 4). Additionally, different images driving the registration were investigated. Experiments were performed for 20 whole-body images of patients with bone metastases. RESULTS: Strategies 1 and 2 showed significant improvement in mosaicing accuracy with respect to the non-registered images (P < 0.006). Strategy 2 based on ADC images increased the alignment accuracy between DWI stations and the T1 whole-body image (P = 0.0009). CONCLUSIONS: A two-step registration strategy, relying on groupwise mosaicing of the ADC stations and subsequent registration to T1 , provided the best compromise between whole-body DWI image quality and multi-modal alignment. Magn Reson Med 79:1684-1695, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28639339 TI - Advancing the field of anti-HLA sensitization management prior to pediatric heart transplantation. PMID- 28639340 TI - Impact of frailty and residual subsyndromal delirium on 1-year functional recovery: A prospective cohort study. AB - AIM: To investigate the association between frailty and incomplete delirium recovery at discharge (residual subsyndromal delirium [RSSD]), and to examine the mediating role of RSSD in the relationship between frailty and functional recovery at 12 months post-delirium. METHODS: This was a prospective observational study of 234 individuals aged >=65 years admitted to a specialized delirium unit. A 20-item frailty index was derived using items from a comprehensive geriatric assessment. Individuals with frailty index >=0.25 were defined as being frail. Diagnosis of delirium was in accordance with the Confusion Assessment Method. RSSD was defined by the Delirium Rating Scale Revised-98 severity score of >=13. We measured functional status (modified Barthel Index) on admission and 12 months post-delirium. We carried out mediation analysis to elucidate the role of baseline frailty and RSSD on 12-month functional recovery. RESULTS: A total of 167 (71%) older adults were available for analysis of 12-month functional status. Frailty was an independent predictor for RSSD (OR 4.1, 95% CI 2.1-8.2, P < 0.001) and functional recovery at 12 months post-delirium (beta = -13.4, 95% CI -24.9 to -1.8, P = 0.02). RSSD significantly mediated the effect of baseline frailty status on functional recovery at 12 months (coefficient = -0.1, 95% CI -0.2 to -0.02, P = 0.02), with 45% of the total effect mediated by RSSD. CONCLUSIONS: Frailty as a risk factor for poor functional recovery in the year post-delirium might be attributable in part to its impact on incomplete delirium recovery at discharge (RSSD). Our findings support screening and interventions for frailty at admission, and extended rehabilitation for frail individuals with RSSD. Geriatr Gerontol Int 2017; 17: 2472-2478. PMID- 28639341 TI - Rigidity of the extracellular part of HER2: Evidence from engineering subdomain interfaces and shared-helix DARPin-DARPin fusions. AB - The second member of the human ErbB family of receptor tyrosine kinases, HER2/hErbB2, is regarded as an exceptional case: The four extracellular subdomains could so far only be found in one fixed overall conformation, designated "open" and resembling the ligand-bound form of the other ErbB receptors. It thus appears to be different from the extracellular domains of the other family members that show inter-subdomain flexibility and exist in a "tethered" form in the absence of ligand. For HER2, there was so far no direct evidence for such a tethered conformation on the cell surface. Nonetheless, alternative conformations of HER2 in vivo could so far not be excluded. We now demonstrate the rigidity of HER2 on the surface of tumor cells by employing two orthogonal approaches of protein engineering: To directly test the potential of the extracellular domain of HER2 to adopt a pseudo-tethered conformation on the cell surface, we first designed HER2 variants with a destabilized interface between extracellular subdomains I and III that would favor deviation from the "open" conformation. Secondly, we used differently shaped versions of a Designed Ankyrin Repeat Protein (DARPin) fusion, recognizing subdomain I of HER2, devised to work as probes for a putative pseudo-tethered extracellular domain of HER2. Combining our approaches, we exclude, on live cells and in vitro, that significant proportions of HER2 deviate from the "open" conformation. PMID- 28639342 TI - The human medial pterygoid muscle: Attachments and distribution of muscle spindles. AB - Published descriptions about the sites of origin of the human medial pterygoid muscle vary and there are few reports on the distribution and density of muscle spindles in this muscle. We aimed to: (1) determine the extent of anatomical variability in the origins and insertions of the superficial and deep heads of the human medial pterygoid muscle and (2) determine the extent of variation in the distribution of spindles in the two heads of the muscle. Thirty-nine human cadaver hemi-heads were dissected and the attachments of the medial pterygoid muscle examined. The whole muscle was removed, weighed, cut into segments and embedded in wax for light microscopy. Sections were stained with Weigert-Van Gieson stain and scanned into digital images. Spindles were manually counted. In seven specimens, the deep head of the muscle arose from the medial surface of the lateral pterygoid plate and the pterygoid fossa. In 28 specimens, the origin extended onto the lateral surface of the medial pterygoid plate. There were abundant muscle spindles in the middle of the muscle, slightly fewer 1 cm toward the insertion, significantly fewer 1 cm toward the origin, and few or no spindles near the origins of the superficial and deep heads or near their insertion. In conclusion, firstly, this study shows that in 72% of the specimens examined, the origin of the medial pterygoid is wider than conventionally described in anatomical textbooks. Secondly, the segmental distribution of muscle spindles is described for the first time. Clin. Anat. 30:1064-1071, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28639343 TI - First case of anaphylaxis after botulinum toxin type A injection. AB - Botulinum toxin type A (BTA) (also known as onabotulinum toxin A) injection is widely used in the field of cosmetic dermatology. Although a few adverse events related to intramuscular BTA injection have been reported, no life-threatening adverse reaction has been documented to date. We report a case of anaphylaxis induced by intramuscular BTA injection into the masseter muscles of a 35-year-old woman. She had previously received injections of the identical BTA product into the same muscles without incident. However, during the reported procedure, symptoms suggestive of angio-oedema and anaphylaxis developed about 5 min after BTA injection. Intramuscular epinephrine was used to manage the reaction. Following this, the patient was found to have an elevated total serum IgE level. We could not perform testing with BTA because of the risk of triggering another episode of anaphylaxis; however, intradermal tests using the identical sterile saline and patch test using the topical anaesthetic cream both showed negative results, thus we strongly suspect BTA as being the cause of anaphylaxis in this case. PMID- 28639344 TI - Intensive care nurses' experiences of caring for obese intensive care patients: A hermeneutic study. AB - AIMS AND OBJECTIVES: To obtain a deeper understanding of qualified intensive care nurses' experiences of caring for obese patients in intensive care. BACKGROUND: Admission of obese patients with complex healthcare needs to intensive care units is increasing. Caring for obese critically ill patients can be challenging and demanding for the intensive care nurse because of the patients' weight, critical situation and physical challenges. There is a gap in knowledge at present about qualified intensive care nurses' experiences of caring for obese patients in intensive care units. DESIGN: A qualitative hermeneutic approach. METHOD: The study took place in 2016 at intensive care units of two different hospitals. Semi structured individual interviews were conducted with 13 qualified intensive care nurses. The interviews were analysed according to a Gadamerian-inspired research method. RESULTS: Intensive care nurses perceived caring for obese intensive care patients as emotionally demanding owing to these patients' vulnerability, dissimilarity and physical challenges compared to normal weight patients. They experienced ambivalent feelings caring for these patients: while they endeavoured to provide good and equal care to all patients, they simultaneously held negative beliefs and attitudes towards obese patients. Furthermore, frustration arose among the intensive care nurses relating to the physically demanding care situations and an unwillingness to care for such patients among some colleagues. CONCLUSION: The qualified intensive care nurses' experiences of caring for obese patients revealed ambivalent feelings, attitudes and beliefs towards these patients, which must be considered in intensive care unit practice as well as in the education of these nurses. RELEVANCE TO CLINICAL PRACTICE: The results have implications for clinical practice with respect to increasing intensive care nurses' awareness of their attitudes and beliefs towards obese intensive care patients and to improve the education of these nurses. PMID- 28639345 TI - Acute flaccid myelitis in childhood: a retrospective cohort study. AB - BACKGROUND AND PURPOSE: Clusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (AFM). Outside these clusters, in countries where polio is not endemic, this poliomyelitic-like illness is rare in childhood and its natural history is not well defined. We describe presenting features, investigation findings and long-term outcome of a series of children with AFM. METHODS: This was a retrospective cohort study. RESULTS: Eight children (six females) aged 3 months to 8 years (median age 5 years) met case criteria. Initial symptoms were pain (n = 7) followed by limb weakness with hypotonia (n = 8). Flaccid paralysis occurred in only three patients. Two had cranial nerve dysfunction. Magnetic resonance imaging of the spinal cord demonstrated grey matter involvement particularly affecting the anterior cord, with longitudinally extensive changes in three children. Cerebrospinal fluid examination showed pleocytosis in six children with raised cerebrospinal fluid protein in five. Nerve conduction and electromyography findings were consistent with a motor neuronopathy. Residual deficits were common, with moderate to severe weakness seen in five patients. Median follow-up was 28 months (range 17-108 months, 30.4 patient years in total). CONCLUSIONS: Acute flaccid myelitis is an uncommon condition in childhood with a high rate of significant long-term morbidity. AFM should be considered in children presenting with acute limb pain and weakness. PMID- 28639346 TI - Adipose Tissue Meal-Derived Fatty Acid Uptake Before and After Diet-Induced Weight Loss in Adults with Overweight and Obesity. AB - OBJECTIVE: This study investigated whether diet-induced weight loss alters indices of in vivo postprandial fat uptake in adipose tissue (AT) and whether these changes are associated with weight regain in adults with overweight and obesity. METHODS: In this randomized controlled trial, 16 (6 male) individuals (BMI: 28-35 kg/m2 ) were randomized to either a low-calorie diet (1,250 kcal/d) for 12 weeks or a very-low-calorie diet (500 kcal/d) for 5 weeks (weight loss [WL] period) followed by a 4-week weight-stable (WS) period (together, the dietary intervention [DI] period) and a 9-month follow-up period. Arteriovenous difference measurements combined with stable isotope labeling ([U-13 C] palmitate) of a mixed meal were used to determine postprandial fatty acid uptake in AT. RESULTS: Body weight was significantly reduced during the WL period (-8.2 +/- 0.6 kg, P < 0.001), remained stable during the WS period (0.4 +/- 0.3 kg, P = 0.150), and increased during follow-up (3.5 +/- 0.8 kg, P = 0.001). Meal-derived in vivo fatty acid uptake dynamics across AT and expression of genes important for fatty acid uptake, storage, and release were not significantly changed during the DI period. CONCLUSIONS: Subcutaneous AT does not appear prone to enhanced meal-derived fatty acid uptake after weight loss, nor were fatty acid uptake dynamics detected as related to weight regain. PMID- 28639347 TI - High-Energy/Power and Low-Temperature Cathode for Sodium-Ion Batteries: In Situ XRD Study and Superior Full-Cell Performance. AB - Sodium-ion batteries (SIBs) are still confronted with several major challenges, including low energy and power densities, short-term cycle life, and poor low temperature performance, which severely hinder their practical applications. Here, a high-voltage cathode composed of Na3 V2 (PO4 )2 O2 F nano-tetraprisms (NVPF-NTP) is proposed to enhance the energy density of SIBs. The prepared NVPF NTP exhibits two high working plateaux at about 4.01 and 3.60 V versus the Na+ /Na with a specific capacity of 127.8 mA h g-1 . The energy density of NVPF-NTP reaches up to 486 W h kg-1 , which is higher than the majority of other cathode materials previously reported for SIBs. Moreover, due to the low strain (~2.56% volumetric variation) and superior Na transport kinetics in Na intercalation/extraction processes, as demonstrated by in situ X-ray diffraction, galvanostatic intermittent titration technique, and cyclic voltammetry at varied scan rates, the NVPF-NTP shows long-term cycle life, superior low-temperature performance, and outstanding high-rate capabilities. The comparison of Ragone plots further discloses that NVPF-NTP presents the best power performance among the state-of-the-art cathode materials for SIBs. More importantly, when coupled with an Sb-based anode, the fabricated sodium-ion full-cells also exhibit excellent rate and cycling performances, thus providing a preview of their practical application. PMID- 28639348 TI - Cell specificity of magnetic cell seeding approach to hydrogel colonization. AB - Tissue-engineered scaffolds require an effective colonization with cells. Superparamagnetic iron oxide nanoparticles (SPIONs) can enhance cell adhesion to matrices by magnetic cell seeding. We investigated the possibility of improving cell attachment and growth on different alginate-based hydrogels using fibroblasts and endothelial cells (ECs) loaded with SPIONs. Hydrogels containing pure alginate (Alg), alginate dialdehyde crosslinked with gelatin (ADA-G) and Alg blended with G or silk fibroin (SF) were prepared. Endothelial cells and fibroblasts loaded with SPIONs were seeded and grown on hydrogels for up to 7 days, in the presence of magnetic field during the first 24 h. Cell morphology (fluorescent staining) and metabolic activity (WST-8 assay) of magnetically seeded versus conventionally seeded cells were compared. Magnetic seeding of ECs improved their initial attachment and further growth on Alg/G hydrogel surfaces. However, we did not achieve an efficient and stable colonization of ADA-G films with ECs even with magnetic cell seeding. Fibroblast showed good initial colonization and growth on ADA-G and on Alg/SF. This effect was further significantly enhanced by magnetic cell seeding. On pure Alg, initial attachment and spreading of magnetically-seeded cells was dramatically improved compared to conventionally-seeded cells, but the effect was transient and diminished gradually with the cessation of magnetic force. Our results demonstrate that magnetic seeding improves the strength and uniformity of initial cell attachment to hydrogel surface in cell-specific manner, which may play a decisive role for the outcome in tissue engineering applications. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2948-2956, 2017. PMID- 28639349 TI - Reconfigurable Chiral Self-Assembly of Peptides through Control of Terminal Charges. AB - Self-assembly of chiral nanostructures is of considerable interest, since the ability to control the chirality of these structures has direct ramifications in biology and materials science. A new approach to design chiral nanostructures from self-assembly of N-(9-fluorenylmethoxycarbonyl)-protected phenylalanine tryptophan-lysine tripeptides is reported. The terminal charges can induce helical twisting of the assembled beta-sheets, enabling the formation of well defined chiral nanostructures. The degree and direction of twisting in the beta sheets can be precisely tailored through in situ pH and temperature modulations. This enables the assembly of reconfigurable chiral nanomaterials with easily adjustable size and handedness. These results offer new insight into the mechanism of helical twist formation, which may enable the precise assembly of highly dynamical materials with potential applications in biomedicine, chiroptics, and chiral sensing. PMID- 28639350 TI - Response to Letter: Novel Electrocardiographic Indices of Arrhythmogenesis and Blood Lead Level. PMID- 28639351 TI - Titanium-released from dental implant enhances pre-osteoblast adhesion by ROS modulating crucial intracellular pathways. AB - It is important to understand the cellular and molecular events that occur at the cell-material interface of implants used for bone repair. The mechanisms involved in the initial stages of osteoblast interactions with the surface of the implant material must be decisive for cell fating surrounding them. In order to address this issue, we decided to investigate if conditioned medium for dental implants was able to modulate murine pre-osteoblast metabolism. First, we determined the concentration of titanium (Ti)-containing conditioned medium and found that it was 2-fold increased (p < 0.0001). We have reported that this conditioned medium significantly up-modulated pre-osteoblast adhesion up to 24 h (p < 0.0001). In parallel, our results showed that both phosphorylations of FAK (focal adhesion kinase) at Y397 (p < 0.0011) and Cofilin at Ser03 (p < 0.0053) were also up modulated, as well as for Rac1 expression (p < 0.0175); both of them are involved with cell adaptation by rearranging cytoskeleton actin filaments. Thereafter, Ti containing medium stimulated ROS (reactive oxygen species) production by pre osteoblast cells, and it is very possible that ROS compromised PTP-1B (protein tyrosine phosphatase 1B) activation since PTP1B was down-phosphorylated (p < 0.0148). The low PTP activity guarantees the phosphorylation of FAK at Y-residue, causing better pre-osteoblast adhesion in response to Ti-containing medium. Altogether, these data indicate that ROS indirectly modulate FAK phosphorylation in response to Ti-released from dental implants. Taken the results in account, these data showed for the first time that the implanted dental device is able to dynamically affect surrounding tissues, mainly by promoting a better performance of the pre-osteoblast cells. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2968-2976, 2017. PMID- 28639352 TI - Reply from authors: the use of blood coagulation products requires a thorough re evaluation. PMID- 28639354 TI - Relationships between social support and student burnout: A meta-analytic approach. AB - This study is a meta-analysis of 19 relevant studies, with 95,434 participants, investigating the relationships between various types of social support and 3 dimensions of student burnout. The overall results indicate that social support is negatively correlated with student burnout. Specifically, school or teacher supports have the strongest negative relationship to student burnout. Social supports from parents and from peers also have a significant negative relationship with student burnout. Among the 3 dimensions of student burnout, inefficacy was more strongly related to social support than emotional exhaustion or cynicism. The results of a moderation analysis suggest that the type of schools (secondary school and postsecondary school) affected the relationships between the overall social support and student burnout. We discuss the implications to ameliorate student burnout. PMID- 28639356 TI - Bias in protected-area location and its effects on long-term aspirations of biodiversity conventions. AB - To contribute to the aspirations of recent international biodiversity conventions, protected areas (PAs) must be strategically located and not simply established on economically marginal lands as they have in the past. With refined international commitments under the Convention on Biological Diversity to target protected areas in places of "importance to biodiversity," perhaps they may now be. We analyzed location biases in PAs globally over historic (pre-2004) and recent periods. Specifically, we examined whether the location of protected areas are more closely associated with high concentrations of threatened vertebrate species or with areas of low agricultural opportunity costs. We found that both old and new protected areas did not target places with high concentrations of threatened vertebrate species. Instead, they appeared to be established in locations that minimize conflict with agriculturally suitable lands. This entrenchment of past trends has substantial implications for the contributions these protected areas are making to international commitments to conserve biodiversity. If protected-area growth from 2004 to 2014 had strategically targeted unrepresented threatened vertebrates, >30 times more species (3086 or 2553 potential vs. 85 actual new species represented) would have been protected for the same area or the same cost as the actual expansion. With the land available for conservation declining, nations must urgently focus new protection on places that provide for the conservation outcomes outlined in international treaties. PMID- 28639355 TI - How do the characteristics of breast cancer diagnostic assessment programmes influence service delivery: A mixed methods study. AB - Diagnostic assessment programmes (DAPs) coordinate multidisciplinary teamwork (MDT), and improve wait times and patient satisfaction. No research has established optimal DAP design. This study explored how DAP characteristics influence service delivery. A mixed methods case study of four breast cancer DAPs was conducted including qualitative interviews with health-care providers and retrospective chart review. Data were integrated using multiple approaches. Twenty-three providers were interviewed; 411 medical records were reviewed. The number of visits and wait times from referral to diagnosis and consultation were lowest at a one-stop model. DAP characteristics (rural-remote region, human resources, referral volume, organisation of services, adherence to service delivery targets and one-stop model) may influence service delivery (number of visits, wait times). MDT, influenced by other DAP characteristics (co-location of staff, patient navigators, team functioning), may also influence service delivery. While the one-stop model may be ideal, all sites experienced similar and unique challenges. Further research is needed to understand how to optimise the organisation and delivery of DAP services. Measures reflecting individual, team and patient-reported outcomes should be used to assess the effectiveness and impact of DAPs in addition to more traditional measures such as wait times. PMID- 28639357 TI - Cerebellar projections to the ventral lateral geniculate nucleus and the thalamic reticular nucleus in the cat. AB - The ventral lateral geniculate nucleus (LGNv) is a retinorecipient part of the ventral thalamus and in cats, it consists of medial (M), medial intermediate (IM), lateral intermediate (IL), lateral (L), and dorsal (D) subdivisions. These subdivisions can be differentiated not only by their cytoarchitecture, but also by their connectivity and putative functions. The LGNv may play a role in visuomotor gating, in that there is evidence of cerebellar afferent projections to the intermediate subdivisions. The cerebellar posterior interpositus (IP) and lateral (LC) nuclei are known to project to IM and IL, but the specifics of these projections are unclear. We hypothesized that the IP and LC project differentially to IM and IL. To evaluate LGNv innervation by the deep cerebellar nuclei, we injected the tract-tracer wheat germ agglutinin-horseradish peroxidase (WGA-HRP) into several different regions of the LGNv and cerebellar nuclei of adult cats in either sex. Small injections into the middle and posterior LGNv retrogradely labeled cells in the ventral part of the IP. However, injections in the anterior regions of the LGNv, with or without diffusion into the thalamic reticular nucleus (Re), retrogradely labeled cells in the ventral part of both the IP and the LC. Confirmatory injections into the IP and LC produced terminal like labeling distributed in IM, IL, and Re; injections mostly localized to the LC resulted in labeling mainly in IM and Re. We concluded that the IP projects to IL whereas the LC projects to IM and Re. PMID- 28639358 TI - Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones. AB - Fluoroquinolones (FQs) have been identified recently as potent inhibitors of pancreatic lipase (PL). The aim of this study was to synthesize novel FQs and triazolofluoroquinolones (TFQs) and to evaluate them in vitro with respect to their antilipolytic efficacy and potency properties. The PL-IC50 values of 12 FQs and TFQs (3 (a-c)-6 (a-c)) were in the range of 12.5-189.1 MUm. These values are further supported by docking studies. The suggested association between obesity and colorectal cancer initiated the evaluation of antiproliferative activity of the new FQs and TFQs against a panel of obesity-related colorectal cells (HT29, HCT116, SW620 CACO2, and SW480). Sulforodamine B colorimetric assay revealed that some derivatives exhibited unselective cytotoxicity against HT29, HCT116, SW620 CACO2, and SW480. Remarkably, FQ 4a's selective cytotoxicity against HCT116 was found valuable with IC50 value of 4.2 MUm which exceeds that of cisplatin with a substantial selective cytotoxicity in periodontal ligament fibroblasts. In conclusion, FQ and TFQ derivatives may unveil new antiobesity and anticancer agents in the future. PMID- 28639360 TI - The mechanism of coupling between oxido-reduction and proton translocation in respiratory chain enzymes. AB - The respiratory chain of mitochondria and bacteria is made up of a set of membrane-associated enzyme complexes which catalyse sequential, stepwise transfer of reducing equivalents from substrates to oxygen and convert redox energy into a transmembrane protonmotive force (PMF) by proton translocation from a negative (N) to a positive (P) aqueous phase separated by the coupling membrane. There are three basic mechanisms by which a membrane-associated redox enzyme can generate a PMF. These are membrane anisotropic arrangement of the primary redox catalysis with: (i) vectorial electron transfer by redox metal centres from the P to the N side of the membrane; (ii) hydrogen transfer by movement of quinones across the membrane, from a reduction site at the N side to an oxidation site at the P side; (iii) a different type of mechanism based on co-operative allosteric linkage between electron transfer at the metal redox centres and transmembrane electrogenic proton translocation by apoproteins. The results of advanced experimental and theoretical analyses and in particular X-ray crystallography show that these three mechanisms contribute differently to the protonmotive activity of cytochrome c oxidase, ubiquinone-cytochrome c oxidoreductase and NADH ubiquinone oxidoreductase of the respiratory chain. This review considers the main features, recent experimental advances and still unresolved problems in the molecular/atomic mechanism of coupling between the transfer of reducing equivalents and proton translocation in these three protonmotive redox complexes. PMID- 28639359 TI - Interobserver variability in the classification of congenital coronary abnormalities: A substudy of the anomalous connections of the coronary arteries registry. AB - OBJECTIVE: The diagnosis of anomalous connections of the coronary arteries (ANOCOR) requires an appropriate identification for the management of the patients involved. We studied the observer variability in the description and classification of ANOCOR between a nonexpert group of physicians and a group of expert physicians, using the ANOCOR cohort. PATIENTS AND DESIGN: Consecutive patients identified by 71 referring cardiologists were included in the ANOCOR cohort. Anomalous connection was diagnosed by invasive and/or computed tomography coronary angiography. Angiographic images were reviewed by an angiographic committee with experience in this field. Both investigators and angiographic committee filled out a questionnaire to classify each anomaly with the type of coronary artery involved, the site of anomalous connection, and the initial course. Observer variability between investigators and angiographic committee was assessed by kappa statistics. Anomalous connection with a preaortic course was defined as at-risk. RESULTS: Among 472 patients of the ANOCOR cohort, 496 abnormalities were identified with a preaortic course present in 31%. The agreement for the type of artery was excellent (kappa = 0.92, 95% CI = 0.86-0.98, P < .05), while the agreement for the site of anomalous connection was moderate (kappa = 0.50, 95% CI = 0.42-0.58, P < .05), and the agreement for the initial course was only fair (kappa = 0.32, 95% CI = 0.28-0.37, P < .05). Observer agreement for the identification of at-risk forms was moderate (kappa = 0.497, 95% CI = 0.40-0.59, P < .05). CONCLUSIONS: Observer variability in the assessment of anomalous connection of the coronary arteries between nonexperienced and experienced physicians can be significant. We found that expert physicians provide a more robust classification in comparison with nonexpert physicians. Therefore, referral to physicians with a relevant experience should be considered, especially if an anomaly at-risk is suspected. PMID- 28639361 TI - Experiences and needs of relatives of people with dementia in acute hospitals-A meta-synthesis of qualitative studies. AB - AIMS AND OBJECTIVES: To present an in-depth analysis of existing qualitative literature concerning experiences and needs of the relatives of patients with dementia in hospitals. BACKGROUND: Relatives are an important resource for the care of patients with dementia in hospitals. They provide necessary information about the patient and can support the patient's care. Simultaneously, they are themselves vulnerable, having specific needs and experiences. A number of studies have been conducted that focus on the perspectives of the relatives. The synthesis of qualitative studies contributes to a more comprehensive understanding of recent study findings. DESIGN: A meta-ethnographic synthesis of qualitative research findings was used. METHODS: The synthesis process followed six defined steps. We located relevant studies through searching the CINAHL, PubMed and PsycInfo databases and through searching journals and reference lists by hand. A list of metaphors was created and translated into one another. Identified metaphors were synthesised and interpreted as a new whole. RESULTS: Relatives of patients with dementia frequently experience a negative cycle of specific worries, negative feelings and resulting roles and functions in hospital due to negative care experiences. CONCLUSIONS: Experiences of relatives are strongly influenced by the attitudes, expertise and communication that they receive from health professionals working in the hospital. The results clearly show how health professionals have the potential to break through the negative cycle and contribute to a more positive feeling about a patient's hospital stay. RELEVANCE TO CLINICAL PRACTICE: Structured and individually planned involvement of the relatives during the hospital care seems to be a key aspect for improving the experiences for the relatives and the patients with dementia. Collaboration with the relatives needs to be valued and supported by the organisation. Also a professional and defined frame for this area of responsibility needs to be provided. PMID- 28639362 TI - The effect of hospital biocide sodium dichloroisocyanurate on the viability and properties of Clostridium difficile spores. AB - : Clostridium difficile is the primary cause of healthcare-associated diarrhoea globally and produces spores which are resistant to commonly used biocides and are able persist on contaminated surfaces for months. This study examined the effect of sublethal concentrations of the biocide sodium dichloroisocyanurate (NaDCC) on the viability of spores produced by 21 clinical isolates of C. difficile representing a range of PCR ribotypes. Spores exposed to 500 ppm NaDCC for 10 min exhibited between a 4-6 log10 reduction in viability which was independent of spore PCR ribotype. The effect of sublethal concentrations of biocide on the surface properties of exosporium positive and negative clinical isolates was determined using a spore adhesion to hydrocarbon (SATH) assay. These isolates differed markedly in their responses suggesting that exposure to biocide can have a profound effect on hydrophobicity and thus the ability of spores to adhere to surfaces. This raises the intriguing possibility that sublethal exposure to NaDCC could inadvertently promote the spread of the pathogen in healthcare facilities. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first to report on changes in Clostridium difficile spore surface property after exposure to sublethal levels of the commonly used biocide sodium dichloroisocyanurate. The implications of these changes to the spore surface include increased adherence of the spores to inorganic surfaces which can directly contribute to persistence and spread of spores within the hospital environment. PMID- 28639363 TI - In-situ Generated and Premade 1-Copper(I) Alkynes in Cycloadditions. AB - The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was discovered in 2002, which has become the most remarkable example for "click chemistry" to date. In CuAAC reaction, 1-copper(I) alkyne has been recognized to be a key intermediate. However, many contradictory experimental results for this intermediate were reported in literature. For example, only the in-situ generated 1-copper(I) alkyne was used, while the premade 1-copper(I) alkyne proved to be inefficient under the standard conditions. The kinetic studies indicated that CuAAC reaction had a strict second-order dependence on Cu(I) and the DFT studies demonstrated that 1-copper(I) alkyne intermediate should be a dinuclear copper(I) complex. But these results were inconsistent with the structure of the premade 1 copper(I) alkyne. Although hundreds of structurally different ligands were reported to significantly enhance the efficiency of CuAAC reaction, their functions were assigned to prevent the oxidation and the disproportionation of Cu(I) ion. Based on the investigation of the references and our works, we proposed that the in-situ generated 1-copper(I) alkyne in CuAAC reaction is not identical with the premade 1-copper(I) alkyne. The ligands may play dual roles to activate the 1-copper(I) alkyne by blocking the polymerization of the in-situ formed 1-copper(I) alkynes and dissociating the polymeric structures of the premade 1-copper(I) alkynes. As a result, we first disclosed that carboxylic acids can function as such activators and a novel carboxylic acid-catalyzed CuAAC strategy was developed, which has been proven to be the most convenient and highly efficient CuAAC method to date. Furthermore, highly efficient and regioselective methods for the syntheses of 1,4,5-trisubstituted 1,2,3-triazoles were developed by using the premade 1-copper(I) alkynes as substrates, in which the novel function of the premade 1-copper(I) alkynes as excellent dipolarophiles was first disclosed and applied. In this article, a series of works reported by our group for the in-situ generated and the premade 1-copper(I) alkynes in cycloadditions are reviewed. PMID- 28639364 TI - Changes in chronic disease management among community health centers (CHCs) in China: Has health reform improved CHC ability? AB - Since the 1980s, China has been criticized for its mode of chronic disease management (CDM) that passively provides treatment in secondary and tertiary hospitals but lacks active prevention in community health centers (CHCs). Since there are few systematic evaluations of the CHCs' methods for CDM, this study aimed to analyze their abilities. On the macroperspective, we searched the literature in China's largest and most authoritative databases and the official websites of health departments. Literature was used to analyze the government's efforts in improving CHCs' abilities to perform CDM. At the microlevel, we examined the CHCs' longitudinal data after the New Health Reform in 2009, including financial investment, facilities, professional capacities, and the conducted CDM activities. A policy analysis showed that there was an increasing tendency towards government efforts in developing CDM, and the peak appeared in 2009. By evaluating the reform at CHCs, we found that there was an obvious increase in fiscal and public health subsidies, large-scale equipment, general practitioners, and public health physicians. The benefited vulnerable population in this area also rose significantly. However, rural centers were inferior in their CDM abilities compared with urban ones, and the referral system is still not effective in China. This study showed that CHCs are increasingly valued in managing chronic diseases, especially after the New Health Reform in 2009. However, we still need to improve collaborative management for chronic diseases in the community and strengthen the abilities of CHCs, especially in rural areas. PMID- 28639365 TI - Vascular Calcification, Vitamin K and Warfarin Therapy - Possible or Plausible Connection? AB - Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast-like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone. The elevated stiffness of the arteries leads to severe vascular complications in brain, heart and kidneys. Recently, evidence from animal experiments as well as clinical and epidemiological results suggests that long-term treatment with warfarin, but not with the novel direct anticoagulants, can increase the risk or even induce vascular calcification in some individuals. Gamma-carboxylation is an enzymatic process not only needed for activation of vitamin K but also other proteins which participate in bone formation and vascular calcification. Thus, reduced expression of the vitamin K-dependent proteins which physiologically inhibit calcification of cellular matrix could be postulated to lead to vascular calcification. Published clinical data, describing at present a few thousand patients, need to be supplemented with controlled studies to confirm this interesting hypothesis. PMID- 28639366 TI - Visually induced analgesia during massage treatment in chronic back pain patients. AB - BACKGROUND: Previous findings suggest that watching sites of experimental and chronic pain can exert an analgesic effect. Our present study investigates whether watching one's back during massage increases the analgesic effect of this treatment in chronic back pain patients. METHODS: Twenty patients with chronic back pain were treated with a conventional massage therapy. During this treatment, patients received a real-time video feedback of their own back. Watching a neutral object, a video of another person of the same sex being massaged, a picture of the own back, and keeping one's eyes closed were used as controls. These conditions were presented in randomized order on five separate days. RESULTS: All conditions yielded significant decreases in habitual pain intensity. The effect of real-time video feedback of the own back on massage treatment was the strongest and differed significantly from the effect of watching a neutral object, but not from the other control conditions, which may have induced slight effects of their own. CONCLUSIONS: Repeated real-time video feedback may be useful during massage treatment of chronic pain. SIGNIFICANCE: This study shows that inducing visual induced analgesia during massage treatment can be helpful in alleviating chronic pain. PMID- 28639367 TI - A polydopamine peptide coating enables adipose-derived stem cell growth on the silicone surface of cochlear implant electrode arrays. AB - The simultaneous application of neurotrophic factors with cochlear implantation is proposed to enhance the bioelectrical interface between electrodes and auditory neurons, and thus improve speech intelligibility in patients with cochlear implants (CIs). In cell-based approaches, the goal is to colonize CIs with cells producing neurotrophic factors. This study aims to evaluate whether a polydopamine (PD) functionalization of the hydrophobic silicone surface of the electrode carrier enables colonization of adipose-derived stem cells known to deliver neurotrophic factors. Surface characteristics of PD-coated silicone samples and electrode carriers were determined, and the proliferation and viability of adipose-derived stem cells (ASCs) on these surfaces were subsequently analyzed. A homogenous PD coating and cell growth with regular morphology was observed on coated silicone samples and electrode arrays. Hydrophilicity and cell viability was significantly enhanced by PD surface modification. Insertion forces of coated electrode arrays did not increase compared with untreated CIs. Hence, PD coating of the silicone surface of CIs might allow for sufficient colonization with ASCs as a continuous source of neurotrophic factors. (c) 2017 Wiley Periodicals, Inc. J Biomater Res Part A: 106B: 1431-1438, 2018. PMID- 28639368 TI - Botulinum toxin: State of the art. AB - Botulinun neurotoxin (BoNT) has emerged as one of the most multipurpose therapeutic agents in modern medicine with more clinical applications than any other drug currently on the market. Initially developed in the treatment of strabismus and neurologic movement disorders, the use of botulinun neurotoxin has been expanding during the past 3 decades to include the treatment of a variety of ophthalmologic, gastrointestinal, urologic, orthopedic, dermatologic, dental, secretory, painful, cosmetic, and other conditions. In addition to onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), and RimabotulinumtoxinB (Myobloc or NeuroBloc) there are other novel botulinun neurotoxin products currently in development. With a better understanding of the cellular mechanisms of botulinun neurotoxin and advances in biotechnology, future botulinun neurotoxin products will likely be even more effective and customized to the specific indication and tailored to the needs of the patients. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28639369 TI - A network analysis to compare biomarker profiles in patients with and without diabetes mellitus in acute heart failure. AB - AIMS: It is unclear whether distinct pathophysiological processes are present among patients with acute heart failure (AHF), with and without diabetes. Network analysis of biomarkers may identify correlative associations that reflect different pathophysiological pathways. METHODS AND RESULTS: We analysed a panel of 48 circulating biomarkers measured within 24 h of admission for AHF in a subset of patients enrolled in the PROTECT trial. In patients with and without diabetes, we performed a network analysis to identify correlations between measured biomarkers. Compared with patients without diabetes (n = 1111), those with diabetes (n = 922) had a higher prevalence of ischaemic heart disease and traditional coronary risk factors. After multivariable adjustment, patients with and without diabetes had significantly different levels of biomarkers across a spectrum of pathophysiological domains, including inflammation (TNFR-1a, periostin), cardiomyocyte stretch (BNP), angiogenesis (VEGFR, angiogenin), and renal function (NGAL, KIM-1) (adjusted P-value <0.05). Among patients with diabetes, network analysis revealed that periostin strongly clustered with C reactive protein and interleukin-6. Furthermore, renal markers (creatinine and NGAL) closely associated with potassium and glucose. These findings were not seen among patients without diabetes. CONCLUSION: Patients with AHF and diabetes, compared with those without diabetes, have distinct biomarker profiles. Network analysis suggests that cardiac remodelling, inflammation, and fibrosis are closely associated with each other in patients with diabetes. Furthermore, potassium levels may be sensitive to changes in renal function as reflected by the strong renal-potassium-glucose correlation. These findings were not seen among patients without diabetes and may suggest distinct pathophysiological processes among AHF patients with diabetes. PMID- 28639370 TI - B0 concomitant field compensation for MRI systems employing asymmetric transverse gradient coils. AB - PURPOSE: Imaging gradients result in the generation of concomitant fields, or Maxwell fields, which are of increasing importance at higher gradient amplitudes. These time-varying fields cause additional phase accumulation, which must be compensated for to avoid image artifacts. In the case of gradient systems employing symmetric design, the concomitant fields are well described with second order spatial variation. Gradient systems employing asymmetric design additionally generate concomitant fields with global (zeroth-order or B0 ) and linear (first-order) spatial dependence. METHODS: This work demonstrates a general solution to eliminate the zeroth-order concomitant field by applying the correct B0 frequency shift in real time to counteract the concomitant fields. Results are demonstrated for phase contrast, spiral, echo-planar imaging (EPI), and fast spin-echo imaging. RESULTS: A global phase offset is reduced in the phase-contrast exam, and blurring is virtually eliminated in spiral images. The bulk image shift in the phase-encode direction is compensated for in EPI, whereas signal loss, ghosting, and blurring are corrected in the fast-spin echo images. CONCLUSION: A user-transparent method to compensate the zeroth-order concomitant field term by center frequency shifting is proposed and implemented. This solution allows all the existing pulse sequences-both product and research-to be retained without any modifications. Magn Reson Med 79:1538-1544, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28639371 TI - A 'movement for improvement'? A qualitative study of the adoption of social movement strategies in the implementation of a quality improvement campaign. AB - Given the difficulties of implementing 'top-down' quality improvements, health service leaders have turned to methods that empower clinicians to co-produce 'bottom-up' improvements. This has involved the adoption of strategies and activities associated with social movements, with clinicians encouraged to participate in collective action towards the shared goal of improvement. This paper examines the adoption of social movement methods by hospital managers as a strategy for implementing a quality improvement 'campaign'. Our case study suggests that, despite the claim of empowering clinicians to develop 'bottom-up' improvements, the use of social movement methods can be more narrowly concerned with engaging clinicians in pre-determined programmes of 'top-down' change. It finds a prominent role for 'hybrid' clinical leaders and other staff representatives in the mobilisation of the campaign, especially for enrolling clinicians in change activities. The work of these 'hybrids' suggests some degree of creative mediation between clinical and managerial interests, but more often alignment with the aspirations of management. The study raises questions about the translation of social movement's theories as a strategy for managing change and re-inventing professionalism. PMID- 28639372 TI - Syntheses, Structures, and Solution Studies of Multicomponent Macrocycles and Cages Based on Versatile Ligands. AB - Different types of multinuclear half-sandwich rhodium macrocycles and cages were designed and synthesized by using two similar multifunctional hydroxamate ligands (pyrazine-2-hydroxamic acid (NaHL1 ) and 4,4'-bipyridine-2-hydroxamic acid (KHL2 )) featuring one monodentate site and two pairs of chelating sites. The RhIII PdII heterometallic macrocycles were constructed by using the semi-open palladium(II) source [Pd(en)Cl2 ] with two free acceptor sites. However, only one kind of macrocycle was found when the shorter ligand L1 was used, while in for the larger ligand, various spectroscopic techniques demonstrated the coexistence of hexanuclear and octanuclear macrocycles in solution and the proportions of both components depended on concentration and temperature. The palladium salt Pd(NO3 )2 , as a source of "naked" Pd2+ , was introduced to assemble the cuboid shaped cage composed of two types of metal ions and three types of organic ligands. In addition, two silver(I)-containing mixed-metal complexes bridged by pyrazine were obtained, in which two forms of decanuclear complex with C2v and C2h point symmetry cocrystallized-one is a polymeric structure and the other is a discrete cage. However, the third form, with D2 point symmetry, was found in the larger cage. PMID- 28639373 TI - Laboratory diagnosis of overt type 2 diabetes in the first trimester of pregnancy. AB - OBJECTIVE: The objective of this study was to compare the use of hemoglobin A1C to oral glucose tolerance testing to diagnose overt type 2 diabetes in the first trimester of pregnancy. The study used a nonexperimental descriptive design to compare the use of the hemoglobin A1C test results to oral glucose tolerance test results. METHODS: The study used a sample of 45 women at high risk for type 2 diabetes in the first trimester of pregnancy. Participants were consented to draw a hemoglobin A1C with their ordered oral glucose tolerance testing for comparison of the two tests' ability to diagnose overt type 2 diabetes. RESULTS: Hemoglobin A1C tests were highly positively correlated with oral glucose tolerance testing for diagnosis of type 2 diabetes in women in the first trimester of pregnancy. CONCLUSION: The research provides beginning evidence that the hemoglobin A1C should be considered as a first-tier diagnostic test for overt type 2 diabetes in the first trimester of pregnancy. PMID- 28639374 TI - SNP-based genetic characterization of the Tulane National Primate Research Center's conventional and specific pathogen-free rhesus macaque (Macaca mulatta) populations. AB - BACKGROUND: The rhesus macaque is an important biomedical model organism, and the Tulane National Primate Research Center (TNPRC) has one of the largest rhesus macaque breeding colonies in the United States. METHODS: SNP profiles from 3266 rhesus macaques were used to examine the TNPRC colony genetic composition over time and across conventional or SPF animals of Chinese and Indian ancestry. RESULTS: Chinese origin animals were the least genetically diverse and the most inbred; however, since their derivation from their conventional forebearers, neither the Chinese nor the Indian SPF animals exhibit any significant loss of genetic diversity or differentiation. CONCLUSIONS: The TNPRC colony managers have successfully minimized loss in genetic variation across generations. Although founder effects and bottlenecks among the Indian animals have been successfully curtailed, the Chinese subpopulation still show some influences from these events. PMID- 28639375 TI - Concise Review: Challenges in Regenerating the Diabetic Heart: A Comprehensive Review. AB - Stem cell therapy is one of the promising regenerative strategies developed to improve cardiac function in patients with ischemic heart diseases (IHD). However, this approach is limited in IHD patients with diabetes due to a progressive decline in the regenerative capacity of stem cells. This decline is mainly attributed to the metabolic memory incurred by diabetes on stem cell niche and their systemic cues. Understanding the molecular pathways involved in the diabetes-induced deterioration of stem cell function will be critical for developing new cardiac regeneration therapies. In this review, we first discuss the most common molecular alterations occurring in the diabetic stem cells/progenitor cells. Next, we highlight the key signaling pathways that can be dysregulated in a diabetic environment and impair the mobilization of stem/progenitor cells, which is essential for the transplanted/endogenous stem cells to reach the site of injury. We further discuss the possible methods of preconditioning the diabetic cardiac progenitor cell (CPC) with an aim to enrich the availability of efficient stem cells to regenerate the diseased diabetic heart. Finally, we propose new modalities for enriching the diabetic CPC through genetic or tissue engineering that would aid in developing autologous therapeutic strategies, improving the proliferative, angiogenic, and cardiogenic properties of diabetic stem/progenitor cells. Stem Cells 2017;35:2009-2026. PMID- 28639376 TI - mfat-1 transgene protects cultured adult neural stem cells against cobalt chloride-mediated hypoxic injury by activating Nrf2/ARE pathways. AB - Ischemic stroke is a devastating neurological disorder and one of the leading causes of death and serious disability in adults. Adult neural stem cell (NSC) replacement therapy is a promising treatment for both structural and functional neurological recovery. However, for the treatment to work, adult NSCs must be protected against hypoxic-ischemic damage in the ischemic penumbra. In the present study, we aimed to investigate the neuroprotective effects of the mfat-1 transgene on cobalt chloride (CoCl2 )-induced hypoxic-ischemic injury in cultured adult NSCs as well as its underlying mechanisms. The results show that in the CoCl2 -induced hypoxic-ischemic injury model, the mfat-1 transgene enhanced the viability of adult NSCs and suppressed CoCl2 -mediated apoptosis of adult NSCs. Additionally, the mfat-1 transgene promoted the proliferation of NSCs as shown by increased bromodeoxyuridine labeling of adult NSCs. This process was related to the reduction of reactive oxygen species. Quantitative real-time polymerase chain reaction and Western blot analysis revealed a much higher expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genes (HO-1, NQO-1, GCLC). Taken together, our findings show that the mfat-1 transgene restored the CoCl2 -inhibited viability and proliferation of NSCs by activating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signal pathway to inhibit oxidative stress injury. Further investigation of the function of the mfat-1 transgene in adult protective mechanisms may accelerate the development of adult NSC replacement therapy for ischemic stroke. PMID- 28639377 TI - Validating the social responsiveness scale for adults with autism. AB - The Social Responsiveness Scale [SRS; Constantino & Gruber, 2005] is a widely used measure of autism symptoms, but its application for the study of adults with autism spectrum disorders has not been fully evaluated. Using a factor structure consistent with The Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-V) criteria for autism spectrum disorder [Frazier et al., 2014], the primary purpose of the current study was to establish the validity of the SRS with a sample of adults with autism spectrum disorder (N = 237). Correlational analyses indicated that SRS factors were highly associated with autism symptoms and behavioral measures, indicating concurrent and predictive validity. Multiple regression results demonstrated that SRS factors were differentially related to measures specific to social or behavioral domains, indicating convergent and discriminant validity. Implications for future research are discussed. Autism Res 2017, 10: 1663-1671. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28639378 TI - Regulation of the fate of dental-derived mesenchymal stem cells using engineered alginate-GelMA hydrogels. AB - Mesenchymal stem cells (MSCs) derived from dental and orofacial tissues provide an alternative therapeutic option for craniofacial bone tissue regeneration. However, there is still a need to improve stem cell delivery vehicles to regulate the fate of the encapsulated MSCs for high quality tissue regeneration. Matrix elasticity plays a vital role in MSC fate determination. Here, we have prepared various hydrogel formulations based on alginate and gelatin methacryloyl (GelMA) and have encapsulated gingival mesenchymal stem cells (GMSCs) and human bone marrow MSCs (hBMMSCs) within these fabricated hydrogels. We demonstrate that addition of the GelMA to alginate hydrogel reduces the elasticity of the hydrogel mixture. While presence of GelMA in an alginate-based scaffold significantly increased the viability of encapsulated MSCs, increasing the concentration of GelMA downregulated the osteogenic differentiation of encapsulated MSCs in vitro due to decrease in the stiffness of the hydrogel matrix. The osteogenic suppression was rescued by addition of a potent osteogenic growth factor such as rh-BMP-2. In contrast, MSCs encapsulated in alginate hydrogel without GelMA were successfully osteo-differentiated without the aid of additional growth factors, as confirmed by expression of osteogenic markers (Runx2 and OCN), as well as positive staining using Xylenol orange. Interestingly, after two weeks of osteo differentiation, hBMMSCs and GMSCs encapsulated in alginate/GelMA hydrogels still expressed CD146, an MSC surface marker, while MSCs encapsulated in alginate hydrogel failed to express any positive staining. Altogether, our findings suggest that it is possible to control the fate of encapsulated MSCs within hydrogels by tuning the mechanical properties of the matrix. We also reconfirmed the important role of the presence of inductive signals in guiding MSC differentiation. These findings may enable the design of new multifunctional scaffolds for spatial and temporal control over the fate and function of stem cells even post-transplantation. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2957-2967, 2017. PMID- 28639379 TI - The In Vitro and In Vivo Biological Activities of the Leaf of Cape Myrtle, Myrsine africana L. AB - The cape myrtle, Myrsine africana L., is a widely used medicinal plant, which has not been well investigated. We assessed the in vivo hepatoprotective and in vitro antiproliferative and antioxidant effects of leaf extracts of M. africana chemically profiled using high-performance liquid chromatography. Three flavonoids were quantified, and gas chromatography-mass spectrometry analysis revealed the presence of common fatty acids. The animal study was conducted on mice treated with CCl4, using three doses each of the methanol and chloroform extract (100, 200 and 300 mg/kg b.w.),with silymarin as a positive control. Hepatoprotective effects were determined by analyzing blood for liver marker and antioxidant enzymes, direct bilirubins and total proteins. The methanol extract (300 mg/kg b.w.) showed the strongest hepatoprotective effects against abnormalities produced by CCl4. The in vivo hepatoprotective effects correlated well with the in vitro antioxidant and antiproliferative activities and with high levels of flavonoids in the extracts. Finally, molecular docking studies of the constituent quercetin were undertaken in silico and several sites of binding to human estrogen receptor (ER) protein, linked with alkaline phosphatase, identified. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28639380 TI - Bilayer PbS Quantum Dots for High-Performance Photodetectors. AB - Due to their wide tunable bandgaps, high absorption coefficients, easy solution processabilities, and high stabilities in air, lead sulfide (PbS) quantum dots (QDs) are increasingly regarded as promising material candidates for next generation light, low-cost, and flexible photodetectors. Current single-layer PbS QD photodetectors suffer from shortcomings of large dark currents, low on-off ratios, and slow light responses. Integration with metal nanoparticles, organics, and high-conducting graphene/nanotube to form hybrid PbS-QD devices are proved capable of enhancing photoresponsivity; but these approaches always bring in other problems that can severely hamper the improvement of the overall device performance. To overcome the hurdles current single-layer and hybrid PbS-QD photodetectors face, here a bilayer QD-only device is designed, which can be integrated on flexible polyimide substrate and significantly outperforms the conventional single-layer devices in response speed, detectivity, linear dynamic range, and signal-to-noise ratio, along with comparable responsivity. The results which are obtained here should be of great values in studying and designing advanced QD-based photodetectors for applications in future flexible optoelectronics. PMID- 28639381 TI - Elastin-like polypeptide switches: A design strategy to detect multimeric proteins. AB - Elastin-Like Polypeptides (ELPs) reversibly phase separate in response to changes in temperature, pressure, concentration, pH, and ionic species. While powerful triggers, biological microenvironments present a multitude of more specific biological cues, such as antibodies, cytokines, and cell-surface receptors. To develop better biosensors and bioresponsive drug carriers, rational strategies are required to sense and respond to these target proteins. We recently reported that noncovalent association of two ELP fusion proteins to a "chemical inducer of dimerization" small molecule (1.5 kDa) induces phase separation at physiological temperatures. Having detected a small molecule, here we present the first evidence that ELP multimerization can also detect a much larger (60 kDa) protein target. To demonstrate this strategy, ELPs were biotinylated at their amino terminus and mixed with tetrameric streptavidin. At a stoichiometric ratio of [4:1], two to three biotin-ELPs associate with streptavidin into multimeric complexes with an apparent Kd of 5 nM. The increased ELP density around a streptavidin core strongly promotes isothermal phase separation, which was tuned to occur at physiological temperature. This phase separation reverses upon saturation with excess streptavidin, which only favors [1:1] complexes. Together, these findings suggest that ELP association with multimeric biomolecules is a viable strategy to deliberately engineer ELPs that respond to multimeric protein substrates. PMID- 28639382 TI - Preferred intervention strategies to improve dietary and physical activity behaviors among African-American mothers and daughters. AB - OBJECTIVE: The objective of this study was to identify cultural- and age appropriate intervention strategies to improve dietary and physical activity (PA) behaviors in African-American adolescent daughters and their mothers. DESIGN AND SAMPLE: A convergent parallel mixed methods design with interactive quantitative and qualitative measures was used. Twenty-four 9th- and 10th-grade African American daughters from a large urban high school and their mothers participated. MEASURES: Measures included the 2013 Youth Risk Behavior Surveillance System dietary and PA questions, 2013 Behavioral Risk Factor Surveillance System dietary and PA questions, and BMI. Focus group questions covered preferred intervention formats and strategies for delivering a dietary and PA intervention. RESULTS: Fifty-five percent of daughters and 92% of mothers were overweight/obese. Mothers tended to prefer the group format (mothers/daughters together or mothers together) for delivering a dietary and PA intervention, while the daughters' delivery preferences were mixed. Top mother/daughter dyad strategy preferences for both dietary and PA were goal setting and use of rewards/prizes. CONCLUSIONS: These findings suggest several dietary and PA obesity intervention strategies that can guide obesity prevention efforts for African-American daughters and their mothers. PMID- 28639383 TI - Longitudinal associations between low morning cortisol in infancy and anger dysregulation in early childhood in a CPS-referred sample. AB - Children who experience early adversity are at increased risk for developing psychopathology, and dysfunction of the hypothalamic pituitary adrenal (HPA) axis is a possible mechanism conferring this risk. This study sought to characterize the association between morning cortisol during different developmental periods and deficits in children's emotion regulation, a core feature of many psychological disorders. Morning cortisol was collected at two time points (i.e., during infancy, M = 13.0 months old, and during early childhood, M = 36.8 months old) from 120 children with histories of child protective services (CPS) involvement. Children completed a lab visit during early childhood (M = 38.6 months old) that involved an observational measure of anger regulation. Results showed that low morning cortisol during infancy, but not early childhood, predicted increased anger dysregulation during early childhood. These results highlight the importance of developmental timing in assessing the effects of HPA axis functioning and suggest that low cortisol during infancy is a risk factor for later emotion regulation difficulties. PMID- 28639384 TI - Nurses' attitudes towards older people care: An integrative review. AB - AIMS AND OBJECTIVES: To examine hospital nurses' attitudes towards caring for older adults and delineate associated factors contributing to their attitudes. BACKGROUND: Population ageing is of international significance. A nursing workforce able to care for the ageing population is critical for ensuring quality older adult care. A synthesis of research related to nurses' attitudes towards older adult care is important for informing care quality and the nursing workforce issues. METHODS: A systematic integrative review process guided the review. Cumulative Index of Nursing and Allied Health Literature and Medline databases were searched for primary research published between 2005-2017. A total of 1,690 papers were screened with 67 papers read in-depth and eight selected for this review that met the inclusion/exclusion criteria. RESULTS: Nurses' held coexisting positive and negative attitudes towards generic and specific aspects of older adult care. Negative attitudes, in particular, were directed at the characteristics of older adults, their care demands or reflected in nurses' approaches to care. Across jurisdictions, work environment, education, experience and demographics emerged as influences on nurses' attitudes. CONCLUSION: There is a paucity of research examining nurses' attitudes towards older adult care. The limited evidence indicates that attitudes towards older people care are complex and contradictory. Influences on nurses' attitudes need further study individually and collectively to build a strong evidence base. Interventional studies are needed as are the development of valid and reliable instruments for measuring nurses' attitudes towards older adult care. RELEVANCE TO CLINICAL PRACTICE: Bolstering postgraduate gerontological preparation is critical for promoting nurses' attitudes towards older adult care. Creating age-friendly work environments, including appropriate resource allocation, is important to support older people care and facilitate positive nursing attitudes. PMID- 28639385 TI - Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. PMID- 28639386 TI - Development of immune response to tissue-restricted self-antigens in simultaneous kidney-pancreas transplant recipients with acute rejection. AB - Simultaneous kidney-pancreas transplantation (SKP Tx) is a treatment for end stage kidney disease secondary to diabetes mellitus. We investigated the role of immune responses to donor human leukocyte antigens (HLA) and tissue-restricted kidney and pancreas self-antigens (KSAgs and PSAgs, respectively) in SKP Tx recipients (SKP TxRs). Sera collected from 39 SKP TxRs were used to determine de novo Abs specific for KSAgs (collagen-IV, Col-IV; fibronectin, FN) and PSAgs (insulin, islet cells, glutamic acid decarboxylase, and pancreas-associated protein-1) by ELISA. KSAg-specific IFN-gamma, IL-17, and IL-10 cytokines were enumerated by ELISpot. Abs to donor HLA classes I and II were determined by Luminex assay. Abs to KSAgs and PSAgs were detectable in recipients with rejection compared with stable recipients (P<.05). Kidney-only rejection recipients had increased Abs against KSAgs compared with stable (P<.05), with no increase in Abs against PSAgs. Pancreas-only rejection recipients showed increased Abs against PSAgs compared to stable (P<.05), with no Abs against KSAgs. SKP TxRs with rejection showed increased frequencies of KSAg-specific IFN gamma and IL-17 with reduction in IL-10-secreting cells. SKP TxRs with rejection developed Abs to KSAgs and PSAgs demonstrated increased frequencies of kidney or pancreas SAg-specific IFN-gamma and IL-17-secreting cells with reduced IL-10, suggesting loss of peripheral tolerance to SAgs. PMID- 28639387 TI - Determining the orientation angle of directional leads for deep brain stimulation using computed tomography and digital x-ray imaging: A phantom study. AB - PURPOSE: Orientating the angle of directional leads for deep brain stimulation (DBS) in an axial plane introduces a new degree of freedom that is indicated by embedded anisotropic directional markers. Our aim was to develop algorithms to determine lead orientation angles from computed tomography (CT) and stereotactic x-ray imaging using standard clinical protocols, and subsequently assess the accuracy of both methods. METHODS: In CT the anisotropic marker artifact was taken as a signature of the lead orientation angle and analyzed using discrete Fourier transform of circular intensity profiles. The orientation angle was determined from phase angles at a frequency 2/360 degrees and corrected for aberrations at oblique leads. In x-ray imaging, frontal and lateral images were registered to stereotactic space and sub-images containing directional markers were extracted. These images were compared with projection images of an identically located virtual marker at different orientation angles. A similarity index was calculated and used to determine the lead orientation angle. Both methods were tested using epoxy phantoms containing directional leads (CartesiaTM, Boston Scientific, Marlborough, USA) with known orientation. Anthropomorphic phantoms were used to compare both methods for DBS cases. RESULTS: Mean deviation between CT and x-ray was 1.5 degrees +/- 3.6 degrees (range: -2.3 degrees to 7.9 degrees ) for epoxy phantoms and 3.6 degrees +/- 7.1 degrees (range: -5.6 degrees to 14.6 degrees ) for anthropomorphic phantoms. After correction for imperfections in the epoxy phantoms, the mean deviation from ground truth was 0.0 degrees +/- 5.0 degrees (range: -12 degrees to 14 degrees ) for x-ray. For CT the results depended on the polar angle of the lead in the scanner. Mean deviation was -0.3 degrees +/- 1.9 degrees (range: 4.6 degrees to 6.6 degrees ) or 1.6 degrees +/- 8.9 degrees (range: -23 degrees to 34 degrees ) for polar angles <= 40 degrees or > 40 degrees . CONCLUSIONS: The results show that both imaging modalities can be used to determine lead orientation angles with high accuracy. CT is superior to x-ray imaging, but oblique leads (polar angle > 40 degrees ) show limited precision due to the current design of the directional marker. PMID- 28639389 TI - Implementing two nurse practitioner models of service at an Australian male prison: A quality assurance study. AB - AIMS AND OBJECTIVES: To examine the quality and safety of nurse practitioner services of two newly implemented nurse practitioner models of care at a correctional facility. BACKGROUND: Nurse practitioners could help to meet the physical and mental health needs of Australia's growing prison population; however, the nurse practitioner role has not previously been evaluated in this context. DESIGN: A quality assurance study conducted in an Australian prison where a primary health nurse practitioner and a mental health nurse practitioner were incorporated into an existing primary healthcare service. The study was guided by Donabedian's structure, processes and outcomes framework. METHODS: Routinely collected information included surveys of staff attitudes to the implementation of the nurse practitioner models (n = 21 staff), consultation records describing clinical processes and time use (n = 289 consultations), and a patient satisfaction survey (n = 29 patients). Data were analysed descriptively and compared to external benchmarks where available. RESULTS: Over the two-month period, the nurse practitioners provided 289 consultations to 208 prisoners. The presenting problems treated indicated that most referrals were appropriate. A significant proportion of consultations involved medication review and management. Both nurse practitioners spent more than half of their time on individual patient-related care. Overall, multidisciplinary team staff agreed that the nurse practitioner services were necessary, safe, met patient need and reduced treatment delays. CONCLUSIONS: Findings suggest that the implementation of nurse practitioners into Australian correctional facilities is acceptable and feasible and has the potential to improve prisoners' access to health services. Structural factors (e.g., room availability and limited access to prisoners) may have reduced the efficiency of the nurse practitioners' clinical processes and service implementation. RELEVANCE TO CLINICAL PRACTICE: Results suggest that nurse practitioner models can be successfully integrated into a prison setting and could provide a nursing career pathway. PMID- 28639390 TI - Design, synthesis, and biological evaluation of a new class of benzo[b]furan derivatives as antiproliferative agents, with in silico predicted antitubulin activity. AB - A new series of 3-benzoylamino-5-(1H-imidazol-4-yl)methylaminobenzo[b]furans were synthesized and screened as antitumor agents. As a general trend, tested compounds showed concentration-dependent antiproliferative activity against HeLa and MCF-7 cancer cell lines, exhibiting GI50 values in the low micromolar range. In most cases, insertion of a methyl substituent on the imidazole moiety improved the antiproliferative activity. Therefore, methyl-imidazolyl-benzo[b]furans compounds were tested in cell cycle perturbation experiments, producing cell cycle arrest with proapoptotic effects. Their core similarity to known colchicine binding site binders led us to further study the structure features as antitubulin agents by in silico protocols. PMID- 28639391 TI - An investigation of the relationship between recurrent spontaneous abortion and memory T follicular helper cells. AB - PROBLEM: Immune tolerance with respect to a semi-allogeneic fetus plays a key role in the establishment of a pregnancy. Memory T follicular helper (Tfh) cells have a central role in the regulation of the adaptive immune response. Much of our knowledge of memory Tfh cells' function comes from immune-related diseases. However, the true physiological characteristics of memory Tfh cells and their mode of action in pregnancy remain unclear. METHODS OF STUDY: Deciduas and blood were obtained from 25 recurrent spontaneous abortion (RSA) patients undergoing surgical abortion and 19 normal women in early pregnancy undergoing elective termination. RSA patients were grouped into antibody-positive patients and antibody-negative patients, respectively. The memory Tfh cells with the CD4+ CXCR5+ PD1+ CCR7- and CD4+ CXCR5+ PD-1+ ICOS+ phenotypes were assessed by flow cytometry. The B cells were evaluated by flow cytometry. A correlation analysis of the subsets of memory Tfh cells and B cells in antibody-positive RSA patients was made by the Pearson test. RESULTS: Memory Tfh cells with the CD4+ CXCR5+ PD1+ CCR7- and CD4+ CXCR5+ PD-1+ ICOS+ phenotypes showed a significant increase in RSA patients compared to women with a normal pregnancy who had chosen termination. When RSA patients were grouped according positive or negative antibodies, it was surprising to find that decidual CD4+ CXCR5+ PD-1+ ICOS+ memory Tfh cells significantly increased in RSA patients with positive antibody compared to RSA patients with negative antibody. However, the percentages of CD4+ CXCR5+ PD1+ CCR7- memory Tfh cells did not change in the deciduas of the two groups. Circulating and decidual B cells significantly increased in antibody-positive RSA patients compared with antibody-negative RSA patients. Correlation analysis indicated a strong association between the decidual CD4+ CXCR5+ PD-1+ ICOS+ memory Tfh cells and B cells in antibody-positive RSA patients. CONCLUSION: These new findings provide unique insights into memory Tfh cells in mediating feto maternal immune tolerance. PMID- 28639393 TI - An Activatable Photosensitizer Targeted to gamma-Glutamyltranspeptidase. AB - We adopted a spirocyclization-based strategy to design gamma-glutamyl hydroxymethyl selenorhodamine green (gGlu-HMSeR) as a photo-inactive compound that would be specifically cleaved by the tumor-associated enzyme gamma glutamyltranspeptidase (GGT) to generate the potent photosensitizer HMSeR. gGlu HMSeR has a spirocyclic structure and is colorless and does not show marked phototoxicity toward low-GGT-expressing cells or normal tissues upon irradiation with visible light. In contrast, HMSeR predominantly takes an open structure, is colored, and generates reactive oxygen species upon irradiation. The gamma glutamyl group thus serves as a tumor-targeting moiety for photodynamic therapy (PDT), switching on tumor-cell-specific phototoxicity. To validate this system, we employed chick chorioallantoic membrane (CAM), a widely used model for preliminary evaluation of drug toxicity. Photoirradiation after gGlu-HMSeR treatment resulted in selective ablation of implanted tumor spheroids without damage to healthy tissue. PMID- 28639392 TI - High-Performance 2.6 V Aqueous Asymmetric Supercapacitors based on In Situ Formed Na0.5 MnO2 Nanosheet Assembled Nanowall Arrays. AB - The voltage limit for aqueous asymmetric supercapacitors is usually 2 V, which impedes further improvement in energy density. Here, high Na content Birnessite Na0.5 MnO2 nanosheet assembled nanowall arrays are in situ formed on carbon cloth via electrochemical oxidation. It is interesting to find that the electrode potential window for Na0.5 MnO2 nanowall arrays can be extended to 0-1.3 V (vs Ag/AgCl) with significantly increased specific capacitance up to 366 F g-1 . The extended potential window for the Na0.5 MnO2 electrode provides the opportunity to further increase the cell voltage of aqueous asymmetric supercapacitors beyond 2 V. To construct the asymmetric supercapacitor, carbon-coated Fe3 O4 nanorod arrays are synthesized as the anode and can stably work in a negative potential window of -1.3 to 0 V (vs Ag/AgCl). For the first time, a 2.6 V aqueous asymmetric supercapacitor is demonstrated by using Na0.5 MnO2 nanowall arrays as the cathode and carbon-coated Fe3 O4 nanorod arrays as the anode. In particular, the 2.6 V Na0.5 MnO2 //Fe3 O4 @C asymmetric supercapacitor exhibits a large energy density of up to 81 Wh kg-1 as well as excellent rate capability and cycle performance, outperforming previously reported MnO2 -based supercapacitors. This work provides new opportunities for developing high-voltage aqueous asymmetric supercapacitors with further increased energy density. PMID- 28639394 TI - Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier. AB - Application of many vital hydrophilic medicines have been restricted by blood brain barrier (BBB) for treatment of brain diseases. In this study, a targeted drug delivery system based on dextran-spermine biopolymer was developed for drug transport across BBB. Drug loaded magnetic dextran-spermine nanoparticles (DS NPs) were prepared via ionic gelation followed by transferrin (Tf) conjugation as targeting moiety. The characteristics of Tf conjugated nanoparticles (TDS-NPs) were analyzed by different methods and their cytotoxicity effects on U87MG cells were tested. The superparamagnetic characteristic of TDS-NPs was verified by vibration simple magnetometer. Capecitabine loaded TDS-NPs exhibited pH-sensitive release behavior with enhanced cytotoxicity against U87MG cells, compared to DS NPs and free capecitabine. Prussian-blue staining and TEM-imaging showed the significant cellular uptake of TDS-NPs. Furthermore, a remarkable increase of Fe concentrations in brain was observed following their biodistribution and histological studies in vivo, after 1 and 7 days of post-injection. Enhanced drug transport across BBB and pH-triggered cellular uptake of TDS-NPs indicated that these theranostic nanocarriers are promising candidate for the brain malignance treatment. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2851 2864, 2017. PMID- 28639395 TI - Spatiotemporally Controllable Peptide-Based Nanoassembly in Single Living Cells for a Biological Self-Portrait. AB - Simultaneous precise localization and activity evaluation of a biomolecule in a single living cell is through an enzyme-specific signal-amplification process, which involves the localized, site-specific self-assembly, and activation of a presignaling molecule. The inactive presignaling tetraphenylethylene (TPE) peptide derivative, TPE-YpYY, is nondetectable and highly biocompatible and these small molecules rapidly diffuse into living cells. Upon safely arriving at an active site, and accessing the catalytic pocket of an enzyme, TPE-YpYY immediately and quantitatively accumulates in situ in response to enzymatic activity, forms an enzyme anchor TPE-YYY nanoassembly, displays aggregation induced emission behavior, and finally lights up the active enzyme, indicating its activity, and allowing its status in living cells to be tracked. This simple and direct self-portrait method can be used to monitor dynamic self-assembly processes in individual living cells and may provide new insights that reveal undiscovered biological processes and that aid in developing biomedical hybrid devices. In the future, this strategy of molecular design can be further expanded to the noninvasive investigation of other bioactive molecules, thus facilitating quantitative imaging. PMID- 28639396 TI - The influence of parental concern on the utility of autism diagnostic instruments. AB - The parental report-based Autism Diagnostic Interview-Revised (ADI-R) and the clinician observation-based Autism Diagnostic Observation Schedule (ADOS) have been validated primarily in U.S. clinics specialized in autism spectrum disorder (ASD), in which most children are referred by their parents because of ASD concern. This study assessed diagnostic agreement of the ADOS-2 and ADI-R toddler algorithms in a more broadly based sample of 679 toddlers (age 35-47 months) from the Norwegian Mother and Child Cohort. We also examined whether parental concern about ASD influenced instrument performance, comparing toddlers identified based on parental ASD concern (n = 48) and parent-reported signs of developmental problems (screening) without a specific concern about ASD (n = 400). The ADOS cutoffs showed consistently well-balanced sensitivity and specificity. The ADI-R cutoffs demonstrated good specificity, but reduced sensitivity, missing 43% of toddlers whose parents were not specifically concerned about ASD. The ADI-R and ADOS dimensional scores agreed well with clinical diagnoses (area under the curve >= 0.85), contributing additively to their prediction. On the ADI-R, different cutoffs were needed according to presence or absence of parental ASD concern, in order to achieve comparable balance of sensitivity and specificity. These results highlight the importance of taking parental concern about ASD into account when interpreting scores from parental report-based instruments such as the ADI-R. While the ADOS cutoffs performed consistently well, the additive contributions of ADI-R and ADOS scores to the prediction of ASD diagnosis underscore the value of combining instruments based on parent accounts and clinician observation in evaluation of ASD. Autism Res 2017, 10: 1672-1686. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28639397 TI - Ovarian polarity and cell shape determination by Btk29A in Drosophila. AB - Drosophila Btk29A is a Tec family nonreceptor tyrosine kinase, the ortholog of which causes X-linked agammaglobulinemia in humans when mutant. In Btk29AficP mutant ovaries, multiple defects are observed: extrapolar cells form ectopically; osk mRNA fails to accumulate posteriorly in mature oocytes; the shape and alignment of follicle cells are grossly distorted. All these phenotypes are rescued by selectively overexpressing the type 2 isoform of wild-type Btk29A in follicle cells. Expression of certain proteins enriched in adherens junctions is markedly affected in Btk29AficP mutants; the anterior-posterior gradient normally observed in the expression of DE-Cadherin and Armadillo are lost and Canoe is sequestered from adherens junctions. Intriguingly, tyrosine phosphorylation of Canoe is reduced in Btk29AficP mutants. It is proposed that Btk29A is required for the establishment of egg chamber polarity presumably through the regulation of subcellular localization of its downstream proteins, including Cno. PMID- 28639399 TI - TP73-AS1 promotes breast cancer cell proliferation through miR-200a-mediated TFAM inhibition. AB - P73 antisense RNA 1T (TP73-AS1 or PDAM) is a long non-coding RNA, which can regulate apoptosis through regulation of p53 signaling-related anti-apoptotic genes. An abnormal change of TP73-AS1 expression was noticed in cancers. The effects of TP73-AS1 in breast cancer (BC) growth and the underlying mechanism remain unclear so far. In the present study, the effect of TP73-AS1 in BC cell lines and clinical tumor samples was detected so as to reveal its role and function. In the present study, TP73-AS1 was specifically upregulated in BC tissues and BC cell lines and was correlated to a poorer prognosis in patients with BC. TP73-AS1 knocking down suppressed human BC cell proliferation in vitro through regulation of TFAM. In our previous study, we demonstrated that miR-200a inhibits BC cell proliferation through targeting TFAM; here we revealed that TP73 AS1 could regulate miR-200a through direct targeting. Moreover, TP73-AS1 might compete with TFAM for miR-200a binding thus to promote TFAM expression. Data from the present study revealed that TP73-AS1 promoted BC cell proliferation through acting as a competing endogenous RNA (ceRNA) by sponging miR-200a. In conclusion, we regarded TP73-AS1 as an oncogenic lncRNA promoting BC cell proliferation and a potential target for human BC treatment. PMID- 28639398 TI - Epstein-Barr viral loads do not predict post-transplant lymphoproliferative disorder in pediatric lung transplant recipients: A multicenter prospective cohort study. AB - Prediction of PTLD after pediatric lung transplant remains difficult. Use of EBV VL in WB has been poorly predictive, while measurement of VL in BAL fluid has been suggested to have enhanced utility. The NIH-sponsored Clinical Trials in Organ Transplantation in Children (CTOTC-03) prospectively obtained serial quantitative measurements of EBV PCR in both WB and BAL fluid after pediatric lung transplantation. Descriptive statistics, contingency analyses, and Kaplan Meier analyses evaluated possible association between EBV and PTLD. Of 61 patients, 34 (56%) had an EBV+PCR (at least once in WB or BAL). EBV donor (D)+patients more often had a positive PCR (D+/recipient (R)-: 13/18; D+/R+: 14/23) compared to EBV D- patients (6/17). Several D-/R- (5/12) patients developed EBV, but none developed PTLD. All four PTLD patients were D+/R- with EBV+PCR. Neither the time to first EBV+PCR nor the CT for PCR positivity in BAL or WB was statistically different between those with and without PTLD. Having an EBV-seropositive donor was associated with increased risk of EBV+PCR in WB. EBV load in BAL was not predictive of PTLD. PMID- 28639400 TI - Motion estimation for cardiac functional analysis using two x-ray computed tomography scans. AB - PURPOSE: This work concerns computed tomography (CT)-based cardiac functional analysis (CFA) with a reduced radiation dose. As CT-CFA requires images over the entire heartbeat, the scans are often performed at 10-20% of the tube current settings that are typically used for coronary CT angiography. A large image noise then degrades the accuracy of motion estimation. Moreover, even if the scan was performed during the sinus rhythm, the cardiac motion observed in CT images may not be cyclic with patients with atrial fibrillation. In this study, we propose to use two CT scan data, one for CT angiography at a quiescent phase at a standard dose and the other for CFA over the entire heart beat at a lower dose. METHODS: We have made the following four modifications to an image-based cardiac motion estimation method we have previously developed for a full-dose retrospectively gated coronary CT angiography: (a) a full-dose prospectively gated coronary CT angiography image acquired at the least motion phase was used as the reference image; (b) a three-dimensional median filter was applied to lower-dose retrospectively gated cardiac images acquired at 20 phases over one heartbeat in order to reduce image noise; (c) the strength of the temporal regularization term was made adaptive; and (d) a one-dimensional temporal filter was applied to the estimated motion vector field in order to decrease jaggy motion patterns. We describe the conventional method iME1 and the proposed method iME2 in this article. Five observers assessed the accuracy of the estimated motion vector field of iME2 and iME1 using a 4-point scale. The observers repeated the assessment with data presented in a new random order 1 week after the first assessment session. RESULTS: The study confirmed that the proposed iME2 was robust against the mismatch of noise levels, contrast enhancement levels, and shapes of the chambers. There was a statistically significant difference between iME2 and iME1 (accuracy score, 2.08 +/- 0.81 versus 2.77 +/- 0.98, P < 0.01) and the improvement by the score of + 0.69 seemed clinically relevant. Inter-observer concordance was good: The inter-class correlation coefficient was 0.63 and Kendall's rank correlation coefficients were in the range of 0.41-0.67 (P < 0.01), respectively. Intra-observer reproducibility between sessions was good with the inter-class correlation coefficient of 0.76. CONCLUSION: We have proposed iME2 method for CT-CFA with two CT scans. The observer study verified the robustness and accuracy of iME2 method and its improved performance over iME1 method. PMID- 28639401 TI - Van der Waals Epitaxial Growth of Atomic Layered HfS2 Crystals for Ultrasensitive Near-Infrared Phototransistors. AB - As a member of the group IVB transition metal dichalcogenides (TMDs) family, hafnium disulfide (HfS2 ) is recently predicted to exhibit higher carrier mobility and higher tunneling current density than group VIB (Mo and W) TMDs. However, the synthesis of high-quality HfS2 crystals, sparsely reported, has greatly hindered the development of this new field. Here, a facile strategy for controlled synthesis of high-quality atomic layered HfS2 crystals by van der Waals epitaxy is reported. Density functional theory calculations are applied to elucidate the systematic epitaxial growth process of the S-edge and Hf-edge. Impressively, the HfS2 back-gate field-effect transistors display a competitive mobility of 7.6 cm2 V-1 s-1 and an ultrahigh on/off ratio exceeding 108 . Meanwhile, ultrasensitive near-infrared phototransistors based on the HfS2 crystals (indirect bandgap ~1.45 eV) exhibit an ultrahigh responsivity exceeding 3.08 * 105 A W-1 , which is 109 -fold higher than 9 * 10-5 A W-1 obtained from the multilayer MoS2 in near-infrared photodetection. Moreover, an ultrahigh photogain exceeding 4.72 * 105 and an ultrahigh detectivity exceeding 4.01 * 1012 Jones, superior to the vast majority of the reported 2D-materials-based phototransistors, imply a great promise in TMD-based 2D electronic and optoelectronic applications. PMID- 28639402 TI - Reply to 'Multiple and Opposite Effects of Angiotensin II Receptor Blockers on the Bioavailability of Epoxyeicosatrienoic Acids'. PMID- 28639403 TI - Writing with Fluid: Structuring Hydrogels with Micrometer Precision by AFM in Combination with Nanofluidics. AB - Hydrogels have many applications in biomedical surface modification and tissue engineering. However, the structuring of hydrogels after their formation represents still a major challenge, in particular due to their softness. Here, a novel approach is presented that is based on the combination of atomic force microscopy (AFM) and nanofluidics, also referred to as FluidFM technology. Its applicability is demonstrated for supramolecular hydrogel films that are prepared from low-molecular weight hydrogelators, such as derivates of 1,3,5-benzene tricarboxamides (BTAs). BTA films can be dissolved selectively by ejecting alkaline solution through the aperture of a hollow AFM-cantilever connected to a nanofluidic controller. The AFM-based force control is essential in preventing mechanical destruction of the hydrogels. The resulting "chemical writing" process is studied in detail and the influence of various parameters, such as applied pressure and time, is validated. It is demonstrated that the achievable structuring precision is primarily limited by diffusion and the aperture dimensions. Recently, various additive techniques have been presented to pattern hydrogels. The here-presented subtractive approach can not only be applied to structure hydrogels from the large class of reversibly formed gels with superior resolution but would also allow for the selective loading of the hydrogels with active substances or nanoparticles. PMID- 28639404 TI - Mechanoresponsiveness of human adipose stem cells on nanocomposite and micro hybrid composite. AB - Resin-based composites are used for bone repair applications and comprise resin matrix and different sized filler particles. Nanometer-sized filler particles improve composite's mechanical properties compared with micrometer-sized filler particles, but whether differences exist in the biological response to these composites is unknown. Natural bone comprises a nanocomposite structure, and nanoscale interactions with extracellular matrix components influence stem cell differentiation. Therefore we hypothesized that nanometer-sized filler particles in resin-based composites enhance osteogenic differentiation of stem cells showing a more bone cell-like response to mechanical loading compared with micrometer-sized filler particles. Pulsating fluid flow (PFF; 5 Hz, mean shear stress: 0.7 Pa; 1 h) rapidly, within 5 min, increased nitric oxide production in human adipose stem cells (hASCs) on nanocomposite, but not on micro-hybrid composite. PFF increased RUNX2 expression in hASCs on micro-hybrid composite, but not on nanocomposite after 2 h post-incubation. PFF did not affect mean cell orientation and shape index of hASCs on both composites. In conclusion, the PFF increased nitric oxide production in hASCs on nanocomposite, and increased osteogenic differentiation of hASCs on micro-hybrid composite suggest different responses to mechanical loading of hASCs on composite with nanometer-sized and micrometer-sized filler particles. This might have important implications for bone tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2986-2994, 2017. PMID- 28639405 TI - Multiple and Opposite Effects of Angiotensin II Receptor Blockers on the Bioavailability of Epoxyeicosatrienoic Acids. PMID- 28639406 TI - Controlling cyanobacterial harmful blooms in freshwater ecosystems. AB - Cyanobacteria's long evolutionary history has enabled them to adapt to geochemical and climatic changes, and more recent human and climatic modifications of aquatic ecosystems, including nutrient over-enrichment, hydrologic modifications, and global warming. Harmful (toxic, hypoxia-generating, food web altering) cyanobacterial bloom (CyanoHAB) genera are controlled by the synergistic effects of nutrient (nitrogen and phosphorus) supplies, light, temperature, water residence/flushing times, and biotic interactions. Accordingly, mitigation strategies are focused on manipulating these dynamic factors. Strategies based on physical, chemical (algaecide) and biological manipulations can be effective in reducing CyanoHABs. However, these strategies should invariably be accompanied by nutrient (both nitrogen and phosphorus in most cases) input reductions to ensure long-term success and sustainability. While the applicability and feasibility of various controls and management approaches is focused on freshwater ecosystems, they will also be applicable to estuarine and coastal ecosystems. In order to ensure long-term control of CyanoHABs, these strategies should be adaptive to climatic variability and change, because nutrient-CyanoHAB thresholds will likely be altered in a climatically more-extreme world. PMID- 28639407 TI - Factorial structure and construct validity of an Italian version of the Fears of Compassion Scales: A study on non-clinical subjects. AB - OBJECTIVES: This study was aimed at investigating the factorial structure and the construct validity of the Italian translation of the Fears of Compassion (FC) Scales in a non-clinical sample (i.e., Fear of Compassion From Others [FCFO], Fear of Compassion Towards Others [FCTO] and Fear of Self-Compassion [FSC]). An exploratory factor analysis was conducted on all the items to investigate the dimensionality of the FC scales. To assess construct validity, correlations between the FC scales and a series of construct-related measures were analysed. DESIGN/METHODS: After being translated into Italian using a back-translation procedure, the questionnaire was administered to a community sample of 298 participants (82 males) with a mean age of 24.31 (SD = 8.75), along with self report measures of psychopathological symptoms, attachment style, self-esteem, satisfaction with life and altruistic behaviour. A behavioural test of altruism was also administered in a subsample of 40 subjects. RESULTS: Thirteen of 38 items did not show adequate psychometric characteristics and thus were removed. The remaining 25 items showed a clear 3-factor solution which explained 48% of the variance. FC Scales were significantly correlated with all the construct related scales administered in the expected direction, with higher effect sizes for FCFO and FSC than FCTO. CONCLUSIONS: Although 13 items were removed, results confirmed the expected three factor solution for the Italian translation of FC scales, and provided new evidence for their construct validity. In this vein, an interesting pattern of correlations emerged with psychiatric symptoms and prosocial behaviour, indicating that FCFO and FSC are more powerful correlates of psychopathology and altruism with respect to FCTO. PRACTITIONER POINTS: Fears of Compassion Scales have been increasingly used in clinical and research settings. The reduced Italian version of the FCS developed in this study is a valid and parsimonious instrument. Fears of receiving compassion from others and from ourselves are more powerful predictors of psychopathological symptoms than fear of giving compassion to others. Fears of Compassion Scales were correlated with both a self-report and a behavioural measure of altruism. PMID- 28639408 TI - Quantifying long-term impact of zoo and aquarium visits on biodiversity-related learning outcomes. AB - Zoos and aquariums aim to achieve lasting impact on their public audiences' awareness of biodiversity, its value, and the steps they can take to conserve it. Here, we evaluate the long-term educational impact of visits to zoos and aquariums on biodiversity understanding and knowledge of actions to help protect biodiversity. A minimum of two years after completing a repeated-measures survey before and after visiting a zoo or aquarium, the same participants were invited to take part in a follow-up online survey. Despite the small number of respondents (n = 161), our study may still represent the best available quantitative evidence pertaining to zoo and aquarium visits' long-term educational impact. We found that improvements in respondents' biodiversity understanding from pre- to post-visit leveled off, staying unchanged in the follow-up survey. In contrast, the improved knowledge of actions to help protect biodiversity from pre- to post-visit showed further improvement from post-visit to delayed post-visit follow-up survey. These results suggest that the immediate positive effects of a zoo or aquarium visit on biodiversity-related learning outcomes may be long lasting and even help lay the groundwork for further improvements over an extended period of time following the visit. PMID- 28639409 TI - Anti-PD-1 antibodies in metastatic uveal melanoma: a treatment option? AB - Uveal melanomas (UMs) are a rare form of cancer with clinical and pathological characteristics distinct from cutaneous melanomas. Ipilimumab has shown efficacy and safety in the treatment of metastatic UM. This provides a rationale for treatment with other immune checkpoint inhibitors. This is a retrospective review of 15 patients with metastatic UM treated between June 2014 and February 2016, who received treatment with the anti-PD-1 Abs pembrolizumab or nivolumab. Patients were treated at two German university hospitals. Therapy was administered at the approved dosing schedules of 2 mg/kg q3w for pembrolizumab and 3 mg/kg q2w for nivolumab. Treatment was given until first tumor assessment and continued if tumor assessment showed disease control. Tumor assessments were performed at baseline and following scans every 12 weeks. Patients were monitored throughout for adverse events. Best response to treatment was stable disease in four patients. Eight out of 15 (53%) patients received treatment until first tumor assessment. As of February 2016, median progression-free survival (PFS) is 3 months (range 0.75-6.75 months) and overall survival (OS) is 5 months (range 1 16 months). Eight out of 15 (53%) patients are still alive (two patients lost to follow-up) with one out of four patients is in ongoing disease control. Patients with multiple organ metastases and elevated serum lactate dehydrogenase did not respond well to treatment. No objective response to PD-1 Ab therapy was seen. Best response to treatment was stable disease in four patients. Treatment was well tolerated with manageable toxicity. PMID- 28639411 TI - Mapping the allosteric sites of the A2A adenosine receptor. AB - The A2A adenosine receptor (A2A AR) is a G protein-coupled receptor that is pharmacologically targeted for the treatment of inflammation, sepsis, cancer, neurodegeneration, and Parkinson's disease. Recently, we applied long-timescale molecular dynamics simulations on two ligand-free receptor conformations, starting from the agonist-bound (PDB ID: 3QAK) and antagonist-bound (PDB ID: 3EML) X-ray structures. This analysis revealed four distinct conformers of the A2A AR: the active, intermediate 1, intermediate 2, and inactive. In this study, we apply the fragment-based mapping algorithm, FTMap, on these receptor conformations to uncover five non-orthosteric sites on the A2A AR. Two sites that are identified in the active conformation are located in the intracellular region of the transmembrane helices (TM) 3/TM4 and the G protein-binding site in the intracellular region between TM2/TM3/TM6/TM7. Three sites are identified in the intermediate 1 and intermediate 2 conformations, annexing a site in the lipid interface of TM5/TM6. Five sites are identified in the inactive conformation, comprising a site in the intracellular region of TM1/TM7 and in the extracellular region of TM3/TM4 of the A2A AR. We postulate that these sites on the A2A AR be screened for allosteric modulators for the treatment of inflammatory and neurological diseases. PMID- 28639412 TI - The role of microRNA-5196 in the pathogenesis of systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by tissue fibrosis and immune abnormalities. Recent evidence suggests that activated circulating monocytes from patients with SSc play an important role in early stages of SSc pathogenesis due to enhanced expression of tissue inhibitor of metalloproteinases 1 (TIMP-1), IL-8 and reactive oxygen species (ROS) induction. However, the exact factors that contribute to chronic inflammation and subsequently fibrosis progression are still unknown. MATERIALS AND METHODS: The expression pattern of IL-8, TIMP-1, AP-1 transcription factor Fra2 and ROS induction in peripheral blood monocytes following DZNep (histone methyltransferase inhibitor) and TLR8 agonist stimulation was investigated. Exogenous microRNA-5196, which is predicted to bind 3'UTR of Fra2 gene, was delivered to reverse profibrotic phenotype in monocytes. Expression of circulating microRNA-5196 was correlated with SSc parameters. RESULTS: DZNep + TLR8 agonist stimulation enhanced profibrotic TIMP-1, IL-8 and ROS generation in HC and SSc monocytes. As opposed by the decrease of miRNA-5196 and antioxidant SOD1 expression in SSc monocytes. Exogenous delivery of microRNA-5196 reduced Fra2 and TIMP-1 expression suggesting that it may be used as a potential modulator of fibrogenesis in SSc. Circulating microRNA-5196 was significantly increased in SSc and positively correlated with CRP level but not with Rodnan skin score or ESR. CONCLUSIONS: These results suggest that microRNA-5196 can be used as a potential biomarker characterising SSc. Overall, this study may open new possibilities for the development of microRNA-5196-based diagnostics and therapy in early phases of SSc. PMID- 28639413 TI - Fully-Inorganic Trihalide Perovskite Nanocrystals: A New Research Frontier of Optoelectronic Materials. AB - All-inorganic trihalide perovskite nanocrystals (NCs) are emerging as a new class of superstar semiconductors with excellent optoelectronic properties and great potential for a broad range of applications in lighting, lasing, photon detection, and photovoltaics. This article provides an up-to-date review on the developments of fully-inorganic trihalide perovskite NCs by emphasizing their controllable solution fabrication strategies, structural phase transformation, tunable optoelectronic properties, stability, as well as their photovoltaic and optoelectronic applications. Among the properties to be surveyed, particular focus is on the size-, shape-, and composition-dependent photoluminescence properties. Finally, by identifying new challenges, suggestions are provided for further research and potential development of this area. PMID- 28639410 TI - Long-term survival benefit of upfront chemotherapy in patients with newly diagnosed borderline resectable pancreatic cancer. AB - The use of neoadjuvant chemotherapy or radiation for borderline resectable pancreatic adenocarcinoma (BL-PDAC) is increasing. However, the impact of neoadjuvant chemotherapy and radiation therapy on the outcome of BL-PDAC remains to be elucidated. We performed a retrospective analysis of 93 consecutive patients who were diagnosed with BL-PDAC and primarily followed at Johns Hopkins Hospital between February 2007 and December 2012. Among 93 patients, 62% received upfront neoadjuvant chemotherapy followed by chemoradiation, whereas 20% received neoadjuvant chemoradiation alone and 15% neoadjuvant chemotherapy alone. Resectability following all neoadjuvant therapy was 44%. Patients who underwent resection with a curative intent had a median overall survival (mOS) of 25.8 months, whereas those who did not undergo surgery had a mOS of 11.9 months. However, resectability and overall survival were not significantly different between the three types of neoadjuvant therapy. Nevertheless, 22% (95% CI, 0.13 0.36) of the 58 patients who received upfront chemotherapy followed by chemoradiation remained alive for a minimum of 48 months compared to none of the 19 patients who received upfront chemoradiation. Among patients who underwent curative surgical resection, 32% (95% CI, 0.19-0.55) of those who received upfront chemotherapy remained disease free at least 48 months following surgical resection, whereas none of the eight patients who received upfront chemoradiation remained disease free beyond 24 months following surgical resection. Neoadjuvant therapy with upfront chemotherapy may result in long-term survival in a subpopulation of patients with BL-PDAC. PMID- 28639414 TI - Brachiaria Grasses (Brachiaria spp.) harbor a diverse bacterial community with multiple attributes beneficial to plant growth and development. AB - Endophytic and plant-associated bacteria were isolated from plants and rhizoplane soil of naturally grown Brachiaria grasses at International Livestock Research Institute in Nairobi, Kenya. Eighty-four bacterial strains were isolated from leaf tissues, root tissues, and rhizoplane soil on nutrient agar and 869 media. All bacterial strains were identified to the lowest possible taxonomic unit using 16S rDNA primers and were characterized for the production of Indole-3-acetic acid, hydrogen cyanide, and ACC deaminase; phosphate solubilization; siderophore production; antifungal properties; and plant biomass production. The 16S rDNA based identification grouped these 84 bacterial strains into 3 phyla, 5 classes, 8 orders, 12 families, 16 genera, and 50 unique taxa. The four most frequently isolated genera were Pseudomonas (23), Pantoea (17), Acinetobacter (9), and Enterobacter (8). The functional characterization of these strains revealed that 41 of 84 strains had a minimum of three plant beneficial properties. Inoculation of maize seedlings with Acinetobacter spp., Microbacterium spp., Pectobacterium spp., Pseudomonas spp., and Enterobacter spp. showed positive effects on seedling biomass production. The ability of Brachiaria grasses to host genetically diverse bacteria, many of them with multiple plant growth-promoting attributes, might have contributed to high biomass production and adaptation of Brachiaria grasses to drought and low fertility soils. PMID- 28639415 TI - Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis. AB - BACKGROUND: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities can reduce oedema and thereby improve vision and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. OBJECTIVES: The 2014 update of this review found high-quality evidence of benefit with antiangiogenic therapy with anti-VEGF modalities, compared to laser photocoagulation, for the treatment of DMO.The objective of this updated review is to compare the effectiveness and safety of the different anti-VEGF drugs in preserving and improving vision and quality of life using network meta-analysis methods. SEARCH METHODS: We searched various electronic databases on 26 April 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham or no treatment in people with DMO. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for pair-wise meta-analysis and we augmented this evidence using network meta-analysis methods. We focused on the relative efficacy and safety of the three most commonly used drugs as interventions of direct interest for practice: aflibercept and ranibizumab, used on-label; and off-label bevacizumab.We collected data on three efficacy outcomes (gain of 15 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters; mean change in best corrected visual acuity (BCVA); mean change in central retinal thickness (CRT)), three safety outcomes (all severe systemic adverse events (SSAEs); all-cause death; arterial thromboembolic events) and quality of life.We used Stata 'network' meta-analysis package for all analyses. We investigated the risk of bias of mixed comparisons based on the variance contribution of each study, having assigned an overall risk of bias to each study. MAIN RESULTS: Twenty-four studies included 6007 participants with DMO and moderate vision loss, of which two studies randomised 265 eyes of 230 participants and one was a cross-over study on 56 participants (62 eyes) that was treated as a parallel-arm trial. Data were collected on drugs of direct interest from three studies on aflibercept (975 eyes), eight studies on bevacizumab (515 eyes), and 14 studies on ranibizumab (1518 eyes). As treatments of indirect interest or legacy treatment we included three studies on pegaptanib (541 eyes), five studies on ranibizumab plus prompt laser (557 eyes), one study on ranibizumab plus deferred laser (188 eyes), 13 studies on laser photocoagulation (936 eyes) and six studies on sham treatment (793 eyes).Aflibercept, bevacizumab and ranibizumab were all more effective than laser for improving vision by 3 or more lines after one year (high-certainty evidence). Approximately one in 10 people improve vision with laser, and about three in 10 people improve with anti-VEGF treatment: risk ratio (RR) versus laser 3.66 (95% confidence interval (CI) 2.79 to 4.79) for aflibercept; RR 2.47 (95% CI 1.81 to 3.37) for bevacizumab; RR 2.76 (95% CI 2.12 to 3.59) for ranibizumab. On average there was no change in visual acuity (VA) with laser after one year, compared with a gain of 1 or 2 lines with anti-VEGF treatment: laser versus aflibercept mean difference (MD) -0.20 (95% CI -0.22 to -0.17) logMAR; versus bevacizumab MD -0.12 (95% CI -0.15 to -0.09) logMAR; versus ranibizumab MD -0.12 (95% CI -0.14 to -0.10) logMAR. The certainty of the evidence was high for the comparison of aflibercept and ranibizumab with laser and moderate for bevacizumab comparison with laser due to inconsistency between the indirect and direct evidence.People receiving ranibizumab were less likely to gain 3 or more lines of VA at one year compared with aflibercept: RR 0.75 (95% CI 0.60 to 0.94), moderate certainty evidence. For every 1000 people treated with aflibercept, 92 fewer would gain 3 or more lines of VA at one year if treated with ranibizumab (22 to 148 fewer). On average people receiving ranibizumab had worse VA at one year (MD 0.08 logMAR units, 95% CI 0.05 to 0.11), moderate-certainty evidence; and higher CRT (MD 39 um, 95% CI 2 um to 76 um; low-certainty evidence). Ranibizumab and bevacizumab were comparable with respect to aflibercept and did not differ in terms of VA: RR of gain of 3 or more lines of VA at one year 1.11 (95% CI 0.87 to 1.43), moderate-certainty evidence, and difference in change in VA was 0.00 (95% CI -0.02 to 0.03) logMAR, moderate-certainty evidence. CRT reduction favoured ranibizumab by -29 um (95% CI -58 um to -1 um, low-certainty evidence). There was no evidence of overall statistical inconsistency in our analyses.The previous version of this review found moderate-certainty evidence of good safety of antiangiogenic drugs versus control. This update used data at the longest available follow-up (one or two years) and found that aflibercept, ranibizumab and bevacizumab do not differ regarding systemic serious adverse events (SSAEs) (moderate- or high-certainty evidence). However, risk of bias was variable, loop inconsistency could be found and estimates were not precise enough on relative safety regarding less frequent events such as arterial thromboembolic events or death (low- or very low-certainty evidence).Two-year data were available and reported in only four RCTs in this review. Most industry-sponsored studies were open-label after one year. One large publicly-funded study compared the three drugs at two years and found no difference. AUTHORS' CONCLUSIONS: Anti-VEGF drugs are effective at improving vision in people with DMO with three to four in every 10 people likely to experience an improvement of 3 or more lines VA at one year. There is moderate-certainty evidence that aflibercept confers some advantage over ranibizumab and bevacizumab in people with DMO at one year in visual and anatomic terms. Relative effects among anti-VEGF drugs at two years are less well known, since most studies were short term. Evidence from RCTs may not apply to real world practice, where people in need of antiangiogenic treatment are often under treated and under-monitored.We found no signals of differences in overall safety between the three antiangiogenic drugs that are currently available to treat DMO, but our estimates are imprecise for cardiovascular events and death. PMID- 28639416 TI - Persistently low lymphocyte counts after FCR therapy for chronic lymphocytic leukemia are associated with longer overall survival. AB - Decreased absolute lymphocyte counts (ALCs) following frontline therapy for chronic lymphocytic leukemia may be associated with disease control, even in patients without evidence of minimal residual disease. We studied the prognostic significance of ALCs during the first year following treatment with fludarabine, cyclophosphamide, and rituximab (FCR). We evaluated 99 patients who achieved a partial response without lymphocytosis (<4.0 * 103 cells/MUL) or better after FCR. Absolute lymphocyte counts were recorded at 3-, 6-, 9-, and 12-month posttreatment and correlated with overall survival (OS) and event-free survival (EFS). For each time point, analyses were limited to patients without lymphocytosis, so as to avoid possible biases from undocumented disease progressions. Lymphopenia (ALC < 1.0 * 103 cells/MUL) at 3 m after FCR (69% of patients n = 68), was associated with a longer OS (5y OS 91% vs 64%, P = .001), as were ALC <= 2 * 103 cells/MUL at 6 m (5y OS 85% vs 48%, P = .004) and ALC <= 1.8 * 103 cells/MUL at 9 m (5y OS 93% vs 54%, P = .009). A normal-range ALC (<=4 * 103 cells/MUL) at 12 m was also associated with a 91% 5y OS. Higher ALCs (but without lymphocytosis) were associated with shorter EFS (median EFS 27 months for ALC > 1.8 vs not reached for ALC <= 0.7 at 9 months, P < .0001). In conclusion, lower ALC levels in the first few months following frontline FCR therapy were associated with longer OS and EFS. Possible explanations may be that lower ALCs reflect deeper clonal suppression or protracted Treg depletion. Absolute lymphocyte count levels may be a cheap and widely available prognostic marker, though the added value for clinical practice is the minimal residual disease era needs to be explored. PMID- 28639417 TI - Auditory processing in autism spectrum disorder: Mismatch negativity deficits. AB - : Children with autism spectrum disorders (ASD) often show changes in (automatic) auditory processing. Electrophysiology provides a method to study auditory processing, by investigating event-related potentials such as mismatch negativity (MMN) and P3a-amplitude. However, findings on MMN in autism are highly inconsistent, partly due to small sample sizes in the studies and differences in MMN paradigms. Therefore, in the current study, MMN and P3a amplitude were assessed in a relatively large sample of children with ASD, using a more extensive MMN paradigm and compared with that of typically developing children (TDC). Thirty-five children (aged 8-12 years) with ASD and 38 age and gender matched TDC were assessed with a MMN paradigm with three types of deviants, i.e., frequency, duration and a combination of these two. MMN elicited by duration and frequency-duration deviants was significantly reduced in the ASD group. P3a amplitude elicited by duration deviants was significantly increased in the ASD group. Reduced MMN in children with ASD suggests that children with ASD may be less responsive to environmentally deviant stimuli at an early (sensory) level. P3a-amplitude was increased in ASD, implying a hyper-responsivity at the attentional level. In addition, as similar MMN deficits are found in schizophrenia, these MMN results may explain some of the frequently reported increased risk of children with ASD to develop schizophrenia later in life. Autism Res 2017, 10: 1857-1865. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Automatic detection of deviant sounds in the environment, such as upcoming traffic, is often affected in children with autism spectrum disorders (ASD). Mismatch negativity (MMN) is a way to quantify automatic deviancy detection, using electroencephalography. In this study, auditory MMN was assessed in 35 children with ASD and 38 matched control children, revealing significantly reduced MMN in the ASD group. This may indicate that children with ASD are less able to automatically detect environmentally deviant stimuli. PMID- 28639419 TI - Examining the role of positive and negative intergroup contact and anti-immigrant prejudice in Brexit. AB - This study examined the interplay of anti-immigrant prejudice and intergroup contact experience on voting intentions within Britain's 2016 referendum on its membership in the European Union. In the days before the referendum, we asked more than 400 British people how they planned to vote. We measured a number of demographic factors expected to predict voting intentions as well as individuals' prejudice towards and intergroup contact experience (positive and negative) with EU immigrants. Anti-immigrant prejudice was a strong correlate of support for Brexit. Negative intergroup contact experience was associated with higher anti immigrant prejudice and, in turn, increased support for 'Leave'. Positive intergroup contact, on the other hand, seemed to play a reparative role, predicting lower prejudice and increasing support for 'Remain'. PMID- 28639418 TI - Clinical course of isolated distal deep vein thrombosis in patients with active cancer: a multicenter cohort study. AB - : Essentials Isolated distal deep vein thrombosis (IDDVT) is frequently associated with cancer. No study has specifically evaluated the long-term clinical course of cancer-associated IDDVT. Patients with cancer-associated IDDVT are at very high risk of symptomatic recurrence and death. We observed low rates of major bleeding during anticoagulation. SUMMARY: Background Although isolated distal deep vein thrombosis (IDDVT) is frequently associated with cancer, no study has specifically evaluated the long-term clinical course of IDDVT in this setting. Aim To provide data on the rate of recurrent venous thromboembolism (VTE), major bleeding events and death in IDDVT patients with active cancer. Patients and Methods Consecutive patients with active cancer and an objective IDDVT diagnosis (January 2011 to September 2014) were included from our files. We collected information on baseline characteristics, IDDVT location and extension, VTE risk factors, and type and duration of anticoagulant treatment. Results A total of 308 patients (mean age 66.2 [standard deviation (SD), 13.2 years]; 57.1% female) with symptomatic IDDVT and a solid (n = 261) or hematologic (n = 47) cancer were included at 13 centers. Cancer was metastatic in 148 (48.1%) patients. All but three (99.0%) patients received anticoagulant therapy, which consisted of low-molecular-weight heparin in 288 (93.5%) patients. Vitamin K antagonists were used for the long-term treatment in 46 (14.9%) patients, whereas all others continued the initial parenteral agent for a mean treatment duration of 4.2 months (SD, 4.6 months). During a total follow-up of 355.8 patient-years (mean, 13.9 months), there were 47 recurrent objectively diagnosed VTEs for an incidence rate of 13.2 events per 100 patient-years. During anticoagulant treatment, the annual incidence of major bleeding was 2.0 per 100 patient-years. Conclusions Cancer patients with IDDVT have a high risk of VTE recurrence. Additional studies are warranted to investigate the optimal intensity and duration of anticoagulant treatment for these patients. PMID- 28639420 TI - The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers. AB - This study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time-points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: group 1 (control group, n = 16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n = 5) with four copies of CES1; group 3 (n = 6) harbouring the G143E polymorphism; group 4 (n = 2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n = 4) harbouring the CES1A1c variant; and group 6 (n = 10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 ng/ml x h in the control group versus 310, 282, 294, 344 and 306 ng/ml x h in groups 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared with the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril. PMID- 28639422 TI - Medaka and zebrafish contactin1 mutants as a model for understanding neural circuits for motor coordination. AB - A spontaneous medaka ro mutant shows abnormal wobbling and rolling swimming behaviors. By positional cloning, we mapped the ro locus to a region containing the gene encoding Contactin1b (Cntn1b), which is an immunoglobulin (Ig) superfamily domain-containing membrane-anchored protein. The ro mutant had a deletion in the cntn1b gene that introduced a premature stop codon. Furthermore, cntn1b mutants generated by the CRISPR/Cas9 system and trans-heterozygotes of the CRISPR mutant allele and ro had abnormal swimming behavior, indicating that the cntn1b gene was responsible for the ro-mutant phenotype. We also established zebrafish cntn1a and cntn1b mutants by transcription activator-like effector nucleases (TALENs). Zebrafish cntn1b but not cntn1a mutants showed abnormal swimming behaviors similar to those in the ro mutant, suggesting that Cntn1b plays a conserved role in the formation or function of the neural circuits that control swimming in teleosts. Although Cntn1-deficient mice have abnormal cerebellar neural circuitry, there was no apparent histological abnormality in the cerebellum of medaka or zebrafish cntn1b mutants. The medaka cntn1b mutants had defective optokinetic response (OKR) adaptation and abnormal rheotaxis (body positioning relative to water flow). Medaka and zebrafish cntn1b mutants are effective models for studying the neural circuits involved in motor learning and motor coordination. PMID- 28639423 TI - Emergency contraceptive pill users' risk perceptions for sexually transmitted infections and future unintended pregnancy. AB - BACKGROUND AND PURPOSE: The availability of emergency contraception pills (ECP) over the counter (OTC) has the potential to reduce the incidence of unintended pregnancy; however, the increased risk for sexually transmitted infection (STI) acquisition, related to unprotected intercourse, has not been adequately addressed. The purpose of this study is to gain insight into risk perceptions for STIs and subsequent unintended pregnancy in women who have purchased ECP OTC. METHODS: Twenty-one women, aged 18-24, attending a private university in an urban setting, who purchased and used ECP OTC participated in 1-h, individual interviews. CONCLUSIONS: Narrative, descriptive findings indicated that these women did not consider themselves at risk for STI or unintended pregnancy, despite having used ECP OTC. Pregnancy prevention was paramount for these women, which overshadowed concerns regarding STIs. IMPLICATIONS FOR PRACTICE: Women at risk for unintended consequences of sexual activity are not fully cognizant of those potential outcomes and do not take measures to prevent their occurrence. The availability of ECP OTC offers protection against unintended pregnancy; however, opportunities for health promotion and prevention counseling may be lost. PMID- 28639424 TI - Parental attitudes toward pediatric use of complementary/alternative medicine in Turkey. AB - PURPOSE: This study was conducted to determine the pediatric usage of complementary/alternative medicine (CAM) by parents in Turkey, the incidence of using these methods, and the factors affecting their use. DESIGN AND METHODS: The sectional and relational design of the study included a sample of 497 parents who took children for treatment at the Maternity and Children's Hospital in Giresun, Turkey. Data for the study were collected via the Personal Information Form and the Evaluation Form for Complementary/Alternative Treatment Use. The data collection tools were filled out by the researchers during the face-to-face interviews. Data obtained from the study were analyzed by Pearson chi-square, Fisher-Freeman-Halton and Fisher's exact (posthoc Bonferroni) tests and Z-test. RESULTS: It was determined that 97.7% of the parents had used at least one CAM method. Moreover, the parents had used CAM methods mostly for respiratory complaints. The CAM methods were most commonly used for the symptoms of fever, diarrhea, and cough. It was observed that the most commonly used alternative methods in the past were vitamin/mineral remedies, cold treatments, and hodja (Islamic teacher) consultations, while the most common alternative methods currently used are massage, music, and cold treatment. In addition, the differences found between CAM users in terms of sociodemographic characteristics were not statistically significant. PRACTICE IMPLICATIONS: It is crucial for nurses to learn the characteristics of the health/disease treatments used by those with whom they work in order to increase the efficiency of the service they provide. Thus, it was recommended that nurses should be knowledgeable and aware of the benefits/side effects, treatment methods, and contraindications of CAM. PMID- 28639421 TI - Penetrance estimate of LRRK2 p.G2019S mutation in individuals of non-Ashkenazi Jewish ancestry. AB - BACKGROUND: Penetrance estimates of the leucine-rich repeat kinase 2 (LRRK2) p.G2019S mutation for PD vary widely (24%-100%). The p.G2019S penetrance in individuals of Ashkenazi Jewish ancestry has been estimated as 25%, adjusted for multiple covariates. It is unknown whether penetrance varies among different ethnic groups. The objective of this study was to estimate the penetrance of p.G2019S in individuals of non-Ashkenazi Jewish ancestry and compare penetrance between Ashkenazi Jews and non-Ashkenazi Jews to age 80. METHODS: The kin-cohort method was used to estimate penetrance in 474 first-degree relatives of 69 non Ashkenazi Jewish LRRK2 p.G2019S carrier probands at 8 sites from the Michael J. Fox LRRK2 Cohort Consortium. An identical validated family history interview was administered to assess age at onset of PD, current age, or age at death for relatives in different ethnic groups at each site. Neurological examination and LRRK2 genotype of relatives were included when available. RESULTS: Risk of PD in non-Ashkenazi Jewish relatives who carry a LRRK2 p.G2019S mutation was 42.5% (95% confidence interval [CI]: 26.3%-65.8%) to age 80, which is not significantly higher than the previously estimated 25% (95% CI: 16.7%-34.2%) in Ashkenazi Jewish carrier relatives. The penetrance of PD to age 80 in LRRK2 p.G2019S mutation carrier relatives was significantly higher than the noncarrier relatives, as seen in Ashkenazi Jewish relatives. CONCLUSIONS: The similar penetrance of LRRK2 p.G2019S estimated in Ashkenazi Jewish carriers and non Ashkenazi Jewish carriers confirms that p.G2019S penetrance is 25% to 42.5% at age 80 in all populations analyzed. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28639426 TI - Equal-tailed confidence intervals for comparison of rates. AB - Several methods are available for generating confidence intervals for rate difference, rate ratio, or odds ratio, when comparing two independent binomial proportions or Poisson (exposure-adjusted) incidence rates. Most methods have some degree of systematic bias in one-sided coverage, so that a nominal 95% two sided interval cannot be assumed to have tail probabilities of 2.5% at each end, and any associated hypothesis test is at risk of inflated type I error rate. Skewness-corrected asymptotic score methods have been shown to have superior equal-tailed coverage properties for the binomial case. This paper completes this class of methods by introducing novel skewness corrections for the Poisson case and for odds ratio, with and without stratification. Graphical methods are used to compare the performance of these intervals against selected alternatives. The skewness-corrected methods perform favourably in all situations-including those with small sample sizes or rare events-and the skewness correction should be considered essential for analysis of rate ratios. The stratified method is found to have excellent coverage properties for a fixed effects analysis. In addition, another new stratified score method is proposed, based on the t-distribution, which is suitable for use in either a fixed effects or random effects analysis. By using a novel weighting scheme, this approach improves on conventional and modern meta-analysis methods with weights that rely on crude estimation of stratum variances. In summary, this paper describes methods that are found to be robust for a wide range of applications in the analysis of rates. PMID- 28639425 TI - High-resolution anorectal manometry: A comparison of solid-state and water perfused catheters. AB - BACKGROUND: Anorectal manometry is the most commonly performed investigation for assessment of anorectal dysfunction. Findings from previous studies comparing water-perfused (WP) and solid-state (SS) techniques in the anorectum are conflicting. We compared anal sphincter pressure at rest and during dynamic maneuvers (squeezing and coughing) in healthy volunteers using SS and WP high resolution anorectal manometry (HR-ARM) employing equivalent catheter configurations, a standardized protocol, and identical data acquisition and analysis software. METHODS: Sixty healthy volunteers (40F; median age: 40; range: 18-74) underwent WP and SS HR-ARM in randomized order. Anal resting pressure, and squeeze and cough increments were measured. Median pressure and 5th and 95th percentiles were calculated for each maneuver and compared using Wilcoxon signed rank test. Bland and Altman plots were used to assess agreement between the systems. The impact of gender and parity was also explored. KEY RESULTS: Anal sphincter pressure measurements during squeeze (P<.001) and cough (P<.001) were significantly higher using SS HR-ARM than WP HR-ARM. No differences were seen at rest between the two types of catheter (nulliparous: P=.304; parous: P=.390; males: P=.167). Normal ranges for SS and WP manometry from this small group of healthy volunteers are presented. CONCLUSIONS & INFERENCES: Greater sensitivity to rapid pressure change is one of the advantages associated with SS HR-ARM. This is reflected in the differences observed during dynamic maneuvers performed during this study. Catheter type should be taken into consideration when selecting normal ranges for comparison to disease states. PMID- 28639427 TI - Resilience dimensions and mental health outcomes in bipolar disorder in a follow up study. AB - The individual process of resilience has been related to positive outcomes in mental disorders. We aimed (a) to identify the resilience domains from the Resilience Questionnaire for Bipolar Disorder that are associated cross sectionally and longitudinally with mental health outcomes in bipolar disorder (BD) and (b) to explore cross-lagged associations among resilience factors. A clinical adult sample of 125 patients diagnosed with BD (62.10% female, mean age = 46.13, SD = 10.89) gave their informed consent and completed a battery of disease-specific tools on resilience, personal recovery, symptomatology, psychosocial functioning, and quality of life, at baseline and at follow-up (n = 63, 58.10% female, mean age = 45.13, SD = 11.06, participation rate = 50.40%). Resilience domains of self-management of BD, turning point, self-care, and self confidence were significantly associated with mental health indicators at baseline. In addition, self-confidence at baseline directly predicted an increase in personal recovery at follow-up, and self-confidence improvement mediated the relationship between interpersonal support and self-care at baseline and personal recovery at follow-up. These findings highlight that resilience domains are significantly associated with positive mental health outcomes in BD and that some predict personal recovery at follow-up. Moreover, some resilience factors improve other resilience factors over time. PMID- 28639429 TI - The HLA-C*05 family allele - C*05:142. AB - The sequencing of exons 2-7 of a likely new HLA-C*05 allele identified the second example of HLA-C*05:142, in a male UK European, within a few months of the first example being found in Germany. C*05:142 differs from C*05:01:01:01 by a single base (395G>C) in exon 3 resulting in an amino acid substitution of R108P. Comprehensive serological HLA-Cw5 typing, using 19 antisera, indicated that C*05:142 encodes a "normal" Cw5 specificity. Failure to identify the involvement of position 108 in published HLA-C epitopes supported this assertion. The likely HLA class I C*05:142-bearing haplotype is A*02:01~C*05:142~B*44:02. This new allele has a maximum frequency of 0.00001, in 34,743 sequenced-based typed subjects, contrasting with that of C*05:01 (allele frequency 0.10441), in our local, largely UK European, blood donors. PMID- 28639428 TI - Relationship between pancreatic intraepithelial neoplasias, pancreatic ductal adenocarcinomas, and single nucleotide polymorphisms in autopsied elderly patients. AB - We comparatively analyzed serially autopsied, elderly Japanese patients (n = 2205) with pancreatic intraepithelial neoplasias (PanINs) and pancreatic ductal adenocarcinomas (PDACs) on the basis of their pancreatic lesions, clinical information, and single nucleotide polymorphisms (SNPs). The incidence of PanIN 1, -2, -3, and PDACs in these patients was 55%, 12%, 1.4%, and 2.4%, respectively. The occurrence of PanINs was associated with female sex, increasing age, and lower body mass index. We did not identify any common SNPs between PanINs and PDACs. There were no common SNPs associated with PanINs and PDACs between men and women. In previously reported pancreatic cancer-associated SNPs, rs3790844 (NR5A2) showed a significant correlation with PDAC in our cohort. Six SNPs (rs7016880, rs10096633, rs10503669, rs12678919, rs17482753, rs328) that were correlated with blood lipid levels were associated with the risk for PDACs. Our data suggest that different clinicopathological characteristics and predispositions may affect pancreatic carcinogenesis in elderly Japanese patients. PMID- 28639430 TI - Talking to healthcare providers about sex in later life: Findings from a qualitative study with older Australian men and women. AB - OBJECTIVE: Healthcare providers (HCPs) can play an important role in supporting the sexual health of older adults; however, we know little about the experiences of older people in talking to HCPs about sex. This article examines older adults' experiences and perceptions of talking to HCPs about sex. METHODS: Semi structured interviews were conducted with 30 men and 23 women aged 60 and older recruited from a national, online survey of older Australians. Data were analysed using a thematic approach. RESULTS: Most participants did not discuss sex with their HCP, and their HCP did not raise it. For those who did discuss sex with a HCP, negative and stigmatising responses were common. Positive responses could facilitate access to sexual health care. CONCLUSION: Older people benefit when HCPs are proactive and ask about sexual health. Education in how to talk about sex with older people would also be beneficial for HCPs. PMID- 28639431 TI - Decrease in Oxidative Stress Parameters after Post-Ischaemic Recombinant Human Erythropoietin Administration in the Hippocampus of Rats Exposed to Focal Cerebral Ischaemia. AB - Recombinant human erythropoietin (rhEpo) is a multi-functional drug with antioxidant potential. However, the underlying molecular mechanisms of its action are still unclear. The purpose of this study was to investigate the effects of rhEpo on the brain infarct volume as well as on the levels of the neuronal damage, oxidative stress parameters and active caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2) and haemeoxygenase-1 (HO-1) expressions in the hippocampi of rats exposed to the right middle cerebral artery occlusion (MCAO) for 1 hr. Ischaemic animals received either vehicle or rhEpo (5000 IU/kg, i.p.) immediately or 3 hr after the induction of ischaemia. Sham-operated, vehicle-treated animals served as the control group. Rats were killed 24 hr after the onset of the ischaemic or sham experimental procedure. MCAO caused ipsilateral brain infarction within the striatum and cortex. In the CA1 region of the hippocampi, we did not find significant neuronal loss, but a statistically significant rise in the active caspase-3 and Nrf2 protein expressions was registered. We detected also significant increases in the hippocampal levels of oxidative stress parameters (thiobarbituric acid-reactive substances, superoxide dismutase, glutathione peroxidase). Post-ischaemic administration of rhEpo significantly reduced the brain infarct volume, decreased levels of all tested oxidative stress parameters and increased the Nrf2 expression level. These findings suggest that decrease in oxidative stress parameters in the hippocampus could be an early indicator of post-ischaemic neuroprotective effect of rhEpo in rats exposed to focal cerebral ischaemia and that this effect could be attributable to additional post-ischaemic activation of Nrf2 endogenous antioxidant system. PMID- 28639433 TI - Luminescence of a Transition Metal Complex Inside a Metamaterial Nanocavity. AB - Modification of the local density of optical states using metallic nanostructures leads to enhancement in the number of emitted quanta and photocatalytic turnover of luminescent materials. In this work, the fabrication of a metamaterial is presented that consists of a nanowire separated from a metallic mirror by a polymer thin film doped with a luminescent organometallic iridium(III) complex. The large spin-orbit coupling of the heavy metal atom results in an excited state with significant magnetic-dipole character. The nanostructured architecture supports two distinct optical modes and their assignment achieved with the assistance of numerical simulations. The simulations show that one mode is characterized by strong confinement of the electric field and the other by strong confinement of the magnetic field. These modes elicit drastic changes in the emitter's photophysical properties, including dominant nanocavity-derived modes observable in the emission spectra along with significant increases in emission intensity and the total decay rate. A combination of simulations and momentum resolved spectroscopy helps explain the mechanism of the different interactions of each optical mode supported by the metamaterial with the excited state of the emitter. PMID- 28639432 TI - Muscle mass as a target to reduce fatigue in patients with advanced cancer. AB - BACKGROUND: Cancer-related fatigue (CRF) reduces quality of life and the activity level of patients with cancer. Cancer related fatigue can be reduced by exercise interventions that may concurrently increase muscle mass. We hypothesized that low muscle mass is directly related to higher CRF. METHODS: A total of 233 patients with advanced cancer starting palliative chemotherapy for lung, colorectal, breast, or prostate cancer were studied. The skeletal muscle index (SMI) was calculated as the patient's muscle mass on level L3 or T4 of a computed tomography scan, adjusted for height. Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-fatigue questionnaire (cut-off for fatigue <34). Multiple linear regression analyses were conducted to study the association between SMI and CRF adjusting for relevant confounders. RESULTS: In this group of patients with advanced cancer, the median fatigue score was 36 (interquartile range 26-44). A higher SMI on level L3 was significantly associated with less CRF for men (B 0.447, P 0.004) but not for women (B - 0.401, P 0.090). No association between SMI on level T4 and the Functional Assessment of Chronic Illness Therapy fatigue score was found (n = 82). CONCLUSIONS: The association between SMI and CRF may lead to the suggestion that male patients may be able to reduce fatigue by exercise interventions aiming at an increased muscle mass. In women with advanced cancer, CRF is more influenced by other causes, because it is not significantly related to muscle mass. To further reduce CRF in both men and women with cancer, multifactorial assessments need to be performed in order to develop effective treatment strategies. PMID- 28639434 TI - Case of ileal herniation through the foramen of Winslow diagnosed preoperatively by CT and treated with laparoscopic surgery. AB - A previously healthy 35-year-old man visited the emergency room complaining of epigastric pain and vomiting. The pain was sudden in onset. His blood tests were within normal limits except for a mild neutrophilia of 14 300/MUL. Enhanced abdominal CT scan showed the small intestine dilated into the space between the portal vein and inferior vena cava from the foramen of Winslow. Under the diagnosis of herniation through the foramen of Winslow (HFW), we performed emergency laparoscopic surgery. Laparoscopy revealed an internal herniation of the dilated small intestine through the foramen of Winslow. Because the herniated small intestine was viable, intestinal resection was unnecessary. We released the incarceration under laparoscopy. HFW is very rare and often overlooked, but abdominal CT examination enabled a precise preoperative diagnosis because of characteristic findings. We should consider the possibility of HFW in patients with internal herniation of unknown origin. Laparoscopic surgery for HFW is effective. PMID- 28639435 TI - Bioinspired Microfibers with Embedded Perfusable Helical Channels. AB - Materials with microchannels have attracted increasing attention due to their promising perfusability and biomimetic geometry. However, the fabrication of microfibers with more geometrically complex channels in the micro- or nanoscale remains a big challenge. Here, a novel method for generating scalable microfibers with consecutive embedded helical channels is presented using an easily made coaxial microfluidic device. The characteristics of the helical channel can be accurately controlled by simply adjusting the flow rate ratio of the fluids. The mechanism of the helix formation process is theorized with newly proposed heterogenerated rope-coil effect, which enhances the tunability of helical patterns and promotes the comprehension of this abnormal phenomenon. Based on this effect, microfibers with embedded Janus channels and even double helical channels are generated in situ by changing the design of the device. The uniqueness and potential applications of these tubular microfibers are also demonstrated by biomimetic supercoiling structures as well as the perfusable and permeable spiral vessel. PMID- 28639436 TI - A High HASBLED Score Identifies Poor Warfarin Control in Patients Treated for Non Valvular Atrial Fibrillation in Australia and Singapore. AB - Warfarin reduces stroke risk in atrial fibrillation (AF) patients. The quality of warfarin control, measured by time in therapeutic range (TTR), impacts outcome and adverse events. One tool evaluating risk of adverse events and potential warfarin control would simplify risk-benefit assessment of warfarin. Recently, HASBLED was demonstrated effective for this purpose, but this was in well controlled patients with deep vein thrombosis. HASBLED as a predictor of warfarin control has not been validated in other populations including differing indications, warfarin control levels and ethnicities. The aim of this study was to determine whether HASBLED can predict warfarin control in patients with AF in Australia and Singapore. Retrospective data were collected for patients receiving warfarin between January and June 2014 in Australia and Singapore. Patient data were used to calculate HASBLED at the start and end of the study period. TTR was calculated for each patient, and mean TTR used for analysis to stratified HASBLED scores. Of the 4370 patients, there were 3199 in Australia and 1171 in Singapore with mean TTRs of 82% and 58%, respectively. At the start of the study, a HASBLED score >=3 predicted significantly lower TTR in Singapore, whilst at the end of the study, this score identified patients with poor control in both Australia and Singapore. A HASBLED score >=3 in patients treated with warfarin can differentiate significantly lower TTRs in Australian and Singapore patients with AF. HASBLED may assess bleed risk and warfarin control, identifying patients at high risk of poor warfarin outcome requiring additional INR monitoring or alternative anticoagulation. PMID- 28639438 TI - Body composition analysis to study long-term training effects in elite male water polo athletes. AB - BACKGROUND: Elite water polo athletes undergo heavy training programs throughout the year, but especially to prepare major competitions, such as the Olympic Games (OG). Optimal athletic performance is a result of many factors, including proper management of the intensity and volume of training, nutrition and recovery between training sessions. When training is excessive in relation to recovery may occur nonfunctional overreaching (NFO). NFO can degenerate into overtraining syndrome resulting in a decrease in athletic performance, with likely changes in body weight and body composition. The aim of this study was to evaluate the relationship between body composition and the tolerance to intense training supported by diet meal plans and to highlight any difference between athletes selected for the OG and not selected ones. METHODS: Twenty-one male elite water polo athletes, 26 to 34 years of age, participated in the study. For three months before the Olympics, athletes have carried out an intense training period based on a detailed program. Only 13 athletes participated to OG (OA), 8 were excluded (NOA). Body weight and height were measured and Body Mass Index was calculated. BC and phase angle was evaluated at the half of first (T0), second (T1), and third (T2) month of training. Also blood analyses were collected at T0 and food intake assessed in all the evaluations. Measurements were carried out at three selected time points throughout the training period (12 weeks), which marked variations in the volume and intensity of the training load. RESULTS: Data analyses showed no statistical difference among the three measurements performed for body weight, body composition and phase angle in all OA group. Furthermore, there was not statistically significant differences between the OA and NOA group for weight, body mass index, body composition and phase angle. CONCLUSIONS: Results of the present study encourage the use of body composition by bioelectrical impedance monitoring system for high-level athletes involved in long and intense training periods to prevent body dehydration and overtraining syndrome. Body cell mass monitoring provides a valuable help to evaluate the effects of training and to prevent any decrease in the performance level. PMID- 28639439 TI - Somatic characteristics and motor fitness of elite and sub-elite Polish male badminton players. AB - BACKGROUND: An appropriate level of somatic and fitness traits is believed to contribute to success in an international badminton competitions however, these have not been sufficiently explored in elite Polish badminton players. Therefore, the aim of the study was to assess somatic build and physical fitness of elite and sub-elite Polish badminton players and to identify key traits that determine achieving sporting success in badminton. METHODS: The study participants comprised 20 men from the Polish Badminton National Teams A (elite; N.=9) and B (sub-elite; N.=11). In all participants body height, arm span, body mass, body fat, fat free mass and Body Mass Index (BMI) were assessed. Fitness tests included two badminton-specific on-court movement tests and cycloergometer test to assess maximal oxygen uptake (VO2max). RESULTS: Studied players did not differ in body height and arm span however, elite players were heavier by about 10 kg and had significantly higher values of BMI and body fat. Irrespectively of sport level, elite and subelite badminton players achieved comparable results in both on-court tests as well as with respect to VO2max (55.9 and 57.2 mL/min/kg, respectively). Cluster analysis allowed to indirectly describe the profile of somatic traits and physical fitness that facilitates achieving success in badminton. CONCLUSIONS: Relatively small body size of badminton players can be considered advantageous in sport competitions. It also seems that aerobic capacity contributes to achieving sport success in badminton to a much lower degree than the badminton-specific on-court skills. PMID- 28639437 TI - Ultrasound-assisted green economic synthesis of hydroxyapatite nanoparticles using eggshell biowaste and study of mechanical and biological properties for orthopedic applications. AB - Nanostructured hydroxyapatite (HAp) is the most favorable candidate biomaterial for bone tissue engineering because of its bioactive and osteoconductive properties. Herein, we report for the first time ultrasound-assisted facile and economic approach for the synthesis of nanocrystalline hydroxyapatite (Ca10 (PO4 )6 (OH)2 ) using recycled eggshell biowaste referred as EHAp. The process involves the reaction of eggshell biowaste as a source of calcium and ammonium dihydrogen orthophosphate as a phosphate source. Ultrasound-mediated chemical synthesis of hydroxyapatite (HAp) is also carried out using similar approach wherein commercially available calcium hydroxide and ammonium dihydrogen orthophosphate were used as calcium and phosphate precursors, respectively and referred as CHAp for better comparison. The prepared materials were characterized by X-ray diffraction, field emission scanning electron microscopy, Fourier transform infrared spectroscopy, and Raman spectroscopy to determine crystal structure, particle morphology, and the presence of chemical functional groups. The nanocrystalline EHAp and CHAp were observed to have spherical morphology with uniform size distribution. Furthermore, mechanical properties such as Vickers hardness, fracture toughness, and compression tests have been studied of the EHAp and CHAp samples showing promising results. Mechanical properties show the influence of calcination at 600 degrees C EHAp and CHAp material. After calcination, in the case of EHAp material an average hardness, mechanical strength, elastic modulus, and fracture toughness were found 552 MPa, 46.6 MPa, 2824 MPa, and 3.85 MPa m1/2 , respectively, while in the case of CHAp 618 MPa, 47.5 MPa, 2071 MPa, and 3.13 MPa m1/2 . In vitro cell studies revealed that the EHAp and CHAp nanoparticles significantly increased the attachment and proliferation of the hFOB cells. Here, we showed that EHAp and CHAp provide promising biocompatible materials that do not affect the cell viability and proliferation with enhancing the osteogenic activity of osteoblasts. Moreover, hFOB cells are found to express Osteocalcin, Osteopontin, Collagen I, Osteonectin, BMP-2 on the EHAp and CHAp bone graft. This study demonstrates the formation of pure nanocrystalline HAp with promising properties justifying the fact that the eggshell biowaste could be successfully used for the synthesis of HAp with good mechanical and osteogenic properties. These findings may have significant implications for designing of biomaterial for use in orthopedic tissue regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2935-2947, 2017. PMID- 28639440 TI - The relationship between jumping performance, isokinetic strength and dynamic postural control in elite youth soccer players. AB - BACKGROUND: The aim of this study was to investigate the relationship between vertical jumping performance, isokinetic strength of knee extensors/flexors, and postural priority and to describe a multiple regression model that accounts for the effects of selected parameters of isokinetic strength and postural priority on vertical jumping performance. METHODS: Thirty-one professional male soccer players, aged from 17 to 20 years, participated in this study (age, mean+/-SD: 18.6+/-1.26 years; height: 1.78+/-0.74 m and weight: 73.1+/-6.77 kg). The correlations between isokinetic knee strength, jumping performance, and postural control were evaluated using the Pearson correlation coefficient. A linear regression model was used to evaluate the effect of hamstrings and quadriceps peak torque of both legs at 60o.s-1, total work of both legs at 240o.s-1, and postural priority on jumping performance. RESULTS: The peak torque of right leg knee flexor (quadriceps) muscles, evaluated at 60o.s-1 speed, showed correlations with counter movement jump, 30 second jumping and squat jump (P=0.005, P=0.003, and P=0.007, respectively). We also observed a strong relationship between counter movement jump and 30 second jumping and peak torque of left leg evaluated at the same speed of 60o.s-1 (P=0.26 and P=0.22, respectively). No significant correlations were found between any of the jumping tests and peak torque of knee extensors of both legs at 60o.s-1. For the 30 second jumping test, it appears that jumping endurance has a significant relationship with total work of knee flexors for right and left legs at 240o.s-1. CONCLUSIONS: The results of this study demonstrate practical implications for soccer performance, but further exploration is required. PMID- 28639441 TI - Effect of periodized high intensity interval training (HIIT) on body composition and attitudes towards hunger in active men and women. AB - BACKGROUND: High intensity interval training (HIIT) increases maximal oxygen uptake similar to aerobic exercise. However, changes in body composition are equivocal in response to HIIT. We examined changes in body composition and dietary restraint in response to 20 sessions of HIIT varying in structure. METHODS: Thirty nine active men and women (age and VO2max=22.5+/-4.4 years and 40.1+/-5.6 mL/kg/min) were randomized to one of three periodized HIIT regimes performed on a cycle ergometer. Before and after training, body composition was assessed using skinfolds (SKF), circumference measures, and Bioelectrical Impedance Analysis (BIA) following standardized procedures. Hunger, restraint, and disinhibition were also measured using the 3-Factor Eating Questionnaire and Power of Food Survey. Control participants (N.=32, age and VO2max=25.6+/-4.4 years and 40.6+/-4.9 mL/kg/min) matched for age and fitness level underwent all testing but did not complete HIIT. RESULTS: There was no change (P>0.05) in body mass, circumferences, or BIA-derived body fat in response to HIIT. However, SKF derived body fat declined (P=0.04) with HIIT, and gender x time (P=0.03) and gender x time x regimen interactions (P=0.04) were shown in that women but not men exhibited significant reductions in body fat. Hunger was reduced from baseline to post-training (P=0.028), but this response was not different in response to HIIT compared to controls. CONCLUSIONS: Twenty sessions of low-volume HIIT reduce body fat in women but not men, but do not alter perceptions of hunger. PMID- 28639442 TI - Weightbearing ankle dorsiflexion range of motion and sagittal plane kinematics during single leg drop jump landing in healthy male athletes. AB - BACKGROUND: Passive ankle dorsiflexion range of motion (DROM) measures have been identified as a risk factor for injury during landings. However, passive measurements might not be indicative of dynamic ankle movement, whereas a weightbearing ROM might be a better tool when evaluating movement. The purpose of this study was to investigate the relationship between weightbearing DROM and sagittal plane landing mechanics in a single leg drop jump task. METHODS: Seventy three male athletes (22.1+/-3.9 years old, height 186.2+/-11 cm, and weight 100.2+/-21.8 kg) performed bilateral modified-lunge tasks and bilateral single leg drop jump landings while 3D kinematic data were collected. Hip, knee, and ankle joint angles were calculated at initial contact (IC) maximum knee flexion (MKF), and total excursion (TE) during a single leg drop jump landing. RESULTS: No bilateral differences in DROM and single leg landing mechanics existed. Decreased ankle DROM was correlated to decreased ankle dorsiflexion at MKF (P=0.00) and TE (P=0.00) for both dominant and non-dominant limbs. Decreased ankle DROM was also correlated to decreased knee flexion at IC (P=0.00), MKF (P=0.00), and TE (P=0.1), for both dominant and non-dominant limbs. Ankle DROM correlated to hip flexion at MKF (r=0.25) and TE (r=0.30) in the dominant limb. CONCLUSIONS: Restrictions in DROM may contribute to a stiff landing with less flexion at the ankle and knee. These findings may be useful in designing training programs aimed at increasing DROM in order to improve an athlete's landing mechanics and decrease risk of injury. PMID- 28639443 TI - Relationships between the handball-specific complex test, non-specific field tests and the match performance score in elite professional handball players. AB - BACKGROUND: This study assessed the validity of the handball-specific complex test (HBCT) and two non-specific field tests in professional elite handball athletes, using the match performance score (MPS) as the gold standard of performance. METHODS: Thirteen elite male handball players (age: 27.4+/-4.8 years; premier German league) performed the HBCT, the Yo-Yo Intermittent Recovery (YYIR) test and a repeated shuttle sprint ability (RSA) test at the beginning of pre-season training. The RSA results were evaluated in terms of best time, total time, and fatigue decrement. Heart rates (HR) were assessed at selected times throughout all tests; the recovery HR was measured immediately post-test and 10 minutes later. The match performance score was based on various handball specific parameters (e.g., field goals, assists, steals, blocks, and technical mistakes) as seen during all matches of the immediately subsequent season (2015/2016). RESULTS: The parameters of run 1, run 2, and HR recovery at minutes 6 and 10 of the RSA test all showed a variance of more than 10% (range: 11-15%). However, the variance of scores for the YYIR test was much smaller (range: 1-7%). The resting HR (r2=0.18), HR recovery at minute 10 (r2=0.10), lactate concentration at rest (r2=0.17), recovery of heart rate from 0 to 10 minutes (r2=0.15), and velocity of second throw at first trial (r2=0.37) were the most valid HBCT parameters. CONCLUSIONS: Much effort is necessary to assess MPS and to develop valid tests. Speed and the rate of functional recovery seem the best predictors of competitive performance for elite handball players. PMID- 28639444 TI - Shuttle versus straight repeated-sprint ability tests and their relationship to anthropometrics and explosive muscular performance in elite handball players. AB - BACKGROUND: This study assessed inter-relationships between shuttle and straight repeated-sprint ability tests and the relationship of each measure to anthropometric and explosive lower limb performance data in elite handball players. METHODS: Twenty-two elite male handball players (18.9+/-0.2 years; body mass: 83.3+/-1.1 kg, height: 1.79+/-2.30 m, body fat: 12.8+/-0.2%) completed tests that included a lower limb force-velocity test of peak power (Wpeak), jumping ability (squat and counter-movement jumps; SJ, CMJ), 1 repetition maximum (1-RM) half back squat, average sprint velocity over 5 m (V-5 m), peak velocity between 25-30 m (Vmax), and Yo-Yo Intermittent Recovery Test level 1 (Yo-Yo IR1), and anthropometric determinations of cross-sectional areas and muscle volumes for leg and thigh muscles. Data were compared with performance on two repeated sprint tests; the straight test (6 * 30 m [RSA30]) and the intermittent test (6*[2*15 m] shuttle sprints [RSA15]). RESULTS: V-5 m, 1-RM, and thigh and leg muscle cross sectional areas and volumes showed relevant relationships to the shuttle RSA test (r2>=0.5). The Yo-Yo IR1 explained the largest percentage of variance in RSA15 total time (60%), and V-5 m also explained 56% of the variance in RSA15 total time. RSA15% fatigue was only related to 1-RM (explained variance: 58%), and the RSA30 test showed no useful correlations with any of the investigated predictors. Multiple-regression analyses using all physical tests explained 91% of the variance in RSA15 total time (P<0.001). CONCLUSIONS: The volume of the leg muscles seems important to power production and repeated sprints over distances of 15 m or less. RSA15 is related to muscular power, maximal strength, speed and endurance performance; however, the straight repeated sprint ability test is not, and thus does not seem relevant for the testing of handball players. PMID- 28639445 TI - Periodized training achieves better autonomic modulation and aerobic performance than non-periodized training. AB - BACKGROUND: The aim of the present research was to analyze autonomic response and aerobic performance after performing three different workloads training distributions. METHODS: Thirty athletes (mean age 38.7+/-9.8 years, height 174.7+/-6.5 cm, body weight 72.0+/-9.8 kg) were randomly divided into three groups of 10 participants each, to perform three different 4-week training programs: in a PRO group, aerobic training intensity increased during the 4 weeks; in a UNI group, aerobic intensity was uniform throughout the program; and in a FRE group, free training was performed. Total power, the very-low-frequency band, the low-frequency (LF) band, the high-frequency (HF) band, LF and HF normalized, basal heart rate, LF/HF ratio and maximal aerobic velocity were measured before and after the 4 weeks of training. RESULTS: A significantly increase (P<0.05) in HF and HF normalized in the PRO group was measured. The basal HR of FRE group increased significantly after the 4-week training program. CONCLUSIONS: After a 4-week training, PRO training workload distribution achieved higher autonomic adaptation than UNI and FRE training workload distribution. This information could help the coaches to develop better training programs and organize correctly the different mesocycles of training during the season to obtain a correct autonomic response of their athletes. PMID- 28639446 TI - Extended Treatment of Venous Thromboembolism. PMID- 28639447 TI - [Clinical Results of the Implantation of Two Types of Multifocal Rotational Asymmetric Intraocular Lenses]. AB - PURPOSE: The aim of the study was evaluation and comparison of clinical results of two types of rotationally asymmetric multifocal intraocular lens (LENTIS Mplus and LENTIS MplusX). MATERIAL AND METHODS: The study included 247 eyes of 124 patients aged 25 - 76 years (mean, 58 years). After phacoemulsification multifocal intraocular lens LENTIS Mplus (group A, n = 141) or LENTIS MplusX (group B, n = 106) was implanted. Patients were divided into two groups according to the type of intraocular lens. Patients were evaluated at 1 month, 3 months and 6 months after surgery. We assessed the uncorrected visual acuity, best corrected visual acuity, subjective refraction, contrast sensitivity and subjective satisfaction. RESULTS: Mean preoperative monocular uncorrected distance visual acuity (UCDVA) in the group A was 0,40 +/- 0,27; in the group B 0,34 +/- 0,25. Postoperatively UCDVA was statistically significant improved in both groups (group A: 1,01 +/- 0,20; group B: 0,90 +/- 0,15). Mean preoperative monocular uncorrected near visual acuity (UCNVA) was Jaeger (J) 12,82 +/- 4,16 (group A), resp. J 12,73 +/- 3,99 (group B). Postoperatively UCNVA was statistically significant improved in both groups (group A: J 1,81 +/- 1,42; group B: J 1,54 +/ 1,72). There was not found statistically significant difference between both groups in these parameters. Contrast sensitivity was evaluated in patients who have undergone clear lens extraction in both eyes. There was not found the statistically significant reduction of contrast sensitivity in both groups. Subjective satisfaction was assessed in the range of marks 1-5. The average mark of the subjective satisfaction ratings in the group A was 1,37; in the group B 1,25. CONCLUSION: Our study found the multifocal intraocular lens LENTIS Mplus and LENTIS MplusX give high-quality distance and near vision and provide high degree of spectacle independence. There was not found statistically significant difference in all parameters between the Group A (implantation Mplus LENTIS) and the Group B (implantation LENTIS MplusX) in our study. However, in our study we have observed higher subjective satisfaction and lower incidence of optical phenomena in the Group of patients with the implantation of intraocular lens LENTIS MplusX.Key words: LENTIS Mplus, LENTIS MplusX, visual acuity, contrast sensitivity, optical phenomen. PMID- 28639448 TI - [HYBRID MONOVISION]. AB - AIM: To evaluate our own results of the use of hybrid monovision technique, in patients after bilateral cataract surgery, where in the dominant eye the monofocal intraocular lens is implanted and in the non-dominant eye the multifocal intraocular lens (IOL) is implanted. MATERIAL AND METHODS: Prospective follow-up of group of 33 patients with bilateral cataract surgery and induced hybrid monovision. In the dominant eye, the hydrophilic monofocal aspheric intraocular lens Auroflex (Aurolab) was implanted, and in the non-dominant eye the hydrophilic multifocal aspheric intraocular lens Seelens (Hanita) was implanted. During the post-operative period, the uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (CDVA), uncorrected near visual acuity (UNVA), best-corrected near visual acuity (CNVA), and distance corrected near visual acuity (DCNVA) were established. Further, the monocular contrast sensitivity, subjective satisfaction, and dysfotopsias appearance were examined. The examinations were held 3 and 6 months after the surgery. RESULTS: In dominant eyes with implanted monofocal lens, UDVA improved from 0.61 +/- 0.39 logMAR preoperatively to 0.03 +/- 0.14 logMAR at 6 months after the surgery. In non-dominant eyes, with implanted multifocal intraocular lens, UDVA improved from 0.30 +/- 0.23 logMAR preoperatively to -0.04 +/- 0.06 logMAR. The average binocular UDVA (bUDVA) was -0.07 +/- 0.08 logMAR and binocular CDVA (bCDVA) -0.12 +/- 0.06. The average UNVA in dominant eyes 6 months after the surgery was 0.62 +/- 0.18 logMAR, in non-dominant eyes 0.18 +/- 0,15 logMAR, binocularly 0.15 +/- 0.11 logMAR. The contrast sensitivity was in the eyes with implanted multifocal IOL slightly worse comparing to the eyes with implanted monofocal lens, albeit only in the space frequency of 6 cycles per degree (CPD) this difference was statistically significant. Subjectively, the presence of dysfotopsia and other problems were very low, the average values of single answers were from 1.3 to 2.1 (on the scale 1 - 5, 1 - no problems and 5 - severe problems). Also, we noticed high percentage of subjective satisfaction with the surgery results (94 %). Six percent of patients wear glasses for near distance as a standard, 42 % of patients wear them occasionally, and 45 % of patients dont use glasses for near distance at all. CONCLUSION: The technique of hybrid monovision is effective, safe, and relatively cheap method solving the loss of accommodation in patients after the cataract surgery. This method extends the spectrum of our possibilities how to solve the loss of accommodation in these patients.Key words: hybrid monovision, multifocal intraocular lens, contrast sensitivity. PMID- 28639449 TI - [OPTIC PROPERTIES OF MYOPIC CORRECTION BY ORTHOKERATOLOGY CONTACT LENSES (A CASE REPORT)]. AB - INTRODUCTION: Orthokeratology lenses present a special type of hard contact lenses, which is used especially for myopic correction. The lenses are applied during the night, when thanks to their special shape cause temporally (reversible) change of the cornea shape. During the day, there is not necessary to wear any other refractive correction. Due to the wearing regimen, there is, comparing to the classical contact lenses, higher risk of health complications. For their safe use, it is necessary to pay attention to the application of lenses of adequate parameters, follow up the care and hygiene precautions, regular controls and early treatment of possible problems. The application of contact lenses should be done by experienced and well-educated expert in contact lens fitting. In the Czech Republic, this method is practically not used. AIM: The aim of the case report was to follow up the course of concrete application of orthokeratology lenses for myopic correction from the optic (refractive) point of view, and to evaluate the optic changes in the system of the eye. In the followed up subject, there were measured subjective changes in refraction, visual acuity, corneal curvature, corneal and whole eye aberrations, and corneal thickness during the period of one month after the beginning of lens application (initial phase). The same parameters were followed-up during one-month period since the termination of lens wearing for three months (second phase). The subject was a woman, 24 years old, myopic, with the refractive error in the right eye -3.0 spherical diopters and astigmatism of -0.25 cylinder in the axis 90 degrees , and in the left eye -2.75 spherical diopters without astigmatism; without ophthalmologic or systemic diseases. The full correction of the refractive error after the orthokeratology lenses application occurred approximately after four nights (wearing the lenses overnight). Concurrently, during the day, slight recurrence to original values was evident. With the decreased refractive error, the uncorrected visual acuity improved accordingly. Further, the flattening of the central cornea was observed, e.g. increasing of the central cornea curvature diameter (maximum change was 0.22 mm in the right and 0.28 mm in the left eye) and slight thinning. The adverse accompanying optic phenomenon was increasing of the aberrations of higher orders, which presented subjectively by decreased visual acuity under mesopic conditions. One month after the termination of contact lenses wearing, all the followed-up parameters returned to original values.Key words: orthokeratology, orthokeratology contact lenses, myopic correction, hard contact lenses, rigid gas-permeable (RGP) lenses. PMID- 28639450 TI - [Bilateral Congenital Multiple Pigmented Vitreous Cysts in a Three-year-old Girl: Ten Years Follow up]. AB - The authors present a case report of a three-year-old female patient with bilateral multiple anterior vitreous cysts. During examination for intermittent esotropia of the right eye was diagnosed not only hypermetropia, astigmatism and anisometropia, but also pigmented changes in peripheral retrolental space of both eyes. Clinical examination under general anaesthesia revealed bilateral multiple pigmented immobile vitreous cysts. There were five almost spherical, translucent, but slightly pigmented cysts on its cover on the right eye and four similar on the left, but visible only with dilated pupils. A dilating of pupils was slow and required more mydriatics than in similar aged children. Follow up period is ten years now. Occlusion therapy of amblyopia was performed to nine years of age. Treatment of refractive error and esotropia with correction for hypermetropia, astigmatism and anisometropia continues. Best corrected visual acuity in thirteen year-old girl is 1,0 in both eyes without any visual disturbances described by patient. Corrected visual acuity in each eye is 1,0, right eye with +3,5 D sph., 3,5D cyl., axis 175 degrees , left eye with +7,5 D sph., -3,0 D cyl., axis 35 degrees . Patient is otherwise healthy and without any mental deficit. Position of all cysts remains unchanged and stabile during the follow up period (with recommendation to avoid hits to the head for all time, mainly in sports). Formation and slow progression of partial cortical cataract in the area of contact of the lens and one cyst in inferonasal quadrant of the lens on the right eye is monitored. A lamellar retinal extrafoveal defect of posterior pole of the right eye was found by OCT imaging.Key words: vitreous cyst, idiopathic, congenital, bilateral, multiple, pigmented, immobile, hypermetropia, astigmatism, anisometropia, esotropia, cortical cataract, retinal lamellar extrafoveal defect, OCT. PMID- 28639451 TI - [TATTOO-ASSOCIATED UVEITIS]. AB - The clinical case of tattoo-associated uveitis was first described by Lubeck and Epstein in 1952. Uveitis is accompanied by induration and hyperemia of tattoo skin, which can precede, follow or manifest simultaneously with uveitis. The diagnosis is determined on clinical grounds after exclusion of other causes. Uveitis is usually bilateral, chronic and vision impairment is variable. Tattoo associated uveitis should be remembered in differential diagnosis due to the growing interest in tattoo.Key words: uveitis, tattoo, masquerade syndrome. PMID- 28639452 TI - [MAGNETIC RESONANCE STRENGTH OF 1.5 T - POSSIBILITIES DETAILED VIEW OF THE OPTIC NERVE]. AB - Due to the increased availability of MRI, this modality is the first choice for patients with a suspected pathology of the optic nerve, chiasm and optic tracts. Magnetic resonance imaging allows to evaluate the optic nerve itself as well as the gain or atrophy, its focal changes; it also allows detailed views of the surrounding structures such as vagina of the optic nerve and the mutual ratio between the full thickness of the nerve and the vagina, and the nerve itself. MR method uses a tissue contrast of an adipose tissue structures to a detailed imaging of the orbit. These data can play an important role not only in the diagnosis of the diseases with ophthalmic symptoms, but also in the diagnosis of the diseases of the nervous system. We are presenting a comprehensive overview of basic sequences used to show the optic nerve and the structures of the orbit as well as highlighting the benefits of their use and emphasizing their limitations. Imaging of the optic nerve and eye sockets may be standardized, and thus make the assessment easier for the following examinations that should be ideally performed using the same equipment and the same protocol display. The issue of imaging on the display unit with the strength of 1.5 Tesla is discussed; it is a machine that is largely represented across the Czech Republic.Key words: magnetic resonance imaging, scanner strength of 1.5 T, optic nerve, optic path, vagina of optic nerve. PMID- 28639454 TI - The role of cardiac MRI in cardio-oncology. PMID- 28639453 TI - Atypical Primary Cutaneous Rosai Dorfman Disease: A Case Report. AB - BACKGROUND: Rosai Dorfman disease (RDD) is a rare disorder that typically presents with bilateral cervical lymphadenopathy and follows a benign course. OBJECTIVE: We present a case of late-onset atypical primary cutaneous RDD that is resistant to treatment modalities described in the literature. METHODS: Case report. RESULTS: An 84-year-old woman presented with a 7-year history of cutaneous lesions histologically consistent with RDD. She later failed initial treatments of acitretin and thalidomide. CONCLUSION: Physicians must be aware of unusual presentations of RDD. Also, further treatment options must be explored for patients resistant to classical management of RDD. PMID- 28639455 TI - Item Response Theory Analysis of the Psychopathic Personality Inventory-Revised. AB - This study examined item and scale functioning in the Psychopathic Personality Inventory-Revised (PPI-R) using an item response theory analysis. PPI-R protocols from 1,052 college student participants (348 male, 704 female) were analyzed. Analyses were conducted on the 131 self-report items comprising the PPI-R's eight content scales, using a graded response model. Scales collected a majority of their information about respondents possessing higher than average levels of the traits being measured. Each scale contained at least some items that evidenced limited ability to differentiate between respondents with differing levels of the trait being measured. Moreover, 80 items (61.1%) yielded significantly different responses between men and women presumably possessing similar levels of the trait being measured. Item performance was also influenced by the scoring format (directly scored vs. reverse-scored) of the items. Overall, the results suggest that the PPI-R, despite identifying psychopathic personality traits in individuals possessing high levels of those traits, may not identify these traits equally well for men and women, and scores are likely influenced by the scoring format of the individual item and scale. PMID- 28639456 TI - Response by Dr Packer to the Letter of Dr Blankfield. PMID- 28639457 TI - Glyoxal toxicity in isolated rat liver mitochondria. AB - Glyoxal is a physiological metabolite formed by lipid peroxidation, ascorbate autoxidation, oxidative degradation of glucose, and degradation of glycated proteins. Glyoxal has been linked to oxidative stress and can cause a number of cellular damages, including covalent modification of amino and thiol groups of proteins to form advanced glycation end products. However, the mechanism of glyoxal toxicity has not been fully understood. In this study, we have focused on glyoxal toxicity in isolated rat liver mitochondria. Isolated mitochondria (0.5 mg protein per milliliter) were prepared from the Wistar rat liver using differential centrifugation and incubated with various concentrations of glyoxal (1, 2.5, 5, 7.5, and 10 mM) for 30 min. The activity of mitochondrial complex II was determined by measurement of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) conversion. The mitochondrial membrane potential (MMP), lipid peroxidation (MDA), reactive oxygen species (ROS) formation, glutathione (GSH) content, and protein carbonylation were also assessed. After an incubation of isolated liver mitochondria with glyoxal, disrupted electron transport chain, increased mitochondrial ROS formation, lipid peroxidation, mitochondrial membrane damage, GSH oxidation, and protein carbonylation ensued as compared to the control group ( p < 0.05). Glyoxal toxicity in isolated rat liver mitochondria was dose-dependent. In conclusion, glyoxal impaired the electron transport chain, which is the cause of increased ROS and MDA production, depletion of GSH, and disruption of MMP. Mitotoxicity of glyoxal might be related to the pathomechanisms involved in diabetes and its complications. PMID- 28639458 TI - Use of computed tomography to define a sacral safe corridor for placement of 2.7 mm cortical screws in feline sacroiliac luxation. AB - Objectives This study aimed to define a safe corridor for 2.7 mm cortical sacroiliac screw insertion in the dorsal plane (craniocaudal direction) using radiography and CT, and in the transverse plane (dorsoventral direction) using CT in feline cadavers. A further aim was to compare the values obtained by CT with those previously reported by radiography in the transverse plane. Methods Thirteen pelvises were retrieved from feline cadavers and dissected to expose one of the articular surfaces of the sacrum. A 2.7 mm screw was placed in the sacrum to a depth of approximately 1 cm in each exposed articular surface. Dorsoventral radiography and CT scanning of each specimen were performed. Multiplanar reconstructions were performed to allow CT evaluation in both the dorsal and transverse planes. Calculations were made to find the maximum, minimum and optimum angles for screw placement in craniocaudal (radiography and CT) and dorsoventral (CT) directions when using a 2.7 mm cortical screw. Results Radiographic measurement showed a mean optimum craniocaudal angle of 106 degrees (range 97-112 degrees ). The mean minimum angle was 95 degrees (range 87-107 degrees ), whereas the mean maximum angle was 117 degrees (108-124 degrees ). Measurement of the dorsal CT scan images showed a mean optimum craniocaudal angle of 101 degrees (range 94-110 degrees ). The mean minimum angle was 90 degrees (range 83-99 degrees ), whereas the mean maximum angle was 113 degrees (104-125 degrees ). The transverse CT scan images showed a mean dorsoventral minimum angle of 103 degrees (range 95-113 degrees ), mean maximum angle of 115 degrees (104 125 degrees ) and mean optimum dorsoventral angle of 111 degrees (102-119 degrees ). Conclusions and relevance An optimum craniocaudal angle of 101 degrees is recommended for 2.7 mm cortical screw placement in the feline sacral body, with a safety margin between 99 degrees and 104 degrees . No single angle can be recommended in the dorsoventral direction and therefore preoperative measuring on individual cats using CT images is recommended to establish the ideal individual angle in the transverse plane. PMID- 28639460 TI - Role of CT scan in diagnosis of renal lymphangiectasia: our single-center experience. AB - BACKGROUND: Renal lymphangiectasia is rarely reported benign renal disorder of lymphatic malformation. Though found incidentally; it presents with nonspecific symptoms and shows characteristic findings in radiological imaging studies. AIM: Here, we report eight patients with symptoms, laboratory and imaging findings compatible with renal lymphangiectasia. This report describes clinical and laboratory characteristics, treatment, Imaging findings and outcome of a series of patients with renal lymphangiectasia and reviews the literature. METHODS AND MATERIAL: Eight patients (mean age 45 years, male:female ratio 3:1) from 1st January 2011 to 30th June 2016; showing renal lymphangiectasia as incidental finding on CT IVP were included in the series. Imaging and laboratory findings were reviewed. Two out of eight patients (25%) underwent aspiration of collection and laboratory findings confirmed the diagnosis of renal lymphangiectasia. Four out of eight patients (50%) did not undergo aspiration of fluid and were offered conservative treatment. Two out of eight patients (25%) were donors for renal transplantation who were managed conservatively. RESULTS: Renal lymphangiectasia was diagnosed on CT IVP. In each case, where aspiration of collection fluid was offered, the laboratory diagnosis of renal lymphangiectasia was confirmed and patients were managed conservatively. However, large collection in one patient was relieved by percutaneous aspiration. CONCLUSIONS: Renal lymphangiectasia can be diagnosed with CT scan and confirmed by laboratory tests. As it may be confused with other cystic lesions of kidney; proper diagnosis and exclusion of other differentials can be effectively offered by CT scan IVP, which can avoid unnecessary invasive treatment options. PMID- 28639459 TI - Approach to the Management of Patients With Hidradenitis Suppurativa: A Consensus Document. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a painful, debilitating, and poorly understood condition, which is suboptimally diagnosed, managed, and treated. Evidence supporting various treatment modalities is sparse. OBJECTIVES: To incorporate scientific evidence and expert opinions to develop useful guidance for the evaluation and management of patients with HS. METHODS: An expert panel of Canadian dermatologists and surgeons developed statements and recommendations based on available evidence and clinical experience. The statements and recommendations were subjected to analysis and refinement by the panel, and voting was conducted using a modified Delphi technique with a prespecified cutoff agreement of 75%. RESULTS: Ten specific statements and recommendations were accepted by the expert panel. These were grouped into 4 domains: diagnosis and assessment, treatment and management, comorbidities and a multidisciplinary approach, and education. CONCLUSIONS: These statements and recommendations will serve to increase awareness of HS and provide a framework for decisions involving diagnosis and management. Evidence suggests that antibacterial and anti-tumour necrosis factor therapies are effective in the treatment of HS. This is supported by the clinical experience of the authors. Further clinical research and the establishment of multidisciplinary management teams will continue to advance management of HS in Canada. PMID- 28639461 TI - Hormonal contraception and breast cancer, what more do we need to know? AB - Most women use hormonal contraception for more than 30 years and for many, this may involve exposure in their older reproductive years when baseline breast cancer risk rises steeply. Overall, the risk of breast cancer diagnosis with exposure to hormonal contraception is very small and outweighed by its contraceptive benefits but despite this, there are still outstanding questions for all methods used in clinical practice due to paucity of available evidence, lack of which should not be taken to imply safety. This is exemplified by the following assumptions: the progestogen-only pill and long-acting reversible contraceptives are 'breast-safe' options in peri-menopausal women, use of the levonorgestrel intrauterine system for the management of endometrial pathology in breast cancer survivors is less likely to promote disease recurrence and the benefit all hormonal contraceptive methods confer in reducing unplanned pregnancy in women at high familial risk outweigh the risk of breast cancer diagnosis. There is no data on risk with the concurrent prescription of hormone replacement therapy in women exhibiting climacteric symptoms who are still menstruating. Advice of GPs and Community Sexual & Reproductive Health specialists will inevitably be sought about some or all these issues and in the absence of conclusive evidence from clinical studies, caution should be applied and women counselled appropriately. PMID- 28639462 TI - Onychomycosis in the 21st Century: An Update on Diagnosis, Epidemiology, and Treatment. AB - Onychomycosis accounts for 50% of all nail disease cases and is commonly caused by dermatophytes. Diabetes, human immunodeficiency virus, immunosuppression, obesity, smoking, and advancing age are predisposing factors of this fungal infection. Potassium hydroxide and culture are considered the current standard for diagnosing onychomycosis, revealing both fungal viability and species identification. Other diagnostic tests currently available include periodic acid Schiff staining, polymerase chain reaction techniques, and fluorescent staining. Across 6 recently published epidemiology studies, the global prevalence of onychomycosis was estimated to be 5.5%, falling within the range of previously reported estimates (2%-8%). Newly approved onychomycosis treatments include efinaconazole, tavaborole, and laser therapy with lasers only approved to temporarily increase the amount of clear nail. Additional onychomycosis treatments being investigated include iontophoresis and photodynamic therapy with small open-label studies reported thus far. Preventative strategies, to help decrease recurrence and reinfection rates, include sanitisation of footwear and prophylactic topical antifungal agents. PMID- 28639463 TI - Adverse Drug Reactions and Cutaneous Manifestations Associated With Anticoagulation. AB - Anticoagulants are amongst the most commonly prescribed medications worldwide. Although rare, localised and systemic drug reactions have been reported with anticoagulants that can lead to significant morbidity and mortality. Some of the first signs of drug reactions to anticoagulants are cutaneous changes that, when recognised early, can prevent significant complications. Dermatologists should be aware of these changes to make an early and accurate diagnosis. This is particularly important in instances of skin-induced necrosis caused by systemic toxicity to anticoagulants. This review discusses adverse drug reactions to the traditional anticoagulants, warfarin and heparin, and the newer direct oral anticoagulants (DOACs) such as the thrombin inhibitor, dabigatran, and the factor Xa inhibitors, rivaroxaban, apixaban, and edoxaban. In particular, this review provides dermatologists with a framework for early diagnosis and management of patients with drug reactions to anticoagulants and alerts them to potential bleeding complications associated with minor procedures. PMID- 28639464 TI - Neurophysiological Analysis of the Genesis Mechanism of EEG During the Interictal and Ictal Periods Using a Multiple Neural Masses Model. AB - Electroencephalography (EEG) is an important method to investigate the neurophysiological mechanism underlying epileptogenesis to identify new therapies for the treatment of epilepsy. The neurophysiologically based neural mass model (NMM) can build a bridge between signal processing and neurophysiology, which can be used as a platform to explore the neurophysiological mechanism of epileptogenesis. Most EEG signals cannot be regarded as the outputs of a single NMM with identical model parameters. The outputs of NMM are simple because the diversity of neural signals in the same NMM is ignored. To improve the simulation of EEG signals, a multiple NMM is proposed, the output of which is the linear combination of the outputs of all NMMs. The NMM number is not fixed and is minimized under the premise of guaranteeing the fitting effect. Orthogonal matching pursuit is used to solve a constrained [Formula: see text] norm minimization problem for NMM number and the strength of every NMM. The results showed that the NMM number was significantly lower during the ictal period than during the interictal period, and the strength of major NMMs increased. This indicates that neural masses fuse into fewer larger neural masses with greater strength. The distribution of excitatory and inhibitory strength during the ictal and interictal periods was similar, whereas the excitation/inhibition ratio was higher during the ictal period than during the interictal period. PMID- 28639465 TI - An Innovative Approach to Addressing the HIV Care Continuum: Implementation of a Clinical Pharmacy Resident in a Veterans Affairs HIV Specialty Clinic. AB - PURPOSE: Engagement of patients in the HIV care continuum and adherence to antiretroviral therapy (ART) continue to limit successful viral suppression. Innovative practices to improve this continuum and ameliorate potential physician shortages are needed. The objective of this evaluation was to determine the clinical benefits of incorporating pharmacy resident involvement on a multidisciplinary team in caring for patients with HIV. METHODS: A single-center pre-post cohort pilot evaluation was conducted at the Tennessee Valley Healthcare Systems VA Medical Center. Patients were enrolled in an HIV pharmacotherapy clinic implemented by an ambulatory care pharmacy resident. The primary end point of the evaluation was the percentage of patients achieving an undetectable plasma HIV viral load after enrollment. Secondary end points included change from baseline in CD4 T-cell count and self-reported adherence. RESULTS: A total of 55 patients were seen in the HIV pharmacotherapy clinic over a 28-week evaluation period. Of those patients with detectable viral load at enrollment, 70% reached viral suppression during follow-up, with a significant 0.75 log10 decrease in the median viral load ( P < .0001 for both). The median CD4 T-cell count increased from 464 to 525 cells/mm3 ( P = .01). Reported adherence, assessed using the Visual Analogue adherence Scale (VAS) increased significantly ( P = .0001). CONCLUSION: After enrollment in an HIV pharmacotherapy clinic, a significant decrease in viral load was seen, as were improvements in secondary end points of CD4 T cells and adherence. These data demonstrate the clinical benefits of pharmacy resident involvement on a multidisciplinary team in caring for patients with HIV. PMID- 28639466 TI - Genetic Characterization of Sarcoptes scabiei from Black Bears (Ursus americanus) and Other Hosts in the Eastern United States. AB - Since the early 1990s there has been an increase in the number of cases and geographic expansion of severe mange in the black bear (Ursus americanus) population in Pennsylvania. Although there are 3 species of mites associated with mange in bears, Sarcoptes scabiei has been identified as the etiologic agent in these Pennsylvania cases. Historically, S. scabiei-associated mange in bears has been uncommon and sporadic, although it is widespread and relatively common in canid populations. To better understand this recent emergence of sarcoptic mange in bears in Pennsylvania and nearby states, we genetically characterized S. scabiei samples from black bears in the eastern United States. These sequences were compared with newly acquired S. scabiei sequences from wild canids (red fox [Vulpes vulpes] and coyote [Canis latrans]) and a porcupine (Erethizon dorsatum) from Pennsylvania and Kentucky and also existing sequences in GenBank. The internal transcribed spacer (ITS)-2 region and cytochrome c oxidase subunit 1 (cox1) gene were amplified and sequenced. Twenty-four ITS-2 sequences were obtained from mites from bears (n = 16), red fox (n = 5), coyote (n = 2), and a porcupine. The sequences from bear samples were identical to each other or differed only at polymorphic bases, whereas S. scabiei from canids were more variable, but 2 were identical to S. scabiei sequences from bears. Eighteen cox1 sequences obtained from mites from bears represented 6 novel haplotypes. Phylogenetic analysis of cox1 sequences revealed 4 clades: 2 clades of mites of human origin from Panama or Australia, a clade of mites from rabbits from China, and a large unresolved clade that included the remaining S. scabiei sequences from various hosts and regions, including sequences from the bears from the current study. Although the cox1 gene was more variable than the ITS-2, phylogenetic analyses failed to detect any clustering of S. scabiei from eastern U.S. hosts. Rather, sequences from black bears grouped into a large clade that included S. scabiei from numerous hosts from Europe, Asia, Africa, and Australia. Collectively, these data suggest that the increasing number of S. scabiei cases in northeastern black bears is not due to the emergence and expansion of a single parasite strain. PMID- 28639467 TI - Ethanol-induced symptoms in patients receiving gemcitabine diluted from a concentrate for solution for infusion containing ethanol. AB - Purpose Ethanol as an excipient is used to enhance the solubility of gemcitabine, but, sometimes, the dose of ethanol a patient may be given is much higher than the dose considered to be toxic. We aimed to assess ethanol-related symptoms and signs in patients receiving two formulations of gemcitabine, with and without ethanol. Methods A randomized double blind cross-over study was conducted. All patients being treated with gemcitabine received two consecutive doses of the drug, one diluted from a concentrate for solution for infusion (CSI) containing ethanol and the other from a lyophilized powder, without ethanol, which was used as control group. After each administration, patients were surveyed in order to assess the appearance of any alcohol consumption symptoms (dizziness, difficulty speaking, unsteady walking, impaired balance, mood swings and slower reactions). Widmark formula and the amount of alcohol measured on the breath (breathalyzer) were used to estimate blood alcohol concentration. Results Twenty-four patients received both formulations and were included in the analysis. Mean administered ethanol dose when prepared from CSI was 15.81 +/- 2.25 g (mean +/- SD). When using CSI gemcitabine, estimated blood ethanol concentration was 0.033 g/dl according to Widmark formula and 0.02 g/dl according to breathalyzer results. Although overall incidence of symptoms was higher in the study group, the difference was not statistically significant (33% vs. 25%; p = 0.53). Conclusions These findings prove there is no difference in the onset of ethanol related symptoms when using CSI instead of lyophilized powder on the reconstitution of gemcitabine. PMID- 28639468 TI - CYP2D6 and CYP2C19 genotyping in psychiatric patients on psychotropic medication in the former Dutch Antilles. AB - AIM: This study was aimed to asses the prevalence of CYP2D6 and CYP2C19 polymorphisms in psychiatric patients and in volunteers from Dutch caribbean origin. METHODS: In total, 435 individuals were genotyped for CYP2D6 and CYP2C19. Of these, 269 were psychiatric patients on psychotropic medication, living in Curacao and 166 were volunteers from the Dutch Caribbean population. RESULTS: No differences in prevalence of alleles were found. CONCLUSION: Although prevalence of alleles appeared to be very different from African and Caucasian populations, the distribution into predicted phenotypes shows an equal distribution as in Caucasians. PMID- 28639470 TI - Identifying Computer-Generated Portraits: The Importance of Training and Incentives. AB - The past two decades have seen remarkable advances in photo-realistic rendering of everything from inanimate objects to landscapes, animals, and humans. We previously showed that despite these tremendous advances, human observers remain fairly good at distinguishing computer-generated from photographic images. Building on these results, we describe a series of follow-up experiments that reveal how to improve observer performance. Of general interest to anyone performing psychophysical studies on Mechanical Turk or similar platforms, we find that observer performance can be significantly improved with the proper incentives. PMID- 28639469 TI - Barriers and facilitators of antiretroviral therapy adherence in rural Eastern province, Zambia: the role of household economic status. AB - In Zambia, more people living with HIV now have access to lifesaving antiretroviral therapy than ever before. However, progress in HIV treatment and care has not always resulted in lower mortality. Adherence remains a critical barrier to treatment success. The objective of this study was to examine the barriers and facilitators of antiretroviral therapy adherence, particularly the role of household economic status. The study included a cross-sectional sample of 101 people living with HIV (PLHIV) in two rural communities in eastern Zambia. Adherence was measured using patient self-assessment and pharmacy information. Household economic status included components such as occupation, income, assets, food security, and debt. Multivariable logistic regression was conducted to examine the associations between household economic factors and adherence. Our findings suggest that the role of economic status on adherence appears to be a function of the economic component. Debt and non-farming-related occupation were consistently associated with non-adherence. The association between assets and adherence depends on the type of asset. Owning more transportation-related assets was consistently associated with non-adherence, whereas owning more livestock was associated with self-reported adherence. Additionally, living in a community with fewer economic opportunities was associated with non-adherence. The associations between place of residence and pharmacy refill adherence and between transportation assets and self-reported adherence were statistically significant. Improving adherence requires a multifaceted strategy that addresses the role of economic status as a potential barrier and facilitator. Programmes that provide economic opportunities and life-skills training may help PLHIV to overcome economic, social, and psychological barriers. PMID- 28639471 TI - An enhancer haplotype may influence BCL11A expression levels and the response to hydroxyurea in beta-thalassemia patients. AB - AIM: To identify the BCL11A intron-2 enhancer linkage disequilibrium (LD) block, harboring two previously identified SNPs, associating with the hydroxyurea response in beta-thalassemia patients and the functional significance of this region. MATERIALS & METHODS: Several neighboring SNPs were genotyped in our cohort. The associating LD block was identified, and its function studied in K562 erythroid cells via CRISPR/Cas9 genome editing. RESULTS: A haplotype harboring three tag SNPs correlated significantly with the HU-response and BCL11A transcript levels in the patients' reticulocytes. Two deletions encompassing this LD block significantly reduced BCL11A transcript levels in K562 cells. CONCLUSION: Our data suggest an essential role for this LD block in BCL11A expression levels and the response to hydroxyurea in beta-thalassemia patients. PMID- 28639473 TI - Revision and New Species of Vasotrema Stunkard, 1926 (Digenea: Schistosomatoidea): Turtle Blood Flukes of North American Softshell Turtles (Testudines: Trionychidae: Apalone spp.). AB - Gulf Coast spiny softshell turtles, Apalone spinifera aspera (Agassiz, 1857) (Testudines: Trionychidae) from Canoe Lake (33 degrees 47'56.16"N, 86 degrees 29'25.02"W; Springville, Alabama) and Round Lake (32 degrees 41'50.91"N, 87 degrees 14'30.39"W; Perry Lakes State Park, Marion, Alabama), were infected by V. robustum Stunkard, 1928 , Vasotrema longitestis Byrd, 1939 , and Vasotrema rileyae n. sp. The new species differs from its congeners by having papillate suckers, a short testis, an ovary dextral to the oviduct, and a pre-ovarian genital pore that is lateral to the ventral sucker. We studied the newly collected specimens and museum specimens of all congeners to revise the diagnosis of Vasotrema Stunkard, 1926 and redescribe and provide an updated dichotomous key to all species of the genus. PMID- 28639472 TI - MicroRNAs as a tool to aid stratification of colorectal cancer patients and to guide therapy. AB - Colorectal cancer is a common type of malignant disease with high rates of morbidity and mortality. Although treatment options have been expanded over the last years, the mainstay of curative treatment remains surgical removal of the tumor-bearing organ. Systemic treatment options include classic cytotoxic drugs as well as some biological agents. Noncoding RNAs are an evolving field in cancer diagnosis, prognosis and possible treatment. Noncoding miRNAs are small molecules with huge impact on gene expression. They have been a substantial part of cancer research for more than a decade. In this review article, the current knowledge of miRNAs and colorectal cancer diagnosis, prognosis and novel or evolving therapeutic concepts are discussed. Examples of how miRNAs might change the management of the disease will be described. PMID- 28639474 TI - Custom, rapid prototype thumb prosthesis for partial-hand amputation: A case report. AB - BACKGROUND: Due to advancements in three-dimensional printing, custom-made prostheses are becoming more viable options for persons with difficult cases of prosthetic management. The purpose of this article was to develop a custom voluntary-closing, body-powered thumb mechanism for a partial-hand amputee who had amputations of the index finger and thumb on the left, non-dominant hand. Case description and methods: The prosthesis model was manufactured using rapid prototype technology and was developed to provide greater force and functionality, and to decrease overall size compared to traditional hand prostheses. Findings and outcomes: Following device iterations and occupational therapy sessions, the patient achieved higher functionality in performing daily tasks such as cooking and cleaning, and in completing the Box and Blocks test, though some limitations still precluded full acceptance of the device. CONCLUSION: This case study represents a unique approach in the development of custom-made devices that may increase prostheses acceptance rates among partial hand amputees. Clinical relevance Many partial-hand amputees report experiencing trouble in finding a device that fits their needs. This study highlights the potential of using rapid prototyping technology to design a prosthesis that meets a user's specific desires. PMID- 28639475 TI - Ecological correlates of multiple sexual partnerships among adolescents and young adults in urban Cape Town: a cumulative risk factor approach. AB - Studies in South Africa have reported unsafe levels of risky sexual behvaiours among adolescents and young adults, with the country reporting the highest burden of HIV/AIDS globally, as well as a high rate of teenage pregnancy. While determinants of risky sexual behaviours have been investigated for factors occurring at the individual and household levels, not fully explored in the literature is the effect of community level factors. Furthermore, it is unclear whether risk factors occurring within the ecology of adolescents and young adults act cumulatively to influence their sexual practices. This article aims to address this knowledge gap using a case study of the Cape Area Panel Study of adolescents and young adults in urban Cape Town, South Africa. The ecological framework was adopted to guide the selection of risk factors at the individual, household, and community levels. Multivariate linear discriminant function analyses were used to select significant risk factors for multiple sexual partnerships and used to produce risk indices for the respondents. The cumulative risk approach was applied to test whether significant risk factors acted cumulatively. Findings point to the importance of ecological factors in influencing outcomes of multiple sexual partnerships among respondents and further demonstrate that ecological risk factors may act cumulatively. These findings are important for South Africa that is grappling with teenage pregnancy and disproportionate HIV epidemic among the youth. PMID- 28639476 TI - Effects of Folic Acid on DNMT1, GAP43, and VEGFR1 in Intrauterine Growth Restriction Filial Rats. AB - OBJECTIVE: To investigate the effect of a folic acid intervention on the outcome of intrauterine growth restriction (IUGR) filial rats and changes in DNA methyltransferase 1 (DNMT1), growth-associated protein 43 (GAP43), and vascular endothelial growth factor receptor 1 (VEGFR1). METHODS: The IUGR animal model was established using a starvation method in pregnant rats. The animals were randomly divided into 4 groups: normal controls, IUGR rats, IUGR rats given folic acid, and IUGR rats given normal saline. After the rats were weighed, the brain tissue was removed and the messenger RNA and protein levels of DNMT1, GAP43, and VEGFR1 were validated by reverse transcription-polymerase chain reaction and western blot. RESULTS: Birth weight was significantly increased after intervention with folic acid compared with the IUGR group, although it remained about 16% lower compared with the normal controls. The expressions of DNMT1 and GAP43, which were significantly upregulated in the IUGR group compared with the normal controls, were decreased with the folic acid intervention. However, there were no significant differences in VEGFR1 expression across groups. CONCLUSION: Brain damage in IUGR rats mainly manifests as delayed myelination or synaptic maturation and rarely as pathological proliferation of blood vessels. Our results strongly support the idea that the application of folic acid during pregnancy might represent a new epigenetic therapy for IUGR. PMID- 28639477 TI - Aberrantly Expressed SALL4 Promotes Cell Proliferation via beta-Catenin/c-Myc Pathway in Human Choriocarcinoma Cells. AB - Sal-like protein 4 (SALL4) has been proved to play a pivotal role in the development and progression of various cancers. Previous studies showed that SALL4 was highly expressed in human choriocarcinoma tissues. However, the role of SALL4 in the biological behavior of human choriocarcinoma cells remains largely unknown. In this study, we first elucidated that SALL4 was highly expressed in human choriocarcinoma cell line JEG-3 and JAR. Sal-like protein 4 knockdown by small interfering RNA (siRNA) decreased c-Myc expression, whereas SALL4 overexpression by transfection of human pLenti-SALL4 construct promoted c-Myc expression. Further data showed that SALL4 overexpression improved cell proliferation of JEG-3 cells, which can be abrogated by c-Myc siRNA. Moreover, our data showed that SALL4 interact with beta-catenin and SALL4 overexpression promoted the localization of beta-catenin in the nucleus and beta-catenin siRNA abrogated SALL4-induced c-Myc expression in JEG-3 cells. These data indicate that aberrantly expressed SALL4 in human choriocarcinoma cells may promote cell proliferation via beta-catenin/c-Myc pathway, indicating that SALL4 may be potential treatment targets of human choriocarcinoma. PMID- 28639478 TI - Relation between capacity and performance in paediatric upper limb prosthesis users. AB - BACKGROUND: The International Classification of functioning, disability and health refers capacity to what an individual can do in a standardised environment and describes performance as what an individual really does and whether the individual encounters any difficulty in the real-life environment. Measures of capacity and performance can help to determine if there is any gap between them that may restrict participation. The aim of this study was to explore the relationship between capacity scores obtained in a standardised clinical setting and proportional ease of performance obtained from a real-life environment. METHODS: The Assessment of Capacity for Myoelectric Control and the Prosthetic Upper Extremity Functional Index were used to assess capacity and performance in 62 prosthetic users (age 3-17). Spearman coefficient and generalised linear model were used to examine the association between these measures. RESULTS: A strong correlation (Spearman = 0.75) was found between the capacity scores and the ease of performance. In both unadjusted and adjusted models, capacity was significantly associated with proportional ease of performance. The adjusted model showed that, by 1 unit increase in the Assessment of Capacity for Myoelectric Control score, the ratio of proportional ease of performance increases by 45%. CONCLUSION: This implies that Assessment of Capacity for Myoelectric Control can be a predictor for ease of performance in real-life environment. Clinical relevance The ACMC scores may serve as an indicator to predict the difficulties that the children may encounter in their home environment. This prediction can help the clinician to make decisions, such that if the child requires more control training or is ready to move on to learn more complex tasks. PMID- 28639479 TI - An evaluation of Health of the Nation Outcome Scales data to inform psychiatric morbidity following the Canterbury earthquakes. AB - OBJECTIVE: Following the onset of the Canterbury, New Zealand earthquakes, there were widespread concerns that mental health services were under severe strain as a result of adverse consequences on mental health. We therefore examined Health of the Nation Outcome Scales data to see whether this could inform our understanding of the impact of the Canterbury earthquakes on patients attending local specialist mental health services. METHOD: Health of the Nation Outcome Scales admission data were analysed for Canterbury mental health services prior to and following the Canterbury earthquakes. These findings were compared to Health of the Nation Outcome Scales admission data from seven other large District Health Boards to delineate local from national trends. Percentage changes in admission numbers were also calculated before and after the earthquakes for Canterbury and the seven other large district health boards. RESULTS: Admission Health of the Nation Outcome Scales scores in Canterbury increased after the earthquakes for adult inpatient and community services, old age inpatient and community services, and Child and Adolescent inpatient services compared to the seven other large district health boards. Admission Health of the Nation Outcome Scales scores for Child and Adolescent community services did not change significantly, while admission Health of the Nation Outcome Scales scores for Alcohol and Drug services in Canterbury fell compared to other large district health boards. Subscale analysis showed that the majority of Health of the Nation Outcome Scales subscales contributed to the overall increases found. Percentage changes in admission numbers for the Canterbury District Health Board and the seven other large district health boards before and after the earthquakes were largely comparable with the exception of admissions to inpatient services for the group aged 4-17 years which showed a large increase. CONCLUSION: The Canterbury earthquakes were followed by an increase in Health of the Nation Outcome Scales scores for attendees of local mental health services compared to other large district health boards. This suggests that patients presented with greater degrees of psychiatric distress, social disruption, behavioural change and impairment as a result of the earthquakes. PMID- 28639480 TI - Managing attention deficit hyperactivity disorder in adults using illicit psychostimulants: A systematic review. AB - CONTEXT: Attention deficit hyperactivity disorder and stimulant use disorder commonly co-exist, and appropriate treatments have not been well established. OBJECTIVE: To provide guidance for treatment of co-existing attention deficit hyperactivity disorder and stimulant use disorder. DATA SOURCES: A systematic review of published English articles using MEDLINE, EMBASE, CINAHL, PsycINFO and Cochrane, utilising consistent search terms. STUDY SELECTION: Randomised controlled trials, comparing any treatment arm with a control group, for participants meeting Diagnostic and Statistical Manual of Mental Disorders or equivalent criteria for both attention deficit hyperactivity disorder and stimulant use disorder. RESULTS: Eight trials were identified for inclusion in this review. Four of eight studies showed improvement in attention deficit hyperactivity disorder outcome measures compared with placebo. Two of six studies that reported substance use outcomes showed improvement in treatment arms compared with placebo. Studies to show effect tended to be those with the highest treatment dosage. CONCLUSION: Evidence for the efficacy of treatment of patients with comorbid stimulant use disorder and attention deficit hyperactivity disorder is limited. Promising outcomes need replication in further studies utilising higher treatment dosage. PMID- 28639482 TI - "Always looking for a new balance": toward an understanding of what it takes to continue working while being diagnosed with relapsing-remitting multiple sclerosis. AB - BACKGROUND: The aim of this study was to gain insight into the meaning of work in the everyday lives of people with relapsing-remitting multiple sclerosis, and the barriers and facilitators to staying in work. METHODS: Nineteen employed adults diagnosed with relapsing-remitting multiple sclerosis participated in narrative interviews. All interviews were transcribed and coded for thematic analysis. RESULTS: For people with relapsing-remitting multiple sclerosis, continuing to work was a precarious balancing act. Five themes influenced this balance: becoming familiar with the disease, adjusting expectations, having an understanding and realistic line manager, seeing work as meaningful life activity and strategic considerations. CONCLUSIONS: People receiving a diagnosis of relapsing-remitting multiple sclerosis have to refamiliarize themselves with their own body in a meaningful way to be able to continue their work. Rehabilitation professionals can support them herein by taking into account not merely functional capabilities but also identity aspects of the body. Medication that stabilizes symptoms supports making the necessary adjustments. A trusting relationship with the line manager is vital for this adaptation process. Additionally, a match between being adequately challenged by work, while still having the capacity to meet those work demands, is needed, as is long-term financial stability. Implications for rehabilitation Rehabilitation professionals can support employees with relapsing-remitting multiple sclerosis by taking into account not merely functional capabilities but also identity aspects of the body. A trusting relationship with the line manager, including a timely disclosure of the diagnosis, is vital for people with relapsing-remitting multiple sclerosis to remain at work. For people with relapsing-remitting multiple sclerosis, there is a delicate balance between being adequately challenged by work while still having the capacity to meet work demands. PMID- 28639481 TI - Supporting decision-making by a health promotion programme: experiences of persons ageing in the context of migration. AB - This study is part of the Promoting Aging Migrants' Capabilities programme that applied person-centred group meetings and one individual home visit to prolong independence in daily activities among people >=70 years who had migrated to Sweden from Finland or the Western Balkan region. With the purpose to understand programme outcomes, the study aimed to explore the participants' everyday experiences of using health-promoting messages exchanged during the programme. Using a grounded theory approach, 12 persons aged 70-83 years were interviewed six months to one year after their participation in the programme. The participants experienced how using health-promoting messages was a dynamic process of how to make decisions on taking action to satisfy health-related needs of oneself or others immediately or deferring action. Five sub-processes were also identified: gaining inner strength, meeting challenges in available resources, being attentive to what is worth knowing, approaching health risks, and identifying opportunities to advocate for others. The results suggest that the programme could develop personal skills to support older people who have migrated to overcome health-related challenges. They further demonstrate the importance of supporting their health literacy before personal resources hinder action, and call for research on programmes to overcome environmental barriers to health. PMID- 28639483 TI - Assessing Narcissism Using Rorschach-Based Imagery and Behavior Validated by Clinician Reports: Studies With Adult Patients and Nonpatients. AB - We evaluate 11 Rorschach variables with potential for assessing grandiosity and narcissism. Seven of these variables were drawn from previous literature: Omnipotence, Idealization, Reflection, Personal Knowledge Justification, Exhibitionism, Magic, and Elevated Mood States; four were developed for this research: Expanded Personal Reference, Narcissistic Devaluation, Narcissistic Deflation, and Narcissistic Denial. Using Rorschach protocols from American normative adults and Italian adult outpatients, the dimensional structure of these variables was evaluated by principal components analysis, and validity was tested by correlations with clinician ratings of narcissism on two scales from the Shedler-Westen Assessment Procedure-200 that were made after at least five sessions with the primary clinician. A cohesive dimension was found in both data sets defined by Expanded Personal Reference, Personal Knowledge Justification, Omnipotence, and Idealization, and it was meaningfully correlated with the clinician ratings of narcissism ( M r = .41). Implications of the findings include the applicability of these variables in clinical practice and research for assessing narcissistic personality dynamics. PMID- 28639484 TI - Detection Test for Language Impairments in Adults and the Aged-A New Screening Test for Language Impairment Associated With Neurodegenerative Diseases: Validation and Normative Data. AB - To date, there is no quick screening test that could be used during routine office visits to accurately assess language disorders in neurodegenerative diseases. To fill this important gap, we developed the Detection Test for Language impairments in Adults and the Aged (DTLA), a quick, sensitive, standardized screening test designed to assess language disorders in adults and the elderly individuals. In Study 1, we describe the development of the DTLA. In Study 2, we report data on the DTLA's validity and reliability. Finally, in Study 3, we establish normative data for the test. The DTLA has good convergent and discriminant validity as well as good internal consistency and test-retest reliability. Norms for the DTLA obtained from a sample of 545 healthy, community dwelling, French-speaking adults from 4 French-speaking countries (Belgium, Canada (Quebec), France, and Switzerland) are provided. The development, validation, and standardization of the DTLA constitute a significant effort to meet the need for a language screening test adapted to neurodegenerative diseases. PMID- 28639486 TI - Estimated Prevalence of the Target Population for Brain-Computer Interface Neurotechnology in the Netherlands. AB - BACKGROUND: People who suffer from paralysis have difficulties participating in society. Particularly burdensome is the locked-in syndrome (LIS). LIS patients are not able to move and speak but are cognitively healthy. They rely on assistive technology to interact with the world and may benefit from neurotechnological advances. Optimal research and design of such aids requires a well-defined target population. However, the LIS population is poorly characterized and the number of patients in this condition is unknown. OBJECTIVE: Here we estimated and described the LIS patient population in the Netherlands to define the target population for assistive (neuro)technology. METHODS: We asked physicians in the Netherlands if they had patients suffering from severe paralysis and communication problems in their files. Physicians responding affirmatively were asked to fill out a questionnaire on the patients' status. RESULTS: We sent out 9570 letters to general practitioners (GPs), who reported 83 patients. After first screening, the GPs of 46 patients received the questionnaire. Based on the responses, 26 patients were classified as having LIS. Extrapolation of these numbers resulted in a prevalence of 0.73 patients per 100 000 inhabitants. Notable results from the questionnaire were the percentage of patients with neuromuscular disease (>50%) and living at home (>70%). CONCLUSIONS: We revealed an etiologically diverse group of LIS patients. The functioning and needs of these patients were, however, similar and many relied on assistive technology. By characterizing the LIS population, our study may contribute to optimal development of assistive (neuro)technology. PMID- 28639485 TI - Increased SHISA3 expression characterizes chronic lymphocytic leukemia patients sensitive to lenalidomide. AB - Lenalidomide is a therapeutically effective drug in chronic lymphocytic leukemia (CLL). Twenty-seven CLL patients were treated with lenalidomide in a phase II clinical trial. Ten patients were grouped as responders (R) and 6 as nonresponders (NR). We evaluated T lymphocytes, NK, monocytes and dendritic cells at baseline and after treatment. A gene expression analysis was performed on 16 CLL samples collected before treatment. The levels of immune cells or immune related cytokines are not different between R and NR patients. However, CLL patients sensitive to lenalidomide clearly show a peculiar gene expression profile in leukemic cells. The most up-regulated gene (fold change = +23 in R vs. NR) is Wnt inhibitor SHISA homolog 3 (SHISA3). SHISA3highCLL are characterized by a restrained activation of Wnt signaling and sensibility to lenalidomide-induced apoptosis. In conclusion, SHISA3 is a candidate gene for the identification of CLL patients who will benefit of lenalidomide treatment as single agent. PMID- 28639487 TI - MRP2/ABCC2 C1515Y polymorphism modulates exposure to lumefantrine during artemether-lumefantrine antimalarial therapy. AB - AIM: To investigate the potential involvement of the hepatic ATP-binding cassette transporters MRP2 and MDR1 in the disposition of lumefantrine (LUM) among patients with uncomplicated Plasmodium falciparum malaria. MATERIALS & METHODS: The tag SNPs MDR1/ABCB1 C3435T and MRP2/ABCC2 C1515Y were determined in two artemether-LUM clinical trials, including a pharmacokinetic/pharmacodynamic study focused on the treatment phase (72 h), and an efficacy trial where day 7 (D7) LUM levels were measured. RESULTS: The 1515YY genotype was significantly associated with higher (p < 0.01) LUM D7 concentrations (median 1.42 MUM), compared with 0.77 MUM for 1515CY and 0.59 MUM for 1515CC. No significant influence of the MDR1/ABCB1 C3435T was found. CONCLUSION: LUM body disposition may be influenced by MRP2/ABCC2 genotype. PMID- 28639488 TI - Prenatal exposure to serotonin reuptake inhibitors and congenital heart anomalies: an exploratory pharmacogenetics study. AB - AIM: To explore the role of pharmacogenetics in determining the risk of congenital heart anomalies (CHA) with prenatal use of serotonin reuptake inhibitors. METHODS: We included 33 case-mother dyads and 2 mother-only (child deceased) cases of CHA in a case-only study. Ten genes important in determining fetal exposure to serotonin reuptake inhibitors were examined: CYP1A2, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC6A4, HTR1A, HTR1B, HTR2A and HTR3B. RESULTS: Among the exposed cases, polymorphisms that tended to be associated with an increased risk of CHA were SLC6A4 5-HTTLPR and 5-HTTVNTR, HTR1A rs1364043, HTR1B rs6296 and rs6298 and HTR3B rs1176744, but none reached statistical significance due to our limited sample sizes. CONCLUSION: We identified several polymorphisms that might potentially affect the risk of CHA among exposed fetuses, which warrants further investigation. PMID- 28639490 TI - The role of special education teachers in facilitating peer relationships among students with mild intellectual disabilities in lower secondary school. AB - BACKGROUND:: Students with intellectual disabilities may lack sufficiently developed skills to initiate qualitatively good social interactions; thus, they might be in need of assistance. This study examined special education teachers' role in facilitating peer relationships among students with mild intellectual disabilities in a mainstream school context. MATERIALS AND METHODS:: The study was based on qualitative semi-structured interviews with nine special education teachers who belong to special education groups in lower secondary schools. A thematic structural analysis was used to identify themes. RESULTS:: The teachers made substantial efforts to promote social competence and ensure optimal conditions to foster peer interactions. An "academic-oriented" education, divergent attitudes, challenges in teacher collaboration, and organizational constraints may be barriers. CONCLUSIONS:: In a mainstream school, the role of special education teachers appears to be dependent on the basic values of the school management in terms of real opportunities to foster peer relationships among students with mild intellectual disabilities. PMID- 28639491 TI - Family-centred services for young children with intellectual disabilities and their families: Theory, policy and practice. AB - This paper outlines the reported discrepancies between the aims of the welfare services in Iceland and the experiences of parents raising young children with intellectual disabilities. Prevailing views on disability and service delivery were also considered. A multi case study design was employed to reflect the situation in different parts of the country. Families of eight children with intellectual disabilities and professionals in three different municipalities formed the cases. The findings reveal a high convergence between the three cases with variations based on individual experiences rather than geographical location. Overall, parents praised the preschools but experienced support services often as fragmented and uncompromising. Particular components of the services were consistently regarded as hard to reach and not in accordance with the needs of the family. Cultural-historical activity theory is introduced as a beneficial framework for further study and system improvement. PMID- 28639489 TI - Healthcare provider education to support integration of pharmacogenomics in practice: the eMERGE Network experience. AB - Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes. PMID- 28639492 TI - Clinical commentary on 'Recurrent natalizumab-related aseptic meningitis in a patient with multiple sclerosis', by Foley et al. AB - This clinical commentary discusses the occurrence of drug-induced aseptic meningitis in patients undergoing natalizumab treatment and other immunotherapies. PMID- 28639493 TI - Pathway analysis to identify genetic variants associated with efficacy of adalimumab in rheumatoid arthritis. AB - AIM: About 30% of rheumatoid arthritis patients have no clinical benefit from TNF inhibitors. Genome-wide association (GWA) and candidate gene studies tested several putative genetic variants for TNF inhibitor efficacy with inconclusive results. Therefore, this study applied a systematic pathway analysis. PATIENTS & METHODS: A total of 325 rheumatoid arthritis patients treated with adalimumab were genotyped for 223 SNPs. We tested the association between SNPs and European League Against Rheumatism response and remission at 14 weeks under the additive genetic model using logistic regression. RESULTS: A total of 3 SNPs located in CD40LG (rs1126535), TANK (rs1267067) and VEGFA (rs25648) showed association with both end points. TNFAIP3 (rs2230926) had the strongest effect related to European League Against Rheumatism response. CONCLUSION: This exploratory study suggests that TNFAIP3, CD40LG, TANK and VEGFA play a role in the response to adalimumab treatment. PMID- 28639494 TI - Status of mental-health services for adolescents with psychiatric morbidity in youth correctional institutions in Lagos. AB - BACKGROUND: High prevalence rates of psychiatric morbidity have been documented among adolescents within youth correctional institutions in Nigeria. However, there has not been prior investigation to determine the capacity for and nature of mental health services being provided in these institutions. OBJECTIVES: To assess psychiatric morbidity among adolescents within youth correctional institutions in Lagos, while simultaneously examining the capacity for and the scope of mental health services. METHODS: Psychiatric morbidity and alcohol/substance use disorder were assessed among 165 respondents using the Strengths and Difficulties Questionnaire, and the CRAFFT screening tool for adolescent substance use disorder. Availability of mental-health services in the institutions was examined using an 'audit protocol'. RESULTS: We found prevalence rates of 18.2% and 15.8% of general psychiatric morbidity and alcohol/ substance use disorder, respectively, among the adolescents. Only about a third (34.3%; n = 20) of the operational staff at the institutions had educational backgrounds relevant to psycho-social services for children/adolescents, while less than a quarter (22.4%, n = 13) has ever received any training in child mental health services. There was no evidence of mental health screening and intervention in the service framework within the institutions. CONCLUSIONS: We concluded that there was evidence for significant mental health service gaps within the youth correctional services in Lagos. PMID- 28639495 TI - Substance use in adolescents with mental illness in Durban, South Africa. AB - Comorbid substance use in adolescents with mental illness is often an indicator of poor treatment outcome. This study aims to determine the prevalence of, and associated risk factors for, substance use in adolescents with mental illness attending a mental health service. Data was collected from hospital records of 162 adolescents, using a structured data sheet, over a two-year period. Substance use was more significant in older adolescents and those with severe mental illness. Sixty-two (38.3%) adolescents used substances. Thirty-seven (38.1%) male adolescents reported substance use compared to 25 (38.5%) female adolescents. Alcohol was the most commonly used substance (n = 48; 29.6%), followed by cannabis (n = 32; 19.8%). There were significant direct associations between substance use and history of abuse or neglect, forensic history, educational setting, admission status, and the psychiatric diagnoses of schizophrenia, other psychotic disorders, and bipolar mood disorder. Inverse associations were found between substance use and adjustment disorders, attention deficit hyperactivity disorder, and intellectual disability. The results of this study indicate an urgent need for substance misuse programmes for at risk youth, and the introduction of dual diagnosis intervention programmes in this age group. PMID- 28639497 TI - Tattoo or no tattoo? A contemporary ethical issue in nursing education. PMID- 28639498 TI - Municipal solid waste incineration (MSWI) fly ash washing pretreatment by biochemical effluent of landfill leachate: a potential substitute for water. AB - Sulfate-rich biochemical effluent of landfill leachate (BEL) resulting from aged refuse bioreactor was employed to wash municipal solid waste incineration (MSWI) fly ash. The dechlorination ability of BEL was found to be nearly equivalent to redistilled water (RW), and the concentrations of lead (Pb) and zinc (Zn) in the washing solution resulting from the BEL washing process were lower than that of the RW washing process. Fourier transform infrared (FTIR) analysis indicated that the formation of calcium sulfate and hydroxides in fly ash after BEL washing and their entrapping function could significantly inhibit the leaching of Pb and Zn. Besides, toxicity characteristic leaching procedure (TCLP) tests showed that the BEL washing treatment did not increase the risk of heavy metals leaching from fly ash, and the leaching concentrations of Pb, Zn, copper (Cu) and cadmium (Cd) of BEL washed fly ash were lower than that of RW washed fly ash, which suggested BEL washing treatment could slightly immobilize heavy metals in fly ash. For MSWI fly ash dechlorination, our present results indicated that BEL used in this batch experiment could be a potential substitute for water. PMID- 28639499 TI - HIV and AIDS-related stigma and discrimination in two referral hospitals in Ethiopia. AB - The aim of the study was to determine the magnitude of HIV and AIDS-related stigma and discrimination (SAD) and its associated factors in healthcare settings. Primary data were collected from June to September 2014 from two referral hospitals located in north-west Ethiopia. The study used pre-test/post test design with a non-equivalent control group using a quantitative approach. Healthcare professionals were divided into strata and then, using the stratified random sampling technique, the study participants were selected from each stratum. The median age of study respondents in the treatment group was 32.2 years with standard deviation (SD) of 7.74. The regressions of stigma for the pre tests of the first hospital and second hospital participants' knowledge about SAD related issues and perceived risk of HIV infection were found to be significantly associated with stigma in the first hospital. In the first hospital, healthcare professionals who felt HIV risk of infection at different contact points with HIV positive patients were more than 13 times more likely to present stigmatising attitudes towards the patients (OR = 13.46, p = 0.005). In the second hospital, only perceived risk of infection was significantly associated with stigma (p = 0.036). Interventions to lessen HIV and AIDS-related SAD in healthcare settings must focus on improving the knowledge, attitudes and practices of healthcare professionals as well as overcoming the institutional barriers existing in the healthcare settings through staff training and hospital strategy development. PMID- 28639500 TI - A review of interprovincial variations in HIV prevalence rates in Zimbabwe. AB - Despite the proven remarkable decline of HIV prevalence in the sub-Saharan Africa region, both sub-regional and within-country disparities in HIV prevalence persist. This paper is a survey of literature on HIV prevalence and spread in Zimbabwe, focusing on provincial differences within the national picture of a decline in new infections. In particular, it raises the question of why prevalence and infection rates seem to be disproportionately higher in Matabeleland relative to other provinces of the country. This disparity cannot be adequately explained on the basis of national behavioural analyses as has been the case. The paper suggests possible additional nuances in the forms of analysis and proposes a change of focus in HIV-prevention strategies from national level to provincial considerations of the multiple factors influencing variations in HIV infection rates at provincial level. Using the different contextual conditions between provinces as a way to examine what might be the additional significant variables, the paper brings variations that go beyond sexual behaviour. PMID- 28639501 TI - From pharmacogenetics to imaging pharmacogenetics: elucidating mechanisms of antidepressant response. PMID- 28639502 TI - Rituximab as first-line treatment for acquired thrombotic thrombocytopenic purpura. AB - Objective To investigate the efficacy and safety of rituximab (RTX) as first-line treatment of acquired thrombotic thrombocytopenic purpura (aTTP). Methods Twenty five patients with acute aTTP and/or severe a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency were admitted to our centre from April 2009 to March 2015. Fourteen patients received RTX plus standard therapy (plasma exchange and corticosteroids) at acute episodes. Haemoglobin, platelet count, schistocytes, lactate dehydrogenase levels, ADAMTS13 activity and its inhibitors, and the ratio of B lymphocytes in the peripheral blood, were monitored. The number of plasma exchange (PEXs), total plasma volume, remission time, relapse ratio, and adverse effects were recorded. Results The median number of PEXs was 5 (2-17) sessions and median total plasma volume was 168.43 ml/kg (62.86-469.52 ml/kg). Patients achieved haematological remission at a median of 15 days (5-22 days), and the median time of immunological remission was 2 weeks (2-8 weeks) with a median follow-up of 13 months (3-61 months). ADAMTS13 activity significantly increased after 2 weeks. The B lymphocyte percentage in peripheral blood was reduced 1 week after the first dose of RTX infusion compared with before treatment (2.21% +/- 5.23% vs 18.47% +/- 7.34%, P = 0.000 [the result of statistical software]), and began to gradually increase 9 months later. Severe adverse effects and relapsing TTP were not observed during therapy and follow-up. However, one patient who had sustained immunological remission died of severe pneumonia 7 months later. Conclusion Although our study was limited by its small sample number and it was a non-controlled, clinical trial, it showed potential benefits of RTX therapy for acute aTTP. RTX may be administered as a first-line therapy for lowering patients' relapse rate in the long term. Randomized, controlled trials of RTX for aTTP are required. PMID- 28639503 TI - Markers of disease and steroid responsiveness in paediatric idiopathic nephrotic syndrome: Whole-transcriptome sequencing of peripheral blood mononuclear cells. AB - Objective To identify markers of disease and steroid responsiveness in paediatric idiopathic nephrotic syndrome. Methods Whole-transcriptome sequencing was performed of peripheral blood mononuclear cells (PBMCs) from patients with NS. Differentially expressed genes (DEGs) were identified in patients with active NS vs those in remission, and those with steroid-sensitive NS (SSNS) vs steroid resistant NS (SRNS). Results A total of 1065 DEGs were identified in patients with NS ( n = 10) vs those in remission ( n = 9). These DEGs correlated with cytokine and/or immune system signalling and the extracellular matrix. Comparisons between SSNS ( n = 6) and SRNS ( n = 4) identified 1890 DEGs. These markers of steroid responsiveness were enriched with genes related to the cell cycle, targets of microRNAs, and genes related to cytokines. Conclusions Meaningful DEGs were identified. Additional studies with larger numbers of patients will provide more comprehensive data. PMID- 28639504 TI - Spatial and Temporal Changes in the Distribution of Blood Fluke Infection in Nicolea gracilibranchis (Polychaeta: Terebellidae), the Intermediate Host for Cardicola orientalis (Digenea: Aporocotylidae), at a Tuna Farming Site in Japan. AB - Fish blood flukes of the genus Cardicola (Digenea: Aporocotylidae) are important pathogens in tuna aquaculture. Recent advances in marine blood fluke research have led to the elucidation of the lifecycles of 3 Cardicola spp. infecting tuna; all 3 flukes utilize terebellid polychaetes as the intermediate host. In our survey, we obtained large numbers of Nicolea gracilibranchis infected by larval Cardicola orientalis at our tuna farming site. To determine the spatial and temporal changes in the distribution of N. gracilibranchis surrounding tuna culture cages and their infection by C. orientalis, we conducted monthly sampling for a period of 1 yr. Terebellids were most abundant on the floats and ropes of culture cages, but a significantly higher proportion of infected N. gracilibranchis was detected on ropes, particularly up to 4 m in depth. Cardicola orientalis infection in N. gracilibranchis was clearly seasonal, with a higher infection rate between April and July. Our findings indicate that the infected terebellids inhabit specific microhabitats, and both abiotic and biotic factors likely influence blood fluke infection in the intermediate terebellid host. This information is important to better understand the general biology of marine aporocotylids and may be useful to develop a control strategy for blood fluke infection in tuna aquaculture. PMID- 28639506 TI - Orthognathic surgery: principles, planning and practice. PMID- 28639507 TI - Corrigendum. PMID- 28639510 TI - Relevant research from orthodontic journals. PMID- 28639508 TI - On the results of clinical studies. PMID- 28639511 TI - In memory of Professor Teiji Tsuruta; great mentor in polymeric biomaterials. PMID- 28639512 TI - The relationship between Nairobi adolescents' media use and their sexual beliefs and attitudes. AB - Adolescents in sub-Saharan Africa are at risk for contracting HIV. Although media campaigns have educated the population as a whole, few studies are available about the time sub-Saharan African youth spend listening to and viewing sexual messages via the entertainment and informational media. The goals of this project were: 1) to investigate what programming Nairobi adolescents access; and 2) to investigate the association between frequency of access and level of focus on physical relationships with adolescents' perceptions of descriptive norms of peer sexual behaviour, and their attitudes regarding men as sex driven, women as sex objects, and dating as a sport. A total of 464 students from 6 Nairobi secondary schools were surveyed. When students' favourite musicians had a strong focus on physical relationships in their songs, those students estimated the prevalence of risky sexual behaviours among their peers higher. These students also endorsed gender stereotypical and casual attitudes about sex. Large amounts of time spend on the Internet was predictive of all sexual attitude variables. Students whose favourite TV programmes had a strong focus on physical relationships also estimated prevalence of peer sexual behaviour as high. PMID- 28639505 TI - Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium. AB - AIM: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. MATERIALS & METHODS: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. RESULTS: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. CONCLUSION: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population. PMID- 28639513 TI - Development of an arthroscopically compatible polymer additive layer manufacture technique. AB - This article describes a proof of concept study designed to evaluate the potential of an in vivo three-dimensional printing route to support minimally invasive repair of the musculoskeletal system. The study uses a photocurable material to additively manufacture in situ a model implant and demonstrates that this can be achieved effectively within a clinically relevant timescale. The approach has the potential to be applied with a wide range of light-curable materials and with development could be applied to create functionally gradient structures in vivo. PMID- 28639514 TI - Analysis of variability in additive manufactured open cell porous structures. AB - In this article, a novel method of analysing build consistency of additively manufactured open cell porous structures is presented. Conventionally, methods such as micro computed tomography or scanning electron microscopy imaging have been applied to the measurement of geometric properties of porous material; however, high costs and low speeds make them unsuitable for analysing high volumes of components. Recent advances in the image-based analysis of open cell structures have opened up the possibility of qualifying variation in manufacturing of porous material. Here, a photogrammetric method of measurement, employing image analysis to extract values for geometric properties, is used to investigate the variation between identically designed porous samples measuring changes in material thickness and pore size, both intra- and inter-build. Following the measurement of 125 samples, intra-build material thickness showed variation of +/-12%, and pore size +/-4% of the mean measured values across five builds. Inter-build material thickness and pore size showed mean ranges higher than those of intra-build, +/-16% and +/-6% of the mean material thickness and pore size, respectively. Acquired measurements created baseline variation values and demonstrated techniques suitable for tracking build deviation and inspecting additively manufactured porous structures to indicate unwanted process fluctuations. PMID- 28639515 TI - Editorial. PMID- 28639516 TI - Accuracy assessment of surgical planning and three-dimensional-printed patient specific guides for orthopaedic osteotomies. AB - This study analyses the accuracy of three-dimensional pre-operative planning and patient-specific guides for orthopaedic osteotomies. To this end, patient specific guides were compared to the classical freehand method in an experimental setup with saw bones in two phases. In the first phase, the effect of guide design and oscillating versus reciprocating saws was analysed. The difference between target and performed cuts was quantified by the average distance deviation and average angular deviations in the sagittal and coronal planes for the different osteotomies. The results indicated that for one model osteotomy, the use of guides resulted in a more accurate cut when compared to the freehand technique. Reciprocating saws and slot guides improved accuracy in all planes, while oscillating saws and open guides lead to larger deviations from the planned cut. In the second phase, the accuracy of transfer of the planning to the surgical field with slot guides and a reciprocating saw was assessed and compared to the classical planning and freehand cutting method. The pre-operative plan was transferred with high accuracy. Three-dimensional-printed patient-specific guides improve the accuracy of osteotomies and bony resections in an experimental setup compared to conventional freehand methods. The improved accuracy is related to (1) a detailed and qualitative pre-operative plan and (2) an accurate transfer of the planning to the operation room with patient-specific guides by an accurate guidance of the surgical tools to perform the desired cuts. PMID- 28639517 TI - Development of finite element model for customized prostheses design for patient with pelvic bone tumor. AB - The aim of this study was to design a hemi-pelvic prosthesis for a patient affected by pelvic sarcoma. To investigate the biomechanical functionality of the pelvis reconstructed with designed custom-made prosthesis, a patient-specific finite element model of whole pelvis with primary ligaments inclusive was constructed based on the computed tomography images of the patient. Then, a finite element analysis was performed to calculate and compare the stress distribution between the normal and implanted pelvis models when undergoing three different static conditions-both-leg standing, single-leg standing for the healthy and the affected one. No significant differences were observed in the stresses between the normal and reconstructed pelvis for both-leg standing, but 20%-40% larger stresses were predicted for the peak stress of the single-leg standing (affected side). Moreover, two- to threefold of peak stresses were predicted within the prostheses compared to that of the normal pelvis especially for single-leg standing case, however, still below the allowable fatigue limitation. The study on the load transmission functionality of prosthesis indicated that it is crucial to carry out finite element analysis for functional evaluation of the designed customized prostheses before three-dimensional printing manufacturing, allowing better understanding of the possible peak stresses within the bone as well as the implants for safety precaution. The finite element model can be equally applicable to other bone tumor model for biomechanical studying. PMID- 28639518 TI - Selective laser melting-enabled electrospinning: Introducing complexity within electrospun membranes. AB - Additive manufacturing technologies enable the creation of very precise and well defined structures that can mimic hierarchical features of natural tissues. In this article, we describe the development of a manufacturing technology platform to produce innovative biodegradable membranes that are enhanced with controlled microenvironments produced via a combination of selective laser melting techniques and conventional electrospinning. This work underpins the manufacture of a new generation of biomaterial devices that have significant potential for use as both basic research tools and components of therapeutic implants. The membranes were successfully manufactured and a total of three microenvironment designs (niches) were chosen for thorough characterisation. Scanning electron microscopy analysis demonstrated differences in fibre diameters within different areas of the niche structures as well as differences in fibre density. We also showed the potential of using the microfabricated membranes for supporting mesenchymal stromal cell culture and proliferation. We demonstrated that mesenchymal stromal cells grow and populate the membranes penetrating within the niche-like structures. These findings demonstrate the creation of a very versatile tool that can be used in a variety of tissue regeneration applications including bone healing. PMID- 28639519 TI - Knee joint kinetics in response to multiple three-dimensional printed, customised foot orthoses for the treatment of medial compartment knee osteoarthritis. AB - The knee adduction moment is consistently used as a surrogate measure of medial compartment loading. Foot orthoses are designed to reduce knee adduction moment via lateral wedging. The 'dose' of wedging required to optimally unload the affected compartment is unknown and variable between individuals. This study explores a personalised approach via three-dimensional printed foot orthotics to assess the biomechanical response when two design variables are altered: orthotic length and lateral wedging. Foot orthoses were created for 10 individuals with symptomatic medial knee osteoarthritis and 10 controls. Computer-aided design software was used to design four full and four three-quarter-length foot orthoses per participant each with lateral posting of 0 degrees 'neutral', 5 degrees rearfoot, 10 degrees rearfoot and 5 degrees forefoot/10 degrees rearfoot. Three-dimensional printers were used to manufacture all foot orthoses. Three dimensional gait analyses were performed and selected knee kinetics were analysed: first peak knee adduction moment, second peak knee adduction moment, first knee flexion moment and knee adduction moment impulse. Full-length foot orthoses provided greater reductions in first peak knee adduction moment (p = 0.038), second peak knee adduction moment (p = 0.018) and knee adduction moment impulse (p = 0.022) compared to three-quarter-length foot orthoses. Dose effect of lateral wedging was found for first peak knee adduction moment (p < 0.001), second peak knee adduction moment (p < 0.001) and knee adduction moment impulse (p < 0.001) indicating greater unloading for higher wedging angles. Significant interaction effects were found for foot orthosis length and participant group in second peak knee adduction moment (p = 0.028) and knee adduction moment impulse (p = 0.036). Significant interaction effects were found between orthotic length and wedging condition for second peak knee adduction moment (p = 0.002). No significant changes in first knee flexion moment were found. Individual heterogeneous responses to foot orthosis conditions were observed for first peak knee adduction moment, second peak knee adduction moment and knee adduction moment impulse. Biomechanical response is highly variable with personalised foot orthoses. Findings indicate that the tailoring of a personalised intervention could provide an additional benefit over standard interventions and that a three dimensional printing approach to foot orthosis manufacturing is a viable alternative to the standard methods. PMID- 28639520 TI - Polyomavirus-associated Prostatitis in Wistar Han Rats Following Immunosuppression in a Chronic Toxicity Study. AB - Chronic prostatitis characterized on light microscopic examination by moderate, multifocal, predominantly lymphocytic inflammation associated with epithelial atypia and intranuclear and cytoplasmic inclusion-like material was identified in the prostate gland of 2 Wistar Han rats administered an immunomodulatory test article in a 6-month chronic toxicity study. Transmission electron microscopy of the prostate glands identified 45-nm, nonenveloped, icosahedral virions arranged in paracrystalline array within the cell nuclei in 1 of the 2 rats. The size, shape, location, and array pattern were most consistent with a polyomavirus. The light and electron microscopic findings after immunosuppression in our case have a resemblance to a polyomavirus recently reported to affect prostate gland epithelium in a colony of immunocompromised X-linked severe combined immune deficiency rats. To the best of our knowledge, this is the first report of light and electronic microscopic lesions in the reproductive tract associated with polyomavirus following chronic immunosuppression in a widely used, wild-type Wistar Han rat. PMID- 28639521 TI - Technology-enhanced focus groups as a component of instrument development. AB - Background Bullying is a critical public health problem and a screening tool for use in healthcare is needed. Focus groups are a common tool for generating qualitative data when developing an instrument and evidence suggests that technology-enhanced focus groups can be effective in simultaneously engaging participants from diverse settings. Aim To examine the use of technology-enhanced focus groups in generating an item pool to develop a youth-bullying screening tool. Discussion The authors explore methodological and ethical issues related to conducting technology-enhanced focus groups, drawing on their experience in developing a youth-bullying measure. They conducted qualitative focus groups with professionals from the front lines of bullying response and intervention. They describe the experience of conducting technology-enhanced focus group sessions, focusing on the methodological and ethical issues that researchers engaging in similar work may encounter. Challenges associated with this methodology include establishing rapport among participants, privacy concerns and limited non-verbal communication. Conclusion The use of technology-enhanced focus groups can be valuable in obtaining rich data from a wide variety of disciplines and contexts. Organising these focus groups was inexpensive and preferred by the study's participants. Implications for practice Researchers should consider using technology-enhanced focus groups to generate data to develop health-related measurement tools. PMID- 28639522 TI - Crowdfunding: an innovative way to fund your project. AB - Background Getting research funded is extremely difficult, with research councils rejecting more than 70% of grant applications ( Else 2014 ). It is even more difficult if you are a junior researcher who doesn't have a track record of being awarded grant money or leading a research project. Crowdfunding may offer a solution. It is a method of raising funds from members of the public online and can offer an alternative to the more formal methods of research funding. Aim To outline how this model works and provide tips on designing a campaign. Discussion The authors provide an overview of the literature regarding this model, as well as a set of resources for future reference when designing a campaign. Conclusion Crowdfunding can provide small amounts of money for your first project. Implications for practice It is expected that clinicians practice evidence based medicine, and research in health environments is commonplace. Crowdfunding can offer you support in becoming more engaged in research. PMID- 28639524 TI - 'While we treat diseases, we do not treat the root cause'. AB - When and why did you develop an interest in research? During my master's degree, I was able to publish my research thesis and was hooked on research. PMID- 28639523 TI - Psychometric testing of inventory of beliefs and attitudes on domestic violence. AB - Background Domestic violence (DV) is an international public health issue associated with adverse health outcomes for adults and children. There have been widespread calls to increase nurses' capacity to respond to DV and improve undergraduate nursing education in this area. However, there are few valid, reliable and contemporary measures of nursing attitudes towards and beliefs concerning DV that are suited for use in evaluating education programmes. Aim To establish the psychometric properties of a newly developed inventory designed to measure nursing students' beliefs about and attitudes towards DV. Discussion Exploratory factor analysis identified five factors, with a Cronbach's alpha of 0.646. The few factors loading>.80 suggest that the instrument has good discriminate validity. The absence of cross-loadings indicate good convergent validity. Conclusion The inventory provides one of the first validated and reliable measures for examining undergraduate nursing students' attitudes towards and beliefs about DV. Implications for practice The instrument is suited for use by nurse educators in assessing the influence of curriculum design and teaching strategies on student beliefs and attitudes. It would also be useful in studies investigating nurses' clinical practice on domestic violence. PMID- 28639525 TI - Considerations when conducting e-Delphi research: a case study. AB - Background E-Delphi is a way to access a geographically dispersed group of experts. It is similar to other Delphi methods but conducted online. E-research methodologies, such as the e-Delphi method, have yet to undergo significant critical discussion. Aim To highlight some of the challenges nurse researchers may wish to consider when using e-Delphi in their research. Discussion This paper provides details about the author's approach to conducting an e-Delphi study in which a group of health literacy nurse experts (n=41) used an online survey platform to identify and prioritise essential health literacy competencies for registered nurses. Conclusion This paper advances methodological discourse about e-Delphi by critically assessing an e-Delphi case study. The online survey platform used in this study was advantageous for the researcher and the experts: the experts could participate at any time and place where the internet was available; the researcher could efficiently access a national group of experts, track responses and analyse data in each round. Implications for practice E Delphi studies create opportunities for nurse researchers to conduct research nationally and internationally. Before conducting an e-Delphi study, researchers should carefully consider the design and methods for collecting data, to avoid challenges that could potentially compromise the quality of the findings. Researchers are encouraged to publish details about their approaches to e-Delphi studies, to advance the state of the science. PMID- 28639526 TI - Using technology in research. AB - [Figure: see text] In the past 25 years, the growth of the internet and associated technology has significantly changed the way in which we communicate, seek information and engage with others across all aspects of our lives ( Meyer et al 2016 ). Academia in particular has been transformed with a growth in online learning and the expanding use of technology in research. PMID- 28639527 TI - Bright lights, bold ideas and remembering Justine Beckett. AB - It was an honour to once again represent Nurse Researcher at the RCN International Nursing Research Conference at Oxford University in April. I enjoyed meeting so many readers and contributors. Your comments and feedback are vital and help make this journal a publication that meets the needs of readers and continues to attract a growing audience. PMID- 28639528 TI - Challenges in accessing and interviewing participants with severe mental illness. AB - Background Interviews are widely used in qualitative research to collect data. However, little has been written about interviewing people with severe mental illness (SMI). Aim To report and analyse an experience of addressing the ethical and practical challenges of interviewing people with SMI. Discussion Semi structured interviews were conducted as part of a doctoral study to explore how service users and healthcare professionals built relationships with each other. Conclusion Although interviewing participants with SMI was challenging, rich data illustrating their experiences were gathered. Careful planning around ethical considerations, such as obtaining informed consent, was required to maximise the opportunities to gather in-depth information during the interviews. The relationship established between researcher and the participants assisted with sensitive disclosures and allowed participants to tell their stories. Implications for research This paper provides strategies to help guide researchers planning interviews with vulnerable populations, including those with SMI. These strategies include how to discuss sensitive issues and promote engagement. Listening to participants' life stories is an intense experience, requiring support for the interviewer to stay neutral during interviews. It is also important to be aware of the differences between the roles of nurse and nurse researcher before undertaking in-depth qualitative interviews, particularly with vulnerable participants. PMID- 28639529 TI - Circular external fixation and cemented PMMA spacers for the treatment of complex tibial fractures and infected nonunions with segmental bone loss. AB - PURPOSE: The purpose of this study was to compare the outcome of combined circular external fixation and cemented polymethylmethacrylate (PMMA) spacer application between a cohort of patients with grade 3 open fractures and infected tibial nonunions and concomitant segmental bone loss. METHODS: The study was designed as a retrospective cohort study. All patients who were treated for complex tibial fractures or infected nonunions with segmental bone loss between 2009 and 2013 were included if they were aged between 16 years and 60 years, sustained acute traumatic grade 3 open tibial fractures, presented with infected nonunion, and were followed up for a minimum of 12 months. Patients with a history of ipsilateral tibial fractures, contralateral lower extremity fractures, polytrauma, chest, or abdominal trauma and patients with head injuries were excluded. Both groups were treated with aggressive debridement, circular external fixation, and antibiotic-impregnated PMMA spacer. Outcome measures were the time in the external fixator (EFT) and the external fixation index (EFI). RESULTS: Twenty-four patients with a mean age of 32 +/- 14.7 years were included. Twelve patients with a mean age of 32 + 14 years and a mean bone defect of 82 + 36 mm were treated for acute complex grade 3 open tibial fractures, and 12 patients with a mean age of 35.1 + 15.7 years and a mean bone defect of 50 + 26 mm were treated for infected nonunions. There was no significant difference ( p = 0.44) between the groups for EFT (249 +/- 99 days-tibial fractures; 255 +/- 142 days infected nonunion). There were significant between group differences ( p = 0.027) for EFI (37.3 +/- 9.1 cm/days-tibial fractures; 56 +/- 14.5 cm/days-infected nonunion). CONCLUSION: The findings of this study suggest that patients were treated for infected nonunion with segmental bone loss using circular external fixation, distraction osteogenesis, and antibiotic-impregnated PMMA spacers, and the spacers may not offer any advantage over a conventional approach using the principles of osteogenesis only. In contrast, antibiotic-impregnated spacers for open tibial trauma were advantageous and reduced the EFI considerably. PMID- 28639530 TI - Mortality and health-related quality of life in patients surgically treated for spondylodiscitis. AB - PURPOSE: To assess mortality, disability, and health-related quality of life (HRQL) in patients surgically treated for spondylodiscitis. METHODS: A retrospective longitudinal study was conducted on all patients surgically treated for spondylodiscitis over a 6-year period at a single tertiary spine center. Indications for surgery, pre- and postoperative neurological impairment, comorbidities, and mortality were recorded. A survey was conducted on all eligible patients with the EuroQol 5-dimension (EQ-5D) questionnaire and Oswestry Disability Index (ODI). RESULTS: Sixty-five patients were diagnosed with spondylodiscitis not related to recent spine surgery. One-year mortality rate was 6%. In all, 36% and 27% had pre- and postoperative neurological impairment, respectively, with only one patient experiencing deterioration postoperatively. At final follow-up (median 2 years), mean ODI was 31% (SD = 22) and mean EQ-5D time trade-off score was 0.639 (SD = 0.262); this was significantly lower than that in the normal population ( p < 0.001). Patients with neurological impairment prior to index surgery had lower EQ-5D scores ( p = 0.005) and higher ODI ( p = 0.02) at final follow-up compared with patients without neurological impairment. CONCLUSIONS: Several years after surgery, patients surgically treated for spondylodiscitis have significantly lower HRQL and more disability than the background population. Neurological impairment prior to index surgery predicts adverse outcome in terms of disability and lower HRQL. PMID- 28639531 TI - Outcome of bone recycling using liquid nitrogen as bone reconstruction procedure in malignant and recurrent benign aggressive bone tumour of distal tibia: A report of four cases. AB - Amputation still considered as primary choice of malignancy treatment in distal tibia. Bone recycling with liquid nitrogen for reconstruction following resection of malignant bone tumours offers many advantages. We presented four patients with osteosarcoma, Ewing sarcoma, adamantinoma and recurrent giant cell tumour over distal tibia. All of the patients underwent wide excision and bone recycling using liquid nitrogen as bone reconstruction. The mean functional Musculoskeletal Tumor Society (MSTS) score was 75% with no infection and local recurrent. The reconstruction provides good local control and functional outcome. PMID- 28639532 TI - Diminished abductor muscular strength in patients with valgus-impacted femoral neck fractures treated by internal fixation: Clinical study and biomechanical considerations. AB - BACKGROUND: Valgus-impacted femoral neck fractures treated with internal fixation occasionally result in unsatisfactory postoperative locomotive function, partially due to muscle shortening and a decrease in the moment arm. This study quantifies the degree of diminished abduction strength both clinically and biomechanically. METHODS: Fifteen patients were enrolled in this study. Twelve patients with fracture healed in valgus-impacted position were further evaluated. Muscular strength around hip was examined, and values between the nonoperated and operated side were compared and analyzed. For the biomechanical study, two three dimensional models were prepared: model I (control model without displacement) and model II (simulated malunion of a 15 degrees valgus-impacted fracture). Two sets of hip flexion angles in each of the models were simulated with flexion angles of 0 degrees and 23 degrees . RESULTS: Mean and standard deviation values for muscle strength from the nonoperative/operative side among the valgus group are as follows: flexion strength was 9.2 +/- 4.0/9.2 +/- 3.2, extension strength was 5.8 +/- 2.8/6.1 +/- 3.2, abduction strength at 0 degrees was 9.1 +/- 3.7/7.4 +/- 3.6, abduction strength at 10 degrees was 6.7 +/- 3.0/5.5 +/- 2.2, and knee extension strength was 15.3 +/- 6.2/15.1 +/- 6.0 (kgf). When comparing values between the nonoperative and operative sides, statistical significance was only observed in abduction strength ( p < 0.01). The biomechanical models prove that valgus impaction decreases the moment arm by approximately 10% at both flexion angle. CONCLUSIONS: A significant decrease in abductor strength at 0 degrees and 10 degrees was observed in the valgus-healed group. This may be related to a decrease in the moment arm. Further research should be done to define the acceptable limit of deformity for the satisfactory postoperative functioning. PMID- 28639533 TI - Comparison of clinical efficacy among remifentanil, nicardipine, and remifentanil plus nicardipine continuous infusion for hypotensive anesthesia during arthroscopic shoulder surgery. AB - PURPOSE: Hypotensive anesthesia is crucial during arthroscopic shoulder surgery to reduce bleeding and allow for clear visibility. The aim of this study was to compare the clinical efficacy of continuous infusion of remifentanil, nicardipine, and remifentanil plus nicardipine to control hypotensive anesthesia in arthroscopic shoulder surgery. METHODS: For this study, we enrolled 45 consecutive patients who were scheduled to have arthroscopic rotator cuff repair surgery and randomly allocated them into remifentanil (group R, n = 15), nicardipine (group N, n = 15), and remifentanil plus nicardipine (group RN, n = 15) groups. During the surgeries, these drugs were administered with continuous infusion. We analyzed the mean arterial pressure (MAP) and heart rate during surgery, stay time in the recovery room, visual analogue scale (VAS) scores, use of antiemetics in the recovery room, and postoperative blood urea nitrogen and creatinine changes. RESULTS: The VAS score in the recovery room was higher for group R (mean 5.6, SD 1.4) than for groups N (mean 3.9, SD 0.9) and RN (mean 4.0, SD 1.1; p = 0.000). There were no statistical differences regarding other clinical variables among the three groups (all p > 0.05) except for MAP at 120 min of surgery between groups N and RN (N: 84.67 (SD 10.7) mmHg, RN: 65.4 (SD 9.2) mmHg, p = 0.027). CONCLUSION: The continuous infusion of remifentanil plus nicardipine appeared to be advantageous for maintaining hypotensive anesthesia until 120 min of arthroscopic shoulder surgery without rebound pain in a postanesthesia care unit. PMID- 28639534 TI - Synthesis of bioadditives of fuels from biodiesel-derived glycerol by esterification with acetic acid on solid catalysts. AB - In this paper, glycerol esterification with acetic acid (AA) was studied on several solid acid catalysts: Al2O3, Al-MCM-41, HPA/SiO2, HBEA, Amberlyst 15 and Amberlyst 36 with the aim of determining the reaction conditions and the nature of the surface acid sites required to produce selectively triacetylglycerol (triacetin). The acidity of the catalysts (nature, density and strength of acid sites) was characterized by temperature-programmed desorption of NH3 and FTIR of adsorbed pyridine. Al2O3 (Lewis acidity) did not show any activity in the reaction. In contrast, highest activity and selectivity to the triacetylated product (triacetin) were obtained on catalysts with Bronsted acidity: Amberlyst 15 and Amberlyst 36. The effect of temperature and molar ratio of AA to glycerol was studied, and the results showed that both parameters have a significant impact on the production of the desired product. Glycerol conversion rate and selectivity to triacetin increased when temperature or AA to glycerol molar ratio were increased, reaching a triacetin yield on Amberlyst 36 of 44% at 393 K and AA to glycerol molar ratio of 6. Deactivation and reusability of Amberlyst 36 were evaluated by performing consecutive catalytic tests. The presence of some irreversible deactivation due to sulfur loss was observed. In addition, the feasibility of using crude glycerol from biodiesel production as reactant was also investigated. Conversion of crude pretreated glycerol yielded values of triacetin and diacetin similar to those obtained with the commercial pure glycerol although at a lower rate. PMID- 28639535 TI - Corrigendum. AB - Cawley N, Tur C, Prados F, et al. Spinal cord atrophy as a primary outcome measure in phase II trials of progressive multiple sclerosis. Mult Scler. Epub ahead of print 18 May 2017. DOI: 10.1177/1352458517709954. On page 9 of this article, the Declaration of Conflicting Interests and Funding statements were incorrect. The correct declarations are shown below. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: A.T. has received honoraria and support for travel from Eisai and EXCEMED. He has received support for travel from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and the National MS Society (USA) as a member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishing as Editor-in-Chief of Multiple Sclerosis. O.C. acts as a consultant for Novartis, Biogen, Roche, Teva, Genzyme and GE Healthcare. She receives an honorarium from AAN as Associate Editor of Neurology. Funding The author(s) declared receipt of the following financial support for the research, authorship and/or publication of this article: This study was funded by the UK MS Society and supported by the National Institute for Health Research University College London Hospital's Biomedical Research Centre. The online version of this article has been updated to reflect the correct declarations. Subsequent versions of the article will also be corrected. The authors apologise for this error and any confusion it may have caused. PMID- 28639536 TI - Recurrent natalizumab-related aseptic meningitis in a patient with multiple sclerosis. AB - Natalizumab is a recombinant humanized monoclonal antibody that decreases T-cell migration into the central nervous system (CNS) through alpha4 integrin:adhesion molecule inhibition, thereby increasing the risk for opportunistic CNS infection. Herein, we report a case of infusion-associated aseptic meningitis in a patient receiving natalizumab. PMID- 28639537 TI - Prehospital identification of trauma patients requiring transfusion: results of a retrospective study evaluating the use of the trauma induced coagulopathy clinical score (TICCS) in 33,385 patients from the TraumaRegister DGU(r). AB - BACKGROUND: Identifying trauma patients that need emergent blood product transfusion is crucial. The Trauma Induced Coagulopathy Clinical Score (TICCS) is an easy-to-measure score developed to meet this medical need. We hypothesized that TICCS would assist in identifying patients that need a transfusion in a large cohort of severe trauma patients from the TraumaRegister DGU(r) (TR-DGU). MATERIALS AND METHODS: A total of 33,385 severe trauma patients were extracted from the TR-DGU for retrospective analysis. The TICCS was adapted for the registry structure. Blood transfusion was defined as the use of at least one unit of red blood cells (RBC) during acute hospital treatment. RESULTS: With an area under the receiving operating curve (AUC) of 0.700 (95% CI: 0.691-0.709), the TICCS appeared to be moderately discriminant for determining the need for RBC transfusion in the trauma population of the TR-DGU. A TICCS cut-off value of >=12 yielded the best trade-off between true positives and false positives. The corresponding positive predictive value and negative predictive values were 48.4% and 89.1%, respectively. CONCLUSION: This retrospective study confirms that the TICCS is a useful and simple score for discriminating between trauma patients with and without the need for emergent blood product transfusion. PMID- 28639540 TI - STS as science or politics? AB - In a recent editorial for this journal, Sergio Sismondo makes two claims. First, he states that STS bears no responsibility for the emergence of post-truth politics. Second, he claims that debates about the nature of expertise that take place within STS are irrelevant in this context. In contrast, we argue that, whether or not STS had a causal influence on the emergence of post-truth politics, there is a clear resonance between the two positions and that the current political climate makes the empirically informed and scientific analysis of expertise and the form of life of science more important than ever. We argue that treating the contribution of STS to these matters as essentially political rather than scientific surrenders any special role we have as experts on the organization and values of science and leaves STS as just one political actor among others. PMID- 28639539 TI - Foreskin and the molecular politics of risk. AB - In this paper, I examine disputes over recent claims that male circumcision reduces HIV risk to suggest a complicated relationship between risk individualization and categorization. Whereas randomized controlled trials (RCTs) conducted in sub-Saharan Africa appear to have provided key evidence for the World Health Organization's endorsement of male circumcision as an HIV prevention strategy, RCTs alone did not provide evidence for the underlying causal mechanism. For that, medical authorities have turned to histo-immunological studies of the foreskin's biomolecular vulnerability to HIV, thus molecularizing risk. Some actors used these studies both as a way of shoring up results of RCTs conducted in sub-Saharan Africa and as an important rationale in arguments for making neonatal circumcision more widely available. Others, however, resisted this move to generalize the RCT results to other parts of the world, citing both contextual differences in HIV transmission patterns and conflicting scientific details regarding the biomolecular basis of the foreskin's susceptibility. Nevertheless, by locating an abstract notion of relative risk in the body itself, I argue that histological studies of foreskin have played a key role in stabilizing male circumcision status as a new risk category, largely independent of a given individual's risk profile. PMID- 28639538 TI - Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. AB - Metabolic syndrome (MetS) represents a cluster of metabolic abnormalities that include hypertension, central obesity, insulin resistance, and atherogenic dyslipidemia, and is strongly associated with an increased risk for developing diabetes and atherosclerotic and nonatherosclerotic cardiovascular disease (CVD). The pathogenesis of MetS involves both genetic and acquired factors that contribute to the final pathway of inflammation that leads to CVD. MetS has gained significant importance recently due to the exponential increase in obesity worldwide. Early diagnosis is important in order to employ lifestyle and risk factor modification. Here, we review the epidemiology and pathogenesis of MetS, the role of inflammation in MetS, and summarize existing natural therapies for MetS. PMID- 28639541 TI - Influence of hyaluronan nasal dressing on clinical outcome after endoscopic sinus surgery: A systematic review and meta-analysis. AB - INTRODUCTION: Hyaluronan nasal dressing might be promising in promoting reepithelialization after endoscopic sinus surgery (ESS). However, the results remain controversial. We conducted a systematic review and meta-analysis to explore the effects of hyaluronan nasal dressing on clinical outcome after ESS. METHODS: Medical literature data bases were systematically searched. Randomized controlled trials (RCT) that assessed the effect of hyaluronan nasal dressing on the outcome after ESS were included. The results were searched and data were extracted and assessed for quality. The primary outcome was reepithelization. Meta-analysis was performed by using the random-effect model. RESULTS: Four RCTs, which involved 352 patients, were included in the meta-analysis. Overall, compared with control intervention, hyaluronan nasal dressing significantly promoted reepithelization (odds ratio [OR] 3.18 [95% confidence interval {CI}, 1.33-7.59]; p = 0.009) and reduced edema (OR 0.45 [95% CI, 0.23-0.89]; p = 0.02) after ESS. However, hyaluronan nasal dressing failed to reduce synechia (OR 0.45 [95% CI, 0.19-1.03]; p = 0.06), crust (OR 1.00 [95% CI, 0.20-5.09]; p = 1.00), and infection (OR 0.84 [95% CI, 0.46-1.53]; p = 0.56) compared with the control group in patients who underwent ESS. CONCLUSION: Compared with "Control intervention" indicates standard nasal dressing without hyaluronan, resorbable hyaluronan nasal dressing could significantly improve reepithelization and decrease edema but had no influence on synechia, crust, and infection after ESS. PMID- 28639542 TI - Fluticasone propionate and fluticasone propionate/salmeterol multidose dry powder inhalers compared with placebo for persistent asthma. AB - BACKGROUND: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) has been developed, which allows for lower doses of fluticasone propionate (Fp) and Fp/salmeterol (FS) for the treatment of patients with asthma. OBJECTIVE: This phase III, multicenter, double-blind, parallel-group study (NCT02141854) evaluated the efficacy and safety of Fp MDPI and FS MDPI versus placebo MDPI. METHODS: Patients aged >=12 years with persistent asthma who previously took an inhaled corticosteroid with or without a long-acting beta-agonist entered a 14- to 21-day run-in period, during which they received single-blind, low-dose Fp MDPI 50 MUg (1 inhalation twice daily [b.i.d.]) and used albuterol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) for rescue. The patients who continued to meet eligibility criteria (N = 728) were randomized to Fp MDPI (100 or 200 MUg), FS MDPI (100 MUg/12.5 MUg or 200 MUg/12.5 MUg), or placebo (1 inhalation b.i.d.). Primary efficacy end points were the change from baseline in forced expiratory volume in 1 second (FEV1) and the baseline-adjusted area under the FEV1 curve 12 hours after the dose at week 12. Secondary efficacy end points were A.M. peak expiratory flow, asthma symptom scores, albuterol HFA MDI use, time to patient withdrawal, Asthma Quality of Life scores, and time to 15% and 12% improvement from baseline in FEV1. Safety end points were monitored. RESULTS: Fp MDPI and FS MDPI significantly improved both primary end points compared with placebo (p < 0.05). FS MDPI significantly improved both end points versus the corresponding Fp MDPI dose (p < 0.05), with improvement also greater for FS MDPI 100 MUg/12.5 MUg versus Fp MDPI 200 MUg (p < 0.05). Both active treatments improved a variety of secondary end points and exhibited a safety profile consistent with the drug classes. CONCLUSION: Delivery of Fp and FS via the novel MDPI provided significant clinical benefits and was well tolerated in patients with persistent asthma. PMID- 28639543 TI - Rapid detection of extended-spectrum-beta-lactamase-producing Enterobacteriaceae in blood cultures using the ESBL NDP test in Cotonou, Benin. AB - PURPOSE: Rapid and inexpensive tests for detecting extended-spectrum-beta lactamase (ESBL)-producing Enterobacteriaceae are needed, particularly in low resource countries where infections with these bacteria constitute a major public health issue. The recently described ESBL NDP test performed well in developed countries. This study was designed to assess performance, cost and feasibility of this test in positive blood cultures, in Cotonou, Benin (West Africa). METHODOLOGY: The test was performed on 175 positive Bactec broth blood cultures containing Enterobacteriaceae, and blindly compared with the double-disc synergy test (DDST) for the phenotypic detection of ESBL producers. RESULTS: There was a complete agreement between the ESBL NDP test and the DDST. On average, the time to give results was 37 min for a sample and the cost was US$ 7.3. CONCLUSION: The ESBL NDP test is rapid, relatively affordable and performed well in our setting. PMID- 28639544 TI - The Never-Ending Promise. AB - The editor-in-chief extends thanks to all contributors to this special focus on nursing leadership in home and community care. Thank you for leadership, thoughtful reflections and call to action. The possibilities for a different "person-centered", "people-powered" home and community-oriented health system can be realized with nursing at the helm. PMID- 28639545 TI - Nursing Leadership in Home and Community Care: An Introduction. AB - There is agreement across all provinces that there is transformation needed in the area of home and community care. Yet, where is the collective voice of nurse leaders in this transformation? The guest editor calls on nurses to respond to this unique opportunity to shape the transformation of our health system, and improve care for patients and their caregivers. PMID- 28639546 TI - Leadership Perspective: Bringing Nursing Back to the Future Through People Powered Care. AB - At a time when there is a growing interest in person- and family-centred care and integrated community-based models, the unique strengths and expertise of home care nursing is a strategic lever for change across all healthcare settings. In this paper, we explore the theme of people-powered care as a universal starting point - a new approach to health and wellness that is anchored in the strengths of people, their networks and the patterns of everyday life. Leveraging key insights from home and community care, along with broader societal shifts towards personalization and empowerment, we discuss how nurses in all areas of the system can lead the way by empowering staff, patients and their families. Finally, we look at the implications for nursing leadership including how our knowledge, skills and abilities must continue to evolve to effectively impact change and enable this vital transformation to occur. PMID- 28639547 TI - Rebuilding the Roots of Patient-Centred Care. AB - In this commentary, Thorne and Stajduhar respond to Sharkey and Lefebre's (2017) thoughts on Bringing Nursing Back to the Future Through People-Powered Care by reflecting on the kinds of structural and ideological conditions that have dismantled the traditional root structure by which the nursing profession nurtured its members and optimized their inherent capacity as champions of placing patients at the centre of care. Although the idea of patient-centred care has great popular appeal in the current context, embedding it meaningfully into a transformed healthcare system will require dedicated attention to addressing the attitudes, discourses and leadership mechanisms within which strong systems of nursing can flourish and thrive. PMID- 28639548 TI - A Leadership Perspective on a Shared Vision for Healthcare. AB - Our country's recent negotiations for a new Health Accord have shone light on the importance of more accessible and better home care. The direction being taken on health funding investments has sent a strong message about healthcare system redesign. It is time to design a healthcare system that moves us away from a hospital-focused model to one that is more effective, integrated and sustainable and one that places a greater emphasis on primary care, community care and home care. The authors of the lead paper (Sharkey and Lefebre 2017) provide their vision for people-powered care and explore the opportunity for nursing leaders to draw upon the unique expertise and insights of home care nursing as a strategic lever to bring about real health system transformation across all settings. Understanding what really matters at the beginning of the healthcare journey and honouring the tenants of partnership and empowerment as a universal starting point to optimize health outcomes along the continuum of care present a very important opportunity. However, as nursing leaders in the health system change, it is important that we extend the conversation beyond one setting. It is essential that as leaders, we seek to design models of care delivery that achieve a shared vision, focused on seamless coordinated care across the continuum that is person-centred. Bringing about real system change requires us to think differently and consider the role of nursing across all settings, collaboratively co-designing so that our collective skills and knowledge can work within a complementary framework. Focusing our leadership efforts on enhancing integration across healthcare settings will ensure that nurses can be important leaders and active decision-makers in health system change. A shared vision for healthcare requires all of us to look beyond the usual practices and structures, hospitals and institutional walls. PMID- 28639549 TI - Integrated Comprehensive Care - A Case Study in Nursing Leadership and System Transformation. AB - Calls for transformational change of our healthcare system are increasingly clear, persuasive and insistent. They resonate at all levels, with those who fund, deliver, provide and receive care, and they are rooted in a deep understanding that the system, as currently rigidly structured, most often lacks the necessary flexibility to comprehensively meet the needs of patients across the continuum of care. The St. Joseph's Health System (SJHS) Integrated Comprehensive Care (ICC) Program, which bundles care and funding across the hospital to home continuum, has reduced fragmentation of care, and it has delivered improved outcomes for patients, providers and the system. This case study explores the essential contribution of nursing leadership to this successful transformation of healthcare service delivery. PMID- 28639550 TI - The Role of Nurse Leaders in Advancing Carer Communication Needs across Transitions of Care: A Call to Action. AB - This paper focuses on the central role of senior nurse leaders in advancing organizational resources and support for communication between healthcare providers and carers that influences patient and carer outcomes during the transition from hospital to the community. A Think Tank (Lobchuk 2012) funded by the Canadian Institutes of Health Research (CIHR) gathered interdisciplinary and intersectoral stakeholders from local, national and international levels to develop a Family Carer Communication Research Collaboration. Workshop stakeholders addressed critical challenges in meeting communication needs of carers as partners with clinicians in promoting safe care for the elderly, chronically or seriously ill or disabled individuals in the community. Key priority areas identified the need to uncover nurse leader perspectives at the system, nurse leader, healthcare provider and patient levels where communication with carers occurs. The overarching outcome from the workshop focuses on the need for nurse leaders to advocate for patients and their families in meeting carer communication needs. The authors' "call to action" requires commitment and investment from nurse leaders in the critical juncture of healthcare delivery to strengthen communication between healthcare providers and carers that influence patient and carer outcomes in seamless transitions of care. PMID- 28639552 TI - Focal seizures with left hemibody piloerection related to left hemisphere cavernous angiomas. PMID- 28639553 TI - Can We Improve Pressure Feedback Methods in Vestibular Evoked Myogenic Potentials by Applying Custom Pressures? AB - OBJECTIVE: The aim of the present study was to use constant and customized pressure levels to improve the feedback method of the blood pressure cuff technique in order to decrease intra-subject and inter-subject variability. MATERIALS AND METHODS: The study was conducted in two stages. In the first stage, the relationship between the pressure level generated in the blood pressure cuff and electromyographic response in the sternocleidomastoid (SCM) muscle was investigated. In the second stage, vestibular evoked myogenic potential (VEMP) measurements were made using a custom-built VEMP chair at a constant pressure level of 40 mmHg (P40) or at 50% of the maximum pressure (Pmax50%) that could be generated by the SCM muscle. RESULTS: VEMP measurements were performed on 100 volunteers consisting of 48 males and 52 females whose ages were between 20 and 68 years. The response rate was 41% on a subject basis and 53% on an ear basis. Response rates were similar in males and females, and they decreased with age. The response rate was significantly lower in 11% of the volunteers who could not generate the stipulated 80 mmHg pressure level. Response rates obtained with P40 and Pmax50% were similar, and p13 and n23 latencies and p13-n23 amplitudes obtained from both sides were also similar. Amplitudes were higher in Pmax50% measurements compared to P40, and amplitudes obtained with P40 levels showed greater variance compared to Pmax50%. CONCLUSION: The use of Pmax50% provided reduced variation compared to P40; however, it did not have significant clinical implications. Further studies are needed for the control of many factors that are related to amplitude variability. PMID- 28639554 TI - Evaluation of Procalcitonin and hs-CRP Levels in Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: The aim of this study was to evaluate procalcitonin and high sensitive c-reactive protein (hs-CRP) levels in idiopathic sudden sensorineural hearing loss (ISSNHL) patients and assess their correlations with the clinical prognosis. MATERIALS AND METHODS: Twenty-three ISSNHL patients were included in the study (group A). The control group was consisted of 19 patients (group B). Procalcitonin and hs-CRP levels were compared between the groups. The relationship between procalcitonin and hs-CRP levels and the configuration of the audiogram, degree of hearing loss [partial or total ( > 90 dB)], and status of improvement (improvement of > 15 dB in the first month PTA) were evaluated. RESULTS: The mean age was 47.91+/-15.73 years (range 21-73 years) and 35.16+/ 15.67 years (range 19-79 years) in groups A and B, respectively. Seven patients (30.4%) had underlying cardiovascular risk factors. Mean procalcitonin levels were 0.057+/-0.025 ug/L and 0.041+/-0.016 ug/L in groups A and B, respectively. Mean hs-CRP levels were 0.461+/-1.335 mg/dL and 0.129+/-0.125 mg/dL in groups A and B, respectively. Procalcitonin levels were significantly higher in group A than in group B (p=0.018). Procalcitonin levels were significantly lower (0.035+/ 0.013 ug/L vs. 0.061+/-0.025 ug/L) in patients with low-frequency hearing loss (p=0.04). ROC analysis of procalcitonin values revealed that area under the curve was 0.80 (p=0.005). A cut-off procalcitonin level of 0.45 ug/L yielded a sensitivity of 90% and specificity of 56.2%. CONCLUSION: In conclusion, as a proinflammatory marker, procalcitonin levels were higher in ISSNHL patients than in healthy controls. The procalcitonin level was significantly lower in upsloping type hearing loss patients. This finding could be regarded as an indirect indicator of pathogenesis. PMID- 28639551 TI - Facet joint injections for people with persistent non-specific low back pain (Facet Injection Study): a feasibility study for a randomised controlled trial. AB - BACKGROUND: The National Institute for Health and Care Excellence (NICE) 2009 guidelines for persistent low back pain (LBP) do not recommend the injection of therapeutic substances into the back as a treatment for LBP because of the absence of evidence for their effectiveness. This feasibility study aimed to provide a stable platform that could be used to evaluate a randomised controlled trial (RCT) on the clinical effectiveness and cost-effectiveness of intra articular facet joint injections (FJIs) when added to normal care. OBJECTIVES: To explore the feasibility of running a RCT to test the hypothesis that, for people with suspected facet joint back pain, adding the option of intra-articular FJIs (local anaesthetic and corticosteroids) to best usual non-invasive care is clinically effective and cost-effective. DESIGN: The trial was a mixed design. The RCT pilot protocol development involved literature reviews and a consensus conference followed by a randomised pilot study with an embedded mixed-methods process evaluation. SETTING: Five NHS acute trusts in England. PARTICIPANTS: Participants were patients aged >= 18 years with moderately troublesome LBP present (> 6 months), who had failed previous conservative treatment and who had suspected facet joint pain. The study aimed to recruit 150 participants (approximately 30 per site). Participants were randomised sequentially by a remote service to FJIs combined with 'best usual care' (BUC) or BUC alone. INTERVENTIONS: All participants were to receive six sessions of a bespoke BUC rehabilitation package. Those randomised into the intervention arm were, in addition, given FJIs with local anaesthetic and steroids (at up to six injection sites). Randomisation occurred at the end of the first BUC session. MAIN OUTCOME MEASURES: Process and clinical outcomes. Clinical outcomes included a measurement of level of pain on a scale from 0 to 10, which was collected daily and then weekly via text messaging (or through a written diary). Questionnaire follow-up was at 3 months. RESULTS: Fifty-two stakeholders attended the consensus meeting. Agreement informed several statistical questions and three design considerations: diagnosis, the process of FJI and the BUC package and informing the design for the randomised pilot study. Recruitment started on 26 June 2015 and was terminated by the funder (as a result of poor recruitment) on 11 December 2015. In total, 26 participants were randomised. Process data illuminate some of the reasons for recruitment problems but also show that trial processes after enrolment ran smoothly. No between-group analysis was carried out. All pain related outcomes show the expected improvement between baseline and follow-up. The mean total cost of the overall treatment package (injection L419.22 and BUC L264.00) was estimated at L683.22 per participant. This is similar to a NHS tariff cost for a course of FJIs of L686.84. LIMITATIONS: Poor recruitment was a limiting factor. CONCLUSIONS: This feasibility study achieved consensus on the main challenges in a trial of FJIs for people with persistent non-specific low back pain. FUTURE WORK: Further work is needed to test recruitment from alternative clinical situations. TRIAL REGISTRATION: EudraCT 2014-000682-50 and Current Controlled Trials ISRCTN93184143. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 30. See the NIHR Journals Library website for further project information. PMID- 28639555 TI - Ginkgo biloba and Lycopene are Effective on Cisplatin Induced Ototoxicity? AB - OBJECTIVE: The purpose of this study was to examine the anti-ototoxic impact of Ginkgo biloba extract and lycopene on the model of cisplatin-induced ototoxicity in rats. MATERIALS AND METHODS: Thirty-two Wistar albino rats were examined with the distortion product otoacoustic emission (DPOAE) test (MADSEN Capella2 ; GN Otometrics, ICS Medical, Chicago USA), and they were randomly divided into four groups. Group 1 (n=8) was defined as the healthy control group. Cisplatin was given intraperitoneally as single dose of 12 mg/kg to group 2 (n=8), group 3 (n=8), and group 4 (n=8). Group 2 was determined as ototoxic control group. G. biloba extract (100 mg/kg) was given to group 3, and 20 mg/kg lycopene was given to group 4 with orogastric feeding tube daily for 10 days. DPOAE test was repeated on day 10 on all the groups. Finally, histopathological examination was performed. The study has been lead in agreement with the principles by the Institutional Animal Care and Use Committee Review Board at Kocaeli University Medical Center (KOU HADYEK- 1/9-14). The animals were treated in accordance with protocols approved by this committee. RESULTS: When DPOAE tests were compared, there was no significant difference in the four groups before the application (p > 0.05). At the end of day 10, in groups 2 to 4, statistically significant changes were observed (p < 0.05). According to the cisplatin group, a significant increase in the DP-grams on G. biloba and lycopene groups was observed (p < 00.5). Corti organ and spiral ganglion neurons of groups 1, 3, and 4 were observed to have weak expression. Strong reactions were determined in organum spirale and some spiral ganglions of the cisplatin group. The striae vascularis damage on group 2 was found to be more significant more compared with groups 3 and 4. CONCLUSION: There is a protective effect of G. biloba and lycopene on cisplatin-dependent ototoxic rat model. PMID- 28639556 TI - Caloric Analysis of Patients with Benign Paroxysmal Positional Vertigo. AB - OBJECTIVE: The aim of this study is to compare nystagmus characteristics after caloric irrigation in patients with lateral canal (LC) and posterior canal (PC) benign paroxysmal positional vertigo (BPPV) and to analyze the role of symptom duration. MATERIALS AND METHODS: A prospective study was conducted in 65 patients with BPPV (20 LC and 45 PC) who were subjected to caloric testing. Average slow phase velocity and nystagmus duration were analyzed. RESULTS: Caloric hypo excitability was 20.4%. It was more evident in patients with apogeotropic-type LC BPPV. The comparison of average slow-phase velocity of the nystagmus and nystagmus duration between selected types of BPPV for pathologic, non-pathologic, and the control ears after warm and cold stimulation was not statistically significant (p>0.05). No correlation was found between caloric results and symptom duration (p>0.05). CONCLUSION: Some patients presented caloric hypo excitability. Reliability of caloric testing to differentiate the ear with normal and abnormal vestibular function in different types of BPPV was low. No difference was found in the analysis of the impact of symptom duration. Caloric testing is not an ideal tool to study BPPV. PMID- 28639557 TI - Effects of Selective Seratonine Re-Uptake Inhibitors on Meniere's Disease. AB - OBJECTIVE: To evaluate the effects of selective serotonin re-uptake inhibitors (SSRIs) on Meniere's disease (MD) on patients who have both MD and generalized anxiety disorder. MATERIALS AND METHODS: All patients were evaluated with neurotologic examination, videonystagmography, audiological tests, and inner ear magnetic resonance imaging. Characteristic history and the evaluation of the patients' vertigo attacks during the attacks were the primary criteria for the diagnosis of MD. According to these parameters, 12 patients were diagnosed with definite MD and also symptoms of generalized anxiety disorder. Escitalopram 10 mg was prescribed to the patients. The clinical records of these patients were reviewed. RESULTS: Eight female and 4 male patients with MD and generalized anxiety disorder were included. The average age was found to be 46.25 years (34 63 years). Magnetic resonance imaging of patients was reported as normal. All patients had unilateral MD. The patients were diagnosed with MD for 2-12 years (mean: 5 years). All patients used betahistine and diuretics before escitalopram. Intratympanic gentamicin was also applied to one patient. After escitalopram medication, no vertigo attack was observed in any of the patients. CONCLUSION: SSRIs may have a central balancing effect on vertigo attacks of MD. Escitalopram can control vertigo attacks in MD. Further studies are needed to support this effect. PMID- 28639558 TI - Exchange interactions in transition metal oxides: the role of oxygen spin polarization. AB - Magnetism of transition metal (TM) oxides is usually described in terms of the Heisenberg model, with orientation-independent interactions between the spins. However, the applicability of such a model is not fully justified for TM oxides because spin polarization of oxygen is usually ignored. In the conventional model based on the Anderson principle, oxygen effects are considered as a property of the TM ion and only TM interactions are relevant. Here, we perform a systematic comparison between two approaches for spin polarization on oxygen in typical TM oxides. To this end, we calculate the exchange interactions in NiO, MnO and hematite (Fe2O3) for different magnetic configurations using the magnetic force theorem. We consider the full spin Hamiltonian including oxygen sites, and also derive an effective model where the spin polarization on oxygen renormalizes the exchange interactions between TM sites. Surprisingly, the exchange interactions in NiO depend on the magnetic state if spin polarization on oxygen is neglected, resulting in non-Heisenberg behavior. In contrast, the inclusion of spin polarization in NiO makes the Heisenberg model more applicable. Just the opposite, MnO behaves as a Heisenberg magnet when oxygen spin polarization is neglected, but shows strong non-Heisenberg effects when spin polarization on oxygen is included. In hematite, both models result in non-Heisenberg behavior. The general applicability of the magnetic force theorem as well as the Heisenberg model to TM oxides is discussed. PMID- 28639559 TI - Pressure-induced superconductivity in CrAs and MnP. AB - Transition-metal monopnictides, CrAs and MnP, were studied over 50 years ago due to the presence of interesting magnetic properties: CrAs forms a double-helical magnetic structure below T N ~ 270 K accompanied by a strong first-order structural transition, while MnP first undergoes a ferromagnetic transition at T C ~ 290 K and then adopts a similar double-helical order below T s ~ 50 K. Both compounds are correlated metals and exhibit distinct anomalies at these characteristic magnetic transitions. By using high pressure as a clean tuning knob, we recently observed superconductivity with a maximum superconducting transition temperature of T c ~ 2 K and 1 K when their helimagnetic orders are suppressed under a critical pressure of P c ~ 0.8 and 8 GPa for CrAs and MnP, respectively. Despite a relatively low T c, CrAs and MnP are respectively the first superconductor among the Cr- and Mn-based compounds in that the electronic density of states at the Fermi energy are dominated by Cr/Mn-3d electrons. These discoveries, in particular the close proximity of superconductivity to the helimagnetic order reminiscent of many unconventional superconducting systems, have attracted considerable attention in the community of superconductivity. The evolution of the helimagnetic order under pressure and its relationship with superconductivity have been actively investigated recently. Much effort has also been devoted to exploring more novel Cr- or Mn-based superconductors, leading to the discovery of quasi-1D A2Cr3As3 (A = K, Rb, Cs) superconductors. In this review article, we will summarize the current progress achieved regarding superconductivity in CrAs and MnP. PMID- 28639560 TI - Mechanical properties of decellularized extracellular matrix coated with TiCaPCON film. AB - For the first time the surface of decellularized extracellular matrix (DECM) was modified via deposition of a multicomponent bioactive nanostructured film for improvement of the DECM's mechanical properties. TiCaPCON films were deposited onto the surface of intact and decellularized ulna, radius, and humerus bones by magnetron sputtering of TiC0.5 + 10%Ca3(PO4)2 and Ti targets in a gaseous mixture of Ar + N2. The film structure was studied using x-ray diffraction, scanning and transmission electron microscopy, and Raman spectroscopy. The films were characterized in terms of their wettability, as well as adhesion strength to the intact bone and DECM substrates. The mechanical properties of TiCaPCON-coated samples were investigated by compression testing. In addition, humerus bones were evaluated during three-point bending tests. The results indicate that the tightly adhered films, uniformly covering the DECM surfaces, possessed hydrophilic characteristics. A maximum improvement in mechanical properties (250%) was observed for coated humerus samples. In case of decellularized radius bones, the compressive strength also increased by 150% after coating. The positive role of TiCaPCON films was less noticeable for ulna bones because of large data scattering. These results clearly indicate that the films acted as a rigid frame that increased the material compressive strength. Compared with intact bones, fracture in the TiCaPCON-coated DECM samples was characterized by rarer and larger cracks generated under higher critical loads. As a result, the samples were crushed into several large pieces and numerous tiny fragments. Although the film deposition increased the bone stiffness, the bending tests revealed that the flexural strength of the coated samples became 20%-25% lower than the strength of the film-free samples. PMID- 28639561 TI - Rise of nano effects in electrode during electrocatalytic CO2 conversion. AB - The electrocatalytic conversion of CO2 into value-added fuels has received increasing attention as a promising way to mitigate the atmospheric CO2 concentration and close the broken carbon-cycle. Early studies, focused on polycrystalline metal electrodes, outlined in detail the overall trends in the catalytic activity and product selectivity of pure metals; however, several inherent limitations were found, such as low current density and high overpotential, which hindered electrocatalytic CO2 reduction from practical application. Fortunately, the recent development of precisely synthesized nanocatalysts has led to several breakthroughs in catalytic CO2 conversion. By carefully controlling the thermodynamic adsorption energies and flow dynamics of reaction intermediates, nanosized electrocatalysts afford more versatile and energetically efficient routes to convert CO2 into desired chemicals. In this article, we review the state-of-the-art nanocatalysts applied for CO2 conversion and discuss newly found phenomena at the local environment near the catalyst surface. The mechanistic understanding of these findings can provide insight into the future design of catalysts for the efficient and selective reduction of CO2. PMID- 28639562 TI - Magnetic skyrmion-based artificial neuron device. AB - Neuromorphic computing, inspired by the biological nervous system, has attracted considerable attention. Intensive research has been conducted in this field for developing artificial synapses and neurons, attempting to mimic the behaviors of biological synapses and neurons, which are two basic elements of a human brain. Recently, magnetic skyrmions have been investigated as promising candidates in neuromorphic computing design owing to their topologically protected particle like behaviors, nanoscale size and low driving current density. In one of our previous studies, a skyrmion-based artificial synapse was proposed, with which both short-term plasticity and long-term potentiation functions have been demonstrated. In this work, we further report on a skyrmion-based artificial neuron by exploiting the tunable current-driven skyrmion motion dynamics, mimicking the leaky-integrate-fire function of a biological neuron. With a simple single-device implementation, this proposed artificial neuron may enable us to build a dense and energy-efficient spiking neuromorphic computing system. PMID- 28639563 TI - The role of apical contractility in determining cell morphology in multilayered epithelial sheets and tubes. AB - A multilayered epithelium is made up of individual cells that are stratified in an orderly fashion, layer by layer. In such tissues, individual cells can adopt a wide range of shapes ranging from columnar to squamous. From histological images, we observe that, in flat epithelia such as the skin, the cells in the top layer are squamous while those in the middle and bottom layers are columnar, whereas in tubular epithelia, the cells in all layers are columnar. We develop a computational model to understand how individual cell shape is governed by the mechanical forces within multilayered flat and curved epithelia. We derive the energy function for an epithelial sheet of cells considering intercellular adhesive and intracellular contractile forces. We determine computationally the cell morphologies that minimize the energy function for a wide range of cellular parameters. Depending on the dominant adhesive and contractile forces, we find four dominant cell morphologies for the multilayered-layered flat sheet and three dominant cell morphologies for the two-layered curved sheet. We study the transitions between the dominant cell morphologies for the two-layered flat sheet and find both continuous and discontinuous transitions and also the presence of multistable states. Matching our computational results with histological images, we conclude that apical contractile forces from the actomyosin belt in the epithelial cells is the dominant force determining cell shape in multilayered epithelia. Our computational model can guide tissue engineers in designing artificial multilayered epithelia, in terms of figuring out the cellular parameters needed to achieve realistic epithelial morphologies. PMID- 28639564 TI - Effect of an Ecological Executive Skill Training Program for School-aged Children with Attention Deficit Hyperactivity Disorder: A Randomized Controlled Clinical Trial. AB - BACKGROUND: As medication does not normalize outcomes of children with attention deficit hyperactivity disorder (ADHD), especially in real-life functioning, nonpharmacological methods are important to target this field. This randomized controlled clinical trial was designed to evaluate the effects of a comprehensive executive skill training program for school-aged children with ADHD in a relatively large sample. METHODS: The children (aged 6-12 years) with ADHD were randomized to the intervention or waitlist groups. A healthy control group was composed of gender- and age-matched healthy children. The intervention group received a 12-session training program for multiple executive skills. Executive function (EF), ADHD symptoms, and social functioning in the intervention and waitlist groups were evaluated at baseline and the end of the final training session. The healthy controls (HCs) were only assessed once at baseline. Repeated measures analyses of variance were used to compare EF, ADHD symptoms, and social function between intervention and waitlist groups. RESULTS: Thirty-eight children with ADHD in intervention group, 30 in waitlist group, and 23 healthy children in healthy control group were included in final analysis. At posttreatment, intervention group showed significantly lower Behavior Rating Inventory of Executive Function (BRIEF) total score (135.89 +/- 16.80 vs. 146.09 +/- 23.92, P= 0.04) and monitoring score (18.05 +/- 2.67 vs. 19.77 +/- 3.10, P= 0.02), ADHD-IV overall score (41.11 +/- 7.48 vs. 47.20 +/- 8.47, P< 0.01), hyperactivity impulsivity (HI) subscale score (18.92 +/- 5.09 vs. 21.93 +/- 4.93, P= 0.02), and inattentive subscale score (22.18 +/- 3.56 vs. 25.27 +/- 5.06, P< 0.01), compared with the waitlist group. Repeated measures analyses of variance revealed significant interactions between time and group on the BRIEF inhibition subscale (F = 5.06, P= 0.03), working memory (F = 4.48, P= 0.04), ADHD-IV overall score (F = 21.72, P< 0.01), HI subscale score (F = 19.08, P< 0.01), and inattentive subscale score (F = 12.40, P< 0.01). Multiple-way analysis of variance showed significant differences on all variables of BRIEF, ADHD-rating scale-IV, and WEISS Functional Impairment Scale-Parent form (WFIRS-P) among the intervention and waitlist groups at posttreatment and HCs at baseline. CONCLUSIONS: This randomized controlled study on executive skill training in a relatively large sample provided some evidences that the training could improve EF deficits, reduce problematic symptoms, and potentially enhance the social functioning in school-aged children with ADHD. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov; NCT02327585. PMID- 28639565 TI - Diagnostic Performance of the GenoType MTBDRplus and MTBDRsl Assays to Identify Tuberculosis Drug Resistance in Eastern China. AB - BACKGROUND: The WHO recently has recommended the GenoType MTBDRplus version 1.0 and MTBDRsl version 1.0 assays for widespread use in countries endemic with drug resistant tuberculosis. Despite this, these assays have rarely been evaluated in China, where the burden of drug-resistant tuberculosis is among the highest globally. METHODS: Mycobacterium tuberculosis clinical isolates were obtained between January 2008 and December 2008. Isolates were tested for drug resistance against rifampicin (RFP) and isoniazid (INH) using the GenoType MTBDRplus assay and drug resistance against ethambutol (EMB), ofloxacin (OFX), and kanamycin (KM) using the Genotype MTBDRsl assay. These results were compared with conventional drug-susceptibility testing (DST). RESULTS: Readable results were obtained from 235 strains by GenoType MTBDRplus assay. Compared to DST, the sensitivity of GenoType MTBDRplus assay to detect RFP, INH, and multidrug resistance was 97.7%, 69.9%, and 69.8%, respectively, whereas the specificity for detecting RFP, INH, and multidrug resistance was 66.7%, 69.2%, and 76.8%, respectively. The sensitivity and specificity of the GenoType MTBDRsl assay were 90.9% and 95.2% for OFX, 77.8% and 99.5% for KM, 63.7% and 86.4% for EMB, respectively. Mutations in codon S531L of the rpoB gene and codon S315T1 of KatG gene were dominated in multidrug-resistant tuberculosis (MDR-TB) strains. CONCLUSIONS: In combination with DST, application of the GenoType MTBDRplus and MTBDRsl assays may be a useful supplementary tool to allow a rapid and safe diagnosis of multidrug resistance and extensively drug-resistant tuberculosis. PMID- 28639566 TI - Research of Medical Expenditure among Inpatients with Unstable Angina Pectoris in a Single Center. AB - BACKGROUND: With the rising incidence as well as the medical expenditure among patients with unstable angina pectoris, the research aimed to investigate the inpatient medical expenditure through the combination of diagnosis-related groups (DRGs) among patients with unstable angina pectoris in a Grade A tertiary hospital to conduct the referential standards of medical costs for the diagnosis. METHODS: Single-factor analysis and multiple linear stepwise regression method were used to investigate 3933 cases between 2014 and 2016 in Beijing Hospital (China) whose main diagnosis was defined as unstable angina pectoris to determine the main factors influencing the inpatient medical expenditure, and decision tree method was adopted to establish the model of DRGs grouping combinations. RESULTS: The major influential factors of inpatient medical expenditure included age, operative method, therapeutic effects as well as comorbidity and complications (CCs) of the disease, and the 3933 cases were divided into ten DRGs by four factors: age, CCs, therapeutic effects, and the type of surgery with corresponding inpatient medical expenditure standards setup. Data of nonparametric test on medical costs among different groups were all significant (P < 0.001, by Kruskal-Wallis test), with R2 = 0.53 and coefficient of variation (CV) = 0.524. CONCLUSIONS: The classification of DRGs by adopting the type of surgery as the main branch node to develop cost control standards in inpatient treatment of unstable angina pectoris is conducive in standardizing the diagnosis and treatment behaviors of the hospital and reducing economic burdens among patients. PMID- 28639567 TI - Spontaneous Coronary Artery Dissection as a Cause of Acute Myocardial Infarction in Young Female Population: A Single-center Study. AB - BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic but a rare and extremely dangerous clinical entity, it has a high prevalence in young female population with acute myocardial infarction (AMI). The previous reports were restricted to other countries' population, but rare in China. Hence, this study aimed to focus on the characteristics of SCAD as a cause of young female AMI population in Jiangsu, China. METHODS: This study enrolled young female AMI patients aged <=50 years who underwent coronary angiography (CAG) and intracoronary imaging in our center between January 2013 and December 2016. Their clinical presentations, risk factors, and CAG characteristics were analyzed. RESULTS: A total of 60 young female AMI (<7 days) patients were enrolled. From their CAG and intracoronary imaging results, the prevalence of SCAD in young female AMI population was 35% (21/60), the prevalence of coronary atherosclerostic heart disease was 65% (39/60). In the SCAD group, 43% (9/21) presented with non-ST-elevation myocardial infarction (NSTEMI) and the remainder presenting as STEMI. SCAD usually occurred in a single vessel (20/21, 95%), especially in left anterior descending artery (14/21, 67%). Eighteen patients (18/21, 86%) underwent conservative treatment, whereas the remaining three patients (3/21, 14%) underwent percutaneous coronary intervention. Regarding the angiographic results of SCAD lesions, intramural hematoma was discriminated in 95% (20/21), and Type I imaging was observed in 5% (1/21), Type II was observed in 67% (14/21), and Type III was 29% (6/21). The average stenosis in the group was 76.9% +/- 20.6%, and the mean lesion length was 36.6 +/- 8.6 mm. CONCLUSIONS: SCAD has a high prevalence in young female AMI population in Jiangsu, China. Discriminating the cause of AMI in young female population is very important. PMID- 28639568 TI - Intraoperative Transesophageal Echocardiography in the Operation of Ebstein's Anomaly: A Retrospective Study. AB - BACKGROUND: Ebstein's anomaly (EA) has various spectrums in clinical and anatomic features. This study aimed to report the experience of two-dimensional intraoperative transesophageal echocardiography (2D-ITEE) during the EA surgery and to analyze the characteristics of the tricuspid valve (TV) by comparing the data from 2D-ITEE with the results from the surgery. METHODS: 2D-ITEE data of 164 patients with EA who were operated in the First Hospital of Tsinghua University between July 2004 and April 2014 were retrospectively analyzed in this study. 2D ITEE was applied in all patients. Downward displacement distances were measured, and the numbers of downward displacement or absent leaflets were compared with that of the surgery and with that of the two-dimensional-transthoracic echocardiogram (2D-TTE). Data comparison was performed using the Chi-square test. RESULTS: The anterior leaflet partial or total downward displacement was 37.76 +/ 17.50 mm in 54 cases, absent in one patient; septal leaflet downward displacement was 29.07 +/- 12.34 mm in 134 cases, absent in 17 cases; and posterior leaflet downward displacement was 43.18 +/- 19.16 mm in 115 cases, absent in 34 cases. Statistically, there was no significant difference between the results from 2D-ITEE and that of 2D-TTE. The consistency rates of 2D-ITEE with operation for septal and posterior leaflets were 93.2% and 96.1%, respectively, while the rate for anterior was only 40.1%, which was significantly different. Color Doppler flow image showed severe regurgitation in 150 cases and moderate in 14 cases. After surgical correction, moderate regurgitation of TV was found in 58 cases with 2D-ITEE, repair was performed again until the effect was satisfied. No complication occurred relating to the use of 2D-ITEE. CONCLUSIONS: 2D-ITEE could help diagnose anterior leaflet, evaluate the effect of TV repair, increase operational success rate, and reduce complication. PMID- 28639569 TI - Performance of Simplified Acute Physiology Score 3 In Predicting Hospital Mortality In Emergency Intensive Care Unit. AB - BACKGROUND: Since the 1980s, severity of illness scoring systems has gained increasing popularity in Intensive Care Units (ICUs). Physicians used them for predicting mortality and assessing illness severity in clinical trials. The objective of this study was to assess the performance of Simplified Acute Physiology Score 3 (SAPS 3) and its customized equation for Australasia (Australasia SAPS 3, SAPS 3 [AUS]) in predicting clinical prognosis and hospital mortality in emergency ICU (EICU). METHODS: A retrospective analysis of the EICU including 463 patients was conducted between January 2013 and December 2015 in the EICU of Peking University Third Hospital. The worst physiological data of enrolled patients were collected within 24 h after admission to calculate SAPS 3 score and predicted mortality by regression equation. Discrimination between survivals and deaths was assessed by the area under the receiver operator characteristic curve (AUC). Calibration was evaluated by Hosmer-Lemeshow goodness of-fit test through calculating the ratio of observed-to-expected numbers of deaths which is known as the standardized mortality ratio (SMR). RESULTS: A total of 463 patients were enrolled in the study, and the observed hospital mortality was 26.1% (121/463). The patients enrolled were divided into survivors and nonsurvivors. Age, SAPS 3 score, Acute Physiology and Chronic Health Evaluation Score II (APACHE II), and predicted mortality were significantly higher in nonsurvivors than survivors (P < 0.05 or P < 0.01). The AUC (95% confidence intervals [CI s]) for SAPS 3 score was 0.836 (0.796-0.876). The maximum of Youden's index, cutoff, sensitivity, and specificity of SAPS 3 score were 0.526%, 70.5 points, 66.9%, and 85.7%, respectively. The Hosmer-Lemeshow goodness-of-fit test for SAPS 3 demonstrated a Chi-square test score of 10.25, P = 0.33, SMR (95% CI) = 0.63 (0.52-0.76). The Hosmer-Lemeshow goodness-of-fit test for SAPS 3 (AUS) demonstrated a Chi-square test score of 9.55, P = 0.38, SMR (95% CI) = 0.68 (0.57 0.81). Univariate and multivariate analyses were conducted for biochemical variables that were probably correlated to prognosis. Eventually, blood urea nitrogen (BUN), albumin,lactate and free triiodothyronine (FT3) were selected as independent risk factors for predicting prognosis. CONCLUSIONS: The SAPS 3 score system exhibited satisfactory performance even superior to APACHE II in discrimination. In predicting hospital mortality, SAPS 3 did not exhibit good calibration and overestimated hospital mortality, which demonstrated that SAPS 3 needs improvement in the future. PMID- 28639570 TI - Menorrhagia and Uterine Volume Associated with Lower Urinary Tract Symptoms in Patients with Adenomyosis. AB - BACKGROUND: Adenomyosis is a gynecological disorder with symptoms most presenting as dysmenorrhea and heavy menstrual bleeding. However, the presence of lower urinary tract symptoms (LUTS) among women with adenomyosis remains unclear. This study was designed to determine the prevalence of LUTS and factors related to the severity of these symptoms in this population. METHODS: From July 2016 to November 2016, a total of 298 untreated symptomatic adenomyosis patients and 280 age-matched controls were enrolled. Demographics, LUTS, pain symptoms, ultrasonographic uterine size, and serum CA125 level were recorded. LUTS were evaluated using the International Prostate Symptom Score (IPSS) questionnaire. Factors related to the severity of LUTS were detected using the logistic regression analysis presented as odds ratio (OR) and 95% confidence interval (CI). RESULTS: Compared with the control group, patients with adenomyosis had a greater IPSS total (4 [2-8] vs. 2 [0-3], Z = -8.159, P 0.001), IPSS storage (2 [1 4] vs. 1[0-2], Z = -7.361 P 0.001), and IPSS voiding (2 [0-4] vs. 0 [0-1], Z = 7.194, P 0.001). Of the patients with adenomyosis, 30.2% had moderate-to-severe lower urinary tract symptoms (IPSS >=8). The most prevalent LUTS were daytime frequency (40.9%), followed by nocturia (24.8%), weak stream (24.2%), and incomplete emptying (23.5%). In study group, patients with an IPSS total score >=8 had higher proportion of menorrhagia (51.1% vs. 30.8%, chi2= 11.162 P= 0.025) and larger uterine volumes (183.3 [109.8-273.8] cm3 vs. 148.5 [96.4-262.7] cm3, Z = -1.441, P= 0.150) compared to patients with an IPSS total score <8. On multivariate logistic regression analysis, patients with menorrhagia were associated with an increased risk of an IPSS total score >=8 (OR: 2.309, 95% CI: 1.310-4.070, P= 0.004), an IPSS storage subscore >=4 (OR: 2.422, 95% CI: 1.395 4.206, P= 0.002), and an IPSS voiding subscore >=5 (OR: 1.971, 95% CI: 1.176 3.302, P= 0.010). However, patients with uterine volume more than 180 cm3 had more than 2-fold risk of bearing IPSS total score >=8 (OR: 2.437, 95% CI: 1.381 4.300, P= 0.002), IPSS storage subscore >=4 (OR: 2.486, 95% CI: 1.433-4.314, P= 0.001), and IPSS voiding subscore >=5 (OR: 2.700, 95% CI: 1.485-4.908, P= 0.001). CONCLUSIONS: Lower urinary tract symptoms are prevalent in patients with symptomatic adenomyosis and greatly affect patients' quality of life. Menorrhagia and large uterine volume could be potential risk factors that increase the occurrence of moderate-to-severe LUTS. PMID- 28639571 TI - Recurrence Factors in Giant Cell Tumors of the Spine. AB - BACKGROUND: Giant cell tumors (GCTs) are benign, locally aggressive tumors. We examined the rate of local recurrence of spinal GCTs and sought to identify recurrence factors in patients who underwent surgery. METHODS: Between 1995 and 2014, 94 mobile spine GCT patients were treated at our hospital, comprising 43 male and 51 female patients with an average age of 33.4 years. Piecemeal intralesional spondylectomy and total en bloc spondylectomy (TES) were performed. Radiotherapy was suggested for recurrent or residual GCT cases. Since denosumab was not available before 2014 in our country, only interferon and/or zoledronic acid was suggested. RESULTS: Of the 94 patients, four underwent conservative treatment and 90 underwent operations. Seventy-five patients (79.8%) were followed up for a minimum of 24 months or until death. The median follow-up duration was 75.3 months. The overall recurrence rate was 37.3%. Ten patients (13.3%) died before the last follow-up (median: 18.5 months). Two patients (2.6%) developed osteogenic sarcoma. The local recurrence rate was 80.0% (24/30) in patients who underwent intralesional curettage, 8.8% (3/34) in patients who underwent extracapsular piecemeal spondylectomy, and 0 (0/9) in patients who underwent TES. The risk factors for local recurrence were lesions located in the cervical spine (P = 0.049), intralesional curettage (P < 0.001), repeated surgeries (P = 0.014), and malignancy (P < 0.001). Malignant transformation was a significant risk factor for death (P < 0.001). CONCLUSIONS: Cervical spinal tumors, curettage, and nonintact tumors were risk factors for local recurrence. Intralesional curettage and malignancy were the most important significant factors for local recurrence and death, respectively. PMID- 28639573 TI - A Transcriptomic Analysis of Physiological Significance of Hypoxia-inducible Factor-1alpha in Myogenesis and Carbohydrate Metabolism of Genioglossus in Mice. AB - BACKGROUND: Chronic intermittent hypoxia is the most remarkable feature of obstructive sleep apnea/hypopnea syndrome and it can induce the change of hypoxia inducible factor-1alpha (HIF-1alpha) expression and contractile properties in the genioglossus. To clarify the role of HIF-1alpha in contractile properties of the genioglossus, this study generated and compared high-throughput RNA-sequencing data from genioglossus between HIF-1alpha conditional knockout (KO) mice and littermate wild-type (WT) mice. METHODS: KO mice were generated with cre-loxP strategy. Gene expression profile analysis was performed using gene enrichment analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of differently expressed messenger RNAs were performed to identify the related pathways and biological functions. Six differentially expressed genes (DEGs) were validated by qualitative reverse transcription polymerase chain reaction. RESULTS: A total of 142 (77 upregulated and 65 downregulated) transcripts were found to exhibit statistically significant difference between the HIF-1alpha-KO and WT mice. GO and KEGG analyses indicated that DEGs included genes involved in "skeletal muscle cell differentiation," "muscle organ development," "glucose metabolic process," "glycogen biosynthetic and metabolic process," etc. CONCLUSION: This study might provide evidence that HIF-1alpha affects the expression of multiple genes involved in the myogenesis, muscle development, and carbohydrate metabolism through transcriptome analysis in conditional HIF-1alpha-KO mice. PMID- 28639572 TI - Relation of Biochemical Parameters with Flow-mediated Dilatation in Patients with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) is one of the high cardiovascular (CV) situations. Endothelial dysfunction, which is a common finding in patients with MetS, is related with increased CV risk. In patients with MetS, the effect of the major CV risk factors, not included in the MetS definition, on endothelial dysfunction is not well known. The aim of this study was to determine the effect of major CV risk factors such as gender, smoking, family history, and biochemical parameters on endothelial dysfunction in patients with MetS. METHODS: The study was performed between December 2010 and August 2014. A total of 55 patients (15 females and 40 males) with MetS and 81 healthy controls (37 females and 44 males) with a body mass index <25 kg/m2 were enrolled in the study. Endothelial dysfunction was measured by flow-mediated dilatation (FMD), oxidative stress parameters; high-sensitivity C-reactive protein (hs-CRP), oxidized low-density lipoprotein (ox-LDL), endothelial nitric oxide synthase (e-NOS), nitric oxide, and cell adhesion markers; von Willebrand factor, and e-selectin. Platelet aggregation (endothelial adenosine diphosphate), total platelet count, and mean platelet volume were additionally analyzed and demographic parameters were explored. Student's t- test, Mann-Whitney U-test, and Chi-square test were used to analyze the results. RESULTS: The fasting blood glucose (z= 3.52, P= 0.001), hs-CRP (z = 3.23, P= 0.004), ox-LDL (z = 2.62, P= 0.013), and e-NOS (z = 2.22, P= 0.026) levels and cardiac risk score (z = 5.23, P< 0.001) were significantly higher in patients with MetS compared with the control group. Smoking was correlated with decreased FMD (chi2 = 9.26, P= 0.002) in MetS patients but not in the control group. CONCLUSIONS: Increased ox-LDL, hs-CRP, and e-NOS are likely to be a result of oxidative stress, a condition in which an imbalance occurs between the production and inactivation of reactive nitrogen and oxygen species. In addition, in patients with MetS, smoking is independently related to endothelial dysfunction. PMID- 28639574 TI - MiR-551b-5p Contributes to Pathogenesis of Vein Graft Failure via Upregulating Early Growth Response-1 Expression. AB - BACKGROUND: Vein graft failure (VGF) is a serious complication of coronary artery bypass graft, although the mechanism remains unclear. The study aimed to investigate the effects of microRNAs (miRNAs) on the endothelial dysfunction involved in VGF. METHODS: Human umbilical vein endothelial cells (HUVECs) were subjected to mechanical stretch stimulation to induce endothelial dysfunction. Genome-wide transcriptome profiling was performed using the Human miRNA OneArray(r) V4 (PhalanxBio Inc., San Diego, USA). The miRNA-messenger RNA (mRNA) network was investigated using gene ontology and Kyoto Encyclopedia of Genes and Genomes. The miR-551b-5p mimic and inhibitor were applied to regulate miR-551b-5p expression in the HUVECs. The 5-ethynyl-2'-deoxyuridine assay, polymerase chain reaction (PCR), and Western blotting (WB) were used to assess HUVECs proliferation, mRNA expression, and protein expression, respectively. The vein graft model was established in early growth response (Egr)-1 knockout (KO) mice and wide-type (WT) C57BL/6J mice for pathological and immunohistochemical analysis. Endothelial cells isolated from the veins of WT and Egr-1 KO mice were subjected to mechanical stretch stimulation; PCR and WB were conducted to confirm the regulatory effect of Egr-1 on Intercellular adhesion molecule (Icam-1). One way analysis of variance and independent t-test were performed for data analysis. RESULTS: Thirty-eight miRNAs were differentially expressed in HUVECs after mechanical stretch stimulation. The bioinformatics analysis revealed that Egr-1 might be involved in VGF and was a potential target gene of miR-551b-5p. The mechanical stretch stimulation increased miR-551b-5p expression by 2.93 +/- 0.08 fold (t = 3.07, P < 0.05), compared with the normal HUVECs. Transfection with the miR-551b-5p mimic or inhibitor increased expression of miR-551b-5p by 793.1 +/- 171.6 fold (t = 13.84, P < 0.001) or decreased by 26.3% +/- 2.4% (t = 26.39, P < 0.05) in the HUVECs, respectively. HUVECs proliferation and EGR-1 mRNA expression were significantly suppressed by inhibiting miR-551b-5p expression (P < 0.05). The lumens of the vein grafts in the Egr-1 KO mice were wider than that in the WT mice. Icam-1 expression was suppressed significantly in the Egr-1 KO vein grafts (P < 0.05). CONCLUSIONS: Increased miR-551b-5p expression leads to endothelial dysfunction by upregulating Egr-1 expression. EGR-1 KO can improve the function of a grafted vein through suppressing Icam-1. PMID- 28639575 TI - Account for Clinical Heterogeneity in Assessment of Catheter-based Renal Denervation among Resistant Hypertension Patients: Subgroup Meta-analysis. AB - BACKGROUND: Catheter-based renal denervation (RDN) is a novel treatment for resistant hypertension (RH). A recent meta-analysis reported that RDN did not significantly reduce blood pressure (BP) based on the pooled effects with mild to severe heterogeneity. The aim of the present study was to identify and reduce clinical sources of heterogeneity and reassess the safety and efficacy of RDN within the identified homogeneous subpopulations. METHODS: This was a meta analysis of 9 randomized clinical trials (RCTs) among patients with RH up to June 2016. Sensitivity analyses and subgroup analyses were extensively conducted by baseline systolic blood pressure (SBP) level, antihypertensive medication change rates, and coronary heart disease (CHD). RESULTS: In all patients with RH, no statistical differences were found in mortality, severe cardiovascular events rate, and changes in 24-h SBP and office SBP at 6 and 12 months. However, subgroup analyses showed significant differences between the RDN and control groups. In the subpopulations with baseline 24-h SBP >=155 mmHg (1 mmHg = 0.133 kPa) and the infrequently changed medication, the use of RDN resulted in a significant reduction in 24-h SBP level at 6 months (P = 0.100 and P= 0.009, respectively). Subgrouping RCTs with a higher prevalent CHD in control showed that the control treatment was significantly better than RDN in office SBP reduction at 6 months (P < 0.001). CONCLUSIONS: In all patients with RH, the catheter-based RDN is not more effective in lowering ambulatory or office BP than an optimized antihypertensive drug treatment at 6 and 12 months. However, among RH patients with higher baseline SBP, RDN might be more effective in reducing SBP. PMID- 28639577 TI - Characteristics of Good's Syndrome in China: A Systematic Review. AB - BACKGROUND: Good's syndrome (GS) is a rare disease characterized by thymoma, hypogammaglobulinemia, low or absent B-cells, decreased T-cells, an inverted CD4+/CD8+ T-cell ratio and reduced T-cell mitogen proliferative responses. GS is difficult to diagnose preoperatively due to its rarity and lack of typical symptoms, the characteristics of Chinese GS patients are still lacking. This study aimed to systematically review all the clinical, laboratory, and immunologic findings of reported cases of Chinese patients with GS. METHODS: We searched for case reports and articles up to January 2017 using PubMed, China National Knowledge Infrastructure, Wangfang database and China Science and Technology Journal Database with the following words in combinations as key words: "thymoma," "hypogammaglobulinemia," and "Good's syndrome." The text words and MeSH terms were entered depending on the databases characteristics. The reference lists from retrieved articles were also screened for additional applicable studies. The authors were restricted to Chinese. There was no language restriction. RESULTS: Forty-seven patients were reported in 27 studies. We found that GS has a nationwide distribution and that most cases (83%) have been described on the mainland of China. The initial clinical presentation is varied, ranging from symptoms related to the thymoma to infections resulting from immunodeficiency. Type AB (50%) is the most common histologic type of thymomas in Chinese GS patients according to the World Health Organization classification of thymomas. With respect to infection, sinopulmonary infection (74%) is the most common type, followed by skin infection (10%) and intestinal tract infection (10%). Diarrhea was presented in 36% of patients, and autoimmune manifestations were presented in 36% of patients. CONCLUSIONS: GS is a rare association of thymoma and immunodeficiency with a poor prognosis. Astute clinical acumen and increased awareness of the clinical and immunological profile of GS are needed to increase early diagnosis, that would benefit improved therapeutic effects. PMID- 28639576 TI - Laparoscopic Versus Open Resection of Small Bowel Gastrointestinal Stromal Tumors: Systematic Review and Meta-Analysis. AB - BACKGROUND: Laparoscopic resection (LAP) for small bowel gastrointestinal stromal tumors (GISTs) is not as common as for stomach. This study aimed to evaluate the safety and efficacy of LAP for small bowel GISTs with systematic review and meta analysis. METHODS: The Web of Science, Cochrane Library, Embase, and PubMed databases before December 2016 were comprehensively searched to retrieve comparative trials of LAP and conventional open resection (OPEN) for GISTs of small bowel with a relevance of review object. These researches reported intraoperative and postoperative clinical course (operation time, blood loss, time to first flatus and oral intake, hospital stay, morbidity, and mortality), oncologic outcomes, and long-term survival status. RESULTS: Six studies involving 391 patients were identified. Compared to OPEN, LAP had associated with a shorter operation time (weighted mean difference [WMD] = -27.97 min, 95% confidence interval [CI]: -49.40--6.54, P < 0.01); less intraoperative blood loss (WMD = 0.72 ml; 95% CI: -1.30--0.13, P = 0.02); earlier time to flatus (WMD = -0.83 day; 95% CI: -1.44--0.22, P < 0.01); earlier time to restart oral intake (WMD = -1.95 days; 95% CI: -3.31--0.60, P < 0.01); shorter hospital stay (WMD = -3.00 days; 95% CI: -4.87--1.13, P < 0.01); and a decrease in overall complications (risk ratio = 0.56, 95% CI: 0.33-0.97, P = 0.04). In addition, the tumor recurrence and long-term survival rate showed that there was no significant difference between the two groups of patients. CONCLUSIONS: LAP for small bowel GISTs is a safe and feasible procedure with shorter operation time, less blood loss, less overall complications, and quicker recovery. Besides, tumor recurrence and the long-term survival rate are similar to open approach. Because of the limitations of this study, methodologically high-quality studies are needed for certain appraisal. PMID- 28639578 TI - Ten Basic Principles about Critical Ultrasonography: Critical Care Practitioners Need to Know. PMID- 28639579 TI - Postherpetic Comedones in Two Chinese Han Patients. PMID- 28639580 TI - Robot-assisted Percutaneous Pedicle Screw Placement Using Three-Dimensional Fluoroscopy: A Preliminary Clinical Study. PMID- 28639581 TI - A Unique Lesion of the Esophageal Mucosal Epithelium: Low-grade Intraepithelial Neoplasia or Basal-layer-type Squamous Cell Carcinoma? PMID- 28639582 TI - Surgical Treatment of a Giant Spontaneous Abdominal Wall Hematoma. PMID- 28639583 TI - Outpatient Surgery in Zhongshan Ophthalmic Center: Promise and Problems. PMID- 28639584 TI - Rehabilitation of Abducens Nerve Palsy after Cholesteatoma Resection at Cerebellopontine Angle by Intraorbital Electroacupuncture. PMID- 28639585 TI - Intraorbital Granular Cell Tumor Involving in Medial Rectus and Optic Nerve. PMID- 28639586 TI - Comparing Shikani Optical Stylet and Macintosh Laryngoscope for Orotracheal Intubation. PMID- 28639587 TI - Reply to "Comparing Shikani Optical Stylet and Macintosh Laryngoscope for Orotracheal Intubation". PMID- 28639588 TI - Reconsidering axillary surgery for early breast cancer. PMID- 28639589 TI - Potential danger of isolated platelet transfusion in patients with dengue infection. PMID- 28639590 TI - Wheezing in children with viral infection & its long-term effects. PMID- 28639591 TI - Manochaitanya programme for better utilization of primary health centres. PMID- 28639592 TI - Current status of lupus nephritis. AB - Systemic lupus erythematosus (SLE) is a systemic disease of unknown aetiology with variable course and prognosis. Lupus nephritis (LN) is one of the important disease manifestations of SLE with considerable influence on patient outcomes. Immunosuppression therapy has made it possible to control the disease with improved life expectancy and quality of life. In the last few decades, various studies across the globe have clarified the role, dose and duration of immunosuppression currently in use and also provided evidence for new agents such as mycophenolate mofetil, calcineurin inhibitors and rituximab. However, there is still a need to develop new and specific therapy with less adverse effects. In this review, the current evidence of the treatment of LN and its evolution, and new classification criteria for SLE have been discussed. Also, rationale for low dose intravenous cyclophosphamide as induction agent followed by azathioprine as maintenance agent has been provided with emphasis on individualized and holistic approach. PMID- 28639594 TI - Viral aetiology of wheezing in children under five. AB - BACKGROUND & OBJECTIVES: Wheezing is a common problem in children under five with acute respiratory infections (ARIs). Viruses are known to be responsible for a considerable proportion of ARIs in children. This study was undertaken to know the viral aetiology of wheezing among the children less than five years of age, admitted to a tertiary care hospital in eastern India. METHODS: Seventy five children, under the age of five years admitted with wheezing, were included in the study. Throat and nasal swabs were collected, and real-time multiplex polymerase chain reaction (PCR) assay was used to screen for influenza 1 and 2, respiratory syncytial virus (RSV), parainfluenza virus (PIV) 1, 2, 3 and 4, rhinovirus, human meta-pneumovirus, bocavirus (HBoV), Coronavirus, adenovirus, Enterovirus and Parechovirus. RESULTS: The total viral detection rate was 28.57 per cent. Viral RNA markers were detected from children diagnosed to be having pneumonia (3 cases), bronchiolitis (9 cases), episodic wheeze (2 cases) and multitrigger wheeze (6 cases). RSV was the most common virus (35%) followed by PIV1, 2 and 3 (20%), HBoV (10%) and rhinovirus (5%). However, mixed infection was observed in 30 per cent of cases. INTERPRETATION & CONCLUSIONS: The study reported the presence of respiratory viral agents in 28.57 per cent of children with wheezing; RSV and PIV were most common, accounting to 55 per cent of the total cases. Mixed infection was reported in 30 per cent of cases. Seasonal variation in the occurrence of these viruses was also noted. Further studies need to be done with a large sample and longer follow up period to verify these findings. PMID- 28639593 TI - Synaptic roles of cyclin-dependent kinase 5 & its implications in epilepsy. AB - There is an urgent need to understand the molecular mechanisms underlying epilepsy to find novel prognostic/diagnostic biomarkers to prevent epilepsy patients at risk. Cyclin-dependent kinase 5 (CDK5) is involved in multiple neuronal functions and plays a crucial role in maintaining homeostatic synaptic plasticity by regulating intracellular signalling cascades at synapses. CDK5 deregulation is shown to be associated with various neurodegenerative diseases such as Alzheimer's disease. The association between chronic loss of CDK5 and seizures has been reported in animal models of epilepsy. Genetic expression of CDK5 at transcriptome level has been shown to be abnormal in intractable epilepsy. In this review various possible mechanisms by which deregulated CDK5 may alter synaptic transmission and possibly lead to epileptogenesis have been discussed. Further, CDK5 has been proposed as a potential biomarker as well as a pharmacological target for developing treatments for epilepsy. PMID- 28639595 TI - Prenatal diagnosis of steroid 21-hydroxylase-deficient congenital adrenal hyperplasia: Experience from a tertiary care centre in India. AB - BACKGROUND & OBJECTIVES: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder with a wide range of clinical manifestations. The disease is attributed to mutations in CYP21A2 gene encoding 21-hydroxylase enzyme. In view of severe phenotype in salt-losing cases, issues related to genital ambiguity in girls and precocity in boys, most families opt for prenatal testing and termination of affected foetus. CAH can be diagnosed in utero through direct molecular analysis of CYP21A2 gene, using DNA extracted from foetal tissues or cells obtained from chorionic villus sampling or amniocentesis. The objective of this study was to evaluate the feasibility and accuracy of prenatal diagnosis (PND) using sequencing and multiplex ligation probe amplification (MLPA) methods in families at risk for CAH. METHODS: Fifteen pregnant women at risk of having an affected offspring with CAH were included in this study. Ten families had previous affected children with salt-wasting/simple virilising form of CAH and five families did not have live children but had a high index of suspicion for CAH in previous children based on history or records. Mutation analysis was carried out by Sanger sequencing and MLPA method. RESULTS: Seven different mutations were identified in 15 families. Deletions and I2g mutation were the most common. Of the 15 foetuses analyzed, nine were unaffected while six were affected. Unaffected foetuses were delivered, they were clinically normal and their genotype was found to be concordant to the prenatal report. All except two families reported in the second trimester. None of the couples opted for prenatal treatment. INTERPRETATION & CONCLUSIONS: Our preliminary findings show that PND by direct mutation analysis along with MLPA is a feasible strategy that can be offered to families at risk. PMID- 28639596 TI - Guillain-Barre syndrome: Demographics, clinical profile & seasonal variation in a tertiary care centre of central India. AB - BACKGROUND & OBJECTIVES: Guillain-Barre syndrome (GBS) is an autoimmune disease and a recognized cause of generalized progressive paralysis worldwide. The present study was aimed to document the clinical findings, demographics and seasonal variations amongst the patients with GBS during the hospital stay. METHODS: A retrospective analysis of 66 referred cases diagnosed as GBS was conducted. Medical records and the data related to age, sex, antecedent illness, duration of symptoms before admission, muscle power graded by the Medical Research Council scale, functional scores, details of Intensive Care Unit complications and need for ventilation were obtained. The patients were divided into four seasonal groups: S1 (spring, February to April), S2 (summer, May to July), S3 (rainy, August to October) and S4 (winter, November to January) and parameters were studied. RESULTS: The mean age of the patients was 40.69 yr. Forty one (62.1%) patients had a history of preceding illness. Forty nine (74.2%) patients showed quadriparesis as most common complaint. Thirty three (50%) patients were of acute inflammatory demyelinating polyneuropathy (AIDP) variant. The highest number of GBS cases (60%) was found in S1 and S2. The maximum duration of hospital stay was observed in S3 group (mean 23 days). INTERPRETATION & CONCLUSIONS: GBS seems to affect all age groups with male preponderance. Most common antecedent event and presenting feature were flu-like illness and quadriparesis, respectively. AIDP was the most common variant. Most cases occurred from February to July (S1 and S2 group) (maximum in July) with preceding influenza and diarrhoea and maximum duration of hospital stay was observed in S3 group. Prospective studies with follow up of GBS patients need to be done to confirm findings. PMID- 28639597 TI - Evaluation of 75 g glucose load in non-fasting state [Diabetes in Pregnancy Study group of India (DIPSI) criteria] as a diagnostic test for gestational diabetes mellitus. AB - BACKGROUND & OBJECTIVES: There is no consensus regarding optimal standard for diagnosis of gestational diabetes mellitus (GDM). In this study, use of 75 g glucose load in non-fasting state [Diabetes in Pregnancy Study Group of India (DIPSI) criteria] as a diagnostic test for GDM in pregnant women was compared with different oral glucose tolerance tests (OGTTs). METHODS: This prospective study included 936 pregnant women, who underwent plasma glucose evaluation two hours after the challenge of 75 g glucose load irrespective of the timing of last meal (DIPSI criteria for GDM). After three days, standard 75 g OGTT was done in all women irrespective of previous plasma glucose value. Accuracy of the first result was compared to OGTT using cut-offs as per the World Health Organization (WHO) and International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria for the diagnosis of GDM. RESULTS: Of the total 936 pregnant women, 73 (7.8%) patients had plasma glucose value >=140 mg/dl when measured two hours after glucose load. When comparing with the WHO and IADPSG criteria, the sensitivity values were 65.1 and 74.1 per cent, respectively, and the corresponding specificity values were 96.3 and 96.9 per cent, respectively. On comparing with the WHO OGTT, only 41 of the 73 (56.2%) were true positives, whereas when IADPSG criteria were used, true positives were 46 (63%). False negative cases were also present when classified by the WHO and IADPSG criteria though in lesser numbers than false positives. The positive predictive values (PPVs) for the WHO and IADPSG criteria were 56.1 and 63 per cent, respectively, and their corresponding negative predictive values were 97.7 and 97.9 per cent, respectively. INTERPRETATION & CONCLUSIONS: Our findings showed that when 75 g glucose load in non-fasting state was used as a diagnostic test for GDM, almost one quarter of patients with GDM escaped diagnosis as sensitivity values were low. On the other hand, some GDM cases were falsely labelled as normal as this test did not account for cases of fasting hyperglycaemia. In addition, comparison with other OGTTs showed low PPVs. Hence, use of DIPSI criteria for diagnosing GDM must be reconsidered till further validation. PMID- 28639598 TI - Haematological profile of patients with mixed-phenotype acute leukaemia from a tertiary care centre of north India. AB - BACKGROUND & OBJECTIVES: Mixed-phenotype acute leukaemia (MPAL) is a rare neoplasm with no definite treatment protocols and a distinctly poor outcome. Advancement in polychromatic flow cytometry has made its identification easier. This prospective study was designed to identify cases of MPAL and study their clinical presentation and haematological profile in a tertiary care hospital in north India. METHODS: Ethylenediaminetetraacetic acid (EDTA)-anticoagulated bone marrow aspirate samples of patients diagnosed as acute leukaemia (AL) on the basis of morphology were utilized for immunophenotyping. A comprehensive panel of fluorochrome-labelled monoclonal antibodies targeting myeloid, B-cell, T-cell and immaturity markers was utilized. The patients diagnosed to have MPAL, on the basis of the World Health Organization 2008 classification, were selected for further analyses. RESULTS: There were 15 (2.99%) patients with MPAL of the total 501 cases of AL. Seven were children, all males and mean age of 5.08+/-3.88 yr. Eight were adults, male:female=6:2 and mean age of 21.43+/-5.74 yr. Eight were diagnosed as B/myeloid and seven were T/myeloid. No association was observed between age and immunophenotype of MPAL. On morphology, 11 were diagnosed as AML and four as ALL, and no specific morphology of blasts was predictive of a MPAL. INTERPRETATION & CONCLUSIONS: MPAL appeared to be a rare neoplasm (2.99% of AL cases). A comprehensive primary panel of monoclonal antibodies should be used to identify this neoplasm known to have a poor outcome. PMID- 28639599 TI - Comparative analysis of Luminex-based donor-specific antibody mean fluorescence intensity values with complement-dependent cytotoxicity & flow crossmatch results in live donor renal transplantation. AB - BACKGROUND & OBJECTIVES: Antibodies specific to donor human leucocyte antigen (HLA) play a critical role in graft rejection and graft loss. In recent years, techniques for their detection have evolved significantly providing an ever increasing degree of sensitivity and specificity, from the conventional cell based assays to the advanced solid-phase system based on the Luminex platform. Consensus is still evolving on the routine employment of all these methods, either stand alone or in combination. The objective of this study was to explore the near-accurate mean fluorescence intensity (MFI) cut-off values detected on Luminex platform predicting the strength of cell-based crossmatch results. METHODS: Serum samples from 116 primary renal transplant recipients awaiting transplantation were tested for the presence of antidonor antibodies by the complement-dependent cytotoxicity (CDC) and flow crossmatch (FCXM) methods with their corresponding donors as well as for HLA-donor-specific antibodies (DSA) detection using a sensitive single antigen bead (SAB) assay. RESULTS: None of the patients having HLA Class I DSA with MFI values <1000 showed positivity for T cell FCXM or CDC crossmatch, while in the group having MFI values between 1000 and 3000, 54 per cent showed positivity for the FCXM but none by the CDC method. However, in the group having MFI values >3000, 95 per cent of cases were positive for FCXM. Further, those groups with MFI values between 3000 and 5000, only 36 per cent were positive for CDC crossmatch, while 90 per cent showed positivity in the group with MFI >7000. INTERPRETATION & CONCLUSIONS: A cut-off MFI value of 3000 for Luminex SAB-based assay was found to significantly correlate with the FCXM positivity while a MFI value of 7000 and above predicted a positive CDC crossmatch. MFI cut-off value obtained as a surrogate marker for CDC and FCXM tests will help in resolving the limitations of different cell-based techniques. PMID- 28639600 TI - Effects of polysaccharide fractions isolated from Caltha palustris L. on the activity of phagocytic cells & humoral immune response in mice with collagen induced arthritis: A comparison with methotrexate. AB - BACKGROUND & OBJECTIVES: The extracts from Caltha palustris L. have been shown to be beneficial for treating arthritis and rheumatism. In this study, the immunomodulatory effects of polysaccharide fractions B and C of C. palustris extracts were studied, using the collagen-induced arthritis (CIA) mouse arthritis experimental model. The aim was to determine the activity of blood phagocytic cells and humoral immune response in CIA mice treated with polysaccharide fractions from C. palustris. METHODS: The effects of fractions B and C of C. palustris were explored by evaluating phagocytic activity of peripheral blood granulocytes and monocytes and humoral immune response in sheep red blood cell (SRBC)-immunized mice. The results were compared with methotrexate (MTX) treatment. Following the onset of CIA, DBA/1J mice were treated for 21 days with B or C fractions (10 mg/kg; i.p.) or MTX (every 48 h, 6.6 mg/kg; i.p.). RESULTS: The results showed that fraction B reduced the level of interleukin (IL)-1beta, boosted nitric oxide synthesis in murine peritoneal macrophages stimulated in vitro with lipopolysaccharide and enhanced the monocyte phagocytic activity. Exposure of SRBC-immunized mice to fraction B and MTX during the course of CIA resulted in decreased total anti-SRBC haemagglutinin titres. INTERPRETATION & CONCLUSIONS: Fraction B of C. palustris polysaccharides modulated macrophage function and exerted beneficial effects on the clinical course of CIA in mice. The results also suggested efficacy of fraction B was comparable to that of MTX treatment for certain parameters. PMID- 28639602 TI - Study of adverse drug reactions in patients with diabetes attending a tertiary care hospital in New Delhi, India. AB - The present prospective observational study was carried out in a tertiary care hospital in New Delhi, India from May 2014 to June 2015 to report adverse drug reactions (ADRs) in patients with type 2 diabetes mellitus (T2DM) using antidiabetic drugs. A total of 220 patients (121 males, 99 females) were enrolled. ADRs were recorded on the prescribed form. Causality and severity assessment was done using Naranjo's probability scale and modified Hartwig and Siegel's severity scale, respectively. Commonly prescribed drugs were biguanides, peptide hormone and sulphonylurea. A total of 26 ADRs were recorded (16 in males and 10 in females). Most commonly observed ADRs were related to endocrine and gastrointestinal system. Severity assessment of ADRs showed seven (26.9%) ADRs as moderate, and 19 (73.1%) as mild. No severe reactions were observed. ADRs were mostly related to endocrine and gastrointestinal system. More information on prescribed drugs and their side effects is required for ensuring patient safety. PMID- 28639601 TI - Faecal microbiota of healthy adults in south India: Comparison of a tribal & a rural population. AB - BACKGROUND & OBJECTIVES: The relevance of the gut microbiota to human health is increasingly appreciated. The objective of this study was to compare the gut microbiota of a group of adult tribals with that of healthy adult villagers in Tamil Nadu, India. METHODS: Faeces were collected from 10 healthy tribal adults (TAs) in the Jawadhi hills and from 10 healthy villagers [rural adults (RAs)] in Vellore district, Tamil Nadu. DNA was extracted, and 456 bp segments comprising hypervariable regions 3 and 4 of the 16S rRNA gene were amplified, barcoded and 454 sequenced. RESULTS: Totally 227,710 good-quality reads were analyzed. TAs consumed a millets-based diet, ate pork every day, and did not consume milk or milk products. RAs consumed a rice-based diet with meat intake once a week. In both groups, Firmicutes was the most abundant phylum, followed by Proteobacteria, Bacteroidetes and Actinobacteria. The median Firmicutes-to-Bacteroidetes ratio was 34.0 in TA and 92.9 in RA groups. Actinobacteria were significantly low in TA, possibly due to non-consumption of milk. Clostridium constituted the most abundant genus in both groups, but was significantly more abundant in TAs than RAs, while Streptococcus was significantly more abundant in RA (P<0.05). Analyses of genetic distance revealed that the microbiota were distinctly different between TA and RA, and principal component analysis using 550 distinct taxonomically identifiable sequences revealed a clear separation of microbiota composition in the two groups. Phylogenetic analysis of major microbiota indicated clustering of microbial groups at different major branch points for TAs and RAs. INTERPRETATION & CONCLUSIONS: Phylum Firmicutes and genus Clostridium constituted the bulk of the faecal microbiota, while significant differences in composition between the groups were probably due to differences in diet and lifestyle. PMID- 28639604 TI - Intraoral malignant melanoma. PMID- 28639603 TI - Serum prolactin levels in patients with psoriasis: Results of a pilot study. PMID- 28639605 TI - [The definition of sepsis. 25-year experience of concept development]. AB - The review, presented in chronological order the stages of formation of the modern definition of sepsis syndrome, since the recommendations of the conciliation conference ACCP/SCCM (1991), the experience of the practical use of which has been extensively critically assessed in future studies. As a result, it formed a strong opinion that the global challenge of early diagnosis of sepsis, under the previously proposed definitive categories have not been solved, moreover, in the scientific community formed a firm belief in the need to make fundamental changes in the definition of the term 'sepsis'. As a result, in 2016 the scientific community were presented the recommendations of the working group 'Sepsis-3', in which sepsis is defined as life-threatening organ dysfunction due to dysregulated response to infection, and fundamentally distinguish them from the former, is a laconic definitions and availability of diagnostic criteria. National expert community to analyze, discuss and define the field of clinical testing 'Sepsis-3' in the Russian Federation. PMID- 28639606 TI - [Non-occlusive form of acute mesenteric circulatory disorders: diagnosis and treatment]. PMID- 28639607 TI - [The school of young academic psychiatrists on the occasion of the 110 birthday of A.V. Snezhnevsky]. PMID- 28639608 TI - [A.S. Nikiforov, M.R. Guseva 'Oftalmoneurology'. M 2014]. PMID- 28639609 TI - [IIId Congress Cerebrovascular Disorders and Stroke]. PMID- 28639610 TI - [Interview with prof. I.A. Voznyuk]. PMID- 28639611 TI - Masked hypertension and effort-reward imbalance at work among 2369 white-collar workers. AB - Hypertension is an important risk factor of cardiovascular diseases, the leading cause of death worldwide. Adverse effects of psychosocial factors at work might increase the risk of masked hypertension, but evidences are still scarce. The objective of this study is then to determine whether adverse psychosocial work factors from the effort-reward imbalance (ERI) model are associated with the prevalence of masked hypertension in a population of white-collar workers. White collar workers were recruited from three public organizations. Blood pressure was measured at the workplace for manually operated measurements (mean of the first three readings taken by a trained assistant) followed by ambulatory measurements (mean of all subsequent readings taken during the working day). Masked hypertension was defined as manually operated BP<140/90 mm Hg and ambulatory BP ?135/85 mm Hg. ERI exposure at work was measured using Siegrist's validated questionnaire. Blood pressure readings were obtained from 2369 workers (participation proportion: 85%). ERI exposure (OR: 1.53 (95% CI: 1.16-2.02) and high efforts at work (OR: 1.61 (95% CI: 1.13-1.29) were associated with masked hypertension, after adjusting for sociodemographic and cardiovascular risk factors. Workers exposed to an imbalance between efforts spent at work and reward had a higher prevalence of masked hypertension. High efforts at work might be of particular importance in explaining this association. Future studies should be designed to investigate how clinicians can include questions on psychosocial work factors to screen for masked hypertension and how workplace interventions can decrease adverse psychosocial exposures to lower BP. PMID- 28639612 TI - Elevated serum retinol-binding protein 4 levels are correlated with blood pressure in prehypertensive Chinese. AB - Retinol-binding protein 4 (RBP4) has been reported involving in the occurrence and development of hypertension. However, to date, few data are available on the correlation between serum RBP4 level and blood pressure (BP) in prehypertension. Therefore, this association was investigated in prehypertensive Chinese. Overall, 160 subjects with prehypertension (Pre-HT group) and 160 subjects with normal BP (NBP group) were recruited in this study. The subjects were divided into the following four subgroups according to body mass index (BMI): obese Pre-HT subgroup; non-obese Pre-HT subgroup; obese NBP subgroup; and non-obese NBP subgroup (n=80 in each). Anthropometric parameters, systolic BP (SBP), diastolic BP (DBP) and several biochemical parameters were measured. Fasting insulin was evaluated by radioimmunoassay. Serum RBP4 level was measured by enzyme-linked immunosorbent assay. The Pre-HT group had higher levels of serum RBP4 level than did the NBP group (P<0.001). Moreover, higher RBP4 levels were identified in the obese Pre-HT subgroup relative to the non-obese Pre-HT subgroup (P=0.005). However, no difference in RBP4 level was identified between the obese and the non obese NBP subgroups (P=0.317). RBP4 level was positively correlated with BMI (r=0.226, P=0.001), SBP (r=0.468, P<0.001) and DBP (r=0.358, P<0.001) after adjustment for age, sex, smoking status and alcohol consumption. The results of the multiple regression analyses demonstrated that RBP4 level was independently associated with SBP (beta=0.427, P<0.001) and DBP (beta=0.338, P<0.001). In conclusion, serum RBP4 level was significantly higher and closely associated with BP in prehypertensive Chinese. PMID- 28639613 TI - Mechanical properties of atomically thin boron nitride and the role of interlayer interactions. AB - Atomically thin boron nitride (BN) nanosheets are important two-dimensional nanomaterials with many unique properties distinct from those of graphene, but investigation into their mechanical properties remains incomplete. Here we report that high-quality single-crystalline mono- and few-layer BN nanosheets are one of the strongest electrically insulating materials. More intriguingly, few-layer BN shows mechanical behaviours quite different from those of few-layer graphene under indentation. In striking contrast to graphene, whose strength decreases by more than 30% when the number of layers increases from 1 to 8, the mechanical strength of BN nanosheets is not sensitive to increasing thickness. We attribute this difference to the distinct interlayer interactions and hence sliding tendencies in these two materials under indentation. The significantly better interlayer integrity of BN nanosheets makes them a more attractive candidate than graphene for several applications, for example, as mechanical reinforcements. PMID- 28639614 TI - A coherent quantum annealer with Rydberg atoms. AB - There is a significant ongoing effort in realizing quantum annealing with different physical platforms. The challenge is to achieve a fully programmable quantum device featuring coherent adiabatic quantum dynamics. Here we show that combining the well-developed quantum simulation toolbox for Rydberg atoms with the recently proposed Lechner-Hauke-Zoller (LHZ) architecture allows one to build a prototype for a coherent adiabatic quantum computer with all-to-all Ising interactions and, therefore, a platform for quantum annealing. In LHZ an infinite range spin-glass is mapped onto the low energy subspace of a spin-1/2 lattice gauge model with quasi-local four-body parity constraints. This spin model can be emulated in a natural way with Rubidium and Caesium atoms in a bipartite optical lattice involving laser-dressed Rydberg-Rydberg interactions, which are several orders of magnitude larger than the relevant decoherence rates. This makes the exploration of coherent quantum enhanced optimization protocols accessible with state-of-the-art atomic physics experiments. PMID- 28639615 TI - Adaptive and freeze-tolerant heteronetwork organohydrogels with enhanced mechanical stability over a wide temperature range. AB - Many biological organisms with exceptional freezing tolerance can resist the damages to cells from extra-/intracellular ice crystals and thus maintain their mechanical stability at subzero temperatures. Inspired by the freezing tolerance mechanisms found in nature, here we report a strategy of combining hydrophilic/oleophilic heteronetworks to produce self-adaptive, freeze-tolerant and mechanically stable organohydrogels. The organohydrogels can simultaneously use water and oil as a dispersion medium, and quickly switch between hydrogel- and organogel-like behaviours in response to the nature of the surrounding phase. Accordingly, their surfaces display unusual adaptive dual superlyophobic in oil/water system (that is, they are superhydrophobic under oil and superoleophobic under water). Moreover, the organogel component can inhibit the ice crystallization of the hydrogel component, thus enhancing the mechanical stability of organohydrogel over a wide temperature range (-78 to 80 degrees C). The organohydrogels may have promising applications in complex and harsh environments. PMID- 28639616 TI - Current rates and mechanisms of subsea permafrost degradation in the East Siberian Arctic Shelf. AB - The rates of subsea permafrost degradation and occurrence of gas-migration pathways are key factors controlling the East Siberian Arctic Shelf (ESAS) methane (CH4) emissions, yet these factors still require assessment. It is thought that after inundation, permafrost-degradation rates would decrease over time and submerged thaw-lake taliks would freeze; therefore, no CH4 release would occur for millennia. Here we present results of the first comprehensive scientific re-drilling to show that subsea permafrost in the near-shore zone of the ESAS has a downward movement of the ice-bonded permafrost table of ~14 cm year-1 over the past 31-32 years. Our data reveal polygonal thermokarst patterns on the seafloor and gas-migration associated with submerged taliks, ice scouring and pockmarks. Knowing the rate and mechanisms of subsea permafrost degradation is a prerequisite to meaningful predictions of near-future CH4 release in the Arctic. PMID- 28639617 TI - Gene therapy for spinomuscular atrophy: a biomedical advance, a missed opportunity for more equitable drug pricing. AB - An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease. This technique represents the first apparently effective therapy for spinal muscular atrophy (SMA) and an important documentation for ASO technology for therapy of neurodegenerative disease. These results with one form of SMA are likely to be relevant for similar applications to other SMA types and are likely to inspire application to a number of other intractable neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis and possibly even the extremely common Parkinson's and Alzheimer's diseases and others. Nevertheless, the scientific and medical importance of this advance is marred by a pricing policy by the corporate sponsors that may complicate accessibility of the drug for some desperate patients. PMID- 28639618 TI - HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation. AB - The human T-lymphotropic virus type 1 (HTLV-1) is efficiently transmitted through cellular contacts. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied in vitro, those facilitating the encounter between infected and target cells remain unknown. In this study, we demonstrate that HTLV-1-infected CD4 T cells secrete a potent chemoattractant, leukotriene B4 (LTB4). LTB4 secretion is dependent on Tax-induced transactivation of the pla2g4c gene, which encodes the cytosolic phospholipase A2 gamma. Inhibition of LTB4 secretion or LTB4 receptor knockdown on target cells reduces T cell recruitment, cellular contact formation and virus propagation in vitro. Finally, blocking the synthesis of LTB4 in a humanized mouse model of HTLV-1 infection significantly reduces proviral load. This results from a decrease in the number of infected clones while their expansion is not impaired. This study shows the critical role of LTB4 secretion in HTLV-1 transmission both in vitro and in vivo. PMID- 28639620 TI - Poly(4-styrenesulfonate)-induced sulfur vacancy self-healing strategy for monolayer MoS2 homojunction photodiode. AB - We establish a powerful poly(4-styrenesulfonate) (PSS)-treated strategy for sulfur vacancy healing in monolayer MoS2 to precisely and steadily tune its electronic state. The self-healing mechanism, in which the sulfur vacancies are healed spontaneously by the sulfur adatom clusters on the MoS2 surface through a PSS-induced hydrogenation process, is proposed and demonstrated systematically. The electron concentration of the self-healed MoS2 dramatically decreased by 643 times, leading to a work function enhancement of ~150 meV. This strategy is employed to fabricate a high performance lateral monolayer MoS2 homojunction which presents a perfect rectifying behaviour, excellent photoresponsivity of ~308 mA W-1 and outstanding air-stability after two months. Unlike previous chemical doping, the lattice defect-induced local fields are eliminated during the process of the sulfur vacancy self-healing to largely improve the homojunction performance. Our findings demonstrate a promising and facile strategy in 2D material electronic state modulation for the development of next generation electronics and optoelectronics. PMID- 28639619 TI - Long noncoding RNA LncHIFCAR/MIR31HG is a HIF-1alpha co-activator driving oral cancer progression. AB - Long noncoding RNAs (lncRNAs) have been implicated in hypoxia/HIF-1-associated cancer progression through largely unknown mechanisms. Here we identify MIR31HG as a hypoxia-inducible lncRNA and therefore we name it LncHIFCAR (long noncoding HIF-1alpha co-activating RNA); we describe its oncogenic role as a HIF-1alpha co activator that regulates the HIF-1 transcriptional network, crucial for cancer development. Extensive analyses of clinical data indicate LncHIFCAR level is substantially upregulated in oral carcinoma, significantly associated with poor clinical outcomes and representing an independent prognostic predictor. Overexpression of LncHIFCAR induces pseudo-hypoxic gene signature, whereas knockdown of LncHIFCAR impairs the hypoxia-induced HIF-1alpha transactivation, sphere-forming ability, metabolic shift and metastatic potential in vitro and in vivo. Mechanistically, LncHIFCAR forms a complex with HIF-1alpha via direct binding and facilitates the recruitment of HIF-1alpha and p300 cofactor to the target promoters. Our results uncover an lncRNA-mediated mechanism for HIF-1 activation and establish the clinical values of LncHIFCAR in prognosis and potential therapeutic strategy for oral carcinoma. PMID- 28639621 TI - Electronic metal-support interaction enhanced oxygen reduction activity and stability of boron carbide supported platinum. AB - Catalysing the reduction of oxygen in acidic media is a standing challenge. Although activity of platinum, the most active metal, can be substantially improved by alloying, alloy stability remains a concern. Here we report that platinum nanoparticles supported on graphite-rich boron carbide show a 50-100% increase in activity in acidic media and improved cycle stability compared to commercial carbon supported platinum nanoparticles. Transmission electron microscopy and x-ray absorption fine structure analysis confirm similar platinum nanoparticle shapes, sizes, lattice parameters, and cluster packing on both supports, while x-ray photoelectron and absorption spectroscopy demonstrate a change in electronic structure. This shows that purely electronic metal-support interactions can significantly improve oxygen reduction activity without inducing shape, alloying or strain effects and without compromising stability. Optimizing the electronic interaction between the catalyst and support is, therefore, a promising approach for advanced electrocatalysts where optimizing the catalytic nanoparticles themselves is constrained by other concerns. PMID- 28639622 TI - Growth-coupled overproduction is feasible for almost all metabolites in five major production organisms. AB - Computational modelling of metabolic networks has become an established procedure in the metabolic engineering of production strains. One key principle that is frequently used to guide the rational design of microbial cell factories is the stoichiometric coupling of growth and product synthesis, which makes production of the desired compound obligatory for growth. Here we show that the coupling of growth and production is feasible under appropriate conditions for almost all metabolites in genome-scale metabolic models of five major production organisms. These organisms comprise eukaryotes and prokaryotes as well as heterotrophic and photoautotrophic organisms, which shows that growth coupling as a strain design principle has a wide applicability. The feasibility of coupling is proven by calculating appropriate reaction knockouts, which enforce the coupling behaviour. The study presented here is the most comprehensive computational investigation of growth-coupled production so far and its results are of fundamental importance for rational metabolic engineering. PMID- 28639623 TI - Imaging quasiperiodic electronic states in a synthetic Penrose tiling. AB - Quasicrystals possess long-range order but lack the translational symmetry of crystalline solids. In solid state physics, periodicity is one of the fundamental properties that prescribes the electronic band structure in crystals. In the absence of periodicity and the presence of quasicrystalline order, the ways that electronic states change remain a mystery. Scanning tunnelling microscopy and atomic manipulation can be used to assemble a two-dimensional quasicrystalline structure mapped upon the Penrose tiling. Here, carbon monoxide molecules are arranged on the surface of Cu(111) one at a time to form the potential landscape that mimics the ionic potential of atoms in natural materials by constraining the electrons in the two-dimensional surface state of Cu(111). The real-space images reveal the presence of the quasiperiodic order in the electronic wave functions and the Fourier analysis of our results links the energy of the resonant states to the local vertex structure of the quasicrystal. PMID- 28639624 TI - Nearest-neighbour resonating valence bonds in YbMgGaO4. AB - Since its proposal by Anderson, resonating valence bonds (RVB) formed by a superposition of fluctuating singlet pairs have been a paradigmatic concept in understanding quantum spin liquids. Here, we show that excitations related to singlet breaking on nearest-neighbour bonds describe the high-energy part of the excitation spectrum in YbMgGaO4, the effective spin-1/2 frustrated antiferromagnet on the triangular lattice, as originally considered by Anderson. By a thorough single-crystal inelastic neutron scattering study, we demonstrate that nearest-neighbour RVB excitations account for the bulk of the spectral weight above 0.5 meV. This renders YbMgGaO4 the first experimental system where putative RVB correlations restricted to nearest neighbours are observed, and poses a fundamental question of how complex interactions on the triangular lattice conspire to form this unique many-body state. PMID- 28639627 TI - Announcement of Requirements and Registration for Million Hearts(r) Hypertension Control Challenge. PMID- 28639626 TI - Circulating miRNAs as biomarkers of kidney disease. AB - Interest in microRNAs (miRNAs) has dramatically increased in recent years not only because they regulate mRNA expression, and thus many physiological or pathophysiological processes, but also because they could serve as biomarkers. Next to analysis of tissue miRNA expression, measurement in body fluids such as blood or urine is attractive because miRNA in microvesicles or bound to protein is very stable. Currently it is unclear whether these circulating miRNAs are tissue and disease specific or represent more general pathologies like inflammation. In addition pre-analytical sample handling and variable analysis techniques affect the results and thus much more work needs to be done before one can draw a final conclusion about their clinical utility. PMID- 28639625 TI - MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis. AB - Current treatments for rheumatoid arthritis (RA) do not reverse underlying aberrant immune function. A genetic predisposition to RA, such as HLA-DR4 positivity, indicates that dendritic cells (DC) are of crucial importance to pathogenesis by activating auto-reactive lymphocytes. Here we show that microRNA 34a provides homoeostatic control of CD1c+ DC activation via regulation of tyrosine kinase receptor AXL, an important inhibitory DC auto-regulator. This pathway is aberrant in CD1c+ DCs from patients with RA, with upregulation of miR 34a and lower levels of AXL compared to DC from healthy donors. Production of pro inflammatory cytokines is reduced by ex vivo gene-silencing of miR-34a. miR-34a deficient mice are resistant to collagen-induced arthritis and interaction of DCs and T cells from these mice are reduced and do not support the development of Th17 cells in vivo. Our findings therefore show that miR-34a is an epigenetic regulator of DC function that may contribute to RA. PMID- 28639628 TI - Multiple socioeconomic deprivation and impact on survival in patients with primary glomerulonephritis. AB - Background: The impact of multiple socio-economic deprivation on patient outcomes in primary renal diseases is unknown. We aimed to assess whether risk of death or requiring renal replacement therapy (RRT) in patients with primary glomerulonephritis (GN) was higher in patients living in an area of multiple socio-economic deprivation. Methods: Patients undergoing native renal biopsy between 2000 and 2014 were identified. Baseline demographics, postcode at time of biopsy, follow-up blood pressure, proteinuria and time to death or RRT were recorded. The Scottish Index of Multiple Deprivation (SIMD) is a multidimensional model used to measure deprivation based on postcode. Using SIMD, patients were separated into tertiles of deprivation. Results: A total of 797 patients were included, 64.2% were male with mean age of 54.1 (standard deviation 17.0) years. Median follow-up was 6.3 (interquartile range 3.7-9.4) years during which 174 patients required RRT and 185 patients died. Patients in the most deprived tertile of deprivation were significantly more likely to die than those in the least deprived tertile [hazard ratio (HR) 2.2, P < 0.001], independent of age, baseline serum creatinine and blood pressure. They were not more likely to require RRT (P = 0.22). The increased mortality risk in the most deprived tertile was not uniform across primary renal diseases, with the association being most marked in focal segmental glomerulosclerosis (HR 7.4) and IgA nephropathy (HR 2.7) and absent in membranous nephropathy. Conclusion: We have demonstrated a significant independent 2-fold increased risk of death in patients with primary GN who live in an area of multiple socio-economic deprivation at the time of diagnosis as compared with those living in less deprived areas. PMID- 28639629 TI - Announcement of Requirements and Registration for Healthy Behavior Challenge. PMID- 28639630 TI - Erratum: Findings of Research Misconduct; Correction. AB - [This corrects the article on p. 36932 in vol. 2016.]. PMID- 28639631 TI - An update on MALDI mass spectrometry based technology for the analysis of fingermarks - stepping into operational deployment. AB - Since 2009, when Matrix Assisted Laser Desorption Ionisation Mass Spectrometry Imaging (MALDI MSI) was firstly reported for the molecular mapping of latent fingermarks, the range of information and operational capabilities have steadily increased. Pioneering work from our Fingermark Research Group exploited different modalities, including Profiling (MALDI MSP), tandem mass spectrometry (MS/MS) and Ion Mobility MS/MS; a number of methodologies were also developed to conquer a main challenge, namely profiling the suspect and their actions prior to or whilst committing the crime. Suspect profiling here is no longer based on behavioural science but complements this discipline and the investigations by detecting and visualising the molecular make-up of fingermarks onto the identifying ridges. This forensic opportunity provides the link between the biometric information (ridge detail) and the corpus delicti or intelligence on the circumstances of the crime. In 2013, a review was published covering the research work and developments of four years supported by the Home Office, UK, and the local regional Police with some insights (and comparison) into similar research being reported employing other mass spectrometric techniques. The present review is an extensive update on the MALDI MS based methods' achievements, limitations and work in progress in fingermark analysis; it also offers an outlook on further necessary research into this subject. The main highlights are the increased number of possible information retrievable around a suspect and the more extended compatibility of this technology. The latter has allowed MALDI MS based methods to integrate well with current forensic fingerprinting, leading to the investigation of real police casework. PMID- 28639634 TI - Copper(ii) catalyzed iodine-promoted oxidative cyclization of 2-amino-1,3,5 triazines and chalcones: synthesis of aroylimidazo[1,2-a][1,3,5]triazines. AB - An efficient copper(ii) catalyzed iodine-promoted synthesis of aroylimidazo[1,2 a][1,3,5]triazines from 2-amino-1,3,5-triazines and chalcones under mild conditions has been developed. The reaction occurred with good yields and excellent regioselectivities, and tolerated chalcone containing functionalities such as ethers, halogens, and nitro groups. The successful application of this methodology for a gram-scale reaction indicates its potential for bulk synthesis. PMID- 28639632 TI - An NHC-phosphinidenyl as a synthon for new group 13/15 compounds. AB - The parent phosphinidene SIMesPH (1) (SIMes = 1,3-bis(2,4,6 trimethylphenyl)imidazolin-2-ylidene) was treated with benzyl potassium to form the metalated species SIMesPK (2), which was used as a synthon for the new group 13/15 cycles and cage compounds [SIMesPGatBu2]2 (3), [SIMesP(GatBu2)2Cl] (4) and [K(SIMesP)3AltBu] (5). PMID- 28639636 TI - Hyperbolic metamaterials for dispersion-assisted directional light emission. AB - A novel method is presented to outcouple high spatial frequency (large-k) waves from hyperbolic metamaterials (HMMs) without the use of a grating. This approach relies exclusively on dispersion engineering, and enables preferential power extraction from the top or from the side of a HMM. Multilayer (ML) HMMs are shown to be better suited for lateral outcoupling, while nanowire HMMs are the most convenient choice for top outcoupling. A 6-fold increase in laterally extracted power is predicted for a dipole-HMM system with a Ag/Si ML operating at lambda = 530 nm, when metallic filling ratio is changed from an unoptimized to the optimized one. This new design concept supports the cost-effective mass production of high-speed HMM optical transmitters. PMID- 28639637 TI - Syntheses, structures and magnetic properties of tetranuclear cubane-type and heptanuclear wheel-type nickel(ii) complexes with 3-methoxysalicylic acid derivatives. AB - Two ferromagnetic multinuclear Ni(ii) clusters, [Ni4L14(MU3-OMe)4(CH3OH)4] (1) and [Ni7(HL2)6(MU3-OMe)6]Cl2 (2), and a mononuclear complex [NiL3].2H2O (3) (HL1 = benzyl 2-hydroxy-3-methoxybenzoate; H2L2 = 1-(2-hydroxy-3-methoxybenzamido)-2 (benzylideneamino)ethane; H2L3 = 1-(2-hydroxy-3-methoxybenzamido)-2 (pyridylmethyleneamino)ethane) were synthesised, and their structures and magnetic behaviours were investigated in detail. 1 has a [Ni4O4] cubane structure while 2 has a wheel-like [Ni@Ni6] arrangement. The temperature-dependent magnetic susceptibilities for 1 and 2 are in accord with the presence of dominating intra cluster ferromagnetic interactions between Ni(ii) ions. The best fits for their behaviours gave the following parameters: J1 = 11.06 cm-1, J2 = 1.43 cm-1, g = 2.29 for 1, and J1 = 6.87 cm-1, J2 = -3.41 cm-1, g = 2.24 for 2. PMID- 28639638 TI - A combined optical and EPR spectroscopy study: azobenzene-based biradicals as reversible molecular photoswitches. AB - Azobenzene compounds are known as versatile examples for photoswitchable systems because of their isomeric cis- and trans-configurations. The switching between these isomers can be reversibly controlled by light excitation. In this study we characterize two members of this class by joining the azobenzene moiety with each two paramagnetic nitroxide spin labels. Two different linkers were chosen to tune the molecular properties. The combined approach using optical and EPR spectroscopy proved the reversibility of photoexcitation and high fatigue resistance. Furthermore, depending on the nature of the linker, PELDOR distance measurements monitored clearly the photo-induced structural changes of the azobenzene unit. Thus, a powerful concept is presented resulting from the combination of these two complementary spectroscopic techniques. PMID- 28639639 TI - A coherent study on the Z-enoate assisted Meyer-Schuster rearrangement. AB - A systematic study has been performed on the Z-enoate assisted Meyer-Schuster rearrangement of propargylic alcohols. The impact of various factors such as temperature, solvent, concentration of a counter ion of an acid, and the nature of the arene nucleophile was studied. The relative nucleophilicity of various arenes estimated in this study is in good agreement with that of Herbert Mayr's nucleophilicity scale. PMID- 28639641 TI - Incorporation of 'click' chemistry glycomimetics dramatically alters triple-helix stability in an adiponectin model peptide. AB - Adiponectin (Adpn) has been shown to be a possible therapeutic for Type II diabetes, however the production of a therapeutic version of Adpn has proved to be challenging. Biological studies have highlighted the importance of the glycosylated lysine residues for the formation of bioactive high molecular weight oligomers of Adpn. Through the use of 'click' glycopeptide mimetics, we investigated the role of glycosylated lysine and serine residues for the formation of triple helical structures of the collagenous domain of Adpn, in the context of a collagen model peptide scaffold. The physical properties of the unglycosylated lysine and serine peptides are compared with their glycosylated analogues. Our results highlight the crucial role of lysine residues for formation of the triple helical structure of Adpn, possibly due to the extension of both intra- and interstrand hydrogen bonding networks. Strikingly, we observed a significant decrease in thermal stability upon incorporation of triazole-linked analogues of glycosylated lysine residues into the adiponectin collageneous domain, indicating possible uses of 'click' glycomimetics for bioengineering applications. PMID- 28639642 TI - Cleavage of ethers in an ionic liquid. Enhancement, selectivity and potential application. AB - The cleavage of a series of ethers was examined in an ionic liquid containing hydrogen bromide. Reactions that did not proceed in either water or DMSO were found to proceed readily in this system, with notable selectivity between the cleavage of the different ether types examined herein. Increasing the proportion of water in the reaction mixture dramatically decreased the rate constant of ether cleavage; this could, in part, be attributed to a decrease in the solvent stabilisation of the transition state. Through analysis of the electronic requirements of the reaction (using substrates containing substituents with different Hammett parameters) and observation of rate enhancements for an ortho substituted system, the importance of the extent of protonation of the ether prior to nucleophilic attack was demonstrated. PMID- 28639643 TI - Palladium-catalyzed C-H alkylation of 2-phenylpyridines with alkyl iodides. AB - Palladium-catalyzed C-H alkylation reaction of 2-phenylpyridines with alkyl iodides has been successfully developed. The palladacycles obtained from 2 phenylpyridines should act as the key intermediates in the alkylation reaction. PMID- 28639645 TI - Developing a ferroelectric nanohybrid for enhanced photocatalysis. AB - We develop a ferroelectric nanohybrid that improves photocatalytic efficiency by reducing the recombination of holes and electron charge carriers. In particular, the size of uniformly dispersed ferroelectric BaTiO3 in the nanohybrid reaches the critical size of a monodomain, which avoids the need for a poling process for switching the ferroelectric polarization. PMID- 28639644 TI - Differential detection and quantification of cyclic AMP and other adenosine phosphates in live cells. AB - A new naphthol-based rhodamine derivative (NpRD) has been developed for the selective and differential detection of adenosine 3',5'-cyclic monophosphate (cAMP) and adenosine phosphates (APs) (ATP, ADP, and AMP) from other nucleotides. The simple detection and quantification of cAMP in human blood cells and in other samples based on the 'turn on' fluorescence properties of this chemosensor through colorimetry or fluorometry makes it unique for probable application in high throughput screening. PMID- 28639646 TI - Monovalent and bivalent cations exchange isotherms for faujasites X and Y. AB - This study addresses the modeling of exchange isotherms for faujasite-type zeolites X and Y with K+, Cs+, Ca2+ and Ba2+ cations based on a large experimental dataset obtained under operating conditions of 0.5 N total normality and an exchange temperature of 80 degrees C. The isotherm models are based on the mass action law. Ideal solution phase is assumed. Heterogeneity of the solid phase is taken into account by using Barrer and Klinowski's approach to multi site exchange. Three types of exchange sites are identified on these zeolites. To each exchange site j corresponds a fitted selectivity coefficient Kj. These parameters, estimated by least square method, evaluate the affinity of the studied cations for the identified exchange site. Globally, these fitted coefficients show that the cations considered present better affinity than Na+, especially for type III sites in faujasite X and type II sites in faujasite Y. For bivalent cations, an exchange with Ba2+ is always more favorable than with Ca2+. On faujasite X, type II sites are more strongly preferred by monovalent cations (with the exception of Cs+) than by bivalent ones. The opposite trend is observed on faujasite Y, even for Cs+. These conclusions have been confirmed and are supported by bibliographic data. PMID- 28639647 TI - Water mediated proton conduction in a sulfonated microporous organic polymer. AB - Polymer membranes (PEMs) within fuel cells (FCs) act as separators and efficient proton conducting electrolytes. Established systems tend to microphase separation into hydrophilic and hydrophobic regions, making these materials prone to water loss at elevated temperatures. Therefore, recent approaches utilize porous materials, which promise stronger interactions between water molecules and the framework, while still providing efficient conductive pathways. Here we show, that the microporous polymer PAF-1 exhibits proton conductivities up to 10-1 S cm 1 under hydrous conditions, after post-synthetic sulfonation. Gas phase sulfonation turned out to be the essential step for introducing a sufficiently large amount of -SO3H groups and thus a high charge carrier concentration upon hydration. While the absolute conductivity of the sulfonated frameworks strongly depends on the water uptake, we found similar activation barriers for all relative humidities. Since water is homogeneously stored in micro- and mesoporous voids, the activation barrier of the interpore conductivity is decisive for the macroscopic properties. PMID- 28639648 TI - A freestanding NiSx porous film as a binder-free electrode for Mg-ion batteries. AB - An ultrathin, freestanding NiSx nanoporous thin-film was developed by facile electrochemical deposition, etching, anodization and chemical vapor treatments. The NiSx nanoporous thin-film shows excellent reversible insertion/extraction of Mg ions and long-term cycling performance, which is an ideal energy storage device for small/micro-size electronic and medical devices. PMID- 28639649 TI - Computational design of cephradine synthase in a new scaffold identified from structural databases. AB - Computational enzyme design exhibits excellent performance for identifying potential scaffolds from structural databases and creating new enzymatic catalysts from naught. Using the active site-matching algorithm ProdaMatch, we identified a new scaffold cocaine esterase from Rhodococcus sp. that showed modest activity (kcat/Km = 0.018 M-1 s-1) towards the hydrolysis of beta-lactam antibiotic cephradine. The identified cocaine esterase scaffold afforded low sequence identity (<30%) with the known beta-lactam synthases, such as penicillin G acylase or alpha-amino acid ester hydrolase, and was able to catalyze the condensation reaction between d-dihydrophenylglycine methyl ester and 7 aminodesacetoxycephalosporanic acid to produce cephradine via a kinetically controlled synthesis. By virtue of the computational enzyme design protocol, hundreds of sequences were predicted in the cocaine esterase scaffold to promote the catalytic activity towards the hydrolytic reaction of cephradine. Moreover, a single mutant (F261T) was experimentally confirmed to have improved the catalytic efficiency by ten times (kcat/Km = 0.193 M-1 s-1), indicating that the novel scaffold cocaine esterase may be potentially redesigned to become an industrially useful cephradine synthase. PMID- 28639650 TI - Mechanisms of H and CO loss from the uracil nucleobase following low energy electron irradiation. AB - Ionising radiation in cells generates secondary low energy electrons (LEEs) which can induce biomolecular damage when incident upon a particular biomolecule. Notable biomolecules include those contained within double-stranded DNA and RNA helices, which upon exposure to LEEs, may form reactive intermediate products that show detriment to their specific structures and functions. Such damaging processes are understood to proceed via dissociative electron attachment (DEA). Using anion resonance stabilisation methods, coupled to state-of-the-art electronic structure methods, and reaction path mapping, the work presented herein highlights the detailed mechanisms associated with molecular elimination of CO and H from the uracil nucleobase following LEE irradiation - providing a rationale for earlier experiments. The results highlight a subset of resonances that show a labile route for forming CO + anionic 1,3-dihydroimidazole (1,3-DHIM ). The nascent 1,3-DHIM anion is itself unstable with respect to N-H bond fission - ultimately forming anionic 1-imidazole (1-IM-) + H products. This hitherto unknown mechanism sheds light on the possible lesion processes that may be encountered by biomolecular constituents when exposed to electron energies analogous to those present in medicinal X-ray diagnostics, aviation and interstellar space. The work also offers some insight into the reactive processes that may have occurred in prebiotic earth. PMID- 28639651 TI - Ru-Catalyzed highly diastereoselective hydrogenation of N-tert-butylsulfinyl ketimines for the synthesis of aryl glycine derivatives. AB - A ruthenium pincer catalyst has been shown to be highly efficient for the hydrogenation of a wide range of alpha-ketimino esters derived from alpha-keto esters and chiral 2-methylpropyl-2-sulfinamide, affording chiral aryl glycine derivatives with high yields and diasteroselectivities (20 examples, dr values up to 99 : 1). PMID- 28639652 TI - Probing single-molecule electron-hole transfer dynamics at a molecule-NiO semiconductor nanocrystalline interface. AB - Interfacial charge transfer dynamics in dye-sensitized NiO nanoparticles are being investigated for photocathodes in p-type dye-sensitized solar cells. In the photoreaction, after fast electron transfer from NiO to a molecule, the recombination of the hole in the nanoparticles with the electron in a reduced molecule plays an important role in the charge separation process and solar energy harvesting. Nevertheless, knowledge of the interfacial charge recombination (CR) rate and its mechanism is still limited due to the complex photoinduced electron and hole dynamics and lack of characterization of the inhomogeneity of the dynamics. Here, we report our work on probing interfacial charge recombination dynamics in Zn(ii)-5,10,15,20-tetra(3 carboxyphenyl)porphyrin (m-ZnTCPP) dye-sensitized NiO nanoparticles by correlating single-molecule fluorescence blinking dynamics with charge transfer dynamics using single-molecule photon-stamping spectroscopy. The correlated analyses of single-molecule fluorescence intensity, lifetime, and blinking reveal the intrinsic distribution and temporal fluctuation of interfacial charge transfer reactivity, which are closely related to site-specific molecular interactions and dynamics. PMID- 28639653 TI - An efficient enzyme-powered micromotor device fabricated by cyclic alternate hybridization assembly for DNA detection. AB - An efficient enzyme-powered micromotor device was fabricated by assembling multiple layers of catalase on the inner surface of a poly(3,4 ethylenedioxythiophene and sodium 4-styrenesulfonate)/Au microtube (PEDOT PSS/Au). The catalase assembly was achieved by programmed DNA hybridization, which was performed by immobilizing a designed sandwich DNA structure as the sensing unit on the PEDOT-PSS/Au, and then alternately hybridizing with two assisting DNA to bind the enzyme for efficient motor motion. The micromotor device showed unique features of good reproducibility, stability and motion performance. Under optimal conditions, it showed a speed of 420 MUm s-1 in 2% H2O2 and even 51 MUm s-1 in 0.25% H2O2. In the presence of target DNA, the sensing unit hybridized with target DNA to release the multi-layer DNA as well as the multi-catalase, resulting in a decrease of the motion speed. By using the speed as a signal, the micromotor device could detect DNA from 10 nM to 1 MUM. The proposed micromotor device along with the cyclic alternate DNA hybridization assembly technique provided a new path to fabricate efficient and versatile micromotors, which would be an exceptional tool for rapid and simple detection of biomolecules. PMID- 28639654 TI - Fast & easy preparation of 3D scaffolds from methyl benzoate by a diversity oriented synthesis strategy based on Diels-Alder and ene-reactions. AB - Thermic dimerization of methyl 1,3-cyclohexadiene 2-carboxylate gave original 3D shape compounds by Diels-Alder cycloaddition and original [6 + 4]-ene reaction. Further selective modifications on an endo [4 + 2] cycloadduct via a diversity oriented synthesis (DOS) strategy quickly led to the preparation of a small library of original 3D scaffolds, providing access to a larger and unexplored chemical space for drug discovery processes. PMID- 28639656 TI - Orthogonal electronic coupling in multicentre arylamine mixed-valence compounds based on a dibenzofulvene-thiophene conjugated bridge. AB - Herein we present organic mixed-valence compounds with an innovative H-shape design, where four redox centres are bridged "vertically" via a dibenzofulvene backbone and "horizontally" via a bis-(dibenzofulvene)-thiophene bridge. These compounds are easily oxidized to stable highly charged radical species which show intense intervalence charge transfer transitions in the near infrared region. Interestingly, depending on the position of the arylamine substituents on the bridge, both vertical and horizontal electron transfer pathways can be optically induced. PMID- 28639657 TI - Exploring the catalytic mechanism of dihydropteroate synthase: elucidating the differences between the substrate and inhibitor. AB - Dihydropteroate synthase (DHPS) catalyzes the condensation of 6-hydroxymethyl-7,8 dihydropterin pyrophosphate (DHPPP) with p-aminobenzoic acid (pABA) and is a well validated target for anti-malarial and anti-bacterial drugs. However, in recent years its utility as a therapeutic target has diminished considerably due to multiple mutations. As such, considerable structural biology and medicinal chemistry effort has been expended to understand and overcome this issue. To date no detailed computational analysis of the protein mechanism has been made despite the detailed crystal structures and multiple mechanistic proposals being made. In this study the mechanistic proposals for DHPS have been systematically investigated using a hybrid QM/MM method. We aimed to compare the energetics associated with SN1 and SN2 processes, whether the SN1 process involves a carbocation or neutral DHP intermediate, uncover the identity of the general base in the catalytic mechanism, and understand the differences in substrate vs. inhibitor reactivity. Our results suggest a reaction that follows an SN1 process with the rate determining step being C-O bond breaking to give a carbocation intermediate. Comparative studies on the inhibitor STZ confirm the experimental observations that it is also a DHPS substrate. PMID- 28639658 TI - Control on the photo-responsive assembly of a stilbene-containing amphiphile by using pillar[5]arene-based host-guest interactions. AB - A supra-amphiphilic system with a tunable supra-amphiphilic type and self assembled morphology was constructed and controlled via light and host-guest interactions based on a water-soluble pillar[5]arene and a stiff-stilbene. PMID- 28639659 TI - Hydrothermal and biomineralization synthesis of a dual-modal nanoprobe for targeted near-infrared persistent luminescence and magnetic resonance imaging. AB - The development of the multimodal probes is of great importance for bioimaging application. Herein, we report the fabrication of a functional nanocomposite from near-infrared (NIR) persistent luminescent nanoparticles (PLNPs) and Gd2O3 as a multimodal probe for in vivo NIR persistent luminescence and magnetic resonance (MR) imaging. Small-sized monodispersed NIR ZnGa2O4:Cr3+ PLNPs (ca. 15 nm) were prepared as the NIR persistent luminescence source by a hydrothermal method while hyaluronic acid (HA) functionalized Gd2O3 (HA-Gd2O3) was synthesized as the MR contrast agent via a biomineralization approach. An EDC/NHS coupling strategy was used to connect the amino functionalized PLNPs and the HA-Gd2O3 to give the HA functionalized multimodal probe. The multimodal probe not only exhibits an excellent NIR persistent luminescence signal, but also exhibits larger longitudinal relaxivity (7.38 mM-1 s-1) than commercial contrast agent Gd-DTPA. Moreover, the HA moieties not only enhance the biocompatibility of the multimodal probe, but also endow the probe with tumor-targeting capability. Both in vitro and in vivo bioimaging experiments demonstrate the potential of the multimodal probe for tumor-targeting NIR persistent luminescence and MR imaging. PMID- 28639660 TI - A flexible, robust and antifouling asymmetric membrane based on ultra-long ceramic/polymeric fibers for high-efficiency separation of oil/water emulsions. AB - Polymeric and ceramic asymmetric membranes have dominated commercial membranes for water treatment. However, polymeric membranes are prone to becoming fouled, while ceramic membranes are mechanically fragile. Here, we report a novel concept to develop asymmetric membranes based on ultra-long ceramic/polymeric fibers, with the combined merits of good mechanical stability, excellent fouling resistance and high oil/water selectivity, in order to meet the stringent requirements for practical oil/water separation. The ultra-long dimensions of ceramic nanofibers/polymeric microfibers endow this novel membrane with mechanical flexibility and robustness, due to the integrated and intertwined structure. This membrane is capable of separating oil/water emulsions with high oil-separation efficiency (99.9%), thanks to its nanoporous selective layer made of ceramic nanofibers. Further, this membrane also displays superior antifouling properties due to its underwater superoleophobicity and ultra-low oil adhesion of the ceramic-based selective layer. This membrane exhibits high water permeation flux (6.8 * 104 L m-2 h-1 bar-1) at low operation pressures, which is attributed to its 3-dimensional (3D) interconnected fiber-based structure throughout the membrane. In addition, the facile fabrication process and inexpensive materials required for this membrane suggest its significant potential for industrial applications. PMID- 28639661 TI - Ferrocene-BODIPYmerocyanine dyads: new NIR absorbing platforms with optical properties susceptible to protonation. AB - Ferrocene-BODIPYmerocyanine dyads 5 and 6 were prepared and characterized by a variety of spectroscopic, electrochemical, and theoretical methods. Experimental and theoretical data on these NIR absorbing compounds are suggestive of unusual susceptibility (for BODIPY chromophores) of the delocalized pi-system in 5 and 6 to protonation and low-potential oxidation of their pi-systems. PMID- 28639662 TI - Recent progress in the catalytic carbene insertion reactions into the silicon hydrogen bond. AB - The following review will explore the historical development of Si-H bond insertion reactions, giving an up-to-date account on the metal catalysts often employed, in addition to an assessment of their strengths and weaknesses. Diazo compounds have great synthetic potential as versatile reagents for the formation of metal carbenes, allowing the selective formation of C-C and C-heteroatom bonds and thus the introduction of functional groups into organic molecules. C-Si bond forming methods, that introduce silicon motifs into organic molecules, rely on catalysts derived from metals such as rhodium, copper, iridium, silver, ruthenium, and iron to achieve the desired activities and selectivities. PMID- 28639663 TI - The electronic transport properties of zigzag phosphorene-like MX (M = Ge/Sn, X = S/Se) nanostructures. AB - Single-layer phosphorene-like MX sheets have aroused new interest and could become a family of nanomaterials in physics and materials science. Using a first principles method combined with non-equilibrium Green's function (NEGF) theory, we study the electronic transport properties of the zigzag phosphorene-like MX (M = Ge/Sn, X = S/Se) nanostructures. The results demonstrate that GeS and GeSe nanoribbons display very similar electronic transport properties. Their current voltage (I-V) curves exhibit an interesting negative differential resistive (NDR) effect and are insensitive to their ribbon widths due to their similar band structures. However, for SnS and SnSe nanoribbons, their electronic transport properties are obviously dependent on their ribbon widths due to their different band structures. Most of the SnS nanoribbons display the current-limited effect. SnSe nanoribbons could also present a NDR effect, which appeared at a lower applied bias. The currents mainly propagate through the phosphorene-like MX nanoribbons along the metal-termination, while little along the S/Se-termination. Moreover, their two-dimensional monolayers present an obvious difference from their one-dimensional structures. These phosphorene-like MX nanostructures have potential applications in nanoelectronics, and could become candidates for nanodevices, such as NDR devices. PMID- 28639664 TI - Double duplex invasion of DNA induced by ultrafast photo-cross-linking using 3 cyanovinylcarbazole for antigene methods. AB - In the creation of double duplex formation with genomic DNA, the probe must be able to invade and hybridize to the duplex DNA. We designed new photoresponsive probes containing CNVK and CNU; these probes have a high double-duplex invasion capability upon photoirradiation. PMID- 28639665 TI - Isolation and identification of l/d-lactate-conjugated bufadienolides from toad eggs revealing lactate racemization in amphibians. AB - Three pairs of bufadienolide l/d-lactate epimers (1-6) were isolated from the eggs of the toad Bufo bufo gargarizans. The structures were elucidated by using spectroscopic methods, X-ray diffraction analysis and a modified Mosher's method. Compounds 1-6 represent the first occurrence of lactate-conjugated bufadienolides in nature, and illustrate the existence of an enzyme-controlled epimerization from l- to d-lactate in amphibians. The biosynthetic pathways, in which two key enzymes might be involved (i.e., lactate racemase and acyltransferase), were proposed. In addition, the biological assays revealed that compounds 1-4 are potent cytotoxic agents against human gastric cancer cells BGC-823 and human lung cancer cells A549 with IC50 values in a range of 8.0 to 80.0 nM. PMID- 28639666 TI - Conformational landscape of the SF6 dimer as revealed by high resolution infrared spectroscopy and complexation with rare gas atoms. AB - Taking advantage of a versatile set-up, combining pulsed pin hole or slit nozzle supersonic expansion with an external cavity quantum cascade laser, the rovibrational absorption spectrum of the SF6 dimer in the nu3 mode region has been revisited at high resolution under various experimental conditions in SF6:He mixtures. Two new rotationally resolved spectral bands have been identified in the range of the parallel band of the dimer spectrum in addition to that previously reported. Among these three spectral features, two of them are assigned to conformations of the dimer (noted #1 and #2), clearly distinguished from their different S-S interatomic distances, i.e. 474 and 480 pm respectively. The third one is assigned to a (SF6)2-He complex, from comparison with additional experiments in which (SF6)2-Rg heterotrimers (Rg = Ne, Ar, Kr, Xe) are observed. A schematic picture of the potential energy landscape of the SF6 dimer in terms of a nearly flat surface is proposed to account for the conformational relaxation observed in the expansions and for the structure of the (SF6)2-Rg heterotrimers, which are exclusively formed from the conformer #2 dimer. Although modelling qualitatively supports this picture, much effort has still to be achieved from a theoretical point of view to reach a quantitative agreement with the present benchmark experimental data both in terms of structure and energetics. PMID- 28639667 TI - Recent progress in surface-enhanced Raman spectroscopy for biological and biomedical applications: from cells to clinics. AB - The application of surface-enhanced Raman spectroscopy (SERS) in biological and biomedical detection schemes is feasible due to its excellent molecular specificity and high sensitivity as well as the capability of SERS to be performed in complex biological compositions. SERS-based investigation of cells, which are the basic structure and functional unit of organisms, represents the starting point of this review. It is demonstrated that SERS provides a deep understanding of living cells as well as their microenvironment which is needed to assess the development of diseases. The clinical relevance of SERS is proved by its application for the detection of cancer cells and tumour margins under in vivo conditions and examples for theranostic approaches are discussed. This review article provides a comprehensive overview of the recent progress within the last 3 years. PMID- 28639668 TI - A strategy for fabrication of controllable 3D pattern containing clusters and nanoparticles inside a solid material. AB - Directly controlling the growth process of clusters and nanoparticles is an effective way to tune their specific properties, which has been considered as a significant issue lying at the heart of nanotechnology. For technological applications, great strides have been made in the assembly of clusters and nanoparticles. However, controllable synthesis of clusters and nanoparticles inside a bulk solid-state medium remains a tremendous challenge, which is important for integrated devices. Here we report a strategy for space-selective control of elemental tellurium (Te) precipitation as clusters or nanoparticles in glass by femtosecond (fs) laser irradiation. After irradiation by a 1 kHz fs laser at 800 nm, Te2 clusters, which emit near-infrared (NIR) light, are observed at the focal point of the laser beam inside the glass sample. By shifting the repetition rate to 250 kHz, a temperature field forms around the focal area that facilitates transformation of Te clusters into nanoparticles. Raman mapping shows that the clusters are localized in the center of the laser-induced microstructure, while the nanoparticles exhibit an annular distribution. The possible mechanisms of generation and distribution of different species are discussed. We have also demonstrated optical data storage and embedded micro grating by using this technique. PMID- 28639669 TI - Plasmon-enhanced fluorescence spectroscopy. AB - Fluorescence spectroscopy with strong emitters is a remarkable tool with ultra high sensitivity for detection and imaging down to the single-molecule level. Plasmon-enhanced fluorescence (PEF) not only offers enhanced emissions and decreased lifetimes, but also allows an expansion of the field of fluorescence by incorporating weak quantum emitters, avoiding photobleaching and providing the opportunity of imaging with resolutions significantly better than the diffraction limit. It also opens the window to a new class of photostable probes by combining metal nanostructures and quantum emitters. In particular, the shell-isolated nanostructure-enhanced fluorescence, an innovative new mode for plasmon-enhanced surface analysis, is included. These new developments are based on the coupling of the fluorophores in their excited states with localized surface plasmons in nanoparticles, where local field enhancement leads to improved brightness of molecular emission and higher detection sensitivity. Here, we review the recent progress in PEF with an emphasis on the mechanism of plasmon enhancement, substrate preparation, and some advanced applications, including an outlook on PEF with high time- and spatially resolved properties. PMID- 28639671 TI - Construction of unique two-dimensional MoS2-TiO2 hybrid nanojunctions: MoS2 as a promising cost-effective cocatalyst toward improved photocatalytic reduction of CO2 to methanol. AB - Two-dimensional MoS2 nanosheets were in situ grown on TiO2 nanosheets to form two dimensional (2D) hybrid nanojunctions, with which MoS2 nanosheets compactly contact with TiO2 to increase the interfacial area. MoS2 was identified as a promising cost-effective substitute for noble metal cocatalysts such as Pt, Au, and Ag, and shows superior activity and selectivity for reducing CO2 to CH3OH in aqueous solution to these metal cocatalysts under UV-vis light irradiation. The photo-luminescence (PL) spectra and transient time-resolved PL decay measurements reveal that the fast electron transfer from TiO2 to MoS2 can minimize charge recombination losses to improve the conversion efficiency of photoreduction. It reveals that Mo-terminated edges of MoS2 nanosheets possess the metallic character and a high d-electron density, and the Mo cation sites may benefit the stabilization of CHxOy intermediates via electrostatic attraction to enhance the CH3OH formation from the reduction of CO2 in aqueous solution. PMID- 28639672 TI - Imaging biofilm-encased microorganisms using carbon dots derived from L. plantarum. AB - Imaging biofilm-encased microorganisms is challenging due to them being shielded by a sticky and strong extracellular polymeric substance matrix that blocks the penetration of dyes, but is especially important for biofilm study. Here, carbon dots, namely CDs-605, were used for successfully imaging biofilm-encased microorganisms. We demonstrated that such CDs-605 could be easily synthesized from L. plantarum by one-step hydrothermal carbonization. The negatively charged CDs-605 were composed of C, H, O, N, P, and S and contained various functional groups, including -OH, -COOH, and -CONH-. For the first time, CDs-605 were found to be capable of imaging biofilm-encased microorganisms, including E. coli, S. oneidensis, P. aeruginosa, S. aures, and T. reesei, demonstrating that the labeling is universal. The labeling method based on CDs-605 did not require incubation, protection from light, or washing, which makes it very convenient. Additionally, CDs-605 did not disturb the biofilm and displayed better photostability compared to the commercial counterpart. CDs-605 can serve as a simple, yet powerful staining agent for biofilm-embedded microorganism imaging, which is vital for gaining a fundamental understanding of biofilm formation and dispersal. PMID- 28639673 TI - Observing the real time formation of phosphine-ligated gold clusters by electrospray ionization mass spectrometry. AB - The early stages of reduction and nucleation of ligated gold clusters in solution are largely unknown due, in part, to high reaction rates and the inherent complexity of the process. This study demonstrates that the addition of a diphosphine ligand, 1-4-bis(diphenylphosphino)butane (L4) to a methanolic solution of the gold precursor, chloro(triphenylphosphine)gold(I) (Au(PPh3)Cl), results in the initial formation of organometallic complexes of the type [Au(L4)x(L4O)y(PPh3)z]+. These initial complexes lower the rate of gold reduction so that the reaction can be directly monitored over time from 1 min to over an hour using on-line electrospray ionization mass spectrometry (ESI-MS). The results indicate that the formation of cationic Au8(L4)42+, Au9(L4)4H2+ and Au10(L4)52+ clusters occurs through specific reaction pathways that may be kinetically controlled by varying either the concentration of reducing agent or the extent of L4 oxidation. Comparison of selected ion chronograms indicates that Au2(L4)2H+ may be an intermediate in the formation of Au8(L4)42+ and Au10(L4)52+ while a variety of chlorinated clusters may be involved in the formation of Au9(L4)4H2+. Additionally, high resolution mass spectrometry enabled the identification of 53 new gold containing species produced under highly oxidative conditions. New intermediate species were identified which aid the understanding of how different size gold clusters may be stabilized during the growth process. PMID- 28639674 TI - Transition from disordered aggregates to ordered lattices: kinetic control of the assembly of a computationally designed peptide. AB - Natural biomolecular self-assembly typically occurs under a narrow range of solution conditions, and the design of sequences that can form prescribed structures under a range of such conditions would be valuable in the bottom-up assembly of predetermined nanostructures. We present a computationally designed peptide that robustly self-assembles into regular arrays under a wide range of solution pH and temperature conditions. Controling the solution conditions provides the opportunity to exploit a simple and reproducible approach for altering the pathway of peptide solution self-assembly. The computationally designed peptide forms a homotetrameric coiled-coil bundle that further self assembles into 2-D plate structures with well-defined inter-bundle symmetry. Herein, we present how modulation of solution conditions, such as pH and temperature, can be used to control the kinetics of the inter-bundle assembly and manipulate the final morphology. Changes in solution pH primarily influence the inter-bundle assembly by affecting the charged state of ionizable residues on the bundle exterior while leaving the homotetrameric coiled-coil structure intact. At low pH, repulsive interactions prevent 2-D lattice nanostructure formation. Near the estimated isoelectric point of the peptide, bundle aggregation is rapid and yields disordered products, which subsequently transform into ordered nanostructures over days to weeks. At elevated temperatures (T = 40 degrees C or 50 degrees C), the formation of disordered, kinetically-trapped products largely can be eliminated, allowing the system to quickly assemble into plate-like nanostructured lattices. Moreover, subtle changes in pH and in the peptide charge state have a significant influence on the thickness of formed plates and on the hierarchical manner in which plates fuse into larger material structures with observable grain boundaries. These findings confirm the ability to finely tune the peptide assembly process to achieve a range of engineered structures with one simple 29-residue peptide building block. PMID- 28639675 TI - Trash to treasure: converting plastic waste into a useful graphene foil. AB - Recycling of plastic waste has commercial value and practical significance for both environmental safety and recovery of resources. To realize trash recycling, a cheap, simple, and safe solid-state chemical vapor deposition method has been developed to convert a series of daily plastic wastes to a high quality graphene foil (GF) at a large scale. The GF possesses a high electrical conductivity of 3824 S.cm-1, which is much higher than that of the conventional free-standing graphene film treated at an extremely high temperature of 2200-2500 degrees C. Further, the GF can act as various flexible elements such as a free-standing electrode in a foldable lithium-ion battery, which shows stable electrochemical performances. On the other hand, it presents a fast and ultra low-voltage responsivity to be used as a flexible electrothermal heater, which generates a temperature of up to 322.6 degrees C at a low input voltage of only 5 V. The convenient trash-to-treasure conversion of plastics to GF provides a unique pathway for waste recycling and opens new application possibilities of graphene in various fields. PMID- 28639676 TI - Diastereoselective [3 + 2] cycloaddition of 3-ylideneoxindoles with in situ generated CF2HCHN2: syntheses of CF2H-containing spirooxindoles. AB - An efficient [3 + 2] cycloaddition of 3-ylideneoxindoles with in situ generated CF2HCHN2 for the syntheses of spirooxindoles has been developed. This methodology gives access to a range of relatively complex spirooxindoles featuring a CF2H group and three contiguous stereogenic centers in up to 84% yield and 99 : 1 trans/cis. PMID- 28639677 TI - Detection of single metal nanoparticle collision events in non-aqueous media. AB - In this work, the detection of metal nanoparticle collision events in a non aqueous solvent-here, toluene and acetonitrile-using gold nanoparticles and a platinum ultramicroelectrode (UME) is reported. The collisions were monitored by the oxidation of tri-n-propylamine (TPrA) under diffusion-dominated conditions. Based on the current response, it was observed that the current steps were indicative of a mediated Faradaic reaction. Current steps as small as 1-2 pA could be clearly observed. Larger current steps were caused by agglomeration of the nanoparticles attributed to the polarity of the mixed solvent. The experimentally observed collisions per second ranged from 0.07 to 0.51, indicating that particle agglomeration in solution occurs rapidly, reversibly and can subsequently cause rapid and, often, repeated collisions. PMID- 28639678 TI - Nitrogen-doped graphene anchored with mixed growth patterns of CuPt alloy nanoparticles as a highly efficient and durable electrocatalyst for the oxygen reduction reaction in an alkaline medium. AB - A highly active and durable CuPt alloy catalyst with trigonal bipyramidal and truncated cube-type mixed morphologies, anchored on the nitrogen-doped graphene (NGr) surface (CuPt-TBTC/NGr), was prepared by a simple and fast method. The obtained CuPt alloy showed improved oxygen reduction reaction (ORR) activity, with a 30 mV positive shift in the half-wave potential value, as compared to the state-of-the-art Pt/C catalyst in a 0.1 M KOH solution. The CuPt alloy with the trigonal bipyramidal morphology possesses porous type inter-connected sides, which help to achieve improved mass transport of oxygen during the ORR. The exposure of the (111) plane of the CuPt alloy further improved the catalytic activity towards the dioxygen reduction in alkaline media. The ORR activity of the NGr-supported CuPt alloy was found to be dependent on the reaction time, and improved activity was obtained on the material derived at a reaction time of 90 min (CuPt-TBTC/NGr-90). The material synthesized at a lower or higher reaction time than 90 min resulted in a partially formed trigonal bipyramidal morphology with more truncated cubes or agglomerated trigonal bipyramidal and truncated cubes with closed type structures, respectively. Along with the high intrinsic ORR activity, CuPt-TBTC/NGr-90 displayed excellent electrochemical stability. Even after repeated 1000 potential cycling in a window ranging from 0.10 to 1.0 V (vs. RHE), the system clearly outperformed the state-of-the-art Pt/C catalyst with 15 and 60 mV positive shifts in the onset and half-wave potentials, respectively. CuPt-TBTC/NGr-90 also exhibited 2.1 times higher mass activity and 2.2 times higher specific activity, compared to Pt/C at 0.90 V (vs. RHE). Finally, a zinc-air battery fabricated with the alloy catalyst as the air electrode displayed a peak power density of 300 mW cm-2, which is much higher than the peak power density of 253 mW cm-2 obtained for the state-of-the-art Pt/C catalyst as the air electrode. PMID- 28639679 TI - On the feasibility of reactions through the fullerene wall: a theoretical study of NHx@C60. AB - We propose a new approach to the synthesis of AHx@fullerene structures via reactions through the fullerene wall. To investigate the feasibility of the approach, the step-by-step hydrogenation of the template endofullerene N@C60 up to NH4@C60 has been studied using DFT and MP2 calculations. Protonation of the endohedral guest through the fullerene wall is competitive with escape of the guest, whereas reaction with a hydrogen atom is less favorable. Each protonation step is highly exothermic, so that less active acids can also protonate the guest with less accumulation of energy. The final product, NH4@C60 is a novel concentric ion pair NH4+@C60- in which the charge-centers of the two ions coincide. PMID- 28639680 TI - Anticancer luminescent gold quantum clusters for in situ cancer-selective marking imaging-targeting. AB - Ultrafine Au quantum clusters (QCs) were synthesized by etching host Au nanoparticles in the presence of ethylenediamine (en) and exhibited both strong photoluminescence (PL) and specific anticancer activity. The cutting-edge feature of this QC compound comprises subnanometer-size rhombohedral Au8, which consists of 8 units of the anticancer motif, namely, an Au+(en) complex (Au(en)QCs), which contributes to photo- and physicochemical stability as well as subcellular theranostic activity in intracellular PL imaging and in situ targeting. Moreover, the Au(en)QCs can be surface-encapsulated by transferrins (Tf) to create TfAu(en)QCs as a multipurpose drug carrier owing to numerous merits, which include cancer-selective biolabeling, high loading/release efficiency, high activity against drug-resistant tumor cells, low toxicity to normal cells, and physiological stability against biothiols, e.g., glutathiones. These versatile features, which are due to intrinsic optical and anticancer properties, provide potential as a single-drug delivery PL probe for preclinical applications, which has yet to be achieved using conventional nanoclusters. PMID- 28639681 TI - Electrical and optical behaviors of SiC(GeC)/MoS2 heterostructures: a first principles study. AB - Hybrid structures have attracted a great deal of attention because of their excellent properties, which can open up a way we could not foresee in materials science and device physics. Here, we investigate the electrical and optical behaviors of SiC(GeC)/MoS2 heterostructures, using first principles calculations based on density functional theory. Non-covalent bonding exists between the junctions due to the weak orbital coupling. Both junctions have optically active band gaps, smaller than that of the SiC or GeC and MoS2 layers, which result in enhanced optical adsorption under visible-light irradiation. A small number of electrons transfer from SiC/GeC to MoS2 causing its n-doping. Furthermore, the charge density states of the valence band maximum and the conduction band minimum are localized at different sides, and thus the electron-hole pairs are spatially separated. Our results provide a potential scheme for photovoltaic materials. PMID- 28639682 TI - Introduction to Force-Dependent Kinematics: Theory and Application to Mandible Modeling. AB - Knowledge of the muscle, ligament, and joint forces is important when planning orthopedic surgeries. Since these quantities cannot be measured in vivo under normal circumstances, the best alternative is to estimate them using musculoskeletal models. These models typically assume idealized joints, which are sufficient for general investigations but insufficient if the joint in focus is far from an idealized joint. The purpose of this study was to provide the mathematical details of a novel musculoskeletal modeling approach, called force dependent kinematics (FDK), capable of simultaneously computing muscle, ligament, and joint forces as well as internal joint displacements governed by contact surfaces and ligament structures. The method was implemented into the anybody modeling system and used to develop a subject-specific mandible model, which was compared to a point-on-plane (POP) model and validated against joint kinematics measured with a custom-built brace during unloaded emulated chewing, open and close, and protrusion movements. Generally, both joint models estimated the joint kinematics well with the POP model performing slightly better (root-mean-square deviation (RMSD) of less than 0.75 mm for the POP model and 1.7 mm for the FDK model). However, substantial differences were observed when comparing the estimated joint forces (RMSD up to 24.7 N), demonstrating the dependency on the joint model. Although the presented mandible model still contains room for improvements, this study shows the capabilities of the FDK methodology for creating joint models that take the geometry and joint elasticity into account. PMID- 28639683 TI - ? AB - Oral lichen planus is a relatively common T-cell mediated inflammatory disease with potential malignant transformation. It may present itself with pain and oral lesions such as ulcers and Wickham?s striae. Treatment includes topical corticosteroids, preferably Clobetasol, immunosuppressive drugs and retinoids. Hyaluronic acid and aloe vera have been proven to be successful. If topical treatment fails, systemic therapy with corticosteroids may be needed. Because of the potential malignant transformation periodic follow-up is mandatory. PMID- 28639684 TI - ? AB - Pyostomatitis vegetans is a disease of the gingiva and the oral mucosa with noticeable, uncommon morphology. Clinical characteristics of this rare disease and considerations regarding differential diagnosis are described. Pyostomatitis vegetans is frequently associated with chronic inflammatory bowel diseases and can, thus, give a diagnostic hint at an existing ulcerative colitis or Crohn?s disease. A therapy plan for pyostomatitis vegetans is presented, which led to remission using local treatment only. The follow-up examination after one year showed that the treatment outcome had remained stable. An unexpected clinical appearance of the gingiva with small, pale pink thickenings after therapy and at follow-up is portrayed. PMID- 28639685 TI - ? PMID- 28639686 TI - ? AB - The comprehensive dental rehabilitation of complex prosthetic cases is often associated with increasing occlusal vertical dimension and transferring horizontal mandibular position in centric relation. The newly defined position of the mandibula should be functionally and esthetically evaluated for a longer time period before irreversible measures are performed. This case report discusses in detail a time-saving and economic direct method for increasing occlusal vertical dimension with long-term provisional composite restorations using a simplified injection molding technique and illustrates the complete intraoral and laboratory workflow. PMID- 28639687 TI - Risk indicators of early childhood caries (ECC) in children with high treatment needs. AB - Early childhood caries (ECC) represents a major health and economic problem worldwide. Its consequences such as early pain experience may affect the immediate and long-term quality of life of the child. In very young and uncooperative children the therapy of ECC is often viable only under general anesthesia. After treatment these affected children have a higher risk for future caries either soon thereafter, or later in life. The aim of the present study was to determine risk indicators and their correlation among children with high caries prevalence and high treatment needs, in order to facilitate the development of targeted prophylaxis programs that would reduce future occurrences of ECC or at least positively influence the outcome. For this purpose, between 2010 and 2014 the parents of these children (n=82) were interviewed in the University Children?s Hospital in Basel (UKBB) prior to the children?s treatment under general anesthesia. The standardized questionnaire included questions regarding the age of the child, the mother?s country of origin, the oral hygiene, and the drinking habits of the child. The analysis shows that the high mean dmft/ dmfs values (dmft: 9.49 and dmfs: 26.35) correlated significantly with the geographic origin of the mother (p<0.05), the beginning of tooth brushing (p<0.05), lack of supervised tooth brushing (p<0.01), and nighttime consumption of sugar-sweetened beverages (p<0.05). In contrast, the duration of breastfeeding and prolonged use of a baby bottle (about 2.5 years) did not have a clear impact on high caries prevalence. PMID- 28639688 TI - Pronounced limb and fibre type differences in subcellular lipid droplet content and distribution in elite skiers before and after exhaustive exercise. AB - KEY POINTS: Although lipid droplets in skeletal muscle are an important energy source during endurance exercise, our understanding of lipid metabolism in this context remains incomplete. Using transmission electron microscopy, two distinct subcellular pools of lipid droplets can be observed in skeletal muscle - one beneath the sarcolemma and the other between myofibrils. At rest, well-trained leg muscles of cross-country skiers contain 4- to 6-fold more lipid droplets than equally well-trained arm muscles, with a 3-fold higher content in type 1 than in type 2 fibres. During exhaustive exercise, lipid droplets between the myofibrils but not those beneath the sarcolemma are utilised by both type 1 and 2 fibres. These findings provide insight into compartmentalisation of lipid metabolism within skeletal muscle fibres. ABSTRACT: Although the intramyocellular lipid pool is an important energy store during prolonged exercise, our knowledge concerning its metabolism is still incomplete. Here, quantitative electron microscopy was used to examine subcellular distribution of lipid droplets in type 1 and 2 fibres of the arm and leg muscles before and after 1 h of exhaustive exercise. Intermyofibrillar lipid droplets accounted for 85-97% of the total volume fraction, while the subsarcolemmal pool made up 3-15%. Before exercise, the volume fractions of intermyofibrillar and subsarcolemmal lipid droplets were 4- to 6-fold higher in leg than in arm muscles (P < 0.001). Furthermore, the volume fraction of intermyofibrillar lipid droplets was 3-fold higher in type 1 than in type 2 fibres (P < 0.001), with no fibre type difference in the subsarcolemmal pool. Following exercise, intermyofibrillar lipid droplet volume fraction was 53% lower (P = 0.0082) in both fibre types in arm, but not leg muscles. This reduction was positively associated with the corresponding volume fraction prior to exercise (R2 = 0.84, P < 0.0001). No exercise-induced change in the subsarcolemmal pool could be detected. These findings indicate clear differences in the subcellular distribution of lipid droplets in the type 1 and 2 fibres of well-trained arm and leg muscles, as well as preferential utilisation of the intermyofibrillar pool during prolonged exhaustive exercise. Apparently, the metabolism of lipid droplets within a muscle fibre is compartmentalised. PMID- 28639689 TI - Management of severe suprastomal collapse with bioabsorbable microplates. PMID- 28639690 TI - Variation in host preferences of malaria mosquitoes is mediated by skin bacterial volatiles. AB - The host preferences of the anthropophilic mosquito species in the Anopheles gambiae complex (Diptera: Culicidae) are mediated by skin bacterial volatiles. However, it is not known whether these mosquitoes respond differentially to skin bacterial volatiles from non-human host species. In this study, the responses of two malaria mosquito species in the An. gambiae complex, Anopheles gambiae s.s. (hereafter, An. gambiae) and Anopheles arabiensis, with different host preferences, to volatiles released from skin bacteria were tested. Skin bacteria collected from human, cow and chicken skin significantly increased trap catches; traps containing bacteria collected from human skin caught the highest proportions of An. gambiae and An. arabiensis. Traps with bacteria of human origin caught a significantly higher proportion of An. gambiae than of An. arabiensis, whereas bacterial volatiles from the chicken attracted significantly higher numbers of An. arabiensis than of An. gambiae. Additionally, An. gambiae showed a specialized response to volatiles from four specific bacteria, whereas An. arabiensis responded equally to all species of bacteria tested. Skin bacterial volatiles may therefore play important roles in guiding mosquitoes with different host preferences. The identification of these bacterial volatiles can contribute to the development of an odour blend that attracts mosquitoes with different host preferences. PMID- 28639691 TI - Distinct controls of leaf widening and elongation by light and evaporative demand in maize. AB - Leaf expansion depends on both carbon and water availabilities. In cereals, most of experimental effort has focused on leaf elongation, with essentially hydraulic effects. We have tested if evaporative demand and light could have distinct effects on leaf elongation and widening, and if short-term effects could translate into final leaf dimensions. For that, we have monitored leaf widening and elongation in a field experiment with temporary shading, and in a platform experiment with 15 min temporal resolution and contrasting evaporative demands. Leaf widening showed a strong (positive) sensitivity to whole-plant intercepted light and no response to evaporative demand. Leaf elongation was (negatively) sensitive to evaporative demand, without effect of intercepted light per se. We have successfully tested resulting equations to predict leaf length and width in an external dataset of 15 field and six platform experiments. These effects also applied to a panel of 251 maize hybrids. Leaf length and width presented quantitative trait loci (QTLs) whose allelic effects largely differed between both dimensions but were consistent in the field and the platform, with high QTL * Environment interaction. It is therefore worthwhile to identify the genetic and environmental controls of leaf width and leaf length for prediction of plant leaf area. PMID- 28639692 TI - The Role of Mothers' Child-Based Worth in Their Affective Responses to Children's Performance. AB - This research examined whether American and Chinese mothers' tendencies to base their worth on children's performance contributes to their affective responses to children's performance. Study 1 used daily interviews to assess mothers' warmth (vs. hostility) and children's school performance (N = 197; Mage = 12.81 years). In Study 2, such affect was observed in the laboratory following children's manipulated performance on cognitive problems (N = 128; Mage = 10.21 years). The more mothers based their worth on children's performance, the more their warmth (vs. hostility) decreased when children failed in Study 1. This pattern was evident only among Chinese mothers in Study 2. In both studies, child-based worth did not contribute to mothers' affective responses to children's success. PMID- 28639693 TI - Thromboelastography may predict risk of grade 2 bleeding in thrombocytopenic patients. AB - BACKGROUND AND OBJECTIVES: Platelet count is used as a prophylactic platelet transfusion trigger, although evidence suggests that it is a poor predictor of bleeding. Thus, alternative tests are required. The primary objective of this study was to compare thromboelastography (TEG) parameters on days with and without bleeding symptoms. The secondary objectives were to investigate the relationship between TEG parameters and haematological variables, fever, C reactive protein (CRP) and platelet transfusion. MATERIALS AND METHODS: This is a prospective, observational pilot study of 13 thrombocytopenic, haemato-oncologic patients, over 17 cycles of chemotherapy. Bleeding assessment was performed daily together with a total platelet count (TPC), reticulated platelet per cent (RPP) and count (RPC), haemoglobin, mean platelet volume, white blood cell count (WBC), CRP and temperature. TEG analyses were performed on weekdays. RESULTS: TEG alpha angle was significantly lower on days with World Health Organization (WHO) grade 2 bleeding than on days without bleeding. Haematologic variables, CRP and platelet transfusion the previous day were associated with the outcome of TEG analysis, but fever was not. CONCLUSION: We found a highly significant correlation between the TEG alpha angle and WHO grade 2 bleeding. This finding suggests that fibrinogen-platelet interactions may affect the bleeding risk in thrombocytopenic patients. PMID- 28639694 TI - Rancidity development of refrigerated rainbow trout (Oncorhynchus mykiss) fillets: comparative effects of in vivo and in vitro lycopene. AB - BACKGROUND: The problem of lipid oxidation in fish during storage is well known and is related to both temperature and storage time. Antioxidants could have a main role in limiting the deteriorative effects of lipid oxidation in fish. The present study aimed to investigate the effect of dietary supplement against postmortem addition of lycopene on the deterioration of trout fillets during storage at 4 +/- 1 degrees C for 12 days. RESULTS: At the end of the feeding trial, no significant differences were observed with respect to the fatty acid composition of different dietary groups. However, a strong positive correlation (r = 0.96) was observed between fillet and diet lycopene levels. Lower indices of lipid oxidation (peroxide value and thiobarbituric acid) and lipid hydrolysis (free fatty acids) were observed in fillets that received lycopene (P < 0.05). Although exogenous lycopene was more effective (P < 0.05) than endogenous lycopene in delaying lipid oxidation, the fatty acid composition of fillets that received dietary lycopene supplement showed a higher stability (P < 0.05) during refrigeration storage. CONCLUSION: Accordingly, based on the time of appearance of off-odors and discoloration in fish fillets, exogenous lycopene, especially at higher levels, was more effective in terms of quality parameters. (c) 2017 Society of Chemical Industry. PMID- 28639695 TI - Glycogen synthase kinase-3beta ablation limits pancreatitis-induced acinar-to ductal metaplasia. AB - Acinar-to-ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase-3beta (GSK-3beta) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK 3beta promotes TGF-alpha-induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK-3beta attenuates caerulein-induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK 3beta ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas-driven cell proliferation. Mechanistically, we show that GSK-3beta regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK-3beta participates in early pancreatitis-induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28639697 TI - Determination of metabolic resistance mechanisms in pyrethroid-resistant and fipronil-tolerant brown dog ticks. AB - Rhipicephalus sanguineus (Latreille) (Ixodida: Ixodidae) is a three-host dog tick found worldwide that is able to complete its' entire lifecycle indoors. Options for the management of R. sanguineus are limited and its' control relies largely on only a few acaricidal active ingredients. Previous studies have confirmed permethrin resistance and fipronil tolerance in R. sanguineus populations, commonly conferred by metabolic detoxification or target site mutations. Herein, five strains of permethrin-resistant and three strains of fipronil-tolerant ticks were evaluated for metabolic resistance using synergists to block metabolic enzymes. Synergist studies were completed with triphenyl phosphate (TPP) for esterase inhibition, piperonyl butoxide (PBO) for cytochrome P450 inhibition, and diethyl maleate (DEM) for glutathione-S-transferase inhibition. Additionally, increased esterase activity was confirmed using gel electrophoresis. The most important metabolic detoxification mechanism in permethrin-resistant ticks was increased esterase activity, followed by increased cytochrome P450 activity. The inhibition of metabolic enzymes did not have a marked impact on fipronil-tolerant tick strains. PMID- 28639696 TI - Modulation of global SUMOylation by Kaposi's sarcoma-associated herpesvirus and its effects on viral gene expression. AB - Some viruses have evolved to exploit the host SUMOylation system to regulate their own replication. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes K bZIP, a SUMO E3 ligase catalyzing the SUMOylation of viral and host proteins. KSHV also encodes replication and transcriptional activator (RTA), a SUMO targeted ubiquitin ligase catalyzing the ubiquitination of SUMOylated proteins and targeting them for degradation. Using chronic KSHV-infected TRE * BCBL-1 RTA cells, the expression kinetics of K-bZIP and RTA, and the global SUMOylation level were detected. The endogenous K-bZIP protein increased dramatically after the induction of the RTA gene that is tetracycline responsive, but then decreased rapidly after peaking at 8 h post tetracycline treatment. Consistently, the global SUMO-conjugated proteins increased and remained at high levels until 8 h, and decreased afterward, correlating with the expression kinetics of RTA and K bZIP. In luciferase reporter assays, transfection of 293T cells with SUMO2 expression plasmid reduced the RTA transactivations of immediate-early genes k8, orf45, and orf50, but enhanced the RTA transactivations of other viral genes including orf57, pan, k2, orf8, and orf73. These results indicated that KSHV might regulate gene expression and viral replication schedule through modulation of the global SUMOylation level, probably via RTA, and RTA-regulated K-bZIP. PMID- 28639698 TI - Definitional Elasticity in the Measurement of Intergenerational Continuity in Substance Use. AB - Increasingly, three generation studies have investigated intergenerational (IG) continuity and discontinuity in substance use and related problem behaviors. However, surprisingly little attention has been paid to the conceptual definition of continuity or to different types of discontinuity (resilience and escalation) or to measurement sensitivity, which affects not only the magnitudes of observed continuity but also factors that correlate with this linkage. This study uses longitudinal data on 427 parent-child dyads from the Rochester IG Study to study continuity and discontinuity in substance use over ages 14-18. Results suggest that the degree of IG continuity, resilience, and escalation in adolescent substance use, as well as correlates of each, depend heavily on how heterogeneity in the behavior is taken into account. PMID- 28639699 TI - An evaluation of asymptomatic Dengue infections among blood donors during the 2014 Dengue outbreak in Guangzhou, China. AB - In 2014, an outbreak of dengue virus (DENV) infection led to 45 171 clinical cases diagnosed in Guangdong province, Southern China. However, the potential risk of blood donors asymptomatically infected with DENV has not been evaluated . In the current study we detected anti-DENV IgG antibody and RNA in volunteer Chinese blood donors. We found that anti-DENV IgG antibody was positively detected in 3.4% (51/1500) and two donors were detected as being DENV RNA positive out of 3000 blood samples. We concluded that the presence of potential DENV in blood donors might be potential risk for blood safety. Therefore, screening for DENV infection should be considered in blood donations during a period of dengue outbreak in high epidemic area of China. PMID- 28639700 TI - Systematic review: health-related quality of life in children and adults with eosinophilic oesophagitis-instruments for measurement and determinant factors. AB - BACKGROUND: Several measures have been used to assess the health-related quality of life (HRQoL) of patients with eosinophilic oesophagitis (EoE). AIMS: To systematically review these HRQoL measures, to appraise measurement properties of specific instruments and to evaluate determinant factors influencing HRQoL in paediatric and adult EoE patients. METHODS: We searched the PubMed, Embase, Scopus, Web of Science (WOS) and PsycINFO databases for documents providing original information on the development of measurement tools and/or evaluation of HRQoL outcomes in EoE patients of all ages. RESULTS: Of the 596 references identified, data was collected from 34 studies (with only 16 of them being published as full papers) including a total of 1,689 individual patients. Three disease-specific HRQoL measures in EoE covering different aspects of patients' lives and developed in English, were scored positive regarding measurement properties. The PedsQL inventory (including parent and child report forms) and the Peds-QoL EoE module were the generic and specific instruments respectively used in children, while the SF-36 and EoE-QoL-A were the most used questionnaires in adults. Patients with EoE show an impaired HRQoL compared to controls, which greatly depends on symptom severity and disease duration. Severity of endoscopic features and female gender may also determine an impaired HRQoL. The effect of treatments on HRQoL requires further assessment. CONCLUSIONS: HRQoL is a relevant outcome that should be considered in clinical practice and research of EoE. Further validation studies in several languages and populations are required to support the use of disease-specific HRQoL measures. PMID- 28639701 TI - Insurance status as a predictor of mortality in patients undergoing head and neck cancer surgery. AB - OBJECTIVE: Explore relationship between insurance status and survival, determine outcomes that vary based on insurance status, and identify potential areas of intervention. STUDY DESIGN: Retrospective cohort analysis of patients who underwent resection of an upper aerodigestive tract malignancy at a single tertiary care hospital during a 5-year period. METHODS: Patients were categorized into four groups by insurance status: Medicaid or uninsured, Medicare and under 65 years of age, Medicare and 65 years or older, and private insurance. Data were collected from the medical record and analyzed with respect to survival and other outcomes. RESULTS: The final cohort consisted of 860 patients. Survival analysis demonstrated a hazard ratio of 2.1 (95% confidence interval [CI], 1.5-3.0) for the Medicaid/uninsured group when compared to the private insurance group. When adjusted for other variables, mortality was still different across insurance groups (P = 0.002). The following also were different across insurance groups: tumor stage (P < 0.001), American Society of Anesthesiologists score (P < 0.001), length of stay (P < 0.001), and complications (P = 0.021). The Medicaid/uninsured group was most likely to have a complication (odds ratio [OR] = 2.10, 95% CI 1.24 3.56, P = 0.006). CONCLUSION: Medicaid/uninsured patients present with more advanced tumors and have poorer survival than privately insured patients. Insurance status is predictive of tumor stage, comorbidity burden, length of stay, and complications. Specifically, the Medicaid/uninsured group had high rates of tobacco use and alcohol abuse, advanced stage tumors, and postoperative complications. Because alcohol abuse and advanced stage also were predictors of poor survival, they may contribute to the survival disparity for socially disadvantaged patients. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2784-2789, 2017. PMID- 28639702 TI - Bone marrow aspirate clot: A technical complication or a smart approach for musculoskeletal tissue regeneration? AB - One of the methods employed to improve healing of damaged tissues is the use of cellular based therapies. A number of regenerative medicine based strategies, from in vitro expanded mesenchymal stem cells (MSCs) to "one-step" procedures using bone marrow (BM) in toto (BM aspirate; BMA) or BM concentrate (BMC), have been developed. Recently, orthopedic researchers focused their attention on the clinical therapeutic potential of BMC and BMA for musculoskeletal regeneration. BMA is reported as an excellent source of cells and growth factors. However, the quality of BM harvest and aspirate is extremely technique-dependent and, due to the presence of megakaryocytes and platelets, BMA is prone to clot. BMA clot formation is usually considered a complication hampering the procedures on both BMC preparation and MSC expansion. Therefore, different protocols have been developed to avoid and/or degrade clots. However, from a biological point of view there is a strong rationale for the use of BMA clot for tissue engineering strategies. This descriptive systematic literature review summarizes preclinical and clinical studies dealing the use of BMA clot for orthopedic procedures and provided some evidence supporting its use as a cell based therapy for cartilage and bone regeneration. Despite these results, there are still few preclinical and clinical studies that carefully evaluate the safety and efficacy of BMA clot in orthopedic procedures. Thus, implementing biological knowledge and both preclinical and clinical studies could help researchers and clinicians to understand if BMA clots can really be considered a possible therapeutic tool. PMID- 28639703 TI - An assessment of differences in costs and health benefits of serology and NAT screening of donations for blood transfusion in different Western countries. AB - BACKGROUND AND OBJECTIVES: The cost-utility of safety interventions is becoming increasingly important as a driver of implementation decisions. The aim of this study was to compare the cost-utility of different blood screening strategies in various settings, and to analyse the extent and cause of differences in health economic results. MATERIALS AND METHODS: For eight Western countries (Australia, Canada, Denmark, Finland, France, The Netherlands, UK and the United States of America), data were collected on donor and recipient populations, blood products, screening tests, and on patient treatment practices and costs. An existing ISBT web-tool model was used to assess the cost-utility of various strategies for HIV, HCV and HBV screening. RESULTS: The cost-utility ratio of serology screening for these eight countries ranges between -11 000 and 92 000 US$ per QALY, and for NAT between -12 000 and 113 000 US$ per QALY when compared to no screening. Combined serology and NAT ranges between 600 and 217 000 US$ per QALY. The incremental cost-utility of NAT after implementation of serology screening ranges from 2 231 000 to 15 778 000 US$ per QALY. CONCLUSION: There are substantial differences in costs per QALY between countries for various HIV, HBV and HCV screening strategies. These differences are primarily caused by costs of screening tests and infection rates in the donor population. Within each country, similar cost per QALY results for serology and NAT compared to no screening, coupled with evidence of limited value of serology and NAT together prompts the need for further discussion on the acceptability of parallel testing by serology and NAT. PMID- 28639704 TI - Genome-wide association analysis identifies potential regulatory genes for eumelanin pigmentation in chicken plumage. AB - Plumage color in chicken is determined by the proportion of eumelanin and pheomelanin pigmentation. As the main ingredient in plumage melanin, eumelanin plays a key role in the dark black, brown and grey coloration. However, very few studies have been performed to identify the related genes and mutations on a genome-wide scale. Herein, a resource family consisting of one backcross population and two F2 cross populations between a black roster and Yukou Brown I parent stockbreed was constructed for identification of genes related to eumelanin pigmentation. Chickens with eumelanin in their plumage were classified as the case group, and the rest were considered the control group. A genome-wide association study of this phenotype and genotypes using Affymetrix 600K HD SNP arrays in this F2 family revealed 13 significantly associated SNPs and in 10 separate genes on chromosomes 1, 2, 3 and 5. Based on previous studies in model species, we inferred that genes, including NUAK family kinase 1 (NUAK1) and sonic hedgehog (SHH), may play roles in the development of neural crest cells or melanoblasts during the embryonic period, which may also affect the eumelanin pigmentation. Our results facilitate the understanding of the genetic basis of eumelanin pigmentation in chicken plumage. PMID- 28639705 TI - Cloning and characterization of iron-superoxide dismutase in Antarctic yeast strain Rhodotorula mucilaginosa AN5. AB - A novel superoxide dismutase gene from Antarctic yeast Rhodotorula mucilaginosa AN5 was cloned, sequenced, and then expressed in Escherichia coli. The R. mucilaginosa AN5 SOD (RmFeSOD) gene was 639 bp open reading frame in length, which encoded a protein of 212 amino acids with a deduced molecular mass of 23.5 kDa and a pI of 7.89. RmFeSOD was identified as iron SOD type with a natural status of homodimer. The recombinant RmFeSOD showed good pH stability in the pH 1.0-9.0 after 1 h incubation. Meanwhile, it was found to behave relatively high thermostability, and maintained more than 80% activity at 50 degrees C for 1 h. By addition of 1 mM metal ions, the enzyme activity increased by Zn2+ , Cu2+ , Mn2+ , and Fe3+ , and inhibited only by Mg2+ . RmFeSOD showed relatively low tolerance to some compounds, such as PMSF, SDS, Tween-80, Triton X-100, DMSO, beta-ME, and urea. However, DTT showed no inhibition to enzyme activity. Using copper stress experiment, the RmFeSOD recombinant E. coli exhibited better growth than non-recombinant bacteria, which revealed that RmFeSOD might play an important role in the adaptability of heavy metals. PMID- 28639706 TI - Exercise for pregnant women with gestational diabetes for improving maternal and fetal outcomes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with both short- and long-term complications for the mother and her baby. Exercise interventions may be useful in helping with glycaemic control and improve maternal and infant outcomes.The original review on Exercise for diabetic pregnant women has been split into two new review titles reflecting the role of exercise for pregnant women with gestational diabetes and for pregnant women with pre-existing diabetes. Exercise for pregnant women with gestational diabetes for improving maternal and fetal outcomes (this review) Exercise for pregnant women with pre existing diabetes for improving maternal and fetal outcomes OBJECTIVES: To evaluate the effects of exercise interventions for improving maternal and fetal outcomes in women with GDM. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (27 August 2016), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (18th August 2016), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing an exercise intervention with standard care or another intervention in pregnant women diagnosed with gestational diabetes. Quasi-randomised and cross-over studies, and studies including women with pre-existing type 1 or type 2 diabetes were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: All selection of studies, assessment of trial quality and data extraction was conducted independently by two review authors. Data were checked for accuracy. MAIN RESULTS: We included 11 randomised trials, involving 638 women. The overall risk of bias was judged to be unclear due to lack of methodological detail in the included studies.For the mother, there was no clear evidence of a difference between women in the exercise group and those in the control group for the risk of pre-eclampsia as the measure of hypertensive disorders of pregnancy (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.01 to 7.09; two RCTs, 48 women; low-quality evidence), birth by caesarean section (RR 0.86, 95% CI 0.63 to 1.16; five RCTs, 316 women; I2 = 0%; moderate-quality evidence), the risk of induction of labour (RR 1.38, 95% CI 0.71 to 2.68; one RCT, 40 women; low-quality evidence) or maternal body mass index at follow-up (postnatal weight retention or return to pre-pregnancy weight) (mean difference (MD) 0.11 kg/m2, 95% CI -1.04 to 1.26; three RCTs, 254 women; I2 = 0%; high-quality evidence). Development of type 2 diabetes, perineal trauma/tearing and postnatal depression were not reported as outcomes in the included studies.For the infant/child/adult, a single small (n = 19) trial reported no perinatal mortality (stillbirth and neonatal mortality) events in either the exercise intervention or control group (low-quality evidence). There was no clear evidence of a difference between groups for a mortality and morbidity composite (variously defined by trials, e.g. perinatal or infant death, shoulder dystocia, bone fracture or nerve palsy) (RR 0.56, 95% CI 0.12 to 2.61; two RCTs, 169 infants; I2 = 0%; moderate-quality evidence) or neonatal hypoglycaemia (RR 2.00, 95% CI 0.20 to 20.04; one RCT, 34 infants; low-quality evidence). None of the included trials pre-specified large-for-gestational age, adiposity (neonatal/infant, childhood or adulthood), diabetes (childhood or adulthood) or neurosensory disability (neonatal/infant) as trial outcomes.Other maternal outcomes of interest: exercise interventions were associated with both reduced fasting blood glucose concentrations (average standardised mean difference (SMD) 0.59, 95% CI -1.07 to -0.11; four RCTs, 363 women; I2 = 73%; T2 = 0.19) and a reduced postprandial blood glucose concentration compared with control interventions (average SMD -0.85, 95% CI -1.15 to -0.55; three RCTs, 344 women; I2 = 34%; T2 = 0.03). AUTHORS' CONCLUSIONS: Short- and long-term outcomes of interest for this review were poorly reported. Current evidence is confounded by the large variety of exercise interventions. There was insufficient high-quality evidence to be able to determine any differences between exercise and control groups for our outcomes of interest. For the woman, both fasting and postprandial blood glucose concentrations were reduced compared with the control groups. There are currently insufficient data for us to determine if there are also benefits for the infant. The quality of the evidence in this review ranged from high to low quality and the main reason for downgrading was for risk of bias and imprecision (wide CIs, low event rates and small sample size). Development of type 2 diabetes, perineal trauma/tearing, postnatal depression, large-for gestational age, adiposity (neonate/infant, childhood or adulthood), diabetes (childhood or adulthood) or neurosensory disability (neonate/infant) were not reported as outcomes in the included studies.Further research is required comparing different types of exercise interventions with control groups or with another exercise intervention that reports on both the short- and long-term outcomes (for both the mother and infant/child) as listed in this review. PMID- 28639707 TI - Dressings and topical agents for treating pressure ulcers. AB - BACKGROUND: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Dressings are widely used to treat pressure ulcers and promote healing, and there are many options to choose from including alginate, hydrocolloid and protease-modulating dressings. Topical agents have also been used as alternatives to dressings in order to promote healing.A clear and current overview of all the evidence is required to facilitate decision-making regarding the use of dressings or topical agents for the treatment of pressure ulcers. Such a review would ideally help people with pressure ulcers and health professionals assess the best treatment options. This review is a network meta-analysis (NMA) which assesses the probability of complete ulcer healing associated with alternative dressings and topical agents. OBJECTIVES: To assess the effects of dressings and topical agents for healing pressure ulcers in any care setting. We aimed to examine this evidence base as a whole, determining probabilities that each treatment is the best, with full assessment of uncertainty and evidence quality. SEARCH METHODS: In July 2016 we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses, guidelines and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of at least one of the following interventions with any other intervention in the treatment of pressure ulcers (Stage 2 or above): any dressing, or any topical agent applied directly to an open pressure ulcer and left in situ. We excluded from this review dressings attached to external devices such as negative pressure wound therapies, skin grafts, growth factor treatments, platelet gels and larval therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. We conducted network meta analysis using frequentist mega-regression methods for the efficacy outcome, probability of complete healing. We modelled the relative effectiveness of any two treatments as a function of each treatment relative to the reference treatment (saline gauze). We assumed that treatment effects were similar within dressings classes (e.g. hydrocolloid, foam). We present estimates of effect with their 95% confidence intervals for individual treatments compared with every other, and we report ranking probabilities for each intervention (probability of being the best, second best, etc treatment). We assessed the certainty (quality) of the body of evidence using GRADE for each network comparison and for the network as whole. MAIN RESULTS: We included 51 studies (2947 participants) in this review and carried out NMA in a network of linked interventions for the sole outcome of probability of complete healing. The network included 21 different interventions (13 dressings, 6 topical agents and 2 supplementary linking interventions) and was informed by 39 studies in 2127 participants, of whom 783 had completely healed wounds.We judged the network to be sparse: overall, there were relatively few participants, with few events, both for the number of interventions and the number of mixed treatment contrasts; most studies were small or very small. The consequence of this sparseness is high imprecision in the evidence, and this, coupled with the (mainly) high risk of bias in the studies informing the network, means that we judged the vast majority of the evidence to be of low or very low certainty. We have no confidence in the findings regarding the rank order of interventions in this review (very low certainty evidence), but we report here a summary of results for some comparisons of interventions compared with saline gauze. We present here only the findings from evidence which we did not consider to be very low certainty, but these reported results should still be interpreted in the context of the very low certainty of the network as a whole.It is not clear whether regimens involving protease-modulating dressings increase the probability of pressure ulcer healing compared with saline gauze (risk ratio (RR) 1.65, 95% confidence interval (CI) 0.92 to 2.94) (moderate-certainty evidence: low risk of bias, downgraded for imprecision). This risk ratio of 1.65 corresponds to an absolute difference of 102 more people healed with protease modulating dressings per 1000 people treated than with saline gauze alone (95% CI 13 fewer to 302 more). It is unclear whether the following interventions increase the probability of healing compared with saline gauze (low-certainty evidence): collagenase ointment (RR 2.12, 95% CI 1.06 to 4.22); foam dressings (RR 1.52, 95% CI 1.03 to 2.26); basic wound contact dressings (RR 1.30, 95% CI 0.65 to 2.58) and polyvinylpyrrolidone plus zinc oxide (RR 1.31, 95% CI 0.37 to 4.62); the latter two interventions both had confidence intervals consistent with both a clinically important benefit and a clinically important harm, and the former two interventions each had high risk of bias as well as imprecision. AUTHORS' CONCLUSIONS: A network meta-analysis (NMA) of data from 39 studies (evaluating 21 dressings and topical agents for pressure ulcers) is sparse and the evidence is of low or very low certainty (due mainly to risk of bias and imprecision). Consequently we are unable to determine which dressings or topical agents are the most likely to heal pressure ulcers, and it is generally unclear whether the treatments examined are more effective than saline gauze.More research is needed to determine whether particular dressings or topical agents improve the probability of healing of pressure ulcers. The NMA is uninformative regarding which interventions might best be included in a large trial, and it may be that research is directed towards prevention, leaving clinicians to decide which treatment to use on the basis of wound symptoms, clinical experience, patient preference and cost. PMID- 28639708 TI - Young Infants' Word Comprehension Given An Unfamiliar Talker or Altered Pronunciations. AB - To understand spoken words, listeners must appropriately interpret co-occurring talker characteristics and speech sound content. This ability was tested in 6- to 14-months-olds by measuring their looking to named food and body part images. In the new talker condition (n = 90), pictures were named by an unfamiliar voice; in the mispronunciation condition (n = 98), infants' mothers "mispronounced" the words (e.g., nazz for nose). Six- to 7-month-olds fixated target images above chance across conditions, understanding novel talkers, and mothers' phonologically deviant speech equally. Eleven- to 14-months-olds also understood new talkers, but performed poorly with mispronounced speech, indicating sensitivity to phonological deviation. Between these ages, performance was mixed. These findings highlight the changing roles of acoustic and phonetic variability in early word comprehension, as infants learn which variations alter meaning. PMID- 28639709 TI - Vesiculobullous variant of erythema elevatum diutinum. AB - The vesiculobullous variant of erythema elevatum diutinum (EED) is a very rare variant of EED. We describe a 16-year-old boy who presented with symmetrical nodular lesions accompanied by vesicles on the dorsa of his hands. Biopsy findings were consistent with EED. The histopathological presence of IgA and neutrophils in the vesicles indicates that the joint action of both is responsible for formation of these subepidermic vesicles. We hypothesize that absence of human leucocyte antigen related to dermatitis herpetiformis (DH) in our patient might have influenced the location and distribution of the lesions, so that they were not typical of DH. We report the second case of the vesiculobullous variant of EED with IgA deposits in the dermoepidermal membrane. To our knowledge, there are only 14 previously reported cases of the vesiculobullous variant of EED. PMID- 28639710 TI - Exploring the use of drug trend data in the regional alcohol and other drug workforce. AB - OBJECTIVE: Drug trend data can inform appropriate policies to minimise drug related harm, as well as assist in early detection and prevention. While Australia has a number of monitoring systems, none operate in regional areas. The aim of this study was to explore how drug trend and other data are used by the regional alcohol and other drug workforce. METHOD: Twenty-one key experts from regional Queensland were interviewed between November 2014 and August 2015. Key experts worked in or had contact with the broader alcohol and other drugs field in the Darling Downs area of Queensland. Interviews were analysed thematically. SETTING: Darling Downs, Queensland. RESULTS: Two themes emerged from the analysis. There were differences in workforce needs, with those in the law and criminal justice areas believing they had access to good, current data. Those in the health sector differed, although the majority indicated that there did appear to be a knowledge gap related to their location in a regional area. CONCLUSIONS: Trends in the use of, and harms related to, substance use are well captured in urban areas, but less so in regional areas. This inhibits both our understanding of where substance use is changing, as well as how to best plan and respond. PMID- 28639711 TI - Late onset congenital dermal melanocytosis - 'Mongolian blue spots' confused as child abuse: Are there more lessons to be learnt? PMID- 28639712 TI - The effect of childcare activities on cognitive status and depression in older adults: gender differences in a 4.4-year longitudinal study. AB - OBJECTIVES: Although involvement in childcare activities seems to promote better physical and mental health in older adults, its impact on cognitive status and depression has not yet been fully elucidated. We aimed to analyze the association between engagement in childcare activities and cognitive and psychological status over a 4.4-year period in community-dwelling older adults. METHODS: Two thousand one hundred four subjects older than 65 years without severe cognitive impairment at baseline were categorized according to the frequency of their involvement in childcare activities (everyday, occasionally, never). The participants' cognitive status and depressive symptoms were evaluated at baseline and after 4.4 years. RESULTS: During the follow-up, 269 (12.8%) new cases of cognitive impairment and 229 (10.9%) new cases of depression were registered. Men engaged in childcare showed an almost 20% lower risk of cognitive impairment and cognitive decline. Women demonstrated similar results, except for those occasionally involved in childcare, who had a higher risk of cognitive decline compared with women who never engaged in it. The risk of developing depression was reduced in men involved daily (OR = 0.44, 95% CI: 0.30-0.62, p < 0.0001) and occasionally in childcare, who also demonstrated a lower risk of exacerbating depressive symptoms compared with subjects who never involved in it. The onset of depression was reduced in women occasionally engaged in childcare (OR = 0.68, 95% CI: 0.56-0.82, p < 0.0001), but not significantly in those daily involved in it. CONCLUSIONS: Involvement of older adults in childcare activities seems to lower the risk of cognitive impairment in both genders and to prevent onset or worsening of depression particularly in older men. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28639713 TI - Rosacea in black South Africans with skin phototypes V and VI. AB - Rosacea is a chronic facial dermatosis considered to affect primarily white patients with light phototype skin, and is poorly documented in black patients. The aim of this study was to document the clinical features of rosacea in patients with phototypes V and VI. An 8-year retrospective chart review of patients with a clinical and histological diagnosis of rosacea or acne rosacea was undertaken. Of 6700 patients, 15 (0.2%) had rosacea. All were of African descent with skin phototype V or VI. Mean age was 47 years, and female : male ratio was 14 : 1. Of the 15 patients, 5 (33%) were positive for human immunodeficiency virus; 5 (33%) had used topical steroids to treat the roseacea; 6 (40%) had phototype V and presented with erythema, telangiectasia and erythematous papules, while 9 (60%) had phototype VI skin and presented with skin coloured papules; and 10 (67%) had histology showing granulomatous rosacea, while 5 (33%) declined a facial skin biopsy. A high index of suspicion is required to diagnose rosacea in black patients as the classic signs of erythema and telangiectasia are difficult to discern. PMID- 28639714 TI - Plasma cytokine IL-6 levels and subjective cognitive decline: preliminary findings. AB - OBJECTIVE: Detection of Alzheimer's disease (AD) prior to clinical inception will be paramount for introducing disease modifying treatments. We have begun collecting baseline characteristics of a community cohort for longitudinal assessment and testing of antecedent blood-based biomarkers. We describe the baseline visit from the first 131 subjects in relationship to a commonly described cytokine, interleukin 6 (IL-6). METHODS: Subjects from the community presented for a free memory screening with varying degrees of memory concern. We quantified the baseline plasma levels of the cytokine IL-6 and assessed cognition (Montreal Cognitive Assessment, MoCA) and mood (Geriatric Depression Scale, GDS) in relationship to their memory concern. RESULTS: Baseline MoCA scores were inversely related to age, and this association was influenced by an AD risk factor, Apolipoprotein E (APOE4) carrier status. The degree of subjective cognitive decline correlated with GDS and was inversely related to MoCA scores. Interleukin 6 levels were related to age, body mass index, and years of education. CONCLUSIONS: It will be important to assess how these baseline IL-6 levels and forthcoming novel biomarkers relate to future cognitive decline. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28639715 TI - Refractory chronic spontaneous urticaria associated with CD4 lymphocytopenia in a patient with thymoma. PMID- 28639716 TI - Expression of the autoantigen TRIM33/TIF1gamma in skin and muscle of patients with dermatomyositis is upregulated, together with markers of cellular stress. AB - Dermatomyositis (DM) is an autoimmune disorder associated with a dysregulation of immune homeostasis of both the innate and adaptive immune system. Earlier data suggested that these two arms of the immune system interconnect in DM. In the current study, we analysed the association of autoantigen expression [adaptive system components: Mi2, transcriptional intermediary factor (TIF)1gamma, small ubiquitin-like modifier 1 activating enzyme subunit (SAE)1, melanoma differentiation-associated protein (MDA)5] with markers of cellular stress (innate system components: MxA, p53) in skin and muscle (immunohistology and gene expression data, respectively). We found that distinctive self-antigens of DM were elevated in both skin and muscle tissue. In particular, TIF1gamma expression was seen in autoimmune diseases including DM, but not in other inflammatory skin disorders. This upregulation was closely associated with p53 expression and type I interferon-regulated inflammation, suggesting that upregulation of autoantigens in the skin and muscle of patients with DM might be driven by cellular stress. Better understanding of these mechanisms could pave the way for new therapeutic concepts focusing on stress reduction. PMID- 28639718 TI - Catalytic Enantioselective Michael Addition Reactions of Tertiary Enolates Generated by Detrifluoroacetylation. AB - This work describes, for the first time, Michael addition reactions of tertiary fluoro-enolates in situ generated by detrifluoroacetylation with 1-(1 (phenylsulfonyl) vinylsulfonyl)benzene. Excellent enantioselectivity and chemical yields were achieved with application of catalysts (10 mol %) derived from Cu(OTf)2 and (1S,2S)-1,2-diphenylethane-1,2-diamine. These reactions show a considerable degree of structural generality and allow the preparation of new types of biologically relevant molecules that contain quaternary C-F stereogenic carbon atoms and feature five-, six-, or seven-membered rings as well as heterocyclic 3-fluoro-2,3-dihydrochromen-4-one moieties. PMID- 28639717 TI - Transvaginal sonographic cervical length in first and second trimesters in a low risk population: a prospective study. AB - OBJECTIVES: To assess cervical length (CL) longitudinally between the first and second trimesters and to determine the proportion of women with short CL. The study also aimed to assess if women with short CL at 19-24 weeks' gestation could be identified at the time of combined first-trimester screening (cFTS) at 11-14 weeks' gestation, in order to determine the potential value of implementation of CL screening for prediction of preterm delivery in a Danish population. METHODS: This was a prospective longitudinal study of women with singleton pregnancy attending three University Hospitals in Denmark for combined first-trimester screening from 1 November 2013 to 1 December 2014. Exclusion criteria were multiple pregnancy, uterine anomaly, cerclage or progesterone treatment at inclusion. CL was measured on transvaginal sonography at 11-14 weeks (Cx1), 19-21 weeks (Cx2) and 23-24 weeks (Cx3), by trained operators as a straight line from external to internal os. Women with CL <= 25 mm were referred to a maternal-fetal medicine specialist for treatment according to a standardized management protocol. RESULTS: Of the 4904 eligible women, 3477 (71%) participated and had Cx1 recorded. Of those, 3232 (93.0%) had CL measured on all three scans. Median Cx1 was 37 mm, and median Cx2 and Cx3 were 40 mm. The proportion of women with CL <= 25 mm increased with gestational age, from 0.41% (95% CI, 0.19-0.62%) at Cx1 to 1.79% (95% CI, 1.34-2.24%) at Cx3. In total, the proportion of women with second-trimester CL (Cx2 or Cx3) <= 25 mm was 2.0% (n = 67), of which 38.8% (n = 26) were detected at 19-21 weeks. The probability of short CL between 19 and 24 weeks was greater for those with shorter first-trimester CL. It was nearly nine fold higher for women with Cx1 <= 25 mm compared with Cx1 >= 35 mm (17% vs 2%). The performance of Cx1 for prediction of short second-trimester CL was 50% at a 10% false-positive rate. It was found that more than 1500 women would need to be screened for short CL at 19-21 weeks to prevent one case of spontaneous preterm delivery before 34 weeks in a population such as the one in this study. CONCLUSIONS: There is an association between first-trimester CL and risk of short cervix in the second trimester. Once short CL was observed, risk of preterm delivery was greatly increased. However, whether universal CL screening should be implemented in this low-risk population depends on cost-benefit analysis taking into account the low proportions of women with short CL and at risk for preterm delivery. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28639719 TI - Understanding Indigenous patient attendance: A qualitative study. AB - OBJECTIVE: To better understand Indigenous patient non-attendance at medical specialty appointments by learning from the patients attending their scheduled outreach ophthalmology clinic appointment. DESIGN, SETTING AND PARTICIPANTS: A qualitative study using face-to-face, semi-structured interviews with 69 Indigenous Australian ophthalmology patients and 8 clinic workers at one urban and one rural Aboriginal Medical Service (AMS) over the period from April 2015 to November 2015. MAIN OUTCOME MEASURES: Explored motivations and enablers for attending patients to guide best practice for specialist outreach clinics. RESULTS: The main themes emerging from the interviews included: clinic staff are persistent in their efforts to organise outreach ophthalmology clinics; both motivated and reluctant patients attend medical appointments; and reluctant patients are more likely to be unaware of their referral pathway. Health literacy and clinic staff triggered the reluctant patient to attend. CONCLUSION: Indigenous patients attend their outreach ophthalmology appointments based on various motivations. Clinic staff who recognise reluctant patients can communicate through a sensitive, patient-centred approach that helps the patient realise the importance of the appointment thus creating motivation and promoting attendance. The efforts of the clinic staff, through their patient reminding, transport provision and patient-centred communication suggest that they are the enablers of Indigenous patient attendance at AMS outreach ophthalmology clinics. PMID- 28639720 TI - Isophthalic Acid-Based HDAC Inhibitors as Potent Inhibitors of HDAC8 from Schistosoma mansoni. AB - Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based HDAC inhibitors were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. The front runner compounds showed submicromolar activity against SmHDAC8 and modest preference for SmHDAC8 over its human orthologue hHDAC8. Docking studies provided insights into the putative binding mode in SmHDAC8 and allowed rationalization of the observed selectivity profile. PMID- 28639721 TI - TRPV4 channels contribute to calcium transients in astrocytes and neurons during peri-infarct depolarizations in a stroke model. AB - Stroke is one of the leading causes of death and long-term disability. In the penumbra, that is, the area surrounding the infarct core, peri-infarct depolarizations (PIDs) are accompanied by strong intracellular calcium elevations in astrocytes and neurons, thereby negatively affecting infarct size and clinical outcome. The dynamics of PIDs and the cellular pathways that are involved during PID formation and progression remain incompletely understood. We have previously shown that inositol triphosphate-gated calcium release from internal stores is a major component of PID-related astroglial calcium signals, but whether external calcium influx through membrane-localized channels also contributes to PIDs has remained unclear. In this study, we investigated the role of two astroglial membrane channels, transient receptor vanilloid 4 (TRPV4) channel and aquaporin-4 (AQP4). We combined in vivo multiphoton microscopy, electrophysiology as well as laser speckle contrast imaging with the middle cerebral artery occlusion stroke model. Using knockout mice and pharmacological inhibitors, we found that TRPV4 channels contribute to calcium influx into astrocytes and neurons and subsequent extracellular glutamate accumulation during PIDs. AQP4 neither influenced PID related calcium signals nor PID-related edema of astrocyte somata. Both channels did not alter the dynamics, frequency and cerebrovascular response of PIDs in the penumbra. These data indicate that TRPV4 channels may represent a potential target to ameliorate the PID-induced calcium overload of astrocytes and neurons during acute stroke. PMID- 28639722 TI - European guideline for the management of scabies. AB - Scabies is caused by Sarcoptes scabiei var. hominis. The disease can be sexually transmitted. Patients' main complaint is nocturnal itch. Disseminated, excoriated, erythematous papules are usually seen on the anterior trunk and limbs. Crusted scabies occurs in immunocompromised hosts and may be associated with reduced or absent pruritus. Recommended treatments are permethrin 5% cream, oral ivermectin and benzyl benzoate 25% lotion. Alternative treatments are malathion 0.5% aqueous lotion, ivermectin 1% lotion and sulphur 6-33% cream, ointment or lotion. Crusted scabies therapy requires a topical scabicide and oral ivermectin. Mass treatment of large populations with endemic disease can be performed with a single dose of ivermectin (200 micrograms/kg of bodyweight). Partner management needs a look-back period of 2 months. Screening for other STI is recommended. Patients and close contacts should avoid sexual contact until completion of treatment and should strictly observe personal hygiene rules when living in crowded spaces. Written information should be provided to suspected cases. PMID- 28639723 TI - Changes in the inspiratory pattern contribute to modulate the sympathetic activity in sino-aortic denervated rats. AB - NEW FINDINGS: What is the central question of this study? Sino-aortic denervated (SAD) rats present normal levels of sympathetic activity and mean arterial pressure. However, neural mechanisms regulating the sympathetic activity in the absence of arterial baroreceptors remain unclear. Considering that respiration modulates the sympathetic activity, we hypothesize that changes in the respiratory network contribute to keep the sympathetic outflow in the normal range after removal of arterial baroreceptors. What is the main finding and its importance? Despite longer inspiration observed in SAD rats, the respiratory sympathetic coupling is working within a normal range of variation. These findings suggest that in the absence of arterial baroreceptors the respiratory modulation of sympathetic activity is maintained within the normal range. The activity of presympathetic neurons is under respiratory modulation, and changes in the central respiratory network may impact on the baseline sympathetic activity and mean arterial pressure. It is well known that after removal of baroreceptor afferents [sino-aortic denervation (SAD)], rats present an unexpected normal level of mean arterial pressure. We hypothesized that changes in the respiratory pattern and in the respiratory modulation of the sympathetic activity contribute to keep the sympathetic outflow within a normal range of variation in the absence of arterial baroreceptors in rats. To study these mechanisms, we recorded perfusion pressure and the activities of phrenic and thoracic sympathetic nerves in male juvenile rats using the working heart brainstem preparation. The time of inspiration significantly increased in SAD rats, and this change was not dependent on the carotid bodies or on the vagal afferents. However, no changes were observed in the perfusion pressure or in the baseline thoracic sympathetic nerves in all phases of the respiratory cycle in SAD rats. Our data show that despite longer inspiratory activity, the baseline sympathetic activity is maintained at a normal level in SAD rats. These findings indicate that the respiratory-sympathetic coupling is normal after SAD and suggest that the respiratory modulation of sympathetic activity is maintained within the normal range after the removal of arterial baroreceptors. PMID- 28639725 TI - Targeting NAD(P)H:Quinone Oxidoreductase (NQO1) in Pancreatic Cancer. AB - NAD(P)H: Quinone oxidoreductase (NQO1) functions as an important part of cellular antioxidant defense by detoxifying quinones, thus preventing the formation of reactive oxygen species. The aims of our study were to determine if NQO1 is elevated in pancreatic cancer specimens and pancreatic cancer cell lines and if so, would compounds previously demonstrated to redox cycle with NQO1 be effective in killing pancreatic cancer cells. Immunohistochemistry of resected pancreatic specimens demonstrated an increased immunoreactivity for NQO1 in pancreatic cancer and pancreatic intraepithelial neoplasia (PanIN) specimens versus normal human pancreas. Immunocytochemistry and Western immunoblots demonstrated inceased immunoreactivity in pancreatic cancer cells when compared to a near normal immortalized human pancreatic ductal epithelial cell line and a colonic epithelial cell line. Streptonigrin, a compound known to cause redox cycling in the presence of NQO1, decreased clonogenic survival and decreased anchorage independent growth in soft agar. Streptonigrin had little effect on cell lines with absent or reduced levels of NQO1. The effects of streptonigrin were reversed in pancreatic cancer cells pretreated with dicumarol, a known inhibitor of NQO1. NQO1 may be a therapeutic target in pancreatic cancer where survival is measured in months. (c) 2006 Wiley-Liss, Inc. PMID- 28639724 TI - Longitudinal changes in global and domain specific cognitive function in the very old: findings from the Newcastle 85+ Study. AB - OBJECTIVE: Ageing is associated with changes in cognition in some, but not all domains. In young-old adults, defined as persons aged 65-84 years, baseline cognitive function has been shown to impact on cognitive trajectories. Whether similar patterns occur in the very-old, defined as persons aged 85 years and over, is not known. METHODS: Longitudinal changes (5 years' follow-up) in global and domain specific cognitive function including memory, attention and speed were investigated in participants from the Newcastle 85+ Study (n = 845). At baseline, participants were grouped using Mini-Mental State Examination cut-off scores and dementia status into the following: not impaired, mildly impaired or severely impaired/dementia groups. RESULTS: Only a limited number of cognitive measures showed significant decline in performance over time. Where observed, change generally occurred only in the severely impaired group. In the severely impaired group, small differences in baseline age were associated with poorer performance over time on most measures. Education was not protective against cognitive decline in any group. CONCLUSIONS: There are individuals who maintain a high level of cognitive function or only show mild impairments even into their ninth decade of life. This group of successful cognitive agers may provide insight for identifying predictors of cognitive integrity in later life. In individuals with severe impairment, cognitive performance shows significant decline over time, especially in measures of attention and speed. Further work to identify those individuals at highest risk of cognitive decline is necessary to implement early support and intervention strategies in this rapidly expanding age group. (c) 2017 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd. PMID- 28639726 TI - Trend of centenarian deaths in Hong Kong between 2001 and 2010. AB - AIM: To examine the trends in the leading causes of deaths in centenarians in Hong Kong. METHODS: Descriptive analyses of vital statistics data on mortality in Hong Kong from 2001 to 2010 were carried out. RESULTS: The number of centenarians' deaths increased by 136% in 10 years, from less than 28 men and 166 women in 2001 to 80 men and 378 women in 2010. During the study period, the top leading cause of death was pneumonia, accounting for 33.8% of all deaths. In contrast, the other leading causes accounted for much smaller percentages; for example, the second and third leading causes were chronic ischemic heart disease and unspecified dementia, and account for 4.3% and 4.2% of the total, respectively. This cause-of-death pattern has remained fairly stable between 2001 and 2010. A total of 985 (30.8%) deaths occurred in January to March. The correlation between the average monthly temperature and the number of deaths was 0.720 (P < 0.01). CONCLUSIONS: The number of deaths continues to increase in Hong Kong. These trends have major implications for healthcare in an aging population. Geriatr Gerontol Int 2017; 17: 931-936. PMID- 28639727 TI - Switching Futile para-Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin-Specific Protease-2 Inhibition, Electrocatalysis, and Quantification. AB - Understanding the correlation between structural features of small-molecule drugs and their mode of action is a fascinating topic and crucial for the drug discovery process. However, in many cases, knowledge of the exact parameters that dictate the mode of action is still lacking. Following a large screening for ubiquitin specific protease 2 (USP2) inhibition, an effective para-quinone-based inhibitor with an unclear mode of action was identified. To gain a deeper understanding of the mechanism of inhibition, a set of para-quinones were prepared and studied for USP2 inhibition, electrocatalysis, and reactive oxygen species (ROS) quantification. The excellent correlation obtained from the above mentioned studies disclosed a distinct pattern of "N-C=O-N" in the bicyclic para quinones to be a crucial factor for ROS generation, and demonstrated that minor changes in such a skeleton drastically altered the ROS-generating ability. The knowledge acquired herein would serve as an important guideline for future medicinal chemistry optimization of related structures to select the preferred mode of action. PMID- 28639728 TI - Prospective use of Ablation Index targets improves clinical outcomes following ablation for atrial fibrillation. AB - AIMS: Late recovery of ablated tissue leading to reconnection of pulmonary veins remains common following radiofrequency catheter ablation for AF. Ablation Index (AI), a novel ablation quality marker, incorporates contact force (CF), time, and power in a weighted formula. We hypothesized that prospective use of our previously published derived AI targets would result in better outcomes when compared to CF-guided ablation. METHODS: Eighty-nine consecutive drug-refractory AF patients (49% paroxysmal) underwent AI-guided ablation (AI-group). AI targets were 550 for anterior/roof and 400 for posterior/inferior left atrial segments. Procedural and clinical outcomes of these patients were compared to 89 propensity matched controls who underwent CF-guided ablation (CF-group). All 178 procedures were otherwise similar, and both groups were followed-up for 12 months. The last 25 patients from each group underwent analysis of all VisiTagsTM for ablation duration, CF, Force-Time Integral, and impedance drop. RESULTS: First-pass pulmonary vein isolation (PVI) was more frequent in AI-group than in CF-group (173 [97%] vs. 149 [84%] circles, P < 0.001), and acute PV reconnection was lower (11 [6%] vs. 24 [13%] circles, P = 0.02). Mean PVI ablation time was similar (AI group: 42 +/- 9 vs. CF-group: 45 +/- 14 minutes, P = 0.14). Median impedance drop for AI-group was significantly higher than in CF-group (13.7 [9-19] Omega vs. 8.8 [5.2-13] Omega, P < 0.001). Two major complications occurred in CF-group and none in AI-group. Atrial tachyarrhythmia recurrence was significantly lower in AI group (15 of 89 [17%]) than in CF-group (33 of 89 [37%], P = 0.002). CONCLUSION: AI-guided ablation is associated with significant improvements in the incidence of acute PV reconnection and atrial tachyarrhythmia recurrence rate compared to CF-guided ablation, potentially due to creation of better quality lesions as suggested by greater impedance drop. PMID- 28639729 TI - Two-Dimensional Metal-Organic Framework Nanosheets for Membrane-Based Gas Separation. AB - Metal-organic framework (MOF) nanosheets could serve as ideal building blocks of molecular sieve membranes owing to their structural diversity and minimized mass transfer barrier. To date, discovery of appropriate MOF nanosheets and facile fabrication of high performance MOF nanosheet-based membranes remain as great challenges. A modified soft-physical exfoliation method was used to disintegrate a lamellar amphiprotic MOF into nanosheets with a high aspect ratio. Consequently sub-10 nm-thick ultrathin membranes were successfully prepared, and these demonstrated a remarkable H2 /CO2 separation performance, with a separation factor of up to 166 and H2 permeance of up to 8*10-7 mol m-2 s-1 Pa-1 at elevated testing temperatures owing to a well-defined size-exclusion effect. This nanosheet-based membrane holds great promise as the next generation of ultrapermeable gas separation membrane. PMID- 28639730 TI - Evaluation of thoracic radiographs as a screening test for dogs and cats admitted to a tertiary-care veterinary hospital for noncardiopulmonary disease. AB - Thoracic radiographs are used as a screening tool for dogs and cats with a variety of disorders that have no clinical signs associated with thoracic structures. However, this practice has never been supported by an evidence-based study. The objective of this retrospective observational study was to determine if certain canine and feline populations have a higher proportion of radiographic abnormalities, and whether any of these abnormalities are associated with patient hospitalization and outcome. Patients were excluded if current or previous examinations revealed evidence of primary respiratory or cardiac disease, malignant neoplasia, or an abnormal breathing pattern consistent with pulmonary pathology. Any notable thoracic change in the radiology report was considered important and evaluated in this study. One hundred and sixty-six of these included patients were dogs and 65 were cats. Of the 166 dog radiographs evaluated, 120 (72.3%) had normal thoracic radiographs, while 46 (27.7%) had radiographic abnormalities. Of the sixty-five cats included, 36 (55.4%) had normal radiographs, while 29 (44.6%) had abnormal radiographs. Canine patients with abnormal radiographs had a significantly higher lactate level (P-value 0.0348) and feline patients with abnormal radiographs had a significantly lower packed cell volume (P-value 0.012). A large proportion of patients that had screening thoracic radiographs (32.5%) had documented abnormalities, but a relatively low percentage (6.5%) of our total population had their clinical plan changed as a consequence of detection of these abnormalities. Findings indicated that abnormal screening thoracic radiographs are more likely in dogs with an elevated lactate and cats with anemia, or a low normal hematocrit. PMID- 28639731 TI - Size Dependence of Doping by a Vacancy Formation Reaction in Copper Sulfide Nanocrystals. AB - Doping of nanocrystals (NCs) is a key, yet underexplored, approach for tuning of the electronic properties of semiconductors. An important route for doping of NCs is by vacancy formation. The size and concentration dependence of doping was studied in copper(I) sulfide (Cu2 S) NCs through a redox reaction with iodine molecules (I2 ), which formed vacancies accompanied by a localized surface plasmon response. X-ray spectroscopy and diffraction reveal transformation from Cu2 S to Cu-depleted phases, along with CuI formation. Greater reaction efficiency was observed for larger NCs. This behavior is attributed to interplay of the vacancy formation energy, which decreases for smaller sized NCs, and the growth of CuI on the NC surface, which is favored on well-defined facets of larger NCs. This doping process allows tuning of the plasmonic properties of a semiconductor across a wide range of plasmonic frequencies by varying the size of NCs and the concentration of iodine. Controlled vacancy doping of NCs may be used to tune and tailor semiconductors for use in optoelectronic applications. PMID- 28639732 TI - Simulated Isotope Exchange Patterns Enable Protein Structure Determination. AB - Understanding the myriad protein-protein interactions required for cell function requires efficient leveraging of biophysical data to drive computational docking. The detailed insight into protein interfaces provided by isotope exchange endows this experimental technique with a unique importance for docking approaches. However, progress in coupling these methods is hindered by the inability to interpret the complex exchange patterns in relation to protein structure. A method to simulate protein isotope exchange patterns from docking outputs is described and its utility to guide the selection of native assemblies demonstrated. Unique signatures are generated for each docking pose, allowing high-throughput ranking of whole docking simulations by pairwise comparison to experimental outputs. Native assemblies are obtained using nothing but their simulated profiles as restraints and experimental difference data for individual proteins are sufficient to drive structure determination for the whole complex. PMID- 28639733 TI - Genetic variants of cell cycle pathway genes predict disease-free survival of hepatocellular carcinoma. AB - Disruption of the cell cycle pathway has previously been related to development of human cancers. However, associations between genetic variants of cell cycle pathway genes and prognosis of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we evaluated the associations between 24 potential functional single nucleotide polymorphisms (SNPs) of 16 main cell cycle pathway genes and disease-free survival (DFS) of 271 HCC patients who had undergone radical surgery resection. We identified two SNPs, i.e., SMAD3 rs11556090 A>G and RBL2 rs3929G>C, that were independently predictive of DFS in an additive genetic model with false-positive report probability (FPRP) <0.2. The SMAD3 rs11556090G allele was associated with a poorer DFS, compared with the A allele [hazard ratio (HR) = 1.46, 95% confidential interval (95% CI) = 1.13-1.89, P = 0.004]; while the RBL2 rs3929 C allele was associated with a superior DFS, compared with the G allele (HR = 0.74, 95% CI = 0.57-0.96, P = 0.023). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had a significant shorter DFS (Ptrend = 0.0001). Further analysis using receiver operating characteristic (ROC) curves showed that the model including the NUGs and known prognostic clinical variables demonstrated a significant improvement in predicting the 1-year DFS (P = 0.011). Moreover, the RBL2 rs3929 C allele was significantly associated with increased mRNA expression levels of RBL2 in liver tissue (P = 1.8 * 10-7 ) and the whole blood (P = 3.9 * 10-14 ). Our data demonstrated an independent or a joint effect of SMAD3 rs11556090 and RBL2 rs3929 in the cell cycle pathway on DFS of HCC, which need to be validated by large cohort and biological studies. PMID- 28639734 TI - Trace determination of five triazole fungicide residues in traditional Chinese medicine samples by dispersive solid-phase extraction combined with ultrasound assisted dispersive liquid-liquid microextraction and UHPLC-MS/MS. AB - A novel and reliable method for determination of five triazole fungicide residues (triadimenol, tebuconazole, diniconazole, flutriafol, and hexaconazol) in traditional Chinese medicine samples was developed using dispersive solid-phase extraction combined with ultrasound-assisted dispersive liquid-liquid microextraction before ultra-high performance liquid chromatography with tandem mass spectrometry. The clean up of the extract was conducted using dispersive solid-phase extraction by directly adding sorbents into the extraction solution, followed by shaking and centrifugation. After that, a mixture of 400 MUL trichloromethane (extraction solvent) and 0.5 mL of the above supernatant was injected rapidly into water for the dispersive liquid-liquid microextraction procedure. The factors affecting the extraction efficiency were optimized. Under the optimum conditions, the calibration curves showed good linearity in the range of 2.0-400 (tebuconazole, diniconazole, and hexaconazole) and 4.0-800 ng/g (triadimenol and flutriafol) with the regression coefficients higher than 0.9958. The limit of detection and limit of quantification for the present method were 0.5-1.1 and 1.8-4.0 ng/g, respectively. The recoveries of the target analytes ranged from 80.2 to 103.2%. The proposed method has been successfully applied to the analysis of five triazole fungicides in traditional Chinese medicine samples, and satisfactory results were obtained. PMID- 28639735 TI - Neonates with cancer and causes of death; lessons from 615 cases in the SEER databases. AB - Neonatal tumors are rare with no standard treatment approaches to these diseases, and the patients experience poor outcomes. Our aim was to determine the distribution of cancers affecting neonates and compare survival between these cancers and older children. We analyzed SEER data (1973-2007) from patients who were younger than 2 years at diagnosis of malignancy. Special permission was granted to access the detailed (i.e., age in months) data of those patients. The Chi-square Log-rank test was used to compare survival between neonates (aged <1 month) and older children (>1 month to <2 years). We identified 615 neonatal cancers (454 solid tumors, 93 leukemia/lymphoma, and 68 CNS neoplasms). Neuroblastoma was the most common neonatal tumor followed by Germ cell tumors. The 5-year overall survival (OS) for all neonates was 60.3% (95% CI, 56.2-64.4). Neonates with solid tumors had the highest 5-year OS (71.2%; 95% CI, 66.9-75.5), followed by those with leukemia (39.1%; 95% CI, 28.3-49.9) or CNS tumors (15%; 95% CI, 5.4-24.6). Except for neuroblastoma, all neonatal tumors showed inferior outcomes compared to that in the older group. The proportion of neonates who died from causes other than cancer was significantly higher than that of the older children (37.9% vs. 16.4%; P < 0.0005). In general, the outcome of neonatal cancers has not improved over the last 34 years. The distribution of neonatal cancer is different than other pediatric age groups. Although the progress in neonatal and cancer care over the last 30 years, only death from noncancer causes showed improvement. Studying neonatal tumors as part of national studies is essential to understand their etiology, determine the best treatment approaches, and improve survival and quality of life for those patients. PMID- 28639736 TI - Primary secondary amine as a sorbent material in dispersive solid-phase extraction clean-up for the determination of indicator polychlorinated biphenyls in environmental water samples by gas chromatography with electron capture detection. AB - A simple, rapid, and novel method has been developed and validated for determination of seven indicator polychlorinated biphenyls in water samples by gas chromatography with electron capture detection. 1 L of water samples containing 30 g of anhydrous sodium sulfate was first liquid-liquid extracted with an automated Jipad-6XB vertical oscillator using n-hexane/dichloromethane (1:1, v/v). The concentrated extract was cleaned up by dispersive solid-phase extraction with 100 mg of primary secondary amine as sorbent material. The linearity of this method ranged from 1.25 to 100 MUg/L, with regression coefficients ranging between 0.9994 and 0.9999. The limits of detection were in the ng/L level, ranging between 0.2 and 0.3 ng/L. The recoveries of seven spiked polychlorinated biphenyls with external calibration method at different concentration levels in tap water, lake water, and sea water were in the ranges of 85-112, 76-116, and 72-108%, respectively, and with relative standard deviations of 3.3-4.5, 3.4-5.6, and 3.1-4.8% (n = 5), respectively. The performance of the proposed method was compared with traditional liquid-liquid extraction and solid-phase extraction clean-up methods, and comparable efficiencies were obtained. It is concluded that this method can be successfully applied for the determination of polychlorinated biphenyls in different water samples. PMID- 28639737 TI - Development and validation of the Workplace Interruptions Measure. AB - In 3 studies, we developed and tested the first comprehensive, self-report measure of workplace interruptions. The Workplace Interruptions Measure (WIM) is based on a typology of interruptions that included intrusions, distractions, discrepancy detections, and breaks. The four-factor structure was reduced to a 12 item measure in Study 1 (N = 317) and confirmed in a diverse sample of employees in Study 2 (N = 160). Study 3 (N = 323) further examined the psychometric properties of the WIM in a sample of university faculty and staff. Studies 2 and 3 demonstrated that both effort-enhancing interruptions (intrusions, distractions, and discrepancy detections) and recovery-enhancing interruptions (breaks) were associated with stressors and strains. Distractions, discrepancy detections, and breaks uniquely predicted strain outcomes beyond other workplace stressors (i.e., quantitative workload, interpersonal conflict, and role conflict). We discuss implications of the WIM for the theory and practice of interruptions research. PMID- 28639738 TI - Impact of postoperative complications on the colorectal cancer survival and recurrence: analyses of pooled individual patients' data from three large phase III randomized trials. AB - This study assessed the impact of postoperative complications on the colorectal cancer survival and recurrence after curative surgery using pooled individual patients' data from three large phase III randomized trials. In total, 5530 patients were included in this study. The patients were classified as those with postoperative complications (C group) and those without postoperative complications (NC group). The risk factors for the overall survival (OS) and the disease-free survival (DFS) were analyzed. Postoperative complications were found in 861 (15.6%) of the 5530 patients. The OS and DFS rates at 5 years after surgery were 68.9% and 74.8%, respectively, in the C group and 75.8% and 82.2%, respectively, in the NC group, values that were significantly different between the two groups (P < 0.001). The multivariate analysis demonstrated that postoperative complications were a significant independent risk factor for the OS and DFS. Postoperative complications can worsen the colorectal cancer survival and risk of recurrence. Surgical morbidity must be considered as a stratification factor in future phase III trials evaluating the effects of adjuvant chemotherapy on colorectal cancer. PMID- 28639739 TI - Philosophical aesthetics and cognitive science. AB - Philosophical aesthetics is the branch of philosophy which explores issues having to do with art, beauty, and related phenomena. Philosophers have often been skeptical about the place of empirical investigation in aesthetics. However, in recent years many philosophical aestheticians have turned to cognitive science to enrich their understanding of their subject matter. Cognitive scientists have, in turn, been inspired by work in philosophical aesthetics. This essay focuses on a representative subset of the areas in which there has been fruitful dialog between philosophical aestheticians and cognitive scientists. We start with some general topics in philosophical aesthetics-the definition of art and the epistemic status of aesthetic judgments. We then move on to discussing research concerning the roles that imagination and perception play in our aesthetic engagement. We conclude with a discussion of the emerging field of experimental philosophical aesthetics. WIREs Cogn Sci 2018, 9:e1445. doi: 10.1002/wcs.1445 This article is categorized under: Philosophy > Value. PMID- 28639740 TI - Declining Rates of Hip Fracture in End-Stage Renal Disease: Analysis From the 2003-2011 Nationwide Inpatient Sample. AB - The incidence of hip fracture in patients with end-stage renal disease (ESRD) is considerably higher than that in the general age- and sex-matched population. Although medical therapy for chronic kidney disease mineral bone disorder (CKD MBD) has changed considerably over the last decade, rates of hip fracture in the entire ESRD population have not been well-characterized. Herein, we evaluated temporal trends in rates of hip fracture, in-hospital mortality, and costs of associated hospital stay in ESRD. We identified hospitalizations for hip fracture from 2003 to 2011 using the Nationwide Inpatient Sample, a representative national database inclusive of all ages and payers. We incorporated data from the United States Renal Data System and the US Census to calculate population specific rates. Between 2003 and 2011, we identified 47,510 hip fractures in the ESRD population. The overall rate of hip fracture was 10.04/1000 person-years. The rate was 3.73/1000 person-years in patients aged less than 65 years, and 20.97/1000 person-years in patients aged 65 or older. Age- and sex-standardized rates decreased by 12.6% from 2003 (10.23/1000 person-years; 95% confidence interval [CI], 7.99/1000 to 12.47/1000) to 2011 (8.94/1000 person-years; 95% CI, 7.12/1000 to 10.75/1000). Hip fracture rates over time were virtually identical in patients aged less than 65 years; however, rates decreased by 15.3% among patients aged 65 years or older; rates declined more rapidly in older women compared with older men (p for interaction = 0.047). In-hospital mortality rate after hip fracture operation declined by 26.7% from 2003 (8.6%; 95% CI, 6.8 to 10.4) to 2011 (6.3%; 95% CI, 4.9 to 7.7). In ESRD, age- and sex-standardized hip fracture rates and associated in-hospital mortality have declined substantially over the last decade. (c) 2017 American Society for Bone and Mineral Research. PMID- 28639742 TI - Two zinc finger proteins from Mycobacterium smegmatis: DNA binding and activation of transcription. AB - Single zinc finger domain containing proteins are very few in number. Of numerous zinc finger proteins in eukaryotes, only three of them like GAGA, Superman and DNA binding by one finger (Dof) have single zinc finger domain. Although few zinc finger proteins have been described in eubacteria, no protein with single C4 zinc finger has been described in details in anyone of them. In this article, we are describing two novel C-terminal C4 zinc finger proteins-Msmeg_0118 and Msmeg_3613 from Mycobacterium smegmatis. We have named these proteins as Mszfp1 (Mycobacterial Single Zinc Finger Protein 1) and Mszfp2 (Mycobacterial Single Zinc Finger Protein 2). Both the proteins are expressed constitutively, can bind to DNA and regulate transcription. It appears that Mszfp1 and Mszfp2 may activate transcription by interacting with RNA polymerase. PMID- 28639741 TI - The impact of comorbidity on mortality in multiple myeloma: a Danish nationwide population-based study. AB - To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1-1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5-3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1-14.9). The median follow-up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4-6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5-1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma. PMID- 28639743 TI - Web alert: Ice microbiology: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 28639745 TI - Feature page. PMID- 28639744 TI - Per diems undermine health interventions, systems and research in Africa: burying our heads in the sand. PMID- 28639746 TI - Acute changes in histopathology and intravascular imaging after catheter-based renal denervation in a porcine model. AB - OBJECTIVES: We first aimed to identify the histopathological changes occurring immediately after renal denervation (RDN) with radiofrequency energy, and then to assess the feasibility of determining procedural success using currently available clinical intravascular imaging techniques. BACKGROUND: Catheter-based RDN has been used as an alternative therapy for hypertension. However, no practical endpoint to determine procedural success during treatment has been established. METHODS: A total of 39 ablation lesions were induced in vivo in eight porcine renal arteries and a total of 15 ablation lesions were induced ex vivo in five excised porcine renal arteries with a radiofrequency delivery device. Acute histological changes and appearance on intravascular imaging of the lesions were investigated with light microscopy, transmission electron microscopy, intravascular ultrasound (IVUS), and optical frequency domain imaging (OFDI). RESULTS: Marked changes were noted in media, adventitia, and perirenal arterial nerves immediately after in vivo ablation. Changes visualized on IVUS were characterized by focal adventitial thickening comprising a relatively echogenic layer around a heterogeneously hypoechoic interior region, and on OFDI as disappearance of the external elastic membrane signals with high scattering of signals in the surface layer. The changes after ex vivo ablation were histopathologically identical to those from in vivo ablation. There were statistically significant positive correlations in measured dimensions (area, depth, width, and diameter) of ablation lesions between histopathology and IVUS/OFDI findings (Pearson correlation coefficients = 0.69-0.77). CONCLUSIONS: These findings suggest that observation of treated renal arteries by IVUS or OFDI immediately after RDN improves the success rate of RDN. PMID- 28639748 TI - Expansion of the phenotype of Kosaki overgrowth syndrome. AB - Skeletal overgrowth is a characteristic of several genetic disorders that are linked to specific molecular signaling cascades. Recently, we established a novel overgrowth syndrome (Kosaki overgrowth syndrome, OMIM #616592) arising from a de novo mutation in PDGFRB, that is, c.1751C>G p.(Pro584Arg). Subsequently, other investigators provided in vitro molecular evidence that this specific mutation in the juxtamembrane domain of PDGFRB causes an overgrowth phenotype and is the first gain-of-function point mutation of PDGFRB to be reported in humans. Here, we report the identification of a mutation in PDGFRB, c.1696T>C p.(Trp566Arg), in two unrelated patients with skeletal overgrowth, further confirming the existence of PDGFRB-related overgrowth syndrome arising from mutations in the juxtamembrane domain of PDGFRB. A review of all four of these patients with an overgrowth phenotype and PDGFRB mutations revealed postnatal skeletal overgrowth, premature aging, cognitive impairment, neurodegeneration, and a prominent connective tissue component to this complex phenotype. From a functional standpoint, hypermorphic mutations in PDGFRB lead to Kosaki overgrowth syndrome, infantile myofibromatosis (OMIM #228550), and Penttinen syndrome (OMIM #601812), whereas hypomorphic mutations lead to idiopathic basal ganglia calcification (OMIM #615007). In conclusion, a specific class of mutations in PDGFRB causes a clinically recognizable syndromic form of skeletal overgrowth. PMID- 28639747 TI - The effect of activation rate on left atrial bipolar voltage in patients with paroxysmal atrial fibrillation. AB - INTRODUCTION: Bipolar voltage is used during electroanatomic mapping to define abnormal myocardium, but the effect of activation rate on bipolar voltage is not known. We hypothesized that bipolar voltage may change in response to activation rate. By examining corresponding unipolar signals we sought to determine the mechanisms of such changes. METHODS AND RESULTS: LA extrastimulus mapping was performed during CS pacing in 10 patients undergoing first time paroxysmal atrial fibrillation ablation. Bipolar and unipolar electrograms were recorded using a PentaRay catheter (4-4-4 spacing) and indifferent IVC electrode, respectively. An S1S2 pacing protocol was delivered with extrastimulus coupling interval reducing from 350 to 200 milliseconds. At each recording site (119 +/- 37 per LA), bipolar peak-to-peak voltage, unipolar peak to peak voltage and activation delay between unipole pairs was measured. Four patterns of bipolar voltage/extrastimulus coupling interval curves were seen: voltage attenuation with plateau voltage >1 mV (48 +/- 15%) or <1 mV (22 +/- 15%), and voltage unaffected by coupling interval with plateau voltage >1 mV (17 +/- 10%) or <1 mV (13 +/- 8%). Electrograms showing bipolar voltage attenuation were associated with significantly greater unipolar voltage attenuation at low (25 +/- 28 mV/s vs. 9 +/- 11 mV/s) and high (23 +/- 29 mV/s vs. 6 +/- 12 mV/s) plateau voltage sites (P < 0.001). There was a small but significant increase in conduction delay between unipole pairs at sites showing bipolar voltage attenuation (P = 0.026). CONCLUSIONS: Bipolar electrogram voltage is dependent on activation rate at a significant proportion of sites. Changes in unipolar voltage and timing underlie these effects. These observations have important implications for use of voltage mapping to delineate abnormal atrial substrate. PMID- 28639749 TI - Evaluation of the in vivo cosmetic efficacy of the MF3 blue cell serum gel. One- and two-month test results. AB - INTRODUCTION: Skin is changing over time showing signs of aging: dryness, increase in visual and tactile roughness, decrease in collagen content and stiffness, and eventually formation of deep and surface wrinkles, and fine lines. METHODS: Eight-week open experimental study was conducted to test efficacy of MF3 Blue Cell Serum Gel. Main criteria to determine product efficacy by following skin biophysical techniques were as follows: skin moisturization, firmness, epidermal and dermal density, skin surface properties and sebum level, reduction in fine lines and wrinkles. Secondary criteria were as follows: participant's opinion during study and product tolerance evaluation. Days 29 and 57 assessments included visual evaluation, skin biophysical techniques, and compliance check. The self-assessment questionnaires completed. RESULTS: After week 8, obtained results showed very good hydration effect of test product, despite the fact being serum gel. Moisturizing increased continuously during study period. Important increases on skin firmness were observed which are in line with typical anti aging claims. Dermal density steady improvement noted especially after 4th week of study, and effect on deep skin layers was due to increase in collagen content and stiffness. Sebum regulation process was evidenced. Further significant roughness reduction in skin surface showed decrease or disappearance of fine lines and wrinkles. Products were well tolerated with no adverse events. Most of participants noticed visible improvement and increase in facial radiance, skin smoothness, and overall skin improvement. CONCLUSION: Twice daily application of MF3 Blue Cell Serum Gel led to significant improvement in skin hydration, firmness, dermal density, sebum regulation, roughness reduction, decrease or disappearance of fine lines and wrinkles. PMID- 28639750 TI - Protein lysine methyltransferase SMYD3 is involved in tumorigenesis through regulation of HER2 homodimerization. AB - HER2 is a receptor tyrosine kinase, which is amplified and overexpressed in a subset of human cancers including breast and gastric cancers, and is indicated in its involvement in progression of cancer. Although its specific ligand(s) has not been detected, HER2 homodimerization, which is critical for its activation, is considered to be dependent on its expression levels. Here, we demonstrate a significant role of HER2 methylation by protein lysine methyltransferase SMYD3 in HER2 homodimerization. We found that SMYD3 trimethylates HER2 protein at lysine 175. HER2 homodimerization was enhanced in the presence of SMYD3, and substitution of lysine 175 of HER2 with alanine (HER2-K175A) reduced the formation of HER2 homodimers. Furthermore, HER2-K175A revealed lower level of autophosphorylation than wild-type HER2. We also identified that knockdown of SMYD3 attenuated this autophosphorylation in breast cancer cells. Our results imply that SMYD3-mediated methylation of HER2 at Lysine 175 may regulate the formation of HER2 homodimer and subsequent autophosphorylation and suggest that the SMYD3-mediated methylation pathway seems to be a good target for development of novel anti-cancer therapy. PMID- 28639751 TI - Gefitinib or erlotinib in previously treated non-small-cell lung cancer patients: a cohort study in Taiwan. AB - Among treatment modalities for lung cancer, the most promising therapy is the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Both erlotinib and gefitinib, the two first-generation EGFR-TKIs, exhibit significant clinical responses for patients with lung adenocarcinoma. However, few studies have compared the effects of these two drugs, and results have been inconclusive because of the small sample sizes in these studies. Therefore, this study was conducted to investigate this issue. This retrospective nationwide cohort study enrolled NSCLC patients who received EGFR-TKIs after previous chemotherapy in Taiwan between 1996 and 2010 from the National Health Insurance Research Database. Clinical response and survival after receiving erlotinib and gefitinib were compared using logistic and Cox regression analyses, respectively. Inverse propensity score weighting and a sensitivity analysis in the EGFR-TKI responder (clinical improvement by taking EGFR-TKIs for 90 days), adherent patients (receiving EGFR-TKI on a daily basis), adenocarcinoma, and adenocarcinoma with second-line TKIs subgroup were performed for bias adjustment. A total of 7222 patients, including 4592 (63.6%) who received gefitinib, were identified. In the survival analysis, erlotinib was associated with a decline in 1-year progression free survival (PFS) (hazard ratio, HR: 1.15 [1.09-1.21]) and overall survival (OS) (HR: 1.10 [1.03-1.18]). The effects of various TKIs were consistent in the 4939 EGFR-TKI responders, adherent subgroup, adenocarcinoma subgroup, and adenocarcinoma with second-line TKIs subgroup. In previously treated EGFT-TKI naive NSCLC patients, those receiving gefitinib exhibited a longer PFS and OS than those receiving erlotinib. Additional large-scale randomized controlled trials are warranted to confirm this finding. PMID- 28639752 TI - Eosinophils in patients with lone atrial fibrillation. AB - BACKGROUND: Inflammation has been evidenced as a critical contributable mechanism for the atrial fibrillation (AF) onset and development. As the consistent inflammatory and oxidative marker, the effects of white blood cell (WBC) and its differential on lone atrial fibrillation (LAF) were investigated in the study. METHODS: A total of 126 patients with paroxysmal LAF who scheduled for rhythm control drug therapy and 120 age- and gender-matched subjects in sinus rhythm were included sequentially. Peripheral blood sample and clinic data were collected during the first evaluation. Recurrence of AF was evaluated by outpatient clinics and telephone visits for the following 12 months. RESULTS: Peripheral eosinophil count, neutrophil count, and left atrial diameter (LAD) were significantly higher in LAF than control. Within a follow-up of 12 months, 56 patients (44.4%) had developed AF recurrence. Patients with AF recurrence had higher eosinophil count and LAD. Univariable analyses showed a statistically significant relationship between eosinophil count (P = 0.042), LAD (P = 0.030), and AF recurrence. Multivariate logistic regression analysis showed that LAD (OR: 1.090 per 1 mm increase; 95% CI: 1.007-1.180; P = 0.032) and eosinophil (OR: 1.643 per 1 * 108 /L increase; 95% CI: 1.047-2.578; P = 0.031) were independent predictors of AF recurrence during antiarrhythmic drug therapy. CONCLUSION: Our results support the association of the WBC response and its components with the LAF. Especially, the peripheral eosinophil and LAD may play important roles in mediating inflammation and atrial remodeling in AF. PMID- 28639754 TI - ? PMID- 28639755 TI - [The combination of GLP-1 analogs and SGLT2 inhibitors : new perspectives ?] AB - Type 2 diabetes therapy has expanded considerably over the last decade. Two anti diabetic therapeutic groups, which are GLP-1 (glucagon-like peptide-1) receptor agonists and SGLT2 inhibitors (sodium-glucose co-transporter-2), have shown efficacy not only on glycemic control but also on weight and other parameters that will be detailed in this article. Cardiovascular safety studies for two of these molecules were shown for the first time to decrease overall and cardiovascular mortality. The combination of these two therapeutic classes provides a logical solution due to their different mechanisms of action. The DURATION-8 study designed to demonstrate the benefits of this combination will also be discussed in this article. PMID- 28639756 TI - [Value of continuous glucose monitoring in type 2 diabetic patients]. AB - Management of type 1 and type 2 diabetes mellitus is getting complex with the apparition of new treatments, but also new technologies. Among these, continuous glucose monitoring systems (CGMS) lead to a better glycemic control and less hypoglycemia in type 1 diabetic patients. Studies are scarce in type 2 diabetes but also seem to show a benefit, particularly in patients using insulin. Nevertheless, type 2 diabetic patients taking advantage of CGMS must be better defined. In any case, a multidisciplinary approach to the use of CGMS and interpretation of data is warranted. PMID- 28639757 TI - [Ketogenic diets : the miraculous solution ?] AB - The treatment of obesity and cardiovascular diseases is one of the most difficult and important challenges nowadays. Weight loss is frequently offered and aimed at improving some of the components of the metabolic syndrome. Among various diets, carbohydrate restriction is popular, specifically ketogenic diets, which are very low in carbohydrates and usually high in fats and /or proteins. Results are controversial, but some benefits such as weight loss and improved glycemic control have been described. Nevertheless, these effects seem to be limited in time. Moreover, these diets are not totally safe and can be associated with some adverse events such as the development of nonalcoholic fatty liver disease. The aim of this review is to discuss the role of ketogenic diets on different cardiovascular risk factors based on available evidence. PMID- 28639753 TI - Screening for ovarian cancer: imaging challenges and opportunities for improvement. PMID- 28639758 TI - [Treatment of type 2 diabetes : risk and benefits of metabolic surgery]. AB - Metabolic surgery is a serious option to treat type 2 diabetes. The latest guidelines consider surgery as one of the first option, especially in patients suffering from severe obesity or those who have uncontrolled diabetes. However, the radicality of metabolic surgery limits its prescription and is difficult to handle. Indeed, criteria of success remain insufficently understood in order to help caregivers to rigorously select the right candidates. This article proposes a review of the literature on the risks and benefits of metabolic surgery for the diabetic obese patient. PMID- 28639759 TI - [Diabetes mellitus secondary to an endocrine pathology : when to think about it ?] AB - An endocrine disease can be associated with glucose intolerance or diabetes mellitus, and the latter can falsely be considered as type 2 diabetes. Glycemic imbalance can be a direct or indirect consequence of excessive hormone production. Endocrine diseases such as acromegaly, Cushing's syndrome and pheochromocytoma can increase glucose production and cause insulin resistance. Hyperthyroidism, hyperaldosteronism, glucagonoma and somatostatinoma lead to hyperglycemia by other physiopathological mechanisms detailed in this article. When a clinical picture suggests an endocrine disease, several analyses need to be done in order to avoid treatment escalation of diabetes. PMID- 28639760 TI - [Euglycemic ketoacidosis : a complication of SGLT2 inhibitors]. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a new category of oral antidiabetics recently indicated for the treatment of type 2 diabetes. Their mechanism of action (inhibition of renal reabsorption of glucose) and the fact that they do not induce hypoglycemia (as monotherapy) make their clinical use interesting. Various adverse events have however been reported regarding these drugs with the euglycemic ketoacidosis being the most serious. In this article we aim to review the possible mechanism of this side effect and recommendations for use of SGLT2 inhibitors by means of a case report. PMID- 28639761 TI - ? PMID- 28639762 TI - ? PMID- 28639763 TI - ? PMID- 28639764 TI - ? PMID- 28639765 TI - ? PMID- 28639766 TI - ? PMID- 28639767 TI - ? PMID- 28639768 TI - ? PMID- 28639769 TI - [Heart and sport]. AB - Physical activity is beneficial for health and the cardiovascular risk profile. However, it can be dangerous in people with cardiac disease that might be asymptomatic. Individuals of all ages and all levels engage in sporting activities. The medical approach is different whether one evaluates a young competitive athlete, a sedentary adult who wants to start a recreational sport or a patient with heart disease who wishes to engage in sport. This article summarizes the various recommendations on the subject. PMID- 28639770 TI - [Long-term physical activity after a myocardial infarction : a permanent challenge]. AB - Cardiac rehabilitation is a well-defined multidisciplinary program with the objective to reduce mortality and morbidity, while also improving the exercise capacity and quality of life of the patient following a myocardial infarction. Despite the fact that a cardiovascular rehabilitation program is now recommended by international guidelines for all patients who have suffered from an acute coronary syndrome, only half of all patients actually participate to such a program in Switzerland. Even worse, especially when taking into consideration the population in Geneva, less than 5 % of patients follow a long-term cardiac maintenance program (phase III). Since 2015, our project has been to encourage patients who have completed a phase II cardiac rehabilitation program, to resume regular physical activity in the long term. PMID- 28639771 TI - [Post-myocardial infarction ventricular septal defect]. AB - Post-myocardial infarction ventricular septal defect corresponds to the rupture of the ventricular septum between the healthy and infarcted parts. It is a rare complication still associated with a high mortality rate. Its diagnostic should be evoked in case of pathologic cardiac auscultation and confirmed by emergent transthoracic echocardiography. Hemodynamic stabilisation, mainly with the insertion of an intra-aortic balloon pump is the first step in the management. The subsequent modality of closure, either surgical or transcatheter, as well as the ideal timing should be discussed in the Heart team. Successful closure decreases the 30-day mortality rate to 30-40 %. PMID- 28639772 TI - [Multidisciplinary cardiogenetic counselling]. AB - Multidisciplinary cardiogenetic consulting offers a global clinical approach to patients suffering from channelopathies or hereditary cardiomyopathies. Mutation is discovered in around 50 % of the cases. Several experts are working together to bring probands and their families useful and necessary informations to help them understanding causes, consequences and support of their disease. This approach is developped in close collaboration with the treating physician. PMID- 28639773 TI - [Paradigm shift in the treatment of atrial fibrillation. The importance of risk factor management]. AB - The prevalence of atrial fibrillation (AF) is constantly rising. Different studies have underlined the correlation between AF and modifiable risk factors such as obesity, obstructive sleep apnea, hypertension and sedentary lifestyle. Treatment of these comorbidities could significantly reduce the AF burden and the recurrence rate after cardioversion or ablation. These data should therefore lead to a paradigm shift in the management of AF. A strategy limited to catheter ablation or to the prescription of an antiarrhythmic drug is not sufficient. By analogy to angioplasty in coronary artery disease, the specific management of AF must be combined with the prevention and treatment of risk factors to increase the success rate. PMID- 28639774 TI - [Discovery of left ventricular hypertrophy during adult echocardiography]. AB - Left ventricular hypertrophy is a common finding during echocardiography. A precise evaluation of the left ventricular wall thickness, ventricular mass and distribution of hypertrophy is crucial both for diagnostic workup, follow-up and for prognostic evaluation. The differential diagnosis of left ventricular hypertrophy includes hypertrophic cardiomyopathies, hypertrophy secondary to abnormal left ventricular filling conditions, hypertrophy linked to intense physical training and the isolated basal septal hypertrophy of the elderly. Amongst the tools at the disposition of the cardiologist, regional analysis of longitudinal strain appears promising in helping distinguish cardiac amyloidosis form other forms of hypertrophy. PMID- 28639776 TI - ? PMID- 28639775 TI - [" Living facing death' : improving Lausanne's medical students " attitude toward end-of-life issues]. AB - The optional course " Living facing death " is the result of an innovative educational approach jointly developed by CHUV's Palliative Care Service, Lausanne's School of Medicine, Medical Ethics Unit and the students' association " Doctors & Death ". It is intended for 3rd and 4th grade medical students and was inspired by previous experiences conducted at Harvard Medical School. Its primary objective is to help students to " take some distances ". A mixed quantitative/qualitative satisfaction questionnaire was administered to all participating students at the completion of the course. It confirms experiential knowledge is a valuable teaching tool to improve medical students' attitude toward end-of-life issues. PMID- 28639777 TI - ? PMID- 28639779 TI - ? PMID- 28639778 TI - ? PMID- 28639780 TI - ? PMID- 28639781 TI - ? PMID- 28639783 TI - Plasmodium falciparum Mortality in Africa between 1990 and 2015. PMID- 28639784 TI - Plasmodium falciparum Mortality in Africa between 1990 and 2015. PMID- 28639785 TI - Risks of MRI in Patients with a Pacemaker or Defibrillator. PMID- 28639786 TI - Maternal Immunization. PMID- 28639787 TI - Recent Advances in Radical C-H Activation/Radical Cross-Coupling. AB - Research and industrial interest in radical C-H activation/radical cross-coupling chemistry has continuously grown over the past few decades. These reactions offer fascinating and unconventional approaches toward connecting molecular fragments with high atom- and step-economy that are often complementary to traditional methods. Success in this area of research was made possible through the development of photocatalysis and first-row transition metal catalysis along with the use of peroxides as radical initiators. This Review provides a brief and concise overview of the current status and latest methodologies using radicals or radical cations as key intermediates produced via radical C-H activation. This Review includes radical addition, radical cascade cyclization, radical/radical cross-coupling, coupling of radicals with M-R groups, and coupling of radical cations with nucleophiles (Nu). PMID- 28639788 TI - Controlled Antibody Release from Degradable Thermoresponsive Hydrogels Cross Linked by Diels-Alder Chemistry. AB - Amine-modified four- and eight-armed poloxamines were prepared and subsequently functionalized with maleimide or furyl groups. Aqueous solutions of these polymers exhibited an immediate gelation at a temperature above 37 degrees C. Concomitantly, Diels-Alder reactions gradually cross-linked and cured the gels. Different ratios between four- and eight-armed macromonomers were used to tune hydrogel stability and mechanical properties. In this way, hydrogel stability could be precisely controlled in the range of 14 to 329 days. Controlled release of the model antibody bevacizumab was achieved over a period of 7, 21, and 115 days. Release profiles were triphasic with a low burst; approximately 87% of the released antibody was intact and displayed functional binding. The hydrogels presented in this study are degradable, nontoxic, rapidly gelling, stable, and provide controlled antibody release. They can be tailored to match the demands of various applications and present an attractive platform for antibody delivery. PMID- 28639789 TI - Anti-Inflammatory Effect of Anti-TNF-alpha SiRNA Cationic Phosphorus Dendrimer Nanocomplexes Administered Intranasally in a Murine Acute Lung Injury Model. AB - Inflammation is an essential component of many lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), or acute lung injury. Our purpose was to design efficient carriers for lung delivery of small interfering RNA (siRNA) targeting tumor necrosis factor (TNF-alpha) in an acute lung injury model. To achieve this goal, two different types of phosphorus-based dendrimers with either pyrrolidinium or morpholinium as terminal protonated amino groups were selected for their better biocompatibility compared to other dendrimers. Dendriplexes containing pyrrolidinium surface groups demonstrated a stronger siRNA complexation, a higher cellular uptake, and enhanced in vitro silencing efficiency of TNF-alpha in the lipopolysaccharide (LPS)-activated mouse macrophage cell line RAW264.7, compared to morpholinium-containing dendriplexes. The better performance of the pyrrolidium dendriplexes was attributed to their higher pKa value leading to a stronger siRNA complexation and improved protection against enzymatic degradation resulting in a higher cellular uptake. The superior silencing effect of the pyrrolidinium dendriplexes, compared to noncomplexed siRNA, was confirmed in vivo in an LPS-induced murine model of short-term acute lung injury upon lung delivery via nasal administration. These data suggest that phosphorus dendriplexes have a strong potential in lung delivery of siRNA for treating inflammatory lung diseases. PMID- 28639791 TI - Insight into the Final Step of the Supramolecular Buildup of Eumelanin. AB - The final step in the supramolecular buildup of eumelanin particles is investigated regarding the involved species and mechanism. Time-resolved in situ light scattering and scanning electron microscopy reveal an aggregation of particles with a narrow size distribution around 40 nm, previously only observed as substructures. These form larger particles with again very uniform size and diameters around 200 nm. Aggregation of each single particle takes only a few minutes to complete, whereas the entire process goes on for at least 3 h, partly due to the kinetics of the precursors. The individual particles also undergo an additional consolidation step toward their final form, which takes up to 24 h. Atomic force microscopy shows that the size before consolidation is around twice the size of the final particles, due to free space between the substructures. Light scattering also reveals that the aggregation is random with respect to where the particles attach, as the shape of aggregates changes from sphere to coil, before it returns to a spherical shape at the end. Application of enzyme mediated autodeposition finally shows the potential to stop the supramolecular buildup at each level, and therefore enables isolation of the respective eumelanin particles at will. This may enable the full potential for melanin materials in nanotechnology deriving from its unique (for biological polymers) properties like paramagnetism, electrical conductivity, and many more. PMID- 28639790 TI - Programmable Assembly of Peptide Amphiphile via Noncovalent-to-Covalent Bond Conversion. AB - Controlling the number of monomers in a supramolecular polymer has been a great challenge in programmable self-assembly of organic molecules. One approach has been to make use of frustrated growth of the supramolecular assembly by tuning the balance of attractive and repulsive intermolecular forces. We report here on the use of covalent bond formation among monomers, compensating for intermolecular electrostatic repulsion, as a mechanism to control the length of a supramolecular nanofiber formed by self-assembly of peptide amphiphiles. Circular dichroism spectroscopy in combination with dynamic light scattering, size exclusion chromatography, and transmittance electron microscope analyses revealed that hydrogen bonds between peptides were reinforced by covalent bond formation, enabling the fiber elongation. To examine these materials for their potential biomedical applications, cytotoxicity of nanofibers against C2C12 premyoblast cells was tested. We demonstrated that cell viability increased with an increase in fiber length, presumably because of the suppressed disruption of cell membranes by the fiber end-caps. PMID- 28639792 TI - Emodiversity and biomarkers of inflammation. AB - There is growing evidence that inflammatory responses may help to explain how emotions get "under the skin" to influence disease susceptibility. Moving beyond examination of individuals' average level of emotion, this study examined how the breadth and relative abundance of emotions that individuals experience emodiversity-is related to systemic inflammation. Using diary data from 175 adults aged 40 to 65 who provided end-of-day reports of their positive and negative emotions over 30 days, we found that greater diversity in day-to-day positive emotions was associated with lower circulating levels of inflammation (indicated by IL-6, CRP, fibrinogen), independent of mean levels of positive and negative emotions, body mass index, anti-inflammatory medications, medical conditions, personality, and demographics. No significant associations were observed between global or negative emodiversity and inflammation. These findings highlight the unique role daily positive emotions play in biological health. (PsycINFO Database Record PMID- 28639793 TI - Cigarette-smoking trajectories of monoracial and biracial Blacks: Testing the intermediate hypothesis. AB - Research on the cigarette-smoking patterns of biracial adolescents and young adults is severely limited. In this study, we tested the intermediate biracial substance-use hypothesis, which suggests that the prevalence of substance use among biracial individuals falls intermediate to their monoracial counterparts. We examined cigarette-smoking trajectories of a de-aggregated sample of biracial Black adolescents and young adults. We used longitudinal data from the National Longitudinal Study of Adolescent and Adult Health (Add Health; Harris et al., 2009). Our sample (N = 9,421) included 4 monoracial groups (Black, White, Hispanic, and American Indian [AI]) and 3 biracial groups (Black-AI, Black Hispanic, and Black-White). Study hypotheses were tested using latent growth curve modeling. We found some support for the intermediate biracial substance-use hypothesis for 2 of 3 biracial groups (Black-American Indian, Black-Hispanic) and 2 of 4 cigarette-use outcomes (lifetime cigarette use, number of cigarettes smoked during past month for regular smokers). The cigarette-use trajectories of biracial Blacks were significantly different from only 1 corresponding monoracial group. Black-AIs and Black Hispanics engage in lifetime cigarette use at comparable rates to monoracial Blacks. Black-Hispanic regular smokers' rate of cigarette smoking is comparable to the higher rates of Hispanics and not to the lower rates of Blacks. Knowledge of the origins, developmental course, and consequences of tobacco use among the biracial population may lead to effective intervention programs and policies for this group. (PsycINFO Database Record PMID- 28639794 TI - Community health workers in diabetes care: A systematic review of randomized controlled trials. AB - INTRODUCTION: Maintaining optimal self-care in managing Type 2 diabetes is a common struggle for patients due to several barriers, including access to quality services, financial insecurity and/or lack of insurance, and emotional distress. Consequently, morbidity and mortality rates are high, alongside rising health care costs. Alternative approaches that address common barriers require further investigation. This systematic review of randomized controlled trials examines the effectiveness of using community health workers (CHWs) in Type 2 diabetes care. This effort is warranted to orient practitioners and researchers to the state of existing knowledge, and to direct clinical practice and future research. METHOD: Data were extracted from 17 peer-reviewed articles; they were examined with respect to theory integration, CHW intervention design, outcome variables, and findings. RESULTS: Approximately one-third of articles explicitly integrated theory into their research conceptualization and design. There was great variation across intervention dosages, attrition rates, and methods of CHW training. Main foci across studies' findings suggest that a CHW intervention has significant impacts on physical health outcomes, diabetes knowledge, self-care behaviors, and emotional distress and well-being. DISCUSSION: Principal implications relate to the need for more research regarding CHW intervention types and methods, and further investigation about the mechanisms of change within a CHW-delivered intervention. Findings support the case for more CHWs in treatment teams to bridge patients with the medical system. This research will serve to better equip providers in the support of patients managing Type 2 diabetes and advance the Triple Aim of health care. (PsycINFO Database Record PMID- 28639795 TI - "You're one of us": Black Americans' use of hypodescent and its association with egalitarianism. AB - Research on multiracial categorization has focused on majority group social perceivers (i.e., White Americans), demonstrating that they (a) typically categorize Black-White multiracials according to a rule of hypodescent, associating them more with their lower status parent group than their higher status parent group, and (b) do so at least in part to preserve the hierarchical status quo. The current work examines whether members of an ethnic minority group, Black Americans, also associate Black-White multiracials more with their minority versus majority parent group and if so, why. The first 2 studies (1A and 1B) directly compared Black and White Americans, and found that although both Blacks and Whites categorized Black-White multiracials as more Black than White, Whites' use of hypodescent was associated with intergroup antiegalitarianism, whereas Blacks' use of hypodescent was associated with intergroup egalitarianism. Studies 2-3 reveal that egalitarian Blacks use hypodescent in part because they perceive that Black-White biracials face discrimination and consequently feel a sense of linked fate with them. This research establishes that the use of hypodescent extends to minority as well as majority perceivers but also shows that the beliefs associated with the use of hypodescent differ as a function of perceiver social status. In doing so, we broaden the social scientific understanding of hypodescent, showing how it can be an inclusionary rather than exclusionary phenomenon. (PsycINFO Database Record PMID- 28639796 TI - Modality-switching in the Simon task: The clash of reference frames. AB - The representation of spatial information related to an event can influence behavior even when location is task-irrelevant, as in the case of Stimulus Response (S-R) compatibility effects on the Simon task. However, unlike single modality situations, which are often used to study the Simon effect, in real-life scenarios various sensory modalities provide spatial information coded in different coordinate systems. Here, we address the expression of S-R compatibility effects in mixed-modality contexts, where events can occur in 1 of various sensory modalities (i.e., vision, touch or audition). The results confirm that, in single-modality cases, Simon effects in vision are expressed in an external spatial frame of reference, while touch information is coded anatomically. Remarkably, when mixing visual and tactile trials in an unpredictable way, the Simon effect disappeared in vision whereas tactile Simon effects remained expressed in their own (anatomical) frame of reference. Mixing visual and auditory stimuli did not obliterate the visual Simon effect and S-R compatibility effects in an external reference frame were evident for both modalities. The extinction of visual Simon effects as a result of mixing visual and tactile modalities can be interpreted as a consequence of the dynamic reorganization of the weights associated to the different sources of spatial information at play. (PsycINFO Database Record PMID- 28639797 TI - The dark side of fluency: Fluent names increase drug dosing. AB - Prior research has demonstrated that high processing fluency influences a wide range of evaluations and behaviors in a positive way. But can high processing fluency also lead to potentially hazardous medical behavior? In 2 controlled experiments, we demonstrate that increasing the fluency of pharmaceutical drug names increases drug dosage. Experiment 1 shows that drugs with fluent names are perceived as safer than those with disfluent names and this effect increases drug dosage for both synthetically produced and herbal drugs. Experiment 2 demonstrates that people chose a higher dosage for themselves and for a child if the drug bears a fluent (vs. disfluent) name. Using linear regression based mediation analysis, we investigated the underlying mechanisms for the effect of fluency on risk perception in more detail. Contrary to prior research, we find that affect, but not familiarity, mediates the fluency-risk link. Our findings suggest that a drug name's fluency is a powerful driver of dosing behavior. (PsycINFO Database Record PMID- 28639798 TI - Working safely at some times and unsafely at others: A typology and within-person process model of safety-related work behaviors. AB - Why do individuals choose to work safely in some instances and unsafely in others? Though this inherently within-person question is straightforward, the preponderance of between-person theory and research in the workplace safety literature is not equipped to answer it. Additionally, the limited way in which safety-related behaviors tend to be conceptualized further restricts understanding of why individuals vary in their safety-related actions. We use a goal-focused approach to conceptually address this question of behavioral variability and contribute to workplace safety research in 2 key ways. First, we establish an updated typology of safety-related behaviors that differentiates behaviors based on goal choice (i.e., safe vs. unsafe behaviors), goal directedness (i.e., intentional vs. unintentional behaviors), and the means of goal pursuit (i.e., commission vs. omission and promotion vs. prevention-focused behaviors). Second, using an expectancy-value theoretical framework to explain variance in goal choice, we establish within-person propositions stating that safety-related goal choice and subsequent behaviors are a function of the target of safety-related behaviors, the instrumentality and resource requirement of behaviors, and the perceived severity, likelihood, and immediacy of the threats associated with behaviors. Taken together, we define what safety-related behaviors are, explain how they differ, and offer propositions concerning when and why they may vary within-persons. We explore potential between-person moderators of our theoretical propositions and discuss the practical implications of our typology and process model of safety-related behavior. (PsycINFO Database Record PMID- 28639799 TI - Aging and confidence judgments in item recognition. AB - We examined the effects of aging on performance in an item-recognition experiment with confidence judgments. A model for confidence judgments and response time (RTs; Ratcliff & Starns, 2013) was used to fit a large amount of data from a new sample of older adults and a previously reported sample of younger adults. This model of confidence judgments allows us to distinguish between changes evidence from memory and changes in decision-related components and it accounts for both RT distributions and response proportions. Older adults took longer to respond than younger adults, older adults exhibited a small decrease in the strength of evidence from memory compared with younger adults and a slight bias toward judging items as "old." The difference in RTs between the 2 age groups was primarily explained by the difference in the nondecision component. Although our small sample size makes the general conclusions about aging tentative, the results are consistent with other research examining the effects of aging in two choice RT tasks and response-signal tasks, and the study demonstrates that confidence judgment choice proportion and RT distribution data from older adults can be fit with the response time and confidence 2 (RTCON2) model. (PsycINFO Database Record PMID- 28639800 TI - Working memory capacity and the antisaccade task: A microanalytic-macroanalytic investigation of individual differences in goal activation and maintenance. AB - The association between working memory capacity (WMC) and the antisaccade task, which requires subjects to move their eyes and attention away from a strong visual cue, supports the claim that WMC is partially an attentional construct (Kane, Bleckley, Conway, & Engle, 2001; Unsworth, Schrock, & Engle, 2004). Specifically, the WMC-antisaccade relation suggests that WMC helps maintain and execute task goals despite interference from habitual actions. Related work has recently shown that mind wandering (McVay & Kane, 2009, 2012a, 2012b) and reaction time (RT) variability (Unsworth, 2015) are also related to WMC and they partially explain WMC's prediction of cognitive abilities. Here, we tested whether mind-wandering propensity and intraindividual RT variation account for WMC's associations with 2 antisaccade-cued choice RT tasks. In addition, we asked whether any influences of WMC, mind wandering, or intraindividual RT variation on antisaccade are moderated by (a) the temporal gap between fixation and the flashing location cue, and (b) whether targets switch sides on consecutive trials. Our quasi-experimental study reexamined a published dataset (Kane et al., 2016) comprising 472 subjects who completed 6 WMC tasks, 5 attentional tasks with mind-wandering probes, 5 tasks from which we measured intraindividual RT variation, and 2 antisaccade tasks with varying fixation-cue gap durations. The WMC-antisaccade association was not accounted for by mind wandering or intraindividual RT variation. WMC's effects on antisaccade performance were greater with longer fixation-to-cue intervals, suggesting that goal activation processes-beyond the ability to control mind wandering and RT variability-are partially responsible for the WMC-antisaccade relation. (PsycINFO Database Record PMID- 28639801 TI - The evolving landscape of Title IX: Predicting mandatory reporters' responses to sexual assault disclosures. AB - Approximately 1 in 4 women is sexually assaulted in college, a problem that federal law has attempted to address with recent changes. Under the evolving landscape of Title IX, and related law, universities nationwide have overhauled their sexual assault policies, procedures, and resources. Many of the new policies designate undergraduate resident assistants (RAs) as Responsible Employees-requiring them to provide assistance and report to the university if a fellow student discloses sexual assault. We investigated factors that predict the likelihood of RAs enacting their policy mandate, that is, reporting sexual assault disclosures to university authorities and referring survivors to sexual assault resources. Based on data from 305 Responsible Employee RAs, we found that likelihood to report and refer varied, depending on RAs' knowledge of reporting procedures and resources, trust in these supports, and perceptions of mandatory reporting policy. Understanding mandatory reporter behavior is crucial, because help-providers' responses can have serious implications for the recovery of sexual assault survivors. Our findings elucidate some effects of changes in the interpretation and implementation of Title IX, with potential to inform the development of more theoretically and empirically informed policies. (PsycINFO Database Record PMID- 28639802 TI - A cross-cultural analysis of the Test of Memory Malingering among Latin American Spanish-speaking adults. AB - Cognitive efforts tests, such as the Test of Memory Malingering (TOMM; Tombaugh, 1997), are widely used internationally, yet there is a dearth of research that has assessed the utility of these measures in different cultures, countries, and languages. This study evaluated the specificity of the TOMM Trial 2 among a sample of 3,590 Spanish-speaking adults residing in 8 Latin American countries (Argentina, Bolivia, Chile, Colombia, Mexico, Paraguay, Peru, and Puerto Rico). Trial 2 TOMM scores were negatively associated with participants' age and positively associated with level of education. Country development, as measured by the United Nations Human Development Index, was also positively associated with TOMM scores. With the widespread use of cognitive efforts tests, this study offers useful insights into the utility of the TOMM in the assessment of Spanish speakers and highlights potential cultural biases that may impact test performance. Furthermore, this study raises concerns about the cross-cultural applicability of the TOMM, particularly when using cut scores established and evaluated primarily on North American, English-speaking samples. Forensic psychologists should be cautious when interpreting TOMM performance with Spanish speaking adults from Latin American countries because it appears that there are cross-cultural differences that influence test performance. (PsycINFO Database Record PMID- 28639803 TI - Determining when to conduct a violence risk assessment: Development and initial validation of the Fordham Risk Screening Tool (FRST). AB - Techniques to assess violence risk are increasingly common, but no systematic approach exists to help clinicians decide which psychiatric patients are most in need of a violence risk assessment. The Fordham Risk Screening Tool (FRST) was designed to fill this void, providing a structured, systematic approach to screening psychiatric patients and determining the need for further, more thorough violence risk assessment. The FRST was administered to a sample of 210 consecutive admissions to the civil psychiatric units of an urban medical center, 159 of whom were subsequently evaluated using the Historical Clinical Risk Management-20, version 3, to determine violence risk. The FRST showed a high degree of sensitivity (93%) in identifying patients subsequently deemed to be at high risk for violence (based on the Case Prioritization risk rating). The FRST also identified all of the patients (100%) rated high in potential for severe violence (based on the Serious Physical Harm Historical Clinical Risk Management 20, version 3, summary risk rating). Sensitivity was more modest when individuals rated as moderate risk were included as the criterion (rather than only those identified as high risk). Specificity was also moderate, screening out approximately half of all participants as not needing further risk assessment. A systematic approach to risk screening is clearly needed to prioritize psychiatric admissions for thorough risk assessment, and the FRST appears to be a potentially valuable step in that process. (PsycINFO Database Record PMID- 28639804 TI - Reflective functioning, physiological reactivity, and overcontrol in mothers: Links with school-aged children's reflective functioning. AB - Theorists argue that parental reflective functioning (PRF) is activated in response to emotions, potentially supporting parenting sensitivity even when arousal is high. That is, when parents become emotionally reactive when interacting with their children, those who can use PRF to understand their children's mental states should be able to parent sensitively, which, in turn, should promote children's ability to understand their own mental states. We test this theory by examining whether, in the face of physiological reactivity, mothers' PRF inhibits one form of parenting insensitivity, overcontrol (OC), and whether this process in turn predicts children's RF. A diverse sample of school age children (N = 106, Mage = 10.27 years) completed a standardized failure paradigm while their mothers were asked to passively observe. Following the stressor, mothers and children independently completed interviews regarding the task, which were later coded for RF with respect to children's mental states. Mothers provided saliva samples before and after the stressor, and after the interview, which were later assayed for cortisol reactivity; maternal behavior during the stressor task was coded for OC. Among mothers with low levels of RF, greater increases in cortisol were associated with more displays of OC, whereas among mothers with high PRF, greater cortisol reactivity was associated with fewer OC behaviors. For low PRF mothers, higher reactivity and OC predicted lower children's PRF for their own experiences. The findings provide initial evidence for a protective function of PRF, and may point toward the importance of promoting PRF in intervention programs to reduce parental OC. (PsycINFO Database Record PMID- 28639806 TI - Math-related career aspirations and choices within Eccles et al.'s expectancy value theory of achievement-related behaviors. AB - Which occupation to pursue is one of the more consequential decisions people make and represents a key developmental task. Yet the underlying developmental processes associated with either individual or group differences in occupational choices are still not well understood. This study contributes toward filling this gap, focusing in particular on the math domain. We examined two aspects of Eccles et al.'s (1983) expectancy-value theory of achievement-related behaviors: (a) the reciprocal associations between adolescents' expectancy and subjective task value beliefs and adolescents' career plans and (b) the multiplicative association between expectancies and values in predicting occupational outcomes in the math domain. Our analyses indicate that adolescents' expectancy and subjective task value beliefs about math and their math- or science-related career plans reported at the beginning and end of high school predict each other over time, with the exception of intrinsic interest in math. Furthermore, multiplicative associations between adolescents' expectancy and subjective task value beliefs about math predict math-related career attainment approximately 15 years after graduation from high school. Gender differences emerged regarding career-related beliefs and career attainment, with male students being more likely than female to both pursue and attain math-related careers. These gender differences could not be explained by differences in beliefs about math as an academic subject. (PsycINFO Database Record PMID- 28639805 TI - How do parent expectations promote child academic achievement in early elementary school? A test of three mediators. AB - Using a longitudinal mediation framework and a low-income sample, this study had 2 aims: (a) to model bidirectional associations between parent academic expectations and child academic outcomes from first through fifth grade, and (b) to explore 3 mediators of parental influence: parent involvement in child schooling, child learning behaviors, and child perceived academic competence. Participants included 356 children and their caregivers (89% mothers) recruited from Head Start centers (58% European American, 25% African American, 17% Latino). At each time point (grades 1, 2, 3, 5), parents rated their academic expectations, teachers rated parent involvement and child learning behaviors, and children rated their self-perceptions of their academic competence. Bidirectional longitudinal associations emerged between parent academic expectations and child academic outcomes. Child learning behaviors mediated this association from first to third grade, whereas child perceived academic competence mediated from second to fifth grade. Parallel cross-lagged models replicated these findings with child academic outcomes assessed using a test of reading achievement and teacher ratings of academic performance. (PsycINFO Database Record PMID- 28639807 TI - The impact of time and repeated exposure on famous person knowledge in amnestic mild cognitive impairment and Alzheimer's disease. AB - OBJECTIVE: Famous people knowledge has been shown to be impaired early in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). However, the question of whether recently acquired knowledge is more impaired than remotely acquired knowledge remains a matter of debate. The aim of this study was to investigate the patterns of semantic memory impairment in aMCI and AD by investigating 2 factors that may influence the retrieval of such knowledge, namely remoteness and frequency of repetition of information over time. METHOD: Three groups (19 controls, 20 aMCI, and 20 AD patients) were compared on a test assessing general and specific biographical knowledge about famous people, where the period of acquired fame (remote vs. recent) and the type of fame (enduring vs. transient) were controlled for. RESULTS: Global performance of aMCI and AD patients was significantly poorer than that of controls. However, different patterns of recall were observed as a function of time and type of fame. A temporal gradient was found in both patient groups for enduring names but not for transient ones, whereby knowledge about remote enduring famous persons was better recalled. Patients were more impaired at questions assessing specific biographical knowledge (unique to an individual) than more general knowledge. CONCLUSIONS: Tests of famous people knowledge offer a unique opportunity to investigate semantic deficits in aMCI and AD, because they make it possible to estimate the time at which memories were acquired, as well as the type of fame. Results are discussed in light of memory consolidation models. (PsycINFO Database Record PMID- 28639808 TI - A quarter century of advances in the statistical analysis of longitudinal neuropsychological data. AB - OBJECTIVE: Over the last 25 years, there has been an unprecedented increase in federal funding for large-scale longitudinal studies, many of which collect neuropsychological or neuroimaging outcome measures. These studies have collected data from thousands of study participants across multiple waves of data collection over many years. With the increased availability of longitudinal data, data sharing policies have become more liberal, thereby offering significant opportunities for interested researchers to carry out their own longitudinal research with these data. At the same time, these opportunities have stimulated new conceptualizations of longitudinal change and have led to the development of novel approaches toward analysis of longitudinal data. My aim is to review these new conceptualizations and novel data analytic approaches. METHOD: In this article, I describe the state of the field a quarter century ago with respect to available longitudinal studies, and I trace the growth of federally funded longitudinal studies over the last 25 years by describing 18 of these projects, many of which are still collecting data. In the second part of this article, I describe changes in the methods used to analyze longitudinal data, transitioning from the paired t test and repeated measures ANOVA to latent change scores, linear mixed effects modeling, and latent growth curve models. Changes in the approach to management of missing data are also discussed. CONCLUSIONS: Future studies should abandon traditional longitudinal analytic methods in favor of contemporary approaches given their increased power, greater accuracy, and widespread availability. (PsycINFO Database Record PMID- 28639809 TI - The advantage of being oneself: The role of applicant self-verification in organizational hiring decisions. AB - In this paper, we explore whether individuals who strive to self-verify flourish or flounder on the job market. Using placement data from 2 very different field samples, we found that individuals rated by the organization as being in the top 10% of candidates were significantly more likely to receive a job offer if they have a stronger drive to self-verify. A third study, using a quasi-experimental design, explored the mechanism behind this effect and tested whether individuals who are high and low on this disposition communicate differently in a structured mock job interview. Text analysis (LIWC) of interview transcripts revealed systematic differences in candidates' language use as a function of their self verification drives. These differences led an expert rater to perceive candidates with a strong drive to self-verify as less inauthentic and less misrepresentative than their low self-verifying peers, making her more likely to recommend these candidates for a job. Taken together, our results suggest that authentic self presentation is an unidentified route to success on the job market, amplifying the chances that high-quality candidates can convert organizations' positive evaluations into tangible job offers. We discuss implications for job applicants, organizations, and the labor market. (PsycINFO Database Record PMID- 28639810 TI - Overstated evidence for short-term effects of violent games on affect and behavior: A reanalysis of Anderson et al. (2010). AB - Violent video games are theorized to be a significant cause of aggressive thoughts, feelings, and behaviors. Important evidence for this claim comes from a large meta-analysis by Anderson and colleagues (2010), who found effects of violent games in experimental, cross-sectional, and longitudinal research. In that meta-analysis, the authors argued that there is little publication or analytic bias in the literature, an argument supported by their use of the trim and-fill procedure. In the present manuscript, we reexamine their meta-analysis using a wider array of techniques for detecting bias and adjusting effect sizes. Our conclusions differ from those of Anderson and colleagues in 3 salient ways. First, we detect substantial publication bias in experimental research on the effects of violent games on aggressive affect and aggressive behavior. Second, after adjustment for bias, the effects of violent games on aggressive behavior in experimental research are estimated as being very small, and estimates of effects on aggressive affect are much reduced. In contrast, the cross-sectional literature finds correlations that appear largely unbiased. Third, experiments meeting the original authors' criteria for methodological quality do not yield larger adjusted effects than other experiments, but instead yield larger indications of bias, indicating that perhaps they were selected for significance. We outline future directions for stronger experimental research. The results indicate the need for an open, transparent, and preregistered research process to test the existence of the basic phenomenon. (PsycINFO Database Record PMID- 28639811 TI - Violent video game effects remain a societal concern: Reply to Hilgard, Engelhardt, and Rouder (2017). AB - A large meta-analysis by Anderson et al. (2010) found that violent video games increased aggressive thoughts, angry feelings, physiological arousal, and aggressive behavior and decreased empathic feelings and helping behavior. Hilgard, Engelhardt, and Rouder (2017) reanalyzed the data of Anderson et al. (2010) using newer publication bias methods (i.e., precision-effect test, precision-effect estimate with standard error, p-uniform, p-curve). Based on their reanalysis, Hilgard, Engelhardt, and Rouder concluded that experimental studies examining the effect of violent video games on aggressive affect and aggressive behavior may be contaminated by publication bias, and these effects are very small when corrected for publication bias. However, the newer methods Hilgard, Engelhardt, and Rouder used may not be the most appropriate. Because publication bias is a potential a problem in any scientific domain, we used a comprehensive sensitivity analysis battery to examine the influence of publication bias and outliers on the experimental effects reported by Anderson et al. We used best meta-analytic practices and the triangulation approach to locate the likely position of the true mean effect size estimates. Using this methodological approach, we found that the combined adverse effects of outliers and publication bias was less severe than what Hilgard, Engelhardt, and Rouder found for publication bias alone. Moreover, the obtained mean effects using recommended methods and practices were not very small in size. The results of the methods used by Hilgard, Engelhardt, and Rouder tended to not converge well with the results of the methods we used, indicating potentially poor performance. We therefore conclude that violent video game effects should remain a societal concern. (PsycINFO Database Record PMID- 28639814 TI - Interventions for alcohol-related risky sexual behaviors among college students: A systematic review. AB - Alcohol-related risky sexual behaviors are common among college students. Though various interventions targeting these behaviors have been examined, the literature does not currently include a review of these strategies. A comprehensive literature search was conducted, yielding 7 randomized controlled trials. Relevant outcome variables included unprotected sex, alcohol in conjunction with sex, and number of sexual partners. Findings suggested that interventions utilizing reminder cues or motivational interviewing-based techniques were largely found to be effective in increasing condom use behaviors among intoxicated individuals, while support for personalized normative feedback (PNF) for the same outcome was mixed. However, PNF interventions were generally effective in reducing alcohol use in conjunction with sex. Finally, though few studies examined number of sexual partners, there are mixed findings for interventions (i.e., motivational interviewing, PNF) targeting this outcome. Overall, there is promising, albeit mixed, evidence of the effectiveness of interventions targeting various alcohol-related risky sexual behaviors among college students. Strengths, limitations, and implications of the findings of this systematic review for future research are discussed. (PsycINFO Database Record PMID- 28639813 TI - Contingency management interventions for tobacco and other substance use disorders in pregnancy. AB - Contingency management (CM) is an effective intervention for reducing use of licit and illicit substances in a variety of populations. Pregnant women are a vulnerable population with much to gain from effective interventions for substance use disorders, and for whom CM interventions may be especially well suited. We reviewed the literature on CM interventions among pregnant women with tobacco and other substance use disorders with 3 aims: (a) describe the effectiveness of CM for reducing use of tobacco and other substances during pregnancy, (b) describe the effects of CM interventions on infant outcomes, and (c) identify needs for future research on CM in pregnancy. Our search strategy revealed 27 primary studies of CM in pregnancy. CM was effective in the majority of studies targeting nicotine abstinence, and results were mixed in studies targeting illicit substances. A variety of methodologies were used within the relatively small number of studies making it difficult to identify underlying mechanisms. Also, very few studies reported maternal and infant outcomes, and significant effects of CM were only apparent when secondary analyses pooled data from multiple studies. Furthermore, there is extremely limited data on the cost effectiveness of CM interventions in pregnancy. Future research should address these 3 areas to better determine the ultimate value of CM as an efficacious treatment for pregnant women with substance use disorders. (PsycINFO Database Record PMID- 28639812 TI - Contingency management treatment for substance use disorders: How far has it come, and where does it need to go? AB - Contingency management (CM) interventions consistently improve substance abuse treatment outcomes, yet CM remains a highly controversial intervention and is rarely implemented in practice settings. This article briefly outlines the evidence base of CM and then describes 4 of the most often-cited concerns about it: philosophical, motivational, durability, and economic. Data supporting and refuting each of these issues are reviewed. The article concludes with suggestions to address these matters and other important areas for CM research and implementation, with the aims of improving uptake of this efficacious intervention in practice settings and outcomes of patients with substance use disorders. (PsycINFO Database Record PMID- 28639815 TI - A multivariate meta-analysis of motivational interviewing process and outcome. AB - Motivational interviewing (MI) theory proposes a process whereby a set of therapist behaviors has direct effects on client outcomes and indirect effects through in-session processes (e.g., client change talk). Despite clear empirical support for the efficacy of MI across settings, the results of studies evaluating proposed links between MI process and outcome have been less clear. In the present study, we used a series of multivariate meta-analyses to test whether there are differential relationships between specific MI-consistent and MI inconsistent therapist behaviors, MI therapist global ratings, client change language, and clinical outcomes. Based on 19 primary studies (N = 2,614), we found a significant relationship between MI-consistent therapist behaviors and greater client change talk, as well as greater client sustain talk. Higher therapist global ratings (empathy and MI spirit) were significantly related to increased MI-consistent behaviors, decreased MI-inconsistent behaviors, increased client change talk, yet also increased client sustain talk. Therapist global ratings were not significantly related to clinical outcomes. Client sustain talk was a significant predictor of worse clinical outcomes, while client change talk was unrelated to outcome. Variability within the correlations indicated that MI consistent and MI-inconsistent therapist behaviors were differentially related to therapist global ratings of empathy and MI spirit. Similar to past research, present findings provide equivocal support for hypothesized MI process outcome relationships. Clinical implications and future areas of MI mechanism research are discussed. (PsycINFO Database Record PMID- 28639816 TI - Review of interventions to reduce ultraviolet tanning: Need for treatments targeting excessive tanning, an emerging addictive behavior. AB - Millions of Americans engage in tanning each year, defined as intentional ultraviolet radiation (UVR) exposure in the form of sunbathing or the use of indoor tanning beds. An emerging body of research suggests that UVR has addictive properties and some tanners engage in excessive tanning. This article provides an overview of the evidence of tanning addiction and a systematic review of existing tanning interventions with the goal of evaluating their potential to impact addicted tanners. Our search identified 24 intervention studies that were summarized and discussed according to 3 primary themes. First, there is a dearth of tanning interventions that target excessive tanning or are designed as treatments for tanning addiction. Second, tanning interventions are primarily educational interventions designed to increase knowledge of the risks of tanning. Third, there are notable aspects of existing tanning interventions that are relevant to addiction science, including the use of brief motivational and cognitive-behavioral-based interventions. Future directions are considered including recommendations for utilizing the existing evidence base to formulate interventions targeting excessive tanners. (PsycINFO Database Record PMID- 28639818 TI - A critical examination of the research and theoretical underpinnings discussed in Thomson, Besner, and Smilek (2016). AB - Thomson, Besner, and Smilek (2016) propose that performance decrements associated with sustained attention are not consistently the result of a decline in perceptual sensitivity. Thomson et al. (2016) present empirical evidence using a novel, nontraditional vigilance task to support their assumptions. However, in the present rebuttal, we argue that the authors have not only have misinterpreted previous research in sustained attention, but also have misapplied those interpretations to their study. Thomson et al. have also neglected key elements of the literature in their argument, including research on expectancy theory and individual differences on vigilance performance. Furthermore, Thomson and colleagues implement an experimental paradigm that is not appropriate for evaluating sensitivity and bias changes in vigilance tasks. Finally, their analyses do not capture the manner in which changes in response bias and sensitivity can manifest in signal detection theory. We discuss the theoretical and experimental issues contained in Thomson et al. (2016) and propose suggestions for future vigilance research in this area. (PsycINFO Database Record PMID- 28639817 TI - A systematic review of treatments for problem gambling. AB - Gambling problems impact 0.2%-4.0% of the population, and research related to treating gambling has burgeoned in the last decades. This article reviews trials for psychosocial treatments of gambling problems. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses Standards, we identified 21 randomized trials. Eleven studies evaluated interventions delivered via multisession, in person therapy: cognitive therapies, cognitive-behavioral (CB) therapies, and motivational interventions (MI) alone or with CB therapies. An additional 10 studies used approaches that involved 1 or fewer in-person sessions; these included workbooks with CB exercises alone or in combination with MI and brief feedback or advice interventions. Although most studies found some benefits of CB therapy (alone or combined with MI) and brief feedback or advice relative to the control condition in the short term, only a handful of studies demonstrated any long-term benefits. Nearly half the studies used waitlist controls, precluding an understanding of long-term efficacy, and standardized outcomes measures are also lacking. Populations also differ markedly across studies, from nontreatment seeking persons who screened positive for gambling problems to those with severe gambling disorder, and these discrepant populations may require different interventions. Although problem gamblers with less pronounced symptoms may benefit from very minimal interventions, therapist contact generally improved outcomes relative to entirely self-directed interventions, and at least some therapist contact may be necessary for patients with more severe gambling pathology to benefit from CB interventions. As treatment services for gambling continue to grow, this review provides timely information on best practices for gambling treatment. (PsycINFO Database Record PMID- 28639820 TI - Adolescent sympathetic activity and salivary C-reactive protein: The effects of parental behavior. AB - OBJECTIVE: This study utilized a novel multisystem approach to investigate the effect of observed parental behavior on the relationship between biological mechanisms associated with disease processes (i.e., autonomic physiology and immune response) among their adolescent children. METHOD: Thirty-three adolescents (23 males), aged 11-13, and their parents participated in a laboratory session in which adolescents provided baseline measures of autonomic (sympathetic) activity, and adolescents and 1 parent participated in a laboratory based dyadic conflict resolution interaction task. This included 3 male parent/male adolescent dyads, 20 female parent/male adolescent dyads, 3 male parent/female adolescent dyads, and 7 female parent/female adolescent dyads. Approximately 3 years later, adolescents provided a salivary measure of C Reactive Protein (sCRP) to index inflammation. RESULTS: Analyses revealed a positive association between sympathetic activity and sCRP, as well as a moderating role of positive parental behavior in this relationship, such that the association between sympathetic activity and sCRP was greater among adolescents whose parents displayed shorter duration of positive affect. CONCLUSIONS: Overall findings indicate parental behavior may influence the association between adolescent sympathetic activity and inflammatory processes. These findings have important implications for understanding the impact of psychosocial factors on biological mechanisms of disease. (PsycINFO Database Record PMID- 28639819 TI - Effects of caregiving status and changes in depressive symptoms on development of physical morbidity among long-term cancer caregivers. AB - OBJECTIVE: Cancer caregiving burden is known to vary across the survivorship trajectory and has been linked with caregivers' subsequent health impairment. Little is known, however, regarding how risk factors during long-term survivorship relate to vulnerability to caregivers' health during that period. This study examined effects of caregiving status and depressive symptoms on development of physical morbidity by 5 years postdiagnosis. METHOD: Family caregivers (N = 491; Mage = 55.78) completed surveys at 2 (Time 1 [T1]) and 5 years (T2) after their care recipients' cancer diagnosis. Demographic and caregiving context variables known to affect caregivers' health were assessed at T1. Self-reported depressive symptoms and a list of physical morbid conditions were assessed at T1 and T2. Caregiving status (former, current, or bereaved) was assessed at T2. RESULTS: Hierarchical negative binomial regression revealed that current caregivers at T2 (p = .02), but not those bereaved by T2 (p = .32), developed more physical morbid conditions between T1 and T2 compared with former caregivers, controlling for other variables. Independently, caregivers reporting either newly emerging or chronically elevated depressive symptoms at T2 (ps < .03), but not those whose symptoms remitted at T2 (p = .61), showed greater development of physical morbidity than did those reporting minimal depressive symptoms at both T1 and T2. CONCLUSIONS: Results highlight the roles of long-term caregiving demands and depressive symptoms in cancer caregivers' premature physical health decline. Clinical attention through the long-term survivorship trajectory should be emphasized for caregivers of patients with recurrent or prolonged illness and to address caregivers' elevated depressive symptoms. (PsycINFO Database Record PMID- 28639821 TI - Perceived discrimination: Associations with physical and cognitive function in older adults. AB - OBJECTIVES: Perceived discrimination has been associated with poor physical and psychological health. There is limited research examining perceived discrimination in older adults, and its effects on health in later life. The aim of this study is to extend research in this area by examining longitudinal associations between reported everyday discrimination and physical and cognitive function in older adults. METHOD: The present study uses a national sample of 4,886 community-dwelling individuals aged 60 years and older from the English Longitudinal Study of Ageing. Perceived discrimination was assessed at baseline by asking participants about the frequency with which they experienced 5 everyday discriminatory situations. Cognitive functioning, comprising tests of recall and a test of verbal fluency, and physical functioning, comprising a timed walk test, were measured identically at baseline and follow-up. Multiple regression analyses were performed, adjusting for sociodemographic and health status variables. RESULTS: At baseline, 39.3% of participants reported being discriminated against at least a few times a year. After adjusting for demographic variables, health status, and depression, baseline discrimination was associated with poorer recall (B = -0.26, 95% CI [-0.44, -0.08]) and slower gait speed (B = -0.02, 95% CI [ 0.03, -0.004]) at follow-up. Discrimination was not associated with poorer verbal fluency (B = -0.12, 95% CI [-0.45, 0.22]) at follow-up. CONCLUSIONS: The experience of discrimination is common among older adults and is associated with poorer physical and cognitive functioning. Addressing issues around discrimination in older adults may contribute to maintaining functioning in later life. (PsycINFO Database Record PMID- 28639822 TI - Exposure to alcohol advertising and adolescents' drinking beliefs: Role of message interpretation. AB - OBJECTIVE: Recent research revealed momentary associations between exposure to alcohol advertising and positive beliefs about alcohol among adolescents (Martino et al., 2016). We reanalyzed those data to determine whether associations depend on adolescents' appraisal of ads. METHOD: Over a 10-month period in 2013, 589 youth, ages 11-14, in the Los Angeles, CA, area, participated in a 14-day ecological momentary assessment, logging all exposures to alcohol advertisements as they occurred and completing brief assessments of their skepticism toward, liking of, and identification with any people in each ad, as well as their alcohol-related beliefs at the moment. Participants also completed measures of their alcohol- related beliefs at random moments of nonexposure throughout each day. Mixed-effects regression models compared beliefs about alcohol at moments of exposure to alcohol advertising that was appraised in a particular way (e.g., with liking, without liking) to beliefs at random moments. RESULTS: When youth encountered ads they appraised positively, their beliefs about alcohol were significantly more positive than when they were queried at random moments. Beliefs in the presence of ads that were not positively appraised were generally similar to beliefs at random moments. CONCLUSION: Youth are active participants in the advertising process. How they respond to and process alcohol advertising strongly moderates the association between exposure and alcohol-related beliefs. More effort is needed to identify attributes of alcohol advertisements, and of youth, that determine how youth process alcohol ads. This information can be used to either limit exposure to problematic ads or make youth more resilient to such exposure. (PsycINFO Database Record PMID- 28639823 TI - Our own action kinematics predict the perceived affective states of others. AB - Our movement kinematics provide useful cues about our affective states. Given that our experiences furnish models that help us to interpret our environment, and that a rich source of action experience comes from our own movements, in the present study, we examined whether we use models of our own action kinematics to make judgments about the affective states of others. For example, relative to one's typical kinematics, anger is associated with fast movements. Therefore, the extent to which we perceive anger in others may be determined by the degree to which their movements are faster than our own typical movements. We related participants' walking kinematics in a neutral context to their judgments of the affective states conveyed by observed point-light walkers (PLWs). As predicted, we found a linear relationship between one's own walking kinematics and affective state judgments, such that faster participants rated slower emotions more intensely relative to their ratings for faster emotions. This relationship was absent when observing PLWs where differences in velocity between affective states were removed. These findings suggest that perception of affective states in others is predicted by one's own movement kinematics, with important implications for perception of, and interaction with, those who move differently. (PsycINFO Database Record PMID- 28639824 TI - Upside-down: Perceived space affects object-based attention. AB - Object-based attention influences the subjective metrics of surrounding space. However, does perceived space influence object-based attention, as well? We used an attentive tracking task that required sustained object-based attention while objects moved within a tracking space. We manipulated perceived space through the availability of depth cues and varied the orientation of the tracking space. When rich depth cues were available (appearance of a voluminous tracking space), the upside-down orientation of the tracking space (objects appeared to move high on a ceiling) caused a pronounced impairment of tracking performance compared with an upright orientation of the tracking space (objects appeared to move on a floor plane). In contrast, this was not the case when reduced depth cues were available (appearance of a flat tracking space). With a preregistered second experiment, we showed that those effects were driven by scene-based depth cues and not object based depth cues. We conclude that perceived space affects object-based attention and that object-based attention and perceived space are closely interlinked. (PsycINFO Database Record PMID- 28639825 TI - Sync or separate? No compelling evidence for unintentional interpersonal coordination between Usain Bolt and Tyson Gay on the 100-meter world record race. AB - In a recent observation article in Journal of Experimental Psychology: Human Perception and Performance (JEP:HPP; Varlet & Richardson, 2015) the 100-m sprint final of the World Championship in Athletics in Berlin of 2009 (i.e., the current world record race) was analyzed. That study reported occurrence of spontaneous, unintentional interpersonal synchronization between Usain Bolt and Tyson Gay, the respective winner and runner-up of that race. In the present commentary article, however, we argue that the results and conclusion of that study cannot be warranted because of methodological shortcomings. We addressed the same research question and reassessed the same race using an alternative data analysis method. These results revealed that as yet there is no sufficient ground to conclude that in the 100-m world record race synchronization occurred between Bolt and Gay. Yet, our reanalysis suggested that even at this very elite level the individual movement frequencies did seem to vary to such an extent that synchronization would theoretically still be possible, thereby providing incentives for further examination of potential unintentional synchronization in coactive sports. (PsycINFO Database Record PMID- 28639826 TI - Imaging Appearance of Advanced Chronic Adhesive Arachnoiditis: A Retrospective Review. AB - OBJECTIVE: Chronic adhesive arachnoiditis (CAA) is rare and has potentially devastating clinical consequences. The objective of this article is to review the clinical features of CAA and describe its appearance on imaging, to increase radiologists' awareness of this challenging diagnosis. MATERIALS AND METHODS: Twenty-nine cases of advanced CAA seen at our institution over 18 years (1995 2013) were retrospectively reviewed. Chart review was performed, with attention given to data on clinical presentation, suspected cause, and interventions performed. All patients underwent MRI, and seven patients also underwent CT myelography. Clinical and imaging features were evaluated and categorized. RESULTS: The 29 patients ranged in age from 23 to 96 years and included 11 women and 18 men. Suspected underlying causative factors included trauma (n = 10), prior surgery (n = 9), nontraumatic subarachnoid hemorrhage (n = 7), infection (n = 3), myelography with iophendylate used as contrast medium (n = 1), Guillain Barre syndrome (n = 1), ankylosing spondylitis (n = 1), and unknown causes (n = 1). Imaging characteristics include loculated CSF collections (n = 23), nerve root clumping, enhancement, and displacement (n = 15), cord swelling with increased T2 signal (n = 12), arachnoid septations (n = 11), cord atrophy (n = 6), syrinx (n = 5), and intrathecal calcifications (n = 3). Ten patients underwent surgical procedures, and most had only brief clinical improvement. CONCLUSION: CAA is a rare cause of devastating neurologic symptoms and chronic pain. The imaging features of CAA range from subtle to severe. Advanced arachnoiditis can present with spinal cord swelling and syrinx formation, which can mimic other disease processes. Inclusion of advanced CAA in the differential diagnosis can prevent unnecessary interventions. PMID- 28639827 TI - The effects of alcohol expectancy and intake on slot machine gambling behavior. AB - Background and aims Although alcohol intake and gambling often co-occur in related venues, there is conflicting evidence regarding the effects of alcohol expectancy and intake on gambling behavior. We therefore conducted an experimental investigation of the effects of alcohol expectancy and intake on slot machine gambling behavior. Methods Participants were 184 (females = 94) individuals [age range: 18-40 (mean = 21.9) years] randomized to four independent conditions differing in information/expectancy about beverage (told they received either alcohol or placebo) and beverage intake [actually ingesting low (target blood alcohol concentration [BAC] < 0.40 mg/L) vs. moderate (target BAC > 0.40 mg/L; ~0.80 mg/L) amounts of alcohol]. All participants completed self-report questionnaires assessing demographic variables, subjective intoxication, alcohol effects (stimulant and sedative), and gambling factors (behavior and problems, evaluation, and beliefs). Participants also gambled on a simulated slot machine. Results A significant main effect of beverage intake on subjective intoxication and alcohol effects was detected as expected. No significant main or interaction effects were detected for number of gambling sessions, bet size and variation, remaining credits at termination, reaction time, and game evaluation. Conclusion Alcohol expectancy and intake do not affect gambling persistence, dissipation of funds, reaction time, or gambling enjoyment. PMID- 28639828 TI - Prevalence of Vertebral Compression Fractures on Routine CT Scans According to L1 Trabecular Attenuation: Determining Relevant Thresholds for Opportunistic Osteoporosis Screening. AB - OBJECTIVE: Radiologists interpreting body CT scans may be the first to identify osteoporosis and associated vertebral fractures. This study correlates L1 trabecular attenuation measurements with prevalent vertebral body fractures in older adults undergoing routine CT. MATERIALS AND METHODS: Mean L1 trabecular attenuation was measured at thoracoabdominal CT in 1966 consecutive adults (983 men and 983 women) 65 years and older (mean age, 74.1 +/- 6.6 [SD] years). Sagittal reconstructions and lateral scouts were analyzed for moderate or severe thoracolumbar vertebral compression fractures according to the Genant semiquantitative assessment method. The diagnostic performance of L1 attenuation for the evaluation of prevalent vertebral fractures was assessed, including ROC curve analysis. RESULTS: A total of 162 (8.2%) individuals (mean age, 78.3 years; 66 men, 96 women) had at least one moderate or severe vertebral fracture. The mean L1 attenuation was 70.2 HU among patients with a prevalent fracture, whereas it was 132.3 HU among patients without fracture (p < 0.001). The prevalence of moderate or severe vertebral compression fractures was 32.5% when L1 attenuation was <= 90 HU. Prevalence increased to 49.2% with L1 attenuation of <= 50 HU. ROC curve analysis determined an optimal threshold of 90 HU (sensitivity = 86.9%, specificity = 83.9%), with a corresponding AUC of 0.895. The odds ratio of having a moderate or severe vertebral compression fracture was 31.9 for L1 attenuation <= 90 HU (95% CI, 20.2-50.5; p < 0.001). CONCLUSION: Patients with moderate or severe vertebral compression fractures have significantly lower L1 attenuation values than patients who do not. L1 attenuation <= 90 HU may represent an optimal threshold for determining risk for osteoporotic vertebral fractures. PMID- 28639829 TI - Increasing Quiet Compliance by Detained Male Adolescents. AB - Some adjudicated adolescents receive treatment for their offenses in residential facilities. Detained adolescents' engagement in either low levels of compliant behavior or excess behavior (e.g., swearing, gestures) while following commands from residential personnel may result in decreased opportunities for those youth to access preferred activities. The current study employed nonconcurrent multiple baseline across participants designs to evaluate the effects of a procedure to increase seven detained adolescents' quiet compliance with academic and vocational demands. Results show that problem behavior decreased to zero or near zero levels for each participant during simulated conditions and suggest that self-control, alone or in combination with a differential reinforcement of low rate behavior for omitting problem behavior, may have been responsible for the behavior changes. We discuss some clinical implications of the findings. PMID- 28639830 TI - First Versus Second Uterine Artery Embolization for Symptomatic Leiomyoma. AB - OBJECTIVE: The purpose of this study was to compare the outcomes of second uterine artery embolization (UAE) with those of first UAE for symptomatic uterine leiomyoma. MATERIALS AND METHODS: In this single-institution retrospective study, between December 1997 and May 2016 first UAE was performed on 423 consecutively registered patients and second UAE on 11 consecutively registered patients to treat leiomyoma. The primary endpoint was infarction of all tumor tissue as seen at postprocedural contrast-enhanced MRI. The secondary endpoints were angiographic findings, embolization, MRI, and clinical outcomes 1 year after UAE. The outcomes were compared between the two groups. Multivariable linear regression analysis was performed to assess independent correlations with tumor infarction. RESULTS: Most of the baseline demographic features and technical outcomes in the two groups were similar. In the second UAE group, all but one uterine artery was reopened. More collateral vessels were observed at the second UAE (1.1/patient versus 0.23/patient, p = 0.043). Contrast-enhanced MRI after UAE revealed that the tumor infarction rate was significantly lower in the second UAE group (69.8 +/- 33.9% vs 96.8 +/- 9.0%, p = 0.025). The difference remained significant after adjustments for possible confounders (p < 0.001). Whether UAE was a first or a second procedure was significantly associated with tumor infarction rate (p < 0.001). The uterine volume reduction rate 1 year after UAE was significantly lower in the second UAE group (33.4 +/- 18.1% versus 46.9 +/- 16.6%, p = 0.008). No other 1-year outcomes were significantly different between the groups. CONCLUSION: Second UAE was effective but inferior to first UAE in that it resulted in less tumor infarction at contrast-enhanced MRI and had a lower uterine volume reduction rate. PMID- 28639831 TI - Diagnostic Performance and Confidence of Contrast-Enhanced Ultrasound in the Differential Diagnosis of Cystic and Cysticlike Liver Lesions. AB - OBJECTIVE: The aims of this study were to assess the diagnostic performance of contrast-enhanced ultrasound (CEUS) in the characterization of atypical cystic and cysticlike focal liver lesions in comparison with conventional US and to determine whether the use of CEUS can reduce the need for further diagnostic workup. SUBJECTS AND METHODS: In a 3-year period 48 patients with 50 atypical cystic and cysticlike lesions found at conventional US underwent CEUS. Diagnostic confirmation was obtained in cytohistopathologic examinations, with other imaging modalities, and in follow-up. Overall, there were 24 cystic lesions and 26 cysticlike solid lesions, specifically 32 benign and 18 malignant lesions. The conventional US and CEUS images and cine loops were reviewed by two blinded readers independently. Sensitivity, specificity, area under the ROC curve (Az), and interobserver agreement were calculated. RESULTS: Diagnostic performance improved after review of CEUS examinations by both readers (conventional US Az = 0.781 vs 0.972; CEUS Az = 0.734 vs 0.957). Interreader agreement increased, although slightly (conventional US weighted kappa = 0.894; CEUS weighted kappa = 0.953). In terms of differential diagnosis, the occurrence of correctly characterized lesions increased after CEUS for both readers (reader 1, 62% to 98%; reader 2, 56% to 96%). CONCLUSION: The development of low-acoustic-power CEUS has made it possible to identify several imaging features of cystic and cysticlike focal liver lesions that, in association with history and clinical findings, may help to correctly characterize them. Our data indicate the usefulness of CEUS in the evaluation of patients with these lesions. PMID- 28639832 TI - Comparing Diagnostic Performance of Digital Breast Tomosynthesis and Full-Field Digital Mammography in a Hybrid Screening Environment. AB - OBJECTIVE: The purpose of this study is to compare the diagnostic performance of screening digital breast tomosynthesis (DBT) to that of full-field digital mammography (FFDM) in a mixed DBT and FFDM imaging environment. MATERIALS AND METHODS: This retrospective observational study consisted of all female patients undergoing screening DBT or FFDM at an academic medical center and outpatient imaging facility between October 2012 and May 2015. Patient demographics and personal history of breast cancer were collected from the electronic medical record. A natural language processing algorithm extracted patients' breast density, current or prior imaging findings, and BI-RADS category from their most recent prior imaging examinations. To control for differential selection of FFDM versus DBT, we applied propensity score matching based on patient age, imaging site, and prior imaging findings. An institutional breast cancer registry identified cancer diagnoses. Primary outcomes of recall rate, cancer detection rate, and positive predictive value 1 (PPV1) were compared between matched FFDM and DBT groups. RESULTS: Among 68,794 screening examinations, we matched 16,264 FFDM with 21,074 DBT examinations (total, 37,338 examinations) using nearest neighbor propensity score matching. Recall rates were 10.3% (1683/16,264) for FFDM and 10.7% (2254/21,074) for DBT (p = 0.26). Cancer detection rates (number of cancers/1000 examinations) were 1.8/1000 for FFDM and 3.8/1000 for DBT (p = 0.005). The PPV1 (number of cancers/number of recalls) was 1.8% (26/1478) for FFDM and 3.6% (37/1036) for DBT (p = 0.006). CONCLUSION: FFDM and DBT recall rates were not significantly different in a mixed FFDM and DBT breast imaging practice. However, the PPV1 of recalled cases and the cancer detection rate (the primary screening objective) were significantly higher with DBT compared with FFDM. PMID- 28639834 TI - Implicit health associations across the adult lifespan. AB - OBJECTIVE: Explicit reports of one's health self-concept (e.g. rate your overall health) are commonly used in research and clinical practice. These measures predict important health outcomes, but rely on conscious introspection so may not fully capture the different components of the health self-concept (e.g. more automatic components) that relate to actual health. This study examined the health-implicit association test (health-IAT), and how it may add to our prediction of health from self-reports. DESIGN: 1004 participants (ages 18-85) completed this web-based study with the health-IAT (assessing self-healthy implicit associations) and explicit assessments of health. MAIN OUTCOME MEASURES: Self-reported measures of physical functioning. RESULTS: The health-IAT was valid and reliable. Older age was correlated with stronger self-healthy implicit associations. Although the health-IAT did not incrementally predict self-reported markers of physical functioning when only controlling for explicit health self concept, it was an incremental predictor once age was entered for all four models tested. CONCLUSIONS: The health-IAT appears to be a valid and reliable new measure that assesses implicit self-concept relating to physical health. Results reveal the potential value of assessing implicit health self-concept in both research and practice, especially when taking into account age. PMID- 28639833 TI - Predictive CT Features of Visceral Pleural Invasion by T1-Sized Peripheral Pulmonary Adenocarcinomas Manifesting as Subsolid Nodules. AB - OBJECTIVE: The objective of our study was to determine whether visceral pleural invasion (VPI) of T1-sized peripheral pulmonary adenocarcinomas manifesting as subsolid nodules (SSNs) abutting the pleural surface or associated with pleural tags can be predicted. MATERIALS AND METHODS: Our study population consisted of 188 T1-sized peripheral pulmonary adenocarcinomas that appeared as SSNs (24 pure ground-glass nodules [GGNs] and 164 part-solid nodules) and underwent surgical resection between January 2007 and December 2013. Logistic regression analysis was performed to identify significant factors in predicting VPI. RESULTS: VPI occurred in 36 of 188 adenocarcinomas (19.1%). There were no cases of VPI in patients with pure GGNs. In part-solid nodules, there were significant differences regarding the presence of pleural contact, presence of pleural thickening, presence of solid portion abutting the pleura, nodule size, solid portion size, solid proportion, interface length, and length of the solid portion contacting the pleura (p < 0.05). Multivariate analysis revealed pleural contact (p < 0.001), pleural thickening (p = 0.003), solid proportion greater than 50% (p = 0.002), and nodule size greater than 20 mm (p = 0.015) as significant independent predictive features for VPI with adjusted odds ratios of 8.300, 3.966, 4.636, and 2.993, respectively. CONCLUSION: In part-solid nodules, the CT features of pleural contact, pleural thickening, solid proportion greater than 50%, and nodule size greater than 20 mm were shown to be significant indicators of VPI by T1-sized peripheral adenocarcinomas. PMID- 28639835 TI - Is it beneficial to perform surgical resection in elderly patients more than 80 years old with advanced gastric cancer? AB - OBJECTIVES: With the aging population, the number of elderly patients diagnosed with gastric cancer is increasing. However, determining treatment strategies for elderly patients with gastric cancer is controversial. The aim of this study is to evaluate the usefulness of surgical treatment on elderly patients aged >=80 years with advanced gastric cancer. METHODS: A total of 147 elderly patients who were diagnosed with advanced gastric cancer from August 2001 to December 2015 were retrospectively analyzed. We compared the clinicopathological features and prognoses of 94 elderly patients (80-85 years) and 53 extreme-elderly patients (>=86 years) according to treatment modalities. RESULTS: In the elderly group, the 3-year overall survival (OS) rates of the surgical resection group and supportive care group were 42.1% and 4.0%, respectively (p < .001). In the extreme-elderly group, the 3-year OS rates of the surgical resection group and supportive care group were 36.4% and 8.0%, respectively (p = .028). The post operative mortality rate of the elderly group and extreme-elderly group was 5.6% and 9.1%, respectively. In the analysis of risk factors associated with survival, surgical resection was a significantly good prognostic factor in the elderly group (hazard ratio [HR] = 0.277; p = .003) compared with supportive care. In the extreme-elderly group, surgical resection was associated with good prognosis but did not reach statistical significance (HR = 0.491; p = .099). CONCLUSIONS: These results suggest that elderly patients aged 80-85 years with advanced gastric cancer could expect a better prognosis with surgical resection. However, extreme elderly patients aged >=86 years should consider the risks and benefits of surgical treatment. PMID- 28639836 TI - Development of a 2-dof uterine manipulator with LED illumination system as a new transvaginal uterus amputation device for gynecological surgeries. AB - BACKGROUND: Hysterectomy, the most common major gynecological operation worldwide, consists of removal of the uterus and can be performed abdominally, vaginally, or laparoscopically. A uterine manipulator is a key device used for uterine manipulation and cannulation in hysterectomies. The challenges of conventional manipulators are to move the uterus in two distinct planes and to identify cervical landmarks during circular cut and coagulation. MATERIAL AND METHODS: In this study, a structural synthesis of the two degrees of freedom parallel manipulator was performed considering the constraints noted by surgeons. Computer-aided design and assembly of the manipulator, the cervicovaginal cap with LEDs, and the external parts were performed before rapid prototyping. The final design of the uterine manipulator was then manufactured from stainless steel and tested on an artificial uterus model using a test chamber. RESULTS: This article presents the design, production and testing processes of an innovative manipulator with a motion capability up to 80 degrees workspace both in the sagittal and coronal planes and an illumination system, easily detectable by the laparoscope, was successfully implemented on the manipulator's cervical cap in order to overcome the drawbacks of conventional uterine manipulators. CONCLUSIONS: Despite all the current studies and uterine manipulators on the market, no research has incorporated all the features mentioned above. PMID- 28639837 TI - Measuring cerebrovascular autoregulation in preterm infants using near-infrared spectroscopy: an overview of the literature. AB - INTRODUCTION: The preterm born infant's ability to regulate its cerebral blood flow (CBF) is crucial in preventing secondary ischemic and hemorrhagic damage in the developing brain. The relationship between arterial blood pressure (ABP) and CBF estimates, such as regional cerebral oxygenation as measured by near-infrared spectroscopy (NIRS), is an attractive option for continuous non-invasive assessment of cerebrovascular autoregulation. Areas covered: The authors performed a literature search to provide an overview of the current literature on various current clinical practices and methods to measure cerebrovascular autoregulation in the preterm infant by NIRS. The authors focused on various aspects: Characteristics of patient cohorts, surrogate measures for cerebral perfusion pressure, NIRS devices and their accompanying parameters, definitions for impaired cerebrovascular autoregulation, methods of measurements and clinical implications. Expert commentary: Autoregulation research in preterm infants has reported many methods for measuring autoregulation using different mathematical models, signal processing and data requirements. At present, it remains unclear which NIRS signals and algorithms should be used that result in the most accurate and clinically relevant assessment of cerebrovascular autoregulation. Future studies should focus on optimizing strategies for cerebrovascular autoregulation assessment in preterm infants in order to develop autoregulation-based cerebral perfusion treatment strategies. PMID- 28639838 TI - Provider perceptions of stigma and discrimination experienced by adolescents and young adults with pHiV while accessing sexual and reproductive health care. AB - Historically, children with perinatally-acquired HIV (PHIV) were viewed as the "innocent victims" as their HIV infection was not acquired through sexual/drug related means. Today, adolescents with PHIV are surviving into young adulthood and are engaging in developmentally expected behaviors such as establishing intimate, sexual relationships. Like other youth, those living with PHIV often need to access sexual and reproductive health (SRH) services. Previous research has documented stigma and discrimination experienced by adult women living with HIV as they try to access SRH care. However, little is known about the experiences of stigma and discrimination encountered by the maturing adolescents and young adults (AYA) with PHIV when accessing services. HIV health care providers (HHCPs) who frequently care for this population are in a unique position to learn about and understand the stigma and discrimination experienced by their patients in formal service settings. HHCPs (n = 57, 28 medical and 29 social service providers) were recruited using snowball sampling, and completed an online survey based on patient-shared experiences of stigma and discrimination when accessing SRH-related health care and social services. Thirty-eight percent (22/57) of providers reported that their patients with PHIV had shared encounters of stigma or discrimination when accessing SRH services. Coded open-ended provider comments indicated that AYA patients experienced challenges with providers who were unfamiliar with PHIV and expressed surprise that someone with PHIV was still alive. Analyses also revealed prejudicial attitudes towards women with HIV. Patients reported being counseled to terminate their pregnancy and lectured about their "poor choices." As AYA with PHIV transition out of pediatric and adolescent care, it is important for providers to simultaneously help them navigate care in other health settings, as well as educate adult health care providers about possible misconceptions of caring for individuals with PHIV. PMID- 28639839 TI - Biocompatible agarose-chitosan coated silver nanoparticle composite for soft tissue engineering applications. AB - With increasing gap in the demand and supply of vital organs for transplantation there is a pressing need to bridge the gap with substitutes. One way to make substitutes is by tissue engineering which involves combining several types of synthetic or biomaterials, cells and growth factors cross-linked together to synthesize a functional scaffold for repair or replacement of non-functional organs. Nanoparticle based composites are gaining importance in tissue engineering due to their ability to enhance cell attachment and proliferation. The current study focuses on synthesizing agarose composites embedded with chitosan-coated silver nanoparticles using glutaraldehyde as the cross-linker. The synthesis of chitosan coated silver nanoparticles within the scaffold was confirmed with UV-visible spectroscopy. Physical and chemical characterization of the synthesized nanoparticles were done by XRD, FTIR, TGA and SEM. DMA showed higher mechanical strength of the scaffolds. The scaffolds showed degradation of ~37% within a span of four weeks. The higher physical support provided by the synthesized scaffolds was shown by in-vitro cell viability assay. Broad spectrum anti-bacterial activity and superior hemocompatibility further showed the advantage it offered for growing cells. Thus a biopolymer based nanocomposite was synthesized, with intended widespread use as scaffold for engineering of soft tissues due to its enhanced biocompatibility and greater surface area for cell growth. PMID- 28639840 TI - Categorical loudness scaling in cochlear implant recipients. AB - OBJECTIVE: This study investigated categorical loudness scaling in a large group of cochlear implant (CI) recipients. DESIGN: Categorical loudness was measured for individually determined sets of current amplitudes on apical, mid and basal electrodes of the Nucleus array. STUDY SAMPLE: Thirty adult subjects implanted with the Nucleus CI. RESULTS: Subjects were generally reliable in categorical loudness scaling. As expected, current levels eliciting the same loudness categories differed across subjects and electrodes in many cases. After scaling the electric levels to remove differences in dynamic ranges across subjects and electrodes, the across-subject loudness functions for the three electrodes were very similar. CONCLUSIONS: Scaled electric current to remove differences in dynamic range, as implemented in the Nucleus processor, ensures uniform loudness across the array and CI recipients. The results also showed that categorical loudness scaling for electric stimulation was similar to that for acoustic stimulation in normal hearing subjects. These findings could be used as a guide for aligning electric and acoustic loudness in CI recipients with contralateral hearing. PMID- 28639841 TI - Effects of a mindfulness-based intervention on symptoms and signs in chronic heart failure: A feasibility study. AB - AIMS: Despite treatment recommended by guidelines, many patients with chronic heart failure remain symptomatic. Evidence is accumulating that mindfulness-based interventions (MBIs) have beneficial psychological and physiological effects. The aim of this study was to explore the feasibility of MBI on symptoms and signs in patients with chronic heart failure in outpatient clinical settings. METHODS: A prospective feasibility study. Fifty stable but symptomatic patients with chronic heart failure, despite optimized guideline-recommended treatment, were enrolled at baseline. In total, 40 participants (median age 76 years; New York Heart Association (NYHA) classification II-III) adhered to the study. Most patients ( n=17) were randomized into MBI, a structured eight-week mindfulness-based educational and training programme, or controls with usual care ( n=16). Primary outcome was self-reported fatigue on the Fatigue severity scale. Secondary outcomes were self-reported sleep quality, unsteadiness/dizziness, NYHA functional classification, walking distance in the six-minute walk test, and heart and respiratory rates. The Mann-Whitney U test was used to analyse median sum changes from baseline to follow-up (week 10+/-1). RESULTS: Compared with usual care (zero change), MBI significantly reduced the self-reported impact of fatigue (effect size -8.0; p=0.0165), symptoms of unsteadiness/dizziness ( p=0.0390) and breathlessness/tiredness related to physical functioning (NYHA class) ( p=0.0087). No adverse effects were found. CONCLUSIONS: In stable but symptomatic outpatients with chronic heart failure, MBI alleviated self-reported symptoms in addition to conventional treatment. The sample size is small and further studies are needed, but findings support the role of MBI as a feasible complementary option, both clinically and as home-based treatment, which might contribute to reduction of the symptom burden in patients diagnosed with chronic heart failure. PMID- 28639842 TI - Evaluation of Plasma TRB3 and Sestrin 2 Levels in Obese and Normal-Weight Children. AB - OBJECTIVE: Obesity in childhood and adolescence is associated with metabolic syndrome and cardiovascular diseases. TRB3 (Tribbles homolog 3) and sestrin 2 are two newly found proteins that have been identified to play an important role in obesity and its complications. AIM: The purpose of this study was to evaluate concentrations of TRB3 and sestrin 2 in plasma of obese and normal-weight children and adolescents, and their association with metabolic and anthropometric parameters. METHODS: Plasma levels of TRB3, sestrin 2, insulin, fasting plasma glucose (FPG), and lipid profile were evaluated in 70 children and adolescents (34 obese and 36 controls). Insulin resistance was calculated using a homeostasis model assessment of insulin resistance. Metabolic syndrome was defined according to IDF criteria. RESULTS: Plasma TRB3 levels of the obese subjects were significantly higher than that of normal weight subjects. TRB3 levels were positively correlated with BMI, BMI z-score, waist circumference, and FPG. The concentration of sestrin 2 was significantly lower in obese subjects compared to normal-weight subjects. A statistically significant positive correlation was observed between plasma concentrations of sestrin 2 and high-density lipoprotein cholesterol. Neither TRB3 nor sestrin 2 were correlated with insulin resistance and metabolic syndrome. CONCLUSION: Both TRB3 and sestrin 2 may contribute to the development of obesity and its complications and can be considered interesting therapeutic target for the treatment of obesity. PMID- 28639843 TI - Characteristics of children with unilateral hearing loss. AB - OBJECTIVE: The purpose of this study was to describe the clinical characteristics of children with unilateral hearing loss (UHL), examine deterioration in hearing, and explore amplification decisions. DESIGN: Population-based data were collected prospectively from time of diagnosis. Serial audiograms and amplification details were retrospectively extracted from clinical charts to document the trajectory and management of hearing loss. SAMPLE: The study included all children identified with UHL in one region of Canada over a 13-year period (2003-2015) after implementation of universal newborn hearing screening. RESULTS: Of 537 children with permanent hearing loss, 20.1% (108) presented with UHL at diagnosis. They were identified at a median age of 13.9 months (IQR: 2.8, 49.0). Children with congenital loss were identified at 2.8 months (IQR: 2.0, 3.6) and made up 47.2% (n = 51), reflecting that a substantial portion had late-onset, acquired or late-identified loss. A total of 42.4% (n = 39) showed deterioration in hearing, including 16 (17.4%) who developed bilateral loss. By study end, 73.1% (79/108) of children had received amplification recommendations. CONCLUSIONS: Up to 20% of children with permanent HL are first diagnosed with UHL. About 40% are at risk for deterioration in hearing either in the impaired ear and/or in the normal hearing ear. PMID- 28639845 TI - Between the Pew and the Pulpit: Can Personality Measures Help Identify Sexually Abusive Clergy? AB - There has been limited conclusive research examining the personality characteristics of clergy who perpetrate abuse. To address this dearth of research, the current study aimed to develop a personality profile that distinguishes clergy members who sexually abuse children from other clergy. Personality and psychopathology were assessed using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and the Millon Clinical Multiaxial Inventory-III (MCMI-III). Data were analyzed from a sample of clergy members, who comprised four comparison groups: clergy members referred to treatment for (a) child sexual abuse, (b) sexual misconduct with adults, (c) general clinical problems, or (d) routine employment evaluations with no previously identified clinical or sexual issues. While differences were found between groups, only the Aggressive/Sadistic scale of the MCMI-III consistently distinguished clerics who sexually abused children from all other clergy members. Findings are discussed in regard to the utility of the MMPI-2 and MCMI-III as a screening tool for clerical applicants for the Catholic Church. PMID- 28639844 TI - Diagnostic sensitivity of cutoff values of IgG4-positive plasma cell number and IgG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IgG4-related disease. AB - OBJECTIVES: This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive plasma cell (PC) number and IgG4-positive/CD138 positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-related disease (IgG4-RD) in typical multiple lesions of patients with IgG4-RD. METHODS: We evaluated IgG4-positive PC number and IgG4 positive/CD138-positive cell ratio in 39 samples from 18 IgG4-RD patients having more than two typical lesions of IgG4-RD. RESULTS: We evaluated 12 submandibular, 12 ophthalmic, six skin, five kidney, two pancreatic, and one bronchus and prostate lesion each in 18 patients with typical clinical, serological, and radiographic features. Concerning IgG4 + PC number per high-power field, most ophthalmic (11/12), kidney (5/5), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (6/12) and skin lesions (0/6) did not. In contrast to the absolute number, all lesions fulfilled the cutoff value of IgG4+/CD138 + cell ratio. In eight cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not. CONCLUSIONS: These results suggest that ICS criteria have different sensitivities among the affected organs for the diagnosis of IgG4-RD. PMID- 28639847 TI - Illusions of specificity in power-laden clinical performance assessment. PMID- 28639846 TI - Antibiotic prophylaxis is not indicated prior to dental procedures for prevention of periprosthetic joint infections. AB - Background and purpose - To minimize the risk of hematogenous periprosthetic joint infection (HPJI), international and Dutch guidelines recommended antibiotic prophylaxis prior to dental procedures. Unclear definitions and contradictory recommendations in these guidelines have led to unnecessary antibiotic prescriptions. To formulate new guidelines, a joint committee of the Dutch Orthopaedic and Dental Societies conducted a systematic literature review to answer the following question: can antibiotic prophylaxis be recommended for patients (with joint prostheses) undergoing dental procedures in order to prevent dental HPJI? Methods - The Medline, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs), reviews, and observational studies up to July 2015. Studies were included if they involved patients with joint implants undergoing dental procedures, and either considered HPJI as an outcome measure or described a correlation between HPJI and prophylactic antibiotics. A guideline was formulated using the GRADE method and AGREE II guidelines. Results - 9 studies were included in this systematic review. All were rated "very low quality of evidence". Additional literature was therefore consulted to address clinical questions that provide further insight into pathophysiology and risk factors. The 9 studies did not provide evidence that use of antibiotic prophylaxis reduces the incidence of dental HPJI, and the additional literature supported the conclusion that antibiotic prophylaxis should be discouraged in dental procedures. Interpretation - Prophylactic antibiotics in order to prevent dental HPJI should not be prescribed to patients with a normal or an impaired immune system function. Patients are recommended to maintain good oral hygiene and visit the dentist regularly. PMID- 28639848 TI - Intraoperative Correction of Femoral Rotational Deformity Using a Conventional Navigation System and a Smartphone: A Novel Technique. AB - The intraoperatively rotational control of femoral shaft fractures treated with a closed intramedullary interlocking nailing is a challenging problem. A novel surgical technique that includes respective insertions of guidewires into the proximal and distal femur under the guidance of a 2-dimensional fluoroscopy-based navigation system and the measurements of the intersection angle subtended by the proximal and distal guidewires with the smartphone positional software has been designed to provide intraoperatively quantitative parameters of femoral rotation deformation. The comparison of these parameters with preoperative measurement values of the contralateral intact femur on computed tomography images was used to align the proximal and distal femur fragments based on periaxial rotation. The purpose of this study was to evaluate its clinical suitability. Ten adult patients with femoral shaft fractures were attempted to correct intraoperatively femoral rotational deformity using this novel technique. The additional operation time was 20.04 +/- 3.27 minutes. The angle of femoral anteversion was 20.85 degrees +/- 4.22 degrees , 38.14 degrees +/- 19.07 degrees , and 22.77 degrees +/- 3.38 degrees in the contralateral intact and preoperatively and postoperatively injured femur, respectively. The mean absolute difference between both limbs was preoperatively 21.55 degrees +/- 10.14 degrees with a statistically significant difference ( P = .005) and postoperatively 3.24 degrees +/- 1.69 degrees with no statistically significant difference ( P = .092). Our results showed this novel technique could become an effective tool to correct intraoperatively rotational malalignment of femoral fractures. PMID- 28639849 TI - Degradation of emerging contaminants by acclimated activated sludge. AB - The emerging organic micro-pollutants (EMOPs) cannot be effectively removed by conventional wastewater treatment processes. In this paper, the most commonly detected EMOPs in the effluent of wastewater treatment plants, including trimethoprim, sulfamethoxazole, carbamazepine, diclofenac, triclosan and methyl 3,5-dichloro-4-hydroxybenzoate, were selected to acclimate activated sludge, to enhance the biodegradation of EMOPs. The results showed that the acclimated activated sludge can significantly enhance the removal of trimethoprim, sulfamethoxazole, diclofenac, triclosan and methyl 3,5-dichloro-4 hydroxybenzoate, but slightly improve the degradation of carbamazepine. The distribution of six EMOPs between water and sludge phases demonstrated that biodegradation made a major contribution to their removal. The maximal degradation rate constants were determined to be 0.9028 (sulfamethoxazole), 0.5374 (trimethoprim), 0.4123 (triclosan), 0.3544 (diclofenac), 0.2534 (methyl 3,5-dichloro-4-hydroxybenzoate) and 0.0224 (carbamazepine). Degradation intermediate products were detected in water phase at the end of the acclimation process through the comparison of high-performance liquid chromatography figures before and after the acclimation process, suggesting that degradation products of EMOPs might be in the effluents. In summary, the acclimation of activated sludge could be an option for removing EMOPs, and more attention should be paid to the degradation products of EMOPs in the effluent. PMID- 28639850 TI - Field-scale electrolysis/ceramic membrane system for the treatment of sewage from decentralized small communities. AB - The electrolysis process adopting copper electrodes and ceramic membrane with pore sizes of 0.1-0.2 MUm were consisted to a system for the treatment of sewage from decentralized small communities. The system was operated under an HRT of 0.1 hour, voltage of 24 V, and TMP of 0.05 MPa. The system showed average removals of organics, nitrogen, phosphorus, and solids of up to 80%, 52%, 92%, and 100%, respectively. Removal of organics and nitrogen dramatically increased in proportion to increment of influent loading. Phosphorus and solids were remarkably eliminated by both electro-coagulation and membrane filtration. The residual particulate constituents could also be removed successfully through membrane process. A system composed of electrolysis process with ceramic membrane would be a compact, reliable, and flexible option for the treatment of sewage from decentralized small communities. PMID- 28639851 TI - Activated carbon of Babassu coconut impregnated with copper nanoparticles by green synthesis for the removal of nitrate in aqueous solution. AB - The present study was conducted to impregnate the surface of a carbon of vegetable origin with copper nanoparticles by the green synthesis method with the aqueous extract of Hibiscus sabdariffa flowers, rich in phenolic compounds, which are responsible for the reduction and impregnation of metal nanoparticles. Batch adsorption assays were conducted aimed at nitrate removal with pure (GAC) and impregnated (IGAC) carbon, for comparative purposes. It was found that impregnation increases the efficiency of the carbon by four times in terms of the maximum adsorption capacity, which was 10.13 mg g-1 at 45 degrees C for GAC and 45.01 mg g-1 at 15 degrees C for IGAC, indicating that this is a promising material for the removal of nitrate in waters with an excess of this ion. PMID- 28639853 TI - Persistent Rule-Following in the Face of Reversed Reinforcement Contingencies: The Differential Impact of Direct Versus Derived Rules. AB - Rule-governed behavior and its role in generating insensitivity to direct contingencies of reinforcement have been implicated in human psychological suffering. In addition, the human capacity to engage in derived relational responding has also been used to explain specific human maladaptive behaviors, such as irrational fears. To date, however, very little research has attempted to integrate research on contingency insensitivity and derived relations. The current work sought to fill this gap. Across two experiments, participants received either a direct rule (Direct Rule Condition) or a rule that involved a novel derived relational response (Derived Rule Condition). Provision of a direct rule resulted in more persistent rule-following in the face of competing contingencies, but only when the opportunity to follow the reinforced rule beforehand was relatively protracted. Furthermore, only in the Direct Rule Condition were there significant correlations between rule-compliance and stress. A post hoc interpretation of the findings is provided. PMID- 28639854 TI - Rapid On-Site Evaluation of Endobronchial Ultrasound-Guided Transbronchial Needle Aspirations for the Diagnosis of Lung Cancer: A Perspective From Members of the Pulmonary Pathology Society. AB - CONTEXT: - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) has emerged as a very useful tool in the field of diagnostic respiratory cytology. Rapid on-site evaluation (ROSE) of EBUS-TBNA not only has the potential to improve diagnostic yield of the procedure but also to triage samples for predictive molecular testing to guide personalized treatments for lung cancer. OBJECTIVE: - To provide an overview of the current status of the literature regarding ROSE of EBUS-TBNA in the diagnosis of lung cancer. DATA SOURCES: - An electronic literature search in PubMed and Google databases was performed using the following key words: cytology, lung cancer, on-site evaluation, rapid on-site evaluation, and ROSE EBUS-TBNA. Only articles published in English were included in this review. CONCLUSIONS: - Rapid on-site evaluation can ensure that the targeted lesion is being sampled and can enable appropriate specimen triage. If available, it should be used with EBUS-TBNA in the diagnosis of lung cancer because it can minimize repeat procedures for additional desired testing (ie, molecular studies). Some studies have shown that ROSE does not adversely affect the number of aspirations, total procedure time of EBUS-TBNA, or the rate of postprocedure complications; it is also helpful in providing a preliminary diagnosis that can reduce the number of additional invasive procedures, such as mediastinoscopy. As EBUS technology continues to evolve, our knowledge of the role of ROSE in EBUS-TBNA for the diagnosis of lung cancer will also continue to grow and evolve. PMID- 28639852 TI - Osteochondritis Dissecans: Etiology, Pathology, and Imaging with a Special Focus on the Knee Joint. AB - This article is a review of the current understanding of the etiology, pathogenesis, and how to diagnose and treat knee osteochondritis dissecans (OCD) followed by an analysis of and outcomes of the treatments available. OCD is seen in children and adolescents with open growth plates (juvenile OCD) and adults with closed growth plates (adult OCD). The etiology of OCD lesions remains unclear and is characterized by an aseptic necrosis in the subchondral bone area. Mechanical factors seem to play an important role. Clinical symptoms are unspecific. Thus, imaging techniques are most important. Regarding treatment, a tremendous number of publications exist. Spontaneous healing is expected unless there is an unstable fragment, and treatment involves rest and different degrees of immobilization until healing. Patients with open physes and low-grade lesions have good results with conservative therapy. When surgery is necessary, the procedure depends on the stage and on the state of the cartilage. With intact cartilage, retrograde procedures are favorable. When the cartilage is damaged, several techniques can be used. While techniques such as drilling and microfracturing produce reparative cartilage, other techniques reconstruct the defect with additional osteochondral grafts or cell-based procedures such as chondrocyte transplantation. There is a tendency toward better results when using procedures that reconstruct the bone and the cartilage and there is also a trend toward better long-term results when comorbidities are treated. Severe grades of osteoarthrosis are rare. PMID- 28639855 TI - Cutaneous and Superficial Soft Tissue CD34+ Spindle Cell Proliferation. AB - CONTEXT: - Cutaneous and superficial soft tissue spindle cell proliferations with CD34 expression represent a unique heterogeneous group of lesions. They can pose diagnostic challenges for unaware pathologists in their daily practice. OBJECTIVE: - To review selected entities of CD34+ spindle cell proliferations in the skin and superficial soft tissue. The effective diagnostic approaches using clinical, histopathologic, and immunophenotypical findings are discussed within a broad spectrum of differential diagnosis. DATA SOURCES: - All information used in the article is obtained from published literature by PubMed search and Internet based search engines. The authors' collective experience and real-life examples are also used. CONCLUSIONS: - Spindle cell proliferations with CD34 positivity can be worked up to a definitive diagnosis by using clinical, histopathologic, and immunophenotypical findings. Familiarity with these entities helps pathologists make the accurate diagnosis. PMID- 28639856 TI - Adverse events are rare after single-dose montelukast exposures in children. AB - STUDY OBJECTIVE: Montelukast sodium is a leukotriene-receptor antagonist approved as a controller medication for chronic asthma and allergic rhinitis in children and adults. We sought to characterize adverse events associated with single montelukast exposures in children ages 5-17 years and to determine whether adverse events were dose related for all-dose and for ultra-high-dose (>=50 mg) exposures. METHODS: This is a retrospective analysis of data from the National Poison Data System for exposures that included montelukast in individuals aged 5 17 years for calendar years 2000-2016. Filters were applied to identify exposure events in which montelukast was the primary exposure and for which the exact or lowest-possible ingested dose was recorded. Characteristics of adverse events were examined using descriptive statistics and multivariable logistic models were used to examine whether associations of montelukast and adverse events were dose related. RESULTS: During the 17-year study period, there were 17,069 montelukast exposures available for analyses. Patients were median [interquartile range] age 7 (5, 9) years, and 10,907 (64%) male gender. Abdominal pain was the most common adverse event (0.23%). There were 618 ultra-high-dose exposures (>=50 mg). These patients had median age 6 (5, 8) years, and 347 (56%) male gender. Abdominal pain was the most common adverse event (1.46%). Increasing ingested dose was associated with abdominal pain (adjusted odds ratio, 1.01, 95% confidence interval 1.01, 1.02) after adjustment for age and gender. No serious or life threatening events were reported. CONCLUSIONS: Single-dose exposures of montelukast up to 445 mg are rarely associated with any adverse events and are not associated with serious or life-threatening adverse events in children aged 5 17 years. PMID- 28639857 TI - Treadmill walking differently affects body composition and metabolic parameters of female rats from normal or small litters. AB - This work assessed whether walking affects bodily development and metabolic parameters of female rats raised in small litters (three pups, group S) or control litters (nine pups, group C). After weaning, some of the rats had five sessions per week of a 30-min treadmill walking (CE and SE), while the others remained sedentary (CS and SS) until the age of 120 days. Exercise caused a reduction of body weight (CS/CE = 1.18), Lee index (CS/CE = 1.04), fasting blood glucose (CS/CE = 1.35), mesenteric (CS/CE = 1.23), and ovarian fat (CS/CE = 1.33) in CE, but only glucose was decreased in SE (SS/SE = 1.16). The diameter of adipocytes decreased to a half in the small-litter groups. Exercise increased subcutaneous (CS/CE = 0.88 and SS/SE = 0.71), but decreased retroperitoneal adipocytes (CS/CE = 1.2 and SS/SE = 1.3). Litter size reduction had little impact on females at the age of 120 days, but the light physical activity seemed insufficient to counteract all the effects of lactational overfeeding. On the other hand, pups from exercised mothers had a decrease in their biometric and glycemic indexes, demonstrating the transgenerational action of regular, although light, exercise. PMID- 28639858 TI - Site-specific associations of muscle thickness with bone mineral density in middle-aged and older men and women. AB - It is unknown whether age-related site-specific muscle loss is associated with areal bone mineral density (aBMD) in older adults. To examine the relationships between aBMD and whole-body muscle thickness distribution, 97 healthy adults (46 women and 51 men) aged 50-78 years volunteered. Total and appendicular lean soft tissue mass, aBMD of the lumbar spine (LS-aBMD) and femoral neck (FN-aBMD) were determined using dual-energy X-ray absorptiometry. Muscle thickness (MT) was measured by ultrasound at nine sites of the body (forearm, upper arm, trunk, upper leg, and lower leg). Relationships of each co-variate with aBMD were tested partialling out the effect of age. aBMD was not correlated with either MT of the trunk or anterior lower leg in either sex. In men, significant and relatively strong correlations were observed between anterior and posterior upper arms, posterior lower leg, and anterior upper leg MT and LS-aBMD or FN-aBMD. In women, significant correlations were observed between anterior and posterior upper legs, posterior lower leg, and anterior upper arm MT and FN-aBMD. LS-aBMD was only correlated with forearm and posterior upper leg MT in women. In conclusion, the site-specific association of MT and aBMD differs between sexes and may be associated with the participants' daily physical activity profile. PMID- 28639859 TI - The application of whole-body vibration in physiotherapy - A narrative review. AB - Whole-body vibration (WBV) training is a very popular kind of practice in sport, fitness and physiotherapy. This work reviews the current knowledge regarding the use and effectiveness of WBV in the physiotherapy. The discrepancies between different authors' results are probably due to divergence in WBV training protocols. The paperwork clearly showed that despite its ultimate effects, exercises on a vibration platform are safe, feasible, and well tolerated by patients with different disorders. This narrative review should help physiotherapists verify therapy programs regarding patients' exposure to WBV. PMID- 28639860 TI - Prediction of lactate threshold using the modified Conconi test in distance runners. AB - This study aimed to examine the validity of the modified Conconi test (CT) to predict lactate threshold (LT) during running. Twelve distance runners randomly performed the modified CT and the incremental test in which LT was determined directly by measuring blood lactate (BLa). Mean values of heart rate (HR) and running speed (RS) at heart rate deflection point (HRDP) obtained through the modified CT were compared with those at LT. Subsequently, the runners who showed a HRDP in the modified CT performed a 30-min prolonged exercise test (PET) at a RS corresponding to HRDP. During this test, the kinetics of BLa and HR were analyzed to determine whether a steady state in these variables could be attained. We succeeded in identifying HRDP in nine of our runners, whereas the remaining three runners showed entirely linear HR response. In those nine runners, no significant difference was found between HR and RS at HRDP and those at LT. Significant correlation was found between HR at HRDP and HR at LT (r = 0.84, p = 0.005), but RS at HRDP was not significantly correlated with RS at LT (r = 0.63, p = 0.07). All nine runners were able to complete the PET with steady state conditions being achieved for both BLa and HR. In conclusion, these findings indicate that the modified CT has a potential to be used as an alternative method for assessment of LT in distance runners presenting a HRDP. PMID- 28639861 TI - Adiponectin and osteocalcin responses to rowing exercise, and the relationship to substrate oxidation in female rowers. AB - This study investigated the effects of acute exercise and menstrual phase on adiponectin and osteocalcin concentrations, and the possible role of these biomarkers in exercise-induced substrate oxidation in rowers. Thirteen female rowers (19.3 +/- 2.3 years; height: 172.7 +/- 3.9 cm; body mass: 66.5 +/- 7.9 kg) performed 1-h rowing ergometer exercise at 70% of maximal oxygen consumption (VO2max) during follicular phase and luteal phase of the menstrual cycle. Oxygen consumption (VO2), total energy expenditure (EE), carbohydrate EE, and lipid EE were assessed during the exercise. Venous blood samples were collected before and after ergometer exercise. No differences (p > 0.05) were observed in substrate oxidation values during exercise across menstrual cycle. Exercise resulted in an acute rise in osteocalcin and no changes in adiponectin at both menstrual cycle phases. Adiponectin and osteocalcin were not related across phase or time (r < 0.211; p > 0.05). Post-exercise adiponectin was related (p < 0.05) to mean VO2 (r = 0.459) and total EE rate (r = 0.598), while post-exercise osteocalcin was correlated (p < 0.05) with mean total (r = 0.411) and lipid (r = 0.557) EE rates. In conclusion, menstrual cycle phase had no effect on substrate oxidation, and adiponectin and osteocalcin responses to acute exercise. It appears that adiponectin and osteocalcin may serve as signals for metabolic reaction to the energy cost of the acute exercise in female rowers. PMID- 28639862 TI - Relationship between biomarkers of muscle damage and redox status in response to a weightlifting training session: effect of time-of-day. AB - The aims of the present study were to: (1) investigate the effect of a weightlifting training session and time-of-day (TOD) upon biological parameters (i.e., oral temperature, hematological, C-reactive protein (CRP), and oxidative stress) and (2) assess their possible link with muscle damage responses. Nine weightlifters (21 +/- 0.5 years) performed, in a randomized order, three Olympic Weightlifting sessions (i.e., at 08:00, 14:00, and 18:00). Blood samples were collected at rest, 3 min and 48 h after each training session. Between pre- and post-training session, ANOVA showed significant increases in oxidative stress markers at the three TODs (p < 0.01) and significant increases for creatine kinase (CK) and lactate dehydrogenase (LDH) only at 08:00 and 18:00 (p < 0.05). At rest, the results showed a significant diurnal variation for the majority of the selected parameters except for malondialdehyde (MDA), total bilirubin, and CRP with higher values observed at 18:00 (p < 0.05). After the training session, given the higher rate of increase during the morning session, these diurnal variations persisted for temperature and WBC (p < 0.01) and were suppressed for CK, LDH, uric acid (UA), catalase, and glutathione peroxidase. The main significant correlations (p < 0.001) were observed between: (1) CK and MDA (r = 0.6) and CK and UA (r = 0.66 and r = 0.82) during the morning and evening training sessions; (2) CK and CRP only during the morning session (r = 0.5); and (3) CRP and WBC during the three training sessions (r = 0.8). In conclusion, the present findings: (1) confirm that the muscle damage responses could be induced by a high level of oxidative stress and (2) suggest to avoid scheduling training sessions in the morning given the higher muscle damage, inflammatory, and oxidative responses at this TOD. PMID- 28639863 TI - Alterations of store-operated calcium entry and cyclopiazonic acid-induced endothelium-derived relaxations in aging rat thoracic aorta. AB - The purpose of our study was to investigate whether endothelium-derived relaxations induced by store depletion are altered in aging rat thoracic aorta. Vascular responses were measured in aortic segments isolated from young (2-4 month) and old (20-24 month) male Sprague-Dawley rats. In phenylephrine contracted intact tissues, receptor-mediated and receptor-independent endothelium derived relaxations were induced by acetylcholine (ACh) and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) blocker cyclopiazonic acid (CPA), respectively. In addition, CPA-induced changes in intracellular calcium levels were monitored in fura-2-loaded endothelium-denuded tissues. Real-time quantitative reverse transcription polymerase chain reaction and western blot analysis were performed to determine the transient receptor potential canonical (TRPC) 4 mRNA and protein levels. Endothelial TRPC4 mRNA levels were apparently decreased in aging rats. Immunoblot analysis showed that TRPC4 protein levels significantly decreased in intact aorta from 20- to 24-month-old rats compared to that from 2- to 4-month-old rats. ACh- and CPA-induced endothelium-dependent relaxations decreased in old rat aorta without any change in direct vasodilation induced by sodium nitroprusside. Store-operated Ca2+ entry (SOCE) induced by CPA was significantly decreased, whereas sarcoplasmic reticulum Ca2+ release was unaffected in endothelium-denuded aging rat aorta. In conclusion, TRPC4 downregulation could be associated with decreased endothelium-dependent vasorelaxations. As endothelial nitric oxide synthase is activated by SOCE induced caveolar internalization, tracking the expression levels of SERCA, ion channels, and/or associated proteins involved in SOCE would lead to the development of novel therapeutics for age-related vasospastic disorders with dysfunctional endothelium. PMID- 28639864 TI - Assessment of exhaled carbon monoxide in exacerbations of chronic obstructive pulmonary disease. AB - Introduction Exhaled carbon monoxide (eCO) has been widely implicated as a pulmonary biomarker in respiratory diseases. The aim of this study was to investigate whether the treatment of patients with severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD) could be aided by monitoring the changes in eCO. Methods The levels of eCO along with routine clinical parameters were analyzed in 29 current smoker and 33 ex-smoker COPD patients, first at the time of hospital admission, and again at discharge following the standard treatment. Patients with AECOPD were also stratified according to sputum bacteria. Results At exacerbation, the levels of eCO were increased in current smokers compared to ex-smokers (6.0 [2.0-9.5] versus 1.0 [1.0-2.0] ppm, p < 0.001). Similarly, eCO levels were higher in smokers after treatment (7.0 [2.0 12.5] versus 1.0 [1.0-2.0] ppm, p < 0.001). Treatment of AECOPD did not affect eCO concentrations. The levels of eCO were not statistically different between bacterial and non-bacterial AECOPD either. Investigating a subgroup of current smoker patients (n = 15), there was a significant correlation between the levels of eCO and blood carboxyhemoglobin concentrations both at exacerbation and discharge. No associations were found between eCO and lung function or blood gas parameters. Conclusion Our results suggest that monitoring eCO during the treatment of AECOPD is of limited clinical value. PMID- 28639865 TI - Efficacy of Rhus coriaria (sumac) juice in reducing muscle pain during aerobic exercise. AB - The main target of this study was to measure the influence of sumac juice drink on muscle indices and pain during an acute, intense exercise for 30 days. Forty healthy volunteers (15-25 years) were involved in aerobic exercise program for 4 weeks. Participants ingested sumac juice or placebo drink twice daily for 30 days. All participants were subjected for the evaluation of pain and estimation of serum: creatine kinase (CK), lactic acid dehydrogenase (LDH), troponin I, hydroxyproline (hyp), total antioxidant capacity (TAC), and in vitro antioxidant activity of sumac juice using pre-validated visual analog scale, colorimetric and immunoassays. The participants of both groups, placebo and sumac, showed an increment in pain scores both during exercise and post-exercise intervals. However, the sumac juice group showed a significant smaller increase in the pain scores compared to the placebo group. Participants in the sumac juice group were more willing to use the drink in the future. They achieved a higher satisfaction of sumac juice in ameliorating and the reduction of pain. Also, the sumac group showed a significant enhancement in the level of CK, LDH, troponin I, hyp, along with significant increase in serum (TAC) compared to the placebo group. The protective activity of muscle may relate to the antioxidant activity of phenolic component(s) in sumac juice as measured by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging (87.9%) and beta-carotene-linoleic acid (68.7%) assays. These data suggest that oral administration of sumac juice may have a beneficial effect on muscle performance among athletes. PMID- 28639866 TI - Protective effects of Vitamin E on CCl4-induced testicular toxicity in male rats. AB - The increased generation of free radicals plays an important role in testicular damage. The present study aimed to investigate the adverse effects of carbon tetrachloride (CCl4) on the reproductive system of male rats as well as to examine whether Vitamin E (VE) is able to ameliorate these effects. The rats were equally divided into three groups: control, CCl4-treated, and CCl4 + VE-treated groups. After 4 weeks of treatment, the decrease in body and testes weights, sperm parameters, and the decrease in serum levels of testosterone, luteinizing hormone, and follicle-stimulating hormone of CCl4-treated rats were ameliorated by VE treatment. The co-administration of VE with CCl4 significantly decreased the level of lipid peroxidation production (malondialdehyde) and increased the activity of anti-oxidant enzymes (superoxide dismutase and catalase) when compared with the CCl4 group. Moreover, VE prevented CCl4-induced severe testicular histopathological lesions and deformities in spermatogenesis. The results demonstrate that VE augments the anti-oxidants' defense mechanism against CCl4-induced reproductive toxicity suggesting a therapeutic role in free radical mediated infertility. PMID- 28639867 TI - Pulmonary function in young females of Kolkata, India - Revisited. AB - Rapid economic and industrial growths imposed significant impact on human health including the pulmonary health. Questions were raised regarding the validity of the existing prediction norms of pulmonary function tests (PFTs) in a particular population. The present study was conducted to investigate the applicability of the existing norms for PFTs in young healthy non-smoking female university students of Kolkata, India. Significant difference was noted in vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in 1 s (FEV1) when the present data were compared with the earlier study in similar population. Correlation statistic revealed significant relationship of age and body height with all the PFT parameters. Body mass had significant correlation with VC, FVC, FEV1 as a percentage of FVC (FEV1%), and peak expiratory flow rate (PEFR). Regression equations have been computed for predicting PFTs from age and body height. There has been a change of PFTs in the studied population for the last couple of decades due to increased environmental pollution in the course of economical and industrial developments. Regression equations computed in this study are not only recommended to predict PFT parameters in the studied population, but they are also considered more reliable owing to their substantially smaller standard error of estimate than those proposed in the previous study. PMID- 28639868 TI - Effect of pectin feeding on obesity development and duodenal alkaline phosphatase activity in Sprague-Dawley rats fed with high-fat/high-energy diet. AB - Purpose The objective of this study was to evaluate whether pectin feeding would affect the small intestinal function and whether these changes would lead to obesity prevention in rats fed with high-fat diet. Three groups of weaned male rats (ad lib. fed; rats fed with diet containing 15% w/w of citrus pectin; restrictedly pair-fed rats) were fed with either a standard diet (9.5% fat) or a high-fat diet (30% fat) for 10 days. Results Our results revealed that pectin feeding led to significant decreases in body weight, energy intake and fat pad weight in rats fed with the standard as well as high-fat diet. Moreover, compared to the restrictedly pair-fed rats, in both groups of rats fed with the diet containing pectin, significant decrease in duodenal alkaline phosphatase (AP) activity was observed in histochemically stained cryostat sections. In contrast, despite their lower energy intake, restrictedly pair-fed rats showed similar fat pad deposition accompanied by unchanged values of AP activity in comparison to the controls. Conclusions Our findings indicate that daily pectin consumption could be beneficial in suppressing body weight gain and reducing probability of obesity risk in rats fed with a high-fat diet. PMID- 28639869 TI - Economic Burden of Inpatient Admission of Ankle Fractures. AB - BACKGROUND: Ankle fractures are among the most prevalent traumatic orthopaedic injuries. A large proportion of patients sustaining operative ankle fractures are admitted directly from the emergency department prior to operative management. In the authors' experience, however, many closed ankle injuries may be safely and effectively managed on an outpatient basis. The aim of this study was to characterize the economic impact of routine inpatient admission of ankle fractures. METHODS: A retrospective review of all outpatient ankle fracture surgery performed by a single foot and ankle fellowship-trained surgeon at a tertiary level academic center in 2012 was conducted to identify any patients requiring postoperative inpatient admission. The National Inpatient Sample was queried for operative management of lateral malleolus, bimalleolar, and trimalleolar ankle fractures in 2012 with regard to national estimates of total volume and length of stay by age. The maximum allowable Medicare inpatient facility reimbursements for diagnosis related group 494 and Medicare outpatient facility reimbursements for Current Procedural Terminology codes 27792, 27814, and 27822 were obtained from the Medicare Acute Inpatient Prospective Pricer and the Medicare Outpatient Pricer Code, respectively. Private facility reimbursement rates were estimated at 139% of inpatient Medicare reimbursement and 280% of outpatient reimbursement, as described in the literature. Surgeon and anesthesiologist fees were considered similar between both inpatient and outpatient groups. A unique stochastic decision-tree model was derived from probabilities and associated costs and evaluated using modified Monte Carlo simulation. RESULTS: Of 76 lateral malleolar, bimalleolar, and trimalleolar ankle fracture open reduction internal fixation cases performed in 2012 by the senior author, 9 patients required admission for polytrauma, medical comorbidities, or age. All 67 outpatients were discharged home the day of surgery. In the 2012 national cohort analyzed, 48,044 estimated inpatient admissions occurred postoperatively for closed ankle fractures. The median length of stay was 3 days for each admission and was associated with an estimated facility reimbursement ranging from $12,920 for Medicare reimbursement of lateral malleolus fractures to $18,613 for private reimbursement of trimalleolar fractures. Outpatient facility reimbursements per case were estimated at $4,125 for Medicare patients and $11,459 for private insurance patients. Nationally, annual inpatient admissions accounted for $796,033,050 in reimbursements, while outpatient surgery would have been associated with $419,327,612 for treatment of these same ankle fractures. CONCLUSION: In the authors' experience, closed lateral malleolus, bimalleolar, and trimalleolar fractures were safely and effectively treated on an outpatient basis. Routine perioperative admission of patients sustaining ankle fractures likely results in more than $367 million of excess facility reimbursements annually in the United States. Even if a 25% necessary admission rate were assumed, routine inpatient admission of ankle fractures would result in a $282 million excess economic burden annually in the United States. Although in certain cases, inpatient admission may be necessary, with value-based decision making becoming increasingly the responsibility of the orthopaedic surgeon, understanding the implications of inpatient stays for ankle fracture surgery can ultimately result in cost savings to the US health care system and patients individually. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 28639870 TI - Advanced Imaging Techniques in the Knee: Benefits and Limitations of New Rapid Acquisition Strategies for Routine Knee MRI. AB - OBJECTIVE: The purpose of this article is to review current and emerging techniques and strategies that can be used to accelerate acquisition times in routine knee MRI. CONCLUSION: Specific techniques reviewed include 3D fast spin echo imaging as well as new approaches to rapid image acquisition techniques (parallel imaging, compressed sensing, simultaneous multislice, and neural network reconstruction techniques) and their potential application to knee MRI. PMID- 28639871 TI - An Innovative Streaming Video System With a Point-of-View Head Camera Transmission of Surgeries to Smartphones and Tablets: An Educational Utility. AB - PURPOSE: In order to engage medical students and residents from public health centers to utilize the telemedicine features of surgery on their own smartphones and tablets as an educational tool, an innovative streaming system was developed with the purpose of streaming live footage from open surgeries to smartphones and tablets, allowing the visualization of the surgical field from the surgeon's perspective. The current study aims to describe the results of an evaluation on level 1 of Kirkpatrick's Model for Evaluation of the streaming system usage during gynecological surgeries, based on the perception of medical students and gynecology residents. METHODS: Consisted of a live video streaming (from the surgeon's point of view) of gynecological surgeries for smartphones and tablets, one for each volunteer. The volunteers were able to connect to the local wireless network, created by the streaming system, through an access password and watch the video transmission on a web browser on their smartphones. Then, they answered a Likert-type questionnaire containing 14 items about the educational applicability of the streaming system, as well as comparing it to watching an in loco procedure. This study is formally approved by the local ethics commission (Certificate No. 53175915.7.0000.5171/2016). RESULTS: Twenty-one volunteers participated, totalizing 294 items answered, in which 94.2% were in agreement with the items affirmative, 4.1% were neutral, and only 1.7% answers corresponded to negative impressions. Cronbach's alpha was .82, which represents a good reliability level. Spearman's coefficients were highly significant in 4 comparisons and moderately significant in the other 20 comparisons. CONCLUSIONS: This study presents a local streaming video system of live surgeries to smartphones and tablets and shows its educational utility, low cost, and simple usage, which offers convenience and satisfactory image resolution, thus being potentially applicable in surgical teaching. PMID- 28639872 TI - Prevalence and associated factors of hearing aid use among older adults in Chile. AB - OBJECTIVE: The aim of this study was to determine the prevalence of use of hearing aids by older adults in Chile and the influence of some variables such as education level, income level and geographic area of residence on the prevalence of hearing aids. DESIGN: A national cross-sectional survey which was carried out in 2009. STUDY SAMPLE: A representative sample of 4766 Chilean older adults aged 60 years and above. RESULTS: The percentage of older adults in Chile who self reported hearing problems and used hearing aids was 8.9%. Such prevalence increased for adults living in urban areas and for those who knew about the new Chilean programme of universal access to health services (AUGE). For older adults who did not know about this programme, significant associations between the use of hearing aids and the variables of age, geographic area of residence, and income level were found. CONCLUSIONS: People's knowledge about AUGE programme may positively influence the use of hearing aids, although a direct effect cannot be attributed. PMID- 28639873 TI - Anesthetic Management of Patients Undergoing Percutaneous Endocardial and Epicardial Left Atrial Appendage Occlusion. AB - Atrial fibrillation is the most common cardiac arrhythmia in adults affecting almost 6 million adults in the United States. The 2 most common comorbidities associated with atrial fibrillation are heart failure and thromboembolic events. Heart failure symptoms may be treated with rate control, antiarrhythmic medications or by catheter ablation. Unfortunately, despite optimal medical management, thromboembolic events still occur. Recently, there has been a great deal of interest and innovation in finding an alternative to chronic anticoagulation. Several percutaneous left atrial appendage occlusion devices have been developed over recent years, some of which have proven to be noninferior to anticoagulation in preventing strokes in atrial fibrillation patients. The 2 most widely used left atrial appendage occlusion devices are the WATCHMAN (Atritech Inc, Plymouth, MN, USA) and the LARIAT (SentreHEART, Palo Alto, CA, USA) devices. After a detailed description of the procedures, the anesthetic considerations of each procedure and management of specific adverse events are discussed within this review. PMID- 28639874 TI - Compression treatment of pelvic congestion syndrome. AB - Aim To study the influence of compression treatment on clinical manifestations and venous hemodynamics of the pelvis in patients with pelvic congestion syndrome. Materials and methods A prospective study of the various options and modes of compression treatment was carried out and included 74 patients with pelvic congestion syndrome in 2008-2015. The patients were divided into three groups. The first group consisted of 48 patients with symptoms of pelvic congestion syndrome and chronic pelvic pain. They used Class II compression shorts. In the second group, there were 14 patients with pelvic congestion syndrome, vulvar varicosities without pelvic pain. They used Class II compression shorts and stockings. In the third group, 12 women with pelvic congestion syndrome and chronic pelvic pain used only the Class II compression stockings. The treatment continued for 14 days. A clinical criterion was the change of severity of chronic pelvic pain. The evaluation of the treatments has been performed using radionuclide venography and emission computed tomography with labeled in vivo red blood cells. Results Group 1: The compression shorts had a positive effect on the disease in 81.3% of patients. Chronic pelvic pain decreased from 6.4 +/- 1.6 to 1.2 +/- 0.7 points. The coefficient of pelvic congestion syndrome (Cpcs) decreased from 1.73 +/- 0.32 to 1.12 +/- 0.27 (p < 0.05). In 18.8% of patients, no positive effect was observed. Group 2: The results of radionuclide venographyshowed accelerating outflow of blood from the lower limbs and reduction of insufficiency of perforating veins. Mean radionuclide transit time decreased in all patients in the tendon, muscle pump parts, popliteal vein and was respectively: 23.6 +/- 2.2 s, 29.6 +/- 3.4 s, 32.3 +/- 4.2 s and after treatment 16.4 +/- 3.1 s, 22.1 +/- 2.5 s, 25.7 +/- 1.9 s (p < 0.05). Group 3: The use of compression stockings class II on the clinical manifestations of pelvic congestion syndrome in the patients. Cpcs also remained unchanged. Conclusion Research has shown the efficiency of class II compression shorts in the treatment of patients with isolated extension of intrapelvic venous plexuses. Class II compression stockings do not have any impact on the clinical manifestations of pelvic congestion syndrome. PMID- 28639875 TI - Short-form 6D assessment in compression module of the American College of Phlebology Patient Reported Outcome Venous Registry. AB - Objective The goal of this American College of Phlebology Patient Reported Outcome Venous Registry analysis was to examine the clinical efficacy of compression stockings using short-form 6D questionnaire (SF-6D). Method SF-6D scores were modeled over time using linear mixed effects model. Changes of SF-6D score from baseline to the last encounter were examined using a paired t-test. Analysis of variance was used to compare changes from baseline in SF-6D scores between C classifications. All analyses were conducted using SAS software, version 9.4 (SAS Institute, Cary NC). Results Baseline mean SF-6D score was 0.83 and at follow-up, 0.85. Mean SF-6D change was +0.02 points (P = .001) over an average time period of 5.5 months. Patients' SF-6D scores were estimated to increase by +0.03 points (P = .005) per year of usage of compression stockings. SF-6D score changes across C classifications did not demonstrate significant differences (P = .265). Conclusion There was an improvement of SF-6D score in the registry participants who used circular knit compression stockings. PMID- 28639876 TI - Meta-Analysis of Social Cognition in Mild Cognitive Impairment. AB - Social cognitive abilities are impaired in Alzheimer disease and other dementias. Recent studies suggested that social cognitive abilities might be also impaired in mild cognitive impairment (MCI). Current meta-analysis aimed to summarize available evidence for deficits in theory of mind (ToM) and emotion recognition in MCI. In this meta-analysis of 17 studies, facial emotion recognition and ToM performances of 513 individuals with MCI and 693 healthy controls were compared. Mild cognitive impairment was associated with significant impairments falling in the medium effect sizes range in ToM ( d = 0.63) and facial emotion recognition ( d = 0.58). Among individual emotions, recognition of fear and sadness were particularly impaired. There were no significant between-group differences in recognition of disgust, happiness, and surprise. Social cognitive deficits were more severe in multidomain MCI. There is a need for longitudinal studies investigating the potential role of social cognitive impairment in predicting conversion to dementia. PMID- 28639879 TI - Comments on "comparing a longitudinal integrated clerkship with traditional hospital-based rotations in a rural setting". PMID- 28639878 TI - Exploring the Phenotype in Mild Cognitive Impairment to Aid the Prediction of Those at Risk of Transitioning to Parkinson Disease and Dementia With Lewy Bodies. AB - To date, only limited research has concurrently investigated the presence of rapid eye movement sleep behavior disorder (RBD) and other features associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB) in people presenting with mild cognitive impairment (MCI). As a first step towards a longitudinal research project, the present study explored the relationships between MCI, RBD, and depression in 108 older adults who presented with subjective memory complaints but were not known to have a neurodegenerative condition. The present study found that RBD was a frequent feature in individuals with MCI (35%). Furthermore, MCI patients with RBD were more likely to exhibit nonamnestic MCI (89%) rather than an amnestic MCI phenotype (chi2 = 4.99, P = .025). Specifically, nonamnestic MCI patients with RBD had selective deficits in executive function and verbal memory, as well as a higher level of depressive symptoms. This cognitive and psychiatric profile is aligned with PD and DLB patients at their time of initial diagnosis and suggests that targeting nonamnestic MCI patients who report RBD with additional biomarker testing including smell, color vision, and neuroimaging (eg, dopamine transporters scan and transcranial ultrasonography) may aid in early diagnosis and prediction of these alpha-synucleinopathies. PMID- 28639880 TI - Cochrane corner - a new IJA feature. PMID- 28639877 TI - Mild Cognitive Impairment and Changes in Everyday Function Over Time: The Importance of Evaluating Both Speed and Accuracy. AB - OBJECTIVES: Research estimates that a significant percentage of individuals with mild cognitive impairment (MCI) experience functional difficulties. In addition to reduced accuracy on measures of everyday function, cross-sectional research has demonstrated that speed of performing instrumental activities of daily living (IADLs) is slowed in individuals with MCI. The present study investigated whether baseline and longitudinal changes in speed and accuracy of IADL performance differed between persons with MCI and cognitively normal peers. DESIGN: Linear mixed models were used to estimate the group differences in longitudinal performance on measures of IADLs. SETTING: Assessments were conducted at university and medical research centers. PARTICIPANTS: The sample consisted of 80 participants with MCI and 80 control participants who were enrolled in the Alzheimer's Disease Research Center's Measuring Independent Living in the Elderly Study. MEASUREMENTS: Instrumental activities of daily living speed and accuracy were directly assessed using selected domains of the Financial Capacity Instrument, the Timed IADL assessment, and driving-related assessments (Useful Field of View, Road Sign Test). RESULTS: Individuals with MCI performed worse on speed and accuracy measures of IADLs in comparison to cognitively normal peers and demonstrated significantly steeper rates of decline over three years in either speed or accuracy in all domains assessed. CONCLUSION: Both speed and accuracy of performance on measures of IADL are valuable indices for early detection of functional change in MCI. The performance pattern may reflect a trade-off between speed and accuracy that can guide clinical recommendations for maintaining patient independence. PMID- 28639881 TI - Suspected Lateral Periodontal Cyst Presenting Concurrently with Canine Acanthomatous Ameloblastoma in a 2-Year-Old Standard Poodle. AB - Lateral periodontal cysts (LPCs) are odontogenic epithelial cysts composed of nonkeratinized epithelial cells that are in the category of developmental cysts, rather than inflammatory cysts. Lateral periodontal cysts are rare both in people and domestic animals; they are associated with vital teeth and located lateral to a tooth root. Lateral periodontal cysts are typically asymptomatic lesions that are characterized radiographically as a unilocular lucency with well-defined corticated borders. Canine acanthomatous ameloblastoma (CAA) is the most common odontogenic neoplasm in dogs and rarely presents as a cystic lesion. This case report describes the diagnosis and treatment of a cyst that occurred as a swelling apical to a gingival mass that was diagnosed histologically as CAA. Surgical management by conservative gingivectomy, cyst enucleation, and bone grafting was an effective treatment in this patient. PMID- 28639882 TI - Management of Oral Anticoagulation Therapy After Gastrointestinal Bleeding: Whether to, When to, and How to Restart an Anticoagulation Therapy. AB - OBJECTIVE: To evaluate current clinical evidence for management of oral anticoagulation therapy after gastrointestinal bleeding (GIB) with an emphasis on whether to, when to, and how to resume an anticoagulation therapy. DATA SOURCES: Relevant articles from MEDLINE, Cochrane Library, and EMBASE databases were identified from 1946 through May 20, 2017, using the keywords: gastrointestinal hemorrhage or gastrointestinal bleeding and antithrombotic therapy or anticoagulation therapy or warfarin or dabigatran or rivaroxaban or apixaban or edoxaban. STUDY SELECTION AND DATA EXTRACTION: All English-language studies assessing management of oral anticoagulation therapy after GIB were evaluated. DATA SYNTHESIS: A total of 9 studies were identified. Four retrospective cohort studies showed that resuming anticoagulation therapy was associated with significantly lower rate of thromboembolism (TE) in the general population. Meta analyses and prospective cohort studies also supported this finding. Two retrospective cohort studies indicated an increase in GIB when anticoagulation reinitiation occurred in less than 7 days without a decrease in TE. Resuming therapy between 7 and 15 days did not demonstrate a significant increase in GIB or TE. A large retrospective study showed that apixaban was associated with the significantly lowest risk of GIB compared with both rivaroxaban and dabigatran. CONCLUSION: Anticoagulation therapy resumption is recommended, with resumption being considered between 7 and 14 days following GIB regardless of the therapy chosen. Data for warfarin management after GIB should be applied with caution to direct oral anticoagulants (DOACs) because of the quicker onset and experimental nature of reversal agents. Apixaban may be a preferred option when restarting a DOAC therapy. PMID- 28639883 TI - Cancer immunotherapy: Breakthrough or "deja vu, all over again"? AB - From the application of Coley's toxin in the early 1900s to the present clinical trials using immune checkpoint regulatory inhibitors, the history of cancer immunotherapy has consisted of extremely high levels of enthusiasm after anecdotal case reports of enormous success, followed by decreasing levels of enthusiasm as the results of controlled clinical trials are available. In this review, this pattern will be documented for the various immunotherapeutic approaches over the years. The sole exception being vaccination against cancer causing viruses, which have already prevented thousands of cancers. We can only hope that the present high level of enthusiasm for the use of immune stimulation by removal of blocks to cancer immunity will be more productive than the incremental improvements using previous immunotherapies. PMID- 28639884 TI - Loss of tumor suppressor miR-126 contributes to the development of hepatitis B virus-related hepatocellular carcinoma metastasis through the upregulation of ADAM9. AB - Hepatocellular carcinoma is the most common histological type of primary liver cancer, which represents the second leading cause of cancer-related mortality. MiR-126 was reported to be downregulated in hepatocellular carcinoma tissues, compared with its levels in noncancerous tissues. However, baseline miR-126 expression levels in hepatitis B virus-related hepatocellular carcinoma patients who did not undergo pre-operational treatment remains unknown since hepatitis B virus infection and pre-operational transcatheter arterial chemoembolization were shown to upregulate miR-126 expression. Here, we demonstrated that miR-126 is generally downregulated in a homogeneous population of pre-operational treatment naive hepatitis B virus-related hepatocellular carcinoma patients (84.0%, 84/100), and its expression is significantly associated with pre-operational alpha-fetoprotein levels ( p < 0.05), microvascular invasion ( p < 0.05), tumor metastasis ( p < 0.05), as well as early recurrence (12 months after surgery; p < 0.01). Furthermore, the results of our study revealed that miR-126 is negatively correlated with ADAM9 expression in hepatitis B virus-related hepatocellular carcinoma patients. Overexpression of miR-126 was shown to attenuate ADAM9 expression in hepatocellular carcinoma cells, which subsequently inhibits cell migration and invasion in vitro. In addition, Cox proportional hazards regression model analysis showed that ADAM9 levels, tumor number, microvascular invasion, and tumor metastasis rate represent independent prognostic factors for shorter recurrence-free survival. In conclusion, we demonstrated that the loss of tumor suppressor miR-126 in hepatitis B virus-related hepatocellular carcinoma cells contributes to the development of metastases through the upregulated expression of its target gene, ADAM9. MiR-126-ADAM9 pathway-based therapeutic targeting may represent a novel approach for the inhibition of hepatitis B virus-related hepatocellular carcinoma metastases. PMID- 28639885 TI - MicroRNA-195 inhibits the proliferation and invasion of pancreatic cancer cells by targeting the fatty acid synthase/Wnt signaling pathway. AB - Emerging evidence suggests that microRNAs are critical regulators of cancer development and progression. MicroRNA-195 has been reported as a cancer-related microRNA in many human cancers. However, the role of microRNA-195 in pancreatic cancer remains largely unknown. Here, we show that microRNA-195 is downregulated in pancreatic cancer tissues and cell line. Also, we show that overexpression of microRNA-195 inhibits the proliferation and invasion of pancreatic cancer cells, whereas suppression of microRNA-195 promotes proliferation and invasion. We show that microRNA-195 directly targets the fatty acid synthase enzyme and negatively regulates the expression of fatty acid synthase. Also, we show that fatty acid synthase expression is inversely correlated with microRNA-195 expression in pancreatic cancer tissues. Moreover, our results show that microRNA-195 inhibits Wnt signaling in pancreatic cancer cells. By restoring fatty acid synthase expression, we were able to reverse the antitumor effects of microRNA-195 in pancreatic cancer cells. Taken together, our findings show that microRNA-195 inhibits pancreatic cancer cell proliferation and invasion by regulating the fatty acid synthase/Wnt signaling pathway, suggesting a tumor suppressive role for microRNA-195 in the development and progression of pancreatic cancer. Thus, inhibiting fatty acid synthase by microRNA-195 may serve as a novel therapeutic approach for the treatment of pancreatic cancer. PMID- 28639886 TI - A competing endogenous RNA network identifies novel mRNA, miRNA and lncRNA markers for the prognosis of diabetic pancreatic cancer. AB - Pancreatic cancer (PaC) is highly associated with diabetes mellitus (DM). However, the mechanisms are insufficient. The study aimed to uncover the underlying regulatory mechanism on diabetic PaC and find novel biomarkers for the disease prognosis. Two RNA-sequencing (RNA-seq) datasets, GSE74629 and GSE15932, as well as relevant data in TCGA were utilized. After pretreatment, differentially expressed genes (DEGs) or miRNAs (DEMs) or lncRNAs (DELs) between diabetic PaC and non-diabetic PaC patients were identified, and further examined for their correlations with clinical information. Prognostic RNAs were selected using KM curve. Optimal gene set for classification of different samples were recognized by support vector machine. Protein-protein interaction (PPI) network was constructed for DEGs based on protein databases. Interactions among three kinds of RNAs were revealed in the 'lncRNA-miRNA-mRNA' competing endogenous RNA (ceRNA) network. A group of 32 feature genes were identified that could classify diabetic PaC from non-diabetic PaC, such as CCDC33, CTLA4 and MAP4K1. This classifier had a high accuracy on the prediction. Seven lncRNAs were tied up with prognosis of diabetic PaC, especially UCA1. In addition, crucial DEMs were selected, such as hsa-miR-214 (predicted targets: MAP4K1 and CCDC33) and hsa-miR 429 (predicted targets: CTLA4). Notably, interactions of 'HOTAIR-hsa-miR-214 CCDC33' and 'CECR7-hsa-miR-429-CTLA4' were highlighted in the ceRNA network. Several biomarkers were identified for diagnosis of diabetic PaC, such as HOTAIR, CECR7, UCA1, hsa-miR-214, hsa-miR-429, CCDC33 and CTLA4. 'HOTAIR-hsa-miR-214 CCDC33' and 'CECR7-hsa-miR-429-CTLA4' regulations might be two important mechanisms for the disease progression. PMID- 28639887 TI - MicroRNA-138 enhances TRAIL-induced apoptosis through interferon-stimulated gene 15 downregulation in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma is a leading cause of cancer-related mortality worldwide. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a potential target for cancer therapy. However, many cancer cells are resistant to TRAIL-induced apoptosis and its mechanism is not well understood. In this study, to identify potential therapeutic targets for TRAIL-resistant cancer cells, we compared the expression levels of interferon-stimulated gene 15 in TRAIL sensitive and TRAIL-resistant hepatocellular carcinoma cell lines. Western blot analysis showed that interferon-stimulated gene 15 expression levels were significantly higher in resistant HLCZ01and Huh7 cells than in sensitive LH86 and SMMC-7721 cells. Interferon-stimulated gene 15 knockdown in resistance cells led to TRAIL sensitivity. Conversely, interferon-stimulated gene 15 overexpression in sensitive cells resulted in TRAIL resistance. Our bioinformatics search detected a putative target sequence for microRNA miR-138 in the 3' untranslated region of the interferon-stimulated gene 15. Real-time quantitative polymerase chain reaction analysis demonstrated that miR-138 was significantly downregulated in TRAIL-resistant cells compared to TRAIL-sensitive cells. Forced expression of miR 138 in resistant cells decreased both messenger RNA and protein levels of interferon-stimulated gene 15, and when exposed to TRAIL, activated poly(adenosine diphosphate-ribose) polymerase, indicating sensitization to TRAIL. The results suggested that miR-138 regulates the interferon-stimulated gene 15 expression by directly targeting the 3' untranslated region of interferon stimulated gene 15 and modulates the sensitivity to TRAIL-induced apoptosis. MiR 138 may be a target for therapeutic intervention in TRAIL-based drug treatments of resistant hepatocellular carcinoma or could be a biomarker to select patients who may benefit from the treatment. PMID- 28639888 TI - Transgelin-2: A potential oncogenic factor. AB - Actin-binding proteins are proteins that could bind to actin or actin fibers. As a member of actin-binding proteins, Transgelin-2 is expressed in smooth muscle cells and non-smooth muscle cells, and its gene, TAGLN2, is differently expressed in all cells and tissues. The deregulation of Transgelin-2 is considered to be correlated with progression of many kinds of diseases, especially the development of malignant tumors, such as invasion, metastasis, and resistance, yet the function and mechanism of action of Transgelin-2 remain elusive. Therefore, we reviewed the basic characteristics and function of Transgelin-2 and its biological role in various types of diseases in order to provide the theoretical basis for further research and new perspectives on cancer development. PMID- 28639889 TI - The association between RARbeta and FHIT promoter methylation and the carcinogenesis of patients with cervical carcinoma: A meta-analysis. AB - The RARbeta and FHIT promoter methylation are observed in some cervical carcinoma. However, the association between RARbeta and FHIT promoter methylation and cervical carcinogenesis remains unclear. This study was carried out to evaluate the correlation between RARbeta or FHIT promoter methylation and cervical carcinogenesis. Eligible publications were searched via online databases. The combined odds ratios and corresponding 95% confidence intervals were calculated and summarized. In all, 17 eligible articles on RARbeta and FHIT promoter methylation were identified in the study. RARbeta promoter methylation was significantly higher in cervical cancer than in cervical intraepithelial neoplasia lesions and normal cervical tissues (odds ratio = 3.90, p = 0.018; odds ratio = 12.98, p < 0.001, respectively). There was more FHIT promoter methylation in cervical cancer than in cervical intraepithelial neoplasia lesions and normal controls (odds ratio = 8.0, p = 0.055; odds ratio = 10.75, p < 0.001, respectively). In addition, FHIT promoter methylation was correlated with clinical stage (advanced stage vs early stage: odds ratio = 2.69, p = 0.056) and tumor grade (high grade vs low grade: odds ratio = 4.11, p < 0.001). RARbeta and FHIT promoter methylation may be associated with the carcinogenesis of cervical cancer. FHIT promoter methylation may play a crucial role in cervical cancer progression. Additional studies with large sample sizes are essential to confirm our findings. PMID- 28639890 TI - MiR-557 works as a tumor suppressor in human lung cancers by negatively regulating LEF1 expression. AB - MicroRNAs play an important role in regulating post-transcriptional gene expression in the progression of various human cancers. In this study, we investigated the role of microRNA-557 in human lung cancer cells. The molecular mechanism of microRNA-557 was also clarified in the proliferation and invasion of human lung cancer cells. Our results showed microRNA-557 levels were obviously decreased in clinical lung cancer specimens and lung cancer cell lines. Cell viability of A549 and NCI-H460 cells transfected with microRNA-557 mimics was significantly decreased than those transfected with negative control mimics. MicroRNA-557 promoted cell death of A549 and NCI-H460 but did not affect the cell apoptosis of lung cancer cells. Overexpression of microRNA-557 inhibited cell invasion of A549 and NCI-H460 cells. TargetScan analysis showed that microRNA-557 might target 3' untranslated region of lymphocyte enhancement factor 1, and the western blotting results showed that transfection of microRNA-557 mimics significantly decreased the levels of lymphocyte enhancement factor 1 in A549 and H460 cells. MicroRNA-557 might work as a tumor suppressor by negatively regulating the expression of lymphocyte enhancement factor 1 in lung cancer cells. PMID- 28639891 TI - Antitumor activity of a Rhodococcus sp. Lut0910 isolated from polluted soil. AB - The actinomycetes strain, lut0910, was isolated from polluted soil and identified as the Rhodococcus species with 99% similarity based on the sequence analysis of 16S recombinant DNA. The extract of this strain demonstrated in vivo and in vitro antitumor activity. The treatment of two human cancer cell lines, hepatocellular carcinoma HepG2 and cervical carcinoma Hela cells, with the lut0910 extract caused the delay in cell propagation in a dose-dependent manner with an IC50 of 73.39 and 33.09 ug/mL, respectively. Also, the oral administration of lut0910 extract to the mice with a solid tumor resulted in the inhibition of tumor growth in comparison with a placebo group. The thymus and spleen indexes were significantly increased in mice groups treated with the lut0910 extract. The histopathological changes of the tumor tissues showed that there were massive necrotic areas in the tumor tissues after treatment with different doses of the lut0910 extract. Our result would provide a new way and potent source for development of new anticancer agent from the polluted environment. PMID- 28639892 TI - JAK2 variations and functions in lung adenocarcinoma. AB - Lung cancer ranks as the first most common cancer and the first leading cause of cancer-related death in China and worldwide. Due to the difficulty in early diagnosis and the onset of cancer metastasis, the 5-year survival rate of lung cancer remains low. JAK2 has emerged as pivotal participant in biological processes, often dysregulated in a range of cancers. Recently our study found that JAK2 might play an important role in lung cancer pathogenesis. While our understanding of JAK2 in the onset and progression of lung cancer is still in its infancy, there is no doubt that understanding the variations and functions of JAK2 will certainly secure strong biomarkers and improve treatment options for lung cancer patients. The expression level of JAK2 mRNA was assayed using RT-PCR. JAK2 mutations and amplification were detected using next-generation sequencing (NGS). The shRNA and overexpression plasmids of JAK2 were conducted. MTT (3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazoliumbromide) assay, Trans-well migration and Matrigel invasion assay were conducted to study the proliferation, migration and invasion abilities of lung adenocarcinoma cells independently. We found that JAK2 mRNA was up-regulated in lung adenocarcinoma tissues when compared with their adjacent non-tumor tissues, and was associated with lymph node metastasis ( p < 0.05). JAK2 V617F and N30S mutations and JAK2 amplification were detected by NGS in plasmid samples in patients with lung adenocarcinoma. Downregulation of JAK2 inhibited the proliferation, migration and invasion abilities of lung adenocarcinoma A549 cells. Moreover, overexpression of JAK2 induced the proliferation, migration and invasion abilities of A549 cells. Thus, the up-regulation, mutation and amplification of JAK2 detected in lung adenocarcinoma may participate in lung cancer progression by regulating cancer cells' proliferation, migration and invasion. PMID- 28639893 TI - Apobec-1 complementation factor regulates cell migration and apoptosis through Dickkopf1 by acting on its 3' untranslated region in MCF7 cells. AB - A1CF (apobec-1 complementation factor) acts as a component of the apolipoprotein B messenger RNA editing complex. Previous researches mainly focused on its post transcriptional cytidine to uridine RNA editing. However, few study reported its role in progression of breast carcinoma cells. Wound healing assay and flow cytometry were applied to detect the migration and apoptosis; western blot, real time polymerase chain reaction, and dual-luciferase assays were applied to investigate the potential regulation mechanism of A1CF-mediated cell migration and apoptosis. Knockdown of A1CF decreased cell migration and enhanced cell apoptosis in MCF7 cells in vitro. Western blot analysis showed that knockdown of A1CF decreased Dickkopf1 but increased c-Myc and beta-catenin expression, and overexpression of A1CF can get opposite results. Knockdown of Dickkopf1 in A1CF overexpressed cells decreased cell migration and enhanced cell apoptosis compared with A1CF-overexpressed cells. Luciferase-fused 3' untranslated region of human Dickkopf1 activity was highly upregulated in A1CF-overexpressed MCF7 cells, but this upregulation can be inhibited by mutating conserved binding motifs of Dickkopf1 3' untranslated region. A1CF played a crucial role in cell migration and survival through affecting 3' untranslated region of Dickkopf1 to upregulate its expression in MCF7 cells. PMID- 28639894 TI - Deregulated expression of Cdc6 as BCR/ABL-dependent survival factor in chronic myeloid leukemia cells. AB - Chronic myeloid leukemia is characterized by the presence of the reciprocal translocation t(9;22) and the BCR/ABL oncogene. The BCR/ABL oncogene activates multiple signaling pathways and involves the dysregulation of oncogenes during the progression of chronic myeloid leukemia. The cell division cycle protein 6, an essential regulator of DNA replication, is elevated in some human cancer cells. However, the expression of cell division cycle protein 6 in chronic myeloid leukemia and the underlying regulatory mechanism remain to be elucidated. In this study, our data showed that cell division cycle protein 6 expression was significantly upregulated in primary chronic myeloid leukemia cells and the chronic myeloid leukemia cell line K562 cells, as compared to the normal bone marrow mononuclear cells. BCR/ABL kinase inhibitor STI571 or BCR/ABL small interfering RNA could significantly downregulate cell division cycle protein 6 messenger RNA expression in K562 cells. Moreover, phosphoinositide 3-kinase/AKT pathway inhibitor LY294002 and Janus kinase/signal transducer and activator of transcription pathway inhibitor AG490 could downregulate cell division cycle protein 6 expression in K562 cells, but not RAS/mitogen-activated protein kinase pathway inhibitor PD98059 had such effect. Cell division cycle protein 6 gene silencing by small interfering RNA effectively resulted in decrease of proliferation, increase of apoptosis, and arrest of cell cycle in K562 cells. These findings have demonstrated that cell division cycle protein 6 overexpression may contribute to the high proliferation and low apoptosis in chronic myeloid leukemia cells and can be regulated by BCR/ABL signal transduction through downstream phosphoinositide 3-kinase/Akt and Janus kinase/signal transducer and activator of transcription pathways, suggesting cell division cycle protein 6 as a potential therapeutic target in chronic myeloid leukemia. PMID- 28639895 TI - Upregulation of miR-199a/b contributes to cisplatin resistance via Wnt/beta catenin-ABCG2 signaling pathway in ALDHA1+ colorectal cancer stem cells. AB - Cisplatin resistance in colorectal cancer largely results from the colorectal cancer stem cells which could be targeted to improve the efficacy of chemotherapy. MicroRNAs are possible modulators of cancer stem cell characteristics and maybe involved in the retention of cancer stem cell chemoresistance. The aim of this study was to investigate the biological function of miR-199a/b on cisplatin resistance in colorectal cancer stem cells and its related mechanisms. Here, ALDHA1+ cells from primary colorectal cancer tissues behaved similar to cancer stem cells and were chemoresistant to cisplatin. The presence of a variable fraction of ALDHA1 was detected in 9 out of 10 colorectal cancer specimens. Significantly, increased miR-199a/b expression was detected in ALDHA1+ colorectal cancer stem cells, accompanied by a downregulation of Gsk3beta and an overexpression of beta-catenin and ABCG2. In patient cohort, enhanced miR 199a/b expression in colorectal cancer tissues was associated with cisplatin response and poor patient survival. In addition, 80% of colorectal cancer samples showed lower level of Gsk3beta than their adjacent normal counterparts. Furthermore, Gsk3beta was the direct target of miR-199a/b. MiR-199a/b regulated Wnt/beta-catenin pathway by targeting Gsk3beta in ALDHA1+ colorectal cancer stem cells. By blocking Wnt/beta-catenin pathway, we implied that ABCG2 lies downstream of Wnt/beta-catenin pathway. ABCG2 was further demonstrated to contribute cisplatin resistance in ALDHA1+ colorectal cancer stem cells and can be regulated by miR-199a/b. Thus, our data suggested that upregulation of miR 199a/b in ALDHA1+ colorectal cancer stem cells contributed to cisplatin resistance via Wnt/beta-catenin-ABCG2 signaling, which sheds new light on understanding the mechanism of cisplatin resistance in colorectal cancer stem cells and facilitates the development of potential therapeutics against colorectal cancer. PMID- 28639896 TI - SGK2 promotes hepatocellular carcinoma progression and mediates GSK-3beta/beta catenin signaling in HCC cells. AB - The phosphoinositide 3-kinase pathway is one of the most commonly altered pathways in human cancers. The serum/glucocorticoid-regulated kinase (SGK) family of serine/threonine kinases consists of three isoforms, SGK1, SGK2, and SGK3. This family of kinases is highly homologous to the AKT kinase family, sharing similar upstream activators and downstream targets. Few studies have investigated the role of SGK2 in hepatocellular carcinoma. Here, we report that SGK2 expression levels were upregulated in hepatocellular carcinoma tissues and human hepatoma cell lines compared to the adjacent normal liver tissues and a normal hepatocyte line, respectively. We found that downregulated SGK2 inhibits cell migration and invasive potential of hepatocellular carcinoma cell lines (SMMC 7721 and Huh-7).We also found that downregulated SGK2 suppressed the expression level of unphosphorylated (activated) glycogen synthase kinase 3 beta. In addition, SGK2 downregulation decreased the dephosphorylation (activation) of beta-catenin by preventing its proteasomal degradation in the hepatocellular carcinoma cell lines. These findings suggest that SGK2 promotes hepatocellular carcinoma progression and mediates glycogen synthase kinase 3 beta/beta-catenin signaling in hepatocellular carcinoma cells. PMID- 28639897 TI - Gene signature based on degradome-related genes can predict distal metastasis in cervical cancer patients. AB - Cervical cancer is one of the leading causes of death in women worldwide, which mainly affects developing countries. The patients who suffer a recurrence and/or progression disease have a higher risk of developing distal metastases. Proteases comprising the degradome given its ability to promote cell growth, migration, and invasion of tissues play an important role during tumor development and progression. In this study, we used high-density microarrays and quantitative reverse transcriptase polymerase chain reaction to evaluate the degradome profile and their inhibitors in 112 samples of patients diagnosed with locally advanced cervical cancer. Clinical follow-up was done during a period of 3 years. Using a correlation analysis between the response to treatment and the development of metastasis, we established a molecular signature comprising eight degradome related genes (FAM111B, FAM111A, CFB, PSMB8, PSMB9, CASP7, PRSS16, and CD74) with the ability to discriminate patients at risk of distal metastases. In conclusion, present results show that molecular signature obtained from degradome genes can predict the possibility of metastasis in patients with locally advanced cervical cancer. PMID- 28639898 TI - Targeting interlukin-6 to relieve immunosuppression in tumor microenvironment. AB - Immunotolerance is one of the hallmarks of malignant tumors. Tumor cells escape from host immune surveillance through various mechanisms resulting in tumor progression and therapeutic resistance. Interlukin-6 is a proinflammatory cytokine involved in many physiological and pathological processes by integrating with multiple intracellular signaling pathways. Aberrant expression of interlukin 6 is associated with the growth, metastasis, and chemotherapeutic resistance in a wide range of cancers. Interlukin-6 exerts immunosuppressive capacity mostly by stimulating the infiltrations of myeloid-derived suppressor cells, tumor associated neutrophils, and cancer stem-like cells via Janus-activated kinase/signal transducer and activator of transcription 3 pathway in tumor microenvironment. On this foundation, blockage of interlukin-6 signal may provide potential approaches to novel therapies. In this review, we introduced interlukin 6 pathways and summarized molecular mechanisms related to interlukin-6-induced immunosuppression of tumor cell. We also concluded recent clinical studies targeting interlukin-6 as an immune-based therapeutic intervention in patients with cancer. PMID- 28639899 TI - TWEAK/Fn14 signaling in tumors. AB - TWEAK (tumor necrosis factor-related weak inducer of apoptosis), a member of the tumor necrosis factor superfamily, acts on cells by binding to its only receptor named Fn14 (fibroblast growth factor-inducible 14). Their engagement activates a number of intracellular signal transduction cascades and consequently leads to cell death, proliferation, migration, or survival depending on the cellular contexts. Studies have indicated that the expression of TWEAK and Fn14 is upregulated in many solid tumors compared with healthy tissues. The activation of TWEAK/Fn14 signaling enhances the proliferation, invasion, and migration of tumor cells. Moreover, the angiogenesis, pro-inflammatory cytokine expression, and epithelial-mesenchymal transitions are promoted upon TWEAK/Fn14 activation. Currently, the tumor necrosis factor receptor-associated factor and nuclear factor kappa B signaling pathways are considered two main downstream pathways activated by TWEAK/Fn14 interaction. In view of these facts, some TWEAK- or Fn14 targeting agents are generated to inhibit the progression of tumors and have achieved initial success in clinical and pre-clinical trials. These agents include monoclonal antibodies, fusion proteins, immunotoxins, and nanoparticles. In addition, some relevant signaling pathways are studied to identify new potential therapeutic targets. Overall, these findings suggest that the TWEAK/Fn14 pathway is critical in the development of tumors, and targeting this signaling is a potential therapeutic approach in future tumor therapy. PMID- 28639900 TI - The novel CXCR4 antagonist, PRX177561, reduces tumor cell proliferation and accelerates cancer stem cell differentiation in glioblastoma preclinical models. AB - Glioblastoma is the most frequent and the most lethal primary brain tumor among adults. Standard of care is the association of radiotherapy with concomitant or adjuvant temozolomide. However, to date, recurrence is inevitable. The CXCL12/CXCR4 pathway is upregulated in the glioblastoma tumor microenvironment regulating tumor cell proliferation, local invasion, angiogenesis, and the efficacy of radio-chemotherapy. In this study, we evaluated the effects of the novel CXCR4 antagonist, PRX177561, in preclinical models of glioblastoma. CXCR4 expression and PRX177561 effects were assessed on a panel of 12 human glioblastoma cells lines and 5 patient-derived glioblastoma stem cell cultures. Next, the effect of PRX177561 was tested in vivo, using subcutaneous injection of U87MG, U251, and T98G cells as well as orthotopic intrabrain inoculation of luciferase-transfected U87MG cells. Here we found that PRX177561 impairs the proliferation of human glioblastoma cell lines, increases apoptosis, and reduces CXCR4 expression and cell migration in response to stromal cell-derived factor 1alpha in vitro. PRX177561 reduced the expression of stem cell markers and increased that of E-cadherin and glial fibrillary acidic protein in U87MG cells consistent with a reduction in cancer stem cells. In vivo, PRX177561 reduced the weight and increased the time to progression of glioblastoma subcutaneous tumors while increasing disease-free survival and overall survival of mice bearing orthotopic tumors. Our findings suggest that targeting stromal cell-derived factor 1 alpha/CXCR4 axis by PRX177561 might represent a novel therapeutic approach against glioblastoma and support further investigation of this compound in more complex preclinical settings in order to determine its therapeutic potential. PMID- 28639901 TI - Downregulation of miR-193a-3p inhibits cell growth and migration in renal cell carcinoma by targeting PTEN. AB - Although miR-193a-3p has been found to be dysregulated in variety of human tumors, little is known about its role in renal cell carcinoma. This study was designed to investigate the function and underlying mechanism of miR-193a-3p in human renal cell carcinoma tissues and cell lines. Here, we demonstrated that the expression of miR-193-3p was increased in renal cell carcinoma tissues and cell lines. In addition, knockdown of miR-193a-3p significantly inhibited cell proliferation and colony formation and induced cells into G1 phase arrest. Meanwhile, the migration potential of 786-O cells was also decreased compared to control group. Furthermore, we identified PTEN as a direct and functional target of miR-193a-3p, at least partly responsible for promoting tumor effect of miR 193a-3p in renal cell carcinoma. Taken together, the findings indicated for the first time that miR-193a-3p functions as a tumor-promoting microRNA by directly targeting PTEN in renal cell carcinoma. PMID- 28639902 TI - Mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. AB - Mild hyperthermia enhances anti-cancer effects of chemotherapy, but the precise biochemical mechanisms involved are not clear. This study was carried out to investigate whether mild hyperthermia sensitizes gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. In total, 20 BABL/c mice of MKN-45 human gastric cancer tumor model were divided into hyperthermia + chemotherapy group, hyperthermia group, chemotherapy group, N acetyl-L-cysteine group, and mock group. Reactive oxygen species production and expression of autophagy-related genes Beclin1, LC3B, and mammalian target of rapamycin were determined. The relationships between tumor growth regression, expression of autophagy-related genes, and reactive oxygen species production were evaluated. Tumor size and wet weight of hyperthermia + chemotherapy group was significantly decreased relative to values from hyperthermia group, chemotherapy group, N-acetyl-L-cysteine group, and mock group ( F = 6.92, p < 0.01 and F = 5.36, p < 0.01, respectively). Reactive oxygen species production was significantly higher in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. The expression levels of Beclin1 and LC3B were significantly higher, while those of mammalian target of rapamycin were significantly lower in hyperthermia + chemotherapy group than in hyperthermia, chemotherapy, and mock groups. Tumor growth regression was consistent with changes in reactive oxygen species production and expression of autophagy-related genes. N-acetyl-L-cysteine inhibited changes in the expression of the autophagy related genes and also suppressed reactive oxygen species production and tumor growth. Hyperthermia + chemotherapy increase expression of autophagy-related genes Beclin1 and LC3B, decrease expression of mammalian target of rapamycin, and concomitantly increase reactive oxygen species generation. These results strongly indicate that mild hyperthermia enhances sensitivity of gastric cancer cells to chemotherapy through reactive oxygen species-induced autophagic death. PMID- 28639903 TI - Targeting the mTOR pathway in breast cancer. AB - Mechanistic target of rapamycin controls cell growth, metabolism, and aging in response to nutrients, cellular energy stage, and growth factors. In cancers including breast cancer, mechanistic target of rapamycin is frequently upregulated. Blocking mechanistic target of rapamycin with rapamycin, first generation and second-generation mechanistic target of rapamycin inhibitors, called rapalogs, have shown potent reduction of breast cancer tumor growth in preclinical models and clinical trials. In this review, we summarize the fundamental role of the mechanistic target of rapamycin pathway in driving breast tumors. Moreover, we also review key molecules involved with aberrant mechanistic target of rapamycin pathway activation in breast cancer and current efforts to target these components for therapeutic gain. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the mechanistic target of rapamycin pathway. PMID- 28639904 TI - Role of JNK signaling in oral cancer: A mini review. AB - JNKs (c-Jun N-terminal kinases) belong to mitogen-activated protein kinases' family and become activated by several growth factors, stress, radiation, and other extracellular signals. In turn, JNK activation results in phosphorylation of downstream molecules involved in many normal cellular processes. Nevertheless, recent data have linked JNK signaling with several pathological conditions, including neurodegenerative diseases, inflammation, and cancer. The role of JNK in cancer remains controversial. Initially, JNK was thought to play a rather oncosuppressive role by mediating apoptosis in response to stress stimuli, inflammatory, or oncogenic signals. However, a number of studies have implicated JNK in malignant transformation and tumor growth. The contradictory functions of JNK in cancer may be due to the diversity of JNK upstream and downstream signaling and are under intensive investigation. This review summarizes current literature focusing on the significance of JNK pathway in cancer development and progression, particularly addressing its role in oral cancer. Understanding the complexity of JNK signaling has the potential to elucidate important molecular aspects of oral cancer, possibly leading to development of novel and individualized therapeutic strategies. PMID- 28639905 TI - High expression of Kruppel-like factor 4 as a predictor of poor prognosis for cervical cancer patient response to radiotherapy. AB - PURPOSE: The aim of this study was to explore the associations of Kruppel-like factor 4 expression with sensitivity to radiation therapy in locally advanced cervical squamous cell carcinoma patients. METHODS: The records of 117 locally advanced cervical squamous cell carcinoma patients were retrospectively reviewed, and Kruppel-like factor 4 expression in cervical carcinoma tissues was examined by immunohistochemical staining. The associations of Kruppel-like factor 4 expression with clinicopathological parameters were analyzed. Survival time was analyzed using Kaplan-Meier analysis and a Cox regression model. RESULTS: Patients being resistant to radiation therapy were associated with advanced International Federation of Gynecology and Obstetrics stage, tumor diameter (>4 cm), and poor differentiation grade. The high Kruppel-like factor 4 expression level was significantly related to resistance to radiation therapy, including radiation therapy non-response, local recurrence, and distant metastasis. The high Kruppel-like factor 4 expression level was also significantly related to the advanced International Federation of Gynecology and Obstetrics stage and poor differentiation grade. Kaplan-Meier analysis indicates that locally advanced cervical squamous cell carcinoma patients with high Kruppel-like factor 4 expression showed worse progression-free survival and overall survival. Univariate and multivariate Cox regression model analyses suggest that the high Kruppel-like factor 4 expression was one of the high-risk factors associated with poor prognosis in locally advanced cervical squamous cell carcinoma patients after radiation therapy. CONCLUSION: Our results suggest that the high Kruppel like factor 4 expression can be used as a novel biomarker to predict radiation therapy resistance and poor prognosis for locally advanced cervical squamous cell carcinoma. PMID- 28639906 TI - Preoperative platelet-to-lymphocyte ratio is a valuable prognostic biomarker in patients with hepatocellular carcinoma undergoing curative liver resection. AB - The Platelet to lymphocyte ratio (PLR) has been reported to predict prognosis of patients with hepatocellular carcinoma (HCC). This study examined the prognostic potential of stratified PLR for HCC patients undergoing curative liver resection. Medical records were retrospectively analyzed for 778 HCC patients undergoing curative liver resection at the Affiliated Tumor Hospital of Guangxi Medical University and the First People's Hospital of Changde between April 2010 and October 2013. Patients were stratified based on quintile analysis of their preoperative PLR, and patients in different quintiles were analyzed for overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier analysis. Independent predictors of death or recurrence were explored using multivariable Cox proportional hazard regression. Higher PLR quintiles were significantly associated with poorer overall survival (p < 0.001). Multivariate analysis showed PLR to be an independent risk factor for OS (p = 0.003). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 2.780, 95% confidence interval (CI): 1.769-4.367, p < 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.534, 95% CI: 1.112-2.117, p = 0.009), this association was not significant after multivariable adjustment (p = 0.220). Subgroup analysis also showed that PLR quintiles were significantly associated with poor OS in patients positive for HBsAg or with cirrhosis (both p < 0.001). Similar results were obtained when PLR was analyzed as a dichotomous variable with cut-off values of 110 and 115. Elevated preoperative PLR may be independently associated with poor OS and DFS in HCC patients following curative resection. PMID- 28639907 TI - Ferrichrome identified from Lactobacillus casei ATCC334 induces apoptosis through its iron-binding site in gastric cancer cells. AB - Ferrichrome is known to be a siderophore, but it was recently identified as a tumor-suppressive molecule derived from Lactobacillus casei ATCC334 ( L. casei). In the present study, we investigated the effects of ferrichrome in gastric cancer cells. Cell lines and xenograft models treated with ferrichrome demonstrated growth suppression. The expression levels of cleaved poly (adenosine diphosphate-ribose) polymerase, and cleaved caspase-9 were increased by ferrichrome treatment. Although the tumor-suppressive effects of ferrichrome were almost completely diminished by the iron chelation, the reduction in the intracellular iron by ferrichrome did not correlate with its tumor-suppressive effects. An exhaustive docking simulation indicated that iron-free ferrichrome can make stable conformations with various mammalian molecules, including transporters and receptors. In conclusion, probiotic-derived ferrichrome induced apoptosis in gastric cancer cells. The iron binding site of ferrichrome is the structure responsible for its tumor suppressive function. PMID- 28639908 TI - Circular RNAs play an important role in late-stage gastric cancer: Circular RNA expression profiles and bioinformatics analyses. AB - Gastric cancer is one of the most common tumors of the digestive system. Here, analysis of the expression profiles of circular RNAs in advanced gastric adenocarcinoma and adjacent normal mucosa tissues revealed differential expression of 306 circular RNAs, among which 273 were predicted to exert regulatory effects on target microRNAs. The downstream pathway networks of circular RNA-microRNA were mapped and the node genes were identified. In particular, we found that the expression of hsa_circ_0058246 was elevated in tumor specimens of patients with poor clinical outcomes. Our collective findings indicate that circular RNAs play a critical role in gastric cancer tumorigenesis. Data from this study provide a new perspective on the molecular pathways underlying metastasis and recurrence of gastric cancer and highlight potential therapeutic targets that may contribute to more effective diagnosis and treatment of the disease. PMID- 28639909 TI - Silencing of NRAGE induces autophagy via AMPK/Ulk1/Atg13 signaling pathway in NSCLC cells. AB - NRAGE has been reported to be overexpressed in cancer cells, especially in lung cancer cells. To determine the role of NRAGE in non-small-cell lung cancer cells, we investigated the effects of NRAGE on autophagy in non-small-cell lung cancer cells. Human A549 and H1299 cells were transfected with NRAGE-specific small interfering RNA. The Cell Counting Kit-8 and plate clone assay showed that downregulation of NRAGE could induce the proliferation in A549 and H1299 cells. In addition, our data suggested that downregulation of NRAGE enhances autophagosome formation by immunofluorescence. We found that knockdown of NRAGE induced autophagy, together with downregulation of P62 and upregulation of LC3-II protein. Furthermore, to elucidate the mechanism of NRAGE in suppressing autophagy, the protein expressions of AMPK, Ulk1, and Atg13 were assessed. Collectively, these results demonstrate the effective anti-autophagic of NRAGE in non-small-cell lung cancer cells through AMPK/Ulk1/Atg13 autophagy signaling pathways. Therefore, NRAGE could be used as a potential therapeutic target for lung cancer. PMID- 28639911 TI - Individualized proximal margin correlates with outcomes in gastric cancers with radical gastrectomy. AB - The length of proximal margin for gastrectomy remains controversial. The proximal margin and its relationships with clinicopathological variables and overall survival of 922 gastric cancers were retrospectively analyzed. Proximal margin was divided into four groups (0-2.0, 2.1-4.0, 4.1-6.0, and >6.0 cm). It indicated that the overall survival was improved with the increase of proximal margin. The proximal margin of 2.1-4.0 cm was associated with a better overall survival for gastric cancers with solitary-type (T1 and T2 stages, N0 stage, tumor-node metastasis stages I and II, tumor size <5 cm, histological G1 and G2, and Bormann type I and II). Futhermore, proximal margin of 4.1-6.0 cm was associated with a better overall survival for gastric cancers with infiltrative-type (T3 and T4 stages, N1 stage, tumor-node-metastasis stage III, tumor size ?5 cm, histological G3 and G4, and Bormann type III and IV). Univariate analysis revealed that T stage, N stage, tumor-node-metastasis stage, histological grade, Bormann type, carcinoembryonic antigen, carbohydrate antigen 199, extent of gastrectomy, tumor location, and proximal margin were significantly associated with overall survival. Multivariate analysis revealed that tumor-node-metastasis stage, histological grade, Bormann type, carcinoembryonic antigen, carbohydrate antigen 199, extent of gastrectomy, and proximal margin were independent prognostic factors for gastric cancers with radical gastrectomy. In conclusion, the proximal margin was an independent prognostic factor for gastric cancer and should be decided individually. Proximal margin of 2.1-4.0 cm and 4.1-6.0 cm were needed for patients with solitary-type and infiltrative-type, respectively. PMID- 28639910 TI - Apatinib for metastatic breast cancer in non-clinical trial setting: Satisfying efficacy regardless of previous anti-angiogenic treatment. AB - Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. This study aimed to evaluate the efficacy and safety of apatinib in metastatic breast cancer (MBC) under non-clinical trial setting, and to study the impact of previous antiangiogenic treatment to the efficacy of apatinib. 52 MBC patients treated with apatinib under non-clinical trial setting in Fudan University Shanghai Cancer Center between January 1st 2015 and October 1st 2016 were included. All patients were included in time-to-treatment failure (TTF) analysis, while 45 patients were enrolled for progression-free survival (PFS) and overall survival (OS) analysis because 7 of the patients with treatment discontinuation due to intolerable toxicities had too short time for efficacy assessment. Impact of previous exposure to antiangiogenic treatment and other factors to patients' survival were analyzed by Log-rank analysis and Cox multivariate analysis. The median PFS, median OS, and median TTF were 4.90 (95% confidence interval [CI] 3.44 - 6.36), 10.3 (unable to calculate 95% CI), and 3.93 (95% CI 1.96 - 5.90) months, respectively. Previous treatment of bevacizumab did not affect the efficacy of apatinib. Previous exposure to anthracycline, age of 60 years or older and palmar-plantar erythrodysesthesia syndrome were independent predictors for prolonged PFS. Discontinuation of treatment was more common in age group of 60 years or older than that in younger group, although the difference was not significant. Although toxicities were generally managable, a previously unrecorded grade 3~4 adverse event of dyspnea has been observed. This study confirmed the encouraging efficacy and manageable safety of apatinib on pretreated MBC patients in non-clinical trial setting. For the first time to our knowledge, this study found that previous treatment of bevacizumab did not affect the efficacy of apatinib, and reported an undocumented severe adverse effect of dyspnea. PMID- 28639912 TI - Increased circulating M2-like monocytes in patients with breast cancer. AB - M2-like tumor-associated macrophages promote breast tumor growth and survival and may migrate into the peripheral blood. However, the frequency of circulating M2 like monocytes in the peripheral blood of breast cancer patients has not been clarified. The objective of this study was to determine the percentages of circulating M2-like monocytes in patients with breast cancer. Immunofluorescence staining for CD68 and CD163 was performed to detect M2-like macrophages in pathological tissues. Flow cytometry was used to assess the frequencies of circulating CD14+CD163+/CD14+CD204+/CD14+CD163+CD204+ M2-like monocytes in 99 breast cancer patients, 56 patients with benign breast disease, and 60 healthy controls. Receiver operating characteristic curve analysis was used to compare the diagnostic values of circulating M2-like monocytes, carcinoembryonic antigen, and cancer antigen 15-3. The associations among circulating M2-like monocytes and clinical breast cancer parameters were analyzed. The number of CD68+CD163+ M2 like macrophages was significantly higher in breast cancer tissues than in benign tissues. In the peripheral blood, CD14+CD163+/CD14+CD204+/CD14+CD163+CD204+ M2 like monocytes were elevated in breast cancer patients compared with normal controls and patients with benign breast disease. The area under the receiver operating curve for circulating CD14+CD163+CD204+ M2-like monocytes was 0.888 (95% confidence interval: 0.839-0.936), a value higher than those for carcinoembryonic antigen and cancer antigen 15-3. High frequencies of circulating CD14+CD204+ and CD14+CD163+CD204+ M2-like monocytes were associated with tumor node-metastasis stage, lymph node metastasis, histological differentiation, and estrogen receptor expression. Circulating M2-like monocytes may serve as a diagnostic biomarker in breast cancer and have a potential role in reflecting breast cancer progression. PMID- 28639914 TI - Long non-coding RNA urothelial carcinoma-associated 1 as a tumor biomarker for the diagnosis of urinary bladder cancer. AB - To investigate the diagnostic value of urothelial carcinoma-associated 1 as a urine biomarker in urinary bladder cancer patients by performing a comprehensive meta-analysis. A comprehensive literature search was conducted by the databases PubMed, Embase, Cochrane Library, China Knowledge Resource Integrated, and Web of Science. The quality of eligible studies was scored with the Quality Assessment of Diagnostic Accuracy Studies. The bivariate meta-analysis model was used to pool the sensitivity, specificity, likelihood ratio, and diagnostic odds ratio. Receiver operating characteristic curves and hierarchical summary receiver operating characteristic models were employed to check the overall test performance in this meta-analysis. Seven publications involving 678 patients and 563 controls were included in this meta-analysis. The pooled sensitivity was 0.84 (95% confidence interval: 0.80-0.88), specificity was 0.87 (95% confidence interval: 0.75-0.94), positive likelihood ratio was 6.5 (95% confidence interval: 3.10-13.62), negative likelihood ratio was 0.18 (95% confidence interval: 0.13 0.25), and diagnostic odds ratio was 36 (95% confidence interval: 13-99). The area under the summary receiver operating characteristic curve was 0.89 (95% confidence interval: 0.86-0.91). Our results indicated that urothelial carcinoma associated 1 was a potential diagnostic biomarker with good specificity and sensitivity in urinary bladder cancer. Further prospective studies with larger cohorts are necessary to evaluate the diagnostic accuracy of urothelial carcinoma associated 1 for urinary bladder cancer. PMID- 28639913 TI - Novel roles of folic acid as redox regulator: Modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma. AB - We provide herein several lines of evidence to substantiate that folic acid (or folate) is a micronutrient capable of functioning as a novel redox regulator on hepatocellular carcinoma. First, we uncovered that folate deficiency could profoundly downregulate two prominent anti-apoptotic effectors including survivin and glucose-regulated protein-78. Silencing of either survivin or glucose regulated protein-78 via small interfering RNA interfering technique established that both effectors could serve as reactive oxygen species sinker proteins. Second, folate deficiency-triggered oxidative-nitrosative stress could strongly induce endoplasmic reticulum stress that in turn could provoke cellular glutathione depletion through the modulation of the following two crucial events: (1) folate deficiency could strongly inhibit Bcl-2 expression leading to severe suppression of the mitochondrial glutathione pool and (2) folate deficiency could also profoundly inhibit two key enzymes that governing cellular glutathione redox regulation including gamma-glutamylcysteinyl synthetase heavy chain, a catalytic enzyme for glutathione biosynthesis, and mitochondrial isocitrate dehydrogenase 2, an enzyme responsible for providing nicotinamide adenine dinucleotide phosphate necessary for regenerating oxidized glutathione disulfide back to glutathione via mitochondrial glutathione reductase. Collectively, we add to the literature new data to strengthen the notion that folate is an essential micronutrient that confers a novel role to combat reactive oxygen species insults and thus serves as a redox regulator via upregulating reactive oxygen species sinker proteins and averting mitochondrial glutathione depletion through proper maintenance of redox homeostasis via positively regulating glutathione biosynthesis, glutathione transporting system, and mitochondrial glutathione recycling process. PMID- 28639915 TI - High expression of TIG3 predicts poor survival in patients with primary glioblastoma. AB - TIG3 (tazarotene-induced gene 3) has been reported to suppress the progression of several malignancies, where this gene is universally downregulated. However, the expression of TIG3 in primary glioblastoma and its relevance to patient's prognosis have not been elaborated. Thus, this study was aimed to evaluate TIG3 expression level in primary glioblastoma and investigate the prognostic value of TIG3 for patients. The Cancer Genome Atlas database was first utilized to analyze the expression and prognostic potential of TIG3 in 528 glioblastoma cases. Compared with control group, glioblastoma showed significantly elevated TIG3 expression (p < 0.001). Log-rank analysis revealed that higher expression of TIG3 was associated with shorter overall survival (358vs 383 days, p = 0.039). Furthermore, TIG3 protein expression detected by immunohistochemistry confirmed positive correlation of TIG3 expression and glioma grade and upregulation of TIG3 in our cohort of 101 primary glioblastoma patients compared to 16 normal brains. Finally, Kaplan-Meier analysis and Cox regression analysis identified high TIG3 expression as an independent risk factor for overall survival of primary glioblastoma patients (overall survival, 10 vs 13 months, p = 0.033; hazard ratio = 1.542, p = 0.046). Together, this study indicated that increased expression of TIG3 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients. We then hypothesize that TIG3 may function in a different pattern in glioblastoma. PMID- 28639916 TI - Benefits of Long Versus Short Thrombolysis Times for Acutely Thrombosed Hemodialysis Native Fistulas. AB - INTRODUCTION: Local thrombolysis with a time of exposure to recombinant tissue plasminogen activator of 15 to 150 minutes is commonly used to declot acutely thrombosed hemodialysis fistulas. The duration of thrombolysis for the restoration of arteriovenous blood flow remains controversial. The aim of this study was to investigate the outcomes of long thrombolysis treatment (LTT, 3 hours or more) and short thrombolysis treatment (STT, less than 3 hours) in our institution. METHODS: We retrospectively analyzed 86 interventional declotting procedures (28 STT and 58 LTT) applied to 86 acutely thrombosed hemodialysis fistulas. The intervention time (IT) following thrombolysis (from the initial fistulography to the end of the angioplasty maneuvers), the time of day of the intervention (ie, during working hours vs off-hours), and the need for temporary catheter placement (TCP) were assessed. Success was defined as complete access recanalization, and major adverse events were defined as ischemia, bleeding, and access rupture. RESULTS: The ITs were reduced after LTT (63.3 [9.3] minutes) compared to STT (106.7 [24.7], P = .01), but there was no difference in success rate (85.7% STT, 89.7% LTT, P = .722). While all (100%, 58/58) of the angioplasty maneuvers after LTT were performed during regular working hours, 75% (21/28) of those following STT were managed during off-hours ( P < .001). Despite the longer treatment, the need for TCP was not increased after LTT (10.7%) compared to STT (12.1%, P = .515), and the major complication rate was reduced (3.4% after LTT and 28.6% after STT, P = .004). CONCLUSION: Long thrombolysis treatment results in shorter and less complicated percutaneous stenosis treatments during regular working hours. Despite the LTT of up to 25 hours until access for dialysis was achieved, no increase in the risks of TCP or major adverse events were observed following LTT. PMID- 28639917 TI - Concomitant Staple Aneurysmorrhaphy and Flow-Calibrated Arteriovenous Fistula Banding Over a Coronary Dilator to Treat Hand Steal Syndrome. AB - BACKGROUND: True venous aneurysm formation can occur in patients with arteriovenous fistulas (AVFs) for hemodialysis but association with steal syndrome is uncommon. METHODS: To describe a case of a patient on chronic hemodialysis through a right brachiocephalic fistula, who presents with associated steal syndrome and true arteriovenous access aneurysm. RESULTS: A 34 year-old female with true AVF aneurysm presented with hand steal syndrome confirmed by noninvasive studies. The patient underwent a successful vein aneurysmorrhaphy with a commercially available stapler device and duplex ultrasound flow-calibrated banding. At 1-year follow-up, she remains pain free and the fistula remains functional with no recurrence of venous aneurysmal degeneration. CONCLUSION: The use of a commercially available surgical stapler devices along with flow-calibrated banding guided by duplex ultrasound over a coronary dilator during the same operation is an elegant, efficacious, and a durable alternative for patients with hand steal syndrome and concomitant AVF aneurysms. PMID- 28639918 TI - Midterm Analysis of Survival and Cause of Death Following Endovascular Abdominal Aortic Aneurysm Repair. AB - PURPOSE: To assess rates of complications, secondary interventions, survival, and cause of death following endovascular abdominal aortic aneurysm (AAA) repair over a 10-year period. MATERIALS AND METHODS: Single-institution retrospective cohort study of all patients undergoing primary endovascular aortic aneurysm repair (EVAR) between July 2006 and June 2015. The population constituted 175 patients with 163 fusiform and 12 saccular AAAs. Of these, 149 (85%) were male, with mean age 75.4 (+/-7.1) years. Patients were followed up until June 30, 2016. Cause of death was determined from the national death register. RESULTS: Mean follow-up was 34.4 (+/-24.4) months. The secondary intervention rate was 9.7%, and there were 4 aneurysm ruptures (0.8% annual incidence). Thirty-day mortality was 0.6%. Survival at 1, 3, and 5 years was 93.1%, 84%, and 64.9%, respectively. Forty eight patients died during follow-up, 3 secondary to rupture, leading to overall and aneurysm-related death rates of 9.7 and 0.6 per 100 person-years. All other deaths were due to nonaneurysm causes, most commonly cardiovascular (n = 15), pulmonary (n = 13), and malignancy (n = 9). Baseline renal impairment ( P < .001), ischemic heart disease ( P < .05), age greater than 75 years ( P < .05), and urgent/emergency EVAR were associated with inferior long-term survival. Type II endoleak negatively influenced fusiform aneurysm sac regression ( P = .02), but there was no association between survival and occurrence of any complication or secondary intervention. CONCLUSION: The majority of deaths during medium-term follow-up post-EVAR are due to nonaneurysm-related causes. Survival is determined by the following baseline factors: renal impairment, ischemic heart disease, advanced age, and the presence of a symptomatic/ruptured aneurysm. PMID- 28639919 TI - Failure of Silicone Catheter Lines: Where, When, and Why. PMID- 28639920 TI - Burnout: Prevalence and Associated Factors Among Radiology Residents in New England With Comparison Against United States Resident Physicians in Other Specialties. AB - OBJECTIVE: The objective of our study was to establish burnout prevalence, associated demographic and program-related factors, and degree of burnout in New England radiology residents relative to residents in other specialties. MATERIALS AND METHODS: A 31-item survey, including nine demographic and program-related questions and the 22-item Maslach Burnout Inventory-Health Services Survey, was sent to all resident members of the New England Roentgen Ray Society (20 programs, 472 residents). Emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA) scores were calculated and stratified using published normative data. Multiple linear regression analysis was performed to identify burnout predictors. Chi-square testing with Bonferroni correction was performed to confirm predictors associated with high burnout. The EE, DP, and PA scores were compared with the results of residents from other specialties. RESULTS: There were 94 responses. High EE, high DP, and low PA scores were reported by 37%, 48%, and 50% of respondents, respectively. EE, DP, and PA scores and rates were low relative to those reported across specialties. Increasing residency year correlated with high EE (p = 0.002) and high DP (p < 0.001). No other factor significantly correlated with burnout. CONCLUSION: A high degree of burnout, increasing over the postgraduate years, was present in more than one third of responding radiology residents but was present in a smaller percentage relative to residents across other specialties. Radiology residents score relatively poorly in PA and therefore addressing PA may be central to improving burnout symptoms overall. PMID- 28639921 TI - Multisystem Imaging Findings of Cystic Fibrosis in Adults: Recognizing Typical and Atypical Patterns of Disease. AB - OBJECTIVE: There is an expanding and increasingly heterogeneous population of adult patients with cystic fibrosis (CF). Although CF is usually diagnosed in children with progressive multisystem involvement, up to 7% of CF cases are currently diagnosed de novo in adults with subtle manifestations distinct from the typical features of classic CF. The purpose of this article is to present the wide spectrum of CF in adults, including both classic and nonclassic variants, with an emphasis on the nonclassic imaging findings. CONCLUSION: Recurrent pancreatitis, chronic sinusitis, and congenital bilateral absence of the vas deferens (CBAVD) are several of the ways in which CF is identified in adult patients with relatively rare mutations and with overall milder manifestations. It is important for radiologists to recognize the wide spectrum of CF to optimally monitor disease progression and response to therapeutic interventions in distinct adult patient populations. PMID- 28639922 TI - Use of Unenhanced MR Lymphography to Characterize Lung Lymphatic Diseases. PMID- 28639923 TI - Reply to "Use of Unenhanced MR Lymphography to Characterize Lung Lymphatic Diseases". PMID- 28639924 TI - Cushing Syndrome: Diagnostic Workup and Imaging Features, With Clinical and Pathologic Correlation. AB - OBJECTIVE: Cushing syndrome (CS) is a constellation of clinical signs and symptoms resulting from chronic exposure to excess cortisol, either exogenous or endogenous. Exogenous CS is most commonly caused by administration of glucocorticoids. Endogenous CS is subdivided into two types: adrenocorticotropic hormone (ACTH) dependent and ACTH independent. CONCLUSION: Cushing disease, which is caused by a pituitary adenoma, is the most common cause of ACTH-dependent CS for which pituitary MRI can be diagnostic, with bilateral inferior petrosal sinus sampling useful in equivocal cases. In ectopic ACTH production, which is usually caused by a tumor in the thorax (e.g., small cell lung carcinoma, bronchial and thymic carcinoids, or medullary thyroid carcinoma) or abdomen (e.g., gastroenteropancreatic neuroendocrine tumors or pheochromocytoma), CT, MRI, and nuclear medicine tests are used for localizing the source of ACTH. In ACTH independent CS, which is caused by various adrenal abnormalities, adrenal protocol CT or MRI is usually diagnostic. PMID- 28639925 TI - Causes of Avascular Hypoechoic Testicular Lesions Detected at Scrotal Ultrasound: Can They Be Considered Benign? AB - OBJECTIVE: The purposes of this study were to determine the cause of avascular hypoechoic lesions detected at scrotal ultrasound and to assess usefulness of sonographic and clinical features in differentiating benign from malignant etiologic factors. MATERIALS AND METHODS: This retrospective study included 58 patients with avascular hypoechoic lesions detected at testicular ultrasound. The sonographic features recorded were lesion size and margins and presence of peripheral vascularity and focal calcifications. Also recorded were patient age, symptoms, risk factors, lesion palpability, and levels of serum tumor markers. The reference standard was pathologic results or at least 2-year stability documented with serial follow-up ultrasound studies. Features associated with malignant, including burnt-out, lesions and benign lesions were examined by Fisher exact test, Wilcox-on rank sum test, and the generalized estimating equations method for multivariable models. RESULTS: Sixty-three lesions were identified in 58 patients; 40 of the 63 (63.5%) were benign. Patients with malignant lesions had elevated serum tumor marker levels more often than patients who had benign lesions (26.1% versus 5.7%, p = 0.043). The clinical palpability of lesions and history of testicular cancer were not statistically significantly different between patients with malignant and those with benign lesions. Poorly defined margins of a lesion and focal calcification within the lesion were more often found in malignant lesions. Maximal size of a lesion and peripheral vascularity were not associated with either the benign or the malignant nature of a lesion. CONCLUSION: Although most avascular hypoechoic testicular lesions are benign, a substantial proportion are malignant. The ultrasound characteristics of a lesion, the patient's clinical presentation, and serum tumor marker status may be useful in differentiating malignant from benign lesions. PMID- 28639926 TI - Medicolegal-Malpractice and Ethical Issues in RadiologyShould CT and MRI Scout Images Be Interpreted? PMID- 28639927 TI - Carotid Artery Plaque Vulnerability Assessment Using Noninvasive Ultrasound Elastography: Validation With MRI. AB - OBJECTIVE: Vulnerable and nonvulnerable carotid artery plaques have different tissue morphology and composition that may affect plaque biomechanics. The objective of this study is to evaluate plaque vulnerability with the use of ultrasound noninvasive vascular elastography (NIVE). MATERIALS AND METHODS: Thirty-one patients (mean [+/- SD] age, 69 +/- 7 years) with stenosis of the internal carotid artery of 50% or greater were enrolled in this cross-sectional study. Elastography parameters quantifying axial strain, shear strain, and translation motion were used to characterize carotid artery plaques as nonvulnerable, neovascularized, and vulnerable. Maximum axial strain, cumulated axial strain, mean shear strain, cumulated shear strain, cumulated axial translation, and cumulated lateral translations were measured. Cumulated measurements were summed over a cardiac cycle. The ratio of cumulated axial strain to cumulated axial translation was also evaluated. The reference method used to characterize plaques was high-resolution MRI. RESULTS: According to MRI, seven plaques were vulnerable, 12 were nonvulnerable without neovascularity, and 12 were nonvulnerable with neovascularity (a precursor of vulnerability). The two parameters cumulated axial translation and the ratio of cumulated axial strain to cumulated axial translation could discriminate between nonvulnerable plaques and vulnerable plaques or determine the presence of neovascularity in nonvulnerable plaques (which was also possible with the mean shear strain parameter). All parameters differed between the non-vulnerable plaque group and the group that combined vulnerable plaques and plaques with neovascularity. The most discriminating parameter for the detection of vulnerable neovascularized plaques was the ratio of cumulated axial strain to cumulated axial translation (expressed as percentage per millimeter) (mean ratio, 39.30%/mm +/- 12.80%/mm for nonvulnerable plaques without neovascularity vs 63.79%/mm +/- 17.59%/mm for vulnerable plaques and nonvulnerable plaques with neovascularity, p = 0.002), giving an AUC value of 0.886. CONCLUSION: The imaging parameters cumulated axial translation and the ratio of cumulated axial strain to cumulated axial translation, as computed using NIVE, were able to discriminate vulnerable carotid artery plaques characterized by MRI from nonvulnerable carotid artery plaques. Consideration of neovascularized plaques improved the performance of NIVE. NIVE may be a valuable alternative to MRI for carotid artery plaque assessment. PMID- 28639928 TI - Peer Review: Is the Process Broken? PMID- 28639929 TI - Successful use of sequential B-cell depletion therapy in lupus. PMID- 28639930 TI - Bradyrhizobium mercantei sp. nov., a nitrogen-fixing symbiont isolated from nodules of Deguelia costata (syn. Lonchocarpus costatus). AB - Some bacteria collectively known as rhizobia can establish symbiotic relationships and the N2-fixation process with several legumes used as green manure, in pastures and for wood production. Symbionts belonging to the genus Bradyrhizobium are predominant in the tropics, and an increasing number of studies report high genetic diversity within the genus. We performed a polyphasic study with two strains belonging to the genus Bradyrhizobium- SEMIA 6399T and SEMIA 6404-isolated from root nodules of Deguelia costata (syn. Lonchocarpus costatus), an important legume native to eastern Brazil. In general, sequences of the 16S rRNA gene were highly conserved in members of the genus Bradyrhizobium, and the two strains were positioned in the Bradyrhizobiumelkanii superclade, sharing 100 % nucleotide identity with Bradyrhizobiumembrapense, Bradyrhizobiumerythrophlei and Bradyrhizobiumviridifuturi. However, multilocus sequence analysis with four housekeeping genes (dnaK, glnII, gyrB and recA) confirmed that the two strains belong to a distinct clade, sharing from 87.7 to 96.1 % nucleotide identity with related species of the genus Bradyrhizobium, being most closely related to B. viridifuturi. Average nucleotide identity of genome sequences between SEMIA 6399T and related species was lower than 92 %, below the threshold of species circumscription. nifH phylogeny clustered the SEMIA strains in a clade separated from other species of the genus Bradyrhizobium, and the nodD phylogeny revealed that SEMIA 6399T presents a more divergent sequence. Other phenotypic and genotypic traits were determined for the new group, and our data support the description of the SEMIA strains as representatives of Bradyrhizobium mercantei sp. nov.; SEMIA 6399T (=CNPSo 1165T=BR 6010T=U675T=LMG 30031T) was chosen as the type strain. PMID- 28639931 TI - ContEst16S: an algorithm that identifies contaminated prokaryotic genomes using 16S RNA gene sequences. AB - Thanks to the recent advancement of DNA sequencing technology, the cost and time of prokaryotic genome sequencing have been dramatically decreased. It has repeatedly been reported that genome sequencing using high-throughput next generation sequencing is prone to contaminations due to its high depth of sequencing coverage. Although a few bioinformatics tools are available to detect potential contaminations, these have inherited limitations as they only use protein-coding genes. Here we introduce a new algorithm, called ContEst16S, to detect potential contaminations using 16S rRNA genes from genome assemblies. We screened 69 745 prokaryotic genomes from the NCBI Assembly Database using ContEst16S and found that 594 were contaminated by bacteria, human and plants. Of the predicted contaminated genomes, 8 % were not predicted by the existing protein-coding gene-based tool, implying that both methods can be complementary in the detection of contaminations. A web-based service of the algorithm is available at www.ezbiocloud.net/tools/contest16s. PMID- 28639932 TI - Staphylococcus epidermidis lipoteichoic acid: exocellular release and ltaS gene expression in clinical and commensal isolates. AB - PURPOSE: Staphylococcus epidermidis ATCC12228 lipoteichoic acid (LTA) inhibits TNFalpha production from keratinocytes that are activated with poly I:C. However, this effect has not been proven in clinical or commensal isolates. METHODOLOGY: The <10 kDa fractions of S. epidermidis isolates from ocular infections (n=56), healthy skin (n=35) and healthy conjunctiva (n=32) were obtained. TNFalpha production was determined by elisa in HaCaT keratinocytes stimulated with poly I:C and with the <10 kDa fractions. LTA in the cytoplasmic membrane and in the <10 kDa fractions of the isolates was determined during bacterial growth by flow cytometry, Western blot and electrospray ionization mass spectrometry. The expression levels of ugtP, ltaA and ltaS were evaluated. RESULTS: Two populations of isolates were found: a population that inhibited TNFalpha production (TNFalpha inhibitor isolates) and a population that did not inhibit it (TNFalpha non inhibitor isolates). The cells from the TNFalpha-inhibitor isolates had less LTA in the cytoplasmic membrane compared to the cells from the TNFalpha non-inhibitor isolates (P<0.05). Similarly, LTA was detected in the supernatants of TNFalpha inhibitor isolates, and it was absent in TNFalpha non-inhibitor isolates. High expression levels of the ugtP and ltaA genes in the 1850I (TNFalpha-inhibitor isolate) and 37HS (TNFalpha non-inhibitor isolate) isolates were found during bacterial growth. However, the ltaS gene had a low expression level (P<0.05) in the 37HS isolate. CONCLUSION: The TNFalpha-inhibitor isolates release LTA due to high expression of the LTA synthesis genes. By contrast, TNFalpha non-inhibitor isolates do not release LTA due to low expression level of the ltaS gene. PMID- 28639933 TI - Saccharomyces jurei sp. nov., isolation and genetic identification of a novel yeast species from Quercus robur. AB - Two strains, D5088T and D5095, representing a novel yeast species belonging to the genus Saccharomyces were isolated from oak tree bark and surrounding soil located at an altitude of 1000 m above sea level in Saint Auban, France. Sequence analyses of the internal transcribed spacer (ITS) region and 26S rRNA D1/D2 domains indicated that the two strains were most closely related to Saccharomyces mikatae and Saccharomyces paradoxus. Genetic hybridization analyses showed that both strains are reproductively isolated from all other Saccharomyces species and, therefore, represent a distinct biological species. The species name Saccharomyces jurei sp. nov. is proposed to accommodate these two strains, with D5088T (=CBS 14759T=NCYC 3947T) designated as the type strain. PMID- 28639934 TI - First description of methyltransferases in extensively drug-resistant Klebsiella pneumoniae isolates from Saudi Arabia. AB - PURPOSE: The resistance determinants for carbapenems, fluoroquinolones and aminoglycosides were characterized in 16 extensively drug-resistant Klebsiella pneumoniae (XDRKPN) strains collected from Saudi hospitals during 2014. METHODOLOGY: PCR and sequencing were used to detect: blaKPC, blaNDM, blaVIM, blaIMP-1,blaOXA-48, blaCTX-M, blaTEM, blaSHV and ampC for beta-lactam resistance; qnrA, qnrB, qnrS, aac(6')-Ib-cr, qepA and mutations of gyrA and parC for fluoroquinolone resistance; and aacA4, aacC2, aadA1, aphA6, armA and rmtB for aminoglycoside resistance. Enterobacterial repetitive intergenic consensus sequence-based PCR was performed to detect the clonal relatedness. RESULTS: All isolates encoded blaCTX-M, aacC2 and aphA6, together with mutations in gyrA and parC. blaOXA-48, blaNDM-1, aadA1, aacA4, qnrB, aac(6')-Ib-cr, armA and/or rmtB were detected in different strains. At least 93.2 % clonal relatedness was detected among these strains. CONCLUSIONS: To our knowledge, this is the first report describing XDRKPN encoding at least seven resistance determinants and harbouring methyltransferases in Saudi Arabia. PMID- 28639935 TI - Neuroimaging tests for clinical psychiatry: Are we there yet? PMID- 28639936 TI - Recognition and management of antidepressant discontinuation syndrome. PMID- 28639937 TI - A multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin compared with standard therapy for the treatment of transverse myelitis in adults and children (STRIVE). AB - BACKGROUND: Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord that affects adults and children and that causes motor, sensory and autonomic dysfunction. There is a prolonged recovery phase, which may continue for many years. Neuromyelitis optica (NMO) is an uncommon relapsing inflammatory central nervous system condition in which TM can be the first presenting symptom. As TM and NMO affect many patients in the prime of their working life, the disorder can impose a significant demand on health resources. There are currently no robust controlled trials in children or adults to inform the optimal treatment of TM. However, treatment with intravenous immunoglobulin (IVIG) is being effectively used in the management of a range of neurological conditions. Although other interventions such as plasma exchange (PLEX) in addition to intravenous (IV) methylprednisolone therapy can be beneficial in TM, PLEX is costly and technically challenging to deliver in the acute setting. IVIG is more readily accessible and less costly. OBJECTIVE: To evaluate whether additional and early treatment with IVIG is of extra benefit in TM compared with standard therapy with IV steroids. DESIGN: A multicentre, single-blind, parallel-group randomised controlled trial of IVIG compared with standard therapy for the treatment of TM in adults and children. PARTICIPANTS: Patients aged >= 1 year diagnosed with either acute first-onset TM or first presentation of NMO. Target recruitment was 170 participants (85 participants per arm). INTERVENTIONS: Participants were randomised 1 : 1 to treatment with IV methylprednisolone only or treatment with IV methylprednisolone plus 2 g/kg of IVIG in divided doses within 5 days of the first commencement of steroid therapy. MAIN OUTCOME MEASURES: Primary outcome measure - American Spinal Injury Association (ASIA) Impairment Scale at 6 months post randomisation, with a good outcome defined by a two-grade change. Secondary and tertiary outcome measures - ASIA motor and sensory scales, Expanded Disability Status Scale, health outcome, quality of life, Client Service Receipt Inventory and International Spinal Cord Injury Pain, Bladder and Bowel Basic Data Sets. RESULTS: In total, 26 participants were screened and two were randomised into the study. With the limited sample size, treatment effect could not be determined. However, we identified barriers to accrual that included strict inclusion criteria, the short enrolment window, challenges associated with the use of the ASIA Impairment Scale as an outcome measure and estimation of the incidence of TM. CONCLUSIONS: The study did not reach the end point and the effect of IVIG in TM/NMO could not be determined. Investigators should be aware of the potential challenges associated with carrying out a rare disease trial with a short enrolment window. The study question is one that still necessitates investigation. Preliminary work to ameliorate the effect of the barriers encountered in this study is vital. TRIAL REGISTRATION: EudraCT 2014-002335-34, ClinicalTrials.gov NCT02398994 and Current Controlled Trials ISRCTN12127581. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 31. See the NIHR Journals Library website for further project information. Funding was also received from Biotest AG, Germany (supply of IVIG) and the Transverse Myelitis Society (excess research cost to facilitate study initiation). PMID- 28639939 TI - Model for a novel membrane envelope in a filamentous hyperthermophilic virus. AB - Biological membranes create compartments, and are usually formed by lipid bilayers. However, in hyperthermophilic archaea that live optimally at temperatures above 80 degrees C the membranes are monolayers which resemble fused bilayers. Many double-stranded DNA viruses which parasitize such hosts, including the filamentous virus AFV1 of Acidianus hospitalis, are enveloped with a lipid containing membrane. Using cryo-EM, we show that the membrane in AFV1 is a ~2 nm thick monolayer, approximately half the expected membrane thickness, formed by host membrane-derived lipids which adopt a U-shaped 'horseshoe' conformation. We hypothesize that this unusual viral envelope structure results from the extreme curvature of the viral capsid, as 'horseshoe' lipid conformations favor such curvature and host membrane lipids that permit horseshoe conformations are selectively recruited into the viral envelope. The unusual envelope found in AFV1 also has many implications for biotechnology, since this membrane can survive the most aggressive conditions involving extremes of temperature and pH. PMID- 28639938 TI - Pilot study of large-scale production of mutant pigs by ENU mutagenesis. AB - N-ethyl-N-nitrosourea (ENU) mutagenesis is a powerful tool to generate mutants on a large scale efficiently, and to discover genes with novel functions at the whole-genome level in Caenorhabditis elegans, flies, zebrafish and mice, but it has never been tried in large model animals. We describe a successful systematic three-generation ENU mutagenesis screening in pigs with the establishment of the Chinese Swine Mutagenesis Consortium. A total of 6,770 G1 and 6,800 G3 pigs were screened, 36 dominant and 91 recessive novel pig families with various phenotypes were established. The causative mutations in 10 mutant families were further mapped. As examples, the mutation of SOX10 (R109W) in pig causes inner ear malfunctions and mimics human Mondini dysplasia, and upregulated expression of FBXO32 is associated with congenital splay legs. This study demonstrates the feasibility of artificial random mutagenesis in pigs and opens an avenue for generating a reservoir of mutants for agricultural production and biomedical research. PMID- 28639941 TI - Promoting international collaboration and creativity in doctoral students. AB - Staff from the Mayo Clinic in the US and the Karolinska Institute in Sweden describe a joint transatlantic course intended to broaden the horizons of the next generation of researchers in the field of regenerative medicine. PMID- 28639942 TI - Commissioning of the tongue-and-groove modelling in treatment planning systems: from static fields to VMAT treatments. AB - Adequate modelling of the multi-leaf collimator (MLC) by treatment planning systems (TPS) is essential for accurate dose calculations in intensity-modulated radiation-therapy. For this reason modern TPSs incorporate MLC characteristics such as the leaf end curvature, MLC transmission and the tongue-and-groove. However, the modelling of the tongue-and-groove is often neglected during TPS commissioning and it is not known how accurate it is. This study evaluates the dosimetric consequences of the tongue-and-groove effect for two different MLC models using both film dosimetry and ionisation chambers. A set of comprehensive tests are presented that evaluate the ability of TPSs to accurately model this effect in (a) static fields, (b) sliding window beams and (c) VMAT arcs. The tests proposed are useful for the commissioning of TPSs and for the validation of major upgrades. With the ECLIPSE TPS, relevant differences were found between calculations and measurements for beams with dynamic MLCs in the presence of the TG effect, especially for the High Definition MLC, small gap sizes and the 1 mm calculation grid. For this combination, dose differences as high as 10% and 7% were obtained for dynamic MLC gaps of 5 mm and 10 mm, respectively. These differences indicate inadequate modelling of the tongue-and-groove effect, which might not be identified without the proposed tests. In particular, the TPS tended to underestimate the calculated dose, which may require tuning of other configuration parameters in the TPS (such as the dosimetric leaf gap) in order to maximise the agreement between calculations and measurements in clinical plans. In conclusion, a need for better modelling of the MLC by TPSs is demonstrated, one of the relevant aspects being the tongue-and-groove effect. This would improve the accuracy of TPS calculations, especially for plans using small MLC gaps, such as plans with small target volumes or high complexities. Improved modelling of the MLC would also reduce the need for tuning parameters in the TPS, facilitating a more comprehensive configuration and commissioning of TPSs. PMID- 28639940 TI - Genetic specification of left-right asymmetry in the diaphragm muscles and their motor innervation. AB - The diaphragm muscle is essential for breathing in mammals. Its asymmetric elevation during contraction correlates with morphological features suggestive of inherent left-right (L/R) asymmetry. Whether this asymmetry is due to L versus R differences in the muscle or in the phrenic nerve activity is unknown. Here, we have combined the analysis of genetically modified mouse models with transcriptomic analysis to show that both the diaphragm muscle and phrenic nerves have asymmetries, which can be established independently of each other during early embryogenesis in pathway instructed by Nodal, a morphogen that also conveys asymmetry in other organs. We further found that phrenic motoneurons receive an early L/R genetic imprint, with L versus R differences both in Slit/Robo signaling and MMP2 activity and in the contribution of both pathways to establish phrenic nerve asymmetry. Our study therefore demonstrates L-R imprinting of spinal motoneurons and describes how L/R modulation of axon guidance signaling helps to match neural circuit formation to organ asymmetry. PMID- 28639943 TI - A bioprintable form of chitosan hydrogel for bone tissue engineering. AB - Bioprinting can be defined as 3D patterning of living cells and other biologics by filling and assembling them using a computer-aided layer-by-layer deposition approach to fabricate living tissue and organ analogs for tissue engineering. The presence of cells within the ink to use a 'bio-ink' presents the potential to print 3D structures that can be implanted or printed into damaged/diseased bone tissue to promote highly controlled cell-based regeneration and remineralization of bone. In this study, it was shown for the first time that chitosan solution and its composite with nanostructured bone-like hydroxyapatite (HA) can be mixed with cells and printed successfully. MC3T3-E1 pre-osteoblast cell laden chitosan and chitosan-HA hydrogels, which were printed with the use of an extruder-based bioprinter, were characterized by comparing these hydrogels to alginate and alginate-HA hydrogels. Rheological analysis showed that all groups had viscoelastic properties. It was also shown that under simulated physiological conditions, chitosan and chitosan-HA hydrogels were stable. Also, the viscosity values of the bio-solutions were in an applicable range to be used in 3D bio printers. Cell viability and proliferation analyses documented that after printing with bio-solutions, cells continued to be viable in all groups. It was observed that cells printed within chitosan-HA composite hydrogel had peak expression levels for early and late stages osteogenic markers. It was concluded that cells within chitosan and chitosan-HA hydrogels had mineralized and differentiated osteogenically after 21 days of culture. It was also discovered that chitosan is superior to alginate, which is the most widely used solution preferred in bioprinting systems, in terms of cell proliferation and differentiation. Thus, applicability and printability of chitosan as a bio printing solution were clearly demonstrated. Furthermore, it was proven that the presence of bone-like nanostructured HA in alginate and chitosan hydrogels improved cell viability, proliferation and osteogenic differentiation. PMID- 28639945 TI - Pulmonary arterial hemodynamic assessment by a novel index in systemic lupus erythematosus patients: pulmonary pulse transit time. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic, inflammatory, and autoimmune connective tissue disease. One of the leading causes of mortality among SLE patients is pulmonary hypertension. The aim of this study was to evaluate the association between echocardiographic findings, including the pulmonary pulse transit time and pulmonary hypertension parameters, in SLE patients. METHODS: Thirty SLE patients (aged 39.9+/-11 years, 28 females) as the study group and 34 age- and sex-matched healthy volunteers (aged 37.9+/-11.5 years, 31 females) as the control group were included in the study. After detailed medical histories were recorded, 12-lead electrocardiography, blood tests, and echocardiography were performed in the groups. In addition to basic echocardiographic measurements, other specialized right ventricular indicators [i.e, Tricuspid Annular Plane Systolic Excursion (TAPSE), estimated pulmonary artery systolic pressure (ePASP), right ventricular dimensions, and myocardial performance index (MPI)] were measured. The pulmonary pulse transit time was defined as the time interval between the R-wave peak in ECG and the corresponding peak late-systolic pulmonary vein flow velocity. RESULTS: The mean disease duration was 121.1+/-49.9 months. The mean age at diagnosis was 35.0+/-15.4 years. The mean RV MPI was higher (p=0.026), mean TAPSE measurements were shorter (p=0.021), and mean ePASP was higher (p=0.036) in the SLE group than in the control group. In addition, pPTT was significantly shorter in the SLE group (p=0.003). pPTT was inversely correlated with disease duration (p<0.001), MPI (p=0.037), and ePASP (p=0.02) and positively correlated with TAPSE (p<0.001). CONCLUSION: SLE patients have higher pPTT values than controls. Further, pPTT shows an inverse correlation with disease duration, MPI, and ePASP and a positive correlation with TAPSE. PMID- 28639944 TI - Clinical impact and efficacy of bedside echocardiography on patient management in pediatric intensive care units (PICUs): A prospective study. AB - OBJECTIVE: To determine the indication and necessity of echocardiographic assessment and therapeutic interventions in critically ill children. METHODS: A total of 140 children, including 75 mechanically ventilated (MV) and 65 spontaneously breathing (SB) children, who were admitted consecutively from March to August 2013 were evaluated prospectively. Data regarding the indication for echocardiography and therapeutic approaches used were documented. For evaluating disease severity, the Pediatric Risk of Mortality Score III (PRISM) was ascertained. The correlation between PRISM score and the requirement of echocardiographic evaluations were analyzed. RESULTS: Patients ages were between 45 days to 18 years. The male-to-female ratio was 1.33. In 35.4% patients who underwent echocardiographic evaluation, no definitive alteration occurred in treatment approach, whereas in the remaining 64.6% patients, decisive or supplemental information was gathered. Echocardiography was indicated in 88% MV children and 46.2% SB children. Echocardiographic evaluation was necessary in MV children and there was a positive correlation between the PRISM score and the requirement of echocardiographic assessment (p<0.001). CONCLUSION: Echocardiographic evaluation is an invaluable tool especially in MV children and the requirement of echocardiographic assessment increases according to clinical severity. Basic training for intensivists in this procedure is crucial and needs to be improved and supported in critically ill. PMID- 28639947 TI - Surface electrocardiogram: Could atrioventricular nodal and His bundle potentials be recorded beat by beat on "Saah electrocardiogram"? AB - OBJECTIVE: The P-QRS-T wave on surface electrocardiogram (ECG) reflects the changes in atrial and ventricular electrical properties. However, the atrioventricular conduction system potentials cannot be recorded to date. This study aimed to explore the possibility of micropotential of the atrioventricular conduction system recorded by surface "SAN-Atrial-AVN-His (Saah) ECG." METHODS: We randomized 100 healthy volunteers (50 females and 50 males; mean age 25.12+/ 1.62 years) to receive "conventional 12-lead ECG" and "Saah ECG," which were recorded by the "Saah ECG" machine. We recorded and further analyzed "conventional 12-lead ECG" and "Saah ECG." According to the microwavelets before the QRS complex, the PR interval was the sum of three intervals: PAs interval (PA interval recorded on surface ECG), AHs interval (AH interval recorded on surface ECG), and HVs interval (HV interval recorded on surface ECG). The PR interval, PAs interval, AHs interval, and HVs interval were measured. RESULTS: Not only the P-QRS-T waves but also the microwavelets before the P wave, before the QRS complex, and after the QRS complex were recorded in 100 healthy volunteers. The PAs interval, AHs interval, and HVs interval were 22-37 (31.23+/-2.93) ms, 60-103 (76.07+/-13.43) ms, and 39-55 (49.29+/-4.44) ms, respectively. The PAs interval, AHs interval, and HVs interval were consistent with the intracardiac measurements (PA, AH, and HV intervals) obtained in previous studies. Compared with female volunteers, male volunteers had a longer AHs interval (p<0.05). CONCLUSION: Not only the P-QRS-T waves but also the microwavelets before the P wave, before the QRS complex, and after the QRS complex were recorded on surface ECG. The wavelets before the QRS complex may be related to atrioventricular nodal, His bundle (bundle branch) potentials. PMID- 28639946 TI - Assessment of left ventricular systolic function in patients with iron deficiency anemia by three-dimensional speckle-tracking echocardiography. AB - OBJECTIVE: The present study aimed to evaluate left ventricular (LV) systolic function in patients with iron deficiency anemia (IDA) by 3 dimensional speckle tracking echocardiography (3DSTE). METHODS: Participants were grouped by hemoglobin (Hb) levels in order to study the effect of anemia on cardiac function. Group A included 40 healthy volunteers. Eighty-three patients who were diagnosed with IDA were divided into 2 groups according to the Hb level. Group B (Hb 9 g/dL) included 44 patients, while group C (Hb 6-9 g/dL) included 39 patients. Left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), left ventricular mass index (LVMI), and left ventricular ejection fraction (LVEF) were calculated by real-time 3-dimensional echocardiography (RT3D). Left ventricular global longitudinal strain (GLS), global area strain (GAS), global radial strain (GRS), and global circumferential strain (GCS) were obtained by 3DSTE. RESULTS: LVMI, LVEDV and LVESV of group C increased and GCS, GRS, GLS, and GAS of group C decreased compared with those of groups A and B (all p<0.05). GAS and GLS decreased significantly compared with other parameters (both p<0.01). CONCLUSION: LV remodeling and LV systolic dysfunction occurred in patients when the hemoglobin level was in the range of 6 9 g/dL. 3DSTE can evaluate LV systolic function in patients with IDA, and GAS and GLS are more sensitive than other parameters. PMID- 28639948 TI - Protective effects of IL28RA siRNA on cardiomyocytes in hypoxia/reoxygenation injury. AB - OBJECTIVE: We demonstrate the protective effects of the siRNA-mediated inhibition of the interleukin-28 receptor alpha (IL28RA) subunit on cardiomyocytes in hypoxia/reoxygenation (H/R) injury and explore the associated mechanism. METHODS: After designing and synthesizing three pairs of siRNA that effectively reduced IL28RA gene expression in vitro (siRNA-6158, siRNA-6160, and siRNA-6162), primary neonatal rat cardiomyocytes were transfected using a liposome transfection method. Six groups were included based on the siRNA that was used and the treatment simulating reperfusion injury: control group, H/R group, H/R+negative control group, H/R+siRNA-6158 group, H/R+siRNA-6160 group, and H/R+siRNA-6162 group. Cell survival and apoptosis rates were measured along with lactate dehydrogenase levels in the cell culture supernatant. Protein levels of IL28RA, phosphatidylinositol 3-kinase, catalytic subunit gamma (PI3KCG), Bcl-2, Bax, and beta-actin were also measured. RESULTS: The H/R+siRNA-6158 and H/R+siRNA-6160 groups had significantly higher survival rates and increased PI3KCG-to-beta-actin and Bcl-2-to-Bax ratios than the the H/R and H/R+negative control groups (p<0.05). The H/R+siRNA-6158 and H/R+siRNA-6160 groups also exhibited reduced rates of apoptosis and reduced IL28RA-to-beta-actin ratios (p<0.05). No significant difference was observed among the H/R+siRNA-6162, H/R, and H/R+negative control groups. CONCLUSION: IL28RA siRNA-6158 and -6160 were able to protect cardiomyocytes from H/R injury by inhibiting apoptosis. This strategy of inhibiting IL28RA gene expression may reduce reperfusion injury in the treatment of patients with acute myocardial infarction. PMID- 28639949 TI - Comet assay in evaluating deoxyribonucleic acid damage after out-of-hospital cardiac arrest. AB - OBJECTIVE: This study aimed to investigate whether out-of-hospital cardiac arrest (OHCA) may induce severe DNA damage measured using comet assay in successfully resuscitated humans and to evaluate a short-term prognostic role. METHODS: In this prospective, controlled, blinded study (1/2013-1/2014), 41 patients (age, 63+/-14 years) successfully resuscitated from non traumatic OHCA and 10 healthy controls (age, 53+/-17 years) were enrolled. DNA damage [double-strand breaks (DSBs) and single-strand breaks (SSBs)] was measured using comet assay in peripheral lymphocytes sampled at admission. Clinical data were recorded (according to Utstein style). A good short-term prognosis was defined as survival for 30 days. RESULTS: Among the patients, there were 71% (29/41) short-term survivors. After OHCA, DNA damage (DSBs and SSBs) was higher (11.0+/-7.6% and 0.79+/-2.41% in tail) among patients than among controls (1.96+/-1.63% and 0.02+/ 0.03% in tail), and it was more apparent for DSBs (p<0.001 and p=0.085). There was no difference in the DNA damage between patients with cardiac and non-cardiac etiology, or between survivors and nonsurvivors. Among Utstein style parameters, ventricular fibrillation, asystole, and early electrical defibrillation influenced DSBs; none of the factors influenced SSBs. Factors influencing survival were SSBs, ventricular fibrillation, length of cardiopulmonary resuscitation by professionals <=15 min, cardiogenic shock, and postanoxic encephalopathy. In contrast to DSBs [area under the curve (AUC)=0.520], SSBs seem to have a potential in prognostication (AUC=0.639). CONCLUSION: This study for the first time demonstrates revelation of DNA damage using comet assay in patients successfully resuscitated from OHCA. Whether DNA damage measured using comet assay may be a prognostic marker remains unknown, although our data may encourage some suggestions. PMID- 28639950 TI - Reactive oxygen species generation and increase in mitochondrial copy number: new insight into the potential mechanism of cytotoxicity induced by aurora kinase inhibitor, AZD1152-HQPA. AB - Aurora-B kinase overexpression plays important roles in the malignant progression of prostate cancer (PCa). AZD1152-HQPA, as an inhibitor of Aurora-B, has recently emerged as a promising agent for cancer treatment. In this study, we aimed to investigate the effects of AZD1152-HQPA on reactive oxygen species (ROS) generation and mitochondrial function in PCa. We used AZD1152-HQPA (Barasertib), a highly potent and selective inhibitor of Aurora-B kinase. The effects of AZD1152-HQPA on cell viability, DNA content, cell morphology, and ROS production were studied in the androgen-independent PC-3 PCa cell line. Moreover, the mitochondrial copy number and the expression of genes involved in cell survival and cancer stem cell maintenance were investigated. We found that AZD1152-HQPA treatment induced defective cell survival, polyploidy, micronuclei formation, cell enlargement, and cell death by significant overexpression of p73, p21 and downregulation of cell cycle-regulatory genes in a drug concentration-dependent manner. Moreover, AZD1152 treatment led to an excessive ROS generation and an increase in the mitochondrial copy number not only in PC-3 but also in several other malignant cells. AZD1152 treatment also led to downregulation of genes involved in the maintenance of cancer stem cells. Our results showed a functional relationship between the aurora kinase inhibition, an increase in mitochondrial copy number, and ROS generation in therapeutic modalities of cancer. This study suggests that the excessive ROS generation may be a novel mechanism of cytotoxicity induced by the aurora kinase inhibitor, AZD1152-HQPA. PMID- 28639952 TI - Toward a comprehensive cancer registration in Germany. AB - This article presents the current status of the implementation of clinical cancer registration across all German federal states that started in 2013 and that is basis for setting up comprehensive clinical and population-based cancer registries (CRs). A nationwide definition of relevant cancers, a common model of passive registration, a standard basic set of data items as well as a sustainable funding are prerequisites for a standardized collection of cancer data in Germany. For the collected information, the tools and methods used for data collection and processing, for statistical analyses and reporting, the potential synergies of a comprehensive CR implementing the tasks of both a clinical CR and a population-based CR become evident. Many different tasks of clinical and population-based CRs have already been implemented in Germany. This includes usage of individual patient data for quality assurance and the certification of cancer centers or comparative analyses on the adherence to guideline recommendations. CRs further provided unselected data on the cancer burden in the underlying populations and actively contribute in a variety of ways to many collaborative research projects on cancer etiology, the effectiveness of screening programs or cancer care, or provide patient or outcome data for clinical or population-based studies. Although many tasks of clinical and population-based CRs have already been implemented, a number of great efforts still lay ahead. Major challenges include the harmonization of data collection, the development of required standards and methods for data processing and usage, but first and foremost, the collection of complete and valid data for the different tasks of comprehensive CRs. PMID- 28639953 TI - Impressive Paget Disease of the Lumbar Spine Masks the Coexisting Multiple Myeloma. AB - Multimodality imaging, including MRI, bone scintigraphy, and FDG PET/CT, was performed to evaluate a 49-year-old man who had right hip and lower limb pain for 4 months because possible malignancy was suspected. All 3 modalities showed obvious Paget disease of the lumbar spine. However, less impressive increased activity was also noted on FDG PET/CT images. Subsequent laboratory tests and pathology examination leads to diagnosis of multiple myeloma. Our case further confirms the notion that it is insufficient to focus on the most obvious and unintentionally overlook the less impressive findings in interpreting nuclear medicine images. PMID- 28639951 TI - Metabolic abnormalities and oxidative stress in lupus. AB - PURPOSE OF REVIEW: Upon antigen exposure, immune cells rely on cell-specific metabolic pathways to mount an efficient immune response. In autoimmunity, failure in critical metabolic checkpoints may lead to immune cell hyperactivation and tissue damage. Oxidative stress in autoimmune patients can also contribute to immune dysregulation and injury to the host. Recent insights into the immune cell metabolism signatures, specifically associated with systemic lupus erythematosus (SLE) and the consequences of heightened oxidative stress in patients, are discussed herein. RECENT FINDINGS: Glucose metabolism inhibitors, mechanistic target of rapamycin pathway modulators, and peroxisome proliferator-activated receptor gamma-activating compounds demonstrate therapeutic benefit in experimental models of lupus. Mitochondrial-derived reactive oxygen species (ROS) and molecular modifications induced by oxidative stress appear to be detrimental in lupus. Effective therapies tailored toward the reconfiguration of metabolic imbalances in lupus immune cells and the reduction of mitochondrial ROS production/availability are currently being tested. SUMMARY: A paucity of knowledge exists regarding the metabolic needs of a number of immune cells involved in the pathogenesis of SLE, including myeloid cells and B cells. Nonetheless, SLE-specific metabolic signatures have been identified and their specific targeting, along with mitochondrial ROS inhibitors/scavengers, could show therapeutic advantage in lupus patients. PMID- 28639954 TI - Rare Endobronchial Inflammatory Myofibroblastic Tumor in Pediatric Patient Detected on PET/CT Imaging. AB - Inflammatory myofibroblastic tumor (IMT) can be seen in all age groups, although it is more common in children and adolescents. We report the FDG PET/CT findings in an 8-year-old boy with endobronchial IMT. Endobronchial IMT is more commonly seen in young adults. PMID- 28639955 TI - Endotracheal Leiomyoma Mimicking Malignancy on 18F-FDG PET/CT in a Patient With Papillary Thyroid Carcinoma. AB - Endotracheal leiomyoma is a rare benign lesion, accounting for approximately 1% of tracheal tumors, and generally occurs in the lower respiratory tract. Because its growth causes airway obstruction symptom, surgical treatment is generally suggested after detection. We report a case with leiomyoma of the cervical endotracheal space showing intense FDG uptake on F-FDG PET/CT mimicking malignancy in a 79-year-old woman with papillary thyroid carcinoma. PMID- 28639956 TI - Small fiber neuropathy: a disabling and underrecognized syndrome. AB - PURPOSE OF REVIEW: To discuss cause, clinical manifestations, diagnostics, and treatment of small fiber neuropathy (SFN). The diagnosis is difficult and can be easily missed. RECENT FINDINGS: SFN causes high morbidity with disabling symptoms and impact on quality of life. Patients may benefit from being diagnosed with SFN, even if no underlying cause is identified and no specific treatment is yet available. Recently, genetic mutations as a possible cause of SFN were identified. Clinical diagnostic criteria have been proposed, but no gold standard exists, and each test has its limitations. The diagnosis requires a combination of typical symptoms, abnormal neurologic findings, and absence of large fiber involvement. Clinicians should be aware of overlapping symptoms of SFN and fibromyalgia. Treatment is often difficult, even when the underlying cause is identified and appropriately treated. Usually, only symptomatic relief of complaints is available. SUMMARY: Awareness of SFN and related symptoms is of great clinical relevance. Guidelines for appropriate diagnostic workup using a stepwise approach involving a combination of tests are warranted. Even if no treatment is available, patients may benefit from timely recognition of SFN. PMID- 28639957 TI - Pulmonary arterial hypertension induced by tyrosine kinase inhibitors. AB - PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of several neoplastic conditions; however, pulmonary arterial hypertension (PAH) has been reported as a complication of TKIs, predominantly with dasatinib. Recent studies have elucidated the potential mechanisms of TKI induced PAH and have better clarified the long-term outcomes. RECENT FINDINGS: In addition to the known association between dasatinib and PAH, several other TKIs have recently been reported to cause PAH, including ponatinib, bosutinib and lapatinib. Dasatinib causes direct pulmonary artery endothelial cell toxicity through the production of mitochondrial reactive oxygen species, but likely requires the presence of a second risk factor to cause PAH. Symptoms and haemodynamic abnormalities frequently resolve after discontinuation of the TKI, but PAH persists in over a third of patients and can reoccur when other TKIs are used, which warrants close follow-up. Rare fatal cases have occurred; therefore, treatment with PAH-specific therapy is recommended for patients with right heart failure or persistent PAH after discontinuation of the TKI. SUMMARY: PAH is a rare but important complication of several TKIs. Management includes discontinuation of the TKI, close follow-up and PAH-specific therapy in severe cases. PMID- 28639958 TI - Pediatric jellyfish envenomation in the Mediterranean Sea. AB - BACKGROUND: Several species of jellyfish native to the western Indian Ocean have entered the Mediterranean Sea through the Suez Canal. Since the late 1980s, each summer Rhopilema nomadica forms swarms as long as 100 km in the southeastern Levant and since the millennium aggregations of additional nonnative jellyfish have been sighted. The aim of this study was to evaluate children seen in the emergency department after jellyfish envenomations and to establish patterns of toxicity associated with this organism. METHODS: A retrospective chart review was performed of all children presenting after jellyfish envenomations to the pediatric emergency department during the jellyfish swarming seasons (June August) between 2010 and 2015. Extracted data included age, location of envenomation, pain scores, local and systemic manifestations, treatment provided in the emergency department and hospital, and disposition. RESULTS: Forty-one patients fulfilled the inclusion criteria; their ages ranged from 1 to 16 years and the median age was 9.4 years. Clinical manifestations were evident in all patients. Pain, present in 100% of patients, and an erythematous, whip-like, linear rash present in 87.8%, were the most common manifestations. The majority of 'burns' associated with jellyfish stings were first and second degree. The upper limb was affected in 34% and the lower limb was affected in 61% of cases. One patient suffered a sting to the abdomen and three patients suffered a sting to the face. Treatment in the emergency department included pain control, with nonsteroidal anti-inflammatory drugs and opiates, and antihistamines and topical corticosteroids in some cases. Nearly 49% of patients were seen during the summer of 2015 alone and seven patients in this group needed hospitalization. Reasons for hospitalization included systemic symptoms such as fever, chills, tachycardia, and muscle spasms. Two patients developed severe cellulitis, one patient had an anaphylactic reaction, and one was admitted to the ICU after suffering an anaphylactic reaction to a sting sustained while surfing. CONCLUSION: The prevalence of the jellyfish swarms and the severity of clinical manifestations because of their envenomations suggest that it should be considered as a health hazard in the Mediterranean Sea. We call for public health authorities in affected countries to initiate a health hazards database, familiarize medical and healthcare staff with the clinical syndromes, train medical and healthcare staff' in appropriate treatment, and initiate and continue public awareness campaigns. PMID- 28639959 TI - 3D Printing: current use in facial plastic and reconstructive surgery. AB - PURPOSE OF REVIEW: To review the use of three-dimensional (3D) printing in facial plastic and reconstructive surgery, with a focus on current uses in surgical training, surgical planning, clinical outcomes, and biomedical research. To evaluate the limitations and future implications of 3D printing in facial plastic and reconstructive surgery. RECENT FINDINGS: Studies reviewed demonstrated 3D printing applications in surgical planning including accurate anatomic biomodels, surgical cutting guides in reconstruction, and patient-specific implants fabrication. 3D printing technology also offers access to well tolerated, reproducible, and high-fidelity/patient-specific models for surgical training. Emerging research in 3D biomaterial printing have led to the development of biocompatible scaffolds with potential for tissue regeneration in reconstruction cases involving significant tissue absence or loss. Major limitations of utilizing 3D printing technology include time and cost, which may be offset by decreased operating times and collaboration between departments to diffuse in house printing costs SUMMARY: The current state of the literature shows promising results, but has not yet been validated by large studies or randomized controlled trials. Ultimately, further research and advancements in 3D printing technology should be supported as there is potential to improve resident training, patient care, and surgical outcomes. PMID- 28639960 TI - What is global surgery? PMID- 28639963 TI - Takotsubo-Like Cardiomyopathy After Loperamide Overdose. PMID- 28639964 TI - Drug-Induced Necrotizing Pancreatitis With a Focus on Canagliflozin. PMID- 28639965 TI - Is selenium supplementation in autoimmune thyroid diseases justified? AB - PURPOSE OF REVIEW: This review provides an appraisal of recent evidence for or against selenium supplementation in patients with autoimmune thyroid diseases, and discusses possible effect mechanisms. RECENT FINDINGS: Epidemiological data suggest an increased prevalence of autoimmune thyroid diseases under conditions of low dietary selenium intake. Two systematic reviews have evaluated controlled trials among patients with autoimmune thyroiditis and report that selenium supplementation decreases circulating thyroid autoantibodies. The immunomodulatory effects of selenium might involve reducing proinflammatory cytokine release. However, clinically relevant effects of selenium supplementation, including improvement in quality of life, are more elusive. In Graves' disease, some, but not all, trials indicate that adjuvant selenium supplementation enhances the restoration of biochemical euthyroidism, and might benefit patients with mild Graves' orbitopathy. SUMMARY: The use of selenium supplementation as adjuvant therapy to standard thyroid medication may be widespread, but a growing body of evidence yields equivocal results. The available evidence from trials does not support routine selenium supplementation in the standard treatment of patients with autoimmune thyroiditis or Graves' disease. However, correction of moderate to severe selenium deficiency may offer benefits in preventing, as well as treating, these disorders. Molecular mechanisms have been proposed, but further studies are needed. PMID- 28639966 TI - Risk of embryopathies with use of antithyroidal medications. AB - PURPOSE OF REVIEW: Hyperthyroidism in pregnant women should be adequately treated to prevent maternal and fetal complications. The treatment of choice in pregnancy is antithyroidal medications (ATDs). The risk of embryopathies associated with the use of Methimazole (MMI) and Propylthiouracil (PTU) in early pregnancy is a matter of clinical attention and concern. This review describes current evidence and how scientific findings are reflected in current clinical guidelines. RECENT FINDINGS: Embryopathies after the use of ATDs were previously mainly described in case reports and considered rare. Recent large observational studies, including nonexposed control groups, have quantified an increased risk of embryopathies associated with use of ATDs during pregnancy. Findings suggest a risk of embryopathies with the use of both MMI and PTU, but the pattern of embryopathies differs, and embryopathies with the use of PTU appear less severe. SUMMARY: Current guidelines highlight the need for clinical attention on the use of ATDs in early pregnancy. Patients managed on ATDs for the treatment of hyperthyroidism should be counseled to report a pregnancy as early as possible. PTU is the recommended treatment in early pregnancy, but if the risk of relapse or worsening of hyperthyroidism is considered low, it is suggested that ATD treatment can be withdrawn followed by frequent monitoring of thyroid function. PMID- 28639967 TI - RAS-positive thyroid nodules. AB - PURPOSE OF REVIEW: The current review focuses on the uncertainty regarding the management of rat sarcoma viral oncogene homolog RAS-positive thyroid nodules. The application of oncogene testing has been heralded for improving risk assessment for indeterminate cytology thyroid nodules and has grown in clinical use. RAS mutations are historically considered oncogenic. However, RAS mutation detection in thyroid nodules has proven problematic, as these mutations are found in benign and malignant lesions. RECENT FINDINGS: RAS-positive thyroid nodules frequently have indeterminate cytology and a finding of a positive RAS mutation identifies a significant number of benign lesions as well as thyroid cancers. Long-term follow-up of RAS-positive nodules with benign cytology shows an indolent course not consistent with eventual malignant transformation. Many RAS positive nodules previously diagnosed as follicular variant of papillary thyroid carcinoma now will be reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features, indicating a more indolent nature of these RAS-positive lesions. SUMMARY: Recent findings have underscored that diagnosis of a RAS-positive thyroid nodule is not synonymous with thyroid malignancy. The ideal clinical and surgical management of these nodules remains challenging. PMID- 28639968 TI - Defining the Cervical Transformation Zone and Squamocolumnar Junction: Can We Reach a Common Colposcopic and Histologic Definition? AB - Quality assurance and research in colposcopy and cervical pathology require standardized terminologies and reporting. However, clinical and histologic definitions of the cervical transformation zone (TZ) and squamocolumnar junction (SCJ) vary considerably. We aimed to identify areas of agreement and areas where work is required to standardize the definitions of the TZ and the SCJ. We conducted a survey among the board members of the European Federation of Colposcopy member societies and members of the International Society of Gynecological Pathologists. Overall, 22 expert colposcopists and 34 gynecologic pathologists responded. There was broad agreement that the TZ is the area where squamous metaplasia has occurred. There was consensus that the original SCJ can appear colposcopically indistinct in cases of maturation of the metaplastic squamous epithelium but can be identified histologically by the presence of the so-called last cervical gland. It was agreed that the border between the metaplastic squamous epithelium and the columnar epithelium on the surface of the cervix is called the new SCJ. Areas where work is required include the questions as to whether the cervical crypts lined by columnar epithelium in the field of squamous metaplasia are an integral part of the TZ or not and whether the individual microscopic borders between the metaplastic squamous epithelium of glandular crypts and the residual columnar epithelium of glandular crypts should be considered as part of the new SCJ or not. This paper is a step in an attempt to standardize colposcopic and histologic definitions among colposcopists and pathologists. PMID- 28639969 TI - The prevalence of irritable bowel syndrome-type symptoms in inflammatory bowel disease patients in remission. AB - OBJECTIVE: Symptoms of irritable bowel syndrome (IBS) are common in inflammatory bowel disease (IBD) and are believed to reflect ongoing inflammation. Consequently, a low prevalence of IBS-type symptoms in IBD patients with normal inflammatory markers is expected. We aimed to investigate the prevalence of IBS type symptoms in IBD patients in biochemical remission (evidenced by low fecal calprotectin levels) and the relationship of these symptoms with fecal calprotectin levels. PATIENTS AND METHODS: In this observational, cross-sectional study, we included all adults with a history of IBD who had calprotectin levels less than 200 ug/g during routine follow-up between August 2014 and May 2015 at our hospital. Patients were excluded if calprotectin was measured because of gastrointestinal complaints. All patients were approached by telephone to evaluate the presence of IBS-type symptoms using Rome III questionnaires. Patients fulfilling IBS criteria were subclassified according to bowel habits. RESULTS: In total, 74 patients were included; 33 (45%, 95% confidence interval: 34-56%) fulfilled the IBS criteria. A larger proportion of Crohn's disease patients with IBS-type symptoms had ileal disease compared with Crohn's disease patients without IBS symptoms (55 vs. 24%; P=0.03). Other characteristics were similar between groups. No difference was found in calprotectin levels between patients with and without IBS-type symptoms (P=0.91). The majority of patients with IBS-type symptoms had diarrhea-predominant or mixed-type IBS (64 and 27% of patients with IBS-type symptoms, respectively). CONCLUSION: The prevalence of IBS type symptoms in IBD patients in biochemical remission is high. A significant proportion of IBS-type symptoms is unrelated to ongoing inflammation and probably reflects 'true IBS'. PMID- 28639970 TI - Hyperuricemia is associated with nonalcoholic fatty liver disease activity score in patients with nonalcoholic fatty liver disease: a systematic review and meta analysis. AB - BACKGROUND: Hyperuricemia is a significant risk factor for nonalcoholic fatty liver disease (NAFLD). It may also have an impact on the histologic severity of NAFLD. However, data on this association are limited. We conducted this meta analysis to investigate the relationship of serum uric acid with liver histologic severity as determined by NAFLD activity score (NAS) in patients with NAFLD. PATIENTS AND METHODS: MEDLINE and EMBASE databases were searched through August 2016 for studies that investigated the association between hyperuricemia and NAS among patients with biopsy-proven NAFLD. Pooled odds ratio and 95% confidence interval were calculated using a random-effects model (generic inverse variance method). The between-study heterogeneity of effect size was quantified using the Q statistic and I. RESULTS: Five observational studies with 777 NAFLD patients were identified. Patients with NAFLD who had hyperuricemia had a high NAS (defined as score of >=5) significantly more often than did those without hyperuricemia with a pooled odds ratio of 2.17 (95% confidence interval: 1.51 3.12). The statistical heterogeneity was low, with I of 16% (Pheterogeneity=0.31). CONCLUSION: In patients with NAFLD, hyperuricemia is associated with a higher degree of histological liver damage. Further studies are required to establish the role of uric acid-lowering therapy among these patients. PMID- 28639971 TI - Effective approaches to address the global cardiovascular disease burden. AB - PURPOSE OF REVIEW: Describe the global burden of cardiovascular disease (CVD), highlight barriers to evidence-based care and propose effective interventions based on identified barriers. RECENT FINDINGS: The global burden of CVD is increasing worldwide. This trend is steeper in lower income countries, where CVD incidence and fatality remains high. Risk factor control, around the world, remains poor, especially in lower and middle-income countries. Barriers at the patient, healthcare provider and health system have been identified. The use of multifaceted interventions that target identified contextual barriers to care, including increasing awareness of CVD and related risk, improving health policy (i.e. taxation of tobacco), improving the availability and affordability of fixed dose combined medications and task-shifting of healthcare responsibilities are potential solutions to improve the global burden of CVD. SUMMARY: There is a need to address identified barriers using evidence-based and multifaceted interventions. Global initiatives, led by the World Heart Federation and the WHO, to facilitate the implementation of such interventions are underway. PMID- 28639972 TI - Imaging in repaired tetralogy of Fallot with a focus on recent advances in echocardiography. AB - PURPOSE OF REVIEW: Imaging is essential for the management of adults with repaired tetralogy of Fallot (rToF). Echocardiography and cardiac magnetic resonance imaging are the central modalities to assess rToF. Here we review recent literature on imaging rToF, focusing on echocardiography and advances in assessment of cardiac mechanics. RECENT FINDINGS: Several two-dimensional, three dimensional, and Doppler echo parameters have been proposed to assess pulmonary regurgitation, right ventricular volumes and ejection fraction, but most of them still have important limitations in their feasibility and reliability compared to cardiac magnetic resonance (CMR). Myocardial deformation imaging to study ventricular and atrial mechanics, regional function, ventricular-ventricular interactions, and electro-mechanical dyssynchrony has yielded insights into the pathophysiologic mechanisms of right ventricular and left ventricular dysfunction; thereby predicting clinical outcomes and exercise capacity, allowing among others, evaluation of the impact of pulmonary valve replacement (PVR). Emerging technologies are expected to further our understanding of the drivers of dysfunction and guide indications and timing of PVR. SUMMARY: Echocardiography and CMR have complementary and overlapping roles in rToF and contribute to our understanding of its pathophysiology and management. PMID- 28639973 TI - Sugar sweetened beverages and cardiometabolic health. AB - PURPOSE OF REVIEW: It is widely accepted that sugar sweetened beverages (SSB) are implicated in weight gain and adverse cardiometabolic heath. To make informed recommendations about SSB, new evidence needs to be considered against existing literature. The present review will provide an update on the epidemiological and trial evidence linking intake of SSB to cardiometabolic outcomes. RECENT FINDINGS: The weight of the evidence from prospective cohort studies supports a strong positive association between intake of SSB and weight gain and risk type 2 diabetes (T2D) and coronary heart disease (CHD) that is independent of adiposity. Associations with stroke are less clear and suggestive of greater risk in women than men. Findings from short-term trials of SSB and markers of cardiometabolic risk including lipids, glucose, blood pressure, and inflammatory cytokines provide mechanistic support for associations with T2D and CHD. Putative underlying mechanisms include adverse glycemic effects and increased hepatic metabolism of fructose. SUMMARY: Conclusive evidence from epidemiological studies and trials on markers of cardiometabolic risk support an etiologic role of SSB in relation to weight gain and risk of T2D and CHD that is independent of weight. Continued efforts to reduce intake of SSB should be encouraged to improve the cardiometabolic health of individuals and populations. PMID- 28639974 TI - An evaluation of CardioPrevent: a technology-enabled, health-behavior change program for the global reduction of cardiovascular risk. AB - PURPOSE OF REVIEW: Cardiovascular diseases (CVDs) are the leading cause of mortality globally. Primary CVD prevention programs have the potential to improve risk factor profiles and, ultimately, the risk of developing CVD. The present study presents an evaluation of CardioPrevent, a global cardiovascular risk reduction program. RECENT FINDINGS: Of the 478 participants enrolled in the CardioPrevent program, 308 and 236 had complete 6-month and 12-month data, respectively at the time of evaluation. At 6 months, the average reduction in the Framingham risk score was -19.5% (median = -26.5%). Women experienced a greater reduction in risk than men (-23.1 vs. -11.4%, P = 0.013). Significant improvements were observed in body composition, blood pressure, low-density lipoproteins, triglycerides, total cholesterol-to-high-density lipoprotein ratio, HbA1c, perceived stress, anxiety, depression, quality of life, physical activity, sitting time, fruit and vegetable consumption, and medication adherence. Improvements seen at 6 months were maintained at 12 months. The majority (98%) of participants were very satisfied with the program and would recommend it to others. SUMMARY: Results of this evaluation identified that CardioPrevent is an effective CVD risk reduction program with high satisfaction rates. CardioPrevent is an effective, scalable program with the capacity to reduce CVD risk among primary care patients. PMID- 28639975 TI - The Authors Respond. PMID- 28639976 TI - Re: Occupational Diesel Exposure, Duration of Employment, and Lung Cancer: An Application of the Parametric G-Formula. PMID- 28639978 TI - Rhetoric or Reality? RN to BSN Graduates Returning to the Bedside. AB - This article reports on a study designed to illuminate the motivation and future goals of RN to BSN degree completion students, specifically to identify whether RNs returning to an online completion program were doing so with the intention of continuing to practice at the bedside. The findings indicate that students are seeking further education for five reasons: 1) to gain entry into a nurse practitioner program, 2) to complete a master's degree program in general, 3) to find opportunities in management, 4) to assume a position as a nurse educator, or 5) to take on a leadership position in general. PMID- 28639980 TI - Improving Student Receptivity to Abortion Care Education. AB - Letting nursing students develop resilience in the presence of moral complexity improves compassionate patient care for women contemplating abortion. Nursing education needs to include quality materials on abortion care in order to create educated providers and citizens. Some students are resistant or conflicted about this topic. A preclass optional, anonymous survey allows students the opportunity to voice concerns about this sensitive topic and guides the instructor in designing class materials. Resulting classroom dialogue is less heated and more collegial, enabling students to examine and process this complex professional practice issue and practice navigating ethical dilemmas. PMID- 28639979 TI - Multi-Options: An Innovative Course Delivery Methodology. AB - Multi-Options is a teaching methodology that allows students to choose the format in which they will attend class. Weekly, they have the choice of attending the face-to-face session, joining synchronously online, or viewing the class asynchronously online at their convenience. Each choice has its own requirements developed to keep the workload uniform for all students. Advantages include conservation of faculty, avoiding the cancellation of poorly populated classes, promoting student independence, and allowing for maximum student flexibility regarding learning style, scheduling needs, and lifestyle. Although technological support and changes to the faculty culture are challenges, initial trials have been successful. PMID- 28639977 TI - Topical Delivery of Immunosuppression to Prolong Xenogeneic and Allogeneic Split Thickness Skin Graft Survival. AB - Cadaveric skin allograft is the current standard of treatment for temporary coverage of large burn wounds. Porcine xenografts are viable alternatives but undergo alpha-1,3-galactose (Gal)-mediated hyperacute rejection and are lost by post-operative day (POD) 3 because of naturally occurring antibodies to Gal in primate recipients. Using baboons, we previously demonstrated that xenografts from GalT-KO swine (lacking Gal) provided wound coverage comparable with allografts with systemic immunosuppression. In this study, we investigate topical immunosuppression as an alternative to prolong xenograft survival. Full-thickness wounds in baboons were created and covered with xenogeneic and allogeneic split thickness skin grafts (STSGs). Animals were treated with slow-release (TyroSphere encapsulated) topical formulations (cyclosporine-A [CSA] or Tacrolimus) applied 1) directly to the STSGs only, or 2) additionally to the wound bed before STSG and 1). Topical CSA did not improve either xenograft or allograft survival (median: treated grafts = 12.5 days, control = 14 days; P = 0.27) with similar results when topical Tacrolimus was used. Pretreatment of wound beds resulted in a significant reduction of xenograft survival compared with controls (10 vs 14 days; P = 0.0002), with comparable results observed in allografts. This observation was associated with marked reduction of inflammation on histology with Tacrolimus and not CSA. Prolongation of allograft and xenograft survival after application to full-thickness wound beds was not achieved with the current formulation of topical immunosuppressants. Modulation of inflammation within the wound bed was effective with Tacrolimus pretreatment before STSG application and may serve as a treatment strategy in related fields. PMID- 28639981 TI - Increasing Nursing Students' Knowledge of Autism Spectrum Disorder by Using a Standardized Patient. AB - Nursing students participated in a simulation using a standardized patient role playing an adolescent with autism spectrum disorder (ASD). The researchers used student feedback to develop and improve a simulation aimed at increasing learner skills and knowledge for treating ASD patients. Students indicated that the standardized patient provided realism not obtained when using static manikins or high-fidelity simulators. Students strongly agreed or agreed that classroom instruction prior to the simulation was important to increasing their knowledge of ASD. Overall, the simulation provided students an opportunity to practice and develop their clinical skills in caring for patients with ASD. PMID- 28639982 TI - Transforming the Nursing Classroom into a Clinical Setting. AB - Providing clinical opportunities for students to gain experience in managing cardiac dysrhythmias is a challenge for nursing faculty. High-risk experiences are often not available for all students or are too life-threatening to entrust to students. Faculty shortages and increasing enrollments add to declines in clinical opportunities. The use of human patient simulation (HPS) has added opportunities to experience high-risk, low-frequency clinical situations. HPS may be employed in the classroom setting to teach content related to dysrhythmia treatments. This innovative approach to HPS utilization engages students and helps them apply theory into clinical nursing practice. PMID- 28639983 TI - Maxillary Sinus Membrane Elevation With Simultaneous Installation of Implants Without the Use of a Graft Material: A Systematic Review. AB - OBJECTIVE: To compare implant treatment outcome after maxillary sinus membrane elevation with simultaneous installation of implants with or without the use of graft material applying the lateral window technique. MATERIALS AND METHODS: MEDLINE/PubMed, Cochrane Library, and Embase search in combination with a hand search of relevant journals was conducted from January 1, 2004 to January 1, 2016. RESULTS: Thirteen studies fulfilled the inclusion criteria. Survival of suprastructures has not been compared within the same study. Short-term implant survival without graft material varied between 96% and 100% compared to 100% for autogenous bone or bone substitutes. No significant difference in bone gain was reported without graft material compared to autogenous bone. The density of newly formed bone increased significantly during the observation period. Bone density was significantly higher in sinuses augmented with blood clot compared to bone substitute, whereas no significant difference was found when compared to autogenous bone. Noncomparative studies demonstrated high long-term implant survival and new bone formation after sinus membrane elevation without graft material. CONCLUSIONS: Sinus membrane elevation without the use of a graft material seems to enhance new bone formation with high implant survival, but long term comparative studies are missing. PMID- 28639984 TI - Impact of Implant Surface Micropatterns on Epithelial Cell Behavior. AB - PURPOSE: This study investigated the effect of topography on cell behavior by screening polydimethylsiloxane (PDMS) molds with different nanoscale micropatterns to determine the ideal surface characteristics for attachment of human epithelial cells. MATERIALS AND METHODS: A soft PDMS mold with regular dot arrays was fabricated based on an aluminum oxide template with ordered nanotube arrays and used as a substrate for cell culture. Cell proliferation, spread, and morphology, as well as features of the extracellular matrix and the actin cytoskeleton were assessed. DISCUSSION: Cells grown on 100-nm regular dot arrays had the highest proliferation rate and spread, with the longest pseudopodia; they showed robust actin distribution relative to the control group. CONCLUSION: Three dimensional PDMS microstructures with 100 nm regular dot arrays were the most effective surface for epithelial cell attachment. These findings can aid in the manufacture of superior materials for use in implants to better integrate into recipient tissue. PMID- 28639985 TI - Implant-Site Related and Patient-Based Factors With the Potential to Impact Patients' Satisfaction, Quality of Life Measures and Perceptions Toward Dental Implant Treatment. AB - OBJECTIVES: The present study aimed at evaluating both the implant site-related and patient-based factors with the potential to affect the extent of patients' satisfaction and also their perceptions regarding dental implant treatment. Potential differences between the esthetic evaluations of dental patients and dental specialists were also considered. MATERIALS AND METHODS: Implant-supported fixed prosthesis (n = 164) in 264 anterior esthetic implant sites were included. Patients' satisfaction, esthetic considerations, and perceptions toward dental implants, were evaluated by both Oral Health Impact Profile-14 (OHIP-14) questionnaire and visual analog scale. Pink Esthetic Score/White Esthetic Score were used for the professional esthetic evaluations of dental specialists. RESULTS: Overall patient satisfaction was high (87.42 +/- 11.86). Compared with implant supported single-tooth restorations, patients with implant-supported bridges had lower OHIP scores (P = 0.001) and were relatively less satisfied with particular aspects of dental implant treatment (eg, cleanability, phonetics, surgical discomfort, and pretreatment information). Generally, type of prosthesis, history of soft/hard tissue augmentation, and reason for tooth loss had a clear impact on the extent of patients' satisfaction, esthetic considerations regarding treatment outcome, and their perceptions toward dental implant treatment (P < 0.05). CONCLUSIONS: Fixed implant-supported restorations generally provide with high levels of satisfaction and oral health-related quality of life. PMID- 28639986 TI - Chitinase-3-like protein-1 (YKL-40) before and after therapy in supraventricular arrhythmias. AB - BACKGROUND: The inflammatory glycoprotein chitinase-3-like protein 1 or YKL-40 has emerged as a potential biomarker of cardiovascular diseases, including atrial fibrillation (AFib). We sought to assess YKL-40 in a wide spectrum of supraventricular arrhythmias besides AFib in comparison with other inflammatory markers. METHODS: We determined serum levels of YKL-40, C-reactive protein (CRP) and IL-6 in 70 patients with AFib, atrial flutter, atrioventricular node reentry tachycardia or other supraventricular tachycardias before, immediately after therapy and 1 week after therapy; 20 healthy patients served as controls. Patients were subsequently followed for 6 months for arrhythmia recurrence. RESULTS: Baseline YKL-40 was significantly elevated in AFib patients [99.5 (65.5,194) ng/ml versus 47.2 (38.9,51.6) ng/ml in controls, P < 0.001], but not in patients with other arrhythmias. YKL-40 levels correlated positively with left atrial volume index (Spearman's rho = 0.853, P < 0.001). Its levels dropped significantly 1 week posttreatment only in AFib (P = 0.009 versus baseline); CRP and IL-6 remained practically stable throughout the study. Arrhythmia recurrence at 6 months occurred in 13 patients (19%), including 11 with AFib and 2 with atrial flutter. Baseline YKL-40 was independently associated with AFib recurrence (adjusted odds ratio = 1.02, 95% confidence interval = 1.00-1.04, P = 0.016). Neither CRP nor IL-6 was associated with AFib recurrence. CONCLUSION: Serum YKL 40 was elevated only in AFib and not in other supraventricular arrhythmias. In AFib, YKL-40 levels were responsive to therapy and predicted long-term recurrence. PMID- 28639987 TI - Antithrombotic strategies in the catheterization laboratory for patients with acute coronary syndromes undergoing percutaneous coronary interventions: insights from the EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units Registry. AB - AIMS: In the last decades, several new therapies have emerged for the treatment of acute coronary syndromes (ACS). We sought to describe real-world patterns of use of antithrombotic treatments in the catheterization laboratory for ACS patients undergoing percutaneous coronary interventions (PCI). METHODS: EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units was a nationwide, prospective registry aimed to evaluate antithrombotic strategies employed in ACS patients in Italy. RESULTS: Over a 3-week period, a total of 2585 consecutive ACS patients have been enrolled in 203 cardiac care units across Italy. Among these patients, 1755 underwent PCI (923 with ST-elevation myocardial infarction and 832 with non-ST-elevation ACS). In the catheterization laboratory, unfractioned heparin was the most used antithrombotic drug in both ST-elevation myocardial infarction (64.7%) and non-ST elevation ACS (77.5%) undergoing PCI and, as aspirin, bivalirudin and glycoprotein IIb/IIIa inhibitors (GPIs) more frequently employed before or during PCI compared with the postprocedural period. Any crossover of heparin therapy occurred in 36.0% of cases, whereas switching from one P2Y12 inhibitor to another occurred in 3.7% of patients. Multivariable analysis yielded several independent predictors of GPIs and of bivalirudin use in the catheterization laboratory, mainly related to clinical presentation, PCI complexity and presence of complications during the procedure. CONCLUSION: In our contemporary, nationwide, all-comers cohort of ACS patients undergoing PCI, antithrombotic therapies were commonly initiated before the catheterization laboratory. In the periprocedural period, the most frequently employed drugs were unfractioned heparin, leading to a high rate of crossover, followed by GPIs and bivalirudin, mainly used during complex PCI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02015624. PMID- 28639988 TI - Stress echo in Italy: state-of-the-art 2015. PMID- 28639989 TI - Use of expenditure analysis to enhance returns on investments in HIV services. AB - PURPOSE OF REVIEW: Globally, the response to the HIV epidemic is at a crisis point. International investments in the HIV response have been essentially flat for 8 years and domestic budgets in low and middle-income countries - still recovering from the global recession - have not been able to fill the resource gap to drive a full-fledged HIV response. Still, efficiencies and prioritization of evidence-based interventions enable a significant scale-up of treatment, but millions more people remain without treatment. This review looks at recent data and research to evaluate interventions that may help close gaps in service provision that undermine testing and treatment programs. RECENT FINDINGS: The President's Emergency Plan for AIDS Relief recently began publicly releasing vast programmatic and expenditure data. These data reveal potential efficiency gaps in testing and treatment programs, particularly in the area of linkage and retention. Interventions such as HIV self-testing have been proposed to help, but whether they can deliver better results remains unclear. Same-day initiation on treatment improves initiation, retention, and viral suppression rates. SUMMARY: Near real-time analysis of data and active response is critical in improving efficiencies in programs. More investment in implementation research is necessary to improve linkage to care and treatment to reach 90-90-90 goals. PMID- 28639990 TI - Recent mobile health interventions to support medication adherence among HIV positive MSM. AB - PURPOSE OF REVIEW: We describe recent mobile health (mHealth) interventions supporting antiretroviral therapy (ART) medication adherence among HIV-positive MSM. RECENT FINDINGS: Keyword searches (1 January 2016-13 May 2017) identified 721 citations. Seven publications reporting on six studies met inclusion criteria. Five studies focused on MSM. Interventions primarily employed text messaging (n = 4), whereas two focused on smartphone apps and one on social media. Three studies measured intervention impact on adherence and found increased ART use intentions (n = 1), self-reported adherence (n = 1), and viral suppression (n = 1, no control group). Other mHealth interventions for HIV positive MSM focused on status disclosure and reducing sexual risk. SUMMARY: mHealth interventions to support ART adherence among MSM show acceptability, feasibility, and preliminary efficacy. No recent mHealth interventions for MSM measured impact on viral suppression compared with a control condition despite earlier (pre-2015) evidence for efficacy. Studies are underway that include multiple features designed to improve adherence within complex smartphone or internet-based platforms. Areas for future growth include overcoming measurement and engagement challenges, developing tools for coordinating patient and provider adherence data, testing combination interventions, and adapting efficacious interventions for new languages and geographic settings. PMID- 28639991 TI - Evaluation of a Nutritional Support Intervention in Malnourished HIV-Infected Children in Bamako, Mali. AB - BACKGROUND: We assessed a nutritional support intervention in malnourished HIV infected children in a HIV-care program of the University Hospital Gabriel Toure, Bamako, Mali. METHODS: All HIV-infected children younger than 15 years were diagnosed for malnutrition between 07 and 12, 2014. Malnutrition was defined according to the WHO growth standards with Z-scores. Two types were studied: acute malnutrition (AM) and chronic malnutrition (CM). All participants were enrolled in a 6-month prospective interventional cohort, receiving Ready-To-Use Therapeutic Food, according to type of malnutrition. The nutritional intervention was offered until child growth reached -1.5 SD threshold. Six-month probability to catch up growth (>-2 SD) was assessed for AM using Kaplan-Meier curves and Cox model. RESULTS: Among the 348 children screened, 198 (57%) were malnourished of whom 158 (80%) children were included: 97 (61%) for AM (35 with associated CM) and 61 (39%) with CM. Fifty-nine percent were boys, 97% were on antiretroviral therapy, median age was 9.5 years (Interquartile Range: 6.7-12.3). Among children with AM, 74% catch-up their growth at 6-month; probability to catch-up growth was greater for those without associated CM (adjusted Hazard Ratio = 1.97, CI 95%: 1.13 to 3.44). Anemia decreased significantly from 40% to 12% at the end of intervention (P < 0.001). CONCLUSIONS: This macronutrient intervention showed 6 month benefits for weight gain and reduced anemia among these children mainly on antiretroviral therapy for years and aged greater than 5 years at inclusion. Associated CM slows down AM recovery and needs longer support. Integration of nutritional screening and care in the pediatric HIV-care package is needed to optimize growth and prevent metabolic disorders. PMID- 28639992 TI - Use of Index Patients to Enable Home-Based Testing in Lesotho. PMID- 28639994 TI - HIV Care Initiation Delay Among Rural Residents in the Southeastern United States, 1996 to 2012. AB - BACKGROUND: Delaying HIV care initiation may lead to greater morbidity, mortality, and further HIV transmission. Rural residence may be associated with delayed diagnosis and linkage to care, with negative clinical outcomes. OBJECTIVE: To examine the association between rural patient residence and CD4 cell count at HIV care initiation in a large HIV clinical cohort in the Southeastern United States. METHODS: We included HIV-infected patients who initiated care between 1996 and 2012 with a geocodable address and no previous history of HIV clinical care. Patient residence was categorized as urban or rural using United States Department of Agriculture Rural Urban Commuting Area codes. Multivariable linear regression models were fit to estimate the association between patient residence and CD4 cell count at HIV care initiation. RESULTS: Among 1396 patients who met study inclusion criteria, 988 had a geocodable address. Overall, 35% of patients resided in rural areas and presented to HIV care with a mean CD4 cell count of 351 cells/mm (SD, 290). Care initiation mean CD4 cell counts increased from 329 cells/mm (SD, 283) in 1996-2003 to 391 cells/mm (SD, 292) in 2008-2012 (P = 0.006). Rural in comparison with urban patients presented with lower CD4 cell counts with an unadjusted and adjusted mean difference of -48 cells/mm [95% confidence interval, -86 to -10) and -37 cells/mm (95% confidence interval: -73 to -2), respectively, consistently observed across calendar years. CONCLUSIONS: HIV care initiation at low CD4 cell counts was common in this Southeastern US cohort and more common among rural area residents. PMID- 28639995 TI - Brief Report: Recovery of Bone Mineral Density After Discontinuation of Tenofovir Based HIV Pre-exposure Prophylaxis. AB - BACKGROUND: Oral tenofovir disoproxil fumarate (TDF) for HIV prevention and treatment is associated with decreases in bone mineral density (BMD). Previous reports suggest that these changes may be reversible after discontinuation of TDF. SETTING: A metabolic substudy of 498 participants in a randomized, placebo controlled HIV prevention trial of oral coformulated TDF with emtricitabine (TDF/FTC, Truvada) for HIV pre-exposure prophylaxis (PrEP) enrolling a global sample of men who have sex with men and trans women. METHODS: Participants underwent dual X-ray absorptiometry to quantify bone mineral density (BMD) in the hip and spine during PrEP and at 2 visits after stopping (median of 23 and 79 weeks post-PrEP, respectively). Results are stratified by pharmacologic measure of TDF/FTC adherence. RESULTS: There was no significant difference in change in hip/spine BMD at any time point between placebo and those with low adherence. Adherent participants had a mean (standard error) BMD change at TDF/FTC discontinuation of -1.02% (0.24) in the hip and -1.84% (0.36) in the spine. After stop, annualized BMD increases of 1.13% per year (0.27) in hip and 1.81% per year (0.36) in spine BMD were observed in adherent participants compared with 0.19% (0.16) and 0.74% (0.21) in the placebo group, respectively (P = 0.003, both comparisons). On average, BMD returned to baseline levels by 1 year after PrEP stop. Recovery was consistent across age, baseline BMD z-score, and treatment duration. CONCLUSIONS: Mean BMD returns to baseline levels within 12-18 months after TDF-based PrEP discontinuation in both hip and spine with consistency across participant subgroups. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov NCT00458393. PMID- 28639997 TI - Parent Education is Changing: A Review of Smartphone Apps. AB - PURPOSE: The purpose was to critique existing parenting apps using established criteria and health literacy guidelines. STUDY DESIGN: Descriptive methodology was used. METHODS: The Apple App Store was searched using the terms parenting, child health, and infant health. To be included, the apps had to have relevant content (parenting, child health, or infant health), be in English, and contain parent education. After eliminating apps that failed to meet inclusion criteria from the original 203 apps, 46 apps were reviewed. The Patient Education Materials Assessment Tool was used to evaluate the health literacy subscales called Understandability and Actionability. Content analysis included Authority, Objectivity, Accuracy, Timeliness, and Usability. RESULTS: The majority of the apps (70%) were in English only. The price ranged from free to $4.99. The purpose, target audience, and topics varied. Although all included apps were for parents, some were for more targeted groups of parents. The source of the information was not presented in 26% of the apps. Most apps took the user to a Web site or an article to read. Functionality of the apps was limited, with none of them providing a customized experience. CLINICAL IMPLICATIONS: Much development and research is needed before mobile health (mHealth) solutions can be recommended by nurses caring for new parents. It is critical that consumers and interdisciplinary professionals be involved in the early design phase of the product to ensure that the end product is acceptable and usable and that it will lead to healthy behaviors. PMID- 28639996 TI - Brief Report: Should Abacavir Be a First-Line Alternative for Adults With HIV in Sub-Saharan Africa? AB - Despite a poor toxicity profile, zidovudine supersedes abacavir (ABC) as an alternative first-line agent in most international treatment guidelines because of concerns about HLA-B*57:01-related ABC-hypersensitivity. We detected one case of HLA-B*57:01 carriage among 513 HIV-infected individuals in Uganda, which, in combination with previous reports, supports the safety of ABC in the region. PMID- 28639999 TI - The Neutrophil-to-Lymphocyte Ratio in Bordetella Pertussis Infection. PMID- 28639998 TI - The New Parent Checklist: A Tool to Promote Parental Reflection. AB - PURPOSE: To design and establish content and face validity of an evidence informed tool that promotes parental self-reflection during the transition to parenthood. STUDY DESIGN AND METHODS: The New Parent Checklist was developed using a three-phase sequential approach: Phase 1 a scoping review and expert consultation to develop and refine a prototype tool; Phase 2 content analysis of parent focus groups; and Phase 3 assessment of utility in a cross-sectional sample of parents completing the New Parent Checklist and a questionnaire. RESULTS: The initial version of the checklist was considered by experts to contain key information. Focus group participants found it useful, appropriate, and nonjudgmental, and offered suggestions to enhance readability, utility, as well as face and content validity. In the cross-sectional survey, 83% of the participants rated the New Parent Checklist as "helpful" or "very helpful" and 90% found the New Parent Checklist "very easy" to use. Open-ended survey responses included predominantly positive feedback. Notable differences existed for some items based on respondents' first language, age, and sex. Results and feedback from all three phases informed the current version, available for download online. CLINICAL IMPLICATIONS: The New Parent Checklist is a comprehensive evidence-informed self-reflective tool with promising content and face validity. Depending on parental characteristics and infant age, certain items of the New Parent Checklist have particular utility but may also require further adaptation and testing. Local resources for information and/or support are included in the tool and could be easily adapted by other regions to incorporate their own local resources. PMID- 28640000 TI - Panton-Valentine Leukocidin Producing Staphylococcus Aureus Facial Pyomyositis Causing Partial Cavernous Sinus Thrombosis. AB - We present a case of subtotal cavernous sinus thrombosis secondary to Panton Valentine leukocidin-associated Staphylococcus aureus pyomyositis of the muscles of mastication in a previously healthy child, who was successfully managed with no residual disease. He was found to have a factor V Leiden heterozygous mutation. We highlight the propensity of Panton-Valentine leukocidin Staphylococcus aureus to induce venous thrombosis at any site but with potential for more severe consequences in the head. We highlight pyomyositis as a differential for periorbital cellulitis and discuss the significance of the factor V Leiden mutation. PMID- 28640001 TI - Reduction in Diarrhea- and Rotavirus-related Healthcare Visits Among Children <5 Years of Age After National Rotavirus Vaccine Introduction in Zimbabwe. AB - BACKGROUND: In Zimbabwe, rotavirus accounted for 41%-56% of acute diarrhea hospitalizations before rotavirus vaccine introduction in 2014. We evaluated rotavirus vaccination impact on acute diarrhea- and rotavirus-related healthcare visits in children. METHODS: We examined monthly and annual acute diarrhea and rotavirus test-positive hospitalizations and Accident and Emergency Department visits among children <60 months of age at 3 active surveillance hospitals during 2012-2016; we compared prevaccine introduction (2012-2013) with postvaccine introduction (2015 and 2016) data for 2 of the hospitals. We examined monthly acute diarrhea hospitalizations by year and age group for 2013-2016 from surveillance hospital registers and monthly acute diarrhea outpatient visits reported to the Ministry of Health and Child Care during 2012-2016. RESULTS: Active surveillance data showed winter seasonal peaks in diarrhea- and rotavirus related visits among children <60 months of age during 2012-2014 that were substantially blunted in 2015 and 2016 after vaccine introduction; the percentage of rotavirus test-positive visits followed a similar seasonal pattern and decrease. Hospital register data showed similar pre-introduction seasonal variation and post-introduction declines in diarrhea hospitalizations among children 0-11 and 12-23 months of age. Monthly variation in outpatient diarrhea related visits mirrored active surveillance data patterns. At 2 surveillance hospitals, the percentage of rotavirus-positive visits declined by 40% and 43% among children 0-11 months of age and by 21% and 33% among children 12-23 months of age in 2015 and 2016, respectively. CONCLUSION: Initial reductions in diarrheal illness among children <60 months of age, particularly among those 0-11 months of age, after vaccine introduction are encouraging. These early results provide evidence to support continued rotavirus vaccination and rotavirus surveillance in Zimbabwe. PMID- 28640002 TI - Trends in Diagnoses Among Hospitalizations of HIV-infected Children and Adolescents in the United States: 2003-2012. AB - OBJECTIVE: Using data from 2003-2012, we updated a previous analysis of trends in hospitalizations of HIV-infected children and adolescents in the United States. METHODS: We used data from the Kids' Inpatient Database of the Healthcare Cost and Utilization Project to derive nationally representative estimates of the number of hospitalizations and the rates per 1000 hospitalizations of select discharge diagnoses and procedures in 2003, 2006, 2009 and 2012 among HIV infected and HIV-uninfected children and adolescents <=18 years, excluding hospitalizations for conditions related to pregnancy/delivery and neonatal diagnoses. We also examined trends in the prevalence of select discharge diagnoses and procedures using multivariable logistic regression models. RESULTS: During 2003-2012, the number of hospitalizations for HIV-infected children declined 58% versus 17% for uninfected, but the odds of having discharge codes for most of the diagnoses and procedures studied, including death during hospitalization, remained higher among HIV-infected compared with uninfected children. Among HIV-infected children, the prevalence of discharge diagnoses for pneumonia, pneumococcal disease and varicella/herpes zoster infections and odds of death during hospitalization decreased over time, while bacterial infections/sepsis and methicillin-resistant Staphylococcus aureus increased. Among HIV-uninfected children, there was no increase in diagnoses of bacterial infection/sepsis, but otherwise trends were similar. CONCLUSIONS: The number of hospitalizations for HIV-infected children declined from 2003 to 2012. The decreased prevalence of several discharge diagnoses and lower risk of death during hospitalization likely reflect improvements in HIV therapies and increased uptake of other preventive strategies. However, the increasing prevalence of discharge diagnoses for bacterial infections/sepsis warrants further attention and monitoring. PMID- 28640003 TI - Infections Associated With Streptococcus Constellatus in Children. AB - Streptococcus constellatus is a viridans Streptococcus belonging to the Anginosus group. It was associated with abscesses in 37 children, 80% of whom had acute appendicitis with perforation and abscess formation in 50%. None of the children was <3 years of age. PMID- 28640004 TI - Ocular Lesions in Congenital Toxoplasmosis in Santa Isabel do Ivai, Parana, Brazil. AB - We verified clinical and psychopedagogic aspects of congenital cases with ocular sequelae, 13 years after toxoplasmosis outbreak in Santa Isabel do Ivai, and current seroprevalence of this zoonosis in pregnant women. Audiologic and ophthalmologic evaluations were performed in congenital cases, in addition to collection of clinical and psychopedagogic data. In pregnant women, current seroprevalence was observed. Among affected teenagers, 2 of 5 are behind in school grade, and 4 of 5 reported learning difficulties, requiring psychopedagogic monitoring, as well as ocular complaints. We observed predominance of small, scarred, dispersed, type II chorioretinal lesions (hypopigmented halo and hyperpigmented central area), and 1 case of ocular relapse. All patients presented normal audiologic assessment. Among 131 pregnant women, 62 (47.3%) were seronegative and 39 (29.8%) were IgG reactive. Only 1 reported acquiring infection during the outbreak. This is one of the few studies in Brazil showing the outcome of congenital toxoplasmosis, a decade after infection, in one of the world's largest outbreaks. PMID- 28640005 TI - Intussusception-related Hospitalizations Among Infants Before and After Private Market Licensure of Rotavirus Vaccines in Taiwan, 2001-2013. AB - INTRODUCTION: Rotavirus is a leading cause of acute gastroenteritis among Taiwanese children. Two globally licensed rotavirus vaccines recommended for inclusion in routine immunization programs that have been available for private market use in Taiwan since 2006 have been associated with a low risk of intussusception in postmarketing studies conducted in several countries. Our objective was to examine trends and characteristics of intussusception hospitalizations in Taiwan among children <12 months of age before and after rotavirus vaccine licensure to provide updated baseline and early postlicensure data. METHODS: We extracted data on intussusception-related hospitalizations among children <12 months of age during 2001-2013 from the National Health Insurance Research Database. We examined patient demographics, clinical outcome and hospitalization trends, focusing on recommended ages for rotavirus vaccination (6-14, 15-24 and 25-34 weeks). We compared mean hospitalization rates for prevaccine licensure years 2001-2005 with those for postvaccine licensure years 2007-2013 using Poisson regression analysis. RESULTS: During 2001-2013, 1998 intussusceptions hospitalizations were recorded. The mean age of hospitalization was 33 weeks. Almost all children recovered; 3 deaths occurred. The overall intussusception hospitalization rate was 75.1 per 100,000; seasonality was not evident. Hospitalization rates were greatest in children >=25 weeks of age and occurred more frequently in boys. Prevaccine and postvaccine licensure trends in annual hospitalization rates did not significantly differ. However, mean hospitalization rates were lower during the postvaccine licensure period for children <12 months of age (rate ratio: 0.84, 95% confidence interval: 0.76-0.92) with the greatest decline among children 25-34 weeks of age (rate ratio: 0.66, 95% confidence interval: 0.55-0.78). CONCLUSIONS: Infant intussusception in Taiwan occurs at a rate within the range of other Asian countries is rare among children <3 months of age, has a male predominance and does not have a clear seasonality pattern. We did not observe a postlicensure increase in intussusception hospitalization rates in children 6-14 weeks of age. PMID- 28640006 TI - Poor gait performance is influenced with decreased vestibulo-ocular reflex in poststroke patients. AB - The vestibulo-ocular reflex (VOR) exerts a significant influence on gait performance. Therefore, a decrease in VOR function could worsen gait impairments in patients with poststroke hemiparesis. The effects of decreased VOR function on gait performance could be further exacerbated by aging-related physical weakness and impaired motor function of the hemiparetic lower limb. The aim of our study was to evaluate the possible synergistic effect of aging and impairment in lower extremity function and the VOR on walking ability of poststroke hemiplegic patients. The VOR was evaluated, using the gaze-stabilization test (GST), in 75 patients with a poststroke hemiplegia. Lower extremity function was assessed using the Fugl-Meyer assessment (FMA-LE). Gait performance was evaluated using the 10-m walking test, the timed up-and-go, and the dynamic gait index (DGI). The relationships between gait performance and age, FMA-LE and GST, as well as whether age, FMA-LE, and/or GST were significant predictors of gait performance were evaluated. The 10-m walking test, timed up-and-go and DGI were significantly correlated to the FMA-LE and GST (P<0.05). On stepwise multiple regression analysis, the GST remained a significant predictor of the DGI (P<0.001). The present study indicates that decreased VOR function after stroke contributes to impairments in gait both in simple and in dual-task walking tests. PMID- 28640007 TI - Evaluation of pulse height control for rapid isometric contractions in college sprinters. AB - The ability of rapid force development is one of the important factors for improving physical performance. It has been known that rapid isometric force is controlled by a central motor program to maintain the rise time relatively constant independent of force amplitude (pulse height control). The advantage of using pulse height control is that it increases the rate of force with force amplitude. However, this strategy is believed to be applicable up to about 50-60% of maximal voluntary contractions (MVC). When the force level increases further, individuals often switch to pulse width control to increase the time to peak force. The aim of this study was to determine the force level (turning point) at which participants switch from pulse height control to pulse width control. This turning point was defined as the maximum force produced by pulse height control. We then attempted to examine whether this turning point is different among participants (control and sprinter groups). Therefore, participants were asked to perform isometric plantar flexions as fast as possible over a wide range of force levels (10-90%MVC). Our results showed that a turning point (%MVC) between two strategies was detected in all participants and the mean values were significantly higher in the sprinter group than that in the control group. Our results suggest that each participant has different limits of force level produced by pulse height control. The sprinter and control groups may use different control strategies for rapid force production at a higher force level. PMID- 28640008 TI - Brain-derived neurotrophic factor propeptide inhibits proliferation and induces apoptosis in C6 glioma cells. AB - There are several forms of brain-derived neurotrophic factor (BDNF), the precursor of BDNF, mature BDNF, and BDNF propeptide. They exert different effects through different transmembrane receptor signaling systems. Precursor of BDNF is enzymatically cleaved, either by intracellular or by extracellular proteases, to generate mature BDNF and its propeptide (BDNF propeptide). The aim of this study was to evaluate the potential molecular mechanisms that underlie the inhibition of glioma cell growth by the BDNF propeptide. To achieve this, we examined the expression of BDNF propeptide in C6 glioma cells. The 3-(4,5-dimethylthiazol-2 Yl)-2,5-diphenyltetrazolium bromide assay and the apoptosis assay were used to assess the effects of the BDNF propeptide on the growth and apoptosis of glioma cells. We found that the BDNF propeptide promoted C6 glioma cell apoptosis and decreased in-vitro cell growth. We also found using western blot that cleaved caspase3 and B cell lymphoma 2 (Bcl2)-associated X protein abundances increased, whereas Bcl2 abundance decreased. Our data suggest that the BDNF propeptide may have an inhibitory effect on glioma through activation of the caspase3 pathway. PMID- 28640009 TI - Augmented Renal Clearance Using Population-Based Pharmacokinetic Modeling in Critically Ill Pediatric Patients. AB - OBJECTIVES: The objectives of this study were to: 1) evaluate the prevalence of augmented renal clearance in critically ill pediatric patients using vancomycin clearance; 2) derive the pharmacokinetic model that best describes vancomycin clearance in critically ill pediatric patients; and 3) correlate vancomycin clearance with creatinine clearance estimated by modified Schwartz or Cockcroft Gault. DESIGN: Retrospective, two-center, cohort study from 2003 to 2016. SETTING: Clinical drug monitoring services in the PICUs at two tertiary care, teaching hospitals. PATIENTS: Children from 1 to 21 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Identify patients with augmented renal clearance (vancomycin clearance >= 130 mL/min/1.73 m used as definition of augmented renal clearance). Derive final population-based pharmacokinetic model and estimate individual patient pharmacokinetic parameters. Compare estimated glomerular filtration rate (modified Schwartz or Cockcroft-Gault depending on age < or >= 17 yr) with vancomycin clearance. Augmented renal clearance was identified in 12% of 250 total subjects. The final population-based pharmacokinetic model for vancomycin clearance (L/hr) was 0.118 * weight (e). Median vancomycin clearance in those with versus without augmented renal clearance were 141.3 and 91.7 mL/min/1.73 m, respectively (p < 0.001). By classification and regression tree analysis, patients who were more than 7.9 years old were significantly more likely to experience augmented renal clearance (17% vs 4.6% in those <= 7.9 yr old; p = 0.002). In patients with augmented renal clearance, 79% of 29 had vancomycin trough concentrations less than 10 ug/mL, compared with 52% of 221 in those without augmented renal clearance (p < 0.001). Vancomycin clearance was weakly correlated to the glomerular filtration rate estimated by the modified Schwartz or Cockcroft-Gault method (Spearman R = 0.083). CONCLUSIONS: Augmented renal clearance was identified in one of 10 critically ill pediatric patients using vancomycin clearance, with an increase of approximately 50 mL/min/1.73 m in those with augmented renal clearance. As augmented renal clearance results in subtherapeutic antibiotic concentrations, optimal dosing is essential in those exhibiting augmented renal clearance. PMID- 28640010 TI - Living Donor Liver Transplantation in Pakistan. PMID- 28640012 TI - Interspecies Organogenesis-Derived Tissues for Transplantation. PMID- 28640013 TI - Promote Your Work in Transplantation. PMID- 28640015 TI - The Effects of Valsartan on Renal Klotho Expression and Oxidative Stress in Alleviation of Cyclosporine Nephrotoxicity: Retraction. PMID- 28640014 TI - Potential Impact of Risk and Loss Aversion on the Process of Accepting Kidneys for Transplantation. AB - Behavioral economic theory suggests that people make decisions based on maximizing perceived value; however, this may be influenced more by the risk of loss rather than of potential gain. Additionally, individuals may seek certainty over uncertainty. These are termed loss aversion and risk aversion, respectively. Loss aversion is particularly sensitive to how the decision is "framed." Thus, labeling a kidney as high Kidney Donor Profile Index results in higher discard rates because this creates a nonlinearity in perceived risk. There is also evidence that the perceived loss due to regulatory sanction results in increased organ discard rates. This may be due to the overuse of terminology that stresses regulatory sanctions and thus perpetuates fear of loss through a form of nudging. Our goal is to point out how these concepts of behavioral economics may negatively influence the decision process to accept these suboptimal organs. We hope to make the community more aware of these powerful psychological influences and thus potentially increase the utilization of these suboptimal organs. Further, we would urge regulatory bodies to avoid utilizing strategies that frame outcomes in terms of loss due to flagging and build models that are less prone to uncertain expected versus observed outcomes. PMID- 28640016 TI - Hydrogen Peroxide Induces Muscle Nociception via Transient Receptor Potential Ankyrin 1 Receptors. AB - BACKGROUND: H2O2 has a variety of actions in skin wounds but has been rarely studied in deep muscle tissue. Based on response to the transient receptor potential ankyrin 1 antagonists after plantar incision, we hypothesized that H2O2 exerts nociceptive effects via the transient receptor potential ankyrin 1 in muscle. METHODS: Nociceptive behaviors in rats (n = 269) and mice (n = 16) were evaluated after various concentrations and volumes of H2O2 were injected into the gastrocnemius muscle or subcutaneous tissue. The effects of H2O2 on in vivo spinal dorsal horn neuronal activity and lumbar dorsal root ganglia neurons in vitro were evaluated from 26 rats and 6 mice. RESULTS: Intramuscular (mean +/- SD: 1,436 +/- 513 s) but not subcutaneous (40 +/- 58 s) injection of H2O2 (100 mM, 0.6 ml) increased nociceptive time. Conditioned place aversion was evident after intramuscular (-143 +/- 81 s) but not subcutaneous (-2 +/- 111 s) injection of H2O2. These H2O2-induced behaviors were blocked by transient receptor potential ankyrin 1 antagonists. Intramuscular injection of H2O2 caused sustained in vivo activity of dorsal horn neurons, and H2O2 activated a subset of dorsal root ganglia neurons in vitro. Capsaicin nerve block decreased guarding after plantar incision and reduced nociceptive time after intramuscular H2O2. Nociceptive time after intramuscular H2O2 in transient receptor potential ankyrin 1 knockout mice was shorter (173 +/- 156 s) compared with wild-type mice (931 +/- 629 s). CONCLUSIONS: The greater response of muscle tissue to H2O2 may help explain why incision that includes deep muscle but not skin incision alone produces spontaneous activity in nociceptive pathways. PMID- 28640017 TI - Reversal of Vecuronium-induced Neuromuscular Blockade with Low-dose Sugammadex at Train-of-four Count of Four: A Randomized Controlled Trial. AB - BACKGROUND: Rocuronium-induced neuromuscular block that spontaneously recovered to a train-of-four count of four can be reversed with sugammadex 0.5 or 1.0 mg/kg. We investigated whether these doses of sugammadex can also reverse vecuronium at a similar level of block. METHODS: Sixty-five patients were randomly assigned, and 64 were analyzed in this controlled, superiority study. Participants received general anesthesia with propofol, sevoflurane, fentanyl, and vecuronium. Measurement of neuromuscular function was performed with acceleromyography (TOF-Watch-SX, Organon Teknika B.V., The Netherlands ). Once the block recovered spontaneously to four twitches in response to train-of-four stimulation, patients were randomly assigned to receive sugammadex 0.5, 1.0, or 2.0 mg/kg; neostigmine 0.05 mg/kg; or placebo. Time from study drug injection to normalized train-of-four ratio 0.9 and the incidence of incomplete reversal within 30 min were the primary outcome variables. Secondary outcome was the incidence of reparalysis (normalized train-of-four ratio less than 0.9). RESULTS: Sugammadex, in doses of 1.0 and 2.0 mg/kg, reversed a threshold train-of-four count of four to normalized train-of-four ratio of 0.9 or higher in all patients in 4.4 +/- 2.3 min (mean +/- SD) and 2.6 +/- 1.6 min, respectively. Sugammadex 0.5 mg/kg reversed the block in 6.8 +/- 4.1 min in 70% of patients (P < 0.0001 vs. 1.0 and 2.0 mg/kg), whereas neostigmine produced reversal in 11.3 +/- 9.7 min in 77% of patients (P > 0.05 vs. sugammadex 0.5 mg/kg). The overall frequency of reparalysis was 18.7%, but this incidence varied from group to group. CONCLUSIONS: Sugammadex 1.0 mg/kg, unlike 0.5 mg/kg, properly reversed a threshold train-of-four count of four vecuronium-induced block but did not prevent reparalysis. PMID- 28640018 TI - Decision to Extubate Brain-injured Patients: Limiting Uncertainty in Neurocritical Care. PMID- 28640019 TI - Mini-fluid Challenge of 100 ml of Crystalloid Predicts Fluid Responsiveness in the Operating Room. AB - BACKGROUND: Mini-fluid challenge of 100 ml colloids is thought to predict the effects of larger amounts of fluid (500 ml) in intensive care units. This study sought to determine whether a low quantity of crystalloid (50 and 100 ml) could predict the effects of 250 ml crystalloid in mechanically ventilated patients in the operating room. METHODS: A total of 44 mechanically ventilated patients undergoing neurosurgery were included. Volume expansion (250 ml saline 0.9%) was given to maximize cardiac output during surgery. Stroke volume index (monitored using pulse contour analysis) and pulse pressure variations were recorded before and after 50 ml infusion (given for 1 min), after another 50 ml infusion (given for 1 min), and finally after 150 ml infusion (total = 250 ml). Changes in stroke volume index induced by 50, 100, and 250 ml were recorded. Positive fluid challenges were defined as an increase in stroke volume index of 10% or more from baseline after 250 ml. RESULTS: A total of 88 fluid challenges were performed (32% of positive fluid challenges). Changes in stroke volume index induced by 100 ml greater than 6% (gray zone between 4 and 7%, including 19% of patients) predicted fluid responsiveness with a sensitivity of 93% (95% CI, 77 to 99%) and a specificity of 85% (95% CI, 73 to 93%). The area under the receiver operating curve of changes in stroke volume index induced by 100 ml was 0.95 (95% CI, 0.90 to 0.99) and was higher than those of changes in stroke volume index induced by 50 ml (0.83 [95% CI, 0.75 to 0.92]; P = 0.01) and pulse pressure variations (0.65 [95% CI, 0.53 to 0.78]; P < 0.005). CONCLUSIONS: Changes in stroke volume index induced by rapid infusion of 100 ml crystalloid predicted the effects of 250 ml crystalloid in patients ventilated mechanically in the operating room. PMID- 28640020 TI - Extubation Success Prediction in a Multicentric Cohort of Patients with Severe Brain Injury. AB - BACKGROUND: Patients with brain injury are at high risk of extubation failure. METHODS: We conducted a prospective observational cohort study in four intensive care units of three university hospitals. The aim of the study was to create a score that could predict extubation success in patients with brain injury. RESULTS: A total of 437 consecutive patients with brain injury were included, and 338 patients (77.3%) displayed successful extubation. In the multivariate analysis, four features were associated with success the day of extubation: age less than 40 yr, visual pursuit, swallowing attempts, and a Glasgow coma score greater than 10. In the score, each item counted as one. A score of 3 or greater was associated with 90% extubation success. The area under the receiver-operator curve was 0.75 (95% CI, 0.69 to 0.81). After internal validation by bootstrap, the area under the receiver-operator curve was 0.73 (95% CI, 0.68 to 0.79). Extubation success was significantly associated with shorter duration of mechanical ventilation (11 [95% CI, 5 to 17 days] vs. 22 days [95% CI, 13 to 29 days]; P < 0.0001), shorter intensive care unit length of stay (15 [95% CI, 9 to 23 days] vs. 27 days [95% CI, 21 to 36 days]; P < 0.0001), and lower in-intensive care unit mortality (4 [1.2%] vs. 11 [11.1%]; P < 0.0001). CONCLUSIONS: Our score exploring both airway functions and neurologic status may increase the probability of successful extubation in patients with severe brain injury. PMID- 28640022 TI - Brain-Dead Donors on Extracorporeal Membrane Oxygenation. AB - OBJECTIVES: To describe donors after brain death with ongoing extracorporeal membrane oxygenation and to analyze the outcome of organs transplanted from these donors. DESIGN: Retrospective analysis of the national information system run by the French Biomedicine Agency (CRISTAL database). SETTING: National registry data of all donors after brain death in France and their organ recipients between 2007 and 2013. PATIENTS: Donors after brain death and their organ recipients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, there were 22,270 brain-dead patients diagnosed in France, of whom 161 with extracorporeal membrane oxygenation. Among these patients, 64 donors on extracorporeal membrane oxygenation and 10,805 donors without extracorporeal membrane oxygenation had at least one organ retrieved. Donors on extracorporeal membrane oxygenation were significantly younger and had more severe intensive care medical conditions (hemodynamic, biological, renal, and liver insults) than donors without extracorporeal membrane oxygenation. One hundred nine kidneys, 37 livers, seven hearts, and one lung were successfully transplanted from donors on extracorporeal membrane oxygenation. We found no significant difference in 1-year kidney graft survival (p = 0.24) and function between recipients from donors on extracorporeal membrane oxygenation (92.7% [85.9-96.3%]) and matching recipients from donors without extracorporeal membrane oxygenation (95.4% [93.0-97.0%]). We also found no significant difference in 1-year liver recipient survival (p = 0.91): 86.5% (70.5-94.1) from donors on extracorporeal membrane oxygenation versus 80.7% (79.8-81.6) from donors without extracorporeal membrane oxygenation. CONCLUSIONS: Brain-dead patients with ongoing extracorporeal membrane oxygenation have more severe medical conditions than those without extracorporeal membrane oxygenation. However, kidney graft survival and function were no different than usual. Brain-dead patients with ongoing extracorporeal membrane oxygenation are suitable for organ procurement. PMID- 28640021 TI - Identifying Distinct Subgroups of ICU Patients: A Machine Learning Approach. AB - OBJECTIVES: Identifying subgroups of ICU patients with similar clinical needs and trajectories may provide a framework for more efficient ICU care through the design of care platforms tailored around patients' shared needs. However, objective methods for identifying these ICU patient subgroups are lacking. We used a machine learning approach to empirically identify ICU patient subgroups through clustering analysis and evaluate whether these groups might represent appropriate targets for care redesign efforts. DESIGN: We performed clustering analysis using data from patients' hospital stays to retrospectively identify patient subgroups from a large, heterogeneous ICU population. SETTING: Kaiser Permanente Northern California, a healthcare delivery system serving 3.9 million members. PATIENTS: ICU patients 18 years old or older with an ICU admission between January 1, 2012, and December 31, 2012, at one of 21 Kaiser Permanente Northern California hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used clustering analysis to identify putative clusters among 5,000 patients randomly selected from 24,884 ICU patients. To assess cluster validity, we evaluated the distribution and frequency of patient characteristics and the need for invasive therapies. We then applied a classifier built from the sample cohort to the remaining 19,884 patients to compare the derivation and validation clusters. Clustering analysis successfully identified six clinically recognizable subgroups that differed significantly in all baseline characteristics and clinical trajectories, despite sharing common diagnoses. In the validation cohort, the proportion of patients assigned to each cluster was similar and demonstrated significant differences across clusters for all variables. CONCLUSIONS: A machine learning approach revealed important differences between empirically derived subgroups of ICU patients that are not typically revealed by admitting diagnosis or severity of illness alone. Similar data-driven approaches may provide a framework for future organizational innovations in ICU care tailored around patients' shared needs. PMID- 28640025 TI - Performance of a Modern Glucose Meter in ICU and General Hospital Inpatients: 3 Years of Real-World Paired Meter and Central Laboratory Results. AB - OBJECTIVE: Due to accuracy concerns, the Food and Drug Administration issued guidances to manufacturers that resulted in Center for Medicare and Medicaid Services stating that the use of meters in critically ill patients is "off-label" and constitutes "high complexity" testing. This is causing significant workflow problems in ICUs nationally. We wished to determine whether real-world accuracy of modern glucose meters is worse in ICU patients compared with non-ICU inpatients. DESIGN: We reviewed glucose results over the preceding 3 years, comparing results from paired glucose meter and central laboratory tests performed within 60 minutes of each other in ICU versus non-ICU settings. SETTING: Seven ICU and 30 non-ICU wards at a 1,300-bed academic hospital in the United States. SUBJECTS: A total of 14,763 general medicine/surgery inpatients and 20,970 ICU inpatients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Compared meter results with near simultaneously performed laboratory results from the same patient by applying the 2016 U.S. Food and Drug Administration accuracy criteria, determining mean absolute relative difference and examining where paired results fell within the Parkes consensus error grid zones. A higher percentage of glucose meter results from ICUs than from non-ICUs passed 2016 Food and Drug Administration accuracy criteria (p < 10) when comparing meter results with laboratory results. At 1 minute, no meter result from ICUs posed dangerous or significant risk by error grid analysis, whereas at 10 minutes, less than 0.1% of ICU meter results did, which was not statistically different from non-ICU results. CONCLUSIONS: Real-world accuracy of modern glucose meters is at least as accurate in the ICU setting as in the non-ICU setting at our institution. PMID- 28640023 TI - Preventing Harm in the ICU-Building a Culture of Safety and Engaging Patients and Families. AB - OBJECTIVE: Preventing harm remains a persistent challenge in the ICU despite evidence-based practices known to reduce the prevalence of adverse events. This review seeks to describe the critical role of safety culture and patient and family engagement in successful quality improvement initiatives in the ICU. We review the evidence supporting the impact of safety culture and provide practical guidance for those wishing to implement initiatives aimed at improving safety culture and more effectively integrate patients and families in such efforts. DATA SOURCES: Literature review using PubMed including evaluation of key studies assessing large-scale quality improvement efforts in the ICU, impact of safety culture on patient outcomes, methodologies for quality improvement commonly used in healthcare, and patient and family engagement. Print and web-based resources from leading patient safety organizations were also searched. STUDY SELECTION: Our group completed a review of original studies, review articles, book chapters, and recommendations from leading patient safety organizations. DATA EXTRACTION: Our group determined by consensus which resources would best inform this review. DATA SYNTHESIS: A strong safety culture is associated with reduced adverse events, lower mortality rates, and lower costs. Quality improvement efforts have been shown to be more effective and sustainable when paired with a strong safety culture. Different methodologies exist for quality improvement in the ICU; a thoughtful approach to implementation that engages frontline providers and administrative leadership is essential for success. Efforts to substantively include patients and families in the processes of quality improvement work in the ICU should be expanded. CONCLUSIONS: Efforts to establish a culture of safety and meaningfully engage patients and families should form the foundation for all safety interventions in the ICU. This review describes an approach that integrates components of several proven quality improvement methodologies to enhance safety culture in the ICU and highlights opportunities to include patients and families. PMID- 28640026 TI - What Is the Relationship Between a Preclerkship Portfolio Review and Later Performance in Clerkships? AB - PURPOSE: Medical educators struggle to find effective ways to assess essential competencies such as communication, professionalism, and teamwork. Portfolio based assessment provides one method of addressing this problem by allowing faculty reviewers to judge performance, as based on a longitudinal record of student behavior. At the Feinberg School of Medicine, the portfolio system measures behavioral competence using multiple assessments collected over time. This study examines whether a preclerkship portfolio review is a valid method of identifying problematic student behavior affecting later performance in clerkships. METHOD: The authors divided students into two groups based on a summative preclerkship portfolio review in 2014: students who had concerning behavior in one or more competencies and students progressing satisfactorily. They compared how students in these groups later performed on two clerkship outcomes as of October 2015: final grades in required clerkships, and performance on a clerkship clinical composite score. They used Mann-Whitney tests and multiple linear regression to examine the relationship between portfolio review results and clerkship outcomes. They used USMLE Step 1 to control for knowledge acquisition. RESULTS: Students with concerning behavior preclerkship received significantly lower clerkship grades than students progressing satisfactorily (P = .002). They also scored significantly lower on the clinical composite score (P < .001). Regression analysis indicated concerning behavior was associated with lower clinical composite scores, even after controlling for knowledge acquisition. CONCLUSIONS: The results show a preclerkship portfolio review can identify behaviors that impact clerkship performance. A comprehensive portfolio system is a valid way to measure behavioral competencies. PMID- 28640024 TI - Molecular Adsorbent Recirculating System Can Reduce Short-Term Mortality Among Patients With Acute-on-Chronic Liver Failure-A Retrospective Analysis. AB - OBJECTIVES: Acute-on-chronic liver failure is associated with numerous consecutive organ failures and a high short-term mortality rate. Molecular adsorbent recirculating system therapy has demonstrated beneficial effects on the distinct symptoms, but the associated mortality data remain controversial. DESIGN: Retrospective analysis of acute-on-chronic liver failure patients receiving either standard medical treatment or standard medical treatment and molecular adsorbent recirculating system. Secondary analysis of data from the prospective randomized Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial by applying the recently introduced Chronic Liver Failure-criteria. SETTING: Medical Departments of University Hospital Muenster (Germany). PATIENTS: This analysis was conducted in two parts. First, 101 patients with acute-on-chronic liver failure grades 1-3 and Chronic Liver Failure-C-Organ Failure liver subscore equals to 3 but stable pulmonary function were identified and received either standard medical treatment (standard medical treatment, n = 54) or standard medical treatment and molecular adsorbent recirculating system (n = 47) at the University Hospital Muenster. Second, the results of this retrospective analysis were tested against the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial. INTERVENTIONS: Standard medical treatment and molecular adsorbent recirculating system. MEASUREMENTS AND MAIN RESULTS: Additionally to improved laboratory variables (bilirubin and creatinine), the short-term mortality (up to day 14) of the molecular adsorbent recirculating system group was significantly reduced compared with standard medical treatment. A reduced 14-day mortality rate was observed in the molecular adsorbent recirculating system group (9.5% vs 50.0% with standard medical treatment; p = 0.004), especially in patients with multiple organ failure (acute-on-chronic liver failure grade 2-3). Concerning the affected organ system, this effect of molecular adsorbent recirculating system on mortality was particularly evident among patients with increased kidney, brain, or coagulation Chronic Liver Failure-C-Organ Failure subscores. Subsequent reanalysis of the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure dataset with adoption of the Chronic Liver Failure-classification resulted in similar findings. CONCLUSIONS: Molecular adsorbent recirculating system treatment was associated with an improved short-term survival of patients with acute-on-chronic liver failure and multiple organ failure. Among these high-risk patients, molecular adsorbent recirculating system treatment might bridge to liver recovery or liver transplantation. PMID- 28640027 TI - Exploring Integration in Action: Competencies as Building Blocks of Expertise. AB - PURPOSE: Competency frameworks such as the CanMEDS roles and the ACGME core competencies may lead to the implicit assumption that physicians can learn and practice individual competencies in isolation. In contrast, models of adaptive expertise suggest that the integration of competencies reflects the capabilities of an expert physician. Thus, educational programming aimed at teaching discrete roles or competencies might overlook expert physician capabilities that are central to patient care. To develop expertise, learning opportunities must reflect expert capabilities. To better understand the relationship between competency-based medical education and expert development, the authors sought to explore how integrated competencies are enacted during patient care by postgraduate medical trainees. METHOD: Using a cognitive ethnographic approach, in 2014-2015 the authors conducted observations and-to refine and elaborate these observations-ad hoc informal interviews with 13 postgraduate trainee participants. Data collection resulted in 92 hours of observation, 26 patient case portraits, and a total of 220 pages of field notes for analysis. Through analysis, the authors identified and examined moments when postgraduate trainees appeared to be simultaneously enacting multiple competencies. RESULTS: The authors identified two key expert capabilities in moments of integrated competence: finding complexity and being patient-centered. They described two mechanisms for these forms of integration: valuing the patient's narrative of their illness, and integrated understanding. CONCLUSIONS: Understanding integrated competencies as the building blocks of expert capabilities, along with recognizing the importance of mechanisms that support integration, offers an opportunity to use existing competency-based frameworks to understand and teach adaptive expertise. PMID- 28640029 TI - Enacting Pedagogy in Curricula: On the Vital Role of Governance in Medical Education. AB - Managing curricula and curricular change involves both a complex set of decisions and effective enactment of those decisions. The means by which decisions are made, implemented, and monitored constitute the governance of a program. Thus, effective academic governance is critical to effective curriculum delivery. Medical educators and medical education researchers have been invested heavily in issues of educational content, pedagogy, and design. However, relatively little consideration has been paid to the governance processes that ensure fidelity of implementation and ongoing refinements that will bring curricular practices increasingly in line with the pedagogical intent. In this article, the authors reflect on the importance of governance in medical schools and argue that, in an age of rapid advances in knowledge and medical practices, educational renewal will be inhibited if discussions of content and pedagogy are not complemented by consideration of a governance framework capable of enabling change. They explore the unique properties of medical curricula that complicate academic governance, review the definition and properties of good governance, offer mechanisms to evaluate the extent to which governance is operating effectively within a medical program, and put forward a potential research agenda for increasing the collective understanding of effective governance in medical education. PMID- 28640028 TI - Assessing and Communicating the Value of Biomedical Research: Results From a Pilot Study. AB - PURPOSE: Assessing the impact of research requires an approach that is sensitive both to the context of the research and the perspective of the stakeholders trying to understand its benefits. Here, the authors report on a pilot that applied such an approach to research conducted at the Collaborative Center for Health Equity (CCHE) of the University of Wisconsin School of Medicine and Public Health. METHOD: The pilot assessed the academic impact of CCHE's work; the networks between CCHE and community partners; and the reach of CCHE's programs, including an attempt to estimate return on investment (ROI). Data included bibliometrics, findings from a stakeholder survey and in-depth interviews, and financial figures. RESULTS: The pilot illustrated how CCHE programs increase the capacity of community partners to advocate for their communities and engage with researchers to ensure that research benefits the community. The results illustrate the reach of CCHE's programs into the community. The authors produced an estimate of the ROI for one CCHE program targeting childhood obesity, and values ranged from negative to positive. CONCLUSIONS: The authors experienced challenges using novel assessment techniques at a small scale including the lack of comparator groups and the scarcity of cost data for estimating ROI. This pilot demonstrated the value of research from a variety of perspectives-from academic to community. It illustrates how metrics beyond grant income and publications can capture the outputs of an academic health center in a way that may better align with the aims of the center and stakeholders. PMID- 28640030 TI - Flipped Classrooms in Graduate Medical Education: A National Survey of Residency Program Directors. AB - PURPOSE: To begin to quantify and understand the use of the flipped classroom (FC)-a progressive, effective, curricular model-in internal medicine (IM) education in relation to residency program and program director (PD) characteristics. METHOD: The authors conducted a survey that included the Flipped Classroom Perception Instrument (FCPI) in 2015 regarding programs' use and PDs' perceptions of the FC model. RESULTS: Among the 368 IM residency programs, PDs at 227 (61.7%) responded to the survey and 206 (56.0%) completed the FCPI. Regarding how often programs used the FC model, 34 of the 206 PDs (16.5%) reported "never"; 44 (21.4%) reported "very rarely"; another 44 (21.4%) reported "somewhat rarely"; 59 (28.6%) reported "sometimes"; 16 (7.8%) reported "somewhat often"; and 9 (4.4%) reported "very often." The mean FCPI score (standard deviation [SD]) for the in-class application factor (4.11 [0.68]) was higher (i.e., more favorable) than for the preclass activity factor (3.94 [0.65]) (P < .001). FC perceptions (mean [SD]) were higher among younger PDs (<= 50 years, 4.12 [0.62]; > 50 years, 3.94 [0.61]; P = .04) and women compared with men (4.28 [0.56] vs. 3.91 [0.62]; P < .001). PDs with better perceptions of FCs had higher odds of using FCs (odds ratio, 4.768; P < .001). CONCLUSIONS: Most IM programs use the FC model at least to some extent, and PDs prefer the interactive in-class components over the independent preclass activities. PDs who are women and younger perceived the model more favorably. PMID- 28640031 TI - Identifying Gaps in the Performance of Pediatric Trainees Who Receive Marginal/Unsatisfactory Ratings. AB - PURPOSE: To perform a derivation study to determine in which subcompetencies marginal/unsatisfactory pediatric residents had the greatest deficits compared with their satisfactorily performing peers and which subcompetencies best discriminated between marginal/unsatisfactory and satisfactorily performing residents. METHOD: Multi-institutional cohort study of all 21 milestones (rated on four or five levels) reported to the Accreditation Council for Graduate Medical Education, and global marginal/unsatisfactory versus satisfactory performance reported to the American Board of Pediatrics. Data were gathered in 2013-2014. For each level of training (postgraduate year [PGY] 1, 2, and 3), mean differences between milestone levels of residents with marginal/unsatisfactory and satisfactory performance adjusted for clustering by program and C-statistics (area under receiver operating characteristic curve) were calculated. A Bonferroni-corrected significance threshold of .0007963 was used to account for multiple comparisons. RESULTS: Milestone and overall performance evaluations for 1,704 pediatric residents in 41 programs were obtained. For PGY1s, two subcompetencies had almost a one-point difference in milestone levels between marginal/unsatisfactory and satisfactory trainees and outstanding discrimination (>= 0.90): organize/prioritize (0.93; C-statistic: 0.91) and transfer of care (0.97; C-statistic: 0.90). The largest difference between marginal/unsatisfactory and satisfactory PGY2s was trustworthiness (0.78). The largest differences between marginal/unsatisfactory and satisfactory PGY3s were ethical behavior (1.17), incorporating feedback (1.03), and professionalization (0.96). For PGY2s and PGY3s, no subcompetencies had outstanding discrimination. CONCLUSIONS: Marginal/unsatisfactory pediatric residents had different subcompetency gaps at different training levels. While PGY1s may have global deficits, senior residents may have different performance deficiencies requiring individualized counseling and targeted performance improvement plans. PMID- 28640032 TI - Trends in P Value, Confidence Interval, and Power Analysis Reporting in Health Professions Education Research Reports: A Systematic Appraisal. AB - PURPOSE: To characterize reporting of P values, confidence intervals (CIs), and statistical power in health professions education research (HPER) through manual and computerized analysis of published research reports. METHOD: The authors searched PubMed, Embase, and CINAHL in May 2016, for comparative research studies. For manual analysis of abstracts and main texts, they randomly sampled 250 HPER reports published in 1985, 1995, 2005, and 2015, and 100 biomedical research reports published in 1985 and 2015. Automated computerized analysis of abstracts included all HPER reports published 1970-2015. RESULTS: In the 2015 HPER sample, P values were reported in 69/100 abstracts and 94 main texts. CIs were reported in 6 abstracts and 22 main texts. Most P values (>=77%) were <=.05. Across all years, 60/164 two-group HPER studies had >=80% power to detect a between-group difference of 0.5 standard deviations. From 1985 to 2015, the proportion of HPER abstracts reporting a CI did not change significantly (odds ratio [OR] 2.87; 95% CI 1.04, 7.88) whereas that of main texts reporting a CI increased (OR 1.96; 95% CI 1.39, 2.78). Comparison with biomedical studies revealed similar reporting of P values, but more frequent use of CIs in biomedicine. Automated analysis of 56,440 HPER abstracts found 14,867 (26.3%) reporting a P value, 3,024 (5.4%) reporting a CI, and increased reporting of P values and CIs from 1970 to 2015. CONCLUSIONS: P values are ubiquitous in HPER, CIs are rarely reported, and most studies are underpowered. Most reported P values would be considered statistically significant. PMID- 28640033 TI - How Attending Physician Preceptors Negotiate Their Complex Work Environment: A Collective Ethnography. AB - PURPOSE: To generate an empiric, detailed, and updated view of the attending physician preceptor role and its interface with the complex work environment. METHOD: In 2013, the authors conducted a modified collective ethnography with observations of internal medicine medical teaching unit preceptors from two university hospitals in Canada. Eleven observers conducted 32 observations (99.5 hours) of 26 preceptors (30 observations [93.5 hours] of 24 preceptors were included in the analysis). An inductive thematic approach was used to analyze the data with further axial coding to identify connections between themes. Four individuals coded the main data set; differences were addressed through discussion to achieve consensus. RESULTS: Three elements or major themes of the preceptor role were identified: (1) competence or the execution of traditional physician competencies, (2) context or the extended medical teaching unit environment, and (3) conduct or the manner of acting or behaviors and attitudes in the role. Multiple connections between the elements emerged. The preceptor role appeared to depend on the execution of professional skills (competence) but also was vulnerable to contextual factors (context) independent of these skills, many of which were unpredictable. This vulnerability appeared to be tempered by preceptors' use of adaptive behaviors and attitudes (conduct), such as creativity, interpersonal skills, and wellness behaviors. CONCLUSIONS: Preceptors not only possess traditional competencies but also enlist additional behaviors and attitudes to deal with context-driven tensions and to negotiate their complex work environment. These skills could be incorporated into role training, orientation, and mentorship. PMID- 28640034 TI - Using a Simulation of a Frustrated Faculty Member During Department Chair Searches: A Proof of Concept Project. AB - PROBLEM: Vitae reviews, interviews, presentations, and reference checks are typical components of searches used to screen and select new department chairs/heads, but these strategies may fail to identify leaders who can communicate effectively with faculty in common, tense situations. APPROACH: Between May 2015 and November 2016, the authors piloted simulation scenarios in four department chair searches at Penn State College of Medicine/Penn State Health to assess candidates' skill at handling common, challenging situations with faculty members. In the scenarios, a frustrated faculty member complains that he/she has too little time for academic pursuits. Candidates were provided the scenario approximately two weeks in advance. They were asked to explain their goals prior to the 10-minute simulation, do the simulation, and then debrief with the search committees, who observed the interactions. OUTCOMES: Approximately two thirds (20/29; 69.0%) of candidates were judged to have successfully passed the simulation and were ultimately advanced. In most cases, the simulations revealed wide variation in candidates' style, substance, and even underlying values that were not otherwise identified through the other parts of the recruitment and screening process. In some cases, candidates who performed well during group and individual interviews did poorly during simulations. NEXT STEPS: The authors will build a larger pool of simulation scenario cases, create a rubric, and formally measure interrater reliability. They will study whether the strategy successfully identifies chairs who will be skilled at navigating common faculty challenges, and if this skill results in greater faculty satisfaction, engagement, and retention. PMID- 28640035 TI - The Professionalism and Integrity in Research Program: Description and Preliminary Outcomes. AB - Violations of rules and regulations in research can cause significant problems for human participants, animal subjects, data integrity, institutions, and investigators. The Professionalism and Integrity in Research Program (PI Program) provides remediation training that addresses the root causes of violations of rules and regulations in research. Through assessments, a three-day workshop, and follow-up coaching calls, the PI Program teaches evidence-based decision-making strategies designed to help researchers to compensate for bias, uncertainty, and work-related stress, and foster the skills needed to oversee research projects in today's complex regulatory environments. Across its first three years (2013 2015), the program trained 39 researchers from 24 different institutions in the United States. Participant evaluations of the program's faculty and workshop content were highly positive (4.7-4.8 and 4.5-4.6, respectively, on a 5-point scale). Preliminary program outcome assessment using validated measures of professional decision making and cognitive distortions in a pre- and postworkshop design indicated significant improvements. A follow-up survey of participants found statistically significant increases in a variety of target behaviors, including training research staff members to foster compliance and research quality, using standard operating procedures to support compliance and research integrity, performing self-audits of research operations, reducing job stressors, actively overseeing the work of the research team, and seeking help when experiencing uncertainty. Assessment of the PI Program was conducted with modest sample sizes, yet evaluation, outcome assessment, and self-reported survey data provided statistically significant evidence of effectiveness in achieving program goals. PMID- 28640036 TI - A Constructive Reframing of Student Roles and Systems Learning in Medical Education Using a Communities of Practice Lens. AB - Health systems are in the midst of a transformation that is being driven by a variety of forces. This has important implications for medical educators because clinical practice environments play a key role in learning and professional development, and evolving health systems are beginning to demand that providers have "systems-ready" knowledge, attitudes, and skills. Such implications provide a clear mandate for medical schools to modify their goals and prepare physicians to practice flexibly within teams and effectively contribute to the improvement of health care delivery. In this context, the concepts of value-added medical education, authentic student roles, and health systems science are emerging as increasingly important. In this Article, the authors use a lens informed by communities of practice theory to explore these three concepts, examining the implications that the communities of practice theory has in the constructive reframing of educational practices-particularly common student roles and experiences-and charting future directions for medical education that better align with the needs of the health care system. The authors apply several key features of the communities of practice theory to current experiential roles for students, then propose a new approach to students' clinical experiences-value added clinical systems learning roles-that provides students with opportunities to make meaningful contributions to patient care while learning health systems science at the patient and population level. Finally, the authors discuss implications for professional role formation and anticipated challenges to the design and implementation of value-added clinical systems learning roles. PMID- 28640037 TI - Epidemiology of Major Depressive Disorder Disability in the US Military: FY 2007 2012. AB - This study assesses the incidence of major depressive disorder (MDD) disability discharge and retirement in the Army, Navy, Marine Corps and Air Force and describes MDD comorbidity. Service members with a disability discharge for either MDD (n = 2,882) or any nonpsychiatric disability (n = 56,145), between fiscal years 2007 and 2012, were included in the study population. Those with MDD disability at first evaluation but not at last evaluation were excluded. The incidence of MDD disability discharge increased significantly in the Army and Air Force between fiscal years 2007 and 2012. MDD disability retirement significantly increased in the Army, Navy, and Air Force. Females, and those who experienced at least one deployment, had higher incidence rates of MDD disability discharge. All services included spinal diseases and posttraumatic stress disorder in their top five comorbid categories. Given the association between trauma and MDD, further research into the role of both combat exposure and injury on MDD is merited. PMID- 28640038 TI - Impact of Noise and Noise Reduction on Processing Effort: A Pupillometry Study. AB - OBJECTIVES: Speech perception in adverse listening situations can be exhausting. Hearing loss particularly affects processing demands, as it requires increased effort for successful speech perception in background noise. Signal processing in hearing aids and noise reduction (NR) schemes aim to counteract the effect of noise and reduce the effort required for speech recognition in adverse listening situations. The present study examined the benefit of NR schemes, applying a combination of a digital NR and directional microphones, for reducing the processing effort during speech recognition. DESIGN: The effect of noise (intelligibility level) and different NR schemes on effort were evaluated by measuring the pupil dilation of listeners. In 2 different experiments, performance accuracy and peak pupil dilation (PPD) were measured in 24 listeners with hearing impairment while they performed a speech recognition task. The listeners were tested at 2 different signal to noise ratios corresponding to either the individual 50% correct (L50) or the 95% correct (L95) performance level in a 4-talker babble condition with and without the use of a NR scheme. RESULTS: In experiment 1, the PPD differed in response to both changes in the speech intelligibility level (L50 versus L95) and NR scheme. The PPD increased with decreasing intelligibility, indicating higher processing effort under the L50 condition compared with the L95 condition. Moreover, the PPD decreased when the NR scheme was applied, suggesting that the processing effort was reduced. In experiment 2, 2 hearing aids using different NR schemes (fast-acting and slow acting) were compared. Processing effort changed as indicated by the PPD depending on the hearing aids and therefore on the NR scheme. Larger PPDs were measured for the slow-acting NR scheme. CONCLUSIONS: The benefit of applying an NR scheme was demonstrated for both L50 and L95, that is, a situation at which the performance level was at a ceiling. This opens the opportunity for new means of evaluating hearing aids in situations in which traditional speech reception measures are shown not to be sensitive. PMID- 28640040 TI - Letters. PMID- 28640039 TI - Levosimendan Prevents and Reverts Right Ventricular Failure in Experimental Pulmonary Arterial Hypertension. AB - BACKGROUND: We investigated whether chronic levosimendan treatment can prevent and revert right ventricular (RV) failure and attenuate pulmonary vascular remodeling in a rat model of pulmonary arterial hypertension (PAH). METHODS AND RESULTS: PAH was induced in rats by exposure to SU5416 and hypoxia (SuHx). The rats were randomized to levosimendan (3 mg.kg.d) initiated before SuHx (n = 10, PREV), levosimendan started 6 weeks after SuHx (n = 12, REV), or vehicle treatment (n = 10, VEH). Healthy control rats received vehicle (n = 10, CONT). Ten weeks after SuHx, RV function was evaluated by echocardiography, magnetic resonance imaging, invasive pressure-volume measurements, histology, and biochemistry. Levosimendan treatment improved cardiac output (VEH vs. PREV 77 +/- 7 vs. 137 +/- 6 mL/min; P < 0.0001; VEH vs. REV 77 +/- 7 vs. 117 +/- 10 mL/min; P < 0.01) and decreased RV afterload compared with VEH (VEH vs. PREV 219 +/- 33 vs. 132 +/- 20 mm Hg/mL; P < 0.05; VEH vs. REV 219 +/- 33 vs. 130 +/- 11 mm Hg/mL; P < 0.01). In the PREV group, levosimendan restored right ventriculoarterial coupling (VEH vs. PREV 0.9 +/- 0.1 vs. 1.8 +/- 0.3; P < 0.05) and prevented the development of pulmonary arterial occlusive lesions (VEH vs. PREV 37 +/- 7 vs. 15 +/- 6% fully occluded lesions; P < 0.05). CONCLUSION: Chronic treatment with levosimendan prevents and reverts the development of RV failure and attenuates pulmonary vascular remodeling in a rat model of PAH. PMID- 28640044 TI - Nurses: We can lead and transform palliative care. PMID- 28640045 TI - Simulation in nursing education. PMID- 28640046 TI - Urgent care: A growing healthcare landscape. PMID- 28640050 TI - Healing old wounds. PMID- 28640051 TI - Emotional intelligence: Five pieces to the puzzle. PMID- 28640052 TI - Limb-girdle muscular dystrophy: What nurses need to know. PMID- 28640053 TI - Team huddles: A winning strategy for safety. PMID- 28640054 TI - Mycoplasma genitalium. PMID- 28640055 TI - Letter to a patient. PMID- 28640056 TI - Beware of amnesic shellfish poisoning. PMID- 28640057 TI - Online resources for victims of sexual violence. PMID- 28640059 TI - Preventing falls in hospitalized older adults. PMID- 28640060 TI - Individualized Estimation of Physical Activity in Older Adults with Type 2 Diabetes. AB - PURPOSE: Compare physical activity intensity in older adults with type 2 diabetes mellitus (T2DM) using individualized, relative cutpoints with standard, absolute cutpoints. METHODS: One hundred older adults with T2DM (68.9 +/- 5.1 yr, 65% male, 32.7 +/- 6.3 kg.m, 7.2% +/- 1.1% glycosylated hemoglobin) completed a two speed walking protocol (varying, walking between 1 and 2.5 mph), followed by a modified Bruce peak exercise test. Participants wore an accelerometer-based physical activity monitor at their waist, and oxygen consumption was measured. Afterward, participants wore the activity monitor for seven consecutive days. Linear equations for each individual were derived from the activity counts and energy expenditure measured during the walking protocol. Relative intensity cutpoints were calculated by using standard classifications of 44% oxygen consumption (VO2)peak to determine moderate and 59% VO2peak to determine vigorous intensity. Average time spent in intensity categories per day were calculated using relative and absolute (moderate, 2020 counts per minute; vigorous, 5999 counts per minute) cutpoints. t-Tests were run to compare estimated time spent in intensity category by cutpoint. RESULTS: Mean VO2peak was 17.9 +/- 4.5 mL.kg.min and relative cutpoints were, on average, 1033.5 counts per minute (SD, 741.2 counts per minute) for moderate and 2211.7 counts per minute (SD, 1512.4) for vigorous activity. Using the relative cutpoints, participants accumulated an average of 157.2 min (SD, 73.7 min) of light, 33.3 min (SD, 35.6 min) of moderate, and 15.6 min (SD, 26.7 min) of vigorous activity per day. Use of the absolute cutpoint resulted in significantly different estimations based on intensity category: light, 200.7 min (SD, 74.7 min; P < 0.05); moderate, 7.1 min (SD, 9.2 min; P < 0.05); and vigorous, 0.006 min (SD, 0.04 min; P < 0.05) of activity per day. CONCLUSIONS: These results suggest utilization of absolute cutpoints may underestimate daily relative intensity levels of physical activity in older adults with T2DM. This misclassification may improperly inform dose response relationships and population-based prevalence of physical activity in these and may extend to other clinically important populations. PMID- 28640061 TI - Intermittent Standing but not a Moderate Exercise Bout Reduces Postprandial Glycemia. AB - PURPOSE: This study aimed to determine whether minimum recommended moderate-to vigorous physical activity (MVPA; 30-min bout of continuous moderate-intensity walking) is sufficient to counteract the detrimental effects of prolonged sitting on postprandial metabolism and if there are any effects of breaking up sitting with intermittent standing when achieving minimum recommended MVPA. METHODS: Fourteen (n = 14) physically inactive healthy adult males underwent four intrahospital 27-h interventions: 9-h continuous sitting (SIT), 15-min standing bouts every 30 min during the 9-h sitting (STAND), 30-min moderate-intensity walking bout followed by 8.5 h of sitting (MVPA), and 30-min moderate-intensity walking bout followed by 15-min standing bouts every 30 min during 8.5 h of sitting (MVPA + STAND). Three standardized meals on intervention day (day 1) and breakfast the following day (day 2) were served. RESULTS: Cumulative postprandial glucose response (incremental area under the curve) was lower in STAND versus SIT (?27%, P = 0.04, effect size [ES] = -0.7) because of decreases in postprandial glucose after breakfast on day 1 (STAND vs SIT: ?40%, P = 0.01, ES = -0.7) and day 2 (STAND vs SIT: ?33%, P = 0.06, ES = -0.6). STAND did not affect postprandial insulin responses. Cumulative postprandial insulin response was lower in MVPA versus SIT (?18%, P = 0.03, ES = -0.3) and MVPA + STAND versus SIT (?26%, P = 0.02, ES = -0.4) because of expected exercise-induced decreases in postprandial insulin after breakfast on day 1 only (MVPA vs SIT: ?36%, P = 0.003, ES = -0.7; MVPA + STAND vs SIT: ?43%, P = 0.0001, ES = -0.8). CONCLUSION: Breaking up prolonged sitting with nonambulatory standing across 9 h acutely reduced postprandial glycemic response during and the day after the intervention independent of insulin levels, whereas a 30-min MVPA bout did not. PMID- 28640062 TI - An Atmospheric Pressure Chemical Ionization MS/MS Assay Using Online Extraction for the Analysis of 11 Cannabinoids and Metabolites in Human Plasma and Urine. AB - BACKGROUND: Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Delta9 tetrahydrocannabinol (THC). Even less is known about other active cannabinoids. METHODS: To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11 hydroxy-Delta9-tetrahydrocannabinol, 11-nor-Delta9-tetrahydrocannabinol-9 carboxylic acid, 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Delta9 tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Delta9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma. RESULTS: In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r > 0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (<15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy. CONCLUSIONS: This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice. PMID- 28640063 TI - Pharmacodynamic Monitoring of Tacrolimus-Based Immunosuppression in CD14+ Monocytes After Kidney Transplantation. AB - BACKGROUND: Monocytes significantly contribute to ischemia-reperfusion injury and allograft rejection after kidney transplantation. However, the knowledge about the effects of immunosuppressive drugs on monocyte activation is limited. Conventional pharmacokinetic methods for immunosuppressive drug monitoring are not cell type-specific. In this study, phosphorylation of 3 signaling proteins was measured to determine the pharmacodynamic effects of immunosuppression on monocyte activation in kidney transplant patients. METHODS: Blood samples from 20 kidney transplant recipients were monitored before and during the first year after transplantation. All patients received induction therapy with basiliximab, followed by tacrolimus (TAC), mycophenolate mofetil, and prednisolone maintenance therapy. TAC whole-blood predose concentrations were determined using an antibody conjugated magnetic immunoassay. Samples were stimulated with phorbol 12 myristate 13-acetate (PMA)/ionomycin, and phosphorylation of p38MAPK, ERK, and Akt in CD14 monocytes was quantified by phospho-specific flow cytometry. RESULTS: Phosphorylation of p38MAPK and Akt in monocytes of immunosuppressed recipients was lower after 360 days compared with before transplantation in the unstimulated samples [mean reduction in median fluorescence intensity 36%; range -28% to 77% for p-p38MAPK and 20%; range -22% to 53% for p-Akt; P < 0.05]. P-ERK was only decreased at day 4 after transplantation (mean inhibition 23%; range -52% to 73%; P < 0.05). At day 4, when the highest whole-blood predose TAC concentrations were measured, p-p38MAPK and p-Akt, but not p-ERK, correlated inversely with TAC (rs = -0.65; P = 0.01 and rs = -0.58; P = 0.03, respectively). CONCLUSIONS: Immunosuppressive drug combination therapy partially inhibits monocyte activation pathways after kidney transplantation. This inhibition can be determined by phospho-specific flow cytometry, which enables the assessment of the pharmacodynamic effects of immunosuppressive drugs in a cell type-specific manner. PMID- 28640064 TI - Predictors of Local Recurrence in Patients With Myxofibrosarcoma. AB - OBJECTIVES: Myxofibrosarcoma (MFS) is reported to have a higher risk of local recurrence (LR) following definitive surgical excision relative to other soft tissue sarcomas. We reviewed our clinical experience treating MFS to investigate predictors of LR. MATERIALS AND METHODS: We retrospectively reviewed treatment outcomes for MFS patients treated at our institution between 1999 and 2015. A total of 52 patients were identified. Median age was 65 years (range, 21 to 86 y). Site of disease was: upper extremity (27%), lower extremity (46%), trunk (15%), pelvic (8%), and head and neck (4%). Patients had low, intermediate, high grade, and unknown grade in: 23%, 8%, 67%, and 2% of tumors, respectively. Tumors were categorized as <=5 cm (35%), >5 cm (56%), or unknown size (9%). In total, 71% received radiotherapy: 19% preoperative, 50% postoperative, and 2% both. All patients underwent surgery. Margins were negative in 71%, close/positive in 21%, and unknown in 8%. In total, 27% of patients received chemotherapy. Univariate Cox regression analysis was utilized to determine associations between clinical and treatment factors with LR. RESULTS: Median follow-up time was 2.9 years (range, 0.4 to 14.3 y). The 3-year actuarial LR, distant metastasis, and overall survival were: 31%, 15%, and 87%, respectively. Predictors of LR were patient age greater than or equal to the median of 65 years (hazard ratio, 13.46, 95% confidence interval, 1.71-106.18, P=0.013), and having close/positive tumor margins (hazard ratio, 3.4, 95% confidence interval, 1-11.53, P=0.049). CONCLUSIONS: In this institutional series of MFS older age and positive/close margins were significantly associated with a higher risk of LR. PMID- 28640066 TI - The Evolution of Oxygen Carrier Solutions for Machine Perfusion. PMID- 28640065 TI - Effectiveness of an Integrated Approach to HIV and Hypertension Care in Rural South Africa: Controlled Interrupted Time-Series Analysis. AB - BACKGROUND: South Africa faces a dual burden of HIV/AIDS and noncommunicable diseases. In 2011, a pilot integrated chronic disease management (ICDM) model was introduced by the National Health Department into selected primary health care (PHC) facilities. The objective of this study was to assess the effectiveness of the ICDM model in controlling patients' CD4 counts (>350 cells/mm) and blood pressure [BP (<140/90 mm Hg)] in PHC facilities in the Bushbuckridge municipality, South Africa. METHODS: A controlled interrupted time-series study was conducted using the data from patients' clinical records collected multiple times before and after the ICDM model was initiated in PHC facilities in Bushbuckridge. Patients >=18 years were recruited by proportionate sampling from the pilot (n = 435) and comparing (n = 443) PHC facilities from 2011 to 2013. Health outcomes for patients were retrieved from facility records for 30 months. We performed controlled segmented regression to model the monthly averages of individuals' propensity scores using autoregressive moving average model at 5% significance level. RESULTS: The pilot facilities had 6% greater likelihood of controlling patients' CD4 counts than the comparison facilities (coefficient = 0.057; 95% confidence interval: 0.056 to 0.058; P < 0.001). Compared with the comparison facilities, the pilot facilities had 1.0% greater likelihood of controlling patients' BP (coefficient = 0.010; 95% confidence interval: 0.003 to 0.016; P = 0.002). CONCLUSIONS: Application of the model had a small effect in controlling patients' CD4 counts and BP, but showed no overall clinical benefit for the patients; hence, the need to more extensively leverage the HIV program for hypertension treatment. PMID- 28640067 TI - Taking Kidneys for Granted? Time to Reflect on the Choices We Make. PMID- 28640069 TI - Exosomes: From Cell Debris to Potential Biomarkers in Transplantation. PMID- 28640070 TI - Early Outcomes of the New UK Deceased Donor Kidney Fast-Track Offering Scheme. AB - BACKGROUND: The UK Kidney Fast-Track Scheme (KFTS) was introduced in 2012 to identify kidneys at high risk of discard and to rapidly facilitate transplantation. A retrospective analysis of kidneys transplanted through the KFTS was undertaken. METHODS: UK Transplant Registry data were collected on deceased donor kidneys implanted between November 1, 2012, and April 30, 2015, (donation after brain death [DBD] donors) and March 1, 2013, and April 30, 2015 (donation after circulatory death [DCD] donors). Posttransplant outcomes included 1-year estimated glomerular filtration rate and death-censored graft survival (DCGS). RESULTS: Over the study period, 523 deceased donor kidneys were transplanted through the KFTS and 4174 via the standard National Kidney Allocation Scheme (NKAS). Kidneys in the KFTS were more likely to be from older diabetic donors, had a higher frequency of poor ex vivo perfusion, had longer cold ischemic times, and were transplanted into older recipients. One-year DCGS of KFTS and NKAS DBD donor kidneys was similar (94% vs 95%; P = 0.70), but for DCD donor kidneys, DCGS was lower in those allocated via the KFTS (91% versus 95%; P = 0.04). Median 1-year estimated glomerular filtration rate for DBD donor kidneys was lower in those allocated via the KFTS (49 vs 52 mL/min per 1.73 m; P = 0.01), but for DCD kidneys, there was no difference (45 vs 48 mL/min per 1.73 m; P = 0.10). CONCLUSIONS: Although KFTS kidneys have less favorable donor, graft, and recipient risk factors than NKAS kidneys, short-term graft and patient outcomes are acceptable. National schemes that identify and rapidly offer kidneys at high risk of discard may contribute to minimizing the unnecessary discard of organs. PMID- 28640071 TI - Worsening of Myasthenia Gravis After Administration of Antipsychotics for Treatment of Schizophrenia: A Case Report and Review of Literature. PMID- 28640072 TI - Improvement in mortality at a National Burn Centre since 2000: Was it the result of increased resources? AB - The aim of this study was to find out whether the charging costs (calculated using interventional burn score) increased as mortality decreased.During the last 2 decades, mortality has declined significantly in the Linkoping Burn Centre. The burn score that we use has been validated as a measure of workload and is used to calculate the charging costs of each burned patient.We compared the charging costs and mortality in 2 time periods (2000-2007 and 2008-2015). A total of 1363 admissions were included. We investigated the change in the burn score, as a surrogate for total costs per patient. Multivariable regression was used to analyze risk-adjusted mortality and burn score.The median total body surface area % (TBSA%) was 6.5% (10-90 centile 1.0-31.0), age 33 years (1.3-72.2), duration of stay/ TBSA% was 1.4 days (0.3-5.3), and 960 (70%) were males. Crude mortality declined from 7.5% in 2000-2007 to 3.4% in 2008-2015, whereas the cumulative burn score was not increased (P = .08). Regression analysis showed that risk adjusted mortality decreased (odds ratio 0.42, P = .02), whereas the adjusted burn score did not change (P = .14, model R 0.86).Mortality decreased but there was no increase in the daily use of resources as measured by the interventional burn score. The data suggest that the improvements in quality obtained have been achieved within present routines for care of patients (multidisciplinary/orientated to patients' safety). PMID- 28640073 TI - Reimbursement and use of intensity-modulated radiation therapy for prostate cancer. AB - The use of intensity-modulated radiation therapy (IMRT) for prostate cancer increased through the mid-2000s, in association with acquisition of the devices by large urology groups. More recently, reimbursement for IMRT in the office setting (generally representing freestanding facilities owned by physicians) has been declining. The aim of the study was to examine trends in IMRT use and related payments in the office versus hospital outpatient setting over time.In this retrospective cohort study, a total of 66,967 men aged 66 years or older, with newly diagnosed prostate cancer from 2007 through 2012 were identified in a 20% national sample of Medicare claims. IMRT use in the office versus hospital outpatient setting was examined over time, adjusted for patient characteristics using multivariable logistic regression models. Mean reimbursement for IMRT treatments and total IMRT-related payments were plotted by year.IMRT use increased from 28.6% to 38.0% of newly diagnosed men with prostate cancer over the study period, exclusively related to growth in the office setting. In particular, use in the office setting increased from 13.2% in 2007 to 22.1%, whereas use in the hospital outpatient setting remained essentially steady throughout the period around 15%. During the same period mean reimbursement for IMRT in the office setting declined from $504 per individual radiation treatment to $381, whereas it increased from $283 to $380 in the hospital outpatient setting. However, total IMRT-related payments in the office setting increased through 2011 due to increased utilization, falling only in 2012 (to $35.7 million from $48.3 million in 2011) related both to continued declines in reimbursement and a large reduction in new cases of prostate cancer.In conclusion, use of IMRT in the physician office setting in men diagnosed with prostate cancer has continued to increase in the face of declining reimbursement. Total payments for IMRT fell only in 2012, following a substantial reduction in new cases of prostate cancer. PMID- 28640074 TI - Bioinformatics analysis of key genes and pathways for hepatocellular carcinoma transformed from cirrhosis. AB - OBJECTIVE: We aimed to identify some pivotal genes and pathways for hepatocellular carcinoma (HCC) transformation from cirrhosis and explore potential targets for treatment of the disease. METHODS: The GSE17548 microarray data were downloaded from Gene Expression Omnibus database, and 37 samples (20 cirrhosis and 17 HCC samples) were used for analysis. The differentially expressed genes (DEGs) in HCC tissues were compared with those in cirrhosis tissues and analyzed using the limma package. Gene ontology-biological process and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed using ClueGO and CluePedia tool kits, and the key KEGG pathway was analyzed using the R package pathview. The regulatory factor miRNA of DEGs was extracted from 3 verified miRNAs-target databases using the multiMiR R package. Moreover, a protein-protein interaction (PPI) network was constructed using the Cytoscape software. RESULTS: DEGs including cyclin-dependent Kinase 1 (CDK1), PDZ binding kinase (PBK), ribonucleotide reductase M2 (RRM2), and abnormal spindle homolog, and microcephaly-associated drosophila (ASPM) were the hub proteins with higher degrees in the PPI network. The cell cycle pathway (CDK1 enriched) and p53 signaling pathway (CDK1 and RRM2 enriched) were significantly enriched by DEGs. CONCLUSION: CDK1, PBK, RRM2, and ASPM may be key genes for HCC transformation from cirrhosis. Furthermore, cell cycle and p53 signaling pathways may play vital mediatory roles; CDK1 may play crucial roles in HCC transformed from cirrhosis via cell cycle and p53 signaling pathways, and RRM2 might be involved in HCC transformed from cirrhosis via the p53 signaling pathway. PMID- 28640075 TI - Maximum voltage gradient technique for optimization of ablation for typical atrial flutter with zero-fluoroscopy approach. AB - Radiofrequency catheter ablation (RFCA) is an established effective method for the treatment of typical cavo-tricuspid isthmus (CTI)-dependent atrial flutter (AFL). The introduction of 3-dimensional electro-anatomic systems enables RFCA without fluoroscopy (No-X-Ray [NXR]). The aim of this study was to evaluate the feasibility and effectiveness of CTI RFCA during implementation of the NXR approach and the maximum voltage-guided (MVG) technique for ablation of AFL.Data were obtained from prospective standardized multicenter ablation registry. Consecutive patients with the first RFCA for CTI-dependent AFL were recruited. Two navigation approaches (NXR and fluoroscopy based as low as reasonable achievable [ALARA]) and 2 mapping and ablation techniques (MVG and pull-back technique [PBT]) were assessed. NXR + MVG (n = 164; age: 63.7 +/- 9.5; 30% women), NXR + PBT (n = 55; age: 63.9 +/- 10.7; 39% women); ALARA + MVG (n = 36; age: 64.2 +/- 9.6; 39% women); and ALARA + PBT (n = 205; age: 64.7 +/- 9.1; 30% women) were compared, respectively. All groups were simplified with a 2 catheter femoral approach using 8-mm gold tip catheters (Osypka AG, Germany or Biotronik, Germany) with 15 min of observation. The MVG technique was performed using step-by-step application by mapping the largest atrial signals within the CTI.Bidirectional block in CTI was achieved in 99% of all patients (P = NS, between groups). In NXR + MVG and NXR + PBT groups, the procedure time decreased (45.4 +/- 17.6 and 47.2 +/- 15.7 min vs. 52.6 +/- 23.7 and 59.8 +/- 24.0 min, P < .01) as compared to ALARA + MVG and ALARA + PBT subgroups. In NXR + MVG and NXR + PBT groups, 91% and 98% of the procedures were performed with complete elimination of fluoroscopy. The NXR approach was associated with a significant reduction in fluoroscopy exposure (from 0.2 +/- 1.1 [NXR + PBT] and 0.3 +/- 1.6 [NXR + MVG] to 7.7 +/- 6.0 min [ALARA + MVG] and 9.1 +/- 7.2 min [ALARA + PBT], P < .001). The total application time significantly decreased in the MVG technique subgroup both in NXR and ALARA (P < .01). No major complications were observed in either groups.Complete elimination of fluoroscopy is feasible, safe, and effective during RFCA of CTI in almost all AFL patients without cardiac implanted electronic devices. The most optimal method for RFCA of CTI-dependent AFL seems to be MVG; however, it required validation of optimal RFCA's parameters with clinical follow-up. PMID- 28640076 TI - Efficacy of methylphenidate for the treatment of mental sequelae after traumatic brain injury. AB - BACKGROUND: This study aimed to evaluate the effect of methylphenidate for treating mental sequelae after traumatic brain injury (TBI). METHODS: Thirty-six patients with TBI were randomly divided into the intervention group and placebo group. The participants in the intervention group received methylphenidate, while subjects in the placebo group were administered a placebo. This study was conducted from January 2014 to December 2016. The outcome measurements included Mental Fatigue Scale, Choice Reaction Time, Compensatory Tracking Task, Mental Arithmetic Test, Digit Symbol Substitution Test, Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), and Hamilton Rating Scale for Depression. In addition, safety was also recorded and assessed. RESULTS: A total of 33 subjects completed the study. Methylphenidate showed greater efficacy than placebo, with decreased scores on the Mental Fatigue Scale, Choice Reaction Time, and Compensatory Tracking Task in the intervention group compared to the placebo group (P < .01, respectively). Furthermore, increased scores on the Mental Arithmetic Test, Digit Symbol Substitution Test, and MMSE in the intervention group, compared to those in the placebo group (P < .01 respectively), were observed. In addition, a significant difference in the scores on the BDI (P = .04) and Hamilton Rating Scale for Depression (P = .005) was observed between the 2 groups. The safety at the end of the 30 week-treatment was similar between the 2 groups (P > .05). CONCLUSION: The results of this study demonstrated that methylphenidate could effectively improve mental fatigue and cognitive functions in patients with TBI. PMID- 28640077 TI - Improvement of peripheral artery disease with Sildenafil and Bosentan combined therapy in a patient with limited cutaneous systemic sclerosis: A case report. AB - RATIONALE: Sildenafil, a phosphodiesterase-5-inhibitor and Bosentan, an endothelin-1-receptor antagonist combined therapy could have beneficial effect in systemic sclerosis (SSc) patients with peripheral artery disease. PATIENT CONCERNS: We report a case of a 48-year-old Black woman, who developed severe left limb claudication and walking limitation following a left femoropopliteal bypass occlusion in 2014. She was a heavy smoker and had a history of right middle cerebral artery ischemic stroke and bilateral Raynaud phenomenon. DIAGNOSES: According to the American College of Rheumatology/European League Against Rheumatism-2013 criteria, diagnosis of limited cutaneous SSc was retained with macrovascular lesions. She was referred for investigation of left limb claudication on treadmill using transcutaneous oxygen pressure measurement during exercise to argue for the vascular origin of the walking impairment. She had a severe left limb ischemia and the maximum walking distance (MWD) she reached was 118 m in March 2015 despite the medical optimal treatment and walking rehabilitation. INTERVENTIONS: Sildenafil, 20 mg tid, was introduced due to active digital ulcers. In July 2015, the MWD increased to 288 m, then to 452 m in December 2015. Adding Bosentan to Sildenafil to prevent recurrent digital ulcers resulted in an MWD of 1576 m. OUTCOMES: Recently, the patient is treated with the combined therapy. She has no more pain during walking and his quality of life has improved. LESSONS: Sildenafil and Bosentan combined therapy was associated in our case with an improvement of MWD without adverse effect. Further clinical trials are necessary to confirm our original observation. PMID- 28640078 TI - Prospective observational pharmacogenetic study of side effects induced by intravenous morphine for postoperative analgesia. AB - Nausea and vomiting are probably the most unpleasant side effects that occur when morphine used. A number of studies have investigated the effect on pain relief of single nucleotide polymorphisms (SNPs) in genes involved in morphine's metabolism, distribution, binding, and cellular action. The mechanism through which morphine causes nausea and vomiting has not been elucidated clearly. We examined all the reported SNPs which are associated with the complications of morphine, including SNPs in genes for phase I and phase II metabolic enzymes, ABC binding cassette drug transporters, kappa and delta opioid receptors, and ion channels implicated in the postreceptor action of morphine.A prospective, observational study in 129 female patients was conducted to investigate the effect of 14 SNPs on nausea or vomiting induced by intravenous patient-controlled analgesia (IVPCA) with morphine after gynecology surgery. Clinical phenotype, subjective complaints, and objective observations were recorded. DNA from blood samples was used to record the SNPs. Eleven SNPs were then analyzed further.No significant association with the presence of phenotype (nausea or vomiting) versus genotype was observed (all P > .05). No significant association with severity of phenotype versus genotype of the 11 SNPs was observed except for unadjusted data for rs2737703.There was no significant difference between severity or incidence of IVPCA morphine-induced nausea and vomiting and genotype (11 SNPs). Further study should perhaps be focused on mRNA and proteinomics rather than SNPs. PMID- 28640079 TI - A genome-wide association scan of biological processes involved in oral lichen planus and oral squamous cell carcinoma. AB - BACKGROUND: In this study, the molecular mechanisms underlying malignant transformation from oral lichen planus (OLP) to oral squamous cell carcinoma (OSCC) were examined. METHODS: High-throughput sequencing of long noncoding RNAs (lncRNAs) and mRNAs of normal subjects and patients with OLP and OSCC was conducted. RNA-seq reads were mapped, lncRNA and mRNA transcripts were assembled, and expression levels were estimated. The targets of lncRNAs were predicted. Finally, Gene Ontology (GO) and pathway enrichment analyses of differentially expressed genes (DEGs) and lncRNA targets were performed. RESULTS: High-quality sequence data were generated and the mapping ratios for OSCC, normal, and OLP samples were high. In total, 820, 656, and 582 DEGs were obtained from OPL vs. normal, OSCC vs. normal, and OSCC vs. OPL, respectively. A total of 1721 known lncRNAs and 133 predicted lncRNAs and targets were obtained. Keratinization was significantly enriched by OSCC-related DEGs, but not OPL-related DEGs. The pathway of olfactory transduction was enriched by OPL- and OSCC-related DEGs. Defense response to virus and viral carcinogenesis were enriched by DEGs and lncRNA targets in all comparisons. GO term related to the metabolic process was enriched by lncRNA targets in the OPL vs normal comparison, and antigen processing and presentation via MHC class I was significantly enriched by lncRNA targets in the other 2 comparisons. CONCLUSION: Keratinization and MHC class I antigen processing and presentation were activated during the malignant transformation from OLP to OSCC. Additionally, the olfactory transduction pathway may be important for OSCC. PMID- 28640080 TI - Immature enteric ganglion cells were observed in a 13-year-old colon signet ring cell carcinoma patient: A case report and literature review. AB - RATIONALE: All the enteric ganglion cells are fully mature by 2 to 5 years of age in human. No one had reported the presentation of immature enteric ganglion cells in elder ones. Colorectal carcinoma is also rare in the adolescent population. The coincidence of these 2 rare events in a 13-year-old boy has never been reported elsewhere, which may suggest some linkage between them. PATIENT CONCERN: A 13-year-old boy presented with progressive abdominal pain and melena for 3 months. Computed tomography (CT) scan and endoscopic ultrasonography showed significant abnormality in the transverse colon characteristic of marked mural thickening. The biopsy results indicated signet ring cell carcinoma. DIAGNOSES: A 13-year-old male patient with advanced colon signet ring cell carcinoma. In addition, immature but not mature ganglion cells could be observed in almost all of the slices of the resected nontumorous area of the specimen. INTERVENTIONS: The transverse colon tumor was resected and the subsequent histopathological examination confirmed the diagnosis of primary colon signet ring cell carcinoma. Then the patient received adjuvant chemotherapy and biological target therapies subsequently. OUTCOMES: After 6 cycles of adjuvant chemotherapy and biological target therapies, metastasis was however detected within a year. LESSONS: In this case, a 13-year-old male patient with advanced colon signet ring cell carcinoma were presented. Unexpectedly, immature ganglion cells could be observed in almost all of the slices of the resected nontumorous area of the specimen. It is critical to raise medical awareness and improve the diagnosis and treatment of the signet ring cell carcinoma. This malignancy and the immature ganglion cells may be associated, possibly caused by some unidentified genetic defects. Genome sequencing, histopathological examination, and long-term follow-up of young patients with related diseases, would help further reveal the potential relationship between tumorigenesis and ganglion cells' immaturity, contributing to understanding the molecular mechanisms. PMID- 28640081 TI - "Direct vision" operation of posterior atlantoaxial transpedicular screw fixation for unstable atlantoaxial fractures: A retrospective study. AB - BACKGROUND: The posterior screw fixation in atlas via posterior arch and lateral mass, also called C1 "pedicle" screw, combined with C2 pedicle screw fixiation has shown better biomechanical stability in unstable atlantoaxial fractures. However, its popularization has to fulfill the limitation imposed by anatomical characteristics. The aim of this study was to explore the manipulation, effect, and safety of the atlantoaxial transpedicular screw fixation under "direct vision" for the treatment of unstable atlantoaxial fracture. METHODS: All the patients diagnosed with unstable atlantoaxial fracture, who received surgery treatment of C1,C2 internal fixation from January 2012 to December 2014 were reviewed. Only these patients that were diagnosed with atlantoaxial unstability secondary to trauma and were treated with atlantoaxial transpedicular screw fixation under "direct vision" and iliac autograft were included. The safety of transpedicular screw placement, postoperative outcome, atlantoaxial stability, autograft fusion, and complications was observed and analyzed retrospectively. The pain visual analog scale (VAS) and the Japanese Orthopedic Association (JOA) score were used as surgical curative effect evaluation standards. RESULTS: We reviewed a total of 92 patients diagnosed with unstable atlantoaxial fracture, who received surgery treatment of C1,C2 internal fixation from January 2012 to December 2014, and 87 patients were treated with atlantoaxial transpedicular screw fixation under "direct vision" and were included this analysis. A total of 306 transpedicular screws in atlas and axis were placed successfully. All cases were followed-up >12 months. The overall breach rate was 11.36%. None of the breaches resulted in new-onset neurological sequela. The neurological status in cases with bilateral upper extremities numbness and lower extremities weakness had improved after surgery. At the latest follow-up, the neck VAS and JOA scores were significantly improved (P < .01) than those preoperatively. No cases demonstrated implantation failure and bone graft absorption on the postoperative x-ray films and CT scans. CONCLUSION: Atlantoaxial transpedicular screw fixation under "direct vision" and iliac autograft for the treatment of unstable atlantoaxial fracture has shown simple manipulation and efficient performance. Thus, the technique of C1-C2 fixation is feasible in treating unstable atlantoaxial fracture. PMID- 28640082 TI - The reliability and validity of a new professionalism assessment scale for young health care workers. AB - With the development of medical technique, many medical challenges have been solved. This cross-sectional study was aimed to assess the reliability and validity of a new developed scale for assessing the professionalism of young health care workers.This cross-sectional population-based study was conducted based on cluster sampling method in 2015. The participants were from 2 medical centers of Nantong city of Jiangsu province in China. The internal consistency reliability was assessed using Cronbach's alpha and split-half reliability coefficients. Construct validity was analyzed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Content, convergent, and discriminant validities were also assessed in this study.Total 749 individuals aged 29.09 +/- 3.91 years old participated in this investigation. There were 745 valid questionnaires and 730 were complete. Cronbach's alpha value (0.944) and the split-half reliability coefficient (0.873) reflected satisfactory internal consistency reliability of this new professionalism assessment scale. EFA extracted a 7-factor model. About 63.4% of the total variance was explained by these factors. However, CFA showed a good model fit after excluding the items with factor loading lower than 0.5. Good discriminant validity of this new developed professionalism assessment scale was also shown (P < .05). However, the evidences for content and convergent validity were not enough in this study.The results showed the satisfactory reliability of this new developed professionalism assessment scale. However, this scale should be modified to improve the validity in further studies. PMID- 28640083 TI - Clinical significance of plasma D-dimer in ovarian cancer: A meta-analysis. AB - BACKGROUND: D-dimer has been widely used for the diagnosis and prognosis of ovarian cancer, but there is still controversy on its prediction value of ovarian cancer. OBJECTIVES: To explore the clinical significance of plasma D-dimer level on ovarian cancer systematically. METHODS: Using PubMed, Cochrane Library, and Web of Science libraries, all the relevant studies for the diagnostic and prognostic value of plasma D-dimer for ovarian cancer and the relationship between elevated D-dimer level and venous thromboembolism (VTE) risk of ovarian cancer were searched till May 30, 2016. Standardized mean difference (SMD), odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) were appropriately pooled. RESULTS: A total of 15 eligible studies involving a total of 1437 cancer patients were included. No significant association was found between high D-dimer level and overall survival of patients with ovarian cancer (HR 1.32, 95% CI: 0.90-1.95, P = .044). However, subgroup analysis indicated that the sample sizes could explain the heterogeneity between studies. And elevated D-dimer could predict increased risk of mortality when the sample sizes were >100 (HR 1.800, 95% CI: 1.283-2.523, P = .845). Besides, plasma D-dimer level was significantly higher in malignant ovarian cancer patients compared with benign controls (SMD 0.774, 95% CI: 0.597-0.951, P = .39), higher in advanced ovarian cancer patients (International Federation of Gynecology and Obstetrics [FIGO] classification III and IV) than in early stage ovarian cancer patients (FIGO classification I and II, SMD 0.611, 95% CI: 0.373-0.849, P = .442). And high D-dimer level indicated high VTE risk (OR 4.068, 95% CI: 2.423-6.829, P = .629) of ovarian cancer patients. CONCLUSION: The plasma D-dimer level in ovarian cancer patients can predict the changes that correlated with disease progression and the VTE risk. But its predictive value for the prognosis of ovarian cancer was significantly dependent on the sample sizes. More well-designed studies with large sample sizes are needed to validate and update the findings of present study. PMID- 28640084 TI - Effect of dexmedetomidine and midazolam for flexible fiberoptic bronchoscopy in intensive care unit patients: A retrospective study. AB - This study aimed to investigate the clinical effectiveness of dexmedetomidine and midazolam for sedation of intensive care unit (ICU) patients requiring flexible fiberoptic bronchoscopy (FFB).This retrospective cohort study included 148 patients from the third ICU ward of the Second Affiliated Hospital of Harbin Medical University (Harbin, China) who received simultaneous invasive mechanical ventilation and FFB between March 2012 and December 2014. Patients were divided into dexmedetomidine (n = 72) and midazolam (n = 76) groups according to sedative mode. The sedative effects, incidence of adverse events, and bronchoscopist satisfaction scores were compared between groups.During FFB, total sedation time and total time of FFB were significantly shorter in the midazolam group (P < .001, respectively), with a lower percentage of these patients requiring propofol for remedial sedation (P < .001). The incidence of FFB-related adverse events (including bronchospasm, cough, and decreased oxygen saturation) was significantly higher in dexmedetomidine group compared with midazolam group (P = .007, .014 and .008, respectively). However, the incidence of other adverse events was not significantly different between groups. In addition, bronchoscopist satisfaction scores were significantly higher in the midazolam compared with dexmedetomidine group (7.72 +/- 1.65 vs 7.08 +/- 1.77; P = .030).For sedation of ICU patients during FFB, combination of midazolam and dexmedetomidine demonstrated an enhanced sedative effect, lower incidence of adverse events, and higher bronchoscopist satisfaction score compared with dexmedetomidine alone, thus represents a suitable alternative sedative for FFB patients. PMID- 28640085 TI - Familial lumbar Scheuermann disease with idiopathic scoliosis in China: First case report. AB - RATIONALE: Given that Scheuermann disease rarely occurs in the lumbar region and that the co-occurrence of Scheuermann disease and idiopathic scoliosis (IS) has not been reported-the etiology of Scheuermann disease and IS is not clear. In this case report, we present familaiar lumbar Scheuermann disease with IS, in a Chinese proband, who was successfully treated with surgery. PATIENT CONCERNS: A 16-year-old boy presented at the Second XiangYa Hospital of Central South University with a chief complaint of kyphotic deformity in the lower back for 4 years and obvious lower back pain. In addition, he complained of limited lumbar activity. And The proband's family history was obtained by routine inquiring. In this Chinese family with 17 members over 3 generations. The 3 patients (proband, proband's sister and father) shared the characteristics of vertebral wedging from L1 to L3 and a kyphosis Cobb angle of 37 degrees , 70 degrees , or 73 degrees , respectively. The main deformity of the proband's mother was at T7-L1 with a Cobb angle of 102 degrees in the coronal plane at T7-L1, thoracic kyphosis of 73 degrees , and lumbar lordosis of 62 degrees . DIAGNOSES: Scheuermann's disease. INTERVENTIONS: Clinical history, physical examination, laboratory tests, and radiographs of those in the pedigree were recorded, and the related literature was reviewed. The proband accepted osteotomy and orthopedic surgery for treatment. OUTCOMES: After 3 months of treatment, postoperative lateral radiographs showed a significantly improved sagittal vertical axis (SVA). The other patients were continued to be seen in follow-up visits. LESSONS: This series of lumbar Scheuermann patients with IS in a pedigree support the genetic contribution to Scheuermann disease. Therefore, this study provides some insight into the genetic etiology of Scheuermann disease with IS. PMID- 28640087 TI - Fatal lactic acidosis in hepatitis B virus-associated decompensated cirrhosis treated with tenofovir: A case report. AB - RATIONALE: Recently tenofovir disoproxil fumarate (TDF) has been widely used as a first-line therapy for chronic hepatitis B (CHB) infection. Although TDF demonstrates successful viral suppression, the possibility of renal failure and lactic acidosis has been proposed with TDF administration, especially in human immunodeficiency virus co-infected patients. However, TDF induced lactic acidosis has never been reported in CHB mono-infected patients. PATIENT CONCERNS: A 59 year-old man received TDF for hepatitis B associated with cirrhosis. After ten days of TDF administration, nausea, vomiting and abdominal pain developed. High anion gap acidosis with elevated lactate level (pH 7.341, pCO2 29.7 mmHg, HCO3- 15.6mmHg, lactate 3.2mmol/L, anion gap 15.4 mEq/L) was developed. DIAGNOSIS: With no infection, normal diagnostic paracentesis, and urinalysis together with high anion gap and increased blood lactate levels suggested lactic acidosis. INTERVENTIONS: TDF was stopped, and haemodialysis was performed to control lactic acidosis. OUTCOMES: Although stopping TDF instantly and treating lactic acidosis using hemodialysis, the patient died. LESSONS: Although, Fatal lactic acidosis is very rare in TDF patient, however, decompensated cirrhotic patients should be closely observed to keep the possibility of lactic acidosis in mind. PMID- 28640086 TI - Diagnostic value of 18F-fluorodeoxyglucose uptake parameters to differentiate rheumatoid arthritis from other types of arthritis. AB - We aimed evaluate F-fluorodeoxyglucose uptake at major joints for differentiating patients with rheumatoid arthritis (RA) from those with non-RA arthritis using F fluorodeoxyglucose (FDG)-positron emission tomography (PET).Eighteen patients with RA (13 women; age, 66.8 +/- 13.2 years) and 17 patients with non-RA (6 women; age, 50.8 +/- 12.5 years) were included. Twelve joints of each patient were examined: shoulder, elbow, wrist, hip, knee, and ankle on both sides. A visual scoring (VS) system was used; quantitative parameters such as maximum standardized uptake value (SUVmax), metabolic active volume (MAV), and total lesion glycolysis (TLG) were evaluated. Total score and value of each parameter were compared between the RA and non-RA groups.Total VS score (mean, 37.7 +/- 9.0 vs 21.9 +/- 7.2; P < .0001) and SUVmax (mean, 28.1 +/- 8.5 vs 17.9 +/- 5.8; P < .001) were significantly higher in the RA group than in the non-RA group. A significant between-group difference was also observed with respect to total MAV (608.3 +/- 370.7 vs 176.5 +/- 217.8; P < .001) and total TLG (1139.3 +/- 759.1 vs 289.5 +/- 395.4; P < .001). Receiver operating characteristic curve analysis revealed that total VS had the highest area under curve (.92), with sensitivity and specificity of 88.9% and 76.4%, respectively.Quantitative PET parameters could differentiate RA from non-RA. Total VS score, however, appears to be the best convenient qualitative tool for diagnosing RA. PMID- 28640088 TI - Safety of tumor necrosis factor-alpha inhibitors for treatment of ankylosing spondylitis: A meta-analysis. AB - BACKGROUND: Ankylosing spondylitis (AS) is a chronic immune-mediated disease affecting the sacroiliac joints and the spine, manifesting with new bone formation and osteopenia. Five tumor necrosis factor-alpha (TNF-alpha) inhibitors (infliximab, etanercept, adalimumab, certolizumab, and golimumab) are available for the treatment of AS, however, the results for the safety of TNF-alpha inhibitors in the treatment of AS are not consistent. METHODS: In this study, we conducted a meta-analysis to determine the safety of TNF-alpha inhibitors compared with placebo in reducing pain, swelling, and inflammation of AS patients. Eight relevant articles including 2049 patients were included for this meta-analysis study. We observed that the incidence of adverse events (RR = 1.22, 95% CI: 1.12-1.33; P = .501, I = 0%) and injection-site reaction (RR = 2.93, 95% CI: 2.02-4.23; P = .691, I = 0%) in AS patients' treatment with TNF-alpha inhibitors was significantly higher than that with placebo. RESULTS: However, there was no significant difference in the incidence of serious adverse event, infection, serious infection, and discontinuations due to adverse event. TNF-alpha inhibitors may be a promising treatment for AS, but carries an increased incidence rate of adverse events and injection-site reaction. CONCLUSION: Due to the existence of the unstable factors, further studies need to be done to verify the result of this study. PMID- 28640089 TI - Functional outcomes of Gartland III supracondylar humerus fractures with early neurovascular complications in children: A retrospective observational study. AB - This was a retrospective observational study. The aim of this study was to evaluate functional outcomes in children treated for Gartland III supracondylar humerus (SCH) fracture with neurovascular (NV) injuries using validated outcome measures. A secondary goal was to determine whether clinical parameters such as age at injury, sex, weight, fracture site, and/or direction of displacement could predict NV injury at the time of fracture or long-term functional outcomes in these patients.One hundred fifty-four patients of Gartland III SCH fractures between March 2004 and May 2013 were studied retrospectively. The patients were divided into 2 groups according to the presence of NV injury. Medical records and radiographs were reviewed to assess several parameters, including age, sex, weight, treatment intervention, the extremity involved, direction of fracture displacement, and NV injury. Functional outcome was assessed on final follow-up using the Pediatric Outcomes Data Collection Instrument (PODCI) and Quick Disabilities of the Arm, Shoulder, and Hand (Quick DASH) outcome measures. Statistical analysis was used to determine the relationship between NV injury and functional outcomes.There were 33 cases with Gartland III SCH fracture associated with NV injuries (10 cases of vascular compromise, 14 cases of neural injury, and 9 cases involving both vascular compromise and neural injury). There were significant differences between the 2 groups in age (P = .048), weight (P = .009), and direction of displacement (P = .004). Vascular compromise and median nerve injury were most common in fractures with posterolateral displacement, and radial nerve injuries were common in fractures with posteromedial displacement. The mean global function score in the PODCI was 91.4 points, and the mean Quick DASH score was 11.7 points, with excellent functional outcomes. No differences in outcomes were identified based upon age, fracture site, sex, weight, direction of displacement, or operative technique in NV injury patients (P > .05).The majority of patients with Gartland III SCH fractures associated with NV injuries returned to a high functioning level after treatment of their injuries. NV injury does not appear to influence functional outcomes. Good functional results can be expected regardless of age, fracture site, sex, weight, direction of displacement, and operative technique. PMID- 28640090 TI - Efficiency of microarray and SNPscan for the detection of hearing loss gene in 71 cases with nonsyndromic hearing loss. AB - We aim to screen the mutations of 3 hearing loss (HL) genes (GJB2, SLC26A4, and 12S rRNA) in 71 cases with nonsyndromic hearing loss (NSHL) using microarray and SNPscan, and identify the roles of nonhotspot mutation of these genes in the screening of NSHL. Seventy-one cases with moderate or severe neurosensory deafness confirmed in our department from July 2014 to December 2015 including 25 Uyghur minorities and 46 Han Chinese were included in this study. The type of mutations in GJB2, SLC26A4, and 12S rRNA genes were detected using microarray and SNPscan, respectively. Statistical difference was noticed in the detection rate of the HL genes in 71 cases. Using microassay, deafness genes were identified in 10 subjects (14.08%), while 22 cases (30.98%) were confirmed with the presence of deafness genes using the SNPscan. Compared with the microarray, remarkable difference was noticed in the detection rate of SNPscan (P < .05). Nonhotspot mutation in GJB2, SLC26A4, and 12S rRNA genes played a crucial role in the pathogenesis of NSHL. SNPscan contributed to elevation of detection rate of NSHL in clinical practice. PMID- 28640091 TI - Comparison of radiofrequency kyphoplasty (RFK) and balloon kyphoplasty (BKP) in the treatment of vertebral compression fractures: A meta-analysis. AB - BACKGROUND: Balloon kyphoplasty (BKP) is a widely adopted minimally invasive treatment for vertebral compression fractures (VCFs), but leakage of cement is a main complication of BKP. A novel vertebral augmentation technique radiofrequency kyphoplasty (RFK) with high viscosity cement was developed in 2009. Here, we aim to evaluate whether RFK can relieve symptoms efficiently and reduce cement leakage. METHODS: A literature search was performed using Pubmed, Embase, and Cochrane CENTRAL until September 30, 2016. Both randomized controlled trial (RCT) and non-RCT studies comparing RFK and BKP were included. The main outcomes included pain relief (VAS), functionality improvement (ODI), operation time, reduction of deformity (vertebral height and kyphosis angle), and incidence of cement leakage. The origin of heterogeneity was further explored by subgroup stratification. RESULTS: A total of 6 studies involving 833 patients with VCFs were included. The reduction of VAS score in the RFK group was 3.96 points more than that in the BKP group (P = .0007) postoperatively, and the improvement persisted until 12 months after the surgery (P < .00001). The operation time was shorter in RFK group than that in BKP group (P = .01). The increase of anterior vertebral height shortly after the operation was 0.53 mm greater in RFK group (P = .01). The decrease of kyphotic angle after RFK was 0.63 degrees and 0.92 degrees greater than that after BKP, both immediately and 6 months after operation (P = .002 and P < .00001, respectively). There was no significant difference between the incidence of cement leakage after RFK and BKP (P = .06). Further subgroup analysis stratified by study design indicated that the incidence of leakage decreased 15% in RFK than BPK (P < .00001) in non-RCT subgroup, but RFK and BKP treatments were equivalent in the RCT studies (P = .86). CONCLUSION: RFK appears to be more effective and safer than BKP in the present meta-analysis. The incidence of cement leakage diverges in RCT and non-RCT studies, so large-sample multicentered RCT studies are required to validate this new surgery system. PMID- 28640092 TI - Glucose metabolism of visceral adipose tissue measured by 18F-FDG PET/CT is related to the presence of colonic adenoma. AB - This study investigated the relationships between the area and metabolic activity of adipose tissue and the presence of colorectal adenoma (CRA). Our institutional review board approved the study and waived informed consent. A total of 212 subjects who underwent fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and colonoscopy for routine health check-ups were enrolled. The volumetric parameters of areas of visceral (VATav), subcutaneous (SATav), and total adipose tissue (TATav) and calculated visceral-to subcutaneous adipose tissue ratio (VSR) and visceral-to-total adipose tissue ratio (VAR) were considered. Metabolic parameters of standardized uptake value (SUV) of visceral (vcSUVmax, vcSUVmean), subcutaneous (scSUVmax, scSUVmean), and calculated visceral-to-subcutaneous adipose tissue ratio (VSRmax, VSRmean) were considered. Anthropometric data of height, weight, body mass index (BMI), waist circumference (WC), body fat mass (BFM), skeletal muscle mass (SMM), and diverse laboratory data were also considered as variables. Sixty-six subjects were placed in the CRA group and 146 subjects in the non-CRA group. The presence of CRA was significantly correlated with older age (P = .001), male sex (P = .041), higher BMI (P = .004), higher WC (P = .001), higher BFM (P = .024), higher VATav (P < .001), higher TATav (P = .004), higher VSR (P < .001), higher VAR (P < .001), lower vcSUVmax (P = .002), lower vcSUVmean (P < .001), and lower VSRmean (P = .002). On multiple regression analysis, vcSUVmax and vcSUVmean were independently associated with the presence of CRA (P = .009 and P = .045). Lower glucose metabolism of visceral adipose tissue was related to the presence of CRA. Our findings identify the value of visceral metabolic dysfunction as a potential surrogate marker of elevated risk for CRA. PMID- 28640093 TI - Correlations of single nucleotide polymorphisms of CRYAA and CRYAB genes with the risk and clinicopathological features of children suffering from congenital cataract. AB - BACKGROUND: The study aims to explore the correlations of the single nucleotide polymorphisms (SNPs) of CRYAA and CRYAB with the risk and clinicopathological features of children with congenital cataract. METHODS: The study enrolled 168 children diagnosed as congenital cataract (case group) and 172 normal children (control group) from May 2015 to May 2016. Genomic DNA extraction was performed using a QIAamp DNA blood mini kit. Polymerase chain reaction (PCR) products were genotyped using an ABI direct sequencer. Haplotype, allele, and genotype frequencies of CRYAA and CRYAB gene polymorphisms analyses were carried out using the SHEsis software. Logistic regression analysis was performed in order to analyze the risk factors for children suffering from congenital cataract. RESULTS: Presence of significant differences between the case and control groups' genotype and allele frequencies of CRYAA rs7278468 and CRYAB rs370803064/rs387907338. TA of CRYAB gene might increase congenital cataract risk in children, while GCG of CRYAA gene and GC of CRYAB gene might decrease congenital cataract risk in children. CRYAA rs7278468, CRYAB rs370803064/rs387907338 polymorphisms were significantly correlated to uncorrected visual acuity, best-corrected visual acuity, nystagmus, visual axis opacification, microcornea, lens opacity, posterior capsular thickening, and degrees of posterior capsule opacification after operation in children with congenital cataract. Logistic regression analysis revealed that the T allele of CRYAA rs7278468, A allele of CRYAB rs370803064, T allele of CRYAB rs387907338, family history, and TA haplotype of CRYAB gene were risk factors for children with congenital cataract. CONCLUSION: Our findings demonstrated that CRYAA rs7278468 and CRYAB rs370803064/rs387907338 are correlated with the risk and clinicopathological features of children suffering from congenital cataract. PMID- 28640094 TI - Effects of first radioiodine ablation on functions of salivary glands in patients with differentiated thyroid cancer. AB - The aim of this study was to evaluate the effects of the first radioactive iodine (I) therapy on functions of salivary glands in patients with differentiated thyroid carcinoma (DTC).There were 36 consented patients with DTC enrolled in this study, who received 3.7 GBq (100mCi) I for ablation after total thyroidectomy. Salivary gland function was assessed using salivary gland scintigraphy in two phases, one 4 hours before and the other 6 months after I therapy (both under thyrotropin stimulation condition). Quantitative parameters including uptake fraction (UF), uptake index (UI), excretion fraction (EF), and excretion ratio (ER) were measured and compared. Blood parameters were also compared. Associations between sex and outcome of the first I therapy as well as individual salivary gland function were measured. Wilcoxon Signed Rank Sum test and chi test were used for statistical analysis.When compared between pre ablation and post-ablation, UF of bilateral parotid and submandibular glands were significantly increased (all P < .01). UI of both submandibular glands were significantly increased (P < .05). This seemingly increased uptake function after the first I therapy was actually compensatory mechanism of salivary gland, which indicated a possible intermediate state after radiation. But salivary glands' secretory function had not changed significantly except for left submandibular gland; we demonstrated that only left submandibular gland showed significantly decreased ER (P < .05). Thyroglobulin and thyroglobulin antibody significantly decreased after I therapy (P < .05). There were no sex differences on therapeutic outcome and salivary gland dysfunctions after the first I therapy. Salivary gland of both males and females could be affected by I therapy.The first I ablative therapy may impair the salivary uptake and secretory function of patients with DTC. There was no association between sex and salivary gland dysfunction. PMID- 28640095 TI - Aldehyde dehydrogenase 1 expression is correlated with poor prognosis in breast cancer. AB - Breast cancer (BC) is one of the most common cancers worldwide, and is a major cause of death in women. Aldehyde dehydrogenase 1 (ALDH1) is a marker of stem cells and cancer stem cells, and its activity correlates with the outcome of various tumors, including BC. This study aimed to analyze the relationship between ALDH1 expression and clinicopathological characters in BC and the prognostic significance of ALDH1.We used quantitative reverse-transcription PCR (qRT-PCR) to detect ALDHA1 mRNA levels in 25 fresh frozen BC samples and matched noncancerous samples. Immunohistochemistry on tissue microarrays was used to analyze protein expression in 137 paraffin-embedded BC tissues and corresponding noncancerous tissues. STATA 16.0 software was used for statistical analysis.The results suggested that levels of both ALDH1 mRNA and protein in BC were significantly higher than in corresponding adjacent breast samples (3.856 +/- 0.3442 vs 1.385 +/- 0.1534, P < .001; 52.6% vs 25.5%, P < .001, respectively). ALDH1 protein expression was also significantly associated with histological grade (P = .017), tumor size (P = .017), and tumor-node-metastasis (TNM) stage (P = .038). Multivariate analysis using the Cox regression model demonstrated that ALDH1 expression (P = .024), molecular typing (P = .046), and TNM classification (P = .034) were independent predictive factors for the outcome of BC. Kaplan-Meier analysis and the log-rank test indicated that patients with high ALDH1 expression, triple-negative BC, and advanced TNM stage had a reduced overall survival time.These data suggest that ALDH1 could be used as a prognostic factor for BC and may provide a useful therapeutic target in the treatment of BC. PMID- 28640096 TI - Effect of transforaminal epidural polydeoxyribonucleotide injections on lumbosacral radiculopathy: A case report. AB - RATIONALE: Transforaminal epidural glucocorticoids administration is widely performed for the management of lumbosacral radiculopathy. However, it may worsen the condition of patients with type 2 diabetes mellitus (DM). Polydeoxyribonucleotide (PDRN) was recently noted as a substitute for glucocorticoids. PATIENT CONCERNS: A 44-year-old male patient was admitted to our pain clinic with symptoms of low back pain with severe pain and tingling sensation of left posterolateral leg. He had type 2 DM medicated with Glimepiride and Metformin. Blood glucose level was 367 mg/dL. He declined to use glucocorticoid. DIAGNOSES: He was diagnosed as left foraminal disc protrusion at L4-5, left subarticular disc protrusion at L5-S1. INTERVENTIONS: Fluoroscopically guided transforaminal epidural PDRN injections were carried out. OUTCOMES: The patient was followed up for more than 6 months and demonstrated good improvement in lumbosacral radiculopathy without any complications. LESSONS: This is the first successful report on epidural injection of PDRN. PMID- 28640097 TI - Role of endoscopic ultrasound and endoscopic resection for the treatment of gastric schwannoma. AB - Endoscopic ultrasound (EUS) and endoscopic resection play an important role in gastric submucosal tumor. However, there were few articles regarding EUS and endoscopic resection of gastric schwannomas. Our aim was to evaluate the role of EUS and endoscopic resection in treating gastric schwannomas.We retrospectively reviewed 14 patients between March 2012 and April 2016 with gastric schwannomas and who received EUS and endoscopic resection. EUS characteristics, endoscopic resection, tumor features, and follow-up were evaluated in all the patients.Fourteen patients were enrolled in the present study. The patients' ages ranged from 25 to 72 years (mean age, 52.6 years). On EUS, all tumors were originating from muscularis propria and hypoechoic. Ten tumors have the extraluminal growth patterns and 4 tumors have the intraluminal growth patterns. Marginal halos were observed in 7 lesions. No cystic change and calcification were found inside the lesions. Complete endoscopic resection was performed in all the patients with no complications occurring in any patients. No recurrence or metastases was found in all patients during the follow-up period.Gastric schwannoma has some characteristics on EUS, but it is difficult to differentiate gastric schwannoma from gastrointestinal stromal tumor. Endoscopic resection is an effective and safe treatment for gastric schwannoma with an excellent follow up outcome. PMID- 28640098 TI - The characteristics of stem cells in human degenerative intervertebral disc. AB - BACKGROUND: The aim of this study is to identify which possessed the best stem cell-like characteristics in 3 kinds of cell in human degenerative intervertebral disc: NPSCs (nucleus pulposus-derived stem cells), AFSCs (annulus fibrosus derived stem cells), or CESCs (cartilage endplate-derived stem cells). METHODS: We separated the disc samples obtained from 15 surgically treated patients with disc degenerative diseases into nucleus pulposus, annulus fibrosus, and cartilage endplate. After cultivating, we used the cell counting kit-8 to analysis the cell activity of 3 kinds of disc tissue-derived stem cell separately; different stem cells were defined with multilineage (osteogenic, chondrogenic, and adipogenic) differentiation. We extracted the total RNA and detected the expression of different lineage differentiation-related genes with the real-time polymerase chain reaction (RT-PCR). RESULTS: Cell morphology of NPSCs, AFSCs, and CESCs did not show significant difference. Cell proliferation capacity of NPSCs and AFSCs was stronger than that of CESCs. The differentiation outcomes showed that osteocyte-like cells were stained red by Alizarin red S, chondrocyte-like cells blue by toluidine blue, and adipocyte-like red by oil red O. The RT-PCR reflected that the expression of different lineage differentiation-related genes of AFSCs was stronger than NPSCs and CESCs. CONCLUSION: In conclusion, we found that the cell morphology was not significantly different among NPSCs, AFSCs, and CESCs. Both differentiation and RT-PCR tests demonstrated that AFSCs had the best stem cell-like characteristics in the human degenerative intervertebral disc. PMID- 28640099 TI - Prognostic impact of Ki-67 in patients with gastric cancer-the importance of depth of invasion and histologic differentiation. AB - Ki-67 protein is a cellular marker for proliferation. The role of Ki-67 as a prognostic biomarker has not been established in gastric cancer. The present study was performed to investigate the significance of Ki-67 expression as a biomarker in early gastric cancer (EGC).With tissue microarray for 320 patients with gastric cancer, we performed immunohistochemical staining for Ki-67. Its clinical significance was analyzed with adjustment via the propensity score matching. For validation, we performed bootstrap resampling.The median follow-up duration was 72 months (range: 3-120 months). Ki-67-high group showed worse prognosis than Ki-67-low group in EGC (5-YSR, 78.9% vs 92.0%, P = .018), but not in advanced gastric cancer (AGC) (5-YSR, 58.5% vs 59.2%, P = .951). Interestingly, in the patients with well-differentiated histology, prognosis for Ki-67-high group was considerably worse than that for Ki-67-low group (5-YSR, 67.0% vs 94.4%, P = .012), but not in those with moderately differentiated (P = .504) and poorly differentiated histology (P = .905). In this cohort, there was a strong correlation between the proportion of EGC and well-differentiated histology (r = 0.215, P = .002). Multivariate analysis also revealed that the high-Ki-67 expression serves as a poor prognostic factor in EGC (HR 4.346, 95% CI 1.397-13.515, P = .011), especially in the well-differentiated histology, but not in all the patients (P = .171). Bootstrap resampling internally validated this result (P = .011).This study suggests that Ki-67 expression may be a good biomarker for prognosis prediction for EGC with well-differentiated histologic type. PMID- 28640100 TI - Level of sensory block after spinal anesthesia as a predictor of hypotension in parturient. AB - When the sensory block level (SBL) is >=T5 or T4, a high incidence of hypotension occurs in parturients after spinal anesthesia. A rapidly ascending SBL is another risk factor for spinal anesthesia-induced hypotension. However, the relationship between the ascension rate of the SBL and spinal anesthesia-induced hypotension remains unclear.After placement in the left lateral position, combined epidural spinal anesthesia was performed on 140 parturients undergoing caesarean section using the following procedure: no volume preloading, injection site of L3-4 or L4 5, injection rate of 0.1 mL/sec, and administration of 10 mg of 0.5% hyperbaric bupivacaine. A receiver-operating characteristic curve was built to estimate the accuracy of the SBL ascension rate in detecting spinal anesthesia-induced hypotension.The mean time interval from spinal injection to placement in the supine position was 136 +/- 10 seconds in all anesthesia procedures. The earliest and most complete records of the SBL started from the 3rd minute after spinal injection. The threshold spread rate corresponding to the highest accuracy for occurrence of hypotension was an SBL of >=T8 at the 3rd minute after spinal injection, with 82% and 88% sensitivity and specificity, respectively.The ascension rate of an SBL of >=T8 at the 3rd minute after spinal injection is as a predictor of hypotension in parturients. PMID- 28640101 TI - Liposomal bupivacaine versus traditional bupivacaine for pain control after total hip arthroplasty: A meta-analysis. AB - BACKGROUND: In the past, the efficacy of local infiltration of liposomal bupivacaine for total hip arthroplasty (THA) patients was in debate. Therefore, this meta-analysis was conducted to determine whether local infiltration of liposomal bupivacaine provides better pain relief after THA. METHODS: We searched Web of Science, PubMed, Embase, and the Cochrane Library databases to the April 2017. Any studies comparing liposomal bupivacaine and traditional bupivacaine were included in our meta-analysis. The outcomes included visual analog scale (VAS) at 24, 48, and 72 hours, total morphine consumption at 24 hours, and the length of hospital stay. We assessed the pooled data using a random-effect model. RESULTS: Six studies were finally included in this meta-analysis. Our pooled data analysis demonstrated that liposomal bupivacaine was more effective than the traditional bupivacaine in terms of VAS at 24 hours (P = .018) and the length of hospital stay (P = .000). There was no significant difference in terms of the VAS at 48 and 72 hours and total morphine consumption at 24 hours (P >.05). CONCLUSION: Compared with the traditional bupivacaine, liposomal bupivacaine shows better pain control at 24 hours and reduces the length of hospital stay after THA. Its economic costs must be assessed in multimodal center randomized controlled trials when being recommended as a long-acting alternative analgesic agent for a THA patient. PMID- 28640102 TI - Complicated atrial tachycardia due to atrial fibrillation originating from the superior vena cava: A case report. AB - INTRODUCTION: The superior vena cava (SVC) can act as an origin of atrial fibrillation (AF). The complex structure and special conductive properties of the SVC can result in complicated atrial tachycardia (AT), atrial flutter, or AF. SYMPTOMS AND CLINICAL FINDINGS: We report a case of the clinical observation of various kinds of AT and AF in 1 patient. Electrophysiological (EP) studies confirmed the muscle sleeve in the SVC to be the primary trigger and the only site or origin of tachycardia in this patient. Furthermore, we describe the mechanism of AT observed in clinic, which was misdiagnosed as multiorigin AF. INTERVENTION AND OUTCOMES: Circumferential pulmonary vein isolation and circumferential SVC isolation resulted in termination of tachycardia. CONCLUSION: We present an atypical case of AF originating from the SVC with unusual intra atrial conduction characteristics and arrhythmogenic pulmonary veins. Stepwise EP studies were conducive to clarify the mechanism of this rare AT. PMID- 28640103 TI - Occupational injuries among pediatric orthopedic surgeons: How serious is the problem? AB - In this cross-sectional study, we surveyed all pediatric orthopedic surgeons in Saudi Arabia using an anonymous electronic questionnaire composed of 23 items to identify the rate of occupational injuries and obtain other relevant information. Thirty-nine participants completed the questionnaire (response rate: 83%). Participants who sustained occupational injuries throughout their careers represented 82.5%. The most injured areas were the hands, eyes, and back by 54.5%, 24.2%, and 15.2%, respectively. Approximately 11.1% were injured while operating on infected patients. Approximately 30.3% reported their injuries to their institution. We concluded that the rate of occupational injuries among pediatric orthopedic surgeons is very high and underreported. PMID- 28640104 TI - The EasyTube during general anesthesia for minor surgery: A randomized, controlled trial. AB - BACKGROUND: The EasyTube (EzT) is a supraglottic airway device that is used for emergency airway situations. Ventilation during general anesthesia should also be feasible, but literature on the EzT is scarce. We evaluated the EzT in comparison with the endotracheal tube (ETT) in its use during general anesthesia in a comparative study. METHODS: A total of 400 patients with American Society of Anesthesiologists (ASA) physical status I to II scheduled for minor surgery in 4 centers were randomized for ventilation via the ETT or EzT. RESULTS: In all patients, the EzT and the ETT could be inserted within 3 attempts. In all EzT patients, the inspiratory and expiratory minute volumes (6.64 +/- 0.71 and 6.34 +/- 0.69 L/min) were sufficient to reach target oxygenation values, similar to ETT patients (P = .59). Mean peak pressure, mean plateau pressure, and mean dynamic compliance did not differ between the groups. Sore throat and blood on the cuff after removal were the most frequent complications in both groups. CONCLUSION: Ventilation for up to 1 hour during general anesthesia in patients with ASA physical status I to II with the EzT is feasible and safe. PMID- 28640105 TI - Glomerulonephritis and granulomatous vasculitis in kidney as a complication of the use of BRAF and MEK inhibitors in the treatment of metastatic melanoma: A case report. AB - RATIONALE: BRAF and MEK inhibitors have significantly improved the prognosis of metastatic melanoma, by inhibiting both the mitogen-activated protein kinase (MAP kinase) pathway. They are associated with infrequent adverse kidney events. Most of these are related to the use of BRAF inhibitors and involve interstitial nephritis with acute tubular necrosis. PATIENT CONCERNS: We report a unique case of glomerulonephritis with renal granulomatous vasculitis in a patient diagnosed with metastatic melanoma treated with BRAF and MEK inhibitors. The patient was a 55-year old woman, who presented a melanoma of the right thigh with pulmonary metastasis. Treatment started in November 2015, with Encorafenib and Binimetinib, new BRAF and MEK inhibitors, respectively. Two months after the beginning of the treatment, there was a worsening of her renal function with significant proteinuria. DIAGNOSES: Kidney biopsy showed extracapillary proliferation in the glomeruli with a granulomatous reaction. INTERVENTIONS AND OUTCOMES: Renal function recovered completely after withdrawal of the chemotherapy. LESSONS: All the reported kidney adverse events secondary to BRAF and MEK inhibitors in the literature are related to the use of BRAF inhibitors. Some previous reported mechanistic investigations also provide insight between BRAF inhibitors and podocytes injuries. Therefore, encorafenib most likely is the main responsible of the disease. However, evidence has emerged that inhibition of the MAP kinase pathway could also enhance autoimmunity. Thus, binimetinib may also have played a role and the combination of BRAF and MEK inhibitors may have facilitated this autoimmune kidney disease. PMID- 28640106 TI - The outcome of eosinophilic granuloma involving unilateral atlantoaxial joint: A case report and literature review. AB - RATIONALE: Solitary eosinophilic granuloma (EG), the most benign, common form of Langerhans cell histiocytosis, has a self-limiting process and is associated with a good prognosis. Immobilization is recommended as the first treatment strategy for solitary EG, although the treatment protocols are still controversial. Radiotherapy and surgery are secondary treatment choices. Lesions of the upper cervical spine react differently to treatment because of their specific anatomical and motor features. PATIENT CONCERNS: We discuss the case of a 29-year old man with axis EG who underwent immobilization, radiotherapy, and finally surgery. DIAGNOSIS: Eosinophilic granuloma (EG). INTERVENTIONS: An initial conservative protocol, including immobilization with a collar and radiotherapy, effectively relieved his neck pain, whereas torticollis secondary to atlantoaxial subluxation was not improved. Therefore, he underwent tumor resection through the anterior approach and spinal reconstruction, fixation, and fusion through the posterior approach. OUTCOMES: The deformity was well corrected and follow-up was satisfactory. LESSONS: Upon review of the literature, we found that EG lesions affecting the axis have more risk factors for instability or deformity, and they have particular anatomical and motor characteristics; thus, they require more consideration and attention in terms of treatment, prognosis, and follow-up. PMID- 28640107 TI - A nomogram prediction of postoperative surgical site infections in patients with perihilar cholangiocarcinoma. AB - Surgical site infection (SSI) is one of the major morbidities after radical resection for perihilar cholangiocarcinoma (PHCC). This study aimed to clarify the risk factors and construct a nomogram to predict SSIs in patients with PHCC.A total of 335 consecutive patients who underwent hepatectomy combined with hepaticojejunostomy between January 2013 and December 2015 were analyzed retrospectively. SSIs, including incisional (superficial and deep) and space/organ infection, were defined according to the Centers for Disease Control and Prevention (CDC)'s National Nosocomial Infection Surveillance (NNIS) system. Risk factors associated with postoperative SSIs were analyzed by univariate and multivariate analyses. A nomogram was developed on the basis of results from the multivariate logistic model and the discriminatory ability of the model was analyzed.PHCC patients had higher organ/space SSI rate than incisional SSI rate after radical resection. Multivariate analysis showed that risk factors indicating postoperative overall SSIs (incisional and organ/space) included coexisting cholangiolithiasis [odds ratio (OR): 6.77; 95% confidence interval (95% CI): 2.40-19.11; P < .001], blood loss >1500 mL (OR: 4.77; 95% CI: 1.45 15.65; P = .010), having abdominal surgical history (OR: 5.85; 95% CI: 1.91 17.97; P = .002), and bile leakage (OR: 15.28; 95% CI: 5.90-39.62; P < .001). The beta coefficients from the multivariate logistic model were used to construct the model for estimation of SSI risk. The scoring model was as follows: -4.12 +1.91 * (coexisting cholangiolithiasis = 1) + 1.77 * (having previous abdominal surgical history = 1) +1.56 * (blood loss >1500 mL = 1) + 2.73 * (bile leakage = 1). The discriminatory ability of the model was good and the area under the receiver operating characteristic (ROC) curve (AUC) was 0.851.In PHCC patients, there may be a relationship between postoperative SSIs and abdominal surgical history, coexisting cholangiolithiasis, bile leakage, and blood loss. The nomogram can be used to estimate the risk of postoperative SSIs in patients with PHCC. PMID- 28640108 TI - Correlation of HLA-DP/DQ polymorphisms with transplant etiologies and prognosis in liver transplant recipients. AB - Previous study has identified that the genetic variants in the human leukocyte antigen (HLA)-DP/DQ region were strongly associated with hepatitis B virus (HBV) infection. But their roles in liver function recovery after hepatic transplantation were still obscure. This study aimed to investigate whether HLA DP/DQ polymorphisms were associated with post-transplant etiologies and prognosis in Chinese liver transplant recipients.A total of 144 liver transplant recipients were enrolled, which were divided into 2 groups according to the transplant etiology: HBV-related disease and non-HBV-related disease. HBV-related disease includes 3 subgroups: liver cirrhosis, hepatocellular carcinoma, and progressive HBV hepatitis. Three single-nucleotide polymorphisms HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were studied in all recipients by high resolution melting curve analysis. Liver function indices (albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyltranspeptidase, direct bilirubin, total bilirubin) and coagulation indices (prothrombin time, platelet, international normalized ratio, fibrinogen) were routinely tested. After transplant, 10 recipients who were positive for HBsAg or with elevation in HBV virus load were regarded as HBV recurrence.No significant association of HLA-DP/DQ polymorphisms with HBV recurrence or transplant etiology was observed (P < .05). Recipients with HLA-DQ (rs7453920) AG and AA genotype had lower direct bilirubin levels than GG genotype individuals, especially on the 14th day after surgery (17.80 vs. 5.35, P = .038). Patients with A alleles displayed earlier liver function recovery than patients with G alleles (7 vs. 6 months). No significant correlation was shown in HLA-DP rs3077 and rs9277535 with HBV infection or liver function recovery (P < .05).Our study concluded that HLA-DP (rs3077 and rs9277535) and HLA-DQ (rs7453920) were not significantly associated with HBV recurrence or HBV susceptibility, but HLA-DQ rs7453920 was related to prognosis of liver transplant recipients. HLA-DQ rs7453920 A might be used as an indicator of earlier recovery and better prognosis after transplantation. PMID- 28640109 TI - Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus. AB - Benzodiazepines are used as first-line treatments for status epilepticus. Fosphenytoin (FPHT) is recommended for second-line therapy; however, intravenous injection of levetiracetam (LEV) may also be effective against status epilepticus. Herein, we compared the efficacy and safety of LEV as a second-line treatment for status epilepticus with FPHT in Japanese patients.Patients with status epilepticus were selected from the database of the Emergency and Critical Care Center of Hitachi General Hospital. The subjects were patients whose status epilepticus was successfully stopped by diazepam, and in whom FPHT or LEV was administered after diazepam. As LEV injections recently became clinically available in Japan, the choice of drug was determined by the treatment period. Thus, 21 patients who were intravenously injected with LEV as a second-line therapy and 42 matched patients (historical controls) who were treated with FPHT (1:2) were selected.The subjects had a mean age of 64.0 +/- 2.2 years, and included 48 males and 15 females. The status epilepticus control rates of the FPHT and LEV groups did not differ significantly (81.0% [34/42] vs 85.1% [18/21], respectively; P = .69). As for serious adverse events, a reduction in blood pressure was observed in the FPHT group, but not in the LEV group. The oral anticonvulsant switching rates of the 2 groups were similar, but the same-drug switching rates of the FPHT and LEV groups were 8.1% and 77.8%, respectively.The efficacy of intravenous LEV injections after status epilepticus was equivalent to that of FPHT, and the incidence of adverse events was lower in the LEV group. LEV is effective and safe at preventing recurrent seizures after status epilepticus following benzodiazepine treatment. PMID- 28640110 TI - Case report of a modified Meso-Rex bypass as a treatment technique for late-onset portal vein cavernous transformation with portal hypertension after adult deceased-donor liver transplantation. AB - RATIONALE: Portal vein thrombosis is a complication after liver transplantation and cavernous transformation of the portal vein (CTPV) is a result of portal vein thrombosis, with symptoms of portal hypertension revealed by an enhanced CT scan. Meso-Rex bypass is an artificial shunt connecting the left portal vein to the superior mesenteric vein and is mainly used for idiopathic cavernomas. This technique is also used for post-transplant portal vein thrombosis in pediatric patients thereby bypassing obstructed sites of the extrahepatic portal vein. Here we report about an adult patient who was treated by connecting the cystic part of the portal vein to the splenic vein instead of the superior mesenteric vein. PATIENTS CONCERN: An adult male patient with post-liver transplantation portal vein cavernous transformation suffered from hypersplenism and elevated hepatic enzymes. DIAGNOSIS: The last follow up revealed irregular and obvious hypersplenism, and splenomegaly had occurred, while an enhanced CT scan revealed serious esophagogastric varices and CTPV in addition to occluded right and common PV trunks. INTERVENTION: The patient was treated by connecting the cystic part of the portal vein to the splenic vein instead of the superior mesenteric vein. OUTCOME: After the operation, a satisfactory velocity was confirmed 1 month postoperatively and the shunt still remained patent at the 6-month postoperation follow-up. LESSONS: A Meso-Rex bypass intervention connecting the left portal vein to the splenic vein instead of the superior mesenteric vein after liver transplantation in an adult patient with right and common portal vein occlusions has been successfully performed as an alternative approach. PMID- 28640111 TI - Comparative safety for cardiovascular outcomes of DPP-4 inhibitors versus glimepiride in patients with type 2 diabetes: A retrospective cohort study. AB - Concerns about the cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors persist. This study sought to determine whether there is a differential risk of hospitalization for cardiovascular diseases (CVDs) between DPP-4 inhibitors and glimepiride.We conducted this retrospective cohort study by using the Korean National Health Insurance Service database from December 1, 2008, to December 31, 2013. The study subjects were new users of DPP-4 inhibitors or glimepiride for type 2 diabetes. Outcome was defined as hospitalization for CVDs, including angina pectoris, myocardial infarction, transient cerebral ischemic attack, heart failure, or cerebrovascular disease or any procedure involving coronary artery bypass grafting or percutaneous coronary intervention. We used a Cox proportional hazard model to estimate the adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs), to assess the risk of CVDs associated with the use of DPP-4 inhibitors compared with glimepiride.The cohort consisted of 1,045,975 patients, with 6504 in the DPP-4 inhibitors group and 13,447 in the glimepiride group. No significant increased risk of total CVDs was found (aHR, 0.87; 95% CI, 0.75-1.01) in the DPP-4 inhibitors versus glimepiride group. A decreased risk of hospitalization for CVDs was found among patients with a history of visit for CVDs (aHR, 0.73; 95% CI, 0.56-0.97) or with >2.5 years' duration of type 2 diabetes (aHR, 0.77; 95% CI, 0.66-0.91) in the DPP-4 inhibitors versus glimepiride group.DPP-4 inhibitors did not increase cardiovascular risk compared with glimepiride regardless of CVD history and diabetes duration. PMID- 28640112 TI - Cement leakage in osteoporotic vertebral compression fractures with cortical defect using high-viscosity bone cement during unilateral percutaneous kyphoplasty surgery. AB - The purpose of this study was to investigate cement leakage (CL) in osteoporotic vertebral compression fractures (OVCFs) with cortical defect using high-viscosity bone cement during unilateral percutaneous kyphoplasty (PKP) surgery.This study included a series of 77 patients (23 males, 54 females) with single level osteoporotic vertebral body fracture (OVCF) who underwent unilateral PKP in our hospital. Preoperative x-ray, computed tomography (CT) scan, and 3-dimensional reconstructions were studied. During the PKP procedure, needle was carefully put to avoid too near to the cortical defect according to CT image. High-viscosity bone cement was used via unilateral PKP. Radiographic outcomes were evaluated by assessment of vertebral body wall breakage, fracture type, and vertebral body change. The exact rate of CL was analyzed.A total of 77 patients with single level OVCF were included in this study. The mean age of the patients was 74.8 +/- 8.0 years. Among these cases, 7 (9.1%) involved the thoracic spine (T3-T10), 60 (77.9%) involved the thoracolumbar spine (T10-L2), and 10 (13.0%) involved the lumbar spine (L3-L5). There were 27 vertebral bodies found posterior wall breakage, 51 vertebral bodies found endplate breakage, and 49 vertebral bodies found anterior-lateral wall breakage. CT scan was more efficient in detecting vertebral body wall breakage and CL than x-ray (P < .001). No neurological symptoms were found after surgery. Both cases with CL (CL group) and cases without cement leakage (NCL group) experienced vertebral height restoration (HR) with similar cement volume CV. There were no significant difference between the two groups about the parameter HR and CV. Severe vertebral body fracture and biconcave fracture had more CL than other groups. OVCF cases with cortical defect had more CL rate than those without cortical defect; however, no significant difference was found in the correlation between vertebral wall breakage and CL.Cortical defect remains a potential risk of CL during PKP surgery. Careful preoperative evaluation and using high-viscosity bone cement during the unilateral PKP procedure could prevent serious leakage and clinical symptoms. PMID- 28640113 TI - Spleen implanting in the fatty liver mimicking hepatocarcinoma in a patient with hepatitis B&C: A case report and literature review. AB - RATIONALE: Ectopic splenic autotransplantation refers to the heterotopic autotransplantation of splenic tissue and no treatment is necessary for it when patient is asymptomatic. Its incidence rate is reported up to 67% among patients with a history of splenic trauma and splenic surgery. The diagnosis of it before operation is really difficult, and it is easy to mimic as other tumors. PATIENT CONCERNS: We reported a 42-year-old man with hepatic splenosis, with history of splenectomy for traumatic splenic rupture 16 years ago and hepatitis B&C. The patient was enrolled with recurrent low back pain for more than 1 month without any treatment. DIAGNOSES: Radiological imaging revealed a subcapsular hepatic nodule, showing "fast-in and fast-out" enhancement. Surgery was performed, and the result of histological diagnosis was hepatic splenosis. INTERVENTIONS: No intervention before segmentectomy of the liver. LESSONS: When imaging of a patient with history of traumatic splenic rupture or splenectomy shows1 or few well circumscribed hepatic nodules with enhancement in dynamic study, we should suspect hepatic splenosis, for the purpose of avoiding unnecessary surgery. PMID- 28640114 TI - Injury of the dentato-rubro-thalamic tract in patients with cerebellar infarct: Case report. AB - RATIONALE: Several studies using diffusion tensor tractography (DTT) have reported on injury in the dentato-rubro-thalamic tract (DRTT) in patients with brain injury. However, there is no study of injury in the DRTT following cerebellar infarct. We report on patients with injury in the DRTT following cerebellar infarct, demonstrated on DTT. PATIENT CONCERNS: Three patients with cerebellar infarct were enrolled in this study. Diffusion tensor imaging data were acquired at 3 weeks (patient 1) and 2 weeks (patients 2 and 3) after onset and the DRTT was reconstructed. The Scale for Assessment and Rating of Ataxiaand the Functional Ambulation Category were used for evaluation of ataxia and gait function. DIAGNOSES AND OUTCOMES: With clinical evaluation, patient 1 scored 18, patient 2 scored 22, and patient 3 scored 28 points on the Scale for Assessment and Rating of Ataxia. On the Functional Ambulation Category patient 1 scored 2, patient 2 scored 2, and patient 3 scored 1 point. DRTT abnormalities were as follows: discontinuation (the upper portion of the left DRTT in the patient 1), narrowing (the lower portion of the left DRTT in patient 2, and the whole right DRTT in the patient 3), and nonreconstruction (the left DRTT in the patient 3). LESSONS: Using DTT, we demonstrated injury in the DRTT in 3 patients with severe ataxia following cerebellar infarct. We believe that evaluation of the DRTT would be helpful in patients who develop ataxia following cerebellar infarct. PMID- 28640115 TI - Management of neovascular glaucoma with intravitreal ranibizumab, panretinal photocoagulation, and subsequent 5-fluorouracil augmented trabeculectomy: A case report. AB - RATIONALE: Neovascular glaucoma (NVG) is one of the most refractory types of glaucoma caused by high ischemic retinal disorders, resulting in severe visual loss. Intravitreal injections of ranibizumab have been reported to have anatomical and functional success in treating NVG. PATIENT CONCERNS-DIAGNOSES INTERVENTIONS: We report a case with neovascular glaucoma due to central retinal vein occlusion who received combination therapy with intravitreal ranibizumab (IVR) injection, panretinal photocoagulation (PRP) and subsequent 5-fluorouracil (5-FU) augmented trabeculectomy. OUTCOMES: One week after IVR injection, the intraocular pressure (IOP) had partially decreased to 33 mmHg, and there was a complete regression of neovascularization of the iris (NVI) and the angle (NVA). PRP was feasible after IVR due to improvement of corneal edema which made an adequate view of the posterior pole of fundus. The surgery of trabeculectomy with 5-FU was performed 2 weeks after IVR to control the IOP. The intraoperative and postoperative courses were uneventful without any adverse complication. Post trabeculectomy, his vision remained stable and the IOP was in the range of 4-15 mmHg without topical antiglaucoma medications. A functioning bleb was maintained and there was no recurrence of NVI and NVA during the complete follow-up period of 6 months. LESSONS: Combined treatment of IVR, PRP, and subsequent 5-FU augmented trabeculectomy is demonstrated to be a possible new paradigm for the management of advanced NVG with angle closure and intractable elevation of IOP. PMID- 28640116 TI - Distribution of somatic mutations of cancer-related genes according to microsatellite instability status in Korean gastric cancer. AB - In studies of the molecular basis of gastric cancer (GC), microsatellite instability (MSI) is one of the key factors. Somatic mutations found in GC are expected to contribute to MSI-high (H) tumorigenesis. We estimated somatic mutation distribution according to MSI status in 52 matched pair GC samples using the Ion Torrent Ion S5 XL with the AmpliSeq Cancer Hotspot panel.Seventy-five (9.8%) somatic variants consisting of 34 hotspot mutations and 41 other likely pathogenic variants were identified in 34 GC samples. The TP53 mutations was most common (35%, 26/75), followed by EGFR (8%, 6/75), HNF1A (8%, 6/75), PIK3CA (8%, 6/75), and ERBB2 (5%, 4/75). To determine MSI status, 52 matched pair samples were estimated using 15 MSI markers. Thirty-nine MS stable (S), 5 MSI-low (L), and 8 MSI-H were classified. GCs with MSI-H tended to have more variants significantly compared with GCs with MS stable (MSS) and MSI-L (standardized J-T statistic = 3.161 for number of variants; P = .002). The mean number of all variants and hotspot mutations per tumor samples only in GCs with MSI-H were 3.9 (range, 1-6) and 1.1 (range, 0-3), respectively. Whereas, the mean number of all variants and hotspot mutations per tumor samples only in GCs with MSS/MSI-L were 1 (0-5)/0.8 (0-1) and 0.5 (0-3)/0.8 (0-1), respectively.In conclusion, GC with MSI-H harbored more mutations in genes that act as a tumor suppressor or oncogene compared to GC with MSS/MSI-L. This finding suggests that the accumulation of MSIs contributes to the genetic diversity and complexities of GC. In addition, targeted NGS approach allows for detection of common and also rare clinically actionable mutations and profiles of comutations in multiple patients simultaneously. Because GC shows distinctive patterns related to ethnics, further studies pertaining to different racial/ethnic groups or cancer types may reinforce our investigations. PMID- 28640117 TI - Incidence of constipation in stroke patients: A systematic review and meta analysis. AB - There is growing awareness of a link between the gut and cardiovascular disease. Constipation is common among individuals who have had a stroke, and it negatively affects social functioning and quality of life. However, no systematic study on the incidence of constipation in stroke patients has been reported.We selected studies included in Medline, Embase, Cochrane database, and Web of Science. Studies were included if they reported the incidence in stroke patients. Two authors selected the studies, extracted the data independently, and assessed these. Subgroup analyses were conducted according to the stroke subtype and stage of stroke.After detailed evaluations, 8 studies (n = 1385 participants) were found that contained data that were suitable for meta-analytic synthesis. A forest plot showed that the incidence of constipation was 48% (95% confidence interval [CI] = 33%-63%). In the analysis of the type of stroke subgroup, the incidence of constipation in patients who had had a hemorrhagic stroke (66% [95% CI = 40-91%]) was higher than that in patients who had experienced an ischemic stroke (51% [95% CI = 27%-75%]). The incidence in the acute stage (45% [95% CI = 36%-54%]) was lower than that in the rehabilitation stage (48% [95% CI = 23% 73%]).Constipation after a stroke event occurs frequently. This finding may raise awareness about bowel complications to allow correct evaluation and proper management. PMID- 28640118 TI - High normotension is associated with future metabolic syndrome but not cardiovascular disease: A 10-year longitudinal study. AB - Hypertension and prehypertension can increase the risk of developing cardiovascular disease (CVD) and diabetes. However, whether the harmful effects of high blood pressure (BP) are also seen with high normotension remains unknown. This 10-year longitudinal follow-up study aimed to investigate the relationships among normal-range BP, metabolic syndrome (MetS), and CVD.A total of 9133 nonmedicated normotensive participants, 4634 males and 4499 females, aged 60 years or older were enrolled in a standard health examination program at 2 academic hospitals and a health screening center in Taiwan. The study subjects were divided into 3 groups according to their BP. The systolic BP (SBP) ranges of groups 1, 2, and 3 were 91 to 100, 101 to 110, and 111 to 119 mmHg, whereas the diastolic BP (DBP) ranges of groups 1, 2, and 3 were 51 to 60, 61 to 70, and 71 to 79 mmHg, respectively.In the SBP3 group, both sexes had a higher odds ratio (OR) for having MetS or abnormal MetS components, except for triglycerides. Females in the DBP3 group had a higher OR for having MetS at baseline. After the follow-up period, the SBP3 group had a significantly higher hazard ratio (HR) for developing MetS. Males in the DBP3 group and females in the DBP2 and DBP3 groups had a significantly higher HR for developing MetS. Neither the SBP3 group nor the DBP3 group had a higher HR for developing nonfatal CVD. In the Kaplan-Meier analysis, SBP and DBP in both sexes showed statistical significance as predictors of MetS, but not of nonfatal CVD.High normotensive elderly individuals have an elevated risk of developing MetS at baseline and within 10 years of follow-up, but they are not at increased risk of CVD. Preventive interventions, such as life style modification, should be offered early even to the apparently healthy elderly. PMID- 28640120 TI - Working hand syndrome: A new definition of non-classified polyneuropathy condition. AB - The aim of this paper was to define an unexplained non-classified polyneuropathy condition as a new neurological disease. This new diagnosis of occupation related polyneuropathy has been named as "WORKING HAND SYNDROME (WHS)."This study collected and compared clinic and electrophysiological analyze data from healthy controls, WHS patients, carpal tunnel syndrome (CTS) patients and polyneuropathy patients. The WHS patients presented to the clinic with pain, numbness, tingling, and burning sensations in their hands that increased significantly during rest and nighttime. However, there was no weakness in the muscles, and the deep tendon reflexes were normal in this disease. The patients had all been working in physically demanding jobs requiring the use of their hands/arms for at least 1 year, but no vibrating tools were used by the patients. All of the cases were men. I supposed that overload caused by an action repeated chronically by the hand/arm may impair the sensory nerves in mentioned hand/arm. In patients with these complaints, for a definitive diagnosis, similar diseases must be excluded. Nonetheless, the specific electrophysiological finding that the sural nerves are normal on the lower sides, as well as the occurrence of sensory axonal polyneuropathy in the sensory nerves without a significant effect on velocity and latency in the work-ups of the upper extremity are enough to make a diagnosis.In conclusion, WHS has been defined as a polyneuropathy and occupational disease. Patients with WHS present with pain, numbness, tingling, and burning sensations in their hands that increases significantly during rest and nighttime. They also use their arms/hands for jobs that require heavy labor. The neurological examinations of patients with WHS are normal. Only the sensory nerves in the upper extremities are affected. This article is suggested to serve as a resource for patients, health care professionals, and members of the neurology community at large. PMID- 28640121 TI - Effects of anatomical characteristics as factors in abdominal aortic aneurysm rupture: CT aortography analysis. AB - The aim of this study was to analyze the anatomical characteristics of patients with ruptured abdominal aortic aneurysms (AAAs) using computed tomography (CT) aortography in order to determine the risk factors for rupture.We retrospectively reviewed the CT aortography findings and medical records of patients with ruptured AAAs who underwent CT aortography between February 2002 and December 2014. Age, sex, blood pressure at the time of rupture, treatment methods used for the ruptured AAAs, and treatment outcomes were analyzed. Statistical analyses were performed to determine the association between the maximum aneurysm diameter, which is considered the standard predictor of aneurysm rupture, and anatomical characteristics such as proximal neck diameter, angle between the suprarenal aorta and the aneurysm neck (alpha angle), angle between the aneurysm neck and aneurysm sac (beta angle), and angles between the abdominal aorta and both iliac arteries.Data were reviewed for a total of 36 patients. The mean maximum diameter of AAAs was 76.84 +/- 21.08 mm. Multivariate analysis adjusted for age and sex indicated statistical correlations between the alpha and beta angles and maximum aneurysm diameter and between the beta angle and iliac artery involvement.Our results suggest that the tortuosity of the aorta tends to be associated with the diameter of AAAs and iliac artery involvement. Investigation of the anatomical characteristics of individual patients using CT aortography is expected to aid in predicting the risk of AAA rupture. PMID- 28640119 TI - Relationships between dorsolateral prefrontal cortex metabolic change and cognitive impairment in first-episode neuroleptic-naive schizophrenia patients. AB - The present study aimed to explore the possible associations between the dorsolateral prefrontal cortex (DLPFC) metabolites and the cognitive function in first-episode schizophrenia (FES).This study included 58 patients with FES (29 males and 29 females; mean age, 22.66 +/- 7.64 years) recruited from the First Affiliated Hospital, College of Medicine, Zhejiang University, and 43 locally recruited healthy controls (16 males and 27 females; mean age, 23.07 +/- 7.49 years). The single-voxel proton magnetic resonance spectroscopy was used to measure the levels of N-acetylaspartate (NAA); complex of glutamate, glutamine, and gamma-aminobutyric acid (Glx); choline-containing compounds; and myo-inositol in the DLPFC. The ratios of metabolites to creatine (Cr) were calculated. The cognitive function was assessed by Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). Correlation analysis was used to assess the relationships between the DLPFC metabolites and the cognitive function.Compared with the healthy controls, the patients with FES showed significantly reduced scores in each part of the MCCB, significantly reduced NAA/Cr, and significantly increased Glx/Cr in the left DLPFC. Poor performance in verbal learning and visual learning was correlated to the reduced NAA/Cr ratio in the left DLPFC.These findings suggest that a lower NAA/Cr ratio in the left DLPFC is associated with the cognitive deficits in patients with FES, and may be an early biochemical marker for the cognitive impairment in schizophrenia. PMID- 28640122 TI - Clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning and prognosis analysis after rescue. AB - This study reports the clinical emergency treatment of 68 critical patients with severe organophosphorus poisoning, and analyzes the prognosis after rescue.The general data of 68 patients with severe organophosphorus poisoning treated in our hospital were retrospectively analyzed. These patients were divided into 2 groups: treatment group, and control group. Patients in the control group received routine emergency treatment, while patients in the treatment group additionally received hemoperfusion plus hemodialysis on the basis of routine emergency treatment. The curative effects in these 2 groups and the prognosis after rescue were compared.Compared with the control group, atropinization time, recovery time of cholinesterase activity, recovery time of consciousness, extubation time, and length of hospital stay were shorter (P < .05); the total usage of atropine was significantly lower (P < .05); Glasgow Coma Score was significantly higher (P < .05); acute physiology and chronic health score (APACHE II) was significantly lower (P < .05); and mortality and poisoning rebound rate was significantly lower (P < .05) in the treatment group.Hemoperfusion and hemodialysis on the basis of routine emergency treatment for critical patients with organophosphorus poisoning can improve rescue outcomes and improve the prognosis of patients, which should be popularized. PMID- 28640123 TI - Recurrent Campylobacter jejuni bacteremia in a patient with hypogammaglobulinemia: A case report. AB - RATIONALE: Although some cases of recurrent bacteremia due to Campylobacter jejuni have been reported in immunocompromised patients, antibiotic treatment strategies to eradicate C. jejuni and prevent recurrent infections in immunocompromised patients have not been established. Authors' experience of such rare cases should be shared for improving patients' outcomes. PATIENT CONCERNS: An 18-year-old boy with hypogammaglobulinemia, who received intravenous immunoglobulin replacement therapy every 3 weeks, was admitted to hospital repeatedly due to recurrent diarrhea and cellulitis of the leg. DIAGNOSES: The patient was admitted 6 times, and among them, C. jejuni was isolated from blood cultures 4 times and stool cultures 2 times. INTERVENTIONS: The patient experienced recurrent C. jejuni enteritis and bacteremia 5 times despite macrolide therapy. Doxycycline was administered for 3 months after the fifth admission. OUTCOMES: Ten months after the completion of doxycycline therapy for 3 months, C. jejuni enteritis relapsed; however, since then, recurrent infection has not occurred for 10 months. LESSONS: Immunocompromised patients can experience recurrent C. jejuni infection despite prolonged antibiotic therapy. Further studies to establish appropriate antibiotic therapy for eradicating colonized C. jejuni and preventing recurrent infection are needed. PMID- 28640124 TI - Comparison of the temperature and humidity in the anesthetic breathing circuit among different anesthetic workstations: Updated guidelines for reporting parallel group randomized trials. AB - BACKGROUND: For patients undergoing general anesthesia, adequate warming and humidification of the inspired gases is very important. The aim of this study was to evaluate the differences in the heat and moisture content of the inspired gases with low-flow anesthesia using 4 different anesthesia machines. METHODS: The patients were divided into 11 groups according to the anesthesia machine used (Ohmeda, Excel; Avance; Drager, Cato; and Primus) and the fresh gas flow (FGF) rate (0.5, 1, and 4 L/min). The temperature and absolute humidity of the inspired gas in the inspiratory limbs were measured at 5, 10, 15, 30, 45, 60, 75, 90, 105, and 120 minutes in 9 patients scheduled for total thyroidectomy or cervical spine operation in each group. RESULTS: The anesthesia machines of Excel, Avance, Cato, and Primus did not show statistically significant changes in the inspired gas temperatures over time within each group with various FGFs. They, however, showed statistically significant changes in the absolute humidity of the inspired gas over time within each group with low FGF anesthesia (P < .05). The anesthesia machines of Cato and Primus showed statistically significant changes in the absolute humidity of the inspired gas over time within each group with an FGF of 4 L/min (P < .05). However, even with low-flow anesthesia, the temperatures and absolute humidities of the inspired gas for all anesthesia machines were lower than the recommended values. CONCLUSION: There were statistical differences in the provision of humidity among different anesthesia workstations. The Cato and Primus workstations were superior to Excel and Avance. However, even these were unsatisfactory in humans. Therefore, additional devices that provide inspired gases with adequate heat and humidity are needed for those undergoing general anesthetic procedures. PMID- 28640125 TI - Targeted sequencing in FGF/FGFR genes and association analysis of variants for mandibular prognathism. AB - To identify variants of the genes in fibroblast growth factors/fibroblast growth factor receptors (FGF/FGFR) signal pathway that predispose to mandibular prognathism (MP) in the general Chinese population systematically.Targeted sequencing of the FGF/FGFR genes was conducted in 176 MP individuals and 155 class I malocclusion controls. The associations of common and rare variants with MP as a categorical phenotype and also continuous malocclusion phenotypes generated by principal component (PC) analysis were analyzed.One common variant, rs372127537, located in the 3'-untranslated region of FGF7 gene, was significantly related to PC1 (P = 4.22 * 10), which explained 23.23% of the overall phenotypic variation observed and corresponded to vertical discrepancies ranging from short anterior face height to long anterior face height, after Bonferroni correction. Also, 15 other variants were associated with PC1-4, although not significant after multiple corrections (P < .05). We also identified 3 variants: rs13317 in FGFR1, rs149242678 in FGF20, and rs79176051 FGF12 associated with MP (P < .05). With respect to rare variant analysis, variants within the FGF12 gene showed significant association with MP (P = .001).Association between FGF/FGFR signaling pathway and MP has been identified. We found a previously unreported SNP in FGF7 significantly related to increased facial height. Also, rare variants within the FGF12 were associated with MP. Our results provide new clues for genetic mechanisms of MP and shed light on strategies for evaluating rare variants that underlie complex traits. Future studies with larger sample sizes and more comprehensive genome coverage, and also in other population are required to replicate these findings. PMID- 28640126 TI - Prolonged methylprednisolone therapy after the pulse treatment for patients with moderate-to-severe paraquat poisoning: A retrospective analysis. AB - This retrospective study aims to evaluate the effect of prolonged methylprednisolone (MP) therapy on the mortality of patients with moderate-to severe paraquat (PQ) poisoning after the pulse treatment.We performed a retrospective analysis of patients with acute moderate-to-severe PQ poisoning that were admitted to the emergency department from May 2012 to August 2016. Out of 138 patients, 60 were treated with pulse treatment (15 mg kg day MP for 3 days) and 78 were treated with prolonged MP therapy after pulse treatment (15 mg kg day MP for 3 days; afterward, the dosage was reduced in half every 2 days, and the MP therapy was terminated until 0.47 mg kg day). Kaplan-Meier method was used to compare the mortality between the 2 groups. Cox proportional hazard models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI).The mortality of the prolonged MP therapy after pulse treatment group was lower than that of the pulse group (47.4% vs 63.3%; log-rank tests, P = .003). According to the multivariate Cox analysis, the prolonged MP therapy after pulse treatment was significantly associated with a lower mortality risk (HR: 0.31, 95% CI: 0.19-0.52, P < .001) compared with the pulse group. In addition, the prolonged MP therapy after pulse treatment caused more incidences of leucopenia than the pulse treatment alone (25.6% vs 11.7%, P = .04).The prolonged MP therapy after pulse treatment can reduce the mortality of moderate-to-severe PQ poisoning patients. PMID- 28640127 TI - Association between KCNE1 G38S gene polymorphism and risk of atrial fibrillation: A PRISMA-compliant meta-analysis. AB - BACKGROUND: Previous case-control studies on association between KCNE1 G38S polymorphism and risk of atrial fibrillation (AF) have been published but because of the conflicting results and small sample size of individual studies, the consolidated result is still controversial. OBJECTIVES: The aim of this study was to explore the relationship between KCNE1 G38S polymorphism and risk of AF. METHODS: We performed a comprehensive literature search on PubMed, Embase, OVID, Web of Science, Wan Fang, and CNKI databases up to March 10, 2017 in English and Chinese languages. Two of the authors individually extracted study data and assessed the study quality using Newcastle-Ottawa scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were combined in different genetic models for evaluation using a random-effect model or fixed-effect model according to interstudy heterogeneity. RESULTS: There were totally 14 independent case-control studies of 2810 patients and 3080 healthy controls included. Significant associations were found between KCNE1 G38S polymorphism and AF in overall population under all genetic models: allelic (OR: 1.34, 95% CI: 1.24-1.45, P < .001), homozygous (OR: 1.90, 95% CI: 1.61-2.24, P < .001), heterozygous (OR: 1.43, 95% CI: 1.21-1.68, P < .001), recessive (OR: 1.42, 95% CI: 1.20-1.69, P < .001), dominant genetic model (OR: 1.62, 95% CI: 1.39-1.89, P < .001). Subgroup analyses indicated similar association in Chinese and white. CONCLUSIONS: The G38S polymorphism in the KCNE1 gene can significantly increase the risk of AF in both Chinese and white. PMID- 28640128 TI - Association between polymorphic CAG repeat lengths in the androgen receptor gene and susceptibility to prostate cancer: A systematic review and meta-analysis. AB - BACKGROUND: Previous studies have been conducted to reveal the relationship between androgen receptor CAG polymorphism and risk of prostate cancer, yet the results were elusive and controversial. Thus, this meta-analysis was performed to clarify this association. METHODS: To obtain the relevant available studies, online databases PubMed, Embase, and Web of science were searched until September 1st, 2016. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of such association. Subgroup analyses were conducted based on ethnicity and source of controls. Moreover, Begg's funnel plots and Egger's linear regression test were conducted to test the publication bias. RESULTS: Overall, our results enrolled 51 studies indicated that significant increased risk of prostate cancer was associated with androgen receptor CAG polymorphism (OR = 0.77, 95% CI: 0.67-0.89). In addition, compared with CAG repeat <20, 22, carriers of ?20, 22 repeats had decreased risk of prostate cancer (cut-off point = 20: OR = 0.27, 95% CI: 0.13-0.52; cut-off point = 22: OR = 0.82, 95% CI: 0.70-0.97). However, when cut-off point = 23, no significant result was detected in such association (pooled OR = 0.88, 95% CI: 0.63-1.24). When cut-off point is 22, the results were positive only in Asian population (OR = 0.53, 95% CI: 0.32-0.89) in the subgroup analysis by ethnicity. Besides, when the studies were stratified by source of controls, the results were not significant in both the subgroup of population-based controls and hospital-based controls. CONCLUSIONS: This meta-analysis suggested the carriers of short polymorphic CAG repeats might increase susceptibility to prostate cancer, which held potential as a detecting marker of the risk of prostate cancer. PMID- 28640129 TI - VACTER syndrome with situs inversus totalis: Case report and a new syndrome. AB - INTRODUCTION: The association of situs inversus totalis (SIT) and VACTERL syndrome an extremely rare coincidence. PATIENTS: The patient was first diagnosed as simple SIT with lumbosacral neoplasms according to the prenatal magnetic resonance imaging (MRI) examination; however, the local hospital ignored the important to physical examination so that missed anal atresia with fistula. The patient was presented to our hospital owing to constipation for 1 week. And then, she was diagnosed as VACTER syndrome with situs inversus totalis. RESULTS: Anorectoplasty was performed to treat constipation, one month later, we performed intramedullary tumor resection and pathological diagnosis of ependymal cyst. Postoperative recovery was uneventful and the baby was doing well at 5-months follow up. CONCLUSION: It is extremely necessary for careful physical examination and detailed auxiliary examination to each system (including echocardiography, MRI, and so on) when diagnosing SIT. Also, recognizing and understanding the spectrum of situs anomalies is important, which aids in the diagnosis of disease and accordingly plan the therapeutic interventions. PMID- 28640130 TI - Impact of hysterosalpingography after operative treatment for ectopic pregnancy in Taiwan: A 16-year Nationwide Population-Based Analysis. AB - By retrieving records from Taiwan's National Health Insurance (NHI) system's database, the current study aimed to investigate the impacts of hysterosalpingography (HSG) to patients after ectopic pregnancy (EP) operations in Taiwan.In this retrospective cohort study, insurance claims data from 1997 to 2013, derived from a cohort of 1 million people randomly sampled to represent all NHI beneficiaries, were analyzed. Patients after ectopic pregnancy (EP) operations were identified via the inclusion of the corresponding NHI procedure codes. We further divided the patients into 2 groups by whether received subsequent HSG, EP-HSG, and EP-no-HSG. Patients with history of previous pregnancies (PP) and subsequent HSG were grouped as PP-HSG. We sought to evaluate the following pregnancies (FP) rate, interval to FP in EP-HSG compared with that in EP-no-HSG, and PP-HSG.EP-HSG had significantly higher FP rate odds ratio than EP-no-HSG (OR, 1.64; 95% CI, 1.24-2.16, P < .001). EP-HSG had lower FP rate odds ratio than that in PP-HSG, but no significant difference (33.1% vs 34.6%, P = .654). The INTERVAL(HSG-FP) in EP-HSG was no significantly different from that in PP-HSG (843.34 +/- 82 days vs 644.72 +/- 24.30 days, P = .077). There was significant positive correlation between FP after EP and number of HSG (r = 0.070, P < .001). There were significant negative correlation between FP and EP age (r = -0.270, P < .001), FP and INTERVAL(EP-HSG) (r = -0.212, P = .001). The multivariate analysis showed that INTERVAL(EP-HSG) less than 1 year is the predictor factor of INTERVAL(EP-FP) (hazard ratio: 1.422; 95% CI: 1.130-1.788; P = .003). It was evident that the longer the INTERVAL(EP-HSG), the lower the FP rate odds ratio; and the older the EP age, the lower the FP rate odds ratio. (OR, 95% CI; >1 year: 0.59, 0.41-0.86; >2 year: 0.42, 0.32-0.55; >25 years old: 0.47, 0.38-0.57; >30 years old: 0.29, 0.24-0.35; >35 years old: 0.12, 0.08-0.18, all P < .001).Receiving HSG after EP, short INTERVAL(EP-HSG), EP age less than 30 years old, had significant positive impacts on the FP. We encourage shortening the INTERVAL(EP-HSG), and the counseling of women on the most appropriate way to conceive thereafter. PMID- 28640131 TI - Paragonimiasis in Children in Southwest China: A retrospective case reports review from 2005 to 2016. AB - BACKGROUND: Paragonimiasis infection has no specific symptoms or typical radiologic findings, leading to the possibility of misdiagnosis. Thus, the objective of this study was to analyze clinical and radiological features, and treatment outcome of paragonimiasis in children in Southwest China to improve the awareness of this disease. METHODS: We retrospectively reviewed the records of children diagnosed with paragonimiasis in West China Second University Hospital between 2005 and 2016. The confirmed diagnosis of paragonimiasis was based on epidemiology history and seropositivity for paragonimiasis and/or detection of paragonimus eggs. Clinical, laboratory, and imaging findings of patients were examined in order to summarize risk factors, clinical characteristics, and treatment outcomes of these patients. RESULTS: A total of 123 patients were included; of them 112 (91.1%) lived in villages and 72 (58.5%) had a history of consuming freshwater crabs. Patients with paragonimiasis most frequently showed respiratory symptoms, including cough (26.0%, 32/123) and tachypnea (16.3%, 20/123), and gastrointestinal symptoms, including abdominal pain (26.8%, 33/123), abdominal distention (22.8%, 28/123), and vomiting (13.0%, 16/123). Laboratory examination showed elevated white blood cell (WBC) counts in the peripheral blood in 89 (72.4%) patients and eosinophilia in 102 (82.9%) patients. Tuberculosis (TB) coinfection was found in 4 (3.3%) patients. Main imaging findings included: effusions (90.4%), lymphadenopathy (40.4%), pulmonary ground-glass opacities (36.2%), cystic lesions (18.1%), and pleural thickening (17.0%). Twenty-nine patients (23.6%) received more than 1 course of praziquantel (PZQ). Additionally, 4 (19.0%) of 21 patients who were discharged from the hospital without complete treatment required rehospitalization for residual serous effusions. Moreover, patients from pericardial effusion group showed longer hospital stays and less elevated WBC counts than those from nonpericardial effusion group. CONCLUSION: Paragonimiasis should be considered in patients from endemic areas, especially in those with gastrointestinal and/or respiratory symptoms, elevated WBC count, eosinophilia, and serous effusions. Additionally, longer hospital stay may be necessary in cases of paragonimiasis associated with pericardial effusions. PMID- 28640132 TI - Treatment outcome of diffuse large B-cell lymphoma involving the head and neck: Two-institutional study for the significance of radiotherapy after R-CHOP chemotherapy. AB - This study was performed to analyze the treatment outcome for diffuse large B cell lymphoma (DLBCL) involving the head and neck and to evaluate the role of radiotherapy in the rituximab era. Fifty-six patients diagnosed with DLBCL involving the head and neck were assessed. All patients were treated with 6 cycles of rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP). After chemotherapy, radiation was delivered to the head and neck area in a median dose of 36 Gy. Radiation was delivered using 3-dimensional radiotherapy (n = 25) or intensity-modulated radiotherapy (n = 31). Primary endpoints were relapse-free survival (RFS), overall survival (OS), and local control rate. After median follow-up time of 45 months, the 5-year RFS and OS rates were 72% and 61%, respectively. Fourteen (25%) of 56 patients relapsed; 1 had a local relapse, 11 had distant relapses, and 2 had both local and distant relapses. The final local control rate after radiotherapy was 94%. Age, performance status, international prognostic index score, and radiotherapy response were significant prognostic factors for both RFS and OS in the multivariate analysis. Incidence of acute grade 3 and 4 hematologic toxicity was 9% and 4%, respectively. Grade 3 nonhematologic toxicity occurred in 2 (4%) patients, and there was no grade 4 nonhematologic toxicity for the irradiated patients. Excellent local control and survival rates can be achieved with R-CHOP followed by radiotherapy in patients with DLBCL involving the head and neck. Treatment-related toxicity after the introduction of modern radiotherapy was acceptable and limited. PMID- 28640133 TI - Effectiveness of education in point-of-care ultrasound-assisted physical examinations in an emergency department: A before-and-after study. AB - Implementation of point-of-care ultrasonography (POCUS)-assisted physical examination (PE) in emergency departments (EDs) was conducted in the ED of an urban tertiary teaching hospital. This study examines the effect of POCUS implementation in emergency medicine departments by using a systematic education program on image acquisition to analyze decision making.Educating staff on POCUS involved a technique related to image acquisition and then accurately diagnosing subsequent POCUS results. The quasi-experimental, uncontrolled before-and-after study was performed to evaluate the education effect. POCUS orders for eligible patients, length of stay (LOS) in ED, and return visits (RVs) to ED between the "before" period (March 1, 2015 to February 28, 2016) and the "after" period (March 1, 2016 to February 28, 2017) were compared. Piecewise regression was used to assess trend differences of LOS and RVs between the periods.A total of 16,942 and 16,287 patients were included in the before and after periods of education, respectively. During the study periods, 966 (6%) and 2801 (18%) POCUS were ordered, respectively (rate difference = 12%; P < .001). Before the education, the median LOS was 6.55 (interquartile rage [IQR]: 6.2-6.75) and the trend slope of LOS was -0.01. After the education, the median LOS was 5.25 (IQR: 4.85-5.45) and the trend slope (the change of which was considered significant, at a P value of .012) was -0.15. Before the education, the median RV rate was 6.4% (IQR: 6.15 6.65) and the trend slope of RVs was -0.01. After the education, the median RVs was 5.25% (IQR: 4.95-5.35) and the trend slope of RVs was also significant, at 0.11.The education of POCUS-PE in ED successfully increased use of POCUS, and reduced the LOS and RV rate in ED. PMID- 28640134 TI - Association between PD-L1 and HPV status and the prognostic value for HPV treatment in premalignant cervical lesion patients. AB - The difference of PD-L1 expression between only HPV-positive patients and premalignant cervical lesion patients did not be reported in present studies. And to test the PD-L1 expression in some cervical cell lesion studies using cervical exfoliated cells sample also was ignored. Meanwhile, the PD-L1 expression as a predictive biomarker still existed controversy. So in the study, first to compare the expression of PD-L1 between only HPV-positive patients and premalignant cervical lesion patients, then to research the association between PD-L1 and HPV status, lastly to explore the possible prognostic value for HPV treatment in premalignant cervical lesion patients.Cervical exfoliated cells samples of 54 premalignant cervical lesion patients with HPV16 infection were collected; meanwhile the cervical exfoliated cells samples from 20 healthy women without HPV infection and 20 patients with only HPV16 infection but cervical cytology normal were collected as 2 control groups. Flow-through hybridization and gene chip (FHGC) was used to detect the HPV type, the PD-L1 expression was tested by Flow cytometry analysis, the methylation-sensitive high-resolution melting (MS-HRM) was used to test the HPV16 L1 gene methylation. The 54 premalignant cervical lesion patients were followed up in 18 months to assess the prognostic value of PD-L1 for HPV treatment.The PD-L1 positive cell rate and mean fluorescence intensity of PD-L1 positive cell in premalignant cervical lesion patients with HPV16 infection were higher than 2 control groups. Mean fluorescence intensity of PD-L1 positive cell were increased in 54 cases when existing multiple HPV status and high HPV16-L1 gene methylation (L1 gene methylation more than 50%). High PD L1 expression (PD-L1 positive cell rate more than 10%), high HPV16-L1 gene methylation, and multiple HPV infection status could prolong the time to clean HPV infection by Kaplan-Meier analysis. Multivariate Cox proportional hazards analysis also showed that all of high PD-L1 expression, high HPV-L1 methylation, and multiple HPV infection status should increase the risk of HPV unclearance in premalignant cervical lesion patients; the hazard ratio (HR) was 2.043 (CI: 1.050 3.973), 2.797 (CI: 1.277-6.122), and 3.050 (CI: 1.406-6.615).PD-L1 expression only was correction with HPV infection when the infection induced the cervical cells to create the lesion. PD-L1 was the risk factor of HPV unclearance in premalignant cervical lesion patients, so anti-PD-L1 therapy could be a potential effectiveness way of HPV infection in premalignant cervical lesion patients. PMID- 28640135 TI - Hospitalization with hypoglycemia in patients without diabetes mellitus: A retrospective study using a national inpatient database in Japan, 2008-2012. AB - We aimed to examine prevalence, patient characteristics, etiology, and clinical outcomes of hospitalized patients who had hypoglycemia without a diagnosis of diabetes mellitus, using a Japanese nationwide database.This was a retrospective observational study using a national database of acute-care inpatients in Japan. Nondiabetic patients aged >=15 years who were hospitalized for hypoglycemia were eligible. We estimated the annual numbers of hospitalized cases in Japan. We also investigated the patient characteristics, and risk factors of in-hospital mortality.We identified 8684 eligible patients out of 22.7 million discharge records between July 2008 and March 2013. The average age was 70.0 years and the average body mass index (BMI) was 19.9 kg/m. Most frequently recorded underlying diseases were malignancies, cerebrovascular diseases, pneumonia, renal failure, and heart failure. The estimated annual numbers of hospitalizations because of hypoglycemia in nondiabetic patients were 5000 to 7000. In-hospital mortality was 14.9%, and predictive factors for poor survival included older age, community hospital, low BMI, coma at admission, urgent admission, renal failure, heart failure, pneumonia, sepsis, chronic liver diseases, and malignancies.Patients without diabetes mellitus but with hypoglycemia had multiple comorbidities and high in-hospital mortality. Clinicians should carefully investigate the etiology of hypoglycemia in nondiabetic patients, and treat the underlying diseases. PMID- 28640136 TI - Cost-effectiveness of neck-specific exercise with or without a behavioral approach versus physical activity prescription in the treatment of chronic whiplash-associated disorders: Analyses of a randomized clinical trial. AB - BACKGROUND: Fifty percent of people injured by whiplash still report neck pain after 1 year and costs associated with whiplash associated disorders (WAD) are mostly attributed to health service and sick-leave costs in chronic conditions. With increasing health care expenditures the economic impact of interventions needs to be considered. OBJECTIVE: To analyze the cost-effectiveness of physiotherapist-led neck-specific exercise without (NSE) or with a behavioral approach (NSEB), or prescription of physical activity (PPA) in chronic WAD, grade 2 to 3. METHODS: This is a secondary cost-effectiveness analysis of a multicenter randomized clinical trial of 216 participants with chronic WAD grade 2 to 3. The interventions were physiotherapist-led neck-specific exercise without or with a behavioral approach, or prescription of physical activity for 12 weeks. Incremental cost-effectiveness ratios (ICERs) were determined after 1 year and bootstrapped cost-effectiveness planes and sensitivity analyses of physiotherapy visits were performed. Health care and production loss costs were included and quality-adjusted life years (QALYs) were estimated, using the Euroqol-5D questionnaire. Comparisons with the Short Form-6D, and neck disability index (NDI) were also made. RESULTS: The 1-year follow-up was completed by 170 participants (79%). Both physiotherapist-led groups improved in health related quality of life. The intervention cost alone, per quality-adjusted life year (QALY) gain in the NSE group was US$ 12,067. A trend for higher QALY gains were observed in the NSEB group but the costs were also higher. The ICERs varied depending on questionnaire used, but the addition of a behavioral approach to neck-specific exercise alone was not cost-effective from a societal perspective (ICER primary outcome $127,800 [95% confidence interval [CI], 37,816-711,302]). The sensitivity analyses confirmed the results. The prescription of physical activity did not result in any QALY gain and the societal costs were not lower. CONCLUSION: Neck-specific exercise was cost-effective from a societal perspective in the treatment of chronic WAD compared with the other exercise interventions. ICERS varied depending on health-related quality of life questionnaires used, but the addition of a behavioral approach was not cost-effective from a societal perspective. The prescription of physical activity did not result in any QALY gain and was thus not considered a relevant option. PMID- 28640137 TI - China's growing contribution to sepsis research from 1984 to 2014: A bibliometric study. AB - BACKGROUND: The aim of this study was to analyze the global trends of sepsis research and investigate China's contribution by comparing the quantity and quality of sepsis-related publications. METHODS: Sepsis-related publications were main retrieved from the Web of Science online database by using the keywords "sepsis" or "septic shock." Bibliometric indicators, including the number of publications, total citation frequency, citation frequency per paper, h-index, research type, orientation, organization, author, journal, and funding support were analyzed. RESULTS: From 1984 to 2014, a total of 70,564 papers regarding sepsis research were published worldwide. 3.60% of which were contributed by authors from Chinese institutions. Although this contribution was less than the Unites States, Germany, England, France or Japan, a notable trend of increase in a number of scientific publications (r = 0.57, P < .001), with an average annual growth rate of 20.78%, was observed. The quality of the publications was relatively low in China. Basic research was a clear dominant representation, accounting for 50.46% of China's sepsis research. The research centers in China were mainly located in Beijing (5 centers), Shanghai (4 centers), and Hong Kong (3 centers). The National Natural Science Foundation of China supported the most Chinese sepsis researches. CONCLUSION: Global sepsis research developed swiftly during the 1984 to 2014 period. The USA was in the forefront of sepsis research. Although the data indicated that China had a large increasing rate of publications, there was a considerable gap in the quality of articles between China and other developed countries. PMID- 28640138 TI - An unusual presentation of multiple myeloma with unilateral sudden vision loss: A case report. AB - RATIONALE: Plasma cell neoplasms are categorized by neoplastic proliferation of a single clone of plasma cells which produce a monoclonal immunoglobulin. Plasma cell neoplasms can present as a solitary plasmacytoma or as multiple myeloma. Both of them can progress to multiple myeloma. Once a diagnosis of plasmacytoma has been made, thorough examinations should be carried out for identifying the disease entity. PATIENT CONCERNS AND DIAGNOSES: Herein, we describe an extraordinary rare case of multiple myeloma with initial presentation of a left sphenoid neoplasm resulting in left-sided headache and rapid deterioration of visual acuity. Histo-pathologic analysis revealed a plasma cell neoplasm with positive immunostaining for cluster of differentiation (CD)138, CD79a, and kappa light chain of immunoglobulin. A bone marrow aspiration was then performed, and the diagnosis of multiple myeloma was then confirmed. INTERVENTIONS AND OUTCOMES: After investigative workup, our patient received chemotherapy, localized radiotherapy, and autologous stem cell transplantation. Her visual acuity recovered to the baseline and she sustained a partial response without subjective discomfort. LESSONS: Extramedullary plasmacytoma is an interesting but infrequent presentation of multiple myeloma. Moreover, involvement of the sphenoid sinus in multiple myeloma resulting in extrinsic optic nerve compression is extremely rare. Clinicians should consider plasmacytoma as a diagnostic possibility when presented with cases of solitary sphenoid neoplasm and rapid progression of clinical course. PMID- 28640139 TI - A PRISMA-compliant systematic review and meta-analysis of the relationship between thyroid disease and different levels of iodine intake in mainland China. AB - BACKGROUND: Low-iodine intake has historically been an issue in China, causing widespread iodine deficiency diseases (IDD). China started to introduce universal salt iodization in 1995, but reports of increased thyroid disease are a concern and appropriate levels of iodine intake must be considered. OBJECTIVE: To assess the prevalence of thyroid disease with different urinary iodine concentrations (UICs) in the general population of those residing in mainland China. Furthermore, we aimed to analyze the relationship between thyroid disease and UIC, to provide guidance in establishing effective health policies regarding iodine intake. METHODS: PubMed, Cochrane, Embase, CNKI, Wan fang, and CQVIP databases were searched for random community-based relevant studies with UIC published before January 2016 in mainland China. Two independent reviewers extracted data from eligible citations, and obtained prevalence of thyroid disease for different UICs, as well as the intergroup interaction P values. RESULTS: Forty-three articles were included. The prevalence of thyroid nodules was 22.3% (95% confidence interval [CI]: 20.6%-24.1%) for the low-iodine group, 25.4% (95% CI: 20.8%-28.8%) for the medium-iodine group, and 6.8% (95% CI: 2.8% 11.5%) for the high-iodine group. In the high-iodine group, the prevalence of thyroid nodules was lower than the other groups. The prevalence of 8.3% (95% CI: 3.8%-17.3%) for subclinical hypothyroidism in the high-iodine group was significantly higher than the low- and medium-iodine groups (P < .01). The prevalence of hypothyroidism in the medium-iodine group was 0.2% (95% CI: 0.1% 0.4%), and was lower than the prevalence of the other 2 groups (P < .01). There was no difference in prevalence of hyperthyroidism in each group. CONCLUSIONS: Thyroid nodules are the most easily detectable thyroid disease. These have a lower prevalence in the high-iodine group. The prevalence of most thyroid diseases is lowest for a UIC ranging from 100 to 299 MUg/L. This serves as a reference for health policy-making with respect to iodine levels. Further studies on this topic should be carried out according to sufficient thyroid cancer data. PMID- 28640140 TI - Aldosterone and renin in cardiac patients referred for catheterization. AB - Little is known regarding alterations of the renin-angiotensin system in patients referred for cardiac catheterization. Here, we measured plasma levels of active renin and aldosterone in patients referred for cardiac catheterization in order to determine the prevalence of elevated renin, aldosterone, and the aldosterone renin ratio.A chemiluminescence assay was used to measure plasma aldosterone concentration (PAC) and active renin levels in 833 consecutive patients, after an overnight fasting and without any medication for least 12 hours. We evaluated associations of the hormonal elevations in relation to hypertension, atrial fibrillation (AF), hypertensive cardiomyopathy, coronary artery disease (CAD), valvular disease, impaired left ventricular ejection fraction (LVEF < 35%), and pulmonary hypertension (arterial pulmonary mean pressure >25 mm Hg).Hyperaldosteronism occurred in around one-third of all examined patients, without significant differences between patients with or without the named cardiac diseases. In a comparison between patients with or without any given cardiac disease condition, renin was significantly elevated in patients with either hypertension (36.4% vs 15.9%), CAD (33.9% vs 22.1%), or impaired LVEF (47.3% vs 24.8%). The angiotensin-renin ratio was elevated in AF patients and in patients with hypertensive cardiomyopathy. Patients with AF and coexisting hypertension had elevated renin more frequently than AF patients without coexisting hypertension (35.3% vs 16.5%; P = .005). Patients with persistent/permanent AF more frequently had elevated renin than patients with paroxysmal AF (34.1% vs 15.8%; P = .007).This prospective study of consecutive cardiac disease patients referred for cardiac catheterization has revealed distinct cardiac disease condition-associated differences in the frequencies of elevations in plasma renin, PAC, and the aldosterone-renin ratio. PMID- 28640141 TI - Smoking status and gene susceptibility play important roles in the development of chronic obstructive pulmonary disease and lung function decline: A population based prospective study. AB - BACKGROUND: We conducted this study to identify the influences and synergistic effects of smoking status and polymorphisms in hedgehog interacting protein (HHIP) on chronic obstructive pulmonary disease (COPD) and lung function decline. METHODS: A cohort containing 306 COPD patients and 743 healthy subjects was recruited from 25,000 subjects. All selected subjects had chronic cough for over 2 years or a smoking history above 20 pack-years. After 8 years, all subjects were divided into 2 cohorts according to whether they had quit smoking or not. A follow-up of all patients was completed after another period of 10 years. Three variants in HHIP were genotyped to investigate the impacts of gene susceptibility on the development of COPD and lung function decline. RESULTS: During the follow up tests, forced expiratory volume in 1 s (FEV1) ratios decreased more significantly in COPD patients than in healthy subjects. For variant rs7654947, FEV1 decreased more significantly in CC and CT subjects than in TT subjects. FEV1 in COPD patients with a CC genotype from smoking cohorts reduced markedly when compared to ex-smoking cohorts (case, 30.75% vs. 35.5%; total, 28% vs. 32%). CONCLUSIONS: Our results showed that smoking and HHIP variant rs7654947 were associated with COPD development and lung function decline. Moreover, we found that cigarette smoking and gene susceptibility have cooperative effects on COPD risk and lung function decline. PMID- 28640142 TI - The derivation and validation of a simple model for predicting in-hospital mortality of acutely admitted patients to internal medicine wards. AB - Limited information is available about clinical predictors of in-hospital mortality in acute unselected medical admissions. Such information could assist medical decision-making.To develop a clinical model for predicting in-hospital mortality in unselected acute medical admissions and to test the impact of secondary conditions on hospital mortality.This is an analysis of the medical records of patients admitted to internal medicine wards at one university affiliated hospital. Data obtained from the years 2013 to 2014 were used as a derivation dataset for creating a prediction model, while data from 2015 was used as a validation dataset to test the performance of the model. For each admission, a set of clinical and epidemiological variables was obtained. The main diagnosis at hospitalization was recorded, and all additional or secondary conditions that coexisted at hospital admission or that developed during hospital stay were considered secondary conditions.The derivation and validation datasets included 7268 and 7843 patients, respectively. The in-hospital mortality rate averaged 7.2%. The following variables entered the final model; age, body mass index, mean arterial pressure on admission, prior admission within 3 months, background morbidity of heart failure and active malignancy, and chronic use of statins and antiplatelet agents. The c-statistic (ROC-AUC) of the prediction model was 80.5% without adjustment for main or secondary conditions, 84.5%, with adjustment for the main diagnosis, and 89.5% with adjustment for the main diagnosis and secondary conditions. The accuracy of the predictive model reached 81% on the validation dataset.A prediction model based on clinical data with adjustment for secondary conditions exhibited a high degree of prediction accuracy. We provide a proof of concept that there is an added value for incorporating secondary conditions while predicting probabilities of in-hospital mortality. Further improvement of the model performance and validation in other cohorts are needed to aid hospitalists in predicting health outcomes. PMID- 28640143 TI - Relationship between postural instability and subcortical volume loss in Alzheimer's disease. AB - The relationship between postural instability and subcortical structure in AD has received less attention. The aims of this study were to assess whether there are differences in the ability to control balance between Alzheimer's disease (AD) and controls, and to investigate the association between subcortical gray matter volumes and postural instability in AD.We enrolled 107 consecutive AD patients and 37 controls. All participants underwent detailed neuropsychological evaluations, T1-weighted MRI at 3 T, and posture assessment using computerized dynamic posturography. We segmented the volumes of 6 subcortical structures of the amygdala, thalamus, caudate nucleus, putamen, globus pallidus and nucleus accumbens, and of hippocampus, using the FMRIBs integrated registration and segmentation tool.All subcortical structures, except for the globus pallidus, were smaller in AD compared with controls on adjusting for age and gender. Falling frequencies in unilateral stance test (UST) and composite scores in sensory organization test (SOT) were worse in AD than in controls. The motor control test did not reveal any differences between groups. On subgroup analyses in AD, the groups with poor performance in UST or SOT exhibited significantly reduced nucleus accumbens and putamen volumes, and nucleus accumbens volume, respectively. The smaller volume of the nucleus accumbens was associated with postural instability in AD (OR [95% CI] 17.847 [2.59-122.80] for UST, 42.827[6.06 302.47] for SOT, all P < .05).AD patients exhibited reduced ability to control balance compared with controls, and this postural instability was associated with nucleus accumbens volume loss. Furthermore, cognitive dysfunction was more prominent in the group with severe postural instability. PMID- 28640144 TI - Is there an association between IFN-gamma +874A/T polymorphism and periodontitis susceptibility?: A meta-analysis. AB - BACKGROUND: Interferon-gamma (IFN-gamma) is a key proinflammatory cytokine which plays a critical role in the pathogenesis and progression of periodontitis. The single nucleotide polymorphism of +874A/T in human IFN-gamma gene can influence the secretion of IFN-gamma and affect periodontitis susceptibility. However, the findings of published studies are inconsistent. Therefore, the goal of this meta analysis is to investigate whether there is an association between IFN-gamma +874A/T polymorphism and periodontitis susceptibility. METHODS: PubMed and the Cochrane Library were searched for eligible clinical studies. The odds ratio (OR) and 95% confidence interval (CI) of each study were pooled to estimate the strength of association between +874A/T and periodontitis. Subgroup analyses were performed to explore whether particular characteristics of studies were related to the overall results. RESULTS: Seven studies and a total of 1252 periodontitis patients and 1622 periodontitis-free control subjects were included. No difference was observed in genotype distribution and allele frequency between periodontitis patients and control (T vs A: OR = 1.01, 95% CI: 0.90-1.13, P = .878; TT vs AA: OR = 1.07, 95% CI: 0.87-1.32, P = .537; AT vs AA: OR = 1.00, 95% CI: 0.81-1.23, P = .996; TT+AT vs AA: OR = 1.00, 95% CI: 0.84-1.19, P = .990; TT vs AA+AT: OR = 1.03, 95% CI: 0.86-1.23, P = .733). Besides, the subgroup analysis based on ethnicity, type of periodontitis, and smoking status failed to identify significant differences in each model, either. CONCLUSIONS: The results of this meta-analysis suggest that IFN-gamma +874 A/T polymorphism may not contribute to periodontitis susceptibility. High quality and well-designed studies which combine genetic and other environmental risk factors are needed to validate this conclusion in the future. PMID- 28640145 TI - Comparison of Implantable Collamer Lens Visian ICL V4 and ICL V4c for high myopia: A cohort study. AB - The aim of this study was to investigate the visual quality of the 2 kinds of intraocular lens: Visian implantable collamer lens (ICL) V4 and Visian ICL V4c implantations for high myopia.Twenty cases (20 eyes) with high myopia who received Visian ICL V4 implantation and 18 cases (18 eyes) with high myopia who received Visian ICL V4c implantation in our hospital from April 1, 2014 to November 31, 2016 were enrolled. In 1-month follow-up, near vision, best corrected distant visual acuity (BCVA), uncorrected distant visual acuity (UDVA), and wavefront aberrations were measured, and compensation factor was calculated.Near vision, UDVA, and BCVA showed no significant difference between ICL V4 implantation and ICL V4c implantation (P >.05). However, high-order aberrations and spherical aberrations were higher in ICL V4c implantation than in ICL V4 implantation (P <.05). Low-order aberrations (defocus and astigmatism), coma, and subjective visual quality had no significant difference between ICL V4 implantation and ICL V4c implantation (P >.05).The 2 kinds of ICL Visian ICL V4 and Visian ICL V4c had similar efficacy of visual quality for high myopia. The presence of the central hole of Visian ICL V4c has no significant effect on visual quality. PMID- 28640146 TI - No association of TNF-alpha-308G/A polymorphisms with head and neck cancer risk: A PRISMA-compliant meta-analysis. AB - BACKGROUND: A number of studies had reported the association between tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms and head and neck cancer (HNC) risk. However, the results remained controversial. Therefore, we performed a meta-analysis to derive a more precise evaluation of the association between TNF-alpha-308G/A polymorphism and overall HNC risk and evaluated influence of cancer types and ethnicities. METHODS: A systematic literature search was performed using Pubmed, Embase, Cochrane Library, and Web of science. In total, we identified 15 studies including 2005 cancer cases and 2876 controls to evaluate the association of TNF-alpha-308G/A polymorphism with risk for HNC. RESULTS: Overall, there was no significant association between TNF-alpha-308G/A polymorphism and the risk of HNC. Furthermore, subgroup analyses were performed according to the types of tumor and the ethnicities, we also found there was no significant association between TNF-alpha-308G/A polymorphism and the risk of NPC and OC, and European and Asian populations had no statistically significant difference in the relationship of TNF-alpha-308G/A polymorphism and HNC susceptibility. CONCLUSION: This meta-analysis indicates that the TNF-alpha 308G/A polymorphism is not associated with HNC risk. In the future, large and well-designed case-control studies are needed to validate our findings. PMID- 28640147 TI - Human photoreceptor cone density measured with adaptive optics technology (rtx1 device) in healthy eyes: Standardization of measurements. AB - The anatomic structures of the anterior segment of the eye enable correct reception of stimuli by the retina, which contains receptors that receive light impulses and transmit them to the visual cortex. The aim of this study was to assess the effect of the size of the sampling window in an adaptive optics (AO) flood-illumination retinal camera (rtx1) on cone density measurements in the eyes of healthy individuals and to investigate the differences in cone density and spacing in different quadrants of the retina. Thirty-three subjects with no ophthalmic or systemic disease underwent a detailed ophthalmologic examination. Photographs of retinal fragments 3 degrees from the fovea were taken using the rtx1 AO retinal camera. We used sampling windows with 3 sizes (50 * 50, 100 * 100, and 250 * 250 MUm). Cone density, spacing, and shape were determined using AOdetect software. The median (interquartile range) cone density was 19,269 (4964) cones/mm. There were statistically significant differences between measurements taken with the 50/50 and 250/250-m windows. There were no significant differences in the cone spacing results between any of the windows examined, but the measurements differed according to location between the superior and temporal quadrants. The most common cone shape was hexagonal (47.6%) for all window sizes and locations. These findings may help in the development of a normative database for variation in cone density in healthy subjects and to allow the best window to be chosen for obtain the most correct values for eccentricity measurements of 3 degrees. In our study, the optimal sampling window was 100 * 100 MUm. PMID- 28640148 TI - Restrictive versus liberal transfusion strategies for red blood cell transfusion after hip or knee surgery: A systematic review and meta-analysis. AB - BACKGROUND: Red blood cell (RBC) transfusions are commonly used in surgical patients, but accompanied by many risks such as metabolic derangement, and allergic and febrile reactions. Indications for transfusion in patients after hip or knee surgery have not been definitively evaluated and remain controversial. We performed a meta-analysis to compare the benefits and harms of restrictive versus liberal transfusion strategies in patients after hip or knee surgery. METHODS: The PubMed, EMBASE, and Cochrane Library databases were searched for relevant studies through September 2015. The main clinical outcomes reported in randomized controlled trials (RCTs) included 30-day mortality, infection rate, cardiogenic complications, and length of hospital stay. The meta-analysis program of the Cochrane Collaboration (RevMan version 5.3.0) was used for data analysis. Statistical heterogeneity was assessed by both Cochran chi-squared test (Q test) and I test. Begg and Egger test were used to assess potential publication bias. RESULTS: We identified 10 eligible RCTs, involving 3788 patients in total. In patients undergoing hip or knee surgery, we found no differences in mortality, or the incidence rates of pneumonia, wound infection, myocardial infarction, or congestive heart failure, between restrictive and liberal thresholds for RBC transfusion (P > .05). CONCLUSION: Restrictive transfusion has no advantage over the liberal strategy. However, considerably less patients received blood transfusion via the restrictive strategy than with the liberal counterpart. Due to variations in the included studies, additional larger scale and well-designed studies are required to validate these conclusions. PMID- 28640149 TI - Analysis of risk factors for intraoperative hemorrhage of cesarean scar pregnancy. AB - The current commonly used treatments for cesarean scar pregnancy (CSP) include multiple treatments such as medication, uterine artery embolization, curettage and surgery, and their combinations. However, every treatment option has risks of excessive hemorrhage from uterus. In this study, we retrospectively analyzed the risk factors for intraoperative hemorrhage of different treatments for CSP patients, with the hope to provide the guidance for CSP treatment.Fifty-eight cases of CSP patients who were treated with curettage after medication, curettage after uterine artery embolization, or surgery were retrospectively analyzed and compared for the clinical efficacy, length of hospital stay, and hemorrhage rate. Further, they were divided into the bleeding group (>=200 mL, 15 cases) and the control group (<200 mL, 43 cases). The hemorrhage-related risk factors were subjected to univariate analysis, including age, pregnant times, delivery times, abortion times or curettage times, the time from last cesarean section, menolipsis time, serum human chorionic gonadotropin level, ultrasound typing, maximum diameter of gestational sac or mass under ultrasound, peritrophoblastic blood flow around the mass, and the distance of gestational sac or mass from the uterine serosa layer. The significant indexes in univariate analysis were further analyzed using both receiver operating characteristic (ROC) analysis and multivariate logistic regression analysis.The success rate, length of hospital stay, and hemorrhage rate were not significantly different among the 3 treatment groups (P > .05). Univariate analysis found that patients in the bleeding group had significantly longer menolipsis time and greater maximum diameter than patients in the control group (P < .05). ROC analysis showed that the optimal cutoff for menolipsis time and maximum diameter were 51 days and 27 mm, respectively, and the areas under their corresponding ROC were 0.680 and 0.787, respectively. Multivariate analysis showed that only the maximum diameter in the retrospective equation was of significance (P < .05, odds ratio: 1.067, 95% confidence interval: 1.014~1.123].All treatments have high success rates and no significant effects on intraoperative bleeding. Both menolipsis time and maximum diameter can be used to predict the risk of intraoperative bleeding, and the latter have a greater predictive value. PMID- 28640150 TI - Evaluation of research topic evolution in psychiatry using co-word analysis. AB - With the rapid increase in the incidence of mental disorders and mental issues, psychiatry has become one of the fastest growing clinical medical disciplines. Development priorities and research foci in this field have evolved over different periods.All the articles in 10 psychiatric journals with the highest impact factors were selected from the Science Citation Index (SCI) in Web of Science from 2001 to 2015. The information visualization software Sci was used to conduct co-word and clustering analyses on these articles. The articles were divided into 3 periods: 2001 to 2005, 2006 to 2010, and 2011 to 2015. Each bibliographic record contained a title, author names, abstract, keywords, references, and other information.During the 3 periods between 2001 and 2015, child and adolescent psychiatry, major depression, schizophrenia, and prefrontal cortex were constant research foci. The brain and meta-analysis gradually became new research foci, although research on symptoms slowly decreased. Molecular genetics was also an area of interest.Using scientometrics technology to visualize research foci can provide us with new ideas and research methods. Co word analysis for the preliminary exploration of research foci and developmental trends in psychiatry is helpful in finding developmental rules, choices of topics, and innovative research. Our study had some limitations. In the future, we should expand our research scope and use a variety of research methods to enrich our results. PMID- 28640151 TI - A case report of hyperosmolar hyperglycemic state in a 7-year-old child: An unusual presentation of first appearance of type 1 diabetes mellitus. AB - RATIONALE: A hyperosmolar hyperglycemic state (HHS) is a rare presentation of a hyperglycemic crisis in children with diabetes mellitus. As this condition can be fatal and has high morbidity, early recognition and proper management are necessary for a better outcome. Here, we report a rare case of HHS as the first presentation of type 1 diabetes mellitus (T1DM) in a 7-year-old girl. PATIENT CONCERNS: The patient was admitted due to polyuria and weight loss in the past few days. The initial blood glucose level was 1167mg/dL. DIAGNOSES: On the basis of clinical manifestations and laboratory results, she was diagnosed with T1DM and HHS. INTERVENTIONS: Treatment was started with intravenous fluid and regular insulin. OUTCOMES: She was discharged without any complications related to HHS and is being followed up in the outpatient clinic with split insulin therapy. LESSONS: As the incidence of T1DM is increasing, emergency physicians and pediatricians should be aware of HHS to make an early diagnosis for appropriate management, as it can be complicated in young children with T1DM. PMID- 28640152 TI - Preseason Workload Volume and High-Risk Periods for Noncontact Injury Across Multiple Australian Football League Seasons. AB - Colby, MJ, Dawson, B, Heasman, J, Rogalski, B, Rosenberg, M, Lester, L, and Peeling, P. Preseason workload volume and high-risk periods for noncontact injury across multiple Australian Football League seasons. J Strength Cond Res 31(7): 1821-1829, 2017-The purpose of this study was to assess the association between preseason workloads and noncontact injury risk in Australian football players. Individual player injury data were recorded over 4 full seasons (2012-15) from one professional club. Noncontact injury incidence (per 1,000 "on legs" field training and game hours) was compared across the preseason, precompetition, and in-season phases to determine relative noncontact injury risk. Preseason workloads (global positioning system-derived total distance run and sprint distance) and individual (fixed) injury risk factors (age, previous injury history) were incorporated into the analysis. A generalized estimating equation with a binary logistic function modeled potential risk factors with noncontact injury for selected periods across the annual cycle. Odds ratios were calculated to determine the relative injury risk. The (preseason) precompetition phase (19.1 injuries per 1,000 hours) and (in-season) rounds 12-17 (16.0 injuries per 1,000 hours) resulted in the highest injury incidence. Low cumulative total distances in late preseason (<108 km) and precompetition (76-88 km) periods were associated with significantly (p <= 0.05) greater injury risk during the in-season phase. In conclusion, these results suggest players are at the greatest injury risk during the precompetition period, with low preseason cumulative workloads associated with increased in-season injury risk. Therefore, strength and conditioning staff should place particular emphasis on achieving at least moderate training loads during and leading into this phase, where competitive game play is first introduced. PMID- 28640153 TI - Hot flashes and the heart: an ongoing enigma. PMID- 28640155 TI - Successful use of the Gellhorn pessary as a second-line pessary in women with advanced pelvic organ prolapse. AB - OBJECTIVE: The primary outcome of this study was the efficacy of the Gellhorn pessary in patients with advanced pelvic organ prolapse (POP) who failed to retain a ring with support pessary, and the secondary outcome is the related factors that influence its successful use. METHODS: Between May 2015 and May 2016, women with POP quantification stage III to IV, who initially failed to place a ring with a support pessary, but were then successfully fitted with a Gellhorn pessary, were included. We performed independent-sample t tests, nonparametric tests, chi-square tests, and logistic regressions for data analysis. RESULTS: A total of 82.3% (65/79) participants were successfully fitted with a Gellhorn pessary at the fitting. At 3 months, 46 participants continued to use the pessary, whereas 19 discontinued use, indicating a success rate of 70.8% (46/65). All the participants were satisfied with their pessary. More than half experienced mild complications such as vaginal erosion or discharge. The presence of predominant prolapse in the anterior wall may be an influential factor for successful pessary use (P < 0.01), whereas a higher body mass index or a history of prior hysterectomy or prolapse surgery was associated with discontinuation. CONCLUSION: For patients with advanced POP who failed to retain a ring with support pessary, the Gellhorn pessary can be offered as a second option. Body mass index, the presence of predominant anterior wall prolapse, and a previous hysterectomy or prolapse surgery may be potential factors influencing the outcomes of Gellhorn pessary use. PMID- 28640154 TI - Vaginal microbiota and genitourinary menopausal symptoms: a cross-sectional analysis. AB - OBJECTIVE: To examine associations between the composition of the vaginal microbiota and genitourinary menopausal symptoms, serum estrogen, and vaginal glycogen. METHODS: For this cross-sectional study, 88 women aged 40 to 62 years, enrolled in a hot flash treatment trial, provided vaginal swabs and a blood sample at enrollment. Bacterial communities were characterized using 16S rRNA PCR and deep sequencing targeting the V3-V4 region. Quantities of Lactobacillus crispatus and Lactobacillus iners were measured using qPCR. Self-reported genitourinary symptoms included: presence and severity of individual symptoms and identification of most bothersome symptom. Glycogen was measured fluorometrically in swab eluate. Serum estradiol (E2) and estrone (E1) were measured by liquid chromatography/mass spectrometry. Associations between bacteria, symptoms, glycogen, and serum estrogens were tested by linear regression or Wilcoxon signed rank test, adjusted for multiple comparisons. Comparisons between groups used Kruskall-Wallis or Fisher's exact test. RESULTS: Of the 88 women, 33 (38%) had a majority of Lactobacillus species, whereas 58 (66%) had any Lactobacillus detected. Over half (53%) reported at least one vulvovaginal symptom (most commonly dryness), but symptoms were not associated with the presence of Lactobacillus species. Women with Lactobacillus-dominant communities had higher unconjugated serum estrone, but no difference in vaginal glycogen levels, compared with those with non-Lactobacillus-dominant communities. Higher serum E2 and E1 were not associated with either higher vaginal glycogen or detection of individual genera. CONCLUSIONS: Presence of Lactobacillus-dominant vaginal microbiota was not associated with fewer vulvovaginal symptoms. Serum estrone was higher in women with Lactobacillus dominance, but vaginal-free glycogen was not associated with composition of the vaginal microbiota. PMID- 28640156 TI - The impact of Fiera, a women's personal care device, on genital engorgement as measured by thermography: a proof-of-principle study. AB - OBJECTIVE: To determine the degree of vasoengorgement of the external genitalia caused by Fiera, a personal care device developed specifically to increase sexual arousal and interest. Time to onset of self-reported genital sexual arousal and development of responsive sexual desire were also measured. METHODS: This nonblinded, prospective cohort, single-site study was conducted in women without sexual dysfunction between the ages of 18 and 70. Each participant underwent a single-visit procedure that established a baseline temperature of the external genitalia, followed by 15 minutes of Fiera use. A post-Fiera temperature assessment lasting 10 minutes was performed. Subjective measures assessed the development of genital arousal and responsive desire as a result of Fiera use. RESULTS: Fourteen premenopausal and 12 postmenopausal participants completed the study. Mean time to reach genital arousal was 5.2 + 4.2 minutes in the premenopausal group, and 4.5 + 4.3 minutes in the postmenopausal group. Statistically significant increases in the temperature of the clitoris and vestibule were demonstrated in both groups up to 10 minutes after removal of Fiera. At the labia, temperature increase was significant up to 8 minutes in the premenopausal group and up to 2 minutes in the postmenopausal group. All of the participants experienced responsive sexual desire as a result of Fiera. CONCLUSIONS: Use of Fiera produced statistically significant increases in the temperature of the external genitalia, markers of vasoengorgement, in both the premenopausal and postmenopausal participants. The onset of genital sexual arousal was rapid in both groups, and responsive sexual desire was experienced by all of the participants. PMID- 28640157 TI - Association of visceral fat area with the presence of depressive symptoms in Chinese postmenopausal women with normal glucose tolerance. AB - OBJECTIVE: Depression is one of the most common mental disorders, and women are more vulnerable to depression than men, particularly during stages of hormonal fluctuations. After menopause, fat accumulation shifts from the subcutaneous area to the visceral area, and the risk of metabolic disorder increases in parallel. The present study aimed to evaluate the association between abdominal fat distribution and the presence of depressive symptoms in postmenopausal women. METHODS: Visceral fat area (VFA) was detected by magnetic resonance imaging. Depressive symptoms were evaluated with Zung's Self-Rating Depression Scale. RESULTS: In all, 437 normoglycemic postmenopausal women with a mean age of 58.4 +/- 5.0 years (mean age at final menstrual period: 50.1 +/- 3.5 years) were enrolled in the present study, including 117 individuals with depressive symptoms and 320 individuals without depressive symptoms. The prevalence of abdominal obesity in women with depressive symptoms was much higher than that in those without depressive symptoms (37.6% vs 27.5%; P = 0.042). Participants with depressive symptoms showed elevated VFA values (74.6 +/- 29.8 vs 65.9 +/- 28.9 cm; P = 0.006). Multivariate stepwise regression analysis demonstrated that VFA was independently correlated with the presence of depressive symptoms (standardized beta = 0.099, P = 0.012). CONCLUSIONS: In Chinese postmenopausal women, visceral fat accumulation was an independent and positive factor significantly associated with the presence of depressive symptoms. PMID- 28640158 TI - Vasomotor symptoms are associated with depressive symptoms in community-dwelling older women. AB - OBJECTIVE: To assess the prevalence of, and factors associated with, moderate-to severe depressive symptoms in community-dwelling older Australian women. METHODS: A questionnaire-based, cross-sectional study was conducted amongst community dwelling older women. Participants were recruited between April and August 2014 from a national database based on the electoral roll. Depressive symptoms were assessed by the Beck Depression Inventory-II (BDI-II) tool. Vasomotor symptoms (VMS), vulvovaginal atrophy (VVA), and pelvic floor symptoms were assessed using validated questionnaires. Women were provided a comprehensive list of psychotropic medications (antidepressants, benzodiazepines, antipsychotics, and mood stabilizers) to identify their use over the preceding month. RESULTS: In all, 1,534 women completed the BDI-II. Overall, 34.2% (95% confidence interval [CI] 31.8%-36.7%) of women had VMS, 6.3% (95% CI 5.2%-7.7%) had moderate-to severe depressive symptoms (BDI-II score >=20), 26.8% (95% CI 24.6%-29.1%) had used any psychotropic medication in the previous month, and 17.5% (95%CI: 15.6 19.5%) had taken an antidepressant.Moderate-to-severe depressive symptoms were more common among women using antidepressants compared with nonusers (16.6% vs 4.3%; P < 0.001). Obesity (adjusted odds ratio [AOR] 2.18, 95% CI 1.17-4.04), living in financially insecure housing (AOR 3.84, 95% CI 2.08-8.08), being a caregiver to another person (AOR 2.39, 95% CI 1.36-4.19), being a smoker (AOR 2.28, 95% CI 1.12-4.66), having VMS (AOR 1.67, 95% CI 1.03-2.62), having pelvic floor dysfunction (AOR 1.78, 95% CI 1.08-2.94), and having vaginal dryness during intercourse (AOR 1.84, 95% CI 1.06-3.22, P < 0.05) were positively and independently associated with moderate-to-severe depressive symptoms. Being currently partnered (AOR 0.57, 95% CI 0.33-0.97) and employed (AOR 0.38, 95% CI 0.16-0.92) were associated with a lower likelihood of depressive symptoms. CONCLUSIONS: In older women, depressive symptoms are common and are associated with social and financial insecurity, and with VMS. PMID- 28640159 TI - Transcranial direct current stimulation effects on menopausal vasomotor symptoms. AB - OBJECTIVE: To assess the effects of transcranial direct current stimulation (tDCS) compared with tDCS-sham on vasomotor symptoms of postmenopausal women. METHODS: Postmenopausal women (N = 30), aged between 45 and 68 years, with at least four episodes of vasomotor symptoms per day, were recruited from a specialized outpatient clinic at a tertiary hospital in the south of Brazil and through a media call after inclusion and exclusion criteria were ensured. Active and tDCS-sham were administered over the motor cortex position (anode electrode) and contralateral supraorbital region (cathode electrode) for 10 consecutive days, except weekends. The number and intensity records of hot flashes were evaluated for 7 days before and along 30 days after the intervention. The Women's Health Questionnaire and the Hamilton Depression Rating Scale were applied to assess the quality of life and the depressive symptoms, respectively. RESULTS: The frequencies of hot flashes per day happened in a similar way in both groups, with a reduction in the first 3 weeks after the intervention. There was a return in hot flash frequencies to baseline in the fourth week (week 0: 79.0 +/- 6.2 and 75.8 +/- 6.0, week 1: 61.6 +/- 9.6 and 57.0 +/- 7.8, week 2: 56.8 +/- 8.9 and 55.9 +/- 7.1, week 3: 56.8 +/- 8.9 and 54.2 +/- 7.2, week 4: 64.9 +/- 10.7, 70.1 +/- 8.9; tDCS-sham and tDCS groups, respectively). In the tDCS group, a trend towards a conversion of intensive hot flashes into mild ones was observed. CONCLUSIONS: Our results suggest that the tDCS technique showed small trends on postmenopausal vasomotor symptoms, justifying searches for more effective methods by which tDCS could reduce hot flashes. PMID- 28640160 TI - Vasomotor symptoms in women in Asia appear comparable with women in Western countries: a systematic review. AB - OBJECTIVE: There is a belief that menopausal symptoms, particularly vasomotor symptoms (VMS), are a Western phenomena and less likely to be experienced in women in Asian countries. This systematic review of the literature was undertaken to evaluate the prevalence of VMS in Asian countries. METHODS: MEDLINE, EMBASE, PsycINFO, CINAHL, SCOPUS, and Google scholar were searched systematically for relevant population-based prevalence studies published between 1981 and 2016. The included studies were assessed for risk of bias using a risk-of-bias tool developed explicitly for the systematic review of prevalence studies. RESULTS: A total of 43 articles, comprising 31,945 women, were included. In South Asian and Middle Eastern countries, the prevalence of VMS in perimenopausal and postmenopausal women reported by studies that used random sampling and validated questionnaires was comparable with that reported for Western countries. The other Asian studies that used convenience-sampling procedures, irrespective of questionnaire validation, provided more disparate results. The reasons for the variation in reporting of prevalences of VMS in the included studies are likely to be a function of methodological issues, rather than ethnic, cultural, or socioeconomic differences. Most of the included studies had a medium-to-high risk of bias. CONCLUSIONS: The reported prevalences of VMS in Asia, particularly in South Asian and Middle Eastern countries, are consistent across studies that used random sampling and validated questionnaires, and are comparable with those in Western countries. Data from nationally representative studies that employ validated instruments are still needed in several Asian countries to ascertain the true prevalence of VMS. PMID- 28640161 TI - Combined data of intravaginal prasterone against vulvovaginal atrophy of menopause. AB - OBJECTIVE: To analyze the effects of intravaginal prasterone obtained in the three randomized clinical studies performed in postmenopausal women suffering from moderate to severe (MS) dyspareunia due to vulvovaginal atrophy (VVA). METHODS: In three independent 12-week prospective, randomized, double-blind, and placebo-controlled clinical studies, the effect of daily intravaginal 0.50% (6.5 mg) prasterone was examined on four co-primary objectives in women having MS pain during sexual activity (dyspareunia), identified as their most bothersome symptom (MBS) of VVA at baseline. RESULTS: In 436 women treated with 0.50% prasterone and 260 women who received placebo, an average 35.1% decrease over placebo in the percentage of parabasal cells (P < 0.0001), an average 7.7% increase in the percentage of superficial cells (P < 0.0001), and a mean 0.72 pH unit decrease in vaginal pH (P < 0.0001) were observed. The severity score of most bothersome symptom dyspareunia was decreased by a 0.46 unit (49%) (P < 0.0001 over placebo), whereas the severity score of MS vaginal dryness decreased by 0.31 unit (P < 0.0001 over placebo). A very positive evaluation was obtained on the acceptability of the technique of administration of the insert, whereas the male partners reported a very positive evaluation of the changes observed in their sexual partner. CONCLUSION: The efficacy data demonstrate highly positive effects on all the symptoms and signs of vulvovaginal atrophy with no significant drug related side effects in line with the physiology of menopause and intracrinology. PMID- 28640162 TI - The Hot Flash Related Daily Interference Scale: cutoffs, minimally important differences, and a revised short version. PMID- 28640163 TI - Mistletoe fig (Ficus deltoidea Jack) leaf extract prevented postmenopausal osteoarthritis by attenuating inflammation and cartilage degradation in rat model. AB - OBJECTIVE: Ficus deltoidea Jack (mistletoe fig) is an ornamental plant found in various parts of the world and used as traditional herbal medicine in some countries. This study investigated the potential use of F deltoidea leaf extract to mitigate osteoarthritis (OA) in ovariectomized (estrogen-deficient postmenopausal model) rats and the mechanisms involved. Diclofenac was used for comparison. METHODS: Sprague-Dawley female rats (12 weeks old) were divided randomly into five groups (n = 6): healthy; nontreated OA; OA + diclofenac (5 mg/kg); OA + extract (200 mg/kg); and OA + extract (400 mg/kg). Two weeks after bilaterally ovariectomy, OA was induced by intra-articular injection of monosodium iodoacetate into the right knee joints. After 28 days of treatment, the rats were evaluated for knee OA via physical (radiological and histological observations), biochemical, enzyme-linked immunosorbent assay, and gene expression analysis, for inflammation and cartilage degradation biomarkers. RESULTS: The osteoarthritic rats treated with the extract, and diclofenac showed significant reduction of cartilage erosion (via radiological, macroscopic, and histological images) compared with untreated osteoarthritic rats. The elevated serum interleukin-1beta, prostaglandin E2, and C-telopeptide type II collagen levels in osteoarthritic rats were significantly reduced by F deltoidea leaf extract comparable to diclofenac. The extract significantly down-regulated the interleukin-1beta, prostaglandin E2 receptor, and matrix metalloproteinase-1 mRNA expressions in the osteoarthritic cartilages, similar to diclofenac. CONCLUSIONS: F deltoidea leaf extract mitigated postmenopausal osteoarthritic joint destruction by inhibiting inflammation and cartilage degradation enzymes, at an effective extract dose equivalent to about 60 mg/kg for humans. The main bioactive compounds are probably the antioxidative flavonoids vitexin and isovitexin. PMID- 28640165 TI - An eHealth approach to treating vasomotor symptoms. PMID- 28640164 TI - Associations between postmenopausal endogenous sex hormones and C-reactive protein: a clearer picture with regional adiposity adjustment? AB - OBJECTIVE: To better understand the pathogenesis of inflammatory-related diseases after menopause, we studied the adiposity-independent association between endogenous sex hormones and C-reactive protein (CRP), a biomarker of inflammation. METHODS: We conducted a secondary, cross-sectional analysis of baseline data from the Alberta Physical Activity and Breast Cancer Prevention Trial (2003-2007), including 319 healthy, postmenopausal women not using hormone therapy. Multivariable linear regression models related serum CRP levels to estrogens, androgens, and sex hormone-binding globulin (SHBG), all on the natural logarithmic scale. Models were adjusted for age, lipids, medication, and former menopausal hormone therapy use, and also for adiposity (body mass index [BMI], per cent body fat [via whole-body dual x-ray absorptiometry], or intra-abdominal fat area [via computed tomography]). RESULTS: Without adiposity adjustment, estrone, total estradiol, and free estradiol were significantly positively associated with CRP, whereas SHBG was significantly inversely associated with CRP. Of all adiposity measures, adjustment for BMI caused the greatest attenuation of CRP-estrogen associations; only free estradiol (beta = 0.24, 95% confidence interval [CI] 0.06, 0.43) and SHBG (beta = -0.37, 95% CI -0.60, -0.13) associations remained significant. Inverse associations between CRP-total testosterone became stronger with BMI adjustment (beta = -0.20, 95% CI -0.40, 0.01). Differential associations across categories of BMI, former hormone therapy use, and years since menopause were suggestive, but not statistically significant (Pheterogeneity > 0.05). CONCLUSIONS: Prospective and systems epidemiological studies are needed to understand whether or not the cross-sectional associations we observed, independent of adiposity, between CRP-SHBG, CRP-total testosterone, and CRP-free estradiol, are causal. PMID- 28640167 TI - Timing of first childbirth and age-related cataract. AB - OBJECTIVE: No studies investigated the effects of age at first childbirth on cataract formation. This study was performed to determine the relationships of age at first childbirth to age-related cataract in postmenopausal women. METHODS: Study population included 7,021 postmenopausal women in the Korea National Health and Nutrition Examination Survey, 2008 to 2012. Participants were subdivided in quartiles according to the age at first childbirth as follows: 13 to 21, 22 to 23, 24 to 25, and 26 to 44 years. We used odds ratios (ORs) and 95% confidence intervals (CIs) to address the relationships between age at first childbirth and age-related cataract with adjustments for confounders. RESULTS: Mean participants' age and age at first childbirth were 64.4 and 23.6 years, respectively. The prevalence of any subtype of age-related cataract was 64.9%. Nuclear cataract prevalence was significantly higher in postmenopausal women with later age at first childbirth (24-25 and 26-44 years) compared with those with the earliest age at first childbirth (13-21 years): ORs (95% CIs) were 1.23 (1.05 1.45) and 1.24 (1.05-1.46), respectively. A significant linear trend across quintile was observed (P = 0.006). Age at first childbirth linearly 4% (OR 1.04, 95% CI 1.01-1.06) and 2% (OR 1.02, 95% CI 1.00-1.04) increased risk for nuclear and cortical cataract formation, respectively. The population-attributable fraction of nuclear cataract caused by the first childbirth at 24 years or later was 4.9% (95% CI 1.20%-8.59%, P = 0.009). CONCLUSIONS: Later age of first childbirth was independently associated with higher risks of nuclear and cortical cataract in postmenopausal women. Further prospective studies are needed to elucidate the role of age at first childbirth in developing age-related cataract. PMID- 28640166 TI - Missing documentation in breast cancer survivors: genitourinary syndrome of menopause. AB - OBJECTIVE: Breast cancer survivors often take hormonal treatments to prevent the recurrence of breast cancer, particularly aromatase inhibitors that can worsen the symptoms of genitourinary syndrome of menopause (GSM) such as dyspareunia, dysuria, and urinary incontinence, all of which may adversely affect survivors' quality of life. Few breast cancer survivors experiencing GSM receive adequate assessment or treatment. METHODS: In this descriptive study, we reviewed medical records for documented GSM and any treatments administered or referrals for treatment in 800 female patients who visited the Breast Cancer Survivorship Clinic at a comprehensive cancer center between July 1, 2010 and June 30, 2011, either at least 5 years after completion of treatment for invasive breast cancer or at least 6 months after completion of treatment for ductal carcinoma in situ. RESULTS: Of the 279 patients with documented symptoms of vaginal atrophy, only 111 (39.8%) had documentation of having received any form of treatment or referral. Of the 71 patients with documented symptoms of urinary tract atrophy, only 33.8% had documentation of having received treatment or referral for treatment. CONCLUSION: Breast cancer survivors often experience GSM due to lack of estrogen. The worrisome lack of documentation of assessment or treatment for GSM in a large breast cancer survivorship practice reveals missed opportunities to improve quality of life. Dissemination of recent progress in the development of GSM assessment tools, patient handouts, and new treatments to providers who care for breast cancer survivors is needed to improve this process. PMID- 28640168 TI - Degree of Postictal Suppression Depends on Seizure Induction Time in Magnetic Seizure Therapy and Electroconvulsive Therapy. AB - OBJECTIVES: Anesthesia is required for both magnetic seizure therapy (MST) and electroconvulsive therapy (ECT), although it has anticonvulsant properties. In this case, bispectral index (BIS) monitoring, a specific electroencephalogram derived monitoring, can be used to find the optimal seizure induction time during anesthesia to elicit adequate seizures. A measurement of seizure adequacy in electroencephalogram is the postictal suppression. The purpose of this study was to investigate the influence of seizure induction time on the degree of postictal suppression by comparing BIS versus no-BIS monitoring in MST and ECT. METHODS: Twenty patients with treatment-resistant depression were randomly assigned to either MST or ECT. Each patient underwent 3 treatments with the determination of seizure induction time by defined prestimulation BIS (BIS condition) and 3 treatments with determination of seizure induction time by controlled clinical trial protocol (no-BIS condition). Statistical analysis was calculated by repeated-measures analysis of variance. RESULTS: The degree of postictal suppression was more pronounced in both MST and ECT, with BIS monitoring. In this connection, no differences between MST and ECT were found. Seizure induction time was significantly later in the BIS condition (181.3 +/- 6 seconds) compared with the no-BIS condition (114.3 +/- 12 seconds) (P < 0.001). CONCLUSIONS: Adequacy of seizures, in the form of the degree of postictal suppression, was superior by determining the seizure induction time with BIS in both MST and ECT. Further research is needed to investigate the correlation between the degree of postictal suppression and treatment response. PMID- 28640169 TI - The Use of Lorazepam and Electroconvulsive Therapy in the Treatment of Catatonia: Treatment Characteristics and Outcomes in 60 Patients. AB - OBJECTIVES: Lorazepam and electroconvulsive therapy (ECT) are effective treatments for catatonia. However, systematic data on these treatments in catatonia are limited. In the present study, we aimed to investigate the clinical and treatment-related characteristics of patients with catatonia who underwent lorazepam and/or ECT. METHODS: Between January 2012 and December 2016, we received 60 patients with catatonia hospitalized in the Gaziantep University Faculty of Medicine Clinic of Psychiatry. Lorazepam and/or ECT were used in the patients' treatment schedule. Treatment results were evaluated using the Bush Francis Catatonia Rating Scale and Clinical Global Impression-Improvement. RESULTS: Thirty-five patients (58.3%) in the sample were in their first catatonic episode. The most common comorbidity was mood disorder (n = 34, 56.7%), whereas the most frequent catatonic sign was mutism (n = 43, 71.7%). Moreover, 31 patients (51.7%) had some form of medical comorbidity. Cerebral abnormalities were detected in computed tomography/magnetic resonance imaging in 22 patients (36.7%). Furthermore, 95% of the patients (n = 57) fully recovered after administration of the treatment. CONCLUSIONS: Lorazepam is a reasonable initial choice in the treatment of catatonia, with rapid consideration for ECT if there is no rapid response to lorazepam. PMID- 28640170 TI - Effectiveness of Electroconvulsive Therapy and Associated Cognitive Change in Schizophrenia: A Naturalistic, Comparative Study of Treating Schizophrenia With Electroconvulsive Therapy. AB - OBJECTIVE: There is limited evidence regarding the relative treatment effectiveness and cognitive effects of different types of electroconvulsive therapy (ECT) in schizophrenia. In this study, we sought to determine the overall effectiveness and compare the symptomatic and cognitive outcomes of patients with schizophrenia who received different modalities of ECT treatment. METHODS: Patients received 1 of 4 of the following ECT modalities: bitemporal ECT with age based dosing, right unilateral ECT with seizure threshold-based dosing, bitemporal ECT with seizure threshold-based dosing, and bifrontal ECT with seizure threshold-based dosing ECT. The Brief Psychiatric Rating Scale (BPRS) and Montreal Cognitive Assessment (MoCA) were administered to 62 patients before and after the ECT course. RESULTS: There was a significant improvement in both the total and psychotic subscales of BPRS and MoCA scores across the patients after the course of ECT. The global improvements in both BPRS and MoCA scores after ECT were not influenced by the type of ECT administered. Age-based dosing, however, was associated with poorer memory outcomes posttreatment. The overall symptomatic response rate, defined as 40% or more reduction in the psychotic subscale of BPRS, was 64.5%. The response rates did not significantly differ between the 4 types of ECT. CONCLUSIONS: Our present findings suggest that an acute course of ECT is effective in schizophrenia and may have cognitive benefits for some patients. PMID- 28640171 TI - Changes in Electroconvulsive Therapy Practice in the Last 12 Years in Hungary. AB - BACKGROUND: Electroconvulsive therapy (ECT) was rarely used in Hungary in 2002, and the majority of patients receiving ECT were diagnosed with schizophrenia. This study aimed to explore the use of ECT in Hungary in 2014. METHODS: Two semi structured questionnaires were sent to all acute adult psychiatric units in Hungary. The first questionnaire contained items concerning ECT use, and the second explored the reasons for not using ECT. RESULTS: Fifty-eight acute psychiatric inpatient units were identified, and 54 replied. Although 27 indicated that they used ECT, only 22 actually performed ECT in 2014. Thirty-one units did not offer ECT at all. In 2014, 174 patients received ECT in Hungary, constituting 0.59% of all inpatients treated in the departments where it was offered, equating to 0.176 patients/10,000 population. The indication for ECT shifted from schizophrenia in 2002 (55.6%) to mood disorders in 2014 (58.5%), but the absolute number of ECT-treated patients with mood disorders (110 vs 102) did not change. Reasons for not using ECT included the lack of an ECT machine, unavailability of an anesthesiologist, lack of finances, and lack of experienced staff. CONCLUSIONS: In view of the high frequency of depression and suicide in Hungary, it is very likely that a significant minority of patients who would benefit from ECT cannot access it, which constitutes a violation of their right to the best possible treatment. The main reasons for the inadequate ECT service are the underfinanced hospital system and a lack of necessary knowledge. PMID- 28640174 TI - Letter from the Editor. PMID- 28640172 TI - Effect of Baseline Anxiety and Depression Symptoms on Selected Outcomes Following Pulmonary Rehabilitation. AB - PURPOSE: Anxiety and depression are prevalent comorbidities in people with chronic respiratory diseases (CRDs). This study sought to quantify the influence of varying degrees of anxiety and depression on functional performance and disease impact in a population with CRDs following pulmonary rehabilitation (PR) intervention. METHODS: The Hospital Anxiety and Depression Scale (HADS), the 6 Minute Walk Test (6MWT), and the Chronic Obstructive Pulmonary Disease Assessment Test (CAT) were assessed pre- and post-PR. Participants were categorized into 3 groups (None, Probable, and Present) based on their level of anxiety and depression. Functional performance and disease impact outcomes were compared pre- and post-PR. RESULTS: Patients consisted of a total of 134 program completers (72 males, 62 females; mean age = 67.8 years). Significant improvements in functional performance with regard to 6MWT scores were observed across all groups postintervention (P < .05). The Present group, in both the anxiety and depression domains, failed to reach a minimally clinically important difference postintervention. The Probable and Present groups achieved a significant improvement in CAT scores postintervention (P < .05). CONCLUSIONS: This study showed that symptoms of anxiety and depression in people with CRDs were significantly related to lower exercise tolerance levels and higher levels of disease impact. People with increased levels of anxiety and depression have the potential to significantly improve disease impact outcomes post-PR. The results demonstrated that the detection and treatment of anxiety and depression symptoms in people with CRDs are likely to be clinically important. PMID- 28640175 TI - Treatment of Genital Melanoma: Are We Ready for Innovative Therapies? PMID- 28640176 TI - Ultrasound-Guided Percutaneous Radiofrequency Ablation of Liver Metastasis From Ovarian Cancer: A Single-Center Initial Experience. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility, effectiveness, and safety of ultrasound-guided percutaneous radiofrequency ablation (RFA) for the treatment of liver metastasis from ovarian cancer (OC). METHODS: A retrospective review was performed on 11 patients (mean age, 53.0 +/- 10.1 years) with 22 liver metastases (mean diameter, 2.0 +/- 0.8 cm) from OC undergone RFA. Radiofrequency ablation was carried out with Starburst XL electrodes (RITA Medical System, Mountain View, CA) or Cool-tip electrodes (Cool-tip Systems; Valleylab, Boulder, CO). The tumor response, time to progression, and survival after RFA were assessed. RESULTS: Complete ablation was achieved for all lesions. The technique effectiveness was 100%. During the follow-up period, local tumor progression was observed in 1 (4.5%) of 22 lesions. The median time to progression was 8.0 months after RFA. Three patients died because of disease progression after 13, 18, and 24 months, respectively. The mean overall survival time after RFA was 53.1 +/- 10.0 months, with the 1-, 3-, and 5-year overall survival rates of 100%, 61%, and 61%, respectively. No major complications were encountered. CONCLUSIONS: Radiofrequency ablation as an alternative treatment strategy is feasible and effective for selected patients with liver metastasis from OC, providing a high rate of local tumor control. PMID- 28640177 TI - The Efficacy of Fibrin Sealant Patches in Reducing the Incidence of Lymphatic Morbidity After Radical Lymphadenectomy: A Meta-Analysis. AB - BACKGROUND: Although pivotal in the oncological management of most tumors, radical lymphadenectomy is associated with a significant number of lymphatic complications. The aim of this meta-analysis is to evaluate the efficacy of fibrinogen sealant patches in reducing lymphadenectomy-related postoperative complications. METHODS/MATERIALS: The electronic databases PubMed, Medline, and Scopus were searched using the terms "lymphadenectomy" or "lymph node dissection" and "TachoSil," "TachoComb," or "fibrin sealant patch." Series evaluating the efficacy of fibrin-thrombin collagen sealant patches were included in the meta analysis. RESULTS: Overall, 26 studies were retrieved through the literature search. Ten studies including 720 patients met selection criteria. The use of fibrin-thrombin sealant patches to the sole scope of reducing lymphadenectomy related complications significantly reduced the incidence of lymphocele, symptomatic lymphocele, the need of percutaneous drainage procedures, the volume of lymph drained, and the duration of the drainage. No effect on wound and/or lymphocele infection was noted. CONCLUSIONS: This meta-analysis demonstrates that the use of fibrin-thrombin sealant patches significantly reduces the total volume of lymph drained, the duration of the drainage, the incidence of lymphocele and symptomatic lymphocele, and the need for postoperative percutaneous drainage procedures. Its use does not affect the incidence of wound or lymphocele infections. PMID- 28640178 TI - Multiple Apocrine Hidrocystomas Successfully Treated With Cryotherapy. PMID- 28640180 TI - Graphene-Ag Hybrids on Laser-Textured Si Surface for SERS Detection. AB - Surface-enhanced Raman scattering (SERS) has been extensively investigated as an effective approach for trace species detection. Silver nanostructures are high sensitivity SERS substrates in common use, but their poor chemical stability impedes practical applications. Herein, a stable and sensitive SERS substrate based on the hybrid structures of graphene/silver film/laser-textured Si (G/Ag/LTSi) was developed, and a simple, rapid, and low-cost fabrication approach was explored. Abundant nanoparticles were directly created and deposited on the Si surface via laser ablation. These aggregated nanoparticles functioned as hotspots after a 30 nm Ag film coating. A monolayer graphene was transferred to the Ag film surface to prevent the Ag from oxidation. The SERS behavior was investigated by detecting R6G and 4-MBT molecules. The experimental results indicate that the maximum enhancement factor achieved by the G/Ag/LTSi substrate is over 107 and less than 23% SERS signals lost when the substrate was exposed to ambient conditions for 50 days. The covering graphene layer played crucial roles in both the Raman signals enhancement and the Ag nanostructure protection. The stable and sensitive SERS performance of G/Ag/LTSi substrate evince that the present strategy is a useful and convenient route to fabricate large-area graphene-silver plasmonic hybrids for SERS applications. PMID- 28640179 TI - Engagement in Pleasant Leisure Activities and Blood Pressure: A 5-Year Longitudinal Study in Alzheimer Caregivers. AB - OBJECTIVE: Elevated blood pressure is a significant public health concern, particularly given its association with cardiovascular disease risk, including stroke. Caring for a loved one with Alzheimer disease has been associated with physical health morbidity, including higher blood pressure. Engagement in adaptive coping strategies may help prevent blood pressure elevation in this population. This 5-year longitudinal study examined whether greater participation in pleasant leisure activities was associated with reduced blood pressure in caregivers. METHODS: Participants were 126 in-home spousal Alzheimer's caregivers (M [SD] age = 74.2 [7.9] years) that completed five yearly assessments. Linear mixed-effects models analysis was used to examine the longitudinal relationship between pleasant leisure activities and caregivers' blood pressure, after adjusting for demographic and health characteristics. RESULTS: Greater engagement in pleasant leisure activities was associated with reduced mean arterial blood pressure (B = -0.08, SE = 0.04, p = .040). Follow-up analyses indicated that engagement in activities was significantly associated with reduced diastolic (B = -0.07, SE = 0.03, p = .030) but not systolic blood pressure (B = -0.10, SE = 0.06, p = .114). In addition, mean arterial blood pressure was significantly reduced when caregiving duties ended because of placement of care recipients in nursing homes (B = -3.10, SE = 1.11, p = .005) or death of the care recipient (B = -2.64, SE = 1.14, p = .021). CONCLUSIONS: Greater engagement in pleasant leisure activities was associated with lowered caregivers' blood pressure over time. Participation in pleasant leisure activities may have cardiovascular health benefits for Alzheimer's caregivers. PMID- 28640181 TI - A Study for Texture Feature Extraction of High-Resolution Satellite Images Based on a Direction Measure and Gray Level Co-Occurrence Matrix Fusion Algorithm. AB - To address the problem of image texture feature extraction, a direction measure statistic that is based on the directionality of image texture is constructed, and a new method of texture feature extraction, which is based on the direction measure and a gray level co-occurrence matrix (GLCM) fusion algorithm, is proposed in this paper. This method applies the GLCM to extract the texture feature value of an image and integrates the weight factor that is introduced by the direction measure to obtain the final texture feature of an image. A set of classification experiments for the high-resolution remote sensing images were performed by using support vector machine (SVM) classifier with the direction measure and gray level co-occurrence matrix fusion algorithm. Both qualitative and quantitative approaches were applied to assess the classification results. The experimental results demonstrated that texture feature extraction based on the fusion algorithm achieved a better image recognition, and the accuracy of classification based on this method has been significantly improved. PMID- 28640182 TI - Paper as Active Layer in Inkjet-Printed Capacitive Humidity Sensors. AB - An inkjet-printed relative humidity sensor based on capacitive changes which responds to different humidity levels in the environment is presented in this work. The inkjet-printed silver interdigitated electrodes configuration on the paper substrate allowed for the fabrication of a functional proof-of-concept of the relative humidity sensor, by using the paper itself as a sensing material. The sensor sensitivity in terms of relative humidity changes was calculated to be around 2 pF/RH %. The response time against different temperature steps from 3 to 85 degrees C was fairly constant (about 4-5 min), and it was considered fast for the aimed application, a smart label. PMID- 28640184 TI - A Carrier Estimation Method Based on MLE and KF for Weak GNSS Signals. AB - Maximum likelihood estimation (MLE) has been researched for some acquisition and tracking applications of global navigation satellite system (GNSS) receivers and shows high performance. However, all current methods are derived and operated based on the sampling data, which results in a large computation burden. This paper proposes a low-complexity MLE carrier tracking loop for weak GNSS signals which processes the coherent integration results instead of the sampling data. First, the cost function of the MLE of signal parameters such as signal amplitude, carrier phase, and Doppler frequency are used to derive a MLE discriminator function. The optimal value of the cost function is searched by an efficient Levenberg-Marquardt (LM) method iteratively. Its performance including Cramer-Rao bound (CRB), dynamic characteristics and computation burden are analyzed by numerical techniques. Second, an adaptive Kalman filter is designed for the MLE discriminator to obtain smooth estimates of carrier phase and frequency. The performance of the proposed loop, in terms of sensitivity, accuracy and bit error rate, is compared with conventional methods by Monte Carlo (MC) simulations both in pedestrian-level and vehicle-level dynamic circumstances. Finally, an optimal loop which combines the proposed method and conventional method is designed to achieve the optimal performance both in weak and strong signal circumstances. PMID- 28640183 TI - Bluetooth Low Energy Mesh Networks: A Survey. AB - Bluetooth Low Energy (BLE) has gained significant momentum. However, the original design of BLE focused on star topology networking, which limits network coverage range and precludes end-to-end path diversity. In contrast, other competing technologies overcome such constraints by supporting the mesh network topology. For these reasons, academia, industry, and standards development organizations have been designing solutions to enable BLE mesh networks. Nevertheless, the literature lacks a consolidated view on this emerging area. This paper comprehensively surveys state of the art BLE mesh networking. We first provide a taxonomy of BLE mesh network solutions. We then review the solutions, describing the variety of approaches that leverage existing BLE functionality to enable BLE mesh networks. We identify crucial aspects of BLE mesh network solutions and discuss their advantages and drawbacks. Finally, we highlight currently open issues. PMID- 28640185 TI - Fourier Transform Infrared Spectroscopy (FT-IR) and Simple Algorithm Analysis for Rapid and Non-Destructive Assessment of Developmental Cotton Fibers. AB - With cotton fiber growth or maturation, cellulose content in cotton fibers markedly increases. Traditional chemical methods have been developed to determine cellulose content, but it is time-consuming and labor-intensive, mostly owing to the slow hydrolysis process of fiber cellulose components. As one approach, the attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy technique has also been utilized to monitor cotton cellulose formation, by implementing various spectral interpretation strategies of both multivariate principal component analysis (PCA) and 1-, 2- or 3-band/-variable intensity or intensity ratios. The main objective of this study was to compare the correlations between cellulose content determined by chemical analysis and ATR FT IR spectral indices acquired by the reported procedures, among developmental Texas Marker-1 (TM-1) and immature fiber (im) mutant cotton fibers. It was observed that the R value, CIIR, and the integrated intensity of the 895 cm-1 band exhibited strong and linear relationships with cellulose content. The results have demonstrated the suitability and utility of ATR FT-IR spectroscopy, combined with a simple algorithm analysis, in assessing cotton fiber cellulose content, maturity, and crystallinity in a manner which is rapid, routine, and non destructive. PMID- 28640186 TI - Analysis of Serotonin Molecules on Silver Nanocolloids-A Raman Computational and Experimental Study. AB - Combined theoretical and experimental analysis of serotonin by quantum chemical density functional calculations and surface-enhanced Raman spectroscopy, respectively, is presented in this work to better understand phenomena related to this neurotransmitter's detection and monitoring at very low concentrations specific to physiological levels. In addition to the successful ultrasensitive analyte detection on silver nanoparticles for concentrations as low as 10-11 molar, the relatively good agreement between the simulated and experimentally determined results indicates the presence of all serotonin molecular forms, such as neutral, ionic, and those oxidized through redox reactions. Obvious structural molecular deformations such as bending of lateral amino chains are observed for both ionic and oxidized forms. Not only does this combined approach reveal more probable adsorption of serotonin into the silver surface through hydroxyl/oxygen sites than through NH/nitrogen sites, but also that it does so predominantly in its neutral (reduced) form, somewhat less so in its ionic forms, and much less in its oxidized forms. If the development of opto-voltammetric biosensors and their effective implementation is envisioned for the future, this study provides some needed scientific background for comprehending changes in the vibrational signatures of this important neurotransmitter. PMID- 28640187 TI - Performance Optimization Design for a High-Speed Weak FBG Interrogation System Based on DFB Laser. AB - A performance optimization design for a high-speed fiber Bragg grating (FBG) interrogation system based on a high-speed distributed feedback (DFB) swept laser is proposed. A time-division-multiplexing sensor network with identical weak FBGs is constituted to realize high-capacity sensing. In order to further improve the multiplexing capacity, a waveform repairing algorithm is designed to extend the dynamic demodulation range of FBG sensors. It is based on the fact that the spectrum of an FBG keeps stable over a long period of time. Compared with the pre collected spectra, the distorted spectra waveform are identified and repaired. Experimental results show that all the identical weak FBGs are distinguished and demodulated at the speed of 100 kHz with a linearity of above 0.99, and the range of dynamic demodulation is extended by 40%. PMID- 28640188 TI - Novel Concrete Temperature Monitoring Method Based on an Embedded Passive RFID Sensor Tag. AB - This paper firstly introduces the importance of temperature control in concrete measurement, then a passive radio frequency identification (RFID) sensor tag embedded for concrete temperature monitoring is presented. In order to reduce the influences of concrete electromagnetic parameters during the drying process, a T type antenna is proposed to measure the concrete temperature at the required depth. The proposed RFID sensor tag is based on the EPC generation-2 ultra-high frequency (UHF) communication protocol and operates in passive mode. The temperature sensor can convert the sensor signals to corresponding digital signals without an external reference clock due to the adoption of phase-locked loop (PLL)-based architecture. Laboratory experimentation and on-site testing demonstrate that our sensor tag embedded in concrete can provide reliable communication performance in passive mode. The maximum communicating distance between reader and tag is 7 m at the operating frequency of 915 MHz and the tested results show high consistency with the results tested by a thermocouple. PMID- 28640189 TI - Automatic Detection and Classification of Pole-Like Objects for Urban Cartography Using Mobile Laser Scanning Data. AB - Mobile laser scanning (MLS) is a modern and powerful technology capable of obtaining massive point clouds of objects in a short period of time. Although this technology is nowadays being widely applied in urban cartography and 3D city modelling, it has some drawbacks that need to be avoided in order to strengthen it. One of the most important shortcomings of MLS data is concerned with the fact that it provides an unstructured dataset whose processing is very time-consuming. Consequently, there is a growing interest in developing algorithms for the automatic extraction of useful information from MLS point clouds. This work is focused on establishing a methodology and developing an algorithm to detect pole like objects and classify them into several categories using MLS datasets. The developed procedure starts with the discretization of the point cloud by means of a voxelization, in order to simplify and reduce the processing time in the segmentation process. In turn, a heuristic segmentation algorithm was developed to detect pole-like objects in the MLS point cloud. Finally, two supervised classification algorithms, linear discriminant analysis and support vector machines, were used to distinguish between the different types of poles in the point cloud. The predictors are the principal component eigenvalues obtained from the Cartesian coordinates of the laser points, the range of the Z coordinate, and some shape-related indexes. The performance of the method was tested in an urban area with 123 poles of different categories. Very encouraging results were obtained, since the accuracy rate was over 90%. PMID- 28640190 TI - trans-Cinnamic and Chlorogenic Acids Affect the Secondary Metabolic Profiles and Ergosterol Biosynthesis by Fusarium culmorum and F. graminearum Sensu Stricto. AB - Plant-derived compounds limiting mycotoxin contamination are currently of major interest in food and feed production. However, their potential application requires an evaluation of their effects on fungal secondary metabolism and membrane effects. In this study, different strains of Fusarium culmorum and F. graminearum sensu stricto were exposed to trans-cinnamic and chlorogenic acids on solid YES media. Fusaria produced phenolic acids, whose accumulation was lowered by exogenous phenolic compounds. In addition, fungi reduced exogenous phenolic acids, leading either to their conversion or degradation. trans-Cinnamic acid was converted to caffeic and ferulic acids, while chlorogenic acid was degraded to caffeic acid. The latter underwent further degradation to protocatechuic acid. Fungal-derived trans-cinnamic acid, as the first intermediate of the shikimate pathway, increased after chlorogenic acid treatment, presumably due to the further inhibition of the conversion of trans-cinnamic acid. Exogenous trans cinnamic and chlorogenic acid displayed the inhibition of mycotoxin production by Fusaria, which appeared to be largely dependent on the phenolic compound and its concentration and the assayed strain. Exogenous phenolic acids showed different effects on ergosterol biosynthesis by fungi. It was found that the production of this membrane sterol was stimulated by trans-cinnamic acid, while chlorogenic acid negatively impacted ergosterol biosynthesis, suggesting that phenolic acids with stronger antifungal activities may upregulate ergosterol biosynthesis by Fusaria. This paper reports on the production of phenolic acids by Fusaria for the first time. PMID- 28640191 TI - Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory. AB - Waddington's epigenetic landscape, a famous metaphor in developmental biology, depicts how a stem cell progresses from an undifferentiated phenotype to a differentiated one. The concept of "landscape" in the context of dynamical systems theory represents a high-dimensional space, in which each cell phenotype is considered as an "attractor" that is determined by interactions between multiple molecular players, and is buffered against environmental fluctuations. In addition, biological noise is thought to play an important role during these cell-fate decisions and in fact controls transitions between different phenotypes. Here, we discuss the phenotypic transitions in cancer from a dynamical systems perspective and invoke the concept of "cancer attractors" hidden stable states of the underlying regulatory network that are not occupied by normal cells. Phenotypic transitions in cancer occur at varying levels depending on the context. Using epithelial-to-mesenchymal transition (EMT), cancer stem-like properties, metabolic reprogramming and the emergence of therapy resistance as examples, we illustrate how phenotypic plasticity in cancer cells enables them to acquire hybrid phenotypes (such as hybrid epithelial/mesenchymal and hybrid metabolic phenotypes) that tend to be more aggressive and notoriously resilient to therapies such as chemotherapy and androgen-deprivation therapy. Furthermore, we highlight multiple factors that may give rise to phenotypic plasticity in cancer cells, such as (a) multi-stability or oscillatory behaviors governed by underlying regulatory networks involved in cell-fate decisions in cancer cells, and (b) network rewiring due to conformational dynamics of intrinsically disordered proteins (IDPs) that are highly enriched in cancer cells. We conclude by discussing why a therapeutic approach that promotes "recanalization", i.e., the exit from "cancer attractors" and re-entry into "normal attractors", is more likely to succeed rather than a conventional approach that targets individual molecules/pathways. PMID- 28640193 TI - Identification of Light-Independent Anthocyanin Biosynthesis Mutants Induced by Ethyl Methane Sulfonate in Turnip "Tsuda" (Brassica rapa). AB - The epidermis of swollen storage roots in purple cultivars of turnip "Tsuda" (Brassica rapa) accumulates anthocyanin in a light-dependent manner, especially in response to UV-A light, of which the mechanism is unclear. In this study, we mutagenized 15,000 seeds by 0.5% (v/v) ethyl methane sulfonate (EMS) and obtained 14 mutants with abnormal anthocyanin production in their epidermis of swollen storage roots. These mutants were classified into two groups: the red mutants with constitutive anthocyanin accumulation in their epidermis of storage roots even in underground parts in darkness and the white mutants without anthocyanin accumulation in the epidermis of storage roots in aboveground parts exposed to sunlight. Test cross analysis demonstrated that w9, w68, w204, r15, r21, r30 and r57 contained different mutations responsible for their phenotypic variations. Further genetic analysis of four target mutants (w9, w68, w204 and r15) indicated that each of them was controlled by a different recessive gene. Intriguingly, the expression profiles of anthocyanin biosynthesis genes, including structural and regulatory genes, coincided with their anthocyanin levels in the epidermis of storage roots in the four target mutants. We proposed that potential genes responsible for the mutations should be upstream factors of the anthocyanin biosynthesis pathway in turnips, which provided resources to further investigate the mechanisms of light-induced anthocyanin accumulation. PMID- 28640194 TI - Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism. AB - To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group (p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-gamma, as well as protein concentrations interleukin (IL)-1beta and interferon-gamma, were lowest in the HM group (p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver. PMID- 28640192 TI - Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. AB - Pancreatic ductal adenocarcinoma (PDAC), which constitutes 90% of pancreatic cancers, is the fourth leading cause of cancer-related deaths in the world. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Most of the available treatments are palliative, with the objective of relieving disease-related symptoms and prolonging survival. Currently, available therapeutic options are surgery, radiation, chemotherapy, immunotherapy, and use of targeted drugs. However, thus far, therapies targeting cancer-associated molecular pathways have not given satisfactory results; this is due in part to the rapid upregulation of compensatory alternative pathways as well as dense desmoplastic reaction. In this review, we summarize currently available therapies and clinical trials, directed towards a plethora of pathways and components dysregulated during PDAC carcinogenesis. Emerging trends towards targeted therapies as the most promising approach will also be discussed. PMID- 28640196 TI - Vitamin D3 and 25-Hydroxyvitamin D3 Content of Retail White Fish and Eggs in Australia. AB - Dietary vitamin D may compensate for inadequate sun exposure; however, there have been few investigations into the vitamin D content of Australian foods. We measured vitamin D3 and 25-hydroxyvitamin D3 (25(OH)D3) in four species of white fish (barramundi, basa, hoki and king dory), and chicken eggs (cage and free range), purchased from five Australian cities. Samples included local, imported and wild-caught fish, and eggs of varying size from producers with a range of hen stocking densities. Raw and cooked samples were analysed using high performance liquid chromatography with photodiode array. Limits of reporting were 0.2 and 0.1 MUg/100 g for vitamin D3 and 25(OH)D3, respectively. The vitamin D3 content of cooked white fish ranged from <0.1 to 2.3 MUg/100 g, and the 25(OH)D3 content ranged from 0.3 to 0.7 MUg/100 g. The vitamin D3 content of cooked cage eggs ranged from 0.4 to 0.8 MUg/100 g, and the 25(OH)D3 content ranged from 0.4 to 1.2 MUg/100 g. The vitamin D3 content of cooked free-range eggs ranged from 0.3 to 2.2 MUg/100 g, and the 25(OH)D3 content ranged from 0.5 to 0.8 MUg/100 g. If, as has been suggested, 25(OH)D3 has five times greater bioactivity than vitamin D3, one cooked serve (100 g) of white fish, and one cooked serve of cage or free range eggs (120 g) may provide 50% or 100%, respectively, of the current guidelines for the adequate intake of vitamin D (5 ug) for Australians aged 1-50 years. PMID- 28640197 TI - Mesoporous Silica Matrix as a Tool for Minimizing Dipolar Interactions in NiFe2O4 and ZnFe2O4 Nanoparticles. AB - NiFe2O4 and ZnFe2O4 nanoparticles have been prepared encased in the MCM (Mobile Composition of Matter) type matrix. Their magnetic behavior has been studied and compared with that corresponding to particles of the same composition and of a similar size (prepared and embedded in amorphous silica or as bare particles). This study has allowed elucidation of the role exerted by the matrix and interparticle interactions in the magnetic behavior of each ferrite system. Thus, very different superparamagnetic behavior has been found in ferrite particles of similar size depending on the surrounding media. Also, the obtained results clearly provide evidence of the vastly different magnetic behavior for each ferrite system. PMID- 28640195 TI - Pharmacogenomic Variants May Influence the Urinary Excretion of Novel Kidney Injury Biomarkers in Patients Receiving Cisplatin. AB - Nephrotoxicity is a dose limiting side effect associated with the use of cisplatin in the treatment of solid tumors. The degree of nephrotoxicity is dictated by the selective accumulation of cisplatin in renal tubule cells due to: (1) uptake by organic cation transporter 2 (OCT2) and copper transporter 1 (CTR1); (2) metabolism by glutathione S-transferases (GSTs) and gamma glutamyltransferase 1 (GGT1); and (3) efflux by multidrug resistance-associated protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). The purpose of this study was to determine the significance of single nucleotide polymorphisms that regulate the expression and function of transporters and metabolism genes implicated in development of acute kidney injury (AKI) in cisplatin treated patients. Changes in the kidney function were assessed using novel urinary protein biomarkers and traditional markers. Genotyping was conducted by the QuantStudio 12K Flex Real-Time PCR System using a custom open array chip with metabolism, transport, and transcription factor polymorphisms of interest to cisplatin disposition and toxicity. Traditional and novel biomarker assays for kidney toxicity were assessed for differences according to genotype by ANOVA. Allele and genotype frequencies were determined based on Caucasian population frequencies. The polymorphisms rs596881 (SLC22A2/OCT2), and rs12686377 and rs7851395 (SLC31A1/CTR1) were associated with renoprotection and maintenance of estimated glomerular filtration rate (eGFR). Polymorphisms in SLC22A2/OCT2, SLC31A1/CTRI, SLC47A1/MATE1, ABCC2/MRP2, and GSTP1 were significantly associated with increases in the urinary excretion of novel AKI biomarkers: KIM-1, TFF3, MCP1, NGAL, clusterin, cystatin C, and calbindin. Knowledge concerning which genotypes in drug transporters are associated with cisplatin-induced nephrotoxicity may help to identify at-risk patients and initiate strategies, such as using lower or fractionated cisplatin doses or avoiding cisplatin altogether, in order to prevent AKI. PMID- 28640198 TI - Experimental Investigation of Magnetic Nanoparticle-Enhanced Microwave Hyperthermia. AB - The objective of this study was to evaluate microwave heating enhancements offered by iron/iron oxide nanoparticles dispersed within tissue-mimicking media for improving efficacy of microwave thermal therapy. The following dopamine coated magnetic nanoparticles (MNPs) were considered: 10 and 20 nm diameter spherical core/shell Fe/Fe3O4, 20 nm edge-length cubic Fe3O4, and 45 nm edge length/10 nm height hexagonal Fe3O4. Microwave heating enhancements were experimentally measured with MNPs dissolved in an agar phantom, placed within a rectangular waveguide. Effects of MNP concentration (2.5-20 mg/mL) and microwave frequency (2.0, 2.45 and 2.6 GHz) were evaluated. Further tests with 10 and 20 nm diameter spherical MNPs dispersed within a two-compartment tissue-mimicking phantom were performed with an interstitial dipole antenna radiating 15 W power at 2.45 GHz. Microwave heating of 5 mg/mL MNP-agar phantom mixtures with 10 and 20 nm spherical, and hexagonal MNPs in a waveguide yielded heating rates of 0.78 +/- 0.02 degrees C/s, 0.72 +/- 0.01 degrees C/s and 0.51 +/- 0.03 degrees C/s, respectively, compared to 0.5 +/- 0.1 degrees C/s for control. Greater heating enhancements were observed at 2.0 GHz compared to 2.45 and 2.6 GHz. Heating experiments in two-compartment phantoms with an interstitial dipole antenna demonstrated potential for extending the radial extent of therapeutic heating with 10 and 20 nm diameter spherical MNPs, compared to homogeneous phantoms (i.e., without MNPs). Of the MNPs considered in this study, spherical Fe/Fe3O4 nanoparticles offer the greatest heating enhancement when exposed to microwave radiation. These nanoparticles show strong potential for enhancing the rate of heating and radial extent of heating during microwave hyperthermia and ablation procedures. PMID- 28640200 TI - Animal-Assisted Interventions in the Classroom-A Systematic Review. AB - The inclusion of animals in educational practice is becoming increasingly popular, but it is unclear how solid the evidence for this type of intervention is. The aim of this systematic review is to scrutinise the empirical research literature relating to animal-assisted interventions conducted in educational settings. The review included 25 papers; 21 from peer-reviewed journals and 4 obtained using grey literature databases. Most studies reported significant benefits of animal-assisted interventions in the school setting. Despite this, studies vary greatly in methods and design, in intervention types, measures, and sample sizes, and in the length of time exposed to an animal. Furthermore, a worrying lack of reference to risk assessment and animal welfare must be highlighted. Taken together, the results of this review show promising findings and emerging evidence suggestive of potential benefits related to animals in school settings. The review also indicates the need for a larger and more robust evidence base driven by thorough and strict protocols. The review further emphasises the need for safeguarding for all involved-welfare and safety are paramount. PMID- 28640199 TI - The Role of Peripheral CNS-Directed Antibodies in Promoting Inflammatory CNS Demyelination. AB - In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This scenario is supported at least in part, by antibodies in conjunction with complement activation in the majority of MS lesions and by deposition of anti aquaporin-4 (AQP-4) antibodies in areas of astrocyte loss in patients with classical NMO. A currently emerging subgroup of AQP-4 negative NMO-SD patients expresses antibodies against myelin oligodendrocyte glycoprotein (MOG), again suggestive of their direct binding to CNS myelin. However, both known entities of anti-CNS antibodies, anti-AQP-4- as well as anti-MOG antibodies, are predominantly found in the serum, which raises the questions why and how a humoral response against CNS antigens is raised in the periphery, and in a related manner, what pathogenic role these antibodies may exert outside the CNS. In this regard, recent experimental and clinical evidence suggests that peripheral CNS-specific antibodies may indirectly activate peripheral CNS autoreactive T cells by opsonization of otherwise unrecognized traces of CNS antigen in peripheral compartments, presumably drained from the CNS by its newly recognized lymphatic system. In this review, we will summarize all currently available data on both possible roles of antibodies in CNS demyelinating disorders, first, directly enhancing damage within the CNS, and second, promoting a peripheral immune response against the CNS. By elaborating on the latter scenario, we will develop the hypothesis that peripheral CNS-recognizing antibodies may have a powerful role in initiating acute flares of CNS demyelinating disease and that these humoral responses may represent a therapeutic target in its own right. PMID- 28640201 TI - Deoxynivalenol Biomarkers in the Urine of UK Vegetarians. AB - Deoxynivalenol (DON) is produced by Fusarium graminearum and is one of the most commonly occurring trichothecenes. Vegetarians are alleged to be a high-risk group for DON exposure due to high intakes of cereals susceptible to the growth of the mycotoxin. This study provides the levels of DON and de-epoxi Deoxynivalenol (DOM-1) in urine analysed by liquid chromatography-mass spectrometry (LC-MS) in UK vegetarians. Over two consecutive days, morning urine samples were collected from 32 vegetarians and 31 UK adult volunteers, and associated food consumption 24 h prior to the sample was recorded. Statistically significant differences between the weight of the UK adults and vegetarians (t = 3.15. df = 61, p <= 0.005 two-tailed) were observed. The mean levels of DON in urine for adults on day 1 was 3.05 ng free DON/mg creatinine, and on day 2 was 2.98 ng free DON/mg creatinine. Even though high mean levels were observed, most adults were within the tolerable daily intake. However, for vegetarians, the mean level of urinary DON on day 1 was 6.69 ng free DON/mg creatinine, and on day 2 was 3.42 ng free DON/mg creatinine. These levels equate to up to 32% of vegetarians exceeding recommended tolerable daily intakes (TDI) of exposure (1 ug/kg b.w./day). PMID- 28640203 TI - Effect of Solution pH on the Adsorption of Paracetamol on Chemically Modified Activated Carbons. AB - Paracetamol adsorption in acidic, neutral and basic media on three activated carbons with different chemistry surfaces was studied. A granular activated carbon (GAC) was prepared from coconut shell; starting from this sample, an oxidized activated carbon (GACo) was obtained by treating the GAC with a boiling solution of 6 M nitric acid, so to generate a greater number of oxygenated surface groups. In addition, a reduced activated carbon (GACr) was obtained by heating the GAC at 1173 K, to remove the oxygenated surface groups. Paracetamol adsorption was higher for GACr due to the lower presence of oxygenated surface functional groups. Moreover, adsorption was highest at neutral pH. The magnitude of the interactions between paracetamol molecules and activated carbons was studied by measuring the immersion enthalpies of activated carbons in solution of paracetamol at different concentrations and pH values and by calculating the interaction enthalpy. The highest value was obtained for GACr in a paracetamol solution of 1000 mg L-1 at pH 7, confirming that paracetamol adsorption is favoured on basic activated carbons at pH values near to neutrality. Finally, the Gibbs energy changes confirmed the latter result, allowing explaining the different magnitudes of the interactions between paracetamol and activated carbons, as a function of solution pH. PMID- 28640202 TI - Evaluation of Legionella Air Contamination in Healthcare Facilities by Different Sampling Methods: An Italian Multicenter Study. AB - Healthcare facilities (HF) represent an at-risk environment for legionellosis transmission occurring after inhalation of contaminated aerosols. In general, the control of water is preferred to that of air because, to date, there are no standardized sampling protocols. Legionella air contamination was investigated in the bathrooms of 11 HF by active sampling (Surface Air System and Coriolis(r)MU) and passive sampling using settling plates. During the 8-hour sampling, hot tap water was sampled three times. All air samples were evaluated using culture-based methods, whereas liquid samples collected using the Coriolis(r)MU were also analyzed by real-time PCR. Legionella presence in the air and water was then compared by sequence-based typing (SBT) methods. Air contamination was found in four HF (36.4%) by at least one of the culturable methods. The culturable investigation by Coriolis(r)MU did not yield Legionella in any enrolled HF. However, molecular investigation using Coriolis(r)MU resulted in eight HF testing positive for Legionella in the air. Comparison of Legionella air and water contamination indicated that Legionella water concentration could be predictive of its presence in the air. Furthermore, a molecular study of 12 L. pneumophila strains confirmed a match between the Legionella strains from air and water samples by SBT for three out of four HF that tested positive for Legionella by at least one of the culturable methods. Overall, our study shows that Legionella air detection cannot replace water sampling because the absence of microorganisms from the air does not necessarily represent their absence from water; nevertheless, air sampling may provide useful information for risk assessment. The liquid impingement technique appears to have the greatest capacity for collecting airborne Legionella if combined with molecular investigations. PMID- 28640204 TI - Fucoidan Does Not Exert Anti-Tumorigenic Effects on Uveal Melanoma Cell Lines. AB - BACKGROUND: The polysaccharide fucoidan is widely investigated as an anti-cancer agent. Here, we tested the effect of fucoidan on uveal melanoma cell lines. METHODS: The effect of 100 uM fucoidan was investigated on five cell lines (92.1, Mel270 OMM1, OMM2.3, OMM2.5) and of 1 ug/mL-1 mg/mL fucoidan in two cell lines (OMM1, OMM2.3). Cell proliferation and viability were investigated with a WST-1 assay, migration in a wound healing (scratch) assay. Vascular Endothelial Growth Factor (VEGF) was measured in ELISA. Angiogenesis was evaluated in co-cultures with endothelial cells. Cell toxicity was induced by hydrogen-peroxide. Protein expression (Akt, ERK1/2, Bcl-2, Bax) was investigated in Western blot. RESULTS: Fucoidan increased proliferation in two and reduced it in one cell line. Migration was reduced in three cell lines. The effect of fucoidan on VEGF was cell type and concentration dependent. In endothelial co-culture with 92.1, fucoidan significantly increased tubular structures. Moreover, fucoidan significantly protected all tested uveal melanoma cell lines from hydrogen peroxide induced cell death. Under oxidative stress, fucoidan did not alter the expression of Bcl-2, Bax or ERK1/2, while inducing Akt expression in 92.1 cells but not in any other cell line. CONCLUSION: Fucoidan did not show anti tumorigenic effects but displayed protective and pro-angiogenic properties, rendering fucoidan unsuitable as a potential new drug for the treatment of uveal melanoma. PMID- 28640205 TI - Lectins from Mycelia of Basidiomycetes. AB - Lectins are proteins of a nonimmunoglobulin nature that are capable of specific recognition of and reversible binding to the carbohydrate moieties of complex carbohydrates, without altering the covalent structure of any of the recognized glycosyl ligands. They have a broad range of biological activities important for the functioning of the cell and the whole organism and, owing to the high specificity of reversible binding to carbohydrates, are valuable tools used widely in biology and medicine. Lectins can be produced by many living organisms, including basidiomycetes. Whereas lectins from the fruit bodies of basidiomycetes have been studied sufficiently well, mycelial lectins remain relatively unexplored. Here, we review and comparatively analyze what is currently known about lectins isolated from the vegetative mycelium of macrobasidiomycetes, including their localization, properties, and carbohydrate specificities. Particular attention is given to the physiological role of mycelial lectins in fungal growth and development. PMID- 28640206 TI - Block-Diagonal Constrained Low-Rank and Sparse Graph for Discriminant Analysis of Image Data. AB - Recently, low-rank and sparse model-based dimensionality reduction (DR) methods have aroused lots of interest. In this paper, we propose an effective supervised DR technique named block-diagonal constrained low-rank and sparse-based embedding (BLSE). BLSE has two steps, i.e., block-diagonal constrained low-rank and sparse representation (BLSR) and block-diagonal constrained low-rank and sparse graph embedding (BLSGE). Firstly, the BLSR model is developed to reveal the intrinsic intra-class and inter-class adjacent relationships as well as the local neighborhood relations and global structure of data. Particularly, there are mainly three items considered in BLSR. First, a sparse constraint is required to discover the local data structure. Second, a low-rank criterion is incorporated to capture the global structure in data. Third, a block-diagonal regularization is imposed on the representation to promote discrimination between different classes. Based on BLSR, informative and discriminative intra-class and inter class graphs are constructed. With the graphs, BLSGE seeks a low-dimensional embedding subspace by simultaneously minimizing the intra-class scatter and maximizing the inter-class scatter. Experiments on public benchmark face and object image datasets demonstrate the effectiveness of the proposed approach. PMID- 28640207 TI - Reverse Gyrase Functions in Genome Integrity Maintenance by Protecting DNA Breaks In Vivo. AB - Reverse gyrase introduces positive supercoils to circular DNA and is implicated in genome stability maintenance in thermophiles. The extremely thermophilic crenarchaeon Sulfolobus encodes two reverse gyrase proteins, TopR1 (topoisomerase reverse gyrase 1) and TopR2, whose functions in thermophilic life remain to be demonstrated. Here, we investigated the roles of TopR1 in genome stability maintenance in S. islandicus in response to the treatment of methyl methanesulfonate (MMS), a DNA alkylation agent. Lethal MMS treatment induced two successive events: massive chromosomal DNA backbone breakage and subsequent DNA degradation. The former occurred immediately after drug treatment, leading to chromosomal DNA degradation that concurred with TopR1 degradation, followed by chromatin protein degradation and DNA-less cell formation. To gain a further insight into TopR1 function, the expression of the enzyme was reduced in S. islandicus cells using a CRISPR-mediated mRNA interference approach (CRISPRi) in which topR1 mRNAs were targeted for degradation by endogenous III-B CRISPR-Cas systems. We found that the TopR1 level was reduced in the S. islandicus CRISPRi cells and that the cells underwent accelerated genomic DNA degradation during MMS treatment, accompanied by a higher rate of cell death. Taken together, these results indicate that TopR1 probably facilitates genome integrity maintenance by protecting DNA breaks from thermo-degradation in vivo. PMID- 28640208 TI - Associations of Drug Lipophilicity and Extent of Metabolism with Drug-Induced Liver Injury. AB - Drug-induced liver injury (DILI), although rare, is a frequent cause of adverse drug reactions resulting in warnings and withdrawals of numerous medications. Despite the research community's best efforts, current testing strategies aimed at identifying hepatotoxic drugs prior to human trials are not sufficiently powered to predict the complex mechanisms leading to DILI. In our previous studies, we demonstrated lipophilicity and dose to be associated with increased DILI risk and, and in our latest work, we factored reactive metabolites into the algorithm to predict DILI. Given the inconsistency in determining the potential for drugs to cause DILI, the present study comprehensively assesses the relationship between DILI risk and lipophilicity and the extent of metabolism using a large published dataset of 1036 Food and Drug Administration (FDA) approved drugs by considering five independent DILI annotations. We found that lipophilicity and the extent of metabolism alone were associated with increased risk for DILI. Moreover, when analyzed in combination with high daily dose (>=100 mg), lipophilicity was statistically significantly associated with the risk of DILI across all datasets (p < 0.05). Similarly, the combination of extensive hepatic metabolism (>=50%) and high daily dose (>=100 mg) was also strongly associated with an increased risk of DILI among all datasets analyzed (p < 0.05). Our results suggest that both lipophilicity and the extent of hepatic metabolism can be considered important risk factors for DILI in humans, and that this relationship to DILI risk is much stronger when considered in combination with dose. The proposed paradigm allows the convergence of different published annotations to a more uniform assessment. PMID- 28640209 TI - Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin. AB - Quinolin-6-yloxyacetamides (QAs) are a chemical class of tubulin polymerization inhibitors that were initially identified as fungicides. Here, we report that QAs are potent anti-proliferative agents against human cancer cells including ones that are drug-resistant. QAs act by disrupting the microtubule cytoskeleton and by causing severe mitotic defects. We further demonstrate that QAs inhibit tubulin polymerization in vitro. The high resolution crystal structure of the tubulin-QA complex revealed that QAs bind to the colchicine site on tubulin, which is targeted by microtubule-destabilizing agents such as colchicine and nocodazole. Together, our data establish QAs as colchicine-site ligands and explain the molecular mechanism of microtubule destabilization by this class of compounds. They further extend our structural knowledge on antitubulin agents and thus should aid in the development of new strategies for the rational design of ligands against multidrug-resistant cancer cells. PMID- 28640210 TI - The Resistance-Amplitude-Frequency Effect of In-Liquid Quartz Crystal Microbalance. AB - Due to the influence of liquid load, the equivalent resistance of in-liquid quartz crystal microbalance (QCM) increases sharply, and the quality factor and resonant frequency decreases. We found that the change in the resonant frequency of in-liquid QCM consisted of two parts: besides the frequency changes due to the mass and viscous load (which could be equivalent to motional inductance), the second part of frequency change was caused by the increase of motional resistance. The theoretical calculation and simulation proved that the increases of QCM motional resistance may indeed cause the decreases of resonant frequency, and revealed that the existence of static capacitance was the root cause of this frequency change. The second part of frequency change (due to the increases of motional resistance) was difficult to measure accurately, and may cause great error for in-liquid QCM applications. A technical method to reduce the interference caused by this effect is presented. The study contributes to the accurate determination of the frequency and amplitude change of in-liquid QCM caused by liquid load, which is significant for the QCM applications in the liquid phase. PMID- 28640211 TI - A Novel Active Imaging Model to Design Visual Systems: A Case of Inspection System for Specular Surfaces. AB - The use of visual information is a very well known input from different kinds of sensors. However, most of the perception problems are individually modeled and tackled. It is necessary to provide a general imaging model that allows us to parametrize different input systems as well as their problems and possible solutions. In this paper, we present an active vision model considering the imaging system as a whole (including camera, lighting system, object to be perceived) in order to propose solutions to automated visual systems that present problems that we perceive. As a concrete case study, we instantiate the model in a real application and still challenging problem: automated visual inspection. It is one of the most used quality control systems to detect defects on manufactured objects. However, it presents problems for specular products. We model these perception problems taking into account environmental conditions and camera parameters that allow a system to properly perceive the specific object characteristics to determine defects on surfaces. The validation of the model has been carried out using simulations providing an efficient way to perform a large set of tests (different environment conditions and camera parameters) as a previous step of experimentation in real manufacturing environments, which more complex in terms of instrumentation and more expensive. Results prove the success of the model application adjusting scale, viewpoint and lighting conditions to detect structural and color defects on specular surfaces. PMID- 28640212 TI - Synthesis and In Vitro Anti-Influenza Virus Evaluation of Novel Sialic Acid (C-5 and C-9)-Pentacyclic Triterpene Derivatives. AB - The emergence of drug resistant variants of the influenza virus has led to a great need to identify novel and effective antiviral agents. In our previous study, a series of sialic acid (C-2 and C-4)-pentacyclic triterpene conjugates have been synthesized, and a five-fold more potent antiviral activity was observed when sialic acid was conjugated with pentacyclic triterpene via C-4 than C-2. It was here that we further reported the synthesis and anti-influenza activity of novel sialic acid (C-5 and C-9)-pentacyclic triterpene conjugates. Their structures were confirmed by ESI-HRMS, 1H-NMR, and 13C-NMR spectroscopic analyses. Two conjugates (26 and 42) showed strong cytotoxicity to MDCK cells in the CellTiter-Glo assay at a concentration of 100 MUM. However, they showed no significant cytotoxicity to HL-60, Hela, and A549 cell lines in MTT assay under the concentration of 10 MUM (except compound 42 showed weak cytotoxicity to HL-60 cell line (10 MUM, ~53%)). Compounds 20, 28, 36, and 44 displayed weak potency to influenza A/WSN/33 (H1N1) virus (100 MUM, ~20-30%), and no significant anti influenza activity was found for the other conjugates. The data suggested that both the C-5 acetylamide and C-9 hydroxy of sialic acid were important for its binding with hemagglutinin during viral entry into host cells, while C-4 and C-2 hydroxy were not critical for the binding process and could be replaced with hydrophobic moieties. The research presented herein had significant implications for the design of novel antiviral inhibitors based on a sialic acid scaffold. PMID- 28640213 TI - The Association of Serum 25-Hydroxyvitamin D Concentrations and Elevated Glycated Hemoglobin Values: A Longitudinal Study of Non-Diabetic Participants of a Preventive Health Program. AB - The prevalence of Type 2 Diabetes (T2D) is sharply on the rise, both in Canada and worldwide. As addressing its root causes, i.e., promotion of healthy lifestyles and weight management, has been largely unsuccessful, new clues for primary prevention seem essential to curbing the increasing public health burden of T2D. In the present study, we examined whether improvements in vitamin D status, i.e., serum 25-hydroxyvitamin D [25(OH)D] concentrations, are paralleled by a reduction in the risk for reaching adverse glycated hemoglobin (HbA1c) levels in a community sample of non-diabetic volunteers participating in a preventive health program that encourages the use of vitamin D. Repeated observations on 6565 participants revealed that serum 25(OH)D concentrations increased from 90.8 to 121.3 nmol/L, HbA1c values decreased from 5.6% to 5.5%, and the prevalence of having HbA1c values >= 5.8% decreased from 29.5% to 17.4% while in the program. Compared to participants who did not increase their 25(OH)D concentrations during follow-up, those who increased their 25(OH)D concentrations with 50 nmol/L or more were 0.74 times as likely to achieve elevated HbA1c values at follow-up (p = 0.03). These findings suggest that public health initiatives that promote vitamin D status along with healthy lifestyles in the population at large may alleviate the future public health burden associated with T2D. PMID- 28640214 TI - A Pilot Randomized Cross-Over Trial to Examine the Effect of Kiwifruit on Satiety and Measures of Gastric Comfort in Healthy Adult Males. AB - : 'Hayward' kiwifruit anecdotally are associated with improved gastrointestinal comfort following the consumption of high protein meals, possibly because of the presence of a protease enzyme, actinidin. The study aimed to use SmartPillTM technology to investigate the acute effect of kiwifruit with actinidin (Actinidia chinensis var. deliciosa 'Hayward') and kiwifruit without actinidin (A. chinensis var. chinensis 'Hort16A') on digestion of a large protein meal. Ten healthy male subjects were recruited. The participants attended the clinic three times, having fasted overnight. They consumed a test meal consisting of 400 g lean steak and two 'Hort16A' or two 'Hayward kiwifruit'. Subjects completed visual analogue scales (VAS) by rating feelings of hunger, satisfaction, fullness, and comfort and swallowed a SmartPillTM before completing further VAS scales. After 5 h, participants consumed an ad libitum lunch to assess satiety. SmartPillTM transponders were worn for five days. There were no significant differences in gastric emptying time, small bowel, or colonic transit time between the two kiwifruit arms of the study measured by SmartPillTM. Similarly, no significant differences were observed in VAS satiety measures or energy consumption at the ad libitum meal. However, the measurement of overall gastric comfort tended to be lower, and bloating was significantly reduced following the consumption of the steak meal with 'Hayward' kiwifruit (p < 0.028). CONCLUSIONS: The SmartPillTM is marketed as a diagnostic tool for patients presenting with gastrointestinal disorders and is usually used with a standard 'SmartBar'. This small pilot study suggests that it is less likely to measure gastric emptying effectively following a high protein meal, as it may be delayed because of the meal's physical consistency. However, green kiwifruit, containing actinidin, may reduce bloating and other measures of gastric discomfort in healthy males. Possible future studies could use repeated measures with more readily digested protein and larger numbers of participants. PMID- 28640215 TI - Correction: Scourboutakos, M.J.; et al. Mismatch between Probiotic Benefits in Trials versus Food Products. Nutrients 2017, 9, 400. AB - n/a. PMID- 28640217 TI - Suboptimal Iodine Concentration in Breastmilk and Inadequate Iodine Intake among Lactating Women in Norway. AB - Breastfed infants depend on sufficient maternal iodine intake for optimal growth and neurological development. Despite this, few studies have assessed iodine concentrations in human milk and there is currently no published data on iodine status among lactating women in Norway. The aim of this study was to assess iodine concentrations in breast milk (BMIC) in lactating women and estimate iodine intake. Five Mother and Child Health Centres in Oslo were randomly selected during 2016, and 175 lactating women between 2nd and 28th weeks postpartum participated. Each of the women provided four breastmilk samples which were pooled and analysed for iodine concentrations. Participants also provided information on iodine intake from food and supplements covering the last 24 h and the habitual iodine intake (food frequency questionnaire). The median (p25, p75 percentiles) BMIC was 68 (45, 98) ug/L and 76% had BMIC <100 ug/L. Only 19% had taken an iodine-containing supplement during the last 24 h. The median 24 h iodine intake from food (p25, p75) was 121 (82, 162) ug/day and the total intake (food and supplements) was 134 (95, 222) ug/day. The majority of lactating women had suboptimal BMIC and inadequate intake of iodine from food and supplements. PMID- 28640218 TI - Studies on the Two Thymine Residues in the Catalytic Core of 10-23 DNAzyme: The Impact on the Catalysis of Their 5-Substituted Functional Groups. AB - In the 15-mer catalytic core of 10-23 DNAzyme, each residue contributes to the catalytic conformation differently. Here, the critically conserved T4 and the least conserved T8 were modified on their 5-position with hydroxyl, imidazolyl, and amino groups with a hydrogen-bonding ability. These external functional groups induced new interactions within the catalytic core, resulting in both negative and positive effects on the catalytic activity of 10-23 DNAzyme, and the different linkages could be used to modulate the effect of the functional groups. The conservation of T4 and T8 could be recognized at the level of the nucleobase, but at the level of the functional group, T4 is not completely conserved. Their 5 methyl groups could be modified for a better performance in terms of the DNAzyme. PMID- 28640216 TI - A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease. AB - Dysregulation of several metabolite pathways, including branched-chain amino acids (BCAAs), are associated with Non-Alcoholic Fatty Liver Disease (NAFLD) and insulin resistance in adults, while studies in youth reported conflicting results. We explored whether, independently of obesity and insulin resistance, obese adolescents with NAFLD display a metabolomic signature consistent with disturbances in amino acid and lipid metabolism. A total of 180 plasma metabolites were measured by a targeted metabolomic approach in 78 obese adolescents with (n = 30) or without (n = 48) NAFLD assessed by magnetic resonance imaging (MRI). All subjects underwent an oral glucose tolerance test and subsets of patients underwent a two-step hyperinsulinemic-euglycemic clamp and/or a second MRI after a 2.2 +/- 0.8-year follow-up. Adolescents with NAFLD had higher plasma levels of valine (p = 0.02), isoleucine (p = 0.03), tryptophan (p = 0.02), and lysine (p = 0.02) after adjustment for confounding factors. Circulating BCAAs were negatively correlated with peripheral and hepatic insulin sensitivity. Furthermore, higher baseline valine levels predicted an increase in hepatic fat content (HFF) at follow-up (p = 0.01). These results indicate that a dysregulation of BCAA metabolism characterizes obese adolescents with NAFLD independently of obesity and insulin resistance and predict an increase in hepatic fat content over time. PMID- 28640220 TI - A Comprehensive Study on the Internet of Underwater Things: Applications, Challenges, and Channel Models. AB - The Internet of Underwater Things (IoUT) is a novel class of Internet of Things (IoT), and is defined as the network of smart interconnected underwater objects. IoUT is expected to enable various practical applications, such as environmental monitoring, underwater exploration, and disaster prevention. With these applications, IoUT is regarded as one of the potential technologies toward developing smart cities. To support the concept of IoUT, Underwater Wireless Sensor Networks (UWSNs) have emerged as a promising network system. UWSNs are different from the traditional Territorial Wireless Sensor Networks (TWSNs), and have several unique properties, such as long propagation delay, narrow bandwidth, and low reliability. These unique properties would be great challenges for IoUT. In this paper, we provide a comprehensive study of IoUT, and the main contributions of this paper are threefold: (1) we introduce and classify the practical underwater applications that can highlight the importance of IoUT; (2) we point out the differences between UWSNs and traditional TWSNs, and these differences are the main challenges for IoUT; and (3) we investigate and evaluate the channel models, which are the technical core for designing reliable communication protocols on IoUT. PMID- 28640219 TI - Topical Application of Trisodium Ascorbyl 6-Palmitate 2-Phosphate Actively Supplies Ascorbate to Skin Cells in an Ascorbate Transporter-Independent Manner. AB - Ascorbic acid (AA) possesses multiple beneficial functions, such as regulating collagen biosynthesis and redox balance in the skin. AA derivatives have been developed to overcome this compound's high fragility and to assist with AA supplementation to the skin. However, how AA derivatives are transferred into cells and converted to AA in the skin remains unclear. In the present study, we showed that AA treatment failed to increase the cellular AA level in the presence of AA transporter inhibitors, indicating an AA transporter-dependent action. In contrast, torisodium ascorbyl 6-palmitate 2-phosphate (APPS) treatment significantly enhanced the cellular AA level in skin cells despite the presence of inhibitors. In ex vivo experiments, APPS treatment also increased the AA content in a human epidermis model. Interestingly, APPS was readily metabolized and converted to AA in keratinocyte lysates via an intrinsic mechanism. Furthermore, APPS markedly repressed the intracellular superoxide generation and promoted viability associated with an enhanced AA level in Sod1-deficient skin cells. These findings indicate that APPS effectively restores the AA level and normalizes the redox balance in skin cells in an AA transporter-independent manner. Topical treatment of APPS is a beneficial strategy for supplying AA and improving the physiology of damaged skin. PMID- 28640221 TI - Use of Chitosan-PVA Hydrogels with Copper Nanoparticles to Improve the Growth of Grafted Watermelon. AB - Modern agriculture requires alternative practices that improve crop growth without negatively affecting the environment, as resources such as water and arable land grow scarcer while the human population continues to increase. Grafting is a cultivation technique that allows the plant to be more efficient in its utilization of water and nutrients, while nanoscale material engineering provides the opportunity to use much smaller quantities of consumables compared to conventional systems but with similar or superior effects. On those grounds, we evaluated the effects of chitosan-polyvinyl alcohol hydrogel with absorbed copper nanoparticles (Cs-PVA-nCu) on leaf morphology and plant growth when applied to grafted watermelon cultivar 'Jubilee' plants. Stomatal density (SD), stomatal index (SI), stoma length (SL), and width (SW) were evaluated. The primary stem and root length, the stem diameter, specific leaf area, and fresh and dry weights were also recorded. Our results demonstrate that grafting induces modifications to leaf micromorphology that favorably affect plant growth, with grafted plants showing better vegetative growth in spite of their lower SD and SI values. Application of Cs-PVA-nCu was found to increase stoma width, primary stem length, and root length by 7%, 8% and 14%, respectively. These techniques modestly improve plant development and growth. PMID- 28640222 TI - Albumin and Hyaluronic Acid-Coated Superparamagnetic Iron Oxide Nanoparticles Loaded with Paclitaxel for Biomedical Applications. AB - Super paramagnetic iron oxide nanoparticles (SPION) were augmented by both hyaluronic acid (HA) and bovine serum albumin (BSA), each covalently conjugated to dopamine (DA) enabling their anchoring to the SPION. HA and BSA were found to simultaneously serve as stabilizing polymers of Fe3O4.DA-BSA/HA in water. Fe3O4.DA-BSA/HA efficiently entrapped and released the hydrophobic cytotoxic drug paclitaxel (PTX). The relative amount of HA and BSA modulates not only the total solubility but also the paramagnetic relaxation properties of the preparation. The entrapping of PTX did not influence the paramagnetic relaxation properties of Fe3O4.DA-BSA. Thus, by tuning the surface structure and loading, we can tune the theranostic properties of the system. PMID- 28640223 TI - Non-Targeted Metabolomics Analysis of the Effects of Tyrosine Kinase Inhibitors Sunitinib and Erlotinib on Heart, Muscle, Liver and Serum Metabolism In Vivo. AB - Background: More than 90 tyrosine kinases have been implicated in the pathogenesis of malignant transformation and tumor angiogenesis. Tyrosine kinase inhibitors (TKIs) have emerged as effective therapies in treating cancer by exploiting this kinase dependency. The TKI erlotinib targets the epidermal growth factor receptor (EGFR), whereas sunitinib targets primarily vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).TKIs that impact the function of non-malignant cells and have on- and off target toxicities, including cardiotoxicities. Cardiotoxicity is very rare in patients treated with erlotinib, but considerably more common after sunitinib treatment. We hypothesized that the deleterious effects of TKIs on the heart were related to their impact on cardiac metabolism. Methods: Female FVB/N mice (10/group) were treated with therapeutic doses of sunitinib (40 mg/kg), erlotinib (50 mg/kg), or vehicle daily for two weeks. Echocardiographic assessment of the heart in vivo was performed at baseline and on Day 14. Heart, skeletal muscle, liver and serum were flash frozen and prepped for non-targeted GC-MS metabolomics analysis. Results: Compared to vehicle-treated controls, sunitinib-treated mice had significant decreases in systolic function, whereas erlotinib-treated mice did not. Non-targeted metabolomics analysis of heart identified significant decreases in docosahexaenoic acid (DHA), arachidonic acid (AA)/ eicosapentaenoic acid (EPA), O-phosphocolamine, and 6-hydroxynicotinic acid after sunitinib treatment. DHA was significantly decreased in skeletal muscle (quadriceps femoris), while elevated cholesterol was identified in liver and elevated ethanolamine identified in serum. In contrast, erlotinib affected only one metabolite (spermidine significantly increased). Conclusions: Mice treated with sunitinib exhibited systolic dysfunction within two weeks, with significantly lower heart and skeletal muscle levels of long chain omega-3 fatty acids docosahexaenoic acid (DHA), arachidonic acid (AA)/eicosapentaenoic acid (EPA) and increased serum O-phosphocholine phospholipid. This is the first link between sunitinib-induced cardiotoxicity and depletion of the polyunsaturated fatty acids (PUFAs) and inflammatory mediators DHA and AA/EPA in the heart. These compounds have important roles in maintaining mitochondrial function, and their loss may contribute to cardiac dysfunction. PMID- 28640224 TI - Nomegestrol Acetate Suppresses Human Endometrial Cancer RL95-2 Cells Proliferation In Vitro and In Vivo Possibly Related to Upregulating Expression of SUFU and Wnt7a. AB - Nomegestrol acetate (NOMAC) has been successfully used for the treatment of some gynecological disorders, and as a combined oral contraceptive with approval in many countries. In this study, we investigated the effects of NOMAC on human endometrial cancer cells in vitro and in vivo. The proliferation of human endometrial cancer cells (RL95-2 and KLE) were assessed using CCK-8 and EdU incorporation assays. Whole-genome cDNA microarray analysis was used to identify the effects of NOMAC on gene expression profiles in RL95-2 cells. RL95-2 xenograft nude mice were treated with NOMAC (50, 100, and 200 mg/kg) or medroxyprogesterone acetate (MPA; 100 and 200 mg/kg) for 28 consecutive days. The results showed that NOMAC significantly inhibited the growth of RL95-2 cells in a concentration-dependent manner, but not in KLE cells. Further investigation demonstrated that NOMAC produced a stronger inhibition of tumor growth (inhibition rates for 50, 100, and 200 mg/kg NOMAC were 24.74%, 47.04%, and 58.06%, respectively) than did MPA (inhibition rates for 100 and 200 mg/kg MPA were 41.06% and 27.01%, respectively) in the nude mice bearing the cell line of RL95-2. NOMAC altered the expression of several genes related to cancer cell proliferation, including SUFU and Wnt7a. The upregulation of SUFU and Wnt7a was confirmed using real-time quantitative polymerase chain reaction and Western blotting in RL95-2 cells and RL95-2 xenograft tumor tissues, but not in KLE cells. These data indicate that NOMAC can inhibit the proliferation of RL95-2 cell in vitro and suppress the growth of xenografts in the nude mice bearing the cell line of RL95-2 in vivo. This effect could be related to the upregulating expression of SUFU and Wnt7a. PMID- 28640226 TI - Trimethylamine Sensors Based on Au-Modified Hierarchical Porous Single Crystalline ZnO Nanosheets. AB - It is of great significance for dynamic monitoring of foods in storage or during the transportation process through on-line detecting trimethylamine (TMA). Here, TMA were sensitively detected by Au-modified hierarchical porous single crystalline ZnO nanosheets (HPSCZNs)-based sensors. The HPSCZNs were synthesized through a one-pot wet-chemical method followed by an annealing treatment. Polyethyleneimine (PEI) was used to modify the surface of the HPSCZNs, and then the PEI-modified samples were mixed with Au nanoparticles (NPs) sol solution. Electrostatic interactions drive Au nanoparticles loading onto the surface of the HPSCZNs. The Au-modified HPSCZNs were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive spectrum (EDS), respectively. The results show that Au-modified HPSCZNs-based sensors exhibit a high response to TMA. The linear range is from 10 to 300 ppb; while the detection limit is 10 ppb, which is the lowest value to our knowledge. PMID- 28640225 TI - Herb-Drug Interaction between the Traditional Hepatoprotective Formulation and Sorafenib on Hepatotoxicity, Histopathology and Pharmacokinetics in Rats. AB - Sorafenib has been used as a standard therapy for advanced hepatocellular carcinoma (HCC). In Asia, patients with HCC are potentially treated with the combination of sorafenib and Chinese herbal medicines to improve the efficiency and reduce the side effects of sorafenib. However, limited information about the herb-drug interactions is available. We hypothesize that the Chinese herbal medicine may exert hepatoprotective effects on the sorafenib-treated group. The aim of this study is to investigate the pharmacokinetic mechanism of drug-drug interactions of sorafenib including interacting with hepatoprotective formulation, Long-Dan-Xie-Gan-Tang formulation (LDXGT) and with two cytochrome P450 3A4 (CYP3A4) inhibitors, grapefruit juice and ketoconazole. Liver enzyme levels and histopathology of liver slices were used to evaluate sorafenib-induced hepatotoxicity and the potential hepatoprotective effects of the LDXGT formulation on subjects treated with the combination of sorafenib and the herbal medicine. In this study, a validated HPLC-photodiode array analytical system was developed for the pharmacokinetic study of sorafenib in rats. As the result of the pharmacokinetic data, pretreatment with the LDXGT formulation did not significantly interact with sorafenib compared with sorafenib oral administration alone. Furthermore, grapefruit juice and ketoconazole did not significantly affect sorafenib metabolism. Furthermore, pretreatment with variable, single or repeat doses of the LDXGT formulation did not suppress or exacerbate the sorafenib-induced hepatotoxicity and histopathological alterations. According to these results, the LDXGT formulation is safe, but has no beneficial effects on sorafenib-induced hepatotoxicity. A detailed clinical trial should be performed to further evaluate the efficacy or adverse effects of the LDXGT formulation in combination with sorafenib in humans. PMID- 28640227 TI - Impact of Mycotoxins Secreted by Aspergillus Molds on the Inflammatory Response of Human Corneal Epithelial Cells. AB - Exposure to molds and mycotoxins not only contributes to the onset of respiratory disease, it also affects the ocular surface. Very few published studies concern the evaluation of the effect of mycotoxin exposure on ocular cells. The present study investigates the effects of aflatoxin B1 (AFB1) and gliotoxin, two mycotoxins secreted by Aspergillus molds, on the biological activity of the human corneal epithelial (HCE) cells. After 24, 48, and 72 h of exposure, cellular viability and inflammatory response were assessed. Both endpoint cell viability colorimetric assays and continuous cell impedance measurements, providing noninvasive real-time assessment of the effect on cells, were performed. Cytokine gene expression and interleukin-8 release were quantified. Gliotoxin appeared more cytotoxic than AFB1 but, at the same time, led to a lower increase of the inflammatory response reflecting its immunosuppressive properties. Real-time cell impedance measurement showed a distinct profile of cytotoxicity for both mycotoxins. HCE cells appeared to be a well-suited in vitro model to study ocular surface reactivity following biological contaminant exposure. Low, but persistent inflammation, caused by environmental factors, such as fungal toxins, leads to irritation and sensitization, and could be responsible for allergic manifestations which, in turn, could lead to mucosal hyper-reactivity. PMID- 28640228 TI - Development and Validation of a High-Throughput Mass Spectrometry Based Urine Metabolomic Test for the Detection of Colonic Adenomatous Polyps. AB - Background: Colorectal cancer is one of the leading causes of cancer deaths worldwide. The detection and removal of the precursors to colorectal cancer, adenomatous polyps, is the key for screening. The aim of this study was to develop a clinically scalable (high throughput, low cost, and high sensitivity) mass spectrometry (MS)-based urine metabolomic test for the detection of adenomatous polyps. Methods: Prospective urine and stool samples were collected from 685 participants enrolled in a colorectal cancer screening program to undergo colonoscopy examination. Statistical analysis was performed on 69 urine metabolites measured by one-dimensional nuclear magnetic resonance spectroscopy to identify key metabolites. A targeted MS assay was then developed to quantify the key metabolites in urine. A MS-based urine metabolomic diagnostic test for adenomatous polyps was established using 67% samples (un-blinded training set) and validated using the remaining 33% samples (blinded testing set). Results: The MS-based urine metabolomic test identifies patients with colonic adenomatous polyps with an AUC of 0.692, outperforming the NMR based predictor with an AUC of 0.670. Conclusion: Here we describe a clinically scalable MS-based urine metabolomic test that identifies patients with adenomatous polyps at a higher level of sensitivity (86%) over current fecal-based tests (<18%). PMID- 28640229 TI - Seasonal Differences in Determinants of Time Location Patterns in an Urban Population: A Large Population-Based Study in Korea. AB - Time location patterns are a significant factor for exposure assessment models of air pollutants. Factors associated with time location patterns in urban populations are typically due to high air pollution levels in urban areas. The objective of this study was to determine the seasonal differences in time location patterns in two urban cities. A Time Use Survey of Korean Statistics (KOSTAT) was conducted in the summer, fall, and winter of 2014. Time location data from Seoul and Busan were collected, together with demographic information obtained by diaries and questionnaires. Determinants of the time spent at each location were analyzed by multiple linear regression and the stepwise method. Seoul and Busan participants had similar time location profiles over the three seasons. The time spent at own home, other locations, workplace/school and during walk were similar over the three seasons in both the Seoul and Busan participants. The most significant time location pattern factors were employment status, age, gender, monthly income, and spouse. Season affected the time spent at the workplace/school and other locations in the Seoul participants, but not in the Busan participants. The seasons affected each time location pattern of the urban population slightly differently, but overall there were few differences. PMID- 28640230 TI - Total Flavonoids of Drynariae Rhizoma Prevent Bone Loss Induced by Hindlimb Unloading in Rats. AB - Drynariae Rhizoma is a kidney-tonifying herb that has a long history in clinical practice for the treatment of bone fractures and joint diseases in China. Flavonoids are considered to be its major active ingredients and are reported to ease bone loss in ovariectomized rats. However, the beneficial effects of the total flavonoids of Drynariae Rhizoma on osteoporosis caused by microgravity or mechanical inactivity remain unknown. This study assessed the effects of total Drynariae Rhizoma flavonoids (DRTF, Qihuang, Beijing, China, national medicine permit No. Z20030007, number of production: 04080081, content of DRTF >=80%) against bone loss induced by simulated microgravity. A hindlimb unloading tail suspended rat model was established to determine the effect of DRTF on bone mineral density (BMD), biomechanical strength and trabecular bone microarchitecture. Twenty-eight male Sprague-Dawley rats were divided into four groups: the baseline, control, hindlimb unloading with vehicle (HLU), and hindlimb unloading treated with DRTF (HLU-DRTF, 75 mg/kg/day) groups. Oral DRTF was administered for 4 weeks. The underlying mechanisms of the DRTF actions on disuse-induced osteoporosis are discussed. The results showed that DRTF treatment significantly increased the BMD and mechanical strength of tail-suspended rats. Enhanced bone turnover markers with HLU treatment were attenuated by DRTF administration. Deterioration of trabecular bone induced by HLU was prevented through elevated bone volume/tissue volume (BV/TV), trabecular number (Tb. N), trabecular thickness (Tb. Th) and decreased trabecular separation (Tb. Sp). The present study provides the first evidence that DRTF prevents bone loss induced by HLU treatment, indicating its potential application in the treatment of disuse induced osteoporosis. PMID- 28640231 TI - Pubertal Stage, Body Mass Index, and Cardiometabolic Risk in Children and Adolescents in Bogota, Colombia: The Cross-Sectional Fuprecol Study. AB - This study explored the association between pubertal stage and anthropometric and cardiometabolic risk factors in youth. A cross-sectional study was conducted in 2877 Colombian children and adolescents (9-17.9 years of age). Weight, height, and waist circumference were measured and body mass index (BMI) was calculated. A biochemical study was performed to determine the cardiometabolic risk index (CMRI). Blood pressure was evaluated and pubertal stage was assessed with the Tanner criteria. Hierarchical multiple regression analyses were performed. The most significant variable (p < 0.05) in the prognosis of cardiometabolic risk was found to be the BMI in both boys and girls. In the case of girls, the pubertal stage was also a CMRI predictive factor. In conclusion, BMI was an important indicator of cardiovascular risk in both sexes. Pubertal stage was associated with cardiovascular risk only in the girls. PMID- 28640232 TI - Why Do Children Engage in Sedentary Behavior? Child- and Parent-Perceived Determinants. AB - Todays children spend a large amount of their time sedentary. There is limited evidence on the determinants of sedentary behavior in children, and qualitative studies are especially lacking. Therefore, this study aimed to explore determinants of children's sedentary behavior from the child- and parent perspective. Qualitative data were collected during concept mapping sessions with four groups of 11-13 years old children (n = 38) and two online sessions with parents (n = 21). Children and parents generated sedentary behavior motives, sorted related motives, and rated their importance in influencing children's sedentary time. Next, multidimensional scaling and hierarchical cluster analysis was performed to create clusters of motives resulting in a concept map. Finally, the researchers named the clusters in the concept map. Concept maps of children yielded eight to ten perceived determinants, and concept maps of parents six to seven. Children and parents identified six similar potential determinants, and both rated as important: Sitting because... "it is the norm (I have to)", and "I can work/play better that way". In addition, children rated "there is nobody to play with" as an important potential determinant for engaging in sedentary behavior. The most important child- and parent perceived determinants were related to the social/cultural and physical environment, indicating that these are promising targets for future interventions. PMID- 28640235 TI - Stereo Vision-Based High Dynamic Range Imaging Using Differently-Exposed Image Pair. AB - In this paper, a high dynamic range (HDR) imaging method based on the stereo vision system is presented. The proposed method uses differently exposed low dynamic range (LDR) images captured from a stereo camera. The stereo LDR images are first converted to initial stereo HDR images using the inverse camera response function estimated from the LDR images. However, due to the limited dynamic range of the stereo LDR camera, the radiance values in under/over-exposed regions of the initial main-view (MV) HDR image can be lost. To restore these radiance values, the proposed stereo matching and hole-filling algorithms are applied to the stereo HDR images. Specifically, the auxiliary-view (AV) HDR image is warped by using the estimated disparity between initial the stereo HDR images and then effective hole-filling is applied to the warped AV HDR image. To reconstruct the final MV HDR, the warped and hole-filled AV HDR image is fused with the initial MV HDR image using the weight map. The experimental results demonstrate objectively and subjectively that the proposed stereo HDR imaging method provides better performance compared to the conventional method. PMID- 28640233 TI - Metabolic Effects of High Glycaemic Index Diets: A Systematic Review and Meta Analysis of Feeding Studies in Mice and Rats. AB - Low glycaemic index (LGI) diets are often reported to benefit metabolic health, but the mechanism(s) responsible are not clear. This review aimed to systematically identify studies investigating metabolic effects of high glycaemic index (HGI) versus LGI diets in mice and rats. A meta-analysis was conducted to calculate an overall effect size, Hedge's standardised mean differences (hereafter d), for each trait, with moderator variables considered in subsequent meta-regressions. Across 30 articles, a HGI diet increased five of the seven traits examined: body weight (d = 0.55; 95% confidence interval: 0.31, 0.79), fat mass (d = 1.08; 0.67, 1.49), fasting circulating insulin levels (d = 0.40; 0.09, 0.71), and glucose (d = 0.80; 0.35, 1.25) and insulin (d = 1.14; 0.50, 1.77) area under the curve during a glucose tolerance test. However, there was substantial heterogeneity among the effects for all traits and the small number of studies enabled only limited investigation of possible confounding factors. HGI diets favour body weight gain, increased adiposity and detrimentally affect parameters of glucose homeostasis in mice and rats, but these effects may not be a direct result of GI per se; rather they may be due to variation in other dietary constituents, such as dietary fibre, a factor which is known to reduce the GI of food and promote health via GI-independent mechanisms. PMID- 28640236 TI - A Decision Mixture Model-Based Method for Inshore Ship Detection Using High Resolution Remote Sensing Images. AB - With the rapid development of optical remote sensing satellites, ship detection and identification based on large-scale remote sensing images has become a significant maritime research topic. Compared with traditional ocean-going vessel detection, inshore ship detection has received increasing attention in harbor dynamic surveillance and maritime management. However, because the harbor environment is complex, gray information and texture features between docked ships and their connected dock regions are indistinguishable, most of the popular detection methods are limited by their calculation efficiency and detection accuracy. In this paper, a novel hierarchical method that combines an efficient candidate scanning strategy and an accurate candidate identification mixture model is presented for inshore ship detection in complex harbor areas. First, in the candidate region extraction phase, an omnidirectional intersected two dimension scanning (OITDS) strategy is designed to rapidly extract candidate regions from the land-water segmented images. In the candidate region identification phase, a decision mixture model (DMM) is proposed to identify real ships from candidate objects. Specifically, to improve the robustness regarding the diversity of ships, a deformable part model (DPM) was employed to train a key part sub-model and a whole ship sub-model. Furthermore, to improve the identification accuracy, a surrounding correlation context sub-model is built. Finally, to increase the accuracy of candidate region identification, these three sub-models are integrated into the proposed DMM. Experiments were performed on numerous large-scale harbor remote sensing images, and the results showed that the proposed method has high detection accuracy and rapid computational efficiency. PMID- 28640237 TI - Broad consent for health care-embedded biobanking: understanding and reasons to donate in a large patient sample. AB - PurposeTo facilitate ethically acceptable and practically successful health care embedded biobanking, the attitudes and understanding of patients and their motivation to participate need to be explored.MethodsA questionnaire study was conducted among 760 outpatients of a northern German university hospital to assess their awareness of, and motivation for giving broad consent to health care embedded biobanking, also addressing the issue of feedback on individual-level research findings.ResultsThe overall willingness to give broad consent was high (86.9%) in our study, even though the subjective and objective understanding of patients was found to be only modest. Most participants who consented did so for prosocial reasons (altruism, solidarity, reciprocity, gratitude), whereas self interest or worries about disadvantages played only a marginal role. Better objective understanding was associated with both a greater demand for feedback on individual research findings and a higher willingness to consent. Intermittent modification of the information material provided by the hospital led to significantly improved objective understanding.ConclusionPatient willingness to give broad consent to health care-embedded biobanking is high, with prosocial reasons driving decision making more than factual knowledge and approval or disapproval of specific consent elements. Future efforts to improve the information material used in health care-embedded biobanking should therefore emphasize prosocial reasons to consent. PMID- 28640238 TI - Treatment of mucopolysaccharidosis type II (Hunter syndrome): results from a systematic evidence review. AB - PurposeA pilot systematic evidence review to establish methodology utility in rare genetic diseases, support clinical recommendations, and identify important knowledge gaps.MethodsBroad-based published/gray-literature searches through December 2015 for studies of males with confirmed mucopolysaccharidosis type II (any age, phenotype, genotype, family history) treated with enzyme replacement therapy or hematopoietic stem cell transplantation. Preset inclusion criteria employed for abstract and full document selection, and standardized methods for data extraction and assessment of quality and strength of evidence.ResultsTwelve outcomes reported included benefits of urinary glycosaminoglycan and liver/spleen volume reductions and harms of immunoglobulin G/neutralizing antibody development (moderate strength of evidence). Less clear were benefits of improved 6-minute walk tests, height, early treatment, and harms of other adverse reactions (low strength of evidence). Benefits and harms of other outcomes were unclear (insufficient strength of evidence). Current benefits and harms of hematopoietic stem cell transplantation are unclear, based on dated, low-quality studies. A critical knowledge gap is long-term outcomes. Consensus on selection of critical outcomes and measures is needed to definitively evaluate treatment safety and effectiveness.ConclusionMinor methodology modifications and a focus on critical evidence can reduce review time and resources. Summarized evidence was sufficient to support guidance development and highlight important knowledge gaps. PMID- 28640240 TI - Pitfalls of trio-based exome sequencing: imprinted genes and parental mosaicism MAGEL2 as an example. PMID- 28640239 TI - Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients. AB - PurposeTemple syndrome (TS14) is a rare imprinting disorder caused by aberrations at the 14q32.2 imprinted region. Here, we report comprehensive molecular and clinical findings in 32 Japanese patients with TS14.MethodsWe performed molecular studies for TS14 in 356 patients with variable phenotypes, and clinical studies in all TS14 patients, including 13 previously reported.ResultsWe identified 19 new patients with TS14, and the total of 32 patients was made up of 23 patients with maternal uniparental disomy (UPD(14)mat), six patients with epimutations, and three patients with microdeletions. Clinical studies revealed both Prader Willi syndrome (PWS)-like marked hypotonia and Silver-Russell syndrome (SRS)-like phenotype in 50% of patients, PWS-like hypotonia alone in 20% of patients, SRS like phenotype alone in 20% of patients, and nonsyndromic growth failure in the remaining 10% of patients in infancy, and gonadotropin-dependent precocious puberty in 76% of patients who were pubescent or older.ConclusionThese results suggest that TS14 is not only a genetically diagnosed entity but also a clinically recognizable disorder. Genetic testing for TS14 should be considered in patients with growth failure plus both PWS-like hypotonia and SRS-like phenotypes in infancy, and/or precocious puberty, as well as a familial history of Kagami-Ogata syndrome due to maternal microdeletion at 14q32.2. PMID- 28640242 TI - Report on the Banbury Summit Meeting on medical genetics training in the genomic era, 23-26 February 2014. PMID- 28640241 TI - Long-read genome sequencing identifies causal structural variation in a Mendelian disease. AB - PurposeCurrent clinical genomics assays primarily utilize short-read sequencing (SRS), but SRS has limited ability to evaluate repetitive regions and structural variants. Long-read sequencing (LRS) has complementary strengths, and we aimed to determine whether LRS could offer a means to identify overlooked genetic variation in patients undiagnosed by SRS.MethodsWe performed low-coverage genome LRS to identify structural variants in a patient who presented with multiple neoplasia and cardiac myxomata, in whom the results of targeted clinical testing and genome SRS were negative.ResultsThis LRS approach yielded 6,971 deletions and 6,821 insertions > 50 bp. Filtering for variants that are absent in an unrelated control and overlap a disease gene coding exon identified three deletions and three insertions. One of these, a heterozygous 2,184 bp deletion, overlaps the first coding exon of PRKAR1A, which is implicated in autosomal dominant Carney complex. RNA sequencing demonstrated decreased PRKAR1A expression. The deletion was classified as pathogenic based on guidelines for interpretation of sequence variants.ConclusionThis first successful application of genome LRS to identify a pathogenic variant in a patient suggests that LRS has significant potential for the identification of disease-causing structural variation. Larger studies will ultimately be required to evaluate the potential clinical utility of LRS. PMID- 28640243 TI - In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics. AB - PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort. PMID- 28640244 TI - Systematic design and comparison of expanded carrier screening panels. AB - PurposeThe recent growth in pan-ethnic expanded carrier screening (ECS) has raised questions about how such panels might be designed and evaluated systematically. Design principles for ECS panels might improve clinical detection of at-risk couples and facilitate objective discussions of panel choice.MethodsGuided by medical-society statements, we propose a method for the design of ECS panels that aims to maximize the aggregate and per-disease sensitivity and specificity across a range of Mendelian disorders considered serious by a systematic classification scheme. We evaluated this method retrospectively using results from 474,644 de-identified carrier screens. We then constructed several idealized panels to highlight strengths and limitations of different ECS methodologies.ResultsBased on modeled fetal risks for "severe" and "profound" diseases, a commercially available ECS panel (Counsyl) is expected to detect 183 affected conceptuses per 100,000 US births. A screen's sensitivity is greatly impacted by two factors: (i) the methodology used (e.g., full-exon sequencing finds more affected conceptuses than targeted genotyping) and (ii) the detection rate of the screen for diseases with high prevalence and complex molecular genetics (e.g., fragile X syndrome).ConclusionThe described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening. PMID- 28640245 TI - The importance of communicating histories of gender assignment and reassignment to genetic laboratories. PMID- 28640246 TI - GWAS signals revisited using human knockouts. AB - PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits. PMID- 28640247 TI - Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup. AB - PurposeHypertrophic cardiomyopathy (HCM) is considered a hereditary autosomal dominant condition, but genetic testing is positive in only half of patients. In patients with negative genetic tests, the inheritance pattern and utility of family screening are unclear.MethodsSubjects with HCM were prospectively enrolled in a registry. A survey at a median follow-up of 4 years determined the yield of family screening.ResultsThe outcome of cardiac screening on 267 family members was reported by 120 survey respondents. Subjects with positive genetic test or family history (n=74, 62%) reported an HCM diagnosis in 34 of 203 first-degree relatives who were screened (17%). Affected family members were diagnosed at a mean age of 30-39 years, and 22 of 34 experienced HCM-related adverse events (65%). Gene test-negative subjects with no prior family history of HCM (n=46, 38%) reported an HCM diagnosis in only 2 of 64 first-degree relatives who were screened (3%, p<0.001). These two individuals were diagnosed at age >40 years without HCM-related adverse events.ConclusionHypertrophic cardiomyopathy is a heterogeneous disorder, only half of which tracks with a Mendelian inheritance pattern. Negative genetic testing and family history indicates a more complex genetic basis corresponding to low risk for family members. PMID- 28640248 TI - Voluntary distance running prevents TNF-mediated liver injury in mice through alterations of the intrahepatic immune milieu. AB - Physical activity confers a broad spectrum of health benefits. Beyond the obvious role in metabolically driven diseases, the role of physical activity in acute liver injury is poorly explored. To study the role of physical activity in acute liver injury, a novel model of voluntary distance running in mice was developed and mice were subjected to acute liver injury induced by N-galactosamine (GalN) and lipopolysaccharide (LPS). Analyses included histological stains, immunoblotting, qRT-PCR and FACS analysis. Voluntary distance running increased to an average of 10.3 km/day after a learning curve. Running lead to a decrease in the absolute numbers of intrahepatic CD4+ T and B lymphocytes and macrophages after 7 weeks. In parallel, hepatic mRNA expression of inflammatory cytokines including IL-6 and IL-1beta, TGF-beta and monocyte chemoattractant protein-1 (MCP 1/CCL2) were suppressed, while TNF-alpha was not affected by exercise. Likewise, expression of the macrophage-specific antigen F4/80 was downregulated 1.6-fold from exercise. Notably, acute liver injury from GaIN/LPS was significantly blunted following 7 weeks of voluntary exercise as determined by liver histology, a 84.6% reduction of alanine aminotransferase (P<0.01) and a 54.6% reduction of aspartate aminotransferase (P<0.05) compared with sedentary mice. Additionally, proinflammatory cytokines, activation of caspase 3 and JNK were significantly lower, while antiapoptotic protein A20 increased. Voluntary distance running alters the intrahepatic immune phenotype producing an environment that is less susceptible to acute liver injury. PMID- 28640250 TI - BH3-only proteins: the thorny end of the ER stress response. PMID- 28640249 TI - MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis. AB - Limitless cell proliferation, evasion from apoptosis, dedifferentiation, metastatic spread and therapy resistance: all these properties of a cancer cell contribute to its malignant phenotype and affect patient outcome. MYBL2 (alias B Myb) is a transcription factor of the MYB transcription factor family and a physiological regulator of cell cycle progression, cell survival and cell differentiation. When deregulated in cancer cells, MYBL2 mediates the deregulation of these properties. In fact, MYBL2 is overexpressed and associated with poor patient outcome in numerous cancer entities. MYBL2 and players of its downstream transcriptional network can be used as prognostic and/or predictive biomarkers as well as potential therapeutic targets to offer less toxic and more specific anti-cancer therapies in future. In this review, we summarize current knowledge on the physiological roles of MYBL2 and highlight the impact of its deregulation on cancer initiation and progression. PMID- 28640251 TI - Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells. AB - Reactive oxygen species (ROS) have a crucial role in cell signaling and cellular functions. Mounting evidences suggest that abnormal increase of ROS is often observed in cancer cells and that this biochemical feature can be exploited for selective killing of the malignant cells. A naturally occurring compound phenethyl isothiocyanate (PEITC) has been shown to have promising anticancer activity by modulating intracellular ROS. Here we report a novel synthetic analog of PEITC with superior in vitro and in vivo antitumor effects. Mechanistic study showed that LBL21 induced a rapid depletion of intracellular glutathione (GSH), leading to abnormal ROS accumulation and mitochondrial dysfunction, evident by a decrease in mitochondrial respiration and transmembrane potential. Importantly, LBL21 exhibited the ability to abrogate stem cell-like cancer side population (SP) cells in non-small cell lung cancer A549 cells associated with a downregulation of stem cell markers including OCT4, ABCG2, SOX2 and CD133. Functionally, LBL21 inhibited the ability of cancer cells to form colonies in vitro and develop tumor in vivo. The therapeutic efficacy of LBL21 was further demonstrated in mice bearing A549 lung cancer xenografts. Our study suggests that the novel ROS-modulating agent LBL21 has promising anticancer activity with an advantage of elimination of stem-like cancer cells. This compound merits further study to evaluate its potential for use in cancer treatment. PMID- 28640252 TI - Long non-coding RNA ATB promotes malignancy of esophageal squamous cell carcinoma by regulating miR-200b/Kindlin-2 axis. AB - Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer related death, especially in China. In addition, the prognosis of late stage patients is extremely poor. However, the biological significance of the long non coding RNA lnc-ATB and its potential role in ESCC remain to be documented. In this study, we investigated the role of lnc-ATB and the underlying mechanism promoting its oncogenic activity in ESCC. Expression of lnc-ATB was higher in ESCC tissues and cell lines than that in normal counterparts. Upregulated lnc-ATB served as an independent prognosis predictor of ESCC patients. Moreover, loss-of function assays in ESCC cells showed that knockdown of lnc-ATB inhibited cell proliferation and migration both in vitro and in vivo. Mechanistic investigation indicated that lnc-ATB exerted oncogenic activities via regulating Kindlin-2, as the anti-migration role of lnc-ATB silence was attenuated by ectopic expression of Kindlin-2. Further analysis showed that lnc-ATB functions as a molecular sponge for miR-200b and Kindlin-2. Dysregulated miR-200b/Kindlin-2 signaling mediated the oncogenic activity of lnc-ATB in ESCC. Our results suggest that lnc ATB predicts poor prognosis and may serve as a potential therapeutic target for ESCC patients. PMID- 28640255 TI - AQP9-induced cell cycle arrest is associated with RAS activation and improves chemotherapy treatment efficacy in colorectal cancer. AB - Aquaporin-9 (AQP9) expression is associated with arsenic sensitivity in leukemia cells. However, the role of AQP9 in regulating tumor sensitivity to adjuvant chemotherapy in colorectal cancer (CRC) has not been elucidated. In this study, we demonstrated that AQP9 can serve as an independent predictive marker for adjuvant chemotherapy in CRC. Patients with high AQP9 expression had higher rate of disease-free survival (DFS) than those with low AQP9 expression. Upregulation of AQP9 was associated with enhanced chemosensitivity to 5-fluorouracil (5-FU) both in vitro and in vivo. Overexpression of AQP9 resulted in an increased intracellular level of 5-FU in CRC cells, hence leading to a higher percentage of apoptosis after 5-FU treatment. Moreover, AQP9 is positively associated with RAS activation and other downstream signaling molecules in CRC. AQP9 overexpression resulted in p21 upregulation and induced S-phase arrest. Taken together, AQP9 enhances the cytotoxic response to 5-FU in CRC cells by simultaneously inducing S phase arrest via activation of RAS signaling and facilitating drug uptake. Our results suggest that AQP9 might be a novel predictor for the benefit of 5-FU based chemotherapy in CRC. The identification of AQP9-induced tumor sensitivity to 5-FU highlights the role of AQP9 in regulating chemosensitivity in CRC. PMID- 28640256 TI - MicroRNA-26a/cyclin-dependent kinase 5 axis controls proliferation, apoptosis and in vivo tumor growth of diffuse large B-cell lymphoma cell lines. AB - Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of non-Hodgkin lymphoma. Despite a favorable therapeutic response to first-line chemo immunotherapy, still 30-40% of patients is refractory, or relapse after this treatment. Thus, alternative strategies must be sought. Previous studies have indicated that cyclin-dependent kinase 5 (CDK5), a serine/threonine protein kinase, is involved in tumor development and progression, and it may represent a potential therapeutic target. However, its role in modulating DLBCL growth and progression remains largely unexplored. In this study, we show that CDK5 and its activator, cyclin-dependent kinase 5 activator 1 (CDK5R1 or p35), are overexpressed in DLBCL cell lines and that signal transducer and activator of transcription 3 (STAT3) phosphorylation and activity is dependent on CDK5 expression in DLBCL. Using public data sets, we also demonstrate that patients with DLBCL show a higher expression of CDK5 compared with healthy individuals. By using loss-of-function approaches, we demonstrate that CDK5's activity regulates proliferation and survival of DLBCL cells. MicroRNAs (miRNAs or miRs) are small noncoding RNAs that negatively regulating gene expression and are involved in cancer initiation and progression. We identify miR-26a as direct regulator of p35 expression and CDK5 activity. We show that miR-26a expression is lower in DLBCL cell lines compared to B lymphocytes and that its ectopic expression leads to a drastic reduction of DLBCL tumor growth in vivo and decreased proliferation, cell cycle progression, and survival in vitro. Remarkably, concomitant overexpression of a 3'-UTR-truncated form of p35 promoted tumor growth in vivo and cell proliferation, cell-cycle progression, and cell survival in vitro. In conclusion, these results demonstrate an important role for miR-26a and CDK5 together in the survival and growth of DLBCL cells, suggesting the existence of potential novel therapeutic targets for the treatment of DLBCL. PMID- 28640258 TI - Effects of a ketamine metabolite on synaptic NMDAR function. PMID- 28640254 TI - Reduced brain UCP2 expression mediated by microRNA-503 contributes to increased stroke susceptibility in the high-salt fed stroke-prone spontaneously hypertensive rat. AB - UCP2 maps nearby the lod score peak of STR1-stroke QTL in the SHRSP rat strain. We explored the potential contribution of UCP2 to the high-salt diet (JD) dependent increased stroke susceptibility of SHRSP. Male SHRSP, SHRSR, two reciprocal SHRSR/SHRSP-STR1/QTL stroke congenic lines received JD for 4 weeks to detect brain UCP2 gene/protein modulation as compared with regular diet (RD). Brains were also analyzed for NF-kappaB protein expression, oxidative stress level and UCP2-targeted microRNAs expression level. Next, based on knowledge that fenofibrate and Brassica Oleracea (BO) stimulate UCP2 expression through PPARalpha activation, we monitored stroke occurrence in SHRSP receiving JD plus fenofibrate versus vehicle, JD plus BO juice versus BO juice plus PPARalpha inhibitor. Brain UCP2 expression was markedly reduced by JD in SHRSP and in the (SHRsr.SHRsp-(D1Rat134-Mt1pa)) congenic line, whereas NF-kappaB expression and oxidative stress level increased. The opposite phenomenon was observed in the SHRSR and in the (SHRsp.SHRsr-(D1Rat134-Mt1pa)) reciprocal congenic line. Interestingly, the UCP2-targeted rno-microRNA-503 was significantly upregulated in SHRSP and decreased in SHRSR upon JD, with consistent changes in the two reciprocal congenic lines. Both fenofibrate and BO significantly decreased brain microRNA-503 level, upregulated UCP2 expression and protected SHRSP from stroke occurrence. In vitro overexpression of microRNA-503 in endothelial cells suppressed UCP2 expression and led to a significant increase of cell mortality with decreased cell viability. Brain UCP2 downregulation is a determinant of increased stroke predisposition in high-salt-fed SHRSP. In this context, UCP2 can be modulated by both pharmacological and nutraceutical agents. The microRNA-503 significantly contributes to mediate brain UCP2 downregulation in JD-fed SHRSP. PMID- 28640253 TI - A role for TSPO in mitochondrial Ca2+ homeostasis and redox stress signaling. AB - The 18 kDa translocator protein TSPO localizes on the outer mitochondrial membrane (OMM). Systematically overexpressed at sites of neuroinflammation it is adopted as a biomarker of brain conditions. TSPO inhibits the autophagic removal of mitochondria by limiting PARK2-mediated mitochondrial ubiquitination via a peri-organelle accumulation of reactive oxygen species (ROS). Here we describe that TSPO deregulates mitochondrial Ca2+ signaling leading to a parallel increase in the cytosolic Ca2+ pools that activate the Ca2+-dependent NADPH oxidase (NOX) thereby increasing ROS. The inhibition of mitochondrial Ca2+ uptake by TSPO is a consequence of the phosphorylation of the voltage-dependent anion channel (VDAC1) by the protein kinase A (PKA), which is recruited to the mitochondria, in complex with the Acyl-CoA binding domain containing 3 (ACBD3). Notably, the neurotransmitter glutamate, which contributes neuronal toxicity in age-dependent conditions, triggers this TSPO-dependent mechanism of cell signaling leading to cellular demise. TSPO is therefore proposed as a novel OMM-based pathway to control intracellular Ca2+ dynamics and redox transients in neuronal cytotoxicity. PMID- 28640257 TI - Tumor-suppressive miR-26a and miR-26b inhibit cell aggressiveness by regulating FUT4 in colorectal cancer. AB - Metastasis is a multistep molecular network process, which is the major cause of death in patients with colorectal cancer (CRC). MicroRNAs (miRNAs) play pivotal roles in tumorigenesis as either tumor suppressors or oncogenes. Increased expression of fucosyltransferase4 (FUT4) has been reported to be associated with the invasive and metastatic properties of CRC. Here to identify potential key miRNAs and their target genes for colorectal cancer (CRC), we compared miRNA expression profiles between metastatic CRC cell SW620 and primary CRC cell SW480. Microarray analysis revealed that there were 85 differentially expressed miRNAs in SW620 cells with highly metastatic potential compared to SW480 cells with lowly metastatic potential. The expression of miR-26a and miR-26b were lower in SW620 cells than in SW480 cells, as well as downregulated in tumor tissues than in adjacent normal tissues of CRC patients. By applying bioinformatic approaches for the prediction of miRNA targeting 3'-UTR of FUT4, we identified FUT4 as one of the miR-26a/26b-targeted genes, while the expression of the target gene exhibited patterns opposite to that of miR-26a/26b in CRC cell lines, tumor tissues and corresponding adjacent tissues. Forced miR-26a/26b expression affected migratory behavior of CRC cells and FUT4 expression, while altered expression of FUT4 in CRC cell lines modulated progression upon transfection with miR-26a/26b mimic or inhibiter. FUT4 also regulated directly aggressiveness of SW620 and SW480 cells. Moreover, statistical analyses revealed that low miR 26a/26b levels and high expression of FUT4 were positively correlated with poor overall survival. The identified CRC-restricted miR-26a and miR-26b might be implicated in cancer progression via their target gene FUT4, suggesting their potential usage in CRC treatment. PMID- 28640261 TI - Correction. PMID- 28640260 TI - Microscopy of the interacting Harper-Hofstadter model in the two-body limit. AB - The interplay between magnetic fields and interacting particles can lead to exotic phases of matter that exhibit topological order and high degrees of spatial entanglement. Although these phases were discovered in a solid-state setting, recent innovations in systems of ultracold neutral atoms-uncharged atoms that do not naturally experience a Lorentz force-allow the synthesis of artificial magnetic, or gauge, fields. This experimental platform holds promise for exploring exotic physics in fractional quantum Hall systems, owing to the microscopic control and precision that is achievable in cold-atom systems. However, so far these experiments have mostly explored the regime of weak interactions, which precludes access to correlated many-body states. Here, through microscopic atomic control and detection, we demonstrate the controlled incorporation of strong interactions into a two-body system with a chiral band structure. We observe and explain the way in which interparticle interactions induce chirality in the propagation dynamics of particles in a ladder-like, real space lattice governed by the interacting Harper-Hofstadter model, which describes lattice-confined, coherently mobile particles in the presence of a magnetic field. We use a bottom-up strategy to prepare interacting chiral quantum states, thus circumventing the challenges of a top-down approach that begins with a many-body system, the size of which can hinder the preparation of controlled states. Our experimental platform combines all of the necessary components for investigating highly entangled topological states, and our observations provide a benchmark for future experiments in the fractional quantum Hall regime. PMID- 28640264 TI - Counterfeit drugs: Fight fake reagents with digital tools. PMID- 28640263 TI - Strong constraints on aerosol-cloud interactions from volcanic eruptions. AB - Aerosols have a potentially large effect on climate, particularly through their interactions with clouds, but the magnitude of this effect is highly uncertain. Large volcanic eruptions produce sulfur dioxide, which in turn produces aerosols; these eruptions thus represent a natural experiment through which to quantify aerosol-cloud interactions. Here we show that the massive 2014-2015 fissure eruption in Holuhraun, Iceland, reduced the size of liquid cloud droplets consistent with expectations-but had no discernible effect on other cloud properties. The reduction in droplet size led to cloud brightening and global mean radiative forcing of around -0.2 watts per square metre for September to October 2014. Changes in cloud amount or cloud liquid water path, however, were undetectable, indicating that these indirect effects, and cloud systems in general, are well buffered against aerosol changes. This result will reduce uncertainties in future climate projections, because we are now able to reject results from climate models with an excessive liquid-water-path response. PMID- 28640265 TI - Genomics: The feline line. PMID- 28640266 TI - Quantum physics: Interactions propel a magnetic dance. PMID- 28640267 TI - Ecology: Document India's floral biodiversity. PMID- 28640268 TI - Consent: Data-sharing for indigenous peoples. PMID- 28640269 TI - Addendum: The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. AB - This corrects the article DOI: 10.1038/nature21361. PMID- 28640271 TI - A massive, dead disk galaxy in the early Universe. AB - At redshift z = 2, when the Universe was just three billion years old, half of the most massive galaxies were extremely compact and had already exhausted their fuel for star formation. It is believed that they were formed in intense nuclear starbursts and that they ultimately grew into the most massive local elliptical galaxies seen today, through mergers with minor companions, but validating this picture requires higher-resolution observations of their centres than is currently possible. Magnification from gravitational lensing offers an opportunity to resolve the inner regions of galaxies. Here we report an analysis of the stellar populations and kinematics of a lensed z = 2.1478 compact galaxy, which-surprisingly-turns out to be a fast-spinning, rotationally supported disk galaxy. Its stars must have formed in a disk, rather than in a merger-driven nuclear starburst. The galaxy was probably fed by streams of cold gas, which were able to penetrate the hot halo gas until they were cut off by shock heating from the dark matter halo. This result confirms previous indirect indications that the first galaxies to cease star formation must have gone through major changes not just in their structure, but also in their kinematics, to evolve into present-day elliptical galaxies. PMID- 28640273 TI - Philosophy: Religion's openness towards science. PMID- 28640272 TI - Zanos et al. reply. PMID- 28640274 TI - Climate science: Clouds unfazed by haze. PMID- 28640275 TI - Protect funding for US earthquake early-warning system. PMID- 28640276 TI - Teeth tell tale of hippo's quick spread across Africa. PMID- 28640277 TI - Ancient oak's youthful genome surprises biologists. PMID- 28640278 TI - China cracks down on fake peer reviews. PMID- 28640279 TI - New journal blacklist, palm-oil ban and the world's top supercomputers. PMID- 28640280 TI - China's genomics giant to make stock-market debut. PMID- 28640281 TI - Track batteries degrading in real time. PMID- 28640282 TI - Heatwaves to soar above the hot air of climate politics. PMID- 28640283 TI - A year on, Brexit brings lessons in uncertainty. PMID- 28640284 TI - The fight to save thousands of lives with sea-floor sensors. PMID- 28640285 TI - Don't let Europe's open-science dream drift. PMID- 28640286 TI - Macron consolidates electoral victory. PMID- 28640289 TI - Consensus structures of the Mo(v) sites of sulfite-oxidizing enzymes derived from variable frequency pulsed EPR spectroscopy, isotopic labelling and DFT calculations. AB - Sulfite-oxidizing enzymes from eukaryotes and prokaryotes have five-coordinate distorted square-pyramidal coordination about the molybdenum atom. The paramagnetic Mo(v) state is easily generated, and over the years four distinct CW EPR spectra have been identified, depending upon enzyme source and the reaction conditions, namely high and low pH (hpH and lpH), phosphate inhibited (Pi) and sulfite (or blocked). Extensive studies of these paramagnetic forms of sulfite oxidizing enzymes using variable frequency pulsed electron spin echo (ESE) spectroscopy, isotopic labeling and density functional theory (DFT) calculations have led to the consensus structures that are described here. Errors in some of the previously proposed structures are corrected. PMID- 28640288 TI - Prognostic Factors for Transplant-Free Survival and Validation of Prognostic Models in Chinese Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid. AB - OBJECTIVES: We aimed to validate the prognostic models for primary biliary cholangitis (PBC) in Chinese patients receiving ursodeoxycholic acid (UCDA), and to compare their performances in predicting the long-term survival. METHODS: Chinese patients with PBC from a tertiary center were identified via electronic search of hospital medical registry. Risk factors associated with adverse events (liver transplantation or death from liver-related causes including hepatocellular carcinoma (HCC) and liver decompensation) were determined. Transplant-free survival was defined as survival free of liver-related death or transplantation. RESULTS: Of the 144 patients, 41 (28.5%) had baseline cirrhosis. The median age at diagnosis was 57.8 years. During a median follow-up of 7.0 years, 40 patients died (21 liver-related; 19 non-liver-related), 12 developed HCC, and 10 underwent transplantations. The 5-, 10-, and 15-year transplant-free survival probabilities were 91.0%, 78.1%, and 58.9%, respectively. Independent risk factors for adverse events were increasing age (hazard ratio (HR) 1.05), cirrhosis (HR 8.53), and suboptimal treatment response (HR 3.06). Aspartate aminotransferase/platelet ratio index at 1 year (APRI-r1) in combination with treatment response optimized the risk stratification. The performances of the GLOBE, UK-PBC scores, Rotterdam criteria, and APRI-r1 were comparable in predicting adverse events. The area under receiver operating curves within 5, 10, and 15 years were as follows-GLOBE score: 0.83, 0.85, and 0.85, respectively; UK PBC score: 0.89, 0.83, and 0.79, respectively; Rotterdam criteria: 0.82, 0.76, and 0.80, respectively; APRI-r1: 0.80, 0.83, and 0.77, respectively. CONCLUSIONS: The UK-PBC, GLOBE scores, Rotterdam criteria, and APRI-r1 had good and comparable prognostic prediction values for Chinese PBC patients receiving UCDA. PMID- 28640287 TI - Cost-Effectiveness of Risk Score-Stratified Hepatocellular Carcinoma Screening in Patients with Cirrhosis. AB - OBJECTIVES: Hepatocellular carcinoma (HCC) surveillance with biannual ultrasound is currently recommended for all patients with cirrhosis. However, clinical implementation of this "one-size-fits-all" approach is challenging as evidenced by its low application rate. We aimed to evaluate the cost-effectiveness of risk stratified HCC surveillance strategies in patients with cirrhosis. METHODS: A Markov decision-analytic modeling was performed to simulate a cohort of 50-year old subjects with compensated cirrhosis. Risk-stratified HCC surveillance strategies was implemented, in which patients were stratified into high-, intermediate-, or low-risk groups by HCC risk biomarker-based scores and assigned to surveillance modalities tailored to HCC risk (2 non-risk-stratified and 14 risk-stratified strategies) and compared with non-stratified biannual ultrasound. RESULTS: Quality-adjusted life expectancy gains for biannual ultrasound in all patients and risk-stratified strategies compared with no surveillance were 1.3 and 0.9-2.1 years, respectively. Compared with the current standard of biannual ultrasound in all cirrhosis patients, risk-stratified strategies applying magnetic resonance imaging (MRI) and/or ultrasound only in high- and intermediate risk patients, without screening in low-risk patients, were cost-effective. Abbreviated MRI (AMRI) for high- and intermediate-risk patients had the lowest incremental cost-effectiveness ratio (ICER) of $2,100 per quality-adjusted life year gained. AMRI in intermediate- and high-risk patients had ICERs <$3,000 across a wide range of HCC incidences. CONCLUSIONS: Risk-stratified HCC surveillance strategies targeting high- and intermediate-risk patients with cirrhosis are cost-effective and outperform the currently recommended non stratified biannual ultrasound in all patients with cirrhosis. PMID- 28640290 TI - Intrinsic 37/35Cl and 18/16O isotope shifts in 195Pt and 103Rh NMR of purely inorganic Pt and Rh complexes as unique spectroscopic fingerprints for unambiguous assignment of structure. AB - Well-resolved intrinsic 1DeltaM(37/35Cl) and 1DeltaM(18/16O) isotope shifts (where M = 195Pt or 103Rh) are visible in the 195Pt NMR peak profiles of relatively kinetically inert [PtCln(H2O)6-n]4-n (n = 1-6) complexes, their corresponding hydroxido [PtCl6-n(OH)n]2- (n = 1-5/6) anions, and [RhCln(H2O)6-n]3 n (n = 3-6) complexes in aqueous solutions at ca. 293 K. Although some such isotope effects have been previously reported, there are very limited published data in the open literature, and the first systematic studies of such intrinsic 1DeltaM(37/35Cl) and 1DeltaM(18/16O) isotope effects are reviewed in this perspective. In high magnetic-field NMR spectrometers, the 195Pt and 103Rh NMR peak profiles acquired within a relatively narrow temperature range (288-300 K) constitute unique 'spectroscopic fingerprints', which allow unambiguous structural assignment in solution. Available data for Pt(iv) and Rh(iii) complexes give rise to intrinsic isotope 1Deltadelta195Pt/103Rh(37/35Cl) profiles, which are extraordinarily sensitive to the structure of a particular complex or its geometric isomer. The profiles of aquated Pt(iv) and Rh(iii) complexes in acidic solutions may be resolved at either an isotopologue level only or at both an isotopologue and an isotopomer level depending on the structure. By contrast, in the series of [PtCl6-n(OH)n]2- (n = 1-6) anions, 1Deltadelta195Pt(37/35Cl) isotope shifts are resolved only at an isotopologue level. Relatively larger 1Delta195Pt(18/16O) isotope shifts obtained by the partial 18O enrichment of both the [PtCln(H2O)6-n]4-n (n = 1-6) and [PtCl6 n(OH)n]2- (n = 1-6) series give rise to remarkable 195Pt NMR peak profiles showing both 37/35Cl and 18/16O shifts. In the [PtCl6-n(OH)n]2- (n = 1-5/6) anions a typical NMR peak profile spanning ~2 ppm only may be resolved at both the isotopologue and isotopomer levels, depending on whether 18/16OH- ions are coordinated trans to chloride ions or not. The potential utility of such 1Delta195Pt(37/35Cl) and 1Delta195Pt(18/16O) isotope shifts in selected practical applications involving such complexes is briefly illustrated. PMID- 28640291 TI - A ferrocene based switchable molecular folding ruler. AB - A 2,2'-bipyridine-appended bis(ferrocene) three tiered molecular folding ruler, can be switched from a folded conformation to an extended conformation by the addition of [Cu(CH3CN)4](PF6) and 6,6'-dimesityl-2,2'-bipyridine. This extension and contraction process could be triggered either chemically or electrochemically and was reversible. PMID- 28640292 TI - Co-ligand tuned pyrimidine-2-carboxylate Mn(ii) complexes from a 2D 63 layer to an interpenetrated srs-net. AB - A 63 2D layer complex [Mn3Cl3(L3)]n.H2O (1) (L = pyrimidine-2-carboxylate) was obtained by assembling 2-cyanopyrimidine and manganese chloride, in which the L ligands were generated in situ. In 1 six-membered Mn rings were constructed from MnII ions and L ligands, which were connected to each other by double chloride anions affording a 2D layer. When the chloride anions in 1 were substituted partly by formate, [Mn4Cl3L4(HCO2)]n (2) was obtained. In 2, the L ligands bridge MnII to give a 1D chain, which was further connected by the double chloride anions and Cl/formate bridges to form a two-fold interpenetrated srs-net. Interestingly, 2 exhibits an obvious SHG response of approximately 0.8 times that of KDP. Furthermore, 2 is an antiferromagnet with a field induced spin flop transition. PMID- 28640293 TI - Collision cross section predictions using 2-dimensional molecular descriptors. AB - Traditional methods for deriving computationally-generated collision cross sections for comparisons with ion mobility-mass spectrometry data require 3 dimensional energy-minimized structures and are often time consuming, preventing high throughput implementation. Here, we introduce a method to predict ion mobility collision cross sections of lipids and peptide analogs important in prebiotic chemistry and other fields. Using less than 100 2-D molecular descriptors this approach resulted in prediction errors of less than 2%. PMID- 28640294 TI - Space-confined synthesis of multilayer Cu-N-doped graphene nanosheets for efficient oxygen electroreduction. AB - Cu-based carbon electrocatalysts for the oxygen reduction reaction are difficult to compare with the corresponding Fe- or Co-based electrocatalytic materials, owing to their insufficient catalytic activity and stability. Herein, as an impressive Cu-based electrocatalyst, a multilayer Cu-N-doped graphene sheet (Cu-N GR) is directly synthesized by the thermal conversion of copper(ii) 2,2' bipyridine in the confined space of lamellar montmorillonites. The open layered morphology of Cu-N-GR materials facilitated the exposure of more active centers and enhanced the flexibility and mobility of charge carriers. Combining the unique electronic properties of layered morphology and the synergistic effect of Cu and N, the obtained Cu-N-GR exhibits surprising results in terms of ORR catalytic activity, particularly in catalytic stability and methanol-tolerant properties in alkaline media. PMID- 28640295 TI - Stabilization of a non-aqueous self-double-emulsifying delivery system of rutin by fat crystals and nonionic surfactants: preparation and bioavailability study. AB - Literature examples of non-aqueous Pickering emulsions stabilized by fat crystals are very rare. Moreover, the applications of rutin are limited due to its low solubility in both water and oils (less than 0.10 mg g-1 and 0.25 mg g-1, respectively). Thus, herein, we developed an optimum formulation of a non-aqueous self-double-emulsifying delivery system (SDEDS) containing rutin and evaluated its oral bioavailability. The new formulation stabilized by fat crystals (glycerol monostearate, GMS) and nonionic surfactants was prepared via a two-step emulsification process. The presence of a mixture of GMS crystals and nonionic surfactants effectively improves the stability of the emulsions. The non-aqueous SDEDS spontaneously forms oil-in-oil-in-water (O/O/W) double emulsions in the gastrointestinal environment with the inner oil phase mainly containing the active ingredients. It is stable at both 4 degrees C and 25 degrees C for 30 days and could enhance the dissolution properties of the active ingredients. Furthermore, the protection of rutin against digestion-mediated precipitation was observed when the formulation contained a high concentration of GMS crystals. The oral absolute bioavailability of rutin obtained from SDEDS (8.62%) is 1.76-fold higher than that of the actives suspension (4.90%). Thus, the non-aqueous SDEDS is an attractive candidate for the encapsulation of water-insoluble and simultaneously oil-insoluble nutrients (such as rutin) and for use in oral delivery applications. PMID- 28640296 TI - Synthesis and photophysical and magnetic studies of ternary lanthanide(iii) complexes of naphthyl chromophore functionalized imidazo[4,5 f][1,10]phenanthroline and dibenzoylmethane. AB - The luminescent ternary lanthanide(iii) complexes [Ln(DBM)3(L1)] and [Ln(DBM)3(L2)] (Ln = Eu and Tb) of dibenzoylmethane (DBM) and 2-(2-naphthyl)-1H imidazo[4,5-f][1,10]phenanthroline (L1) and 2-(2-hydroxy-1-naphthyl)-1H imidazo[4,5-f][1,10]phenanthroline (L2) are reported in this work. The naphthyl chromophore functionalized imidazophenanthroline ligands L1 and L2 are structurally characterized by using single crystal X-ray diffraction: (L1), a = 14.933(4) A, b = 7.4965(13) A, c = 15.999(4) A, alpha = gamma = 90 degrees , beta = 102.670(7) degrees , V = 1747.4(6) A3, Z = 4, monoclinic, P21/c and (L2), a = 7.8555(11) A, b = 26.216(4) A, c = 10.0748(17) A, alpha = gamma = 90 degrees , beta = 96.799(7) degrees , V = 2060.2(6) A3, Z = 4, monoclinic, P21/n. A photophysical study reveals that the ligands L1 and L2 sensitize europium(iii) emission. The complexes [Eu(DBM)3(L1)] and [Eu(DBM)3(L2)] exhibit the characteristic emission of the Eu(iii) ion at 298 and 77 K. The terbium(iii) complexes [Tb(DBM)3(L1)] and [Tb(DBM)3(L2)] exhibit only ligand centred fluorescence at room temperature, while metal centred emission is observed at 77 K. The non-luminescence of the Tb(iii) center at room temperature is due to the proximity of the triplet states of the ligands to the 5D4 level of the Tb(iii) ion. DC magnetic susceptibility studies have been conducted on the Tb(iii) complexes in a 1 T field over the temperature range 20-300 K. The complexes display room temperature (300 K) chiMT values of 9.69 and 10.21 cm3 mol-1 K, respectively. A gradual decrease in the chiMT values is observed on reducing the temperature and reached the value of 7.80 and 6.60 cm3 mol-1 K, respectively, at 20 K. The decrease in the chiMT values as the temperature is lowered could be attributed to the depopulation of the Zeeman split crystal field levels. PMID- 28640297 TI - Preparation of tetrazine-containing [2 + 1] complexes of 99mTc and in vivo targeting using bioorthogonal inverse electron demand Diels-Alder chemistry. AB - The aim of this work was to synthesize and evaluate [2 + 1] 99mTc(i) polypyridine complexes containing tetrazines, which along with the corresponding Re(i) complexes, represent a new class of isostructural nuclear and turn-on luminescent probes that can be derivatized and targeted using bioorthogonal chemistry. To this end, [2 + 1] complexes of 99mTc(i) of the type [99mTc(CO)3(N^N)(L)] (N^N = bathophenanthroline disulfonate (BPS) or 2,2'-bipyridine (bipy)), where the monodentate ligand (L) was a tetrazine linked to the metal through an imidazole derivative, were prepared. The desired products were obtained in nearly quantitative radiochemical yield by adding [99mTc(CO)3(N^N)(OH2)]n to the imidazole-tetrazine ligand and heating at 60 degrees C for 30 min. Measurement of the reaction kinetics between the tetrazine and (E)-cyclooct-4-enol revealed a second-order rate constant of 8.6 * 103 M-1 s-1 at 37 degrees C, which is suitable for in vivo applications that require rapid coupling. Stability studies showed that the metal complexes were resistant to ligand challenge and exhibited reasonable protein binding in vitro. Biodistribution studies of the more water soluble BPS derivative in normal mice, one hour after administration of a bisphosphonate derivative of trans-cyclooctene (TCO-BP), revealed high activity concentrations in the knee (9.3 +/- 0.3 %ID g-1) and shoulder (5.3 +/- 0.7 %ID g 1). Using the same pretargeting approach, SPECT/CT imaging showed that the [2 + 1] tetrazine complex localized to implanted skeletal tumors. This is the first report of the preparation of 99mTc complexes of BPS and demonstration that their tetrazine derivatives can be used to prepare targeted imaging probes by employing bioorthogonal chemistry. PMID- 28640298 TI - Ellagitannin-rich bioactive extracts of Tuberaria lignosa: insights into the radiation-induced effects in the recovery of high added-value compounds. AB - Ellagitannins are polyphenols responsible for a number of bioactivities and health-promoting effects. These industrially important molecules can be affected by post-harvest treatments and recovery processes, but little is known about the irradiation-induced effects on their integrity, bioactivity and extractability. Herein, the impact of gamma radiation on the production of ellagitannin-rich extracts was investigated using Tuberaria lignosa as a case study. These effects were compared with those induced in flavonoids and organic acids. The extracts were particularly rich in hydrophilic antioxidants (measured by in vitro assays). The recovery of different phytochemicals was favoured by longer extraction times. Ellagitannins (mainly punicalagin derivatives) were extracted better from samples irradiated at 5 kGy and were not significantly affected by the 10 kGy dose. However, the total contents of flavonoids and organic acids were decreased by the consequent increase in irradiation dose. Therefore, this study supports the use of gamma radiation for processing T. lignosa, aiming to obtain ellagitannin-rich bioactive extracts. PMID- 28640299 TI - Anchoring groups for photocatalytic water oxidation on metal oxide surfaces. AB - Surface anchoring groups are needed to attach molecular units to photoanodes for photocatalytic water oxidation. The anchoring group must be hydrolytically stable and oxidation resistant under a variety of pH conditions. They must sometimes be electrically conducting for efficient light-induced electron injection from a photosensitizer to a metal oxide, but other times not conducting for accumulation of oxidizing equivalents on a water-oxidation catalyst. Commonly used anchors such as carboxylic acids and phosphonic acids have limited stability in aqueous environments, leading to surface hydrolysis and loss of catalytic function. More hydrolytically stable anchors, such as silatranes and hydroxamic acids, which are oxidation resistant and stable under acidic, neutral, and basic conditions, are more suitable for photoanode applications. Hydroxamic acids can be incorporated into dye molecules to give high electron injection efficiency due to their electrical conductivity and strong electronic coupling to the metal oxide surface. In contrast, silatranes, once bound as siloxanes, have diminished electronic coupling making them useful as catalyst anchors. PMID- 28640300 TI - Identifying the bottleneck of water oxidation by ab initio analysis of in situ optical absorbance spectrum. AB - Hematite's (alpha-Fe2O3) major limitation to efficiently splitting water using sunlight is the low rate of the oxygen evolution reaction (OER). Thus, identifying the OER rate limiting step is a cornerstone to enhancing the current under low applied potential. Different measurement techniques showed similar absorption difference spectra during a change in applied potential on the hematite anode below and above the onset of the OER in the dark and under light. This absorption change was shown to result from surface modification during the OER, but the specific surface species could not be resolved. On the basis of ab initio calculations, we analyze the calculated absorption spectra in relation to previous measurements. We provide for the first time solid evidence to specify H2O + *O -> *OOH + H+ + e- as the rate limiting step and *O as the bottleneck intermediate of the hematite OER. PMID- 28640301 TI - Synthesis of zwitterionic palladium complexes and their application as catalysts in cross-coupling reactions of aryl, heteroaryl and benzyl bromides with organoboron reagents in neat water. AB - N-(3-Chloro-2-quinoxalinyl)-N'-arylimidazolium salts (aryl = 2,6 diisopropylphenyl [HL1Cl]Cl, aryl = mesityl [HL2Cl]Cl) have been synthesized by treating 2,3-dichloroquinoxaline with the corresponding N'-arylimidazole in neat water. Facile reactions of these imidazolium salts with Pd(PPh3)4 and Pd2(dba)3/PPh3 (dba = dibenzyledene acetone) at 50 degrees C have afforded zwitterionic palladium(ii) complexes [Pd(HL1)(PPh3)Cl2] (I) and [Pd(HL2)(PPh3)Cl2] (II) in excellent yields. I and II have been tested for their ability to catalyze Suzuki-Miyaura cross coupling (SMC) reactions in neat water/K2CO3 and are found to be highly active for carrying out these reactions between aryl bromides and organoboron reagents. Furthermore, the scope of the catalyst I was also examined by employing (hetero)aryl bromides, hydrophilic aryl bromides, benzyl bromides and various organoboron reagents. More than 80 aryl/benzyl bromide-arylboronic acid combinations were screened in neat water/K2CO3 and it was found that I was a versatile catalyst, which produced biaryls/diarylmethanes in excellent yields. A TON of 82 000 was achieved by using I. Studies on the mechanism have also been carried out to investigate the involvement of carbene complexes in the catalytic path. Poison tests and a two phase test were also conducted and the results are reported. PMID- 28640302 TI - Influence of substituents on DNA and protein binding of cyclometalated Ir(iii) complexes and anticancer activity. AB - Synthesis of terpyridyl based ligands 3-([2,2':6',2''-terpyridin]-4'-yl)-7 methoxy-2-(methylthio)-quinolone, (L1); 3-([2,2':6',2''-terpyridin]-4'-yl)-6 methoxyquinolin-2(1H)-one, (L2); 3-([2,2'-:6',2''-terpyridin]-4'-yl)-6 methylquinolin-2(1H)-one (L3) and cyclometalated iridium(iii) complexes [[Ir(ppy)2L1]+PF6- (1), [Ir(ppy)2L2]+PF6- (2), [Ir(ppy)2L3]+PF6- (3) (2 phenylpyridine = Hppy)] involving these ligands has been described. The ligands L1-L3 and complexes 1-3 have been thoroughly characterized by elemental analyses, spectral studies (IR, 1H, 13C NMR, UV/vis and fluorescence) ESI-MS, and the structure of 3 has been unambiguously authenticated by single crystal X-ray analyses. UV/vis, fluorescence and circular dichroism spectroscopic studies showed rather efficient binding of 1 with CT-DNA (calf thymus DNA) and BSA (bovine serum albumin) relative to 2 and 3. Molecular docking studies unveiled binding of 1-3 with minor groove of CT-DNA via van der Waal's forces and electrostatically with the hydrophobic moiety of HSA (human serum albumin). The ligands and complexes exhibited moderate cytotoxicity towards MDA-MB-231 (breast cancer cell line) and significant influence on HeLa (cervical cancer cell line) cells. Cytotoxicity, morphological changes, and apoptosis have been followed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay, Hoechst 33342/PI (PI = propidium iodide) staining, cell cycle analysis by FACS (fluorescence activated cell sorting), and ROS (reactive oxygen species) generation by DCFH-DA (dichlorodihydrofluorescein diacetate) dye. Confocal microscopy images revealed that the drug efficiently initiates apoptosis in the cell cytosol. The IC50 values showed superior cytotoxicity of 1-3 against the HeLa cell line relative to cisplatin, and their ability to induce apoptosis is in the order 1 > 2 > 3. PMID- 28640303 TI - Novel adenine/thymine photodimerization channels mapped by PCM/TD-DFT calculations on dApT and TpdA dinucleotides. AB - Despite the biological relevance of AT-rich DNA sequences, the excited state paths associated with the photochemical reactions involving adenine and thymine stacked pairs have never been characterized, and the structure of the most abundant photoproduct in DNA is unknown. PCM/TD-M052X calculations on dApT and TpdA unveil the paths leading to the main photoproduct in TpdA, provide new insights into the reasons why it is not formed in dApT and show the existence of a new photochemical path, which could produce the precursor of the most abundant genomic AT/TA photoproduct. Our calculations confirm that anti/anti conformers are photochemically active and show that the dynamical solvation effects could significantly modulate the reaction yields. PMID- 28640304 TI - Addressing the characterisation challenge to understand catalysis in MOFs: the case of nanoscale Cu supported in NU-1000. AB - We explore the dynamic structure and reactivity of Cu species supported on NU 1000. By combining pair distribution function (PDF) analysis and difference envelope density (DED) analysis of in situ synchrotron-based X-ray scattering data, we simultaneously probe the local structure of supported Cu-species, their distribution within NU-1000 and distortions of the NU-1000 lattice under conditions relevant to catalysis and catalyst activation. These analyses show that atomic layer deposition (ALD) of Cu in NU-1000 (Cu-AIM) leads to the formation of Cu-oxo clusters within the small pores that connect the triangular and hexagonal channels. Exposure of Cu-AIM to a reducing atmosphere at 200 degrees C produces metallic Cu0 of two distinct particle sizes: ~4 nm nanoparticles and small sub-nanometer clusters. The size of these nanoparticles appears to be constrained by NU-1000 pore dimensions, with evidence of the sub nanometer clusters being bound within the triangular channels flanked by pyrene rings. This supported Cu0-NU-1000 system is catalytically active for gas-phase ethylene hydrogenation. Exposure of the catalyst to oxidative atmosphere re oxidises the Cu species to a Cu2O cuprite phase. The dynamic restructuring of the system in different chemical environments underscores the importance of probing these systems in situ. PMID- 28640305 TI - Immobilization of catalytic virus-like particles in a flow reactor. AB - A functional microfluidic reactor is constructed by the immobilization of gold containing virus-based protein cages that catalyze the reduction of nitro-arenes with high efficiency. PMID- 28640306 TI - Tip-enhanced Raman spectroscopy - from early developments to recent advances. AB - An analytical technique operating at the nanoscale must be flexible regarding variable experimental conditions while ideally also being highly specific, extremely sensitive, and spatially confined. In this respect, tip-enhanced Raman scattering (TERS) has been demonstrated to be ideally suited to, e.g., elucidating chemical reaction mechanisms, determining the distribution of components and identifying and localizing specific molecular structures at the nanometre scale. TERS combines the specificity of Raman spectroscopy with the high spatial resolution of scanning probe microscopies by utilizing plasmonic nanostructures to confine the incident electromagnetic field and increase it by many orders of magnitude. Consequently, molecular structure information in the optical near field that is inaccessible to other optical microscopy methods can be obtained. In this general review, the development of this still-young technique, from early experiments to recent achievements concerning inorganic, organic, and biological materials, is addressed. Accordingly, the technical developments necessary for stable and reliable AFM- and STM-based TERS experiments, together with the specific properties of the instruments under different conditions, are reviewed. The review also highlights selected experiments illustrating the capabilities of this emerging technique, the number of users of which has steadily increased since its inception in 2000. Finally, an assessment of the frontiers and new concepts of TERS, which aim towards rendering it a general and widely applicable technique that combines the highest possible lateral resolution and extreme sensitivity, is provided. PMID- 28640307 TI - Healthy properties of green and white teas: an update. AB - Green tea has been consumed for centuries in Japan, China and Morocco. White tea, which is considered a variety of green tea, is mostly consumed in China and is very appreciated for its flavor. Currently the consumption of both types of tea has been extended to the western countries even as a functional ingredient. A group of polyphenols called catechins stands out among their bioactive components, the most abundant being the (-) epigallocatechin gallate, with high antioxidant power. Teas also contain other phenolic compounds such as gallic, caffeic, chlorogenic or cinnamic acids, quercetin and proanthocyanidols, caffeine, theophylline, l-theanine and minerals such as fluorine, manganese or chromium. Investigations have mainly been focused on their antioxidant potential and their implication in the prevention and treatment of degenerative diseases. Several studies have evaluated their role in cardiovascular diseases, body weight control, bone mass increase, protection against neurodegenerative diseases and improvement of type 2 diabetes, among other pathologies. The main points of controversy are the design and interpretation of epidemiological and human intervention studies and the lack of information on catechins availability, metabolism and biotransformation. This review compiles and analyzes the latest peer-reviewed papers published from 2002 up to February 2017, including systematic reviews and meta-analyses. PMID- 28640308 TI - Photoconductivity and magnetoconductance effects on vacuum vapor deposition films of weak charge-transfer complexes. AB - Thin films of weak charge-transfer (CT) complexes (pyrene/dimethylpyromellitdiimide or pyrene/pyromellitic dianhydride) were prepared on an interdigitated platinum electrode by vacuum vapor deposition. Their photoconductivity and magnetoconductance (MC) effects were investigated, and mobile triplet excitons (probably CT excitons) were detected by time-resolved ESR (TRESR) at room temperature. The MC effect on the photocurrent was observed and analyzed by quantum-mechanical simulation assuming two types of collision mechanisms between the electron and hole carriers and between the trapped triplet excitons and mobile carriers. A successful simulation was achieved when the parameters (g, D, E, and polarization) determined by TRESR and the effective hyperfine splitting estimated from an ab initio molecular-orbital calculation were used. PMID- 28640309 TI - Computational analysis of histidine mutations on the structural stability of human tyrosinases leading to albinism insurgence. AB - Misfolding and structural alteration in proteins lead to serious malfunctions and cause various diseases in humans. Mutations at the active binding site in tyrosinase impair structural stability and cause lethal albinism by abolishing copper binding. To evaluate the histidine mutational effect, all mutated structures were built using homology modelling. The protein sequence was retrieved from the UniProt database, and 3D models of original and mutated human tyrosinase sequences were predicted by changing the residual positions within the target sequence separately. Structural and mutational analyses were performed to interpret the significance of mutated residues (N180, R202, Q202, R211, Y363, R367, Y367 and D390) at the active binding site of tyrosinases. CSpritz analysis depicted that 23.25% residues actively participate in the instability of tyrosinase. The accuracy of predicted models was confirmed through online servers ProSA-web, ERRAT score and VERIFY 3D values. The theoretical pI and GRAVY generated results also showed the accuracy of the predicted models. The CCA negative correlation results depicted that the replacement of mutated residues at His within the active binding site disturbs the structural stability of tyrosinases. The predicted CCA scores of Tyr367 (-0.079) and Q/R202 (0.032) revealed that both mutations have more potential to disturb the structural stability. MD simulation analyses of all predicted models justified that Gln202, Arg202, Tyr367 and D390 replacement made the protein structures more susceptible to destabilization. Mutational results showed that the replacement of His with Q/R202 and Y/R363 has a lethal effect and may cause melanin associated diseases such as OCA1. Taken together, our computational analysis depicts that the mutated residues such as Q/R202 and Y/R363 actively participate in instability and misfolding of tyrosinases, which may govern OCA1 through disturbing the melanin biosynthetic pathway. PMID- 28640310 TI - Spectroscopic evidence for cofactor-substrate interaction in the radical-SAM enzyme TYW1. AB - TYW1 is a metalloenzyme involved in the modifications of guanosine 37 of Phe-tRNA of Eukaryota and Archaea. It catalyzes the second step of Wybutosine biosynthesis, which consists of the formation of the tricyclic compound imG-14 from m1G using pyruvate and SAM (S-adenosyl-methionine) as co-substrates. Two [4Fe-4S] clusters are needed in the catalytic process. One effects the reductive binding of SAM, which initiates the radical reaction that inserts a C-C moiety into m1G. The other [4Fe-4S] cluster binds the pyruvate molecule that provides the C-C motif. Using a combination of EPR and Mossbauer spectroscopy, we have been able to probe the binding of both cofactors to the FeS clusters. The results highlight an interaction between pyruvate and SAM, indicating that they bind in close vicinity inside the catalytic pocket. They also indicate a chelating binding mode of pyruvate to the accessible Fe site of the corresponding FeS cluster. This binding mode has been used to construct a docking model of holoTYW1 with pyruvate and SAM, which is consistent with the spectroscopic findings. PMID- 28640311 TI - SERS - facts, figures and the future. PMID- 28640312 TI - Speciation in human blood of Metvan, a vanadium based potential anti-tumor drug. AB - The first report on the anti-cancer activity of the compound Metvan, [VIVO(Me2phen)2(SO4)], where Me2phen is 4,7-dimethyl-1,10-phenanthroline, dates back to 2001. Although it was immediately identified as one of the most promising multitargeted anti-cancer V compounds, no development on the medical experimentation was carried out. One of the possible reasons is the lack of information on its speciation in aqueous solution and its thermodynamic stability, factors which influence the transport in the blood and the final form which reaches the target organs. To fill this gap, in this work the speciation of Metvan in aqueous solution and human blood was studied by instrumental (EPR, electronic absorption spectroscopy, ESI-MS and ESI-MS/MS), analytical (pH potentiometry) and computational (DFT) methods. The results suggested that Metvan transforms at physiological pH into the hydrolytic species cis [VO(Me2phen)2(OH)]+ and that both citrate and proteins (transferrin and albumin in the blood serum, and hemoglobin in the erythrocytes) form mixed complexes, denoted [VO(Me2phen)(citrH-1)]2- and VO-Me2phen-Protein with the probable binding of His-N donors. The measurements with erythrocytes suggest that Metvan is able to cross their membrane forming mixed species VO-Me2phen-Hb. The redox stability in cell culture medium was also examined, showing that ca. 60% is oxidized to VV after 5 h. Overall, the speciation of Metvan in the blood mainly depends on the V concentration: when it is larger than 50 MUM, [VO(Me2phen)(citrH-1)]2- and VO Me2phen-Protein are the major species, while for concentrations lower than 10 MUM, (VO)(hTf) is formed and Me2phen is lost. Therefore, it is plausible that the pharmacological activity of Metvan could be due to the synergic action of free Me2phen, and VIVO and VVO/VVO2 species. PMID- 28640313 TI - Expanding applications of SERS through versatile nanomaterials engineering. AB - Surface-enhanced Raman scattering (SERS) spectroscopy has evolved into a cross disciplinary analytical technique by unveiling relevant chemical, biological, material, and structural information. The focus of this review is on two critical properties for successfully expanding applications of SERS spectroscopy: quality of the plasmonic substrate and molecule localization to the substrate. In this review, we discuss recent work on quantifying SERS distance dependence, key factors for substrate characterization and performance evaluation, expansion of SERS applications through substrate development for UV plasmonics and short distance capture strategies for optimizing analyte-surface structures. After surveying the recent developments of these seemingly disparate fields, we suggest new research directions that may originate from a synergistic blend of all the herein discussed topics. Finally, we discuss major challenges and open questions related to the application of SERS for understanding of chemical processes at the nanoscale, with special interest on in situ catalysts and biosensing. PMID- 28640314 TI - Theory of 2D crystals: graphene and beyond. AB - This tutorial review presents an overview of the basic theoretical aspects of two dimensional (2D) crystals. We revise essential aspects of graphene and the new families of semiconducting 2D materials, like transition metal dichalcogenides or black phosphorus. Minimal theoretical models for various materials are presented. Some of the exciting new possibilities offered by 2D crystals are discussed, such as manipulation and control of quantum degrees of freedom (spin and pseudospin), confinement of excitons, control of the electronic and optical properties with strain engineering, or unconventional superconducting phases. PMID- 28640315 TI - Formation and field-driven dynamics of nematic spheroids. AB - Unlike the canonical application of liquid crystals (LCs), LC displays, emerging technologies based on LC materials are increasingly leveraging the presence of nanoscale defects. The inherent nanoscale characteristics of LC defects present both significant opportunities as well as barriers for the application of this fascinating class of materials. Simulation-based approaches to the study of the effects of confinement and interface anchoring conditions on LC domains has resulted in significant progress over the past decade, where simulations are now able to access experimentally-relevant length scales while simultaneously capturing nanoscale defect structures. In this work, continuum simulations were performed in order to study the dynamics of micron-scale nematic LC spheroids of varying shape. Nematic spheroids are one of the simplest inherently defect containing LC structures and are relevant to polymer-dispersed LC-based "smart" window technology. Simulation results include nematic phase formation and external field-switching dynamics of nematic spheroids ranging in shape from oblate to prolate. Results include both qualitative and quantitative insight into the complex coupling of nanoscale defect dynamics and structure transitions to micron-scale reorientation. Dynamic mechanisms are presented and related to structural transitions in LC defects present in the nematic domain. Domain averaged metrics including order parameters and response times are determined for a range of experimentally-accessible electric field strengths. These results have both fundamental and technological relevance, in that increased understanding of LC dynamics in the presence of defects is a key barrier to continued advancement in the field. PMID- 28640316 TI - Electrospun graphene-wrapped Na6.24Fe4.88(P2O7)4 nanofibers as a high-performance cathode for sodium-ion batteries. AB - Na6.24Fe4.88(P2O7)4 is one of the intensively investigated polyanionic compounds and has shown high rate discharge capacity, but its relatively low electronic conductivity hampers the high performance of the batteries. Herein for the first time we report new graphene wrapped Na6.24Fe4.88(P2O7)4 composite nanofibers (NFPO@C@rGO) made from electrospinning for cathodes of SIBs to achieve an even higher performance with a highly stable discharge capacity of ~99 mA h g-1 at a current density of 40 mA g-1 after 320 cycles, which is 1.6 times higher than that of the pristine Na6.24Fe4.88(P2O7)4 (NFPO@C) composite. In particular, the NFPO@C@rGO composite cathode exhibits an even higher discharge rate capacity of ~53.9 mA h g-1 at a current density of 1280 mA g-1 (11C) than that of ~40 mA h g 1 at a current density of 1100 mA g-1 (9.4C) for the reported best high discharge rate performance of NFPO. The superior cycling and high rate capability are attributed to the unique spinning vein fiber based porous structure offering a good intimate contact between NFPO@C and graphene for great electronic conductivity, fast ionic transport, a large reaction surface and a strong solid structure preventing collapse during cycling, thus achieving a high rate discharge performance and high cycling stability. PMID- 28640317 TI - Octyl gallate, a food additive with potential beneficial properties to treat Helicobacter pylori infection. AB - Helicobacter pylori infection is marked by intense production of reactive oxygen species (ROS) through the activation of neutrophils that are constantly attracted to the infected gastric mucosa. Here, gallic acid and its alkyl esters were evaluated as compounds able to act as antimicrobial agents and inhibitors of ROS released by H. pylori-activated neutrophils simultaneously. We found that the higher hydrophobicity caused by esterification of gallic acid led to a significant increase in its ability as a cytotoxic agent against H. pylori, a scavenger of ROS and an inhibitor of NADPH oxidase in neutrophils. Octyl gallate, a widely used food additive, showed the highest antimicrobial activity against H. pylori, with a minimum inhibitory concentration (MIC) value of 125 MUg mL-1, whereas gallic acid had a MIC value higher than 1000 MUg mL-1. The production of superoxide anion radicals was almost 100% abolished by the addition of 10 MUM (2.82 MUg mL-1) octyl gallate, whereas gallic acid inhibited around 20%. A similar tendency was also found when measuring the production of hypochlorous acid. The protective effect of the esters was cytochemically confirmed. In conclusion, this study showed that hydrophobicity is a crucial factor to obtain a significant anti-ROS and anti-H. pylori activity. Finally, it highlights octyl gallate, a food additive widely used in the food industry, as a promising molecule in the treatment of H. pylori infection. PMID- 28640318 TI - K2CO3 catalyzed regioselective synthesis of thieno[2,3-b]thiochromen-4-one oximes: access to the corresponding amine and nitroso derivatives. AB - An unprecedented and efficient method for the synthesis of useful thieno[2,3 b]thiochromen-4-one oximes is accomplished via a thio[3 + 2] cyclization reaction of 4-hydroxydithiocoumarins and trans-beta-nitrostyrenes in the presence of 10 mol% K2CO3 in ethanol under reflux conditions. Furthermore, hitherto, these precursors were converted into the corresponding 2-amino thieno[2,3-b]thiochromen 4-one and 2-nitroso thieno[2,3-b]thiochromen-4-one derivatives respectively. The salient features of the present protocol are mild reaction conditions, shorter reaction times, good yields and unexpected formation of C-C and C-S bonds in a regioselective manner. PMID- 28640319 TI - Observational constraints on particle acidity using measurements and modelling of particles and gases. AB - In many parts of the world, the implementation of air quality regulations has led to significant decreases in SO2 emissions with minimal impact on NH3 emissions. In Canada and the United States, the molar ratio of NH3 : SO2 emissions has increased dramatically between 1990 and 2014. In many regions of North America, this will lead the molar ratio of NHx : SO4, where NHx is the sum of particle phase NH4+ and gas phase NH3, and SO4 is the sum of particle phase HSO4- and SO42 , to exceed 2. A thermodynamic model (E-AIM model II) is used to investigate the sensitivity of particle pH, and the gas-particle partitioning of NHx and inorganic nitrate, to the atmospheric NHx : SO4 ratio. Steep increases in pH and the gas fraction of NHx are found as NHx : SO4 varies from below 1 to above 2. The sensitivity of the gas fraction of nitrate also depends strongly on temperature. The results show that if NHx : SO4 exceeds 2, and the gas and particle phase NHx are in equilibrium, the particle pH will be above 2. Observations of the composition of particulate matter and gas phase NH3 from two field campaigns in southern Canada in 2007 and 2012 have median NHx : SO4 ratios of 3.8 and 25, respectively. These campaigns exhibited similar amounts of NH3, but very different particle phase loadings. Under these conditions, the pH values calculated using the observations as input to the E-AIM model were in the range of 1-4. The pH values were typically higher at night because the higher relative humidity increased the particle water content, diluting the acidity. The assumption of equilibration between the gas and particle phase NHx was evaluated by comparing the observed and modelled gas fraction of NHx. In general, E-AIM was able to reproduce the partitioning well, suggesting that the dominant constituents contributing to particle acidity were measured, and that the estimated pH values were realistic. These results suggest that regions of the world where the ratio of NH3 : SO2 emissions is beginning to exceed 2 on a molar basis may be experiencing rapid increases in aerosol pH of 1-3 pH units. This could have important consequences for the rates of condensed phase reactions that are acid-catalyzed. PMID- 28640320 TI - Molecular signature of coronary stent thrombosis: oxidative stress and innate immunity cells. AB - The clinical impact of in-stent thrombosis is high because it is associated with high mortality and 20 % of the patients suffer a recurrent event within the two following years. The aim of this study was to characterise the morphologic and proteomic profile of in-stent thrombi (IST) in comparison to thrombi developed on native coronary arteries (CT) to identify a differential molecular signature. The study included 45 patients with ST-elevation-myocardial-infarction (STEMI) treated by primary-percutaneous-intervention and thrombus aspiration: 21 had IST and 24 had CT. Thrombi were characterised by morphologic immunohistochemical analysis and differential proteomic profiling (2-DE+MALDI-TOF/TOF). Bioinformatic analysis revealed differences in proteins related to oxidative-stress and cell death/survival. IST showed a higher content of structural proteins (gelsolin, actin-cytoplasmic-1, tropomyosin, and myosin) together with an imbalance in redox homeostasis related proteins (increased superoxide-dismutase and decreased peroxiredoxin-2 thrombus content), and a coordinated increase of chaperones (HSP60 and HSC70) and cellular quality control-related proteins (26S-protease regulatory-subunit-7). These changes were reflected into a significant decrease in HSC70 systemic levels and a significant increase in advanced-oxidation-protein products (AOPP) indicative of increased oxidative stress-mediated protein damage in IST. Our results reveal an imbalance in redox-related proteins indicative of an exacerbated oxidative-stress that leads to an accumulation of AOPP serum levels in IST. Moreover, the coordinated increase in chaperones and regulatory proteins reflects the activation of intracellular protection mechanisms to maintain protein integrity in IST. The failure to counterbalance the stress situation could trigger cellular apoptosis leading to the destabilization of the thrombus and to a worse prognosis of IST-STEMI-patients. PMID- 28640321 TI - Effects of direct oral anticoagulants on lupus anticoagulant assays in a real life setting. AB - Laboratory diagnosis of lupus anticoagulant (LA) is based on prolongation in at least one coagulation assay (diluted Russell's viper venom time - dRVVT or activated partial thromboplastin time - aPTT), which normalises after addition of phospholipids. Both assays may be influenced by anticoagulants and therefore LA should not be tested during warfarin or heparin treatment. It has been shown (primarily in vitro) that direct oral anticoagulants (DOACs - dabigatran [DAB], rivaroxaban [RIV] and apixaban [API]) may also influence LA testing. We tested the effects of DOACs on assays routinely used for the diagnosis of LA in patients treated with these drugs in a real-life setting. Plasma from patients with atrial fibrillation treated with DAB (n=30), RIV (n=20) and API (n=17) and not known to have LA were tested using dRVVT (LA-screen and LA-confirm, Life Diagnostics) and aPTT (PTT-LA, Diagnostica Stago and aPTT Actin FS, Siemens Healthcare Diagnostics) assays. According to the diagnostics algorithm, dRVVT and aPTT ratios of <1.2 were considered negative, ratios of >1.4 positive, while if the ratios were 1.2-1.4 LA could not be ruled out. Plasma concentrations varied between 8-172 ug/l for DAB, 8-437 ug/l for RIV and 36-178 ug/l for API. LA diagnosis was negative in only eight (27 %) plasma samples from patients treated with DAB, and in five (25 %) and four samples (24 %) from patients treated with RIV and API, respectively. LA Positivity (dRVVT and aPTT ratios >1.4) was found in 5 cases (17 %) among patients treated with DAB, in 10 cases (50 %) treated with RIV and in 7 cases (41 %) treated with API. A concentration-dependent effect of DOACs on dRVVT-based parameters was observed, particularly as regards DAB. At lower concentrations, RIV and API had only minor effects on the confirmatory tests (below 100 ug/l and 70 ug/l, respectively). Our results suggest that a risk of overestimation of LA detection is present in samples from patients treated with DOACs. Therefore, LA testing should not be performed during treatment with DOACs. Prolongation in confirmatory assays may be helpful for the recognition of false positivity, especially as regards DAB. PMID- 28640322 TI - Effectiveness and safety of rivaroxaban versus warfarin for treatment and prevention of recurrence of venous thromboembolism. AB - The efficacy and safety or rivaroxaban versus enoxaparin/vitamin K antagonist for treatment and prevention recurrence of venous thromboembolism (VTE) was demonstrated in the randomised EINSTEIN trials. We assessed the effectiveness and safety of rivaroxaban versus warfarin in VTE patients managed in routine practice. Using US MarketScan claims from 1/2012-6/2015, we included adults with a primary diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) during a hospitalisation/emergency department visit, newly-initiated on rivaroxaban or warfarin within 30-days after the VTE and with >=180-days of continuous medical/prescription benefits prior to the VTE (baseline). Patients with a claim for anticoagulation at baseline were excluded. Recurrent VTE, major bleeding, intracranial haemorrhage (ICH) and gastrointestinal bleeding (GIB) were assessed. Differences in baseline characteristics between cohorts were adjusted for using inverse probability of treatment weights based on propensity-scores. Patients had a maximum of 12-months period of follow-up post-VTE or until endpoint occurrence, switch/discontinuation of index anticoagulation, insurance disenrollment or end-of-follow-up. Cox regression was performed and reported as hazard ratios (HRs) with 95 % confidence intervals (CIs). In total, 13,609 rivaroxaban and 32,244 warfarin users experiencing VTE were included. Rivaroxaban was associated with an 19 % (95 %CI=10-27 %) reduction in recurrent VTE and a 21 % (95 %CI=4-35 %) reduction in major bleeding hazard versus warfarin. Rivaroxaban was also associated with significantly decreased hazards of ICH (HR=0.40) and GIB (HR=0.72). Rivaroxaban appears to reduce patients' hazard of both recurrent VTE and major bleeding in routine practice. These results appear consistent with EINSTEIN and post-marketing registry studies. PMID- 28640323 TI - Lys 42/43/44 and Arg 12 of thrombin-activable fibrinolysis inhibitor comprise a thrombomodulin exosite essential for its antifibrinolytic potential. AB - The thrombin-thrombomodulin (TM) complex activates thrombin-activable fibrinolysis inhibitor (TAFI) more efficiently than thrombin alone. The exosite on TAFI required for its TM-dependent activation by thrombin has not been identified. Based on previous work by us and others, we generated TAFI variants with one or more of residues Lys 42, Lys 43, Lys 44 and Arg 12 within the activation peptide mutated to alanine. Mutation of one, two, or three Lys residues or the Arg residue alone decreased the catalytic efficiency of TAFI activation by thrombin-TM by 2.4-, 3.2-, 4.7-, and 15.0-fold, respectively, and increased the TAFI concentrations required for half-maximal prolongation of clot lysis times (K1/2) by 3-, 4,- 15-, and 24-fold, respectively. Mutation of all four residues decreased the catalytic efficiency of TAFI activation by 45.0-fold, increased the K1/2 by 130-fold, and abolished antifibrinolytic activity in a clot lysis assay at physiologic levels of TAFI. Similar trends in the antifibrinolytic activity of the TAFI variants were observed when plasma clots were formed using HUVECs as the source of TM. When thrombin was used as the activator, mutation of all four residues reduced the rate of activation by 1.1-fold compared with wild type TAFI, suggesting that these mutations only impacted activation kinetics in the presence of TM. Surface plasmon resonance data suggest that mutation of the four residues abrogates TM binding with or without thrombin. Therefore, Lys 42, Lys 43, Lys 44 and Arg 12 are critical for the interaction of TAFI with the thrombin-TM complex, which modulates its antifibrinolytic potential. PMID- 28640324 TI - New paradigms in venous thromboprophylaxis of medically ill patients. AB - Acutelly-ill hospitalised medical patients are at risk of venous thromboembolism (VTE), both in-hospital and in the immediate post-discharge period, and mortality from VTE is thought to be particularly high in this patient population. However, despite previous mandates from international antithrombotic guidelines such as those of the American College of Chest Physicians (ACCP) for the "universal" use of thromboprophylaxis in hospitalised medical patients, global audits suggest that implementation of thromboprophylaxis continues to be challenging because of the perceived higher risk of bleeding and lower risk of VTE than that reported in clinical trials. Recent population-based studies also reveal that a "universal" hospital-only thromboprophylactic strategy does not reduce the community burden of VTE from this population, which may constitute nearly one quarter of the attributable risk of VTE. Lastly, four large randomised placebo-controlled trials of extended thromboprophylaxis have failed to show a definitive net clinical benefit in hospitalised medical patients. Recent large-scale efforts in deriving and validating scored VTE and bleed risk assessment models (RAMs) have been completed in the medically-ill population. In addition, an elevated D-dimer as a new biomarker to identify at-VTE risk medically ill patients has also undergone prospective evaluation. This paper will review current concepts of VTE and bleed risk in hospitalised medical patients, both in the hospital as well as the post hospital discharge period, and will discuss new paradigms of thromboprophylaxis in this population using an individualised, patient-centered approach. PMID- 28640325 TI - The deformed reform. PMID- 28640326 TI - Bill of Law 4,302: outsourcing, albeit late. PMID- 28640327 TI - [Gender and age differences in social support and body mass index in adults in Greater Metropolitan Rio de Janeiro, Brazil]. AB - The objective was to investigate gender and age differences in the association between dimensions of social support and body mass index (BMI) in a sample of 1,465 adults (20 to 59 years) in a population-based study in Duque de Caxias, Rio de Janeiro State, Brazil. Anthropometry was conducted by trained evaluators and social support obtained by the Medical Outcomes Study, adapted and validated for the Brazilian population. The analyses were performed with multiple linear regressions, stratified by gender and age bracket, considering the sample's expansion factor and complex design. Obesity prevalence was 28% in women and 16.2% in men. After adjusting for confounders, a negative association was observed between social support and BMI in men 40-49 years of age, and in emotional support/information (beta = -2.04), and positive social interaction (beta = -2.40). There was a positive association for social support and BMI in men 50-59 years of age in emotional support/information (beta = 1.84). The study indicates that social support can protect against obesity in men in some dimensions and age brackets. However, social support does not appear to be a protective factor in women. PMID- 28640328 TI - [Validity and reproducibility of an Internet-based questionnaire (Web-CAAFE) to evaluate the food consumption of students aged 7 to 15 years]. AB - The study evaluated the validity and reproducibility of the food consumption section of the questionnaire Food Intake and Physical Activity of School Children (Web-CAAFE), an Internet-based software for the qualitative measurement of food consumption by recalling the previous day. A total of 390 students in grades 2 to 5 (7 to 15 years) of a semi-integral public school participated in the study. The validity was tested by comparing the report in the Web-CAAFE and the direct observation of food consumed in the school in the previous day. The reproducibility was evaluated in a sub-sample of 92 schoolchildren, by comparing repeated reports in the Web-CAAFE on the same day. Probabilities of accuracy in the Web-CAAFE report in relation to the observation (matches, omissions and intrusions and respective 95% confidence intervals) among seven food groups were estimated through multinomial logistic regression. The average for the match rate was 81.4% (variation: 62% sweets and 98% beans); for the omission rate was 16.2% (variation between 2.1% dairy products and 28.5% sweets); for the intrusion rate was 7.1% (variation between 1.3% beans and 13.8% cereals). Sweets, cereals and processed foods, snack foods and fried foods simultaneously exhibited higher rates of omission and intrusion. Students 10 years of age or older had lower probabilities of intruding food items. There were no significant variations in the accuracy of the report between repeated measures. The Web-CAAFE was a valid and reliable instrument for the evaluation of food consumption, when applied to students in grades 2 to 5 of public schools. PMID- 28640329 TI - Association of adverse oral health outcomes with socioeconomic inequalities and dental needs in Brazilian adolescents. AB - This study aimed to explore the relations between adverse oral outcomes and socioeconomic, demographic, and self-rated oral health variables and to describe their distribution. Principal component analysis was conducted on data from adolescents in the Brazilian National Oral Health Survey (N = 5,445). Higher loadings were found for crowding (0.6), maxillary and mandibular irregularities (0.5), and count of communitary periodontal index (CPI) sextants with bleeding and dental calculus (0.5). The mean rates for periodontal and occlusal disorders were at least two times higher in adolescents from lower income families and those reporting the need for dental prostheses, as well as those dissatisfied with their dental and overall oral health. Increased mean rates of occlusal disorders were associated with schooling delay and history of toothache in the previous six months. The mean scores suggested accumulation of at least one of the negative oral health indicators in the lower income strata, among adolescents with schooling delay, and in those reporting dental needs. The results suggest priorities for planning and monitoring as a function of oral health requirements. PMID- 28640330 TI - [Incorporation of Information and Communication Technologies and quality of primary healthcare in Brazil]. AB - Information and Communication Technologies (ICTs) are means to handle information, streamline communication, and contribute to patient care. This article describes the incorporation of Information and Communication Technologies in primary care and its association with quality, based on the Brazilian National Program for the Improvement of Access and Quality in Primary Care (PMAQ in portuguese). This was a cross-sectional study with 17,053 teams. An Index of Incorporation of ICTs was created, which included: information infrastructure, systems, and utilization. Regression analysis was used to assess associations. Only 13.5% of the teams had a high degree of ICTs. The strongest association was seen in the utilization of information. ICTs can contribute to improving quality of primary care. PMID- 28640331 TI - Health needs of street market saleswomen: access, connection and welcoming as integral practices. AB - Objective: To analyze the health needs of street market saleswomen of the Mercado Publico (Public Market) of a municipality in Northeastern Brazil. Method: Qualitative, exploratory and descriptive study, with fifteen saleswomen in a public market. Data production means included semi-structured interviews, April May 2016. Results: Data were analyzed using the analysis of technical content technique, from which the following theme category emerged: "Access needs to health services and professional humanized practices." The women in the study highlighted the guarantee of access, connection and welcoming as driving practices for the recognition of health needs confronting the health-disease process and comprehensive care. Conclusions: Being welcomed, identifying needs and producing a bond will contribute to these women recognizing themselves as subjects of their needs, strengthening their autonomy, empowerment and self-care. PMID- 28640332 TI - Pregnant teenagers' group: contributions to prenatal care. AB - Objective: To describe changes in nurses' care following the implementation of a group of pregnant teenagers in prenatal care based on the expectations and experiences of pregnant teenagers. Method: Qualitative and descriptive study conducted from February to November 2013 at a Primary Care Unit in Fortaleza, Ceara, Brazil, through focus groups with 16 adolescents from the group of pregnant women in the second or third trimester of pregnancy. The analysis identified central ideas and units of meanings that formed the categories. Results: The strategy of a group of pregnant teenagers, which provides a space for coexistence and the establishment of ties encourages these individuals to talk about their needs, re-signifying their ties. Educational strategies to promote self-care of pregnant teenagers and care for their babies involve the sharing of experiences, doubts and beliefs. Conclusion: Considerations and suggestions of the adolescents contributed to guide nurses' practice and provide a strategic space of care and support for pregnant adolescents in primary care. PMID- 28640333 TI - Establishment of lactaton rooms in public and private companies: potentialities and difficulties. AB - Objective: To know how managers of public and private companies view lactation support rooms and their implantation. Method: This is study is based on qualitative, exploratory, and descriptive research. Twenty managers from Greater Florianopolis participated in the research, in 2015. Data were collected by means of semi-structured/projective interviews, and subjected to content analysis associated with Atlas.ti software. Results: Data analysis led to the following two categories: difficulties and facilities of establishing a lactation room, with a predominance of financial difficulties and the lack of physical space. Dialectically, the subjects also recognised the low cost involved, which facilitates establishment. Conclusion: Financial, cultural, and political aspects make it difficult to set up lactation rooms, but the importance of this measure was acknowledged. Although the success of breastfeeding partly depends on these support rooms, it also requires multiple actions, especially the effective participation of nurses and other health workers. PMID- 28640334 TI - Instruments for articulating the network of attention to women in situation of violence: collective construction. AB - Objective: This paper aims at identifying all the necessary information to build instruments which are designed to facilitate the professional integration of services to women in situation of violence with a view to the establishment of a network of attention. Method: Qualitative study, convergent, whose information has been produced from February to August 2015 by 10 group meetings, with 32 participants from the Integrated Working Group to Confront Violence in Santa Maria-RS, located at the Universidade Federal de Santa Maria. Using thematic content analysis. Results: It defined the flow direction; the points to compose the network; what it would take to communicate among services: identification of wife and family, report on the situation and the continuity of care. Conclusions: There is a need for an institutional formalization of constructed devices. The articulation between the services requires communication, involvement and commitment of the professionals to ensure the continuity of care. PMID- 28640335 TI - Construction and content validation of checklist for patient safety in emergency care. AB - Objective: To construct and validate a checklist for patient safety in emergency care. Method: This is methodological research conducted in Curitiba, in 2015, with construction and validation stages. The checklist was based on the guidelines of the Brazilian patient safety programme and validated online using the Delphi method, with a questionnaire, and with the participation of 23 Brazilian specialists in the first round and 20 in the second round. The data were analysed using the Content Validity Index (CVI), Cronbach's alpha, and Fisher's Exact Test. Results: We produced a checklist with 18 valid and reliable items (94% of CVI, Cronbach's alpha = 0.91). Conclusions: The checklist comprises patient safety actions and items to predict risk situations, corrective actions, and promote safety in emergency services and other health-related contexts. PMID- 28640336 TI - Sugars levels of four sugarcane genotypes in different stem portions during the maturation phase. AB - Maturation is a characteristic of sugarcane plant (Saccharum spp.) and even when grown under the same soil and climate conditions the varieties differ on the maturation curve. Thus, studies that allow establishing maturation curves of different sugarcane genotypes in the local soil and climate may indicate the proper harvesting period to ensure better quality of the raw material. This study aimed to analyze the levels of soluble sugars during the maturation phase and assess the technological and productivity indexes of four irrigated sugarcane genotypes in the region of Rio Largo, Alagoas. The experiment was conducted in randomized blocks in a 4 x 2 x 5 factorial: four genotypes (RB92579, RB98710, RB99395 and RB961003), two stem portions (internodes 1-4 and internodes 5-8) and five seasons (82, 49, 25, 13 and 3 days before harvesting), each treatment with three replications. Internodes 1-4 showed the highest levels of reducing sugars, while the largest accumulation of sucrose and total soluble solids occurred in internodes 5-8. RB99395 genotype showed more stability in the sugar levels during sugarcane maturation, which can indicate early maturation and high agricultural yield. PMID- 28640337 TI - Thermodynamic bounds for existence of normal shock in compressible fluid flow in pipes. AB - The present paper is concerned with the thermodynamic theory of the normal shock in compressible fluid flow in pipes, in the lights of the pioneering works of Lord Rayleigh and G. Fanno. The theory of normal shock in pipes is currently presented in terms of the Rayleigh and Fanno curves, which are shown to cross each other in two points, one corresponding to a subsonic flow and the other corresponding to a supersonic flow. It is proposed in this paper a novel differential identity, which relates the energy flux density, the linear momentum flux density, and the entropy, for constant mass flow density. The identity so obtained is used to establish a theorem, which shows that Rayleigh and Fanno curves become tangent to each other at a single sonic point. At the sonic point the entropy reaches a maximum, either as a function of the pressure and the energy density flux or as a function of the pressure and the linear momentum density flux. A Second Law analysis is also presented, which is fully independent of the Second Law analysis based on the Rankine-Hugoniot adiabatic carried out by Landau and Lifshitz (1959). PMID- 28640338 TI - Publish and perish in the hands of predatory journals. PMID- 28640340 TI - Terrestrial impact structures as geoheritage: an assessment method of their scientific value and its application to Brazil. AB - Terrestrial impact structures are geological and geomorphological features with particular importance to understand the history and evolution of the planet. Impact structures are scattered around the world but in many countries these features are under threat, essentially due to anthropic factors. Impact structures with higher scientific value should be considered as geological heritage and, consequently, be subjected to geoconservation strategies. In order to select the most important impact structures to be properly conserved and managed, this paper proposes a quantitative assessment method of the scientific value of these structures. The eight Brazilian impact structures were used to test this method that has the potential to be applied to any geological context in any country. The structures known as Araguainha Dome-MT and Serra da Cangalha TO reached a higher scientific value, which justifies the need to develop geoconservation strategies and a proper management. PMID- 28640339 TI - Special metabolites isolated from Urochloa humidicola (Poaceae). AB - This study aims to identify special metabolites in polar extracts from Urochloa humidicola (synonym Brachiaria humidicola) that have allelopathic effects and induce secondary photosensitization in ruminants. The compounds were isolated and identified via chromatographic and spectroscopic techniques. The compounds 4 hydroxy-3-methoxy-benzoic acid, trans-4-hydroxycinnamic acid, and p-hydroxy benzoic acid; the flavonols isorhamnetin-3-O-beta-d-glucopyranoside and methyl quercetin-3-O-beta-d-glucuronate; and kaempferitrin, quercetin-3-O-alpha-l rhamnopyranoside, and tricin were identified in the extract from the leaves of Urochloa humidicola. Two furostanic saponins, namely, dioscin and 3-O-alpha-l rhamnopyranosyl-(1-4)-[alpha-l-rhamnopyranosyl-(1-2)]-beta-d-glucopyranosyl penogenin, as well as catechin-7-O-beta-d-glucopyranoside were identified in the methanolic extract obtained from the roots of this plant. This species features a range of metabolites that may be toxic for animals if used in food and may interfere with the growth medium, thereby inhibiting the development of other species. PMID- 28640341 TI - Carbonate Buildups in the Pernambuco Basin, NE Brazil. AB - The Pernambuco Basin represents one of the most prominent regions for deep water oil and gas exploration off the Brazilian coast. This study aims to identify and describe the occurrence of carbonate buildups in the offshore regions of the basin. The study was based on an analysis of a set of 143 2D time-migrated seismic sections that cover the offshore region of the Pernambuco Basin. An interpretation of the seismic dataset was used to define the main seismic sequences related to the main regional pulses of deposition and to identify three main groups of carbonate buildups: 1) shelf margin reefs, 2) patch reefs, and 3) isolated carbonate buildups. The carbonate buildups formed in two main intervals during post-rift sequences of the Santonian-Maastrichtian and Paleocene-Middle Miocene, which extend the known periods of carbonate deposit formation in the basin. The formation of carbonate buildups was controlled by the tectonic evolution of the Pernambuco Plateau, which created a series of paleotopographic highs that enabled the establishment of oceanographically and climatically favorable conditions for carbonate formation and deposition. These findings are important for understanding the evolution of the basin and for future evaluations of its petroleum potential. PMID- 28640342 TI - Applicability of geomechanical classifications for estimation of strength properties in Brazilian rock masses. AB - Many authors have been proposed several correlation equations between geomechanical classifications and strength parameters. However, these correlation equations have been based in rock masses with different characteristics when compared to Brazilian rock masses. This paper aims to study the applicability of the geomechanical classifications to obtain strength parameters of three Brazilian rock masses. Four classification systems have been used; the Rock Mass Rating (RMR), the Rock Mass Quality (Q), the Geological Strength Index (GSI) and the Rock Mass Index (RMi). A strong rock mass and two soft rock masses with different degrees of weathering located in the cities of Ouro Preto and Mariana, Brazil; were selected for the study. Correlation equations were used to estimate the strength properties of these rock masses. However, such correlations do not always provide compatible results with the rock mass behavior. For the calibration of the strength values obtained through the use of classification systems, stability analyses of failures in these rock masses have been done. After calibration of these parameters, the applicability of the various correlation equations found in the literature have been discussed. According to the results presented in this paper, some of these equations are not suitable for the studied rock masses. PMID- 28640343 TI - The peculiar breeding biology of the Amazonian frog Allobates subfolionidificans (Aromobatidae). AB - Allobates subfolionidificans is a vulnerable and endemic leaf-litter frog from the state of Acre, Brazilian Amazonia. We monitored a population of A. subfolionidificans through regular censuses and mark-recapture of 181 individuals during an entire breeding season to characterize its reproductive behavior. The space use of A. subfolionidificans individuals differed between sexes, with males using smaller and more segregated spaces. Males defended territories and were aggressive against same-sex individuals, which was not the case in females. The daily cycle of calling activity showed peaks in the morning and in the afternoon, and the occurrence of reproductive events was positively correlated with monthly rainfall. The breeding behavior comprised vocal and tactile interactions, although the species lacked reproductive amplexus. Egg and larvae attendance, as well as tadpole transport to water environments was performed mostly by males but occasionally by females, probably in cases of desertion by the father. This species is characterized by performing courtship, mating, oviposition, as well as egg and larvae attendance exclusively on the under surface of leaves, a unique behavior among members of the superfamily Dendrobatoidea. PMID- 28640344 TI - Screening of plant extracts and fractions on Aedes aegypti larvae found in the state of Mato Grosso do Sul (linnaeus, 1762) (culicidae). AB - The constant use of chemical insecticides for Aedes aegypti control has caused resistance in the mosquito populations. Thus, the objective of this study was to analyze the larvicidal potential of extracts and fractions of plants on A. aegypti larvae. The analysis included sixty one extracts and twenty five fractions of fifty botanical species at concentrations of 0.25; 0.12; 0.06 to 0.03 mg mL-1; 4 replications and one negative control of dechlorinate water and 1% DMSO; and a positive control with rotenone. The toxicity index in descending order with LC50 for the most active of the extracts selected were ethanol extract of Ormosea arborea (0.111 mg mL-1) seeds and ethanol extracts of leaves such as Piper hispidum (0.169 mg mL-1), Solanum variabile (0.188 mg mL-1), O. arborea (0.238 mg mL-1), Turnera umifolia (0.242 mg mL-1) and Piper hispidum (0.567 mg mL 1). For plant fractions, the most active were chloroform (0.192 mg mL-1) and hexane (0.342 mg mL-1) P. aduncum leaves, hexane fraction (0.415 mg mL-1) and methanol extract (0.625 mg mL-1) of Spermacocea latifolia leaves. Regarding the extract of T. umifolia single species, there is no bibliographic report on their degree of efficiency as an insecticide. PMID- 28640345 TI - Abundance of the reef-building Petaloconchus varians (Gastropoda: Vermetidae) on intertidal rocky shores at Ilha Grande Bay, southeastern Brazil. AB - The reef-building vermetid Petaloconchus varians occurs in the western Atlantic Ocean, from the Caribbean Sea to the southern coast of Brazil. The present study evaluated the abundance of P. varians on intertidal rocky shores in Ilha Grande Bay (Rio de Janeiro State), and characterized their reefs, describing the species density, besides the weight and the belt width of the reefs. Petaloconchus varians reefs were recorded at 25 sites, with rocky shores exposed to different wave action (very sheltered, sheltered, semi-exposed and exposed) and slopes (10 degrees to 46 degrees ). Clusters of individuals constructed large reefs along the middle intertidal zone, creating a wide belt (38 cm to 2 m). The density of P. varians and the weight of the reefs ranged from 620 to 2,559 ind.100 cm-2 and from 100 to 1,500 g.100 cm-2, respectively. Considering that the species was last reported from the area in the mid-20th century, the present study suggests that P. varians reefs are becoming dominant in the intertidal zone of rocky shores in Ilha Grande Bay. This is a contribution to knowledge of this ecosystem in Ilha Grande Bay, in view of local or global ecological changes. PMID- 28640346 TI - N deposition affects allelopathic potential of Amaranthus retroflexus with different distribution regions. AB - This study aims to determine the allelopathic potential of Amaranthus retroflexus (Ar) with different climatic zones on seed germination and growth of A. tricolor (At) treated with a gradient N addition. Ar leaf extracts only displayed significantly allelopathic potential on the underground growth of Ar but not the aboveground growth of At. The allelopathic potential of Ar leaf extracts on root length of At were enhanced under N addition and there may be a N-concentration dependent relationship. The effects of the extracts of Ar leaves that collected from Zhenjiang on seed germination and growth of At may be higher than that collected from Jinan especially on root length of At under medium N addition. This reason may be the contained higher concentration of secondary metabolites for the leaves of plants that growths in high latitudes compare with that growth in low latitudes. This phenomenon may also partly be attributed to the fact that Ar originated in America and/or south-eastern Asia which have higher similarity climate conditions as Zhenjiang rather than Jinan. The allelopathic potential of Ar on seed germination and growth of acceptor species may play an important role in its successful invasion especially in the distribution region with low latitudes. PMID- 28640347 TI - Psychotria viridis: Chemical constituents from leaves and biological properties. AB - The phytochemical study of hexane, chloroform and methanol extracts from leaves of Psychotria viridis resulted in the identification of: the pentacyclic triterpenes, ursolic and oleanolic acid; the steroids, 24-methylene-cycloartanol, stigmasterol and beta-sitosterol; the glycosylated steroids 3-O-beta-D-glucosyl beta-sitosterol and 3-O-beta-D-glucosyl-stigmasterol; a polyunsaturated triterpene, squalene; the esters of glycerol, 1-palmitoylglycerol and triacylglycerol; a mixture of long chain hydrocarbons; the aldehyde nonacosanal; the long chain fat acids hentriacontanoic, hexadecanoic and heptadenoic acid; the ester methyl heptadecanoate; the 4-methyl-epi-quinate and two indole alkaloids, N,N-dimethyltryptamine (DMT) and N-methyltryptamine. The chemical structures were determined by means of spectroscopic (IR, 1H and 13C NMR, HSQC, HMBC and NOESY) and spectrometric (CG-MS and LCMS-ESI-ITTOF) methods. The study of biologic properties of P. viridis consisted in the evaluation of the acetylcholinesterase inhibition and cytotoxic activities. The hexane, chloroform, ethyl acetate and methanol extracts, the substances 24-methylene-cycloartanol, DMT and a mixture of 3-O-beta-D-glucosyl-beta-sitosterol and 3-O-beta-D-glucosyl-stigmasterol showed cholinesterase inhibiting activity. This activity induced by chloroform and ethyl acetate extracts was higher than 90%. The methanol and ethyl acetate extracts inhibit the growth and/or induce the death of the tumor cells strains B16F10 and 4T1, without damaging the integrity of the normal cells BHK and CHO. DMT also demonstrated a marked activity against tumor cell strains B16F10 and 4T1. PMID- 28640348 TI - Global patterns of aboveground carbon stock and sequestration in mangroves. AB - In order to contribute to understand the factors that control the provisioning of the ecosystem service of carbon storage by mangroves, data on carbon stock and sequestration in the aboveground biomass (AGB) from 73 articles were averaged and tested for the dependence on latitude, climatic parameters, physiographic types and age. Global means of carbon stock (78.0 +/- 64.5 tC.ha-1) and sequestration (2.9 +/- 2.2 tC.ha-1.yr-1) showed that mangroves are among the forest ecosystems with greater capacity of carbon storage in AGB per area. On the global scale, carbon stock increases toward the equator (R2=0.22) and is dependent on 13 climatic parameters, which can be integrated in the following predictive equation: Carbon Stock in AGB = -16.342 + (8.341 x Isothermality) + (0.021 x Annual Precipitation) [R2=0.34; p < 0.05]. It was shown that almost 70% of carbon stock variability is explained by age. Carbon stock and sequestration also vary according to physiographic types, indicating the importance of hydroperiod and edaphic parameters to the local variability of carbon stock. By demonstrating the contribution of local and regional-global factors to carbon stock, this study provides information to the forecast of the effects of future climate changes and local anthropogenic forcings on this ecosystem service. PMID- 28640349 TI - Use of GC/MS to identify chemical constituents and cytotoxic activity of the leaves of Phoradendron mucronatum and Phoradendron microphyllum (Viscaceae). AB - Phoradendron mucronatum and P. microphyllum are plants that found in tropical and subtropical areas, used in traditional medicine and popularly known as mistle thrush. The aim of this study was to identify the chemical constituents of different leaf extracts from P. mucronatum and P. microphyllum and assess cytotoxic activity against strains from a human tumour cells. Extracts obtained with hexane, dichloromethane, chloroform and ethyl acetate from the leaves were analysed by gas chromatography coupled with mass spectrometry (GC-MS) and the cytotoxicity was assessed by the MTT method (bromide (3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide)). The tested human tumour cells were NCI H292 (human pulmonar mucoepidermoid carcinoma), MCF-7 (human breast adenocarcinoma) and HEp-2 (epidermoid carcinoma of the larynx). Analysis by GC/MS of the extracts from leaves of P. microphyllum and P. mucronatum detected 51 different compounds, such as alkaloids, diterpenes, triterpenes, sterols, alcohols, aldehydes, fatty acids and hydrocarbons. In the cytotoxic evaluation, hexane and ethyl acetate extracts from the leaves P. microphyllum inhibited cell growth of NCI-H292 strains (72.97%) and HEp-2 (87.53%), respectively. The extracts of P. mucronatum species showed an inhibitory effect towards NCI-H292 (83.19%/hexane), MCF-7 (88.69%/dichloromethane) and HEp-2 (93.40%/hexane). The extracts showed cytotoxic activity against the tested strains, especially the P. mucronatum, which presented the highest percentages of inhibition of cell growth. PMID- 28640351 TI - Occurrence of Dendrocephalus brasiliensis Pesta, 1921 (Crustacea, Anostraca) in the Caras river, southern Ceara, Brazil. AB - Occurrence of Dendrocephalus brasiliensis Pesta, 1921 (Crustacea, Anostraca) in the Caras river, southern Ceara, Brazil. The specimens were collected in March and April 2014. The new occurrence extends the distribution and update area of occupancy of the species, which is characterized by a specific habitat: temporary lakes. PMID- 28640350 TI - Development of a real-time PCR assay for the detection of the golden mussel ( Limnoperna fortunei , Mytilidae) in environmental samples. AB - The golden mussel, Limnoperna fortunei, is among the most devastating invasive species in freshwater habitats worldwide, leading to severe environmental disturbances and economic losses. Therefore, management efforts would be greatly improved by methods that efficiently detect and quantify the abundance of the golden mussel in freshwater habitats, particularly in early stages of colonization. In this study, we describe a highly-sensitive real-time PCR assay targeting a 100-bp region of the COI mitochondrial gene of the golden mussel. The method was able to detect as little as 0.225 pg of target DNA. This assay represents an important contribution to surveillance methods, as well as to optimize field measures to contain and manage populations of the golden mussel in its introduced range. PMID- 28640352 TI - Synthesis and evaluation of arylamidine derivatives for new antimicrobial and cytotoxic activities. AB - A series of arylamidines 3a-j was designed, synthesized and investigated for antimicrobial activity. Structures of the compounds were confirmed by IR, 1H-NMR and 13C-NMR and a 2D spectroscopic study was performed. A preliminary screening of the antimicrobial tests clearly showed that three out of ten arylamidines, viz, 3f, 3g and 3i, were effective against all the gram-negative bacteria: Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella enteric; and against the yeast, candida albicans. Further, the Minimum Inhibitory Concentrations (MIC) against the bacteria and yeast were determined. All compounds 3a-d, 3f, 3g, 3i and 3j were also investigated for their low cytotoxic effects on tested cell lines. Compounds 3d and 3f were the most effective derivatives against HL-60 and HEp-2 cells, respectively, with IC50 value (2ug/mL), and low normal cells toxicity. PMID- 28640353 TI - Ecology of the non-native snail Sinotaia cf quadrata (Caenogastropoda: Viviparidae). A study in a lowland stream of South America with different water qualities. AB - Sinotaia quadrata is a snail native from Asia recorded for the first time in South America in 2009 in central Argentina. In 2015, this species was also found in a lowland stream with different water qualities. Our aims were to contribute to the knowledge of its population ecology and to compare the individuals from the two locations anatomically. Snails were searched at 6 sites, where physicochemical and hydraulic parameters were measured. Biological samples were also taken at two sites (S3 and S4) to study the population traits of S. cf quadrata (density, size structure, fecundity and sex ratio) and to assess the water quality through macroinvertebrates' biological indices (richness, diversity and IBPamp). Physicochemical and biological parameters allowed us classifying sites as "moderately polluted" (S3) and "heavily polluted" (S4). At S4, the population showed a lower density, larger individuals, higher fecundity and a scarce representation of young snails. The differences observed in the radula and mantle border of snails from the two geographical regions might be attributed to environmental differences. We conclude that this species is tolerant to a wide range of environmental variables which, along with its high fecundity and morphological plasticity, could allow this species to colonize neighbor streams. PMID- 28640354 TI - Hepatic toxicity caused by PLGA-microspheres containing usnic acid from the lichen C ladonia substellata (AHTI) during pregnancy in Wistar rats. AB - This study aimed to evaluate the teratogenic and hepatotoxic potential of the usnic acid encapsulated into PLGA-microspheres. In total, 12 female Wistar rats in pregnancy were randomly distributed in the control group (n= 6) that received 1.0 mL of physiological solution and treatment group (n= 6) that received 25 mg/kg of encapsulated usnic acid by oral administration. All females were euthanized at day 20 of pregnancy and their fetuses were removed and analyzed. During the pregnancy was observed a reduction in weight gain. There was no difference in serum transaminases levels analyzed as well as any difference in liver weight in both groups. The histomorphometric analysis of the liver from the treatment group revealed an increase in number of hepatocytes and a decrease in nuclear area of these cells. Moreover, no alteration was observed in cell area of hepatocytes or number of Kupffer cells. The fetuses had an increase in total number of hepatocytes and a reduction in the amount of megakaryocytes. These results show the hepatotoxic potential of usnic acid during pregnancy. However, its toxicity can be minimized by encapsulation in microspheres. PMID- 28640355 TI - Screening of melon genotypes for resistance to vegetable leafminer and your phenotypic correlations with colorimetry. AB - Melon is one of the most important vegetable crops in the world. With short cycle in a system of phased planting, phytosanitary control is compromised, and a great volume of agricultural chemicals is used to control vegetable leafminer. Genetic control is an ideal alternative to avoid the damage caused by this insect. Thus, the aim of this study was to evaluate Cucumis accessions in regard to resistance to leafminer and correlate the variables analyzed. Fifty-four accessions and four commercial hybrids of melon were tested. The study was divided into two experiments: with and with no choice. The following characteristics were evaluated: with choice, in field - subjective score based on the infestation and the number of mines per leaf; and with no choice, in cage - number of mines per leaf, chlorophyll content, and leaf colorimetry. The results showed variability among the accessions and some genotypes showed favorable results for resistance in both experiments. There was correlation between the two variables in the experiment in the field. The accessions CNPH 11-282, CNPH 06-1047, and CNPH 11 1077 are the most recommended for future breeding programs with aim on introgression of resistance to vegetable leafminer in melon. PMID- 28640356 TI - Diameter distribution in a Brazilian tropical dry forest domain: predictions for the stand and species. AB - Currently, there is a lack of studies on the correct utilization of continuous distributions for dry tropical forests. Therefore, this work aims to investigate the diameter structure of a brazilian tropical dry forest and to select suitable continuous distributions by means of statistic tools for the stand and the main species. Two subsets were randomly selected from 40 plots. Diameter at base height was obtained. The following functions were tested: log-normal; gamma; Weibull 2P and Burr. The best fits were selected by Akaike's information validation criterion. Overall, the diameter distribution of the dry tropical forest was better described by negative exponential curves and positive skewness. The forest studied showed diameter distributions with decreasing probability for larger trees. This behavior was observed for both the main species and the stand. The generalization of the function fitted for the main species show that the development of individual models is needed. The Burr function showed good flexibility to describe the diameter structure of the stand and the behavior of Mimosa ophthalmocentra and Bauhinia cheilantha species. For Poincianella bracteosa, Aspidosperma pyrifolium and Myracrodum urundeuva better fitting was obtained with the log-normal function. PMID- 28640358 TI - Legal and health dilemmas challenging India's e-cigarette endorsement. PMID- 28640359 TI - Cancer drug wastage: The hidden cost in value-based cancer care delivery. PMID- 28640357 TI - RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement. AB - BACKGROUND: Studies of chromosomal rearrangements and fusion transcripts have elucidated mechanisms of tumorigenesis and led to targeted cancer therapies. This study was aimed at identifying novel fusion transcripts in esophageal adenocarcinoma (EAC). METHODS: To identify new fusion transcripts associated with EAC, targeted RNA sequencing and polymerase chain reaction (PCR) verification were performed in 40 EACs and matched nonmalignant specimens from the same patients. Genomic PCR and Sanger sequencing were performed to find the breakpoint of fusion genes. RESULTS: Five novel in-frame fusion transcripts were identified and verified in 40 EACs and in a validation cohort of 15 additional EACs (55 patients in all): fibroblast growth factor receptor 2 (FGFR2)-GRB2-associated binding protein 2 (GAB2) in 2 of 55 or 3.6%, Niemann-Pick C1 (NPC1)-maternal embryonic leucine zipper kinase (MELK) in 2 of 55 or 3.6%, ubiquitin-specific peptidase 54 (USP54)-calcium/calmodulin dependent protein kinase II gamma (CAMK2G) in 2 of 55 or 3.6%, megakaryoblastic leukemia (translocation) 1 (MKL1) fibulin 1 (FBLN1) in 1 of 55 or 1.8%, and CCR4-NOT transcription complex subunit 2 (CNOT2)-chromosome 12 open reading frame 49 (C12orf49) in 1 of 55 or 1.8%. A genomic analysis indicated that NPC1-MELK arose from a complex interchromosomal translocation event involving chromosomes 18, 3, and 9 with 3 rearrangement points, and this was consistent with chromoplexy. CONCLUSIONS: These data indicate that fusion transcripts occur at a stable frequency in EAC. Furthermore, our results indicate that chromoplexy is an underlying mechanism that generates fusion transcripts in EAC. These and other fusion transcripts merit further study as diagnostic markers and potential therapeutic targets in EAC. Cancer 2017;123:3916-24. (c) 2017 American Cancer Society. PMID- 28640360 TI - Decision-support networks of women newly diagnosed with breast cancer. AB - BACKGROUND: Little is known about the size and characteristics of the decision support networks of women newly diagnosed with breast cancer and whether their involvement improves breast cancer treatment decisions. METHODS: A population based sample of patients newly diagnosed with breast cancer in 2014 and 2015, as reported to the Georgia and Los Angeles Surveillance, Epidemiology, and End Results registries, were surveyed approximately 7 months after diagnosis (N = 2502; response rate, 68%). Network size was estimated by asking women to list up to 3 of the most important decision-support persons (DSPs) who helped them with locoregional therapy decisions. Decision deliberation was measured using 4 items assessing the degree to which patients thought through the decision, with higher scores reflecting more deliberative breast cancer treatment decisions. The size of the network (range, 0-3 or more) was compared across patient-level characteristics, and adjusted mean deliberation scores were estimated across levels of network size using multivariable linear regression. RESULTS: Of the 2502 women included in this analysis, 51% reported having 3 or more DSPs, 20% reported 2, 18% reported 1, and 11% reported not having any DSPs. Married/partnered women, those younger than 45 years, and black women all were more likely to report larger network sizes (all P < .001). Larger support networks were associated with more deliberative surgical treatment decisions (P < .001). CONCLUSIONS: Most women engaged multiple DSPs in their treatment decision making, and involving more DSPs was associated with more deliberative treatment decisions. Future initiatives to improve treatment decision making among women with breast cancer should acknowledge and engage informal DSPs. Cancer 2017;123:3895-903. (c) 2017 American Cancer Society. PMID- 28640362 TI - The impact of cancer drug wastage on economic evaluations. AB - BACKGROUND: The objective of this study was to determine the impact of modeling cancer drug wastage in economic evaluations because wastage can result from single-dose vials on account of body surface area- or weight-based dosing. METHODS: Intravenous chemotherapy drugs were identified from the pan-Canadian Oncology Drug Review (pCODR) program as of January 2015. Economic evaluations performed by drug manufacturers and pCODR were reviewed. Cost-effectiveness analyses and budget impact analyses were conducted for no-wastage and maximum wastage scenarios (ie, the entire unused portion of the vial was discarded at each infusion). Sensitivity analyses were performed for a range of body surface areas and weights. RESULTS: Twelve drugs used for 17 indications were analyzed. Wastage was reported (ie, assumptions were explicit) in 71% of the models and was incorporated into 53% by manufacturers; this resulted in a mean incremental cost effectiveness ratio increase of 6.1% (range, 1.3%-14.6%). pCODR reported and incorporated wastage for 59% of the models, and this resulted in a mean incremental cost-effectiveness ratio increase of 15.0% (range, 2.6%-48.2%). In the maximum-wastage scenario, there was a mean increase in the incremental cost effectiveness ratio of 24.0% (range, 0.0%-97.2%), a mean increase in the 3-year total incremental budget costs of 26.0% (range, 0.0%-83.1%), and an increase in the 3-year total incremental drug budget cost of approximately CaD $102 million nationally. Changing the mean body surface area or body weight caused 45% of the drugs to have a change in the vial size and/or quantity, and this resulted in increased drug costs. CONCLUSIONS: Cancer drug wastage can increase drug costs but is not uniformly modeled in economic evaluations. Cancer 2017;123:3583-90. (c) 2017 American Cancer Society. PMID- 28640361 TI - Global and targeted serum metabolic profiling of colorectal cancer progression. AB - BACKGROUND: Patients with colorectal adenoma polyps (PLPs) are at higher risk for developing colorectal cancer (CRC). However, the development of improved and robust biomarkers to enable the screening, surveillance, and early detection of PLPs and CRC continues to be a challenge. The aim of this study was to identify biomarkers of progression to CRC through metabolomic profiling of human serum samples with a multistage approach. METHODS: Metabolomic profiling was conducted with the Metabolon platform for 30 CRC patients, 30 PLP patients, and 30 control subjects, and this was followed by the targeted validation of the top metabolites in an additional set of 50 CRC patients, 50 PLP patients, and 50 controls with liquid chromatography-tandem mass spectrometry. Unconditional multivariate logistic regression models, adjusted for covariates, were used to evaluate associations with PLP and CRC risk. RESULTS: For the discovery phase, 404 serum metabolites were detected, with 50 metabolites showing differential levels between CRC patients, PLP patients, and controls (P for trend < .05). After validation, the 3 top metabolites (xanthine, hypoxanthine, and d-mannose) were validated: lower levels of xanthine and hypoxanthine and higher levels of d mannose were found in PLP and CRC cases versus controls. A further exploratory analysis of metabolic pathways revealed key roles for the urea cycle and caffeine metabolism associated with PLP and CRC risk. In addition, a joint effect of the top metabolites with smoking and a significant interaction with the body mass index were observed. An analysis of the ratio of hypoxanthine levels to xanthine levels indicated an association with CRC progression. CONCLUSIONS: These results suggest the potential utility of circulating metabolites as novel biomarkers for the early detection of CRC. Cancer 2017;123:4066-74. (c) 2017 American Cancer Society. PMID- 28640363 TI - Small-molecule stabilization of the p53 - 14-3-3 protein-protein interaction. AB - 14-3-3 proteins are positive regulators of the tumor suppressor p53, the mutation of which is implicated in many human cancers. Current strategies for targeting of p53 involve restoration of wild-type function or inhibition of the interaction with MDM2, its key negative regulator. Despite the efficacy of these strategies, the alternate approach of stabilizing the interaction of p53 with positive regulators and, thus, enhancing tumor suppressor activity, has not been explored. Here, we report the first example of small-molecule stabilization of the 14-3-3 - p53 protein-protein interaction (PPI) and demonstrate the potential of this approach as a therapeutic modality. We also observed a disconnect between biophysical and crystallographic data in the presence of a stabilizing molecule, which is unusual in 14-3-3 PPIs. PMID- 28640366 TI - Race and research in the southern United States: Approaching the elephant in the room. PMID- 28640365 TI - The Caenorhabditis elegans WRN helicase promotes double-strand DNA break repair by mediating end resection and checkpoint activation. AB - The protein associated with Werner syndrome (WRN), is involved in DNA repair, checkpoint activation, and telomere maintenance. To better understand the involvement of WRN in double-strand DNA break (DSB) repair, we analyzed the combinatorial role of WRN-1, the Caenorhabditis elegans WRN helicase, in conjunction with EXO-1 and DNA-2 nucleases. We found that WRN-1 cooperates with DNA-2 to resect DSB ends in a pathway acting in parallel to EXO-1. The wrn-1 mutants show an aberrant accumulation of replication protein A (RPA) and RAD-51, and the same pattern of accumulation is also observed in checkpoint-defective strains. We conclude that WRN-1 plays a conserved role in the resection of DSB ends and mediates checkpoint signaling, thereby influencing levels of RPA and RAD 51. PMID- 28640364 TI - A phase 2 study of the efficacy and biomarker on the combination of transarterial chemoembolization and axitinib in the treatment of inoperable hepatocellular carcinoma. AB - BACKGROUND: A surge of vascular endothelial growth factor (VEGF) after transarterial chemoembolization (TACE) may contribute to tumor progression. Axitinib is a potent antiangiogenic agent with main activity against VEGF receptors 1 to 3. To the authors' knowledge, its role in combination with TACE for the treatment of patients with inoperable hepatocellular carcinoma (HCC) is unclear. METHODS: A phase 2 clinical trial (ClinicalTrials.gov identifier NCT01352728) was conducted to evaluate the combination treatment. Patients with inoperable HCC who were potential candidates for TACE initiated treatment with axitinib at a dose of 5 mg twice daily and were evaluated for the need for TACE every 8 weeks. Axitinib was withheld 24 hours before TACE, and resumed 24 hours afterward when fulfilling predefined criteria. Radiologic assessment was conducted every 8 weeks. The primary endpoint was the 2-year overall survival (OS) rate. RESULTS: A total of 50 patients were recruited from March 2011 to April 2014. The mean age of the patients was 61.8 years, and 46 patients (92%) had hepatitis B infection. The Barcelona Clinic Liver Cancer stage B/C percentage was 76% (38 cases)/24% (12 cases). The 2-year OS rate was 43.7%, and the median OS was 18.8 months in the intention-to-treat population. Among the evaluable population (44 patients), 40.9% (18 patients) and 27.3% (12 patients) achieved complete and partial responses, respectively. Common grade 3 or above axitinib related complications included hand-foot skin reaction (14%) and hypertension (24%). The presence of hypertension during treatment was found to be an independent prognosticator (hazard ratio, 0.563; P = .0073) suggestive of a contributory role of axitinib to efficacy. CONCLUSIONS: The combination of axitinib and TACE was potentially efficacious for patients with inoperable HCC with a high radiologic response rate. Cancer 2017;123:3977-85. (c) 2017 American Cancer Society. PMID- 28640367 TI - Culturally sensitive assessment of attachment in children aged 18-40 months in a South African township. AB - The objective of our work is to study the possible relevance nonwestern cultural traditions have on the concordance of attachment patterns assessed in mothers and their young children. The attachment of 46 toddlers and their mothers, living in a black township in Johannesburg, South Africa, was assessed using scores derived from mother-child observations in the home (Attachment Q-Sort) and an interview (Working Model of the Child Interview). Mothers also had a semistructured psychiatric interview. Agreement between home observations and interview ratings was 29% for secure and 71% for insecure attachment when U.S.-developed scoring criteria for the interview were used. Agreement increased to 81% for secure and 67% for insecure attachment when the same protocols were rescored, using a culturally modified scoring system, developed by local cultural experts. This study suggests that verbal representations of attachment patterns are more influenced by cultural traditions than are actual parent-child interactions. PMID- 28640369 TI - Cultural influences on early family relationships. PMID- 28640368 TI - Response to commentary: Ethical dimensions of the BEIP. PMID- 28640370 TI - Insiders and outsiders: Levels of collaboration in research partnerships across resource divides. AB - With increasing recognition of the health and psychosocial challenges in developing countries, more research in these countries is essential. Research collaborations between wealthier and less wealthy countries are, however, complex. A partnership model has been proposed which emphasizes the importance of mutually respectful and beneficial relationships in international research. Using an example of a mother-infant intervention project in South Africa we describe the elements of an equitable partnership model of research. An issue which has been overlooked, however, is the reality of power differentials within the poorer countries themselves. We show that there are many intersecting levels of relationships within intercountry research, and suggest that power dynamics within countries deserves equal attention as international issues. Based on our experiences, we present some tentative guidelines for international research which builds long-term capacity and recognizes the importance of multiple levels of analysis and interaction. PMID- 28640371 TI - Infants and young children living in youth-headed households in Rwanda: Implications of emerging data. AB - The HIV/AIDS epidemic has already produced millions of orphans in Africa and the peak of the orphan epidemic has not yet been reached. One emerging social trend associated with premature parental death is the formation of households headed by youth aged 13-24. In Rwanda, specific sociocultural factors have supported the formation of youth-headed households (YHH) in the wake of both the 1994 genocide and the ongoing HIV/AIDS epidemic. There is no published data on the health and socioemotional functioning of children under 5 living in YHH. Survey data from 692 YHH in one region of Rwanda yielded a subsample of 89 homes which contained one or more children under 5 (n=104). These data reveal that a majority of young children living in YHH's is in fair or poor health. Heads of household themselves report high levels of depressive symptoms and social isolation; reports of emotional distress among the youngest children in the homes are associated with reports of higher symptomatology among heads of household. Findings are interpreted in light of the sociocultural context of Rwanda and the implications of the data for intervention are considered. PMID- 28640373 TI - Cross cultural research during infancy: Methodological considerations. PMID- 28640372 TI - How does culture promote the early development of identity? PMID- 28640374 TI - International collaboration in infant mental health: Pitfalls, challenge, and a way forward. PMID- 28640375 TI - Commentary: Ethical considerations in international research collaboration: The Bucharest early intervention project. PMID- 28640376 TI - Culture, diagnostic assessment, and identity: Defining concepts. PMID- 28640377 TI - Infants in the multicultural world. PMID- 28640378 TI - Ethical considerations in international research collaboration: The Bucharest early intervention project. AB - The Bucharest Early Intervention Project (BEIP) is the first ever randomized controlled trial of foster care as an alternative to institutional care for young children. It involved a collaboration between American investigators and Romanian health and child protection professionals. We present a brief description of the Romanian context and the project itself before discussing a number of ethical issues raised by the project. Organized around a discussion of exploitation, risk/benefit ratio, and cultural sensitivity, we evaluate a number of ethical issues involved in the BEIP using the Ethical Clinical Research Framework and the Fair Benefits Framework. Based on this review, we conclude that notwithstanding challenging ethical dilemmas, the benefits of the project outweighed its risks. Throughout the planning and implementation of the project, ethical issues were a central focus of discussion among the investigators and in the collaboration between Americans and Romanians. Thoughtful discussions from multiple perspectives are necessary to conduct research that is ethically sound and scientifically meaningful. PMID- 28640380 TI - The evolution of problem and social competence behaviors during toddlerhood: A prospective population-based cohort survey. AB - Research in developmental psychopathology has long been preoccupied with rather broad categories of behavior, but we know little about the specific behaviors that comprise these categories. The objective of this study was to: (a) estimate the prevalence of problem and social competence behaviors in the general population of children at 17 months of age, and (b) describe the continuity and discontinuity in the degree to which children exhibit these behaviors between 17 and 29 months of age. The results show that frequent problem behaviors are not typical of children under two years of age. Further, the results suggest that it is possible to distinguish between different types of problem behaviors before two years of age. In addition, the results show that gender differences in some problem behaviors are already present before two years of age, and increase in magnitude during toddlerhood. Finally, the results show that interindividual differences in problem behaviors observed before two years of age are stable. The predictive accuracy of frequent problem behaviors in children at 17 months of age was limited, however, with often a majority of toddlers not behaving this way a year later. Overall, our results suggest that toddlerhood represents a critical period when behavioral and emotional problems of potentially clinical significance emerge. Pediatricians should routinely ask parents to report the frequency of their young children's problem behaviors during child health supervision visits so that children whose frequent problem behaviors persist over time can be identified and possibly referred for treatment. PMID- 28640381 TI - A case study of traumatic stress disorder in a 5-month-old infant following surgery. AB - This case study of a 5-month-old infant describes the symptoms of trauma following a surgical procedure (cranial remodeling) with short-term hospital stay. The infant showed a symptomatology similar to that found in other studies of hospitalization during the preverbal period, and fit the diagnosis of traumatic stress disorder according to the DC:0-3. The therapy was implemented by the parents in consultation with the author. The approach was based on an exposure therapy model (flooding) using a somatic trauma trigger that occurred spontaneously in the context of a normal caretaking routine. The infant was allowed to have a full-blown emotional response during several treatment sessions. The outcome was positive, with the disappearance of some symptoms of traumatic stress disorder after the first week, and no remaining symptoms after two months. Periodic follow-up evaluations for one year revealed normal development with no return of symptoms. The symptoms, treatment, and outcomes are discussed in the context of behavioral learning theory and emotional processing theory. The role of crying during flooding therapy is discussed, and an emotional release theory emphasizing the therapeutic value of crying is proposed. Six cautionary guidelines are offered for the use of intense exposure therapy with infants. PMID- 28640379 TI - Comparative and correlative assessments of cytokine, complement and antibody patterns in paediatric type 1 diabetes. AB - One of the most widespread and effective environmental factors is the infection with enteroviruses (EVs) which accelerate beta cell destruction in type 1 diabetes (T1D). This study represented a comparison between diabetic EV+ and EV- children as well as correlation analysis between autoantibodies, T1D markers, cytokines, complement activation products and anti-coxsackievirus (CV) immunoglobulin (Ig)G. EV RNA was detected in Egyptian children with T1D (26.2%) and healthy controls (0%). Detection of anti-CV IgG in T1D-EV+ resulted in 64% positivity. Within T1D-EV+ , previously diagnosed (PD) showed 74 versus 56% in newly diagnosed (ND) children. Comparisons between populations showed increased levels of haemoglobin A1c (HbA1c), C-reactive protein (CRP), nitric oxide (NO), glutamic acid decarboxylase and insulin and islet cell autoantibodies [glutamic acid decarboxylase autoantibodies (GADA), insulin autoantibodies (IAA) and islet cell cytoplasmic autoantibodies (ICA), respectively], interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL -10, IL -12, IL 17, C3d and sC5-9 in T1D-EV+ versus T1D-EV- . Conversely, both IL-20 and transforming growth factor (TGF-beta) decreased in T1D-EV+ versus EV- , while IL 4, -6 and -13 did not show any changes. Correlation analysis showed dependency of accelerated autoimmunity and beta cell destruction on increased IFN-gamma, IL-12 and IL-17 versus decreased IL-4, -6 and -13. In conclusion, IFN-gamma, IL-12 and IL-17 played an essential role in exacerbating EV+ -T1D, while C3d, sC5b -9, IL 10 and -20 displayed distinct patterns. PMID- 28640382 TI - Symptoms of attention-deficit/hyperactivity disorder in first-time expectant women: Relations with parenting cognitions and behaviors. AB - The relationship between maternal symptoms of attention-deficit/hyperactivity disorder (ADHD) and parenting cognitions and behaviors was studied in 86 first time expectant women. Women high on ADHD symptoms were less likely to be married, less likely to have obtained at least some university education, and less likely to report that they wanted to get pregnant at the time they became pregnant. As predicted, ADHD symptoms were positively correlated with symptoms of anxiety and depression, and predicted less positive prenatal expectations regarding the infant and the future maternal role and lower maternal self-efficacy. Contrary to predictions, ADHD did not predict any incremental variance in maternal stressful life events or social support. Symptoms of ADHD were negatively correlated with attendance at recommended prenatal checkups, but were unrelated to other behaviors during pregnancy. Findings suggest that even prior to any contact with their infant, women with ADHD symptoms have maladaptive cognitions regarding their expectations of motherhood and parenting abilities. As a result, they may benefit from early interventions that focus on attenuating the potential negative effects that these maladaptive cognitions might have on the mother-infant relationship and later developmental outcomes for their children. PMID- 28640383 TI - A proposed adaptation of DC: 0-3R for primary care, developmental research, and prevention of mental disorders. AB - The development of the Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (DC: 0-3; Zero to Three: National Center for Clinical Infant Programs, 1994) has been an important step in the field of infant mental health. In this paper, we propose some additions to the existing classification system. These additions include the development of criteria for infant, toddler, and family strengths, and the development of criteria for symptomatology that represents risk for disorder, but not fully manifest disorder. These additions will give DC: 0-3R greater potential for use in the primary health care of children, thereby increasing the system's utility in diagnosing and preventing infant mental health problems. PMID- 28640384 TI - Negative emotionality, attachment quality, and behavior problems in early childhood. AB - Negative emotionality, as well as attachment security and disorganization, are seen as major contributors to social adjustment and maladjustment in childhood. However, relatively little is known about whether infant negative emotionality and attachment quality operate together to affect developing behavior problems. The present study thus aims to contribute to this question. Participants were 64 healthy firstborn children and their primary caregivers. Negative emotionality was assessed at the infant ages of 4, 8, and 12 months using laboratory routines. At 18 months, the Strange Situation procedure was conducted to assess infant attachment security and disorganization, and at 30 months, the child's behavior problems were assessed within a structured clinical interview. Attachment security and attachment disorganization were significantly associated with subsequent behavior problems. There was no significant relation between infant negative emotionality and behavior problems. However, there were indications of a stronger association between attachment disorganization and behavior problems in infants high in negative emotionality. The results underpin the importance of attachment quality as well as negative emotionality in social adjustment. Disorganized attachment precedes poor adjustment, especially in infants high in negative emotionality. PMID- 28640386 TI - Photoresponsive Smart Coloration Electrochromic Supercapacitor. AB - Electrochromic devices have been widely adopted in energy saving applications by taking advantage of the electrode coloration, but it is critical to develop a new electrochromic device that can undergo smart coloration and can have a wide spectrum in transmittance in response to input light intensity while also functioning as a rechargeable energy storage system. In this study, a photoresponsive electrochromic supercapacitor based on cellulose-nanofiber/Ag nanowire/reduced-graphene-oxide/WO3 -composite electrode that is capable of undergoing "smart" reversible coloration while simultaneously functioning as a reliable energy-storage device is developed. The fabricated device exhibits a high coloration efficiency of 64.8 cm2 C-1 and electrochemical performance with specific capacitance of 406.0 F g-1 , energy/power densities of 40.6-47.8 Wh kg-1 and 6.8-16.9 kW kg-1 . The electrochromic supercapacitor exhibits excellent cycle reliability, where 75.0% and 94.1% of its coloration efficiency and electrochemical performance is retained, respectively, beyond 10 000 charge discharge cycles. Cyclic fatigue tests show that the developed device is mechanically durable and suitable for wearable electronics applications. The smart electrochromic supercapacitor system is then integrated with a solar sensor to enable photoresponsive coloration where the transmittance changes in response to varying light intensity. PMID- 28640385 TI - Cost-effectiveness analysis of consolidation with brentuximab vedotin for high risk Hodgkin lymphoma after autologous stem cell transplantation. AB - BACKGROUND: In a recent randomized, placebo-controlled trial, consolidation treatment with brentuximab vedotin (BV) decreased the risk of Hodgkin lymphoma (HL) progression after autologous stem cell transplantation (ASCT). However, the impact of BV consolidation on overall survival, quality of life, and health care costs remain unclear. METHODS: A Markov decision-analytic model was constructed to measure the costs and clinical outcomes for BV consolidation therapy compared with active surveillance in a cohort of patients aged 33 years who were at risk for HL relapse after ASCT. Life-time costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each post ASCT strategy. RESULTS: After quality-of-life adjustments and standard discounting, upfront BV consolidation was associated with an improvement of 1.07 QALYs compared with active surveillance plus BV as salvage. However, the strategy of BV consolidation led to significantly higher health care costs ($378,832 vs $219,761), resulting in an ICER for BV consolidation compared with active surveillance of $148,664/QALY. If indication-specific pricing was implemented, then the model-estimated BV price reductions of 18% to 38% for the consolidative setting would translate into ICERs of $100,000 and $50,000 per QALY, respectively. These findings were consistent on 1-way and probabilistic sensitivity analyses. CONCLUSIONS: BV as consolidation therapy under current US pricing is unlikely to be cost effective at a willingness-to-pay threshold of $100,000 per QALY. However, indication-specific price reductions for the consolidative setting could reduce ICERs to widely acceptable values. Cancer 2017. (c) 2017 American Cancer Society. Cancer 2017;123:3763-3771. (c) 2017 American Cancer Society. PMID- 28640388 TI - Electrostatic-Driven Exfoliation and Hybridization of 2D Nanomaterials. AB - Here, direct and effective electrostatic-driven exfoliation of tungsten trioxide (WO3 ) powder into atomically thin WO3 nanosheets is demonstrated for the first time. Experimental evidence together with theoretical simulations clearly reveal that the strong binding of bovine serum albumin (BSA) on the surface of WO3 via the protonation of ?NH2 groups in acidic conditions leads to the effective exfoliation of WO3 nanosheets under sonication. The exfoliated WO3 nanosheets have a greatly improved dispersity and stability due to surface-protective function of BSA, and exhibit a better performance and unique advantages in applications such as visible-light-driven photocatalysis, high-capacity adsorption, and fast electrochromics. Further, simultaneous exfoliation and hybridization of WO3 and MoS2 nanosheets are demonstrated to form hybrid WO3 /MoS2 nanosheets through respective electrostatic and hydrophobic interaction processes. In addition, this electrostatic-driven exfoliation strategy is applied to exfoliate ultrathin black-phosphorus nanosheets from its bulk to exhibit a greatly improved stability due to the surface protection by BSA. Overall, the work presented not only presents a facile and effective route to fabricate 2D materials but also brings more opportunities to exploit unusual exotic and synergistic properties in resulting hybrid 2D materials for novel applications. PMID- 28640387 TI - DNA mismatch repair deficiency and hereditary syndromes in Latino patients with colorectal cancer. AB - BACKGROUND: The landscape of hereditary syndromes and clinicopathologic characteristics among US Latino/Hispanic individuals with colorectal cancer (CRC) remains poorly understood. METHODS: A total of 265 patients with CRC who were enrolled in the Hispanic Colorectal Cancer Study were included in the current study. Information regarding CRC risk factors was elicited through interviews, and treatment and survival data were abstracted from clinical charts. Tumor studies and germline genetic testing results were collected from medical records or performed using standard molecular methods. RESULTS: The mean age of the patients at the time of diagnosis was 53.7 years (standard deviation, 10.3 years), and 48.3% were female. Overall, 21.2% of patients reported a first-degree or second-degree relative with CRC; 3.4% met Amsterdam I/II criteria. With respect to Bethesda guidelines, 38.5% of patients met at least 1 criterion. Of the 161 individuals who had immunohistochemistry and/or microsatellite instability testing performed, 21 (13.0%) had mismatch repair (MMR)-deficient (dMMR) tumors. dMMR tumors were associated with female sex (61.9%), earlier age at the time of diagnosis (50.4 +/- 12.4 years), proximal location (61.9%), and first-degree (23.8%) or second-degree (9.5%) family history of CRC. Among individuals with dMMR tumors, 13 (61.9%) had a germline MMR mutation (MutL homolog 1 [MLH1] in 6 patients; MutS homolog 2 [MSH2] in 4 patients; MutS homolog 6 [MHS6] in 2 patients; and PMS1 homolog 2, mismatch repair system component [PMS2] in 1 patient). The authors identified 2 additional MLH1 mutation carriers by genetic testing who had not received immunohistochemistry/microsatellite instability testing. In total, 5.7% of the entire cohort were confirmed to have Lynch syndrome. In addition, 6 individuals (2.3%) had a polyposis phenotype. CONCLUSIONS: The percentage of dMMR tumors noted among Latino individuals (13%) is similar to estimates in non-Hispanic white individuals. In the current study, the majority of individuals with dMMR tumors were confirmed to have Lynch syndrome. Cancer 2017. (c) 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. Cancer 2017;123:3732 3743. (c) 2017 American Cancer Society. PMID- 28640390 TI - Transiently disordered tails accelerate folding of globular proteins. AB - Numerous biological proteins exhibit intrinsic disorder at their termini, which are associated with multifarious functional roles. Here, we show the surprising result that an increased percentage of terminal short transiently disordered regions with enhanced flexibility (TstDREF) is associated with accelerated folding rates of globular proteins. Evolutionary conservation of predicted disorder at TstDREFs and drastic alteration of folding rates upon point-mutations suggest critical regulatory role(s) of TstDREFs in shaping the folding kinetics. TstDREFs are associated with long-range intramolecular interactions and the percentage of native secondary structural elements physically contacted by TstDREFs exhibit another surprising positive correlation with folding kinetics. These results allow us to infer probable molecular mechanisms behind the TstDREF mediated regulation of folding kinetics that challenge protein biochemists to assess by direct experimental testing. PMID- 28640389 TI - Efficacy and safety of recombinant human lymphotoxin-alpha derivative with cisplatin and fluorouracil in patients with metastatic esophageal squamous cell carcinoma: A randomized, multicenter, open-label, controlled, phase 2b trial. AB - BACKGROUND: Recombinant human lymphotoxin-alpha derivative (rhLTalpha-Da) is a lymphotoxin-alpha derivative that is missing 27 N-terminal amino acid residues. Previous studies indicated a benefit from the addition of rhLTalpha-Da to cisplatin-based treatment in patients with metastatic esophageal squamous cell carcinoma. The current study was conducted to evaluate the efficacy and safety of rhLTalpha-Da plus cisplatin and fluorouracil (PF) in patients with mESCC. METHODS: Patients from 15 centers in China were randomly assigned (1:1:1) to 3 arms (arm A, PF plus 10 MUg/m2 daily rhLTalpha-Da; arm B, PF plus 20 MUg/m2 daily rhLTalpha-Da; arm C, PF alone). The primary endpoints included progression-free survival (PFS) and the confirmed overall response rate (ORR). An exploratory analysis was performed to evaluate the role of serum tumor necrosis factor receptor II (TNFR II) in predicting the efficacy of rhLTalpha-Da. RESULTS: Between September 2010 and May 2013, 150 patients were enrolled. No significant differences in either PFS or ORR were observed between the 3 arms. However, in a small subset of patients who had low serum TNFR II levels, the median PFS was significantly longer for those in arm B than for these in other 2 arms (7.2 months [95% confidence interval, 5.1-8.6 months] for arm B vs 3.5 months [95% confidence interval, 1.7-5.5 months] for arm A [P = .022] and 4.0 months [95% confidence interval, 3.2-6.3 months] for arm C [P = .027]). The addition of rhLTalpha-Da significantly increased the incidence of chills (P < .001). CONCLUSIONS: rhLTalpha-Da combined with the PF regimen failed to improve PFS and ORR in patients with mESCC, except in a small subset that had low serum TNFR II concentrations. Cancer 2017;123:3986-94. (c) 2017 American Cancer Society. PMID- 28640391 TI - Selective sweeps of mitochondrial DNA can drive the evolution of uniparental inheritance. AB - Although the uniparental (or maternal) inheritance of mitochondrial DNA (mtDNA) is widespread, the reasons for its evolution remain unclear. Two main hypotheses have been proposed: selection against individuals containing different mtDNAs (heteroplasmy) and selection against "selfish" mtDNA mutations. Recently, uniparental inheritance was shown to promote adaptive evolution in mtDNA, potentially providing a third hypothesis for its evolution. Here, we explore this hypothesis theoretically and ask if the accumulation of beneficial mutations provides a sufficient fitness advantage for uniparental inheritance to invade a population in which mtDNA is inherited biparentally. In a deterministic model, uniparental inheritance increases in frequency but cannot replace biparental inheritance if only a single beneficial mtDNA mutation sweeps through the population. When we allow successive selective sweeps of mtDNA, however, uniparental inheritance can replace biparental inheritance. Using a stochastic model, we show that a combination of selection and drift facilitates the fixation of uniparental inheritance (compared to a neutral trait) when there is only a single selective mtDNA sweep. When we consider multiple mtDNA sweeps in a stochastic model, uniparental inheritance becomes even more likely to replace biparental inheritance. Our findings thus suggest that selective sweeps of beneficial mtDNA haplotypes can drive the evolution of uniparental inheritance. PMID- 28640393 TI - Malagasy cichlids differentially limit impacts of body shape evolution on oral jaw functional morphology. AB - Patterns of trait covariation, such as integration and modularity, are vital factors that influence the evolution of vertebrate body plans. In functional systems, decoupling of morphological modules buffers functional change in one trait by reducing correlated variation with another. However, for complex morphologies with many-to-one mapping of form to function (MTOM), resistance to functional change may also be achieved by constraining morphological variation within a functionally stable region of morphospace. For this research, we used geometric morphometrics to evaluate the evolution of body shape and its relationship with jaw functional morphology in two independent radiations of endemic Malagasy cichlid (Teleostei: Cichlidae). Our results suggested that the two subfamilies used different strategies to mitigate impacts of body shape variation on a metric of jaw function, maxillary kinematic transmission (MKT): (1) modularity between cranial and postcranial morphologies, and (2) integration of body and jaw evolution, with jaw morphologies varying in a manner that limits change in MKT. This research shows that, unlike modularity, MTOM allows traits to retain strong evolutionary covariation while still reducing impacts on functionality. These results suggest that MTOM, and its influence on the evolution of correlated traits, is likely much more widespread than is currently understood. PMID- 28640392 TI - Calcineurin inhibitors exacerbate coronary arteritis via the MyD88 signalling pathway in a murine model of Kawasaki disease. AB - Calcineurin inhibitors (CNIs) have been used off-label for the treatment of refractory Kawasaki disease (KD). However, it remains unknown whether CNIs show protective effects against the development of coronary artery lesions in KD patients. To investigate the effects of CNIs on coronary arteries and the mechanisms of their actions on coronary arteritis in a mouse model of KD, we performed experiments with FK565, a ligand of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in wild-type, severe combined immunodeficiency (SCID), caspase-associated recruitment domain 9 (CARD9)-/- and myeloid differentiation primary response gene 88 (MyD88)-/- mice. We also performed in vitro studies with vascular and monocytic cells and vascular tissues. A histopathological analysis showed that both cyclosporin A and tacrolimus exacerbated the NOD1-mediated coronary arteritis in a dose-dependent manner. Cyclosporin A induced the exacerbation of coronary arteritis in mice only in high doses, while tacrolimus exacerbated it within the therapeutic range in humans. Similar effects were obtained in SCID and CARD9-/- mice but not in MyD88-/- mice. CNIs enhanced the expression of adhesion molecules by endothelial cells and the cytokine secretion by monocytic cells in our KD model. These data indicated that both vascular and monocytic cells were involved in the exacerbation of coronary arteritis. Activation of MyD88-dependent inflammatory signals in both vascular cells and macrophages appears to contribute to their adverse effects. Particular attention should be paid to the development of coronary artery lesions when using CNIs to treat refractory KD. PMID- 28640395 TI - From Borane to Borylene without Reduction: Ambiphilic Behavior of a Monovalent Silylisonitrile Boron Species. AB - Deprotonation of [(cAAC)BH2 (CN)] provided clean access to the stable boryl anion, [(cAAC)BH(CN)]- . Whereas the addition of soft electrophiles occurred at the nucleophilic boron center, harder silyl electrophiles added to the harder terminal cyano nitrogen. The resulting [(cAAC)BH(CNSiPh3 )] species behaved like a silylium boryl nucleophile as well as a neutral silylisonitrile borylene. PMID- 28640394 TI - In-scan and scan-rescan assessment of LV in- and outflow volumes by 4D flow MRI versus 2D planimetry. AB - PURPOSE: To evaluate the in-scan and scan-rescan consistency of left ventricular (LV) in- and outflow assessment from 1) 2D planimetry; 2) 4D flow magnetic resonance imaging (MRI) with retrospective valve tracking, and 3) 4D flow MRI with particle tracing. MATERIALS AND METHODS: Ten healthy volunteers (age 27 +/- 3 years) underwent multislice cine short-axis planimetry and whole-heart 4D flow MRI on a 3T MRI scanner twice with repositioning between the scans. LV in- and outflow was compared from 1) 2D planimetry; 2) 4D flow MRI with retrospective valve tracking over the mitral valve (MV) and aortic valve (AV), and 3) 4D flow MRI with particle tracing through forward and backward integration of velocity data. RESULTS: In-scan consistency between MV and AV flow volumes is excellent for both 4D flow MRI methods with r >= 0.95 (P <= 0.001). In-scan AV and MV flow by retrospective valve tracking shows good to excellent correlations versus AV and MV flow by particle tracing (r >= 0.81, P <= 0.004). Scan-rescan SV assessment by 2D planimetry shows excellent reproducibility (intraclass correlation [ICC] = 0.98, P < 0.001, coefficient of variation [CV] = 7%). Scan rescan MV and AV flow volume assessment by retrospective valve tracking shows strong reproducibility (ICCs >= 0.89, P <= 0.05, CVs = 12%), as well as by forward and backward particle tracing (ICCs >= 0.90, P <= 0.001, CVs <= 11%). Multicomponent particle tracing shows good scan-rescan reproducibility (ICCs >= 0.81, P <= 0.007, CVs <= 16%). CONCLUSION: LV in- and outflow assessment by 2D planimetry and 4D flow MRI with retrospective valve tracking and particle tracing show good in-scan consistency and strong scan-rescan reproducibility, which indicates that both 4D flow MRI methods are reliable and can be used clinically. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018;47:511-522. PMID- 28640398 TI - Mother's attachment representations of their premature infant at 6 and 18 months after birth. AB - The effects of premature birth on attachment have generally been examined from the infant's perspective. There is a lack of data concerning parental attachment representations toward a premature child. Because of the psychological stress engendered in parents confronted with a premature birth, we hypothesized that their attachment representations would be altered during the first months after the hospital discharge. Fifty families with a premature infant (25-33 gestation weeks) and a control group of 30 families with a full-term infant participated to the study. Perinatal risks were evaluated during hospitalization. To assess mothers' representations of their infant, the Working Model of the Child Interview (WMCI, Zeanah & Benoit, 1995 & Benoit, Zeanah, Parker, Nicholson, & Coolbear, 1997) were administered when their children were 6 and 18 months old. The severity of the perinatal risks was found to have an impact on the mothers' attachment representations. At six months, only 20% of the mothers of a prematurely born infant (30% at 18 months) had secure attachment representations, vs. 53% for the control group (57% at 18 months). Furthermore, mothers of low risk premature infants more often had disengaged representations, whereas distorted representations were more frequent in the high-risk group of premature children. These findings suggest that the parental response to a premature birth is linked to the severity of postnatal risks. The fact that secure attachment representations are affected in mothers of low-risk infants just as much as they are in mothers of high-risk infants points to the need to conduct further studies aimed at evaluating whether preventive intervention for both low-risk and high risk premature will be helpful. PMID- 28640396 TI - An anatomical study of plate-rod fixation in feline tibiae. AB - OBJECTIVE: To investigate the feasibility of placing bi-cortical cortex (B-cort) or mono-cortical locking screws (M-lock) in a plate-rod construct applied to the feline tibia in combination with different intramedullary (IM) pins. METHODS: Twenty-four feline tibiae of cats were divided into 4 groups, corresponding to IM pin sizes filling approximately 30% (1.0 mm), 40% (1.4 mm), 45% (1.6 mm), and 50% (1.8 mm) of the medullary canal. Computed tomography (CT) was performed to trace potential screw trajectories in each group. A 12-hole, 2.4 mm locking compression plate was then applied on the medial aspect of the tibia. M-lock and B-cort screws were inserted subsequently in each plate hole. Success rates of screw insertion based on CT analysis and cadaveric simulation were compared with screw type, IM pin diameter, and anatomic location as variables. RESULTS: Screw insertion rates were underestimated on CT compared to cadaveric specimens. During cadaveric simulation, B-cort screws could be inserted in all specimens in the 3 most proximal plate holes and in at least 1 of the 3 distal plate holes. The smallest pin size (30%) allowed placement of a greater number of B-cort screws (P < .05) compared to other pins. Fewer B-cort screws could be inserted in the distal diaphyseal region (P < .05) compared to other regions. A total of 99.3% of M-lock screws could be inserted regardless of IMP size. CLINICAL SIGNIFICANCE: Plate rod constructs can include bicortical screws in the proximal and distal metaphysis, and monocortical screws in the diaphysis, combined with an IM pin filling up to 50% of the medullary canal. PMID- 28640397 TI - Preventing preschool externalizing behavior problems through video-feedback intervention in infancy. AB - In the present study (1) intervention effects on children's preschool behavior problems were evaluated in a high risk sample with an overrepresentation of insecure adult attachment representations in 77 first-time mothers, and (2) predictors and correlates of child problem behavior were examined. Early short term video-feedback intervention to promote positive parenting (VIPP) focusing on maternal sensitivity and implemented in the baby's first year of life significantly protected children from developing clinical Total Problems at preschool age. Also, compared with the control group, fewer VIPP children scored in the clinical range for Externalizing Problems. No intervention effects on Internalizing clinical problem behavior were found. The VIPP effects on Externalizing and Total clinical Problems were not mediated by VIPP effects on sensitivity and infant attachment or moderated by mother or child variables. Maternal satisfaction with perceived support appeared to be associated with less children's Internalizing, Externalizing, and Total Problems. More research is needed to find the mechanisms triggered by VIPP, but the outcomes could be considered as promising first steps in the prevention of disturbing, externalizing behavior problems in young children. PMID- 28640399 TI - Reduction of disrupted caregiver behavior using modified interaction guidance. AB - The present study is a reanalysis of a preexisting study examining the usefulness of the Atypical Maternal Behavior Instrument for Assessment and Classification (AMBIANCE; Bronfman, Parsons, & Lyons-Ruth, 1999) measure as an indicator of efficacy in reducing disrupted caregiver behavior in two brief interventions. The current study examines the rate of change in the display of disrupted caregiver behavior over the course of an attachment-based intervention (Modified Interaction Guidance) in a group of 11 caregiver-infant dyads referred to a tertiary care clinic for feeding problems. The AMBIANCE was utilized as an indicator of change in disrupted behavior following an assessment feedback session and three intervention sessions. Results showed a significant decrease in the total display of disrupted caregiver behaviors, as well as a change in classification from disrupted to not-disrupted, after receiving both feedback from the assessment and the first treatment session. A qualitative analysis of the data further revealed different patterns of change between caregivers. These findings provide preliminary empirical support suggesting that a reduction of disrupted caregiver behavior can be observed relatively quickly after the commencement of the Modified Interaction Guidance intervention. PMID- 28640402 TI - The Importance of the Modifying Behaviours During the Inter-Pregnancy Period. PMID- 28640401 TI - Two-stage approach for risk estimation of fetal trisomy 21 and other aneuploidies using computational intelligence systems. AB - OBJECTIVE: To estimate the risk of fetal trisomy 21 (T21) and other chromosomal abnormalities (OCA) at 11-13 weeks' gestation using computational intelligence classification methods. METHODS: As a first step, a training dataset consisting of 72 054 euploid pregnancies, 295 cases of T21 and 305 cases of OCA was used to train an artificial neural network. Then, a two-stage approach was used for stratification of risk and diagnosis of cases of aneuploidy in the blind set. In Stage 1, using four markers, pregnancies in the blind set were classified into no risk and risk. No-risk pregnancies were not examined further, whereas the risk pregnancies were forwarded to Stage 2 for further examination. In Stage 2, using seven markers, pregnancies were classified into three types of risk, namely no risk, moderate risk and high risk. RESULTS: Of 36 328 unknown to the system pregnancies (blind set), 17 512 euploid, two T21 and 18 OCA were classified as no risk in Stage 1. The remaining 18 796 cases were forwarded to Stage 2, of which 7895 euploid, two T21 and two OCA cases were classified as no risk, 10 464 euploid, 83 T21 and 61 OCA as moderate risk and 187 euploid, 50 T21 and 52 OCA as high risk. The sensitivity and the specificity for T21 in Stage 2 were 97.1% and 99.5%, respectively, and the false-positive rate from Stage 1 to Stage 2 was reduced from 51.4% to ~1%, assuming that the cell-free DNA test could identify all euploid and aneuploid cases. CONCLUSION: We propose a method for early diagnosis of chromosomal abnormalities that ensures that most T21 cases are classified as high risk at any stage. At the same time, the number of euploid cases subjected to invasive or cell-free DNA examinations was minimized through a routine procedure offered in two stages. Our method is minimally invasive and of relatively low cost, highly effective at T21 identification and it performs better than do other existing statistical methods. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28640403 TI - The baby's place in the world. PMID- 28640400 TI - Little evidence for intralocus sexual conflict over the optimal intake of nutrients for life span and reproduction in the black field cricket Teleogryllus commodus. AB - There is often large divergence in the effects of key nutrients on life span (LS) and reproduction in the sexes, yet nutrient intake is regulated in the same way in males and females given dietary choice. This suggests that the sexes are constrained from feeding to their sex-specific nutritional optima for these traits. Here, we examine the potential for intralocus sexual conflict (IASC) over optimal protein and carbohydrate intake for LS and reproduction to constrain the evolution of sex-specific nutrient regulation in the field cricket, Teleogryllus commodus. We show clear sex differences in the effects of protein and carbohydrate intake on LS and reproduction and strong positive genetic correlations between the sexes for the regulated intake of these nutrients. However, the between-sex additive genetic covariance matrix had very little effect on the predicted evolutionary response of nutrient regulation in the sexes. Thus, IASC appears unlikely to act as an evolutionary constraint on sex specific nutrient regulation in T. commodus. This finding is supported by clear sexual dimorphism in the regulated intake of these nutrients under dietary choice. However, nutrient regulation did not coincide with the nutritional optima for LS or reproduction in either sex, suggesting that IASC is not completely resolved in T. commodus. PMID- 28640404 TI - Ghosts and angels: Intergenerational patterns in the transmission and treatment of the traumatic sequelae of domestic violence. AB - The article discusses the impact of exposure to domestic violence on infants, toddlers, and preschoolers; the manifestations of post-traumatic stress disorder in the first years of life; and the parameters of Child-Parent Psychotherapy as a relationship-based treatment that aims at enhancing the parent's effectiveness as a protector as a means of restoring the child's momentum towards healthy development. Obstacles to the child's mental health and to the success of treatment are discussed, with particular attention to the adverse effects of parental psychopathology and of environmental stressors such as poverty, cultural marginalization, and lack of access to resources. It is argued that the infant mental health clinician working with traumatized children and their families needs to adopt a therapeutic approach that actively incorporates collaboration with other service systems, including pediatric care, childcare, law enforcement, child protective services, and the courts, in order to provide ecologically sound and culturally competent treatment. PMID- 28640405 TI - Detecting infants in need: Are complicated measures really necessary? AB - The object of this paper was to study how the Baby Alarm Distress Scale (ADBB), developed as a simple screening tool for front line professionals working with infants, correlates with the more detailed assessment method of the Global Rating Scale (GRS) for Mother-Infant Interaction at two and four months. A sample of 127 eight- to eleven-week-old infants was videotaped in free interaction with their mothers, and infant interaction behavior was rated with both methods by independent researchers. Compared to the GRS infant scales the sensitivity of the ADBB, using the recommended cutoff point of 5 or more, was 0.77 and specificity 0.80. In further analyses it was found that deviant ratings of two items of the ADBB, the quality of eye contact between the infant and the caregiver and assessment of the sense of relationship between the infant and the caregiver, were the items most strongly associated with poor interaction skills of the infant on the GRS. Mothers of infants found deviant in the ADBB performed more poorly in the interaction with their infants when compared to mothers of infants found healthy in the ADBB. For the purpose of detecting deviations in infant interaction skills as signs of possible problems in early parent-infant interaction the ADBB seems to be a sufficiently sensitive and specific instrument. However, the results of this study still need to be tested with larger samples and against other observation methods. PMID- 28640406 TI - Withdrawal behavior and depression in infancy. AB - This paper describes the history of the concept of infant depression, which has been at the beginning of the discipline of infant mental health, and reviews classification and diagnosis issues, along with some animal models. Several diagnostic criteria have yielded different prevalence rates, and some being unrealistic, but we still do not know when infant depression begins, what its outcome is, and what are its different aspects. It is suggested that infant depression needs a certain amount of emotional and cognitive development to unfold, and that it might not exist before 18-24 months of age, a crossover during which major autoreflexive, cognitive, and emotional abilities emerge. Depression could be an outcome of attachment disorganization in infancy, as depression and disorganization seem to share the same learned helpnessness psychopathological process. Developmental psychopathology considers trouble more from a dimensional point of view rather than from a categorical one, and more as the result of several factors with a sequential action rather than the effect of a genetic disorder with direct expression. Before the limit of 18-24 months, the concept of relational withdrawal seems more applicable and useful. PMID- 28640407 TI - Presidential address: Early parent-infant interaction and mental health. AB - The importance and meaning of early mother-infant interaction and their possible connection with developmental psychopathology and child psychiatry practice are presented. In an experimental study healthy mothers and their infants were kept together immediately after delivery instead of separating them. Correlation was found between early interactive behavior and later outcome measurements. Other effects of early contact were evaluated with the help of interviews, questionnaires, developmental screening, analyses of videotapes, and are discussed. In another study the outcome of a longitudinal, prospective 30-year follow-up on a group of former infant-patients at the Child Guidance Clinics in Stockholm was the subject of investigation. A major finding was that some 60% of this very young population suffered from a number of serious difficulties and problems later on, which is not very encouraging. PMID- 28640408 TI - When the bough breaks the cradle will fall: Promoting the health and well being of infants and toddlers in juvenile court. AB - Approximately one-third of the children in the child welfare system are under the age of six. These children are almost invisible in our juvenile courts. It is now clear from the emerging science of early childhood development that during the first few years of life, children develop the foundation and capabilities on which all subsequent development builds. Living in emotional and environmental impoverishment and deprivation provides a poor foundation for healthy development. These very young and vulnerable children are exhibiting disproportionate developmental and cognitive delays, medical problems, and emotional disorders. However, there is growing evidence that early planned interventions can help. The juvenile court must take a leadership role in focusing on the very young child and learning more about risk, prevention, and early intervention in order to facilitate the healing process. PMID- 28640409 TI - Behavioral Control Dynamics and Developmental Outcomes in Infants Prenatally Exposed to Cocaine. AB - This study longitudinally examined the associations between mother-infant interactions at 15 months and behavioral and cognitive outcomes at 36 months of age in a sample of at-risk, young children. Participants for the current study were 58 infants/toddlers prenatally exposed to cocaine and their maternal caregivers. These infants were from a low socioeconomic status background and were part of an intervention setting. When the children were 12, 15, and 36 months, they participated in research sessions with their maternal caregivers. Cognitive development at 12 months and maternal and infant behavior at 15 months were measured to predict behavioral and cognitive outcome at 36 months. Higher levels of maternal control at 15 months were marginally significant in predicting higher levels of problem behavior at 36 months whereas higher levels of infant resistance to control predicted lower levels of problem behavior. Furthermore, control-resistant behavior displayed by infants was a unique buffer against problem behavior, even after controlling for maternal factors and cognitive abilities. These findings suggest that maternal control attempts and infant reactions to those maternal control behaviors play an important role in the development of adaptive and maladaptive behavior patterns during early childhood. PMID- 28640410 TI - Reference to Emotion States During Narrative Co-Construction With Three-Year-Old Kibbutz Children: Comparison of Mother-Child and Metapelet-Child Dyads. AB - In this study of young kibbutz children, we considered similarities and differences between mother-child dyads and metapelet (nonmaternal female caregiver)-child dyads on their rates of mentioning positive and negative emotion states and emotion calls during narrative co-construction from a text-free picture book illustrating emotionally charged situations. Thirty-two kibbutz children approximately 3 years of age, their mothers, and their metaplot (i.e., plural of metapelet) were observed during co-construction from the picture book. All participants (mothers, metaplot, children with mothers, and children with metaplot) mentioned more negative emotion states and emitted more negative emotion calls than positive ones. Children mentioned less emotion states than adults. No differences were found between mothers and metaplot in the number of emotion states mentioned, but mothers used significantly more emotion calls than did the metaplot, and their children tended to reciprocate. The influence of the context and type of relationship on emotion regulation is discussed. PMID- 28640411 TI - The Effect of Maternal Depressed Mood on Infant Emotional Reaction in a Surprise Eliciting Situation. AB - The purpose of this study is to examine the claim that an infant's ability to respond appropriately to an emotional situation varies according to the emotional state of the mother. Surprise expressions in mother and child were examined both in terms of paralinguistic aspects of surprise vocalizations as well as facial expressions. Seventy-two infants and their mothers (mean age=8 months, range=5-11 months) were video- and audiotaped in their homes. Half of the infants, matched for age and gender, had mothers who reported depressed mood. Infants of mothers with depressed mood showed significantly fewer components of facial expressions of surprise compared with infants of nondepressed mothers. Mothers with depressed mood exclaimed surprise with a significantly lower pitch (mean F0 =386.13 Hz) compared to nondepressed mothers (mean F0 =438.10 Hz). Furthermore, mothers with depressed mood showed fewer associations between elements of emotional expression than the nondepressed group. Infants' expressions of surprise are influenced by maternal mood, resulting in reduced expression of the emotion in infants of mothers with depressed mood. These results are discussed in terms of coordination of vocal parameters in mother-infant dyadic interaction. PMID- 28640412 TI - How Do Mothers Feel About Their Very Low Birth Weight Infants? Development of a New Measure. AB - The early relationship between a mother and her very low birth weight (VLBW; <1.5 kg) infant may be difficult to evaluate. Therefore, we aimed to develop a useful and practical method to describe a mother's early relationship with her VLBW infant. Mothers (mean age=27 years, 46% married) of 119 singleton VLBW infants (mean BW=1,056 g, mean GA=28 weeks) admitted to the neonatal ICU at Rainbow Babies and Children's Hospital completed a novel questionnaire regarding their feelings about their infant at 3 weeks' postnatal age, and at 35 weeks', 40 weeks' (term), and 4 months' postmenstrual ages. Factor analysis of initial interview data was used to construct subscales to measure unique domains hypothesized to underpin the beginning maternal-infant relationship. Three subscales were identified: (a) The Worry subscale focuses on the mother's concerns about her infant's current medical condition and future development, (b) the Enjoyment subscale examines the mother's positive feelings about and responsiveness to her infant, and (c) the Separation Anxiety subscale examines the mother's mental anxiety about being physically separated from her infant. Statistical and clinical validation of the subscales produced positive supporting evidence that the subscales are a meaningful measure of the mother-infant relationship. We have developed a unique and practical measure for describing the early mother-VLBW infant relationship. PMID- 28640413 TI - Sleep Architecture in Infants of Substance-Abusing Mothers. AB - This longitudinal, year-long study compared sleep-wake state organization in two groups of infants-infants whose mothers abused substances during their pregnancies and nonexposed, typically developing, age-matched comparison infants to determine whether differences in sleep-wake state organization existed between the two groups. Seventeen infants of mothers who were participating in a parent infant residential treatment program for substance abuse were enrolled. Their sleep-wake state organization over the first year of life was compared to that of 17 age-matched comparison infants. The intent was to follow each infant on five occasions over the first year of life using established methods of time-lapse videosomnography to record sleep-wake state organization; however, attrition in the substance-abusing group was problematic. Some sleep-wake variables (i.e., Active Sleep%, Quiet Sleep%, Awake%, number of nighttime awakenings) were similar for both groups of infants at comparable ages across the first year. Total sleep time and the longest sustained sleep period (sleep continuity variables) differed significantly at some of the ages measured. Although overall sleep architecture appears highly resilient and well organized, some indications of sleep fragmentation and shortened nighttime sleep periods were observed in the substance-exposed infants. More research is needed to explain why sleep continuity variables and not sleep-state proportion variables differed between the two groups. PMID- 28640414 TI - The Prenatal Lausanne Trilogue Play: A New Observational Assessment Tool of the Prenatal Co-Parenting Alliance. AB - The goal of this study is to present a new observational assessment tool, the prenatal Lausanne Trilogue Play situation (LTP). Expectant parents were asked to role play their first meeting with their baby using a doll, and the videotaped interaction was subsequently coded. Scores were correlated with measures of the couples' marital satisfaction as well as the postnatal family alliance 3 months after the baby's birth. Results showed that the prenatal co-parenting alliance was positively linked to both fathers' marital satisfaction as well as to the postnatal family alliance at 3 months. Thus, the prenatal LTP allows for assessment of the prenatal co-parenting alliance at the interactional level. It predicts the place the parents will afford their baby after birth and can contribute to methods of clinical assessment and prevention. PMID- 28640415 TI - Maternal limit-setting in toddlerhood: Socialization strategies for the development of self-regulation. AB - Early findings from the Prohibition Coding Scheme (PCS; Houck & LeCuyer, 1995; LeCuyer-Maus & Houck, 2002; Medvin & Spieker, 1985) revealed that maternal limit setting styles with toddlers were differentially related to later child social competence, self-concept, and delay of gratification. For this study, the PCS was revised to provide more information about the specific strategies mothers used during limit-setting in relation to those outcomes. Results from the PCS-Revised (PCS-R; LeCuyer & Houck, 2004) included that the more time mothers spent actively distracting their toddlers away from a prohibited object during limit-setting, as early as 12 months, the longer their children could delay gratification at age 5 years. Mothers who spent more time sensitively following and being engaged in their toddler's own interests (other than the prohibited object), again as early as 12 months, had more socially competent children with more developed self concepts at age 3 years. Maternal use of reasoning statements later in toddlerhood also related to higher levels of social competence. Maternal limits and prohibitions were not related to these outcomes, and appeared to contribute to the development of self-regulation mainly by creating the opportunity for the use of other, less directive strategies. The findings indicate that these strategies may be important to include in intervention programs for the promotion of toddler and child development of self-regulation. PMID- 28640416 TI - Maternal depression: A review of relevant treatment approaches for mothers and infants. AB - The negative impact of postpartum depression on the mother-infant relationship and infant development more generally has been well documented. Compared to infants of nondepressed mothers, infants of depressed mothers have been shown to be less securely attached to their caregivers and often have cognitive, emotional, and behavioral deficits that persist well into childhood. Recent evidence has suggested that reduction of maternal depressive symptoms may itself not be sufficient to prevent negative effects on children. Rather, treatments that target the mother-infant relationship may have great potential in providing a buffer against the potentially damaging effects of postpartum depression. Based on our review of several treatment-outcome studies, we conclude that mother infant psychotherapies and home-based interventions are generally efficacious in their goal of ameliorating detrimental consequences for children of depressed mothers. Nonetheless, the field must continue to investigate the extent to which treatment gains are maintained over time and the mechanisms by which protective effects occur. It is likely that the most efficacious treatment approaches will be those that address the needs of the mother, the infant, and their relationship. PMID- 28640417 TI - Antecedents of mothers' emotional and cognitive responses to infant distress: The role of family, mother, and infant characteristics. AB - The antecedents of mothers' emotional and cognitive responses to infant distress were examined. Participants were 67 mothers and their infants. Mothers completed questionnaires assessing their experiences in the family of origin and current marital relationships both pre- and postnatally and their coping strategies prenatally. Infant temperament was observed at 6 months, and mothers were interviewed about their emotional and cognitive responses to infant distress 2 years later to assess their emotional competencies (i.e., accurate identification of negative emotions, emotion efficacy, emotional responses to infant distress, and emotion goals). A childhood history of emotional rejection was negatively associated with empathy and efficacy and positively associated with negative emotions. The association between childhood history and some emotional competencies was moderated by current marital dysfunction, engaged coping, and positive intervening relationships. Maternal marital styles and coping strategies and infant temperament correlated with emotional competencies. Theoretical and clinical implications are discussed from an attachment theory perspective. PMID- 28640418 TI - Impact of mother interactive style on infant affect among babies exposed to alcohol in utero. AB - This study examined the ability of infants prenatally exposed to alcohol to regulate their affect during and after a stressor. Specifically, the Still-Face Paradigm (Tronick, Als, Adamson, Wise, ' Brazelton, 1978) was used as a stress induction paradigm to assess both mother-infant interaction and infant self regulation. In addition to the mothers' interactive style, the effect of mothers' drinking during and after pregnancy on the infant was explored. Participants were 76 six-month-old infants and their mothers. Infant affect and maternal interaction style was coded second-by-second for the 6 min of the Still-Face Paradigm. Results indicated that infants whose mothers made fewer attempts at engaging them during the play portion of the still-face (e.g., either watched their infant or paid minimal attention to their infant) showed greater negative affect in contrast to infants whose mothers played in an interactive manner. A gender effect was found among female infants. That is, female infants whose mothers drank more during pregnancy showed greater negative affect. The study demonstrates the possibility of early identification of negativity in infants with prenatal alcohol exposure. The impact of mother-child relationship on emotional regulation of infants prenatally alcohol exposed may be a target of future intervention and further study. PMID- 28640420 TI - Introduction to the special issue on early preventive intervention and home visiting. PMID- 28640419 TI - To regulate, or not to regulate? The devious history of cerebral blood flow control. PMID- 28640421 TI - Pre- and postnatal antecedents of a home-visiting intervention and family developmental outcome. AB - This is a study of the pre- and postnatal antecedents of select indices of 6 to 24 months mother-child and child social-emotional development. The following hypotheses guided the study: 1. That a mother who is secure before the birth of her child will be more involved in the work of the home-visiting intervention, and will by child age 24 months be more responsive to the needs of her child, encourage the autonomy of her child, and use verbal and positive forms of control. In this relationship context, the 2 year-olds would expect to be cared for, show more autonomy, and respond positively to the mother's control. 2. That in a regression mode of analysis, the following five antecedents will be additional predictors of the 2 year outcome: (a) the 1-month mother responsiveness and the infant irritability, (b) the 6 month mother's partner and family support, and (c) the mother's involvement in the work of the intervention in the 7-to 12-months period. Repeated measures analysis of variance and stepwise regression analysis showed that the mother's prebirth secure/autonomous state was associated with the outcome in the 6- to 24-month period and her involvement in the work of the intervention, and that the latter was consistently a significant antecedent of the 24-month outcome. The implications of outcome being anticipated by both family characteristics and the mother's involvement in the intervention are discussed. PMID- 28640422 TI - Nurse home visiting: Perspectives from nurses. AB - Nurses working in the Nurse Family Partnership (NFP) program provide intensive home-visitation services for first-time, low-income mothers. The goals are to improve maternal health outcomes, child health and development outcomes, and to enhance maternal life-course development; however, many of the families face significant psychosocial and mental health issues that can impede progress achieving their goals. Because of the importance of the nurse-client relationship in achieving positive outcomes, these non-mental-health nurses must shift their approaches and techniques from a medical to a psychosocial model. In this article, we examine the role of the nurse in the NFP and present results of focus groups with experienced NFP nurses regarding their perspectives, challenges, and rewards in conducting this work. PMID- 28640423 TI - A prevention and promotion intervention program in the field of mother-infant relationship. PMID- 28640424 TI - The process and promise of mental health augmentation of nurse home-visiting programs: Data from the Louisiana Nurse-Family Partnership. AB - The Nurse-Family Partnership (NFP) model is a well-studied and effective preventive intervention program targeting first-time, impoverished mothers and their families. Data documenting the negative impact of maternal depression and partner violence on the developing young child can be used to make a strong case for augmenting NFP programs to focus on mental health problems impacting the mother-child relationship. This article reviews the rationale for and process of augmenting an NFP program in Louisiana. Data on the prevalence of depression and partner violence in our sample are presented alongside a training protocol for nurses and mental health consultants designed to increase the focus on infant mental health. The use of a weekly case conference and telephone supervision of mental health consultants as well as reflections on the roles of the mental health consultant and the nurse supervisor are presented. PMID- 28640426 TI - The nurse-family partnership: An evidence-based preventive intervention. AB - Pregnancy and the early years of the child's life offer an opportune time to prevent a host of adverse maternal, child, and family outcomes that are important in their own right, but that also reflect biological, behavioral, and social substrates in the child and family that affect family formation and future life trajectories. This article summarizes a 27-year program of research that has attempted to improve early maternal and child health and future life options with prenatal and infancy home visiting by nurses. The program is designed for low income mothers who have had no previous live births. The home-visiting nurses have three major goals: to improve the outcomes of pregnancy by helping women improve their prenatal health, to improve the child's health and development by helping parents provide more sensitive and competent care of the child, and to improve parental life course by helping parents plan future pregnancies, complete their education, and find work. The program has been tested in three separate large-scale, randomized controlled trials with different populations living in different contexts. Results from these trials indicate that the program has been successful in achieving two of its most important goals: (a) the improvement of parental care of the child as reflected in fewer injuries and ingestions that may be associated with child abuse and neglect and better infant emotional and language development; and (b) the improvement of maternal life course, reflected in fewer subsequent pregnancies, greater work-force participation, and reduced dependence on public assistance and food stamps. The impact on pregnancy outcomes is equivocal. In the first trial, the program also produced long-term effects on the number of arrests, convictions, emergent substance use, and promiscuous sexual activity of 15-year-old children whose nurse-visited mothers were low income and unmarried when they registered in the study during pregnancy. In general, the impact of the program was greater on those segments of the population at greater risk for the particular outcome domain under examination. Since 1996, the program has been offered for public investment outside of research contexts. Careful attention has been given to ensuring that organizational and community contexts are favorable for development of the program, to providing excellent training and guidance to the nurses in their use of the program's visit-by-visit guidelines, to monitoring the functioning of the program with a comprehensive clinical information system, and to improving the performance of the programs over time with continuous improvement strategies. PMID- 28640427 TI - Can we differentiate sensory over-responsivity from anxiety symptoms in toddlers? perspectives of occupational therapists and psychologists. AB - Suppose a toddler becomes distressed after hearing a loud noise or when getting messy; are these indicators of sensory over-responsiveness or indicators of anxiety? There is little evidence regarding the distinction between sensory over responsivity and anxiety disorders in toddlers. This construct validity study examined differences between occupational therapists' and psychologists' judgments of behaviors as representing sensory processing disorders (SPD) versus anxiety disorders. Twenty-four occupational therapists and 25 psychologists completed a mailed survey, rating items from sensory and anxiety scales as representing sensory and/or anxiety disorders in toddlers, and analyzing cases of toddlers with these disorders. Occupational therapists were more likely to rate items as representing SPD than psychologists, and occupational therapists were more certain of the distinction of the sensory scales from anxiety. For the case designed to present a general anxiety disorder and the one designed to present sensory over-responsivity, more occupational therapists diagnosed as sensory over responsive, while more psychologists diagnosed with a general anxiety disorder. The overlap in judgments of sensory over-responsivity and anxiety supports the notion that these constructs in part reflect different professionals' perspectives upon behaviors as well as the difficulty in distinguishing these constructs in toddlers. PMID- 28640428 TI - Preventive pediatric mental health care: A co-location model. AB - Current practice recommendations in both the fields of infant mental health and pediatrics support the co-location of mental health professionals into the pediatric setting. Multiple policy reports and statements of the past 5 years have repeatedly argued the need for coordination and integration between mental health care and pediatrics (Halfon, Regalado, McLearn, Kuo, & Wright, 2003; Osofsky, 2004). The pediatric office is recognized as a universally accessed, nonstigmatized setting, ideal for the assessment and treatment of early childhood mental health problems. However, barriers to this type of care are rampant, including time limitations on the part of pediatricians, inadequate reimbursement structures, inadequate training of pediatricians, and insufficient connections between medical and mental health providers. An innovative response to these barriers is the co-location of a mental health professional in the pediatric practice to provide pediatrician education and appropriate screening, assessment, referral, and treatment of young patients. This article describes a successful program of this type situated in the Bronx, NY, where a psychologist with expertise in infant mental health spends 25 hours per week in a large pediatric practice to address the developmental and mental health needs of children aged 0 3 years old. Preliminary descriptive data regarding the patient population, screening scores, and disposition are presented. PMID- 28640429 TI - The development of maternal self-esteem. AB - Although an important theoretical concept, little is known about the development of maternal self-esteem. This study explores the significance of maternal cognitions, psychopathological symptoms, and child temperament in the prediction of prenatal and postnatal maternal self-esteem. During pregnancy 162 women completed measures assessing their unhealthy core beliefs, psychopathological symptoms, and self-esteem. At 1 year postpartum 87 of these women completed measures assessing their self-esteem and their child's temperament. Overall maladaptive maternal core beliefs and psychopathological symptoms during pregnancy explained 19% of the variance in prenatal maternal self-esteem. Forty two percent of the variance in maternal self-esteem at 1 year could be explained by a combination of prenatal maternal self-esteem, mental health symptoms, maternal core beliefs, and more unsociable infant temperament. Underlying maternal cognitive structures may be important in determining the development of maternal self-esteem. PMID- 28640430 TI - The helping relationship and program participation in early childhood home visiting. AB - As researchers have focused on better understanding those circumstances under which home visiting can lead to positive effects on parent and child outcomes, there has been growing interest in examining variation in the experiences of families within these programs, including the quality of the helping relationships between home visitors and parents. The current study examined how participating mothers perceive the helping relationship, using information collected from the Early Head Start National Research and Evaluation Project. Results suggest that although maternal report of the helping relationship is biased towards positive ratings, it remains a significant predictor of program participation, over and above general program satisfaction. Implications for measurement development and program interventions are discussed. PMID- 28640431 TI - Influence of adolescent maternal characteristics on infant development. AB - The present study proposed that several adolescent maternal variables would be associated with infant development. Using a sample of 71 adolescent mother-infant dyads, the study examined the relative influences of the adolescent's level of separation-individuation (Separation-Individuation Process Inventory), feelings of attachment towards the infant (Maternal Postnatal Attachment Scale), and feelings of anxiety regarding separation (Maternal Separation Anxiety Scale) on infant mental and motor development (Bayley Scales of Infant Development, 2nd ed.). As it was assumed that the adolescent's perceptions of being parented would provide the foundation for each of these independent variables, this factor was also included (Parental Bonding Instrument). In the current sample, adolescent separation-individuation was the only maternal psychological variable to uniquely predict infant development, but only on the mental scale. Present findings highlight the importance of considering critical developmental processes of adolescence when exploring cognitive functioning and other outcomes in infants of adolescents. A number of possible mechanisms for the influence of separation individuation are considered in the discussion. PMID- 28640432 TI - Favourable changes in mortality in people with diabetes: US NHANES 1999-2010. AB - AIMS: Diabetes-related complications have declined during the past two decades. We aimed to examine whether mortality in people with diabetes improved over time in the 1999 to 2010 National Health and Nutrition Examination Survey (NHANES). METHODS: We conducted a prospective cohort study using 1999 to 2004 and 2005 to 2010 data from the NHANES. For primary analyses, we compared the unadjusted, age adjusted and multivariable-adjusted hazard ratios (HR) for mortality outcomes (total, cardiovascular, cardiac and cancer deaths) of the participants with diabetes with those without diabetes using Cox proportional hazard models. RESULTS: For each mortality outcome, HR (95% confidence interval) in diabetic participants during the period 2005 to 2010 was lower than that during the period 1999 to 2004 (all-cause death, 2.76 [1.87-4.08] vs 4.23 [2.57-6.98]; cardiovascular death, 2.70 [1.20-6.04] vs 8.82 [3.28-23.70]; cardiac death, 2.45 [0.98-6.09] vs 15.55 [7.01-34.50]; cancer death, 2.33 [0.87-6.23] vs 3.03 [1.20 7.65]). Compared with mortality outcome during the period 1999 to 2004, greater declines in mortality during the period 2005 to 2010 were observed for cardiovascular (-54.0%) and cardiac deaths (-64.8%). In age-adjusted and multivariable-adjusted models, the cumulative event rates for total, cardiovascular and cardiac deaths were not significantly different between participants with and without diabetes during the period 2005-2010; this was not the case during the period 1999-2004. The leading cause of death was malignant neoplasm during the period 2005-2010. CONCLUSION: Considerably improved outcomes for total, cardiovascular and cardiac deaths were observed in people with diabetes during the 2005 to 2010 NHANES compared to the 1999 to 2004 NHANES. PMID- 28640433 TI - Glycemic Improvement with a Fixed-dose combination of DPP-4 inhibitor + metformin in patients with Type 2 diabetes (GIFT study). AB - This study investigates changes in A1C following a switch from dual therapy of metformin and DPP-4 inhibitor to a fixed-dose combination (FDC) of metformin + DPP-4 inhibitor following the introduction of the FDC in the provincial formulary. The LMC Diabetes Registry was queried retrospectively for patients with type 2 diabetes, aged between 18 and 80 years with at least one A1C recorded prior and >=3 months post-switch. Five hundred and sixty-eight subjects with mean age 64 +/- 12 years and mean A1C 7.7% +/- 1.2% met study criteria. Overall, A1C was 0.3% lower post-switch to FDC (P < .01). In stratified analysis, subjects with baseline A1C between 7% and 10% had 0.4% lower A1C (P < .01), with 31% of these subjects reaching target A1C <=7%, post-switch. A1C reduction was greater among patients with a higher baseline pill burden: 0.4% among those using >=10 pills/day vs. 0.1% for those with <10 pills/day (P = .02). In this real-world study, switching to FDC of metformin + DPP-4 inhibitor was associated with a significant improvement in A1C. Switching to FDC, especially in patients with high pill burden, can improve A1C goal achievement in clinical practice. PMID- 28640435 TI - Adjusting the Chemical Bonding of SnO2 @CNT Composite for Enhanced Conversion Reaction Kinetics. AB - Carbon nanotubes (CNTs) with excellent electron conductivity are widely used to improve the electrochemical performance of the SnO2 anode. However, the chemical bonding between SnO2 and CNTs is not clearly elucidated despite it may affect the lithiation/delithiation behavior greatly. In this work, an SnO2 @CNT composite with Sn?C and Sn?O?C bonds as a linkage bridge is reported and the influence of the Sn?C and Sn?O?C bonds on the lithium storage properties is revealed. It is found that the Sn?C bond can act as an ultrafast electron transfer path, facilitating the reversible conversion reaction between Sn and Li2 O to form SnO2 . Therefore, the SnO2 @CNT composite with more Sn?C bond shows high reversible capacity and nearly half capacity contributes from conversion reaction. It is opposite for the SnO2 @CNT composite with more Sn?O?C bond that the electrons cannot be transferred directly to CNTs, resulting in depressed conversion reaction kinetics. Consequently, this work can provide new insight for exploration and design of metal oxide/carbon composite anode materials in lithium ion battery. PMID- 28640434 TI - Catechol-O-Methyltransferase Genotype and Gait Speed Changes over 10 Years in Older Adults. AB - OBJECTIVES: To determine the association between catechol-O-methyltransferase (COMT) genotype and 6-m walk time and to determine whether these associations are quadratic in nature, similar to previously reported U-shaped associations between dopamine and gait and cognition. DESIGN: Prospective cohort study. SETTING: Health, Aging and Body Composition Study. PARTICIPANTS: Black (n = 850) and white (n = 1,352) men and women with a mean age of 73.5 +/- 2.85 at baseline. MEASUREMENTS: Mixed models were used to assess the association between the COMT genotype and 6-m walk time, cross-sectionally and longitudinally over 10 years. Models were assessed unstratified and stratified according to race because allele distributions were different between white and black participants. RESULTS: There was a significant U-shaped association between COMT genotype and 6-m walk time: those with higher (Val/Val) and lower (Met/Met) dopamine slowed more over 10 years (0.22 +/- 0.02 seconds per visit and 0.23 +/- 0.02 seconds per visit, respectively) than those with the intermediate (Met/Val) dopamine (0.20 +/- 0.02 seconds per visit) (P = .005). Stratified results showed a significant relationship in black (P = .01) but not white (P = .15) participants. CONCLUSION: These findings indicate a role of dopaminergic regulation of gait speed in community-dwelling older adults and of prefrontal cortex involvement in gait performance. Future work should investigate the molecular integrity of dopaminergic networks and gait changes over time and structural changes in the brain with COMT and gait decline in older adults. PMID- 28640436 TI - Two-step irradiance schedule versus single-dose cold compress for pain control during 5-aminolevulinic acid-based photodynamic therapy of condyloma acuminatum. AB - OBJECTIVE: The purpose of this study was to investigate the effect of two-step irradiance schedule in relieving pain during PDT of CA. METHODS: The study was a prospective, controlled trial of 141 CA patients who were randomly divided into Group A (two-step irradiance schedule) and Group B (single-dose cold compress). The numeric rating scales (NRS) of patients' pain were recorded at 5, 10, 15, and 20 minutes during each PDT. RESULTS: The efficacy of PDT and NRS scores of patients in the two groups were compared. There was no significant difference in gender, age, lesion site, and disease course between the two groups (P > 0.05). In addition, the cure rate of patients in the two groups was not significantly different (97.1% vs. 95.8%, chi2 = 0.000, P = 1.000). However, the NRS scores at different time points and number of PDT sessions were significantly different (F = 198.233 and 165.224, respectively, P < 0.05). The NRS scores of patients in Group A were significantly lower than those of patients in Group B (F = 82.762, P < 0.0001). Moreover, the NRS scores at different positions were significantly different (F = 28.286, P < 0.0001). The NRS scores of penis were significantly lower than those of the vulva and crissum (P < 0.05). CONCLUSIONS: Compared with single-dose cold compress, two-step irradiance schedule could more significantly reduce the patients' pain degree during treatment, especially for vulva and crissum. Lasers Surg. Med. 49:908-912, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28640437 TI - Repeated evolution of vertebrate pollination syndromes in a recently diverged Andean plant clade. AB - Although specialized interactions, including those involving plants and their pollinators, are often invoked to explain high species diversity, they are rarely explored at macroevolutionary scales. We investigate the dynamic evolution of hummingbird and bat pollination syndromes in the centropogonid clade (Lobelioideae: Campanulaceae), an Andean-centered group of ~550 angiosperm species. We demonstrate that flowers hypothesized to be adapted to different pollinators based on flower color fall into distinct regions of morphospace, and this is validated by morphology of species with known pollinators. This supports the existence of pollination syndromes in the centropogonids, an idea corroborated by ecological studies. We further demonstrate that hummingbird pollination is ancestral, and that bat pollination has evolved ~13 times independently, with ~11 reversals. This convergence is associated with correlated evolution of floral traits within selective regimes corresponding to pollination syndrome. Collectively, our results suggest that floral morphological diversity is extremely labile, likely resulting from selection imposed by pollinators. Finally, even though this clade's rapid diversification is partially attributed to their association with vertebrate pollinators, we detect no difference in diversification rates between hummingbird- and bat-pollinated lineages. Our study demonstrates the utility of pollination syndromes as a proxy for ecological relationships in macroevolutionary studies of certain species-rich clades. PMID- 28640440 TI - Frequency-dependent inhibition of bladder function by saphenous nerve stimulation in anesthetized rats. AB - AIMS: Percutaneous tibial nerve stimulation (PTNS) is an effective neuromodulation therapy for treating overactive bladder (OAB). The therapeutic effects are achieved by repeatedly applying electrical stimulation through a percutaneous needle electrode that is used to target the tibial nerve (TN). Anatomical studies indicate there can be multiple saphenous nerve (SAFN) branches located near the site of electrical stimulation, and therefore we investigated the possibility of evoking a bladder-inhibitory reflex by electrically activating the SAFN. MATERIALS AND METHODS: Acute experiments were conducted in 26 urethane anesthetized rats. Changes in bladder contraction rate (BCR) and bladder capacity were measured in response to 10-min SAFN stimulation trials. Electrical pulses were applied at 25 uA and at stimulation frequencies between 2 Hz and 50 Hz. RESULTS: We report that SAFN stimulation at 20 Hz was most effective at reflexively decreasing the BCR (53.8 +/- 5.4% from baseline) and also increasing the bladder capacity (145.8 +/- 43.5% from baseline). In contrast, SAFN stimulation at other frequencies yielded inconsistent changes in bladder function. Carry-over effects were minimized by randomizing the sequence of SAFN stimulation trials and also by allowing the bladder to return to the baseline conditions. CONCLUSIONS: With notable changes in both the BCR and bladder capacity, our findings provide evidence of a novel bladder-inhibitory reflex in anesthetized rats that is mediated by the SAFN. Further work is needed to determine the clinical relevance of this neural pathway. PMID- 28640438 TI - Readability, content analysis, and racial/ethnic diversity of online living kidney donation information. AB - More than three-fourths of adults in the USA use the Internet to access health related information. Adults exploring the possibility of living donation should have access to online content that is readable and comprehensive. We simulated a search of online information about living kidney donation and evaluated readability, topics covered, and racial/ethnic diversity of 21 websites meeting inclusion criteria (eg, hosted by a nonprofit or patient advocacy organization, English content, based in USA). Using standard readability metrics, 62% of sites were classified as "Difficult to read" and none achieved the recommended reading level of sixth grade. On average, websites covered 18.5 (62%) of 30 recommended information topics (range: 7 to 28) and only 2.1 (23%) of 9 racial/ethnic diversity items (range: 0 to 6). Overall, the most common nonprofit or patient advocacy organization websites do not meet the readability standards established by the National Institutes of Health and the American Medical Association, many lack fundamental information about living kidney donation, and most are not racially/ethnically diverse. We encourage the transplant community to consider playing a more active role in improving the overall quality of online information disseminated to the general public. Further, there is a need to more critically examine the accuracy of online living donation content in future investigations. PMID- 28640439 TI - Skin-Inspired Multifunctional Autonomic-Intrinsic Conductive Self-Healing Hydrogels with Pressure Sensitivity, Stretchability, and 3D Printability. AB - The advent of conductive self-healing (CSH) hydrogels, a class of novel materials mimicking human skin, may change the trajectory of the industrial process because of their potential applications in soft robots, biomimetic prostheses, and health monitoring systems. Here, the development of a mechanically and electrically self healing hydrogel based on physically and chemically cross-linked networks is reported. The autonomous intrinsic self-healing of the hydrogel is attained through dynamic ionic interactions between carboxylic groups of poly(acrylic acid) and ferric ions. A covalent cross-linking is used to support the mechanical structure of the hydrogel. Establishing a fair balance between the chemical and physical cross-linking networks together with the conductive nanostructure of polypyrrole networks leads to a double network hydrogel with bulk conductivity, mechanical and electrical self-healing properties (100% mechanical recovery in 2 min), ultrastretchability (1500%), and pressure sensitivity. The practical potential of CSH hydrogels is further revealed by their application in human motion detection and their 3D-printing performance. PMID- 28640441 TI - Adipose Tissue-Derived Omentin-1 Function and Regulation. AB - Omentin-1, also known as intelectin-1, is a recently identified novel adipocytokine of 313 amino acids, which is expressed in visceral (omental and epicardial) fat as well as mesothelial cells, vascular cells, airway goblet cells, small intestine, colon, ovary, and plasma. The level of omentin-1 expression in (pre)adipocytes is decreased by glucose/insulin and stimulated by fibroblast growth factor-21 and dexamethasone. Several lines of experimental evidence have shown that omentin-1 plays crucial roles in the maintenance of body metabolism and insulin sensitivity, and has anti-inflammatory, anti atherosclerotic, and cardiovascular protective effects via AMP-activated protein kinase/Akt/nuclear factor-kappaB/mitogen-activated protein kinase (ERK, JNK, and p38) signaling. Clinical studies have indicated the usage of circulating omentin 1 as a biomarker of obesity, metabolic disorders including insulin resistance, diabetes, and metabolic syndrome, and atherosclerotic cardiovascular diseases. It is also possible to use circulating omentin-1 as a biomarker of bone metabolism, inflammatory diseases, cancers, sleep apnea syndrome, preeclampsia, and polycystic ovary syndrome. Decreased omentin-1 levels are generally associated with these diseases. However, omentin-1 increases to counteract the acute phase after onset of these diseases. These findings indicate that omentin-1 may be a negative risk factor for these diseases, and also act as an acute-phase reactant by its anti-inflammatory and atheroprotective effects. Therapeutic strategies to restore omentin-1 levels may be valuable for the prevention or treatment of these diseases. Weight loss, olive oil-rich diet, aerobic training, and treatment with atorvastatin and antidiabetic drugs (metformin, pioglitazone, and exenatide) are effective means of increasing circulating omentin-1 levels. This review provides insights into the potential use of omentin-1 as a biomarker and therapeutic target for these diseases. (c) 2017 American Physiological Society. Compr Physiol 7:765-781, 2017. PMID- 28640442 TI - Endocrine Function after Bariatric Surgery. AB - Obesity increases the risks of metabolic disorders including type 2 diabetes mellitus (T2DM). Bariatric surgery is the most successful therapeutic option that causes sustained weight loss and improvements in obesity comorbidities. Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are two of the most frequently performed bariatric surgeries. Despite their different anatomical rearrangement, they have remarkably similar success in both weight loss and T2DM remission. Interestingly, they also both cause a wide range of endocrine changes. Many of these endocrine changes are reflected specifically within the intestine and are implicated as mechanisms for the metabolic success of surgery. However, while most of the work shows that these hormonal changes are associated with the metabolic changes after surgery, causation has been difficult to ascertain. Here, we review the endocrine changes after RYGB and VSG and explore their mechanistic role in the success of bariatric surgery. Further, we explore important changes in gastrointestinal function and the role of these changes in the increase in postprandial endocrine responses after bariatric surgery. (c) 2017 American Physiological Society. Compr Physiol 7:783-798, 2017. PMID- 28640443 TI - Pathophysiology of Aortic Stenosis and Mitral Regurgitation. AB - The global impact of the spectrum of valve diseases is a crucial, fast-growing, and underrecognized health problem. The most prevalent valve diseases, requiring surgical intervention, are represented by calcific and degenerative processes occurring in heart valves, in particular, aortic and mitral valve. Due to the increasing elderly population, these pathologies will gain weight in the global health burden. The two most common valve diseases are aortic valve stenosis (AVS) and mitral valve regurgitation (MR). AVS is the most commonly encountered valve disease nowadays and affects almost 5% of elderly population. In particular, AVS poses a great challenge due to the multiple comorbidities and frailty of this patient subset. MR is also a common valve pathology and has an estimated prevalence of 3% in the general population, affecting more than 176 million people worldwide. This review will focus on pathophysiological changes in both these valve diseases, starting from the description of the anatomical aspects of normal valve, highlighting all the main cellular and molecular features involved in the pathological progression and cardiac consequences. This review also evaluates the main approaches in clinical management of these valve diseases, taking into account of the main published clinical guidelines. (c) 2017 American Physiological Society. Compr Physiol 7:799-818, 2017. PMID- 28640444 TI - Impact of Growth Hormone on Regulation of Adipose Tissue. AB - Increasing prevalence of obesity and obesity-related conditions worldwide has necessitated a more thorough understanding of adipose tissue (AT) and expanded the scope of research in this field. AT is now understood to be far more complex and dynamic than previously thought, which has also fueled research to reevaluate how hormones, such as growth hormone (GH), alter the tissue. In this review, we will introduce properties of AT important for understanding how GH alters the tissue, such as anatomical location of depots and adipokine output. We will provide an overview of GH structure and function and define several human conditions and cognate mouse lines with extremes in GH action that have helped shape our understanding of GH and AT. A detailed discussion of the GH/AT relationship will be included that addresses adipokine production, immune cell populations, lipid metabolism, senescence, differentiation, and fibrosis, as well as brown AT and beiging of white AT. A brief overview of how GH levels are altered in an obese state, and the efficacy of GH as a therapeutic option to manage obesity will be given. As we will reveal, the effects of GH on AT are numerous, dynamic and depot-dependent. (c) 2017 American Physiological Society. Compr Physiol 7:819-840, 2017. PMID- 28640445 TI - Ubiquitin Ligases and Posttranslational Regulation of Energy in the Heart: The Hand that Feeds. AB - Heart failure (HF) is a costly and deadly syndrome characterized by the reduced capacity of the heart to adequately provide systemic blood flow. Mounting evidence implicates pathological changes in cardiac energy metabolism as a contributing factor in the development of HF. While the main source of fuel in the healthy heart is the oxidation of fatty acids, in the failing heart the less energy efficient glucose and glycogen metabolism are upregulated. The ubiquitin proteasome system plays a key role in regulating metabolism via protein degradation/regulation of autophagy and regulating metabolism-related transcription and cell signaling processes. In this review, we discuss recent research that describes the role of the ubiquitin-proteasome system (UPS) in regulating metabolism in the context of HF. We focus on ubiquitin ligases (E3s), the component of the UPS that confers substrate specificity, and detail the current understanding of how these E3s contribute to cardiac pathology and metabolism. (c) 2017 American Physiological Society. Compr Physiol 7:841-862, 2017. PMID- 28640446 TI - C1q/TNF-Related Protein 3 (CTRP3) Function and Regulation. AB - As the largest endocrine organ, adipose tissue secretes many bioactive molecules that circulate in blood, collectively termed adipokines. Efforts to identify such metabolic regulators have led to the discovery of a family of secreted proteins, designated as C1q tumor necrosis factor (TNF)-related proteins (CTRPs). The CTRP proteins, adiponectin, TNF-alpha, as well as other proteins with the distinct C1q domain are collectively grouped together as the C1q/TNF superfamily. Reflecting profound biological potency, the initial characterization of these adipose tissue derived CTRP factors finds wide-ranging effects upon metabolism, inflammation, and survival-signaling in multiple tissue types. CTRP3 (also known as CORS26, cartducin, or cartonectin) is a unique member of this adipokine family. In this review we provide a comprehensive overview of the research concerning the expression, regulation, and physiological function of CTRP3. (c) 2017 American Physiological Society. Compr Physiol 7:863-878, 2017. PMID- 28640447 TI - Role of SERCA Pump in Muscle Thermogenesis and Metabolism. AB - In muscle cells, the sarcoplasmic reticulum (SR) not only acts as a Ca2+ store, but also regulates the contractile characteristics of the muscle. Ca2+ release from the SR is the primary mechanism for activating muscle contraction and reuptake of Ca2+ by the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump causes muscle relaxation. The SERCA pump isoforms are encoded by three genes, SERCA 1, 2, and 3, which are differentially expressed in muscle and determine SR Ca2+ dynamics by affecting the rate and amount of Ca2+ uptake, thereby affecting SR store and release of Ca2+ in muscle. In muscle, small molecular weight proteins, including Phospholamban (PLB) and Sarcolipin (SLN), also regulate the SERCA pump. Regulation of the SERCA pump by PLB or SLN affects cytosolic Ca2+ dynamics and changes in cytosolic Ca2+ not only affect contractile function, but also mitochondrial ATP production. Recent studies have shown that alterations in cytosolic Ca2+ affects Ca2+ entry into mitochondria and ATP production; thus, Ca2+ serves as an integrating signal between muscle contraction-dependent energy demand and mitochondrial energy production. In addition, changes in cytosolic Ca2+ can affect Ca2+ signaling pathways modulating gene expression and muscle growth. An emerging area of research shows that SR Ca2+ cycling is also a player in muscle-based nonshivering thermogenesis. Recent data shows that SERCA uncoupling by SLN leads to increased ATP hydrolysis and heat production. Our studies, using genetically altered mouse models of SLN, show that SLN/SERCA interaction plays an important role in muscle thermogenesis and metabolism, which will be discussed here, in great length. (c) 2017 American Physiological Society. Compr Physiol 7:879-890, 2017. PMID- 28640450 TI - Network Supervision of Adult Experience and Learning Dependent Sensory Cortical Plasticity. AB - The brain is capable of remodeling throughout life. The sensory cortices provide a useful preparation for studying neuroplasticity both during development and thereafter. In adulthood, sensory cortices change in the cortical area activated by behaviorally relevant stimuli, by the strength of response within that activated area, and by the temporal profiles of those responses. Evidence supports forms of unsupervised, reinforcement, and fully supervised network learning rules. Studies on experience-dependent plasticity have mostly not controlled for learning, and they find support for unsupervised learning mechanisms. Changes occur with greatest ease in neurons containing alpha-CamKII, which are pyramidal neurons in layers II/III and layers V/VI. These changes use synaptic mechanisms including long term depression. Synaptic strengthening at NMDA-containing synapses does occur, but its weak association with activity suggests other factors also initiate changes. Studies that control learning find support of reinforcement learning rules and limited evidence of other forms of supervised learning. Behaviorally associating a stimulus with reinforcement leads to a strengthening of cortical response strength and enlarging of response area with poor selectivity. Associating a stimulus with omission of reinforcement leads to a selective weakening of responses. In some preparations in which these associations are not as clearly made, neurons with the most informative discharges are relatively stronger after training. Studies analyzing the temporal profile of responses associated with omission of reward, or of plasticity in studies with different discriminanda but statistically matched stimuli, support the existence of limited supervised network learning. (c) 2017 American Physiological Society. Compr Physiol 7:977-1008, 2017. PMID- 28640449 TI - Polycystic Kidney Disease. AB - Renal cysts, which arise from renal tubules, can be seen in a variety of hereditary and nonhereditary entities. Common mechanisms associated with renal cyst formation include increased cell proliferation, epithelial fluid secretion, and extracellular matrix remodeling. Hereditary polycystic kidney disease (PKD) is seen as a component of numerous diseases. Autosomal dominant (AD) PKD is the most common potentially fatal hereditary disease in humans, causes renal failure in approximately 50% of affected individuals, and accounts for approximately 5% of end stage renal disease cases in the United States. ADPKD is caused by mutation in one of two genes-85% of cases are caused by mutation in PKD1 on chromosome 16 and 15% of cases are caused by mutation in PKD2 on chromosome 4. Polycystin-1, encoded by PKD1, is a large protein, has multiple transmembrane spanning domains, has extracellular regions suggesting a role in cell-cell or cell-matrix interactions, has intracellular domains suggesting a role in signal transduction, and can physically interact with Polycystin-2. Polycystin-2 is smaller, has transmembrane domains, can act as a cation channel with calcium permeability, and may be regulated by Polycystin-1. These proteins, and many others associated with cystic kidney disease, localize to primary cilia, which may act as flow sensors in the kidney; cystic kidney diseases have also been termed ciliopathies. An increasing number of intracellular mechanisms, which are abnormally regulated in PKD, have been described and are potential targets for therapy, which is lacking in this common hereditary disease. (c) 2017 American Physiological Society. Compr Physiol 7:945-975, 2017. PMID- 28640451 TI - Cardiac Fibrosis and Arrhythmogenesis. AB - Myocardial injury, mechanical stress, neurohormonal activation, inflammation, and/or aging all lead to cardiac remodeling, which is responsible for cardiac dysfunction and arrhythmogenesis. Of the key histological components of cardiac remodeling, fibrosis either in the form of interstitial, patchy, or dense scars, constitutes a key histological substrate of arrhythmias. Here we discuss current research findings focusing on the role of fibrosis, in arrhythmogenesis. Numerous studies have convincingly shown that patchy or interstitial fibrosis interferes with myocardial electrophysiology by slowing down action potential propagation, initiating reentry, promoting after-depolarizations, and increasing ectopic automaticity. Meanwhile, there has been increasing appreciation of direct involvement of myofibroblasts, the activated form of fibroblasts, in arrhythmogenesis. Myofibroblasts undergo phenotypic changes with expression of gap-junctions and ion channels thereby forming direct electrical coupling with cardiomyocytes, which potentially results in profound disturbances of electrophysiology. There is strong evidence that systemic and regional inflammatory processes contribute to fibrogenesis (i.e., structural remodeling) and dysfunction of ion channels and Ca2+ homeostasis (i.e., electrical remodeling). Recognizing the pivotal role of fibrosis in the arrhythmogenesis has promoted clinical research on characterizing fibrosis by means of cardiac imaging or fibrosis biomarkers for clinical stratification of patients at higher risk of lethal arrhythmia, as well as preclinical research on the development of antifibrotic therapies. At the end of this review, we discuss remaining key questions in this area and propose new research approaches. (c) 2017 American Physiological Society. Compr Physiol 7:1009-1049, 2017. PMID- 28640453 TI - Corrigendum. AB - Diabetic cardiomyopathy (DCM) was first recognized more than four decades ago and occurred independent of cardiovascular diseases or hypertension in both type 1 and type 2 diabetic patients. The exact mechanisms underlying this disease remain incompletely understood. Several pathophysiological bases responsible for DCM have been proposed, including the presence of hyperglycemia, nonenzymatic glycosylation of large molecules (e.g., proteins), energy metabolic disturbance, mitochondrial damage and dysfunction, impaired calcium handling, reactive oxygen species formation, inflammation, cardiac cell death, and cardiac hypertrophy and fibrosis, leading to impairment of cardiac contractile functions. Increasing evidence also indicates the phenomenon called "metabolic memory" for diabetes induced cardiovascular complications, for which epigenetic modulation seemed to play an important role, suggesting that the aforementioned pathogenic bases may be regulated by epigenetic modification. Therefore, this review aims at briefly summarizing the current understanding of the pathophysiological bases for DCM. Although how epigenetic mechanisms play a role remains incompletely understood now, extensive clinical and experimental studies have implicated its importance in regulating the cardiac responses to diabetes, which are believed to shed insight into understanding of the pathophysiological and epigenetic mechanisms for the development of DCM and its possible prevention and/or therapy. (c) 2017 American Physiological Society. Compr Physiol 7:693-711, 2017. PMID- 28640452 TI - Role of Epicardial Adipose Tissue in Health and Disease: A Matter of Fat? AB - Epicardial adipose tissue (EAT) is a small but very biologically active ectopic fat depot that surrounds the heart. Given its rapid metabolism, thermogenic capacity, unique transcriptome, secretory profile, and simply measurability, epicardial fat has drawn increasing attention among researchers attempting to elucidate its putative role in health and cardiovascular diseases. The cellular crosstalk between epicardial adipocytes and cells of the vascular wall or myocytes is high and suggests a local role for this tissue. The balance between protective and proinflammatory/profibrotic cytokines, chemokines, and adipokines released by EAT seem to be a key element in atherogenesis and could represent a future therapeutic target. EAT amount has been found to predict clinical coronary outcomes. EAT can also modulate cardiac structure and function. Its amount has been associated with atrial fibrillation, coronary artery disease, and sleep apnea syndrome. Conversely, a beiging fat profile of EAT has been identified. In this review, we describe the current state of knowledge regarding the anatomy, physiology and pathophysiological role of EAT, and the factors more globally leading to ectopic fat development. We will also highlight the most recent findings on the origin of this ectopic tissue, and its association with cardiac diseases. (c) 2017 American Physiological Society. Compr Physiol 7:1051-1082, 2017. PMID- 28640454 TI - Direct quantification of gamma H2AX by cell-based high throughput screening for evaluation of genotoxicity of pesticides in a human thyroid cell lines. AB - Genotoxicity is thought to be the cause of many cancers. Genotoxicity due to environmental toxins may be partly responsible for the dramatic increase in the incidence of papillary thyroid cancer over the past two decades. Here, we present a fully automatable assay platform that directly quantifies the phosphorylation of nuclear histone gamma H2AX (gammaH2AX), a specific cellular marker for DNA double strand breaks (DSBs) via immunohistochemistry and laser scanning cytometry. It multiplexes gammaH2AX with total cell number measured as propidium iodide and calculates the percentage of cells with DSBs. Validation of this assay using NTHY-ori-3-1 human thyroid cells and etoposide showed that it was an excellent choice for high throughput applications. We used the assay to test the genotoxic effects of the EPA Toxcast Phase 1 pesticide library of 309 compounds. Compounds were evaluated in dose response and the DSB was quantified. We found that 19 pesticides induce DSB in vitro, highlighting a need to further assess these pesticides for their long-term oncogenic effects on the thyroid gland. Environ. Mol. Mutagen. 58:522-528, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28640455 TI - Adjunct fixation with a Kirschner wire or a plate for lateral unicondylar humeral fracture stabilization. AB - OBJECTIVE: To compare the biomechanical properties of using an interfragmentary 1.6 mm Kirschner wire or a 2.7 mm reconstruction plate as adjunctive epicondylar stabilization in simulated comminuted lateral unicondylar humeral fractures stabilized with a transcondylar 4.5 mm cortical screw. STUDY DESIGN: Cadaveric biomechanical assessment. SAMPLE POPULATION: Paired humeri harvested from 9 young, skeletally mature dogs. METHODS: Simulated comminuted lateral unicondylar humeral fractures were stabilized with a transcondylar 4.5 mm cortical screw placed in lag fashion. Adjunct fixations consisting of a 1.6 mm Kirschner wire on one side, and a 2.7 mm reconstruction plate on the contralateral side, were tested within paired humeri. Repaired humeri were axially loaded to failure and construct stiffness, yield load, and load to failure were obtained from the load deformation curves. RESULTS: Stiffness (mean +/- SD: 577 +/- 245 vs 310 +/- 71 N/mm; P = .01), yield load (mean +/- SD: 2389 +/- 572 vs 1017 N +/- 292; P = .0002), and load at failure (mean +/- SD: 3351 +/- 358 vs 1693 +/- 363 N; P = .009) were greater in constructs incorporating a reconstruction plate rather than a Kirschner wire. CONCLUSION: Our results support the recommendation for adjunct fixation of comminuted lateral unicondylar humeral fractures with an epicondylar plate. PMID- 28640456 TI - First environmental sample containing plasmid-mediated colistin-resistant ESBL producing Escherichia coli detected in Norway. AB - We hereby report the detection of the plasmid borne mcr-1 gene conferring colistin resistance in an extended-spectrum beta-lactamase (ESBL) producing Escherichia coli ST10 strain retrieved from seawater at a public beach in Norway. The sample was collected in September 2010 and was investigated by whole-genome sequencing in 2016. This report illustrates that E. coli strains carrying plasmid mediated colistin resistance genes have also reached areas where this drug is hardly used at all. Surveillance of colistin resistance in environmental, veterinary, and human strains is warranted also in countries where colistin resistance is rare in clinical settings. PMID- 28640457 TI - Primordial-like enzymes from bacteria with reduced genomes. AB - The first cells probably possessed rudimentary metabolic networks, built using a handful of multifunctional enzymes. The promiscuous activities of modern enzymes are often assumed to be relics of this primordial era; however, by definition these activities are no longer physiological. There are many fewer examples of enzymes using a single active site to catalyze multiple physiologically-relevant reactions. Previously, we characterized the promiscuous alanine racemase (ALR) activity of Escherichia coli cystathionine beta-lyase (CBL). Now we have discovered that several bacteria with reduced genomes lack alr, but contain metC (encoding CBL). We characterized the CBL enzymes from three of these: Pelagibacter ubique, the Wolbachia endosymbiont of Drosophila melanogaster (wMel) and Thermotoga maritima. Each is a multifunctional CBL/ALR. However, we also show that CBL activity is no longer required in these bacteria. Instead, the wMel and T. maritima enzymes are physiologically bi-functional alanine/glutamate racemases. They are not highly active, but they are clearly sufficient. Given the abundance of the microorganisms using them, we suggest that much of the planet's biochemistry is carried out by enzymes that are quite different from the highly active exemplars usually found in textbooks. Instead, primordial-like enzymes may be an essential part of the adaptive strategy associated with streamlining. PMID- 28640458 TI - Long-term graft survival in patients with chronic antibody-mediated rejection with persistent peritubular capillaritis treated with intravenous immunoglobulin and rituximab. AB - Chronic antibody-mediated rejection (cAMR) is the major cause of premature renal allograft loss and is resistant to therapy with 12-month graft failure of up to 50% reported. We examined the duration of graft survival and associates of graft failure in patients with donor-specific antibody-positive cAMR and treatment resistant peritubular capillaritis between June 2007 and October 2010. Those with advanced interstitial fibrosis (n=5) were excluded. Included patients (n=24) received treatment with high-dose intravenous immunoglobulin and fixed-dose rituximab (500 mg). Compared with previous reports, the study group experienced prolonged graft survival (median 82.1 months). Graft loss was predicted by eGFR and degree of proteinuria at diagnosis but not by donor-specific HLA antibody class or intensity, nor individual or summed Banff scores. Allograft biopsies were further examined for infiltrating leukocyte subtypes and location with high numbers of glomerular leukocytes, particularly macrophages, independently associated with an increased risk of graft failure. This study suggests that patients with cAMR and persistent microcirculatory inflammation, excluding those with advanced histological damage, can expect prolonged graft survival when treated with IVIg and rituximab. Trial level evidence is required to validate this observation. Further examination of the role of macrophages in cAMR is warranted. PMID- 28640459 TI - Antidepressant Use in Pregnancy and the Risk of Attention Deficit with or without Hyperactivity Disorder in Children. AB - BACKGROUND: The association between antidepressant (AD) use during pregnancy and the risk of attention deficit with or without hyperactivity disorder (ADHD) in children is debated. We investigated the risk of ADHD associated with overall and class-specific antidepressant exposure in utero. METHODS: We designed a register based cohort study using the Quebec Pregnancy/Children Cohort (QPC). A total of 144 406 singleton full-term live-born from 1998 to 2009 were included. Cox proportional hazards regression models were used to estimate unadjusted and adjusted hazard ratio with 95% confidence interval (CI). RESULTS: During 542 897 person-years of follow-up, 4564 (3.2%) infants were identified with ADHD. The mean age at first ADHD diagnosis was 6.3 +/- 2.3 years (range 0-11 years), and the mean age at first ADHD medication use was 7.0 +/- 1.5 years. Adjusting for potential confounders, including maternal history of depression/anxiety and ADHD, AD use during the 2nd or 3rd trimester of pregnancy was associated with an increased risk of (HR 1.3, 95% CI 1.0, 1.6; 134 exposed cases). More specifically, tricyclic use was associated with an increased risk of ADHD (HR 1.8, 95% CI 1.0, 3.1; 16 exposed cases); SSRI and SNRI use were not associated with increased ADHD risk. CONCLUSION: This study suggests that AD use during the 2nd and 3rd trimester of pregnancy, specifically tricyclics, is an independent risk factor for ADHD in children above and beyond the risk associated with maternal depression/anxiety or ADHD. However, residual confounding by indication severity could not be completely ruled out. PMID- 28640460 TI - Giant Peak Voltage of Thermopower Waves Driven by the Chemical Potential Gradient of Single-Crystalline Bi2 Te3. AB - The self-propagating exothermic chemical reaction with transient thermovoltage, known as the thermopower wave, has received considerable attention recently. A greater peak voltage and specific power are still demanded, and materials with greater Seebeck coefficients have been previously investigated. However, this study employs an alternative mechanism of transient chemical potential gradient providing an unprecedentedly high peak voltage (maximum: 8 V; average: 2.3 V) and volume-specific power (maximum: 0.11 W mm-3 ; average: 0.04 W mm-3 ) using n-type single-crystalline Bi2 Te3 substrates. A mixture of nitrocellulose and sodium azide is used as a fuel, and ultraviolet photoelectron spectroscopy reveals a significant downshift in Fermi energy (~5.09 eV) of the substrate by p-doping of the fuel. The induced electrical potential by thermopower waves has two distinct sources: the Seebeck effect and the transient chemical potential gradient. Surprisingly, the Seebeck effect contribution is less than 2.5% (~201 mV) of the maximum peak voltage. The right combination of substrate, fuel doping, and anisotropic substrate geometry results in an order of magnitude greater transient chemical potential gradient (~5.09 eV) upon rapid removal of fuel by exothermic chemical reaction propagation. The role of fuel doping and chemical potential gradient can be viewed as a key mechanism for enhanced heat to electric conversion performance. PMID- 28640461 TI - Dynamic Kinetic Spiroketalization/Oxa-Michael Addition Cascade of Alkoxyboronates and Peroxyacetals: Enantio- and Diastereoselective Synthesis of Benzannulated Spiroketals. AB - A unified dynamic kinetic spiroketalization/enantioselective oxa-Michael addition cascade of an aromatic ketone tethered to an alkoxyboronate and an enone moiety has been developed using cinchona alkaloid based amino-thiourea/squaramide organocatalysts to provide isobenzofuran-based benzannulated spiroketals with high diastereoselectivities and excellent enantioselectivities. Further, a dynamic kinetic peroxy-hemiacetalization/dynamic kinetic spiroketalization/enantioselective oxa-Michael addition cascade of the above substrates provides the corresponding exo-peroxy-benzannulated spiroketals with outstanding enantio- and diastereoselectivities. PMID- 28640462 TI - Hybrid Lead Halide Perovskites for Ultrasensitive Photoactive Switching in Terahertz Metamaterial Devices. AB - The recent meteoric rise in the field of photovoltaics with the discovery of highly efficient solar-cell devices is inspired by solution-processed organic inorganic lead halide perovskites that exhibit unprecedented light-to-electricity conversion efficiencies. The stunning performance of perovskites is attributed to their strong photoresponsive properties that are thoroughly utilized in designing excellent perovskite solar cells, light-emitting diodes, infrared lasers, and ultrafast photodetectors. However, optoelectronic application of halide perovskites in realizing highly efficient subwavelength photonic devices has remained a challenge. Here, the remarkable photoconductivity of organic-inorganic lead halide perovskites is exploited to demonstrate a hybrid perovskite metamaterial device that shows extremely low power photoswitching of the metamaterial resonances in the terahertz part of the electromagnetic spectrum. Furthermore, a signature of a coupled phonon-metamaterial resonance is observed at higher pump powers, where the Fano resonance amplitude is extremely weak. In addition, a low threshold, dynamic control of the highly confined electric field intensity is also observed in the system, which could tremendously benefit the new generation of subwavelength photonic devices as active sensors, low threshold optically controlled lasers, and active nonlinear devices with enhanced functionalities in the infrared, optical, and the terahertz parts of the electromagnetic spectrum. PMID- 28640463 TI - Exciton Recombination in Formamidinium Lead Triiodide: Nanocrystals versus Thin Films. AB - The optical properties of the newly developed near-infrared emitting formamidinium lead triiodide (FAPbI3 ) nanocrystals (NCs) and their polycrystalline thin film counterpart are comparatively investigated by means of steady-state and time-resolved photoluminescence. The excitonic emission is dominant in NC ensemble because of the localization of electron-hole pairs. A promisingly high quantum yield above 70%, and a large absorption cross-section (5.2 * 10-13 cm-2 ) are measured. At high pump fluence, biexcitonic recombination is observed, featuring a slow recombination lifetime of 0.4 ns. In polycrystalline thin films, the quantum efficiency is limited by nonradiative trap-assisted recombination that turns to bimolecular at high pump fluences. From the temperature-dependent photoluminescence (PL) spectra, a phase transition is clearly observed in both NC ensemble and polycrystalline thin film. It is interesting to note that NC ensemble shows PL temperature antiquenching, in contrast to the strong PL quenching displayed by polycrystalline thin films. This difference is explained in terms of thermal activation of trapped carriers at the nanocrystal's surface, as opposed to the exciton thermal dissociation and trap mediated recombination, which occur in thin films at higher temperatures. PMID- 28640464 TI - Mothers' representations of their infants and parenting behavior: Associations with personal and social-contextual variables in a high-risk sample. AB - Associations between mothers' psychological distress, experiences of verbal and violent relational conflict, representations of the relationships with their infants, and parenting behavior were examined in 100 African American mothers of 17- to 20-month-old infants. Maternal representations of infants were assessed via the Working Model of the Child Interview (WMCI; Zeanah, Benoit, Hirshberg, & Barton, 1986). Results showed that mothers who experienced more conflict with their own mothers had increased odds of having disengaged representations of the relationship with their infants. Mothers who experienced more conflict with their infants' fathers had increased odds of having distorted views of their infants. Mothers who reported more hostile psychological symptomalogy had greater odds of not having a balanced representation of their infants (distorted or disengaged). Additionally, mothers with disengaged representations were less sensitive, more passive, and used less encouragement and guidance with their children. Maternal hostility and conflict were directly related to parenting and were not mediated by representations. Results show that representations and parenting behavior are linked and multiply determined. PMID- 28640465 TI - Anxiety affects the relationship between parents and their very low birth weight infants. AB - The goal of this study was to examine the medical and sociodemographic factors associated with parental anxiety following the birth of a very low birth weight infant (VLBW, below 1500 g), and to determine the impact of anxiety on the behavior of parents with their VLBW infants in the Neonatal Intensive Care Unit (NICU). The parents of 88 VLBW infants were recruited through the NICU of a tertiary-care hospital, approximately 2 weeks following delivery. Parents completed self-report questionnaires measuring anxiety, marital quality, and social support. Prior to discharge, each parent was observed twice during a feeding interaction with the infant. Maternal anxiety was greater when their infants were smaller in terms of birth weight and younger in gestational age. Maternal education, marital status, and country of origin, as well as social support and marital quality, were also associated with anxiety. Paternal anxiety was not related to socioeconomic status or infant medical risk, but was associated with country of origin, social support, and marital quality. For both mothers and fathers, anxiety was a better predictor of parental behavior than was infant medical risk. These findings suggest the need to intervene with anxious parents in order to promote satisfactory parent-infant relationships. PMID- 28640466 TI - Parental representations and subclinical changes in postpartum mood. AB - Parents commonly experience a depressed mood in the immediate postpartum period, and a smaller proportion experience clinical postpartum depression. Among other factors, mental representations of early parenting experience appear to contribute to the development of major depressive disorder. The present study examines the role of mental representations of early parenting in subclinical fluctuations of parental mood in the peripartum period. Forty-one middle-class mothers and thirty-six fathers were interviewed on three occasions from late in their pregnancy until three months postpartum. Ratings of social support and past history of depression were obtained along with ratings of parents' perceptions of their early parenting experiences. Parents' perception of their own maternal care was significantly predictive of peripartum fluctuations in mood. Parents who perceived their own mothers as less caring showed more dysphoria at 8 months gestation, and at 2 weeks and 3 months postpartum. Perceptions of maternal protectiveness or fathers' caring and protectiveness were not related to prenatal or postpartum mood fluctuations. Both mothers and fathers who perceived their mothers as affectionless and/or controlling were more likely to experience fluctuations in mood in the peripartum period. A past history of one or more episodes of major depression and ratings of perceived social support were also associated with more peripartum mood fluctuation. These findings suggest that early parenting experiences set the threshold for how vulnerable parents are in the peripartum period to the depressive costs of engaging with a new infant. PMID- 28640467 TI - The development and evaluation of the intervention model for the Florida Infant Mental Health Pilot Program. AB - The focus of this paper is on the development and evaluation of an intervention model for Florida's Infant and Young Child Mental Health Pilot Program, designed to identify families with children at risk for abuse and neglect, and to provide clinical evaluation and treatment services. The evaluation model, intervention strategies, and results presented in this paper are all part of the Florida pilot project developed as a response to the recommendations of the state's Strategic Plan for Infant Mental Health. Funded by the Florida legislature, the 3-year, multisite pilot was designed to provide earlier identification, better evaluation, and more effective treatment services for high-risk children under the age of three. The target population was children either at risk for out-of home placement due to abuse and neglect, or those already in the child welfare system or adjudicated dependent by the state. The goals of the pilot project were: 1) to reduce the occurrence and re-occurrence of abuse and neglect; 2) to enhance the child's developmental functioning; 3) to improve the parent-child relationship; 4) to increase expeditious permanency placements; 5) to develop a model for intervention and treatment that could potentially be replicated in different sites; and 6) to document the components of a quality infant mental health intervention model and evaluate its effectiveness. PMID- 28640468 TI - Dominance among unfamiliar peers starts in infancy. AB - Dominance has been conceived for a long time in terms of asymmetry in agonistic conflicts. But this conception has shown its limits in the complexity of children's social worlds. Today, dominance is rather conceived in terms of asymmetry in resource control within children's dyads. Some observational studies have been done in this context, but only on small groups of familiar children and often up to 3 years of age. Our aim was to reveal whether asymmetry in resource control would occur between younger children who met each other for the first time in the presence of an attractive toy. We observed 201 dyads of 19-month-old unfamiliar peers in four repetitive competitive sessions for a toy. Resource control and asymmetry between participants were highly consistent between sessions. The level of asymmetry in resource control between participants was very high. This asymmetry was influenced neither by gender nor by age, and coercive behaviors in the situation, physical aggression rated by parents, birth order, and day-care habits did not account for the asymmetry in our setting. However, body size at birth (although not at the time of testing) and anxiety rated by parents contributed significantly to the asymmetry in resource control. PMID- 28640469 TI - Still-face and separation effects on depressed mother-infant interactions. PMID- 28640470 TI - Contingent first-trimester screening for aneuploidies with cell-free DNA in a Danish clinical setting. AB - OBJECTIVES: The primary aim of this study was to compare the screening performance for trisomy 21 (T21) between combined first-trimester screening (cFTS) with referral for invasive testing at a T21 risk >= 1 in 300, and contingent screening consisting of referral for invasive testing at a cFTS-T21 risk >= 1 in 100 and referral for cell-free DNA (cfDNA) testing at a cFTS-T21 risk between 1 in 100 and 1 in 1000. Secondary aims were to compare the incidence of fetuses diagnosed with trisomy 18 (T18), trisomy 13 (T13) or sex chromosome aneuploidy, and examine the association between fetal fraction of cfDNA in maternal blood and maternal/fetal characteristics. METHODS: Women with a singleton pregnancy and a cFTS-T21 risk of >= 1 in 1000 were recruited consecutively from two Danish hospitals between August 2014 and May 2015. First trimester combined screening was based on maternal age, nuchal translucency thickness and levels of pregnancy-associated plasma protein A (PAPP-A) and beta human chorionic gonadotropin (beta-hCG). Blood samples for cfDNA testing were analyzed for risks of T21, T18, T13 and sex chromosomal aneuploidies. cfDNA analysis was conducted blinded to the cFTS assessment and karyotype results. Pregnancy outcomes and pre- and postnatal karyotypes were obtained from the Danish Fetal Medicine Database. RESULTS: Among 6449 women who underwent cFTS risk assessment, 869 (13.5%) had a T21 risk of >= 1 in 1000 and 597 were included for cfDNA testing. Among these, there were 15 cases of T21, one case of T18 and two cases of T13. The sensitivity for detection of T21 was 100% using both screening strategies, while specificity increased significantly (P < 0.0001) from 97.0% using the cFTS strategy to 98.8% using the contingent approach. The sensitivity for detection of T21, T18 and T13 increased from 94.4% using the cFTS strategy to 100% using the contingent approach, with overlapping CIs, while specificity increased significantly (P < 0.0001) from 97.1% for cFTS to 98.9% for the contingent strategy. Seven pregnancies were categorized as being at increased risk of a sex chromosomal aneuploidy by cfDNA testing but chromosome analysis was discordant, corresponding to a false-positive rate of 1.2%. The fetal fraction decreased significantly with increasing maternal weight and increased significantly with the level of beta-hCG and PAPP-A and among female fetuses, in both univariate and multivariate analyses. CONCLUSIONS: In a clinical setting with efficient cFTS, contingent screening offering women with a cFTS risk of >= 1 in 100 an invasive test and women with a risk from 1 in 100 to 1 in 1000 a cfDNA test had the same sensitivity for T21, T18 and T13, but significantly increased specificity, when compared with offering an invasive test to all women with a risk of >= 1 in 300. Implementing contingent screening would therefore reduce significantly the number of invasive tests performed at no loss of sensitivity. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28640472 TI - Social support and postpartum depressive symptomatology: The mediating role of maternal self-efficacy. AB - Research shows that social support and maternal self-efficacy are inversely related to postpartum depression; however, little is known about the mechanisms by which these variables impact on depressive symptomatology. This study uses path analysis to examine the proposal that maternal self-efficacy mediates the effects of social support on postpartum depressive symptomatology. Primiparous women (n=247) completed questionnaires during their last trimester and then again at 4 weeks' postpartum (n=192). It was hypothesized that higher levels of parental support, partner support, and maternal self-efficacy would be associated with lower levels of depressive symptomatology postpartum and that the relationship between social support and depressive symptomatology would be mediated by maternal self-efficacy. Results indicated that as expected, higher parental support and maternal self-efficacy were associated with lower levels of depressive symptomatology postpartum. Partner support was found to be unrelated to both depressive symptomatology and maternal self-efficacy. Results from the path analysis supported the mediation model. Findings suggest that parental support lowers depressive symptomatology by the enhancement of maternal self efficacy. PMID- 28640471 TI - Prognostic significance of cystic lymph nodal metastasis in nasopharyngeal carcinoma. AB - BACKGROUND: The purpose of this study was to determine the prevalence of cystic lymph nodal metastasis (CLNM) and its prognostic value in patients with nasopharyngeal carcinoma (NPC). METHODS: A retrospective review was conducted on 257 patients with NPC, analyzing the presence of CLNM on MRI or CT scans. Oncologic outcomes were performed using the Kaplan-Meier analysis. RESULTS: One hundred eleven patients (43.2%) had CLNM at diagnosis. Overall, patients with CLNM had a poorer disease-specific survival (DSS; P < .001) and overall survival (OS; P < .001) compared with patients without CLNM. When analyzed according to nodal status, CLNM was associated with a higher rate of distant metastasis recurrence (P = .007), a poorer DSS (P < .001), and a poorer OS (P < .001) among patients with N2 disease. CONCLUSION: The prevalence of CLNM was 43.2%. In patients with N2 disease, the presence of CLNM was significantly associated with a poorer DSS, OS, and increased risk of distant metastasis recurrence. PMID- 28640473 TI - Kangaroo mother care and mother-premature infant dyadic interaction. AB - The aim of this study was to investigate the psychological impact of Kangaroo Mother Care (KMC) on mother-infant bonding in cases of premature delivery. Examined variables were mother-infant relationships, maternal anxiety levels, and infant interactive signals. The KMC method requires that babies be undressed and held upright between their mother's breasts for a minimum of 1 hr a day, from birth until they are discharged from hospital. The present study examined 40 premature infants and their mothers, with 21 dyads experiencing KMC and 19 receiving traditional care (TC). Maternal emotional stress was assessed with the Parent Stress Index-Short Form questionnaire (Abidin, 1990), and mother-newborn interactive style was assessed with the Nursing Child Assessment Feeding Scale (Barnard, 1975). Results revealed a better mother-infant interactive style, a significant decrease in maternal emotional stress, and better infant ability to make requests and respond to parental interactive style in the KMC group. PMID- 28640474 TI - Prenatal views of baby and parenthood: Association with sociodemographic and pregnancy factors. AB - The aim of the present study was to explore whether sociodemographic and pregnancy factors are associated with the content of prenatal maternal representations about the child and maternity. The study was designed as a questionnaire-based, anonymous, cross-sectional study. Participants were 391 pregnant women in routine follow-up visits enrolled from 14 maternity care centers in Southwestern Finland. Measures consisted of self-report questionnaires for background data and adjective lists (i.e., semantic differentials) regarding the mother's prenatal view of this child, herself, child's father, and own mother as-mother. Of the nine background factors explored in this study, two factors had significant associations with the content of prenatal representations: a number of children under 7 years of age in the household and (b) planning of the current pregnancy. Prenatal maternal representations about the child, self, partner, and own mother were more negative in content, especially if the mother already had two to three children under 7 years of age, if this pregnancy was not planned, or both. Background factors which did not have significant associations with the content of any prenatal representations included social class, previous abortions, duration of gestation, and somatic problems in this pregnancy. The results are important considering the previous research findings on the role of prenatal representations for the quality of postnatal maternal interactive behavior with the child, intergenerational transmission of attachment security, and developmental outcome of the child later, even in school age. The factors found in this study to have significance for the content of prenatal representations are routinely asked in all maternity care practice and do not need any arrangements to be explored. The results suggest that professionals working in maternity care should pay more attention to the subgroups of pregnant women with many small children in the family and/or whose pregnancy is unplanned. Their need for support in the relationship with this particular child should be especially attended to. PMID- 28640475 TI - Sustained withdrawal behavior in clinic-referred and nonreferred infants. AB - To examine the relations between infants' sustained withdrawal behavior and children's mental health status and maternal and child relational behavior, 36 clinic-referred and 43 control infants were evaluated. Families were visited at home, mother-child free play and feeding interactions were videotaped, and mothers completed self-report measures. Interactions were coded for sustained withdrawal using the Alarm Distress Baby Scale (ADBB; Guedeney and Fermanian, 2001) and for global relational patterns with the Coding of Interactive Behavior (CIB; Feldman, 1998). Higher ADBB scores were found for the referred group, with many infants (38.9% ) scoring above the clinical cutoff (vs. 11.6% in the control group). More negative relational patterns were found for the withdrawn group in terms of higher maternal intrusiveness, lower reciprocity, and lower child involvement. Associations were found between maternal and child behavior during play and feeding and child sustained withdrawal behavior at play. Sustained withdrawal also was associated with unpredictable child temperament and lower sense of parental self-efficacy. Maternal depressive symptoms were higher in the referred group and correlated with maternal and child relational patterns. The findings contribute to the construct and discriminant validity of the CIB and the ADBB coding systems, and suggest that sustained withdrawal may serve as a risk indicator for early socioemotional disorders. PMID- 28640448 TI - Overview of the Muscle Cytoskeleton. AB - Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease. (c) 2017 American Physiological Society. Compr Physiol 7:891-944, 2017. PMID- 28640476 TI - Histogram analyses of diffusion kurtosis indices and apparent diffusion coefficient in assessing liver regeneration after ALPPS and a comparative study with portal vein ligation. AB - PURPOSE: To investigate the value of diffusion kurtosis imaging (DKI) histogram analysis in assessing liver regeneration and the microstructure basis after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), in comparison with portal vein ligation (PVL). MATERIALS AND METHODS: Thirty rats were divided into the ALPPS, PVL, and control groups. Histograms of DKI using a 3T magnetic resonance imaging (MRI) scanner were performed for corrected apparent diffusion (D), kurtosis (K), and apparent diffusion coefficient (ADC). Mean, median, skewness, kurtosis, and the percentiles (5th , 25th , 50th , 75th , and 95th ) were generated and compared, and radiologic pathologic correlations were evaluated. RESULTS: There were more significant volume increases of the right median lobe after ALPPS than PVL (P = 0.0304/0.0017). The ALPPS group had larger hepatocyte size (P = 0.009/0.000), higher Ki-67 and hepatocyte growth factor expression (P = 0.001-0.036) compared with both PVL and control groups. Mean, median, 5th , 25th , 50th , 75th percentiles of D map in ALPPS were lower than the control group (P = 0.001 0.022). Skewness and 75th , 95th percentiles of K map in ALPPS were higher than the PVL group (P = 0.011-0.042). No differences existed in the ADC map between groups (P = 0.073-0.291). Mean, median, 5th , 25th , 50th percentiles of D map, and 5th percentile of K map showed significant correlations with hepatocyte size (r = -0.582 to -0.426); no significant correlations were found in ADC parameters (P = 0.460-0.934). CONCLUSION: ALPPS induced true accelerated liver hypertrophy, superior to that seen with PVL. Histogram analysis of diffusion kurtosis indices may provide added values in evaluating liver regeneration and the intrinsic microstructure basis after ALPPS in comparison with the standard monoexponential ADC. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: Stage 2 J. Magn. Reson. Imaging 2018;47:729-736. PMID- 28640477 TI - Is a prolonged second stage of labor too long? PMID- 28640478 TI - Usefulness of office examination with narrow band imaging for the diagnosis of head and neck squamous cell carcinoma and follow-up of premalignant lesions. AB - BACKGROUND: The purpose of this study was to evaluate the value of narrow band imaging (NBI) examination in the office for the diagnosis and follow-up of upper airway premalignant and malignant lesions. METHODS: Four hundred eighty lesions were evaluated with white light endoscopy (WLE) and NBI before a biopsy/excision. Additionally, 151 premalignant lesions were followed up without proven biopsy. Carcinoma-free survival was calculated. The learning curve was analyzed. RESULTS: Overall, the accuracy improved from 74.1% with WLE to 88.9% with NBI, being relevant in all anatomic subsites. The accuracy of NBI increased significantly with increasing experience (area under the curve [AUC] >0.9). After a follow-up of 25 months, 14 of 151 lesions (9.3%) converted into carcinoma. The 4-year carcinoma-free survival rate was 86.4%. The 4-year carcinoma-free survival rate differed significantly between lesions classified as benign/mild dysplasia versus those presenting as moderate/severe dysplasia (88.9% vs 73.5%; P = .018). CONCLUSION: The NBI provided a greater accuracy than WLE and showed promising usefulness for the follow-up of premalignant lesions. PMID- 28640479 TI - Visible Light Photocatalysis of 6pi Heterocyclization. AB - Photo-mediated 6pi cyclization is a valuable method for the formation of fused heterocyclic systems. Here we demonstrate that irradiation of cyclic 2 aryloxyketones with blue LED light in the presence of an IrIII complex leads to efficient and high yielding arylation across a panoply of substrates by energy transfer. 2-Arylthioketones and 2-arylaminoketones also cyclize effectively under these conditions. Quantum calculation demonstrates that the reaction proceeds via conrotatory ring closure in the triplet excited state. Subsequent suprafacial 1,4 hydrogen shift and epimerization leads to the observed cis-fused products. PMID- 28640480 TI - Improving the quality of prison research: A qualitative study of ex-offender service user involvement in prison suicide prevention research. AB - BACKGROUND: Suicide is the leading cause of avoidable death in prisons worldwide and suicide prevention is an international priority. Consequently, there is an urgent need to develop evidence-based treatments. We conducted a randomized controlled trial of a novel suicide prevention psychological therapy for male prisoners. To promote ecological validity by addressing the "real-world" situation of suicidal prisoners, we involved a consultant group of ex-offenders with past experience of being suicidal during imprisonment. Service user involvement in prison research is challenging and underdeveloped. OBJECTIVE: We aimed to investigate the ex-offender service user consultants' experiences of being involved in the research. DESIGN: Individual qualitative interviews were conducted and analysed using an Interpretative Phenomenology Analysis (IPA) framework. SETTING/PARTICIPANTS: The study was conducted at a university in North England, UK, comprising four ex-offenders with experience of being suicidal during past imprisonments. RESULTS: Two superordinate themes were identified: "Working Together" depicted participants' perceptions of the pivotal role of good relationships with researchers, and "Journey of Change" outlined how participants' involvement in the research impacted on their personal lives. DISCUSSION: Little is known about how to successfully involve ex-offender service users in research. Our results indicate the conditions necessary for successfully engaging ex-offender service users in research and have important implications for improving the quality of prison research. CONCLUSIONS: Involving forensic service users in research is feasible and should be encouraged, as despite certain challenges, it is highly rewarding both for the research and the ex offender service users. PMID- 28640482 TI - Organogelator-Cellulose Composite for Practical and Eco-Friendly Marine Oil-Spill Recovery. AB - Marine oil spills pose serious threats to the ecosystem and economy. There is much interest in developing sorbents that can tackle such spills. We have developed a novel sorbent by impregnating cellulose pulp with a sugar-derived oleogelator, 1,2:5,6-di-O-cyclohexylidene-mannitol. The gelator molecules mask the surface-exposed hydroxyl groups of cellulose fibrils by engaging them in H bonding and expose their hydrophobic parts making the fibers temporarily hydrophobic (water contact angle 110 degrees ). This sorbent absorbs oil effectively, selectively and instantly from oil-water mixtures due to its hydrophobicity. Then the gelator molecules get released uniformly in the oil and later self-assemble to fibers, as evident from SEM analysis, congealing the oil within the matrix. This hierarchical entrapment of the oil by non-covalent polymeric fibers within a covalent polymer matrix makes the gel very strong (230 fold increase in the yield stress) and rigid, making it suitable for practical use. PMID- 28640481 TI - Using analytic morphomics to describe body composition associated with post kidney transplantation diabetes mellitus. AB - BACKGROUND: Better risk assessment tools are needed to predict post transplantation diabetes mellitus (PTDM). Using analytic morphomic measurements from computed tomography (CT) scans, we aimed to identify specific measures of body composition associated with PTDM. METHODS: We retrospectively reviewed 99 non-diabetic kidney transplant recipients who received pre-transplant CT scans at a single institution between 1/2005 and 5/2014. Analytic morphomic techniques were used to measure abdominal adiposity, abdominal size, and psoas muscle area and density, standardized by gender. We measured the associations of these morphomic factors with PTDM. RESULTS: One-year incidence of PTDM was 18%. The morphomic factors significantly associated with PTDM included visceral fat area (OR=1.84 per standard deviation increase, P=.020), body depth (OR=1.79, P=.035), and total body area (OR=1.67, P=.049). Clinical factors significantly associated with PTDM included African American race (OR=3.01, P=.044), hypertension (OR=2.97, P=.041), and dialysis vintage (OR=1.24 per year on dialysis, P=.048). Body mass index was not associated with PTDM (OR=1.05, P=.188). On multivariate modeling, visceral fat area was an independent predictor of PTDM (OR=1.91, P=.035). CONCLUSIONS: Analytic morphomics can identify pre-transplant measurements of body composition that are predictive of PTDM in kidney transplant recipients. Pre-transplant imaging contains a wealth of underutilized data that may inform PTDM prevention strategies. PMID- 28640483 TI - Decreased cancer-independent life expectancy in the head and neck cancer population. AB - BACKGROUND: Aside from cancer mortality, patients with head and neck cancer have increased mortality risk. Identifying patients with the greatest loss of cancer independent life expectancy can guide comprehensive survivorship programs. METHODS: Age-based survival data from the Surveillance, Epidemiology, and End Result (SEER) database for patients with head and neck cancer were censored for mortality from the index cancer. Life expectancy and years of life lost (YLL) referenced to the general population were calculated. Cox proportional regression models produced hazard ratios (HRs). RESULTS: Cancer-independent life expectancy for patients with head and neck cancer is 6.5 years shorter than expected. The greatest hazard and impact of other-cause mortality was associated with black race (HR 1.23; YLL 8.55), stage IV (HR 1.60; YLL 7.92), Medicaid (HR 1.55; YLL 12.9), and previous marriage (HR 1.49; YLL 11.4). CONCLUSION: Patients with head and neck cancer lives are foreshortened independent of their cancer diagnosis necessitating management of noncancer mortality to maximize overall survival. PMID- 28640484 TI - Reporting of imaging diagnostic accuracy studies with focus on MRI subgroup: Adherence to STARD 2015. AB - PURPOSE: To evaluate adherence of diagnostic accuracy studies in imaging journals to the STAndards for Reporting of Diagnostic accuracy studies (STARD) 2015. The secondary objective was to identify differences in reporting for magnetic resonance imaging (MRI) studies. MATERIALS AND METHODS: MEDLINE was searched for diagnostic accuracy studies published in imaging journals in 2016. Studies were evaluated for adherence to STARD 2015 (30 items, including expanded imaging specific subitems). Evaluation for differences in STARD adherence based on modality, impact factor, journal STARD adoption, country, subspecialty area, study design, and journal was performed. RESULTS: Adherence (n = 142 studies) was 55% (16.6/30 items, SD = 2.2). Index test description (including imaging-specific subitems) and interpretation were frequently reported (>66% of studies); no important differences in reporting of individual items were identified for studies on MRI. Infrequently reported items (<33% of studies) included some critical to generalizability (study setting and location) and assessment of bias (blinding of assessor of reference standard). New STARD 2015 items: sample size calculation, protocol reporting, and registration were infrequently reported. Higher impact factor (IF) journals reported more items than lower IF journals (17.2 vs. 16 items; P = 0.001). STARD adopter journals reported more items than nonadopters (17.5 vs. 16.4 items; P = 0.01). Adherence varied between journals (P = 0.003). No variability for study design (P = 0.32), subspecialty area (P = 0.75), country (P = 0.28), or imaging modality (P = 0.80) was identified. CONCLUSION: Imaging accuracy studies show moderate adherence to STARD 2015, with only minor differences for studies evaluating MRI. This baseline evaluation will guide targeted interventions towards identified deficiencies and help track progress in reporting. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:523-544. PMID- 28640485 TI - Pyrethroid concentrations and persistence following indoor application. AB - Residential indoor environments are potential sources of exposure to pyrethroids, which have low acute toxicity to humans but are allergenic and suspected endocrine disruptors. The present study evaluated the persistence of the pyrethroids cypermethrin and beta-cyfluthrin on indoor surfaces and in house dust. Cypermethrin and beta-cyfluthrin were applied and maintained on aluminum foils and in dust samples for 112 d under controlled conditions and for 12 mo in a test house; periodically, they were quantified by high-performance liquid chromatography. Cypermethrin and beta-cyfluthrin concentrations showed decreases of 10.1% and 7.7% on aluminum foils, and 12.7% and 16.4% in dust, respectively, at 112 d under controlled conditions. In the test house, cypermethrin and beta cyfluthrin concentrations decreased by 40.3% and 60.2% on aluminum foils, and 29.6% and 56.2% in dust at the end of the study. The results show the considerable persistence of cypermethrin and beta-cyfluthrin indoors and indicate the risk of exposure to these products. Environ Toxicol Chem 2017;36:2895-2898. (c) 2017 SETAC. PMID- 28640486 TI - Dendrimer-Based Signal Amplification of Click-Labelled DNA in Situ. AB - The in vivo incorporation of alkyne-modified bases into the genome of cells is today the basis for the efficient detection of cell proliferation. Cells are grown in the presence of ethinyl-dU (EdU), fixed and permeabilised. The incorporated alkynes are then efficiently detected by using azide-containing fluorophores and the CuI -catalysed alkyne-azide click reaction. For a world in which constant improvement in the sensitivity of a given method is driving diagnostic advancement, we developed azide- and alkyne-modified dendrimers that allow the establishment of sandwich-type detection assays that show significantly improved signal intensities and signal-to-noise ratios far beyond that which is currently possible. PMID- 28640488 TI - Commentary: Difficulties assessing social and emotional behavior in large-scale national studies. AB - Innovations in the assessment of emotional development provide new opportunities to track behavioral undercontrol from early childhood to adolescence and adulthood. Less attention is given to the assessment and measurement of negative affect. Questionnaires used to measure emotions and emotion-regulated behavior have strong psychometric properties. Large-scale population studies provide challenges for large assessment batteries and place great pressure for the use of short forms, but it is not always clear that short forms share the psychometrics strengths of their longer versions. Use of narratives provides opportunities to gain deeper insights into the child's experiential world. Overall, the diverse set of measurement tools that has been developed to assess emotion-regulated behavior during the earliest years contributes to our ability to design effective prevention programs or intervention strategies to shift developmental pathways. PMID- 28640487 TI - A qualitative study exploring the difficulties influencing decision making at the end of life for people with dementia. AB - BACKGROUND: Dementia is a progressive neurodegenerative condition characterized by declining functional and cognitive abilities. The quality of end of life care for people with dementia in the UK can be poor. Several difficult decisions may arise at the end of life, relating to the care of the person with dementia, for example management of comorbidities. OBJECTIVE: To explore difficulties in decision making for practitioners and family carers at the end of life for people with dementia. DESIGN: Qualitative methodology using focus groups and semi structured interviews and thematic analysis methods. SETTINGS AND PARTICIPANTS: Former (n=4) and current (n=6) family carers of people with experience of end of life care for a person with dementia were recruited from an English dementia voluntary group in 2015. A further 24 health and care professionals were purposively sampled to include a broad range of expertise and experience in dementia end of life care. RESULTS: Four key themes were identified as follows: challenges of delivering coherent care in dynamic systems; uncertainty amongst decision makers; internal and external conflict amongst decision makers; and a lack of preparedness for the end of life. Overarching difficulties such as poor communication, uncertainty and conflict about the needs of the person with dementia as well as the decision maker's own role can characterize decision making at the end of life. CONCLUSIONS: This study suggests that decision making at the end of life for people with dementia has the potential to be improved. More planning earlier in the course of dementia with an on-going approach to conversation may increase preparedness and family carers' expectations of end of life. PMID- 28640489 TI - New directions in measuring young children's emotional development. PMID- 28640490 TI - Measuring socioemotional functioning in a national birth cohort study. AB - An accumulating body of research suggests that the capacities children acquire that prepare them for learning in formal educational settings are multilevel and complex with multiple contributing factors that begin in infancy. A new U.S. longitudinal study, the Early Childhood Longitudinal Study, Birth Cohort (ECLS B), is designed to enable researchers to examine how an array of children's capacities and skills function individually and jointly to promote or hinder the acquisition of school readiness. The ECLS-B follows a nationally representative sample of 10,688 children born in the U.S. in 2001. Baseline data on the children and their families were collected at 9 months of age with follow-up at ages 2, 4, and kindergarten entry. Information on study children's socioemotional development is derived from several sources: videotaped mother-child interactions, parent interviews, and field staff observations. Because attachment is such an important indicator of children's socioemotional development during the toddler period, the study devoted considerable resources to designing an attachment measure. The Toddler Attachment Sort-45 (TAS-45) was designed to meet the need for a simple yet valid measure that did not require extensive training for field staff to administer easily. The TAS-45 generates the classical attachment categories and security and dependency scores. PMID- 28640491 TI - With a little help from my friends?: Self-regulation in groups of young children. AB - This study examined self-regulation in preschool children (mean age=51 months; 47% boys) using three situational assessments tapping delay of gratification and motor control. Assessments represented a novel adaptation for use with both individual (N=116) and groups (N=44) of four familiar peers in ecologically valid settings. Results suggest that preschoolers demonstrate an increasing ability to self-regulate with age, as well as some evidence for girls performing better than boys on the Gift Wrap situational assessment. Children were less able to demonstrate self-regulation in the peer group context as compared to individual assessments. Differences between age groups and gender were not significant when children were assessed with their peers. The influence of peers on self regulation behavior is a complex relationship with no clear patterns identified in this research. Implications for future research and assessment efforts are discussed. PMID- 28640492 TI - Conundrums in the use of observational measures of socioemotional behavior. AB - The potential for translation of observational measures of social and emotional behavior used in small-scale studies for use in large-, possibly national-scale, studies of child development is currently an unresolved challenge. To begin to address this issue, the advantages and disadvantages to using observational measures of social and emotional behavior are discussed. In addition, alternatives to observational measures that may be helpful in assessing social and emotional behavior are considered with special emphasis on the benefits of cognitive measures. PMID- 28640493 TI - Applying the Infant-Toddler Social & Emotional Assessment (ITSEA) and Brief-ITSEA in early intervention. AB - To examine the internal consistency and validity of the Infant-Toddler Social and Emotional Assessment (ITSEA) and Brief-ITSEA (BITSEA) parent-report questionnaires in an early intervention sample. A sociodemographically diverse sample of 192 parents of 11- to 36-month-old children referred to early intervention programs completed surveys containing the ITSEA, BITSEA, and Child Behavior Checklist (CBCL). Parents were interviewed with the Vineland Adaptive Behavior Scales. Evaluators blind to children's status on the ITSEA and BITSEA rated child behavior during developmental assessments. Finally, a subsample of 71 children was administered the Mullen Scales of Early Learning. Findings support the internal consistency of the ITSEA and BITSEA, with the majority of Cronbach's alphas above .70. Supporting validity, ITSEA and BITSEA problem scores correlated significantly with CBCL Internalizing and Externalizing scores (rs=.28 to .78), as well as with observational ratings of problem behaviors on constructs paralleling the ITSEA domains (rs=.21 to .45). In contrast, ITSEA Competence and BITSEA Competence demonstrated moderate negative associations with CBCL scores (rs=-.39 to -.43). Finally, ITSEA Competence and BITSEA Competence correlated significantly with developmental level on the Mullen, Vineland Socialization, and observational ratings of competence (rs=.25 to .43). Emphasizing the importance of addressing social-emotional issues in early intervention settings, 58.6% of children had high social-emotional/behavioral problems and/or low competence on the ITSEA; 39.8% had high ITSEA Problems and 38.5% had low ITSEA Competence. Results indicate the need to assess social-emotional adjustment in early intervention settings and support the use of the ITSEA and BITSEA for this purpose. PMID- 28640494 TI - Using narratives to assess competencies and risks in young children: Experiences with high risk and normal populations. AB - The young child's mental representations convey a wealth of information about his/her early moral and emotional construction of reality. The MacArthur Story Stem Battery (MSSB) is a unique, child-friendly tool for assessing socioemotional development in young children (3-6 years). The technique provides incomplete stories (stems), which are completed by the child using their own verbalizations and actions with doll figures. A sensitive examiner scaffolds appropriate boundaries for the task. The MSSB has demonstrated adequate psychometric properties and initial studies suggest the MSSB can tap important prosocial competencies as well as features indicative of psychopathology and distress. The MSSB has been translated and used in a number of countries across the world, in part due to the measure's clinical utility to quickly assess children at the level of representation. Current innovations reviewed emphasize the use of the MSSB for assessment in clinical and at-risk populations. A table summarizing key clinically relevant articles on the MSSB is referenced throughout the paper. PMID- 28640495 TI - Control of Mus81 nuclease during the cell cycle. AB - DNA replication and homologous recombination involve the formation of branched DNA structures that physically link chromosomes. Such DNA-based connections, which arise during S-phase, are typically disengaged prior to entry into mitosis, in order to ensure proper chromosome segregation. Exceptions can, however, occur: replication stress, or elevated levels of DNA damage, may cause cells to enter mitosis with unfinished replication as well as carrying recombination intermediates, such as Holliday junctions. Hence, cells are equipped with pathways that recognize and process branched DNA structures, and evolved mechanisms to enhance their function when on the verge of undergoing cell division. One of these pathways utilizes the structure-selective endonuclease Mus81, which is thought to facilitate the resolution of replication and recombination intermediates. Mus81 function is known to be enhanced upon entry into M phase in budding yeast and human cells. Based on recent findings, we discuss here an updated model of Mus81 control during the cell cycle. PMID- 28640496 TI - Distance decay relationships in foliar fungal endophytes are driven by rare taxa. AB - Foliar fungal endophytes represent a diverse and species-rich plant microbiome. Their biogeography provides essential clues to their cryptic relationship with hosts and the environment in which they disperse. We present species composition, diversity, and dispersal patterns of endophytic fungi associated with needles of Pinus taeda trees across regional scales in the absence of strong environmental gradients as well as within individual trees. An empirical designation of rare and abundant taxa enlightens us on the structure of endophyte communities. We report multiple distance-decay patterns consistent with effects of dispersal limitation, largely driven by community changes in rare taxa, those taxonomic units that made up less than 0.31% of reads per sample on average. Distance-decay rates and community structure also depended on specific classes of fungi and were predominantly influenced by rare members of Dothideomycetes. Communities separated by urban areas also revealed stronger effects of distance on community similarity, confirming that host density and diversity plays an important role in symbiont biogeography, which may ultimately lead to a mosaic of functional diversity as well as rare species diversity across landscapes. PMID- 28640497 TI - Multiple asymptomatic papules on the face and thorax. PMID- 28640500 TI - See You in Vienna. PMID- 28640498 TI - Management of proliferative verrucous leukoplakia: Justification for a conservative approach. AB - BACKGROUND: Proliferative verrucous leukoplakia (PVL) is a progressive, multifocal, exophytic form of leukoplakia with high rates of malignant transformation. The purpose of this study was to evaluate a cohort of patients with PVL in a single tertiary referral clinic. METHOD: Cases meeting accepted diagnostic criteria were reviewed with regard to their pathology, demographic characteristics, management, and outcomes. Human papillomavirus (HPV) testing was undertaken on a subset. RESULTS: Almost half of the 48 patients with PVL (48%; n = 23) underwent malignant transformation after a median 23.4 months. The characteristics of this cohort were similar to those previously described, but management was notably more conservative. Conservative management of PVL was used in 92% of our patients, but the clinical outcomes seem comparable with previously described cohorts in which PVL was predominantly treated by surgical excision. All HPV testing was negative. CONCLUSION: Aggressive surgical intervention in the premalignant phase of PVL may not influence the rate of malignant transformation. PMID- 28640499 TI - Triplet Harvesting with a Simple Aromatic Carbonyl. AB - The efficiency of organic light-emitting diodes crucially depends on triplet harvesters. These accept energy from triplet correlated electron hole pairs and convert it into light. Here, experimental evidence is given that simple aromatic carbonyls, such as thioxanthone, could serve this purpose. In these compounds, the emissive 1 pipi* excitation may rapidly equilibrate with an upper triplet state (3 npi*). This equilibrium may persist for nanoseconds. Population of the 3 npi* state via energy transfer from an electron hole pair should result in fluorescence emission and thereby triplet harvesting. To demonstrate the effect, solutions of 1,4-dichlorobenzene (triplet sensitizer) and thioxanthone (harvester) were excited at 266 nm with a nanosecond laser. The emission decay reveals a 100 ns decay absent in the thioxanthone only sample. This matches predictions for an energy transfer limited by diffusion and gives clear evidence that thioxanthone can convert triplet excitations into light. PMID- 28640501 TI - Pruriginous follicular porokeratosis. PMID- 28640502 TI - Erythematous plaques of the vulvo-perineal region: diagnostic role of dermatoscopy. PMID- 28640503 TI - Diary. PMID- 28640504 TI - Sustained Posttransplantation Diabetes Is Associated With Long-Term Major Cardiovascular Events Following Liver Transplantation. AB - Cardiovascular disease is a leading cause of death among liver transplant (LT) recipients. With a rising burden of posttransplantation metabolic disease, increases in cardiovascular-related morbidity and mortality may reduce life expectancy after LT. It is unknown if the risk of long-term major cardiovascular events (MCEs) differs among LT recipients with varying diabetic states. We performed a retrospective cohort study of LT recipients from 2003 through 2013 to compare the incidence of MCEs among patients (1) without diabetes, (2) with pretransplantation diabetes, (3) with de novo transient posttransplantation diabetes, and (4) with de novo sustained posttransplantation diabetes. We analyzed 994 eligible patients (39% without diabetes, 24% with pretransplantation diabetes, 16% with transient posttransplantation diabetes, and 20% with sustained posttransplantation diabetes). Median follow-up was 54.7 months. Overall, 12% of patients experienced a MCE. After adjustment for demographic and clinical variables, sustained posttransplantation diabetes was the only state associated with a significantly increased risk of MCEs (subdistribution hazard ratio 1.95, 95% confidence interval 1.20-3.18). Patients with sustained posttransplantation diabetes mellitus had a 13% and 27% cumulative incidence of MCEs at 5 and 10 years, respectively. While pretransplantation diabetes has traditionally been associated with cardiovascular disease, the long-term risk of MCEs is greatest in LT recipients with sustained posttransplantation diabetes mellitus. PMID- 28640506 TI - Ultrasound training in obstetrics and gynecology in Europe: satisfaction survey. PMID- 28640505 TI - Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N 6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population. AB - Inter-individual differences in arsenic metabolism have been linked to arsenic related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic inorganic arsenic (iAs) metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = -1.9%, 95% CI: -3.3, -0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR = 0.3; 95% CI: 0.1-0.6) and lung cancer (OR = 0.6; 95% CI: 0.2-1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease. Environ. Mol. Mutagen. 58:411 422, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28640507 TI - A liver-specific gene expression panel predicts the differentiation status of in vitro hepatocyte models. AB - : Alternative cell sources, such as three-dimensional organoids and induced pluripotent stem cell-derived cells, might provide a potentially effective approach for both drug development applications and clinical transplantation. For example, the development of cell sources for liver cell-based therapy has been increasingly needed, and liver transplantation is performed for the treatment for patients with severe end-stage liver disease. Differentiated liver cells and three-dimensional organoids are expected to provide new cell sources for tissue models and revolutionary clinical therapies. However, conventional experimental methods confirming the expression levels of liver-specific lineage markers cannot provide complete information regarding the differentiation status or degree of similarity between liver and differentiated cell sources. Therefore, in this study, to overcome several issues associated with the assessment of differentiated liver cells and organoids, we developed a liver-specific gene expression panel (LiGEP) algorithm that presents the degree of liver similarity as a "percentage." We demonstrated that the percentage calculated using the LiGEP algorithm was correlated with the developmental stages of in vivo liver tissues in mice, suggesting that LiGEP can correctly predict developmental stages. Moreover, three-dimensional cultured HepaRG cells and human pluripotent stem cell derived hepatocyte-like cells showed liver similarity scores of 59.14% and 32%, respectively, although general liver-specific markers were detected. CONCLUSION: Our study describes a quantitative and predictive model for differentiated samples, particularly liver-specific cells or organoids; and this model can be further expanded to various tissue-specific organoids; our LiGEP can provide useful information and insights regarding the differentiation status of in vitro liver models. (Hepatology 2017;66:1662-1674). PMID- 28640509 TI - Meeting the needs of critical care patients after discharge home: a qualitative exploratory study of patient perspectives. AB - BACKGROUND: With improved survival rates in critical care, increasing focus is being placed on survivorship and how best to support patients in returning to their former activity. Little is known about what support patients themselves view as important, and this has implications for the efficacy and acceptability of services provided. OBJECTIVES: To describe former critical care patients' perspectives on the support needed to optimize recovery. STUDY DESIGN: This is a qualitative exploratory study of the experiences of support received by critical care survivors. RESEARCH METHODOLOGY: Semi-structured interviews were undertaken with 12 critical care survivors recruited from a charity and a patient and public involvement group. The interviews were analysed using thematic analysis to describe patterns in the participants' experiences. FINDINGS: Four themes of support were described: effective management of transfer anxiety, tailored information provision, timely access to services and a supportive social network. CONCLUSION: Survivors of critical care should be equipped with information about their critical care stay, ongoing health issues and recovery and should be provided with holistic care at home. Critical care follow up was an effective way of meeting many of these needs, but this needs to be flexible to be useful to attendees. Peer support groups (face-to-face and online) provided information, reassurance, a social network and an avenue for those who had longer-lasting problems than current services provide for. RELEVANCE TO CLINICAL PRACTICE: Whilst there are commonalities in the problems faced by critical care survivors, recovery is highly individualized, and current support services do not have sufficient flexibility to cater for this. This study shows that many survivors experience after-effects of critical care that outlast the support they are given. These longer-term survivors are often excluded from research studies because of fears of recall bias, resulting in poor understanding of their experiences. PMID- 28640508 TI - Intraglomerular gap junctions enhance interglomerular synchrony in a sparsely connected olfactory bulb network. AB - KEY POINTS: Despite sparse connectivity, population-level interactions between mitral cells (MCs) and granule cells (GCs) can generate synchronized oscillations in the rodent olfactory bulb. Intraglomerular gap junctions between MCs at the same glomerulus can greatly enhance synchronized activity of MCs at different glomeruli. The facilitating effect of intraglomerular gap junctions on interglomerular synchrony is through triggering of mutually synchronizing interactions between MCs and GCs. Divergent connections between MCs and GCs make minimal direct contribution to synchronous activity. ABSTRACT: A dominant feature of the olfactory bulb response to odour is fast synchronized oscillations at beta (15-40 Hz) or gamma (40-90 Hz) frequencies, thought to be involved in integration of olfactory signals. Mechanistically, the bulb presents an interesting case study for understanding how beta/gamma oscillations arise. Fast oscillatory synchrony in the activity of output mitral cells (MCs) appears to result from interactions with GABAergic granule cells (GCs), yet the incidence of MC-GC connections is very low, around 4%. Here, we combined computational and experimental approaches to examine how oscillatory synchrony can nevertheless arise, focusing mainly on activity between 'non-sister' MCs affiliated with different glomeruli (interglomerular synchrony). In a sparsely connected model of MCs and GCs, we found first that interglomerular synchrony was generally quite low, but could be increased by a factor of 4 by physiological levels of gap junctional coupling between sister MCs at the same glomerulus. This effect was due to enhanced mutually synchronizing interactions between MC and GC populations. The potent role of gap junctions was confirmed in patch-clamp recordings in bulb slices from wild-type and connexin 36-knockout (KO) mice. KO reduced both beta and gamma local field potential oscillations as well as synchrony of inhibitory signals in pairs of non-sister MCs. These effects were independent of potential KO actions on network excitation. Divergent synaptic connections did not contribute directly to the vast majority of synchronized signals. Thus, in a sparsely connected network, gap junctions between a small subset of cells can, through population effects, greatly amplify oscillatory synchrony amongst unconnected cells. PMID- 28640511 TI - Tropical Medicine & International Health March 2014. PMID- 28640510 TI - Paediatric intensive care nurses' decision-making around gastric residual volume measurement. AB - BACKGROUND: Measuring gastric residual volume (GRV) to guide enteral feeding is a common nursing practice in intensive care units, yet little evidence supports this practice. In addition, this practice has been shown to potentially contribute to inadequate energy delivery in intensive care, which remains a problem in critically ill children. AIMS: We aimed to explore paediatric intensive care nurses' decision-making surrounding this practice. METHODS: This is a cross-sectional electronic survey in a single mixed general and cardiac surgical PICU in the UK. RESULTS: The response rate was 59% (91/154), and responding nurses were experienced, with a mean PICU experience of 10.5 years (SD 8.09). The three main reasons for stopping or withholding enteral feeds were: the volume of GRV obtained (67%), the appearance of this gastric aspirate (40%) and the overall clinical condition of the child (23%). Most nurses reported checking GRV primarily to determine 'feed tolerance' (97%) as well as confirming feeding tube position (94%). Nurses' perceived harms from high GRV were: the risk of pulmonary aspiration (44%), malabsorption of feeds (20%) and the risk of vomiting (19%). GRV was measured frequently in this PICU, with 58% measuring GRV before every feed, 27% measuring every 4 h and 17% measuring every 6 h. The majority of nurses (84%) stated they would be worried or very worried if they could not measure GRV routinely. CONCLUSIONS: PICU nurses' decision-making surrounding initiating and withholding enteral feeds and determining 'feed tolerance' remains heavily based on GRV. PICU nurses have significant fears around patient harm if they do not measure GRV routinely. RELEVANCE TO CLINICAL PRACTICE: This nursing practice is likely to be one of the factors that impair the delivery of enteral nutrition in critically ill children, and as such, its validity and usefulness needs to be challenged and studied in future research. PMID- 28640512 TI - A major responder to ipilimumab and nivolumab in metastatic uveal melanoma with concomitant autoimmunity. AB - The use of immune checkpoint inhibition has led to major improvements in outcome for patients with metastatic cutaneous melanoma. The combination of ipilimumab and nivolumab has demonstrated greater activity over single-agent immunotherapy in phase III trials. Clinical trials of combination CTLA-4 and PD-1 inhibition are underway in uveal melanoma, for which there are currently no data. Here, we present the case of a 74-year-old male patient with metastatic uveal melanoma, who was treated with a combination of ipilimumab and nivolumab. He developed sequential autoimmune transaminitis, diabetes and uveitis, which necessitated discontinuation of maintenance nivolumab 3 months after commencement of treatment. The patient continues to demonstrate an ongoing partial response 10 months from the initial combination immunotherapy, with the evidence of depigmentation of the primary ocular tumour. PMID- 28640513 TI - Mechanistic Insight into Nanoparticle Surface Adsorption by Solution NMR Spectroscopy in an Aqueous Gel. AB - Engineering nanoparticle (NP) functions at the molecular level requires a detailed understanding of the dynamic processes occurring at the NP surface. Herein we show that a combination of dark-state exchange saturation transfer (DEST) and relaxation dispersion (RD) NMR experiments on gel-stabilized NP samples enables the accurate determination of the kinetics and thermodynamics of adsorption. We used the former approach to describe the interaction of cholic acid (CA) and phenol (PhOH) with ceria NPs with a diameter of approximately 200 nm. Whereas CA formed weak interactions with the NPs, PhOH was tightly bound to the NP surface. Interestingly, we found that the adsorption of PhOH proceeds via an intermediate, weakly bound state in which the small molecule has residual degrees of rotational diffusion. We believe the use of aqueous gels for stabilizing NP samples will increase the applicability of solution NMR methods to the characterization of nanomaterials. PMID- 28640515 TI - Carbon Dots as Fillers Inducing Healing/Self-Healing and Anticorrosion Properties in Polymers. AB - Self-healing is the way by which nature repairs damage and prolongs the life of bio entities. A variety of practical applications require self-healing materials in general and self-healing polymers in particular. Different (complex) methods provide the rebonding of broken bonds, suppressing crack, or local damage propagation. Here, a simple, versatile, and cost-effective methodology is reported for initiating healing in bulk polymers and self-healing and anticorrosion properties in polymer coatings: introduction of carbon dots (CDs), 5 nm sized carbon nanocrystallites, into the polymer matrix forming a composite. The CDs are blended into polymethacrylate, polyurethane, and other common polymers. The healing/self-healing process is initiated by interfacial bonding (covalent, hydrogen, and van der Waals bonding) between the CDs and the polymer matrix and can be optimized by modifying the functional groups which terminate the CDs. The healing properties of the bulk polymer-CD composites are evaluated by comparing the tensile strength of pristine (bulk and coatings) composites to those of fractured composites that are healed and by following the self-healing of scratches intentionally introduced to polymer-CD composite coatings. The composite coatings not only possess self-healing properties but also have superior anticorrosion properties compared to those of the pure polymer coatings. PMID- 28640514 TI - De-novo abnormal uteroplacental circulation in third trimester: pregnancy outcome and pathological implications. AB - OBJECTIVE: Hypertensive disorders of pregnancy (HDP) are associated with impaired placentation, as evidenced by abnormal uterine artery (UtA) Doppler. In normal pregnancy, mean UtA pulsatility index (PI) shows a progressive decline with gestational age (GA). However, previous studies have reported that a proportion of pregnancies demonstrate worsening UtA Doppler in later pregnancy. The aim of this study was to investigate the incidence of HDP according to the change in mean UtA-PI between the second and third trimesters. METHODS: This was a retrospective cohort study of singleton pregnancies between March 1997 and March 2016 that underwent longitudinal UtA Doppler assessment in the second and third trimesters. All parameters were converted into centiles or multiples of the median (MoM), adjusting for GA. The study cohort was divided into two groups, according to change in mean UtA-PI between the second and third trimesters (those with a decrease or no change and those with an increase). HDP included women who developed pre-eclampsia and/or gestational hypertension. Logistic regression analysis was used to adjust for potential confounders. RESULTS: The analysis included 5887 pregnancies. The incidence of HDP was significantly higher in the group with increasing mean UtA-PI compared with those without (7.9% vs 5.8%; P = 0.002). Logistic regression analysis demonstrated that both third-trimester UtA PI MoM (odds ratio (OR), 7.35; 95% CI, 4.66-11.6; P < 0.001) and stable or decrease in UtA-PI MoM between the second and third trimesters (OR, 0.43; 95% CI, 0.31-0.60; P < 0.001) were significant independent predictors for the development of HDP. CONCLUSION: Worsening of UtA Doppler is associated with HDP, independent of the value recorded in the second trimester. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28640516 TI - DAMP molecular IL-33 augments monocytic inflammatory storm in hepatitis B precipitated acute-on-chronic liver failure. AB - BACKGROUND & AIMS: Patients with acute-on-chronic liver failure (ACLF) usually exhibit defective monocyte function and excessive systemic inflammatory response. Interleukin-33 (IL-33) acts as a danger-associated molecular pattern (DAMP) to modulate immune response. However, the role of IL-33 in regulating monocyte function during hepatitis B-precipitated ACLF (HB-ACLF) in response to lipopolysaccharide (LPS) has not been clear. METHODS: In this study, the levels of IL-33/ST2 in blood and liver samples collected from patients with HB-ACLF, chronic hepatitis B (CHB) and normal controls and the associated of those findings with disease severity were analysed. HLA-DR and CD80 expression, phagocytosis capacity, cytokine secretion and MAP kinase activation induced by LPS were detected to explore the role of IL-33/ST2 signal in regulating monocyte function in patients. RESULTS: The expression levels of IL-33/ST2 were significantly increased in peripheral blood and livers of patients with HB-ACLF, as compared with patients with CHB and controls. It was found that serum IL-33 level was associated with severity of liver disease. Treatment with IL-33 on monocytes significantly increased HLA-DR, CCR2 and CD80 expression, enhanced LPS stimulated TNF-alpha, IL-6 and IL-1beta secretion, but did not affect the phagocytic capacity. Furthermore, IL-33 signalling enhanced the ERK1/2 activation of monocytes in response to LPS. CONCLUSIONS: DAMP molecular IL-33 augmented the 'storm' of monocytic inflammation in response to LPS through ERK1/2 activation during HB-ACLF. PMID- 28640517 TI - Hepatocellular carcinoma in South America: Evaluation of risk factors, demographics and therapy. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Most studies addressing the epidemiology of HCC originate from developed countries. This study reports the preliminary findings of a multinational approach to characterize HCC in South America. METHODS: We evaluated 1336 HCC patients seen at 14 centres in six South American countries using a retrospective study design with participating centres completing a template chart of patient characteristics. The diagnosis of HCC was made radiographically or histologically for all cases according to institutional standards. Methodology of surveillance for each centre was following AASLD or EASL recommendations. RESULTS: Sixty-eight percent of individuals were male with a median age of 64 years at time of diagnosis. The most common risk factor for HCC was hepatitis C infection (HCV, 48%), followed by alcoholic cirrhosis (22%), Hepatitis B infection (HBV, 14%) and NAFLD (9%). We found that among individuals with HBV-related HCC, 38% were diagnosed before age 50. The most commonly provided therapy was transarterial chemoembolization (35% of HCCs) with few individuals being considered for liver transplant (<20%). Only 47% of HCCs were diagnosed during surveillance, and there was no difference in age of diagnosis between those diagnosed incidentally vs by surveillance. Nonetheless, being diagnosed during surveillance was associated with improved overall survival (P = .01). CONCLUSIONS: Our study represents the largest cohort to date reporting characteristics and outcomes of HCC across South America. We found an important number of HCCs diagnosed outside of surveillance programmes, with associated increased mortality in those patients. PMID- 28640519 TI - A solitary reddish nodule on the upper back of a middle-aged woman. PMID- 28640518 TI - A Carborane-Containing Fluorophore as a Stain of Cellular Lipid Droplets. AB - The use of fluorescent markers and probes greatly enhances biological investigations but relies on the provision of an array of fluorophores with diverse properties. Herein we report a novel carborane-containing coumarin, 5, which is sufficiently lipophilic to localise in cellular lipid droplets. In non polar solvents which show comparable polarities to those of a lipid environment, compound 5 exhibits a fluorescence quantum yield two orders of magnitude greater than found in aqueous solvents, adding a further degree of selectivity to lipid droplet imaging. Compound 5 can stain lipid droplets in ex vivo adipocytes as well as in cultured cells, and can be utilised in flow cytometry as well as confocal microscopy. PMID- 28640520 TI - Helicobacter pylori Seropositivity and Childhood Neurodevelopment, the Rhea Birth Cohort in Crete, Greece. AB - BACKGROUND: Limited evidence exists on the association between exposure to Helicobacter pylori infection early in life, including fetal life, and neurodevelopment in childhood. METHODS: We used prospective data on 352 mother child pairs and cross-sectional data on 674 children to assess the association of maternal and child's H. pylori seropositivity correspondingly on child's neurodevelopment at age four in the Rhea birth cohort in Crete, Greece. Blood levels of immunoglobulin G antibodies to 12 H. pylori proteins were measured using multiplex serology. Child's neurodevelopment at age four was assessed using the McCarthy Scales of Children's Abilities. Linear regression models were used to explore the associations after adjusting for potential confounders. RESULTS: Helicobacter pylori seroprevalence (95% CI) in cord blood, representing maternal status, was 41.5% (36.3%, 46.8%) and in 4 years old children was 6.5% (95% CI 4.8%, 8.7%). Children of H. pylori seropositive mothers had lower score in the general cognitive (-3.87, 95% CI -7.02, -0.72), verbal (-2.96, 95% CI -6.08, 0.15), perceptual performance (-3.37, 95% CI -6.60, -0.15), quantitative (-2.85, 95% CI -6.28, 0.58), and memory scale (-3.37, 95% CI -6.67, -0.07) compared to those of seronegative mothers. Seropositivity in cord blood specifically to GroEl and NapA - two of the 12 H. pylori proteins investigated - was associated with lower scores in almost all scales. At age four, H. pylori seropositive children performed worst in neurodevelopment assessment compared to their seronegative counterparts although no association reached statistically significant level. CONCLUSIONS: Helicobacter pylori infection in early life may be an important but preventable risk factor for poor neurodevelopment. PMID- 28640521 TI - PET/MRI for evaluating subclinical inflammation of ulcerative colitis. AB - PURPOSE: To explore the utility of integrated positron emission tomography (PET) / magnetic resonance imaging (MRI) for evaluating subclinical inflammation in patients with ulcerative colitis (UC). MATERIALS AND METHODS: This prospective study was approved by the Institutional Review Board and informed consent was obtained. Between November 2015 and April 2016, 19 consecutive patients with UC in clinical remission were enrolled. These patients underwent 18F fluorodeoxyglucose PET/MRI (3T) and colonoscopy. Serum high-sensitivity C reactive protein (hs-CRP) and fecal calprotectin (FC) levels were also obtained. The findings of colonoscopy were graded using the Mayo endoscopic subscore. Quantitative (minimum apparent diffusion coefficient [ADCmin ] and maximum standardized uptake value [SUVmax ]), semiquantitative, and qualitative parameters of PET/MRI were evaluated and correlated with colonoscopic findings. RESULTS: In per-segment analysis, ADCmin was significantly lower and SUVmax and ratio of SUVmax to ADCmin were significantly higher in the colonic segments with active inflammation (Mayo endoscopic subscore >=2) (P < 0.05). Qualitative MRI score, PET activity grade, and PET/MRI score were also significantly higher in the colonic segments with active inflammation (P < 0.05). Among these parameters, the ratio of SUVmax to ADCmin exhibited the highest area under the receiver operating characteristic curve (AUC) (0.763). In per-patient analysis, the AUC of PET activity grade was 0.778, higher than those of hs-CRP (0.589) and FC (0.722). Using a combined index of FC and PET, an even higher AUC (0.867) was achieved. CONCLUSION: PET/MRI is a potentially useful tool in identifying subclinical inflammation in patients with UC. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:737-745. PMID- 28640522 TI - Defective Tungsten Oxide Hydrate Nanosheets for Boosting Aerobic Coupling of Amines: Synergistic Catalysis by Oxygen Vacancies and Bronsted Acid Sites. AB - Adsorption and activation of molecules on a surface holds the key to heterogeneous catalysis toward aerobic oxidative reactions. To achieve high catalytic activities, a catalyst surface should be rationally tailored to interact with both organic substrates and oxygen molecules. Here, a facile bottom up approach to defective tungsten oxide hydrate (WO3 .H2 O) nanosheets that contain both surface defects and lattice water is reported. The defective WO3 .H2 O nanosheets exhibit excellent catalytic activity for aerobic coupling of amines to imines. The investigation indicates that the oxygen vacancies derived from surface defects supply coordinatively unsaturated sites to adsorb and activate oxygen molecules, producing superoxide radicals. More importantly, the Bronsted acid sites from lattice water can contribute to enhancing the adsorption and activation of alkaline amine molecules. The synergistic effect of oxygen vacancies and Bronsted acid sites eventually boosts the catalytic activity, which achieves a kinetic rate constant of 0.455 h-1 and a turnover frequency of 0.85 h 1 at 2 h, with the activation energy reduced to ~35 kJ mol-1 . This work provides a different angle for metal oxide catalyst design by maneuvering subtle structural features, and highlights the importance of synergistic effects to heterogeneous catalysts. PMID- 28640523 TI - Computer-aided diagnostics in digital pathology. PMID- 28640524 TI - Carbon-Coated Li3 VO4 Spheres as Constituents of an Advanced Anode Material for High-Rate Long-Life Lithium-Ion Batteries. AB - Lithium-ion batteries are receiving considerable attention for large-scale energy storage systems. However, to date the current cathode/anode system cannot satisfy safety, cost, and performance requirements for such applications. Here, a lithium ion full battery based on the combination of a Li3 VO4 anode with a LiNi0.5 Mn1.5 O4 cathode is reported, which displays a better performance than existing systems. Carbon-coated Li3 VO4 spheres comprising nanoscale carbon-coating primary particles are synthesized by a morphology-inheritance route. The observed high capacity combined with excellent sample stability and high rate capability of carbon-coated Li3 VO4 spheres is superior to other insertion anode materials. A high-performance full lithium-ion battery is fabricated by using the carbon coated Li3 VO4 spheres as the anode and LiNi0.5 Mn1.5 O4 spheres as the cathode; such a cell shows an estimated practical energy density of 205 W h kg-1 with greatly improved properties such as pronounced long-term cyclability, and rapid charge and discharge. PMID- 28640525 TI - Early stages in the biogenesis of eukaryotic beta-barrel proteins. AB - The endosymbiotic organelles mitochondria and chloroplasts harbour, similarly to their prokaryotic progenitors, beta-barrel proteins in their outer membrane. These proteins are encoded on nuclear DNA, translated on cytosolic ribosomes and imported into their target organelles by a dedicated machinery. Recent studies have provided insights into the import into the organelles and the membrane insertion of these proteins. Although the cytosolic stages of their biogenesis are less well defined, it is speculated that upon their synthesis, chaperones prevent beta-barrel proteins from aggregation and keep them in an import competent conformation. In this Review, we summarize the current knowledge about the biogenesis of beta-barrel proteins, focusing on the early stages from the translation on cytosolic ribosomes to the recognition on the surface of the organelle. PMID- 28640527 TI - Is it time for Timm? (a case history). PMID- 28640526 TI - Development and characterization of a 99m Tc-tricarbonyl-labelled estradiol derivative obtained by "Click Chemistry" with potential application in estrogen receptors imaging. AB - Assessment of the presence of estrogen receptors in breast cancer is crucial for treatment planning. With the objective to develop a potential agent for estrogen receptors imaging, we present the development and characterization of a 99m Tc tricarbonyl-labelled estradiol derivative. Using ethinylestradiol as starting material, an estradiol derivative bearing a 1,4-disubstituted 1,2,3-triazole containing tridentate ligand system was synthesized by "Click Chemistry" and fully characterized. Labelling with high yield and radiochemical purity was achieved through the formation of a 99m Tc-tricarbonyl complex. The radiolabelled compound was stable, exhibited moderate binding to plasma protein (approximately 33%) and lipophilicity in the adequate range (logP 1.3 +/- 0.1 at pH 7.4). Studies in MCF7 showed promising uptake values (approximately 2%). However, more than 50% of the activity is quickly released from the cell. Biodistribution experiments in normal rats confirmed the expected "in vivo" stability of the radiotracer but showed very high gastrointestinal and liver activity, which is inconvenient for in vivo applications. Taking into consideration the well documented influence of the chelating system in the physicochemical and biological behaviour of technetium-labelled small biomolecules, research will be continued using the same pharmacophore but different complexation modalities of technetium. PMID- 28640528 TI - Evaluation of a novel metal-organic framework as an adsorbent for the extraction of multiclass pesticides from coconut palm (Cocos nucifera L.): An analytical approach using matrix solid-phase dispersion and liquid chromatography. AB - We report the synthesis, characterization, and application of [Zn(1,4 benzenedicarboxylate)(H2 O)2 ]n , Zn(1,4-benzenedicarboxylate)0.99 (NH2 -1,4 benzenedicarboxylate)0.01 (H2 O)2 ]n , [Zn(1,4-benzenedicarboxylate)0.95 (NH2 1,4-benzenedicarboxylate)0.05 (H2 O)2 ]n , and [Zn(1,4-benzenedicarboxylate)0.9 (NH2 -1,4-benzenedicarboxylate)0.1 (H2 O)2 ]n as sorbents for the extraction of multiclass pesticides from coconut palm. Liquid chromatography with ultraviolet diode array detection was used as the analysis technique, and the experiments were performed at one fortification level (0.1 MUg/g). The recoveries were 47-67, 51-70, 58-72, and 64-76% for [Zn(1,4-benzenedicarboxylate)(H2 O)2 ]n , Zn(1,4 benzenedicarboxylate)0.99 (NH2 -1,4-benzenedicarboxylate)0.01 (H2 O)2 ]n , [Zn(1,4-benzenedicarboxylate)0.95 (NH2 -1,4-benzenedicarboxylate)0.05 (H2 O)2 ]n , and [Zn(1,4-benzenelate)0.95 (NH2 -1,4-benzenedicarboxylate)0.05 (H2 O)2 ]n , and [Zn(1,4-benzenedicarboxylate)0.9 (NH2 -1,4-benzenedicarboxylate)0.1 (H2 O)2 ]n , respectively, with relative standard deviation ranging from 1 to 7% (n = 3). Detection and quantification limits were 0.01-0.05 and 0.05-0.2 MUg/g, respectively, for the different pesticides studied. The method developed was linear over the range tested (0.01-10.0 MUg/g) with r2 > 0.9991. A direct comparison of [Zn(1,4-benzenedicarboxylate)0.9 (NH2 -1,4-benzenedicarboxylate)0.1 (H2 O)2 ]n with the commercially available neutral alumina showed that [Zn(1,4 benzenedicarboxylate)0.9 (NH2 -1,4-benzenedicarboxylate)0.1 (H2 O)2 ]n was a similar extracting phase for the pesticides investigated. PMID- 28640529 TI - Effect of everolimus vs calcineurin inhibitors on quality of life in heart transplant recipients during a 3-year follow-up: Results of a randomized controlled trial (SCHEDULE). AB - The Scandinavian heart transplant everolimus de novo study with early calcineurin inhibitors avoidance (SCHEDULE) trial was a 12 month, randomized, open-label, parallel-group trial that compared everolimus (EVR; n=56) to conventional CsA (n=59) immunosuppression. Previously, we reported that EVR outperformed CsA in improving renal function and coronary artery vasculopathy, despite a higher rejection rate with EVR. This study aimed to compare the effects of these treatments on quality of life (QoL). Within five post-operative days, patients (mean age 50+/-13 years, 27% women) were randomized to EVR or a standard CsA dosage (CsA group). This study assessed quality of life (QoL), based on the Short Form-36, EuroQol-5D, and Beck Depression Inventory (BDI). Assessments were performed pre-HTx and 12 and 36 months post-HTx. At 12 and 36 months, the groups showed similar improvements in Short Form-36 measures (at pre-HTx, 12 and 36 months the values were as follows: Physical component summary: EVR: 31.5+/-110.9, 49.1+/-9.7, and 47.9+/-10.6; P<.01; CsA: 32.5+/-8.2, 48.4+/-8.5, and 46.5+/-11.5; P<.01; mental component summary: EVR: 46.0+/-12.0, 51.7+/-11.9, and 52.1+/-13.0; P<.01; CsA: 38.2+/-12.5, 53.4+/-7.1, and 54.3+/-13.0; P<.01); similar decrease in mean BDI (EVR: 10.9+/-10.2, 5.4+/-4.7, and 8.1+/-9.0; P<.01; CsA: 11.8+/-7.1, 6.3+/-5.4, and 6.2+/-6.5; P<.01); and similar Euro Qol-improvements. Thus, in this small-sized study, EVR-based and conventional CsA immunosuppressive strategies produced similar QoL improvements. PMID- 28640530 TI - How does age affect the outcome of kidney transplantation in elderly recipients? AB - The aging of the on-dialysis population raises the issue of whether to propose elderly patients for kidney transplantation and how to manage their immunosuppression. This study aimed to analyze the outcome of kidney transplantation on an Italian series of elderly recipients. We included in this retrospective study all patients over 60 years, receiving a deceased-donor kidney transplantation from January 2004 to December 2014 in two north Italian Centers. We analyzed the correlation of recipient age with graft's and patient's survival, delayed graft function, acute cellular rejection (ACR), surgical complications, infections, and glomerular filtration rate. Four hundred and fifty-two patients with a median age of 65 years were included in the study. One-, 3-, and 5-year patient's and graft's survival were, respectively, of 98.7%, 93%, 89% and 94.4%, 87.9%, 81.4%. The increasing recipient age was an independent risk factor only for the patient's (P=.008) and graft's survival (P=.002). ACR and neoplasia were also associated to a worse graft survival. The reduced graft survival in elderly kidney recipients seems to be related more to the increasing recipient's age than to the donor's features. In this population, the optimization of organ allocation and immunosuppression may be the key factors to endorse improvements. PMID- 28640532 TI - Nonvolatile Perovskite-Based Photomemory with a Multilevel Memory Behavior. AB - Solution-processable organic-inorganic hybrid perovskite materials with a wealth of exotic semiconducting properties have appeared as the promising front-runners for next-generation electronic devices. Further, regarding its well photoresponsibility, various perovskite-based photosensing devices are prosperously developed in recent years. However, most exploited devices to date only transiently transduce the optical signals into electrical circuits while under illumination, which necessitates using additional converters to further store the output signals for recording the occurrence of light stimulation. Herein, a nonvolatile perovskite-based floating-gate photomemory with a multilevel memory behavior is demonstrated, for which a floating gate comprising a polymer matrix impregnated with perovskite nanoparticles is employed. Owing to the well photoresponsibility introduced by the embedded nanoparticles, the device is enabled to access multiple wavelength response and the functionalities of recording power/time-dependent illumination under no vertical electrical field. Intriguingly, a nonvolatility of photorecording exceeding three months with a high On/Off current ratio over 104 can be achieved. PMID- 28640531 TI - Apparent diffusion coefficient in estrogen receptor-positive and lymph node negative invasive breast cancers at 3.0T DW-MRI: A potential predictor for an oncotype Dx test recurrence score. AB - PURPOSE: To measure the apparent diffusion coefficient (ADC) values in estrogen receptor-positive (ER+) and axillary lymph node-negative (LN-) invasive breast cancer and investigate the correlation of ADC with Oncotype Dx test recurrence scores (ODxRS). MATERIALS AND METHODS: This was a Health Insurance Portability and Accountability Act (HIPAA)-compliant single-site retrospective study. Patients underwent preoperative 3.0T MRI scans with additional diffusion-weighted imaging sequential scans (b = 0, 600 and b = 0, 1000 s/mm2 ) from January 2011 to 2013. The study population included 31 ER+/LN- invasive breast cancers, which underwent ODxRS genomic testing. ADC600 and ADC1000 parametric maps were generated, and ADC values were calculated from a user-drawn region of interest. ODxRS predicts 10-year recurrence risk in individual patients: low (RS <18), intermediate (RS: 18-30), or high (RS >30). All breast lesions, including subgroups of invasive ductal carcinoma (IDC) lesions and mass-only lesions were dichotomized by RS scores, low-risk versus intermediate/high-risk, and statistical analysis was performed using Mann-Whitney's test (statistical significance at P < 0.05) and receiver operating characteristic (ROC) curves. Multivariate analysis was also performed. RESULTS: Invasive breast cancers, when scored as low-risk by ODxRS, had significantly higher ADC values compared with intermediate/high-risk lesions for both ADC600 (P = 0.007) and ADC1000 (P = 0.008) mean values. This was true both when analyzing only mass-lesions (P = 0.03 and 0.01) or only IDCs (P = 0.001 and 0.009). CONCLUSION: Preliminary findings suggest that lesion ADC values correlate with recurrence risk likelihood stratified using ODxRS. Hence, ADC is a potential surrogate biomarker for tumor aggressiveness. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:401-409. PMID- 28640533 TI - High-risk squamous cell carcinoma of the ear - A potential role for sentinel node biopsy. AB - BACKGROUND: Squamous cell carcinomas (SCCs) of the external ear have a significant rate of metastasis. The purpose of this study was to present analyzed factors associated with auricular SCC metastasis in order to identify a group that may benefit from sentinel lymph node biopsy (SLNB). METHODS: We performed a retrospective review of all operable SCCs between 2009 and 2014. The association between high-risk features and metastasis were analyzed. RESULTS: One hundred eighty-nine auricular SCCs were excised. Local recurrence was noted in 11% and 9.5% developed metastases. Cartilage, perineural, and lymphovascular invasion were significantly associated with metastasis, as were increased tumor depth and diameter (P < .001). All patients with metastasis developed nodal disease. CONCLUSION: Factors, including poor differentiation, perineural, cartilage, and lymphovascular invasion, are associated with auricular SCC metastasis. Patients with 2 or more high-risk features may benefit from SLNB in order to identify and treat early nodal disease and possibly reduce the risk of further spread. PMID- 28640534 TI - Dynamics of transcriptomic response to infection by the nematode Heterorhabditis bacteriophora and its bacterial symbiont Photorhabdus temperata in Heliothis virescens larvae. AB - Entomopathogenic nematodes in the Heterorhabditis genus and their symbiotic Photorhabdus bacteria are important biocontrol agents of insect pests and models for the study of microbe-host interactions. In this work, we used larvae of the tobacco budworm (Heliothis virescens) as a model to study its defensive mechanisms against Heterorhabditis bacteriophora nematodes carrying symbiotic Photorhabdus temperata. We first determined time points of initial nematode entry and release of bacteria into the haemolymph to perform transcriptional analysis of insect gene expression during these steps in the infective process. RNA Sequencing analyses were then performed to profile differential gene expression in the insect during nematode invasion, bacterial release and final steps of infection, relative to the untreated controls. Our results support the theory that insect immune response genes are induced upon nematode invasion, but the majority of these genes are suppressed upon the release of bacteria by the nematodes into the haemolymph. Overall, these findings provide information on the dynamics of the insect's response to a progressing infection by this entomopathogenic nematode-bacteria complex and facilitate development of Hel. virescens as a pest model for future functional studies of the key insect defence factors. PMID- 28640535 TI - Reply. PMID- 28640536 TI - Dynamic Self-Assembly of Magnetic/Polymer Composites in Rotating Frames of Reference. AB - Small ferromagnetic particles suspended in a rotating viscous polymer and subjected to an external static magnetic field dynamically self-assemble into open-lattice, periodic structures. Depending on the orientation of the magnetic field with respect to the system's axis of rotation, these structures range from arrays of parallel plates to single, double, triple, or even quaternary helices. Dynamic self-assembly in this rotating frame of reference can be explained by an interplay between magnetic, dipole-dipole, viscous drag, and centripetal forces. Once formed, the dynamic aggregates can be made permanent by thermally curing the polymer matrix. PMID- 28640537 TI - Changes in the biomechanical properties of a single cell induced by nonthermal atmospheric pressure micro-dielectric barrier discharge plasma. AB - Mechanical properties of a single cell are closely related to the fate and functions of the cell. Changes in mechanical properties may cause diseases or cell apoptosis. Selective cytotoxic effects of nonthermal atmospheric pressure micro-dielectric barrier discharge (DBD) plasma have been demonstrated on cancer cells. In this work, changes in the mechanical properties of a single cell induced by nonthermal atmospheric pressure micro-DBD plasma were investigated using atomic force microscopy (AFM). Two cervical cancer cell lines (HeLa and SiHa) and normal human fibroblast cells (HFBs) were exposed to micro-DBD plasma for various exposure times. The elasticity of a single cell was determined by force-distance curve measurement using AFM. Young's modulus was decreased by plasma treatment for all cells. The Young's modulus of plasma-treated HeLa cells was decreased by 75% compared to nontreated HeLa cells. In SiHa cells and HFBs, elasticity was decreased slightly. Chemical changes induced by the plasma treatment, which were observed by Raman spectroscopy, were also significant in HeLa cells compared to SiHa cells and HFBs. These results suggested that the molecular changes induced by micro-DBD plasma were related to cell mechanical changes. PMID- 28640539 TI - Levels of Evidence. PMID- 28640538 TI - Whole-lesion histogram analysis of the apparent diffusion coefficient: Evaluation of the correlation with subtypes of mucinous breast carcinoma. AB - PURPOSE: To evaluate the utility of the whole-lesion histogram apparent diffusion coefficient (ADC) for characterizing the heterogeneity of mucinous breast carcinoma (MBC) and to determine which ADC metrics may help to best differentiate subtypes of MBC. MATERIALS AND METHODS: This retrospective study involved 52 MBC patients, including 37 pure MBC (PMBC) and 15 mixed MBC (MMBC). The PMBC patients were subtyped into PMBC-A (20 cases) and PMBC-B (17 cases) groups. All patients underwent preoperative diffusion-weighted imaging (DWI) at 1.5T and the whole lesion ADC assessments were generated. Histogram-derived ADC parameters were compared between PMBC vs. MMBC and PMBC-A vs. PMBC-B, and receiver operating characteristic (ROC) curve analysis was used to determine optimal histogram parameters for differentiating these groups. RESULTS: The PMBC group exhibited significantly higher ADC values for the mean (P = 0.004), 25th (P = 0.004), 50th (P = 0.004), 75th (P = 0.006), and 90th percentiles (P = 0.013) and skewness (P = 0.021) than did the MMBC group. The 25th percentile of ADC values achieved the highest area under the curve (AUC) (0.792), with a cutoff value of 1.345 * 10-3 mm2 /s, in distinguishing PMBC and MMBC. The PMBC-A group showed significantly higher ADC values for the mean (P = 0.049), 25th (P = 0.015), and 50th (P = 0.026) percentiles and skewness (P = 0.004) than did the PMBC-B group. The 25th percentile of the ADC cutoff value (1.476 * 10-3 mm2 /s) demonstrated the best AUC (0.837) among the ADC values for distinguishing PMBC-A and PMBC-B. CONCLUSION: Whole-lesion ADC histogram analysis enables comprehensive evaluation of an MBC in its entirety and differentiating subtypes of MBC. Thus, it may be a helpful and supportive tool for conventional MRI. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:391-400. PMID- 28640541 TI - Design and fabrication of dual-targeted delivery system based on gemcitabine conjugated human serum albumin nanoparticles. AB - Dual-targeted drug delivery system has established their reputation as potent vehicles for cancer chemotherapies. Herein, gemcitabine (Gem) was conjugated to human serum albumin (HSA) via dithiodipropionic anhydride (DTDPA) to fabricate Gem-HSA nanoparticles. It was hypothesized that this system can enhance the low stability of Gem and can improve its intracellular delivery. Furthermore, folate was applied as targeting agent on HSA nanoparticles for increasing the tumor selectivity of Gem. In order to evaluate the structural properties of synthesized products, 1 H NMR and FT-IR were performed. Moreover, HPLC was implemented for confirming the conjugation between HSA and Gem. Nanoparticles have shown spherical shape with negative charge. The release rate of Gem was dependent to the concentration of glutathione and pH. Folate-targeted HSA nanoparticles have shown higher cytotoxicity, cellular uptake and apoptosis induction on folate receptor overexpressing MDA-MB-231 cells in comparison to non-targeted nanoparticles. Finally, it is considered that the developed dual-targeted nanoparticles would be potent in improving the stability and efficacy of intracellular delivery of Gem and its selective delivery to cancer cells. This article is protected by copyright. All rights reserved. PMID- 28640542 TI - Listen, Look and Learn. PMID- 28640540 TI - The effects of advanced age and serum alpha1 -acid glycoprotein on docetaxel unbound exposure and dose-limiting toxicity in cancer patients. AB - AIM: alpha1 -Acid glycoprotein (AAG), which is a major binding protein of docetaxel, is considered to be a determinant for docetaxel pharmacokinetics. However, there are no reports about the impact of serum AAG on pharmacokinetics and pharmacodynamics in elderly patients treated with docetaxel. The aim of this prospective study was to elucidate the effects of advanced age and serum AAG on docetaxel unbound exposure and neutropenia, dose-limiting toxicity, in cancer patients. METHODS: Docetaxel was administered at 60 mg m-2 to 51 patients with non-small cell lung cancer, 17 of whom were >=75 years of age. Pharmacokinetics, unbound fraction (fu), neutropenia, serum protein levels of AAG and albumin, as well as baseline absolute neutrophil count (ANC) were assessed during the first course. Population pharmacokinetic and pharmacodynamic analyses were performed to evaluate the influence of clinically relevant factors on docetaxel pharmacokinetics and neutropenia. RESULTS: Clearance of docetaxel and degree of fu were significantly associated with serum AAG level, but not with age. Area under the concentration-time curve of unbound docetaxel (fu.AUC) was significantly higher in patients aged >=75 years (0.389 MUg.h ml-1 , 95% CI; 0.329-0.448 MUg.h ml-1 ) compared with patients aged <75 years (0.310 MUg.h ml-1 , 95% CI; 0.268-0.352 MUg.h ml-1 ). Percent decrease in ANC at nadir related to fu.AUC, and was dependent on baseline ANC. CONCLUSION: Regardless of ageing, serum level of AAG determines docetaxel unbound exposure and related dose limiting toxicity. Serum AAG level and ANC at baseline appear to be predictive of neutropenia for patients of all ages following the administration of docetaxel. PMID- 28640543 TI - Evolutionary-Optimized Photonic Network Structure in White Beetle Wing Scales. AB - Most studies of structural color in nature concern periodic arrays, which through the interference of light create color. The "color" white however relies on the multiple scattering of light within a randomly structured medium, which randomizes the direction and phase of incident light. Opaque white materials therefore must be much thicker than periodic structures. It is known that flying insects create "white" in extremely thin layers. This raises the question, whether evolution has optimized the wing scale morphology for white reflection at a minimum material use. This hypothesis is difficult to prove, since this requires the detailed knowledge of the scattering morphology combined with a suitable theoretical model. Here, a cryoptychographic X-ray tomography method is employed to obtain a full 3D structural dataset of the network morphology within a white beetle wing scale. By digitally manipulating this 3D representation, this study demonstrates that this morphology indeed provides the highest white retroreflection at the minimum use of material, and hence weight for the organism. Changing any of the network parameters (within the parameter space accessible by biological materials) either increases the weight, increases the thickness, or reduces reflectivity, providing clear evidence for the evolutionary optimization of this morphology. PMID- 28640545 TI - Magnetic resonance imaging of the brain and spine, 5th edition. PMID- 28640544 TI - Interactions of Neurons with Physical Environments. AB - Nerve growth strongly relies on multiple chemical and physical signals throughout development and regeneration. Currently, a cure for injured neuronal tissue is an unmet need. Recent advances in fabrication technologies and materials led to the development of synthetic interfaces for neurons. Such engineered platforms that come in 2D and 3D forms can mimic the native extracellular environment and create a deeper understanding of neuronal growth mechanisms, and ultimately advance the development of potential therapies for neuronal regeneration. This progress report aims to present a comprehensive discussion of this field, focusing on physical feature design and fabrication with additional information about considerations of chemical modifications. We review studies of platforms generated with a range of topographies, from micro-scale features down to topographical elements at the nanoscale that demonstrate effective interactions with neuronal cells. Fabrication methods are discussed as well as their biological outcomes. This report highlights the interplay between neuronal systems and the important roles played by topography on neuronal differentiation, outgrowth, and development. The influence of substrate structures on different neuronal cells and parameters including cell fate, outgrowth, intracellular remodeling, gene expression and activity is discussed. Matching these effects to specific needs may lead to the emergence of clinical solutions for patients suffering from neuronal injuries or brain-machine interface (BMI) applications. PMID- 28640547 TI - Abbreviations. PMID- 28640548 TI - Returning the treasure to babies: Infant mental health and Early Head Start. PMID- 28640546 TI - Treatment at high-volume facilities and academic centers is independently associated with improved survival in patients with locally advanced head and neck cancer. AB - BACKGROUND: The treatment of head and neck cancers is complex and associated with significant morbidity, requiring multidisciplinary care and physician expertise. Thus, facility characteristics, such as clinical volume and academic status, may influence outcomes. METHODS: The current study included 46,567 patients taken from the National Cancer Data Base who were diagnosed with locally advanced invasive squamous cell carcinomas of the oropharynx, larynx, and hypopharynx and were undergoing definitive radiotherapy. High-volume facilities (HVFs) were defined as the top 1% of centers by the number of patients treated from 2004 through 2012. Multivariable Cox regression and propensity score matching were performed to account for imbalances in covariates. RESULTS: The median follow-up was 55.1 months. Treatment at a HVF (hazard ratio, 0.798; 95% confidence interval, 0.753-0.845 [P<.001]) and treatment at an academic facility (hazard ratio, 0.897; 95% confidence interval, 0.871-0.923 [P<.001]) were found to be independently associated with improved overall survival in multivariable analysis. In propensity score-matched cohorts, the 5-year overall survival rate was 61.6% versus 55.5% for patients treated at an HVF versus lower-volume facilities, respectively (P<.001). Similarly, the 5-year overall survival rate was 52.3% versus 49.7% for patients treated at academic versus nonacademic facilities (P<.001). Analysis of facility volume as a continuous variable demonstrated continual improvement in survival with an increased number of patients treated. The impact of facility volume and academic designation on survival was observed when using a variety of thresholds to define HVF, and across the vast majority of subgroups, including both oropharyngeal and nonoropharyngeal subsites. CONCLUSIONS: Patients with locally advanced head and neck squamous cell carcinoma who are undergoing curative radiotherapy at HVFs and academic centers appear to have improved survival. Cancer 2017;123:3933-42. (c) 2017 American Cancer Society. PMID- 28640549 TI - Pathways to prevention: A training and technical assistance initiative to increase program capacity to address infant mental health issues in Early Head Start. AB - This article provides an overview of a training and consultation program aimed at enhancing the capacity of Early Head Start (EHS) and Migrant and Seasonal Head Start (MSHS) programs to address infant mental health issues from a promotion, prevention, and treatment perspective. This program was implemented by the Early Head Start National Resource Center (EHS NRC), operated by ZERO TO THREE. The EHS NRC is funded by the Head Start Bureau to provide a diverse array of training and technical assistance support services to Early Head Start programs throughout the country. In the fall of 2001, ZERO TO THREE was funded to design and implement the Pathways Initiative. While ZERO TO THREE was not funded to test the efficacy of the Pathways Initiative as a research intervention similar to other papers described in this special issue, we worked creatively to identify resources that allowed us to engage an external evaluator to look at both process and outcome measures. This paper describes the consultation program, evaluation activities, and key lessons learned. PMID- 28640550 TI - Infant mental health and family support: Contributions of Early Head Start to an integrated model for community-based early childhood programs. AB - This paper analyzes the experiences of an Early Head Start (EHS) program in adopting and implementing an infant mental health (IMH) approach in its work with community families. Through qualitative methods (participant observation, qualitative interviews, and case studies), we examined the strategies used, and the challenges encountered, by program staff as they applied IMH principles in their home-visiting interventions with families whose lives involve significant economic, social, and psychological stressors. Our study identified four elements crucial to an effective IMH initiative: (1) teamwork, especially the use of transdisciplinary teams to review family cases, (2) reflective supervision, (3) development of an integrated and empathic understanding of the child's needs and the parent's challenges in meeting those needs, and (4) a dynamic ecological understanding of children, families, and communities in which psychosocial and socioeconomic factors are viewed as mutually important and interactive. We argue that each of these elements both builds on and enhances long-standing dimensions of this EHS program's family support approach, creating an innovative and integrated model of IMH and family support that could prove of value in many community-based programs serving children and families whose emotional health is affected by everyday experiences of economic and social inequality. PMID- 28640551 TI - Putting knowledge into policy: Toward an infant-toddler policy agenda. PMID- 28640552 TI - Early Head Start and infant mental health. PMID- 28640553 TI - Risk for maternal depression and child aggression in Early Head Start families: A test of ecological models. AB - Current literature indicates that risk for maternal depression is substantial in low-income families. A large body of research also indicates that when mothers are depressed, children are at risk for a number of developmental difficulties. While mutual influence between child and parental difficulties has been noted, few studies examine risk factors for both depression and child aggression within ecological models. The present cross-site study examined the unique and additive contributions of contextual factors, including SES and family functioning, on maternal depression and child aggression in Early Head Start families. A multiethnic sample of parents and their children, between the ages of 12 and 43 months, participated in this study. Families came from five Early Head Start programs across the United States, representing both urban and rural areas. Structural equation models (SEM) demonstrate mutual links between depression and aggression, mediated at least in part by ecological factors. SEM indicated that 36.4% of the variance in child aggression is accounted for in a model linking aggressive behavior to parent depression, stress, and couple-level functioning, as well as other family interaction variables. A second model focusing on maternal depression revealed that 44.5% of the variance in maternal depression was accounted for through family factors, including couple-related support and satisfaction and parenting stress. In this second model, child aggression was indirectly linked to maternal depression. These data have important implications for programs serving at-risk families. PMID- 28640554 TI - The explication of a mentor model, videotaping, and reflective consultation in support of infant mental health. AB - Infant mental health, as concept and intervention, is poorly understood by most practitioners in education settings. Direct-service personnel often lack appropriate knowledge, training, skills, and confidence in recognizing and addressing infant mental health problems. While programs and policymakers increasingly acknowledge the need to offer infant mental health services in order to prevent or mediate poor developmental outcomes among young children, effective methods of realizing an infant mental health initiative remain elusive. This qualitative study of five early education programs examines the use of mentors trained in clinical psychology or social work to support educators in delivering infant mental health services. The perspectives of administrators, direct-service providers, and mentors help us understand what constitutes successful infant mental health mentoring in general, and videotaping in combination with reflective consultation in particular. PMID- 28640556 TI - It takes time: Impacts of Early Head Start that lead to reductions in maternal depression two years later. AB - The Early Head Start Research and Evaluation Project, a random-assignment evaluation, found a broad pattern of positive impacts for children and families. However, there were no program impacts on depression or use of mental health services by the time children reached age 3, at the end of the Early Head Start (EHS) program. This paper presents recent findings from the follow-up study in the spring prior to the children entering kindergarten, when a positive program impact emerged for reducing maternal depression. Results show that earlier program impacts on children and parents (when children were 2 and 3 years of age) mediated, or led to, the delayed impact on maternal depression. The combination of the most promising child factors accounted for over 57% of the later impact on depression, while the most promising parent factors accounted for over 35% of the later impact on depression. Implications for EHS programs are discussed. PMID- 28640557 TI - Infant mental health and Early Head Start: The glass is half full. PMID- 28640558 TI - The early promotion and intervention research consortium (E-PIRC): Five approaches to improving infant/toddler mental health in Early Head Start. AB - One planned consequence of the national Infant Mental Health Forum held in the United States in 2000 was the funding of five research projects conducted in Early Head Start (EHS) programs. Each project strengthened existing programs by integrating infant/toddler mental health approaches and testing the outcomes on infant/toddler development, behavior, and parent-child interactions. In two of the projects, the effect of offering enrichment for EHS staff was tested. The other three projects tested the effect of services offered directly to parents and children. This article describes the five projects and the theories, methods, and outcome measures used. In order to understand more fully the elevated risk factors in these families and the consequences for mental health in their infants and toddlers, a common set of measures was developed. Data have been used to explore the common threats to mental health and the factors that moderate the impact on infants and toddlers. PMID- 28640559 TI - Management of monochorionic twin pregnancy discordant for body-stalk anomaly. PMID- 28640560 TI - Integration of Biomolecules with Metal-Organic Frameworks. AB - Owing to the progressive development of metal-organic-frameworks (MOFs) synthetic processes and considerable potential applications in last decade, integrating biomolecules into MOFs has recently gain considerable attention. Biomolecules, including lipids, oligopeptides, nucleic acids, and proteins have been readily incorporated into MOF systems via versatile formulation methods. The formed biomolecule-MOF hybrid structures have shown promising prospects in various fields, such as antitumor treatment, gene delivery, biomolecular sensing, and nanomotor device. By optimizing biomolecule integration methods while overcoming existing challenges, biomolecule-integrated MOF platforms are very promising to generate more practical applications. PMID- 28640561 TI - ? PMID- 28640562 TI - [Vaping (electronic cigarette): how to advise smokers in 2017 ?] AB - Questions about electronic cigarettes, also called electronic nicotine delivery systems (ENDS), are very common when advising patients to stop smoking in medical practice. It is widely recognized that the risks of vaping are significantly lower than those of smoking, although there are uncertainties about its long-term health effects. Some studies suggest that vaping helps to stop smoking. Effective smoking cessation medications should be recommended in first line but vaping should not be discouraged when patients choose to use this device, as the main aim is smoking cessation. This paper proposes recommendations about vaping in common situations in medical practice with smokers. PMID- 28640563 TI - [Smoking, vaping and cardiovascular risk : an update]. AB - It is well known that tobacco smoking increases cardiovascular (CV) mortality and morbidity, however, smoking cessation is often neglected compared to other CV risk factors. Behavioral counseling as well as smoking cessation treatments are efficient and do not increase the risk of CV events when used for a defined duration. Electronic nicotine delivery systems (ENDS) contain potentially cardiotoxic substances but in lower concentrations than in cigarettes. The CV effect of ENDS is to date difficult to assess and depends on the type of device used and its mode of consumption. For smokers with a known CV disease who have quit smoking using ENDS, it is recommended that they stop using them as soon as they have stabilized. PMID- 28640564 TI - [Design and user-testing of a decision aid comparing medications for smoking cessation]. AB - Medications for smoking cessation, such as nicotine replacement, bupropion and varenicline have comparable efficacy, but present different advantages and drawbacks, making patient-specific preferences important when choosing a medication for smoking cessation. Through 3 PDCA cycles (Plan-Do-Check-Act), we developed and user-tested a decision aid for use during consultations. It contains the most relevant information for choosing a smoking cessation medication and is freely available online. The methodology used for its development could be employed for other decision aids for preference-sensitive decisions. PMID- 28640565 TI - [Protection from exposure to second-hand tobacco smoke in the canton of Vaud : review and outcomes]. AB - At the beginning of the 2000's the dissemination of scientific evidence, public opinion shift and the example of private or public workplaces led the Latin part of Switzerland to plead for a comprehensive smoke-free ban. In the canton of Vaud, the smoke-free public places law entered into force on September 15th 2009 after a 3-year process initiated by a popular initiative. Key factors included public awareness and information actions, civil society engagement and the involvement of every stakeholder. Smoke-free public- and workplaces led to health improvements in the general population and an evolving social norm towards tobacco use. These outcomes are still challenged by the development of new tobacco products. PMID- 28640566 TI - [The Scientific Commission of the Swiss Cigarette Manufacturers Association : a historical overview]. AB - The Scientific Commission (SC) of the Swiss Cigarette Manufacturers Association (SCMA) has been active between 1962 and the end of the 1990s. The commission fulfilled multiple tasks in the service of the tobacco industry : planning of external joint research, public relations work, lobbying, and collaboration with public authorities as well as organisations with a similar mission as the SC itself. In addition, it monitored research on smoking and health, reviewed studies that were detrimental to the cigarette manufacturers' interest and organized pro-tobacco scientific meetings. The commission was thus a powerful tool at the disposal of the tobacco industry. It also had a major impact on public health through perpetuating the pseudo-controversy about the negative effects of smoking on health. PMID- 28640567 TI - [Recommendations for the use of antiemetic drugs by the general practitioner]. AB - Nausea is a common symptom among patients affected by chronic diseases or undergoing various treatments. Because nausea can result from many origins, there is a large differential diagnosis to explore. Its pathophysiology relies on numerous neurotransmitters, on which 5 types of antiemetic antagonists are effective (NK-1 receptor antagonists, antiserotoninergic, antidopaminergic, antihistaminic and anticholinergic agents). Glucocorticoids and benzodiazepines are also used to treat some types of nausea. Choosing the appropriate antiemetic can improve quality of life and treatment compliance. PMID- 28640568 TI - [Patients : becoming a person before being a partner]. AB - Do patients and health care professionals wish to become partners in the relationship of care ? While many tend to think like that, it is far from certain that this is really the case. Data collected by the Espace Patients&Proches, where users of the Lausanne University Hospital are allowed to complain about health care-related problems, show that patients, their relatives, and health care professionals suffer from a process of de-subjectivization owing to the increasing technologization and standardization of care. Indeed, they want to be recognized as subjects before even thinking of becoming partners. Neither patients, their relatives, nor health care professionals call for a symmetrical relationship yet ; such attempts may moreover be experienced as painful. PMID- 28640569 TI - ? PMID- 28640570 TI - ? PMID- 28640571 TI - ? PMID- 28640572 TI - ? PMID- 28640573 TI - ? PMID- 28640574 TI - ? PMID- 28640575 TI - ? PMID- 28640576 TI - The Effect of Aromatherapy on Insomnia and Other Common Symptoms Among Patients With Acute Leukemia AB - Purpose/Objectives: To determine if the use of aromatherapy improves insomnia and other common symptoms in hospitalized patients with newly diagnosed acute leukemia. Design: A randomized, crossover, washout trial. Setting: An inpatient acute leukemia unit at the Arthur G. James Cancer Hospital and Richard L. Solove Research Institute of the Wexner Medical Center at Ohio State University in Columbus. Sample: 50 patients who were newly diagnosed with acute leukemia and hospitalized to receive their initial four weeks of intensive induction chemotherapy. Methods: Patients were offered a choice of three scents to be used during the trial: lavender, peppermint, or chamomile. Each patient was randomized to receive either the chosen aromatherapy intervention or a placebo intervention during alternate weeks, with a washout period in between. Sleep quality and other common symptoms were measured. Main Research Variables: Aromatherapy, sleep, insomnia, pain, tiredness, drowsiness, nausea, lack of appetite, shortness of breath, depression, anxiety, and well-being. Findings: Most patients reported poor quality sleep at baseline, but aromatherapy had a statistically significant positive impact. Improvements were noted in tiredness, drowsiness, lack of appetite, depression, anxiety, and well-being because of aromatherapy. Conclusions: Aromatherapy is a viable intervention for improving insomnia and other symptoms commonly experienced by patients with acute leukemia. Implications for Nursing: Oncology nurses can employ aromatherapy safely and inexpensively, and with minimal training, as an effective tool in decreasing many symptoms that plague patients with leukemia. Patients can exercise a greater sense of control over their treatment environments through the use of aromatherapy. PMID- 28640577 TI - Laser Ablation Molecular Isotopic Spectrometry for Molecules Formation Chemistry in Femtosecond-Laser Ablated Plasmas. AB - Recently, laser ablated molecular isotopic spectrometry (LAMIS) has expanded its capability to explore molecules formation mechanism in laser-induced plasma in addition to isotope analysis. LAMIS is a powerful tool for tracking the origination of atoms that is involved in formation of investigated molecules by labeling atoms with their isotopic substitution. The evolutionary formation pathways of organic molecules, especially of C2 dimers and CN radicals, were frequently reported. However, very little is known about the formation pathways for metallic radicals and heterodimers in laser ablated plasma. This research focuses on elucidating the formation pathways of AlO radicals in femtosecond laser ablated plasma from 18O-labeled Al2O3 pellet. Plasmas expanding with strong forward bias in the direction normal to the sample surface were generated in the wake of a weakly ionized channel created by a femtosecond laser. The formation mechanism of AlO and influence of air were investigated with multiple plasma diagnostic methods such as monochromatic fast gating imaging, spatiotemporal resolved optical emission spectroscopy, and LAMIS. An advanced LAMIS fitting procedure was used to deduce the spatiotemporal distributions of Al18O and Al16O number densities and also their ratios. We found that the Al16O/Al18O number density ratio is higher for plasma portion closer to the sample surface, which suggests that chemical reactions between the plasma plume and ambient air are more intense at the tail of the plasma. The results also reveals that direct association of free Al and O atoms is the main mechanism for the formation of AlO at the early stage of the plasma. To the contrast, chemical reactions between plasma materials and ambient oxygen molecules and the isotope exchange effect are the dominant mechanisms of the formation of AlO and evolution of Al16O/Al18O number density ratio at the late stage of the plasma. PMID- 28640578 TI - Insect Analogue to the Lotus Leaf: A Planthopper Wing Membrane Incorporating a Low-Adhesion, Nonwetting, Superhydrophobic, Bactericidal, and Biocompatible Surface. AB - Nature has produced many intriguing and spectacular surfaces at the micro- and nanoscales. These small surface decorations act for a singular or, in most cases, a range of functions. The minute landscape found on the lotus leaf is one such example, displaying antiwetting behavior and low adhesion with foreign particulate matter. Indeed the lotus leaf has often been considered the "benchmark" for such properties. One could expect that there are animal counterparts of this self-drying and self-cleaning surface system. In this study, we show that the planthopper insect wing (Desudaba danae) exhibits a remarkable architectural similarity to the lotus leaf surface. Not only does the wing demonstrate a topographical likeness, but some surface properties are also expressed, such as nonwetting behavior and low adhering forces with contaminants. In addition, the insect-wing cuticle exhibits an antibacterial property in which Gram-negative bacteria (Porphyromonas gingivalis) are killed over many consecutive waves of attacks over 7 days. In contrast, eukaryote cell associations, upon contact with the insect membrane, lead to a formation of integrated cell sheets (e.g., among human stem cells (SHED-MSC) and human dermal fibroblasts (HDF)). The multifunctional features of the insect membrane provide a potential natural template for man-made applications in which specific control of liquid, solid, and biological contacts is desired and required. Moreover, the planthopper wing cuticle provides a "new" natural surface with which numerous interfacial properties can be explored for a range of comparative studies with both natural and man-made materials. PMID- 28640579 TI - Rapid and Robust Quantification of p-Xyleneselenocyanate in Plasma via Derivatization. AB - p-Xyleneselenocyanate (p-XSC) is one of the most investigated selenium compounds in cancer-prevention and -therapy. Despite the potent anticancer property, there is still no proper method to perform the quantitative analysis of p-XSC in plasma. In this investigation, we aimed at developing a method based on liquid chromatography-mass spectrometry (LC-MS) for the measurement of p-XSC in plasma. Direct deproteinization was first used to extract parent p-XSC from plasma, but failed to achieve high recovery rate (<2%) due to formation of selenium-sulfur bond between p-XSC and plasma protein. To overcome this problem, we modified the extraction method to three steps: (1) break the selenium-sulfur bond by tris(2 carboxyethyl)phosphine; (2) stabilize the newly formed intermediate selenol by N ethylmaleimide; (3) deproteinization. This three-step method efficiently recovered bound p-XSC by more than 75%. In in vivo study, p-XSC was injected intravenously into mice and plasma was collected for LC-MS analysis. Consistently, p-XSC was undetectable in its parent form, whereas the bound form was readily quantified, employing the modified extraction method. In summary, we describe a novel, robust, and sensitive method for quantification of p-XSC in plasma. The present method will enable pharmacokinetic and pharmacodynamic studies of p-XSC in both clinical and preclinical settings. PMID- 28640581 TI - Molecular Insight into Water Desalination across Multilayer Graphene Oxide Membranes. AB - Transport of ionic solutions through graphene oxide (GO) membranes is a complicated issue because the complex and tortuous structure inside makes it very hard to clarify. Using molecular dynamics (MD) simulations, we investigated the mechanism of water transport and ion movement across multilayer GO. The significant flow rate is considerably influenced by the structural parameters of GO membranes. Because of the size effect on a shrunken real flow area, there is disagreement between the classical continuum model and nanoscaled flow. To eliminate the variance, we obtained modified geometrical parameters from density analysis and used them in the developed hydrodynamic model to give a precise depiction of water flow. Four kinds of solutions (i.e., NaCl, KCl, MgCl2, and CaCl2) and different configurational GO sheets were considered to clarify the influence on salt permeation. It is found that the abilities of permeation to ions are not totally up to the hydration radius. Even though the ionic hydration shell is greater than the opening space, the ions can also pass through the split because of the special double-deck hydration structure. In the structure of GO, a smaller layer separation with greater offsetting gaps could substantially enhance the membrane's ability to reject salt. This work establishes molecular insight into the effects of configurational structures and salt species on desalination performance, providing useful guidelines for the design of multilayer GO membranes. PMID- 28640582 TI - Thermoelectric Performance of Se/Cd Codoped SnTe via Microwave Solvothermal Method. AB - Extensive attention has been focused on thermoelectric performance optimization of SnTe because of its potential in waste heat recovery. Here, we fabricate high thermoelectric performance Se/Cd codoped SnTe octahedral particles by microwave stimulated solvothermal method. The SnTe-based octahedral particles have sizes ranging from several micrometers to hundreds of nanometers, forming dense bulks after spark plasma sintering. Combined with the strong point defect scattering by Se and Cd dopants, a low thermal conductivity of 1.8 W m-1 K-1 at 773 K is obtained in the Se/Cd codoped Sn0.98Cd0.02Te0.9Se0.1 sample. Se and Cd dopants can optimize the band structure of SnTe and boost the power factors, resulting in a promising peak ZT of ~0.78 at 773 K in the Se/Cd codoped Sn0.98Cd0.02Te0.9Se0.1 sample, which is significantly higher than those of undoped SnTe and Se-doped SnTe samples. PMID- 28640580 TI - A Bioinspired Alginate-Gum Arabic Hydrogel with Micro-/Nanoscale Structures for Controlled Drug Release in Chronic Wound Healing. AB - Biopolymeric hydrogels have drawn increasing research interest in biomaterials due to their tunable physical and chemical properties for both creating bioactive cellular microenvironment and serving as sustainable therapeutic reagents. Inspired by a naturally occurring hydrogel secreted from the carnivorous Sundew plant for trapping insects, here we have developed a bioinspired hydrogel to deliver mitsugumin 53 (MG53), an important protein in cell membrane repair, for chronic wound healing. Both chemical compositions and micro-/nanomorphological properties inherent from the natural Sundew hydrogel were mimicked using sodium alginate and gum arabic with calcium ion-mediated cross-linking. On the basis of atomic force microscopy (AFM) force measurements, an optimal sticky hydrogel scaffold was obtained through orthogonal experimental design. Imaging and mechanical analysis showed the distinct correlation between structural morphology, adhesion characteristics, and mechanical properties of the Sundew inspired hydrogel. Combined characterization and biochemistry techniques were utilized to uncover the underlying molecular composition involved in the interactions between hydrogel and protein. In vitro drug release experiments confirmed that the Sundew-inspired hydrogel had a biphasic-kinetics release, which can facilitate both fast delivery of MG53 for improving the reepithelization process of the wounds and sustained release of the protein for treating chronic wounds. In vivo experiments showed that the Sundew-inspired hydrogel encapsulating with rhMG53 could facilitate dermal wound healing in mouse model. Together, these studies confirmed that the Sundew-inspired hydrogel has both tunable micro-/nanostructures and physicochemical properties, which enable it as a delivery vehicle for chronic wounding healing. The research may provide a new way to develop biocompatible and tunable biomaterials for sustainable drug release to meet the needs of biological activities. PMID- 28640583 TI - Fluffy and Ordered Graphene Multilayer Films with Improved Electromagnetic Interference Shielding over X-Band. AB - Highly ordered nitrogen-doped graphene multilayer films with large interlayer void are successfully fabricated by thermal annealing of the compact stacking graphene oxide/copper phthalocyanine (GO/CuPc) multilayer films. Scanning electron microscopic (SEM), X-ray diffraction (XRD), Raman, X-ray photoelectron spectroscopic (XPS), and electrical conductivity measurements indicate that the breakaway of oxygen functional groups on/in the GO sheets at high temperature and the in situ pyrolysis of CuPc molecules in the interlayer of graphene sheets synergistically facilitate the restoration of GO in graphitization, the effective nitrogen doping by replacing carbon atoms in graphene frameworks, the retention of layer-by-layer stacking structure of graphene sheets in plane, and the formation of interlayer voids, leading to the enhancement in the electrical conductivity (3.64 * 103 S/m). In addition, due to the formation of a Fabry-Perot resonance cavity in the unique layer-by-layer stacking structure with larger interlayer voids, constructive interference of internal reflections aligned between parallel reflecting planes endows the fluffy graphene multilayer films with excellent electromagnetic interference (EMI) shielding effectiveness (exceeds 25 dB in all X-bands). The optimal shielding effectiveness is up to 55.2 dB with a smaller thickness of 0.47 mm, which makes it possible to become a practical EMI shielding material with a distinct competitive advantage. PMID- 28640584 TI - Spectroscopic Evidence for a H Bond Network at Y356 Located at the Subunit Interface of Active E. coli Ribonucleotide Reductase. AB - The reaction catalyzed by E. coli ribonucleotide reductase (RNR) composed of alpha and beta subunits that form an active alpha2beta2 complex is a paradigm for proton-coupled electron transfer (PCET) processes in biological transformations. beta2 contains the diferric tyrosyl radical (Y122.) cofactor that initiates radical transfer (RT) over 35 A via a specific pathway of amino acids (Y122. ? [W48] ? Y356 in beta2 to Y731 ? Y730 ? C439 in alpha2). Experimental evidence exists for colinear and orthogonal PCET in alpha2 and beta2, respectively. No mechanistic model yet exists for the PCET across the subunit (alpha/beta) interface. Here, we report unique EPR spectroscopic features of Y356.-beta, the pathway intermediate generated by the reaction of 2,3,5-F3Y122.-beta2/CDP/ATP with wt-alpha2, Y731F-alpha2, or Y730F-alpha2. High field EPR (94 and 263 GHz) reveals a dramatically perturbed g tensor. [1H] and [2H]-ENDOR reveal two exchangeable H bonds to Y356.: a moderate one almost in-plane with the pi-system and a weak one. DFT calculation on small models of Y. indicates that two in plane, moderate H bonds (rO-H ~1.8-1.9 A) are required to reproduce the gx value of Y356. (wt-alpha2). The results are consistent with a model, in which a cluster of two, almost symmetrically oriented, water molecules provide the two moderate H bonds to Y356. that likely form a hydrogen bond network of water molecules involved in either the reversible PCET across the subunit interface or in H+ release to the solvent during Y356 oxidation. PMID- 28640585 TI - Thermally and Electrically Triggered Triple-Shape Memory Behavior of Poly(vinyl acetate)/Poly(lactic acid) Due to Graphene-Induced Phase Separation. AB - This work aimed to develop a facile and broadly applicable method for fabricating multistimuli responsive triple-shape memory polymers (SMPs). Hence, herein the SMPs were prepared through the simple physical blending of two commercially available biopolymers, poly(lactic acid) (PLA) and poly(vinyl acetate) (PVAc), in the presence of robust and conductive graphene nanoplatelets. Interestingly, atomic force microscopy observations and thermal analyses revealed that the presence of nanofillers led to phase separation and appearance of two well separated transition temperatures in the blend of these two miscible polymers. Consequently, shape memory results showed that the unfilled blend of PLA/PVAc with a single thermal transition can only show moderate heat triggered dual-shape memory behavior. While, PLA/PVAc/graphene nanocomposite blends demonstrated excellent thermally and electrically actuated triple-shape memory effects besides their remarkable dual-shape memory behavior. In addition, electrical conductivity of the blend was enhanced by ~14 orders of magnitude in the presence of graphene. More interestingly, electroactive shape recovery experiments exhibited that depending on the applied voltage, temporary shapes in each region of sample can be either individually or simultaneously recovered. PMID- 28640586 TI - Self-Supported Bi2MoO6 Nanowall for Photoelectrochemical Water Splitting. AB - The nanowall has been regarded as a promising architecture for highly efficient photoelectrochemical (PEC) water splitting due to various advantages, such as open geometry, highly reactive facets, independent contact with current collector, and so forth. Here, a vertically aligned Bi2MoO6 nanosheet array, which is also called a nanowall, is first achieved directly on the ITO glass by a facile solvothermal approach. The structural features not only offer multiple superiorities for PEC processes, but also provide the bridge for in-depth insights of intrinsic features of Bi2MoO6 photoanodes. A quantitative analysis of the electrochemical process declares that the utilization of photogenerated charges in the Bi2MoO6 nanowall has been optimized, but the main obstacle comes from the severe bulk recombination and low efficiencies of charge separation. This evaluation both enriches the visual assessment methods and directs clear guidance for future improvement, which could serve as a beacon for well-directed and economic photoelectrode amelioration, to shorten the road toward ideal photoelectrodes. PMID- 28640587 TI - Silica Nanoparticle as a Lymph Node Targeting Platform for Vaccine Delivery. AB - Nanoparticles have emerged as the platform of choice to improve the efficacy and safety of subunit vaccines. A major challenge underlying the use of nanomaterials in vaccines lies in the particle designs that can efficiently target and activate the antigen-presenting cells, especially dendritic cells. Here we show a toll like receptor 9 (TLR-9) agonist and antigen coloaded, silica nanoparticles (SiNPs) are able to accumulate in antigen presenting cells in the draining lymph nodes after injection. Vaccine loaded SiNPs led to dramatically enhanced induction of antigen-specific B and T cell responses as compared to soluble vaccines, which in turn drove a protective antitumoral immunity in a murine tumor model. Additionally, SiNP vaccines greatly reduced the production of systemic proinflammatory cytokines and completely abrogated splenomegaly, key systemic toxicities of TLR-9 agonists that limit their advances in clinical applications. Our results demonstrate that structure-optimized silica nanocarriers can be used as an effective and safe platform for targeted delivery of subunit vaccines. PMID- 28640588 TI - Calcitonin-Loaded Thermosensitive Hydrogel for Long-Term Antiosteopenia Therapy. AB - Effective antiosteopenia therapy can be achieved by designing long-term protein/peptide drug delivery systems for bone trabecula restoration. Here we show that a complex of salmon calcitonin and oxidized calcium alginate (sCT-OCA) was prepared and loaded into a thermosensitive copolymer hydrogel for long-term antiosteopenia treatment. The triblock copolymer, poly(d,l-lactic acid-co glycolic acid)-b-poly(ethylene glycol)-b-poly(d,l-lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) exhibited sol-gel transition at body temperature. The sustained release of sCT from the in situ gelling system was determined by both the degradation of the hydrogel and the decomposition of the sCT-OCA complex. This system showed sustained effects in reducing serum calcium and bone trabecula reconstruction in the treatment of glucocorticoid-induced osteopenia in rats for approximately 30 days after a single subcutaneous injection, which may shed light on antiosteopenia therapy in the future. PMID- 28640589 TI - Ru(bpy)32+ Incorporated Luminescent Polymer Dots: Double-Enhanced Electrochemiluminescence for Detection of Single-Nucleotide Polymorphism. AB - Encapsulating a large amount of electrochemiluminescence (ECL) active molecules into one nanoparticle for single-target recognition can greatly improve the sensitivity of the ECL assay. This work used luminescent conjugated polymer as a carrier to synthesize Ru(bpy)32+-doped polymer dots (RuPdots). The RuPdots with an average size of 20 nm and encapsulation of about 1354 Ru(bpy)32+ showed greatly enhanced ECL emission. Using tripropylamine as a coreactant, the resonance energy transfer from the excited polymer dots to the encapsulated Ru(bpy)32+ was demonstrated, which led to a 15.7-fold higher ECL emission than that of Ru(bpy)32+ with the same amount at the gold electrode. By coupling the double-enhanced ECL signal of this nanostructure with the specific ligase detection reaction, a sensitive ECL biosensor was constructed for specific detection of a single-nucleotide polymorphism (SNP). Using mutant KRAS gene as a model target, the ECL SNP detection method showed a linear range from 1 fM to 1 nM and a detection limit of 0.8 fM. The designed RuPdots provided a novel signal amplification strategy and could be used as a universal label for ultrasensitive ECL biodetection. PMID- 28640590 TI - Chlorin e6 Functionalized Theranostic Multistage Nanovectors Transported by Stem Cells for Effective Photodynamic Therapy. AB - Approaches to achieve site-specific and targeted delivery that provide an effective solution to reduce adverse, off target side effects are urgently needed for cancer therapy. Here, we utilized a Trojan-horse-like strategy to carry photosensitizer Chlorin e6 conjugated porous silicon multistage nanovectors with tumor homing mesenchymal stem cells for targeted photodynamic therapy and diagnosis. The inherent versatility of multistage nanovectors permitted the conjugation of photosensitizers to enable precise cell death induction (60%) upon photodynamic therapy, while simultaneously retaining the loading capacity to load various payloads, such as antitumor drugs and diagnostic nanoparticles. Furthermore, the mesenchymal stem cells that internalized the multistage nanovectors conserved their proliferation patterns and in vitro affinity to migrate and infiltrate breast cancer cells. In vivo administration of the mesenchymal stem cells carrying photosensitizer-conjugated multistage nanovectors in mice bearing a primary breast tumor confirmed their tropism toward cancer sites exhibiting similar targeting kinetics to control cells. In addition, this approach yielded in a > 70% decrease in local tumor cell viability after in vivo photodynamic therapy. In summary, these results show the proof-of-concept of how photosensitizer conjugated multistage nanovectors transported by stem cells can target tumors and be used for effective site-specific cancer therapy while potentially minimizing potential negative side effects. PMID- 28640591 TI - Managing Psychotropic Medications in Complex, Real-World Patients Using Comprehensive Therapeutic Drug Monitoring. AB - There are multiple treatment options for depression, anxiety, psychosis, and other psychiatric disorders, and psychiatry patients are often comorbid with complex, polypharmacy treatment regimens. Unlike cardiovascular disease and diabetes, there are no readily available biomarkers to gauge treatment success with psychotropic medications, often resulting in subjective determination of medication therapy effectiveness. The physiochemical properties of psychiatric medications in general lend themselves to quantitative measurement in blood, offering an avenue to optimize treatment for each patient. Herein, we describe a novel application that employs comprehensive therapeutic drug monitoring of both psychiatric and nonpsychiatric medications to holistically personalize therapy for complex psychiatry patients. PMID- 28640593 TI - DNA Condensation Induced by a Star-Shaped Hexameric Cationic Surfactant. AB - The interactions between a star-shaped hexameric cationic quaternary ammonium surfactant PAHB and calf thymus DNA and induced DNA condensation were investigated by zeta-potential, dynamic light scattering, atomic force microscopy, isothermal titration calorimetry, ethidium bromide exclusion assay, circular dichroism, and cytotoxicity assay. With the addition of PAHB, long extended DNA molecules exhibit successive conformational transitions from elongated coil to a partially condensed cluster-like aggregate, to a globules-on a-string structure, and then to a fully condensed globule until the saturation point of interaction between PAHB and DNA, which is slightly above their charge neutralization point. The efficient condensation is mainly produced by the strong attractive electrostatic interaction between the multiple positively charged headgroups of PAHB and negatively charged phosphate groups of DNA, and the hydrophobic interaction among the multiple alkyl chains of PAHB. Moreover the transition of the DNA conformation is also affected by the transitions of PAHB molecular conformation from star-shaped to claw-like and pyramid-like. Although the DNA conformation is significantly changed by PAHB, the DNA secondary structure does not display obvious variations, and the PAHB/DNA mixture does not show cytotoxicity when DNA is partially condensed. These results indicate that star-shaped oligomeric cationic surfactant is a potential condensing agent for gene transfection. PMID- 28640592 TI - Identification of a Small Molecule Activator for AphB, a LysR-Type Virulence Transcriptional Regulator in Vibrio cholerae. AB - AphB is a LysR-type transcriptional regulator (LTTR) that cooperates with a second transcriptional activator, AphA, at the tcpPH promoter to initiate expression of the virulence cascade in Vibrio cholerae. Because it is not yet known whether AphB responds to a natural ligand in V. cholerae that influences its ability to activate transcription, we used a computational approach to identify small molecules that influence its activity. In silico docking was used to identify potential ligands for AphB, and saturation transfer difference nuclear magnetic resonance was subsequently employed to access the validity of promising targets. We identified a small molecule, BP-15, that specifically binds the C-terminal regulatory domain of AphB and increases its activity. Interestingly, molecular docking predicts that BP-15 does not bind in the putative primary effector-binding pocket located at the interface of RD-I and RD II as in other LTTRs, but rather at the dimerization interface. The information gained in this study helps us to further understand the mechanism by which transcriptional activation by AphB is regulated by suggesting that AphB has a secondary ligand binding site, as observed in other LTTRs. This study also lays the groundwork for the future design of inhibitory molecules to block the V. cholerae virulence cascade, thereby preventing the devastating symptoms of cholera infection. PMID- 28640594 TI - Biomedical Diagnostics Enabled by Integrated Organic and Printed Electronics. AB - Organic and printed electronics integration has the potential to revolutionize many technologies, including biomedical diagnostics. This work demonstrates the successful integration of multiple printed electronic functionalities into a single device capable of the measurement of hydrogen peroxide and total cholesterol. The single-use device employed printed electrochemical sensors for hydrogen peroxide electroreduction integrated with printed electrochromic display and battery. The system was driven by a conventional electronic circuit designed to illustrate the complete integration of silicon integrated circuits via pick and place or using organic electronic circuits. The device was capable of measuring 8 MUL samples of both hydrogen peroxide (0-5 mM, 2.72 * 10-6 A.mM-1) and total cholesterol in serum from 0 to 9 mM (1.34 * 10-8 A.mM-1, r2 = 0.99, RSD < 10%, n = 3), and the result was output on a semiquantitative linear bar display. The device could operate for 10 min via a printed battery, and display the result for many hours or days. A mobile phone "app" was also capable of reading the test result and transmitting this to a remote health care provider. Such a technology could allow improved management of conditions such as hypercholesterolemia. PMID- 28640595 TI - Detection and Characterization of Small Molecule Interactions with Fibrillar Protein Aggregates Using Microscale Thermophoresis. AB - Neurodegenerative diseases such as Parkinson's and Alzheimer's disease share the pathological hallmark of fibrillar protein aggregates. The specific detection of these protein aggregates by positron emission tomography (PET) in the patient brain can yield valuable information for diagnosis and disease progression. However, the identification of novel small compounds that bind fibrillar protein aggregates has been a challenge. In this study, microscale thermophoresis (MST) was applied to assess the binding affinity of known small molecule ligands of alpha-synuclein fibrils, which were also tested in parallel in a thioflavin T fluorescence competition assay for further validation. In addition, a MST assay was also developed for the detection of the interaction between a variety of small molecules and tau fibrils. The results of this study demonstrate that MST is a powerful and practical methodology to quantify interactions between small molecules and protein fibrillar aggregates, which suggests that it can be applied for the identification and development of PET radioligands and potentially of therapeutic candidates for protein misfolding diseases. PMID- 28640597 TI - Positive-Charge Functionalized Mesoporous Silica Nanoparticles as Nanocarriers for Controlled 2,4-Dichlorophenoxy Acetic Acid Sodium Salt Release. AB - Because of its relatively high water solubility and mobility, 2,4-dichlorophenoxy acetic acid (2,4-D) has a high leaching potential threatening the surface water and groundwater. Controlled release formulations of 2,4-D could alleviate the adverse effects on the environment. In the present study, positive-charge functionalized mesoporous silica nanoparticles (MSNs) were facilely synthesized by incorporating trimethylammonium (TA) groups onto MSNs via a postgrafting method. 2,4-D sodium salt, the anionic form of 2,4-D, was effectively loaded into these positively charged MSN-TA nanoparticles. The loading content can be greatly improved to 21.7% compared to using bare MSNs as a single encapsulant (1.5%). Pesticide loading and release patterns were pH, ionic strength and temperature responsive, which were mainly dominated by the electrostatic interactions. Soil column experiments clearly demonstrated that MSN-TA can decrease the soil leaching of 2, 4-D sodium salt. Moreover, this novel nanoformulation showed good bioactivity on target plant without adverse effects on the growth of nontarget plant. This strategy based on electrostatic interactions could be widely applied to charge carrying agrochemicals using carriers bearing opposite charges to alleviate the potential adverse effects on the environment. PMID- 28640596 TI - Drug-Target Kinetics in Drug Discovery. AB - The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug target kinetics into predictions of drug activity. PMID- 28640598 TI - Structural and Light-Absorption Characteristics of Complex Water-Insoluble Organic Mixtures in Urban Submicrometer Aerosols. AB - Submicrometer aerosols in the urban atmosphere of Nagoya, Japan, were collected in late winter and early spring, and the water-insoluble organic matter (WISOM) in the samples were fractionated into six subfractions based on their polarities by using solvent and normal-phase solid-phase extractions: nonpolar (F1), low polar (F2 and F3), and medium-polar (F4, F5, and F6) fractions. The overall structural characteristics of these subfractions were then analyzed using Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and high-resolution aerosol mass spectrometry. Quantitative information related to the overall chemical characteristics of the WISOM in the different polarity fractions, including their elemental compositions, the relative abundances of different functional groups and their fragments from electron impact ionization, was obtained. These water-insoluble fractions accounted for half of the total light absorption by the extracted aerosol matter at 400 nm. The contributions of the medium-polar fractions to both the total organic carbon and light absorption by the extracts were dominant among the contributions from the six subfractions. Large molecules with aromatic and heteroatomic (O and N) groups, including charge transfer complexes, might have greatly contributed to the light absorption by the fraction F4, which is the largest fraction of the extracted water-insoluble organic matter. PMID- 28640599 TI - A High-Throughput DNA-Sequencing Approach for Determining Sources of Fecal Bacteria in a Lake Superior Estuary. AB - Current microbial source-tracking (MST) methods, employed to determine sources of fecal contamination in waterways, use molecular markers targeting host-associated bacteria in animal or human feces. However, there is a lack of knowledge about fecal microbiome composition in several animals and imperfect marker specificity and sensitivity. To overcome these issues, a community-based MST method has been developed. Here, we describe a study done in the Lake Superior-Saint Louis River estuary using SourceTracker, a program that calculates the source contribution to an environment. High-throughput DNA sequencing of microbiota from a diverse collection of fecal samples obtained from 11 types of animals (wild, agricultural, and domesticated) and treated effluent (n = 233) was used to generate a fecal library to perform community-based MST. Analysis of 319 fecal and environmental samples revealed that the community compositions in water and fecal samples were significantly different, allowing for the determination of the presence of fecal inputs and identification of specific sources. SourceTracker results indicated that fecal bacterial inputs into the Lake Superior estuary were primarily attributed to wastewater effluent and, to a lesser extent, geese and gull wastes. These results suggest that a community-based MST method may be another useful tool for determining sources of aquatic fecal bacteria. PMID- 28640601 TI - Initiation of the Electrochemical Reduction of CO2 by a Singly Reduced Ruthenium(II) Bipyridine Complex. AB - The one-electron reduction of [CpRu(bpy)NCCH3]PF6 (Cp = cyclopentadienyl; bpy = 2,2'-bipyridine), abbreviated as [Ru-S]+, where S = CH3CN, in CO2-saturated acetonitrile initiates a cascade of rapid electrochemical and chemical steps (ECEC) at an electrode potential of ca. 100 mV positive of the first reduction of the ruthenium complex. The overall two-electron process leads to the generation of a CO-bound ruthenium complex, [Ru-CO]+, and carbonate, as independently confirmed by NMR spectroscopy. Simulations of the cyclic voltammograms using DigiElch together with density functional theory based calculations reveal that the singly reduced ruthenium complex [Ru-S]0 binds CO2 at a rate of ca. 105 M-1 s 1 at almost zero driving force. Subsequent to CO2 binding, all of the steps leading up to deoxygenation are highly exergonic and rapid. A model of the potential energy profile of the CO2 approach to the Ru center in the singly reduced manifold reveals a direct correlation between the reactivity toward CO2 and the nucleophilicity at the metal center influenced by different ligand environments. Through the binding of CO2 after the first reduction, overpotentials associated with consecutive electrochemical reductions are avoided. This work therefore provides an important design principle for engineering transition-metal complexes to activate CO2 under low driving forces. PMID- 28640602 TI - Dietary N-Carbamylglutamate Supplementation in a Reduced Protein Diet Affects Carcass Traits and the Profile of Muscle Amino Acids and Fatty Acids in Finishing Pigs. AB - The aim of this study was to investigate whether dietary N-carbamylglutamate (NCG) supplementation in a reduced protein diet affected carcass traits and meat quality in finishing pigs. A total of 120 gilts were randomly assigned to one of four treatments for 40 days, including a standard protein diet (SP), a reduced protein diet supplemented with 1.7% l-alanine (RP + Ala), a reduced protein diet supplemented with 1.0% l-arginine (RP + Arg), and a reduced protein diet supplemented with 0.1% NCG and 1.7% l-alanine (RP + NCG). NCG supplementation increased the endogenous synthesis of l-arginine. The RP + NCG diet significantly increased the loin eye area (p < 0.05) and tended to decrease the 10th rib fat depth (p = 0.08). NCG supplementation in a reduced protein diet was effective to produce functional pork with a high content of leucine (p < 0.05). The composition of several omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) but not the ratio of omega-6/omega-3 PUFAs in muscles was altered in finishing pigs with dietary NCG supplementation. In conclusion, the RP + NCG diet is effective to increase the longissimus dorsi muscle area, decrease back fat accretion, and produce functional pork with a high content of leucine but without a negative impact on the muscle fatty acid profile in finishing pigs. PMID- 28640600 TI - Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis. AB - During catalysis by liver alcohol dehydrogenase (ADH), a water bound to the catalytic zinc is replaced by the oxygen of the substrates. The mechanism might involve a pentacoordinated zinc or a double-displacement reaction with participation by a nearby glutamate residue, as suggested by studies of human ADH3, yeast ADH1, and some other tetrameric ADHs. Zinc coordination and participation of water in the enzyme mechanism were investigated by X-ray crystallography. The apoenzyme and its complex with adenosine 5'-diphosphoribose have an open protein conformation with the catalytic zinc in one position, tetracoordinated by Cys-46, His-67, Cys-174, and a water molecule. The bidentate chelators 2,2'-bipyridine and 1,10-phenanthroline displace the water and form a pentacoordinated zinc. The enzyme-NADH complex has a closed conformation similar to that of ternary complexes with coenzyme and substrate analogues; the coordination of the catalytic zinc is similar to that found in the apoenzyme, except that a minor, alternative position for the catalytic zinc is ~1.3 A from the major position and closer to Glu-68, which could form the alternative coordination to the catalytic zinc. Complexes with NADH and N-1 methylhexylformamide or N-benzylformamide (or with NAD+ and fluoro alcohols) have the classical tetracoordinated zinc, and no water is bound to the zinc or the nicotinamide rings. The major forms of the enzyme in the mechanism have a tetracoordinated zinc, where the carboxylate group of Glu-68 could participate in the exchange of water and substrates on the zinc. Hydride transfer in the Michaelis complexes does not involve a nearby water. PMID- 28640603 TI - Changes in Light Absorptivity of Molecular Weight Separated Brown Carbon Due to Photolytic Aging. AB - Brown carbon (BrC) consists of those organic compounds in atmospheric aerosols that absorb solar radiation and may play an important role in planetary radiative forcing and climate. However, little is known about the production and loss mechanisms of BrC in the atmosphere. Here, we study how the light absorptivity of BrC from wood smoke and secondary BrC generated from the reaction of ammonium sulfate with methylglyoxal changes under photolytic aging by UVA radiation in the aqueous phase. Owing to its chemical complexity, BrC is separated by molecular weight using size exclusion chromatography, and the response of each molecular weight fraction to aging is studied. Photolytic aging induced significant changes in the light absorptivity of BrC for all molecular weight fractions; secondary BrC was rapidly photoblenched, whereas for wood smoke BrC, both photoenhancement and photobleaching were observed. Initially, large biomass burning BrC molecules were rapidly photoenhanced, followed by slow photolysis. As a result, large BrC molecules dominated the total light absorption of aged biomass burning BrC. These experimental results further support earlier observations that large molecular weight BrC compounds from biomass burning can be relatively long-lived components in atmospheric aerosols, thus more likely to have larger impacts on aerosol radiative forcing and could serve as biomass burning tracers. PMID- 28640604 TI - Parametrization of a Reactive Force Field (ReaxFF) for Molecular Dynamics Simulations of Si Nanoparticles. AB - A novel computational approach, based on classical reactive molecular dynamics simulations (RMD) and quantum chemistry (QC) global energy optimizations, is proposed for modeling large Si nanoparticles. The force field parameters, which can describe bond breaking and formation, are derived by reproducing energetic and structural properties of a set of Si clusters increasing in size. These reference models are obtained through a new protocol based on a joint high temperature RMD/low temperature Basin Hopping QC search. The different procedures of estimating optimal force field parameters and their performance are discussed in detail. PMID- 28640605 TI - High-Pressure Synthesis, Crystal Structure, and Magnetic and Transport Properties of a Six-Layered SrRhO3. AB - A SrRhO3 polytype with six-layered (6M) structure was synthesized under high pressure and high temperature. The crystal structure was obtained by refining X ray powder diffraction with the monoclinic space group C2/c with lattice parameters a = 5.5650(1) A, b = 9.5967(2) A, c = 14.0224(4) A, and beta = 92.846(2) degrees . It is isostructural with SrIrO3 synthesized under ambient pressure and consists of dimers of the face-shared Rh(2)O6 octahedra connected by their vertices to the corner-shared Rh(1)O6 octahedra along the c axis with a stacking of SrO3 layers in the sequence of CCHCCH, where C and H denote cubic and hexagonal closed packing, respectively. With increasing pressure, the 6M SrRhO3 transforms to an orthorhombic perovskite (Pv) phase, having a = 5.5673(1) A, b = 5.5399(2) A, c = 7.8550(2) A in the space group Pbnm. A pressure-temperature phase diagram shows that the 6M-Pv phase boundary moves to lower temperatures with increasing pressure. Both the 6M and the Pv phases of SrRhO3 were characterized by magnetic susceptibility, resistivity, and thermopower; they are all metals with an enhanced and temperature-dependent magnetic susceptibility; no long-range magnetic order has been found. The polytype structures are normally found in ABO3 oxides with the geometric tolerance factor t > 1. SrRhO3 represents another example (in addition to SrIrO3) where the polytype 6M structure can be stabilized with a t < 1. PMID- 28640606 TI - Pharmacokinetics of Mequindox and Its Marker Residue 1,4-Bisdesoxymequindox in Swine Following Multiple Oral Gavage and Intramuscular Administration: An Experimental Study Coupled with Population Physiologically Based Pharmacokinetic Modeling. AB - Mequindox (MEQ) is a quinoxaline-N,N-dioxide antibiotic used in food-producing animals. MEQ residue in animal-derived foods is a food safety concern. The tissue distribution of MEQ and its marker residue 1,4-bisdesoxymequindox (M1) were determined in swine following oral gavage or intramuscular injection twice daily for 3 days. The experimental data were used to construct a flow-limited physiologically based pharmacokinetic (PBPK) model. The model predictions correlated with available data well. Monte Carlo analysis showed that the times needed for M1 concentrations to fall below limit of detection (5 MUg/kg) in liver for the 99th percentile of the population were 27 and 34 days after oral gavage and intramuscular administration twice daily for 3 days, respectively. This population PBPK model can be used to predict depletion kinetic profiles and tissue residues of MEQ's marker residue M1 in swine and as a foundation for scaling to other quinoxaline-N,N-dioxide antibiotics and to other animal species. PMID- 28640607 TI - Primary and Photochemically Aged Aerosol Emissions from Biomass Cookstoves: Chemical and Physical Characterization. AB - Secondary organic aerosol (SOA) formation during photo-oxidation of primary emissions from cookstoves used in developing countries may make important contributions to their climate and air quality impacts. We present results from laboratory experiments with a field portable oxidation flow reactor (F-OFR) to study the evolution of emissions over hours to weeks of equivalent atmospheric aging. Lab tests, using dry red oak, measured fresh and aged emissions from a 3 stone fire (TSF), a "rocket" natural draft stove (NDS), and a forced draft gasifier stove (FDGS), in order of increasing modified combustion efficiency (MCE) and decreasing particulate matter emission factors (EF). SOA production was observed for all stoves/tests; organic aerosol (OA) enhancement factor ranged from 1.2 to 3.1, decreasing with increased MCE. In primary emissions, OA mass spectral fragments associated with oxygenated species (primary biomass burning markers) increased (decreased) with MCE; fresh OA from FDGS combustion was especially oxygenated. OA oxygenation increased with further oxidation for all stove emissions, even where minimal enhancement was observed. More efficient stoves emit particles with greater net direct specific warming than TSFs, with the difference increasing with aging. Our results show that the properties and evolution of cookstove emissions are a strong function of combustion efficiency and atmospheric aging. PMID- 28640608 TI - Numerical Difficulties Computing Electrostatic Potentials Near Interfaces with the Poisson-Boltzmann Equation. AB - Many researchers compute surface maps of the electrostatic potential (phi) with the Poisson-Boltzmann (PB) equation to relate the structural information obtained from X-ray and NMR experiments to biomolecular functions. Here we demonstrate that the usual method of obtaining these surface maps of phi, by interpolating from neighboring grid points on the solution grid generated by a PB solver, generates large errors because of the large discontinuity in the dielectric constant (and thus in the normal derivative of phi) at the surface. The Cartesian Poisson-Boltzmann solver contains several features that reduce the numerical noise in surface maps of phi: First, CPB introduces additional mesh points at the Cartesian grid/surface intersections where the PB equation is solved. This procedure ensures that the solution for interior mesh points only references nodes on the interior or on the surfaces; similarly for exterior points. Second, for added points on the surface, a second order least-squares reconstruction (LSR) is implemented that analytically incorporates the discontinuities at the surface. LSR is used both during the solution phase to compute phi at the surface and during postprocessing to obtain phi, induced charges, and ionic pressures. Third, it uses an adaptive grid where the finest grid cells are located near the molecular surface. PMID- 28640609 TI - Enantioselective Copper-Catalyzed Arylation-Driven Semipinacol Rearrangement of Tertiary Allylic Alcohols with Diaryliodonium Salts. AB - A copper-catalyzed enantioselective arylative semipinacol rearrangement of allylic alcohols using diaryliodonium salts is reported. Chiral Cu(II) bisoxazoline catalysts initiate an electrophilic alkene arylation, triggering a 1,2-alkyl migration to afford a range of nonracemic spirocyclic ketones with high yields, diastereo- and enantioselectivities. PMID- 28640610 TI - The Role of Denitrification in Stormwater Detention Basin Treatment of Nitrogen. AB - The nitrogen (N) cycling dynamics of four stormwater basins, two often saturated sites ("Wet Basins") and two quick draining sites ("Dry Basins"), were monitored over a ~ 1-year period. This study paired stormwater and greenhouse gas monitoring with microbial analyses to elucidate the mechanisms controlling N treatment. Annual dissolved inorganic N (DIN) mass reductions (inflow minus outflow) were greater in the Dry Basin than in the Wet Basin, 2.16 vs 0.75 g N m 2 yr-1, respectively. The Dry Basin infiltrated a much larger volume of water and thus had greater DIN mass reductions, even though incoming and outgoing DIN concentrations were statistically the same for both sites. Wet Basins had higher proportions of denitrification genes and potential denitrification rates. The Wet Basin was capable of denitrifying 58% of incoming DIN, whereas the Dry Basin only denitrified 1%. These results emphasize the need for more mechanistic attention to basin design because the reductions calculated by comparing inflow and outflow loads may not be relevant at watershed scales. Denitrification is the only way to fully remove DIN from the terrestrial environment and receiving waterbodies. Consequently, at the watershed scale the Wet Basin may have better overall DIN treatment. PMID- 28640612 TI - CRISPR/Cas9-Based Genome Editing for Disease Modeling and Therapy: Challenges and Opportunities for Nonviral Delivery. AB - Genome editing offers promising solutions to genetic disorders by editing DNA sequences or modulating gene expression. The clustered regularly interspaced short palindromic repeats (CRISPR)/associated protein 9 (CRISPR/Cas9) technology can be used to edit single or multiple genes in a wide variety of cell types and organisms in vitro and in vivo. Herein, we review the rapidly developing CRISPR/Cas9-based technologies for disease modeling and gene correction and recent progress toward Cas9/guide RNA (gRNA) delivery based on viral and nonviral vectors. We discuss the relative merits of delivering the genome editing elements in the form of DNA, mRNA, or protein, and the opportunities of combining viral delivery of a transgene encoding Cas9 with nonviral delivery of gRNA. We highlight the lessons learned from nonviral gene delivery in the past three decades and consider their applicability for CRISPR/Cas9 delivery. We also include a discussion of bioinformatics tools for gRNA design and chemical modifications of gRNA. Finally, we consider the extracellular and intracellular barriers to nonviral CRISPR/Cas9 delivery and propose strategies that may overcome these barriers to realize the clinical potential of CRISPR/Cas9-based genome editing. PMID- 28640611 TI - Lattice-Hydride Mechanism in Electrocatalytic CO2 Reduction by Structurally Precise Copper-Hydride Nanoclusters. AB - Copper electrocatalysts can reduce CO2 to hydrocarbons at high overpotentials. However, a mechanistic understanding of CO2 reduction on nanostructured Cu catalysts has been lacking. Herein we show that the structurally precise ligand protected Cu-hydride nanoclusters, such as Cu32H20L12 (L is a dithiophosphate ligand), offer unique selectivity for electrocatalytic CO2 reduction at low overpotentials. Our density functional theory (DFT) calculations predict that the presence of the negatively charged hydrides in the copper cluster plays a critical role in determining the selectivity of the reduction product, yielding HCOOH over CO with a lower overpotential. The HCOOH formation proceeds via the lattice-hydride mechanism: first, surface hydrides reduce CO2 to HCOOH product, and then the hydride vacancies are readily regenerated by the electrochemical proton reduction. DFT calculations further predict that hydrogen evolution is less competitive than HCOOH formation at the low overpotential. Confirming the predictions, electrochemical tests of CO2 reduction on the Cu32H20L12 cluster demonstrate that HCOOH is indeed the main product at low overpotential, while H2 production dominates at higher overpotential. The unique selectivity afforded by the lattice-hydride mechanism opens the door for further fundamental and applied studies of electrocatalytic CO2 reduction by copper-hydride nanoclusters and other metal nanoclusters that contain hydrides. PMID- 28640613 TI - Molecular Recognition Under Interfacial Conditions: Calix[4]pyrrole-Based Cross linkable Micelles for Ion Pair Extraction. AB - An anthracene-functionalized, long-tailed calix[4]pyrrole 1, containing both an anion-recognition site and cation-recognition functionality, has been synthesized and fully characterized. Upon ion pair complexation with FeF2, receptor 1 self assembles into multimicelles in aqueous media. This aggregation process is ascribed to a change in polarity from nonpolar to amphiphilic induced upon concurrent anion and cation complexation and permits molecular recognition-based control over chemical morphology under interfacial conditions. Photoirradiation of the micelles serves to cross-link the anthracene units thus stabilizing the aggregates. The combination of ion pair recognition, micelle formation, and cross linking can be used to extract FeF2 ion pairs from bulk aqueous solutions. The present work helps illustrate how molecular recognition and self-assembly may be used to control the chemistry of extractants at interfaces. PMID- 28640614 TI - Role of Polymeric Coating on the Phosphate Availability as a Fertilizer: Insight from Phosphate Release by Castor Polyurethane Coatings. AB - The coating of fertilizers with polymers is an acknowledged strategy for controlling the release of nutrients and their availability in soil. However, its effectiveness in the case of soluble phosphate fertilizers is still uncertain, and information is lacking concerning the chemical properties and structures of such coatings. Here, an oil-based hydrophobic polymer system (polyurethane) is proposed for the control of the release of phosphorus from diammonium phosphate (DAP) granules. This material was systematically characterized, with evaluation of the delivery mechanism and the availability of phosphate in an acid soil. The results indicated that thicker coatings can change the maximum nutrient availability toward longer periods, such as 4.5-7.5 wt % DAP coated, that presented the highest concentrations at 336 h, as compared to 168 h for uncoated DAP. In contrast, DAP treated with 9.0 wt % began to increase the concentration after 168 h until it results in maximum release at 672 h. These effects could be attributed to the homogeneity of the polymer and the porosity. The strategy successfully provided long-term availability of a phosphate source. PMID- 28640616 TI - Twist of a Silicon-Silicon Double Bond: Selective Anti-Addition of Hydrogen to an Iminodisilene. AB - Hydrogenation of alkenes with C?C bonds is a ubiquitous reaction in organic chemistry. However, this transformation remains unknown for heavier counterparts, disilenes with Si?Si bonds. Here we report the isolation of (Z) diiminodisilyldisilene 2 featuring a highly trans-bent and twisted structure and the longest silicon-silicon double bond reported to date. In silico studies suggested that the Si?Si bond in 2 is described as very weak double donor acceptor bond. We utilized the remarkable electronic and structural features of this product to achieve the first demonstration of hydrogen activation by a multiply bonded silicon compound under ambient conditions. Interestingly, NMR and X-ray analysis gave exclusively racemic (RR/SS)-1,2-disilane 3a, indicating a stereospecific trans-hydrogenation of the Si?Si bond. In-depth calculations revealed that in strong contrast to the reactivity of C?C bonds, a concerted anti addition pathway was favored due to the twisted structure of 2. PMID- 28640615 TI - Reduction of Dinitrogen to Ammonia Catalyzed by Molybdenum Diamido Complexes. AB - [Ar2N3]Mo(N)(O-t-Bu), which contains the conformationally rigid pyridine-based diamido ligand, [2,6-(ArNCH2)2NC5H3]2- (Ar = 2,6-diisopropylphenyl), can be prepared from H2[Ar2N3], butyllithium, and (t-BuO)3Mo(N). [Ar2N3]Mo(N)(O-t-Bu) serves as a catalyst or precursor for the catalytic reduction of molecular nitrogen to ammonia in diethyl ether between -78 and 22 degrees C in a batchwise manner with CoCp*2 as the electron source and Ph2NH2OTf as the proton source. Up to ~10 equiv of ammonia can be formed per Mo with a maximum efficiency in electrons of ~43%. PMID- 28640617 TI - 5-Methylhydantoin: From Isolated Molecules in a Low-Temperature Argon Matrix to Solid State Polymorphs Characterization. AB - The molecular structure, vibrational spectra and photochemistry of 5 methylhydantoin (C4H6N2O2; 5-MH) were studied by matrix isolation infrared spectroscopy and theoretical calculations at the DFT(B3LYP)/6-311++G(d,p) theory level. The natural bond orbital (NBO) analysis approach was used to study in detail the electronic structure of the minimum energy structure of 5-MH, namely the specific characteristics of the sigma and pi electronic systems of the molecule and the stabilizing orbital interactions. UV irradiation of 5-MH isolated in argon matrix resulted in its photofragmentation through a single photochemical pathway, yielding isocyanic acid, ethanimine, and carbon monoxide, thus following a pattern already observed before for the parent hydantoin and 1 methylhydantoin molecules. The investigation of the thermal properties of 5-MH was undertaken by differential scanning calorimetry (DSC), polarized light thermal microscopy (PLTM) and Raman spectroscopy. Four different polymorphs of 5 MH were identified. The crystal structure of one of the polymorphs, for which it was possible to grow up suitable crystals, was determined by X-ray diffraction (XRD). Two of the additional polymorphs were characterized by powder XRD, which confirmed the molecules pack in different crystallographic arrangements. PMID- 28640618 TI - Dynamic Roughness Ratio-Based Framework for Modeling Mixed Mode of Droplet Evaporation. AB - The spatiotemporal evolution of an evaporating sessile droplet and its effect on lifetime is crucial to various disciplines of science and technology. Although experimental investigations suggest three distinct modes through which a droplet evaporates, namely, the constant contact radius (CCR), the constant contact angle (CCA), and the mixed, only the CCR and the CCA modes have been modeled reasonably. Here we use experiments with water droplets on flat and micropillared silicon substrates to characterize the mixed mode. We visualize that a perfect CCA mode after the initial CCR mode is an idealization on a flat silicon substrate, and the receding contact line undergoes intermittent but recurring pinning (CCR mode) as it encounters fresh contaminants on the surface. The resulting increase in roughness lowers the contact angle of the droplet during these intermittent CCR modes until the next depinning event, followed by the CCA mode of evaporation. The airborne contaminants in our experiments are mostly loosely adhered to the surface and travel along with the receding contact line. The resulting gradual increase in the apparent roughness and hence the extent of CCR mode over CCA mode forces appreciable decrease in the contact angle observed during the mixed mode of evaporation. Unlike loosely adhered airborne contaminants on flat samples, micropillars act as fixed roughness features. The apparent roughness fluctuates about the mean value as the contact line recedes between pillars. Evaporation on these surfaces exhibits stick-jump motion with a short-duration mixed mode toward the end when the droplet size becomes comparable to the pillar spacing. We incorporate this dynamic roughness into a classical evaporation model to accurately predict the droplet evolution throughout the three modes, for both flat and micropillared silicon surfaces. We believe that this framework can also be extended to model the evaporation of nanofluids and the coffee-ring effect, among others. PMID- 28640619 TI - Optimization and Automation of the Construction of Smooth Free Energy Profiles. AB - An adaptive procedure is introduced to construct smooth analytical profiles of the free energy along a reaction coordinate using sampled data from multiple biased simulations. The procedure is based upon identifying problematic regions encountered in maximum likelihood estimators of the profile where there are statistically relevant discrepancies between the empirical and parametrized cumulative distribution functions and preferentially improving the construction of the parametric profile in these regions. The method is designed to produce continuous and smooth analytical fits that satisfy statistical goodness-of-fit tests with a minimum number of parameters. The accuracy of the profile obtained from the adaptive construction is compared by numerical computation to that of smooth interpolations based on an optimally chosen weighted histogram method for a solvated ion pair system and for an activated process for which the analytical form of the potential of mean force is available. In the model where the exact profile is known, the adaptive procedure is shown to reduce the integrated error relative to the optimal histogram construction by a factor of 3 or more in the typical case where the sampling is not extensive. It is demonstrated that the adaptive procedure can be used to produce statistically accurate smooth analytical representations of the free energy profile that can be evaluated with little computational effort and require little user input. PMID- 28640620 TI - Using Complementary NMR Data Sets To Detect Inconsistencies and Model Flaws in the Structure Determination of Human Interleukin-4. AB - The derivation of protein structure from values of observable quantities measured in NMR experiments is a rather nontrivial task due to (i) the limited number of data compared to degrees of freedom of a protein, (ii) the uncertainty inherent to the function connecting an observable quantity to molecular structure, (iii) the finite quality of biomolecular models and force fields used in structure refinement, and (iv) the conformational freedom of a protein in aqueous solution, which requires extensive conformational sampling and appropriate conformational averaging when calculating or restraining to sets of NMR data. The protein interleukin-4 (IL-4) has been taken as a test case using NOE distances, S2 order parameters, and 3J-couplings as test data and the former two types of data as restraints. It is shown that, by combining sets of different, complementary NMR data as restraints in MD simulations, inconsistencies in the data or flaws in the model and procedures used to derive protein structure from NMR data can be detected. This leads to an improved structural interpretation of such data particularly in more mobile loop regions. PMID- 28640621 TI - Transformation of Methylene Acetals to Bromoformates with a Combination of Trimethyl(phenylthio)silane and N-Bromosuccinimide. AB - A novel transformation reaction of methylene acetals, using a combination of trimethyl(phenylthio)silane (PhSTMS) and N-bromosuccinimide (NBS) under mild reaction conditions, is described. Various methylene acetals were converted to their corresponding bromoformates in good to high yields. Under the given conditions, the reaction proceeded via a radical pathway. Further transformation of bromoformates to their corresponding epoxides was achieved by treatment with NaOMe. PMID- 28640623 TI - Reactions of Sulfur-Containing Organic Compounds and Peptides in 1-Ethyl-3-methyl imidazolium Acetate. AB - The neat ionic liquid (IL) [C2mim][OAc] is not just capable of dissolving thiol- and disulfide-containing compounds, but is able to chemically react with them without addition of any catalytic reagent. Through the analysis of four small organic molecules and a cysteine-containing peptide we could postulate a general reaction mechanism. Here, the imidazolium-carbenes preferentially react with the disulfide bond, but not thiol group. Moreover, the imidazole moiety was found to abstract the sulfur atom from the cysteine residue, providing an alternative way to transform Cys residues, which were artificially inserted into a peptide sequence in order to perform native chemical ligation (NCL) of two peptide fragments. Finally, the chemical reaction of [C2mim][OAc] with a cysteine containing biomolecules can be tuned or even suppressed through the addition of at least 30% of water to the reaction mixture. PMID- 28640624 TI - Synthesis of 4-Acylpyrazoles from Saturated Ketones and Hydrazones Featured with Multiple C(sp3)-H Bond Functionalization and C-C Bond Cleavage and Reorganization. AB - In this paper, an efficient and convenient one-pot synthesis of diversely substituted 4-acylpyrazole derivatives via copper-catalyzed one-pot cascade reactions of saturated ketones with hydrazones is reported. Mechanistically, the formation of the title compounds involves the in situ formation of an enone intermediate through the dehydrogenation of a saturated ketone and the [2 + 3] cyclization of the enone with hydrazone followed by an aromatization-driven C-C bond cleavage and reorganization. To our knowledge, this is the first example in which the biologically and pharmaceutically important yet otherwise difficult-to obtain 4-acylpyrazole derivatives are directly prepared from saturated ketones and hydrazones featured with multiple aliphatic C-H bond functionalization and C C bond cleavage and reorganization. Compared with literature methods, this novel process has advantages such as simple and economical starting materials, a sustainable oxidant, excellent regioselectivity, and good efficiency. PMID- 28640625 TI - Dust Effects on Nucleation Kinetics and Nanoparticle Product Size Distributions: Illustrative Case Study of a Prototype Ir(0)n Transition-Metal Nanoparticle Formation System. AB - The question is addressed if dust is kinetically important in the nucleation and growth of Ir(0)n nanoparticles formed from [Bu4N]5Na3(1,5-COD)IrI.P2W15Nb3O62 (hereafter [(COD)Ir.POM]8-), reduced by H2 in propylene carbonate solvent. Following a concise review of the (often-neglected) literature addressing dust in nucleation phenomena dating back to the late 1800s, the nucleation and growth kinetics of the [(COD)Ir.POM]8- precatalyst system are examined for the effects of 0.2 MUm microfiltration of the solvent and precatalyst solution, of rinsing the glassware with that microfiltered solvent, of silanizing the glass reaction vessel, for the addition of <0.2 MUm gamma-Al2O3 (inorganic) dust, for the addition of flame-made carbon-based (organic) dust, and as a function of the starting, microfiltered [(COD)Ir.POM8-] concentration. Efforts to detect dust and its removal by dynamic light scattering and by optical microscopy are also reported. The results yield a list of eight important conclusions, the four most noteworthy of which are (i) that the nucleation apparent rate "constant" k1obs(bimol) is shown to be slowed by a factor of ~5 to ~7.6, depending on the precise experiment and its conditions, just by the filtration of the precatalyst solution using a 0.20 MUm filter and rinsing the glassware surface with 0.20 MUm filtered propylene carbonate solvent; (ii) that simply employing a 0.20 MUm filtration step narrows the size distribution of the resulting Ir(0)n nanoparticles by a factor of 2.4 from +/-19 to +/-8%, a remarkable result; (iii) that the narrower size distribution can be accounted for by the slowed nucleation rate constant, k1obs(bimol), and by the unchanged autocatalytic growth rate constant, k2obs(bimol), that is, by the increased ratio of k2obs(bimol)/k1obs(bimol) that further separates nucleation from growth in time for filtered vs unfiltered solutions; and (iv) that five lines of evidence indicate that the filterable component of the solution, which has nucleation rate enhancing and size-dispersion broadening effects, is dust. PMID- 28640626 TI - Photocatalytic Hydrazonyl Radical-Mediated Radical Cyclization/Allylation Cascade: Synthesis of Dihydropyrazoles and Tetrahydropyridazines. AB - A novel photocatalytic hydrazonyl radical-mediated radical cyclization/allylation cascade reaction of beta,gamma-unsaturated hydrazones is developed using allyl sulfones and Morita-Baylis-Hillman adduct as allyl sources, which provides an efficient and practical access to various diversely functionalized dihydropyrazoles and tetrahydropyridazines. The reaction is enabled by controllable generation of hydrazonyl radicals via an oxidative deprotonation electron transfer strategy and selective trapping of the resultant C-centered radicals under visible light irradiation. PMID- 28640627 TI - Chemical Modification of n-Type-Material Naphthalene Diimide on ITO for Efficient and Stable Inverted Polymer Solar Cells. AB - To provide orthogonal solvent processable surface modification and improve the device stability of bulk-heterojunction polymer solar cells (PSCs), n-type semiconducting material naphthalene diimide (NDI) was chemically introduced onto the ITO surface as a cathode interlayer (CIL) using 3-bromopropyltrimethoxysilane (BrTMS) as a coupling agent. After modification, the work function of ITO can be decreased from 4.70 to 4.23 eV. The modified ITO cathode was applied in inverted PSCs based on PTB7-Th:PC71BM. With the CIL modification, a champion power conversion efficiency (PCE) of 5.87% was achieved, showing a dramatic improvement compared to that of devices (PCE = 3.58%) without CIL. More importantly, with these chemical bonded interlayers, the stability of inverted PSCs was greatly enhanced. The improved PCE and stability can be attributed to the increased open circuit voltage and the formation of robust chemical bonds in NDI-TMS films, respectively. This study demonstrated that chemical modification of ITO with n type semiconducting materials provides an avenue for not only solving the solvent orthogonal problem but also improving the device performance in terms of the PCE and the stability. PMID- 28640628 TI - Oriented Gold Nanorods and Gold Nanorod Chains within Smectic Liquid Crystal Topological Defects. AB - We show that the use of oriented linear arrays of smectic A defects, the so called smectic oily streaks, enables the orientation of gold nanorods (GNRs) for a large range of GNR diameters, ranging from 7 to 48 nm, and for various ligands. For the small GNRs it enables oriented end-to-end small chains of GNRs when the density is increased from around 2 GNRs/MUm2 to around 6 GNRs/MUm2. We have characterized the orientation of single GNRs by spectrophotometry and two-photon luminescence (TPL). A strongly anisotropic absorption of the composites and an on off switching of GNR luminescence, both controlled by incident light polarization, are observed, revealing an orientation of the GNRs mostly parallel to the oily streaks. A more favorable trapping of GNRs by smectic dislocations with respect to ribbon-like defects is thus demonstrated. The dislocations appear to be localized at a specific localization, namely, the summit of rotating grain boundaries. Combining plasmonic absorption measurements, TPL measurements, and simulation of the plasmonic absorption, we show that the end-to-end GNR chains are both dimers and trimers, all parallel to each other, with a small gap between the coupled GNRs, on the order of 1.5 nm, thus associated with a large red-shift of 110 nm of the longitudinal plasmonic mode. A motion of the GNRs along the dislocations appears as a necessary ingredient for the formation of end-to-end GNR chains, the gap value being driven by the balance between the attracting van der Waals interactions and the steric repulsion between the GNRs and leading to interdigitation of the neighboring ligands. We thus obtain electromagnetic coupling of nanorods controlled by light polarization. PMID- 28640629 TI - Divergent Coupling of beta,gamma-Unsaturated alpha-Ketoesters with Simple Olefins: Vinylation and [2 + 2] Cycloaddition. AB - Catalytic direct conjugate addition and [2 + 2] cycloaddition reactions of beta,gamma-unsaturated alpha-ketoesters with simple olefins have been developed, affording vinylation products and functionalized cyclobutanes, respectively, in good yields with high regioselectivity. PMID- 28640630 TI - Suzuki-Miyaura Cross-Coupling of N-Acylpyrroles and Pyrazoles: Planar, Electronically Activated Amides in Catalytic N-C Cleavage. AB - The formation of C-C bonds from amides by catalytic activation of the amide bond has been thus far possible by steric distortion. Herein, we report the first example of a general Pd-catalyzed Suzuki-Miyaura cross-coupling of planar amides enabled by the combination of (i) electronic-activation of the amide nitrogen in N-acylpyrroles and pyrazoles and (ii) the use of a versatile Pd-NHC catalysis platform. The origin and selectivity of forming acylmetals, including the role of twist, are discussed. PMID- 28640622 TI - Catalytic Asymmetric Synthesis of Butenolides and Butyrolactones. AB - gamma-Butenolides, gamma-butyrolactones, and derivatives, especially in enantiomerically pure form, constitute the structural core of numerous natural products which display an impressive range of biological activities which are important for the development of novel physiological and therapeutic agents. Furthermore, optically active gamma-butenolides and gamma-butyrolactones serve also as a prominent class of chiral building blocks for the synthesis of diverse biological active compounds and complex molecules. Taking into account the varying biological activity profiles and wide-ranging structural diversity of the optically active gamma-butenolide or gamma-butyrolactone structure, the development of asymmetric synthetic strategies for assembling such challenging scaffolds has attracted major attention from synthetic chemists in the past decade. This review offers an overview of the different enantioselective synthesis of gamma-butenolides and gamma-butyrolactones which employ catalytic amounts of metal complexes or organocatalysts, with emphasis focused on the mechanistic issues that account for the observed stereocontrol of the representative reactions, as well as practical applications and synthetic potentials. PMID- 28640631 TI - Photoinduced Oxidative Formylation of N,N-Dimethylanilines with Molecular Oxygen without External Photocatalyst. AB - A photoinduced oxidative formylation of N,N-dimethylanilines with molecular oxygen in the absence of an external photocatalyst was developed and provided the corresponding formamides in good yields under mild reaction conditions. Investigations indicated that both the starting material and product act as photosensitizers and that 1O2 coexists with O2*- during the reaction through energy transfer and single electron transfer process. PMID- 28640632 TI - Gut Microbiota, Nitric Oxide, and Microglia as Prerequisites for Neurodegenerative Disorders. AB - Regulating fluctuating endogenous nitric oxide (NO) levels is necessary for proper physiological functions. Aberrant NO pathways are implicated in a number of neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease. The mechanism of NO in oxidative and nitrosative stress with pathological consequences involves reactions with reactive oxygen species (e.g., superoxide) to form the highly reactive peroxynitrite, hydrogen peroxide, hypochloride ions and hydroxyl radical. NO levels are typically regulated by endogenous nitric oxide synthases (NOS), and inflammatory iNOS is implicated in the pathogenesis of neurodegenerative diseases, in which elevated NO mediates axonal degeneration and activates cyclooxygenases to provoke neuroinflammation. NO also instigates a down-regulated secretion of brain-derived neurotrophic factor, which is essential for neuronal survival, development and differentiation, synaptogenesis, and learning and memory. The gut-brain axis denotes communication between the enteric nervous system (ENS) of the GI tract and the central nervous system (CNS) of the brain, and the modes of communication include the vagus nerve, passive diffusion and carrier by oxyhemoglobin. Amyloid precursor protein that forms amyloid beta plaques in AD is normally expressed in the ENS by gut bacteria, but when amyloid beta accumulates, it compromises CNS functions. Escherichia coli and Salmonella enterica are among the many bacterial strains that express and secrete amyloid proteins and contribute to AD pathogenesis. Gut microbiota is essential for regulating microglia maturation and activation, and activated microglia secrete significant amounts of iNOS. Pharmacological interventions and lifestyle modifications to rectify aberrant NO signaling in AD include NOS inhibitors, NMDA receptor antagonists, potassium channel modulators, probiotics, diet, and exercise. PMID- 28640633 TI - Exploring a Proximity-Coupled Co Chain on Pb(110) as a Possible Majorana Platform. AB - Linear chains of magnetic atoms proximity coupled to an s-wave superconductor are predicted to host Majorana zero modes at the chain ends in the presence of strong spin-orbit coupling. Specifically, iron (Fe) chains on Pb(110) have been explored as a possible system to exhibit topological superconductivity and host Majorana zero modes [ Nadj-Perge , S. et al., Science 2014 , 346 , 602 - 607 ]. Here, we study chains of the transition metal cobalt (Co) on Pb(110) and check for topological signatures. Using spin-polarized scanning tunneling spectroscopy, we resolve ferromagnetic order in the d bands of the chains. Interestingly, also the subgap Yu-Shiba-Rusinov (YSR) bands carry a spin polarization as was predicted decades ago. Superconducting tips allow us to resolve further details of the YSR bands and in particular resonances at zero energy. We map the spatial distribution of the zero-energy signal and find it delocalized along the chain. Hence, despite the ferromagnetic coupling within the chains and the strong spin orbit coupling in the superconductor, we do not find clear evidence of Majorana modes. Simple tight-binding calculations suggest that the spin-orbit-split bands may cross the Fermi level four times which suppresses the zero-energy modes. PMID- 28640634 TI - Structure Prediction for Surface-Induced Phases of Organic Monolayers: Overcoming the Combinatorial Bottleneck. AB - Structure determination and prediction pose a major challenge to computational material science, demanding efficient global structure search techniques tailored to identify promising and relevant candidates. A major bottleneck is the fact that due to the many combinatorial possibilities, there are too many possible geometries to be sampled exhaustively. Here, an innovative computational approach to overcome this problem is presented that explores the potential energy landscape of commensurate organic/inorganic interfaces where the orientation and conformation of the molecules in the tightly packed layer is close to a favorable geometry adopted by isolated molecules on the surface. It is specifically designed to sample the energetically lowest lying structures, including the thermodynamic minimum, in order to survey the particularly rich and intricate polymorphism in such systems. The approach combines a systematic discretization of the configuration space, which leads to a huge reduction of the combinatorial possibilities with an efficient exploration of the potential energy surface inspired by the Basin-Hopping method. Interfacing the algorithm with first principles calculations, the power and efficiency of this approach is demonstrated for the example of the organic molecule TCNE (tetracyanoethylene) on Au(111). For the pristine metal surface, the global minimum structure is found to be at variance with the geometry found by scanning tunneling microscopy. Rather, our results suggest the presence of surface adatoms or vacancies that are not imaged in the experiment. PMID- 28640635 TI - Total Synthesis of Huperzine Q. AB - The total synthesis of huperzine Q was accomplished. The synthesis features the construction of the cis-hydrindane skeleton via a Diels-Alder reaction and a ring contraction reaction of an epoxyketone. PMID- 28640636 TI - Cross-Reactive Synbody Affinity Ligands for Capturing Diverse Noroviruses. AB - Noroviruses are the most common cause of acute gastroenteritis in the developed world. Noroviruses are a diverse group of nonenveloped RNA viruses that are continuously evolving. This leads to the rise of immunologically distinct strains of the same genotype on a frequent basis. This diversity presents a unique challenge for detection and tracking of new strains, with the continuous need for new norovirus affinity ligands. Our group developed a family of bivalent synbody affinity ligands using a virus-like particle (VLP) from the 2006 GII.4 Minerva strain of norovirus. We produced more than 20 synbodies with low nanomolar dissociation constants (KD < 10 nM) for GII.4 VLP. We measured binding affinity for four synbodies against VLPs from multiple GI and GII genotypes and found that the synbodies were broadly cross-reactive with affinities that ranged from 0.5 to 8 nM. We tested the ability of these synbodies to capture norovirus from dilute solutions and found that one synbody could capture GII.4 from a 200 000-fold dilution from a norovirus positive stool sample. When these synbodies were tested for the ability to capture of multiple genotypes, we found that four different genotypes were recognized. These data demonstrate that the synbody approach can generate multiple affinity ligands for future use in norovirus detection and possible therapeutic development. PMID- 28640637 TI - Designing Transmitter Ligands That Mediate Energy Transfer between Semiconductor Nanocrystals and Molecules. AB - Molecular control of energy transfer is an attractive proposition because it allows chemists to synthetically tweak various kinetic and thermodynamic factors. In this Perspective, we examine energy transfer between semiconductor nanocrystals (NCs) and pi-conjugated molecules, focusing on the transmitter ligand at the organic-inorganic interface. Efficient transfer of triplet excitons across this interface allows photons to be directed for effective use of the entire solar spectrum. For example, a photon upconversion system composed of semiconductor NCs as sensitizers, bound organic ligands as transmitters, and molecular annihilators has the advantage of large, tunable absorption cross sections across the visible and near-infrared wavelengths. This may allow the near-infrared photons to be harnessed for photovoltaics and photocatalysis. Here we summarize the progress in this recently reported hybrid upconversion platform and point out the challenges. Since triplet energy transfer (TET) from NC donors to molecular transmitters is one of the bottlenecks, emphasis is on the design of transmitters in terms of molecular energetics, photophysics, binding affinity, stability, and energy offsets with respect to the NC donor. Increasing the efficiency of TET in this hybrid platform will increase both the up- and down conversion quantum yields, potentially exceeding the Shockley-Queisser limit for photovoltaics and photocatalysis. PMID- 28640638 TI - Enzyme-Mediated Conversion of Flavin Adenine Dinucleotide (FAD) to 8-Formyl FAD in Formate Oxidase Results in a Modified Cofactor with Enhanced Catalytic Properties. AB - Flavins, including flavin adenine dinucleotide (FAD), are fundamental catalytic cofactors that are responsible for the redox functionality of a diverse set of proteins. Alternatively, modified flavin analogues are rarely found in nature as their incorporation typically results in inactivation of flavoproteins, thus leading to the disruption of important cellular pathways. Here, we report that the fungal flavoenzyme formate oxidase (FOX) catalyzes the slow conversion of noncovalently bound FAD to 8-formyl FAD and that this conversion results in a nearly 10-fold increase in formate oxidase activity. Although the presence of an enzyme-bound 8-formyl FMN has been reported previously as a result of site directed mutagenesis studies of lactate oxidase, FOX is the first reported case of 8-formyl FAD in a wild-type enzyme. Therefore, the formation of the 8-formyl FAD cofactor in formate oxidase was investigated using steady-state kinetics, site-directed mutagenesis, ultraviolet-visible, circular dichroism, and fluorescence spectroscopy, liquid chromatography with mass spectrometry, and computational analysis. Surprisingly, the results from these studies indicate not only that 8-formyl FAD forms spontaneously and results in the active form of FOX but also that its autocatalytic formation is dependent on a nearby arginine residue, R87. Thus, this work describes a new enzyme cofactor and provides insight into the little-understood mechanism of enzyme-mediated 8alpha-flavin modifications. PMID- 28640639 TI - Alkaline Earth-Centered CO Homologation, Reduction, and Amine Carbonylation. AB - Reactions of beta-diketiminato magnesium and calcium hydrides with 1 atm of CO result in a reductive coupling process to produce the corresponding derivatives of the cis-ethenediolate dianion. Computational (DFT) analysis of this process mediated by Ca, Sr, and Ba highlights a common mechanism and a facility for the reaction that is enhanced by increasing alkaline earth atomic weight. Reaction of CO with PhSiH3 in the presence of the magnesium or calcium hydrides results in catalytic reduction to methylsilane and methylene silyl ether products, respectively. These reactions are proposed to ensue via the interception of initially formed group 2 formyl intermediates, an inference which is confirmed by a DFT analysis of the magnesium-centered reaction. The computational results identify the rate-determining process, requiring traversal of a 33.9 kcal mol-1 barrier, as a Mg-H/C-O sigma-bond metathesis reaction, associated with the ultimate cleavage of the C-O bond. The carbonylation reactivity is extended to a variety of magnesium and calcium amides. With primary amido complexes, which for calcium include a derivative of the parent [NH2]- anion, CO insertion is facile and ensues with subsequent nitrogen-to-carbon migration of hydrogen to yield a variety of dinuclear and, in one case, trinuclear formamidate species. The generation of initial carbenic carbamoyl intermediates is strongly implicated through the isolation of the CO insertion product of a magnesium N-methylanilide derivative. These observations are reinforced by a DFT analysis of the calcium centered reaction with aniline, which confirms the exothermicity of the formamidate formation (DeltaH = -67.7 kcal mol-1). Stoichiometric reduction of the resultant magnesium and calcium formamidates with pinacolborane results in the synthesis of the corresponding N-borylated methylamines. This takes place via a sequence of reactions initiated through the generation of amidatohydridoborate intermediates and a cascade of reactivity that is analogous to that previously reported for the deoxygenative hydroboration of organic isocyanates catalyzed by the same magnesium hydride precatalyst. Although a sequence of amine formylation and deoxygenation may be readily envisaged for the catalytic utilization of CO as a C1 source in the production of methylamines, our observations demonstrate that competitive amine-borane dehydrocoupling is too facile under the conditions of 1 atm of CO employed. PMID- 28640640 TI - Dialkylammonium tert-Butylmethylphosphinites: Stable Intermediates for the Synthesis of P-Stereogenic Ligands. AB - The preparation of shelf-stable crystalline salts of tert-butylmethylphosphinous acid borane 1 is described. X-ray analysis of diisopropylammonium tert butylmethylphosphinite borane 6 revealed the presence of a cyclic hydrogen-bond network in the solid state which accounts for an increased melting point and stability. Dialkylammonium phosphinite boranes are convenient precursors of the chiral tert-butylmethylphosphine fragment. Compound 6 can be used directly in SN2@P reactions with various nucleophiles to yield valuable P-stereogenic intermediates and ligands. PMID- 28640641 TI - First-Principles Calculation of Pt Surface Energies in an Electrochemical Environment: Thermodynamic Driving Forces for Surface Faceting and Nanoparticle Reconstruction. AB - Platinum is a widely used catalyst in aqueous and electrochemical environments. The size and shape of Pt nanoparticles and the faceting (and roughness) of extended Pt surfaces change during use in these environments due to dissolution, growth, and reconstruction. Further, many Pt nanoparticle synthesis techniques are carried out in an aqueous environment. The surface structures formed are impacted by the relative surface energies of the low index facets in these environments. Density functional theory is used to calculate the surface energy of the low index facets of platinum as a function of electrochemical potential and coverage of adsorbed hydrogen, hydroxide, oxygen, and the formation of surface oxide in an aqueous environment. Whereas Pt(111) is the lowest energy bare surface in vacuum, the strong adsorption of hydrogen to Pt(100) at low potentials and of hydroxide to Pt(110) and oxygen to Pt(100) at high potentials drives these surfaces to be more stable in an electrochemical environment. We experimentally conditioned a polycrystalline platinum electrode by cycling the potential and find a growth in the total area as well as in the fraction of 110 and 100 sites, which are lower in energy at potentials where dissolved Pt is deposited or surface oxide is reduced. Further, we find that the lower surface energy of Pt(100) at low potentials may play a role in the growth of tetrahexahedral nanoparticles seen on square wave cycling of spherical Pt nanoparticles. Wulff constructions are presented as a function of Pt electrode potential. PMID- 28640642 TI - Epidemiological characteristics of hyperhomocysteinemia and H-type hypertension in the elderly in Beijing, China. AB - Hyperhomocysteinemia (HHcy) is an important risk factor for atherosclerosis related diseases, and H-type hypertension (HHT) is becoming a major health-care concern in China. We assessed the prevalence of HHcy and HHT in the elderly in a retrospective study based on data obtained from the Beijing Longitudinal Study of Aging. This cross-sectional study comprised 1460 people in the general population (638 males and 822 females) aged >=60 years dwelling in an urban district, a suburb, and an outer suburb of Beijing in 2012. Statistical sampling techniques included cluster, stratification, and random selection. Basic information and physical examination data were collected by trained staff, and the levels of plasma homocysteine (Hcy) were measured. Our results showed that the mean concentration of plasma Hcy was 21.3 MUmol/L in the elderly population (24.2 MUmol/L for males and 19.0 MUmol/L for females; 22.5 MUmol/L for rural residents and 20.4 MUmol/L for urban residents); 74.4% of the subjects were considered to have HHcy (86.2% of males and 63.8% of females; 75.8% of rural and 73.0% of urban residents), and 50.2% were considered to have HHT (55.2% of males and 45.7% of females; 51.8% of rural and 48.8% of urban residents). Our study findings indicated that the prevalence of HHcy and HHT was high among elderly persons in Beijing. PMID- 28640643 TI - Obstructive Sleep Apnea and Diabetes Mellitus. 'Seeing' beyond Glycemic Control. PMID- 28640645 TI - Breastfeeding's Role in the Neurobiology of Parenting. PMID- 28640644 TI - Nebivolol alleviates aortic remodeling through eNOS upregulation and inhibition of oxidative stress in l-NAME-induced hypertensive rats. AB - PURPOSE: To investigate the effect and mechanism of nebivolol on aortic remodeling in N-nitro-l-arginine methyl ester (l-NAME)-induced hypertension. METHODS: Male Sprague-Dawley rats were treated with equal volumes of drinking water or l-NAME (60 mg/kg/day), alone or in combination with nebivolol (8 mg/kg/day) or atenolol (80 mg/kg/day) by gavage for 8 weeks. Systolic blood pressure (SBP), aortic morphometry, plasma nitric oxide (NO) levels, nitric oxide synthase (NOS) activity, and relaxation of aorta to acetylcholine were determined. Protein expression of endothelial NOS (eNOS), Akt, and NADPH oxidase (Nox) was evaluated. RESULTS: l-NAME-treated rats showed an elevated SBP associated with aortic remodeling. l-NAME-treated rats showed reduced plasma NO levels and NOS activity and increased reactive oxygen species (ROS). Protein expression of eNOS, eNOS phosphorylated at Ser1177 (p-eNOS), Akt, and Akt phosphorylated at Ser473 (p-Akt) decreased, whereas that of Nox2, Nox4, and p22phox increased in the aortas from l-NAME-treated rats. Nebivolol treatment reduced SBP and ameliorated aortic remodeling. The effects of nebivolol were accompanied by increasing NO levels, NOS activity, and expression of eNOS, p eNOS, Akt, and p-Akt, as well as reduction of ROS generation and Nox2, Nox4, and p22phox expression. These effects of nebivolol were not reproduced by atenolol. CONCLUSION: Our data indicate a protective role of nebivolol on the high blood pressure and vascular remodeling induced by l-NAME. The beneficial vascular effect of nebivolol is mediated by the upregulation of eNOS and inhibition of oxidative stress. PMID- 28640646 TI - An enzyme-linked immunosorbent assay for monoester-type aconitic alkaloids and its application in the pharmacokinetic study of benzoylhypaconine in rats. AB - A new enzyme-linked immunosorbent assay (ELISA) method for quantitative determination of monoester-type aconitic alkaloids was developed. The antibodies derived from the immunogen of benzoylmesaconine (BM) could be electively affined to benzoylaconitine-type alkaloids with an ester bond (14-benzoyl-), especially to benzoylhypaconine (BH, 140.02% of cross-reactivity). The effective working range of BH was 1 ng/ml to 5 MUg/ml; the lower limit of detection and the quantification were 0.35 and 0.97 ng/ml, respectively. The values of CV for intra day and inter-day assays and recovery ratios were in acceptable ranges. The results of stability experiments were also satisfactory. This validated method was employed for pharmacokinetic study of BH in rats and the bioavailability orally administered was estimated to be 16.3%. PMID- 28640647 TI - Influence of PRKCH gene polymorphism on antihypertensive response to amlodipine and telmisartan. AB - This study aimed to evaluate the effect of PRKCH rs2230500 genetic polymorphism on efficacy of amlodipine and telmisartan for patients with hypertension. A total of 136 essential hypertension (EH) patients were treated with amlodipine (70 patients) or telmisartan (66 patients), respectively. Genetic polymorphism was genotyped by Sanger sequencing. Both baseline and post-treatment blood pressure (BP) and heart rate were measured to evaluate the influence of genetic polymorphism on the antihypertensive response. No significant difference in the absolute decrease in diastolic blood pressure (DBP),systolic blood pressure (SBP), and mean arterial pressure (MAP) was observed among PRKCH rs2230500 genotypes after 4-week amlodipine or telmisartan therapy (p > 0.05). However, when compared with carriers or GG genotype, the antihypertensive effect of PRKCH rs2230500 GA/AA carriers was superior in telmisartan treatment group. PRKCH rs2230500 gene polymorphism is significantly related to the efficiency in telmisartan therapy (p = 0.02). The PRKCH rs2230500 may influence the antihypertensive efficacy of telmisartan in Chinese EH patients, and further studies are needed to confirm these findings. PMID- 28640648 TI - Extracellular Vesicle Transfer from Mesenchymal Stromal Cells Modulates Macrophage Function in Acute Lung Injury. Basic Science and Clinical Implications. PMID- 28640649 TI - Asthma Attacks in Children: Does Blocking IgE Reduce Rhinovirus Infections? PMID- 28640650 TI - Exposure Interaction: A Lifelong Phenomenon with Relevance to Chronic Obstructive Pulmonary Disease. PMID- 28640651 TI - Association of the lipoprotein lipase gene Ser447Ter polymorphism with hypertension and blood pressure variation: evidence from an updated meta analysis. AB - The polymorphism of lipoprotein lipase (LPL) gene Ser447Ter (S447X) has long been linked to hypertension and blood pressure variation, but the established data remained controversial. To better elucidate this inconsistency, a meta-analysis was conducted. We comprehensively searched electronic databases, including Pubmed, EMBASE, China National Knowledge Infrastructure (CNKI), Web of Science, for all literatures with the last update on February 2016. The strength of association was calculated by using odds ratios (ORs) and weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs). Further stratified analyses, cumulative meta-analysis analysis, and sensitivity analyses were performed. A total of 14 studies (3592 cases and 4643 controls) for hypertension and 14 studies (n = 9254) for blood pressure were included. Overall, significant associations were revealed between S447X polymorphism and hypertension risk using allelic comparison (OR = 0.86, 95%CI 0.77 to 0.96), heterozygote comparison (OR = 0.85, 95%CI 0.75 to 0.96), and the dominant model (OR = 0.85, 95%CI 0.75 to 0.96), especially in Asians. Furthermore, in subgroup analyses restricted to the population-based controls studies, the high-quality studies, and the large sample size studies, these significant associations were still observed. As for blood pressure association, significant reductions of systolic blood pressure (WMD = -1.25 mmHg, 95%CI -2.25 to -0.25 mmHg) and diastolic blood pressure (WMD = -1.91 mmHg, 95%CI -3.25 to -0.56 mmHg) levels were found using dominant model. No publication bias was observed in any comparison model. Therefore, current meta-analysis suggested that the LPL S447X polymorphism is likely to be a protective factor in the development of hypertension. PMID- 28640652 TI - Protective effect against brain tissues oxidative damage as a possible mechanism for beneficial effects of L-arginine on lipopolysaccharide induced memory impairment in rats. AB - L-Arginine (LA) and nitric oxide (NO) have been suggested to have some effects on learning, memory, brain tissues oxidative damage, and neuroinflammation. In this study, protective effect against brain tissues oxidative damage as a possible mechanism for beneficial effects of LA on lipopolysaccharide (LPS) induced memory impairment was investigated. The rats were grouped into and treated by (1) control (saline), (2) LPS (1 mg/kg, IP), (3) LA (200 mg/kg) - LPS (4) LA. In passive avoidance (PA) test, LPS administration shortened the latency to enter the dark compartment in LPS group compared to control (p < .001) which was accompanied with a high level of malondialdehyde (MDA) and NO metabolite concentrations in the hippocampal tissues (p < .001and p < .05, respectively). Pretreatment with LA prolonged the latency in LA-LPS group compared with LPS group (p < .01-.001) and re-stored MDA and NO metabolites in the hippocampal tissues (p < .05). LPS also reduced superoxide dismutase (SOD) and catalase (CAT) activities and thiol content in the hippocampal tissues in LPS group compared to control (p < .05 and p < .001, respectively) which improved by LA when it was administered before LPS in LA-LPS group (p < .05 and p < .001). Finally, the serum TNFalpha level of LPS group was higher than the control (p < .01) while, in LA-LPS group it was lower than LPS group (p < .01). It seems that the beneficial effects of LA on memory impairment of LPS-treated rats may be due to its protective effects against brain tissues oxidative damage. PMID- 28640653 TI - Epithelial-Mesenchymal Transition: A Necessary New Therapeutic Target in Chronic Obstructive Pulmonary Disease? PMID- 28640654 TI - Reply: Epithelial-Mesenchymal Transition: A Necessary New Therapeutic Target in Chronic Obstructive Pulmonary Disease? PMID- 28640655 TI - Usual Interstitial Pneumonia Can Be Detected in Transbronchial Biopsies Using Machine Learning. AB - RATIONALE: Usual interstitial pneumonia (UIP) is the histopathologic hallmark of idiopathic pulmonary fibrosis. Although UIP can be detected by high-resolution computed tomography of the chest, the results are frequently inconclusive, and pathology from transbronchial biopsy (TBB) has poor sensitivity. Surgical lung biopsy may be necessary for a definitive diagnosis. OBJECTIVES: To develop a genomic classifier in tissue obtained by TBB that distinguishes UIP from non-UIP, trained against central pathology as the reference standard. METHODS: Exome enriched RNA sequencing was performed on 283 TBBs from 84 subjects. Machine learning was used to train an algorithm with high rule-in (specificity) performance using specimens from 53 subjects. Performance was evaluated by cross validation and on an independent test set of specimens from 31 subjects. We explored the feasibility of a single molecular test per subject by combining multiple TBBs from upper and lower lobes. To address whether classifier accuracy depends upon adequate alveolar sampling, we tested for correlation between classifier accuracy and expression of alveolar-specific genes. RESULTS: The top performing algorithm distinguishes UIP from non-UIP conditions in single TBB samples with an area under the receiver operator characteristic curve (AUC) of 0.86, with specificity of 86% (confidence interval = 71-95%) and sensitivity of 63% (confidence interval = 51-74%) (31 test subjects). Performance improves to an AUC of 0.92 when three to five TBB samples per subject are combined at the RNA level for testing. Although we observed a wide range of type I and II alveolar specific gene expression in TBBs, expression of these transcripts did not correlate with classifier accuracy. CONCLUSIONS: We demonstrate proof of principle that genomic analysis and machine learning improves the utility of TBB for the diagnosis of UIP, with greater sensitivity and specificity than pathology in TBB alone. Combining multiple individual subject samples results in increased test accuracy over single sample testing. This approach requires validation in an independent cohort of subjects before application in the clinic. PMID- 28640656 TI - Measuring exertion time, duty cycle and hand activity level for industrial tasks using computer vision. AB - Two computer vision algorithms were developed to automatically estimate exertion time, duty cycle (DC) and hand activity level (HAL) from videos of workers performing 50 industrial tasks. The average DC difference between manual frame-by frame analysis and the computer vision DC was -5.8% for the Decision Tree (DT) algorithm, and 1.4% for the Feature Vector Training (FVT) algorithm. The average HAL difference was 0.5 for the DT algorithm and 0.3 for the FVT algorithm. A sensitivity analysis, conducted to examine the influence that deviations in DC have on HAL, found it remained unaffected when DC error was less than 5%. Thus, a DC error less than 10% will impact HAL less than 0.5 HAL, which is negligible. Automatic computer vision HAL estimates were therefore comparable to manual frame by-frame estimates. Practitioner Summary: Computer vision was used to automatically estimate exertion time, duty cycle and hand activity level from videos of workers performing industrial tasks. PMID- 28640657 TI - Retinal Findings on OCT in Systemic Conditions. AB - PURPOSE: Imaging technology has advanced by leaps and bounds in the recent past and has resulted in a much greater understanding of ocular diseases. The aim of this review article is to summarize optical coherence tomography (OCT) findings of various systemic conditions. METHOD: A systematic literature search of the Medline/PubMed database was performed. English articles up to April 2015 were included. Terms used for search included: Alzheimer's Disease; Multiple Sclerosis; Parkinson's Disease; Behcet's Disease; Schizophrenia; Migraine; Obstructive Sleep Apnea Syndrome; Neurofibromatosis; Sickle Cell Disease; Renal diseases; Lupus Retinopathy; Valsalva Retinopathy; Whiplash Retinopathy; Shaken Baby Syndrome; Choroidal metastases; Intracranial Hypertension; Drug toxicity; Deferoxamine; Sildenafil; Tamoxifen; Hydroxychloroquine; Chloroquine; Ethambutol; Lead; Sickle Cell Disease; and Thalassemia along with OCT. RESULTS: Studies have shown that inner retinal thinning could be the earliest sign of neurological diseases and may help to differentiate individuals with abnormalities. Outer retinal damage was noted in cancer-related retinopathy and secondary to drug toxicity as a diagnostic sign. This review article summarizes the OCT findings and their importance in early diagnosis, treatment, and follow-up in a varying spectrum of systemic diseases including neurological diseases, hematological diseases, cancer-related retinopathies, and systemic drug toxicity. CONCLUSION: OCT findings are useful to predict the probability of a disease, to diagnose it early, to differentiate between healthy and unhealthy tissue, and to assess the effect of therapeutic interventions in many systemic diseases. PMID- 28640658 TI - Advancing the Certified in Public Health Examination: A Job Task Analysis. AB - OBJECTIVES: In 2014, the National Board of Public Health Examiners performed a job task analysis (JTA) to revise the Certified in Public Health (CPH) examination. The objectives of this study were to describe the development, administration, and results of the JTA survey; to present an analysis of the survey results; and to review the implications of this first-ever public health JTA. METHODS: An advisory committee of public health professionals developed a list of 200 public health job tasks categorized into 10 work domains. The list of tasks was incorporated into a web-based survey, and a snowball sample of public health professionals provided 4850 usable responses. Respondents rated job tasks as essential (4), very important (3), important (2), not very important (1), and never performed (0). RESULTS: The mean task importance ratings ranged from 2.61 to 3.01 (important to very important). The highest mean ratings were for tasks in the ethics domain (mean rating, 3.01). Respondents ranked 10 of the 200 tasks as the most important, with mean task rankings ranging from 2.98 to 3.39. We found subtle differences between male and female respondents and between master of public health and doctor of public health respondents in their rankings. CONCLUSION: The JTA established a set of job tasks in 10 public health work domains, and the results provided a foundation for refining the CPH examination. Additional steps are needed to further modify the content outline of the examination. An empirical assessment of public health job tasks, using methods such as principal components analysis, may provide additional insight. PMID- 28640659 TI - PHLDA1 (pleckstrin homology-like domain, family A, member 1) knockdown promotes migration and invasion of MCF10A breast epithelial cells. AB - PHLDA1 (pleckstrin homology-like domain, family A, member 1) is a multifunctional protein that plays distinct roles in several biological processes including cell death and therefore its altered expression has been identified in different types of cancer. Progressively loss of PHLDA1 was found in primary and metastatic melanoma while its overexpression was reported in intestinal and pancreatic tumors. Previous work from our group showed that negative expression of PHLDA1 protein was a strong predictor of poor prognosis for breast cancer disease. However, the function of PHLDA1 in mammary epithelial cells and the tumorigenic process of the breast is unclear. To dissect PHLDA1 role in human breast epithelial cells, we generated a clone of MCF10A cells with stable knockdown of PHLDA1 and performed functional studies. To achieve reduced PHLDA1 expression we used shRNA plasmid transfection and then changes in cell morphology and biological behavior were assessed. We found that PHLDA1 downregulation induced marked morphological alterations in MCF10A cells, such as changes in cell-to-cell adhesion pattern and cytoskeleton reorganization. Regarding cell behavior, MCF10A cells with reduced expression of PHLDA1 showed higher proliferative rate and migration ability in comparison with control cells. We also found that MCF10A cells with PHLDA1 knockdown acquired invasive properties, as evaluated by transwell Matrigel invasion assay and showed enhanced colony-forming ability and irregular growth in low attachment condition. Altogether, our results indicate that PHLDA1 downregulation in MCF10A cells leads to morphological changes and a more aggressive behavior. PMID- 28640660 TI - Chromosome territory relocation paradigm during DNA damage response: Some insights from molecular biology to physics. AB - Among the many facets of DNA damage response (DDR), relocation of chromosome territories (CTs) is most intriguing. We have previously reported that cisplatin induced DDR in human dermal fibroblasts led to relocation of CTs 12, 15 from the nuclear periphery to its interior while CTs 19, 17 repositioned from the interior to its periphery. Studies of CT relocation remain nascent as we begin unraveling the role of key players in DDR to demonstrate its mechanistic basis. Consolidating our recent reports, we argue that gammaH2AX-signaling leads to enhanced recruitment of nuclear myosin 1 (NM1) to chromatin, which via its motor function, results in CT repositioning. Next, we invoke a novel systems-level theory that subsumed CTs as pairs, not solo entities, to present the physical basis for plasticity in interphase CT arrangement. Subsequently, we posited that our systems-level theory describes a unified physical basis for non-random positioning of CTs in interphase nuclei across disparate eukaryotes. PMID- 28640661 TI - Attrition from antiretroviral treatment services among pregnant and non-pregnant patients following adoption of Option B+ in Haiti. AB - BACKGROUND: Access to antiretroviral therapy (ART) has expanded in Haiti because of the adoption of Option B+ and the revision of treatment guidelines. Retention in care and treatment varies greatly and few studies have examined retention rates, particularly among women enrolled in Option B+. OBJECTIVE: To assess attrition among pregnant and non-pregnant patients initiating ART following adoption of Option B+ in Haiti. METHODS: Longitudinal data of adult patients initiated on ART from October 2012 through August 2014 at 73 health facilities across Haiti were analyzed using a survival analysis framework to determine levels of attrition. The Kaplan-Meier method and Cox proportional hazards regression were used to examine risk factors associated with attrition. RESULTS: Among 17,059 patients who initiated ART, 7627 (44.7%) were non-pregnant women, 5899 (34.6%) were men, and 3533 (20.7%) were Option B+ clients. Attrition from the ART program was 36.7% at 12 months (95% CI: 35.9-37.5%). Option B+ patients had the highest level of attrition at 50.4% at 12 months (95% CI: 48.6-52.3%). While early HIV disease stage at ART initiation was protective among non-pregnant women and men, it was a strong risk factor among Option B+ clients. In adjusted analyses, key protective factors were older age (p < 0.0001), living near the health facility (p = 0.04), having another known HIV-positive household member (p < 0.0001), having greater body mass index (BMI) (p < 0.0001), pre-ART counseling (p < 0.0001), and Cotrimoxazole prophylaxis during baseline (p < 0.01). Higher attrition was associated with rapidly starting ART after enrollment (p < 0.0001), anemia (p < 0.0001), and regimen tenofovir+lamivudine+nevirapine (TDF+3TC+NVP) (p < 0.001). CONCLUSIONS: ART attrition in Haiti is high among adults, especially among Option B+ patients. Identifying newly initiated patients most at risk for attrition and providing appropriate interventions could help reduce ART attrition. PMID- 28640662 TI - Using probiotics in clinical practice: Where are we now? A review of existing meta-analyses. AB - The scientific literature has demonstrated that probiotics have a broad spectrum of activity, although often the results are contradictory. This study provides a critical overview of the current meta-analyses that have evaluated the efficacy of probiotics in physiologic and pathological conditions, such as metabolic disease, antibiotic-associated and Clostridium difficile-associated diarrhea, IBS, constipation, IBD, chemotherapy-associated diarrhea, respiratory tract infection, ventilator-associated pneumonia, NAFLD, liver encephalopathy, periodontitis, depression, vaginosis, urinary tract infections, pancreatitis, incidence of ventilator-associated pneumonia, hospital infection and stay in ICU, mortality of post-trauma patients, necrotising enterocolitis in premature infants. Only for antibiotic- and Clostridium difficile-associated diarrhea, and respiratory tract infections the effects of probiotics are considered "evidence based." Concerning other fields, meta-analyses lacks to define type and biologic effect of probiotic strains, as well as the outcome in a disease state. Therefore, the results presented should be a stimulus for further studies which will provide clinical recommendations. PMID- 28640663 TI - Glycosylation profile and biological activity of Remicade(r) compared with Flixabi(r) and Remsima(r). AB - As biosimilars enter the market, comparisons of product quality are needed. Manufacturing differences may lead to differences in critical quality attributes, which affect efficacy. Therefore, critical quality attributes (structure and biological activity) of Remicade(r) and of 2 biosimilar products (Flixabi(r)/Renflexis(r) and Remsima(r)/Inflectra(r)) were determined. We assessed binding to tumor necrosis factor in a fluorescence competitive binding assay; potency in a luciferase reporter gene assay; percentages of galactosylated glycan, afucose plus high mannosylated glycans, and charged glycan; FcgammaRIIIa (CD16) binding (assessed by 3 methods); and antibody-dependent cell-mediated cytotoxicity (ADCC) in the NK92-CD16a cell line and in peripheral blood mononuclear cells (PBMC). The results of Fab-related activity were similar for all products. Compared with Remicade(r), Flixabi(r) had a lower percentage of charged glycan, and Remsima(r) had a higher percentage of galactosylated glycan and a lower percentage of afucose plus high mannosylated glycans. Whereas Remsima(r) and Remicade(r) are expressed in a Sp2/0 cell line, Flixabi(r) is expressed in a CHO cell line. Despite this difference, galactosylated glycans from the 3 products were not correlated with the expression system. The results of all 3 methods used in this study indicated that FcgammaRIIIa binding was lower with Remsima(r) than with Remicade(r). The percentage of ADCC in NK92-CD16a cells was lower with Remsima(r) and higher with Flixabi(r) compared with Remicade(r), but was similar for all 3 products in PBMC. Surface expression of CD16 was 5.7 fold greater on NK92-CD16a cells than on PBMC. Combined percentages of afucosylated and high mannosylated glycans were positively correlated with FcgammaRIIIa binding and ADCC in NK92-CD16 cells, while no correlation was observed in PBMC. PMID- 28640664 TI - ?Somos iguales? Using a structural violence framework to understand gender and health inequities from an intersectional perspective in the Peruvian Amazon. AB - BACKGROUND: In the Peruvian Amazon, historical events of colonization and political marginalization intersect with identities of ethnicity, class and geography in the construction of gender and health inequities. Gender-based inequalities can manifest in poor health outcomes via discriminatory practices, healthcare system imbalances, inequities in health research, and differential exposures and vulnerabilities to diseases. Structural violence is a comprehensive framework to explain the mechanisms by which social forces such as poverty, racism and gender inequity become embodied as individual experiences and health outcomes, and thus may be a useful tool in structuring an intersectional analysis of gender and health inequities in Amazonian Peru. OBJECTIVE: The aim of this paper is to explore the intersection of gender inequities with other social inequalities in the production of health and disease in Peru's Amazon using a structural violence approach. DESIGN: Exploratory qualitative research was performed in two Loreto settings - urban Iquitos and the rural Lower Napo River region - between March and November 2015. This included participant observation with prolonged stays in the community, 46 semi-structured individual interviews and three group discussions. Thematic analysis was performed to identify emerging themes related to gender inequalities in health and healthcare and how these intersect with layered social disadvantages in the reproduction of health and illness. We employed a structural violence approach to construct an intersectional analysis of gender and health inequities in Amazonian Peru. RESULTS: Our findings were arranged into five interrelated domains within a gender, structural violence and health model: gender as a symbolic institution, systemic gender-based violence, interpersonal violence, the social determinants of health, and other health outcomes. Each domain represents one aspect of the complex associations between gender, gender inequity and health. Through this model, we were able to explore: gender, health and intersectionality; structural violence; and to highlight particular local gender and health dynamics. Intersecting influences of poverty, ethnicity, geography and gender served as significant barriers to healthcare in both rural and urban settings. PMID- 28640666 TI - First Report of an Adult Tapeworm (Cestoda: Diphyllobothriidea) in a Southern Sea Otter (Enhydra lutris nereis). AB - We present a novel case of an intestinal cestode infection in a southern sea otter (Enhydra lutris nereis). The cestode species Diphyllobothrium tetrapterum (syn. Diplogonoporus tetrapterus) was confirmed genetically. Stable isotope analysis of whiskers collected from the sea otter did not confirm the consumption of fish as the route of exposure. PMID- 28640665 TI - mRNA localization in metazoans: A structural perspective. AB - Asymmetric localization of mRNAs is a widespread gene regulatory mechanism that is crucial for many cellular processes. The localization of a transcript involves multiple steps and requires several protein factors to mediate transport, anchoring and translational repression of the mRNA. Specific recognition of the localizing transcript is a key step that depends on linear or structured localization signals, which are bound by RNA-binding proteins. Genetic studies have identified many components involved in mRNA localization. However, mechanistic aspects of the pathway are still poorly understood. Here we provide an overview of structural studies that contributed to our understanding of the mechanisms underlying mRNA localization, highlighting open questions and future challenges. PMID- 28640667 TI - Restricting retrotransposons: ADAR1 is another guardian of the human genome. AB - ADAR1 is an enzyme that belongs to the Adenosine Deaminases Acting on RNA (ADARs) family. These enzymes deaminate adenosines to inosines (RNA editing A-to-I) within double-stranded RNA regions in transcripts. Since inosines are recognized as guanosines by the cellular machinery, RNA editing mediated by ADARs can either lead to the formation of an altered protein (recoding) or affect different aspects of RNA metabolism. Recently, a proteomic analysis led to the identification of novel ADAR1-associated factors and found that a good fraction of them is shared with the Long Interspersed Element 1 (LINE-1 or L1) ribonucleoparticles (RNPs). This evidence suggested a possible role of ADAR1 in regulating the L1 life cycle. By taking advantage of the use of cell culture retrotransposition assays, a novel function of this deaminase as an inhibitor of L1 retrotransposition was demonstrated. These results pave the way toward a better comprehension of the mechanisms of restriction of retrotransposons. PMID- 28640669 TI - Cellular Components, Including Stem-Like Cells, of Preterm Mother's Mature Milk as Compared with Those in Her Colostrum: A Pilot Study. AB - PARTICIPATING AND STUDY OBJECTIVE: Whether the preterm mothers' mature milk retains the same cellular components as those in colostrum including stem-like cell, cell adhesion molecules, and immune cells. PARTICIPANTS: A total of five preterm mothers were recruited for the study having an average age of 30.2 years and gestational age of 29.8 weeks from the Pristine Women's Hospital, Kolhapur. Colostrum milk was collected within 2-5 days and matured milk was collected 20-30 days after delivery from the same mothers. METHODOLOGY: Integral cellular components of 22 markers including stem cells, immune cells, and cell adhesion molecules were measured using flowcytometry. OUTCOME: Preterm mature milk was found to possess higher expressions of hematopoietic stem cells, mesenchymal stem like cells, immune cells, few cell adhesion molecules, and side population cells than colostrum. CONCLUSION: The increased level of these different cell components in mature milk may be important in the long-term preterm baby's health growth. Further similar research in a larger population of various gestational ages and lactation stages of preterm mothers is warranted to support these pilot findings. PMID- 28640668 TI - Absence of the Fragile X Mental Retardation Protein results in defects of RNA editing of neuronal mRNAs in mouse. AB - The fragile X syndrome (FXS), the most common form of inherited intellectual disability, is due to the absence of FMRP, a protein regulating RNA metabolism. Recently, an unexpected function of FMRP in modulating the activity of Adenosine Deaminase Acting on RNA (ADAR) enzymes has been reported both in Drosophila and Zebrafish. ADARs are RNA-binding proteins that increase transcriptional complexity through a post-transcriptional mechanism called RNA editing. To evaluate the ADAR2-FMRP interaction in mammals we analyzed several RNA editing re coding sites in the fmr1 knockout (KO) mice. Ex vivo and in vitro analysis revealed that absence of FMRP leads to an increase in the editing levels of brain specific mRNAs, indicating that FMRP might act as an inhibitor of editing activity. Proximity Ligation Assay (PLA) in mouse primary cortical neurons and in non-neuronal cells revealed that ADAR2 and FMRP co-localize in the nucleus. The ADAR2-FMRP co-localization was further observed by double-immunogold Electron Microscopy (EM) in the hippocampus. Moreover, ADAR2-FMRP interaction appeared to be RNA independent. Because changes in the editing pattern are associated with neuropsychiatric and neurodevelopmental disorders, we propose that the increased editing observed in the fmr1-KO mice might contribute to the FXS molecular phenotypes. PMID- 28640670 TI - Rationale and Design of the Lung Cancer Screening Implementation. Evaluation of Patient-Centered Care Study. AB - Screening for lung cancer using low-dose computed tomography has been demonstrated to reduce lung cancer-related mortality and is being widely implemented. Further research in this area is needed to assess the impact of screening on patient-centered outcomes. Here, we describe the design and rationale for a new study entitled Lung Cancer Screening Implementation: Evaluation of Patient-Centered Care. The protocol is composed of an interconnected series of studies evaluating patients and clinicians who are engaged in lung cancer screening in real-world settings. The primary goal of this study is to evaluate communication processes that are being used in routine care and to identify best practices that can be readily scaled up for implementation in multiple settings. We hypothesize that higher overall quality of patient clinician communication processes will be associated with lower levels of distress and decisional conflict as patients decide whether or not to participate in lung cancer screening. This work is a critical step toward identifying modifiable mechanisms that are associated with high quality of care for the millions of patients who will consider lung cancer screening. Given the enormous potential benefits and burdens of lung cancer screening on patients, clinicians, and the healthcare system, it is important to identify and then scale up quality communication practices that positively influence patient-centered care. PMID- 28640671 TI - Regulation of a muralytic enzyme-encoding gene by two non-coding RNAs. AB - Non-coding regulatory RNAs fine-tune gene expression post-transcriptionally. In the streptomycetes, rpfA - encoding a muralytic enzyme required for establishing and exiting dormancy - is flanked by non-coding regulatory RNA elements both upstream (riboswitch) and downstream [antisense small RNA (sRNA)]. In Streptomyces coelicolor, the upstream riboswitch decreases rpfA transcript abundance in response to the second messenger cyclic di-AMP, itself involved in cell wall metabolism and dormancy. There is, however, no obvious expression platform associated with this riboswitch and consequently, its mechanism of action is entirely unknown. Using in vitro transcription assays, we discovered that the rpfA riboswitch promoted premature transcription termination in response to cyclic di-AMP. Through an extensive mutational analysis, we determined that attenuation required ligand binding and involved an unusual extended stem-loop region unique to a subset of rpfA riboswitches in the actinobacteria. At the other end of the rpfA gene, an antisense sRNA, termed Scr3097, is expressed opposite the predicted rpfA terminator. Using northern blotting, we found that Scr3097 accumulation mirrored that of the rpfA mRNA. In liquid culture, we detected Scr3097 exclusively in exponential-phase cells, and in plate-grown culture, we observed the sRNA primarily in differentiating cultures. Using mutational analyses, we found that the sRNA increased rpfA mRNA abundance in cells. Taken together, our work revealed multiple regulatory RNAs controlling rpfA expression in the streptomycetes. PMID- 28640672 TI - Consistency in patient-reported outcomes after total hip replacement. AB - Purpose - The primary objective in this study was to describe the patient reported outcome measures (PROMs) of total hip replacement (THR) patients 6 years after index surgery. Second, we sought to analyze how the preoperative, 1- and 6 year outcomes were associated. Patients and methods - By assessing the Swedish Hip Arthroplasty Register (SHAR), 15,755 patients with complete follow-up were included in the study group. 1-year and 6-year response rates were 93% and 87%. PROMs used by the SHAR include the EQ-5D instrument, and 2 modified visual analogue scales, 1 for pain and 1 for satisfaction. We used a multivariable linear regression model to examine the relationship between preoperative, 1-year, and 6-year outcome. Results - On average, patient-reported outcomes 6 years after THR were satisfactory. Though there was some deterioration in all mean 6-year PROMs, the patient-reported outcome after 6 years strongly resembled that of the 1-year results. The 1-year follow-up was the strongest factor associated with the 6-year results. Interpretation - There is little deterioration in patient reported outcomes 6 years after THR compared with the 1-year results. Although the 1-year follow-up was the strongest predictor of the 6-year results it could not alone explain the results, thus supporting the utility of the 6-year follow up in THR patients. PMID- 28640673 TI - The End of Written Informed Consent for HIV Testing: Not With a Bang but a Whimper. AB - In 2014, only two states in the United States still mandated specific written informed consent for HIV testing and, after years of controversy, New York ended this requirement, leaving only Nebraska. New York's shift to opt-out testing meant that a singular feature of what had characterized the exceptionalism surrounding HIV testing was eliminated. We trace the history of debates on written informed consent nationally and in New York State. Over the years of dispute from when HIV testing was initiated in 1985 to 2014, the evidence about the benefits and burdens of written informed consent changed. Just as important was the transformation of the political configuration of HIV advocacy and funding, both nationwide and in New York State. What had for years been the subject of furious debate over what a rational and ethical screening policy required came to an end without the slightest public protest. (Am J Public Health. 2017;107:1259-1265. doi:10.2105/AJPH.2017.303819). PMID- 28640674 TI - Racial/Ethnic Minority Older Adults' Perspectives on Proposed Medicaid Reforms' Effects on Dental Care Access. AB - To examine how proposed Medicaid reform plans are experienced by racial/ethnic minority older adults and what the implications are for their ability to access dental care through Medicaid, from 2013 to 2015 we conducted focus groups in northern Manhattan, New York, New York, among African American, Dominican, and Puerto Rican adults aged 50 years and older. Participants reported problems with affording copayments for care, complicated health and social issues, the need for vision and dental care close to home, and confusion about and stigmatization with Medicaid coverage. Federal, state, and local public health agencies can help by clarifying and simplifying Medicaid plans and sustaining benefits that older adults need to live healthy and dignified lives. PMID- 28640675 TI - Health-Related Quality of Life Among US Workers: Variability Across Occupation Groups. AB - OBJECTIVES: To examine the health-related quality of life among workers in 22 standard occupation groups using data from the 2013-2014 US Behavioral Risk Factor Surveillance System. METHODS: We examined the health-related quality of life measures of self-rated health, frequent physical distress, frequent mental distress, frequent activity limitation, and frequent overall unhealthy days by occupation group for 155 839 currently employed adults among 17 states. We performed multiple logistic regression analyses that accounted for the Behavioral Risk Factor Surveillance System's complex survey design to obtain prevalence estimates adjusted for potential confounders. RESULTS: Among all occupation groups, the arts, design, entertainment, sports, and media occupation group reported the highest adjusted prevalence of frequent physical distress, frequent mental distress, frequent activity limitation, and frequent overall unhealthy days. The personal care and service occupation group had the highest adjusted prevalence for fair or poor self-rated health. CONCLUSIONS: Workers' jobs affect their health-related quality of life. PMID- 28640676 TI - Personally Identifiable Information in State Laws: Use, Release, and Collaboration at Health Departments. AB - Despite benefits to sharing data among public health programs, confidentiality laws are often presumed to obstruct collaboration or data sharing. We present an overview of the use and release of confidential, personally identifiable information as consistent with public health interests and identify opportunities to align data-sharing procedures with use and release provisions in state laws to improve program outcomes. In August 2013, Centers for Disease Control and Prevention staff and legal researchers from the National Nurse-Led Care Consortium conducted a review of state laws regulating state and local health departments in 50 states and the District of Columbia. Nearly all states and the District of Columbia employ provisions for the general use and release of personally identifiable information without patient consent; disease-specific use or release provisions vary by state. Absence of law regarding use and release provisions was noted. Health departments should assess existing state laws to determine whether the use or release of personally identifiable information is permitted. Absence of direction should not prevent data sharing but prompt an analysis of existing provisions in confidentiality laws. PMID- 28640677 TI - Constant Lethality of Gunshot Injuries From Firearm Assault: United States, 2003 2012. AB - OBJECTIVES: To investigate the validity of the apparent downward trend in the national case-fatality rate for gunshot wounds from assault. METHODS: We reanalyzed the estimated annual number of nonfatal firearm injuries the National Electronic Injury Surveillance System reported from 2003 to 2012. We adjusted the estimates for discontinuities created by the substitution of 1 hospital for another in the sample and for a downward trend in the percentage of gunshot injuries classified as "unknown circumstance." Firearm homicide data are from the Centers for Disease Control and Prevention, Web-based Injury Statistics Query and Reporting System. RESULTS: The unadjusted National Electronic Injury Surveillance System estimate increased by 49%, yielding a decline in the case-fatality rate from 25% to 18%. Our adjustments eliminated these trends; the case-fatality rate was 22% in both 2003 and 2012. CONCLUSIONS: With reasonable adjustments, the trend in nonfatal injuries from interpersonal firearms assault tracks the flat trend in firearms homicides, suggesting that there was no increase in firearms violence during this period. The case-fatality rate did not change, and trauma care improvements did not influence the firearms homicide trend. PMID- 28640679 TI - Crash Fatality Rates After Recreational Marijuana Legalization in Washington and Colorado. AB - OBJECTIVES: To evaluate motor vehicle crash fatality rates in the first 2 states with recreational marijuana legalization and compare them with motor vehicle crash fatality rates in similar states without recreational marijuana legalization. METHODS: We used the US Fatality Analysis Reporting System to determine the annual numbers of motor vehicle crash fatalities between 2009 and 2015 in Washington, Colorado, and 8 control states. We compared year-over-year changes in motor vehicle crash fatality rates (per billion vehicle miles traveled) before and after recreational marijuana legalization with a difference in-differences approach that controlled for underlying time trends and state specific population, economic, and traffic characteristics. RESULTS: Pre recreational marijuana legalization annual changes in motor vehicle crash fatality rates for Washington and Colorado were similar to those for the control states. Post-recreational marijuana legalization changes in motor vehicle crash fatality rates for Washington and Colorado also did not significantly differ from those for the control states (adjusted difference-in-differences coefficient = +0.2 fatalities/billion vehicle miles traveled; 95% confidence interval = -0.4, +0.9). CONCLUSIONS: Three years after recreational marijuana legalization, changes in motor vehicle crash fatality rates for Washington and Colorado were not statistically different from those in similar states without recreational marijuana legalization. Future studies over a longer time remain warranted. PMID- 28640678 TI - Hurricane Sandy (New Jersey): Mortality Rates in the Following Month and Quarter. AB - OBJECTIVES: To describe changes in mortality after Hurricane Sandy made landfall in New Jersey on October 29, 2012. METHODS: We used electronic death records to describe changes in all-cause and cause-specific mortality overall, in persons aged 76 years or older, and by 3 Sandy impact levels for the month and quarter following Hurricane Sandy compared with the same periods in earlier years adjusted for trends. RESULTS: All-cause mortality increased 6% (95% confidence interval [CI] = 2%, 11%) for the month, 5%, 8%, and 12% by increasing Sandy impact level; and 7% (95% CI = 5%, 10%) for the quarter, 5%, 8%, and 15% by increasing Sandy impact level. In elderly persons, all-cause mortality rates increased 10% (95% CI = 5%, 15%) and 13% (95% CI = 10%, 16%) in the month and quarter, respectively. Deaths that were cardiovascular disease-related increased by 6% in both periods, noninfectious respiratory disease-related by 24% in the quarter, infection-related by 20% in the quarter, and unintentional injury related by 23% in the month. CONCLUSIONS: Mortality increased, heterogeneous by cause, for both periods after Hurricane Sandy, particularly in communities more severely affected and in the elderly, who may benefit from supportive services. PMID- 28640680 TI - Polysubstance Use Among US Women of Reproductive Age Who Use Opioids for Nonmedical Reasons. AB - OBJECTIVES: To determine the prevalence and patterns of polysubstance use among US reproductive-aged women who use opioids for nonmedical purposes. METHODS: We used the National Survey of Drug Use and Health (2005-2014) data on female respondents aged 18 to 44 years reporting nonmedical opioid use in the past 30 days (unweighted n = 4498). We categorized patterns of polysubstance use in the past 30 days, including cigarettes, binge drinking, and other legal and illicit substances and reported prevalence adjusted for age, race/ethnicity, and educational attainment. RESULTS: Of all women with nonmedical opioid use, 11% reported only opioid use. Polysubstance use was highest in non-Hispanic White women and women with lower educational attainment. The most frequently used other substances among women using opioids nonmedically were cigarettes (56.2% smoked > 5 cigarettes per day), binge drinking (49.7%), and marijuana (32.4%). Polysubstance use was similarly prevalent among pregnant women with nonmedical opioid use. CONCLUSIONS: Polysubstance use is highly prevalent among US reproductive-aged women reporting nonmedical opioid use. Public Health Implications. Interventions are needed that address concurrent use of multiple substances. PMID- 28640681 TI - Crowdsourced Health Data: Comparability to a US National Survey, 2013-2015. AB - OBJECTIVES: To determine the generalizability of crowdsourced, electronic health data from self-selected individuals using a national survey as a reference. METHODS: Using the world's largest crowdsourcing platform in 2015, we collected data on characteristics known to influence cardiovascular disease risk and identified comparable data from the 2013 Behavioral Risk Factor Surveillance System. We used age-stratified logistic regression models to identify differences among groups. RESULTS: Crowdsourced respondents were younger, more likely to be non-Hispanic and White, and had higher educational attainment. Those aged 40 to 59 years were similar to US adults in the rates of smoking, diabetes, hypertension, and hyperlipidemia. Those aged 18 to 39 years were less similar, whereas those aged 60 to 75 years were underrepresented among crowdsourced respondents. CONCLUSIONS: Crowdsourced health data might be most generalizable to adults aged 40 to 59 years, but studies of younger or older populations, racial and ethnic minorities, or those with lower educational attainment should approach crowdsourced data with caution. Public Health Implications. Policymakers, the national Precision Medicine Initiative, and others planning to use crowdsourced data should take explicit steps to define and address anticipated underrepresentation by important population subgroups. PMID- 28640682 TI - Vocal Timbre and the Classification of Respondent Sex in US Phone-Based Surveys. AB - OBJECTIVES: To characterize the conflict of sex and gender identity variables in the 2014 Behavioral Risk Factor Surveillance System (BRFSS) sample and examine how this may affect the administration of sex-related health behavior items to transgender participants. METHODS: We conducted a secondary analysis of the 2014 BRFSS gender identity, sex, and sex-related health behavior variables. Twenty states administered the gender-identity variables (n = 154 062), and 691 respondents identified as transgender in the survey (0.4%). We examined conflict among sex, gender identity, and gender-related variables, and compared conflicting and nonconflicting groups across 4 sociodemographic characteristics. RESULTS: Nearly one third of respondents (27.8%; n = 171) who identified as transgender received sex-specific items that conflicted with their natal sex, thereby reducing the already small subsample of valid responses. There were no significant differences between conflicting and nonconflicting groups on the basis of region, age, race/ethnicity, or type of interview. CONCLUSIONS: Public health surveys should ask respondents to self-identify their sex and gender identity. Interviewer assumptions of respondents' sex may lead to erroneous collection of sex- and gender-based items, inhibit survey administration, and create problems in data quality. PMID- 28640683 TI - The Public Health Practitioner of the Future. AB - The requisite capacities and capabilities of the public health practitioner of the future are being driven by multiple forces of change, including public health agency accreditation, climate change, health in all policies, social media and informatics, demographic transitions, globalized travel, and the repercussions of the Affordable Care Act. We describe five critical capacities and capabilities that public health practitioners can build on to successfully prepare for and respond to these forces of change: systems thinking and systems methods, communication capacities, an entrepreneurial orientation, transformational ethics, and policy analysis and response. Equipping the public health practitioner with the requisite capabilities and capacities will require new content and methods for those in public health academia, as well as a recommitment to lifelong learning on the part of the practitioner, within an increasingly uncertain and polarized political environment. PMID- 28640684 TI - Judicial Bypass for Minors Seeking Abortions in Arkansas Versus Other States. AB - OBJECTIVES: To describe demographic characteristics and abortion timing of minors in Arkansas who obtained an abortion through a judicial bypass, and to contrast the frequency of judicial bypass in other states in the United States. METHODS: We used individual-level data on all abortions to minors (n = 2624) performed in Arkansas from 2005 to 2014 and aggregated data from 10 additional states on abortions obtained through a judicial bypass. We characterized correlates of the judicial bypass and its association with the timing of abortion. RESULTS: Minors in Arkansas who used the courts were more likely to be 17 years of age, nonresidents of Arkansas, Hispanic, and with fewer previous pregnancies than their younger, resident, non-Hispanic White, and multigravida counterparts; 7.7% of abortions to minors were obtained via a bypass in 11 states, but only 2% if Texas and Arkansas are excluded. CONCLUSIONS: The demographics of minors who obtain an abortion through a judicial bypass differ significantly from those who have parental consent, and there is widespread variation in the proportion of bypass cases across states. PMID- 28640685 TI - Understanding and Improving Arterial Roads to Support Public Health and Transportation Goals. AB - Arterials are types of roads designed to carry high volumes of motorized traffic. They are an integral part of transportation systems worldwide and exposure to them is ubiquitous, especially in urban areas. Arterials provide access to diverse commercial and cultural resources, which can positively influence community health by supporting social cohesion as well as economic and cultural opportunities. They can negatively influence health via safety issues, noise, air pollution, and lack of economic development. The aims of public health and transportation partially overlap; efforts to improve arterials can meet goals of both professions. Two trends in arterial design show promise. First, transportation professionals increasingly define the performance of arterials via metrics accounting for pedestrians, cyclists, transit riders, and nearby residents in addition to motor vehicle users. Second, applying traffic engineering and design can generate safety, air quality, and livability benefits, but we need evidence to support these interventions. We describe the importance of arterials (including exposures, health behaviors, effects on equity, and resulting health outcomes) and make the case for public health collaborations with the transportation sector. PMID- 28640686 TI - Prevalence of Financial Fraud and Scams Among Older Adults in the United States: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The financial exploitation of older adults was recently recognized by the Centers for Disease Control and Prevention as a serious public health problem. Knowledge of the prevalence of elder financial exploitation is mostly limited to the category of financial abuse, which occurs in relationships involving an expectation of trust. Little is known about the other major category of elder financial exploitation-elder financial fraud and scams, which is perpetrated by strangers. A valid estimate of elder financial fraud-scam prevalence is necessary as a foundation for research and prevention efforts. OBJECTIVES: To estimate the prevalence of elder financial fraud-scam victimization in the United States based on a systematic review and meta analysis. SEARCH METHODS: Multiple investigators independently screened titles and abstracts and reviewed relevant full-text records from PubMed, Medline, PsycINFO, Criminal Justice Abstracts, Social Work Abstracts, and AgeLine databases. SELECTION CRITERIA: To maximize the validity and generalizability of prevalence estimation, we restricted eligibility to general population-based studies (English speaking, 1990 onward) using state- or national-level probability sampling and collecting data directly from older adults. DATA COLLECTION AND ANALYSIS: Information on elder financial fraud-scam prevalence and study-level characteristics was extracted independently by 2 investigators. Meta analysis of elder financial fraud-scam prevalence used generalized mixed models with individual studies as levels of a random classification factor. MAIN RESULTS: We included 12 studies involving a total of 41 711 individuals in the meta-analysis. Overall pooled elder financial fraud-scam prevalence (up to 5-year period) across studies was 5.6% (95% confidence interval [CI] = 4.0%, 7.8%), with a 1-year period prevalence of 5.4% (95% CI = 3.2%, 7.6%). Studies using a series of questions describing specific fraud-scam events to measure victimization found a significantly higher prevalence (7.1%; 95% CI = 4.8%, 9.4%) than studies using a single, general-question self-report assessment approach (3.6%; 95% CI = 1.8%, 5.4%). AUTHOR'S CONCLUSIONS: Elder financial fraud and scams is a common problem, affecting approximately 1 of every 18 cognitively intact, community-dwelling older adults each year; it requires further attention from researchers, clinicians, and policymakers. Elder financial fraud-scam prevalence findings in this study likely underestimate the true population prevalence. We provide methodological recommendations to limit older adult participation and reporting bias in future population-based research. Public Health Implications. Elder financial exploitation victimization is associated with mortality, hospitalization, and poor physical and mental health. Health care professionals working with older adults likely routinely encounter patients who are fraud-scam victims. Validation of instruments to screen for elder financial fraud and scams in clinical settings is an important area of future research. Without effective primary prevention strategies, the absolute scope of this problem will escalate with the growing population of older adults. PMID- 28640687 TI - Dust Exposure and Coccidioidomycosis Prevention Among Solar Power Farm Construction Workers in California. AB - OBJECTIVES: To investigate if work activities, dust exposure, and protection measures were associated with a 2011 to 2014 coccidioidomycosis outbreak among workers constructing 2 solar farms in California. METHODS: In 2013, we mailed self-administered questionnaires to employees who were onsite at the solar farms where the outbreak occurred to identify cases of clinical coccidioidomycosis and compare with asymptomatic workers by using multivariate logistic regression. RESULTS: When we compared 89 workers with clinical coccidioidomycosis to 325 asymptomatic workers, frequently being in a dust cloud or storm (odds ratio [OR] = 5.93; 95% confidence interval [CI] = 3.18, 11.06) significantly increased the odds of clinical coccidioidomycosis, whereas frequently wetting soil before soil disturbing activity (OR = 0.42; 95% CI = 0.24, 0.75) was protective. When we controlled for being in a dust cloud or storm, frequent soil disturbance significantly increased the odds of clinical coccidioidomycosis only among those who reported wearing a respirator infrequently (OR = 2.31; 95% CI = 1.27, 4.21). CONCLUSIONS: Utilization of personal and employer-driven safety practices and increased coccidioidomycosis awareness among construction workers should be considered during the planning of any construction work in coccidioidomycosis endemic regions to prevent occupational infections and outbreaks. PMID- 28640688 TI - Unintentional Poisoning in China, 1990 to 2015: The Global Burden of Disease Study 2015. AB - OBJECTIVES: To estimate the unintentional poisoning burden and risk factors in China from 1990 to 2015. METHODS: We extracted data from the Global Burden of Disease Study 2015 to compare mortality, prevalence, disability-adjusted life years (DALYs), years of life lost, years lived with a disability, and risk factors of unintentional poisoning in China. We determined the median of the percent change and 95% uncertainty interval for the period between 1990 and 2015. RESULTS: The age-standardized unintentional poisoning death rate decreased by 61.8% from 1990 (4.1 per 100 000) to 2015 (1.6 per 100 000). The age-standardized prevalence decreased from 1990 (87.9 per 100 000) to 2010 (39.0 per 100 000), but rebounded in 2015 (42.6 per 100 000). All risk factors combined accounted for 14.9% of unintentional poisoning DALYs in 2015. The leading risk factors for unintentional poisoning DALYs were alcohol and drug use and occupational risks. CONCLUSIONS: China has made substantial progress in reducing the mortality attributable to unintentional poisoning, but the prevalence and absolute number of patients has been increasing again since 2010. The growing contribution from alcohol and drug use requires increased attention. PMID- 28640689 TI - Deciphering Suicide and Other Manners of Death Associated with Drug Intoxication: A Centers for Disease Control and Prevention Consultation Meeting Summary. AB - Manner of death (MOD) classification (i.e., natural, accident, suicide, homicide, or undetermined cause) affects mortality surveillance and public health research, policy, and practice. Determination of MOD in deaths caused by drug intoxication is challenging, with marked variability across states. The Centers for Disease Control and Prevention hosted a multidisciplinary meeting to discuss drug intoxication deaths as they relate to suicide and other MOD. The meeting objectives were to identify individual-level, system-level, and place-based factors affecting MOD classification and identify potential solutions to classification barriers. Suggested strategies included improved standardization in death scene investigation, toxicology, and autopsy practice; greater accountability; and creation of job aids for investigators. Continued collaboration and coordination of activities are needed among stakeholders to affect prevention efforts. PMID- 28640690 TI - A new layer of rRNA regulation by small interference RNAs and the nuclear RNAi pathway. AB - Ribosome biogenesis drives cell growth and proliferation, but mechanisms that modulate this process remain poorly understood. For a long time, small rRNA sequences have been widely treated as non-specific degradation products and neglected as garbage sequences. Recently, we identified a new class of antisense ribosomal siRNAs (risiRNAs) that downregulate pre-rRNA through the nuclear RNAi pathway in C. elegans. risiRNAs exhibit sequence characteristics similar to 22G RNA while complement to 18S and 26S rRNA. risiRNAs elicit the translocation of the nuclear Argonaute protein NRDE-3 from the cytoplasm to nucleus and nucleolus, in which the risiRNA/NRDE complex binds to pre-rRNA and silences rRNA expression. Interestingly, when C. elegans is exposed to environmental stimuli, such as cold shock and ultraviolet illumination, risiRNAs accumulate and further turn on the nuclear RNAi-mediated gene silencing pathway. risiRNA may act in a quality control mechanism of rRNA homeostasis. When the exoribonuclease SUSI-1(ceDis3L2) is mutated, risiRNAs are dramatically increased. In this Point of View article, we will summarize our understanding of the small antisense ribosomal siRNAs in a variety of organisms, especially C. elegans, and their possible roles in the quality control mechanism of rRNA homeostasis. PMID- 28640692 TI - Comparison of Gadolinium Concentrations within Multiple Rat Organs after Intravenous Administration of Linear versus Macrocyclic Gadolinium Chelates. AB - Purpose To compare gadolinium tissue concentrations of multiple linear and macrocyclic chelates in a rat model to better understand the scope and extent of tissue deposition following multiple intravenous doses of gadolinium-based contrast agent (GBCA). Materials and Methods In this Institutional Animal Care and Use Committee-approved study, healthy rats received 20 intravenous injections of 2.5 mmol gadolinium per kilogram (gadolinium-exposed group) or saline (control group) over a 26-day period. Unenhanced T1 signal intensities of the dentate nucleus were measured from magnetic resonance (MR) images obtained prior to GBCA injection and 3 days after final injection. Rat brain and renal, hepatic, and splenic tissues were harvested 7 days after final injection and subjected to inductively coupled plasma mass spectrometry and transmission electron microscopy for quantification and characterization of gadolinium deposits. Results Gadolinium deposition in brain tissue significantly varied with GBCA type (F = 31.2; P < .0001), with median concentrations of 0 MUg gadolinium per gram of tissue (95% confidence interval [CI]: 0, 0.2) in gadoteridol-injected rats, 1.6 MUg gadolinium per gram of tissue (95% CI: 0.9, 4.7) in gadobutrol-injected rats, 4.7 MUg gadolinium per gram of tissue (95% CI: 3.5, 6.1) in gadobenate dimeglumine-injected rats, and 6.9 MUg gadolinium per gram of tissue (95% CI: 6.2, 7.0) in gadodiamide-injected rats; a significant positive dose-signal intensity correlation was identified (rho = 0.93; P < .0001). No detectable neural tissue deposition or MR imaging signal was observed in control rats (n = 6). Similar relative differences in gadolinium deposition were observed in renal, hepatic, and splenic tissues at much higher tissue concentrations (P < .0001). Gadolinium deposits were visualized directly in the endothelial capillary walls and neural interstitium in GBCA-injected rats, but not in control rats. Conclusion Tissue deposition of gadolinium was two- to fourfold higher following administration of the linear agents gadodiamide and gadobenate dimeglumine compared with the macrocyclic agents gadobutrol and gadoteridol. These findings suggest that organ tissue deposition is reduced but not eliminated following administration of macrocyclic GBCA chelates in lieu of linear chelates. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28640691 TI - The nesprin-cytoskeleton interface probed directly on single nuclei is a mechanically rich system. AB - The cytoskeleton provides structure and plays an important role in cellular function such as migration, resisting compression forces, and transport. The cytoskeleton also reacts to physical cues such as fluid shear stress or extracellular matrix remodeling by reorganizing filament associations, most commonly focal adhesions and cell-cell cadherin junctions. These mechanical stimuli can result in genome-level changes, and the physical connection of the cytoskeleton to the nucleus provides an optimal conduit for signal transduction by interfacing with nuclear envelope proteins, called nesprins, within the LINC (linker of the nucleus to the cytoskeleton) complex. Using single-molecule on single nuclei assays, we report that the interactions between the nucleus and the cytoskeleton, thought to be nesprin-cytoskeleton interactions, are highly sensitive to force magnitude and direction depending on whether cells are historically interfaced with the matrix or with cell aggregates. Application of ~10-30 pN forces to these nesprin linkages yielded structural transitions, with a base transition size of 5-6 nm, which are speculated to be associated with partial unfoldings of the spectrin domains of the nesprins and/or structural changes of histones within the nucleus. PMID- 28640693 TI - Evaluation of Screening US-detected Breast Masses by Combined Use of Elastography and Color Doppler US with B-Mode US in Women with Dense Breasts: A Multicenter Prospective Study. AB - Purpose To investigate the value of the combined use of elastography and color Doppler ultrasonography (US) with B-mode US for evaluation of screening US detected breast masses in women with dense breasts. Materials and Methods This prospective, multicenter study included asymptomatic women with dense breasts who were referred for screening US between November 2013 and December 2014. Eligible women had a newly detected breast mass at conventional B-mode US screening, for which elastography and color Doppler US were performed. The following outcome measures were compared between B-mode US and the combination of B-mode US, elastography, and color Doppler US: area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value (PPV), and the number of false-positive findings at screening US. Results Among 1021 breast masses (mean size, 1.0 cm; range, 0.3-3.0 cm) in 1021 women (median age, 45 years), 68 were malignant (56 invasive). Addition of elastography and color Doppler US to B-mode US increased the AUC from 0.87 (95% confidence interval [CI]: 0.82, 0.91) to 0.96 (95% CI: 0.95, 0.98; P < .001); specificity from 27.0% (95% CI: 24.2%, 29.9%) to 76.4% (95% CI: 73.6%, 79.1%; P < .001) without loss in sensitivity (95% CI: -1.5%, 1.5%; P > .999); and PPV from 8.9% (95% CI: 7.0%, 11.2%) to 23.2% (95% CI: 18.5%, 28.5%; P < .001), while avoiding 67.7% (471 of 696) of unnecessary biopsies for nonmalignant lesions. Conclusion Addition of elastography and color Doppler US to B-mode US can increase the PPV of screening US in women with dense breasts while reducing the number of false positive findings without missing cancers. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28640694 TI - Assessment of Rectal Tumors with Shear-Wave Elastography before Surgery: Comparison with Endorectal US. AB - Purpose To compare the value of endorectal ultrasonography (US) with shear-wave elastography (SWE) in staging rectal tumors before surgery. Materials and Methods This prospective study was approved by the institutional review board and written informed consent was obtained. In a pilot cohort from April 2015 to January 2016, 70 patients with rectal adenocarcinomas and/or adenomas confirmed with histopathologic examination underwent both endorectal US and SWE. Tumor stiffness and three regions of reference backgrounds, as well as tumor stiffness ratios (SRs) versus these backgrounds, were analyzed. The optimal staging feature was selected by using receiver operating characteristic analysis, and the concordance rate with pathologic stage was analyzed and compared with endorectal US. The results were validated in an independent cohort of 30 patients from February 2016 to July 2016. Results In the pilot study, from rectal adenoma to stage T3 cancers, the tumor stiffness, stiffness of peritumoral fat, tumor SR versus distant perirectal fat, and tumor SR versus normal rectal wall were significantly increased (all P < .05, correlation coefficients between SWE features and pathologic T stages were 0.589-0.853). Receiver operating characteristic analysis of tumor staging demonstrated that tumor stiffness was the optimal feature with the highest area under the receiver operating characteristic curve (AUC = 0.991 1.000). The cutoff values of stage T1, T2, and T3 cancers were 26.9 kPa, 70.3 kPa, and 112.0 kPa, respectively. For SWE, the diagnostic concordance rate with pathologic stage (95.7%, weighted kappa = 0.962) was higher than that of endorectal US (75.7%, weighted kappa = 0.756). In the validation cohort, similar findings were revealed for diagnostic concordance rate (93.3% vs 76.7%; weighted kappa = 0.927 vs 0.651) and diagnostic performance of tumor staging (AUC = 0.950 1.000 vs 0.700-0.833). Conclusion By using the feature of tumor stiffness at SWE, the accuracy of preoperative staging for rectal tumors was improved compared with endorectal US in the pilot study, but was not significantly different in the validation cohort, potentially due to small sample size. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28640695 TI - Gadolinium Brain Deposition after Macrocyclic Gadolinium Administration: A Pediatric Case-Control Study. AB - Purpose To determine whether signal intensity (SI) in T1 sequences as a potential indicator of gadolinium deposition increases after repeated administration of the macrocyclic gadolinium-based contrast agents (GBCAs) gadoteridol and gadoterate meglumine in a pediatric cohort. Materials and Methods This retrospective case control study of children with brain tumors who underwent nine or more contrast material-enhanced brain magnetic resonance (MR) imaging studies from 2008 to 2015 was approved by the local ethics board. Informed consent was obtained for MR imaging. Twenty-four case patients aged 5-18 years and appropriate control patients with nonpathologic MR neuroimaging findings (and no GBCA administration), matched for age and sex, were inculded. SI was measured on unenhanced T1-weighted MR images for the following five regions of interest (ROIs): the dentate nucleus (DN), pons, substantia nigra (SN), pulvinar thalami, and globus pallidus (GP). Paired t tests were used to compare SI and SI ratios (DN to pons, GP to thalamus) between case patients and control patients. Pearson correlations between relative signal changes and the number of GBCA administrations and total GBCA dose were calculated. Results The mean number of GBCA administrations was 14.2. No significant differences in mean SI for any ROI and no group differences were found when DN-to-pons and GP-to-pulvinar ratios were compared (DN-to-pons ratio in case patients: mean, 1.0083 +/- 0.0373 [standard deviation]; DN-to-pons ratio in control patients: mean, 1.0183 +/- 0.01917; P = .37; GP-to-pulvinar ratio in case patients: mean, 1.1335 +/- 0.04528; and GP-to-pulvinar ratio in control patients: mean, 1.1141 +/- 0.07058; P = .29). No correlation was found between the number of GBCA administrations or the total amount of GBCA administered and signal change for any ROI. (Number of GBCA applications: DN: r = -0.254, P = .31; pons: r = -0.097, P = .65; SN: r = 0.194, P = .38; GP: r = -0.175, P = .41; pulvinar: r = -0.067, P = .75; total amount of administered GBCA: DN: r = 0.091, P = .72; pons: r = 0.106, P = .62; SN: r = -0.165, P = .45; GP: r = 0.111, P = .61; pulvinar: r = 0.173, P = .42.) Conclusion Multiple intravenous administrations of these macrocyclic GBCAs in children were not associated with a measurable increase in SI in T1 sequences as an indicator of brain gadolinium deposition detectable by using MR imaging. Additional imaging and pathologic studies are needed to confirm these findings. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28640696 TI - Insights From Molecular Profiling of Adult Glioma. AB - The comprehensive molecular profiling of cancer has resulted in new insights into the biology and classification of numerous tumor types. In the case of primary brain tumors that commonly affect adults, an emerging set of disease-defining biomarker sets is reshaping existing diagnostic entities that had previously been defined on the basis of their microscopic appearance. Substantial progress has been made in this regard for common primary brain tumors in adults, especially diffuse gliomas, where large-scale profiling efforts have led to the incorporation of highly prevalent molecular alterations that promote a biologically based classification as an adjunct to the traditional histopathologic approach. The growing awareness that histologically indistinguishable tumors can be divided into more precise and biologically relevant subgroups has demanded a more global routine approach to biomarker assessment. These considerations have begun to intersect with the decreasing costs and availability of genome-wide analysis tools and, thus, incorporation into routine practice. We review how molecular profiling already has led to an evolution in the classification of brain tumors. In addition, we discuss the likely trajectory of incorporation of global molecular profiling platforms into the routine clinical classification of adult brain tumors. PMID- 28640697 TI - Current Clinical Challenges in Childhood Ependymoma: A Focused Review. AB - Ependymoma is a locally aggressive tumor with metastatic potential that arises in diverse locations throughout the brain and spine in children. Tumor and treatment may result in significant morbidity. Cure remains elusive for many patients owing to diverse biology and resistance to conventional therapy. The implementation of systematic postoperative irradiation in clinical trials during the past 20 years has increased the proportion of patients achieving durable disease control with excellent results, as measured by objective functional outcome measures. Clinical, pathologic, and molecular risk stratification should be used to refine treatment regimens for children with ependymoma to reduce the risk of complications associated with therapy and increase the rate of disease control in the setting of combined modality or more intensive therapy. This review covers standards of care and current clinical trials for children with ependymoma, emphasizing the history and evolution of treatment regimens during the past 20 years and the clinical questions they hoped to address. PMID- 28640698 TI - Pediatric Gliomas: Current Concepts on Diagnosis, Biology, and Clinical Management. AB - Gliomas are the most common CNS tumors in children and adolescents, and they show an extremely broad range of clinical behavior. The majority of pediatric gliomas present as benign, slow-growing lesions classified as grade I or II by the WHO classification of CNS tumors. These pediatric low-grade gliomas (LGGs) are fundamentally different from IDH-mutant LGGs occurring in adults, because they rarely undergo malignant transformation and show excellent overall survival under current treatment strategies. However, a significant fraction of gliomas develop over a short period of time and progress rapidly and are therefore classified as WHO grade III or IV high-grade gliomas (HGGs). Despite all therapeutic efforts, they remain largely incurable, with the most aggressive forms being lethal within months. Thus, the intentions of neurosurgeons, pediatric oncologists, and radiotherapists to improve care for pediatric patients with glioma range from increasing quality of life and preventing long-term sequelae in what is often a chronic, but rarely life-threatening disease (LGG), to uncovering effective treatment options to prolong patient survival in an almost universally fatal setting (HGG). The last decade has seen unprecedented progress in understanding the molecular biology underlying pediatric gliomas, fueling hopes to achieve both goals. Large-scale collaborative studies around the globe have cataloged genomic and epigenomic alterations in gliomas across ages, grades, and histologies. These studies have revealed biologic subgroups characterized by distinct molecular, pathologic, and clinical features, with clear relevance for patient management. In this review, we summarize hallmark discoveries that have expanded our knowledge in pediatric LGGs and HGGs, explain their role in tumor biology, and convey our current concepts on how these findings may be translated into novel therapeutic approaches. PMID- 28640699 TI - Brain Tumor Imaging. AB - Modern imaging techniques, particularly functional imaging techniques that interrogate some specific aspect of underlying tumor biology, have enormous potential in neuro-oncology for disease detection, grading, and tumor delineation to guide biopsy and resection; monitoring treatment response; and targeting radiotherapy. This brief review considers the role of magnetic resonance imaging and spectroscopy, and positron emission tomography in these areas and discusses the factors that limit translation of new techniques to the clinic, in particular, the cost and difficulties associated with validation in multicenter clinical trials. PMID- 28640702 TI - Diffuse Infiltrating Oligodendroglioma and Astrocytoma. AB - The new 2016 WHO brain tumor classification defines different diffuse gliomas primarily according to the presence or absence of IDH mutations ( IDH-mt) and combined 1p/19q loss. Today, the diagnosis of anaplastic oligodendroglioma requires the presence of both IDH-mt and 1p/19q co-deletion, whereas anaplastic astrocytoma is divided into IDH wild-type ( IDH-wt) and IDH-mt tumors. IDH-mt tumors have a more favorable prognosis, and tumors with low-grade histology especially tend evolve slowly. IDH-wt tumors are not a homogeneous entity and warrant further molecular testing because some have glioblastoma-like molecular features with poor clinical outcome. Treatment consists of a resection that should be as extensive as safely possible, radiotherapy, and chemotherapy. Trials of patients with newly diagnosed grade II or III glioma have shown survival benefit from adding chemotherapy to radiotherapy compared with initial treatment using radiotherapy alone. Both temozolomide and the combination of procarbazine, lomustine, and vincristine provide survival benefit. In contrast, trials that compare single modality treatment of chemotherapy alone with radiotherapy alone did not observe survival differences. Currently, for patients with grade II or III gliomas who require postsurgical treatment, the preferred treatment consists of a combination of radiotherapy and chemotherapy. Low-grade gliomas with favorable characteristics are slow-growing tumors. When deciding on the timing of postsurgical treatment with radiotherapy and chemotherapy, both clinical and molecular factors should be taken into account, but a more conservative approach can be considered initially in some of these patients. The factor that best predicts benefit of chemotherapy in grade II and III glioma remains to be established. PMID- 28640700 TI - CNS Tumors in Neurofibromatosis. AB - Neurofibromatosis (NF) encompasses a group of distinct genetic disorders in which affected children and adults are prone to the development of benign and malignant tumors of the nervous system. The purpose of this review is to discuss the spectrum of CNS tumors arising in individuals with NF type 1 (NF1) and NF type 2 (NF2), their pathogenic etiologies, and the rational treatment options for people with these neoplasms. This article is a review of preclinical and clinical data focused on the treatment of the most common CNS tumors encountered in children and adults with NF1 and NF2. Although children with NF1 are at risk for developing low-grade gliomas of the optic pathway and brainstem, individuals with NF2 typically manifest low-grade tumors affecting the cranial nerves (vestibular schwannomas), meninges (meningiomas), and spinal cord (ependymomas). With the identification of the NF1 and NF2 genes, molecularly targeted therapies are beginning to emerge, as a result of a deeper understanding of the mechanisms underlying NF1 and NF2 protein function. As we enter into an era of precision oncology, a more comprehensive awareness of the factors that increase the risk of developing CNS cancers in affected individuals, coupled with a greater appreciation of the cellular and molecular determinants that maintain tumor growth, will undoubtedly yield more effective therapies for these cancer predisposition syndromes. PMID- 28640703 TI - Integrating Evidence-Based Medicine for Treatment of Spinal Metastases Into a Decision Framework: Neurologic, Oncologic, Mechanicals Stability, and Systemic Disease. AB - Patients with cancer are frequently affected by spinal metastases. Treatment is palliative, with the principle goals of pain relief, preservation of neurologic function, and improvement in quality of life. In the past decade, we have witnessed a dramatic change in the treatment paradigms due to the development of improved surgical strategies and systemic and radiation therapy. The most important change to these paradigms has been the integration of spinal stereotactic radiosurgery (SSRS), allowing delivery of tumoricidal radiation doses with sparing of nearby organs at risk. High-dose SSRS provides durable tumor control when used either as definitive therapy or as a postoperative adjuvant therapy. Integration of SSRS has fundamentally changed the indications for and type of surgery performed for metastatic spine tumors. Although the role for surgical intervention is well established, a clear trend toward less aggressive, often minimally invasive techniques has been observed. Targeted therapies are also rapidly changing the way cancer is being treated and have demonstrated improved survival for a number of malignancies. As these treatment decisions become more complex, a multidisciplinary approach including medical oncologists, radiation oncologists, surgeons, interventionalists, and pain specialists is required. In this article, the current evidence affecting the treatment of spinal metastases is integrated into a decision framework that considers four principal assessments of a patient's spine disease: NOMS (neurologic, oncologic, mechanical instability, and systemic disease). PMID- 28640701 TI - Primary CNS Lymphoma. AB - Primary CNS lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma that is typically confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. The prognosis of patients with PCNSL has improved during the last decades with the introduction of high-dose methotrexate. However, despite recent progress, results after treatment are durable in half of patients, and therapy can be associated with late neurotoxicity. PCNSL is an uncommon tumor, and only four randomized trials and one phase III trial have been completed so far, all in the first-line setting. To our knowledge, no randomized trial has been conducted for recurrent/refractory disease, leaving many questions unanswered about optimal first-line and salvage treatments. This review will give an overview of the presentation, evaluation, and treatment of immunocompetent patients with PCNSL. PMID- 28640704 TI - Immunotherapy for Brain Tumors. AB - Glioblastoma (GBM) is the most lethal form of brain tumor and remains a large, unmet medical need. This review focuses on recent advances in the neurosciences that converge with the broader field of immuno-oncology. Recent findings in neuroanatomy provide a basis for new approaches of cellular therapies for tumors that involve the CNS. The ultimate success of immunotherapy in the CNS will require improved imaging technologies and methods for analysis of the tumor microenvironment in patients with GBM. It is likely that combinatorial approaches with targeted immunotherapies will be required to exploit the vulnerabilities of GBM and other brain tumors. PMID- 28640705 TI - Genomic Analysis of Childhood Brain Tumors: Methods for Genome-Wide Discovery and Precision Medicine Become Mainstream. AB - Recent breakthroughs in next-generation sequencing technology and complementary genomic platforms have transformed our capacity to interrogate the molecular landscapes of human cancers, including childhood brain tumors. Numerous high throughput genomic studies have been reported for the major histologic brain tumor entities diagnosed in children, including interrogations at the level of the genome, epigenome, and transcriptome, many of which have yielded essential new insights into disease biology. The nature of these discoveries has been largely platform dependent, exemplifying the usefulness of applying different genomic and computational strategies, or integrative approaches, to address specific biologic and/or clinical questions. The goal of this article is to summarize the spectrum of molecular profiling methods available for investigating genomic aspects of childhood brain tumors in both the research and the clinical setting. We provide an overview of the main next-generation sequencing and array based technologies currently being applied in this field and draw from key examples in the recent neuro-oncology literature to illustrate how these genomic approaches have profoundly advanced our understanding of individual tumor entities. Moreover, we discuss the current status of genomic profiling in the clinic and how different platforms are being used to improve patient diagnosis and stratification, as well as to identify actionable targets for informing molecularly guided therapies, especially for patients for whom conventional standard-of-care treatments have failed. Both the demand for genomic testing and the main challenges associated with incorporating genomics into the clinical management of pediatric patients with brain tumors are discussed, as are recommendations for incorporating these assays into future clinical trials. PMID- 28640706 TI - Adult Glioblastoma. AB - Glioblastoma (GBM) is a rare tumor and one of the most challenging malignancies to treat in all of oncology. Although advances have been made in the treatment of GBM, encouraging outcomes typically are not observed; patients diagnosed with these tumors generally have a dismal prognosis and poor quality of life as the disease progresses. This review summarizes the clinical presentation of GBM, diagnostic methods, evidentiary basis for the current standards of care, and investigational approaches to treat or manage GBM. Because the track record for developing effective therapies for GBM has been dismal, we also review the challenges to successful therapeutic and biomarker development. PMID- 28640708 TI - Medulloblastoma: From Myth to Molecular. AB - Current therapies for medulloblastoma were introduced primarily in the 1980s and consist of predominantly cytotoxic, nontargeted approaches. Mortality from medulloblastoma remains significant. In addition, many survivors suffer from severe treatment-related effects of radiation and cytotoxic chemotherapy. Further intensification of nonspecific therapy is unlikely to offer additional benefits, because survival rates have reached a plateau. Recent publications in medulloblastoma have revolved largely around the recognition that medulloblastoma per se does not exist, but rather, that there are a group of histologically similar but clinically and molecularly distinct entities that have been grouped under that rubric. Distinguishing the four molecular subgroups of medulloblastoma wingless (WNT), sonic hedgehog (SHH), group 3, and group 4-in the daily treatment of patients, as well in the setting of clinical trials, is an important challenge in the near term for the pediatric neuro-oncology community. The preponderance of morbidity in treating patients with medulloblastoma is secondary to the treatment or prophylaxis of leptomeningeal metastases, and the cause of most deaths is leptomeningeal metastases. Recurrence of medulloblastoma is a nearly universally fatal event, with no significant salvage rate. The extent of spatial and temporal intratumoral heterogeneity as medulloblastoma metastasizes to leptomeninges and as it evolves in the face of radiation and cytotoxic chemotherapy is just beginning to be understood as a major barrier to therapeutic success. Pediatric neuro-oncology clinicians and scientists must now determine how best to incorporate rapid changes in our biologic understanding of medulloblastoma into the next generation of upfront clinical trials, with the goal of both improving survival for the highest-risk patients and improving quality of life for survivors. PMID- 28640707 TI - Response Assessment in Neuro-Oncology Clinical Trials. AB - Development of novel therapies for CNS tumors requires reliable assessment of response and progression. This requirement has been particularly challenging in neuro-oncology for which contrast enhancement serves as an imperfect surrogate for tumor volume and is influenced by agents that affect vascular permeability, such as antiangiogenic therapies. In addition, most tumors have a nonenhancing component that can be difficult to accurately quantify. To improve the response assessment in neuro-oncology and to standardize the criteria that are used for different CNS tumors, the Response Assessment in Neuro-Oncology (RANO) working group was established. This multidisciplinary international working group consists of neuro-oncologists, medical oncologists, neuroradiologists, neurosurgeons, radiation oncologists, neuropsychologists, and experts in clinical outcomes assessments, working in collaboration with government and industry to enhance the interpretation of clinical trials. The RANO working group was originally created to update response criteria for high- and low-grade gliomas and to address such issues as pseudoresponse and nonenhancing tumor progression from antiangiogenic therapies, and pseudoprogression from radiochemotherapy. RANO has expanded to include working groups that are focused on other tumors, including brain metastases, leptomeningeal metastases, spine tumors, pediatric brain tumors, and meningiomas, as well as other clinical trial end points, such as clinical outcomes assessments, seizures, corticosteroid use, and positron emission tomography imaging. In an effort to standardize the measurement of neurologic function for clinical assessment, the Neurologic Assessment in Neuro Oncology scale was drafted. Born out of a workshop conducted by the Jumpstarting Brain Tumor Drug Development Coalition and the US Food and Drug Administration, a standardized brain tumor imaging protocol now exists to reduce variability and improve reliability. Efforts by RANO have been widely accepted and are increasingly being used in neuro-oncology trials, although additional refinements will be needed. PMID- 28640709 TI - Brain Tumors: Challenges and Opportunities to Cure. PMID- 28640710 TI - Brain Tumor Stem Cells Remain in Play. PMID- 28640711 TI - EFFECTS OF SEASON AND POSTMORTEM CHANGES ON BLOOD ANALYTES IN PYRENEAN CHAMOIS (RUPICAPRA PYRENAICA PYRENAICA). AB - Our objectives were to evaluate the effects of the 1) season, and 2) postmortem changes on serum biochemistries related with metabolism in Pyrenean chamois (Rupicapra pyrenaica pyrenaica). Serum samples from 98 animals obtained from 2009 to 2012 were included. To investigate seasonal influences on blood parameters, the Pyrenean chamois were captured in drive-nets during the feed abundant (FA; n=32) and food deficient (FD; n=35) seasons. To evaluate the possible differences in biochemistry analytes when sampling live or dead animals, we used serum samples from 32 captured animals and 31 dead animals (obtained during controlled hunting) in the FA season. Significant increases in high-density lipoprotein cholesterol (24%), nonesterified fatty acids (NEFA, 190%), total antioxidant capacity (68%), and haptoglobin (33%) were observed in FD when compared with FA seasons. Albumin and insulin-like growth factor-1 (IGF-1) showed statistically significant decreases of 10% and 11%, respectively, in samples taken in the FD season compared to the FA season. Statistically significant higher concentrations were found in serum low-density lipoprotein cholesterol (22%), triglycerides (28%), acetylcholinesterase (50%), NEFA (383%), albumin (18%), IGF-1 (53%), cortisol (959%), and paraoxonase-1 (20%) in samples collected from live animals compared to samples collected from dead ones. We demonstrated that season should be taken into account when evaluating serum biochemistries in Pyrenean chamois because, in the FD season, these animals present lipid mobilization, decreased albumin and IGF-1, and increased total antioxidant capacity compared with the FA season. In addition, if samples are taken from dead animals, observed decreases in serum low-density lipoprotein cholesterol, triglycerides, albumin, paraoxonase 1, acetylcholinesterase, NEFA, cortisol, IGF-1, and an increase in haptoglobin should be expected. PMID- 28640712 TI - Detection of Wellfleet Bay Virus Antibodies in Sea Birds of the Northeastern USA. AB - Wellfleet Bay virus (WFBV) is a recently described orthomyxovirus isolated from the tissues of Common Eiders (Somateria mollissima) collected during recurrent mortality events on Cape Cod, Massachusetts, US. Coastal Massachusetts is the only location where disease or mortality associated with this virus has been detected in wild birds, and a previous seroprevalence study found a significantly higher frequency of viral exposure in eiders from this location than from other areas sampled in North America. This suggests that coastal Massachusetts is an epicenter of WFBV exposure, but the reason for this is unknown. Opportunistic sampling of sympatric species and testing of banked serum was used to investigate potential host range and spatiotemporal patterns of WFBV exposure. Antibodies were detected in Herring Gulls (Larus argentatus), Ring-billed Gulls (Larus delawarensis), a White-winged Scoter (Melanitta fusca), and a Black Scoter (Melanitta nigra). These findings demonstrate the likely occurrence of fall/winter transmission, expand our understanding of the host range of the virus, and provide further insight into the epidemiology of WFBV in the northeastern US. PMID- 28640713 TI - DISPERSAL HAZARDS OF PSEUDOGYMNOASCUS DESTRUCTANS BY BATS AND HUMAN ACTIVITY AT HIBERNACULA IN SUMMER. AB - Bats occupying hibernacula during summer are exposed to Pseudogymnoascus destructans (Pd), the causative agent of white-nose syndrome (WNS), and may contribute to its dispersal. Furthermore, equipment and clothing exposed to cave environments are a potential source for human-assisted spread of Pd. To explore dispersal hazards for Pd during the nonhibernal season, we tested samples that were collected from bats, the environment, and equipment at hibernacula in the eastern US between 18 July-22 August 2012. Study sites included six hibernacula known to harbor bats with Pd with varying winter-count impacts from WNS and two hibernacula (control sites) without prior history of WNS. Nucleic acid from Pd was detected from wing-skin swabs or guano from 40 of 617 bats (7% prevalence), including males and females of five species at five sites where WNS had previously been confirmed as well as from one control site. Analysis of guano collected during summer demonstrated a higher apparent prevalence of Pd among bats (17%, 37/223) than did analysis of wing-skin swabs (1%, 4/617). Viable Pd cultured from wing skin (2%, 1/56) and low recapture rates at all sites suggested bats harboring Pd during summer could contribute to pathogen dispersal. Additionally, Pd DNA was detected on clothing and trapping equipment used inside and near hibernacula, and Pd was detected in sediment more readily than in swabs of hibernaculum walls. Statistically significant differences in environmental abundance of Pd were not detected among sites, but prevalence of Pd differed between sites and among bat species. Overall, bats using hibernacula in summer can harbor Pd on their skin and in their guano, and demonstration of Pd on clothing, traps, and other equipment used at hibernacula during summertime within the WNS-affected region indicates risk for pathogen dispersal during the nonhibernal season. PMID- 28640715 TI - Runner up 2017. PMID- 28640716 TI - The unknowns in tissue viability. PMID- 28640714 TI - An unexplored brain-gut microbiota axis in stroke. AB - Microbiota research, in particular that of the gut, has recently gained much attention in medical research owing to technological advances in metagenomics and metabolomics. Despite this, much of the research direction has focused on long term or chronic effects of microbiota manipulation on health and disease. In this addendum, we reflect on our recent publication that reported findings addressing a rather unconventional hypothesis. Bacterial pneumonia is highly prevalent and is one of the leading contributors to stroke morbidity and mortality worldwide. However, microbiological cultures of samples taken from stroke patient with a suspected case of pneumonia often return with a negative result. Therefore, we proposed that post-stroke infection may be due to the presence of anaerobic bacteria, possibly those originated from the host gut microbiota. Supporting this, we showed that stroke promotes intestinal barrier breakdown and robust microbiota changes, and the subsequent translocation of selective bacterial strain from the host gut microbiota to peripheral tissues (i.e. lung) induces post-stroke infections. Our findings were further supported by various elegant studies published in the past 12 months. Here, we discuss and provide an overview of our key findings, supporting studies, and the implications for future advances in stroke research. PMID- 28640717 TI - Wound care research: why do it? PMID- 28640718 TI - Setting up recovery clinics and promoting service user involvement. AB - Service user involvement in mental health has gained considerable momentum. Evidence from the literature suggests that it remains largely theoretical rather than being put into practice. The current nature of acute inpatient mental health units creates various challenges for nurses to put this concept into practice. Recovery clinics were introduced to bridge this gap and to promote service user involvement practice within the current care delivery model at Kent and Medway NHS and Social Care Partnership Trust. It has shaped new ways of working for nurses with a person-centred approach as its philosophy. Service users and nurses were involved in implementing a needs-led and bottom-up initiative using Kotter's change model. Initial results suggest that it has been successful in meeting its objectives evidenced through increased meaningful interactions and involvement in care by service users and carers. The clinics have gained wide recognition and have highlighted a need for further research into care delivery models to promote service user involvement in these units. PMID- 28640719 TI - Using simulated practice in pre-registration education to explore mental health issues. AB - UK policy advocates that all nurses should have the skills to work with individuals experiencing mental health problems. However, barriers exist in that mental health placements for child student nurses are brief or difficult to arrange. This hinders opportunities to develop a therapeutic working relationship with young people, consolidate skills and ultimately develop confidence in working with young people presenting with mental health problems. A 3-day simulated practice strategy with child nursing students was designed to give students the knowledge, skills and confidence to work with young people who present to services with mental health problems. Students were approached 6 months after their simulated practice training to evaluate their opportunities to put their skills into practice while on placement. Once back in practice, 100% of students said they had improved confidence in working with young people who present with mental health problems. PMID- 28640720 TI - Fungating wounds: management and treatment options. AB - This article defines fungating wounds and considers the underlying cause, location and presentation. The clinical challenges presented by fungating wounds are discussed, with reference to evidence-based care delivery. This includes wound assessment, cleansing, debridement and management of malodour, infection, bleeding and exudate. Guidance on the use of wound management dressings is considered in relation to symptom management. The importance of clinical decision making and educational preparation in the delivery of evidenced-based care for those with fungating wounds is emphasised. A conclusion is made that the clinician can support the patient with a fungating wound by the delivery of evidenced-based care. PMID- 28640721 TI - The introduction and evaluation of a pressure ulcer risk assessment tool for photopheresis outpatients. AB - Chronic graft-versus-host disease (cGVHD) patients are at high risk of compromised skin integrity, and of developing pressure ulcers, which may bleed and/or become infected. The Rotherham Outpatient Screening Tool (ROST) was adapted from the Waterlow score and the Malnutrition Universial Screening Tool (MUST) to suit patients attending an outpatient unit for photopheresis. A review of the screening tool highlighted patients at a higher risk of developing pressure damage during treatment and therefore the unit was able to reduce this risk by the provision of a pressure-relieving cushion (Repose). PMID- 28640723 TI - Intravitreal injections service: a patient experience evaluation. AB - INTRODUCTION: This survey has been conducted following the introduction of nurse led intravitreal injections clinics at the Great Western Hospital. A team of 5 nurses regularly carry out an average of 90 injections per week. METHODS: A series of 169 consecutive injection patients have been offered the study questionnaire between 28 January 2016 and 28 February 2016; patients with no previous experience with a nurse injector were excluded. RESULTS: 76.9% strongly agree that the nurse is more friendly and sensitive to their needs. Only 12.4% strongly agree that a doctor will be more suitable to deliver the injections. Seventy-five percent stated that they were very happy with the care, while 0.4% thought a nurse would be unsafe; 69.2% feel more comfortable asking questions when with a nurse injector. Anxiety and nervousness were found to be the main two symptoms experienced by patients around the time of injections (27.8% and 34.9%, respectively). DISCUSSION: The questionnaire was designed based on the feedback from the local friends and family test. A clear majority of patients gave highly positive feedback about nurse injectors. Considering patients' individual needs at the time of injections, such as allergies or points that needs clarification, helps in overcoming some of the psychological complications of treatment. PMID- 28640722 TI - Stroke: ineffective tube securement reduces nutrition and drug treatment. AB - Stroke patients with dysphagia often depend on nutrition, hydration and medication via nasogastric (NG) feeding tubes. Securing tubes using tape is associated with repeated tube loss. In this study, the authors determined cause and effect by auditing tube placement methods, delays incurred, duration and costs. Of 202 NG tube placements in 75 patients, 67 placements occurred in 17 patients over a full course of enteral nutrition (EN) and 40 of these placements were tracked. Tubes were secured by tape in 100%, mittens 31% and special observation 5.4%. However, over an EN course, inadvertent tube loss occurred in 82% of patients and was associated with age (p=0.049) and mitten use (p<0.001): 64% of tubes were lost due to patients and 9% slipped. Average 'tube life' was 2 days, less than 25% of the EN episode (p<0.001). While tube placement occurred within 2.55 hours of request, X-ray confirmation led to a delay in feed and drugs of 8-9 hours per tube placement and loss of 18.8% of feeding time per EN episode. Delays exceeded the 1-hour and 4-hour limits for antibiotics and other medicines in 20% and 80%, respectively. In the 17 tracked patients, it was estimated that 55% of the L5979 direct costs could be saved by nasal bridle use. In conclusion, most tubes studied were lost to inadvertent tube removal, leading to clinically significant delays to nutrition, hydration and drug treatments; this may impair recovery. Reducing tube loss is likely to reduce patient distress, treatment cost and enhance recovery. PMID- 28640724 TI - Enteral feeding for nutritional support in critically ill patients. AB - Omorogieva Ojo, Senior Lecturer in Primary Care at the University of Greenwich, O.Ojo@greenwich.ac.uk , highlights key recommendations on enteral nutrition for patients in critical care. PMID- 28640725 TI - From staff nurse to nurse consultant. AB - John Fowler, educational consultant and part-time university chaplain, examines the role of clinically based nurses in caring for the spiritual needs of patients who are Buddhists. PMID- 28640726 TI - A self-administration of medication pilot project: patient and nurse views. PMID- 28640727 TI - Urology study day: Leeds 2016. AB - Last year, urology nurses and continence nurse specialists took part in the second of two study days on urology. The events were delivered by the British Journal of Nursing with programme support in association with the British Association of Urology Nurses and Hollister Inc. Below are reports of some of the presentations. PMID- 28640728 TI - Wound-bed preparation: a vital step in the healing process. AB - Non-healing wounds are a significant burden to healthcare systems, where it is estimated that 4-5% of the adult population has a problem wound at any one time ( Guest et al, 2017 ). It is suggested that infection is the most frequent complication in non-healing wounds where it can prolong patient treatment times and increase resource use ( Gottrup et al, 2013 ). Wound infection develops as a result of an imbalance between the patient's immune system and the conditions in the wound, which subsequently can promote bacterial proliferation ( Wounds UK, 2013 ). It can impact on the patient by delaying wound healing, increasing the risk of amputation and life-threatening conditions, and reducing quality of life. The use of antibiotics to treat wound infections has decreased due to the increased risk of antibiotic resistance ( Swanson et al, 2014 ). As a result alternative strategies for preventing and managing wound infection have been adopted, including wound debridement and the use of topical antiseptic/antimicrobial agents. PMID- 28640729 TI - Why self-care is key to providing high-quality care to others. AB - Jo McCormick, Consultant Nurse and Associate Director of Nursing, Belfast Health and Social Care Trust, Joanna.McCormick@belfasttrust.hscni.net , and Sally Hayes, Director of Strategy, Planning and Resources at the Open University, share their insights from undertaking a Florence Nightingale Leadership Scholarship. PMID- 28640731 TI - Making their voices heard. PMID- 28640730 TI - Treating patients with venous leg ulcers in the acute setting: part 1. AB - Leg ulcers present with a variety of aetiologies, sometimes in combination. The most common aetiology is venous, with treament involving compression, elevation and exercise; the most common treatment setting is the community. However, people with leg ulcers do sometimes require admission to hospital for conditions and situations which may, or may not, be ulcer-related. There is a lack of contemporary evidence on the experience of inpatients and insufficient analysis of the impact on healing and complications to the lower limb when patients with leg ulcers and compression therapy are admitted to hospital. Admission to hospital presents an ideal opportunity for a focus on leg care and potentially enhancing healing rates of patients. The reality for patients with venous leg ulceration being treated with compression therapy is that this does not continue if they are admitted to hospital as inpatients-having been interrupted for MRSA screening and skin assessment, often no-one is available to reinstate the therapy. This article highlights key issues in the ongoing care of these patients and offers suggestions for basic management until a more acceptable and evidence based solution can be found. Part 2 will deal with the preparation for discharge and options for the treatment of patients who are not already in the care of community services. PMID- 28640733 TI - STPs need money to succeed. PMID- 28640732 TI - Do nurse staffing levels affect patient mortality in acute secondary care? AB - This systematic literature review explores and considers whether registered nurse staffing levels affect patient mortality in acute secondary care settings. A discussion makes particular reference to the philosophical foundations of contrasting research approaches used within the literature. At the time of writing, the author was a modern matron for surgery, managing the ear, nose and throat; head and neck; airway; and reconstructive plastic surgery services in a large acute teaching hospital in central London. Effective management and leadership of acute clinical areas requires appropriate nurse:patient ratios. In practice settings, patient to staff ratios are based on care being provided by highly skilled and competent nurses providing best-quality, evidence-based practice. PMID- 28640734 TI - Cost-effective wound management: a survey of 1717 nurses. AB - Delivering high-quality wound care requires a mix of knowledge and skills, which nurses aim to update by attending educational events such as conferences and study days. This article describes the data obtained from 30 educational study days, which took place across England, Scotland and Wales. It will explore nurses' knowledge in relation to the cost-effectiveness and clinical efficacy of current wound care practices, based on the answers of 1717 delegates that attended the events. It will also outline the results in relation to reducing expenditure on wound dressings and the importance of performing an accurate wound assessment. PMID- 28640735 TI - Improving patient safety in the NHS: the culture change agents. AB - John Tingle, Reader in Health Law at Nottingham Trent University, and Jen Minford, Junior Doctor Coordinator, Nottingham University Hospitals NHS Trust, look at the role of patient safety culture change agents in the NHS. PMID- 28640736 TI - Compassionate leadership counts. AB - Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, discusses how attitudes to leadership styles have changed and reflects on the role of compassionare leadership in improving care. PMID- 28640737 TI - Professionalism in practice. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses a new publication from the Nursing and Midwifery Council that offers a toolkit designed to strengthen professionalism in nursing. PMID- 28640738 TI - Evaluation of the effect and mechanism of action of local phenytoin in treatment of vitiligo. AB - There are many theories explaining vitiligo such as genetic, autoimmune, neural, free radicals, biochemical, intrinsic defect, melanocytorrhagy, and convergent theories. Phenytoin is a widely used anticonvulsant, which is used in cutaneous medicine for treatment of ulcers and epidermolysis bullosa. The aim of this study is to assess the effectiveness of topical phenytoin gel in the treatment of vitiligo patients and explaining the underlying mechanism using immunohistochemistry for evaluation of HMB45, CD4, and CD8. Only 9 patients out of 28 experienced response to phenytoin in the form of dull, white color change and light brown color. Post-phenytoin treatment biopsies showed decreased density of inflammation, increased melanin and increased HMB45 positive cells together with an increased number of CD4 positive lymphocytes and decreased number of CD8 positive lymphocytes. These observations did not reach significant level (P > 0.05). A high percentage of CD4 positive lymphocytes was significantly associated with a long duration of vitiligo (p = 0.03) and segmental vitiligo type (p = 0.02). The current study applied phenytoin as 2% concentrated gel for 3 months, which is a relatively short duration without observed side effects throughout the period. These results indicate that topical phenytoin of low concentrations may have beneficial effects through immunomodulatory activity by affecting CD4 and CD8 counts and subsequently the ratio between them. Further studies are recommended to combine phenytoin with other antivitiligo agents as local corticosteroids or phototherapy to clarify if it could potentiate their effects. PMID- 28640740 TI - Differential effects of isc operon mutations on the biosynthesis and activity of key anaerobic metalloenzymes in Escherichia coli. AB - Escherichia coli has two machineries for the synthesis of FeS clusters, namely Isc (iron-sulfur cluster) and Suf (sulfur formation). The Isc machinery, encoded by the iscRSUA-hscBA-fdx-iscXoperon, plays a crucial role in the biogenesis of FeS clusters for the oxidoreductases of aerobic metabolism. Less is known, however, about the role of ISC in the maturation of key multi-subunit metalloenzymes of anaerobic metabolism. Here, we determined the contribution of each iscoperon gene product towards the functionality of the major anaerobic oxidoreductases in E. coli, including three [NiFe]-hydrogenases (Hyd), two respiratory formate dehydrogenases (FDH) and nitrate reductase (NAR). Mutants lacking the cysteine desulfurase, IscS, lacked activity of all six enzymes, as well as the activity of fumaratereductase, and this was due to deficiencies in enzyme biosynthesis, maturation or FeS cluster insertion into electron-transfer components. Notably, based on anaerobic growth characteristics and metabolite patterns, the activity of the radical-S-adenosylmethionine enzyme pyruvate formate-lyase activase was independent of IscS, suggesting that FeS biogenesis for this ancient enzyme has different requirements. Mutants lacking either the scaffold protein IscU, the ferredoxin Fdx or the chaperones HscA or HscB had similar enzyme phenotypes: five of the oxidoreductases were essentially inactive, with the exception being the Hyd-3 enzyme, which formed part of the H2-producing formate hydrogenlyase (FHL) complex. Neither the frataxin-homologue CyaY nor the IscX protein was essential for synthesis of the three Hyd enzymes. Thus, while IscS is essential for H2 production in E. coli, the other ISC components are non essential. PMID- 28640739 TI - Hepatitis B virus core antigen mutations predict post-operative prognosis of patients with primary hepatocellular carcinoma. AB - The aim of this study was to explore the relationship between hepatitis B virus (HBV) core antigen (HBc) mutations and the post-operative prognosis of HBV related hepatocellular carcinoma (HCC). In total, 98 patients suffering from HBV related HCC and treated with surgery were enrolled, with a 48 month follow-up. The preCore/Core region of the HBV genome from tumour tissue (TT) and paired adjacent non-tumour tissue (ANTT) of these patients was sequenced, and a phylogenetic tree was reconstructed. The correlations between the viral features and evolutionary divergence of preCore/Core amino acid sequences from 67 paired TTs and ANTTs were analysed. Cox proportional hazard model analysis was applied for post-operative hazard risk evaluation. Phylogenetic analysis revealed that all of the sequences were ascribed to genotype C. The evolutionary divergence of amino acid sequences from matched TTs and ANTTs was significantly negatively correlated with serum and intrahepatic HBV DNA levels. Multivariate analysis showed that the HBc E77 mutation was associated with shorter overall survival, and HBc S87 and P156 mutations were independent risk factors for relapse. Furthermore, in contrast to with patients without the S87 mutation, no correlation was observed between serum HBV DNA and intrahepatic HBV DNA in HCC patients with the S87 mutation. Analysis of the intrahepatic sequence may advance our understanding of viral status; thus, it is useful for prognosis prediction for HBV-related HCC. PMID- 28640741 TI - An endophytic Fusarium sp. isolated from Monarda citriodora produces the industrially important plant-like volatile organic compound hexanal. AB - An endophytic fungus, MC_25L, has been isolated from the leaves of MonardacitriodoraCerv. ex Lag., a medicinal and aromatic herb from the northwestern Himalayas. It produces a fruity fragrance while growing on potato dextrose agar, suggesting that it is producing volatile organic compounds (VOCs). The endophyte inhibited the growth of plant pathogens such asSclerotiniasp. and Aspergillusflavus by virtue of VOCs. Identification of MC_25L based on morphological and microscopic features, as well as ITS-based rDNA sequence analysis, revealed that it is a Fusariumsp. GC-MS analysis revealed that this endophyte produces a unique array of VOCs, in particular hexanal, p fluoroanisole, pentafluoropropionic acid 2-ethylhexyl, (5E)-5-ethyl-2-methyl-5 hepten-3-one, 2-butyl-2-hexanol, (7E)-2-methyl-7-hexadecene and acoradiene. Three major compounds were hexanal, (5E)-5-ethyl-2-methyl-5-hepten-3-one and acoradiene, and they account for around 84.57 % of the total VOCs. Moreover, of interest was the presence of hexanal, which has applications in the food and cosmetic industries, as well as in mycofumigation. This is the first report of a fungal endophyte producing the industrially important plant-like VOC hexanal. Hexanal is also active biologically. Thus this study indicates that Fusariumsp. (MC_25L) is a potential candidate for the up-scaling of hexanal. PMID- 28640742 TI - Identification of amino acids within norovirus polymerase involved in RNA binding and viral replication. AB - Until recently, molecular studies on human norovirus (HuNoV), a major causative agent of gastroenteritis, have been hampered by the lack of an efficient cell culture system. Murine norovirus-1 (MNV-1) has served as a surrogate model system for norovirus research, due to the availability of robust cell culture systems and reverse genetics. To identify amino acids involved in RNA synthesis by the viral RNA-dependent RNA polymerase (NS7), we constructed NS7 mutants in which basic amino acids surrounding the catalytic site were substituted with alanine. Electrophoretic mobility shift assay revealed that these residues are important for RNA binding, particularly R396. Furthermore, in vitro RNA synthesis and reverse genetics were used to identify conserved amino acids essential for RNA synthesis and viral replication. These results provide additional functional insights into highly conserved amino acids in NS7 and provide potential methods of rational attenuation of norovirus replication. PMID- 28640743 TI - Glucose consumption in carbohydrate mixtures by phosphotransferase-system mutants of Escherichia coli. AB - Escherichia coli lacking the glucose phosphotransferase system (PTS), mannose PTS and glucokinase are supposedly unable to grow on glucose as the sole carbon source (Curtis SJ, Epstein W. J Bacteriol 1975;122:1189-1199). We report that W ptsG manZ glk (ALS1406) grows slowly on glucose in media containing glucose with a second carbon source: ALS1406 metabolizes glucose after that other carbon source, including arabinose, fructose, glycerol, succinate or xylose, is exhausted. Galactose is an exception to this rule, as ALS1406 simultaneously consumes both galactose and glucose. The ability of ALS1406 to metabolize glucose in a xylose-glucose mixture was unchanged by an additional knockout in any single gene involved in carbohydrate transport and utilization, including agp (periplasmic glucose-1-phosphatase), galP (galactose permease), xylA (xylose isomerase), alsK (allose kinase), crr (glucose PTS enzyme IIA), galK (galactose kinase), mak (mannokinase), malE (maltose transporter), malX (maltose PTS enzyme IIBC), mglB (methyl-galactose transporter subunit), nagE (N-acetyl glucosamine PTS enzyme IICBA), nanK (N-acetyl mannosamine kinase) or pgm (phosphoglucose mutase). Glucose metabolism was only blocked by the deletion of two metabolic genes, pgi (phosphoglucose isomerase) and zwf (glucose-6-phosphate 1 dehydrogenase), which prevents the entry of glucose-6-phosphate into the pentose phosphate and Embden-Meyerhof-Parnas pathways. Carbon-limited steady-state studies demonstrated that xylose must be sub-saturating for glucose to be metabolized, while nitrogen-limited studies showed that xylose is partly converted to glucose when xylose is in excess. Under transient conditions, ALS1406 converts almost 25 % (mass) xylose into glucose as a result of reversible transketolase and transaldolase and the re-entry of carbon into the pentose phosphate pathway via glucose-6-phosphate 1-dehydrogenase. PMID- 28640744 TI - ICTV Virus Taxonomy Profile: Polyomaviridae. AB - The Polyomaviridae is a family of small, non-enveloped viruses with circular dsDNA genomes of approximately 5 kbp. The family includes four genera whose members have restricted host range, infecting mammals and birds. Polyomavirus genomes have also been detected recently in fish. Merkel cell polyomavirus and raccoon polyomavirus are associated with cancer in their host; other members are human and veterinary pathogens. Clinical manifestations are obvious in immunocompromised patients but not in healthy individuals. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Polyomaviridae, which is available at www.ictv.global/report/polyomaviridae. PMID- 28640745 TI - The amino terminal subdomain of glycoprotein Gc of Schmallenberg virus: disulfide bonding and structural determinants of neutralization. AB - Orthobunyaviruses are enveloped viruses that can cause human and animal diseases. A novel and major member is the Schmallenberg virus (SBV), the etiological agent of an emerging disease of ruminants that has been spreading all over Europe since 2011. The glycoproteins Gn and Gc of orthobunyaviruses mediate the viral entry, and specifically Gc is a major target for the humoral immune response. For example, the N terminal subdomain of the SBV glycoprotein Gc is targeted by neutralizing monoclonal antibodies that recognize conformational epitopes. Here, we determined the structural features of the N terminus of Gc, and analysed its interaction with monoclonal antibodies. We were able to demonstrate that one of two N-glycosylation sites is essential for secretion and interaction with a subset of Gc-specific monoclonal antibodies. Furthermore, four disulfide bonds (S S) were identified and the deletion of the third S-S blocked reactivity with another subset of mAbs with virus-neutralizing and non-neutralizing activity. The mutagenesis of the N-glycosylation sites and the disulfide bonds strongly indicated the independent folding of two subdomains within the SBV Gc N terminus. Further, the epitopes recognized by a panel of mAbs could be grouped into two clusters, as revealed by fine mapping using chimeric proteins. Combining the disulfide bonding and epitope mapping allowed us to generate a structural model of the SBV Gc N-terminus. This novel information about the role and structure of the amino terminal region of SBV Gc is of general relevance for the design of antivirals and vaccines against this virus. PMID- 28640748 TI - Spike detection using a multiresolution entropy based method. AB - Correct interpretation of neural mechanisms depends on the accurate detection of neuronal activities, which become visible as spikes in the electrical activity of neurons. In the present work, a novel entropy based method is proposed for spike detection which employs the fact that transient spike events change the entropy level of the neural time series. In this regard, the time-dependent entropy method can be used for detecting spike times, where the entropy of a selected segment of a neural time series, using a sliding window approach, is calculated and the time of the events are highlighted by sharp peaks in the output of the time-dependent entropy method. It is shown that the length of the sliding window determines the resolution of the time series in entropy space, therefore, the calculation is performed with a different window length for obtaining a multiresolution transform. The final decision threshold for detecting spike events is applied to the point-wise product of the time dependent entropy calculations with different resolutions. The proposed detection method has been assessed using several simulated and real neural data sets. The results show that the proposed method detects spikes in their exact times while compared with other traditional methods, relatively lower false alarm rate is obtained. PMID- 28640747 TI - A single amino acid change in the non-structural NV protein impacts the virulence phenotype of Viral hemorrhagic septicemia virus in trout. AB - Novirhabdoviruses like the Viral hemorrhagic septicemia virus (VHSV) are rhabdoviruses infecting fish. In the current study, RNA genomes of different VHSV field isolates classified as high, medium or low virulent phenotypes have been sequenced by next-generation sequencing and compared. Various amino acid changes, depending on the VHSV phenotype, have been identified in all the VHSV proteins. As a starting point, we focused our study on the non-virion (NV) non-structural protein in which an arginine residue (R116) is present in all the virulent isolates and replaced by a serine/asparagine residue S/N116 in the attenuated isolates. A recombinant virus derived from a virulent VHSV strain in which the NV R116 residue has been replaced by a serine, rVHSVNVR116S, was generated by reverse genetics and used to infect juvenile trout. We showed that rVHSVNVR116S was highly attenuated and that surviving fish were almost completely protected from a challenge with the wild-type VHSV. PMID- 28640746 TI - A chromosome 4 trisomy contributes to increased fluconazole resistance in a clinical isolate of Candida albicans. AB - Candida albicans is an important opportunistic fungal pathogen capable of causing both mucosal and disseminated disease. Infections are often treated with fluconazole, a front-line antifungal drug that targets the biosynthesis of ergosterol, a major component of the fungal cell membrane. Resistance to fluconazole can arise through a variety of mechanisms, including gain-of-function mutations, loss of heterozygosity events and aneuploidy. The clinical isolate P60002 was found to be highly resistant to azole-class drugs, yet lacked mutations or chromosomal rearrangements known to be associated with azole resistance. Transcription profiling suggested that increased expression of two putative drug efflux pumps, CDR11 and QDR1, might confer azole resistance. However, ectopic expression of the P60002 alleles of these genes in a drug susceptible strain did not increase fluconazole resistance. We next examined whether the presence of three copies of chromosome 4 (Chr4) or chromosome 6 (Chr6) contributed to azole resistance in P60002. We established that Chr4 trisomy contributes significantly to fluconazole resistance, whereas Chr6 trisomy has no discernible effect on resistance. In contrast, a Chr4 trisomy did not increase fluconazole resistance when present in the standard SC5314 strain background. These results establish a link between Chr4 trisomy and elevated fluconazole resistance, and demonstrate the impact of genetic background on drug resistance phenotypes in C. albicans. PMID- 28640750 TI - In-vivo monitoring of infection via implantable microsensors: a pilot study. AB - The most common complication after implantation of foreign material is infection, leading to implant failure and severe patient discomfort. Smoldering-infections proceed inapparently and might not get verified by radiological diagnostics. Early identification of this type of infection might significantly reduce the rate of complications. Therefore, we manufactured a microsensor strip in a hybrid of thin-film and laminate technology in a wafer-level process. It comprises electrochemical, amperometric microsensors for glucose, oxygen and lactate as well as an integrated reference electrode. Microsensors have been implanted in the mouse dorsal skin fold chamber, which got inoculated with a human-pathogen bacterial strain. A selective signal could be measured for all parameters and time points. The infection led to measurable changes of the wound environment as given by a decrease of the oxygen- as well as the glucose-concentration while the lactate concentration increased markedly over time. The given results in this study are the first hints on a promising new tool and should therefore be interpreted as a proof of the principle to show the functionality of the microsensors in an in vivo setting. These microsensors could be used to monitor smoldering infections of implantable foreign materials reducing foreign implant associated complications. PMID- 28640749 TI - Enamel shear bond strength of different primers combined with an orthodontic adhesive paste. AB - AIM: The aim of this study was a comparison of shear bond strength (SBS) on tooth enamel of different primers combined with the adhesive paste Transbond XT. MATERIALS AND METHODS: Forty bovine teeth were used in order to create 40 test blocks. The blocks were divided into four groups of 10 blocks each: group A - sample primer (SP); group B - Opal Seal (OS); group C - Transbond Plus SEP (TSEP); group D - Transbond XT Primer (TXT). After surface preparation and application of the primer, respectively, two stainless steel brackets were fixed on each tooth by using Transbond XT. Accordingly, 80 brackets were debonded (n=20). Shear bond strength and adhesive remnant index (ARI) scores were evaluated. Statistical analyses were performed by using the Student's t-test and Mann-Whitney U test. RESULTS: All tested groups revealed high shear bond strength in a similar size range. There were no significant differences between the groups concerning shear bond strength. The ARI scores of group C showed significantly lower ARI scores (0 and 1) than that of group D. Apart from that there was no statistical difference. CONCLUSION: In combination with the adhesive paste Transbond XT, all tested primers were suitable for fixing orthodontic brackets. The primers could be changed according to the clinical situation. PMID- 28640751 TI - False spectra formation in the differential two-channel scheme of the laser Doppler flowmeter. AB - Noise in the differential two-channel scheme of a classic laser Doppler flowmetry (LDF) instrument was studied. Formation of false spectral components in the output signal due to beating of electrical signals in the differential amplifier was found out. The improved block-diagram of the flowmeter was developed allowing to reduce the noise. PMID- 28640752 TI - Argumentation: A Methodology to Facilitate Critical Thinking. AB - Caring is a difficult nursing activity that involves a complex nature of a human being in need of complex decision-making and problem solving through the critical thinking process. It is mandatory that critical thinking is facilitated in general and in nursing education particularly in order to render care in diverse multicultural patient care settings. This paper aims to describe how argumentation can be used to facilitate critical thinking in learners. A qualitative, exploratory and descriptive design that is contextual was used. Purposive sampling method was used to draw a sample and Miles and Huberman methodology of qualitative analysis was used to analyse data. Lincoln and Guba's strategies were employed to ensure trustworthiness, while Dhai and McQuoid Mason's principles of ethical consideration were used. Following data analysis the findings were integrated within literature which culminated into the formulation of guidelines that can be followed when using argumentation as a methodology to facilitate critical thinking. PMID- 28640753 TI - Mechanism of antihypertensive effect of Mucuna pruriens L. seed extract and its isolated compounds. AB - Background In the search of safe and effective lead molecules from natural sources, Mucuna pruriens (MP) L. (Fabaceae) seeds were utilized for exploring the antihypertensive potential. Traditionally, it is used as diuretic and hypotensive. Methods Bioassay-guided fractions were utilized for the isolation of active compounds by column chromatography. IC50 value, enzyme kinetics and inhibition mechanism were determined. In vivo time and dose-dependent hypotensive study followed by changes in mean arterial pressure (MAP) induced by angiotensin I (3 nmol/kg), angiotensin II (3 nmol/kg), and bradykinin (10 nmol/kg) in anesthetized rats was done. Plasma and tissue angiotensin I-converting enzyme (ACE) activities were also determined. Results Phytochemical analysis by spectroscopic techniques revealed the presence of known compounds like genistein, ursolic acid and L-DOPA from the ethyl acetate and water fraction, respectively. In vitro study revealed MP ethyl acetate (MPEA) fraction and genistein as the most active fraction (IC50 156.45 ug/mL) and compound (IC50 253.81 uM), respectively. Lineweaver-Burk plots revealed a non-competitive mode of inhibition. ACE protein precipitation was the suggested mechanism for inhibition. The extract showed a time- and dose-dependent decrease in MAP. Genistein was able to dose-dependently reduce the MAP, up to 53+/-1.5 mmHg (40 mg/kg, i.v.). As compared to control, it showed a dose-dependent decrease in plasma ACE activity of 40.61 % and 54.76 % at 10 mg/kg and 20 mg/kg, respectively. It also decreased the ACE activity in the aorta (107.67nM/ml min at 10 mg, p<0.001; 95.33nM/ml min at 20 mg p<0.001). Captopril was used as a standard for various in vitro and in vivo assays. Conclusions The study revealed the antihypertensive potential of MP seed compounds via ACE inhibition. PMID- 28640754 TI - Raised TSH is associated with endothelial dysfunction in Metabolic Syndrome: A case control study. AB - INTRODUCTION: Endothelial dysfunction has been considered as one of the important factors in pathogenesis of Metabolic Syndrome (Met S). Subclinical hypothyroidism (SCH) has also been reported to be associated with Met S. The aim of our study is to evaluate the association of raised TSH with mediators of endothelial dysfunction in Met S with Subclinical hypothyroidism as compared to healthy controls. METHODS: Study population consisted of 100 subjects, out of which 50 were cases of Met S and 50 were healthy controls. Met S group were further divided into two, based on the presence & absence of SCH. Serum insulin, T3, T4, TSH were measured by chemiluminescence based immunoassay (CLIA). Serum nitric oxide (NO) levels were measured by Modified Griess's method and serum endothelin 1 (ET-1) levels were measured by ELISA. RESULTS: Out of 50 cases of Met S, SCH was diagnosed in 22. The mean serum TSH levels were significantly higher in Met S cases as compared to healthy controls (5.7 +/- 1.2 MUIU/mL vs. 2.3 +/- 1.6 MUIU/mL, P <0.0001). Mean serum NO levels were significantly lower in Met S cases as compared to healthy control (15.4 +/- 10 MUM vs. 21 +/- 10 MUM, p = 0.009). Mean serum ET-1 levels were significantly higher in Met S cases as compared to healthy controls (2.68 +/- 1.7 fmol/mL vs. 2.1 +/- 0.84 fmol/mL, p = 0.011). On Pearson's correlation analysis, TSH showed positive correlation with ET-1 (r = 0.341, p = 0.001) and negative correlation with NO (r = -0.331, p = 0.001). Binary logistic regression analysis showed that TSH, NO and ET-1 has significant odd's ratio for predicting Met S. CONCLUSION: Met S cases were screened for thyroid abnormalities and found to have 44% of SCH along with co-existing endothelial dysfunction. Raised TSH in SCH could cause endothelial dysfunction which may lead to Met S and associated co-morbidities. Present study gives new insight in linking endothelial dysfunction and raised TSH in Met S. Therefore, Met S cases should be screened for SCH and treated appropriately to attenuate endothelial dysfunction and associated comorbidities in Met S. PMID- 28640756 TI - Single-lead f-wave extraction using diffusion geometry. AB - OBJECTIVE: A novel single-lead f-wave extraction algorithm based on the modern diffusion geometry data analysis framework is proposed. APPROACH: The algorithm is essentially an averaged beat subtraction algorithm, where the ventricular activity template is estimated by combining a newly designed metric, the 'diffusion distance', and the non-local Euclidean median based on the non-linear manifold setup. We coined the algorithm [Formula: see text]. MAIN RESULTS: Two simulation schemes are considered, and the new algorithm [Formula: see text] outperforms traditional algorithms, including the average beat subtraction, principal component analysis, and adaptive singular value cancellation, in different evaluation metrics with statistical significance. SIGNIFICANCE: The clinical potential is shown in the real Holter signal, and we introduce a new score to evaluate the performance of the algorithm. PMID- 28640757 TI - Novel domain wall dynamics in synthetic antiferromagnets. AB - In this article, we review fascinating new mechanisms on recently observed remarkable current driven domain wall motion in nanowires formed from perpendicularly magnetized synthetic antiferromagnets interfaced with heavy metallic layers, sources of spin-orbit torques. All the associated torques such as volumetric adiabatic and non-adiabatic spin-transfer-torque, spin-orbit torques, shape anisotropy field torques, Dzyaloshinkii-Moriya interaction torques and most importantly a new powerful torque, exchange coupling torque, will be discussed based on an analytical model that provides an intuitive description of domain wall dynamics in synthetic ferromagnets as well as synthetic antiferromagnets. In addition, the current driven DW motion in the presence of in plane fields will be investigated, thus deepening our knowledge about the role of the exchange coupling torque, which will be of potential use for application to various novel spintronic devices. PMID- 28640755 TI - Chemical composition and biological activities of leaf and fruit essential oils from Eucalyptus camaldulensis. AB - The chemical composition of the essential oils from the leaves and fruit of Eucalyptus camaldulensis grown in Mersin, Turkey was analyzed using gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) techniques. The biological activities (antibacterial and antifungal) were examined using the agar well diffusion method. The main leaf oil constituents were p-cymene (42.1%), eucalyptol (1,8-cineole) (14.1%), alpha-pinene (12.7%) and alpha-terpinol (10.7%). The main constituents of the fruit oil were eucalyptol (1,8-cineole) (34.5%), p-cymene (30.0%), alpha-terpinol (15.1%) and alpha-pinene (9.0%). Our results showed that both types of oils are rich in terms of monoterpene hydrocarbons and oxygenated monoterpenes. The leaf and fruit essential oils of E. camaldulensis significantly inhibited the growth of Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Escherichia coli and Streptococcus sp.) bacteria (p<0.05). The oils also showed fungicidal activity against Candida tropicalis and C. globrata. Leaf essential oils showed more activity than fruit essential oils, probably due to the higher p-cymene concentration in leaves. PMID- 28640758 TI - Consecutive ultra-short-term heart rate variability to track dynamic changes in autonomic nervous system during and after exercise. AB - OBJECTIVE: Quantitative measurement of the dynamic changes in autonomic nervous system (ANS) during and after exercise has great significance in clinical, sports training and other fields. A consecutive ultra-short-term (30 s, UST) heart rate variability (HRV) method was proposed to track the exercise-induced autonomic control of heart rate (HR). APPROACH: Twenty-three healthy young men participated in the study. The first four stages of the Modified Bruce Protocol (S0-S3) were performed. Six HRV indices, i.e. HF (power of high frequency ranged from 0.15 to 0.4 Hz), LF (power of low frequency ranged from 0.04 to 0.15 Hz), LF/HF, SD1 and SD2 of Poincare plot, and SD2/SD1, over 30 s were calculated every 5 s over 3 min RR time series during, as well as after, exercise. MAIN RESULTS: The results showed that during exercise, SD1, SD2, HF and LF dropped down quickly and tended to stabilize. Particularly, SD1 and HF showed a slight upward trend in the lower three stages while the declining time of SD2 in S3 lasted longer than the other stages. SD2/SD1 increased rapidly first and then decreased slowly. The values of SD2/SD1 in S3 remained higher than those in the other stages. After exercise, SD1, SD2, HF and LF kept increasing first and then declined slowly or fluctuated with decaying amplitudes. SD2/SD1 increased initially, then decreased and fluctuated slightly. SIGNIFICANCE: Compared with the indices in frequency domain, the Poincare indices were more sensitive and accurate in UST measurement of ANS during exercise. The results demonstrated that the UST method could characterize the dynamic changing tendency of ANS during and after exercise and quantify the differences of changes in ANS induced by exercise with different intensities. In particular, the vagal branch functioned dominantly in controlling HR in S0 but the effect of the sympathetic branch on HR enhanced with the increase of exercise intensity. In addition, the transient changes of ANS related with the sudden onset of exercise could also be reflected, despite perhaps being limited by the computation window width to some extent. Thus, the consecutive UST Poincare indices could provide a feasible and simple method to measure quantitatively the exercise-induced dynamic changes in ANS. PMID- 28640759 TI - Electroactive beta-crystalline phase inclusion and photoluminescence response of a heat-controlled spin-coated PVDF/TiO2 free-standing nanocomposite film for a nanogenerator and an active nanosensor. AB - The electroactive beta-phase is most desirable due to its highest piezo-, pyro- and ferroelectric properties in poly(vinylidene fluoride) (PVDF). Induction of the beta-phase is successfully accomplished in titanium dioxide (TiO2) nanoparticles (NPs) doped spin-coated PVDF nanocomposite (PNC) films. The optimized yields of beta-phase and homogeneous ultra-smooth free-standing PNC film is utilized in a mechanical-energy harvesting application by fabricating a nanogenerator (NG) where the typical electrical poling step is not undertaken. Under a repeated human finger touch and release process, it delivers an open circuit voltage of 5 V. Moreover, the physical sensing capabilities of the NG are examined through harvesting mechanical energy from mouse clicking of a laptop and wrist pulse detection, which indicates that it can also be used as a nanosensor. The blue photoluminescence centred at 444 nm, which was also observed in PNC films, makes us anticipate a new type of photonic application where the design feasibility of hybrid sensors, i.e. electromechanical and photonic combination, is also possible. PMID- 28640760 TI - Successful Treatment of Angiolymphoid Hyperplasia With Eosinophilia With Arterial Ligation and Pulsed Dye Laser. PMID- 28640762 TI - Management of Patient Experience With ATX-101 (Deoxycholic Acid Injection) for Reduction of Submental Fat: ERRATUM. PMID- 28640761 TI - Commentary on Development of Basal Cell Carcinoma With Squamous Differentiation During Vismodegib Treatment. PMID- 28640763 TI - The Effectiveness of Matrix Cauterization With Bichloracetic Acid in the Treatment of Ingrown Toenails: ERRATUM. PMID- 28640764 TI - The Efficacy of Massage in Reducing Nodule Formation After Poly-L-Lactic Acid Administration for Facial Volume Loss: A Randomized, Evaluator-Blinded Clinical Trial: ERRATUM. PMID- 28640765 TI - Imaging Approaches for Contact Lens Deposition. AB - Deposition on contact lenses (CLs) starts quickly after their application to the ocular surface. Deposits may be composed of tear film components or other extraneous substances. These deposits have been related to various adverse conditions of the eye, leading to reduced biocompatibility between the CLs and the ocular surface. Analysis of these deposits is essential to better elucidate the relationship between these deposits and their adverse reactions so that better methods of increasing biocompatibility can be developed. Although methods such as enzymatic assays are available for quantitative analysis, they do not provide a complete picture of the deposition (e.g., lack of morphological details), and therefore, the use of imaging methods that can provide both qualitative and quantitative information about the deposits may be more preferable. Therefore, a search of the peer-reviewed literature that focused on imaging methods in the analysis of deposits on CLs was conducted. Various methods of imaging deposits in-vitro, in-vivo, or ex-vivo have been described along with the associated results. Imaging methods using fluorescence-based techniques and scanning electron microscopy appear to be the most frequently used methods. Some of the described methods not only provided morphologies but also identified the types of various deposits that were attached to the CLs. Various CL materials possessed different deposition morphologies and different quantities of the attached deposits. Further imaging studies performed in conjunction with other methods that could identify and quantify the deposits at a molecular level are recommended. PMID- 28640766 TI - Impact of Recurrence of Ovarian Cancer on Quality of Life and Outlook for the Future. AB - OBJECTIVE: Ovarian cancer recurs in most patients, with a 5-year survival rate less than 30%. Quality of life is an increasingly important issue in patients with cancer, but there are limited data in women with recurrent ovarian cancer in this regard. MATERIALS AND METHODS: We used an ad hoc questionnaire to compare changes in health perceptions, burden of disease, and expectations for the future quality of life in women with and without recurrence of ovarian cancer. A total of 173 women were included, 116 with relapse and 57 without, undergoing follow-up in a routine clinical setting. RESULTS: Substantial differences were seen in self assessed health status between women with and without recurrence; 33.6% and 82.4% of women with and without recurrence rated their health as good to excellent, respectively. More patients with recurrence of disease reported limitations in moderate activity than those without. Furthermore, 79.0% of women without recurrence reported that pain did not affect or only slightly affected daily activities, compared with 28.2% with recurrence. Most women with recurrence (59.5%) reported that they were able to do less than they wanted to because of their emotional status compared with only 15.8% of women without recurrence. In addition, 66.4% of women with recurrence referred that they had problems concentrating at work and home versus 26.3% of women without recurrence. CONCLUSIONS: From this survey, it is clear that relapse of disease has a negative psychological and physical impact, highlighting the importance of time without recurrence and the need for effective treatment in the long term. PMID- 28640767 TI - Surgical and Pathological Outcomes of Laparoscopic Versus Abdominal Radical Hysterectomy With Pelvic Lymphadenectomy and/or Para-aortic Lymph Node Sampling for Bulky Early-Stage Cervical Cancer. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to compare the feasibility, morbidity, and recurrence rate of total laparoscopic radical hysterectomy (LRH) with those of abdominal radical hysterectomy (ARH) for bulky early-stage cervical cancer. METHODS: We performed a retrospective cohort study of 112 patients with stage IB1 or IIA2 cervical cancer in which the tumor diameter was 3 cm or greater. All patients underwent LRH (n = 30) or ARH (n = 82) with pelvic lymphadenectomy and/or para-aortic lymph node sampling between May 2011 and November 2014. Perioperative outcomes were compared between the 2 surgical groups. RESULTS: The laparoscopic approach consisted of 4 trocar insertions. Age, tumor diameter, and pelvic lymph nodes significantly differed between the 2 cohorts. Body mass index, International Federation of Gynecology and Obstetrics stage, histologic type and grade, deep stromal invasion, lymphovascular space invasion, positive margins, and adjuvant therapy were not significantly different between the 2 cohorts. Laparoscopic radical hysterectomy exhibited favorable results compared with ARH in terms of operating time, blood loss, intestinal exhaust time, and length of hospital stay. In addition, recurrence was observed in 5 LRH patients (16.7%) and 9 ARH patients (11.7%). CONCLUSIONS: The surgical outcomes of LRH with pelvic lymphadenectomy and/or para-aortic lymph node sampling exhibited a similar therapeutic efficacy to those of the ARH approach. PMID- 28640768 TI - Perceptions of Cardiology Administrators About Cardiac Rehabilitation in South America and the Caribbean. AB - BACKGROUND: Cardiac rehabilitation (CR) programs can address the cardiovascular disease epidemic in South America. However, there are factors limiting CR access at the patient, provider, and system levels. The latter 2 have not been extensively studied. The objective of this study was to investigate cardiology administrator's awareness and knowledge of CR and perceptions regarding resources for CR. METHODS: This study was cross-sectional and observational in design. Cardiology administrators from South American and Caribbean countries were invited to participate by members of a professional association. Participants completed a questionnaire online. Descriptive analysis was performed and differences in CR knowledge, awareness, perception, and attitudes regarding CR were described overall, by institution funding source (private vs public) and presence of within-institution CR (yes vs no). RESULTS: Most of the 55 respondents from 8 countries perceived CR as important for outpatient care (mean +/- SD = 4.83 +/- 0.38 out of 5; higher scores indicating more positive perceptions), with benefits including reduced hospital readmissions (4.31 +/- 0.48) and length of stay (4.64 +/- 0.71 days), not only for cardiac patients but for those with other vascular conditions (4.34 +/- 0.68 days). Those working in public institutions (50.9%) and in institutions without a CR program (25.0%) were not as aware of, and less likely to value, CR services (P < .05). Only 13.2% of programs had dedicated funding. CONCLUSIONS: Similar to findings from high-income settings, cardiology administrators and cardiologists in South America value CR as part of cardiac patient care, but funding and availability of programs restrict capacity to deliver these services. PMID- 28640769 TI - Physiological Profile and Activity Pattern of Minor Gaelic Football Players. AB - Cullen, BD, Roantree, M, McCarren, A, Kelly, DT, O'Connor, PL, Hughes, SM, Daly, PG, and Moyna1, NM. Physiological profile and activity pattern of minor Gaelic football players. J Strength Cond Res 31(7): 1811-1820, 2017-The purpose of this study was to evaluate the physiological profile and activity pattern in club- and county-level under-18 (U-18) Gaelic football players relative to playing position. Participants (n = 85) were analyzed during 17 official 15-a-side matches using global positioning system technology (SPI Pro X II; GPSports Systems, Canberra, Australia) and heart rate (HR) telemetry. During the second part of this study, 63 participants underwent an incremental treadmill test to assess their maximal oxygen uptake (V[Combining Dot Above]o2max) and peak HR (HRmax). Players covered a mean distance of 5,774 +/- 737 m during a full 60 minute match. The mean %HRmax and %V[Combining Dot Above]O2max observed during the match play were 81.6 +/- 4.3% and 70.1 +/- 7.75%, respectively. The playing level had no effect on the distance covered, player movement patterns, or %HRmax observed during match play. Midfield players covered significantly greater distance than defenders (p = 0.033). Playing position had no effect on %HRmax or the frequency of sprinting or high-intensity running during match play. The frequency of jogging, cruise running, striding (p = 0.000), and walking (p = 0.003) was greater in the midfield position than in the forward position. Time had a significant effect (F(1,39) = 33.512, p-value = 0.000, and (Equation is included in full-text article.)= 0.462) on distance covered and %HRmax, both of which showed a reduction between playing periods. Gaelic football is predominantly characterized by low-to-moderate intensity activity interspersed with periods of high-intensity running. The information provided may be used as a framework for coaches in the design and prescription of training strategies. Positional specific training may be warranted given the comparatively greater demands observed in the midfield playing position. Replicating the demands of match play in training may reduce the decline in distance covered and %HRmax observed during the second half of match play. PMID- 28640770 TI - Physiological Responses and Time-Motion Analysis of Small Combat Games in Kickboxing: Impact of Ring Size and Number of Within-Round Sparring Partners. AB - Ouergui, I, Houcine, N, Marzouki, H, Davis, P, Franchini, E, Gmada, N, and Bouhlel, E. Physiological responses and time-motion analysis of small combat games in kickboxing: impact of ring size and number of within-round sparring partners. J Strength Cond Res 31(7): 1840-1846, 2017-The study aimed to investigate the physiological responses and time-structure of small combat games (SCGs) in kickboxing according to ring sizes and number of sparring partners. Twenty athletes from regional (n = 13) and national levels (n = 7) participated in the study (mean +/- SD, age: 20.3 +/- 0.9 years; height: 177 +/- 4.8 cm; body mass: 71.8 +/- 10.5 kg). Blood lactate concentration [La] was measured before and after bouts, and the delta (Delta) was determined. Heart rate (HR) was measured throughout and HR and rating of perceived exertion (RPE) were also measured postbout. The HRpre, HRmean, and percentage of peak HR (%HRpeak) were used for analysis. The HRpeak was determined during a cycle ergometer graded exercise test. Each athlete was confronted by 1 (1 vs. 1; no sparring partner change), 2 (1 vs. 2) and 4 opponents (1 vs. 4) within-round (sparring partner change every 1 minute or 30 seconds, respectively) in different ring sizes (i.e., 2*2 m, 4*4 m, and 6*6 m). All combats were recorded and analyzed to determine the duration of different activity phases (high-intensity activities [HIA], low-intensity actions [LIA], and referee pause [P]). Results showed that values for HRpre and HRmean when opposed by a single individual (1 vs. 1) were lower than other conditions (all p < 0.001). Moreover, %HRpeak values in 1 vs. 1 were lower than in other conditions and higher in 4 * 4 m compared with other sizes. [La]pre, post, and the Delta did not differ among all conditions (p > 0.05). The RPE scores were lower in 1 vs. 1 compared with other conditions (p < 0.001), with no ring sizes effect (p > 0.05). For time-motion variables, HIA values were lower in 1 vs. 1 than in the 2 other conditions and was longer in 2 * 2 m compared with 4 * 4 m and 6 * 6 m, whereas LIA values were higher in 1 vs. 1 and lower in the 2 * 2 m. In conclusion, SCGs seem to be a good form of exercise for sufficient cardiovascular conditioning specific to kickboxing activity in comparison with data from previous studies. PMID- 28640771 TI - Comparison of Jamar and Bodygrip Dynamometers for Handgrip Strength Measurement. AB - Guerra, RS, Amaral, TF, Sousa, AS, Fonseca, I, Pichel, F, and Restivo, MT. Comparison of Jamar and Bodygrip dynamometers for handgrip strength measurement. J Strength Cond Res 31(7): 1931-1940, 2017-Studies that compared the agreement between Jamar and other models of dynamometers for handgrip strength (HGS) measurement have exhibited variability in the provided results. The lack of comparability between dynamometers led to the development of the Bodygrip dynamometer. This study aims to examine the reliability of the Bodygrip for HGS measurement, to compare it with the Jamar, and to explore the HGS differences between instruments considering the ergonomic effect of using the Bodygrip with 2 different handles. A cross-sectional study was conducted in free-living (n = 114, 18-89 years) and inpatient (n = 50, 65-93 years) volunteers. Nondominant HGS was tested randomly with the Jamar and Bodygrip, the latter using 2 different handles curved and straight types. Handgrip strength was obtained for each participant under the same conditions. Each individual performed 2 HGS measurements with each dynamometer, and the maximum HGS value was considered for dynamometers comparison. Differences in the maximum HGS value between the 2 devices (Jamar Bodygrip), intraclass correlation coefficients (ICCs), Bland and Altman plots, and limits of agreement were obtained. Correlation between the highest HGS measurement obtained for the nondominant hand with the Jamar and with the Bodygrip using each handle was excellent (ICCs: 0.93-0.95). Mean differences of 0.5 (limits of agreement: -4.6; 3.5) kgf with the curved handle and of 1.0 (-7.7; 9.7) kgf with the straight handle for the free-living participants were obtained, whereas for inpatients these values were -1.0 (-3.8; 1.9) kgf and 2.1 (-3.3; 7.5) kgf, respectively, for the curved and straight handles. The Bodygrip is comparable to the Jamar in free-living adults and in hospitalized older adults, exhibiting excellent interinstrument reliability. The Bodygrip with the curved handle produces results closer to the Jamar when compared with Bodygrip with the straight handle, which emphasizes the importance of grip handle ergonomics to measurement reliability. PMID- 28640772 TI - The Effect of a Carbohydrate Mouth Rinse on Upper-Body Muscular Strength and Endurance. AB - Dunkin, JE and Phillips, SM. The effect of a carbohydrate mouth rinse on upper body muscular strength and endurance. J Strength Cond Res 31(7): 1948-1953, 2017 Carbohydrate (CHO) mouth rinsing rapidly increases corticomotor output and maximal muscle force production, which could enhance muscular strength and endurance during resistance exercise. However, previous research has found no effect of CHO rinsing on muscular strength or endurance. The current study altered the CHO rinse composition and frequency and the muscular endurance test to further investigate the effects of a CHO mouth rinse on upper-body muscular strength and endurance. Twelve recreationally resistance-trained men (mean +/- SD age 22 +/- 1 year, height 179.2 +/- 1.8 cm, body mass 80.9 +/- 6.1 kg) completed a bench press protocol (1 repetition maximum [RM] test followed by repetitions to failure at 40% of 1RM) on 3 occasions. Subjects rinsed 25 ml of an 18% CHO solution or a placebo for 10 seconds before 1RM and repetitions to failure and completed a no-rinse control condition. Felt arousal (FA) was measured before and after each rinse, heart rate (HR) was measured before and after both exercise protocols, and rating of perceived exertion (RPE) was recorded after repetitions to failure. Rinsing did not influence 1RM (p = 0.680, (Equation is included in full-text article.)= 0.03), repetitions to failure (p = 0.677, (Equation is included in full-text article.)= 0.04), or exercise volume (load * reps; p = 0.600, (Equation is included in full-text article.)= 0.05). There were no significant treatment effects on heart rate (p = 0.677, (Equation is included in full-text article.)= 0.04), FA (p = 0.674, (Equation is included in full-text article.)= 0.04) or rating of perceived exertion (p = 0.604, (Equation is included in full-text article.)= 0.05). A CHO mouth rinse does not improve upper body muscular strength or endurance. PMID- 28640774 TI - The Difference Between Countermovement and Squat Jump Performances: A Review of Underlying Mechanisms With Practical Applications. AB - Van Hooren, B and Zolotarjova, J. The difference between countermovement and squat jump performances: a review of underlying mechanisms with practical applications. J Strength Cond Res 31(7): 2011-2020, 2017-Two movements that are widely used to monitor athletic performance are the countermovement jump (CMJ) and squat jump (SJ). Countermovement jump performance is almost always better than SJ performance, and the difference in performance is thought to reflect an effective utilization of the stretch-shortening cycle. However, the mechanisms responsible for the performance-enhancing effect of the stretch-shortening cycle are frequently undefined. Uncovering and understanding these mechanisms is essential to make an inference regarding the difference between the jumps. Therefore, we will review the potential mechanisms that explain the better performance in a CMJ as compared with a SJ. It is concluded that the difference in performance may primarily be related to the greater uptake of muscle slack and the buildup of stimulation during the countermovement in a CMJ. Elastic energy may also have a small contribution to an enhanced CMJ performance. Therefore, a larger difference between the jumps is not necessarily a better indicator of high intensity sports performance. Although a larger difference may reflect the utilization of elastic energy in a small-amplitude CMJ as a result of a well developed capability to co-activate muscles and quickly build up stimulation, a larger difference may also reflect a poor capability to reduce the degree of muscle slack and build up stimulation in the SJ. Because the capability to reduce the degree of muscle slack and quickly build up stimulation in the SJ may be especially important to high-intensity sports performance, training protocols might concentrate on attaining a smaller difference between the jumps. PMID- 28640773 TI - Salivary Mitochondrial DNA Copy Number Is Associated With Exercise Ventilatory Efficiency. AB - Chen, Y, Hill, HZ, Lange, G, and Falvo, MJ. Salivary mitochondrial DNA copy number is associated with exercise ventilatory efficiency. J Strength Cond Res 31(7): 2000-2004, 2017-Mitochondrial DNA copy number (mtDNAcn) is an index of mitochondrial content and is responsive to changes in exercise training volume. Therefore, assessment of mtDNAcn may help to optimize exercise prescription and aid in athlete monitoring. Although previous work has assessed mtDNAcn derived from skeletal muscle and blood using invasive approaches, no study has examined salivary mtDNAcn and its relationship with sport performance. Fifteen adults (32.2 +/- 7.1 years) volunteered to participate in this study. Each participant provided a saliva sample for the analysis of mtDNAcn via real-time polymerase reaction. In addition, participants completed an exercise challenge test to assess oxygen consumption relative to body weight (V[Combining Dot Above]O2.kg) and ventilatory efficiency (VE/V[Combining Dot Above]CO2). Using multiple linear regression, we examined the association of V[Combining Dot Above]O2.kg and VE/V[Combining Dot Above]CO2 with salivary mtDNAcn, adjusting for self-reported physical activity (min.wk). Greater mtDNAcn was associated with lower VE/V[Combining Dot Above]CO2 (p < 0.01) and higher V[Combining Dot Above]O2.kg (p < 0.05). In our model adjusted for physical activity, greater mtDNAcn remained associated with lower VE/V[Combining Dot Above]CO2 (beta = -0.186; 95% confidence interval [CI], -0.348 to -0.025; p < 0.05), but not with V[Combining Dot Above]O2.kg (beta = -0.022; 95% CI, -0.113 to 0.063). Our findings suggest that salivary mtDNAcn is associated with ventilatory efficiency, which may reflect enhanced exercise efficiency as a consequence of greater total mitochondrial content. As saliva collection is noninvasive, stable at room temperature, and less costly in comparison to skeletal muscle and blood, future studies may consider using saliva for the evaluation of mitochondrial content for the purposes of monitoring exercise training as well as optimizing exercise prescription. PMID- 28640777 TI - A Salute to the Editor: Basil A. Pruitt, Jr., M.D. 1995-2011. PMID- 28640776 TI - Early fever after trauma: Does it matter? AB - BACKGROUND: Fever is strongly associated with poor outcome after traumatic brain injury (TBI). We hypothesized that early fever is a direct result of brain injury and thus would be more common in TBI than in patients without brain injury and associated with inflammation. METHODS: We prospectively enrolled patients with major trauma with and without TBI from a busy Level I trauma center intensive care unit (ICU). Patients were assigned to one of four groups based on their presenting Head Abbreviated Injury Severity Scale scores: multiple injuries: head Abbreviated Injury Scale (AIS) score greater than 2, one other region greater than 2; isolated head: head AIS score greater than 2, all other regions less than 3; isolated body: one region greater than 2, excluding head/face; minor injury: no region with AIS greater than 2. Early fever was defined as at least one recorded temperature greater than 38.3 degrees C in the first 48 hours after admission. Outcome measures included neurologic deterioration, length of stay in the ICU, hospital mortality, discharge Glasgow Outcome Scale-Extended, and plasma levels of seven key cytokines at admission and 24 hours (exploratory). RESULTS: Two hundred sixty-eight patients were enrolled, including subjects with multiple injuries (n = 59), isolated head (n = 97), isolated body (n = 100), and minor trauma (n = 12). The incidence of fever was similar in all groups irrespective of injury (11-24%). In all groups, there was a significant association between the presence of early fever and death in the hospital (6-18% vs. 0-3%), as well as longer median ICU stays (3-7 days vs. 2-3 days). Fever was significantly associated with elevated IL-6 at admission (50.7 pg/dL vs. 16.9 pg/dL, p = 0.0067) and at 24 hours (83.1 pg/dL vs. 17.1 pg/dL, p = 0.0025) in the isolated head injury group. CONCLUSION: Contrary to our hypothesis, early fever was not more common in patients with brain injury, though fever was associated with longer ICU stays and death in all groups. Additionally, fever was associated with elevated IL-6 levels in isolated head injury. LEVEL OF EVIDENCE: Prognostic and Epidemiological study, level III. PMID- 28640778 TI - A cohort study of blunt cerebrovascular injury screening in children: Are they just little adults? AB - BACKGROUND: Blunt cerebrovascular injuries (BCVIs) are rare with nonspecific predictors, making optimal screening critical. Radiation concerns magnify these issues in children. The Eastern Association for the Surgery of Trauma (EAST) criteria, the Utah score (US), and the Denver criteria (DC) have been advocated for pediatric BCVI screening, although direct comparison is lacking. We hypothesized that current screening guidelines inaccurately identify pediatric BCVI. METHODS: This was a retrospective cohort study of pediatric trauma patients treated from 2005 to 2015 with radiographically confirmed BCVI. Our primary outcome was a false-negative screen, defined as a patient with a BCVI who would not have triggered screening. RESULTS: We identified 7,440 pediatric trauma admissions, and 96 patients (1.3%) had 128 BCVIs. Median age was 16 years (13, 17 years). A cervical-spine fracture was present in 41%. There were 83 internal carotid injuries, of which 73% were Grade I or II, as well as 45 vertebral injuries, of which 76% were Grade I or II, p = 0.8. More than one vessel was injured in 28% of patients. A cerebrovascular accident (CVA) occurred in 17 patients (18%); eight patients were identified on admission, and nine patients were identified thereafter. The CVA incidence was similar in those with and without aspirin use. The EAST screening missed injuries in 17% of patients, US missed 36%, and DC missed 2%. Significantly fewer injuries would be missed using DC than either EAST or US, p < 0.01. CONCLUSIONS: Blunt cerebrovascular injury does occur in pediatric patients, and a significant proportion of patients develop a CVA. The DC appear to have the lowest false-negative rate, supporting liberal screening of children for BCVI. Optimal pharmacotherapy for pediatric BCVI remains unclear despite a relative high incidence of CVA. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 28640779 TI - Nonoperative management rather than endovascular repair may be safe for grade II blunt traumatic aortic injuries: An 11-year retrospective analysis. AB - BACKGROUND: The Society of Vascular Surgery (SVS) guidelines currently suggest thoracic endovascular aortic repair (TEVAR) for grade II-IV and nonoperative management (NOM) for grade I blunt traumatic aortic injury (BTAI). However, there is increasing evidence that grade II may also be observed safely. The purpose of this study was to compare the outcome of TEVAR and NOM for grade I-IV BTAI and determine if grade II can be safely observed with NOM. METHODS: The records of patients with BTAI from 2004 to 2015 at a Level I trauma center were retrospectively reviewed. Patients were separated into two groups: TEVAR versus NOM. All BTAIs were graded according to the SVS guidelines. Minimal aortic injury (MAI) was defined as BTAI grade I and II. Failure of NOM was defined as aortic rupture after admission or progression on subsequent computed tomography (CT) imaging requiring TEVAR or open thoracotomy repair (OTR). Statistical analysis was performed using Mann-Whitney U and chi tests. RESULTS: A total of 105 adult patients (>=16 years) with BTAI were identified over the 11-year period. Of these, 17 patients who died soon after arrival and 17 who underwent OTR were excluded. Of the remaining 71 patients, 30 had MAI (14 TEVAR vs. 16 NOM). There were no failures in either group. No patients with MAI in either group died from complications of aortic lesions. Follow-up CT imaging was performed on all MAI patients. Follow-up CT scans for all TEVAR patients showed stable stents with no leak. Follow-up CT in the NOM group showed progression in two patients neither required subsequent OTR or TEVAR. CONCLUSIONS: Although the SVS guidelines suggest TEVAR for grade II-IV and NOM for grade I BTAI, NOM may be safely used in grade II BTAI. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 28640781 TI - Hydrogen gas inhalation inhibits progression to the "irreversible" stage of shock after severe hemorrhage in rats. AB - BACKGROUND: Mortality of hemorrhagic shock primarily depends on whether or not the patients can endure the loss of circulating volume until radical treatment is applied. We investigated whether hydrogen (H2) gas inhalation would influence the tolerance to hemorrhagic shock and improve survival. METHODS: Hemorrhagic shock was achieved by withdrawing blood until the mean arterial blood pressure reached 30-35 mm Hg. After 60 minutes of shock, the rats were resuscitated with a volume of normal saline equal to four times the volume of shed blood. The rats were assigned to either the H2 gas (1.3% H2, 26% O2, 72.7% N2)-treated group or the control gas (26% O2, 74% N2)-treated group. Inhalation of the specified gas mixture began at the initiation of blood withdrawal and continued for 2 hours after fluid resuscitation. RESULTS: The survival rate at 6 hours after fluid resuscitation was 80% in H2 gas-treated rats and 30% in control gas-treated rats (p < 0.05). The volume of blood that was removed through a catheter to induce shock was significantly larger in the H2 gas-treated rats than in the control rats. Despite losing more blood, the increase in serum potassium levels was suppressed in the H2 gas-treated rats after 60 minutes of shock. Fluid resuscitation completely restored blood pressure in the H2 gas-treated rats, whereas it failed to fully restore the blood pressure in the control gas-treated rats. At 2 hours after fluid resuscitation, blood pressure remained in the normal range and metabolic acidosis was well compensated in the H2 gas-treated rats, whereas we observed decreased blood pressure and uncompensated metabolic acidosis and hyperkalemia in the surviving control gas-treated rats. CONCLUSIONS: H2 gas inhalation delays the progression to irreversible shock. Clinically, H2 gas inhalation is expected to stabilize the subject until curative treatment can be performed, thereby increasing the probability of survival after hemorrhagic shock. PMID- 28640782 TI - Perioperative Venous Thromboembolism: A Review. AB - Venous thromboembolism (VTE) is a significant problem in the perioperative period, increasing patient morbidity, mortality, and health care costs. It is also considered the most preventable of the major postoperative complications. Despite widespread adoption of prophylaxis guidelines, it appears that morbidity from the disease has not substantially changed within the past 2 decades. It is becoming clear that current prophylaxis efforts are not sufficient. Using more potent anticoagulants may decrease the incidence of VTE, but increase the risk for bleeding and infection. Much has been learned about the pathophysiology of venous thrombogenesis in recent years. Beyond the "traditional coagulation cascade," which anticoagulants modulate, there is a growing appreciation for the roles of tissue factor, monocytes, neutrophils, neutrophil extracellular traps, microvesicles, and platelets in thrombus initiation and propagation. These recent studies explain to some degree why aspirin appears to be remarkably effective in preventing thrombus propagation. Endothelial dysfunction, traditionally thought of as a risk factor for arterial thrombosis, plays an important role within the cusps of venous valves, a unique environment where the majority of venous thrombi originate. This suggests a role for newer treatment modalities such as statins. Not all patients have an equal likelihood of experiencing a VTE, even when undergoing high-risk procedures, and better tools are required to accurately predict VTE risk. Only then will we be able to effectively individualize prophylaxis by balancing the risks for VTE against the risks associated with treatment. Given the different cell types and pathways involved in thrombogenesis, it is likely that multimodal treatment regimens will be more effective, enabling the use of lower and safer doses of hemostatic modulating therapies such as anticoagulants, antithrombotics, and antiplatelet medications. PMID- 28640783 TI - The Implementation of a Preoperative Transthoracic Echocardiography Consult Service by Anesthesiologists. AB - We describe a preoperative transthoracic echocardiography consult service led by anesthesiologists. The implementation process and the patient cohort are described. Preoperative transthoracic echocardiographic examinations were mostly performed in patients undergoing intermediate- or high-risk noncardiac surgery and in patients with a higher calculated mortality risk. All transthoracic echocardiographic examinations were interpreted by anesthesiologists. PMID- 28640784 TI - A Limitation of Intensive Care Unit Sedation Using Volatile Anesthetics. PMID- 28640785 TI - Physiologic Considerations in Trauma Patients Undergoing Resuscitative Endovascular Balloon Occlusion of the Aorta. AB - Resuscitative endovascular balloon occlusion of the aorta is a new procedure for adjunctive management of critically injured patients with noncompressible torso or pelvic hemorrhage who are in refractory hemorrhagic shock, ie, bleeding to death. The anesthesiologist plays a critical role in management of these patients, from initial evaluation in the trauma bay to definitive care in the operating room and the critical care unit. A comprehensive understanding of the effects of resuscitative endovascular balloon occlusion of the aorta is essential to making it an effective component of hemostatic resuscitation. PMID- 28640786 TI - A Standardized Approach for Transfusion Medicine Support in Patients With Morbidly Adherent Placenta. AB - BACKGROUND: The incidence of placenta accreta (PA) has increased from 0.8 to 3.0 in 1000 pregnancies, driven by increased rates of cesarean deliveries (32.2% in 2014) of births in the United States. The average blood loss for a delivery complicated by PA ranges from 2000 to 5000 mL, frequently requiring substantial transfusion medicine support. We report our own institutional multidisciplinary approach for managing such patients, along with transfusion medicine outcomes, in this setting over a 5-year period. METHODS: We reviewed records for patients referred to our program in placental disorders from July 1, 2009, to July 1, 2014. A placental disorders preoperative checklist was implemented to ensure optimal management of patients with peripartum hemorrhage. RESULTS: Of 136 patients whose placentas were reviewed postpartum, 21 had PA, 39 had microscopic PA, 17 had increta, 17 had percreta, and 42 had no accreta (of which 11 had placenta previa). For each subtype, the percentage of patients receiving blood products were 71% (PA), 28% (microscopic PA), 82% (increta), 82% (percreta), and 19% (no accreta). Among patients with PA or variants, 89% of patients with PA or variants underwent postpartum hysterectomy, compared to only 5% of patients with no or microscopic PA. CONCLUSIONS: Based on our experience and on the findings of our retrospective analysis, patients presenting with either antepartum radiological evidence or clinical suspicion of morbidly adherent placenta will benefit from a standardized protocol for clinical management, including transfusion medicine support. We found that massive hemorrhage is predictable when abnormal placentation is identified predelivery and that blood product support is substantial regardless of the degree of placental invasiveness. The protocol at our institution provides immediate access to sufficient volumes and types of blood products at delivery for patients at highest risk for life threatening obstetric hemorrhage. Therefore, for patients with a diagnosis of morbidly adherent placenta scheduled for planned cesarean delivery with possible hysterectomy, a programmatic checklist that mobilizes a multidisciplinary team, including proactive transfusion medicine support, represents best practices. PMID- 28640787 TI - In Response. PMID- 28640788 TI - The Use of Continuous Extended Criteria Graft Perfusion Will Lead to an Increase in Transplantable Organs. PMID- 28640790 TI - MicroRNA-155 Deficiency in Kupffer Cells Ameliorates Liver Ischemia-Reperfusion Injury in Mice. AB - BACKGROUND: MicroRNA-155 (miR-155) is known to be involved in autoimmune diseases, inflammation, and transplantation. However, its role in a warm hepatic ischemia-reperfusion (IR) model has not been fully elucidated. METHODS: Partial hepatic IR was performed in wild-type and miR-155-deficient mice treated with or without GdCl3, and then the serum transaminase concentration and histology were analyzed. Kupffer cells (KCs) were isolated from the liver after IR, and immunohistochemistry was used to evaluate activation and polarization. In addition, the mRNA concentrations of various inflammatory cytokines were measured. Macrophages were obtained from the abdominal cavity and challenged with or without lipopolysaccharide to determine the influence of miR-155 deficiency on macrophage polarization in vitro. Furthermore, we used in vitro coculture assays to determine the effect of miR-155 deficiency on hepatocyte apoptosis induced directly by KCs. RESULTS: miR-155 deficiency ameliorated liver IR injury, and inhibition of KCs by GdCl3 abolished this protective effect. miR-155 deficiency decreased CD80, CD86, and major histocompatibility complex class II expression in KCs after IR and tipped the M1/M2 balance toward an anti-inflammatory profile, where proinflammatory cytokine secretion was suppressed and IL-10 was enhanced. In addition, hepatocyte apoptosis was reduced in coculture with miR-155-deficient KCs in vitro. CONCLUSIONS: miR-155 deficiency plays an effective role in attenuating liver IR injury likely by regulating the activation and inflammatory response, as well as modifying the polarization of KCs. PMID- 28640789 TI - Complement-Mediated Enhancement of Monocyte Adhesion to Endothelial Cells by HLA Antibodies, and Blockade by a Specific Inhibitor of the Classical Complement Cascade, TNT003. AB - BACKGROUND: Antibody-mediated rejection (AMR) of most solid organs is characterized by evidence of complement activation and/or intragraft macrophages (C4d + and CD68+ biopsies). We previously demonstrated that crosslinking of HLA I by antibodies triggered endothelial activation and monocyte adhesion. We hypothesized that activation of the classical complement pathway at the endothelial cell surface by HLA antibodies would enhance monocyte adhesion through soluble split product generation, in parallel with direct endothelial activation downstream of HLA signaling. METHODS: Primary human aortic endothelial cells (HAEC) were stimulated with HLA class I antibodies in the presence of intact human serum complement. C3a and C5a generation, endothelial P-selectin expression, and adhesion of human primary and immortalized monocytes (Mono Mac 6) were measured. Alternatively, HAEC or monocytes were directly stimulated with purified C3a or C5a. Classical complement activation was inhibited by pretreatment of complement with an anti-C1s antibody (TNT003). RESULTS: Treatment of HAEC with HLA antibody and human complement increased the formation of C3a and C5a. Monocyte recruitment by human HLA antibodies was enhanced in the presence of intact human serum complement or purified C3a or C5a. Specific inhibition of the classical complement pathway using TNT003 or C1q-depleted serum significantly reduced adhesion of monocytes in the presence of human complement. CONCLUSIONS: Despite persistent endothelial viability in the presence of HLA antibodies and complement, upstream complement anaphylatoxin production exacerbates endothelial exocytosis and leukocyte recruitment. Upstream inhibition of classical complement may be therapeutic to dampen mononuclear cell recruitment and endothelial activation characteristic of microvascular inflammation during AMR. PMID- 28640791 TI - Octogenarian Liver Grafts Reaching Centennial Age After Transplantation. PMID- 28640792 TI - Alloimmunization After Cryopreserved Arterial Allografts in a Patient on a Kidney Transplantation Waiting List. PMID- 28640793 TI - Intraoperative Computed Tomography (CT) for Treating Giant Carotid Intracavernous Aneurysms. AB - BACKGROUND Giant carotid intracavernous aneurysm refers to those lesions larger than 2.5 cm and derived from a cavernous segment, accounting for about 30% of all intracranial tumors. Dynamic CT perfusion imaging (PCT) is a common method recently employed to evaluate cerebral perfusion. This study investigated the efficacy and clinical application of intraoperative CT in the surgery for giant symptomatic carotid intracavernous aneurysm. MATERIAL AND METHODS A retrospective analysis was performed on 23 cases with giant symptomatic carotid intracavernous aneurysm. BTO testing was performed before surgery. Differential treatments were performed based on the condition of aneurysm, and some patients received intraoperative PCT. Postoperative anti-coagulation was given with DSA or CTA follow-up examinations at 3-6 months, 1 year, and 2 years after surgery. RESULTS A total of 17 patients received aneurysm isolation coupled with high-flow bypass surgery. Among those, 9 developed early-onset neurological function after surgery, with gradual recover within 6 months. One coma patient died 25 months after discharge. One patient had aneurysm isolation with clapping of anterior communicating artery, and the other 5 cases received artery clapping only. In those patients, 4 had improvement at early phase, while 1 patient had numbness of the oculomotor nerve. Six patients received surgery in the CT room, including 5 cases with single proximal ligation of the internal carotid artery plus 1 aneurysm isolation combined with high-flow bypass surgery. CONCLUSIONS Intraoperative PCT can provide objective evidence and effective evaluation of cerebral perfusion. PMID- 28640794 TI - QuickStats: Percentage* of Adults Aged >=18 Years Who Reported Having a Severe Headache or Migraine in the Past 3 Months,? by Sex and Age Group - National Health Interview Survey,S United States, 2015. AB - In 2015, 20.0% of women and 9.7% of men aged >=18 years had a severe headache or migraine in the past 3 months. Overall and for each age group, women aged >=18 years were more likely than men to have had a severe headache or migraine in the past 3 months. For both sexes, a report of a severe headache or migraine in the the past 3 months decreased with advancing age, from 11.0% among men aged 18-44 years to 3.4% among men aged >=75 years and from 24.7% among women aged 18-44 years to 6.3% among women aged >=75 years. PMID- 28640795 TI - Progress Toward Containment of Poliovirus Type 2 - Worldwide, 2017. AB - The Global Polio Eradication Initiative (GPEI) continues to make progress toward the eradication target. Only one of the three serotypes, wild poliovirus (WPV) type 1 (WPV1), is still circulating, and the numbers of cases and countries with endemic transmission are at record lows. With the certification of wild poliovirus type 2 (WPV2) eradication in 2015 and the global replacement of trivalent oral poliovirus vaccine (tOPV) containing Sabin poliovirus types 1, 2, and 3 with bivalent OPV containing only Sabin poliovirus types 1 and 3 during April-May 2016, poliovirus type 2 (PV2) is now an eradicated pathogen. However, in eight countries (Cameroon, Chad, Democratic Republic of Congo, Mozambique, Niger, Nigeria, Pakistan, and Syria), monovalent type 2 OPV (mOPV2) was authorized for large-scale outbreak control after tOPV withdrawal (1). Poliovirus containment, an evolving area of work that affects every country, aims to ensure that all PV2 specimens are safely contained to minimize the risk for reintroducing the virus into communities. This report summarizes the current status of poliovirus containment and progress since the last report (2), and outlines remaining challenges. Within 30 countries, 86 facilities have been designated by the relevant national authorities (usually the Ministry of Health) to become poliovirus-essential facilities for the continued storage or handling of PV2 materials; each country is responsible for ensuring that these facilities meet all biorisk management requirements. PMID- 28640796 TI - Erratum: Vol. 66, No. 22. AB - In the report "Japanese Encephalitis Surveillance and Immunization - Asia and Western Pacific Regions, 2016," on page 581, in the table "Characteristics of Japanese encephalitis (JE) surveillance in countries with JE virus transmission risk, 2016," and on page 582, in the table "Characteristics of Japanese encephalitis (JE) immunization programs in countries with JE virus transmission risk, 2016," Taiwan should have been indented beneath China. The corrected tables with added indents can be found at http://apps.who.int/iris/bitstream/10665/255639/1/WER9223.pdf. PMID- 28640797 TI - Rural and Urban Differences in Air Quality, 2008-2012, and Community Drinking Water Quality, 2010-2015 - United States. AB - PROBLEM/CONDITION: The places in which persons live, work, and play can contribute to the development of adverse health outcomes. Understanding the differences in risk factors in various environments can help to explain differences in the occurrence of these outcomes and can be used to develop public health programs, interventions, and policies. Efforts to characterize urban and rural differences have largely focused on social and demographic characteristics. A paucity of national standardized environmental data has hindered efforts to characterize differences in the physical aspects of urban and rural areas, such as air and water quality. REPORTING PERIOD: 2008-2012 for air quality and 2010 2015 for water quality. DESCRIPTION OF SYSTEM: Since 2002, CDC's National Environmental Public Health Tracking Program has collaborated with federal, state, and local partners to gather standardized environmental data by creating national data standards, collecting available data, and disseminating data to be used in developing public health actions. The National Environmental Public Health Tracking Network (i.e., the tracking network) collects data provided by national, state, and local partners and includes 21 health outcomes, exposures, and environmental hazards. To assess environmental factors that affect health, CDC analyzed three air-quality measures from the tracking network for all counties in the contiguous United States during 2008-2012 and one water-quality measure for 26 states during 2010-2015. The three air-quality measures include 1) total number of days with fine particulate matter (PM2.5) levels greater than the U.S. Environmental Protection Agency's (EPA's) National Ambient Air Quality Standards (NAAQS) for 24-hour average PM2.5 (PM2.5 days); 2) mean annual average ambient concentrations of PM2.5 in micrograms per cubic meter (mean PM2.5); and 3) total number of days with maximum 8-hour average ozone concentrations greater than the NAAQS (ozone days). The water-quality measure compared the annual mean concentration for a community water system (CWS) to the maximum contaminant level (MCL) defined by EPA for 10 contaminants: arsenic, atrazine, di(2-ethylhexyl) phthalate (DEHP), haloacetic acids (HAA5), nitrate, perchloroethene (PCE), radium, trichloroethene (TCE), total trihalomethanes (TTHM), and uranium. Findings are presented by urban-rural classification scheme: four metropolitan (large central metropolitan, large fringe metropolitan, medium metropolitan, and small metropolitan) and two nonmetropolitan (micropolitan and noncore) categories. Regression modeling was used to determine whether differences in the measures by urban-rural categories were statistically significant. RESULTS: Patterns for all three air-quality measures suggest that air quality improves as areas become more rural (or less urban). The mean total number of ozone days decreased from 47.54 days in large central metropolitan counties to 3.81 days in noncore counties, whereas the mean total number of PM2.5 days decreased from 11.21 in large central metropolitan counties to 0.95 in noncore counties. The mean average annual PM2.5 concentration decreased from 11.15 MUg/m3 in large central metropolitan counties to 8.87 MUg/m3 in noncore counties. Patterns for the water-quality measure suggest that water quality improves as areas become more urban (or less rural). Overall, 7% of CWSs reported at least one annual mean concentration greater than the MCL for all 10 contaminants combined. The percentage increased from 5.4% in large central metropolitan counties to 10% in noncore counties, a difference that was significant, adjusting for U.S. region, CWS size, water source, and potential spatial correlation. Similar results were found for two disinfection by-products, HAA5 and TTHM. Arsenic was the only other contaminant with a significant result. Medium metropolitan counties had 3.1% of CWSs reporting at least one annual mean greater than the MCL, compared with 2.4% in large central counties. INTERPRETATION: Noncore (rural) counties experienced fewer unhealthy air-quality days than large central metropolitan counties, likely because of fewer air pollution sources in the noncore counties. All categories of counties had a mean annual average PM2.5 concentration lower than the EPA standard. Among all CWSs analyzed, the number reporting one or more annual mean contaminant concentrations greater the MCL was small. The water-quality measure suggests that water quality worsens as counties become more rural, in regards to all contaminants combined and for the two disinfection by-products individually. Although significant differences were found for the water-quality measure, the odds ratios were very small, making it difficult to determine whether these differences have a meaningful effect on public health. These differences might be a result of variations in water treatment practices in rural versus urban counties. PUBLIC HEALTH ACTION: Understanding the differences between rural and urban areas in air and water quality can help public health departments to identify, monitor, and prioritize potential environmental public health concerns and opportunities for action. These findings suggest a continued need to develop more geographically targeted, evidence-based interventions to prevent morbidity and mortality associated with poor air and water quality. PMID- 28640799 TI - Screening for Syphilis and Other Sexually Transmitted Infections in Pregnant Women - Guam, 2014. AB - Prenatal screening and treatment for sexually transmitted infections (STIs) can prevent adverse perinatal outcomes. In Guam, the largest of the three U.S. territories in the Pacific, primary and secondary syphilis rates among women increased 473%, from 1.1 to 6.3 per 100,000 during 2009-2013 (1). In 2013, the first congenital syphilis case after no cases since 2008 was reported (1,2). Little is known about STI screening coverage and factors associated with inadequate screening among pregnant women in Guam. This study evaluated the prevalence of screening for syphilis, human immunodeficiency virus (HIV), chlamydia, and gonorrhea, and examined correlates of inadequate screening among pregnant women in Guam. Data came from the medical records of a randomly selected sample of mothers with live births in 2014 at a large public hospital. Bivariate analyses and multivariable models using Poisson regression were conducted to determine factors associated with inadequate screening for syphilis and other STIs. Although most (93.5%) women received syphilis screening during pregnancy, 26.8% were not screened sufficiently early to prevent adverse pregnancy outcomes. Many women were not screened for HIV infection (31.1%), chlamydia (25.3%), or gonorrhea (25.7%). Prenatal care and insurance were important factors affecting STI screening during pregnancy. Prenatal care providers play an important role in preventing congenital infections. Policies and programs increasing STI and HIV services for pregnant women and improved access to and use of prenatal care are essential for promoting healthy mothers and infants. PMID- 28640800 TI - HIV Testing, Linkage to HIV Medical Care, and Interviews for Partner Services Among Youths - 61 Health Department Jurisdictions, United States, Puerto Rico, and the U.S. Virgin Islands, 2015. AB - Identifying persons living with human immunodeficiency virus (HIV) who are unaware of their infection, linking them to HIV medical care, and reducing health disparities are important national goals (1). Of the 8,841 teens and young adults aged 13-24 years (collectively referred to as youths in this report) who received a diagnosis of HIV in 2014, 70% were young men who have sex with men (MSM) (2). In the same year, an estimated 52% of young MSM living with HIV were unaware of their infection compared with 15% among all persons living with HIV (3). An average of 22% of high school students who have had sexual intercourse and 33% of young adults (persons aged 18-24 years) reported ever receiving an HIV test (4). CDC recommends screening all persons aged 13-64 years, with annual rescreening for persons at high risk for HIV infection (5). Analysis of CDC-funded program data for youths submitted by 61 health departments in 2015 revealed that young MSM, who accounted for 83% of new diagnoses among all youths in non-health care facilities, received 28% of HIV tests.* The 2020 national goal is to link at least 85% of HIV-positive persons to HIV medical care within 30 days of diagnosis. In this analysis, 66% of youths who received positive test results for HIV infection were linked to care within 90 days of diagnosis. Increasing the number of youths at risk for HIV infection who are tested for HIV on a regular basis and ensuring that youths who receive positive test results for HIV are rapidly linked to and retained in appropriate medical care, including early initiation of antiretroviral therapy, are essential steps for reducing HIV infection in this vulnerable population. PMID- 28640801 TI - Hollywood raising awareness of smoking-related diseases: can it proactively counteract the impact of smoking in movies?-the final mission of Star Trek's Mr Spock. AB - This corrects the article DOI: 10.1038/npjpcrm.2016.52. PMID- 28640802 TI - Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse. AB - Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. In order to study their pathogenesis we undertook a systematic genetic and biochemical study of Drosophila pex16 and pex2 mutants. These mutants are short-lived with defects in locomotion and activity. Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. In addition, mutant flies are starvation sensitive and are very sensitive to glucose deprivation exhibiting dramatic shortening of lifespan and hyperactivity on low-sugar food. We use bioinformatic transcriptional profiling to examine gene co-regulation between peroxisomal genes and other metabolic pathways and we observe that the expression of peroxisomal and carbohydrate pathway genes in flies and mouse are tightly correlated. Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. Moreover mice lacking peroxisomes exhibit defective carbohydrate metabolism at the same key steps in carbohydrate breakdown. Our data indicate an unexpected link between these two metabolic processes and suggest metabolism of carbohydrates could be a new therapeutic target for patients with PBD. PMID- 28640798 TI - Evaluation of Placental and Fetal Tissue Specimens for Zika Virus Infection - 50 States and District of Columbia, January-December, 2016. AB - Zika virus infection during pregnancy can cause congenital microcephaly and brain abnormalities (1), and detection of Zika virus RNA in clinical and tissue specimens can provide definitive laboratory evidence of recent Zika virus infection. Whereas duration of viremia is typically short, prolonged detection of Zika virus RNA in placental, fetal, and neonatal brain tissue has been reported and can provide key diagnostic information by confirming recent Zika virus infection (2). In accordance with recent guidance (3,4), CDC provides Zika virus testing of placental and fetal tissues in clinical situations where this information could add diagnostic value. This report describes the evaluation of formalin-fixed paraffin-embedded (FFPE) tissue specimens tested for Zika virus infection in 2016 and the contribution of this testing to the public health response. Among 546 live births with possible maternal Zika virus exposure, for which placental tissues were submitted by the 50 states and District of Columbia (DC), 60 (11%) were positive by Zika virus reverse transcription-polymerase chain reaction (RT-PCR). Among 81 pregnancy losses for which placental and/or fetal tissues were submitted, 18 (22%) were positive by Zika virus RT-PCR. Zika virus RT-PCR was positive on placental tissues from 38/363 (10%) live births with maternal serologic evidence of recent unspecified flavivirus infection and from 9/86 (10%) with negative maternal Zika virus immunoglobulin M (IgM) where possible maternal exposure occurred >12 weeks before serum collection. These results demonstrate that Zika virus RT-PCR testing of tissue specimens can provide a confirmed diagnosis of recent maternal Zika virus infection. PMID- 28640803 TI - Brain network eigenmodes provide a robust and compact representation of the structural connectome in health and disease. AB - Recent research has demonstrated the use of the structural connectome as a powerful tool to characterize the network architecture of the brain and potentially generate biomarkers for neurologic and psychiatric disorders. In particular, the anatomic embedding of the edges of the cerebral graph have been postulated to elucidate the relative importance of white matter tracts to the overall network connectivity, explaining the varying effects of localized white matter pathology on cognition and behavior. Here, we demonstrate the use of a linear diffusion model to quantify the impact of these perturbations on brain connectivity. We show that the eigenmodes governing the dynamics of this model are strongly conserved between healthy subjects regardless of cortical and sub cortical parcellations, but show significant, interpretable deviations in improperly developed brains. More specifically, we investigated the effect of agenesis of the corpus callosum (AgCC), one of the most common brain malformations to identify differences in the effect of virtual corpus callosotomies and the neurodevelopmental disorder itself. These findings, including the strong correspondence between regions of highest importance from graph eigenmodes of network diffusion and nexus regions of white matter from edge density imaging, show converging evidence toward understanding the relationship between white matter anatomy and the structural connectome. PMID- 28640804 TI - Boolean analysis reveals systematic interactions among low-abundance species in the human gut microbiome. AB - The analysis of microbiome compositions in the human gut has gained increasing interest due to the broader availability of data and functional databases and substantial progress in data analysis methods, but also due to the high relevance of the microbiome in human health and disease. While most analyses infer interactions among highly abundant species, the large number of low-abundance species has received less attention. Here we present a novel analysis method based on Boolean operations applied to microbial co-occurrence patterns. We calibrate our approach with simulated data based on a dynamical Boolean network model from which we interpret the statistics of attractor states as a theoretical proxy for microbiome composition. We show that for given fractions of synergistic and competitive interactions in the model our Boolean abundance analysis can reliably detect these interactions. Analyzing a novel data set of 822 microbiome compositions of the human gut, we find a large number of highly significant synergistic interactions among these low-abundance species, forming a connected network, and a few isolated competitive interactions. PMID- 28640805 TI - High-confidence assessment of functional impact of human mitochondrial non synonymous genome variations by APOGEE. AB - 24,189 are all the possible non-synonymous amino acid changes potentially affecting the human mitochondrial DNA. Only a tiny subset was functionally evaluated with certainty so far, while the pathogenicity of the vast majority was only assessed in-silico by software predictors. Since these tools proved to be rather incongruent, we have designed and implemented APOGEE, a machine-learning algorithm that outperforms all existing prediction methods in estimating the harmfulness of mitochondrial non-synonymous genome variations. We provide a detailed description of the underlying algorithm, of the selected and manually curated training and test sets of variants, as well as of its classification ability. PMID- 28640806 TI - Good enough practices in scientific computing. AB - Computers are now essential in all branches of science, but most researchers are never taught the equivalent of basic lab skills for research computing. As a result, data can get lost, analyses can take much longer than necessary, and researchers are limited in how effectively they can work with software and data. Computing workflows need to follow the same practices as lab projects and notebooks, with organized data, documented steps, and the project structured for reproducibility, but researchers new to computing often don't know where to start. This paper presents a set of good computing practices that every researcher can adopt, regardless of their current level of computational skill. These practices, which encompass data management, programming, collaborating with colleagues, organizing projects, tracking work, and writing manuscripts, are drawn from a wide variety of published sources from our daily lives and from our work with volunteer organizations that have delivered workshops to over 11,000 people since 2010. PMID- 28640807 TI - Lack of a peroxiredoxin suppresses the lethality of cells devoid of electron donors by channelling electrons to oxidized ribonucleotide reductase. AB - The thioredoxin and glutaredoxin pathways are responsible of recycling several enzymes which undergo intramolecular disulfide bond formation as part of their catalytic cycles such as the peroxide scavengers peroxiredoxins or the enzyme ribonucleotide reductase (RNR). RNR, the rate-limiting enzyme of deoxyribonucleotide synthesis, is an essential enzyme relying on these electron flow cascades for recycling. RNR is tightly regulated in a cell cycle-dependent manner at different levels, but little is known about the participation of electron donors in such regulation. Here, we show that cytosolic thioredoxins Trx1 and Trx3 are the primary electron donors for RNR in fission yeast. Unexpectedly, trx1 transcript and Trx1 protein levels are up-regulated in a G1-to S phase-dependent manner, indicating that the supply of electron donors is also cell cycle-regulated. Indeed, genetic depletion of thioredoxins triggers a DNA replication checkpoint ruled by Rad3 and Cds1, with the final goal of up regulating transcription of S phase genes and constitutive RNR synthesis. Regarding the thioredoxin and glutaredoxin cascades, one combination of gene deletions is synthetic lethal in fission yeast: cells lacking both thioredoxin reductase and cytosolic dithiol glutaredoxin. We have isolated a suppressor of this lethal phenotype: a mutation at the Tpx1-coding gene, leading to a frame shift and a loss-of-function of Tpx1, the main client of electron donors. We propose that in a mutant strain compromised in reducing equivalents, the absence of an abundant and competitive substrate such as the peroxiredoxin Tpx1 has been selected as a lethality suppressor to favor RNR function at the expense of the non-essential peroxide scavenging function, to allow DNA synthesis and cell growth. PMID- 28640808 TI - Transmembrane helical interactions in the CFTR channel pore. AB - Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene affect CFTR protein biogenesis or its function as a chloride channel, resulting in dysregulation of epithelial fluid transport in the lung, pancreas and other organs in cystic fibrosis (CF). Development of pharmaceutical strategies to treat CF requires understanding of the mechanisms underlying channel function. However, incomplete 3D structural information on the unique ABC ion channel, CFTR, hinders elucidation of its functional mechanism and correction of cystic fibrosis causing mutants. Several CFTR homology models have been developed using bacterial ABC transporters as templates but these have low sequence similarity to CFTR and are not ion channels. Here, we refine an earlier model in an outward (OWF) and develop an inward (IWF) facing model employing an integrated experimental molecular dynamics simulation (200 ns) approach. Our IWF structure agrees well with a recently solved cryo-EM structure of a CFTR IWF state. We utilize cysteine cross-linking to verify positions and orientations of residues within trans membrane helices (TMHs) of the OWF conformation and to reconstruct a physiologically relevant pore structure. Comparison of pore profiles of the two conformations reveal a radius sufficient to permit passage of hydrated Cl- ions in the OWF but not the IWF model. To identify structural determinants that distinguish the two conformations and possible rearrangements of TMHs within them responsible for channel gating, we perform cross-linking by bifunctional reagents of multiple predicted pairs of cysteines in TMH 6 and 12 and 6 and 9. To determine whether the effects of cross-linking on gating observed are the result of switching of the channel from open to close state, we also treat the same residue pairs with monofunctional reagents in separate experiments. Both types of reagents prevent ion currents indicating that pore blockage is primarily responsible. PMID- 28640809 TI - Development of ELISAs for diagnosis of acute typhoid fever in Nigerian children. AB - Improved serodiagnostic tests for typhoid fever (TF) are needed for surveillance, to facilitate patient management, curb antibiotic resistance, and inform public health programs. To address this need, IgA, IgM and IgG ELISAs using Salmonella enterica serovar Typhi (S. Typhi) lipopolysaccharide (LPS) and hemolysin E (t1477) protein were conducted on 86 Nigerian pediatric TF and 29 non-typhoidal Salmonella (NTS) cases, 178 culture-negative febrile cases, 28 "other" (i.e., non Salmonella) pediatric infections, and 48 healthy Nigerian children. The best discrimination was achieved between TF and healthy children. LPS-specific IgA and IgM provided receiver operator characteristic areas under the curve (ROC AUC) values of 0.963 and 0.968, respectively, and 0.978 for IgA+M combined. Similar performance was achieved with t1477-specific IgA and IgM (0.968 and 0.968, respectively; 0.976 combined). IgG against LPS and t1477 was less accurate for discriminating these groups, possibly as a consequence of previous exposure, although ROC AUC values were still high (0.928 and 0.932, respectively). Importantly, discrimination between TF and children with other infections was maintained by LPS-specific IgA and IgM (AUC = 0.903 and 0.934, respectively; 0.938 combined), and slightly reduced for IgG (0.909), while t1477-specific IgG performed best (0.914). A similar pattern was seen when comparing TF with other infections from outside Nigeria. The t1477 may be recognized by cross-reactive antibodies from other acute infections, although a robust IgG response may provide some diagnostic utility in populations where incidence of other infections is low, such as in children. The data are consistent with IgA and IgM against S. Typhi LPS being specific markers of acute TF. PMID- 28640811 TI - Comparing bee species responses to chemical mixtures: Common response patterns? AB - Pollinators in agricultural landscapes can be exposed to mixtures of pesticides and environmental pollutants. Existing mixture toxicity modelling approaches, such as the models of concentration addition and independent action and the mechanistic DEBtox framework have been previously shown as valuable tools for understanding and ultimately predicting joint toxicity. Here we apply these mixture models to investigate the potential to interpret the effects of semi chronic binary mixture exposure for three bee species: Apis mellifera, Bombus terrestris and Osmia bicornis within potentiation and mixture toxicity experiments. In the potentiation studies, the effect of the insecticide dimethoate with added propiconazole fungicide and neonicotinoid insecticide clothianidin with added tau-fluvalinate pyrethroid acaricide showed no difference in toxicity compared to the single chemical alone. Clothianidin toxicity showed a small scale, but temporally conserved increase in exposure conducted in the presence of propiconazole, particularly for B. terrestris and O. bicornis, the latter showing a near three-fold increase in clothianidin toxicity in the presence of propiconazole. In the mixture toxicity studies, the dominant response patterns were of additivity, however, binary mixtures of clothianidin and dimethoate in A. mellifera, B. terrestris and male O. bicornis there was evidence of a predominant antagonistic interaction. Given the ubiquitous nature of exposures to multiple chemicals, there is an urgent need to consider mixture effects in pollinator risk assessments. Our analyses suggest that current models, particularly those that utilise time-series data, such as DEBtox, can be used to identify additivity as the dominant response pattern and also those examples of interactions, even when small-scale, that may need to be taken into account during risk assessment. PMID- 28640810 TI - LASSIM-A network inference toolbox for genome-wide mechanistic modeling. AB - Recent technological advancements have made time-resolved, quantitative, multi omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE) for gene regulatory networks (GRNs). LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets. The rationale behind LASSIM is that biological GRNs can be simplified using a limited subset of core genes that are assumed to regulate all other gene transcription events in the network. The LASSIM method is implemented as a general-purpose toolbox using the PyGMO Python package to make the most of multicore computers and high performance clusters, and is available at https://gitlab.com/Gustafsson-lab/lassim. As a method, LASSIM works in two steps, where it first infers a non-linear ODE system of the pre specified core gene expression. Second, LASSIM in parallel optimizes the parameters that model the regulation of peripheral genes by core system genes. We showed the usefulness of this method by applying LASSIM to infer a large-scale non-linear model of naive Th2 cell differentiation, made possible by integrating Th2 specific bindings, time-series together with six public and six novel siRNA mediated knock-down experiments. ChIP-seq showed significant overlap for all tested transcription factors. Next, we performed novel time-series measurements of total T-cells during differentiation towards Th2 and verified that our LASSIM model could monitor those data significantly better than comparable models that used the same Th2 bindings. In summary, the LASSIM toolbox opens the door to a new type of model-based data analysis that combines the strengths of reliable mechanistic models with truly systems-level data. We demonstrate the power of this approach by inferring a mechanistically motivated, genome-wide model of the Th2 transcription regulatory system, which plays an important role in several immune related diseases. PMID- 28640812 TI - Challenges in preparing and implementing a clinical trial at field level in an Ebola emergency: A case study in Guinea, West Africa. AB - During the large Ebola outbreak that affected West Africa in 2014 and 2015, studies were launched to evaluate potential treatments for the disease. A clinical trial to evaluate the effectiveness of the antiviral drug favipiravir was conducted in Guinea. This paper describes the main challenges of the implementation of the trial in the Ebola treatment center of Gueckedou. Following the principles of the Good Clinical Research Practices, we explored the aspects of the community's communication and engagement, ethical conduct, trial protocol compliance, informed consent of participants, ongoing benefit/risk assessment, record keeping, confidentiality of patients and study data, and roles and responsibilities of the actors involved. We concluded that several challenges have to be addressed to successfully implement a clinical trial during an international medical emergency but that the potential for collaboration between research teams and humanitarian organizations needs to be highlighted. PMID- 28640814 TI - A novel algorithm identifies stress-induced alterations in mitochondrial connectivity and inner membrane structure from confocal images. AB - Mitochondria exist as a highly interconnected network that is exquisitely sensitive to variations in nutrient availability, as well as a large array of cellular stresses. Changes in length and connectivity of this network, as well as alterations in the mitochondrial inner membrane (cristae), regulate cell fate by controlling metabolism, proliferation, differentiation, and cell death. Given the key roles of mitochondrial dynamics, the process by which mitochondria constantly fuse and fragment, the measure of mitochondrial length and connectivity provides crucial information on the health and activity of various cell populations. However, despite the importance of accurately measuring mitochondrial networks, the tools required to rapidly and accurately provide this information are lacking. Here, we developed a novel probabilistic approach to automatically measure mitochondrial length distribution and connectivity from confocal images. This method accurately identified mitochondrial changes caused by starvation or the inhibition of mitochondrial function. In addition, we successfully used the algorithm to measure changes in mitochondrial inner membrane/matrix occurring in response to Complex III inhibitors. As cristae rearrangements play a critical role in metabolic regulation and cell survival, this provides a rapid method to screen for proteins or compounds affecting this process. The algorithm will thus provide a robust tool to dissect the molecular mechanisms underlying the key roles of mitochondria in the regulation of cell fate. PMID- 28640816 TI - Topographic Independent Component Analysis reveals random scrambling of orientation in visual space. AB - Neurons at primary visual cortex (V1) in humans and other species are edge filters organized in orientation maps. In these maps, neurons with similar orientation preference are clustered together in iso-orientation domains. These maps have two fundamental properties: (1) retinotopy, i.e. correspondence between displacements at the image space and displacements at the cortical surface, and (2) a trade-off between good coverage of the visual field with all orientations and continuity of iso-orientation domains in the cortical space. There is an active debate on the origin of these locally continuous maps. While most of the existing descriptions take purely geometric/mechanistic approaches which disregard the network function, a clear exception to this trend in the literature is the original approach of Hyvarinen and Hoyer based on infomax and Topographic Independent Component Analysis (TICA). Although TICA successfully addresses a number of other properties of V1 simple and complex cells, in this work we question the validity of the orientation maps obtained from TICA. We argue that the maps predicted by TICA can be analyzed in the retinal space, and when doing so, it is apparent that they lack the required continuity and retinotopy. Here we show that in the orientation maps reported in the TICA literature it is easy to find examples of violation of the continuity between similarly tuned mechanisms in the retinal space, which suggest a random scrambling incompatible with the maps in primates. The new experiments in the retinal space presented here confirm this guess: TICA basis vectors actually follow a random salt-and-pepper organization back in the image space. Therefore, the interesting clusters found in the TICA topology cannot be interpreted as the actual cortical orientation maps found in cats, primates or humans. In conclusion, Topographic ICA does not reproduce cortical orientation maps. PMID- 28640813 TI - Identification of a Sjogren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. AB - Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 * 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 * 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease. PMID- 28640815 TI - An autonomous metabolic role for Spen. AB - Preventing obesity requires a precise balance between deposition into and mobilization from fat stores, but regulatory mechanisms are incompletely understood. Drosophila Split ends (Spen) is the founding member of a conserved family of RNA-binding proteins involved in transcriptional regulation and frequently mutated in human cancers. We find that manipulating Spen expression alters larval fat levels in a cell-autonomous manner. Spen-depleted larvae had defects in energy liberation from stores, including starvation sensitivity and major changes in the levels of metabolic enzymes and metabolites, particularly those involved in beta-oxidation. Spenito, a small Spen family member, counteracted Spen function in fat regulation. Finally, mouse Spen and Spenito transcript levels scaled directly with body fat in vivo, suggesting a conserved role in fat liberation and catabolism. This study demonstrates that Spen is a key regulator of energy balance and provides a molecular context to understand the metabolic defects that arise from Spen dysfunction. PMID- 28640818 TI - Ankylosing spondylitis patients at risk of poor radiographic outcome show diminishing spinal radiographic progression during long-term treatment with TNF alpha inhibitors. AB - OBJECTIVE: To investigate the influence of patient characteristics on the course of spinal radiographic progression in a large prospective longitudinal cohort study of ankylosing spondylitis (AS) patients treated long-term with TNF-alpha inhibitors. METHODS: Consecutive patients from the Groningen Leeuwarden AS (GLAS) cohort starting TNF-alpha inhibitors with spinal radiographs at least available at baseline and 6 years of follow-up were included. Radiographs were scored using mSASSS by two independent readers. Generalized estimating equations (GEE) were used to explore the associations between baseline characteristics and spinal radiographic progression. The course of radiographic progression in patients with and without risk factors for poor radiographic outcome was investigated using different time models (linear and non-linear). Single linear imputation was used in case of missing radiographic data at the intermediate (2 or 4 years) follow-up visits. RESULTS: 80 AS patients were included with mean baseline mSASSS 8.7+/ 13.3. Baseline syndesmophytes, male gender, older age, longer symptom duration, smoking, and higher BMI were significantly associated with more radiographic damage over time. GEE analysis in patients with these risk factors revealed that radiographic progression followed a non-linear course with mean mSASSS progression rates reducing from max. 2.8 units over 0-2 years to min. 0.9 units over 4-6 years. The GEE model revealed a linear course with overall very low progression (<=1 mSASSS units/2yrs) in patients without risk factors. Complete case analysis in 53 patients showed similar results. CONCLUSION: AS patients at risk of poor radiographic outcome showed the highest but diminishing spinal radiographic progression during long-term treatment with TNF-alpha inhibitors. PMID- 28640817 TI - An R-CaMP1.07 reporter mouse for cell-type-specific expression of a sensitive red fluorescent calcium indicator. AB - Genetically encoded calcium indicators (GECIs) enable imaging of in vivo brain cell activity with high sensitivity and specificity. In contrast to viral infection or in utero electroporation, indicator expression in transgenic reporter lines is induced noninvasively, reliably, and homogenously. Recently, Cre/tTA-dependent reporter mice were introduced, which provide high-level expression of green fluorescent GECIs in a cell-type-specific and inducible manner when crossed with Cre and tTA driver mice. Here, we generated and characterized the first red-shifted GECI reporter line of this type using R CaMP1.07, a red fluorescent indicator that is efficiently two-photon excited above 1000 nm. By crossing the new R-CaMP1.07 reporter line to Cre lines driving layer-specific expression in neocortex we demonstrate its high fidelity for reporting action potential firing in vivo, long-term stability over months, and versatile use for functional imaging of excitatory neurons across all cortical layers, especially in the previously difficult to access layers 4 and 6. PMID- 28640819 TI - The importance of data quality for generating reliable distribution models for rare, elusive, and cryptic species. AB - The availability of spatially referenced environmental data and species occurrence records in online databases enable practitioners to easily generate species distribution models (SDMs) for a broad array of taxa. Such databases often include occurrence records of unknown reliability, yet little information is available on the influence of data quality on SDMs generated for rare, elusive, and cryptic species that are prone to misidentification in the field. We investigated this question for the fisher (Pekania pennanti), a forest carnivore of conservation concern in the Pacific States that is often confused with the more common Pacific marten (Martes caurina). Fisher occurrence records supported by physical evidence (verifiable records) were available from a limited area, whereas occurrence records of unknown quality (unscreened records) were available from throughout the fisher's historical range. We reserved 20% of the verifiable records to use as a test sample for both models and generated SDMs with each dataset using Maxent. The verifiable model performed substantially better than the unscreened model based on multiple metrics including AUCtest values (0.78 and 0.62, respectively), evaluation of training and test gains, and statistical tests of how well each model predicted test localities. In addition, the verifiable model was consistent with our knowledge of the fisher's habitat relations and potential distribution, whereas the unscreened model indicated a much broader area of high-quality habitat (indices > 0.5) that included large expanses of high elevation habitat that fishers do not occupy. Because Pacific martens remain relatively common in upper elevation habitats in the Cascade Range and Sierra Nevada, the SDM based on unscreened records likely reflects primarily a conflation of marten and fisher habitat. Consequently, accurate identifications are far more important than the spatial extent of occurrence records for generating reliable SDMs for the fisher in this region. We strongly recommend that practitioners avoid using anecdotal occurrence records to build SDMs but, if such data are used, the validity of resulting models should be tested with verifiable occurrence records. PMID- 28640820 TI - Whole genome analysis of selected human and animal rotaviruses identified in Uganda from 2012 to 2014 reveals complex genome reassortment events between human, bovine, caprine and porcine strains. AB - Rotaviruses of species A (RVA) are a common cause of diarrhoea in children and the young of various other mammals and birds worldwide. To investigate possible interspecies transmission of RVAs, whole genomes of 18 human and 6 domestic animal RVA strains identified in Uganda between 2012 and 2014 were sequenced using the Illumina HiSeq platform. The backbone of the human RVA strains had either a Wa- or a DS-1-like genetic constellation. One human strain was a Wa-like mono-reassortant containing a DS-1-like VP2 gene of possible animal origin. All eleven genes of one bovine RVA strain were closely related to those of human RVAs. One caprine strain had a mixed genotype backbone, suggesting that it emerged from multiple reassortment events involving different host species. The porcine RVA strains had mixed genotype backbones with possible multiple reassortant events with strains of human and bovine origin.Overall, whole genome characterisation of rotaviruses found in domestic animals in Uganda strongly suggested the presence of human-to animal RVA transmission, with concomitant circulation of multi-reassortant strains potentially derived from complex interspecies transmission events. However, whole genome data from the human RVA strains causing moderate and severe diarrhoea in under-fives in Uganda indicated that they were primarily transmitted from person-to-person. PMID- 28640821 TI - Noise reduction in single time frame optical DNA maps. AB - In optical DNA mapping technologies sequence-specific intensity variations (DNA barcodes) along stretched and stained DNA molecules are produced. These "fingerprints" of the underlying DNA sequence have a resolution of the order one kilobasepairs and the stretching of the DNA molecules are performed by surface adsorption or nano-channel setups. A post-processing challenge for nano-channel based methods, due to local and global random movement of the DNA molecule during imaging, is how to align different time frames in order to produce reproducible time-averaged DNA barcodes. The current solutions to this challenge are computationally rather slow. With high-throughput applications in mind, we here introduce a parameter-free method for filtering a single time frame noisy barcode (snap-shot optical map), measured in a fraction of a second. By using only a single time frame barcode we circumvent the need for post-processing alignment. We demonstrate that our method is successful at providing filtered barcodes which are less noisy and more similar to time averaged barcodes. The method is based on the application of a low-pass filter on a single noisy barcode using the width of the Point Spread Function of the system as a unique, and known, filtering parameter. We find that after applying our method, the Pearson correlation coefficient (a real number in the range from -1 to 1) between the single time frame barcode and the time average of the aligned kymograph increases significantly, roughly by 0.2 on average. By comparing to a database of more than 3000 theoretical plasmid barcodes we show that the capabilities to identify plasmids is improved by filtering single time-frame barcodes compared to the unfiltered analogues. Since snap-shot experiments and computational time using our method both are less than a second, this study opens up for high throughput optical DNA mapping with improved reproducibility. PMID- 28640823 TI - Estimating the number of secondary Ebola cases resulting from an unsafe burial and risk factors for transmission during the West Africa Ebola epidemic. AB - BACKGROUND: Safely burying Ebola infected individuals is acknowledged to be important for controlling Ebola epidemics and was a major component of the 2013 2016 West Africa Ebola response. Yet, in order to understand the impact of safe burial programs it is necessary to elucidate the role of unsafe burials in sustaining chains of Ebola transmission and how the risk posed by activities surrounding unsafe burials, including care provided at home prior to death, vary with human behavior and geography. METHODOLOGY/PRINCIPAL FINDINGS: Interviews with next of kin and community members were carried out for unsafe burials in Sierra Leone, Liberia and Guinea, in six districts where the Red Cross was responsible for safe and dignified burials (SDB). Districts were randomly selected from a district-specific sampling frame comprised of villages and neighborhoods that had experienced cases of Ebola. An average of 2.58 secondary cases were potentially generated per unsafe burial and varied by district (range: 0-20). Contact before and after death was reported for 142 (46%) contacts. Caregivers of a primary case were 2.63 to 5.92 times more likely to become EVD infected compared to those with post-mortem contact only. Using these estimates, the Red Cross SDB program potentially averted between 1,411 and 10,452 secondary EVD cases, reducing the epidemic by 4.9% to 36.5%. CONCLUSIONS/SIGNIFICANCE: SDB is a fundamental control measure that limits community transmission of Ebola; however, for those individuals having contact before and after death, it was impossible to ascertain the exposure that caused their infection. The number of infections prevented through SDB is significant, yet greater impact would be achieved by early hospitalization of the primary case during acute illness. PMID- 28640822 TI - Effective treatment options for musculoskeletal pain in primary care: A systematic overview of current evidence. AB - BACKGROUND & AIMS: Musculoskeletal pain, the most common cause of disability globally, is most frequently managed in primary care. People with musculoskeletal pain in different body regions share similar characteristics, prognosis, and may respond to similar treatments. This overview aims to summarise current best evidence on currently available treatment options for the five most common musculoskeletal pain presentations (back, neck, shoulder, knee and multi-site pain) in primary care. METHODS: A systematic search was conducted. Initial searches identified clinical guidelines, clinical pathways and systematic reviews. Additional searches found recently published trials and those addressing gaps in the evidence base. Data on study populations, interventions, and outcomes of intervention on pain and function were extracted. Quality of systematic reviews was assessed using AMSTAR, and strength of evidence rated using a modified GRADE approach. RESULTS: Moderate to strong evidence suggests that exercise therapy and psychosocial interventions are effective for relieving pain and improving function for musculoskeletal pain. NSAIDs and opioids reduce pain in the short-term, but the effect size is modest and the potential for adverse effects need careful consideration. Corticosteroid injections were found to be beneficial for short-term pain relief among patients with knee and shoulder pain. However, current evidence remains equivocal on optimal dose, intensity and frequency, or mode of application for most treatment options. CONCLUSION: This review presents a comprehensive summary and critical assessment of current evidence for the treatment of pain presentations in primary care. The evidence synthesis of interventions for common musculoskeletal pain presentations shows moderate-strong evidence for exercise therapy and psychosocial interventions, with short-term benefits only from pharmacological treatments. Future research into optimal dose and application of the most promising treatments is needed. PMID- 28640824 TI - Molecular diagnosis of Plasmodium ovale by photo-induced electron transfer fluorogenic primers: PET-PCR. AB - Accurate diagnosis of malaria infections continues to be challenging and elusive, especially in the detection of submicroscopic infections. Developing new malaria diagnostic tools that are sensitive enough to detect low-level infections, user friendly, cost effective and capable of performing large scale diagnosis, remains critical. We have designed novel self-quenching photo-induced electron transfer (PET) fluorogenic primers for the detection of P. ovale by real-time PCR. In our study, a total of 173 clinical samples, consisting of different malaria species, were utilized to test this novel PET-PCR primer. The sensitivity and specificity were calculated using nested-PCR as the reference test. The novel primer set demonstrated a sensitivity of 97.5% and a specificity of 99.2% (95% CI 85.2-99.8% and 95.2-99.9% respectively). Furthermore, the limit of detection for P. ovale was found to be 1 parasite/MUl. The PET-PCR assay is a new molecular diagnostic tool with comparable performance to other commonly used PCR methods. It is relatively easy to perform, and amiable to large scale malaria surveillance studies and malaria control and elimination programs. Further field validation of this novel primer will be helpful to ascertain the utility for large scale malaria screening programs. PMID- 28640826 TI - Allele specific CAPS marker development and characterization of chalcone synthase gene in Indian mulberry (Morus spp., family Moraceae). AB - Chalcone synthase (CHS) is an essential enzyme in the phenylpropanoid pathway that catalyzes the first step in flavonoid biosynthesis in plants under diverse environmental stress. We have used CHS as a candidate gene in mulberry and developed Single Nucleotide Polymorphism (SNP) based co-dominant Cleaved Amplified Polymorphic Sequence (CAPS) marker associated with the CHS locus. The segregation pattern of the marker was studied in an F1 population derived from a hybridization program between two mulberry genotypes showing polymorphism for the CHS locus. Differential CHS activity of the recombinants has been correlated with the segregation pattern of the marker. Homology modelling and docking studies are performed for both the identified CHS alleles and correlated with respective CHS activity. Phenotyping of Powdery Mildew infected F1 population indicated a probable association with the CAPS marker. PMID- 28640825 TI - Olfactory learning without the mushroom bodies: Spiking neural network models of the honeybee lateral antennal lobe tract reveal its capacities in odour memory tasks of varied complexities. AB - The honeybee olfactory system is a well-established model for understanding functional mechanisms of learning and memory. Olfactory stimuli are first processed in the antennal lobe, and then transferred to the mushroom body and lateral horn through dual pathways termed medial and lateral antennal lobe tracts (m-ALT and l-ALT). Recent studies reported that honeybees can perform elemental learning by associating an odour with a reward signal even after lesions in m-ALT or blocking the mushroom bodies. To test the hypothesis that the lateral pathway (l-ALT) is sufficient for elemental learning, we modelled local computation within glomeruli in antennal lobes with axons of projection neurons connecting to a decision neuron (LHN) in the lateral horn. We show that inhibitory spike-timing dependent plasticity (modelling non-associative plasticity by exposure to different stimuli) in the synapses from local neurons to projection neurons decorrelates the projection neurons' outputs. The strength of the decorrelations is regulated by global inhibitory feedback within antennal lobes to the projection neurons. By additionally modelling octopaminergic modification of synaptic plasticity among local neurons in the antennal lobes and projection neurons to LHN connections, the model can discriminate and generalize olfactory stimuli. Although positive patterning can be accounted for by the l-ALT model, negative patterning requires further processing and mushroom body circuits. Thus, our model explains several-but not all-types of associative olfactory learning and generalization by a few neural layers of odour processing in the l-ALT. As an outcome of the combination between non-associative and associative learning, the modelling approach allows us to link changes in structural organization of honeybees' antennal lobes with their behavioural performances over the course of their life. PMID- 28640828 TI - Bovine leukemia virus linked to breast cancer in Australian women and identified before breast cancer development. AB - Bovine leukemia virus (BLV), a common virus of cattle globally, was believed for decades not to infect humans. More recent techniques (in situ PCR and DNA sequencing) enabled detection of BLV in human breast tissue, and determination of its significant association with breast cancer in a US population. Using similar techniques to study 96 Australian women, we report here detection of retrotranscribed BLV DNA in breast tissue of 40/50(80%) of women with breast cancer versus 19/46(41%) of women with no history of breast cancer, indicating an age-adjusted odds ratio and confidence interval of 4.72(1.71-13.05). These results corroborate the findings of the previous study of US women with an even higher odds ratio for the Australian population. For 48 of the subjects, paired breast tissue samples, removed 3-10 years apart in two unrelated procedures, were available. For 23/31 (74%) of these, in which the first specimen was diagnosed as nonmalignant (benign or premalignant) and the second as malignant, BLV was already present in benign breast tissue years 3-10 years before the malignancy was diagnosed. This is consistent with the supposition of a causative temporal relationship between BLV infection and subsequent development of cancer. PMID- 28640827 TI - The application of multi-baseline digital close-range photogrammetry in three dimensional imaging and measurement of dental casts. AB - OBJECTIVE: To explore a new technique for reconstructing and measuring three dimensional (3D) models of orthodontic plaster casts using multi-baseline digital close-range photogrammetry (MBDCRP) with a single-lens reflex camera. STUDY DESIGN: Thirty sets of orthodontic plaster casts that do not exhibit severe horizontal overlap (>2 mm) between any two teeth were recorded by a single-lens reflex camera with 72 pictures taken in different directions. The 3D models of these casts were reconstructed and measured using the open source software MeshLab. These parameters, including mesio-distal crown diameter, arch width, and arch perimeter, were recorded six times on both the 3D digital models and on plaster casts by two examiners. Statistical analysis was carried out using the Bland-Altman method to measure agreement between the novel method and the traditional calliper method by calculating the differences between mean values. RESULTS: The average differences between the measurements of the photogrammetric 3D models and the plaster casts were 0.011-0.402mm. The mean differences between measurements obtained by the photogrammetric 3D models and the dental casts were not significant except for the lower arch perimeter (P>0.05), and all the differences were regarded as clinically acceptable (<0.5 mm). CONCLUSIONS: Measurements obtained by MBDCRP are compared well with those obtained from plaster casts, indicating that MBDCRP is an alternate way to store and measure dental plaster casts without severe horizontal overlap between any two teeth. PMID- 28640829 TI - An exploration of collaborative scientific production at MIT through spatial organization and institutional affiliation. AB - Academic research is increasingly cross-disciplinary and collaborative, between and within institutions. In this context, what is the role and relevance of an individual's spatial position on a campus? We examine the collaboration patterns of faculty at the Massachusetts Institute of Technology, through their academic output (papers and patents), and their organizational structures (institutional affiliation and spatial configuration) over a 10-year time span. An initial comparison of output types reveals: 1. diverging trends in the composition of collaborative teams over time (size, faculty versus non-faculty, etc.); and 2. substantively different patterns of cross-building and cross-disciplinary collaboration. We then construct a multi-layered network of authors, and find two significant features of collaboration on campus: 1. a network topology and community structure that reveals spatial versus institutional collaboration bias; and 2. a persistent relationship between proximity and collaboration, well fit with an exponential decay model. This relationship is consistent for both papers and patents, and present also in exclusively cross-disciplinary work. These insights contribute an architectural dimension to the field of scientometrics, and take a first step toward empirical space-planning policy that supports collaboration within institutions. PMID- 28640830 TI - Optimal sequencing strategies for identifying disease-associated singletons. AB - With the increasing focus of genetic association on the identification of trait associated rare variants through sequencing, it is important to identify the most cost-effective sequencing strategies for these studies. Deep sequencing will accurately detect and genotype the most rare variants per individual, but may limit sample size. Low pass sequencing will miss some variants in each individual but has been shown to provide a cost-effective alternative for studies of common variants. Here, we investigate the impact of sequencing depth on studies of rare variants, focusing on singletons-the variants that are sampled in a single individual and are hardest to detect at low sequencing depths. We first estimate the sensitivity to detect singleton variants in both simulated data and in down sampled deep genome and exome sequence data. We then explore the power of association studies comparing burden of singleton variants in cases and controls under a variety of conditions. We show that the power to detect singletons increases with coverage, typically plateauing for coverage > ~25x. Next, we show that, when total sequencing capacity is fixed, the power of association studies focused on singletons is typically maximized for coverage of 15-20x, independent of relative risk, disease prevalence, singleton burden, and case-control ratio. Our results suggest sequencing depth of 15-20x as an appropriate compromise of singleton detection power and sample size for studies of rare variants in complex disease. PMID- 28640831 TI - Ribosomal DNA copy number loss and sequence variation in cancer. AB - Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number. Despite the importance of rDNA for cellular function, we know virtually nothing about what governs its copy number, stability, and sequence in the mammalian genome due to challenges associated with mapping and analysis. We applied computational and droplet digital PCR approaches to measure rDNA copy number in normal and cancer states in human and mouse genomes. We find that copy number and sequence can change in cancer genomes. Counterintuitively, human cancer genomes show a loss of copies, accompanied by global copy number co variation. The sequence can also be more variable in the cancer genome. Cancer genomes with lower copies have mutational evidence of mTOR hyperactivity. The PTEN phosphatase is a tumor suppressor that is critical for genome stability and a negative regulator of the mTOR kinase pathway. Surprisingly, but consistent with the human cancer genomes, hematopoietic cancer stem cells from a Pten-/- mouse model for leukemia have lower rDNA copy number than normal tissue, despite increased proliferation, rRNA production, and protein synthesis. Loss of copies occurs early and is associated with hypersensitivity to DNA damage. Therefore, copy loss is a recurrent feature in cancers associated with mTOR activation. Ribosomal DNA copy number may be a simple and useful indicator of whether a cancer will be sensitive to DNA damaging treatments. PMID- 28640833 TI - Investigation of Pseudomonas fluorescens strain 3JW1 on preventing and reducing aflatoxin contaminations in peanuts. AB - Pseudomonas fluorescens strain 3JW1, which has a broad-spectrum antimicrobial activity, was studied to investigate whether it affects the amounts of aflatoxin B1 (AFB1) produced by Aspergillus flavus. It was found that the bacterium reduced the amounts of AFB1 in potato dextrose broth (PDB) and peanut medium by 97.8% and 99.4%, respectively. It also reduced AFB1 by ~183 MUg/kg (55.8%) when applied onto peanut kernels. This strain reduced AFB1 via three mechanisms. First, it significantly inhibited A. flavus growth; second, our data showed that strain 3JW1 inhibits aflatoxin biosynthesis by A. flavus; and third, P. fluorescens strain 3JW1 is capable of degrading AFB1 at a rate as high as 88.3% in 96 hours. This is the first report demonstrating that Pseudomonas fluorescens can reduce toxin contamination caused by A. flavus on peanut kernels. Our findings indicate that P. fluorescens strain 3JW1 had multiple effects including reducing A. flavus infection and aflatoxin contamination. And the results also highlight the potential applications of the strain 3JW1 for the biological control of aflatoxin contamination in peanuts and other susceptible crops. PMID- 28640832 TI - Sarpogrelate hydrochloride ameliorates diabetic nephropathy associated with inhibition of macrophage activity and inflammatory reaction in db/db mice. AB - The aim of this study was to evaluate the effects of sarpogrelate hydrochloride (SH), a selective serotonin 2A receptor antagonist, on diabetic nephropathy in a type 2 diabetes mouse model. We treated db/m and db/db mice with SH (30 mg/kg/day) for 12 weeks. Rat renal proximal tubule cells (NRK-52E) and mouse macrophages (Raw 264.7) were stimulated by high glucose (30 mM glucose) or LPS (100 ng/ml) with or without SH (20 MUM). We found that SH treatment increased serum adiponectin level and decreased urinary albumin, macrophage infiltration to glomeruli, and renal inflammatory and fibrosis signals, which were highly expressed in diabetic mice. Proximal tubule cells treated with high glucose (30 mM) also showed increased inflammatory and fibrosis signals. However, SH (20 MUM) treatment reduced these changes. Moreover, SH treatment inhibited LPS-stimulated macrophage migration and activation. These findings suggest that SH ameliorates diabetic nephropathy not only by suppressing macrophage infiltration, but also by anti-inflammatory and anti-fibrotic effects. PMID- 28640834 TI - Overexpression of GmFDL19 enhances tolerance to drought and salt stresses in soybean. AB - The basic leucine zipper (bZIP) family of transcription factors plays an important role in the growth and developmental process as well as responds to various abiotic stresses, such as drought and high salinity. Our previous work identified GmFDL19, a bZIP transcription factor, as a flowering promoter in soybean, and the overexpression of GmFDL19 caused early flowering in transgenic soybean plants. Here, we report that GmFDL19 also enhances tolerance to drought and salt stress in soybean. GmFDL19 was determined to be a group A member, and its transcription expression was highly induced by abscisic acid (ABA), polyethylene glycol (PEG 6000) and high salt stresses. Overexpression of GmFDL19 in soybean enhanced drought and salt tolerance at the seedling stage. The relative plant height (RPH) and relative shoot dry weight (RSDW) of transgenic plants were significantly higher than those of the WT after PEG and salt treatments. In addition, the germination rate and plant height of the transgenic soybean were also significantly higher than that of WT plants after various salt treatments. Furthermore, we also found that GmFDL19 could reduce the accumulation of Na+ ion content and up-regulate the expression of several ABA/stress responsive genes in transgenic soybean. We also found that GmFDL19 overexpression increased the activities of several antioxidative enzyme and chlorophyll content but reduced malondialdehyde content. These results suggested that GmFDL19 is involved in soybean abiotic stress responses and has potential utilization to improve multiple stress tolerance in transgenic soybean. PMID- 28640835 TI - Bilateral blockade of MEK- and PI3K-mediated pathways downstream of mutant KRAS as a treatment approach for peritoneal mucinous malignancies. AB - Mucinous colorectal adenocarcinomas (MCAs) are clinically and morphologically distinct from nonmucinous colorectal cancers (CRCs), show a distinct spectrum of genetic alterations (higher KRAS mutations, lower p53, high MUC2), exhibit more aggressive behavior (more prone to peritoneal dissemination and lymph node involvement) and are associated with poorer response to chemotherapy with limited treatment options. Here, we report the effectiveness of combinatorial targeting of two KRAS-mediated parallel pathways in reducing MUC2 production and mucinous tumor growth in vitro and in vivo. By knockdown of mutant KRAS we show that, mutant KRAS (a) is necessary for MUC2 production in vitro and (b) synergistically engages PI3K/AKT and MEK/ERK pathways to maintain MUC2 expression in MCA cells. These results define a novel and a previously undescribed role for oncogenic KRAS in mucinous cancers. MCA cells were sensitive to MEK inhibition suggesting cellular dependence ('addiction') of KRAS-mutant MCA cells on hyperactivation of the MEK-driven pathway. Interestingly, MCA cells, though initially sensitive, were later resistant to PI3K single agent inhibition. Our studies suggest that this resistance involves dynamic rewiring of signaling circuits mediated through relief of RTK inhibition and MEK-ERK rebound activation. This resistance however, could be overcome by co-targeting of PI3K and MEK. Our studies thus provide a rational basis for MEK- and PI3K-targeted combination therapy for not only KRAS mutant MCA but also for other related mucinous neoplasms that overproduce MUC2 and have a high rate of KRAS mutations such as pseudomyxoma peritonei. PMID- 28640836 TI - Craniofacial similarity analysis through sparse principal component analysis. AB - The computer-aided craniofacial reconstruction (CFR) technique has been widely used in the fields of criminal investigation, archaeology, anthropology and cosmetic surgery. The evaluation of craniofacial reconstruction results is important for improving the effect of craniofacial reconstruction. Here, we used the sparse principal component analysis (SPCA) method to evaluate the similarity between two sets of craniofacial data. Compared with principal component analysis (PCA), SPCA can effectively reduce the dimensionality and simultaneously produce sparse principal components with sparse loadings, thus making it easy to explain the results. The experimental results indicated that the evaluation results of PCA and SPCA are consistent to a large extent. To compare the inconsistent results, we performed a subjective test, which indicated that the result of SPCA is superior to that of PCA. Most importantly, SPCA can not only compare the similarity of two craniofacial datasets but also locate regions of high similarity, which is important for improving the craniofacial reconstruction effect. In addition, the areas or features that are important for craniofacial similarity measurements can be determined from a large amount of data. We conclude that the craniofacial contour is the most important factor in craniofacial similarity evaluation. This conclusion is consistent with the conclusions of psychological experiments on face recognition and our subjective test. The results may provide important guidance for three- or two-dimensional face similarity evaluation, analysis and face recognition. PMID- 28640837 TI - Identification and prediction of alternative transcription start sites that generate rod photoreceptor-specific transcripts from ubiquitously expressed genes. AB - Transcriptome complexity is substantially increased by the use of multiple transcription start sites for a given gene. By utilizing a rod photoreceptor specific chromatin signature, and the RefSeq database of established transcription start sites, we have identified essentially all known rod photoreceptor genes as well as a group of novel genes that have a high probability of being expressed in rod photoreceptors. Approximately half of these novel rod genes are transcribed into multiple mRNA and/or protein isoforms through alternative transcriptional start sites (ATSS), only one of which has a rod-specific epigenetic signature and gives rise to a rod transcript. This suggests that, during retina development, some genes use ATSS to regulate cell type and temporal specificity, effectively generating a rod transcript from otherwise ubiquitously expressed genes. Biological confirmation of the relationship between epigenetic signatures and gene expression, as well as comparison of our genome-wide chromatin signature maps with available data sets for retina, namely a ChIP-on-Chip study of Polymerase-II (Pol-II) binding sites, ChIP-Seq studies for NRL- and CRX- binding sites and DHS (University of Washington data, available on UCSC mouse Genome Browser as a part of ENCODE project) fully support our hypothesis and together accurately identify and predict an array of new rod transcripts. The same approach was used to identify a number of TSS that are not currently in RefSeq. Biological conformation of the use of some of these TSS suggests that this method will be valuable for exploring the range of transcriptional complexity in many tissues. Comparison of mouse and human genome-wide data indicates that most of these alternate TSS appear to be present in both species, indicating that our approach can be useful for identification of regulatory regions that might play a role in human retinal disease. PMID- 28640838 TI - Next generation sequencing of the clonal IGH rearrangement detects ongoing mutations and interfollicular trafficking in in situ follicular neoplasia. AB - Follicular lymphoma (FL) is characterized genetically by a significant intraclonal diversity of rearranged immunoglobulin heavy chain (IGH) genes and a substantial cell migration activity (follicular trafficking). Recently, in situ follicular neoplasia (ISFN), characterized by accumulations of immunohistochemically strongly BCL2-positive, t(14;18)+ clonal B cells confined to germinal centers in reactive lymph nodes, has been identified as a precursor lesion of FL with low risk of progression to manifest FL. The extent of ongoing somatic hypermutation of rearranged IGH genes and interfollicular trafficking in ISFN is not known. In this study we performed an in depth analysis of clonal evolution and cell migration patterns in a case of pure ISFN involving multiple lymph nodes. Using laser microdissection and next generation sequencing (NGS) we documented significant intraclonal diversity of the rearranged IGH gene and extensive interfollicular migration between germinal centers of the same lymph node as well as between different lymph nodes. Furthermore, we identified N glycosylation motifs characteristic for FL in the CDR3 region. PMID- 28640839 TI - Assessment of recall error in self-reported food consumption histories among adults-Particularly delay of interviews decrease completeness of food histories Germany, 2013. AB - INTRODUCTION: Poor recall during investigations of foodborne outbreaks may lead to misclassifications in exposure ascertainment. We conducted a simulation study to assess the frequency and determinants of recall errors. METHODS: Lunch visitors in a cafeteria using exclusively cashless payment reported their consumption of 13 food servings available daily in the three preceding weeks using a self-administered paper-questionnaire. We validated this information using electronic payment information. We calculated associated factors on misclassification of recall according to time, age, sex, education level, dietary habits and type of servings. RESULTS: We included 145/226 (64%) respondents who reported 27,095 consumed food items. Sensitivity of recall was 73%, specificity 96%. In multivariable analysis, for each additional day of recall period, the adjusted chance for false-negative recall increased by 8% (OR: 1.1;95%-CI: 1.06, 1.1), for false-positive recall by 3% (OR: 1.03;95%-CI: 1.02, 1.05), for indecisive recall by 12% (OR: 1.1;95%-CI: 1.08, 1.15). Sex and education-level had minor effects. DISCUSSION: Forgetting to report consumed foods is more frequent than reporting food-items actually not consumed. Bad recall is strongly enhanced by delay of interviews and may make hypothesis generation and testing very challenging. Side dishes are more easily missed than main courses. If available, electronic payment data can improve food-history information. PMID- 28640840 TI - Applying artificial intelligence to disease staging: Deep learning for improved staging of diabetic retinopathy. AB - PURPOSE: Disease staging involves the assessment of disease severity or progression and is used for treatment selection. In diabetic retinopathy, disease staging using a wide area is more desirable than that using a limited area. We investigated if deep learning artificial intelligence (AI) could be used to grade diabetic retinopathy and determine treatment and prognosis. METHODS: The retrospective study analyzed 9,939 posterior pole photographs of 2,740 patients with diabetes. Nonmydriatic 45 degrees field color fundus photographs were taken of four fields in each eye annually at Jichi Medical University between May 2011 and June 2015. A modified fully randomly initialized GoogLeNet deep learning neural network was trained on 95% of the photographs using manual modified Davis grading of three additional adjacent photographs. We graded 4,709 of the 9,939 posterior pole fundus photographs using real prognoses. In addition, 95% of the photographs were learned by the modified GoogLeNet. Main outcome measures were prevalence and bias-adjusted Fleiss' kappa (PABAK) of AI staging of the remaining 5% of the photographs. RESULTS: The PABAK to modified Davis grading was 0.64 (accuracy, 81%; correct answer in 402 of 496 photographs). The PABAK to real prognosis grading was 0.37 (accuracy, 96%). CONCLUSIONS: We propose a novel AI disease-staging system for grading diabetic retinopathy that involves a retinal area not typically visualized on fundoscopy and another AI that directly suggests treatments and determines prognoses. PMID- 28640842 TI - Living in the waterfalls: A new species of Trichomycterus (Siluriformes: Trichomycteridae) from Tabay stream, Misiones, Argentina. AB - A new species assigned to the genus Trichomycterus from the area of the waterfalls of Tabay stream, Parana River basin, Misiones, Argentina, is described. Trichomycterus ytororo sp. nov. is distinguished from all other species in the genus by the presence of 31-35 dorsal procurrent caudal-fin rays and the combination of some external characters such as: coloration, number of pectoral-fin rays and pores of the laterosensory canals. The new taxon belongs to a presumably monophyletic group of species composed of T. crassicaudatus, T. igobi, and T. stawiarski based on the presence of 24 or more thickly ossified and rigid procurrent caudal-fin rays with a slender distal tip extending along the tips of at least ten neural spines. PMID- 28640841 TI - A sorghum (Sorghum bicolor) mutant with altered carbon isotope ratio. AB - Recent efforts to engineer C4 photosynthetic traits into C3 plants such as rice demand an understanding of the genetic elements that enable C4 plants to outperform C3 plants. As a part of the C4 Rice Consortium's efforts to identify genes needed to support C4 photosynthesis, EMS mutagenized sorghum populations were generated and screened to identify genes that cause a loss of C4 function. Stable carbon isotope ratio (delta13C) of leaf dry matter has been used to distinguishspecies with C3 and C4 photosynthetic pathways. Here, we report the identification of a sorghum (Sorghum bicolor) mutant with a low delta13C characteristic. A mutant (named Mut33) with a pale phenotype and stunted growth was identified from an EMS treated sorghum M2 population. The stable carbon isotope analysis of the mutants showed a decrease of 13C uptake capacity. The noise of random mutation was reduced by crossing the mutant and its wildtype (WT). The back-cross (BC1F1) progenies were like the WT parent in terms of 13C values and plant phenotypes. All the BC1F2 plants with low delta13C died before they produced their 6th leaf. Gas exchange measurements of the low delta13C sorghum mutants showed a higher CO2 compensation point (25.24 MUmol CO2.mol-1air) and the maximum rate of photosynthesis was less than 5MUmol.m-2.s-1. To identify the genetic determinant of this trait, four DNA pools were isolated; two each from normal and low delta13C BC1F2 mutant plants. These were sequenced using an Illumina platform. Comparison of allele frequency of the single nucleotide polymorphisms (SNPs) between the pools with contrasting phenotype showed that a locus in Chromosome 10 between 57,941,104 and 59,985,708 bps had an allele frequency of 1. There were 211 mutations and 37 genes in the locus, out of which mutations in 9 genes showed non-synonymous changes. This finding is expected to contribute to future research on the identification of the causal factor differentiating C4 from C3 species that can be used in the transformation of C3 to C4 plants. PMID- 28640843 TI - Metabolic milieu associates with impaired skeletal characteristics in obesity. AB - High leptin concentration, low-grade inflammation, and insulin resistance often coexist in obese subjects; this adverse metabolic milieu may be the main culprit for increased fracture risk and impaired bone quality seen in patients with type 2 diabetes. We examined the associations of leptin, hs (high sensitivity)- CRP and insulin resistance with bone turnover markers (BTMs) and bone characteristics in 55 young obese adults (median BMI 40 kg/m2) and 65 non-obese controls. Mean age of the subjects was 19.5 +/- 2.5 years (mean +/- SD). Concentrations of leptin, adiponectin, hs-CRP, MMP-8 and TIMP-1, fasting plasma glucose and insulin (to calculate HOMA), BTMs (BAP, P1NP, CTX-1, and TRAC5b) were measured. Bone characteristics were determined with pQCT at radius and tibia, and with DXA for central sites. Leptin, hs-CRP and HOMA correlated inversely with BTMs: the partial coefficients were 1.5-1.9 fold higher in males than in females. After adjusting for age, BMI, and other endocrine factors, leptin displayed an independent effect in males on radial bone mass (p = 0.019), tibial trabecular density (p = 0.025) and total hip BMD (p = 0.043), with lower densities in males with high leptin. In females, the model adjusting for age, BMI, and other endocrine factors, revealed that hs-CRP had independent effects on radial bone mass (p = 0.034) and lumbar spine BMD (p = 0.016), women with high hs-CRP having lower values. Partial correlations of adiponectin and TIMP-1 with bone characteristics were discrepant; MMP-8 showed no associations. In conclusion, in young obese adults and their controls, leptin, hs-CRP and HOMA associate inversely with BTMs and bone characteristics. Leptin appears to be the key independent effector in males, whereas hs-CRP displayed a predominant role in females. PMID- 28640844 TI - The G8 screening tool enhances prognostic value to ECOG performance status in elderly cancer patients: A retrospective, single institutional study. AB - BACKGROUND: Some elderly cancer patients, even with good Eastern Cooperative Oncology Group performance status (ECOG-PS), have poor survival outcomes and cannot tolerate standard therapy. Few studies have detailed the associations between the G8 screening tool, ECOG-PS, and overall survival (OS) in such patients. METHODS: Cancer patients, aged 70 years or older, were assessed for G8 and classified into three groups according to their G8 score: <11 as the low score group, 11-14 as the intermediate score group, and >14 as the high score group. We retrospectively analyzed the association between G8 score and OS in all patients and for each ECOG-PS-categorized group. RESULTS: Out of 264 enrolled patients, most patients (87%) with solid tumor were categorized as TNM stage IV. ECOG-PS was 0 or 1 in 215 patients and >=2 in 48; there was missing data for one patient. Among all patients, the low score group with a median OS of 7.7 months survived significantly less than both the high score group with a median OS of 25.6 months [Hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.96-6.63; p < 0.0001] and the intermediate score group with a median of 15.6 months (HR 1.83; 95% CI, 1.28-2.65; p < 0.001). In the multivariate analysis, TNM stage and G8 score were independent prognostic factors for OS. When patients with an ECOG-PS of 0 or 1 were analyzed, patients with a lower G8 score showed significantly shorter OS than patients with a higher score when any two groups were compared. CONCLUSION: This novel classification of the G8 score contributes to prompt identification of patients with poor prognosis and improved the prognostic value of ECOG-PS. Using G8 with ECOG-PS may be helpful in deciding treatment for elderly patients with advanced cancer. PMID- 28640845 TI - Is self-assessment of medical abortion using a low-sensitivity pregnancy test combined with a checklist and phone text messages feasible in South African primary healthcare settings? A randomized trial. AB - OBJECTIVE: To evaluate feasibility of self-assessment of medical abortion outcome using a low-sensitivity urine pregnancy test, checklist and text messages. The study assessed whether accurate self-assessment required a demonstration of the low-sensitivity urine pregnancy test or if verbal instructions suffice. METHODS: This non-inferiority trial enrolled 525 adult women from six public sector abortion clinics. Eligible women were undergoing medical abortion at gestations within 63 days. Consenting women completed a baseline interview, received standard care with mifepristone and home-administration of misoprostol. All were given a low-sensitivity urine pregnancy test and checklist for use 14 days later, sent text reminders, and asked to attend in-clinic follow-up after two weeks. Women were randomly assigned 1:1 to an instruction-only group (n = 262; issued with pre-scripted instructions on the low-sensitivity pregnancy test), or a demonstration group (n = 263; performed practice tests guided by lay health workers). The primary outcome was accurate self-assessment of incomplete abortion, defined as needing additional misoprostol or vacuum aspiration. Analysis was by intention to treat and a non-inferiority margin was set to six percentage points. Women's acceptability of their abortion procedure and preferences for follow-up were also assessed. RESULTS: Follow-up was 81% for abortion outcome, confirmed in-clinic at two weeks or self-reported within six months. Non-inferiority of instruction-only to a demonstration was inconclusive for accurate self-assessment (risk difference for instruction-only demonstration: -2.5%; 95%CI: -9% to 4%). Comparing instruction-only to demonstration groups, 99% and 100% found the pregnancy test easy to do; and 91% and 93% respectively chose the pregnancy test, checklist and text messages for abortion outcome assessment in the future. CONCLUSION: Routine self-assessment using a low-sensitivity pregnancy test, checklist and text messages is feasible and preferred by women attending South African primary care abortion clinics. Counselling with additional emphasis on prompt recognition of ongoing pregnancies is recommended. TRIAL REGISTRATION: ClinicalTrials.gov NCT02231619. PMID- 28640846 TI - Endothelial angiogenesis is directed by RUNX1T1-regulated VEGFA, BMP4 and TGF beta2 expression. AB - Tissue angiogenesis is intimately regulated during embryogenesis and postnatal development. Defected angiogenesis contributes to aberrant development and is the main complication associated with ischemia-related diseases. We previously identified the increased expression of RUNX1T1 in umbilical cord blood-derived endothelial colony-forming cells (ECFCs) by gene expression microarray. However, the biological relevance of RUNX1T1 in endothelial lineage is not defined clearly. Here, we demonstrate RUNX1T1 regulates the survival, motility and tube forming capability of ECFCs and EA.hy926 endothelial cells by loss-and gain-of function assays, respectively. Second, embryonic vasculatures and quantity of bone marrow-derived angiogenic progenitors are found to be reduced in the established Runx1t1 heterozygous knockout mice. Finally, a central RUNX1T1 regulated signature is uncovered and VEGFA, BMP4 as well as TGF-beta2 are demonstrated to mediate RUNX1T1-orchested angiogenic activities. Taken together, our results reveal that RUNX1T1 serves as a common angiogenic driver for vaculogenesis and functionality of endothelial lineage cells. Therefore, the discovery and application of pharmaceutical activators for RUNX1T1 will improve therapeutic efficacy toward ischemia by promoting neovascularization. PMID- 28640847 TI - Heart rate lowering treatment leads to a reduction in vulnerable plaque features in atherosclerotic rabbits. AB - OBJECTIVE: To investigate the effect of a heart rate (HR) lowering agent (Ivabradine) on features of atherosclerotic plaque vulnerability with magnetic resonance imaging (MRI), ultrasound imaging, and histology. APPROACH AND RESULTS: Atherosclerosis was induced in the abdominal aorta of 19 rabbits. Nine rabbits were treated with Ivabradine (17 mg/kg/day) during the entire study period. At week 14, imaging was performed. Plaque size was quantified on contrast-enhanced T1-weighted MR images. Microvascular flow, density, and permeability was studied with dynamic contrast-enhanced MRI. Plaque biomechanics was studied by measuring the aortic distension with ultrasound. After, animals were sacrificed and histology was performed. HR was reduced by 16% (p = 0.026) in Ivabradine-treated animals. No differences in absolute and relative vessel wall beat-to-beat distension were found, but due to the reduction in HR, the frequency of the biomechanical load on the plaque was reduced. Plaque size (MR and histology) was similar between groups. Although microvessel density (histology) was similar between groups, AUC and Ktrans, indicative for plaque microvasculature flow, density, and permeability, were decreased by 24% (p = 0.029) and 32% (p = 0.037), respectively. Macrophage content (relative RAM11 positive area) was reduced by 44% (p<0.001) on histology in Ivabradine-treated animals. CONCLUSIONS: HR lowering treatment with Ivabradine in an atherosclerotic rabbit model is associated with a reduction in vulnerable plaque features. The current study suggests that HR reduction may be beneficial for inducing or maintaining a more stable plaque phenotype. PMID- 28640848 TI - Easy labeling of proliferative phase and sporogonic phase of microsporidia Nosema bombycis in host cells. AB - Microsporidia are eukaryotic, unicellular parasites that have been studied for more than 150 years. These organisms are extraordinary in their ability to invade a wide range of hosts including vertebrates and invertebrates, such as human and commercially important animals. A lack of appropriate labeling methods has limited the research of the cell cycle and protein locations in intracellular stages. In this report, an easy fluorescent labeling method has been developed to mark the proliferative and sporogonic phases of microsporidia Nosema bombycis in host cells. Based on the presence of chitin, Calcofluor White M2R was used to label the sporogonic phase, while beta-tubulin antibody coupled with fluorescence secondary antibody were used to label the proliferative phase by immunofluorescence. This method is simple, efficient and can be used on both infected cells and tissue slices, providing a great potential application in microsporidia research. PMID- 28640849 TI - Motility in blastogregarines (Apicomplexa): Native and drug-induced organisation of Siedleckia nematoides cytoskeletal elements. AB - Recent studies on motility of Apicomplexa concur with the so-called glideosome concept applied for apicomplexan zoites, describing a unique mechanism of substrate-dependent gliding motility facilitated by a conserved form of actomyosin motor and subpellicular microtubules. In contrast, the gregarines and blastogregarines exhibit different modes and mechanisms of motility, correlating with diverse modifications of their cortex. This study focuses on the motility and cytoskeleton of the blastogregarine Siedleckia nematoides Caullery et Mesnil, 1898 parasitising the polychaete Scoloplos cf. armiger (Muller, 1776). The blastogregarine moves independently on a solid substrate without any signs of gliding motility; the motility in a liquid environment (in both the attached and detached forms) rather resembles a sequence of pendular, twisting, undulation, and sometimes spasmodic movements. Despite the presence of key glideosome components such as pellicle consisting of the plasma membrane and the inner membrane complex, actin, myosin, subpellicular microtubules, micronemes and glycocalyx layer, the motility mechanism of S. nematoides differs from the glideosome machinery. Nevertheless, experimental assays using cytoskeletal probes proved that the polymerised forms of actin and tubulin play an essential role in the S. nematoides movement. Similar to Selenidium archigregarines, the subpellicular microtubules organised in several layers seem to be the leading motor structures in blastogregarine motility. The majority of the detected actin was stabilised in a polymerised form and appeared to be located beneath the inner membrane complex. The experimental data suggest the subpellicular microtubules to be associated with filamentous structures (= cross-linking protein complexes), presumably of actin nature. PMID- 28640850 TI - No evidence for punishment in communally nursing female house mice (Mus musculus domesticus). AB - Punishment is claimed as an important mechanism to stabilise costly cooperation in humans, but its importance in social animals has been questioned recently due to both conceptual considerations and a lack of empirical evidence (only few published studies). We empirically tested whether there is evidence for punishment in communally nursing house mice (Mus musculus domesticus, direct descendants of "wild" animals). Communally breeding females pool their litters and raise all offspring together, indiscriminately caring for own and other offspring. Such a situation resembles a public good and provides scope for exploitation if females vary in their relative contributions to the joint nest (offspring number). We allowed two females to communally breed and conducted removal experiments both in the presence and absence of pups. We aimed to test whether reduced investment by one of the females (induced through separation from the partner and their combined offspring for 4 or 12 hours) leads to increased aggression by the other female after the reunion. We found no evidence for punishment, on the contrary, females increased socio-positive behaviours. The costs of losing a partner in a communally breeding species might be too high and hinder the evolution of punishment. Our findings add to a growing list of examples questioning the role of punishment in cooperating non-human animals and emphasise the importance of empirical testing of its assumptions and predictions. PMID- 28640851 TI - Ligand-mediated and tertiary interactions cooperatively stabilize the P1 region in the guanine-sensing riboswitch. AB - Riboswitches are genetic regulatory elements that control gene expression depending on ligand binding. The guanine-sensing riboswitch (Gsw) binds ligands at a three-way junction formed by paired regions P1, P2, and P3. Loops L2 and L3 cap the P2 and P3 helices and form tertiary interactions. Part of P1 belongs to the switching sequence dictating the fate of the mRNA. Previous studies revealed an intricate relationship between ligand binding and presence of the tertiary interactions, and between ligand binding and influence on the P1 region. However, no information is available on the interplay among these three main regions in Gsw. Here we show that stabilization of the L2-L3 region by tertiary interactions, and the ligand binding site by ligand binding, cooperatively influences the structural stability of terminal base pairs in the P1 region in the presence of Mg2+ ions. The results are based on molecular dynamics simulations with an aggregate simulation time of ~10 MUs across multiple systems of the unbound state of the Gsw aptamer and a G37A/C61U mutant, and rigidity analyses. The results could explain why the three-way junction is a central structural element also in other riboswitches and how the cooperative effect could become contextual with respect to intracellular Mg2+ concentration. The results suggest that the transmission of allosteric information to P1 can be entropy-dominated. PMID- 28640853 TI - Required coefficient of friction in the anteroposterior and mediolateral direction during turning at different walking speeds. AB - This study investigated the required coefficient of friction (RCOF) and the tangent of center of mass (COM)-center of pressure (COP) angle in the mediolateral (ML) and anteroposterior (AP) directions during turning at different walking speeds. Sixteen healthy young adults (8 males and 8 females) participated in this study. The participants were instructed to conduct trials of straight walking and 90 degrees step and spin turns to the right at each of three self selected speeds (slow, normal, and fast). The ML and AP directions during turning gait were defined using the orientation of the pelvis to construct a body-fixed reference frame. The RCOF values and COM-COP angle tangent in the ML direction during turning at weight acceptance phase were higher than those during straight walking, and those values increased with increasing walking speed. The ML component of the RCOF and COM-COP tangent values during weight acceptance for step turns were higher than those for spin turns. The mean centripetal force during turning tended to increase with an increase in walking speed and had a strong positive correlation with the RCOF values in the ML direction (R = 0.97 during the weight acceptance phase; R = 0.95 during the push-off phase). Therefore, turning, particularly step turn, is likely to cause lateral slip at weight acceptance because of the increased centripetal force compared with straight walking. Future work should test at-risk population and compare with the present results. PMID- 28640852 TI - Differential roles of 3-Hydroxyflavone and 7-Hydroxyflavone against nicotine induced oxidative stress in rat renal proximal tubule cells. AB - Plant flavonoids are well known as antioxidants against oxidative stress induced by exposure to external pollutants. Nicotine (NIC) is one of those agents which increases renal oxidative stress, an important factor in the pathogenesis of renal epithelial injury in smokers. Although several studies had been conducted on flavonoids and oxidative stress, the mechanism of the protective pathways are not fully understood. Here, we present studies on antioxidant properties of two mono-hydroxyflavone isomers, 3-hydroxyflanove (3HF)- and 7-hydroxyflavone (7HF), against nicotine-associated oxidative stress and injury in cultured renal proximal tubule cells and correlate their antioxidant properties with their chemical structure. Our data clearly demonstrates, for the first time, that while both 3HF and 7HF protect renal cells from NIC-associated cytotoxicity, the mechanism of their action is different: 3HF elicits protective activity via the PKA/CREB/MnSOD pathway while 7HF does so via the ERK/Nrf2/HO-1 pathway. Molecular docking and dynamics simulations with two major signaling pathway proteins showed significant differences in the binding energies of 3HF (-5.67 and -7.39 kcal.mol 1) compared to 7HF (-5.41 and -8.55 kcal.mol-1) in the matrices of CREB and Keap1 Nrf2 proteins respectively, which corroborate with the observed differences in their protective properties in the renal cells. The implications of this novel explorative study is likely to promote the understanding of the mechanisms of the antioxidative functions of different flavones. PMID- 28640854 TI - Maternal BMI and diabetes in pregnancy: Investigating variations between ethnic groups using routine maternity data from London, UK. AB - OBJECTIVE: To investigate the ethnicity-specific association between body mass index (BMI) and diabetes in pregnancy, with a focus on the appropriateness of using BMI cut-offs to identify pregnant women at risk of diabetes. STUDY DESIGN: Analysis of routinely-collected data from a maternity unit in London, UK. Data were available on 53 264 women delivering between 2004 and 2012. Logistic regression was used to explore the association between diabetes in pregnancy and BMI among women of different ethnicities, and adjusted probability estimates were used to derive risk equivalent cut-offs. ROC curve analysis was used to assess the performance of BMI as a predictor of diabetes in pregnancy. RESULTS: The prevalence of diabetes in pregnancy was 2.3% overall; highest in South and East Asian women (4.6% and 3.7%). In adjusted analysis, BMI category was strongly associated with diabetes in all ethnic groups. Modelled as a continuous variable with a quadratic term, BMI was an acceptable predictor of diabetes according to ROC curve analysis. Applying a BMI cut-off of 30 kg/m2 would identify just over half of Black women with diabetes in pregnancy, a third of White (32%) and South Asian (35%) women, but only 13% of East Asian women. The 'risk equivalent' (comparable to 30 kg/m2 in White women) threshold for South Asian and East Asian women was approximately 21 kg/m2, and 27.5 kg/m2 for Black women. CONCLUSIONS: This study suggests that current BMI thresholds are likely to be ineffective for diabetes screening in South and East Asian women, as many cases of diabetes will occur at low BMI levels. Our results suggest that East Asian women appear to face a similarly high risk of diabetes to South Asian women. Current UK guidelines recommend diabetes screening should be offered to all pregnant South Asian women; extending this recommendation to include women of East Asian ethnicity may be appropriate. PMID- 28640855 TI - The effect of subpressure on the bond strength of resin to zirconia ceramic. AB - OBJECTIVE: This study was conducted to investigate the effect of subpressure on the bond strength of resin to zirconia ceramic. The subpressure would create a pressure gradient which could clean out the bubbles in the adhesives or bonding interface. METHODS: Twenty-eight pre-sintered zirconia discs were fabricated. Half of them were polished (group P, n = 14), and the rest were sandblasted (group S, n = 14). After sintered,the surface roughness of the zirconia discs was measured. Then, they were randomly divided into two subgroups (n = 7). The groups were named as follows: PC: P + no additional treatments; PP: P + 0.04 MPa after application of adhesives; SC: S + no additional treatments; and SP: S + 0.04 MPa after application of adhesives. Resin columns were bonded to the zirconia specimens to determine shear bond strength (SBS). The bonding interfaces were observed and the fracture modes were evaluated. Statistical analysis was performed on all data. RESULTS: The surface roughness of group S was significantly higher than that of group P (P<0.05). The SBS values were PC = 13.48 +/- 0.7 MPa, PP = 15.22 +/- 0.8 MPa, SC = 17.23 +/- 0.7 MPa and SP = 21.68 +/- 1.4 MPa. There were significant differences among the groups (P<0.05). Scanning electron microscopy (SEM) results showed that the adhesives of group SP and PP were closer and denser to the zirconia ceramic than that of group PC and SC. The proportion of the mixed fracture mode significantly increased after adding subpressure (P< 0.05). CONCLUSION: Subpressure can improve the shear bond strength of resin to zirconia ceramics and increase micro-infiltration between the adhesives and the zirconia ceramics, especially on the rough surfaces. PMID- 28640856 TI - Correction: MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma. AB - [This corrects the article DOI: 10.1371/journal.pone.0085935.]. PMID- 28640858 TI - Early growth stages salinity stress tolerance in CM72 x Gairdner doubled haploid barley population. AB - A doubled haploid (DH) population of barley (Hordeum vulgare L.) generated from salinity tolerant genotype CM72 and salinity sensitive variety Gairdner was studied for salinity stress tolerance at germination, seedling emergence and first leaf full expansion growth stages. Germination study was conducted with deionized water, 150 mM and 300 mM NaCl treatments. Seedling stage salinity tolerance was conducted with three treatments: control, 150 mM NaCl added at seedling emergence and first leaf full expansion growth stages. Results from this study revealed transgressive phenotypic segregations for germination percentage and biomass at seedling stage. Twelve QTL were identified on chromosomes 2H-6H each explaining 10-25% of the phenotypic variations. A QTL located at 176.5 cM on chromosome 3H was linked with fresh weight per plant and dry weight per plant in salinity stress induced at first leaf full expansion growth stage, and dry weight per plant in salinity stress induced at seedling emergence. A stable QTL for germination at both 150 and 300 mM salinity stress was mapped on chromosome 2H but distantly located from a QTL linked with seedling stage salinity stress tolerance. QTL, associated markers and genotypes identified in this study play important roles in developing salinity stress tolerant barley varieties. PMID- 28640857 TI - Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse. AB - : The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. CONCLUSION: Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents. PMID- 28640859 TI - Toxic effects of atrazine on porcine oocytes and possible mechanisms of action. AB - Because atrazine is a widely used herbicide, its adverse effects on the reproductive system have been extensively researched. In this study, we investigated the effects of atrazine exposure on porcine oocyte maturation and the possible mechanisms. Our results showed that the rates of oocyte maturation significantly decreased after treatment with 200 MUM atrazine in vitro. Atrazine treatment resulted in abnormal spindle morphology but did not affect actin distribution. Atrazine exposure not only triggered a DNA damage response but also decreased MPF levels in porcine oocytes. Our results also revealed that atrazine worsened porcine oocyte quality by causing excessive accumulation of superoxide radicals, increasing cathepsin B activity, and decreasing the GSH level and mitochondrial membrane potential. Furthermore, atrazine decreased developmental competence of porcine oocytes up to the blastocyst stage and changed some properties: cell numbers, apoptosis, and related gene expression levels. Collectively, our results indicate that porcine oocyte maturation is defective after atrazine treatment at least through disruption of spindle morphology, MPF activity, and mitochondrial function and via induction of DNA damage, which probably reduces developmental competence. PMID- 28640860 TI - The path to specialist multidisciplinary care in amyotrophic lateral sclerosis: A population- based study of consultations, interventions and costs. AB - BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological condition that requires coordinated, multidisciplinary clinical management. ALS is prone to misdiagnosis as its signs and symptoms may be non-specific, which may prolong patients' journey to multidisciplinary ALS care. METHODS: Using chart review and national register data, we have detailed the journey of a national cohort of ALS patients (n = 155) from the time of first symptom to presentation at a multidisciplinary clinic (MDC). Key milestones were analysed, including frequency of consultations, clinical interventions, and associated economic cost. RESULTS: A majority of patients was male (60%), 65 years of age and over (54%), and had spinal onset ALS (72%). Time from onset of first symptoms to ALS diagnosis was a mean of 15.1 months (median, 11). There was a mean interval of 17.4 months (median 12.5) from first symptoms to arrival at the MDC, and a mean of 4.09 (median, 4) consultations with health care professionals. Electromyography and nerve conduction studies were among the most common interventions. Direct referral by a general practitioner (GP) to a neurologist was associated with reduced cost, but not reduced diagnostic delay. Bulbar ALS was associated with shorter time from symptom onset to diagnosis. Neurologist consultation in the first three consultations was associated with lower costs prior to the ALS clinic attendance but not a shorter time from first symptom to final diagnosis. Mean cost prior to attending the MDC was ?3,486 per patient. CONCLUSIONS: Expedited referral to the multidisciplinary ALS clinic would have reduced costs by an estimated ?2,072 per patient. Development of a standardised pathway with early referral to neurology of patients with suspected symptoms of ALS could limit unnecessary interventions and reduce cost of care. PMID- 28640863 TI - Induced pluripotent stem cell-derived limbal epithelial cells (LiPSC) as a cellular alternative for in vitro ocular toxicity testing. AB - Induced pluripotent stem cells hold great potential to produce unlimited amount of differentiated cells as cellular source for regenerative medicine but also for in vitro drug screening and cytotoxicity tests. Ocular toxicity testing is mandatory to evaluate the risks of drugs and cosmetic products before their application to human patients by preventing eye irritation or insult. Since the global ban to use animals, many human-derived alternatives have been proposed, from ex-vivo enucleated postmortem cornea, primary corneal cell culture and immortalized corneal epithelial cell lines. All of them share limitations for their routine use. Using an improved protocol, we derived limbal epithelial cells from human induced pluripotent stem cells, named LiPSC, that are able to be passaged and differentiate further into corneal epithelial cells. Comparative RT qPCR, immunofluorescence staining, flow cytometry analysis and zymography assays demonstrate that LiPSC are morphologically and molecularly similar to the adult stem cells. Moreover, contrary to HCE, LiPSC and primary limbal cells display similarly sensitive to cytotoxicity treatment among passages. Our data strongly suggest that LiPSC could become a powerful alternative cellular model for cosmetic and drug tests. PMID- 28640861 TI - Inhibition of NF-kappaB improves the stress resistance and myogenic differentiation of MDSPCs isolated from naturally aged mice. AB - A decline in the regenerative capacity of adult stem cells with aging is well documented. As a result of this decline, the efficacy of autologous stem cell therapies is likely to decline with increasing donor age. In these cases, strategies to restore the function of aged stem cells would have clinical utility. Globally, the transcription factor NF-kappaB is up-regulated in aged tissues. Given the negative role that NF-kappaB plays in myogenesis, we investigated whether the age-related decline in the function of muscle-derived stem/progenitor cells (MDSPCs) could be improved by inhibition of NF-kappaB. Herein, we demonstrate that pharmacologic or genetic inhibition of NF-kappaB activation increases myogenic differentiation and improves resistance to oxidative stress. Our results suggest that MDSPC "aging" may be reversible, and that pharmacologic targeting of pathways such as NF-kappaB may enhance the efficacy of cell-based therapies. PMID- 28640862 TI - A biosystems approach to identify the molecular signaling mechanisms of TMEM30A during tumor migration. AB - Understanding the molecular mechanisms underlying cell migration, which plays an important role in tumor growth and progression, is critical for the development of novel tumor therapeutics. Overexpression of transmembrane protein 30A (TMEM30A) has been shown to initiate tumor cell migration, however, the molecular mechanisms through which this takes place have not yet been reported. Thus, we propose the integration of computational and experimental approaches by first predicting potential signaling networks regulated by TMEM30A using a) computational biology methods, b) our previous mass spectrometry results of the TMEM30A complex in mouse tissue, and c) a number of migration-related genes manually collected from the literature, and subsequently performing molecular biology experiments including the in vitro scratch assay and real-time quantitative polymerase chain reaction (qPCR) to validate the reliability of the predicted network. The results verify that the genes identified in the computational signaling network are indeed regulated by TMEM30A during cell migration, indicating the effectiveness of our proposed method and shedding light on the regulatory mechanisms underlying tumor migration, which facilitates the understanding of the molecular basis of tumor invasion. PMID- 28640864 TI - Targeting breast cancer cells by MRS1477, a positive allosteric modulator of TRPV1 channels. AB - There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells. This indicates that MCF7 cells not only express functional TRPV1 channels, but also produce endogenous TRPV1 agonists. We investigated the effects of MRS1477 and capsaicin on cell viability, caspase-3 and -9 activities and reactive oxygen species production in MCF7 cells. The fraction of apoptotic cells was increased after 3 days incubation with capsaicin (10 MUM) paralleled by increased reactive oxygen species production and caspase activity. These effects were even more pronounced, when cells were incubated with MRS1477 (2 MUM) either alone or together with CAPS (10 MUM). Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477. Whole-cell patch clamp recordings revealed that capsaicin-evoked TRPV1-mediated current density levels were increased after 3 days incubation with MRS1477 (2 MUM). However, the tumor growth in MCF7 tumor-bearing immunodeficient mice was not significantly decreased after treatment with MRS1477 (10 mg/ kg body weight, i.p., injection twice a week). In conclusion, in view of a putative in vivo treatment with MRS1477 or similar compounds further optimization is required. PMID- 28640865 TI - Association between suicide-related ideations and affective temperaments in the Japanese general adult population. AB - BACKGROUND: Suicide rates are vastly higher in Japan than in many other countries, although the associations between affective temperaments and suicide related ideations in the general adult population remain unclear. Therefore, we aimed to elucidate these associations in the present study. METHODS: We analyzed data from 638 Japanese volunteers who completed both the Patient Health Questionnaire (PHQ-9) and the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Auto-questionnaire (TEMPS-A). Participants were then divided into three groups based on PHQ-9 summary scores and responses to the suicide-related ideation item: non-depressive control group (NC; N = 469), depressive symptoms without suicide-related ideations group (non-SI; N = 135), and depressive symptoms with suicide-related ideations group (SI; N = 34). The depressive symptoms were defined for PHQ-9 summary scores >=5, and the suicide-related ideations were defined for PHQ-9 #9 score >=1. We then compared TEMPS-A scores among the groups using Kruskal-Wallis tests. Then the 95% confidence intervals of differences in TEMPS-A subscale scores between the NC and non-SI groups, or between NC and SI groups, were calculated. RESULTS: Participants of the SI group exhibited significantly higher scores on the depressive, irritable, and anxious temperament subscales than those of the non-SI group. Similarly, women of the SI group exhibited significantly higher scores of the depressive and irritable temperament subscales than women of the non-SI group, while men of the SI group exhibited significantly higher depressive temperament scores than those of the non-SI group. Among all participants and only men, cyclothymic subscale scores were higher in those of the SI group than the non-SI group (not significant), although the 95% confidence intervals did not overlap. LIMITATIONS: The cross sectional study design was the main limitation. CONCLUSIONS: Depressive, irritable, and anxious temperaments are significant risk factors for suicide related ideations in the Japanese general adult population. Furthermore, irritable temperament in women and depressive temperament in men are associated with suicide-related ideations. PMID- 28640867 TI - Correction: L-Ferritin Binding to Scara5: A New Iron Traffic Pathway Potentially Implicated in Retinopathy. AB - [This corrects the article DOI: 10.1371/journal.pone.0106974.]. PMID- 28640866 TI - Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest). AB - Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript (Mest), a paternally-expressed imprinted gene belonging to the alpha/beta-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated with adipose tissue expansion (ATE). To elucidate a role for MEST in ATE, mice were developed with global and adipose tissue inactivation of Mest. Mice with homozygous (MestgKO) and paternal allelic (MestpKO) inactivation of Mest were born at expected Mendelian frequencies, showed no behavioral or physical abnormalities, and did not perturb expression of the Mest locus-derived microRNA miR-335. MestpKO mice fed HFD showed reduced ATE and adipocyte hypertrophy, improved glucose tolerance, and reduced WAT expression of genes associated with hypoxia and inflammation compared to littermate controls. Remarkably, caloric intake and energy expenditure were unchanged between genotypes. Mice with adipose tissue inactivation of Mest were phenotypically similar to MestpKO, supporting a role for WAT MEST in ATE. Global profiling of WAT gene expression of HFD-fed control and MestpKO mice detected few differences between genotypes; nevertheless, genes with reduced expression in MestpKO mice were associated with immune processes and consistent with improved glucose homeostasis. Ear-derived mesenchymal stem cells (EMSC) from MestgKO mice showed no differences in adipogenic differentiation compared to control cells unless challenged by shRNA knockdown of Gpat4, an enzyme that mediates lipid accumulation in adipocytes. Reduced adipogenic capacity of EMSC from MestgKO after Gpat4 knockdown suggests that MEST facilitates lipid accumulation in adipocytes. Our data suggests that reduced diet induced ATE in MEST-deficient mice diminishes hypoxia and inflammation in WAT leading to improved glucose tolerance and insulin sensitivity. Since inactivation of Mest in mice has minimal additional effects aside from reduction of ATE, an intervention that mitigates MEST function in adipocytes is a plausible strategy to obviate obesity and type-2-diabetes. PMID- 28640868 TI - Functional metabolomics as a tool to analyze Mediator function and structure in plants. AB - Mediator is a multiprotein transcriptional co-regulator complex composed of four modules; Head, Middle, Tail, and Kinase. It conveys signals from promoter-bound transcriptional regulators to RNA polymerase II and thus plays an essential role in eukaryotic gene regulation. We describe subunit localization and activities of Mediator in Arabidopsis through metabolome and transcriptome analyses from a set of Mediator mutants. Functional metabolomic analysis based on the metabolite profiles of Mediator mutants using multivariate statistical analysis and heat-map visualization shows that different subunit mutants display distinct metabolite profiles, which cluster according to the reported localization of the corresponding subunits in yeast. Based on these results, we suggest localization of previously unassigned plant Mediator subunits to specific modules. We also describe novel roles for individual subunits in development, and demonstrate changes in gene expression patterns and specific metabolite levels in med18 and med25, which can explain their phenotypes. We find that med18 displays levels of phytoalexins normally found in wild type plants only after exposure to pathogens. Our results indicate that different Mediator subunits are involved in specific signaling pathways that control developmental processes and tolerance to pathogen infections. PMID- 28640869 TI - Development of an automated size-based filtration system for isolation of circulating tumor cells in lung cancer patients. AB - Circulating tumor cells (CTCs), defined as tumor cells circulating in the peripheral blood of patients with solid tumors, are relatively rare. Diagnosis using CTCs is expected to help in the decision-making for precision cancer medicine. We have developed an automated microcavity array (MCA) system to detect CTCs based on the differences in size and deformability between tumor cells and normal blood cells. Herein, we evaluated the system using blood samples from non small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients. To evaluate the recovery of CTCs, preclinical experiments were performed by spiking NSCLC cell lines (NCI-H820, A549, NCI-H23 and NCI-H441) into peripheral whole blood samples from healthy volunteers. The recovery rates were 70% or more in all cell lines. For clinical evaluation, 6 mL of peripheral blood was collected from 50 patients with advanced lung cancer and from 10 healthy donors. Cells recovered on the filter were stained. We defined CTCs as DAPI-positive, cytokeratin positive, and CD45-negative cells under the fluorescence microscope. The 50 lung cancer patients had a median age of 72 years (range, 48-85 years); 76% had NSCLC and 20% had SCLC, and 14% were at stage III disease whereas 86% were at stage IV. One or more CTCs were detected in 80% of the lung cancer patients (median 2.5). A comparison of the CellSearch system with our MCA system, using the samples from NSCLC patients, confirmed the superiority of our system (median CTC count, 0 versus 11 for CellSearch versus MCA; p = 0.0001, n = 17). The study results suggest that our MCA system has good clinical potential for diagnosing CTCs in lung cancer. PMID- 28640870 TI - Dominance of community-associated methicillin-resistant Staphylococcus aureus clones in a maternity hospital. AB - BACKGROUND: Methicillin- resistant Staphylococcus aureus (MRSA) is a major pathogen causing healthcare- and community- acquired infections. The purpose of this study was to characterize MRSA isolated at the Maternity Hospital between 2006 and 2011 for their genetic relatedness. MATERIALS AND METHODS: The MRSA isolates were investigated using a combination of antibiogram, Staphylococcal chromosome cassette mec (SCCmec) and spa typing to determine their relatedness to MRSA isolated in other Kuwait hospitals. The isolates were also investigated for the carriage of genes for Pantone valentine Leukocidin (PVL). RESULTS: A total of 103 MRSA obtained from 64 neonates, 17 adult patients and 12 healthcare workers. The isolates were resistant to Kanamycin (46.6%), gentamicin (40.8%), trimethoprim (32%), ciprofloxacin (22.3%), fusidic acid (16.5%), tetracycline (19.4%), erythromycin (15.5%), clindamycin (15.5%), streptomycin (11.6%) high level mupirocin (2.9%) and chloramphenicol (0.9%). Twenty (19.4%) of the isolates were multiresistant. Thirty-one (30.0%) isolates were positive for PVL. Molecular typing revealed the presence of 11 clonal complexes and 23 clones with ST5-V t002, (N = 22), ST22-IV-t223 (N = 18), ST22-IV-t852 (N = 10), ST80-IV-t044 (N = 7), ST5-V-t688 (N = 5), ST772-V-t657 (N = 5) and ST239-III-t860 (N = 4) constituting 66.9% of the isolates. Other clones were isolated sporadically. The number of MRSA isolates increased from two in 2006 to 22 in 2011 with a peak of 43 in 2008. CONCLUSION: The study revealed a high prevalence of community associated MRSA Maternity hospital. The MRSA population consisted of known strains, such as ST239-III-t680, ST22-IV-t223/t852 and ST80-IV-t044, that were reported previously in Kuwait and novel strains such as ST5-V-t002, and several sporadic strains obtained for the first time in the Maternity hospital. This study has provided an initial data which will serve as a platform for future comparative studies on the distribution of MRSA clones in the Maternity hospital in Kuwait. PMID- 28640872 TI - Correction: Management of chronic Hepatitis C at a primary health clinic in the high-burden context of Karachi, Pakistan. AB - [This corrects the article DOI: 10.1371/journal.pone.0175562.]. PMID- 28640871 TI - Nomogram to predict rectal toxicity following prostate cancer radiotherapy. AB - BACKGROUND: To identify predictors of acute and late rectal toxicity following prostate cancer radiotherapy (RT), while integrating the potential impact of RT technique, dose escalation, and moderate hypofractionation, thus enabling us to generate a nomogram for individual prediction. METHODS: In total, 972 patients underwent RT for localized prostate cancer, to a total dose of 70 Gy or 80 Gy, using two different fractionations (2 Gy or 2.5 Gy/day), by means of several RT techniques (3D conformal RT [3DCRT], intensity-modulated RT [IMRT], or image guided RT [IGRT]). Multivariate analyses were performed to identify predictors of acute and late rectal toxicity. A nomogram was generated based on the logistic regression model used to predict the 3-year rectal toxicity risk, with its accuracy assessed by dividing the cohort into training and validation subgroups. RESULTS: Mean follow-up for the entire cohort was 62 months, ranging from 6 to 235. The rate of acute Grade >=2 rectal toxicity was 22.2%, decreasing when combining IMRT and IGRT, compared to 3DCRT (RR = 0.4, 95%CI: 0.3-0.6, p<0.01). The 5-year Grade >=2 risks for rectal bleeding, urgency/tenesmus, diarrhea, and fecal incontinence were 9.9%, 4.5%, 2.8%, and 0.4%, respectively. The 3-year Grade >=2 risk for overall rectal toxicity increased with total dose (p<0.01, RR = 1.1, 95%CI: 1.0-1.1) and dose per fraction (2Gy vs. 2.5Gy) (p = 0.03, RR = 3.3, 95%CI: 1.1-10.0), and decreased when combining IMRT and IGRT (RR = 0.50, 95% CI: 0.3-0.8, p<0.01). Based on these three parameters, a nomogram was generated. CONCLUSIONS: Dose escalation and moderate hypofractionation increase late rectal toxicity. IMRT combined with IGRT markedly decreases acute and late rectal toxicity. Performing combined IMRT and IGRT can thus be envisaged for dose escalation and moderate hypofractionation. Our nomogram predicts the 3-year rectal toxicity risk by integrating total dose, fraction dose, and RT technique. PMID- 28640873 TI - Healthy aging of the left ventricle in relationship to cardiovascular risk factors: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Understanding the relationship of cardiovascular structure and function to age is confounded by the high prevalence of traditional risk factors in the United States. The purpose of the study is to compare left ventricular (LV) and aortic structural, and functional parameters in individuals with and without traditional risk factors in a population-based cohort. METHODS AND RESULTS: 3015 study participants (48% men, age 55-94, mean 69.01+/-9.17 years) in the Multi-Ethnic Study of Atherosclerosis (MESA) underwent cardiovascular magnetic resonance (CMR) imaging from 2010-2012. Absence of cardiovascular (CV) risk factors (no hypertension, diabetes or impaired fasting glucose, obesity, smoking or hypercholesterolemia) was infrequent, occurring in just 314 (10.4%, 38% men) of 3015 participants. In multivariable analyses adjusting for age, sex and race, individuals with CV risk factors had significantly larger LV mass index (by 17%) and lower LV contractibility (circumference strain, lower by 14%). Indexed LV volumes and stroke volume were inversely associated with age, but such relationships were not statistically significant in risk-free male subjects (p>0.05). Men with CV risk factors showed positive association of CMR T1 indices of myocardial fibrosis with age. Aortic function was similar in individuals with and without risk factors; age was associated with decline of aortic function in both CV and no CV risk factor groups. CONCLUSION: Our results support that LV structure and function are better preserved in senescent hearts in the absence of traditional cardiovascular risk factors, and such protection is more prominent in men than in women. PMID- 28640874 TI - Risk factors are different for deep and lobar remote hemorrhages after intravenous thrombolysis. AB - BACKGROUND AND PURPOSE: Remote parenchymal haemorrhage (rPH) after intravenous thrombolysis is defined as hemorrhages that appear in brain regions without visible ischemic damage, remote from the area of ischemia causing the initial stroke symptom. The pathophysiology of rPH is not clear and may be explained by different underlying mechanisms. We hypothesized that rPH may have different risk factors according to the bleeding location. We report the variables that we found associated with deep and lobar rPH after intravenous thrombolysis. METHODS: This is a descriptive study of patients with ischemic stroke who were treated with intravenous thrombolysis. These patients were included in a multicenter prospective registry. We collected demographic, clinical and radiological data. We evaluated the number and distribution of cerebral microbleeds (CMB) from Magnetic Resonance Imaging. We excluded patients treated endovascularly, patients with parenchymal hemorrhage without concomitant rPH and stroke mimics. We compared the variables from patients with deep or lobar rPH with those with no intracranial hemorrhage. RESULTS: We studied 934 patients (mean age 73.9+/-12.6 years) and 52.8% were men. We observed rPH in 34 patients (3.6%); 9 (0.9%) were deep and 25 (2.7%) lobar. No hemorrhage was observed in 900 (96.6%) patients. Deep rPH were associated with hypertensive episodes within first 24 hours after intravenous thrombolysis (77.7% vs 23.3%, p<0.001). Lobar rPH were associated with the presence of CMB (53.8% vs 7.9%, p<0.001), multiple (>1) CMB (30.7% vs 4.4%, p = 0.003), lobar CMB (53.8% vs 3.0%, p<0.001) and severe leukoaraiosis (76.9% vs 42%, p = 0.02). CONCLUSIONS: A high blood pressure within the first 24 hours after intravenous thrombolysis is associated with deep rPH, whereas lobar rPH are associated with imaging markers of amyloid deposition. Thus, our results suggest that deep and lobar rPH after intravenous thrombolysis may have different mechanisms. PMID- 28640875 TI - Percutaneous coronary intervention in left main coronary artery disease with or without intravascular ultrasound: A meta-analysis. AB - This meta-analysis compared IVUS-guided with angiography-guided PCI to determine the effect of IVUS on the mortality in patients with LM CAD. Current guidelines recommend intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) in patients with left main coronary artery disease (LM CAD; Class IIa, level of evidence B). A systematic search of the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases was conducted to identify randomized or non-randomized studies comparing IVUS-guided PCI with angiography-guided PCI in LM CAD. Ten studies (9 non-randomized and 1 randomized) with 6,480 patients were included. The primary outcome was mortality including all-cause death and cardiac death. Compared with angiography-guide PCI, IVUS guided PCI was associated with significantly lower risks of all-cause death (risk ratio [RR] 0.60, 95% confidence interval [CI] 0.47-0.75, p<0.001), cardiac death (RR 0.47, 95% CI 0.33-0.66, p<0.001), target lesion revascularization (RR 0.43, 95% CI 0.25-0.73, p = 0.002), and in-stent thrombosis (RR 0.28, 95% CI 0.12-0.67, p = 0.004). Subgroup analyses indicated the beneficial effect of IVUS-guide PCI was consistent across different types of studies (unadjusted non-randomized studies, propensity score-matched non-randomized studies, or randomized trial), study populations (Asian versus non-Asian), and lengths of follow-up (<3 years versus >=3 years). IVUS-guided PCI in LM CAD significantly reduced the risks of all-cause death by ~40% compared with conventional angiography-guided PCI. PROSPERO registration number: CRD 42017055134. PMID- 28640876 TI - Reliability and performance of commercial RNA and DNA extraction kits for FFPE tissue cores. AB - Cancer biomarker studies often require nucleic acid extraction from limited amounts of formalin-fixed, paraffin-embedded (FFPE) tissues, such as histologic sections or needle cores. A major challenge is low quantity and quality of extracted nucleic acids, which can limit our ability to perform genetic analyses, and have a significant influence on overall study design. This study was aimed at identifying the most reliable and reproducible method of obtaining sufficient high-quality nucleic acids from FFPE tissues. We compared the yield and quality of nucleic acids from 0.6-mm FFPE prostate tissue cores across 16 DNA and RNA extraction protocols, using 14 commercially available kits. Nucleic acid yield was determined by fluorometry, and quality was determined by spectrophotometry. All protocols yielded nucleic acids in quantities that are compatible with downstream molecular applications. However, the protocols varied widely in the quality of the extracted RNA and DNA. Four RNA and five DNA extraction protocols, including protocols from two kits for dual-extraction of RNA and DNA from the same tissue source, were prioritized for further quality assessment based on the yield and purity of their products. Specifically, their compatibility with downstream reactions was assessed using both NanoString nCounter gene expression assays and reverse-transcriptase real-time PCR for RNA, and methylation-specific PCR assays for DNA. The kit deemed most suitable for FFPE tissue was the AllPrep kit by Qiagen because of its yield, quality, and ability to purify both RNA and DNA from the same sample, which would be advantageous in biomarker studies. PMID- 28640877 TI - Identification of C/EBPalpha as a novel target of the HPV8 E6 protein regulating miR-203 in human keratinocytes. AB - Patients suffering from Epidermodysplasia verruciformis (EV), a rare inherited skin disease, display a particular susceptibility to persistent infection with cutaneous genus beta-human papillomavirus (beta-HPV), such as HPV type 8. They have a high risk to develop non-melanoma skin cancer at sun-exposed sites. In various models evidence is emerging that cutaneous HPV E6 proteins disturb epidermal homeostasis and support carcinogenesis, however, the underlying mechanisms are not fully understood as yet. In this study we demonstrate that microRNA-203 (miR-203), a key regulator of epidermal proliferation and differentiation, is strongly down-regulated in HPV8-positive EV-lesions. We provide evidence that CCAAT/enhancer-binding protein alpha (C/EBPalpha), a differentiation-regulating transcription factor and suppressor of UV-induced skin carcinogenesis, directly binds the miR-203 gene within its hairpin region and thereby induces miR-203 transcription. Our data further demonstrate that the HPV8 E6 protein significantly suppresses this novel C/EBPalpha/mir-203-pathway. As a consequence, the miR-203 target DeltaNp63alpha, a proliferation-inducing transcription factor, is up-regulated, while the differentiation factor involucrin is suppressed. HPV8 E6 specifically down-regulates C/EBPalpha but not C/EBPbeta expression at the transcriptional level. As shown in knock-down experiments, C/EBPalpha is regulated by the acetyltransferase p300, a well described target of cutaneous E6 proteins. Notably, p300 bound significantly less to the C/EBPalpha regulatory region in HPV8 E6 expressing keratinocytes than in control cells as demonstrated by chromatin immunoprecipitation. In situ analysis confirmed congruent suprabasal expression patterns of C/EBPalpha and miR-203 in non-lesional skin of EV-patients. In HPV8-positive EV-lesions both factors are potently down-regulated in vivo further supporting our in vitro data. In conclusion our study has unraveled a novel p300/C/EBPalpha/mir-203-dependent mechanism, by which the cutaneous HPV8 E6 protein may expand p63-positive cells in the epidermis of EV-patients and disturbs fundamental keratinocyte functions. This may drive HPV-mediated pathogenesis and may potentially also pave the way for skin carcinogenesis in EV-patients. PMID- 28640878 TI - Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy. AB - Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified new candidate adaptive loci that appear to have been directly modified by disease pressures given their significant associations with CAD genetic risk. These candidates were all uniquely and consistently associated with many different male and female reproductive traits suggesting selection may have also targeted these because of their direct effects on fitness. We found that CAD loci are significantly enriched for lifetime reproductive success relative to the rest of the human genome, with evidence that the relationship between CAD and lifetime reproductive success is antagonistic. This supports the presence of antagonistic-pleiotropic tradeoffs on CAD loci and provides a novel explanation for the maintenance and high prevalence of CAD in modern humans. Lastly, we found that positive selection more often targeted CAD gene regulatory variants using HapMap3 lymphoblastoid cell lines, which further highlights the unique biological significance of candidate adaptive loci underlying CAD. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD. PMID- 28640880 TI - Correction: Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients. AB - [This corrects the article DOI: 10.1371/journal.pone.0177503.]. PMID- 28640879 TI - Dual targeting of a virus movement protein to ER and plasma membrane subdomains is essential for plasmodesmata localization. AB - Plant virus movement proteins (MPs) localize to plasmodesmata (PD) to facilitate virus cell-to-cell movement. Numerous studies have suggested that MPs use a pathway either through the ER or through the plasma membrane (PM). Furthermore, recent studies reported that ER-PM contact sites and PM microdomains, which are subdomains found in the ER and PM, are involved in virus cell-to-cell movement. However, functional relationship of these subdomains in MP traffic to PD has not been described previously. We demonstrate here the intracellular trafficking of fig mosaic virus MP (MPFMV) using live cell imaging, focusing on its ER-directing signal peptide (SPFMV). Transiently expressed MPFMV was distributed predominantly in PD and patchy microdomains of the PM. Investigation of ER translocation efficiency revealed that SPFMV has quite low efficiency compared with SPs of well characterized plant proteins, calreticulin and CLAVATA3. An MPFMV mutant lacking SPFMV localized exclusively to the PM microdomains, whereas SP chimeras, in which the SP of MPFMV was replaced by an SP of calreticulin or CLAVATA3, localized exclusively to the nodes of the ER, which was labeled with Arabidopsis synaptotagmin 1, a major component of ER-PM contact sites. From these results, we speculated that the low translocation efficiency of SPFMV contributes to the generation of ER-translocated and the microdomain-localized populations, both of which are necessary for PD localization. Consistent with this hypothesis, SP deficient MPFMV became localized to PD when co-expressed with an SP chimera. Here we propose a new model for the intracellular trafficking of a viral MP. A substantial portion of MPFMV that fails to be translocated is transferred to the microdomains, whereas the remainder of MPFMV that is successfully translocated into the ER subsequently localizes to ER-PM contact sites and plays an important role in the entry of the microdomain-localized MPFMV into PD. PMID- 28640881 TI - T3SS effector VopL inhibits the host ROS response, promoting the intracellular survival of Vibrio parahaemolyticus. AB - The production of antimicrobial reactive oxygen species by the nicotinamide dinucleotide phosphate (NADPH) oxidase complex is an important mechanism for control of invading pathogens. Herein, we show that the gastrointestinal pathogen Vibrio parahaemolyticus counteracts reactive oxygen species (ROS) production using the Type III Secretion System 2 (T3SS2) effector VopL. In the absence of VopL, intracellular V. parahaemolyticus undergoes ROS-dependent filamentation, with concurrent limited growth. During infection, VopL assembles actin into non functional filaments resulting in a dysfunctional actin cytoskeleton that can no longer mediate the assembly of the NADPH oxidase at the cell membrane, thereby limiting ROS production. This is the first example of how a T3SS2 effector contributes to the intracellular survival of V. parahaemolyticus, supporting the establishment of a protective intracellular replicative niche. PMID- 28640882 TI - Quantitation of underivatized branched-chain amino acids in sport nutritional supplements by capillary electrophoresis with direct or indirect UV absorbance detection. AB - The branched-chain amino acids (BCAAs) including leucine (Leu), isoleucine (Ile) and valine (Val) play a pivotal role in the human body. Herein, we developed capillary electrophoresis (CE) coupled with conventional UV detector to quantify underivatized BCAAs in two kinds of sport nutritional supplements. For direct UV detection at 195 nm, the BCAAs (Leu, two enantiomers of Ile and Val) were separated in a background electrolyte (BGE) consisting of 40.0 mmol/L sodium tetraborate, and 40.0 mmol/L beta-cyclodextrin (beta-CD) at pH 10.2. In addition, the indirect UV detection at 264 nm was achieved in a BGE of 2.0 mmol/L Na2HPO4, 10.0 mmol/L p-aminosalicylic acid (PAS) as UV absorbing probe, and 40.0 mmol/L beta-CD at pH 12.2. The beta-CD significantly benefited the isomeric separation of Leu, L- and D-Ile. The optimal conditions allowed the LODs (limit of detections) of direct and indirect UV absorption detection to be tens MUmol/L level, which was comparable to the reported CE inline derivatization method. The RSDs (relative standard deviations) of migration time and peak area were less than 0.91% and 3.66% (n = 6). Finally, CE with indirect UV detection method was applied for the quantitation of BCAAs in two commercial sport nutritional supplements, and good recovery and precision were obtained. Such simple CE method without tedious derivatization process is feasible of quality control and efficacy evaluation of the supplemental proteins. PMID- 28640883 TI - An artificial EMG generation model based on signal-dependent noise and related application to motion classification. AB - This paper proposes an artificial electromyogram (EMG) signal generation model based on signal-dependent noise, which has been ignored in existing methods, by introducing the stochastic construction of the EMG signals. In the proposed model, an EMG signal variance value is first generated from a probability distribution with a shape determined by a commanded muscle force and signal dependent noise. Artificial EMG signals are then generated from the associated Gaussian distribution with a zero mean and the generated variance. This facilitates representation of artificial EMG signals with signal-dependent noise superimposed according to the muscle activation levels. The frequency characteristics of the EMG signals are also simulated via a shaping filter with parameters determined by an autoregressive model. An estimation method to determine EMG variance distribution using rectified and smoothed EMG signals, thereby allowing model parameter estimation with a small number of samples, is also incorporated in the proposed model. Moreover, the prediction of variance distribution with strong muscle contraction from EMG signals with low muscle contraction and related artificial EMG generation are also described. The results of experiments conducted, in which the reproduction capability of the proposed model was evaluated through comparison with measured EMG signals in terms of amplitude, frequency content, and EMG distribution demonstrate that the proposed model can reproduce the features of measured EMG signals. Further, utilizing the generated EMG signals as training data for a neural network resulted in the classification of upper limb motion with a higher precision than by learning from only measured EMG signals. This indicates that the proposed model is also applicable to motion classification. PMID- 28640884 TI - Human lagochilascariasis-A rare helminthic disease. AB - Lagochilascariasis is a parasitic disease caused by a helminth of the order Ascaroidea, genus Lagochilascaris that comprises 6 species, among which only Lagochilascaris minor Leiper, 1909, is implicated in the human form of the disease. It is remarkable that the majority of cases of human lagochilascariasis in the Americas have been reported in Brazil. The natural definitive hosts of this parasite seem to be wild felines and canines. Lagochilascariasis is mostly a chronic human disease that can persist for several years, in which the parasite burrows into the subcutaneous tissues of the neck, paranasal sinuses, and mastoid. L. minor exhibits remarkable ability to migrate through the tissues of its hosts, destroying even bone tissue. Fatal cases have been described in which the parasite was found in the lungs or central nervous system. Treatment is often palliative, with recurrence of lesions. This paper summarizes the main features of the disease and its etiologic agent, including prevalence, life cycle, clinical course, and treatment. PMID- 28640885 TI - Phylogeography of a tough rock survivor in European dry grasslands. AB - Phylogeographic analyses of plants in Europe have revealed common glacial refugia and migration routes for several trees and herbs with arctic-alpine distributions. The postglacial histories of dry grassland species in central Europe have rarely been analyzed, even though the extremely species-rich habitat is threatened. Sedum album (Crassulaceae) is a common inhabitant of rocky sites in central European dry grasslands. We inferred the phylogeographic history of S. album over its distribution range in Europe. Genetic diversity within and differentiation between 34 S. album populations was examined using AFLP markers. Population isolation was indicated based on the rarity of the fragments and by isolation-by-distance effects. We sequenced the trnL-trnF region in 32 populations and used chloroplast microsatellites to analyze chloroplast haplotype distributions. Two distinct S. album lineages were detected. One lineage was comprised of populations from eastern and central parts of central Europe, and the Apennine Peninsula. A second lineage was comprised of populations from the Iberian Peninsula and western and northern parts of central Europe. Glacial refugia were identified based on the accumulation of ancient chloroplast haplotypes, high diversity of AFLP fragments within populations, and high levels of rare fragments in Liguria, Serbia, the Apennine and Iberian peninsulas. Cryptic refugia were detected in the Czech Republic and Slovakia. Isolation by distance was present all over the distribution range, and it was separately detected in southwestern and central Europe. In western Europe, where a contact zone between the two lineages can be expected, no isolation by distance was detected. Our results suggest migration routes of S. album northeastward from glacial refugia in southern Iberia, northward from the Apennine Peninsula, and northward and westward from the southeastern parts of central Europe. Therefore, central European grasslands were recently colonized by northern cryptic populations and source populations originating in the east and the Apennine Peninsula. PMID- 28640886 TI - Epigenomic diversification within the genus Lupinus. AB - Deciphering the various chemical modifications of both DNA and the histone compound of chromatin not only leads to a better understanding of the genome-wide organisation of epigenetic landmarks and their impact on gene expression but may also provide some insights into the evolutionary processes. Although both histone modifications and DNA methylation have been widely investigated in various plant genomes, here we present the first study for the genus Lupinus. Lupins, which are members of grain legumes (pulses), are beneficial for food security, nutrition, health and the environment. In order to gain a better understanding of the epigenetic organisation of genomes in lupins we applied the immunostaining of methylated histone H3 and DNA methylation as well as whole-genome bisulfite sequencing. We revealed variations in the patterns of chromatin modifications at the chromosomal level among three crop lupins, i.e. L. angustifolius (2n = 40), L. albus (2n = 50) and L. luteus (2n = 52), and the legume model plant Medicago truncatula (2n = 16). Different chromosomal patterns were found depending on the specific modification, e.g. H3K4me2 was localised in the terminal parts of L. angustifolius and M. truncatula chromosomes, which is in agreement with the results that have been obtained for other species. Interestingly, in L. albus and L. luteus this modification was limited to one arm in the case of all of the chromosomes in the complement. Additionally, H3K9me2 was detected in all of the analysed species except L. luteus. DNA methylation sequencing (CG, CHG and CHH contexts) of aforementioned crop but also wild lupins such as L. cosentinii (2n = 32), L. digitatus (2n = 36), L. micranthus (2n = 52) and L. pilosus (2n = 42) supported the range of interspecific diversity. The examples of epigenetic modifications illustrate the diversity of lupin genomes and could be helpful for elucidating further epigenetic changes in the evolution of the lupin genome. PMID- 28640887 TI - Epidermal growth factor promotes cyclin G2 degradation via calpain-mediated proteolysis in gynaecological cancer cells. AB - Cyclin G2 (CCNG2) is an atypical cyclin that functions to inhibit cell cycle progression and is often dysregulated in human cancers. We have previously shown that cyclin G2 is highly unstable and can be degraded through the ubiquitin/proteasome pathway. Furthermore, cyclin G2 contains a PEST domain, which has been suggested to act as a signal for degradation by multiple proteases. In this study, we determined if calpains, a family of calcium dependent proteases, are also involved in cyclin G2 degradation. The addition of calpain inhibitors or silencing of calpain expression by siRNAs strongly enhanced cyclin G2 levels. On the other hand, incubation of cell lysates with purified calpains or increasing the intracellular calcium concentration resulted in a decrease in cyclin G2 levels. Interestingly, the effect of calpain was found to be dependent on the phosphorylation of cyclin G2. Using a kinase inhibitor library, we found that Epidermal Growth Factor (EGF) Receptor is involved in cyclin G2 degradation and treatment with its ligand, EGF, induced cyclin G2 degradation. In addition, the presence of the PEST domain is necessary for calpain and EGF action. When the PEST domain was completely removed, calpain or EGF treatment failed to trigger degradation of cyclin G2. Taken together, these novel findings demonstrate that EGF-induced, calpain-mediated proteolysis contributes to the rapid destruction of cyclin G2 and that the PEST domain is critical for EGF/calpain actions. PMID- 28640888 TI - Mechanisms of acute neurovascular protection with AT1 blockade after stroke: Effect of prestroke hypertension. AB - Stroke is a leading cause of adult disability worldwide. Improving stroke outcome requires an orchestrated interplay that involves up regulation of pro-survival pathways and a concomitant suppression of pro-apoptotic mediators. In this investigation, we assessed the involvement of eNOS in the AT1 blocker-mediated protective and pro-recovery effects in animals with hypertension. We also evaluated the effect of acute eNOS inhibition in hypertensive animals. To achieve these goals, spontaneously hypertensive rats (SHR) were implanted with blood pressure transmitters, and randomized to receive either an eNOS inhibitor (L-NIO) or saline one hour before cerebral ischemia induction. After 3 hours of ischemia, animals were further randomized to receive either candesartan or saline at the time of reperfusion and sacrificed either 24 hours or 7 days later. Candesartan induced an early protective effect that was independent of eNOS inhibition (50% improvement in motor function). However, the protective effect of candesartan was associated with about five fold up regulation of BDNF expression and about three fold reduction in ER stress markers, in an eNOS dependent manner. The early benefit of a single dose of candesartan, present at 24 hours after stroke, was diminished at 7 days, perhaps due to a failure to induce an angiogenic response in these hypertensive animals. In conclusion, our findings demonstrate an early prorecovery effect of candesartan at both functional and molecular levels. Candesartan induced prorecovery signaling was mediated through eNOS. This effect was not maintained at 7 days after experimental ischemia. PMID- 28640890 TI - Systematic review and meta-analysis of initial management of pneumothorax in adults: Intercostal tube drainage versus other invasive methods. AB - OBJECTIVES: The ideal invasive management as initial approach for pneumothorax (PTX) is still under debate. The purpose of this systematic review and meta analysis was to examine the evidence for the effectiveness of intercostal tube drainage and other various invasive methods as the initial approach to all subtypes of PTX in adults. METHODS: Three databases were searched from inception to May 29, 2016: MEDLINE, EMBASE, and the Cochrane CENTRAL. Randomised controlled trials that evaluated intercostal tube drainage as the control and various invasive methods as the intervention for the initial approach to PTX in adults were included. The primary outcome was the early success rate of each method, and the risk ratios (RRs) were used for an effect size measure. The secondary outcomes were recurrence rate, hospitalization rate, hospital stay, and complications. RESULTS: Seven studies met our inclusion criteria. Interventions were aspiration in six studies and catheterization connected to a one-way valve in one study. Meta-analyses were conducted for early success rate, recurrence rate, hospitalization rate, and hospital stay. Aspiration was inferior to intercostal tube drainage in terms of early success rate (RR = 0.82, confidence interval [CI] = 0.72 to 0.95, I2 = 0%). While aspiration and intercostal tube drainage showed no significant difference in the recurrence rate (RR = 0.84, CI = 0.57 to 1.23, I2 = 0%), aspiration had shorter hospital stay than intercostal tube drainage (mean difference = -1.73, CI = -2.33 to -1.13, I2 = 0%). Aspiration had lower hospitalization rate than intercostal tube drainage, but marked heterogeneity was present (RR = 0.38, CI = 0.19 to 0.76, I2 = 85%). CONCLUSION: Aspiration was inferior to intercostal tube drainage in terms of early resolution, but it had shorter hospital stay. The recurrence rate of aspiration and intercostal tube drainage did not differ significantly. The efficacy of catheterization connected to a one-way valve was inconclusive because of the small number of relevant studies. (Registration of study protocol: PROSPERO, CRD42016037866). PMID- 28640889 TI - Contrasting academic and lay press print coverage of the 2013-2016 Ebola Virus Disease outbreak. AB - Under a traditional paradigm, only those with the expected background knowledge consume academic literature. The lay press, as well as government and non government agencies, play a complementary role of extracting findings of high interest or importance and translating them for general viewing. The need for accurate reporting and public advising is paramount when attempting to tackle epidemic outbreaks through behavior change. Yet, public trust in media outlets is at a historic low. The Crisis and Emergency Risk Communication (CERC) model for media reporting on public health emergencies was established in 2005 and has subsequently been used to analyze media reporting on outbreaks of influenza and measles as well as smoking habits and medication compliance. However, no media analysis had yet been performed on the 2013-2016 Ebola Virus Disease (EVD) outbreak. This study compared the EVD information relayed by lay press sources with general review articles in the academic literature through a mixed-methods analysis. These findings suggest that comprehensive review articles could not serve as a source to clarify and contextualize the uncertainties around the EVD outbreak, perhaps due to adherence to technical accuracy at the expense of clarity within the context of outbreak conditions. This finding does not imply inferiority of the academic literature, nor does it draw direct causation between confusion in review articles and public misunderstanding. Given the erosion of the barriers siloing academia, combined with the demands of today's fast-paced media environment, contemporary researchers should realize that no study is outside the public forum and to therefore consider shifting the paradigm to take personal responsibility in the process of accurately translating their scientific words into public policy actions to best serve as a source of clarity. PMID- 28640892 TI - Novel resistance to Cydia pomonella granulovirus (CpGV) in codling moth shows autosomal and dominant inheritance and confers cross-resistance to different CpGV genome groups. AB - Commercial Cydia pomonella granulovirus (CpGV) products have been successfully applied to control codling moth (CM) in organic and integrated fruit production for more than 30 years. Since 2005, resistance against the widely used isolate CpGV-M has been reported from different countries in Europe. The inheritance of this so-called type I resistance is dominant and linked to the Z chromosome. Recently, a second form (type II) of CpGV resistance in CM was reported from a field population (NRW-WE) in Germany. Type II resistance confers reduced susceptibility not only to CpGV-M but to most known CpGV isolates and it does not follow the previously described Z-linked inheritance of type I resistance. To further analyze type II resistance, two CM strains, termed CpR5M and CpR5S, were generated from parental NRW-WE by repeated mass crosses and selection using the two isolates CpGV-M and CpGV-S, respectively. Both CpR5M and CpR5S were considered to be genetically homogeneous for the presence of the resistance allele(s). By crossing and backcrossing experiments with a susceptible CM strain, followed by resistance testing of the offspring, an autosomal dominant inheritance of resistance was elucidated. In addition, cross-resistance to CpGV-M and CpGV-S was detected in both strains, CpR5M and CpR5S. To test the hypothesis that the autosomal inheritance of type II resistance was caused by a large interchromosomal rearrangement involving the Z chromosome, making type I resistance appear to be autosomal in these strains; fluorescence in situ hybridization with bacterial artificial chromosome probes (BAC-FISH) was used to physically map the Z chromosomes of different CM strains. Conserved synteny of the Z-linked genes in CpR5M and other CM strains rejects this hypothesis and argues for a novel genetic and functional mode of resistance in CM populations with type II resistance. PMID- 28640891 TI - Baculoviral delivery of CRISPR/Cas9 facilitates efficient genome editing in human cells. AB - The CRISPR/Cas9 system is a highly effective tool for genome editing. Key to robust genome editing is the efficient delivery of the CRISPR/Cas9 machinery. Viral delivery systems are efficient vehicles for the transduction of foreign genes but commonly used viral vectors suffer from a limited capacity in the genetic information they can carry. Baculovirus however is capable of carrying large exogenous DNA fragments. Here we investigate the use of baculoviral vectors as a delivery vehicle for CRISPR/Cas9 based genome-editing tools. We demonstrate transduction of a panel of cell lines with Cas9 and an sgRNA sequence, which results in efficient knockout of all four targeted subunits of the chromosomal passenger complex (CPC). We further show that introduction of a homology directed repair template into the same CRISPR/Cas9 baculovirus facilitates introduction of specific point mutations and endogenous gene tags. Tagging of the CPC recruitment factor Haspin with the fluorescent reporter YFP allowed us to study its native localization as well as recruitment to the cohesin subunit Pds5B. PMID- 28640893 TI - Oroxylin A promotes retinal ganglion cell survival in a rat optic nerve crush model. AB - PURPOSE: To investigate the effect of oroxylin A on the survival of retinal ganglion cells (RGC) and the activation of microglial cells in a rat optic nerve (ON) crush model. METHODS: Oroxylin A (15mg/Kg in 0.2ml phosphate-buffered saline) or phosphate-buffered saline (PBS control) was immediately administered after ON crush once by subcutaneous injection. Rats were euthanized at 2 weeks after the crush injury. The density of RGC was counted by retrograde labeling with FluoroGold and immunostaining of retina flat mounts for Brn3a. Electrophysiological visual function was assessed by flash visual evoked potentials (FVEP). TUNEL assay, immunoblotting analysis of glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in the retinas, and immunohistochemistry of GFAP in the retinas and ED1 in the ON were evaluated. RESULTS: Two weeks after the insult, the oroxylin A treated group had significantly higher FG labeled cells and Brn3a+ cells suggesting preserved RGC density in the central and mid-peripheral retinas compared with those of the PBS-treated group. FVEP measurements showed a significantly better preserved latency of the P1 wave in the ON-crushed, oroxylin A-treated rats than the ON-crushed, PBS treated rats. TUNEL assays showed fewer TUNEL positive cells in the ON-crushed, oroxylin A-treated rats. The number of ED1 positive cells was reduced at the lesion site of the optic nerve in the ON crushed, oroxylin A-treated group. Increased GFAP expression in the retina was reduced greatly in ON-crushed, oroxylin A-treated group. Furthermore, administration of oroxylin A significantly attenuated ON crush insult-induced iNOS and COX-2 expression in the retinas. CONCLUSIONS: These results demonstrated that oroxylin A hasss neuroprotective effects on RGC survival with preserved visual function and a decrease in microglial infiltration in the ONs after ON crush injury. PMID- 28640894 TI - Characterization and analysis of long non-coding rna (lncRNA) in In Vitro- and Ex Vivo-derived cardiac progenitor cells. AB - Recent advancements in cell-based therapies for the treatment of cardiovascular disease (CVD) show continuing promise for the use of transplanted stem and cardiac progenitor cells (CPCs) to promote cardiac restitution. However, a detailed understanding of the molecular mechanisms that control the development of these cells remains incomplete and is critical for optimizing their use in such therapy. Long non-coding (lnc) RNA has recently emerged as a crucial class of regulatory molecules involved in directing a variety of critical biological processes including development, homeostasis and disease. As such, a rising body of evidence suggests that they also play key regulatory roles in CPC development, though many questions remain regarding the expression landscape and specific identity of lncRNA involved in this process. To address this, we performed whole transcriptome sequencing of two murine CPC populations-Nkx2-5 EmGFP reporter sorted embryonic stem (ES) cell-derived and ex vivo, cardiosphere-derived-in an effort to characterize their lncRNA profiles and potentially identify novel CPC regulators. The resulting sequencing data revealed an enrichment in both CPC populations for a panel of previously-identified lncRNA genes associated with cardiac differentiation. Additionally, a total of 1,678 differentially expressed and as-of-yet unannotated, putative lncRNA genes were found to be enriched for in the two CPC populations relative to undifferentiated ES cells. PMID- 28640895 TI - The interplay of climate, intervention and imported cases as determinants of the 2014 dengue outbreak in Guangzhou. AB - Dengue is a fast spreading mosquito-borne disease that affects more than half of the population worldwide. An unprecedented outbreak happened in Guangzhou, China in 2014, which contributed 52 percent of all dengue cases that occurred in mainland China between 1990 and 2015. Our previous analysis, based on a deterministic model, concluded that the early timing of the first imported case that triggered local transmission and the excessive rainfall thereafter were the most important determinants of the large final epidemic size in 2014. However, the deterministic model did not allow us to explore the driving force of the early local transmission. Here, we expand the model to include stochastic elements and calculate the successful invasion rate of cases that entered Guangzhou at different times under different climate and intervention scenarios. The conclusion is that the higher number of imported cases in May and June was responsible for the early outbreak instead of climate. Although the excessive rainfall in 2014 did increase the success rate, this effect was offset by the low initial water level caused by interventions in late 2013. The success rate is strongly dependent on mosquito abundance during the recovery period of the imported case, since the first step of a successful invasion is infecting at least one local mosquito. The average final epidemic size of successful invasion decreases exponentially with introduction time, which means if an imported case in early summer initiates the infection process, the final number infected can be extremely large. Therefore, dengue outbreaks occurring in Thailand, Singapore, Malaysia and Vietnam in early summer merit greater attention, since the travel volumes between Guangzhou and these countries are large. As the climate changes, destroying mosquito breeding sites in Guangzhou can mitigate the detrimental effects of the probable increase in rainfall in spring and summer. PMID- 28640896 TI - Beneficial effects of a gait used while wearing a kimono to decrease the knee adduction moment in healthy adults. AB - The knee adduction moment (KAM) relates to medial knee osteoarthritis (OA). Several gait modifications to reduce the KAM for the prevention of knee OA have been studied. Most of the modifications, however, involve voluntary changes in leg alignment. Here we investigated the biomechanical effects for reducing the KAM of a walking style with a small trunk rotation and arm swing gait, which is a natural walking style used while wearing a kimono (Nanba walk) that shifts the ground reaction force toward the stance leg (reduced lever arm). Twenty-nine healthy adults (21.5 +/- 0.6 years) participated in the present study. A three dimensional analysis system with 10 cameras and 1 force plate was used to obtain the KAM and other biomechanical data. Surface electromyography (EMG) of the hip and trunk muscles (internal obliquus abdominal muscle: IO, external obliquus abdominal muscle: EO, multifidus muscle: MF, and gluteus medius muscle: Gmed) was also assessed, and integrated EMG (iEMG) of the four muscles was assessed in the first and second halves of the stance phase. The 1st and 2nd peak KAMs were significantly decreased during Nanba walking (0.40+/-0.09 and 0.37+/-0.13 Nm/kg) compared with normal walking (0.45+/-0.09 and 0.45+/-0.13 Nm/kg; P = 0.002, P<0.001, respectively). The lever arm lengths at the 1st and 2nd peak KAMs were also significantly decreased during Nanba walking compared with normal walking (p = 0.023 and p<0.001, respectively). The iEMGs of IO, EO and Gmed muscles during the first half, and the iEMGs of EO and GM during the second half of the stance phase were significantly increased during Nanba walking compared with normal walking. The Nanba gait modification could be a useful strategy for reducing the KAM with high activation of the trunk and hip joint muscles for the prevention and/or treatment of medial knee OA. PMID- 28640897 TI - Impact of selected non-steroidal anti-inflammatory pharmaceuticals on microbial community assembly and activity in sequencing batch reactors. AB - This study covers three widely detected non-steroidal anti-inflammatory pharmaceuticals (NSAIDs), diclofenac (DCF), ibuprofen (IBP) and naproxen (NPX), as NSAIDs pollutants. The objective is to evaluate the impact of NSAIDs at their environmental concentrations on microbial community assembly and activity. The exposure experiments were conducted under three conditions (5 MUg L-1 DCF, 5 MUg L-1 DCF+5 MUg L-1 IBP and 5 MUg L-1 DCF+5 MUg L-1 IBP+ 5 MUg L-1 NPX) in sequencing batch reactors (SBRs) for 130 days. Removals of COD and NH4+-N were not affected but total nitrogen (TN) removal decreased. IBP and NPX had the high removal efficiencies (79.96% to 85.64%), whereas DCF was more persistent (57.24% to 64.12%). In addition, the decreased removals of TN remained the same under the three conditions (p > 0.05). The results of oxidizing enzyme activities, live cell percentages and extracellular polymeric substances (EPS) indicated that NSAIDs damaged the cell walls or microorganisms and the mixtures of the three NSAIDs increased the toxicity. The increased Shannon-Wiener diversity index suggested that bacterial diversity was increased with the addition of selected NSAIDs. Bacterial ribosomal RNA small subunit (16S) gene sequencing results indicated that Actinobacteria and Bacteroidetes were enriched, while Micropruina and Nakamurella decreased with the addition of NSAIDs. The enrichment of Actinobacteria and Bacteroidetes indicated that both of them might have the ability to degrade NSAIDs and thereby could adapt well with the presence of NSAIDs. PMID- 28640898 TI - Competition between influenza A virus subtypes through heterosubtypic immunity modulates re-infection and antibody dynamics in the mallard duck. AB - Our overall hypothesis is that host population immunity directed at multiple antigens will influence the prevalence, diversity and evolution of influenza A virus (IAV) in avian populations where the vast subtype diversity is maintained. To investigate how initial infection influences the outcome of later infections with homologous or heterologous IAV subtypes and how viruses interact through host immune responses, we carried out experimental infections in mallard ducks (Anas platyrhynchos). Mallards were pre-challenged with an H3N8 low-pathogenic IAV and were divided into six groups. At five weeks post H3N8 inoculation, each group was challenged with a different IAV subtype (H4N5, H10N7, H6N2, H12N5) or the same H3N8. Two additional pre-challenged groups were inoculated with the homologous H3N8 virus at weeks 11 and 15 after pre-challenge to evaluate the duration of protection. The results showed that mallards were still resistant to re-infection after 15 weeks. There was a significant reduction in shedding for all pre-challenged groups compared to controls and the outcome of the heterologous challenges varied according to hemagglutinin (HA) phylogenetic relatedness between the viruses used. There was a boost in the H3 antibody titer after re-infection with H4N5, which is consistent with original antigenic sin or antigenic seniority and suggest a putative strategy of virus evasion. These results imply competition between related subtypes that could regulate IAV subtype population dynamics in nature. Collectively, we provide new insights into within-host IAV complex interactions as drivers of IAV antigenic diversity that could allow the circulation of multiple subtypes in wild ducks. PMID- 28640899 TI - Normative 3D opto-electronic stereo-photogrammetric posture and spine morphology data in young healthy adult population. AB - DESIGN: Observational cross-sectional study. The current study aims to yield normative data: i.e., the physiological standard for 30 selected quantitative 3D parameters that accurately capture and describe a full-skeleton, upright-standing attitude. Specific and exclusive consideration was given to three distinct categories: postural, spine morphology and pelvic parameters. To capture such 3D parameters, the authors selected a non-ionising 3D opto-electronic stereo photogrammetric approach. This required the identification and measurement of 27 body landmarks, each specifically tagged with a skin marker. As subjects for the measurement of these parameters, a cohort of 124 asymptomatic young adult volunteers was recruited. All parameters were identified and measured within this group. Postural and spine morphology data have been compared between genders. In this regard, only five statistically significant differences were found: pelvis width, pelvis torsion, the "lumbar" lordosis angle value, the lumbar curve length, and the T12-L5 anatomically-bound lumbar angle value. The "thoracic" kyphosis mean angle value was the same in both sexes and, even if, derived from skin markers placed on spinous processes it resulted in perfect agreement with the X-ray based literature. As regards lordosis, a direct comparison was more difficult because methods proposed in the literature differ as to the number and position of vertebrae under consideration, and their related angle values. However, when the L1 superior-L5 inferior end plate Cobb angle was considered, these results aligned strongly with the existing literature. Asymmetry was a standard postural-spinal feature for both sexes. Each subject presented some degree of leg length discrepancy (LLD) with MU = 9.37mm. This was associated with four factors: unbalanced posture and/or underfoot loads, spinal curvature in the frontal plane, and pelvis torsion. This led to the additional study of the effect of LLD equalisation influence on upright posture, relying on a sub-sample of 100 subjects (51 males, 49 females). As a result of the equalisation, about 82% of this sub-sample showed improvement in standing posture, mainly in the frontal plane; while in the sagittal plane less than 1/3 of the sub-sample showed evidence of change in spinal angles. A significant variation was found in relation to pelvis torsion: 46% of subjects showed improvement, 49% worsening. The method described in study presents several advantages: non-invasive aspect; relatively short time for a complete postural evaluation with many clinically useful 3D and 2D anatomical/biomechanical/clinical parameters; analysis of real neutral unconstrained upright standing posture. PMID- 28640900 TI - Predictors of exclusive breastfeeding and consumption of soft, semi-solid or solid food among infants in Boucle du Mouhoun, Burkina Faso: A cross-sectional survey. AB - INTRODUCTION: Exclusive breastfeeding is among the most effective interventions for preventing child mortality. The objectives of this paper are to describe infant feeding knowledge and practices in Boucle du Mouhoun, Burkina Faso; to identify predictors of exclusive breastfeeding among infants <6 months, and consumption of soft, semi-solid or solid food among infants 6-11 months; to describe mothers' sources of information regarding breastfeeding. METHODS: A cross-sectional survey (n = 2288) of a representative sample of women aged 15-49 years with at least one live birth in past year took place during June and July 2015. Crude and multivariable random-effects logistic regressions were used to identify factors predictive of exclusive breastfeeding and consumption of soft, semi-solid or solid food. RESULTS: 30% of infants <6 months were exclusively breastfed; 67% of infants age 6-11 months consumed soft, semi-solid or solid food the day and night before the interview. 2% of infants age 6-11 months had a minimum acceptable diet. There was strong evidence of a positive association between knowledge and practice of exclusive breastfeeding, nonetheless 60% of mothers who correctly identified that an infant should be exclusively breastfed for 6 months did not breastfeed their infant exclusively. Only 42% of mothers reported receiving advice on breastfeeding from a health worker, despite all mothers having contact with a health worker at least once during pregnancy or postpartum. CONCLUSION: Given poor practices and low levels of knowledge, targeted interventions are needed to improve infant nutrition in Boucle du Mouhoun during antenatal, delivery and postnatal care. Most women now deliver in a facility in Burkina Faso; increased attention should be paid to ensuring that existing guidelines relating to support and counselling for infant feeding are adhered to. Factors such as social norms are also important and these should be investigated in more detail using qualitative methods. PMID- 28640901 TI - MRSA infections in Norway: A study of the temporal evolution, 2006-2015. AB - BACKGROUND: Norway has one of the lowest prevalences of methicillin-resistant Staphylococcus aureus (MRSA) infections in the world. This study exploits the extensive data on MRSA infections in the Norwegian surveillance system to investigate the important factors defining the MRSA epidemiology. METHODS: We performed a quasi-Poisson regression of the monthly notification rate (NR) of MRSA infections reported from January 2006 to December 2015, comparing the time trend among people with an immigrant vs. Norwegian background and domestic vs. imported infections, stratified by age groups. FINDINGS: A total of 5289 MRSA infections were reported during the study period, of which 2255 (42.6%) were acquired in Norway, 1370 (25.9%) abroad, and 1664 (31.5%) with an unknown place of acquisition. Overall, the monthly NR increased significantly from 2006 to 2015 (+0.8% each month). The monthly increase in immigrants (+1.3%) was steeper than that in people with a Norwegian background (+0.6%). There was a significant growth (+0.4%) in the rate of domestically acquired infections, however, the NR of infections acquired abroad increased faster (+0.8%). For both imported and domestic infections, the increase occurred in persons aged < 70 years. INTERPRETATION: Our analysis suggests that immigration and importation, especially among persons aged < 40 years, represent important factors for the increasing notification rate of MRSA infections in Norway. PMID- 28640902 TI - Hepatitis B virus reactivation and antiviral prophylaxis during lung cancer chemotherapy: A systematic review and meta-analysis. AB - BACKGROUND: Antiviral drugs have been recommended as prophylaxis for the reactivation of hepatitis B virus (HBV) infection in cancer patients undergoing chemotherapy. However, screening and antiviral prophylaxis for lung cancer remain controversial because of insufficient evidence. PURPOSE: In this study, we investigate the absolute risk for HBV reactivation and the prophylactic effects of antiviral drugs in hepatitis B surface antigen (HBsAg)-positive lung cancer patients during chemotherapy. METHODS: We searched Pubmed, Embase, Cochrane, Web of Science and SinoMed from inception until 28 November 2016, and identified all potential relevant references with or without prophylactic use of antiviral therapy in HBsAg-positive lung cancer patients during chemotherapy. The primary outcome was the incidence of HBV reactivation, the secondary outcomes were the incidence of hepatitis, chemotherapy disruption and mortality. RESULTS: Eleven studies involving 794 patients were analyzed. The incidences of HBV reactivation in control group and antiviral prophylaxis group ranged from 0% to 38% (median, 21%, 95% CI: 0.17-0.25) and 0% to 7% (median, 4%, 95% CI: 0.02-0.06), respectively. Antiviral prophylaxis had significantly reduced the risk for HBV reactivation (RR, 0.22 [95% CI: 0.13-0.37], p< 0.0001), hepatitis (RR, 0.35 [95% CI: 0.22-0.56], p<0.0001) and chemotherapy disruption (RR: 0.29 [95% CI, 0.15 0.55], p<0.0002) compared to those without antiviral prophylaxis. There was no significant heterogeneity in the comparisons, and a fixed-model was used. CONCLUSION: The risks of HBV reactivation and relevant complications are high in HBsAg-positive lung cancer patients receiving chemotherapy, and available evidences support HBV screening for antiviral prophylaxis before initiation of chemotherapy for lung cancer patients. PMID- 28640903 TI - Type 2B von Willebrand disease with or without large multimers: A distinction of the two sides of the disorder is long overdue. AB - Most, but not all patients with type 2B von Willebrand disease (VWD)-which features gain-of-function mutations in the A1 domain of von Willebrand factor (VWF)-have no circulating large VWF multimers. Similarities and differences were analysed in 33 type 2B patients, 12 with a normal and 21 with an abnormal multimer pattern, to see whether they should be considered separately. The minimum aggregating dose of ristocetin was similarly reduced in both patient groups, and modulated by their underlying VWF mutations. Platelet VWF content was normal in all patients lacking in large multimers, but sometimes reduced in those with a normal multimer pattern. All the former patients and none of the latter had persistent or transient thrombocytopenia. A short VWF half-life (affecting plasma VWF levels) was seen in both groups, but more pronounced in patients without large multimers. Bleeding scores were also high in all patients, but more so in those without large multimers, apparently regardless of their platelet count. The marked phenotypic heterogeneity of type 2B VWD concerns not only patients' VWF multimer pattern, but also their bleeding risk, and consequently their appropriate treatment too. Hence the need to clearly distinguish between type 2B VWD with normal or abnormal VWF multimers. PMID- 28640905 TI - An efficient method for transgenic callus induction from Vitis amurensis petiole. AB - Transformation is the main platform for genetic improvement and gene function studies in plants. However, the established somatic embryo transformation system for grapevines is time-consuming and has low efficiency, which limits its utilization in functional genomics research. Vitis amurensis is a wild Vitis species with remarkable cold tolerance. The lack of an efficient genetic transformation system for it has significantly hindered the functional identification of cold stress related genes in the species. Herein, an efficient method was established to produce transformed calli of V. amurensis. Segments of petioles from micropropagated plantlets of V. amurensis exhibited better capacity to differentiate calli than leaf-discs and stem segments, and thus was chosen as target tissue for Agrobacterium-mediated transformation. Both neomycin phosphotransferase II (NPTII) and enhanced green fluorescent protein (eGFP) genes were used for simultaneous selection of transgenic calli based on kanamycin resistance and eGFP fluorescence. Several parameters affecting the transformation efficiency were optimized including the concentration of kanamycin, Agrobacterium stains, bacterial densities, infection treatments and co-cultivation time. The transgenic callus lines were verified by checking the integration of NPTII gene into calli genomes, the expression of eGFP gene and the fluorescence of eGFP. Up to 20% of the petiole segments produced transformed calli after 2 months of cultivation. This efficient transformation system will facilitate the functional analysis of agronomic characteristics and related genes not only in V. amurensis but also in other grapevine species. PMID- 28640906 TI - Quadratic trigonometric B-spline for image interpolation using GA. AB - In this article, a new quadratic trigonometric B-spline with control parameters is constructed to address the problems related to two dimensional digital image interpolation. The newly constructed spline is then used to design an image interpolation scheme together with one of the soft computing techniques named as Genetic Algorithm (GA). The idea of GA has been formed to optimize the control parameters in the description of newly constructed spline. The Feature SIMilarity (FSIM), Structure SIMilarity (SSIM) and Multi-Scale Structure SIMilarity (MS SSIM) indices along with traditional Peak Signal-to-Noise Ratio (PSNR) are employed as image quality metrics to analyze and compare the outcomes of approach offered in this work, with three of the present digital image interpolation schemes. The upshots show that the proposed scheme is better choice to deal with the problems associated to image interpolation. PMID- 28640904 TI - Correlation of disease severity with body weight and high fat diet in the FATZO/Pco mouse. AB - Obesity in many current pre-clinical animal models of obesity and diabetes is mediated by monogenic mutations; these are rarely associated with the development of human obesity. A new mouse model, the FATZO mouse, has been developed to provide polygenic obesity and a metabolic pattern of hyperglycemia and hyperinsulinemia, that support the presence of insulin resistance similar to metabolic disease in patients with insulin resistance/type 2 diabetes. The FATZO mouse resulted from a cross of C57BL/6J and AKR/J mice followed by selective inbreeding for obesity, increased insulin and hyperglycemia. Since many clinical studies have established a close link between higher body weight and the development of type 2 diabetes, we investigated whether time to progression to type 2 diabetes or disease severity in FATZO mice was dependent on weight gain in young animals. Our results indicate that lighter animals developed metabolic disturbances much slower and to a lesser magnitude than their heavier counterparts. Consumption of a diet containing high fat, accelerated weight gain in parallel with disease progression. A naturally occurring and significant variation in the body weight of FATZO offspring enables these mice to be identified as low, mid and high body weight groups at a young age. These weight groups remain into adulthood and correspond to slow, medium and accelerated development of type 2 diabetes. Thus, body weight inclusion criteria can optimize the FATZO model for studies of prevention, stabilization or treatment of type 2 diabetes. PMID- 28640908 TI - Evaluating diagnostic tests for bovine tuberculosis in the southern part of Germany: A latent class analysis. AB - Germany has been officially free of bovine tuberculosis since 1996. However, in the last years there has been an increase of bovine tuberculosis cases, particularly in the southern part of Germany, in the Allgau region. As a consequence a one-time tuberculosis surveillance program was revisited with different premortal and postmortal tests. The aim of this paper was to estimate diagnostic sensitivities and specificities of the different tests used within this surveillance program. In the absence of a perfect test with 100% sensitivity and 100% specificity, thus in the absence of a gold standard, a Bayesian latent class approach with two different datasets was performed. The first dataset included 389 animals, tested with single intra-dermal comparative cervical tuberculin (SICCT) test, PCR and pathology; the second dataset contained 175 animals, tested with single intra-dermal cervical tuberculin (SICT) test, Bovigam(r) assay, pathology and culture. Two-way conditional dependencies were considered within the models. Additionally, inter-laboratory agreement (five officially approved laboratories) of the Bovigam(r) assay was assessed with Cohen's kappa test (21 blood samples). The results are given in posterior means and 95% credibility intervals. The specificities of the SICT test, SICCT test, PCR and pathology ranged between 75.8% [68.8-82.2%] and 99.0% [96.8-100%]. The Bovigam(r) assay stood out with a very low specificity (6.9% [3.6-11.1%]), though it had the highest sensitivity (95.7% [91.3-99.2%]). The sensitivities of the SICCT test, PCR, SICT test, pathology and culture varied from 57.8% [48.0-67.6%] to 88.9% [65.5-99.7%]. The prevalences were 19.8% [14.6-26.5%] (three-test dataset) and 7.7% [4.2-12.3%] (four-test dataset). Among all pairwise comparisons the highest agreement was 0.62 [0.15-1]). In conclusion, the specificity of the Bovigam(r) assay and the inter-laboratory agreement were lower than expected. PMID- 28640907 TI - Accelerometer measured levels of moderate-to-vigorous intensity physical activity and sedentary time in children and adolescents with chronic disease: A systematic review and meta-analysis. AB - CONTEXT: Moderate-to-vigorous physical activity (MVPA) and sedentary time (ST) are important for child and adolescent health. OBJECTIVE: To examine habitual levels of accelerometer measured MVPA and ST in children and adolescents with chronic disease, and how these levels compare with healthy peers. METHODS: Data sources: An extensive search was carried out in Medline, Cochrane library, EMBASE, SPORTDiscus and CINAHL from 2000-2017. Study selection: Studies with accelerometer-measured MVPA and/or ST (at least 3 days and 6 hours/day to provide estimates of habitual levels) in children 0-19 years of age with chronic diseases but without co-morbidities that would present major impediments to physical activity. In all cases patients were studied while well and clinically stable. RESULTS: Out of 1592 records, 25 studies were eligible, in four chronic disease categories: cardiovascular disease (7 studies), respiratory disease (7 studies), diabetes (8 studies), and malignancy (3 studies). Patient MVPA was generally below the recommended 60 min/day and ST generally high regardless of the disease condition. Comparison with healthy controls suggested no marked differences in MVPA between controls and patients with cardiovascular disease (1 study, n = 42) and type 1 diabetes (5 studies, n = 400; SMD -0.70, 95% CI -1.89 to 0.48, p = 0.25). In patients with respiratory disease, MVPA was lower in patients than controls (4 studies, n = 470; SMD -0.39, 95% CI -0.80, 0.02, p = 0.06). Meta analysis indicated significantly lower MVPA in patients with malignancies than in the controls (2 studies, n = 90; SMD -2.2, 95% CI -4.08 to -0.26, p = 0.03). Time spent sedentary was significantly higher in patients in 4/10 studies compared with healthy control groups, significantly lower in 1 study, while 5 studies showed no significant group difference. CONCLUSIONS: MVPA in children/adolescents with chronic disease appear to be well below guideline recommendations, although comparable with activity levels of their healthy peers except for children with malignancies. Tailored and disease appropriate intervention strategies may be needed to increase MVPA and reduce ST in children and adolescents with chronic disease. PMID- 28640910 TI - Correction: BteA Secreted from the Bordetella bronchiseptica Type III Secetion System Induces Necrosis through an Actin Cytoskeleton Signaling Pathway and Inhibits Phagocytosis by Macrophages. AB - [This corrects the article DOI: 10.1371/journal.pone.0148387.]. PMID- 28640909 TI - HIV-Tat regulates macrophage gene expression in the context of neuroAIDS. AB - Despite the success of cART, greater than 50% of HIV infected people develop cognitive and motor deficits termed HIV-associated neurocognitive disorders (HAND). Macrophages are the major cell type infected in the CNS. Unlike for T cells, the virus does not kill macrophages and these long-lived cells may become HIV reservoirs in the brain. They produce cytokines/chemokines and viral proteins that promote inflammation and neuronal damage, playing a key role in HIV neuropathogenesis. HIV Tat is the transactivator of transcription that is essential for replication and transcriptional regulation of the virus and is the first protein to be produced after HIV infection. Even with successful cART, Tat is produced by infected cells. In this study we examined the role of the HIV Tat protein in the regulation of gene expression in human macrophages. Using THP-1 cells, a human monocyte/macrophage cell line, and their infection with lentivirus, we generated stable cell lines that express Tat-Flag. We performed ChIP-seq analysis of these cells and found 66 association sites of Tat in promoter or coding regions. Among these are C5, CRLF2/TSLPR, BDNF, and APBA1/Mint1, genes associated with inflammation/damage. We confirmed the association of Tat with these sequences by ChIP assay and expression of these genes in our THP-1 cell lines by qRT-PCR. We found that HIV Tat increased expression of C5, APBA1, and BDNF, and decreased CRLF2. The K50A Tat-mutation dysregulated expression of these genes without affecting the binding of the Tat complex to their gene sequences. Our data suggest that HIV Tat, produced by macrophage HIV reservoirs in the brain despite successful cART, contributes to neuropathogenesis in HIV-infected people. PMID- 28640911 TI - Evolution of microRNA in primates. AB - MicroRNA play an important role in post-transcriptional regulation of most transcripts in the human genome, but their evolution across the primate lineage is largely uncharacterized. A particular miRNA can have one to thousands of messenger RNA targets, establishing the potential for a small change in sequence or overall miRNA structure to have profound phenotypic effects. However, the majority of non-human primate miRNA is predicted solely by homology to the human genome and lacks experimental validation. In the present study, we sequenced thirteen species representing a wide range of the primate phylogeny. Hundreds of miRNA were validated, and the number of species with experimentally validated miRNA was tripled. These species include a sister taxon to humans (bonobo) and basal primates (aye-aye, mouse lemur, galago). Consistent with previous studies, we found the seed region and mature miRNA to be highly conserved across primates, with overall structural conservation of the pre-miRNA hairpin. However, there were a number of interesting exceptions, including a seed shift due to structural changes in miR-501. We also identified an increase in the number of miR-320 paralogs throughout primate evolution. Many of these non-conserved miRNA appear to regulate neuronal processes, illustrating the importance of investigating miRNA to learn more about human evolution. PMID- 28640912 TI - Signaling C-type lectin receptors in antimycobacterial immunity. PMID- 28640913 TI - Temporal patterns of Deepwater Horizon impacts on the benthic infauna of the northern Gulf of Mexico continental slope. AB - The Deepwater Horizon oil spill occurred in spring and summer 2010 in the northern Gulf of Mexico. Research cruises in 2010 (approximately 2-3 months after the well had been capped), 2011, and 2014 were conducted to determine the initial and subsequent effects of the oil spill on deep-sea soft-bottom infauna. A total of 34 stations were sampled from two zones: 20 stations in the "impact" zone versus 14 stations in the "non-impact" zone. Chemical contaminants were significantly different between the two zones. Polycyclic aromatic hydrocarbons averaged 218 ppb in the impact zone compared to 14 ppb in the non-impact zone. Total petroleum hydrocarbons averaged 1166 ppm in the impact zone compared to 102 ppm in the non-impact zone. While there was no difference between zones for meiofauna and macrofauna abundance, community diversity was significantly lower in the impact zone. Meiofauna taxa richness over the three sampling periods averaged 8 taxa/sample in the impact zone, compared to 10 taxa/sample in the non impact zone; and macrofauna richness averaged 25 taxa/sample in the impact zone compared to 30 taxa/sample in the non-impact zone. Oil originating from the Deepwater Horizon oil spill reached the seafloor and had a persistent negative impact on diversity of soft-bottom, deep-sea benthic communities. While there are signs of recovery for some benthic community variables, full recovery has not yet occurred four years after the spill. PMID- 28640914 TI - Kinetic analysis of an anion exchange absorbent for CO2 capture from ambient air. AB - This study reports a preparation method of a new moisture swing sorbent for CO2 capture from air. The new sorbent components include ion exchange resin (IER) and polyvinyl chloride (PVC) as a binder. The IER can absorb CO2 when surrounding is dry and release CO2 when surrounding is wet. The manuscript presents the studies of membrane structure, kinetic model of absorption process, performance of desorption process and the diffusivity of water molecules in the CO2 absorbent. It has been proved that the kinetic performance of CO2 absorption/desorption can be improved by using thin binder and hot water treatment. The fast kinetics of P 100-90C absorbent is due to the thin PVC binder, and high diffusion rate of H2O molecules in the sample. The impressive is this new CO2 absorbent has the fastest CO2 absorption rate among all absorbents which have been reported by other up-to date literatures. PMID- 28640915 TI - Physiological and genomic features of a novel violacein-producing bacterium isolated from surface seawater. AB - Strains JW1T and JW3, isolated from surface seawater of the Arabian Sea, were subjected to polyphasic taxonomic analysis. Cells of both strains were Gram-stain negative, aerobic, and rod-shaped. They formed violet pigment and produced violacein. On the basis of 16S rRNA gene sequence analysis, strains JW1T and JW3 showed high 16S rRNA gene sequence similarity with Pseudoalteromonas byunsanensis JCM12483T (98.2%), P. shioyasakiensis SE3T (97.8%), P. arabiensis JCM 17292T (97.3%), and P. gelatinilytica NH153T (97.1%). The 16S rRNA gene sequence similarity between JW1T and JW3 was 100%. Phylogenetic analyses revealed that both strains fell within the cluster of the genus Pseudoalteromonas and represented an independent lineage. The average nucleotide identity and in silico DNA-DNA hybridization values between JW1T and type strains of the closely related Pseudoalteromonas species were 70.9-83.3% and 20.0-26.4%, respectively. The sole respiratory quinone in both strains is ubiquinone 8 (Q-8). The principal fatty acids are summed feature 3 (C16:1omega7c and/or iso-C15:0 2OH), C18:1omega7c, and C16:0. The major polar lipids are phosphatidylethanolamine, phosphatidylglycerol, one unidentified glycolipid, one unidentified aminolipid, and one unidentified phospholipid. The DNA G+C content was 43.3 mol%. Differential phylogenetic distinctiveness, chemotaxonomic differences, and phenotypic properties indicated that strains JW1T and JW3 could be differentiated from the Pseudoalteromonas species with validly published names. Therefore, it is proposed that strains JW1T and JW3 represent a novel species of the genus Pseudoalteromonas, for which the name Pseudoalteromonas amylolytica sp. nov. (type strain, JW1T = CGMCC 1.15681T = KCTC 52406T = MCCC 1K02162T) is proposed. PMID- 28640916 TI - Severe hearing impairment and risk of depression: A national cohort study. AB - OBJECTIVE: Hearing impairment is suggested to be associated with depression in the elderly. The present study evaluated the risk of depression after hearing impairment in all age groups matched by age, sex, income, and region of residence. METHODS: The Korean Health Insurance Review and Assessment Service National Patient Samples were collected for a period from 2002 to 2013. Hearing impairment was defined as a hearing threshold >= 60 dB in both ears or as >= 80 dB in one ear and >= 40 dB in one ear. Hearing-impaired participants performed a pure tone audiometry test 3 times and an auditory brainstem response threshold test once. The 6,136 hearing-impaired participants were matched 1:4 with 24,544 controls with no reported hearing impairment for age, sex, income, and region of residence. Depression was investigated based on the International Classification of Disease-10 codes F31 (bipolar affective disorder) through F39 (unspecified mood disorder) by a psychiatrist from 2002 through 2013. The crude (simple) and adjusted (age, sex, income, region of residence, dementia, hypertension, diabetes, and dyslipidemia) hazard ratio (HR) of hearing impairment on depression were analyzed using Cox-proportional hazard model. RESULTS: The rate of depression was significantly higher in the severe hearing-impaired group than in the control group (7.9% vs. 5.7%, P < 0.001). Severe hearing impairment increased the risk of depression (adjusted HR = 1.37, 95% confidence interval [CI] = 1.24 1.52, P < 0.001). In a subgroup analysis, young (0-29 years old), middle-aged (30 59 years old), and old (>= 60 years old) severe hearing-impaired groups showed significantly increased risk of depression compared to controls with no reported hearing impairment. In accordance with income level, severe hearing impairment elevated depression in the low and high income groups, but not in the middle income group. CONCLUSION: Severe hearing impairment increased the risk of depression independently of age, sex, region, past medical histories, and income (in low and high income persons but not in middle income persons). PMID- 28640918 TI - Identifying key demographic parameters of a small island-associated population of Indo-Pacific bottlenose dolphins (Reunion, Indian Ocean). AB - Photo-identification surveys of Indo-Pacific bottlenose dolphins were conducted from 2009 to 2014 off Reunion Island (55 degrees E33'/21 degrees S07'), in the Indian Ocean. Robust Design models were applied to produce the most reliable estimate of population abundance and survival rate, while accounting for temporary emigration from the survey area (west coast). The sampling scheme consisted of a five-month (June-October) sampling period in each year of the study. The overall population size at Reunion was estimated to be 72 individuals (SE = 6.17, 95%CI = 61-85), based on a random temporary emigration (gamma") of 0.096 and a proportion of 0.70 (SE = 0.03) distinct individuals. The annual survival rate was 0.93 (+/-0.018 SE, 95%CI = 0.886-0.958) and was constant over time and between sexes. Models considering gender groups indicated different movement patterns between males and females. Males showed null or quasi-null temporary emigration (gamma" = gamma' < 0.01), while females showed a random temporary emigration (gamma") of 0.10, suggesting that a small proportion of females was outside the survey area during each primary sampling period. Sex specific temporary migration patterns were consistent with movement and residency patterns observed in other areas. The Robust Design approach provided an appropriate sampling scheme for deriving island-associated population parameters, while allowing to restrict survey effort both spatially (i.e. west coast only) and temporally (five months per year). Although abundance and survival were stable over the six years, the small population size of fewer than 100 individuals suggested that this population is highly vulnerable. Priority should be given to reducing any potential impact of human activity on the population and its habitat. PMID- 28640919 TI - The measles epidemic trend over the past 30 years in a central district in Shanghai, China. AB - BACKGROUND: Measles vaccination over the past 50 years has greatly reduced the incidence of measles. However, measles among migrants and the resulting changes in epidemiological characteristics have brought new challenges to the elimination of measles. We aim to describe the measles epidemic trend over the past 30 years in a central district in Shanghai, China. METHODS: The present study was conducted in the Jing'an District, which is located in the center of Shanghai. Based on historical surveillance data of measles, we calculated the incidence of measles among local residents and migrants separately. Next, we classified all of the cases of the measles among local residents between 1984 and 2015 into 8 age groups and 5 birth cohorts. Finally, we calculated the measles incidence in each time period by the different age groups and birth cohorts, to understand the measles epidemic trend over past 30 years in the Jing'an District. RESULTS: A total of 103 cases of measles were reported from the Jing'an District, Shanghai, from 1984 to 2015. For infants less than 1 year of age and adults over 30 years of age, the incidence of measles continued to rise over the past 30 years. For a specific birth cohort, the incidence of measles after measles vaccination declined initially, and was then followed by a rebound. CONCLUSIONS: The incidence of measles in older adults and infants increased in some developed regions, which slows the process of measles elimination. This suggested that the population immunity against measles after measles vaccination would gradually reduce with time. We recommend supplemental immunization against measles in adults in order to reduce the immunity decline, especially for migrants. PMID- 28640917 TI - Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways. AB - Hantaviruses infect humans via inhalation of virus-contaminated rodent excreta. Infection can cause severe disease with up to 40% mortality depending on the viral strain. The virus primarily targets the vascular endothelium without direct cytopathic effects. Instead, exaggerated immune responses may inadvertently contribute to disease development. Mononuclear phagocytes (MNPs), including monocytes and dendritic cells (DCs), orchestrate the adaptive immune responses. Since hantaviruses are transmitted via inhalation, studying immunological events in the airways is of importance to understand the processes leading to immunopathogenesis. Here, we studied 17 patients infected with Puumala virus that causes a mild form of hemorrhagic fever with renal syndrome (HFRS). Bronchial biopsies as well as longitudinal blood draws were obtained from the patients. During the acute stage of disease, a significant influx of MNPs expressing HLA DR, CD11c or CD123 was detected in the patients' bronchial tissue. In parallel, absolute numbers of MNPs were dramatically reduced in peripheral blood, coinciding with viremia. Expression of CCR7 on the remaining MNPs in blood suggested migration to peripheral and/or lymphoid tissues. Numbers of MNPs in blood subsequently normalized during the convalescent phase of the disease when viral RNA was no longer detectable in plasma. Finally, we exposed blood MNPs in vitro to Puumala virus, and demonstrated an induction of CCR7 expression on MNPs. In conclusion, the present study shows a marked redistribution of blood MNPs to the airways during acute hantavirus disease, a process that may underlie the local immune activation and contribute to immunopathogenesis in hantavirus infected patients. PMID- 28640921 TI - Correction: Experiences of severe childhood maltreatment, depression, anxiety and alcohol abuse among adults in Finland. AB - [This corrects the article DOI: 10.1371/journal.pone.0177252.]. PMID- 28640920 TI - Pathogen-specific mortality in very low birth weight infants with primary bloodstream infection. AB - OBJECTIVE: Mortality in very low birth weight infants following microbiology confirmed primary bloodstream infections varies with the type of causative pathogen. Given evidence from other studies that infections with gram negative bacteria and fungi cause a higher case fatality risk. We tried to confirm this in a nation-wide multi-center trial. METHODS: A cohort of 55,465 very low birth weight infants from 242 neonatal departments participating in the German national neonatal infection surveillance system NEO-KISS was used to investigate differences in the case fatality risk of microbiology confirmed primary bloodstream infections according to individual pathogens. Cox proportional hazard regression analyses were performed with the outcomes death and time from microbiology confirmed primary bloodstream infections. The results were adjusted to the recorded risk factors and hospital and department characteristics. RESULTS: A total of 4 094 very low birth weight infants with microbiology confirmed primary bloodstream infections were included in the analysis. The crude case fatality risk was 5.7%. The Cox proportional hazard regression analysis with adjustment for available risk factors revealed that microbiology confirmed primary bloodstream infections caused by Klebsiella spp. (HR 3.17 CI95 1.69 5.95), Enterobacter spp. (HR 3.42 CI95 1.86-6.27), Escherichia coli (HR 3.32 CI95 1.84-6.00) and Serratia spp. (HR 3.30 CI95 1.44-7.57) were associated with significantly higher case fatality risk compared to Staphylococcus aureus. After adjusting, case fatality risk of Candida albicans causing microbiology confirmed primary bloodstream infections was not higher than that of S. aureus. CONCLUSION: In very low birth weight infants, bloodstream infections caused by gram negative pathogens have an increased case fatality risk compared to bloodstream infections caused by gram positive pathogens. This should be considered for prevention and therapy. Further research should address the specific risk factors for case fatality of C. albicans bloodstream infections. PMID- 28640922 TI - Changes in hemp secondary fiber production related to technical fiber variability revealed by light microscopy and attenuated total reflectance Fourier transform infrared spectroscopy. AB - Interest in hemp (Cannabis sativa L.) is increasing due to the development of a new range of industrial applications based on bast fibers. However the variability of bast fiber yield and quality represents an important barrier to further exploitation. Primary and secondary fiber content was examined in two commercial hemp varieties (Fedora 17, Santhica 27) grown under contrasted sowing density and irrigation conditions. Both growing conditions and hemp varieties impact stem tissue architecture with a large effect on the proportion of secondary fibers but not primary fibers. Attenuated total reflectance infrared spectroscopy allowed the discrimination of manually-isolated native primary fibers and secondary fibers but did not reveal any clustering according to growing conditions and variety. Infrared data were confirmed by wet chemistry analyses that revealed slight but significant differences between primary and secondary fiber cell wall composition. Infrared spectroscopy of technical fibers obtained after mechanical defibering revealed differences with native primary, but not secondary fibers and also discriminated samples obtained from plants grown under different conditions. Altogether the results suggested that the observed variability of hemp technical fibers could be partially explained by i) differences in secondary fiber production and ii) differential behavior during mechanical defibering resulting in unequal separation of primary and secondary fibers. PMID- 28640924 TI - Correction: Accuracy of the Fluorescence-Activated Cell Sorting Assay for the Aquaporin-4 Antibody (AQP4-Ab): Comparison with the Commercial AQP4-Ab Assay Kit. AB - [This corrects the article DOI: 10.1371/journal.pone.0162900.]. PMID- 28640923 TI - How much detail is needed in modeling a transcranial magnetic stimulation figure 8 coil: Measurements and brain simulations. AB - BACKGROUND: Despite TMS wide adoption, its spatial and temporal patterns of neuronal effects are not well understood. Although progress has been made in predicting induced currents in the brain using realistic finite element models (FEM), there is little consensus on how a magnetic field of a typical TMS coil should be modeled. Empirical validation of such models is limited and subject to several limitations. METHODS: We evaluate and empirically validate models of a figure-of-eight TMS coil that are commonly used in published modeling studies, of increasing complexity: simple circular coil model; coil with in-plane spiral winding turns; and finally one with stacked spiral winding turns. We will assess the electric fields induced by all 3 coil models in the motor cortex using a computer FEM model. Biot-Savart models of discretized wires were used to approximate the 3 coil models of increasing complexity. We use a tailored MR based phase mapping technique to get a full 3D validation of the incident magnetic field induced in a cylindrical phantom by our TMS coil. FEM based simulations on a meshed 3D brain model consisting of five tissues types were performed, using two orthogonal coil orientations. RESULTS: Substantial differences in the induced currents are observed, both theoretically and empirically, between highly idealized coils and coils with correctly modeled spiral winding turns. Thickness of the coil winding turns affect minimally the induced electric field, and it does not influence the predicted activation. CONCLUSION: TMS coil models used in FEM simulations should include in-plane coil geometry in order to make reliable predictions of the incident field. Modeling the in-plane coil geometry is important to correctly simulate the induced electric field and to correctly make reliable predictions of neuronal activation. PMID- 28640925 TI - A novel underwater dam crack detection and classification approach based on sonar images. AB - Underwater dam crack detection and classification based on sonar images is a challenging task because underwater environments are complex and because cracks are quite random and diverse in nature. Furthermore, obtainable sonar images are of low resolution. To address these problems, a novel underwater dam crack detection and classification approach based on sonar imagery is proposed. First, the sonar images are divided into image blocks. Second, a clustering analysis of a 3-D feature space is used to obtain the crack fragments. Third, the crack fragments are connected using an improved tensor voting method. Fourth, a minimum spanning tree is used to obtain the crack curve. Finally, an improved evidence theory combined with fuzzy rule reasoning is proposed to classify the cracks. Experimental results show that the proposed approach is able to detect underwater dam cracks and classify them accurately and effectively under complex underwater environments. PMID- 28640928 TI - The State of the Art in Pulmonary Vein Stenosis -Diagnosis & Treatment. AB - Pulmonary vein stenosis is a rare but serious complication of pulmonary vein isolation to treat atrial fibrillation. Pulmonary vein angioplasty/stenting has emerged as the treatment of choice for significantly stenotic veins. Guidelines for post ablation evaluation of the pulmonary veins, including the timing and method of surveillance for possible stenosis, the criteria for intervention, the technical aspects of intervention, and finally the surveillance post intervention, are still being developed. The relatively high rate of restenosis after intervention in a subset of patients remains a great challenge. A better understanding of the pathophysiology underlying this syndrome is needed to appropriately answer many of the remaining questions. The goal of this manuscript is to describe what has been learned about this complication and its treatment from a relatively large experience in a single institution over the past decade, and provide a comprehensive review of the existing literature in order to shed as much light on the subject as is possible, while at the same time exposing the areas that need further study. PMID- 28640926 TI - Clinimetric properties of hip abduction strength measurements obtained using a handheld dynamometer in individuals with a lower extremity amputation. AB - INTRODUCTION: Suitable handheld dynamometer (HHD)-techniques to test hip abduction strength in individuals with a lower extremity amputation, irrespective of their amputation level are absent. The aim of this study was to optimise a HHD technique and to test its reproducibility and validity. METHODS: This study involved three phases, in which two techniques were evaluated. Both HHD techniques used a lever-arm of 22 centimetre. HHD-technique 1 used a break technique. After obtaining within-session test-retest reproducibility (phase 1) we optimised the HHD-technique by adding a fixation-belt and using a make technique (HHD-technique 2). We tested the within-session test-retest and inter rater reproducibility (phase 2) and the validity (phase 3) of HHD-technique 2 using an isokinetic dynamometer. New cohorts of participants were recruited for each phase. RESULTS: Phase 1: we tested HHD-technique 1 in 26 participants with a lower extremity amputation. It was test-retest reproducible (ICC3.1agreement: 0.80-0.92, standard error of measurement (SEM): 3.1-4.4 Nm and smallest detectable change (SDC): 8.6-12.3 Nm). There were questions regarding the validity of the measurement, because the mean muscle torque of the residual limb and sound limb were similar, which is uncommon. Phase 2: reproducibility of HHD technique 2 was tested in 44 participants with a lower extremity amputation. It was test-retest reproducible (ICC3.1agreement: 0.96-0.97, SEM: 3.9-4.7 Nm and SDC: 10.9-12.9 Nm) but not inter-rater reproducible despite having good reliability (ICC3.1agreement: 0.92, SEM: 6.9-7.6 Nm and SDC: 19.2-21.2 Nm). Systematic bias and bias related to the magnitude of the muscle torque was suspected. Phase 3: the concurrent validity was established in 30 healthy participants (r = 0.84). Systematic bias in measurement error was present, including a consistent overestimation of the muscle torque of 28% using the HHD. CONCLUSION: HHD-technique 2 is a test-retest reproducible and valid measuring technique The technique may be further optimised by the use of an external device to stabilise the HHD. PMID- 28640927 TI - The Role of Atrial Fibrillation Catheter Ablation in Patients with Congestive Heart Failure: "Burning"for a Cure. AB - Atrial Fibrillation (AF) and congestive heart failure (CHF) often co-exist. Catheter ablation is increasingly used to cure AF related to CHF.Clinical evidence supports the feasibil- ity of catheter ablation as a treatment option in drug refractory AF patients with CHF.Investiga- tors have reported an improvement in ejection fraction, quality of life, and functional capacity. PMID- 28640929 TI - Modulation of tumor microenvironment by chemopreventive natural products. AB - The tumor microenvironment provides a niche in which cancer cells and their surrounding stromal cells reside and in which their interactions occur. The cross talk between cancer and stromal cells in the tumor microenvironment promotes many biological processes to support cancer cell growth, invasion, angiogenesis, and metastasis. Recently, not only cancer cells but also multiple types of surrounding stromal cells, including endothelial cells, immune cells, and fibroblasts in the tumor microenvironment, have been recognized to be attractive targets for reducing resistance to anticancer therapy and tumor recurrence. Many natural products present in fruits, vegetables, herbs, spices, and some marine organisms have been reported to inhibit, delay, or reverse multistage carcinogenesis and to inhibit the proliferation of cancerous cells and the self renewal capacity of preexisting cancer stem-like cells. Some of these naturally occurring chemopreventive and anticarcinogenic substances can modulate the signal transduction involved in maintaining the activities/functions of stromal cells and their interactions with cancer cells within the tumor microenvironment. PMID- 28640930 TI - Orotracheal intubation in infants performed with a stylet versus without a stylet. AB - BACKGROUND: Neonatal endotracheal intubation is a common and potentially life saving intervention. It is a mandatory skill for neonatal trainees, but one that is difficult to master and maintain. Intubation opportunities for trainees are decreasing and success rates are subsequently falling. Use of a stylet may aid intubation and improve success. However, the potential for associated harm must be considered. OBJECTIVES: To compare the benefits and harms of neonatal orotracheal intubation with a stylet versus neonatal orotracheal intubation without a stylet. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE; Embase; the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and previous reviews. We also searched cross-references, contacted expert informants, handsearched journals, and looked at conference proceedings. We searched clinical trials registries for current and recently completed trials. We conducted our most recent search in April 2017. SELECTION CRITERIA: All randomised, quasi randomised, and cluster-randomised controlled trials comparing use versus non-use of a stylet in neonatal orotracheal intubation. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed results of searches against predetermined criteria for inclusion, assessed risk of bias, and extracted data. We used the standard methods of the Cochrane Collaboration, as documented in the Cochrane Handbook for Systemic Reviews of Interventions, and of the Cochrane Neonatal Review Group. MAIN RESULTS: We included a single-centre non-blinded randomised controlled trial that reported a total of 302 intubation attempts in 232 infants. The median gestational age of enrolled infants was 29 weeks. Paediatric residents and fellows performed the intubations. We judged the study to be at low risk of bias overall. Investigators compared success rates of first-attempt intubation with and without use of a stylet and reported success rates as similar between stylet and no-stylet groups (57% and 53%) (P = 0.47). Success rates did not differ between groups in subgroup analyses by provider level of training and infant weight. Results showed no differences in secondary review outcomes, including duration of intubation, number of attempts, participant instability during the procedure, and local airway trauma. Only 25% of all intubations took less than 30 seconds to perform. Study authors did not report neonatal morbidity nor mortality. We considered the quality of evidence as low on GRADE analysis, given that we identified only one unblinded study. AUTHORS' CONCLUSIONS: Current available evidence suggests that use of a stylet during neonatal orotracheal intubation does not significantly improve the success rate among paediatric trainees. However, only one brand of stylet and one brand of endotracheal tube have been tested, and researchers performed all intubations on infants in a hospital setting. Therefore, our results cannot be generalised beyond these limitations. PMID- 28640931 TI - Ischemia-responsive protein 94 is a key mediator of ischemic neuronal injury induced microglial activation. AB - Neuroinflammation, especially activation of microglia, the key immune cells in the brain, has been proposed to contribute to the pathogenesis of ischemic stroke. However, the dynamics and the potential mediators of microglial activation following ischemic neuronal injury are not well understood. In this study, using oxygen/glucose deprivation and reoxygenation with neuronal and microglial cell cultures as an in vitro model of ischemic neuronal injury, we set out to identify neuronal factors released from injured neurons that are capable of inducing microglial activation. Conditioned media (CM) from hippocampal and cortical neurons exposed to oxygen/glucose deprivation and reoxygenation induced significant activation of microglial cells as well as primary microglia, evidenced by up-regulation of inducible nitric oxide synthase, increased production of nitrite and reactive oxygen species, and increased expression of microglial markers. Mechanistically, neuronal ischemia-responsive protein 94 (Irp94) was a key contributor to microglial activation since significant increase in Irp94 was detected in the neuronal CM following ischemic insult and immunodepletion of Irp94 rendered ischemic neuronal CM ineffective in inducing microglial activation. Ischemic insult-augmented oxidative stress was a major facilitator of neuronal Irp94 release, and pharmacological inhibition of NADPH oxidase significantly reduced the ischemic injury-induced neuronal reactive oxygen species production and Irp94 release. Taken together, these results indicate that neuronal Irp94 may play a pivotal role in the propagation of ischemic neuronal damage. Continued studies may help identify Irp94 and/or related proteins as potential therapeutic targets and/or diagnostic/prognostic biomarkers for managing ischemia-associated brain disorders. PMID- 28640933 TI - Could ivabradine be a new treatment for the short QT syndrome? PMID- 28640932 TI - Potential of a cure in patients with colorectal liver metastases and concomitant extrahepatic disease: Methodological issues. PMID- 28640934 TI - Substrate specificity and safener inducibility of the plant UDP-glucose-dependent family 1 glycosyltransferase super-family. AB - Plants contain large numbers of family 1 UDP-glucose-dependent glycosyltransferases (UGTs), including members that conjugate xenobiotics. Arabidopsis contains 107 UGT genes with 99 family members successfully expressed as glutathione transferase (GST)-fusion proteins in E. coli. A high-throughput catalytic screen was developed based on quantification of the fusion by measuring GST activity. UGT activity using UDP-glucose as donor was then determined using 11 synthetic acceptors bearing hydroxyl, amino and thiol groups that had been shown to undergo conjugation in plant extracts. In total, 44 UGTs, largely members of the D and E groups, were active towards xenobiotics, glucosylating phenol and thiol acceptors. In contrast, N-glucosyltransferase (NGT) activity was almost exclusively restricted to a single enzyme, UGT72B1. Using DNA microarrays, the induction of UGT transcripts following treatment with the herbicide safener fenclorim was compared in Arabidopsis and rice. D and L group members were the most safener-inducible UGTs in both species. The respective Arabidopsis enzymes showed low conjugating activity towards xenobiotics. Using Genevestigator, a small group of safened D and L UGTs were consistently induced in response to biotic and abiotic stress suggestive of protective activities beyond xenobiotic detoxification in both species. The induction of other detoxifying gene families following treatment with fenclorim, namely cytochromes P450 and glutathione transferases, further confirmed the selective enhancement of related subfamily members in the two species giving new insight into the safening response in cereals, where herbicide tolerance is enhanced compared with dicots, which are unresponsive to these treatments. PMID- 28640935 TI - Additive effect of radiosensitization by 2-deoxy-D-glucose delays DNA repair kinetics and suppresses cell proliferation in oral squamous cell carcinoma. AB - BACKGROUND: It has well known that, compared to normal cells, tumor cells have a different manner of energy metabolism, which influences the sensitivity of radiotherapy. However, whether inhibition of glycolysis enhances the efficacy of radiotherapy is a matter of debate in oral squamous cell carcinoma (OSCC). The aim of this study was to characterize whether the combination of radiotherapy with the glucose inhibitor 2-deoxy-D-glucose (2-DG) affected DNA repair kinetics. METHODS: To compare the synergistic effect of 2-DG, we examined the cell survival after treatment with radiation, 2-DG, and a combination of the two in five OSCC cell lines and one lip fibroblast cell line, determined using clonogenic survival assay. Changes in the protein levels of DNA repair kinetics such as PARP, Rad51, and Ku-70 were analyzed by Western blotting. Then, using one of the five OSCC cell lines, we assessed the inhibition of xenograft tumor growth in vivo. RESULTS: We found that 2-DG with radiation induced significant inhibition of cell proliferation in cell line SAS (P<.01, one-way ANOVA). Radiation treatment was associated with decreased expression of the DNA repair markers. In additional, combinational treatment with 2-DG and radiation significantly inhibited the xenograft tumor growth compared to the control (P<.05), and treatment with 2-DG or radiation alone. CONCLUSIONS: Our study suggests that 2-DG has synergistic cytotoxic effects when combined with radiotherapy, which might lead to the design of an effective metabolic target therapy in vitro and in vivo. PMID- 28640936 TI - Preparation, Single-Molecule Manipulation, and Energy Transfer Investigation of a Polyfluorene-graft-DNA polymer. AB - Conjugated polymers have been intensively studied due to their unique optical and electronic properties combined with their physical flexibility and scalable bottom up synthesis. Although the bulk qualities of conjugated polymers have been extensively utilized in research and industry, the ability to handle and manipulate conjugated polymers at the nanoscale lacks significantly behind. Here, the toolbox for controlled manipulation of conjugated polymers was expanded through the synthesis of a polyfluorene-DNA graft-type polymer (poly(F-DNA)). The polymer possesses the characteristics associated with the conjugated polyfluorene backbone, but the protruding single-stranded DNA provides the material with an exceptional addressability. This study demonstrates controlled single-molecule patterning of poly(F-DNA), as well as energy transfer between two different polymer-DNA conjugates. Finally, highly efficient DNA-directed quenching of polyfluorene fluorescence was shown. PMID- 28640937 TI - Dreams and creative problem-solving. AB - Dreams have produced art, music, novels, films, mathematical proofs, designs for architecture, telescopes, and computers. Dreaming is essentially our brain thinking in another neurophysiologic state-and therefore it is likely to solve some problems on which our waking minds have become stuck. This neurophysiologic state is characterized by high activity in brain areas associated with imagery, so problems requiring vivid visualization are also more likely to get help from dreaming. This article reviews great historical dreams and modern laboratory research to suggest how dreams can aid creativity and problem-solving. PMID- 28640938 TI - Obstructive sleep apnoea and polycystic ovary syndrome: A comprehensive review of clinical interactions and underlying pathophysiology. AB - Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of reproductive age. PCOS is associated with multiple comorbidities including, obesity, insulin resistance and type 2 diabetes, as well as mood disorders and impaired quality of life (QoL). Obstructive sleep apnoea (OSA) is also a common medical condition that is often undiagnosed, particularly in women. OSA is associated with a similar spectrum of comorbidities to that observed in PCOS, including manifestations of the metabolic syndrome and impaired QoL, whilst obesity frequently constitutes a common denominator in the pathophysiology of both OSA and PCOS. Hence, it is not surprising that OSA and PCOS may coexist in women of reproductive age, and the current clinical guidelines on the management of PCOS recommend screening for OSA symptoms in overweight/obese women with PCOS. In this review, we examine the relationship between OSA and PCOS and explore the potential underlying mechanisms that link these two conditions. PMID- 28640939 TI - Global transcriptome and coexpression network analyses reveal cultivar-specific molecular signatures associated with seed development and seed size/weight determination in chickpea. AB - Seed development is an intricate process regulated via a complex transcriptional regulatory network. To understand the molecular mechanisms governing seed development and seed size/weight in chickpea, we performed a comprehensive analysis of transcriptome dynamics during seed development in two cultivars with contrasting seed size/weight (small-seeded, Himchana 1 and large-seeded, JGK 3). Our analysis identified stage-specific expression for a significant proportion (>13%) of the genes in each cultivar. About one half of the total genes exhibited significant differential expression in JGK 3 as compared with Himchana 1. We found that different seed development stages can be delineated by modules of coexpressed genes. A comparative analysis revealed differential developmental stage specificity of some modules between the two cultivars. Furthermore, we constructed transcriptional regulatory networks and identified key components determining seed size/weight. The results suggested that extended period of cell division during embryogenesis and higher level of endoreduplication along with more accumulation of storage compounds during maturation determine large seed size/weight. Further, we identified quantitative trait loci-associated candidate genes harboring single nucleotide polymorphisms in the promoter sequences that differentiate small- and large-seeded chickpea cultivars. The results provide a valuable resource to dissect the role of candidate genes governing seed development and seed size/weight in chickpea. PMID- 28640940 TI - Regioselective Direct C-Alkenylation of Indoles. AB - The direct introduction of alkenyl groups into the indole framework avoiding its preliminary functionalization can be carried out using different synthetic strategies. Transition-metal complexes facilitate the C-H activation of indoles or alkenes allowing an efficient Csp2 - Csp2 bond formation. The hydroindolation of alkynes catalyzed by the same metal complexes or various acidic promoters can also be pursued for the alkenylation process. Conjugate addition of electron-poor alkenes and direct condensation of carbonyl derivatives with indoles are also of interest for this purpose. The regiochemical control can be exploited using the intrinsic C-3 reactivity of the indole ring. The introduction of a suitable directing group at the nitrogen atom allows the preparation of C-2 alkenylated derivatives by transition metal catalyzed reactions. This review collects the fundamental contributions in this field reported in literature during the last fifteen years. PMID- 28640941 TI - PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours. AB - AIMS: Neuroblastoma shows considerable histological overlap with other small round blue cell tumours. PHOX2B, a transcription factor that is essential for autonomic nervous system development, has been reported as an immunohistochemical marker for neuroblastoma. The aim of this study was to validate the specificity and diagnostic utility of PHOX2B for peripheral neuroblastic tumours. METHODS AND RESULTS: We evaluated 240 cases (133 in whole-tissue sections; 107 in tissue microarrays), including 76 peripheral neuroblastic tumours (median age 2 years; including four adults) and 164 other tumours: 44 Wilms tumours; 20 Ewing sarcomas; 10 each of CIC-rearranged round cell sarcomas, poorly differentiated synovial sarcomas, lymphoblastic lymphomas, alveolar rhabdomyosarcomas, embryonal rhabdomyosarcomas, mesenchymal chondrosarcomas, Merkel cell carcinomas, olfactory neuroblastomas, and melanomas; and five each of NUT midline carcinomas and desmoplastic small round cell tumours. Immunohistochemistry for PHOX2B was performed with a rabbit monoclonal antibody. PHOX2B positivity was defined as the presence of nuclear immunoreactivity in >=5% of cells. PHOX2B was positive in 70 (92%) peripheral neuroblastic tumours, including 68 of 72 (94%) paediatric and two of four (50%) adult cases. Furthermore, PHOX2B was consistently negative in all non-peripheral neuroblastic tumours, with staining being absent in 160 cases and limited in four cases. CONCLUSION: PHOX2B is a highly sensitive and specific immunohistochemical marker for peripheral neuroblastic tumours, including neuroblastoma. PHOX2B reliably distinguishes neuroblastoma from histological mimics such as Wilms tumour, Ewing sarcoma, and CIC-rearranged round cell sarcoma. PHOX2B negativity in two of four adult neuroblastoma cases raises the possibility that some adult neuroblastomas are of a different lineage than paediatric cases. PMID- 28640943 TI - Dimensioning the Term Carbenoid. AB - The current use of the term carbenoid is discussed, particularly in the context of carbene transfer reactions from diazo compounds, in which intermediates of type Ln M=CR1 R2 , or one of its resonance forms, are tagged which such a name. We discuss this issue, on the basis of the data evidencing the metal-carbene nature of those intermediates, as well as the existence of carbenoids of type (N2 )(M)CR1 R2 en route to the formation to Ln M=CR1 R2' from diazo reagents. We propose the exclusive use of the carbenoid term to species of type (X)(M)CR1 R2 with a tetrasubstituted carbon center that upon loss of X afford an effective carbene transfer process. PMID- 28640944 TI - Rare complication of gastrojejunostomy. PMID- 28640942 TI - Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells. AB - The success of immune system-based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTACTM molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti-CD3 scFv antibody) were previously shown to redirect CD8+ and CD4+ T cells against tumours. Here we present evidence that IMCgp100 (ImmTAC recognizing a peptide derived from the melanoma-specific protein, gp100, presented by HLA-A*0201) efficiently redirects and activates effector and memory cells from both CD8+ and CD4+ repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD8+ T cells redirected by IMCgp100 are potent killers of melanoma cells. Furthermore, CD4+ effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMCgp100. The majority of T cell subsets belonging to both the CD8+ and CD4+ repertoires secrete key pro-inflammatory cytokines (tumour necrosis factor-alpha, interferon-gamma, interleukin-6) and chemokines (macrophage inflammatory protein-1alpha-beta, interferon-gamma-inducible protein-10, monocyte chemoattractant protein-1). At an individual cell level, IMCgp100-redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti cancer response. This study demonstrates that IMCgp100 induces broad immune responses that extend beyond the induction of CD8+ T cell-mediated cytotoxicity. These findings are of particular importance because IMCgp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma. PMID- 28640945 TI - Production of human vitronectin in Nicotiana benthamiana using the INPACT hyperexpression platform. AB - Human vitronectin (hVN) is a glycoprotein that functions as a cell adhesion molecule and a regulator of coagulation in blood plasma and the extracellular matrix. In vitro, hVN is added to serum-free media in order to promote the adhesion of animal cells to tissue culture surfaces and the proliferation of undifferentiated stem cells. Here, we report the production of hVN in Nicotiana benthamiana using the inducible In Plant ACTivation (INPACT) hyperexpression platform. N. benthamiana plants were transformed with an INPACT expression cassette encoding hVN, and both the Tobacco yellow dwarf virus Rep/RepA activator and Tomato bushy stunt virus p19 gene under the transcriptional control of the ethanol-inducible AlcR:alcA gene switch. hVN expression was maximal 4-5 days postactivation of the INPACT platform with a dilute ethanol solution, and crude yields of the recombinant protein reached a maximum of 643 +/- 78 mg/kg fresh weight. A three-stage purification protocol was developed using heparin and polyhistidine tag affinity binding and size exclusion filtration, resulting in a plant-made hVN product of >90% purity. Storage conditions for plant-made hVN were identified that maximized the capacity of the recombinant protein to promote cell adhesion. Critically, plant-made hVN was shown to be functionally equivalent to commercial, plasma-derived hVN at promoting one-half maximal attachment of murine fibroblast cells (BALB-C/3T3) in serum-free medium at <0.1 MUg/cm2 to tissue culture plasticware. The INPACT platform represents an attractive means of producing large quantities of functional, animal-free hVN for in vitro applications. PMID- 28640946 TI - Physicians' Non-Uniform Approach to Prescribing Drugs to Older Patients - A Qualitative Study. AB - Multi-morbidity and polypharmacy are common in older patients and increase their susceptibility to adverse drug events and hospitalizations. Rational drug prescription is critical; however, little is known about physicians' perspectives on how to prescribe drugs for older patients. The aim of this study was to explore physicians' approach to prescribe drugs to older patients, including identifying the drugs that physicians perceive to be risk drugs for older patients and comparing them with established lists of potentially inappropriate medications. Short semi-structured interviews were conducted with 50 medical specialists in 23 different specialities throughout Denmark who had contact with older patients. Content analysis was performed to identify the relevant themes. Regardless of their medical or surgical background and how often they prescribed drugs for older patients in daily work, all physicians expressed a cautious approach when prescribing risk drugs. Despite their shared caution, physicians had different strategies for prescribing drugs to older patients. The following strategies were identified: (1) 'Start low, go slow', (2) 'Trial and error', (3) 'Dose reduction', and (4) 'Never prescribe'. The most frequently mentioned risk drugs considered to cause hospitalization were vitamin K antagonists, opioids and diuretics; these drugs are relatively highly consistent with established lists of PIMs. Physicians were relatively knowledgeable about risk drugs. Although the physicians agreed that a cautious approach was needed when prescribing drugs for older people, there was no consensus about how to best accomplish this in practice. PMID- 28640947 TI - Clinico-molecular analysis of eleven patients with Hermansky-Pudlak type 5 syndrome, a mild form of HPS. AB - Hermansky-Pudlak syndrome (HPS), first described in 1959, is a rare form of syndromic oculocutaneous albinism associated with bleeding diathesis and in some cases pulmonary fibrosis and granulomatous colitis. All 10 HPS types are caused by defects in vesicle trafficking of lysosome-related organelles (LRO) proteins. The HPS5 protein associates with HPS3 and HPS6 to form the biogenesis of lysosome related organelles complex-2 (BLOC-2). Here, we report the clinical and genetic data of 11 patients with HPS-5 analyzed in our laboratory. We report 11 new pathogenic variants. The 11 patients present with ocular features that are typical for albinism, with mild hypopigmentation, and with no other major complication, apart from a tendency to bleed. HPS-5 therefore appears as a mild form of HPS, which is often clinically undistinguishable from mild oculocutaneous or ocular forms of albinism. Molecular analysis is therefore required to establish the diagnosis of this mild HPS form, which has consequences in terms of prognosis and of clinical management of the patients. PMID- 28640948 TI - High-level betaIII-tubulin overexpression occurs in most head and neck cancers but is unrelated to clinical outcome. AB - BACKGROUND: betaIII-tubulin (TUBB3) is an isotype of microtubules, which are involved in crucial cellular roles including maintenance of cell shape, intracellular transport, and mitosis. Overexpression of TUBB3 was found to be associated with poor prognosis and resistance to tubulin-binding drugs and in several solid tumors including head and neck squamous cell carcinomas (HNSCC). Considering the potential high importance of a prognostic biomarker in these cancers, this study aimed to investigate the clinical relevance of immunohistochemical TUBB3 expression in HNSCC. METHODS: Tissue microarray (TMA) sections containing samples from 667 cancers of oral cavity, oro- and hypopharynx, and larynx for which follow-up data were available were analyzed for TUBB3 expression by immunohistochemistry. RESULTS: Over 90% of our analyzed cancers showed unequivocal cytoplasmic TUBB3 expression. Staining was considered weak in 69 (15.5%), moderate in 149 (33.5%), and strong in 188 (42.2%) of cancers. The frequent TUBB3 overexpression showed no significant correlation with pathological grading, tumor stage, nodal status, or surgical margin and had no impact on patient outcomes. CONCLUSION: Despite lacking prognostic utility in HNSCC, the remarkable high prevalence of TUBB3 expression in HNSCC emphasizes its putative relevance as a target for future drugs targeting TUBB3. PMID- 28640949 TI - Flawed Assumptions: Ethical Problems With Proposed Presumed Consent Legislation. PMID- 28640950 TI - Development of a Monte Carlo multiple source model for inclusion in a dose calculation auditing tool. AB - PURPOSE: The Imaging and Radiation Oncology Core Houston (IROC-H) (formerly the Radiological Physics Center) has reported varying levels of agreement in their anthropomorphic phantom audits. There is reason to believe one source of error in this observed disagreement is the accuracy of the dose calculation algorithms and heterogeneity corrections used. To audit this component of the radiotherapy treatment process, an independent dose calculation tool is needed. METHODS: Monte Carlo multiple source models for Elekta 6 MV and 10 MV therapeutic x-ray beams were commissioned based on measurement of central axis depth dose data for a 10 * 10 cm2 field size and dose profiles for a 40 * 40 cm2 field size. The models were validated against open field measurements consisting of depth dose data and dose profiles for field sizes ranging from 3 * 3 cm2 to 30 * 30 cm2 . The models were then benchmarked against measurements in IROC-H's anthropomorphic head and neck and lung phantoms. RESULTS: Validation results showed 97.9% and 96.8% of depth dose data passed a +/-2% Van Dyk criterion for 6 MV and 10 MV models respectively. Dose profile comparisons showed an average agreement using a +/ 2%/2 mm criterion of 98.0% and 99.0% for 6 MV and 10 MV models respectively. Phantom plan comparisons were evaluated using +/-3%/2 mm gamma criterion, and averaged passing rates between Monte Carlo and measurements were 87.4% and 89.9% for 6 MV and 10 MV models respectively. CONCLUSIONS: Accurate multiple source models for Elekta 6 MV and 10 MV x-ray beams have been developed for inclusion in an independent dose calculation tool for use in clinical trial audits. PMID- 28640952 TI - Label-Free Dynamic Mass Redistribution and Bio-Impedance Methods for Drug Discovery. AB - Label-free biosensors are increasingly employed in drug discovery. Cell-based biosensors provide valuable insights into the biological consequences of exposing cells and tissues to chemical agents and the underlying molecular mechanisms associated with these effects. Optical biosensors based on the detection of dynamic mass redistribution (DMR) and impedance biosensors using cellular dielectric spectroscopy (CDS) capture changes of the cytoskeleton of living cells in real time. Because signal transduction correlates with changes in cell morphology, DMR and CDS biosensors are exquisitely suited for recording integrated cell responses in an unbiased, yet pathway-specific manner without the use of labels that may interfere with cell function. Described in this unit are several experimental approaches utilizing optical label-free system capturing dynamic mass redistribution (DMR) in living cells (Epic System) and an impedance based CDS technology (CellKey). In addition, potential pitfalls associated with these assays and alternative approaches for overcoming such technical challenges are discussed. (c) 2017 by John Wiley & Sons, Inc. PMID- 28640953 TI - Overview of Transgenic Mouse Models of Myeloproliferative Neoplasms (MPNs). AB - Myeloproliferative neoplasms (MPNs) are a class of hematologic diseases characterized by aberrant proliferation of one or more myeloid lineages and progressive bone marrow fibrosis. In 2005, seminal work by multiple groups identified the JAK2V617F mutation in a significant fraction of MPN patients. Since that time, murine models of JAK2V617F have greatly enhanced the understanding of the role of aberrant JAK-STAT signaling in MPN pathogenesis and have provided an in vivo pre-clinical platform that can be used to develop novel therapies. From early retroviral transduction models to transgenics, and ultimately conditional knock-ins, murine models have established that JAK2V617F alone can induce an MPN-like syndrome in vivo. However, additional mutations co occur with JAK2V617F in MPNs, often in proteins involved in epigenetic regulation that can dramatically influence disease outcomes. In vivo modeling of these mutations in the context of JAK2V617F has provided additional insights into the role of epigenetic dysregulation in augmenting MPN hematopoiesis. In this overview, early murine model development of JAK2V617F is described, with an analysis of its effects on the hematopoietic stem/progenitor cell niche and interactions with downstream signaling elements. This is followed by a description of more recent in vivo models developed for evaluating the effect of concomitant mutations in epigenetic modifiers on MPN maintenance and progression. Mouse models of other driver mutations in MPNs, including primarily calreticulin (CALR) and Tpo-receptor (MPL), which occur in a significant percentage of MPN patients with wild-type JAK2, are also briefly reviewed. (c) 2017 by John Wiley & Sons, Inc. PMID- 28640954 TI - The Ussing Chamber Assay to Study Drug Metabolism and Transport in the Human Intestine. AB - The Ussing chamber is an old but still powerful technique originally designed to study the vectorial transport of ions through frog skin. This technique is also used to investigate the transport of chemical agents through the intestinal barrier as well as drug metabolism in enterocytes, both of which are key determinants for the bioavailability of orally administered drugs. More contemporary model systems, such as Caco-2 cell monolayers or stably transfected cells, are more limited in their use compared to the Ussing chamber because of differences in expression rates of transporter proteins and/or metabolizing enzymes. While there are limitations to the Ussing chamber assay, the use of human intestinal tissue remains the best laboratory test for characterizing the transport and metabolism of compounds following oral administration. Detailed in this unit is a step-by-step protocol for preparing human intestinal tissue, for designing Ussing chamber experiments, and for analyzing and interpreting the findings. (c) 2017 by John Wiley & Sons, Inc. PMID- 28640951 TI - The value of visual field testing in the era of advanced imaging: clinical and psychophysical perspectives. AB - White-on-white standard automated perimetry (SAP) is widely used in clinical and research settings for assessment of contrast sensitivity using incremental light stimuli across the visual field. It is one of the main functional measures of the effect of disease upon the visual system. SAP has evolved over the last 40 years to become an indispensable tool for comprehensive assessment of visual function. In modern clinical practice, a range of objective measurements of ocular structure, such as optical coherence tomography, have also become invaluable additions to the arsenal of the ophthalmic examination. Although structure function correlation is a highly desirable determinant of an unambiguous clinical picture for a patient, in practice, clinicians are often faced with discordance of structural and functional results, which presents them with a challenge. The construction principles behind the development of SAP are used to discuss the interpretation of visual fields, as well as the problem of structure-function discordance. Through illustrative clinical examples, we provide useful insights to assist clinicians in combining a range of clinical results obtained from SAP and from advanced imaging techniques into a coherent picture that can help direct clinical management. PMID- 28640955 TI - In-solution antibody harvesting with a plant-produced hydrophobin-Protein A fusion. AB - Purification is a bottleneck and a major cost factor in the production of antibodies. We set out to engineer a bifunctional fusion protein from two building blocks, Protein A and a hydrophobin, aiming at low-cost and scalable antibody capturing in solutions. Immunoglobulin-binding Protein A is widely used in affinity-based purification. The hydrophobin fusion tag, on the other hand, has been shown to enable purification by two-phase separation. Protein A was fused to two different hydrophobin tags, HFBI or II, and expressed transiently in Nicotiana benthamiana. The hydrophobins enhanced accumulation up to 35-fold, yielding up to 25% of total soluble protein. Both fused and nonfused Protein A accumulated in protein bodies. Hence, the increased yield could not be attributed to HFB-induced protein body formation. We also demonstrated production of HFBI Protein A fusion protein in tobacco BY-2 suspension cells in 30 l scale, with a yield of 35 mg/l. Efficient partitioning to the surfactant phase confirmed that the fusion proteins retained the amphipathic properties of the hydrophobin block. The reversible antibody-binding capacity of the Protein A block was similar to the nonfused Protein A. The best-performing fusion protein was tested in capturing antibodies from hybridoma culture supernatant with two-phase separation. The fusion protein was able to carry target antibodies to the surfactant phase and subsequently release them back to the aqueous phase after a change in pH. This report demonstrates the potential of hydrophobin fusion proteins for novel applications, such as harvesting antibodies in solutions. PMID- 28640956 TI - miR-188 promotes senescence of lineage-negative bone marrow cells by targeting MAP3K3 expression. AB - Lineage-negative bone marrow cells (lin-BMCs) have reparative potential for overcoming endothelial dysfunction and reducing cardiovascular risk. Here, we found that miR-188 is upregulated and mitogen-activated protein kinase kinase kinase 3 (MAP3K3) is downregulated in aged lin-BMCs, whereas their expression is reversed in young lin-BMCs. We identified and confirmed MAP3K3 as a direct target of miR-188. MiR-188 overexpression or MAP3K3 silencing in young lin-BMCs increases p16 and p21 expression, enhances cell senescence, and decreases the ability for cell proliferation, migration, and tube formation. Conversely, miR 188 suppression in aged lin-BMCs yields the opposite results. We further found that MAP3K3 is involved in miR-188-induced promotion of lin-BMC senescence. All data reveal that miR-188 induces lin-BMC senescence by targeting MAP3K3 expression, thus, providing new theoretical basis for the prevention and treatment of cardiovascular diseases. PMID- 28640957 TI - Restoration of cutaneous pigmentation by transplantation to mice of isogeneic human melanocytes in dermal-epidermal engineered skin substitutes. AB - Autologous engineered skin substitutes (ESS) containing melanocytes (hM) may restore pigmentation and photoprotection after grafting to full-thickness skin wounds. In this study, normal hM were isolated from discard skin, propagated with or without tyrosinase inhibitors, cryopreserved, recovered into culture, and added to ESS (ESS-P) before transplantation. ESS-P were incubated in either UCMC160/161 or UCDM1 medium, scored for hM densities, and grafted to mice. The results showed that sufficient hM can be propagated to expand donor tissue by 100 fold; incubation of hM in tyrosinase inhibitors reduced pigment levels but did not change hM recovery after cryopreservation; hM densities in ESS-P were greater after incubation in UCDM1 than UCMC160 medium; hM were localized to the dermal epidermal junction of ESS-P; and UCDM1 medium promoted earlier pigment distribution and density. These results indicate that hM can be incorporated into ESS-P efficiently to restore cutaneous pigmentation and UV photoprotection after full-thickness skin loss conditions. PMID- 28640958 TI - Recommendations for revision of Chinese diagnostic criteria for metabolic syndrome: A nationwide study. AB - BACKGROUND: Diagnostic criteria for metabolic syndrome (MS) proposed by the Chinese Diabetes Society (CDS) may have limitations because an additional 2-h postprandial plasma glucose (2-h PPG) test is required to diagnose hyperglycemia. The aim of this study was to revise the CDS-MS criteria by removing the 2-h PPG test and determining the optimal fasting plasma glucose (FPG) cut-off for a diagnosis of hyperglycemia in the Chinese population. METHODS: The study population was from the 2007-08 China Diabetes and Metabolic Disorders Study. The optimal FPG diagnostic cut-off value was determined using receiver operating characteristic curves. Hyperglycemia defined using CDS-MS criteria was the end point. Agreement between different diagnostic methods was assessed using kappa values. RESULTS: The study enrolled 46 239 participants (mean age 44.95 years). The optimal diagnostic cut-off for FPG was found to be 5.62 mmol/L, which showed a sensitivity of 66.92%, a specificity of 89.09%, and an area under the curve of 0.848. Using this diagnostic criterion, the standardized prevalence of MS was similar to that using the CDS-MS criteria (18.26% vs 17.89%, respectively), with both values being lower than those obtained using conventional international criteria (20.64-26.67%). Compared with the CDS-MS criteria, the recommended FPG cut-off showed better agreement (kappa) with international criteria: 0.695, 0.774, and 0.730 with the International Diabetes Federation (IDF), revised Adult Treatment Panel III, and Joint Interim Statement of the IDF criteria, respectively. CONCLUSIONS: We recommend eliminating the 2-h PPG blood test and lowering the FPG diagnostic cut-off value to 5.6 mmol/L in the CDS-MS diagnostic criteria. PMID- 28640959 TI - The deeper self: an expanded view of consciousness. AB - As science continues to explore the mysteries of the unconscious, two critical questions remain. First, can unconscious impulses, desires, and feelings be willfully raised to the level of the conscious self?, and, if so, would the unveiling of unconscious mechanisms lead to genuine self-knowledge or empowerment? Second, can we methodically tap into the unconscious to gear ourselves along more creative lines? If the unconscious is a source of intuitive and creative inspiration, how might a more expansive understanding of consciousness help us to flourish? How can we harness the intuitive parts of ourselves to think "outside the box," transcending the limitations of preconceived categories? And along those same lines, how would an expanded view of the unconscious frame our spiritual experiences or offer spiritual nourishment? Writer Siri Hustvedt, historian of psychology Sonu Shamdasani, and neuropsychologist Mark Solms will tackle everything from noetic experiences and the role of intuition to the phenomenon of peak experience and Jung's "collective unconscious." PMID- 28640961 TI - Reply to 'Incidence, clinicopathological features and fusion transcript landscape of translocation renal cell carcinomas'. PMID- 28640960 TI - Ferulic acid alleviates symptoms of preeclampsia in rats by upregulating vascular endothelial growth factor. AB - Preeclampsia is a complication affecting pregnant women worldwide, which leads to maternal and fetal morbidity and mortality. In this study, we evaluated the efficacy of ferulic acid (FA) on an Nomega -nitro-L-arginine methyl ester hydrochloride (L-NAME) induced rat model of preeclampsia. L-NAME was administered to pregnant rats to induce preeclampsia. 48 rats were divided into three experimental groups (n=16 each): control group, preeclampsia group and preeclampsia with FA treatment (preeclampsia+FA). Physiological characteristics such as urine volume, total urine protein and blood pressure were assessed. Expressions levels of urinary nephrin and podocin mRNAs were analyzed by RT-PCR. Levels of renal vascular endothelial growth factor (VEGF), renal soluble fms-like tyrosine kinase-1 (sFlt-1) and serum placenta growth factor (PlGF) were also examined. Urine volume, total urine protein and blood pressure were markedly increased in preeclampsia group rats compared to control (P<.05), which were then significantly reduced in preeclampsia+FA group (P<.05). Expressions of urinary nephrin and podocin mRNAs, levels of VEGF, sFlt-1 and PlGF were also reversed in preeclampsia+FA group compared to preeclampsia rats (P<.05). We hereby report for the first time, FA alleviates preeclampsia symptoms in a rat preeclampsia model, supporting its potential value in treating preeclampsia. PMID- 28640962 TI - Awareness of Suicide Risk and Communication Between Health Care Professionals and Next-of-Kin of Suicides in the Month Before Suicide. AB - Based on psychological autopsy data, the study compared awareness of suicide risk in the deceased among next-of-kin (NOK) and health care professionals (HCPs), and communication between these two groups in the month before death. The NOKs had significantly more knowledge about the decedent's suicide warning signs than the HCPs (90.5% vs. 44.6%). Contact between NOK and HCP was initiated more often by the family than the HCPs (29.4% vs. 5.9%). The study found communication gaps between HCPs and NOK and stresses the need for suicide prevention strategies strengthening communication between these two groups. PMID- 28640963 TI - A Truncated Molecular Star. AB - A pentanuclear coordination complex assembled from any palladium(II) component and non-chelating ligands is hitherto unreported. The pentanuclear complex [Pd5 (L1)5 (L2)5 ](BF4 )10 , 1 reported here was prepared by the spontaneous complexation of [Pd(DMSO)4 ](BF4 )2 with the non-chelating bidentate ligands 1,4 phenylenebis(methylene) diisonicotinate, L1 and 4,4'-bipyridine, L2 in a one-pot method at room temperature. The planar polycyclic complex 1 with outer diameters of ~3 nm is termed as a "molecular star" owing to its resemblance with a pentagram shape. Interim paths leading to the star were also probed to decipher related dynamics of the system. PMID- 28640964 TI - Targeted mutagenesis in tetraploid switchgrass (Panicum virgatum L.) using CRISPR/Cas9. AB - The CRISPR/Cas9 system has become a powerful tool for targeted mutagenesis. Switchgrass (Panicum virgatum L.) is a high yielding perennial grass species that has been designated as a model biomass crop by the U.S. Department of Energy. The self-infertility and high ploidy level make it difficult to study gene function or improve germplasm. To overcome these constraints, we explored the feasibility of using CRISPR/Cas9 for targeted mutagenesis in a tetraploid cultivar 'Alamo' switchgrass. We first developed a transient assay by which a non-functional green fluorescent protein gene containing a 1-bp frameshift insertion in its 5' coding region was successfully mutated by a Cas9/sgRNA complex resulting in its restored function. Agrobacterium-mediated stable transformation of embryogenic calli derived from mature caryopses averaged a 3.0% transformation efficiency targeting the genes of teosinte branched 1(tb1)a and b and phosphoglycerate mutase (PGM). With a single construct containing two sgRNAs targeting different regions of tb1a and tb1b genes, primary transformants (T0) containing CRISPR/Cas9-induced mutations were obtained at frequencies of 95.5% (tb1a) and 11% (tb1b), respectively, with T0 mutants exhibiting increased tiller production. Meanwhile, a mutation frequency of 13.7% was obtained for the PGM gene with a CRISPR/Cas9 construct containing a single sgRNA. Among the PGM T0 mutants, six are heterozygous and one is homozygous for a 1-bp deletion in the target region with no apparent phenotypical alterations. We show that CRISPR/Cas9 system can generate targeted mutagenesis effectively and obtain targeted homozygous mutants in T0 generation in switchgrass, circumventing the need of inbreeding. PMID- 28640967 TI - Acta Physiologica Award: outperforming original articles from 2015 to 2017. PMID- 28640966 TI - Linking the degree of virilization in females with congenital adrenal hyperplasia to genotype. AB - Mutations of CYP21A2 variably decrease 21-hydroxylase activity and result in a spectrum of disease expressions in patients with congenital adrenal hyperplasia (CAH). We examined the association between CYP21A2 mutations and virilization (Prader score) in females with CAH. The study population included 187 CAH females with fully characterized CYP21A2 mutations. One hundred fifty-eight patients were sorted into groups by expected enzyme activity (percent of normal activity) of the less severely affected allele: (A) null, 0%; (B) I2G, 1%; (C) I172N, 2%; and (D) V281L, >2%. We observed an inverse relationship between virilization and residual enzyme activity (P < 0.001). Subjects in group A or B had a significantly higher likelihood (unadjusted odds ratio: 16; P < 0.001) of developing severe virilization compared with those in group C. Surprisingly, 24% of group D patients, whose mutation is usually associated with nonclassical (NC) CAH, had severe virilization. Among subjects with the NC P30L mutation, 66% expressed unexpected virilization. Virilization, usually leading to extensive reconstructive surgery, is highly likely in patients with null or I2G mutations; however, NC mutations (P30L/V281L) may also lead to unexpected virilization. These findings have implications for prenatal counseling and highlight the need for additional investigations into other factors that influence virilization in CAH. PMID- 28640965 TI - Atypical depression and double depression predict new-onset cardiovascular disease in U.S. adults. AB - BACKGROUND: Although depression is a risk factor for cardiovascular disease (CVD), it is unknown whether this risk varies across depressive disorder subtypes. Thus, we investigated atypical major depressive disorder (MDD) and double depression as predictors of new-onset CVD in a nationally representative sample of U.S. adults. METHODS: Prospective data from 28,726 adults initially free of CVD who participated in Wave 1 (2001-2002) and Wave 2 (2004-2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were examined. Lifetime depressive disorder subtypes (Wave 1) and incident CVD (Wave 2) were determined by structured interviews. RESULTS: We identified 1,116 incident CVD cases. In demographics adjusted models, the atypical MDD group had a higher odds of incident CVD than the no depression history (OR = 2.19, 95% CI: 1.71-2.81, P < .001), dysthymic disorder only (OR = 1.61, 95% CI: 1.08-2.39, P = .019), and nonatypical MDD (OR = 1.46, 95% CI: 1.11-1.91, P = .006) groups. Likewise, the double depression group had a higher odds of incident CVD than the no depression history (OR = 2.17, 95% CI: 1.92-2.45, P < .001), dysthymic disorder only (OR = 1.59, 95% CI: 1.16-2.19, P = .004), and MDD only (OR = 1.46, 95% CI: 1.20-1.77, P < .001) groups. Relationships were similar but attenuated after adjustment for CVD risk factors and anxiety disorders. CONCLUSIONS: Adults with atypical MDD or double depression may be subgroups of the depressed population at particularly high risk of new-onset CVD. Thus, these subgroups may (a) be driving the overall depression-CVD relationship and (b) be in need of earlier and/or more intense CVD primary prevention efforts to reduce their excess CVD burden. PMID- 28640968 TI - The impact of Andean Patagonian mycoflora in the search for new lead molecules. AB - Secondary metabolites from fungi have become a major source of chemical innovation in programs searching for lead molecules with bioactivities, especially over the last 50 years. In this review, we discuss the fundamental considerations in the discovery of molecules for agricultural and medicinal uses. This group of organisms possesses a strong potential for scientific and industrial communities. Recently, the incorporation of new technologies for the artificial cultivation of fungi and the use of better equipment to isolate and identify active metabolites has allowed the discovery of leading molecules for the design of new and safer drugs and pesticides. The geographical region including the Patagonian Andes mountains harbors a wide diversity of fungi, many of them still unknown and so far associated with Chilean-Argentinian Andean endemic forests. There have been very few chemical studies of the fungi located in this region. However, those few studies have allowed the discovery of new molecules. We argue that the richness of fungal biodiversity in this region offers an interesting source for the discovery of bioactive molecules for the basic and applied sciences. PMID- 28640969 TI - Control of breathing and ventilatory acclimatization to hypoxia in deer mice native to high altitudes. AB - AIM: We compared the control of breathing and heart rate by hypoxia between high- and low-altitude populations of Peromyscus mice, to help elucidate the physiological specializations that help high-altitude natives cope with O2 limitation. METHODS: Deer mice (Peromyscus maniculatus) native to high altitude and congeneric mice native to low altitude (Peromyscus leucopus) were bred in captivity at sea level. The F1 progeny of each population were raised to adulthood and then acclimated to normoxia or hypobaric hypoxia (12 kPa, simulating hypoxia at ~4300 m) for 5 months. Responses to acute hypoxia were then measured during stepwise reductions in inspired O2 fraction. RESULTS: Lowlanders exhibited ventilatory acclimatization to hypoxia (VAH), in which hypoxia acclimation enhanced the hypoxic ventilatory response, made breathing pattern more effective (higher tidal volumes and lower breathing frequencies at a given total ventilation), increased arterial O2 saturation and heart rate during acute hypoxia, augmented respiratory water loss and led to significant growth of the carotid body. In contrast, highlanders did not exhibit VAH - exhibiting a fixed increase in breathing that was similar to hypoxia-acclimated lowlanders - and they maintained even higher arterial O2 saturations in hypoxia. However, the carotid bodies of highlanders were not enlarged by hypoxia acclimation and were similar in size to those of normoxic lowlanders. Highlanders also maintained consistently higher heart rates than lowlanders during acute hypoxia. CONCLUSIONS: Our results suggest that highland deer mice have evolved high rates of alveolar ventilation and respiratory O2 uptake without the significant enlargement of the carotid bodies that is typical of VAH in lowlanders, possibly to adjust the hypoxic chemoreflex for life in high-altitude hypoxia. PMID- 28640970 TI - Prevalence of new psychoactive substances and prescription drugs in the Belgian driving under the influence of drugs population. AB - Driving under the influence of drugs (DUID) is a worldwide problem. Several countries have adopted DUID legislations which prove their deterrent effect and impact on road safety. However, the use of new psychoactive substances (NPS) and prescription drugs is not known, as the applied roadside screening tests have not yet been adapted for these compounds. In this study, 558 blood samples obtained during roadside controls in Belgium (January to August 2015) after a positive Drugwipe 5S(r) test and 199 oral fluid (OF) samples obtained from negatively screened test pads were analyzed. The NPS positivity rate was 7% in blood, while it reached 11% in OF. NPS detected were: diphenidine, ketamine, 4 fluoroamphetamine, 2-amino-indane, methoxetamine, alpha-PVP, methiopropamine, a mix of 5-MAPB/5-EAPB, TH-PVP, mephedrone, methedrone, 4-methylethylcathinone, 5 MeO-DALT, 4-Acetoxy-DiPT, AB Fubinaca, FUB-JWH018, JWH020, trifluoromethylphenylpiperazine, and ethylphenidate. Moreover, 17% of blood samples (and 5% of OF) contained an analgesic drug, 10% (0.5%) a benzodiazepine/hypnotic, 5% (2%) an antidepressant, 2% (3%) an antipsychotic, 2% an antiepileptic drug, and 1% methylphenidate. The presence of NPS in the young (and predominately male) DUID population is proven. Furthermore, a high level of poly-drug use including combinations of NPS, licit, and drugs of abuse was observed. Further research concerning the development of on-site NPS detection techniques should be established. Meanwhile, the effects of combined drug use on driving ability and the physical/psychological signs after NPS use should be performed to improve the on-site DUID detection of NPS by police officers, so they can engage in blood sampling for a general unknown screening. PMID- 28640971 TI - Enhanced recovery programme following laparoscopic colorectal resection for elderly patients. AB - BACKGROUND: The aim of this study was to investigate the feasibility and safety of an enhanced recovery programme (ERP) in patients aged >=75 years who undergo laparoscopic surgery for colorectal cancer. METHODS: Patients were divided into two groups according to perioperative management: the ERP group (Group A, n = 94) and the conventional perioperative care group (Group B, n = 157). The postoperative outcomes were compared between two groups. RESULTS: There were no differences in terms of age, gender, American Society of Anesthesiologists score, operative time or blood loss between two groups. Postoperative return of gastrointestinal function was significantly faster in Group A compared to Group B, including time to first flatus (2 versus 3 days, P < 0.001), first stool (3 versus 4 days, P = 0.001) and oral intake (1 versus 4 days, P < 0.001). Group A was associated with lower overall postoperative complication rate (26.6% versus 44.6%, P = 0.004) and general complication rate (14.9% versus 31.2%, P = 0.004). The median postoperative hospital stay was 6 days in Group A and 8 days in Group B (P < 0.001), respectively. CONCLUSIONS: ERP following laparoscopic colorectal resection for elderly patients is associated with faster postoperative recovery, shorter postoperative hospital stay and fewer complications compared with conventional perioperative care. PMID- 28640972 TI - Understanding adaptogenic activity: specificity of the pharmacological action of adaptogens and other phytochemicals. AB - Adaptogens are stress-response modifiers that increase an organism's nonspecific resistance to stress by increasing its ability to adapt and survive. The classical reductionist model is insufficiently complex to explain the mechanistic aspects of the physiological notion of "adaptability" and the adaptogenic activity of adaptogens. Here, I demonstrate that (1) the mechanisms of action of adaptogens are impossible to rationally describe using the reductionist concept of pharmacology, whereas the network pharmacology approach is the most suitable method; and (2) the principles of systems biology and pharmacological networks appear to be more suitable for conceptualizing adaptogen function and are applicable to any phytochemical. Molecular targets, signaling pathways, and networks common to adaptogens have been identified. They are associated with stress hormones and key mediators of the regulation of homeostasis. In this context, the mechanisms of action of adaptogens are specifically related to stress-protective activity and increased adaptability of the organism. Consequently, adaptogens exhibit polyvalent beneficial effects against chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, cancer, and other aging-related diseases. Current and potential uses of adaptogens are mainly related to stress-induced fatigue and cognitive function, mental illness, and behavioral disorders. Their prophylactic use by healthy subjects to ameliorate stress and prevent age-related diseases appears to be justified. It is very unlikely that the pharmacological activity of any phytochemical is specific and associated only with one type of receptor, particularly adaptogenic compounds, which affect key mediators of the adaptive stress response at intracellular and extracellular levels of communication. PMID- 28640973 TI - Production of red-flowered oilseed rape via the ectopic expression of Orychophragmus violaceus OvPAP2. AB - Oilseed rape (Brassica napus L.), which has yellow flowers, is both an important oil crop and a traditional tourism resource in China, whereas the Orychophragmus violaceus, which has purple flowers, likely possesses a candidate gene or genes to alter the flower colour of oilseed rape. A previously established B. napus line has a particular pair of O. violaceus chromosomes (M4) and exhibits slightly red petals. In this study, the transcriptomic analysis of M4, B. napus (H3), and O. violaceus with purple petals (OvP) and with white petals (OvW) revealed that most anthocyanin biosynthesis genes were up-regulated in both M4 and OvP. Read assembly and sequence alignment identified a homolog of AtPAP2 in M4, which produced the O. violaceus transcript (OvPAP2). The overexpression of OvPAP2 via the CaMV35S promoter in Arabidopsis thaliana led to different levels of anthocyanin accumulation in most organs, including the petals. However, the B. napus overexpression plants showed anthocyanin accumulation primarily in the anthers, but not the petals. However, when OvPAP2 was driven by the petal specific promoter XY355, the transgenic B. napus plants produced red anthers and red petals. The results of metabolomic experiments showed that specific anthocyanins accumulated to high levels in the red petals. This study illustrates the feasibility of producing red-flowered oilseed rape, thereby enhancing its ornamental value, via the ectopic expression of the OvPAP2 gene. Moreover, the practical application of this study for insect pest management in the crop is discussed. PMID- 28640974 TI - RESISTANCE TO POWDERY MILDEW8.1 boosts pattern-triggered immunity against multiple pathogens in Arabidopsis and rice. AB - The Arabidopsis gene RESISTANCE TO POWDERY MILDEW8.1 (RPW8.1) confers resistance to virulent fungal and oomycete pathogens that cause powdery mildew and downy mildew, respectively. However, the underlying mechanism remains unclear. Here, we show that ectopic expression of RPW8.1 boosts pattern-triggered immunity (PTI) resulting in enhanced resistance against different pathogens in both Arabidopsis and rice. In Arabidopsis, transcriptome analysis revealed that ectopic expression of RPW8.1-YFP constitutively up-regulates expression of many pathogen-associated molecular pattern (PAMP-)-inducible genes. Consistently, upon PAMP application, the transgenic line expressing RPW8.1-YFP exhibited more pronounced PTI responses such as callose deposition, production of reactive oxygen species, expression of defence-related genes and hypersensitive response-like cell death. Accordingly, the growth of a virulent bacterial pathogen was significantly inhibited in the transgenic lines expressing RPW8.1-YFP. Conversely, impairment of the PTI signalling pathway from PAMP cognition to the immediate downstream relay of phosphorylation abolished or significantly compromised RPW8.1-boosted PTI responses. In rice, heterologous expression of RPW8.1-YFP also led to enhanced resistance to the blast fungus Pyricularia oryzae (syn. Magnaporthe oryzae) and the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). Taken together, our data suggest a surprising mechanistic connection between RPW8.1 function and PTI, and demonstrate the potential of RPW8.1 as a transgene for engineering disease resistance across wide taxonomic lineages of plants. PMID- 28640976 TI - Subconductance states of mitochondrial chloride channels: implication for functionally-coupled tetramers. AB - Recently, it has been discovered that isoforms of intracellular chloride channels (CLIC) are present in cardiac mitochondria. By reconstituting rat cardiac mitochondrial chloride channels into bilayer lipid membranes, we detected three equally separated subconductance states with conductance increment of 45 pS and < 2% occupancy. The observed rare events of channel decomposition into substates, accompanied by disrupted gating, provide an insight into channel quaternary structure. Our findings suggest that the observed channels work as four functionally coupled subunits with synchronized gating. We discuss the putative connection of channel activity from native mitochondria with the recombinant CLIC channels. However, conclusive evidence is needed to prove this connection. PMID- 28640977 TI - Neurogenic bowel dysfunction: Clinical management recommendations of the Neurologic Incontinence Committee of the Fifth International Consultation on Incontinence 2013. AB - BACKGROUND: Evidence-based guidelines for the management of neurological disease and lower bowel dysfunction have been produced by the International Consultations on Incontinence (ICI). These are comprehensive guidelines, and were developed to have world-wide relevance. AIMS: To update clinical management of neurogenic bowel dysfunction from the recommendations of the 4th ICI, 2009. MATERIALS AND METHODS: A series of evidence reviews and updates were performed by members of the working group. The resulting guidelines were presented at the 2012 meeting of the European Association of Urology for consultation, and modifications applied to deliver evidence based conclusions and recommendations for the scientific report of the 5th edition of the ICI in 2013. RESULTS: The current review is a synthesis of the conclusions and recommendations, including the algorithms for initial and specialized management of neurogenic bowel dysfunction. The pathophysiology is described in terms of spinal cord injury, multiple sclerosis, and Parkinson's disease. Assessment requires detailed history and clinical assessment, general investigations, and specialized testing, if required. Treatment primarily focuses on optimizing stool consistency and regulating bowel evacuation to improve quality of life. Symptom management covers conservative and interventional measures to promote good habits and assist stool evacuation, along with prevention of incontinence. Education is essential to achieving optimal bowel management. DISCUSSION: The review offers a pragmatic approach to management in the context of complex pathophysiology and varied evidence base. PMID- 28640975 TI - NAC transcription factor JUNGBRUNNEN1 enhances drought tolerance in tomato. AB - Water deficit (drought stress) massively restricts plant growth and the yield of crops; reducing the deleterious effects of drought is therefore of high agricultural relevance. Drought triggers diverse cellular processes including the inhibition of photosynthesis, the accumulation of cell-damaging reactive oxygen species and gene expression reprogramming, besides others. Transcription factors (TF) are central regulators of transcriptional reprogramming and expression of many TF genes is affected by drought, including members of the NAC family. Here, we identify the NAC factor JUNGBRUNNEN1 (JUB1) as a regulator of drought tolerance in tomato (Solanum lycopersicum). Expression of tomato JUB1 (SlJUB1) is enhanced by various abiotic stresses, including drought. Inhibiting SlJUB1 by virus-induced gene silencing drastically lowers drought tolerance concomitant with an increase in ion leakage, an elevation of hydrogen peroxide (H2 O2 ) levels and a decrease in the expression of various drought-responsive genes. In contrast, overexpression of AtJUB1 from Arabidopsis thaliana increases drought tolerance in tomato, alongside with a higher relative leaf water content during drought and reduced H2 O2 levels. AtJUB1 was previously shown to stimulate expression of DREB2A, a TF involved in drought responses, and of the DELLA genes GAI and RGL1. We show here that SlJUB1 similarly controls the expression of the tomato orthologs SlDREB1, SlDREB2 and SlDELLA. Furthermore, AtJUB1 directly binds to the promoters of SlDREB1, SlDREB2 and SlDELLA in tomato. Our study highlights JUB1 as a transcriptional regulator of drought tolerance and suggests considerable conservation of the abiotic stress-related gene regulatory networks controlled by this NAC factor between Arabidopsis and tomato. PMID- 28640978 TI - Correction. PMID- 28640979 TI - Correction. PMID- 28640981 TI - Correction. PMID- 28640982 TI - Mechanisms of sphingosine-1-phosphate-mediated vasoconstriction of rat afferent arterioles. AB - AIM: Sphingosine-1-phosphate (S1P) influences resistance vessel function and is implicated in renal pathological processes. Previous studies revealed that S1P evoked potent vasoconstriction of the pre-glomerular microvasculature, but the underlying mechanisms remain incompletely defined. We postulated that S1P mediated pre-glomerular microvascular vasoconstriction involves activation of voltage-dependent L-type calcium channels (L-VDCC) and the rho/rho kinase pathway. METHODS: Afferent arteriolar reactivity was assessed in vitro using the blood-perfused rat juxtamedullary nephron preparation, and diameter was measured during exposure to physiological and pharmacological agents. RESULTS: Exogenous S1P (10-9 -10-5 mol L-1 ) evoked concentration-dependent vasoconstriction of afferent arterioles. Superfusion with nifedipine, a L-VDCC blocker, increased arteriolar diameter by 39 +/- 18% of baseline and significantly attenuated the S1P-induced vasoconstriction. Superfusion with the rho kinase inhibitor, Y-27632, increased diameter by 60 +/- 12% of baseline and also significantly blunted vasoconstriction by S1P. Combined nifedipine and Y-27632 treatment significantly inhibited S1P-induced vasoconstriction over the entire concentration range tested. In contrast, depletion of intracellular Ca2+ stores with the Ca2+ -ATPase inhibitors, thapsigargin or cyclopiazonic acid, did not alter the S1P-mediated vasoconstrictor profile. Scavenging reactive oxygen species (ROS) or inhibition of nicotinamide adenine dinucleotide phosphate oxidase activity significantly attenuated S1P-mediated vasoconstriction. CONCLUSION: Exogenous S1P elicits potent vasoconstriction of rat afferent arterioles. These data also demonstrate that S1P-mediated pre-glomerular vasoconstriction involves activation of L-VDCC, the rho/rho kinase pathway and ROS. Mobilization of Ca2+ from intracellular stores is not required for S1P-mediated vasoconstriction. These studies reveal a potential role for S1P in the modulation of renal microvascular tone. PMID- 28640983 TI - Multiplexed CRISPR/Cas9-mediated metabolic engineering of gamma-aminobutyric acid levels in Solanum lycopersicum. AB - In recent years, the type II CRISPR system has become a widely used and robust technique to implement site-directed mutagenesis in a variety of species including model and crop plants. However, few studies manipulated metabolic pathways in plants using the CRISPR system. Here, we introduced the pYLCRISPR/Cas9 system with one or two single-site guide RNAs to target the tomato phytoene desaturase gene. An obvious albino phenotype was observed in T0 regenerated plants, and more than 61% of the desired target sites were edited. Furthermore, we manipulated the gamma-aminobutyric acid (GABA) shunt in tomatoes using a multiplex pYLCRISPR/Cas9 system that targeted five key genes. Fifty-three genome-edited plants were obtained following single plant transformation, and these samples represented single to quadruple mutants. The GABA accumulation in both the leaves and fruits of genomically edited lines was significantly enhanced, and the GABA content in the leaves of quadruple mutants was 19-fold higher than that in wild-type plants. Our data demonstrate that the multiplex CRISPR/Cas9 system can be exploited to precisely edit tomato genomic sequences and effectively create multisite knockout mutations, which could shed new light on plant metabolic engineering regulations. PMID- 28640984 TI - Is it right to ignore learning-curve patients? Laparoscopic colorectal trials. AB - BACKGROUND: Increasingly complex, technically demanding surgical procedures utilizing emerging technologies have developed over recent decades and are recognized as having long 'learning curves'. This raises significant new issues. Ethically and scientifically, the outcome of a patient in the learning curve is as important as the outcome of a patient outside the learning curve. The aim of this study is to highlight just one aspect of our approach to learning-curve patients that should change. METHODS: The protocols of multicentre, prospective, randomized trials of patients undergoing either traditional open or laparoscopic surgery for colorectal cancer were reviewed. The number of patients excluded from the published trial results because they were in surgeons' learning curves was calculated. The seven editorials accompanying these publications were also examined for any mention of these patients. RESULTS: The eight studies identified had similar designs. All patients in the surgeons' laparoscopic learning curves, which were often several years long, were excluded from the actual trials. The total number of patients included in the trial publications was 5680. The number of patients excluded because they were in the surgeons' laparoscopic learning curves was >10 605. In none of the studies or accompanying editorials is there any mention of the total number of patients in the surgeons' learning curves, these patients' outcomes or how inclusion of their outcomes might have affected the overall results. CONCLUSION: Learning curves are inescapable in modern medicine. Our recognition of patients in these curves should evolve, with more data about them included in trial publications. PMID- 28640985 TI - The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C. AB - The frontotemporal lobar degeneration (FTLD) protein progranulin (PGRN) is essential for proper lysosomal function. PGRN localizes in the lysosomal compartment within the cell. Prosaposin (PSAP), the precursor of lysosomal saposin activators (saposin A, B, C, D), physically interacts with PGRN. Previously, we have shown that PGRN and PSAP facilitate each other's lysosomal trafficking. Here, we report that the interaction between PSAP and PGRN requires the linker region of saposin B and C (BC linker). PSAP protein with the BC linker mutated, fails to interact with PGRN and deliver PGRN to lysosomes in the biosynthetic and endocytic pathways. On the other hand, PGRN interacts with PSAP through multiple granulin motifs. Granulin D and E bind to PSAP with similar affinity as full-length PGRN. Read the Editorial Comment for this article on page 154. PMID- 28640986 TI - Antimonene Quantum Dots: Synthesis and Application as Near-Infrared Photothermal Agents for Effective Cancer Therapy. AB - Photothermal therapy (PTT) has shown significant potential for cancer therapy. However, developing nanomaterials (NMs)-based photothermal agents (PTAs) with satisfactory photothermal conversion efficacy (PTCE) and biocompatibility remains a key challenge. Herein, a new generation of PTAs based on two-dimensional (2D) antimonene quantum dots (AMQDs) was developed by a novel liquid exfoliation method. Surface modification of AMQDs with polyethylene glycol (PEG) significantly enhanced both biocompatibility and stability in physiological medium. The PEG-coated AMQDs showed a PTCE of 45.5 %, which is higher than many other NMs-based PTAs such as graphene, Au, MoS2 , and black phosphorus (BP). The AMQDs-based PTAs also exhibited a unique feature of NIR-induced rapid degradability. Through both in vitro and in vivo studies, the PEG-coated AMQDs demonstrated notable NIR-induced tumor ablation ability. This work is expected to expand the utility of 2D antimonene (AM) to biomedical applications through the development of an entirely novel PTA platform. PMID- 28640987 TI - Independent Effects of Apolipoprotein E and Cerebrovascular Burden on Later-Life Depression: The Wisconsin Longitudinal Study. AB - OBJECTIVE: Studies evaluating the effect of apolipoprotein E (APOE) on vascular depression are sparse, employ heterogeneous methods, and yield inconsistent results. One possibility is that APOE is a moderator of another predictor such as cerebrovascular burden. This longitudinal study examines the relationships between APOE, cerebrovascular burden, and depressive symptomatology in a large cohort sample from midlife to later life. METHODS: Data include 3,203 participants across 18 years (1993-2011) from the Wisconsin Longitudinal Study (baseline mean age = 53 years). Depressive symptomatology was measured using the Center for Epidemiologic Studies Depression scale. Cerebrovascular burden was operationalized as hypertension, high blood sugar or diabetes, and other heart problems. APOE genotyping was completed using saliva samples. Hypotheses were examined via a moderated path model and binary logistic regression. RESULTS: Results supported the hypothesized path model (root mean square error of approximation = 0.041; comparative fit index = 0.959); however, APOE-conferred risk was not a significant moderator of the 2004 or 2011 vascular depression effect and only approached significance as a predictor of depression in 2011 (P = .079). The logistic regression yielded APOE as a significant predictor of clinically significant depressive symptoms in 2011 (P = .02, Exp(B) = 1.197). CONCLUSIONS: The present findings suggest that APOE may influence expression of depressive symptomatology as adults age into and beyond their mid-70s but do not indicate APOE as a moderator of vascular depression. Results posit a potential explanation for inconsistent past findings. PMID- 28640988 TI - Does Half-Life Matter After Antipsychotic Discontinuation? A Relapse Comparison in Schizophrenia With 3 Different Formulations of Paliperidone. AB - OBJECTIVE: To evaluate the effect of 1 oral and 2 distinct long-acting injectable (LAI) formulations of the same antipsychotic on times to relapse following medication discontinuation. METHODS: Data were drawn from 3 similarly designed, multicenter, double-blind, placebo-controlled, randomized-withdrawal studies of paliperidone in adults with a schizophrenia diagnosis (according to DSM-IV criteria for >= 1 year before screening): once-daily extended-release oral paliperidone (ORAL paliperidone), once-monthly paliperidone palmitate (PP1M), and once-every-3-months paliperidone palmitate (PP3M). In a post hoc analysis, we compared median time to relapse across the treatment-withdrawal arms of the 3 studies using final analysis datasets. Time to relapse in the withdrawal arm of each study was examined using log-rank tests and Cox proportional hazards models. RESULTS: Four hundred forty-nine patients were withdrawn from 3 paliperidone formulations: 101 from ORAL paliperidone, 203 from PP1M, and 145 from PP3M. Postwithdrawal median (95% confidence interval [CI]) days to relapse were 58 days (42-114 days) for ORAL paliperidone, 172 days (134-222 days) for PP1M, and 395 days (274 days-not reached) for PP3M (P < .0001, pairwise comparisons). Relapse risk was significantly lower (P < .001) for patients who withdrew from either PP formulation relative to ORAL paliperidone and additionally for patients who withdrew from PP3M relative to PP1M. CONCLUSIONS: Results demonstrate that 50% of patients who withdrew treatment from ORAL paliperidone, PP1M, or PP3M remained relapse free for approximately 2 months, 6 months, and 13 months, respectively. This may be relevant for risk mitigation strategies in schizophrenia, a condition in which interruptions in maintenance antipsychotic treatment are commonplace and unpredictable. LAI antipsychotic formulations may provide substantial delays over oral equivalents in times to relapse when patients discontinue therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00086320, NCT00111189, and NCT01529515. PMID- 28640989 TI - Stimulant Treatment Trajectories Are Associated With Neural Reward Processing in Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: The past decades have seen a surge in stimulant prescriptions for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants acutely alleviate symptoms and cognitive deficits associated with ADHD by modulating striatal dopamine neurotransmission and induce therapeutic changes in brain activation patterns. Long-term functional changes after treatment are unknown, as long-term studies are scarce and have focused on brain structure. In this observational study (2009-2012), we investigated associations between lifetime stimulant treatment history and neural activity during reward processing. METHODS: Participants fulfilling DSM-5 criteria for ADHD (N = 269) were classified according to stimulant treatment trajectory. Of those, 124 performed a monetary incentive delay task during magnetic resonance imaging, all in their nonmedicated state (nEARLY&INTENSE = 51; nLATE&MODERATE = 49; nEARLY&MODERATE = 9; nNAIVE = 15; mean age = 17.4 years; range, 10-26 years). Whole-brain analyses were performed with additional focus on the striatum, concentrating on the 2 largest treatment groups. RESULTS: Compared to the late-and-moderate treatment group, the early-and-intense treatment group showed more activation in the supplementary motor area and dorsal anterior cingulate cortex (SMA/dACC) during reward outcome (cluster size = 8,696 mm3; PCLUSTER < .001). SMA/dACC activation of the control group fell in between the 2 treatment groups. Treatment history was not associated with striatal activation during reward processing. CONCLUSIONS: Our findings are compatible with previous reports of acute increases of SMA/dACC activity in individuals with ADHD after stimulant administration. Higher SMA/dACC activity may indicate that patients with a history of intensive stimulant treatment, but currently off medication, recruit brain regions for cognitive control and/or decision-making upon being rewarded. No striatal or structural changes were found. PMID- 28640990 TI - Opiate Antagonists Do Not Interfere With the Clinical Benefits of Stimulants in ADHD: A Double-Blind, Placebo-Controlled Trial of the Mixed Opioid Receptor Antagonist Naltrexone. AB - OBJECTIVE: Methylphenidate activates MU-opioid receptors, which are linked to euphoria. MU-Opioid antagonists, such as naltrexone, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential. This study assessed whether the combination of naltrexone with methylphenidate is well tolerated while preserving the clinical benefits of stimulants in subjects with attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate from January 2013 to July 2015. Spheroidal Oral Drug Absorption System (SODAS) methylphenidate was administered twice daily, was titrated to approximately 1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with a test dose of immediate-release methylphenidate. The primary outcome measure was the Adult ADHD Investigator Symptom Report Scale (AISRS). RESULTS: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS methylphenidate and randomly assigned to naltrexone 50 mg or placebo. Thirty-one subjects completed the study through week 3, and 25 completed through week 6. Throughout 6 weeks of blinded naltrexone and open methylphenidate treatment, the coadministration of naltrexone with methylphenidate did not interfere with the clinical effectiveness of methylphenidate for ADHD symptoms. Additionally, the combination of naltrexone and methylphenidate did not produce an increase in adverse events compared with methylphenidate alone. CONCLUSIONS: Our findings provide support for the concept of combining opioid receptor antagonists with stimulants to provide an effective stimulant formulation with less abuse potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01673594. PMID- 28640992 TI - Crystalline Organic Pigment-Based Field-Effect Transistors. AB - Three conjugated pigment molecules with fused hydrogen bonds, 3,7 diphenylpyrrolo[2,3-f]indole-2,6(1H,5H)-dione (BDP), (E)-6,6'-dibromo-[3,3' biindolinylidene]-2,2'-dione (IIDG), and 3,6-di(thiophen-2-yl)-2,5-dihydropyrrolo [3,4-c]pyrrole-1,4-dione (TDPP), were studied in this work. The insoluble pigment molecules were functionalized with tert-butoxylcarbonyl (t-Boc) groups to form soluble pigment precursors (BDP-Boc, IIDG-Boc, and TDPP-Boc) with latent hydrogen bonding. The single crystals of soluble pigment precursors were obtained. Upon simple thermal annealing, the t-Boc groups were removed and the soluble pigment precursor molecules with latent hydrogen bonding were converted into the original pigment molecules with fused hydrogen bonding. Structural analysis indicated that the highly crystalline soluble precursors were directly converted into highly crystalline insoluble pigments, which are usually only achievable by gas-phase routes like physical vapor transport. The distinct crystal structure after the thermal annealing treatment suggests that fused hydrogen bonding is pivotal for the rearrangement of molecules to form a new crystal in solid state, which leads to over 2 orders of magnitude enhancement in charge mobility in organic field effect transistor (OFET) devices. This work demonstrated that crystalline OFET devices with insoluble pigment molecules can be fabricated by their soluble precursors. The results indicated that a variety of commercially available conjugated pigments could be potential active materials for high-performance OFETs. PMID- 28640993 TI - Locking-In Optimal Nanoscale Structure Induced by Naphthalenediimide-Based Polymeric Additive Enables Efficient and Stable Inverted Polymer Solar Cells. AB - Operational stability and high performance are the most critical issues that must be addressed in order to propel and advance the current polymer solar cell (PSC) technology to the next level, such as manufacturing and mass production. Herein, we report a high power conversion efficiency (PCE) of 11.2%, together with an excellent device stability in PTB7-Th:PC71BM-based PSCs in the inverted structure by introducing the n-type P(NDI2OD-T2) macromolecular additive (>75% PCE retention at high temperature up to 120 degrees C, >97% PCE retention after 6 months in inert conditions, >93% PCE retention after 2 months in air with encapsulation, and >80% PCE retention after 140 h in air without encapsulation). The PCE is the highest value ever reported in the single-junction systems based on the PTB7 family and is also comparable to the previously reported highest PCE of inverted PSCs. These promising results are attributed to the efficient optimization and stabilization of the blend film morphology in the photoactive layer, achieved using the P(NDI2OD-T2) additive. From the perspective of manufacturing, our studies demonstrate a promising pathway for fabricating low cost PSCs with high efficiency as well as long-term stability. PMID- 28640991 TI - A Risk Algorithm for the Persistence of Suicidal Thoughts and Behaviors During College. AB - OBJECTIVE: The primary aims of this study are to (a) identify patterns of suicidal thoughts and behaviors (STB) during college among students with lifetime pre-matriculation STB and (b) develop a risk-screening algorithm for persistence of pre-matriculation STB during college. METHODS: Data come from the Leuven College Surveys, a series of prospective cohort studies of all incoming KU Leuven University freshmen. In the academic year 2012-2013, 4,889 incoming freshmen (73.2% response rate) provided baseline data on sociodemographic variables, childhood-adolescent traumatic experiences, 12-month stressful experiences, 12 month mental disorders, 12-month STB, and severity markers of pre-matriculation STB. A total of 2,566 students (69.3% conditional response rate) participated in 12- and 24-month follow-up surveys during the first 2 college years. RESULTS: Thirteen percent (weighted n = 535) of incoming freshmen reported lifetime pre matriculation STB. Of those, 28.0% reported 12-month STB in 1 follow-up assessment, and another 27.7%, in both follow-up assessments. High persistence of STB (ie, 12-month STB in 2 follow-up assessments) was most strongly associated with severity markers of pre-matriculation STB, with odds ratios in the 2.4-10.3 range and population attributable risk proportions between 9.2% and 50.8%. When the aim was for less than 50% of false-positive cases (positive predictive value = 54.4%), a multivariate predictive risk algorithm (cross-validated area under the curve = 0.79) situated 59.9% of highly persistent cases among the 30% respondents with highest baseline predicted risk. CONCLUSIONS: An individualized web-based screening approach is a promising strategy to identify students at the time of university entrance who may be at high risk for STB persistence during their academic career. PMID- 28640994 TI - Promotion of Electrocatalytic Hydrogen Evolution Reaction on Nitrogen-Doped Carbon Nanosheets with Secondary Heteroatoms. AB - Dual heteroatom-doped carbon materials are efficient electrocatalysts via a synergistic effect. With nitrogen as the primary dopant, boron, sulfur, and phosphorus can be used as secondary elements for co-doped carbons. However, evaluation and analysis of the promotional effect of B, P, and S to N-doped carbons has not been widely researched. Here we report a robust platform that is constructed through polydopamine to prepare N,B-, N,P-, and N,S-co-doped carbon nanosheets, characterized by similar N species content and efficient B, P, and S doping. Systematic investigation reveals S to have the greatest promotional effect in hydrogen evolution reactions (HER) followed by P and that B decreases the activity of N-doped carbons. Experimental and theoretical analyses show the secondary heteroatom promotional effect is impacted by the intrinsic structures and extrinsic surface areas of both materials, i.e., electronic structures exclusively determine the catalytic activity of active sites, while large surface areas optimize apparent HER performance. PMID- 28640995 TI - Colloidal Gold Nanoparticles Induce Changes in Cellular and Subcellular Morphology. AB - Exposure of cells to colloidal nanoparticles (NPs) can have concentration dependent harmful effects. Mostly, such effects are monitored with biochemical assays or probes from molecular biology, i.e., viability assays, gene expression profiles, etc., neglecting that the presence of NPs can also drastically affect cellular morphology. In the case of polymer-coated Au NPs, we demonstrate that upon NP internalization, cells undergo lysosomal swelling, alterations in mitochondrial morphology, disturbances in actin and tubulin cytoskeleton and associated signaling, and reduction of focal adhesion contact area and number of filopodia. Appropriate imaging and data treatment techniques allow for quantitative analyses of these concentration-dependent changes. Abnormalities in morphology occur at similar (or even lower) NP concentrations as the onset of reduced cellular viability. Cellular morphology is thus an important quantitative indicator to verify harmful effects of NPs to cells, without requiring biochemical assays, but relying on appropriate staining and imaging techniques. PMID- 28640996 TI - Polyoxometalate-Based Radiosensitization Platform for Treating Hypoxic Tumors by Attenuating Radioresistance and Enhancing Radiation Response. AB - Radioresistance is one of the undesirable impediments in hypoxic tumors, which sharply diminishes the therapeutic effectiveness of radiotherapy and eventually results in the failure of their treatments. An attractive strategy for attenuating radioresistance is developing an ideal radiosensitization system with appreciable radiosensitization capacity to attenuate tumor hypoxia and reinforce radiotherapy response in hypoxic tumors. Therefore, we describe the development of Gd-containing polyoxometalates-conjugated chitosan (GdW10@CS nanosphere) as a radiosensitization system for simultaneous extrinsic and intrinsic radiosensitization, by generating an overabundance of cytotoxic reactive oxygen species (ROS) using high-energy X-ray stimulation and mediating the hypoxia inducible factor-1a (HIF-1a) siRNA to down-regulate HIF-1alpha expression and suppress broken double-stranded DNA self-healing. Most importantly, the GdW10@CS nanospheres have the capacity to promote the exhaustion of intracellular glutathione (reduced GSH) by synergy W6+-triggered GSH oxidation for sufficient ROS generation, thereby facilitating the therapeutic efficiency of radiotherapy. As a result, the as-synthesized GdW10@CS nanosphere can overcome radioresistance of hypoxic tumors through a simultaneous extrinsic and intrinsic strategy to improve radiosensitivity. We have demonstrated GdW10@CS nanospheres with special radiosensitization behavior, which provides a versatile approach to solve the critical radioresistance issue of hypoxic tumors. PMID- 28640997 TI - From 1D Polymers to 2D Polymers: Preparation of Free-Standing Single-Monomer Thick Two-Dimensional Conjugated Polymers in Water. AB - Recently, investigation on two-dimensional (2D) organic polymers has made great progress, and conjugated 2D polymers already play a dynamic role in both academic and practical applications. However, a convenient, noninterfacial approach to obtain single-layer 2D polymers in solution, especially in aqueous media, remains challenging. Herein, we present a facile, highly efficient, and versatile "1D to 2D" strategy for preparation of free-standing single-monomer-thick conjugated 2D polymers in water without any aid. The 2D structure was achieved by taking advantage of the side-by-side self-assembly of a rigid amphiphilic 1D polymer and following topochemical photopolymerization in water. The spontaneous formation of single-layer polymer sheets was driven by synergetic association of the hydrophobic interactions, pi-pi stacking interactions, and electrostatic repulsion. Both the supramolecular sheets and the covalent sheets were confirmed by spectroscopic analyses and electron microscope techniques. Moreover, in comparison of the supramolecular 2D polymer, the covalent 2D polymer sheets exhibited not only higher mechanical strength but also higher conductivity, which can be ascribed to the conjugated network within the covalent 2D polymer sheets. PMID- 28640999 TI - Common and Potentially Prebiotic Origin for Precursors of Nucleotide Synthesis and Activation. AB - We have recently shown that 2-aminoimidazole is a superior nucleotide activating group for nonenzymatic RNA copying. Here we describe a prebiotic synthesis of 2 aminoimidazole that shares a common mechanistic pathway with that of 2 aminooxazole, a previously described key intermediate in prebiotic nucleotide synthesis. In the presence of glycolaldehyde, cyanamide, phosphate and ammonium ion, both 2-aminoimidazole and 2-aminooxazole are produced, with higher concentrations of ammonium ion and acidic pH favoring the former. Given a 1:1 mixture of 2-aminoimidazole and 2-aminooxazole, glyceraldehyde preferentially reacts and cyclizes with the latter, forming a mixture of pentose aminooxazolines, and leaving free 2-aminoimidazole available for nucleotide activation. The common synthetic origin of 2-aminoimidazole and 2-aminooxazole and their distinct reactivities are suggestive of a reaction network that could lead to both the synthesis of RNA monomers and to their subsequent chemical activation. PMID- 28641000 TI - Magnetic Properties of the Distorted Kagome Lattice Mn3(1,2,4-(O2C)3C6H3)2. AB - Kagome lattice types have been of intense interest as idealized examples of extended frustrated spin systems. Here we demonstrate how the use of neutron diffraction and inelastic neutron scattering coupled with spin wave theory calculations can be used to elucidate the complex magnetic interactions of extended spin networks. We show that the magnetic properties of the coordination polymer Mn3(1,2,4-(O2C)3C6H3)2, a highly distorted kagome lattice, have been erroneously characterized as a canted antiferromagnet in previous works. Our results demonstrate that, although the magnetic structure is ferrimagnetic, with a net magnetic moment, frustration persists in the system. We conclude by showing that the conventions of the Goodenough-Kanamori rules, which are often applied to similar magnetic exchange interactions, are not relevant in this case. PMID- 28641001 TI - Atropisomerism in Tertiary Biaryl 2-Amides: A Study of Ar-CO and Ar-Ar' Rotational Barriers. AB - A rotational barrier study was performed on eight tertiary biaryl 2-amides using variable-temperature (VT) NMR and exchange (EXSY) spectroscopy experiments. Seven out of the eight 2-amido-2'-methylbiphenyls with additional 3- and 6-substitution patterns (1-7) were found to have approximately similar rotational barriers (DeltaG?Tc = 56.5-67.5 kJ/mol). However, for both 3- and 6-substitution (8), the rotational barrier was found to be significantly higher (DeltaG? = 102.6-103.8 kJ/mol). Computational studies performed on all eight compounds gave results in good agreement with the experimental rotational barriers. A transition state in which atropisomerism occurs by a cooperative rotation of the Ar-CO and Ar-Ar' bonds depending on substituent location is proposed. PMID- 28640998 TI - Oximes and Hydrazones in Bioconjugation: Mechanism and Catalysis. AB - The formation of oximes and hydrazones is employed in numerous scientific fields as a simple and versatile conjugation strategy. This imine-forming reaction is applied in fields as diverse as polymer chemistry, biomaterials and hydrogels, dynamic combinatorial chemistry, organic synthesis, and chemical biology. Here we outline chemical developments in this field, with special focus on the past ~10 years of developments. Recent strategies for installing reactive carbonyl groups and alpha-nucleophiles into biomolecules are described. The basic chemical properties of reactants and products in this reaction are then reviewed, with an eye to understanding the reaction's mechanism and how reactant structure controls rates and equilibria in the process. Recent work that has uncovered structural features and new mechanisms for speeding the reaction, sometimes by orders of magnitude, is discussed. We describe recent studies that have identified especially fast reacting aldehyde/ketone substrates and structural effects that lead to rapid-reacting alpha-nucleophiles as well. Among the most effective new strategies has been the development of substituents near the reactive aldehyde group that either transfer protons at the transition state or trap the initially formed tetrahedral intermediates. In addition, the recent development of efficient nucleophilic catalysts for the reaction is outlined, improving greatly upon aniline, the classical catalyst for imine formation. A number of uses of such second- and third-generation catalysts in bioconjugation and in cellular applications are highlighted. While formation of hydrazone and oxime has been traditionally regarded as being limited by slow rates, developments in the past 5 years have resulted in completely overturning this limitation; indeed, the reaction is now one of the fastest and most versatile reactions available for conjugations of biomolecules and biomaterials. PMID- 28641002 TI - Mechanistic Study of SmI2/H2O and SmI2/Amine/H2O-Promoted Chemoselective Reduction of Aromatic Amides (Primary, Secondary, Tertiary) to Alcohols via Aminoketyl Radicals. AB - Samarium(II) iodide-water and samarium(II) iodide-water-amine complexes have been recognized as valuable reagents for the selective generation of aminoketyl radicals from amides and derivatives. The resulting aminoketyl radicals can undergo reduction or reductive cyclization pathways, providing a powerful method for (i) direct synthesis of alcohols from amides by the challenging N-C bond scission and (ii) synthesis of nitrogen-containing heterocycles via polarity reversal of the amide bond. This report describes mechanistic investigation into samarium(II) iodide-water and samarium(II) iodide-water-amine-mediated generation of benzylic aminoketyl radicals from aromatic primary, secondary, and tertiary amides (benzamides). The mechanistic experiments suggest that the rate and selectivity of the reduction is closely dependent on the water concentration and the type of amide undergoing the reduction. The data also suggest that benzylic aminoketyl radicals generated in the reduction of benzamides are significantly more dependent on the electronic effects of alpha-substitution than the corresponding aminoketyl radicals generated by single-electron transfer to unactivated aliphatic amides; however, little variation in terms of steric influence of N-substituents is observed. These observations will have implications for the design of reductive processes involving Sm(II)-mediated reduction of amides and reductive umpolung cyclizations via aminoketyl radicals as a key step. PMID- 28641003 TI - Synthesis and Anti-inflammatory Evaluation of 2-Aminobenzaldehydes via Ir(III) Catalyzed C-H Amidation of Aldimines with Acyl Azides. AB - The aldimine-directed C-H amidation of various arenes with N-acyl azides as amidation surrogates under cationic iridium(III) catalysis is described. This transformation efficiently provides a range of 2-aminobenzaldehyde derivatives with excellent site selectivity and functional group compatibility. The resulting 2-aminobenzaldehyde framework provides facile access to a range of biologically interesting heterocycles. In addition, all synthetic compounds were screened for anti-inflammatory activity against interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) with lipopolysaccharide (LPS)-induced RAW264.7 cells. Generally, a range of ortho-amidated benzaldehydes displayed promising inhibitory activity against IL-1beta and TNF-alpha compared to dexamethasone as a positive control. Notably, compounds (3ae and 4ac) were found to exhibit potent anti-inflammatory activity stronger than that of dexamethasone. PMID- 28641004 TI - Performance of the G0W0 Method in Predicting the Electronic Gap of TiO2 Nanoparticles. AB - Using a relativistic all-electron description and numerical atomic-centered orbital basis set, the performance of the G0W0 method on the electronic band gap of (TiO2)n nanoparticles (n = 1-20) is investigated. Results are presented for G0W0 on top of hybrid (PBE0 and a modified version with 12.5% of Fock exchange) functionals. The underestimation of the electronic band gap from Kohn-Sham orbital energies is corrected by the quasiparticle energies from the G0W0 method, which are consistent with the variational DeltaSCF approach. A clear correlation between both methods exists regardless of the hybrid functional employed. In addition, the vertical ionization potential and electron affinity from quasiparticle energies show a systematic correlation with the DeltaSCF calculated values. On the other hand, the shape of the nanoparticles promotes some deviations on the electronic band gap. In conclusion, this study shows the following: (i) A systematic correlation exists between band gaps, ionization potentials, and electron affinities of TiO2 nanoparticles as predicted from variational DeltaSCF and G0W0 methods. (ii) The G0W0 approach can be successfully used to study the electronic band gap of realistic size nanoparticles at an affordable computational cost with a DeltaSCF accuracy giving results that are directly related with those from photoemission spectroscopy. (iii) The quasiparticle energies are explicitly required to shed light on the photocatalytic properties of TiO2. (iv) The G0W0 approach emerges as an accurate method to investigate the photocatalytic properties of both nanoparticles and extended semiconductors. PMID- 28641005 TI - Electron Crystallography Reveals Atomic Structures of Metal-Organic Nanoplates with M12(MU3-O)8(MU3-OH)8(MU2-OH)6 (M = Zr, Hf) Secondary Building Units. AB - Nanoscale metal-organic frameworks (nMOFs) have shown tremendous potential in cancer therapy and biomedical imaging. However, their small dimensions present a significant challenge in structure determination by single-crystal X-ray crystallography. We report here the structural determination of nMOFs by rotation electron diffraction (RED). Two isostructural Zr- and Hf-based nMOFs with linear biphenyldicarboxylate (BPDC) or bipyridinedicarboxylate (BPYDC) linkers are stable under intense electron beams to allow the collection of high-quality RED data, which reveal a MOF structure with M12(MU3-O)8(MU3-OH)8(MU2-OH)6 (M = Zr, Hf) secondary building units (SBUs). The nMOF structures differ significantly from their UiO bulk counterparts with M6(MU3-O)4(MU3-OH)4 SBUs and provide the foundation for clarifying the structures of a series of previously reported nMOFs with significant potential in cancer therapy and biological imaging. Our work clearly demonstrates the power of RED in determining nMOF structures and elucidating the formation mechanism of distinct nMOF morphologies. PMID- 28641006 TI - DFT Simulation of Structural and Optical Properties of 9-Aminoacridine Half Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA. AB - In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru(II) anticancer agent and two new closely related Rh(III) and Ir(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, omegaB97X, omegaB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2 SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the omegaB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl3) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to omegaB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices. PMID- 28641007 TI - Palladium-Catalyzed SN2'-Cyclization of Ambivalent (Bromoalkadienyl)malonates: Preparation of Medium- to Large-Membered Endocyclic Allenes. AB - A palladium-catalyzed reaction for preparing various endocyclic allenes was developed. The substrates for the reaction were readily available omega (pronucleophile-tethered)-3-bromo-1,3-alkadienes, and a palladium-catalyst facilitated their unimolecular SN2'-cyclization in the presence of potassium tert butoxide to give the corresponding 9- to 16-membered endocyclic allenes in fair yields of up to 67% together with the dimeric 16- to 32-membered endocyclic bis allenes and other oligomeric/polymeric intermolecular reaction products. For higher yields of the monomeric endocyclic allenes, the reaction needed to be conducted under high-dilution conditions. Using a chiral palladium catalyst, axially chiral endocyclic allenes were obtained in up to 70% ee. PMID- 28641009 TI - Metal Halide Perovskites as Mixed Electronic-Ionic Conductors: Challenges and Opportunities-From Hysteresis to Memristivity. AB - Metal halide perovskites are promising candidates for many classes of different optoelectronic devices. Apart from being a semiconductor, they additionally show ionic conductivity. It expresses itself in slow response times, reversible degradation, and hysteresis in the current-voltage characteristics of solar cells. This Perspective gives a condensed overview about experiments and theory on ion migration in metal halide perovskites focusing on its effects in solar cells. Apart from being a potential stability concern for photovoltaics, ion migration paired with the excellent optoelectronic properties of this material offers opportunities for novel devices such as optically controlled memristors and switchable diodes. PMID- 28641008 TI - Hypoxia-Induced Changes in the Fibroblast Secretome, Exosome, and Whole-Cell Proteome Using Cultured, Cardiac-Derived Cells Isolated from Neonatal Mice. AB - Cardiac fibroblasts (CFs) represent a major subpopulation of cells in the developing and adult heart. Cardiomyocyte (CM) and CF intercellular communication occurs through paracrine interactions and modulate myocyte development and stress response. Detailed proteomic analysis of the CF secretome in normal and stressed conditions may offer insights into the role of CF in heart development and disease. Primary neonatal mouse CFs were isolated and cultured for 24 h in 21% (normoxic) or 2% (hypoxic) O2. Conditioned medium was separated to obtain exosomes (EXO) and EXO-depleted secretome fractions. Multidimensional protein identification technology was performed on secreted fractions. Whole cell lysate data were also generated to provide subcellular context to the secretome. Proteomic analysis identified 6163 unique proteins in total. Statistical (QSpec) analysis identified 494 proteins differentially expressed between fractions and oxygen conditions. Gene Ontology enrichment analysis revealed hypoxic conditions selectively increase expression of proteins with extracellular matrix and signaling annotations. Finally, we subjected CM pretreated with CF secreted factors to hypoxia/reoxygenation. Viability assays suggested altered viability due to CF-derived factors. CF secretome proteomics revealed differential expression based on mode of secretion and oxygen levels in vitro. PMID- 28641010 TI - Alpha-Mangostin Reverses Multidrug Resistance by Attenuating the Function of the Multidrug Resistance-Linked ABCG2 Transporter. AB - The ATP-binding cassette (ABC) drug transporter ABCG2 can actively efflux a wide variety of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular accumulation of these drugs. Therefore, the overexpression of ABCG2 often contributes to the development of multidrug resistance (MDR) in cancer cells, which is one of the major obstacles to successful cancer chemotherapy. Moreover, ABCG2 is highly expressed in various tissues including the intestine and blood-brain barrier (BBB), limiting the absorption and bioavailability of many therapeutic agents. For decades, the task of developing a highly effective synthetic inhibitor of ABCG2 has been hindered mostly by the intrinsic toxicity, the lack of specificity, and complex pharmacokinetics. Alternatively, considering the wide range of diversity and relatively nontoxic nature of natural products, developing potential modulators of ABCG2 from natural sources is particularly valuable. alpha-Mangostin is a natural xanthone derived from the pericarps of mangosteen (Garcinia mangostana L.) with various pharmacological purposes, including suppressing angiogenesis and inducing cancer cell growth arrest. In this study, we demonstrated that at nontoxic concentrations, alpha-mangostin effectively and selectively inhibits ABCG2 mediated drug transport and reverses MDR in ABCG2-overexpressing MDR cancer cells. Direct interactions between alpha-mangostin and the ABCG2 drug-binding site(s) were confirmed by stimulation of ATPase activity and by inhibition of photolabeling of the substrate-binding site(s) of ABCG2 with [125I]iodoarylazidoprazosin. In summary, our findings show that alpha-mangostin has great potential to be further developed into a promising modulator of ABCG2 for reversing MDR and for its use in combination therapy for patients with MDR tumors. PMID- 28641011 TI - Exploiting One-Dimensional Exciton-Phonon Coupling for Tunable and Efficient Single-Photon Generation with a Carbon Nanotube. AB - Condensed-matter emitters offer enriched cavity quantum electrodynamical effects due to the coupling to external degrees of freedom. In the case of carbon nanotubes, a very peculiar coupling between localized excitons and the one dimensional acoustic phonon modes can be achieved, which gives rise to pronounced phonon wings in the luminescence spectrum. By coupling an individual nanotube to a tunable optical microcavity, we show that this peculiar exciton-phonon coupling is a valuable resource to enlarge the tuning range of the single-photon source while keeping an excellent exciton-photon coupling efficiency and spectral purity. Using the unique flexibility of our scanning fiber cavity, we are able to measure the efficiency spectrum of the very same nanotube in the Purcell regime for several mode volumes. Whereas this efficiency spectrum looks very much like the free-space luminescence spectrum when the Purcell factor is small (large mode volume), we show that the deformation of this spectrum at lower mode volumes can be traced back to the strength of the exciton-photon coupling. It shows an enhanced efficiency on the red wing that arises from the asymmetry of the incoherent energy exchange processes between the exciton and the cavity. This allows us to obtain a tuning range up to several hundred times the spectral width of the source. PMID- 28641012 TI - Regioselective Direct C-4 Functionalization of Indole: Total Syntheses of (-) Agroclavine and (-)-Elymoclavine. AB - An efficient rhodium-catalyzed method for direct C-H functionalization at the C4 position of unprotected indoles has been developed. The utility of this method is demonstrated by the concise total syntheses of agroclavine and elymoclavine in a divergent manner. These syntheses feature a Pd-catalyzed asymmetric allylic alkylation reaction to assemble the triyclic indole moiety, and a ring-closing metathesis reaction to form the D ring. PMID- 28641013 TI - Synthesis of 2,3-Benzodiazepines via Rh(III)-Catalyzed C-H Functionalization of N Boc Hydrazones with Diazoketoesters. AB - An efficient Rh(III)-catalyzed C-H activation protocol has been developed for the synthesis of 2,3-benzodiazepines with use of N-Boc hydrazones and diazoketoesters as substrates. The reaction features retention of the C?N and N-N bonds and selective cleavage of the N-Boc moiety. PMID- 28641014 TI - N-Heterocyclic Carbene Boryl Iodides Catalyze Insertion Reactions of N Heterocyclic Carbene Boranes and Diazoesters. AB - Boron-hydrogen bond insertion reactions of N-heterocyclic carbene (NHC) boranes and diazoesters can be catalyzed by NHC-boryl iodides and produce stable alpha NHC-boryl esters. The conditions of the reaction resemble the previous rhodium catalyzed transformations (only the catalyst is different); however, the mechanisms of the two reactions are probably very different. The new boryl iodide catalyzed method is adept at producing alpha-substituted-alpha-NHC-boryl esters, and this has led to a family of NHC-boryl esters with amino acid and amino-acid like side chains. PMID- 28641015 TI - A Regioselective Approach to Trisubstituted Pyrazoles via Palladium-Catalyzed Oxidative Sonogashira-Carbonylation of Arylhydrazines. AB - A palladium-catalyzed oxidative carbonylation of arylhydrazines and alkynes with balloon pressure CO/O2 to afford trisubstituted pyrazoles in a one-pot manner has been developed. The formation of trisubstituted pyrazoles involves a sequential C N bond cleavage, carbonylation, Sonogashira coupling, Michael addition, and intramolecular condensation cyclization tandem process. An unprecedented oxidative Sonogashira-carbonylation reaction of arylhydrazine plays a key role for such a facile approach to pyrazoles. PMID- 28641016 TI - From Hydrindane to Decalin: A Mild Transformation through a Dyotropic Ring Expansion. AB - An unexpected ring expansion converting hydrindane cores into decalins has been observed. The process occurs under very mild conditions and with exquisite transfer of chiral information. The ring expansion provides access to decorated decalins with complete stereocontrol. The reaction mechanism is studied in order to gain insight into the underlying causes for the low thermal requirements in this reaction and the nature of the chirality transfer process. Interestingly, both result from an unprecedented dyotropic reaction involving a mesylate group. PMID- 28641017 TI - NANPDB: A Resource for Natural Products from Northern African Sources. AB - Natural products (NPs) are often regarded as sources of drugs or drug leads or simply as a "source of inspiration" for the discovery of novel drugs. We have built the Northern African Natural Products Database (NANPDB) by collecting information on ~4500 NPs, covering literature data for the period from 1962 to 2016. The data cover compounds isolated mainly from plants, with contributions from some endophyte, animal (e.g., coral), fungal, and bacterial sources. The compounds were identified from 617 source species, belonging to 146 families. Computed physicochemical properties, often used to predict drug metabolism and pharmacokinetics, as well as predicted toxicity information, have been included for each compound in the data set. This is the largest collection of annotated natural compounds produced by native organisms from Northern Africa. While the database includes well-known drugs and drug leads, the medical potential of a majority of the molecules is yet to be investigated. The database could be useful for drug discovery efforts, analysis of the bioactivity of selected compounds, or the discovery of synthesis routes toward secondary metabolites. The current version of NANPDB is available at http://african-compounds.org/nanpdb/ . PMID- 28641018 TI - Three-Dimensional Imaging of Transparent Tissues via Metal Nanoparticle Labeling. AB - Chemical probes are key components of the bioimaging toolbox, as they label biomolecules in cells and tissues. The new challenge in bioimaging is to design chemical probes for three-dimensional (3D) tissue imaging. In this work, we discovered that light scattering of metal nanoparticles can provide 3D imaging contrast in intact and transparent tissues. The nanoparticles can act as a template for the chemical growth of a metal layer to further enhance the scattering signal. The use of chemically grown nanoparticles in whole tissues can amplify the scattering to produce a 1.4 million-fold greater photon yield than obtained using common fluorophores. These probes are non-photobleaching and can be used alongside fluorophores without interference. We demonstrated three distinct biomedical applications: (a) molecular imaging of blood vessels, (b) tracking of nanodrug carriers in tumors, and (c) mapping of lesions and immune cells in a multiple sclerosis mouse model. Our strategy establishes a distinct yet complementary set of imaging probes for understanding disease mechanisms in three dimensions. PMID- 28641019 TI - Correction, article no. 3671: Importance of the patient's clinical questionnaire for the diagnosis of skin cancer through teledermatology in remote areas of Brazil. PMID- 28641020 TI - Comparison of the Buschke Selective Reminding Test and the California Verbal Learning Test-Second Edition in a stroke population. AB - There are many tests of learning and memory; however, not all yield analogous results and thus are not interchangeable. This study examined the relationship between the California Verbal Learning Test-Second Edition (CVLT-II) and the Buschke Selective Reminding Test (SRT) in a stroke population. Data from stroke inpatients (N = 102) referred for rehabilitation were collected from medical records. Both tests were administered, as part of a larger neuropsychological assessment. Analyses were conducted on Z-scores from the List Total, Learning, and Long Delay Free Recall (LDFR) subscales of the two tests. SRT and CVLT-II scores were significantly correlated (r = .34 to .52, all p values <.001). However, scores were significantly worse on the SRT compared to the CVLT-II (d = .90 to - 1.46, all p values <.001). Left hemisphere strokes performed worse than right hemisphere strokes on both tests; however, this trend was not significant. The SRT appeared to be more sensitive to impairment than the CVLT-II; thus, the two tests may not be interchangeable in a stroke population. PMID- 28641021 TI - Genetic screening: birthright or earned with age? PMID- 28641022 TI - A Randomized Single Dose Parallel Study on Enhancement of Nitric Oxide in Serum and Saliva with the Use of Natural Sports Supplement in Healthy Adults. AB - Sports supplements that stimulate the production of nitric oxide (NO) are widely promoted agents in the sports nutrition domain, and nitric oxide plays an important role to enhance the cardiovascular and physical fitness of the sports participants. The purpose of the study is to investigate whether oral intake of a sports nutritional supplement (Fitnox) is able to increase nitrate (NO3-) and nitrite (NO2-) levels in blood serum and saliva of healthy adults. Fitnox is a unique blend of Kaempferia parviflora methoxy flavones, pomegranate peel polyphenols, and Moringa oleifera leaf saponins. Twenty-four healthy male adults were equally divided and underwent the double-blind, placebo-controlled clinical trial with a single oral dose of sports nutrition formulation (250 mg capsules); blood and saliva samples were analyzed at different time intervals by high performance liquid chromatography (HPLC). After administration of Fitnox (250 mg capsule as single dose), NO3- and NO2- levels in serum and saliva were found to be significantly higher (p <.05) than in the placebo group in 24 hours. Pharmacokinetic parameters such as the area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf), AUC calculated to the last measured concentration (AUC0-t), maximum drug serum concentrations (Cmax), time of maximum concentration in serum observed (Tmax), and time required for the concentration of the drug to reach half of its original value (Thalf) were also statistically significant (p <.05) compared with the placebo. The results indicate that a single oral dose of Fitnox is able to increase the NO3- and NO2- levels considerably in the body relative to placebo for at least 12 hours. Therefore, Fitnox can improve the overall performance of sport participants and enhance physical endurance. PMID- 28641023 TI - Cardiovascular event incidence and cost in type 2 diabetes mellitus: a Medicare claims-based actuarial analysis. AB - OBJECTIVE: To assess the economic burden of cardiovascular events in Medicare beneficiaries with type 2 diabetes mellitus (T2DM). METHODS: This claims-based actuarial analysis queried 2013 and 2014 Medicare 5% samples, defining a denominator of fee-for-service beneficiaries. Average per patient per month allowed cost ($PPPM) was calculated for T2DM, demographically adjusted non-T2DM, and denominator. Per member per month allowed cost ($PMPM) was calculated by dividing total population cost by member months in the denominator. Costs of five pre-specified cardiovascular events were calculated as a contribution to denominator $PMPM, as contribution to $PPPM in T2DM, and as incremental cost. RESULTS: During the study period, 22.1% of Medicare fee-for-service beneficiaries had T2DM; of these, 9.68% experienced a cardiovascular event or cardiovascular related death. T2DM cost represented 37.9% of total allowed $PMPM for the denominator. Average total allowed $PPPM for a T2DM beneficiary was $1,834, compared with $850 for a non-T2DM beneficiary (2.2-times higher). Annual rates of myocardial infarction, stroke, unstable angina admission, heart failure admission, and coronary revascularization in T2DM were 3.3-, 2.4-, 3.2-, 4.0-, and 2.8-times higher than in non-T2DM, and utilization of health services was also greater in T2DM. Cardiovascular events in T2DM accounted for 50% of denominator cardiovascular event cost; 3.6% of denominator population $PMPM was attributable to cardiovascular events in T2DM. Risk-adjusted incremental cardiovascular event cost represented 18.1% of $PPPM in T2DM or 6.9% of $PMPM in the denominator population. CONCLUSIONS: Cardiovascular events in Medicare fee for-service beneficiaries with T2DM contribute substantially to Medicare cardiovascular events, resource utilization, and cost. PMID- 28641024 TI - Perinatal mortality classification: an analysis of 112 cases of stillbirth. AB - This was a retrospective cohort analysis of stillbirths that occurred from January 2004 to December 2013 in our institution. We compared Tulip and Wigglesworth classification systems on a cohort of stillbirths and analysed the main differences between these two classifications. In this period, there were 112 stillbirths of a total of 31,758 births (stillbirth rate of 3.5 per 1000 births). There were 99 antepartum deaths and 13 intrapartum deaths. Foetal autopsy was performed in 99 cases and placental histopathological examination in all of the cases. The Wigglesworth found 'unknown' causes in 47 cases and the Tulip classification allocated 33 of these. Fourteen cases remained in the group of 'unknown' causes. Therefore, the Wigglesworth classification of stillbirths results in a higher proportion of unexplained stillbirths. We suggest that the traditional Wigglesworth classification should be substituted by a classification that manages the available information. PMID- 28641025 TI - Relationship between length and width of the purple line and foetal head descent in active phase of labour. AB - Purple line is one of the non-invasive methods to assess the progress of labour. This longitudinal observational study was performed on 350 women during the active phase of labour. We assessed the relationship between length and width of the purple line and foetal head descent. Women were examined in the lateral position and researcher recorded the presence or absence of the line before each vaginal examination. Where present length and width of the line was measured using a disposable tape measure. The purple line appeared in 75.3% of 350 women during the active phase of labour. There was a positive correlation between length of the purple line and station of the foetal head (r = +0.29, p = .001). There was also a medium positive correlation between width of the purple line and the station of the foetal head (r = +0.71, p < -.001). There is a positive correlation between purple line and station of the foetal head. Where the purple line is present, measurement of it may reduce the number of vaginal examinations, especially when the single aim is to measure station of the foetal head. Further research is needed to confirm the current finding in other races. IMPACT STATEMENT Current knowledge on the subject: In the literature, purple line is one of the non-invasive methods to assess the progress of cervical dilatation and foetal head descent in labour. Failure of the foetal head is the second most common indication for performing surgical deliveries. Progression of labour has been evaluated by vaginal examination for the assessment of cervical dilatation and foetal head station. Vaginal examinations can be unpleasant, intrusive, embarrassing and so painful for women. Researchers suggested to explore whether the line is also present in women across other ethnic and racial groups and they also suggested further researches to examine the width of purple line. The contribution made by the results of this study: The results of this study add to the growing body of research on progression of labour that the purple line appeared in most of Iranian women during the active phase of labour. There was a positive correlation between length and width of the purple line and station of the foetal head. The implications are of these findings for clinical practice and further research: The results of this study can be used reduce the number of vaginal examinations, especially when the single aim is to measure station of the foetal head. Further research is needed to confirm the current finding in other races. PMID- 28641026 TI - Sociodemographic factors associated with female genital cutting among women of reproductive age in Nigeria. AB - OBJECTIVES: The aims of the study were to determine the prevalence of female genital cutting (FGC) among women of reproductive age in Nigeria and identify the sociodemographic factors associated with the practice. METHODS: A secondary analysis of the 2013 Nigeria Demographic and Health Survey was carried out in 38,948 women of reproductive age (15-49 years). RESULTS: The prevalence of FGC among respondents was almost 25%, most of whom (82%) had undergone the procedure when they were under 5 years of age. Traditional circumcisers performed 72.2% of all procedures. Type 2 was the common form (62.6%) of FGC. Almost a quarter of respondents (23.1%) wanted the practice to continue. Women aged 45-49 years were approximately twice as likely to have undergone FGC compared with women aged 15 19 years (odds ratio [OR] 2.41; 95% confidence interval [CI] 1.99, 2.92; p < .001). Women from parts of Nigeria other than the North East zone were significantly more likely to have experienced FGC (p < .001). Women of Yoruba ethnicity were significantly more likely to have experienced FGC compared with women of Hausa/Fulani ethnicity (OR 4.86; 95% CI 3.03, 8.12; p < .001). CONCLUSIONS: Our findings have programmatic implications for ending the practice of FGC in Nigeria. Elimination efforts should be intensified among women of Yoruba ethnicity. To instigate behavioural change, communication interventions should particularly target residents in parts of Nigeria other than the North East zone. PMID- 28641027 TI - Effect of an educational intervention in "spirituality and health" on knowledge, attitudes, and skills of students in health-related areas: A controlled randomized trial. AB - BACKGROUND: To date there have been no randomized studies that assess whether "Spirituality and Health" (S/H) programs are, indeed, effective, or not. We sought to evaluate if an intervention in teaching S/H fosters competence changes in healthcare students. METHODS: A randomized controlled trial was carried out. Students were randomized into two groups: an Intervention Group (a theoretical practical course in S/H) and a control group (waiting list). Students' S/H knowledge, attitudes, and skills (through a simulated patient) were assessed. RESULTS: A total of 49 students were evaluated. Students in the intervention group received higher scores on knowledge tests, felt more comfortable and prepared to talk about religious/spiritual beliefs with patients, more readily recognized importance of hospital chaplains, and more frequently held the opinion that addressing spirituality is important. Furthermore, a breaking down of S/H barriers was identified. Students also demonstrated more ability in obtaining a patient's spiritual history when compared to the control group. CONCLUSIONS: There were some differences on knowledge, attitudes, and spiritual history skills between students who participated in the S/H teaching strategy and students who have not been exposed to the theme. These results might foster discussion for the development of new educational strategies about the subject. PMID- 28641028 TI - Minilaparoscopic myomectomy with trans-vaginal specimen extraction: a case report. PMID- 28641029 TI - Gender differences in the trajectory classes of depressive symptoms in Korean older adults. AB - OBJECTIVES: This study aimed (1) to identify gender-specific heterogeneous longitudinal patterns of depressive symptoms, (2) to explore the effects of economic status and various health conditions as risk factors in depressive symptom trajectories. METHOD: Data came from the Korean Longitudinal Study of Aging (2006-2012) focuing on older adults aged 65 and older. Latent class growth analysis was used to identify the depressive symptom trajectory groups. Multinomial logistic regression was used to examine the association between economic and health status changes and the depresison trajectories. RESULTS: Among older women, three change groups were identified: stable low, stable high, and moderate but slightly increasing groups. Among older men, four groups were found: stable low, moderate but rapidly increasing, high but decreasing, and moderate but slightly increasing groups. Among women, poverty experience and sustained poor health, particularly constantly low cognition, were significantly associated with the stable high group. Among men, deteriorating economic and health status were significant predictors of membership in the most vulnerable subgroup, the moderate but rapidly increasing group. CONCLUSION: This study demonstrated among older adults, depressive symptoms change heterogeneously by gender. Identification of the most at risk subgroups among older men and women provides important initial empirical information to target clinical programs and policy development. PMID- 28641030 TI - Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. AB - OBJECTIVES: This study evaluated acceptability, user satisfaction, body weight control and general well-being of estetrol (E4) combined with either drospirenone (DRSP) or levonorgestrel (LNG). METHODS: In this open-label, multi-centre, dose finding, 6-cycle study, 396 healthy women of reproductive age were randomised into five treatment groups in a 24/4-day regimen: 15 mg or 20 mg E4 combined with either 3 mg DRSP or 150 MUg LNG, and as reference estradiol valerate (E2V) combined with dienogest (DNG). Data on acceptability, user well-being, satisfaction and body weight were collected. RESULTS: The number of completers was the highest in the 15 mg E4/DRSP group (91.1%), and the lowest for 20 mg E4/LNG (70.1%). The largest proportion of treatment satisfaction was reported for 15 mg E4/DRSP (73.1%), and the lowest for 15 mg E4/LNG (50.6%). The number of women willing to continue with the assigned study treatment was the highest in the 15 mg E4/DRSP group (82.1%) and the lowest for 20 mg E4/LNG (58.3%). Well being with E4/DRSP combinations was statistically significantly better than with E4/LNG combinations: OR (95% CI) 2.00 (1.13; 3.53) and 1.93 (1.06; 3.56) for 15 and 20 mg E4, respectively, and comparable to E2V/DNG. Proportion of women with a 2 kg or more weight loss after 3 and 6 cycles was the highest in the 15 mg E4/DRSP group (30.7 and 36.7%, respectively). CONCLUSIONS: The present study shows that 15 mg estetrol combined with 3 mg DRSP is associated with a high-user acceptability and satisfaction, and with a favourable body weight control. PMID- 28641031 TI - Treatment options for nonalcoholic steatohepatitis - a safety evaluation. AB - INTRODUCTION: There is an urgent as yet unmet need to develop highly effective and safe therapeutics for nonalcoholic fatty liver disease (NAFLD). The remarkable progress in understanding NAFLD pathogenesis allowed the identification of injury pathways which may be recruited as therapy targets. Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis. Expert opinion: Current therapies continue to remain suboptimal. Weight loss is effective but hard to achieve. Traditional and endoscopic bariatric procedures are promising although more randomized trials are needed and the long-term safety remains to be established. Clinical trials have demonstrated the efficacy of several drugs for the treatment of NASH. Of these, there remains some uncertainty about the long-term safety of vitamin E. Pioglitazone is associated with osteopenia, fluid retention and weight gain. Obeticholic acid causes pruritus in a substantial proportion of subjects and elafibranor has been associated with transient rises in creatinine. Several exciting therapies are under development and results of clinical and post-marketing trials will help elucidate their safety. PMID- 28641032 TI - Targeting Rho GTPase effector p21 activated kinase 4 (PAK4) suppresses p-Bad microRNA drug resistance axis leading to inhibition of pancreatic ductal adenocarcinoma proliferation. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and therapy resistant malignancy. Mutant K-Ras, found in >90% of refractory PDAC, acts as a molecular switch activating Rho GTPase signaling that in turn promotes a plethora of pro-survival molecules and oncogenic microRNAs. We investigated the impact of Rho GTPase effector protein p21 activated kinase 4 (PAK4) inhibition on pro survival p-Bad and oncogenic miRNA signaling. We demonstrate that the dual NAMPT and PAK4 modulators (KPT-9274 and KPT-9307) inhibit PDAC cell proliferation through down-regulation of Bad phosphorylation and up-regulation tumor suppressive miRNAs (miR-145, let-7c, let-7d, miR-34c, miR320 and miR-100). These results suggest that targeting PAK4 could become a promising approach to restore pro-apoptotic function of Bad and simultaneously activate tumor suppressive miRNAs in therapy resistant PDAC. PMID- 28641033 TI - Evaluation of planned bicanalicular nasolacrimal tube retention in treating punctal stenosis or occlusion secondary to trachoma. AB - This article evaluates retaining bicanalicular silicone nasolacrimal tube in patients susceptible to restenosis after punctoplasty. Sixty-nine eyes (38 patients) suffering from epiphora due to stenosis or occlusion of both punctae were included in this prospective study. All had 3 snip punctoplasty and bicanalicular silicone nasolacrimal duct insertion. Cases associated with proximal canalicular stenosis or obstructions were excluded. Tolerance to tube presence until the time of loss or removal was evaluated using a score (0 to 2). Average age was 49.71 +/- 11.09 years. Tachomatous lesions were detected in all cases of punctal stenosis (48 eyes/69.57%) and membranous occlusion (21 eyes/30.43%). Common canalicular obstruction was additionally found in 12 eyes (17.39%). Absolute improvement was detected in 85% of cases and mean time for tube retention was (29.6 +/- 10.2 months) with no difference in presence of common canalicular obstruction (P value: 0.138). Isolated punctal affection favoured tube retention that was well tolerated throughout the follow-up period (P value <0.001). Silicone bicanalicular nasolacrimal tube is an available option for treating acquired punctal stenosis. It is tolerated especially in cases suffering from isolated punctal stenosis. Tube retention could be of value in patients who are at risk of re-occlusion following tube removal. PMID- 28641034 TI - Imaging of proximal lacrimal system with time domain anterior segment optical coherence tomography in Asian Indian population. AB - This article reports proximal lacrimal system parameters using Anterior Segment Optical Coherence Tomography (ASOCT-Visante) in an apparently normal Asian Indian population with assessment of any correlation between tear meniscus height and punctal diameter. This was a prospectively designed observational study that included healthy adults, who volunteered for optical coherence tomography imaging (OCT) of their proximal lacrimal system. Time domain ASOCT (Visante) images of the punctum and proximal canaliculus were captured using the high resolution corneal scan protocol. External lacrimal punctal diameter (ELP), internal lacrimal punctal diameter (ILP), vertical canalicular length (VCL) and tear meniscus height (TMH) were calculated. Statistical analysis was performed using Pearson's correlation test. Our study had 100 normal subjects with mean age 24.14 years, range 15-38 years. ASOCT (Visante) with advantage of deeper penetration was able to image canaliculus in all cases. The mean TMH, ELP, ILP and VCL was 252.7 +/- 67.98 MUm, 382.2 +/- 103.14MUm, 140.7 +/- 67.29 MUm and 811.8 +/- 253.7 MUm, respectively, in 100 normal subjects. No correlation was found between ELP, ILP and TMH (Pearson's Correlation; r = -0.355, p > 0.05 for all). ASOCT (VisanteTM) is a non-invasive and easy to use objective tool for imaging proximal lacrimal system. Further studies are required to validate normative data and correlate with microscopic findings of lacrimal system. PMID- 28641036 TI - Modelling error distribution in the ground reaction force during an induced acceleration analysis of running in rear-foot strikers. AB - The objective of this study was to develop and evaluate a methodology for quantifying the contributions of modelling error terms, as well as individual joint torque, gravitational force and motion-dependent terms, to the generation of ground reaction force (GRF), whose true value can be measured with high accuracy using a force platform. Dynamic contributions to the GRF were derived from the combination of (1) the equations of motion for the individual segments, (2) the equations for constraint conditions arising from the connection of adjacent segments at joints, and (3) the equations for anatomical constraint axes at certain joints. The contribution of the error term was divided into four components caused by fluctuation of segment lengths, geometric variation in the constraint joint axes, and residual joint force and moment errors. The proposed methodology was applied to the running motion of thirteen rear-foot strikers at a constant speed of 3.3 m/s. Modelling errors arose primarily from fluctuations in support leg segment lengths and rapid movement of the virtual joint between the foot and ground during the first 20% of stance phase. The magnitudes of these error contributions to the vertical and anterior/posterior components of the GRF are presented alongside the non-error contributions, of which the joint torque term was the largest. PMID- 28641035 TI - Hypoglycemia Patients and Transport by EMS in Alameda County, 2013-15. AB - OBJECTIVE: To estimate the rate, characteristics, and dispositions of hypoglycemia events among persons who received care from Alameda County, California, Emergency Medical Services (EMS). METHODS: This study was based on data for 601,077 Alameda County EMS encounters during 2013-15. Subjects were defined as having hypoglycemia if EMS personnel recorded a primary impression of hypoglycemia or low blood glucose (<60 mg/dl or "unspecified low"). The outcome of interest was patient transport or non-transport to an emergency department or other care setting; we excluded 33,177 (6%) encounters which lacked clear disposition outcomes. RESULTS: Among 567,900 eligible encounters, 8,332 (1.47%) were attributed to hypoglycemia, of which 1,125 (13.5%) were not transported. Non transport was more likely among males, adult patients age <60, initial blood glucose >60 mg/dl or EMS arrival time 18:00-6:00. CONCLUSIONS: Without an understanding of EMS encounters and non-transport rates, surveillance based solely on emergency department and hospital data will significantly underestimate rates of severe hypoglycemia. Additionally, given that hypoglycemia is often safely and effectively treated by non-physicians, EMS protocols should provide guidance for non-transport of hypoglycemic patients whose blood glucose levels have normalized. PMID- 28641038 TI - Interaction of tinnitus suppression and hearing ability after cochlear implantation. AB - OBJECTIVES: To study the postoperative impact of cochlear implants (CIs) on tinnitus, as well as the impact of tinnitus on speech recognition with CI switched on. METHODS: Fifty-two postlingual deafened CI recipients (21 males and 31 females) were assessed using an established Tinnitus Characteristics Questionnaire and Tinnitus Handicap Inventory (THI) before and after cochlear implantation. The tinnitus loudness was investigated when CI was switched on and off in CI recipients with persistent tinnitus. The relation between tinnitus loudness and recipients' satisfaction of cochlear implantation was analyzed by the visual analogue scale (VAS) score. RESULTS: With CI 'OFF', 42 CI recipients experienced tinnitus postimplant ipsilaterally and 44 contralaterally. Tinnitus was totally suppressed ipsilateral to the CI with CI 'ON' in 42.9%, partially suppressed in 42.9%, unchanged in 11.9% and aggravated in 2.4%. Tinnitus was totally suppressed contralaterally with CI 'ON' in 31.8% of CI recipients, partially suppressed in 47.7%, unchanged in 20.5%. Pearson correlation analysis showed that tinnitus loudness and the results of cochlear implant patients satisfaction was negatively correlated (r = .674, p < .001). CONCLUSION: The study suggests six-month CI activation can be effective for suppressing tinnitus. The tinnitus loudness may affect patients' satisfaction with the use of CI. PMID- 28641037 TI - Powdery mildews on lilac in western North America include Phyllactinia syringae, sp. nov. AB - Two powdery mildews, Erysiphe syringae and the previously undescribed Phyllactinia syringae, sp. nov., occur on lilac in western North America. Phyllactinia syringae is found on common lilac, whereas E. syringae is found on Chinese lilac and, occasionally, common lilac. Infection by P. syringae is extremely unobtrusive until formation of a hypophyllous mycelial mat with chasmothecia in late fall. Infection by E. syringae in late summer is conspicuous, with its thick, superficial mycelial mat on the leaf upper surface detracting from the aesthetic appearance of the bush. PMID- 28641039 TI - An empirical investigation of campus demographics and reported rapes. AB - OBJECTIVE: Rape on college campuses continues to be a pervasive public health issue with approximately 11% of women experiencing rape while in college. As such, it is important to examine factors unique to college campuses that influence the occurrences of rape. METHODS: Using data from 1,423 four-year universities (public and private with at least 1,000 students) from the Office of Education and the Clery Act (2014), we examined institutional risk factors, such as tuition, liquor violations, Greek-life, athletic programs, institution type (public vs. private), and geographical location. RESULTS: Public institutions with higher tuition, more liquor violations, and greater numbers of fraternity men and athletes were more likely to report rape on their campuses. CONCLUSIONS: Findings suggest that there are university-level characteristics which may increase certain campuses propensity toward violence against women. PMID- 28641040 TI - "Drunkorexia": Understanding eating and physical activity behaviors of weight conscious drinkers in a sample of college students. AB - OBJECTIVE: Behaviors of weight conscious drinkers (BWCD) include disordered eating, excessive physical activity (PA), and heavy episodic drinking. Considering that approximately 25% of the college students report BWCD, it is important to investigate what characteristics increase the likelihood of college students engaged in BWCD for both moderate and vigorous PAs. PARTICIPANTS: A total of 510 college students were recruited from a large, public southeastern university. METHODS: Participants completed a cross-sectional survey during the spring 2015 semester. RESULTS: Of 510 respondents, 11.2% reported moderate PA based BWCD and 14.7% reported vigorous PA-based BWCD. Weight loss intention, BMI and Greek affiliation predicted both moderate and vigorous BWCD. CONCLUSIONS: Study findings suggest that Greek-affiliated students and students with weight loss intentions might be at an increased risk for BWCD. Along with promoting lower levels of alcohol consumption, college practitioners should consider discussing issues of weight and body image with college students as they relate to maladaptive drinking behavior. PMID- 28641041 TI - Virulence regulation during late infection by a fish pathogen; sense and sensibility of bacteria may lead to novel vaccine development strategy. PMID- 28641042 TI - Resolving the Melampsora epitea complex. AB - Melampsora epitea (Pucciniales, Basidiomycota) has been widely known as the main rust pathogen on willows, but its species boundary has been extremely confusing. Melampsora epitea was often confused with several morphologically similar species, such as M. arctica, M. humilis, and M. epiphylla. Recent DNA-based studies using specimens from North America and Europe suggested that M. epitea was a complex of several phylogenetic species. In this study, we examined the species boundary of M. epitea based on rDNA phylogeny and the general mixed Yule coalescent (GMYC) model from 534 specimens. Twelve distinct species corresponding to 10 known species and 2 new species were recognized from East Asian specimens. We also evaluated the association of morphological characteristics, geographic origins, and host ranges with phylogenetic relationships. Our results revealed that several previously overlooked morphological characters in uredinial and telial stages were informative in delimiting M. epitea and allied species. Two novel species, M. salicis-futurae and M. salicis-triandrae, are described and compared with closely related species. A lectotype for M. epitea and epitypes for M. epitea, M. epiphylla, and M. humilis are designated to stabilize the use of names. PMID- 28641043 TI - Radiogenomics of High-Grade Serous Ovarian Cancer: Multireader Multi Institutional Study from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group. AB - Purpose To evaluate interradiologist agreement on assessments of computed tomography (CT) imaging features of high-grade serous ovarian cancer (HGSOC), to assess their associations with time-to-disease progression (TTP) and HGSOC transcriptomic profiles (Classification of Ovarian Cancer [CLOVAR]), and to develop an imaging-based risk score system to predict TTP and CLOVAR profiles. Materials and Methods This study was a multireader, multi-institutional, institutional review board-approved, HIPAA-compliant retrospective analysis of 92 patients with HGSOC (median age, 61 years) with abdominopelvic CT before primary cytoreductive surgery available through the Cancer Imaging Archive. Eight radiologists from the Cancer Genome Atlas Ovarian Cancer Imaging Research Group developed and independently recorded the following CT features: characteristics of primary ovarian mass(es), presence of definable mesenteric implants and infiltration, presence of other implants, presence and distribution of peritoneal spread, presence and size of pleural effusions and ascites, lymphadenopathy, and distant metastases. Interobserver agreement for CT features was assessed, as were univariate and multivariate associations with TTP and CLOVAR mesenchymal profile (worst prognosis). Results Interobserver agreement for some features was strong (eg, alpha = .78 for pleural effusion and ascites) but was lower for others (eg, alpha = .08 for intraparenchymal splenic metastases). Presence of peritoneal disease in the right upper quadrant (P = .0003), supradiaphragmatic lymphadenopathy (P = .0004), more peritoneal disease sites (P = .0006), and nonvisualization of a discrete ovarian mass (P = .0037) were associated with shorter TTP. More peritoneal disease sites (P = .0025) and presence of pouch of Douglas implants (P = .0045) were associated with CLOVAR mesenchymal profile. Combinations of imaging features contained predictive signal for TTP (concordance index = 0.658; P = .0006) and CLOVAR profile (mean squared deviation = 1.776; P = .0043). Conclusion These results provide some evidence of the clinical and biologic validity of these image features. Interobserver agreement is strong for some features, but could be improved for others. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28641044 TI - The effects of short versus long inter-set rest intervals in resistance training on measures of muscle hypertrophy: A systematic review. AB - Although the effects of short versus long inter-set rest intervals in resistance training on measures of muscle hypertrophy have been investigated in several studies, the findings are equivocal and the practical implications remain unclear. In an attempt to provide clarity on the topic, we performed a systematic literature search of PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, and Physiotherapy Evidence Database (PEDro) electronic databases. Six studies were found to have met the inclusion criteria: (a) an experimental trial published in an English-language peer-reviewed journal; (b) the study compared the use of short (<=60 s) to long (>60 s) inter-set rest intervals in a traditional dynamic resistance exercise using both concentric and eccentric muscle actions, with the only difference in resistance training among groups being the inter-set rest interval duration; (c) at least one method of measuring changes in muscle mass was used in the study; (d) the study lasted for a minimum of four weeks, employed a training frequency of >=2 resistance training days per week, and (e) used human participants without known chronic disease or injury. Current evidence indicates that both short and long inter-set rest intervals may be useful when training for achieving gains in muscle hypertrophy. Novel findings involving trained participants using measures sensitive to detect changes in muscle hypertrophy suggest a possible advantage for the use of long rest intervals to elicit hypertrophic effects. However, due to the paucity of studies with similar designs, further research is needed to provide a clear differentiation between these two approaches. PMID- 28641045 TI - Beyond Income: A Social Justice Approach to Assessing Poverty among Older Adults with Chronic Kidney Disease. AB - How social workers define and assess poverty is a matter of economic and social justice. Recent conceptual and measurement advances point to a multidimensional definition of poverty which captures material, social, and political deprivations. Using data from a survey, this article describes how nephrology social workers assess poverty among older adults living with a chronic kidney disease (N = 52). Results suggest respondents already conceive of poverty as a multidimensional experience, support awareness-raising about poverty, and primarily assess poverty by employment status, income, access to transportation, and education. Opportunities to expand poverty assessment in future work are promising. PMID- 28641046 TI - Exploring the Health Needs of Aging LGBT Adults in the Cape Fear Region of North Carolina. AB - This study explored issues of culturally sensitive healthcare practice and needs among lesbian, gay, bisexual and transgender aging adults in coastal North Carolina. Survey data results indicated the largest problem was a history of verbally harassment and need for culturally sensitive healthcare. In conclusion, culturally sensitive interventions are needed to address the health disparities and unique needs of LGBT aging adults. Cultural sensitivity training for service providers is suggested as a vital step in addressing health disparities of aging LGBT adults. Implications for research include further exploration of health related needs of these often hidden and underserved population groups. PMID- 28641047 TI - The interaction of distress tolerance and intolerance of uncertainty in the prediction of symptom reduction across CBT for social anxiety disorder. AB - Distress tolerance (DT) and intolerance of uncertainty (IU) have been identified as transdiagnostic processes that predict symptom severity across a range of distinct anxiety disorders. However, the joint effect of these two variables on therapeutic outcome has not yet been examined. It is possible that DT and IU may both impact on treatment response to cognitive-behavioural therapy (CBT) in clients with anxiety, as clients with weak DT and strong IU may be less likely to engage in exposure and cognitive restructuring tasks across treatment due to their associated distress. The purpose of this study was to examine the interaction of DT and IU as predictors of post-treatment symptom severity and treatment response to group CBT in participants with primary DSM-IV-TR diagnosed social anxiety disorder (SAD). Participants (N = 95) with SAD completed 12 weeks of manualized group CBT. Results of multilevel longitudinal analysis demonstrated an interaction effect, such that lower DT and higher IU predicted higher SAD symptom severity across the course of therapy. The findings are discussed in terms of clinical implications for the disorder-specific and transdiagnostic treatment of anxiety disorders. PMID- 28641048 TI - Updates and current challenges in microRNA research for personalized medicine in ovarian cancer. AB - INTRODUCTION: Ovarian cancer (OC) is the second most common and the most lethal of the gynecological malignancies. Currently, there exists no effective screening tool for OC. MicroRNAs (miRNAs) are endogenous 18-23 nucleotide non-coding RNAs that refine gene expression. MiRNAs have been found to be aberrantly expressed in OC tumor tissue as well as detectable in biological fluids such as the blood, urine, and ascites and have been proposed as biomarkers and therapeutic targets for OC. Areas covered: This review summarizes the current knowledge regarding the application of miRNAs as diagnostic, prognostic, and predictive biomarkers in OC. It describes the various tissues allowing for the analysis of miRNAs such as tumor tissue, blood, ascites and urine. It also highlights the potential of miRNAs as a therapy in other cancers and how these therapies may be applied to ovarian cancer. Expert opinion: The study of miRNAs is an innovative and promising field for the diagnosis and treatment of ovarian cancer. Methodological issues surrounding their detection and application therapeutically remain, such as the study of various OC histotypes within the same cohort, the choice of 'normal tissue' for comparison and the difficulties surrounding the choice of a normalization miRNA. PMID- 28641049 TI - A study of physicians' experiences with recommending HPV vaccines to adolescent boys. AB - Assessing physicians' experiences in HPV vaccine recommendation and delivery to adolescent boys is essential to providing an understanding of the issues of vaccine acceptance and an insight for policymakers to enhance HPV vaccinations among adolescent boys. Between January and April 2014 a mail survey was conducted using physicians in Malaysia known to provide either one or both HPV vaccine (Gardasil and Cervarix) immunisation services. A total of 357 completed questionnaires were received (response rate 22.5%). Of these, 335 physicians see adolescent boys aged 11 to 18 years old in their practice. Only 26.3% (n = 88) recommended the HPV vaccine to these boys. A total of 46.6% (n = 41) have successfully given the HPV vaccine to adolescent boys. A lack of proper guidelines from the health authorities regarding the recommendation of HPV vaccine to the boys (37.2%) and a lack of awareness of the availability of the vaccine for boys (32.8%) were the most commonly cited reasons for non recommendation. Impact statement Recommending the HPV vaccine for adolescent boys remains a challenge for physicians. Our study provides evidence of challenges and barriers faced by Malaysian physicians who recommend the HPV vaccines (Gardasil and Cervarix) in their practices. In this study, physicians reported HPV vaccine uptake by adolescent boys was very poor. A lack of proper guidelines from the health authorities regarding the recommendation of HPV vaccine to boys and a lack of awareness of the availability of the vaccine for boys were the most commonly cited reasons for non-recommendation. Physicians viewed that support and encouragement from the health authorities are needed to promote the recommendation of the HPV vaccine to adolescent boys. Physicians were also of the opinion that the lay public should be educated about the availability of the HPV vaccine for boys, and its benefits, safety and efficacy, and the high susceptibility of boys to getting HPV infections. The findings provide insights that could be helpful to policymakers or high-level decision-makers of the potential strategies to enhance HPV uptake among adolescent boys. PMID- 28641050 TI - Thrifty Females, Frisky Males: Winter Energetics of Hibernating Bats from a Cold Climate. AB - Mammalian hibernation consists of energy-saving torpor bouts (periods of controlled reduction in body temperature [Tb]) interspersed with brief arousals to normothermic Tb. Frequency and duration of torpor bouts and arousals can affect winter survival and are thought to be influenced by an optimization balancing the energetic benefits of prolonged torpor against the physiological and ecological costs (e.g., accumulation of metabolic wastes). Female little brown bats (Myotis lucifugus) spend their fat reserves more slowly than males during winter, presumably so they can emerge from hibernation in good condition to initiate pregnancy. We used temperature telemetry over three winters to test a prediction of the optimization hypothesis that female M. lucifugus would use longer torpor bouts and/or shorter arousals than males. Females did conserve energy relative to males by adjusting the magnitude and duration of arousals but not the duration of torpor bouts. Although torpor bout duration did not vary by sex for adults, it did vary by age. Adults initially used longer torpor bouts than young-of-the-year, but this difference declined as cave temperature warmed in spring. Males and females in better condition spent more energy during hibernation, again via increased arousal duration rather than decreased torpor bout duration. Longer arousals by males could increase reproductive fitness if males mate with torpid females throughout winter. Our results highlight demographic differences in winter behavior for small hibernators facing extreme energy limitation in cold climates and illustrate the influence that reproductive costs have on hibernation energetics. PMID- 28641051 TI - Beneficial Role of Citrus Fruit Polyphenols Against Hepatic Dysfunctions: A Review. AB - Alcoholic liver diseases and virus-induced hepatic dysfunctions are prevalent in western countries. Evidence also suggests that hyperglycemia and insulin resistance are key players in the development of hepatic diseases and their complications. Since the comorbid diseases like obesity, diabetes and vascular dysfunctions primarily affect liver, the modern therapies against other hepatic dysfunctions are becoming a major challenge to treat. In addition to these, polypharmacy and adverse drug reactions (ADRs) are further aggravating the phenomenon. Production of interleukins (IL) 1beta, tumor necrosis factors (TNF) alpha, nuclear factor (NF) kappaB, activator protein (AP) 1, macrophage inflammatory protein (MIP), toll-like receptor (TLR) 4, and several other harmful cytokines are often evaluated for clinical significance in hepatic complications as recommended by much evidence. On the other hand, transforming growth factors (TGF) beta, matrix metalloproteinases, and extracellular matrix- (ECM-) mediated hepatic fibrosis have been identified as major targets. However, modern medicines rely not only on synthetic compounds but also on herbal sources. Traditional therapies are gradually being acknowledged due to having fewer ADRs and other complications. Citrus fruits are generally seen all over the world and offer a great value as seasonal fruit. Several important biologically active components such as polyphenols, flavonols, carbohydrates, amino acids, and oils have been isolated from this family. Evidence suggests that polyphenol-based therapies have already proved their high potency against the production of inflammatory cytokines and profibrogenic factors. Along with the prevention of oxidative stress, these molecules hinder the generation of free radicals. Furthermore, polyphenols induce several defensive genes such as Nrf2, AMPK, superoxide dismutase, catalase, heme oxygenase (HO), Sirt1, and other important functional proteins to serve mitochondrial biogenesis. Therefore, this review will try to establish some molecular theories between citrus polyphenols and liver dysfunctions. PMID- 28641052 TI - Editorial. PMID- 28641053 TI - The discovery and development of romidepsin for the treatment of T-cell lymphoma. AB - INTRODUCTION: Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34-35% and 25-38%, with complete response (CR) rates of 6% and 15-18%, respectively. Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T cell lymphoma. Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It's also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma. PMID- 28641054 TI - Behavioral interventions to reduce nickel exposure in a nickel processing plant. AB - Nickel is a widely-used material in many industries. Although there is enough evidence that occupational exposure to nickel may cause respiratory illnesses, allergies, and even cancer, it is not possible to stop the use of nickel in occupational settings. Nickel exposure, however, can be controlled and reduced significantly in workplaces. The main objective of this study was to assess if educational intervention of hygiene behavior could reduce nickel exposure among Indonesian nickel smelter workers. Participants were randomly assigned to three intervention groups (n = 99). Group one (n = 35) received only an educational booklet about nickel, related potential health effects and preventive measures, group two (n = 35) attended a presentation in addition to the booklet, and group three (n = 29) received personal feedback on their biomarker results in addition to the booklet and presentations. Pre- and post-intervention air sampling was conducted to measure concentrations of dust and nickel in air along with worker's blood and urine nickel concentrations. The study did not measure significant differences in particles and nickel concentrations in the air between pre- and post-interventions. However, we achieved significant reductions in the post intervention urine and blood nickel concentrations which can be attributed to changes in personal hygiene behavior. The median urinary nickel concentration in the pre-intervention period for group one was 52.3 ug/L, for group two 57.4 ug/L, and group three 43.2 ug/L which were significantly higher (p< = 0.010) than those measured in the post-intervention period for each of the groups with 8.5 ug/L, 9.6 ug/L, and 8.2 ug/L, respectively. A similar pattern was recorded for serum nickel with significantly (p < 0.05) higher median concentrations measured in the pre-intervention period for group one 1.7 ug/L, and 2.0 ug/L for group 2 and group 3 compared with the post intervention median serum nickel levels of 0.1 ug/L for all groups. The study showed that educational interventions can significantly reduce personal exposure levels to nickel among Indonesian nickel smelter workers. PMID- 28641055 TI - Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis. AB - INTRODUCTION: Natalizumab is a humanized monoclonal antibody highly effective in relapsing-remitting multiple sclerosis (MS). Important concerns about its safety have been pointed out mainly because of the risk of progressive multifocal leukoencephalopathy (PML), caused by the opportunistic John-Cunningham virus (JCV). Areas covered: This review analyzes all the safety aspects related to the use and safety of natalizumab in MS patients. Other than PML, post-marketing, safety red-flags have been reported, as liver or haematological serious adverse events. Pregnancy evidences will be pointed out. The risk of PML depends on: concomitant or previous immunosuppression, exposure duration, anti-JCV antibody level. In natalizumab-related PML the average survival is 77%; prognostic features and information for the earliest identification of PML have been identified to maximally reduce its incidence, mortality and morbidity. Expert opinion: Natalizumab is a highly effective drug for MS patients but its safety issues represent a relevant limitation and impose strict clinical surveillance of treated patients. Some post-marketing safety red-flags have been pointed out, with higher attention to severe liver failures and limphoma cases. If PML and its consequences are considered the most relevant issues, a continuous surveillance must be maintained also regarding other possible SAEs like liver diseases and malignancies. PMID- 28641057 TI - Child anthropometry data quality from Demographic and Health Surveys, Multiple Indicator Cluster Surveys, and National Nutrition Surveys in the West Central Africa region: are we comparing apples and oranges? AB - BACKGROUND: There has been limited work comparing survey characteristics and assessing the quality of child anthropometric data from population-based surveys. OBJECTIVE: To investigate survey characteristics and indicators of quality of anthropometric data in children aged 0-59 months from 23 countries in the West Central Africa region. METHODS: Using established methodologies and criteria to examine child age, sex, height, and weight, we conducted a comprehensive assessment and scoring of the quality of anthropometric data collected in 100 national surveys. RESULTS: The Multiple Indicator Cluster Surveys (MICS) and Demographic and Health Surveys (DHS) collected data from a greater number of younger children than older children while the opposite was found for the National Nutrition Surveys (NNS). Missing or implausible height/weight data proportions were 12% and 8% in MICS and DHS compared to 3% in NNS. Average data quality scores were 14 in NNS, 33 in DHS, and 41 in MICS. CONCLUSIONS: Although our metric of data quality suggests that data from the NNS appear more consistent and robust, it is equally important to consider its disadvantages related to access and lack of broader socioeconomic information. In comparison, the DHS and MICS are publicly-accessable for research and provide socioeconomic context essential for assessing and addressing the burden of undernutrition within and between countries. The strengths and weaknesses of data from these three sources should be carefully considered when seeking to determine the burden of child undernutrition and its variation within countries. PMID- 28641056 TI - The odd couple: using biomedical and intersectional approaches to address health inequities. AB - BACKGROUND: Better understanding and addressing health inequities is a growing global priority. OBJECTIVE: In this paper, we contribute to the literature examining complex relationships between biological and social dimensions in the field of health inequalities. Specifically, we explore the potential of intersectionality to advance current approaches to socio-biological entwinements. DESIGN: We provide a brief overview of current approaches to combining both biological and social factors in a single study, and then investigate the contributions of an intersectional framework to such work. RESULTS: We offer a number of concrete examples of how intersectionality has been used empirically to bring both biological and social factors together in the areas of HIV, post traumatic stress disorder, female genital circumcision/mutilation/cutting, and cardiovascular disease. CONCLUSION: We argue that an intersectional approach can further research that integrates biological and social aspects of human lives and human health and ultimately generate better and more precise evidence for effective policies and practices aimed at tackling health inequities. PMID- 28641058 TI - Acute kinematics changes in marathon runners using different footwear. AB - The effects of running with or without shoes on injury prevention have been extensively studied, and several investigations have assessed biomechanical differences between them. However, findings are not consensual and further insights on biomechanical load associated with differently shod or barefoot conditions may be needed. This study aimed to observe if habitually shod marathon runners show acute alterations when running barefoot or with minimalist shoes, and to determine whether the running kinematical adaptations of wearing minimalist shoes were similar to barefoot running. Twelve male marathon runners ran on the treadmill at their average marathon pace in different footwear conditions: habitual running shoes, minimalist shoes, and barefoot. High resolution infrared cameras and visual 3D software were used to assess kinematic data. The following parameters were studied: foot strike angle, cycle time, stance time, normalized stride length, hip, knee, and ankle angular position at initial contact, and their respective range-of-motion (ROM) during stance phase. Contrary to the expectations, it was found that highly trained habitually shod elite marathon runners changed their lower limb kinematic pattern both when running barefoot or wearing minimalist shoes. Minimalist shoes showed a trend towards intermediate biomechanical effects between running with and without shoes. PMID- 28641059 TI - The latent structure of social anxiety disorder and the performance only specifier: a taxometric analysis. AB - Social anxiety disorder (SAD) is often treated as a discrete diagnostic entity that represents a naturally occurring class, though empirical evidence largely supports a dimensional conceptualization of social fears. Further, the inclusion of a "performance only" specifier in the DSM-5 implies that individuals who experience intense social anxiety exclusively in performance situations are distinct from those with broader social fears. The purpose of the present research was to examine the latent structure of SAD and the DSM-5 "performance only" specifier in a large nonclinical sample (n = 2019). Three taxometric procedures (MAXCOV, MAMBAC, and L-Mode) were applied to indicators derived from two commonly used measures of social anxiety. Results yielded convergent evidence indicating that social anxiety exhibits a dimensional latent structure. Further, social performance anxiety demonstrates continuous relationships with milder social fears, suggesting that the "performance only" specifier may not represent a discrete entity. The implications of these findings for the assessment, diagnosis, classification, and treatment of social anxiety are discussed. PMID- 28641060 TI - Effective preventive interventions to support parents of young children: Illustrations from the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD). AB - Secure attachment relationships are essential for children's current and later development. From attachment theory and research, it can be derived that sensitive parenting is the key to positive parent-child relationships. Is it possible to design effective interventions to enhance sensitive parenting? In this article, we review elements that are crucial for effective attachment-based interventions, and we proceed with illustrations from the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD). We describe how this intervention program was developed, how it has been implemented in practice in different types of families and in daycare settings, and how effective the program is. We conclude that intervention programs like the VIPP-SD could play an important role in the community by serving families in need of parenting support. PMID- 28641061 TI - Positive parenting as responsible care: Risks, protective factors, and intervention evaluation. AB - In this themed issue of the Journal of Prevention & Intervention in the Community, the first four contributions provide knowledge on factors that can support or hinder positive parenting throughout children's lives. In particular, the first article examined the spillover of work stressors on parenting behaviors and the role of spousal support as a moderator of stress spillover. The second contribution examines the association between parents' promotion of volitional functioning and adopted children's sense of strength of family bonds and belonging to the adoptive family. The third article analyzes the negative impact of intrusive parenting on young adult children's romantic relationship quality and couple identity, and the fourth article examines parents' autonomous and controlled motivations to transmit values to their adolescent children and their associations with parents' socialization goals. Finally, the last two articles present the contents and evaluation of two parenting programs. The fifth article illustrates the development, content, and efficacy of an attachment-based intervention for parenting: the Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD); the sixth article presents a qualitative evaluation of a group-based program focused on promoting parents' identity together with parenting skills: The Groups for Family Enrichment_Parent version (GFE_P). PMID- 28641062 TI - The difficulty of being a professional, a parent, and a spouse on the same day: Daily spillover of workplace interactions on parenting, and the role of spousal support. AB - Designing parenting interventions and preventions requires knowledge on the factors and processes that shape parenting behaviors. Using data collected over 10 days, during the last hour of work and before going to bed, this study examined the spillover of interpersonal work stresses into positive and negative parenting behaviors. Data were collected among 103 couples who had at least one child between the age of one and eight years. Of particular interest was the role of received emotional spousal support as a moderator of stress spillover. Dyadic variants of multilevel models were used to analyze the data. The results showed that on days on which mothers or fathers reported stressful interpersonal interactions in the workplace, they also reported less positive parenting behaviors. In addition, mothers reported more negative parenting behaviors on days characterized by these kinds of work experiences. Mothers and fathers were found to report more positive parenting behaviors, and mothers less negative parenting behaviors, on the days on which they received more spousal support. Received spousal support also moderated spillover of work stress into parenting behaviors and this finding was found to be gender-specific: for mothers, support enhanced spillover into positive behaviors, and for fathers, it enhanced spillover into negative parenting behaviors. PMID- 28641063 TI - Launching adoptees into adulthood: Mothers' and fathers' promotion of volitional functioning. AB - In the psychological literature, there is growing evidence that parental support of children's volitional functioning is one of the most prominent protective factors during adolescence and the transition to adulthood. According to the Self Determination Theory, children cope best with developmental tasks when they acquire a sense of self-governance and self-endorsed functioning. In the field of adoption research, however, the parental promotion of volitional functioning (PVF) and its relation to the adopted child's development are still underinvestigated. The present study involved 160 Italian internationally adopted adolescents and emerging adults and both their parents. It was aimed at examining the extent to which PVF, as reported by each family member, was related to the child's adoptive filiation. Overall, findings showed significant associations between maternal and paternal PVF and adoptive filiation that, however, varied according to the informant and to the child's gender and age. Results have been discussed in relation to the intervention with adoptive parents and children. PMID- 28641064 TI - A qualitative evaluation of a preventive intervention for parents: The Groups for Family Enrichment_Parent version (GFE_P). AB - The traditional objective of parenting enrichment programs is to train parents' abilities and specific competences, but less attention is paid to promoting participants' reflection on their parental identity. These programs are generally delivered to groups of parents, though the group is rarely considered a specific tool to promote changes in participants' relational functioning. The Groups for Family Enrichment_Parent version (GFE_P; Iafrate, Donato, & Bertoni, 2010 ; Iafrate & Rosnati, 2007 ) focus on parental identity in addition to parental competences and skills and purposely use the group of parents as an educational tool, adopting a semistructured format. In this article, we first introduce the characteristics of GFE_P, then we present the results of a qualitative evaluation of an application of this intervention to a group of Italian parents. Findings from the process evaluation showed that participants actively contributed to the development of themes during the intervention. Result evaluation suggested that the recognition of key aspects of parental identity can be an important prerequisite to the acquisition of better parenting skills. Implications for parenting programs design are discussed. PMID- 28641065 TI - Motivations and contents of parent-child value transmission. AB - This study focused on parents' motivations to transmit values to their adolescent children. According to Self-Determination Theory, controlled motivations (i.e., external and introjected)-which refer to doing something because it leads to approval or rewards-and autonomous motivations (i.e., identified and integrated) which refer to doing something because it is perceived as inherently worthy-were examined. 325 Italian parental couples, with one child aged between 14 and 18 years, filled out a self-report questionnaire. Results showed that in value transmission, both parents were primarily moved by autonomous motivations, although for fathers, external motivations were more important than for mothers. Both paternal and maternal motivations resulted to be related with the values parents would like their children to endorse. In particular, the more parents felt volitional in transmitting values, the more they gave importance to self transcendence in their children's socialization; the more parents were guided by controlled motivations, the more they would like their children to endorse conservation values. Implications of this research and its possible developments are discussed. PMID- 28641066 TI - Free to love? The role of intrusive parenting for young adult children's romantic relationship quality. AB - Intrusive parenting is a form of boundary disturbance in the parent-child relationship which has been consistently associated with children's maladjustment. The present study examines the role of intrusive parenting for young adult children's romantic relationship quality. Relying on data from a two wave longitudinal study among young couples in transition to marriage in Italy, we investigated the link between young adults' perceived intrusive parenting and change in their romantic relationship quality from 6 months before marriage to 18 months after marriage, as well as the mediating role of change in the capacity to include the partner in the self. Data were analyzed using actor-partner interdependence modeling. Perceived intrusive parenting negatively predicted change in inclusion of the other in the self and change in romantic relationship quality for both partners. For females, change in their capacity of inclusion of the other in the self fully mediated the association between their perceived intrusive parenting and change in their own and partner's relationship quality. Limitations and implications for practice are discussed. PMID- 28641068 TI - Centric relation-intercuspal position discrepancy and its relationship with temporomandibular disorders. A systematic review. AB - OBJECTIVE: The objective of this study is to assess the relationship between centric relation-intercuspal position discrepancy (CR-ICP discrepancy) and temporomandibular disorders (TMDs), by systematically reviewing the literature. MATERIALS AND METHODS: A systematic research was performed between 1960 and 2016 based on electronic databases: PubMed, Cochrane Library, Medline, Embase, Scopus, EBSCOhost, BIREME, Lilacs and Scielo, including all languages. Analytical observational clinical studies were identified. Two independent authors selected the articles. PICO format was used to analyze the studies. The Newcastle-Ottawa Scale (NOS) was used to verify the quality of the evidence. RESULTS: Four hundred and sixty-seven potentially eligible articles were identified. Twenty studies were analyzed, being grouped according to intervention in studies in orthodontic patients (n = 3) and studies in subjects without intervention (n = 17). Quality of evidence was low, with an average score of 3.36 according to Newcastle-Ottawa Scale. In most studies, the presence of CR-ICP discrepancy is associated with the presence of muscle (pain) and joint disorders (noise, disc displacement, pain, crepitus, osteoarthritis and osteoarthrosis). However, the lack of consistency of the results reported reduces the validity of the studies making it impossible to draw any definite conclusions. CONCLUSIONS: Because of the heterogeneity of the design and methodology and the low quality of the articles reviewed, it is not possible to establish an association between CR-ICP discrepancy and TMD. The consequence of CR-ICP discrepancy on the presence of TMD requires further research, well-defined and validated diagnostic criteria and rigorous scientific methodologies. Longitudinal studies are needed to identify CR-ICP discrepancy as a possible risk factor for the presence of TMD. PMID- 28641069 TI - The Present Retirement Crisis and How Social Workers Can Respond. AB - Research on Americans' retirement readiness indicates a wide range of preparedness for the golden years. Called a "crisis" by researchers, retirement for some may include significant choices: continued employment or utilization of social welfare services. This article describes factors contributing to the retirement crisis and roles social workers can play in assisting older retirees. Disparity in household retirement savings exists by ethnicity. On the front lines serving aging individuals and their families, social work professionals are well situated to collaborate with individuals, and other providers, to address financial, social and emotional pillars necessary in facilitating a safe and secure retirement. PMID- 28641070 TI - ELMO proteins transduce G protein-coupled receptor signal to control reorganization of actin cytoskeleton in chemotaxis of eukaryotic cells. AB - Chemotaxis, which is chemoattractant-guided directional cell migration, plays major roles in recruitment of neutrophils, the metastasis of cancer cells, and the development of the model organism Dictyostelium discoideum. These cells share remarkable similarities in the signaling pathways by which they control chemotaxis. They all use a G protein-coupled receptor (GPCR)-mediated signal transduction pathway to sense the chemotactic gradient to guide cell migration. Diverse chemokines activate Rac through conserved GPCR signaling pathways. ELMO proteins are an evolutionarily conserved, essential component of the ELMO/Dock complex, which functions as a guanine nucleotide exchange factor (GEF) for small G protein Rac activation. The linkages between the GPCR-initiated gradient sensing compass and the Rac-mediated migrating machinery have long been missing. Here, we summarize recent findings on ELMO proteins that directly interact with G protein and transduce GPCR signaling to control the reorganization of actin-based cytoskeleton through regulating Rac activation during chemotaxis, first in D. discoideum and then in mammalian cancer cells. This represents an evolutionarily conserved signaling shortcut from GPCR to the actin cytoskeleton. PMID- 28641071 TI - Giving It Our Best Shot? Human Papillomavirus and Hepatitis B Virus Immunization Among Refugees, Massachusetts, 2011-2013. AB - INTRODUCTION: The receipt rate of hepatitis B virus vaccine among adolescents in the United States is high, while the receipt rate of human papillomavirus vaccine is low. Rates have not been closely studied among refugees, whose home countries have high rates of disease caused by these viruses. METHODS: We examined human papillomavirus and hepatitis B virus immunization rates among 2,269 refugees aged 9 to 26 years who resettled in Massachusetts from 2011 through 2013. This was a secondary analysis of data from their medical screenings. We used binary logistic regression to assess characteristics associated with immunization and bivariate analyses to compare refugee immunization rates with those of the general US population. RESULTS: Forty-five percent of US adolescents aged 13 to 17 years received 1 dose of human papillomavirus vaccine, compared with 68% of similarly aged refugees. Males (adjusted odds ratio [aOR], 0.62; 95% confidence interval [CI], 0.52-0.74), refugees older than 13 years (aOR, 0.74; 95% CI, 0.60-0.93), and refugees not from Sub-Saharan Africa (aOR, 0.74; 95% CI, 0.59-0.92) were less likely to receive human papillomavirus vaccine, while arrivals in 2012 through 2013 were more likely (aOR, 1.6; 95% CI, 1.3-1.9) than those arriving in 2011. Refugees older than 13 years were less likely to receive 2 doses of hepatitis B virus vaccine (aOR, 0.49; 95% CI, 0.37-0.63) than older refugees. CONCLUSION: Specialized post-arrival health assessment may improve refugees' immunization rates. PMID- 28641072 TI - Overweight, Obesity, and Extreme Obesity Among Mississippi Adults, 2001-2010 and 2011-2015. AB - INTRODUCTION: In 2015, about 1.5 million adults in Mississippi were overweight or obese. Obesity is associated with increased risk for diabetes and cardiovascular problems. We examined trends in the prevalence of overweight, obesity, and extreme obesity from 2001 through 2010 and 2011 through 2015. METHODS: We used data from the Mississippi Behavioral Risk Factor Surveillance System to analyze trends in the prevalence of overweight, obesity, and extreme obesity among adults from 2001 through 2010 and 2011 through 2015. Joinpoint software was used to examine annual percentage change (APC) in the prevalence of each condition overall and by sex and race. RESULTS: We observed a significant decrease in overweight prevalence from 2001 to 2010, both overall (APC, -1.3%) and among men (APC, -2.0%), blacks (APC, -1.0%), and whites (APC, -1.5%), but not among women. The overall prevalence of both obesity (APC, 2.9%) and extreme obesity (APC, 3.6%) increased significantly, and these increases occurred across all subgroups for both obesity (men APC, 3.5%; women APC, 2.5%; blacks APC, 1.9%; and whites APC, 3.8%) and extreme obesity (men APC, 6.7%; women APC, 2.5%; blacks APC, 2.2%; and whites APC, 5.0%). From 2011 to 2015, the only significant change was an increase in the prevalence of extreme obesity among whites (APC, 2.6%). CONCLUSION: The increasing proportion of adult Mississippians in the 2 highest risk BMI categories warrants urgent community and clinical obesity interventions. Community-tailored and sustained obesity prevention, treatment, and control programs that include diet and physical activity are needed to address the obesity epidemic. PMID- 28641073 TI - Gonorrhoea testing and positivity in non-remote Aboriginal Community Controlled Health Services. AB - : Background Gonorrhoea occurs at high levels in young Aboriginal and Torres Strait Islander people living in remote communities, but there are limited data on urban and regional settings. An analysis was undertaken of gonorrhoea testing and positivity at four non-remote Aboriginal Community Controlled Health Services participating in a collaborative research network. METHODS: This was a retrospective analysis of clinical encounter data derived from electronic medical records at participating services. Data were extracted using the GRHANITE program for all patients aged 15-54 years from 2009 to 2013. Demographic characteristics and testing and positivity for gonorrhoea were calculated for each year. RESULTS: A total of 2971 patients (2571 Aboriginal and/or Torres Strait Islander) were tested for gonorrhoea during the study period. Among Aboriginal and/or Torres Strait Islander patients, 40 (1.6%) tested positive. Gonorrhoea positivity was associated with clinic location (higher in the regional clinic) and having had a positive chlamydia test. By year, the proportion of patients aged 15-29 years tested for gonorrhoea increased in both men (7.4% in 2009 to 15.9% in 2013) and women (14.8% in 2009 to 25.3% in 2013). Concurrent testing for chlamydia was performed on 86.3% of testing occasions, increasing from 75% in 2009 to 92% in 2013. Factors related to concurrent testing were sex and year of test. CONCLUSIONS: The prevalence of gonorrhoea among young Aboriginal and/or Torres Strait Islander people in non-remote settings suggests that the current approach of duplex testing for chlamydia and gonorrhoea simultaneously is justified, particularly for women. PMID- 28641074 TI - Development of novel antigen receptors for CAR T-cell therapy directed toward solid malignancies. AB - Development of chimeric antigen receptor (CAR) T cells have led to remarkable successes in the treatment of B-cell malignancies with anti-CD19 CAR. Here we discuss the development of novel antigen receptors for use in solid malignancies with respect to target antigens, receptor design, and T cell manipulations. PMID- 28641076 TI - Elevated CD26 Expression by Skin Fibroblasts Distinguishes a Profibrotic Phenotype Involved in Scar Formation Compared to Gingival Fibroblasts. AB - Compared to skin, wound healing in oral mucosa is faster and produces less scarring, but the mechanisms involved are incompletely understood. Studies in mice have linked high expression of CD26 to a profibrotic fibroblast phenotype, but this has not been tested in models more relevant for humans. We hypothesized that CD26 is highly expressed by human skin fibroblasts (SFBLs), and this associates with a profibrotic phenotype distinct from gingival fibroblasts (GFBLs). We compared CD26 expression in human gingiva and skin and in gingival and hypertrophic-like scar-forming skin wound healing in a pig model, and used three-dimensional cultures of human GFBLs and SFBLs. In both humans and pigs, nonwounded skin contained abundantly CD26-positive fibroblasts, whereas in gingiva they were rare. During skin wound healing, CD26-positive cells accumulated over time and persisted in forming hypertrophic-like scars, whereas few CD26-positive cells were present in the regenerated gingival wounds. Cultured human SFBLs displayed significantly higher levels of CD26 than GFBLs. This was associated with an increased expression of profibrotic genes and transforming growth factor-beta signaling in SFBLs. The profibrotic phenotype of SFBLs partially depended on expression of CD26, but was independent of its catalytic activity. Thus, a CD26-positive fibroblast population that is abundant in human skin but not in gingiva may drive the profibrotic response leading to excessive scarring. PMID- 28641075 TI - Postconditioning with Intralipid emulsion protects against reperfusion injury in post-infarct remodeled rat hearts by activation of ROS-Akt/Erk signaling. AB - The clinically used lipid emulsion Intralipid (ILE) reduces ischemia reperfusion injury in healthy rodent hearts. We tested whether ILE is cardioprotective in postinfarct remodeled hearts. Post-infarct remodeled and sham Sprague-Dawley rat hearts were perfused in working mode and subjected to ischemia (15 minutes) and reperfusion (30 minutes). Left ventricular (LV) work was measured in hearts that were untreated or that received ILE (1%) postconditioning administered at the onset of reperfusion, or the reactive oxygen species (ROS) scavenger N-(2 mercaptopropionyl)-glycine (10 MUM) alone or in combination with ILE. Mitochondrial O2 consumption was measured in LV muscle fibers. Acetyl CoA production was calculated from the oxidation of [U-14C]glucose and [9,10 3H]palmitate. ROS production was assessed by loss of aconitase activity as well as by release of hydrogen peroxide. Phosphorylation of Akt, Erk1/2, and STAT3 were used to evaluate protection signaling. Remodeled hearts exhibited LV dysfunction and signs of hypertrophy consistent with significant postinfarct remodeling. ILE postconditioning enhanced the recovery of postischemic LV function in remodeled hearts, preserved energy metabolism in mitochondria, accelerated palmitate oxidation and acetyl CoA production, and activated Akt/Erk/STAT3 in a ROS-dependent manner. Protection by ILE postconditioning evolved rapidly within the first minutes of reperfusion without evidence of additional cardiotonic effects due to provision of supplementary energy substrates potentially released from ILE during reperfusion. ILE represents a novel and clinically feasible cardioprotective strategy that is highly effective in remodeled hearts. Our data provide a rationale for the clinical evaluation of ILE postconditioning where ILE is administered as a bolus at the onset of reperfusion. PMID- 28641077 TI - Inhibition of Early Growth Response 1 in the Hippocampus Alleviates Neuropathology and Improves Cognition in an Alzheimer Model with Plaques and Tangles. AB - A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, lowers amyloid-beta (Abeta) pathology, and improves cognition in the 3xTg-AD mouse model. Egr-1 silencing does not affect levels of cyclin-dependent protein kinase 5 (Cdk5), glycogen synthase kinase 3beta, protein phosphatase 1, or protein phosphatase 2A, but reduces p35 subunit of Cdk5. Egr-1 silencing also reduces levels of beta secretase 1 (BACE-1) and BACE-1-cleaved amyloid precursor protein (APP) metabolites (secreted APPbeta, C99, Abeta40, and Abeta42) but has no effect on presenilin 1 and presenilin 2. In hippocampal primary neurons, Egr-1 binds to BACE-1 and p35 promoters, enhances tau phosphorylation, activates Cdk5 and BACE 1, and accelerates amyloidogenic APP processing. Blocking Cdk5 action blocks Egr 1-induced tau phosphorylation but has no effect on BACE-1 activation and amyloidogenic APP processing. Blocking BACE-1 action, on the other hand, blocks Egr-1-induced amyloidogenic APP processing but does not affect tau phosphorylation. Egr-1 regulates tau phosphorylation and Abeta synthesis in the brain by respectively controlling activities of Cdk5 and BACE-1, suggesting that Egr-1 is a potential therapeutic candidate for the treatment of AD. PMID- 28641078 TI - Signal dimensionality and the emergence of combinatorial structure. AB - In language, a small number of meaningless building blocks can be combined into an unlimited set of meaningful utterances. This is known as combinatorial structure. One hypothesis for the initial emergence of combinatorial structure in language is that recombining elements of signals solves the problem of overcrowding in a signal space. Another hypothesis is that iconicity may impede the emergence of combinatorial structure. However, how these two hypotheses relate to each other is not often discussed. In this paper, we explore how signal space dimensionality relates to both overcrowding in the signal space and iconicity. We use an artificial signalling experiment to test whether a signal space and a meaning space having similar topologies will generate an iconic system and whether, when the topologies differ, the emergence of combinatorially structured signals is facilitated. In our experiments, signals are created from participants' hand movements, which are measured using an infrared sensor. We found that participants take advantage of iconic signal-meaning mappings where possible. Further, we use trajectory predictability, measures of variance, and Hidden Markov Models to measure the use of structure within the signals produced and found that when topologies do not match, then there is more evidence of combinatorial structure. The results from these experiments are interpreted in the context of the differences between the emergence of combinatorial structure in different linguistic modalities (speech and sign). PMID- 28641079 TI - Reply by Authors. PMID- 28641080 TI - Editorial Comment. PMID- 28641081 TI - Editorial Comment. PMID- 28641082 TI - Mesh Sling Removals: Why, When, How and Consequences. PMID- 28641083 TI - Editorial Comment. PMID- 28641084 TI - Reply by Authors. PMID- 28641085 TI - Editorial Comment. PMID- 28641086 TI - Editorial Comment. PMID- 28641087 TI - Room to Grow-What is the Current Role of Neuromodulation in Pediatric Bowel Bladder Dysfunction? PMID- 28641089 TI - Combined time-lapse magnetic resonance imaging and modeling to investigate colloid deposition and transport in porous media. AB - Colloidal particles can act as vectors of adsorbed pollutants in the subsurface, or be themselves pollutants. They can reach the aquifer and impair groundwater quality. The mechanisms of colloid transport and deposition are often studied in columns filled with saturated porous media. Time-lapse profiles of colloid concentration inside the columns have occasionally been derived from magnetic resonance imaging (MRI) data recorded in transport experiments. These profiles are valuable, in addition to particle breakthrough curves (BTCs), for testing and improving colloid transport models. We show that concentrations could not be simply computed from MRI data when both deposited and suspended colloids contributed to the signal. We propose a generic method whereby these data can still be used to quantitatively appraise colloid transport models. It uses the modeled suspended and deposited particle concentrations to compute modeled MRI data that are compared to the experimental data. We tested this method by performing transport experiments with sorbing colloids in sand, and assessed for the first time the capacity of the model calibrated from BTCs to reproduce the MRI data. Interestingly, the dispersion coefficient and deposition rate calibrated from the BTC were respectively overestimated and underestimated compared with those calibrated from the MRI data, suggesting that these quantities, when determined from BTCs, need to be interpreted with care. In a broader perspective, we consider that combining MRI and modeling offers great potential for the quantitative analysis of complex MRI data recorded during transport experiments in complex environmentally relevant porous media, and can help improve our understanding of the fate of colloids and solutes, first in these media, and later in soils. PMID- 28641088 TI - Application of zeolite/hydrous zirconia composite as a novel sediment capping material to immobilize phosphorus. AB - A unique sediment-capping agent consisting of a zeolite/hydrous zirconia composite (ZHZ) was developed and tested for P-immobilization in the overlying water and sediment cores from a freshwater pond. In the ZHZ, NaP1 zeolite was covered with hydrous zirconia, which existed as an amorphous phase. Experimental results in pond water indicated that ZHZ could efficiently remove soluble reactive phosphorus. The 28-day sediment incubation experiments showed that capping sediment with ZHZ resulted in a more efficient, rapid and sustained decrease in P concentration when compared with the traditional alum treatment method. Furthermore, ZHZ increased the sediment stability, resulting in the lowest turbidity, total phosphorus and soluble reactive phosphorus concentrations in overlying water following artificially induced resuspension of sediment. Phosphorus fractionation of sediment showed that the dominant P form transferred from HCl-extractable P to residual P, and the most release-sensitive P (labile P and reductant reactive P) was decreased after ZHZ application. Overall, ZHZ is a highly effective P-immobilization material. ZHZ has high potential as a sediment capping material to control internal P loading in eutrophic water bodies. PMID- 28641090 TI - Injunctive safety norms, young worker risk-taking behaviors, and workplace injuries. AB - Injunctive safety norms (ISNs) refer to perceptions of others' expectations of one's safety-related conduct. Drawing on a sample of Canadian young workers (n=11,986;M age=17.90years; 55% males), we study the relationships among four sources of non-work-related (i.e., parents, siblings, friends, teachers), two sources of work-related (i.e., supervisors, co-workers) ISNs, young workers' self reported work-related risk-taking behaviors, and workplace injuries. Structural equation modeling suggests that ISNs from parents, supervisors, and co-workers were related to less frequent work-related risk-taking behaviors, and with fewer workplace injuries via less frequent work-related risk-taking behaviors. In addition, ISNs from supervisors were directly associated with fewer workplace injuries. In contrast, ISNs from teachers and siblings were not associated with work-related risk-taking behaviors, but ISNs from siblings were associated with fewer work injuries. Finally, ISNs from friends were associated with more frequent work-related risk-taking and more frequent work injuries via more frequent work-related risk-taking. This study draws attention to the relative roles of non-work sources of social influence and provides some evidence of how ISNs might be related to young workers' work-related risk-taking behaviors and their workplace injuries. It also contributes to practice by suggesting specific interventions that parents, supervisors, and co-workers could undertake to reduce young workers' work-related risk-taking and workplace injuries, namely encouraging youth to be safe at work. PMID- 28641091 TI - Increasing rates of Clostridium difficile infection in Mexican hospitals. AB - INTRODUCTION: The epidemiology of Clostridium difficile infection (CDI) has changed in the last two decades. There is a lack of information regarding incidence and severity of CDI, especially in the developing world. METHODS: This was a retrospective and observational study from four hospitals of three Mexican cities. Patients were diagnosed with CDI when presented with loose stools and had at least one of the following tests positive: toxins assay, real-time PCR, or an endoscopic image compatible with pseudomembranous colitis. CDI was classified according to international guidelines. Demographic and clinical data as well as information regarding total hospital admissions, total length-of-hospital stay, and other variables related to hospitalization were gathered from the epidemiology and administration departments of each hospital. RESULTS: A total of 2050 hospital beds were analyzed with 288,171 patients hospitalized accumulating 1,576,446 days of hospitalization during the study period. The average rate of CDI per 1000 hospital-days was lower than the rates reported in the US and Europe, although in 2015 CDI rates were almost persistently above the mean rate for the study period. More than half of PCR positive patients were ribotype 027. CONCLUSION: Hospital rates of CDI are increasing in Mexican hospitals with a predominance of infections caused by ribotype 027. PMID- 28641092 TI - Nuclear mechanotransduction: sensing the force from within. AB - The cell nucleus is a hallmark of eukaryotic evolution, where gene expression is regulated and the genome is replicated and repaired. Yet, in addition to complex molecular processes, the nucleus has also evolved to serve physical tasks that utilize its optical and mechanical properties. Nuclear mechanotransduction of externally applied forces and extracellular stiffness is facilitated by the physical connectivity of the extracellular environment, the cytoskeleton and the nucleoskeletal matrix of lamins and chromatin. Nuclear mechanosensor elements convert applied tension into biochemical cues that activate downstream signal transduction pathways. Mechanoregulatory networks stabilize a contractile cell state with feedback to matrix, cell adhesions and cytoskeletal elements. Recent advances have thus provided mechanistic insights into how forces are sensed from within, that is, in the nucleus where cell-fate decision-making is performed. PMID- 28641093 TI - Hematological parameters and red blood cell morphological abnormality of Glucose 6-Phosphate dehydrogenase deficiency co-inherited with thalassemia. AB - OBJECTIVE/BACKGROUND: Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and thalassemia are genetically independent hemolytic disorders. Co-inheritance of both disorders may affect red blood cell pathology to a greater extent than normally seen in either disorder alone. This study determines the prevalence and evaluates hematological changes of G-6-PD deficiency and thalassemia co inheritance. METHODS: G-6-PD deficiency was screened from 200 male thalassemia blood samples using a fluorescent spot test. Hematological parameters and red blood cell morphology were evaluated among G-6-PD deficiency/thalassemia co inheritance, G-6-PD deficiency alone, thalassemia alone, and normal individuals. RESULTS: G-6-PD deficiency was detected together with hemoglobin (Hb) E heterozygote, Hb E homozygote, beta-thalassemia trait, and beta-thalassemia/Hb E, alpha-thalassemia-2 trait, and Hb H disease. Hb level, hematocrit, mean cell volume, and mean cell Hb of G-6-PD deficiency co-inherited with asymptomatic thalassemia carriers show significantly lower mean values compared to carriers with only the same thalassemia genotypes. Higher mean red blood cell distribution width was observed in G-6-PD deficiency co-inherited with Hb E heterozygote, as with numbers of hemighost cells in G-6-PD deficiency/thalassemia co-inheritance compared to those with either disorder. Apart from Hb level, hematological parameters of co-inheritance disorders were not different from individuals with a single thalassemia disease. CONCLUSION: G-6-PD deficiency co-inherited with thalassemia in males was present in 10% of the participants, resulting in worsening of red blood cell pathology compared with inheritance of thalassemia alone. PMID- 28641094 TI - Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. AB - Despite the refinements in molecular methods for the detection of cytomegalovirus (CMV) and the advent of highly effective preemptive strategies, CMV remains a leading cause of morbidity and mortality in hematopoietic cell transplant (HCT) recipients. CMV can cause tissue-invasive disease including pneumonia, hepatitis, colitis, retinitis, and encephalitis. Mortality in HCT recipients with CMV disease can be as high as 60%. CMV infection has been associated with increased risk of secondary bacterial and fungal infections, increased risk of graft-versus host disease, and high rates of non-relapse mortality following HCT. The risk of CMV is highly dependent on the donor (D) and the recipient (R) serostatus (D /R+>D+/R+>D+/R->D-/R-). Among allogeneic HCT recipients, high-dose corticosteroids, T-cell depletion, graft-versus-host disease, and mismatched or unrelated donors constitute the main predisposing factors. However, not all seropositive individuals with these risk factors develop CMV, which strongly suggests that host factors, such as those regulating CMV-specific T-cell responses, play a major role in predisposition to CMV in HCT recipients. Here, we discuss emerging concepts in CMV infection in HCT with emphasis on immunological factors that govern CMV reactivation and the applicability of immune monitoring to understand correlates of pathogenesis and its potential to guide clinical decision making. PMID- 28641095 TI - High dose chemotherapy and autologous stem cell transplantation in relapsed or refractory Hodgkin lymphoma: Emerging questions, newer agents, and changing paradigm. AB - Primary treatment for adult and pediatric patients with Hodgkin lymphoma (HL) using current multiagent anthracycline-based chemotherapy with or without radiation therapy will cure approximately >70% of the patients; >95% for early stage with a favorable risk profile and 70-75% with advanced stage and high risk features. Managing refractory and relapsed disease, however, remains a challenge. High dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT) can salvage 40-70% of patients with relapsed or refractory HL. Two randomized trials in relapsed and refractory patients showed superior progression free survival. This presentation addresses some of the salient differences and changes in the management that have evolved over the last decade and have either already affected, or are likely to affect the outcome of HDC auto-SCT. The following will discussed. 1. Historic trials and other emerging issues impacting the outcome of HDC auto-SCT. 2. Changes in the primary treatment and response adapted therapy. 3. Evaluation and validation of prognostic factors at the time of first failure. 4. Selection of salvage chemotherapy. 5. Conditioning regimens. 6. Consolidation after HDC auto-SCT. 7. Management of failures of HDC auto-SCT. 8. Availability of financial resources in various healthcare systems. Enrolment in clinical trials should be encouraged. PMID- 28641096 TI - Hematopoietic stem cell transplantation for sickle cell disease: The changing landscape. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for sickle cell disease (SCD); however, its use is limited by lack of suitable human leukocyte antigen (HLA)-matched donors and decreased application in older patients with significant morbidity. Myeloablative, HLA identical sibling transplantation in children with SCD offers excellent long-term survival, with overall and event-free survival rates of 95% and 92%, respectively. However, the risk of graft-versus-host-disease, infections, infertility, and other long-term transplant complications, further limits its widespread use. Recent approaches using reduced intensity conditioning (RIC) are associated with lower toxicity, allowing extension of this modality to children and adults with significant morbidity; however, these approaches are also associated with increased risk of graft failure. The optimal RIC regimen that strikes the optimal balance between maximizing the rate of stable engraftment while minimizing transplant-related morbidity and mortality is unknown. Alternative donor transplants, most prominently, partial HLA-mismatched related transplants (haploidentical), are being investigated with promising initial results. This review will discuss long-term results of HLA-matched sibling HSCT for SCD, and recent updates on HLA-matched unrelated donor and unrelated umbilical cord blood HSCT for SCD. PMID- 28641097 TI - Long-term complications after hematopoietic cell transplantation. AB - The prevalence of autologous and allogeneic hematopoietic cell transplantation (HCT) survivors continues to increase. Among patients whose disease remains in remission for the first 2-5years after transplantation, it is estimated that approximately 80-90% will be alive over the subsequent 10years. However, the relative mortality rates of such patients continue to remain higher than those of their general population peers, with late complications contributing to significant long-term morbidity and mortality. Late effects in HCT survivors include secondary cancers, organ specific complications, late infections, quality of life impairments, psychosocial issues, sexual and fertility concerns, financial toxicity, and issues around return to work/school. A patient-centric and multidisciplinary approach to HCT survivorship care with collaborative and coordinated care from transplant centers and community healthcare providers is necessary to ensure their long-term health. Lifelong follow-up of HCT survivors is recommended, with established guidelines serving as the template for providing screening and preventive care based on patient-specific exposures. This review discussed common late complications, models for care delivery, and gaps and priorities for future research in the field of HCT survivorship. PMID- 28641098 TI - Trends in hematopoietic stem cell transplant activity in Lebanon. AB - Hematopoietic stem cell transplantation (HSCT) has been accessible to the population residing in Lebanon and surrounding countries since 1997. HSCT programs were developed in two major hospitals in Beirut: American University of Beirut Medical Center (AUBMC) and Makassed General Hospital. Mount Lebanon Hospital initiated an autologous HSCT activity later. Between 2012 and 2016, the HSCT activity in Lebanon reached a total of 897 transplants, among which 303 (33.8%) were allogeneic HSCT and 594 (66.2%) were autologous HSCT. Overall, autologous HSCT activity has remained stable over the past 5years, whereas allogeneic HSCT activity has seen a steep increase between 2012 and 2013 followed by a modest increase later. Haploidentical transplantation has mushroomed and represented almost half of allogeneic HSCT activity in 2016. AUBMC and Makassed General Hospital are members of the European Blood and Marrow Transplantation (EBMT) and East Mediterranean Blood and Marrow Transplantation groups, and AUBMC has been accredited by JACIE (Joint Accreditation Committee - ISCT & EBMT) since 2016. The past 5years have seen an increase in HSCT-related research and publications, mainly from AUBMC. These research activities were predominantly focused on personalized conditioning for allogeneic HSCT and post-transplant maintenance therapy. PMID- 28641099 TI - Reduced-intensity versus myeloablative allogeneic transplantation. AB - Allotransplantation cures patients by cytoreduction and the graft-versus-tumor (leukemia; graft-versus-leukemia [GVL]) alloresponse; both eliminate residual disease. The spectrum of conditioning intensity influences toxicities and non relapse mortality. The spectrum of tumor sensitivity to the GVL response influences relapse. Balancing tolerable toxicities (influenced by patients' performance status and comorbidities) is also influenced by the graft. Intense immunosuppression (for engraftment and graft-versus-host disease prevention) may constrain the immunologic potency of the graft and limit the antineoplastic capacity of the transplant, thus requiring more intense or more effective conditioning regimens to limit the risks of relapse and permit satisfactory disease-free survival. PMID- 28641101 TI - Copy Number Variation in Tourette Syndrome. AB - In the current issue of Neuron, Huang et al. (2017) provide new insights from a consortium study of Tourette syndrome pinpointing copy number variations that are involved in the genomic architecture and implicate genes of interest. PMID- 28641100 TI - Bruton's tyrosine kinase (BTK) as a promising target in solid tumors. AB - Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors. PMID- 28641102 TI - Live or Die? Depends on Who You Are. AB - In this issue of Neuron, Welsbie et al. (2017) and Norsworthy et al. (2017) implicate the transcription factor Sox11 as a key player after optic nerve injury in DLK signaling of RGC cell death, and in RGC regeneration and survival but only in certain RGCs. PMID- 28641103 TI - Staring at the Clock Face in Drosophila. AB - Liang et al. (2017) demonstrate how neuropeptides from two groups of clock cells appear to be responsible for the fly's circadian neurons becoming active at different times of day. By delaying the activity of their clock cell targets, they give rise to morning and evening behavior. PMID- 28641104 TI - Constructing the External World. AB - In this issue of Neuron, Pluta et al. (2017) find a novel map of external space in primary somatosensory cortex, generated by multi-whisker interactions during active touch. PMID- 28641105 TI - It's Not All Fun and Games: Sports, Concussions, and Neuroscience. AB - Few items grab the public's attention like sports, from extremes of great victory to injury and defeat. No injury currently arouses stronger interest than concussion. Giza et al., discuss how neuroscience can provide balance between physical activity and TBI, and guide thoughtful discourse and policy. PMID- 28641107 TI - The Persistence and Transience of Memory. AB - The predominant focus in the neurobiological study of memory has been on remembering (persistence). However, recent studies have considered the neurobiology of forgetting (transience). Here we draw parallels between neurobiological and computational mechanisms underlying transience. We propose that it is the interaction between persistence and transience that allows for intelligent decision-making in dynamic, noisy environments. Specifically, we argue that transience (1) enhances flexibility, by reducing the influence of outdated information on memory-guided decision-making, and (2) prevents overfitting to specific past events, thereby promoting generalization. According to this view, the goal of memory is not the transmission of information through time, per se. Rather, the goal of memory is to optimize decision-making. As such, transience is as important as persistence in mnemonic systems. PMID- 28641106 TI - Antisense Oligonucleotides: Translation from Mouse Models to Human Neurodegenerative Diseases. AB - Multiple neurodegenerative diseases are characterized by single-protein dysfunction and aggregation. Treatment strategies for these diseases have often targeted downstream pathways to ameliorate consequences of protein dysfunction; however, targeting the source of that dysfunction, the affected protein itself, seems most judicious to achieve a highly effective therapeutic outcome. Antisense oligonucleotides (ASOs) are small sequences of DNA able to target RNA transcripts, resulting in reduced or modified protein expression. ASOs are ideal candidates for the treatment of neurodegenerative diseases, given numerous advancements made to their chemical modifications and delivery methods. Successes achieved in both animal models and human clinical trials have proven ASOs both safe and effective. With proper considerations in mind regarding the human applicability of ASOs, we anticipate ongoing in vivo research and clinical trial development of ASOs for the treatment of neurodegenerative diseases. PMID- 28641108 TI - High-Speed and Scalable Whole-Brain Imaging in Rodents and Primates. AB - Subcellular resolution imaging of the whole brain and subsequent image analysis are prerequisites for understanding anatomical and functional brain networks. Here, we have developed a very high-speed serial-sectioning imaging system named FAST (block-face serial microscopy tomography), which acquires high-resolution images of a whole mouse brain in a speed range comparable to that of light-sheet fluorescence microscopy. FAST enables complete visualization of the brain at a resolution sufficient to resolve all cells and their subcellular structures. FAST renders unbiased quantitative group comparisons of normal and disease model brain cells for the whole brain at a high spatial resolution. Furthermore, FAST is highly scalable to non-human primate brains and human postmortem brain tissues, and can visualize neuronal projections in a whole adult marmoset brain. Thus, FAST provides new opportunities for global approaches that will allow for a better understanding of brain systems in multiple animal models and in human diseases. PMID- 28641110 TI - Sox11 Expression Promotes Regeneration of Some Retinal Ganglion Cell Types but Kills Others. AB - At least 30 types of retinal ganglion cells (RGCs) send distinct messages through the optic nerve to the brain. Available strategies of promoting axon regeneration act on only some of these types. Here we tested the hypothesis that overexpressing developmentally important transcription factors in adult RGCs could reprogram them to a "youthful" growth-competent state and promote regeneration of other types. From a screen of transcription factors, we identified Sox11 as one that could induce substantial axon regeneration. Transcriptome profiling indicated that Sox11 activates genes involved in cytoskeletal remodeling and axon growth. Remarkably, alpha-RGCs, which preferentially regenerate following treatments such as Pten deletion, were killed by Sox11 overexpression. Thus, Sox11 promotes regeneration of non-alpha-RGCs, which are refractory to Pten deletion-induced regeneration. We conclude that Sox11 can reprogram adult RGCs to a growth-competent state, suggesting that different growth-promoting interventions promote regeneration in distinct neuronal types. PMID- 28641111 TI - Structural Insights into Modulation of Neurexin-Neuroligin Trans-synaptic Adhesion by MDGA1/Neuroligin-2 Complex. AB - Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) bind directly to neuroligin-1 (NL1) and neuroligin-2 (NL2), thereby respectively regulating excitatory and inhibitory synapse development. However, the mechanisms by which MDGAs modulate NL activity to specify development of the two synapse types remain unclear. Here, we determined the crystal structures of human NL2/MDGA1 Ig1-3 complex, revealing their stable 2:2 arrangement with three interaction interfaces. Cell-based assays using structure guided, site-directed MDGA1 mutants showed that all three contact patches were required for the MDGA's negative regulation of NL2-mediated synaptogenic activity. Furthermore, MDGA1 competed with neurexins for NL2 via its Ig1 domain. The binding affinities of both MDGA1 and MDGA2 for NL1 and NL2 were similar, consistent with the structural prediction of similar binding interfaces. However, MDGA1 selectively associated with NL2, but not NL1, in vivo. These findings collectively provide structural insights into the mechanism by which MDGAs negatively modulate synapse development governed by NLs/neurexins. PMID- 28641109 TI - Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome. AB - Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 * 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 * 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6 156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS. PMID- 28641112 TI - Molecular Mechanism of MDGA1: Regulation of Neuroligin 2:Neurexin Trans-synaptic Bridges. AB - Neuroligins and neurexins promote synapse development and validation by forming trans-synaptic bridges spanning the synaptic cleft. Select pairs promote excitatory and inhibitory synapses, with neuroligin 2 (NLGN2) limited to inhibitory synapses and neuroligin 1 (NLGN1) dominating at excitatory synapses. The cell-surface molecules, MAM domain-containing glycosylphosphatidylinositol anchor 1 (MDGA1) and 2 (MDGA2), regulate trans-synaptic adhesion between neurexins and neuroligins, impacting NLGN2 and NLGN1, respectively. We have determined the molecular mechanism of MDGA action. MDGA1 Ig1-Ig2 is sufficient to bind NLGN2 with nanomolar affinity; its crystal structure reveals an unusual locked rod-shaped array. In the crystal structure of the complex, two MDGA1 Ig1 Ig2 molecules each span the entire NLGN2 dimer. Site-directed mutagenesis confirms the observed interaction interface. Strikingly, Ig1 from MDGA1 binds to the same region on NLGN2 as neurexins do. Thus, MDGAs regulate the formation of neuroligin-neurexin trans-synaptic bridges by sterically blocking access of neurexins to neuroligins. PMID- 28641114 TI - A Critical Role of Presynaptic Cadherin/Catenin/p140Cap Complexes in Stabilizing Spines and Functional Synapses in the Neocortex. AB - The formation of functional synapses requires coordinated assembly of presynaptic transmitter release machinery and postsynaptic trafficking of functional receptors and scaffolds. Here, we demonstrate a critical role of presynaptic cadherin/catenin cell adhesion complexes in stabilizing functional synapses and spines in the developing neocortex. Importantly, presynaptic expression of stabilized beta-catenin in either layer (L) 4 excitatory neurons or L2/3 pyramidal neurons significantly upregulated excitatory synaptic transmission and dendritic spine density in L2/3 pyramidal neurons, while its sparse postsynaptic expression in L2/3 neurons had no such effects. In addition, presynaptic beta catenin expression enhanced release probability of glutamatergic synapses. Newly identified beta-catenin-interacting protein p140Cap is required in the presynaptic locus for mediating these effects. Together, our results demonstrate that cadherin/catenin complexes stabilize functional synapses and spines through anterograde signaling in the neocortex and provide important molecular evidence for a driving role of presynaptic components in spinogenesis in the neocortex. PMID- 28641113 TI - Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons. AB - Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases. PMID- 28641115 TI - Feature Integration Drives Probabilistic Behavior in the Drosophila Escape Response. AB - Animals rely on dedicated sensory circuits to extract and encode environmental features. How individual neurons integrate and translate these features into behavioral responses remains a major question. Here, we identify a visual projection neuron type that conveys predator approach information to the Drosophila giant fiber (GF) escape circuit. Genetic removal of this input during looming stimuli reveals that it encodes angular expansion velocity, whereas other input cell type(s) encode angular size. Motor program selection and timing emerge from linear integration of these two features within the GF. Linear integration improves size detection invariance over prior models and appropriately biases motor selection to rapid, GF-mediated escapes during fast looms. Our findings suggest feature integration, and motor control may occur as simultaneous operations within the same neuron and establish the Drosophila escape circuit as a model system in which these computations may be further dissected at the circuit level. VIDEO ABSTRACT. PMID- 28641117 TI - Structural components of nuclear integrity with gene regulatory potential. AB - The nucleus is a mechanosensitive and load-bearing structure. Structural components of the nucleus interact to maintain nuclear integrity and have become subjects of exciting research that is relevant to cell and developmental biology. Here we outline the boundaries of what is known about key architectural elements within the nucleus and highlight their potential structural and transcriptional regulatory functions. PMID- 28641116 TI - Mechanisms for Selective Single-Cell Reactivation during Offline Sharp-Wave Ripples and Their Distortion by Fast Ripples. AB - Memory traces are reactivated selectively during sharp-wave ripples. The mechanisms of selective reactivation, and how degraded reactivation affects memory, are poorly understood. We evaluated hippocampal single-cell activity during physiological and pathological sharp-wave ripples using juxtacellular and intracellular recordings in normal and epileptic rats with different memory abilities. CA1 pyramidal cells participate selectively during physiological events but fired together during epileptic fast ripples. We found that firing selectivity was dominated by an event- and cell-specific synaptic drive, modulated in single cells by changes in the excitatory/inhibitory ratio measured intracellularly. This mechanism collapses during pathological fast ripples to exacerbate and randomize neuronal firing. Acute administration of a use- and cell type-dependent sodium channel blocker reduced neuronal collapse and randomness and improved recall in epileptic rats. We propose that cell-specific synaptic inputs govern firing selectivity of CA1 pyramidal cells during sharp-wave ripples. PMID- 28641118 TI - Mechanisms for fast cell migration in complex environments. AB - Cell migration depends on a combination of the cell's intrinsic capacity to move and the proper interpretation of external cues. This multistep process enables leukocytes to travel long distances in organs in just a few hours. This fast migration is partly due to the leukocytes' high level of plasticity, which helps them to adapt to a changing environment. Here, we review recent progress in understanding the mechanisms used by leukocytes to move rapidly and efficiently in intricate anatomical landscapes. We shall focus on specific cytoskeletal rearrangements used by neutrophils and dendritic cells to migrate within confined environments. Lastly, we will describe the properties that facilitate the rapid migration of leukocyte in complex tissue geometries. PMID- 28641119 TI - Maternal progesterone levels are modulated by maternal BMI and predict birth weight sex-specifically in human pregnancies. AB - OBJECTIVE: Successful pregnancy outcome is the result of a tailored adaptation of the maternal endocrine and immune system throughout gestation. We aimed to investigate if maternal endocrine, anthropometric and life style factors assessed longitudinally throughout pregnancy allow prediction of birth weight. STUDY DESIGN: Data on maternal factors and obstetrical characteristics from 220 pregnancies from a German prospective pregnancy cohort were analyzed using univariate and multivariate regression models. The association between maternal progesterone levels at the end of the 1st (gw 12-14), the 2nd (gw 22-24) and the 3rd trimester (gw 34-36) and birth weight of children born at term was examined. Interaction terms were included to identify possible sex-specific associations. Furthermore, associations between maternal and obstetric characteristics and progesterone levels were tested. RESULTS: After controlling for possible confounders, progesterone in the 2nd trimester emerged as an independent predictor for birth weight in pregnancies with female (p=0.01), but not male fetuses (p=0.6). In female fetuses each increase of progesterone by 1ng/ml in the 2nd trimester was associated with an increase of birth weight by 6.8g (95% CI=1.44-12.24). Maternal 1st trimester BMI showed a significant inverse correlation to progesterone levels throughout gestation (p<0.0001 in the 1st and 2nd, p=0.01 in the 3rd trimester). This inverse association between maternal BMI and progesterone levels was confined to overweight women. CONCLUSION: Our data support that maternal progesterone levels have the potential to serve as early biomarker for reduced birth weight and underpins the importance of normal weight when entering the reproductive phase. PMID- 28641120 TI - The cognitive bases of the development of past and future episodic cognition in preschoolers. AB - The aim of this study was to use a minimalist framework to examine the joint development of past and future episodic cognition and their underlying cognitive abilities in 3- to 5-year-old Turkish preschoolers. Participants engaged in two main tasks, a what-where-when (www) task to measure episodic memory and a future prediction task to measure episodic future thinking. Three additional tasks were used for predicting children's performance in the two main tasks: a temporal language task, an executive function task, and a spatial working memory task. Results indicated that past and future episodic tasks were significantly correlated with each other even after controlling for age. Hierarchical multiple regressions showed that, after controlling for age, the www task was predicted by executive functions, possibly supporting binding of episodic information and by linguistic abilities. The future prediction task was predicted by linguistic abilities alone, underlining the importance of language for episodic past and future thinking. PMID- 28641121 TI - Is inhibitory control involved in discriminating pseudowords that contain the reversible letters b and d? AB - Children tend to confuse reversible letters such as b and d when they start learning to read. According to some authors, mirror errors are a consequence of the mirror generalization (MG) process that allows one to recognize objects independently of their left-right orientation. Although MG is advantageous for the visual recognition of objects, it is detrimental for the visual recognition of reversible letters. Previous studies comparing novice and expert readers demonstrated that MG must be inhibited to discriminate reversible single letters. In this study, we investigated whether MG must also be inhibited by novice readers to discriminate between two pseudowords containing reversible letters. Readable pseudowords, rather than words, were used to mimic early non-automatic stages of reading when reading is achieved by decoding words through grapheme phoneme pairing and combination. We designed a negative priming paradigm in which school-aged children (10-year-olds) were asked to judge whether two pseudowords were identical on the prime and whether two animals were identical on the probe. Children required more time to determine that two animals were mirror images of each other when preceded by pseudowords containing the reversible letter b or d than when preceded by different pseudowords containing the control letter f or t (Experiment 1) or by different pseudowords that differed only by the target letter f or k (Experiment 2). These results suggest that MG must be inhibited to discriminate between pseudowords containing reversible letters, generalizing the findings regarding single letters to a context more representative of the early stages of reading. PMID- 28641122 TI - Working with parents to treat anxiety-disordered children: A proof of concept RCT evaluating Fear-less Triple P. AB - Little is known about the efficacy of parent-only interventions and the maintenance of gains over time with anxiety-disordered children and adolescents. The current study aimed to evaluate the efficacy of a 6-session parent-focused intervention (Fear-less Triple P) in reducing children's anxiety symptomatology. The parents of 61 anxiety-disordered children (7-14 years) were randomly assigned to either the 6-session parent-only group CBT intervention or a wait-list control (WL) group. Diagnostic and questionnaire measures were administered at post treatment; as well as 3-, 6- and 12 months following the completion of treatment. Families in the WL group were re-assessed after 6 weeks (the duration of the active intervention) and were then offered the intervention. The parent-only intervention produced superior outcomes for children on diagnostic and questionnaire measures. The percentages of children free of any anxiety diagnosis following the intervention were 38.7% (post-treatment); 58.6% (3-mth); 69.2% (6 mth); and 84% (12-mth). At the post-treatment assessment point, 3.4% of children in the WL group were free of any anxiety diagnosis. Mother and child questionnaire measures demonstrated gains from pre to post-treatment that were maintained over time. This proof of concept study suggests that the brief, parent only intervention evaluated is an efficacious treatment approach for child anxiety disorders. A parent-only, group CBT intervention such as the one described here offers a cost-effective, low intensity alternative to traditional child-focused interventions. PMID- 28641123 TI - The Practice Environment Scale of the Nursing Work Index: An updated review and recommendations for use. AB - OBJECTIVES: The Practice Environment Scale of the Nursing Work Index (PES-NWI) is an instrument, which measures the nursing practice environment - defined as factors that enhance or attenuate a nurse's ability to practice nursing skillfully and deliver high quality care. The purpose of this paper is to provide an updated review of the Practice Environment Scale of the Nursing Work Index's use to date and provide recommendations that may be helpful to nursing leaders and researchers who plan to use this instrument. DESIGN: A narrative review of quantitative studies. DATA SOURCES: PubMed, EMBASE, and the Cumulative Index to Nursing & Allied Health Literature were searched to identify relevant literature using the search terms, Practice Environment Scale of the Nursing Work Index and PES-NWI. REVIEW METHODS: Studies were included if they were published in English between 2010 and 2016 and focused on the relationship between the Practice Environment Scale of the Nursing Work Index and patient, nurse, or organizational outcomes. Data extraction focused on the reported survey scores and the significance and strength of the reported associations. RESULTS: Forty-six articles, from 28 countries, were included in this review. The majority reported significant findings between the nursing practice environment and outcomes. Although some modifications have been made, the instrument has remained primarily unchanged since its development. Most often, the scores regarding staffing and resource adequacy remained the lowest. CONCLUSION: The frequency of use of this instrument has remained high. Many researchers advocate for a move beyond the study of the connection between the Practice Environment Scale and nurse, patient, and organizational outcomes. Research should shift toward identifying interventions that improve the environment in which nurses practice and determining if changing the environment results in improved care quality. PMID- 28641124 TI - Neural repair by NT3-chitosan via enhancement of endogenous neurogenesis after adult focal aspiration brain injury. AB - The latent regenerative potential of endogenous neural stem/progenitor cells (NSCs) in the adult mammalian brain has been postulated as a likely source for neural repair. However, the inflammatory and inhibitory microenvironment after traumatic brain injury (TBI) prohibits NSCs from generating new functional neurons to restore brain function. Here we report a biodegradable material, chitosan, which, when loaded with neurotrophin-3 (NT3) and injected into the lesion site after TBI, effectively engaged endogenous NSCs to proliferate and migrate to the injury area. NSCs differentiate and mature into functional neurons, forming nascent neural networks that further integrate into existing neural circuits to restore brain function. Three main actions of NT3-chitosan, i.e., pro-neurogenesis, anti-inflammation, and pro-revascularization, elicit significant regeneration after TBI. Our study suggests that through creating an optimal microenvironment, endogenous NSCs are capable of executing neural repair, thus widening the therapeutic strategies to treat TBI and perhaps stroke or other neurological conditions. PMID- 28641125 TI - An altered REDOX environment, assisted by over-expression of fetal hemoglobins, protects from inflammatory colitis and reduces inflammatory cytokine expression. AB - C5BL/6 female mice receiving dextran sodium sulfate in their drinking water develop an acute inflammatory colitis within 7d, with weight loss, histopathologic signs of inflammation, and colonic expression of inflammatory cytokines. In previous studies we have reported that increased inflammatory cytokine expression in aged mice can be attenuated by oral gavage of a crude fetal extract containing glutathione (GSH), MPLA and fetal hemoglobin, or more specifically by injection of a combination of these purified reagents. We speculated that this combination led to an altered tissue redox environment in which the immune response developed, thus regulating inflammation. Accordingly, we used wild-type (WT) C57BL/6 mice, or mice lacking either murine beta Hemoglobin major (HgbbetamaKO) or minor (HgbbetamiKO) as recipients of DSS in their drinking water, and followed development of colitis both clinically and by inflammatory cytokine production, before/after oral treatment of mice with a crude fetal liver extract. Mice lacking an intact fetal hemoglobin chain (HgbbetamiKO) developed severe colitis, with enhanced colonic expression of inflammatory cytokines, which could not be rescued by extract, unlike WT and HgbbetamaKO animals. Moreover, disease in both WT and HgbbetamaKO animals could also be attenuated by exposure to 5-hydroxymethyl furfural (5HMF), hydroxyurea or rapamycin. The former has been used as an alternative means of stabilizing the conformation of adult hemoglobin in a manner which mimicks the oxygen-affinity of fetal hemoglobin, while we show that both hydroxyurea and rapamycin augment expression of murine fetal hemoglobin chains. Our data suggests there may be a clinical value in exploring agents which alter local REDOX environments as an adjunctive treatment for colitis and attenuating inflammatory cytokine production. PMID- 28641126 TI - DNA requirements for interaction of the C-terminal region of Ku80 with the DNA dependent protein kinase catalytic subunit (DNA-PKcs). AB - Non-homologous end joining (NHEJ) is the major pathway for the repair of ionizing radiation induced DNA double strand breaks (DSBs) in human cells. Critical to NHEJ is the DNA-dependent interaction of the Ku70/80 heterodimer with the DNA dependent protein kinase catalytic subunit (DNA-PKcs) to form the DNA-PK holoenzyme. However, precisely how Ku recruits DNA-PKcs to DSBs ends to enhance its kinase activity has remained enigmatic, with contradictory findings reported in the literature. Here we address the role of the Ku80 C-terminal region (CTR) in the DNA-dependent interaction of Ku70/80 with DNA-PKcs using purified components and defined DNA structures. Our results show that the Ku80 CTR is required for interaction with DNA-PKcs on short segments of blunt ended 25bp dsDNA or 25bp dsDNA with a 15-base poly dA single stranded (ss) DNA extension, but this requirement is less stringent on longer dsDNA molecules (35bp blunt ended dsDNA) or 25bp duplex DNA with either a 15-base poly dT or poly dC ssDNA extension. Moreover, the DNA-PKcs-Ku complex preferentially forms on 25 bp DNA with a poly-pyrimidine ssDNA extension.Our work clarifies the role of the Ku80 CTR and dsDNA ends on the interaction of DNA-PKcs with Ku and provides key information to guide assembly and biology of NHEJ complexes. PMID- 28641127 TI - Deep brain stimulation of subthalamic nucleus helps in improving late phase motor planning in Parkinson's disease. AB - OBJECTIVE: Deep brain stimulation of subthalamic nucleus (DBS-STN) is a well accepted treatment for Parkinson's disease (PD) but its effect on motor planning in the disease is yet unclear. This study examines the effect of switching the stimulation ON and OFF on components of bereitschaftspotentials in PD. PATIENTS AND METHODS: Scalp bereitschaftspotentials were recorded during self-paced right wrist extensions at Fz, Cz, Pz, C3 and C4 sites in patients on DBS-STN plus medications (DBS-STN group) as treatment modality or on medications only (Med group) and compared with age matched healthy controls. In DBS-STN group, the potentials were recorded in stimulation ON, stimulation OFF, and again after re switching stimulation ON-2. Offline analysis of potentials was done to calculate peak amplitude, late slope (-500 to 0ms) and early slope (-1500 to -500ms). RESULTS: We observed that the two components of bereitschaftspotentials in stimulation ON state were comparable to those in age matched controls. The late slope was found to be significantly reduced during stimulation OFF as compared to stimulation ON at Cz (p<0.001), C3 (p<0.001) and C4 (p<0.01) electrode sites. This parameter failed to improve on re-switching stimulation ON at Cz (p<0.01). No significant change was observed in early part of bereitschaftspotentials among any of the conditions. CONCLUSION: Our study shows that DBS-STN along with anti parkinsonian medications helps in improving both components of bereitschaftspotentials in PD. Switching stimulation OFF for fifteen minutes principally affects the late component i.e. the execution part of motor planning; which cannot be reversed by re-switching ON. Thus the chronic and acute effects of switching DBS-STN ON are different and principally affect the later part of motor planning. PMID- 28641128 TI - Expectancy of impairment attenuates marijuana-induced risk taking. AB - BACKGROUND: Marijuana use has been associated with increased risk-taking and impulsive behavior. While pharmacologic effects of marijuana can lead to inhibitory impairment, expectancy of potential impairment may result in compensatory behavioral response by decreasing impulsive decisions and risky behaviors. With the increases in marijuana use and related problems, a better understanding of the individual characteristics associated with marijuana intoxication and risky behavior is needed. This study examined the role of impairment expectancies in marijuana's acute effects on behavioral measures of impulsivity and risk-taking. METHODS: Participants (N=136) were regular marijuana users. A balanced placebo design (BPD) was used crossing marijuana administration (i.e., 0% Tetrahydrocannabinol (THC) vs. 2.8% THC) with stimulus expectancy (i.e., Told Placebo vs. Told THC). Marijuana outcome expectancies were measured by self-report and dependent measures included a number of behavioral impulsivity tasks and the balloon analogue risk task (BART). RESULTS: Among participants who received THC, higher expectancies for cognitive-behavioral impairment (CBI) were related to lower risk-taking on the BART. Among those who received placebo, there was no association between CBI expectancies and BART performance. CBI expectancies did not moderate the stimulus expectancy effect on the BART nor drug or stimulus expectancy effects on impulsivity measures. CONCLUSIONS: Results provide initial evidence that expectancies of greater impairment are associated with compensatory behavior on a risk-taking task under acute marijuana intoxication. Future studies should examine the role of impairment expectancies on risk behaviors of substantial public health concern, such as driving while under the influence of marijuana. PMID- 28641129 TI - Moderate and vigorous physical activity patterns among marijuana users: Results from the 2007-2014 National Health and Nutrition Examination Surveys. AB - The relationship between marijuana use and recreational physical activity has yet to be explored in the United States. Our aim was to examine this relationship in a population-based sample of 20-to-59-year olds (N=12,618) using 2007-2014 National Health and Nutrition Examination Surveys. Marijuana use was categorized as never (reference group), past (previously but not within the last 30-days), and current (>1day in the last 30-days) use. Current users were further categorized based on frequency of use (light, moderate, and heavy users). Physical activity was self-reported as moderate (small increase in heartrate/breathing for >10min; MPA) and vigorous (large increase in heartrate/breathing for >10min; VPA). Adjusted odds ratios (AOR) for the relationship between marijuana use and physical activity were estimated via logistic regression models. The majority of the overall sample reported either past (40.5%) or current (12.6%) marijuana use. Marijuana users had a lower prevalence of moderate physical activity than never users (current: 51.9%, past: 50.4%, never: 55.3%, p=0.001). Current (66.8%) and past (67.9%) marijuana users also had a lower prevalence of vigorous physical activity than never users (71.9%, p=0.001). Current and past users had lower odds of recreational MPA (current user AOR: 0.66, 95% CI: 0.50-0.87; past user AOR: 0.78, 95% CI: 0.62 0.98) than never users. As the frequency of marijuana use increased, time spent on MPA decreased. Results suggest that current and past marijuana users were less likely to report recreational MPA than never users. Future studies should examine the potential mechanisms and temporality of this relationship. PMID- 28641130 TI - Sexual orientation, minority stress, social norms, and substance use among racially diverse adolescents. AB - BACKGROUND: Sexual minority adolescents are more likely than their heterosexual peers to use substances. This study tested factors that contribute to sexual orientation disparities in substance use among racially and ethnically diverse adolescents. Specifically, we examined how both minority stress (i.e., homophobic bullying) and social norms (i.e., descriptive and injunctive norms) may account for sexual orientation disparities in recent and lifetime use of four substances: tobacco, alcohol, marijuana, and prescription drugs. PROCEDURES: A probability sample of middle and high school students (N=3012; aged 11-18 years old; 71.2% racial and ethnic minorities) using random cluster methods was obtained in a mid size school district in the Southeastern United States. RESULTS: Sexual minority adolescents were more likely than heterosexual adolescents to use substances, experience homophobic bullying, and report higher descriptive norms for close friends and more permissive injunctive norms for friends and parents. While accounting for sociodemographic characteristics, multiple mediation models concurrently testing all mediators indicated that higher descriptive and more permissive injunctive norms were significant mediators of the associations between sexual orientation and recent and lifetime use of the four substances, whereas homophobic bullying was not a significant mediator of the associations between sexual orientation and recent and lifetime use of any of the substances. CONCLUSIONS: Descriptive and injunctive norms, in conjunction with minority stress, are important to consider in explaining sexual orientation disparities in substance use among racially diverse adolescents. These results have implications for substance use interventions among sexual minority adolescents. PMID- 28641132 TI - Heritability of lifetime ecstasy use. AB - BACKGROUND: Ecstasy is a widely used psychoactive drug that users often take because they experience positive effects such as increased euphoria, sociability, elevated mood, and heightened sensations. Ecstasy use is not harmless and several immediate and long term side effects have been identified. Lifetime ecstasy use is likely to be partly influenced by genetic factors, but no twin study has determined the heritability. Here, we apply a classical twin design to a large sample of twins and siblings to estimate the heritability of lifetime ecstasy use. METHODS: The sample comprised 8500 twins and siblings aged between 18 and 45 years from 5402 families registered at the Netherlands Twin Registry. In 2013 2014 participants filled out a questionnaire including a question whether they had ever used ecstasy. We used the classical twin design to partition the individual differences in liability to ecstasy use into that due to genetic, shared environmental, and residual components. RESULTS: Overall, 10.4% of the sample had used ecstasy during their lifetime, with a somewhat higher prevalence in males than females. Twin modelling indicated that individual differences in liability to lifetime ecstasy use are for 74% due to genetic differences between individuals, whereas shared environmental and residual factors explain a small proportion of its liability (5% and 21%, respectively). Although heritability estimates appeared to be higher for females than males, this difference was not significant. CONCLUSIONS: Lifetime ecstasy use is a highly heritable trait, which indicates that some people are genetically more vulnerable to start using ecstasy than others. PMID- 28641131 TI - Children's brain activation during risky decision-making: A contributor to substance problems? AB - OBJECTIVE: Among young children excessive externalizing behaviors often predict adolescent conduct and substance use disorders. Adolescents with those disorders show aberrant brain function when choosing between risky or cautious options. We therefore asked whether similarly aberrant brain function during risky decision making accompanies excessive externalizing behaviors among children, hypothesizing an association between externalizing severity and regional intensity of brain activation during risky decision-making. METHOD: Fifty-eight (58) 9-11 year-old children (both sexes), half community-recruited, half with substance-treated relatives, had parent-rated Child Behavior Checklist Externalizing scores. During fMRI, children repeatedly chose between doing a cautious behavior earning 1 point or a risky behavior that won 5 or lost 10 points. Conservative permutation-based whole-brain regression analyses sought brain regions where, during decision-making, activation significantly associated with externalizing score, with sex, and with their interaction. RESULTS: Before risky responses higher externalizing scores were significantly, negatively associated with neural activation (t's: 2.91-4.76) in regions including medial prefrontal cortex (monitors environmental reward-punishment schedules), insula (monitors internal motivating states, e.g., hunger, anxiety), dopaminergic striatal and midbrain structures (anticipate and mediate reward), and cerebellum (where injuries actually induce externalizing behaviors). Before cautious responses there were no significant externalizing:activation associations (except in post hoc exploratory analyses), no significant sex differences in activation, and no significant sex-by-externalizing interactions. CONCLUSIONS: Among children displaying more externalizing behaviors extensive decision-critical brain regions were hypoactive before risky behaviors. Such neural hypoactivity may contribute to the excessive real-life risky decisions that often produce externalizing behaviors. Substance exposure, minimal here, was a very unlikely cause. PMID- 28641133 TI - ABC transporters in megakaryopoiesis and platelet activity. AB - ATP-binding cassette (ABC) is a family of transporters that facilitates the translocation of substrates across cell membrane using its ATPase subunit. These transporters have key roles in multidrug resistance, lipid homeostasis, antigen processing, immunity, cell proliferation and hematopoiesis. Some ABC transporters are selectively expressed on megakaryocyte progenitor, megakaryocyte and its cellular fragment platelet. However, the role of ABC transporters in hemostasis and thrombosis were not well explored until recently. Studies of both human genetic diseases and genetically-manipulated animal models have greatly improved our understanding of ABC transporters in regulating hematopoiesis particularly megakaryopoiesis and/or platelet activity. Human genome wide association studies (GWAS) have also unraveled the association between ABC transporters and thrombopoiesis in general population. Therefore, this review aims to summarize the recent advances in our understanding of how ABC transporters regulate megakaryopoiesis and platelet activity, the underlining mechanisms and their association with atherosclerosis and atherothrombosis. Last, the emerging therapeutic targets to slow down atherosclerosis development and prevent atherothrombosis via ABC transporters or downstream pathways will also be discussed. PMID- 28641134 TI - Adverse childhood experiences (ACE) and adult attachment interview (AAI) in a non clinical population. AB - Adverse childhood experiences (ACE) tend to be interrelated rather than independently occurring. There is a graded effect associated with ACE exposure and pathology, with an increase when ACE exposure is four or more. This study examined a sample of active individuals (n=129) to determine distribution patterns and relationships between ACEs, attachment classification, unresolved mourning (U), and disclosure difficulty. The results of this study demonstrated a strong relationship between increased ACEs and greater unresolved mourning. Specifically, the group differences for individuals who experienced no ACE (n=42, 33%), those with 1-3 ACEs (n=48, 37.8%), and those with >=4 ACEs (n=37, 29.1%) revealed a pattern in which increased group ACE exposure was associated with greater lack of resolution for past trauma/loss experiences, more adult traumatic events, and more difficulty disclosing past trauma. Despite >=4 ACEs, 51.4% of highly exposed individuals were classified as secure in the Adult Attachment Interview. Resilience in this group may be related to a combination of attachment security, college education, and engagement in meaningful activities. Likewise, adversity may actually encourage the cultivation of more social support, goal efficacy, and planning behaviors; factors that augment resilience to adversity. PMID- 28641135 TI - Variation in prevention of child maltreatment by Dutch child healthcare professionals. AB - Child maltreatment (CM) is a common condition with a large impact on the victim and society. In the Netherlands, the preventive child healthcare (CHC) aims to protect children against such threats. However, several studies indicate that the efficacy in this area may be suboptimal for many CHC professionals. Therefore, this study aims to map the practice variation in the primary and secondary prevention of CM, by CHC physicians and nurses. This mixed-methods study used interviews to identify relevant topics and develop an online questionnaire. All CHC organizations in the Netherlands (n=45) were asked to forward this questionnaire to their professionals. Practice variation was described with domain scores and item response distributions. Multi-level analysis was used to assess case mix-corrected variance between organizations. Interview participants (n=11) expected suboptimal care in 35 topics which they considered important for prevention of CM, resulting in a 15min questionnaire. Nearly two-thirds of the organizations (n=29) agreed to forward the questionnaire to their employees. The response rate was 42% (n=1104). Suboptimal care and practice variation was found in all domains (i.e. communication, medical expertise, collaboration, involvement in prevention of CM, and improvement opportunities), mostly caused by intra organization variance. Significant inter-organization variance was found for collaboration (variance partition coefficient 6-7%) and involvement (2-3%). Furthermore, the majority of the respondents (96%) reported fear in acting upon suspicions of CM. Substantial suboptimal care and practice variation in prevention of CM warrant action from authorities, CHC training institutes, CHC organizations, and professionals. PMID- 28641136 TI - Age exacerbates abnormal protein expression in a mouse model of Down syndrome. AB - The Ts65Dn is a popular mouse model of Down syndrome (DS). It displays DS relevant features of learning/memory deficits and age-related loss of functional markers in basal forebrain cholinergic neurons. Here we describe protein expression abnormalities in brain regions of 12-month-old male Ts65Dn mice. We show that the magnitudes of abnormalities of human chromosome 21 and non-human chromosome 21 orthologous proteins are greater at 12 months than at ~6 months. Age-related exacerbations involve the number of components affected in the mechanistic target of rapamycin pathway, the levels of components of the mitogen activated protein kinase pathway, and proteins associated with Alzheimer's disease. Among brain regions, the number of abnormalities in cerebellum decreased while the number in cortex greatly increased with age. The Ts65Dn is being used in preclinical evaluations of drugs for cognition in DS. Most commonly, drug evaluations are tested in ~4- to 6-month-old mice. Data on age-related changes in magnitude and specificity of protein perturbations can be used to understand the molecular basis of changes in cognitive ability and to predict potential age related specificities in drug efficacies. PMID- 28641137 TI - Real-time PCR methods for the detection of blown pack spoilage causing Clostridium species; C. estertheticum, C. gasigenes and C. ruminantium. AB - A set of real-time PCR methods for the detection of C. estertheticum, C. gasigenes and C. ruminantium, the causative agents of blown pack spoilage (BPS) in vacuum packaged beef, was developed. Robust validation of the sensitivity and specificity was carried out in the three matrices (beef meat drip, wet environmental swabs and dry environmental swabs) as encountered in our testing laboratory and against Clostridium strains (n=76) and non-Clostridium strains (n=36). It was possible to detect 4-5 spores per ml for C. estertheticum, 2 spores per ml for C. gasigenes and 8 spores per ml for C. ruminantium, without the need for enrichment of the samples. This high sensitivity is particularly important for the beef sector, not just for testing spoiled product but also in the early detection of contaminated beef and in validation of sporicidal cleaning procedures for critical pieces of equipment such as the vacuum packaging machine, which have the potential to contaminate large volumes of product. PMID- 28641138 TI - Changes in lipid peroxidation in stay-green leaves of tobacco with senescence induced synthesis of cytokinins. AB - The involvement of reactive oxygen species (ROS) in the progress of leaf senescence has long been suggested, but there are contrasting results to either support or deny the positive correlation between the senescence progression and the level of ROS-triggered lipid peroxidation. The inconsistency among reported results can partly be attributed to the poor specificity of the most commonly employed colorimetric assay and changes in the ratio of dry weight/fresh weight during leaf senescence. In this study we determined the end-product of lipid peroxidation malondialdehyde (MDA) by GS-MS, and analyzed its changes during senescence of tobacco leaves as calculated on dry weight basis. In leaves of the wild type plants the MDA level did not change during senescence. In the mutant PSAG12::IPT leaves stayed green because of the elevated synthesis of cytokinins, but the MDA level was much higher in comparison to WT when leaves of the same age were compared. These results clearly show that lipid peroxidation is not associated with leaf senescence, at least in tobacco. This GS-MS method can be used to judge the involvement of lipid peroxidation in senescence in other species. PMID- 28641139 TI - Hormonal profile and the role of cell expansion in the germination control of Cerrado biome palm seeds. AB - Little information is currently available concerning the mechanisms controlling palm seed germination. We compared the anatomical and physiological aspects of seeds of two neotropical palm species showing different levels of dormancy. The seeds of Attalea vitrivir and Butia capitata were evaluated for the endogenous contents of hormones (ABA, GAs, CKs, BRs, IAA, JA, SA and the ethylene precursor ACC) in their cotyledonary petiole and operculum (structures involved in germination control), the force necessary to displace the operculum, endo-beta mannanase activities, and embryo cell elongation. The analyses were carried out on with intact dry and imbibed seeds as well as with seeds with the operculum mechanically removed, 2, 5 and 10 days after sowing. The germinabilities of the intact seeds of A. vitrivir and B. capitata were 68% and 3%, respectively; the removal of the operculum increased germination to more than 90% in both species. Reductions of ABA and increases in GAs contents coincided with cell elongation, although there is no evidence that hormonal balance and endo-beta-mannanase activity are involved in operculum weakening. The ratio between the embryo length and the force required for operculum displacement (EL/OF) was found to be 1.9 times greater in A. vitrivir than in B. capitata, which means that very small elongations in each cell would be sufficient to promote germination, resulting in a lower level of dormancy in the former species. EL/OF and cell growth control are therefore important for defining dormancy level in palm seeds. PMID- 28641140 TI - Effect of C1-INH on ischemia/reperfusion injury in a porcine limb ex vivo perfusion model. AB - Revascularization of an amputated limb within 4-6h is essential to avoid extensive ischemia/reperfusion (I/R) injury leading to vascular leakage, edema and tissue necrosis. I/R injury is a pathological inflammatory condition that occurs during reperfusion of an organ or tissue after prolonged ischemia. It is characterized by a complex crosstalk between endothelial cell activation and the activation of plasma cascades. Vasculoprotective pharmacological intervention to prevent I/R injury might be an option to prolong the time window between limb amputation and successful replantation. We used C1-easterase inhibitor (C1-INH) in this study because of its known inhibitory effects on the activation of the complement, coagulation and kinin cascades. Forelimbs of 8 large white pigs were amputated, subjected to ischemia, and then reperfused with autologous whole blood. All limbs were exposed to 9h of cold ischemia at 4 degrees C. After 2h of cold ischemia the limbs were either perfused with of C1-INH (1U/ml in hydroxyethyl starch, n=8) or hydroxyethyl starch alone (n=7). After completion of the 9-h ischemia period, all limbs were ex vivo perfused with heparinized autologous whole blood for 12h using a pediatric heart lung machine to simulate in vivo revascularization. Our results show that I/R injury in the control group led to a significant elevation of tissue deposition of IgG and IgM, complement C3b/c, C5b-9 and MBL. Also, activation of the kinin system was significantly increased, namely bradykinin in plasma, and expression of bradykinin receptors 1 and 2 in tissue. In addition, markers for endothelial integrity like expression of CD31, VE-cadherin and heparan sulfate proteoglycans were decreased in reperfused tissue. Limb I/R injury also led to activation of the coagulation cascade with a significant elevation of fibrin and thrombin deposition and increased fibrinogen-like protein-2 expression. C1-INH treated limbs showed much less activation of plasma cascades and better protection of endothelial integrity compared to the reperfused control limbs. In conclusion, the use of the cytoprotective drug C1-INH significantly reduced I/R injury by protecting the vascular endothelium as well as the muscle tissue from deposition of immunoglobulins, complement and fibrin. PMID- 28641142 TI - Optical, electrical and ferromagnetic studies of ZnO:Fe diluted magnetic semiconductor nanoparticles for spintronic applications. AB - In the present investigation, diluted magnetic semiconductor (Zn1-xFexO) nanoparticles with different doping concentrations (x=0, 0.02, 0.04, 0.06, and 0.08) were successfully synthesized by sol-gel auto-combustion method. The crystal structure, morphology, optical, electrical and magnetic properties of the prepared samples were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), energy dispersive analysis using x-rays (EDAX), ultraviolet visible spectrophotometer, fluorescence spectroscope (FS), vibrating sample magnetometer (VSM) and broad band dielectric spectrometer (BDS). XRD results reveal that all the samples possess hexagonal wurtzite crystal structure with good crystalline quality. The absence of impurity phases divulge that Fe ions are well incorporated into the ZnO crystal lattice. The substitutional incorporation of Fe3+ at Zn sites is reflected in optical absorption spectra of the samples. Flouorescence spectra of the samples show a strong near-band edge related UV emission as well as defect related visible emissions. The semiconducting behavior of the samples has been confirmed through electrical conductivity measurements. Magnetic measurements indicated that all the samples possess ferromagnetism at room temperature. PMID- 28641141 TI - RAG2 involves the Igkappa locus demethylation during B cell development. AB - The genes encoding the immunoglobulin kappa light chain are assembled during B cell development by V(D)J recombination. For efficient rearrangement, the Igkappa locus must undergo a series of epigenetic changes. One such epigenetic mark is DNA methylation. The mechanism that the Igkappa locus is selectively demethylated at the pre-B cell stage has not previously been characterized. Here, we employed bisulfite DNA-modification assays to analyze the methylation status of the Igkappa locus in primary pre-B cells from RAG-deficient mice with pre-rearranged Igh knock-in allele. We observed that the Igkappa locus was hypermethylated in RAG2-deficient pre-B cells but hypomethylated in RAG1-deficient pre-B cells, indicating that wild-type (WT) RAG2 involves the Igkappa locus demethylation in a RAG1-independent manner prior to rearrangement. We generated a series of RAG2 mutants between residue 350 and 383. We showed that these mutants mediated the Igkappa rearrangement but failed to regulate the Igkappa gene demethylation. We further analyzed that these mutants could increase RAG recombinase activity in vivo. We conclude that residues 350-383 region are responsible for endogenous Igkappa locus demethylation at pre-B cells. We propose that WT RAG2 has an intrinsic function to regulate the Igkappa locus demethylation. PMID- 28641143 TI - Spectroscopic and thermodynamic studies of light harvesting perylenediimide derivative - zinc porphyrin complex in aqueous media. AB - Self-assembly of perylene derivative such as N,N'-bis(2(trimethylammonium iodide) ethylene)perylene-3,4,9,10-tetracarboxyldiimide (TAIPDI) can produce one dimensional form (1D) in an aqueous media. The ability of one-dimensional TAIPDI to form light harvesting complex with water-soluble zinc porphyrin (ZnTPPS4) via the pi-pi and electrostatic interactions has been described. Owing to electronic interactions between the pi-systems, the complex formation is accompanied by pronounced absorption spectral changes in the UV/Vis absorption bands. The formation constant of the ZnTPPS4-TAIPDI complex has been determined as 2.60*104M 1 suggests a moderately stable complex. The steady-state fluorescence measurements exhibited fluorescence quenching of both the singlet TAIPDI and ZnTPPS4 because of the electron transfer process from the electron-donating ZnTPPS4 to the electron-accepting TAIPDI. Based on the picosecond time-resolved fluorescence, the rate and quantum yield of the electron transfer were found to be 2.47*1010s-1 and 0.99, respectively, indicating fast and efficient electron transfer. The thermodynamic parameters of the complex formation have been determined from the stopped-flow measurements. The interaction between ZnTPPS4 and TAIPDI occurs in two steps, a fast and reversible step followed by a slow and irreversible one. The activation parameters for the complex formation (DeltaH#=22+/-5kJmol-1 and DeltaS#=-123+/-18JK-1mol-1), (DeltaH#=133+/-4kJmol-1 and DeltaS#=167+/-13Jmol-1K-1) were determined from variable temperature studies for the "on" and the "off" of the first step and DeltaS#=246+/-37.89Jmol-1K-1 and DeltaH#=130+/-11kJmol-1 for the second step. The negative and positive DeltaS# values found for the interaction reactions are consistent with an associative interaction for the first step followed by dissociative mechanism for both the "off" and the second step. PMID- 28641144 TI - Impact of Saccharomyces cerevisiae and Torulaspora delbrueckii starter cultures on cocoa beans fermentation. AB - Aim of this work was to study the impact of mixed cultures of Saccharomyces cerevisiae and Torulaspora delbrueckii and T. delbrueckii monoculture on the fermentation process conducted on two different cocoa hybrids, PS1319 and SJ02, in Bahia, Brazil. This was performed throughout studying physico-chemical changes during the fermentation process and analyzing volatile compounds and sensory analysis of chocolates. (GTG)5-PCR fingerprinting was used to type isolates at strain level allowing to assess the implantation of the starter cultures added. Resulted clusters were composed by T. delbrueckii strains isolated during the first 24h of fermentation. On the contrary, S. cerevisiae, the most strongly fermenting ethanol-tolerant species, took over the fermentation at a second stage. Quantification data of T. delbrueckii during spontaneous fermentation confirm the attitude of this species of not being so commonly involved in this process. This study also showed that the inoculum influenced the PS1319 hybrid end-product quality, changing analytic profile and sensory perception of chocolates. No big influences were recorded for SJ02 hybrid, but this may be improved. In combination with S. cerevisiae, T. delbrueckii had a positive influence on the analytical profile of chocolates. The application of starter cultures did change the aroma profile of the resulting chocolate as determined by GC-MS; in some case the differences observed had a significantly impact on the consumer perception of the chocolates. PMID- 28641145 TI - Lack of association between deletion polymorphism of BIM gene and in vitro drug sensitivity in B-cell precursor acute lymphoblastic leukemia. AB - A deletion polymorphism in the BIM gene was identified as an intrinsic mechanism for resistance to tyrosine kinase inhibitor in chronic myeloid leukemia patients in East Asia. BIM is also involved in the responses to glucocorticoid and chemotherapy in acute lymphoblastic leukemia (ALL), suggesting a possible association between deletion polymorphism of BIM and the chemosensitivity of ALL. Thus, we analyzed 72 B-cell precursor (BCP)-ALL cell lines established from Japanese patients. Indeed, higher BIM gene expression was associated with good in vitro sensitivities to glucocorticoid and chemotherapeutic agents used in induction therapy. We also analyzed the methylation status of the BIM gene promoter by next generation sequencing of genome bisulfite PCR products, since genetic polymorphism could be insignificant when epigenetically inactivated. Hypermethylation of the BIM gene promoter was associated with lower BIM gene expression and poorer sensitivity to vincristine. Of note, however, the prevalence of a deletion polymorphism was not associated with the BIM gene expression level or drug sensitivities in BCP-ALL cell lines, in which the BIM gene was unmethylated. These observations suggest that an association of a deletion polymorphism of BIM and the response to induction therapy in BCP-ALL may be clinically minimal. PMID- 28641146 TI - Early development and predictors of morphological awareness: Disentangling the impact of decoding skills and phonological awareness. AB - BACKGROUND: Morphological Awareness (MA) has been demonstrated to be influential on the reading outcomes of children and adults. Yet, little is known regarding MA's early development. AIM: The aim of this study is to better understand MA at different stages of development and its association with Phonological Awareness (PA) and reading. METHODS AND PROCEDURES: In a longitudinal design the development of MA was explored in a group of pre-reading children with a family risk of dyslexia and age-matched controls from kindergarten up to and including grade 2. OUTCOMES AND RESULTS: MA deficits were observed in the group with literacy difficulties at all time points. PA was only found to make a significant contribution to MA development at the early stages of formal reading instruction. While first-grade decoding skills were found to contribute significantly to MA in second grade. CONCLUSIONS: Evidence supporting a bidirectional relation was found and supports the need for adequate MA intervention and explicit instruction for "at risk" children in the early stages of literacy instruction. PMID- 28641147 TI - Suicidal thoughts and behaviors among women firefighters: An examination of associated features and comparison of pre-career and career prevalence rates. AB - BACKGROUND: Women protective service workers die by suicide at a higher rate than women workers in other occupational groups. However, no study has examined rates and correlates of suicidal thoughts and behaviors among women firefighters, despite the potential for these data to inform suicide screening, prevention, and intervention initiatives. The purpose of this study is to describe and compare pre-career and career rates of suicidal thoughts and behaviors and identify their sociodemographic and occupational correlates among women firefighters. METHODS: Data were obtained from 313 current U.S. women firefighters who completed a web based survey (mean age = 37.30y, SD = 9.70y, 92.7% White). RESULTS: Pre-career rates of suicide ideation, plans, attempts, and non-suicidal self-injury (NSSI) were found to be 28.4%, 10.2%, 5.8%, and 11.2%, respectively. Career rates of suicide ideation, plans, attempts, and NSSI were found to be 37.7%, 10.9%, 3.5%, and 9.3%, respectively. Pre-career rates of suicide ideation (OR = 4.760, 95% CI = 2.820-8.034, p < 0.001), plans (OR = 4.867, 95% CI = 2.067-11.463, p < 0.001), attempts (OR = 7.175, 95% CI = 1.726-29.828, p = 0.007), and NSSI (OR = 9.676, 95% CI = 4.130-22.670, p < 0.001) were significantly associated with career suicidality. With few exceptions, neither sociodemographic characteristics nor firefighter experiences were associated with career suicidal symptoms. LIMITATIONS: Study limitations include a cross-sectional design and convenience sample recruitment strategy. CONCLUSIONS: Women firefighters report elevated rates of suicidal thoughts and behaviors. Suicidal symptoms occurring prior to one's tenure as a firefighter-and not solely an aspect of firefighter career experiences-should be considered in suicide risk screening, prevention, and intervention initiatives. Studies examining modifiable suicide risk factors and correlates (e.g., psychiatric symptoms, workplace harassment) are needed. PMID- 28641148 TI - Non-suicidal self-injury and suicide attempts in a New Zealand birth cohort. AB - BACKGROUND: Non-suicidal self-injury (NSSI) and suicide attempts are related, but distinct behaviors. The primary aim of the current study was to identify factors that distinguish those with different lifetime histories of self-injury. A secondary aim was to test whether lifetime history of self-injury at age 26 predicted current suicide ideation at age 32. METHODS: Participants were 26 year olds from a large birth cohort with a lifetime history of no self-injury (n = 466), a lifetime history of NSSI (n = 191), or a lifetime history of NSSI and a suicide attempt (NSSI+SA; n = 52). They were compared on a history of psychiatric disorders, 12-month suicide ideation, lifetime history of childhood sexual abuse, and lifetime exposure to suicide. RESULTS: An anxiety disorder, a substance dependence disorder, suicide ideation, and a history of childhood sexual abuse distinguished the NSSI+SA and NSSI only groups. Longitudinal results demonstrated that a history of NSSI predicted future suicide ideation after adjusting for other selected risk factors. LIMITATIONS: The majority of analyses are cross sectional which limits inferences about causality. The retrospective self-report for lifetime behavior could be subject to reporting biases. CONCLUSIONS: Adults with a history of NSSI and adults with a history of NSSI and a suicide attempt are clinically distinct groups that are both at risk of future suicide ideation. Identifying and treating NSSI could be a key preventive factor in reducing subsequent suicide risk. PMID- 28641149 TI - Thyroid autoimmunity in bipolar disorder: A systematic review. AB - BACKGROUND: Accumulating evidence points to the pathophysiological relevance between immune dysfunction and mood disorders. High rates of thyroid dysfunction have been found in patients with bipolar disorder (BD), compared to the general population. A systematic review of the relationship between BD and thyroid autoimmunity was performed. METHODS: Pubmed, EMBASE and PsycINFO databases were searched up till January 28th, 2017. This review has been conducted according to the PRISMA statements. Observational studies clearly reporting data among BD patients and the frequency of autoimmune thyroid pathologies were included. RESULTS: 11 original studies met inclusion criteria out of 340 titles first returned from the global search. There is evidence of increased prevalence of circulating thyroid autoantibodies in depressed and mixed BD patients, while there is no evidence showing a positive relationship between BD and specific autoimmune thyroid diseases. There is a controversy about the influence of lithium exposure on circulating thyroid autoantibodies, even if most of studies seem not to support this association. A study conducted on bipolar twins suggests that autoimmune thyroiditis is related to the genetic vulnerability to develop BD rather than to the disease process itself. Females are more likely to develop thyroid autoimmunity. LIMITATIONS: The samples, study design and outcomes were heterogeneous. CONCLUSION: Thyroid autoimmunity has been suggested to be an independent risk factor for bipolar disorder with no clear association with lithium exposure and it might serve as an endophenotype for BD. PMID- 28641150 TI - Polyamine and tyramine involvement in NaCl-induced improvement of Cd resistance in the halophyte Inula chrithmoides L. AB - The aim of the present work was to analyze the impact of salinity on the plant response to Cd toxicity in the Mediterranean halophyte species Inula crithmoides. For this purpose, cuttings were cultivated hydroponically during 21d in the presence of 0, 25 or 50MUM CdCl2 combined or not with 0, 100, 200 and 400mM NaCl. The obtained data demonstrated that, in the absence of Cd, NaCl strongly increased plant growth (the maximal dry weight being observed at 100mM) and enhanced the Na+/K+ ratio in the shoot. Cd alone strongly affected plant growth in this halophyte. However, in Cd-treated plants, NaCl protected Inula crithmoides from Cd toxicity and contributed to reduce Cd absorption and translocation. Small aliphatic polyamine (putrescine, spermidine, spermine) increased in response to both NaCl and CdCl2, the highest concentration in plants being observed when both agents are present in the medium. The recorded increase preferentially concerned the polyamine bound fraction, which might be related to their involvement in the protection of endogenous cellular structures. The aromatic monoamine tyramine also strongly increased in response to Cd toxicity and its putative role is discussed in relation to conjugation processes. Salinity and Cd increased ammonium/nitrate ratio in leaves and roots and the involvement of stress-induced modification of N nutrition on polyamine oversynthesis is also discussed. PMID- 28641151 TI - alpha-TIP aquaporin distribution and size tonoplast variation in storage cells of Vicia faba cotyledons at seed maturation and germination stages. AB - Vacuoles have been shown to undergo deep modifications in relation to plant developmental stages and in the maintaining the cellular homeostasis. In this context, we studied the variations of the vacuolar membrane size and alpha-TIP aquaporin distribution at early and advanced seed stages of maturation, germination and embryo growth in Vicia faba cotyledon storage cells. PMID- 28641152 TI - Urea-induced ROS accelerate senescence in endothelial progenitor cells. AB - BACKGROUND AND AIMS: The pathogenic events responsible for the reduction of endothelial progenitor cell (EPC) number and function seen in patients with chronic renal failure (CRF) are poorly understood. Here we investigate the hypothesis that increased concentrations of urea associated with CRF increase ROS production directly in EPCs, causing abnormalities associated with coronary artery disease risk. METHODS: Human EPCs were isolated from peripheral blood mononuclear cells of healthy donors and cultured in the presence or absence of 20 mmol/L urea. RESULTS: Urea at concentrations seen in CRF induced ROS production in cultured EPCs. Urea-induced ROS reduced the number of endothelial cell colony forming units, uptake and binding of Dil-Ac-LDL and lectin-1, and the ability to differentiate into CD31- and vascular endothelial growth factor receptor 2 positive cells. Moreover, urea-induced ROS generation accelerated the onset of EPC senescence, leading to a senescence-associated secretory phenotype (SASP). Normalization of mitochondrial ROS production prevented each of these effects of urea. CONCLUSIONS: These data suggest that urea itself causes both reduced EPC number and increased EPC dysfunction, thereby contributing to the pathogenesis of cardiovascular disease in CRF patients. PMID- 28641154 TI - Serum albumin-adjusted glycated albumin as a better indicator of glycemic control in Type 2 diabetes mellitus patients with short duration of hemodialysis. AB - AIMS: Serum albumin-adjusted glycated albumin (adjusted GA) is reportedly a better predictor of mortality than GA in patients with Type 2 diabetes mellitus (T2DM) on hemodialysis (HD). We compared how accurately GA and adjusted GA reflected glycemic control in these patients. METHODS: We enrolled 31 patients with T2DM on HD. They were divided into two groups according to duration of HD: <=6months (short HD group, N=16) and >6months (long HD group, N=15). GA or adjusted GA and parameters of glycemic control obtained by continuous glucose monitoring were measured, and the correlations between these were analyzed. RESULTS: GA and adjusted GA were significantly correlated with mean glucose levels (r=0.400, P=0.025 and r=0.508, P=0.0037) in all patients. Similar results were obtained in the long HD group (GA: r=0.554, P=0.032; adjusted GA: r=0.604, P=0.017). However, in the short HD group, adjusted GA (r=0.502, P=0.047) but not GA (r=0.340, P=0.20) was significantly correlated with mean glucose levels. CONCLUSIONS: Adjusted GA may be a better indicator than GA for evaluating glycemic control in T2DM patients with short duration of HD. PMID- 28641153 TI - Lipoprotein(a) and coronary atheroma progression rates during long-term high intensity statin therapy: Insights from SATURN. AB - BACKGROUND & AIMS: Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle that associates with major adverse cardiovascular events (MACE). We examined relationships between Lp(a) measurements and changes in coronary atheroma volume following long-term maximally-intensive statin therapy in coronary artery disease patients. METHODS: Study of coronary atheroma by intravascular ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Baseline and follow-up Lp(a) levels were measured in 915 of the 1039 SATURN participants, and were correlated with changes in percent atheroma volume (DeltaPAV). RESULTS: Mean age was 57.7 +/- 8.6 years, 74% were men, 96% were Caucasian, with statin use prior to study enrolment occurring in 59.3% of participants. Baseline [median (IQR)] LDL-cholesterol (LDL-C) and measured Lp(a) levels (mg/dL) were 114 (99, 137) and 17.4 (7.6, 52.9) respectively; follow-up measures were 60 (47, 77), and 16.5 (6.7, 57.7) (change from baseline: p < 0.001, p = 0.31 respectively). At baseline, there were 676 patients with Lp(a) levels <50 mg/dL [median Lp(a) of 10.9 mg/dL], and 239 patients with Lp(a) levels >= 50 mg/dL [median Lp(a) of 83.2 mg/dL]. Quartiles of baseline and follow-up Lp(a) did not associate with DeltaPAV. Irrespective of the achieved LDL-C (=70 mg/dL), neither baseline nor on-treatment (=median) Lp(a) levels significantly associated with DeltaPAV. No significant differences were observed in DeltaPAV in Lp(a) risers versus non-risers, nor in those patients with baseline or on-treatment Lp(a) levels 50 mg/dL. CONCLUSIONS: In coronary artery disease patients prescribed long-term maximally intensive statin therapy with low on-treatment LDL-C levels, measured Lp(a) levels (predominantly below the 50 mg/dL threshold) do not associate with coronary atheroma progression. Alternative biomarkers may thus associate with residual cardiovascular risk in such patients. PMID- 28641155 TI - Depression and cancer risk: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the associations between depression and incident cancer risk. STUDY DESIGN: Systematic review and meta-analysis. METHODS: The Cochrane Library, Web of Science, MEDLINE, and PubMed databases were searched to identify studies. The quality of included studies was assessed using the Newcastle Ottawa Scale. Risk ratios (RRs) were used to measure effect size. A random-effects model was applied to synthesize the associations between depression and cancer risk. A forest plot was produced to visually assess RRs and 95% confidence intervals (CIs). Heterogeneity across studies was assessed using the I-squared statistic. A funnel plot was generated to assess potential publication bias, and Egger's regression was applied to test the symmetry of the funnel plot. RESULTS: In total, 1,469,179 participants and 89,716 incident cases of cancer from 25 studies were included. Depression was significantly associated with overall cancer risk (RR = 1.15, 95% CI: 1.09-1.22) and with liver cancer (RR = 1.20, 95% CI: 1.01 1.43) and lung cancer (RR = 1.33, 95% CI: 1.04-1.72). Subgroup analysis of studies in North America resulted in a significant summary relative risk (RR = 1.30, 95% CI: 1.15-1.48). No significant associations were found for breast, prostate, or colorectal/colon cancer. The average Newcastle Ottawa score was 7.56 for all included studies. CONCLUSION: Our findings showed a small and positive association between depression and the overall occurrence risk of cancer, as well as liver cancer and lung cancer risks. However, multinational and larger sample studies are required to further research and support these associations. Moreover, confounding factors such as cigarette smoking and alcohol use/abuse should be considered in future studies. PMID- 28641156 TI - Mild C(sp3)-H functionalization of dihydrosanguinarine and dihydrochelerythrine for development of highly cytotoxic derivatives. AB - A series of C(6)-substituted dihydrobenzo[c]phenanthridines were synthesized by mild copper-catalyzed C(sp3)-H functionalization of dihydrosanguinarine (2) and dihydrochelerythrine (3) with certain nucleophiles selected to enhance cytotoxicity against human breast, colorectal, and prostate cancer cell lines. We also investigated the cytotoxicity of our previously reported C(6)-functionalized N-methyl-5,6-dihydrobenzo[c]phenanthridines 1a-1e to perform structure-activity relationship (SAR) studies. Among the target compounds, five beta-aminomalonates (1a, 1b, 2a, 2b, and 3b), one alpha-aminophosphonate (2c), and one nitroalkyl derivative (2h) exhibited half maximal inhibitory concentration (IC50) values in the range of 0.6-8.2 MUM. Derivatives 1b, 2b and 2h showed the lowest IC50 values, with 2b being the most potent with values comparable to those of the positive control doxorubicin. On the basis of their IC50 values, derivatives 1a, 1b, 2a, 2b, 2h, and 3b were selected to evaluate the apoptotic PC-3 cell death at 10 MUM by flow cytometry using propidium iodide and fluorescein isothiocyanate conjugated Annexin V dual staining. The results indicated that the cytotoxic activity of the tested compounds in PC-3 cells is due to the induction of apoptosis, with 1a and 2h being the most active (55% of early apoptosis induction). Our preliminary SAR study showed that the incorporation of specific malonic esters, dialkyl phosphites and nitro alkanes on scaffolds 1-3 significantly enhanced their cytotoxic properties. Moreover, it appears that the electron donating 7,8-methylenedioxy group allowed derivatives of 2 to exhibit higher cytotoxicity than derivatives of 1 and 3. The present results suggest that derivatives 2b and 2h may be considered as potential lead compounds for the development of new anticancer agents. PMID- 28641157 TI - Design, synthesis and structure-activity relationship studies of a novel focused library of 2,3,4-substituted oxazolidines with antiproliferative activity against cancer cell lines. AB - In the present work we describe the synthesis and antiproliferative evaluation of a focused library of 30 novel oxazolidines designed by modification of N substituent, by ring variation, by alkyl variation or by extension of the structure. It was noted that carbamate and N,O-aminal groups were essential for activity. In general, replacement of the phenyl ring with pyridinyl was not tolerated. However, the introduction of a second phenyl ring with an appropriate spacer at the 3- or 4-position of the first phenyl ring generally enhanced the cytotoxic profile. Among all the prepared compounds, 24 was the most potent compound found in this class, being active on four of five cancer cell lines and it was 5-fold and 10-fold more potent than the lead compounds against HL60 and JURKAT cells, respectively. In addition, it showed relevant activity against MCF 7 and HCT-116 cells, which were resistant to lead. Moreover, 24 showed little antiproliferative activity against VERO, indicating low toxicity to normal cells. Thus, this compound has the potential to be developed as an anticancer agent. PMID- 28641158 TI - Determinants of cortisol during pregnancy - The ABCD cohort. AB - BACKGROUND: Psychosocial stress during pregnancy has been proposed as a major contributor of glucocorticoid-mediated programming of the fetal hypothalamic pituitary adrenal (HPA) axis, with later adverse health consequences. However, evidence linking maternal stress to maternal cortisol values during pregnancy is inconclusive. A possible explanation for this is that other maternal factors overshadow any potential effects of stress on cortisol levels. We studied a large cohort of pregnant women with extensive data on pregnancy characteristics to determine the respective contributions of biological, environmental and psychosocial stress factors to cortisol levels in pregnancy. METHODS: We used data from 3039 women from the Amsterdam Born Children and their Development-study cohort. Serum cortisol was measured in blood, collected at the first prenatal visit, at different gestational ages (median=91days, range=40-256days), and at various time points during the day (median=11:45h, range=08:00-18:30h). We assessed associations between maternal serum cortisol in pregnancy and biological factors, lifestyle factors and stress factors, including depression, anxiety, pregnancy-related anxiety, work stress, parenting stress and fatigue. RESULTS: In multivariable analysis, variables that were associated with higher cortisol levels in pregnancy were lower maternal age [1.5nmol/l, 95%CI (0.6-2.4)], being nulliparous [21.5 nmol/l (15.9-27.1)], lower pre-pregnancy body mass index (BMI) [1.3nmol/l (0.3-2.4)], higher C-reactive protein (CRP) [1.0nmol/l (0.4-1.5)], carrying a female fetus [9.2nmol/l (1.8-16.5)], non-smoking [14.2nmol/l (0.6 27.7)], sufficient sleep [8.5nmol/l (0.9-16.1)], and being unemployed [12.7nmol/l (2.2-23.2)]. None of the psychosocial stressors was significantly associated with serum cortisol levels in pregnancy. A total of 32% of all variance in cortisol was explained by gestational age, maternal age, time of day, parity, pre pregnancy BMI, CRP, fetal sex, smoking behavior, self-reported sleep sufficiency, and employment. CONCLUSIONS: Our data suggest that maternal cortisol during pregnancy is mainly affected by biological and lifestyle factors, but not by psychosocial factors. We suggest that psychosocial stress in pregnancy might program the fetus through other mechanisms than through altering maternal cortisol levels. PMID- 28641159 TI - A model to calculate the progression of the centre of pressure under the foot during gait analysis. AB - Pedobarography and the centre of pressure (COP) progression is useful to understand foot function. Pedobarography is often unavailable in gait laboratories or completed asynchronously to kinematic and kinetic data collection. This paper presents a model that allows calculation of COP progression synchronously using force plate data. The model is an adjunct to Plug In-Gait and was applied to 49 typically developing children to create reference COP data. COP progressions were noted to spend 8% of stance behind the ankle joint centre, traverse lateral of the longitudinal axis of the foot through the midfoot for 76% of stance and finishing past the second metatarsal head on the medial side for 16% of stance. It is hoped the model will bridge the information gap for gait laboratories lacking pedobarography during foot assessments and will open up the possibility of retrospective research into COP progression based indices on kinematic data. PMID- 28641160 TI - Effects of hip joint centre mislocation on gait kinematics of children with cerebral palsy calculated using patient-specific direct and inverse kinematic models. AB - Joint kinematics can be calculated by Direct Kinematics (DK), which is used in most clinical gait laboratories, or Inverse Kinematics (IK), which is mainly used for musculoskeletal research. In both approaches, joint centre locations are required to compute joint angles. The hip joint centre (HJC) in DK models can be estimated using predictive or functional methods, while in IK models can be obtained by scaling generic models. The aim of the current study was to systematically investigate the impact of HJC location errors on lower limb joint kinematics of a clinical population using DK and IK approaches. Subject-specific kinematic models of eight children with cerebral palsy were built from magnetic resonance images and used as reference models. HJC was then perturbed in 6mm steps within a 60mm cubic grid, and kinematic waveforms were calculated for the reference and perturbed models. HJC perturbations affected only hip and knee joint kinematics in a DK framework, but all joint angles were affected when using IK. In the DK model, joint constraints increased the sensitivity of joint range of-motion to HJC location errors. Mean joint angle offsets larger than 5 degrees were observed for both approaches (DK and IK), which were larger than previously reported for healthy adults. In the absence of medical images to identify the HJC, predictive or functional methods with small errors in anterior-posterior and medial-lateral directions and scaling procedures minimizing HJC location errors in the anterior-posterior direction should be chosen to minimize the impact on joint kinematics. PMID- 28641161 TI - Postural control in blind individuals: A systematic review. AB - Postural control (PC) requires the interaction of the three sensory systems for a good maintenance of the balance, and in blind people, lack of visual input can harm your PC. Thus the objective is to perform a literature review concerning role of sight in the maintenance of PC and the adaptation of brain structures when vision is absent. Studies were searched from Pubmed, and EMBASE that included individuals with congenital blindness. Articles studying person with acquired blindness or low vision was excluded from this review. 26 out of 322 articles were selected for review, and we found that 1) blind individuals exhibit PC deficits and that is compensated by the intensification of the remaining systems; 2) Neuroplastic adaptation occurs throughout the entire cerebral cortex; and 3) Sensorimotor stimulation and transcranial direct current stimulation seem to be a rehabilitation strategy. According to this review, the findings suggest that improved remaining sensations in the presence of adaptations and neuroplasticity, does not translate into better postural control performance. Regarding rehabilitation strategies, more studies are needed to show which therapeutic modality best contributes to postural control. PMID- 28641162 TI - Triterpenoids and sterols from the grains of Echinochloa utilis Ohwi & Yabuno and their cytotoxic activity. AB - Two new tetracyclic triterpenoids, echinochlorins C (1) and D (2), and sawamilletin (3) with new spectroscopic data were isolated from Echinochloa utilis Ohwi & Yabuno grains, along with one known triterpenoid (4) and eight sterols (5-12). Their structures were elucidated by spectroscopic data analyses (IR, UV, MS, and NMR). These compounds were tested in vitro cytotoxic activities against the human tumor-cell lines (HeLa, HL-60, and MCF-7). Compounds 6 and 8 displayed potential cytotoxic activity against HeLa, with IC50 values of 3.1+/ 0.9 and 3.2+/-0.8MUM, respectively. This finding indicated that tetracyclic triterpenoids isolated from E. utilis may have potential beneficial effects for the treatment of cancer. PMID- 28641163 TI - 6-shogaol induces autophagic cell death then triggered apoptosis in colorectal adenocarcinoma HT-29 cells. AB - 6-shogaol is a phytochemical of dietary ginger, we found that 6-shogaol could induced both autophagic and apoptotic death in human colon adenocarcinoma (HT-29) cells. Results of this study showed that 6-shogal induced cell cycle arrest, autophagy, and apoptosis in HT-29 cells in a time sequence. After 6h, 6-shogal induced apparent G2/M arrest, then the HT-29 cells formed numerous autophagosomes in each phase of the cell cycle. After 18h, increases in acidic vesicles and LAMP 1 (Lysosome-associated membrane proteins 1) showed that 6-shogaol had caused autophagic cell death. After 24h, cell shrinkage and Caspase-3/7 activities rising, suggesting that apoptotic cell death had increased. And after 48h, the result of TUNEL assay indicated the highest occurrence of apoptosis upon 6 shogaol treatment. It appeared that apoptosis is triggered by autophagy in 6 shogaol treated HT-29 cells, the damage of autophagic cell death initiated apoptosis program. PMID- 28641164 TI - Protective effects of flavonoids against Alzheimer's disease-related neural dysfunctions. AB - Senile ages of human life is mostly associated with developmental of several neurological complicated conditions including decreased cognition and reasoning, increased memory loss and impaired language performance. Alzheimer's disease (AD) is the most prevalent neural disorder associated with dementia, consisting of about 70% of dementia reported cases. Failure of currently approved chemical anti AD therapeutic agents has once again brought up the idea of administering naturally occurring compounds as effective alternative and/or complementary regimens in AD treatment. Polyphenol structured neuroprotecting agents are group of biologically active compounds abundantly found in plants with significant protecting effects against neural injuries and degeneration. As a subclass of this family, Flavonoids are potent anti-oxidant, anti-inflammatory and signalling pathways modulatory agents. Phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen activated protein kinase (MAPK) pathways are both affected by Flavonoids. Regulation of pro-survival transcription factors and induction of specific genes expression in hippocampus are other important anti AD therapeutic activities of Flavonoids. These agents are also capable of inhibiting specific enzymes involved in phosphorylation of tau proteins including beta-secretases, cyclin dependent kinase 5 and glycogen synthase. Other significant anti AD effects of Flavonoids include neural rehabilitation and lost cognitive performance recovery. In this review, first we briefly describe the pathophysiology and important pathways involved in pathology of AD and then describe the most important mechanisms through which Flavonoids demonstrate their significant neuroprotective effects in AD therapy. PMID- 28641165 TI - Identifying seizure clusters in patients with psychogenic nonepileptic seizures. AB - The present study explored how seizure clusters may be defined for those with psychogenic nonepileptic seizures (PNES), a topic for which there is a paucity of literature. The sample was drawn from a multisite randomized clinical trial for PNES; seizure data are from participants' seizure diaries. Three possible cluster definitions were examined: 1) common clinical definition, where >=3 seizures in a day is considered a cluster, along with two novel statistical definitions, where >=3 seizures in a day are considered a cluster if the observed number of seizures statistically exceeds what would be expected relative to a patient's: 1) average seizure rate prior to the trial, 2) observed seizure rate for the previous seven days. Prevalence of clusters was 62-68% depending on cluster definition used, and occurrence rate of clusters was 6-19% depending on cluster definition. Based on these data, clusters seem to be common in patients with PNES, and more research is needed to identify if clusters are related to triggers and outcomes. PMID- 28641166 TI - Care coordination at a pediatric accountable care organization (ACO): A qualitative analysis. AB - OBJECTIVE: Care coordinators may help manage care for children with chronic illness. Their role in pediatric epilepsy care is understudied. We aimed to qualitatively describe the content of a care coordination intervention for children with epilepsy. METHODS: We conducted nine semi-structured interviews and one focus group with care coordinators at a pediatric accountable care organization (ACO) in Ohio. The care coordinators used a modified version of a published care coordination checklist for children with epilepsy (Patel AD, 2014). We analyzed transcripts using thematic analysis. We focused on (1) the content of the intervention; and (2) perceptions of facilitators and barriers to improve outcomes, with an emphasis on epilepsy specific facilitators and barriers. RESULTS: Care coordinators interacted with children and families in multiple contexts (phone calls, physician visits, home visits), and included relationship building (developing rapport and trust between families and the health system), communication (transmission of information between the child, family, physician, and other care providers), and service (help with housing, transportation, scheduling, liaison with community resources, etc.). Facilitators and barriers of care coordination included factors related to parents, physicians, health system, payers, and community. Epilepsy-specific barriers included stigma (felt & enacted) and the anxiety associated with clinical uncertainty. Epilepsy related facilitators included a seizure action plan, written educational materials, and an epilepsy specific care coordination checklist. CONCLUSION: In addition to facilitators and barriers common to many care coordination programs, pediatric epilepsy care coordinators should be particularly aware of epilepsy stigma and clinical uncertainty. A care coordination checklist and epilepsy focused educational materials written to accommodate people with low health literacy may provide additional benefit. Further research is required to understand the effect of care coordination on costs, use of health services, seizure control, and quality of life for children with epilepsy. PMID- 28641167 TI - Exploring the role of knowledge of condition and psycho-social profiles of young people with epilepsy during transition. AB - Transitioning from paediatric to adult care can be a particularly challenging time for young people with epilepsy and research has shown that there are a range of factors which may influence a young person's ability to successfully cope with this difficult time. The following study aimed to explore the psychosocial characteristics of this transitioning population, as well as investigate how knowledgeable the young person and their parent/carer are of their own condition throughout transition. Young people with epilepsy were recruited from two specialist epilepsy clinics in the North West and allocated to one of three groups; Group 1 pre-transition, Group 2 transitioning, and Group 3 post transition. Results found that the young person's knowledge increased significantly throughout transition, whilst parent/carer's knowledge decreased. In addition, anxiety was found to be significantly lower in Group 2 (transitioning group) compared to Group 1 (pre-transition) and Group 3 (post transition) and a number of significant gender differences were also identified across the groups. The study highlights the importance of considering all relevant psychosocial factors, such as anxiety, gender and the degree of knowledge the individual holds of their own condition during the transition process in order to develop psycho-educational programmes and transition pathways. PMID- 28641168 TI - Aicardi syndrome and cognitive abilities: A report of five cases. AB - Aicardi syndrome is a rare neurodevelopmental disorder with agenesis of corpus callosum, chorioretinal lacunae, and infantile spasms as the main features. The outcome is in general severe, with poor cognitive development and difficult-to treat epilepsy. In this study, we assessed the level of cognitive function of five girls with Aicardi syndrome, using normed population based tests and questionnaires. Their cognitive abilities varied from mild to profound intellectual disabilities. The more severe the epilepsy, the poorer were the cognitive skills. To the best of our knowledge, this is the first study that systematically applies validated cognitive assessment tools to study patients with this syndrome. Knowledge about cognitive functioning is crucial for providing optimal special education and finding appropriate alternative communication with parents and caregivers. PMID- 28641169 TI - Association between switching antiepileptic drug products and healthcare utilization: A systematic review. AB - AIMS: There is ongoing concern whether switching between different antiepileptic drug (AED) products may compromise patient care. We systematically reviewed changes in healthcare utilization following AED switch. METHODS: We searched MEDLINE and EMBASE databases (1980-October 2016) for studies that assessed the effect of AED switching in patients with epilepsy on outpatient visits, emergency room visits, hospitalization and hospital stay duration. RESULTS: A total of 14 articles met the inclusion criteria. All were retrospective studies. Four provided findings for specific AEDs only (lamotrigine, topiramate, phenytoin and divalproex), 9 presented pooled findings from multiple AEDs, and 1 study provided both specific (lamotrigine, topiramate, oxcarbazepine, and levetiracetam) and pooled findings. Three studies found an association between a switch of topiramate and an increase in healthcare utilization. Another three studies found that a brand-to-generic lamotrigine switch was not associated with an increased risk of emergently treated events (ambulance use, ER visits or hospitalization). The outcomes of the pooled AED switch studies were inconsistent; 5 studies reported an increased healthcare utilization while 5 studies did not. CONCLUSION: Studies that have examined the association between an AED switch and a change in healthcare utilization report conflicting findings. Factors that may explain these inconsistent outcomes include inter-study differences in the type of analysis undertaken (pooled vs individual AED data), the covariates used for data adjustment, and the type of switch examined. Future medical claim database studies employing a prospective design are encouraged to address these and other factors in order to enhance inter-study comparability and extrapolation of findings. PMID- 28641170 TI - Efficacy and safety of eslicarbazepine acetate monotherapy for partial-onset seizures: Experience from a multicenter, observational study. AB - Eslicarbazepine acetate (ESL, AptiomTM) is a once-daily anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). Historical-controlled trials investigating the use of ESL as monotherapy have demonstrated a favorable efficacy and tolerability profile in patients with POS. This prospective, non interventional study recruited POS patients in 17 hospitals in Spain. After a 3 month baseline period, ESL therapy was initiated as 400mg QD and up-titrated to an optimal maintenance dose based on clinical response and tolerance. The incidence of seizures was assessed via seizure calendars and the nature and severity of adverse events (AEs) were also recorded. A total of 117 patients (aged 9-87years) enrolled in the study and were treated with ESL at either 400mg/day (3.4% patients), 800mg/day (61% patients), 1200mg/day (27.1% patients) or 1600mg/day (8.5% patients). At 3months, 82.0% (n=72) of patients achieved a >=50% reduction in seizure frequency, compared to 79.7% (n=67) of patients at 6months and 83.0% (n=49) at 12months. Patients who suffered secondary generalized tonic-clonic (SGTC) seizures had seizure-free rates of 71% (n=27), 69.6% (n=29), and 72.7% (n=16) at 3, 6, and 12months, respectively. Overall, 18 patients (15.3%) reported AEs of instability and dizziness (n=9), somnolence (n=3), mild hyponatremia (n=3), headache (n=1), hypertriglyceridemia (n=1), and allergic reaction (n=1), which caused ESL discontinuation of ESL treatment. ESL is effective and well tolerated as monotherapy for patients with POS, which supports previous findings. Early use is supported by its frequent use as monotherapy in this study and lack of severe side effects. PMID- 28641171 TI - Electromyographic analysis of rotator cuff muscles in patients with rotator cuff tendinopathy: A systematic review. AB - The shoulder is inherently an unstable joint which heavily relies on the neuromuscular activation of the rotator cuff (RC) complex for stability during movement. Currently, there is no consensus regarding how the activity of RC muscles is affected among individuals with a RC tendinopathy (RCTe). This study reviewed the evidence of studies comparing the electromyographic (EMG) activity of any RC muscle of shoulders with a symptomatic RCTe to asymptomatic shoulders. Eight databases were searched. Data from 343 participants (201 symptomatic and 209 asymptomatic shoulders) were analyzed from 10 out of 402 included studies. Strong evidence for the infraspinatus and supraspinatus during isometric contractions and limited evidence for the supraspinatus and infraspinatus during isokinetic contractions suggest that the muscular activity is not altered among individuals with a RCTe during these types of contraction. Very limited evidence indicates reduced muscle activity for the infraspinatus and subscapularis in the presence of a RCTe during isotonic contractions, and no alterations for the supraspinatus or teres minor were identified. Lastly, conflicting to moderate evidence suggests alterations in RC muscle activity during unrestrained movements and swimming. These findings indicate that EMG deficits associated with a RCTe can best be appreciated during unrestrained movements. PMID- 28641172 TI - The impact of speed and time on gait dynamics. AB - To determine the effects of speed on gait previous studies have examined young adults walking at different speeds; however, the small number of strides may have influenced the results. The aim of this study was to investigate the immediate and long-term impact of continuous slow walking on the mean, variability and structure of stride-to-stride measures. Fourteen young adults walked at a constant pace on a treadmill at three speeds (preferred walking speed (PWS), 90% and 80% PWS) for 30 min each. Spatiotemporal gait parameters were computed over six successive 5-min intervals. Walking slower significantly decreased stride length, while stride period and width increased. Additionally, stride period and width variability increased. Signal regularity of stride width increased and decreased in stride period. Persistence of stride period and width increased significantly at slower speeds. While several measures changed during 30min of walking, only stride period variability and signal regularity revealed a significant speed and time interaction. Healthy young adults walking at slower than preferred speeds demonstrated greater persistence and signal regularity of stride period while spatiotemporal changes such as increased stride width and period variability arose. These results suggest that different control processes are involved in adapting to the slower speeds. PMID- 28641173 TI - Population dynamics of electrogenic microbial communities in microbial fuel cells started with three different inoculum sources. AB - Microbial fuel cells (MFCs) are one of the bioelectrochemical systems that exploit microorganisms as biocatalysts to degrade organic matters and recover energy as electric power. Here, we explored how the established electrogenic microbial communities were influenced by three different inoculum sources; anaerobic sludge of the wastewater plant, rice paddy field soil, and coastal lagoon sediment. We periodically characterized both electricity generation with sucrose consumption and 16S rRNA-basis microbial community composition. The electrochemical features of MFCs were slightly different among three inocula, and the lagoon sediment-inoculated MFC showed the highest performance in terms of the treatment time. Meanwhile, although the inoculated microbial communities were highly diverse and quite different, only twelve genera affiliated with delta Proteobacteria, gamma-Proteobacteria, Bacilli, Clostridia/Negativicutes or Bacteroidetes were abundantly enriched in all MFC anode communities. Within them, several fermentative genera were clearly different due to the inocula, while the inocula-specific phylotypes were identified in an electrogenic genus Geobacter. The relative abundances of phylotypes closely-related to Geobacter metallireducens were increased in later stages of all the sucrose-fed MFCs. These results indicate that key microbial members for the functional electrogenic community widely exist in natural ecosystems, but the community members presenting in inoculum sources affected the MFC performances. PMID- 28641174 TI - New insights into the oleate flotation response of feldspar particles of different sizes: Anisotropic adsorption model. AB - The anisotropic adsorption of sodium oleate (NaOL) on feldspar surfaces was investigated to elucidate the different flotation properties of feldspar particles of four different size ranges. Microflotation experiments showed that the feldspar flotation recovery of particles with sizes spanning different ranges decreased in the order 0-19>19-38>45-75>38-45MUm. Zeta potential and FTIR measurements showed that NaOL was chemically adsorbed on the Al sites of the feldspar surface. The anisotropic surface energies and broken bond densities estimated by density functional theory calculations showed that, although feldspar mostly exposed (010) and (001) surfaces, only the (001) surfaces contained the Al sites needed for NaOL adsorption. The interaction energies calculated by molecular dynamics simulations confirmed the more favorable NaOL adsorption on (001) than (010) surfaces, which may represent the main cause for the anisotropic NaOL adsorption on feldspar particles of different sizes. SEM measurements showed that the main exposed surfaces on coarse and fine feldspar particles were the side (010) and basal (001) ones, respectively. A higher fraction of Al-rich (001) surfaces is exposed on fine feldspar particles, resulting in better floatability compared with coarse particles. XPS and adsorption measurements confirmed that the Al content on the feldspar surface varied with the particle size, explaining the different NaOL flotation of feldspar particles of different sizes. Therefore, the present results suggest that coarsely ground ore should be used for the separation of feldspar gangue minerals. Further improvements in the flotation separation of feldspar from associated valuable minerals can be achieved through selective comminution or grinding processes favoring the exposure of (010) surfaces. PMID- 28641175 TI - Atmospheric dust deposition on soils around an abandoned fluorite mine (Hammam Zriba, NE Tunisia). AB - The present study focuses on the eolian dispersion and dust deposition, of major and trace elements in soils in a semi-arid climate, around an old fluorite (CaF2) and barite (BaSO4) mine, located in Hammam Zriba in Northern Tunisia. Ore deposits from this site contain a high amount of metal sulphides constituting heavy metal pollution in the surrounding environment. Samples of waste from the surface of mine tailings and agricultural topsoil samples in the vicinity of the mine were collected. The soil samples and a control sample from unpolluted area, were taken in the direction of prevailing northwest and west winds. Chemical analysis of these solids was performed using both X-ray fluorescence and X-ray diffraction. To determine the transfer from mine wastes to the soils, soluble fraction was performed by inductively coupled plasma and ionic chromatography. The fine grained size fraction of the un-restored tailings, still contained significant levels of barium, strontium, sulphur, fluorine, zinc and lead with mean percentages (wt%) of 30 (calculated as BaO), 13 (as SrO), 10 (as SO3), 4 (F), 2 (Zn) and 1.2 (Pb). Also, high concentrations of cadmium (Cd), arsenic (As) and mercury (Hg) were found with an averages of 36, 24 and 1.2mgkg-1, respectively. As a result of the eolian erosion of the tailings and their subsequent wind transport, the concentrations of Ba, Sr, S, F, Zn and Pb were extremely high in the soils near to the tailings dumps, with 5%, 4%, 7%, 1%, 0.8% and 0.2%, respectively. Concentration of major pollutants decreases with distance, but they were high even in the farthest samples. Same spatial distribution was observed for Cd, As and Hg. While, the other elements follow different spatial patterns. The leaching test revealed that most elements in the mining wastes, except for the anions, had a low solubility despite their high bulk concentrations. According the 2003/33/CE Decision Threshold, some of these tailings samples were considered as hazardous. Furthermore, other waste samples, considered non hazardous, were not inert. In contrast, the SO42-, Ba, Pb and Sb leachable contents measured in most of the soil samples were relatively high, exceeding the inert threshold for landfill disposal of wastes. PMID- 28641176 TI - Epilepsy and Pregnancy: For healthy pregnancies and happy outcomes. Suggestions for service improvements from the Multispecialty UK Epilepsy Mortality Group. AB - Between 2009 and 2012 there were 26 epilepsy-related deaths in the UK of women who were pregnant or in the first post-partum year. The number of pregnancy related deaths in women with epilepsy (WWE) has been increasing. Expert assessment suggests that most epilepsy-related deaths in pregnancy were preventable and attributable to poor seizure control. While prevention of seizures during pregnancy is important, a balance must be struck between seizure control and the teratogenic potential of antiepileptic drugs (AEDs). A range of professional guidance on the management of epilepsy in pregnancy has previously been issued, but little attention has been paid to how optimal care can be delivered to WWE by a range of healthcare professionals. We summarise the findings of a multidisciplinary meeting with representation from a wide group of professional bodies. This focussed on the implementation of optimal pregnancy epilepsy care aiming to reduce mortality of epilepsy in mothers and reduce morbidity in babies exposed to AEDs in utero. We identify in particular -What stage to intervene - Golden Moments of opportunities for improving outcomes Which Key Groups have a role in making change -When - 2020 vision of what these improvements aim to achieve. -How to monitor the success in this field We believe that the service improvement ideas developed for the UK may provide a template for similar initiatives in other countries. PMID- 28641177 TI - A 30-year history of MPAN case from Russia. AB - We present a patient with progressive spastic ataxia, with dystonia and anarthria undiagnosed until detailed genetic analysis revealed an MPAN mutation. Highlighting the worldwide MPAN distribution, a 30year history of absent diagnosis and the impact and cost saving of an early but detailed genetic analysis in complex progressive movement disorders, particularly the anarthric NBIA group. PMID- 28641178 TI - Stimulatory effect of Aggregatibacter actinomycetemcomitans DNA on proinflammatory cytokine expression by human gingival fibroblasts. AB - OBJECTIVE: While different virulence factors have been reported of Aggregatibacter actinomycetemcomitans (Aa), there is little information about the stimulatory effect of its DNA. The main purpose of this study was to assess the inflammatory response of human gingival fibroblasts (HGFs) stimulated with A. actinomycetemcomitans DNA. DESIGN: Cytokine levels of IL-6, IL-1alpha and TNF alpha were measured on the supernatant of HGFs activated with 10, 25, 50 and 100MUg/ml DNA of Aa during 24h. Primary cultures of HGFs were infected with Aa and its DNA at different times and concentrations to compare its cytotoxic effect. Cell damage and adhesion of Aa to HGFs were evaluated under light microscopy and Scanning electron microscopy respectively. RESULTS: There was a statistical difference (p<0.05) in cytokine expression in HGFs activated by bacterial DNA with a dose dependent on IL-6 expression and a significantly elevated expression of IL-1alpha and TNF-alpha compared to Human DNA negative control. Substantial morphological alterations were observed after infection of A. actinomycetemcomitans in HGFs but not with bDNA exposure. Aggregatibacter actinomycetemcomitans showed a high rate of adhesion and cell damage to HGFs after 30min. CONCLUSIONS: Genomic DNA of A. actinomycetemcomitans could be a factor in the pathogenesis of periodontitis that might play a major role in the inflammatory response. PMID- 28641179 TI - Quantitative study of the proportion of the pore volume of human fluorotic enamel filled by resin infiltrant. AB - AIM: Capillarity theory predicts that the pore volume infiltrated by a liquid in a body with tubular capillaries is directly proportional to the capillary radius. The expected volume available for infiltration is the loosely bound water volume, which can be related to the capillary radii. We tested the hypothesis that the proportion of the pore volume infiltrated by resin infiltrant (Vratioresin) is correlated and agrees with the proportion of the pore volume with loosely bound water ( [Formula: see text] ). DESIGN: Seven human fluorotic third molars (4 unerupted and 3 erupted; TF scores 4 to 7; fluoride content of inner coronal dentin ranged from 143 to 934MUg Fluoride/g) were prepared and resin infiltration was performed during 10min in fluorotic enamel ground sections. Penetration depths were measured (polarizing microscopy and CLSM) and mineral volume and non mineral volumes were measured at histological points (n=92) along transversal lines traced from the enamel surface to the enamel-dentin junction. RESULTS: No well-mineralized surface layer was found. Infiltration depths ranged from 250MUm to 900MUm. Vratioresin ranged from 1.8 to 17.7% (mean of 10.13%+/-4.1%), was lower than [Formula: see text] (p<0.00001 Hedge's g=1.51, 95% CI: 1.18/1.83), and correlated positively with [Formula: see text] (R=0.684; 95% CI: 0.557/0.780) and negatively with the air volume remained after infiltration (R=-0.79; 95% CI: 0.698/-0.780). [Formula: see text] exceeded Vratioresin in 5% (1/4 of [Formula: see text] ) on average. CONCLUSION: [Formula: see text] and Vratioresin correlated well, but lacked good agreement. Organic matter, firmly bound water and air remained in enamel pores after resin infiltration. PMID- 28641180 TI - Potential chemotherapeutic effects of diosgenin, zoledronic acid and epigallocatechin-3-gallate on PE/CA-PJ15 oral squamous cancer cell line. AB - OBJECTIVE: To study the potential chemotherapeutic effects of Diosgenin, zoledronic acid and Epigallocatechin-3-gallate on oral squamous cell cancer (OSCC). MATERIALS AND METHODS: Cell viability, migration, apoptosis and cell cycle evaluation assays were performed in order to assess the effects of different doses of Diosgenin, zoledronic acid and Epigallocatechin-3-gallate on the PE/CA-PJ15 cell line. RESULTS: Doses of 100MUM of diosgenin or zoledronic acid reduced cell viability significantly after 72h (p<0.001), as well as increasing apoptosis (p<0.05 and p<0.01 respectively). All three agents reduced cell migration and altered the cell cycle, each at a different phase of the cycle. CONCLUSION: while DG and ZA reduced cell viability, increased apoptosis, inhibited cell migration and modified the cell cycle in different ways, EGCG only modified the cell cycle and reduced cell migration. These agents present a potential chemotherapeutic effect on PE/CA-PJ15 OSSC cell line, which have to be further studied. PMID- 28641181 TI - The caveolae dress code: structure and signaling. AB - Over the past decade, interest in caveolae biology has peaked. These small bulb shaped plasma membrane invaginations of 50-80nm diameter present in most cell types have been upgraded from simple membrane structures to a more complex bona fide organelle. However, although caveolae are involved in several essential cellular functions and pathologies, the underlying molecular mechanisms remain poorly defined. Following the identification of caveolins and cavins as the main caveolae constituents, recent studies have brought new insight into their structural organization as a coat. In this review, we discuss how these new data on caveolae can be integrated in the context of their role in signaling and pathophysiology. PMID- 28641182 TI - Unraveling the complexities of the velocity dependency of E. coli retention and release parameters in saturated porous media. AB - Escherichia coli transport and release experiments were conducted to investigate the pore-water velocity (v) dependency of the sticking efficiency (alpha), the fraction of the solid surface area that contributed to retention (Sf), the percentage of injected cells that were irreversibly retained (Mirr), and cell release under different (10-300mM) ionic strength (IS) conditions. Values of alpha, Sf, and Mirr increased with increasing IS and decreasing v, but the dependency on v was greatest at intermediate IS (30 and 50mM). Following the retention phase, successive increases in v up to 100 or 150mday-1 and flow interruption of 24h produced negligible amounts of cell release. However, excavation of the sand from the columns in excess electrolyte solution resulted in the release of >80% of the retained bacteria. These observations were explained by: (i) extended interaction energy calculations on a heterogeneous sand collector; (ii) an increase in adhesive strength with the residence time; and (iii) torque balance consideration on rough surfaces. In particular, alpha, Sf, and Mirr increased with IS due to lower energy barriers and stronger primary minima. The values of alpha, Sf, and Mirr also increased with decreasing v because the adhesive strength increased with the residence time (e.g., an increased probability to diffuse over the energy barrier) and lower hydrodynamic forces diminished cell removal. The controlling influence of lever arms at microscopic roughness locations and grain-grain contacts were used to explain negligible cell removal with large increases in v and large amounts of cell recovery following sand excavation. Results reveal the underlying causes (interaction energy, torque balance, and residence time) of the velocity dependency of E. coli retention and release parameters (ksw, alpha, and Sf) that are not accounted for in colloid filtration theory. PMID- 28641183 TI - Size partitioning and mixing behavior of trace metals and dissolved organic matter in a South China estuary. AB - The Jiulong River estuary, located in the southeastern China, suffered from metal pollution due to industrial effluent releases. Mixing of effluent and estuarine water may have significantly affected the size distribution of trace metals and their environmental fate. In the present study, colloidal size distribution of organic matter and selected metals were quantified using asymmetric flow field flow fractionation (AF4) and ICP-MS. We demonstrated a dominance of dissolved metals in the 1-10kDa fraction, and metals such as Cu, Zn, Ni, Co, Pb, Cd and Mn were mostly regulated by terrestrial fulvic acid. The larger inorganic colloids played a limited role, although Fe reduction was likely to affect the size partitioning of colloidal Mn. The holding pond represented a source of trace metals and chromophoric and humic-like dissolved organic matter to the estuary. Scavenging or removal behavior became evident following the intermittent mixing, and the small sized colloidal organic complexes were responsible for binding and stabilizing trace metals. Variations in particle size distributions indicated different sources, fates and geochemical controls of the metals. Our results highlighted the impacts of both natural and anthropogenic processes on the transformation of trace metals among phases in this dynamic estuary system. PMID- 28641184 TI - Estimation of U.S. sewer residence time distributions for national-scale risk assessment of down-the-drain chemicals. AB - Sewer residence time (the amount of time a given volume of wastewater resides in a sewer system prior to treatment) can have a significant influence on predictions of environmental fate and transport of wastewater constituents and corresponding risk assessment. In this study, a geographic information systems based approach for estimating the distribution of sewer residence times for the U.S. was developed using road networks as a spatial proxy for sewer networks. The suitability of the approach was evaluated using case study municipalities, and the approach was subsequently extrapolated to 3422 wastewater treatment facilities of varying size across the U.S. to estimate a national distribution of sewer residence times. The estimated national median residence time for the U.S. was 3.3h. Facilities serving smaller municipalities (<1 million gallons per day) had comparatively shorter sewer residence times to facilities serving larger municipalities, though the latter comprise a greater proportion of overall national wastewater volume. The results of this study provide an important data resource in combination with chemical in-sewer biodegradation data to enable probabilistic risk assessment of consumer product chemicals disposed of down the drain. PMID- 28641185 TI - Mechanistic understanding of low methylmercury bioaccessibility from crayfish (Procambarus clarkii) muscle tissue. AB - Recent research indicates that dietary exposure to mercury and other metals from crayfish consumption poses a human health concern, particularly in regions with high crayfish-consuming populations. To better understand consumption risk from methylmercury (MeHg), we quantified MeHg bioaccessibility in edible tail muscle of cooked red swamp crayfish (Procambarus clarkii, collected from seven cities in China), versus cooked fillet tissue of two finfish species: yellow croaker (Larimichthys polyactis) and snakehead (Channa argus). Results indicated that digestive solubilization rate (DSR) of MeHg in crayfish (7.8+/-3.9% for restaurant-crayfish and 9.8+/-0.8% for market-crayfish) was lower than the rate in yellow croaker (25.8+/-2.7%) and snakehead (26.2+/-4.7%) tissue, suggesting that relatively low MeHg bioaccessibility in crayfish may reduce dietary exposure to humans. Three possible mechanisms for the reduced MeHg DSR in crayfish tissue were examined: MeHg-Se interactions, MeHg subcellular fractionation, and Hg-amino acid binding. Selenium concentrations were comparable among the examined species, and no significant relationship was observed between tissue Se and MeHg DSR. Similarly, observed differences in subcellular fractionation of MeHg could not explain the species-specific MeHg DSR. Therefore, MeHg-Se interactions and MeHg subcellular fractionation do not explain the relatively low MeHg bioaccessibility in crayfish. Significantly higher cysteine and arginine content was found in crayfish than in the finfish. We suspect that the lower MeHg bioaccessibility of crayfish tail muscle may be attributed to the higher cysteine concentrations, and thus, stronger MeHg-protein binding in crayfish. These results support the interpretation that bioaccessibility differences will alter risk interpretations for MeHg, especially when comparing hazard across aquatic food types. PMID- 28641186 TI - Composition of dissolved organic matter (DOM) from periodically submerged soils in the Three Gorges Reservoir areas as determined by elemental and optical analysis, infrared spectroscopy, pyrolysis-GC-MS and thermally assisted hydrolysis and methylation. AB - Soil-derived dissolved organic matter (DOM) has a major influence in biogeochemical processes related to contaminant dynamics and greenhouse gas emissions, due to its reactivity and its bridging role between the soil and aquatic systems. Within the Three Gorges Reservoir (TGR, China) area, an extensive water-fluctuation zone periodically submerges the surrounding soils. Here we report a characterization study of soil-derived DOM across the TGR areas, using elemental and optical analysis, infrared spectroscopy (FTIR), pyrolysis-GC MS (Py-GC-MS) and thermally assisted hydrolysis and methylation (THM-GC-MS). The results showed that the soil DOM from the TGR area is a mixture of "allochthonous" (i.e., plant-derived/terrigenous) and "autochthonous" (i.e., microbial) origins. The terrigenous DOM is composed primarily of phenolic and aliphatic structures from lignin and aliphatic biopolymers (i.e. cutin, suberin), respectively. Multivariate statistics differentiated between two fractions of the microbial DOM, i.e. chitin-derived, perhaps from fungi and arthropods in soil, and protein-derived, partially sourced from algal or aquatic organisms. Molecular proxies of source and degradation state were in good agreement with optical parameters such as SUVA254, the fluorescence index (FI) and the humification index (HIX). The combined use of elemental analysis, fluorescence spectroscopy, and Py-GC-MS provides rigorous and detailed DOM characterization, whereas THM-GC MS is useful for more precise but qualitative identification of the different phenolic (cinnamyl, p-hydroxyphenyl, guaiacyl, syringyl and tannin-derived) and aliphatic materials. With the multi-methodological approach used in this study, FTIR was the least informative, in part, because of the interference of inorganic matter in the soil DOM samples. The soil DOM from the TGR's water fluctuation zone exhibited considerable compositional diversity, mainly related to the balance between DOM source (microbial- or plant-derived), local vegetation and anthropogenic activities (e.g., agriculture). Finally, the relationship between DOM composition and its potential reactivity with substances of environmental concerns in the TGR area are also discussed. PMID- 28641187 TI - Multi-criteria Decision Support System (DSS) for optimal locations of Soil Aquifer Treatment (SAT) facilities. AB - Managed Aquifer Recharge is a wide-spread well-established groundwater engineering method which is largely seen as sound and sustainable solution to water scarcity hydrologically sensitive areas, such as the Circum Mediterranean. The process of site selection for the installation of a MAR facility is of paramount importance for the feasibility and effectiveness of the project itself, especially when the facility will include the use of waters of impaired quality as a recharge source, as in the case of Soil-Aquifer-Treatment systems. The main objective of this study is to present the developed framework of a multi-criteria Decision Support System (DSS) that integrates within a dynamic platform the main groundwater engineering parameters associated with MAR applications together with the general geographical features which determine the effectiveness of such a project. The proposed system will provide an advanced coupled DSS-GIS tool capable of handling local MAR-related issues -such as hydrogeology, topography, soil, climate etc., and spatially distributed variables -such as societal, economic, administrative, legislative etc., with special reference to Soil Aquifer-Treatment technologies. PMID- 28641188 TI - Risk assessment of triclosan released from sewage treatment plants in European rivers using a combination of risk quotient methodology and Monte Carlo simulation. AB - Iotan this study a probabilistic risk assessment was applied to investigate the environmental risks for the European aquatic environment associated with triclosan (TCS) occurrence in treated wastewater. The concentrations of TCS in effluents of European Sewage Treatment Plants (STPs) were recorded through literature review, while toxicity data was collected for three groups of aquatic organisms (algae, Daphnia magna and fish). The ratio of Measured Environmental Concentration (MEC) and Predicted No Effect Concentration (PNEC), expressed as a Risk Quotient (RQ), was calculated for risk characterization, while Monte Carlo simulation was applied to quantify the associated uncertainty. TCS monitoring data was available for 349 STPs located in 15 out of the 50 European countries. Its mean concentrations in STPs effluents ranged between 2.2ngL-1 and 47,800ngL 1. Higher TCS concentrations were observed in primarily treated wastewater; whereas no differences among countries or among secondary and tertiary effluents on the basis of the whole set of collected data were found. The 95th percentile of RQ for TCS was higher than 1 (in algae) for rivers with dilution factors (DFs) equal to or lower than 100, when the maximum concentration values were used, whereas the 95th percentile of RQ exceeded 1 for rivers with DFs up to 10, in cases where the calculations were based on mean concentration values. The probability that RQ exceeds 1 in rivers (for algae) ranged from 0.2% (DF=1000) to 45% (DF=2), when calculations are based on mean concentration values. The corresponding probabilities in rivers with DFs equal to 2 for Daphnia magna and fish were 0.7% and 0.4%, respectively. We propose that TCS monitoring should be intensified, especially on smaller rivers, to verify the findings of this study for possible environmental risks. PMID- 28641189 TI - Qualitative and quantitative simulation of androgen receptor antagonists: A case study of polybrominated diphenyl ethers. AB - Recently, great attention has been paid to the identification and prediction of the androgen disrupting potencies of polybrominated diphenyl ethers (PBDEs). However, few existing models can discriminate active and inactive compounds, which make the quantitative prediction process including the quantitative structure-activity relationship (QSAR) technique unreliable. In this study, different grouping methods were investigated and compared for qualitative identification, including molecular docking and molecular dynamics simulations (MD). The results showed that qualitative identification based on MD, which is lab-independent, accurate and closer to the real transcriptional activation process, could separate 90.5% of active and inactive chemicals and was preferred. The 3D-QSAR models built as the quantitative simulation method showed r2 and q2 values of 0.513 and 0.980, respectively. Together, a novel workflow combining qualitative identification and quantitative simulations was generated with processes including activeness discrimination and activity prediction. This workflow, for analyzing the antagonism of androgen receptor (AR) of PBDEs is not only allowing researchers to reduce their intense laboratory experiments but also assisting them in inspecting and adjusting their laboratory systems and results. PMID- 28641190 TI - Synchronous mucinous adenocarcinoma of the recto sigmoid revealed by and seeding an anal fistula. (A case report and review of the literature). AB - INTRODUCTION: There are few cases of synchronous rectal adenocarcinoma revealed by an anal fistula. The diagnosis of synchronous mucinous adenocarcinoma of the recto sigmoid and anal canal remains difficult. The chronic anal fistula can be mistaken as the common manifestation of a benign perianal abscess or fistula. CASE PRESENTATION: We present a rare case of a Greek Caucasian 79year old male patient with anal fistula and a recurrent perianal abscess who subsequently was found to have developed synchronous rectosigmoid and perianal mucinous adenocarcinoma on biopsy. The histological exam revealed mucinous adenocarcinoma in two sites, representing two tumors, cells were immunopositive for cytokeratin 20 and negative in cytokeratin 7. The patient underwent "laparoscopic extralevator abdominoperineal excision " with both lesions being resected. There is no recurrence after four years of follow up. CONCLUSIONS: This case highlights the importance of high suspicion, further investigation and the need of biopsy in all anal fistulae. PMID- 28641191 TI - Early anastomotic stricture occurring after colectomy that responded well to Transanal decompression and local steroid therapy: A case report. AB - INTRODUCTION: Anastomotic strictures occurring after colectomy are a most challenging postoperative complication for gastroenterological surgeons. Reports documenting anastomotic strictures developing in the early postoperative phase are scant, and no established treatment is available. PRESENTATION OF CASE: A 78 year-old man who had undergone a laparoscopic left hemicolectomy for lower colon cancer presented on postoperative day 12 because of abdominal pain and no bowel movement. Endoluminal decompression was performed with a transanal decompression tube, and local steroid treatment was administered by concurrent intralesional steroid injection (ILe-SI) and intraluminal steroid instillation (ILu- SI). The anastomotic stricture promptly improved. The patient recovered uneventfully, with no recurrence of anastomotic stricture. DISCUSSION: A transanal decompression tube should be inserted and placed in a cautious manner within a short period of time. ILe-SI in the large intestine requires an understanding of potential adverse events and complications, as well as fully informed consent from the patient. ILu-SI has been reported to be an effective treatment for the management of strictures in various regions. To the best of our knowledge, however, this is the first report to document the treatment of an anastomotic stricture of the colorectum by ILu-SI. CONCLUSION: Transanal decompression therapy combined with local steroid local treatment might promptly improve anastomotic strictures occurring after colectomy. PMID- 28641192 TI - Obstructive neonatal atrial myxoma. AB - INTRODUCTION: Cardiac myxoma is a benign neoplasm representing the most common primary cardiac tumor in adults, however it is unusual in neonates. It is represented by an endocardial mass that occupies the cardiac chamber. Although the majority of myxomas are attached to the fossa ovalis of the interatrial septum, they also attach to the walls of the cardiac chambers and to valve leaflets surfaces. Approximately 75% of myxomas are found in the left atrium, 20% are located in the right atrium, and rarely in the ventricles. PRESENTATION OF CASE: We describe a rare case of neonatal cardiac myxoma arising from interatrial septum, causing significant mechanical obstruction to blood flow through tricuspid valve, in an otherwise normal newborn. The patient underwent successful excision of the myxoma with an uneventful recovery [1]. DISCUSSION: Cardiac tumors are rare in children, thus an understanding of the common types of benign and malignant paediatric cardiac tumors and their imaging features, is important because the epidemiology and tumor types differ from those encountered in adults. CONCLUSION: Large neonatal myxoma is exceptionally rare and even more infrequent is the surgical excision in the first day of life. PMID- 28641193 TI - Acute hemobilia from a pseudoaneurysm of the cystic artery arising from the left hepatic artery: Case report and literature review. AB - INTRODUCTION: Hemobilia represents only 6% of all causes of upper gastrointestinal bleeding. PRESENTATION OF CASE: We report a rare case of a bleeding pseudoaneurysm of the cystic artery, due to a re-activation of a chronic cholecystitis, which arose with a mixed symptomatology: jaundices and hematemesis. DISCUSSION: The rarity of our patient is increased for some vascular anatomic variations detected by Computed Tomography that influenced the management of the disease. Our patient was treated by endovascular embolization of the pseudoaneurysm and subsequent cholecystectomy. CONCLUSION: About pseudoaneurysm of the cystic artery only few cases have been already reported and to date there are no guidelines for its management. We describe both diagnostic features and therapeutic strategies in comparison to the most recent literature. PMID- 28641194 TI - Use of a long distally fixed intramedullary stem to treat a periprosthetic femoral fracture following total hip arthroplasty using a thrust plate hip prosthesis: A case report. AB - INTRODUCTION: The thrust plate hip prosthesis (TPP; Zimmer, Winterthur, Switzerland) is a hip prosthesis that is no longer in production. Few reports have focused on periprosthetic fractures following total hip arthroplasty (THA) with the use of a TPP. PRESENTATION OF CASE: We report a 57-year-old woman with a periprosthetic femoral fracture 13 years after THA with the use of a TPP. A plain radiograph showed a displaced subtrochanteric fracture of the right femur just below the distal tip of the lateral plate without implant loosening. She underwent revision surgery with a long distally fixed intramedullary stem in conjunction with a plate and cable system. Three months after surgery, bone union was confirmed using radiography and the patient was clinically asymptomatic. DISCUSSION: We encountered three major problems while planning surgical treatment, these being, discontinuation of the TPP system, loss of proximal femoral cancellous bone, and difficulties with the type of subtrochanteric fracture. After considering these problems, we planned revision surgery using a long distally fixed intramedullary stem in conjunction with a plate and cable system. CONCLUSION: This case shows that sufficient implant preparation based on precise preoperative planning is necessary to obtain good clinical results for the surgical treatment of periprosthetic femoral fractures following THA with the use of a TPP. PMID- 28641195 TI - Biotransformation in the zebrafish embryo -temporal gene transcription changes of cytochrome P450 enzymes and internal exposure dynamics of the AhR binding xenobiotic benz[a]anthracene. AB - Not much is known about the biotransformation capability of zebrafish (Danio rerio) embryos. For understanding possible toxicity differences to adult fish, it might be crucial to understand the biotransformation of chemicals in zebrafish embryos i.e. as part of toxicokinetics. The biotransformation capabilities were analysed for two different stages of zebrafish embryos in conjunction with the internal concentrations of a xenobiotic. Zebrafish embryos of the late cleavage/early blastula period (2-26 hpf) and the early pharyngula period (26-50 hpf) were exposed for 24 h to the AhR binding compound benz[a]anthracene (BaA). Time dependent changes in cyp transcription (cyp1a, cyp1b1, cyp1c1 and cyp1c2) as well as concentration & time-dependent courses of BaA in the fish embryo and the exposure medium were analysed. Additionally, the CYP mediated formation of biotransformation products was investigated. We found correlations between transcriptional responses and the internal concentration for both exposure types. These correlations were depending on the start of the exposure i.e. the age of the exposed embryo. While no significant induction of the examined gene transcripts was observed in the first 12 h of exposure beginning in the blastula period a correlation was apparent when exposure started later i.e. in the pharyngula period. A significant induction of cyp1a was detected already after 1.5 h of BaA exposure. Gene transcripts for cyp1b1, cyp1c1 and cyp1c2 showed expressions distinctly different from cyp1a and were, in general, less inducible by BaA in both exposure windows. The toxicokinetic analysis showed that the biotransformation capability was fivefold higher in the older fish embryos. Biotransformation products of phase I reactions were found between 32 hpf and 50 hpf and were tentatively identified as benz[a]anthracene-phenol and benz[a]anthracene-dihydrodiol-epoxide. In conclusion, not only duration but also onset of exposure in relation to the developmental stage of zebrafish embryos is important in the analysis and interpretation of effects due to different biotransformation capabilities. PMID- 28641196 TI - C1-C2 alkyl aminiums in urban aerosols: Insights from ambient and fuel combustion emission measurements in the Yangtze River Delta region of China. AB - We measured low molar-mass alkyl aminiums (methylaminium, dimethylaminium, ethylaminium and diethylaminium) in urban aerosols in the Yangtze River Delta region of eastern China in August 2014 and from November 2015 to May 2016. After examining artifact formation on sample filters, methylaminium, dimethylaminium and ethylaminium concentrations were quantified. The three C1-C2 aminiums exhibited a unimodal size distribution that maximized between 0.56 and 1.0 MUm. Their concentrations in PM2.5 were 5.7 +/- 3.2 ng m-3, 7.9 +/- 5.4 ng m-3 and 20.3 +/- 16.6 ng m-3, respectively, with higher concentrations during the daytime and in warm seasons. On new particle growth days, amine uptake to particles larger than 56 nm was barely enhanced. The molar ratios of individual aminium/NH4+ in PM2.5 were on the order of 10-4 and 10-3. Aminiums were thus far less to out-compete ammonium (NH4+) in neutralizing acidic species in particle sizes down to 56 nm. Abundant nitrate (NO3-/SO42- molar ratio = ~3) and its correlation to methylaminium and ethylaminium implied that nitrate might be more important aminium salt than sulfate in urban aerosols of this area. Direct measurement of particle-phase amine emission from coal and biomass burning showed that coal burning is an important atmospheric amine source, considering coal burning is top-ranked particulate matter source in China. PMID- 28641197 TI - Effects of organophosphorus flame retardant TDCPP on normal human corneal epithelial cells: Implications for human health. AB - Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is one of the most detected organophosphorus flame retardants (OPFRs) in the environment, especially in indoor dust. Continuous daily exposure to TDCPP-containing dust may adversely impact human cornea. However, its detrimental effects on human corneal epithelium are largely unknown. In this study, we investigated the cell apoptosis in normal human corneal epithelial cells (HCECs) after TDCPP exposure and elucidated the underlying molecular mechanisms. Our data indicated a dose-dependent decrease of cell viability after TDCPP exposure with LC50 at 202 MUg/mL. A concentration dependent apoptotic sign was observed in HCECs after exposing to >=2 MUg/mL TDCPP. Endoplasmic reticulum stress induction was evidenced by up-regulation of its biomarker genes (ATF-4, CHOP, BiP, and XBP1). Furthermore, alternation of Bcl 2/Bax expression, mitochondrial membrane potential loss, cellular ATP content decrease, and caspase-3 and -9 activity increase were observed after exposing to 2 or 20 MUg/mL TDCPP. Taken together, the data implicated the involvement of endoplasmic reticulum stress in TDCPP-induced HCEC apoptosis, probably mediated by mitochondrial apoptotic pathway. Our findings showed TDCPP exposure induced toxicity to human cornea. Due to TDCPP's presence at high levels in indoor dust, further study is warranted to evaluate its health risk on human corneas. PMID- 28641198 TI - Combined computational-experimental approach to predict blood-brain barrier (BBB) permeation based on "green" salting-out thin layer chromatography supported by simple molecular descriptors. AB - The objective of this paper is to build QSRR/QSAR model for predicting the blood brain barrier (BBB) permeability. The obtained models are based on salting-out thin layer chromatography (SOTLC) constants and calculated molecular descriptors. Among chromatographic methods SOTLC was chosen, since the mobile phases are free of organic solvent. As consequences, there are less toxic, and have lower environmental impact compared to classical reserved phases liquid chromatography (RPLC). During the study three stationary phase silica gel, cellulose plates and neutral aluminum oxide were examined. The model set of solutes presents a wide range of log BB values, containing compounds which cross the BBB readily and molecules poorly distributed to the brain including drugs acting on the nervous system as well as peripheral acting drugs. Additionally, the comparison of three regression models: multiple linear regression (MLR), partial least-squares (PLS) and orthogonal partial least squares (OPLS) were performed. The designed QSRR/QSAR models could be useful to predict BBB of systematically synthesized newly compounds in the drug development pipeline and are attractive alternatives of time-consuming and demanding directed methods for log BB measurement. The study also shown that among several regression techniques, significant differences can be obtained in models performance, measured by R2 and Q2, hence it is strongly suggested to evaluate all available options as MLR, PLS and OPLS. PMID- 28641199 TI - Influence of weight bearing visual feedback on movement symmetry during sit to stand task. AB - BACKGROUND: Weight-bearing asymmetry is common in individuals with hip osteoarthritis and after total hip arthroplasty. Including symmetry training to the rehabilitation programs may normalize movement strategies during dynamic tasks. The purpose of this study was to evaluate the immediate influences of real time visual feedback of weight distribution on the interlimb movement symmetry during the sit-to-stand task, before and after total hip arthroplasty, and to determine whether physical impairments affect the response to visual feedback. METHODS: Subjects before and after total hip arthroplasty participated in three- dimensional motion analysis. Subjects completed 3 trials of sit-to-stand task in two conditions; "without visual feedback" and "with visual feedback". Outcome measures were the interlimb symmetry of vertical ground reaction force, and joint kinematics and kinetics. Pain and strength of lower limbs were assessed. FINDINGS: Compared to "without visual feedback" condition, subjects moved with greater symmetry of vertical ground reaction force and joint kinetics when visual feedback was received. However, subjects continued to demonstrate interlimb difference for joint kinetics and vertical ground reaction force in the visual feedback condition. The increase in symmetry was not strongly influenced by physical impairments and subjects before and after total hip arthroplasty responded similarly to the feedback. INTERPRETATIONS: We concluded that in a single session, the visual feedback of weight bearing distribution had a positive immediate effect on movement symmetry during the sit-to-stand task. Future studies that assess long-term retention and functional benefits are warranted before visual feedback is incorporated in rehabilitation for this patient population. PMID- 28641200 TI - Severe hepatitis under combined immunotherapy: Resolution under corticosteroids plus anti-thymocyte immunoglobulins. PMID- 28641201 TI - Pelvic and hip kinematics during single-leg drop-landing are altered in sports participants with long-standing groin pain: A cross-sectional study. AB - OBJECTIVES: The aim of this study was to determine the differences in three dimensional pelvic and hip kinematics during a single-leg drop-landing task in active sports participants with long-standing groin pain compared to healthy matched controls. DESIGN: This was a descriptive study incorporating a cross sectional design. SETTING: The study was conducted at the Unit for Human Movement Analysis, Stellenbosch University, South Africa. PARTICIPANTS: The study sample was comprised of 20 male club level soccer, rugby, running and cycling participants between the ages of 18 and 55 years. Ten cases with long-standing groin pain and ten asymptomatic matched controls participated. MAIN OUTCOME MEASURES: Three-dimensional pelvic and hip kinematics were captured with an optical motion capture system during a single-leg drop-landing task. RESULTS: Participants with groin pain landed with more downward lateral pelvic tilt (0.77 degrees , p = 0.01, r = 0.35), hip abduction (2.05 degrees , p < 0.001. r = 0.49), and hip external rotation (0.86 degrees , p = 0.03, r = 0.29) at initial contact and more pelvic internal rotation (1.06 degrees , p = 0.02, r = 0.30) at lowest vertical position than the healthy controls. CONCLUSIONS: Sports participants with long-standing groin pain have altered pelvic and hip kinematics during single-leg drop-landing compared to healthy controls. The kinematic differences may contribute towards the persistent nature of groin pain, although these strategies may also be present as a result of the presence or the expectation of pain. PMID- 28641202 TI - Pathological narcissism and maladaptive self-regulatory behaviours in a nationally representative sample of Canadian men. AB - Clinical observation has linked externalizing coping strategies such as substance overuse and aggressive behaviours with narcissistic personality dysfunction. This study examined the relationship between pathological narcissism and maladaptive self-regulatory behaviours among Canadian men. An online survey was distributed among a stratified, nationally representative sample of 1000 men from across Canada. The survey included brief self-report measures of pathological narcissism, maladaptive externalizing coping behaviours, and general psychological distress. After controlling for the effects of age and general psychological distress, pathological narcissism was found to be significantly associated with alcohol overuse and aggressive behaviour. Significant though modest interaction effects were found between pathological narcissism and age - with regards to drug use - and distress - with regards to risk-taking behaviour. The findings point to the need for attention to narcissistic dysfunction as a clinical and public health issue among men. PMID- 28641203 TI - Current trends in electrochemical sensing and biosensing of DNA methylation. AB - DNA methylation plays an important role in physiological and pathological processes. Several genetic diseases and most malignancies tend to be associated with aberrant DNA methylation. Among other analytical methods, electrochemical approaches have been successfully employed for characterisation of DNA methylation patterns that are essential for the diagnosis and treatment of particular diseases. This article discusses current trends in the electrochemical sensing and biosensing of DNA methylation. Particularly, it provides an overview of applied electrode materials, electrode modifications and biorecognition elements applications with an emphasis on strategies that form the core DNA methylation detection approaches. The three main strategies as (i) bisulfite treatment, (ii) cleavage by restriction endonucleases, and (iii) immuno/affinity reaction were described in greater detail. Additionally, the availability of the reviewed platforms for early cancer diagnosis and the approval of methylation inhibitors for anticancer therapy were discussed. PMID- 28641204 TI - Towards dosimetry for photodynamic diagnosis with the low-level dose of photosensitizer. AB - BACKGROUND: Contemporary medicine does not concern the issue of dosimetry in photodynamic diagnosis (PDD) but follows the photosensitizer (PS) producers recommendation. Most preclinical and clinical PDD studies indicate a considerable variation in the possibility of visualization and treatment, as e.g. in case of cervix lesions. Although some of these variations can be caused by the different histological subtypes or various tumor geometries, the issue of varying PS concentration in the tumor tissue volume is definitely an important factor. Therefore, there is a need to establish the objective and systematic PDD dosimetry protocol regarding doses of light and photosensitizers. METHODS: Four different irradiation sources investigated in PDD (literature) were used for PS excitation. The PS luminescence was examined by means of the non-imaging (spectroscopic) and imaging (wide- and narrow-field of view) techniques. The methodology for low-level intensity photoluminescence (PL) characterization and dedicated image processing algorithm for PS luminescence images analysis were proposed. Further, HeLa cells' cultures penetration by PS was studied by a confocal microscopy. RESULTS: Reducing the PS dose with the choice of proper photoexcitation conditions decreases the PDD procedure costs and the side effects, not affecting the diagnostic efficiency. We determined in vitro the minimum incubation time and photosensitizer concentration of Photolon for diagnostic purposes, for which the Photolon PL can still be observed. It was demonstrated that quantification of PS concentration, choice of proper photoexcitation source, appropriate adjustment of light dose and PS penetration of cancer cells may improve the low-level luminescence photodynamic diagnostics performance. CONCLUSIONS: Practical effectiveness of the PDD strongly depends on irradiation source parameters (bandwidth, maximum intensity, half-width) and their optimization is the main conditioning factor for low-level intensity and low-cost PDD. PMID- 28641205 TI - Muscilage characterization, biochemical and enzymatic activities of laser irradiated Lagenaria siceraria seedlings. AB - Laser stimulation effect on L. siceraria seed mucilage, biochemicals and enzymatic activities during early growth stages were investigated. The laser density power of 1mW/cm2 for 3 and 5min treatments were performed and various responses i.e., seedlings mucilage, biochemical and enzymatic activities were studied. Laser treatment of L. siceraria seeds enhanced the biochemical as well as the enzymatic activities. TPC (total phenolic contents),TFC (total flavonoids contents), TSS (total soluble sugar), reducing sugar, proline contents, total soluble protein and nitrogen contents were recorded higher in laser treated groups versus control. Mucilage from L. siceraria seed coat was also characterized. The pre-sowing seeds were treated with laser radiation for 3 and 5min. TPC, TFC, proline contents, total soluble protein and nitrogenous compounds contents, ascorbic acid contents were recorded higher at 3min. The laser irradiation effect on TSS, hydrogen peroxide (H2O2), malondialdehyde (MDA) was insignificant versus control. The SOD (superoxide dismutase) and POD (peroxidase), AMY (amylase), CAT (catalase) activities were recorded higher for 5min laser treatment. Results revealed that He-Ne continuous wave-laser pre sowing seed irradiation affected the seed coat mucilage, biochemical and enzymatic activities positively and this treatment could possibly be used to enhance the L. siceraria productivity. Future study will be focused on growth at later stages and yield characteristics of L. siceraria. PMID- 28641206 TI - Efficacy of surgical laser therapy in the management of oral pigmented lesions: A systematic review. AB - BACKGROUND: Oral pigmentation, especially in the gingiva poses esthetic problems. Laser therapy has been widely used for cosmetic therapy in dentistry. The aim of the present study was to systematically review the efficacy of surgical laser therapy (SLT) in the management of oral pigmented lesions (OPL). MATERIALS AND METHODS: The addressed focused question was "Is SLT effective in the management of OPL?" Databases (MEDLINE via PubMed; EMBASE; Cochrane Central Register of Controlled Trials and Cochrane Oral Health Group Trials Register databases) were searched from 1970 up to and including February 2017. RESULTS: Ten studies were included. The reported number of OPL ranged between 8 and 140. Oral pigmented sites included, gingiva, buccal and labial mucosa, alveolar mucosa and lips. Lasers used in the studies included Q-switched alexandrite, Neodymium-doped yttrium aluminium garnet, diode, Erbium: yttrium aluminium garnet and carbon dioxide laser. Laser wavelength, power output and number of irradiations were 635 10,600nm, 1-10W and 1 to 9 times, respectively. The follow up period ranged from 6 to 24months. All studies reported SLT to be effective in the treatment of OPL. In five studies, recurrence of OPL occurred which ranged from 21.4% to 45%. CONCLUSIONS: Lasers are effective in the management of OPL including physiologic gingival pigmentation, smokers' melanosis and pigmentation in Laugier-Hunziker syndrome. Different laser types (CO2, Er:YAG and Diode) showed comparable outcomes in the treatment of OPL. PMID- 28641207 TI - ROS and calcium signaling mediated pathways involved in stress responses of the marine microalgae Dunaliella salina to enhanced UV-B radiation. AB - UV-B ray has been addressed to trigger common metabolic responses on marine microalgae, however, the upstream events responsible for these changes in marine microalgae are poorly understood. In the present study, a species of marine green microalgae Dunaliella salina was exposed to a series of enhanced UV-B radiation ranging from 0.25 to 1.00 KJ.m-2 per day. The role of ROS and calcium signaling in the D. salina responses to UV-B was discussed. Results showed that enhanced UV B radiation markedly decreased the cell density in a dose-dependent manner, but the contents of protein and glycerol that were essential for cell growth increased. It suggested that it was cell division instead of cell growth that UV B exerted negative effects on. The subcellular damages on nuclei and plasmalemma further evidenced the hypothesis. The nutrient absorption was affected with UV-B exposure, and the inhibition on PO43- uptake was more serious compared to NO3- uptake. UV-B radiation promoted reactive oxygen species (ROS) formation and thiobarbituric acid reactive substances (TBARS) contents, decreased the redox status and altered the antioxidant enzyme activities. The addition of the ROS scavenger and the glutathione biosynthesis precursor N-acetyl-l-cysteine (NAC) alleviated the stress degree, implying ROS-mediated pathway was involved in the stress response to UV-B radiation. Transient increase in Ca2+-ATPase was triggered simultaneously with UV-B exposure. Meanwhile, the addition of an intracellular free calcium chelator aggravated the damage of cell division, but exogenous calcium and ion channel blocker applications did not, inferring that endogenously initiated calcium signaling played roles in response to UV-B. Cross talk analysis showed a relatively clear relationship between ROS inhibition and Ca2+-ATPase suppression, and a relation between Ca2+ inhibition and GPx activity change was also observed. It was thus presumed that ROS-coupled calcium signaling via the glutathione cycle was involved in the response of marine microalgae to UV B stimuli. PMID- 28641208 TI - An associative account of the development of word learning. AB - Word learning is a notoriously difficult induction problem because meaning is underdetermined by positive examples. How do children solve this problem? Some have argued that word learning is achieved by means of inference: young word learners rely on a number of assumptions that reduce the overall hypothesis space by favoring some meanings over others. However, these approaches have difficulty explaining how words are learned from conversations or text, without pointing or explicit instruction. In this research, we propose an associative mechanism that can account for such learning. In a series of experiments, 4-year-olds and adults were presented with sets of words that included a single nonsense word (e.g. dax). Some lists were taxonomic (i.,e., all items were members of a given category), some were associative (i.e., all items were associates of a given category, but not members), and some were mixed. Participants were asked to indicate whether the nonsense word was an animal or an artifact. Adults exhibited evidence of learning when lists consisted of either associatively or taxonomically related items. In contrast, children exhibited evidence of word learning only when lists consisted of associatively related items. These results present challenges to several extant models of word learning, and a new model based on the distinction between syntagmatic and paradigmatic associations is proposed. PMID- 28641209 TI - Adsorption of NO2 molecules on armchair phosphorene nanosheet for nano sensor applications - A first-principles study. AB - The electronic and NO2 adsorption properties of hydrogenated armchair phosphorene nanosheet device is investigated through density functional theory (DFT) and non equilibrium Green's function method (NEGF). The armchair phosphorene nanosheet is used for the detection of NO2 gas in phosphorene molecular device. The DOS spectrum demonstrates the change in peak maxima due to transfer of electrons between NO2 gas and phosphorene base material. The change in the peak amplitude is observed along the valance band as well as in the conduction band in the transmission spectrum of phosphorene device. I-V characteristics support the change in the current upon adsorption of NO2 gas molecule on phosphorene molecular device. Using formation energy, structural stability of phosphorene nanosheet has been studied. The adsorption properties of NO2 on phosphorene nanosheet have also been investigated with the help of adsorption energy, Mulliken charge and Bader charge analysis. In order to ascertain the selectivity of NO2 gas along phosphorene molecular device in the ambient condition, the adsorption behavior of O2 and CO2 is also studied. The findings of the present work confirm that phosphorene molecular device can be used as a NO2 gas sensor and also the influence of Al substitution in phosphorene nanosheet device is explored and reported. PMID- 28641210 TI - Comparative analysis of polyspecificity of the endogenous tRNA synthetase of different expression host towards photocrosslinking amino acids using an in silico approach. AB - Photo-induced covalent crosslinking has emerged as the powerful strategy for analyzing and characterizing the protein-protein interaction and mapping protein 3D conformations. In the last decades, a number of photocrosslinking amino acids have been reported but only a few have been efficiently utilized for photocrosslinking purposes. Recently, incorporation of diazirine containing photoactivatable analogs such as photo-methionine, photo-leucine, photo isoleucine and photo-lysine into target proteins were accomplished in live cells (Human A549cells, HEK 293) by depleting corresponding natural amino acid and supplementing these analogs in the medium. Likewise, incorporation of photo methionine and photo-leucine is also reported in E. coli. Incorporation of these unnatural amino acids were demonstrated only in a limited number species, thereby conventional methods have been utilized for the protein-protein interaction study in other species. With this in mind, we studied in silico analysis of polyspecificity of four endogenous tRNA synthetases (LeuRS, IleRS, MetRS, and LysRS) from six different species such as Escherichia coli, Pseudomonas fluorescens, Corynebacterium glutamicum, Saccharomyces cerevisiae, Aspergillus oryzae and Homo sapiens towards its photocrosslinking amino acids. In addition, here we describe the active site similarity of different protein bio-factories. Based on the active site similarity and similar binding mode, we predicted that the endogenous tRNA synthetases of all the species are reactive to corresponding photoactivatable analogs. This is the first in silico study to demonstrate that the photocrosslinking unnatural amino acids are recognized by the endogenous tRNA synthetases of different protein expression biofactories. PMID- 28641211 TI - Specific interactions between androgen receptor and its ligand: ab initio molecular orbital calculations in water. AB - The Androgen Receptor (AR) is a family of nuclear receptor proteins and a ligand activated transcription factor. Since its abnormal activation can cause the progression of prostate cancer, numerous types of antagonists against AR have been developed as promising agents for treating prostate cancers. We here investigated the specific interactions between AR and several types of non steroid agents at an electronic level, using ab initio molecular simulations based on molecular mechanics and ab initio fragment molecular orbital (FMO) methods From the results obtained by FMO, we proposed novel agents as potent ligands against AR and investigated the binding properties between AR and these agents to confirm that some of them can bind more strongly with AR than the existing non-steroid agents and can be strongly effective ligands against AR. PMID- 28641212 TI - Association of gene polymorphisms of four components of renin-angiotensin aldosterone system and preeclampsia in South African black women. AB - OBJECTIVE: To investigate the association of the gene polymorphisms of: angiotensinogen (AGT), renin (REN), angiotensin II receptor 1 (AT1R) and angiotensin II receptor 2 (AT2R), in the pathogenesis of PE in South African Black women. METHODOLOGY (STUDY DESIGN): 603 pregnant women; 246 normotensive and 357 with PE (early-onset=187, late-onset=170), were recruited. Each study group was subdivided into HIV infected and uninfected groups. The distribution and frequencies of gene polymorphisms of AGT (M235T), REN (C-5312T), AT1R (A1166C) and AT2R (C3123A) were determined in purified DNA by Real Time Polymerase Chain Reaction. RESULTS: The distribution of T allele and TT genotype of AGT in PE were significantly higher than the normotensive group (95% vs 91%, OR 1.9, 95%CI 1.2 3.1, p=0.0051; 90% vs 83%, OR 1.84, 95%CI 1.11-3.05, p=0.01) respectively. The distributions of genotypes of REN, AT1R and AT2R were similar in PE and normotensive groups. CONCLUSION: The T allele of AGT may play a role in the pathogenesis of PE. The genotypes of REN, AT1R and AT2R were not associated with the development of PE. PMID- 28641213 TI - Measurement properties of screening and diagnostic tools for autism spectrum adults of mean normal intelligence: A systematic review. AB - BACKGROUND: The autism spectrum (AS) is a multifaceted neurodevelopmental variant associated with lifelong challenges. Despite the relevant importance of identifying AS in adults for epidemiological, public health, and quality of life issues, the measurement properties of the tools currently used to screen and diagnose adults without intellectual disabilities (ID) have not been assessed. OBJECTIVES: This systematic review addresses the accuracy, reliability, and validity of the reported AS screening and diagnostic tools used in adults without ID. METHODS: Electronic databases and bibliographies were searched, and identified papers evaluated against inclusion criteria. The PRISMA statement was used for reporting the review. We evaluated the quality of the papers using the COSMIN Checklist for psychometric data, and QUADAS-2 for diagnostic data. For the COSMIN assessment, evidence was considered to be strong when several methodologically good articles, or one excellent article, reported consistent evidence for or against a measurement property. For the QUADAS ratings, evidence was considered to be "satisfactory" if at least one study was rated with a low risk of bias and low concern about applicability. RESULTS: We included 38 articles comprising 32 studies, five reviews, and one book chapter and assessed nine tools (three diagnostic and six screening, including eight of their short versions). Among screening tools, only AQ-50, AQ-S, and RAADS-R and RAADS-14 were found to provide satisfactory or intermediate values for their psychometric properties, supported by strong or moderate evidence. Nevertheless, risks of bias and concerns on the applicability of these tools limit the evidence on their diagnostic properties. We found that none of the gold standard diagnostic tools used for children had satisfactory measurement properties. CONCLUSION: There is limited evidence for the measurement properties of the screening and diagnostic tools used for AS adults with a mean normal range of measured intelligence. This may lessen the validity of conclusions and public health decisions on an important fraction of the adult autistic population. This not only justifies further validation studies of screening and diagnostic tools for autistic adults, but also supports the parallel use of self-reported information and clinical expertise with these instruments during the diagnostic process. PMID- 28641215 TI - Worry and cognitive control predict course trajectories of anxiety in older adults with late-life depression. AB - BACKGROUND: Many older adults with depressive disorder manifest anxious distress. This longitudinal study examines the predictive value of worry as a maladaptive cognitive emotion regulation strategy, and resources necessary for successful emotion regulation (i.e., cognitive control and resting heart rate variability [HRV]) for the course of anxiety symptoms in depressed older adults. Moreover, it examines whether these emotion regulation variables moderate the impact of negative life events on severity of anxiety symptoms. METHODS: Data of 378 depressed older adults (CIDI) between 60 and 93 years (of whom 144 [41%] had a comorbid anxiety disorder) from the Netherlands Study of Depression in Older Adults (NESDO) were used. Latent Growth Mixture Modeling was used to identify different course trajectories of six-months BAI scores. Univariable and multivariable longitudinal associations of worry, cognitive control and HRV with symptom course trajectories were assessed. RESULTS: We identified a course trajectory with low and improving symptoms (57.9%), a course trajectory with moderate and persistent symptoms (33.5%), and a course trajectory with severe and persistent anxiety symptoms (8.6%). Higher levels of worry and lower levels of cognitive control predicted persistent and severe levels of anxiety symptoms independent of presence of anxiety disorder. However, worry, cognitive control and HRV did not moderate the impact of negative life events on anxiety severity. CONCLUSIONS: Worry may be an important and malleable risk factor for persistence of anxiety symptoms in depressed older adults. Given the high prevalence of anxious depression in older adults, modifying worry may constitute a viable venue for alleviating anxiety levels. PMID- 28641216 TI - Psychoeducational groups for adults with ADHD and their significant others (PEGASUS): A pragmatic multicenter and randomized controlled trial. AB - OBJECTIVE: To examine the feasibility, efficacy, and effectiveness of PEGASUS, a group-based structured psychoeducation for adults with ADHD and their significant others. METHOD: A pragmatic parallel group add-on design multicenter randomized controlled trial was conducted, comparing an 8-session treatment with PEGASUS (allocated n=97; 48 with ADHD and 49 with significant others) to treatment as usual (TAU, allocated n=82; 39 with ADHD and 43 significant others). Participants (individuals with ADHD and significant others) were recruited from five psychiatric outpatient departments and block randomized to PEGASUS or TAU. Knowledge about ADHD was measured using the ADHD 20 scale pre- and post intervention and served as primary outcome. RESULTS: Knowledge about ADHD (d=0.97 [95% CI: 0.61-1.31]) increased following PEGASUS participation compared to TAU. Improvements were also observed in secondary outcomes e.g. global life satisfaction (d=0.25 [95% CI: from -0.09 to 0.59]). Overall treatment satisfaction was good. Over 90% of the participants completed the program. Post intervention data was obtained from n=89 in PEGASUS group and n=70 in TAU group and analyses were conducted per protocol. No important adverse effects or side effects were observed. CONCLUSIONS: Group-based structured psychoeducation PEGASUS for adults with ADHD and their significant others is a feasible, efficacious, and effective treatment option to increase ADHD knowledge and general life satisfaction in psychiatric outpatient care. PMID- 28641214 TI - Motor system dysfunction in the schizophrenia diathesis: Neural systems to neurotransmitters. AB - Motor control is a ubiquitous aspect of human function, and from its earliest origins, abnormal motor control has been proposed as being central to schizophrenia. The neurobiological architecture of the motor system is well understood in primates and involves cortical and sub-cortical components including the primary motor cortex, supplementary motor area, dorsal anterior cingulate cortex, the prefrontal cortex, the basal ganglia, and cerebellum. Notably all of these regions are associated in some manner to the pathophysiology of schizophrenia. At the molecular scale, both dopamine and gamma-Aminobutyric Acid (GABA) abnormalities have been associated with working memory dysfunction, but particularly relating to the basal ganglia and the prefrontal cortex respectively. As evidence from multiple scales (behavioral, regional and molecular) converges, here we provide a synthesis of the bio-behavioral relevance of motor dysfunction in schizophrenia, and its consistency across scales. We believe that the selective compendium we provide can supplement calls arguing for renewed interest in studying the motor system in schizophrenia. We believe that in addition to being a highly relevant target for the study of schizophrenia related pathways in the brain, such focus provides tractable behavioral probes for in vivo imaging studies in the illness. Our assessment is that the motor system is a highly valuable research domain for the study of schizophrenia. PMID- 28641218 TI - On the overlap of vital exhaustion and depression. PMID- 28641217 TI - The aggressor at the mirror: Psychiatric correlates of deliberate self-harm in male prison inmates. AB - BACKGROUND: Deliberate self-harm (DSH) causes important concern in prison inmates as it worsens morbidity and increases the risk for suicide. The aim of the present study is to investigate the prevalence and correlates of DSH in a large sample of male prisoners. METHODS: A cross-sectional study evaluated male prisoners aged 18+ years. Current and lifetime psychiatric diagnoses were assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders - DSM-IV Axis I and Axis II Disorders and with the Addiction Severity Index-Expanded Version. DSH was assessed with The Deliberate Self-Harm Inventory. Multivariable logistic regression models were used to identify independent correlates of lifetime DSH. RESULTS: Ninety-three of 526 inmates (17.7%) reported at least 1 lifetime DSH behavior, and 58/93 (62.4%) of those reported a DSH act while in prison. After multivariable adjustment (sensitivity 41.9%, specificity 96.1%, area under the curve=0.854, 95% confidence interval CI=0.811-0.897, P<0.001), DSH was significantly associated with lifetime psychotic disorders (adjusted Odds Ratio aOR=6.227, 95% CI=2.183-17.762, P=0.001), borderline personality disorder (aOR=6.004, 95% CI=3.305-10.907, P<0.001), affective disorders (aOR=2.856, 95% CI=1.350-6.039, P=0.006) and misuse of multiple substances (aOR=2.024, 95% CI=1.111-3.687, P=0.021). CONCLUSIONS: Borderline personality disorder and misuse of multiple substances are established risk factors of DSH, but psychotic and affective disorders were also associated with DSH in male prison inmates. This points to possible DSH-related clinical sub groups, that bear specific treatment needs. PMID- 28641220 TI - Predicting semantic features in Chinese: Evidence from ERPs. AB - This article reports two ERP studies that exploited the classifier system of Mandarin Chinese to investigate semantic prediction. In Mandarin, in certain contexts, a noun has to be preceded by a classifier, which has to match the noun in semantically-defined features. In both experiments, an N400 effect was elicited in response to a classifier that mismatched an up-coming predictable noun, relative to a matching classifier. Among the mismatching classifiers, the N400 effect was graded, being smaller for classifiers that were semantically related to the predicted word, relative to classifiers that were semantically unrelated to the predicted word. Given that the classifier occurred before the predicted word, this result shows that fine-grained semantic features of nouns can be pre-activated in advance of bottom-up input. The studies thus extend previous findings based on a more restricted range of highly grammaticalized features such as gender or animacy in Indo-European languages (Szewczyk & Schriefers, 2013; Van Berkum, Brown, Zwitserlood, Kooijman, & Hagoort, 2005; Wicha, Bates, Moreno, & Kutas, 2003). PMID- 28641221 TI - A 'curse of knowledge' in the absence of knowledge? People misattribute fluency when judging how common knowledge is among their peers. AB - Knowledge can be a curse: Once we have acquired a particular item of knowledge it tends to bias, or contaminate, our ability to reason about a less informed perspective (referred to as the 'curse of knowledge' or 'hindsight bias'). The mechanisms underlying the curse of knowledge bias are a matter of great import and debate. We highlight two mechanisms that have been proposed to underlie this bias-inhibition and fluency misattribution. Explanations that involve inhibition argue that people have difficulty fully inhibiting or suppressing the content of their knowledge when trying to reason about a less informed perspective. Explanations that involve fluency misattribution focus on the feelings of fluency with which the information comes to mind and the tendency to misattribute the subjective feelings of fluency associated with familiar items to the objective ease or foreseeability of that information. Three experiments with a total of 359 undergraduate students provide the first evidence that fluency misattribution processes are sufficient to induce the curse of knowledge bias. These results add to the literature on the many manifestations of the curse of knowledge bias and the many types of source misattributions, by revealing their role in people's judgements of how common, or widespread, one's knowledge is. The implications of these results for cognitive science and social cognition are discussed. PMID- 28641219 TI - Comparison of brand versus generic antiepileptic drug adverse event reporting rates in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). AB - OBJECTIVE: Despite the cost saving role of generic anti-epileptic drugs (AEDs), debate exists as to whether generic substitution of branded AEDs may lead to therapeutic failure and increased toxicity. This study compared adverse event (AE) reporting rates for brand vs. authorized generic (AG) vs. generic AEDs. Since AGs are pharmaceutically identical to brand but perceived as generics, the generic vs. AG comparison minimized potential bias against generics. METHODS: Events reported to the U.S. Food and Drug Administration Adverse Event Reporting System between January 2004 to March 2015 with lamotrigine, carbamazepine, and oxcarbazepine listed as primary or secondary suspect were classified as brand, generic, or AG based on the manufacturer. Disproportionality analyses using the reporting odds ratio (ROR) assessed the relative rate of reporting of labeled AEs compared to reporting these events with all other drugs. The Breslow-Day statistic compared RORs across brand, AG, and other generics using a Bonferroni corrected P<0.01. RESULTS: A total of 27,150 events with lamotrigine, 13,950 events with carbamazepine, and 5077 events with oxcarbazepine were reported, with generics accounting for 27%, 41%, and 32% of reports, respectively. Although RORs for the majority of known AEs were different between brand and generics for all three drugs of interest (Breslow-Day P<0.001), RORs generally were similar for AG and generic comparisons. Generic lamotrigine and carbamazepine were more commonly involved in reports of suicide or suicidal ideation compared with the respective AGs based on a multiple comparison-adjusted P<0.01. SIGNIFICANCE: Similar AED reporting rates were observed for the AG and generic comparisons for most outcomes and drugs, suggesting that brands and generics have similar reporting rates after accounting for generic perception biases. Disproportional suicide reporting was observed for generics compared with AGs and brand, although this finding needs further study. PMID- 28641222 TI - Theoretical evaluation on selective adsorption characteristics of alkali metal based sorbents for gaseous oxidized mercury. AB - Alkali metal-based sorbents are potential for oxidized mercury (Hg2+) selective adsorption but show hardly effect to elemental mercury (Hg0) in flue gas. Density functional theory (DFT) was employed to investigate the Hg0 and HgCl2 adsorption mechanism over alkali metal-based sorbents, including calcium oxide (CaO), magnesium oxide (MgO), potassium chloride (KCl) and sodium chloride (NaCl). Hg0 was found to weakly interact with CaO (001), MgO (001), KCl (001) and NaCl (001) surfaces while HgCl2 was effectively adsorbed on top-O and top-Cl sites. Charge transfer and bond population were calculated to discuss the covalency and ionicity of HgCl2 bonding with the adsorption sites. The partial density of states (PDOS) analysis manifests that HgCl2 strongly interacts with surface sites through the orbital hybridizations between Hg and top O or Cl. Frontier molecular orbital (FMO) energy and Mulliken electronegativity are introduced as the quantitative criteria to evaluate the reactivity of mercury species and alkali metal-based sorbents. HgCl2 is identified as a Lewis acid and more reactive than Hg0. The Lewis basicity of the four alkali metal-based sorbents is predicted as the increasing order: NaCl < MgO < KCl < CaO, in consistence with the trend of HgCl2 adsorption energies. PMID- 28641223 TI - Paternal bisphenol a diet changes prefrontal cortex proteome and provokes behavioral dysfunction in male offspring. AB - Relatively little attention has been given paternal effects on next generation. Given that Bisphenol A (BPA), a ubiquitous compound in maternal diet, may disrupt brain development and behavior, we hypothesized that paternal BPA diet (PBD) could affect offspring development. Prefrontal cortex (PFC), a vital brain region, is involved in emotion and social behavior. To test whether PBD could alter developing PFC, we carried out a proteomics approach for PFC in male juvenile offspring that responded to PBD (50 mg BPA/kg diet). We found that PBD altered the expressions of binding immunoglobulin protein (BIP), CCAAT/-enhancer binding protein homologous protein (CHOP) and B-cell lymphoma-2 (BCL-2), which could reflect endoplasmic reticulum (ER) stress. In addition, downregulation of myelinogenesis genes and myelin basic protein (MBP) could provoke myelin deficiency. Furthermore, PBD significantly increased anxiety-like behavior and impaired social behavior in male offspring. Taken together, these results revealed the alterations of ER stress and myelin destruction related molecules induced by PBD might be a potential mechanism for the behavior deficits in their male offspring. These findings remind us of the importance of paternal effects in the further environmental exposure research. PMID- 28641224 TI - Elemental copper nanoparticle toxicity to anaerobic ammonium oxidation and the influence of ethylene diamine-tetra acetic acid (EDTA) on copper toxicity. AB - Soluble ions released by elemental copper nanoparticles (Cu0 NP) are toxic to key microorganisms of wastewater treatment processes. However, their toxicity to anaerobic ammonium oxidation (anammox) has not yet been studied. Chelating agents occurring in wastewater may decrease copper ions (Cu2+) concentration and consequently, decrease copper toxicity. This study evaluated Cu0 NP and CuCl2 toxicity to anammox and the influence of ethylene diamine-tetra acetic acid (EDTA) on copper toxicity. Bioassays were supplemented with Cu0 NP or CuCl2 with and without EDTA. Anammox activities were used to calculate inhibition constants (Ki). Results showed that Cu0 NP are toxic to anammox. Ki constants with respect to added copper were 1.8- and 2.81-fold larger (less toxic) in EDTA-containing assays for Cu0 NP and CuCl2, respectively, compared to EDTA-free assays. Additionally, Ki constants calculated in EDTA-free assays with respect the measured dissolved copper concentration were 0.023 mM Cu0 NP and 0.014 mM CuCl2. The similarity of these Ki constants indicates that Cu0 NP toxicity to anammox is caused by the release of Cu2+. Finally, severe toxicity caused by 0.315 mM and Cu0 NP 0.118 mM CuCl2 was attenuated by 88-100% when 0.14 mM EDTA was supplied. Toxicity attenuation likely occurred because EDTA complexed Cu2+ ions, thus, decreasing their bioavailability. Overall, this study indicates that Cu0 NP and CuCl2 are toxic to anammox, and furthermore, that EDTA attenuates Cu0 NP and CuCl2 toxicity to anammox by complexing Cu2+ ions. PMID- 28641225 TI - Investigation of dissociation constants for individual and total naphthenic acids species using ultra performance liquid chromatography ion mobility time-of-flight mass spectrometry analysis. AB - Ultra-performance liquid chromatography ion mobility time-of-flight mass spectrometry (UPLC-IM-TOFMS) was utilized for the analysis of naphthenic acids (NAs) in fractions of pH-dependent sequential liquid-liquid extractions from oil sands process-affected water. Ion-mobility separation technique allowed the differentiation of OyS-NAs (2 <= y <= 4) from Ox-NAs (2 <= x <= 5) via drift time versus retention time separations. The results indicated that the addition of S atom to the O2-NA molecule led to a lower increase in the dissociation constant (pKa) compared to that caused by the addition of O atom. Because additional O is present as OH while the S atom is present as the CSC structure, the latter does not involve into the deprotonation process directly. The pKa value decreased along with increasing carbon number and |Z| number for O2-, O3-, O4-, and O2S-NA species, except for O5-, O3S-, and O4S-NA species, each of which are comprised of chemical structures with distinct functional groups. A calculation model was developed to estimate pKa values for individual and total NA species via nonlinear regression curve fitting, utilizing the relative abundances of detected NA species. pKa values were calculated as 3.9 for total NAs, 3.3 for O2-NAs, 4.4 for O3-NAs, 7.3 for O4-NAs, and 4.1 for O2S-NAs. Knowledge of NAs pKa is crucially important for the comprehensive understanding of their potential transformation route and toxicity as well as for the development of water remediation applications. Both the ion-mobility separation technique and the new calculation model could be widely applied for the investigation of other complicated pollutants present in water and wastewater. PMID- 28641226 TI - Evaluation of trace element concentration in cancerous and non-cancerous tissues of human stomach. AB - Gastric cancer has a high mortality rate in west of Iran. Various environmental elements are proposed as cancer risk factors including trace elements. Trace elements can induce initiation or progression of carcinogenesis via oxidative stress and DNA injury. The aim of this study was to measure and compare some trace element concentration (Ca, Cu, Fe, As, Mg, Ni, Cd and Cr) in gastric cancer tissues and normal tissues. For this purpose, 35 patients with gastric cancer and 30 without any cancer were biopsied. Biopsies were taken from cancerous tissue and non-cancerous tissue of gastric cancer patients and gastric tissue of normal patients. The analysis of trace elements was performed using Inductively coupled plasma mass spectrometry (ICP-MS). Data analysis was carried out using SPSS and STATA 12 software. The research found that the concentrations of Fe, Mg, and As were higher in cancerous tissues compared with non-cancerous tissues whereas Cr, Cu, Ca, and Ni concentrations were higher in non-cancerous tissues of cancerous patients. When comparisons were made for cancer and normal samples, copper was the only metal, which was significantly higher in cancerous samples (p < 0.05) and Cr mean concentration in normal tissues was significantly higher compared with cancerous tissues (P = 0.02). Chi-Square test showed that there was no significant relationship in the demographic information between cancerous and normal patients except for location with K2 = 7.604. Increased Cu and As concentration in gastric patients (both tissues) propose that these elements may have carcinogenic effects, although further study is suggested. PMID- 28641227 TI - Presence, distribution and risk assessment of polycyclic aromatic hydrocarbons in rice-wheat continuous cropping soils close to five industrial parks of Suzhou, China. AB - Polycyclic aromatic hydrocarbons (PAHs) accumulated in agricultural soils are likely to threaten human health and ecosystem though the food chain, therefore, it is worth to pay more attention to soil contamination by PAHs. In this study, the presence, distribution and risk assessment of 16 priority PAHs in rice-wheat continuous cropping soils close to industrial parks of Suzhou were firstly investigated. The concentrations of the total PAHs ranged from 125.99 ng/g to 796.65 ng/g with an average of 352.94 ng/g. Phenanthrene (PHE), fluoranthene (FLT), benzo [a] anthracene (BaA) and pyrene (PYR) were the major PAHs in those soil samples. The highest level of PAHs was detected in the soils around Chemical plant and Steelworks, followed by Printed wire board, Electroplate Factory and Paper mill. The composition of PAHs in the soils around Chemical plant was dominated by 3-ring PAHs, however, the predominant compounds were 4, 5-ring PAHs in the soils around other four factories. Meanwhile, the concentration of the total PAHs in the soils close to the factories showed a higher level of PAHs in November (during rice harvest) than that in June (during wheat harvest). Different with other rings of PAHs, 3-ring PAHs in the soils around Chemical plant and Steelworks had a higher concentration in June. The results of principal component analysis and isomeric ratio analysis suggested that PAHs in the studied areas mainly originated from biomass, coal and petroleum combustion. The risk assessment indicated that higher carcinogenic risk was found in those sites closer to the industrial park. PMID- 28641228 TI - Relationships between past and present pesticide applications and pollution at a watershed outlet: The case of a horticultural catchment in Martinique, French West Indies. AB - The understanding of factors affecting pesticide transfers to catchment outlet is still at a very early stage in tropical context, and especially on tropical volcanic context. We performed on-farm pesticide use surveys during 87 weeks and monitored pesticides in water weekly during 67 weeks at the outlet of a small catchment in Martinique. We identified three types of pollution. First, we showed long-term chronic pollution by chlordecone, diuron and metolachlor resulting from horticultural practices applied 5-20 years ago (quantification frequency higher than 80%). Second, we showed peak pollution. High amounts of propiconazole and fosthiazate applied at low frequencies caused river pollution peaks for weeks following a single application. Low amounts of diquat and diazinon applied at low frequencies also caused pollution peaks. The high amounts of glyphosate applied at high frequency resulted into pollution peaks by glyphosate and aminomethylphosphonic acid (AMPA) in 6 and 20% of the weeks. Any intensification of their uses will result in higher pollution levels. Third, relatively low amounts of glufosinate-ammonium, difenoconazol, spinosad and metaldehyde were applied at high frequencies. Unexpectedly, such pesticides remained barely detected (<1.5%) or undetected in water samples. We showed that AMPA, fosthiazate and propiconazole have serious leaching potential. They might result in future chronic pollution of shallow aquifers alimenting surface water. We prove that to avoid the past errors and decrease the risk of long-term pollution of water resources, it is urgent to reduce or stop the use of pesticides with leaching potential by changing agricultural practices. PMID- 28641229 TI - Effects of short-term invasion of Spartina alterniflora and the subsequent restoration of native mangroves on the soil organic carbon, nitrogen and phosphorus stock. AB - The exotic cordgrass Spartina alterniflora has severely invaded the mangrove wetlands in southern China and ecological restoration using native mangroves was conducted in an attempt to control this invasive species. In this study, the contents and pools of soil organic carbon (SOC), total nitrogen (TN) and total phosphorus (TP) were quantified to investigate the invasive effects of S. alterniflora and then to evaluate whether the ecological restoration of native mangrove could reverse those effects. S. alterniflora only showed significantly higher organic carbon content in the surface 0-10 cm of soil than in the uninvaded mudflat. The high delta13C values in the surface soil of the invaded habitat demonstrated that S. alterniflora contributed 42.6-62.2% of the organic carbon. The SOC for invasive S. alterniflora and newly restored mangroves (4 years and 14 years) was not enhanced in comparison to the unvegetated mudflat. S. alterniflora significantly increased the surface soil TN content, but decreased the available phosphorus content and TP density. The TN densities increased gradually with the mangrove restoration, while the TP densities were only slightly influenced. The results suggested that short-term invasion of S. alterniflora and subsequent mangrove restoration did not alter SOC or TN pool sizes, but S. alterniflora was shown to affect the potential carbon storage capacity produced by the mangroves in the Zhangjiang Estuary. PMID- 28641230 TI - Combining chemometric tools for assessing hazard sources and factors acting simultaneously in contaminated areas. Case study: "Mar Piccolo" Taranto (South Italy). AB - Almost all marine coastal ecosystems possess complex structural and dynamic characteristics, which are influenced by anthropogenic causes and natural processes as well. Revealing the impact of sources and factors controlling the spatial distributions of contaminants within highly polluted areas is a fundamental propaedeutic step of their quality evaluation. Combination of different pattern recognition techniques, applied to one of the most polluted Mediterranean coastal basin, resulted in a more reliable hazard assessment. PCA/CA and factorial ANOVA were exploited as complementary techniques for apprehending the impact of multi-sources and multi-factors acting simultaneously and leading to similarities or differences in the spatial contamination pattern. The combination of PCA/CA and factorial ANOVA allowed, on one hand to determine the main processes and factors controlling the contamination trend within different layers and different basins, and, on the other hand, to ascertain possible synergistic effects. This approach showed the significance of a spatially representative overview given by the combination of PCA-CA/ANOVA in inferring the historical anthropogenic sources loading on the area. PMID- 28641231 TI - Association between timing of intubation and outcome in critically ill patients: A secondary analysis of the ICON audit. AB - PURPOSE: The optimal timing of endotracheal intubation in critically ill patients requiring invasive mechanical ventilation remains undefined. MATERIAL AND METHODS: In a secondary analysis of the large, prospective ICON database, we used a piecewise proportional hazards model to compare outcomes in patients who underwent intubation early (within two days after intensive care unit [ICU] admission) or later. RESULTS: After excluding 5340 patients already intubated on admission or with therapeutic limitation, 4729 patients were analyzed, of whom 4074 never underwent intubation. Of the remaining 655 patients, 449 underwent intubation early and 206 later. Despite similar severity scores on ICU admission, unadjusted ICU (27.6 vs. 18.2%) and hospital (33.3 vs. 23.4%) mortality rates were higher in patients intubated later than in those intubated earlier, as were ICU (9 [5-16] vs. 4 [2-9] days) and hospital (24 [9-35] vs. 13 [7-24] days) lengths-of-stay (all p<0.001). After adjustment, the hazard for ICU and hospital death was significantly greater >10days after ICU admission for patients intubated late. CONCLUSIONS: In this large cohort of critically ill patients requiring intubation, intubation >2days after admission was associated with increased mortality later in the hospital course. PMID- 28641232 TI - On the aquatic toxicity of substituted phenols to Chlorella vulgaris: QSTR with an extended novel data set and interspecies models. AB - This study provides for the first time the 96-h toxicity of 16 nitro- and methyl- substituted phenols to Chlorella vulgaris. Enabling the circulation of new ecotoxicity data has expanded the previously reported toxicity data set of 30 phenols to C. vulgaris by our laboratory. In this respect, high quality, single source algal toxicity data, generated in the same laboratory according to a REACH (Registration, Evaluation, Authorization and Restriction of CHemicals) compatible endpoint, provided a sound basis to explore quantitative structure-toxicity relationship (QSTR), which can be used for regulatory purposes. Of the developed linear models on a new data set, the selected one was applied to a data set lack of toxicity values, and prediction ability of the model was discussed. Interspecies relations were sought related to Pseudokirchneriella subcapitata and Tetrahymena pyriformis. The developed models displayed decent predictivity, which can be used to predict the toxicity of untested phenols on C. vulgaris. PMID- 28641233 TI - Large eddy simulation and experimental study on vented gasoline-air mixture explosions in a semi-confined obstructed pipe. AB - In this work, LES simulation coupled with a TFC sub-grid combustion model has been performed in a semi-confined pipe (L/D=10, V=10L) in the presence of four hollow-square obstacles (BR=49.8%) with circular hollow cross-section, in order to study the premixed gasoline-air mixture explosions. The comparisons between simulated results and experimental results have been conducted. It was found that the simulated results were in good agreement with experimental data in terms of flame structures, flame locations and overpressure time histories. Moreover, the interaction between flame propagation process and obstacles, overpressure dynamics were analyzed. In addition, the effects of initial gasoline vapor concentration (lean (phi=1.3%), stoichiometric (phi=1.7%) and rich (phi=2.1%)), and the number of obstacles (from 1 to 4) were also investigated by experiments. Some of the experimental results have been compared with the literature data. It is found that the explosion parameters of gasoline-air mixtures (e.g. the maximum overpressure peaks, average overpressure growth rates, etc.) are different from some other fuels such as hydrogen, methane and LPG, etc. PMID- 28641234 TI - Improved boundary segmentation of skin lesions in high-frequency 3D ultrasound. AB - In this article, we propose a segmentation algorithm for skin lesions in 3D high frequency ultrasound images. The segmentation is done on melanoma and Basal-cell carcinoma tumors, the most common skin cancer types, and could be used for diagnosis and surgical excision planning in a clinical context. Compared with previously proposed algorithms, which tend to underestimate the size of the lesion, we propose two new boundary terms which provide significant improvements of the accuracy. The first is a probabilistic boundary expansion (PBE) term designed to broaden the segmented area at the boundaries, which uses the feature asymmetry criterion. The second is a curvature dependent regularization (CDR), which aims at overcoming the tendency of standard regularization to shrink segmented areas. On a clinical dataset of 12 patients annotated by a dermatologist, the proposed algorithm has a comparable Dice index but increases the sensitivity by 26%. The proposed algorithm improves the sensitivity for all lesions, and the obtained sensitivity is close to that of the intra-observer variability. PMID- 28641235 TI - Computer-aided training sensorimotor cortex functions in humans before the upper limb transplantation using virtual reality and sensory feedback. AB - One of the biggest problems of upper limb transplantation is lack of certainty as to whether a patient will be able to control voluntary movements of transplanted hands. Based on findings of the recent research on brain cortex plasticity, a premise can be drawn that mental training supported with visual and sensory feedback can cause structural and functional reorganization of the sensorimotor cortex, which leads to recovery of function associated with the control of movements performed by the upper limbs. In this study, authors - based on the above observations - propose the computer-aided training (CAT) system, which generating visual and sensory stimuli, should enhance the effectiveness of mental training applied to humans before upper limb transplantation. The basis for the concept of computer-aided training system is a virtual hand whose reaching and grasping movements the trained patient can observe on the VR headset screen (visual feedback) and whose contact with virtual objects the patient can feel as a touch (sensory feedback). The computer training system is composed of three main components: (1) the system generating 3D virtual world in which the patient sees the virtual limb from the perspective as if it were his/her own hand; (2) sensory feedback transforming information about the interaction of the virtual hand with the grasped object into mechanical vibration; (3) the therapist's panel for controlling the training course. Results of the case study demonstrate that mental training supported with visual and sensory stimuli generated by the computer system leads to a beneficial change of the brain activity related to motor control of the reaching in the patient with bilateral upper limb congenital transverse deficiency. PMID- 28641236 TI - Analytical evidences of the use of iron-gall ink as a pigment on miniature paintings. AB - Iron-gall ink (IGI) has been used by scribes for writing since at least the 4th century CE. Another typical use of this ink was for drawing: many Old Masters created beautiful sketches in brown-black hues. Despite its widespread use to draw lines, it seems like IGI was hardly used for painting as well. In fact, the number of identification on manuscripts is very low at present. This could be partially due to a lack of reliable diagnostic information. In this work we tried to better define the possibility of identifying IGI as a pigment on illuminate manuscripts, evaluating the pros and cons of three different techniques: UV visible diffuse reflectance spectrophotometry with optic fibres (FORS), Raman spectroscopy and XRF spectrometry. With concern to in situ non-invasive analysis, Raman spectroscopy has the best diagnostic power but FORS seems to provide the better compromise between selectivity and ease of application. Moreover, new analytical evidences was given on the particular use of IGI by ancient illuminators: a non-invasive and micro-invasive diagnostic survey on Western manuscripts datable in the range 6-16th centuries was carried out showing that, apart from its widespread use as an ink for writing and drawing, IGI was largely used as a pigment too. The large number of identification obtained allows us to hypothesise that this pigment was used all through medieval Europe up to at least the Renaissance, where its use is already documented in drawing. The occurrence of IGI in miniature paintings older than 6th century or more recent than 16th century cannot be excluded, as is its use beyond Europe; further measurements could instead widen the time range and the geographic area. Nevertheless, the present study allows shedding a new light on the use of this colourant all along the period of medieval and Renaissance miniature painting art. PMID- 28641237 TI - Tunable excited-state intramolecular proton transfer reactions with NH or OH as a proton donor: A theoretical investigation. AB - Excited-state intramolecular proton transfer (ESIPT) reactions occurring in the S1 state for five molecules, which possess five/six-membered ring intramolecular NH...N or OH...N hydrogen bonds bearing quinoline or 2-phenylpyridine moiety, have been described in detail by the time-dependent density functional theory (TD DFT) approach using the B3LYP hybrid functional. For the five molecules, the constrained potential energy profiles along the ESIPT reactions show that proton transfer is barrierless in molecules possessing six-membered ring intramolecular H-bonds, which is smoother than that with certain barriers in five-membered ring H-bonding systems. For the latter, chemical modification by a more strong acid group can lower the ESIPT barrier significantly, which harnesses the ESIPT reaction from a difficult type to a fast one. The energy barrier of the ESIPT reaction depends on the intensity of the intramolecular H-bond, which can be measured with the topological descriptors by topology analysis of the bond critical point (BCP) of the intramolecular H-bond. It is found that when the value of electron density rho(r) at BCP is bigger than 0.025a.u., the corresponding molecule might go through an ultrafast and barrierless ESIPT process, which opens a new scenario to explore the ESIPT reactions. PMID- 28641238 TI - Water-soluble fraction of petroleum induces genotoxicity and morphological effects in fat snook (Centropomus parallelus). AB - Petroleum hydrocarbons are one of the primary organic chemicals found in water bodies, and the water-soluble fraction of petroleum (WSFP) may be responsible for much of the toxic effects. In the present study, genotoxicity assays and histopathological analysis of the gills were analyzed for two experimental protocols: 1) Juvenile Centropomus parallelus were exposed to different concentrations of WFSP (0%, 25%, 50% and 75%) for 96h; 2) A second fish group was exposed to 50% WFSP for 168h followed by a post-exposure period for 168h in clean water (recovery). The total benzene, toluene, ethyl benzene and xylene (BTEX) and polycyclic aromatic hydrocarbon (PAH) concentrations at time 0 were 254MUgL-1 and 4.72MUgL-1 in 25%; 552.9MUgL-1 and 9.36MUgL-1 in 50%; and 842.4MUgL-1 and 9.97MUgL-1 in 75% WSFP, respectively. Based on the alkaline comet assay, the damage index (DI) values of fish exposed to 25% WSFP for 96h were significantly higher than those in the control group, and in the micronucleus test, the higher damage values were found in fish exposed to 75% WSFP. Furthermore, this last genotoxic test showed recovery after 168h. At all concentrations of WSFP, several histopathological changes were observed, and overall, most of these changes observed in the gills were classified as proliferative changes and represented a protective mechanism against pollutant uptake. Based on the recovery experiment, the damage was also significantly reduced after recovery. Our results showed that short-term exposure to WSFP compounds triggered cellular alterations in C. parallelus, but total recovery did not occur with time. Additionally, the different periods of exposure were not sufficient to induce severe gill damage in C. parallelus. Moreover, this fish demonstrated its usefulness as a sentinel species. PMID- 28641240 TI - Placing Sites on the Edge of Planar Silicon Microelectrodes Enhances Chronic Recording Functionality. AB - OBJECTIVE: This study aims to identify the impact of using edge sites over center sites on a planar silicon microelectrode array. METHODS: We used custom-designed, silicon-substrate multisite microelectrode arrays with sites on the center, edge, and tip. We compared their single unit recording capability, noise level, impedance, and histology to identify the differences between each site location. Wide and narrow devices were used to evaluate if the differences are consistent and meet theoretical expectations. RESULTS: On the wide device, significantly more number of edge sites were functional than center sites over the course of 8 weeks with generally higher signal-to-noise amplitude ratio. On the narrow device, edge sites also performed generally better than center sites, but the differences were not significant and smaller than wide devices. The data from the tip sites were inconclusive. CONCLUSION: Edge sites outperformed center sites in terms of single unit recording capability. This benefit decreased as the device gets narrower and the distance to center sites decreases. SIGNIFICANCE: We showed that a simple alteration to the site placement can greatly enhance the functionality of silicon microelectrodes. This study promotes the idea that not only the substrate but also the site architecture needs attention to lengthen the lifetime of neural implants. PMID- 28641239 TI - Automatic Recognition of fMRI-Derived Functional Networks Using 3-D Convolutional Neural Networks. AB - Current functional magnetic resonance imaging (fMRI) data modeling techniques, such as independent component analysis and sparse coding methods, can effectively reconstruct dozens or hundreds of concurrent interacting functional brain networks simultaneously from the whole brain fMRI signals. However, such reconstructed networks have no correspondences across different subjects. Thus, automatic, effective, and accurate classification and recognition of these large numbers of fMRI-derived functional brain networks are very important for subsequent steps of functional brain analysis in cognitive and clinical neuroscience applications. However, this task is still a challenging and open problem due to the tremendous variability of various types of functional brain networks and the presence of various sources of noises. In recognition of the fact that convolutional neural networks (CNN) has superior capability of representing spatial patterns with huge variability and dealing with large noises, in this paper, we design, apply, and evaluate a deep 3-D CNN framework for automatic, effective, and accurate classification and recognition of large number of functional brain networks reconstructed by sparse representation of whole-brain fMRI signals. Our extensive experimental results based on the Human Connectome Project fMRI data showed that the proposed deep 3-D CNN can effectively and robustly perform functional networks classification and recognition tasks, while maintaining a high tolerance for mistakenly labeled training instances. This study provides a new deep learning approach for modeling functional connectomes based on fMRI data. PMID- 28641241 TI - Influence of Shoulder Kinematic Estimate on Joint and Muscle Mechanics Predicted by Musculoskeletal Model. AB - GOAL: Little information is available in the existing literature regarding the influence of the scapular kinematic estimate method on musculoskeletal analysis. This study aimed to assess the propagation of errors due to the method used for scapular kinematics reconstruction in the workflow of musculoskeletal modeling (joint kinematics, joint torques, muscle force, and joint reaction force) in shoulder and upper-limb movements. METHODS: Two participants performed functional (arm elevation and rotation), daily life (eating and reaching pants pockets), and sports movements (a simulated throwing maneuver). Shoulder kinematics were obtained with five multibody kinematics methods: intracortical pins (Pins, reference method), International Society of Biomechanics (ISB), Jackson (Jack), Projection (Proj), and Ellipsoid (Ell) methods. For the five kinematics methods, joint torques, muscle forces, and glenohumeral joint reaction forces were computed with the Delft Shoulder and Elbow musculoskeletal model. RESULTS: Differences up to 30 degrees in glenohumeral joint kinematics, compared to the Pins method, resulted in differences less than 3 N.m in joint torque estimation. However, these also resulted in differences up to 50 and 831 N in the muscle force and joint reaction force estimate, respectively, in comparison to the reference method (Pins). No method yielded the worst or best results in comparison to the Pins method but the differences were task-specific. CONCLUSION: We concluded that shoulder biomechanical studies based on skin markers should be completed with caution when assessing joint angles, muscle forces, and glenohumeral joint reaction forces, while researchers may be more confident with the evaluation of shoulder joint torques. PMID- 28641242 TI - Arrhythmia Mechanism and Scaling Effect on the Spectral Properties of Electroanatomical Maps With Manifold Harmonics. AB - INTRODUCTION: Spatial and temporal processing of intracardiac electrograms provides relevant information to support the arrhythmia ablation during electrophysiological studies. Current cardiac navigation systems (CNS) and electrocardiographic imaging (ECGI) build detailed 3-D electroanatomical maps (EAM), which represent the spatial anatomical distribution of bioelectrical features, such as activation time or voltage. OBJECTIVE: We present a principled methodology for spectral analysis of both EAM geometry and bioelectrical feature in CNS or ECGI, including their spectral representation, cutoff frequency, or spatial sampling rate (SSR). METHODS: Existing manifold harmonic techniques for spectral mesh analysis are adapted to account for a fourth dimension, corresponding to the EAM bioelectrical feature. Appropriate scaling is required to address different magnitudes and units. RESULTS: With our approach, simulated and real EAM showed strong SSR dependence on both the arrhythmia mechanism and the cardiac anatomical shape. For instance, high frequencies increased significantly the SSR because of the "early-meets-late" in flutter EAM, compared with the sinus rhythm. Besides, higher frequency components were obtained for the left atrium (more complex anatomy) than for the right atrium in sinus rhythm. CONCLUSION: The proposed manifold harmonics methodology opens the field toward new signal processing tools for principled EAM spatiofeature analysis in CNS and ECGI, and to an improved knowledge on arrhythmia mechanisms. PMID- 28641243 TI - eCurves: A Temporal Shape Encoding. AB - OBJECTIVE: This paper presents a framework for temporal shape analysis to capture the shape and changes of anatomical structures from three-dimensional+t(ime) medical scans. METHOD: We first encode the shape of a structure at each time point with the spectral signature, i.e., the eigenvalues and eigenfunctions of the Laplace operator. We then expand it to capture morphing shapes by tracking the eigenmodes across time according to the similarity of their eigenfunctions. The similarity metric is motivated by the fact that small-shaped deformations lead to minor changes in the eigenfunctions. Following each eigenmode from the beginning to end results in a set of eigenmode curves representing the shape and its changes over time. RESULTS: We apply our encoding to a cardiac dataset consisting of series of segmentations outlining the right and left ventricles over time. We measure the accuracy of our encoding by training classifiers on discriminating healthy adults from patients that received reconstructive surgery for Tetralogy of Fallot (TOF). The classifiers based on our encoding significantly surpass deformation-based encodings of the right ventricle, the structure most impacted by TOF. CONCLUSION: The strength of our framework lies in its simplicity: It only assumes pose invariance within a time series but does not assume point-to-point correspondence across time series or a (statistical or physical) model. In addition, it is easy to implement and only depends on a single parameter, i.e., the number of curves. PMID- 28641245 TI - Data Visualization with Structural Control of Global Cohort and Local Data Neighborhoods. AB - A typical objective of data visualization is to generate low-dimensional plots that maximally convey the information within the data. The visualization output should help the user not only identify the local neighborhood structure of individual samples, but also obtain a global view of the relative positioning and separation between cohorts. Here, we propose a novel visualization framework designed to satisfy these needs. By incorporating additional cohort positioning and discriminative constraints into local neighbor preservation models through the use of computed cohort prototypes, effective control over the arrangements and proximities of data cohorts can be obtained. We introduce various embedding and projection algorithms based on objective functions addressing the different visualization requirements. Their underlying models are optimized effectively using matrix manifold procedures to incorporate the problem constraints. Additionally, to facilitate large-scale applications, a matrix decomposition based model is also proposed to accelerate the computation. The improved capabilities of the new methods are demonstrated using various state-of-the-art dimensionality reduction algorithms. We present many qualitative and quantitative comparisons, on both synthetic problems and real-world tasks of complex text and image data, that show notable improvements over existing techniques. PMID- 28641244 TI - Computerized Lung Sound Screening for Pediatric Auscultation in Noisy Field Environments. AB - GOAL: Chest auscultations offer a non-invasive and low-cost tool for monitoring lung disease. However, they present many shortcomings, including inter-listener variability, subjectivity, and vulnerability to noise and distortions. This work proposes a computer-aided approach to process lung signals acquired in the field under adverse noisy conditions, by improving the signal quality and offering automated identification of abnormal auscultations indicative of respiratory pathologies. METHODS: The developed noise-suppression scheme eliminates ambient sounds, heart sounds, sensor artifacts, and crying contamination. The improved high-quality signal is then mapped onto a rich spectrotemporal feature space before being classified using a trained support-vector machine classifier. Individual signal frame decisions are then combined using an evaluation scheme, providing an overall patient-level decision for unseen patient records. RESULTS: All methods are evaluated on a large dataset with 1000 children enrolled, 1-59 months old. The noise suppression scheme is shown to significantly improve signal quality, and the classification system achieves an accuracy of 86.7% in distinguishing normal from pathological sounds, far surpassing other state-of-the art methods. CONCLUSION: Computerized lung sound processing can benefit from the enforcement of advanced noise suppression. A fairly short processing window size ( s) combined with detailed spectrotemporal features is recommended, in order to capture transient adventitious events without highlighting sharp noise occurrences. SIGNIFICANCE: Unlike existing methodologies in the literature, the proposed work is not limited in scope or confined to laboratory settings: This work validates a practical method for fully automated chest sound processing applicable to realistic and noisy auscultation settings. PMID- 28641246 TI - Gracker: A Graph-Based Planar Object Tracker. AB - Matching-based algorithms have been commonly used in planar object tracking. They often model a planar object as a set of keypoints, and then find correspondences between keypoint sets via descriptor matching. In previous work, unary constraints on appearances or locations are usually used to guide the matching. However, these approaches rarely utilize structure information of the object, and are thus suffering from various perturbation factors. In this paper, we proposed a graph-based tracker, named Gracker, which is able to fully explore the structure information of the object to enhance tracking performance. We model a planar object as a graph, instead of a simple collection of keypoints, to represent its structure. Then, we reformulate tracking as a sequential graph matching process, which establishes keypoint correspondence in a geometric graph matching manner. For evaluation, we compare the proposed Gracker with state-of the-art planar object trackers on three benchmark datasets: two public ones and a newly collected one. Experimental results show that Gracker achieves robust tracking results against various environmental variations, and outperforms other algorithms in general on the datasets. PMID- 28641247 TI - Modeling Task fMRI Data Via Deep Convolutional Autoencoder. AB - Task-based functional magnetic resonance imaging (tfMRI) has been widely used to study functional brain networks under task performance. Modeling tfMRI data is challenging due to at least two problems: the lack of the ground truth of underlying neural activity and the highly complex intrinsic structure of tfMRI data. To better understand brain networks based on fMRI data, data-driven approaches have been proposed, for instance, independent component analysis (ICA) and sparse dictionary learning (SDL). However, both ICA and SDL only build shallow models, and they are under the strong assumption that original fMRI signal could be linearly decomposed into time series components with their corresponding spatial maps. As growing evidence shows that human brain function is hierarchically organized, new approaches that can infer and model the hierarchical structure of brain networks are widely called for. Recently, deep convolutional neural network (CNN) has drawn much attention, in that deep CNN has proven to be a powerful method for learning high-level and mid-level abstractions from low-level raw data. Inspired by the power of deep CNN, in this paper, we developed a new neural network structure based on CNN, called deep convolutional auto-encoder (DCAE), in order to take the advantages of both data-driven approach and CNN's hierarchical feature abstraction ability for the purpose of learning mid-level and high-level features from complex, large-scale tfMRI time series in an unsupervised manner. The DCAE has been applied and tested on the publicly available human connectome project tfMRI data sets, and promising results are achieved. PMID- 28641249 TI - EIT Imaging Regularization Based on Spectral Graph Wavelets. AB - The objective of electrical impedance tomographic reconstruction is to identify the distribution of tissue conductivity from electrical boundary conditions. This is an ill-posed inverse problem usually solved under the finite-element method framework. In previous studies, standard sparse regularization was used for difference electrical impedance tomography to achieve a sparse solution. However, regarding elementwise sparsity, standard sparse regularization interferes with the smoothness of conductivity distribution between neighboring elements and is sensitive to noise. As an effect, the reconstructed images are spiky and depict a lack of smoothness. Such unexpected artifacts are not realistic and may lead to misinterpretation in clinical applications. To eliminate such artifacts, we present a novel sparse regularization method that uses spectral graph wavelet transforms. Single-scale or multiscale graph wavelet transforms are employed to introduce local smoothness on different scales into the reconstructed images. The proposed approach relies on viewing finite-element meshes as undirected graphs and applying wavelet transforms derived from spectral graph theory. Reconstruction results from simulations, a phantom experiment, and patient data suggest that our algorithm is more robust to noise and produces more reliable images. PMID- 28641248 TI - Method for Simulating Dose Reduction in Digital Breast Tomosynthesis. AB - This paper proposes a new method of simulating dose reduction in digital breast tomosynthesis, starting from a clinical image acquired with a standard radiation dose. It considers both signal-dependent quantum and signal-independent electronic noise. Furthermore, the method accounts for pixel crosstalk, which causes the noise to be frequency-dependent, thus increasing the simulation accuracy. For an objective assessment, simulated and real images were compared in terms of noise standard deviation, signal-to-noise ratio (SNR) and normalized noise power spectrum (NNPS). A two-alternative forced-choice (2-AFC) study investigated the similarity between the noise strength of low-dose simulated and real images. Six experienced medical physics specialists participated on the study, with a total of 2 160 readings. Objective assessment showed no relevant trends with the simulated noise. The relative error in the standard deviation of the simulated noise was less than 2% for every projection angle. The relative error of the SNR was less than 1.5%, and the NNPS of the simulated images had errors less than 2.5%. The 2-AFC human observer experiment yielded no statistically significant difference ( =0.84) in the perceived noise strength between simulated and real images. Furthermore, the observer study also allowed the estimation of a dose difference at which the observer perceived a just noticeable difference (JND) in noise levels. The estimated JND value indicated that a change of 17% in the current-time product was sufficient to cause a noticeable difference in noise levels. The observed high accuracy, along with the flexible calibration, make this method an attractive tool for clinical image based simulations of dose reduction. PMID- 28641250 TI - Deep Convolutional Neural Network for Inverse Problems in Imaging. AB - In this paper, we propose a novel deep convolutional neural network (CNN)-based algorithm for solving ill-posed inverse problems. Regularized iterative algorithms have emerged as the standard approach to ill-posed inverse problems in the past few decades. These methods produce excellent results, but can be challenging to deploy in practice due to factors including the high computational cost of the forward and adjoint operators and the difficulty of hyperparameter selection. The starting point of this paper is the observation that unrolled iterative methods have the form of a CNN (filtering followed by pointwise nonlinearity) when the normal operator (H*H, where H* is the adjoint of the forward imaging operator, H) of the forward model is a convolution. Based on this observation, we propose using direct inversion followed by a CNN to solve normal convolutional inverse problems. The direct inversion encapsulates the physical model of the system, but leads to artifacts when the problem is ill posed; the CNN combines multiresolution decomposition and residual learning in order to learn to remove these artifacts while preserving image structure. We demonstrate the performance of the proposed network in sparse-view reconstruction (down to 50 views) on parallel beam X-ray computed tomography in synthetic phantoms as well as in real experimental sinograms. The proposed network outperforms total variation-regularized iterative reconstruction for the more realistic phantoms and requires less than a second to reconstruct a 512 * 512 image on the GPU. PMID- 28641251 TI - Robust Face Recognition With Kernelized Locality-Sensitive Group Sparsity Representation. AB - In this paper, a novel joint sparse representation method is proposed for robust face recognition. We embed both group sparsity and kernelized locality-sensitive constraints into the framework of sparse representation. The group sparsity constraint is designed to utilize the grouped structure information in the training data. The local similarity between test and training data is measured in the kernel space instead of the Euclidian space. As a result, the embedded nonlinear information can be effectively captured, leading to a more discriminative representation. We show that, by integrating the kernelized local sensitivity constraint and the group sparsity constraint, the embedded structure information can be better explored, and significant performance improvement can be achieved. On the one hand, experiments on the ORL, AR, extended Yale B, and LFW data sets verify the superiority of our method. On the other hand, experiments on two unconstrained data sets, the LFW and the IJB-A, show that the utilization of sparsity can improve recognition performance, especially on the data sets with large pose variation. PMID- 28641252 TI - An Embedded Marked Point Process Framework for Three-Level Object Population Analysis. AB - In this paper, we introduce a probabilistic approach for extracting the complex hierarchical object structures from the digital images used by various vision applications. The proposed framework extends conventional marked point process (MPP) models by: 1) admitting object-subobject ensembles in parent-child relationships; and 2) allowing corresponding objects to form coherent object groups, by a Bayesian segmentation of the population. Different from earlier, highly domain specific attempts on MPP generalization, the proposed model is defined at an abstract level, providing clear interfaces for applications in various domains. We also introduce a global optimization process for the multi layer framework for finding optimal entity configurations, considering the observed data, prior knowledge, and interactions between the neighboring and the hierarchically related objects. The proposed method is demonstrated in three different application areas: built in area analysis in remotely sensed images, traffic monitoring on airborne, and mobile laser scanning (Lidar) data and optical circuit inspection. A new benchmark database is published for the three test cases, and the model's performance is quantitatively evaluated. PMID- 28641253 TI - A Closed-Form Solution to Single Underwater Camera Calibration Using Triple Wavelength Dispersion and Its Application to Single Camera 3D Reconstruction. AB - In this paper, we present a new method to estimate the housing parameters of an underwater camera by making full use of triple wavelength dispersion. Our method is based on an important finding that there is a closed-form solution to the distance from the camera center to the refractive interface once the refractive normal is known. The correctness of this finding is mathematically proved in this paper. To the best of our knowledge, such a finding has not been studied or reported, and hence is never proved theoretically. As well, the refractive normal can be estimated by solving a set of linear equations using wavelength dispersion. Our method does not require any calibration target, such as a checkerboard pattern, which may be difficult to manipulate when the camera is deployed deep undersea. Extensive experiments have been carried out which include simulations to verify the correctness and robustness to noise of our method and real experiments. The results of real experiments show that our method works as expected. The accuracy of our results is evaluated against the ground truth in both simulated and real experiments. Finally, we also show how we can apply dispersion to compute the 3D shape of an object using one single camera. PMID- 28641254 TI - Sparse Image Reconstruction on the Sphere: Analysis and Synthesis. AB - We develop techniques to solve ill-posed inverse problems on the sphere by sparse regularization, exploiting sparsity in both axisymmetric and directional scale discretized wavelet space. Denoising, inpainting, and deconvolution problems and combinations thereof, are considered as examples. Inverse problems are solved in both the analysis and synthesis settings, with a number of different sampling schemes. The most effective approach is that with the most restricted solution space, which depends on the interplay between the adopted sampling scheme, the selection of the analysis/synthesis problem, and any weighting of the l1 norm appearing in the regularization problem. More efficient sampling schemes on the sphere improve reconstruction fidelity by restricting the solution-space and also by improving sparsity in wavelet space. We apply the technique to denoise Planck 353-GHz observations, improving the ability to extract the structure of Galactic dust emission, which is important for studying Galactic magnetism. PMID- 28641255 TI - Piecewise Linear Approximation of Vector-Valued Images and Curves via Second Order Variational Model. AB - Variational models are known to work well for addressing image restoration/regularization problems. However, most of the methods proposed in the literature are defined for scalar inputs and are used on multiband images (such as RGB or multispectral imagery) by the composition of a simple band-wise processing. This involves suboptimal results and may introduce artifacts. Only in a few cases, variational models are extended to the case of vector-valued inputs. However, the known implementations are restricted to the first-order models, while the second-order models are never considered. Thus, typical problems of the first-order models, such as the staircasing effect cannot be overtaken. This paper considers a second-order functional model to function approximation with free discontinuities given by Blake-Zisserman (BZ) and proposes an efficient minimization algorithm in the case of vector-valued inputs. In the BZ model, the Hessian of the solution is penalized outside a set of finite length, therefore the solution is forced to be piecewise linear. Moreover, the model allows the formation of free discontinuities and free gradient discontinuities. The proposed algorithm is applied to difficult color image restoration/regularization problems and to piecewise linear approximation of curves in space. PMID- 28641256 TI - A Novel Fast Tensor-Based Preconditioner for Image Restoration. AB - Image restoration is one of the main parts of image processing. Mathematically, this problem can be modeled as a large-scale structured ill-posed linear system. Ill-posedness of this problem results in low-convergence rate of iterative solvers. For speeding up the convergence, preconditioning usually is used. Despite the existing preconditioners for image restoration, which are constructed based on approximations of the blurring matrix, in this paper, we propose a novel preconditioner with a different viewpoint. Here, we show that image restoration problem can be modeled as a tensor contractive linear equation. This modeling enables us to propose a new preconditioner based on an approximation of the blurring tensor operator. Due to the particular structure of the blurring tensor for zero boundaries, we show that the truncated higher order singular value decomposition of the blurring tensor is obtained very fast and so could be used as a preconditioner. Experimental results confirm the efficiency of this new preconditioner in image restoration and its outperformance in comparison with the other well-known preconditioners. PMID- 28641257 TI - Fast Segmentation From Blurred Data in 3D Fluorescence Microscopy. AB - We develop a fast algorithm for segmenting 3D images from linear measurements based on the Potts model (or piecewise constant Mumford-Shah model). To that end, we first derive suitable space discretizations of the 3D Potts model, which are capable of dealing with 3D images defined on non-cubic grids. Our discretization allows us to utilize a specific splitting approach, which results in decoupled subproblems of moderate size. The crucial point in the 3D setup is that the number of independent subproblems is so large that we can reasonably exploit the parallel processing capabilities of the graphics processing units (GPUs). Our GPU implementation is up to 18 times faster than the sequential CPU version. This allows to process even large volumes in acceptable runtimes. As a further contribution, we extend the algorithm in order to deal with non-negativity constraints. We demonstrate the efficiency of our method for combined image deconvolution and segmentation on simulated data and on real 3D wide field fluorescence microscopy data. PMID- 28641258 TI - Quality Assessment of Perceptual Crosstalk on Two-View Auto-Stereoscopic Displays. AB - Crosstalk is one of the most severe factors affecting the perceived quality of stereoscopic 3D images. It arises from a leakage of light intensity between multiple views, as in auto-stereoscopic displays. Well-known determinants of crosstalk include the co-location contrast and disparity of the left and right images, which have been dealt with in prior studies. However, when a natural stereo image that contains complex naturalistic spatial characteristics is viewed on an auto-stereoscopic display, other factors may also play an important role in the perception of crosstalk. Here, we describe a new way of predicting the perceived severity of crosstalk, which we call the Binocular Perceptual Crosstalk Predictor (BPCP). BPCP uses measurements of three complementary 3D image properties (texture, structural duplication, and binocular summation) in combination with two well-known factors (co-location contrast and disparity) to make predictions of crosstalk on two-view auto-stereoscopic displays. The new BPCP model includes two masking algorithms and a binocular pooling method. We explore a new masking phenomenon that we call duplicated structure masking, which arises from structural correlations between the original and distorted objects. We also utilize an advanced binocular summation model to develop a binocular pooling algorithm. Our experimental results indicate that BPCP achieves high correlations against subjective test results, improving upon those delivered by previous crosstalk prediction models. PMID- 28641259 TI - Face Hallucination Using Linear Models of Coupled Sparse Support. AB - Most face super-resolution methods assume that low- and high-resolution manifolds have similar local geometrical structure; hence, learn local models on the low resolution manifold (e.g., sparse or locally linear embedding models), which are then applied on the high-resolution manifold. However, the low-resolution manifold is distorted by the one-to-many relationship between low- and high resolution patches. This paper presents the Linear Model of Coupled Sparse Support (LM-CSS) method, which learns linear models based on the local geometrical structure on the high-resolution manifold rather than on the low resolution manifold. For this, in a first step, the low-resolution patch is used to derive a globally optimal estimate of the high-resolution patch. The approximated solution is shown to be close in the Euclidean space to the ground truth, but is generally smooth and lacks the texture details needed by the state of-the-art face recognizers. Unlike existing methods, the sparse support that best estimates the first approximated solution is found on the high-resolution manifold. The derived support is then used to extract the atoms from the coupled low- and high-resolution dictionaries that are most suitable to learn an up scaling function for every facial region. The proposed solution was also extended to compute face super-resolution of non-frontal images. Extensive experimental results conducted on a total of 1830 facial images show that the proposed method outperforms seven face super-resolution and a state-of-the-art cross-resolution face recognition method in terms of both quality and recognition. PMID- 28641260 TI - Nested Conjugate Gradient Algorithm With Nested Preconditioning for Non-Linear Image Restoration. AB - We develop a novel optimization algorithm, which we call nested non-linear conjugate gradient (CG) algorithm (NNCG), for image restoration based on quadratic data fitting and smooth non-quadratic regularization. The algorithm is constructed as a nesting of two conjugate gradient iterations. The outer iteration is constructed as a preconditioned non-linear CG algorithm; the preconditioning is performed by the inner CG iteration that is linear. The inner CG iteration, which performs preconditioning for outer CG iteration, itself is accelerated by an another FFT-based non-iterative preconditioner. We prove that the method converges to a stationary point for both convex and non-convex regularization functionals. We demonstrate experimentally that proposed method outperforms the well-known majorization-minimization method used for convex regularization, and a non-convex inertial-proximal method for non-convex regularization functional. PMID- 28641261 TI - Robust Web Image Annotation via Exploring Multi-Facet and Structural Knowledge. AB - Driven by the rapid development of Internet and digital technologies, we have witnessed the explosive growth of Web images in recent years. Seeing that labels can reflect the semantic contents of the images, automatic image annotation, which can further facilitate the procedure of image semantic indexing, retrieval, and other image management tasks, has become one of the most crucial research directions in multimedia. Most of the existing annotation methods, heavily rely on well-labeled training data (expensive to collect) and/or single view of visual features (insufficient representative power). In this paper, inspired by the promising advance of feature engineering (e.g., CNN feature and scale-invariant feature transform feature) and inexhaustible image data (associated with noisy and incomplete labels) on the Web, we propose an effective and robust scheme, termed robust multi-view semi-supervised learning (RMSL), for facilitating image annotation task. Specifically, we exploit both labeled images and unlabeled images to uncover the intrinsic data structural information. Meanwhile, to comprehensively describe an individual datum, we take advantage of the correlated and complemental information derived from multiple facets of image data (i.e., multiple views or features). We devise a robust pairwise constraint on outcomes of different views to achieve annotation consistency. Furthermore, we integrate a robust classifier learning component via l2,p loss, which can provide effective noise identification power during the learning process. Finally, we devise an efficient iterative algorithm to solve the optimization problem in RMSL. We conduct comprehensive experiments on three different data sets, and the results illustrate that our proposed approach is promising for automatic image annotation. PMID- 28641262 TI - Scalable Multi-View Semi-Supervised Classification via Adaptive Regression. AB - With the advent of multi-view data, multi-view learning has become an important research direction in machine learning and image processing. Considering the difficulty of obtaining labeled data in many machine learning applications, we focus on the multi-view semi-supervised classification problem. In this paper, we propose an algorithm named multi-view semi-supervised classification via adaptive regression (MVAR) to address this problem. Specifically, regression-based loss functions with l2,1 matrix norm are adopted for each view and the final objective function is formulated as the linear weighted combination of all the loss functions. An efficient algorithm with proved convergence is developed to solve the non-smooth l2,1 -norm minimization problem. Regressing to class labels directly makes the proposed algorithm efficient in calculation and can be applied to large-scale data sets. The adaptively optimized weight coefficients balance the contributions of different views automatically, which makes the performance robust against the existence of low-quality views. With the learned projection matrices and bias vectors, predictions for out-of-sample data can be easily made. To validate the effectiveness of MVAR, comparisons are made with some benchmark methods on real-world data sets and in the scene classification scenario as well. The experimental results demonstrate the effectiveness of our proposed algorithm. PMID- 28641263 TI - Radian: Visual Exploration of Traceroutes. AB - Several projects deploy probes in the Internet. Probes are systems that continuously perform traceroutes and other networking measurements (e.g., ping) towards selected targets. Measurements can be stored and analyzed to gain knowledge on several aspects of the Internet, but making sense of such data requires suitable methods and tools for exploration and visualization. We present Radian, a tool that allows to visualize traceroute paths at different levels of detail and to animate their evolution during a selected time interval. We also describe extensive tests of the tool using traceroutes performed by RIPE Atlas Internet probes. PMID- 28641264 TI - A Single-Channel EOG-Based Speller. AB - Electrooculography (EOG) signals, which can be used to infer the intentions of a user based on eye movements, are widely used in human-computer interface (HCI) systems. Most existing EOG-based HCI systems incorporate a limited number of commands because they generally associate different commands with a few different types of eye movements, such as looking up, down, left, or right. This paper presents a novel single-channel EOG-based HCI that allows users to spell asynchronously by only blinking. Forty buttons corresponding to 40 characters displayed to the user via a graphical user interface are intensified in a random order. To select a button, the user must blink his/her eyes in synchrony as the target button is flashed. Two data processing procedures, specifically support vector machine (SVM) classification and waveform detection, are combined to detect eye blinks. During detection, we simultaneously feed the feature vectors extracted from the ongoing EOG signal into the SVM classification and waveform detection modules. Decisions are made based on the results of the SVM classification and waveform detection. Three online experiments were conducted with eight healthy subjects. We achieved an average accuracy of 94.4% and a response time of 4.14 s for selecting a character in synchronous mode, as well as an average accuracy of 93.43% and a false positive rate of 0.03/min in the idle state in asynchronous mode. The experimental results, therefore, demonstrated the effectiveness of this single-channel EOG-based speller. PMID- 28641265 TI - A New Method for Neural Spike Alignment: The Centroid Filter. AB - Recordings made directly from the nervous system are a key tool in experimental electrophysiology and the development of bioelectronic medicines. Analysis of these recordings involves the identification of signals from individual neurons, a process known as spike sorting. A critical and limiting feature of spike sorting is the need to align individual spikes in time. However, electrophysiological recordings are made in extremely noisy environments that seriously limit the performance of the spike-alignment process. We present a new centroid-based method and demonstrate its effectiveness using deterministic models of nerve signals. We show that spike alignment in the presence of noise is possible with a 30 dB reduction in minimum SNR compared with the conventional methods. We present a mathematical analysis of the centroid method, characterizing its fundamental operation and performance. Furthermore, we show that the centroid method lends itself particularly well to hardware realization, and we present results from a low-power implementation that operates on an FPGA, consuming ten times less power than conventional techniques - an important property for implanted devices. Our centroid method enables the accurate alignment of spikes in sub-0 dB SNR recordings and has the potential to enable the analysis of spikes in a wider range of environments than has been previously possible. Our method thus has the potential to influence significantly the design of electrophysiological recording systems in the future. PMID- 28641266 TI - An Approach to Identifying Phenomena Accompanying Micro and Nanoparticles in Contact With Irregular Vessel Walls. AB - The objective of this paper is to present the method for determining the nature and values of the forces needed to set micro and nanoparticles sitting immobile at the blood vessel wall in motion. The problem was tackled in two ways. Microparticles were examined as objects coming into contact with the wall with the actual large arteriole-type vessel structure. The forces acting on microparticles 10, 30, and [Formula: see text] in diameter were determined: drag force FD , lift force FL , electrostatic force FE , and gravity force FG . Fluid structure interaction analysis was used to research the problem. However, nanoparticles were examined as objects coming into contact with the endothelial surface layer (ESL). Resistance forces during the movement of nanoparticles 20, 50, and 100 nm in diameter in the ESL were determined. The same was done for aggregates of nanoparticles 50 nm in diameter. Local irregularities in wall surface are important for microparticles. Small irregularities with the small values of electrostatic force FE can effectively stop the particle. In the case of nanoparticles, the key is the interaction of the particle with ESL. The research methodology presented can be used to better understand the particle blood vessel wall interaction phenomena, leading to a more informed particle movement control. The new application of known calculation methods presented in this paper can be successfully used as an additional tool that simplifies planning and design of strategies for drug delivery by means of micro and nanoparticles. PMID- 28641267 TI - A CPU/MIC Collaborated Parallel Framework for GROMACS on Tianhe-2 Supercomputer. AB - Molecular Dynamics (MD) is the simulation of the dynamic behavior of atoms and molecules. As the most popular software for molecular dynamics, GROMACS cannot work on large-scale data because of limit computing resources. In this paper, we propose a CPU and Intel(r) Xeon Phi Many Integrated Core (MIC) collaborated parallel framework to accelerate GROMACS using the offload mode on a MIC coprocessor, with which the performance of GROMACS is improved significantly, especially with the utility of Tianhe-2 supercomputer. Furthermore, we optimize GROMACS so that it can run on both the CPU and MIC at the same time. In addition, we accelerate multi-node GROMACS so that it can be used in practice. Benchmarking on real data, our accelerated GROMACS performs very well and reduces computation time significantly. Source code: https://github.com/tianhe2/gromacs-mic. PMID- 28641268 TI - NewGOA: Predicting New GO Annotations of Proteins by Bi-Random Walks on a Hybrid Graph. AB - A remaining key challenge of modern biology is annotating the functional roles of proteins. Various computational models have been proposed for this challenge. Most of them assume the annotations of annotated proteins are complete. But in fact, many of them are incomplete. We proposed a method called NewGOA to predict new Gene Ontology (GO) annotations for incompletely annotated proteins and for completely un-annotated ones. NewGOA employs a hybrid graph, composed of two types of nodes (proteins and GO terms), to encode interactions between proteins, hierarchical relationships between terms and available annotations of proteins. To account for structural difference between GO terms subgraph and proteins subgraph, NewGOA applies a bi-random walks algorithm, which executes asynchronous random walks on the hybrid graph, to predict new GO annotations of proteins. Experimental study on archived GO annotations of two model species (H. Sapiens and S. cerevisiae) shows that NewGOA can more accurately and efficiently predict new annotations of proteins than other related methods. Experimental results also indicate the bi-random walks can explore and further exploit the structural difference between GO terms subgraph and proteins subgraph. The supplementary files and codes of NewGOA are available at: http://mlda.swu.edu.cn/codes.php?name=NewGOA. PMID- 28641269 TI - A Model-Based Tool for the Analysis and Design of Gene Regulatory Networks. AB - Computational and mathematical models have significantly contributed to the rapid progress in the study of gene regulatory networks (GRN), but researchers still lack a reliable model-based framework for computer-aided analysis and design. Such tool should both reveal the relation between network structure and dynamics and find parameter values and/or constraints that enable the simulated dynamics to reproduce specific behaviors. This paper addresses these issues and proposes a computational framework that facilitates network analysis or design. It follows a modeling cycle that alternates phases of hypothesis testing with parameter space refinement to ultimately propose a network that exhibits specified behaviors with the highest probability. Hypothesis testing is performed via qualitative simulation of GRNs modeled by a class of nonlinear and temporal multiscale ODEs, where regulation functions are expressed by steep sigmoid functions and incompletely known parameter values by order relations only. Parameter space refinement, grounded on a method that considers the intrinsic stochasticity of regulation by expressing network uncertainty with fluctuations in parameter values only, optimizes parameter stochastic values initialized by probability distributions with large variances. The power and ease of our framework is demonstrated by working out a benchmark synthetic network to get a synthetic oscillator. PMID- 28641271 TI - Joint Attributes and Event Analysis for Multimedia Event Detection. AB - Semantic attributes have been increasingly used the past few years for multimedia event detection (MED) with promising results. The motivation is that multimedia events generally consist of lower level components such as objects, scenes, and actions. By characterizing multimedia event videos with semantic attributes, one could exploit more informative cues for improved detection results. Much existing work obtains semantic attributes from images, which may be suboptimal for video analysis since these image-inferred attributes do not carry dynamic information that is essential for videos. To address this issue, we propose to learn semantic attributes from external videos using their semantic labels. We name them video attributes in this paper. In contrast with multimedia event videos, these external videos depict lower level contents such as objects, scenes, and actions. To harness video attributes, we propose an algorithm established on a correlation vector that correlates them to a target event. Consequently, we could incorporate video attributes latently as extra information into the event detector learnt from multimedia event videos in a joint framework. To validate our method, we perform experiments on the real-world large-scale TRECVID MED 2013 and 2014 data sets and compare our method with several state-of-the-art algorithms. The experiments show that our method is advantageous for MED. PMID- 28641270 TI - Force-Rate Cues Reduce Object Deformation Necessary to Discriminate Compliances Harder than the Skin. AB - Grasping and manipulating an object requires us to perceive its material compliance. Compliance is thought to be encoded by relationships of force, displacement, and contact area at the finger pad. Prior work suggests that objects must be sufficiently deformed to become discriminable, but the utility of time-dependent cues has not been fully explored. The studies herein find that the availability of force-rate cues improve compliance discriminability so as to require less deformation of stimulus and finger pad. In particular, we tested the impact of controlling force-rate and displacement-rate cues in passive touch psychophysical experiments. An ink-based method to mark the finger pad was used to measure contact area per stimulus, simultaneously with displacement and force. Compliances spanned a range harder and softer than the finger pad. The results indicated harder compliances were discriminable at lower peak forces when the stimulus control mode was displacement-rate (0.5 N) compared to force-rate (1.3 N). That is, when displacement-rate was controlled to be equal between the two compliances, the resultant force-rate psychophysical cues could be more readily discriminated. In extending prior studies, while some magnitude of finger pad deformation may be sufficient for discriminability, temporal cues tied to force afford more efficient judgments. PMID- 28641272 TI - Aggregation Analysis for Competitive Multiagent Systems With Saddle Points via Switching Strategies. AB - This paper addresses the aggregation issues of competitive multiagent systems (CMASs) consisting of competitive agents with multimodes and saddle points. In such CMASs, due to existing mutual competitions, every agent is equipped with finite multimodes, and every mode in any agent is described as a second-order linear time-invariant (LTI) control system. When the origin is the same saddle point of all modes of agents, to investigate aggregation of the CMASs with switching strategies, we first use switched LTI systems with saddle points to formulate such CMASs. Then, two new stability concepts, called initial-state dependent (ISD) stability and initial-state-independent (ISI) stability, are defined for the CMASs. Based on these new stability concepts, a practical criterion of local/global ISI asymptotic aggregation is proposed for the CMASs. A local/global ISD/ISI asymptotical-stabilizing-control observed as distributed controls of multimodes, stabilizing-switching-paths, and a corresponding algorithm are all designed for local/global aggregation of such CMASs with switching delays. Finally, a numerical example illustrates the effectiveness and practicality of our new results. PMID- 28641273 TI - Learning and Recognition of Clothing Genres From Full-Body Images. AB - According to the theory of clothing design, the genres of clothes can be recognized based on a set of visually differentiable style elements, which exhibit salient features of visual appearance and reflect high-level fashion styles for better describing clothing genres. Instead of using less discriminative low-level features or ambiguous keywords to identify clothing genres, we proposed a novel approach for automatically classifying clothing genres based on the visually differentiable style elements. A set of style elements, that are crucial for recognizing specific visual styles of clothing genres, were identified based on the clothing design theory. In addition, the corresponding salient visual features of each style element were identified and formulated with variables that can be computationally derived with various computer vision algorithms. To evaluate the performance of our algorithm, a dataset containing 3250 full-body shots crawled from popular online stores was built. Recognition results show that our proposed algorithms achieved promising overall precision, recall, and -score of 88.76%, 88.53%, and 88.64% for recognizing upperwear genres, and 88.21%, 88.17%, and 88.19% for recognizing lowerwear genres, respectively. The effectiveness of each style element and its visual features on recognizing clothing genres was demonstrated through a set of experiments involving different sets of style elements or features. In summary, our experimental results demonstrate the effectiveness of the proposed method in clothing genre recognition. PMID- 28641274 TI - An Efficient Multiple Variants Coordination Framework for Differential Evolution. AB - Differential evolution (DE) is recognized as a simple but powerful algorithm in the family of evolutionary algorithms. Over the past two decades, many advanced DE variants with significantly improved performance have been proposed. However, the variants may only achieve the best performance on a certain type of functions. Moreover, a specific optimizer may not always be suitable for the whole optimization process. To overcome these weaknesses, this paper proposes a multiple variants coordination (MVC) framework with two mechanisms, namely, the multiple variants adaptive selecting mechanism and the multiple variants adaptive solutions preserving mechanisms (MV-APM). In MVC, the evolution process is divided into nonoverlap segments with equal numbers of generations. Each segment includes the learning generations (LGs) and executing generations (EGs). In LG, all the candidate DE optimizers are utilized independently. The best performing optimizer is determined and then utilized in EG in the same segment. Furthermore, MV-APM maintains the population by adaptively preserving promising solutions generated by multiple optimizers. Numerical experiments on the CEC2014 benchmark suit show that the proposed MVC framework can significantly improve the performance of the baseline algorithms and the resulted algorithm significantly outperform the start-of-the-art and up-to-date DEs. Moreover, as a general framework, MVC can also be applied to coordinate multiple improved DE variants to further enhance their performance. PMID- 28641275 TI - A case series of surgically diagnosed idiopathic aortitis in a Canadian centre: a retrospective study. AB - BACKGROUND: Idiopathic aortitis became recognized relatively recently, and the body of knowledge concerning this condition is scarce. We aimed to determine the frequency of idiopathic aortitis in aortic specimens, the clinical, laboratory and radiologic characteristics at diagnosis and during follow-up, and the approach to investigation, treatment and monitoring taken by the treating physicians. METHODS: We identified cases of aortitis diagnosed on pathological specimens of the aorta between Jan. 1, 2003, and July 31, 2013, at The Ottawa Hospital by reviewing the hospital's pathology database. Charts of identified patients were reviewed, and data on patient demographic characteristics, clinical features, laboratory and imaging tests, treatment and outcomes were analyzed. RESULTS: A total of 684 aortic specimens were analyzed during the study period; 47 cases of aortitis were identified, 32 of which were idiopathic. Twenty-one patients (66%) had complete imaging of branch vessels at baseline, 16 (76%) of whom had additional aortic or branch vessel lesions. Twelve patients (38%) received corticosteroids postoperatively. Over a mean follow-up period of 47.5 months, among the 12 patients (38%) who had complete imaging of branch vessels at least once, new aortic or branch lesions were diagnosed in 5 (42%); 3/32 patients (9%) required additional vascular surgery; and a new systemic condition was diagnosed in 2/32 (6%). INTERPRETATION: Idiopathic aortitis is commonly discovered incidentally on examination of the pathological specimen following ascending aortic aneurysm repair. No guidelines exist for the investigation, treatment and follow-up of this condition, resulting in great variability of practice. Good-quality prospective studies are needed to address the many unanswered clinical questions regarding idiopathic aortitis and to allow formulation of more definitive recommendations. PMID- 28641276 TI - Atherosclerosis and the Hydrogen Sulfide Signaling Pathway - Therapeutic Approaches to Disease Prevention. AB - Hydrogen sulfide (H2S) is now admitted as a third gasotransmitter together with nitric oxide (NO) and carbon monoxide (CO), albeit it was originally considered as a foul and poisonous gas. Endogenous H2S production in mammalian cells is counting on the three enzymes acting on cysteine. Involvement of H2S in various physiological and pathological processes has been extensively studied in the last fifteen years. Mounting evidence suggests that H2S is able to protect against atherosclerosis development and progression. Exogenous H2S supplement has salutary effects on atherogenesis, and reduction of the endogenous H2S level accelerates atherosclerosis. The anti-atherosclerotic mechanisms of H2S have been descried in different aspects, including endothelium preservation, antioxidative action, anti-inflammatory responses, vasorelaxation, regulation of ion channels, etc. However, further investigation is still needed to help us gain more insights into the fundamental underlying mechanisms, and that will allow us to design better therapeutic applications of H2S in the treatment of atherosclerosis. PMID- 28641277 TI - Association of the CFH Y402H Polymorphism with the 1-Year Response of Exudative AMD to Intravitreal Anti-VEGF Treatment in the Brazilian Population. AB - AIM: Evidence of the relationship between the polymorphism of the complement factor H (CFH) gene at position 402 (Y402H) and the response to the treatment of wet AMD is controversial. The aim of this study was to compare the functional and morphological 1-year evolution of patients with exudative AMD treated with antivascular endothelial growth factor (VEGF) drugs with the CFH Y402H polymorphism in the Brazilian population. METHODS: Forty-six patients treated for wet AMD with bevacizumab or ranibizumab in a pro re nata regimen were included. The evolution of best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and the number of injections over 1 year of follow-up were correlated with CFH genotypes. RESULTS: The analysis of variance for the difference between the BCVA denoted as logMAR (logarithm of the minimum angle of resolution) values showed an improvement at 1 year when compared to baseline (p = 0.039). Profile contrast analysis showed that this difference was significant only in the group without the C allele (p = 0.049), without significance in patients presenting with the risk allele (p = 0.241). CRT showed a mean reduction at 1 year compared to baseline (p < 0.001). Significant differences in the profile contrast test were found in the group without the C allele (p < 0.001) and in patients with the risk allele (p = 0.002). No difference was found in the number of injections among the different groups (p = 0.787). CONCLUSIONS: The presence of the risk allele of the Y402H polymorphism in the CFH gene was related to a less favorable evolution over 1 year in this sample of the Brazilian population with exudative AMD who were being treated with anti-VEGF drugs. In agreement with similar previous studies, this study concludes that the CFH risk genotypes may affect the disease response to treatment. PMID- 28641278 TI - Astragaloside-IV Alleviates Heat-Induced Inflammation by Inhibiting Endoplasmic Reticulum Stress and Autophagy. AB - BACKGROUND: Thermal injury is the main cause of pulmonary disease in stroke after burn and can be life threatening. Heat-induced inflammation is an important factor that triggers a series of induces pathological changes. However, this mechanism underlying heat-induced inflammation in thermal inhalation injury remains unclear. Studies have revealed that astragaloside-IV (AS-IV), a natural compound extracted from Astragalus membranaceus, has protective effects in inflammatory diseases. Here, we investigated whether the protective effects of AS IV occur because of the suppression of heat-induced endoplasmic reticulum (ER) stress and excessive autophagy Methods: AS-IV was administered to Wistar rats after thermal inhalation injury and 16HBE140-cells were treated with AS-IV. TNF alpha, IL-6, and IL-8 levels were determined by ELISA and real-time PCR. ER stress and autophagy were determined by western blot. Autophagic flux was measured by recording the fluorescence emission of the fusion protein mRFP-GFP LC3 by dynamic live-cell imaging. RESULTS: AS-IV had protective effects against heat-induced reactive oxygen species production and attenuated ER stress. AS IV alleviated heat-induced excessive autophagy in vitro and in vivo. Excessive autophagy was attenuated by the PERK inhibitor GSK2656157 and eIF2alpha siRNA, suggesting that heat stress-induced autophagy can activate the PERK-eIF2alpha pathway. Beclin 1 and Atg5 siRNAs inhibited the upregulation of the inflammatory cytokines TNF-alpha, IL-6, and IL-8 after heat exposure. CONCLUSIONS: Thus, AS-IV may attenuate inflammatory responses by disrupting the crosstalk between autophagy and the PERK-eIF2alpha pathway and may be an ideal agent for treating inflammatory pulmonary diseases. PMID- 28641280 TI - 17th Quadrennial Meeting of the World Society for Stereotactic and Functional Neurosurgery. Berlin, Germany, June 26-29, 2017: Abstracts. PMID- 28641279 TI - Editorial Board / Contents / Imprint. PMID- 28641281 TI - Complementary and Alternative Medicine: A Clinical Study in 1,016 Hematology/Oncology Patients. AB - INTRODUCTION: Surveys state a widespread use of complementary and alternative medicine (CAM) in patients with malignant diseases. CAM methods might potentially interfere with the metabolization of tumor-specific therapy. However, there is little communication about CAM use in hematology/oncology patients between patients, CAM providers, and oncologists. PATIENTS AND METHODS: A self administered questionnaire was handed out to all patients attending to the hematology/oncology outpatient clinic of Regensburg University Hospital. Subsequently, a chart review of all CAM users was performed. RESULTS: Questionnaires of 1,016 patients were analyzed. Of these patients, 30% used CAM, preferably vitamins and micronutrients. Main information sources for CAM methods were physicians/nonmedical practitioners and friends/relatives. CAM therapies were provided mainly by licensed physicians (29%), followed by nonmedical practitioners (14%) and the patients themselves (13%). Although 62% of the CAM users agreed that the oncologist may know about their CAM therapy, a chart entry about CAM use was found only in 41%. CONCLUSION: CAM is frequently used by hematology/oncology patients. Systematic communication about CAM is essential to avoid possible drug interactions. PMID- 28641282 TI - Health-Related Genetic Direct-to-Consumer Tests in the German Setting: The Available Offer and the Potential Implications for a Solidarily Financed Health Care System. AB - BACKGROUND: The global genetic direct-to-consumer (DTC) market will reach a volume of USD 230 billion in 2018. The expenditures for this genetic analysis are borne by the customer, whereas consequential costs may arise for a solidarily financed system. In a first step, it is essential to gain an overview of the currently available offer in the German setting. METHODS: In April 2016, we conducted a systematic internet search in the Google search engine. In November 2016, we updated the information of the webpages in terms of country, language, types of health-related tests, additional offer of non-health-related DTC test, information about sensitivity and specificity, certification and accreditation, costs as well as reference to German Act on Genetic Testing. RESULTS: Thirty-five webpages were included in the final overview. A plurality of different predictive analysis options was identified. Price information was not available for all offered genetic analyses. Costs for predictive analysis in one disease vary between EUR 90 and 990, for predictive package analysis between EUR 232.18 and 375, and for genetic lifestyle analysis between EUR 84.55 and 570.20. CONCLUSIONS: Genetic results may lead to uncertainty and anxiety; therefore, subsequent costs for a solidarily financed system may arise. Genetic DTC tests may have an influence on different players on the micro-, meso- and macro-levels, which may have a cost-cutting or cost-increasing effect on health-care expenditures. The increased interest in genetic analysis as well as the possibility of worldwide internet-based access to genetic tests requires population-wide education. PMID- 28641283 TI - [Healing of Amyotrophic Lateral Sclerosis: A Case Report]. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy. CASE REPORT: In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3 dimercaptopropanesulfate (DMPS; overall 86 * 250 mg in 3 years) in combination with alpha-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 ug/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely. CONCLUSIONS: The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials. PMID- 28641284 TI - [Complementary Medicine: A Serious Option as We Are Facing the Problem of Bacterial Antibiotic Resistance]. PMID- 28641285 TI - Role of Glycyrrhizin in the Reduction of Inflammation in Diabetic Kidney Disease. AB - BACKGROUND: Diabetic kidney disease (DKD) is one of the most debilitating complications of type 2 diabetes. Recent evidence suggests chronic inflammation to be one of the causal factors of DKD. The mechanisms entailed are not completely elucidated except that a variety of cytokines play a major role in this process. High mobility group box 1 (HMGB1) is a pro-inflammatory toll-like receptor-4 (TLR4)-binding cytokine that is involved in inflammation-associated gene expression. This investigation was designed to assess the involvement of HMGB1, TLR-4, and nuclear factor (NF)-kappaB in the development of DKD and to evaluate that whether blocking HMGB1 by its natural inhibitor Glycyrrhizin (GLC) can reduce the progression of the disease. METHODS: Studies were carried out in 8 10-weeks old Zucker diabetic fatty (ZDF) and lean, age- and gender-matched rats. At 10 weeks of age, ZDF rats as compared to controls, showed hyperglycemia, without proteinuria. After 8-10 weeks of the development of diabetes, ZDF animals that showed proteinuria were treated with GLC for 4 weeks. In addition, normal rat kidney (NRK-52E) cells with epithelial-like morphology were comparatively treated with GLC under hyperglycemic condition in vitro. RESULTS: Substantial increase in the expression of HMGB1, TLR4, and NF-kappaB in vivo and in vitro under hyperglycemic conditions was observed as compared to normoglycemic conditions. The overexpression of HMGB1, TLR4, NF-kappaB, and glomerular injury marker nestin was significantly ameliorated by GLC administration. CONCLUSION: Our findings suggest that hyperglycemia-induced HMGB1 activation in ZDF rats may contribute to the progression of DKD. PMID- 28641286 TI - Effect of Bexarotene on Platelet Activation and Apoptosis. AB - BACKGROUND/AIMS: The retinoid X receptor (RXRs) stimulator Bexarotene ((4-[1 (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl] benzoic acid) is used for the treatment of several malignancies. Bexarotene is at least in part effective by stimulation of apoptosis of tumor cells. Moreover, Bexarotene triggers eryptosis, the suicidal death of erythrocytes. Similar to erythrocytes, blood platelets lack nuclei but are nevertheless able to enter an apoptosis-like phenotype, characterized by caspase activation, cell shrinkage and cell membrane scrambling with phospha-tidylserine translocation to the cell surface. Platelet apoptosis is triggered by increase of cytosolic Ca2+-activity ([Ca2+]i), which further leads to degranulation and integrin activation. Platelet activation and apoptosis could be elicited by thrombin or collagen related peptide (CRP). The present study explored whether treatment of platelets with bexarotene modifies platelet activation and apoptosis following exposure to thrombin or CRP. METHODS: Platelets isolated from wild-type mice were exposed for 30 minutes to bexarotene (6 ug/ml) without or with an additional treatment with thrombin (0.01 U/ml) or CRP (2 ug/ml or 5 ug/ml). Flow cytometry was employed to estimate cytosolic Ca2+ activity ([Ca2+]i) from Fluo-3 fluorescence, platelet degranulation from P selectin abundance, integrin activation from alphaIIbbeta3 integrin abundance, caspase activity utilizing an Active Caspase-3 Staining kit, phosphatidylserine abundance from annexin-V-binding, and relative platelet volume from forward scatter. RESULTS: In the absence of thrombin or CRP, the administration of bexarotene slightly but significantly increased [Ca2+]i, but did not significantly modify P-selectin abundance, activated alphaIIbbeta3 integrin, annexin-V-binding, cell volume, or caspase activity. Exposure of platelets to thrombin or CRP was followed by significant increase of [Ca2+]i, P-selectin abundance, active alphaIIbbeta3 integrin, annexin-V-binding, and caspase activity. The effects of thrombin on [Ca2+]i, annexin-V-binding, cell volume, and caspase activity as well as the effects of CRP on [Ca2+]i, P-selectin abundance, activated alphaIIbbeta3 integrin, annexin-V-binding, cell volume, and caspase activity were significantly augmented in the presence of bexarotene. CONCLUSIONS: Bexarotene sensitizes blood platelets for thrombin and/or CRP induced activation and apoptosis. PMID- 28641287 TI - Chrysophanol Suppressed Glutamate-Induced Hippocampal Neuronal Cell Death via Regulation of Dynamin-Related Protein 1-Dependent Mitochondrial Fission. AB - Chrysophanic acid, or chrysophanol, is an anthraquinone found in Rheum palmatum, which was used in the preparation of oriental medicine in ancient China. The hippocampus plays a major role in controlling the activities of the short- and long-term memory. It is one of the major regions affected by excessive cell death in Alzheimer's disease. Therefore, neuronal cell-death modulation in the hippocampus is important for maintaining neuronal function. We investigated chrysophanol's effects on glutamate-induced hippocampal neuronal cell death. Chrysophanol reduced glutamate-induced cell death via suppression of proapoptotic factors and reactive oxygen species generation. Furthermore, it downregulated glutamate-induced mitochondrial fission by inhibiting dynamin-related protein 1 (Drp1) dephosphorylation. Thus, chrysophanol suppressed hippocampal neuronal cell death via inhibition of Drp1-dependent mitochondrial fission, and can be used as a therapeutic agent for treating neuronal cell death-mediated neurodegenerative diseases. PMID- 28641288 TI - The Crista Fenestra and Its Impact on the Surgical Approach to the Scala Tympani during Cochlear Implantation. AB - OBJECTIVE: The aim of this work was to describe the dimensions of the crista fenestra and determine its presence by means of high-resolution computed tomography (CT) for the purpose of cochlear implantation via the round window approach. METHODS: A series of 10 adult human temporal bones underwent high resolution CT scanning and were further dissected for microscopic study of the round window niche. RESULTS: In all of the specimens, the round window membrane was fully visualized after the complete removal of bony overhangs. The crista fenestra was identified as a sharp bony crest located in the anterior and inferior borders of the niche; its area ranged from 0.28 to 0.80 mm2 (mean 0.51 +/- 0.18). The proportion of the area occupied by the crista fenestra in the whole circumference of the round window ranged from 23 to 50% (mean 36%). We found a moderate positive correlation between the area of the niche and the dimensions of the crista fenestra (Spearman rho: 0.491). In every case, high resolution CT scanning was unable to determine the presence of the crista fenestra. CONCLUSION: The crista fenestra occupies a variable but expressive area within the bony round window niche. Narrower round window niches tended to house smaller crests. The presence of the crista fenestra is an important obstacle to adequate access to the scala tympani. Nevertheless, a high-resolution CT scan provides no additional preoperative information with regard to its presence for the purpose of surgical access to the scala tympani via the round window niche. PMID- 28641289 TI - Impact of Comorbid Irritable Bowel Syndrome on Treatment Outcome in Non-Erosive Reflux Disease on Long-Term Proton Pump Inhibitor in Japan. AB - BACKGROUND/AIMS: Irritable bowel syndrome (IBS) frequently coexists with non erosive reflux disease (NERD). Efficacy of long-term proton pump inhibitor (PPI) treatment on NERD with or without IBS is controversial. The impact of comorbid IBS in NERD on quality of life (QOL) remains uncertain. We verified the hypothesis that NERD patients with IBS symptoms demonstrated poor responses to long-term PPI treatments, deteriorated QOL, and high frequency of psychological deviations in Japan. METHODS: In all, 141 NERD patients who had been taking PPIs for more than 6 months were enrolled and analyzed. Patient profiles were assessed by GerdQ, IBS Severity Index (IBSSI-J)/Gastrointestinal Symptoms Rating Scale (GSRS)/SF-8, and Hospital Anxiety and Depression Scale (HADS). RESULTS: IBS existed in 37 out of 141 NERD patients. Patients with IBS (the positive-IBS group) demonstrated significantly higher frequencies of extant reflux symptoms than those without IBS (64.9 vs. 40.4%). In the positive-IBS group, 40.5% were classified as middle grade by IBSSI-J. The SF-8 and GSRS scores in this group were significantly lower than those without IBS (the negative-IBS group). Prevalence of depression and anxiety by HADS in the positive-IBS group was significantly higher than that in the negative-IBS group. CONCLUSION: These results proved the hypothesis that considering comorbid IBS among NERD patients on long-term PPI seems recommended in Japan. PMID- 28641290 TI - Long-Term Follow-Up of Choroidal Neovascularization due to Angioid Streaks with pro re nata Intravitreal Anti-VEGF Treatment. AB - PURPOSE: To evaluate the long-term outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) drugs with a pro re nata (PRN) regimen for the treatment of choroidal neovascularization (CNV) secondary to angioid streaks (AS). METHODS: This is a retrospective, multicenter, noncomparative case series of consecutive AS eyes affected by treatment-naive CNV. A complete ophthalmologic examination was performed every 30-45 days after the loading phase, including fluorescein angiography and/or optical coherence tomography. RESULTS: In all, 52 eyes of 39 patients were treated with intravitreal bevacizumab and/or ranibizumab and followed up for a mean of 33.8 months. The best corrected visual acuity at baseline was 20/40, and it deteriorated by an average of 6.8 ETDRS letters per year (p < 0.001). We performed an average of 5.1, 6.5, and 6.8 injections at the 1-, 2-, and 3-year follow-up, respectively. CONCLUSIONS: Intravitreal anti-VEGF drugs in a PRN regimen with close monitoring appear to slow the progression of CNV in AS, but they do not prevent the affected eyes from progressive visual loss. PMID- 28641291 TI - Surgical Management of Patients with Neuroendocrine Neoplasms of the Appendix: Appendectomy or More. AB - BACKGROUND: Appendiceal neuroendocrine neoplasms (ANEN) are mostly indolent tumours treated effectively with simple appendectomy. However, controversy exists regarding the necessity of oncologic right hemicolectomy (RH) in patients with histologic features suggestive of more aggressive disease. We assess the effects of current guidelines in selecting the surgical strategy (appendectomy or RH) for the management of ANEN. Methods/Aims: This is a retrospective review of all ANEN cases treated over a 14-year period at 3 referral centres and their management according to consensus guidelines of the European and the North American Neuroendocrine Tumor Societies (ENETS and NANETS, respectively). The operation performed, the tumour stage and grade, the extent of residual disease, and the follow-up outcomes were evaluated. RESULTS: Of 14,850 patients who had appendectomies, 215 (1.45%) had histologically confirmed ANEN. Four patients had synchronous non-ANEN malignancies. One hundred and ninety-three patients had index appendectomy. Seventeen patients (7.9%) had lymph node metastases within the mesoappendix. Forty-nine patients underwent RH after appendectomy. The percentages of 30-day morbidity and mortality after RH were 2 and 0%, respectively. Twelve patients (24.5%) receiving completion RH were found to have lymph node metastases. Two patients had liver metastases, both of them synchronous. The median follow-up was 38.5 months (range 1-143). No patient developed disease recurrence. Five- and 10-year overall survival for all patients with ANEN as the only malignancy was both 99.05%. CONCLUSIONS: The current guidelines appear effective in identifying ANEN patients at risk of harbouring nodal disease, but they question the oncological relevance of ANEN lymph node metastases. RH might present an overtreatment for a number of patients with ANEN. PMID- 28641292 TI - The Incidence, Clinical Significance, and Treatment Effects of Depression in Cardiac Resynchronization Therapy Recipients. AB - OBJECTIVES: Chronic heart failure (HF) is associated with significantly increased prevalence of depression. The aim of the study was to assess the incidence and clinical impact of depression as well as the effectiveness of depression treatment in HF patients. METHODS: A prospective interventional trial included 285 consecutive cardiac resynchronization therapy recipients. Patients underwent a psychiatric examination at the time of implantation and then it was routinely repeated at 3, 6, and 12 months after the procedure, and every 6 months thereafter. One hundred and thirty-five (47.4%) patients with depression were included in the depression group, whereas the control group was comprised of 150 patients free of depression. Sixty-eight (50.4%) subjects received antidepressants (treated group), whereas the observational group had 67 (49.6%) depressed patients who refused to take antidepressants. RESULTS: Depression remission was achieved in 51 (75.0%) patients from the treated group. Long-term mortality and HF hospitalization rates were significantly higher in the depression group than in the control group (20.7 vs. 11.3% and 32.6 vs. 19.2%, respectively). However, remission from depression was associated with a 40% reduction in the relative risk of major adverse cardiac events (MACE). CONCLUSIONS: Patients with HF and concomitant depression are at higher risk of MACE compared with those free of depression. Effective antidepressant treatment may significantly improve long-term outcomes in this population. PMID- 28641293 TI - Measuring Concurrent Polydrug Use in General Populations: A Critical Assessment. AB - BACKGROUND/AIMS: Polydrug use is a complicated phenomenon that is measured in a wide variety of different ways. Using Finland as an example, we aimed to demonstrate how the prevalence and prevalence trends of concurrent polydrug use (CPU) varied in the general population based on the different measurements used. METHODS: Population-based Drug Surveys conducted every 4 years during 1998-2014 were used. CPU was measured with different measurements: strict, medial and loose definition of CPU, which were based on different combinations of alcohol, illicit drugs, pharmaceutical drugs and cigarettes used during the last 12 months/30 days. Logistic regression was used to estimate the p values for assessing trends. RESULTS: Depending on the measurements used, the prevalence of CPU in 2014 varied between 2.0 and 18.7%. Different definitions also produced contradictory trends of CPU: there was a modest increase in prevalence if it was measured with a medial (p < 0.001) or strict (p = 0.054) definition, but when measured with the loose definition (only measure that included smoking), there was a decrease in prevalence (p < 0.001). CONCLUSIONS: The prevalence of CPU varies greatly depending on the measurement used, as does the course of the prevalence trends. The concept of simultaneous polydrug use may capture the phenomenon better compared to the concept of CPU. PMID- 28641294 TI - The Impact of Gender on Tumour Stage in In-House Complications and Choice of Urinary Diversion: Results of the Austrian Cystectomy Registry. AB - INTRODUCTION AND OBJECTIVES: Bladder cancer is characterized by gender-dependent disparities. To further address this issue, we analysed a prospective, multicentre cystectomy registry. METHODS: An online database was developed that included patient demographics, intra/perioperative data, surgical data and in house complications. RESULTS: Four hundred fifty-eight patients (112 [24.5%] women and 346 [75.5%] men) were analysed. Men and women were comparable regarding age (mean 68 years), body mass index (mean 26.5) and the mean Charlson score (4.8). Women had more advanced tumour-stages (pT3/pT4; women: 57.1%; men: 48.1%). The rate of incontinent urinary diversion was higher in women (83.1%) than in men (60.2%) and in a multivariate analysis, the strongest predictors were M+ status (OR 11.2), female gender (OR 6.9) and age (OR 6.5). Women had a higher intraoperative blood transfusion rate. The overall rate of in-house complications was similar in both genders (men: 32.0%, women: 32.6%). Severe (Clavien-Dindo grade >2) medical (women: 6.3%; men: 5.2%) and surgical (women: 21.5%; men: 14.4%) in-house complications, however, were more frequent in women. CONCLUSIONS: This multicentre registry demonstrates several gender-related differences in patients undergoing radical cystectomy. The higher transfusion rate, the rare use of orthotopic bladder substitutes and the higher in-house complication rate underline the higher complexity of this procedure in women. PMID- 28641295 TI - Diagnosis, Assessment, and Therapeutic Strategy for Colorectal Mixed Adenoneuroendocrine Carcinoma. AB - Colorectal mixed adenoneuroendocrine carcinoma (MANEC), which acts like an aggressive tumor, is a rare clinical manifestation on which only a limited amount of literature exists. Surgical resection by regional lymphadenectomy is considered as the only curative treatment for colorectal MANEC, and adjuvant chemotherapy or radiotherapy is recommended because of its high recurrence rate. Colorectal MANEC is frequently diagnosed at an advanced stage, when it is unresectable, and chemotherapy plays a central role in its treatment. Pathological confirmation of the target lesion component is critical for regimen selection. If the lesion comprises an adenocarcinomatous component, a regimen for colorectal adenocarcinoma should be administered. For lesions comprising mainly a neuroendocrine carcinomatous component, cisplatin combined with etoposide or irinotecan has proven to be clinically appropriate. Everolimus, a mechanistic target of rapamycin pathway inhibitor, also improves survival. Sunitinib malate, another molecular targeting agent, is effective for treating neuroendocrine carcinoma; however, the evidence on its effectiveness for treating gastrointestinal neuroendocrine carcinoma is insufficient. PMID- 28641296 TI - [Commentary on the Article 'Healing of Amyotrophic Lateral Sclerosis: A Case Report' by Mangelsdorf et al.] PMID- 28641297 TI - Factor Analysis and Psychometric Properties of the Minnesota Nicotine Withdrawal Scale and the Minnesota Nicotine Withdrawal Scale-Revised: Italian Version. AB - BACKGROUND/AIMS: We run Exploratory and Confirmatory Factor Analyses of the Minnesota Nicotine Withdrawal Scale (MNWS) and of the MNWS-Revised (MNWS-R). Psychometric properties were also explored. METHODS: Adult Italian smokers, 366 in all, were assessed via the MNWS-R together with rating scales measuring cigarette dependence, alcohol use, anxiety sensitivity and negative affect at baseline and after 3 months. RESULTS: The MNWS showed good psychometric properties (alpha = 0.85; rtt = 0.59) and a unidimensional factor structure. The 2-factor model of MNWS-R had the best fit and the factors were labelled psychological symptoms (alpha = 0.86; rtt = 0.59) and associated somatic features (alpha = 0.64; rtt = 0.45). CONCLUSIONS: MNWS showed 1 factor; MNWS-R showed 2 relatively dependent factors. The results need to be replicated in smokers in withdrawal. PMID- 28641298 TI - Generation of a DNA-Launched Reporter Replicon Based on Dengue Virus Type 2 as a Multipurpose Platform. AB - Dengue viruses (DENV) have become the most important arthropod-borne viruses, causing dengue and severe dengue fever in at least 50-100 million cases each year, mainly in tropical and subtropical countries. During recent years, important advances in the molecular biology concerning the life cycle of these viruses have allowed the manipulation and generation of recombinant viruses and replicons with multiple applications, mainly in viral biology and the screening of antiviral compounds. In the present study, we describe the construction of an enhanced green fluorescent protein-bearing DENV replicon under the control of the cytomegalovirus immediate early promoter. Following a rational in silico design and cloning by standard molecular biology techniques, a reporter DENV-2 replicon and a replication-deficient mutant were constructed, and characterized by confocal microscopy and real-time RT-PCR. The results showed successful transcription, translation, and autonomous viral RNA replication of the DENV replicon from its DNA clone. This novel DENV replicon will allow the study of viral replication and testing of antiviral candidates without the need for in vitro transcription. PMID- 28641299 TI - Monocyte Subsets Are Differentially Lost from the Circulation during Acute Inflammation Induced by Human Experimental Endotoxemia. AB - Three human monocyte subsets are recognized with different functions in the immune system: CD14++/CD16- classical monocytes (CM), CD14++/CD16+ intermediate monocytes (IM) and CD14+/CD16++ non-classical monocytes (NCM). Increased IM and NCM percentages have been reported under inflammatory conditions, yet little is known about monocyte subsets at the onset of inflammation. The human endotoxemia model is uniquely capable of studying the first phases of acute inflammation induced by intravenous injection of 2 ng/kg bodyweight lipopolysaccharide (LPS) into healthy volunteers. After that, monocyte subset counts, activation/differentiation status and chemokine levels were studied over 24 h. The numbers of all subsets were decreased by >95% after LPS injection. CM numbers recovered first (3- 6 h), followed by IM (6-8 h) and NCM numbers (8-24 h). Similarly, increased monocyte counts were observed first in CM (8 h), followed by IM and NCM (24 h). Monocytes did not display a clear activated phenotype (minor increase in CD11b and CD38 expression). Plasma levels of CCL2, CCL4 and CX3CL1 closely resembled the cell numbers of CM, IM and NCM, respectively. Our study provides critical insights into the earliest stages of acute inflammation and emphasizes the necessity to stain for different monocyte subsets when studying the role of monocytes in disease, as neither function nor kinetics of the subsets overlap. PMID- 28641301 TI - Fluoride in Dental Biofilm Varies across Intra-Oral Regions. AB - Information on differences in biofilm fluoride concentration across intra-oral regions may help explain the distribution of caries within the dentition. The aim of this cross-sectional study was to describe the fluoride concentration in saliva and in biofilm fluid and biofilm solids across 6 intra-oral regions. Unstimulated whole saliva was collected from 42 participants and biofilm harvested from the buccal sites in the 4 molar and 2 anterior regions. Samples were collected at least 1 h after use of fluoride dentifrice. No attempt was made to control the participants' food consumption or use of other topical agents. Centrifuged saliva, biofilm fluid, and biofilm solids were analysed for fluoride using a fluoride ion-selective electrode, adapted for microanalysis. Fluoride in biofilm varied across intra-oral regions. The mean biofilm fluid fluoride concentrations across the oral cavity ranged from 11.6 to 16.8 uM, being statistically significantly higher in the upper anterior region than in any other region. In all regions the fluoride concentration in biofilm fluid was higher than in saliva. For biofilm solids the fluoride concentration was highest in the lower anterior region (2,461 MUmol/kg) and lowest in the lower molar regions (388 and 406 MUmol/kg, respectively). Within biofilm, the solids contained most of the fluoride (81 to >99%). The biofilm fluid fluoride concentration was significantly positively associated with salivary fluoride and only marginally associated with that of biofilm solids. In conclusion, this study has shown pronounced differences in fluoride distribution across intra-oral regions and compartments. This shows that the sampling site is a crucial factor for studies of biofilm fluoride. PMID- 28641302 TI - 7-Hexagon Multifocal Electroretinography for an Objective Functional Assessment of the Macula in 14 Seconds. AB - PURPOSE: We present the multifocal electroretinogram (mfERG) with a 7-hexagon array as an objective test of macular function that can be recorded in 14 s. We provide normal values and investigate its reproducibility and validity. METHODS: Healthy participants underwent mfERG testing according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards using the Espion Profile/D310 multifocal ERG system (Diagnosys, LLC, Lowell, MA, USA). One standard recording of a 61-hexagon array and 2 repeated recordings of a custom 7 hexagon array were obtained. RESULTS: A total of 13 subjects (mean age 46.9 years) were included. The median response densities were 12.5 nV/deg2 in the center and 5.2 nV/deg2 in the periphery. Intereye correlations were strong in both the center (rhoCenter = 0.821; p < 0.0001) and the periphery (rhoPeriphery = 0.862; p < 0.0001). Intraeye correlations were even stronger: rhoCenter = 0.904 with p < 0.0001 and rhoPeriphery = 0.955 with p < 0.0001. Bland-Altman plots demonstrated an acceptable retest mean difference in both the center and periphery, and narrow limits of agreement. We found strong correlations of the center (rhoCenter = 0.826; p < 0.0001) and periphery (rhoPeriphery = 0.848; p < 0.0001), with recordings obtained by the 61-hexagon method. CONCLUSIONS: The 7 hexagon mfERG provides reproducible results in agreement with results obtained according to the ISCEV standard. PMID- 28641300 TI - Prenatal Diagnosis of Dextrocardia with Complex Congenital Heart Disease Using Fetal Intelligent Navigation Echocardiography (FINE) and a Literature Review. AB - Fetal dextrocardia is a type of cardiac malposition where the major axis from base to apex points to the right side. This condition is usually associated with a wide spectrum of complex cardiac defects. As a result, dextrocardia is conceptually difficult to understand and diagnose on prenatal ultrasound. The advantage of four-dimensional sonography with spatiotemporal image correlation (STIC) is that this modality can facilitate fetal cardiac examination. A novel method known as fetal intelligent navigation echocardiography (FINE) allows automatic generation of nine standard fetal echocardiography views in normal hearts by applying intelligent navigation technology to STIC volume datasets. In fetuses with congenital heart disease, FINE is also able to demonstrate abnormal cardiac anatomy and relationships when there is normal cardiac axis and position. However, this technology has never been applied to cases of cardiac malposition. We report herein for the first time, a case of fetal dextrocardia and situs solitus with complex congenital heart disease in which the FINE method was invaluable in diagnosing multiple abnormalities and defining complex anatomic relationships. We also review the literature on prenatal sonographic diagnosis of dextrocardia (with an emphasis on situs solitus), as well as tricuspid atresia with its associated cardiac features. PMID- 28641303 TI - MicroRNA-122a Regulates Zonulin by Targeting EGFR in Intestinal Epithelial Dysfunction. AB - BACKGROUND/AIMS: This study aimed to investigate the role of microRNA (miR)-122a in regulating zonulin during the modulation of intestinal barrier. METHODS: Zonulin proteins and their target gene expression were analyzed in miR-122a overexpressing cell lines and in the target gene of epidermal growth factor receptor (EGFR). An mmu-miR-122a intestinal epithelial conditional transgenic (miR-122a-TG) mouse model was established to investigate EGFR and zonulin expression. MiR-122a was also detected in the clinical specimens of inflammatory bowel disease. RESULTS: EGFR was identified as a target gene of miR-122a. The expression level of miR-122a was positively correlated with that of zonulin. The expression level of zonulin was significantly increased, whereas the expression level of EGFR was significantly decreased in the miR-122a-TG mice and in the corresponding primary epithelial culture (P < 0.05). These results were consistent with the data of the clinical specimens. CONCLUSIONS: miR-122a could be a positive factor of zonulin by targeting EGFR, which increased the intestinal epithelial permeability in vivo and in vitro. PMID- 28641304 TI - Hyperemesis Gravidarum: A Review of Recent Literature. AB - BACKGROUND: In the United States, hyperemesis gravidarum is the most common cause of hospitalization during the first half of pregnancy and is second only to preterm labor for hospitalizations in pregnancy overall. In approximately 0.3-3% of pregnancies, hyperemesis gravidarum is prevalent and this percentage varies on account of different diagnostic criteria and ethnic variation in study populations. Despite extensive research in this field, the mechanism of the disease is largely unknown. Although cases of mortality are rare, hyperemesis gravidarum has been associated with both maternal and fetal morbidity. The current mainstay of treatment relies heavily on supportive measures until improvement of symptoms as part of the natural course of hyperemesis gravidarum, which occurs with progression of gestational age. However, studies have reported that severe, refractory disease manifestations have led to serious adverse outcomes and to termination of pregnancies. SUMMARY: Despite extensive research in the field, the pathogenesis of hyperemesis gravidarum remains unknown. Recent literature points to a genetic predisposition in addition to previously studied factors such as infectious, psychiatric, and hormonal contributions. Maternal morbidity is common and includes psychological effects, financial burden, clinical complications from nutritional deficiencies, gastrointestinal trauma, and in rare cases, neurological damage. The effect of hyperemesis gravidarum on neonatal health is still debated in literature with conflicting results regarding outcomes of birth weight and prematurity. Available therapy options remain largely unchanged in the past several decades and focus on parenteral antiemetic medications, electrolyte repletion, and nutritional support. Most studies of therapeutic options do not consist of randomized control studies and cross-study analysis is difficult due to considerable variation of diagnostic criteria. Key Messages: Hyperemesis gravidarum carries a significant burden on maternal health and US health care. Most published research on pathogenesis is observational and suggests multifactorial associations with hyperemesis gravidarum. Precise, strictly defined criteria for clinical diagnosis are likely to benefit meta analyses of further research studies regarding pathogenesis as well as therapeutic options. PMID- 28641305 TI - Incidence of Autoimmune Myasthenia Gravis in a Health Maintenance Organization in Buenos Aires, Argentina. AB - BACKGROUND: Different epidemiological studies, especially in Europe, have estimated the incidence density of myasthenia gravis (MG) to range between 1.7 and 21.3/1,000,000/person-year; however, data from regions such as Latin America are scarce. This study is aimed at estimating the incidence and prevalence of acquired MG in Buenos Aires, Argentina. METHODS: The study population comprised of affiliates of the Italian Hospital Medical Care Program, a prepaid health maintenance organization located in Buenos Aires. The evaluation method for case detection included a retrospective search from January 1, 2006, through December 31, 2012. RESULTS: Of the 60 cases identified, 36 (60%) were females. The median age at diagnosis was 69 years (IQR 51.5-79). The mean age at diagnosis was 63.3 years (SD +/-20). A total of 28 patients (46.7%) had generalized MG and 32 had ocular MG (53.3%). Thirty five patients (58.3%) had acetylcholine receptor antibodies and 2 (3.3%) had muscle-specific receptor tyrosine kinase antibodies. The crude incidence density (ID) of MG was 61.33 per 1,000,000 person-years (95% CI 47.62-79.99). The adjusted ID for the Argentinean population was 38.8 per 1,000,000 person-years (95% CI 27.09-50.51) and for the Buenos Aires population was 47.49 (95% CI 34.73-60.25). CONCLUSIONS: The results obtained are similar to those published for other geographical areas. PMID- 28641306 TI - A New Perspective on Isotretinoin Treatment of Hidradenitis Suppurativa: A Retrospective Chart Review of Patient Outcomes. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a disease characterized by the development of painful, deep-seeded nodules and abscesses. Treatment guidelines include a combination of lifestyle, surgical, and medical interventions. Isotretinoin has not been included in the treatment guidelines due to the limited number of studies and conflicting reports of efficacy. OBJECTIVES: The purpose of this study is to evaluate the clinical response to isotretinoin in HS patients and to determine whether there is a particular patient population that may benefit more from this treatment. METHODS: A retrospective chart review was conducted on all HS patients treated with isotretinoin within the years of 2014 2016. Sex, age, weight, history of acne, Hurley stage, and treatment dose and duration were extracted from patient charts. RESULTS: Of the 25 patients included in the study, 32% (8/25) had no response, 32% (8/26) showed partial response, and 36% (9/25) demonstrated complete response to isotretinoin treatment. Complete response was seen only in Hurley stage I and II patients. Hurley III patients made up 50% of the non-responders. Those with any sort of treatment response were more likely to be female, younger, weigh less, and have a higher prevalence of acne compared to non-responders. LIMITATIONS: This is a retrospective chart review with a small sample size of 25 patients. CONCLUSIONS: Physicians should consider isotretinoin as a potential treatment for HS, as it may be beneficial in patients with mild and moderate disease and patients who are female, younger, weigh less, and have a personal history of acne. PMID- 28641307 TI - Human equilibrative nucleoside transporter 1 gene expression is associated with gemcitabine efficacy in advanced leiomyosarcoma and angiosarcoma. AB - BACKGROUND: The expression of human equilibrative nucleoside transporter 1 (hENT1), the major gemcitabine transporter into cells, has been thoroughly investigated as a predictive marker of response to gemcitabine in pancreatic cancer and biliary tract cancers. Since gemcitabine is widely used in the treatment of leiomyosarcoma and angiosarcoma, we investigated the correlation between hENT1 expression and gemcitabine efficacy in these sarcoma subtypes. METHODS: We retrospectively identified 71 patients affected by advanced angiosarcoma (26) or leiomyosarcoma (45) treated within five Italian referral centres for sarcoma; among them, 49 patients (15 angiosarcoma, 34 leiomyosarcoma) were treated with gemcitabine. All tumour samples were analysed for hENT1 expression by real-time PCR. Median 2-DeltaCt value was used as the cutoff to dichotomise patients into 'high' expression and 'low' expression groups. Kaplan Meier analysis was performed to estimate progression-free survival (PFS) and overall survival (OS). RESULTS: We found a significant association between high hENT1 expression levels and favourable outcome in terms of PFS and OS compared to cases with low hENT1 expression in leiomyosarcoma treated with gemcitabine (PFS: 6.8 vs 3.2 months, P=0.004; OS: 14.9 vs 8.5 months, P=0.007). In addition, hENT1 overexpression correlated with a significant improvement in PFS (9.3 vs 4.5 months; P=0.02) and OS (20.6 vs 10.8 months; P=0.001) in angiosarcoma patients treated with gemcitabine. CONCLUSIONS: Our study suggests that higher hENT1 expression are associated to gemcitabine efficacy both in patients with advanced leiomyosarcoma and angiosarcoma. PMID- 28641309 TI - Sequential versus concurrent chemotherapy for adjuvant breast cancer: does dose intensity matter? PMID- 28641308 TI - Detection of phosphatidylserine-positive exosomes for the diagnosis of early stage malignancies. AB - BACKGROUND: There has been increasing interest in the detection of tumour exosomes in blood for cancer diagnostics. Most studies have focussed on miRNA and protein signatures that are surrogate markers for specific tumour types. Because tumour cells and tumour-derived exosomes display phosphatidylserine (PS) in their outer membrane leaflet, we developed a highly sensitive ELISA-based system that detects picogram amounts of exosomal phospholipid in plasma as a cancer biomarker. METHODS: This report describes the development of a highly specific and sensitive ELISA for the capture of PS-expressing tumour exosomes in the blood of tumour-bearing mice. To monitor the relationship between tumour burden and tumour exosome plasma concentrations, plasma from one transplantable breast cancer model (MDA-MB-231) and three genetic mouse models (MMTV-PyMT; breast and KIC and KPC; pancreatic) were screened for captured exosomal phospholipid. RESULTS: We show that quantitative assessment of PS-expressing tumour exosomes detected very early-stage malignancies before clinical evidence of disease in all four model systems. Tumour exosome levels showed significant increases by day 7 after tumour implantation in the MDA-MB-231 model while palpable tumours appeared only after day 27. For the MMTV-PyMT and KIC models, tumour exosome levels increased significantly by day 49 (P?0.0002) and day 21 (P?0.001) while tumours developed only after days 60 and 40, respectively. For the KPC model, a significant increase in blood exosome levels was detected by day 70 (P=0.023) when only preinvasive lesions are microscopically detectable. CONCLUSIONS: These data indicate that blood PS exosome levels is a specific indicator of cancer and suggest that blood PS is a biomarker for early-stage malignancies. PMID- 28641310 TI - Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy. AB - BACKGROUND: Complete tumour response (pCR) to neo-adjuvant chemo-radiotherapy for rectal cancer is associated with a reduction in local recurrence and improved disease-free and overall survival, but is achieved in only 20-30% of patients. Drug repurposing for anti-cancer treatments is gaining momentum, but the potential of such drugs as adjuncts, to increase tumour response to chemo radiotherapy in rectal cancer, is only just beginning to be recognised. METHODS: A systematic literature search was conducted and all studies investigating the use of drugs to enhance response to neo-adjuvant radiation in rectal cancer were included. 2137 studies were identified and following review 12 studies were extracted for full text review, 9 studies were included in the final analysis. RESULTS: The use of statins or aspirin during neo-adjuvant therapy was associated with a significantly higher rate of tumour downstaging. Statins were identified as a significant predictor of pCR and aspirin users had a greater 5-year progression-free survival and overall survival. Metformin use was associated with a significantly higher overall and disease-free survival, in a subset of diabetic patients. CONCLUSIONS: Aspirin, metformin and statins are associated with increased downstaging of rectal tumours and thus may have a role as adjuncts to neoadjuvant treatment, highlighting a clear need for prospective randomised controlled trials to determine their true impact on tumour response and overall survival. PMID- 28641311 TI - Characterisation of blood-derived exosomal hTERT mRNA secretion in cancer patients: a potential pan-cancer marker. AB - BACKGROUND: Telomerase (human telomerase reverse transcriptase (hTERT)) is considered a hallmark of cancer. The aim of our study was to evaluate the feasibility of the detection of hTERT transcripts in serum as a 'pan-cancer' diagnostic method. METHODS: Human telomerase reverse transcriptase mRNA levels were determined in serum and serum-derived exosomes from 133 patients with different malignancies and 45 healthy controls. In four patients hTERT mRNA levels were measured in different clinical stages. RESULTS: Human telomerase reverse transcriptase transcript was absent in all controls and was variably detected in 67.5% of patients with all cancer types. A correlation between hTERT transcript levels and the clinical course was found in several cases. CONCLUSIONS: Human telomerase reverse transcriptase mRNA levels may reflect the tumour burden and the clinical status of the patient. In patients with detectable levels, this assay may potentially serve as a diagnostic and follow-up 'pan cancer' marker. Owing to the large variety of patients and small sample size in each diagnosis, the statistical power is limited and will be explored further in larger groups. PMID- 28641314 TI - No additional prognostic value for MRE11 in squamous cell carcinomas of the anus treated with chemo-radiotherapy. AB - BACKGROUND: The majority of anal cancers (84-95%) are driven by infection with human papillomavirus (HPV). HPV-positive tumours show significantly better responses to chemo-radiotherapy when compared with HPV-negative tumours. HPV infection is linked to alterations in DNA damage response proteins, including MRE11. MRE11 is a potential predictive biomarker for response to radiotherapy in muscle-invasive bladder cancer and may hold predictive power in other cancers. METHODS: Using a previously reported cohort, we evaluated the levels of MRE11 in anal cancer and assessed its predictive value in this disease. RESULTS: We found no association between the level of MRE11 and relapse-free survival following chemo-radiotherapy. CONCLUSIONS: MRE11 has no predictive value in the analysis of relapse-free survival after chemo-radiotherapy in anal cancer and does not add to the prognostic value of p16 and tumour-infiltrating lymphocyte scores. Further investigation into the role of DNA repair proteins in anal cancer is required. PMID- 28641313 TI - Evaluation of serum microRNA biomarkers for gastric cancer based on blood and tissue pools profiling: the importance of miR-21 and miR-331. AB - BACKGROUND: High stability and disease-specific disarrangements suggest that microRNA molecules (miRNAs) present in body fluids are ideally suited for diagnostic applications, including gastric cancer (GC). However, the actual source of circulating miRNA biomarkers in GC has not been adequately evaluated, particularly in the Western populations that have some distinct characteristics compared with Asian patients. METHODS: Twenty treatment-naive patients with GC along with 20 cancer-free controls were recruited. miRCURY LNA miRNA microarrays were used for miRNA expression profiling in primary tumours and adjacent healthy mucosa. Differentially expressed serum miRNAs were identified with a high throughput TaqMan OpenArray technology in tumour-draining veins of the portal system, as well as peripheral blood of the patients and controls. RESULTS: Tissue profiling identified 108 sequences differentially expressed between primary tumours and adjacent mucosa (87 upregulated and 21 downregulated). Twenty miRNAs found in serum of GC patients showed expression levels higher than in controls. However, only seven of these molecules were overexpressed in primary tumours (miR 130a, miR-331, miR-19a, miR-223, miR-106a, miR-21, and miR-374). Moreover, expression of miR-331 and miR-21 was significantly higher in the peripheral circulation compared to tumour-draining veins of the portal system. CONCLUSIONS: The results indicate that the majority of potential serum miRNA biomarkers may originate from tissues other than the primary tumour. PMID- 28641315 TI - Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. AB - BACKGROUND: Sequential anthracyclines and taxanes are standard adjuvant chemotherapy for patients with high-risk axillary node-positive breast cancer. We compared a sequential to a concurrent regimen in high-risk node-negative early breast cancer. METHODS: Patients were eligible if they had tumours >2 cm or T1c with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40% and vascular, lymphovascular or perineural invasion. They were randomised to receive four cycles of epirubicin 90 mg m-2 followed by four cycles of docetaxel 75 mg m 2 (sequential regimen) or six cycles of epirubicin 75 mg m-2 plus docetaxel 75 mg m-2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with G-CSF prophylaxis only for the concurrent arm. The primary endpoint was disease-free survival (DFS). RESULTS: Between 2001 and 2013, 658 women received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 years, 43.9% of the patients were premenopausal and of the tumours 44.2% were ?2 cm, 52.7% histological grade 3 and 35.3% hormone receptor-negative. After a median follow-up of 70.5 months, there were 29 (8.8%) vs 42 (12.8%) disease relapses (P=0.102) and 11 (3.3%) vs 19 (5.8%) deaths (P=0.135), in the sequential and concurrent arm, respectively. The 5-year DFS rates were 92.6% vs 88.2% for sequential and concurrent arm, respectively (hazard ratio (HR): 1.591; 95% confidence interval (CI): 0.990-2.556; P=0.055). Toxicity included grade 2-4 neutropenia in 54% vs 41% (P=0.001), febrile neutropenia 2.7% vs 6.1% (P=0.06), nausea/vomiting 18.5% vs 12.4% (P=0.03) of patients in the sequential and concurrent arm. There were no toxic deaths. CONCLUSIONS: Sequential compared with the concurrent administration of anthracyclines and taxanes is associated with a non-significant but possibly clinically meaningful improvement in DFS. In the era of molecular selection of patients for adjuvant chemotherapy, this study offers valuable information for the optimal administration of anthracyclines and taxanes in patients with node-negative disease. PMID- 28641312 TI - Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer. AB - BACKGROUND: Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. METHODS: Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). RESULTS: Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. CONCLUSIONS: Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC. PMID- 28641317 TI - Reply to 'Comment on 'The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta analysis''. PMID- 28641316 TI - A cancer geography paradox? Poorer cancer outcomes with longer travelling times to healthcare facilities despite prompter diagnosis and treatment: a data-linkage study. AB - BACKGROUND: Rurality and distance from cancer treatment centres have been shown to negatively impact cancer outcomes, but the mechanisms remain obscure. METHODS: We analysed the impact of travel time to key healthcare facilities and mainland/island residency on the cancer diagnostic pathway (treatment within 62 days of referral, and within 31 days of diagnosis) and 1-year mortality using a data-linkage study with 12 339 patients. RESULTS: After controlling for important confounders, mainland patients with more than 60 min of travelling time to their cancer treatment centre ((OR 1.42; 95% CI 1.25-1.61) and island dwellers (OR 1.32; 95% CI 1.09-1.59) were more likely to commence cancer treatment within 62 days of general practitioner (GP) referral and within 31 days of their cancer diagnosis compared with those living within 15 min. Island-dweller patients were more likely to have their diagnosis and treatment started on the same or next day (OR 1.72; 95% CI 1.31-2.25). Increased travelling time to a cancer treatment centre was associated with increased mortality to 1 year (30-59 min (HR 1.21; 95% CI 1.05-1.41), >60 min (HR 1.18; 95% CI 1.03-1.36), island dweller (HR 1.17; 95% CI 0.97-1.41). CONCLUSIONS: Island dwelling and greater mainland travel burden was associated with more rapid cancer diagnosis and treatment following GP referral even after adjustment for advanced disease; however, these patients also experienced a survival disadvantage compared with those living nearer. Cancer services may need to be better configured to suit the different needs of dispersed populations. PMID- 28641318 TI - Comment on 'The impact of vitamin D pathway genetic variation and circulating 25 hydroxyvitamin D on cancer outcome: systematic review and meta-analysis'. PMID- 28641320 TI - Transcutaneous oximetry measurements of the leg: comparing different measuring equipment and establishing values in healthy young adults. AB - INTRODUCTION: Transcutaneous oximetry measurement (TCOM) is a non-invasive method of determining oxygen tension at the skin level using heated electrodes. AIM: To compare TCOM values generated by different machines and to establish lower limb TCOM values in a cohort of healthy individuals younger than 40 years of age. METHOD: Sixteen healthy, non-smoking volunteers aged 18 to 39 years were recruited. TCOM was obtained at six locations on the lower leg and foot using three different Radiometer machines. Measurements were taken with subjects lying supine, breathing air. RESULTS: Except for one sensor site, there were no statistical differences in measurements obtained by the different TCOM machines. There was no statistical difference in measurements comparing left and right legs. Room air TCOM values for the different lower leg sites were (mean (SD) in mmHg): lateral leg 61.5 (9.2); lateral ankle 61.1 (9.7); medial ankle 59.1 (10.8); foot, first and second toe 63.4 (10.6); foot, fifth toe 59.9 (13.2) and plantar foot 74.1 (8.8). The overall mean TCOM value for the lower limb was 61 (10.8; 95% confidence intervals 60.05-62.0) mmHg. CONCLUSION: Lower-leg TCOM measurements using different Radiometer TCOM machines were comparable. Hypoxia has been defined as lower-leg TCOM values of less than 40 mmHg in non-diabetic patients and this is supported by our measurements. The majority (96.9%) of the lower leg TCOM values in healthy young adults are above the hypoxic threshold. PMID- 28641319 TI - Understanding scuba diving fatalities: carbon dioxide concentrations in intra cardiac gas. AB - INTRODUCTION: Important developments in the diagnosis of scuba diving fatalities have been made thanks to forensic imaging tool improvements. Multi-detector computed tomography (MDCT) permits reliable interpretation of the overall gaseous distribution in the cadaver. However, due to post-mortem delay, the radiological interpretation is often doubtful because the distinction between gas related to the dive and post-mortem decomposition artifactual gases becomes less obvious. METHODS: We present six cases of fatal scuba diving showing gas in the heart and other vasculature. Carbon dioxide (CO2) in cardiac gas measured by gas chromatography coupled to thermal conductivity detection were employed to distinguish decomposition from embolism based on the detection of decomposition gases (hydrogen, hydrogen sulfide and methane) and to confirm arterial gas embolism (AGE) or post-mortem offgasing diagnoses. A Radiological Alteration Index (RAI) was calculated from the scan. RESULTS: Based on the dive history, the intra-cadaveric gas was diagnosed as deriving from decomposition (one case, minimal RAI of 61), post-mortem decompression artifacts (two cases, intermediate RAI between 60 and 85) and barotrauma/AGE (three cases, maximal RAI between 85 and 100), illustrating a large distribution inside the bodies. CONCLUSION: MDCT scans should be interpreted simultaneously with compositional analysis of intra cadaveric gases. Intra-cadaveric gas sampling and analysis may become useful tools for understanding and diagnosing scuba diving fatalities. In cases with short post-mortem delays, the CO2 concentration of the cardiac gas provides relevant information about the circumstances and cause of death when this parameter is interpreted in combination with the diving profile. PMID- 28641321 TI - Identifying and acting on potentially inappropriate care? Inadequacy of current hospital coding for this task. AB - INTRODUCTION: Recent Australian attempts to facilitate disinvestment in healthcare, by identifying instances of 'inappropriate' care from large Government datasets, are subject to significant methodological flaws. Amongst other criticisms has been the fact that the Government datasets utilized for this purpose correlate poorly with datasets collected by relevant professional bodies. Government data derive from official hospital coding, collected retrospectively by clerical personnel, whilst professional body data derive from unit-specific databases, collected contemporaneously with care by clinical personnel. AIM: Assessment of accuracy of official hospital coding data for hyperbaric services in a tertiary referral hospital. METHODS: All official hyperbaric-relevant coding data submitted to the relevant Australian Government agencies by the Royal Hobart Hospital, Tasmania, Australia for financial year 2010-2011 were reviewed and compared against actual hyperbaric unit activity as determined by reference to original source documents. RESULTS: Hospital coding data contained one or more errors in diagnoses and/or procedures in 70% of patients treated with hyperbaric oxygen that year. Multiple discrete error types were identified, including (but not limited to): missing patients; missing treatments; 'additional' treatments; 'additional' patients; incorrect procedure codes and incorrect diagnostic codes. Incidental observations of errors in surgical, anaesthetic and intensive care coding within this cohort suggest that the problems are not restricted to the specialty of hyperbaric medicine alone. Publications from other centres indicate that these problems are not unique to this institution or State. CONCLUSIONS: Current Government datasets are irretrievably compromised and not fit for purpose. Attempting to inform the healthcare policy debate by reference to these datasets is inappropriate. Urgent clinical engagement with hospital coding departments is warranted. PMID- 28641322 TI - Scuba diving and otology: a systematic review with recommendations on diagnosis, treatment and post-operative care. AB - Scuba diving is a popular recreational and professional activity with inherent risks. Complications related to barotrauma and decompression illness can pose significant morbidity to a diver's hearing and balance systems. The majority of dive-related injuries affect the head and neck, particularly the outer, middle and inner ear. Given the high incidence of otologic complications from diving, an evidence-based approach to the diagnosis and treatment of otic pathology is a necessity. We performed a systematic and comprehensive literature review including the pathophysiology, diagnosis, and treatment of otologic pathology related to diving. This included inner, middle, and outer ear anatomic subsites, as well as facial nerve complications, mal de debarquement syndrome, sea sickness and fitness to dive recommendations following otologic surgery. Sixty-two papers on diving and otologic pathology were included in the final analysis. We created a set of succinct evidence-based recommendations on each topic that should inform clinical decisions by otolaryngologists, dive medicine specialists and primary care providers when faced with diving-related patient pathology. PMID- 28641323 TI - Ischaemia-reperfusion injury and hyperbaric oxygen pathways: a review of cellular mechanisms. AB - Ischaemia-induced tissue injury has wide-ranging clinical implications including myocardial infarction, stroke, compartment syndrome, ischaemic renal failure and replantation and revascularization. However, the restoration of blood flow produces a 'second hit' phenomenon, the effect of which is greater than the initial ischaemic event and characterizes ischaemia-reperfusion (IR) injury. Some examples of potential settings of IR injury include: following thrombolytic therapy for stroke, invasive cardiovascular procedures, solid organ transplantation, and major trauma resuscitation. Pathophysiological events of IR injury are the result of reactive oxygen species (ROS) production, microvascular vasoconstriction, and ultimately endothelial cell-neutrophil adhesion with subsequent neutrophil infiltration of the affected tissue. Initially thought to increase the amount of free radical oxygen in the system, hyperbaric oxygen (HBO) has demonstrated a protective effect on tissues by influencing the same mechanisms responsible for IR injury. Consequently, HBO has tremendous therapeutic value. We review the biochemical mechanisms of ischaemia-reperfusion injury and the effects of HBO following ischaemia-reperfusion. PMID- 28641324 TI - Treatment preferences for decompression illness amongst Singapore dive physicians. AB - INTRODUCTION: Owing to the scarcity of randomized controlled trials to guide treatment for decompression illness (DCI), there are many unanswered questions about its management. Apart from reviews and expert opinion, surveys that report practice patterns provide information about useful management strategies. Hence, this study aimed to identify current treatment preferences for DCI amongst diving physicians in Singapore. METHODS: An anonymous web-based questionnaire was sent to known diving physicians in Singapore. The demographics of the respondents were captured. Respondents were asked about their preferred management for five different DCI scenarios. RESULTS: The response rate was 74% (17 of 23 responses). All respondents chose to recompress patients described in the five scenarios. Regarding the number of recompression sessions, "one additional session after no further improvement in signs and symptoms" was the most common end point of treatment across all the scenarios (47 of 85 responses). Analgesics would be used by five physicians, three would use lidocaine and two steroids as adjuvant therapies. CONCLUSIONS: Apart from the general agreement that recompression is indicated for DCI, there was no strong consensus regarding other aspects of management. This survey reinforces the need for robust RCTs to validate the existing recommendations for DCI treatment. PMID- 28641325 TI - Superior canal dehiscence syndrome associated with scuba diving. AB - A 28-year-old female diver presented with dizziness and difficulty clearing her left ear whilst scuba diving. Her pure-tone audiometry and tympanometry were normal. Testing of Eustachian tube function revealed tubal stenosis. Video oculography revealed a predominantly torsional nystagmus while the patient was in the lordotic position. Fistula signs were positive. High-resolution computed tomography (HRCT) of the temporal bone revealed a diagnosis of bilateral superior semicircular canal dehiscence (SCDS). Cervical vestibular-evoked myogenic potential (cVEMP) testing showed that the amplitude of the cVEMP measured from her left ear was larger than that from the right. In electronystagmography (ENG), nose-pinched Valsalva manoeuvres caused eye movements to be mainly directed counterclockwise with a vertical component. Tullio phenomenon was also positive for both ears. SCDS patients tend to be misdiagnosed and misunderstood; common misdiagnoses in these cases are alternobaric vertigo (AV), inner ear barotrauma, and inner-ear decompression sickness. It is difficult to diagnose vertigo attacks after scuba diving as SCDS; however, when the patient develops sound- and/or pressure-induced vertical-torsional nystagmus, HRCT should be conducted to confirm a diagnosis of SCDS. PMID- 28641326 TI - A technical diving-related burns case: treatment in a remote location. AB - Injuries suffered as a result of a rebreather oxygen explosion and fire occurred to a diver on vacation in the island state of Chuuk, Micronesia. The medical and logistical management of the diver in a remote location are described. The mechanism of both the fire and the subsequent blast and burn injuries are discussed. Prevention of and preparation for such incidents are discussed in the context of the increasing frequency of dive and adventure travel to remote areas. PMID- 28641327 TI - Correction to Mathieu D, Marroni A, Kot J: Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment. Diving Hyperb Med. 2017 Mar;47(1):24-32. AB - Consistent with the Committee on Publication Ethics guidelines, we the above authors are initiating a partial retraction and correction of our paper: Mathieu D, Marroni A, Kot J: Tenth European Consensus Conference on Hyperbaric Medicine: recommendations for accepted and non-accepted clinical indications and practice of hyperbaric oxygen treatment. Diving Hyperb Med. 2017 Mar;47(1):24-32. We wish to make the following statement: "Regardless of the strict process of editing and proof-reading of tables included in the above-mentioned publication, we received some comments from readers which showed us that imperfect layout of Table 1 and incorrect layout of Table 2 changed significantly the conclusions which could be drawn from them. Table 1 described the relation between strength of recommendations given by the Jury of the Consensus Conference and the level of evidence based on the GRADE system. There should be a clear and straight relation showing that Level 1 "strong recommendation" should be based on GRADE A "high level of evidence (LOE)", Level 2 "weak recommendation" should be based on GRADE B "moderate LOE", Level 3 "neutral recommendation" should be based on GRADE C "low LOE" and finally no recommendation should be given when only GRADE D "very low LOE" are present. Note that there is no change to the content of the table, but only visual representation of this relationship. Table 2 has been incorrectly printed. In fact, there is no GRADE A LOE. All X marks placed in the column A should be moved to the right, to GRADE B LOE. In the same way, all X marks placed in the column B should be moved to the right, to GRADE C LOE. We voluntarily retract these tables from the above-mentioned publication, expressing our regret for the situation." PMID- 28641328 TI - ECHM Consensus Conference and levels of evidence. AB - The ECHM Consensus Conference on indications for hyperbaric oxygen treatment (HBOT) was a welcome update of the evidence for HBOT use. However, clarification is requested in relation to how the GRADE system (Grades of Recommendation, Assessment, Development and Evaluation) was modified and how levels of evidence were applied in the case of idiopathic sudden sensorineural hearing loss (ISSHL). GRADE has a low kappa value for inter-observer agreement, so is modification valid? The original GRADE criteria, using consensus, grades evidence (defined as high, low and very low) and uses this to adjust the strength of recommendations. Randomised controlled trials (RCTs) score highly. The ECHM have modified the GRADE system without explanation, assigning grades as levels 1 to 4 and have asserted that RCTs which are double-blinded constitute level 1 or 2 evidence. This has important implications for HBOT research. The term double-blinded is not used in the abstract, which leads the reader to wonder; where do RCTs which are not double-blinded fit in? The ECHM, by including the term double blinded as a requirement for level 1 or 2, has lifted the evidence bar. Does this constitute a form of research "bracket creep"? Double-blinding is viewed by many to require a 'sham' treatment in hyperbaric research. Many conditions require multiple doses requiring daily hospital attendance with associated costs of lost time from work and daily transport costs. Even with a crossover after the sham, a requirement of many ethics committees, the lost time for a patient is a considerable burden. Delaying HBOT until crossover in those randomised to the control group in a disease that has a narrow therapeutic temporal window, such as idiopathic sudden sensorineural hearing loss (ISSHL), may affect the chance of recovery. Double blinding is logistically difficult with HBOT. A sham treatment may be achieved by using air instead of oxygen; however, this exposes the non-intervention group to a risk that the intervention group does not have, that of decompression sickness (DCS). This may be considered to be unethical. Researchers have used hypoxic air mixtures to compensate for the higher oxygen partial pressure at depth as the control, but this is complex and increases the nitrogen load (and thus the risk of DCS). RCTs which control by other methods should still be considered high level evidence (as the original GRADE system recognised). Many indications for HBOT have multiple therapies against which to compare, which could act as a control. The requirement for double-blinding to achieve level 1 or 2 evidence may hamper research; an unintended negative consequence. There is lack of consistency of definitions in relation to levels of evidence used by the ECHM. The authors state that for clinical research the levels of evidence are; levels A to F, which they defined. The ECHM jury used a grading scale of level 1 to 4. For ISSHL, this results in a recommendation to treat based on level B evidence. Is this the same as level 2 in their modified system? This is confusing. The authors have not explained why they modified the GRADE system which is itself non-validated. The lack of references to the publications which provide the foundation for the strength of the recommendations leaves the reader unable to determine the true strength of the evidence. The GRADE system has been criticised as it dissociates recommendations from the evidence that the recommendation is founded upon. Further, the application of the GRADE system has been questioned when strong recommendations are made with it as this may cause ethics committees to question whether equipoise exists, further hampering research. How do we present a well designed trial for ISSHL to an ethics committee when a strong recommendation has already been made despite the Cochrane review on ISSHL concluding there is a need for large, well designed RCTs in this area? PMID- 28641329 TI - ECHM Consensus Conference and levels of evidence - Reply. AB - Dr Sherlock asks for clarification on the approach adopted by the European Committee on Hyperbaric Medicine (ECHM) to assessing evidence for establishing indications for hyperbaric oxygen treatment (HBOT). Firstly, regardless of the strict process of editing and proof-reading of tables included in the above mentioned publication, we received comments from some readers that identified imperfect layout of Table 1 and incorrect layout of Table 2 which significantly changed the conclusions to be drawn from them. This concerned both the details of the methodology used and description of the ECHM recommendations and associated levels of evidence. Therefore, those tables are republished in their correct forms in this issue, hoping that this will explain at least some of the doubts and misunderstandings. Both the Editor and ourselves apologise for these errors of publication. Secondly, in the ECHM Consensus Conference methodology, we scored the evidence for clinical studies requiring double-blind randomised controlled trials (RCT) as Level A and B when, at the same time, some scoring scales require simply 'RCT', as correctly pointed out by Dr Sherlock. Long experience in organising evidence based medicine (EBM) meetings and discussions has taught us that RCTs that are not double blinded are often criticised as having serious potential bias and so are denied as level A evidence. Although we acknowledge that double blinding a clinical study in HBOT is a source of difficulty, we chose a priori to consider only double-blinded RCTs in our grading scale to avoid endless discussions about this potential bias. We are well aware that doing so means that Level A evidence is a difficult target for the hyperbaric community. We agree that many evidence scoring systems have a low level of inter-observer agreement. This is why we treat the Consensus Conference as a valuable tool that provides a better opportunity for discussing the evidence than analysis by a small group of 'experts'. This is because the whole process is transparent and available to all participants' comments and input. The final process of voting by the audience after the general discussion thus truly reflects the position of the professional hyperbaric community in Europe on the issued recommendations. By these two mechanisms, the blind application of disputable evidence scoring systems may be avoided or, at least, decreased. Thirdly, the problem of 'sham' treatments in hyperbaric research has been raised. While this has been discussed many times in the past, hyperbaric research is not the sole field where such sham treatment raises some difficulty. Surgery is probably the best example where RCTs with control arms utilising sham surgical procedures (possibly including the administration of anaesthesia) are rare and can raise major ethical problems. Nevertheless, from an EBM viewpoint, the difficulty of designing a double-blind study is never taken into account during evaluation of clinical studies. Finally, Dr Sherlock pointed out her doubts on the recommendations issued by the ECHM on idiopathic sudden sensorineural hearing loss (ISSHL). While there is no possibility to cite here the full experts' report on that issue presented during the conference, we understand that a detailed report from the Conference is being prepared for publication. In brief, the strength of evidence has been scored as Level B, in general agreement with the last Cochrane review and the UHMS Committee report. Based on this level of evidence, the Type 1 recommendation was issued with the agreement of the large majority of the Consensus Conference participants. PMID- 28641330 TI - Use of Shorter Intramedullary Guide for Ipsilateral Total Knee Arthroplasty following Prior Total Hip Arthroplasty. AB - Alignment after total knee arthroplasty (TKA) plays an important role with respect to patient satisfaction and implant survivorship. In patients undergoing ipsilateral TKA with prior total hip arthroplasty (THA), the femoral intramedullary (IM) guide cannot be fully inserted into the femoral canal because of the prior THA. The purpose of this study was to determine the effect of femoral component alignment using a shorter IM guide during TKA in patients with an ipsilateral THA. We identified 42 patients undergoing ipsilateral TKA with the use of a short IM guide in the setting of a prior THA. A matched cohort group was identified from our total joint registry that included 42 patients who underwent primary TKA. The surgical goal was to achieve 5 degrees of valgus on the femoral side and 0 degree on the tibial side with an overall postoperative tibial-femoral angle of 5 degrees of valgus. Patients were evaluated clinically using Knee Society pain scores (KSSs), function scores, and with radiography. Both the tibial-femoral limb alignment and the femoral component alignment were compared using Student's t-test. There were no significant differences between the two groups with respect to sex, age, body mass index (BMI), pre- and postoperative KSSs. There was a statistically significant difference between the two groups with respect to radiographic tibial-femoral limb alignment, 4.33 degrees of valgus in the short stem THA-TKA group versus 5.4 degrees of valgus in the TKA group (p < 0.04); however, this difference did not correlate to a difference in postoperative outcomes. An adequate tibial-femoral component alignment was achieved in patients undergoing ipsilateral TKA with prior THA using a shortened IM femoral guide. PMID- 28641331 TI - [Surgical Treatment of Pseudotumours of the Lung]. AB - INTRODUCTION: Pseudotumour of the lung is a collective term for various subentities. Some subgroups are considered to be intermediary malignant tumours. A pseudotumour is a rare condition, which makes it difficult to estimate its incidence and prevalence. METHODS: Retrospective analysis of all surgically treated patients between 2008 and 2015 diagnosed with a pseudotumour of the lung. The primary endpoint of this study was to estimate the rates of local recurrence and metastasis. Secondary endpoints were to determine the nomenclature, medical history, treatment, and the perioperative course. RESULTS: Out of 27 patients (10 females and 17 males) with a median age of 58 years, 19 patients (70%) had an inflammatory pseudotumour (IPT), and four patients (15%) had an inflammatory myofibroblastoma (IMT). Two patients had a pneumocytoma/histiocytoma. A preoperative pulmonary infection was present in 12 (44%) patients. The average tumour size was 2.1 cm (0.8 - 5.3 cm), with the lower pulmonary lobes being mostly affected (52%). One enucleation, 20 atypical wedge resections and six anatomical resections were performed. This was done in a minimally invasive procedure (VATS) in 48% of cases (13/27). R0 resection was achieved in 93% of cases (25/27). Complications occurred in seven (26%) patients. The difference between the duration of hospital stay (mean duration 8 days) after open resection and VATS was minimal (8.8 vs. 7.2 days). Patients were followed up over a period of 4 years, during which time only one patient developed a tumour recurrence, which led to the patient's death, although she had had a R0 resection of an IMT. CONCLUSIONS: The treatment of choice for pseudotumours of the lung is R0 resection, preferably with VATS. Most patients have a benign course of disease, although relapses are possible in some cases, especially in IMT. Follow-up monitoring is necessary for IMT. The application of a uniform nomenclature and classification would be a sensible approach. PMID- 28641332 TI - Executive Dysfunctions Predict Self-Restricted Driving Habits in Elderly People with or without Alzheimer's Dementia. AB - Introduction The purpose of this study was to elucidate the impact of specific cognitive functions on self-restricted driving habits in healthy elderly drivers and patients suffering from mild cognitive impairment (MCI) and Alzheimer's dementia (AD). Method Our study population included 35 cognitively healthy controls, 10 MCI patients, and 16 patients with AD. All participants completed a neuropsychological examination and a self-reported questionnaire assessing driving habits and patterns. Results In challenging driving conditions, patients with MCI or AD showed significantly more driving self-restriction than healthy subjects (effect size d=1.06, p=0.007). Ordinal regression analysis across the entire group revealed that deficits in executive functions and reaction had a higher impact on driving restriction (p=0.002) than deficits in memory functions (p=0.570). Additionally, our data showed that 40% of patients with mild to moderate AD still drive in challenging conditions. Discussion Our results illustrate that elderly individuals use self-imposed driving restrictions as compensatory strategies. These restrictions increase with cognitive decline mainly in the field of executive functions, but they do not change once patients convert from MCI to AD. PMID- 28641333 TI - Validation of Brain Angiotensin System Blockade as a Novel Drug Target in Pharmacological Treatment of Neuropsychiatric Disorders. AB - Retreat in psychiatric drug development results in innovative medication decline that might be at least partially overcome by adjunct therapy. New evidence from clinical studies has shown a possible role for brain Renin-Angiotensin System (RAS) in both affective and psychotic disorders. Simultaneously, rapidly accumulating data from basic studies indicate effectiveness of central RAS blockade in much broader range of neuropsychiatric disease. Recent findings implicate brain RAS, especially Angiotensin II (Ang II), in neural pathophysiology of mental disorders through neuroendocrine modulation and effects on neurotransmitter release, mostly noradrenaline, acetylcholine and dopamine. The potential effects of angiotensin-converting-enzyme (ACE) inhibition and angiotensin type 1 receptor (AT1R) blockade on treatment of mental disorders are a matter of considerable interest. This review describes involvement of brain RAS in pathophysiology of neuropsychiatric disorders and an intriguing possibilities of improvement in pharmacological treatment outcome, where using angiotensin converting-enzyme inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB), goes beyond blood pressure control. PMID- 28641334 TI - Ventral C1 Fracture Combined with Congenital Posterior Cleft: What to Do? AB - BACKGROUND AND OBJECTIVE: We present a treatment approach for a rare condition of patients with a ventral C1 fracture and a congenital cleft in the posterior arch (half-ring Jefferson fracture) with an intact transverse atlantal ligament. Our technique aims to achieve stability of the atlanto-occipital and atlantoaxial joints while preserving mobility of the upper cervical spine. PATIENTS AND METHODS: Two male patients, 43 years and 29 years of age, respectively, were admitted to our hospital due to a fracture of the ventral arch of the atlas with no damage of the transverse atlantal ligament. Both men also presented a congenital cleft of the posterior arch. Initial conservative management with a halo-thoracic vest was performed in one case and failed. As a result, surgical treatment was performed in both cases using bilateral C1 mass screws and a transverse connector. RESULTS: The patients showed no neurologic deficits on follow-up examination 4 weeks after surgery with a full range of head and neck motion. Computed tomography (CT) showed no dislocation of the implanted material with good dorsal alignment and a stable ventral fracture distance. Follow-up CT showed osseous stability in both cases with the beginning of bony ossification of the bone graft. CONCLUSION: Isolated instable fractures of the ventral arch of the atlas with a congenital cleft of the posterior arch with no damage of the transverse atlantal ligament can be stabilized using bilateral C1 mass screws and a transverse connector preserving upper cervical spine mobility. PMID- 28641335 TI - Jumping Mechanography as a Complementary Testing Tool for Motor Function in Children with Hereditary Motor and Sensory Neuropathy. PMID- 28641337 TI - [In process]. PMID- 28641336 TI - Suppression of Forkhead Box Protein O1 (FOXO1) Transcription Factor May Promote Adrenocortical Tumorigenesis. AB - Despite recent comprehensive genetic analyses, molecular evidence for a pathophysiological continuum linking benign adrenocortical adenoma (ACA) and highly aggressive adrenocortical carcinoma (ACC) is still elusive. Using human tumor samples and the established ACC cell line SW-13, this study investigated potential regulatory roles for FOXO transcription factors, in modulating adrenocortical tumorigenesis. Adrenocortical tumor specimens (20 ACAs, 10 ACCs, and 9 normal adrenal tissue samples) obtained from 30 patients were analyzed for ubiquitously expressed FOXO transcription factors, FOXO1 and FOXO3 using qRT-PCR and immunohistochemistry. The SW-13 ACC cells were used to study the phenotypic effects of FOXO regulation in vitro. While FOXO3 expression remained unchanged in ACCs, FOXO1 expression was found to be significantly downregulated in 19/20 ACAs and 9/10 ACCs (p<0.0001 and p<0.05, respectively), suggesting a global role for FOXO1 suppression in promoting and maintaining adrenocortical dedifferentiation. Silencing of FOXO1 in SW-13 cells resulted in significant loss of viability (p<0.001) mediated by apoptosis as determined by quantitative Annexin V immunofluorescence analysis (p<0.01). FOXO1 silencing also augmented the migratory behavior of SW-13 cells (p<0.0001), suggesting distinct roles for FOXO1 in promoting viability and controlled motility of adrenocortical cells. PMID- 28641338 TI - ? PMID- 28641339 TI - ? PMID- 28641340 TI - ? PMID- 28641341 TI - ? PMID- 28641342 TI - ? PMID- 28641343 TI - ? PMID- 28641344 TI - ? PMID- 28641345 TI - ? PMID- 28641347 TI - ? PMID- 28641346 TI - ? PMID- 28641348 TI - ? PMID- 28641349 TI - ? PMID- 28641351 TI - ? PMID- 28641350 TI - [Laparoscopic-assisted mobilisation and resection of a sacrococcygeal teratoma Altman type III]. AB - Objective This video is a step-by-step illustration of the laparoscopic-assisted mobilisation and resection of a sacrococcygeal teratoma Altman type III. Indication Laparoscopic supralevatory tumour mobilisation is an established method in selected centres and can be the initial step in approaching sacrococcygeal teratomas with an intrapelvic portion, facilitating a complete (R0) resection. Method Laparoscopic surgery is performed in supine position with a 5 mm umbilical trocar, a 5 mm trocar in the right upper abdomen, and two 3 mm trocars in the left middle and lower abdomen. We use a 5 mm 45 degrees optic and 3 mm laparoscopic grasping forceps as well as Overholt clamps. For coagulation, a laparoscopic 5 mm diathermy Sealer (LigaSureTM, Covidien, Neustadt) is used. Conclusion In selected tumours, laparoscopic assisted tumour mobilisation enables surgeons to clearly identify and ligate the primary tumour-supplying vascular structures at the beginning of the operation, thereby avoiding the risk of major bleeding throughout the subsequent tumour mobilisation. The laparoscopic approach also allows an accurate dissection and mobilisation of the supralevatory tumour parts under direct vision. After repositioning the patient into the prone position, infralevatory preparation can be carried out safely and fast in the conventional sacral approach without any major risk of bleeding. PMID- 28641352 TI - [Do General Surgeons Feel Adequately Prepared for the Complex Questions Associated with the Handling of Multi-Resistant Pathogens? - Results of the MR2 Survey]. AB - Background At the present time, there is no evidence available as to the knowledge of general surgeons regarding multi-resistant pathogens (MRP) and the rational use of antibiotic medication (antibiotic stewardship/ABS) compared with physicians from other disciplines. Methods As part of the MR2 survey (Multiinstitutional Reconnaissance of practice with MultiResistant bacteria - a survey focussing on German hospitals), a questionnaire comprising 4 + 35 items was distributed to urologists, internists, gynaecologists and general surgeons in 18 hospitals. Multivariate regression models were applied to assess the impact of each discipline affiliation on predefined endpoints. Results 456 evaluable surveys were analysed. The response rate of surgeons (156/330; 47%) and physicians from other disciplines (300/731; 41%) did not differ significantly. Based on their self-assessment, surgeons indicated a significantly lower certainty regarding the correct choice of dose, frequency and duration of antibiotic treatment (p = 0.005), the decision between intravenous or oral application (p = 0.005), as well as the accurate interpretation of microbiological reports (p = 0.023). Both surgeons and doctors from other disciplines rated their knowledge of ABS as limited. An insignificant difference was found between surgeons and non-surgeons regarding the knowledge of E. coli resistance against Ciprofloxacin in their own hospital (27.6 vs. 35.3% estimated the correct category; p = 0.114), with 64% of surgeons underestimating the local resistance rates. Both physician groups assumed that the frequent use of broad spectrum antibiotics is substantially responsible for the increase in MRP. However, in the given case study of a highly symptomatic female patient with uncomplicated urinary tract infection, both physician groups were almost equally likely to propose treatment with a broad-spectrum antibiotic (34.0 vs. 29.3%; p = 0.331). Based on the results of the multivariate models, there were no significant differences between surgeons and non-surgeons with regard to both the attendance of training courses related to MRP/ABS over the past 12 months and the quality of discharge summaries in their hospitals regarding the correct listing of MRP. Conclusion In due consideration of the results of the MR2 survey, mandatory ABS programs should be implemented in hospitals, including regular training of physicians regardless of their discipline. PMID- 28641353 TI - [Negative Pressure Wound Therapy: Randomised Controlled Trials from 2000 to 2015]. AB - Background Negative pressure wound therapy is believed to promote wound healing. However, the results from randomised controlled trials (RCTs) are inconsistent. Systematic reviews indicate unclear evidence, due in part to low-quality RCTs, calling for more RCTs of higher quality. Methods This study aimed to ascertain the number of RCTs as well as systematic reviews on RCTs published during the time period from 2000 to 2015. Various search strategies were used to identify studies in PubMed, Cochrane Library, Google, references lists of retrieved articles, and institutions that issue evidence reports. The study also aimed to investigate the quality of included RCTs. It evaluated whether or not the randomisation methodology was comprehensibly described and conclusions were based on acceptable endpoints. Results The search for studies resulted in 456 different references, which included a total of 49 RCTs and 81 systematic reviews. Randomisation was comprehensibly described in 37% (18 out of 49 RCTs) and concealment of allocation in 10% (5?out of 49 RCTs). Conclusions were based on acceptable endpoints in 55% (27 out of 49 RCTs). A superior efficacy of NPWT versus standard was stated in 65% (32 out of 49 RCTs). In studies based on acceptable endpoints, this proportion was 16% (8 out of 49 RCTs). Systematic reviews repeatedly included identical study data. Conclusion The published literature, reviewed over a period of more than 16 years, contains more systematic reviews incorporating secondary data from other RCTs than actual RCTs reporting primary clinical data. Many RCTs seem to be of low quality, which considerably limits the validity of the corresponding conclusions. The ongoing production of potentially unreliable RCTs and redundant systematic reviews does not seem to provide convincing answers to crucial clinical research questions. Therefore, a change in strategy should be contemplated to observe individual characteristics of the respective persons and the wounds in question. PMID- 28641354 TI - [Acute Liver Failure, Acute-On-Chronic Liver Failure, Hepatorenal Syndrome, Hepatopulmonary Syndrome and Portopulmonary Hypertension, Artificial Liver Support on the ICU]. AB - Background Acute hepatic dysfunction in the form of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) is a disease with a high risk of mortality and requires interdisciplinary intensive care. Aim This article explains the nomenclature, pathophysiology, prognosis and possible treatment options of ALF and ACLF, including the possibilities of extracorporeal liver support therapy at the point of liver transplantation (LTx). Method Narrative review with a selective literature review and representative case studies. Results/Corner Points ALF and ACLF may have several causes and are associated with high mortality. The causes of ALF must be accurately diagnosed because targeted treatment options are available. Both ALF and ACLF may require a liver transplantation for the patient's survival. For ALF and ACLF there are different criteria for decision-making on liver transplantation and graft allocation. For extracorporeal liver support therapy, two methods have been established (MARS [molecuar adsorbent recirculating system] and FPSA [fractionated plasma separation and adsorption] Prometheus(r)). Both approaches may have the potential to increase the probability of survival of patients with ALF or ACLF. In some cases they can be used for bridging to liver transplantation, in individual cases also for primary poison elimination, e.g. after Amatoxin ingestion. Both methods are not suitable for long-term therapy. Conclusion Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are serious diseases with a high risk of mortality. Affected patients should receive immediate interdisciplinary intensive care in a (tertiary) centre with the aim to clarify the cause of the disease as well as possible treatment options with respect to available extracorporeal liver support therapy and liver transplantation. PMID- 28641356 TI - [Tracheal Surgery]. AB - Surgery of the trachea is a specialised field in which many disciplines work jointly due to the variety of indications and the extended topography. Not only because of its particular functional importance, but also because of its complex morphology, anatomy and physiology, this organ represents a special therapeutic challenge. A variety of diseases require surgical procedures of the trachea; the therapeutic strategy is influenced both by the disease itself as well as patient dependent parameters. Regardless of the nature of the underlying disorder, good results require a high level of expertise in airway management, a careful diagnosis and interventional planning as well as an experienced surgical team that masters extended operative techniques. An optimal treatment decision always requires a multidisciplinary assessment of the patient's individual situation by interventional pulmonologists, thoracic surgeons, visceral surgeons, ENT (ear, nose and throat) surgeons and anaesthesiologists. PMID- 28641357 TI - [The German Thorax Registry: Implementation of an Established Tool of Perioperative Health Care Research]. AB - The collection of clinical treatment data in registry databases is an important aspect of health services research. It allows for a critical evaluation of the safety, efficacy and cost-effectiveness of clinical treatment concepts in large patient populations. The findings of registry research represent real-world patients and treatment structures as they are not limited by strict inclusion criteria or unrealistic conditions as applied in prospective clinical trials. The implementation of the German Thorax Registry has enabled the collection and analysis of data on the interdisciplinary care (thoracic surgery, anaesthesiology, intensive care, pain management) of patients undergoing thoracic surgery. Under the auspices of the German Society of Anaesthesiology and Intensive Care Medicine and the German Society of Thoracic Surgery, a registry of the Hospital of the University Witten/Herdecke-Cologne, purely surgical at first, was expanded in close cooperation with the University Hospital of Freiburg. After a comprehensive data protection concept was drafted and a test phase completed, the German Thorax Registry was officially launched in January 2016. Most notably, participating hospitals profit from the registry's "benchmarking" services. "Benchmarking", i.e. the comparison of treatment quality between different hospitals, enables participants to identify individual profiles, strengths and weaknesses on a nation-wide level and follow their own progress over the course of several years. An online database for data entry and benchmarking is always accessible (www.thoraxregister.de). In October 2016, the spectrum of participants was expanded to include all hospitals performing at least 50 thoracic operations a year. PMID- 28641358 TI - [Pain Treatment After Thoracic Surgery]. AB - The treatment of pain after thoracic surgery is a challenge and takes place in the individual clinics mostly according to clinic internal standards. It exists no currently valid S3 guideline for the treatment of acute perioperative and posttraumatic pain. For an effective pain treatment as well individual pain experience as the pain intensity of the various thoracic surgical procedures must be considered. Regular pain assessment with appropriate methods and their documentation form the basis for adequate and adapted pain therapy.There are a number of different pain therapy methods, non-medicamentous and drug-based methods, whose effectiveness is described in the literature partially different. For the treatment of acute postoperative pain after thoracic surgery, mainly drug related procedures are used, except for physiotherapy as a non-medicamentous method. Increasingly, alternative procedures for the peridural catheter as a therapeutic gold standard in the treatment of pain after thoracic surgery are used. Their application can be integrated into a therapeutic algorithm. PMID- 28641359 TI - [To have concern of prejudice to the authorized medical expert]. AB - In civil and criminal court cases, the medical expert must follow certain (legal) regulations which in general are not conveyed as part of his/hers medical education. The medical experts should observe, that they are themselves not the investigators, but rather only aids to the court. Above and beyond that, the medical experts must conduct themselves in such a manner as to avoid at all times any appearance of prejudice during the course of the judicial proceedings. PMID- 28641360 TI - [Strategies on the treatment of nerve injuries accompanied by severe soft tissue damage - Consensus statement of the German-Speaking Society for Microsurgery of Peripheral Nerves and Vessels]. AB - Nerve injuries with severe soft tissue damage are rare and demand a complex and individualized treatment approach, in order to limit medical and socioeconomic consequences. Since uniform systematic evidence so far is lacking, inconsistent therapy standards are implemented depending on individual experiences and background of respective microsurgeons.In order to provide best conditions for further healing, basic expert consensus statements were developed in a workshop on the 38th Annual Meeting of the German-speaking Community for Microsurgery of the Peripheral Nerves and Vessels (DAM).Statements were consented in regard of the aspects: timing of nerve and soft tissue repair, techniques of nerve repair, as well as rehabilitation and healing process control. PMID- 28641361 TI - Maternal Alcohol Use Disorder and Risk of Child Contact with the Justice System in Western Australia: A Population Cohort Record Linkage Study. AB - BACKGROUND: Early contact with the justice system is associated with a multitude of negative outcomes across the life course. This includes an increased risk of ongoing justice contact, social disadvantage and marginalization, and mental health and substance use issues. Children whose mothers have an alcohol use disorder may be at risk of early justice system contact, and we sought to quantify this relationship in a Western Australian cohort. METHODS: This population cohort study made use of linked administrative data. Those in-scope for the study were women who had a birth recorded on the Midwives Notification System (1983 to 2007). The exposed cohort were mothers who had an alcohol-related diagnosis (ICD9/10), recorded on administrative data. This included mental and behavioral disorders which were alcohol related, diseases which could be entirely attributed to alcohol and other ICD alcohol codes. These women were considered to have an alcohol use disorder, which was a proxy for heavy drinking. The comparison cohort was frequency-matched sample with no alcohol-related diagnosis identified on administrative data sets. RESULTS: After adjusting for potential confounders, children whose mothers had a maternal alcohol use disorder had a significantly increased odds of justice contact when compared to those whose mothers had no diagnosis (odds ratio [OR] = 1.79, 95% confidence interval [CI] = 1.60 to 1.99). Additional significant maternal factors associated with child justice contact included being Indigenous (OR = 5.14, 95% CI = 4.54 to 5.81), low maternal age, low socioeconomic status, being unmarried, and a history of a mental health problems. Significant child-level factors, which were associated with increased odds of justice contact, included being male, a mental health diagnosis, child protection contact, parity, and academic failure. CONCLUSIONS: Children who were exposed to a maternal alcohol use disorder had significantly increased odds of contact with the justice system. Additional risk was associated with being Indigenous and with markers of social disadvantage. These results suggest that prevention and early intervention services should span across agencies in an effort to reduce risk. PMID- 28641362 TI - Estimating the potential cost of a high dose immune tolerance induction (ITI) therapy relative to the cost of a combined therapy of a low dose ITI therapy with bypassing agent prophylaxis. AB - INTRODUCTION: The International Immune Tolerance Study (I-ITI) demonstrated comparable success rates between low (FVIII 50 IU/kg/TIW) and high dose (FVIII 200 IU/kg/day) regimens. While costlier, the high dose ITI regimen achieved shorter time-to-treatment success with fewer bleeding episodes compared to the low dose ITI regimen. Adding bypassing agent prophylaxis (BAP) to a low dose ITI regimen may reduce bleeding while still being less costly than high dose ITI. AIM AND METHODS: An economic model was developed to compare high dose ITI to low dose ITI with BAP. All model inputs were derived from clinical trials. The I-ITI study indicated a median time to negative inhibitor titre of 4.6 and 9.2 months and average number of bleeds/patient of 4.2 and 9.9 for the high and low dose regimens respectively. Based on the BAP trials, aPCC (85 U/kg/TIW) and rFVIIa (90 MUg/kg/day) achieved a 62% and 45% reduction in bleeding frequency respectively. Cost analysis was from a US third party payer perspective and limited to drug costs. One-way, two-way and probabilistic sensitivity analyses were performed. RESULTS: Costs of low dose ITI with aPCC prophylaxis until negative inhibitor titre is achieved was 24.0% less compared to high dose ITI. Low dose ITI with rFVIIa prophylaxis cost 46.5% more compared to high dose ITI. Model results were robust in the majority of the sensitivity analyses. CONCLUSION: A low dose ITI regimen with aPCC prophylaxis may be cost saving compared to a high dose ITI regimen with the potential to reduce morbidity by lowering the risk for breakthrough bleeds. PMID- 28641363 TI - A phase III randomized controlled study on the efficacy and improved bowel function of prolonged-release (PR) oxycodone-naloxone (up to 160/80 mg daily) vs oxycodone PR. AB - BACKGROUND: Oxycodone/naloxone (OXN PR) is a prolonged-release formulation containing oxycodone and naloxone in a 2:1 ratio. This study aimed to evaluate the tolerability and efficacy of doses up to OXN160/80 mg PR compared with oxycodone prolonged-release formulation (OxyPR) in a randomised controlled trial. METHODS: Two hundred and forty-three patients were randomised to treatment with OXN PR (n = 123) or OxyPR (n = 120) during the 5-week double-blind study. Measured were: opioid-induced constipation [bowel function index score (BFI)]; analgesic efficacy (NRS 0-10); daily laxative rescue medication use; rescue medication use, and the number of complete spontaneous bowel movements (CSBMs) per week. A subanalysis was conducted in cancer patients. RESULTS: Greater reductions in mean BFI scores were reported for the OXN PR group compared with OxyPR from Week 1 onwards; at Week 5 the mean change from baseline was -32.5 versus -14.2. Average 24-h pain scores were low and remained stable in the range 3-4 in both treatment groups. Analgesic rescue medication use was similar between the groups. Patients receiving OXN PR used significantly lower mean daily doses of laxative rescue medication than those receiving OxyPR (P = 0.006). The number of CSBM in the OXN PR group approximately doubled compared with a 25% decrease in the OxyPR group. Comparable results to the total study population were reported in the cancer patient subgroup. CONCLUSIONS: OXN PR in daily doses of up to 160/80 mg significantly improves bowel function compared with equivalent doses of OxyPR while still providing comparable analgesic efficacy. SIGNIFICANCE: Effective analgesia can be achieved using oxycodone/naloxone PR up to 160/80 mg daily without compromising bowel function. A similar outcome was reported in cancer and non-cancer patients. PMID- 28641364 TI - Access to Coverage and Care for People with Preexisting Conditions: How Has it Changed Under the ACA? AB - ISSUE: Prior to the Affordable Care Act (ACA), people with preexisting health conditions could be denied insurance coverage or charged higher rates. If the law is repealed, these protections could be diluted or lost altogether. GOALS: Assess the ACA's impact on coverage and access for people with preexisting conditions and compare their coverage gains with state high-risk-pool enrollment pre-ACA. METHODS: Analysis of Behavioral Risk Factor Surveillance System data for the period 2011-13 to 2015. KEY FINDINGS AND CONCLUSIONS: Between 2013 and 2015, 16.5 million nonelderly adults gained coverage following full ACA implementation. Of those, 2.6 million had preexisting conditions that could have otherwise precluded them from coverage because of discriminatory denials and pricing; 9.4 million had conditions that could have otherwise affected insurance cost. We found strong correlations between these coverage gains and access to care. Coverage and access gains for people with preexisting conditions were unrelated to the size or existence of the state high-risk pools that 35 states funded for such individuals pre-ACA. Our findings suggest that proposals to replace current protections for people with preexisting conditions with high-risk pools are unlikely to be sufficient to maintain the ACA's gains. PMID- 28641366 TI - Human Papillomavirus Vaccine Effectiveness Against Incident Genital Warts Among Female Health-Plan Enrollees, United States. AB - We examined the effectiveness of human papillomavirus vaccination by dose number and spacing against incident genital warts in a cohort of 64,517 female health plan enrollees in the United States during 2006-2012. Eligible recipients were classified into groups by regimen: 0, 1, 2 (<6 months apart), 2 (>=6 months apart), or 3 doses. They were followed until a genital wart diagnosis, loss to follow-up, or the end of study. Propensity score weights were used to balance baseline differences across groups. To account for latent genital warts before vaccination, we applied 6- and 12-month buffer periods from last and first vaccine dose, respectively. Incidence rates and hazard ratios were calculated using Poisson regression and Cox models. The propensity score-weighted incidence rate per 100,000 person-years was 762 among unvaccinated participants. Using 6- and 12-month buffer periods, respectively, incidence rates were 641 and 257 for 1 dose, 760 and 577 for the 2-dose (<6-month interval) regimen, 313 and 194 for the 2-dose (>=6-month interval) regimen, and 199 and 162 among 3-dose vaccinees; vaccine effectiveness was 68% and 76% for the 2-dose (>=6-month interval) regimen and 77% and 80% in 3-dose vaccinees compared with unvaccinated participants. Vaccine effectiveness was not significant among vaccinees receiving 1-dose and 2 dose (<6-month interval) regimens compared with unvaccinated participants. Our findings contribute to a better understanding of the real-world effectiveness of HPV vaccination. PMID- 28641365 TI - Ultrasonography-guided 14-gauge core biopsy of the breast: results of 7 years of experience. AB - PURPOSE: This study assessed the outcomes of ultrasound (US)-guided core needle biopsies (CNBs) of breast lesions with at least 2 years of follow-up to determine the false-negative rate and to evaluate the diagnostic accuracy of CNB. METHODS: We retrospectively analyzed 13,254 consecutive US-guided 14-gauge CNBs for breast lesions. We excluded biopsies if non-malignant biopsy result was not confirmed by surgical excision or US-guided vacuum-assisted biopsy, or fewer than 2 years of follow-up data were available. A total of 4,186 biopsies were excluded, and 9,068 breast masses from 7,039 women were included. The pathologic findings from each CNB were assessed using the standard diagnostic reference, defined based on the results of surgical excision, vacuum-assisted biopsy, or at least 2 years of long term imaging follow-up. The false-negative rate and underestimation rate were calculated. RESULTS: Of the 9,068 CNBs, benign pathology was found in 64.2%, high risk results in 3.5%, and malignant results in 32.3%. Of the 5,821 benign CNBs, an additional malignancy was found at excision in 63 lesions, leading to a false negative rate of 2.0% (63 of 3,067). The underestimation rate was 33.6% (111 of 330) for ductal carcinoma in situ and 24.5% (79 of 322) for high-risk results at surgical excision. Most false-negative diagnoses (84.1%, 53 of 63) were recognized through imaging-histology correlations, and immediate rebiopsies were performed. Ten malignancies (15.9%, 10 of 63) had delayed diagnoses and showed progression in follow-up US imaging. CONCLUSION: US-guided 14-gauge CNB provided optimal diagnostic information. Imaging-histology correlations and appropriate imaging follow-up should be performed to avoid delayed diagnoses. PMID- 28641367 TI - Annual Crop-Yield Variation, Child Survival, and Nutrition Among Subsistence Farmers in Burkina Faso. AB - Whether year-to-year variation in crop yields affects the nutrition, health, and survival of subsistence-farming populations is relevant to the understanding of the potential impacts of climate change. However, the empirical evidence is limited. We examined the associations of child survival with interannual variation in food crop yield and middle-upper arm circumference (MUAC) in a subsistence-farming population of rural Burkina Faso. The study was of 44,616 children aged <5 years included in the Nouna Health and Demographic Surveillance System, 1992-2012, whose survival was analyzed in relation to the food crop yield in the year of birth (which ranged from 65% to 120% of the period average) and, for a subset of 16,698 children, to MUAC, using shared-frailty Cox proportional hazards models. Survival was appreciably worse in children born in years with low yield (full-adjustment hazard ratio = 1.11 (95% confidence interval: 1.02, 1.20) for a 90th- to 10th-centile decrease in annual crop yield) and in children with small MUAC (hazard ratio = 2.72 (95% confidence interval: 2.15, 3.44) for a 90th- to 10th-centile decrease in MUAC). These results suggest an adverse impact of variations in crop yields, which could increase under climate change. PMID- 28641370 TI - Reply: Trazodone to change the risk of neurodegeneration: bedside to bench. PMID- 28641368 TI - Glomerular Hyperfiltration in Obese African American Hypertensive Patients Is Associated With Elevated Urinary Mitochondrial-DNA Copy Number. AB - BACKGROUND: Glomerular hyperfiltration may contribute to the high incidence of renal disease in Obese African Americans essential hypertensive (ObAAEH) patients, but the precise mechanisms responsible for renal injury have not been elucidated. Mitochondria are important determinants of renal injury in hypertension, and increased levels of mitochondrial DNA (mtDNA) in the urine may indicate renal mitochondrial injury. We hypothesized that urine mtDNA copy numbers would be higher in ObAAEH compared to Caucasian essential hypertensive (CEH) patients. METHODS: We prospectively measured systemic, renal vein (RV), inferior vena cava (IVC), and urinary copy number of the mtDNA genes COX3 and ND1 by quantitative-PCR in CEH and ObAAEH patients during constant sodium intake and antihypertensive regimens, and compared them with healthy volunteers (HV) (n = 23 each). RESULTS: Blood pressure was similarly elevated in CEH and ObAAEH, while glomerular filtration rate (GFR) was higher and age lower in ObAAEH. Urinary (but not plasma) COX3 and ND1 were higher in CEH compared to HV, and further elevated in ObAAEH patients. COX3 and ND1 renal gradients (RV-IVC) were higher in ObAAEH vs. CEH, and their urinary levels directly correlated with GFR. In multivariate analysis, GFR remained the only predictor of elevated urinary COX3 and ND1 levels. CONCLUSIONS: Urinary fragments of the mitochondrial genome are elevated in ObAAEH patients and correlate with glomerular hyperfiltration. A positive gradient across the kidney in ObAAEH suggests selective renal release. These results are consistent with mitochondrial injury that may aggravate renal damage and accelerate hypertension-related morbidity/mortality rates in ObAAEH. PMID- 28641369 TI - Markers of Inflammation and Incident Breast Cancer Risk in the Women's Health Study. AB - Chronic inflammation may be a risk factor for the development and progression of breast cancer, yet it is unknown which inflammatory biomarkers and pathways are especially relevant. The present study included 27,071 participants (mean age = 54.5 years) in the Women's Health Study who were free of cancer and cardiovascular disease at enrollment (1992-1995), with baseline measures of 4 inflammatory biomarkers: high-sensitivity C-reactive protein, fibrinogen, N acetyl side-chains of acute phase proteins, and soluble intercellular adhesion molecule-1. We used Cox proportional hazards regression models to evaluate associations between baseline concentrations of biomarkers and incident breast cancer, and adjusted for baseline and time-varying factors such as age and body mass index. Self-reported invasive breast cancer was confirmed against medical records for 1,497 incident cases (90% postmenopausal). We observed different patterns of risk depending on the inflammatory biomarker. There was a significant direct association between fibrinogen and breast cancer risk (for quintile 5 vs. quintile 1, adjusted hazard ratio = 1.25, 95% confidence interval: 1.03, 1.51; P for trend = 0.01). In contrast, soluble intercellular adhesion molecule-1 was inversely associated with breast cancer (for quintile 5 vs. quintile 1, adjusted hazard ratio = 0.79, 95% confidence interval: 0.66, 0.94; P for trend = 0.02). N acetyl side-chains of acute phase proteins and high-sensitivity C-reactive protein were not associated with breast cancer. The complex association of chronic inflammation and breast cancer may be considered when formulating anti inflammatory cancer prevention or intervention strategies. PMID- 28641371 TI - Effects of changes in leaf properties mediated by methyl jasmonate (MeJA) on foliar absorption of Zn, Mn and Fe. AB - Background and Aims: Foliar fertilization to overcome nutritional deficiencies is becoming increasingly widespread. However, the processes of foliar nutrient absorption and translocation are poorly understood. The present study aimed to investigate how cuticular leaf properties affect the absorption of foliar-applied nutrients in leaf tissues. Methods: Given that methyl jasmonate (MeJA) can cause alterations in leaf properties, we applied 1 mm MeJA to sunflower (Helianthus annuus), tomato (Solanum lycopersicum) and soybean (Glycine max) to assess changes in leaf properties. Using traditionally analytical approaches and synchrotron-based X-ray fluorescence microscopy, the effects of these changes on the absorption and translocation of foliar-applied Zn, Mn and Fe were examined. Key Results: The changes in leaf properties caused by the application of MeJA increased foliar absorption of Zn, Mn and Fe up to 3- to 5-fold in sunflower but decreased it by 0.5- to 0.9-fold in tomato, with no effect in soybean. These changes in the foliar absorption of nutrients could not be explained by changes in overall trichome density, which increased in both sunflower (86%) and tomato (76%) (with no change in soybean). Similarly, the changes could be not attributed to changes in stomatal density or cuticle composition, given that these properties remained constant. Rather, the changes in the foliar absorption of Zn, Mn and Fe were related to the thickness of the cuticle and epidermal cell wall. Finally, the subsequent translocation of the absorbed nutrients within the leaf tissues was limited (<1.3mm) irrespective of treatment. Conclusions: The present study highlights the potential importance of the combined thickness of the cuticle and epidermal cell wall in the absorption of foliar-applied nutrients. This information will assist in increasing the efficacy of foliar fertilization. PMID- 28641372 TI - Comparison of Sociodemographic and Health-Related Characteristics of UK Biobank Participants With Those of the General Population. AB - The UK Biobank cohort is a population-based cohort of 500,000 participants recruited in the United Kingdom (UK) between 2006 and 2010. Approximately 9.2 million individuals aged 40-69 years who lived within 25 miles (40 km) of one of 22 assessment centers in England, Wales, and Scotland were invited to enter the cohort, and 5.5% participated in the baseline assessment. The representativeness of the UK Biobank cohort was investigated by comparing demographic characteristics between nonresponders and responders. Sociodemographic, physical, lifestyle, and health-related characteristics of the cohort were compared with nationally representative data sources. UK Biobank participants were more likely to be older, to be female, and to live in less socioeconomically deprived areas than nonparticipants. Compared with the general population, participants were less likely to be obese, to smoke, and to drink alcohol on a daily basis and had fewer self-reported health conditions. At age 70-74 years, rates of all-cause mortality and total cancer incidence were 46.2% and 11.8% lower, respectively, in men and 55.5% and 18.1% lower, respectively, in women than in the general population of the same age. UK Biobank is not representative of the sampling population; there is evidence of a "healthy volunteer" selection bias. Nonetheless, valid assessment of exposure-disease relationships may be widely generalizable and does not require participants to be representative of the population at large. PMID- 28641373 TI - Estimating Influenza Vaccine Effectiveness With the Test-Negative Design Using Alternative Control Groups: A Systematic Review and Meta-Analysis. AB - One important assumption in case-control studies is that control selection should be independent of exposure. Nevertheless, it has been hypothesized that virus interference might lead to a correlation between receipt of influenza vaccination and increased risk of infection with other respiratory viruses. We investigated whether such a phenomenon might affect a study design commonly used to estimate influenza vaccine effectiveness (VE). We searched publications in MEDLINE, PubMed, and Web of Science. We identified 12 studies using the test-negative design (2011-2017) that reported VE estimates separately derived by 3 alternative control groups: 1) all patients testing negative for influenza (FLU), VEFLU-; 2) patients who tested positive for other/another respiratory virus (ORV), VEORV+; and 3) patients who tested negative for all viruses in the panel (PAN), VEPAN-. These included VE estimates from 7 countries for all age groups from 2003/2004 to 2013/2014. We observed no difference in vaccination coverage between the ORV positive and PAN-negative control groups. A total of 63 VEFLU- estimates, 62 VEORV+ estimates, and 33 VEPAN- estimates were extracted. Pooled estimates of the difference in VE (DeltaVE) were very similar between groups. In meta-regression, no association was found between the selection of control group and VE estimates. In conclusion, we did not find any differences in VE estimates based on the choice of control group. PMID- 28641374 TI - Intergenerational Socioeconomic Mobility and Adult Depression: The CONSTANCES Study. AB - ABSTARCT: Using data from the nationally representative Consultants des Centres d'Examens de Sante (CONSTANCES) study in France (2012-2014; n = 67,057), we assessed the relationship between intergenerational socioeconomic mobility and adult depression (Center for Epidemiological Studies-Depression Scale scores of >=16 in men or >=20 in women) and antidepressant use. Socioeconomic position was ascertained by occupational grade (childhood: maternal and paternal measures prior to age 15 years combined; adulthood: participant's own). We used logistic regression models adjusted for sociodemographic characteristics, parental history of psychiatric disorders and suicide, health behaviors, and chronic health problems. Compared with the reference group (persistently high socioeconomic circumstances), participants in other groups had elevated levels of depression (for upward mobility, multivariate odds ratios (OR) = 1.21; intermediate socioeconomic position, 1.28; downward mobility, 1.66; persistently low socioeconomic position, 1.82). Downward mobility and persistently low socioeconomic position were also associated with elevated odds of antidepressant use (for downward mobility, multivariate OR = 1.24; for persistently low socioeconomic position, 1.36). In supplementary analyses, the association of socioeconomic mobility with depression was stronger in women than in men and among younger participants (aged 18-29 years) than among older participants. Factors that contribute to depression risk and socioeconomic inequalities in this area appeared to be at play already in childhood; this should be acknowledged by clinicians and policymakers. PMID- 28641375 TI - Trazodone to change the risk of neurodegeneration: bedside to bench. PMID- 28641376 TI - Height, Weight, and Aerobic Fitness Level in Relation to the Risk of Atrial Fibrillation. AB - Tall stature and obesity have been associated with a higher risk of atrial fibrillation (AF), but there have been conflicting reports of the effects of aerobic fitness. We conducted a national cohort study to examine interactions between height or weight and level of aerobic fitness among 1,547,478 Swedish military conscripts during 1969-1997 (97%-98% of all 18-year-old men) in relation to AF identified from nationwide inpatient and outpatient diagnoses through 2012 (maximal age, 62 years). Increased height, weight, and aerobic fitness level (but not muscular strength) at age 18 years were all associated with a higher AF risk in adulthood. Positive additive and multiplicative interactions were found between height or weight and aerobic fitness level (for the highest tertiles of height and aerobic fitness level vs. the lowest, relative excess risk = 0.51, 95% confidence interval (CI): 0.40, 0.62; ratio of hazard ratios = 1.50, 95% CI: 1.34, 1.65). High aerobic fitness levels were associated with higher risk among men who were at least 186 cm (6 feet, 1 inch) tall but were protective among shorter men. Men with the combination of tall stature and high aerobic fitness level had the highest risk (for the highest tertiles vs. the lowest, adjusted hazard ratio = 1.70, 95% CI: 1.61, 1.80). These findings suggest important interactions between body size and aerobic fitness level in relation to AF and may help identify high-risk subgroups. PMID- 28641378 TI - Staff Perceptions of Key Factors Guiding Nursing Home Search and Selection Within the Veterans Health Administration. AB - Background and Objectives: Veterans enter nursing homes (NHs) for short-term postacute, rehabilitation, respite, or end-of-life care. They also enter NHs on a long-term basis due to frailty, disability, functional deficits, and cognitive impairment. Little is known about how a particular NH is chosen once the decision to enter a NH has been made. This study identified VA staff perceptions of the key factors influencing the search and selection of NHs within the Veterans Health Administration (VHA). Research Design and Methods: Data derived from 35 semistructured interviews with discharge planning and contracting staff from 12 Veterans Affairs Medical Centers (VAMCs). Results: VA staff placed a premium on Veteran and family preferences in the NH selection process, though VA staff knowledge and familiarity with placement options established the general parameters within which NH placement decisions were made. Geographic proximity to Veterans' homes and families was a major factor in NH choice. Other key considerations included Veterans' specialty care needs (psychiatric, postacute, ventilator) and Veteran/facility demographics (age, race/ethnicity, Veteran status). VA staff tried to remain neutral in NH selection, thus instructing families to visit facilities and review publicly available quality data. VA staff report that amenities (private rooms, activities, smoking) and aesthetics (cleanliness, smell, layout, decor) often outweighed objective quality indicators in Veteran and family decision making. Discussion and Implications: Findings suggest that VAMCs facilitate Veteran and family decision making around NH selection. They also suggest that VAMCs endeavor to identify and recruit a broader array of higher quality NHs to better match the specific needs of Veterans and families to the choice set available. PMID- 28641377 TI - Paternal Care in Biparental Rodents: Intra- and Inter-individual Variation. AB - Parental care by fathers, although rare among mmmals, can be essential for the survival and normal development of offspring in biparental species. A growing body of research on biparental rodents has identified several developmental and experiential influences on paternal responsiveness. Some of these factors, such as pubertal maturation, interactions with pups, and cues from a pregnant mate, contribute to pronounced changes in paternal responsiveness across the course of the lifetime in individual males. Others, particularly intrauterine position during gestation and parental care received during postnatal development, can have long-term effects on paternal behavior and contribute to stable differences among individuals within a species. Focusing on five well-studied, biparental rodent species, we review the developmental and experiential factors that have been shown to influence paternal responsiveness, and consider their roles in generating both intra- and inter-individual variation. We also review hormones and neuropeptides that have been shown to modulate paternal care and discuss their potential contributions to behavioral differences within and between males. Finally, we discuss the possibility that vasopressinergic and possibly oxytocinergic signaling within the brain, modulated by gonadal steroid hormones, may represent the "final common pathway" mediating effects of developmental and experiential variables on intra- and inter-individual variation in paternal care. PMID- 28641382 TI - Metabolic arithmetic: do two wrongs make a right? PMID- 28641381 TI - Supraventricular tachyarrhythmias in patients with a persistent left superior vena cava. AB - Aims: A persistent left superior vena cava (PLSVC) is the most common thoracic venous anomaly. This venous anomaly can impact the evaluation and treatment of supraventricular tachyarrhythmia (SVA). The aim of this study was to assess the proportion and characteristics of PLSVC in adult SVA patients. Methods and results: From July 2002 to July 2012, clinical and procedural data from databases of 10 cardiac electrophysiology laboratories in the Yeungnam region of the Republic of Korea were reviewed. Of 6662 adult SVA patients who underwent an EP study or catheter ablation of SVA during the 10-year study period, 18 patients had PLSVC (mean age 47.6 +/- 14.8 years, 10 men). The proportion of PLSVC in adult SVA patients was 0.27% (18/6662). SVA type and procedural outcomes of radiofrequency (RF) catheter ablation in these patients were investigated and the results were as follows: successful slow pathway modification in six of seven patients with atrioventricular nodal reentrant tachycardia (AVNRT), successful ablation of accessory pathway in three of four patients with atrioventricular reentrant tachycardia, and successful ablation of atrial tachycardia (cavotricuspid isthmus-dependent in two, septal macroreentry in one, focal from the PLSVC in one) in three of four patients. In one patient with junctional tachycardia, catheter ablation failed. In two patients with atrial fibrillation, catheter ablation was successful. Conclusion: Among adult SVA patients who underwent an EP study or RF catheter ablation during the 10-year study period, 0.27% had PLSVC. The most common type of SVA was AVNRT. The success rate of catheter ablation was 82% in SVA patients with PLSVC. There were no procedure related complications. PMID- 28641379 TI - Clinical events preceding switching and discontinuation of oral anticoagulant treatment in patients with atrial fibrillation. AB - Aims: Switching between oral anticoagulants and treatment discontinuation are common events related to therapy with non-vitamin K antagonist oral anticoagulants (NOACs). However, knowledge on the reasons leading to these treatment changes is scarce. The aim of this study was to identify clinical events preceding anticoagulant switching and NOAC discontinuation during oral anticoagulant therapy in patients with atrial fibrillation. Methods and results: We performed a nationwide register-based study including Danish atrial fibrillation patients initiating a NOAC between August 2011 and February 2016 (n = 50 623). We explored potential reasons leading to changes in anticoagulant treatment by identifying clinical events preceding switches from vitamin K antagonists (VKA) to NOAC, switches from NOAC to VKA, and discontinuations of NOACs. Among 23 531 anticoagulant users changing treatment, we identified 13 295 switches from VKA to NOAC, 5206 switches from NOAC to VKA, and 8995 discontinuations of NOACs. Approximately half of all treatment changes were preceded by a hospitalization. A relevant specific clinical event or procedure was identified prior to 18.3% of switches from VKA to NOAC, prior to 23.0% of switches from NOAC to VKA, and prior to 26.6% of discontinuations. Switches from VKA to NOAC were most often preceded by thromboembolic events (7.0%), whereas cardioversion was the most common specific event prior to a switch from NOAC to VKA (11.4%). Discontinuations were most often preceded by bleeding events (7.6%). Conclusion: For about one in five patients, treatment changes during anticoagulant therapy were preceded by a major clinical event. However, the majority of patients changed treatment for reasons not recorded in health registries. PMID- 28641380 TI - Cohort Profile: The Melbourne Collaborative Cohort Study (Health 2020). PMID- 28641383 TI - Neuroprotection in stroke: the importance of collaboration and reproducibility. AB - Acute ischaemic stroke accounts for 6.5 million deaths per year, and by 2030 will result in the annual loss of over 200 million disability-adjusted life years globally. There have been considerable recent advances in the gold standard of acute ischaemic stroke treatment, some aspects of which-aspirin to prevent recurrence, and treating patients in specialized stroke wards-are widely applicable. Recanalization of the occluded artery through thrombolysis and/or endovascular thrombectomy is restricted to only a small proportion of patients, due to contra-indications and the costs associated with establishing the infrastructure to deliver these treatments. The use of neuroprotective agents in stroke has been a notable failure of translation from medical research into clinical practice. Yet, with the advent of endovascular thrombectomy and the ability to investigate patients in much greater detail through advanced imaging modalities, neuroprotective agents can and should be re-examined as adjunct therapies to recanalization. In parallel, this requires appropriate planning on behalf of the preclinical stroke research community: there is a need to reinvestigate these therapies in a more collaborative manner, to enhance reproducibility through reduced attrition, improved reporting, and adopting an approach to target validation that more closely mimics clinical trials. This review will describe some of the novel strategies being used in stroke research, and focus on a few key examples of neuroprotective agents that are showing newfound promise in preclinical models of stroke therapy. Our primary aim is to give an overview of some of the challenges faced by preclinical stroke research, and suggest potential ways to improve translational success. PMID- 28641385 TI - Development of an electronic medical record-based child physical abuse alert system. AB - Objective: Physical abuse is a leading cause of pediatric morbidity and mortality. Physicians do not consistently screen for abuse, even in high-risk situations. Alerts in the electronic medical record may help improve screening rates, resulting in early identification and improved outcomes. Methods: Triggers to identify children < 2 years old at risk for physical abuse were coded into the electronic medical record at a freestanding pediatric hospital with a level 1 trauma center. The system was run in "silent mode"; physicians were unaware of the system, but study personnel received data on children who triggered the alert system. Sensitivity, specificity, and negative and positive predictive values of the child abuse alert system for identifying physical abuse were calculated. Results: Thirty age-specific triggers were embedded into the electronic medical record. From October 21, 2014, through April 6, 2015, the system was in silent mode. All 226 children who triggered the alert system were considered subjects. Mean (SD) age was 9.1 (6.5) months. All triggers were activated at least once. Sensitivity was 96.8% (95% CI, 92.4-100.0%), specificity was 98.5% (95% CI, 98.3.5-98.7), and positive and negative predictive values were 26.5% (95% CI, 21.2-32.8%) and 99.9% (95% CI, 99.9-100.0%), respectively, for identifying children < 2 years old with possible, probable, or definite physical abuse. Discussion/Conclusion: Triggers embedded into the electronic medical record can identify young children with who need to be evaluated for physical abuse with high sensitivity and specificity. PMID- 28641384 TI - Acute Testosterone Deficiency Alters Adipose Tissue Fatty Acid Storage. AB - Context: Although the long-term effects of testosterone on adipose tissue lipid metabolism in men have been defined, the short-term regulation of these effects is not well understood. Objective: We examined the effects of acute testosterone withdrawal on subcutaneous abdominal and femoral adipose tissue fatty acid (FA) storage and cellular mechanisms. Design: This was a prospective, randomized trial. Setting: Mayo Clinic Clinical Research Unit. Patients or Participants: Thirty-two male volunteers ages 18 to 50 participated in these studies. Interventions: Volunteers were randomized to receive (1) no treatment (control), (2) injections (7.5 mg) of Lupron(r), or (3) Lupron and testosterone (L+T) replacement for 49 days, resulting in 4 weeks of sex steroid suppression in the Lupron group. Main Outcome Measures: We measured body composition, fat cell size, adipose tissue meal FA and direct free FA storage, lipoprotein lipase (LPL), acyl coenzyme A synthetase (ACS), diacylglycerol acyltransferase activities, and CD36 content. Results: Compared with control and L+T groups, acute testosterone deficiency resulted in greater femoral adipose tissue meal FA storage rates, fasting and fed LPL activity, and ACS activity. Conclusions: These results suggest that in men, testosterone plays a tonic role in restraining FA storage in femoral adipose tissue via suppression of LPL and ACS activities. FA storage mechanisms in men appear sensitive to short-term changes in testosterone concentrations. PMID- 28641387 TI - Imaging, superior mesenteric vein (SMV) sign and bowel ischaemia. PMID- 28641386 TI - The neurosteroid pregnenolone reverts microtubule derangement induced by the loss of a functional CDKL5-IQGAP1 complex. AB - CDKL5 is a protein kinase that plays a key role for neuronal functions as testified by the onset of complex neuronal dysfunctions in patients with genetic lesions in CDKL5. Here we identify a novel interactor of CDKL5, IQGAP1, a fundamental regulator of cell migration and polarity. In accordance with a functional role of this interaction, depletion of CDKL5 impairs cell migration and impedes the localization of IQGAP1 at the leading edge. Moreover, we demonstrate that CDKL5 is required for IQGAP1 to form a functional complex with its effectors, Rac1 and the microtubule plus end tracking protein CLIP170. These defects eventually impact on the microtubule association of CLIP170, thus deranging their dynamics. CLIP170 is a cellular target of the neurosteroid pregnenolone; by blocking CLIP170 in its active conformation, pregnenolone is capable of restoring the microtubule association of CLIP170 in CDKL5 deficient cells and rescuing morphological defects in neurons devoid of CDKL5. These findings provide novel insights into CDKL5 functions and pave the way for target specific therapeutic strategies for individuals affected with CDKL5-disorder. PMID- 28641389 TI - Acute tryptophan depletion: the first method validation in an avian species (Gallus gallus domesticus). AB - Acute tryptophan depletion (ATD) is a valuable non-invasive nutritional tool in human and rodent research to study dysfunctions of the serotonergic system and related behavioral disorders. Serotonergic dysfunction is thought to be involved in the pathology of feather pecking behavior of laying hens, one of the most relevant welfare and production issues in modern intensive egg-production systems. ATD temporarily compromises the influx of tryptophan (TRP) across the blood brain barrier which reduces central availability of TRP, the substrate for serotonin (5-HT) synthesis. However, ATD has never before been developed and evaluated in birds. We hereby report that ATD in laying hens effectively depletes plasma levels of TRP to 50% of the baseline concentration, 4 hours after administration. Furthermore, ATD reduces the ratios of TRP towards aromatic amino acids (AAA) by 60% and the ratio of TRP towards large neutral amino acids (LNAA) by 70%, three hours after administration. Further studies will be needed to determine the effects of peripheral depletion on brain TRP and 5-HT levels in birds. However, our study showed for the first time in an avian species that ATD causes lowering of plasma TRP and the ratio in plasma of TRP towards other AAA or LNAA. PMID- 28641388 TI - Recognition of the Component Odors in Mixtures. AB - Natural olfactory stimuli are volatile-chemical mixtures in which relative perceptual saliencies determine which odor-components are identified. Odor identification also depends on rapid selective adaptation, as shown for 4 odor stimuli in an earlier experimental simulation of natural conditions. Adapt-test pairs of mixtures of water-soluble, distinct odor stimuli with chemical features in common were studied. Identification decreased for adapted components but increased for unadapted mixture-suppressed components, showing compound identities were retained, not degraded to individual molecular features. Four additional odor stimuli, 1 with 2 perceptible odor notes, and an added "water adapted" control tested whether this finding would generalize to other 4-compound sets. Selective adaptation of mixtures of the compounds (odors): 3 mM benzaldehyde (cherry), 5 mM maltol (caramel), 1 mM guaiacol (smoke), and 4 mM methyl anthranilate (grape-smoke) again reciprocally unmasked odors of mixture suppressed components in 2-, 3-, and 4-component mixtures with 2 exceptions. The cherry note of "benzaldehyde" (itself) and the shared note of "methyl anthranilate and guaiacol" (together) were more readily identified. The pervasive mixture-component dominance and dynamic perceptual salience may be mediated through peripheral adaptation and central mutual inhibition of neural responses. Originating in individual olfactory receptor variants, it limits odor identification and provides analytic properties for momentary recognition of a few remaining mixture-components. PMID- 28641390 TI - Racial and Ethnic Disparities in the Incidence of Esophageal Cancer in the United States, 1992-2013. AB - Racial and ethnic disparities in the incidence of esophageal cancer have not been thoroughly characterized with quantitative health-disparity measures. Using data from 1992-2013 from 13 US cancer registries in the Surveillance, Epidemiology, and End Results database, we assessed such disparities according to histological type, based on a variety of disparity metrics. The age-standardized incidence rate of squamous cell carcinoma (SCC) was highest among black persons, while adenocarcinoma mainly affected white men. The rate of SCC decreased over time in all racial/ethnic groups, and this was most pronounced in black persons (by 5.7% per year among men and 5.0% among women). The adenocarcinoma rate rose among non Hispanic whites and among black men. Racial/ethnic disparities in the incidence of total esophageal cancer decreased over time, which was due mainly to reduced disparities in SCC. The 2 absolute disparity measures-range difference and between-group variance-for adenocarcinoma rose by 3.2% and 6.8% per year, respectively, in men and by 1.8% and 5.3% per year, respectively, in women. This study demonstrates decreased racial/ethnic disparities in the incidence of esophageal SCC over time in the United States, while disparities increased in adenocarcinoma incidence as measured on the absolute scale. PMID- 28641391 TI - A multicentre study to improve clinical interpretation of proteinase-3 and myeloperoxidase anti-neutrophil cytoplasmic antibodies. PMID- 28641392 TI - Association of Alcohol With Mortality After Traumatic Brain Injury. AB - Although alcohol exposure results in reduced mortality after traumatic brain injury (TBI) in animal models, clinical trials based on proposed mechanisms have been disappointing and have reported conflicting results. Methodological issues common to many of these clinical studies may have contributed to the spurious results. Our objective was to evaluate the association between blood alcohol concentration (BAC) and in-hospital mortality after TBI, and overcome methodological problems of prior studies. We conducted a retrospective cohort study on individuals treated for isolated TBI (n = 1,084) at the R Adams Cowley Shock Trauma Center (Baltimore, Maryland) from 1997 to 2012. We excluded individuals with injury to other body regions and examined multiple cutpoints of BAC. Our primary outcome was in-hospital mortality. In adjusted logistic regression models, the upper level of each blood alcohol categorization from 0.10 g/dL (odds ratio = 0.63, 95% confidence interval: 0.40, 0.97) through 0.30 g/dL (odds ratio = 0.25, 95% confidence interval: 0.08, 0.84) was associated with reduced risk of mortality after TBI compared with individuals with undetectable BAC. In sensitivity analyses among individuals without penetrating brain injuries (95% firearm-related) (n = 899), the protective association was eliminated. This study provides evidence that the observed protective association between BAC and in-hospital mortality after TBI resulted from bias introduced by inclusion of penetrating injuries. PMID- 28641393 TI - A technical review of subvalvular techniques for repair of ischaemic mitral regurgitation and their associated echocardiographic and survival outcomes. AB - Subvalvular techniques are gaining ground as adjunct procedures for addressing ischaemic mitral regurgitation. The aim of this study was to describe the different techniques and assess their results. A systematic review of the literature was performed. The end points of interest were recurrence of mitral regurgitation, cardiac events and early and late echocardiographic measurements. After initial screening, 450 articles were identified, of which 24 provided the best available evidence on the topic. The different subvalvular techniques had similar mortality rates when compared with the standard restrictive annuloplasty. Recurrence of mitral regurgitation was of lower degree and the remodelling process was better for these techniques. Reoperation rates were also quite low. The subvalvular techniques showed superiority, addressing more successfully the leaflet tethering. However, larger randomized studies are needed to confirm these early positive results. PMID- 28641394 TI - Reoperative analysis after mitral valve repair with glutaraldehyde-treated autologous pericardium. AB - OBJECTIVES: We reviewed reoperations following mitral valve repair (MVR) that used glutaraldehyde-treated autologous pericardium for mitral regurgitation (MR) to analyse the durability and risk factors for reoperation. METHODS: We retrospectively analysed 144 patients (mean age 57.9 years) who underwent MVR using glutaraldehyde-treated pericardium from March 1992 to December 2011. A total of 19 reoperations were necessary during the follow-up period (mean 6.9 years). The follow-up rate was 97.8%. RESULTS: At initial MVR, there were no differences in mitral leaflet augmentation applied to the anterior or posterior leaflets (P = 0.75 and P = 0.40) in both groups. Reoperations were required in 19 patients, and the mean interval between initial and redo operations was 6.7 years. Indications for reoperation included recurrent MR (n = 8), progressive mitral stenosis (n = 8) and recurrent infective endocarditis (n = 3). The rates of freedom from reoperation at 5, 10 and 15 years were 95.2 +/- 1.9%, 83.5 +/- 4.8% and 66.9 +/- 8.5%, respectively. Four patients underwent redo MVR for recurrent MR, and the remaining 15 patients underwent mitral valve replacement. The freedom from reoperation rate in the group who underwent leaflet augmentation was statistically lower than that in the non-augmentation group (96.9 +/- 2.2% vs 93.4 +/- 3.2% at 5 years and 89.7 +/- 4.5% vs 68.8 +/- 13.7% at 10 years; log rank, P = 0.008). Predictors of reoperation were absence of leaflet augmentation (P = 0.086, hazard ratio = 0.194) and persistent MR (P = 0.003, hazard ratio = 5.759). CONCLUSIONS: We must regularly pay careful attention to implanted pericardium, especially when augmented, as it constitutes a risk factor for reoperations. In addition, secure MVR is mandatory to control persistent MR. PMID- 28641395 TI - Effect of in ovo injection of corticotropin-releasing hormone on the timing of hatching in broiler chickens. AB - In chicken embryos, intravenous injection of corticotropin-releasing hormone (CRH) causes the release of both corticosteroids and thyroid hormones. These hormones initiate and enhance the hatching process, raising the possibility that CRH treatment of the late chicken embryo could accelerate hatching and/or decrease the spread of hatching. We performed a series of exploratory tests to investigate whether in ovo delivery methods of CRH other than intravenous injection that are more practical in a commercial setting, affect hatching time in broilers. Corticotropin-releasing hormone was injected into the air cell, albumen, or amniotic fluid of broiler breeder eggs, in the last week of embryonic development. Average incubation duration was significantly decreased by 22 h when 2 MUg of CRH was injected into the air cell on embryonic day 18 (E18) of Cobb eggs. Acceleration of hatching (but only by 8 h) was also seen for Ross chicks when CRH was injected daily into the albumen between E10 and E18. However, repeats of both experiments did not show consistent effects of CRH on hatching time; in most experiments performed, CRH did not affect hatching time. We speculate that the effectiveness of CRH uptake via these delivery methods and/or the duration and magnitude of the thyroxine and corticosterone response to CRH is not sufficient to have a substantial effect on hatching time. We therefore conclude that in ovo CRH treatment does not seem a feasible option as a practical tool to increase hatchery productivity or to investigate the effects of CRH agonists and antagonists on hatching. PMID- 28641396 TI - Geneticization in MIM/OMIM(r)? Exploring Historic and Epistemic Drivers of Contemporary Understandings of Genetic Disease. AB - Prior to the genomic sequencing era, the bible for those working in clinical genetics was McKusick's Mendelian Inheritance in Man (MIM), which appeared in multiple editions between the 1960s and the late 1990s. This catalogue was organized according to general patterns of inheritance and focused on phenotypes. Beginning in the mid-1980s, it was replaced by Online Mendelian Inheritance in Man (OMIM(r)), a continuously updated catalogue documenting molecular relationships between genetic variation and phenotypic expression. This paper explores this resource's evolution with attention to how disease is distinguished from clinically irrelevant variation and how phenotypic similarities are captured in cases where there is no obvious genotypic association. It is argued that hybrid compromises are encoded into OMIM(r); in addition to serving its key original purpose of being a diagnostic catalogue, it also began to record detectable variations in the genome even if they were not known to be associated with phenotypically visible disorders or even phenotypic variations. Although the impacts of geneticization have been well recognized, particularly in popular media, this example allows exploration of some of the historic, epistemic, and methodological causes that underlie tendencies toward disease geneticization in contemporary medicine, while highlighting that such gene-focused strategies may in fact be warranted in some contexts. PMID- 28641397 TI - Myocardial scar location as detected by cardiac magnetic resonance is associated with the outcome in heart failure patients undergoing surgical ventricular reconstruction. AB - OBJECTIVES: Post-infarction myocardial scar causes adverse left ventricular remodelling and negatively affects the prognosis. We sought to investigate whether scar extent and location obtained by cardiac magnetic resonance may affect the reverse remodelling and survival of heart failure patients undergoing surgical ventricular reconstruction. METHODS: From January 2011 to December 2015, 151 consecutive patients with previous myocardial infarction and left ventricular remodelling underwent surgical ventricular reconstruction at our Institution, of which 88 (58%) patients had a preoperative protocol-standardized late gadolinium enhancement (LGE)-cardiac magnetic resonance examination during the week before surgery. We excluded 40 patients with devices (26%), 15 patients with irregular heart rhythm (permanent atrial fibrillation, 10% not included in the device group) or mixed contraindications (severe claustrophobia or presence of material magnetic resonance not compatible). Among the 145 survivors, 11 patients received an implantable cardioverter defibrillator after surgery (mostly for persistent low ejection fraction) and were excluded as well, yielding a total of 59 patients (48 men, aged 65 +/- 9 years) who repeated a protocol-standardized LGE-cardiac magnetic resonance examination even 6 months postoperatively and therefore represent the study population. Patients were grouped according to the presence of LGE in the antero-basal left ventricular segments (Group A) or the absence of LGE in the same segments (Group B). The postoperative left ventricular end systolic volume index was considered the primary end-point. RESULTS: After surgery, left ventricular end-systolic volume index and end-diastolic volume index significantly decreased (P < 0.001, for both), while diastolic sphericity index and ejection fraction significantly increased (P = 0.015 and P < 0.001, respectively). The presence of LGE in the antero-basal left ventricular segments (10 patients, Group A) was the only independent predictor of outcome (P = 0.02) at multivariate analysis, being the postoperative left ventricular end-systolic volume index significantly higher compared to that of patients of Group B (49 patients) (78 +/- 26 ml/m2 vs 55 +/- 20 ml/m2, P = 0.003). Furthermore, patients with a postoperative left ventricular end-systolic volume index >60 ml/m2 showed a higher risk of cardiac events (hazard ratio = 3.67, P = 0.02). CONCLUSIONS: In patients undergoing surgical ventricular reconstruction, LGE scar location affects the left ventricular reverse remodelling, which in turn might limit the survival benefit. PMID- 28641398 TI - Pregnancy in hypertrophic cardiomyopathy. PMID- 28641399 TI - CompAnnotate: a comparative approach to annotate base-pairing interactions in RNA 3D structures. AB - The analysis of RNA tertiary structure is hindered by the fact that not too many structural data are available and a significant amount of them are in low resolution. Due to the atomic coordinate errors posed by the limitations of low resolution RNA three-dimensional structures, it becomes a critical challenge to extract key geometric characteristics of RNA, particularly, the interaction of bases. To address this issue, we have devised a comparative method, named CompAnnotate, that utilizes more precise structural information of high resolution homologs to annotate the base-pairing interactions in the low resolution structures, by aligning and making comparative geometric assessments. The benchmarking results show that our method can improve the annotations of the existing methods significantly. We have achieved different levels of improvements for various methods and datasets, including an example of significant sensitivity and precision enhancement from 28 to 57% and from 53 to 82%, respectively. PMID- 28641401 TI - Environmental stressors and cardiovascular disease: the evidence is growing. PMID- 28641400 TI - Cytosolic delivery of siRNA by ultra-high affinity dsRNA binding proteins. AB - Protein-based methods of siRNA delivery are capable of uniquely specific targeting, but are limited by technical challenges such as low potency or poor biophysical properties. Here, we engineered a series of ultra-high affinity siRNA binders based on the viral protein p19 and developed them into siRNA carriers targeted to the epidermal growth factor receptor (EGFR). Combined in trans with a previously described endosome-disrupting agent composed of the pore-forming protein Perfringolysin O (PFO), potent silencing was achieved in vitro with no detectable cytotoxicity. Despite concerns that excessively strong siRNA binding could prevent the discharge of siRNA from its carrier, higher affinity continually led to stronger silencing. We found that this improvement was due to both increased uptake of siRNA into the cell and improved pharmacodynamics inside the cell. Mathematical modeling predicted the existence of an affinity optimum that maximizes silencing, after which siRNA sequestration decreases potency. Our study characterizing the affinity dependence of silencing suggests that siRNA carrier affinity can significantly affect the intracellular fate of siRNA and may serve as a handle for improving the efficiency of delivery. The two-agent delivery system presented here possesses notable biophysical properties and potency, and provide a platform for the cytosolic delivery of nucleic acids. PMID- 28641403 TI - A molasses habitat-derived fungus Aspergillus tubingensis XG21 with high beta fructofuranosidase activity and its potential use for fructooligosaccharides production. AB - The industrial microorganisms used for fructooligosaccharides (FOS) synthesis are generally fermented with sucrose as carbon source to induce the production of beta-fructofuranosidase (FFase) having transfructosylation activity. Consequently, isolation of novel FFase producers from a sucrose-enriched biotope would help improve FOS productivity and reduce the process cost. Here, three fungi isolated from a unique sugarcane molasses habitat were found to possess FFase activity and one of them, XG21, exhibited a high capacity to synthesize FOS. Analysis of its morphological properties and ribosomal internal transcribed spacer (ITS) sequence allowed the taxonomic position to be assigned and it was thus identified as Aspergillus tubingensis XG21. It could utilize various potential carbon sources for vigorous growth, but only produced high-level FFase activity on sucrose. Furthermore, the transfructosylation ability and FOS synthesis were analyzed by TLC and HPLC. During the transfructosylation reaction, an increase in sucrose concentration led to the remarkable enhancement in FOS formation with the maximum content of up to 56.9% within 8 h. Finally, the sugarcane molasses was used to cultivate A. tubingensis XG21 and the optimal FFase activity reached up to 558.3 U/g, which was 88.9% higher than that with sucrose as carbon source. These results indicate that A. tubingensis XG21 can be considered as a new genetic resource adapted to cheaply available carbon sources for FOS production. PMID- 28641402 TI - EC-tagging allows cell type-specific RNA analysis. AB - Purification of cell type-specific RNAs remains a significant challenge. One solution involves biosynthetic tagging of target RNAs. RNA tagging via incorporation of 4-thiouracil (TU) in cells expressing transgenic uracil phosphoribosyltransferase (UPRT), a method known as TU-tagging, has been used in multiple systems but can have limited specificity due to endogenous pathways of TU incorporation. Here, we describe an alternative method that requires the activity of two enzymes: cytosine deaminase (CD) and UPRT. We found that the sequential activity of these enzymes converts 5-ethynylcytosine (EC) to 5 ethynyluridine monophosphate that is subsequently incorporated into nascent RNAs. The ethynyl group allows efficient detection and purification of tagged RNAs. We show that 'EC-tagging' occurs in tissue culture cells and Drosophila engineered to express CD and UPRT. Additional control can be achieved through a split-CD approach in which functional CD is reconstituted from independently expressed fragments. We demonstrate the sensitivity and specificity of EC-tagging by obtaining cell type-specific gene expression data from intact Drosophila larvae, including transcriptome measurements from a small population of central brain neurons. EC-tagging provides several advantages over existing techniques and should be broadly useful for investigating the role of differential RNA expression in cell identity, physiology and pathology. PMID- 28641404 TI - pH rather than nitrification and urease inhibitors determines the community of ammonia oxidizers in a vegetable soil. AB - Nitrification inhibitors and urease inhibitors, such as nitrapyrin and N-(n butyl) thiophosphoric triamide (NBPT), can improve the efficiencies of nitrogen fertilizers in cropland. However, their effects on ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) across different soil pH levels are still unclear. In the present work, vegetable soils at four pH levels were tested to determine the impacts of nitrification and urease inhibitors on the nitrification activities, abundances and diversities of ammonia oxidizers at different pHs by real-time PCR, terminal restriction fragment length polymorphism (T-RFLP) and clone sequence analysis. The analyses of the abundance of ammonia oxidizers and net nitrification rate suggested that AOA was the dominate ammonia oxidizer and the key driver of nitrification in acidic soil. The relationships between pH and ammonia oxidizer abundance indicated that soil pH dominantly controlled the abundance of AOA but not that of AOB. The T-RFLP results suggested that soil pH could significantly affect the AOA and AOB community structure. Nitrapyrin decreased the net nitrification rate and inhibited the abundance of bacterial amoA genes in this vegetable soil, but exhibited no effect on that of the archaeal amoA genes. In contrast, NBPT just lagged the hydrolysis of urea and kept low NH4+-N levels in the soil at the early stage. It exhibited no or slight effects on the abundance and community structure of ammonia oxidizers. These results indicated that soil pH, rather than the application of urea, nitrapyrin and NBPT, was a critical factor influencing the abundance and community structure of AOA and AOB. PMID- 28641405 TI - Biotransformation of ferulic acid to protocatechuic acid by Corynebacterium glutamicum ATCC 21420 engineered to express vanillate O-demethylase. AB - Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) is a lignin-derived phenolic compound abundant in plant biomass. The utilization of FA and its conversion to valuable compounds is desired. Protocatechuic acid (3,4-dihydroxybenzoic acid, PCA) is a precursor of polymers and plastics and a constituent of food. A microbial conversion system to produce PCA from FA was developed in this study using a PCA-producing strain of Corynebacterium glutamicum F (ATCC 21420). C. glutamicum strain F grown at 30 degrees C for 48 h utilized 2 mM each of FA and vanillic acid (4-hydroxy-3-methoxybenzoic acid, VA) to produce PCA, which was secreted into the medium. FA may be catabolized by C. glutamicum through proposed (I) non-beta-oxidative, CoA-dependent or (II) beta-oxidative, CoA-dependent phenylpropanoid pathways. The conversion of VA to PCA is the last step in each pathway. Therefore, the vanillate O-demethylase gene (vanAB) from Corynebacterium efficiens NBRC 100395 was expressed in C. glutamicum F (designated strain FVan) cultured at 30 degrees C in AF medium containing FA. Strain C. glutamicum FVan converted 4.57 +/- 0.07 mM of FA into 2.87 +/- 0.01 mM PCA after 48 h with yields of 62.8% (mol/mol), and 6.91 mM (1064 mg/L) of PCA was produced from 16.0 mM of FA after 12 h of fed-batch biotransformation. Genomic analysis of C. glutamicum ATCC 21420 revealed that the PCA-utilization genes (pca cluster) were conserved in strain ATCC 21420 and that mutations were present in the PCA importer gene pcaK. PMID- 28641406 TI - Novel antimicrobial activities of a peptide derived from a Japanese soybean fermented food, Natto, against Streptococcus pneumoniae and Bacillus subtilis group strains. AB - We recently isolated a tumoricidal peptide from Natto, a Japanese traditional fermented food. In the present study, antimicrobial activity of the Natto peptide was examined. The peptide consisted of 45 amino acid residues, and its structure was predicted to be rich in alpha-helix. It excreted antimicrobial activity only against Streptococcus pneumoniae and Bacillus subtilis group (B. subtilis, Bacillus pumilus, and Bacillus licheniformis). Lesser antimicrobial activity was observed for Streptococcus species other than S. pneumoniae. Hemolysate or hemin was required for the antimicrobial activity of the peptide. The Natto peptide damages the cell membrane of B. subtilis. On the other hand, chain morphology was induced in S. pneumoniae, which is naturally diplococcus, during the early phases of the Natto peptide treatment; following that the cells were rapidly lysed. This suggested that the Natto peptide displayed a novel narrow spectrum of bactericidal activity and inhibited cell separation during cell division of S. pneumoniae. PMID- 28641407 TI - Efficacy of ezetimibe combined with atorvastatin in the treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of ezetimibe combined with atorvastatin in treatment of carotid artery plaque in patients with type 2 diabetes mellitus complicated with coronary heart disease (CHD). METHODS: A total of 100 patients with carotid atherosclerosis (CAS) confirmed by ultrasound and diagnosed with type 2 diabetes mellitus and CHD were randomly assigned to atorvastatin group (atorvastatin 20 mg/day) or combined treatment group (ezetimibe 10 mg/day and atorvastatin 20 mg/day). All those patients were followed for 12 months. Serum lipid, ALT, AST, and CK were measured before and after treatment. Ultrasonography was used to evaluate the stability of carotid artery plaques. RESULTS: After 12 months of treatment, the level of TC, TG, LDL C, hs-CRP, FPG and HbA1c decreased in both groups compared with before treatment. TC, TG, LDL-C and hs-CRP in the combined treatment group were much lower than that in the atorvastatin group (P<0.05). The IMT and plaque area in the two groups were lower than that before the treatment (P<0.05). IMT and plaques area in the combined treatment group is much lower than that in the atorvastatin group after treatment. There was no significant difference in two groups on the level of ALT, AST, CK compared with baseline after treatment. CONCLUSIONS: The effect of combined use of atorvastatin and ezetimibe was better than atorvastatin alone, which can effectively reduce the blood lipid levels in diabetic patients with CHD and improve plaque stability. Both treatment regimens were safe and well tolerated. PMID- 28641408 TI - Extended use of sulodexide, apixaban, rivaroxaban and dabigatran in venous thromboembolism: indirect comparison of clinical trials. PMID- 28641409 TI - Citric Acid Modulated Growth of Oriented Lead Perovskite Crystals for Efficient Solar Cells. AB - Solar cells made of lead perovskite crystals have attracted much attention for their high performance, but far less attention as a subject of crystal engineering. Here, we report that citric acid (CA) and chloride anion, working together, modulate crystal growth of CH3NH3PbI3, producing sub-mm-sized cuboid crystals-a morphology more suitable for close packing in a thin film than the commonly observed elongated dodecahedral morphology. By using a 15 wt % CA-doped precursor solution, we formed a single layer of large, flat, and oriented cuboid crystals with minimum crystal domain boundaries and maximum contact with neighboring layers, and fabricated an archetypal inverted-structured device of 4 mm2 area, which showed, reproducibly and with little hysteresis, 16.75% power conversion efficiency (PCE), 26% higher than the PCE obtained for a polycrystalline film made without CA doping. Under weaker irradiation of a 1 cm2 device, the PCE improved from 14.52% (one sun) to 20.4% (0.087 suns). Under illumination with white light emitting diode, a 10 wt % CA-doped device showed PCE of 28.1%, suggesting an advantage of PVK-SCs for indoor applications. Further studies on crystal growth modulation will be beneficial for manufacturing efficient and stable lead perovskite solar cells. PMID- 28641410 TI - Modeling Aquatic Toxicity through Chromatographic Systems. AB - Environmental risk assessment requires information about the toxicity of the growing number of chemical products coming from different origins that can contaminate water and become toxicants to aquatic species or other living beings via the trophic chain. Direct toxicity measurements using sensitive aquatic species can be carried out but they may become expensive and ethically questionable. Literature refers to the use of chromatographic measurements that correlate to the toxic effect of a compound over a specific aquatic species as an alternative to get toxicity information. In this work, we have studied the similarity in the response of the toxicity to different species and we have selected eight representative aquatic species (including tadpoles, fish, water fleas, protozoan, and bacteria) with known nonspecific toxicity to chemical substances. Next, we have selected four chromatographic systems offering good perspectives for surrogation of the eight selected aquatic systems, and thus prediction of toxicity from the chromatographic measurement. Then toxicity has been correlated to the chromatographic retention factor. Satisfactory correlation results have been obtained to emulate toxicity in five of the selected aquatic species through some of the chromatographic systems. Other aquatic species with similar characteristics to these five representative ones could also be emulated by using the same chromatographic systems. The final aim of this study is to model chemical products toxicity to aquatic species by means of chromatographic systems to reduce in vivo testing. PMID- 28641411 TI - Development of a Liquid Chromatography-High Resolution Mass Spectrometry Metabolomics Method with High Specificity for Metabolite Identification Using All Ion Fragmentation Acquisition. AB - High-resolution mass spectrometry (HRMS)-based metabolomics approaches have made significant advances. However, metabolite identification is still a major challenge with significant bottleneck in translating metabolomics data into biological context. In the current study, a liquid chromatography (LC)-HRMS metabolomics method was developed using an all ion fragmentation (AIF) acquisition approach. To increase the specificity in metabolite annotation, four criteria were considered: (i) accurate mass (AM), (ii) retention time (RT), (iii) MS/MS spectrum, and (iv) product/precursor ion intensity ratios. We constructed an in-house mass spectral library of 408 metabolites containing AMRT and MS/MS spectra information at four collision energies. The percent relative standard deviations between ion ratios of a metabolite in an analytical standard vs sample matrix were used as an additional metric for establishing metabolite identity. A data processing method for targeted metabolite screening was then created, merging m/z, RT, MS/MS, and ion ratio information for each of the 413 metabolites. In the data processing method, the precursor ion and product ion were considered as the quantifier and qualifier ion, respectively. We also included a scheme to distinguish coeluting isobaric compounds by selecting a specific product ion as the quantifier ion instead of the precursor ion. An advantage of the current AIF approach is the concurrent collection of full scan data, enabling identification of metabolites not included in the database. Our data acquisition strategy enables a simultaneous mixture of database-dependent targeted and nontargeted metabolomics in combination with improved accuracy in metabolite identification, increasing the quality of the biological information acquired in a metabolomics experiment. PMID- 28641412 TI - Anti-Perovskite Li-Battery Cathode Materials. AB - Through single-step solid-state reactions, a series of novel bichalcogenides with the general composition (Li2Fe)ChO (Ch = S, Se, Te) are successfully synthesized. (Li2Fe)ChO (Ch = S, Se) possess cubic anti-perovskite crystal structures, where Fe and Li are completely disordered on a common crystallographic site (3c). According to Goldschmidt calculations, Li+ and Fe2+ are too small for their common atomic position and exhibit large thermal displacements in the crystal structure models, implying high cation mobility. Both compounds (Li2Fe)ChO (Ch = S, Se) were tested as cathode materials against graphite anodes (single cells); They perform outstandingly at very high charge rates (270 mA g-1, 80 cycles) and, at a charge rate of 30 mA g-1, exhibit charge capacities of about 120 mA h g-1. Compared to highly optimized Li1-xCoO2 cathode materials, these novel anti perovskites are easily produced at cost reductions by up to 95% and, yet, possess a relative specific charge capacity of 75%. Moreover, these iron-based anti perovskites are comparatively friendly to the environment and (Li2Fe)ChO (Ch = S, Se) melt congruently; the latter is advantageous for manufacturing pure materials in large amounts. PMID- 28641413 TI - Cation Dynamics in Mixed-Cation (MA)x(FA)1-xPbI3 Hybrid Perovskites from Solid State NMR. AB - Mixed-cation organic lead halide perovskites attract unfaltering attention owing to their excellent photovoltaic properties. Currently, the best performing perovskite materials contain multiple cations and provide power conversion efficiencies up to around 22%. Here, we report the first quantitative, cation specific data on cation reorientation dynamics in hybrid mixed-cation formamidinium (FA)/methylammonium (MA) lead halide perovskites. We use 14N, 2H, 13C, and 1H solid-state MAS NMR to elucidate cation reorientation dynamics, microscopic phase composition, and the MA/FA ratio, in (MA)x(FA)1-xPbI3 between 100 and 330 K. The reorientation rates correlate in a striking manner with the carrier lifetimes previously reported for these materials and provide evidence of the polaronic nature of charge carriers in PV perovskites. PMID- 28641416 TI - Water-anion hydrogen bonding dynamics: Ultrafast IR experiments and simulations. AB - Many of water's remarkable properties arise from its tendency to form an intricate and robust hydrogen bond network. Understanding the dynamics that govern this network is fundamental to elucidating the behavior of pure water and water in biological and physical systems. In ultrafast nonlinear infrared experiments, the accessible time scales are limited by water's rapid vibrational relaxation (1.8 ps for dilute HOD in H2O), precluding interrogation of slow hydrogen bond evolution in non-bulk systems. Here, hydrogen bonding dynamics in bulk D2O were studied from the perspective of the much longer lived (36.2 ps) CN stretch mode of selenocyanate (SeCN-) using polarization selective pump-probe (PSPP) experiments, two-dimensional infrared (2D IR) vibrational echo spectroscopy, and molecular dynamics simulations. The simulations make use of the empirical frequency mapping approach, applied to SeCN- for the first time. The PSPP experiments and simulations show that the orientational correlation function decays via fast (2.0 ps) restricted angular diffusion (wobbling-in-a-cone) and complete orientational diffusive randomization (4.5 ps). Spectral diffusion, quantified in terms of the frequency-frequency correlation function, occurs on two time scales. The initial 0.6 ps time scale is attributed to small length and angle fluctuations of the hydrogen bonds between water and SeCN-. The second 1.4 ps measured time scale, identical to that for HOD in bulk D2O, reports on the collective reorganization of the water hydrogen bond network around the anion. The experiments and simulations provide details of the anion-water hydrogen bonding and demonstrate that SeCN- is a reliable vibrational probe of the ultrafast spectroscopy of water. PMID- 28641417 TI - Spectral line shapes in linear absorption and two-dimensional spectroscopy with skewed frequency distributions. AB - The effect of Gaussian dynamics on the line shapes in linear absorption and two dimensional correlation spectroscopy is well understood as the second-order cumulant expansion provides exact spectra. Gaussian solvent dynamics can be well analyzed using slope line analysis of two-dimensional correlation spectra as a function of the waiting time between pump and probe fields. Non-Gaussian effects are not as well understood, even though these effects are common in nature. The interpretation of the spectra, thus far, relies on complex case to case analysis. We investigate spectra resulting from two physical mechanisms for non-Gaussian dynamics, one relying on the anharmonicity of the bath and the other on non linear couplings between bath coordinates. These results are compared with outcomes from a simpler log-normal dynamics model. We find that the skewed spectral line shapes in all cases can be analyzed in terms of the log-normal model, with a minimal number of free parameters. The effect of log-normal dynamics on the spectral line shapes is analyzed in terms of frequency correlation functions, maxline slope analysis, and anti-diagonal linewidths. A triangular line shape is a telltale signature of the skewness induced by log normal dynamics. We find that maxline slope analysis, as for Gaussian dynamics, is a good measure of the solvent dynamics for log-normal dynamics. PMID- 28641418 TI - Measuring the carrier dynamics of photocatalyst micrograins using the Christiansen effect. AB - The optical measurement of photocatalyst materials is subject to Mie scattering when the particle size is comparable to the wavelength of the probe light. A novel approach was developed to deal with this scattering problem in the transient spectroscopy of photocatalyst micrograins using the Christiansen effect because the probe light in the vicinity of the Christiansen frequency can be transmitted. Scattering theory was used to analyze the transient spectra of micrograins and estimate the extinction coefficient at the Christiansen frequency. The Drude-Lorentz model was used to calculate the complex refractive index considering the contributions from both phonons and free carriers. We found that the net photogenerated carrier density was linearly correlated with the absorbance at the Christiansen frequency. With the parameters obtained from Raman scattering measurements, the absolute net carrier density was also determined. We further demonstrated the versatility of this method by applying it to the photogenerated carrier dynamics of intrinsic 6H-SiC grains. The transient broadband mid-IR spectra were measured by the pump-probe technique, and the transient absolute net carrier density was estimated. The carrier relaxation dynamics was fitted with three components with lifetime constants that agreed well with those obtained for SiC by transient broadband THz conductivity spectroscopy. We predict that this method could be extended to other photocatalytic materials with suitable probe frequencies. PMID- 28641419 TI - Thermodynamic formulation of the barrier for heterogeneous pinned nucleation: Implication to the crossover scenarios associated with barrierless and homogeneous nucleation. AB - The effect of contact line pinning on nucleation is reported using continuum thermodynamics. Based on the principle of the free-energy maximization, closed form expressions in the dimensionless form for the free-energy of the three-phase metastable system and the thermodynamic barrier are formulated with respect to the system geometry and the substrate wettability. The condition of maximality limits the dynamic contact angle within the cluster-phase-phobic regime. The dimensionless nucleation barrier or the potency factor can be divided into two components related to the system geometry and the pinning effect. Depending on the relative value of the equilibrium and the critical dynamic contact angle, the contact line pinning can either have favorable or adverse effects. Associated pinning-depinning transition can also lead to the crossovers related to barrierless and homogeneous nucleation. Contact line tension is found to have a considerable effect during these transitional scenarios. Complete wetting transition associated with barrierless nucleation can take place due to the presence of tensile (negative) line tension. On the other hand, complete drying transition related to homogeneous nucleation can occur when line tension is compressive (positive) in nature. The pinning has a favorable effect only when the substrate wettability is within the cluster-phase-philic regime. There can be favorable, adverse, or no pinning effects when the substrate wettability is within the cluster-phase-phobic regime. Although the contact line is pinned, the minimum value of the potency factor is obtained when equilibrium and dynamic contact angles are equal. PMID- 28641420 TI - NH3 as unique non-classical content-former within clathrate hydrates. AB - High quality FTIR spectra of aerosols of NH3-THF and NH3-TMO binary clathrate hydrates (CHs) have been measured. Our recently developed all-vapor sub-second approach to clathrate-hydrate formation combined with computational studies has been used to identify vibrational spectroscopic signatures of NH3 within the gas hydrates. The present study shows that there are three distinct NH3 types, namely, classical small-cage NH3, nonclassical small-cage NH3, and NH3 within the hydrate network. The network ammonia does not directly trigger the non-classical CH structure. Rather, the ammonia within the network structure perturbs the water bonding, introducing orientational defects that are stabilized by small and/or large cage guest molecules through H-bonding. This unusual behavior of NH3 within CHs opens a possibility for catalytic action of NH3 during CH-formation. Furthermore, impacts over time of the small-cage NH3-replacement molecules CO2 and CH4 on the structure and composition of the ternary CHs have been noted. PMID- 28641421 TI - Effective empirical corrections for basis set superposition error in the def2 SVPD basis: gCP and DFT-C. AB - With the aim of mitigating the basis set error in density functional theory (DFT) calculations employing local basis sets, we herein develop two empirical corrections for basis set superposition error (BSSE) in the def2-SVPD basis, a basis which-when stripped of BSSE-is capable of providing near-complete-basis DFT results for non-covalent interactions. Specifically, we adapt the existing pairwise geometrical counterpoise (gCP) approach to the def2-SVPD basis, and we develop a beyond-pairwise approach, DFT-C, which we parameterize across a small set of intermolecular interactions. Both gCP and DFT-C are evaluated against the traditional Boys-Bernardi counterpoise correction across a set of 3402 non covalent binding energies and isomerization energies. We find that the DFT-C method represents a significant improvement over gCP, particularly for non covalently-interacting molecular clusters. Moreover, DFT-C is transferable among density functionals and can be combined with existing functionals-such as B97M-V to recover large-basis results at a fraction of the cost. PMID- 28641423 TI - Dynamics, magnetic properties, and electron binding energies of H2O2 in water. AB - Results for the magnetic properties and electron binding energies of H2O2 in liquid water are presented. The adopted methodology relies on the combination of Born-Oppenheimer molecular dynamics and electronic structure calculations. The Keal-Tozer functional was applied for predicting magnetic shieldings and H2O2 intramolecular spin-spin coupling constants. Electron binding energies were calculated with electron propagator theory. In water, H2O2 is a better proton donor than proton acceptor, and the present results indicate that this feature is important for understanding magnetic properties in solution. In comparison with the gas-phase, H2O2 atoms are deshielded in water. For oxygen atoms, the deshielding is mainly determined by structural/conformational changes. Hydrogen bond interactions explain the deshielding of protons in water. The predicted chemical shift for the H2O2 protons in water (delta~11.8 ppm) is in good agreement with experimental information (delta=11.2 ppm). The two lowest electron binding energies of H2O2 in water (10.7+/-0.5 and 11.2+/-0.5 eV) are in reasonable agreement with experiment. In keeping with data from photoelectron spectroscopy, an ~1.6 eV red-shift of the two first ionisation energies relative to the gas-phase is observed in water. The strong dependence of magnetic properties on changes of the electronic density in the nuclei environment is illustrated by a correlation between the sigma(17O) magnetic shielding constant and the energy gap between the [2a] lowest valence and [1a] core orbitals of H2O2. PMID- 28641422 TI - Structure and mobility of water confined in AlPO4-54 nanotubes. AB - We performed molecular dynamics simulations of water confined within AlPO4-54 nanotubes. AlPO4-54 is an artificial material made of AlO4 and of PO4 in tetrahedra arranged in a periodic structure forming pores of approximately 1.3 nm in diameter. This makes AlPO4-54 an excellent candidate for practical applications, such as for water filtration and desalination. In this work, the structural and dynamical properties of the confined water are analyzed for various temperatures and water loadings. We find that the water structure is controlled by the heterogeneity of the nanopore surface with the water molecules located preferentially next to the surface of oxygens of AlPO4-54; consequently, at very low densities, water forms helicoidal structures in string-like arrangements. PMID- 28641425 TI - First infrared investigations of OCS-H2O, OCS-(H2O)2, and (OCS)2-H2O complexes isolated in solid neon: Highlighting the presence of two isomers for OCS-H2O. AB - For the first time, complexes involving carbonyl sulfide (OCS) and water molecules are studied by FTIR in solid neon. Many new absorption bands close to the known fundamental modes for the monomers give evidence for at least three (OCS)n-(H2O)m complexes, noted n:m. With the help of theoretical calculations, two isomers of the 1:1 complex are clearly identified. Concentration effects combined with a detailed vibrational analysis allow for the identification of transitions for the 1:1, 1:2, and 2:1 complexes. Anharmonic coupling constants have been derived from the observations of overtones and combinations. PMID- 28641424 TI - The role of multivalency in the association kinetics of patchy particle complexes. AB - Association and dissociation of particles are elementary steps in many natural and technological relevant processes. For many such processes, the presence of multiple binding sites is essential. For instance, protein complexes and regular structures such as virus shells are formed from elementary building blocks with multiple binding sites. Here we address a fundamental question concerning the role of multivalency of binding sites in the association kinetics of such complexes. Using single replica transition interface sampling simulations, we investigate the influence of the multivalency on the binding kinetics and the association mechanism of patchy particles that form polyhedral clusters. When the individual bond strength is fixed, the kinetics naturally is very dependent on the multivalency, with dissociation rate constants exponentially decreasing with the number of bonds. In contrast, we find that when the total bond energy per particle is kept constant, association and dissociation rate constants turn out rather independent of multivalency, although of course still very dependent on the total energy. The association and dissociation mechanisms, however, depend on the presence and nature of the intermediate states. For instance, pathways that visit intermediate states are less prevalent for particles with five binding sites compared to the case of particles with only three bonds. The presence of intermediate states can lead to kinetic trapping and malformed aggregates. We discuss implications for natural forming complexes such as virus shells and for the design of artificial colloidal patchy particles. PMID- 28641426 TI - Assessment of two hybrid van der Waals density functionals for covalent and non covalent binding of molecules. AB - Two hybrid van der Waals density functionals (vdW-DFs) are developed using 25% Fock exchange with (i) the consistent-exchange vdW-DF-cx functional [K. Berland and P. Hyldgaard, Phys. Rev. B 89, 035412 (2014)] and (ii) with the vdW-DF2 functional [K. Lee et al., Phys. Rev. B 82, 081101 (2010)]. The ability to describe covalent and non-covalent binding properties of molecules is assessed. For properties related to covalent binding, atomization energies (G2-1 set), molecular reaction energies (G2RC set), and ionization energies (G21IP set) are benchmarked against experimental reference values. We find that hybrid-vdW-DF-cx yields results that are rather similar to those of the standard non-empirical hybrid PBE0 [C. Adamo and V. Barone, J. Chem. Phys. 110, 6158 (1999)], with mean average deviations (MADs) of 4.9 and 5.0 kcal/mol for the G2-1 set, respectively. In this comparison, experimental reference values are used, back corrected by wavefunction-based quantum-chemistry calculations of zero-point energies. Hybrid vdW-DF2 follows somewhat different trends, showing on average significantly larger deviations from the reference energies, with a MAD of 14.5 kcal/mol for the G2-1 set. Non-covalent binding properties of molecules are assessed using the S22 benchmark set of non-covalently bonded dimers and the X40 set of dimers of small halogenated molecules, using wavefunction-based quantum chemistry results as references. For the S22 set, hybrid-vdW-DF-cx performs better than standard vdW-DF-cx for the mostly hydrogen-bonded systems, with MAD dropping from 0.6 to 0.3 kcal/mol, but worse for purely dispersion-bonded systems, with MAD increasing from 0.2 to 0.6 kcal/mol. Hybrid-vdW-DF2 offers a slight improvement over standard vdW-DF2. Similar trends are found for the X40 set, with hybrid-vdW-DF-cx performing particularly well for binding energies involving the strongly polar hydrogen halides, but poorly for systems with tiny binding energies. Our study of the X40 set reveals the potential of mixing Fock exchange with vdW-DF, but also highlights shortcomings of the hybrids constructed here. The solid performance of hybrid-vdW-DF-cx for covalent-bonded systems, as well as the strengths and issues uncovered for non-covalently bonded systems, makes this study a good starting point for developing even more accurate hybrid vdW-DFs. PMID- 28641427 TI - A quantum-mechanical perspective on linear response theory within polarizable embedding. AB - We present a derivation of linear response theory within polarizable embedding starting from a rigorous quantum-mechanical treatment of a composite system. To this aim, two different subsystem decompositions (symmetric and nonsymmetric) of the linear response function are introduced and the pole structures as well as residues of the individual terms are discussed. In addition to providing a thorough justification for the descriptions used in polarizable embedding models, this theoretical analysis clarifies which form of the response function to use and highlights complications in separating out subsystem contributions to molecular properties. The basic features of the presented expressions and various approximate forms are illustrated by their application to a composite model system. PMID- 28641428 TI - Liquid-liquid phase transition in an ionic model of silica. AB - Recent equation of state calculations [E. Lascaris, Phys. Rev. Lett. 116, 125701 (2016)] for an ionic model of silica suggest that it undergoes a density-driven, liquid-liquid phase transition (LLPT) similar to the controversial transition hypothesized to exist in deeply supercooled water. Here, we perform extensive free energy calculations to scrutinize the model's low-temperature phase behavior and confirm the existence of a first-order phase transition between two liquids with identical compositions but different densities. The low-density liquid (LDL) exhibits tetrahedral order, which is partially disrupted in the high-density liquid (HDL) by the intrusion of additional particles into the primary neighbor shell. Histogram reweighting methods are applied to locate conditions of HDL-LDL coexistence and the liquid spinodals that bound the two-phase region. Spontaneous liquid-liquid phase separation is also observed directly in large-scale molecular dynamics simulations performed inside the predicted two-phase region. Given its clear LLPT, we anticipate that this model may serve as a paradigm for understanding whether similar transitions occur in water and other tetrahedral liquids. PMID- 28641429 TI - Fluids in porous media. IV. Quench effect on chemical potential. AB - It appears to be a common sense to measure the crowdedness of a fluid system by the densities of the species constituting it. In the present work, we show that this ceases to be valid for confined fluids under some conditions. A quite thorough investigation is made for a hard sphere (HS) fluid adsorbed in a hard sphere matrix (a quench-annealed system) and its corresponding equilibrium binary mixture. When fluid particles are larger than matrix particles, the quench annealed system can appear much more crowded than its corresponding equilibrium binary mixture, i.e., having a much higher fluid chemical potential, even when the density of each species is strictly the same in both systems, respectively. We believe that the insight gained from this study should be useful for the design of functionalized porous materials. PMID- 28641430 TI - Water flow in carbon nanotubes: The effect of tube flexibility and thermostat. AB - Although the importance of temperature control in nonequilibrium molecular dynamics simulations is widely accepted, the consequences of the thermostatting approach in the case of strongly confined fluids are underappreciated. We show the strong influence of the thermostatting method on the water transport in carbon nanotubes (CNTs) by considering simulations in which the system temperature is controlled via the walls or via the fluid. Streaming velocities and mass flow rates are found to depend on the tube flexibility and on the thermostatting algorithm, with flow rates up to 20% larger when the walls are flexible. The larger flow rates in flexible CNTs are explained by a lower friction coefficient between water and the wall. Despite the lower friction, a larger solid-fluid interaction energy is found for flexible CNTs than for rigid ones. Furthermore, a comparison of thermostat schemes has shown that the Berendsen and Nose-Hoover thermostats result in very similar transport rates, while lower flow rates are found under the influence of the Langevin thermostat. These findings illustrate the significant influence of the thermostatting methods on the simulated confined fluid transport. PMID- 28641431 TI - Second order Moller-Plesset and coupled cluster singles and doubles methods with complex basis functions for resonances in electron-molecule scattering. AB - The method of complex basis functions is applied to molecular resonances at correlated levels of theory. Moller-Plesset perturbation theory at second order and equation-of-motion electron attachment coupled-cluster singles and doubles (EOM-EA-CCSD) methods based on a non-Hermitian self-consistent-field reference are used to compute accurate Siegert energies for shape resonances in small molecules including N2-, CO-, CO2-, and CH2O-. Analytic continuation of complex ??-trajectories is used to compute Siegert energies, and the ??-trajectories of energy differences are found to yield more consistent results than those of total energies. The ability of such methods to accurately compute complex potential energy surfaces is investigated, and the possibility of using EOM-EA-CCSD for Feshbach resonances is explored in the context of e-helium scattering. PMID- 28641432 TI - Local structure of dilute aqueous DMSO solutions, as seen from molecular dynamics simulations. AB - The information about the structure of dimethyl sulfoxide (DMSO)-water mixtures at relatively low DMSO mole fractions is an important step in order to understand their cryoprotective properties as well as the solvation process of proteins and amino acids. Classical MD simulations, using the potential model combination that best reproduces the free energy of mixing of these compounds, are used to analyze the local structure of DMSO-water mixtures at DMSO mole fractions below 0.2. Significant changes in the local structure of DMSO are observed around the DMSO mole fraction of 0.1. The array of evidence, based on the cluster and the metric and topological parameters of the Voronoi polyhedra distributions, indicates that these changes are associated with the simultaneous increase of the number of DMSO water and decrease of water-water hydrogen bonds with increasing DMSO concentration. The inversion between the dominance of these two types of H-bonds occurs around XDMSO = 0.1, above which the DMSO-DMSO interactions also start playing an important role. In other words, below the DMSO mole fraction of 0.1, DMSO molecules are mainly solvated by water molecules, while above it, their solvation shell consists of a mixture of water and DMSO. The trigonal, tetrahedral, and trigonal bipyramidal distributions of water shift to lower corresponding order parameter values indicating the loosening of these orientations. Adding DMSO does not affect the hydrogen bonding between a reference water molecule and its first neighbor hydrogen bonded water molecules, while it increases the bent hydrogen bond geometry involving the second ones. The close-packed local structure of the third, fourth, and fifth water neighbors also is reinforced. In accordance with previous theoretical and experimental data, the hydrogen bonding between water and the first, the second, and the third DMSO neighbors is stronger than that with its corresponding water neighbors. At a given DMSO mole fraction, the behavior of the intensity of the high orientational order parameter values indicates that water molecules are more ordered in the vicinity of the hydrophilic group while their structure is close-packed near the hydrophobic group of DMSO. PMID- 28641433 TI - Why are GGAs so accurate for reaction kinetics on surfaces? Systematic comparison of hybrid vs. nonhybrid DFT for representative reactions. AB - "Jacob's Ladder" of approximate exchange-correlation (XC) functionals in Kohn Sham density functional theory are widely accepted to have systematic errors in reaction barriers. The first-rung local spin-density approximation (LDA) typically predicts barriers below generalized gradient approximations, which in turn predict barriers below experiment and below fourth-rung hybrid functionals incorporating a fraction of exact exchange. We show that several reactions from previous literature reports, as well as new simulations of carbon-carbon coupling in the Fischer-Tropsch process, do not follow this conventional picture. We introduce the AB9 test set of nine abnormal reaction barriers, in which density gradient corrections and exact exchange admixture tend to lower rather than to raise predicted barriers. Comparisons of normal and abnormal reactions rationalize this phenomenon in terms of how density gradient and exact-exchange corrections stabilize transition states relative to reaction intermediates. Multireference diagnostics confirm that this behavior is not merely a consequence of multireference character. Benchmarks of the AB9 set, using the best available ab initio reference values, highlight the role of symmetry breaking and show surprisingly good performance from both the LDA and "Rung 3.5" functionals. This motivates benchmarks of the AB9 set in future XC functional development. PMID- 28641434 TI - First principles study of 2D layered organohalide tin perovskites. AB - This article describes the structure and the electronic properties of a series of layered perovskites of a general formula (A+)2(SnX4)-2 where X = I, Br and A+ is an organic cation, either formamidinium, 1-methylimidazolium, or phenylethylammonium. For each system, two conformations are considered, with eclipsed or staggered stacking of the adjacent inorganic layers. Geometry optimizations are performed at the density functional theory level with generalized gradient approximation (GGA) functional and semiempirical correction for dispersion energies; band profiles and bandgaps are computed including both spin orbit coupling (SOC) and correlation (GW) effects through an additive scheme. The theoretical procedures are validated by reproducing the experimental data of a well known 3D tin iodide perovskite. The results, combined with the calculations previously reported on PbI4 analogues, allow us to discuss the effect of cation, metal, and halide substitution in these systems and in particular to explore the possibility of changing the electronic bandgap as required by different applications. The balance of SOC and GW effects depends on the chemical nature of the studied perovskites and strongly influences the value of the simulated bandgap. PMID- 28641435 TI - Validating and implementing modified Filinov phase filtration in semiclassical dynamics. AB - The Mixed Quantum-Classical Initial Value Representation (MQC-IVR) is a recently introduced approximate semiclassical (SC) method for the calculation of real-time quantum correlation functions. MQC-IVR employs a modified Filinov filtration (MFF) scheme to control the overall phase of the SC integrand, extending the applicability of SC methods to complex systems while retaining their ability to accurately describe quantum coherence effects. Here, we address questions regarding the effectiveness of the MFF scheme in combination with SC dynamics. Previous work showed that this filtering scheme is of limited utility in the context of semiclassical wavepacket propagation, but we find that the MFF is extraordinarily powerful in the context of correlation functions. By examining trajectory phase and amplitude contributions to the real-time SC correlation function in a model system, we clearly demonstrate that the MFF serves to reduce noise by damping amplitude only in regions of highly oscillatory phase leading to a reduction in computational effort while retaining accuracy. Further, we introduce a novel and efficient MQC-IVR formulation that allows for linear scaling in computational cost with the total simulation length, a significant improvement over the more-than quadratic scaling exhibited by the original method. PMID- 28641436 TI - Doping as a means to probe the potential dependence of dopamine adsorption on carbon-based surfaces: A first-principles study. AB - In this work, we study the adsorption characteristics of dopamine (DA), ascorbic acid (AA), and dopaminequinone (DAox) on carbonaceous electrodes. Our goal is to obtain a better understanding of the adsorption behavior of these analytes in order to promote the development of new carbon-based electrode materials for sensitive and selective detection of dopamine in vivo. Here we employ density functional theory-based simulations to reach a level of detail that cannot be achieved experimentally. To get a broader understanding of carbonaceous surfaces with different morphological characteristics, we compare three materials: graphene, diamond, and amorphous carbon (a-C). Effects of solvation on adsorption characteristics are taken into account via a continuum solvent model. Potential changes that take place during electrochemical measurements, such as cyclic voltammetry, can also alter the adsorption behavior. In this study, we have utilized doping as an indirect method to simulate these changes by shifting the work function of the electrode material. We demonstrate that sp2- and sp3-rich materials, as well as a-C, respond markedly different to doping. Also the adsorption behavior of the molecules studied here differs depending on the surface material and the change in the surface potential. In all cases, adsorption is spontaneous, but covalent bonding is not detected in vacuum. The aqueous medium has a large effect on the adsorption behavior of DAox, which reaches its highest adsorption energy on diamond when the potential is shifted to more negative values. In all cases, inclusion of the solvent enhances the charge transfer between the slab and DAox. Largest differences in adsorption energy between DA and AA are obtained on graphene. Gaining better understanding of the behavior of the different forms of carbon when used as electrode materials provides a means to rationalize the observed complex phenomena taking place at the electrodes during electrochemical oxidation/reduction of these biomolecules. PMID- 28641437 TI - Structure and binding energy of the H2S dimer at the CCSD(T) complete basis set limit. AB - This study presents results for the binding energy and geometry of the H2S dimer which have been computed using Moller-Plesset perturbation theory (MP2, MP4) and coupled cluster (CCSD, CCSD(T)) calculations with basis sets up to aug-cc-pV5Z. Estimates of De, EZPE, Do, and dimer geometry have been obtained at each level of theory by taking advantage of the systematic convergence behavior toward the complete basis set (CBS) limit. The CBS limit binding energy values of De are 1.91 (MP2), 1.75 (MP4), 1.41 (CCSD), and 1.69 kcal/mol (CCSD[T]). The most accurate values for the equilibrium S-S distance rSS (without counterpoise correction) are 4.080 (MP2/aug-cc-pV5Z), 4.131 (MP4/aug-cc-pVQZ), 4.225 (CCSD/aug cc-pVQZ), and 4.146 A (CCSD(T)/aug-cc-pVQZ). This study also evaluates the effect of counterpoise correction on the H2S dimer geometry and binding energy. As regards the structure of (H2S)2, MPn, CCSD, and CCSD(T) level values of rSS, obtained by performing geometry optimizations on the counterpoise-corrected potential energy surface, converge systematically to CBS limit values of 4.099 (MP2), 4.146 (MP4), 4.233 (CCSD), and 4.167 A (CCSD(T)). The corresponding CBS limit values of the equilibrium binding energy De are 1.88 (MP2), 1.76 (MP4), 1.41 (CCSD), and 1.69 kcal/mol (CCSD(T)), the latter in excellent agreement with the measured binding energy value of 1.68 +/- 0.02 kcal/mol reported by Ciaffoni et al. [Appl. Phys. B 92, 627 (2008)]. Combining CBS electronic binding energies De with EZPE predicted by CCSD(T) vibrational second-order perturbation theory calculations yields Do = 1.08 kcal/mol, which is around 0.6 kcal/mol smaller than the measured value of 1.7 +/- 0.3 kcal/mol. Overall, the results presented here demonstrate that the application of high level calculations, in particular CCSD(T), in combination with augmented correlation consistent basis sets provides valuable insight into the structure and energetics of the hydrogen sulfide dimer. PMID- 28641438 TI - Erratum: "Stochastic multi-reference perturbation theory with application to the linearized coupled cluster method" [J. Chem. Phys. 146, 044107 (2017)]. PMID- 28641439 TI - High-pressure phase transition of alkali metal-transition metal deuteride Li2PdD2. AB - A combined theoretical and experimental study of lithium palladium deuteride (Li2PdD2) subjected to pressures up to 50 GPa reveals one structural phase transition near 10 GPa, detected by synchrotron powder x-ray diffraction, and metadynamics simulations. The ambient-pressure tetragonal phase of Li2PdD2 transforms into a monoclinic C2/m phase that is distinct from all known structures of alkali metal-transition metal hydrides/deuterides. The structure of the high-pressure phase was characterized using ab initio computational techniques and from refinement of the powder x-ray diffraction data. In the high pressure phase, the PdD2 complexes lose molecular integrity and are fused to extended [PdD2]infinity chains. The discovered phase transition and new structure are relevant to the possible hydrogen storage application of Li2PdD2 and alkali metal-transition metal hydrides in general. PMID- 28641440 TI - Accurate excitation energies of molecules and oligomers from a semilocal density functional. AB - Excitation energy plays an important role in energy conversion, biological processes, and optical devices. In this work, we apply the Tao-Mo (TM) nonempirical meta-generalized gradient approximation and the combination TMTPSS (TMx + TPSSc), with TPSSc being the correlation part of the original TPSS (Tao Perdew-Staroverov-Scuseria) to study excitation energies of small molecules and oligomers. Our test set consists of 17 molecules with 134 total excited states, including singlet, triplet, valence, and Rydberg excited states. Our calculation shows that both the TMTPSS and TM functionals yield good overall performance, with mean absolute errors (MAEs) of 0.37 eV and 0.42 eV, respectively, outperforming commonly used semilocal functionals LSDA (MAE = 0.55 eV), PBE (MAE = 0.58 eV), and TPSS (MAE = 0.47 eV). In particular, TMTPSS can yield nearly the same accuracy of B3LYP (MAE = 0.36 eV), with lower computational cost. The accuracy for semilocal density functional theory continues to hold for conjugated oligomers, but they become less accurate than hybrid functionals, due to the insufficient nonlocality. PMID- 28641441 TI - The closo-Si12C12 molecule from cluster to crystal: Effects of hydrogenation and oligomerization on excited states. AB - Excited state properties of chain and cyclic oligomers of closo-Si12C12 moieties are calculated using time-dependent density functional theory methods. Ultraviolet, visible, and near-infrared photo-absorption properties are described for oligomers that form by linking closo-Si12C12 monomer moieties through Si-Si bonds. Natural transition orbitals for electron and hole states of stationary state excitons in oligomers were compared to understand how exciton states are influenced by oligomer structure. Depending on the structure, some prominent excited states have large electron-hole charge separation while others do not; some exhibit exciton delocalization while others do not. With increasing oligomer length, the character of the transition between silicon and carbon regions tends to be maintained. And the extent of exciton delocalization and charge separation for an excitation is strongly influenced by the number and types of Si-Si links between oligomer units. We find that cyclic quadramers have spectroscopy properties akin to those of J-aggregates, including the tendency to collapse oligomer excitation transition energies into a narrow single peak. Hydrogenation influences some excited state distributions and energies. Phase behaviors reveal electron state or hole state equivalence in certain molecules that are differently hydrogenated, illustrating the potential for near-resonant exciton transfer between adjacent donor and acceptor species. PMID- 28641442 TI - Structural relaxation and thermal conductivity of high-pressure formed, high density di-n-butyl phthalate glass and pressure induced departures from equilibrium state. AB - We report a study of structural relaxation of high-density glasses of di-n-butyl phthalate (DBP) by measuring thermal conductivity, kappa, under conditions of pressure and temperature (p,T) designed to modify both the vibrational and configurational states of a glass. Various high-density glassy states of DBP were formed by (i) cooling the liquid under a fixed high p and partially depressurizing the glass, (ii) isothermal annealing of the depressurized glass, and (iii) pressurizing the glass formed by cooling the liquid under low p. At a given low p, kappa of the glass formed by cooling under high p is higher than that of the glass formed by cooling under low p, and the difference increases as glass formation p is increased. kappa of the glass formed under 1 GPa is ~20% higher at ambient p than kappa of the glass formed at ambient p. On heating at low p, kappa decreases until the glass to liquid transition range is reached. This is the opposite of the increase in kappa observed when a glass formed under a certain p is heated under the same p. At a given high p, kappa of the low density glass formed by cooling at low p is lower than that of the high-density glass formed by cooling at that high p. On heating at high p, kappa increases until the glass to liquid transition range is reached. The effects observed are due to a thermally assisted approach toward equilibrium at p different from the glass formation p. In all cases, the density, enthalpy, and entropy would change until the glasses become metastable liquids at a fixed p, thus qualitatively relating kappa to variation in these properties. PMID- 28641443 TI - Dissecting the accountability of parameterized and parameter-free single-hybrid and double-hybrid functionals for photophysical properties of TADF-based OLEDs. AB - Organic light emitting diodes (OLEDs) based on thermally activated delayed fluorescence (TADF) emitters are an attractive category of materials that have witnessed a booming development in recent years. In the present contribution, we scrutinize the accountability of parameterized and parameter-free single-hybrid (SH) and double-hybrid (DH) functionals through the two formalisms, full time dependent density functional theory (TD-DFT) and Tamm-Dancoff approximation (TDA), for the estimation of photophysical properties like absorption energy, emission energy, zero-zero transition energy, and singlet-triplet energy splitting of TADF molecules. According to our detailed analyses on the performance of SHs based on TD-DFT and TDA, the TDA-based parameter-free SH functionals, PBE0 and TPSS0, with one-third of exact-like exchange turned out to be the best performers in comparison to other functionals from various rungs to reproduce the experimental data of the benchmarked set. Such affordable SH approximations can thus be employed to predict and design the TADF molecules with low singlet-triplet energy gaps for OLED applications. From another perspective, considering this point that both the nonlocal exchange and correlation are essential for a more reliable description of large charge-transfer excited states, applicability of the functionals incorporating these terms, namely, parameterized and parameter-free DHs, has also been evaluated. Perusing the role of exact-like exchange, perturbative-like correlation, solvent effects, and other related factors, we find that the parameterized functionals B2pi-PLYP and B2GP PLYP and the parameter-free models PBE-CIDH and PBE-QIDH have respectable performance with respect to others. Lastly, besides the recommendation of reliable computational protocols for the purpose, hopefully this study can pave the way toward further developments of other SHs and DHs for theoretical explorations in the field of OLEDs technology. PMID- 28641444 TI - Toward Mentoring in Palliative Social Work: A Narrative Review of Mentoring Programs in Social Work. AB - BACKGROUND: Mentoring by an experienced practitioner enhances professional well being, promotes resilience, and provides a means of addressing poor job satisfaction and high burnout rates among medical social workers. This is a crucial source of support for social workers working in fields with high risk of compassion fatigue and burnout like palliative care. Implementing such a program, however, is hindered by differences in understanding and application of mentoring practice. AIM: This narrative review of mentoring practice in social work seeks to identify key elements and common approaches within successful mentoring programs in social work that could be adapted to guide the design of new mentoring programs in medical social work. Methodology and Data Sources: A literature search of mentoring programs in social work between January 1, 2000, and December 31, 2015, using Pubmed, CINAHL, OVID, ERIC, Scopus, Cochrane and ScienceDirect databases, involving a senior experienced mentor and undergraduate and/or junior postgraduates, was carried out. A total of 1302 abstracts were retrieved, 22 full-text articles were analyzed, and 8 articles were included. RESULTS: Thematic analysis of the included articles revealed 7 themes pertaining to the mentoring process, outcomes and barriers, and the characteristics of mentoring relationships, mentors, mentees, and host organizations. DISCUSSION AND CONCLUSION: Common themes in prevailing mentoring practices help identify key elements for the design of an effective mentoring program in medical social work. We conclude with a discussion of the implications of these findings upon clinical practice in palliative care and on sustaining such a program. PMID- 28641446 TI - [Miscellaneous]. PMID- 28641445 TI - Subcutaneous Botulinum Toxin Injection for Post-Thoracotomy Pain Syndrome in Palliative Care: A Case Report. AB - Post-thoracotomy pain syndrome (PTPS) is a traumatic neuropathy that can affect as many as 50% of patients undergoing thoracotomy. Patients are often refractory to conservative management and may require multiple analgesics for adequate pain control. Botulinum toxin, derived from Clostridium botulinum, has many uses in treating conditions involving spasticity, dystonia, chronic migraine, and a variety of pain disorders including neuropathies. Botulinum toxin type A injections may provide an alternative or adjunct to improve symptom management in patients with PTPS. PMID- 28641448 TI - Negative inotropism of terpenes on guinea pig left atrium: structure-activity relationships. AB - The aim of this work was to evaluate the pharmacological effect of seven structurally related terpenes on the contractility of cardiac muscle. The effect of terpenes was studied on isolated electrically driven guinea pig left atrium. From concentration-response curves for inotropic effect were determined the EC50 and relative potency of such terpenes. Our results revealed that all terpenes, except phytol, showed ability to reduce the contractile response of guinea pig left atrium. Further, relative potency was directly related to the number of isoprene units and to the lipophilicity of the compounds. For example, sesquiterpenes farnesol and nerolidol showed higher relative potency when compared with the monoterpenes citronellol, geraniol and nerol. We can conclude that most of the evaluated terpenes showed a promising negative inotropism on the atrial muscle. Future studies are necessary to investigate their action mechanism. PMID- 28641450 TI - Musculoskeletal dysfunction in migraine patients. AB - Objective The aim of this project was to evaluate the prevalence and pattern of musculoskeletal dysfunctions in migraine patients using a rigorous methodological approach and validating an international consensus cluster of headache assessment tests. Methods A physiotherapist, blinded towards the diagnosis, examined 138 migraine patients (frequent episodic and chronic), recruited at a specialised headache clinic, and 73 age and gender matched healthy controls following a standardised protocol. Eleven tests, previously identified in an international consensus procedure, were used to evaluate cervical and thoracic musculoskeletal dysfunctions. Results Primary analyses indicated statistically significant differences across groups for the total number of trigger points, flexion rotation test, thoracic screening, manual joint testing of the upper cervical spine, cranio-cervical flexion test, and reproduction and resolution. Ninety three percent of the assessed patients had at least three musculoskeletal dysfunctions. Post-hoc tests showed significant differences between episodic or chronic migraine patients and healthy controls, but not between migraine groups. Conclusions A standardised set of six physical examination tests showed a high prevalence of musculoskeletal dysfunctions in migraine patients. These dysfunctions support a reciprocal interaction between the trigeminal and the cervical systems as a trait symptom in migraine. PMID- 28641449 TI - The positive eating scale: relationship with objective health parameters and validity in Germany, the USA and India. AB - OBJECTIVE: The prevailing focus regarding eating behaviour is on restriction, concern, worry and pathology. In contrast, the purpose of the present studies was to focus on a positive relationship with eating in non-clinical samples from Germany, the USA and India. DESIGN: In Study 1, the Positive Eating Scale (PES) was tested and validated in a large longitudinal sample (T1: N = 772; T2: N = 510). In Study 2, the PES was tested in online samples from the USA, India and Germany (total N = 749). MAIN OUTCOME MEASURES: Health risk status was measured in Study 1 with objective health parameters (fasting serum glucose, triglycerides, high-density lipoprotein cholesterol, blood pressure, waist circumference, BMI). RESULTS: Study 1 revealed acceptable psychometric properties of the PES, internal consistency (alpha = .87), as well as test-retest reliability after six months (r = .67). Importantly, a positive relationship with eating was associated with decreased health risk factors six months later. In Study 2, the structure of the PES was confirmed for German, Indian and US American adults, suggesting validity across remarkably different eating environments. CONCLUSION: A positive relationship with eating might be a fruitful starting point for prevention and intervention programmes promoting physical and psychological health. PMID- 28641451 TI - Short sleep duration and poor sleep quality among migraineurs: A population-based study. AB - Background Sleep disturbances are closely related to migraine. Nevertheless, information regarding the impact of short sleep duration and poor sleep quality on the clinical presentation of migraine at population level is limited. Methods This study was a nationwide population-based survey on adults aged 19-69 years. Headache frequency (attacks/month) and intensity (visual analogue scale, 0-10) were documented. Short sleep duration and poor sleep quality were defined as average sleep duration <6 h/day and Pittsburgh Sleep Quality Index score >5, respectively. The association of sleep parameters with headache frequency and intensity was analysed among migraineurs. Results Of 2695 participants, 143 (5.3%) had migraine. Headache frequency was significantly higher among migraineurs with short sleep duration (2.0 [1.0-12.0] vs. 1.0 [0.3-4.0], p = 0.048) and poor sleep quality (2.0 [0.6-4.7] vs. 1.0 [0.2-3.0], p = 0.009) than among those without. However, headache intensity was similar between migraineurs with short sleep duration and poor sleep quality. Multiple linear regression analyses revealed that short sleep duration was a significant contributing factor for headache frequency (beta = 0.210, p = 0.015). Conclusions Self-reported short sleep duration (<6 h per day) is associated with an increased headache frequency among migraineurs in a population-based setting. PMID- 28641452 TI - Anti-inflammatory and antiproliferative activities of Ixora brevifolia Benth. (Rubiaceae). AB - The crude extract and fractions from the branches of Ixora brevifolia, a tree found in the Brazilian Cerrado, were tested for anti-inflammatory and in vitro antiproliferative effects. The crude extract and n-hexane fraction exhibited significant inhibition of ear oedema in mice, while n-hexane-precipitated and chloroform fractions strongly inhibited the myeloperoxidase activity in ear tissue. The n-hexane and n-hexane-precipitated fractions showed strong growth inhibition for glioma cell line and the hydromethanolic fraction inhibited the growth of leukaemia cell line. PMID- 28641454 TI - Correction to: Ayurvedic college education, reifying biomedicine and the need for reflexivity. PMID- 28641453 TI - Accuracy of Limited-Montage Electroencephalography in Monitoring Postanoxic Comatose Patients. AB - BACKGROUND: Continuous EEG (cEEG) monitoring may help to identify the small percentage of adults with hypoxic-ischemic encephalopathy (HIE) who will regain consciousness if allowed sufficient time. However, the limited yield in this population has led some to question the cost-effectiveness cEEG monitoring in this population. We hypothesized that limited-montage cEEG could provide essentially the same neurophysiologic information at lower cost. In this proof of concept study, we aim to demonstrate the potentials of limited channel EEG in prognostication in postanoxic patients. METHODS: We retrospectively reviewed cEEG data from cases monitored at our institution with conventional 21-channel EEG over a 6-month period. Twenty-eight cases were identified in which patients with HIE underwent cEEG for at least 24 hours. Gold-standard findings were determined by conventional visual analysis of the full cEEG, and 2 independent electroencephalographers scored the same data using only limited-montage (4 channel) views. The sensitivity and specificity of limited-montage cEEG review were compared with conventional analysis. We also compared the relative costs of conventional and limited-montage EEG. RESULTS: Using 4-channel limited montage cEEG, reviewers were able to classify accurately background continuity (in 88%), background amplitude (in 81%), maximum background frequency (in 70%), periodic epileptiform discharges, including a seizure (in 92%) and sporadic discharges (in 91%). All epileptiform features were detected with greater than 90% sensitivity and specificity. Eye movement artifact seen over bifrontal electrodes gave false positive detections of periodic epileptiform discharges in 31% of cases. CONCLUSIONS: Limited-channel continuous EEG monitoring can provide meaningful electrophysiological data that can be used for prognostication in postanoxic comatose patients. Limited channel EEG can be a cost-effective alternative to conventional EEG monitoring in post-anoxic comatose patients. PMID- 28641455 TI - Modulation of cisplatin cytotoxic activity against leiomyosarcoma cells by epigallocatechin-3-gallate. AB - The aim of this study was to investigate the cytotoxic effect cisplatin in combination with epigallocatechin-3-gallate (EGCG) on leiomyosarcoma cells (LMS cells) in order to identify a less toxic but equally effective alternative. Assays for cell proliferation, colony formation efficiency, induction of apoptosis and cell cycle arrest were performed using the IC50 of cisplatin (8.6 MUMU) as a reference value and a concentration of EGCG (30 MUMU) that caused a non-significant reduction in cell proliferation. Pre-treatment of cells with EGCG for 24 h before the addition of cisplatin increased cytotoxicity up to 8.5% (p < 0.05) and the number of apoptotic cells by 40%. Epigallocatechin-3-gallate failed to alter S-phase cell cycle arrest induced by cisplatin and to modulate cisplatin effects on mitochondrial function. These results indicate that pre-treatment with EGCG could be used as an adjunctive therapy to maximise effectiveness of chemotherapy. PMID- 28641456 TI - A new antiviral pregnane from a gorgonian-derived Cladosporium sp. fungus. AB - A new pregnane, 3alpha-hydroxy-7-ene-6,20-dione (1), and five known steroids (2 6), along with one known steroidal glycoside (7) were obtained from the fungus Cladosporium sp. WZ-2008-0042 cultured from a gorgonian Dichotella gemmacea collected from the South China Sea. The structure and absolute configuration of the new compound (1) were elucidated by comprehensive spectroscopic data and X ray diffraction data. The compound has a rare configuration of 3alpha-OH that is different from most of pregnanes. All of the isolated compounds were evaluated for their antiviral activities against respiratory syncytial virus (RSV). Among them, 1 exhibited potential antiviral activity with the IC50 value of 0.12 mM. PMID- 28641457 TI - Antiglioma pseurotin A from marine Bacillus sp. FS8D regulating tumour metabolic enzymes. AB - Pseurotin A was isolated from a culture of marine Bacillus sp. FS8D and showed to be active against the proliferation of four different glioma cells with IC50 values of 0.51-29.3 MUM. It has been found that pseurotin A downregulated the expression of tumour glycolytic enzymes pyruvate kinase M2 (PKM2) and lactate dehydrogenase 5 (LDH5) and upregulated the expression of pyruvate dehydrogenase beta (PDHB), adenosine triphosphate synthase beta (ATPB) and cytochrome C (Cyto C), the important regulators for tricarboxylic acid cycle and oxidative phosphorylation. The data suggested that targeting multiple metabolic enzymes might be one of the antiglioma mechanisms of pseurotin A. PMID- 28641459 TI - A new ent-kaurane diterpene derivative from the stems of Eurya chinensis R.Br. AB - One new ent-kaurane diterpene derivative (1), along with four known diterpenes, was isolated from the stems of Eurya chinensis R.Br. The structure of the new compound was established by extensive analysis of mass spectrometric and 1D and 2D NMR spectroscopic data. Compound 1 showed moderate anti-inflammatory activities with IC50 value of 8.12 MUM. This is the first example of diterpenoids with 4-hydroxy-4-(2-hydroxyethyl)-1-hydroxyl-cyclohexanoyl substituent. PMID- 28641460 TI - Variability in strength of red yeast rice supplements purchased from mainstream retailers. AB - The United States Food and Drug Administration (FDA) has introduced manufacturing standards for dietary supplements, including red yeast rice, to assure their identity, purity, strength, and composition. One supplement commonly used to self treat high cholesterol, red yeast rice, may contain monacolin K, an ingredient identical to prescription lovastatin. We examined whether FDA's manufacturing standards led to standard concentrations of the statin monacolin K in red yeast rice supplements. We analyzed 28 brands of red yeast rice supplements by ultra high performance liquid chromatography-diode array detector-quadrupole time-of flight mass spectrometry for monacolin K content. Monacolin K was not detected in two brands. In the 26 brands that contained monacolin K, the quantity ranged more than 60-fold from 0.09 to 5.48 mg per 1200 mg of red yeast rice. Following the manufacturers' recommendations for daily servings, the quantity of monacolin K consumed per day would range more than 120-fold from 0.09 to 10.94 mg. Despite FDA manufacturing standards, strength and composition of red yeast rice supplements sold at mainstream retail stores in the United States remains unpredictable. PMID- 28641461 TI - The impact of data errors on the outcome of randomized clinical trials. AB - Background/aims Considerable human and financial resources are typically spent to ensure that data collected for clinical trials are free from errors. We investigated the impact of random and systematic errors on the outcome of randomized clinical trials. Methods We used individual patient data relating to response endpoints of interest in two published randomized clinical trials, one in ophthalmology and one in oncology. These randomized clinical trials enrolled 1186 patients with age-related macular degeneration and 736 patients with metastatic colorectal cancer. The ophthalmology trial tested the benefit of pegaptanib for the treatment of age-related macular degeneration and identified a statistically significant treatment benefit, whereas the oncology trial assessed the benefit of adding cetuximab to a regimen of capecitabine, oxaliplatin, and bevacizumab for the treatment of metastatic colorectal cancer and failed to identify a statistically significant treatment difference. We simulated trial results by adding errors that were independent of the treatment group (random errors) and errors that favored one of the treatment groups (systematic errors). We added such errors to the data for the response endpoint of interest for increasing proportions of randomly selected patients. Results Random errors added to up to 50% of the cases produced only slightly inflated variance in the estimated treatment effect of both trials, with no qualitative change in the p value. In contrast, systematic errors produced bias even for very small proportions of patients with added errors. Conclusion A substantial amount of random errors is required before appreciable effects on the outcome of randomized clinical trials are noted. In contrast, even a small amount of systematic errors can severely bias the estimated treatment effects. Therefore, resources devoted to randomized clinical trials should be spent primarily on minimizing sources of systematic errors which can bias the analyses, rather than on random errors which result only in a small loss in power. PMID- 28641462 TI - Microbiological control and antibacterial action of a propolis-containing mouthwash and control of dental plaque in humans. AB - Propolis is a bee product with several biological properties. This study aimed at investigating a propolis-containing mouthwash, its organoleptic properties, microbial contamination and its antibacterial action in vitro. This mouthwash was assessed in vivo to control dental plaque in humans. The presence of microorganisms was analyzed and the minimum inhibitory concentration against Streptococcus mutans was determined. A comparative study was done in vivo using propolis, chlorhexidine, and propolis plus chlorhexidine in lower concentrations for 14 days. Dental plaque was analyzed by the Patient Hygiene Performance (PHP) index. The odontological product was yellow, cloudy, free of microbial contamination, and exerted an inhibitory action in vitro. Individuals who used a propolis-containing mouthwash for 14 consecutive days in combination or not to chlorhexidine showed a similar PHP index to chlorhexidine alone. The product exerted an antibacterial action in vitro and in vivo, exhibiting a positive action in the control of dental plaque. PMID- 28641463 TI - A new dimeric diarylpropane from Horsfieldia tetratepala. AB - Five compounds, including a new dimeric diarylpropane, were isolated from the petroleum ether extract of the twigs and leaves of Horsfieldia tetratepala. The structures of these compounds were elucidated by spectroscopic analysis. Moreover, the antiproliferative activities of these compounds were tested on cancer cell lines, but none is active. PMID- 28641464 TI - Ultrasound-guided hydrodissection for assisting percutaneous microwave ablation of renal cell carcinomas adjacent to intestinal tracts: a preliminary clinical study. AB - PURPOSE: To evaluate the safety and efficacy of the clinical application of hydrodissection under ultrasound (US) guidance for assisting percutaneous microwave ablation (MWA) for the treatment of renal cell carcinomas (RCCs) adjacent to the intestinal tract. MATERIALS AND METHODS: From April 2014 to December 2016, clinical data from 24 patients with 25 RCCs were retrospectively analysed. Percutaneous MWA under the assistance of US-guided hydrodissection were performed to treat RCCs with a mean maximal diameter of 3.80 +/- 1.60 cm because the distance between the index tumour and the adjacent intestinal tracts were less than 0.5 cm on imaging. The separation success rate of the hydrodissection, technique efficacy rate of the MWA, local tumour progression (LTP), complications, and renal function including serum creatinine (Cr) and blood urea nitrogen (BUN) were assessed. RESULTS: In total, 28 sessions of hydrodissection and MWA procedures were performed (one procedure in 22 patients and two procedures in 3 patients), and the separation success rate was 100% (28/28). The technique efficacy rate was 100% (25/25), and no LTP occurred. One patient exhibited a major complication (4.2%). Minor complications in 5 patients (20.8%) and side effects in 12 patients (50.0%) occurred. Compared with the pre-MWA levels, there were no significant differences in serum Cr and BUN 1-day post-MWA and at the last follow-up. CONCLUSIONS: US-guided hydrodissection assistance for percutaneous MWA could be a safe and effective alternative for selected patients with RCCs adjacent to the intestinal tracts and can achieve good local tumour control and renal function preservation. PMID- 28641465 TI - Initial evaluation of psychometric properties of a structured work task application for the Assessment of Work Performance in a constructed environment. AB - PURPOSE: The Swedish Social Insurance Administration has developed a new assessment tool for sickness insurance. This study is a part of the initial evaluation of the application, called the Assessment of Work Performance, Structured Activities, and focuses on evaluation of the psychometric properties of social validity, content validity, and utility. MATERIALS AND METHODS: This was a qualitative study using semi-structured telephone interviews with occupational therapists. A convenience sample was used and participants who fulfilled inclusion criteria (n = 15) were interviewed. Data were analyzed using content analysis with a directed approach. RESULTS: The results indicate that the application provides valuable information and that it is socially valid. Assessors found work tasks suitable for a diverse group of clients and reported that clients accepted the assessments. Improvements were suggested, for example, expanding the application with more work tasks. CONCLUSION: The instrument has benefits; however, further development is desired. The use of a constructed environment in assessments may be a necessary option to supplement a real environment. But depending on organizational factors such as time and other resources, the participants had different opportunities to do so. Further evaluations regarding ecological validity are essential to ensure that assessments are fair and realistic when using constructed environments. Implications for rehabilitation This study indicates that assessment in a constructed environment can provide a secure and protected context for clients being assessed. Psychometric evaluations are a never-ending process and this assessment instrument needs further development. However, this initial evaluation provides guidance in development of the instrument but also what studies to give priority to. It is important to evaluate social validity in order to ensure that clients and assessors perceive assessment methods fair and meaningful. In this study, participants found the work tasks appropriate and usable when assessing their clients but client's perspective must also be included in following studies. This assessment instrument is the only activity-based assessment instrument within the Swedish Social Security Insurance. Psychometric evaluations are important since it affects so many individuals in Sweden. PMID- 28641466 TI - A model of lipid rearrangements during pore formation in the DPPC lipid bilayer. AB - CONTEXT: The molecular bases of pore formation in the lipid bilayer remain unclear, as do the exact characteristics of their sizes and distributions. To understand this process, numerous studies have been performed on model lipid membranes including cell-sized giant unilamellar vesicles (GUV). The effect of an electric field on DPPC GUV depends on the lipid membrane state: in the liquid crystalline phase the created pores have a cylinder-like shape, whereas in the gel phase a crack has been observed. OBJECTIVE: The aim of the study was to investigate the geometry of pores created in a lipid bilayer in gel and liquid crystalline phases in reference to literature experimental data. METHODS: A mathematical model of the pore in a DPPC lipid bilayer developed based on the law of conservation of mass and the assumption of constant volume of lipid molecules, independent of their conformation, allows for analysis of pore shape and accompanying molecular rearrangements. RESULTS: The membrane area occupied by the pore of a cylinder-like shape is greater than the membrane area occupied by lipid molecules creating the pore structure (before pore appearance). Creation of such pores requires more space, which can be achieved by conformational changes of lipid chains toward a more compact state. This process is impossible for a membrane in the most compact, gel phase. DISCUSSION AND CONCLUSIONS: We show that the geometry of the pores formed in the lipid bilayer in the gel phase must be different from the cylinder shape formed in the lipid bilayer in a liquid crystalline state, confirming experimental studies. Furthermore, we characterize the occurrence of the 'buffer' zone surrounding pores in the liquid crystalline phase as a mechanism of separation of neighbouring pores. PMID- 28641469 TI - The effect of counselling on preconception lifestyle and awareness in Iranian women contemplating pregnancy: a randomized control trial. AB - PURPOSE: This study was conducted to determine the effect of counselling on preconception lifestyle and awareness about it in healthy women planning to get pregnant. METHODS: This study was conducted on 152 women aged 18-35 who planned to get pregnant within the next year. Using block randomization, the participants were assigned into a counselling and a control group (n = 76 per group). The intervention group attended six group counselling sessions, twice per week, over 3 weeks. The preconception lifestyle questionnaire and preconception lifestyle awareness questionnaire were completed by the participants before the intervention and 4 and 8 weeks after the intervention. The repeated measure ANOVA was used to analyse the data. RESULTS: The two groups were matching in terms of their sociodemographic characteristics and the baseline scores of preconception lifestyle and awareness about preconception lifestyle. The mean score of preconception lifestyle (adjusted mean difference = 0.17; 95% confidence interval = 0.13-0.21) and awareness about preconception lifestyle (7.8; 8.7-6.9) showed statistically significant improvements in the intervention group compared to the control group. CONCLUSIONS: Preconception lifestyle group counselling is associated with increased awareness and improved lifestyle in women planning to get pregnant. PMID- 28641467 TI - Green tea polyphenol EGCG causes anti-cancerous epigenetic modulations in acute promyelocytic leukemia cells. AB - Green tea (Camellia sinensis) catechin epigallocatechin-3-gallate (EGCG) has been shown to possess diverse anti-cancerous properties. We demonstrated EGCG ability to inhibit acute promyelocytic leukemia (APL) cell proliferation and cause apoptosis. In addition, quantitative real-time polymerase chain reaction (RT qPCR) analysis revealed elevated expression of genes associated with cell cycle arrest and differentiation (p27, PCAF, C/EBPalpha, and C/EBPE). Furthermore, EGCG caused anti-cancerous epigenetic changes: downregulation of epigenetic modifiers DNMT1, HDAC1, HDAC2, and G9a was observed by RT-qPCR analysis. Reduced amount of H3K9me2 after treatment with EGCG confirmed G9a downregulation. Polycomb repressive complex 2 (PRC2) core components were also shown to be downregulated in gene and protein level. Chromatin immunoprecipitation (ChIP) analysis revealed that EGCG treatment enhanced hyperacetylated H4 and acetylated H3K14 histones binding to the promoter regions of p27, PCAF, C/EBPalpha, and C/EBPE and reduced binding effect to PRC2 core component genes EZH2, SUZ12, and EED. Our results indicate that EGCG, as cell proliferation inhibitor and epigenetic modifier, might be useful for APL treatment. PMID- 28641468 TI - Association between immunoglobulin heavy-chain variable region mutational status and isolated favorable baseline genomic aberrations in chronic lymphocytic leukemia. AB - Immunoglobulin heavy-chain variable region (IGHV) mutational status and karyotype abnormalities are important prognostic factors in chronic lymphocytic leukemia (CLL). The goal was to assess the impact of IGHV in CLL patients with isolated favorable genetic aberrations (del13q, trisomy 12, or negative fluorescence in situ hybridization [FISH]). We studied 273 CLL patients with both IGHV mutational status and cytogenetic information: 145 with isolated del13q 49 with sole trisomy 12 and 79 with negative FISH. After a median follow-up of 7.8 years, patients with del13q-unmutated IGHV had a shorter time to first treatment (TFT) (2.98 vs. 17.44 years; p < .001) and shorter overall survival (10.45 years vs. not reached; p = .0026). Patients with negative FISH-unmutated IGHV had shorter TFT (p = .02) (3.10 vs. 9.75 years, p = .053). IGHV status did not influence clinical outcomes in trisomy 12 CLL. In conclusion, IGHV mutational status shows prognostic impact in CLL patients with good prognosis genomic features. PMID- 28641470 TI - Do psychosocial predictors affect the following days' cortisol awakening response? Expanding the temporal frame with which to explore morning cortisol. AB - Much of the extant cortisol awakening response (CAR) literature posits that CAR is an anticipatory response to perceived demands later that same day. However, expanding and switching the temporal order of cortisol and psychosocial influences may motivate more flexible approaches to understanding the dynamic relationship between mind and body, including cumulative strain on the HPA axis. This study was novel because we used two models to explore the effects of one day's emotion regulation and cortisol levels on cortisol and CAR the following day in 100 mildly stressed adults aged 50-81 years old, which contrasts with the more common CAR-anticipatory-response design. In the first model, High negative affect-variation on day 1 predicted a higher risk of having a flat CAR the next day, relative to the moderate-affect-variation group (RR = 10.10, p < .05). In the second model, higher bedtime cortisol on day 1 was positively associated with waking cortisol (beta = .293, p < .01) and flatter CAR slopes on day 2 (beta = .422, p < .001). These results show that morning cortisol intercepts and slopes may be associated with previous days' affect variability and levels of bedtime cortisol. These results also suggest that anticipation of demands may extend to the previous day, rather than just the morning of the demand, indicating a broader temporal framework for the study of CAR. PMID- 28641474 TI - MYC gene rearrangement in diffuse large B-cell lymphoma does not confer a worse prognosis following dose-adjusted EPOCH-R. PMID- 28641473 TI - Co-targeting intracellular pH and essential amino acid uptake cooperates to induce cell death of T-ALL/LL cells. AB - Cancer cells reprogram their metabolism to optimize their growth and proliferation in the host microenvironment. For this purpose, they enhance the uptake of extracellular nutrients and deal with the metabolic waste products through the overexpression of numerous membrane proteins including amino-acid transporters (LAT1) and acid-base regulating enzymes, such as carbonic anhydrases (CAs). Here we describe the anti-tumoral effects of a new class of CAXII inhibitors, the glycosyl coumarins on T-ALL/LL cells. These effects appeared to be mediated through inhibition of mTOR/Akt pathway and c-myc downregulation. Interestingly, we show that the combined targeting of amino acid fluxes and pH regulators provides a promising therapeutic strategy in the future of T-ALL/LL management. PMID- 28641472 TI - Long-term health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma receiving lenalidomide and dexamethasone. AB - The FIRST trial demonstrated that continuous therapy with lenalidomide and dexamethasone (Rd) prolongs overall survival (OS) and improves health-related quality of life (HRQoL) during the first 18 months of therapy in newly diagnosed multiple myeloma (NDMM) patients. However, patient-reported HRQoL data were not collected after 18 months. We therefore estimated HRQoL scores based on time varying data collected during progression-free follow-up after 18 months. During the initial 18 months of Rd, observed changes from baseline were within the 95% confidence interval of the predictive models at 33 of 35 time points across 7 HRQoL scores. Predicted scores after 18 months of therapy showed that observed HRQoL improvements during therapy were maintained or improved. Therefore, the survival gain observed with Rd does not come at a cost of declining HRQoL during continuous therapy beyond 18 months, supporting long-term Rd as a standard of care for initial myeloma therapy. PMID- 28641471 TI - Evaluation of immunomodulatory effects of zearalenone in mice. AB - Zearalenone (ZEA) is a non-steroidal estrogenic mycotoxin produced by Fusarium species. The toxicity of ZEA has been evaluated for reproductive and developmental effects; however, there is little evidence about its acute toxicity or general immunotoxicity. In the present study, immune regulatory functions were investigated in mice that had been exposed to ZEA (5 or 20 mg/kg BW) daily for 14 days. Results showed that sub-populations of CD4+, CD8+ and CD11c+ cells in the spleen and CD4+, CD8+ and F4/80+ cells in the mesenteric lymph nodes (MLN) of ZEA (20 mg/kg)-exposed hosts were decreased compared to those in the control mice. However, CD19+ and CD11c+ cells were increased in the MLN of the ZEA mice and CD4+CD25+Foxp3+ cells were decreased in the spleen and MLN. There were differential changes in the immune cell populations of the small intestine of the ZEA mice as well, depending on small intestine location. In ex vivo experiments, ZEA treatments resulted in increased proliferative capacities of mitogen-induced splenocytes and MLN cells; such changes were paralleled by significant increases in interferon (IFN)-gamma production. With regard to serum isotypes, IgM levels were decreased and IgE levels were increased in the 20 mg/kg ZEA-treated mice. Mucosal IgA levels were decreased in the duodenum and vagina of these hosts. Serum analyzes also revealed that tumor necrosis factor (TNF)-alpha levels were decreased and interleukin (IL)-6 levels increased as a result of ZEA exposures. ZEA treatment also led to increased apoptosis in the spleen and Peyer's patches; these changes were associated with changes in the ratios of Bax:Bcl-2. Following priming with different TLR ligands, ZEA exposure led to differentially modulated TLR signaling and variable production of pro- and anti-inflammatory cytokines in RAW 264.7 macrophage cells. Taken together, these results indicated that ZEA could alter the normal expression/function of different immune system components and this would likely lead to immunomodulation in situ. PMID- 28641475 TI - Care and not wealth is a predictor of wasting and stunting of 'The Coffee Kids' of Jimma Zone, southwest Ethiopia. AB - BACKGROUND: The generation of cash from agricultural products is the mainstay of the livelihood of many households in developing countries. However, critics of cash cropping have highlighted its influence on dietary diversity and availability of food at the household level, eroding the potential for optimal child caring practices. METHODS: A community-based cross-sectional survey was carried out in three randomly selected coffee-producing districts of Jimma Zone in southwest Ethiopia. The underlying causes of malnutrition, food access, hygiene and care were assessed using the household food insecurity access scale, morbidity reports and infant and young child feeding practice core indicators of the World Health Organization. Anthropometric data were converted into weight for age, height for age, body mass index for age and weight for height Z-scores to determine child nutritional outcomes. RESULTS: Prevalence of underweight, wasting, stunting and thinness were 14.2%, 9.1%, 24.1% and 9.9%, respectively. Multivariable logistic regression showed that children with suboptimal meal frequency were more than three times more likely to develop wasting (AOR = 3.3, p < 0.0001). Female children were twice as likely to develop wasting compared with males (AOR = 2.00, 4.1, p = 0.05). Children with suboptimal dietary diversity were almost four times as likely to develop stunting (AOR = 3.95, p < 0.0001). Those who were not exclusively breastfed during their first 6 months were almost five times as likely to develop stunting (AOR = 4.66, p < 0.0001). CONCLUSIONS: The findings imply that in coffee-producing areas, child caring practices are stronger independent predictors of nutritional status than wealth or economic indicators alone. PMID- 28641476 TI - Direct medical costs of accidental falls for adults with transfemoral amputations. AB - BACKGROUND: Active individuals with transfemoral amputations are provided a microprocessor-controlled knee with the belief that the prosthesis reduces their risk of falling. However, these prostheses are expensive and the cost effectiveness is unknown with regard to falls in the transfemoral amputation population. The direct medical costs of falls in adults with transfemoral amputations need to be determined in order to assess the incremental costs and benefits of microprocessor-controlled prosthetic knees. OBJECTIVE: We describe the direct medical costs of falls in adults with a transfemoral amputation. STUDY DESIGN: This is a retrospective, population-based, cohort study of adults who underwent transfemoral amputations between 2000 and 2014. METHODS: A Bayesian structural time series approach was used to estimate cost differences between fallers and non-fallers. RESULTS: The mean 6-month direct medical costs of falls for six hospitalized adults with transfemoral amputations was US$25,652 (US$10,468, US$38,872). The mean costs for the 10 adults admitted to the emergency department was US$18,091 (US$-7,820, US$57,368). CONCLUSION: Falls are expensive in adults with transfemoral amputations. The 6-month costs of falls resulting in hospitalization are similar to those reported in the elderly population who are also at an increased risk of falling. Clinical relevance Estimates of fall costs in adults with transfemoral amputations can provide policy makers with additional insight when determining whether or not to cover a prescription for microprocessor-controlled prosthetic knees. PMID- 28641478 TI - Obituary: Dr Dimitri Tassiopoulos. PMID- 28641477 TI - Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death. AB - Death in the fetal, perinatal, and early infant age-group has a multitude of causes, a proportion of which is presumed to be genetic. Defining a specific genetic aberration leading to the death is problematic at this young age, due to limited phenotype-genotype correlation inherent in the underdeveloped phenotype, the inability to assess certain phenotypic traits after death, and the problems of dealing with rare disorders. In this study, our aim was to increase the yield of identification of a defined genetic cause of an early death. Therefore, we employed whole genome sequencing and bioinformatic filtering techniques as a comprehensive, unbiased genetic investigation into 16 fetal, perinatal, and early infant deaths, which had undergone a full autopsy. A likely genetic cause was identified in two cases (in genes; COL2A1 and RYR1) and a speculative genetic cause in a further six cases (in genes: ARHGAP35, BBS7, CASZ1, CRIM1, DHCR7, HADHB, HAPLN3, HSPG2, MYO18B, and SRGAP2). This investigation indicates that whole genome sequencing is a significantly enabling technology when determining genetic causes of early death. PMID- 28641479 TI - Norms and normalisation: understanding lesbian, gay, bisexual, transgender and queer youth, suicidality and help-seeking. AB - Young people who identify as lesbian, gay, bisexual, and queer transgender have elevated rates of suicidality. Despite the increased risk, there is a paucity of research on lesbian, gay, bisexual, transgender and queer help-seeking and suicidality. We report on a UK sequential exploratory, two-stage, mixed-method study. Stage 1 involved 29 online and face-to-face semi-structured interviews with lesbian, gay, bisexual, transgender and queer youth aged 16-25 years old. Stage 2 utilised an online youth questionnaire employing a community-based sampling strategy (n = 789). Results indicated that participants only asked for help when they reached a crisis point because they were normalising their emotional distress. Those who self-harmed, had attempted or planned suicide or had experience of abuse related to their sexuality or gender were most likely to seek help. Results suggested that the reluctance to seek help was due to three interconnecting factors: negotiating sexuality, gender, mental health and age norms; being unable to talk about emotions; and coping and self-reliance. Policies aiming to prevent lesbian, gay, bisexual, transgender and queer youth suicide recognise that norms and normalising processes connected to sexual orientation and gender identity are additional difficulties that youth have accessing mental health support. PMID- 28641481 TI - Septicaemia caused by Elizabethkingia-sp in a 'healthy' Sri Lankan man. PMID- 28641480 TI - How HIV patients construct liveable identities in a shame based culture: the case of Singapore. AB - This article interrogates the mainstream healthcare narrative that frames human immunodeficiency virus (HIV) as a chronic disease, and triangulates it with the lived experiences of people with HIV in Singapore. It also examines how HIV patients reconstruct their identities after the diagnosis of HIV. Four HIV patients (two males and two females) were interviewed in depth by an experienced medical social worker. Findings revealed that even as the illness trajectory of HIV has shifted from a terminal condition to a chronic one, living with HIV continues to be fraught with difficulty as society, especially in the Asian context, perceives HIV with much fear and disapproval. The participants had an overwhelming sense of shame when they were initially diagnosed with HIV and they had to reconstruct a liveable identity by containing the shroud of shame, reinforcing their normative identities and constructing new ones. These strategies help them to keep their shame at bay. This paper also unpacks nuanced insights of shame experienced by Chinese HIV patients in an Asian city dominated by Confucian values. PMID- 28641482 TI - Insights into eukaryotic evolution from transmembrane domain lengths. AB - Biological membranes, comprised of proteins anchored by their trans-membrane domains (TMDs) creating a semi-permeable phase with lipid constituents, serve as 'checkposts' for not only intracellular trafficking in eukaryotic cells but also for material transactions of all living cells with external environments. Hydropathy (or hydrophobicity) plots of 'bitopic' proteins (i.e. having single alpha-helical TMDs) are routinely utilized in biochemistry texts for predicting their TMDs. The number of amino acids (i.e. TMD length) embedded as alpha-helices may serve as indicators of thickness of biological membranes in which they reside under assumptions that are universally applied for fixing window sizes for identifying TMDs using hydropathy plots. In this work we explore variations in thickness of different eukaryotic biological membranes (reflected by TMD lengths of their resident proteins) over evolutionary time scales. Rigorous in silico analyses of over 23,000 non-redundant membrane proteins residing in different subcellular locations from over 200 genomes of fungi, plants, non-mammalian vertebrates and mammals, reveal that differences in plasma membrane and organellar TMD lengths have decreased over time (scales) of eukaryotic cellular evolution. While earlier work has indicated decreasing differences in TMD lengths with increasing 'perceived' organismal complexity, this work is the first report on TMD length variations as a function of evolutionary time of eukaryotic cellular systems. We report that differences in TMD lengths of bitopic proteins residing in plasma membranes and other intra-cellular locations have decreased with evolutionary time, suggesting better/more avenues of intracellular trafficking in the emergence of eukaryotic organisms. PMID- 28641484 TI - Protective effect of hesperetin against haloperidol-induced orofacial dyskinesia and catalepsy in rats. AB - OBJECTIVES: The present study was designed to evaluate the effect of hesperetin on haloperidol-induced orofacial dyskinesia and catalepsy in Wistar male albino rats. METHODS: Haloperidol (1 mg/kg, ip) was administered for 21 successive days to induce orofacial dyskinesia and catalepsy. Hesperetin (50 and 100 mg/kg, po) was administered 10 min prior to the injection of haloperidol for 21 successive days. Vacuous chewing movements (VCMs), tongue protrusions, catalepsy, and locomotor activity scores were recorded on 7th, 14th, and 22nd day of drug treatment. After behavioral testing, animals were sacrificed and various biochemical parameters such as brain levels of dopamine, serotonin, malondialdehyde, and reduced glutathione (GSH); and superoxide dismutase (SOD) and catalase activities were estimated. RESULTS: Chronic administration of haloperidol significantly increased VCMs, tongue protrusions, and catalepsy in rats. It also produced hypolocomotion in rats. Hesperetin significantly inhibited haloperidol-induced VCMs, tongue protrusions, and catalepsy. Haloperidol significantly increased brain levels of malondialdehyde, decreased brain GSH, SOD, and catalase activities; and also decreased brain dopamine and serotonin levels. Hesperetin significantly reversed haloperidol-induced increase in brain oxidative stress and decrease in brain dopamine and serotonin levels. DISCUSSION: Hesperetin significantly ameliorated haloperidol-induced orofacial dyskinesia and catalepsy possibly through alleviation of oxidative stress and increase in brain dopamine and serotonin levels. Thus, hesperetin may be explored further as a possible therapeutic agent for clinical management of neuroleptic drug-induced tardive dyskinesia. PMID- 28641483 TI - Good performance of platinum-based chemotherapy for high-grade gastroenteropancreatic and unknown primary neuroendocrine neoplasms. AB - To evaluate efficacy and safety of platinum and etoposide combination in the treatment of advanced gastroenteropancreatic (GEP) and unknown primary (CUP) neuroendocrine carcinomas (NEC), we analysed the records of 21 consecutive patients treated with this regimen from 1999 to 2012. Objective responses were obtained in 11 patients (52%) and disease stability (DS) in 5 (24%). Median progression-free survival (PFS) was 7 months (95% CI, 5.33-8.66). Median overall survival (OS) was 16 months (95% CI, 14.97-17.03). Patients with limited liver disease had a significantly (p = 0.002) better PFS than patients with extrahepatic disease at diagnosis with 9 months (95% CI, 7.14-10.85) vs. 4 months (95% CI, 1.60-6.40). Two patients experienced durable complete response (30 and 90 months). The most common grade 3-4 toxicities were neutropenia (61%), anaemia (50%), nausea and vomiting (27%) and fatigue (22%). The platinum plus etoposide regimen has an acceptable toxicity profile and is effective in patients with GEP and CUP-NECs. PMID- 28641485 TI - Microarray-Based Gene Expression Analysis for Veterinary Pathologists: A Review. AB - High-throughput, genome-wide transcriptome analysis is now commonly used in all fields of life science research and is on the cusp of medical and veterinary diagnostic application. Transcriptomic methods such as microarrays and next generation sequencing generate enormous amounts of data. The pathogenetic expertise acquired from understanding of general pathology provides veterinary pathologists with a profound background, which is essential in translating transcriptomic data into meaningful biological knowledge, thereby leading to a better understanding of underlying disease mechanisms. The scientific literature concerning high-throughput data-mining techniques usually addresses mathematicians or computer scientists as the target audience. In contrast, the present review provides the reader with a clear and systematic basis from a veterinary pathologist's perspective. Therefore, the aims are (1) to introduce the reader to the necessary methodological background; (2) to introduce the sequential steps commonly performed in a microarray analysis including quality control, annotation, normalization, selection of differentially expressed genes, clustering, gene ontology and pathway analysis, analysis of manually selected genes, and biomarker discovery; and (3) to provide references to publically available and user-friendly software suites. In summary, the data analysis methods presented within this review will enable veterinary pathologists to analyze high-throughput transcriptome data obtained from their own experiments, supplemental data that accompany scientific publications, or public repositories in order to obtain a more in-depth insight into underlying disease mechanisms. PMID- 28641486 TI - Advances in meta-analysis methodologies contribute to advances in research accumulation: comments on Cheung & Hong and Johnson et al. PMID- 28641487 TI - MicroRNA-337 inhibits cell proliferation and invasion of cervical cancer through directly targeting specificity protein 1. AB - Cervical cancer is the fourth most commonly occurring malignancy in females worldwide. Accumulated studies have demonstrated that the aberrant expression of microRNAs plays important roles in tumorigenesis and tumor development and potentially serves as therapeutic targets in various cancers including cervical cancer. Therefore, the identification of specific microRNAs contributed to cervical cancer formation and progression would provide critical clues for the treatments for patients with this disease. In this study, we aimed to detect microRNA-337 expression pattern and investigate the biological roles of microRNA 337 in the regulation of the malignant phenotypes of cervical cancer and its underlying mechanisms. We found that microRNA-337 expression was significantly downregulated in cervical cancer tissues and cell lines. In addition, its aberrant expression levels were positively correlated with tumor size, International Federation of Gynecology and Obstetrics stage, and lymph node metastasis of cervical cancer. The ectopic expression of microRNA-337 suppressed cell proliferation and invasion of cervical cancer in vitro. Furthermore, specificity protein 1 was identified as a direct target of microRNA-337 in cervical cancer. The expression of specificity protein 1 increased in cervical cancer tissues and negatively correlated with microRNA-337 expression level. Moreover, rescue experiments revealed that upregulation of specificity protein 1 could rescue the effects of microRNA-337 on cervical cancer cells. Taken together, these findings collectively demonstrate that microRNA-337 exerts its tumor-suppressing roles in cervical cancer by directly targeting specificity protein 1, thereby indicating a potential novel potential therapeutic target for patients with cervical cancer. PMID- 28641488 TI - UCA1 involved in the metformin-regulated bladder cancer cell proliferation and glycolysis. AB - Despite great scientific advances have been achieved in cancer treatment in recent years, the death rate of bladder cancer has been staying at a high level. Metformin, a widely-used and low-cost diabetes medicine, might have the potential of anticancer. The aim of this study was to evaluate the effects of metformin on bladder cancer cells and to identify potential molecular targets and signaling pathways. Bladder cancer 5637 cells transfected with either pcDNA/UCA1 vector or pcDNA3.1 empty vector were treated with various doses of metformin for different periods of time, and then cell proliferation and glycolysis were assessed. Reverse transcription polymerase chain reaction and Western blotting were applied to examine the expression of long non-coding RNA UCA1 and mammalian target of rapamycin-signal transducer and activator of transcription pathway molecules. We found metformin inhibited bladder cancer cell proliferation in a dose- and time dependent manner. UCA1-overexpressed 5637 cells showed increased proliferation and glycolysis compared with control cells. Metformin downregulated both endogenous and exogenous UCA1 expression, leading to the inhibition of mammalian target of rapamycin-signal transducer and activator of transcription 3-hexokinase 2 signaling pathway. Our study provided the first evidence that metformin inhibited proliferation and glycolysis in cancer cells through regulation of long non-coding RNA UCA1. The discovery also suggested the important roles of long non coding RNA in chemoprevention, which is a property of metformin. PMID- 28641490 TI - Preserved imitation in contrast to limited free application of comfortable hand actions in intellectually able young adults with an autism spectrum disorder. AB - Imitation problems are commonly reported in children with an autism spectrum disorder. However, it has not yet been determined whether imitation problems persist into young adulthood. In this study, we investigated imitation skills of 20 intellectually able young adults with autism spectrum disorder relative to 19 age-matched neurotypical adults. For this purpose, we used a bar-transport task, which evokes the application of the end-state comfort principle. Specifically, we examined whether young adults with autism spectrum disorder imitated the means end structure of a demonstrator's bar-transport action with and without application of the end-state comfort principle (imitation task). In addition, we examined whether participants spontaneously applied the end-state comfort principle during a similar bar-transport task (free execution task). Results revealed that young adults with autism spectrum disorder imitated the means-end structure of observed actions to the same degree as neurotypical adults ( p = 0.428). In contrast, they applied the end-state comfort principle less often during free executed actions ( p = 0.035). Moreover, during these actions, they were slower to place the bar into the penholder ( p = 0.023), which contributed to the reduced efficiency of their performance. Findings suggest that imitation abilities of young adults with autism spectrum disorder are preserved and that observing others' actions might promote more efficient action planning in this population. PMID- 28641489 TI - Screening of several biological activities induced by different sesquiterpene lactones isolated from Centaurea behen L. and Rhaponticum repens (L.) Hidalgo. AB - This study aims to evaluate the in vitro cytotoxic, in vitro and in ovo anti angiogenic effects and antimicrobial activity of sesquiterpene lactones (SLs) from two plants Centaurea behen and Rhaponticum repens (L.). Five SLs, including cynaropicrin (1), 4beta,15-dehydro-3-dehydrosolstitialin A (2), aguerin B (3), janerin (4), cebellin E (5), and a flavone hispidulin (6) were isolated from C. behen (compounds 1-3) and R. repens (compounds 4-6). Cynaropicrin (1) and aguerin B (3) were characterised by strong cytotoxic activities against A2780 cells with IC50 values of 1.15 and 1.62 MUg mL-1, respectively, comparable to that of doxorubicin (IC50 = 1.17 MUg mL-1). The anti-angiogenic study showed the remarkable inhibitory effect of cynaropicrin (1) and aguerin B (3) on the proliferation and migration of HUVECs. In addition, cynaropycrin and aguerin B exhibited significant angio-inhibitory effects in CAM assay. These findings may be useful for the development of novel chemotherapeutic agents for the treatment of cancer. PMID- 28641491 TI - Nicotine and cigarette smoke modulate Nrf2-BDNF-dopaminergic signal and neurobehavioral disorders in adult rat cerebral cortex. AB - BACKGROUND: Nicotine and cigarette smoking (CS) are associated with addiction behavior, drug-seeking, and abuse. However, the mechanisms that mediate this association especially, the role of brain-derived neurotrophic factor (BDNF), dopamine (DA), and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in the cerebral cortex, are not fully known. Therefore, we hypothesized that overexpression of BDNF and DA, and suppression of Nrf2 contribute to several pathological and behavioral alterations in adult cerebral cortex. Methodology/Principal Observations: We treated Wistar rats with different doses of oral nicotine and passive CS for 4-week (short-term) and 12-week (long-term) duration, where doses closely mimic the human smoking scenario. Our result showed dose-dependent association of anxiogenic and depressive behavior, and cognitive interference with neurodegeneration and DNA damage in the cerebral cortex upon exposure to nicotine/CS as compared to the control. Further, the results are linked to upregulation of oxidative stress, overexpression of BDNF, DA, and DA marker, tyrosine hydroxylase (TH), with concomitant downregulation of ascorbate and Nrf2 expression in the exposed cerebral cortex when compared with the control. CONCLUSION/SIGNIFICANCE: Overall, our data strongly suggest that the intervention of DA and BDNF, and depletion of antioxidants are important factors during nicotine/CS-induced cerebral cortex pathological changes leading to neurobehavioral impairments, which could underpin the novel therapeutic approaches targeted at tobacco smoking/nicotine's neuropsychological disorders including cognition and drug addiction. PMID- 28641492 TI - The Economy and Suicide. PMID- 28641494 TI - Behavioural Regulation in Exercise Questionnaire in people with schizophrenia: construct validity of the Portuguese versions. AB - PURPOSE: People with schizophrenia have low physical activity levels that can be explained by the restriction in motivation. The Behavioural Regulation in Exercise Questionnaire-2 is a 19-item scale commonly used to assess five different motivational subtypes for physical activity. However, there are limited psychometric analyses of this version in the schizophrenia context. Moreover, there is a lack of information related to the psychometric properties of version 3 of this questionnaire, with 24 items and six different motivational subtypes. The aim of this study was to examine the construct validity of both Portuguese versions in people with schizophrenia. METHODS: A total of 118 persons with schizophrenia were included (30 women). Cronbach's alpha was used for internal consistency, Pearson's correlation for the retained motivation-types, confirmatory factor analysis for the structural validity of version 2 and exploratory factor analysis for the factor structure of version 3. RESULTS AND CONCLUSIONS: Analyses of version 2 provided an adequate fit index for the structure of the five factors. Exploratory analyses suggested retaining 2 factors of version 3. The results of this study suggest that version 3 was an appropriate measure to assess controlled and autonomous motivation for physical activity in people with schizophrenia and support its use in clinical practice and research. Implications for Rehabilitation This study supports the need to identify the reasons why people with schizophrenia practice physical activity. For that purpose, it is important to use valid and cost-effective instruments. The Portuguese version of BREQ-2 confirmed a 5-factor model and showed adequate fit for the application in people with schizophrenia. However, the incremental indices values were lower than expected. The Portuguese version of BREQ-3 showed acceptable psychometric properties to assess controlled and autonomous motivation for physical activity in people with schizophrenia. PMID- 28641495 TI - Mixing local anaesthetics, corticosteroid, and ketorolac tromethamine leads to no extreme pH or precipitation. PMID- 28641497 TI - A Neuropsychiatric Analysis of the Cotard Delusion. AB - Cotard's syndrome, a condition in which the patient denies his or her own existence or the existence of body parts, is a rare illness that has been reported in association with several neuropsychiatric diagnoses. The majority of published literature on the topic is in the form of case reports, many of which are several years old. The authors evaluated associated diagnoses, neuroimaging, and treatments recorded in patients diagnosed with Cotard's syndrome at their institution. A search of the Mayo Clinic database for patients with mention of signs and symptoms associated with Cotard's in their records between 1996 and 2016 was conducted. The electronic medical records of the identified patients were then reviewed for evidence of a true diagnosis of Cotard's. Clinical and neuroimaging data were also recorded for these patients. The search identified 18 patients, 14 of whom had Cotard delusions. Two of the 14 were excluded due to them being under age 18. The resulting 12 patients had a median age of 52 years (range: 30-85 years). On neuroimaging, four patients exhibited frontal lobe changes, four demonstrated generalized volume loss, and five had ischemic changes; seven patients demonstrated right-sided or bilateral hemisphere lesions. Treatments included ECT, pharmacotherapy, behavioral therapy, psychotherapy, rehydration, and removal of offending drugs. To conclude, Cotard delusions occur in the context of a relatively wide spectrum of neurological, psychiatric, and medical disorders and present with various neural changes. Nondominant hemisphere lesions may play a role in the pathophysiology. A number of effective treatments are available. PMID- 28641496 TI - Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study. AB - The cannabinoid-1 receptor (CB1R) agonist Delta9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The alpha2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits. PMID- 28641498 TI - Glucocorticoid Receptor Genetic Variants and Response to Fluoxetine in Major Depressive Disorder. AB - Hyperactivity of the hypothalamic pituitary adrenocortical (HPA) axis is one of the main clinical findings in depression. The HPA axis is interrelated with glucocorticoid signaling via glucocorticoid receptors (GCRs). Thus, functional genetic variants on GCRs might influence therapeutic outcomes in depression. The aim of the present study was to investigate the association between three functional polymorphisms (rs41423247, rs6195, and rs6189/rs6190) on GCR and response to fluoxetine in a group of depressed patients. One hundred newly diagnosed patients completed 6 weeks of fluoxetine treatment. Response to treatment was defined as a 50% decrease in the Hamilton Depression Rating Scale score. Variants of rs41423247, rs6195, and rs6189/rs6190 polymorphisms were determined in extracted DNAs using PCR-RFLP method. Regarding rs41423247 polymorphism, carriers of the CG and GG genotype responded significantly better to fluoxetine compared with CC carriers (p=0.008, OR=3.3, 95% CI=1.35-8.07). Moreover, the G allele of rs41423247 polymorphism was strongly associated with response to fluoxetine (p=0.032, OR=2.2, 95% CI=1.09-4.44). There was no significant association between different genotypes and alleles of rs6195, rs6189/rs6190 variants, and response to fluoxetine (p=0.213 and 0.99, respectively). In conclusion, rs41423247 polymorphism might be a predictor for better response to fluoxetine. These findings support the idea that some variants of the GCR might contribute to interindividual variability of response to antidepressants. PMID- 28641499 TI - A comprehensive model for heat-induced radio-sensitisation. AB - Combined radiotherapy (RT) and hyperthermia (HT) treatments may improve treatment outcome by heat induced radio-sensitisation. We propose an empirical cell survival model (AlphaR model) to describe this multimodality therapy. The model is motivated by the observation that heat induced radio-sensitisation may be explained by a reduction in the DNA damage repair capacity of heated cells. We assume that this repair is only possible up to a threshold level above which survival will decrease exponentially with dose. Experimental cell survival data from two cell lines (HCT116, Cal27) were considered along with that taken from the literature (baby hamster kidney [BHK] and Chinese hamster ovary cells [CHO]) for HT and combined RT-HT. The AlphaR model was used to study the dependence of clonogenic survival on treatment temperature, and thermal dose R2 >= 0.95 for all fits). For HT survival curves (0-80 CEM43 at 43.5-57 degrees C), the number of free fit AlphaR model parameters could be reduced to two. Both parameters increased exponentially with temperature. We derived the relative biological effectiveness (RBE) or HT treatments at different temperatures, to provide an alternative description of thermal dose, based on our AlphaR model. For combined RT-HT, our analysis is restricted to the linear quadratic arm of the model. We show that, for the range used (20-80 CEM43, 0-12 Gy), thermal dose is a valid indicator of heat induced radio-sensitisation, and that the model parameters can be described as a function thereof. Overall, the proposed model provides a flexible framework for describing cell survival curves, and may contribute to better quantification of heat induced radio-sensitisation, and thermal dose in general. PMID- 28641500 TI - Levels of 8-oxo-dGsn and 8-oxo-Gsn in random urine are consistent with 24 h urine in healthy subjects and patients with renal disease. AB - Oxidatively generated damage to nucleic acids may play an important role in the pathophysiological processes of a variety of diseases. 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxo-dGsn) and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) are oxidatively generated products of DNA and RNA, respectively. Our previous studies have suggested that the amounts of 8-oxo-dGsn and 8-oxo-Gsn in urine were considerably higher than other body fluid or tissue. The aim of this study was to investigate whether 8-oxo-dGsn and 8-oxo-Gsn levels in random urine samples are consistent with those in 24 h urine samples in healthy subjects and patients with renal disease. A total of 16 healthy subjects and 104 renal disease patients were enrolled in this study, and their random and 24 h urine samples were collected. The levels of urinary 8-oxo-dGsn and 8-oxo-Gsn were quantified by LC-MS/MS and corrected by creatinine. Regardless of healthy subjects or renal disease patients, the levels of oxidised nucleosides in random urine samples were consistent with 24 h urine samples. Regardless of the age bracket, there is no significant difference between random samples and 24 h urine samples. In conclusion, 8-oxo-dGsn and 8-oxo-Gsn levels in random urine samples could replace those in 24 h urine samples, and were considered as the representative of the level of systemic oxidative stress for the whole day. PMID- 28641501 TI - Hematological Characterizations and Molecular Diagnostic Aspects of Hb Wiangpapao [alpha44(CE2)Pro->Ser (alpha1), CCG>TCG; HBA1: c.133C>T], a New alpha-Globin Variant Found in a Pregnant Thai Woman. AB - We report the hematological parameters and provide a rapid molecular analysis method for detection of Hb Wiangpapao [alpha44(CE2)Pro->Ser, CCG>TCG; HBA1: c.133C>T], a new alpha-globin variant found in a pregnant Thai woman. Her red cell indices were measured by an automated blood counter. The results were: red blood cell (RBC) count 4.03 * 1012/L, Hb 13.1 (g/dL), packed cell volume (PCV) 0.39 L/L, mean corpuscular volume (MCV) 97.0 fL, mean corpuscular hemoglobin (Hb) (MCH) 32.5 pg, mean corpuscular Hb concentration (MCHC) 33.4 g/dL, and RBC distribution width (RDW) 9.4%. The Hb typing by high performance liquid chromatography (HPLC) showed 13.6% abnormal Hb at a retention time of 2.20 min. that was difficult to distinguish from Hb A. On the capillary electrophoresis (CE) electropherogram, this hemoglobinopathy peak did not separate from the Hb A peak. DNA sequencing showed a C>T transition at the first position of codon 44 (CCG>TCG) of the alpha1-globin gene that led to a substitution of proline for serine. This mutation has not been recorded in the public databases. Therefore, we named it Hb Wiangpapao as it was first discovered in the Wiangpapao District, Chiang Rai, Thailand. The multiplex allele-specific polymerase chain reaction (ASPCR) for detection of Hb Wiangpapao was developed and revealed a 510 bp specifically amplified fragment. The better understanding of hematological characterizations and the newly developed multiplex ASPCR for diagnosis of Hb Wiangpapao are useful for genetic counseling and family education. PMID- 28641502 TI - Ordering theories: Typologies and conceptual frameworks for sociotechnical change. AB - What theories or concepts are most useful at explaining socio technical change? How can - or cannot - these be integrated? To provide an answer, this study presents the results from 35 semi-structured research interviews with social science experts who also shared more than two hundred articles, reports and books on the topic of the acceptance, adoption, use, or diffusion of technology. This material led to the identification of 96 theories and conceptual approaches spanning 22 identified disciplines. The article begins by explaining its research terms and methods before honing in on a combination of fourteen theories deemed most relevant and useful by the material. These are: Sociotechnical Transitions, Social Practice Theory, Discourse Theory, Domestication Theory, Large Technical Systems, Social Construction of Technology, Sociotechnical Imaginaries, Actor Network Theory, Social Justice Theory, Sociology of Expectations, Sustainable Development, Values Beliefs Norms Theory, Lifestyle Theory, and the Unified Theory of Acceptance and Use of Technology. It then positions these theories in terms of two distinct typologies. Theories can be placed into five general categories of being centered on agency, structure, meaning, relations or norms. They can also be classified based on their assumptions and goals rooted in functionalism, interpretivism, humanism or conflict. The article lays out tips for research methodology before concluding with insights about technology itself, analytical processes associated with technology, and the framing and communication of results. An interdisciplinary theoretical and conceptual inventory has much to offer students, analysts and scholars wanting to study technological change and society. PMID- 28641503 TI - Embolization of a large progressive symptomatic desmoid tumor in the rectus muscle of a female patient with multiple sclerosis: a case report. AB - INTRODUCTION: Desmoid tumors are benign tumors, yet can lead to significant morbidity due to aggressive local expansions. Treatment starts with a wait-and see policy, however, more aggressive treatments like broad margin resection surgery might be necessary in case of tumor progression. PATIENTS AND METHODS: We report the case of a 26-year-old female with a symptomatic desmoid tumor in the left rectus muscle. The initial wait-and-see policy led to an increase in tumor size and progression of symptoms. Computed tomography (CT) angiography revealed a dominant arterial blood supply via a branch of the inferior epigastric artery. We then performed a super selective embolization of the dominant arterial blood supply, to avoid the need for broad margin resection. RESULTS: At three months follow-up, the patient was asymptomatic and magnetic resonance imaging (MRI) showed no residual tumor. At nine months follow-up, MRI scan reconfirmed the successful outcome. CONCLUSIONS: Embolization of a primary supplying vessel of a desmoid tumor is a viable treatment option. However, scientific evidence remains limited and further research is mandatory for inclusion in evidence based treatment algorithms. PMID- 28641504 TI - Nutrition and Health editorial. PMID- 28641505 TI - In Utero Exposure to Di( n-butyl)phthalate Induces Morphological and Biochemical Changes in Rats Postpuberty. AB - Pregnant Sprague-Dawley rats were orally administered di( n-butyl)phthalate (DBP; 100 mg/kg/day) on gestation days (GD) 12 to 21. We investigated the male offspring and probed morphological alterations in Sertoli cells at 7, 9, 14, and 17 weeks of age. Parameters assessed in this study included offspring number, sex ratios, body weights, testis weights, seminiferous tubule (ST) profile numbers and diameters, number of vimentin-labeled Sertoli cells, and both testosterone and follicle-stimulating hormone (FSH) levels. Testicular weight/body weight ratios and the numbers and diameters of ST in maximum transverse testicular sections were statistically similar at weeks 7 and 9; however, at weeks 14 and 17, they were statistically different and displayed higher BrdU-positive Sertoli cells/Sertoli cell ratios in the DBP treatment group. Noteworthily, the serum FSH levels were higher and testicular testosterone levels were lower in the DBP treatment group. To our knowledge, the present study is the first to report that in utero DBP exposure significantly increased Sertoli cell numbers and their cellular proliferation from postpuberty to adulthood, with a significant decrease in testicular testosterone and an increase in FSH. PMID- 28641506 TI - Regulatory Forum Opinion Piece*: Imaging Applications in Toxicologic Pathology Recommendations for Use in Regulated Nonclinical Toxicity Studies. AB - Available imaging systems for use in preclinical toxicology studies increasingly show utility as important tools in the toxicologic pathologist's armamentarium, permit longitudinal evaluation of functional and morphological changes in tissues, and provide important information such as organ and lesion volume not obtained by conventional toxicology study parameters. Representative examples of practical imaging applications in toxicology research and preclinical studies are presented for ultrasound, positron emission tomography/single-photon emission computed tomography, optical, magnetic resonance imaging, and matrix-assisted laser desorption ionization-imaging mass spectrometry imaging. Some of the challenges for making imaging systems good laboratory practice-compliant for regulatory submission are presented. Use of imaging data on a case-by-case basis as part of safety evaluation in regulatory submissions is encouraged. PMID- 28641508 TI - Is Longevity a Heritable Trait? Evidence for Non-genomic Influence from an Extended Longevity Phenotype of Drosophila melanogaster. AB - BACKGROUND: Although genetic variations are heritable, some quantitative traits like longevity may have non-genomic influence on heritability. Laboratory selected inbred strains of extended longevity phenotype of Drosophila offer an opportunity to study the inheritance of longevity. OBJECTIVE: The aim of the study was to examine the heritability of longevity in an extended longevity phenotype of Drosophila melanogaster using reciprocal cross effects in F1 and F2 generations. METHODS: Lifespan variations of virgin and mated flies in parent, F1 and F2 generations were investigated using reciprocal crosses between normal and long lifespan lines of inbred population of D. melanogaster. Heterosis, narrow sense heritability, recombination loss, maternal effect and overdominance with respect to survivorship in virgin and mated flies were analyzed. RESULTS: Virgin flies lived longer than mated flies. There was no significant effect of mid parent heterosis, recombination loss and overdominance on variations in longevity, whereas, significant maternal effect and narrow-sense heritability were observed in mated and virgin flies, respectively. CONCLUSION: Absence of heterosis in our study population of Drosophila phenotypes could be due to the lack of genetic heterogeneity. The heritability of the longevity trait in an inbred extended longevity phenotype depends on the variations in genetic and environmental factors. PMID- 28641507 TI - The ACVP/STP Coalition for Veterinary Pathology Fellows Celebrates 32 New Training Positions. AB - Since its creation in 2004, the Coalition for Veterinary Pathology Fellows, a partnership between the American College of Veterinary Pathologists and the Society of Toxicologic Pathology, has established 32 new training positions backed by US$7.4 million in financial support from private sponsors. PMID- 28641509 TI - Brain Information Sharing During Visual Short-Term Memory Binding Yields a Memory Biomarker for Familial Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) as a disconnection syndrome which disrupts both brain information sharing and memory binding functions. The extent to which these two phenotypic expressions share pathophysiological mechanisms remains unknown. OBJECTIVE: To unveil the electrophysiological correlates of integrative memory impairments in AD towards new memory biomarkers for its prodromal stages. METHODS: Patients with 100% risk of familial AD (FAD) and healthy controls underwent assessment with the Visual Short-Term Memory binding test (VSTMBT) while we recorded their EEG. We applied a novel brain connectivity method (Weighted Symbolic Mutual Information) to EEG data. RESULTS: Patients showed significant deficits during the VSTMBT. A reduction of brain connectivity was observed during resting as well as during correct VSTM binding, particularly over frontal and posterior regions. An increase of connectivity was found during VSTM binding performance over central regions. While decreased connectivity was found in cases in more advanced stages of FAD, increased brain connectivity appeared in cases in earlier stages. Such altered patterns of task-related connectivity were found in 89% of the assessed patients. CONCLUSIONS: VSTM binding in the prodromal stages of FAD are associated to altered patterns of brain connectivity thus confirming the link between integrative memory deficits and impaired brain information sharing in prodromal FAD. While significant loss of brain connectivity seems to be a feature of the advanced stages of FAD increased brain connectivity characterizes its earlier stages. These findings are discussed in the light of recent proposals about the earliest pathophysiological mechanisms of AD and their clinical expression. PMID- 28641510 TI - Recent Advances on the Role of Neurogenesis in the Adult Brain: Therapeutic Potential in Parkinson's and Alzheimer's Diseases. AB - BACKGROUND: Generation of nascent functional neurons from neural stem cells in the adult brain has recently become largely accepted by the neuroscience community. In adult mammals including humans, the process of neurogenesis has been well documented in two brain regions; the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. METHOD: Some evidence has indicated neurogenesis in other regions of the adult mammalian brain such as the neocortex, cerebellum, striatum, amygdala and hypothalamus. These discoveries question a long standing dogma on nervous system regeneration and provide medical science with potential new strategies to harness the process of neurogenesis for treating neurological disabilities and neurodegenerative diseases. CONCLUSION: In this current review, we address the most recent advances on the role of neurogenesis in the adult brain and therapeutic potential in the two most common neurodegenerative disorders, Parkinson's and Alzheimer's diseases. PMID- 28641511 TI - Microbial Lipase Mediated by Health Beneficial Modification of Cholesterol and Flavors in Food Products: A Review. AB - BACKGROUND: The tremendous need of lipase for varied applications in biotechnology increases its economical value in food and allied industries. Patents suggest that lipase has an impressive number of applications viz. enhancements of flavor in food products (Cheese, butter, alcoholic beverages, milk chocolate and diet control food stuffs), detergent industry in removing oil, grease stain, organic chemical processing, textile industry, oleochemical industry, cosmetic industry and also as therapeutic agents in pharmaceutical industries. OBJECTIVE: This communication extends the frontier of lipase catalyzed benefits to human body by lowering serum cholesterol and enhancement of flavor in different food products. METHODS: Among all, multiple innovations going on in the field of lipase applications are widening its scope in food industries consistently. Therefore, in the present work an effort has been made to explore the utilization of lipase in the field of food product enhancement. RESULTS: Supplementation of food products with lipase results in modification of its physical, chemical and biochemical properties by enhancing its therapeutic activity. CONCLUSION: Lipases are the most important enzymes used in food industries. They are utilized as industrial catalysts for lipid hydrolysis. Because of lipases hydrolysis nature it is widely exploited to catalyze lipids or fats in different food products and enhancement of food flavors. PMID- 28641512 TI - Molecular Docking and Molecular Dynamics Simulation Based Approach to Explore the Dual Inhibitor Against HIV-1 Reverse Transcriptase and Integrase. AB - BACKGROUND: HIV integrase (IN) and reverse transcriptase (RT) are key enzymes for the replication of HIV-1. DNA polymerase and ribonuclease H (RNase H) are the two catalytic domains of HIV-1 RT which are validated as drug targets because of their essence for replication. IN and RNase H domain of RT shares striking structural similarity; it contains conserved DDE triad (two aspartates and one glutamate) and a pair of divalent Mg2+/Mn2+ ions at their catalytic core domain. OBJECTIVE: To search for novel compounds with dual inhibition of IN and RNase H for the drug development against both wild and drug-resistant strains of HIV. METHODS: In the present work, attempts have been made to search compounds against both IN and the RNase H domain of RT. Using structure-based virtual screening approach; Asinex database of small molecules was screened against the viral IN. Top thirty ranked hits obtained, were further evaluated against RNase H domain of RT using Extra Precision (XP) mode of Glide docking. Furthermore, eleven common potential hits were observed which were subjected to the in-silico prediction of drug-likeness properties. Later on, molecular dynamics simulation was performed for the best common active hit (AS6), in the complex with selected enzymes. RESULT: In silico screening of Asinex database compounds against IN and RNase H resulted in total seven compounds namely AS3, AS5, AS6, AS15, AS17, AS18, and AS20 having dual inhibition activity. CONCLUSION: This study warrants the dual inhibition activity of AS6 against IN and RNase H confirms its anti-HIV activity. PMID- 28641513 TI - Antioxidant, Antigenotoxic and Cytotoxic Activity of Anthocephalus cadamba (Roxb.) Miq. Bark Fractions and their Phytochemical Analysis using UPLC-ESI-QTOF MS. AB - BACKGROUND: Anthocephalus cadamba is used in traditional and folklore medicinal system. OBJECTIVES: In order to validate its traditional medicinal claim, the present study was designed to assess antioxidant, antigenotoxic and cytotoxic activity of fractions from Anthocephalus cadamba bark and to identify their active phytoconstituents. METHODS: The four fractions viz. hexane (HACB), chloroform (CACB), ethylacetate (EACB) and nbutanol (NACB) were fractionated from the crude methanol extract from bark of A. cadamba. All fractions were evaluated for antiradical efficacy using various in vitro antioxidant assays and for antigenotoxicity by SOS chromotest using E. coli PQ37 tester strain. Cytotoxic potential was checked using MTT assay. RESULTS: Among the four fractions, EACB and NACB exhibited promising radical quenching potential in DPPH, ABTS, superoxide anion radical scavenging and pBR322 plasmid DNA nicking assays. All the fractions were evaluated for genotoxic and antigenotoxic activity in SOS chromotest using E. coli PQ37 tester strain. Results revealed that fractions were non-genotoxic and have potential to suppress the genotoxicity induced by 4NQO (4 nitroquinoline-1-oxide) and AFB1 (aflatoxin B1). NACB was found to inhibit the growth of colon (COLO 205) cancer cells with GI50 of 54.36 ug/ml. To identify bioactive principles in the active fractions, NACB and EACB were subjected to UPLC-electrospray-ionization-quadrupole time-of-flight mass spectrometry which revealed the presence of 3beta-isodihyrocadambine-oxide, cadambine, phelasin A/B, 3beta- dihydrocadambine and 3'-O-caffeoylsweroside like compounds. CONCLUSIONS: Overall results revealed that A. cadamba is a rich source of antioxidant, antigenotoxic and cytotoxic constituents which may find their significance in various food and pharmaceutical products. PMID- 28641514 TI - Clinically Relevant Biomarkers in Acute Heart Failure: An Update. AB - BACKGROUND: Acute Heart Failure (AHF), owing to the difficulties in diagnosis, prognostic stratification and patient-related management, is still associated with unusually high morbidity and mortality. The advent of novel biomarkers apart from natriuretic peptides involved in myocardial injury, neuro-hormonal activation, and ventricular remodeling augurs immense hope in redefining the biomarker-based approach towards AHF. METHODS: A thorough review of the available literature including latest review articles from distinguished experts, textbook references and guidelines from leading cardiological societies worldwide as well as the latest trials, encompassing various biomarkers known in AHF was conducted. The most relevant ones were chosen as references for the current review article. RESULTS: Biomarkers such as midregional proatrial natriuretic peptide, soluble ST2, highly-sensitive troponin, and midregional proadrenomedullin are some such examples that have passed various stages of substantiation while there is an array of potential biomarkers innascent stages like osteopontin, CTGF, GDF-15 and TGF beta-1 awaiting further reiteration. Not only the diagnosis of AHF itself but the evaluation of co-morbidities using markers like PCT, hematologic markers or acute kidney injury markers like NGAL present a new perspective to the management of AHF. CONCLUSION: This review article outlines the current status of the most relevant cardiac biomarkers related to AHF. PMID- 28641515 TI - The Development of Stem Cell-Based Treatment for Liver Failure. AB - BACKGROUND: Liver failure is a devastating clinical syndrome with a persistently mortality rate despite advanced care. Orthotopic liver transplantation protected patients from hepatic failure. Yet, limitations including postoperative complications, high costs, and shortages of donor organs defect its application. The development of stem cell therapy complements the deficiencies of liver transplantation, due to the inherent ability of stem cells to proliferate and differentiate. OBJECTIVE: Understand the source of stem cells, as well as the advantages and disadvantages of stem cell therapy. METHOD: Based on published papers, we discussed the cell sources and therapeutic effect of stem cells. We also summarized the pros and cons, as well as optimization of stem cell-based treatment. Finally outlook future prospects of stem cell therapy. RESULTS AND CONCLUSION: Stem cells may be harvested from a variety of human tissues, and then used to promote the convalescence of hepatocellular function. The emergence of the co-cultured system, tissueengineered technology and genetic modfication has further enhanced the functionality of stem cells. However, the tumorigenicity, the low survival rate and the scarcity of long-term treatment effect are obstacles for the further development of stem cell therapy. In this review, we highlight current research findings and present the future prospects in the area of stem cell-based treatment for liver failure. PMID- 28641516 TI - Updated Regulatory Considerations for Nanomedicines. AB - BACKGROUND: Nanomedicine is a branch which deals with medicinal products, devices, nonbiological complex drugs and antibody-nanoparticle conjugates and general health products that are manufactured using nanotechnology. OBJECTIVE: Nano-medicine provides the same efficacies as traditional medicines owing to their improved solubility and bioavailability with reduced dosages. However, there are currently safety concerns due to the difficulties related to nanomaterial characterization; this might be the reason for unawareness of such medicines among the patients. The absence of clear regulatory guidelines further complicates matters, as it makes the path to registering them with regulatory bodies difficult. However, some products have overcome these obstacles and have been registered. While there are many international initiatives to harmonize the regulatory requirements and helps the industry to determine the most important characteristics that influence in vivo product performance. CONCLUSION: This review focuses on the various types of nanopharmaceuticals, and developments process with strategies tailored to upcoming regulations may satisfy the patients' needs. PMID- 28641517 TI - The Case for Cannabinoid CB1 Receptors as a Target for Bronchodilator Therapy for beta-agonist Resistant Asthma. AB - Although beta2-receceptor agonists are powerful bronchodilators and are at the forefront of asthma symptom relief, patients who use them frequently develop partial resistance to them. This can be a particularly serious problem during severe attacks, where high dose beta2-agonist treatment is the front line therapy. Alternative bronchodilators are urgently needed. In this article we review the evidence for the bronchodilator effects of the cannabinoid CB1 receptor tetrahydrocannabinol (THC) and suggest that the mechanisms of action for these effects are sufficiently independent of the mechanisms of standard bronchodilators to warrant clinical investigation. Specifically, clinical trials testing the bronchodilator effects of THC in beta2 agonist resistant asthmatic patients would show whether THC could fill the role of rescue bronchodilator in cases of beta2 agonist resistance. PMID- 28641518 TI - GRP78 Influences Chemoresistance and Prognosis in Cancer. AB - BACKGROUND: Resistance to therapy is a major hindrance to patient survival in cancer, underscoring a critical need to elucidate the underlying mechanisms responsible for chemoresistance. Research has demonstrated that endoplasmic reticulum (ER) stress plays a significant role in allowing cells to survive conditions that would normally elicit cell death. Specifically, elevated expression of GRP78, the master regulator of the unfolded protein response (UPR), has been shown to induce chemoresistance and serves as a indictor of poor prognosis in patients. OBJECTIVE: Evaluating the expression of GRP78 and its downstream targets in a wide range of cancers may allow clinicians to predict resistance to a number of commonly used therapies. Moreover, understanding the mechanism(s) of action GRP78 uses to regulate chemoresistance will accelerate the development of more efficacious treatment strategies that target GRP78 to abrogate chemoresistance. RESULTS: This mini-review highlighted the roles of targets downstream of GRP78 and explored their mechanisms related to cellular survival. Furthermore, a summary of the connection between GRP78 expression and patient prognosis was provided. Lastly, strategies for targeting GRP78, in order to improve treatment efficacy, was explored. CONCLUSIONS: GRP78 maintains an important role in regulating signaling pathways that control cell survival and this review draws attention to its value as a prognostic marker and therapeutic target. PMID- 28641519 TI - Neural Stem Cells and Human Induced Pluripotent Stem Cells to Model Rare CNS Diseases. AB - BACKGROUND & OBJECTIVE: Despite the great effort spent over recent decades to unravel the pathological mechanisms underpinning the development of central nervous system disorders, most of them still remain unclear. In particular, the study of rare CNS diseases is hampered by the lack of postmortem samples and of reliable epidemiological studies, thus the setting of in vitro modeling systems appears essential to dissect the puzzle of genetic and environmental alterations affecting neural cells viability and functionality. The isolation and expansion in vitro of embryonic (ESC) and fetal neural stem cells (NSC) from human tissue have allowed the modeling of several neurological diseases "in a dish" and have also provided a novel platform to test potential therapeutic strategies in a pre clinical setting. In recent years, the development of induced pluripotent stem cell (iPS) technology has added enormous value to the aforementioned approach, thanks to their capability for generating diseaserelevant cell phenotypes in vitro and to their perspective use in autologous transplantation. However, while the potentiality of ESC, NSC and iPS has been widely sponsored, the pitfalls related to the available protocols for differentiation and the heterogeneity of lines deriving from different individuals have been poorly discussed. Here we present pro and contra of using ESC, NSC or iPS for modeling rare diseases like Lysosomal Storage disorders and Motor Neuron Diseases. CONCLUSION: In this view, the advent of gene editing technologies is a unique opportunity to standardize the data analysis in preclinical studies and to tailor clinical protocols for stem cell-mediated therapy. PMID- 28641520 TI - Try To Remember: Interplay Between Memory And Substance Use Disorder. AB - Memories associated with substance use disorders, or substance-associated cues increase the likelihood of craving and relapse during abstinence. There is growing consensus that manipulation of synaptic plasticity may reduce the strength of substance abuse-related memories. On the biological front, there are new insights that suggest memories associated with substance use disorder may follow unique neurobiological pathways that render them more accessible to pharmacological intervention. In parallel to this, research in neurochemistry has identified several potential candidate molecules that could influence the formation and maintenance of long-term memory. Drugs that target these molecules (blebbistatin, isradipine and zeta inhibitory peptide) have shown promise at the preclinical stage. In this review, we shall provide an overview of the evolving understanding on the biochemical mechanisms involved in memory formation and expound on the premise that substance use disorder is a learning disorder. PMID- 28641521 TI - LncRNA HOTAIR Polymorphisms Association with Cancer Susceptibility in Different Tumor Types. AB - Single nucleotide polymorphisms (SNPs) in non-coding RNAs (ncRNA) molecules affect gene and protein expression and generate genetic variability influencing the risk of tumor diseases. HOTAIR locates at the heart of the cell memory gene program and represents a prototype of long non coding RNA (LncRNA) due to its capacity to regulate in-trans a distant chromosome landscape. Aberrant expression of HOTAIR is frequently associated with pathogenesis and mostly with metastatic progression of several human cancers. Different polymorphisms, particularly present in intronic sequences, as well as in promoter regions of HOTAIR, are often associated with its aberrant expression, patient prognosis, and cancer susceptibility in different tumor phenotypes. In this minireview, we have summarized the main SNPs in HOTAIR sequence and their relation with cancer risk in several types of solid tumors. PMID- 28641522 TI - Advances on PPARgamma Research in the Emerging Era of Precision Medicine. AB - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily that functions as a ligand-inducible transcription factor. It regulates glucose and lipid metabolism, immunity, and cellular growth and differentiation. Thiazolidinediones (TZDs) are potent insulin sensitizers that function by activating PPARs, with a high specificity for PPARgamma. Due to their ability to preserve pancreatic beta cell function and reduce insulin resistance, TZDs have become one of the most prescribed classes of medications for type 2 diabetes (T2D) since their approval by the US Food and Drug Administration (FDA) and initial use in 1997. OBJECTIVE: However, adverse effects, including weight gain, bone loss, fluid retention, congestive heart failure, and risk to bladder cancer, have weakened the benefits of TZDs in T2D therapies. Therefore, there is an urgent need to have a deeper understanding of regulatory mechanisms of PPARgamma expression and activity so that novel classes of PPARgamma-modulating therapeutics with fewer or weaker side effects can be developed. CONCLUSION: This article systematically reviews PPARgamma's mechanisms of action and multilayer regulations. In addition, novel classes of therapeutics modulating PPARgamma and new direction of research on genetic variants that affect PPARgamma function and antidiabetic drug response are highlighted, which sheds light on PPARgamma as a promising target for developing safer and precision medicine based therapeutic strategies. PMID- 28641523 TI - Radiosensitizing Effect of Electrochemotherapy: A Systematic Review of Protocols and Efficiency. AB - BACKGROUND: Electrochemotherapy (ECT) is a combination of electroporation (EP) and chemotherapy and has been reported as a potential radiosensitizing agent for radiation therapy. OBJECTIVE: The main objective of this study was to systematically review of the literature to evaluate the effectiveness of ECT in sensitization of tumors to ionization radiation. In addition, the clinical considerations and mechanisms of action of radiosensitizing effect are discussed. RESULTS: Nine studies were included in this review. Bleomycin and cisplatin showed radiosensitizing effects in combined protocols with EP. EP enhances the cytotoxicity of bleomycin and cisplatin by factor of 1000 and 100, respectively. The mechanism of action of these drugs is induction of single and double strand breaks in DNA molecule. Moreover, the two main mechanisms of EP are increasing drug uptake in the tumor cells and generating reactive oxygen species. A single session ECT before radiotherapy can significantly enhance the tumor response. CONCLUSION: ECT is effective for different cell lines and tumors with different levels of radiosensitivity. Our findings show that ECT can be further translated into the clinic and can be matched by singledose irradiation as well as in the fractionated regime. PMID- 28641524 TI - The Bio-Psycho-Social Dimension In Women's Sexual Desire: 'Argumentum Ad Novitatem'. AB - Sexual desire includes complex motivation and drive. In the context of biological and cognitive-emotive state art of science, it is often a neglected field in medicine. With regard to the treatment, study on women's sexual function received less attention compared to the men's sexuality. In the past, this endeavor was relatively not well disseminated in the scientific community. Recently, there was a revolutionized surge of drug targets available to treat women with low sexual desire. It is timely to review the relevant biological approach, especially in the context of pharmacotherapy to understand this interesting clinical entity which was modulated by numerous interactive psychosocial inter-play and factors. The complex inter-play between numerous dimensional factors lends insights to understand the neural mechanism, i.e. the rewards centre pathway and its interaction with external psychosocial stimulus, i.e. relationship and meaningful life events. The role of hormones i.e. oxytocin and testosterone regulation and neurotransmitters i.e. dopamine and serotonin modulation was pivotal as reflected by the introduction of a molecule of flibanserin, a full agonist of the 5-HT1A and partial agonist of D4 to treat pre-menopausal women with low sexual desire. Based on this fundamental scientific core knowledge, we suggest an outline of on know-how introduction for sex therapy (i.e. "inner-self" and "outer-self") where the role of partner is narrated and also highlighted on the use of pharmacological agent as an adjunct scope of therapy, i.e. phosphodiasterase-5 (PDE-5) inhibitors and hormonal treatment in helping the patient with low sexual desire. PMID- 28641525 TI - 1,1'-Carbonyldiimidazole (CDI) Mediated Facile Synthesis, Structural Characterization, Antimicrobial Activity, and in-silico Studies of Coumarin- 3 carboxamide Derivatives. AB - BACKGROUND: Despite the availability of a variety of antibacterial agents, re emergence of pathogenic bacteria is still a serious medical concern. So, identification of new, safer, and selective antibacterial agents is the key interest in the medicinal chemistry research. METHOD: To explore the antimicrobial activity of coumarin-3-carboxamides for a range of bacterial and fungal strains, twenty eight derivatives were synthesized by the reaction of coumarin-3-carboxylic acid with a variety of aniline derivatives in the presence of 1,1'-carbonyldiimidazole (CDI). All compounds were structurally characterized by different spectroscopic techniques EI-MS, HREI-MS, 1H-NMR, 13C-NMR, and evaluated for antimicrobial activities (antibacterial and antifungal). RESULTS: A number of compounds showed good to weak antibacterial activity against various strains of Gram-positive and Gram-negative bacteria. Amongst them, compound 28 displayed noticeable inhibition against five strains of Gram-positive (Bacillus subtilis, Corynebacterium xerosis, Staphylococcus aureus, Streptococcus faecalis, and MRSA) and four strains of Gram-negative bacteria (Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter aerogene, and Shigella dysenteria). However, none of the compounds showed antifungal activity against tested fungi. MIC values were determined for most of the active compounds 2, 15, and 28 against particular bacterial cultures. In silico studies were performed on the most active compound 28 in order to specify and verify the target for antibacterial activity of synthetic coumarin-3-carboxamide derivatives. The cytotoxicity of these compounds on mammalian cells is unknown yet but we are planning to carry out research on the cytotoxic aspect of these compounds in future. CONCLUSION: The newly identified compounds may serve as lead molecules for the future research regarding the identification of new antibacterial agents. PMID- 28641526 TI - Biology-Oriented Synthesis (BIOS) of Piperine Derivatives and their Comparative Analgesic and Antiinflammatory Activities. AB - BACKGROUND: Serious side effects such as gastric intestinal ulcer, bleeding etc. are associated with most of the antiinflammatory and analgesic drugs. So, there is a need to search novel, potent, and safer antiinflammatory and analgesic drug. METHOD: Based on "biology-oriented synthesis approach", piperine alkaloid was isolated from Piper nigrum L. and some derivatives of piperine having azomethine, sulfamoyl, propanoyl, acetamoyl and heterocyclic oxadiazole were synthesized. The structures of synthetic derivatives were confirmed by using different spectroscopic techniques such as 1H-, 13C-NMR, EI-MS, and IR. Melting points were also determined for all compounds. Piperine and its all the synthetic derivatives were subjected to comparative in vivo evaluation of analgesic and antiinflammatory activities at the oral dose of 6 mg/kg/day. Analgesic activity was evaluated by tail immersion, hot plate and acetic acid writhing methods. While, antiinflammatory activity was evaluated by carrageenan-induced paw inflammation. In silico studies of all synthetic compounds was also conducted on COX-2 and adenosine kinase enzymes. RESULTS: A number of derivatives showed enhanced antiinflammatory and analgesic activities as compared to piperine and standard drug diclofenac. CONCLUSION: The newly identified molecules may serve as lead for the future research in connection of potent and safer antiinflammatory and analgesic drug candidate. PMID- 28641527 TI - Design, Synthesis, and Biological Evaluation of C-2 Substituted 3Hthieno[ 2,3 d]pyrimidin-4-one Derivatives as Novel FGFR1 Inhibitors. AB - BACKGROUND: Thienopyrimidinone is a newly designed, selective fibroblast growth factor receptor 1 (FGFR1) inhibitor with an excellent anticancer effect. OBJECTIVE: The goal of the present study was to design and synthesize better FGFR1 inhibitors through modifications of the lead compound thienopyrimidinone. METHODS: In the present study, a series of C-2 substituted derivatives of thienopyrimidinone, namely L1-L16, were synthesized, and their inhibitory effects on FGFR1 were evaluated. The anti-proliferative activities of these compounds were assessed by MTT assay. RESULTS: Among the novel derivatives, L11 was found to exert remarkable FGFR1 inhibitory activity (79.93% at 10 uM) and anti proliferative activity, with IC50 values of 2.1, 2.5, and 3.5 .M in the FGFR1 overexpressing cell lines, H460, HT-1197, and B16F10, respectively. CONCLUSION: Our newly synthesized thienopyrimidinone derivatives may be candidate FGFR1 inhibitors for future development as novel anticancer agents. PMID- 28641528 TI - Drug Design, Synthesis and In Vitro Evaluation of Substituted Benzofurans as Hsp90 Inhibitors. AB - BACKGROUND: Heat shock protein 90 is a molecular chaperone required for the stability and function of several client proteins that promote cancer cell growth and/or survival. Discovery of Hsp90 inhibitors has emerged as an attractive target of research in cancer therapeutics. Natural products like geldanamycin and radicicol are established Hsp90 inhibitors, but face limitations with toxicity and inactivity, by in vivo studies respectively. However, they lay the logical starting point for the design of novel synthetic or semi-synthetic congeners as Hsp90 inhibitors. OBJECTIVE: In this article, the structure based drug design of substituted 2-aryl/heteroarylidene-6- hydroxybenzofuran-3(2H)-one analogues to optimize and mimic the pharmacophoric interactions of the valid Hsp90 inhibitor radicicolis focused. METHOD: In silico docking study was performed by Surflex dock-Geom (SYBYL- X 1.2 drug discovery suite) and the designed ligands were chemically synthesized by conventional method using resorcinol and chlororesorcinol as starting materials. Two dimensional chemical similarity search was carried out to identify the chemical space of 'SY' series in comparison with reported Hsp90 inhibitors. The in vitro cell proliferation assay (resazurin reduction method) and proteomic investigation (DARTS) was carried out on whole cell lysate to evaluate anticancer activity. RESULTS: The chemical structures of all the synthesized compounds were confirmed by IR, 1H-NMR and Mass spectral analysis. The results of chemical similarity search show that SY series fit it in the chemical space defined by existing Hsp90 inhibitors. In vitro cell proliferation assay, against human melanoma and breast cancer cell lines, identified 'SY3' as the promising anticancer agent amongst the series. CONCLUSION: Docking studies, 2D chemical similarity search, resazurin reduction assay and qualitative proteomic analysis identify 'SY3'as a promising Hsp90 inhibitor amongst the series. PMID- 28641529 TI - iRNA-2methyl: Identify RNA 2'-O-methylation Sites by Incorporating Sequence Coupled Effects into General PseKNC and Ensemble Classifier. AB - OBJECTIVE: Being a kind of post-transcriptional modification (PTCM) in RNA, the 2'-Omethylation modification occurs in the processes of life development and disease formation as well. Accordingly, from the angles of both basic research and drug development, we are facing a challenging problem: given an uncharacterized RNA sequence formed by many nucleotides of A (adenine), C (cytosine), G (guanine), and U (uracil), which one can be of 2-O'-methylation modification, and which one cannot? Unfortunately, so far no computational method whatsoever has been developed to address such a problem. METHOD: To fill this empty area, we propose a predictor called iRNA-2methyl. It is formed by incorporating a series of sequence-coupled factors into the general PseKNC (pseudo nucleotide composition), followed by fusing 12 basic random forest classifier into four ensemble predictors, with each aimed to identify the cases of A, C, G, and U along the RNA sequence concerned, respectively. RESULTS: Rigorous jackknife cross-validations have indicated that the success rates are very high (>93%). For the convenience of most experimental scientists, a user friendly web-server for iRNA-2methyl has been established at http://www.jci bioinfo.cn/iRNA-2methyl, by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved. CONCLUSION: The proposed predictor iRNA-2methyl will become a very useful bioinformatics tool for medicinal chemistry, helping to design effective drugs against the diseases related to the 2'-Omethylation modification. PMID- 28641530 TI - Method Development in Forensic Toxicology. AB - BACKGROUND: In the field of forensic toxicology, the quality of analytical methods is of great importance to ensure the reliability of results and to avoid unjustified legal consequences. A key to high quality analytical methods is a thorough method development. METHODS: The presented article will provide an overview on the process of developing methods for forensic applications. RESULTS: This includes the definition of the method's purpose (e.g. qualitative vs quantitative) and the analytes to be included, choosing an appropriate sample matrix, setting up separation and detection systems as well as establishing a versatile sample preparation. CONCLUSION: Method development is concluded by an optimization process after which the new method is subject to method validation. PMID- 28641531 TI - Application of Alphaviral Vectors for Immunomodulation in Cancer Therapy. AB - BACKGROUND: The lack of specific and efficient cancer therapies has influenced the development of novel approaches, such as immunotherapy, which from its original application of immunogenic protein delivery has developed into the use of more sophisticated recombinant gene delivery methods to achieve better safety and efficacy profiles. This approach involves viral and non-viral delivery systems. METHODS: Expression vectors have been engineered for alphaviruses, including Semliki Forest virus, Sindbis virus and Venezuelan equine encephalitis virus. For immunotherapeutic applications, recombinant particles, RNA replicons and layered DNA vectors that express tumor-associated antigens (TAAs) and cytokines have been studied in animal models and in a few clinical trials. RESULTS: Immunization studies with TAAs and cytokines have elicited strong antibody responses and vaccination has provided protection against challenges with tumor cells in mouse models. Furthermore, the combination of TAAs and cytokines, antibodies and growth factors and the co-administration of chemotherapeutics and bacteriabased adjuvants have enhanced immunogenicity. Intratumoral and systemic delivery of recombinant alphavirus particles has demonstrated significant tumor regression and prolonged survival rates in rodent tumor models. CONCLUSION: Alphavirus-based immunotherapy represents a rapid and efficient method for prophylactic and therapeutic applications in animal models. PMID- 28641532 TI - Trimethylamine N-oxide (TMAO) as a New Potential Therapeutic Target for Insulin Resistance and Cancer. AB - BACKGROUND: The intake of animal products in food has been associated with both the development of insulin resistance and gastrointestinal cancers (GIC). Through the digestion of animal protein and other constituents of animal products, the commensal bacteria in the gut (the gut microbiota) forms metabolites that can contribute to the development of both insulin resistance and cancer. Trimethylamine-N-Oxide (TMAO) is such a molecule and has recently drawn a lot of attention as it may be a risk factor for - and a link between - the gut microbiota and cardiovascular and renal disease. Further, TMAO is anticipated to have significance as a biomarker of - or even an independent risk factor for - other undesirable conditions, including insulin resistance and GIC. TMAO originates from a precursor, trimethylamine (TMA) that is a metabolite of various precursors; mainly choline and carnitine from ingested foods. METHODS: We review the literature on TMAO as a shared risk factor and/or pathway between insulin resistance and GIC risk and take the reader through the literature of interventions that could reduce formation of TMAO and thereby the risk of insulin resistance and GIC. The purpose of the work is to generate a hypothesis to be tested in preclinical and clinical studies. RESULTS: TMAO seems to be associated with both insulin resistance and GIC risk and also with atherosclerotic cardiovascular disease. One shared pathway is the formation of N-Nitroso compounds, a group of metabolites that can cause DNA-damage and epigenetic changes. Levels of TMAO can be reduced by limiting the dietary intake of certain foods, most importantly animal products. Further, certain drugs, namely Meldonium and 3,3-dimethyl- 1-butanol, may inhibit the formation of TMAO by inhibiting bacterial enzymes. CONCLUSIONS: The TMAO pathway and its metabolites are possibly involved in the development of two major health problems: insulin resistance and cancer. Within these pathways novel therapeutic targets may be identified. Further research is needed in order to verify existing or develop new pharmacological agents that modify these pathways and reduce the risk of insulin resistance and GIC. PMID- 28641534 TI - Interest of Single Hair Analysis to Document Drug Exposure: Literature Review and a Case Report Involving Zuclopenthixol. AB - The analysis of hair to detect drugs and drugs of abuse is performed in various contexts, including child protection cases, abstinence control programs, and workplace drug testing. This alternative matrix offers several advantages, such as a large detection window (months) and non-invasive collection. Segmental analysis of multiple hair strands for drugs and metabolites has been widely reported in the literature over the past three decades, whereas a review of the literature showed that there are only 26 articles that report the analysis of a single hair. They focus on two approaches: mass spectrometry imaging techniques, which improve the resolution of dating an intoxication or conventional methods, such as gas chromatography mass spectrometry and liquid chromatography tandem mass spectrometry (LC-MS/MS). Improved sensitivity of LC-MS/MS techniques allows the evaluation of drug content in segments of a single hair. However, the units used to express the results vary, and depend on the authors. Following a review of the literature, we present a case that illustrates drug analyses both in a strand of hair and a single hair. In this case of exposure of a child to zuclopenthixol (ZPT), the analysis of ZPT in a single segmented hair by LC-MS/MS strengthened the presumption of a single administration. PMID- 28641536 TI - Overview of Forensic Toxicology, Yesterday, Today and in the Future. AB - BACKGROUND: The scope of forensic toxicology has been tremendously expanded over the past 50 years. From two general sections forensic toxicology can be further classified into 8-9 sections. METHODS: The most outstanding improvement in forensic toxicology is the changes brought by instrumental development. The field of forensic toxicology was revolutionized by the development of immunoassay and benchtop GC-MS in the 1980's and LC-MS-MS in 2000's. Detection of trace amounts of analytes has allowed the use of new specimens such as hair and oral fluids, along with blood and urine. Over a longer period of time, continuous efforts have been made to efficiently extract and separate drug and poison from biological fluids. International endeavors to develop high quality standards and guidelines for drugs and poisons in biological specimens and to promote them in order to increase reliability of laboratories are also part of the recent advancement of forensic toxicology. Interpretation of postmortem toxicology encompasses various factors including postmortem redistribution and stability. RESULTS: Considering the recent trend, the interpretation of toxicological results should account for autopsy findings, crime scene information, and related medical history. The fields of forensic toxicology will continuously develop to improve analysis of target analytes from various specimens, quality assurance program, and results interpretation. In addition, the development of analytical techniques will also contribute further advancement of forensic toxicology. CONCLUSION: The societies of forensic toxicologists, such as TIAFT, will play an important role for the advancement of forensic toxicology by collaborating and sharing ideas between toxicologists from both developed and developing countries. PMID- 28641535 TI - HIV-1 Transcription Inhibitors Increase the Synthesis of Viral Non-Coding RNA that Contribute to Latency. AB - BACKGROUND: HIV-1 can be preserved in long-lived resting CD4+ T- and myeloid cells, forming a viral reservoir in tissues of the infected individuals. Infected patients primarily receive cART, which, to date, is the most efficient treatment against HIV/AIDS. However, the major problem in the eradication of HIV-1 from patients is the lack of therapeutic approaches to recognize the latent HIV-1 provirus and to eliminate latently infected cells. RESULTS: In the current review, we describe the effect of HIV-1 transcriptional inhibitors CR8#13 and F07#13 using a series of in vitro and in vivo assays. We found that both of these compounds regulate p-TEFb in infected cells, and terminate transcription at two sites, either at the LTR or early gag regions. The resulting short transcripts are termed TAR and TAR-gag, respectively. These nascent RNAs are capable of binding to SWI/SNF components, including mSin3A/HDAC-1 complex and potentially serve as a scaffolding RNA. Both TAR and TAR-gag are detected as large complexes from treated infected cells when using chromatography. Both transcripts are non coding in T-cells and monocytes, and potentially recruit suppressive factors along with RNAbinding proteins to the DNA resulting in Transcriptional Gene Silencing (TGS). Finally, these compounds suppress activated virus when using a latent humanized mouse model. CONCLUSION: Collectively, these data implicate transcription inhibitors as regulators of the viral promoter through short non coding RNAs and chromatin remodeling factors. These RNAs give specificity toward either viral DNA and/or nascent mRNA when functioning as TGS. PMID- 28641537 TI - LSD Detection and Interpretation in Hair. AB - Lysergic acid diethylamide (LSD) is a powerful hallucinogen, active at very low dosages, with, as a direct consequence, potential difficulties to be detected and quantified in a clinical or forensic context, in body fluids and even more in hair. The aim of this work is to review literature data related to hair analysis of LSD with a particular focus on the main issues encountered in LSD detection in hair. Results of LSD investigation in hair remain difficult to interpret regarding the very sparse data available on LSD concentrations in hair (n=10). The possibility of pubic hair contamination by urine, as well as the lack of data about LSD incorporation and stability in pubic and head hair, further challenges the interpretation of negative or positive results. The absence of LSD in head hair should be carefully considered, as it does not formally exclude LSD consumption. In all cases of positive results, the interpretation of LSD concentrations in hair remains uncertain and it seems utopian to distinguish repeated intake from single exposure using LSD hair concentration values. Furthermore, a positive result in pubic hair cannot be used to formally prove repeated use of LSD, even in the case of a documented recent use of LSD. PMID- 28641533 TI - Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression. PMID- 28641538 TI - GLT-1 Upregulation as a Potential Therapeutic Target for Ischemic Brain Injury. AB - Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system, which plays an important role in many aspects of normal brain function such as neural development, motor functions, learning and memory etc. However, excessive accumulation of glutamate in the extracellular fluid will induce excitotoxicity which is considered to be a major mechanism of cell death in brain ischemia. There is no enzyme to decompose the glutamate in extracellular fluid, so extracellular glutamate homeostasis within the central nervous system is mainly regulated by the uptake activity of excitatory amino acid transporters. Among the five excitatory amino acid transporters, glial glutamate transporter-1 (GLT-1) is responsible for 90% of total glutamate uptake. Thus, GLT-1 is essential for maintaining the appropriate level of extracellular glutamate, and then limiting excitotoxicity of glutamate in central nervous system. Therefore, the regulation of GLT-1 might be a potential therapeutic target for ischemic brain injury. This review summarizes recent advances including our findings in the methods or medicine that could protect neurons against brain ischemic injury via upregulation of GLT-1 and discuss the possible application of these strategies. PMID- 28641540 TI - Metallothionein is a Potential Therapeutic Strategy for Amyotrophic Lateral Sclerosis. AB - Lou Gehrig's disease, a synonym of amyotrophic lateral sclerosis, is an adult onset lethal neurodegenerative disorder. Irrespective of extensive efforts to elucidate the pathogenesis of the disease and searches for therapies, no favorable pharmacotherapeutic strategies have yet to be proposed. In a popular rodent model of ALS, G93A SOD1 strain of mouse, intracellular copper conditions were geared toward copper accumulation inside cells, resulting in an acceleration of oxidative stress and apoptotic process. Disruption of intracellular copper homeostasis was common to transgenic mice expressing human mutant SOD1s. In this review, the novel hypothesis that disruption of intracellular copper homeostasis could be involved in the development of the disease was introduced. Based upon the hypothesis, therapeutic outcomes of agents that are capable of correcting and/or modifying intracellular copper homeostasis are described. Administration of ammonium tetrathiomolybdate, a selective intracellular copper chelator, delayed onset, slowed progression, and prolonged survival of a rodent model of the disease (G93A SOD1 mice). Metallothionein is a low molecular weight, cysteine rich, metal-binding cytoplasmic protein that has beneficial properties in detoxification of toxic heavy metals, homeostatic regulation of intracellular essential trace elements, including copper, antioxidant, and antiapoptotic roles. In animal experiments of the G93A SOD1 mice, an increase of metallothionein proteins by means of induction by exercise or dexamethasone, genetic overexpression, or intraperitoneal administration, all resulted in a preferable outcome. The therapeutic effects were not inferior to those of approved drugs for ALS in humans. These observations suggest that metallothionein could be worth investigating the therapeutic potential in clinical use. PMID- 28641541 TI - "Stress" is 80 Years Old: From Hans Selye Original Paper in 1936 to Recent Advances in GI Ulceration. AB - The first scientific publication on 'general adaption syndrome', or as we know today 'biologic stress' has been published in Nature in 1936 by the 29-year old Hans Selye. His results in that short publication that contained no references or illustrations, were based on experiments in rats that were exposed to severe insults/ stressors, but his idea about a 'nonspecific bodily response' originated from his observations of sick patients whom he had seen as a medical student and young clinician. Autopsy of stressed rats revealed three major, grossly visible changes: hyperemia and enlargement of the adrenals, atrophy of the thymus and lymph nodes as well as hemorrhagic gastric erosions/ulcers (the "stress triad"). Based on this and additional observations, he concluded that the key master organ in stress reactions is the adrenal cortex (although he also accepted the limited and short lasting effect of catecholamines released from the adrenal medulla) which stimulated by an increased secretion of ACTH, secreted by the anterior pituitary gland. He thus identified the first molecular mediators of the stress reaction, i.e., steroids released from the adrenal cortex that we call today glucocorticoids, based on his classification and naming of steroids. At the end of a very productive life in experimental medicine, Selye recognized that under both unpleasant and demanding stressors as well as positive, rewarding stimuli adrenal cortex releases the same glucocorticoids and only certain brain structures may distinguish the stimuli under distress and eustress - terms he introduced in 1974, that also contained his last definition of stress: the nonspecific response of the body on any demand on it. After brief description of the history of stress research, the rest of this review is focused on one element of stress triad, i.e., gastroduodenal ulceration, especially its pathogenesis, prevention and treatment. Following a short description of acute gastroprotection, discovered by one of Selye's students, we discuss new molecular mediators of gastroduodenal ulceration like dopamine and new drugs that either only heal (very potently, on molar basis) or prevent and heal ulcers like sucralfate derivatives and the relatively new peptide BPC-157. We conclude that despite the extensive and multidisciplinary research on stress during the last 80 years, a lot of basic and clinical research is needed to better understand the manifestations, central and peripheral molecular regulators of stress response, especially the modes of prevention/management of distress or its transformation into eustress and the treatment of stress-related diseases. PMID- 28641542 TI - Functional Nanoparticles and their Interactions with Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) have become one of the most important cell sources for regenerative medicine. However, some mechanisms of MSC-based therapy are still not fully understood. The clinical outcome may be restricted by some MSC related obstacles such as the low survival rate, differentiation into undesired lineages and malignant transformation. In recent years, with the emergence of nanotechnology, various types of multifunctional nanoparticles (NPs) have been designed, prepared and explored for bio-related applications. There is high potential of NPs in biomedical applications, attributed to the high capacity of cellular internalization in MSCs and their multiple functionalities. They can be used either as labeling agent to track MSCs for mechanism study or as gene/drug delivery carriers to regulate the cellular behavior and functions of MSCs. However, the application of NPs may be accompanied by some undesirable effects, as some NPs can induce cell death, inhibit cell proliferation or influence the differentiation of MSCs. Aiming to provide a comprehensive understanding of the interaction between NPs and MSCs, recent progress in the design and preparation of multifunctional NPs is summarized in this review, mechanisms of cellular internalization of the NPs are discussed, the main applications of multifunctional NPs in MSCs are highlighted and overview about cellular response of MSCs to different NPs is given. Future studies aiming on design and development of NPs with multifunctionality may open a new field of applying nanotechnology in stem cell-based therapy. PMID- 28641539 TI - Role of Host Factors on the Regulation of Tat-Mediated HIV-1 Transcription. AB - BACKGROUND: The viral transactivator Tat protein is a key modulator of HIV-1 replication, as it regulates transcriptional elongation from the integrated proviral genome. Tat recruits the human transcription elongation factor b, and other host proteins, such as the super elongation complex, to activate the cellular RNA polymerase II, normally stalled shortly after transcription initiation at the HIV promoter. By means of a complex set of interactions with host cellular factors, Tat determines the fate of viral activity within the infected cell. The virus will either actively replicate to promote dissemination in blood and tissues, or become dormant mostly in memory CD4+ T cells, as part of a small but long-living latent reservoir, the main obstacle for HIV eradication. OBJECTIVE: In this review, we summarize recent advances in the understanding of the multi-step mechanism that regulates Tat-mediated HIV-1 transcription and RNA polymerase II release, to promote viral transcription elongation. Early events of the human transcription elongation factor b release from the inhibitory 7SK small nuclear ribonucleoprotein complex and its recruitment to the HIV promoter will be discussed. Specific roles of the super elongation complex subunits during transcription elongation, and insight on recently identified cellular factors and mechanisms regulating HIV latency will be detailed. CONCLUSION: Understanding the complexity of HIV transcriptional regulation by host factors may open the door for development of novel strategies to eradicate the resilient latent reservoir. PMID- 28641543 TI - Zein-based Nanocarriers as Potential Natural Alternatives for Drug and Gene Delivery: Focus on Cancer Therapy. AB - Protein nanocarriers possess unique merits including minimal cytotoxicity, numerous renewable sources, and high drug-binding capability. In opposition to delivery carriers utilizing hydrophilic animal proteins, hydrophobic plant proteins (e.g, zein) have great tendency in fabricating controlled-release particulate carriers without additional chemical modification to stiffen them, which in turn evades the use of toxic chemical crosslinkers. Moreover, zein is related to a class of alcohol-soluble prolamins and generally recognized as safe (GRAS) carrier for drug delivery. Various techniques have been adopted to fabricate zein-based nanoparticulate systems including phase separation coacervation, spray-drying, supercritical anti-solvent approach, electrospinning and self-assembly. This manuscript reviews the recent advances in the zein-based colloidal nano-carrier systems such as nanospheres, nanocapsules, micelles and nanofibers with a special focus on their physicochemical characteristics and drug delivery applications. PMID- 28641544 TI - Post Mortem Redistribution of Drugs: Current State of Knowledge. AB - BACKGROUND: Drug concentrations obtained from post mortem samples do not necessarily reflect the concentrations at the time of death, and variations of concentration may be observed between different sites and/or different sampling times. These phenomena, collectively termed post mortem redistribution, concern numerous molecules (medications, drugs of abuse, gases, etc.) and can complicate the interpretation of toxicological analyses. METHODS: Literature review. RESULTS: The mechanisms that cause these phenomena are complex and often intricate. Certain organs, which concentrate the molecules before death, may release them very early in the vascular sector. The gastrointestinal tract, liver, lungs and myocardium are mainly concerned. Cell autolysis also plays a part in drug release. Furthermore, micro-organisms (mainly bacteria and yeasts) which colonize the organism during putrefaction may cause neoformation and/or the degradation of certain molecules. Lastly, it appears that the physicochemical and pharmacokinetic profile of xenobiotics, notably their lipophilic nature, their ionization state and their volume of distribution may be factors likely to influence redistribution phenomena. Some recommendations concerning anatomic sampling sites, sampling methods and sample storage make it possible to limit these phenomena. PMID- 28641545 TI - Role of Bradykinin in the Regulation of Endothelial Nitric Oxide Synthase Expression by Cardiovascular Drugs. AB - NO produced by eNOS plays important roles in the cardiovascular system. Alterations in eNOS activity and expression occur in various cardiovascular disorders and eNOS constitutes a therapeutic target. In addition to posttranslational modifications of eNOS that affect eNOS activity, transcriptional and post-transcriptional regulation of eNOS expression also controls eNOS-derived NO production. Bradykinin is an important determinant of vascular function and participates in the regulation of eNOS activity and expression. A number of currently used drugs or investigational molecules targeting specific ion channels, enzymes or receptors, including dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors, statins, AT1 receptor blockers and angiotensin-(1-7), increase eNOS expression and activity. In this context, activation of bradykinin B2 receptors appears to be a common step for these drugs to promote eNOS expression, which certainly contributes to their therapeutic actions. PMID- 28641546 TI - Targeting Astrocytes for Treating Neurological Disorders: Carbon Monoxide and Noradrenaline-Induced Increase in Lactate. AB - There are at least three reasons why brain astrocytes represent a new target for treating neurological disorders. First, although the human neocortex represents over 80% of brain mass, neurons are outnumbered by non-neuronal cells, including astrocytes, a neuroglial cell type. Second, as in neurons, vesicle-based release of transmitters is present in astrocytes, however with much slower kinetics than in neurons. Third, astrocytes contain glycogen, which can be transformed to L lactate in glycolysis. L-lactate is considered to be a fuel and a signalling molecule involved in cognition and neuroprotection. The mechanisms of neuroprotection are unclear but may be linked to carbon monoxide, a product of the heme oxygenase, an evolutionarily conserved cellular cytoprotectant. Increased levels of local carbon monoxide arising from heme oxygenase activity may increase L-lactate, but direct measurements of cytosolic L-lactate are lacking. A fluorescence resonance energy transfer-based nanosensor selective for L-lactate was used to monitor cytosolic levels of L-lactate while cultured astrocytes were exposed to carbon monoxide. The results revealed that in astrocytes exposed to carbon monoxide there is no significant increase in L lactate, however, when noradrenaline, a potent glycogenolytic agent, is applied, cytosolic levels of Llactate are increased, but strongly attenuated in astrocytes pretreated with carbon monoxide. These first measurements of carbon monoxide modulated L-lactate levels in astrocytes provide evidence that the L-lactate and heme oxygenase neuroprotective systems may interact. In conclusion, not only the abundance of astrocytes but their signalling capacity using vesicles and metabolites, such as L-lactate, are valid targets for neurological disorders. PMID- 28641548 TI - Pediatric Cutaneous Graft Versus Host Disease: A Review. AB - BACKGROUND: Graft versus host disease (GVHD) is a significant complication following hematopoietic stem cell transplantation in the pediatric population. The most common clinical manifestation of GVHD is in the skin. This article will present a review of key concepts related to pediatric cutaneous GVHD, including pathophysiology, clinical epidemiology, diagnosis, and treatment options. OBJECTIVE: GVHD is an immune-mediated process characterized by an inflammatory immune response in acute GVHD and mixed inflammatory and fibrotic states in chronic GVHD. The clinical presentations of cutaneous GVHD are heterogeneous. METHOD: Acute cutaneous GVHD classically presents as an erythematous morbilliform eruption appearing within a few weeks after transplantation. Chronic cutaneous GVHD may manifest as poikiloderma, lichenoid lesions, or sclerodermatous changes. The sclerodermatous form of cutaneous GVHD is associated with substantial long term morbidity, including joint contractures, myalgias, and mobility restriction. RESULTS: First-line pharmacologic treatment options typically include corticosteroids and in some cases, calcineurin inhibitors. Biologics and immunotherapies are an active area of investigation for GVHD that is refractory to corticosteroid treatment. Non-pharmacologic treatment options that have shown benefit for cutaneous GVHD include extracorporeal photopheresis and phototherapy. CONCLUSION: Accurate diagnosis and treatment of cutaneous GVHD is essential to preventing and alleviating the long-term sequelae and morbidity associated with this condition. PMID- 28641547 TI - Recent Advances on the Role of microRNAs in both Insulin Resistance and Cancer. AB - BACKGROUND: Insulin resistance is a pathological condition characterized by the failure of target cells to uptake and metabolize glucose in response to insulin. In particular, the elevated concentrations of glucose, insulin and free insulin growth factor-1, which result from insulin resistance, may generate a pro inflammatory and protumorigenic state. These alterations may underlie the increased risk to develop various types of cancer as well as the worse cancer prognosis observed in obese and diabetic patients. MicroRNAs are short molecules of noncoding endogenous RNA, which are involved in several physio-pathological conditions like glucose homeostasis, lipid metabolism, insulin signaling and resistance. MicroRNAs play also a crucial role in tumorigenesis, acting as oncomirs or tumor suppressors depending on the cell context. METHODS: Here, we recapitulate the role of certain microRNAs that are associated with both insulin resistance and cancer, and discuss their potential to be considered as therapeutic targets. RESULTS: Several studies have highlighted the action of diverse microRNAs in the aforementioned disorders. For instance, three microRNA clusters namely miR-103/107, miR-221/222 and miR-29 have been found to be upregulated in insulin resistance and certain types of cancer. These microRNAs have been shown to target genes like PTEN, Dicer and caveolins that are largely involved in important processes relevant to both insulin resistance and cancer. CONCLUSION: Certain microRNAs may represent potential drug targets common to both insulin resistance and cancer. In particular, the inhibition of miR-103/107, miR 221/222 and miR-29 may be taken into account in novel pharmacological approaches aiming to treat these two disorders. PMID- 28641549 TI - Relevance of Cat and Dog Sensitization by Skin Prick Testing in Childhood Eczema and Asthma. AB - BACKGROUND: Household animal dander has been implicated as aeroallergen in childhood atopic diseases. Many parents seek healthcare advice if household pet keeping may be detrimental in atopic eczema (AE), allergic rhinitis and asthma. AIM: We investigated if skin sensitization by cat/dog dander was associated with disease severity and quality of life in children with AE. METHODS: Demographics, skin prick test (SPT) results, disease severity (Nottingham eczema severity score NESS), Children Dermatology Life Quality Index (CDLQI), blood IgE and eosinophil counts of a cohort of AE patients were reviewed. RESULTS: 325 AE patients followed at a pediatric dermatology clinic were evaluated. Personal history of asthma was lowest (20%) in the dog-dander-positive-group but highest (61%) in bothcat- and-dog-dander-positive group (p=0.007). Binomial logistic regression ascertained that catdander sensitization was associated with increasing age (adjusted odds ratio [aOR], 1.056; 95% Confidence Interval [CI], 1.006 to 1.109; p=0.029), dust-mite sensitization (aOR, 4.625; 95% CI, 1.444 to 14.815; p=0.010), food-allergen sensitization (aOR, 2.330; 95% CI, 1.259 to 4.310; p=0.007) and keeping-cat-ever (aOR, 7.325; 95% CI, 1.193 to 44.971; p=0.032); whereas dogdander sensitization was associated with dust-mite sensitization (aOR, 9.091; 95% CI, 1.148 to 71.980; p=0.037), food-allergen sensitization (aOR, 3.568; 95% CI, 1.341 to 9.492; p=0.011) and keeping-dog-ever (aOR, 6.809; 95% CI, 2.179 to 21.281; p=0.001). However, neither cat nor dog sensitization were associated with asthma, allergic rhinitis, parental or sibling atopic status, disease severity or quality of life. CONCLUSION: Physicians should advise parents that there is no direct correlation between AE severity, quality of life, asthma or allergic rhinitis with cutaneous sensitization to cats or dogs. Sensitized patients especially those with concomitant asthma and severe symptoms may consider non furry alternatives if they plan to have a pet. Highly sensitized individuals, especially those with asthma co-morbidity, may have to remove their pet for a trial period to determine if symptoms improve. PMID- 28641550 TI - Bier Spots - Report of Two Cases and Review of the Literature. AB - BACKGROUND: Bier spots are asymptomatic white anemic macules with irregular shape located on the upper limbs and less often on the lower limbs and trunkus. They are observed predominantly in youg males and may be idiopathic or associated with other conditions. OBJECTIVE: We report two cases with Bier spots in which videodermatoscopy and nailfold capillaroscopy were performed. RESULTS: Patient 1 was a 34-year-old otherwise healthy male who presented with white spots on his upper limbs for 10 years. Dermoscopy revealed marked narrowing of skin capillaries within the borders of white macules whereas capillaroscopy pattern was normal. Patient 2 was a 20-year-old female with symptoms of Raynaud's phenomenon who presented with white spots on the volar aspects of her hands for 2 years. The capillaroscopy showed abnormal findings with presence of homogenous enlarged capillaries. CONCLUSION: Bier spots do not require any treatment. The associated conditions found should be monitored. PMID- 28641551 TI - Nailfold Capillaroscopy Within and Beyond the Scope of Connective Tissue Diseases. AB - BACKGROUND: Nailfold capillaroscopy is a noninvasive instrumental method for morphological analysis of the nutritive capillaries in the nailfold area. In rheumatology, it is a method of choice among instrumental modalities for differential diagnosis between primary and secondary Raynaud's phenomenon (RP) in systemic rheumatic diseases. RP is a common diagnostic problem in rheumatology. Defining the proper diagnosis is a prerequisite for administration of the appropriate treatment. Thus, nailfold capillaroscopic examination is of crucial importance for the every-day practice of the rheumatologists and is currently gaining increasing attention. The most specific capillaroscopic changes are observed in Systemic Sclerosis (SSc). Due to the high prevalence of the capillaroscopic changes in this clinical entity and their early appearance, they could be used for early and very early diagnosis of the disease. More recently, "scleroderma" type capillaroscopic changes have been defined as diagnostic criterion in the new EULAR/ACR classification criteria for SSc together with the presence of scleroderma-related autoantibodies, RP, telangiectasia and other clinical signs. Capillaroscopic changes in other connective tissue diseases and in different rheumatic-like conditions like those in diabetes mellitus (e.g., diabetic stiff-hand syndrome) and paraneoplastic syndromes associated with microvascular pathology should be interpreted properly in order to obtain precise diagnosis in the shortest possible differential diagnostic process. PMID- 28641552 TI - A Review of the Psychometric Properties and Use of the Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) in Clinical Research. AB - BACKGROUND: Several Patient-Reported Outcome Measures (PROMs) have been used in studies of Rheumatoid Arthritis (RA). Most of these assess Health-Related Quality of Life (HRQL). The exception is the Rheumatoid Arthritis Quality of Life questionnaire (RAQoL). This scale measures the impact of RA and its treatment from the patient's perspective, making it suitable for determining the value patients gain from interventions. OBJECTIVE: This review collates literature reporting on the efficacy of the RAQoL as a measure of patient value in clinical studies. METHOD: A literature search was conducted to identify published articles reporting on the use of the RAQoL. Psychometric and clinical research studies were included in the review. RESULTS: Sixty-three full articles were identified. Psychometric analyses demonstrated that the RAQoL meets the requirements for internal consistency, reproducibility and construct validity. There is evidence to support the unidimensionality and responsiveness of the RAQoL. The measure has been used in a wide range of research studies including interventional, correlational and nonexperimental studies. Several studies found the RAQoL to be sensitive to change following interventions. CONCLUSION: The RAQoL has excellent psychometric properties and can detect the impact of both clinical and non clinical interventions. As a patient-centric measure of patient value, the RAQoL will also prove valuable in big data analytics and for use in outcomes-based reimbursement (OBR). PMID- 28641553 TI - Capillaroscopy in Routine Diagnostics: Potentials and Limitations. AB - BACKGROUND: Nailfold capillaroscopy is a safe and useful investigational tool that allows an early detection and a qualitative description of the microvascular abnormalities in patients with Raynaud's phenomenon secondary to scleroderma spectrum disorders. Nowadays, the role of capillaroscopy in the diagnosis of systemic sclerosis is well known. Capillaroscopy has been included in the new 2013 classification criteria for systemic sclerosis and is considered a key investigation in the very early phases of the disease. CONCLUSION: Because of its potential value in monitoring disease progression and treatment response, nailfold capillaroscopy may also have a role in the management of overt systemic sclerosis. RESULTS: Its application in scleroderma-spectrum disorders in which a microvascular component is suspected may also provide new insights into their pathophysiology. PMID- 28641554 TI - Future of Spermatogonial Stem Cell Culture: Application of Nanofiber Scaffolds. AB - BACKGROUND: Spermatogonial stem cells (SSCs) are unique in mammals because they can transmit genetic information from generation to generation and it is of significant importance. In testes, Sertoli cells, peritubular myoid cells, Leydig cells and other interstitial cells contribute to the spermatogonial stem cell "niche". So, creation of niche in an in vitro condition that mimics the in vivo environment is essential to maintain functional characteristic of SSCs. OBJECTIVE: In this review, we describe the impact of nanofiber scaffolds on the culture of SSCs derived from human-to-mouse. RESULTS: Nanofiber Matrices mimic the architecture and size scale of the natural extracellular matrix (ECM). The scaffold provides more three-dimensional (3D), biomimicking and topographical signals to the cells and results in a more physiologically relevant cellular phenotype. Several investigators use different nanofiber scaffold-like carbon nanotubes (CNTs) scaffold, poly-L-lactic acid (PLLA) nanofiber scaffold, 3D soft agar culture system, human serum albumin (HSA)/tri calcium phosphate nanoparticles (TCPNPs) and electrospun polyamide nanofiber for proliferation and maintenance of self-renewal activity of the SSCs. CONCLUSION: Application of nanofiber scaffolds for in vitro culture of the SSCs may produce spermatogonial stem cells that can be used in regenerative medicine, tissue engineering, assisted reproductive technology and in the treatment of infertility in pre pubertal cancer patients. PMID- 28641555 TI - Supervised Machine Learning Methods Applied to Predict Ligand- Binding Affinity. AB - BACKGROUND: Calculation of ligand-binding affinity is an open problem in computational medicinal chemistry. The ability to computationally predict affinities has a beneficial impact in the early stages of drug development, since it allows a mathematical model to assess protein-ligand interactions. Due to the availability of structural and binding information, machine learning methods have been applied to generate scoring functions with good predictive power. OBJECTIVE: Our goal here is to review recent developments in the application of machine learning methods to predict ligand-binding affinity. METHOD: We focus our review on the application of computational methods to predict binding affinity for protein targets. In addition, we also describe the major available databases for experimental binding constants and protein structures. Furthermore, we explain the most successful methods to evaluate the predictive power of scoring functions. RESULTS: Association of structural information with ligand-binding affinity makes it possible to generate scoring functions targeted to a specific biological system. Through regression analysis, this data can be used as a base to generate mathematical models to predict ligandbinding affinities, such as inhibition constant, dissociation constant and binding energy. CONCLUSION: Experimental biophysical techniques were able to determine the structures of over 120,000 macromolecules. Considering also the evolution of binding affinity information, we may say that we have a promising scenario for development of scoring functions, making use of machine learning techniques. Recent developments in this area indicate that building scoring functions targeted to the biological systems of interest shows superior predictive performance, when compared with other approaches. PMID- 28641556 TI - Pharmacogenetic and Pharmacokinetic Dose Individualization of the Taxane Chemotherapeutic Drugs Paclitaxel and Docetaxel. AB - BACKGROUND: The taxane drugs paclitaxel and docetaxel, widely used on cancer chemotherapy, are currently dosed mainly based on body-surface area. This approach is associated with wide interindividual variability in drug exposure, leading to suboptimal dosing for many patients. METHODS: The available evidence supporting dose individualization strategies for paclitaxel and docetaxel were reviewed, focusing mainly on the application of therapeutic drug monitoring by a priori pharmacogenetic data or a posteriori drug measurements in biological fluids. The PubMed database was searched, in the period of 1987-2017, using the keywords pharmacogenetics, metabolic genotyping, dose individualization, therapeutic drug monitoring, personalized medicine, taxanes paclitaxel and docetaxel, either alone or in combination. RESULTS: The current knowledge of pharmacology of the taxane drugs paclitaxel and docetaxel, mainly its pharmacokinetics and the proteins responsible for their biotransformation and transport, along with the genetic polymorphism responsible for variations in the activities of these proteins, opens new opportunities for dose selection for individual patients. CONCLUSION: Considering the relation between systemic exposure to these drug and clinical responses, a posteriori TDM, with measurement of drug concentrations in plasma of treated patients, is currently the most straightforward approaches for dose individualization of paclitaxel and docetaxel. PMID- 28641557 TI - Cyclic Dipeptides: Secondary Metabolites Isolated from Different Microorganisms with Diverse Biological Activities. AB - Cyclic dipeptides are the simplest peptide derivatives commonly found in nature. These chiral molecules are easily synthesized from readily available alpha-amino acids using a simple methodology. They are privileged structures with the ability to bind to a wide range of receptors and have a broad variety of biological and pharmacological activities. We will give a brief overview of their status giving and interesting reference list about the last works. PMID- 28641558 TI - Bis(2-aminoimidazolines) and Bisguanidines: Synthetic Approaches, Antiparasitic Activity and DNA Binding Properties. AB - BACKGROUND: Parasitic diseases caused by protozoan parasites of the genus Trypanosoma and Plasmodium cause some of the deadliest and disabling human infections in tropical and subtropical areas. Diphenyl-based bis(2 phenylimino)imidazolidines and bisguanidines are extremely potent antiparasitic agents against Trypanosoma brucei (etiological agent of African trypanosomiasis) and Plasmodium falciparum (etiological agent of severe malaria). Many of these compounds are also curative in mouse models of stage 1 African trypanosomiasis representing promising leads for the development of antitrypanosomal drugs. In addition, different classes of bis(2-iminoimidazolidines) and bisguanidines have been shown to have antimicrobial activity against other pathogens (e.g. bacteria, fungi, parasitic worms). Due to their structural and physicochemical properties, these dibasic compounds, which are dications at physiological pH, are prone to bind to the minor groove of DNA at AT-rich sites. In several cases, such interaction is thought to be responsible for their antimicrobial activity. RESULTS: In this review, we give a comprehensive view of the synthetic methods used to introduce the 2-aminoimidazoline scaffold in a molecule. Synthetic routes that give access to these cyclic guanidines (i.e. unsubstituted, 1-, 4-, and 5 substituted 2-aminoimidazolines) are detailed. The in vitro and in vivo antiprotozoal activity of bis(2-aminoimidazolines) and bisguanidines against kinetoplastid parasites (T. brucei, T. cruzi, Leishmania), Plasmodium spp. and other pathogens (e.g. ESKAPE bacteria, Candida spp., M. tuberculosis, E. multilocularia) is also reviewed. Finally, the targets that are involved in the antimicrobial activity (e.g. DNA) or other biological activities (e.g. alpha adrenergic receptors, imidazoline binding sites, kinases) of this class of dicationic compounds are discussed. PMID- 28641559 TI - A Stepwise Approach for the Isolation and the Identification of Chemically Reactive Exofacial Protein Thiols. AB - BACKGROUND: The plasma membrane controls the selective internalization of (macro)molecules through different mechanisms, often relaying on specialized outward-facing carriers such as exofacial proteins thiols (EPTs). Although the interchange of critical thiols and disulphides between EPTs and exogenous cargoes is the first critical event, the identification of specific cell interactors remains to be thoroughly explored. Besides, it is likewise evident that only the relatively little suite of EPTs truly reactive can be considered theranostic targets. OBJECTIVE: We were aimed at developing a stepwise procedure for the isolation and identification of a subset of EPTs, that we named chemically reactive EPS, which are potential theranostic targets. METHOD: In the present study, EPTs that displayed permissive sulfhydryls on the surface of live cells in vitro underwent i) chemo-selective capture by means of thiolated superparamagnetic microbeads (isolation step), followed by ii) their prompt release via disulphide breakage through the addition of DTT reducing agent (elution step) and iii) analysis by means of SDS-PAGE and LCMS/ MS (identification step). RESULTS: In total cell lysates, most of the proteins recovered were intracellular. Conversely, this methodology allowed a 2.6-fold enrichment in chemically reactive EPTs recovered and identified, corresponding up to 37% of the total cellular proteins. The key element of our approach was the reversible chemo-selective capture through disulphide linkages between chemically reactive EPTs and free thiols on microbeads. CONCLUSION: We devised an enabling methodology to selectively pick up, recover and characterize chemically reactive EPTs. PMID- 28641560 TI - Functional and Catalytic Characterization of the Detoxifying Enzyme Haloalkane Dehalogenase from Rhizobium leguminosarum. AB - BACKGROUND: Haloalkane dehalogenases (EC 3.8.1.5, HLDs) are alpha/beta-hydrolases which catalyze the irreversible cleavage of carbon-halogen bonds of haloalkanes, producing an alcohol, a halide and a hydrogen ion. Haloalkanes are acutely toxic to animals and humans and their toxic effects are mainly observed in the liver, kidneys and central nervous system. OBJECTIVE: In the present work, the haloalkane dehalogenase from Rhizobium leguminosarum bv. trifolii (DrlA) was characterized. METHOD: Reverse transcription polymerase chain reaction analysis and enzyme activity assays revealed that the DrlA gene expression in R. leguminosarum bv. trifolii is induced by 1,2- dibromoethane (1,2-DBE) during the early exponential phase. The gene of the enzyme was isolated, cloned and expressed in E. coli Rosetta (DE3). RESULTS: Recombinant DrlA displays its high catalytic activity towards 1,2-DBE and the long-chain haloalkane 1-iodohexane. Limited activity was observed for other aliphatic and cyclic haloalkanes, indicating that the enzyme displays restricted substrate specificity, compared to other bacterial HLDs. Homology modelling and phylogenetic analysis suggested that the enzyme belongs to the HLD-II subfamily and shares the same overall fold and domain organization as other bacterial HLDs, however major variations were identified at the hydrophobic substrate-binding cavity, the cap domain and the entrance of the main tunnel that affect the size of the active site pocket and the substrate recognition mechanism. CONCLUSION: This work sheds new light on the environmental fate and toxicity of 1,2-DBE and provides new knowledge on the structure, function and diversity of HLDs for developing applications in toxicology. PMID- 28641561 TI - Induction of Humoral and Cellular Immune Responses in Mice by Multiepitope Vaccines Composing of Both T and B Lymphocyte Epitopes of MAGE-A3 which are Recombined into HBcAg. AB - BACKGROUND: Melanoma-associated antigen-A3 (MAGE-A3) is a tumor specific antigen and a potential candidate for cancer immunotherapy. We had screened three immunodominant multiepitopes of MAGE-A3, and identified these multiepitope peptides had significantly higher reactivity to serum samples from gastric cancer patients. However, the immune responses of three multiepitope peptides carried by HBcAg in mice have not been investigated. OBJECTIVES: The main objective of this study was to analyze the humoral and cellular immune responses in mice induced by these three multiepitope vaccines of MAGE-A3. METHODS: Three multiepitopes of MAGE-A3 (MAGE-A3(EPI-1, or -2, or -3)) were respectively inserted at HBcAg major immunodominant region (HBcAg(MIR)) of the pET21a(+)/HBcAg(MIR) recombinant plasmid. These recombinant chimeras were identified by PCR, and transfected respectively into E. Coli Ressotta strain. The expression products of rHBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) were purified respectively by Ni2+ chelated affinity column, and then confirmed by SDS-PAGE and Western-blot analysis.Purified three rHBcAg(MIR)/MAGE-A3 multiepitopes were administrated respectively into BALB/c (H-2Kd) mice by intradermal injection. The production of rHBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) specific IgG in serum from immunized mice were measured by ELISA. Spleen cells from all immunized mice were harvested after one week of last immunization for lymphocyte proliferation assay and cytotoxic T-lymphocyte assay. RESULTS: PCR and Sequencing analysis showed the presence of the required gene fragment in pET21a(+)/ HBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) recombinant plasmid. Purified rHBcAg(MIR)/MAGE-A3(EPI-1, or -2, or -3) could be probed specifically by McAb of 6*his-tag. ELISA analysis indicated that serum from immunized mice with rHBcAg(MIR)/MAGE-A3(EPI-1, -2, or -3) proteins could be discerned specifically by complete MAGE-A3 protein, and high level of antibodies in immune serum were obtained, and all antibody titers could reach above 1:1600. The splenocytes from groups of rHBcAg(MIR)/MAGE-A3(EPI-1,-2, or 3), stimulated respectively with corresponding peptides showed the higher proliferative responses comparing with control groups of HBcAg(MIR) or PBS (p<0.05, respectively). Splenocytes from mice immunized with rHBcAg(MIR)/MAGE-A3 (EPI-1, or -2, or -3) could killed target cells effectively, and there were significant difference of CTL activities compared with control groups of HBcAg(MIR), or PBS (p<0.05, respectively) at any ratio of effector : target. CONCLUSION: Our results indicated MIR in HBcAg presenting platform could present MAGE-A3 multiepitopes efficiently and induced significant humoral or cellular immunity. The immune strategy based on multiepitopeimmunization could have potential for preventing or controlling MAGE-A3 associated malignant disease. PMID- 28641562 TI - Structural Characterization of Amyloid beta17-42 Dimer by Potential of Mean Force Analysis: Insights from Molecular Dynamics Simulations. AB - BACKGROUND: Recent experiments with Amyloid beta1-42 peptide have indicated that the initial dimerization of Abeta1-42 monomers to form amyloid dimers stand out as a key event in the generation of toxic oligomers. However, the structural characterization of Abeta1-42 dimer at the atomistic level and the dimerization mechanism by which Abeta1-42 peptides co-aggregate still remains not clear. OBJECTIVE: In the present study, the process of Abeta17-42 peptide dimerization which is known to play an important role in the plaque formation in Alzheimer's disease was evaluated in terms of potential of mean force. METHODS: The Abeta17 42 dimer was constructed using PatchDock server. We have used molecular dynamics (MD) simulation with the umbrella sampling methodology to compute the Potential of Mean Force for the dimerization of Abeta17-42. The global minima structure at the minimum distance of separation was isolated from the calculated free energy profile and the interactions involved in the formation of the dimer structure were examined. Protein-protein interfaces and the residueresidue interactions vital for generation of the dimer complexes were also evaluated. RESULTS: The simulation results elucidated the interaction between the monomeric units to be governed primarily by the hydrophobic and hydrogen bonds. The resultant Abeta17 42 dimer was found to have an increased beta-strands propensity at the hydrophobic regions encompassing the CHC region. Furthermore, specific hydrophobic residues were found to play a vital role in the formation of the dimer complex. CONCLUSION: From the results we may therefore conclude hydrophobic region encompassing the CHC region to be crucial in dimerization process. The findings from this study provide detailed information for the complex process of early events of Abeta aggregation. PMID- 28641563 TI - Pentapeptide Prosequence Enhances Expression and Structure Folding of Recombinant Thermomyces lanuginosus Lipase in Pichia pastoris. AB - BACKGROUND: Propeptides of lipases have been demonstrated to influence many properties of their mature proteins as intramolecular chaperones. However, the working mechanism of propeptides may be different. OBJECTIVES: The main objective of this study was to determine the role of pentapeptide prosequence of Thermomyces lanuginosus lipase (TLL) through its effect on the recombinant expression of TLL in P. pastoris, and explore the possible function mechanism with its hydrophobicity. METHODS: We have synthesized a codon-optimized TLL gene coTLL with a Kex2 cleavage site "- KREAEA-" directly after the propeptide "SPIRR ", and obtained expression vector pP-kTL through cloning it into pPIC9K. TL gene without the propeptide and pTL gene with a propeptide directed linked to mature TLL lipase, were also amplified and cloned into pPIC9K to obtain the expression vector pP-TL and pP-pTL. pTL-P and pTL-VP gene variants with mutation in pentapeptide prosequence of TLL were obtained used the site-directed mutation with the pP-pTL plasmid as the template. The recombinant proteins were expressed in P. pastoris GS115. Lipase activity was determined by a spectrophotometric method previously reported using para-nitrophenyl palmitate (pNPP) as the substrate and the thermostability of lipases of TLL was analyzed by incubating at different temperatures (70 degrees C and 80 degrees C) for 5h and molecular dynamics simulation. RESULTS: The average lipase activity of recombinant strains GS-pTL reached 434.32 U/mL, higher than that of GS-TL 377.71 U/mL. The fermentation result of the recombinant strains with modified propeptide showed that the extracellular lipase activity of GS-pTL-VP variant reached 483.29 U/mL, increasing by 11.27% compared with that of GS-pTL (434.32 U/mL). Further analysis performed on the lipase stabilities with propeptide variants by molecular dynamics simulation showed that the RMSD of variant pTL-VP was similar to that of pTL. CONCLUSION: This study revealed that the propeptide "SPIRR-" sequence is beneficial for enhancing TLL expression. In addition, the function of TLL propeptide was identified to be related to its hydrophobicity, implying that propeptide might play a role in assisting the formation of the hydrophobic protein core and accelerate the protein folding process. This work inspired us to attach more emphasis on the propeptide of other lipases for improving their recombinant expression, structure folding and enzymatic properties. PMID- 28641564 TI - Investigation on the Interaction of Pseudomonas syringae Effector AvrPto with AtRabE1d GTPase. AB - BACKGROUND: The tomato bacterial speck is a worldwide disease. It is caused by the infection of pathogenic Pseudomonas syringae pv. tomato which delivers the effector AvrPto into the host cells via the type III secretion system. AvrPto interacts with a Rab8 subfamily protein in the GTP-bound form and participates in the response to pathogen infection, but the pathogenic mechanism involved remains elusive. OBJECTIVES: The main objective of this study was to investigate on the interrelationship of AvrPto with AtRabE1d and Pto, which would allow us to have a deeper understanding of the pathogen mechanism of bacterial speck mediated by avirulent AvrPto and provides theoretic support for the prevention and cure of tomato bacterial speck disease. METHODS: AvrPto8-159 and AtRabE1d13-185Q74L proteins were expressed in Escherichia coli expression system, purified via nickel affinity chromatography and size exclusion chromatography, and identified by SDS-PAGE. The interaction of AvrPto8-159 with AtRabE1d13-185Q74L was confirmed in vitro based on the fluorescence resonance energy transfer. In addition, the affinity of AvrPto8-159 with AtRabE1d13-185Q74L:GTP was determined using the fluorescence polarization based equilibrium titration. The comparison of the complex structural model of AtRabE1d with AvrPto, which was docked and refined by Patchdock and FireDock softwares. RESULTS: AvrPto8-159 and AtRabE1d13-185Q74L can be expressed and purified well in E.coli. FRET between AvrPto8-159 with GFP-tag and mantGTP-load AtRabE1d13-185Q74L was observed slightly in vitro for the first time. On the other hand, deploying DsRed of AtRabE1d13-185Q74L as FRET partner with GFP, AvrPto was shown to interact with AtRabE1d more significantly with increasing concentrations of DsRed-AtRabE1d13-185Q74L. The equilibrium dissociation constant of AvrPto8-159 with AtRabE1d13-185Q74L:GTP was determined to be 13.5 MUM. CONCLUSION: This work reports preparation and interaction of AvrPto8-159 with AtRabE1d13- 185Q74L. AvrPto8-159 exhibited medium affinity with AtRabE1d13-185Q74L based on the fluorescence polarization. From the structural model of the complex AvrPto:AtRabE1d, AvrPto interacted with AtRabE1d and Pto proteins with completely different biding sites. PMID- 28641565 TI - D-Amino Acid Analogues of the Antimicrobial Peptide CDT Exhibit Anti- Cancer Properties in A549, a Human Lung Adenocarcinoma Cell Line. AB - INTRODUCTION: The importance of the antitumor activity of some antimicrobial peptides (AMPs) is being increasingly recognized. The antimicrobial peptide, tachyplesin, has been shown to exhibit anticancer properties and a linear, cysteine deleted analogue (CDT), was found to retain its antibacterial function. OBJECTIVES: The objective was to test CDT and related analogues against normal mammalian, bacterial, and cancer cells to determine their effectiveness and then utilize specific assays to determine a possible mechanism of action. METHODS: We used sequence reversal and D-amino acids to synthesize four CDT analogues by solid phase peptide synthesis. A number of assays were used including liposome dye-leakage, antibacterial activity against both Gram-positive and Gram-negative bacterial strains, hemolytic assays, methyl thiazolyl tetrazolium (MTT), and apoptosis to examine their effectiveness as both AMPs and anti-cancer peptides (ACPs). We then tested the analogues for their ability to inhibit proliferation of the human lung cancer cell line, A549. RESULTS: We found that D-CDT exhibited the best bactericidal properties of those tested and was not damaging to red blood cells. Both D-CDT and reverse D-CDT showed a dose-dependent reduction of cell viability. However, D-CDT was most effective with an IC50 of 9.814 MUM, a value 9-fold lower than that calculated for reverse D-CDT (90.16 MUM). Apoptosis does not appear to be a mechanism by which D-CDT exerts its anticancer properties since > 100 MUM was required to increase activation of caspase 3. Moreover, the ERK1/2 pathway is also unlikely since only a modest (20%) decrease of activity was observed with > 100 MUM D-CDT. However, D-CDT was found to operate via a hyaluronan (HA)-dependent mechanism as pretreatment of the cells with hyaluronidase decreased the cytotoxic effects of D-CDT on A549 cells and increased its IC50 29-fold to 283.9 MUM. CONCLUSION: D-CDT is both an effective AMP and ACP, and likely exerts its anticancer effects through both membranolytic as well as an HA-mediated mechanism. PMID- 28641566 TI - Is it Possible to Treat Osteosarcoma Using Oligonucleotides Confined into Controlled Release Drug Delivery Systems? AB - PURPOSE: The present study aimed to analyze the researches that are at the experimental phase concerning osteosarcoma treatment. The researches included drug delivery systems which allow controlled release and imbue small interfering /micro- ribonucleic acid. METHODS: Without any language preference, we searched US National Library of Medicine National Institutes of Health, Embase, OVID, Cochrane Library database of clinical trials from 1843 to May 25, 2016 and traced all the references of incorporated documents. The data were evaluated using descriptive statistics and the results are shown as frequency (%). RESULTS: We haven't encountered any drug delivery system in which Small interfering ribonucleic acid/ micro ribonucleic acid oligonucleotides were embedded successfully against osteosarcoma. There has been only one research in which hairpin-ribonucleic acid was embedded. CONCLUSION: It was considered that drug delivery system enabling controlled oligonucleotide release in the treatment period of osteosarcoma was not projected for the clinical use. However, it cannot be neglected that the mentioned experimental studies with regard to osteosarcoma treatment establish the basis of target therapies. The method in question looks promising regarding effective treatment of osteosarcoma in the future. PMID- 28641567 TI - Contribution and Value of Biomarkers in Acute Aortic Syndromes. AB - BACKGROUND: Acute aortic syndromes, being mostly underdiagnosed due to unspecific symptoms, are associated with high morbidity and mortality. Diagnosis carried out by transesophageal echocardiography, computed tomography and magnetic resonance imaging. However, there are lots of biochemical assays being investigated, but none of them used reliably to identify acute aortic syndromes. Biomarkers could accelerate the diagnostic time with cost effective way and could get place in definitive diagnostic algorithm of acute aortic syndrome. This review aims to identify contribution and value of biomarkers in acute aortic syndromes. METHODS: We searched the contribution and value of biomarkers such as D - Dimer, Smooth muscle myosin heavy chain (sm - MHC), Calponin, and Soluble elastin fragments (sELAF) in acute aortic syndromes at the literature. RESULTS: Twenty two actual papers were included in this review for searching the contribution and value of biomarkers in the acute aortic syndromes. CONCLUSION: Biomarkers accelerate the diagnosis and direct patients to imaging modalities with a risk classification. Plenty of biomarkers have been investigated so far but none of them were used in clinical routine. Currently none of the biomarkers can reliably identify acute aortic syndromes. Each of them has some limitation in term of sensitivity or specificity. Although, there is no single biomarker that can be safely used but a combination of the assays may increase the sensitivities and specificities. PMID- 28641568 TI - An Expanding Role of Biomarkers in Pulmonary Arterial Hypertension. AB - BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a chronic disease which may cause or result from multiple cardiopulmonary disorders. The disease has complex pathophysiological mechanisms and involves many systematic, cellular and molecular changes. Therefore, it is crucial to find out underlying mechanisms and detect biomarkers to achieve early and proper diagnosis, evaluating disease severity, for follow-up and monitor response to treatment. Many biomarkers for PAH have been investigated but yet no such biomarker has been found specific and easily accessible to use for the patients. This review aims to identify an expanding role of biomarkers in PAH. METHOD: We searched an expanding role of biomarkers such as asymmetric dimethylarginine (ADMA), von Willebrand factor (vWF) and endothelin for PAH in the literature. RESULTS: Thirty-four actual papers were included in this review for searching an expanding role of biomarkers in the PAH. CONCLUSION: The search for a proper biomarker for PAH patients is an ongoing process. Currently we do not have a PAH-specific, easily accesible, low priced biomarker for PAH patients. One of the reasons of that is that PAH has a complex etiology and the diesase eventually alters multiple systems. So far, only BNP/NT-proBNP has been mainly approved and widely used for risk assesment in patients with PAH. Ongoing studies, development in the technology and understanding the underlying mechanisms in the pathophysiology of PAH, will eventually lead us to find proper biomarker(s), for PAH, which will also improve patient outcomes and decrease treatment costs in PAH. PMID- 28641569 TI - A Review on Defects of Dendritic Cells in Common Variable Immunodeficiency. AB - BACKGROUND AND OBJECTIVES: Common variable immunodeficiency (CVID) is the most important primary disorder that is associated with clinical complications including recurrent infections, malignancy and autoimmune diseases. The genetic cause of CVID is mostly unknown and only a few genetic causes are identified. The various options are proposed for determining the etiology of CVID patients, such as T- and B-cell defects, Toll-like receptors (TLRs) impairments, altered cytokine production as well as blemished dendritic cells (DCs). The patients with CVID show a reduction in number and frequency of DCs in blood, an altered expression of cell surface molecules, and defective activation through toll-like receptors (TLRs). Also loss of IFNalpha has a critical role in B-cell impairments of CVID patients. The aim of this review is to collect under one umbrella, all the recent knowledge about DCs defects of CVID patients. METHODS: This review covers basic information about physiology of DCs followed by reports of DCs situation in CVID. CONCLUSION: According to the results of researches assessing DCs frequency and function in CVID, the roll of DCs in the pathogenesis of CVID cannot be ruled out. The article is expected to encourage the researchers to do comprehensive researches about complex connections between DCs and other immune cells in CVID. PMID- 28641571 TI - Erratum to: Long-lasting effect of obesity on skeletal muscle transcriptome. PMID- 28641570 TI - 1h Post-load Blood Glucose in the Identification of Proatherogenic Cardiometabolic Profile in Obesity. AB - BACKGROUND AND AIM: Current data show that 1h oral glucose tolerance test (OGTT) blood glucose (1h-BG) might identify persons at increased risk of developing type 2 diabetes and cardiovascular diseases more precisely than fasting blood glucose (FBG) and 2h OGTT blood glucose (2h-BG). The aim of study was to determine whether is justified to use 1h-BG over traditional blood glucose measurements, in cardiometabolic profiling of obese individuals. METHOD: Cross-sectional study enrolled 60 obese individuals without previous history of diabetes and other cardiometabolic disorders. Anthropometrical, ultrasound and laboratory examinations were conducted. RESULTS: All three parameters significantly directly correlated with age, body mass index, waist circumference, erythrocyte sedimentation rate, C-reactive protein, triglycerides and glycated hemoglobin. FBG and 1h-BG significantly directly correlated with alanine transaminase, gammaglutamyltransferase and total cholesterol. FBG significantly directly correlated with fibrinogen and aspartate transaminase, 1h-BG with systolic blood pressure and 2h-BG with diastolic blood pressure. None of parameters significantly correlated with gender, total white blood cell count, uric acid, 25 hydroxyvitamin D, high density lipoprotein cholesterol, low density lipoprotein cholesterol, serum adiponectin and albuminuria. Differences in correlation coefficients were not statistically significant. Individuals with 1h-BG >8.6 mmol/l had much more proatherogenic cardiometabolic profile, as well as higher incidence of dysglycemia, metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) than ones with 1h-BG <8.6 mmol/l, but all differences were driven by the average value of glycemia. There were no statistically significant differences in ability of predicting MetS, NAFLD and pathologically increased carotid artery intima media thickness among analyzed glucose metabolism parameters. CONCLUSION: 1h-BG is not superior to FBG and 2h-BG in the identification of proatherogenic cardiometabolic profile in obesity. PMID- 28641572 TI - A child with hypertension and ambiguous genitalia - an uncommon variant of congenital adrenal hyperplasia: a case report. AB - BACKGROUND: Deficiency in 11beta-hydroxylase as a cause of congenital adrenal hyperplasia is uncommon. It should be considered in the differential diagnosis of hypertension with virilization in any prepubescent child. CASE PRESENTATION: A 12 year-old Asian boy from eastern Nepal presented with pain in his abdomen and hypertension. He was raised as a male but had absent testicles since birth and had precocious puberty. Plasma testosterone, follicle-stimulating hormone, and luteinizing hormone were below baseline level. Basal 17-hydroxyprogesterone was elevated. Magnetic resonance imaging of his pelvis showed presence of Mullerian structures and karyotyping revealed 46,XX genotype. A clinical diagnosis of 11beta-hydroxylase deficiency was made in view of hypertension with severe virilization in a 46,XX individual. Our patient's legal guardian was unwilling for our patient to change gender and because our patient is underage, the condition was well explained to his parents. He was managed with steroids and antihypertensive drugs. He was on regular follow-up; after 2 years there was no hypertension but he developed true puberty with functional ovaries. He was prescribed leuprolide (gonadotropin-releasing hormone analogue), letrozole (aromatase inhibitor), and a continuation of antihypertensive drugs. CONCLUSIONS: This case highlights the importance of a thorough physical examination of the external genitalia at birth and appropriate referral, and addresses issues in the management of such a disorder. Ethical issues pertaining to consent and who is entitled to give it should be clear so that the affected individual will have optimal psychological development and quality of life. PMID- 28641573 TI - Ancient water bottle use and polycyclic aromatic hydrocarbon (PAH) exposure among California Indians: a prehistoric health risk assessment. AB - BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are the main toxic compounds in natural bitumen, a fossil material used by modern and ancient societies around the world. The adverse health effects of PAHs on modern humans are well established, but their health impacts on past populations are unclear. It has previously been suggested that a prehistoric health decline among the native people living on the California Channel Islands may have been related to PAH exposure. Here, we assess the potential health risks of PAH exposure from the use and manufacture of bitumen-coated water bottles by ancient California Indian societies. METHODS: We replicated prehistoric bitumen-coated water bottles with traditional materials and techniques of California Indians, based on ethnographic and archaeological evidence. In order to estimate PAH exposure related to water bottle manufacture and use, we conducted controlled experiments to measure PAH contamination 1) in air during the manufacturing process and 2) in water and olive oil stored in a completed bottle for varying periods of time. Samples were analyzed with gas chromatography/mass spectrometry (GC/MS) for concentrations of the 16 PAHs identified by the US Environmental Protection Agency (EPA) as priority pollutants. RESULTS: Eight PAHs were detected in concentrations of 1-10 MUg/m3 in air during bottle production and 50-900 ng/L in water after 2 months of storage, ranging from two-ring (naphthalene and methylnaphthalene) to four-ring (fluoranthene) molecules. All 16 PAHs analyzed were detected in olive oil after 2 days (2 to 35 MUg/kg), 2 weeks (3 to 66 MUg/kg), and 2 months (5 to 140 MUg/kg) of storage. CONCLUSIONS: For ancient California Indians, water stored in bitumen coated water bottles was not a significant source of PAH exposure, but production of such bottles could have resulted in harmful airborne PAH exposure. PMID- 28641574 TI - Intermittent low platelet counts hampering diagnosis of X-linked thrombocytopenia in children: report of two unrelated cases and a novel mutation in the gene coding for the Wiskott-Aldrich syndrome protein. AB - BACKGROUND: Thrombocytopenia can occur in different circumstances during childhood and although immune thrombocytopenia is its most frequent cause, it is important to consider other conditions, especially when there is a persistent or recurrent low platelet count. We report two cases of intermittent thrombocytopenia, previously misdiagnosed as immune thrombocytopenia. CASES PRESENTATION: Both cases described were boys who presented with an intermittent pattern of thrombocytopenia, with a persistently low mean platelet volume. In both patients, peripheral blood smear revealed small platelets and flow cytometry showed low expression of Wiskott-Aldrich syndrome protein (WASP) in leucocytes. Molecular analysis of the first case identified a mutation in exon 2 of the gene coding for WASP, leading to a p.Thr45Met amino acid change and confirming the diagnosis of X-linked thrombocytopenia. In the second case, a novel missense mutation in exon 2 of the gene coding for WASP was detected, which resulted in a p.Pro58Leu amino acid change. CONCLUSION: These two rare presentations of thrombocytopenia highlight the importance of evaluating the peripheral blood smear in the presence of recurrent or persistent thrombocytopenia and show that failing to do so can lead to misdiagnoses. Since thrombocytopenia may be found in pediatric outpatient clinic, increased awareness among general pediatricians will help to improve the differential diagnosis of this condition. PMID- 28641575 TI - Phylogenetic and paleobotanical evidence for late Miocene diversification of the Tertiary subtropical lineage of ivies (Hedera L., Araliaceae). AB - BACKGROUND: Hedera (ivies) is one of the few temperate genera of the primarily tropical Asian Palmate group of the Araliaceae, which extends its range out of Asia to Europe and the Mediterranean basin. Phylogenetic and phylogeographic results suggested Asia as the center of origin and the western Mediterranean region as one of the secondary centers of diversification. The bird-dispersed fleshy fruits of ivies suggest frequent dispersal over long distances (e.g. Macaronesian archipelagos), although reducing the impact of geographic barriers to gene flow in mainland species. Genetic isolation associated with geographic barriers and independent polyploidization events have been postulated as the main driving forces of diversification. In this study we aim to evaluate past and present diversification patterns in Hedera within a geographic and temporal framework to clarify the biogeographic history of the genus. RESULTS: Phylogenetic (biogeographic, time divergence and diversification) and phylogeographic (coalescence) analyses using four DNA regions (nrITS, trnH-psbA, trnT-trnL, rpl32) revealed a complex spatial pattern of lineage divergence. Scarce geographic limitation to gene flow and limited diversification are observed during the early-mid Miocene, followed by a diversification rate increase related to geographic divergence from the Tortonian/Messinian. Genetic and palaeobotanical evidence points the origin of the Hedera clade in Asia, followed by a gradual E-W Asian extinction and the progressive E-W Mediterranean colonization. The temporal framework for the E Asia - W Mediterranean westward colonization herein reported is congruent with the fossil record. Subsequent range expansion in Europe and back colonization to Asia is also inferred. Uneven diversification among geographic areas occurred from the Tortonian/Messinian onwards with limited diversification in the newly colonized European and Asian regions. Eastern and western Mediterranean regions acted as refugia for Miocene and post-Miocene lineages, with a similar role as consecutive centers of centrifugal dispersal (including islands) and speciation. CONCLUSIONS: The Miocene Asian extinction and European survival of Hedera question the general pattern of Tertiary regional extinction of temperate angiosperms in Europe while they survived in Asia. The Tortonian/Messinian diversification increase of ivies in the Mediterranean challenges the idea that this aridity period was responsible for the extinction of the Mediterranean subtropical Tertiary flora. Differential responses of Hedera to geographic barriers throughout its evolutionary history, linked to spatial isolation related to historical geologic and climatic constraints may have shaped diversification of ivies in concert with recurrent polyploidy. PMID- 28641576 TI - Euthanasia for people with psychiatric disorders or dementia in Belgium: analysis of officially reported cases. AB - BACKGROUND: Euthanasia for people who are not terminally ill, such as those suffering from psychiatric disorders or dementia, is legal in Belgium under strict conditions but remains a controversial practice. As yet, the prevalence of euthanasia for people with psychiatric disorders or dementia has not been studied and little is known about the characteristics of the practice. This study aims to report on the trends in prevalence and number of euthanasia cases with a psychiatric disorder or dementia diagnosis in Belgium and demographic, clinical and decision-making characteristics of these cases. METHODS: We analysed the anonymous databases of euthanasia cases reported to the Federal Control and Evaluation Committee Euthanasia from the implementation of the euthanasia law in Belgium in 2002 until the end of 2013. The databases we received provided the information on all euthanasia cases as registered by the Committee from the official registration forms. Only those with one or more psychiatric disorders or dementia and no physical disease were included in the analysis. RESULTS: We identified 179 reported euthanasia cases with a psychiatric disorder or dementia as the sole diagnosis. These consisted of mood disorders (N = 83), dementia (N = 62), other psychiatric disorders (N = 22) and mood disorders accompanied by another psychiatric disorder (N = 12). The proportion of euthanasia cases with a psychiatric disorder or dementia diagnosis was 0.5% of all cases reported in the period 2002-2007, increasing from 2008 onwards to 3.0% of all cases reported in 2013. The increase in the absolute number of cases is particularly evident in cases with a mood disorder diagnosis. The majority of cases concerned women (58.1% in dementia to 77.1% in mood disorders). All cases were judged to have met the legal requirements by the Committee. CONCLUSIONS: While euthanasia on the grounds of unbearable suffering caused by a psychiatric disorder or dementia remains a comparatively limited practice in Belgium, its prevalence has risen since 2008. If, as this study suggests, people with psychiatric conditions or dementia are increasingly seeking access to euthanasia, the development of practice guidelines is all the more desirable if physicians are to respond adequately to these highly delicate requests. PMID- 28641577 TI - A case report of septic shock syndrome caused by S. pneumoniae in an immunocompromised patient despite of vaccination. AB - BACKGROUND AND CASE PRESENTATION: We report a case of septic shock syndrome caused by Streptococcus pneumoniae in a patient who had undergone splenectomy due to an autoimmune lymphoproliferative syndrome (ALPS), which is characterized as a dysfunction of immunoregulation. Although the patient was vaccinated with a conjugated polysaccharide vaccine after the splenectomy, he was still susceptible to S. pneumoniae infection, because the isolated serovar (24F), a serovar long thought to be apathogenic, is not covered by any vaccine currently approved, neither a conjugated nor an unconjugated polysaccharide one. CONCLUSIONS: This case demonstrates that, due to presence of different serovars, also infections with bacteria against which patients are vaccinated have to be considered as differential diagnosis. Although vaccine development has extended the coverage of S. pneumoniae from 7 to 23 serovars within recent years, there is still demand for novel vaccines which can provide broader protection also against so-thought "apathogenic" strains, especially for groups at high risk. PMID- 28641579 TI - LPS alters the immuno-phenotype of glioma and glioma stem-like cells and induces in vivo antitumor immunity via TLR4. AB - BACKGROUND: This study examined the ability of lipopolysaccharide (LPS) to affect glioma and glioma stem-like cells (GSCs) in vitro and to induce antitumor immunity in vivo and the role of TLR4 in these processes. METHODS: Using RT-PCR and immunohistochemistry, we examined the expression of TLR4 in 34 glioblastoma clinical samples. Using real time-PCR, western blot and ELISA analyses, the effect of LPS stimulation on the expression of immune related molecules was evaluated in RG2 and U87 GSCs. Control or LPS-pretreated RG2 GSCs were intracranially or subcutaneously implanted into wild-type or nude Fisher 344 rats. Histopathological examinations were used to assess tumor progression and immune infiltration and Kaplan-Meier analyses to compare survival times of the animal models. RESULTS: TLR4 was highly expressed in glioblastoma clinical samples. In vitro LPS stimulation for 6 h significantly altered expression of immune related molecules in RG2 and U87 GSCs. However, prolonged LPS stimulation diminished this effect. Rats inoculated intracranially with LPS-pretreated RG2 GSCs survived significantly longer than rats inoculated with control RG2 GSCs. In vivo, LPS-pretreated RG2 GSCs expressed higher levels of MHC molecules, CXCL10 and TNF-alpha and recruited more CD8+ lymphocytes. However, intratumoral LPS treatment was not equally beneficial. Furthermore, the in vitro and in vivo effects of LPS stimulation appeared to be largely TLR4-dependent. CONCLUSION: LPS pretreatment promotes the recognition and eradication of tumor GSCs in vivo when the immune function of the tumor-bearing host is intact. In addition, our data indicate a complex relationship between bacterial infection and glioma prognosis. PMID- 28641578 TI - Methylome analysis of extreme chemoresponsive patients identifies novel markers of platinum sensitivity in high-grade serous ovarian cancer. AB - BACKGROUND: Despite an early response to platinum-based chemotherapy in advanced stage high-grade serous ovarian cancer (HGSOC), the majority of patients will relapse with drug-resistant disease. Aberrant epigenetic alterations like DNA methylation are common in HGSOC. Differences in DNA methylation are associated with chemoresponse in these patients. The objective of this study was to identify and validate novel epigenetic markers of chemoresponse using genome-wide analysis of DNA methylation in extreme chemoresponsive HGSOC patients. METHODS: Genome wide next-generation sequencing was performed on methylation-enriched tumor DNA of two HGSOC patient groups with residual disease, extreme responders (>=18 months progression-free survival (PFS), n = 8) and non-responders (<=6 months PFS, n = 10) to platinum-based chemotherapy. DNA methylation and expression data of the same patients were integrated to create a gene list. Genes were validated on an independent cohort of extreme responders (n = 21) and non-responders (n = 31) using pyrosequencing and qRT-PCR. In silico validation was performed using publicly available DNA methylation (n = 91) and expression (n = 208) datasets of unselected advanced stage HGSOC patients. Functional validation of FZD10 on chemosensitivity was carried out in ovarian cancer cell lines using siRNA mediated silencing. RESULTS: Integrated genome-wide methylome and expression analysis identified 45 significantly differentially methylated and expressed genes between two chemoresponse groups. Four genes FZD10, FAM83A, MYO18B, and MKX were successfully validated in an external set of extreme chemoresponsive HGSOC patients. High FZD10 and MKX methylation were related with extreme responders and high FAM83A and MYO18B methylation with non-responders. In publicly available advanced stage HGSOC datasets, FZD10 and MKX methylation levels were associated with PFS. High FZD10 methylation was strongly associated with improved PFS in univariate analysis (hazard ratio (HR) = 0.43; 95% CI, 0.27-0.71; P = 0.001) and multivariate analysis (HR = 0.39; 95% CI, 0.23-0.65; P = 0.003). Consistently, low FZD10 expression was associated with improved PFS (HR = 1.36; 95% CI, 0.99 1.88; P = 0.058). FZD10 silencing caused significant sensitization towards cisplatin treatment in survival assays and apoptosis assays. CONCLUSIONS: By applying genome-wide integrated methylome analysis on extreme chemoresponsive HGSOC patients, we identified novel clinically relevant, epigenetically-regulated markers of platinum-sensitivity in HGSOC patients. The clinical potential of these markers in predictive and therapeutic approaches has to be further validated in prospective studies. PMID- 28641583 TI - PREVALENCE AND RISK FACTORS OF INFERTILITY IN TURKEY: EVIDENCE FROM DEMOGRAPHIC AND HEALTH SURVEYS, 1993-2013. AB - SummaryThe inability to have children affects couples worldwide and causes emotional and psychological distress in both men and women. Turkey is a country that lays particular emphasis on the issue of infertility, especially after experiencing a dramatic fertility decline over the last two decades. This study aimed to understand the changes in the prevalence of infertility in Turkey using three different approaches: the DHS Approach, the Constructed Approach and the Current Duration Approach. Furthermore, the factors contributing to elevated risks of infertility as derived from the Constructed Approach were investigated using four different logistic regression models. The data came from the 1993, 1998, 2003, 2008 and 2013 Demographic and Health Surveys conducted by the Hacettepe University Institute of Population Studies. The findings of the Constructed and Current Duration Approaches suggested that the prevalence of infertility decreased markedly from 1993 to 2013 in Turkey. This decline was the result of improvements in maternal health care services in Turkey, as well as an increase in the use of Assisted Reproductive Technology (ART), from 1.9% in 2008 to 4.1% in 2013. The results of the final logistic regression model suggested that the risk of infertility was significantly higher among women aged between 35 and 49 (p<0.01), uneducated women (p<0.01), women whose age at first marriage was over 30 (p<0.01), women defined as overweight (p<0.05) and women whose age at menarche was less than 12 years (p<0.05). This is the first nationwide study to examine the prevalence of infertility and its socio-demographic risk factors in Turkey, a developing country; previous studies have established these risk factors mainly in developed countries. PMID- 28641580 TI - Marked regional endothelial dysfunction in mottled skin area in patients with severe infections. AB - BACKGROUND: Mottling around the knee, reflecting a reduced skin blood flow, is predictive of mortality in patients with septic shock. However, the causative pathophysiology of mottling remains unknown. We hypothesized that the cutaneous hypoperfusion observed in the mottled area is related to regional endothelial dysfunction. METHODS: This was a prospective, observational study in a medical ICU in a tertiary teaching hospital. Consecutive adult patients with sepsis admitted to ICU were included. After resuscitation, endothelium-dependent vasodilation in the skin circulation was measured before and after iontophoresis of acetylcholine (Ach) in the forearm and the knee area. We analyzed the patterns of induced vasodilatation according to the presence or absence of mottling and vital status at 14 days. RESULTS: We evaluated 37 septic patients, including 11 without and 26 with septic shock. Overall 14-day mortality was 22%. Ten patients had mottling around the knee (10/37, 27%). In the knee area, the increased skin blood flow following iontophoresis of Ach was lower in patients with mottled skin as compared to patients without mottled skin (area under curve (AUC) 3280 (2643 6440) vs. 7980 (4233-19,707), both P < 0.05). In the forearm area, the increased skin blood flow following iontophoresis of Ach was similar in patients with and without mottled skin. Among patients with septic shock, the increased skin blood flow following iontophoresis of Ach in the knee area was significantly lower in non-survivors as compared to survivors at 14 days (AUC 3256 (2600-4426) vs. 7704 (4539-15,011), P < 0.01). In patients with septic shock, the increased skin blood flow in the forearm area following iontophoresis of Ach was similar in survivors and non-survivors at 14 days. CONCLUSION: Mottling is associated with regional endothelial dysfunction in patients with septic shock. Endothelial dysfunction in the knee skin area was more pronounced in non-survivors than in survivors. PMID- 28641581 TI - Thyrotoxic and pheochromocytoma multisystem crisis: a case report. AB - BACKGROUND: Thyrotoxic crisis and pheochromocytoma multisystem crisis are rare, life-threatening, emergency endocrine diseases with various clinical manifestations. Here we report a case of a patient who simultaneously developed thyrotoxic crisis and pheochromocytoma multisystem crisis and required intensive cardiovascular management. CASE PRESENTATION: A 60-year-old Asian man experienced nausea and vomiting, and subsequently developed dyspnea and cold sweats while farming. His serum free thyroxine, free triiodothyronine, and thyrotropin receptor antibody levels were elevated at 2.9 ng/dL, 7.2 pg/dL, and 4.7 IU/L, respectively. Serum thyrotropin levels were suppressed at less than 0.01 MUIU/mL. Thyroid echography demonstrated no thyroid swelling (23 * 43 mm). A whole body computed tomography was performed for systemic evaluation. This revealed exophthalmos and a mass of size 57 * 64 mm in the anterior pararenal space. Based on these findings, we made an initial diagnosis of thyrotoxic crisis secondary to exacerbation of Grave's hyperthyroidism. Treatment was begun with an iodine agent at a dose of 36 mg/day, thiamazole at a dose of 30 mg/day, and hydrocortisone at a dose of 300 mg daily for 3 consecutive days. To control tachycardia, continuous intravenously administered propranolol and diltiazem infusions were given. At the same time, small doses of doxazosin and carvedilol were used for both alpha and beta adrenergic blockade. On hospital day 5, his blood pressure and serum catecholamine concentrations (adrenalin 42,365 pg/mL, dopamine 6409 pg/mL, noradrenalin 72,212 pg/mL) were still high despite higher beta blocker and calcium channel blocker doses. These findings contributed to the diagnosis of pheochromocytoma multisystem crisis with simultaneous thyrotoxic crisis. We increased the doses of doxazosin and carvedilol, which stabilized his hemodynamic status. On hospital day 16, metaiodobenzylguanidine scintigraphy showed high accumulation in the right adrenal gland tumor. After retroperitoneal laparoscopic adrenalectomy on hospital day 33, his condition stabilized. He was discharged on hospital day 58. CONCLUSIONS: Since he required more intensive cardiovascular management for thyrotoxic crisis, beta blockade was increased under intensive care unit monitoring even though initial alpha blockade is recommended in pheochromocytoma. When these crises occur simultaneously, cardiovascular management can be very challenging. PMID- 28641584 TI - Crotoxin stimulates an M1 activation profile in murine macrophages during Leishmania amazonensis infection. AB - American tegumentary leishmaniasis is caused by different species of Leishmania. This protozoan employs several mechanisms to subvert the microbicidal activity of macrophages and, given the limited efficacy of current therapies, the development of alternative treatments is essential. Animal venoms are known to exhibit a variety of pharmacological activities, including antiparasitic effects. Crotoxin (CTX) is the main component of Crotalus durissus terrificus venom, and it has several biological effects. Nevertheless, there is no report of CTX activity during macrophage - Leishmania interactions. Thus, the main objective of this study was to evaluate whether CTX has a role in macrophage M1 polarization during Leishmania infection murine macrophages, Leishmania amazonensis promastigotes and L. amazonensis-infected macrophages were challenged with CTX. MTT [3 (4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide] toxicity assays were performed on murine macrophages, and no damage was observed in these cells. Promastigotes, however, were affected by treatment with CTX (IC50 = 22.86 ug mL 1) as were intracellular amastigotes. Macrophages treated with CTX also demonstrated increased reactive oxygen species production. After they were infected with Leishmania, macrophages exhibited an increase in nitric oxide production that converged into an M1 activation profile, as suggested by their elevated production of the cytokines interleukin-6 and tumour necrosis factor alpha and changes in their morphology. CTX was able to reverse the L. amazonensis mediated inhibition of macrophage immune responses and is capable of polarizing macrophages to the M1 profile, which is associated with a better prognosis for cutaneous leishmaniasis treatment. PMID- 28641582 TI - A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study. AB - BACKGROUND: Convulsive status epilepticus (CSE) is the most common life threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. METHODS/DESIGN: 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. DISCUSSION: This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in children presenting with CSE in whom benzodiazepines have failed. This study will provide the first high quality evidence for management of paediatric CSE post first-line benzodiazepines. TRIAL REGISTRATION: Prospectively registered with the Australian and New Zealand Clinical Trial Registry (ANZCTR): ACTRN12615000129583 (11/2/2015). UTN U1111-1144 5272. ConSEPT protocol version 4 (12/12/2014). PMID- 28641585 TI - Cancer-bereaved siblings' positive and negative memories and experiences of illness and death: A nationwide follow-up. AB - OBJECTIVE: Our aim was to explore bereaved siblings' positive and negative memories and experiences of their brother's or sister's illness and death. METHOD: In our nationwide Swedish study, 174 of 240 (73%) bereaved siblings participated, and 70% responded to two open-ended statements, which focused on siblings' positive and negative memories and experiences of illness and death. The data were analyzed using systematic text condensation. RESULTS: The bereaved siblings' responses were categorized into four different themes: (1) endurance versus vulnerability, (2) family cohesion versus family conflicts, (3) growth versus stagnation, and (4) professional support versus lack of professional support. The first theme expressed endurance as the influence that the ill siblings' strong willpower, good mood, and stamina in their difficult situation had on healthy siblings, whereas vulnerability was expressed as the feeling of emptiness and loneliness involved with having an ill and dying sibling. In the second theme, family cohesion was expressed as the bonds being strengthened between family members, whereas family conflicts often led siblings to feel invisible and unacknowledged. In the third theme, most siblings expressed the feeling that they grew as individuals in the process of their brother's or sister's illness and death, whereas others experienced stagnation because of the physical and mental distress they bore throughout this time, often feeling forgotten. In the last theme-professional support-most siblings perceived physicians and staff at the hospital as being warm, kind, and honest, while some siblings had negative experiences. SIGNIFICANCE OF RESULTS: The study shows that bereaved siblings can have positive memories and experiences. The significance of the positive buffering effect on bereaved siblings' own endurance, personal growth, family cohesion, and social support should be noted. This knowledge can be valuable in showing healthcare professionals the importance of supporting the siblings of children with cancer throughout the cancer trajectory and afterwards into bereavement. PMID- 28641586 TI - Access, Education and Policy Awareness: Predictors of Influenza Vaccine Acceptance Among VHA Healthcare Workers. AB - OBJECTIVE To identify predictors of influenza vaccine acceptance among VHA healthcare workers (HCWs), with emphasis on modifiable factors related to promotion campaigns. DESIGN Survey. SETTING National single-payer healthcare system with 140 hospitals and 321,000 HCWs. PARTICIPANTS National voluntary sample of HCWs in the Veterans Health Administration (VHA) system. METHODS We invited a random sample of 5% of all VHA HCWs to participate. An 18-item intranet based survey inquired about occupation, vaccination status, employer policy, and local campaign efforts. RESULTS The response rate was 17.4%. Of 2,502 initial respondents, 2,406 (96.2%) provided usable data. This sample includes respondents from all 140 VA hospitals. Self-reported influenza vaccination rates were highest among physicians (95.6%) and licensed independent providers (88.3%). Nonclinical staff (80.7%) reported vaccine uptake similar to other certified but nonlicensed providers (81.2%). The strongest predictor of vaccine acceptance among VHA HCWs was individual awareness of organizational policy. Vaccine acceptance was also higher among HCWs who reported more options for access to vaccination and among those in facilities with more education activities. CONCLUSIONS Influenza vaccine acceptance varied significantly by employee awareness of employer policy and on site access to vaccine. Employer-sponsored activities to increase access continue to show positive returns across occupations. Local influenza campaign efforts to educate HCWs may have reached saturation in this target group. These results suggest that focused communications to increase HCW awareness and understanding of employer policy can drive further increase in influenza vaccination acceptance. Infect Control Hosp Epidemiol 2017;38:970-975. PMID- 28641587 TI - Existential isolation. PMID- 28641588 TI - HEALTH TECHNOLOGY PERFORMANCE ASSESSMENT: REAL-WORLD EVIDENCE FOR PUBLIC HEALTHCARE SUSTAINABILITY. AB - OBJECTIVES: Health technology financing is often based on randomized controlled trials (RCTs), which are often the same ones used for licensing. Because they are designed to show the best possible results, typically Phase III studies are conducted under ideal and highly controlled conditions. Consequently, it is not surprising that technologies do not always perform in real life in the same way as controlled conditions. Because financing (and price paid) decisions can be made with overestimated results, health authorities need to ask whether health systems achieve the results they expect when they choose to pay for a technology. The optimal way to answer this question is to assess the performance of financed technologies in real-world settings. Health technology performance assessment (HTpA) refers to the systematic evaluation of the properties, effects, and/or impact of a health intervention or health technology in the real world to provide information for investment/disinvestment decisions and clinical guideline updates. The objective is to describe the development and principal aspects of the Guideline for HTpA commissioned by the Brazilian Ministry of Health. METHODS: Our methods used include extensive literature review, refinement with experts across countries, and public consultation. RESULTS: A comprehensive guideline was developed, which has been adopted by the Brazilian government. CONCLUSION: We believe the guideline, with its particular focus on disinvestment, along with the creation of a specific program for HTpA, will allow the institutionalization and continuous improvement of the scientific methods to use real-world evidence to optimize available resources not only in Brazil but across countries. PMID- 28641589 TI - Modality-Dependent or Modality-Independent Processing in Mental Arithmetic: Evidence From Unimpaired Auditory Multiplication for a Patient With Left Frontotemporal Stroke. AB - OBJECTIVES: Mental arithmetic is essential to daily life. Researchers have explored the mechanisms that underlie mental arithmetic. Whether mental arithmetic fact retrieval is dependent on surface modality or knowledge format is still highly debated. Chinese individuals typically use a procedure strategy for addition; and they typically use a rote verbal strategy for multiplication. This provides a way to examine the effect of surface modality on different arithmetic operations. METHODS: We used a series of neuropsychological tests (i.e., general cognitive, language processing, numerical processing, addition, and multiplication in visual and auditory conditions) for a patient who had experienced a left frontotemporal stroke. RESULTS: The patient had language production impairment; but preserved verbal processing concerning basic numerical abilities. Moreover, the patient had preserved multiplication in the auditory presentation rather than in the visual presentation. The patient suffered from impairments in an addition task, regardless of visual or auditory presentation. CONCLUSIONS: The findings suggest that mental multiplication could be characterized as a form of modality-dependent processing, which was accessed through auditory input. The learning strategy of multiplication table recitation could shape the verbal memory of multiplication leading to persistence of the auditory module. (JINS, 2017, 23, 692-699). PMID- 28641590 TI - Measles elimination and immunisation: national surveillance trends in Japan, 2008 2015. AB - Measles elimination relies on vaccination programmes. In Japan, a major outbreak started in 2007. In response, 5-year two-dose catch-up vaccination programme was initiated in April 2008 for children 13-16-years-old. In this study, we analysed the epidemic curves, incidence rates for each age group, virus genotype, vaccination coverage and ratio of measles gelatin particle agglutination (PA) antibody using surveillance data for 2008-2015. Monthly case counts markedly decreased as vaccination coverage increased. D5, which is the endemic virus type, disappeared after 2011, with the following epidemic caused by imported viruses. Most cases were confirmed to have a no-dose or single-dose vaccination status. Although the incidence rate among all age groups ?5-years-old decreased during the study period, for children <5-years-old, the incidence rate remained relatively high and increased in 2014. The ratio of PA antibody (?1:128 titres) increased for the majority of age groups, but with a decrease for specific age groups: the 0-5 months and the 2-4, 14, 19 and most of the 26-55- and the 60-year old groups (-1 to -9%). This seems to be the result of higher vaccination coverage, which would result in decreasing natural immunity booster along with decreasing passive immunity in infants whose mothers did not have the natural immunity booster. The 20-29- and 30-39-year-old age groups had higher number of cases, suggesting that vaccination within these age groups might be important for eliminating imported viruses. PMID- 28641591 TI - Foucault Retires to the Gym: Understanding Embodied Aging in the Third Age. AB - In light of recent social pressures leading to a reimagining of the "Third Age" as a time of constant activity rather than repose and relaxation, this article explores the pressure on individuals to age "successfully" by engaging in physical activity in later life. Through semi-structured interviews with 15 retired or semi-retired gym-goers (eight women and seven men), the article examines how this call to increased activity impacts the ways active mid-life and older adults understand themselves and others. Drawing on Foucault's understandings of the productive nature of power, we argue that those who perceive themselves as successfully heeding the call to active aging position themselves in contrast to inactive peers. Within a neoliberal framework, these participants self-identify as morally responsible citizens who, as a result of engagement in fitness activities, are authorized to survey and discipline the bodies of those "others" who will not or cannot engage in regular exercise. PMID- 28641592 TI - CONCEPTUALIZATIONS OF THE SOCIETAL PERSPECTIVE WITHIN ECONOMIC EVALUATIONS: A SYSTEMATIC REVIEW. AB - OBJECTIVES: The aim of this study was to investigate how the societal perspective is conceptualized in economic evaluations and to assess how intersectoral costs and benefits (ICBs), that is, the costs and benefits pertaining to sectors outside the healthcare sector, impact their results. METHODS: Based on a search in July 2015 using PubMed, Embase, CINAHL, and PsychINFO, a systematic literature review was performed for economic evaluations which were conducted from a societal perspective. Conceptualizations were assessed in NVivo version 11 using conventional and directed content analysis. Trial-based evaluations in the fields of musculoskeletal and mental disorders were analyzed further, focusing on the way ICBs impact the results of economic evaluations. RESULTS: A total of 107 studies were assessed, of which 74 (69.1 percent) provided conceptualizations of the societal perspective. These varied in types of costs included and in descriptions of cost bearers. Labor productivity costs were included in seventy two studies (67.3 percent), while only thirty-eight studies (35.5 percent) included other ICBs, most of which entailed informal care and/or social care costs. ICBs within the educational and criminal justice sectors were each included five times. Most of the trial-based evaluations analyzed further (n = 21 of 28) reported productivity costs. In nine, these took up more than 50 percent of total costs. In several studies, criminal justice and informal care costs were also important. CONCLUSIONS: There is great variety in the way the societal perspective is conceptualized and interpreted within economic evaluations. Use of the term "societal perspective" is often related to including merely productivity costs, while other ICBs could be relevant as well. PMID- 28641593 TI - Preliminary Evidence for an Association Between the Composition of the Gut Microbiome and Cognitive Function in Neurologically Healthy Older Adults. AB - OBJECTIVES: Dysbiosis of the gut microbiome is implicated in numerous human health conditions. Animal studies have linked microbiome disruption to changes in cognitive functioning, although no study has examined this possibility in neurologically healthy older adults. METHODS: Participants were 43 community dwelling older adults (50-85 years) that completed a brief cognitive test battery and provided stool samples for gut microbiome sequencing. Participants performing>=1 SD below normative performance on two or more tests were compared to persons with one or fewer impaired scores. RESULTS: Mann Whitney U tests revealed different distributions of Bacteroidetes (p=.01), Firmicutes (p=.02), Proteobacteria (p=.04), and Verrucomicrobia (p=.003) between Intact and Impaired groups. These phyla were significantly correlated with cognitive test performances, particularly Verrucomicrobia and attention/executive function measures. CONCLUSIONS: The current findings suggest that composition of the gut microbiome is associated with cognitive test performance in neurologically healthy older adults. Future studies are needed to confirm these findings and explore possible mechanisms. (JINS, 2017, 23, 700-705). PMID- 28641594 TI - Relationship between abdominal obesity and alcohol drinking pattern in normal weight, middle-aged adults: the Korea National Health and Nutrition Examination Survey 2008-2013. AB - OBJECTIVE: Abdominal obesity is associated with obesity-related health risks regardless of body weight. The present study aimed to determine whether alcohol drinking pattern is associated with abdominal obesity in normal-weight, middle aged adults. DESIGN: Cross-sectional study using complex sampling design analyses. SETTING: The Korea National Health and Nutrition Examination Survey, which was conducted from 2008 to 2013. SUBJECTS: Normal-weight participants aged 40-69 years with BMI of 18.5-25.0 kg/m2 (n 11 289, 4491 men and 6798 women) were included. Abdominal obesity was defined as waist circumference >=90 cm for men or >=85 cm for women. Alcohol drinking pattern was assessed by self-report on questionnaires. RESULTS: Among 11 289 normal-weight participants, 7.9 % (n 379) of men and 7.6 % (n 609) of women had abdominal obesity. Both men and women who consumed a higher quantity of alcohol per drinking occasion had higher odds (OR; 95 % CI) for abdominal obesity compared with individuals who consumed fewer than 2 drinks (1.86; 1.04, 3.32 for >=10 drinks/typical occasion in men; and 3.28; 1.13, 9.46 in women). Men who binge drink every day had higher odds for abdominal obesity (2.10; 1.21, 3.63). In both sexes, frequency of alcohol drinking was not associated with normal-weight abdominal obesity. CONCLUSIONS: Our study showed that the amount of alcohol drinking per occasion influenced abdominal obesity in normal-weight, middle-aged individuals that may have impacted obesity-related health risks. Healthy alcohol drinking habits need to be controlled for prevention of abdominal obesity even among persons with normal weight. PMID- 28641595 TI - Swiss Stained-Glass Panels: An Analytical Study. AB - The history and iconography of Swiss stained glass dating between the 16th and 18th centuries are well studied. However, the chemical and morphological characteristics of the glass and glass paints, particularly the nature of the raw materials, the provenance of the glass, and the technology used to produce it are less well understood. In this paper, we studied two sets of samples from stained glass panels attributed to Switzerland, which date from the 16th to 17th centuries: the first set comes from Pena National Palace collection, the second from Vitrocentre Romont. The aims were to identify the materials used in the production of the glass, to find out more about their production origin and to characterize the glass paints. Both glass and the glass paints were analysed by particle-induced X-ray emission; the paints were additionally analysed by scanning electron microscopy-electron-dispersive X-ray spectroscopy (SEM-EDS). The results show that the glass from both sets was probably produced in the same region and that wood ash was used as a fluxing agent. Different recipes have been used to make the blue enamels. However, the cobalt ore used as a coloring agent in all of the blue enamels came from the mining district in Schneeberg, Germany. PMID- 28641596 TI - Types and prevalence of extended-spectrum beta-lactamase producing Enterobacteriaceae in poultry. AB - For several billion years, bacteria have developed mechanisms to resist antibacterial substances. In modern time, antibiotics are frequently used in veterinary and human medicine for prevention and treatment of diseases, globally still also for their growth promoting effects as feed additives. This complex situation has evolved in accelerating development and prevalence of multi-drug resistant bacteria in livestock and people. Extended-spectrum beta-lactamase (ESBL) producing bacteria are resistant to a wide range of beta-lactam antibiotics. They are currently considered as one of the main threats for the treatment of infections in humans and animals. In livestock and animal products, poultry and poultry products show the highest prevalence of ESBL-producers with CTX-M-1, TEM-52 and SHV-12 being the most common ESBL-types in poultry. Escherichia coli and Salmonella spp. are the bacteria in poultry, which carry ESBL-genes most frequently. ESBL-producing bacteria are present at every level of the poultry production pyramid and can be detected even in the meconium of newly hatched chicks. The environment close to poultry barns shows high prevalence rates of these bacteria and contributes to an ongoing infection pressure with further ESBL-types. Probiotics have been shown to successfully reduce ESBL producers in chicken, as well as ESBL-gene transfer. Other feed additives, such as zinc and copper, increase the prevalence of ESBL-producing bacteria when fed to animals. To our best knowledge, this is the first publication presenting a comparative overview of the prevalence of ESBL-types using data from different countries. To reduce the hazard for public health from poultry carrying high numbers of ESBL-producers, preventive measurements must include the surrounding environment and avoidance of antibiotic usage at all levels of the production pyramid. The first results, of the research on the impact of feed additives on the spread of ESBL-genes, indicate the diet as a further, possible magnitude of influence. PMID- 28641597 TI - Self-regulation as a predictor of patterns of change in externalizing behaviors from infancy to adolescence. AB - We examined associations between specific self-regulatory mechanisms and externalizing behavior patterns from ages 2 to 15 (N = 443). The relation between multiple self-regulatory indicators across multiple domains (i.e., physiological, attentional, emotional, and behavioral) at age 2 and at age 5 and group membership in four distinct externalizing trajectories was examined. By examining each of these self-regulatory processes in combination with one another, and therefore accounting for their shared variance, we aimed to better understand which specific self-regulatory skills were associated most strongly with externalizing behavioral patterns. Findings suggest that behavioral inhibitory control and emotion regulation are particularly important in distinguishing between children who show normative declines in externalizing behaviors across early childhood and those who demonstrate high levels through adolescence. PMID- 28641598 TI - Progress towards elimination of trans-fatty acids in foods commonly consumed in four Latin American cities. AB - OBJECTIVE: To assess progress towards the elimination of trans-fatty acids (TFA) in foods after the 2008 Pan American Health Organization (PAHO) recommendation of virtual elimination of TFA in Latin America. DESIGN: A descriptive, comparative analysis of foods that were likely to contain TFA and were commonly consumed in four cities in Latin America. SETTING: San Jose (Costa Rica), Mexico City (Mexico), Rio de Janeiro (Brazil), Buenos Aires (Argentina). SUBJECTS: Foods from each city were sampled in 2011; TFA content was analysed using GC. TFA of selected foods was also monitored in 2016. RESULTS: In 2011-2016, there was a significant decrease in the content of TFA in the sampled foods across all sites, particularly in Buenos Aires (from 12.6-34.8 % range in 2011-2012 to nearly 0 % in 2015-2016). All sample products met the recommended levels of TFA content set by the PAHO. TFA were replaced with a mixture of saturated and unsaturated fats. CONCLUSIONS: Our results indicate a virtual elimination of TFA from major food sources in the cities studied. This could be due to a combination of factors, including recommendations by national and global public health authorities, voluntary and/or mandatory food reformulation made by the food industry. PMID- 28641599 TI - Association between level of exposure to death and dying and professional quality of life among palliative care workers. AB - : ABSTRACTBackground:Exposure to the death and dying of others is an anxiety provoking condition that can contribute to psychological stress. However, the results of empirical studies that evaluated work-related outcomes among physicians and nurses with repeated exposure to dying patients are not consistent. OBJECTIVE: Our aim was to evaluate whether a high level of exposure to death and dying (LED) can increase the risk for poor professional quality of life (ProQoL) in most healthcare workers, but it can also improve ProQoL in a subset of healthcare workers with specific characteristics. METHOD: We employed a cross-sectional survey designed to better understand the role of LED as a predictor of ProQoL among healthcare workers. SETTING AND PARTICIPANTS: Comparison of physicians and nurses with high LED (home-based palliative care units) with a matched group of physicians and nurses with low LED (primary care units) and evaluation of possible interaction effects among LED, death anxiety (DA), and engagement as predictors of ProQoL. RESULTS: The final sample included 110 questionnaires from the high-LED group (response rate = 39%) and 131 from the low-LED (response rate = 24%) group. Workers with high LED reported an increased level of compassion satisfaction (CS) and low to moderate levels of burnout (BU) and secondary traumatic stress (STS), with no significant differences with respect to other healthcare providers. Although levels of CS, STS, and BU did not differ between groups, a univariate MANOVA revealed that the interaction effect of LED * Engagement reduced levels of CS and that the interaction effect of LED * DA increased STS among workers with high LED. SIGNIFICANCE OF RESULTS: LED was significantly correlated with ProQoL among healthcare workers with high LED due to the reported interaction effect. These findings imply, for the first time, that there is a possible correlation between engagement and the risk for poor ProQoL among workers with high LED. Further research is essential to gain a better understanding of this issue. PMID- 28641600 TI - The influence of food consumption and socio-economic factors on the relationship between zinc and iron intake and status in a healthy population. AB - OBJECTIVE: To examine Zn and Fe nutritional status of a healthy population by means of anthropometric, dietary and biochemical measurements and to investigate the relationship of usual Zn and Fe dietary intakes to Zn and Fe status. In addition, to examine the impact of food choices and socio-economic factors on Fe and Zn dietary intakes and status with the aim to identify groups at risk of dietary deficiency and suggest factors that may influence the status of these nutrients. DESIGN: Food consumption was assessed by 24 h recall questionnaires. Twenty biochemical parameters were measured, of which Hb, haematocrit, erythrocyte count and plasma concentrations of Fe and Zn were directly related to Fe and Zn nutrition. The prevalence of study participants with inadequate micronutrient intakes was calculated using the Estimated Average Requirement cut point method. SETTING: Serbia, Europe. SUBJECTS: Apparently healthy adults (25-65 years of age). RESULTS: Mean daily Zn and Fe intakes were 9.1 mg and 11.6 mg for males and 7.3 mg and 9.4 mg for females, respectively. Five per cent of the study population had inadequate dietary Fe intake and 15-25 % had inadequate Zn intake. Lower Hb concentrations were measured in women with lower Zn intakes. No differences in Fe and Zn intakes and status among various socio-economic groups were observed, except for Fe intake between the low-income and affluent groups. CONCLUSIONS: Regular follow-ups are needed to ensure that potential deficiencies of Zn and Fe do get recognized and addressed in a timely manner. PMID- 28641601 TI - The impact of traumatic stress on Pavlovian biases. AB - BACKGROUND: Disturbances in Pavlovian valuation systems are reported to follow traumatic stress exposure. However, motivated decisions are also guided by instrumental mechanisms, but to date the effect of traumatic stress on these instrumental systems remain poorly investigated. Here, we examine whether a single episode of severe traumatic stress influences flexible instrumental decisions through an impact on a Pavlovian system. METHODS: Twenty-six survivors of the 2011 Norwegian terror attack and 30 matched control subjects performed an instrumental learning task in which Pavlovian and instrumental associations promoted congruent or conflicting responses. We used reinforcement learning models to infer how traumatic stress affected learning and decision-making. Based on the importance of dorsal anterior cingulate cortex (dACC) for cognitive control, we also investigated if individual concentrations of Glx (=glutamate + glutamine) in dACC predicted the Pavlovian bias of choice. RESULTS: Survivors of traumatic stress expressed a greater Pavlovian interference with instrumental action selection and had significantly lower levels of Glx in the dACC. Across subjects, the degree of Pavlovian interference was negatively associated with dACC Glx concentrations. CONCLUSIONS: Experiencing traumatic stress appears to render instrumental decisions less flexible by increasing the susceptibility to Pavlovian influences. An observed association between prefrontal glutamatergic levels and this Pavlovian bias provides novel insight into the neurochemical basis of decision-making, and suggests a mechanism by which traumatic stress can impair flexible instrumental behaviours. PMID- 28641602 TI - Milk replacers supplemented with either L-arginine or L-carnitine potentially improve muscle maturation of early reared low birth weight piglets from hyperprolific sows. AB - As a result of the selection for genotypes with greater sow prolificacy, litter size increased and, concomitantly, average litter birth weight and early postnatal survival rates of low birth weight (L-BtW) offspring decreased. This study compared the impact of l-carnitine (CAR) and l-arginine (ARG) supplemented with a milk replacer and fed to L-BtW piglets born from large litters from days 7 to 28 of age on growth performance, carcass composition, organ and Semitendinosus muscle (STM) development. A total of 30 female and castrated Swiss Large White piglets weaned at 7 days of age were assigned to three milk replacer diets containing either no supplement (CON), CAR (0.40 g/piglet per day) or ARG (1.08 g/kg BW per day). Piglets were kept in pairs in rescue decks (0.54 m2). They were weighed daily and daily allowance of both, feed and ARG, was adjusted accordingly. Thus, feed allowance depended on growth. Each day, the milk replacer was prepared with water (1:4). Feed (allowance: 60 g dry matter/kg BW per day) was offered daily in six equal rations. Feed intake and feed efficiency was assessed for the pairs and apparent total tract-energy and -protein digestibility was determined from days 21 to 28 of age. On day 28, piglets were euthanized, blood samples were collected and the whole STM and organs were weighed. In STM, the size and metabolic properties of myofibers were determined. No difference in growth performance was found between dietary treatments, but piglets from the CAR group tended (P<0.10) to grow faster during the 1st experimental week and consume more feed from days 14 to 21 as compared with piglets of the CON group. A setback in growth in the last week in the CAR group coincided with the lower (P<0.05) energy and protein digestibility. Dietary treatments had no effect on STM and organ weight and myofiber size. Compared with the other groups, there were trends (P<0.10) for blood serum urea and glucose level to be greater in CAR and for non esterified fatty acid level to be greater in ARG piglets. The greater (P<0.05) ratio of lactate dehydrogenase to either citrate synthase or beta-hydroxyacyl-CoA dehydrogenase indicated that the relative importance of the glycolytic compared with the oxidative pathway was greater in STM of CAR and ARG compared with CON piglets. These results suggest that ARG and CAR supplements were beneficial for muscle maturation whereas findings on phenotypic traits were rather unsystematic. PMID- 28641604 TI - Prevalence and genetic diversity of blood parasite mixed infections in Spanish terrapins, Mauremys leprosa. AB - Blood parasites such as haemogregarines and haemosporidians have been identified in almost all groups of vertebrates and may cause serious damages to their hosts. However, very little is known about biodiversity of these parasites and their effects on some groups of reptiles such as terrapins. Moreover, the information on virulence from blood parasites mixed infection is largely unknown in reptiles. With this aim, we investigated for the first time the prevalence and genetic diversity of blood parasites from one genus of haemoparasitic aplicomplexan (Hepatozoon) in two populations of Spanish terrapins (Mauremys leprosa), a semi aquatic turtle from southwestern Europe with a vulnerable conservation status. We also examined the association between mixed blood parasite infection and indicators of health of terrapins (body condition, haematocrit values and immune response). Blood parasite infection with Hepatozoon spp was detected in 46.4% of 140 examined terrapins. The prevalence of blood parasites infection differed between populations. We found two different lineages of blood parasite, which have not been found in previous studies. Of the turtles with infection, 5.7% harboured mixed infection by the two lineages. There was no difference in body condition between uninfected, single-infected and mixed-infected turtles, but mixed-infected individuals had the lowest values of haematocrit, thus revealing the negative effects of blood parasite mixed infections. Immune response varied among terrapins with different infection status, where mixed infected individuals had higher immune response than uninfected or single-infected terrapins. PMID- 28641603 TI - Molecular detection of Sarcocystis lutrae in the European badger (Meles meles) in Scotland. AB - Neck samples from 54 badgers and 32 tongue samples of the same badgers (Meles meles), collected in the Lothians and Borders regions of Scotland, were tested using polymerase chain reactions (PCRs) directed against the 18S ribosomal DNA and the internal transcribed spacer (ITS1) region of protozoan parasites of the family Sarcocystidae. Positive results were obtained from 36/54 (67%) neck and 24/32 (75%) tongue samples using an 18S rDNA PCR. A 468 base pair consensus sequence that was generated from the 18S rDNA PCR amplicons (KX229728) showed 100% identity to Sarcocystis lutrae. The ITS1 PCR results revealed that 12/20 (60%) neck and 10/20 (50%) tongue samples were positive for Sarcocystidae DNA. A 1074 bp consensus sequence was generated from the ITS1 PCR amplicons (KX431307) and showed 100% identity to S. lutrae. Multiple sequence alignments and phylogenetic analysis support the finding that the rDNA found in badgers is identical to that of S. lutrae. This parasite has not been previously reported in badgers or in the UK. Sarcocystis lutrae has previously only been detected in tongue, skeletal muscle and diaphragm samples of the Eurasian otter (Lutra lutra) in Norway and potentially in the Arctic fox (Vulpes lagopus). PMID- 28641605 TI - State-dependent parasitism by a facultative parasite of fruit flies. AB - Parasites can evolve phenotypically plastic strategies for transmission such that a single genotype can give rise to a range of phenotypes depending on the environmental condition. State-dependent plasticity in particular can arise from individual differences in the parasite's internal state or the condition of the host. Facultative parasites serve as ideal model systems for investigating state dependent plasticity because individuals can exhibit two life history strategies (free-living or parasitic) depending on the environment. Here, we experimentally show that the ectoparasitic mite Macrocheles subbadius is more likely to parasitize a fruit fly host if the female mite is mated; furthermore, the propensity to infect increased with the level of starvation experienced by the mite. Host condition also played an important role; hosts infected with moderate mite loads were more likely to gain additional infections in pairwise choice tests than uninfected flies. We also found that mites preferentially infected flies subjected to mechanical injury over uninjured flies. These results suggest that a facultative parasite's propensity to infect a host (i.e. switch from a free-living strategy) depends on both the parasite's internal state and host condition. Parasites often live in highly variable and changing environments, an infection strategy that is plastic is likely to be adaptive. PMID- 28641606 TI - Solving the challenge of the blood-brain barrier to treat infections caused by Trypanosoma evansi: evaluation of nerolidol-loaded nanospheres in mice. AB - Despite significant advances in therapies against Trypanosoma evansi, its effective elimination from the central nervous system (CNS) remains a difficult task. The incapacity of trypanocidal drugs to cross the blood-brain barrier (BBB) after systemic administrations makes the brain the main refuge area for T. evansi. Nanotechnology is showing great potential to improve drug efficacy, such as nerolidol-loaded nanospheres (N-NS). Thus, the aim of this study was to investigate whether the treatment with N-NS was able to cross the BBB and to eliminate T. evansi from the CNS. High-performance liquid chromatography revealed that N-NS can cross the BBB of T. evansi-infected mice, while free nerolidol (F N) neither the trypanocidal drug diminazene aceturate (D.A.) were not detected in the brain tissue. Polymerase chain reaction revealed that 100% of the animals treated with N-NS were negatives for T. evansi in the brain tissue, while all infected animals treated with F-N or D.A. were positives. Thus, we concluded that nanotechnology improves the therapeutic efficacy of nerolidol, and enables the transport of its active principle through the BBB. In summary, N-NS treatment can eliminate the parasite from the CNS, and possesses potential to treat infected animals. PMID- 28641607 TI - The use of nesiritide in patients with critical cardiac disease. AB - OBJECTIVE: We evaluated the use of nesiritide in children with critical CHD, pulmonary congestion, and inadequate urine output despite undergoing conventional diuretic therapy. DESIGN: We conducted a retrospective analysis of 11 patients with critical CHD, comprising 18 infusions, each of which occurred during separate hospitalisations. Haemodynamic parameters were assessed, and the stage of acute kidney injury was determined before and throughout the duration of therapy using a standardised definition of acute kidney injury - The Kidney Disease: Improving Global Outcomes criteria. Patients Children with critical CHD, pulmonary congestion, and inadequate urinary output despite undergoing diuretic therapy were included. Measurements and main results The use of nesiritide was associated with a significant decrease in the maximum and minimum heart rate values and with a trend towards a significant decrease in maximum systolic blood pressure and maximum and minimum central venous pressures. Urine output increased but was not significant. Serum creatinine levels decreased significantly during the course of therapy (-0.26 mg/dl [-0.50, 0.0], p=0.02), and the number of patients who experienced a decrease in the stage of acute kidney injury of 2 or more - where a change in the stage of acute kidney disease of 2 or more was possible, that is, baseline stage >1 - was highly significant (five of 12 patients, 42%, p<0.001). CONCLUSIONS: Nesiritide had a favourable impact on haemodynamics, and its use was not associated with deterioration of renal function in patients with critical CHD. PMID- 28641608 TI - HOSPITAL-BASED HEALTH TECHNOLOGY ASSESSMENT IN BRAZIL: AN OVERVIEW OF THE INITIAL EXPERIENCES. AB - OBJECTIVES: Hospital-based health technology assessment (HTA) has become increasingly important in Brazil due to its strategic importance to promote adoption, incorporation, dissemination, and disinvestment of technologies. A strategy to foster hospital-based HTA was implemented in 2009 by creating hospital-based HTA nuclei (NATS) at university hospitals and other strategic hospitals. METHODS: Between 2011 and 2012, we interviewed board members in twenty three NATS located in all geographic regions of Brazil to assess their general characteristics, scientific output, and challenges. RESULTS: Of the total, 65 percent of the NATS belonged to teaching institutions, with 44 percent associated with federal universities. The bulk of their output was in the form of mini-HTA reports. Centers in the Southeast and South of Brazil had the highest production compared with other regions. Lack of expertise and low levels of advanced training were identified as limiting factors in the majority of centers. CONCLUSIONS: The experience of the initial twenty-three NATS could be considered positive and has led to the creation of new ones around Brazil. Regional disparities in workload, production, and technical training should be targeted by new policies toward hospital-based HTA in Brazil. The limits and possibilities for intensifying the strategy relate to continuous investment in priority studies, which simultaneously, allow professionals who work in hospitals to receive continued education and produce relevant HTA work in a timely manner. PMID- 28641609 TI - A systematic review of the psychometric properties, usability and clinical impacts of mobile mood-monitoring applications in young people. AB - BACKGROUND: Mobile mood-monitoring applications are increasingly used by mental health providers, widely advocated within research, and a potentially effective method to engage young people. However, little is known about their efficacy and usability in young populations. METHOD: A systematic review addressing three research questions focused on young people: (1) what are the psychometric properties of mobile mood-monitoring applications; (2) what is their usability; and (3) what are their positive and negative clinical impacts? Findings were synthesised narratively, study quality assessed and compared with evidence from adult studies. RESULTS: We reviewed 25 articles. Studies on the psychometric properties of mobile mood-monitoring applications were sparse, but indicate questionable to excellent internal consistency, moderate concurrent validity and good usability. Participation rates ranged from 30% to 99% across studies, and appeared to be affected by methodological factors (e.g. payments) and individual characteristics (e.g. IQ score). Mobile mood-monitoring applications are positively perceived by youth, may reduce depressive symptoms by increasing emotional awareness, and could aid in the detection of mental health and substance use problems. There was very limited evidence on potential negative impacts. CONCLUSIONS: Evidence for the use of mood-monitoring applications in youth is promising but limited due to a lack of high-quality studies. Future work should explicate the effects of mobile mood-monitoring applications on effective self-regulation, clinical outcomes across disorders and young people's engagement with mental health services. Potential negative impacts in this population should also be investigated, as the adult literature suggests that application use could potentially increase negativity and depression symptoms. PMID- 28641610 TI - [Biological Characteristics of Microvesicles Secreted by Human Peripheral Blood Hematopoietic Stem Cells]. AB - OBJECTIVE: To investigate the effects of microvesicles(MV) isolated from human peripheral blood hematopoietic stem cells(PB-HSC) on immune regulation and hematopoiesis. METHODS: PB-HSCs were separated by density-gradient centrifugation and cultrued. The supernatants of PB-HSC at 48 h were harvested for isolation and purification of MV by using ultracentrifugation. The electron microscopy was used to observe the morphology of MV. The protein level in MV was quantified through bicinchoninic acid(BCA) protein assay. Flow cytometry was used to detect the immunophenotype of MV. Human peripheral blood mononuclear cells(PB-MNC) were isolated from healthy donor and treated with isolated MV. After being co-cultured for 12 h, confocal microscopy was used to observe the action mode of MV on PB MNC. After being co-cultured for 48 h, the levels of IL-2, IL-6, IL-8, IL-10, IFN gamma and TNF-alpha were detected by ELISA. Flow cytometry was used to detect the changes of T cell subsets and the activation of T cell subsets as well as intracellular cytokine staining after co-culture for 48 h. The methylcellulose was used to assess the hematopoiesis-supportive function of MV as well as co cultured supernatants. RESULTS: The eletron microscopy revealed that MV were elliptical membrane vesicles. The protein amount in MV ranges from 29 to 110 ug. Flow cytometry showed that MV expressed mix markers on the surface, especially highly expressed MV specific marker CD63(85.86%) and hematopoietic stem cell marker CD34(33.52%). After being co-cultured for 12 h, confocal microscopy showed that MV were merged with PB-MNC. After being co-cultured for 48 h, ELISA showed that the secretion of cytokines IL-6,IL-8, IL-10 as well as TNF-alpha was increased while the level of IL-2 and IFN-gamma was not changed much. The results of flow cytometry showed that there was no significant change in T cell subsets and T cell activation. Staining of intracellular factor showed that IL-8 was increased significantly in CD11c+ cells. The colony-forming experiments revealed that MV and the co-cultured supernatants could facilitate the colony formation. CONCLUSION: MV isolated from PB-HSC have immune-regulatery function and can prornote hematopoiesis. PMID- 28641611 TI - [DMSO Promotes Hematopoietic Differentiation of Human Embryonic Stem Cells in vitro]. AB - OBJECTIVE: To explore the role of dimethyl sulfoxide (DMSO) in the hematopoietic differentiation of human embryonic stem cells (hESCs). METHODS: The role of DMSO in hematopoietic differentiation of hESC was investigated by using a established stepwise hematopoietic differentiation system from hESC, immunofluorescouse assay and flow cytometry. Furthermore, the window phase of DMSO action was explored by adding it to the different stage of hematopoietic differentiation. RESULTS: Immunofluorescence and flow cytometry analysis showed that DMSO significantly promoted the generation of CD43+ hematopoietic progenitor cells (HPC). The flow cytometry demonstrated that DMSO profoundly promoted the generation of APLNR+ lateral plate mesoderm cells and CD31+CD34+ hemogenic endothelium progenitors (HEP). The addition of DMSO in the window phase of lateral plate mesoderm cell generation could markedly improve the generation of hematopoietic progenitor cells. CONCLUSION: DMSO promotes hematopoietic differentiation of hESC through enhancing the generation of APLNR positive lateral plate mesoderm cells. The addition of DMSO in the window phase of lateral plate mesoderm cell generation can significantly improve the generation of hematopoietic progenitor cells. PMID- 28641612 TI - [Expression and Significance of HIF-1alpha in Erythropoiesis of Secondary Iron Overload Disease after Irradiation Damage]. AB - OBJECTIVE: To study the expression of hypoxia inducible factor 1alpha(HIF-1alpha) of iron-overloaded in irradiated mice and its effect on erythropoiesis. METHODS: Twenty mice were randomly divided into 4 groups: Ctrl (control group), IR (irradiation group), IO (irradiation + iron overload group), and RAPA (rapamycin treatment group). The iron overload model was verified. The CFU-E (colony forming unit-erythroid) and BFU-E(burst colony forming unit-erythroid) were cultured; flow cytometry was used to detect the ratios of early stage (Ter119+CD71-) to late stage (Ter119+CD71+) of primitive erythroblasts; RT-PCR was used to detect the mRNA expression of HIF-1alpha and its related signal molecules in bone marrow cells. RESULTS: The expression of HIF-1alpha in IR and IO group was significantly higher than that in Ctrl group, and that in IO group was significantly higher than IR group (P<0.05). The ratio of late stage primitive erythroblasts, the number of CFU-E and BFU-E in both IR and IO group were lower than those in Ctrl group, and those in IO group were significantly lower than those in IR group (P<0.05). Compared with Ctrl group, the expression of HIF-1alpha related signal pathway molecules in both IR and IO group was significantly decreased (P<0.05). Compared with IO group, the expression of HIF-1alpha and its related signal molecules in RAPA(mTOR inhibitor) group was decreased significantly (P<0.05), the number of BFU-E was increased significantly(P<0.05). CONCLUSION: Irradiation induces the increase of HIF-1alpha and the decrease of the ability of hematopoietic colony formation and the ratio of late stage primitive erythroblasts. Iron overload can aggravate the injury. mTOR inhibitor rapamycin can partially alleviate the injury, suggesting that iron overload can lead to injury of erythropoiesis through HIF-1alpha. PMID- 28641613 TI - [Prostaglandin E2 Receptor 4 Agonist Promotes Human CD34+ Cell Proliferation in vitro by Activating Wnt/beta-Catenin Signaling Pathway]. AB - OBJECTIVE: To investigate the potential signaling pathway that regulates the proliferation of human CD34+ cells stimulated by prostaglandin E2 receptor 4 agonist (EP4A) in vitro. METHODS: Twenty samples of peripheral blood containing stem cells were collected from the G-CSF mobilized healthy donors in our department of hematology. Human CD34+ cells were isolated by magnetic activated cell sorting (MACS) microbeads kit. The Cell Counting Kit-8 (CCK8) assay was used to determine the optimal concentration and time of EP4A to promote human CD34+ cell proliferation in vitro. Under the optimal condition, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect mRNA level of beta catenin, and Western blot was used to assay protein expression of beta-catenin and P-GSK-3beta in human CD34+ cells treated with EP4A. RESULTS: Culturing with 10 umol/L EP4A for 72 h, it was found that EP4A promoted human CD34+ cell proliferation significantly, and the proliferation rate of human CD34+ cells was 1.36 times higher than that of the control(P=0.002). Under the optimal condition, it was also found that EP4A enhanced the beta-catenin expression at both mRNA and protein levels, and up-regulated phosphorylation of GSK-3beta in human CD34+ cells, but these effects could be inhibited by the EP4A antagonist EP4AA. CONCLUSION: EP4A can enhance human CD34+ cell proliferation in vitro by activating Wnt/beta-catenin signaling pathway. PMID- 28641615 TI - [Expression and Asymmetric Division of Numb in Leukemia Cell K562 Line]. AB - OBJECTIVE: To investigate the role of asymmetric division in leukemia cells through detection of expression and asymmetric division of Numb in differentiated and undifferentiated K562 cells. METHODS: Firstly, Hemin was used to induce K562 cell differentiation, and the expression of Numb was detected by the real-time quantitative RT-PCR and flow cytometry. After K562 cells were synchronized by nocodazole, the Numb protein was labeled by immunohistochemical staining, followed by the determination of the terminally differentiated cells through confocal microscopy. The fluorescence intensity was calculated by Image J software, and the cell division pattern was analyzed on the basis of the fluorescence intensities of Numb in 2 divided daughter cells. RESULTS: Compared with the undifferentiated K562 cells, the level of Numb mRNA expression increased 2.3 times (P<0.001). The ratio of Numb positive cells was(67.37+/-5.01)% in differentiated K562 cells, while that was (43.97+/-5.72)% in undifferentiated K562 cells (P<0.01). Compared with undifferentiated K562 cells, the ratio of cells with asymmetric division in differentiated K562 cells increased 18.3%, the percentage of cells with symmetry self-renewal reduced 49.7%(P<0.001) and that with symmetry differentiation increased 32%(P<0.001). CONCLUSION: In differentiated K562 cells, expression of Numb and proportion of cells with asymmetric division were higher than that in undifferentiated cells. With the differentiation of leukemia cells, the proportion of cells with asymmetrical division increases, and the proportion of cells with symmetrical self-renewal decreases. The stemness of leukemia cells is maintained mainly through the symmetrical self-renewal. PMID- 28641614 TI - [Effect of MicroRNA-214 on Migration of Cord Blood CD34+ Cells Induced by Bone Marrow Mesenchymal Stem Cells]. AB - OBJECTIVE: To investigate the possible effect of MicroRNA-214 (miR-214) on migration of umbilical cord blood CD34+ hematopoietic stem/progenitor cells induced by BM-MSC. METHODS: After transfection of the inhibitor or mimic of miR 214, the cultured supernatant of BM-MSC were collected respectively. The expression of miR-214 in BM-MSC was detected by real time quantitative PCR, the effect of supernatant on CD34+ cell migration was evaluated by chemotaxis assays. The levels of chemokine(SDF-1) secreted by BM-MSC in the supernatant were detected by ELISA. RESULTS: The cultured supernatant of BM-MSC could promote the migration of CD34+ cells. Compared with the group without transfection or negative control(NC) group, the transfection with miR-214 mimic could promote the migration of CD34+ cells (P<0.01), while the migration rate in miR-214 inhibitor groups decreased significantly (P<0.01). Further study found that the concentration of SDF-1 was not changed notably in all groups (P>0.05), as compared with the control group. CONCLUSION: miR-214 signalings may indirectly increase the migration of CD34+ hematopoietic stem/progenitor cells by modulating BM-MSC functions, which may not significantly correlate with the chemokine SDF-1 secreted by BM-MSC. PMID- 28641616 TI - [Effect of LPXN Overexpression on the Proliferation, Adhesion and Invasion of THP 1 Cells and Its Mechamisms]. AB - OBJECTIVE: To explore the effect of LPXN overexpression on the proliferation, adhesion and invasion of THP-1 cells and its possible mechanism. METHODS: A THP-1 cell line with stable overexpression of LPXN was constucted by using a lentivirus method, CCK-8 was used to detect the proliferation of cells, adhesion test was used to evaluate adhesion ablity of cells to Fn. Transwell assay was used to detect the change of invasion capability. Western blot was used to detect expression of LPXN, ERK, pERK and integrin alpha4, alpha5, beta1, the Gelatin zymography was applied to detect activity of MMP2/MMP9 secreted by the THP-1 cells. RESULTS: Successful establishment of THP-1 cells with LPXN overexpression (THP-1 LPXN) was confirmed with Western blot. THP-1 LPXN cells were shown to proliferate faster than the control THP-1 vector cells. Adhesion to Fn and expression of ERK, integrin alpha4, alpha5 and beta1 in the THP-1 LPXN cells were higher than that in the control cells. Invasion across matrigel and enhanced activity of MMP2 could be detected both in the THP-1 LPXN cells as compared with the control cells. CONCLUSION: Ectopically ovexpression of LPXN may promote proliferation of THP-1 cells through up-regulation of ERK; promote adhesion of THP-1 cells through up-regulating the integrin alpha4/beta1 as well as integrin alpha5/beta1 complex; promote invasion of THP-1 cells through activating MMP2. PMID- 28641617 TI - [Biological Characteristics and Therapeutic Efficacy of 103 Patients with Acute Erythroleukemia]. AB - OBJECTIVE: To investigate the biological characteristics and therapeutic efficacyt of acute erythroleukemia (AEL,AML-M6). METHODS: Blood cell count, liver function, lactate dehydrogenase level, coagulation, morphology, immunology, cell genetics and molecular biology were retrospectively analyzed in 103 cases of acute erythroleukemia patients admitted in our department from May 2016 to June 2009. The therapeutic efficacy was observed by means of remission rate, relapse rate, relapse-free survival and overall survival. RESULTS: The medians of white blood cells, granulocyte, hemoglobin and platelet were 3.04*109/L, 0.67*109/L, 66 g/L, and 45*109/L,respectively. Nucleated red blood cells were found in the peripheral blood smears from 71.1% of AEL patients. None of the patients showed abnormal coagulation function. Flow cytometry analysis indicated that CD13 (93.5%),CD117(89.1%), HLA-DR(87.0%), and CD34 (80.0%) were highly expressed in AEL, and lymphoid antigens of CD4 (42.9%) and CD7(28.9%) were expressed in partial patients. Karyotype analysis in 82 patients showed 52.4% (43/82) normal karyotype, 41.5% (34/82) abnormal karyotype, and 6.1% (5/82) failed tests. In the 34 cases with abnormal karyotype, there were 14(41.2%) cases with simple chromosomal abnomality and 20(58.8%) cases with complex karyotype. The positive rate of fusion gene accounted for 16.7% in 60 patients, and the gene mutations accounted for 77.8% in 27 patients. Among 103 cases of AEL, 81 cases were treated with chemotherapy, but 66 cases can be used for therapeutic analysis, as a results the total complete remission rate derived from 2 courses of treatment was 45.5% (30/66). The relapse rate was 36.7% (11/30), and the median relapse time was 15.5 months (6.2-50 months). The median survival time of 66 patients for therapeutic analysis was 29 months. The median survival time of CR patients was very significantly longer than that of the non-CR patients(P=0.001). The 5 year survival rate of CR patients was 65%, the median time of relapse-free survival (RFS) was 46.2 months and 3-years RFS was 58%. CONCLUSION: AEL is characterized by the highly expressed CD34 antigen, and complex karyotype. Although AEL has lower CR rate and poor prognosis, CR patients can achieve long-term survival and have good quality of life. PMID- 28641618 TI - [Clinical and Cytogenetic Characteristics of Two AML Patients with High-level MLL Expression]. AB - OBJECTIVE: To investigate the clinical and cytogenetic characteristics of high level mixed-lineage leukaemia (MLL) gene amplification in patients with acute myeloid leukemia (AML). METHODS: The clinical and cytogenetic data of 2 AML patients with high-level MLL amplification from January 2010 to August 2016 were analyzed retrospectively. RESULTS: The two AML cases were in middle-aged population. They were diagnosed as FAB subtype M5b and M2a respectively. Both of them had complex karyotypes with the aberrations of chromosome 11. One case was confirmed as MLL-PTD involving exons 2-9 by RT-PCR and sequencing. The other case without MLL-PTD was further analyzed by CytoScan HD analysis. The CMA results showed partial gain of 11q accompanied with partial loss in 11q, deletion of regions in 3p, 3q, 4q, 5q, 7q, 8q, 10p, 10q, 12p and 18q, as well as gain of 4p. CONCLUSION: The co-existence of -5/5q-, -7/7q- and highly complex karyotype may accelerate the poor prognosis. Thus how those cytogenetic abnormalities influencing the disease prognosis need to be further explored. PMID- 28641619 TI - [Correlation between Dynamic Change of IL-32 Level and Disease Development in Acute Leukemia Patients]. AB - OBJECTIVE: To investigate the correlation between dynamic change of IL-32 level and disease development in the patients with acute leukemia(AL) and to explore its clinical significance. METHODS: The serum IL-32 levels and IL-32 mRNA expression in 82 cases of AL and 30 healthy persons were measured by ELISA and real-time PCR. RESULTS: Compared with healthy persons, the serum IL-32 protein level and IL-32 mRNA expression in AL, acute lymphoblastic leukemia(ALL) and acute non-lymphocytic leukemia(ANLL) groups all were significantly higher(P<0.05). The serum level of IL-32 protein and mRNA expression in newly diagnosed, PR and relapsed ALL and ANLL groups were all higher than those in the control group(P<0.05), and the serum protein level of IL-32 in relapsed ALL and ANLL groups were higher than that in other stage group(P<0.05). The serum levels of IL-32 protein and mRNA were not significantly different between CR and control group(P>0.05). CONCLUSION: The IL-32 in the peripheral blood of patients with AL has been found to be closely related with the occurrence and development of disease, therefore, monitoring the dynamic changes of serum IL-32 level would contribute to the clinical judgment of the severity, the IL-32 levels can be used as indicators for the therapeutic efficacy for AL. PMID- 28641620 TI - [Role of Microparticles Derived from Acute Promyelocytic Leukemia Cells in Coagulopathy]. AB - OBJECTIVE: To evaluate the role of microparticle (MP) derived from acute promyelocytic leukemia (APL) cells and tissue factor (TF) carried by the MP in hypercoagulable state, and the effect of treatment with cytotoxic chemotherapy/differentiating agents on procoagulant activity (PCA) of these MP. METHODS: Bone marrow mononuclear cells (BMMNC) were extracted from 5 APL patients and 5 sex- and age- matched patients with iron deficiency anemia as controls. The cells were cultured in vitro for 48 h, then MP-rich culture medium and MP-free culture medium were harvested and MP was further obtained from certain volume of MP-rich culture medium. Subsequently, TF expression on MP was measured by ELISA. PCA of MP-rich culture medium or MP-free culture medium was assessed with thrombin generation assay. The role of TF on MP-related PCA was evaluated using anti-human TF antibody. In addition, APL cells were treated with all-trans retinoic acid (ATRA), arsenic trioxide (ATO) or daunorubicin (DNR) for 48 h, then MP-rich culture medium were harvested and the PCA was determined. RESULTS: No TF expression was found in the MP released from bone marrow MNC in control group, whereas the obvious TF expression was found in the MP originated from BMMNC of APL. MP from both APL and control BM-MNC had obvious PCA. However, compared with the MP derived from control MNC, the MP from APL BM-MNC induced significantly higher PCA. TF played a crucial role in the PCA of APL BM-MNC derived MP, while played no role in that of MP from control MNCs. DNR-treating APL BM-MNC resulted in an increase in the PCA of MP, whereas ATO or ATRA exposure lead to exactly the opposite results. CONCLUSION: MP derived from APL BM-MNC posseses obvious PCA. TF plays a crucial role in the MP-related PCA. The PCA of MP increases after treating APL BM-MNC with chemotherapy agent DNR and decreases following exposure of APL BM-MNC to differentiating agents ATRA or ATO. PMID- 28641621 TI - [Effect of Down-Regulatory Nucleostemin Expression on Autophagy Activities in p53 Null HL-60 Leukemia Cells]. AB - OBJECTIVE: Based on previous microarry and bioinformatic analysis results, to investigate the effect of nucleostemin(NS) expression down-regulation on autophagy activity in p53 null HL-60 leukemia cells, so as to provide evidence for studying mechanisms of p53-independent signal pathway of NS in details. METHODS: The autophagy activity of HL-60 cells after down-regulation of NS expression was detected with acidine orange staining, Western blot and transmission electron mcrioscope technique. RESULTS: The expression level of NS in test groups was lower than that in blank control and negative control groups after HL-60 cells were readily transinfected by lentivirus. The result of acidine orange staining showed that the number of acid vesicular organelle in test groups(22.4+/-0.76)% was higher than that in blank control groups(3.1+/-0.28)% and negative control groups(6.2+/-0.64)% (P<0.05). Western blot showed that the ratio of LC3II/LC3I in test groups(1.537+/-0.072) was higher than that in blank control and negative control groups (1.010+/-0.039) and (0.608+/-0.008). The result of transmission electron mcrioscopy also showed that the number of autophagosomes in test group(8.7+/-3.1) was higher than that in the blank control and negative control groups(4.2+/-1.2) and (2.3+/-0.5). CONCLUSION: Autophagy activty can be enhanced after the level of NS was down regulated. The change indicates the signaling transductions screened by bioinformatic analysis may be one of p53-independent pathway of NS, which lays a foundation for contineously studying key points of p53-independent signal pathway of NS. PMID- 28641622 TI - [Variation of LNK Gene in Chronic Myeloid Leukemia]. AB - OBJECTIVE: To compare the mutation and single nucleotide polymorphism (SNP) of LNK gene between chronic myeloid leukemia(CML) and control groups, and to explore the relationship between LNK gene variation and the occurrence of CML. METHODS: A total of 36 patients with CML were selected, 46 healthy persons were used as normal controls. DNA was extracted from bone marrow and peripheral blood, BCR/ABL1 fusion gene was detected by Q-PCR. The whole exon of LNK gene was amplified by PCR. The amplified sequences included the Rs3184504 (C/T) and Rs78894077 (A/C/G/T) affecting the expression of amino acids in LNK gene, and the Rs7973120 (A/T) unaffecting the expression of the amino acids. The mutations and SNP of LNK gene were analyzed by DNA sequencing. RESULTS: Thirty-six cases of CML had BCR/ABL1 mutation, while no mutation was found in the control group. One case of CML had LNK heterozygous mutation (A300V), and the mutation rate was 2.8%, no mutation was seen in normal control group. Rs3184504: C/T allele frequency was 50%/50% in the control group, 94.4%/5.6% in the CML group, and the C allele in CML group was significantly higher than that in the control group; CC genotype accounted for 94.4% (P<0.01). Rs78894077: C/T allele in the control group was 9.8%/90.2%, in CML group was 16.7%/83.3%, the difference was not statistically significant(P>0.05); but CC genotype in CML group was very statistically significant higher than that in control group(P<0.01). Rs7973120: A/T allele frequency was 10.9%/89.1% in the control group, 25%/75% in the CML group, the LNK A allele in CML group was very significantly higher than that in control group (P<0.01). CONCLUSION: CML patients have been confirmed to have LNK mutation; the SNPs of LNK are related with the development of CML, and the most CML patients carry the LNK Rs3184504 C allele and the Rs7973120 A allele. PMID- 28641623 TI - [Analysis of Clinical Characteristics and Therapeutic Efficacy in 61 Adult Patients with Acute Lymphoblastic Leukemia]. AB - OBJECTIVE: To investigate the clinical characteristics and curative effect in 61 adult patients with acute lymphoblastic leukemia (ALL). METHODS: The clinical data of 61 patients (>=15 years old) with ALL enrolled from January 2010 to December 2014 were studied retrospectively. The relationship between clinical characteristics and curative effect was analyzed. The univariate and multivariate analyses related with the overall survival (OS) and disease free survival (DFS) were conducted by using the method of COX regression analysis. RESULTS: Forty four patients obtained complete remission (CR) in all 61 cases. The total CR rate was 72.13%. Age of onset, WBC count at first visit, CNS involvement or not, status of myeloid antigen expression and Ph chromosome condition were the important factors affecting the CR rate (P<0.05). The 2 years OS rate of all the 61 cases was 28.13%, the median OS time was 11 months (95% CI 9.58-12.42). The 2 years OS rate and DFS rate of the 44 patients in CR were 39.57% and 34.29% respectively. As showed by univariate analysis, the age of onset, WBC count at first visit, whether achieved CR or not after induction chemotherapy, and whether accepted consolidation therapy or allo-HSCT therapy after CR were factors affecting the prognosis of adult ALL patients. The result of multivariate analysis showed that the older age (P=0.001), induction chemotherapy did not achieve CR (P=0.018) and patients did not received consolidation after CR(P=0.005) , all these were independent risk factors for DFS. CONCLUSION: The CR rate after induction chemotherapy is high in adult ALL patients, but the OS rate is low. To achieve CR and to maintain consolidation treatment after CR may be helpful to improve the long-term survival. PMID- 28641624 TI - [Relationship between Peripheral Blood White Blood Cell Count and Early Death Rate in Patients with Acute Promyelocytic Leukemia]. AB - OBJECTIVE: To investigate the relationship between peripheral white blood cell count and early death rate of the patients with acute promyelocytic leukemia (APL). METHODS: Through retrospective study, the relationship of early death rate in 116 cases newly diagnosed APL patients with maximum of peripheral blood white blood cell count should be analyzed before and after induction therapy as well as in the whole course of disease during the past 8 years. RESULTS: There was a close relationship between the peripheral white blood cell count and the early death rate in APL patients. Peripheral blood white blood cell count in the early died patients was significantly higher than that of the survival patients (P<0.05). ROC analysis showed that the highest risk threshold of peripheral white cell count was 70*109/L (P<0.05) before treatment, while the highest risk threshold after treatment and in the whole course of disease were 96.4*109/L(P<0.05) and 91.5*109/L(P<0.01) respectively. The dealth rate of patients with highest risk threshold was significantly increased (P<0.05). CONCLUSION: The highest peripheral blood white blood cell count closely relates with the early death rate of patients at different time points in the whole course of disease. Control of peripheral white blood cell count may effectively reduce the early death rate of APL patients. PMID- 28641625 TI - [Effect of GSTP1 and MTHFR Gene Polymorphism on Side Effects of HD-MTX in ALL Children]. AB - OBJECTIVE: To Study the effect of C677T and MTHFR gene polymorphism on side effects of HD-MTX in ALL children. METHODS: The gene polymorphism of C677T A303G and MTHFR C677T were detected by PCR in 98 ALL children from January 2014 to January 2016. The side effects during HD-MTX therapy were observed, and the relationship among GSTP1, MTHFR gene polymorphism and incidence of side effect of HD-MTX were analyzed. RESULTS: Among 98 ALL children, the gene variation was observed in 61 ALL children (62.24%). Polymorphism study on C677T A303G showed that the gene frequency of A was 84.69%, while that of G was 15.31%; for polymorphism of MTHFR C677T, gene frequency of C was 66.33%, and that of T was 33.67%. Seven patients(7.14%) experienced with bone marrow supression, 23 patients(23.47%) with liver function damage, 15 patients(15.31%) with renal function damage, 48 patients(48.98%) with gastrointestinal reactions and 46 patients(46.94%) with mucosal lesions. After adjustment of sex, age, risk stratification and dosage of MTX, the gene polymorphism had no significant relationship with bone marrow suppression, gastrointestinal reactions and mucosal lesions(P>0.05). However, the number of the mutant genes had statistically significant relationship with liver and renal function damage(P<0.05). CONCLUSION: The risk of side effects during HD-MTX therapy increases in ALL children with combined mutation of MTHFR and C677T. PMID- 28641626 TI - [Clinical Significance of Minimal Residual Disease in Risk Stratification and Prognosis of Childhood B-lineage Acute Lymphoblastic Leukemia]. AB - OBJECTIVE: To explore clinical significance of monitoring the level of minimal residual disease (MRD) at different time point in the risk stratification and prognosis of Childhood B-lineage Acute Lymphoblastic Leukemia. METHODS: Three hundred and eighty cases of children's B-ALL from Augest 2008 to January 2013 in our hospital were enrolled in this study. MRD levels were detected at day 15, day 33 and week 12 after initial chemotherapy. The event-free survival(EFS) and overall survival (OS) were measured on the basis of MRD levels at different stages of chemotherapy and were compared by Kaplan Meier analyses. RESULTS: The patient's age, initial white blood cell count, chromosome, MLL, BCR/ABL, pretreatment reaction, bone marrow MRD at days 33 were closely related with the 5 year EFS rate. Multiparameter flow cytometry showed the marked MRD and unmarked MRD were not significantly different between their 5-year EFS rate(P>0.05), and the every immune phenotype was also no significantly different between the 5-year EFS rate(P>0.05). The children with MRD>=10-2 at day 15(P<0.01), MRD>=10-3 at day 33 (P<0.01) and MRD>=10-3 on week 12(P<0.01) have a decreased 5-year EFS rate and overall survival, which related with poor prognosis obviously. The 5-year EFS rates at the MRD<10-4(negative), 10-4-10-3, 10-3-10-2 and >=10-2 at day 33 were 86.6+/-2.7%, 77.5+/-4.9%, 70.1+/-8.0%, and 44.8+/-9.9%(P<0.01) with significant difference respectively; the 5-year OS rate was 89.5+/-2.7%, 80+/-4.9%, 76.0+/ 7.8%, and 53.2+/-10.1% with statistically significant difference(P<0. 01). CONCLUSION: The MRD>=10-2 at day 33 is a high risk factor for significant reduction of the 5-year EFS rate and the 5-year OS rate of children with B-ALL. Thus, dynamic monitoring the MRD level can predict relapse of B-ALL after remission. PMID- 28641627 TI - [Mechanism of Apoptosis for Resveratrol-mediated Reversing the Drug-resistance of AML HL-60/ADR cells]. AB - OBJECTIVE: To explore the mechanism of apoptosis for resvertrol-mediated reversing the drug-resistance of AML HL-60/ADR cells. METHODS: The HL-60/ADR cells were divided into 4 groups: control group, adriamycin (ADR)-treated group, resveratrol(Res)-treated group and ADR+Res-treated group. The inhibitory rate of cell proliferation was analyzed by CCK-8 method. The auto-fluorescence intensity of intracellular ADR and the apoptotic rate of HL-60/ADR cells were detected by flow cytometry. The mRNA expression levels of multidrug-resistance associated protein-1(MRP1), anti-apoptotic gene BCL-2 and pro-apoptotic gene BAX were analyzed by real-time fluorescence quantitative RT-PCR. The protein expression levels of MRP1, BCL-2 and BAX were detected by Western blot. RESULTS: The maximal inhibition rates of cell proliferation were 44%, 61%, 76% and 81%, respectively in different concentration of Res (25, 50, 100, 200 umol/L) and with concentration-dependent manner(r=0.876, P<0.05). Compared with ADR group (IC50: 8.534+/-1.111 umol/L), the half inhibitory concentration (IC50) of HL-60/ADR cells [(1.591+/-0.373) umol/L] decreased significantly in ADR+Res group(P<0.05). The auto-fluorescence intensity of ADR in HL-60/ADR cells of ADR+Res group increased significantly (P<0.05). The apoptotic rate of HL-60/ADR cells in Res or ADR+Res group increased significantly (P<0.05). The mRNA expression levels of MRP1 and Bcl-2 in Res or ADR+Res groups decreased and BAX increased significantly (P<0.05). The protein expression levels of MRP1 and BCL-2 were decreased, BAX increased significantly in Res or ADR+Res group (P<0.05). CONCLUSION: Resveratrol shows the effect of reversing the drug resisitance of HL-60/ADR cells in acute myeloid leukemia, possibly via promoting the apoptosis of HL-60/ADR cells and inhibiting the expression of MRP1, which may be related with the inhibition of BCL-2 expression and the promotion of BAX expression. PMID- 28641628 TI - [Mechanisms of Astragalus Polysaccharids Synergized with Doxorubicin against Drug Resistance in HL-60/A Cells]. AB - OBJECTIVE: To explore the synergistic anti-tumor mechanism of astragalus polysaccharids(APS) combined with doxorubicin in HL-60/A cells. METHODS: The phenotype of HL-60/A was identified by using RT-PCR, Wester blot and CCK-8, the antitumor effect of astragalus polysaccharids combined with doxorubicin on HL 60/A cells was detected by CCK-8, the apoptosis of HL-60/A after treating with different drugs was detected by Annexin-V, the caspase casade activation was detected by Wester blot, the effect of astragalus polysaccharids on expression and function of multidrug resistance protein (MRP) was detected by using real time quantitative PCR and Western blot. RESULTS: HL-60/A cells displayed obvious characteristics of resistance to doxorubicin, whose resistance were about 27 times that of its sensitive cell line HL-60. In addition, it was further found that astragalus polysaccharids could obviously increase the cell growth inhibition, induce cell apoptosis and caspase cascade activation, decrease the expression of MRP and increase the drug concentration in HL-60/A when combined with doxorubicin. CONCLUSION: Astragalus polysaccharids combined with doxorubicin can effectively overcome the drug resistance of HL-60/A. The mechanism may be associated with decreasing the expression of MRP, inhibiting drug efflux and increasing the intracellular drug concentration, then inducing HL-60/A cell apoptosis. PMID- 28641629 TI - [Ratio of Primary Bone Marrow Cells after Induction Chemothrapy for Two Weeks in the Patients with Ph- ALL and Its Influence on Complete Remission and Overall Progrosis]. AB - OBJECTIVE: To investigate the influence of bone marrow blasts ratio after induction chemotherapy for 2 weeks in patients with Ph- ALL, and it's influence on complete remission (CR) and overall prognosis. METHODS: A total of 172 patients with Ph- ALL in our hospital from March 2012 to February 2016 were selected. The bone marrow blast ratio was analyzed by the receiver-operating characteristic curve (ROC) in patients after induction chemotherapy for 2 weeks, at same time its influence on CR and overall prognosis of Ph- ALL patients was evaluated. RESULTS: The cutoff value of CR was 0.075, its area under ROC was 0.763; the comparison of area under ROC with Az=0.5 showed statistically significant difference, therefore 172 patients with Ph- ALL were grouped according to bone marrow blast ratio after induction chemotherapy for 2 weeks: 104 cases (60.5%) with bone marrow blast ratio <0.075, 68 cases (39.5%) with bone marrow blast ratio >=0.075. The Ph- ALL patinets with bone marrow blast ratio <0.075 who achieved CR and finally achieved CR after induction chemotherapy for 4 weeks acconnted for 89 (85.6%) and 99(95.2%) respectively, which were significantly higher than those in Ph- ALL patients with bone marrow blast ratio>=0.075, [29(42.6%) and 52 (76.5%)](P<0.05). In addition, the influencing factor clinically reducing the OS and DFS rate of patients and enhancing the ralapse rate of patients were mainly chemotherapy, the failure of induction chemotherapy (patients did not achieve CR after induction therapy for 4 weeks), the bone marrow blast ratio>=0.075 after induction treatment for 2 weeks, and CNSL at diagnosis and so on, while the enhaced WBC count at diagnosis was poor factor affecting the DFS rate of patients. CONCLUSION: After induction chemotherapy for 2 weeks, the elevated bone marrow blast ratio in Ph- ALL patients will be infavourable to CR, and the overall prognosis is poor. PMID- 28641630 TI - [SDF-1alpha/CXCR4 Mediated Drug Resistance Can be Reversed by Ibrutinib in Acute Lymphoblastic Leukemia]. AB - OBJECTIVE: To explore the effect of Ibrutinib on the chemoresistance mediated by SDF-1alpha/CXCR4 axis in ALL cells. METHODS: Flow cytometry was used to detect the apoptosis of cell line and expression of surface membrane CXCR4, Western blot was used to determine the expression level of CXCR4, ERK and Bcl-xL proteins, qPCR was used to assay the mRNA level of CXCR4. RESULTS: Ibrutinib enhanced the apoptosis induced by adriamycin(ADR) (17.100+/-4.3% to 28.133+/-3.16%); Ibrutinib inhibited the phosphorylation of CXCR4 induced by SDF-1alpha and with concentration- and time- dependent manner (r24h=-0.99659, r48h=-0.99764, r= 0.99980). Ibrutinib inhibited the expression and activity of CXCR4 downstream signaling molecules pERK and BCL-xL. CONCLUSION: Ibrutinib can enhance the sensitivity of SUP-B15 to ADR, reverse SDF-1alpha/CXCR4-mediated chemoresistance in Ph+ acute lymphoblastic leukemia cells. This mechanism of ibrutinib may be assosiated with inhibiting CXCR4/ERK/BCL-xL. PMID- 28641631 TI - [Characteristics and Prognostic Significance of Cytogenetic Abnormalities in Diffuse Large B-Cell Lymphoma Patients with Bone Marrow Involvement]. AB - OBJECTIVE: To investigate the cytogenetic abnormalitis in patients with diffuse large B-cell lymphoma(DLBCL) patients with bone marrow involvement and their influence on prognosis. METHODS: Conventional karyotyping was performed on bone marrow specimens in 47 DLBCL patients with histologically confirmed bone marrow involvement(BMI). The karyotyping results of bone marrow, the characteristics and clinical effect of chromosomal abnormalities were analysed. RESULTS: In 47 DLBCL cases with BMI, the chromosomal abnormalities were detected in 25(53%) cases. Among them, complex karyotype was more frequent, being noted in 19(40%) patients. The most frequently involved chromosomes were chromosome 1 and 18(both 26%), others were chromosome 3(23%), 6(19%), 7, 8 and 14(13%). Among all karyotype changes, the most common numerical aberrations, in decreasing order of incidence, were trisomy 3(13%), trisomy 5, trisomy 7, trisomy 12, trisomy 18 and loss of 21(6%,each), and the most predominant structural aberrations, in decreasing order of incidence, were 1q+(17%), 1p+, 6q-, 8q+, 14q+, 18p+, 18q+ and aberrations involving band 2p21-p23 (6%,each). The prognostic impact analysis of both clinical features and cytogenetic aberrations revealed that IPI>=3 (P=0.03) or the presence of chromosomal abnormalities (P=0.005) were significantly related with poor progression free survival(PFS), and IPI>=3 (P=0.024), lactate dehydrogenase(LDH)>= three times of the upper limit of normal (P=0.027) and the presence of chromosomal abnormalities (P=0.001) predominantly related with poor overall survival(OS). In multivariate analysis, the presence of chromosomal abnormalities was the only independently adverse factor for PFS(P=0.037, HR 2.323) and OS(P=0.015, HR 2.833). The analysis of prognostic effects of specific chromosomal aberrations showed that patients with specific cytogenetic abnormalities of 1q+, 8q+, +12, 12q+, 18p+ and aberrations involving band 2p21-23 had significantly poor PFS, and patients with specific cytogenetic abnormalities of 1q+, +3, +5, +7, 8q+, +12, 12q+ and aberrations involving band 2p21-23 had significantly poor OS. When the above mentioned specific chromosomal aberrations were analyzed with clinical covariate, the presence of chromosomal aberration of 8q+ (P=0.022, HR 2.701) and IPI>=3 (P=0.043, HR 2.949) were independently poor prognostic factors for PFS, and 1q+ (P=0.032, HR 2.973) was the independently poor prognostic factor for OS. CONCLUSION: In DLBCL patients with BMI, the presence of chromosomal abnormalities is the only independently poor factor for PFS and OS, and among them, the specific cytogenetic aberrations of 8q+ or 1q+ have an independently poor prognostic impact on PFS or OS, respectively, which need to be further studied. PMID- 28641632 TI - [Clinical Efficacy of EPOCH+/-R Followed by DICE+/-R Regimen for Primary Breast Diffuse Large B-Cell Lymphoma]. AB - OBJECTIVE: To explore the clinical efficacy and safety of EPOCH+/-R followed by DICE+/-R regimen for primary breast diffuse large B-cell lymphoma. METHODS: Forty three patients with primary breast diffuse large B-cell lymphoma were admitted in our hosptial from January 2000 to April 2016. Among them 24 patients were treated with CHOP+/-R regimen, 19 patients were treated with EPOCH+/-R followed by DICE+/ R regimen. The clinical efficacy, survival rate and adverse effects were observed and compared between them. RESULTS: The complete rate in EPOCH+/-R followed by DICE+/-R regimen group was higher than that in the CHOP+/-R group (84.2% vs 70.8%), and the relapsed rate was lower in EPOCH+/-R followed by DICE+/-R regimen group than that in the CHOP+/-R group (6.25% vs 35.3%). Progression-free survival (PFS) and overall survival (OS) rates of 5 years after diagnosis in the EPOCH+/-R followed by DICE+/-R group were significantly higher as compared with that in CHOP+/-R group (PFS, 75% vs 47.4%, P=0.035; OS, 73.3% vs 45.2%, P= 0.043). Treatment-related hematologic adverse events were more serious in the EPOCH+/-R followed by DICE+/-R group(63.2% vs 25%). However, these adverse events were controlled and no treatment-related deaths were observed. Multivariate analysis showed that age (P=0.008; 95% CI, 0.026 to 0.579), radiotherapy (P=0.045; 95% CI, 1.028 to 14.719) and LDH level (P=0.007; 95% CI, 0.017 to 0.531) were independent prognostic factors for 5 year overall survival. CONCLUSION: EPOCH+/-R followed by DICE+/-R regimen is an effective and safe treatment regimen for PB-DLBCL. Prognostic factors for survival are age, LDH level and radiotherapy. PMID- 28641633 TI - [Change of NK Cell Number in Peripheral Blood of Patients with Mantle Cell Lymphoma and Its Clinical Significance]. AB - OBJECTIVE: To investigate the clinical significance of peripheral blood NK cell number change in patients with mantle cell lymphoma. METHODS: Eight-four patients with mantle cell lymphoma treated in our hospital from November 2003 to November 2011 were studied, the venous blood was collected from all patients and detected with flow cytometry. The age, sex, pathologic type, B-symptoms, clinical stage, absolute NK count(ANKC), hemoglobin(Hb), lactate dehydrogenase(LDH) and beta2 microglobulin(beta2-MG) levels, bone marrow involuement(BMI) and the international prognostic index of mantle cell lymphoma(MIPI) were recorded. All patients were followed up. RESULTS: There were no significant differences in ANKC among different age, sex, B symptom, Ann Arbor stages, Hb, LDH and beta2-MG levels, BMI and MIPI of patients with MCL(P>0.05). The sensitivity and specificity of ANKC were 76.6% and 73.8%, respectively. The optimal throshold of ANKC was 0.10*109/L and AUC was 0.798(95% CI: 0.689-0.902)(P<0.01). The 3 year PFS rate in patients with ANKC>=0.10*109/L was higher than that in patients with ANKC<0.10*109/L(68.2% vs 32.10%)(P<0.01). The 3 year-OS rate in patients with ANKC>=0.10*109/L was significantly higher than that in patients with ANKC<0.10*109/L (85.1% vs 43.8%)(P<0.01). Multivariate analysis showed that the independent predictors of PFS and OS in patients with MCL were ANKC and MIPI(P<0.05). CONCLUSION: The ANKC in peripheral blood has an important value for judging the prognosis of patients with MCL and can be used as an important index to judge the disease status of patients with MCL. PMID- 28641634 TI - [Significance of Simultaneous Analysis of Bone Marrow Smear and Bone Marrow Biopsy in the Diagnosis of Lymphoma]. AB - OBJECTIVE: To explore the value of bone marrow smear combined with biopsy in the diagnosis of lymphoma. METHODS: Clinical data of 50 cases of lymphoma from our hospital were analyzed retrospectively, and the results of the bone marrow smear and the bone marrow biopsy were compared simultaneously. RESULTS: The decision for the degree of bone marrow hyperplasia in bone marrow biopsy slice was superior to that in smear, and the active or highly active hyperplasia of nucleated cells were observed in all the bone marrow biopsies; the lymphomatic cells were observed in bone marrow smear of the 12 patients(24%), but the bone marrow biopsies showed a higher detection rate of lymphomatic cells 44% in 22 patients(P<0.05); The hyperplasia of bone marrow fibrous tissue, mainly mild to moderate, were the common in cases with bone marrow involvement and the severity of bone marrow fibrosis positively correlated with the number of lymphomatic cells. CONCLUSION: Biopsy combined with aspiration can improve the accuracy of diagnosis in lymphoma with bone marrow involvement. PMID- 28641635 TI - [Application of miR-182 for Determination of Glucocorticoid-Resistant Patients with Lymphoid Malignancy]. AB - OBJECTIVE: To validate the clinical relationship between miR-182 and glucocorticoid-resistance in patients with lymphoid malignancy. METHODS: Real time quantitative PCR(qRT-PCR) was employed to detect the expression of miR-182 in lymphoma patients (68 cases, the specimens indluded bone marrow of 20 cases, and plasma of 48 cases), multiple myeloma patients (24 cases, the specimens included bone marrow of 14 cases and plasma of 10 cases), ALL patients (3 cases, specimen was plasma of 3 cases) and non-lymphotic system disorder patients (18 cases, specimens included bone marrow of 8 cases and plasma of 10 cases). RESULTS: The expression of miR-182 in refractory lymphoblastic tumor patients was significantly higher than that in initial treatment group (P<0.05); the expression of miR-182 in initial treatment patients was not significantly different from the controls. The expression level of miR-182 in plasma of lymphoid malignancy patient significantly correlated with their used dosage of corticosteroids (P<0.05). When the expression level of miR-182 in bone marrow cells was 10.09, its sensitivity and specificity for diagnosis were 100% and 88.2% respectively; when the expression level of miR-182 in plasma was 1.393, its sensitivity and specificity for diagnosis of glucocorticoid resistance of lymphoblastic tumor cells were 90.9% and 51.3% respectively. CONCLUSION: The expression of miR-182 in lymphoblastic tumor with glucocorticoid resistance is significantly up-regulated, suggesting that the glucocorticoid resistance of lymphoblastic tumor is related with the over-expression of miR-182. The miR-182 is expected as a new biomarker for the diagnosis of glucocorticoid resistant lymphoblastic tumor. PMID- 28641636 TI - [Short and Long Term Clinical Efficacy of IMRT and CRT for Treatment of Patients with ENKTL]. AB - OBJECTIVE: To compare the short and long term clinical efficacy for treatment of patients with extranodal nasal-type NK/T-cell lymphoma(ENKTL) by intensity modulated radiotherapy(IMRT) and conventional radiotheraphy(CRT). METHODS: Sixty three cases of early ENKTL were divided into the IMRT group of (33 cases) and CRT group(30 cases). The short effects, overall survival(OS) of 3 years, progression free survival(PFS) of 3 years, acute radiation injury and late adverse reactions to radiation were compared between 2 group. RESULTS: The rate of overall response rate(ORR) were not significantly between the 2 groups(P>0.05); the OS of 3 years and PFS of 3 years were not different significantly between the 2 groups(P>0.05); the OS of 3 years and PFS of 3 years were not different significantly between the chemotherapy and non-chemotherapy group(P>0.05); the incidence and severity of oral mucosa reaction, myelosuppression, skin reaction and dry mouth were not significantly different between the 2 groups(P>0.05); the incidence of late dry mouth and swallowing obstruction feeling in the IMRT group were significantly lower than those in CRT group (P<0.05); the rate of late hearing loss, visual loss and mouth openin restriction were not different between the 2 groups(P>0.05). CONCLUSION: The short and long term clinical efficacy of IMRT and CRT for the patients with ENKTL is the same; however, the adverse radiation reactions of IMRT are lower, showing a positive significance for improvment of prognosis improving. PMID- 28641637 TI - [Clinical Efficacy and Safety of CMOD Regimen as the First Treatment for Aged New diagnosed Patients with Peripheral T-cell Lymphoma]. AB - OBJECTIVE: To investigate clinical efficacy and safety of CMOD regimen as the first treatment for the aged new-diagnosed patients with peripheral T-cell lymphoma. METHODS: Seventy-six patients diagnosed as peripheral T cell lymphoma according to chemotherapy were divided into the 2 group: A and B groups. The patients in A group received CMOD regimen (38 cases) and the patients in B group received CHOP regiment (38 cases). The clinical efficacy, PFS (progression-free survival), OS and the adverse reactions in the 2 groups were compared. RESULTS: The total effeciency rate was not statistically different between CMOD(64.52%) and CHOP groups (58.06%) (P>0.05). The adverse reactions in 2 groups were as follows: myelosuppression, mucositis, gastrointestinal reactions, fever, liver dysfunction, neurotoxicity, and alopecia etc. The incidence of alopecia and the grade III and IV of neutropenia in the CMOD group (34.21%, 13.16%) were statistically significantly lower than those in the CHOP group (84.21%, 34.21%) (P<0.05). The progression-free survival and 1-year overall survival of observation group (10.98+/-2.23 months, 14.43+/-2.48 months) were significantly higher than those in the CHOP group(8.31+/-2.62 months, 10.93+/-2.07 months) (P<0.05). CONCLUSION: The clinical efficacy of CMOD regimen has been confirmed to be equivalent with CHOP regimen for the aged new-diagnosed patients with peripheral T-cell lymphoma. This regimen can prolong the progression-free survival and overall survival to some extent and reduce the incidence of hair loss and neutropenia, which may be applied to the clinical practice. PMID- 28641638 TI - [Change of Plasma Interleukin-17 Level in Patients with Extranodal NK/T-Cell Lymphoma and Its Clinical Significance]. AB - OBJECTIVE: To investigate the clinical significance of interleukin-17 (IL-17) level in patients with extranodal NK/T-cell lymphoma(ENKTL). METHODS: Eighty patients with nasal ENKTL who received radiotherapy, chemotherapy or radiotherapy combined with chemotherapy from January 2011 to January 2012 were enrolled in the study. Eighty healthy volunteers were selected as the controls (control group). About 5 ml of peripheral blood was collected from all patients and controls. IL 17 level was determined by ELISA. The age, sex, ECOG score, B symptoms, LDH level, lymph node involvment, Ann Arbor stage, IPI, KPI, peripheral blood lymphocyte and lymph node metastasis, number of lymphocytes and monocytes in peripheral blood were recorded. All patients were followed up for 3 year progression-free survival (PFS) and overall survival (OS). RESULTS: The average IL-17 level in patients with ENKTL was 6.48 pg/ml and the average concentration of IL-17 in control group was 0.56 pg/ml (P<0.01). The level of IL-17 in patients with B-symptoms and lymph node involvement was significantly higher than that in the control group. The differences in IL-17 level were not statistically significant among patients with different age, sex, ECOG, LDH, Ann Arbor stage, IPI, KPI, lymphocyte count and monocyte cell count. The sensitivity and specificity of IL-17 were 74.5% and 73.7% respectively, and the optimal threshold was 3.49 pg/ml and AUC was 0.799 (95% CI: 0.688-0.909) (P<0.01). The PFS and OS were longer in the patients with IL-17<=3.49 pg/ml and longer in the patients without lymph node involvement and Ann Arbor I. Multivariate analysis showed that independent predictors of PFS and OS in patients with ENKTL were plasma IL-17 levels and age (P<0.05). CONCLUSION: ENKTL patients with different clinical characteristics have different levels of IL-17, the different level of IL-17 has different effects on prognosis of patients with ENKTL. PMID- 28641639 TI - [Clinical Features and Response to Treatment in Newly Diagnosed Multiple Myeloma Patients with Deletion 17P]. AB - OBJECTIVE: To investigate the clinical features and response to therapies in multiple myeloma (MM) patients with del (17p). METHODS: A total of 122 newly diagnosed MM patients hospitalized in the Department of Hematology of Peking University Third Hospital between October 2012 and September 2016 were analyzed retrospectively. The fluorescent in situ hybridization(FISH) and G-binding staining were used for detection of cytogenetic abnormalities. These MM patients with del (17p) were divided into non-bortezomib chemotherapy (VAD or CHOP) group and bortezomib chemotherapy (PAD or PCD) group. Response criteria was according to IMWG criteria, including complete remission (CR), very good partial remission (VGPR), partial remission (PR), stable disease (SD), overall response rate (ORR) was defined as CR+VGPR+PR. The Kaplan-Meier method was used to evaluate overall survival (OS) and progressive free survival (PFS). RESULTS: Cytogenetic abnormalities were detected in 60 patients, and the frequency of del(17p) was 10.7% (13 of the 122 patients). For the 13 MM patients with del(17p), median age was 59 years old, male vs female ratio was 8:5, 7 patients were found to have soft tissue plasmacytoma at the time of diagnosis, and IgG accounted for 61.5% (8/13). The frequency of coexisting other cytogenetic abnormalities was 53.8% (7/13); del(13q14) (D13S319 and/or RB1) accounted for 30.8%(4/13), and gain (1q21) 23.1%(3/13), 13 patients were able to be evaluated for the response, ORR were 33.3%(2/6) vs 100.0%(7/7), VGPR 0% vs 57.1%, PR 33.3% vs 42.9%, PD 50.0% vs 0% in non-bortezomib chemotherapy and bortezomib groups, respectively (P=0.042). 4 patients received 50 Gy radiotherapy for soft tissue plasmacytoma, no responses were observed. With a median follow up of 14(2.0-40)months, median PFS and OS time were 6(95% CI0.9-11.1) months and 21(95% CI9.0-33.0) months, respectively. Median OS in bortezomib groups was significant longer than that in the non bortezomib groups, not reachable vs 10.8(95%CI3.4-16.6) months (P=0.017). CONCLUSION: MM with del(17p) shows high frequency of soft tissue plasmacytoma, and high prevalence of coexisting gain(1q21) and del(13q14). These patients are not sensitive to non-bortezomib chemotherapy or radiotherapy, and has a poor survival. Bortezomib are able to improve the outcome of these MM patients. PMID- 28641640 TI - [Application of CD138 Immunomagnetic Sorting Myeloma Cells Combined with Fluorescence in Situ Hybridization for Detecting Cytogenetic Abnormalities of Multiple Myeloma]. AB - OBJECTIVE: To investigate the efficiency of direct fluorescence in situ hybridization (D-FISH) versus FISH on CD138 immunomagnetic sorting myeloma cells (MACS-FISH) to detect the cytogenetic abnormalities of multiple myeloma. METHODS: Thirty-one patients with multiple myeloma (MM) were detected by D-FISH and MACS FISH, using 5 probes, including 1q21, D13S319, RB1, IgH, P53. The IgH rearrangement positive patients were further examined by 3 IgH rearrangement subtype FISH probes including IgH/FGFR3, IgH/MAF and IgH/CCND1. RESULTS: Metaphase karyotyping revealed cytogenetic abnormalities in 5 cases (16.1%), clonal aberrations were detected in 13 cases(41.9%) by D-FISH, while 25 case(80.6%) with clonal aberrations by MACS-FISH. The results between these 2 FISH methods were significantly different (P=0.042). The detection frequency of clonal aberration by each probes of D-FISH was 22.6%,25.8%,29%,38.7% and 9.7% respectively for 1q21 amplification, D13S319 deletion,RB1 deletion, IgH rearrangement and P53 deletion, compared with 48.4%,45.2%,48.4%,67.7% and 16.1% respectively by MACS-FISH. The 2 FISH methods were well consistent when the percentage of plasma cells was >=20% in bone marrow smears. When the percentage of plasma cells was<20% in bone marrow smears, the difference between these 2 methods was very statistically significant (P=0.00). CONCLUSION: MACS-FISH can obviously improve the detection efficiency of cytogenetic abnormalities in patients with MM. Conventional cytogenetics combined with MACS-FISH is an ideal efficient method to detect the cytogenetic abnormalities in MM patients, and should be applied widely, especially for those patients with the plasma cells <20% in bone marrow smears. PMID- 28641641 TI - [Expression of Insulin-Like Growth Factor Binding Protein 7 Gene in Multiple Myeloma Cell Line and Methylation Regulation]. AB - OBJECTIVE: To investigate the expression of insulin-like growth factor binding protein 7 (IGFBP7 ) gene in multiple myeloma cell line U266, and study the effect of 5-aza-2'-deoxycytidine (5-aza-dc) on proliferation of U266 cells. METHODS: multiple myeloma cell line U266 was cultured in vitro. The bone marrow mononuclear cells from healthy persons(N-BMMNC) were collected and used as normal controls. The IGFBP7 mRNA expression of U266 cells and N-BMMNC were detected by real-time fluorescence quantitative PCR, the DNA methylation status of the IGFBP7 CpG island was measured by using methylation-specific PCR(MSP). The different concentrations of 5-aza-dc (5 umol/L, 10 umol/L, 20 umol/L) were used to treat U266 cells for 48 hours, the RT-PCR and Western blot were used to detect the effect of IGFBP7 mRNA and protein expressions, the cell growth curve and Annexin V/PI were analyzed by flow cytometry. RESULTS: As compared with normal BMMNC, the lower expression of IGFBP7 gene was found in U266 cells, the obvious hypermethylation of the CpG island in the IGFBP7 promoter was observed. After treatment of U266 treating with different concentrations of 5-aza-dc, the IGFBP7 mRNA expression was up-regulated dose-dependently(P<0.05), the U266 cells grew slowly and apoptosis rates were enhanced dose-dependently. CONCLUSION: As the hypermethylalion of CpG island in IGFBP7 promoter is a frequent event in lower expression of IGFBP7 gene in U226 cells, the 5-aza-dc can up-regulate the expression of IGFBP7 , and can inhibit cell proliferation through induction of cell apoptosis and arrest of cell cycle. PMID- 28641642 TI - [Clinical Efficacy of Cellular Immuotherapy Combined with Bortezomib for the Treatment of Patients with Multiple Myeloma]. AB - OBJECTIVE: To study the clinical efficacy of cellular immunotherapy combined with bortezomib for treatment of patients with multiple myeloma. METHODS: A total of 76 patients with multiple myeloma in our hospital from October 2012 to October 2013 were selected and randomly divided into 2 groups: the patients in 1 group (38 cases) were treated with cellular immunotherapy combined with chemotherapy including bortezomib (combined therapy group), the patients in other group(38 cases) were treated with only chemotherapy including bortezomib(single chemotherapy as control group). The treatment remission rate, the expression changes of immunophenotype, progression-free survival(PFS) and adverse reactions were compared in the 2 groups. RESULTS: The total remission rate of combined therapy group was significantly higher than that in the control group (P<0.05); the positive rates of CD38+, CD56+ and CD138+ in combined therapy group were all significantly lower than those in control group, and the CD19+ was significantly higher (P<0.05). The PFS rates of 1, 2 and 3 years in the combined therapy group were all significantly higher than those in the control group (P<0.05). The incidence of fatigue, rash, peripheral neuropathy, anemia and granulocyte deficiency in the combined therapy group was all significantly lower than that in the control group (P<0.05). CONCLUSION: Cellular immunotherapy combined with bortezomib can significantly improve the remission rate, prolong survival, and significantly decrease adverse event rate of multiple myeloma patients. PMID- 28641643 TI - [Change of Plasma Interleukin-16 Level in Patients with Multiple Myeloma and Its Clinical Significance]. AB - OBJECTIVE: To investigate the change of plasma IL-16 level in patients with multiple myeloma(MM) and its clinical significance. METHODS: Sixty-two patients with multiple myeloma were admitted in our hospital from June 2008 to June 2015. Forty healthy volunteers were selected as control group. The peripheral blood of all the patients and healthy volunteers were collected before the treatment of patients. The levels of IL-16, Cys-C, LDH and beta2-MG were measured. ROC curve was used to analyze the optimal IL-16 thresholds in MM patients. Kaplan-Meier method was used to analyze the factors affecting overall survival. RESULTS: The levels of IL-16, Cys-C, LDH and beta2-MG in the MM group were significantly higher than those in the control group (P<0.05). The levels of IL-16, Cys-C, LDH and beta2-MG in patients with different ISS were significantly different (P<0.05). The levels of IL-16, Cys-C, LDH and beta2-MG in ISS III groups were higher than those in ISS I and ISS II groups(P<0.05). When the IL-16 concentration was 171.26 ng/L, the AUC was 0.787 (P<0.01), and the sensitivity and specificity were 82.25% and 75.80%, respectively, when the IL-16 threshold was predicted by ROC curve analysis. The 3-year overall survival rates of patients with IL-16<=171.26 ng/L and IL-16>171.26 ng/L were 91.93% and 51.61%, respectively (P<0.01). Multivariate analysis showed that the changes of IL-16 levels were significantly related with overall survival (P<0.01). CONCLUSION: The level of IL-16 in peripheral blood of patients with multiple myeloma has been cofirmed to be significantly elevated, and the elevated IL-16 is closely related with the prognosis. PMID- 28641644 TI - [Clinical Significance of Mean Platelet Volume Determination in Multiple Myeloma]. AB - OBJECTIVE: To investigate the clinical significance of mean platelet volume(MPV) in patients with multiple myeloma(MM). METHODS: The clinical data of 198 patients with MM admitted in our hospital from March 2008 to March 2015 were collected and analyzed. The clinical data included the Ig type, hemoglobin level, platelet count, creatinine, calciumion albumin, beta2-MG, LDH, plasmocytes in bone marrow, MPV, complications such as diabetes, a history of venous thromboembolism (VTE) and arterial events such as coronary artery disease, cerebrovascular disease, thrombosis and blood clotting. All patients were divided into low MPV group (<=8.50 fl) and high MPV group (>8.50 fl). The biochemical parameters and prognosis of the 2 groups were compared. RESULTS: When MPV was 8.50 fl, the higest sensitivety and specificity were 55.56% and 80.00% respectively. The area under curve (AUC) was 0.656 (95% CI: 0.515-0.797), the IgA type, creatinine level and IgH rearrangement in MM patients were related with MPV. The ratio of IgA and IgH rearrangements in patients with low MPV was higher than that in patients with high MPV, and the ratio of patients with creatinine >176.8 umol/L was lower than that of patients with high MPV (P<0.05). The age, sex, ECOG PS, complications, ISS stage, hemoglobin level, platelet count, calcium ion, albumin, beta2 microglobulin, lactate dehydrogenase and bone marrow plasma cell ratio were not statistically significantly different between the 2 groups. Patients with low MPV had a shorter OS (P=0.039) than those with higher MPV. Univariate analysis showed that MPV, BM plasma cell ratio and age>60 years correleted with OS. Multivariate analysis showed that the low MPV and BM plasma cell ratio were correlated with shorter OS (P<0.05). CONCLUSION: The low MPV is correlated with poor prognosis in patients with MM and may serve as an important indicator for disease progression and prognosis of patients with MM. PMID- 28641645 TI - [Subtype and Functional Biomarker Changes of NK Cells in Peripheral Blood of Patients with Myelodysplastic Syndrome]. AB - OBJECTIVE: To analyze the subtype and functional biomarker expression changes of natural kill cells(NK) in peripheral blood of patients with myelodysplastic syndrome(MDS) and normal people, so as to evaluate the relationships between these changes and hematopoietic functions and to explore the role of NK cells in the pathogenesis of MDS. METHODS: The quantity of NK cells and the expression of biomarkers(NKp30,NKp46,NKG2A) on NK cells were detected by flow cytometry in 35 MDS patients from 2015 to 2016 in our hospital and 34 normal controls. The correlation between these changes and hematopoietic functions, including the percentages of neutrophil(ANC), hemoglobin in peripheral blood and the hematopoietic function in bone marrow(CD34+%) were evaluated. RESULTS: The percentage and quantity of NK cells and CD56dim NK cells in MDS patients were significantly lower than those in normal controls(P<0.05); the percentage of CD56bright NK cells was higher than that in controls. The percentage of CD56dim NK cells in NK cells of MDS patients was significantly lower than that of controls; the percentage of CD56bright NK cells in NK cells of MDS patients was significantly higher than that of controls. The expression of NKp30 and NKp46 of MDS patients was significantly lower than that of controls. In MDS group, the percentage of NK cells and CD56dim NK cells of peripheral blood lymphocytes in high risk MDS group was significantly lower than that in low risk MDS group. The percentage of NK and CD56dim NK cells negatively correlated with that of CD34+% in bone marrow, but positively correlated with ANC and Hb. The CD34+% in bone marrow negatively correlated with expression of NKp46, but positively correlated with expression of NKG2A. CONCLUSION: The decrease of NK number and function may cause the immune surveillance and lead to disease progression. PMID- 28641646 TI - [Clinical Characteristics and Long-Term Outcome of 125 Chinese Young Patients with Essential Thrombocythemia]. AB - OBJECTIVE: To investigate the clinical characteristics and long-term outcome of Chinese young patients (<=40 years) with essential thrombocythemia(ET), and to develop a thrombosis predicting model specific for young patients with ET, so as to provide a new evidence for risk stratification and treatment. METHODS: Medical records of 125 Chinese young patients with newly diagnosed of ET were retrospectively analyzed. RESULTS: The median age at diagnosis was 32 (18-40) years old, with 37 males and 88 females. During follow-up, 18 patients (14.4%) experienced major thrombotic events. JAK2 V617F (HR=8.895, P=0.001), history of thrombosis (HR=8.001, P<0.001) and WBC>=12.0*109/L (HR=5.225, P=0.002) were independent risk factors for thrombosis. The incidence of thrombosis and risk factors in young patients were different from that in general ET population, so a thrombosis predicting model specific for young patients with ET was developed. In this model, JAK2 V617F (score 2), history of thrombosis (score 2) and WBC>=12.0*109/L (score 1) were used to divide the patients into low risk (score 0), intermediate risk (score 1-2) and high risk (score>=3) groups. These 3 groups exhibited significantly different thrombosis-free survival (chi2=32.223, P<0.001). Antiplatelet treatment could prevent the occurrence of thrombosis (HR=0.081, P<0.001), while cytoreductive agents significantly decreased the risk of thrombosis only in intermediate and high risk groups (14.3% vs 36.4%, chi2=4.416, P=0.036). Seven patients (5.6%) evolved to myelofibrosis, and one of them finally progressed in to acute leukemia. The only risk factor for evolution was WBC>=15.0*109/L (chi2=5.434, P=0.020). Neither antiplatelet treatment nor cytoreductive agents could prevent disease progression. CONCLUSION: The incidence of thrombosis and risk factors in young patients with ET are different from that in general ET population. The thrombosis-predicting model specific for young patients with ET is useful for guiding therapeutic decisions. PMID- 28641647 TI - [Clinical Significance of Serum Thrombopoietin Levels in Patients with Aplastic Anaemia]. AB - OBJECTIVE: To evaluate the clinical significance of thrombopoietin (TPO) level in diagnosis of pateints with aplastic anaemia (AA). METHODS: The TPO levels in sera from 54 AA patients and 119 healthy controls were examined. A total of 92 samples were collected from AA patients including 43 samples harvested at diagnosis, 23 samples in the cytopenic period after treatment, and 26 samples of patients in partial (n=10) or complete remission (n=16) following immunosuppressive treatment. Serum TPO levels were assessed by a sandwich-antibody ELISA that utilized a polyclonal rabbit antiserum for both capture and signal. RESULTS: Serum samples from normal donors revealed a mean TPO level of 95.3+/-54.0 pg/ml, the mean TPO levels in AA sera collected at diagnosis and before onset of treatment were 2728+/-1074 pg/ml (P<0.001) compared with normal controls; mean platelet count at that time: 27*109/L). Serum TPO levels of AA patients in partial or complete remission after immunosuppressive treatment were significantly lower than TPO levels at diagnosis (P<0.001). However, despite normal platelet counts (mean 167*109/L), TPO levels remained significantly elevated in complete remission (mean TPO 1009+/-6590 pg/ml (P<0.001) compared with normal controls. There was a significant negative correlation between serum TPO levels and platelet counts in AA patients (coefficient of correlation r= 0.70, P<0.001). CONCLUSION: TPO levels are highly elevated in sera of patients with AA. Thrombopoietin did not return to normal levels in remission, indicating normal platelet count in remission of AA needs sustained high level of TPO. PMID- 28641648 TI - [Change of Thrombelastography in Children's DIC and Analysis of Its Sensitivity and Specificity for Diagnosis of DIC]. AB - OBJECTIVE: To investigate the influence of thrombelastography index changes on its sensitivity and specificity for diagnosis of disseminated intravascular coagulation (DIC) in children. METHODS: A total of 149 children with DIC in our hospital from June 2013 to June 2016 were selected in DIC group, while 106 cases of non-DIC, including healthy children and children with diseases easily confused with DIC, were selected as non-DIC(control) group. The thrombelastography, D dimer, coagulation functions including prothrombintime (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and fibin degradation product (FDP), congental coagulation disorders and platelet count were detected in DIC and non DIC groups; the statistics of data was performed and the sensitivity and specificity of thromelastraphy indexes such as R time, alpha angle MA value and A value were evaluated; the relationship of DIC with indexes was analyzed. Moreover, the result difference of thromelastography and routine coagulation function test was compared at diagnosis of DIC. RESULTS: According to statistical analysis of clinical data in 2 groups, the average R time in non-DIC group was significantly less than that in DIC group (P<0.05); the average alpha angle in non-DIC group was larger than that in DIC group (P<0.05), both the MA and A values in the non-DIC group were significantly higher than those in DIC group (P<0.05). The specificity of routine coagulation function test for diagnosis of DIC was as follow: PT-27.2%, APTT-42.2%, international normalized ratio(INR) 47.9%, FIB-44.4%, FDP-42.7% and D-dimer-68.3%, which were significantly lower than that of R time,alpha angle and MA value for diagnosis of DIC (85.1%, 74.1% and 73%). The alpha angle and MA value of healthy children were greater than those of children with severe liver disease(P<0.05). while the average R time of healthy children was less than that of children with severe liver disease(P<0.05), but the difference of A value between them did not statistically significant (P>0.05) . The average R time of healthy children was less than that of children with congenital coagulation disorders (P<0.05). but there was no significant differences in alpha angle MA and Avalues between them. CONCLUSION: As compared with routine coagulation function test, the thrombelastography shows more high specificity for diagnosis of DIC, and can more precisely diagnose the DIC; moreover, the thrombelastography combined with roatime coagulation function test can more early find and diagnose the DIC in children, therefore it can improve the survival rate of children with DIC. PMID- 28641649 TI - [Hemostatic Effect of Spleen-invigorating, Qi-replenishing and Blood-containing Formula on Simvastatin-induced Zebrafish Hemorrhage Model]. AB - OBJECTIVE: To investigate the hemostatic effect of spleen-invigorating, qi replenishing and blood-containing formula on simvastatin-induced zebrafish hemorrhage model, and to compare with the effect of clearing heat and cooling blood formula. METHODS: Zebrafishes from breed A B line were treated with 0.5 umol/L simvastatin for 24 hours to establish zebrafishes hemorrhage model. Under strict blinded experimental conditions, the above mentioned zebrafishes were then treated with experimental drug of different concentrations at the maximum non lethal dose. The intervention effect of spleen-invigorating, qi-replenishing and blood-containing formula was comprehensively assessed by examining the main observational parameters, such as bleeding reduction rate and hemostasis rate while referring to additional parameters, such as blood flow, improvement rate of blood flow, velocity of movement, improvement rate of motion, which are characteristics of spleen qi deficiency. RESULTS: When the hemostatic effect of experimental drug B1 at the concentrations of 500 and 1 000 ug/ml, zebrafish bleeding rates were 30% and 15%, the hemostatic rate was 60% and 80%, respectively; when the experimental drug B2 at concentration of 500 and 1 000 ug/ml, Zebrafish bleeding rates were 45% and 40%, the hemostatic rate was 40% and 47%, respectively, showing that experimental drug B1 was superior to B2 in terms of decreasing bleeding rate and improving hemostatic effect in zebrafish. In the equal concentration, the experimental drug B1 was superior to B2 in terms of increasing and improving the blood flow of hemorrhagic zebrafish. Promotion and improvement of motion: in equal concentration, experimental drug B1 was superior to B2 in terms of promoting the motion velocity and increasing the improving rate of motion in zebrafish. CONCLUSION: The spleen-invigorating, qi-replenishing and blood-containing formula displays a good hemostatic effect on simvastatin-induced hemorrhage of zebrafish. It also boosts the blood flow and motion velocity in hemorrhagic zebrafish, therefore, providing an experimental basis for the treatment of syndrome of spleen failing to control blood by spleen-invigorating, qi-replenishing and blood-containing formula. PMID- 28641650 TI - [Changes of Thrombopoietin Levels in Patients with Acute Inflammatory Disease and Its Significance]. AB - OBJECTIVE: To investigate the changes of TPO levels in patients with acute inflammatory response disease of different etiologies. METHODS: In the case control study, 65 patients with acute inflammatory response disease were enrolled in the case group (15 patients with acute myocardial infarction, 15 patients with acute cerebral infarction, 25 patients with acute trauma and 10 patients with acute pneumonia), and 42 healthy subjects were selected as the control group. The levels of TPO in peripheral blood and blood cell counts between the case group and the control group were compared by Student's t test for examing whether the level of TPO in acute inflammation states was higher than that in healthy people. And, by using Kruskal-Wallis H test and Nemenyi test, subsequent subgroup compaison was performed to assess whether there was a difference in TPO levels under the condition of inflammation of different etiologies and at different levels. RESULTS: Compared with the control group,serum TPO levels in case group were significantly higher (181.11+/-35.38 vs 96.13+/-9.7 pg/ml)(P<0.001), and the white blood cell count in case group (9.64+/-3.43)*109/L was higher than that in control group(7.35+/-1.49)*109/L(P<0.001), but the platelet count in the case group was not statistically different from that in the control group (P=0.313). In the further subgroup analysis, it was found that changes in TPO level were different in different levels of inflammation. The level of TPO in patients with inflammatory disease of high level(acute trauma, acute pneumonia) was greatly higher than that in patients with inflammatory disease of low level(acute myocardial infarction, acute cerebral infarction) (P<0.05), and there was no statistically significant difference in platelet count among subgroups. CONCLUSION: In acute inflammation states, the increase of serum TPO levels does not correlate with platelet counts, but correlates with inflammation levels, and TPO may act as an acute response protein to protect the body. PMID- 28641651 TI - [Effect of Infusion of Recipient Spleen Cells at Different Time after Murine Haploidentical Hematopoietic Stem Cell Transplantation on Graft Versus Host Disease]. AB - OBJECTIVE: To explore the effect of infusing G-CSF mobilized recipient spleen cells at different time after haploidentical stem cell transplantation(HSCT) on graft-versus-host disease (GVHD) in mice and its possible mechanism. METHODS: Forty mice after HSCT were randomly divided into 4 groups (n=10): GVHD positive control group (control group), 1st d recipient cell infusion group after transplantation (+1 d group), 4th d recipient cell infusion group after transplantation(+4 d group), 7th d recipient cell infusion group after transplantation(+7 d group). The mice in control group were injected the normal saline of same equivalent with experimental group which were given the same amount of G-CSF-mobilized recipient spleen cells. The general manifestation and pathological change of GVHD were observed. The expression changes of CD3+CD4+, CD3+CD8+ cell subsets and FasL in peripheral blood were detected by flow cytometry. RESULTS: The incidence of GVHD was significantly decreased in +4 d group and the median survival time was longer than 60 days, which was significantly higher than that of control group (24 d), +1 d group (21 d), +7 d group (28 d). (P<0.01, P<0.01, P<0.01). The Fasl expression of peripheral blood T lymphocytes in +4 d group were significantly lower than that in the other 3 groups(P<0.05). CONCLUSION: The +4 d infusion of G-CSF mobilized recipient spleen cells on 4th day after haploidentical HSC transplantation can inhibit the expression of FasL in donor T lymphocytes, and significantly reduce the incidence of GVHD. PMID- 28641652 TI - [Significance of Monitoring Minimal Residual Disease by Flow Cytometry in Acute Leukemia Patients Underwent Nonmyeloablative Allo-HSCT]. AB - OBJECTIVE: To explore the value of dynamically monitoring minimal residual disease (MRD) by flow cytometry before and after non-myeloablative allo-HSCT (NST) for prediction of acute leukemia(AL) relapse after transplantation. METHODS: The clinical data of 51 AL patients underwent NST were analyzed retrospectively in Department of Hematology of Affiliated Hospital of Academy of Military Medical Sciences from January 2011 to December 2015. All AL patients achieved the morphologic complete remission of bone marrow before transplantation. The bone marrow samples were collected for monitoring of MRD within 35 days before transplant, every month till 3 months after transplant, every 3 months till 24 months after transplant, and then every 6 months after 2 years of transplant. According to the MRD cutoff value of 0.2%, the AL patients were divided into high level MRD group (18 cases) which was defined as MRD>=0.2% after transplantantion at least for 1 time, and low level MRD group (33 cases) which was defined as MRD<0.2% after transplant all the time. 2 year cumulative relapse rate in 2 groups were compared. RESULTS: Two-year relapse rates were 6.1% and 50% in low-level MRD group and high-level MRD group post NST(P=0.001)respectively. Multivariate analysis indicated that the risk of relapse in high level MRD group was 5.84 times of low level MRD group(P=0.036). MRD>=0.2% post transplant was an independent risk factor for leukemia relapse post NST. The mortality rate was 81.8% and 46.3%(P<0.05) in relapse and non relapse groups respectively. CONCLUSION: Dynamically monitoring MRD by FCM is a crucial tool for early relapse estimation of acute leukemia in adult patients after allogeneic nonmyeloablative hematopoietic stem cell transplantation. MRD>=0.2% after transplant can be used as a early valuable evidence for predicting relapse and guiding active medical intervention. PMID- 28641653 TI - [Risk Factors and Therapeutic Outcome of Intestinal Acute Graft Versus Host Disease in Acute Leukemia Patients after Haploidentical Peripheral Hematopoietic Stem Cell Transplantation]. AB - OBJECTIVE: To investigate the risk factors and therapeutic outcome of acute graft versus host disease (aGVHD) in patients with acute leukemia after haploidentical peripheral hematopoietic stem cell transplantation. METHODS: The clinical data of 19 cases of acute leukemia underwent haploidentical hematopoietic stem cell transplanttion during January 2010 and December 2010 were retrospectively analyzed. The effects of patients sex, donor-recipient sex difference, donor age, conditioning regimen, dosage of anti-thymocyte globulin(ATG), mononuclear cell and CD34+ cell counts on the intestinal aGVHD were analyzed by Logistic regression. RESULTS: Intestinal aGVHD occurred in 5 cases with 1 case at stage II 3 cases at stage III and 1 case at stage IV on the 7th, 22th, 27th, 70th and 154th day after transplantation, respectively. Single factor analysis showed that the patient's sex, donor-recipient sex difference, donor age, dosage of ATG, mononuclear cell and CD34+ cell counts were not related with the occurrence of the intestinal aGVHD, and the conditoning regimen was the risk factor for the intestinal aGVHD. 2 cases among 5 cases with intestinal aGVHD were treated with methylprednisolone at dosage of 1 mg/kg per day, 1 case was treated with methylprednisolone therapy combined with tacrolimus. 2 cases of methylprednisolone-resistance were treated with CD25 monoclonal antibody. Intestinal aGVHD of all patients was improved after the above-mentioned treatment. CONCLUSION: Conditioning regimen of haploidentical peipheral hematopoieitc stem cell transplantaion has effects on the intestinal aGVHD, which needs to be confirmed by further research. PMID- 28641654 TI - [Efficacy and Safety of Posaconazoleon for Primary Antifungal Prophylaxis against Invasive Fungal Disease in Patients with Stem Cell Transplantation]. AB - OBJECTIVE: To investigate the efficacy and clinical safety of posaconazoleon primary antifungal prophylaxis against invasive fungal disease (IFD) in patients with stem cell transplantation. METHODS: At the start from preconditioning regimen, 45 patients without IFD were administered with posaconazoleon until neutrophils greater than 0.5*109/L, 35 patients treated with micafungin were enrolled in control group. The incidence, risk factors of IFD and side effects of medicines were evaluated. RESULTS: Of the total 80 patients, 13(16%) had IFD within 100 days after allo-HSCT. The overall survival was significantly different between patients with or without IFD by Kaplan-Meier survival curve analysis (P<0.05). Out of the 45 cases in posaconazoleon group, IFD occurred in 4 cases (9%). In contrast, the incidence of IFD in control group was 26%(9 out of 35) (P<0.05). The risk factors of IFD and side effects were not significantly different between 2 groups(P>0.05). CONCLUSION: The primary prevention efficancy of IFD by posaconazoleon after allo-HSCT is much better than that of micafungin with well tolerability and satisfactory efficacy. PMID- 28641655 TI - [IL-1beta-Treated Bone Marrow Mesenchymal Stem Cells Enhances Osteogenetic Potential via NF-kappaB Pathway]. AB - : Obsjective:To investigate the effects of differentaction time of IL-1beta on the osteogenic capacity of bone marrow mensenchymal cells(BMMSC) and the role of nuclear factor-kappaB (NF-kB) pathway. METHODS: BMMSC isolated from normal donors was treated with IL-1beta for 1 or 7 days, respectively. Alkaline phosphatase (ALP) and alizarin red(AR) stainings were used to detect the osteogenic differentiation potential of BMMSC. The mRNA expression of EphB4, IGF-1 and OPG in BMMSC was measured by real-time PCR. The immunohistochemistry was employed to measure the expression of bone morphgenetic protein-2(BMP-2) and p-Smad1/5/8 in BMMSC. Furthermore, the Western blot was used for the detection of ikappaBalpha and phospho-ikappaBalpha (p-ikBalpha) in IL-1beta-treated BMMSC. And the results of IL-1beta-treated BMMSC were compared with control group. RESULTS: Compared with control group, the osteogenetic potential of IL-1beta-treated BMMSC was enhanced, but the pro-osteogenic differentiation effect of IL-1beta was remarkedly inhibited in the presence of NF-kB pathway inhibitor PDTC. The total ikBalpha level of IL-1beta-treated BMMSC was lower (P<0.05), and phospho ikappaBalpha (p-ikappaBalpha) level was higher (P<0.05). Besides, BMP-2 expression was higher (P<0.05) in the IL-1beta-treated BMMSC, however, p Smad1/5/8 protien level was not significantly different among IL-1beta-treated for 1 d, 7 d and control groups (P<0.05). And the mRNA expression levels of IGF 1, EphB4 and OPG in BMMSC were up-regulated after IL-1beta treatment (P<0.05). In addition, the osteoblastogenesis of BMMSC treated with IL-1beta for 7 days was significantly different from those treated only for 1 day. CONCLUSION: Prolonging IL-1beta treatment can enhance the osteogenetic differentiation of BMMSC more significantly. And this osteogenetic alteration of BMMSC occurs via its NF-kappaB pathway, but not via BMP-2/Smad pathway. PMID- 28641656 TI - [Effect of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells on the Proliferation and Apoptosis of Leukemic Cells and Its Mechanism]. AB - OBJECTIVE: To investigate the effects of human umbilical cord blood-derived mesenchymal stem cells(HUCMSC) on the leukemic cell line HL-60 and acute lymphoblastic leukemia cell line Jurkat as well as the role of CXCL12/CXCR4. METHODS: HL-60 cells and Jurkat cells were co-cultured with human umbilical cord blood mesenchymal stem cell (HUCMSC), and the model was treated with G-CSF, AMD3100 and their combination. The cell viability and cell cycle were measured by Cell Counting Kit-8 (CCK-8), the apoptosis and the cell-cycle analysis were assessed by flow cytometry with the Annexin V/PI double staining. The expression of surface CXCR4 protein and total CXCR4 protein of leukemic cells were detected by flow cytometry and Western blot respectively. RESULTS: HUCMSC could decrease the viability of HL-60 cells and Jurkat cells, as well as the percentage of apoptotic cells, they could also increase the number of G0/G1 cells, while G-CSF and AMD3100 could reduce the proliferation of HL-60 cells and Jurkat cells in HUCMSC co-culture model, destructed the anti-apoptotic effect of HUCMSC on HL-60 cells and Jurkat cells, and the combination of 2 drugs resulted in a synergistic effect. The G-CSF could reduce the expression of surface CXCR4 protein and total CXCR4 protein in leukemic cells, while AMD3100 could only decrease the expression of surface CXCR4 protein of leukemia cell membrane, having no effect on the expression of CXCR4 protein in cytoplasm. CONCLUSION: Human umbilical cord blood mesenchymal stem cells can inhibit the proliferation and apoptosis of acute leukemia cells and increase the number of G0/G1 phase cells in leukemic cells. The AMD3100 can decrease the expression of surface CXCR4 protein in leukemia cells, G-CSF can decrease expression of total CXCR4 protein as well as membrane CXCR4 protein. Both of them can block the CXCL12/CXCR4 signal axis, weakening the relationship between leukemia cells and microenvironment. And on the basic of HUCMSC influenced leukemia cells' growth and proliferation, the cell viability will be weakened, its apoptosis will be promoted, and the percentage of G0/G1 phase cells in leukemia cells will be decreased. PMID- 28641657 TI - [Affected Factors of Separating Erythrocytes by Discontinuous of Density Gradient Centrifugation]. AB - OBJECTIVE: To study the affected factors of the separation of red blood cells by discontinuous density gradient method, and to establish the optimal operating conditions of percoll for the separation of erythrocytes. METHODS: The osmolality of different ratio of Percoll and 1.5 mol/L NaCl were 9:1, 10:1, 11:1, 12:1, 13:1 ratio, was detected respectively. The isotonic osmolality ratio was selected as optimum stock isotonic Percoll solution(SIP). Evaluation criteria: All the different density cells were separated sufficiently by centrifugation, there is little red cell retention and entrainment phenomena. The separation efficacy of different red cell suspension concentration, different centrifugal force, different centrifugal speed, different temperature and different time were compared. RESULTS: The separation efficacy of red cell suspension concentration which not exceed 50% was better than above 50%, efficacy of 4 000*g was superior to 3 000*g and 2 000*g, 2-8 centrifugal acceleration and deceleration centrifugal could obtain the satisfactory efficacy, the 4 degrees C layered effect was more stable than room temperature, the separation effect of 20 min was better than 15 min and 10 min. CONCLUSION: Percoll and 1.5 mol/L NaCl 12:1 to 11:1 can be used as stock isotonic percoll solution, preferentially selected 4 degrees C as centrifugal conditions. When conditions of separation was satisfied, the centrifugal acceleration and deceleration is 2-8, the optimal centrifugal effect can be obtained with the decrease of erythrocyte suspension concentration, with centrifugation time prolonging and centrifugal force increasing. PMID- 28641658 TI - [Effects of Different Storage Time and Temperature on Coagulation Function of Fresh Frozen Plasma after Thawing]. AB - OBJECTIVE: To investigate the coagulation function changes of fresh frozen plasma storaged at different storage time and temperature after thawing. METHODS: Forty unit of fresh frozen plasma were collected, and thawed at 37 degrees C for 25 minutes. Each unit was divided into 2 halves: one was stored at (4+/-2) degrees C for 72 hours and the other one was stored at (25+/-2) degrees C for 72 hours. At the time point of 0, 4, 24, 48 and 72 h, thromboela-stogram TEG was measured for all samples. At the the same time, factors V,VII,VIII and IX, APTT and PT were also measured for all the samples. Blood culture for all the samples was used to discover aerobic and anaerobic bacteria. RESULTS: All the samples could form a stable blood clot after thawing for 72 h, and the blood culture results of all samples were negative. Significant changes were observed in ACT and TMA between 0 h and other test time, but there was no difference between 4 degrees C and 25 degrees C. The activity of factor V was significantly different between 4 degrees C and 25 degrees C after storing for 48 and 72 hours, which was reduced faster at 25 degrees C. CONCLUSION: Although part of the coagulation factor activity were attenuated after fresh frozen plasma being thawed and stored for 72 hours at different temperature, but all samples can form stable blood clots. Fresh frozen plasma stored for more than 72 hrs after thawing can be used to supplement the coagulation factors to patient. PMID- 28641659 TI - [Experimental Study on Neonatal ABO or RhD Compatible Blood Transfusion]. AB - OBJECTIVE: To investigate the safety and effectiveness of neonatal ABO or Rh(D) by using compatible blood transfusion through retrospective analysis of data from cases received compatible blood transfusion and type matched blood transfusion. METHODS: The clinical data of 26 cases of neonatal compatible blood transfusion in Chinese Nanchang area from January 2014 to October 2016 were collected, and 26 cases of neonatal type-matched blood transfusion were selected according to ratio of 1:1 cases. The efficiency and safety index of 26 patients compatible blood transfusion were compared with that of type-matched blood transfusion. The efficiency indexes included: patients' basic characteristics, red blood cell (RBC) count, hemoglobin (Hb) level, hematocrit (Hct), and the safety indexes contain Hb level and indirect bilirubin (IBiL) value before and after blood transfusion, irregular antibody screening, direct antiglobulin test (DAT) results and the adverse reactions of blood transfusion. RESULTS: The age, sex, days of hospitalization between compatible blood transfusion and type matched blood transfusion were not statistically significantly different (P>0.05). The Hb level before transfusion, blood transfusion volume and the increase of Hb, Hct and RBC were not statistically significantly different between two groups (P>0.05). The values of Hb, Hct and RBC in 2 groups significantly increased at the day 1 after blood transfusion (P<0.05). No blood transfusion adverse reaction occurred in 2 groups. The IBiL value significantly decreased in compatible blood transfusion patients at the day 1 after blood transfusion (P<0.05). No new irregular antibodies had been detected after transfusion in all patients, and the others' DAT and screening for irregular antibodies were negative except 22 patients with neonatal hemolysis. The values of Hb and IBiL statistically significantly differenence were not in 12 patients between 1d, 3d, 7d after blood transfusion (P>0.05). CONCLUSION: The efficiency and safety between compatible blood transfusion and type matched blood transfusion are the same in neonatal blood transfusion. Compatible blood transfusion is a safe and effective in clinical blood transfusion. PMID- 28641660 TI - [Comparison of Laboratory Indexes and Therapeutic Efficacy between Two Kinds of Different RBC Transfusion in AIHA Patients]. AB - OBJECTIVE: To investigate the effect of 2 kinds of red blood cells (RBC) on the laboratorial indexes and therapeutic efficacy of patients with autoimmune hemolytic anemia (AIHA). METHODS: The clinical data of 120 patients with AIHA from June 2015 to June 2016 were analyzed retrospectively. These 120 patients were divided into A goup and B group. The patients in A group (60 cases) were infused with washed RBC, while the patients in B group (60 cases) were infused with WBC-deplated RBC. The changes of laboratotial indexes, clinical symptoms and incidence of adverse reactions in 2 groups before treatment and at 24 hourse after treatment as well as the therapeutic efficacy and improvement status of clinical symptoms were compared. RESULTS: The RBC count and Hb level in 2 groups after treating for 1 day were significantly higher than those before treatment (P<0.01), while the TBIL level and reticulocyte (Ret) count were significantly lower than those before treatment (P<0.01). However, the RBC, Hb, TBIL levels and Ret count in 2 groups before and after treatment showed no statistical difference (P>0.05); the improvement of clinical symptoms, complex therapeutic efficacy and incidence of adverse reactions in 2 groups after treatment also showed no significantly difference (P>0.05). CONCLUSION: Both washed and leukocyte-deplated RBC can alleviate the anemia in patients with AIHA in short-time, but the leucocyte-deplated RBC is more expensive, suggesting that the wased RBC is more practical for treatment of AIHA patients. PMID- 28641661 TI - [Clinical and Pathologic Features of Myeloid Sarcoma]. AB - OBJECTIVE: To explore the clinicopathologic features, differential diagnosis and therapy of myeloid sarcoma. METHODS: The clinical data including clinical manifestations, laboratorial tests, histopathologicical examination, immunohistochemistry and clinical prognosis of 10 patients with myeloid sarcoma were analyzed retrospectively. Among 10 patients, 5 male and 5 female, aged 23 to 71 years old (median = 36 years). RESULTS: 2 cases of myeloid sarcoma were secondary from chronic myeloid leukemia, and 1 cases of myeloid sarcoma occurred after the allogeneic hematopoietic stem cell transplantation due to acute myeloid leukemia, and the others lacked the anamnesis of malignancies. The neoplasms occurred at bone, brain, skin, breast, epididymis, uterine cervix, small intestine, ovary and lymph nodes. Microscopically, the tumor cells were round or oval, which infiltrated diffusely or arranged in single-file. The cytoplasm was scarce and immature eosinophils were scattered. The nuclei were round, oval or focally irregular, and the mitosis was visible. The neoplasms were positive for MPO, CD34, CD43, CD45, CD99 and CD117 by immunohistochemical staining. 4 patients progressed into acute myeloid leukemia from 2 to 10 months after the diagnosis of myeloid sarcoma. All of them achieved complete remission after inductive chemotherapy, but 3 patients relapsed from 3 to 12 months after remission and only survived for 14 to 23 months. 4 patients were treated by using chemotherapy before bone marrow abnormality, and with the disease-free survival for 1 to 48 months. CONCLUSION: Myeloid sarcoma needs to be distinguished from lymphoblastic lymphoma, Burkitt's lymphoma, blastic plasmacytoid dendritic cell neoplasms and so on. The diagnosis and differential diagnosis of myeloid sarcoma are dependent on the pathological and immunohisto-chemical features. The chemotherapy and allogeneic hematopoietic stem cell transplantation of acute myeloid leukemia are the main methods for treatment of myeloid sarcoma. PMID- 28641662 TI - [Effect of PDK1 on Neutrophil Differentiation]. AB - OBJECTIVE: To knock out PDK1 by using Vav-Cre and observe the effects of PDK1 knock out on the ratio, number and differentiation of neutrophil. METHODS: The PDK1 expression level of Vav-Cre;PDK1lox/lox mouse in the bone marrow cells was analyzed by RT-PCR. The effect of PDK1 on hematopoietic progenitor was observed by CFU-C assay, and the effect of PDK1 on the ratio and number of neutrophil was detected by flow cytometric analysis. RESULTS: The RNA expression level of bone marrow cells of Vav-Cre;PDK1lox/lox mouse was dramatically lower than that of the control mouse. The number of functional GMP was lower in Vav-Cre;PDK1lox/lox mouse in contrast to controls. The percentage and number of neutrophil were lower, but the percentage of premyelocyte/myelocytes was more than 2 times in Vav Cre;PDK1lox/lox group compared with control groups. CONCLUSION: PDK1 affects the process of the differention of hematopoietic stem cells to GMP, the neutrophil differention and maturation. PMID- 28641663 TI - [Expression Changes of Hepcidin and Ferroportin 1 in Murine Model of Iron Overload]. AB - OBJECTIVE: To investigate the changes of hepcidin and ferropotin 1 expression in murine model of iron overload. METHODS: The murine model of iron overload was established, C57BL/6 mice were injected with iron dextran intraperitoneally (10 mg) every 3 days for 4 weeks. Blood routine, serum ferritin and pathological sections were tested at the appointed time-point respectively (before iron injection, 2 weeks and 4 weeks after treatment of iron injection). The serum hepcidin was assayed by enzyme-linked immunosorbent method. The expression of ferroportin 1 in bone marrow cells was detected by RT-PCR and Western blot, respectively. The labile iron pool of bone marrow cells was measured by flow cytometry. RESULTS: The absolute number and percentage of reticulocytes in the iron-overloaded mice were significantly decreased along with the increase of iron injection times (r=-0.938, r=-0.947), while no significant change was found in the number of white blood cells, hemoglobin level and platelet count. The level of serum ferritin was increased along with increase of iron injection time (r=0.894). Iron overload was found in pathological sections of different organs. Furthermore, serum hepcidin was increased along with increase of iron injection time (r=0.957). RT-PCR and Western blot analyses showed that the expressions of ferroportin 1 at mRNA and protein level were increased in the murine model of iron overload (P<0.05). Labile iron pool in bone marrow cells was also found to be increased in the murine model of iron overload(P<0.05). CONCLUSION: The expressions of hepcidin and ferroportin 1 are increase in a murine model of iron overload, which may be contributed to the suppression effect on erythropoiesis in bone marrow. PMID- 28641664 TI - [Research Progress of Cell Immunotherapy in Treatment of Hematological Malignancies-Review]. AB - Cell immunotherapy, as an important mean of tumor therapy, infuses a large number of immune effector cells amplified in vitro to the patients, resulting in the anti-tumor effect. There have been a series techniques of cell immunotherapy, including T lymphocyte therapy, dendritic cell-based immune cell therapy, natural killer cell therapy, gamma delta T cell therapy and so on. The preparation and culture conditions, anti-tumor mechanism, target cells etc of these immune cells are not the same, the each with its advantages and disadvantages. Many clinical studies have showed that the patients with a variety of tumors including hematological malignancies, who adopted cell immuno-therapy, had the prolonged survival, an improved quality of life, and with the less adverse reactions. This review summarizes the available data on the characteristics of different cell immunotherapies and their application in hematological malignancies. PMID- 28641665 TI - [Research Progress of Ras/Raf/MEK/ERK Signaling Pathways in Leukemia-Review]. AB - Ras/Raf/MEK/ERK signaling pathway plays an important role in the occurrence and development of leukemia. Using the inhibitors of key signaling components in the signaling pathway is new strategy for the treatment of leukemia. In recent years, the screening of these inhibitors and their in vitro and in vivo researches have become a hot spot in the field of treatment. In vivo and in vitro experiments and early clinical studies have shown that these inhibitors have good effect and application prospects in the treatment of leukemia. This review focuses on the recent advances of the role of Ras/Raf/MEK/ERK signaling pathway in the occurence, development and treatment of leukemia. PMID- 28641666 TI - [Rare Blood Group and its Progress of Research in Transfusion Medicine -Review]. AB - As one of key factors for transfusion reaction, rare blood group has attached lots of attention for a long time. The proportion of the people population with rare blood group is actually low, however, the improper disposition caused by human error always leads to severe medical accident, showing its undoubted importance in transfusion medicine. Recently, more research about rare blood group are reported. Therefore, this review summarizes the development of this aspect, including mainly rare blood group, the detection of blood group phenotype, and the way of transfusion for rare blood group. PMID- 28641667 TI - [Research Progress on Genetic Factors and Hemophilia A Clotting Factor Inhibitor Review]. AB - Hemophilia A (Hemophilia A, HA) is an X-linked recessive hereditary coagulation function disorder, the deficiency and dysfunction of blood coagulation were caused by the mutations of gene encoding clotting factor VIII. The treatment of hemophilia A still depends on the replacement therapy with blood coagulation factor. However, the repeated infusion of clotting factor will produce the neutralizing antibody against FVIII, then resulting in one of the serious complications. The reports on the incidence of inhibitor are different at home and abroad. Due to diverse factors, the inhibitors of hemophilia A clotting factor mainly can be divided into genetic and environmental factors, In this review, the inhibitors of hemophilia A clotting factor and their risk factors are briefly summarized. PMID- 28641668 TI - [Clinical Significance and Detection Techniques of Minimal Residual Disease in Multiple Myeloma-Review]. AB - The outcomes for the patients with multiple myeloma (MM) have been improved substantially in both progression-free survival and overall survival in the past decade. Many patients are now achieving a complete response to treatments. Extensive data indicate that the information about minimal residual disease (MRD) can be used potentially as a biomarker to evaluate the efficacy of different treatment strategies instead of overall survival. Consequently, highly sensitive assays have been already used in progress for detection of MRD in the patients with MM, such as multiparameter flow cytometry, polymerase chain reaction(PCR), next-generation sequencing and positron emission tomography/computed tomography. This review presents an overview of the clinical significance of MRD in patients with MM and charactemitics of four detection techniques for MRD. PMID- 28641669 TI - Effect of Biological and Mass Transfer Parameter Uncertainty on N2O Emission Estimates from WRRFs. AB - This research used the detailed activated sludge model (ASM) to investigate the effect of parameter uncertainty on nitrous oxide (N2O) emissions from biological wastewater treatment systems. Monte Carlo simulations accounted for uncertainty in the values of the microbial growth parameters and in the volumetric mass transfer coefficient for dissolved oxygen (kLaDO), and the results show that the detailed ASM predicted N2O emission of less than 4% (typically 1%) of the total influent loading. Uncertainties in kLaDO were further investigated in experiments, which showed that lower values of kLaDO generated higher soluble N2O levels. The detailed ASM likely requires revision to account for abiotic reactions and other factors that cause higher levels of N2O emission. PMID- 28641670 TI - Novel Stokesian Metrics that Quantify Collision Efficiency, Floc Strength, and Discrete Settling Behavior. AB - Novel parameters were developed to predict the effluent quality and settling behavior in clarifiers that cannot conventionally be achieved using either the conventional flux theory or overflow rates. Simple batch experiments based on the critical settling velocity (CSV) selection were used as the basis for the development of three novel parameters: intrinsic settling classes (ISC), threshold of flocculation/flocculation limitation (TOF/alpha), and floc strength. ISC was proven to accurately (+/-2%) determine the granule fraction and discrete particle distribution. TOF quantified the minimum solids concentration needed to form large flocs and was directly linked to collision efficiency. In hybrid systems, an exponential fitting on a CSV matrix was proposed to quantify the collision efficiency of flocs (alpha). Shear studies were conducted to quantify floc strength. The methods were applied to a wide spectrum of sludge types to show the broad applicability and sensitivity of the novel methods. PMID- 28641671 TI - Occurrence of Aerobic and Anaerobic Bacteria in the Consumer End of a Water Distribution System. AB - In this study, mixed species biofilm formation including sulphate-reducing bacteria (SRB) on polypropylene surface and bacteriology of network water were investigated in a model water distribution system during a nine-month period. Water and biofilm samples were analyzed for the enumeration of aerobic heterotrophic bacteria (AHB), anaerobic heterotrophic bacteria (ANHB) and SRB. The number of live/dead bacteria was also analyzed by epifluorescence microscopy. In addition, extracellular polysaccharide substances (EPS) extraction, carbohydrate analysis and scanning electron microscope observation were performed. A biofilm with heterogeneous structure formed on the polypropylene surface of the model water distribution system. Live/dead staining data indicated that biofilm matured in the first month. It was observed that especially AHB entered into a viable but not culturable state because of the temperature decrease. It was also noted that temperature is an important environmental factor especially for planktonic SRB. The quantity of carbohydrate significantly decreased according to the temperature. PMID- 28641672 TI - Determination of Five Alternative Antifouling Agents Found Along the Korean Coasts. AB - Since the ban of tri-butyl tin, other various alternative antifouling agents have been used. In this study, the contamination levels from these antifouling agents were examined in the main harbors in Korea. The sampled harbors were classified into four types and the levels of contamination from the antifouling agents were analyzed. The highest degree of contamination was found in the big harbors, followed by the fishing harbors, harbors near agricultural areas, and military and coast guard harbors. In addition, an increase in the number of ships that entered the ports significantly influenced the contamination by the antifouling agents. Correlation analysis was conducted to characterize the alternative antifouling agents. The results revealed strong correlations between the dichlofluanid and chlorothalonil, and between the chlorothalonil and TCMTB, because unlike Irgarol 1051 and SEA-NINE 211, which are used only as antifouling agents, chlorothalonil, dichlofluanid, and TCMTB are also used in agriculture. PMID- 28641673 TI - Renewable Modified Cellulose Bearing Chelating Schiff Base for Adsorptive Removal of Heavy Metal Ions and Antibacterial Action. AB - A novel approach toward chemically modified cellulose bearing active chelating Schiff base with hydroxyl group (Cell-Hy) was synthesized. The modified cellulose was examined for its heavy metal ion uptake potential from aqueous solution. The chemical and structural features of the adsorbent were characterized by Fourier transform infrared spectroscopy (FT-IR), solid state 13C-NMR, Scanning Electron Microscopy (SEM), and energy dispersive analysis of X-ray (EDAX) observations. The experimental conditions and adsorption parameters, including pH, initial metal ion concentration, adsorbent dosage, temperature, and contact time were optimized for the removal of Cu(II) and Pb(II) ions. Kinetic parameters, equilibrium adsorption capacities, and correlation coefficients for pseudo-first order, pseudo-second-order, and intraparticle diffusion models were carried out. The data obtained from the adsorption of Cu(II) and Pb(II) onto Cell-Hy were subjected to Langmuir and Freundlich isotherm models. Thermodynamic parameters have also been evaluated. The antibacterial activity of modified cellulose was tested toward specific bacterial species. PMID- 28641674 TI - Removal of Organic Matter and Etodolac from Pharmaceutical Industry Wastewater by PAC Adsorption. AB - The removal of organic matter and etodolac (an anti-inflammatory pharmaceutical) from a real process wastewater by using powdered activated carbon (PAC) adsorption before and after Fenton oxidation has been studied. The wastewater sample is collected from the final stage of chemical synthesis of a pharmaceutical (etodolac). Fenton oxidation resulted with decrease in chemical oxygen demand (84% removal) and etodolac concentration was reduced to 0.7 mg L-1. Optimum adsorption equilibrium conditions were found as t = 16 hours, and m = 10 g L-1. The Freundlich model showed the best fit for the adsorption of both wastewater with R2 values of 0.89 and 0.99. Lower pseudo-second-order rate constant (k2) (0.067 < 2.62) obtained from the adsorption of raw wastewater with higher organic matter concentration confirms the chemisorption of the adsorbates onto the PAC. Pore surface mass diffusion with R2 value of 0.92 was found as rate controlling step for adsorption process with Fenton pre-treated wastewater. PMID- 28641675 TI - The Application of Solar Cells in the Electrokinetic Remediation of Metal Contaminated Sediments. AB - In this study, solar cells were used to generate an electric field for the electrokinetic remediation of metal contaminated sediment (Nickel, Cadmium, Zinc). For determination of metals mobility, bioavailability and potential toxicity, sequential extraction procedure, simultaneously extracted metals (SEM) and acid-volatile sulphide ratios (AVS) were performed before, during and after treatment.After 21 days of treatment, 63% Ni, 82% Cd and 58% Zn was removed from the anode region. The application of the electric field changed the chemical composition of the sediments. The risk assessment analysis based on pseudo total metals content, the risk assessment code and the relationship between SEM and AVS, indicates that a simple singular approach for risk assessment analysis and evaluation of the quality of sediments is not enough. PMID- 28641677 TI - Education Research. PMID- 28641678 TI - Cognitive Deterioration in Moderate and Severe Hypobaric Hypoxia Conditions. AB - BACKGROUND: Hypoxia continues to present risks in military aviation. Hypoxia symptoms include sensory and cognitive effects; of these, it is important to identify which components of operator performance are most vulnerable to hypoxia induced decline in order to determine which sensory modality is most effective for alerting an impaired aviator of an imminent hypoxic episode. METHODS: A study was performed in a hypobaric chamber to characterize deterioration of cognitive performance under moderate (MH) and severe (SH) hypoxia conditions, culminating in subjects' inability to perform tasks. Subjects operated a synthetic workstation, performing multiple simultaneous tasks during hypobaric exposures equivalent to 5486 m (18,000 ft) MH and 7620 m (25,000 ft) SH ascents. Performance was compared across baseline, altitude exposure, and recovery periods within MH vs. SH altitude profiles. Ascents lasted until at least one of a list of termination criteria was met, at which point the chamber was returned to ground level pressure and the subject resumed workstation performance during recovery. RESULTS: SH conditions generated greater deficits than MH conditions, and these more severe effects hastened the termination of exposures (5 vs. 18 min mean duration, respectively). Workstation performance collapsed rapidly on SH exposure, with Mathematics and Auditory Monitoring tasks proving vulnerable to breakdown. In MH exposures, these tasks exhibited impaired accuracy (declining 11% and 9%, respectively) and speed, with declines in Auditory Monitoring lingering into recovery. DISCUSSION: The relative robustness of memory and visual monitoring vs. the vulnerability of mathematical and auditory processing suggest that care should be taken designing purely auditory cockpit hypoxia warning alerts.Beer JMA, Shender BS, Chauvin D, Dart TS, Fischer J. Cognitive deterioration in moderate and severe hypobaric hypoxia conditions. Aerosp Med Hum Perform. 2017; 88(7):617-626. PMID- 28641679 TI - Normobaric Hypoxia and Submaximal Exercise Effects on Running Memory and Mood State in Women. AB - BACKGROUND: An acute bout of exercise can improve cognitive function in normoxic and hypoxic conditions. However, limited research supports the improvement of cognitive function and mood state in women. The purpose of this study was to examine the effects of hypoxia and exercise on working memory and mood state in women. METHODS: There were 15 healthy women (age = 22 +/- 2 yr) who completed the Automated Neuropsychological Assessment Metrics-4th Edition (ANAM), including the Running Memory Continuous Performance Task (RMCPT) and Total Mood Disturbance (TMD) in normoxia (21% O2), at rest in normoxia and hypoxia (12.5% O2), and during cycling exercise at 60% and 40% Vo2max in hypoxia. RESULTS: RMCPT was not significantly impaired at 30 (100.3 +/- 17.2) and 60 (96.6 +/- 17.3) min rest in hypoxia compared to baseline in normoxia (97.0 +/- 17.0). However, RMCPT was significantly improved during exercise (106.7 +/- 20.8) at 60% Vo2max compared to 60 min rest in hypoxia. Following 30 (-89.4 +/- 48.3) and 60 min of exposure to hypoxia (-79.8 +/- 55.9) at rest, TMD was impaired compared with baseline (-107.1 +/- 46.2). TMD was significantly improved during exercise (-108.5 +/- 42.7) at 40% Vo2max compared with 30 min rest in hypoxia. Also, RMCPT was significantly improved during exercise (104.0 +/- 19.1) at 60% Vo2max compared to 60 min rest in hypoxia (96.6 +/- 17.3). DISCUSSION: Hypoxia and an acute bout of exercise partially influence RMCPT and TMD. Furthermore, a moderate-intensity bout of exercise (60%) may be a more potent stimulant for improving cognitive function than low-intensity (40%) exercise. The present data should be considered by aeromedical personnel performing cognitive tasks in hypoxia.Seo Y, Gerhart HD, Stavres J, Fennell C, Draper S, Glickman EL. Normobaric hypoxia and submaximal exercise effects on running memory and mood state in women. Aerosp Med Hum Perform. 2017; 88(7):627-632. PMID- 28641681 TI - The Effects of Training on Anxiety and Task Performance in Simulated Suborbital Spaceflight. AB - INTRODUCTION: In commercial spaceflight, anxiety could become mission-impacting, causing negative experiences or endangering the flight itself. We studied layperson response to four varied-length training programs (ranging from 1 h-2 d of preparation) prior to centrifuge simulation of launch and re-entry acceleration profiles expected during suborbital spaceflight. We examined subject task execution, evaluating performance in high-stress conditions. We sought to identify any trends in demographics, hemodynamics, or similar factors in subjects with the highest anxiety or poorest tolerance of the experience. METHODS: Volunteers participated in one of four centrifuge training programs of varied complexity and duration, culminating in two simulated suborbital spaceflights. At most, subjects underwent seven centrifuge runs over 2 d, including two +Gz runs (peak +3.5 Gz, Run 2) and two +Gx runs (peak +6.0 Gx, Run 4) followed by three runs approximating suborbital spaceflight profiles (combined +Gx and +Gz, peak +6.0 Gx and +4.0 Gz). Two cohorts also received dedicated anxiety-mitigation training. Subjects were evaluated on their performance on various tasks, including a simulated emergency. RESULTS: Participating in 2-7 centrifuge exposures were 148 subjects (105 men, 43 women, age range 19-72 yr, mean 39.4 +/- 13.2 yr, body mass index range 17.3-38.1, mean 25.1 +/- 3.7). There were 10 subjects who withdrew or limited their G exposure; history of motion sickness was associated with opting out. Shorter length training programs were associated with elevated hemodynamic responses. Single-directional G training did not significantly improve tolerance. DISCUSSION: Training programs appear best when high fidelity and sequential exposures may improve tolerance of physical/psychological flight stressors. The studied variables did not predict anxiety-related responses to these centrifuge profiles.Blue RS, Bonato F, Seaton K, Bubka A, Vardiman JL, Mathers C, Castleberry TL, Vanderploeg JM. The effects of training on anxiety and task performance in simulated suborbital spaceflight. Aerosp Med Hum Perform. 2017; 88(7):641-650. PMID- 28641680 TI - Ophthalmological Evaluation of Integrated Resistance and Aerobic Training During 70-Day Bed Rest. AB - INTRODUCTION: We evaluated ophthalmic changes in healthy individuals who underwent integrated resistance and aerobic training (iRAT) during 70-d 6 degrees head-down tilt (HDT) bed rest (BR). METHODS: Participants were selected using NASA standard screening procedures. Standardized NASA BR conditions were implemented. Subjects were randomly assigned to the iRAT protocol or no exercise during HDTBR. Weekly ophthalmic examinations were performed in the sitting (pre/post-BR only) and HDT (BR only) positions. Mixed-effects linear models compared pre- and post-HDTBR intraocular pressure (IOP), Spectralis OCT circumpapillary retinal nerve fiber layer (cpRNFL) thickness, and peripapillary retinal thickness observations between groups. RESULTS: Six controls and nine exercisers completed the study. There was an overall effect of BR on our outcomes. Except Goldmann IOP (mean pre/post difference in controls and exercisers: -0.47 mmHg vs. +1.14 mmHg), the magnitude of changes from baseline was not significantly different between groups. There was a +1.38 mmHg and a +1.63 mmHg iCare IOP increase during BR in controls and exercisers, respectively. Spectralis OCT detected a +1.33 MUm average cpRNFL thickness increase in both groups, and a +9.77 MUm and a +6.65 MUm peripapillary retinal thickening post-BR in controls and exercisers, respectively. Modified Amsler grid, red dot test, confrontational visual field, color vision, and stereoscopic fundus photography were unremarkable. CONCLUSIONS: HDTBR for 70 d induced peripapillary retinal thickening and cpRNFL thickening without visible signs of optic disc edema. The magnitude of such changes was not different between controls and exercisers. A slight IOP increase during BR subsided post-BR. Further study should evaluate whether different physical exercise paradigms may prevent/mitigate the risk of space-related visual impairment.Taibbi G, Cromwell RL, Zanello SB, Yarbough PO, Ploutz-Snyder RJ, Godley BF, Vizzeri G. Ophthalmological evaluation of integrated resistance and aerobic training during 70-day bed rest. Aerosp Med Hum Perform. 2017; 88(7):633-640. PMID- 28641682 TI - Health Effects of Airline Cabin Environments in Simulated 8-Hour Flights. AB - INTRODUCTION: Commercial air travel is usually without health incidents. However, there is a view that cabin environments may be detrimental to health, especially flights of 8 h or more. Concerns have been raised about deep vein thrombosis, upper respiratory tract infections, altitude sickness, and toxins from the engines. METHODS: Passenger cabin simulators were used to achieve a comparative observational study with 8-h flights at pressures equivalent to terrestrial altitudes of ground, 4000, 6000, and 8000 ft. Biomarkers of thrombosis (D-Dimer), inflammation (interleukin-6), and respiratory dysfunction (FEV1) and oxygen saturation (Spo2) were measured, as well as pulse and blood pressure. The wellbeing of the passengers was also monitored. RESULTS: During 36 flights, 1260 healthy subjects [626 women (F) and 634 men (M) (mean age = 43, SD = 16)] were assessed. Additionally, 72 subjects with chronic obstructive pulmonary disease (F = 32, M = 40, mean age = 48, SD = 17) and 74 with heart failure (F = 50, M = 24, mean age = 54, SD = 14) contributed to 11 flights. Additionally, 76 normal controls were observed while engaged in a usual day's work (F = 38, M = 38, mean age = 39, SD = 15). There were no health-significant changes in D-Dimer, interleukin-6, or FEV1. Spo2 varied as expected, with lowest values at 8000 ft and in patients with cardiopulmonary disease. The only differences from the controls were the loss of the normal diurnal variations in interleukin-6 and D Dimer. DISCUSSION: This very large, comparative, controlled study provides much reassurance for the traveling public, who use airline flights of up to 8 h. We did not show evidence of the development of venous thrombosis, inflammation, respiratory embarrassment, nor passenger distress. No significant symptoms or adverse effects were reported.Ideal Cabin Environment (ICE) Research Consortium of the European Community 6th Framework Programme. Health effects of airline cabin environments in simulated 8-hour flights. Aerosp Med Hum Perform. 2017; 88(7):651-656. PMID- 28641683 TI - A Review of General Aviation Safety (1984-2017). AB - INTRODUCTION: General aviation includes all civilian aviation apart from operations involving paid passenger transport. Unfortunately, this category of aviation holds a lackluster safety record, accounting for 94% of civil aviation fatalities. In 2014, of 1143 general aviation accidents, 20% were fatal compared with 0 of 29 airline mishaps in the United States. Herein, research findings over the past 30 yr will be reviewed. Accident risk factors (e.g., adverse weather, geographical region, post-impact fire, gender differences) will be discussed. The review will also summarize the development and implementation of stringent crashworthiness designs with multi-axis dynamic testing and head-injury protection and its impact on mitigating occupant injury severity. The benefits and drawbacks of new technology and human factor considerations associated with increased general aviation automation will be debated. Data on the safety of the aging general aviation population and increased drug usage will also be described. Finally, areas in which general aviation occupant survival could be improved and injury severity mitigated will be discussed with the view of equipping aircraft with 1) crash-resistant fuel tanks to reduce post-impact conflagration; 2) after-market ballistic parachutes for older aircraft; and 3) current generation electronic locator beacons to hasten site access by first responders.Boyd DD. A review of general aviation safety (1984-2017). Aerosp Med Hum Perform. 2017; 88(7):657-664. PMID- 28641685 TI - Distortion of Prospective Time Production Underwater. AB - BACKGROUND: The few prior studies of time perception underwater have reached contradictory conclusions as to how, and if, time perception becomes distorted when submerged. The current paper expands upon this limited data by describing two studies of prospective time production in scuba divers. METHODS: Study 1 (N = 32) compared performance on a 30-s interval time production task in deep water (35 m-42 m/~115-138 ft) with a shallow water control (3-12 m/~10-39 ft). Using the same task, study 2 (N = 31) tested performance at the surface and at a range of depths underwater (1 m/3 ft; 11 m/36 ft; 20 m/66 ft; 30 m/98 ft; 40 m/131 ft). RESULTS: Study 1 revealed time production to be significantly longer in deep water compared to shallow water. In study 2 time production at the surface was not significantly different from that at 1 m, but productions at 11-40 m were significantly longer than at both 1 m and on the surface. Time productions between 11-40 m did not differ significantly. DISCUSSION: It was concluded that divers judge less time to have passed underwater than is objectively the case from a depth of 11 m, but that this effect does not deteriorate significantly once past 11 m. The cause of this distortion of time perception underwater was suggested to be the action of gas narcosis.Hobbs MB, Kneller W. Distortion of prospective time production underwater. Aerosp Med Hum Perform. 2017; 88(7):677 681. PMID- 28641686 TI - A Case Study of Human Roll Tilt Perception in Hypogravity. AB - BACKGROUND: Increased gravito-inertial acceleration, or hypergravity, such as produced in a centrifuge or in an aircraft coordinated turn, causes humans to systematically overestimate their roll tilt in the dark. This is known as the "G excess" illusion. We have previously modified a mathematical observer model of dynamic orientation perception to replicate these illusory tilt perceptions. This modified model also made a novel, previously untested, prediction that humans would underestimate acute roll tilt in reduced gravitational environments (hypogravity). CASE REPORT: In the current study, we used aircraft parabolic flight to test this prediction in a single subject. Roll tilt perception was reported using a subjective visual vertical task in which the subject aligned an illuminated line, presented in a head mounted display, with their perceived direction of down. The same subject made reports during hypogravity parabolas (0.165 G and 0.38 G, corresponding to lunar and Martian gravity, respectively), hypergravity maneuvers (1.6 G during a pull out maneuver and 1.2 G during a coordinated turn), and 1-G control conditions (both on the ground and in straight and level flight). As hypothesized, the subject significantly underestimated roll tilt in the hypogravity environments by approximately 40% compared to 1-G reports while overestimating roll tilt in the hypergravity environments. DISCUSSION: The amount of underestimation observed was quantitatively consistent with that predicted a priori by the modified observer model. We propose the term "G shortage" illusion for the underestimation of roll tilt in hypogravity. This illusion may have implications for aircraft pilots and astronauts.Clark TK, Young LR. A case study of human roll tilt perception in hypogravity. Aerosp Med Hum Perform. 2017; 88(7):682-687. PMID- 28641687 TI - Preparing Safety Cases for Operating Outside Prescriptive Fatigue Risk Management Regulations. AB - INTRODUCTION: Transport operators seeking to operate outside prescriptive fatigue management regulations are typically required to present a safety case justifying how they will manage the associated risk. This paper details a method for constructing a successful safety case. METHODS: The method includes four elements: 1) scope (prescriptive rules and operations affected); 2) risk assessment; 3) risk mitigation strategies; and 4) monitoring ongoing risk. A successful safety case illustrates this method. It enables landing pilots in 3 pilot crews to choose the second or third in-flight rest break, rather than the regulatory requirement to take the third break. Scope was defined using a month of scheduled flights that would be covered (N = 4151). These were analyzed in the risk assessment using existing literature on factors affecting fatigue to estimate the maximum time awake at top of descent and sleep opportunities in each break. Additionally, limited data collected before the new regulations showed that pilots flying at landing chose the third break on only 6% of flights. RESULTS: A prospective survey comparing subjective reports (N = 280) of sleep in the second vs. third break and fatigue and sleepiness ratings at top of descent confirmed that the third break is not consistently superior. The safety case also summarized established systems for fatigue monitoring, risk assessment and hazard identification, and multiple fatigue mitigation strategies that are in place. DISCUSSION: Other successful safety cases have used this method. The evidence required depends on the expected level of risk and should evolve as experience with fatigue risk management systems builds.Gander P, Mangie J, Wu L, van den Berg M, Signal L, Phillips A. Preparing safety cases for operating outside prescriptive fatigue risk management regulations. Aerosp Med Hum Perform. 2017; 88(7):688-696. PMID- 28641688 TI - You're the Flight Surgeon. AB - Mitchell AL. You're the flight surgeon: aviator with myocardial ischemia. Aerosp Med Hum Perform. 2017; 88(7):697-700. PMID- 28641689 TI - You're the Flight Surgeon. AB - Solana NM. You're the flight surgeon: black spot poison ivy. Aerosp Med Hum Perform. 2017; 88(7):700-702. PMID- 28641684 TI - Novel Indications for Commonly Used Medications as Radiation Protectants in Spaceflight. AB - BACKGROUND: In the space environment, the traditional radioprotective principles of time, distance, and shielding become difficult to implement. Additionally, the complex radiation environment inherent in space, the chronic exposure timeframe, and the presence of numerous confounding variables complicate the process of creating appropriate risk models for astronaut exposure. Pharmaceutical options hold tremendous promise to attenuate acute and late effects of radiation exposure in the astronaut population. Pharmaceuticals currently approved for other indications may also offer radiation protection, modulation, or mitigation properties along with a well-established safety profile. Currently there are only three agents which have been clinically approved to be employed for radiation exposure, and these only for very narrow indications. This review identifies a number of agents currently approved by the U.S. Food and Drug Administration (FDA) which could warrant further investigation for use in astronauts. Specifically, we examine preclinical and clinical evidence for statins, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), metformin, calcium channel blockers, beta adrenergic receptor blockers, fingolimod, N acetylcysteine, and pentoxifylline as potential radiation countermeasures.McLaughlin MF, Donoviel DB, Jones JA. Novel indications for commonly used medications as radiation protectants in spaceflight. Aerosp Med Hum Perform. 2017; 88(7):665-676. PMID- 28641690 TI - The Lockheed XC-35 and Harry Armstrong, M.D.: Development of the First Practical Pressurized Cabin Airplane. PMID- 28641691 TI - This Month in Aerospace Medicine History. PMID- 28641692 TI - AsMA Annual Award Winners. PMID- 28641693 TI - [Evidence and Practice of Enhanced Lung Recovery after Surgery ?in Patients Undergoing Lung Surgery]. AB - The clinic application pathway is a variant of the enhanced recovery after surgery (ERAS), which based disease and team. What are the published evidence is conducive to enhanced lung recovery after surgery (ELRAS) in clinical implementation. This article mainly from the perioperative management can adopt the measures and methods were retrospectively analyzed. The measures of education and assessment of the risk factors and prevention is emphasized in preoperative. The minimally invasive surgery and process optimization is adopted by surgeon. Postoperative focus on symptom management, such as pain is the first attention. PMID- 28641694 TI - [MiR-133b Affect the Proliferation and Drug Sensitivity in A549 Lung Cancer Stem Cells by Targeting PKM2]. AB - BACKGROUND: It has been proven that miR-133b could inhibit cancer cell growth, the expression level of miR-133b was significant reduction in lung cancer tissue and serum of patients, and increase the radiation sensitivity of squamous cell carcinoma by targeting PKM2, but the exist mechanisms is not clear. The aim of this study is to explore the effect of miR-133b on proliferation in A549 lung cancer stem cells and drug sensitivity in DDP, and to explore the relationship between miR-133b and PKM2 gene, as well as the effect of cancer stem cells. METHODS: Using miRBase and miRNAMap database to sequence comparison miR-133b and PKM2 gene. Using immune magnetic separation method to select the CD133+/CD34+ lung cancer stem cells from A549 cells, and using flow cytometry to detect the purity. The expression of miR-133b mRNA was detected by real-time fluorescence quantitative PCR (qRT-PCR). Cell proliferation was detected by CCK8 assay. 15 MUg/mL DDP was treated to cells which was transfected with miR-133b, and apoptosis was detected by flow Cytometry at 0 h, 12 h, 24 h, 72 h. The expression of PKM2 protein was detected by Western blot. RESULTS: Gene binding site report that PKM2 gene may be the target gene of miR-133b; the results of flow cytometry showed that the purity of CD133+/CD34+ stem cells was (92.15+/-4.27)%. qRT-PCR results showed that compared with the control group, after overexpression of miR 133b, miR-133b was up-regulated and miR-133b was down regulated after miR-133b inhibition (P<0.05). Compared with the control group, cell proliferation of miR 133b mimics group was significantly decreased (P<0.05), PKM2 protein levels were significantly lower (P<0.05); and cell proliferation of the miR-133b inhibitor group and PKM2 level was increased (P<0.05). The apoptosis of miR-133b mimics group was significantly higher than that of control group (P<0.05) after DDP treatment with 12 h. The expression of PKM2 protein in miR-133b mimics+DDP group was significantly lower than that in control group (P<0.05). CONCLUSIONS: Overexpression of miR-133b can inhibit the growth and proliferation of lung cancer stem cells by down regulating PKM2, and can enhance the sensitivity of lung cancer stem cells to DDP. PMID- 28641695 TI - [Relationship between EGFR Mutations and Pathological Classification and ?Specimen of Lung Adenocarcinoma]. AB - BACKGROUND: With the development of genetic mutations and targeted drugs, accurate therapy of lung adenocarcinoma attracts much more attention, and more research is focued on epidermal growth factor receptor (EGFR). It is unclear whether the result of EGFR mutation and pathology type is consistent with different specimens. In our study, by comparing the relationship between EGFR mutations and pathological classification of lung adenocarcinoma in surgical resection of specimen and biopsy specimen, to discuss the relationship between EGFR mutations and pathological classification of and the influence of specimen type on EGFR gene detection. METHODS: A total of 163 cases of surgical resection of sample of lung adenocarcinoma (pulmonary resection and pulmonary lobectomy) and 173 cases of biopsy specimen [mucosa biopsy, needle biopsy of lung, and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)] were performed by gene sequencing method and amplification refractory mutation system (ARMS) and the majority of the type was confirmed (lepidic, acinar, papillary, micropapillary, solid) according to the classification of lung adenocarcinoma in 2015 World Health Organization (WHO). The statistics was used in surgical and biopsy sample respectively. RESULTS: The gene mutation of EGFR in surgical and biopsy sample of lung adenocarcinoma was 62.58% (102/163) and 65.9% (114/173) respectively, and no significant difference was found (P>0.05). The mutation of EGFR in female was predominant both of the two groups (P<0.05). The mutation rate of EGFR over the age of 60 was significantly lower than that below 60 in surgical specimen, while it was not related to age in biopsy sample. The constituent ratio of pathology type was different in the two groups (chi2=8.04, P<0.05). Among 102 cases of lung adenocarcinoma in surgical specimen, the acinar took up the highest proportion (54.9%), followed by the lepidic (23.53%) and the papillary (17.65%). The solid adenocarcinoma accounted for the minimal percentage (3.9%). The mutation of 19 and 21 exon alone was most common. The mutation rate of 21 exon in the lepidic was higher than that in the acinar and papillary (P<0.05), but the mutation rate of 19 exon in the papillary was higher than that in the lepidic (P<0.05). There was no significant difference of 19 and 21 exon in the acinar and papillary. Among 114 cases of lung adenocarcinoma in the biopsy specimen, the most percentage was the acinar (48.25%), the lepidic was secondly, and the papillary, micropapillary and solid adenocarcinoma was the minimal. The exon mutation of 19 and 21 exon alone was most common, while no obvious difference of 19 and 21 exon was found in different pathology classifications (P>0.05). CONCLUSIONS: The mutation rate of EGFR of lung adenocarcinoma in surgical resected specimen and biopsy specimen was not found difference, which was related to sex, and the female was predominant. The mutation rate of surgical specimen was higher in the young, while that of biopsy specimen was not related to the age. Apparent difference of the pathology type proportion was found in the two groups. The mutation of 19 and 21 exon alone was most common. The mutation of EGFR in surgical specimens was related to pathology types. The percentage of the lepidic adenocarcinoma was highest in the mutation of 21 exon alone. Among the mutation of 19 exon alone, the papillary was predominant. There was no obvious relationship between the mutation of 19 and 21 exon alone and pathology type in biopsy sample. PMID- 28641696 TI - [Validation of the Mandarin Chinese Version of the Leicester Cough Questionnaire in Patients Undergoing Lung Resection for Patients with Lung Disease]. AB - BACKGROUND: The Mandarin Chinese version of the Leicester Cough Questionnaire (LCQ-MC) is a symptom specific questionnaire designed to assess the impact of cough severity, a major symptom of postoperative patients undergoing lung resection is cough. The aim of this study is to validate the LCQ-MC in patients with lung operation. METHODS: Totally 121 patients undergone the lung operation of single medical team, from September 2015 to April 2016 in the Thoracic Surgery Department of West China hospital Sichuan University, were investigated by LCQ-MC before and after operation. We analyzed and calculated the preoperative and postoperative scores of LCQ-MC and Cronbach alpha. RESULTS: 1The mean LCQ-MC score in preoperative (19.57+/-1.73) was significant higher than postoperative (17.71+/-2.72) (P=0.041). 2The Cronbach alpha in preoperative (0.87) and postoperative (0.89) was significant higher than 0.7. 3The preoperative scores of LCQ-MC (19.31+/-1.84) was significantly lower in postoperative cough group than in without postoperative cough group (19.97+/-1.46) (P=0.038). The postoperative scores of LCQ-MC (16.67+/-2.91) was significantly lower in postoperative cough group than in without postoperative cough group (19.30+/-1.32) (P=0.001). 4There was no statistical difference (P=0.936) between postoperative LCQ-MC score (17.75+/-2.51) in lobectomy group and non-lobectomy group (17.79+/-3.04). CONCLUSIONS: The LCQ-MC can assess the condition of cough after thoracoscopic surgery in patients with pulmonary disease.?. PMID- 28641697 TI - [Clinical Value of Cell Block in the Diagnosis of Malignant Pleural Effusion]. AB - BACKGROUND: Malignant pleural effusion (MPE) is due tumor which arises from the mesothelium or metastases from tumor origniating other sites. Generally, the prognosis of MPE is poor, in the premise of reducing the pain of patients, as soon as possible make clear the property of pleural effusion and cause of the disesease, rightly and quickly, providing effective information for subsequent treatment. METHODS: The cell block of 103 patients by using natural sedimentation or plasma coagulation method combined with HE staining and immunohistochemical staining method maked clear diagnosis and compared with other methods. RESULTS: 90 patients were diagnosed by cell block section from 103 patients who had MPE (diagnostic rate 87.4%); 32 cases were diagnosed by cell block section only, 74 cases pointed out that the pathological type , 23 cases even pointed out the primary lesions; 71 cases examined other invasive methods at the same time, the diagnostic rate was 87.3% and 81.7%; the detection rate of cell block section and cytological smear in detecting malignant tumor cells was 86.7%and 44.0% respectively. CONCLUSIONS: Cell block can not only increase the diagnosis, in contrast to cytological smear, and own the same diagnostic rate compared with other invasive methods, but also can confirm pathological type and primary lesion; especially, for other invasive methods, cell block method is a preferable complementary method, and that cell block method maybe the only way for some patients. PMID- 28641698 TI - [Expression of Serum LncRNA HOTAIR in Non-small Cell Lung Cancer ?and Its Clinical Significance]. AB - BACKGROUND: The expression of long noncoding RNA HOX antisense RNA (HOTAIR) is abnormal in a variety of tumors. The aim of this study is to explore the serum levels and clinical significance of HOTAIR in patients with non-small cell lung cancer (NSCLC). METHODS: The serum levels of HOTAIR were detected by real-time quantitative polymerase chain reaction (PCR) in 64 NSCLC patients and 64 normal controls. The relationships between the serum levels of HOTAIR and clinical pathological parameters were analyzed. RESULTS: Compared with normal controls, the serum levels of HOTAIR in patients with NSCLC increased significantly (P<0.01). The serum levels of HOTAIR were correlated with tumor size, tumor-node metastasis (TNM) stage and lymph node metastasis (P<0.05), but not with age, gender, smoking, differentiation and histology (P>0.05). CONCLUSIONS: The serum levels of HOTAIR in patients with NSCLC are significantly higher, and HOTAIR may be involved in the pathogenesis of NSCLC. PMID- 28641699 TI - [Quantitative Imaging Assessment of Tumor Response to Chemoradiation ?in Lung Cancer]. AB - Precision medicine demands accurate assessment of tumor response to therapies with the purpose of timely optimization or adjustment of the given treatment regimens. Chemoradiation remains the standard of care in advanced lung cancers and imaging-based noninvasive response evaluation could improve therapeutic efficacy and reduce treatment-related severe side effects. In this review, we overviewed the applications and pitfalls of major imaging modalities in response evaluation in lung cancer from a quantitative perspective. The development of radiomics will provide more precise information for treatment predicting, evaluation and prognosis. PMID- 28641700 TI - [Molecular Imaging in vivo Detection of EGFR Mutations in Non-small Cell Lung Cancer]. AB - An ever increasing number of drugs directed as epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) bring a new revolution for non-small cell lung cancer (NSCLC) therapy, and many large scales of studies show that only people with EGFR-sensitive mutation can benefit from these drugs. The main method of EGFR mutation detection is to analyze the DNA sequence of EGFR, which can be the lung cancer tissue, pleural fluid tumor cells, circulating tumor cells and peripheral blood free DNA obtained by surgery or puncture, the biggest drawback is that the heterogeneity of EGFR mutation cannot be analyzed. However, with the development of molecular imaging, the development of EGFR-targeted molecular probes based on positron emission computed tomography-computed tomography (PET CT) has made it possible to reveal the EGFR mutations in lung cancer tissues in vivo, and can detect the heterogeneity of EGFR mutations. This article reviews all the results and progress of molecular probes targeting EGFR mutations. PMID- 28641702 TI - [Prospect and Current Situation of Immune Checkpoint Inhibitors ?in First-line Treatment in Advanced Non-small Cell Lung Cancer Patients]. AB - With the breakthroughs achieved of programmed death-1 (PD-1)/PD-L1 inhibitors monotherapy as first-line and second-line treatment in advanced non-small cell lung cancer (NSCLC), the treatment strategy is gradually evolving and optimizing. Immune combination therapy expands the benefit population and improves the curative effect. A series of randomized phase III trials are ongoing. In this review, we discuss the prospect and current situation of immune checkpoint inhibitors in first-line treatment in advanced NSCLC patients. PMID- 28641701 TI - [Recent Advances and Future Strategies for Small Cell Lung Cancer]. AB - Small cell lung cancer (SCLC) is a malignant tumor with a very high mortality rate. The current standard of care includes surgery, chemotherapy and radiotherapy. The clinical benefit of therapies was disappointing. Recently, many clinical trials about target therapy and immunotherapy are processing. This review will focus on current therapy and future research direction of SCLC. PMID- 28641704 TI - Understanding the factors that make public participation effective in health policy and planning: a realist synthesis. AB - Although researchers argue for the importance of involving the public in developing health policy, there has been little focus on central research questions - such as what techniques of public participation work, in what circumstances, and why. This paper presents a realist synthesis which identifies and explains the underlying mechanisms and specific contextual factors that lead to effective public participation in health policy and planning. Peer-reviewed, English language literature was searched, which resulted in 77 articles for review and synthesis. This synthesis uncovered the underlying mechanism of 'political commitment' that generates public participation effectiveness. The other three possible underlying mechanisms, namely: 'partnership synergy', 'inclusiveness' and 'deliberativeness', were found to potentially provide further explanation on public participation effectiveness for health policy and planning. The findings of this review provide evidence that can be useful to health practitioners and decision-makers to actively involve the public when drafting public health policies and programs and, more importantly, guide them in deciding which strategies to best employ for which contexts. PMID- 28641705 TI - Citizen participation in health services co-production: a roadmap for navigating participation types and outcomes. AB - Primary healthcare managers are required to include citizens in service co-design and co-production. Health policy guidance appears deceptively simple and largely outlines how people could participate in a range of health services activities. Policy tends to neglect outcomes assessment, and a multidisciplinary academic literature corpus is large and complex to navigate for practical, time-poor managers. In this paper, we set out to provide a summary 'map' of key concepts in participation to assist managers in aligning participants, activities, expected outcomes and outcome indicators, and to consider contextual factors that could affect participation processes and outcomes. The intention is a practical tool for planning and evaluation of participation. The map is built drawing on policy guidance, literature and authors' experiences of implementing and researching health services participation. PMID- 28641703 TI - A randomised controlled trial to assess the cost-effectiveness of intensive versus no scheduled follow-up in patients who have undergone resection for colorectal cancer with curative intent. AB - BACKGROUND: Intensive follow-up after surgery for colorectal cancer is common practice but lacks a firm evidence base. OBJECTIVE: To assess whether or not augmenting symptomatic follow-up in primary care with two intensive methods of follow-up [monitoring of blood carcinoembryonic antigen (CEA) levels and scheduled imaging] is effective and cost-effective in detecting the recurrence of colorectal cancer treatable surgically with curative intent. DESIGN: Randomised controlled open-label trial. Participants were randomly assigned to one of four groups: (1) minimum follow-up (n = 301), (2) CEA testing only (n = 300), (3) computerised tomography (CT) only (n = 299) or (4) CEA testing and CT (n = 302). Blood CEA was measured every 3 months for 2 years and then every 6 months for 3 years; CT scans of the chest, abdomen and pelvis were performed every 6 months for 2 years and then annually for 3 years. Those in the minimum and CEA testing only arms had a single CT scan at 12-18 months. The groups were minimised on adjuvant chemotherapy, gender and age group (three strata). SETTING: Thirty-nine NHS hospitals in England with access to high-volume services offering surgical treatment of metastatic recurrence. PARTICIPANTS: A total of 1202 participants who had undergone curative treatment for Dukes' stage A to C colorectal cancer with no residual disease. Adjuvant treatment was completed if indicated. There was no evidence of metastatic disease on axial imaging and the post-operative blood CEA level was <= 10 ug/l. MAIN OUTCOME MEASURES: Primary outcome Surgical treatment of recurrence with curative intent. Secondary outcomes Time to detection of recurrence, survival after treatment of recurrence, overall survival and quality-adjusted life-years (QALYs) gained. RESULTS: Detection of recurrence During 5 years of scheduled follow-up, cancer recurrence was detected in 203 (16.9%) participants. The proportion of participants with recurrence surgically treated with curative intent was 6.3% (76/1202), with little difference according to Dukes' staging (stage A, 5.1%; stage B, 7.4%; stage C, 5.6%; p = 0.56). The proportion was two to three times higher in each of the three more intensive arms (7.5% overall) than in the minimum follow-up arm (2.7%) (difference 4.8%; p = 0.003). Surgical treatment of recurrence with curative intent was 2.7% (8/301) in the minimum follow-up group, 6.3% (19/300) in the CEA testing group, 9.4% (28/299) in the CT group and 7.0% (21/302) in the CEA testing and CT group. Surgical treatment of recurrence with curative intent was two to three times higher in each of the three more intensive follow-up groups than in the minimum follow-up group; adjusted odds ratios (ORs) compared with minimum follow-up were as follows: CEA testing group, OR 2.40, 95% confidence interval (CI) 1.02 to 5.65; CT group, OR 3.69, 95% CI 1.63 to 8.38; and CEA testing and CT group, OR 2.78, 95% CI 1.19 to 6.49. Survival A Kaplan-Meier survival analysis confirmed no significant difference between arms (log-rank p = 0.45). The baseline-adjusted Cox proportional hazards ratio comparing the minimum and intensive arms was 0.87 (95% CI 0.67 to 1.15). These CIs suggest a maximum survival benefit from intensive follow-up of 3.8%. Cost-effectiveness The incremental cost per patient treated surgically with curative intent compared with minimum follow-up was L40,131 with CEA testing, L43,392 with CT and L85,151 with CEA testing and CT. The lack of differential impact on survival resulted in little difference in QALYs saved between arms. The additional cost per QALY gained of moving from minimum follow-up to CEA testing was L25,951 and for CT was L246,107. When compared with minimum follow-up, combined CEA testing and CT was more costly and generated fewer QALYs, resulting in a negative incremental cost-effectiveness ratio (-L208,347) and a dominated policy. LIMITATIONS: Although this is the largest trial undertaken at the time of writing, it has insufficient power to assess whether or not the improvement in detecting treatable recurrence achieved by intensive follow-up leads to a reduction in overall mortality. CONCLUSIONS: Rigorous staging to detect residual disease is important before embarking on follow-up. The benefit of intensive follow-up in detecting surgically treatable recurrence is independent of stage. The survival benefit from intensive follow-up is unlikely to exceed 4% in absolute terms and harm cannot be absolutely excluded. A longer time horizon is required to ascertain whether or not intensive follow-up is an efficient use of scarce health-care resources. Translational analyses are under way, utilising tumour tissue collected from Follow-up After Colorectal Surgery trial participants, with the aim of identifying potentially prognostic biomarkers that may guide follow-up in the future. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41458548. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 32. See the NIHR Journals Library website for further project information. PMID- 28641707 TI - Analysis of transmitted HIV drug resistance from 2005 to 2015 in Victoria, Australia: a comparison of the old and the new. AB - : Background Baseline genotyping is part of standard-of-care treatment. It reveals that transmitted drug resistance (TDR) continues to be important for the management of HIV infection. Attention is typically focused on determining whether resistance to the protease inhibitors (PI) and reverse transcriptase inhibitors (RTI) occurs. However, the increasing use of integrase inhibitors (INIs) raises a concern that TDR to this class of antiretroviral drug may also occur. METHODS: PI and RTI drug resistance genotyping was performed on blood samples collected between 2005 and 2015 from 772 treatment-naive Victorian patients infected with HIV within the previous 12 months. Integrase genotyping was performed on 461 of the 485 patient samples collected between 2010 and 2015. RESULTS: In the period 2005-10, 39 of 343 patients (11.4%) had at least one PI- or RTI-associated mutation, compared with 34 of 429 (7.9%) during the period 2011 15. Compared with 2005-10, during 2011-15 there was a significant decline in the prevalence of the non-nucleoside-associated mutation K103N and the nucleoside associated mutations at codons M41 and T215. One patient was detected with a major INI resistance mutation, namely G118R. However, this mutation is rare and its effect on susceptibility is unclear. A small number of patients (n=12) was infected with HIV containing accessory resistance mutations in the integrase gene. CONCLUSIONS: The lack of transmitted resistance to INIs is consistent with a low level of resistance to this class of drugs in the treated population. However, continued surveillance in the newly infected population is warranted as the use of INIs increases. PMID- 28641706 TI - Delayed onset of puberty in male offspring from bisphenol A-treated dams is followed by the modulation of gene expression in the hypothalamic-pituitary testis axis in adulthood. AB - Bisphenol A (BPA) is a synthetic endocrine-disrupting chemical of high prevalence in the environment, which may affect the function of the hypothalamic-pituitary testis (HPT) axis in adult rats. The aim of the present study was to evaluate whether exposure to BPA during hypothalamic sexual differentiation at doses below the reproductive no observable adverse effect level of the World Health Organization causes changes in the regulation of the HPT axis. For this, 0.5 or 5mgkg-1 BPA was injected subcutaneously to the mothers from gestational day 18 to postnatal day (PND) 5. In adulthood (PND90), the mRNA expression of genes related to HPT axis was evaluated in hypothalamus, pituitary and testis. Hypothalamic expression of gonadotrophin-releasing hormone (Gnrh) and estrogen receptor 2 (Esr2) mRNA was increased in both BPA-treated groups compared to control group. In the pituitary, follicle stimulating hormone beta subunit (Fshb) and androgen receptor (Ar) mRNA expression was increased compared to control group in rats treated with 0.5mgkg-1 of BPA, whereas estrogen receptor 1 (Esr1) mRNA expression was only increased in the group treated with 5mgkg-1of BPA, compared to control group. In the testis, there was increased expression of FSH receptor (Fshr) and inhibin beta B subunit (Inhbb) transcripts only in rats treated with 0.5mgkg-1 of BPA. Serum testosterone and LH concentrations were increased in the group treated with 5mgkg-1of BPA. The results of the present study demonstrate for the first time that perinatal exposure to low doses of BPA during the critical period of hypothalamic sexual differentiation modifies the activity of the HPT axis in the offspring, with consequences for later life in adult rats. PMID- 28641708 TI - Rates of advertised condomless sex in the online profiles of private sex workers: a cross-sectional study. AB - This study aimed to assess the level of condomless sex advertised online by private sex workers (PSW) in Sydney. In 2015, 750 online profiles of PSW, including 339 female, 53 male and 39 transgender PSWs, were reviewed. It was found that PSWs advertise protected anal and vaginal sex. However, 50% of female PSW advertised condomless oral sex. Age less than 25 years was associated with advertised condomless oral sex (odds ratio 1.56; 95% confidence interval 1.03 2.37; P=0.037). Online platforms are widely used for advertising, especially by female PSWs. Levels of condom use advertised reflect that of other studies of sex workers in Sydney. PMID- 28641710 TI - AJMS - 10 Years of Growth. PMID- 28641709 TI - ? PMID- 28641711 TI - A New Beginning. PMID- 28641712 TI - Wireless: The Life and Death of Guglielmo Marconi. AB - With little training in physics, Guglielmo Marconi developed the invention that stunned the world by wirelessly connecting ships and continents. Ten years before his death, he sustained a myocardial infarction followed by unmistakable angina pectoris. His personality and unhappy family life limited his ability to cope with his disease and to deal with Italy's most respected physicians. But their descriptions of his diagnosis and management are surprisingly few. Poor record keeping, intentional news suppression of his failing health or limited medical opportunities could be the reason for this lack of information. He died in 1937 when the value of electrocardiograms and X-rays were recognized (he had neither), but therapeutic options were severely limited. To gain insight into his care, we compared contemporary Italian understanding of coronary heart disease to British and American teachings. When he died of an acute coronary syndrome, heart failure and dysrhythmias, he was attended only by medical staff, but by none of his large family. PMID- 28641713 TI - Assessment Tools for Use During Anesthesia-Centric Pediatric Advanced Life Support Training and Evaluation. AB - BACKGROUND: Pediatric perioperative cardiac arrests are rare events that require rapid, skilled and coordinated efforts to optimize outcomes. We developed an assessment tool for assessing clinician performance during perioperative critical events termed Anesthesia-centric Pediatric Advanced Life Support (A-PALS). Here, we describe the development and evaluation of the A-PALS scoring instrument. METHODS: A group of raters scored videos of a perioperative team managing simulated events representing a range of scenarios and competency. We assessed agreement with the reference standard grading, as well as interrater and intrarater reliability. RESULTS: Overall, raters agreed with the reference standard 86.2% of the time. Rater scores concerning scenarios that depicted highly competent performance correlated better with the reference standard than scores from scenarios that depicted low clinical competence (P < 0.0001). Agreement with the reference standard was significantly (P < 0.0001) associated with scenario type, item category, level of competency displayed in the scenario, correct versus incorrect actions and whether the action was performed versus not performed. Kappa values were significantly (P < 0.0001) higher for highly competent performances as compared to lesser competent performances (good: mean = 0.83 [standard deviation = 0.07] versus poor: mean = 0.61 [standard deviation = 0.14]). The intraclass correlation coefficient (interrater reliability) was 0.97 for the raters' composite scores on correct actions and 0.98 for their composite scores on incorrect actions. CONCLUSIONS: This study provides evidence for the validity of the A-PALS scoring instrument and demonstrates that the scoring instrument can provide reliable scores, although clinician performance affects reliability. PMID- 28641714 TI - Hepatitis C Treatment in Patients With Porphyria Cutanea Tarda. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a common susceptibility factor for porphyria cutanea tarda (PCT). Experience on HCV treatment in patients with PCT is limited. Recently, HCV treatment has improved with direct-acting antivirals (DAA). We review our experience on HCV treatment in patients with PCT with older and newer regimens. MATERIALS AND METHODS: A retrospective chart review was conducted. HCV treatment was attempted 22 times in 13 patients with PCT (5 attempts in 1, 2 in 5 and 1 in the other 7 patients). RESULTS: Before starting HCV treatment, PCT was in complete remission in 16, partial remission in 2, unknown status in 2 and active in 2 instances. PCT relapsed during therapy 6 times (all interferon-based regimens and 2 including telaprevir), 4 requiring treatment interruption. Treatment was interrupted for reasons other than PCT relapse in 2 patients treated with interferon-based regimens. To prevent PCT recurrence, hydroxychloroquine was continued during HCV therapy 6 times (3 interferon regimens, 2 ribavirin regimens without interferon and 1 DAA alone). Twelve patients achieved sustained viral response, 3 with interferon regimens and 9 with DAA. Two patients with active PCT were treated with DAA, with reduction of plasma porphyrins in 1 and normalization in the other at the end of HCV therapy. CONCLUSIONS: HCV treatment regimens including interferon or ribavirin may precipitate PCT relapse. Hydroxychloroquine may be useful to prevent such relapses. In this limited experience, DAA were not associated with PCT relapse. Studies are needed to examine DAA as a primary PCT treatment in HCV-infected patients. PMID- 28641715 TI - Urinary Tract Infections Due to Nontyphoidal Salmonella. AB - BACKGROUND: We sought to establish the characteristics of symptomatic nontyphoidal Salmonella (NTS) urinary tract infection (UTI) without concomitant gastroenteritis (GE) as a separate clinical entity. MATERIALS AND METHODS: We conducted a retrospective cohort single-center study and reviewed all cases of NTS bacteriuria between 1995 and 2016. Patients were assigned to a group according to their clinical presentation, namely, symptomatic NTS UTI without GE, GE with NTS bacteriuria or isolated asymptomatic NTS bacteriuria. We compared the characteristics of patients in the NTS UTI group to those of the latter 2 groups. RESULTS: NTS bacteriuria was found in 77 patients, of which 61 had records available for review. Twenty-one patients (including 17 adults) presented with NTS UTI, 30 patients presented with features of GE with NTS bacteriuria and 10 patients had asymptomatic NTS bacteriuria. NTS UTI was not significantly associated with older age, male sex, diabetes, immunosuppressive states or urologic abnormalities. There was a significant difference in the proportion of patients with an underlying urologic malignancy in the NTS UTI group (4 of 17 patients [23.5%]) as compared to those in the other groups (0 of 24 patients), P = 0.023. CONCLUSIONS: A unique group of patients with symptomatic NTS UTI without GE was identified. A significant association with urologic malignancies was demonstrated in patients with NTS UTI compared to those with GE and NTS bacteriuria or asymptomatic NTS bacteriuria. PMID- 28641716 TI - The Effects of Pleural Plaques on Longitudinal Lung Function in Vermiculite Miners of Libby, Montana. AB - BACKGROUND: This study was conducted to assess associations of pleural plaques (PP) and longitudinal lung function in vermiculite miners of Libby, Montana who are occupationally exposed to asbestos. High-resolution computed tomography (HRCT) was used to identify asbestos-related findings in former Libby vermiculite miners. We investigated annual lung function decline in miners with PP only and compared them to miners with normal HRCT findings. MATERIALS AND METHODS: HRCTs from 128 miners were categorized into the following 4 diagnostic groups: (1) normal computed tomography scan (n = 9); (2) PP only (n = 72); (3) PP and interstitial fibrosis (n = 26) and (4) additional HRCT abnormalities (n = 21) such as rounded atelectasis, diffuse pleural thickening, pleural effusions or pulmonary nodules or tumor >1cm in diameter. Random intercept and slope linear mixed-effect regression models identified differences in lung function decline between miners with asbestos-associated outcomes and those with normal HRCT. Models were adjusted for follow-up time, body mass index, smoking status, latent exposure period and employment years. Interactions for smoking status with age and smoking status with pleural plaque severity were examined. RESULTS: Miners with PP only did not have an accelerated decline in lung function between 40 and 80 years. Miners with PP and additional HRCT abnormalities displayed significantly accelerated declines in forced expiratory volume in 1 second and diffusing capacity of the lungs for carbon monoxide (P = 0.05 and P < 0.01, respectively). Plaque severity did not affect lung function decline. However, smokers with extensive plaques displayed accelerated loss in diffusing capacity of the lungs for carbon monoxide and forced expiratory volume in 1 second when compared to nonsmoking miners with mild plaque formation. CONCLUSIONS: PP alone did not significantly affect lung function decline in vermiculite miners of Libby, Montana. PMID- 28641717 TI - Soluble CD14 Subtype-A New Biomarker in Predicting the Outcome of Critically Ill Septic Patients. AB - BACKGROUND: We evaluated the role of presepsin (soluble CD14 subtype, sCD14-ST) in predicting the outcome of critically ill septic patients in parallel with procalcitonin and C-reactive protein. METHODS: This study was an observational, prospective study that enrolled 58 surgical and medical intensive care unit patients with suspected sepsis. All studied subjects were retrospectively stratified into survivors and nonsurvivors based on 28 days survival and according to microbiological results in blood culture positive and negative groups. Plasma and serum samples from each patient were collected at admission (T 0), after 24-48 hours (T-1) and after 7 days (T-2). Statistics were obtained using Student's t test and ANOVA, as well as Bonferroni post hoc test. Receiver operating characteristic (ROC) analysis was also performed. RESULTS: Presepsin levels were significantly higher at T-0 (P = 0.0007), at T-1 (P < 0.0001) and at T-2 (P < 0.0001) in nonsurvivors versus survivors at the same time point. Presepsin concentrations were significantly increased at T-0 (P = 0.0073), T1 (P = 0.0111) and T2 (P = 0.0167) in patients with positive blood cultures in comparison to patients with negative cultures at the same time. For all time periods evaluated, presepsin data from nonsurviving and surviving individuals were subjected to ROC analysis that demonstrated an excellent accuracy and significant area under the ROC curve (P < 0.0001). Results of multivariate analysis indicated presepsin as a predictive independent variable among prognosis markers at T-0 (P = 0.016). CONCLUSIONS: Presepsin revealed an optimal prognostic performance in patients with severe sepsis and provided interesting diagnostic value. Prediction of outcome in critically ill patients is crucial to optimize management decisions and level of treatment. PMID- 28641718 TI - Alterations in Lipid Profile, Zinc and Copper Levels and Superoxide Dismutase Activities in Normal Pregnancy and Preeclampsia. AB - BACKGROUND: Increased oxidative stress (OS) and lipid peroxidation may be involved in the pathogenesis of preeclampsia (PE). We conducted a case-control study to evaluate the levels of plasma lipids and trace elements as well as activity of superoxide dismutase (SOD) in PE. MATERIALS AND METHODS: The study consisted of 100 patients who had been diagnosed with PE and 100 normotensive pregnant women who underwent medical checkups that served as the control group. Lipid profile, zinc (Zn) and copper (Cu) levels and SOD activities were measured in the plasma of all subjects. RESULTS: Our results showed that the plasma levels of triglycerides and SOD activity were significantly elevated and the levels of Zn and Cu were significantly reduced in patients with PE compared with healthy controls. Increased levels of SOD may indicate antioxidant protective mechanisms against OS in PE-complicated pregnancies. This finding may suggest an involvement of OS in the pathophysiology of PE. CONCLUSION: This study demonstrated a significant negative correlation between SOD activity and levels of trace elements. Furthermore, we suggest that higher triglyceride levels and SOD activity combined with lower Zn and Cu levels may be associated with an increased risk of PE. PMID- 28641719 TI - Surfactant Protein D Inhibits Interleukin-12p40 Production by Macrophages Through the SIRPalpha/ROCK/ERK Signaling Pathway. AB - OBJECTIVE: Interleukin (IL)-12 has a pivotal profibrotic role in the development of idiopathic pulmonary fibrosis (IPF). Medical research trials based on IPF registry databases have actively recruited patients. Surfactant protein D (SP-D) is a useful biomarker in patients with IPF. SP-D binds to signal regulatory protein alpha (SIRPalpha), which acts as an inhibitory receptor, and this SP D/SIRPalpha interaction may have an anti-inflammatory effect. Accordingly, the inhibitory effect of SP-D on IL-12p40 production by lipopolysaccharide (LPS) stimulated macrophages was investigated. MATERIALS AND METHODS: Human granulocyte macrophage colony-stimulating factor (GM-CSF)-stimulated macrophages (day 9 of culture) was used to investigate IL-12p40 production after stimulation with SP-D. RESULTS: GM-CSF was found to upregulate SIRPalpha expression by macrophages. PD98059 (an extracellular signal-regulated kinase [ERK] inhibitor) blunted induction of SIRPalpha expression by GM-CSF. SP-D significantly attenuated IL 12p40 production by macrophages after stimulation with LPS. Silencing of SIRPalpha/beta/gamma significantly reversed this inhibitory effect of SP-D. In contrast, neither SB023580 (a p38alpha/beta MAPK inhibitor) nor BIRB796 (a p38gamma/delta MAPK inhibitor) attenuated the inhibitory effect of SP-D on LPS stimulated production of IL-12p40. Silencing of SHP also had no influence on this effect of SP-D. Interestingly, a Rho-associated protein kinase (ROCK) inhibitor (Y-27632) abolished the inhibition of LPS-stimulated IL-12p40 production by SP-D, whereas silencing of ERK 2 significantly blunted this effect of Y-27632. CONCLUSIONS: These findings suggest that SP-D inhibits LPS-stimulated production of IL-12p40 via the SIRPalpha/ROCK/ERK signaling pathway. PMID- 28641720 TI - Fenofibrate Attenuates Hypertension in Goldblatt Hypertensive Rats: Role of 20 Hydroxyeicosatetraenoic Acid in the Nonclipped Kidney. AB - BACKGROUND: There is vast evidence that the renin-angiotensin system is not the sole determinant of blood pressure (BP) elevation in human renovascular hypertension or the relevant experimental models. This study tested the hypothesis that kidney deficiency of 20-hydroxyeicosatetraenoic acid (20-HETE), a product of cytochrome P450 (CYP)-dependent omega-hydroxylase pathway of arachidonic acid metabolism, is important in the pathophysiology of the maintenance phase of 2-kidney, 1-clip (2K1C) Goldblatt hypertension. MATERIALS AND METHODS: In 2K1C Goldblatt rats with established hypertension, angiotensin II, angiotensin 1-7, 20-HETE concentrations and gene expression of CYP4A1 enzyme (responsible for 20-HETE formation) of the nonclipped kidney were determined. We examined if 14 days' administration of fenofibrate, a lipid-lowering drug, would increase CYP4A1 gene expression and renal 20-HETE formation, and if increased 20 HETE concentrations in the nonclipped kidney would decrease BP (telemetric measurements). RESULTS: CYP4A1 gene expression, 20-HETE and angiotensin 1-7 concentrations were lower and angiotensin II levels were higher in the nonclipped kidney of 2K1C rats than in sham-operated rats. Fenofibrate increased CYP4A1 gene expression and 20-HETE concentration in the nonclipped kidney and significantly decreased BP in 2K1C rats but did not restore it to normotensive range. The treatment did not change BP in sham-operated rats. CONCLUSIONS: Our results suggest that alterations in the RAS and CYP-dependent omega-hydroxylase metabolites of arachidonic acid in the nonclipped kidneys are both important in the pathophysiology of the maintenance phase of 2K1C Goldblatt hypertension. Therefore, fenofibrate treatment effectively attenuated hypertension, probably via stimulation of 20-HETE formation in the nonclipped kidney. PMID- 28641722 TI - Novel Findings in HIV, Immune Reconstitution Disease and Strongyloides stercoralis Infection. AB - We report the successful treatment of an HIV-infected patient with progressive strongyloidiasis as a component of immune reconstitution disease and a review of the literature on this topic. In our experience, pre- and post-antiretroviral therapy intestinal biopsies support a novel mechanism of immune reconstitution disease to Strongyloides stercoralis. We conclude that extended, dual antihelminthic therapy and temporary discontinuation of antiretroviral therapy may be effective in similar patients. PMID- 28641723 TI - Left Main Coronary Artery Thrombosis With Acute Myocardial Infarction: A Management Dilemma. AB - Left main coronary artery (LMCA) thrombosis with acute myocardial infarction is a rare condition with very high mortality. The low incidence of this condition and exclusion of patients with LMCA thrombosis from clinical trials prevent the development of optimal management strategy in these patients. Therefore, there are no clear-cut guidelines describing an evidence-based approach for this condition. We describe a patient with LMCA thrombosis presenting with acute myocardial infarction, who was found to have hypercoagulable state related to homocysteinemia on further work-up. This case highlights the challenges faced during the management of this rare condition due to lack of clear-cut guidelines describing an evidence-based approach. PMID- 28641724 TI - Methemoglobinemia Caused by Indoxacarb Poisoning. PMID- 28641725 TI - Burkholderia cepacia-Associated Hemorrhagic Pericardial Effusion. PMID- 28641726 TI - Recurrence of Cytomegalovirus Viremia Causing Gastrointestinal Tract Bleeding at Different Sites in an Immuno-competent Patient. PMID- 28641727 TI - Metastatic Hepatoid Carcinoma of the Pancreas: First Description of Treatment With Capecitabine and Temozolomide. PMID- 28641721 TI - Effective Self-Management Interventions for Patients With Lupus: Potential Impact of Peer Mentoring. AB - Systemic lupus erythematosus (SLE) is associated with significant mortality, morbidity and cost for the individual patient and society. In the United States, African Americans (AAs) have 3-4 times greater prevalence of lupus, risk of developing lupus at an earlier age and lupus-related disease activity, organ damage and mortality compared with whites. Evidence-based self-management interventions that incorporate both social support and health education have reduced pain, improved function and delayed disability among patients with lupus. However, AAs and women are still disproportionately affected by lupus. This article presents the argument that peer mentoring may be an especially effective intervention approach for AA women with SLE. SLE peers with a track record of success in lupus management and have a personal perspective that clinicians often lack. This commonality and credibility can establish trust, increase communication and, in turn, decrease disparities in healthcare outcomes. PMID- 28641728 TI - Ocular Manifestations of Blood Dyscrasias. PMID- 28641729 TI - Dextrocardia With Situs Inversus and Levo-Transposition of Great Vessels. PMID- 28641730 TI - Benign-Appearing Pheochromocytoma With Late Recurrence. PMID- 28641731 TI - Renal Infarction due to Renal Artery Dissection: A Diagnostic Challenge. PMID- 28641732 TI - Rehabilitation of symptomatic atraumatic degenerative rotator cuff tears: A clinical commentary on assessment and management. AB - STUDY DESIGN: Clinical Commentary. INTRODUCTION: Atraumatic rotator cuff (RC) disease, is one of the most common cause of shoulder pain, which encompasses a continuum from tendinopathy to full thickness cuff tears. Extrinsic, intrinsic and environmental factors have been implicated in the pathophysiology of this disorder, affecting the clinical presentation of symptoms including pain and irritability. Successful rehabilitation of symptomatic atraumatic degenerative rotator cuff (SADRC) tears must address the underlying mechanisms causing dysfunction and correct modifiable factors. PURPOSE OF THE STUDY: The purpose of this paper is to review the shoulder complex anatomy, introduce atraumatic degenerative RC pathology, differentiate between symptomatic and asymptomatic degenerative RC tears, propose an assessment and introduce the Rotator Cuff Protocol 1 (RCP1) designed by the clinical reasoning of one of the lead authors (LW) as a rehabilitation management approach for those clients who present with SADRC tears. METHODS/RESULTS/DISCUSSION: N/A for clinical commentary. CONCLUSIONS: The ability to identify SADRC tears should consider shoulder anatomy, extrinsic, intrinsic and environmental factors, and the consideration for the natural history of atraumatic partial and full thickness tears in the general population. A thorough clinical history and examination, which includes shoulder symptom modification tests, allows the examiner to determine at what phase the patient may start their exercise program. The RCP1 is a program that has been used clinically by many therapists and clients over the years and research is underway to test this protocol in atraumatic rotator cuff disease including SADRC tears. LEVEL OF EVIDENCE: 5. PMID- 28641733 TI - Rotator cuff tendon surgery and postoperative therapy. PMID- 28641734 TI - Acute proximal humeral fractures in adults. AB - STUDY DESIGN: Clinical commentary. INTRODUCTION: Proximal humeral fractures (PHF) are the third most common fracture in the elderly with an increased incidence expected in the coming years with the aging population, causing an important burden to the healthcare system. The management of PHF is challenging due to its complexity and the wide variety of fractures and treatment options. PURPOSE: The objective of this clinical commentary is to update the available evidence on clinical presentation, classification, imaging, medical treatment, and rehabilitation of acute PHF. METHODS/RESULTS/DISCUSSION: N/A for clinical commentary. CONCLUSIONS: The first step to a successful management of PHF is the clinical and radiographic examination of the shoulder, which enables the physician to classify the fracture and choose the appropriate treatment option. The Neer and OA classifications are commonly used and are based on the identification of the fractured parts of the humerus, as well as the displacement of the fragments. In case of non-displaced or minimally displaced fractures, a conservative treatment, consisting of initial immobilization and a rehabilitation program will be chosen. Displaced or unstable fractures will be managed operatively. Different surgical options exist and will vary according to the fracture type, patient's age, and functional needs, followed by rehabilitation. LEVEL OF EVIDENCE: 5. PMID- 28641735 TI - Anatomical and biomechanical framework for shoulder arthroplasty rehabilitation. AB - This article provides an anatomical and biomechanical framework for the postoperative management and progression of treatment for shoulder arthroplasty. The clinical relevance of normal shoulder anatomy, biomechanics, and pathomechanics related to this surgery is emphasized to provide the reader with an understanding of the rationale for treatment. We review the rehabilitation implications of surgical indications and technique for both traditional total shoulder arthroplasty and reverse total shoulder arthroplasty procedures with an emphasis on biomechanical considerations. Relevant factors that affect rehabilitation outcomes are discussed along with supporting evidence from the literature. Principles to guide and progress treatment are highlighted with a discussion on return to sports with the ultimate objective of providing a comprehensive approach for successful rehabilitation. PMID- 28641736 TI - A comprehensive rehabilitation program for posterior instability of the shoulder. AB - Posterior shoulder instability is recognised as being less prevalent than anterior instability, however the diagnosis of this pathology is easily overlooked or missed and this may contribute to an underestimation of prevalence. Recently, there has been increasing recognition of this condition and consequently a greater requirement for knowledge of diagnostic procedures and treatment directions. Currently there is limited research into the conservative management of posterior instability, although it is recommended as first-line treatment prior to surgical review, particularly in those with an atraumatic instability mechanism. The aim of this paper is to outline a comprehensive rehabilitation program for the conservative management of posterior instability with a focus on scapular and humeral head control. The information provided includes extensive written information, flowcharts, figures and a table of management parameters that will provide therapists with adequate detail to replicate the program in the clinical setting. PMID- 28641737 TI - Exploring experiences, barriers, and enablers to home- and class-based exercise in rotator cuff tendinopathy: A qualitative study. AB - STUDY DESIGN: Qualitative study. INTRODUCTION: Adherence is paramount to the successful outcome of exercise-based treatment. PURPOSE OF STUDY: The barriers and enablers to adherence to a home- and class-based exercise program were explored in this qualitative study. METHODS: Semi-structured interviews were carried out to establish common themes relating to the participants' experiences during a year-long randomized controlled trial. RESULTS/DISCUSSION: Twelve participants were interviewed. The main enablers to exercise were highlighted as equipment, perceived benefit from the exercises, and longer and more intensive monitoring. Barriers included the lack of motivation, lack of equipment, and pain. CONCLUSIONS: Implications for practice are incorporating enablers and addressing barriers including self-discharge from classes; the importance of longer term follow-up and the benefits of adopting exercise into a well established routine may provide potential benefits. LEVEL OF EVIDENCE: N/A. PMID- 28641738 TI - Shoulder proprioception: How is it measured and is it reliable? A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Constituents of proprioception include our awareness of the position (joint position sense [JPS]) and motion (kinesthesia) of our limbs in space. Proprioceptive deficits are associated with musculoskeletal disorders but remain a challenge to quantify, particularly at the shoulder. PURPOSE OF THE STUDY: To report the psychometric values of validity, reliability, and responsiveness for shoulder JPS and/or kinesthesia protocols. METHODS: A review of 5 databases was conducted from inception to July 2016 for studies reporting a psychometric property of a shoulder proprioception protocol. The included studies were evaluated using the QualSyst checklist and COSMIN 4 point scale. RESULTS: Twenty-one studies were included, yielding 407 participants and 553 evaluated shoulders (n). The included studies support excellent methodological scores using the QualSyst checklist (88.1 +/- 9.9%) and good psychometric scores with the COSMIN for reliability (71.1%) and moderate-to-low quality score (50%) for criterion validity. Weighted average intraclass correlation coefficients (ICCs) for intrarater reliability were highest for passive JPS and kinesthesia, ICC = 0.92 +/- 0.07 (n = 214) and ICC = 0.92 +/- 0.04 (n = 74), respectively. The most reliable movement and tool are internal rotation at 90 degrees of abduction, ICC = 0.88 +/- 0.01 (n = 53), and the dynamometer, ICC = 0.92 +/- 0.88 (n = 225). Only 2 studies quantify an aspect of validity and no responsiveness indices were reported among the included studies. CONCLUSION: Based on the results of the included studies, the evaluation of shoulder proprioception is most reliable when using a passive protocol with an isokinetic dynamometer for internal rotation at 90 degrees of shoulder abduction. Standardized protocols addressing the psychometric properties of shoulder proprioception measures are needed. LEVEL OF EVIDENCE: Level 1a: systematic review. PMID- 28641739 TI - Writing for Publication: Your Obligation to the Profession. PMID- 28641740 TI - The Power of Language Nutrition for Children's Brain Development, Health, and Future Academic Achievement. AB - Language Nutrition, a term created to describe language exposure that is rich in quality and quantity and delivered in the context of social interactions, is crucial for a child's development and is strongly associated with his/her future literacy, academic achievement, and health. However, significant differences in children's early language environments contribute to disparities in their educational and health trajectories. Interventions, including book distribution programs, coaching parents to enrich their child's language environment, and public awareness campaigns, have all been shown to positively influence a child's access to language-rich interactions. Incorporating Language Nutrition coaching and literacy promotion into pediatrics is a promising platform for building the capacity of parents to provide language exposure to their children. By teaching parents both how and why to treat their child as a conversational partner and by modeling such interactions, pediatric health care providers can help parents set their children on a pathway toward literacy, educational success, and health. PMID- 28641741 TI - Editorial changes. PMID- 28641742 TI - The Good and Bad News About New Drugs for Treating Alopecia Areata. PMID- 28641743 TI - Professor Joaquin Pinol Aguade: An Important Figure in Dermatology. PMID- 28641744 TI - Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD. AB - Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9*10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data. PMID- 28641745 TI - Long-term stability of an injection-molded zirconia bone-level implant: A testing protocol considering aging kinetics and dynamic fatigue. AB - OBJECTIVE: Separately addressing the fatigue resistance (ISO 14801, evaluation of final product) and aging behavior (ISO 13356, standardized sample) of oral implants made from yttria-stabilized zirconia proved to be insufficient in verifying their long-term stability, since (1) implant processing is known to significantly influence transformation kinetics and (2) aging, up from a certain level, is liable to decrease fatigue resistance. Therefore, the aim of this investigation was to apply a new testing protocol considering environmental conditions adequately inducing aging during dynamic fatigue. METHODS: Zirconia implants were dynamically loaded (107 cycles), hydrothermally aged (85 degrees , 60 days) or subjected to both treatments simultaneously. Subsequent, monoclinic intensity ratios (Xm) were obtained by locally resolved X-ray microdiffraction (MU-XRD2). Transformation propagation was monitored at cross-sections by MU-Raman spectroscopy and scanning electron microscopy (SEM). Finally, implants were statically loaded to fracture. Linear regression models (fracture load) and mixed models (Xm) were used for statistical analyses. RESULTS: All treatments resulted in increased fracture load (p<=0.005), indicating the formation of transformation induced compressive stresses around surface defects during all treatment modalities. However, only hydrothermal and combinational treatment were found to increase Xm (p<0.001). No change in Xm was observed for solely dynamically loaded samples (p>=0.524). Depending on the variable observed, a monoclinic layer thickness of 1-2MUm (SEM) or 6-8MUm (Raman spectroscopy) was measured at surfaces exposed to water during treatments. SIGNIFICANCE: Hydrothermal aging was successfully induced during dynamic fatigue. Therefore, the presented setup might serve as reference protocol for ensuring pre-clinically long-term reliability of zirconia oral implants. PMID- 28641746 TI - Special issue: "At the Intersection of DNA Replication and Genome Maintenance: from Mechanisms to Therapy". PMID- 28641747 TI - Preface. PMID- 28641748 TI - Abnormal lung development in congenital diaphragmatic hernia. AB - The outcomes of patients diagnosed with congenital diaphragmatic hernia (CDH) have recently improved. However, mortality and morbidity remain high, and this is primarily caused by the abnormal lung development resulting in pulmonary hypoplasia and persistent pulmonary hypertension. The pathogenesis of CDH is poorly understood, despite the identification of certain candidate genes disrupting normal diaphragm and lung morphogenesis in animal models of CDH. Defects within the lung mesenchyme and interstitium contribute to disturbed distal lung development. Frequently, a disturbance in the development of the pleuroperitoneal folds (PPFs) leads to the incomplete formation of the diaphragm and subsequent herniation. Most candidate genes identified in animal models have so far revealed relatively few strong associations in human CDH cases. CDH is likely a highly polygenic disease, and future studies will need to reconcile how disturbances in the expression of multiple genes cause the disease. Herein, we summarize the available literature on abnormal lung development associated with CDH. PMID- 28641749 TI - Congenital diaphragmatic hernia: The role of multi-institutional collaboration and patient registries in supporting best practice. AB - Among congenital malformations, congenital diaphragmatic hernia (CDH) is distinguished by its relatively low occurrence rate, need for resource intensive, integrated multidisciplinary care, and widespread variation in practice and outcome. Although randomized controlled trials (RCTs) are considered the gold standard for generating evidence, they are poorly suited to the study of a condition like CDH due to challenges in illness severity adjustment, unpredictability in clinical course and the impact limitations of studying a single intervention at a time. An alternative to RCTs for comparative effectiveness research for CDH is the patient registry, which aggregates multi institutional condition-specific patient level data into a large CDH-specific database for the dual purposes of collaborative research and quality improvement across participating sites. This article discusses patient registries from the perspective of structure, data collection and management, and privacy protection that guide the use of registry data to support collaborative, multidisciplinary research. Two CDH-specific registries are described as illustrative examples of the "value proposition" of registries in improving the evidence basis for best practices for CDH. PMID- 28641750 TI - Predicting outcomes in congenital diaphragmatic hernia. AB - Identification of CDH infant populations at high risk for mortality postnatally may help to develop targeted care strategies, guide discussions surrounding palliation and contribute to standardizing reporting and benchmarking, so that care strategies at different centers can be compared. Clinical prediction rules are evidence-based tools that combine multiple predictors to estimate the probability that a particular outcome in an individual patient will occur. In CDH, a suitable clinical prediction rule can stratify high- and low-risk populations and provide the ability to tailor management strategies based on severity. The ideal prediction tool for infants born with CDH would be validated in a large population, generalizable, easily applied in a clinical setting and would clearly discriminate patients at the highest and lowest risk of death. To date, 4 postnatal major clinical prediction rules have been published and validated in the North American CDH population. These models contain variables such as birth weight, Apgar score, blood gases, as well as measures of pulmonary hypertension, and associated anomalies. In an era of standardized care plans and population-based strategies, the appropriate selection and application of a generalizable tool to provide an opportunity for benchmarking, policy creation, and centralizing the care of high-risk populations. A well-designed clinical prediction tool remains the most practical and expedient way to achieve these goals. PMID- 28641751 TI - Fetal imaging and therapy for CDH-Current status. AB - In congenital diaphragmatic hernia (CDH), herniation of the abdominal organs into the fetal chest causes pulmonary hypoplasia and pulmonary hypertension, the main causes of neonatal mortality. As antenatal ultrasound screening improves, the risk of postnatal death can now be better predicted, allowing for the identification of fetuses that might most benefit from a prenatal intervention. Fetoscopic tracheal occlusion is being evaluated in a large international randomized controlled trial. We present the antenatal imaging approaches that can help identify fetuses that might benefit from antenatal therapy, and review the evolution of fetal surgery for CDH to date. PMID- 28641752 TI - Congenital diaphragmatic hernia-associated pulmonary hypertension. AB - Congenital diaphragmatic hernia (CDH) is a complex entity wherein a diaphragmatic defect allows intrathoracic herniation of intra-abdominal contents and both pulmonary parenchymal and vascular development are stifled. Pulmonary pathology and pathophysiology, including pulmonary hypoplasia and pulmonary hypertension, are hallmarks of CDH and are associated with disease severity. Pulmonary hypertension (PH) is sustained, supranormal pulmonary arterial pressure, and among patients with CDH (CDH-PH), is driven by hypoplastic pulmonary vasculature, including alterations at the molecular, cellular, and tissue levels, along with pathophysiologic pulmonary vasoreactivity. This review addresses the basic mechanisms, altered anatomy, definition, diagnosis, and management of CDH-PH. Further, emerging therapies targeting CDH-PH and PH are explored. PMID- 28641753 TI - Cardiac dysfunction in congenital diaphragmatic hernia: Pathophysiology, clinical assessment, and management. AB - Cardiac dysfunction is an important consequence of pulmonary hypertension in congenital diaphragmatic hernia and a determinant of disease severity. Increased afterload leads to right ventricular dilatation and diastolic dysfunction. Septal displacement and dysfunction impair left ventricular function, which may also be compromised by fetal hypoplasia. Biventricular failure contributes to systemic hypotension and hypoperfusion. Early and regular echocardiographic assessment of cardiac function and pulmonary artery pressure can guide therapeutic decision making, including choice and timing of pulmonary vasodilators, cardiotropes, ECMO, and surgery. PMID- 28641754 TI - Ventilation modalities in infants with congenital diaphragmatic hernia. AB - Neonates with congenital diaphragmatic hernia are among the more complex patients to support with mechanical ventilation. They have particular features that add to the difficulties already present in the neonatal patient. A ventilation strategy tailored to the patient's underlying physiology rather than mode of ventilation is a crucial issue for clinicians treating these delicate patients. PMID- 28641755 TI - ECMO in CDH: Is there a role? AB - Despite wide use and decades of experience, survival of congenital diaphragmatic hernia (CDH) patients treated with extra-corporeal membrane oxygenation (ECMO), as reported by the extra-corporeal life support organization (ELSO), remains unchanged at 50%. High-survival rates both with and without utilizing ECMO have been reported, fueling questions about the utility of ECMO support in this difficult population. This review looks at data from the Congenital Diaphragmatic Hernia Study Group and individual center reports, to evaluate the role of ECMO in CDH, focusing on defining the patients most likely to benefit, and discussing how those benefits can best be achieved. These data show that ECMO improves survival in those CDH patients who are most severely affected, but potential complications of ECMO delivery outweigh benefit in patients with less severely affected. Improved results can be expected by minimizing ECMO complications, and by improving rates of CDH repair in patients that require ECMO. PMID- 28641756 TI - Regenerative medicine solutions in congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) remains a major challenge and associated mortality is still significant. Patients have benefited from current therapeutic options, but most severe cases are still associated to poor outcome. Regenerative medicine is emerging as a valid option in many diseases and clinical trials are currently happening for various conditions in children and adults. We report here the advancement in the field which will help both in the understanding of further CDH development and in offering new treatment options for the difficult situations such as repair of large diaphragmatic defects and lung hypoplasia. The authors believe that advancements in regenerative medicine may lead to increase of CDH patients' survival. PMID- 28641757 TI - Long-term follow-up of congenital diaphragmatic hernia. AB - Increased survival of patients with congenital diaphragmatic hernia has created a unique cohort of children, adolescent, and adult survivors with complex medical and surgical needs. Disease-specific morbidities offer the opportunity for multiple disciplines to unite together to provide long-term comprehensive follow up, as well as an opportunity for research regarding late outcomes. These children can exhibit impaired pulmonary function, altered neurodevelopmental outcomes, nutritional insufficiency, musculoskeletal changes, and specialized surgical needs that benefit from regular monitoring and intervention, particularly in patients with increased disease severity. Below we aim to characterize the specific challenges that these survivors face as well as present an algorithm for a multidisciplinary long-term follow-up program. PMID- 28641759 TI - Evaluation of a methodology to validate National Death Index retrieval results among a cohort of U.S. service members. AB - PURPOSE: Accurate knowledge of the vital status of individuals is critical to the validity of mortality research. National Death Index (NDI) and NDI-Plus are comprehensive epidemiological resources for mortality ascertainment and cause of death data that require additional user validation. Currently, there is a gap in methods to guide validation of NDI search results rendered for active duty service members. The purpose of this research was to adapt and evaluate the CDC National Program of Cancer Registries (NPCR) algorithm for mortality ascertainment in a large military cohort. METHODS: We adapted and applied the NPCR algorithm to a cohort of 7088 service members on active duty at the time of death at some point between 2001 and 2009. We evaluated NDI validity and NDI-Plus diagnostic agreement against the Department of Defense's Armed Forces Medical Examiner System (AFMES). RESULTS: The overall sensitivity of the NDI to AFMES records after the application of the NPCR algorithm was 97.1%. Diagnostic estimates of measurement agreement between the NDI-Plus and the AFMES cause of death groups were high. CONCLUSIONS: The NDI and NDI-Plus can be successfully used with the NPCR algorithm to identify mortality and cause of death among active duty military cohort members who die in the United States. PMID- 28641760 TI - Heeding the call for less casual causal inferences: the utility of realized (quantitative) causal effects. PMID- 28641758 TI - Maternal intake of fried foods and risk of gestational diabetes mellitus. AB - PURPOSE: We examined the relationship of maternal periconceptional (i.e., before conception and early pregnancy) intake of fried foods with gestational diabetes mellitus (GDM) risk. METHODS: In a prospective birth cohort in Seattle and Tacoma, Washington State, USA, we assessed maternal periconceptional fried food intake using a food frequency questionnaire among 3414 participants. We used multivariable generalized linear regression models to derive estimates of relative risks (RRs; and 95% confidence intervals, 95% CIs) of GDM in relation to the intake of different types of fried foods (i.e., fried fish, fried chicken, fried potatoes, chips, and donuts). RESULTS: A total of 169 GDM incident cases were identified in this cohort (4.96%). Compared with no fried fish intake, fried fish intake >1 servings/month was associated with 68% higher GDM risk (adjusted RR and 95% CI; 1.68 [1.16, 2.45]; Ptrend = .019). After adjusting for confounders, the RRs (95% CI) of GDM relative to fried chicken intake were 1.0, 1.44 (0.98, 2.09), and 1.81 (1.22, 2.70) for none, <=1 and > 1 servings/month intake of fried chicken, respectively (Ptrend = .002). Dietary intake of fried potatoes, snack chips or donuts was not significantly associated with higher GDM risk. Limitations of our study include the lack of information about frying methods and the intake of fried foods at home and away from home. CONCLUSIONS: Regular intake of fried fish and fried chicken are associated with elevated GDM risk. PMID- 28641761 TI - Editorial overview: Cell regulation: 1000 Flavors including chocolate and chili peppers. PMID- 28641762 TI - Laparoscopic versus robotic surgery for hepatocellular carcinoma: the first 46 consecutive cases. AB - BACKGROUND: Hepatocellular carcinoma has a growing incidence worldwide, and represents a leading cause of death in patients with cirrhosis. Nowadays, minimally invasive approaches are spreading in every field of surgery and in liver surgery as well. MATERIALS AND METHODS: We retrospectively reviewed demographics, clinical, and pathologic characteristics and short-term outcomes of patients who had undergone minimally invasive resections for hepatocellular carcinoma at our institution between June 2012 and May 2016. RESULTS: No significant differences in demographics and comorbidities were found between patients in the laparoscopic (n = 24) and robotic (n = 22) groups, except for the rates of cirrhotic patients (91.7% and 68.2%, respectively, P = 0.046). Perioperative data analysis showed that the operative time (mean, 211 and 318 min, respectively, P < 0.001) was the only parameter in favor of laparoscopy. Conversely, robotic-assisted resections were related to less Clavien I-II postoperative complications (22 cases versus 13 cases; P = 0.03). As regards resection margins, the two groups were similar with no statistically significant differences in rates of disease-free resection margins. CONCLUSIONS: A modern hepatobiliary center should offer both open and minimally invasive approaches to liver disease to provide the best care for each patient, according to the individual comorbidities, risk factors, and personal quality of life expectations. Our results show that the robotic approach is a reliable tool for accurate oncologic surgery, comparable to the laparoscopic approach. Robotic surgery also allows the surgeon to safely approach liver segments that are difficult to resect in laparoscopy, namely segments I-VII-VIII. PMID- 28641763 TI - Retraction notice to "Downregulation of miR-204 expression correlates with poor clinical outcome of glioma patients" [Hum Pathol 2017; 63: 46-52]. PMID- 28641764 TI - Are static and functional balance abilities related in individuals with Multiple Sclerosis? AB - BACKGROUND: In people with Multiple Sclerosis (pwMS), balance assessment is essential in estimating the risk of falls, monitoring disease progression and verifying the effectiveness of rehabilitative treatment. Clinical tools and instrumental techniques are available for testing static and dynamic balance, but the relationship between such abilities is still not clear. Having information about this link would be important in properly planning the type and number of tests to administer. METHODS: One hundred and six pwMS (Expanded Disability Status Scale, EDSS 0-6.5) stratified in three sub-groups (Class 1 EDSS 0-1.5, Class 2 EDSS 2-4 and Class 3 EDSS 4.5-6.5) and 42 healthy controls (HC) participated in the study. All underwent static posturography and instrumented Timed-Up-and-Go (TUG) performed using a wearable inertial sensor. Raw data were processed to extract postural sway features, overall duration of TUG and its main sub-phases (i.e. sit-to-stand, 180 degrees turns and stand-to-sit). RESULTS: All sway parameters of pwMS of Classes 2 and 3, as well as total TUG duration and time necessary to perform 180 degrees turns, were found significantly higher than HC and Class 1 participants. However, poor correlations were found between sway and TUG parameters. When pwMS are grouped, small/moderate correlations (in the range 0.20-0.41) were found between all sway parameters and total TUG duration. CONCLUSIONS: Static and dynamic balance in pwMS appear scarcely correlated, although both worsen as disability increases. This implies that they should be separately assessed using specific tests to have a complete view of postural control performance in MS. PMID- 28641765 TI - Investigation of the prognostic value of adipokines in multiple sclerosis. AB - BACKGROUND: Adipokines may be involved in multiple sclerosis (MS) as well as other inflammatory diseases. This study aimed to analyze the value of serum adipokine levels as biomarkers in determining the clinical progression of MS. METHODS: A total of 90 subjects including 40 healthy individuals and 50 MS patients [24 with classical clinical course of MS (C-MS), 26 with benign MS (B MS)] were recruited for this study. The levels of serum adipokines and inflammatory mediators were measured using immunoassay methods. RESULTS: The levels of adiponectin, MCP-1, TNF-alpha and IL-6 were significantly higher in C MS patients compared with B-MS patients and healthy controls. Only adiponectin and MCP-1 levels remained significantly high after Bonferroni correction. Adiponectin, MCP-1 and TNF-alpha levels showed a modest correlation with expanded disability status scale (EDSS) scores, which disappeared after Bonferroni correction. CONCLUSIONS: Our findings suggest the potential role of adipokines in pathogenesis and clinical progression of MS. Adiponectin and MCP-1 might potentially serve as prognostic biomarkers in MS. PMID- 28641766 TI - Amyloid PET in pseudotumoral multiple sclerosis. AB - BACKGROUND: Pseudotumoral multiple sclerosis is a rare form of demyelinating disease of the central nervous system. Positron emission tomography (PET) using amyloid-tracers has also been suggested as a marker of damage in white matter lesions in multiple sclerosis due to the nonspecific uptake of these tracers in white matter. METHOD: We present the case of a 59 year-old woman with a pathological-confirmed pseudotumoral multiple sclerosis, who was studied with the amyloid tracer 18F-florbetaben. The patient had developed word-finding difficulties and right hemianopia twelve years ago. In that time, MRI showed a lesion on the left hemisphere with an infiltrating aspect in frontotemporal lobes. Brain biopsy showed demyelinating areas and inflammation. During the following years, two new clinical relapses occurred. RESULTS: 18F-florbetaben PET showed lower uptake in the white matter lesion visualized in the CT and MRI images. Decreased tracer uptake was also observed in a larger area of the left hemisphere beyond the lesions observed on MRI or CT. White matter lesion volume on FLAIR was 44.2mL, and tracer uptake change between damaged white matter and normal appearing white matter was - 40.5%. Standardized uptake value was inferior in the pseudotumoral lesion than in the other white matter lesions. CONCLUSION: We report the findings of amyloid PET in a patient with pseudotumoral multiple sclerosis. This case provides further evidence on the role of amyloid PET in the assessment of white matter and demyelinating diseases. PMID- 28641768 TI - Disease reactivation following fingolimod withdrawal in multiple sclerosis: Two case reports. AB - BACKGROUND: Severe multiple sclerosis reactivation following second line treatment withdrawal, defined "rebound syndrome", is becoming a prominent issue to consider when deciding to discontinue a treatment. In particular disease recurrence after cessation of fingolimod is actually poorly characterized as to date, only case reports and small case series have been described. CASE PRESENTATION: We herewith describe 2 cases of severe disease reactivation associated to a high number of brain gadolinium enhancing lesions at magnetic resonance imaging (MRI) despite high dose steroid treatment, observed a few weeks after cessation of fingolimod administration, causing a substantial and persistent worsening of patient disability that required long term hospitalization. The severity of the neurological symptom worsening and of the brain lesion largely exceeded the disease activity observed during treatment. CONCLUSIONS: Our patients developed a rebound syndrome after ceasing fingolimod treatment, defined as the development of severe neurological symptoms and multiple new or enhancing lesions exceeding previous activity. Further analysis are needed to identify patients at greatest risk of a rebound syndrome. PMID- 28641767 TI - Prehistoric enemies within: The contribution of human endogenous retroviruses to neurological diseases. Meeting report: "Second International Workshop on Human Endogenous Retroviruses and Disease", Washington DC, March 13th and 14th 2017. AB - The Second International Workshop on Human Endogenous Retroviruses and Disease, Washington DC, March 13-14 2017 brought together international basic and clinical scientists investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases. PMID- 28641769 TI - Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation. AB - OBJECTIVE: The objective of this study is to longitudinally analyze the uptake of [11C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment. METHODS: Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patient's white matter (VT ratio=VTr), to consider physiologic variability. RESULTS: Test-retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing lesions present within 5 patients (p=0.001). Moreover, VTr of the sum of non-enhancing lesions showed a moderate decrease (p=0.03). No longitudinal changes were detected in normal appearing white matter, the thalamus and cortical grey matter. CONCLUSION: A reduction in PK11195 uptake was observed in both enhancing and chronic lesions after the start of natalizumab. PK11195 PET can be used as tool to assess the longitudinal change in MS lesions. PMID- 28641770 TI - Does vagotomy protect against multiple sclerosis? AB - OBJECTIVES: To examine the association between vagotomy and multiple sclerosis. METHODS: We conducted a matched cohort study of all patients who underwent truncal or super-selective vagotomy and a comparison cohort, by linking Danish population-based medical registries (1977-1995). Hazard ratios (HRs) for multiple sclerosis, adjusting for potential confounders were computed by means of Cox regression analysis. RESULTS: Median age of multiple sclerosis onset corresponded to late onset multiple sclerosis. No association with multiple sclerosis was observed for truncal vagotomy (0-37 year adjusted HR=0.91, 95% confidence interval [CI]: 0.48-1.74) or super-selective vagotomy (0-37 year adjusted HR=1.28, 95% CI: 0.79-2.09) compared with the general population. INTERPRETATION: We found no association between vagotomy and later risk of late onset multiple sclerosis. PMID- 28641771 TI - Fatigue in Multiple Sclerosis: Is it related to cytokines and hypothalamic pituitary-adrenal axis? AB - BACKGROUND: Fatigue is a common symptom of Multiple Sclerosis (MS) that diminishes the quality of life of patients, but its exact mechanism remains poorly understood. There is not a generally adopted scale to determine MS fatigue. Studies that investigated physiopathology of fatigue symptom have shown dysregulation of hypothalamic-pituitaryadrenal (HPA) axis. In the current study, we aimed to compare the results obtained with two separate scales, namely the Fatigue Severity Scale (FSS) and the Neurological Fatigue Index-Multiple Sclerosis (NFI-MS), and assess the relationship between fatigue and serum IL 1beta, TNF-alpha, IL-35, IL-2, IL-10, ACTH, cortisol, alpha-MSH, beta-MSH, gamma MSH and CLIP (Corticotropinlike intermediate lobe peptide) in MS patients categorized as fatigued and non-fatigued on the basis of FSS scores. METHODS: For the study, a total of 54 (29 females, 25 males) patients diagnosed with RRMS including 26 with fatigue symptom (48.1%), and 26 healthy controls (13 females, 13 males) were enrolled. A FSS score >=36 was considered as cut-off score to separate fatigued patients from nonfatigued patients. RESULTS: A significant positive correlation was determined between FSS score and NFI-MS scale, NFI-MS 1, NFI-MS 2, NFI-MS 3 and NFI-MS 4 scores. IL-1beta, IL-10 and TNF-alpha levels did not differ between patient and control groups. IL-35 and IL-2 levels were significantly higher among MS patients (p<0.01). However, no difference was observed between fatigued and nonfatigued patients in the cytokines and HPA parameters studied. ACTH, cortisol and alpha-MSH were significantly higher in MS group (p=0.02, p<0.01 and p<0.01, respectively). CLIP level was significantly low in MS patient group (p<0.01). CONCLUSION: NFI-MS scale is equally sensitive as FSS scale for assessment of MS fatigue; thus, it may also be widely used to evaluate that symptom. Generally HPA axis is hyperactive in MS patients, but it is not correlated with fatigue in our study. For the first time, levels of CLIP (a type of melanocortin) are studied, and determined to be lower among MS patients. Elevated levels of IL-35 and IL-2 suggest that these cytokines may have a prominent role in MS pathophysiology and can be investigated as potential targets for development of novel therapies. PMID- 28641772 TI - Susac Syndrome: A differential diagnosis of white matter lesions. AB - INTRODUCTION: Susac Syndrome is an autoimmune endotheliopathy affecting capillaries and precapillary arterioles of the brain, inner ear and retina. The classic symptom triad includes visual disturbances, hypoacusia, and encephalopathy, but is rarely fully manifest at onset. The syndrome typically follows an active fluctuating monophasic course. Typical imaging findings on brain magnetic resonance show central fiber microischemias/microinfarctions of the corpus callosum known as "snow balls", as well as lineal infarcts and upper callosal fiber involvement. Fluorescein angiography and tonal audiometry are important tools to confirm diagnosis, even in patients who are asymptomatic for visual or auditory disturbances. We describe 8 patients with Susac Syndrome treated at our center and compare findings to those of other published case series. METHODS: Eight adults with Susac Syndrome diagnosed between January 2007 and August 2016 at our center, in Buenos Aires, Argentina are described. Magnetic Brain Resonance, fluorescein angiography, tonal audiometry, a complete serologic battery and lumbar puncture were performed to all patients. RESULTS: The majority of patients were males, and average age at diagnosis was 37.5 years (range: 22-52 yrs). Two patients presented full clinical triad at onset, while the remaining developed visual and/or auditory disturbances later during the course of disease. All cases manifested varied neurological symptoms including pyramidal and/or sensory tract symptoms, amnesic disorders, ataxia and vertigo. Psychiatric manifestations such as disinhibition, aggressive behavior, paranoid ideation and hallucinations were also present. Seven patients suffered at least one relapse. Typical central corpus callosum fiber ischemias/infarcts, also known as snowball lesions were visible in all patients. Spokes, icicles, periventricular lesions and internal capsule "string of beads" patterns were observed on diffusion weighted images. Four cases presented fornix microischemias/microinfarctions, 5 juxtacortical involvement and 3 infratentorial infarcts. Leptomeningeal involvement was evident in only 1 patient after rabies vaccination. Fluorescein angiography was abnormal in 7 cases. Tonal audiometry revealed unilateral hypoacusia in 5 patients, 3 with low frequency hearing loss. Immunosuppressive treatment was indicated in all cases. Patient follow up ranged between 6 months and 9 years, only 1 patient was lost to follow up after three years. CONCLUSION: Susac Syndrome is probably both underdiagnosed and misdiagnosed. Early and aggressive immunosuppressive treatment is indicated in order to prevent potential disabilities. PMID- 28641773 TI - Incidence of tonic spasms as the initial presentation of pediatric multiple sclerosis in Slovenia. AB - Tonic spasms (TS) are involuntary movement patterns that can present in patients with multiple sclerosis (MS). They have been first described decades ago, but are frequently missed and misdiagnosed, particularly in the pediatric MS patients and if appearing ahead of hallmark neurological signs and symptoms of MS. Slovenia is a country with the population of about 2 million people. In the years from 1992 to 2016, we have treated 57 sequential pediatric patients with MS at our hospital, which is the only tertiary medical institution for treating children with MS in the country. We present the only two MS patients, a 17-year-old girl and a 14-year-old boy, whose first manifestation of MS were TS. This allowed us to estimate the incidence of TS in pediatric MS patients in Slovenia. PMID- 28641774 TI - Membranous nephropathy with Neuromyelitis optica spectrum disorder. AB - Membranous nephropathy (MN) accompanying Neuromyelitis optica spectrum disorders (NMOSD) has rarely been described previously. We recently presented a 45-year-old Chinese male presenting with recurrent lower extremity pitting edema, or eyelid edema, proteinuria and hyperlipidemia. especially intractable hiccup and vomiting, painful tonic spasm (PTS) as the revealing symptom of a demyelinating disorder of central nervous system. The kindey biopsy specimen showed MN stage 2. Serological testing revealed antibodies AQP4, MRI head and spine revealed medulla oblongata and C1-C2 cervical vertebra lesions. Treatment with methylprednisolone, cyclophosphamide, azathioprine resulted in consistent clinical improvement. PMID- 28641775 TI - Is Toxoplasma gondii infection protective against multiple sclerosis risk? AB - BACKGROUND: Parasitic infections may play a protective role in neurodegenative diseases. OBJECTiVE: To determine the association between Toxoplasma gondii (T. gondii) infection and Multiple Sclerosis (MS). METHODS: One hundred fifteen patients with MS were included in the study. Sixty age and gender-matched healthy subjects were recruited as controls. Subjects were assessed for clinical and demographic parameters. The presence of specific IgG antibodies against T. gondii microorganism was searched by using an enzyme immunoassay test in the sera of the subjects. RESULTS: T. gondii seropositivity was found to be lower in MS patients than in healthy controls (33.9% vs. 55%, p=0.007). Mean age and disease duration of the patients were 41.15+/-11.20 (18-74) and 1.90+/-1.44 (0-6) years, respectively. MS patients with a high IgG titer had lower expanded disability status scale (EDSS) scores (p=0.001) and lower annualized relapse rates (ARR) (p=0.005). There was no significant association between T. gondii seropositivity and disease duration (p=0.598). Female MS patients tended to have higher T. gondii seropositivity than males although the difference did not reach statistical significance (p=0.192). We found a negative correlation between T. gondii seropositivity and both EDSS scores (r=-0.322, p<0.001) and ARR (r=-0.263, p=0.004). CONCLUSiON: We found a negative association between T. gondii infection and the presence of MS. Furthermore, parasite infected MS patients had experienced fewer relapses with lower disability scores supporting the hypothesis of immunomodulatory effects of parasitic infections in autoimmune diseases. Further studies are required to establish the protective role of parasitic infections in MS. PMID- 28641776 TI - The 'Field Hypothesis': rebound activity after stopping disease-modifying therapies. PMID- 28641777 TI - Role of PARL-PINK1-Parkin pathway in adipocyte differentiation. AB - OBJECTIVE: Adipogenesis determines the number of adipocytes which is increased when individuals become obese. Mitochondria undergo remarkable morphological and functional changes during adipogenesis. PTEN-induced kinase 1 (PINK1) is pivotal to maintain mitochondrial homeostasis in neural cells. The present study aimed at investigating effects of PINK1 on adipogenesis and energy metabolism. METHODS: Expression of presenilin associated rhomboid-like protein (PARL), PINK1 and Parkin, as well as the interaction among these proteins was temporally examined during adipogenesis. In addition, the alterations of mitochondrial mass and the energy metabolism were also analyzed. RESULTS: Adipogenic process can be dissected into 3 stages according to the participation of PARL-PINK1-Parkin system. (1) When pre-adipocytes are switched to differentiation, f-PINK1 is subjected to PARL cleavage to generate s-PINK1 at the early stage of differentiation (0-4day). Mitochondrial mass is increased for generating ambient energy to meet the demands for cellular remodeling. (2) At the second stage (5 6day), s-PINK1 persistently accumulates in mitochondria and translocates into cytoplasm to mediate Parkin degradation. Mitochondria are fragmented to reduce their mass. (3) At the late stage (7-8day), only residual autophagy activity is remained when excess mitochondria have been eliminated. This mitochondria clearance maintains energy consumption of mature adipocytes at the minimal levels for storing energy. PARL silencing aborts adipogenesis by inhibiting PPARgamma expression and the finely-orchestrated events. CONCLUSIONS: Our findings reveal the sequential adipogenic events directed by PARL-PINK1-Parkin system, add more evidence supporting the convergence of pathogenesis leading to neurodegenerative and metabolic diseases, and provide substantial information for developing novel therapeutic strategies by manipulating adipogenesis. PMID- 28641778 TI - Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy. AB - OBJECTIVE: Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by partial lack of subcutaneous fat. METHODS: This multicenter prospective observational study included data from 56 subjects with FPLD (18 independent Turkish families). Thirty healthy controls were enrolled for comparison. RESULTS: Pathogenic variants of the LMNA gene were determined in nine families. Of those, typical exon 8 codon 482 pathogenic variants were identified in four families. Analysis of the LMNA gene also revealed exon 1 codon 47, exon 5 codon 306, exon 6 codon 349, exon 9 codon 528, and exon 11 codon 582 pathogenic variants. Analysis of the PPARG gene revealed exon 3 p.Y151C pathogenic variant in two families and exon 7 p.H477L pathogenic variant in one family. A non pathogenic exon 5 p.R215Q variant of the LMNB2 gene was detected in another family. Five other families harbored no mutation in any of the genes sequenced. MRI studies showed slightly different fat distribution patterns among subjects with different point mutations, though it was strikingly different in subjects with LMNA p.R349W pathogenic variant. Subjects with pathogenic variants of the PPARG gene were associated with less prominent fat loss and relatively higher levels of leptin compared to those with pathogenic variants in the LMNA gene. Various metabolic abnormalities associated with insulin resistance were detected in all subjects. End-organ complications were observed. CONCLUSION: We have identified various pathogenic variants scattered throughout the LMNA and PPARG genes in Turkish patients with FPLD. Phenotypic heterogeneity is remarkable in patients with LMNA pathogenic variants related to the site of missense mutations. FPLD, caused by pathogenic variants either in LMNA or PPARG is associated with metabolic abnormalities associated with insulin resistance that lead to increased morbidity. PMID- 28641780 TI - Associations of maternal prenatal smoking with umbilical cord blood hormones: the Project Viva cohort. AB - BACKGROUND: Maternal smoking during pregnancy is associated with low fetal growth and adverse cardiometabolic health in offspring. However, hormonal pathways underlying these associations are unclear. Therefore, we examined maternal smoking habits and umbilical cord blood hormone profiles in a large, prospective cohort. METHODS: We studied 978 mother/infant pairs in Project Viva, a Boston area cohort recruited 1999-2002. We categorized mothers as early pregnancy smokers, former smokers, or never smokers. Outcomes were cord blood concentrations of IGF-1, IGF-2, IGFBP-3, leptin, adiponectin, insulin, and C peptide. We used linear regression models adjusted for maternal pre-pregnancy body mass index (BMI), race/ethnicity, parity, education, and infant sex. We conducted analyses in the full cohort and stratified by infant sex. RESULTS: Thirteen percent of women were early pregnancy smokers, 20% former smokers, and 68% never smokers. Infants of early pregnancy smokers had lower IGF-1 adjusted for IGFBP-3 [-5.2ng/mL (95% CI: -8.6, -1.7)], with more pronounced associations in girls [-10.7ng/mL (95% CI: -18.5, -2.9) vs. -4.0ng/mL (95% CI: -8.4, 0.4) for boys]. Early pregnancy smoking was not associated with cord blood hormones other than IGF-1. Infants of former smokers had a cord blood hormone profile similar to infants of never smokers. CONCLUSIONS: As compared to mothers who never smoked, early pregnancy smokers had infants with lower cord blood IGF-1 which could prime adverse metabolic outcomes. This provides further reason to support smoking cessation programs in women of reproductive age. PMID- 28641781 TI - Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes. AB - CONTEXT: Gestational diabetes is commonly linked to development of type 2 diabetes mellitus (T2DM). There is a need to characterize metabolic changes associated with gestational diabetes in order to find novel biomarkers for T2DM. OBJECTIVE: To find potential pathophysiological mechanisms and markers for progression from gestational diabetes mellitus to T2DM by studying the metabolic transition from pregnancy to postpartum. DESIGN: The metabolic transition profile from pregnancy to postpartum was characterized in 56 women by mass spectrometry based metabolomics; 11 women had gestational diabetes mellitus, 24 had normal glucose tolerance, and 21 were normoglycaemic but at increased risk for gestational diabetes mellitus. Fasting serum samples collected during trimester 3 (gestational week 32+/-0.6) and postpartum (10.5+/-0.4months) were compared in diagnosis-specific multivariate models (orthogonal partial least squares analysis). Clinical measurements (e.g., insulin, glucose, lipid levels) were compared and models of insulin sensitivity and resistance were calculated for the same time period. RESULTS: Women with gestational diabetes had significantly increased postpartum levels of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, and their circulating lipids did not return to normal levels after pregnancy. The increase in BCAAs occurred postpartum since the BCAAs did not differ during pregnancy, as compared to normoglycemic women. CONCLUSIONS: Postpartum levels of specific BCAAs, notably valine, are related to gestational diabetes during pregnancy. PMID- 28641782 TI - High prevalence of apolipoprotein B dyslipoproteinemias in non-alcoholic fatty liver disease: The lifelines cohort study. AB - OBJECTIVE: Cardiovascular disease (CVD) is a major adverse consequence of non alcoholic fatty liver disease (NAFLD). The association of NAFLD with various apolipoprotein B (apoB) dyslipoproteinemias is unclear. We determined the prevalence of specific apoB dyslipoproteinemias in subjects with suspected NAFLD. METHODS: This study was conducted among 22,865 fasting adults living in the northern part of the Netherlands (Lifelines Cohort Study). Six apoB dyslipoproteinemias were defined using an algorithm derived from apoB, total cholesterol and triglycerides. NAFLD was defined as Fatty Liver Index (FLI) >=60. Advanced hepatic fibrosis was defined as NAFLD fibrosis score (NFS) >=0.676. RESULTS: 4790 participants (20.9%) had an FLI>=60. NAFLD subjects were older, more likely to be men, more obese and more often had diabetes and metabolic syndrome (P<0.001 for each). Among NAFLD subjects, any apoB dyslipoproteinemia was present in 61.5% vs. 16.5% in subjects without NAFLD (P<0.001). Elevated chylomicrons were not observed in NAFLD. In univariate analysis, NAFLD was associated with a higher prevalence of each apoB dyslipoproteinemia vs. subjects with an FLI<60 (P<0.001), except for low density lipoprotein (LDL) dyslipoproteinemia. Additionally, each apoB dyslipoproteinemia was independently associated with NAFLD in age- and sex-adjusted logistic regression analysis, including the apoB dyslipoproteinemias together (P<0.001). The prevalence of apoB dyslipoproteinemias was not altered in subjects with NFS >=0.676. CONCLUSIONS: NAFLD rather than advanced hepatic fibrosis is independently associated with increased prevalence of chylomicrons+very low-density lipoproteins (VLDL) remnants, VLDL, LDL and VLDL+LDL dyslipoproteinemias. ApoB dyslipoproteinemias may contribute to increased CVD risk associated with NAFLD. PMID- 28641783 TI - Abnormal levels of adipokines in adolescent offspring of women with type 1 diabetes - Results from the EPICOM study. AB - AIMS/HYPOTHESIS: To investigate long-term consequences of diabetes during pregnancy, we determined adiponectin and leptin levels in adolescents born by women with type 1 diabetic (T1D) or non-diabetic mothers, and determined associations between adiponectin and leptin levels in adolescence and the magnitude of intrauterine hyperglycemia. RESEARCH DESIGN AND METHODS: We measured serum adiponectin and leptin and calculated leptin to adiponectin ratio (LAR) in 271 offspring of T1D women (index offspring) (13-20years), and 297 matched control offspring. Anthropometry included total body fat (TBF) by dual-energy X ray absorptiometry and an oral glucose tolerance test. RESULTS: Adiponectin levels were lower in index females (-8.0% (95% CI; -13.9, -1.6)), but not in index males (0.4% (95% CI; -7.3, 8.6)). Leptin levels were approximately 30% higher in index than control offspring, irrespective of gender. In males, this was seen despite similar TBF in index and control offspring. LAR was increased in index offspring (both males and females) compared with control offspring. There were no association between offspring adiponectin and maternal HbA1c levels in pregnancy. Leptin and LAR seemed to be associated with third trimester HbA1c levels in females in unadjusted, but not adjusted analyses. CONCLUSION: Male and female offspring of women with T1D demonstrated increased serum leptin and LAR, whereas serum adiponectin was reduced in females only. These results suggest that abnormal regulation of adipokines is a consequence of being born to mothers with T1D. No direct association between maternal glycemic control and adiponectin and leptin levels or LAR in the adolescence was found. CLINICAL TRIAL REGISTRATION NUMBER: NCT01559181. PMID- 28641784 TI - Ultrasonographic fatty liver indicator detects mild steatosis and correlates with metabolic/histological parameters in various liver diseases. AB - BACKGROUND AND AIMS: Fatty liver is a common feature of different types of liver diseases. The sensitivity and specificity of ultrasonography for diagnosing fatty liver are variable. A semi-quantitative ultrasound score, i.e., the ultrasonographic fatty liver indicator (US-FLI), is closely associated with metabolic/histological variables in patients with nonalcoholic fatty liver disease (NAFLD). The main aims of this study were to assess the diagnostic performance of US-FLI in detecting varying degrees of histological steatosis, and to examine the association of US-FLI with metabolic/histological parameters in 352 biopsied patients with various chronic liver diseases (173 with hepatitis C [HCV], 23 with hepatitis B [HBV], 123 with NAFLD and 33 with other etiologies). RESULTS: US-FLI accurately detected mild steatosis (minimum amount 10% on histology) with a cut-off value >=2 (sensitivity 90.1%, specificity 90%), moderate steatosis (>=30%) with a cut-off value >=3 (sensitivity 86.4%, specificity 92.5%) and severe steatosis (>66%) with a cut-off value >=5 (sensitivity 88.5%, specificity 87%). US-FLI was correlated with steatosis percentage in each liver disease group as well as with lobular inflammation, ballooning, portal fibrosis, grading and staging in patients with NAFLD or HCV. US-FLI was also correlated with waist circumference, body mass index and insulin resistance both in the whole sample and in each liver disease group. CONCLUSIONS: US-FLI accurately identifies histological severity and is correlated with metabolic parameters in patients with various steatogenic liver diseases. US-FLI is an easy and versatile tool for the screening of steatosis and the metabolic health of these patients. PMID- 28641779 TI - Macrophage functions in lean and obese adipose tissue. AB - Interactions between macrophages and adipocytes influence both metabolism and inflammation. Obesity-induced changes to macrophages and adipocytes lead to chronic inflammation and insulin resistance. This paper reviews the various functions of macrophages in lean and obese adipose tissue and how obesity alters adipose tissue macrophage phenotypes. Metabolic disease and insulin resistance shift the balance between numerous pro- and anti-inflammatory regulators of macrophages and create a feed-forward loop of increasing inflammatory macrophage activation and worsening adipocyte dysfunction. This ultimately leads to adipose tissue fibrosis and diabetes. The molecular mechanisms underlying these processes have therapeutic implications for obesity, metabolic syndrome, and diabetes. PMID- 28641785 TI - Acute detachment of hexokinase II from mitochondria modestly increases oxygen consumption of the intact mouse heart. AB - OBJECTIVE: Cardiac hexokinase II (HKII) can translocate between cytosol and mitochondria and change its cellular expression with pathologies such as ischemia reperfusion, diabetes and heart failure. The cardiac metabolic consequences of these changes are unknown. Here we measured energy substrate utilization in cytosol and mitochondria using stabile isotopes and oxygen consumption of the intact perfused heart for 1) an acute decrease in mitochondrial HKII (mtHKII), and 2) a chronic decrease in total cellular HKII. METHODS/RESULTS: We first examined effects of 200nM TAT (Trans-Activator of Transcription)-HKII peptide treatment, which was previously shown to acutely decrease mtHKII by ~30%. In Langendorff-perfused hearts TAT-HKII resulted in a modest, but significant, increased oxygen consumption, while cardiac performance was unchanged. At the metabolic level, there was a nonsignificant (p=0.076) ~40% decrease in glucose contribution to pyruvate and lactate formation through glycolysis and to mitochondrial citrate synthase flux (6.6+/-1.1 vs. 11.2+/-2.2%), and an 35% increase in tissue pyruvate (27+/-2 vs. 20+/-2pmol/mg; p=0.033). Secondly, we compared WT and HKII+/- hearts (50% chronic decrease in total HKII). RNA sequencing revealed no differential gene expression between WT and HKII+/- hearts indicating an absence of metabolic reprogramming at the transcriptional level. Langendorff-perfused hearts showed no significant differences in glycolysis (0.34+/-0.03MUmol/min), glucose contribution to citrate synthase flux (35+/ 2.3%), palmitate contribution to citrate synthase flux (20+/-1.1%), oxygen consumption or mechanical performance between WT and HKII+/- hearts. CONCLUSIONS: These results indicate that acute albeit not chronic changes in mitochondrial HKII modestly affect cardiac oxygen consumption and energy substrate metabolism. PMID- 28641786 TI - Association of apolipoprotein-CIII (apoC-III), endothelium-dependent vasodilation and peripheral neuropathy in a multi-ethnic population with type 2 diabetes. AB - BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common complication of Type 2 diabetes (T2D). Apart from hyperglycemia, its pathogenesis is poorly understood. Apolipoprotein-CIII (apoC-III) associated with triglyceride metabolism, is a risk factor for cardiovascular disease. Its role in DPN is not well-established. We studied the associations of apoC-III, endothelial function and DPN. METHODS: In patients with T2D, anthropometric data, fasting blood, and urine were collected for biochemistry and urine albumin/creatinine measurements (uACR). Endothelial function assessments were performed by laser Doppler flowmetry/imaging. DPN was considered present if there was an abnormal finding in monofilament (<=8 of 10 points) or neurothesiometer testing>=25V on either foot. Plasma apoC-III was assessed by ELISA. RESULTS: Monofilament and neurothesiometer readings were measured in 1981 patients, mean age 57.4+/-10.8 years old. DPN prevalence was 10.8% (n=214). Patients with DPN compared to those without, were significantly older (p<0.0001), with longer duration of T2D (p<0.0001), had higher BMI (p=0.006), higher glucose (p=0.015) and HbA1c (p<0.0001), Systolic blood pressure (SBP) (p<0.0001), lower eGFR (p<0.0001), higher urine ACR (p<0.0001), poorer endothelium-dependent and endothelium-independent vasodilation (both p<0.0001), higher VCAM-1 (p<0.0001) and higher apoC-III [285.3 (195.2 405.6) vs 242.9(165.0-344.0) MUg/ml]. After adjustment, log transformed apoC-III, remained independently associated with the presence of DPN (B=0.965, SE=0.397, p=0.015). CONCLUSION: Plasma apoC-III is higher in patients with DPN. Apart from its known association with lipids and macrovascular complications, this study suggests its association with DPN. Whether regulating apoC-III metabolism may be an important new therapeutic approach to managing dyslipidemia and microvascular complications in T2D remains to be proven in future mechanistic and clinical studies. PMID- 28641787 TI - Social jet-lag potentiates obesity and metabolic syndrome when combined with cafeteria diet in rats. AB - BACKGROUND/OBJECTIVES: Modern lifestyle promotes shifted sleep onset and shifted wake up time between weekdays and weekends, producing a condition termed "social jet lag." Disrupted sleep promotes increased appetite for carbohydrate and fat rich food, which in long term leads to overweight, obesity and metabolic syndrome. In order to mimic the human situation we produced an experimental model of social-jet lag (Sj-l). With this model, we explored the link between shifted sleep time with consumption of a cafeteria diet (CafD) and the development of obesity and metabolic syndrome. SUBJECTS/METHODS: The first experiment was designed to create and confirm the model of Sj-l. Rats (n=8-10/group) were exposed to a shifted sleep time protocol achieved by placing the rats in slow rotating wheels from Monday to Friday during the first 4h of the light period, while on weekends they were left undisturbed. The second experiment (n=8 12/group) explored the combined effect of Sj-l with the opportunity to ingest CafD. All protocols lasted 12weeks. We evaluated the development of overweight and indicators of metabolic syndrome. The statistical significance for all variables was set at P<0.05. RESULTS: Sj-l alone did not affect body weight gain but induced significant changes in cholesterol in metabolic variables representing a risk factor for metabolic syndrome. Daily restricted access to CafD in the day or night induced glucose intolerance and only CafD during the day led to overweight. Sj-l combined with CafD induced overconsumption of the diet, potentiated body weight gain (16%) and promoted 5 of the criteria for metabolic syndrome including high insulin and dislipidemia. CONCLUSION: Present data provide an experimental model of social-jet lag that combined with overconsumption of CafD, and maximized the development of obesity and metabolic syndrome. Importantly, access to CafD during the night did not lead to overweight nor metabolic syndrome. PMID- 28641788 TI - Non-alcoholic fatty liver disease: A sign of systemic disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease. PMID- 28641789 TI - Lipodystrophy: Time for a global registry and randomized clinical trials to assess efficacy, safety and cost-effectiveness of established and novel medications. PMID- 28641791 TI - Low-Hanging Fruit for a Healthy Old Age. PMID- 28641790 TI - Ideal Cardiovascular Health, Mortality, and Vascular Events in Elderly Subjects: The Three-City Study. AB - BACKGROUND: The benefit of ideal cardiovascular health (CVH) on health-related outcomes in middle-aged patients is firmly established. In the growing elderly population, the high prevalence of comorbidities and medications for chronic diseases may offset such benefit. OBJECTIVES: This study analyzed the association of ideal CVH with mortality, incident coronary heart disease, and stroke events in elderly individuals from the community. METHODS: Between 1999 and 2001, 9,294 men and women, noninstitutionalized and aged 65 years and over were examined, and thereafter followed up for the occurrence of vascular events and mortality within the Three-City Study. Hazard ratios (HRs) were estimated by Cox proportional hazard model and compared subjects with 3 to 4 and subjects with 5 to 7 ideal metrics with those with 0 to 2 ideal metrics, respectively. RESULTS: The mean age was 73.8 +/- 5.3 years, and 36.7% were men. Only 5% of the participants had >=5 metrics at the ideal level. After a median follow-up of 10.9 years and 8.6 years, respectively 1,987 deaths and 680 adjudicated coronary heart disease or stroke events had occurred. In multivariate analysis, the risk of mortality and of vascular events decreased across the categories of ideal metrics. In particular, in subjects with >=5 metrics at the ideal level (compared with those with <=2), there was a 29% (hazard ratio [HR]: 0.71; 95% confidence interval [CI]: 0.55 to 0.90) decreased risk of all-cause mortality and 67% (HR: 0.33; 95% CI: 0.19 to 0.57) for coronary heart disease and stroke combined (p for trend <0.001). CONCLUSIONS: Even in the elderly, higher CVH status is highly beneficial regarding mortality and vascular event risks. PMID- 28641793 TI - Acute Heart Failure: One Syndrome or Many? PMID- 28641792 TI - Hospitalization for Recently Diagnosed Versus Worsening Chronic Heart Failure: From the ASCEND-HF Trial. AB - BACKGROUND: It is unclear how patients hospitalized for acute heart failure (HF) who are long-term chronic HF survivors differ from those with more recent HF diagnoses. OBJECTIVES: The goal of this study was to evaluate the influence of HF chronicity on acute HF patient profiles and outcomes. METHODS: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized 7,141 hospitalized patients with acute HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. The present analysis compared patients according to duration of HF diagnosis before index hospitalization by using pre-specified cutoffs (0 to 1 month [i.e., "recently diagnosed"], >1 to 12 months, >12 to 60 months, and >60 months). RESULTS: Overall, 5,741 (80.4%) patients had documentation of duration of HF diagnosis (recently diagnosed, n = 1,536; >1 to 12 months, n = 1,020; >12 to 60 months, n = 1,653; and >60 months, n = 1,532). Across HF duration groups, mean age ranged from 64 to 66 years, and mean ejection fraction ranged from 29% to 32%. Compared with patients with longer HF duration, recently diagnosed patients were more likely to be women with nonischemic HF etiology, higher baseline blood pressure, better baseline renal function, and fewer comorbidities. After adjustment, compared with recently diagnosed patients, patients with longer HF duration were associated with more persistent dyspnea at 24 h (>1 to 12 months, odds ratio [OR]: 1.20; 95% confidence interval [CI]: 0.97 to 1.48; >12 to 60 months, OR: 1.34; 95% CI: 1.11 to 1.62; and >60 months, OR: 1.31; 95% CI: 1.08 to 1.60) and increased 180-day mortality (>1 to 12 months, hazard ratio [HR]: 1.89; 95% CI: 1.35 to 2.65; >12 to 60 months, HR: 1.82; 95% CI: 1.33 to 2.48; and >60 months, HR: 2.02; 95% CI: 1.47 to 2.77). The influence of HF duration on mortality was potentially more pronounced among female patients (interaction p = 0.05), but did not differ according to age, race, prior ischemic heart disease, or ejection fraction (all interactions, p >= 0.23). CONCLUSIONS: In this acute HF trial, patient profile differed according to duration of the HF diagnosis. A diagnosis of HF for <=1 month before hospitalization was independently associated with greater early dyspnea relief and improved post-discharge survival compared to patients with chronic HF diagnoses. The distinction between de novo or recently diagnosed HF and worsening chronic HF should be considered in the design of future acute HF trials. (A Study Testing the Effectiveness of Nesiritide in Patients With Acute Decompensated Heart Failure; NCT00475852). PMID- 28641795 TI - Door-to-Furosemide Therapy in the ED: New Quality Metric or Just a Piece of the Puzzle? PMID- 28641794 TI - Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure. AB - BACKGROUND: Acute heart failure (AHF) is a life-threatening disease requiring urgent treatment, including a recommendation for immediate initiation of loop diuretics. OBJECTIVES: The authors prospectively evaluated the association between time-to-diuretic treatment and clinical outcome. METHODS: REALITY-AHF (Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure) was a prospective, multicenter, observational cohort study that primarily aimed to assess the association between time to loop diuretic treatment and clinical outcome in patients with AHF admitted through the emergency department (ED). Door-to-furosemide (D2F) time was defined as the time from patient arrival at the ED to the first intravenous furosemide injection. Patients with a D2F time <60 min were pre-defined as the early treatment group. Primary outcome was all-cause in-hospital mortality. RESULTS: Among 1,291 AHF patients treated with intravenous furosemide within 24 h of ED arrival, the median D2F time was 90 min (IQR: 36 to 186 min), and 481 patients (37.3%) were categorized as the early treatment group. These patients were more likely to arrive by ambulance and had more signs of congestion compared with the nonearly treatment group. In-hospital mortality was significantly lower in the early treatment group (2.3% vs. 6.0% in the nonearly treatment group; p = 0.002). In multivariate analysis, earlier treatment remained significantly associated with lower in-hospital mortality (odds ratio: 0.39; 95% confidence interval: 0.20 to 0.76; p = 0.006). CONCLUSIONS: In this prospective multicenter, observational cohort study of patients presenting at the ED for AHF, early treatment with intravenous loop diuretics was associated with lower in-hospital mortality. (Registry focused on very early presentation and treatment in emergency department of acute heart failure syndrome; UMIN000014105). PMID- 28641796 TI - Cardiac Sympathetic Denervation for Refractory Ventricular Arrhythmias. AB - BACKGROUND: Cardiac sympathetic denervation (CSD) has been shown to reduce the burden of implantable cardioverter-defibrillator (ICD) shocks in small series of patients with structural heart disease (SHD) and recurrent ventricular tachyarrhythmias (VT). OBJECTIVES: This study assessed the value of CSD and the characteristics associated with outcomes in this population. METHODS: Patients with SHD who underwent CSD for refractory VT or VT storm at 5 international centers were analyzed by the International Cardiac Sympathetic Denervation Collaborative Group. Kaplan-Meier analysis was used to estimate freedom from ICD shock, heart transplantation, and death. Cox proportional hazards models were used to analyze variables associated with ICD shock recurrence and mortality after CSD. RESULTS: Between 2009 and 2016, 121 patients (age 55 +/- 13 years, 26% female, mean ejection fraction of 30 +/- 13%) underwent left or bilateral CSD. One-year freedom from sustained VT/ICD shock and ICD shock, transplant, and death were 58% and 50%, respectively. CSD reduced the burden of ICD shocks from a mean of 18 +/- 30 (median 10) in the year before study entry to 2.0 +/- 4.3 (median 0) at a median follow-up of 1.1 years (p < 0.01). On multivariable analysis, pre procedure New York Heart Association functional class III and IV heart failure and longer VT cycle lengths were associated with recurrent ICD shocks, whereas advanced New York Heart Association functional class, longer VT cycle lengths, and a left-sided-only procedure predicted the combined endpoint of sustained VT/ICD shock recurrence, death, and transplantation. Of the 120 patients taking antiarrhythmic medications before CSD, 39 (32%) no longer required them at follow up. CONCLUSIONS: CSD decreased sustained VT and ICD shock recurrence in patients with refractory VT. Characteristics independently associated with recurrence and mortality were advanced heart failure, VT cycle length, and a left-sided-only procedure. PMID- 28641797 TI - Sympathetic Denervation to Treat Refractory Ventricular Tachycardia: Do We Have the Nerve? PMID- 28641799 TI - The Continued Search for Physiological Pacing: Where Are We Now? AB - Cardiac pacing is an effective treatment for patients with bradycardia due to sinus node dysfunction or atrioventricular block. Despite decades of technological advances, the optimal ventricular pacing site to mimic normal human ventricular physiology and best hemodynamic response remains elusive. Beginning with atrial synchronous right ventricular (RV) apical pacing, the search has continued through alternate RV pacing sites, minimizing RV pacing, biventricular pacing, left ventricular (LV) pacing, and His-bundle pacing. Understanding the deleterious effects of long-term RV apical pacing in vulnerable populations has created tremendous interest in alternate pacing options. This paper reviews the current status of available pacing options, with particular focus on His-bundle pacing. Permanent His-bundle pacing has emerged as the leading candidate for physiological pacing because it provides nearly normal electrical activation of both ventricles and thereby avoids ventricular dyssynchrony. Synchronized LV pacing, multisite LV pacing, and LV endocardial pacing offer promise as novel pacing options in select patients. PMID- 28641800 TI - Effect of Changes in Visa Policies and Procedures on Fellows-in-Training and Early Career Cardiologists. PMID- 28641801 TI - Subcutaneous Implantable Cardioverter-Defibrillator Implantation Without Defibrillation Testing. PMID- 28641802 TI - Impact of Changes in Consensus Diagnostic Recommendations on the Echocardiographic Prevalence of Diastolic Dysfunction. PMID- 28641803 TI - History Repeating?: The Logics of History. PMID- 28641804 TI - Reply: History Repeating? The Logics of History. PMID- 28641805 TI - The Feasibility of Transcatheter Mitral Valve Replacement for Patients With Symptomatic Mitral Regurgitation. PMID- 28641798 TI - HIV-1-Associated Atherosclerosis: Unraveling the Missing Link. AB - Cardiovascular disease, including atherosclerosis and atherosclerosis-associated complications, is an increasing cause of morbidity and mortality in human immunodeficiency virus (HIV) patients in the post-antiretroviral therapy era. HIV alone accelerates atherosclerosis. Antiretroviral therapy; HIV-associated comorbidities, such as dyslipidemia, drug abuse, and opportunistic infections; and lifestyle are risk factors for HIV-associated atherosclerosis. However, our current understanding of HIV-associated atherogenesis is very limited and has largely been obtained from clinical observation. There is a pressing need to experimentally unravel the missing link between HIV and atherosclerosis. Understanding these mechanisms will help to better develop and design novel therapeutic interventions for the treatment of HIV-associated cardiovascular disease. HIV mainly infects T cells and macrophages resulting in the induction of oxidative and endoplasmic reticulum stress, the formation of the inflammasome, and the dysregulation of autophagy. These mechanisms may contribute to HIV associated atherogenesis. In this review, we will summarize our current understanding and propose potential mechanisms of HIV-associated atherosclerosis. PMID- 28641806 TI - Reply: The Feasibility of Transcatheter Mitral Valve Replacement for Patients With Symptomatic Mitral Regurgitation. PMID- 28641807 TI - Correction. PMID- 28641808 TI - Effect of ZIKA virus on adult eyes. PMID- 28641809 TI - Re-emerging infectious diseases from the past: Hysteria or real risk? AB - BACKGROUND: Work on human remains and old biological samples is a potential source of contamination by conventional or atypical infectious agents. Similarly, current and future environmental changes are a source of resurgence of ancient epidemic diseases. To what extent are anthropologists sorcerer apprentices (especially those working on ancient samples, i.e. paleo-anthropologists)? Are ancient skeletons, palaeosols and museum objects with a biological component at risk for current populations? Unless there are unfounded fears and undue risk... What can be learned from the recent scientific literature and the common sense of the researchers? METHODS: We have attempted to compile data from the literature and from our personal experience in the fields of anthropology, clinical medicine and epidemiology, in order to grasp the reality of the risk to the human population. RESULTS: It appears that the risk is real, but extremely limited. Specific and simple protective measures must be taken in terms of overall and individual health, both in the field and in the laboratory. CONCLUSION: These data are important for the internist, due to the possibility of atypical infections, both in specialized workers and in populations at risk (environmental context). PMID- 28641810 TI - More than 3 hours and less than 3 years old. Safety of anesthetic procedures in children under 3 years of age, subject to surgeries of more than 3 hours. PMID- 28641811 TI - Tension pneumocephalus following suboccipital sitting craniotomy in the pediatric population. AB - BACKGROUND: Sitting craniotomy often results in entrapment of air in fluid-filled intracranial cavities. Gas under pressure exerts a deleterious effect on adjacent nervous tissue, resulting in clinical deterioration. AIM OF STUDY: To assess the incidence of tension pneumocephalus (TP) and to define risk factors associated therewith. MATERIAL AND METHOD: Analysis included 100 consecutive patients (57 boys, 43 girls, mean age 9.7 y) undergoing suboccipital sitting craniotomy since 2012 to 2014. RESULTS: In our material (n=100) TP was seen in 7 cases, asymptomatic pneumocephalus (AP) in 77 and no pneumocephalus (NP) in 16. Tumor types encountered were typical for pediatric population. In the TP group (n=7) the ratio of low-grade to high-grade tumors was 5:2, in the AP group (n=77) 2:1 and in the NP group (n=16) 1:1. Preoperative hydrocephalus was present in 21 cases (21%, mean incidence), thereof 3 in the TP group (3/7; 42.8%), 12 in AP group (12/77; 15.5%) and 6 in the NP group (6/16; 37.5%). All TP patients received an emergency external drainage, thereof 4 required a permanent ventriculo-peritoneal shunt (57.1%), while AP and NP patients combined (n=93) required a permanent shunt in 4 cases only (4.3%). TP-associated morbidity (n=2) consisted in a significant deterioration of neurological condition. CONCLUSIONS: TP is a relatively rare but potentially serious complication of suboccipital sitting craniotomy. Risk factors for TP are low-grade tumor and pre-existing long standing hydrocephalus. TP requires emergency decompression by temporary external drainage. TP patients significantly more often require a permanent CSF shunt. PMID- 28641812 TI - Continuum-based models and concepts for the transport of nanoparticles in saturated porous media: A state-of-the-science review. AB - Environmental applications of nanoparticles (NP) increasingly result in widespread NP distribution within porous media where they are subject to various concurrent transport mechanisms including irreversible deposition, attachment/detachment (equilibrium or kinetic), agglomeration, physical straining, site-blocking, ripening, and size exclusion. Fundamental research in NP transport is typically conducted at small scale, and theoretical mechanistic modeling of particle transport in porous media faces challenges when considering the simultaneous effects of transport mechanisms. Continuum modeling approaches, in contrast, are scalable across various scales ranging from column experiments to aquifer. They have also been able to successfully describe the simultaneous occurrence of various transport mechanisms of NP in porous media such as blocking/straining or agglomeration/deposition/detachment. However, the diversity of model equations developed by different authors and the lack of effective approaches for their validation present obstacles to the successful robust application of these models for describing or predicting NP transport phenomena. This review aims to describe consistently all the important NP transport mechanisms along with their representative mathematical continuum models as found in the current scientific literature. Detailed characterizations of each transport phenomenon in regards to their manifestation in the column experiment outcomes, i.e., breakthrough curve (BTC) and residual concentration profile (RCP), are presented to facilitate future interpretations of BTCs and RCPs. The review highlights two NP transport mechanisms, agglomeration and size exclusion, which are potentially of great importance in controlling the fate and transport of NP in the subsurface media yet have been widely neglected in many existing modeling studies. A critical limitation of the continuum modeling approach is the number of parameters used upon application to larger scales and when a series of transport mechanisms are involved. We investigate the use of simplifying assumptions, such as the equilibrium assumption, in modeling the attachment/detachment mechanisms within a continuum modelling framework. While acknowledging criticisms about the use of this assumption for NP deposition on a mechanistic (process) basis, we found that its use as a description of dynamic deposition behavior in a continuum model yields broadly similar results to those arising from a kinetic model. Furthermore, we show that in two dimensional (2-D) continuum models the modeling efficiency based on the Akaike information criterion (AIC) is enhanced for equilibrium vs kinetic with no significant reduction in model performance. This is because fewer parameters are needed for the equilibrium model compared to the kinetic model. Two major transport regimes are identified in the transport of NP within porous media. The first regime is characterized by higher particle-surface attachment affinity than particle particle attachment affinity, and operative transport mechanisms of physicochemical filtration, blocking, and physical retention. The second regime is characterized by the domination of particle-particle attachment tendency over particle-surface affinity. In this regime although physicochemical filtration as well as straining may still be operative, ripening is predominant together with agglomeration and further subsequent retention. In both regimes careful assessment of NP fate and transport is necessary since certain combinations of concurrent transport phenomena leading to large migration distances are possible in either case. PMID- 28641813 TI - Sensors and bioassays powered by upconverting materials. AB - In recent years, considerable efforts have been done to better understand the peculiar emission properties of upconverting materials due to their widespread applications in different and important technological fields such as upconversion based photoactivated cancer therapies, photoactivated drug-delivery, magnetic resonance imaging contrast agents, bioimaging. However, one of the most promising applications of upconverting materials concerns the field of sensing, due to their unique emission properties. In fact, the minimal autofluorescence, blinking, photo-bleaching, and high photostability makes them an excellent alternative to organic dyes or quantum dots. This article reviews the state-of the-art, design, and sensing strategies of upconversion-based sensing platforms, with special attention to upconverting nanoparticles, as well as how the incorporation of these materials into pre-existing diagnostic tests and bioassays have improved their capabilities for the detection of different kinds of analytes. PMID- 28641814 TI - An interferometric technique to study capillary waves. AB - We describe a new interferometric technique to study gas-liquid and liquid-liquid interfaces. Bubbles and drops are subjected to an alternating electric field which excites capillary oscillations at the interface, if charged. Bubble or drop deformation is detected by the change of the internal optical path of a laser beam crossing perpendicular to the oscillation axis. Due to the closed geometry, a discrete spectrum of stationary oscillation frequencies (normal modes) is excited. The interferometric nature of the measurement and the resonant nature of the oscillation modes concur in allowing for high sensitivity, in the sub nanometric region. We present a detailed description of the experimental setup and examples of applications of the technique to the study of both gas-liquid and liquid-liquid interfaces, either naked or with adsorbed surfactant monolayers, for bubbles and drops with diameter~1mm. In particular, the resonance frequencies and the width of the resonance peaks depend on the surface tension and the viscous dampening, respectively. We show that, by this new technique, properties of the interface can be accessed with confidence at the sub-nanometer scale, and surface phenomena, like the monolayer phase transition or the peculiarities of adsorption/desorption processes, can be unraveled in concentration regimes which are too low for existing methods. PMID- 28641815 TI - Impulsive stabilization of fractional differential systems. AB - This paper investigates the impulsive stabilization problem of fractional differential systems (FDSs in short). Both the global exponential stability and ultimate boundedness criteria are established using Lyapunov functions, algebraic inequality techniques and boundedness of Mittag-Leffler functions. It is shown that unstable and unbounded FDSs can be stable and bounded respectively under impulsive control. Examples and simulations are also provided to demonstrate the effectiveness of the derived theoretical results. PMID- 28641817 TI - [Preventing violence in schizophrenia with cognitive remediation]. AB - OBJECTIVES: The association between schizophrenia and violence represents an important issue in psychiatry. Often highly publicized, violent acts raise the question of their detection, prevention, management and treatment. There is no single, direct and exclusive link between aggressiveness and the underlying psychiatric disorder. On the contrary, the processes underlying this violence are multiple and interlinked. In addition to static and dynamic risk factors, cognitive deficits play an important role in the genesis and maintenance of violent and aggressive behavior. METHODS: Using recent data from the international literature and the main databases, we first clarify the role played by cognitive deficits in the violence of patients with schizophrenia. We then evaluate the place of psychosocial interventions such as cognitive remediation and social cognitive training in managing the violent and aggressive behavior of these patients. RESULTS: Executive functions and working memory are the most studied neurocognitive functions in the field of violence in schizophrenia. Impulsivity, lack of cognitive flexibility, lack of adaptation and inhibition of automatic motor responses, and altered anger regulation may explain this relationship. Three main components of social cognition are associated with violent behaviors in schizophrenia: (1) the recognition of facial emotions through the inoperability of systems of "emotional monitoring", violent inhibition and recognition of informative facial zones; (2) the theory of the mind through the erroneous interpretation of the intentions of others; (3) the attributional style through the preferentially aggressive over interpretation of social situations and weak capacities of introspection. Overall, cognitive biases inhibit response in a socially acceptable manner and increase the risk of responding impulsively and aggressively to a stressful or provocative situation. In this context, we studied the place held by psychosocial interventions in the management of the violent and aggressive behaviors of these patients. Various cognitive remediation programs have shown their feasibility in people with schizophrenia and neurocognitive deficits with a history of violence as well as their effectiveness in reducing violence, mainly by reducing impulsivity. Similarly, specific programs dedicated to social cognitive training such as Social Cognition and Interaction Training (SCIT), Reasoning and Rehabilitation Mental Health Program (R&R2 MHP) and Metacognitive Training (MCT) have shown their positive impact on the control and reduction of global aggressive attitudes and on the numbers of physical and verbal aggressive incidents in schizophrenia. The improvement of social cognition would be achieved through the amendment of interpersonal relationships and social functioning. These interventions are effective at different stages of disease progression, in patients with varied profiles, on violent attitudes in general and on the number of verbal and physical attacks, whether for in-patients or out-patients. Beneficial effects can last up to 12months after termination of the study program. The interest of these interventions is preventive if the subject never entered in a violent register or curative in case of a personal history of violence. This type of care can be considered from a symptomatic point of view by limiting downstream the heavy consequences of such acts, but also etiologically by acting on one of the causes of violent behavior. Compliance with the eligibility criteria, carrying out a prior functional analysis and confirmation of the major impulsive part of the patient's violence are prerequisites for the use of these programs. Similarly, the early introduction of such therapies, their repetition over time and the integration of the patient into a comprehensive process of psychosocial rehabilitation will ensure the best chance of success. CONCLUSIONS: Some cognitive impairments appear to have their place in the genesis, progression and maintenance of violent acts of individuals with schizophrenia. Their management thus opens new therapeutic perspectives such as cognitive remediation, still rarely used in this aim, to complement the action of the traditional care tools. However, further therapeutic trials are needed before considering cognitive remediation and social cognitive training as central care modalities in the therapeutic control of violence in schizophrenia. PMID- 28641816 TI - [Association between the violence in the community and the aggressive behaviors of psychotics during their hospitalizations]. AB - BACKGROUND: Violence is a common issue in psychiatry and has multiple determiners. The aim of this study is to assess the psychotic inpatients' violence in association with the violence of the neighborhood from which the patients are drawn and to estimate the impact of this environmental factor with regard to other factors. METHOD: A prospective multicenter study was led in nine French cities. Eligible patients were psychotic involuntary patients hospitalized in the cities' psychiatric wards. During their treatments, any kind of aggressive behavior by the patients has been reported by the Overt Aggression Scale (OAS). RESULTS: From June 2010 to May 2011, 95 patients have been included. Seventy-nine per cent of the patients were violent during their hospitalizations. In a bivariate analysis, inpatient violence was significantly associated with different factors: male gender, patient violence history, substance abuse, manic or mixed disorder, the symptoms severity measured by the BPRS, the insight degree and the city crime rate. In a multivariate analysis, the only significant factors associated with the patients' violence were substance abuse, the symptoms severity and the crime rates from the different patients' cities. CONCLUSION: These results suggest that violence within the psychotic patients' neighborhood could represent a risk of violence during their treatments. PMID- 28641818 TI - The role of Kruppel-like factor 14 in the pathogenesis of atherosclerosis. AB - The Kruppel-like factor (KLF) family, as the SP/XKLF transcription factors, plays important roles in regulating the expression of genes required for the proper execution of important biological and pathological processes. Recent studies have demonstrated that KLF14, a member of the KLF family, participates in the initiation and progression of atherosclerotic cardiovascular disease (CVD). From the molecular function aspect, this review focuses on the impact of KLF14 mediated regulation in major atherosclerosis-related diseases and pathological processes, such as insulin resistance, type 2 diabetes, dyslipidemia, inflammation, obesity, metabolic syndrome, cell proliferation and differentiation. This review was designed to help understand the roles of KLF14 in the pathogenesis of atherosclerosis and define KLF14 as a potential disease biomarker and a novel therapeutic target in CVD. PMID- 28641820 TI - Using Twitter to Amplify Your Presence During Radiology Meetings. PMID- 28641819 TI - Dynamic contrast-enhanced MR imaging of carotid vasa vasorum in relation to coronary and cerebrovascular events. AB - BACKGROUND AND AIMS: Dynamic contrast-enhanced MR imaging (DCE-MRI) provides a noninvasive approach to the functional status of carotid adventitial vasa vasorum. Contrast extravasation rate, or Ktrans, derived from kinetic modeling of adventitial enhancement, has been correlated with plaque neovascularization and inflammation. This study sought to clarify the clinical implications of Ktrans by evaluating its relationship with documented cardiovascular events (CVE). METHODS: Seventy patients with carotid plaque at clinical ultrasound examination were recruited and imaged with a previously-described bright-blood DCE-MRI protocol (spatial resolution: 0.55 * 0.58 mm2; time resolution: 18 s). Patients were classified by the presence of documented coronary and/or cerebrovascular events. Adventitial Ktrans was estimated via kinetic modeling of outer wall enhancement as captured by DCE-MRI. RESULTS: After excluding six patients with insufficient image quality, 64 patients (66 +/- 12 years, 51 male) had DCE-MRI measurements. Patients with documented CVE showed significantly higher adventitial Ktrans than those without (0.056 +/- 0.024 versus 0.034 +/- 0.008 min-1, p < 0.001), whereas comparable measurements were seen among the subgroups with CVE (p > 0.05): 0.054 +/- 0.027 min-1 in patients with coronary events alone, 0.056 +/- 0.018 min-1 in patients with cerebrovascular events alone, and 0.069 +/- 0.022 min-1 in patients with both. Carotid adventitial Ktrans was negatively correlated with time since clinical event (Spearman's rho = -0.40, p = 0.003). CONCLUSIONS: Patients with documented CVE demonstrated increased rate of contrast extravasation from carotid adventitial vasa vasorum on DCE-MRI irrespective of the territory of events. Systemic factors implicated in the pathophysiology of acute atherothrombotic events may influence the functional status of adventitial vasa vasorum. PMID- 28641821 TI - Insurance coverage among women diagnosed with a gynecologic malignancy before and after implementation of the Affordable Care Act. AB - OBJECTIVE: The Patient Protection and Affordable Care Act (ACA) included provisions to expand insurance coverage by expanding Medicaid eligibility, providing subsidies of private coverage and enforcing an individual mandate. The objective of this study is to examine the impact of the ACA on insurance rates among women diagnosed with a gynecologic malignancy. METHODS: Using Surveillance, Epidemiology, and End Results 18 registries database, women newly diagnosed with cervical, uterine or ovarian cancer between 2008 and 2014 were identified. Insurance rates were examined before and after the passage of the ACA (2011) as well as before (January 2011-December 2013) versus after (January 2014-December 2014) Medicaid expansion to examine the impact of specific provisions. Rates of insurance were then compared between states that elected for expansion of Medicaid in 2014 vs. those states that had not. RESULTS: Among 181,866 diagnosed with cervical, uterine or ovarian cancer, there was a significant increase in patients enrolled in Medicaid after 2011. Between 2011 and 2014, there was a significant decrease in the rates of uninsured for all cancer types (p=0.001). Uninsured rates decreased by 50% for those diagnosed with uterine and ovarian cancer (6% to 3% and 8% to 4% respectively, p<=0.001), and by 25% in cervical cancer (8.9% to 6.7%, p=0.001) after January 2014. Decreases in the rate of the uninsured and associated increases in insurance coverage were only observed in states which expanded Medicaid coverage (p<=0.001). CONCLUSIONS: The Affordable Care Act resulted in expanded insurance coverage for women diagnosed with a gynecologic cancer, however, the impact was significantly increased in states which increased their Medicaid eligibility in 2014. PMID- 28641823 TI - Comments regarding: Cooper LF, Stanford C, Feine J, McGuire M. Prospective assessment of CAD-CAM zirconia abutment and lithium disilicate crown restorations: 2.4 year results. J Prosthet Dent 2016;116:33-9. PMID- 28641822 TI - Interim rehabilitation of occlusal vertical dimension using a double-crown retained removable dental prosthesis with polyetheretherketone framework. AB - Polyetheretherketone (PEEK) is a polymeric material that has recently been introduced in dentistry and can be used as framework material for fixed and removable dental prostheses. This clinical report describes the fabrication of a double-crown-retained prosthesis with a PEEK framework in a patient with a substantially diminished occlusal vertical dimension. The insertion of the removable dental prosthesis with a PEEK framework resulted in the functional and esthetic rehabilitation of the patient; however, removable dental prostheses fabricated from PEEK should currently be regarded as interim restorations because of the limited available scientific evidence. PMID- 28641824 TI - A Newly Discovered Manuscript of Charles T. Jackson, MD: "History of the Patenting of the Application of Sulphuric Ether for the Production of Insensibility". AB - In 2016, the Wood Library-Museum of Anesthesiology, Schaumburg, IL, acquired an unpublished 11-page manuscript written by Charles Thomas Jackson, MD, (1805 1880). The undated manuscript, now fully transcribed, provides Jackson's perspective of the first 6 weeks of the ether discovery, from early October 1846 to mid-November 1846. It chronicles Jackson's observations and discussions pertaining to United States Patent No. 4848, granted to him and William Thomas Green Morton, MD, (1819-1868). Jackson's manuscript did not yield new information on the discovery of surgical etherization or the subsequent dispute between him and Morton. The manuscript may, nevertheless, be one of the earliest documents on etherization known to have been written by Jackson. PMID- 28641825 TI - 'Yours Sincerely, Barney': Ralph Waters, Barindra Sircar, and the Training of an International Anesthesiologist. AB - In 1936, Ralph Milton Waters accepted a proposal to train an Indian physician who could return home and become the first native anesthesiologist in the subcontinent. Waters founded the United States' first anesthesiology residency in 1927 and in 1937 welcomed Barindra Sircar, MBBS, to the University of Wisconsin in Madison. Sircar trained with Waters for two years and did further training with Robert Macintosh and Ivan Magill. He became one of the first specialty trained anesthesiologists in India and founded the Indian Society of Anaesthesiologists. Fifty-six letters between Sircar and Waters are preserved in the University of Wisconsin archives. The men corresponded until at least 1949, when Waters retired and the archive ends. Sircar's letters were always signed with the nickname he received as a resident: "Yours Sincerely, Barney." PMID- 28641826 TI - The Chemical History of Morphine: An 8000-year Journey, from Resin to de-novo Synthesis. AB - Evidence of human use of opium dates back as far as the sixth millennium BCE. Ancient societies through the Renaissance period created a variety of opium products, proliferating its common use and subsequent addiction. Because the active moiety was not known at this time, the potency of these opium concoctions could neither be predicted nor controlled. The first step in identifying opium's active ingredient, morphine, was its chemical isolation in the early 1800s by Wilhelm Serturner. The subsequent elucidation of morphine's chemical formula and Sir Robert Robinson's derivation of morphine's structural formula, which won him the 1947 Nobel Prize in Chemistry, round out 150 years of the incremental advances in our chemical understanding of morphine. Nevertheless, our attempts to synthesize morphine, despite our advanced knowledge in synthetic chemistry, are still no match for the plant-based extraction of morphine from the poppy plant. The status quo remains problematic socially, economically, and politically; the relationships between the countries laboriously growing poppy plants to extract morphine and those countries importing these painkillers are unstable at best. In this study, we contrast the cumulative scientific discoveries that have led to our current chemical knowledge of morphine with the centuries-old natural method of morphine production that still dominates the opioid market today. PMID- 28641827 TI - Isoflurane and the Coronary Steal Controversy of the 1980s: Origin, Resolution, and Legacy. AB - Isoflurane was introduced for general clinical use in North America in 1981. Shortly thereafter, in 1983, a study suggested that the anesthetic was a potent coronary vasodilator that could cause coronary steal and myocardial ischemia in patients with coronary artery disease. Myocardial ischemia results from small vessel dilation which leads to increased blood flow to well-perfused myocardium and decreased blood flow to myocardium with borderline perfusion. This action of isoflurane raised concerns and threatened its use. By the early 1990s, these concerns were resolved by carefully performed clinical and experimental studies demonstrating no evidence of adverse cardiac changes during isoflurane administration as long as hemodynamic variables were tightly controlled. Indeed, the controversy sparked by the 1983 study led to a chain of experimental studies that ultimately demonstrated ironically that isoflurane has a preconditioning, cardioprotective effect. This chapter in anesthesia history underscores the importance of allowing the passage of time before assessing the clinical and scientific impact of a research finding. PMID- 28641828 TI - From Picking to Massaging: Analgesia From Mexican Mustang Liniment. PMID- 28641829 TI - "Dr. Townsend's Oxygenated Air" and "Oxygen" as a Cure for Chronic Disease. PMID- 28641830 TI - Morphine Zwitterion. PMID- 28641831 TI - Two components of the new ESPEN diagnostic criteria for malnutrition are independent predictors of lung function in hospitalized patients with chronic obstructive pulmonary disease (COPD). AB - INTRODUCTION: Low fat free mass index (FFMI) is a component of the ESPEN diagnosis criteria of malnutrition, that only when accompanied with weight loss is considered to be a determinant of malnutrition. Our aims were to assess the prevalence of malnutrition in patients with chronic obstructive pulmonary disease (COPD) applying the ESPEN criteria, and to examine the ability of different components of the criteria to predict COPD severity, length of stay (LOS), hospital readmissions within 30 days and mortality. METHODS: Subjects were COPD patients (n = 121) admitted to Landspitali University Hospital from March 2015 to March 2016. Patients were screened for nutritional risk using Icelandic screening tool (ISS) and NRS-2002. Body composition was measured by bioelectrical impedance analysis (BIA). Lung function was measured by spirometry. RESULTS: The prevalence of malnutrition according to the ESPEN criteria was 21%. The association between nutritional assessment, applying different components of the ESPEN criteria, and COPD severity was highly significant, with the highest risk being associated with low FFMI OR (95% CI) 4.77 (2.03, 11.20; p < 0.001). There was a trend towards higher risk of hospitalization for >7 days in subjects with low FFMI (OR 2.46 95% CI 0.92, 6.59; p = 0.074) and increased risk of 6 and 9 months' mortality (OR 2.72 95% CI 0.88, 8.39, P = 0.082 and OR 2.72 95% CI 0.94, 7.87, P = 0.065, respectively) in subjects diagnosed as malnourished by the ESPEN criteria. CONCLUSION: This study describes the prevalence of malnutrition in hospitalized COPD patients using the ESPEN criteria from 2015. Our findings suggest that FFMI could be used independently of weight loss for the diagnosis of malnutrition in COPD patients, although there remain some problems associated with its measurement in the clinical setting. PMID- 28641832 TI - Ionic liquid based vortex assisted liquid-liquid microextraction combined with liquid chromatography mass spectrometry for the determination of bisphenols in thermal papers with the aid of response surface methodology. AB - A sensitive, rapid and efficient ionic liquid-based vortex assisted liquid-liquid microextraction (IL-VALLME) with Liquid Chromatography Mass spectrometry (LC MS/MS) method is proposed for the determination of bisphenols in thermal paper. Extraction factors were systematically optimized by response surface methodology. Experimental factors showing significant effects on the analytical responses were evaluated using design of experiment. The limit of detection for Bisphenol-A (BPA) and Bisphenol-S (BPS) in thermal paper were 1.25 and 0.93MUgkg-1 respectively. The dynamic linearity range for BPA was between 4 and 100MUgkg-1 and the determination of coefficient (R2) was 0.996. The values of the same parameters were 3-100MUgkg-1 and 0.998 for BPS. The extraction recoveries of BPA and BPS in thermal paper were 101% and 99%. Percent relative standard deviation (% RSD) for matrix effect and matrix match effects were not more than 10%, for both bisphenols. The proposed method uses a statistical approach for the analysis of bisphenols in environmental samples, and is easy, rapid, requires minimum organic solvents and efficient. PMID- 28641833 TI - Glyoxal and methylglyoxal as urinary markers of diabetes. Determination using a dispersive liquid-liquid microextraction procedure combined with gas chromatography-mass spectrometry. AB - Glyoxal (GO) and methylglyoxal (MGO) are alpha-oxoaldehydes that can be used as urinary diabetes markers. In this study, their levels were measured using a sample preparation procedure based on salting-out assisted liquid-liquid extraction (SALLE) and dispersive liquid-liquid microextraction (DLLME) combined with gas chromatography-mass spectrometry (GC-MS). The effect of the derivatization reaction with 2,3-diaminonaphthalene, the addition of acetonitrile and sodium chloride to urine, and the DLLME step using the acetonitrile extract as dispersant solvent and carbon tetrachloride as extractant solvent were carefully optimized. Quantification was performed by the internal standard method, using 5-bromo-2-chloroanisole. The intraday and interday precisions were lower than 6%. Limits of detection were 0.12 and 0.06ngmL-1, and enrichment factors 140 and 130 for GO and MGO, respectively. The concentrations of these alpha-oxoaldehydes in urine were between 0.9 and 35.8ngg-1 levels (creatinine adjusted). A statistical comparison of the analyte contents of urine samples from non-diabetic and diabetic patients pointed to significant differences (P=0.046, 24 subjects investigated), particularly regarding MGO, which was higher in diabetic patients. The novelty of this study compared with previous procedures lies in the treatment of the urine sample by SALLE based on the addition of acetonitrile and sodium chloride to the urine. The DLLME procedure is performed with a sedimented drop of the extractant solvent, without a surfactant reagent, and using acetonitrile as dispersant solvent. Separation of the analytes was performed using GC-MS detection, being the analytes unequivocal identified. The proposed procedure is the first microextraction method applied to the analysis of urine samples from diabetic and non-diabetic patients that allows a clear differentiation between both groups using a simple analysis. PMID- 28641834 TI - Establishment and molecular modeling study of maltodextrin-based synergistic enantioseparation systems with two new hydroxy acid chiral ionic liquids as additives in capillary electrophoresis. AB - Discovering more superior performance of ionic liquids for the separation science has triggered increasing interest. In this work, two new Hydroxy acid-based chiral ionic liquids (CILs) (tertramethylammonium-d-pantothenate (TMA-d-PAN), tertramethylammonium-d-quinate (TMA-d-QUI)) were designed and first used as additives to establish the maltodextrin-based synergistic systems for enantioseparation in capillary electrophoresis (CE). Compared to traditional single maltodextrin chiral separation system, significantly improved separations of all tested drugs in the CIL/Maltodextrin synergistic systems were obtained. Some parameters (CIL concentration, maltodextrin concentration, buffer pH, and applied voltage) in the TMA-d-PAN/Maltodextrin synergistic system have been examined and optimized for analytes. The molecular docking software AutoDock was applied to simulate the recognition process and surmise feasible resolution mechanism in the Maltodextrin/CILs synergistic systems, which has certain guiding value. PMID- 28641835 TI - Rapid purification of diastereoisomers from Piper kadsura using supercritical fluid chromatography with chiral stationary phases. AB - Supercritical fluid chromatography (SFC) with chiral stationary phases (CSPs) is an advanced solution for the separation of achiral compounds in Piper kadsura. Analogues and stereoisomers are abundant in natural products, but there are obstacles in separation using conventional method. In this paper, four lignan diastereoisomers, (-)-Galbelgin, (-)-Ganschisandrin, Galgravin and (-) Veraguensin, from Piper kadsura were separated and purified by chiral SFC. Purification strategy was designed, considering of the compound enrichment, sample purity and purification throughput. Two-step achiral purification method on chiral preparative columns with stacked automated injections was developed. Unconventional mobile phase modifier dichloromethane (DCM) was applied to improve the sample solubility. Four diastereoisomers was prepared at the respective weight of 103.1mg, 10.0mg, 152.3mg and 178.6mg from 710mg extract with the purity of greater than 98%. PMID- 28641836 TI - Late outcomes of pulmonary embolism: The post-PE syndrome. AB - The post-Pulmonary Embolism (post-PE) syndrome is being increasingly recognized as a long-term consequence of PE. Its most severe manifestation, chronic thromboembolic pulmonary hypertension (CTEPH), affects a small proportion of PE survivors. However, many more with less severe post-PE syndrome have reduced quality of life and functional capacity. The pathophysiology is incompletely understood, but involves unresolved pulmonary artery thrombi, right ventricular damage, and abnormal gas exchange. Treatment has only been established for CTEPH, and further studies are required to determine how less severe forms of the post PE syndrome should be treated and if preventive strategies can reduce its incidence. PMID- 28641837 TI - Corrigendum to "Metaphyseal locking plate as an external fixator for open tibial fracture: Clinical outcomes and biomechanical assessment" [Injury 48/2 (2017) 501 505]. PMID- 28641839 TI - The Prematurely Stopped Clinical Trial: An Unfinished Symphony. PMID- 28641841 TI - DAPT Duration After Drug-Eluting Stent Implantation: No News Is Good News. PMID- 28641840 TI - 6- Versus 24-Month Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents in Patients Nonresistant to Aspirin: Final Results of the ITALIC Trial (Is There a Life for DES After Discontinuation of Clopidogrel). AB - OBJECTIVES: The aim of this study was to test the hypothesis that 6-month dual antiplatelet therapy (DAPT) is noninferior to 24-month DAPT in aspirin-sensitive patients. BACKGROUND: The ITALIC (Is There a Life for DES After Discontinuation of Clopidogrel) trial showed that rates of bleeding and thrombotic events at 1 year were much the same with 6 versus 12 months of DAPT after percutaneous coronary intervention with second-generation drug-eluting stents. In this report, 2-year follow-up is presented. METHODS: In a multicenter randomized study, patients with confirmed nonresistance to aspirin undergoing drug-eluting stent implantation were allocated to 6 or 24 months of DAPT. The primary endpoint was a composite of death, myocardial infarction, urgent target vessel revascularization, stroke, and major bleeding at 12 months post-percutaneous coronary intervention. The secondary endpoints comprised the same composite endpoint at 24 months and each individual component. RESULTS: Overall, 2,031 patients from 70 centers were screened; 926 were randomized to 6-month and 924 to 24-month DAPT. Noninferiority was demonstrated for 6- versus 12-month DAPT, with an absolute risk difference of 0.11% (95% confidence interval: -1.04% to 1.26%; p = 0.0002). At 2 years, the composite endpoint was unchanged, at 3.5% for 6 months and 3.7% for 24 months (p = 0.79), and rates of myocardial infarction (1.3% vs. 1.0%; p = 0.51), stroke (0.6% vs. 0.8%; p = 0.77), and target vessel revascularization (1.0% vs. 0.3%; p = 0.09) were likewise similar. There was a trend toward higher mortality with longer DAPT (2.2% vs. 1.2%; p = 0.11). Four patients (0.4%) in the 24-month group and none in the 6-month group had major bleeding. CONCLUSIONS: Two-year outcomes in the ITALIC trial confirmed the 1-year results and showed that patients receiving 6-month DAPT after percutaneous coronary intervention with second-generation drug-eluting stent have similar outcomes to those receiving 24-month DAPT. PMID- 28641843 TI - Bioresorbable Scaffold: Balancing Risks to Promissory Benefits? PMID- 28641842 TI - Long-Term Clinical Outcomes of Patients Treated With Everolimus-Eluting Bioresorbable Stents in Routine Practice: 2-Year Results of the ISAR-ABSORB Registry. AB - OBJECTIVES: The aim of this study was to report clinical outcomes in patients treated in routine practice 2 years after everolimus-eluting bioresorbable stent (BRS) implantation. BACKGROUND: Long-term results in patients undergoing BRS implantation in routine clinical practice are sparse, and existing evidence from randomized trials considers mostly selected patients. METHODS: The ISAR-ABSORB registry enrolled consecutive patients undergoing BRS implantation in routine clinical practice at 2 high-volume centers in Germany. Angiographic follow-up was scheduled after 6 to 8 months and clinical follow-up to 24 months. The primary endpoint was the composite of death, myocardial infarction, or target lesion revascularization, and secondary endpoints included individual components of the primary endpoint and definite stent thrombosis. Event rates were calculated using the Kaplan-Meier method. RESULTS: A total of 419 patients were included. The mean age was 66.6 +/- 10.9 years, 31.5% had diabetes, and 39.0% presented with acute coronary syndrome. Forty-nine percent of lesions were considered complex (American College of Cardiology/American Heart Association type B2 or C), and 13.1% were bifurcation lesions. The mean reference vessel diameter was 2.89 +/- 0.46 mm. At 2 years, the primary endpoint had occurred in 21.6% of patients: death in 6.3%, myocardial infarction in 3.9%, target lesion revascularization in 16.0%, and definite stent thrombosis in 3.8%. CONCLUSIONS: Long-term follow-up of patients treated with BRS in routine practice showed higher event rates than expected. Future studies are required to determine the impact of changes in implantation technique and to define the optimal duration of dual antiplatelet therapy in these patients. PMID- 28641845 TI - New Insights Into an Old Problem. PMID- 28641844 TI - The In Vivo Morphology of Post-Infarct Ventricular Septal Defect and the Implications for Closure. AB - OBJECTIVES: The aim of this study was to define the dynamic in vivo morphology of post-infarct ventricular septal defect (PIVSD), which has not been previously described in living patients. BACKGROUND: PIVSD is a devastating complication of acute myocardial infarction. METHODS: The anatomic features of PIVSD, as demonstrated by computed tomography or magnetic resonance imaging, were retrospectively reviewed. RESULTS: Thirty-two PIVSDs were assessed, 16 left coronary artery and 16 right coronary artery PIVSDs. PIVSDs were large (mean maximum dimension 26.5 +/- 11.5 mm, mean area 5.2 +/- 4.2 cm2) and oval (mean eccentricity index 1.7 +/- 0.5), with thin margins (diastolic mean thickness 5 mm from the edge of the PIVSD 6.4 +/- 3.0mm), and only 22% of PIVSDs were entirely confined to the septum. The defects could be larger in diastole or systole. The stem of the largest available Amplatzer occluder stem (St. Jude Medical, St. Paul, Minnesota) filled only 50% of defects. Patients with small defects may survive without closure. Without closure, those with large defects die. If accepted for closure, PIVSD size and coronary territory did not predict survival >1 year (overall 60%). CONCLUSIONS: This is the first detailed anatomic description of PIVSD in living patients. Defects may be larger in systole or diastole, meaning that single-phase measurement is unsuitable. Its complex nature means that the most commonly available occluder device is frequently unsuitable. Successful closure leads to prolonged survival and should be attempted where possible. This study may lead to improved patient selection, closure techniques, and device design. PMID- 28641838 TI - Dual Antiplatelet Therapy for 6 Versus 18 Months After Biodegradable Polymer Drug Eluting Stent Implantation. AB - OBJECTIVES: The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a multicenter randomized investigation of the noninferiority of short term versus long-term dual antiplatelet therapy (DAPT) in patients with implantation of the Nobori drug-eluting stent (DES) (Terumo, Tokyo, Japan), which has a biodegradable abluminal coating. BACKGROUND: The optimum duration of DAPT for patients with a biodegradable polymer-coated DES is unclear. METHODS: The subjects were 3,773 patients with stable or acute coronary syndromes undergoing Nobori stent implantation. They were randomized 1:1 to receive DAPT for 6 or 18 months. The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (all-cause mortality, myocardial infarction, stroke, and major bleeding) from 6 to 18 months after stenting. Intention-to-treat analysis was performed in 3,307 patients who were followed for at least 6 months. RESULTS: NACCE occurred in 34 patients (2.1%) receiving short-term DAPT and 24 patients (1.5%) receiving long-term DAPT (difference 0.6%, 95% confidence interval [CI]: 1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of -2%, noninferiority of short-term DAPT was confirmed. Mortality was 1.0% with short term DAPT versus 0.4% with long-term DAPT, whereas myocardial infarction was 0.2% versus 0.1%, and major bleeding was 0.7% versus 0.7%, respectively. The estimated probability of NACCE was lower in the long-term DAPT group (hazard ratio: 1.44, 95% CI: 0.86 to 2.43). CONCLUSIONS: Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227). PMID- 28641847 TI - LOTUS Valve: Increasing the Pace of Device Iterations. PMID- 28641846 TI - Conduction Abnormalities and Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement Using the Repositionable LOTUS Device: The United Kingdom Experience. AB - OBJECTIVES: The authors report the incidence of pacemaker implantation up to hospital discharge and the factors influencing pacing rate following implantation of the LOTUS bioprosthesis (Boston Scientific, Natick, Massachusetts) in the United Kingdom. BACKGROUND: Transcatheter aortic valve replacement (TAVR) is associated with a significant need for permanent pacemaker implantation. Pacing rates vary according to the device used. The REPRISE II (Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus Valve System) trial reported a pacing rate of 29% at 30 days after implantation of the LOTUS device. METHODS: Data were collected retrospectively on 228 patients who had the LOTUS device implanted between March 2013 and February 2015 across 10 centers in the United Kingdom. Twenty-seven patients (12%) had pacemakers implanted pre-procedure and were excluded from the analysis. RESULTS: Patients were aged 81.2 +/- 7.7 years; 50.7% were male. The mean pre-procedural QRS duration was 101.7 +/- 20.4 ms. More than one-half of the cohort (n = 111, 55%) developed new left bundle branch block (LBBB) following the procedure. Permanent pacemakers were implanted in 64 patients (32%) with a median time to insertion of 3.0 +/- 3.4 days. Chief indications for pacing were atrioventricular (AV) block (n = 46, 72%), or LBBB with 1st degree AV block (n = 11, 17%). Amongst those who received a pacemaker following TAVR the pre-procedural electrocardiogram findings included: No conduction disturbance (n = 41, 64%); 1st degree AV block (n = 10, 16%); right bundle branch block (n = 6, 9%) and LBBB (n = 5, 8%). LBBB (but not permanent pacemaker) occurred more frequently in patients who had balloon aortic valvuloplasty before TAVR (odds ratio [OR]: 1.25; p = 0.03). Pre-procedural conduction abnormality (composite of 1st degree AV block, hemiblock, right bundle branch block, LBBB) was independently associated with the need for permanent pacemaker (OR: 2.54; p = 0.048). The absence of aortic valve calcification was also associated with a higher pacing rate (OR: 0.55; p = 0.031). Multivariate regression analysis did not show an independent association between depth of implant, valve oversizing, balloon post-dilatation, and the need for pacing post procedure. CONCLUSIONS: Following implantation of the repositionable LOTUS valve, 55% of patients developed LBBB and 32% of patients required a pacemaker during their index hospital admission. Patients with pre-procedural conduction disturbance and non-calcified aortic valves were more likely to need pacing. No other anatomic features were identified with increased pacing requirement with the LOTUS device. PMID- 28641849 TI - Embolic Protection Devices in the Spotlight. PMID- 28641848 TI - The Use of Embolic Protection Devices Is Associated With a Lower Stroke and Death Rate After Carotid Stenting. AB - OBJECTIVES: The aim of this study was to analyze the association between intraprocedural and periprocedural variables and in-hospital stroke or death rate after carotid artery stenting. BACKGROUND: In Germany, all open surgical and endovascular procedures on the extracranial carotid artery must be documented in a statutory nationwide quality assurance database. METHODS: A total of 13,086 carotid artery stenting procedures for asymptomatic (63.9%) or symptomatic carotid stenosis (mean age 69.7 years, 69.7% men) between 2009 and 2014 were recorded. The following variables were analyzed: stent design, stent material, neurophysiological monitoring, periprocedural antiplatelet medication, and use of an embolic protection device. The primary outcome was in-hospital stroke or death. Major stroke or death, any stroke, and death, all until discharge, were secondary outcomes. Adjusted relative risks (RRs) were assessed using multilevel multivariable regression analyses. RESULTS: The primary outcome occurred in 2.4% of the population (1.7% in asymptomatic and 3.7% in symptomatic patients). The multivariable analysis showed an independent association between the use of an embolic protection device and lower in-hospital rates of stroke or death (adjusted RR: 0.65; 95% confidence interval [CI]: 0.50 to 0.85), major stroke or death (adjusted RR: 0.60; 95% CI: 0.43 to 0.84), and stroke (adjusted RR: 0.57; 95% CI: 0.43 to 0.77). Regarding the occurrence of in-hospital death, there was no significant association (adjusted RR: 0.78; 95% CI: 0.46 to 1.35). None of the outcomes was associated with stent design, stent material, neurophysiological monitoring, or antiplatelet medication. CONCLUSIONS: The use of an embolic protection device was independently associated with lower in-hospital risk for stroke or death, major stroke or death, and stroke. PMID- 28641850 TI - Anomalous Origin of Left Main Coronary Artery From Innominate Artery. PMID- 28641851 TI - Percutaneous Coronary Intervention Outcomes in Very Elderly Patients From a Single Large-Volume Tertiary Care Center, Specifically Focusing on Nonagenarians. PMID- 28641852 TI - Bioresorbable Everolimus-Eluting Vascular Scaffold for Long Coronary Lesions: A Subanalysis of the International, Multicenter GHOST-EU (Gauging coronary Healing with bioresorbable Scaffolding plaTforms in EUrope) Registry. PMID- 28641853 TI - Reply: Bioresorbable Everolimus-Eluting Vascular Scaffold for Long Coronary Lesions: A Subanalysis of the International, Multicenter GHOST-EU (Gauging coronary Healing with bioresorbable Scaffolding plaTforms in EUrope) Registry. PMID- 28641854 TI - Permanent Pacemaker Implantation Following Transcatheter Aortic Valve Replacement. PMID- 28641855 TI - Reply: Permanent Pacemaker Implantation Following Transcatheter Aortic Valve Replacement. PMID- 28641856 TI - Change: Out With the Old, In With the New. PMID- 28641857 TI - Correction. PMID- 28641858 TI - Correction. PMID- 28641859 TI - Correction. PMID- 28641860 TI - Noninvasive blood potassium measurement using signal-processed, single-lead ecg acquired from a handheld smartphone. AB - OBJECTIVE: We have previously used a 12-lead, signal-processed ECG to calculate blood potassium levels. We now assess the feasibility of doing so with a smartphone-enabled single lead, to permit remote monitoring. PATIENTS AND METHODS: Twenty-one hemodialysis patients held a smartphone equipped with inexpensive FDA-approved electrodes for three 2min intervals during hemodialysis. Individualized potassium estimation models were generated for each patient. ECG calculated potassium values were compared to blood potassium results at subsequent visits to evaluate the accuracy of the potassium estimation models. RESULTS: The mean absolute error between the estimated potassium and blood potassium 0.38+/-0.32 mEq/L (9% of average potassium level) decreasing to 0.6 mEq/L using predictors of poor signal. CONCLUSIONS: A single-lead ECG acquired using electrodes attached to a smartphone device can be processed to calculate the serum potassium with an error of 9% in patients undergoing hemodialysis. SUMMARY: A single-lead ECG acquired using electrodes attached to a smartphone can be processed to calculate the serum potassium in patients undergoing hemodialysis remotely. PMID- 28641861 TI - Permanent His Bundle Pacing in Intra-Hisian Conduction Block: Mechanistic Insights. AB - We are reporting a patient with discrete intra-His conduction block and describe a refined technique of permanent His bundle pacing assuring reliable ventricular capture. Meticulous mapping of the site of block with lead placement distal to the site of block and non-selective His bundle pacing with local myocardial capture as an additional safety back up appears to be the technique of choice. PMID- 28641862 TI - Perioperative beta blockers and statins for noncardiac surgery patients with coronary stents. AB - IMPORTANCE: Recent publications report that perioperative initiation of statin therapy is associated with improved outcomes particularly among patients with increased cardiac risk. However, findings on associations with beta blocker (BB) initiation are mixed. OBJECTIVE: This study examines associations between perioperative statin and BB use in a national sample of patients with cardiac stents. DESIGN: Retrospective cohort study. SETTING: VA Medical Centers nationwide. PARTICIPANTS: We identified Veterans Affairs (VA) patients undergoing non-cardiac surgery in the within two years after stent placement between October 2002 and September 2011 with BB and/or statin prescriptions within one year prior to surgery. Using VA inpatient data we identified major adverse cardiac or cerebrovascular events (MACCE) within 30 days of surgery. General usage patterns and percent of days covered by medication were calculated as additional markers of medication use. Adjusted logistic regression was used to examine associations between medication use and 30-day postoperative outcomes. RESULTS: 23,537 patients underwent surgery within 2 years following stent placement, of whom 20,566 (88.6%) had prescriptions for beta blockers and statins within 365 days prior to surgery. Of those, 13,501 (65.6%) used both BB and statins prior to surgery, while 2626 (12.8%) used only BB, 2346 (11.4%) used only statins, and 2093 (10.2%) used neither. In fully adjusted models, the only significant association was between perioperative statin use and decreased mortality (OR 0.65, 95% CI 0.48-0.87). CONCLUSIONS: Our results suggest that maintaining statin therapy perioperatively is associated with reduced 30 day mortality in stented patients undergoing non-cardiac surgery who have previously been prescribed both beta blockers and statins. PMID- 28641863 TI - A comparison of different heat maintenance methods implemented during a simulated half-time period in professional Rugby Union players. AB - OBJECTIVES: In thermoneutral conditions, half-time is associated with reductions in body temperature that acutely impair performance. This laboratory-based study compared active, passive, and combined methods of half-time heat maintenance. DESIGN: Randomised, counterbalanced, cross-over. METHODS: After a standardised warm-up (WU) and 15min of rest, professional Rugby Union players (n=20) completed a repeated sprint test (RSSA1). Throughout a simulated half-time (temperature: 20.5+/-0.3 degrees C; humidity: 53+/-5%), players then rested (Control) or wore a survival jacket (Passive) for 15min, or performed a 7min rewarm-up after either 8min of rest (Active), or 8min of wearing a survival jacket (Combined). A second RSSA (RSSA2) followed. Core temperature (Tcore) and peak power output (PPO; during countermovement jumps; CMJ) were measured at baseline, post-RSSA1, pre RSSA2. RESULTS: All half-time interventions attenuated reductions in Tcore (0.62+/-0.28 degrees C) observed in Control (Passive: -0.23+/-0.09 degrees C; Active: -0.17+/-0.09 degrees C; Combined: -0.03+/-0.10 degrees C, all p<0.001) but Combined preserved Tcore the most (p<0.001). All half-time interventions attenuated the 385+/-137W reduction in Control PPO (Passive: -213+/-79W; Active: 83+/-72W; Combined: +10+/-52W; all p<0.001); with best PPO maintenance in Combined (p<=0.001). The fastest sprints occurred in RSSA2 in Combined (6.74+/ 0.21s; p<0.001) but Passive (6.82+/-0.04s) and Active (6.80+/-0.05s) sprints were 0.4% (p=0.011) and 0.8% (p=0.002) quicker than Control (6.85+/-0.04s), respectively. CONCLUSIONS: While the efficacy of passive and active heat maintenance methods was supported throughout a simulated half-time, a combined approach to attenuating heat losses appeared the most beneficial for Tcore and subsequent PPO and sprint performance in professional Rugby Union players. PMID- 28641864 TI - [On site-screening for Chagas disease supported by a community intervention: can it improve accessibility for diagnosis and treatment?] PMID- 28641865 TI - Influence of baseline MELD score in the efficacy of treatment of hepatitis C with simeprevir and sofosbuvir. AB - INTRODUCTION: There are few published studies on predictors of response to treatment with sofosbuvir and simeprevir in HCV patients. OBJECTIVE: The objective of the study was to analyse possible predictors of response to simeprevir (SMV) and sofosbuvir (SOF) in patients infected with hepatitis C genotypes 1 or 4. PATIENTS AND METHODS: Prospective observational cohort study in 12 hospitals. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). RESULTS: 204 patients (62.3% male, mean age 55 years) were included: 186 (91.2%) genotype 1 (60.3% 1b 25% 1a) and 18 (8.8%) genotype 4. 132 (64.7%) cirrhotic (87.9% Child A), 33 (16.2%) F3, 31 (15.2%) F2, 8 (3.9%) F0-1. 80.8% MELD<10. 93 (45.6%) naive. Ribavirin was added in 68 (33.3%). Mean baseline viral load 2,151,549 IU/ml (SD: 2,391,840). Treatment duration 12 weeks in 93.1%. 4 discontinued therapy: suicide, psychotic attack, hyperbilirubinaemia and liver cancer recurrence. 190 (93.1%) achieved SVR12. There were no differences in SVR12 depending on the genotype, treatment duration, ribavirin use, prior therapy, viral load (VL) or baseline platelets. In univariate analysis, undetectable VL at 4 weeks (p=0.042), absence of cirrhosis (p=0.021), baseline albumin >= 4g/dl (p=0.001) and MELD<10 (p<0.0001) were associated with higher SVR12. In multivariate analysis, only baseline MELD score <10 patients had higher SVR12 (p<0.001). CONCLUSIONS: The combination of simeprevir and sofosbuvir in patients infected with genotype 1 and 4 hepatitis C is highly effective. It is a safe therapy, especially in patients without ribavirin. This combination was more effective in patients with a MELD score below 10. PMID- 28641866 TI - T-bet expressing B cells - Novel target for autoimmune therapies? AB - Autoimmune diseases affect more than 23.5million Americans. Traditional therapies for autoimmune diseases involve immunosuppressive drugs that globally dampen immune responses or target and kill large populations of normal immune cells. Both approaches lead to severe dysfunction of the immune system increasing the risk of infections and cancer. Therefore, a more targeted approach, modulating only the pathogenic autoimmune response, would be tremendously beneficial for autoimmune patients. However, only some novel targets involved in pathogenic autoimmune response have been discovered and it is likely that more remain, currently unknown. Here we review the data that have recently been described about T-bet+ B cells (also known as ABCs). Some data suggest that this B cell subset includes cells that are pathogenic in autoimmune responses. Therefore procedures that target these cells might be useful in autoimmune therapies. PMID- 28641867 TI - Motivational pathways of occupational and organizational turnover intention among newly registered nurses in Canada. AB - BACKGROUND: Staff turnover is a major issue for health care systems. In a time of labor shortage, it is critical to understand the motivational factors that underlie turnover intention in newly licensed nurses. PURPOSE: To examine whether different forms of motivation (the reasons for which nurses engage in their work) predict intention to quit the occupation and organization through distinct forms (affective and continuance) and targets (occupation and organization) of commitment. METHODS: Cross-sectional data were collected from a sample of 572 French-Canadian newly registered nurses working in public health care in the province of Quebec, Canada. The hypothesized model was tested by structural equation modeling. FINDINGS: Autonomous motivation (nurses accomplish their work primarily out of a sense of pleasure and satisfaction or because they personally endorse the importance or value of their work) negatively predicts intention to quit the profession and organization through target-specific affective commitment. However, although controlled motivation (nurses accomplish their work mainly because of internal or external pressure) is positively associated with continuance commitment to the occupation and organization, it directly predicts, positively so, intention to quit the occupation and organization. CONCLUSION: These results highlight the complexity of the motivational processes at play in the turnover intention of novice nurses, revealing distinct forms of commitment that explain how motivation quality is related simultaneously to intention to quit the occupation and organization. Health care organizations are advised to promote autonomous over controlled motivation to retain newly recruited nurses and sustain the future of the nursing workforce. PMID- 28641868 TI - Quality of articles published in predatory nursing journals. AB - BACKGROUND: Predatory journals exist in nursing and lack the safeguards of traditional publishing practices. PURPOSE: To examine the quality of articles published in predatory nursing journals. METHOD: Randomly selected articles (n = 358) were reviewed for structural content and eight quality indicators. FINDINGS: Two-thirds (67.4%) of the articles were published between 2014 and 2016, demonstrating the acceleration of publications in predatory nursing journals. The majority (75.9%) of the articles were research reports. Most followed the IMRAD presentation of a research report but contained errors, or the study was not pertinent to the nursing discipline. CONCLUSIONS: Nursing research published in predatory journals may appear legitimate by conforming to an expected structure. However, a lack of quality is apparent, representing inadequate peer review and editorial processes. Poor quality research erodes the scholarly nursing literature. PMID- 28641869 TI - Ischemic enteritis with unusual presentation. PMID- 28641870 TI - Antibiotic activity and concentrations in clinical samples from patients with chronic bacterial prostatitis. AB - OBJECTIVES: Chronic bacterial prostatitis (CBP) is the most common urological disease in patients younger than 50 years, whose long-standing symptoms could be related to an inappropriate therapeutic regimen. The objective was to analyse the sensitivity of microorganisms isolated from patients with CBP and measure the weekly antibiotic concentrations in serum, semen and urine. MATERIAL AND METHODS: For the antibiotic sensitivity study, 60 clinical isolates were included between January 2013 and December 2014 from semen samples from patients with microbiologically confirmed CBP. Broth microdilution was performed on the samples. For the antibiotic concentration study from January to May 2014, urine, blood and semen samples were collected weekly, over 4 weeks of treatment from 8 patients with positive cultures for CBP. The concentrations were measured using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). RESULTS: The antibiotics fosfomycin and nitrofurantoin had the highest activity (95.2% in both cases). The mean antibiotic concentrations in semen during the 4 weeks studied were as follows: 1.68mg/L, 8.30mg/L, 2.61mg/L, 0.33mg/L and 2.90mg/L, respectively, for patients 1 to 5, who were treated with levofloxacin; 1.625mg/L for patient 6, who was treated with ciprofloxacin; 2.67mg/L for patient 7, who was treated with ampicillin; and 1.05mg/L for patient 8, who was treated with doxycycline. Higher concentrations were obtained in the urine samples than in serum and semen, the latter 2 of which were comparable. CONCLUSIONS: Fosfomycin is proposed as the primary alternative to the empiric treatment of CBP due to its high in vitro activity. The antibiotic concentration in semen was higher than the minimal inhibitory concentration against the aetiological agent, although microbiological negativisation was not always correlated with a favourable clinical outcome. PMID- 28641872 TI - Analysis of historical articles published in Actas Urologicas Espanolas. AB - OBJECTIVE: On the 40th anniversary of the edition of Actas Urologicas Espanolas, we assess the articles on history to determine the proportion represented, analysing the study subjects and their relevance, getting to know the authors, the main study centres and the interest that the studies offer for understanding the specialty. MATERIAL AND METHODS: We extracted as many subjects of historic content from the journal as were published between January 1976 and December 2016. RESULT: There were 103 historical studies representing 3% of the total number of articles, with a mean of 2.57 articles published annually, written by 127 separate urologists. As first author, there were 59 articles, and as coauthors, there were 68. The main activity came from 21 of the main university hospitals in Spain, and 43 of the articles were personal articles signed by a single individual. Their content mainly covers the facts of Spanish urology from the Renaissance to the 20th century, with special emphasis on the profile of Spanish specialists. Data on 22 of these specialists are provided in 37 articles. The evolution of diagnostic and treatment procedures, both medical and surgical, are well reflected, as are a number of diseases. CONCLUSION: Most of the studies are personal works of historical research and represent 3% of the total number of articles. As a whole, the quality is high, and the articles provide data with interesting details and useful reviews, giving them considerable value, as well as forming a precious compendium for the understanding of the history of Spanish urology. These articles are highly recommended reading. PMID- 28641871 TI - The Patient's Comorbidity Burden Correlates with the Erectile Dysfunction Severity. AB - OBJECTIVE: To explore the potential relationship between erectile dysfunction (ED), low testosterone levels, and the Charlson Comorbidity Index (CCI). MATERIAL AND METHODS: Cross-sectional study on patients referred to the andrology unit in 7 Spanish centers. The ED was diagnosed and graded using the International Index of Erectile Function (IIEF-5) score. Total testosterone, the prevalence of each comorbidity, and the CCI were compared between patients with different grades of ED. Besides, the correlation between total testosterone and the CCI score, the influence of each comorbidity, and the ED severity on the CCI was assessed in a multiple linear regression. RESULTS: The study included 430 men with a mean age of 61 years. The mean CCI was 3.5, and mean total testosterone 15.2 nmol/L; 389 (91%) subjects had some grade of ED: 97 (23%) mild, 149 (35%) mild-to-moderate, 86 (20%) moderate, and 57 (13%) severe. The increase in ED severity was significantly associated with a decrease in total testosterone (P=.002), and an increase in the CCI score (P<.001). Testosterone levels were significantly lower in patients with obesity, diabetes, hypercholesterolemia, and hypertriglyceridemia (P<.05). However, only the prevalence of diabetes and hypertension was significantly associated with the severity of ED. The multivariate analysis including variables related to all assessed comorbidities, total testosterone levels, and the DE severity significantly predicted the CCI score (P<.001, R2=.426). The severity of ED significantly contributed to this model (P=.011), but total testosterone did not (P=.204). CONCLUSIONS: The CCI is significantly associated with the ED severity, but it shows a weak correlation with the testosterone levels. PMID- 28641873 TI - Targeting DNA repair for precision radiotherapy: Balancing the therapeutic ratio. AB - Genomic instability is underpinned by defects in the DNA damage response and DNA repair pathways. Subsequent clonal selection and adaption can lead to a mutator phenotype and tumor aggression. Importantly, tumor cell sensitivity to chemotherapy and radiotherapy can depend highly on the cellular capacity to repair DNA damage within and between tumor types. Annotation of functional defects in DNA damage response and DNA repair function may allow for the development of novel prognostic biomarkers. This information could also be used to predict therapeutic response, including predicting responses following inhibition of DNA repair. Herein, we highlight the increasing potential for annotating and targeting DNA repair defects in patients undergoing precision radiotherapy. PMID- 28641874 TI - PRIMA, non nocere. PMID- 28641876 TI - What are the health research needs for the Sendai Framework? PMID- 28641875 TI - Prevention of incisional hernia with prophylactic onlay and sublay mesh reinforcement versus primary suture only in midline laparotomies (PRIMA): 2-year follow-up of a multicentre, double-blind, randomised controlled trial. AB - BACKGROUND: Incisional hernia is a frequent long-term complication after abdominal surgery, with a prevalence greater than 30% in high-risk groups. The aim of the PRIMA trial was to evaluate the effectiveness of mesh reinforcement in high-risk patients, to prevent incisional hernia. METHODS: We did a multicentre, double-blind, randomised controlled trial at 11 hospitals in Austria, Germany, and the Netherlands. We included patients aged 18 years or older who were undergoing elective midline laparotomy and had either an abdominal aortic aneurysm or a body-mass index (BMI) of 27 kg/m2 or higher. We randomly assigned participants using a computer-generated randomisation sequence to one of three treatment groups: primary suture; onlay mesh reinforcement; or sublay mesh reinforcement. The primary endpoint was incidence of incisional hernia during 2 years of follow-up, analysed by intention to treat. Adjusted odds ratios (ORs) were estimated by logistic regression. This trial is registered at ClinicalTrials.gov, number NCT00761475. FINDINGS: Between March, 2009, and December, 2012, 498 patients were enrolled to the study, of whom 18 were excluded before randomisation. Therefore, we included 480 patients in the primary analysis: 107 were assigned primary suture only, 188 were allocated onlay mesh reinforcement, and 185 were assigned sublay mesh reinforcement. 92 patients were identified with an incisional hernia, 33 (30%) who were allocated primary suture only, 25 (13%) who were assigned onlay mesh reinforcement, and 34 (18%) who were assigned sublay mesh reinforcement (onlay mesh reinforcement vs primary suture, OR 0.37, 95% CI 0.20-0.69; p=0.0016; sublay mesh reinforcement vs primary suture, 0.55, 0.30-1.00; p=0.05). Seromas were more frequent in patients allocated onlay mesh reinforcement (34 of 188) than in those assigned primary suture (five of 107; p=0.002) or sublay mesh reinforcement (13 of 185; p=0.002). The incidence of wound infection did not differ between treatment groups (14 of 107 primary suture; 25 of 188 onlay mesh reinforcement; and 19 of 185 sublay mesh reinforcement). INTERPRETATION: A significant reduction in incidence of incisional hernia was achieved with onlay mesh reinforcement compared with sublay mesh reinforcement and primary suture only. Onlay mesh reinforcement has the potential to become the standard treatment for high-risk patients undergoing midline laparotomy. FUNDING: Baxter; B Braun Surgical SA. PMID- 28641877 TI - [Update on cutaneous dirofilariasis]. AB - Dirofilariasis is a worldwide zoonotic infection that rarely affects humans and is caused by filarial nematodes of the genus Diroflaria transmitted by mosquitoes. Cutaneous dirofilariasis, due to D. repens, presents as inflammatory lesions that develop into subcutaneous nodules. These clinical symptoms may be consistent with Wells' cellulitis. Diagnosis of dirofilariasis involves demonstration of the presence of the nematode during skin biopsy and identification of the worm through macroscopic, histological and PCR analysis. Surgical resection of the nodule remains the gold standard treatment. The number of cases of human cutaneous dirofilariasis has increased in the recent years and the disease must not be misdiagnosed. PMID- 28641878 TI - Diagnosis and Management of Pleural Transudates. AB - Various clinical trials have been published on the optimal clinical management of patients with pleural exudates, particularly those caused by malignant tumors, while little information is available on the diagnosis and treatment of pleural transudates. The etiology of pleural transudates is wide and heterogeneous, and they can be caused by rare diseases, sometimes constituting a diagnostic challenge. Analysis of the pleural fluid can be a useful procedure for establishing diagnosis. Treatment should target not only the underlying disease, but also management of the pleural effusion itself. In cases refractory to medical treatment, invasive procedures will be necessary, for example therapeutic thoracentesis, pleurodesis with talc, or insertion of an indwelling pleural catheter. Little evidence is currently available and no firm recommendations have been made to establish when to perform an invasive procedure, or to determine the safest, most efficient approach in each case. This article aims to describe the spectrum of diseases that cause pleural transudate, to review the diagnostic contribution of pleural fluid analysis, and to highlight the lack of evidence on the efficacy of invasive procedures in the management and control of pleural effusion in these patients. PMID- 28641880 TI - High effectiveness of repeated levosimendan cycles in a patient with advanced heart failure. PMID- 28641879 TI - Mycobacterium xenopi and squamous cell carcinoma of the lung. PMID- 28641881 TI - Peripheral blood regulatory T cell counts as a predictive biomarker for the outcome of kidney transplant: A systematic review. AB - BACKGROUND AND OBJECTIVE: Circulating regulatory T cells could become a suitable biomarker for kidney recipients. The objective of this study was to evaluate the effect of mammalian target of rapamycin (mTOR) inhibitors on regulatory T cell numbers, and the clinical interest of this effect. MATERIAL AND METHODS: Systematic review of published and unpublished studies. Worldwide databases or repositories. Randomised controlled trials and cohort studies comparing regulatory T cell counts and rejection episodes between patients with and without mTOR inhibitors were searched. Correlation of regulatory T cells-glomerular filtration rate might be supplied. Co-dependency regulatory T cells-mTOR inhibitors efficacy was evaluated. RESULTS: Five trials and 9 studies were included. Clinical differences made it difficult to obtain quantitative estimates of the effect of immunosuppression on regulatory T cell numbers. Nevertheless, we found that there are higher regulatory T cell numbers under treatment with sirolimus or everolimus. Rejection episodes were similar under calcineurin inhibitors and mTOR inhibitors despite different regulatory T cell numbers. Pooled correlation regulatory T cells-glomerular filtration rate was, prospectively 0.114 (95% confidence interval [95% CI] 0.062-0.406), and retrospectively 0.13 (95% CI 0.0-0.361). There is direct evidence although of low level (biomarker-stratified randomisation) on the co-dependency regulatory T cells-mTOR inhibitors efficacy. CONCLUSIONS: Regulatory T cells counts may be associated with better outcomes under treatment with mTOR inhibitors (anti rejection efficacy), considering that there is a relationship between these cells and kidney graft function. REGISTRATION: PROSPERO (CRD42016046285). PMID- 28641883 TI - Petroleum oil removal by immobilized bacterial cells on polyurethane foam under different temperature conditions. AB - In this work, a mixed biofilm composed by Pseudomonas monteilii P26 and Gordonia sp. H19 was formed using polyurethane foam (PUF) as immobilization support, for crude oil removal from artificial sea water. Fresh immobilized cells and immobilized cells that were stored at 4 degrees C for two months before use were assessed. The oil removal assays were carried out at microcosm scale at 4, 15 and 30 degrees C. A viability loss of P. monteilii P26 was observed after the storage. The highest removal value (75%) was obtained at 30 degrees C after 7days using fresh immobilized cells on PUF. Enhanced oil bioremoval was obtained at 4 degrees C and 15 degrees C with the previously stored immobilized cells compared to the fresh immobilized cells. Crude oil sorption on the different systems was responsible for the removal of 22-33% oil at the different temperatures. In conclusion, an economic tool for petroleum bioremediation is proposed. PMID- 28641882 TI - Ferredoxin-dependent bilin reductases in eukaryotic algae: Ubiquity and diversity. AB - Linear tetrapyrroles (bilins) are produced from heme by heme oxygenase, usually forming biliverdin IXalpha (BV). Fungi and bacteria use BV as chromophore for phytochrome photoreceptors. Oxygenic photosynthetic organisms use BV as a substrate for ferredoxin-dependent bilin reductases (FDBRs), enzymes that produce diverse reduced bilins used as light-harvesting pigments in phycobiliproteins and as photoactive photoreceptor chromophores. Bilin biosynthesis is essential for phototrophic growth in Chlamydomonas reinhardtii despite the absence of phytochromes or phycobiliproteins in this organism, raising the possibility that bilins are more generally required for phototrophic growth by algae. We here leverage the recent expansion in available algal transcriptomes, cyanobacterial genomes, and environmental metagenomes to analyze the distribution and diversification of FDBRs. With the possible exception of euglenids, FDBRs are present in all photosynthetic eukaryotic lineages. Phylogenetic analysis demonstrates that algal FDBRs belong to the three previously recognized FDBR lineages. Our studies provide new insights into FDBR evolution and diversification. PMID- 28641884 TI - Oxidative stress profiles in brain point out a higher susceptibility of fish to waterborne divalent mercury compared to dietary organic mercury. AB - This study examines, for the first time, the neurotoxicity of Hg(II) and MeHg in fish (Diplodus sargus) in a time-course comparative perspective and considering realistic exposure levels and routes. Both forms followed an identical time variation pattern of accumulation in the brain, but dietary MeHg was more efficiently transported to the brain. MeHg was substantially eliminated from the brain in 28days of depuration, which did not occur for Hg(II). Moreover, Hg(II) displayed a high neurotoxicity potential, as unveiled by the poor activation of brain antioxidant defenses and recurrent oxidative damage (as protein oxidation), while the opposite was recorded upon MeHg exposure. These results highlight the need to include Hg(II) in future environmental health assessment plans, preventing an underestimation of the risk for wild fish populations, which has probably been occurring due to the long-standing idea of the higher toxicity of MeHg in comparison with inorganic Hg forms. PMID- 28641885 TI - Remote sensing and water quality indicators in the Korean West coast: Spatio temporal structures of MODIS-derived chlorophyll-a and total suspended solids. AB - The Yellow Sea is a shallow marginal sea with a large tidal range. In this study, ten areas located along the western coast of the Korean Peninsula are investigated with respect to remotely sensed water quality indicators derived from NASA MODIS aboard of the satellite Aqua. We found that there was a strong seasonal trend with spatial heterogeneity. In specific, a strong six-month phase lag was found between chlorophyll-a and total suspended solid owing to their inversed seasonality, which could be explained by different dynamics and environmental settings. Chlorophyll-a concentration seemed to be dominantly influenced by temperature, while total suspended solid was largely governed by local tidal forcing and bottom topography. This study demonstrated the potential and applicability of satellite products in coastal management, and highlighted find that remote-sensing would be a promising tool in resolving orthogonality of large spatio-temporal scale variabilities when combining with proper time series analyses. PMID- 28641886 TI - Genome-wide expression in veterans with schizophrenia further validates the immune hypothesis for schizophrenia. AB - This study aimed to test whether a dysregulation of gene expression may be the underlying cause of previously reported elevated levels of inflammatory cytokines in veterans with schizophrenia. We performed a genome-wide expression analysis in peripheral blood mononuclear cells from veterans with schizophrenia and controls, and our results show that 167 genes and putative loci were differently expressed between groups. These genes were enriched primarily for pathways related to inflammatory mechanisms and formed networks related to cell death and survival, immune cell trafficking, among others, which is in line with previous reports and further validates the inflammatory hypothesis of schizophrenia. PMID- 28641887 TI - Central serotonergic function in patients with predominantly negative symptoms of schizophrenia. PMID- 28641889 TI - WITHDRAWN: Mut Res special section "Protein modifications in DNA repair and cancer". PMID- 28641888 TI - Oral vaccination of wildlife against rabies: Differences among host species in vaccine uptake efficiency. AB - Oral vaccination using attenuated and recombinant rabies vaccines has been proven a powerful tool to combat rabies in wildlife. However, clear differences have been observed in vaccine titers needed to induce a protective immune response against rabies after oral vaccination in different reservoir species. The mechanisms contributing to the observed resistance against oral rabies vaccination in some species are not completely understood. Hence, the immunogenicity of the vaccine virus strain, SPBN GASGAS, was investigated in a species considered to be susceptible to oral rabies vaccination (red fox) and a species refractory to this route of administration (striped skunk). Additionally, the dissemination of the vaccine virus in the oral cavity was analyzed for these two species. It was shown that the palatine tonsils play a critical role in vaccine virus uptake. Main differences could be observed in palatine tonsil infection between both species, revealing a locally restricted dissemination of infected cells in foxes. The absence of virus infected cells in palatine tonsils of skunks suggests a less efficient uptake of or infection by vaccine virus which may lead to a reduced response to oral vaccination. Understanding the mechanisms of oral resistance to rabies virus vaccine absorption and primary replication may lead to the development of novel strategies to enhance vaccine efficacy in problematic species like the striped skunk. PMID- 28641890 TI - A comparative research of different ensemble surrogate models based on set pair analysis for the DNAPL-contaminated aquifer remediation strategy optimization. AB - Surrogate-based simulation-optimization technique is an effective approach for optimizing the surfactant enhanced aquifer remediation (SEAR) strategy for clearing DNAPLs. The performance of the surrogate model, which is used to replace the simulation model for the aim of reducing computation burden, is the key of corresponding researches. However, previous researches are generally based on a stand-alone surrogate model, and rarely make efforts to improve the approximation accuracy of the surrogate model to the simulation model sufficiently by combining various methods. In this regard, we present set pair analysis (SPA) as a new method to build ensemble surrogate (ES) model, and conducted a comparative research to select a better ES modeling pattern for the SEAR strategy optimization problems. Surrogate models were developed using radial basis function artificial neural network (RBFANN), support vector regression (SVR), and Kriging. One ES model is assembling RBFANN model, SVR model, and Kriging model using set pair weights according their performance, and the other is assembling several Kriging (the best surrogate modeling method of three) models built with different training sample datasets. Finally, an optimization model, in which the ES model was embedded, was established to obtain the optimal remediation strategy. The results showed the residuals of the outputs between the best ES model and simulation model for 100 testing samples were lower than 1.5%. Using an ES model instead of the simulation model was critical for considerably reducing the computation time of simulation-optimization process and maintaining high computation accuracy simultaneously. PMID- 28641891 TI - Inter-arm systolic blood pressure differences, relations with future vascular events and mortality in patients with and without manifest vascular disease. AB - BACKGROUND: Inter-arm systolic blood pressure difference (SBPD) is an easily obtained patient characteristic which relates to vascular disease. We aimed to identify determinants of large inter-arm SBPD and to investigate the relation between inter-arm SBPD and vascular events in patients with and without manifest vascular disease. METHODS: In a cohort of 7344 patients with manifest vascular disease or vascular risk factors alone enrolled in the Second Manifestations of ARTerial disease (SMART) study, single bilateral non-simultaneous blood pressure measurements were performed. Logistic and Cox regression was used to identify determinants of large inter-arm SBPD (>=15mmHg) and to investigate the relation between inter-arm SBPD and vascular events (composite of non-fatal myocardial infarction, stroke, and vascular mortality) and all-cause mortality. RESULTS: In all patients the median inter-arm SBPD was 7mmHg (IQR 3-11) and 1182 (16%) patients had inter-arm SBPD >=15mmHg. Higher age, higher systolic blood pressure, diabetes mellitus, peripheral artery disease, carotid artery stenosis, higher carotid intima-media thickness, and lower ankle-brachial indices were related to large inter-arm SBPD (>=15mmHg). Each 5mmHg increase in inter-arm SBPD was related to a 12% higher risk of vascular events in patients without manifest vascular disease (HR 1.12; 95% CI 1.00-1.27), whereas no relation was apparent in patients with manifest vascular disease (HR 0.98; 95% CI 0.93-1.04, interaction p value 0.036). Inter-arm SBPD was not related to all-cause mortality (HR 1.05; 95% CI 0.93-1.19). CONCLUSIONS: Inter-arm SBPD relates to a higher risk of vascular events in patients without manifest vascular disease, whereas this relation is not apparent in patients with manifest vascular disease. PMID- 28641892 TI - Fighting fake medicines: First quality evaluation of cardiac drugs in Africa. AB - BACKGROUND: The growing menace of poor quality and falsified drugs constitutes a major hazard, compromising healthcare and patient outcomes. Efforts to assess drug standards worldwide have almost exclusively focused on anti-microbial drugs; with no study to date on cardiovascular drugs. Our study aims to assess quality of seven routinely used cardiovascular medications (anticoagulants, antihypertensives and statins) in ten Sub-Saharan African countries. METHODS: Drugs were prospectively collected using standardized methods between 2012 and 2014 from licensed (random pharmacies) and unlicensed (street-markets) places of sale in Africa. We developed a validated reversed-phase liquid chromatography with tandem mass spectrometry method to accurately quantify the active ingredient in a certified public laboratory. Three quality categories were defined based on the ratio of the measured to the expected dosage of the active ingredient: A (good quality): 95% to 105%, B (low quality): 85 to 94.99% or 105.01 to 115%, C (very low quality): <85% or >115%. RESULTS: All expected medicines (n=3468 samples) were collected in Benin, Burkina-Faso, Congo-Brazzaville, the Democratic Republic of Congo, Guinea, Cote d'Ivoire, Mauritania, Niger, Togo and Senegal. Out of the 1530 samples randomly tested, poor quality (types B and C) was identified in 249 (16.3%) samples. The prevalence of poor quality was significantly increased in certain specific drugs (amlodipine 29% and captopril 26%), in generic versions (23%) and in drugs produced in Asia (35%). The proportion of poor quality reached 50% when drugs produced in Asia were sold in street-markets. CONCLUSION: In this first study assessing the quality of cardiovascular drugs in Africa, we found a significant proportion of poor quality drugs. This requires continued monitoring strategies. PMID- 28641893 TI - Recent development of transition metal complexes with in vivo antitumor activity. AB - The often severe side effects displayed by currently used platinum and ruthenium complexes have motivated researchers to design and develop transition metal-based anti-tumor agents with reduced toxicity. Distinct from organic anti-tumor drugs, transition metal complexes possess several properties that render them as promising scaffolds for anti-cancer drug discovery. While a vast number of metal complexes have been synthesized and reported to be promising and potent in vitro anticancer active compounds, fewer have shown efficacy in in vivo models. The demonstration of in vivo potency is an essential step for lead candidates for clinical trials. In this review, we highlight examples of transition metal-based complexes that have shown in vivo anti-tumor activities that have been described in recent years. PMID- 28641895 TI - Placebo pills provided without deception may help to reduce pain and disability in people with chronic low back pain [synopsis]. PMID- 28641894 TI - Carbon assimilation and losses during an ocean acidification mesocosm experiment, with special reference to algal blooms. AB - A mesocosm experiment was conducted in Wuyuan Bay (Xiamen), China, to investigate the effects of elevated pCO2 on bloom formation by phytoplankton species previously studied in laboratory-based ocean acidification experiments, to determine if the indoor-grown species performed similarly in mesocosms under more realistic environmental conditions. We measured biomass, primary productivity and particulate organic carbon (POC) as well as particulate organic nitrogen (PON). Phaeodactylum tricornutum outcompeted Thalassiosira weissflogii and Emiliania huxleyi, comprising more than 99% of the final biomass. Mainly through a capacity to tolerate nutrient-limited situations, P. tricornutum showed a powerful sustained presence during the plateau phase of growth. Significant differences between high and low CO2 treatments were found in cell concentration, cumulative primary productivity and POC in the plateau phase but not during the exponential phase of growth. Compared to the low pCO2 (LC) treatment, POC increased by 45.8 101.9% in the high pCO2 (HC) treated cells during the bloom period. Furthermore, respiratory carbon losses of gross primary productivity were found to comprise 39 64% for the LC and 31-41% for the HC mesocosms (daytime C fixation) in phase II. Our results suggest that the duration and characteristics of a diatom bloom can be affected by elevated pCO2. Effects of elevated pCO2 observed in the laboratory cannot be reliably extrapolated to large scale mesocosms with multiple influencing factors, especially during intense algal blooms. PMID- 28641896 TI - There's an app for that! iOrtho+ Special Tests and Manual Techniques is a useful resource for students and recently graduated physiotherapists. PMID- 28641897 TI - Erratum to "Development of an instrument for community-level health related social capital among Japanese older people: The JAGES project" [J Epidemiol 27 (5) (2017) 221-227]. PMID- 28641898 TI - Sclerosing odontogenic carcinoma: current diagnostic and management considerations concerning a most unusual neoplasm. AB - Sclerosing odontogenic carcinoma (SOC) is a primary intraosseous carcinoma of the jaws that has been listed as a separate entity for the first time in the latest version of the World Health Organization classification of Head and Neck Tumours (2017). The aim of this study was to analyse and interpret the existing literature on SOC in the context of a clinical case treated in the authors' department. A systematic search of the PubMed database was performed in accordance with the PRISMA guidelines, yielding nine cases of SOC reported so far. In summary, characteristic clinical and radiological features of SOC include asymptomatic swelling, location predominantly in the mandible, tumour primarily lytic in appearance, presence of cortical bone destruction, and lack of metastatic spread. Due to the rarity of the disease, close collaboration between oral/maxillofacial surgeons and pathologists is crucial to avoid misdiagnosis. With complete excision, no recurrence of SOC should be expected. PMID- 28641900 TI - Synovial chondromatosis of the temporomandibular joint with intracranial extension-report of two cases. AB - Synovial chondromatosis of the temporomandibular joint is a rare condition, and only 10 cases with intracranial extension have been reported in the literature. Two cases of synovial chondromatosis with intracranial extension, followed up for 3 to 9 years, are reported here. The surgical treatment modality is described for each case. PMID- 28641899 TI - Obstructive sleep apnoea in craniofacial microsomia: analysis of 755 patients. AB - A retrospective cohort study was set up to analyse the prevalence and treatment of obstructive sleep apnoea (OSA) in relation to the severity of the deformity in patients with craniofacial microsomia (CFM). This study included a population of 755 patients with CFM from three craniofacial centres. Medical charts were reviewed for severity of the deformity, types of breathing difficulty, age at which breathing difficulty first presented, treatment for OSA, and treatment outcome. In total, 133 patients (17.6%) were diagnosed with OSA. Patients with Pruzansky IIB/III classification or bilateral craniofacial microsomia were significantly more often diagnosed with OSA than unilaterally affected patients of Pruzansky I/IIA classification. The initial treatment of OSA consisted of adenotonsillectomy, tracheotomy, or non-invasive positive pressure ventilation. Thirty-seven patients received more than one treatment (range 1-3). In this study, the prevalence of OSA in patients with CFM was higher than the prevalence in the healthy population described in the literature. Although several treatment modalities are available for the treatment of OSA in patients with CFM, treatment should be individualized and based on clinical symptoms, the severity of the deformity, and comorbidities. PMID- 28641901 TI - Putting evaluation capacity building in context: Reflections on the Ontario Brain Institute's Evaluation Support Program. AB - This article, in three parts, reflects on the content of the six articles included in the forum. It begins with a description of the Evaluation Support Program, emphasizing its key attributes. Next, it raises two points regarding ECB theory: (1) the need to become clearer about the concepts and terms used to describe and study this phenomenon, and (2) the potential value of social science theory to understand ECB and improve its practice. The article concludes with practical ideas for improving ECB: (1) framing it as an educative act, which assigns the evaluator the critical role of evaluation teacher/coach; and (2) the importance of never assuming that an ECB effort begins in unchartered territory, but rather that it builds on people's knowledge, skills, attitudes, and previous experiences. PMID- 28641902 TI - [Hodgkin's disease as a cause of fever of unknown origin in the elderly]. PMID- 28641903 TI - [Effectiveness of physical exercise on fitness in frail older adults: A systematic review of randomised trials]. AB - Performing exercise to maintain a good physical condition is crucial to improve and prevent frailty in older adults. The aim of this review was to assess the beneficial effects of physical exercise on fitness in frail older adults. A thorough literature search of randomised clinical trials (RCT) in the last 15 years was performed on different electronic databases. The methodological assessment of studies was obtained using the PEDro scale. Ten RCT were included, providing a final sample of 1,130 individuals. Scores on the PEDro scale ranged from 5 to 8/10. Multicomponent training programs seem to be the best strategy to improve fitness outcomes. Further studies should be performed in order to optimise the design of supervised exercise programs, and further research is needed in hospital and institutionalised settings. PMID- 28641904 TI - [Relevance of transjugular liver biopsy in acute liver failure in the elderly]. PMID- 28641905 TI - High Gpx1 expression predicts poor survival in laryngeal squamous cell carcinoma. AB - OBJECTIVE: Several studies have demonstrated that abnormal glutathione peroxidases 1 (Gpx1) expression can influence the biological behavior of malignant cells. However, the roles of Gpx1 in laryngeal squamous cell carcinoma (LSCC) remain unknown. The purpose of this study is to analyze the Gpx1 expression and prognostic significance in LSCC patients. METHODS: Gpx1 mRNA levels in laryngeal tissues were determined by qRT-PCR. Meanwhile, We examined the expression levels of Gpx1 protein in 140 primary tumor tissues and 28 cases of normal tissues by immunohistochemistry (IHC) analysis on tissue microarrays (TMA). RESULTS: Our results revealed that the frequency of high Gpx1 was significantly higher in cancer tissue compared to normal surgical margins; Gpx1 expression correlated with clinical features and overall survival (OS). Gpx1 overexpression was significantly associated with lymph node metastasis (P=0.023) and TNM stage (P=0.008); Kaplan-Meier survival curves revealed that patients with high Gpx1 expression had worse prognoses than patients with low Gpx1 expression; By multivariate analysis, we revealed that high Gpx1 expression level (HR 2.101, 95%CI 1.011-4.367; P=0.047) was an independent prognostic factor of survival in LSCC patients. CONCLUSION: We speculate that Gpx1 can be applied to predict the prognosis in LSCC patients. PMID- 28641906 TI - Pharmaceutical and biomedical analysis of cannabinoids: A critical review. AB - Cannabis products have recently regained much attention due to the high pharmacological potential of their cannabinoid content. In this review, the most widely used sample preparation strategies for the extraction of cannabinoids are described for the specific application to either plant materials or biological matrices. Several analytical techniques are described pointing out their respective advantages and drawbacks. In particular, chromatographic methods, such as TLC, GC and HPLC, are discussed and compared in terms of selectivity and sensitivity. Various detection methods are also presented based on the specific aim of the cannabinoids analysis. Lastly, critical considerations are mentioned with the aim to deliver useful suggestions for the selection of the optimal and most suitable method of analysis of cannabinoids in either biomedical or cannabis derived samples. PMID- 28641907 TI - Is fusion superior to non-fusion for the treatment of thoracolumbar burst fracture? A systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this meta-analysis was to compare the efficacy and safety between patients with thoracolumbar burst fracture who underwent posterior fixation alone (non-fusion) and supplemented with fusion. METHODS: A comprehensive search of related literature was performed in PubMed, Embase and the Cochrane library. Clinical outcomes (LBOS and VAS), surgical outcomes (operation time, blood loss, hospital stay and perioperative complications), and radiographic outcomes (kyphotic angle, decreased vertebral body height and segmental motion) were assessed in the meta-analysis. Data analysis was conducted with RevMan 5.3 software. RESULTS: Five RCTs and three retrospective studies including a total of 445 cases were identified. We found that there was no significant difference in terms of LBOS, VAS, implant-related complications, kyphotic and VBH parameters. However, there was a significant difference regarding blood loss, operation time, segmental motion and donor site pain between fusion and non-fusion. CONCLUSION: This meta-analysis demonstrated that posterior fixation alone could achieve satisfactory clinical and radiological results in treating thoracolumbar burst fracture. Moreover, posterior fixation without fusion was superior to additional fusion with less blood loss, shorter operation time, better segmental motion and lower donor site pain. PMID- 28641908 TI - The Uncertain Economics of Insurance Enabling More Emergency Department Visits. PMID- 28641909 TI - Effect of the Affordable Care Act Medicaid Expansion on Emergency Department Visits: Evidence From State-Level Emergency Department Databases. AB - STUDY OBJECTIVE: We assess whether the expansion of Medicaid under the Patient Protection and Affordable Care Act (ACA) results in changes in emergency department (ED) visits or ED payer mix. We also test whether the size of the change in ED visits depends on the change in the size of the Medicaid population. METHODS: Using all-capture, longitudinal, state data from the Agency for Healthcare Research and Quality's Fast Stats program, we implemented a difference in-difference analysis, which compared changes in ED visits per capita and the share of ED visits by payer (Medicaid, uninsured, and private insurance) in 14 states that did and 11 states that did not expand Medicaid in 2014. Analyses controlled for state-level demographic and economic characteristics. RESULTS: We found that total ED use per 1,000 population increased by 2.5 visits more in Medicaid expansion states than in nonexpansion states after 2014 (95% confidence interval [CI] 1.1 to 3.9). Among the visit types that could be measured, increases in ED visits were largest for injury-related visits and for states with the largest changes in Medicaid enrollment. Compared with nonexpansion states, in expansion states the share of ED visits covered by Medicaid increased 8.8 percentage points (95% CI 5.0 to 12.6), whereas the uninsured share decreased by 5.3 percentage points (95% CI -1.7 to -8.9). CONCLUSION: The ACA's Medicaid expansion has resulted in changes in payer mix. Contrary to other studies of the ACA's effect on ED visits, our study found that the expansion also increased use of the ED, consistent with polls of emergency physicians. PMID- 28641910 TI - Dependence of Boiling Histotripsy Treatment Efficiency on HIFU Frequency and Focal Pressure Levels. AB - Boiling histotripsy (BH) is a high-intensity focused ultrasound (HIFU)-based method of mechanical tissue fractionation that utilizes millisecond-long bursts of HIFU shock waves to cause boiling at the focus in milliseconds. The subsequent interaction of the incoming shocks with the vapor bubble mechanically lyses surrounding tissue and cells. The acoustic parameter space for BH has been investigated previously and an inverse dependence between the HIFU frequency and the dimensions of a BH lesion has been observed. The primary goal of the present study was to investigate in more detail the ablation rate and reliability of BH in the frequency range relevant to treatment of deep abdominal tissue targets (1 2 MHz). The second goal was to investigate the effect of focal peak pressure levels and shock amplitude on BH lesion formation, given a constant duty factor, a constant ratio of the pulse duration to the time to reach boiling and a constant number of BH pulses. A custom-built 12-element sector array HIFU transducer with F-number = 1.05 was used in all experiments. BH pulses at 5 different frequencies (1, 1.2, 1.5, 1.7 and 1.9 MHz) were delivered to optically transparent polyacrylamide gel phantoms and ex vivo bovine liver and myocardium tissue to observe cavitation and boiling bubble activity with high-speed photography and B-mode ultrasound imaging, correspondingly. In gel phantoms, a cavitation bubble cloud was shown to form prefocally and to shield the focus in all exposures at 1 and 1.2 MHz and in the highest amplitude exposures at 1.5-1.7 MHz; shielding was not observed at 1.9 MHz. In ex vivo tissue, this shielding effect was observed in 25% of exposures when peak negative in situ pressure exceeded 10.2 MPa at 1 MHz and 14.5 MPa at 1.5 MHz. When shielding occurred, the exposures resulted in mild tissue disruption in the prefocal region, but not liquefaction. The dimensions of liquefied lesions followed the inverse proportionality trend with frequency; consequently, the frequency range of 1.2 1.5 MHz appeared to be preferable for BH exposures in terms of the compromise between the ablation rate and reliability. The lesion size was independent of the duration of the BH pulses (or the total "HIFU on" time), provided that the number of pulses was constant and boiling was induced within each pulse. Thus, the use of shorter (1 ms vs. 10 ms), higher amplitude BH pulses allowed up to 10-fold reduction in treatment time for a given duty factor. PMID- 28641911 TI - Image Fusion of Real-Time Ultrasonography with Computed Tomography: Factors Affecting the Registration Error and Motion of Focal Hepatic Lesions. AB - Factors affecting the registration error (RE) and motion of focal hepatic lesions (FHLs) in image fusion of real-time ultrasonography (US) with computed tomography (CT) images were prospectively assessed by focusing on respiratory movement and FHL location. Real-time US and pre-acquired CT images at end-inspiration were fused with FHLs for 103 patients. Three-dimensional US data containing FHLs were obtained during end-inspiratory/expiratory phases. Multivariate analysis revealed that diaphragm motion (p < 0.001), chronic liver disease (p = 0.02) and the absolute difference in distance between the FHL and the central portal vein (CPV) during respiration (p = 0.03) were the independent factors that revealed the maximum effect on RE. In contrast, diaphragm motion (p < 0.001) and distance between the FHL and CPV at inspiration (p = 0.036) revealed the maximum effect on FHL motion. In conclusion, RE and FHL motion are affected by the degree of respiratory movement and the location of the FHL. Therefore, image fusion with CT images should be used with caution if the degree of respiratory motion is significant or if the FHL is located at the periphery of the liver. PMID- 28641912 TI - A 2-Year Holistic Health and Stress Intervention: Results of an RCT in Clergy. AB - INTRODUCTION: This study sought to determine the effect of a 2-year, multicomponent health intervention (Spirited Life) targeting metabolic syndrome and stress simultaneously. DESIGN: An RCT using a three-cohort multiple baseline design was conducted in 2010-2014. SETTING/PARTICIPANTS: Participants were United Methodist clergy in North Carolina, U.S., in 2010, invited based on occupational status. Of invited 1,745 clergy, 1,114 consented, provided baseline data, and were randomly assigned to immediate intervention (n=395), 1-year waitlist (n=283), or 2-year waitlist (n=436) cohorts for a 48-month trial duration. INTERVENTION: The 2-year intervention consisted of personal goal setting and encouragement to engage in monthly health coaching, an online weight loss intervention, a small grant, and three workshops delivering stress management and theological content supporting healthy behaviors. Participants were not blinded to intervention. MAIN OUTCOME MEASURES: Trial outcomes were metabolic syndrome (primary) and self-reported stress and depressive symptoms (secondary). Intervention effects were estimated in 2016 in an intention-to-treat framework using generalized estimating equations with adjustment for baseline level of the outcome and follow-up time points. Log-link Poisson generalized estimating equations with robust SEs was used to estimate prevalence ratios (PRs) for binary outcomes; mean differences were used for continuous/score outcomes. RESULTS: Baseline prevalence of metabolic syndrome was 50.9% and depression was 11.4%. The 12-month intervention effect showed a benefit for metabolic syndrome (PR=0.86, 95% CI=0.79, 0.94, p<0.001). This benefit was sustained at 24 months of intervention (PR=0.88; 95% CI=0.78, 1.00, p=0.04). There was no significant effect on depression or stress scores. CONCLUSIONS: The Spirited Life intervention improved metabolic syndrome prevalence in a population of U.S. Christian clergy and sustained improvements during 24 months of intervention. These findings offer support for long-duration behavior change interventions and population-level interventions that allow participants to set their own health goals. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov NCT01564719. PMID- 28641913 TI - A five year review of paediatric burns and social deprivation: Is there a link? AB - AIM: To establish if there is a correlation between burn incidence and social deprivation in order to formulate a more effective burns prevention strategy. METHODS: A quantitative retrospective review of International Burn Injury Database (IBID) was carried out over a period from 2006 to 2011 to obtain data for children referred to our burns centre in West Midlands. Social deprivation scores for geographical areas were obtained from Office of National Statistics (ONS). Statistical analysis was carried out using Graphpad Prism. RESULTS: 1688 children were reviewed at our burns centre. Statistical analysis using Pearson correlation coefficient showed a slight association between social deprivation and increasing burn incidence r2=0.1268, 95% confidence interval 0.018-0.219, p value<0.0001. There was a slight male preponderance (58%). The most common mechanism of injury was scalding (61%). The most commonly affected age group were 1-2 year olds (38%). There were statistically significant differences in the ethnicity of children with significantly more children from Asian and African backgrounds being referred compared to Caucasian children. We found that appropriate first aid was administered in 67% of cases overall. We did not find a statistically significant link between first aid provision and social deprivation score. DISCUSSION: There was only a slight positive correlation between social deprivation and burn incidence. However, there did not seem to be any change in mechanism of burn in the most deprived groups compared to overall pattern, nor was there a significant difference in appropriate first aid provision. CONCLUSION: It would seem that dissemination of burn prevention strategies and first aid advice need to be improved across all geographical areas as this was uniformly lacking and the increased burn incidence in more socially deprived groups, although present, was not statistically significant. PMID- 28641914 TI - Interactive home telehealth and burns: A pilot study. AB - OBJECTIVE: The objective of this study is to review our experience incorporating Interactive Home Telehealth (IHT) visits into follow-up burn care. METHODS: A retrospective review of all burn patients participating in IHT encounters over the course of 15 months was performed. Connections were established through secure video conferencing and call-routing software. Patients connected with a personal computer or tablet and providers connected with a desktop computer with a high-definition web camera. In some cases, high-definition digital images were emailed to the provider prior to the virtual consultation. For each patient, the following was collected: (1) patient and injury demographics (diagnosis, prognosis, and clinical management), (2) total number of encounters, (3) service for each encounter (burn, psychiatry, and rehabilitation), (4) length of visit, including travel distance and time saved and, (5) complications, including re admissions and connectivity issues. RESULTS: 52 virtual encounters were performed with 31 patients during the first year of the pilot project from March 2015 to June 2016. Mean age of the participant was 44 years (range 18-83 years). Mean total burn surface area of the participant was 12% (range 1-80%). Average roundtrip travel distance saved was 188 miles (range 4-822 miles). Average round trip travel time saved was 201min (range 20-564min). There were no unplanned re admissions and no complications. Five connectivity issues were reported, none of which prevented completion of the visit. CONCLUSIONS: Interactive Home Telehealth is a safe and feasible modality for delivering follow-up care to burn patients. Burn care providers benefit from the potential to improve outpatient clinic utilization. Patients benefit from improved access to multiple members of their specialized burn care team, as well as cost-reductions for patient travel expenses. Future studies are needed to ensure patient and provider satisfaction and to further validate the significance, cost-effectiveness and safety. PMID- 28641916 TI - Methylated spirit burns following traditional hair dressing practice. AB - Methylated spirit burns have been reported following domestic uses such as igniting fondues. It has also been used as an accelerant for self-immolation. We report the first documented case of severe methylated spirit burns sustained during traditional hair dressing. Increased awareness on the dangers of methylated spirit as well as making it less readily available for domestic use is warranted. PMID- 28641915 TI - The antimicrobial spectrum of Xeroform(r). AB - INTRODUCTION/BACKGROUND: Xeroform(r) is a petrolatum-based fine mesh gauze containing 3% bismuth tribromophenate. Bismuth, similar to other metals, has antimicrobial properties. Xeroform(r) has been used for decades in burn and plastic surgery as a donor site dressing and as a covering for wounds or partial thickness burns. Despite this, the antimicrobial spectrum of Xeroform(r) remains largely unknown. We examined the in-vitro efficacy of Xeroform(r) against common burn pathogens using zone-of-inhibition methodology in a commercial research facility. METHODS/DESIGN: Pure strains of 15 common burn pathogens including Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-sensitive Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Pseudomonas aeruginosa, Enterobacter cloacae, Escherichia coli, Candida albicans, Vancomycin resistant Enterococcus, Acinetobacter baumennii, Klebsiella pneumonia, Extended spectrum beta-lactamase producing Klebsiella, Beta hemolytic Streptococcus pyogenes, Proteus mirabilis, Serratia marcescens, and Salmonella enterica ssp. Enterica were inoculated at a strength of 106-1010 CFU/ml onto appropriate agar plates. A sterile 1 in2 Xeroform(r) square was placed in the center of each plate, and the Zone of Inhibition (ZOI) was measured following 18-24h of incubation at 37 degrees C. A second bismuth pharmaceutical (bismuth subsalicylate, Pepto Bismol(r)) was then tested using the same methodology against the same strains of MRSA, MSSA, E. coli, K. pneumonia and S. marcescens. Finally, 3% w/v bismuth tribromophenate in glycerol suspension was tested against 13 burn pathogens for antimicrobial activity independent of the Xeroform(r) dressing by measure of Zone of Inhibition. RESULTS/FINDINGS: For Xeroform(r), none of the fifteen pathogens had a measurable zone of inhibition on any plate. Bismuth subsalicylate showed a zone of inhibition for MSSA in 3 plates (mean of 47.2mm), in one of three plates for MRSA (13.8mm), and in one of three plates for S. marcesens (89.6mm). There was no zone of inhibition seen for K. pneumonia or E. coli. Bismuth tribromophenate, when not bound to Xeroform(r) showed activity against 12 of 13 pathogens. CONCLUSIONS/IMPLICATIONS: While bismuth subsalicylate, and bismuth tribromophenate unbound to Xeroform(r) demonstrate antimicrobial activity, it appears that Xeroform(r) dressings do not. The utility of Xeroform(r) in burn medicine may relate more to use as an impervious dressing than to antimicrobial effect. Donor sites are clean surgical wounds and clean partial thickness burns may have minimal colonization present. In such circumstances, an inactive and impervious dressing may be all that is necessary to promote wound healing. PMID- 28641917 TI - Complications in tissue expansion: A logistic regression analysis for risk factors. AB - BACKGROUND: Tissue expansion is frequently used in reconstructive surgery. Although the surgical procedure is typically considered simple, reported complication rates of tissue expansions exceed 40%. There is little evidence concerning risk factors for complications in tissue expansion in body regions other than breast. The aim was to determine risk factors for complications in non breast tissue expansion. METHODS: 34 patients treated with subcutaneous tissue expanders between 2005 and 2014 were analyzed. Demographic data, body-mass index (BMI), mean arterial blood pressure (MAP), treatment indications, expansion site, previous expansion therapies in the same body region, smoking history, as well as expander characteristics (shape, volume, and filling mechanism) were ascertained. Complications were assessed and ranked according to severity based on the Clavien Dindo classification. Binary logistic regression analysis adjusted for clinical characteristics was used. A p<0.05 was considered as statistically significant. RESULTS: Complications were observed in 26 out of 71 expanders analyzed (36.6%), of whom 10 led to therapy failure. Expanders used in the limbs, female gender, and high expander volume turned out as significant risk factors. Patients with both a high MAP and low BMI developed tissue necrosis significantly more often (p=0.002). The use of tissue expansion after a burn was not associated with an increased risk for complications. CONCLUSIONS: This is the first study revealing female gender and low BMI as risk factors in tissue expander surgery. Thus, careful patient selection is mandatory to avoid complications in tissue expansion. Burn patients do not develop complications more often. PMID- 28641918 TI - Resistance of mice to Leptospira infection and correlation with chemokine response. AB - Leptospirosis is globally widespread neglected disease, affecting most mammalian species. Clinical signs can be confused with other diseases which make the diagnosis and treatment difficult. Chemokines and cytokines are known for their role in the inflammatory and immune response to infections. The profile determination of chemokines' expressions in the course of infection may elucidate the defense mechanisms of the host and support the search for effective treatment strategies. We investigated the mechanisms of innate immunity through the comparison of chemokines induced during infection with L. interrogans in mice with different levels of susceptibility. We used lung and spleen tissues samples of mice from C3H/HeJ, C3H/HePas and Balb/c, respectively sensitive, intermediate susceptibility and resistant to the pathogen. The inoculation of L. interrogans in C3H/HeJ mice led a comparatively smaller change in chemokines expression in both spleen and lung tissues. In samples from spleens and lungs of C3H/HePas and Balb/c the higher increases occurred on CXCL9, CXCL16, CXCL5, CCL8 and CCL5 in Balb/c. Given the same genetic background, the differences in the responses of C3H/HePas compared to C3H/HeJ mice strongly suggest the role of chemokines for the survival of parental strain. Therefore, the greatest increase in CXC chemokines appears to be efficient to induce migration of cells to the secondary lymphoid organs and affected tissues, which is important to control infection. Overall, CXC chemokines are important for the activation and attraction of T cell and may influence the course and control of the infection in resistant Balb/c mice. PMID- 28641919 TI - Prevalence of Candida africana and Candida dubliniensis, in vulvovaginal candidiasis: First Turkish Candida africana isolates from vulvovaginal candidiasis. AB - INTRODUCTION: Candida africana and C. dubliniensis are closely related species of C. albicans. Current phenotypic methods are not suitable to accurately distinguish all the species belonging to the C. albicans complex. Several molecular-based methods have recently been designed for discriminating among closely related Candida species. The aim of this study was to establish the prevalence of C. dubliniensis and C. africana in vulvovaginal samples with phenotypic and genotypic methods. MATERIALS AND METHODS: We re-examined 376 vulvovaginal C. albicans complex isolates. All the isolates were identified with morphological features and HWP1 gene polymorphisms. ITS and D1/D2 sequencing, carbohydrate assimilation, MALDI-TOF MS profiles and antifungal susceptibilities were evaluated for C. africana and C. dubliniensis isolates. RESULTS: Of the 376 isolates, three C. africana and three C. dubliniensis isolates (0.8% and 0.8% prevalence, respectively) were identified by molecular methods (HPW1, ITS and D1/D2) Phenotypically, C. africana differed from C. albicans and C. dubliniensis by formation of no/rare pseudohyphae, absence of chlamydospores and, the development of turquoise green colonies on CHROMagar. MALDI-TOF MS and API ID 32C could not revealed C. africana isolates. C. africana and C. dubliniensis isolates showed very low MIC values for all the tested antifungals. DISCUSSION: This first report of C. africana from Turkey provides additional data for epidemiological, phenotypic features and antimicrobial susceptibility profiles. This study also highlights the importance of using genotypic methods in combination with phenotypic methods. PMID- 28641920 TI - [Ortographic standarization]. PMID- 28641921 TI - Genome-wide association and interaction studies of CSF T-tau/Abeta42 ratio in ADNI cohort. AB - The pathogenic relevance in Alzheimer's disease (AD) presents a decrease of cerebrospinal fluid amyloid-beta42 (Abeta42) burden and an increase in cerebrospinal fluid total tau (T-tau) levels. In this work, we performed genome wide association study (GWAS) and genome-wide interaction study of T-tau/Abeta42 ratio as an AD imaging quantitative trait on 843 subjects and 563,980 single nucleotide polymorphisms (SNPs) in ADNI cohort. We aim to identify not only SNPs with significant main effects but also SNPs with interaction effects to help explain "missing heritability". Linear regression method was used to detect SNP SNP interactions among SNPs with uncorrected p-value <=0.01 from the GWAS. Age, gender, and diagnosis were considered as covariates in both studies. The GWAS results replicated the previously reported AD-related genes APOE, APOC1, and TOMM40, as well as identified 14 novel genes, which showed genome-wide statistical significance. Genome-wide interaction study revealed 7 pairs of SNPs meeting the cell-size criteria and with bonferroni-corrected p-value <=0.05. As we expect, these interaction pairs all had marginal main effects but explained a relatively high-level variance of T-tau/Abeta42, demonstrating their potential association with AD pathology. PMID- 28641922 TI - Diffusion weighted imaging and time in acute ischemic stroke, is there any relation? AB - BACKGROUND AND PURPOSE: Diffusion-weighted MRI (DWI) is useful for patient selection during the first 6hours after stroke onset. The main aim of this study was to investigate the relationship between the time from stroke symptom onset and stroke volume assessed using DWI. MATERIALS AND METHODS: We evaluated 203 patients with anterior circulation stroke who were admitted to Montpellier's Stroke Unit and for whom a DWI ASPECT score (DWI-ASPECTS) was obtained during the first 6hours from symptom onset. Patients were classified according to the number of hours after the onset of symptoms that DWI was performed. Two experienced neuroradiologists independently calculated the DWI-ASPECTS, which was classified by the size of the stroke volume in three groups: 0-3, 4-6 and 7-10. RESULTS: No relationship was found between temporal groups and the DWI-ASPECTS. The number of patients who reached each of the 3 classified stroke volumes was not different between the temporal groups. CONCLUSION: There is no correlation in our findings between the time of stroke symptom onset and the DWI-ASPECT score during the first 6hours from stroke onset. PMID- 28641923 TI - Rhodobacteraceae on the marine brown alga Fucus spiralis are abundant and show physiological adaptation to an epiphytic lifestyle. AB - Macroalgae harbour specific microbial communities on their surface that have functions related to host health and defence. In this study, the bacterial biofilm of the marine brown alga Fucus spiralis was investigated using 16S rRNA gene amplicon-based analysis and isolation of bacteria. Rhodobacteraceae (Alphaproteobacteria) were the predominant family constituting 23% of the epibacterial community. At the genus level, Sulfitobacter, Loktanella, Octadecabacter and a previously undescribed cluster were most abundant, and together they comprised 89% of the Rhodobacteraceae. Supported by a specific PCR approach, 23 different Rhodobacteraceae-affiliated strains were isolated from the surface of F. spiralis, which belonged to 12 established and three new genera. For seven strains, closely related sequences were detected in the 16S rRNA gene dataset. Growth experiments with substrates known to be produced by Fucus spp. showed that all of them were consumed by at least three strains, and vitamin B12 was produced by 70% of the isolates. Since growth of F. spiralis depends on B12 supplementation, bacteria may provide the alga with this vitamin. Most strains produced siderophores, which can enhance algal growth under iron-deficient conditions. Inhibiting properties against other bacteria were only observed when F. spiralis material was present in the medium. Thus, the physiological properties of the isolates indicated adaption to an epiphytic lifestyle. PMID- 28641924 TI - Random survival forest with space extensions for censored data. AB - Prediction capability of a classifier usually improves when it is built from an extended variable space by adding new variables from randomly combination of two or more original variables. However, its usefulness in survival analysis of censored time-to-event data is yet to be verified. In this research, we investigate the plausibility of space extension technique, originally proposed for classification purpose, to survival analysis. By combing random subspace, bagging and extended space techniques, we develop a random survival forest with space extensions algorithm. According to statistical analysis results, we show that the proposed model outperforms or at least comparable to popular survival models such as random survival forest, rotation survival forest, Cox proportional hazard and boosting survival models on well-known benchmark datasets. PMID- 28641925 TI - Safety, pharmacokinetics and sialic acid production after oral administration of N-acetylmannosamine (ManNAc) to subjects with GNE myopathy. AB - GNE myopathy is a rare, autosomal recessive, inborn error of sialic acid metabolism, caused by mutations in GNE, the gene encoding UDP-N-acetyl glucosamine-2-epimerase/N-acetylmannosamine kinase. The disease manifests as an adult-onset myopathy characterized by progressive skeletal muscle weakness and atrophy. There is no medical therapy available for this debilitating disease. Hyposialylation of muscle glycoproteins likely contributes to the pathophysiology of this disease. N-acetyl-D-mannosamine (ManNAc), an uncharged monosaccharide and the first committed precursor in the sialic acid biosynthetic pathway, is a therapeutic candidate that prevents muscle weakness in the mouse model of GNE myopathy. We conducted a first-in-human, randomized, placebo-controlled, double blind, single-ascending dose study to evaluate safety and pharmacokinetics of ManNAc in GNE myopathy subjects. Single doses of 3 and 6g of oral ManNAc were safe and well tolerated; 10g was associated with diarrhea likely due to unabsorbed ManNAc. Oral ManNAc was absorbed rapidly and exhibited a short half life (~2.4h). Following administration of a single dose of ManNAc, there was a significant and sustained increase in plasma unconjugated free sialic acid (Neu5Ac) (Tmax of 8-11h). Neu5Ac levels remained above baseline 48h post-dose in subjects who received a dose of 6 or 10g. Given that Neu5Ac is known to have a short half-life, the prolonged elevation of Neu5Ac after a single dose of ManNAc suggests that intracellular biosynthesis of sialic acid was restored in subjects with GNE myopathy, including those homozygous for mutations in the kinase domain. Simulated plasma concentration-time profiles support a dosing regimen of 6g twice daily for future clinical trials. PMID- 28641927 TI - From Prokaryotes to Cancer: Glutamine Flux in Multicellular Units. AB - Bacteria in nature reside in organized communities, termed biofilms, which are composed of multiple individual cells adhering to each other. Similarly, tumors are a multicellular mass with distinct cellular phenotypes. Both tumors and biofilms are considered to be an active interphase between unicellular and multicellular life states. Because both of these units depend on glutamine for growth and survival, we review here glutamine flux within them as a readout for intra- and inter-commensal metabolism. We suggest that the difference between glutamine fluxes in these cellular communities lies mainly in their global multicellular metabolic organization. Both the differences and similarities described here should be taken into account when considering glutamine-targeting therapeutic approaches. PMID- 28641926 TI - Targeting the GM-CSF receptor for the treatment of CNS autoimmunity. AB - In multiple sclerosis (MS), there is a growing interest in inhibiting the pro inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Ralpha) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Ralpha blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM CSF Ralpha+ myeloid cells. Collectively, this study reveals a pivotal role of GM CSF in disease relapses and the benefit of GM-CSF Ralpha blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS. PMID- 28641929 TI - Initiation and Engagement with Methadone Treatment among Pregnant and Postpartum Women. AB - PURPOSE: The purpose of this study was to explore perceptions of experiences and challenges with methadone maintenance treatment (MMT) and obstetrical care among pregnant and postpartum women enrolled in a methadone maintenance program. RESEARCH DESIGN: The study featured a grounded theory approach including two focus groups with pregnant and postpartum methadone users at a methadone maintenance clinic in Worcester, Massachusetts. Two research team members conducted and recorded focus groups, which took approximately 45 minutes to 1 hour. Grounded theory was used to guide data analysis and open coding, where transcripts were reviewed line by line to create code definitions as concepts emerged inductively from the data. RESULTS: Five emergent themes were derived from the data: 1) guilt, coupled with fear of negative outcomes for their infant, dictates women's MMT treatment decisions; 2) finding obstetricians with experience treating pregnant women using methadone can be a challenge; 3) methadone clinic physicians are instrumental in helping women find the right methadone dose during pregnancy; 4) some women had strong preferences for methadone over buprenorphine; and 5) women face substantial substance abuse treatment challenges after delivery. CONCLUSIONS: Women experience substantial challenges engaging in MMT during the perinatal period. Additional challenges arise from finding obstetrical providers who have experience with MMT and are willing to care for pregnant women. This study may provide a starting point for future interventions seeking to improve care coordination between substance abuse treatment and prenatal care programs. PMID- 28641931 TI - Transfer of Antibiotic Resistance in Staphylococcus aureus. AB - Staphylococcus aureus is a serious human pathogen with remarkable adaptive powers. Antibiotic-resistant clones rapidly emerge mainly by acquisition of antibiotic-resistance genes from other S. aureus strains or even from other genera. Transfer is mediated by a diverse complement of mobile genetic elements and occurs primarily by conjugation or bacteriophage transduction, with the latter traditionally being perceived as the primary route. Recent work on conjugation and transduction suggests that transfer by these mechanisms may be more extensive than previously thought, in terms of the range of plasmids that can be transferred by conjugation and the efficiency with which transduction occurs. Here, we review the main routes of antibiotic resistance gene transfer in S. aureus in the context of its biology as a human commensal and a life threatening pathogen. PMID- 28641928 TI - BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development. AB - Craniosynostosis is caused by premature fusion of one or more sutures in an infant skull, resulting in abnormal facial features. The molecular and cellular mechanisms by which genetic mutations cause craniosynostosis are incompletely characterized, and many of the causative genes for diverse types of syndromic craniosynostosis have not yet been identified. We previously demonstrated that augmentation of BMP signaling mediated by a constitutively active BMP type IA receptor (ca-BmpR1A) in neural crest cells (ca1A hereafter) causes craniosynostosis and superimposition of heterozygous null mutation of Bmpr1a rescues premature suture fusion (ca1A;1aH hereafter). In this study, we superimposed heterozygous null mutations of the other two BMP type I receptors, Bmpr1b and Acvr1 (ca1A;1bH and ca1A;AcH respectively hereafter) to further dissect involvement of BMP-Smad signaling. Unlike caA1;1aH, ca1A;1bH and ca1A;AcH did not restore the craniosynostosis phenotypes. In our in vivo study, Smad dependent BMP signaling was decreased to normal levels in mut;1aH mice. However, BMP receptor-regulated Smads (R-Smads; pSmad1/5/9 hereafter) levels were comparable between ca1A, ca1A;1bH and ca1A;AcH mice, and elevated compared to control mice. Bmpr1a, Bmpr1b and Acvr1 null cells were used to examine potential mechanisms underlying the differences in ability of heterozygosity for Bmpr1a vs. Bmpr1b or Acvr1 to rescue the mut phenotype. pSmad1/5/9 level was undetectable in Bmpr1a homozygous null cells while pSmad1/5/9 levels did not decrease in Bmpr1b or Acvr1 homozygous null cells. Taken together, our study indicates that different levels of expression and subsequent activation of Smad signaling differentially contribute each BMP type I receptor to BMP-Smad signaling and craniofacial development. These results also suggest differential involvement of each type 1 receptor in pathogenesis of syndromic craniosynostoses. PMID- 28641930 TI - The Role of the Fungal Cell Wall in the Infection of Plants. AB - The polysaccharide-rich wall, which envelopes the fungal cell, is pivotal to the maintenance of cellular integrity and for the protection of the cell from external aggressors - such as environmental fluxes and during host infection. This review considers the commonalities in the composition of the wall across the fungal kingdom, addresses how little is known about the assembly of the polysaccharide matrix, and considers changes in the wall of plant-pathogenic fungi during on and in planta growth, following the elucidation of infection structures requiring cell wall alterations. It highlights what is known about the phytopathogenic fungal wall and what needs to be discovered. PMID- 28641932 TI - Myositis ossificans in elbow mimicking soft tissue sarcoma: Similar clinical and radiological findings. PMID- 28641933 TI - The role of sleep in regulating structural plasticity and synaptic strength: Implications for memory and cognitive function. AB - Dendritic spines are the major sites of synaptic transmission in the central nervous system. Alterations in the strength of synaptic connections directly affect the neuronal communication, which is crucial for brain function as well as the processing and storage of information. Sleep and sleep loss bidirectionally alter structural plasticity, by affecting spine numbers and morphology, which ultimately can affect the functional output of the brain in terms of alertness, cognition, and mood. Experimental data from studies in rodents suggest that sleep deprivation may impact structural plasticity in different ways. One of the current views, referred to as the synaptic homeostasis hypothesis, suggests that wake promotes synaptic potentiation whereas sleep facilitates synaptic downscaling. On the other hand, several studies have now shown that sleep deprivation can reduce spine density and attenuate synaptic efficacy in the hippocampus. These data are the basis for the view that sleep promotes hippocampal structural plasticity critical for memory formation. Altogether, the impact of sleep and sleep loss may vary between regions of the brain. A better understanding of the role that sleep plays in regulating structural plasticity may ultimately lead to novel therapeutic approaches for brain disorders that are accompanied by sleep disturbances and sleep loss. PMID- 28641934 TI - Radiology Resident Education: In Defense of the Socratic Method. PMID- 28641935 TI - Fatty Acid-Modified Gapmer Antisense Oligonucleotide and Serum Albumin Constructs for Pharmacokinetic Modulation. AB - Delivery technologies are required for realizing the clinical potential of molecular medicines. This work presents an alternative technology to preformulated delivery systems by harnessing the natural transport properties of serum albumin using endogenous binding of gapmer antisense oligonucleotides (ASOs)/albumin constructs. We show by an electrophoretic mobility assay that fatty acid-modified gapmer and human serum albumin (HSA) can self-assemble into constructs that offer favorable pharmacokinetics. The interaction was dependent on fatty acid type (either palmitic or myristic acid), number, and position within the gapmer ASO sequence, as well as phosphorothioate (PS) backbone modifications. Binding correlated with increased blood circulation in mice (t1/2 increased from 23 to 49 min for phosphodiester [PO] gapmer ASOs and from 28 to 66 min for PS gapmer ASOs with 2* palmitic acid modification). Furthermore, a shift toward a broader biodistribution was detected for PS compared with PO gapmer ASOs. Inclusion of 2* palmitoyl to the ASOs shifted the biodistribution to resemble that of natural albumin. This work, therefore, presents a novel strategy based on the proposed endogenous assembly of gapmer ASOs/albumin constructs for increased circulatory half-life and modulation of the biodistribution of gapmer ASOs that offers tunable pharmacokinetics based on the gapmer modification design. PMID- 28641937 TI - Learning disability in a son and premature ovarian failure as clinical pointers to identify a premutation on the X chromosome in a female with long-standing tremor. PMID- 28641936 TI - Combined vaginoplasty technique for male-to-female sex reassignment surgery: Operative approach and outcomes. AB - BACKGROUND: Several therapy options exist for male-to-female (MTF) transgenders desiring sex reassignment. Surgery includes numerous different procedures. Of those, vaginoplasty is predominant and aims at providing attractive esthetics and fully functional genitals. This study aimed to present the surgical results of our modified combined vaginoplasty technique in a consecutive patient cohort. METHODS: We included 40 MTF transgender patients who underwent a two-stage sex reassignment surgery (SRS) in an observational prospective study between September 2012 and January 2014. Demographic characteristics, medical and surgical history, operative details, and outcomes after surgery were documented. Postoperatively, 23 patients received a pelvic examination following the standardized protocol. RESULTS: Measured vaginal depth was 11.77-14.99 cm depending on the size of the dilator used (25-40 mm). Vaginal, clitoral, and labial sensitivities were intact and favorable in all examined patients. Nineteen women (47.5%) opted for breast augmentations to achieve a feminine cosmesis, making it the most common nongenital operation. Complications were mostly minor and temporary. Severe adverse events, such as wound infections (n = 3), colon injuries (3), short (1) or narrow (1) vaginas, or partial clitoral necroses (1), were rare and immediately addressed by the surgical team. No vaginal construction was lost, and no secondary reconstructive approaches were required. CONCLUSION: Satisfactory physical results and favorable low rates of complications endorse our combined technique for MTF SRS. These findings, however, need to be confirmed by other research groups as well. Therefore, in our opinion, MTF SRS remains an evolving area of development, whose research is aiming to establish a state-of the-art surgical technique. PMID- 28641938 TI - Administration of a leptin antagonist during the neonatal leptin surge induces alterations in the redox and inflammatory state in peripubertal /adolescent rats. AB - The importance of the neonatal leptin surge in rodents in neurodevelopmental processes has aroused curiosity in its implication in other physiological systems. Given the role of leptin in neuro-immune interactions, we hypothesized that the neonatal leptin surge could have an effect on the oxidative and inflammatory stress situations of both systems. We blocked the neonatal leptin surge by a leptin antagonist and measured several parameters of oxidative and inflammatory stress in the spleen, hypothalamus and adipose tissue of peripubertal/adolescent rats. The treated rats showed lower activity of several antioxidant enzymes in the spleen and their leukocytes released lower levels of mitogen-stimulated IL-10 and IL-13 and higher levels of TNF-alpha. In conclusion, the neonatal leptin surge may have a key role in the establishment of adequate redox and inflammatory states in the immune system, which is important for the generation of adequate immune responses and to obtain and maintain good health. PMID- 28641939 TI - Low-molecular-weight protein tyrosine phosphatase expression as a prognostic factor for men with metastatic hormone-naive prostate cancer. AB - OBJECTIVES: Recent studies have demonstrated that up-front docetaxel combined with androgen deprivation therapy (ADT) prolongs survival in some patients with metastatic hormone-naive prostate cancer (mHNPC). However, new biomarkers for selecting personalized treatment strategies for mHNPC are warranted. We evaluated the value of low-molecular-weight protein tyrosine phosphatase (LMW-PTP) expression as a prognosticator in men with mHNPC. METHODS AND MATERIALS: A total of 48 men with mHNPC diagnosed from 2003 to 2009 were enrolled in this study. Prostate cancer tissues obtained by needle biopsies were immunohistochemically stained for LMW-PTP. Correlations between LMW-PTP expression and clinicopathological characteristics were then assessed. RESULTS: At the time of analysis, 29 (60.4%) patients were alive, whereas 15 (31.3%) and 4 (8.3%) died of prostate cancer and nonprostate cancer, respectively. Of these, 29 (60.4%) had low LMW-PTP expression and 19 (39.6%) had high expression. Median overall survival (OS) for patients with high LMW-PTP expression was not reached and that for patients with low LMW-PTP expression was 23.8 months. High LMW-PTP expression was significantly correlated with a shorter OS compared with low LMW-PTP expression (P = 0.01). Moreover, multivariate analysis showed that Gleason score (>=8 vs.<=7; HR = 5.8, 95% CI: 1.3-26.5, P = 0.02) and LMW-PTP expression (high vs. low; HR = 2.7, 95% CI: 1.0-7.2, P = 0.04) were independent prognostic factors for OS. CONCLUSIONS: LMW-PTP is a potential biomarker to predict OS in patients with mHNPC. PMID- 28641940 TI - Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development. AB - DNA replication is a prerequisite for cell proliferation, yet it can be increasingly challenging for a eukaryotic cell to faithfully duplicate its genome as its size and complexity expands. Dormant origins now emerge as a key component for cells to successfully accomplish such a demanding but essential task. In this perspective, we will first provide an overview of the fundamental processes eukaryotic cells have developed to regulate origin licensing and firing. With a special focus on mammalian systems, we will then highlight the role of dormant origins in preventing replication-associated genome instability and their functional interplay with proteins involved in the DNA damage repair response for tumor suppression. Lastly, deficiencies in the origin licensing machinery will be discussed in relation to their influence on stem cell maintenance and human diseases. PMID- 28641941 TI - Role of recombination and replication fork restart in repeat instability. AB - Eukaryotic genomes contain many repetitive DNA sequences that exhibit size instability. Some repeat elements have the added complication of being able to form secondary structures, such as hairpin loops, slipped DNA, triplex DNA or G quadruplexes. Especially when repeat sequences are long, these DNA structures can form a significant impediment to DNA replication and repair, leading to DNA nicks, gaps, and breaks. In turn, repair or replication fork restart attempts within the repeat DNA can lead to addition or removal of repeat elements, which can sometimes lead to disease. One important DNA repair mechanism to maintain genomic integrity is recombination. Though early studies dismissed recombination as a mechanism driving repeat expansion and instability, recent results indicate that mitotic recombination is a key pathway operating within repetitive DNA. The action is two-fold: first, it is an important mechanism to repair nicks, gaps, breaks, or stalled forks to prevent chromosome fragility and protect cell health; second, recombination can cause repeat expansions or contractions, which can be deleterious. In this review, we summarize recent developments that illuminate the role of recombination in maintaining genome stability at DNA repeats. PMID- 28641944 TI - Effect of antimony-oxide on the shielding properties of some sodium-boro-silicate glasses. AB - Some sodium-silicate-boro-antimonate glasses having the molecular composition [(20) Na2O - (20) SiO2 - (60-x) B2O3 - (x) Sb2O3 (where x takes the values 0, 5 ... or 20)] have been prepared by the melt quenching method. The melting and annealing temperatures were 1500 and 650K respectively. The amorphous nature of the prepared samples was confirmed by using X-ray diffraction analysis. Both the experimental and empirical density and molar volume values showed gradual increase with increasing Sb2O3 content. The empirical densities showed higher values than those obtained experimentally, while the empirical molar volume values appeared lower than those obtained experimentally, which confirm the amorphous nature and randomness character of the studied samples. The experimentally obtained shielding parameters were approximately coincident with those obtained theoretically by applying WinXCom program. At low gamma-ray energies (0.356 and 0.662MeV) Sb2O3 has approximately no effect on the total Mass Attenuation Coefficient, while at high energies it acts to increase the total Mass Attenuation Coefficient gradually. The obtained Half Value Layer and Mean Free Path values showed gradual decrease as Sb2O3 was gradually increased. Also, the Total Mass Attenuation Coefficient values obtained between about 0.8 and 3.0MeV gamma-ray energy showed a slight decrease, as gamma-ray photon energy increased. This may be due to the differences between the Attenuation Coefficients of both antimony and boron oxides at various gamma-ray photon energies. However, it can be stated that the addition of Sb2O3 into sodium-boro silicate glasses increases the gamma-ray Attenuation Coefficient and the best sample is that contains 20 mol% of Sb2O3, which is operating well at 0.356 and 0.662MeV gamma-ray. PMID- 28641942 TI - The Top1 paradox: Friend and foe of the eukaryotic genome. AB - Topoisomerases manage the torsional stress associated with the separation of DNA strands during transcription and DNA replication. Eukaryotic Topoisomerase I (Top1) is a Type IB enzyme that nicks and rejoins only one strand of duplex DNA, and it is especially important during transcription. By resolving transcription associated torsional stress, Top1 reduces the accumulation of genome destabilizing R-loops and non-B DNA structures. The DNA nicking activity of Top1, however, can also initiate genome instability in the form of illegitimate recombination, homologous recombination and mutagenesis. In this review, we focus on the diverse, and often opposing, roles of Top1 in regulating eukaryotic genome stability. PMID- 28641946 TI - He who rests, rusts. PMID- 28641945 TI - Surveillance after positive colonoscopy based on adenoma characteristics. AB - BACKGROUND: Patients with adenomatous polyps are at increased risk for developing colorectal cancer based on the characteristics and number of polyps, but less is known about the individual and combined contribution of these factors. This study aimed to better characterize the risk of advanced adenoma and cancer in patients with positive baseline colonoscopy. METHODS: Patients who had polyps at baseline colonoscopy were included in this retrospective cohort study (N=1165) and were categorized into 6 groups: (1) 1-2 non-advanced adenomas (NAA's), (2) >=3 NAA's, (3) advanced tubular adenoma, (4) small tubulovillous adenoma (TVA), (5) large TVA and (6) multiple advanced adenomas (MAA's). Findings at surveillance colonoscopy were documented in each group. RESULTS: The combined incidence of advanced adenoma, >=3 NAA's, and colorectal cancer at surveillance colonoscopy was significantly higher in the baseline large TVA (29.2%) than small TVA groups (13.5%, P<0.001), as well as in the MAA's group (44.1%) compared with large TVA group (P=0.02). The incidence of colorectal cancer, however, was not significantly different between the groups. CONCLUSIONS: The size of the polyp and the number of advanced lesions are more important than its histology for predicting the risk of high-risk metachronous lesions at follow-up. PMID- 28641943 TI - Template-switching during replication fork repair in bacteria. AB - Replication forks frequently are challenged by lesions on the DNA template, replication-impeding DNA secondary structures, tightly bound proteins or nucleotide pool imbalance. Studies in bacteria have suggested that under these circumstances the fork may leave behind single-strand DNA gaps that are subsequently filled by homologous recombination, translesion DNA synthesis or template-switching repair synthesis. This review focuses on the template switching pathways and how the mechanisms of these processes have been deduced from biochemical and genetic studies. I discuss how template-switching can contribute significantly to genetic instability, including mutational hotspots and frequent genetic rearrangements, and how template-switching may be elicited by replication fork damage. PMID- 28641947 TI - Effectiveness of human spermatozoa biomarkers as indicators of structural damage during cryopreservation. AB - Human spermatozoa cryopreservation techniques are used to maintain and protect male fertility in cases such as infertility and malignancy treatments. However, during cryopreservation, the spermatozoa's metabolic rate is reduced and they undergo dramatic functional and structural changes owing to exposure to cryoprotectants and freezing-thawing procedures. While the effects of cryopreservation on cells are documented, to date the induced cryodamage on structural and/or functional sperm biomarkers is not well established at multivariate scale. To address this question, we performed basic sperm analysis, sperm DNA fragmentation assessment, spontaneous acrosome reaction measurement, and cytoskeleton evaluation after thawing samples from subjects with normal and low-quality semen. A cryodamage rate was used to determine the effects of the freeze-thaw process on spermatozoa. In addition, a Principal Component Analysis (PCA) was used for data reduction and to evaluate sperm-specific patterns during the cryopreservation process. We found that the vitality, progressive motility and sperm count from low-quality samples after cryopreservation show higher damage rates (>=40%) than in normal sperm samples. However, cytoskeleton, DNA, tail and mid-piece and acrosome display the highest cryodamage rates (~50-99%) and are equally susceptible to cryopreservation-induced damage in both low- and normal-quality semen samples. Overall, the evaluation of these parameters provides meaningful information about different aspects of sperm functionality after cryopreservation. PMID- 28641948 TI - Optimally capturing latency dynamics in models of tuberculosis transmission. AB - Although different structures are used in modern tuberculosis (TB) models to simulate TB latency, it remains unclear whether they are all capable of reproducing the particular activation dynamics empirically observed. We aimed to determine which of these structures replicate the dynamics of progression accurately. We reviewed 88 TB-modelling articles and classified them according to the latency structure employed. We then fitted these different models to the activation dynamics observed from 1352 infected contacts diagnosed in Victoria (Australia) and Amsterdam (Netherlands) to obtain parameter estimates. Six different model structures were identified, of which only those incorporating two latency compartments were capable of reproducing the activation dynamics empirically observed. We found important differences in parameter estimates by age. We also observed marked differences between our estimates and the parameter values used in many previous models. In particular, when two successive latency phases are considered, the first period should have a duration that is much shorter than that used in previous studies. In conclusion, structures incorporating two latency compartments and age-stratification should be employed to accurately replicate the dynamics of TB latency. We provide a catalogue of parameter values and an approach to parameter estimation from empiric data for calibration of future TB-models. PMID- 28641949 TI - Reduced protein expressions of cytomembrane GABAARbeta3 at different postnatal developmental stages of rats exposed prenatally to valproic acid. AB - Decreased inhibition plays an extremely important role in pathogenesis of autism spectrum disorder (ASD). Therefore, we aimed to determine whether expression levels of the gamma-aminobutyric acid type A receptor beta3 subunit (GABAARbeta3), K+-Cl- cotransporter 2 (KCC2), and Na+-K+-Cl- cotransporter 1 (NKCC1) related to inhibition transmission are changed in a sodium valproate induced rat model of ASD. Decreased expression levels of membrane GABAARbeta3 (m GABAARbeta3) and KCC2 as well as increased endocytosis of GABAARs were found in the model group. However, there were no significant differences in expression of total GABAARbeta3 and NKCC1 between the control and model groups. In addition, we observed growth retardation, impaired spatial memory, limited exploration, increased anxiety, and reduced sociability in the model group. These results suggest alterations in m-GABAARbeta3 levels, KCC2 levels, and trafficking of GABAARs in rats prenatally exposed to valproic acid and advance our understanding of the pathogenesis of ASD. PMID- 28641950 TI - Cholinergic signaling plasticity maintains viscerosensory responses during Aspiculuris tetraptera infection in mice small intestine. AB - Intestinal parasites alter gastrointestinal (GI) functions like the cholinergic function. Aspiculuris tetraptera is a pinworm frequently observed in laboratory facilities, which infests the mice cecum and proximal colon. However, little is known about the impact of this infection on the GI sensitivity. Here, we investigated possible changes in spontaneous mesenteric nerve activity and on the mechanosensitivity function of worm-free regions of naturally infected mice with A. tetraptera. Infection increased the basal firing of mesenteric afferent nerves in jejunum. Our findings indicate that nicotinic but not muscarinic receptors, similarly affect spontaneous nerve firing in control and infected animals; these axons are mainly vagal. No difference between groups was observed on spontaneous activity after nicotinic receptor inhibition. However, and contrary to the control group, during infection, the muscarinic signaling was shown to be elevated during mechanosensory experiments. In conclusion, we showed for the first time that alterations induced by infection of the basal afferent activity were independent of the cholinergic function but changes in mechanosensitivity were mediated by muscarinic, but not nicotinic, receptors and specifically by high threshold nerve fibers (activated above 20mmHg), known to play a role in nociception. These plastic changes within the muscarinic signaling would function as a compensatory mechanism to maintain a full mechanosensory response and the excitability of nociceptors during infection. These changes indicate that pinworm colonic infection can target other tissues away from the colon. PMID- 28641951 TI - Necrotizing fasciitis attended in the Emergency Department in a tertiary Hospital: Evaluation of the LRINEC scale. AB - AIM: To describe mortality and complications of patients seen in the emergency room, diagnosed with necrotizing soft tissue infection (NSTI) and the correlation of such complications with the Laboratory Risk Indicator for Necrotizing fasciitis scale (LRINEC). METHODS: Retrospective observational study including patients with a diagnosis of NSTI in the emergency room of a tertiary hospital over 7 years. The results are shown as median, interquartile range and absolute range for quantitative variables. In the case of qualitative variables, the results are shown as absolute and relative frequency. The comparison between the categories of the LRINEC scale was performed through a post-hoc comparison from a non-parametric ANOVA analysis. Comparisons between LRINEC groups in the qualitative variables were performed using Fisher's Exact test. RESULTS: 24 patients with a mean age of 51.9 years were identified. The LRINEC scale was used on 21 patients: in 10, the value indicated low risk (<6), in 4 it indicated intermediate risk (6 or 7) and in 7 it indicated high risk (>=8). The amputation rate in patients with low, intermediate and high risk was 10%, 25% and 66% respectively with a mortality of 4.2%. There was an increase in hospital stay between the low and high level of the scale (p=0,007). CONCLUSIONS: In general, a change in the prognosis between the medium and high levels of the LRINEC scale could not be recorded, but was recorded in hospital stay between the low and the high level, practically tripling the median of days of hospital stay. PMID- 28641953 TI - Is it necessary a scale to evaluate the posttraumatic psychiatric sequelae? PMID- 28641952 TI - The effect of tissue-segmented attenuation maps on PET quantification with a special focus on large arteries. AB - OBJECTIVES: Accuracy on quantitative PET image analysis relies on the correct application of attenuation correction which is one of the major challenges for PET/MRI that remains to be solved. The purpose of this study is to evaluate the effect of MRI-based attenuation maps and the use of flexible coils on the quantitative accuracy of PET images with a special focus on large arteries. MATERIALS AND METHODS: PET/CT data from eight oncologic patients was used. PET data was reconstructed using attenuation maps with different level of detail emulating several approaches available on current PET/MRI scanners. PET images obtained with CT-based and MRI-based attenuation maps were compared to evaluate the quantitative biases obtained. The quantitative effect produced by flexible MRI receiver coils on the attenuation maps was also studied. RESULTS: The use of simpler attenuation maps produced increased biases between PET data reconstructed with CT-based and MRI-based attenuation maps for fat, non-fat soft-tissues and bone. Biases in lung were very high due to the large heterogeneity and inter patient variability of the lung. The quantification on large arteries had small deviations except for the case when flexible coils were used. The TBR provided smaller biases in all cases as it cancelled out the similar deviations obtained for arteries and reference veins. CONCLUSIONS: Simplified attenuation maps used on PET/MRI significantly increase the quantitative variability of PET images especially on lungs and bones. The quantification of PET images acquired with PET/MRI scanners applied to studies of atherosclerosis has small deviations, especially when the TBR is considered. PMID- 28641954 TI - Interventional rheumatology: the competence of Brazilian rheumatologists. AB - OBJECTIVES: Describe Brazilian rheumatologists's competence in interventional rheumatology; assess the association between this ability and demographic and training variables. METHODS: A cross-sectional study with 500 Brazilian rheumatologists. Participants were assessed by self-administered questionnaire consisting of demographics, training, practice in office and knowledge in interventional rheumatology data. RESULTS: 463 participants had their data analyzed. The mean age was 40.2 years (+/-11.2). 70% had performed periarticular injections and 78% had performed intra-articular injections. The sample was divided into three groups: non-interventionist, little interventionist and very interventionist. The non-interventionist group showed (p<0.001-0.04) higher mean age, lower proportion of university bond, lower training history, higher proportion of graduates in the Southeast country, and higher proportion of graduates in the 1980s to 1989. The very interventionist group showed higher (p<0.001-0.018) proportion of adult rheumatologists, higher proportion of university bond, longer training time with greater practice of complex procedures, and higher proportion of graduates, trained and with private practice in the South country. Variables most associated with the very interventionist subgroup are performing axial intra-articular injections (OR: 7.4, p<0.001), synovial biopsy (OR: 5.75, p=0.043), image-guided IAI (OR: 4.16, p<0.001), viscosupplementation (OR=3.41, p<0.001), joint lavage (OR=3.22, p=0.019), salivary gland biopsy (OR=2.16, p=0.034) and over 6-month training (OR: 2.16, p=0.008). CONCLUSIONS: Performing more complex invasive procedures and over 6 month training in interventional rheumatology were variables associated with enhanced interventional profile. PMID- 28641955 TI - Molecular identification of novel phlebovirus sequences in European ticks. AB - In recent years the number of newly described tick-borne phleboviruses has been steadily growing. Some of these novel viruses are highly pathogenic in humans, e.g. the Heartland and severe fever with thrombocytopenia syndrome virus. We aimed to analyse ticks sampled across Europe to investigate the diversity of phleboviruses using a comprehensive PCR-based screening approach. A total of 4387 ticks were collected from the vegetation in regions of France, Belgium, Germany, Sweden, and Estonia, respectively. Ticks were pooled and 22/979 pools tested positive using a PCR targeting the large (L) segment of phleboviruses. Phylogenetic analysis of a 500-bp fragment of the L segment showed a distinct novel clade provisionally named Glabbeek/Osterholz group (Belgium and Germany). In addition, sequences from ticks sampled in France clustered together with the recently described Antigone virus from Greece and AnLuc from Portugal. Our results extend the current diversity of phleboviruses in Europe. Future research should address the ecological processes driving the occurrence of phleboviruses and the impact of these novel phleboviruses for public health. PMID- 28641956 TI - Antibacterial efficacy of nisin, bacteriophage P100 and sodium lactate against Listeria monocytogenes in ready-to-eat sliced pork ham. AB - The effectiveness of bacteriophage P100, nisin and sodium lactate, individually and in combination, in inhibiting Listeria monocytogenes in ready-to-eat pork ham slices was assessed. The antimicrobials were applied to the surfaces of ready-to eat pork ham slices, which were inoculated with a mixture of L. monocytogenes. Among the individual antimicrobial treatments, bacteriophage P100 was the most effective, decreasing L. monocytogenes to undetectable levels at zero and 72h post-infection. Sodium lactate was the least effective treatment. Treatment with nisin at zeroh significantly reduced initial cell density (p<0.05). However, this pattern was not observed at 72h of storage. A significant difference (p<0.05) existed between the results of separate bacteriophage and nisin treatments after refrigerated storage, but not immediately upon inoculation of the bacteria. The results showed that the use of bacteriophage P100 is the method of choice for the control of bacteria. PMID- 28641957 TI - Kindler syndrome complicated by invasive squamous cell carcinoma of the palate. AB - INTRODUCTION: Kindler syndrome is a very rare, autosomal recessive genodermatosis characterized by skin fragility and photosensitivity in infancy with progressive poikiloderma. CASE REPORT: We report the case of a young woman with a history of Kindler syndrome predominantly characterized by extensive involvement of the oropharyngeal mucosa. The patient presented with an ulcerative lesion of the palate. Computed tomography and biopsy concluded on unresectable invasive squamous cell carcinoma of the hard palate. Neoadjuvant chemotherapy was proposed, but the patient died after the first course of chemotherapy in a context of severe gastrointestinal mucositis and generalized sepsis. DISCUSSION: Mucosal manifestations of Kindler syndrome have been described in the literature, but very few cases of malignant transformation to squamous cell carcinoma have been reported, although it is a very well known, long-term complication of this disease. To our knowledge, this is the second reported case of Kindler syndrome complicated by invasive squamous cell carcinoma of the hard palate. PMID- 28641959 TI - [Author's reply]. PMID- 28641958 TI - [An earlier diagnosis of depression]. AB - Data of the last decade indicate that, in the Western world and also in Spain, an important part of general practicioners' consultations are related to mental health, but depression is consistently underdiagnosed. Causes are lack of time and back-up, as well as lack of specific training. In Spain, there is no national health service primary care database with actualized clinical information as to mental health. There is evident clinical interest in a more agile diagnostic, resulting from a recollection of data from voluntary selective screening and continuing evaluation of adult depression along the model used by other National Health Systems. PMID- 28641960 TI - [Involuntary commitment of the psychiatric patient: legal regulations and critical aspects]. AB - Traditionally, medical care received by psychiatric patients involved their separation from the society through their isolation in closed institutions, thereby setting a stigmatising trend on the sick, and by extension on mental illness, a practice that somehow has remained until now. The profound changes in the field of psychiatry have been important and are reflected in the therapeutic field, as well as in the legislative one, and have contributed to establish changes concerning the social opinion about psychiatric patients. The purpose of this article is to review, from the critical perspective, the current legislative framework concerning the situation of involuntary psychiatric commitment as a therapeutic measure in the psychiatric patient, as well as the legal medical practice which indicates the lack of legal skills and ethical and professional conduct arising in the field of primary care. PMID- 28641961 TI - Wnt5a and its signaling pathway in angiogenesis. AB - Wnt5a, a secreted glycoprotein, belongs to the noncanonical Wnt family involved in a wide range of organism development and tissue homeostasis. Wnt5a and its signaling pathway can regulate fundamental cellular processes, including specification of cell fate, proliferation, and survival. Accumulating evidence indicates that Wnt5a exhibits dual effects on angiogenesis. The formation of new blood vessels derives from pre-existing vessels via canonical and non-canonical Wnt pathways, depending on cell types, receptors, downstream effectors, and microenvironment. Given that the regulation of angiogenesis has been implicated in many diseases, such as cancer, neovascular eye diseases, and cardiovascular diseases, these findings suggest that Wnt5a may be a potential target for the treatment of angiogenesis-related diseases. PMID- 28641962 TI - Flat-detector CT angiography in the evaluation of neuro-Behcet disease. PMID- 28641964 TI - Metal nanoparticles in dermatology and cosmetology: Interactions with human skin cells. AB - Nanotechnology is a rapidly developing branch of science, which studies control of phenomena and materials sized below 100 nm. Nanotechnology is applicable in many areas of life and medicine including skin care and personal hygiene. The nanoparticles (NPs) of metals and metal oxides are increasingly used in dermatology and cosmetology, especially in prevention and treatment of bacterial and fungal infections, in protection against the harmful effects of the sun and in preparations reducing the visibility of scars by accelerating the repair processes of skin cells. NPs may also be used for skin care and dermatological treatments to improve the quality of life of patients. Nanodermatology and nanocosmetology offer effective, safe, fast-acting product formulations, thus minimizing the side effects of the products used so far. The unique properties of NPs: high surface area relative to the size as well as the ability to penetrate biological membranes and barriers greatly reduces systemic dose thus potential side effects and toxicity. Recent studies show very promising clinical potential of NPs to serve as controlled release and delivery systems for drugs/active substances. In addition, NPs can be used in diagnostic imaging of skin diseases. However, NPs may also carry a risk of cytotoxicity and side effects. The present review focuses on the use of metal and metal oxide NPs in dermatology and cosmetology and their interactions with skin cells. PMID- 28641963 TI - Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. AB - Retigabine, currently used as antiepileptic drug, has a wide range of potential medical uses. Administration of the drug in patients can lead to QT interval prolongation in the electrocardiogram and to cardiac arrhythmias in rare cases. This suggests that the drug may perturb the electrical properties of the heart, and the underlying mechanisms were investigated here. Effects of retigabine on currents through human cardiac ion channels, heterologously expressed in tsA-201 cells, were studied in whole-cell patch-clamp experiments. In addition, the drug's impact on the cardiac action potential was tested. This was done using ventricular cardiomyocytes isolated from Langendorff-perfused guinea pig hearts and cardiomyocytes derived from human induced pluripotent stem cells. Further, to unravel potential indirect effects of retigabine on the heart which might involve the autonomic nervous system, membrane potential and noradrenaline release from sympathetic ganglionic neurons were measured in the absence and presence of the drug. Retigabine significantly inhibited currents through hKv11.1 potassium, hNav1.5 sodium, as well as hCav1.2 calcium channels, but only in supra therapeutic concentrations. In a similar concentration range, the drug shortened the action potential in both guinea pig and human cardiomyocytes. Therapeutic concentrations of retigabine, on the other hand, were sufficient to inhibit the activity of sympathetic ganglionic neurons. We conclude that retigabine- induced QT interval prolongation, and the reported cases of cardiac arrhythmias after application of the drug in a typical daily dose range, cannot be explained by a direct modulatory effect on cardiac ion channels. They are rather mediated by indirect actions at the level of the autonomic nervous system. PMID- 28641965 TI - Animal models of psychoactive drug use and addiction - Present problems and future needs for translational approaches. AB - Drug addiction is a psychiatric disorder based on a dysfunction of the brain. It frequently develops from a controlled drug consumption and drug instrumentalization (DI). Thereby, DI is the use of a drug to improve specific non-drug related behaviors, beyond the drug's direct positive or negative reinforcing effects. Currently available pharmacotherapies for drug addiction show low effect size and rather limited long-term efficacy, which suggests that current theories on addiction are still insufficient in how they capture the phenomenon and how they allow predictions for highly efficient treatments. This opinion review attempts a critical analysis of some aspects of current addiction neuroscience using animal models. As a result, (1) animal models that cover previously neglected types of drug memories in controlled drug use are suggested. (2) Animal models for drug instrumentalization are warranted. Animal models of drug addiction should consider that addiction develops predominantly in individuals with mental and/or environmental challenges. It is suggested (3) to preferentially use animal models with similar mental and environmental challenges to model the transition of controlled to compulsive drug use. (4) Animal models should in the future also capture the important aspect of the motivation to self medicate in order to ameliorate a negative emotional/physical state. Potential pharmaco-treatments of addiction, in order to later achieve compliance in humans, should be tested for their systemic self-administration in order to self-medicate a drug-induced aversive state. This may allow a better understanding of the fundamental differences between an organism that shows controlled psychoactive drug consumption as an integral part of a 'normal' behavioral repertoire and one in a pathological condition with compulsive drug abuse. PMID- 28641966 TI - No Clinical Difference Comparing General, Regional, and Combination Anesthesia in Hip Arthroplasty: A Multicenter Cohort-Study Regarding Perioperative Pain Management and Patient Satisfaction. AB - BACKGROUND: Steadily increasing numbers of hip arthroplasties are reported in the past years. Different types of anesthetic methods for surgery itself as well as pain management programs have been established. It is one of the main goals to reduce postoperative pain levels and guarantee better and faster mobilization in the postoperative period. The present study aims to compare the use of general and regional spinal anesthesia and their combination regarding perioperative pain management and patient satisfaction. METHODS: All patients included in the present study had undergone primary hip arthroplasty. Parameters were analyzed on the first postoperative day within the scope of the "Quality Improvement in Postoperative Pain Management" project, which is conducted nationwide in 49 orthopedic departments at the time of data evaluation. RESULTS: From 2009-2015, 18,118 patients underwent primary hip arthroplasty and have been evaluated. Demographic and general patient data were homogenous. The need for opioids was significantly higher in patients where general and combination anesthesia was applied (P < .001, respectively). Pain scores and pain management satisfaction were significantly better in regional and combination anesthesia (P < .001, respectively). CONCLUSION: We were able to show a highly significant advantage in the use of regional or the combination of regional and general anesthesia in comparison with general anesthesia alone in hip arthroplasty regarding patients' satisfaction and the requirement of opioid pain medication, although maybe below clinical relevance. PMID- 28641967 TI - Fluoroscopically Guided Acetabular Component Positioning: Does It Reduce the Risk of Malpositioning in Obese Patients? AB - BACKGROUND: Obesity has been described as an independent risk factor for acetabular component malpositioning. The purpose of this study was to determine if this could be overcome by use of fluoroscopic navigation in total hip arthroplasty (THA). METHODS: The first, postoperative, standing, anteroposterior pelvis radiographs from 1599 consecutive patients who underwent fluoroscopic guided THAs via anterior approach during a six-year period were obtained. We retrospectively reviewed this prospectively collected data. Inclination and anteversion were measured as described by Barrack et al. Intraoperative target ranges for inclination and anteversion angles were 30 degrees -50 degrees and 5 degrees -25 degrees . Patients were divided into 3 cohorts by body mass index, nonobese (<30 kg/m2) obese (between 30 and 40 kg/m2) and morbidly obese (>40 kg/m2), looking for significant differences in acetabular component positioning. RESULTS: Of the 1599 patients, 1065 were nonobese, 506 obese, and 28 morbidly obese. Overall, average inclination was 37.7 degrees and anteversion was 16.3 degrees . Regarding inclination, 95.0% of cups were positioned in the safe zone, 95.7% for anteversion, and 91.2% for both inclination and anteversion. Analysis of each cohort individually revealed an average inclination of 37.5 degrees in the nonobese, 37.9 degrees in the obese, and 39.9 degrees in the morbidly obese patients. For anteversion, each group's averages were 16.1 degrees , 16.5 degrees , and 16.0 degrees , respectively. There was no significant relationship between a patient's body mass index and cup position for inclination (P = .867), anteversion (P = .673), or both inclination and anteversion (P = .624). CONCLUSION: Fluoroscopy is a useful tool for achieving a targeted acetabular component orientation in direct anterior THA, irrespective of patient BMI. PMID- 28641968 TI - Femoral Nerve Catheters Improve Home Disposition and Pain in Hip Fracture Patients Treated With Total Hip Arthroplasty. AB - BACKGROUND: Opioids have been the mainstay of treatment in the physiologically young geriatric hip fracture patient undergoing total hip arthroplasty (THA). However opioid-related side effects increase morbidity. Regional anesthesia may provide better analgesia, while decreasing opioid-related side effects. The goal of this study was to examine the effect of perioperative continuous femoral nerve blockade with regards to pain scores, opioid-related side effects and posthospital disposition in hip fracture patients undergoing THA. METHODS: Twenty nine consecutive geriatric hip fracture patients (22 women/7 men) underwent THA. Average follow-up was 8.3 months (6 weeks-39 months). Fifteen patients were treated with standard analgesia (SA). Fourteen patients received an ultrasound guided insertion of a femoral nerve catheter after radiographic confirmation of a hip fracture. All complications and readmissions that occurred within 6 weeks of surgery were noted. RESULTS: Continuous femoral nerve catheter (CFNC) patients were discharged home more frequently than SA patients (43% for CFNC vs 7% for SA; P = .023). CFNC patients reported lower average pain scores preoperatively (P < .0001), on postoperative day 1 (P = .005) and postoperative day 2 (P = .037). Preoperatively, CFNC patients required 61% less morphine equivalent (P = .007). CFNC patients had a lower rate of opioid-related side effects compared with SA patients (7% vs 47%; P = .035). CONCLUSION: CFNC patients were discharged to home more frequently. Use of a CFNC decreased daily average patient-reported pain scores, preoperative opioid usage, and opioid-related side effects after THA for hip fracture. Based on these data, we recommend routine use of perioperative CFNC in hip fracture patients undergoing THA. PMID- 28641969 TI - Determining 3D Kinematics of the Hip Using Video Fluoroscopy: Guidelines for Balancing Radiation Dose and Registration Accuracy. AB - BACKGROUND: Video fluoroscopy is a technique currently used to retrieve the in vivo three-dimensional kinematics of human joints during activities of daily living. Minimization of the radiation dose absorbed by the subject during the measurement is a priority and has not been thoroughly addressed so far. This issue is critical for the motion analysis of the hip joint, because of the proximity of the gonads. The aims of this study were to determine the x-ray voltage and the irradiation angle that minimize the effective dose and to achieve the best compromise between delivered dose and accuracy in motion retrieval. METHODS: Effective dose for a fluoroscopic study of the hip was estimated by means of Monte Carlo simulations and dosimetry measurements. Accuracy in pose retrieval for the different viewing angles was evaluated by registration of simulated radiographs of a hip prosthesis during a prescribed virtual motion. RESULTS: Absorbed dose can be minimized to about one-sixth of the maximum estimated values by irradiating at the optimal angle of 45 degrees from the posterior side and by operating at 80 kV. At this angle, accuracy in retrieval of internal-external rotation is poorer compared with the other viewing angles. CONCLUSION: The irradiation angle that minimizes the delivered dose does not necessarily correspond to the optimal angle for the accuracy in pose retrieval, for all rotations. For some applications, single-plane fluoroscopy may be a valid lower dose alternative to the dual-plane methods, despite their better accuracy. PMID- 28641970 TI - The Interaction of Caseload and Usage in Determining Outcomes of Unicompartmental Knee Arthroplasty: A Meta-Analysis. AB - BACKGROUND: Outcomes after unicompartmental knee arthroplasty (UKA) are variable and influenced by caseload (UKA/y) and usage (percentage of knee arthroplasty that are UKA), which relates to indications. This meta-analysis assesses the relative importance of these factors. METHODS: MEDLINE (Ovid), Embase (Ovid), and Web of Science (ISI) were searched for consecutive series of cemented Phase 3 Oxford medial UKA. The primary outcome was revision rate/100 observed component years (% pa) with subgroup analysis based on caseload and usage. RESULTS: Forty six studies (12,520 knees) with an annual revision-rate ranging from 0% to 4.35% pa, mean 1.21% pa (95% confidence interval [CI], 0.97-1.47), were identified. In series with mean follow-up of 10-years, the revision-rate was 0.63% pa (95% CI, 0.46-0.83), equating to a 94% (95% CI, 92%-95%) 10-year survival. Aseptic loosening, lateral arthritis, bearing dislocation, and unexplained pain were the predominant failure mechanisms with revision for patellofemoral problems and polyethylene wear exceedingly rare. The lowest revision-rates were achieved with caseload >24 UKA/y (0.88% pa; 95% CI, 0.63-1.61) and usage >30% (0.69% pa; 95% CI, 0.50-0.90). Usage was more important than caseload; with high usage (>=20%), the revision-rate was low, whether the caseload was high (>12 UKA/y) or low (<=12 UKA/y; (0.94% pa; 95% CI, 0.69-1.23 and 0.85% pa; 95% CI, 0.65-1.08), respectively); with low usage (<20%), the revision-rate was high, whether the caseload was high or low (1.58% pa; 95% CI, 0.57-3.05 and 1.76% pa; 95% CI, 1.21 2.41, respectively). CONCLUSION: To achieve optimum results, surgeons, whether high or low caseload, should adhere to the recommended indications such that >=20%, or ideally >30% of their knee arthroplasties are UKA. If they do this, then they can expect to achieve results similar to those of the long-term series, which all had high usage (>20%) and an average 10-year survival of 94%. PMID- 28641971 TI - Comorbidities Have a Greater Impact Than Age Alone in the Outcomes of Octogenarian Total Knee Arthroplasty. AB - BACKGROUND: Increasing age and various comorbidities are known risk factors for complications after total knee arthroplasty (TKA), but data on the impact of total comorbidity burden is scarce. We investigated the effect of age and total comorbidity burden on outcomes after primary TKA in octogenarians (OGs). METHODS: A matched-pair comparison study was conducted using prospectively collected TKA registry data in a large tertiary institution. Between 2006 and 2011, consecutive OGs undergoing primary unilateral TKA, with minimum 2-year follow-up, were matched 1:1 with younger controls based on demographic and surgical variables. We compared the Charlson comorbidity index (CCI), complication rate, length of stay (LOS), 30-day readmission, and 2-year reoperation rate. Multivariate analysis was performed to determine the effects of age and CCI on each outcome. RESULTS: There were 209 OGs and 209 controls. OGs were significantly older (mean age 82.1 vs 66.1 years, P < .001) and had higher CCI. OGs had longer mean LOS (6.3 vs 5.4 days, P = .001), and a trend for more complications and readmissions. The complication rate increased from 7.5% for CCI = 0, to 33.3% for CCI >=3 (P = .005). The LOS increased from 5.4 days for CCI = 0, to 9.6 days for CCI >=3 (P < .001). Multivariate analysis showed that higher CCI was an independent risk factor for complications and longer LOS, whereas age was not. CONCLUSION: Comorbidity burden has a greater impact than age alone on TKA outcomes in OGs. Well-selected OGs remain good candidates for TKA. PMID- 28641972 TI - Equal Primary Fixation of Resurfacing Stem, but Inferior Cup Fixation With Anterolateral vs Posterior Surgical Approach. A 2-Year Blinded Randomized Radiostereometric and Dual-energy X-Ray Absorptiometry Study of Metal-on-Metal Hip Resurfacing Arthroplasty. AB - BACKGROUND: The anterolateral (AntLat) surgical approach may spare the blood supply to the femoral head and improve the accuracy of cup positioning in metal on-metal hip resurfacing arthroplasty. Thereby, potentially lessen complications such as avascular head necrosis, femoral neck narrowing and fracture, improve implant fixation, and lessen periprosthetic bone mineral density (BMD) loss. METHODS: Between November 2008 and January 2012, a randomized clinical trial was performed at Aarhus University Hospital. A total of 49 patients (28 males) were allocated to metal-on-metal hip resurfacing arthroplasty by the AntLat (n = 25) or the posterior (Post; n = 24) surgical approach. Patients were followed with radiostereometric analysis, measurements of periprosthetic BMD, clinical outcome scores of Harris hip score and visual analogue scale, serum metal ions, and conventional radiographs. RESULTS: At 3 months, cups in the AntLat group had higher total translations of mean 1.00 +/- 0.70 mm vs mean 0.64 +/- 0.45 mm in the post group (P = .04), and higher total rotations of mean 2.44 degrees +/- 1.36 degrees vs mean 1.39 degrees +/- 1.17 degrees in the Post group (P = .002). All migrations of cup and stem were similar at 1 and 2 years postoperative (P > .07). At 1 year, periprosthetic BMD since postoperative at the medial side of the stem was reduced to mean 98.45% +/- 8.57% in the AntLat group, and increased to mean 105.57% +/- 11.07% in the Post group (P = .02), but measurements were comparable at 2 years (P = .05). CONCLUSION: Cups inserted by the AntLat approach migrated more until 3 months postoperative. This illustrates a less good primary cup fixation with the AntLat approach; however, all cups were well-fixed after 3 months' follow-up indicating a good secondary fixation. PMID- 28641973 TI - Changes in Hip, Knee, and Ankle Coronal Alignments After Total Hip Arthroplasty With Transverse Femoral Shortening Osteotomy for Unilateral Crowe Type IV Developmental Dysplasia of the Hip. AB - BACKGROUND: To investigate changes in lower extremity coronal alignment in patients with unilateral Crowe type IV developmental dysplasia of the hip who underwent total hip arthroplasty with transverse femoral shortening osteotomy. METHODS: We reviewed the preoperative and 1-year postoperative full-length lower extremity radiographs of 25 patients. Femoral offset (FO), mechanical hip-knee ankle angle, anatomical axis, mechanical axis deviation (MAD), mechanical lateral proximal femoral angle, anatomical medial proximal femoral angle, mechanical lateral distal femoral angle, anatomical lateral distal femoral angle, knee joint line congruency angle, mechanical medial proximal tibial angle, mechanical lateral distal tibial angle, ankle joint line orientation angle, tibial plafond talus angle, extremity length, and pelvic obliquity were measured on both the operative and nonoperative sides. RESULTS: Postoperatively, there were significant changes in FO (P = .001), hip-knee-ankle angle (P = .004), MAD (P = .016), mechanical lateral proximal femoral angle (P = .001), anatomical medial proximal femoral angle (P = .012), mechanical lateral distal femoral angle (P = .043), and ankle joint line orientation angle (P = .012) on the operative side. Only MAD (P = .035) changed significantly on the nonoperative side. CONCLUSION: Modification of FO and reconstruction of hip joint anatomy led to neutralization of knee and ankle valgus alignment. Effects on the nonoperative side were minimal. PMID- 28641974 TI - Prostate Cancer Local Recurrence Detected With Both 18F-Fluciclovine and PSMA targeted 18F-DCFPyL PET/CT. AB - We present the case of a 79-year-old man with an elevated postprostatectomy prostate-specific antigen level who was sequentially imaged with positron emission tomography/computed tomography (PET/CT) using 18F-fluciclovine followed by PSMA-targeted 18F-DCFPyL. Although both imaging tests successfully identified the same pelvic recurrence, each radiotracer had its relative merits. This case highlights the differences between these two PET radiotracers, which are increasingly being used to image men with recurrent prostate cancer. PMID- 28641975 TI - Engendering drug problems: Materialising gender in the DUDIT and other screening and diagnostic 'apparatuses'. AB - It is widely accepted that alcohol and other drug consumption is profoundly gendered. Just where this gendering is occurring, however, remains the subject of debate. We contend that one important and overlooked site where the gendering of substance consumption and addiction is taking place is through AOD research itself: in particular, through the addiction screening and diagnostic tools designed to measure and track substance consumption and problems within populations. These tools establish key criteria and set numerical threshold scores for the identification of problems. In many of these tools, separate threshold scores for women and men are established or recommended. Drawing on Karen Barad's concept of post-humanist performativity, in this article we examine the ways in which gender itself is being materialised by these apparatuses of measurement. We focus primarily on the Drug Use Disorders Identification Test (DUDIT) tool as an exemplar of gendering processes that operate across addiction tools more broadly. We consider gendering processes operating through tools questions themselves and we also examine the quantification and legitimation processes used in establishing gender difference and the implications these have for women. We find tools rely on and reproduce narrow and marginalising assumptions about women as essentially fragile and vulnerable and simultaneously reinforce normative expectations that women sacrifice pleasure. The seemingly objective and neutral quantification processes operating in tools naturalise gender as they enact it. PMID- 28641976 TI - National surveillance of surgical site infection: response to Lamagni et al. PMID- 28641977 TI - A novel fluorescent probe reveals starvation controls the commitment of amyloid precursor protein to the lysosome. AB - Alzheimer's disease is the most important cause of dementia but there is no therapy that has been demonstrated to stop or slow disease progression. Amyloid precursor protein (APP) is the source of amyloid-beta (Abeta), which aggregates in Alzheimer's disease to form toxic oligomeric species. The endo-lysosomal system can clear APP and Abeta from the cell if these molecular species are trafficked through to the lysosome. Currently, there are no easy methods available for the analysis of lysosomal APP trafficking. We therefore generated a fusion protein (tandem-fluorescent, or tf-APP) that allows detection of changes in APP trafficking using accessible techniques such as flow cytometry. This permits rapid analysis or screening of genes and compounds that alter APP processing in the cell. Using our novel molecular probe, we determined that starvation induces trafficking of APP and APP-carboxy-terminal fragments (APP CTFs) to the degradative endo-lysosomal network. In line with this finding, suppression of mTOR signalling using AZD8055 also strongly induced trafficking of APP to the endo-lysosomal system. Remarkably, activation of mTOR signalling via RHEB over-expression inhibited the starvation-induced autophagy but did not affect trafficking of tf-APP. These results show tf-APP can be used to determine how APP is trafficked through the lysosomal system of the cell. This molecular probe is therefore useful for determining the molecular mechanism behind the commitment of APP to the degradative pathway or for screening compounds that can induce this effect. This is important as clearance of APP and APP-CTF provides an important potential therapeutic strategy for Alzheimer's disease. PMID- 28641978 TI - ANGPTL4 T266M variant is associated with reduced cancer invasiveness. AB - Angiopoietin-like 4 (ANGPTL4) is a secretory protein that can be cleaved to form an N-terminal and a C-terminal protein. Studies performed thus far have linked ANGPTL4 to several cancer-related and metabolic processes. Notably, several point mutations in the C-terminal ANGPTL4 (cANGPTL4) have been reported, although no studies have been performed that ascribed these mutations to cancer-related and metabolic processes. In this study, we compared the characteristics of tumors with and without wild-type (wt) cANGPTL4 and tumors with cANGPTL4 bearing the T266M mutation (T266M cANGPTL4). We found that T266M cANGPTL4 bound to integrin alpha5beta1 with a reduced affinity compared to wt, leading to weaker activation of downstream signaling molecules. The mutant tumors exhibited impaired proliferation, anoikis resistance, and migratory capability and had reduced adenylate energy charge. Further investigations also revealed that cANGPTL4 regulated the expression of Glut2. These findings may explain the differences in the tumor characteristics and energy metabolism observed with the cANGPTL4 T266M mutation compared to tumors without the mutation. PMID- 28641980 TI - Cardiomyocyte specific overexpression of a 37 amino acid domain of regulator of G protein signalling 2 inhibits cardiac hypertrophy and improves function in response to pressure overload in mice. AB - Regulator of G protein signalling 2 (RGS2) is known to play a protective role in maladaptive cardiac hypertrophy and heart failure via its ability to inhibit Gq- and Gs- mediated GPCR signalling. We previously demonstrated that RGS2 can also inhibit protein translation and can thereby attenuate cell growth. This G protein independent inhibitory effect has been mapped to a 37 amino acid domain (RGS2eb) within RGS2 that binds to eukaryotic initiation factor 2B (eIF2B). When expressed in neonatal rat cardiomyocytes, RGS2eb attenuates both protein synthesis and hypertrophy induced by Gq- and Gs- activating agents. In the current study, we investigated the potential cardioprotective role of RGS2eb by determining whether RGS2eb transgenic (RGS2eb TG) mice with cardiomyocyte specific overexpression of RGS2eb show resistance to the development of hypertrophy in comparison to wild type (WT) controls. Using transverse aortic constriction (TAC) in a pressure overload hypertrophy model, we demonstrated that cardiac hypertrophy was inhibited in RGS2eb TG mice compared to WT controls following four weeks of TAC. Expression of the hypertrophic markers atrial natriuretic peptide (ANP) and beta myosin heavy chain (MHC-beta) was also reduced in RGS2eb TG compared to WT TAC animals. Furthermore, cardiac function in RGS2eb TG TAC mice was significantly improved compared to WT TAC mice. Notably, cardiomyocyte cell size was significantly decreased in TG compared to WT TAC mice. These results suggest that RGS2 may limit pathological cardiac hypertrophy at least in part via the function of its eIF2B-binding domain. PMID- 28641981 TI - US emergency department visits for adults with abdominal and pelvic pain (2007 13): Trends in demographics, resource utilization and medication usage. PMID- 28641982 TI - Temporal artery and axillary thermometry comparison with rectal thermometry in children presenting to the ED. AB - BACKGROUND: Accurate temperature readings, often obtained rectally, are an important part of the initial evaluation of pediatric patients in the Emergency Department. Temporal artery thermometry (TAT) is one way to noninvasively measure temperature. We sought to compare the accuracy of axillary and temporal artery temperatures compared to rectal. METHODS: This prospective study included children age 0-36months presenting to the Emergency Department of a large military treatment facility. Rectal, axillary, and temporal artery temperatures were obtained. Test characteristics (sensitivity, specificity, NPV, PPV) were reported. The effect of cutoff values 99.9 degrees F, 100.4 degrees F, and 102.2 degrees F on test characteristics were also evaluated. RESULTS: The sensitivities of axillary and temporal artery thermometry to detect rectal fever is 11.5% and 61.5% respectively. Cutoff values did not significantly alter test characteristics. In this study, temporal artery thermometry was 0.2 degrees C lower than rectal temperature, axillary measurement was 0.9 degrees C below the reference standard. Mean temperature difference in the febrile group between TAT and rectal thermometry was >0.5 degrees C compared with a mean temperature difference 0.05 degrees C in afebrile patients. CONCLUSION: The findings of our study do not support using axillary thermometry to screen pediatric patients for fever in the emergency department. TAT cannot be recommended as a rectal thermometry replacement where height and duration of fever are used in pediatric disease prediction models. TAT may have a role in screening for fever in the appropriate pediatric patient population like primary orthopedic or trauma presentations where the balance between device precision, data capture and patient comfort may favor use of TAT. PMID- 28641983 TI - Patient preference to participate in shared decision making for performing a CT scan in the emergency department. PMID- 28641979 TI - Sexual dimorphism in the fetal cardiac response to maternal nutrient restriction. AB - Poor maternal nutrition causes intrauterine growth restriction (IUGR); however, its effects on fetal cardiac development are unclear. We have developed a baboon model of moderate maternal undernutrition, leading to IUGR. We hypothesized that the IUGR affects fetal cardiac structure and metabolism. Six control pregnant baboons ate ad-libitum (CTRL)) or 70% CTRL from 0.16 of gestation (G). Fetuses were euthanized at C-section at 0.9G under general anesthesia. Male but not female IUGR fetuses showed left ventricular fibrosis inversely correlated with birth weight. Expression of extracellular matrix protein TSP-1 was increased (p<0.05) in male IUGR. Expression of cardiac fibrotic markers TGFbeta, SMAD3 and ALK-1 were downregulated in male IUGRs with no difference in females. Autophagy was present in male IUGR evidenced by upregulation of ATG7 expression and lipidation LC3B. Global miRNA expression profiling revealed 56 annotated and novel cardiac miRNAs exclusively dysregulated in female IUGR, and 38 cardiac miRNAs were exclusively dysregulated in males (p<0.05). Fifteen (CTRL) and 23 (IUGR) miRNAs, were differentially expressed between males and females (p<0.05) suggesting sexual dimorphism, which can be at least partially explained by differential expression of upstream transcription factors (e.g. HNF4alpha, and NFkappaB p50). Lipidomics analysis of fetal cardiac tissue exhibited a net increase in diacylglycerol and plasmalogens and a decrease in triglycerides and phosphatidylcholines. In summary, IUGR resulting from decreased maternal nutrition is associated with sex-dependent dysregulations in cardiac structure, miRNA expression, and lipid metabolism. If these changes persist postnatally, they may program offspring for higher later life cardiac risk. PMID- 28641984 TI - Bi-objective approach for placing ground and air ambulance base and helipad locations in order to optimize EMS response. AB - Shortening the travel time of patient transfer has clinical implications for many conditions such as cardiac arrest, trauma, stroke and STEMI. As resources are often limited precise calculations are needed. In this paper we consider the location problem for both ground and aerial emergency medical services. Given the uncertainty of when patients are in need of prompt medical attention we consider these demand points to be uncertain. We consider various ways in which ground and helicopter ambulances can work together to make the whole process go faster. We develop a mathematical model that minimizes travel time and maximizes service level. We use a compromising programming method to solve this bi-objective mathematical model. For numerical experiments we apply our model to a case study in Lorestan, Iran, using geographical and population data, and the location of the actual hospital based in the capital of the province. Results show that low accessibility locations are the main focus of the proposed problem and with mathematical modeling access to a hospital is vastly improved. We also found out that once the budget reaches a certain point which suffices for building certain ambulance bases more investments does not necessarily result in less travel time. PMID- 28641985 TI - Single-step colony assay for screening antibody libraries. AB - We describe a method, single-step colony assay, for simple and rapid screening of single-chain Fv fragment (scFv) libraries. Colonies of Escherichia coli expressing the scFv library are formed on a hydrophilic filter that is positioned in contact with a membrane coated with an antigen. scFv expression is triggered upon treatment of colonies with an induction reagent, following which scFvs are secreted from the cells and diffused to the antigen-coated membrane. scFvs that exhibit binding affinity for the antigen are captured by the membrane-immobilized antigen. Lastly, detection of scFv binding of the antigen on the membrane allows identification of the clones on the filter that express antigen-specific scFvs. We tested this methodology by using an anti-rabbit IgG scFv, scFv(A10B), and a rat immune scFv library. Experiments conducted using scFv(A10B) revealed that this method improves scFv expression during the colony assay. By using our method to screen an immune library of 3*103 scFv clones, we established several clones exhibiting affinity for the antigen. Moreover, we tested 7 other antigens, including peptides, and successfully identified positive clones. We believe that this simple procedure and controlled scFv expression of the single-step colony assay could make the antibody screening both rapid and reliable and lead to successful isolation of positive clones from antibody libraries. PMID- 28641987 TI - Food deprivation in F0 generation and hypercaloric diet in F1 generation reduce F2 generation astrogliosis in several brain areas after immune challenge. AB - AIMS: The effects of maternal food restriction during gestation in F0 generation followed by hypercaloric diet (HD) during puberty in F1 generation (F1HD) were investigated on astrocyte behavior of F2 generation. Also, the astrocyte behavior, after an immune challenge, was examined by the immunohistochemical expression of glial fibrillary acidic protein (GFAP) in several brain areas. METHODS: The body weight gain (BW) during development and in postnatal day (PND) 90-95, the retroperitoneal fat weight (RPF), and the size of larger and smaller adipocytes in the F1 generation were assessed to observe the effects of HD in female rats. The BW, RPF weight and size of smaller and larger adipocytes was also measured to evaluate the transgenerational effects of F0 and F1 diets on F2 generation, treated or not with lipopolysaccharide (LPS). KEY FINDINGS: The F1HD group exhibited a higher BW gain than the F1 treated with normocaloric diet (ND, group F1ND), from weaning to PND65. In the frontal/parietal cortex, nucleus accumbens, hypothalamic arcuate/periventricular nuclei, molecular/granular layers of the cerebellum areas, excepting the pons, GFAP expression was greater in F1HD group relative to F1ND group. A reduced GFAP expression was observed in both groups born from F1 generation fed with HD (groups F2HDS and F2HDLPS) in relation to F2 generation born from dams fed with ND (groups F2NDS and F2NDLPS), independently of LPS challenge. SIGNIFICANCE: These data show an attenuation of LPS effect on GFAP expression, probably by a transgenerational effect of both maternal food deprivation in F0 generation and HD in F1 generation. PMID- 28641986 TI - Novel spectrophotometric technique for rapid determination of extractable PHA using Sudan black dye. AB - Classical techniques employed to determine the amount of extractable poly(hydroxyalkanoate)s (PHAs) from cells, are laborious and destructive. Sudan black staining is commonly used in the laboratory to investigate the presence of intracellular PHA. The aim of the present study was to develop a low-cost alternative technique to achieve a quick determination of extractable intracellular PHA. This methodology employs a basic laboratory spectroscopy equipment and Sudan black dye for spectra determination. The correlation between the content of PHA in cell samples taken directly from the culture flask and its spectra was determined using partial least square regression analysis and simple linear regression analysis. The best fit obtained for calibration correlation analysis (R2=0.944, RSE: 1.24%), together with the good extractable PHA predictions (RSE=0.51%) demonstrate that the proposed methodology constitutes a fast way with high potential for the determination of extractable PHA. Based on its simplicity and flexibility, its application would be suitable in routine monitoring and rapid quantification in large-scale processes involving PHA metabolism. PMID- 28641989 TI - The value of physicians' affect-oriented communication for patients' recall of information. AB - OBJECTIVE: The aim of this paper is to discuss experimental research investigating the effect of physicians' affect-oriented communication on patients' recall of information provided during medical consultations, with a special focus on the mediating role of emotional stress in that relation. METHODS & RESULTS: A search of experimental research literature was conducted, resulting in six research articles experimentally investigating the relations of interest, all using a video-vignettes design. A summary of results is provided and discussed. CONCLUSIONS: The research reviewed in this paper provides evidence for the causal and mostly positive influence of several forms of affect-oriented communication on patients' recall of medical information. Results indicate that reducing emotional stress may not be the underlying mechanism through which physicians' communication influences patients' recall. PRACTICE IMPLICATIONS: The obtained insights will help educators to teach evidence-based medical communication skills and to scientifically validate the importance of these skills for patients' recall of information. Advancing physicians' communication skills with evidence-based training will contribute to the professionalism that is the hallmark of good quality of care. PMID- 28641988 TI - Wavy multistratified amacrine cells in the monkey retina contain immunoreactive secretoneurin. AB - The goals of this study were to describe the morphology, neurotransmitter content and synaptic connections of neurons in primate retinas that contain the neuropeptide secretoneurin. Amacrine cells were labeled with antibodies to secretoneurin in macaque and baboon retinas. Their processes formed three distinct plexuses in the inner plexiform layer: one in the outermost stratum, one in the center and one in the innermost stratum. In light microscopic double immunolabeling experiments, GABA was colocalized with secretoneurin in these cells, but glycine transporter 1 and Substance P were not. ON bipolar cell axon terminals labeled with antibody to the cholecystokinin precursor, G6-gly, have ON responses to stimulation of short wavelength sensitive (S) cones. Axons of these bipolar cells made contacts with amacrine cell dendrites containing secretoneurin. Secretoneurin-IR amacrine cells also made contacts with retinal ganglion cell dendrites labeled with antibody to the photopigment melanopsin, which have OFF responses to stimulation of S cones. Using electron microscopic immunolabeling, 436 synapses from macaque retina were analyzed. Axons from bipolar cells were identified by their characteristic synaptic ribbons; their synaptic densities were asymmetric like those of excitatory synapses in the brain. Amacrine cells made and received conventional synapses with symmetric synaptic densities, like those of inhibitory synapses in the brain. Ganglion cell dendrites were identified by their absence of presynaptic specializations; they received inputs from both amacrine cells and bipolar cells. The majority of inputs to the secretoneurin-IR amacrine cells were from other amacrine cells, but they also received 21% of their input from bipolar cells. They directed most of their output, 54%, to amacrine cells, but there were many synapses onto bipolar cell axons and ganglion cell dendrites, as well. The synaptic connections were very similar in the three plexuses with one notable exception; output synapses to bipolar cells were significantly less common in the innermost one, where the S-ON bipolar cells terminate. Taken together, these findings suggest that the secretoneurin-IR amacrine cells in primates receive excitatory input from S-ON bipolar cells and, in turn, inhibit intrinsically photosensitive retinal ganglion cells. PMID- 28641990 TI - Do negative emotions expressed during follow-up consultations with adolescent survivors of childhood cancer reflect late effects? AB - OBJECTIVE: To explore whether negative emotions expressed by adolescent cancer survivors during follow-up consultations were associated with potential late effects (persisting disease or treatment-related health problems). METHODS: We video-recorded 66 follow-up consultations between 10 pediatricians and 66 adolescent survivors of leukemia, lymphoma or stem-cell transplantations. In transcripts of the recordings, we identified utterances coded as both 1) expressions of negative emotions (VR-CoDES), and 2) late effect-related discussions. Principles of thematic content analysis were used to investigate associations between the two. RESULTS: Of the 66 video-recorded consultations, 22 consultations contained 56 (49%) utterances coded as both emotional concerns and discussions of potential late effects. Negative emotions were most commonly associated with late effects such as fatigue ("I'm struggling with not having energy"), psychosocial distress ("When I touch this (scar) I become nauseous"), pain ("I'm wondering how long I am going to have this pain?"), and treatment related effects on physical appearance ("Am I growing?"). CONCLUSIONS: Negative emotions expressed by adolescent cancer survivors during follow-up consultations were frequently associated with potential late effects. These late effects were not the medically most serious ones, but reflected issues affecting the adolescents' daily life. PRACTICE IMPLICATION: Eliciting and exploring patients' emotional concerns serve as means to obtain clinically relevant information regarding potential late effect and to provide emotional support. PMID- 28641991 TI - Vitality training-A mindfulness- and acceptance-based intervention for chronic pain. AB - Chronic non-malign pain has a substantial impact on all parts of an individual's life. Mindfulness- and acceptance- based interventions are increasingly offered to help people manage their pain and strengthening their health promoting resources. In this paper, we present a mindfulness- and acceptance-based intervention, the Vitality Training Programme (VTP), to mitigating pain and accompanying symptoms and increasing pain coping abilities. Based on a clinical case presentation, we discuss how the VTP can help individuals to live a better life with pain. The VTP has been evaluated in two randomised controlled trials and two qualitative studies. Existing evidence is presented. Finally, based on a recently published theoretical model, we present some possible common explanatory mechanisms across various mindfulness- and acceptance-based interventions that might also apply to the VTP. PMID- 28641992 TI - Filling in memory gaps through emotional communication; promising pathways in caring for persons with dementia. AB - OBJECTIVE: To explore in what way emotional communication can enhance the memory of people with (different types of) dementia. METHODS: Relevant studies published after 2000 were searched using the terms: dementia, positive, words, communication, recall, and memory. Papers were included that reported results of studies with people with dementia that investigated memory effects of communication with either an emotionally valent content or context. RESULTS: Twelve papers grouped under four prevailing themes (pictures, facial emotions, stories and words) are described. The studies provide mixed results: in some studies negative emotional information enhances memory in older people with dementia, in other studies positive emotional information is helpful or hardly any effect is found. CONCLUSION: Emotional communication seems to enhance memory in people with dementia. None of the studies described focused on the association between personally relevant, emotionally valent information and memory, so further research is needed. PRACTICE IMPLICATIONS: Caregivers in dementia care should realize that 1) the information they provide might carry an emotional valence, and 2) this valence might influence the extent to which people with dementia remember information. PMID- 28641993 TI - Peer-review for selection of oral presentations for conferences: Are we reliable? AB - INTRODUCTION: Although peer-review for journal submission, grant-applications and conference submissions has been called 'a counter- stone of science', and even 'the gold standard for evaluating scientific merit', publications on this topic remain scares. Research that has investigated peer-review reveals several issues and criticisms concerning bias, poor quality review, unreliability and inefficiency. The most important weakness of the peer review process is the inconsistency between reviewers leading to inadequate inter-rater reliability. AIM OF THE PAPER: To report the reliability of ratings for a large international conference and to suggest possible solutions to overcome the problem. METHODS: In 2016 during the International Conference on Communication in Healthcare, organized by EACH: International Association for Communication in Healthcare, a calibration exercise was proposed and feedback was reported back to the participants of the exercise. RESULTS: Most abstracts, as well as most peer reviewers, receive and give scores around the median. Contrary to the general assumption that there are high and low scorers, in this group only 3 peer reviewers could be identified with a high mean, while 7 has a low mean score. Only 2 reviewers gave only high ratings (4 and 5). Of the eight abstracts included in this exercise, only one abstract received a high mean score and one a low mean score. Nevertheless, both these abstracts received both low and high scores; all other abstracts received all possible scores. DISCUSSION: Peer-review of submissions for conferences are, in accordance with the literature, unreliable. New and creative methods will be needed to give the participants of a conference what they really deserve: a more reliable selection of the best abstracts. PRACTICE IMPLICATIONS: More raters per abstract improves the inter rater reliability; training of reviewers could be helpful; providing feedback to reviewers can lead to less inter-rater disagreement; fostering negative peer review (rejecting the inappropriate submissions) rather than a positive (accepting the best) could be fruitful for selecting abstracts for conferences. PMID- 28641994 TI - Emotions in communication skills training - experiences from general practice to Porsche maintenance. AB - The emphasis on skills in communication training of physicians has gained momentum over the last 30 years. Furthermore, a specific focus on skills to address emotions has been suggested and more recently supported by empirical studies. In this paper we use the Expanded Four Habits Model to illustrate how a structured consultation model supplemented with specific skills to address emotions is considered useful in medical and non-medical settings. The primacy of emotions in different types of professional encounters is discussed in relation to education and practice. PMID- 28641995 TI - Acetylator Status Impacts Amifampridine Phosphate (FirdapseTM) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function. AB - PURPOSE: The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (FirdapseTM) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes. METHODS: This was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations. FINDINGS: Amifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC0-infinity and Cmax were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC0-infinity was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC0 infinity, approximately 1.8-fold; Cmax, approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC0-infinity from normal to severe RI. No new tolerability findings were observed. IMPLICATIONS: A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting FirdapseTM administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35. PMID- 28641996 TI - Impact of Paliperidone Palmitate Versus Oral Atypical Antipsychotics on Health Care Resource Use and Costs in Veterans With Schizophrenia and Comorbid Substance Abuse. AB - PURPOSE: Almost half of all patients diagnosed with schizophrenia have a history of substance abuse (SA). However, data on treatment of schizophrenia with paliperidone palmitate (PP) among patients with comorbid SA are limited. The objective of this study was to compare all-cause and SA-related health care resource utilization and costs in veterans with schizophrenia and co-occurring SA who were treated with PP versus oral atypical antipsychotics (OAAs). METHODS: Veterans Health Administration electronic health record data were used to conduct a retrospective longitudinal study in veterans with schizophrenia who initiated PP or OAA between January 1, 2010 and June 30, 2016, had >=12 months of enrollment before treatment initiation (baseline), were diagnosed with SA, and had >=1 Global Assessment of Functioning score during baseline. Differences in baseline characteristics were adjusted for using inverse probability of treatment weighting. Adjusted cost differences and incidence rate ratios (IRR) for the association between PP versus OAA and all-cause and SA-related health care costs and health care resource utilization in the 12 months after treatment initiation were estimated with corresponding 95% CIs using weighted linear and Poisson regression models, respectively. FINDINGS: Of 6872 veterans in the study, 1684 (25%) and 5188 (75%) were treated with PP and OAA, respectively. After adjustment, PP was associated with fewer all-cause inpatient (IRR = 0.88; 95% CI, 0.85 to 0.90), mental health-related inpatient (IRR = 0.88; 95% CI, 0.85 to 0.91), and long-term care stays (IRR = 0.53; 95% CI, 0.44 to 0.64), but more frequent mental health intensive case management visits (IRR = 1.51; 95% CI, 1.49 to 1.53) compared with OAA (all P < 0.001). Similarly, PP was associated with significantly lower rates of SA-related inpatient stays (IRR = 0.80; 95% CI, 0.77 to 0.83), mental health stays (IRR = 0.85; 95% CI, 0.82 to 0.88), long-term care stays (IRR = 0.22; 95% CI, 0.15 to 0.32), and outpatient visits (IRR = 0.78; 95% CI, 0.77 to 0.79) than OAA (all P < 0.001). Relative to OAA, patients treated with PP also had lower mean annual all-cause (cost difference = -$10,473; 95% CI, -$17,827 to -$3491) and SA-related (cost difference = -$8457; 95% CI, -$12,710 to -$3638) medical costs (all P < 0.001). IMPLICATIONS: PP was associated with significant total medical cost savings resulting from fewer hospitalizations and lower rates of SA-related health care resource utilization compared with OAA in patients with schizophrenia and comorbid SA. Thus, PP appears to be a valuable treatment option for patients in this subpopulation. PMID- 28641997 TI - Uterine Artery Embolization and Surgical Methods for the Treatment of Symptomatic Uterine Leiomyomas: A Systemic Review and Meta-analysis Followed by Indirect Treatment Comparison. AB - PURPOSE: There is significant discussion and uncertainty about the optimal management of symptomatic uterine leiomyomas (SULs). Nonsurgical procedures such as uterine artery embolization (UAE) have been developed. The goal of this study was to conduct a meta-analysis and an indirect treatment comparison to examine the comparative efficacy and safety of the surgical procedures to treat SULs compared with UAE. METHODS: MEDLINE, EMBASE, Lilacs, and the Cochrane Central Register of Controlled Trials databases were searched from inception to February 2016. Ten randomized controlled trials comparing UAE versus hysterectomy, myomectomy, and laparoscopic occlusion of the uterine arteries in patients with SUL published in a peer-reviewed journal were included. Two reviewers independently selected studies, assessed quality, and extracted data. Discrepancies were resolved through consensus. FINDINGS: Data from 986 patients submitted to UEA (n = 527) or surgery (n = 459) were analyzed. UAE had a lower risk of major complications (risk ratio [RR], 0.45 [95% CI, 0.22-0.95]; P = 0.04)and a higher risk of minor complications (RR, 1.65 [95% CI, 1.32-2.06]; P < 0.00001); UAE had a higher risk of re-intervention up to 2 years (RR, 3.74 [95% CI, 1.76-7.96]; P = 0.0006) and up to 5 years (RR, 5.01 [95% CI, 1.37-18.39]; P = 0.02); UAE had a similar risk of follicle-stimulating hormone levels >40 IU/L after 6 months (RR, 1.76 [95% CI, 0.24-12.95]; P = 0.58)and of recommending the procedure to another patient up to 5 years after treatment (RR, 1.00 [95% CI, 0.87-1.14]; P = 0.94). The indirect comparison between myomectomy and hysterectomy found that the 2 procedures were similar in the studied outcomes. IMPLICATIONS: Compared with surgery, UAE had lower rates of major complications with an increased risk of re-intervention up to 2 and 5 years after the first procedure. UAE compared with surgery had a similar risk of ovarian failure and similar recommendation of the procedure to another patient. However, the number of trials was limited, and there was a high risk of bias in at least 2 domains. None of the trials blinded the participants and personnel or the outcome assessment. PROSPERO identifier: CRD42015026319. PMID- 28641998 TI - Construction of a hepatitis B virus neutralizing chimeric monoclonal antibody recognizing escape mutants of the viral surface antigen (HBsAg). AB - Hepatitis B virus (HBV) infection is a global burden on the health-care system and is considered as the tenth leading cause of death in the world. Over 248 million patients are currently suffering from chronic HBV infection worldwide and annual mortality rate of this infection is 686000. The "a" determinant is a hydrophilic region present in all antigenic subtypes of hepatitis B surface antigen (HBsAg), and antibodies against this region can neutralize the virus and are protective against all subtypes. We have recently generated a murine anti-HBs monoclonal antibody (4G4), which can neutralize HBV infection in HepaRG cells and recognize most of the escape mutant forms of HBsAg. Here, we describe the production and characterization of the chimeric human-murine antibody 4G4 (c 4G4). Variable region genes of heavy and light chains of the m-4G4 were cloned and fused to constant regions of human kappa and IgG1 by splice overlap extension (SOE) PCR. The chimeric antibody was expressed in Chinese Hamster Ovary (CHO)-K1 cells and purified from culture supernatant. Competition ELISA proved that both antibodies bind the same epitope within HBsAg. Antigen-binding studies using ELISA and Western blot showed that c-4G4 has retained the affinity and specificity of the parental murine antibody, and displayed a similar pattern of reactivity to 13 escape mutant forms of HBsAg. Both, the parental and c-4G4 showed a comparably high HBV neutralization capacity in cell culture even at the lowest concentration (0.6MUg/ml). Due to the ability of c-4G4 to recognize most of the sub-genotypes and escape mutants of HBsAg, this antibody either alone or in combination with other anti-HBs antibodies could be considered as a potent alternative for Hepatitis B immune globulin (HBIG) as an HBV infection prophylactic or for passive immunotherapy against HBV infection. PMID- 28642000 TI - Initial experience with the HeartMate percutaneous heart pump in circulatory failure. PMID- 28641999 TI - Effect of pharmacist care on medication adherence and cardiovascular outcomes among patients post-acute coronary syndrome: A systematic review. AB - BACKGROUND: The impact of collaborative and multidisciplinary health care on the outcomes of care in patients with acute coronary syndromes (ACS) is well established in the literature. However, there is lack of high quality evidence on the role of pharmacist care in this setting. OBJECTIVE: This systematic review aimed to evaluate the impact of pharmacist care on patient outcomes (readmission, mortality, emergency visits, and medication adherence) in patients with ACS at or post-discharge. METHODS: The following electronic databases and search engines were searched from their inception to September 2016: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, Scopus, Campbell Library, Database of Abstracts of Reviews of Effects (DARE), Health System Evidence, Global Health Database, Joanna Briggs Institute Evidence-Based Practice Database, Academic Search Complete, ProQuest, PROSPERO, and Google Scholar. Studies were included if they evaluated the impact of pharmacist's care (compared with no pharmacist's care or usual care) on the outcomes of rehospitalization, mortality, and medication adherence in patients post-ACS discharge. Comparison of the outcomes with relevant statistics was summarized and reported. RESULTS: A total of 17 studies [13 randomized controlled trials (RCTs) and four non randomized clinical studies] involving 8391 patients were included in the review. The studies were of variable quality (poor to good quality) or risk of bias (moderate to critical risk). The nature and intensity of pharmacist interventions varied among the studies including medication reconciliation, medication therapy management, discharge medication counseling, motivational interviewing, and post discharge face-to-face or telephone follow-up. Pharmacist-delivered interventions significantly improved medication adherence in four out of 12 studies. However, these did not translate to significant improvements in the rates of readmissions, hospitalizations, emergency visits, and mortality among ACS patients. CONCLUSIONS: Pharmacist care of patients discharged after ACS admission was not associated with significant improvement in medication adherence or reductions in readmissions, emergency visits, and mortality. Future studies should use well designed RCTs to assess the short- and long-terms effects of pharmacist interventions in ACS patients. PMID- 28642001 TI - Regarding mechanical circulatory support in adults with congenital heart disease: Is it time to lower the threshold for use? PMID- 28642002 TI - Development of Geriatric Mental Health Learning Objectives for Medical Students: A Response to the Institute of Medicine 2012 Report. AB - America is aging as the population of older adults increases. The shortage of geriatric mental health specialists means that most geriatric mental healthcare will be provided by physicians who do not have specialty training in geriatrics. The Institute of Medicine Report of 2012 highlighted the urgent need for development of national competencies and curricula in geriatric mental health for all clinicians. Virtually all physicians can expect to treat older patients with mental health symptoms, yet currently there are no widely accepted learning objectives in geriatric mental health specific for medical students. The authors describe the development of a set of such learning objectives that all medical students should achieve by graduation. The iterative process included initial drafting by content experts from five medical schools with input and feedback from a wider group of geriatric psychiatrists, geriatricians, internists, and medical educators. The final document builds upon previously published work and includes specific knowledge, attitudes and skills in six key domains: Normal Aging, Mental Health Assessment of the Geriatric Patient, Psychopharmacology, Delirium, Depression, and Dementia. These objectives address a pressing need, providing a framework for national standards and curriculum development. PMID- 28642003 TI - Strabismus and binocular diplopia due to advanced glaucomatous visual field loss. AB - PURPOSE: To describe a small series of patients with glaucoma whose strabismus and binocular diplopia were due to advanced visual field loss and inability to maintain sensory and motor fusion. METHODS: This study is an observational case series of 3 patients with binocular diplopia, associated with variable strabismus, which was due to advanced visual field loss. RESULTS: Specific characteristics of the strabismus associated with advanced glaucomatous visual field loss were a subjective floating second image and marked variability of the prism and alternate cover measurements. Measured hypertropia changed in magnitude over a few seconds or a few minutes (even in 1 patient to a hypotropia), which distinguishes this specific type of strabismus from other types of comitant or incomitant strabismus associated with glaucoma. Although visual acuity was 20/400 or better in both eyes in all patients, there was advanced visual field loss in at least one eye. All patients responded poorly to prism, but their symptoms improved with a Bangerter filter applied to the spectacle lens or a MIN occlusion lens to further blur the worse-seeing eye. CONCLUSIONS: Variable strabismus associated with advanced glaucomatous visual field loss appears to be a distinct clinical entity that should be distinguished from other types of strabismus associated with glaucoma. Management of this specific type of strabismus is limited by inadequate visual field to fuse, analogous to hemifield slide, and therefore prism and/or strabismus surgery is unlikely to be successful. Primary treatment options include optical blur with Bangerter filters or a MIN occlusion lens although some patients prefer to ignore the second image. PMID- 28642004 TI - Removal of Entrapped Transoesophageal Echocardiography Probe Under the Guidance of Fluoroscopic Imaging. PMID- 28642005 TI - Expression, purification, and crystallization of type 1 isocitrate dehydrogenase from Trypanosoma brucei brucei. AB - Isocitrate dehydrogenases (IDHs) are metabolic enzymes that catalyze the oxidative decarboxylation of isocitrate to alpha-ketoglutarate. Depending on the electron acceptor and subcellular localization, these enzymes are classified as NADP+-dependent IDH1 in the cytosol or peroxisomes, NADP+-dependent IDH2 and NAD+ dependent IDH3 in mitochondria. Trypanosoma brucei is a protozoan parasite that causes African sleeping sickness in humans and Nagana disease in animals. Here, for the first time, a putative glycosomal T. brucei type 1 IDH (TbIDH1) was expressed in Escherichia coli and purified for crystallographic study. Surprisingly, the putative NADP+-dependent TbIDH1 has higher activity with NAD+ compared with NADP+ as electron acceptor, a unique characteristic among known eukaryotic IDHs which encouraged us to crystallize TbIDH1 for future biochemical and structural studies. Methods of expression and purification of large amounts of recombinant TbIDH1 with improved solubility to facilitate protein crystallization are presented. PMID- 28642006 TI - Exoenzyme activity and possibility identification of Candida dubliniensis among Candida albicans species isolated from vaginal candidiasis. AB - OBJECTIVES: Vulvovaginal candidiasis (VVC) or vaginal candidiasis is a common fungal infection of the genitals causing inflammation, irritation, itching, and vaginal discharge. Common yeast infections are caused by the yeast species C. albicans. However, there are other species of Candida such as C. dubliniensis which are considered as the causative agents of this infection. Hydrolytic enzymes such as proteinase and coagulase are known as virulence factors. The aim of this study was the molecular confirmation and differentiation of C. dubliniensis among C. albicans strains isolated from women with vulvovaginal candidiasis by PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) and the evaluation of proteinase and coagulase activities. METHODS: A total of 100 C. albicans strains isolated from women with vulvovaginal candidiasis referred to Shiraz medical clinics were enrolled in the study. All the isolates were primarily identified by conventional methods. PCR-RFLP method was used for the confirmation and identification of C. albicans and C. dubliniensis. Moreover, in vitro proteinase and coagulase activities of these isolates were evaluated using bovine serum albumin media and classical rabbit plasma tube test. RESULTS: As a result, PCR-RFLP identified 100% of the isolates as C. albicans, and no C. dubliniensis could be identified in this study. 84% of the isolates showed proteinase activity, whereas coagulase activity was only detected in 5% of the isolates. CONCLUSIONS: This study reveals that C. dubliniensis plays no role in vaginal candidiasis in Iranian patients. Proteinase production could be an essential virulence factor in C. albicans pathogenicity, but coagulase activity has less potential in this matter. PMID- 28642007 TI - Which fractionation of radiotherapy is best for limited-stage small-cell lung cancer? PMID- 28642009 TI - Mice in the early stage of liver steatosis caused by a high fat diet are resistant to thioacetamide-induced hepatotoxicity and oxidative stress. AB - Lipogenesis is stimulated in the liver by an unfolded protein response (UPR) to endoplasmic reticulum stress under a variety of pathological conditions and results in the accumulation of lipids in hepatocytes. Assuming that UPR is a protective mechanism against stress, we hypothesized that the accumulated lipids might have a beneficial function. We prepared mice with fatty livers by feeding two types of high-calorie diets; a lard-rich high-calorie diet (LHD) or a menhaden oil-containing high-calorie diet (MHD), for two weeks and treated them, as well as control diet (CD)-fed mice, with thioacetamide (TAA), a liver toxicant. When a lethal dose (500mg/kg) of TAA was administered, the LHD-fed mice and the MHD-fed mice survived longer than those fed with CD. The accumulated lipids appeared to be associated with protecting the liver against TAA toxicity (200mg/kg). Consistently, lipid-loaded Hepa 1-6 cells showed a partial resistance to hydrogen peroxide toxicity compared to those cultured in conventional media. In conclusion, while sustained steatosis impairs liver function and leads to hazardous conditions, lipids that transiently accumulate as the result of UPR or other stimuli may exert a beneficial function in the liver at least partly through scavenging reactive oxygen species. PMID- 28642008 TI - Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. AB - BACKGROUND: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer. METHODS: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged >=18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1.5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up. FINDINGS: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1.18 [95% CI 0.95-1.45]; p=0.14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5.3% [95% CI -3.2% to 13.7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0.05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0.85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0.70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once daily group). INTERPRETATION: Survival outcomes did not differ between twice daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting. FUNDING: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups). PMID- 28642011 TI - Comparison of Indian Council for Medical Research and Lunar Databases for Categorization of Male Bone Mineral Density. AB - The mainstay of diagnosis of osteoporosis is dual-energy X-ray absorptiometry (DXA) scan measuring areal bone mineral density (BMD) (g/cm2). The aim of the present study was to compare the Indian Council of Medical Research database (ICMRD) and the Lunar ethnic reference database of DXA scans in the diagnosis of osteoporosis in male patients. In this retrospective study, all male patients who underwent a DXA scan were included. The areal BMD (g/cm2) was measured at either the lumbar spine (L1-L4) or the total hip using the Lunar DXA machine (software version 8.50) manufactured by GE Medical Systems (Shanghai, China). The Indian Council of Medical Research published a reference data for BMD in the Indian population derived from the population-based study conducted in healthy Indian individuals, which was used to analyze the BMD result by Lunar DXA scan. The 2 results were compared for various values using statistical software SPSS for Windows (version 16; SPSS Inc., Chicago, IL). A total 238 male patients with a mean age of 57.2 yr (standard deviation +/-15.9) were included. Overall, 26.4% (66/250) and 2.8% (7/250) of the subjects were classified in the osteoporosis group according to the Lunar database and the ICMRD, respectively. Out of the 250 sites of the DXA scan, 28.8% (19/66) and 60.0% (40/66) of the cases classified as osteoporosis by the Lunar database were reclassified as normal and osteopenia by ICMRD, respectively. In conclusion, the Indian Council of Medical Research data underestimated the degree of osteoporosis in male subjects that might result in deferring of treatment. In view of the discrepancy, the decision on the treatment of osteoporosis should be based on the multiple fracture risk factors and less reliably on the BMD T-score. PMID- 28642010 TI - Magnetic nanogels as dual triggered anticancer drug delivery: Toxicity evaluation on isolated rat liver mitochondria. AB - This study aimed to evaluate bio-safety of magnetic chitosan nanogels as dual triggered drug carrier for doxorubicin through analysis of mitochondrial function. In the present study, chitosan/TPP nanogels containing magnetite nanoparticles (NPs) were prepared according to the ionotropic gelation method as novel pH-sensitive magnetic nanogels. The NPs showed outstanding entrapment efficiency for doxorubicin (76.6%) with a sustained and high extent of drug release in the acidic media (pH=5-7) compared to the neutral media. Various mitochondrial functional parameters including complex II activity, MDA amount, GSH level, membrane potential collapse, swelling, apoptosis and release of cytochrome c were used to investigate the bio-safety of the nanogels. The findings revealed that the extent of mitochondrial dysfunction of doxorubicin were in the order of free doxorubicin>doxorubicin loaded magnetic nanogels=>doxorubicin loaded Nanogels. The results also revealed that the nanogels and the magnetite nanogels seem to possess promising capability as a safe carrier in comparison of the toxic potential effect of free doxorubicin. PMID- 28642012 TI - Evaluation of a Device Combining an Inferior Vena Cava Filter and a Central Venous Catheter for Preventing Pulmonary Embolism Among Critically Ill Trauma Patients. AB - PURPOSE: To evaluate efficacy and safety of a novel device that combines an inferior vena cava (IVC) filter and central venous catheter (CVC) for prevention of pulmonary embolism (PE) in critically ill patients. MATERIALS AND METHODS: In a multicenter, prospective, single-arm clinical trial, the device was inserted at the bedside without fluoroscopy and subsequently retrieved before transfer from the intensive care unit (ICU). The primary efficacy endpoint was freedom from clinically significant PE or fatal PE 72 hours after device removal or discharge, whichever occurred first. Secondary endpoints were incidence of acute proximal deep venous thrombosis (DVT), catheter-related thrombosis, catheter-related bloodstream infections, major bleeding events, and clinically significant thrombus (occupying > 25% of volume of filter) detected by cavography before retrieval. RESULTS: The device was placed in 163 critically ill patients with contraindications to anticoagulation; 151 (93%) were critically ill trauma patients, 129 (85%) had head or spine trauma, and 102 (79%) had intracranial bleeding. The primary efficacy endpoint was achieved for all 163 (100%) patients (95% confidence interval [CI], 97.8%-100%, P < .01). Diagnosis of new or worsening acute proximal DVT was time dependent with 11 (7%) occurring during the first 7 days. There were no (0%) catheter-related bloodstream infections. There were 5 (3.1%) major bleeding events. Significant thrombus in the IVC filter occurred in 14 (8.6%) patients. Prophylactic anticoagulation was not initiated for a mean of 5.5 days +/- 4.3 after ICU admission. CONCLUSIONS: This novel device prevented clinically significant and fatal PE among critically ill trauma patients with low risk of complications. PMID- 28642014 TI - Acute hemodynamic effects of intravenous adenosine in patients with associated pulmonary arterial hypertension: Comparison with intravenous epoprostenol. AB - Exogenous intravenous (IV) adenosine and epoprostenol are effective vasodilator agents, causing a substantial reduction in pulmonary vascular resistance in patients affected by idiopathic pulmonary arteriolar hypertension (PAH). Their action, in patients with PAH associated with other pathological conditions, is not well defined. In the present paper the authors retrospectively analyzed the acute hemodynamic effects of intravenous adenosine and epoprostenol in 30 consecutive patients (mean age: 58 +/- 15 years; 21 females, and 9 males) affected by PAH associated with other pathological conditions, as determined by changes from baseline in systemic and pulmonary hemodynamic parameters. Acute IV administration of adenosine decreased pulmonary vascular resistance index (PVRI) by 3 Wood U/m2 (- 20%) compared to baseline (p = 0.02). We noted a slight, not significant, decrease in mean pulmonary artery pressure (mPAP) of 4 mmHg. Cardiac index (CI) increased by 0.5 L/min/m2 (15% increase respect to baseline; p = 0.03). The heart rate and mean systemic blood pressure (BP) did not change significantly. Acute IV administration of epoprostenol decreased PVRI by 6 mmHg ( 40%) respect to baseline (p < 0.0001). CI increased by 1.4 L/min/m2 (p < 0.0001); while mPAP decreased by 5 mmHg (nearly 10%) (p = 0.04). This decrease of mPAP was accompanied by a mean BP decrease of 11 mmHg compared to baseline (p = 0.003). Our results indicates that, in patients with PAH associated with other pathological conditions, adenosine is predominantly a positive inotropic agent; and epoprostenol a potent vasodilator of both pulmonary and systemic vessels, and a strong positive inotropic agent. PMID- 28642015 TI - Convergent and unidirectional evolution of extremely long aedeagi in the largest feather mite genus, Proctophyllodes (Acari: Proctophyllodidae): Evidence from comparative molecular and morphological phylogenetics. AB - Proctophyllodid feather mites (400+ species) are permanent (full-time) symbionts commonly occurring on passerine birds. Phenotypic evolution of these mites appears to be greatly influenced by characters related to reproduction (>87.5% of a total of 32 taxonomically important discrete characters) and male genitalic characters (21.9%). Because sexual selection could the major evolutionary driver in this system, we test the theoretical expectation that genitalic or sexually dimorphic characters should evolve more rapidly and divergently then other characters. We inferred a time-calibrated molecular phylogeny (6 genes, 8571 nt aligned, no missing data) for 133 taxa of proctophyllodid mites and 40 outgroups. Comparisons of the average number of character state changes inferred on 10,696 Bayesian stationary trees indicate that male genitalic or sexually dimorphic characters do not evolve significantly faster than other characters (p=0.537 and p=0.819, respectively). However, among the male genitalic characters, a trait related to the relative length of the aedeagus experienced extremely fast rates of evolution and was detected as a statistical outlier. In this character, the transitions between short, long, and several intermediate states occurred in both directions. In contrast, the evolution of extremely long aedeagi (nearly as long as the body) occurred unidirectionally and irreversibly. This surprising result may be due to constraints imposed by the female spermathecal canal, which, in species where males have extremely long aedeagi, is also very long and may impede pumping sperm by short aedeagi. In proctophyllodid mites, extremely long aedeagi evolved independently five times in five different monophyletic lineages. Several of these lineages were lumped together by taxonomists to form easy-to-distinguish but apparently artificial species-groups. Male genitalic characters, thus, can introduce false synapomorphies that could affect morphology-based phylogenetic inference. For the most species-rich genus, Proctophyllodes, we develop a predictive classification of species-groups that reconciles molecular and morphological data. PMID- 28642013 TI - Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection. AB - Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a pulmonary pathogen of major global concern. A key feature of Mtb infection in primates is the formation of granulomas, dense cellular structures surrounding infected lung tissue. These structures serve as the main site of host-pathogen interaction in TB, and thus to effectively treat TB we must clarify mechanisms of granuloma formation and their function in disease. Fibrotic granulomas are associated with both good and bad disease outcomes. Fibrosis can serve to isolate infected tissue from healthy tissue, but it can also cause difficulty breathing as it leaves scars. Little is known about fibrosis in TB, and data from non-human primates is just beginning to clarify the picture. This work focuses on constructing a hybrid multi-scale model of fibrotic granuloma formation, in order to identify mechanisms driving development of fibrosis in Mtb infected lungs. We combine dynamics of molecular, cellular, and tissue scale models from previously published studies to characterize the formation of two common sub-types of fibrotic granulomas: peripherally fibrotic, with a cuff of collagen surrounding granulomas, and centrally fibrotic, with collagen throughout granulomas. Uncertainty and sensitivity analysis, along with large simulation sets, enable us to identify mechanisms differentiating centrally versus peripherally fibrotic granulomas. These findings suggest that heterogeneous cytokine environments exist within granulomas and may be responsible for driving tissue scale morphologies. Using this model we are primed to better understand the complex structure of granulomas, a necessity for developing successful treatments for TB. PMID- 28642016 TI - Electrospun vascular scaffold for cellularized small diameter blood vessels: A preclinical large animal study. AB - : The strategy of vascular tissue engineering is to create a vascular substitute by combining autologous vascular cells with a tubular-shaped biodegradable scaffold. We have previously developed a novel electrospun bilayered vascular scaffold that provides proper biological and biomechanical properties as well as structural configuration. In this study, we investigated the clinical feasibility of a cellularized vascular scaffold in a preclinical large animal model. We fabricated the cellularized vascular construct with autologous endothelial progenitor cell (EPC)-derived endothelial cells (ECs) and smooth muscle cells (SMCs) followed by a pulsatile bioreactor preconditioning. This fully cellularized vascular construct was tested in a sheep carotid arterial interposition model. After preconditioning, confluent and mature EC and SMC layers in the scaffold were achieved. The cellularized constructs sustained the structural integrity with a high degree of graft patency without eliciting an inflammatory response over the course of the 6-month period in sheep. Moreover, the matured EC coverage on the lumen and a thick smooth muscle layer were formed at 6months after transplantation. We demonstrated that electrospun bilayered vascular scaffolds in conjunction with autologous vascular cells may be a clinically applicable alternative to traditional prosthetic vascular graft substitutes. STATEMENT OF SIGNIFICANCE: This study demonstrates the utility of tissue engineering to provide platform technologies for rehabilitation of patients recovering from severe, devastating cardiovascular diseases. The long term goal is to provide alternatives to vascular grafting using bioengineered blood vessels derived from an autologous cell source with a functionalized vascular scaffold. This novel bilayered vascular construct for engineering blood vessels is designed to offer "off-the-shelf" availability for clinical translation. PMID- 28642017 TI - Patterns of Care and Temporal Trends in Ischemic Stroke Management: A Brazilian Perspective. AB - BACKGROUND AND PURPOSE: Demonstration of an improvement process of quality indicators in stroke care is essential to obtain certification as a primary stroke center (PSC). Our aim was to evaluate factors that influence temporal trends in quality indicators of ischemic stroke (IS) in a Brazilian hospital. METHODS: We evaluated patients discharged with IS from a tertiary hospital from January 2009 to December 2013. Ten predefined performance measures selected by the Get With the Guidelines-Stroke program were assessed. We also compared 5 quality indicators available from a secondary community hospital for the first year of the series to those found in the tertiary hospital. RESULTS: We evaluated 551 patients at the tertiary stroke center (median age 77.0 years [interquartile range 64.0-84.0]; 58.4% were men). The quality indicators that improved with time were the use of cholesterol-lowering therapy (P = .02) and stroke education (P = .04). The median composite perfect care did not consistently improve throughout the period (P = .13). After a multivariable adjustment, only thrombolytic treatment (odds ratio [OR] 2.06, P < .01), dyslipidemia (OR 2.03, P < .01), and discharge in a Joint Commission International's (JCI) visit year (OR 1.8, P < .01) remained as predictors of a perfect care index of 85% or higher. The quality indicators with worse performance (anticoagulation for atrial fibrillation and cholesterol reduction) were similar in the tertiary and secondary community hospitals. CONCLUSIONS: We found a significant improvement in some quality indicators across the years in a PSC located in Latin America. The overall perfect care measure did not improve and was influenced by being discharged in a JCI visit year, having dyslipidemia, and having undergone thrombolytic treatment. PMID- 28642018 TI - Clinical Study of 27 Patients with Medial Medullary Infarction. AB - BACKGROUND: Medial medullary infarction (MMI) is a rare ischemic stroke. Frequency of each neurological finding in MMI was different in each study. METHODS: We retrospectively evaluated the medical records of patients with cerebral infarction who were admitted between March 1998 and October 2015. Patients in our study were diagnosed as having MMI by magnetic resonance image examination. RESULTS: Of 2727 patients with ischemic stroke, 27 patients (20 males and 7 females) had MMI. The MMI was complicated by infarcts located in the pons (n = 6), cerebellum (n = 2), and lateral medulla (n = 1). One patient had bilateral MMI. Large-artery atherosclerosis was the most common etiology. Motor weakness of the extremities was the most common neurological finding. Diminished contralateral superficial sensation was more common than diminished contralateral vibratory sensation, and these 2 types of sensory disturbance were often complicated. The patients with large MMI significantly more often accompanied diminished touch (P = .003), pain (P = .017), and vibratory (P = .019) sensation. Facial weakness was shown more common contralateral to the infarcts than ipsilateral (n = 8 contralateral, n = 1 ipsilateral). Lingual palsy was also more common contralateral to the lesions (n = 3 contralateral, n = 1 ipsilateral). One patient alone fulfilled the classical Dejerine triad. CONCLUSIONS: In MMI, motor weakness of extremities was commonly shown, and complication of diminished sensations indicated the large infarcts. As for facial weakness and lingual palsy, the supranuclear type was more prominent than the infranuclear type. PMID- 28642019 TI - Re: Declan G. Murphy, Christopher J. Sweeney, Bertrand Tombal. "Gotta Catch 'em All" or Do We? Pokemet Approach to Metastatic Prostate Cancer. Eur Urol 2017;72:1 3. PMID- 28642020 TI - Reply to Saeid Safiri and Erfan Ayubi's Letter to the Editor re: Nicholas J. Giacalone, William U. Shipley, Rebecca H. Clayman, et al. Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience. Eur Urol 2017;71:952-60. Methodological Issues to Avoid Misinterpretation. PMID- 28642021 TI - Reply to Lorenzo Marconi, Steven MacLennan, Thomas B.L. Lam, et al's Letter to the Editor re: Maria Carmen Mir, Ithaar Derweesh, Francesco Porpiglia, Homayoun Zargar, Alexandre Mottrie, Riccardo Autorino. Partial Nephrectomy Versus Radical Nephrectomy for Clinical T1b and T2 Renal Tumors: A Systematic Review and Meta analysis of Comparative Studies. Eur Urol 2017;71:606-17. PMID- 28642022 TI - Papillary Renal Cell Carcinoma: A Family Portrait. PMID- 28642023 TI - Reply to Isabel Heidegger, Renate Pichler, and Andreas Pircher's Letter to the Editor re: Erik Bovinder Ylitalo, Elin Thysell, Emma Jernberg, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol 2017;71:776-87. PMID- 28642024 TI - rTMS with a two-coil array: Safety and efficacy for treatment resistant major depressive disorder. AB - BACKGROUND: Therapeutic repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a standard of care for individuals with major depressive disorder (MDD) who do not benefit from, or are unable to tolerate, antidepressant pharmacotherapy. Depth of stimulation is limited with currently approved figure eight coils and larger coils capable of deeper penetration may be associated with loss of stimulation focality and undesired recruitment of motor cortex. A second generation 2-coil array rTMS system was designed to target converging brain pathways for potentially deeper prefrontal cortex stimulation. METHODS: A randomized, double-blind, sham-controlled trial examined the safety and efficacy of an investigational 2-coil rTMS device. Antidepressant treatment-resistant or treatment-intolerant MDD patients (n = 92) received 20 daily rTMS treatments with coil centers positioned over left dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC). 10 Hz stimulation (maximum summated power for both coils <= 120% motor threshold) was delivered. Primary efficacy endpoint was change in HAMD-24 score from baseline to the conclusion of treatments. RESULTS: Data from n = 75 (per-protocol sample) showed significantly greater improvement (mean HAMD-24 change) over time for the active (n = 38) versus sham (n = 37) group after 20 sessions (F = 7.174; p = 0.008) and also at the one-month follow-up (F = 6.748; p = 0.010). Response rates were 55.3% (active) versus 32.4% (sham) (p = 0.063); remission rates were 26.3% versus 18.9% (p > 0.05). Other secondary outcomes were generally supportive. CONCLUSIONS: The results confirmed safety and acute efficacy of the 2-coil rTMS device. Despite modest sample size, primary outcome was clinically and statistically significant, and the effect size was comparable with those reported for regulatory trials with FDA-cleared devices. PMID- 28642025 TI - Total Laparoscopic Resection Surgery for a Cervical Carcinoma that Recurred in the Pelvic Sidewall After Radical Hysterectomy and Adjuvant Concurrent Chemoradiotherapy. AB - STUDY OBJECTIVE: To show total laparoscopic resection of a cervical carcinoma that recurred at the left pelvic sidewall after radical hysterectomy and concurrent chemoradiotherapy (CCRT). DESIGN: A step-by-step demonstration of the technique in a surgical video, including the strategy for achieving complete surgical resection with negative margins (R0 resection) (Canadian Task Force Classification III). SETTING: For high-risk cervical carcinoma, radical hysterectomy and adjuvant CCRT is the standard treatment, but even this multimodal therapy cannot prevent recurrence. When the recurrent mass is localized in the pelvic cavity, R0 resection offers the most promise; however, for laterally recurring cervical carcinoma, the resectability rate is low, owing mainly to severe adhesion and fibrosis, and thus the morbidity and mortality rates are high. Because laparoscopy optimizes visualization and provides for meticulous dissection, laparoscopic surgery can be advantageous over open surgery for resection of cervical carcinoma recurring at the pelvic sidewall after radical hysterectomy and adjuvant CCRT. INTERVENTIONS: A 48-year-old woman with stage IB2 cervical adenocarcinoma had undergone radical hysterectomy, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, and, because lymph node metastasis was found in the removed lymph nodes, adjuvant CCRT. At 6 months after completion of this multimodal therapy, a recurrent mass was detected at the left pelvic sidewall. The mass involved the left ureter, bladder, left internal iliac vessels, and endopelvic fascia, and left renal function was unrecoverable. Tumor excision and left nephroureterectomy were performed laparoscopically. The total operating time was 608 minutes, blood loss volume was 250 mL, and blood transfusion was not required. Complete tumor clearance (R0 resection) was achieved by resection of the left internal iliac vessels, left internal obturator muscle, left pubococcygeal muscle, left ureter, and bladder. There were no postoperative complications. Institutional Review Board approval was obtained through our local Ethics Committee in Cancer Institute hospital. CONCLUSION: Complete laparoscopic resection surgery for recurrent cervical carcinoma at the pelvic sidewall after radical hysterectomy and adjuvant CCRT is technically feasible. The good visualization and meticulous dissection provided during laparoscopic surgery make the approach advantageous for the management of laterally recurrent cervical carcinoma. PMID- 28642026 TI - Laparoscopic Resection of Pelvic Sidewall Recurrent Cervical Cancer: Feasibility Does Not Always Equate with Clinical Indication. PMID- 28642027 TI - [Monitoring devices and their alarms: incident reports suggest problems with device knowledge]. AB - Missing or false device alarms pose a risk in clinical practice. Publications from the United States suggest that alarm errors are not only caused by technical issues but to a considerable degree result from user-device interaction problems. To safely operate a medical device, users have to thoroughly understand both device behavior and device functioning. They also need to foresee the exact consequences of their interactions with the device. This can be challenging, especially if a device has multiple functions, is applied in various use contexts or networked with other devices - as is often the case with patient monitors. In this case, human error in operating a device may not necessarily be detected, but is experienced as device failure. If medical device failures occur in German hospitals that are associated with a risk to the patient, the user, or other persons, they have to be reported to the Federal Institute for Drugs and Medical Devices (Bundesinstitut fur Arzneimittel und Medizinprodukte, BfArM). In the present study, we analyzed reports to the BfArM (received between 01/2009 and 12/2015) about loss or failure of the alarm function of patient monitors. It was found that the perceived 'faulty' behavior of the device was the device's intended behavior in almost half of these reports. Hence, the person who detected this fault was not sufficiently acquainted with the device and/or its configuration. Examples of knowledge deficits related to various aspects of device knowledge. Further studies are needed to find out whether these findings are suggestive of more general knowledge deficits among clinical staff and to explore the underlying reasons. PMID- 28642028 TI - Discovery of novel 5-oxa-2,6-diazaspiro[3.4]oct-6-ene derivatives as potent, selective, and orally available somatostatin receptor subtype 5 (SSTR5) antagonists for treatment of type 2 diabetes mellitus. AB - Somatostatin receptor subtype 5 (SSTR5) has emerged as a novel attractive drug target for type 2 diabetes mellitus. Starting from N-benzyl azetidine derivatives 1 and 2 as in-house hit compounds, we explored the introduction of a carboxyl group into the terminal benzene of 1 to enhance SSTR5 antagonistic activity by the combination of the substituents at the 3-position of the isoxazoline. Incorporation of a carboxyl group at the 4-position of the benzene ring resulted in a significant enhancement in potency, however, the 4-benzoic acid derivative 10c exhibited moderate human ether-a-go-go related gene (hERG) inhibitory activity. A subsequent optimization study revealed that replacement of the 4 benzoic acid with an isonipecotic acid dramatically reduced hERG inhibition (5.6% inhibition at 30MUM) by eliminating pi-related interaction with hERG K+ channel, which resulted in the identification of 1-(2-((2,6-diethoxy-4'-fluorobiphenyl-4 yl)methyl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)piperidin-4-carboxylic acid 25a (hSSTR5/mSSTR5 IC50=9.6/57nM). Oral administration of 25a in high-fat diet fed C57BL/6J mice augmented insulin secretion in a glucose-dependent manner and lowered blood glucose concentration. PMID- 28642029 TI - Azobenzene-containing photoswitchable proteasome inhibitors with selective activity and cellular toxicity. AB - A series of azobenzene-containing peptidic boronate esters was prepared and the activity of the thermally adapted states (TAS), enriched in trans isomer, and the photostationary states (PSS), enriched in cis isomer, for each compound were evaluated against beta5 and beta1 proteasome subunits. Compounds with a sterically demanding phenyl-substituted azobenzene at P2 (4c), and a less sterically demanding unsubstituted azobenzene at the N-terminus (5a), showed the greatest difference in activity between the two states. In both cases, the more active trans-enriched TAS had activity comparable to bortezomib and delanzomib. Furthermore, cis-enriched 4c inhibited tumor growth in both breast and colorectal carcinoma cell lines. Significantly, the initial trans-enriched TAS of 4c was not cytotoxic against the non-malignant MCF-10A cells. PMID- 28642030 TI - Cyclic MOG35-55 ameliorates clinical and neuropathological features of experimental autoimmune encephalomyelitis. AB - EAE is induced to susceptible mice using linear peptides of myelin proteins of the central nervous system. Specific peptide motifs within the peptide-binding groove of the MHC peptide-complex determines the affinity of the peptide in each animal and the consequent T-cell receptor recognition and activation of the cell. Altered peptide ligand (APL) vaccination is a novel approach based on an effort to induce T-cell tolerance or alter cytokine profile from pro-inflammatory to anti-inflammatory. In the present study we synthesized the MOG35-55 peptide and altered its 3-dimensional conformation to make it a cyclic one (c-MOG35-55). EAE was induced in C57BL/6 mice and pathology was studied on acute and chronic phase of the disease. Our data indicates that c-MOG35-55 peptide alone induces a mild transient acute phase without chronic axonopathy. Administration of the c-MOG35 55 peptide at a 1:1 ratio during disease induction significantly ameliorates clinical disease and underlying pathology, such as demyelination and axonopathy in the acute and chronic phases. Binding and structural studies revealed milder interactions between the c-MOG35-55 and mouse or human MHC class II alleles (H2 IAb and HLA-DR2). Collectively, we provide data supporting for the first time the concept that the cyclic modification of an established encephalitogenic peptide ameliorates the clinical outcomes and underlying pathological processes of EAE. Such a cyclic modification of linear peptides could provide a novel treatment approach for future, patient-selective, immunomodulative treatments of multiple sclerosis. PMID- 28642031 TI - Clustering of MS2 spectra using unsupervised methods to aid the identification of secondary metabolites from Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an important opportunistic pathogen that produces a large arsenal of small molecule virulence factors and quorum sensing signal molecules. The annotation of these secondary metabolites in untargeted, mass spectrometry-based metabolomics is difficult, as many of them cannot be found in common metabolite databases, and as manual annotation is tedious. We therefore developed an algorithm named CluMSID that uses cosine similarities of product ion spectra and neutral loss patterns in combination with unsupervised clustering methods such as multidimensional scaling, density based clustering and hierarchical clustering to group structurally similar compounds and hence facilitate their annotation. The use of this tool allowed us to find clusters for several classes of primary and secondary metabolites, and helped identifying spectral similarities that would have gone unnoticed in standard untargeted metabolomics data analysis workflows. CluMSID enabled the annotation of 27 previously undescribed members of the canonical classes of alkyl quinolone quorum sensing signal molecules and provided evidence for the postulation of a new putative alkyl quinolone class. The CluMSID script written in R is open source and can be used by anyone in the metabolomics and natural product research community. PMID- 28642032 TI - Apoptosis and Necroptosis as Host Defense Strategies to Prevent Viral Infection. AB - Antiviral transcriptional responses and regulated cell death are crucial components of the host response to virus infection. However, in contrast to the signaling pathways that promote antiviral transcription, those that initiate cell death following virus infection are less understood. Several recent studies have identified pattern recognition receptors (PRRs) of the mammalian innate immune system that activate cell death pathways. These same receptors also have established roles in the induction of antiviral gene expression. In this review we discuss the mechanisms by which PRRs can serve dual roles as initiators of inflammatory gene expression and as inducers of apoptosis and necroptosis following virus infection. PMID- 28642033 TI - ATG4B inhibitors with a benzotropolone core structure block autophagy and augment efficiency of chemotherapy in mice. AB - Autophagy is a cell survival mechanism hijacked by advanced tumors to endure a rough microenvironment. Late autophagy inhibitors such as (hydroxy)chloroquine have been used clinically to halt tumor progression with modest success. However, given the toxic nature of these compounds and their lack of specificity, novel targets should be considered. We recently identified a benzotropolone derivative that significantly inhibited the essential autophagy protein ATG4B. Therefore, we synthesized and tested additional benzotropolone compounds to identify a promising ATG4B inhibitor that impairs autophagy both in vitro and in vivo. A compound library containing 27 molecules with a benzotropolone backbone was synthesized and screened for inhibition of recombinant ATG4B. Depending on the benzotropolone compound, inhibition of recombinant ATG4B ranged from 3 to 82%. Active compounds were evaluated in cellular assays to confirm inhibition of ATG4B and suppression of autophagy. Seven compounds inhibited processing of the autophagy protein LC3 and autophagosome formation. Compound UAMC-2526 was selected for further in vivo use because of its fair plasma stability. This compound abolished autophagy both in nutrient-deprived GFP-LC3 mice and in CD1-/- Foxn1nu mice bearing HT29 colorectal tumor xenografts. Moreover, addition of UAMC 2526 to the chemotherapy drug oxaliplatin significantly improved inhibition of tumor growth. Our data indicate that suppression of autophagy via ATG4B inhibition is a feasible strategy to augment existing chemotherapy efficacy and to halt tumor progression. PMID- 28642034 TI - Cyclooxygenase-2 promotes pulmonary intravascular macrophage accumulation by exacerbating BMP signaling in rat experimental hepatopulmonary syndrome. AB - BACKGROUND AND AIMS: One central factor in hepatopulmonary syndrome (HPS) pathogenesis is intravascular accumulation of activated macrophages in small pulmonary arteries. However, molecular mechanism underlying the macrophage accumulation in HPS is unknown. In this study, we aimed to explore whether elevated COX-2 induces the Bone morphogenic protein-2 (BMP-2)/Crossveinless-2 (CV 2) imbalance and then activation of BMP signaling pathway promotes the macrophage accumulation in Common Bile Duct Ligation (CBDL) rat lung. METHODS: The COX 2/PGE2 signaling activation, the BMP-2/CV-2 imbalance and the activation of Smad1 were evaluated in CBDL rat lung and in cultured pulmonary microvascular endothelial cells (PMVECs) under the HPS serum stimulation. The effects of Parecoxib (COX-2 inhibitor), BMP-2 and CV-2 recombinant proteins on 4-week CBDL rat lung were determined, respectively. RESULTS: The COX-2/PGE2 signaling pathway was activated in CBDL rat lung in vivo and PMVECs in vitro, which was due to the activation of NF-kappaB P65. The inhibition of COX-2 by Parecoxib reduced macrophage accumulation, decreased lung angiogenesis and improved HPS. Meanwhile, the CBDL rat lung secreted more BMP-2 but less CV-2, and the imbalance between BMP-2 and CV-2 exacerbated the BMP signaling activation thus promoting the macrophage accumulation and lung angiogenesis. The BMP-2/CV-2 imbalance is dependent on the COX-2/PGE2 signaling pathway, and thus the effects of this imbalance can be reversed by adminstration of Parecoxib. CONCLUSION: Our findings indicate that inhibition of COX-2 by parecoxib can improve the HPS through the repression of BMP signaling and macrophage accumulation. PMID- 28642035 TI - Improving the efficacy of hormone therapy in breast cancer: The role of cholesterol metabolism in SERM-mediated autophagy, cell differentiation and death. AB - Breast cancer (BC) is one of the most common female cancers in the world, with estrogen receptor (ER)-positive BC the most frequent subtype. Tamoxifen (Tam) is an effective drug that competitively binds to the ER and is routinely used for the treatment of ER-positive BC. However, a number of ER-positive BC do not respond to Tam treatment and acquired resistance is often observed, constituting a major challenge for extending patient life expectancy. The mechanisms responsible for these treatment failures remain unclear, indicating the requirement for other targets and better predictors for patient response to Tam. One of Tam's off-targets of interest is the microsomal antiestrogen binding site (AEBS), a multiproteic complex made up of the cholesterol-5,6-epoxide hydrolase (ChEH) enzymes that are involved in the late stages of cholesterol biosynthesis. Tam and other selective ER modulators stimulate oxidative stress and inhibit the ChEH subunits at pharmacological doses, triggering the production and accumulation of cholesterol-5,6-epoxide metabolites responsible for BC cell differentiation and death. However, inhibition of the cholesterogenic activity of the AEBS subunits also induces the accumulation of sterol precursors, which triggers a survival autophagy to impair Tam's efficacy. Altogether, these studies have highlighted the involvement of cholesterol metabolism in the pharmacology of Tam that has provided new clues on how to improve its therapeutic efficacy in both BC and other cancers as well as offering a new rationale for developing more efficient drugs for BC treatment. PMID- 28642036 TI - Transcription factor decoy technology: A therapeutic update. AB - Targeting transcription factors represents one possibility to interfere with a known activated regulatory pathway that promotes disease. Double-stranded transcription factor decoy (TFD) oligodeoxynucleotides (ODN) are therapeutic drug candidates, which are able to specifically target and neutralize key transcription factors involved in the pathogenesis of a given disease. These short double-stranded TFD molecules mimic the consensus DNA binding site of a specific transcription factor in the promoter region of its target genes. Therefore, it is possible to exploit this nucleic acid-based drug class for the treatment of diseases caused by aberrant expression of such target genes the products of which are involved in disease initiation and progression. This research update focuses firstly on the mechanism of action of TFD molecules. Long term effects of such ODNs depend on their stability and the efficiency by which they are delivered to the target tissue and taken up by their target cells. Hence structural modifications like e.g., single-stranded TFD molecules hybridising to itself to form an intramolecular hairpin molecule or circular ODNs assuming a dumbbell configuration, intended to enhance both stability and efficacy, are addressed. Also specific drug delivery methods like ultrasound-targeted microbubble destruction with TFD ODN-coated microbubbles or adeno-associated viral (AAV) vectors for tissue-specific transduction and long-term TFD molecule expression in non-dividing cells will be discussed. Finally, current therapeutic applications of TFD ODN will be summarized. PMID- 28642037 TI - Testosterone regulates 3T3-L1 pre-adipocyte differentiation and epididymal fat accumulation in mice through modulating macrophage polarization. AB - Low testosterone levels are strongly related to obesity in males. The balance between the classically M1 and alternatively M2 polarized macrophages also plays a critical role in obesity. It is not clear whether testosterone regulates macrophage polarization and then affects adipocyte differentiation. In this report, we demonstrate that testosterone strengthens interleukin (IL) -4-induced M2 polarization and inhibits lipopolysaccharide (LPS)-induced M1 polarization, but has no direct effect on adipocyte differentiation. Cellular signaling studies indicate that testosterone regulates macrophage polarization through the inhibitory regulative G-protein (Galphai) mainly, rather than via androgen receptors, and phosphorylation of Akt. Moreover, testosterone inhibits pre adipocyte differentiation induced by M1 macrophage medium. Lowering of serum testosterone in mice by injecting a luteinizing hormone receptor (LHR) peptide increases epididymal white adipose tissue. Testosterone supplementation reverses this effect. Therefore, our findings indicate that testosterone inhibits pre adipocyte differentiation by switching macrophages to M2 polarization through the Galphai and Akt signaling pathways. PMID- 28642038 TI - Functional characterization of 21 allelic variants of dihydropyrimidinase. AB - Dihydropyrimidinase (DHP, EC 3.5.2.2), encoded by the gene DPYS, is the second enzyme in the catabolic pathway of pyrimidine and of fluoropyrimidine drugs such as 5-fluorouracil, which are commonly used in anticancer treatment; DHP catalyzes the hydrolytic ring opening of dihydrouracil and dihydro-5-fluorouracil. DPYS mutations are known to contribute to interindividual variations in the toxicity of fluoropyrimidine drugs, but the functional characterization of DHP allelic variants remains inadequate. In this study, in vitro analysis was performed on 22 allelic variants of DHP by transiently expressing wild-type DHP and 21 DHP variants in 293FT cells and characterizing their enzymatic activities by using dihydrouracil and dihydro-5-fluorouracil as substrates. DHP expression levels and oligomeric forms were determined using immunoblotting and blue native PAGE, respectively, and the stability of the DHP variants was assessed by examining the proteins in variant-transfected cells treated with cycloheximide or bortezomib. Moreover, three kinetic parameters, Km, Vmax, and intrinsic clearance (Vmax/Km), for the hydrolysis of dihydrouracil and dihydro-5-fluorouracil were determined. We found that 5/21 variants showed significantly decreased intrinsic clearance as compared to wild-type DHP, and that 9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation. The band patterns observed in the immunoblotting of blue native gels corresponded to DHP activity, and, notably, 18/21 DHP variants exhibited decreased or null enzymatic activity and these variants also showed a drastically reduced ability to form large oligomers. Thus, detection of DPYS genetic polymorphisms might facilitate the prediction severe adverse effects of fluoropyrimidine-based treatments. PMID- 28642039 TI - Development and validation of a screening instrument to identify cardiometabolic predictors of mortality in older individuals with cancer: Secondary analysis of the Australian Longitudinal Study of Ageing (ALSA). AB - OBJECTIVE: The objective of this study was to identify significant cardiometabolic predictors of mortality among older cancer survivors and develop and validate a screening instrument to assess individual risk of mortality. MATERIALS AND METHODS: Retrospective cohort study used collected data from the ALSA. Cox proportional hazards model was used to derive the risk equation for mortality that could be evaluated at 10years. Measures of discrimination and calibration were calculated in the validation cohort. RESULTS: The equation was developed using 294 cancer survivors and validated in 127 different cancer survivors. Significant cardiometabolic predictors of mortality included in the final model are age, sex, history of cerebrovascular disease, non-adherence to exercise guidelines (150min moderate activity per week), and smoking. Discrimination and calibration were acceptable with minimal differences in C statistics (0.0442, 95% CI: -0.0149 to 0.103) and adjusted R2 values (0.0407, 95% CI: -0.181 to 0.0998) between the development and validation cohorts, respectively. CONCLUSION: We have developed and validated the first screening tool to predict cardiometabolic risk of mortality in older cancer survivors and defined centile values for risk classification. Further validation and research on the usability and usefulness of the tool in clinical practice are recommended in order to target cancer survivors for interventions. Cost effectiveness of such an approach should also be examined. PMID- 28642040 TI - Global geriatric oncology: Achievements and challenges. AB - The aging of the population is a global challenge. The number of older adults is rapidly growing, leading to an increase in the prevalence of noncommunicable diseases associated with aging, such as cancer. Worldwide, older adults account for approximately half of all cancer cases, and this proportion is projected to increase globally. Furthermore, the majority of older adults live in less developed regions, where health systems are generally ill-equipped to provide care for complex chronic conditions. Worldwide, there is paucity of geriatric training, and most of the oncology workforce lacks the skills and knowledge to provide comprehensive care for older patients. Various initiatives aimed at providing adequate clinical care for older adults, increasing the geriatric skills and knowledge of healthcare professionals, and developing geriatric oncology research, have been successfully implemented. However, most developments in geriatric oncology have taken place in high-income countries, and there are still large inequalities in the availability of clinical, educational, and research initiatives across different regions of the world. This article provides an overview of geriatric oncology initiatives in Asia, Europe, Australia and New Zealand, Latin America, and the United States and Canada. Understanding the achievements and challenges of geriatric oncology around the world, and fostering international collaboration in research and training are essential for improving the care of all older adults with cancer. PMID- 28642041 TI - Interaction of polyhedral oligomeric silsesquioxanes and dipalmitoylphosphatidylcholine at the air/water interface: Thermodynamic and rheological study. AB - Polyhedral oligomeric silsesquioxanes (POSS) derivatives containing open silsesquioxane cage bear great potential for biomedical applications and therefore their lateral interactions with phospholipids, major biomembranes and drug vehicles constituent, should be studied in detail. That is why the properties of surface films by two POSS-derivatives, POSS-polyethylene glycol (POSS-PEG) and POSS-perfluoroalkyl (POSS-OFP), pure and in presence of 1,2 dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC) were studied using Langmuir surface balance. Side chains of opposite nature (PEG is hydrophilic; OFP is hydrophobic) were selected, so that to evaluate their impact on polymers' surface properties. Two types of measurements were performed: (i) the miscibility of POSS derivatives with DPPC was evaluated via thermodynamic analysis of the surface pressure (pi)-area (A) isotherms and (ii) the dilatational rheology of selected POSS-polymer containing films was studied by the stress relaxation method. Fourier transformation analysis of the relaxation transients allows to access films' dynamic interfacial properties in broad frequency range (10-5-1Hz). Film morphology was monitored with Brewster Angle Microscopy. PEG moiety enabled POSS PEG to stably incorporate in DPPC films, modifying their equilibrium and dynamic properties. In contrast OFP chains excluded from interactions with other molecules and diminished PEG-OFP amphiphilicity. Therefore at high packing densities (pi>=25mN/m) PEG-OFP was expelled from the air/water interface in DPPC/PEG-OFP mixtures, and the binary films equilibrium and dynamic surface properties were determined primarily by DPPC. Thus the choice of POSS side chains can play key role in biomedical applications depending on whether strong or weak incorporation of POSS-polymers in lipid environment is aimed for. PMID- 28642042 TI - Changes in membrane biophysical properties induced by the Budesonide/Hydroxypropyl-beta-cyclodextrin complex. AB - Budesonide (BUD), a poorly soluble anti-inflammatory drug, is used to treat patients suffering from asthma and COPD (Chronic Obstructive Pulmonary Disease). Hydroxypropyl-beta-cyclodextrin (HPbetaCD), a biocompatible cyclodextrin known to interact with cholesterol, is used as a drug-solubilizing agent in pharmaceutical formulations. Budesonide administered as an inclusion complex within HPbetaCD (BUD:HPbetaCD) required a quarter of the nominal dose of the suspension formulation and significantly reduced neutrophil-induced inflammation in a COPD mouse model exceeding the effect of each molecule administered individually. This suggests the role of lipid domains enriched in cholesterol for inflammatory signaling activation. In this context, we investigated the effect of BUD:HPbetaCD on the biophysical properties of membrane lipids. On cellular models (A549, lung epithelial cells), BUD:HPbetaCD extracted cholesterol similarly to HPbetaCD. On large unilamellar vesicles (LUVs), by using the fluorescent probes diphenylhexatriene (DPH) and calcein, we demonstrated an increase in membrane fluidity and permeability induced by BUD:HPbetaCD in vesicles containing cholesterol. On giant unilamellar vesicles (GUVs) and lipid monolayers, BUD:HPbetaCD induced the disruption of cholesterol-enriched raft-like liquid ordered domains as well as changes in lipid packing and lipid desorption from the cholesterol monolayers, respectively. Except for membrane fluidity, all these effects were enhanced when HPbetaCD was complexed with budesonide as compared with HPbetaCD. Since cholesterol-enriched domains have been linked to membrane signaling including pathways involved in inflammation processes, we hypothesized the effects of BUD:HPbetaCD could be partly mediated by changes in the biophysical properties of cholesterol-enriched domains. PMID- 28642043 TI - Mitochondrial Cx43, an important component of cardiac preconditioning. AB - Connexin 43 (Cx43) forms gap junction channels that are essential for the propagation of electrical depolarization in cardiomyocytes, but also with important roles in the pathophysiology of reperfusion injury. However, more recent studies have shown that Cx43 has also important functions independent from intercellular communication between adjacent cardiomyocytes. Some of these actions have been related to the presence of Cx43 in the mitochondria of these cells (mitoCx43). The functions of mitoCx43 have not been completely elucidated, but there is strong evidence indicating that mitoCx43 modulates mitochondrial respiration at respiratory complex I, production of radical oxygen species and ATP synthesis. These functions of mitoCx43 modulate mitochondrial and cellular tolerance to reperfusion after prolonged ischemia and are necessary for the cardioprotective effect of ischemic preconditioning. In the present review article we discuss available knowledge on these functions of mitoCx43 in relation to reperfusion injury, the molecular mechanisms involved and explore the possibility that mitoCx43 may constitute a new pharmacological target in patients with ST-segment elevation myocardial infarction (STEMI). This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve. PMID- 28642044 TI - Crossregulation between the insertion of Hexadecylphosphocholine (miltefosine) into lipid membranes and their rheology and lateral structure. AB - Hexadecylphosphocholine (HePC, miltefosine) is an alkylphospholipid used clinically for the topical treatment of cancer and against leishmaniasis. The mechanism of action of HePC, not yet elucidated, involves its insertion into the plasma membrane, affecting lipid homeostasis. It has also been proposed that HePC directly affects lipid raft stability and function in cell membranes. The present work deals with two main questions in the understanding of the action of HePC: the bases for membrane selectivity and as a membrane perturbator agent. We explored the interaction of HePC with lipid monolayers and bilayer vesicles, combining monolayer penetration experiments, Brewster angle microscopy and differential scanning calorimetry. Several membrane compositions were tested to explore different rheological conditions, phase states and lateral structures. Additionally, the kinetics between the soluble and the membrane form of HePC was explored. Our results showed an increase in elasticity induced by HePC incorporation in all the membranes studied. Differential incorporation was found for membranes in different phase states, supporting a preferential partitioning and a higher dynamic kinetics of HePC incorporation into fluid membranes in comparison with condensed or liquid-ordered ones. This effect resulted in phase equilibrium displacement in phospholipids and membranes containing liquid-ordered domains. The presence of cholesterol or ergosterol induced a fast incorporation and slow desorption of HePC from sterol-containing monolayers, favoring a long residence period within the membrane. This contributes to a better understanding of the HePC regulation of membrane-mediated events and lipid homeostasis. PMID- 28642045 TI - Mutations on FtsZ lateral helix H3 that disrupt cell viability hamper reorganization of polymers on lipid surfaces. AB - FtsZ filaments localize at the middle of the bacterial cell and participate in the formation of a contractile ring responsible for cell division. Previous studies demonstrated that the highly conserved negative charge of glutamate 83 and the positive charge of arginine 85 located in the lateral helix H3 bend of Escherichia coli FtsZ are required for in vivo cell division. In order to understand how these lateral mutations impair the formation of a contractile ring,we extend previous in vitro characterization of these mutants in solution to study their behavior on lipid modified surfaces. We study their interaction with ZipAand look at their reorganization on the surface. We found that the dynamic bundling capacity of the mutant proteins is deficient, and this impairment increases the more the composition and spatial arrangement of the reconstituted system resembles the situation inside the cell: mutant proteins completely fail to reorganize to form higher order aggregates when bound to an E.coli lipid surface through oriented ZipA.We conclude that these surface lateral point mutations affect the dynamic reorganization of FtsZ filaments into bundles on the cell membrane, suggesting that this event is relevant for generating force and completing bacterial division. PMID- 28642047 TI - Erectile Dysfunction in Young Men-A Review of the Prevalence and Risk Factors. AB - INTRODUCTION: Erectile dysfunction (ED) is an important health concern that can significantly affect a man's psychosocial well-being. ED has traditionally been considered a disease of old age; however, contemporary evidence suggests a growing incidence of ED in men younger than 40 years. The process of achieving an erection is multifaceted; there are many potential mechanisms that can be disrupted. It is critical to identify the specific causes of ED before proceeding with potentially costly and invasive therapeutic options. Advances in diagnostic and treatment modalities offer opportunities to identify and manage young men with ED. AIM: To provide an update on the prevalence and risk factors of ED in young men and to provide a framework to guide clinicians in identifying and managing the affected young man. METHODS: Comprehensive review of the literature pertaining to ED in young men. MAIN OUTCOME MEASURES: ED in young men was assessed by outlining the prevalence according to recent epidemiologic studies. The pathophysiology, diagnostic considerations, risk factors, and etiologies were reviewed. RESULTS: Large multinational studies have estimated the prevalence of ED in young men to be as high as 30%. Several studies have stratified the etiologies of ED into psychogenic and organic causes. Psychogenic etiologies of ED include depression, anxiety, and partner-related difficulties. These patients tend to experience sudden onset of symptoms, with decreased libido and good quality of spontaneous or self-stimulated erections. Organic etiologies include vasculogenic, endocrinologic, neurogenic, iatrogenic, and structural components. These patients usually experience gradual onset of symptoms and a low to normal libido. Conservative treatments such as phosphodiesterase type 5 inhibitors continue to be the mainstay treatment. CONCLUSIONS: ED in young men is an increasingly common condition. A careful diagnostic evaluation should focus on the identification of any underlying etiology to ensure appropriate management of patients. Nguyen HMT, Gabrielson AT, Hellstrom WJG. Erectile Dysfunction in Young Men-A Review of the Prevalence and Risk Factors. Sex Med Rev 2017;5:508-520. PMID- 28642046 TI - Prostate-specific antigen percentage: An early predictive tool after iodine-125 interstitial brachytherapy for prostate cancer. AB - BACKGROUND: After interstitial prostate iodine-125 brachytherapy (BT), prostate specific antigen (PSA) evolution in time could predict overall biochemical relapse, but, considering the single patient, it is influenced by the presentation PSA amount and by the prostatic volume. It is also challenging to differentiate a PSA bounce from a biochemical relapse. PURPOSE: To determine the usefulness of PSA percentage (PP) defined as the rate between PSA presented by a patient at time "t" and the PSA that the same patient had presented at the time of diagnosis (t0) assumed as 100% in predicting biochemical relapse and in differentiating them from PSA Bounces. METHODS AND MATERIALS: We included 721 patients from Milan S. Raffaele Turro (399) and Lucca Campo di Marte (then S. Luca) Hospital (322). The mean age of patients was 66.5 years (range, 50-79). Mean followup was 150 months (range, 24-180). For each patient, PSA was recorded before and after iodine-125 BT, and PPs were calculated. Cox regression model, relative operating characteristic curves, and Kaplan-Meier regression model were elaborated, and a cutoff of 20% was defined. RESULTS: We observed that PP >20% is an independent variable highly associated with relapse risk (p < 0.0001) with a sensitivity of 79.7%, a specificity of 82%, and an hazard ratio of 12.1, since the 6 months of followup. A PSA increase above the nadir should be because of bounce (sensitivity and specificity of 81.4%, p < 0.0001) if patient had experienced at 6 months a PP <20%. CONCLUSIONS: PP might represent an early and useful tool, predictive of clinical outcome in patients after BT for prostate cancer. PMID- 28642048 TI - Sexual Consequences of Post-SSRI Syndrome. AB - INTRODUCTION: Sexual dysfunctions are well-known side effects of selective serotonin reuptake inhibitor (SSRI) use. Altered libido, erectile dysfunction, vaginal dryness, ejaculatory disorders, and orgasmic problems are frequently reported by patients treated with SSRIs. Moreover, these antidepressant-emergent sexual dysfunctions do not always resolve after discontinuation of the medication and can persist indefinitely. These complaints are termed post-SSRI sexual dysfunctions (PSSD). AIM: To examine the existence of this clinical entity, possible theoretical mechanisms, possible risk factors, and possible treatment modalities. METHODS: Through literature research and clinical experience, the available information about PSSD is reviewed. MAIN OUTCOME MEASURES: Summary of the current literature with insights into possible causes and management options. RESULTS: There are some indications that antidepressant-emergent sexual dysfunctions do not always resolve after discontinuation of the medication and can persist indefinitely in some individuals. Although some or all sexual side effects that start with the use of SSRIs might continue after stopping the medication, other sexual complaints can develop. Decreased capacity to experience sexual pleasure is the most frequent characteristic of this syndrome. CONCLUSION: The research and understanding of PSSD remain limited and not well understood; however, the data support the existence of PSSD, which can have a substantial effect on the quality of life of these patients. More research is warranted to show the cause and possible mechanisms of PSSD that could lead to the correct diagnosis and treatment. Reisman Y. Sexual Consequences of Post-SSRI Syndrome. Sex Med Rev 2017;5:429-433. PMID- 28642049 TI - Post-Prostatectomy Incontinence: How Common and Bothersome Is It Really? AB - INTRODUCTION: The implications of post-prostatectomy urinary incontinence (PPI) on quality of life pose a matter of great concern for urologists and patients alike. Efforts to mitigate this devastating complication have met with varying degrees of success and the literature has shown a discrepancy between patient- and surgeon-reported outcomes. AIM: To describe the multifactorial physiology of PPI, its evaluation, and its effect on health-related quality of life and sexual function and to review preoperative predictive factors for PPI and explore the disparity between patient- and surgeon-reported outcomes. METHODS: We selected a representative sample of principal studies addressing these topics pertaining to PPI. The search was executed by a relevant term search on PubMed from 1994 to the present. MAIN OUTCOME MEASURES: The main topics of consideration in this review are pathophysiology, predictors and prevalence, and methods of evaluating PPI. We also report on findings on the role of PPI in sexual activity, surgical methods to prevent PPI, and variability in methods of outcome reporting. RESULTS: The application of various measures to prevent PPI has had variable success and efforts to further refine and widely implement improvements have been complicated by the heterogeneity in measurements used to report and compare outcomes. CONCLUSION: Patient age, incontinence definitions, and preoperative baseline incontinence make collecting and interpreting urinary function data after radical prostatectomy challenging. Confusion in the literature is compounded by the discrepancy between patient- and surgeon-reported outcomes. On a patient physician level, there is the issue of potentially under-counseling patients during preoperative discussions on the profound impact of PPI on quality of life in general and on sexual function and satisfaction in particular. Trofimenko V, Myers JB, Brant WO. Post-Prostatectomy Incontinence: How Common and Bothersome Is It Really? Sex Med Rev 2017;5:536-543. PMID- 28642050 TI - The Drosophila Thioester containing Protein-4 participates in the induction of the cellular immune response to the pathogen Photorhabdus. AB - The function of thioester-containing proteins (TEPs) in the immune defense of the fruit fly Drosophila melanogaster is yet mostly unexplored. Recently, we showed the involvement of TEP4 in the activation of humoral and phenoloxidase immune responses of Drosophila against the pathogenic bacteria Photorhabdus luminescens and Photorhabdus asymbiotica. Here, we investigated the participation of Tep4 in the cellular defense of Drosophila against the two pathogens. We report significantly lower numbers of live and dead plasmatocytes in the tep4 mutants compared to control flies in response to Photorhabdus infection. We also find fewer crystal cells in the control flies than in tep4 mutants upon infection with Photorhabdus. Our results further suggest that Drosophila hemocytes constitute a major source for the transcript levels of Tep4 in flies infected by Photorhabdus. Finally, we show that Tep4 participates in the phagocytic function in Drosophila adult flies. Collectively our data support the protective role for TEP4 in the cellular immune response of Drosophila against the entomopathogen Photorhabdus. PMID- 28642051 TI - A revisited concept: Contact inhibition of growth. From cell biology to malignancy. AB - In cell biology, contact inhibition refers to two different but closely related phenomena, contact inhibition of locomotion and contact inhibition of proliferation, exhibited by fibroblasts when in contact with one another. Normal fibroblasts migrate across the surface of a culture dish until they make contact with a neighboring cell. Further cell migration is then inhibited, and normal cells adhere to each other, forming an orderly array of cells on the culture dish surface. Tumor cells, in contrast, continue moving after contact with their neighbors, migrating over adjacent cells, and growing in disordered, multilayered patterns. Not only the movement but also the proliferation of many normal cells is inhibited by cell-cell contact, and cancer cells are characteristically insensitive to such contact inhibition. PMID- 28642052 TI - Impact of planetary ball mills on corn stover characteristics and enzymatic digestibility depending on grinding ball properties. AB - The impact of planetary mill pretreatment on corn stover size, crystallinity, and enzyme digestibility was investigated based on the grinding ball properties in an effort to reduce energy consumption. Alumina, zirconia, and steel balls were used, of which steel balls had the highest specific gravity but the lowest surface roughness while alumina balls had the lowest specific gravity and the highest roughness. The planetary mill pretreatment effectively reduced the size and crystallinity of the corn stover for all the ball types. Steel balls showed the highest size reduction effect in short milling time such as a 20min and alumina balls were effective at improving the surface area of the corn stover in a 60min milling time. The use of alumina balls resulted in the highest enzyme digestibility with a glucose yield of 91.9% when the milling time was 60min. PMID- 28642053 TI - From low-cost substrates to Single Cell Oils synthesized by oleaginous yeasts. AB - As new feedstock for biofuels, microbial oils have received worldwide attentions due to their environmentally-friendly characters. Microbial oil production based on low-cost raw materials is significantly attractive to the current biodiesel refinery industry. In terms of SCOs production, oleaginous yeast has numerous advantages over bacteria, molds and microalgae based on their high growth rate and lipid yield. Numerous efforts have been made on the competitive lipid production combining the use of cheap raw materials as substrates by yeasts. In this paper, we provided an overview of lipid metabolism in yeast cells. New advances using oleaginous yeast as a cell factory for high-value lipid production from various low-cost substrates are also reviewed, and the enhanced strategies based on synergistic effects of oleaginous yeast and microalgae in co-culture are discussed in details. PMID- 28642054 TI - Development of a Tailored Thyroid Gland Phantom for Fine-Needle Aspiration Cytology by Three-Dimensional Printing. AB - BACKGROUND: Fine-needle aspiration cytology (FNAC) is a challenging and risky procedure for inexperienced clinicians to perform because of the proximity of the thyroid to the jugular veins, carotid arteries, and trachea. A phantom model for transfixion practice would help train clinicians in FNAC. OBJECTIVE: To fabricate a tailored phantom with consideration for authenticity of size, touch, feel, and ultrasonographic (US) characteristics. METHODS: A three-dimensional (3D) digital model of the human neck was reconstructed from computed tomography data of a subject. This model was used to create 3D-printed templates for various organs that require US visualization. The templates were injected with polymers that provided similar degrees of ultrasound permeability as the corresponding organs. For fabrication of each organ, the respective molds of organs, blood vessels, thyroid gland, and tumor were injected with the material. The fabricated components were then removed from the templates and colored. Individual components were then positioned in the neck mold, and agar gel was poured in. The complete phantom was then removed from the mold. Thereafter, 45 medical doctors and students performed ultrasound-guided FNAC using the phantom, following which they were queried regarding the value of the phantom. RESULTS: The structure, US characteristics, and elasticity of the phantom were similar to those of the human subject. In the survey, all 45 participants replied that they found the phantom useful for FNAC training, and 30 medical students professed increased interest in thyroid diseases after using the phantom. CONCLUSIONS: We successfully fabricated a tailored thyroid gland phantom for transfixion practice. As most of the phantom parts are injected in molds fabricated using a 3D printer, they can be easily reproduced once the molds are fabricated. This phantom is expected to serve as an effective and fully tailored training model for practicing thyroid gland transfixion. PMID- 28642055 TI - Korean translation and validation of the WHOQOL-DIS for people with spinal cord injury and stroke: Methodological issues. PMID- 28642056 TI - Can Stem Cells Ameliorate the Pancreatic Damage Induced by Streptozotocin in Rats? AB - BACKGROUND: Stem cell therapy holds great promise for the repair of injured tissues and organs, and it is one of the most promising therapies for diabetes mellitus. Therefore, the present study was undertaken to elucidate the antidiabetic effect of both mesenchymal stem cells (MSCs) and insulin-producing cells (IPCs) on streptozotocin (STZ)-induced diabetes in rats. MATERIALS AND METHODS: MSCs were derived from bone marrow of male albino rats. MSCs were characterized morphologically and by Cluster of differentiation (CD-ve34) and (CD+ve105). They were then differentiated into IPCs, and both MSCs and IPCs were infused independently into tail veins of rats with STZ-induced diabetes. RESULTS: MSC and IPC therapy significantly improved the body weight and serum insulin, alpha-amylase, adiponectin, creatinine, total cholesterol, triacylglycerol, interleukin-6, tumour necrosis factor-alpha, liver L-malonaldehyde and glycogen levels in the STZ-induced diabetes model. CONCLUSIONS: Bone marrow-derived MSCs have the capacity to differentiate into IPCs capable of controlling the blood glucose level in rats with STZ-induced diabetes. Furthermore, treatment with MSCs and IPCs can improve aberrant biochemical parameters in an STZ-induced diabetes model. PMID- 28642057 TI - Novel multifunctional dental cement to prevent enamel demineralization near orthodontic brackets. AB - OBJECTIVES: White spot lesions due to biofilm acid-induced enamel demineralization are prevalent in orthodontic treatments. The aim of this study was to develop a novel bioactive multifunctional cement with protein-repellent, antibacterial and remineralizing capabilities, and investigate the effects on enamel hardness and lesion depth in vitro for the first time. MATERIALS AND METHODS: 2-Methacryloyloxyethyl phosphorylcholine (MPC), dimethylaminohexadecyl methacrylate (DMAHDM), and nanoparticles of amorphous calcium phosphate (NACP) were incorporated into a resin-modified glass ionomer (RMGI). Extracted human premolars had brackets bonded via four groups: (1) Transbond XT (TB), (2) RMGI (GC Ortho LC), (3) RMGI+MPC+DMAHDM, (4) RMGI+MPC+DMAHDM+NACP. Demineralization was induced via a dental plaque microcosm biofilm model. Samples were tested using polarized light microscopy (PLM) for lesion depth. Enamel hardness was tested for different groups. RESULTS: Incorporating MPC, DMAHDM and NACP did not affect enamel bond strength. "RMGI+MPC+DMAHDM+NACP" group had the least lesion depth in enamel (p<0.05). Groups with NACP had the highest enamel hardness (p<0.05). Mineral loss (DeltaS) in enamel for NACP group was about one third that for RMGI control. "RMGI+MPC+DMAHDM" had greater effect on demineralization inhibition, compared to RMGI and TB controls. "RMGI+MPC+DMAHDM+NACP" was more effective in protecting enamel prisms from dissolution by biofilm acids, compared to RMGI and TB control groups. CONCLUSION: The Novel "RMGI+MPC+DMAHDM+NACP" cement substantially reduced enamel demineralization adjacent to orthodontic brackets, yielding much less lesion depth and greater enamel hardness under biofilm acid attacks than commercial controls. The clinical significance is that the novel multi-agent (RMGI+MPC+DMAHDM+NACP) method is promising for a wide range of preventive and restorative applications to combat caries. PMID- 28642058 TI - Ex vivo investigation on the postoperative integrity of the apical constriction after the sole use of electronic working length determination. AB - AIM: The present study investigated the accuracy of root canal preparation with regard to the integrity of the apical constriction (AC) using two different working length determination approaches: (1) the electronic method of working length determination (EWLD), and (2) the radiologic "gold standard" method (GS). METHODOLOGY: Simulation models were constructed by arranging extracted human teeth by means of silicon bolstered gingiva masks, along with a conductive medium (alginate). Electronic working length determination (group 1; EWLD) and radiologic plus initial electronic working length determination for posterior comparability (group 2; GS) preceded manual root canal preparation of teeth in both groups. Master cones were inserted according to working lengths obtained from the group specific method. Subsequently, root apices (n=36) were longitudinally sectioned using a diamond-coated bur. The distance between the achieved apical endpoint of the endodontic preparation and the apical constriction (AC) was measured using digital photography. Then, distances between radiologically identified apical endpoints and AC (GS-AC) were compared with the corresponding distances EWLD-AC. Moreover, the postoperative status of the AC was examined with regard to both preparation approaches. RESULTS: Differences between distances GS-AC and EWLD-AC were not statistically significant (p >0.401) (Mann Whitney-U). Among EWLD samples, 83% of the master cones exhibiting tugback at final insertion terminated close to the apical constriction (+/-0.5 mm), and no impairment of the minor diameter's integrity was observed. CONCLUSIONS: The sole use of EWLD allowed for a high accuracy of measurements and granted precise preparation of the apical regions. PMID- 28642059 TI - New trends on obesity and NAFLD in Asia. AB - Traditionally, obesity and its related diseases have been considered a problem in Western countries. However, in the past two decades, urbanisation in many Asian countries has led to a sedentary lifestyle and overnutrition, setting the stage for the epidemic of obesity. This article reviews the epidemiological trend of obesity in Asia, with special emphasis on the emerging condition of non-alcoholic fatty liver disease (NAFLD). Currently, the population prevalence of NAFLD in Asia is around 25%, like many Western countries. While hepatocellular carcinoma and end-stage liver disease secondary to NAFLD remain uncommon, a rising trend has emerged. Around 8-19% of Asians with body mass indexes less than 25kg/m2 are also found to have NAFLD, a condition often described as "lean" or "non-obese" NAFLD. Although this condition is generally less severe than that in more obese patients, steatohepatitis and fibrotic disease are well recognized. Central adiposity, insulin resistance and weight gain are major risk factors, and genetic predisposition, such as the PNPLA3 polymorphism appears to be more important in the development of NAFLD in the non-obese population. Lifestyle modification remains the cornerstone of management for obesity and NAFLD, but few patients can achieve adequate weight reduction and even fewer can maintain the weight in the long run. While pharmacological agents have entered phase III development for steatohepatitis, Asian patients are under-represented in most drug trials. Future studies should define the optimal management of obesity and NAFLD in Asia. PMID- 28642060 TI - Microsurgically Assisted Inguinal Hernia Repair and Simultaneous Male Fertility Procedures: Rationale, Technique and Outcomes. AB - PURPOSE: Inguinal herniorrhaphy is the most common general surgical procedure. It is associated with frequent complications such as recurrence in 2.0% to 14.1% of cases with mesh as well as postoperative hematoma in 4.5% of cases, reduced sensation in 0% to 42.8%, chronic postoperative pain in 5.1%, vasal injury in 0.1% to 0.53% and infection in 3% to 6%. Drawing on our experience with the operating microscope for varicocelectomy, vasectomy reversal and repair of iatrogenic vasal obstruction from hernia repair, we applied the operating microscope for inguinal hernia repair. This study describes the rationale, technique and outcomes of microsurgically assisted inguinal hernia repair. MATERIALS AND METHODS: A total of 291 microsurgically assisted inguinal hernia repairs were performed in 253 men by the same urologist (MG). Simultaneous microsurgical varicocelectomy or other testicular procedures were performed in 83% of cases. All were open repairs through an inguinal incision with the vas deferens, ilioinguinal nerve, genital branch of the genitofemoral nerve, and spermatic vasculature identified and preserved. Median followup was 8.6 months. Outcomes were assessed by examination, pain reporting and pathology reports. RESULTS: Chronic postoperative pain, sensory loss, infection, hematoma, vasal injury and recurrence were assessed. The incidence of hematoma was 0.85%. No recurrent hernia, chronic postoperative pain, sensory loss, infection or vasal injury was reported. CONCLUSIONS: Using an operating microscope the complications of inguinal hernia repair, such as vasal obstruction, testicular atrophy, recurrence, infection, hematoma, chronic postoperative pain and loss of sensation, are minimized. Microsurgically assisted hernia repair is a promising technique, especially when performed by a urologist who simultaneously performs microsurgical varicocelectomy or procedures involving spermatic cord structures or the testis. PMID- 28642061 TI - The basic reproduction number of vector-borne plant virus epidemics. AB - The basic reproduction number R0 is a key parameter in plant disease epidemiology, which largely determines whether or not an epidemic will occur in a plant population. The next generation matrix approach to deriving and calculating the basic reproduction number of a plant virus epidemic is described. The approach is illustrated through a series of examples of increasing complexity, ranging from the simplest case of one vector transmitting one virus to a single host, to the case of multiple vectors, to combined horizontal (vector) and vertical (seed) transmission, and where vector control using insecticides is practised. The importance of parameters representing host and vector population dynamics and their interaction in the absence of disease is stressed, and the constraints these place on the calculation of the basic reproduction number. Finally, mention is made of further elaborations to the approach that could prove useful in plant virus epidemiology. PMID- 28642062 TI - LRH-1 senses signaling from phosphatidylcholine to regulate the expansion growth of digestive organs via synergy with Wnt/beta-catenin signaling in zebrafish. AB - Liver receptor homolog-1 (LRH-1) is an orphan nuclear receptor that is critical for the growth and proliferation of cancer cells and other biological processes, including lipid transportation and metabolism, sexual determination and steroidogenesis. However, because homozygous lrh-1-/- mice die in utero, the regulatory mechanisms involved in embryonic development mediated by this receptor are poorly understood. In the present study, we performed transcription activator like effector nuclease (TALEN)-mediated loss-of-function assays, taking advantage of zebrafish external fertilization, to investigate the function of lrh-1. The digestive organs were affected by lrh-1 depletion as a result of cell-cycle arrest (at the checkpoint of G1 to S phase), but not cell apoptosis. Biochemical analysis revealed that LRH-1 augments the transcriptional activity of beta catenin 1 and 2 via physical interactions. Screening the specific ligand(s) sensed by LRH-1 during organogenesis revealed that phosphatidylcholine (PC), a potential ligand, is the upstream target of LRH-1 during endoderm development. These data provide evidence for the crosstalk between the PC/LRH-1 and Wnt/beta catenin signaling pathways during the expansion growth of endoderm organs. PMID- 28642063 TI - Differential gene network analysis from single cell RNA-seq. PMID- 28642064 TI - The genetic basis of deafness in populations of African descent. AB - Hearing loss is the most common sensorineural disorder worldwide and is associated with more than 1000 mutations in more than 90 genes. While mutations in genes such as GJB2 (gap-junction protein beta 2) and GJB6 (gap-junction protein beta 6) are highly prevalent in Caucasian, Asian, and Middle Eastern populations, they are rare in both native African populations and those of African descent. The objective of this paper is to review the current knowledge regarding the epidemiology and genetics of hearing loss in African populations with a focus on native sub-Saharan African populations. Environmental etiologies related to poor access to healthcare and perinatal care account for the majority of cases. Syndromic etiologies including Waardenburg, Pendred and Usher syndromes are uncommon causes of hearing loss in these populations. Of the non-syndromic causes, common mutations in GJB2 and GJB6 are rarely implicated in populations of African descent. Recent use of next-generation sequencing (NGS) has identified several candidate deafness genes in African populations from Nigeria and South Africa that are unique when compared to common causative mutations worldwide. Researchers also recently described a dominant mutation in MYO3a in an African American family with non-syndromic hearing loss. The use of NGS and specialized panels will aid in identifying rare and novel mutations in a more cost- and time effective manner. The identification of common hearing loss mutations in indigenous African populations will pave the way for translation into genetic deafness research in populations of African descent worldwide. PMID- 28642066 TI - Dying for a Cause: Regulated Necrosis of Tissue-Resident Macrophages upon Infection. PMID- 28642065 TI - Severe and resistant hypertension in an older woman with claudication. AB - Coarctation of the aorta is an uncommon cause of treatment-resistant hypertension in adults. It is typically detected and treated in infancy or childhood with surgical or endovascular procedures. Most cases of recurrence of coarctation after repair occur in childhood or early adulthood; recurrence in older persons (>70 years) has rarely been reported. A 73-year-old woman was referred to us for the management of treatment-resistant hypertension accompanied by symptoms of claudication and headaches, which had resulted in multiple emergency room visits. Of note, 58 years earlier, a graft from the left subclavian artery had been used to bypass an aortic coarctation. During a hospitalization for severe hypertension accompanied by acute kidney injury and heart failure, diagnostic angiography revealed a complete thrombotic occlusion of the left subclavian-artery-to descending-aorta bypass graft and a tight coarctation in the descending thoracic aorta. Balloon angioplasty and stenting across the coarctation was only transiently effective; subsequently, an ascending-to-descending graft was placed distal to the coarctation, and within a few days, the blood pressure levels and claudication improved markedly. This case demonstrates that hypertension specialists should suspect the possibility of recurrence of a coarctation in older patients who present with resistant hypertension and have a remote history of coarctation repair. Although such late recurrences are not common, as illustrated in our patient, surgical intervention may contribute to significant improvement in blood pressure control and prevent future complications. PMID- 28642067 TI - Caloric restriction protects livers from ischemia/reperfusion damage by preventing Ca2+-induced mitochondrial permeability transition. AB - Caloric restriction (CR) promotes lifespan extension and protects against many pathological conditions, including ischemia/reperfusion injury to the brain, heart and kidney. In the liver, ischemia/reperfusion damage is related to excessive mitochondrial Ca2+ accumulation, leading to the mitochondrial permeability transition. Indeed, liver mitochondria isolated from animals maintained on CR for 4 months were protected against permeability transition and capable of taking up Ca2+ at faster rates and in larger quantities. These changes were not related to modifications in mitochondrial respiratory activity, but rather to a higher proportion of ATP relative to ADP in CR liver mitochondria. Accordingly, both depletion of mitochondrial adenine nucleotides and loading mitochondria with exogenous ATP abolished the differences between CR and ad libitum (AL) fed groups. The prevention against permeability transition promoted by CR strongly protected against in vivo liver damage induced by ischemia/reperfusion. Overall, our results show that CR strongly protects the liver against ischemia/reperfusion and uncover a mechanism for this protection, through a yet undescribed diet-induced change in liver mitochondrial Ca2+ handling related to elevated intramitochondrial ATP. PMID- 28642068 TI - Chloramphenicol decreases CB1 receptor expression in the nucleus accumbens and prefrontal cortex and prevents amphetamine-induced conditioned place preference in rats. AB - Drug dependence seems to involve a learning and memory process. Since learning and memory depend on protein synthesis, drug dependence may depend on protein synthesis, too. Drug-induced reward is a crucial effect for the development of drug-dependence. We used chloramphenicol (CAP, a protein synthesis inhibitor), to evaluate its effects on amphetamine (amph)-seeking behavior, on CB1R expression and on protein synthesis in general, in specific areas of the brain. Two groups of Wistar adult male rats were subjected to amph-induced conditioned place preference (CPP). Rats in group 1 received amph and were kept in the chamber for 30min. Once this period elapsed, they received a subcutaneous injection of saline (veh) and were returned to their home-cage. Rats in group 2 were also treated with amph but received CAP (150mg/kgsc) instead of saline. Once CPP was evaluated rats were sacrificed and the prefrontal cortex (PFC), the nucleus accumbens (NAcc) and the hippocampus (Hipp) were isolated and prepared for CB1R Western blot analysis. A vivarium reared group of rats was added as a non-experimentally manipulated control group. Results indicate that group 1 developed CPP while increasing CB1R expression in the NAcc. Group 2 did not develop CPP, had lower CB1R expression in the PFC and lacked the CB1R increase in the NAcc observed in the amph+veh group. These results support the notion that among the underlying mechanisms for amph-seeking reward is an increase in CB1R, further supporting an interaction between dopamine/endocannabinoids in CPP learning. PMID- 28642069 TI - Chronic choline supplementation improves cognitive and motor performance via modulating oxidative and neurochemical status in rats. AB - Choline, an essential nutrient, accounts for multiple functions in the body and brain. While its beneficial effects on healthy adults are not clear, choline supplementation is important during pregnancy for brain development, in elderly patients for support of cognitive performance and in patients with neurological disorders to reduce memory deficits. Thus, the aim of this study is to investigate whether choline administration in healthy adult rats beneficially impacts cognitive and locomotor performance, and associated oxidative and neurochemical outcomes. Two groups, control and choline, received tap water and choline bitartrate, respectively at the dose equivalent to adequate intake for five weeks. Food intake and body weight were monitored daily. Behavioral analysis comprising assessment of cognitive performance (by novel object recognition, passive avoidance and Morris Water Maze test) and locomotor performance (by Open field, Kondziela's inverted screen and beam walking test) were performed. Following testing, rats were decapitated and brain samples were collected for estimation of acetylcholine, redox profile and monoamine measurements. The results showed that chronic choline administration significantly improves cognitive and locomotor performance accompanied by a reduction in oxidative stress, enhanced cholinergic neurotransmission and monoamine levels in the brain of healthy adult rats. Hence, chronic choline intake was found to improve behavioral, oxidative and neurochemical outcomes in the normal population, so it can be suggested that choline tablets can be used as a safe and effective supplement for improving the neurological health of normal individuals and that they might also be beneficial in preventing cognitive and motor disorders later in life. PMID- 28642070 TI - Conceptualising compensation in neurodevelopmental disorders: Reflections from autism spectrum disorder. AB - Within research into neurodevelopmental disorders, little is known about the mechanisms underpinning changes in symptom severity across development. When the behavioural presentation of a condition improves/symptoms lessen, this may be because core underlying atypicalities in cognition/neural function have ameliorated. An alternative possibility is 'compensation'; that the behavioural presentation appears improved, despite persisting deficits at cognitive and/or neurobiological levels. There is, however, currently no agreed technical definition of compensation or its behavioural, cognitive and neural characteristics. Furthermore, its workings in neurodevelopmental disorders have not been studied directly. Here, we review current evidence for compensation in neurodevelopmental disorders, using Autism Spectrum Disorder as an example, in order to move towards a better conceptualisation of the construct. We propose a transdiagnostic framework, where compensation represents the processes responsible for an observed mismatch between behaviour and underlying cognition in a neurodevelopmental disorder, at any point in development. Further, we explore potential cognitive and neural mechanisms driving compensation and discuss the broader relevance of the concept within research and clinical settings. PMID- 28642071 TI - The link between motor and cognitive development in children born preterm and/or with low birth weight: A review of current evidence. AB - The current review focuses on evidence for a link between early motor development and later cognitive skills in children born preterm or with Low Birth Weight (LBW). Studies with term born children consistently show such a link. Motor and cognitive impairments or delays are often seen in children born preterm or with LBW throughout childhood and studies have established a cross-sectional association between the two. However, it is not yet clear if, and if so, how, motor and cognitive skills are longitudinally interrelated in these children. Longitudinal studies with this population including measures of motor development during the first year of life and cognitive measures at later measurement points were included. The 17 studies included usually show a link between level and/or quality of motor development during the first year of life and later cognitive skills in children born preterm and/or with LBW. However, given the small number of studies, and a possible effect of early interaction between motor and cognitive skills affecting this relation, more work is clearly needed. PMID- 28642072 TI - Recombinant Human Thrombopoietin Promotes Platelet Engraftment and Improves Prognosis of Patients with Myelodysplastic Syndromes and Aplastic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation. AB - Poor platelet graft function (PPGF) is a significant complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, no optimal treatment has been recommended. This study investigated aspects of platelet recovery after allo-HSCT, including prognostic value and the effect of recombinant human thrombopoietin (rhTPO). We retrospectively analyzed 275 patients who received allo-HSCT in our center. Of them, 135 (49.1%) patients had good platelet graft function (GPGF) and 140 (50.9%) had PPGF. The latter included 59 (21.5%) patients with primary PPGF and 81 (29.4%) with secondary PPGF. Multivariate analysis showed that male gender (P = .024), lower CD34+ cell count (P = .04), and no use of rhTPO (P <.001) were associated with PPGF. The 3-year overall survival rate of patients with PPGF (58%) was significantly less than that of patients with GPGF (82%; P <.001). We further analyzed the effect of rhTPO on prognosis of patients after allo-HSCT. Although no advantage was apparent when analyzing the entire cohort, for patients with myelodysplastic syndromes and aplastic anemia, rhTPO was associated with a significant survival advantage (P = .014). PMID- 28642073 TI - Synthesis of biogenic Ag@Pd Core-shell nanoparticles having anti-cancer/anti microbial functions. AB - Biogenic Ag@Pd core-shell nanoparticles were greenly synthesized within two plant extracts aiming at enhanced anticancer/bactericidal functions. These functions were verified for the two Pd@Ag biogenic core-shell nanoparticles (BCSnp) with constant Pd to several Ag contents. BCSnp were synthesized within two extracts of Almond nuts and Black Berry fruits, four samples each, through simple, low cost and echo friendly microwave route. The BCSnp Surface Plasmon Resonance (SPR) was detected via UV/visible spectrophotometer. Their morphology was assessed using High-Resolution Transmission Electron Microscope and Field Emission Scanning Electron Microscope supplemented with EDAX. Particle size/zeta potential of the achieved nanoparticles was measured. The active reducing groups were depicted by FTIR while XRD assessed nanoparticles crystallinity. The enhanced particle size distribution as proved by UV and band gap energies, imparted better functionality by the Almond extract compared to the berry one due to its protein content. Cytotoxicity against human breast cancer (MCF7) and liver cancer (HEPG2) cell lines were followed and compared to the normal Wish cells. The antimicrobial impact against gram-negative (G-veo) E. coli, gram-positive (G+ve) S. aureus bacteria and mycotic strain C. albicans species were verified and compared to antibiotics. A significant inhibition of cancer cell growth of MCF 7 and HEPG2 compared to Wish normal cells and doxorubicin is assessed. A discriminative effect was recorded for G-ve compared to G+ve, along with Mycotic strain C. albicans is achieved. The obtained BCSnp are proposed for cancer therapy and bactericidal applications with improved efficiency applying the nanomedicine approach. Tailorable properties can be obtained by tuning the individual structures. PMID- 28642074 TI - Comment on "Serum uric acid is associated with better executive function in men but not in women: Baseline assessment of the ELSA-Brasil study". PMID- 28642075 TI - Greenhouse gas emissions from different municipal solid waste management scenarios in China: Based on carbon and energy flow analysis. AB - Waste management is a major source of global greenhouse gas (GHG) emissions and many opportunities exist to reduce these emissions. To identify the GHG emissions from waste management in China, the characteristics of MSW and the current and future treatment management strategies, five typical management scenarios were modeled by EaseTech software following the principles of life cycle inventory and analyzed based on the carbon and energy flows. Due to the high organic fraction (50-70%) and moisture content (>50%) of Chinese municipal solid waste (MSW), the net GHG emissions in waste management had a significant difference from the developed countries. It was found that the poor landfill gas (LFG) collection efficiency and low carbon storage resulted landfilling with flaring and landfilling with biogas recovery scenarios were the largest GHG emissions (192 and 117 kgCO2-Eq/t, respectively). In contrast, incineration had the best energy recovery rate (19%), and, by grid emissions substitution, led to a substantial decrease in net GHG emissions (-124 kgCO2-Eq/t). Due to the high energy consumption in operation, the unavoidable leakage of CH4 and N2O in treatment, and the further release of CH4 in disposing of the digested residue or composted product, the scenarios with biological treatment of the organic fractions after sorting, such as composting or anaerobic digestion (AD), did not lead to the outstanding GHG reductions (emissions of 32 and -36 kgCO2-Eq/t, respectively) as expected. PMID- 28642076 TI - The effect of initial organic load of the kitchen waste on the production of VFA and H2 in dark fermentation. AB - Dark fermentation of kitchen wastes was studied in batch bioreactors, with no pH adjustment, to evaluate the effect of the initial organic load on the process performance in terms of volatile fatty acids and H2 production. Initial organic load of the kitchen wastes ranged from 4.1 to 48.2gVS/L. Acetic and butyric acids were produced in the largest amount. At the initial organic load of 48.2KWgVS/L the highest concentration of volatile fatty acids was 9.81g/L. The maximum production yield of H2 (76.1mL/gVS) was found for the initial organic load of kitchen wastes at 14.3gVS/L. The carbon balance calculation showed that the maximum CO2 yield of 0.34 gC/gC was attained in the bioreactor with the initial organic load of 14.3gVS/L. The microbiological analysis revealed that the predominant microorganisms in the dark fermentation process were Bacteroidetes, Firmicutes, Spirochaetes and WWE1 at phyla level. PMID- 28642077 TI - Recovery of tin from metal powders of waste printed circuit boards. AB - To avoid the adverse effects of tin on the smelting process used to recover copper from metal powders of waste printed circuit boards, an effective process is proposed that selectively extracts tin and its associated metals. That impacts of alkaline pressure oxidation leaching parameters on metal conversion were systematically investigated. The results showed that Sn, Pb, Al and small amounts of Zn in the metal powders were leached out, leaving copper residue. By optimizing the conditions, leaching recovery of 98.2%, 77.6%, 78.3 and 6.8% for Sn, Pb, Al and Zn, respectively, were achieved. Subsequently, more than 99.9% of Pb and Zn in the leaching solution were removed as a mixture of PbS-ZnS in the purification process, which can be used as a raw material in Pb smelting. Approximately 86.2% of Sn in the purified solution was recovered by electrowinning, and the purity of the cathode tin was over 99.8%. PMID- 28642078 TI - Experimental tests on commercial Sweet Product Residue (SPR) as a suitable feed for anaerobic bioenergy (H2+CH4) production. AB - Food stores can find themselves in the position of having to dispose of different types of products, such as snacks, confectionery, prepackaged food, drinks and others, Sweet Product Residue (SPR), which presents a great opportunity to produce energy through Anaerobic Digestion (AD), due to its high sugar, carbohidrate and fat contents. In order to valorise SPR, this paper takes into consideration the all necessary treatments; owing the fact that the refuses are constitute by an organic part and packaging (plastic, paper and their combinations), a pretreatment able to remove the latter is necessary. SPR refuse was initially subjected to novel pretreatment approach: extrusion at 200atm to remove the packaging, and a Basic Pre-treatment (BP) then tested through a Two Stage AD (TSAD) process, for H2 and CH4 productions. The experimental results were analysed considering three parameters: Efficiency (xi), which takes into account the quantity of the energy produced as hydrogen plus methane that the bioreaction is able to extract; Efficacy (eta), which takes into account the efficiency of the actual test, compared with that obtained from a reference test carried out with glucose; Energy Sustainability Index (ESI), which takes into account the total amount of energy produced as H2 plus CH4, and the amount of energy consumed to pre-treat the refuse. The effectiveness of the extrusion process in removing the packaging was very high: about 80% of the organic part present in the SPR was recovered. The obtained results have pointed out that SPR is suitable for energy valorization process: xi=50%, eta=0.67 and ESI=24.4, without the need of basic pre-treatment. PMID- 28642079 TI - Common and distinct brain networks underlying panic and social anxiety disorders. AB - Although panic disorder (PD) and phobic disorders are independent anxiety disorders with distinct sets of diagnostic criteria, there is a high level of overlap between them in terms of pathogenesis and neural underpinnings. Functional connectivity research using resting-state functional magnetic resonance imaging (rsfMRI) shows great potential in identifying the similarities and differences between PD and phobias. Understanding common and distinct networks between PD and phobic disorders is critical for identifying both specific and general neural characteristics of these disorders. We review recent rsfMRI studies and explore the clinical relevance of resting-state functional connectivity (rsFC) in PD and phobias. Although findings differ between studies, there are some meaningful, consistent findings. Social anxiety disorder (SAD) and PD share common default mode network alterations. Alterations within the sensorimotor network are observed primarily in PD. Increased connectivity in the salience network is consistently reported in SAD. This review supports hypotheses that PD and phobic disorders share common rsFC abnormalities and that the different clinical phenotypes between the disorders come from distinct brain functional network alterations. PMID- 28642082 TI - Clinical trial of the effects of vitamin D supplementation on psychological symptoms and metabolic profiles in maintenance methadone treatment patients. AB - BACKGROUND: Vitamin D deficiency may be associated with some complications including nonspecific musculoskeletal pain and periodontal disease in maintenance methadone treatment (MMT) patients. This study was designed to determine the effect of vitamin D supplementation on psychological symptoms and metabolic profiles in MMT patients. METHODS: This randomized, double-blind, placebo controlled, clinical trial was carried out among 68 MMT patients. Participants were randomly allocated to receive either 50,000IU vitamin D supplements (n=34) or placebo (n=34) every 2weeks for 12weeks. Fasting blood samples were taken at baseline and post-intervention to evaluate relevant variables. RESULTS: After the 12-week intervention, serum 25(OH) vitamin D levels significantly increased in the intervention group compared with the placebo group (+8.1+/-4.9 vs. -0.4+/ 3.0, P<0.001). In addition, vitamin D supplementation significantly improved Pittsburgh Sleep Quality Index (-1.5+/-2.2 vs. -0.2+/-2.3, P=0.02) and Beck Depression Inventory (-4.8+/-7.3 vs. -1.5+/-6.1, P=0.04) compared with the placebo. Patients who received vitamin D supplements had significantly decreased fasting plasma glucose (-7.5+/-10.6 vs. +0.3+/-10.7mg/dL, P=0.004), serum insulin levels (-3.6+/-5.3 vs. -0.9+/-3.5 MUIU/mL, P=0.01), homeostasis model of assessment-insulin resistance (-1.0+/-1.3 vs. -0.2+/-0.7, P=0.003), serum triglycerides (-9.6+/-30.8 vs. +15.6+/-30.2mg/dL, P=0.001), total- (-8.7+/-20.9 vs. +11.0+/-27.4mg/dL, P=0.001) and LDL-cholesterol (-11.1+/-17.9 vs. +5.9+/ 27.5mg/dL, P=0.004) compared with the placebo. Additionally, vitamin D intake resulted in a significant decrease in serum high sensitivity C-reactive protein ( 2.2+/-4.2 vs. +2.0+/-3.7mg/L, P<0.001), and significant increases plasma total antioxidant capacity (+26.2+/-99.8 vs. -86.3+/-127.5mmol/L, P<0.001) and glutathione levels (+292.3+/-172.4 vs. +48.9+/-208.9MUmol/L, P<0.001) compared with the placebo. There was no significant effect of vitamin D supplementation on serum HDL-cholesterol, and other markers of insulin metabolism, inflammation and oxidative stress. CONCLUSIONS: Totally, taking 50,000IU vitamin D supplement every 2weeks for 12weeks in MMT patients had beneficial effects on psychological symptoms and few metabolic profiles. PMID- 28642081 TI - Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information. AB - INTRODUCTION: Cannabis and agonists of the brain cannabinoid receptor (CB1R) produce acute memory impairments in humans. However, the extent to which cannabinoids impair the component processes of encoding and retrieval has not been established in humans. The objective of this analysis was to determine whether the administration of Delta9-Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, impairs encoding and/or retrieval of verbal information. MATERIALS AND METHODS: Healthy subjects were recruited from the community. Subjects were administered the Rey-Auditory Verbal Learning Test (RAVLT) either before administration of THC (experiment #1) (n=38) or while under the influence of THC (experiment #2) (n=57). Immediate and delayed recall on the RAVLT was compared. Subjects received intravenous THC, in a placebo-controlled, double-blind, randomized manner at doses known to produce behavioral and subjective effects consistent with cannabis intoxication. RESULTS: Total immediate recall, short delayed recall, and long delayed recall were reduced in a statistically significant manner only when the RAVLT was administered to subjects while they were under the influence of THC (experiment #2) and not when the RAVLT was administered prior. CONCLUSIONS: THC acutely interferes with encoding of verbal memory without interfering with retrieval. These data suggest that learning information prior to the use of cannabis or cannabinoids is not likely to disrupt recall of that information. Future studies will be necessary to determine whether THC impairs encoding of non-verbal information, to what extent THC impairs memory consolidation, and the role of other cannabinoids in the memory-impairing effects of cannabis. CLINICAL TRIAL INFORMATION: Cannabinoids, Neural Synchrony, and Information Processing (THC-Gamma) http://clinicaltrials.gov/ct2/show/study/NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http://clinicaltrials.gov/ct2/show/NCT00678730 NCT00678730. PMID- 28642083 TI - Colorectal surgery and enhanced recovery: Impact of a simulation-based care pathway training curriculum. AB - BACKGROUND: The aim was to determine whether a simulation-based care pathway approach (CPA) curriculum could improve compliance for enhanced recovery programs (ERP), and residents' participation in laparoscopic colorectal surgery (LCS). Indeed, trainee surgeons have limited access to LCS as primary operator, and ERP have improved patients' outcomes in colorectal surgery (CS). METHODS: All residents of our department were trained in a simulation-based CPA: perioperative training consisted in virtual patients built according to guidelines in both ERP and CS, whilst intraoperative training involved a virtual reality simulator curriculum. Twenty consecutive patients undergoing CS were prospectively included before (n=10) and after (n=10) the training. All demographic and perioperative data were prospectively collected, including compliance for ERP. Residents' participation as primary operator in LCS was measured. RESULTS: Five residents (PGY 4-7) were enrolled. None had performed LCS as primary operator. Overall satisfaction and usefulness were both rated 4.5/5, usefulness of pre-, post- and intraoperative training was rated 5/5, 4.5/5 and 4/5, respectively. Residents' participation in LCS significantly improved after the training (0% (0-100) vs. 82.5% (10-100); P=0.006). Pre- and intraoperative data were comparable between groups. Postoperative morbidity was also comparable. Compliance for ERP improved at Day 2 in post-training patients (3 (30%) vs. 8 (80%); P=0.035). Length of stay was not modified. CONCLUSIONS: A simulated CPA curriculum to training in LCS and ERP was correctly implemented. It seemed to improve compliance for ERP, and promoted residents participation as primary operator without adversely altering patients' outcomes. PMID- 28642084 TI - Floating stoma and abdominal negative-pressure therapy. PMID- 28642085 TI - Comparison of glutathione levels measured using optimized monochlorobimane assay with those from ortho-phthalaldehyde assay in intact cells. AB - Fluorometric glutathione assays have been generally preferred for their high specificity and sensitivity. An additional advantage offered by fluorescent bimane dyes is their ability to penetrate inside the cell. Their ability to react with glutathione within intact cells is frequently useful in flow cytometry and microscopy. Hence, the aims of our study were to use monochlorobimane for optimizing a spectrofluorometric glutathione assay in cells and then to compare that assay with the frequently used ortho-phthalaldehyde assay. We used glutathione-depleting agents (e.g., cisplatin and diethylmalonate) to induce cell impairment. For glutathione assessment, monochlorobimane (40MUM) was added to cells and fluorescence was detected at 394/490nm. In addition to the regularly used calculation of glutathione levels from fluorescence change after 60min, we used an optimized calculation from the linear part of the fluorescence curve after 10min of measurement. We found that 10min treatment of cells with monochlorobimane is sufficient for evaluating cellular glutathione concentration and provides results entirely comparable with those from the standard ortho phthalaldehyde assay. In contrast, the results obtained by the standardly used evaluation after 60min of monochlorobimane treatment provided higher glutathione values. We conclude that measuring glutathione using monochlorobimane with the here-described optimized evaluation of fluorescence signal could be a simple and useful method for routine and rapid assessment of glutathione within intact cells in large numbers of samples. PMID- 28642080 TI - Impact of juvenile chronic stress on adult cortico-accumbal function: Implications for cognition and addiction. AB - Repeated exposure to stress during childhood is associated with increased risk for neuropsychiatric illness, substance use disorders and other behavioral problems in adulthood. However, it is not clear how chronic childhood stress can lead to emergence of such a wide range of symptoms and disorders in later life. One possible explanation lies in stress-induced disruption to the development of specific brain regions associated with executive function and reward processing, deficits in which are common to the disorders promoted by childhood stress. Evidence of aberrations in prefrontal cortex and nucleus accumbens function following repeated exposure of juvenile (pre- and adolescent) organisms to a variety of different stressors would account not only for the similarity in symptoms across the wide range of childhood stress-associated mental illnesses, but also their persistence into adulthood in the absence of further stress. Therefore, the goal of this review is to evaluate the current knowledge regarding disruption to executive function and reward processing in adult animals or humans exposed to chronic stress over the juvenile period, and the underlying neurobiology, with particular emphasis on the prefrontal cortex and nucleus accumbens. First, the role of these brain regions in mediating executive function and reward processing is highlighted. Second, the neurobehavioral development of these systems is discussed to illustrate how juvenile stress may exert long lasting effects on prefrontal cortex-accumbal activity and related behavioral functions. Finally, a critical review of current animal and human findings is presented, which strongly supports the supposition that exposure to chronic stress (particularly social aggression and isolation in animal studies) in the juvenile period produces impairments in executive function in adulthood, especially in working memory and inhibitory control. Chronic juvenile stress also results in aberrations to reward processing and seeking, with increased sensitivity to drugs of abuse particularly noted in animal models, which is in line with greater incidence of substance use disorders seen in clinical studies. These consequences are potentially mediated by monoamine and glutamatergic dysfunction in the prefrontal cortex and nucleus accumbens, providing translatable therapeutic targets. However, the predominant use of male subjects and social-based stressors in preclinical studies points to a clear need for determining how both sex differences and stressor heterogeneity may differentially contribute to stress-induced changes to substrates mediating executive function and reward processing, before the impact of chronic juvenile stress in promoting adult psychopathology can be fully understood. PMID- 28642086 TI - Geographical outcome disparities in infection occurrence after colorectal surgery: An analysis of 58,096 colorectal surgical procedures. AB - BACKGROUND: Despite improved surgical practices and in-hospital surveillance systems, surgical site infections remain a major public health problem worldwide and often require readmission to hospital. The aim was to apply an advance and innovative spatial analysis approach to identify spatial pattern and clustering (hotspots) of surgical site infection rate (CSIR), and quantifying disparities across communities. METHODS: We used the Admitted Patient Data Collection for patients aged 18 years and over who underwent colorectal surgery in a public hospital between 2002 and 2013 in the Australian State of New South Wales (NSW). The colorectal surgical infection rate (CSIR) was computed. We assessed geographical variation and clustering in CSIR patterning to demonstrate spatial pattern and clustering across communities in NSW, Australia. RESULTS: There were 58,096 colorectal surgical procedures conducted in NSW from 2002 to 2013. The overall occurrence of CSIR was 9.64% (95%CI 9.40-9.88%). We found significant clusters of both high and low CSIR in outer regional and remote areas of NSW. CONCLUSION: Use of advanced spatial analyses allows identification of hotspots/clusters of adverse events that can help policy makers and clinicians better understand national patterns and initiate research to address disparities/geographical variation, and clustering of adverse events after surgery. PMID- 28642088 TI - Effect of pre-emptive pregabalin on pain management in patients undergoing laparoscopic cholecystectomy: A systematic review and meta-analysis. AB - BACKGROUND: Pre-emptive pregabalin might be beneficial to the patients undergoing laparoscopic cholecystectomy. However, the results remained controversial. We conducted a systematic review and meta-analysis to explore the effect of pregabalin on pain management of patients undergoing laparoscopic cholecystectomy. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of pregabalin versus placebo on laparoscopic cholecystectomy were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcome was pain scores Meta-analysis was performed using random-effect model. RESULTS: Six RCTs involving 434 patients were included in the meta-analysis. Overall, compared with control intervention, pregabalin intervention was found to significantly reduce the pain scores (Std. mean difference = -0.57; 95% CI = 0.85 to -0.29; P < 0.0001) and postoperative fentanyl consumption (Std. mean difference = -1.74; 95% CI = -2.31 to -1.16; P < 0.00001), improve Ramsay Sedation score (Std. mean difference = 1.03; 95% CI = 0.46 to 1.60; P = 0.0004), but demonstrated no influence on nausea and vomiting (RR = 0.82; 95% CI = 0.57 to 1.19; P = 0.30), as well as headache (RR = 0.95; 95% CI = 0.55 to 1.64; P = 0.86). CONCLUSIONS: Compared to control intervention, pregabalin intervention was found to significantly reduce the pain scores and postoperative fentanyl consumption, and improve Ramsay Sedation score in patients undergoing laparoscopic cholecystectomy, but had no influence on nausea and vomiting, as well as headache. PMID- 28642087 TI - Contemporary prevalence, in-hospital outcomes, and prognostic determinants of triple valve surgery: National database review involving 5,234 patients. AB - BACKGROUND: Triple valve surgery (TVS) remains a challenging procedure with limited existing literature. We aim to evaluate the prevalence, in-hospital outcomes, and prognostic determinants of TVS in the current era. MATERIALS AND METHODS: We reviewed the Nationwide Inpatient Sample database from 2003 to 2012 and included all patients who underwent aortic valve replacement (AVR) combined with mitral valve replacement (MVR) or repair (MVRep) and tricuspid valve replacement (TVR) or repair (TVRep). Logistic regression analysis was used to identify independent predictors of in-hospital mortality and propensity score matching was adopted to compare groups receiving different operations. RESULTS: Overall, 5234 patients were included. In-hospital mortality was 13.9%. Major adverse events occurred in 42.9% of the cases (44.9%, 40.3%, 44.4% and 74.2% in the AVR + MVR + TVR, AVR + MVR + TVRep, AVR + MVRep + TVRep and AVR + MVRep + TVR groups respectively, p < 0.05 for all intergroup comparisons). In-hospital mortality in the AVR + MVR + TVR, AVR + MVR + TVRep, AVR + MVRep + TVRep and AVR + MVRep + TVR groups was 19.9%, 13.3%, 12.9% and 0% respectively (p < 0.05 for all intergroup comparisons). At regression analysis, age, reoperation, and urgent/emergent operation were independent predictors of in-hospital mortality. Patients submitted to tricuspid valve repair and mitral and tricuspid repair had a 62% and 63% mortality risk reduction (OR:0.380, CI:0.19-0.76 p = 0.006 and OR:0.37, CI:0.18-0.78 p = 0.009 respectively). In the propensity matched comparisons, in-hospital mortality was statistically similar (p = 0.08 for AVR + MVR + TVR vs. AVR + MVR + TVRep comparison and p = 0.06 for AVR + MVR + TVR vs. AVR + MVRep + TVRep comparison). CONCLUSIONS: TVS is associated with significant in-hospital mortality and morbidity. The use of valve repair strategies for the mitral and tricuspid valves can positively impact postoperative outcomes. PMID- 28642089 TI - Involvement of MAPK, Akt/GSK-3beta and AMPK/mTOR signaling pathways in protection of remote glial cells from axotomy-induced necrosis and apoptosis in the isolated crayfish stretch receptor. AB - Severe mechanical nerve injury such as axotomy can lead to neuron degeneration and death of surrounding glial cells. We showed that axotomy not only mechanically injures glial cells at the cutting location, but also induces necrosis or apoptosis of satellite glial cells remote from the transection site. Therefore, axon integrity is necessary for survival of surrounding glial cells. We used the crayfish stretch receptor that consists of a single mechanoreceptor neuron enveloped by satellite glial cells as a simple, but informative model object in the study of the role of various signaling proteins in axotomy-induced death of remote glial cells. After axon transection, stretch receptors were isolated and incubated in saline in the presence or without specific inhibitors of various signaling proteins. Inhibition of MEK1/2, p38, Akt, GSK-3beta and mTOR increased axotomy-induced apoptosis of remote glial cells, whereas inhibition of ERK1/2 and GSK-3beta enhanced necrosis. This suggests the involvement of these signaling proteins in protective, antiapoptotic and antinecrotic processes in the remote satellite glia surrounding the axotomized mechanoreceptor neuron. PMID- 28642090 TI - Vaginal Sacral Colpopexy: A Natural Orifice Approach to a Gold Standard Procedure. AB - STUDY OBJECTIVE: A transvaginal approach to sacral colpopexy has a natural appeal to those interested in minimally invasive pelvic reconstructive surgery. Development of an effective technique has been frustrated because of the technical difficulty of confining the dissection and placement of mesh to the retroperitoneal space. The objective of this prospective study is to describe the technique and report the outcomes of a transvaginal, retroperitoneal sacral colpopexy. DESIGN: Prospective cohort study (Canadian Task Force Design classification II-2). SETTING: Urogynecology of Southern Alabama private practice. PATIENTS: Women with stage 2 or greater apical prolapse. INTERVENTIONS: Surgical repair of apical prolapse using vaginal sacral colpopexy. MEASUREMENTS AND RESULTS: Over a 1-year period, 15 posthysterectomy patients with stage 2 or greater vaginal prolapse were recruited and consented to vaginal sacral colpopexy. Primary outcome was success of the repair, with success defined as a combination of objective and subjective parameters using pelvic organ prolapse quantification measures, and quality of life questionnaires. Secondary outcomes were complications and operating time. One case converted to a native tissue repair. The vaginal sacral colpopexy was completed in the remaining 14. Eleven patients have been followed for 1 year or longer. Two patients did not return after their 6-week examination because of chronic illness. They were contacted by telephone over 2 years after the surgery and expressed total satisfaction with the operation and the outcome. One patient was seen at 3 months and was noted to have an excellent anatomic result; however, a pelvic organ prolapse quantification evaluation was not done. She has been totally lost to further follow-up. There was 1 mechanical failure in which the titanium tacks securing the apex to the anterior longitudinal ligament dislodged and a second case with a stage 2 posterior compartment defect. One incidental cystotomy, and 1 incidental proctotomy occurred. These were both small, remote from the site of the vaginal mesh, and did not prevent completion of the procedure. There were no mesh-related complications. Mean operating time was 123 minutes. CONCLUSION: In this small pilot study, a transvaginal retroperitoneal sacral colpopexy is described and is demonstrated to be feasible and safe. Based on the experience gained, changes in technique have been implemented to prevent future mechanical tack failures. Assuming that these changes will be successful in preventing apical recurrence due to dislodgement of mesh from the anterior longitudinal ligament, a larger study is planned to determine efficacy. Inherent advantages of the transvaginal approach are discussed, including a favorable morbidity profile, full access to all compartments, short operating times, and decreased costs. PMID- 28642091 TI - A "See and Treat" Office Procedure for Retained Products of Conception Removal After Normal Vaginal Delivery Using Manual Vacuum Aspiration: Preliminary Efficacy and Reproductive Outcomes. AB - STUDY OBJECTIVE: To compare the efficacy and reproductive outcomes of an ultrasound-guided manual vacuum aspiration (MVA) procedure with the widely accepted operative hysteroscopic (OH) procedure in the removal of retained products of conception (RPOCs) after normal vaginal delivery. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A university-affiliated tertiary medical center. PATIENTS: Eighty-six patients after normal vaginal delivery diagnosed with RPOCs from 2005 through 2015. This study was approved by the local institutional review board. INTERVENTIONS: Treatment with either MVA or OH for patients diagnosed with RPOCs. MEASUREMENTS AND MAIN RESULTS: Of 86 patients, 23 underwent remnant removal by ultrasound guided MVA using a 6- to 7-mm catheter in a "see and treat" office procedure. Sixty-three patients underwent remnant removal using the OH procedure. Follow-up included sonographic examination 3 to 5 weeks after the procedure and long-term follow-up on complications and reproductive outcomes. Successful remnant evacuation and the overall complications rates were similar when comparing the MVA group and the OH group (95.7% vs 96.8% and 4.3% vs 4.7%, respectively). Conception rates and miscarriage rates were comparable in the MVA and OH groups (78.6% vs 72.2% and 9.1% vs 14.8%, respectively). CONCLUSION: Preliminary results from 23 patients suggest that MVA is an efficient procedure with low complication rates and satisfactory reproductive outcomes. It does not require anesthesia or operating room facilities, allowing an immediate and inexpensive "see and treat" option for RPOCs. Further larger controlled trials are required. PMID- 28642092 TI - Chemokine CCL17 is expressed by dendritic cells in the CNS during experimental autoimmune encephalomyelitis and promotes pathogenesis of disease. AB - The CC chemokine ligand 17 (CCL17) and its cognate CC chemokine receptor 4 (CCR4) are known to control leukocyte migration, maintenance of TH17 cells, and regulatory T cell (Treg) expansion in vivo. In this study we characterized the expression and functional role of CCL17 in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). Using a CCL17/EGFP reporter mouse model, we could show that CCL17 expression in the CNS can be found in a subset of classical dendritic cells (DCs) that immigrate into the CNS during the effector phase of MOG-induced EAE. CCL17 deficient (CCL17-/-) mice exhibited an ameliorated disease course upon MOG-immunization, associated with reduced immigration of IL-17 producing CD4+ T cells and peripheral DCs into the CNS. CCL17-/- DCs further showed equivalent MHC class II and costimulatory molecule expression and an equivalent capacity to secrete IL-23 and induce myelin-reactive TH17 cells when compared to wildtype DCs. In contrast, their transmigration in an in vitro model of the blood-brain barrier was markedly impaired. In addition, peripheral Treg cells were enhanced in CCL17-/- mice at peak of disease pointing towards an immunoregulatory function of CCL17 in EAE. Our study identifies CCL17 as a unique modulator of EAE pathogenesis regulating DC trafficking as well as peripheral Treg cell expansion in EAE. Thus, CCL17 operates at distinct levels and on different cell subsets during immune response in EAE, a property harboring therapeutic potential for the treatment of CNS autoimmunity. PMID- 28642093 TI - Functional characterization of 3-ketosteroid 9alpha-hydroxylases in Rhodococcus ruber strain chol-4. AB - The 3-Ketosteroid-9alpha-Hydroxylase, also known as KshAB [androsta-1,4-diene 3,17-dione, NADH:oxygen oxidoreductase (9alpha-hydroxylating); EC 1.14.13.142)], is a key enzyme in the general scheme of the bacterial steroid catabolism in combination with a 3-ketosteroid-Delta1-dehydrogenase activity (KstD), being both responsible of the steroid nucleus (rings A/B) breakage. KshAB initiates the opening of the steroid ring by the 9alpha-hydroxylation of the C9 carbon of 4-ene 3-oxosteroids (e.g. AD) or 1,4-diene-3-oxosteroids (e.g. ADD), transforming them into 9alpha-hydroxy-4-androsten-3,17-dione (9OHAD) or 9alpha-hydroxy-1,4 androstadiene-3,17-dione (9OHADD), respectively. The redundancy of these enzymes in the actinobacterial genomes results in a serious difficulty for metabolic engineering this catabolic pathway to obtain intermediates of industrial interest. In this work, we have identified three homologous kshA genes and one kshB gen in different genomic regions of R. ruber strain Chol-4. We present a set of data that helps to understand their specific roles in this strain, including: i) description of the KshAB enzymes ii) construction and characterization of DeltakshB and single, double and triple DeltakshA mutants in R. ruber iii) growth studies of the above strains on different substrates and iv) genetic complementation and biotransformation assays with those strains. Our results show that KshA2 isoform is needed for the degradation of steroid substrates with short side chain, while KshA3 works on those molecules with longer side chains. KshA1 is a more versatile enzyme related to the cholic acid catabolism, although it also collaborates with KshA2 or KshA3 activities in the catabolism of steroids. Accordingly to what it is described for other Rhodococcus strains, our results also suggest that the side chain degradation is KshAB-independent. PMID- 28642094 TI - Investigation of the component in Artemisia annua L. leading to enhanced antiplasmodial potency of artemisinin via regulation of its metabolism. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The chemical matrix of the herb Artemisia annua L. (A. annua), from which artemisinin (QHS) is isolated, can enhance both the bioavailability and efficacy of QHS. However, the exact mechanism of this synergism remains unknown. The biotransformation of QHS and potential "enzyme inhibitors" in plant matrix could be of great importance in understanding the improved efficacy of QHS in A. annua, which has been limited to the synergism with flavonoid components. AIM OF THE STUDY: To investigate the component in A. annua extracts (MAE) leading to enhanced antiplasmodial potency of QHS via regulation of its metabolism. The efficacy of QHS in combination with the synergistic component was also evaluated. MATERIALS AND METHODS: The total MAE extract and its three MAE fractions (MAE-I eluted using 3% methanol, MAE-II eluted using 50% methanol and MAE-III eluted using 85% methanol) were obtained from dry plant materials and prepared after lyophilization. The pharmacokinetic profiles of QHS and its major phase I metabolite monohydroxylated artemisinin (QHS-M) were investigated in healthy rats after a single oral administration of QHS in each MAE extract. Major components isolated from the target MAE fraction were evaluated for their enzyme inhibition. The antimalarial activity of QHS in combination with the potential synergistic component against Plasmodium falciparum was studied in vivo (murine Plasmodium yoelii). The recrudescence and survival time of infected mice were also recorded after drug treatment. RESULTS: Compared to pure QHS, a 2-fold increase in QHS exposure (AUC and Cmax) was found in healthy rats after a single oral dose of QHS in the total MAE extract or its fraction MAE-III. In addition, metabolic biotransformation of QHS to the metabolite QHS-M (mediated by CYP3A) was inhibited by MAE or MAE-III. Among nine major components isolated from MAE-III (five sesquiterpenenes, three flavonoids and one phenolic acid), only arteannuin B (AB) showed an inhibition of CYP3A4 (IC50 1.2MUM). The synergism between QHS and AB was supported using in vivo antiplasmodial assay and a pharmacokinetic study in mice. Unfortunately, the synergism cannot reduce the rate of recrudescence. CONCLUSIONS: AB was one of main contributors in A. annua leading to enhanced antiplasmodial potency of QHS via regulation of its metabolism. The final recrudescence indicated the careful use of A. annua for malaria treatment unless additional contributing components or antiplasmodial mechanism were found. PMID- 28642095 TI - Ginsenoside Rg1 alleviates corticosterone-induced dysfunction of gap junctions in astrocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenoside Rg1 (Rg1), one of the major bioactive ingredients of Panax ginseng C. A. Mey, has neuroprotective effects in animal models of depression, but the mechanism underlying these effects is still largely unknown AIM OF THE STUDY: Gap junction intercellular communication (GJIC) dysfunction is a potentially novel pathogenic mechanism for depression. Thus, we investigated that whether antidepressant-like effects of Rg1 were related to GJIC. MATERIALS AND METHODS: Primary rat prefrontal cortical and hippocampal astrocytes cultures were treated with 50MUM CORT for 24h to induce gap junction damage. Rg1 (0.1, 1, or 10MUM) or fluoxetine (1MUM) was added 1h prior to CORT treatment. A scrape loading and dye transfer assay was performed to identify the functional capacity of gap junctions. Western blot was used to detect the expression and phosphorylation of connexin43 (Cx43), the major component of gap junctions. RESULTS: Treatment of primary astrocytes with CORT for 24h inhibited GJIC, decreased total Cx43 expression, and increased the phosphorylation of Cx43 at serine368 in a dose-dependent manner. Pre-treatment with 1MUM and 10MUM Rg1 significantly improved GJIC in CORT-treated astrocytes from the prefrontal cortex and hippocampus, respectively, and this was accompanied by upregulation of Cx43 expression and downregulation of Cx43 phosphorylation. CONCLUSION: These findings provide the first evidence indicating that Rg1 can alleviate CORT-induced gap junction dysfunction, which may have clinical significance in the treatment of depression. PMID- 28642096 TI - Pine needle extract prevents hippocampal memory impairment in acute restraint stress mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The Pinus densiflora leaf has been traditionally used to treat mental health disorders as a traditional Chinese medicine. Here we examined the ethnopharmacological relevance of pine needle on memory impairment caused by stress. AIM OF THE STUDY: To elucidate the possible modulatory actions of 30% ethanolic pine needle extract (PNE) on stress-induced hippocampal excitotoxicity, we adopted an acute restraint stress mouse model. MATERIALS AND METHODS: Mice were orally administered with PNE (25, 50, or 100mg/kg) or ascorbic acid (100mg/kg) for 9 days, and were then subjected to restraint stress (6h/day) for 3 days (from experimental day 7-9). To evaluate spatial cognitive and memory function, the Morris water maze was performed during experimental days 5-9. RESULTS: Restraint stress induced the memory impairment (the prolonged escape latency and cumulative path-length, and reduced time spent in the target quadrant), and these effects were significantly prevented by PNE treatment. The levels of corticosterone and its receptor in the sera/hippocampus were increased by restraint stress, which was normalized by PNE treatment. Restraint stress elicited the hippocampal excitotoxicity, the inflammatory response and oxidative injury as demonstrated by the increased glutamate levels, altered levels of tumor necrosis factor (TNF)-alpha and imbalanced oxidant-antioxidant balance biomarkers. Two immunohistochemistry activities against glial fibrillary acidic protein (GFAP)-positive astrocytes and neuronal nuclei (NeuN)-positive neurons supported the finding of excitotoxicity especially in the cornu ammonis (CA)3 region of the hippocampus. Those alterations were notably attenuated by administration of PNE. CONCLUSIONS: The above findings showed that PNE has pharmacological properties that modulate the hippocampal excitotoxicity-derived memory impairment under severe stress conditions. PMID- 28642097 TI - Are two-dimensional measured frontal plane angles related to three-dimensional measured kinematic profiles during running? AB - OBJECTIVES: To investigate the temporal relationship between two-dimensional measured frontal plane joint angles and three-dimensional measured kinematic profiles during the stance phase of running, and to assess the intra- and intertester reliability of the two-dimensional angles. DESIGN: Observational study. SETTING: Research laboratory. PARTICIPANTS: Fifteen injury-free elite athletes. MAIN OUTCOME MEASURES: Contralateral pelvic drop (CPD), femoral adduction (FA), hip adduction (HA) and knee valgus (KV) were measured at the deepest landing position during midstance with two-dimensional video analysis during running. CPD, HA and knee abduction were measured continuously during the entire stance phase through three-dimensional motion analysis. One-dimensional statistical parametric mapping was used to examine the temporal relationships between the two-dimensional angles and three-dimensional kinematic profiles. In addition, intra-class correlation coefficients (ICC) were calculated to assess the intra- and intertester reliability of the two-dimensional angles. RESULTS: Two-dimensional CPD, FA and HA were significantly related to the three dimensional HA kinematic profile. Two-dimensional CPD was significantly related to the three-dimensional CPD kinematic profile. No significant relationship was found between two-dimensional KV and three-dimensional knee abduction. Excellent intra- and intertester reliability was found for the two-dimensional angles (ICC 0.90-0.99). CONCLUSIONS: These findings support implementing two-dimensional video analysis to evaluate CPD and HA during running. PMID- 28642099 TI - Developmental cardiovascular physiology of the olive ridley sea turtle (Lepidochelys olivacea). AB - Our understanding of reptilian cardiovascular development and regulation has increased substantially for two species the American alligator (Alligator mississippiensis) and the common snapping turtle (Chelydra serpentina) during the past two decades. However, what we know about cardiovascular maturation in many other species remains poorly understood or unknown. Embryonic sea turtles have been studied to understand the maturation of metabolic function, but these studies have not addressed the cardiovascular system. Although prior studies have been pivotal in characterizing development, and factors that influence it, the development of cardiovascular function, which supplies metabolic function, is unknown in sea turtles. During our investigation we focused on quantifying how cardiovascular morphological and functional parameters change, to provide basic knowledge of development in the olive ridley sea turtle (Lepidochelys olivacea). Embryonic mass, as well as mass of the heart, lungs, liver, kidney, and brain increased during turtle embryo development. Although heart rate was constant during this developmental period, arterial pressure approximately doubled. Further, while embryonic olive ridley sea turtles lacked cholinergic tone on heart rate, there was a pronounced beta adrenergic tone on heart rate that decreased in strength at 90% of incubation. This beta adrenergic tone may be partially originating from the sympathetic nervous system at 90% of incubation, with the majority originating from circulating catecholamines. Data indicates that olive ridley sea turtles share traits of embryonic functional cardiovascular maturation with the American alligator (Alligator mississippiensis) but not the common snapping turtle (Chelydra serpentina). PMID- 28642098 TI - Quantifying left atrial structure and function using single-plane tissue-tracking cardiac magnetic resonance. AB - PURPOSE: Left atrial (LA) structure and function are important markers of adverse cardiovascular outcomes. Tissue-tracking cardiovascular magnetic resonance (CMR) accurately quantifies LA volume, strain, and strain rate based on biplane long axis imaging. We aimed to assess the accuracy of the LA indices quantification from single-plane tissue-tracking CMR. METHODS: We included 388 subjects (mean age 57+/-13, male 70%) whose cine CMR images in sinus rhythm were available in both four-chamber and two-chamber views: 162 patients from the Prospective Observational Study of Implantable Cardioverter-Defibrillators (PROSE-ICD) Study, 208 patients from atrial fibrillation cohort, and 18 healthy volunteers. The group was divided into the training set (n=291) and the test set (n=97). In the training set, we compared the LA indices derived from biplane imaging and single plane imaging (a four-chamber view), and developed regression equations. In the test set, we used the regression equations to estimate the LA indices from the single-plane imaging, and quantified the accuracy of the estimation against the LA indices from the biplane. RESULTS: In the training set, all the LA indices from the single-plane imaging tended to be systematically underestimated compared with those from the biplane imaging, however, the correlation coefficient was high (r2=0.73-0.90, p<0.001). In the test set, LA volumetric indices showed excellent reproducibility (intra-class correlation coefficient (ICC): 0.91-0.92) with relatively low variability (16.3-22.3%); For LA strain and strain rate indices, reproducibility was excellent (ICC: 0.81-0.93), however, the variability was slightly higher than that of volumetric indices (21.7-25.4%). CONCLUSIONS: LA volumetric indices measured from single-plane tissue-tracking CMR are highly accurate and reproducible with reference to those derived from the standard biplane imaging. The reproducibility of LA strain and strain rate indices from single-plane tissue-tracking CMR is excellent but the variability is higher than that of the volumetric indices. PMID- 28642100 TI - JCL roundtable: Future of the lipid laboratory: Using the laboratory to manage the patient (part 2). AB - The measurement of cholesterol and triglycerides as indicators of metabolic disorders and most particularly of vascular disease risk has been of growing importance to physicians and epidemiologists over the past century. This was refocused on the lipoproteins, the specific packages in blood that carry these lipids, by John Gofman, MD, PhD, and Don Fredrickson, MD, more than 50 years ago. We continue to learn about the metabolism of these large molecular structures and their relationship to arteriosclerosis as new genetic and interventional studies are published. The clinical laboratory has evolved to provide more focused information with measures that can help us assess risk and target our therapy more effectively. In this roundtable discussion, I had the opportunity to talk with physicians who consider lipoprotein management to be central features of their practice every day. They personally care for patients with metabolic disorders in which the lipoproteins have caused disease or are predicted to do so. They are well-versed on the way that science is leading us in our field. I believe that you will learn from their view of current needs regarding lipoprotein measures and the changes that may derive from ongoing scientific studies in our field. PMID- 28642101 TI - Introduction of fluorine to phenyl group of 4-(2-pyrimidinylamino)benzamides leading to a series of potent hedgehog signaling pathway inhibitors. AB - In present study, a novel series of fluorine containing 4-(2 pyrimidinylamino)benzamide analogues were designed and synthesized. The hedgehog (Hh) signaling inhibitory activities for these compounds were evaluated by a luciferase reporter method. The preliminary SAR was discussed and many compounds showed potent Hh signaling inhibitory activities. Compound 15h displayed the most potent inhibitory activity, with an IC50 of 0.050nM. This paper finds the introduction of fluorine to the 4-(2-pyrimidinylamino)benzamide scaffold can lead to a novel series of potent Hh signaling pathway inhibitors. PMID- 28642102 TI - Varic acid analogues from fungus as PTP1B inhibitors: Biological evaluation and structure-activity relationships. AB - Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential therapies for diabetes and obesity have attracted much attention in recent years. Six varic acid analogues were isolated from two strains of fungi and evaluated for PTP1B inhibition activities. The structure-activity relationships were also characterized and predicted by molecular modeling. Further kinetic studies indicated the reversible and competitive inhibition manner of varic acid analogues. Trivaric acid showed insulin-sensitizing effect not only in vitro but also in vivo, representing a promising lead compound for further optimization. PMID- 28642103 TI - Chimeric analogs of human beta-defensin 1 and theta-defensin disrupt pre established bacterial biofilms. AB - Antibiofilm activity of several human defensin analogs that have the ability to kill planktonic bacteria, against pre-established biofilms of Escherichia coli MG1655 and Staphylococcus aureus NCTC 8530 were examined. Linear and linear fatty acylated analogs did not show any activity while disulfide constrained analogs disrupted pre-established S. aureus biofilms. Chimeric analogs of human beta defensin 1 and theta-defensin, hBTD-1 and [d]hBTD-1 were highly active against S. aureus biofilms. Among the analogs tested, only the d-enantiomer [d]hBTD-1 showed activity against E. coli biofilm. Our study provides insights into the structural requirements for the eradication of pre-established biofilms in defensin analogs. PMID- 28642105 TI - Crotalaria (Monocrotaline) Pulmonary Hypertension: The Fiftieth Anniversary. PMID- 28642104 TI - Design, synthesis and SAR of a novel series of heterocyclic phenylpropanoic acids as GPR120 agonists. AB - A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents. PMID- 28642106 TI - Extracorporeal Membrane Oxygenation for Adult Respiratory Failure: 2017 Update. AB - The use of extracorporeal membrane oxygenation (ECMO) for respiratory failure in adults is growing rapidly, driven in large part by advances in technology, which have made ECMO devices easier to implement and safer and more efficient. Accompanying this increase in use is a nearly exponential increase in ECMO related literature. However, the great majority of the literature is composed of retrospective observational data, often in the form of single-center studies with relatively small numbers of subjects. The overall lack of high-quality data, including prospective randomized trials, makes it difficult to justify the rate at which ECMO use is increasing and calls attention to the need for more rigorously designed studies. Nonetheless, given its ability to support patients with severe gas exchange impairment and the potential for it to minimize the deleterious effects of invasive mechanical ventilation, there appears to be a legitimate role for ECMO in severe respiratory failure in adults. PMID- 28642107 TI - Venous Thrombosis After Electrophysiology Procedures: A Systematic Review. AB - BACKGROUND: Femoral venous access for catheter introduction represents the cornerstone of electrophysiology (EP) procedures. Limited data are available regarding postprocedure VTE. The aim of this systematic review is to determine the incidence of DVT and pulmonary embolism (PE) associated with femoral vein catheterization during EP procedures. METHODS: An electronic search was conducted for studies documenting the incidence of DVT and PE after EP procedures. Studies were classified as atrial fibrillation (AF) or non-AF ablation procedures. RESULTS: Two thousand eight-hundred sixty-four studies were evaluated, 16 of which were included in the analysis. The incidence of DVT after AF and non-AF ablations reached as high as 0.33% and 2.38%, respectively, with a pooled incidence of 0% (95% CI, 0%-0.0003%) and 0.24% (95% CI, 0.08%-0.39%), respectively. The incidence of PE was 0.29% after AF ablation and ranged from 0% to 1.67% for non-AF procedures; the pooled incidence after non-AF ablations was 0.12% (95% CI, 0%-0.25%). Asymptomatic DVT was documented in up to 21.2% of patients. Hematomas occurred in 1.05% of AF ablations (95% CI, 0.30%-1.8%) and 0.3% of non-AF ablations (95% CI, 0.09%-0.51%). CONCLUSIONS: A lower incidence of symptomatic DVT and PE was observed after AF ablations as opposed to non-AF ablations, likely due to the use of routine periprocedural anticoagulation. Asymptomatic DVTs appear to be common, although their significance is unclear. Future studies are required to weigh the risk of hematoma against the risk of VTE associated with the use of prophylactic anticoagulation after non-AF ablation procedures. PMID- 28642108 TI - Investing in New Technology in Pulmonary Medicine: Navigating the Tortuous Path to Success. AB - The introduction of new technologies offers the promise to advance medicine. This occurs alongside improved efforts to control costs of health care by hospital administrators, the Centers for Medicare & Medicaid Services' (CMS) pivot to value programs, and commercial payers' efforts to reduce reimbursement. These trends present a challenge for the pulmonologist, among others, who must navigate increasingly complex and highly scrutinized evaluation processes used to secure new technology (NT). Health-care providers are turning toward value assessments while simultaneously tasked with the mission of offering state of the art technologies and services. Pulmonologists desiring NT are thus faced with increased scrutiny in their evaluation of costs and clinical data to support investments. Consideration of this scrutiny and further evidence to temper the evaluation will improve the likelihood of adoption and patient access to clinically impactful technology. The identification of this evidence may provide a comprehensive view of the clinical and economic benefits of such technologies to both administrators and pulmonary clinicians. It is imperative that all parties involved in the decision process work collaboratively to deploy value added and clinically impactful technologies. Although a physician group might invest in such NT, the capital required often leads such decisions to a larger organization such as a hospital, health-care system, or privately owned entity. This article aims to provide a framework for pulmonary clinicians to better understand the processes that purchasers use to evaluate NT, the pressures that influence their consideration, and what resources may be leveraged toward success. PMID- 28642109 TI - Neoaortic Xenoprosthetic Grafts for Treatment of Mycotic Aneurysms and Infected Aortic Grafts. AB - BACKGROUND: There is no international consensus regarding the optimum management of infected aortae (mycotic aneurysms, infected aortic grafts). Neoaortoiliac reconstruction has advantages over extra-anatomical bypass grafting; however, the use of autologous vein is associated with venous hypertension and compartment syndrome, alternatively cadaveric homografts are associated with high rates of perianastomotic hemorrhage, limb occlusion, and pseudoaneurysm. Arterial repair using xenoprosthetic patches is associated with lower infection rates compared to the use of prosthetic material. The aim of this case series and literature review is to report the use of xenoprosthetic bovine biomaterial for neoaortic repair of mycotic aneurysmal disease and infected aortic grafts. METHODS: Patients with evidence of infected aortic grafts or mycotic aneurysms who were suitable for open aortic surgery were included. Following removal of the graft/excision of the aneurysmal sac, a 10 * 16 cm XenoSure Biologic Surgical Patch (LeMaitre, Germany) was rolled into a tube, or bifurcated tube graft, and secured with prolene sutures. Proximal and distal anastomoses were conducted as per standard aortic anastomoses. Patients were continued on long-term antibiotics and surveyed with computerized tomography at 1, 3, 6, and 12 months. RESULTS: Six patients underwent bovine aortic repair between 2013 and 2015: an infected Dacron aortobi iliac graft causing iliac pseudoaneurysm, an infected Dacron aortic graft from open repair later relined with endovascular stent graft, a mycotic iliac aneurysm, and 3 mycotic aortic aneurysms. All were treated with bovine reconstructed aortic grafts or patches. Patients had a median age of 69.5 years (range 67-75), with perioperative and 30-day mortality of 0%. Median follow-up was 13 months (range 2-23). Postoperative contrast-enhanced computed tomography revealed no evidence of infection at the operative site in all patients. Freedom from reinfection and reintervention was 100%. CONCLUSIONS: Xenoprosthetic (bovine) neoaortic grafts are an alternative method to treat infected aortae with excellent short-term freedom from infection and reintervention. Optimum duration of postoperative antibiotic therapy remains undetermined. Further cases and longer follow-up are required to determine the true efficacy of this technique. PMID- 28642111 TI - Response to Editorial, who can be a legitimate author on an article? PMID- 28642110 TI - PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection. AB - Herpes simplex virus type-1 (HSV-1) infection leads to impaired corneal sensation and, in severe cases, to corneal ulceration, melting and perforation. Here, we explore the potential therapeutic action of pigment epithelial-derived factor (PEDF) plus docosahexaenoic acid (DHA) on corneal inflammation and nerve regeneration following HSV-1 infection. Rabbits inoculated with 100,000 PFU/eye of HSV-1 strain 17Syn+ were treated with PEDF + DHA or vehicle. PEDF + DHA treatment resulted in a biphasic immune response with stronger infiltration of CD4+T cells, neutrophils and macrophages at 7-days post-treatment (p.t.) that was significantly decreased by 14 days, compared to the vehicle-treated group. Screening of 14 immune-related genes by q-PCR showed that treatment induced higher expression of IFN-gamma and CCL20 and inhibition of IL-18 by 7 days in the cornea. PEDF + DHA-treated animals developed less dendritic corneal lesions, opacity and neovascularization. Corneal nerve density increased at 12-weeks p.t. with functional recovery of corneal sensation. Treatment with PEDF + DHA that was postponed by 3 weeks also showed increased nerve density when compared to vehicle. Our data demonstrate that PEDF + DHA promotes resolution of the inflammatory response to the virus and, most importantly, induces regeneration of damaged corneal nerves vital for maintaining ocular surface homeostasis. PMID- 28642112 TI - Breastfeeding during pregnancy: A systematic review. AB - BACKGROUND: The consequences of breastfeeding during pregnancy (BDP) have not been clearly established. Available studies have addressed isolated aspects of this issue using different methodologies, often resulting in contradictory results. To our knowledge, no systematic review has assessed and compared these studies, making it difficult to obtain a clear picture of the consequences of BDP. AIM: To review and summarise all the scientific evidence relating to BDP, and determine whether this evidence is sufficient to establish clear implications for the mother, breastmilk, breastfed child, current pregnancy, and ultimately, the newborn. METHODS: We conducted a systematic review of the English and Spanish literature published between 1990 and 2015 using Cinahl, PubMed, IME, CUIDEN, Cochrane Library, Web of Science and PyscINFO. FINDINGS: 3278 publications were identified from databases, their titles and abstracts were checked to ensure the studies were related to the subject and met the selection criteria. Only 19 studies met all requirements and were included in the review. CONCLUSIONS AND IMPLICATIONS: Data suggest that BDP does not affect the way pregnancies end or even birth weights. However, several questions remain unanswered. Specifically, it is unclear how BDP affects maternal nutritional status in developed countries, the growth and health of breastfed siblings, the composition of breastmilk, or the growth of the newborn after delivery. Further studies of BDP are needed with larger samples, adequate methodology and proper control of the main confounders. PMID- 28642113 TI - Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis. AB - Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs. PMID- 28642114 TI - beta-d-glucan from Antrodia Camphorata ameliorates LPS-induced inflammation and ROS production in human hepatocytes. AB - A water soluble Antrodia Camphorata polysaccharide was composed of beta-d-glucan, coded as ACP1. ACP1 was derived from cultured Antrodia Camphorata powder, which was extracted, separated and purified by DEAE-52 column and Sephadex G-100 chromatography. The molecular weight of ACP1 was 1.72*104Da, and ACP1 consisted of glucose and galactose in the mole ratio of 2.21:1. Structural identification by FTIR, GC-MS and NMR, inferred that ACP1 consisted of ->1,3)-linked-beta-d-Glcp (6->, ->3)-linked-beta-d-Glcp-(1->, and ->6)-linked-alpha-d-Galp-(1->, with terminal beta-d-Glcp and beta-d-Galp. The anti-inflammation and anti-oxidation effects of ACP1 were examined in LPS-treated L02 cells in this study. The results demonstrated that ACP1 not only attenuated ROS production, but also decreased expressions of TNF-alpha and IL-1beta. Furthermore, ACP1 reduced the proteins expression of NOX1, NOX2 and NOX4, as well as phosphorylation of ERK, p38 and Akt. The results suggested ACP1 was very likely to alleviate oxidation and inflammation via the suppression of NADPH oxidase activation and inhibition of ERK, p38 and Akt signaling pathways. PMID- 28642116 TI - Contrast-induced nephropathy: Basic concepts, pathophysiological implications and prevention strategies. AB - Contrast-induced nephropathy (CIN) is reversible acute renal failure observed following administration of iodinated contrast media (CM) during angiographic or other medical procedures such as urography. There are various mechanisms through which CM develop their nephrotoxic effects, including oxidative stress and apoptosis. CIN is a real-life, albeit not very rare, entity. Exact pathophysiology remains obscure and no standard diagnostic criteria apply. The Acute Kidney Injury Network criteria was recently employed but its incidence/clinical significance warrants further clarification based on recent methodological advancements, because most published studies to date were contaminated by bias. The current study is a comprehensive review conducted to provide an overview of the basic concepts of CIN and summarize recent knowledge on its pathophysiology and the evidence supporting potential prevention strategies. CIN is expected to increase morbidity, hospital stay and mortality, while all patients scheduled to receive CM should undergo risk assessment for CIN and high-risk patients may be considered candidates for prevention strategies. The value of using compounds with antioxidant properties other than sodium bicarbonate, remains controversial, warranting further clinical investigation. PMID- 28642115 TI - Anti-TNFalpha therapy in inflammatory lung diseases. AB - Increased levels of tumor necrosis factor (TNF) alpha have been linked to a number of pulmonary inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sarcoidosis, and interstitial pulmonary fibrosis (IPF). TNFalpha plays multiple roles in disease pathology by inducing an accumulation of inflammatory cells, stimulating the generation of inflammatory mediators, and causing oxidative and nitrosative stress, airway hyperresponsiveness and tissue remodeling. TNFalpha-targeting biologics, therefore, present a potentially highly efficacious treatment option. This review summarizes current knowledge on the role of TNFalpha in pulmonary disease pathologies, with a focus on the therapeutic potential of TNFalpha-targeting agents in treating inflammatory lung diseases. PMID- 28642118 TI - Current state of the art for cardiac arrhythmia gene therapy. AB - Cardiac arrhythmias are a leading cause of morbidity and mortality. Currently available therapeutic options lack sufficient efficacy and safety. Gene therapy has been proposed for treatment of cardiac arrhythmias. This review will discuss the current state of development for arrhythmia gene therapy. So far, all published studies are short-term, proof-of-concept animal studies. Potential replacement of cardiac pacemakers has been shown for combination gene therapy using the HCN2 gene and either the gene for adenylate cyclase, the skeletal muscle isoform of the sodium channel, or a dominant negative mutant of the potassium channel responsible for resting membrane potential. Atrial fibrillation has been prevented by gene transfer of either a dominant negative mutant of a repolarizing potassium channel, a gap junction, or an siRNA directed against caspase 3. Inherited arrhythmia syndromes have been corrected by replacement of the causative genes. Post-infarct ventricular tachycardia has been reduced by gene therapy with the skeletal muscle sodium channel and connexins and eliminated with the dominant negative mutant of the potassium channel responsible for resting membrane potential. These ideas show considerable promise. Long-term efficacy and safety studies are required to see if they can become viable therapies. PMID- 28642117 TI - Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases. AB - Eicosanoids are biologically active lipid signaling molecules derived from polyunsaturated fatty acids. Many of the actions of eicosanoid metabolites formed by cyclooxygenase and lipoxygenase enzymes have been characterized, however, the epoxy-fatty acids (EpFAs) formed by cytochrome P450 enzymes are newly described by comparison. The EpFA metabolites modulate a diverse set of physiologic functions that include inflammation and nociception among others. Regulation of EpFAs occurs primarily via release, biosynthesis and enzymatic transformation by the soluble epoxide hydrolase (sEH). Targeting sEH with small molecule inhibitors has enabled observation of the biological activity of the EpFAs in vivo in animal models, greatly contributing to the overall understanding of their role in the inflammatory response. Their role in modulating inflammation has been demonstrated in disease models including cardiovascular pathology and inflammatory pain, but extends to neuroinflammation and neuroinflammatory disease. Moreover, while EpFAs demonstrate activity against inflammatory pain, interestingly, this action extends to blocking chronic neuropathic pain as well. This review outlines the role of modulating sEH and the biological action of EpFAs in models of pain and inflammatory diseases. PMID- 28642120 TI - Transfusion challenges in hematology oncology and hematopoietic stem cell transplant - Literature review and local experience. AB - Transfusion medicine plays a vital role in the supportive care of patients receiving therapy for hematology, oncology and hematopoietic stem cell transplants (HSCT). With advances in therapy with more intensive chemotherapy or radiotherapy, patients usually develop cytopenias and need frequent transfusion support with packed red blood cells, granulocyte transfusion or platelets to support them until they recover from the effect of therapy. HSCT poses unique challenges for transfusion medicine, since transplant recipients may require substantial transfusion support due to cytopenias associated with toxic medications, decreased marrow reserve, infection or their malignancy. Transfusion support has many complications, mainly immune mediated and infectious complications. Jehovah's Witness patients deny transfusions of blood products as a therapeutic option and, consequently, management of their disease with chemotherapy and stem cell transplant after myeloablative therapy is quite challenging. This review describes the challenges of transfusion support in managing hemato-oncology and stem cell transplant patients and highlights a local experience in transplanting two Jehovah's Witness patients. PMID- 28642119 TI - Targeting inflammation for the treatment of alcoholic liver disease. AB - Alcoholic liver disease (ALD) is a leading cause of chronic liver disease with a wide spectrum of manifestations including simple steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Liver injury in ALD is caused by chronic inflammation, which has been actively investigated as a therapeutic target for the treatment of ALD for over the last four decades. In this review, we summarize a wide variety of inflammatory mediators that have been shown to contribute to the pathogenesis of ALD, and discuss the therapeutic potential of these mediators for the treatment of ALD. PMID- 28642121 TI - Transfusion and alternatives therapeutic support for oncology patients with hematological problems: "Are we doing more harm than benefit"? PMID- 28642122 TI - Identifying modifiers of Huntington's disease progression. PMID- 28642123 TI - Multiple sclerosis tremor: are technical advances enough? PMID- 28642125 TI - Safety and efficacy of dual-lead thalamic deep brain stimulation for patients with treatment-refractory multiple sclerosis tremor: a single-centre, randomised, single-blind, pilot trial. AB - BACKGROUND: Efficacy in previous studies of surgical treatments of refractory multiple sclerosis tremor using lesioning or deep brain stimulation (DBS) has been variable. The aim of this study was to investigate the safety and efficacy of dual-lead thalamic DBS (one targeting the ventralis intermedius-ventralis oralis posterior nucleus border [the VIM lead] and one targeting the ventralis oralis anterior-ventralis oralis posterior border [the VO lead]) for the treatment of multiple sclerosis tremor. METHODS: We did a single centre, single blind, prospective, randomised pilot trial at the University of Florida Center for Movement Disorders and Neurorestoration clinic (Gainesville, FL, USA). We recruited adult patients with a clinical diagnosis of multiple sclerosis tremor refractory to previous medical therapy. Before surgery to implant both leads, we randomly assigned patients (1:1) to receive 3 months of optimised single-lead DBS either VIM or VO. We did the randomisation with a computer-generated sequence, using three blocks of four patients, and independent members of the Center did the assignment. Patients and all clinicians other than the DBS programming nurse were masked to the choice of lead. Patients underwent surgery 1 month after their baseline visit for implantation of the dual lead DBS system. A pulse generator and two extension cables were implanted in a second surgery 3-4 weeks later. Patients then received an initial 3-month period of continuous stimulation of either the VIM or VO lead followed by blinded safety assessment of their tremor with the Tolosa-Fahn-Marin Tremor Rating Scale (TRS) during optimised VIM or VO lead stimulation at the end of the 3 months. After this visit, both leads were activated in all patients for an additional 3 months, and optimally programmed during serial visits as dictated by a prespecified programming algorithm. At the 6-month follow-up visit, TRS score was measured, and mood and psychological batteries were administered under four stimulation conditions: VIM on, VO on, both on, and both off (the order of testing was chosen by a computer-generated random sequence, assigned by independent members of the centre, and enacted by an unmasked DBS programming nurse). Each of four stimulation settings were tested over 4 consecutive days, with stimulation settings held constant for at least 12 h before testing. The primary outcome was change in mean total TRS score at the 6 month postoperative assessment with both leads activated, compared with the preoperative baseline mean TRS score. Analysis was by intention to treat. Safety was analysed in all patients who received the surgical implantation except in one patient who discontinued before the safety assessment. This trial is registered with ClinicalTrials.gov, number NCT00954421. FINDINGS: Between Jan 16, 2007, and Dec 17, 2013, we enrolled 12 patients who were randomly assigned either to 3 initial months of VIM-only or VO-only stimulation. One patient from the VO-only group developed an infection necessitating DBS explantation, and was excluded from the assessment of the primary outcome. Compared with the mean baseline TRS score of 57.0 (SD 10.2), the mean score at 6 months decreased to 40.1 (17.6), 29.6% reduction; t=-0.28, p=0.03. Three of 11 patients did not respond to surgical intervention. One patient died suddenly 2 years after surgery, but this was judged to be unrelated to DBS implantation. Serious adverse events included a superficial wound infection in one patient that resolved with antibiotic therapy, and transient altered mental status and late multiple sclerosis exacerbation in another patient. The most common non-serious adverse events were headache and fatigue. INTERPRETATION: Dual lead thalamic DBS might be a safe and effective option for improving severe, refractory multiple sclerosis tremor. Larger studies are necessary to show whether this technique is widely applicable, safe in the long-term, and effective in treating multiple sclerosis tremor or other severe tremor disorders. FUNDING: US National Institutes of Health, the Cathy Donnellan, Albert E Einstein, and Birdie W Einstein Fund, and the William Merz Professorship. PMID- 28642126 TI - Molecular and hydrodynamic properties of human epidermal growth factor receptor HER2 extracellular domain and its homodimer: Experiments and multi-scale simulations. AB - BACKGROUND: In a broad range of human carcinomas gene amplification leads to HER2 overexpression, which has been proposed to cause spontaneous dimerization and activation in the absence of ligand. This makes HER2 attractive as a therapeutic target. However, the HER2 homodimerization mechanism remains unexplored. It has been suggested that the "back-to-back" homodimer does not form in solution. Notwithstanding, very recently the crystal structure of the HER2 extracellular domain homodimer formed with a "back-to-head" interaction has been resolved. We intend to explore the existence of such interactions. METHODS: A combination of experiments, molecular dynamics and hydrodynamic modeling were used to monitor the transport properties of HER2 in solution. RESULTS & CONCLUSIONS: We have detected the HER2 extracellular domain homodimer in solution. The results show a high degree of molecular flexibility, which ultimately leads to quite higher values of the intrinsic viscosity and lower values of diffusion coefficient than those corresponding to globular proteins. This flexibility obeys to the open conformation of the receptor and to the large fluctuations of the different domains. We also report that for obtaining the correct hydrodynamic constants from the modeling one must consider the glycosylation of the systems. GENERAL SIGNIFICANCE: Conformational features of epidermal growth factor receptors regulate their hydrodynamic properties and control their activity. It is essential to understand the dynamics of these systems and the role of the specific domains involved. To find biophysical correlations between dynamics and macroscopic transport properties is of general interest for researches working in this area. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue. PMID- 28642127 TI - Exploiting sequence and stability information for directing nanobody stability engineering. AB - BACKGROUND: Variable domains of camelid heavy-chain antibodies, commonly named nanobodies, have high biotechnological potential. In view of their broad range of applications in research, diagnostics and therapy, engineering their stability is of particular interest. One important aspect is the improvement of thermostability, because it can have immediate effects on conformational stability, protease resistance and aggregation propensity of the protein. METHODS: We analyzed the sequences and thermostabilities of 78 purified nanobody binders. From this data, potentially stabilizing amino acid variations were identified and studied experimentally. RESULTS: Some mutations improved the stability of nanobodies by up to 6.1 degrees C, with an average of 2.3 degrees C across eight modified nanobodies. The stabilizing mechanism involves an improvement of both conformational stability and aggregation behavior, explaining the variable degree of stabilization in individual molecules. In some instances, variations predicted to be stabilizing actually led to thermal destabilization of the proteins. The reasons for this contradiction between prediction and experiment were investigated. CONCLUSIONS: The results reveal a mutational strategy to improve the biophysical behavior of nanobody binders and indicate a species-specificity of nanobody architecture. GENERAL SIGNIFICANCE: This study illustrates the potential and limitations of engineering nanobody thermostability by merging sequence information with stability data, an aspect that is becoming increasingly important with the recent development of high-throughput biophysical methods. PMID- 28642128 TI - Immunomodulation of Parkinson's disease using Mucuna pruriens (Mp). AB - Immune control is associated with nigrostriatal neuroprotection for Parkinson's disease (PD); though its direct cause and effect relationships have not yet been realized and modulating the immune system for therapeutic gain has been openly discussed. While the pathobiology of PD remains in study, neuroinflammation is thought to speed nigrostriatal degeneration. The neuroinflammatory cascade associated with PD begins with aggregation of misfolded or post-translationally modified alpha-synuclein (alpha-syn). Such aggregation results in neuronal cell death and the presence of chronically activated glia (microglia and astroglia), leading to the production of proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta), IL-6, and enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and cyclooxygenase-2 (COX-2). These changes in the glial phenotype can affect the central nervous system (CNS) microenvironment by producing a pro-inflammatory milieu that speeds PD pathogenesis. Mucuna pruriens (Mp) is the most popular drug in Ayurveda, the Indian system of medicine. Several reports have suggested that it possesses analgesic, anti-inflammatory, anti-neoplastic, anti-epileptic and anti-microbial activities. Mp contain L-DOPA and ursolic acid which has an anti-inflammatory property. There are very few literatures which show the immunomodulatory activity of Mp in PD, several researchers have tried to work on the immunomodulatory activity of Mp in some other diseases. The results of several studies show that Mp modulate the immune components like TNF-alpha, IL-6, IFN-lambda, IL-1beta, iNOS and IL-2 in the CNS. It also modulates the activity of the transcription factor NF-kB which plays an important role in the progression of the PD. Thus, by altering these cytokines or transcription factors, Mp protects or prevents the progression of PD. Thus in this review we try to explore the immunomodulatory activity of Mp in PD. PMID- 28642129 TI - Fucoxanthin inhibits profibrotic protein expression in vitro and attenuates bleomycin-induced lung fibrosis in vivo. AB - Pulmonary fibrosis, a potentially fatal disease, results from acute and chronic interstitial lung diseases. Fucoxanthin (Fx), a carotenoid found in brown seaweed, shows a wide range of pharmacological activities. In this study, we investigated the antifibrotic effects of fucoxanthin and their underlying molecular mechanisms in transforming growth factor-beta1 (TGF-beta1)-stimulated human pulmonary fibroblasts (HPFs). Thus, the effects of Fx on TGF-beta1-induced expression of fibrotic factors, such as alpha-smooth muscle actin (alpha-SMA), type 1 collagen, fibronectin, and interleukin-6 (IL-6), in HPFs were investigated. We performed an enzyme-linked immunosorbent assay (ELISA), and a western blot analysis to elucidate the mechanisms underlying the antifibrotic effects of Fx in TGF-beta1-stimulated cells. The contractile activity of HPFs was measured using a collagen gel contraction assay. We also investigated the effects of Fx on inflammation and fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. We observed that Fx inhibited the TGF-beta1-induced expression of alpha-SMA, type 1 collagen, fibronectin, and IL-6 in HPFs. Similarly, markedly inhibition of TGF-beta1-induced phosphorylation of p-38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and Smad2/Smad3 (Smad2/3) was observed after Fx treatment. Collagen contraction also significantly decreased on fucoxanthin treatment. Intraperitoneal injection of Fx (10mg/kg) in mice inhibited BLM-induced lung fibrosis and type I collagen protein expression. Overall, our findings suggest that Fx may be effective in the treatment of pulmonary fibrosis owing to its potent antifibrotic activity. PMID- 28642130 TI - mir-155 expression is downregulated in kidney transplant patients with human cytomegalovirus infection. AB - MicroRNAs are small, noncoding RNAs that control expression of target genes through inhibiting protein translation or inducing degradation of mRNA transcripts of target genes. According to the latest update, 2578 unique mature miRNAs are currently annotated in the human genome and participate in the regulation of multiple events, such as cellular proliferation or apoptosis. Herpesvirus family comprehends many viruses able to control and modulate host cell processes permitting the survival by a latency phase after primary infection. Recently has been attested that Human Cytomegalovirus, which belongs to Herpesvirus family, can alter human miRNAs expression in vitro, and, in particular, downregulate mir-155 expression. In this study 20 kidney transplant patients positive to Human Cytomegalovirus infection and 11 negative were enrolled. The patients' positive to Human Cytomegalovirus infections have been subdivided into two groups: one group including patients with a low viral load and one including patients with a high viral load. The mir-155 expression profile has been evaluated by a stem-loop Real Time PCR in all these conditions to observe differences among the groups and compare the results obtained with the literature. The comparison between kidney transplant patients negative to Human Cytomegalovirus infection and patients with a high viral load showed a not significant difference in terms of mir-155 expression. However, considering low viral load group or the group including both high and low viral load patients, mir-155 expression levels decreased significantly. Considering this data together, it is possible confirm data published before and assert that Human Cytomegalovirus is responsible of mir-155 downregulation. PMID- 28642131 TI - miR-217 suppresses proliferation and promotes apoptosis in cardiac myxoma by targeting Interleukin-6. AB - Cardiac myxoma (CM) is a prevalent primary cardiac tumor. miR-217 plays a vital role in tumorigenesis of various cancers, however, its role and underlying molecular mechanism in human CM remain poorly understood. Here, we reported that the expression of miR-217 was downregulated in CM tissues and inversely correlated with the expression of Interleukin-6 (IL-6) mRNA. Gain-of-function analysis indicated that overexpression of miR-217 inhibited the proliferation and promoted the apoptosis of the primary CM cells. Bioinformatics analysis showed that IL-6 was a direct target gene of miR-217, which is confirmed by the dual luciferase assays. Moreover, downregulation of IL-6 by small interference RNA (siRNA) mimicked the tumor-suppressive effects of miR-217 in CM. Furthermore, rescue experiments pointed out that restoration of IL-6 expression abrogated the anti-proliferative and pro-apoptotic effect induced by miR-217 overexpression in CM cells. Taken together, we validated that miR-217 could act as a tumor suppressor in CM by directly targeting 3'UTR of IL-6 gene, indicating that manipulation of miR-217 may be a potential therapeutic strategy for CM patients. PMID- 28642133 TI - S-allylmercaptocysteine suppresses the growth of human gastric cancer xenografts through induction of apoptosis and regulation of MAPK and PI3K/Akt signaling pathways. AB - Gastric cancer remains as a common lethal malignancy worldwide. Developing novel anti-gastric cancer drugs with minimal side effects is necessary to address this public health issue. S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, has been demonstrated as a suppressive agent against tumors. In this study, we examined the effect of SAMC on human gastric carcinoma growth in vivo and explored the underlying mechanism. Human gastric cancer SGC-7901 cells were inoculated subcutaneously in BALB/c nude mice. When xenograft tumors reached about 100 mm3, mice were treated with SAMC for 30 days. We observed that SAMC administration in mice effectively delayed the growth of SGC-7901 xenografts without signs of toxicity. TUNEL staining confirmed that the tumors from SAMC-treated mice exhibited a markedly higher apoptotic index. Mechanistic studies suggested that this activity may arise from its effects on the caspase activation and modulation of MAPK and PI3K/Akt signaling pathways. Taken together, these data support development of SAMC as a potential agent for gastric cancer therapy. PMID- 28642132 TI - Unphosphorylated STAT3 regulates the antiproliferative, antiviral, and gene inducing actions of type I interferons. AB - Type I interferon (IFNalpha/beta) induces antiviral and antiproliferative responses in cells through the induction of IFN-stimulated genes (ISGs). Although the roles of IFN-activated STAT1 and STAT2 in the IFN response are well described, the function of STAT3 is poorly characterized. We investigated the role of STAT3 in the biological response to IFNalpha/beta in mouse embryonic fibroblasts (MEFs) with a germ line deletion of STAT3. These STAT3 knockout (STAT3-KO) MEFs were reconstituted with STAT3 or the F705-STAT3 mutant (unphosphorylated STAT3) where the canonical Y705 tyrosine phosphorylation site was mutated. We show that both STAT3 and unphosphorylated STAT3 expression enhance the sensitivity of MEFs to the antiviral, antiproliferative and gene inducing actions of IFN. By chromatin immunoprecipitation assays, unphosphorylated STAT3 appears to bind, albeit weakly, to select gene promoters to enhance their expression. These results suggest that unphosphorylated STAT3 plays an important role in the IFN response pathway. PMID- 28642135 TI - LIGHT is increased in patients with coronary disease and regulates inflammatory response and lipid metabolism in oxLDL-induced THP-1 macrophages. AB - Inflammation is critical for the progression of hyperlipidemia. Although the exact mechanism through which inflammation affects hyperlipidemia is not very clear, evidence suggests that the tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT)LIGHT might regulate lipid metabolism. In this study we investigated the expression of LIGHT in patients with different stages of coronary disease. The expression of lipid metabolism-related enzymes and inflammation-related proteins were further explored in oxidized low-density lipoproteins (oxLDL)-induced THP-1 macrophages. We found that LIGHT is highly expressed and companied with severe inflammations in patients with coronary disease. LIGHT significantly enhanced inflammation response in oxLDL-induced THP 1 macrophages. We further demonstrated that LIGHT markedly decreased the levels of lipolytic genes and increased the expressions of lipogenic genes in oxLDL induced THP-1 macrophages. In addition, our results showed that LIGHT exerts its pro-inflammatory and pro-lipogenesis roles through activating nuclear factor kappa B (NF-kappaB) signaling pathway. Taken together our study has demonstrated that LIGHT NF-kappaB-dependently exacerbates inflammation response and promotes lipid accumulation, and provided a new potential target for treatment of hyperlipidemia-related disease. PMID- 28642134 TI - Mitochondrial potassium channels in cell death. AB - Mitochondria are intracellular organelles involved in several processes from bioenergetics to cell death. In the latest years, ion channels are arising as new possible targets in controlling several cellular functions. The discovery that several plasma membrane located ion channels have intracellular counterparts, has now implemented this consideration and the number of studies enforcing the understanding of their role in different metabolic pathways. In this review, we will discuss the recent updates in the field, focusing our attention on the involvement of potassium channels during mitochondrial mediated apoptotic cell death. Since mitochondria are one of the key organelles involved in this process, it is not surprising that potassium channels located in their inner membrane could be involved in modulating mitochondrial membrane potential, ROS production, and respiratory chain complexes functions. Eventually, these events lead to changes in the mitochondrial fitness that prelude to the cytochrome c release and apoptosis. In this scenario, both the inhibition and the activation of mitochondrial potassium channels could cause cell death, and their targeting could be a novel pharmacological way to treat different human diseases. PMID- 28642136 TI - A novel hepatitis B virus-derived cis-acting sequence that enhances expression of transgenes delivered by plasmid vectors in eukaryote cell culture systems. AB - We tested the effectiveness of a novel 13-bp hepatitis B virus (HBV)-derived cis acting element (CAE) (ACCTCGACAAGGC), called the DT2 CAE, in augmenting transgene expression delivered by plasmid vectors in eukaryotic cells. The addition of the DT2 CAE just upstream of the start codon of several different target proteins (luciferase, EGFP, LHB, HBsAg, and MIF) in DNA plasmid constructs enhanced their translation in a posttranscriptional manner, irrespective of cell type (cell lines or primary cells) or promoter (CMV or HBV preS1 promoters), suggesting its feasibility for enhanced protein production in eukaryotic cell systems. In conclusion, a novel HBV-derived DT2 CAE could be used effectively for enhanced protein production in eukaryotic cell culture systems. PMID- 28642137 TI - Overexpression cdc42 attenuates isoflurane-induced neurotoxicity in developmental brain of rats. AB - Nowadays many children receive operations with general anesthesia. Isoflurane is a commonly-used general anesthetic. Numbers of studies demonstrated that isoflurane induced neurotoxicity and neurobehavioral deficiency in young rats, however, the underlying mechanism remained unknown. Cell division cycle 42 (cdc42) played an important role in regulating synaptic vesicle trafficking and actin dynamics in neuron, which closely linked to synaptic plasticity and dendritic spine formation. Meanwhile, cdc42 also involved in many neurodegenerative diseases. However, whether cdc42 provided a protective role in isoflurane induced synaptogenesis dysfunction still unknown. As the upstream of cdc42, calcium/Calmodulin-dependent protein kinase II (CaMKII) interacts with ion channels such as VDCCs and N-methyl-d-aspartate receptors (NMDARs), which closely associated with neuroapoptosis and cognitive deficiency in developing brain. The phosphorylation of CaMKIIalpha at Thr 286 plays an important role in introduction and maintenance of long-term potentiation (LTP). Therefore, we investigated the effect of isoflurane on cdc42 and its upstream Calcium/Calmodulin-dependent protein kinase II (CaMKII) and its downstream p21 activated kinase 3 (PAK3), then determined whether CaMKIIalpha/cdc42/PAK3 signaling pathway was involved in neurotoxicity and cognitive deficiency induced by isoflurane. Our study found that isoflurane induced neurotoxicity and resulted in cognitive impairment in young rats through suppressed CaMKIIalpha/cdc42/PAK3 signaling pathway. Cdc42 over-expression could reverse neurotoxicity and improve cognitive impairment induced by isoflurane. PMID- 28642138 TI - Molecular cloning of chicken TET family genes and role of chicken TET1 in erythropoiesis. AB - Ten-eleven translocation (TET) methylcytosine dioxygenase has potential as an active eraser to regulate the genomic DNA methylation status. We herein cloned chicken TET (cTET) family genes, and confirmed their functions. Quantitative reverse-transcription PCR showed that cTET1 was strongly expressed in erythrocytes throughout development. This cTET1 expression pattern, together with the results of methylated or hydroxymethylated DNA immunoprecipitation, suggests that cTET1 contributes to demethylation around the promoter region of the definitive-type beta-globin gene betaAlpha in erythroid cells. The knockdown of cTET1 in T2ECs chicken erythroid progenitor cells suppressed the induction of betaAlpha expression under differentiation conditions. These results suggest that cTET1 plays an important role in erythroid cell differentiation. PMID- 28642139 TI - Clinical characteristics and epidemiology of sepsis in the neonatal intensive care unit in the era of multi-drug resistant organisms: A retrospective review. AB - BACKGROUND: Sepsis in the neonatal intensive care unit (NICU) remains one of the most significant causes of morbidity and mortality, especially for preterm newborns. Multi-drug resistant organisms (MDROs) are emerging as important pathogens that cause neonatal sepsis in NICU. Therefore, studying the epidemiology, clinical features, and outcome caused by MDROs vs. non-MDROs, and identifying risk factors that may predispose patients to sepsis by MDROs are important. METHODS: Episodes of blood culture-proven sepsis (age: 0-90 days) in the NICU at our institution from January 2012 to December 2015 were retrospectively reviewed. Collected data included demographics, signs at time of sepsis, laboratory values, microbiologic results, and final outcome. We compared clinical and laboratory data and final outcome for patients with sepsis due to MDROs vs. non-MDROs. Multivariate analysis was performed on variables with a P value of <0.05 from univariate analysis. RESULTS: Sixty-eight episodes of sepsis (ages 0-54 days, median 7 days; 34 female; 81% premature) were caused by Gram negative bacteria (n = 42; 62%), Gram-positive bacteria (n = 21; 31%), or Candida (n = 5; 7%). The most common organisms that were isolated were Acinetobacter baumannii (27%), Klebsiella pneumoniae (22%), coagulase-negative staphylococcus (CoNS) (18%), group B streptococcus (10%), and Escherichia coli (6%). Compared with non-MDROs (n = 16; 31%, excluding CoNS and Candida), MDROs (n = 35; 69%) were associated with higher mortality (P = 0.002) and more delay in providing targeted antimicrobial therapy (P = 0.002) (based on antimicrobial susceptibility tests). Sepsis due to the most resistant organisms (A. baumannii and K. pneumoniae Carbapenemase [KPC]-producing bacteria, n = 20; 39%) was associated with higher mortality (P = 0.001) and significantly associated with exposure to carbapenem and vancomycin before onset of sepsis (cases exposed = 13/20; 65%, P < 0.001). CONCLUSION: MDROs are the most common cause of sepsis at our NICU and are associated with higher mortality compared with non-MDROs. Previous exposure to carbapenem and vancomycin was associated with sepsis caused by the most resistant organisms. PMID- 28642140 TI - Emergence of carbapenem-resistant Enterobacteriaceae isolated from patients in a university hospital in Saudi Arabia. Epidemiology, clinical profiles and outcomes. AB - Carbapenemase-producing Enterobacteriaceae have been steadily spreading worldwide during the last decade. Nine patients were identified prospectively and were followed during their hospitalization course to identify the epidemiology, clinical profiles and outcomes. These patients had one or more cultures positive for a CRE isolate, contributing to a total of eleven positive cultures from various sites without including duplicates of isolates obtained from the same site. Isolates from these patients included five Klebseilla pneumoniae, three Escherichia coli, and one Enterobacter aerogenes. Five isolates were grown from blood cultures, three from wound cultures, one from urine cultures, one from respiratory cultures and one from an abscess collection. Five survived the hospital course. The other five patients died due to severe sepsis, septic shock or multi-organ failure. Of the nine isolates of CRE identified for which molecular analysis were available, four K. pneumonia were confirmed as blaNDM and one as OXA-48. For the purpose of controlling the spread of CRE in our institution, we recommend considering active surveillance cultures and screening patients transferred from other hospitals or coming from highly endemic settings at admission for these organisms. PMID- 28642141 TI - Added diagnostic value and impact on antimicrobial therapy of 16S rRNA PCR and amplicon sequencing on resected heart valves in infective endocarditis: a prospective cohort study. AB - OBJECTIVES: For adequate management and therapy of infective endocarditis (IE), identification of the causative pathogen is crucial but molecular testing results are not currently included in diagnostic criteria. The added diagnostic value and impact on antimicrobial therapy of 16S rRNA PCR and amplicon sequencing (16S rRNA PCR) performed on excised heart valves from patients with IE was evaluated alongside the effect of pre-operative antibiotics on the performance of blood culture (BC), valve culture (VC) and 16S rRNA PCR. METHODS: All patients undergoing valve surgery for definite or possible IE, according to modified Duke Criteria, were prospectively included from July 2013 up to and including June 2016. RESULTS: In all, 127 patients were included. Sensitivity for detecting the causative micro-organism in 120 post-operative definite IE patients was 26% for VC and 87% for BC and 16S rRNA PCR. 16S rRNA PCR, VC and BC were equally sensitive for different valve types and causative pathogens. In 27 (21%) definite IE patients, 16S rRNA PCR clarified discrepant culture results or was the only method identifying the causative pathogen. In 12 (10%) post-operative definite IE cases, molecular testing results influenced antimicrobial therapy. CONCLUSIONS: The very good performance characteristics, added diagnostic value and impact on antimicrobial therapy of molecular testing of heart valves should support the incorporation of molecular testing in diagnostic criteria and guidelines for IE. PMID- 28642143 TI - Biofilm formation by Microsporum canis. PMID- 28642142 TI - Epidemiology and outcomes of bloodstream infections in 177 severe burn patients from an industrial disaster: a multicentre retrospective study. AB - OBJECTIVES: To determine the characteristics of bloodstream infections (BSIs) and to evaluate the impact of BSIs on mortality in severe burn patients. METHODS: A retrospective observational study was conducted in 20 tertiary hospitals. A total of 185 patients who experienced a massive dust explosion in eastern China were included. RESULTS: After exclusion, 177 patients were analysed. The median total body surface area (TBSA) burned was 95% (interquartile range 85%-98%). Inhalation injuries occurred in 97.2%. The overall 90-day mortality was 35% (62/177). During the study period, 120 (67.8%) patients developed 253 episodes of BSI with 323 unique causative pathogens. Sixty-six episodes were polymicrobial infections. Catheter-related BSIs (CRBSIs) accounted for 41.5% of the episodes. Acinetobacter baumannii (19.5%), Klebsiella pneumoniae (13.9%) and Candida (12.7%) were the most common organisms. Antimicrobial resistance was found in 63.5% of the isolates, particularly in Gram-negative bacteria. Patients who developed BSIs had a greater illness severity at admission to the intensive care unit, and worse outcomes. After adjusting for demographics, severity of illness and treatment characteristics in a multivariate logistic model, there was a trend toward BSI increasing the risk of 90-day mortality (adjusted OR 3.4; 95% CI 0.9-12.9; p=0.069). In subgroup analyses, CRBSIs (adjusted OR 5.7; 95% CI 1.3-24.9; p=0.021 versus no BSI) and polymicrobial BSIs (adjusted OR 6.1; 95% CI 1.3-28.1; p=0.020 versus no BSI) had greater risk of 90-day mortality. CONCLUSIONS: A strikingly high rate of BSIs was observed in severe burn patients. Gram-negative organisms and fungi were the leading causes. CRBSIs and polymicrobial BSIs were associated with high mortality. PMID- 28642144 TI - Performance of Aspergillus PCR in cerebrospinal fluid for the diagnosis of cerebral aspergillosis. AB - OBJECTIVES: Cerebral aspergillosis is a rare but often fatal form of invasive aspergillosis that remains difficult to diagnose. The literature has shown the value of Aspergillus PCR in blood-derived samples for the diagnosis of invasive aspergillosis but provides far less information for cerebrospinal fluid (CSF) in cerebral aspergillosis. Here, we evaluated the usefulness of an Aspergillus PCR assay performed on CSF for the diagnosis of cerebral aspergillosis. METHODS: This retrospective study involved 72 patients with suspected cerebral aspergillosis for a total of 88 CSF samples in whom CSF Aspergillus PCR was performed. RESULTS: Seventeen patients had proven/probable invasive aspergillosis according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria, including 12 cases of proven/probable cerebral aspergillosis. Aspergillus PCR in CSF was positive in nine of the twelve patients with cerebral aspergillosis, i.e. 75% sensitivity. In contrast, CSF culture was positive for Aspergillus in only two patients. In the non-cerebral aspergillosis group (60 patients), PCR was positive in one patient, i.e. 98.3% specificity. In this particular population of high-risk patients with suspicion of cerebral aspergillosis, the disease incidence was 16.7%. Therefore, the positive and negative predictive values of PCR were 90% and 95.2%, respectively. CONCLUSION: The results of this study indicate that Aspergillus PCR in CSF is an interesting tool that may eliminate the need for cerebral biopsy in patients with suspected cerebral aspergillosis. PMID- 28642145 TI - New and improved? A review of novel antibiotics for Gram-positive bacteria. AB - BACKGROUND: The number of antibiotics in the pipeline targeting Gram-positive pathogens has increased in recent years. AIMS: This narrative review aims to provide a summary of existing evidence on efficacy, microbiological spectrum and safety of novel systemic antibiotics that have either recently been licensed or completed phase III trials, and possess activity predominantly against Gram positive organisms. SOURCES: A review of the published literature via the MEDLINE database was performed. In addition, ongoing trials were identified through a search of the clinical trial registration platform clinicaltrials.gov, and when necessary, pharmaceutical companies responsible for the development of the drug were contacted for further information. CONTENT: Data on development, microbiological spectrum, pharmacokinetic/pharmacodynamic properties, clinical efficacy, safety and cost are presented for the new cephalosporins ceftaroline and ceftobiprole; the lipoglycopeptides dalbavancin, oritavancin and telavancin; the fluoroquinolones delafloxacin, nemonoxacin and zabofloxacin; the dihydrofolate-reductase inhibitor iclaprim; the pleuromutilin lefamulin; and the tetracycline omadacycline. IMPLICATIONS: Although promising, these new antibiotics have so far been tested in non-severe infections whose treatment is generally uncomplicated and whose aetiologies were not predominantly multidrug resistant pathogens. None of the new antibiotics have shown superiority to standard care, and none have been investigated for patient-relevant outcomes. Safety and pharmacokinetic data continue to be lacking. How these new drugs are to be integrated into the current armamentarium remains to be established. PMID- 28642146 TI - Is antimicrobial stewardship cost-effective? A narrative review of the evidence. AB - AIMS: This narrative review aimed to collate recent evidence on the cost effectiveness and cost-benefit of antimicrobial stewardship (AMS) programmes, to address the question 'is AMS cost-effective?', while providing resources and guidance for future research in this area. SOURCES: PubMed was searched for studies assessing the cost-effectiveness, cost-utility or cost-benefit of AMS interventions in humans, published from January 2000 to March 2017, with no setting inclusion/exclusion criteria specified. Reference lists of retrieved reviews were searched for additional articles. CONTENT: Recent evidence on the cost-effectiveness and cost-benefit of AMS is described, studies suggest persuasive and structural AMS interventions may provide health economic benefits to the hospital setting. However, overall, cost-effectiveness evidence for AMS is severely limited, especially for the community setting. Recommendations for future research in this area are therefore provided, including discussion of appropriate health economic methodological choice. IMPLICATIONS: Health systems have a finite and decreasing resource, decision makers currently do not have necessary evidence to assess whether AMS programmes provide sufficient benefits. Although the evidence-base of the cost-effectiveness of AMS is increasing, it remains inadequate for investment decision-making. Robust health economics research needs to be completed to enhance the generalizability and usability of cost-effectiveness results. PMID- 28642147 TI - The role of tigecycline in the management of Clostridium difficile infection: a retrospective cohort study. AB - OBJECTIVE: We aimed to compare the outcomes of patients with C.difficile infection (CDI) treated either with tigecycline associated with vancomycin, or with vancomycin alone. METHODS: This single-centre retrospective cohort study included all adults hospitalized from September 2014 through August 2015 for symptomatic, incident CDI confirmed by polymerase chain reaction for C. difficile toxin in stools. The primary outcome was the rate of favourable outcome, defined as a composite of clinical response (resolution of symptoms without need for additional CDI therapy) and achieving discharge without CDI-related surgery or intensive care; a secondary outcome was CDI recurrence. We constructed a non parsimonious logistic regression model to calculate a propensity score (PS) for those receiving tigecycline. RESULTS: In all, 266 patients were included: 62 patients received both vancomycin and tigecycline, and 204 patients received vancomycin alone. The patients from the two groups were similar regarding demographics and comorbidities but patients in the tigecycline group had a more severe CDI. A favourable outcome in the tigecycline group versus the vancomycin group was found in 50/62 (81%) versus 193/204 (95%). We matched patients receiving tigecycline or not according to the PS and 86 patients (43 pairs) could be matched. The OR for favourable outcome with tigecycline in the matched analysis was 0.92 (95% CI 0.60-1.44; p 0.74). The rate of CDI recurrences was 8/62 (13%) in the tigecycline group versus 39/204 (19%) in the vancomycin group (p 0.2). CONCLUSION: Adding tigecycline to CDI standard therapy did not increase the clinical cure nor reduce the rate of CDI recurrences. PMID- 28642148 TI - Biological activity of glatiramer acetate on Treg and anti-inflammatory monocytes persists for more than 10years in responder multiple sclerosis patients. AB - Glatiramer acetate (GA) is a widely used treatment for multiple sclerosis (MS), with incompletely defined mechanism of action. Short-term studies suggested its involvement in the modulation of anti-inflammatory cytokines and regulatory T cells (Treg), while long-term effect is still unknown. To investigate this aspect, we analyzed by flow-cytometry peripheral-blood Treg, natural killer (NK), CD4 and CD8 T-cells and anti-inflammatory CD14+CD163+ monocytes from 37 healthy donor and 90 RRMS patients divided in untreated, treated with GA for 12months and from 34 to 192months. While NK, CD4 and CD8 T-cells did not show any significant differences among groups over time, we demonstrated that GA increased the anti inflammatory monocytes and restored the Treg level in both GA-treated groups. Both these effects are a characteristic of responder patients and are observed not just in short-term but even after as long as a decade of GA treatment. PMID- 28642149 TI - Activated mGluR5 protects BV2 cells against OGD/R induced cytotoxicity by modulating BDNF-TrkB pathway. AB - Activated Metabotropic glutamate receptors 5(mGluR5) exhibits protective effects against ischemic brain damage, but the underlying mechanisms are not clearly known. Brain-derived neurotrophic factor (BDNF), as a valuable member of neurotrophic factor family, exerts its protection by combining with its high affinity receptor tyrosine protein kinase B (TrkB). To investigate the role of activated mGluR5 against oxygen-glucose deprivation (OGD)/reoxygenation (R) mediated cytotoxicity, the cell viability, apoptosis, the release of inflammatory cytokines and accumulation of reactive oxygen species (ROS) were evaluated in BV2 cells (Microglia cell line) with or without OGD/R exposure. Our data show that CHPG (the selective mGluR5 agonist) pretreatment, as an mGluR5 agonist, protected BV2 cells against OGD/R-induced cytotoxicity, apoptosis, the release of inflammatory cytokines, and the accumulation of ROS. However, these effects were significantly reversed by the mGluR5 antagonist MPEP pretreatment. Our data also show that the expressions of BDNF and TrkB were significantly decreased in BV2 cells with OGD/R exposure. CHPG pretreatment significantly enhanced the expressions of BDNF and TrkB in BV2 cells with OGD/R exposure. However, the increased expressions were significantly abrogated by MPEP pretreatment. In addition, inhibition of BDNF/TrKB pathway by K252a also attenuated the protective effects of activated mGluR5 against OGD/R-induced cytotoxicity, apoptosis and the release of inflammatory cytokines. Morever, pretreatment with exogenous BDNF protected BV2 cells against OGD/R induced apoptosis and release of inflammatory cytokines. These data suggested that BDNF/TrKB pathway may be involved in regulating activated mGluR5' protective effects against OGD/R induced cytotoxicity in BV2 cells. PMID- 28642150 TI - Inter-limb transfer of kinematic adaptation in individuals with motor difficulties. AB - A previous study suggested that adults with greater motor difficulties demonstrated less adaptation under a regular error feedback schedule (gain=1:1) but reached a similar level of adaptation compared to controls when feedback was enhanced (gain=1:2). In light of these findings, the present study examined inter limb transfer after adults adapted to visuomotor distortions with their dominant hand on either regular or enhanced feedback schedules. Results revealed that successful transfer related to the magnitude of adaptation with their dominant hand regardless of the individuals' motor abilities on the regular feedback schedule. When the feedback was enhanced, the transfer was not related to either the adaptation of the dominant hand or individuals' motor abilities. We argue that a stable internal model is essential for inter-limb transfer in kinematic adaptation. PMID- 28642124 TI - Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study. AB - BACKGROUND: Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. METHODS: We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003-13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. FINDINGS: Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0.674), and with age at onset (TRACK-HD, r=0.315; REGISTRY, r=0.234). The meta analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1.12 * 10-10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2.94 * 10-8DHFR p=8.37 * 10-7 MTRNR2L2 p=2.15 * 10-9) and to a lesser extent in REGISTRY (MSH3 p=9.36 * 10-4DHFR p=8.45 * 10-4MTRNR2L2 p=1.20 * 10-3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1.58 * 10-8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0.4 units per year (95% CI 0.16-0.66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0.12 units per year (95% CI 0.06-0.18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. INTERPRETATION: The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. FUNDING: The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain. PMID- 28642151 TI - The role of the LB structural loop and its interactions with the PDZ domain of the human HtrA3 protease. AB - Human HtrA3 protease is a proapoptotic protein, involved in embryo implantation and oncogenesis. In stress conditions the protease is activated by removal of its N-terminal domain. The activated form, DeltaN-HtrA3L is a homotrimer composed of the protease (PD) and PDZ domains. The LB structural loop of the PD is longer by six amino acid residues than its counterparts of other human HtrA proteins and interacts with the PDZ in a way not observed in other known HtrA structures. By size exclusion chromatography of the DeltaN-HtrA3L mutated variants we found that removal of the additional LB loop residues caused a complete loss of the proper trimeric structure while impairing their interactions with the PDZ domain decreased the amount of the trimers. This indicates that the LB loop participates in stabilization of the DeltaN-HtrA3L oligomer structure and suggests involvement of the LB-PDZ interactions in the stabilization. Removal of the additional LB loop residues impaired the DeltaN-HtrA3L activity against the peptide and protein substrates, including the antiapoptotic XIAP protein, while a decrease in the LB PDZ interaction caused a diminished efficiency of the peptide cleavage. These results indicate that the additional LB residues are important for the DeltaN HtrA3L proteolytic activity. Furthermore, a monomeric form of the DeltaN-HtrA3L is proteolytically inactive. In conclusion, our results suggest that the expanded LB loop promotes the DeltaN-HtrA3L activity by stabilizing the protease native trimeric structure. PMID- 28642152 TI - G-quadruplex dynamics. AB - G-quadruplexes (GQs) are four-stranded nucleic acid secondary structures formed by guanosine (G)-rich DNA and RNA sequences. It is becoming increasingly clear that cellular processes including gene expression and mRNA translation are regulated by GQs. GQ structures have been extensively characterized, however little attention to date has been paid to their conformational dynamics, despite the fact that many biological GQ sequences populate multiple structures of similar free energies, leading to an ensemble of exchanging conformations. The impact of these dynamics on biological function is currently not well understood. Recently, structural dynamics have been demonstrated to entropically stabilize GQ ensembles, potentially modulating gene expression. Transient, low-populated states in GQ ensembles may additionally regulate nucleic acid interactions and function. This review will underscore the interplay of GQ dynamics and biological function, focusing on several dynamic processes for biological GQs and the characterization of GQ dynamics by nuclear magnetic resonance (NMR) spectroscopy in conjunction with other biophysical techniques. This article is part of a Special Issue entitled: Biophysics in Canada, edited by Lewis Kay, John Baenziger, Albert Berghuis and Peter Tieleman. PMID- 28642153 TI - Characterization of the differential coregulator binding signatures of the Retinoic Acid Receptor subtypes upon (ant)agonist action. AB - Retinoic Acid Receptor alpha (RARalpha/NR1B1), Retinoic Acid Receptor beta (RARbeta/NR1B2) and Retinoic Acid Receptor gamma (RARgamma/NR1B3) are transcription factors regulating gene expression in response to retinoids. Within the RAR genomic pathways, binding of RARs to coregulators is a key intermediate regulatory phase. However, ligand-dependent interactions between the wide variety of coregulators that may be present in a cell and the different RAR subtypes are largely unknown. The aim of this study is to characterize the coregulator binding profiles of RARs in the presence of the pan-agonist all-trans-Retinoic Acid (AtRA); the subtype-selective agonists Am80 (RARalpha), CD2314 (RARbeta) and BMS961 (RARgamma); and the antagonist Ro415253. To this end, we used a microarray assay for coregulator-nuclear receptor interactions to assess RAR binding to 154 motifs belonging to >60 coregulators. The results revealed a high number of ligand-dependent RAR-coregulator interactions among all RAR variants, including many binding events not yet described in literature. Next, this work confirmed a greater ligand-independent activity of RARbeta compared to the other RAR subtypes based on both higher basal and lower ligand-driven coregulator binding. Further, several coregulator motifs showed selective binding to a specific RAR subtype. Next, this work showed that subtype-selective agonists can be successfully discriminated by using coregulator binding assays. Finally this study demonstrated the possible applications of a coregulator binding assay as a tool to discriminate between agonistic/antagonistic actions of ligands. The RAR coregulator interactions found will be of use to direct further studies to better understand the mechanisms driving the eventual actions of retinoids. PMID- 28642155 TI - Uptake and desorption of hydrophilic compounds from human stratum corneum. AB - Small, polar compounds, both ionic and uncharged, partition into human stratum corneum immersed in aqueous solutions to an extent comparable to the water volume fraction of the tissue, then desorb in two phases. The fast phase has a time constant on the order of a few minutes, whereas the slow phase occurs over many hours. A physical model for this behavior involving a combination of tranverse diffusion through the tissue and lateral diffusion and exchange with skin appendages is presented. This concept is probed using excised human stratum corneum exposed to aqueous solutions of radiolabeled sodium chloride, tetraethyl ammonium bromide and mannitol, plus previously published data on six other compounds of varying molecular size and polarity. The fast phase desorption process becomes unimportant for lipophilic compounds. Slow phase desorption rates are size-selective, with larger species desorbing much more slowly than smaller ones. Interpreting the size-selectivity in terms of smooth cylindrical pores using the centerline approximation leads to an optimum pore radius of about 8 12A, depending on the model chosen. PMID- 28642156 TI - TGFbeta/SMAD/microRNA-486-3p Signaling Axis Mediates Keratin 17 Expression and Keratinocyte Hyperproliferation in Psoriasis. AB - Keratin 17 (K17) is strongly expressed in psoriatic lesions but not healthy skin, and plays a crucial role in disease pathogenesis. The mechanism of aberrant K17 expression in psoriasis has not been fully elucidated. MicroRNAs are short, single-stranded, noncoding RNAs that play important roles in regulating gene expression. Psoriasis exhibits a specific microRNA expression profile distinct from that of healthy skin. In this study, we showed that miR-486-3p was markedly reduced in psoriatic epidermis and negatively correlated with the psoriasis area and severity index score. Its expression repressed K17 protein expression and decreased proliferation in a keratinocyte cell line overexpressing K17 (LV K17) compared with controls. Our data indicated that miR-486-3p was regulated by a transforming growth factor-beta (TGFbeta)/SMAD pathway and possibly mediated the downregulation of K17 protein in TGFbeta-treated keratinocytes. Finally, the decreased expression of TGFbeta receptor I in psoriatic epidermis inactivated the TGFbeta/SMAD pathway, leading to K17 overexpression and cell proliferation. Collectively, our findings demonstrated that a TGFbeta/SMAD/miR-486-3p signaling axis in keratinocytes regulated K17 expression and cell proliferation. We conclude that the loss of miR-486-3p in psoriatic epidermis leads to K17 protein overexpression and contributes to the pathogenesis of psoriasis. Overexpression of miR-486-3p may therefore be a therapeutic option for psoriasis. PMID- 28642157 TI - Genome comparisons of two Taiwanese community-associated methicillin-resistant Staphylococcus aureus ST59 clones support the multi-origin theory of CA-MRSA. AB - Sequence type (ST) 59 is an epidemic lineage of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) in Asia. Two ST59 clones are prevalent in Taiwan: the Taiwan clone (TW) causes severe infections, whereas the Asian Pacific clone (AP) is usually commensal. In this study, we sequenced the genome and transcriptome of the representative strains of these two clones and found their differences to focus on three mobile genetic elements: TW carries SCCmec Type VT, Panton-Valentine leucocidin (PVL)-encoding prophage PhiSa2, whereas AP carries SCCmec Type IV and staphylokinase (SAK)-encoding prophage PhiSa3. The anti-virulent role of SAK was confirmed using murine skin and bloodstream infection models. PhiSa3 usually integrates into the hlb gene, but in AP was found to be integrated at the genomic island nuSabeta. The mutation of the attB site "TGTATCCAAACTGG" to "TGTATCCGAATTGG" led to a failure in the integration of PhiSa3 in hlb, prompting atypical integration at other sites. The sak gene possessed remarkably different patterns of distribution among the different STs of S. aureus. We conclude that the atypical integration of PhiSa3 may help S. aureus adapt to the human host habitat and that the subsequent loss of PhiSa3 contributes toward the development of a virulent CA-MRSA lineage for wider horizontal transmission. PMID- 28642154 TI - A boosting skin vaccination with dissolving microneedle patch encapsulating M2e vaccine broadens the protective efficacy of conventional influenza vaccines. AB - The biodegradable microneedle patch (MNP) is a novel technology for vaccine delivery that could improve the immunogenicity of vaccines. To broaden the protective efficiency of conventional influenza vaccines, a new 4M2e-tFliC fusion protein construct containing M2e sequences from different subtypes was generated. Purified fusion protein was encapsulate into MNPs with a biocompatible polymer for use as a boosting vaccine. The results demonstrated that mice receiving a conventional inactivated vaccine followed by a skin-applied dissolving 4M2e-tFliC MNP boost could better maintain the humoral antibody response than that by the conventional vaccine-prime alone. Compared with an intramuscular injection boost, mice receiving the MNP boost showed significantly enhanced cellular immune responses, hemagglutination-inhibition (HAI) titers, and neutralization titers. Increased frequency of antigen-specific plasma cells and long-lived bone marrow plasma cells was detected in the MNP boosted group as well, indicating that skin vaccination with 4M2e-tFliC facilitated a long-term antibody-mediated immunity. The 4M2e-tFliC MNP-boosted group also possessed enhanced protection against high lethal dose challenges against homologous A/PR/8/34 and A/Aichi/2/68 viruses and protection for a majority of immunized mice against a heterologous A/California/07/2009 H1N1 virus. High levels of M2e specific immune responses were observed in the 4M2e-tFliC MNP-boosted group as well. These results demonstrate that a skin-applied 4M2e-tFliC MNP boosting immunization to seasonal vaccine recipients may be a rapid approach for increasing the protective efficacy of seasonal vaccines in response to a significant drift seen in circulating viruses. The results also provide a new perspective for future exploration of universal influenza vaccines. PMID- 28642158 TI - Genetic diversity of environmental Vibrio cholerae O1 strains isolated in Northern Vietnam. AB - Cholera epidemics have been recorded periodically in Vietnam during the seventh cholera pandemic. Since cholera is a water-borne disease, systematic monitoring of environmental waters for Vibrio cholerae presence is important for predicting and preventing cholera epidemics. We conducted monitoring, isolation, and genetic characterization of V. cholerae strains in Nam Dinh province of Northern Vietnam from Jul 2013 to Feb 2015. In this study, four V. cholerae O1 strains were detected and isolated from 110 analyzed water samples (3.6%); however, none of them carried the cholera toxin gene, ctxA, in their genomes. Whole genome sequencing and phylogenetic analysis revealed that the four O1 isolates were separated into two independent clusters, and one of them diverged from a common ancestor with pandemic strains. The analysis of pathogenicity islands (CTX prophage, VPI-I, VPI-II, VSP-I, and VSP-II) indicated that one strain (VNND_2014Jun_6SS) harbored an unknown prophage-like sequence with high homology to vibriophage KSF-1 phi and VCY phi, identified from Bangladesh and the USA, respectively, while the other three strains carried tcpA gene with a distinct sequence demonstrating a separate clonal lineage. These results suggest that the aquatic environment can harbor highly divergent V. cholera strains and serve as a reservoir for multiple V. cholerae virulence-associated genes which may be exchanged via mobile genetic elements. Therefore, continuous monitoring and genetic characterization of V. cholerae strains in the environment should contribute to the early detection of the sources of infection and prevention of cholera outbreaks as well as to understanding the natural ecology and evolution of V. cholerae. PMID- 28642159 TI - Identification and comparison of RCMV ALL 03 open reading frame (ORF) among several different strains of cytomegalovirus worldwide. AB - BACKGROUND: Rat cytomegalovirus ALL-03 (Malaysian strain) which was isolated from a placenta and uterus of a house rat, Rattus rattus diardii has the ability to cross the placenta and infecting the fetus. To further elucidate the pathogenesis of the Malaysian strain of Rat Cytomegalovirus ALL-03 (RCMV ALL-03), detailed analysis on the viral genome sequence is crucial. METHODS: Genome sequencing of RCMV ALL-03 was carried out in order to identify the open reading frame (ORF), homology comparison of ORF with other strains of CMV, phylogenetic analysis, classifying ORF with its corresponding conserved genes, and determination of functional proteins and grouping of gene families in order to obtain fundamental knowledge of the genome. RESULTS: The present study revealed a total of 123 Coding DNA sequences (CDS) from RCMV ALL-03 with 37 conserved ORF domains as with all herpesvirus genomes. All the CDS possess similar function with RCMV-England followed by RCMV-Berlin, RCMV-Maastricht, and Human CMV. The phylogenetic analysis of RCMV ALL-03 based on conserving genes of herpes virus showed that the Malaysian RCMV isolate is closest to RCMV-English and RCMV-Berlin strains, with 99% and 97% homology, respectively. Similarly, it also demonstrated an evolutionary relationship between RCMV ALL-03 and other strains of herpesviruses from all the three subfamilies. Interestingly, betaherpesvirus subfamily, which has been shown to be more closely related with gammaherpesviruses as compared to alphaherpesviruses, shares some of the functional ORFs. In addition, the arrangement of gene blocks for RCMV ALL-03, which was conserved among herpesvirus family members was also observed in the RCMV ALL-03 genome. CONCLUSION: Genomic analysis of RCMV ALL-03 provided an overall picture of the whole genome organization and it served as a good platform for further understanding on the divergence in the family of Herpesviridae. PMID- 28642160 TI - A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy. AB - Dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot-Marie-Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population. PMID- 28642161 TI - Digenic inheritance of mutations in the cardiac troponin (TNNT2) and cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated cardiomyopathy. AB - Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c.2863G > A; p.D955N in the Myosin Heavy Polypeptide 7 gene (MYH7). Sanger sequencing and co-segregation analysis in the remaining family members supported the coexistence of these digenic mutations in affected members of the family. Carriers of either variant alone were asymptomatic. In summary, we find that digenic inheritance of two novel variants in DCM related genes is associated with a severe form of DCM. Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families, and this report emphasizes the importance of comprehensive screening of DCM related genes, even after the identification of a single disease-causing mutation. PMID- 28642163 TI - Perianal structures in myrmecophilous subterranean aphids (Insecta: Hemiptera: Aphididae) - Comparative morphology of trophobiotic organ with its first description in Lachninae. AB - Scanning electron microscopy (SEM) and light stereoscopic microscopy (LSM) were used for the first time to elucidate the external morphology of the so called "trophobiotic organ" on the end of abdomen of apterous viviparous females of six aphid species (Insecta: Hemiptera: Aphididae), representatives of the myrmecophilous, subterranean aphids from the subfamilies Anoeciinae (Anoecia furcata), Eriosomatinae (Forda formicaria, Geoica utricularia, Tetraneura ulmi), and Lachninae (Protrama flavescens, Trama troglodytes). We examined and compared the external morphology in the parthenogenetic generation living on roots of deciduous plants. FE-SEM images based on HMDS preparation techniques revealed great similarity of perianal structures even between not closely related groups. Rectangular, vertically positioned anal plate, extremely shortened cauda and setae around the anus seem to be common features of these aphids. However, some differences in the number and length of setae, their arrangement and inclination of anal plate may be observed. The discussion focuses on the adaptive importance of such modifications, with respect to underground life mode and myrmecophily, but with reservations concerning living in galls by representatives of Eriosomatinae, which is hypothesized to be a factor driving the development of such modifications of perianal structures in this group of aphids. PMID- 28642162 TI - NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield. AB - BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition. PMID- 28642164 TI - Joint loading and proximal tibia subchondral trabecular bone microarchitecture differ with walking gait patterns in end-stage knee osteoarthritis. AB - OBJECTIVES: To (1) stratify patient subgroups according to their distinct walking gait patterns in end-stage knee osteoarthritis (OA); (2) compare measures of joint loading and proximal tibia subchondral trabecular bone (STB) microarchitecture among these gait subgroups. DESIGN: Twenty-five knee OA patients undergoing total knee arthroplasty (TKA) had pre-operative gait analysis. Following surgery, excised tibial plateaus were micro-CT-scanned and STB microarchitecture analysed in four tibial condylar regions of interest. Peak knee moments were input to k-means cluster analysis, to identify subgroups with homogeneous gait patterns. Joint loading and STB microarchitecture parameters were compared among gait subgroups (Kruskal-Wallis, Bonferroni-corrected Mann Whitney U tests). RESULTS: Three gait subgroups were revealed: biphasics (n = 7), flexors (n = 9), counter-rotators (n = 9). Peak knee adduction moment (KAM) and KAM impulse were significantly higher (P < 0.05) in biphasics than in flexors and counter-rotators (KAM = -0.65, -0.40 and -0.21 Nm/kg, respectively), suggesting a higher medial-to-lateral tibiofemoral load ratio in biphasics. Interestingly, STB medial-to-lateral bone volume fraction (BV/TV) ratio was also significantly higher (more than double) in biphasics and flexors than in counter-rotators (2.24, 2.00 and 1.00, respectively), whereas in biphasics it was only 10% higher than in flexors and not significantly so. CONCLUSIONS: Within the confines of the limited sample size, data suggests that different mechanisms between the biphasic and flexor gait subroups may generate comparable loads upon the tibial plateau and corresponding bony responses, despite significantly lower KAM indices in flexors. Hence, in flexor gait OA patients, conservative treatments designed to reduce KAM, may not be appropriate. Understanding joint loading among walking gait patterns and relationships to bone microarchitecture may aid at identifying/improving management of persons at risk for developing knee OA. PMID- 28642165 TI - Can the way pigs are handled alter behavioural and physiological measures of affective state? AB - Research on human-animal relationship in animal production has been mainly focused on its effect on stress, productivity and meat quality. Only few studies have assessed its effects on the animals' affective state. In the present study, the influence of positive and negative handling (pH and NH, respectively) on affective state and fear as assessed by the cognitive bias test, the novel object test and the defence cascade test was studied in 56 pigs. Serum, saliva and hair were sampled during the study for the analysis of cortisol concentration. Results showed no differences between pH and NH pigs in the behavioural tests, which may be either due to the lack of previous handling effect on the test results, the lack of validity or the low sensitivity of these tests or a combination of them. Moreover, no differences were found in cortisol concentrations between handling groups. However, correlations between tests were found (p<0.05) suggesting that there are individual factors such as the fear level, the motivation or the coping style, that have a similar effect on the response to these tests. Moreover, pigs who were more fearful had higher (r=0.37; p=0.014) levels of serum cortisol at slaughter. PMID- 28642166 TI - Frontal Alpha Oscillations and Attentional Control: A Virtual Reality Neurofeedback Study. AB - Two competing views about alpha oscillations suggest that cortical alpha reflect either cortical inactivity or cortical processing efficiency. We investigated the role of alpha oscillations in attentional control, as measured with a Stroop task. We used neurofeedback to train 22 participants to increase their level of alpha amplitude. Based on the conflict/control loop theory, we selected to train prefrontal alpha and focus on the Gratton effect as an index of deployment of attentional control. We expected an increase or a decrease in the Gratton effect with increase in neural learning depending on whether frontal alpha oscillations reflect cortical idling or enhanced processing efficiency, respectively. In order to induce variability in neural learning beyond natural occurring individual differences, we provided half of the participants with feedback on alpha amplitude in a 3-dimensional (3D) virtual reality environment and the other half received feedback in a 2D environment. Our results showed variable neural learning rates, with larger rates in the 3D compared to the 2D group, corroborating prior evidence of individual differences in EEG-based learning and the influence of a virtual environment. Regression analyses revealed a significant association between the learning rate and changes on deployment of attentional control, with larger learning rates being associated with larger decreases in the Gratton effect. This association was not modulated by feedback medium. The study supports the view of frontal alpha oscillations being associated with efficient neurocognitive processing and demonstrates the utility of neurofeedback training in addressing theoretical questions in the non neurofeedback literature. PMID- 28642168 TI - The posterior parietal cortex as integrative hub for whisker sensorimotor information. AB - Our daily life consists of a continuous interplay between incoming sensory information and outgoing motor plans. Particularly during goal-directed behavior and active exploration of the sensory environment, brain circuits are merging sensory and motor signals. This is referred to as sensorimotor integration and is relevant for locomotion, vision or tactile exploration. The somatosensory (tactile) system is an attractive modality to study sensorimotor integration in health and disease, motivated by the need for revolutionary technology that builds upon conceptual understanding of sensorimotor integration, such as brain machine-interfaces and neuro-prosthetics. In this perspective, we focus on the rat whisker system and put forward the posterior parietal cortex as a potential circuit where sensorimotor integration could occur during active somatosensation. PMID- 28642167 TI - Mice lacking Gpr37 exhibit decreased expression of the myelin-associated glycoprotein MAG and increased susceptibility to demyelination. AB - GPR37 is an orphan G protein-coupled receptor that is predominantly expressed in the brain and found at particularly high levels in oligodendrocytes. GPR37 has been shown to exert effects on oligodendrocyte differentiation and myelination during development, but the molecular basis of these actions is incompletely understood and moreover nothing is known about the potential role(s) of this receptor under demyelinating conditions. To shed light on the fundamental biology of GPR37, we performed proteomic studies comparing protein expression levels in the brains of mice lacking GPR37 and its close relative GPR37-like 1 (GPR37L1). These studies revealed that one of the proteins most sharply decreased in the brains of Gpr37/Gpr37L1 double knockout mice is the myelin-associated glycoprotein MAG. Follow-up Western blot studies confirmed this finding and demonstrated that genetic deletion of Gpr37, but not Gpr37L1, results in strikingly decreased brain expression of MAG. Further in vitro studies demonstrated that GPR37 and MAG form a complex when expressed together in cells. As loss of MAG has previously been shown to result in increased susceptibility to brain insults, we additionally assessed Gpr37-knockout (Gpr37-/-) vs. wild-type mice in the cuprizone model of demyelination. These studies revealed that Gpr37-/ mice exhibit dramatically increased loss of myelin in response to cuprizone, yet do not show any increased loss of oligodendrocyte precursor cells or mature oligodendrocytes. These findings reveal that loss of GPR37 alters oligodendrocyte physiology and increases susceptibility to demyelination, indicating that GPR37 could be a potential drug target for the treatment of demyelinating diseases such as multiple sclerosis. PMID- 28642169 TI - A novel method to quantify base substitution mutations at the 10-6 per bp level in DNA samples. AB - Somatic base substitution mutations of frequencies at the 10-6/bp level are expected to be present in many biomedical samples, such as tissues exposed to carcinogenic factors and exhausted stem cells. However, measurement of such rare mutations has been very difficult in human DNA samples. Here, we invented the use of 100 copies of genomic DNA as a template for amplicon deep sequencing so that a real mutation in a single DNA molecule would be detected at a variant allele frequency of 1% while sequencing errors have less frequency. In addition, we selected 15,552 error-resistant base positions whose mutation frequency was expected to reflect that of base positions that can drive carcinogenesis or potentially even of the entire genome. The validity of the method was first confirmed by the successful detection of mutations premixed at the frequency of 0.1%. Second, increasing mutation frequencies (4-60 * 10-6/bp) were successfully detected in cells treated with increasing doses of one of two mutagens, and their signature mutations were detected. The ratio of non-synonymous mutations to synonymous mutations time-dependently decreased after treatment with a mutagen, supporting the neutral theory of molecular evolution for somatic mutations. Importantly, gastric mucosae exposed to Helicobacter pylori infection was shown to have significantly higher mutation frequency than those without. These results demonstrated that our new method can be used to measure rare base substitution mutations at the 10-6/bp level, and is now ready for a wide range of applications. PMID- 28642170 TI - lncRNA DANCR promotes tumor progression and cancer stemness features in osteosarcoma by upregulating AXL via miR-33a-5p inhibition. AB - lncRNAs regulate the initiation and progression of osteosarcoma, although the mechanism by which this occurs remains unknown. The present study shows that over expression of the lncRNA DANCR increased osteosarcoma cell proliferation, migration, and invasion in vitro, as well as promoted xenograft tumor growth and lung metastasis in vivo. Mechanistically, DANCR promoted osteosarcoma progression by mediating cancer stem cells (CSCs) features. Moreover, pull-down assays and luciferase reporter assays indicated that DANCR upregulated expression of the receptor tyrosine kinase AXL by competitively binding to miR-33a-5p. Furthermore, DANCR enhanced the expression of proteins downstream of the AXL-Akt pathway. DANCR was consistently significantly increased in osteosarcoma tissues, and its expression was positively correlated with tumor size and metastasis as an independent poor prognostic factor. Furthermore, both in patient tumors and xenograft tumors, DANCR expression was positively related to AXL and negatively related to miR-33a-5p. Taken together, our results suggest that DANCR is a crucial upregulator of osteosarcoma and an independent predictor of prognosis. DANCR increases CSCs function by upregulating AXL via competitively binding to miR-33a-5p, and this function is sequentially performed through the PI3K-Akt signaling pathway. PMID- 28642171 TI - Macrophage migration inhibitory factor promotes osteosarcoma growth and lung metastasis through activating the RAS/MAPK pathway. AB - Emerging evidence suggests that the tumour microenvironment plays a critical role in osteosarcoma (OS) development. Thus, cytokine immunotherapy could be a novel strategy for OS treatment. In this study, we explored the role of macrophage migration inhibitory factor (MIF), an important cytokine in OS progression, and investigated the anti-tumour effects of targeting MIF in OS. The results showed that MIF significantly increased in the tissue and serum samples of OS patients and was associated with tumour size, pulmonary metastasis and the survival rate of OS patients. We verified a positive correlation between MIF and p-ERK1/2 in OS patients. The in vitro results indicated that MIF could activate the RAS/MAPK pathway in a time- and dose-dependent manner, thereby promoting cell proliferation and migration. Furthermore, shRNA targeting MIF significantly inhibited tumour growth and lung metastasis in a mouse xenograft model and orthotopic model of OS. Additionally, inhibition of MIF significantly enhanced the sensitivity of OS cells to cisplatin and doxorubicin. Our findings suggest that immunotherapy targeting MIF to block the RAS/MAPK kinase cascade may represent a feasible and promising approach for OS treatment. PMID- 28642172 TI - EGFR T790M ctDNA testing platforms and their role as companion diagnostics: Correlation with clinical outcomes to EGFR-TKIs. AB - Somatic mutation in the epidermal growth factor receptor (EGFR) predict clinical response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) and is a promising target for personalised medicine. EGFR mutations have prognostic value. Initially patients respond well to tyrosine kinase inhibitors but finally they would develop resistance and about 50% of this resistance can be attributed to the emergence of EGFR resistant mutation, T790M. This necessitates the need for genetic testing for clinical management of patients. Molecular testing has become the standard of care in patients with NSCLCs based on the recommendations of standard guidelines. Though there are several platforms for EGFR mutation detection, highly sensitive platforms for clinical applicability as companion diagnostics for ctDNA based testing are emerging. Due to the dynamic changes in the T790M mutation during tyrosine kinase inhibitor (TKI) treatment, real-time monitoring of these genetic alterations is mandate for planning treatment strategies. With the advent of third generation TKIs that potentially target T790M, improvement in clinical outcome is documented in patients with NSCLCs. Managing these outcomes with appropriate companion diagnostics using ctDNA in early detection of these genetic alterations will improve patient care. PMID- 28642173 TI - Protein functional effector sncRNAs (pfeRNAs) in lung cancer. AB - PIWI-interacting RNA Likes (piR-Ls) were recently reported to regulate functions of their target phospho-Proteins (p-Proteins) in somatic lung cells. However, the mechanism underlying this functionality remains unclear. piR-Ls interact with their targets through direct binding but do not follow base-pairing rules, known to have important roles at levels of transcription, RNA processing and translation for small non-coding RNA (sncRNA). These observations imply a fundamentally different type of sncRNA with behavior that causes a molecular response in their target p-Proteins. Furthermore, the interaction of piR-Ls with their targets regulates the functional efficacy of target p-Proteins. In addition, except for writers (kinase) and erasers (phosphatase), the functional efficacy of p-Proteins on their readers still remains unknown. It is reasonable to consider the existence of protein functional effector sncRNAs (pfeRNAs), which were identified by deep sequencing the immunoprecipitation products of antibodies targeting phosphorylated residues in proteins, as well as by functional analysis. pfeRNAs harbor unique features in size distribution, 3' terminal modification, shared core sequences, and functional manner, and could be new players in lung physiological and pathological conditions. PMID- 28642174 TI - Increased Levels of Soluble Cluster of Differentiation 40 Ligand, Matrix Metalloproteinase 9, and Matrix Metalloproteinase 2 Are Associated with Carotid Plaque Vulnerability in Patients with Ischemic Cerebrovascular Disease. AB - OBJECTIVES: The objectives of this study were to examine the correlation between the level of serum inflammatory markers and the stability of carotid plaques in patients with ischemic cerebrovascular disease and to assess the ability of each inflammatory marker to identify vulnerable carotid plaques. METHODS: For the early identification of vulnerable carotid plaques, 65 patients with carotid plaques were divided into a stable plaque group (n = 21) and an unstable plaque group (n = 44) according to magnetic resonance imaging characteristics. The unstable plaque group was divided into an unstable unruptured plaque group (n = 29) and an unstable ruptured plaque group (n = 15) according to whether the fibrous cap was ruptured. The levels of serum soluble cluster of differentiation 40 ligand (sCD40L), matrix metalloproteinase (MMP)-9, and MMP-2 were measured by enzyme-linked immunosorbent assay. RESULTS: The levels of serum sCD40L and MMP-9 in the unstable plaque group, the unstable unruptured plaque group and the ruptured plaque group were significantly higher than those in the stable plaque group (P < 0.05). There was no significant difference in the MMP-2 level between the stable plaque group and unstable plaque group (P = 0.056). The MMP-2 levels in the stable plaque group, unstable unruptured plaque group, and ruptured plaque group were not different (P = 0.095). The carotid plaques and the positive rate of MMP-9 of >=84.09 ng/mL were statistically significant, suggesting increased vulnerability. CONCLUSIONS: Serum levels of sCD40L and MMP-9 are associated with the stability of carotid plaques. Higher levels of serum sCD40L and MMP-9 may suggest that the plaques are vulnerable or have ruptured. PMID- 28642175 TI - Subventricular Zone Involvement Characterized by Diffusion Tensor Imaging in Glioblastoma. AB - BACKGROUND: Glioblastomas have a poor prognosis, possibly because of a subpopulation of therapy-resistant stem cells within the heterogeneous glioblastoma. Because the subventricular zone is the main source of neural stem cells, we aimed at characterizing the subventricular zone using diffusion tensor imaging (DTI) to show subventricular zone involvement in glioblastoma. METHODS: We prospectively included 93 patients with primary glioblastomas who underwent preoperative DTI. The nonenhancing high fluid-attenuated inversion recovery (FLAIR) signal was used to describe the infiltrative tumor margin. We used a 5-mm margin surrounding the lateral ventricles to define the subventricular zone. The subventricular zone with high FLAIR was compared with the subventricular zone without high FLAIR, control high FLAIR outside the subventricular zone and control contralateral normal-appearing white matter. Normalized DTI parameters were calculated and compared between the different regions. RESULTS: The subventricular zone with high FLAIR showed increased isotropic p values compared with the subventricular zone without high FLAIR (t126 = 3.9; P < 0.001) and control regions (t179 = 1.9; P = 0.046). Anisotropic q and fractional anisotropy values were lower in regions with high FLAIR compared with the subventricular zone without high FLAIR (t181 = 11.6, P < 0.001 and t184 =12.4, P < 0.001, respectively). CONCLUSION: DTI data showed that the subventricular zone is involved in glioblastoma with increased isotropic p values in the subventricular zone with high FLAIR, indicating tumor infiltration. PMID- 28642176 TI - Microsurgical Bypass Training Rat Model: Part 2-Anastomosis Configurations. AB - BACKGROUND: Mastery of microsurgical anastomosis is key to achieving good outcomes in cerebrovascular bypass procedures. Animal models (especially rodents) provide an optimal preclinical bypass training platform. However, the existing models for practicing different anastomosis configurations have several limitations. OBJECTIVE: We sought to optimize the use of the rat's abdominal aorta and common iliac arteries (CIA) for practicing the 3 main anastomosis configurations commonly used in cerebrovascular surgery. METHODS: Thirteen male Sprague-Dawley rats underwent inhalant anesthesia. The abdominal aorta and the CIAs were exposed. The distances between the major branches of the aorta were measured to find the optimal location for an end-to-end anastomosis. Also, the feasibility of performing side-to-side and end-to-side anastomoses between the CIAs was assessed. RESULTS: All bypass configurations could be performed between the left renal artery and the CIA bifurcation. The longest segments of the aorta without major branches were 1) between the left renal and left iliolumbar arteries (16.9 mm +/- 4.6), and 2) between the right iliolumbar artery and the aortic bifurcation (9.7 mm +/- 4.7). The CIAs could be juxtaposed for an average length of 7.6 mm +/- 1.3, for a side-to-side anastomosis. The left CIA could be successfully reimplanted on to the right CIA at an average distance of 9.1 mm +/- 1.6 from the aortic bifurcation. CONCLUSIONS: Our results show that rat's abdominal aorta and CIAs may be effectively used for all the anastomosis configurations used in cerebral revascularization procedures. We also provide technical nuances and anatomic descriptions to plan for practicing each bypass configuration. PMID- 28642177 TI - Protective Functions of PJ34, a Poly(ADP-ribose) Polymerase Inhibitor, Are Related to Down-Regulation of Calpain and Nuclear Factor-kappaB in a Mouse Model of Traumatic Brain Injury. AB - OBJECTIVES: Poly(ADP-ribose) polymerase (PARP), calpain, and nuclear factor kappaB (NF-kappaB) are reported to participate in inflammatory reactions in pathologic conditions and are involved in traumatic brain injury. The objective of this study was to investigate whether PARP participates in inflammation related to calpain and NF-kappaB in a mouse model of controlled cortical impact (CCI). METHODS: PJ34 (10 mg/kg), a selective PARP inhibitor, was administered intraperitoneally 5 minutes and 8 hours after experimental CCI. We then performed a histopathologic analysis, and we measured calpain activity and protein levels in all animals. The cytosolic, mitochondria, and nuclear fractions were prepared and used to determine the levels of PARP, calpastatin, NF-kappaB p65, inhibitory kappaB-alpha, tumor necrosis factor-alpha, interleukin-1beta, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2. We then measured blood-brain barrier disruption using electron microscopy at 6 and 24 hours after CCI. RESULTS: Treatment with PJ34 markedly reduced the extent of both cerebral contusion and edema, improved neurologic scores, and attenuated blood-brain barrier damage resulting from CCI. Our data showed that the cytosolic and nuclear fractions of calpain and NF-kappaB were up-regulated in the injured cortex and that these changes were reversed by PJ34. Moreover, PJ34 significantly enhanced the calpastatin and inhibitory-kappaB levels and decreased the levels of inflammatory mediators. CONCLUSIONS: PARP inhibition by PJ34 suppresses the overactivation of calpain and the production of inflammatory factors that are caused by NF-kappaB activation and attenuates neuronal cell death in a mouse model of CCI. PMID- 28642178 TI - Neurologic Outcome After Decompressive Craniectomy: Predictors of Outcome in Different Pathologic Conditions. AB - OBJECTIVE: Decompressive craniectomy (DC) has been proposed as a lifesaving treatment in patients with elevated intracranial pressure, but its effectiveness on reaching a favorable neurologic outcome remains unclear. We identified predictors of outcome in a large, single-center cohort of patients undergoing DC for different pathologic conditions. METHODS: This retrospective study included all patients undergoing DC from 2006 to 2014. The 1-year outcome, assessed using the Glasgow Outcome Scale (GOS), was dichotomized into favorable (GOS 4-5) and unfavorable (GOS 1-3) outcome. Predictors of outcome were identified by analyzing patient characteristics. RESULTS: DC was performed in 204 patients for ischemic stroke (n = 57), traumatic brain injury (n = 50), aneurysmal subarachnoid hemorrhage (aSAH) (n = 44), intracerebral hemorrhage (ICH) (n = 29), cerebral venous thrombosis (CVT) (n = 14), or other indications (n = 10). Overall, 69 (34%) patients survived favorably, 39 (19%) survived unfavorably, and 96 (47%) died. Higher age, poor Glasgow Coma Scale score, intubated status before DC, bilateral absence of pupillary light reflexes, DC for aSAH, and additional surgeries after DC (excluding cranioplasty) were significant predictors of unfavorable outcome. When patients were sorted for pathologic conditions and predictors of outcome, favorable outcome rates differed remarkably, ranging from 91% for CVT patients undergoing uncomplicated DC to 0% for aSAH patients undergoing DC for secondary infarction or ICH patients with unilateral or bilateral abnormal pupillary light reflexes upon admission. CONCLUSIONS: Long term neurologic outcome after DC differed remarkably among subpopulations of patients, with favorable outcome rates ranging from 0% to >90%. PMID- 28642179 TI - Analysis of Outcomes of Multidisciplinary Management of Gliosarcoma: A Single Center Study, 2000-2013. AB - BACKGROUND: Gliosarcoma is a rare tumor of the central nervous system with a reported incidence of ~2%-8% of all gliomas. We reviewed the outcomes of patients treated at our institution over a 14-year period from 2000 to 2013 to characterize overall survival (OS) and progression-free survival as well as to elucidate the additive effect of chemoradiotherapy. METHODS: From January 1, 2000 to December 31, 2013, we retrospectively reviewed the clinical notes of all patients treated at our institution with a histopathologic diagnosis of gliosarcoma. This review yielded 21 patients whose clinicoradiologic data were analyzed with respect to age, sex, ethnicity, preoperative/postoperative Glasgow Coma Scale and Karnofsky Performance Scale, location, extent of resection, methylguanine DNA methyl transferase methylation status, and administration of adjuvant therapy. RESULTS: The median age was 58 years (range, 40-80 years) with a male preponderance (1.6:1). Tumor location was mainly temporal (n = 6) but also parietal (n = 5), frontal (n = 4), multilobar (n = 4), and cerebellar (n = 1). Surgical resection was deemed to be total in 15 patients and subtotal in 6 patients. Methylguanine DNA methyl transferase methylation status was available for only 5 patients, with a methylation rate of 60% (3/5) and no impact on survival. Nine patients received both radiotherapy and chemotherapy (OS, 7.9 months), 7 received radiotherapy only (OS, 5.7 months), and 5 patients received no adjuvant therapy (OS, 1.4 months). The overall median survival was 5.7 months (range, 1-21.5 months) and median progression-free survival was 5 months (range, 1.4-12.4 months). CONCLUSIONS: Despite an overall poor prognosis, a multimodality approach aiming for complete resection followed by radiotherapy and chemotherapy appears to be associated with better outcomes. PMID- 28642180 TI - Obese (Body Mass Index >30) Patients Have Greater Functional Improvement and Reach Equivalent Outcomes at 12 Months Following Decompression Surgery for Symptomatic Lumbar Stenosis. AB - OBJECTIVE: To evaluate effect of obesity on 12-month functional outcomes after surgery for lumbar stenosis in adult patients. METHODS: Data were collected on patients treated with lumbar laminectomy for symptomatic lumbar spinal stenosis as part of an observational registry and analyzed using a retrospective cohort study design. Patients with body mass index (BMI) >30 were compared with patients with BMI <30 with respect to baseline, 3-month, and 12-month functional status, adjusted for potential confounders. RESULTS: There were 101 patients. At baseline, patients with BMI >30 had significantly more back pain (P < 0.001), more leg pain (P < 0.001), lower EuroQol 5 dimensions questionnaire (EQ-5D) scores (P < 0.001), and higher Oswestry Disability Index (ODI) scores (P < 0.001). Both low- and high-BMI groups had significant improvement in back pain, leg pain, EQ-5D scores, and ODI scores after decompression (all P < 0.001). At 3 months postoperatively, high-BMI patients continued to report greater leg pain (P = 0.063) and higher ODI score (P = 0.064) relative to low-BMI patients. By 12 months, there was no difference between low- and high-BMI patients in back pain (P = 0.929), leg pain (P = 0.638), EQ-5D score (P = 0.733), or ODI score (P = 0.214). CONCLUSIONS: The difference between low- and high-BMI patients trended toward significance for leg pain and ODI score at 3 months, but this difference disappeared by 12 months. This suggests that obese patients with symptomatic lumbar spinal stenosis may require longer to recover after decompression but can expect to reach equivalent outcomes of similarly treated patients with BMI <30. PMID- 28642182 TI - The Effect of Morbid Obesity on Subarachnoid Hemorrhage Prognosis in the United States. AB - OBJECTIVE: The association between obesity and nontraumatic subarachnoid hemorrhage (SAH) patient outcome is unclear. The aim of this study was to determine the impact of morbid obesity (body mass index >=40 kg/m2) on nontraumatic SAH outcomes. METHODS: Using the Nationwide Inpatient Sample, we identified hospitalized, nontraumatic SAH patients who received their diagnoses from 2008 to 2013 and tested the effect of obesity on their mortality and clinical outcomes. Odds ratios were estimated with a mixed effects linear logistic model with adjustment for hospital clustering. All statistical testing was 2-sided, with a significance level of 5%. RESULTS: Out of 224,561 discharged patients with a diagnosis of nontraumatic SAH, 4714 (2.10%) were defined as morbidly obese. Patients with morbid obesity were younger (54.3 +/- 0.44 vs. 59.5 +/- 0.08 years; P < 0.001) and had longer length of stay (LOS) (13 +/- 0.46 vs. 11.5 +/- 0.06 days; P = 0.002). Morbid obesity was associated with significantly higher hospital costs (P < 0.001) and charges (P < 0.001). The risk of acute respiratory failure was higher in morbidly obese patients (odds ratio [OR] 1.49, 95% confidence interval [CI]: 1.3-1.71, P < 0.001). In a multivariate analysis of hospital mortality, obesity had a negative impact on mortality (OR 0.83, 95% CI: 0.74-0.92, P < 0.001). Overall, in-hospital mortality was associated with age, morbid obesity, LOS, clipping and coiling, and acute respiratory failure but not the symptomatic vasospasm. CONCLUSIONS: Morbid obesity is associated with increased LOS, hospital costs and charges and with acute respiratory failure. However, it is also associated with a decrease in hospital mortality. PMID- 28642181 TI - Surgical Outcome of Growth Hormone-Secreting Pituitary Adenoma with Empty Sella Using a New Classification. AB - OBJECTIVE: To investigate outcomes and identified risk factors affecting cure and intraoperative cerebrospinal fluid leak after transsphenoidal surgery using a new classification for growth hormone-secreting pituitary adenoma associated with empty sella. METHODS: In this retrospective cohort study, 51 patients enrolled from January 2010 to June 2016 were categorized into 3 groups using a new classification scheme: grade A, whole tumor occupation area beneath a horizontal line drawn along the lowest level of empty sella; grade B, tumor occupation area that crossed the horizontal line on 1 side; and grade C, tumor occupation area that crossed the horizontal line on 2 sides. Clinical data were collected and analyzed. RESULTS: Cure rate for grade A patients (88.24%; 15/17) was significantly higher than cure rate for grade B (55.00%; 11/20) and grade C (50.00%; 7/14) patients. Occurrence of cerebrospinal fluid leaks in grade C patients (35.71%; 5/14) was higher than in grade A patients (5.88%; 1/17). Logistic regression analysis indicated that risk factors affecting cure included large maximum tumor diameter (P = 0.009, odds ratio [OR] = 1.222), high preoperative fasting growth hormone level (P = 0.031, OR = 1.088), and high classification (P = 0.017, OR = 4.485). Risk factor affecting intraoperative cerebrospinal fluid leak was high classification (P = 0.039, OR = 3.580). CONCLUSIONS: Transsphenoidal surgery is the current optimal treatment strategy. Empty sella increases the difficulty of surgery with a higher incidence of complications. The new classification scheme was better for predicting the surgical outcome for this disease. PMID- 28642183 TI - Giant Bicompartmental Cystic Tentorial Schwannoma Mimicking a Meningioma. AB - BACKGROUND: Intracranial schwannomas most commonly arise from the vestibulocochlear nerve and less frequently from trigeminal, facial, and hypoglossal nerves. Intracranial schwannomas unrelated to cranial nerves are very rare; only approximately 50 cases have been reported in the literature. Tentorial schwannoma (TS) is even rarer, with only 13 cases reported to date. We present a rare case of giant TS. CASE DESCRIPTION: A 21-year-old man presented with generalized headache and dizziness for the past 6 months and worsening of symptoms for the past 2 months. On evaluation, he was found to have a cystic lesion arising from the right tentorium with multiple internal septa and fluid levels, with both supratentorial and infratentorial extension. The presence of a dural tail sign and tentorial origin led us to make a preoperative diagnosis of tentorial meningioma. The patient underwent complete excision, and a diagnosis of TS was made based on histopathologic analysis. CONCLUSIONS: TSs are extremely rare. Knowledge of radiologic and morphologic features can be helpful in making a preoperative diagnosis. The dural tail sign, which is considered a characteristic feature of meningioma, is commonly seen in TS as well, and thus TS should always be considered in the differential diagnosis of lesions arising from the tentorium. PMID- 28642184 TI - Use of platelet-rich plasma (PRP) in microsurgery. AB - Platelet-rich plasma (PRP) is currently used for its property to improve tissue regeneration and wound healing. Platelet derived growth factors are involved in tissue regeneration and new vessels formation that could improve a free flap survival. Nevertheless to validate the use of regenerative medicine in microsurgery further large and robust human clinical trials are needed. PMID- 28642185 TI - Place of 3D printing in facial epithesis. AB - Facial rehabilitation from facial epithets is part of the facial surgeon's therapeutic arsenal. The primary technique requires taking imprints on the patient, which has major drawbacks such as discomfort and difficulties for precisely recording anatomical surfaces. In this paper, we present a technical improvement in the design of facial epithesis, introducing application of a 3D printing technology. By exploiting digital data in DICOM format, it is possible to produce a digital copy of an epithesis. Based on this copy a model can be printed and then used to support the final prosthesis. PMID- 28642186 TI - Mandibular anterior segmental subapical osteotomy for incisor axis correction. AB - INTRODUCTION: Mandibular incisor axis correction can be challenging in non extraction orthodontic treatment planning. Mandibular anterior segmental subapical osteotomy (MASSO) is a surgical approach, which can be used to reposition incisor axis, improve occlusal function and enhance the soft tissue profile. METHODS: Twenty-eight patients, mean age 22.6 years (16-39, SD=6.69), were treated for MASSO for correction of Class II dentoskeletal deformity, in addition to other orthognathic procedures. Retrospective analysis was performed on lateral cephalogram measurements, at the end of presurgical orthodontics and 6 months after completion of post-surgical orthodontics. RESULTS: Mandibular incisor axis was corrected from a presurgical incisor to mandibular plane angle group mean of 109 degrees (94-122, SD=7.97) to 95 degrees (88-105, SD=3.79). Patients were followed for an average of 31 months after treatment completion, with no detected dentoskeletal complication or relapse. CONCLUSION: MASSO is an efficient and safe surgical procedure for incisor axis correction. PMID- 28642187 TI - Cheiloplasty associated to a palatal obturator in a preterm infant with a cleft lip and palate. AB - INTRODUCTION: Preterm infants are commonly treated by non-invasive ventilation (NIV) and nasal continuous positive airway pressure (CPAP), which are associated with fewer complications than nasotracheal intubation. In preterm infants with a cleft lip and palate, this method of respiratory management is difficult or impossible to perform because of air leakage through the cleft defect. CASE: We report a male infant who was born at 29 weeks of gestation with a left complete unilateral cleft lip and palate. Birth weight was 900 grammes. Because of the cleft, we have any problems to ventile this infant. We decide to close the cleft prematurely on day 17 after multidisciplinary discussion. DISCUSSION: NIV cannot be performed with the usual equipment in very premature infants with a cleft lip and palate because of air leakage through the cleft defect. Very few studies report pre term infant with cleft lip and palate and his difficulties of ventilation. This is the first case reported to perform cheiloplasty on a 900g preterm infant. PMID- 28642188 TI - Costal graft as a support for bone regeneration after mandibular juvenile ossifying fibroma resection: An unusual case report. AB - Spontaneous regeneration of bone tissue after mandibular resection is rare in adults, although it does often take place in children. Periosteum conservation appears to play a major role in this healing process. We here report regarding a 5-year-old boy who exhibited a large mandibular trabecular juvenile ossifying fibroma. The lesion was treated by mandibulectomy, with careful preservation of the periosteal layer and immediate reconstruction with a costal graft by an intraoral approach. Monitoring over the course of a year revealed spontaneous mandibular regeneration, and it allowed for a series of measurements of the graft to be made. During this follow-up period, the mandibular height increased from 41.5% to 75.2% (P=0.0008) of the height of the unaffected mandibular height, while the width grew from 34.4% to 82.8% (P=0.0078) of the width of the healthy side, thus demonstrating the importance of a conservative approach regarding the periosteum in such situations. The costal graft acted as a support for bone regeneration by immobilizing the remaining bone fragments and by preventing soft tissue prolapse. PMID- 28642189 TI - How to produce pre-shaped rigid arch bars using low-cost 3D printing technology - A technical note. AB - Numerous oral and maxillofacial procedures in dentate patients begin with the fixation of occlusions. While several techniques exist to perform mandibulo maxillary fixation, many surgeons use arch bars in common practice. In cases of severe craniofacial traumas or jaw malformations, such as temporomandibular joint ankylosis, it may be impossible to use rigid arch bars. This technical note reports on the development of a technique to produce pre-shaped rigid arch bars using 3D printing technology. We take the case of a patient who presents Le Fort 1, Le Fort 2 and Le Fort 3 fractures as well as a central palatine disjunction, an angular mandibular fracture and bilateral zygomatic fractures. We specify the indications and limitations of this technique. PMID- 28642190 TI - Complications associated with surgically assisted rapid palatal expansion without pterygomaxillary separation. AB - INTRODUCTION: The purpose of this retrospective clinical study was to evaluate the surgical complications associated with the surgically assisted rapid palatal expansion (SARPE) which does not involve pterygomaxillary separation (PMS). PATIENTS AND METHODS: A total of 40 (25 females, 15 males) skeletally mature patients, who had the diagnosis of maxillary transverse maxillary deficiency (TMD), were treated surgically under local or general anesthesia. The mean follow up time was 6 months. RESULTS: Recorded perioperative and postoperative complications were discussed within the current literature. No serious complications were observed intraoperatively. Eight patients (20%) showed postoperative complications including neurosensory deficits, maxillary sinus infection, epistaxis, fistula formation and incisional dehiscence. DISCUSSION: Neurosensory deficits were the most common findings. The present findings suggest that minor complications were observed associated with SARPE without PMS. The technique may be performed safely also under local anesthesia. PMID- 28642191 TI - New aspects in free flap surgery: Mini-perforator flaps and extracorporeal flap perfusion. AB - BACKGROUND: The scope of microvascular tissue transfer in the Head and Neck reaches from coverage of simple soft tissue defects to complex 3-D reconstructions using multiple or chimeric flaps. This paper summarises the presentation given at the Congress of the French Society of Oral and Maxillofacial Surgery in Marseille 2017. It was the aim of our work to add further elements to this wide spectrum of reconstructive possibilities. METHODS: For patients with small intraoral soft tissue defects in whom the use of a radial forearm flap would not be justified because of its donor site morbidity, but who nevertheless would take a benefit from a small free flap, we used mini-perforator flaps from the lower leg. These flaps were raised with negligible morbidity. Moreover, for patients necessarily needing a free flap, but having vessel depleted, irradiated necks, we have developed a first idea of extracorporeal flap perfusion to make microvascular anastomoses unnecessary. RESULTS: Using donor sites from the lower leg, mini-soleus and medial sural perforator flaps were raised to cover defects of 2*3 to 2*4cm at the anterior floor of the mouth or lateral tongue. The success rate was 91%, and despite their small size, the flaps helped to maintain the mobility of the tongue. The donor site morbidity was minimal. After extensive experimental work on small animals and human tissue, four flaps could successfully be transferred so far by means of extracorporeal perfusion. In these patients, autonomisation took place between 5 and 12 days. CONCLUSIONS: Although microvascular tissue transfer already allows for reconstruction in almost any possible defect constellation, mini-perforator flaps and machine-perfused transplants seem to represent new aspects of free flap surgery, being useful extensions of the reconstructive surgeon's armament. PMID- 28642192 TI - Applications of 3D orbital computer-assisted surgery (CAS). AB - INTRODUCTION: The purpose of the present report is to describe the indications for use of 3D orbital computer-assisted surgery (CAS). PATIENTS AND METHODS: We analyzed the clinical and radiological data of all patients with orbital deformities treated using intra-operative navigation and CAD/CAM techniques at the Hopitaux Universitaires de Geneve, Switzerland, between 2009 and 2016. We recorded age and gender, orbital deformity, technical and surgical procedure and postoperative complications. RESULTS: One hundred and three patients were included. Mean age was 39.5years (range, 5 to 84years) and 85 (87.5%) were men. Of the 103 patients, 96 had intra-operative navigation (34 for primary and 3 for secondary orbito-zygomatic fractures, 15 for Le Fort fractures, 16 for orbital floor fractures, 10 for combined orbital floor and medial wall fractures, 7 for orbital medial wall fractures, 3 for NOE (naso-orbito-ethmoidal) fractures, 2 for isolated comminuted zygomatic arch fractures, 1 for enophthalmos, 3 for TMJ ankylosis and 2 for fibrous dysplasia bone recontouring), 8 patients had CAD/CAM PEEK-PSI for correction of residual orbital bone contour following craniomaxillofacial trauma, and 1 patient had CAD/CAM surgical splints and cutting guides for correction of orbital hypertelorism. Two patient (1.9%) required revision surgery for readjustment of an orbital mesh. The 1-year follow up examination showed stable cosmetic and dimensional results in all patients. CONCLUSION: This study demonstrated that the application of 3D orbital CAS with regards to intra-operative navigation and CAD/CAM techniques allowed for a successful outcome in the patients presented in this series. PMID- 28642193 TI - Unusual X-RAY finding after mandibular reconstruction. PMID- 28642196 TI - GDF5 significantly augments the bone formation induced by an injectable, PLGA fiber-reinforced, brushite-forming cement in a sheep defect model of lumbar osteopenia. AB - BACKGROUND CONTEXT: Biodegradable calcium phosphate cement (CPC) represents a promising option for the surgical treatment of osteoporotic vertebral fractures. Because of augmented local bone catabolism, however, additional targeted delivery of bone morphogenetic proteins with the CPC may be needed to promote rapid and complete bone regeneration. PURPOSE: In the present study, an injectable, poly(l lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming cement (CPC) containing the bone morphogenetic protein GDF5 was tested in a sheep lumbar osteopenia model. STUDY DESIGN/SETTING: This is a prospective experimental animal study. METHODS: Defined bone defects (diameter 5 mm) were placed in aged, osteopenic female sheep. Defects were treated with fiber-reinforced CPC alone (L4; CPC+fibers) or with CPC containing different dosages of GDF5 (L5; CPC+fibers+GDF5; 1, 5, 100, and 500 ug GDF5; n=5 or 6 each). The results were compared with those of untouched controls (L1). Three and 9 months postoperation, structural and functional effects of the CPC (+/-GDF5) were assessed ex vivo by measuring (1) bone mineral density (BMD); (2) bone structure, that is, bone volume/total volume (assessed by micro-computed tomography and histomorphometry), trabecular thickness, and trabecular number; (3) bone formation, that is, osteoid volume/bone volume, osteoid surface/bone surface, osteoid thickness, mineralized surface/bone surface, mineral apposition rate, and bone formation rate/bone surface; (4) bone resorption, that is, eroded surface/bone surface; and (5) compressive strength. RESULTS: Compared with untouched controls (L1), both CPC+fibers (L4) and CPC+fibers+GDF5 (L5) numerically or significantly improved all parameters of bone formation, bone resorption, and bone structure. These significant effects were observed both at 3 and 9 months, but for some parameters they were less pronounced at 9 months. Compared with CPC without GDF5, additional significant effects of CPC with GDF5 were demonstrated for BMD and parameters of bone formation and structure (bone volume/total volume, trabecular thickness, and trabecular number, as well as mineralized surface/bone surface). The GDF5 effects were dose-dependent (predominantly in the 5-100 ug range) at 3 and 9 months. CONCLUSIONS: GDF5 significantly enhanced the bone formation induced by a PLGA fiber-reinforced CPC in sheep lumbar osteopenia. The results indicated that a local dose as low as <=100 ug GDF5 may be sufficient to augment middle to long term bone formation. The novel CPC+GDF5 combination may thus qualify as an alternative to the bioinert, supraphysiologically stiff poly(methyl methacrylate) cement currently applied for vertebroplasty/kyphoplasty of osteoporotic vertebral fractures. PMID- 28642197 TI - Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. AB - BACKGROUND AND AIMS: The risk of hepatocellular cancer (HCC) after sustained virological response (SVR) with direct-acting antivirals (DAA) is unclear. Our aim was to examine the risk and determinants of HCC in patients cured with DAA. METHODS: We conducted a retrospective cohort study of hepatitis C virus patients who were treated with DAA in any of the 129 Veterans Health Administration hospitals between January 1, 2015 and December 31, 2015. We calculated the annual incidence rates of HCC by SVR. We used Cox regression models to compare the risk of HCC in patients with vs those without SVR and to identify factors associated with incident HCC among patients with SVR. We reviewed a sample of HCC patients for tumor size and stage at diagnosis. RESULTS: Among 22,500 patients treated with DAA (19,518 with SVR; 2982 without SVR), the mean (standard deviation) age was 61.6 (6.1) years, and 39.0% had cirrhosis. There were 271 new cases of HCC, including 183 in patients with SVR. Compared with patients without SVR, those with SVR had a significantly reduced risk of HCC (0.90 vs 3.45 HCC/100 person years; adjusted hazard ratio, 0.28, 95% CI=0.22-0.36). Patients with cirrhosis had the highest annual incidence of HCC after SVR (1.82 vs 0.34/100 person-years in patients without cirrhosis; adjusted hazard ratio, 4.73. 95% CI, 3.34-6.68). Most (>44.8%) HCC were classified as stage I. Maximum size of the largest lesion was <=5 cm in over 75% of cases. CONCLUSIONS: Among patients treated with DAA, SVR was associated with a considerable reduction in the risk of HCC. We did not find any evidence to suggest that DAAs promote HCC. However, in patients with SVR, the absolute risk of HCC remained high in patients with established cirrhosis. These patients should be considered for ongoing HCC surveillance. PMID- 28642194 TI - Breaking fat: The regulation and mechanisms of lipophagy. AB - Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). While the field of lipophagy research is relatively young, an expansion of research in this area over the past several years has greatly advanced our understanding of lipophagy. Since its original characterization in fasted liver, the contribution of lipophagy is now recognized in various organisms, cell types, metabolic states and disease models. Moreover, recent studies provide exciting new insights into the underlying mechanisms of lipophagy induction as well as the consequences of lipophagy on cell metabolism and signaling. This review summarizes recent work focusing on LDs and lipophagy as well as highlighting challenges and future directions of research as our understanding of lipophagy continues to grow and evolve. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28642199 TI - Chemical profile and anti-leishmanial activity of three Ecuadorian propolis samples from Quito, Guayaquil and Cotacachi regions. AB - Three propolis samples were collected from different regions of Ecuador (Quito, Guayaquil and Cotacachi) and their methanolic extracts were prepared. Preliminary information supplied by TLC and NMR data, allowed us to define two main types of propolis: Cotacachi propoli sample (CPS), rich in flavonoids and Quito and Guayaquil samples (QPS and GPS) containing triterpenic alcohols and acetyl triterpenes as the main constituents. Two different approaches based on RP-HPLC preparative procedure and NMR structural determination (CPS) and GC-MS analysis (QPS and GPS) were successfully used for the chemical characterization of their major compounds. All three propolis extracts were able to inhibit Leishmania amazonensis growth but propolis sample rich in flavonoids was the most active (IC50=17.1+/-1.7MUg/mL). In the literature this is the first study on propolis from Ecuador. PMID- 28642198 TI - Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor. AB - BACKGROUND: Intestinal fibrosis resulting in (sub)obstruction is a common complication of Crohn's disease (CD). Rho kinases (ROCKs) play multiple roles in TGFbeta-induced myofibroblast activation that could be therapeutic targets. Because systemic ROCK inhibition causes cardiovascular side effects, we evaluated the effects of a locally acting ROCK inhibitor (AMA0825) on intestinal fibrosis. METHODS: Fibrosis was assessed in mouse models using dextran sulfate sodium (DSS) and adoptive T-cell transfer. The in vitro and ex vivo effects of AMA0825 were studied in different cell types and in CD biopsy cultures. RESULTS: ROCK is expressed in fibroblastic, epithelial, endothelial, and muscle cells of the human intestinal tract and is activated in inflamed and fibrotic tissue. Prophylactic treatment with AMA0825 inhibited myofibroblast accumulation, expression of pro fibrotic factors, and accumulation of fibrotic tissue without affecting clinical disease activity and histologic inflammation in 2 models of fibrosis. ROCK inhibition reversed established fibrosis in a chronic DSS model and impeded ex vivo pro-fibrotic protein secretion from stenotic CD biopsies. AMA0825 reduced TGFbeta1-induced activation of myocardin-related transcription factor (MRTF) and p38 mitogen-activated protein kinase (MAPK), down-regulating matrix metalloproteinases, collagen, and IL6 secretion from fibroblasts. In these cells, ROCK inhibition potentiated autophagy, which was required for the observed reduction in collagen and IL6 production. AMA0825 did not affect pro-inflammatory cytokine secretion from other ROCK-positive cell types, corroborating the selective in vivo effect on fibrosis. CONCLUSIONS: Local ROCK inhibition prevents and reverses intestinal fibrosis by diminishing MRTF and p38 MAPK activation and increasing autophagy in fibroblasts. Overall, our results show that local ROCK inhibition is promising for counteracting fibrosis as an add-on therapy for CD. PMID- 28642200 TI - Enhancement of solubility and dissolution rate of baicalein, wogonin and oroxylin A extracted from Radix scutellariae. AB - Baicalein, wogonin, and oroxylin A are three major hydrophobic components in the extract of Radix scutellariae with wide spectrum of pharmacological applications. The purpose of this study was to enhance the solubility, dissolution rate and stability of baicalein, wogonin and oroxylin A by solid dispersion (SD) technique. SD of the extract with various polymers was prepared to select the best carrier. Solubility study, chemical stability study and dissolution study were performed to characterize the SD. The solubility of all three components, after forming solid dispersion with povidone K-30 (PVP K-30) was significantly increased in pH 6.8 medium at room temperature. Stability study conducted for 80days elucidated that the SD in powder state was fairly stable without the aid of Vitamin C (VC). VC was required as antioxidant to impart stability to baicalein in aqueous medium. The dissolution test of the SD of three components, admixed with VC at the weight ratio of 1:6 (Radix scutellariae extract: VC, w/w) exhibited faster dissolution rate with 100% release of all components. Pharmacokinetic study of baicalein solid dispersion revealed that AUC and Cmax significantly increased by solid dispersion preparation. Thus, the current developed method, being simple, economical and effective, can be useful for the production of soluble dosage forms of the extract of Radix scutellariae in commercial scale. PMID- 28642201 TI - Combination of coenzyme Q10-loaded liposomes with ultrasound targeted microbubbles destruction (UTMD) for early theranostics of diabetic nephropathy. AB - Diabetic nephropathy (DN) is one of the most common and lethal microvascular complications of diabetes. This study aimed to explore whether coenzymeQ10 (CoQ10) as an antioxidant combined with ultrasound-targeted microbubble destruction (UTMD) could reverse the progress of early diabetic nephropathy (DN). CoQ10 has great potential to treat early DN. However, the clinical application of CoQ10 has been limited because of its low aqueous solubility and non-specific distribution. Therefore, CoQ10-loaded liposomes (CoQ10-lip) were prepared and combined with ultrasound microbubbles for the early theranostics of DN. CoQ10-lip exhibited a good round morphology with a diameter of 183+/-1.7nm and a negative zeta potential of -25.3mV, which was capable of prolonging the release of the encapsulated CoQ10. The early DN rat models were induced by streptozotocin (STZ) and confirmed by contrast-enhanced ultrasound (CEUS) and 24-h urinary albumin. After the administration of CoQ10-lip combined with the UTMD technique to rats with early DN, the morphology and function of the kidney were evaluated by ultrasonography, histological and molecular analyses. The renal hemodynamics were significantly improved, moreover, 24-h urinary protein, and oxidative stress indexes were modulated after treatment with CoQ10-lip+UTMD indicating recovery of renal function. An elevated level of Nphs2 protein and reduced caspase 3 level indicated the preservation of podocytes and inhibition of cell apoptosis after CoQ10-lip+UTMD treatment. The molecular mechanism was associated with the upregulation of Bcl-2 and the downregulation of Bax. Moreover, the combination of CoQ10-lip and ultrasound microbubbles demonstrated a better protective effect on the damaged kidney than the other groups (free CoQ10 or CoQ10-lip+/- UTMD). Conclusively, CoQ10-lip in combination with ultrasound microbubbles might be a potential strategy to reverse the progress of early DN. PMID- 28642195 TI - How lipid droplets "TAG" along: Glycerolipid synthetic enzymes and lipid storage. AB - Triacylglycerols (TAG) serve as the predominant form of energy storage in mammalian cells, and TAG synthesis influences conditions such as obesity, fatty liver, and insulin resistance. In most tissues, the glycerol 3-phosphate pathway enzymes are responsible for TAG synthesis, and the regulation and function of these enzymes is therefore important for metabolic homeostasis. Here we review the sites and regulation of glycerol-3-phosphate acyltransferase (GPAT), acylglycerol-3-phosphate acyltransferase (AGPAT), lipin phosphatidic acid phosphatase (PAP), and diacylglycerol acyltransferase (DGAT) enzyme action. We highlight the critical roles that these enzymes play in human health by reviewing Mendelian disorders that result from mutation in the corresponding genes. We also summarize the valuable insights that genetically engineered mouse models have provided into the cellular and physiological roles of GPATs, AGPATs, lipins and DGATs. Finally, we comment on the status and feasibility of therapeutic approaches to metabolic disease that target enzymes of the glycerol 3-phosphate pathway. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. PMID- 28642202 TI - Engineering of multifunctional temperature-sensitive liposomes for synergistic photothermal, photodynamic, and chemotherapeutic effects. AB - Heterogeneity of cancer cells and drug resistance require multiple therapeutic approaches for comprehensive treatment. In this study, temperature-sensitive liposomes containing anti-cancer agent tanespimycin (17-AAG) and photosensitizer IR 820 were developed for combination of phototherapy and chemotherapy. The temperature-sensitive liposomes composed of DPPC, cholesterol, DSPE-PEG, 17-AAG, and IR 820 (LP-AI) at weight ratio of 35/15/3/2/2 were formulated as a thin film using extrusion and evaluated for particle size, morphology and drug release profile. Furthermore, the anticancer effect of combined therapy was examined in vitro and in vivo in SCC-7 and MCF-7 cell lines. As a result, LP-AI was prepared at particle size of 166.7+/-1.3nm, PDI of 0.153+/-0.012, and zeta-potential of 32.6+/-0.8mV. After NIR irradiation (660 and 808nm laser), LP-AI could generate heat and ROS and enhance drug release from nanoparticles which were useful to kill the cancer cells. These were confirmed by in vitro cytotoxicity as well as in vivo effective ablation of tumors. In conclusion, fast drug release and enhanced treatment efficacy of LP-AI indicate the potential of integrating photo- and chemotherapy for synergistic anti-cancer effects. PMID- 28642203 TI - Developments of Polysorbate (Tween) based microemulsions: Preclinical drug delivery, toxicity and antimicrobial applications. AB - The present review deals with the progress of Polysorbates (Tween) based microemulsions in drug delivery. PEGylated Sorbitan Fatty Acid Esters (Tweens/Polysorbates) are one of the most used non-ionic surfactants. Particularly, Polysorbates based microemulsion has been widely used for enhancing solubilization of poorly soluble drugs. This article deals with underlying the preclinical factors which affect the solubilization efficacy of Tween formulations, implication of pharmaceutically accepted vectors in terms of absorption, bioavailability, biological fate and potential toxicity. Antimicrobial activity of Tween microemulsion formulations has also been addressed emphasising the role of Tween. The review contains comprehensive knowledge/literature related to physicochemical parameters and biological fate of different Polysorbates and takes into account all the parameters and observations that make Tween a very convenient and safe choice for the use as pharmaceutical excipient for microemulsion formulations. PMID- 28642204 TI - Co-delivery of paclitaxel and anti-survivin siRNA via redox-sensitive oligopeptide liposomes for the synergistic treatment of breast cancer and metastasis. AB - The overexpression of survivin in breast cancer cells is an important factor of paclitaxel (PTX) resistance in breast cancer. To overcome PTX resistance and improve the antitumor effect of PTX, we developed a novel liposome-based nanosystem (PTX/siRNA/SS-L), composed of a redox-sensitive cationic oligopeptide lipid (LHSSG2C14) with a proton sponge effect, natural soybean phosphatidylcholine (SPC), and cholesterol for co-delivery of PTX and anti survivin siRNA, which could specifically downregulate survivin overexpression. PTX/siRNA/SS-L exhibited high encapsulation efficiency and rapid redox-responsive release of both PTX and siRNA. Moreover, in vitro studies on the 4T1 breast cancer cells revealed that PTX/siRNA/SS-L offered significant advantages over other experimental groups, such as higher cellular uptake, successful endolysosomal escape, reduced survivin expression, the lowest cell viability and wound healing rate, as well as the highest apoptosis rate. In particular, in vivo evaluation of 4T1 tumor-bearing mice showed that PTX/siRNA/SS-L had lower toxicity and induced a synergistic inhibitory effect on tumor growth and pulmonary metastasis. Collectively, the collaboration of anti-survivin siRNA and PTX via redox-sensitive oligopeptide liposomes provides a promising strategy for the treatment of breast cancer and metastasis. PMID- 28642205 TI - Radial Endoscopic Ultrasound for the Diagnosis of Chronic Schistosomiasis in the Colorectum. PMID- 28642206 TI - Obesity and Risk of Nonalcoholic Fatty Liver Disease: A Comparison of Bioelectrical Impedance Analysis and Conventionally-Derived Anthropometric Measures. PMID- 28642207 TI - Arabidopsis thaliana sucrose phosphate synthase (sps) genes are expressed differentially in organs and tissues, and their transcription is regulated by osmotic stress. AB - Sucrose is synthesized from UDP-Glc and Fru-6-phosphate via the activity of sucrose-phosphate synthase (SPS) enzymes, which produce Suc-6-phosphate. Suc-6 phosphate is rapidly dephosphorylated by phosphatases to produce Suc and inorganic phosphate. Arabidopsis has four sps genes encoding SPS enzymes. Of these enzymes, AtSPS1F and AtSPS2F have been grouped with other dicotyledonous SPS enzymes, while AtSPS3F and AtSPS4F are included in groups with both dicotyledonous and monocotyledonous SPS enzymes. In this work, we generated Arabidopsis thaliana transformants containing the promoter region of each sps gene fused to gfp::uidA reporter genes. A detailed characterization of expression conferred by the sps promoters in organs and tissues was performed. We observed expression of AtSPS1F, AtSPS2F and AtSPS3F in the columella roots of the plants that support sucrose synthesis. Hence, these findings support the idea that sucrose synthesis occurs in the columella cells, and suggests that sucrose has a role in this tissue. In addition, the expression of AtSPS4F was identified in embryos and suggests its participation in this developmental stage. Quantitative transcriptional analysis of A. thaliana plants grown in media with different osmotic potential showed that AtSPS2F and AtSPS4F respond to osmotic stress. PMID- 28642208 TI - Assessing the efficacy of imagery-enhanced cognitive behavioral group therapy for social anxiety disorder: Study protocol for a randomized controlled trial. AB - Cognitive behavior group therapy (CBGT) is effective for social anxiety disorder (SAD), but a substantial proportion of patients do not typically achieve normative functioning. Cognitive behavioral models of SAD emphasize negative self imagery as an important maintaining factor, and evidence suggests that imagery is a powerful cognitive mode for facilitating affective change. This study will compare two group CBGT interventions, one that predominantly uses verbally-based strategies (VB-CBGT) and another that predominantly uses imagery-enhanced strategies (IE-CBGT), in terms of (a) efficacy, (b) mechanisms of change, and (c) cost-effectiveness. This study is a parallel groups (two-arm) single-blind randomized controlled trial. A minimum of 96 patients with SAD will be recruited within a public outpatient community mental health clinic in Perth, Australia. The primary outcomes will be self-reported symptom severity, caseness (SAD present: yes/no) based on a structured diagnostic interview, and clinician-rated severity and life impact. Secondary outcomes and mechanism measures include blind observer-rated use of safety behaviors, physiological activity (heart rate variability and skin conductance level) during a standardized speech task, negative self-beliefs, imagery suppression, fear of negative and positive evaluation, repetitive negative thinking, anxiety, depression, self consciousness, use of safety behaviors, and the EQ-5D-5L and TiC-P for the health economic analysis. Homework completion, group cohesion, and working alliance will also be monitored. The outcomes of this trial will inform clinicians as to whether integrating imagery-based strategies in cognitive behavior therapy for SAD is likely to improve outcomes. Common and distinct mechanisms of change might be identified, along with relative cost-effectiveness of each intervention. PMID- 28642209 TI - Acceptability and feasibility of a randomized clinical trial of oral naltrexone vs. placebo for women living with HIV infection: Study design challenges and pilot study results. AB - BACKGROUND: Women living with HIV/AIDS who drink alcohol are at increased risk for adverse health outcomes, but there is little evidence on best methods for reducing alcohol consumption in this population. We conducted a pilot study to determine the acceptability and feasibility of conducting a larger randomized clinical trial of naltrexone vs. placebo to reduce alcohol consumption in women living with HIV/AIDS. METHODS: We designed the trial with input from community and scientific review. Women with HIV who reported current hazardous drinking (>7 drinks/week or >=4 drinks per occasion) were randomly assigned to daily oral naltrexone (50mg) or placebo for 4months. We evaluated willingness to enroll, adherence to study medication, treatment side effects, and drinking and HIV related outcomes. RESULTS: From 2010 to 2012, 17 women enrolled (mean age 49years, 94% African American). Study participation was higher among women recruited from an existing HIV cohort study compared to women recruited from an outpatient HIV clinic. Participants took 73% of their study medication; 82% completed the final assessment (7-months). Among all participants, mean alcohol consumption declined substantially from baseline to month 4 (39.2 vs. 12.8 drinks/week, p<0.01) with continued reduction maintained at 7-months. Drinking reductions were similar in both naltrexone and placebo groups. CONCLUSIONS: A pharmacologic alcohol intervention was acceptable and feasible in women with HIV, with reduced alcohol consumption noted in women assigned to both treatment and placebo groups. However, several recruitment challenges were identified that should be addressed to enhance recruitment in future alcohol treatment trials. PMID- 28642210 TI - Rationale and Design for a Randomized Comparison of Efficacy and Safety between Aspirin and Clopidogrel in Atrial Fibrillation Patients with Low Stroke Risk: CESAC-AF trial. AB - BACKGROUND: Atrial fibrillation (AF) increases the risk of thromboembolic stroke. An oral anticoagulant should be administrated to prevent stroke in patients with moderate stroke risk (ie, CHA2DS2-VASc score>2). If the stroke risk is low (i.e. the score=1), however, antiplatelet agent such as aspirin is widely used. Aspirin can cause peptic ulcer disease (PUD) while its alternative, clopidogrel, theoretically does not. OBJECTIVE: To elucidate the efficacy and safety between aspirin and clopidogrel, a multicenter randomized controlled trial was designed in AF patients with low stroke risk. METHODS: According to sample size estimation based on previous literature, a total of 1560 AF patients with low stroke risk will be randomly assigned into 4 different groups dependent upon initial esophagogastroduodenoscopy (EGD) results: two mono-antiplatelet treatment groups with either aspirin 100mg or clopidogrel 75mg for 1year; two antiplatelet agent and proton pump inhibitor (PPI) combination groups. Follow-up EGD will be performed at 1year. RESULTS: The clinical follow-up will be performed for 1year after enrollment. The primary efficacy endpoint is to compare the annual stroke rate between aspirin and clopidogrel treatment groups. The primary safety endpoint is to compare the prevalence of drug-induced gastrointestinal (GI) and intracranial hemorrhage and upper-GI response including PUD based on EGD after 1year. CONCLUSIONS: This trial will determine whether clopidogrel is noninferior in stroke prevention and superior in reduction of GI events including PUD to aspirin in AF patients with low stroke risk. (ClinicalTrials.gov: NCT02960126). PMID- 28642212 TI - Filtering Entities to Optimize Identification of Adverse Drug Reaction From Social Media: How Can the Number of Words Between Entities in the Messages Help? AB - BACKGROUND: With the increasing popularity of Web 2.0 applications, social media has made it possible for individuals to post messages on adverse drug reactions. In such online conversations, patients discuss their symptoms, medical history, and diseases. These disorders may correspond to adverse drug reactions (ADRs) or any other medical condition. Therefore, methods must be developed to distinguish between false positives and true ADR declarations. OBJECTIVE: The aim of this study was to investigate a method for filtering out disorder terms that did not correspond to adverse events by using the distance (as number of words) between the drug term and the disorder or symptom term in the post. We hypothesized that the shorter the distance between the disorder name and the drug, the higher the probability to be an ADR. METHODS: We analyzed a corpus of 648 messages corresponding to a total of 1654 (drug and disorder) pairs from 5 French forums using Gaussian mixture models and an expectation-maximization (EM) algorithm . RESULTS: The distribution of the distances between the drug term and the disorder term enabled the filtering of 50.03% (733/1465) of the disorders that were not ADRs. Our filtering strategy achieved a precision of 95.8% and a recall of 50.0%. CONCLUSIONS: This study suggests that such distance between terms can be used for identifying false positives, thereby improving ADR detection in social media. PMID- 28642213 TI - Development of a Web-Based Intervention for Addressing Distress in Caregivers of Patients Receiving Stem Cell Transplants: Formative Evaluation With Qualitative Interviews and Focus Groups AB - BACKGROUND: Caregivers of cancer patients experience significant burden and distress including depression and anxiety. We previously demonstrated the efficacy of an eight session, in-person, one-on-one stress management intervention to reduce distress in caregivers of patients receiving allogeneic hematopoietic stem cell transplants (allo-HSCT). OBJECTIVE: The objective of this study was to adapt and enhance the in-person caregiver stress management intervention to a mobilized website (eg, tablet, smartphone, or computer-based) for self-delivery in order to enhance dissemination to caregiver populations most in need. METHODS: We used an established approach for development of a mhealth intervention, completing the first two research and evaluation steps: Step One: Formative Research (eg, expert and stakeholder review from patients, caregivers, and palliative care experts) and Step Two: Pretesting (eg, Focus Groups and Individual Interviews with caregivers of patients with autologous HSCT (auto HSCT). Step one included feedback elicited for a mock-up version of Pep-Pal session one from caregiver, patients and clinician stakeholders from a multidisciplinary palliative care team (N=9 caregivers and patient stakeholders and N=20 palliative care experts). Step two included two focus groups (N=6 caregivers) and individual interviews (N=9 caregivers) regarding Pep-Pal's look and feel, content, acceptability, and potential usability/feasibility. Focus groups and individual interviews were audio-recorded. In addition, individual interviews were transcribed, and applied thematic analysis was conducted in order to gain an in-depth understanding to inform the development and refinement of the mobilized caregiver stress management intervention, Pep-Pal (PsychoEducation and skills for Patient caregivers). RESULTS: Overall, results were favorable. Pep-Pal was deemed acceptable for caregivers of patients receiving an auto-HSCT. The refined Pep-Pal program consisted of 9 sessions (Introduction to Stress, Stress and the Mind Body Connection, How Thoughts Can Lead to Stress, Coping with Stress, Strategies for Maintaining Energy and Stamina, Coping with Uncertainty, Managing Changing Relationships and Communicating Needs, Getting the Support You Need, and Improving Intimacy) delivered via video instruction through a mobilized website. CONCLUSIONS: Feedback from stakeholder groups, focus groups, and individual interviews provided valuable feedback in key areas that was integrated into the development of Pep-Pal with the goal of enhancing dissemination, engagement, acceptability, and usability. PMID- 28642215 TI - What Motivates Young Adults to Talk About Physical Activity on Social Network Sites? AB - BACKGROUND: Electronic word-of-mouth on social network sites has been used successfully in marketing. In social marketing, electronic word-of-mouth about products as health behaviors has the potential to be more effective and reach more young adults than health education through traditional mass media. However, little is known about what motivates people to actively initiate electronic word of-mouth about health behaviors on their personal pages or profiles on social network sites, thus potentially reaching all their contacts on those sites. OBJECTIVE: This study filled the gap by applying a marketing theoretical model to explore the factors associated with electronic word-of-mouth on social network sites about leisure-time physical activity. METHODS: A Web survey link was sent to undergraduate students at one of the Midwestern universities and 439 of them completed the survey. RESULTS: The average age of the 439 participants was 19 years (SD=1 year, range: 18-24). Results suggested that emotional engagement with leisure-time physical activity (ie, affective involvement in leisure-time physical activity) predicted providing relevant opinions or information on social network sites. Social network site users who perceived stronger ties with all their contacts were more likely to provide and seek leisure-time physical activity opinions and information. People who provided leisure-time physical activity opinions and information were more likely to seek opinions and information, and people who forwarded information about leisure-time physical activity were more likely to chat about it. CONCLUSIONS: This study shed light on the application of the electronic word-of-mouth theoretical framework in promoting health behaviors. The findings can also guide the development of future social marketing interventions using social network sites to promote leisure-time physical activity. PMID- 28642211 TI - The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study: Design and methods to address mental healthcare gaps in India. AB - INTRODUCTION: Depression and diabetes are highly prevalent worldwide and often co exist, worsening outcomes for each condition. Barriers to diagnosis and treatment are exacerbated in low and middle-income countries with limited health infrastructure and access to mental health treatment. The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study tests the sustained effectiveness and cost-effectiveness of a multi-component care model for individuals with poorly controlled diabetes and depression in diabetes clinics in India. MATERIALS AND METHODS: Adults with diabetes, depressive symptoms (Patient Health Questionnaire 9 score>=10), and >=1 poorly-controlled cardiometabolic indicator (either HbA1c>=8.0%, SBP>=140mmHg, and/or LDL>=130mg/dl) were enrolled and randomized to the intervention or usual care. The intervention combined collaborative care, decision-support, and population health management. The primary outcome is the between-arm difference in the proportion of participants achieving combined depression response (>=50% reduction in Symptom Checklist score from baseline) AND one or more of: >=0.5% reduction in HbA1c, >=5mmHg reduction in SBP, or >=10mg/dl reduction in LDL-c at 24months (12-month intervention; 12-month observational follow-up). Other outcomes include control of individual parameters, patient-centered measures (i.e. treatment satisfaction), and cost effectiveness. RESULTS: The study trained seven care coordinators. Participant recruitment is complete - 940 adults were screened, with 483 eligible, and 404 randomized (196 to intervention; 208 to usual care). Randomization was balanced across clinic sites. CONCLUSIONS: The INDEPENDENT model aims to increase access to mental health care and improve depression and cardiometabolic disease outcomes among complex patients with diabetes by leveraging the care provided in diabetes clinics in India (clinicaltrials.gov number: NCT02022111). PMID- 28642214 TI - Dupuytren Disease: Is There Enough Comprehensive Patient Information on the Internet? AB - BACKGROUND: Dupuytren disease is a chronic nonmalign fibroproliferative disorder that causes finger contractures via proliferation of new tissue under the glabrous skin of the hand, resulting in multiple functional limitations for the patient. As many surgical therapy options exist, patients suffering from this condition actively search for information in their environment before consulting a health professional. OBJECTIVE: As little is known about the quality of Web based patient information, the aim of this study was to conduct its systematic evaluation using a validated tool. METHODS: A total of 118 websites were included, and qualitative and quantitative assessment was performed using the modified Ensuring Quality Information for Patients (EQIP) tool. This standardized and reproducible tool consists of 36 items to assess available information in three categories: contents, identification, and structure data. Scientific data with restricted access, duplicates, and irrelevant websites were not included. RESULTS: Only 32 websites addressed more than 19 items, and the scores did not significantly differ among the website developers. The median number of items from the EQIP tool was 16, with the top websites addressing 28 out of 36 items. The quality of the newly developed websites did not increase with passing time. CONCLUSIONS: This study revealed several shortcomings in the quality of Web-based information available for patients suffering from Dupuytren disease. In the world of continuously growing and instantly available Web-based information, it is the health providers' negligence of the last two decades that there are very few good quality, informative, and educative websites that could be recommended to patients. PMID- 28642216 TI - What Predicts Online Health Information-Seeking Behavior Among Egyptian Adults? A Cross-Sectional Study. AB - BACKGROUND: Over the last decade, the Internet has become an important source of health-related information for a wide range of users worldwide. Yet, little is known about the personal characteristics of Egyptian Internet users who search for online health information (OHI). OBJECTIVE: The aim of the study was to identify the personal characteristics of Egyptian OHI seekers and to determine any associations between their personal characteristics and their health information-seeking behavior. METHODS: This cross-sectional questionnaire study was conducted from June to October 2015. A Web-based questionnaire was sent to Egyptian users aged 18 years and older (N=1400) of a popular Arabic-language health information website. The questionnaire included (1) demographic characteristics; (2) self-reported general health status; and (3) OHI-seeking behavior that included frequency of use, different topics sought, and self reported impact of obtained OHI on health behaviors. Data were analyzed using descriptive statistics and multiple regression analysis. RESULTS: A total of 490 participants completed the electronic questionnaire with a response rate equivalent to 35.0% (490/1400). Regarding personal characteristics, 57.1% (280/490) of participants were females, 63.4% (311/490) had a university level qualification, and 37.1% (182/490) had a chronic health problem. The most commonly sought OHI by the participants was nutrition-related. Results of the multiple regression analysis showed that 31.0% of the variance in frequency of seeking OHI among Egyptian adults can be predicted by personal characteristics. Participants who sought OHI more frequently were likely to be female, of younger age, had higher education levels, and good self-reported general health. CONCLUSIONS: Our results provide insights into personal characteristics and OHI seeking behaviors of Egyptian OHI users. This will contribute to better recognize their needs, highlight ways to increase the availability of appropriate OHI, and may lead to the provision of tools allowing Egyptian OHI users to navigate to the highest-quality health information. PMID- 28642217 TI - An Interactive, Mobile-Based Tool for Personal Social Network Data Collection and Visualization Among a Geographically Isolated and Socioeconomically Disadvantaged Population: Early-Stage Feasibility Study With Qualitative User Feedback. AB - BACKGROUND: Personal social networks have a profound impact on our health, yet collecting personal network data for use in health communication, behavior change, or translation and dissemination interventions has proved challenging. Recent advances in social network data collection software have reduced the burden of network studies on researchers and respondents alike, yet little testing has occurred to discover whether these methods are: (1) acceptable to a variety of target populations, including those who may have limited experience with technology or limited literacy; and (2) practical in the field, specifically in areas that are geographically and technologically disconnected, such as rural Appalachian Kentucky. OBJECTIVE: We explored the early-stage feasibility (Acceptability, Demand, Implementation, and Practicality) of using innovative, interactive, tablet-based network data collection and visualization software (OpenEddi) in field collection of personal network data in Appalachian Kentucky. METHODS: A total of 168 rural Appalachian women who had previously participated in a study on the use of a self-collected vaginal swab (SCVS) for human papillomavirus testing were recruited by community-based nurse interviewers between September 2013 and August 2014. Participants completed egocentric network surveys via OpenEddi, which captured social and communication network influences on participation in, and recruitment to, the SCVS study. After study completion, we conducted a qualitative group interview with four nurse interviewers and two participants in the network study. Using this qualitative data, and quantitative data from the network study, we applied guidelines from Bowen et al to assess feasibility in four areas of early-stage development of OpenEddi: Acceptability, Demand, Implementation, and Practicality. Basic descriptive network statistics (size, edges, density) were analyzed using RStudio. RESULTS: OpenEddi was perceived as fun, novel, and superior to other data collection methods or tools. Respondents enjoyed the social network survey component, and visualizing social networks produced thoughtful responses from participants about leveraging or changing network content and structure for specific health-promoting purposes. Areas for improved literacy and functionality of the tool were identified. However, technical issues led to substantial (50%) data loss, limiting the success of its implementation from a researcher's perspective, and hindering practicality in the field. CONCLUSIONS: OpenEddi is a promising data collection tool for use in geographically isolated and socioeconomically disadvantaged populations. Future development will mitigate technical problems, improve usability and literacy, and test new methods of data collection. These changes will support goals for use of this tool in the delivery of network-based health communication and social support interventions to socioeconomically disadvantaged populations. PMID- 28642219 TI - Controls on cosmetic treatments are "completely inadequate," report warns. PMID- 28642218 TI - The Effectiveness of Information Technology-Supported Shared Care for Patients With Chronic Disease: A Systematic Review. AB - BACKGROUND: In patients with chronic disease, many health care professionals are involved during treatment and follow-up. This leads to fragmentation that in turn may lead to suboptimal care. Shared care is a means to improve the integration of care delivered by various providers, specifically primary care physicians (PCPs) and specialty care professionals, for patients with chronic disease. The use of information technology (IT) in this field seems promising. OBJECTIVE: Our aim was to systematically review the literature regarding the effectiveness of IT supported shared care interventions in chronic disease in terms of provider or professional, process, health or clinical and financial outcomes. Additionally, our aim was to provide an inventory of the IT applications' characteristics that support such interventions. METHODS: PubMed, Scopus, and EMBASE were searched from 2006 to 2015 to identify relevant studies using search terms related to shared care, chronic disease, and IT. Eligible studies were in the English language, and the randomized controlled trials (RCTs), controlled trials, or single group pre-post studies used reported on the effects of IT-supported shared care in patients with chronic disease and cancer. The interventions had to involve providers from both primary and specialty health care. Intervention and IT characteristics and effectiveness-in terms of provider or professional (proximal), process (intermediate), health or clinical and financial (distal) outcomes-were extracted. Risk of bias of (cluster) RCTs was assessed using the Cochrane tool. RESULTS: The initial search yielded 4167 results. Thirteen publications were used, including 11 (cluster) RCTs, a controlled trial, and a pre-post feasibility study. Four main categories of IT applications were identified: (1) electronic decision support tools, (2) electronic platform with a call-center, (3) electronic health records, and (4) electronic communication applications. Positive effects were found for decision support-based interventions on financial and health outcomes, such as physical activity. Electronic health record use improved PCP visits and reduced rehospitalization. Electronic platform use resulted in fewer readmissions and better clinical outcomes-for example, in terms of body mass index (BMI) and dyspnea. The use of electronic communication applications using text-based information transfer between professionals had a positive effect on the number of PCPs contacting hospitals, PCPs' satisfaction, and confidence. CONCLUSIONS: IT-supported shared care can improve proximal outcomes, such as confidence and satisfaction of PCPs, especially in using electronic communication applications. Positive effects on intermediate and distal outcomes were also reported but were mixed. Surprisingly, few studies were found that substantiated these anticipated benefits. Studies showed a large heterogeneity in the included populations, outcome measures, and IT applications used. Therefore, a firm conclusion cannot be drawn. As IT applications are developed and implemented rapidly, evidence is needed to test the specific added value of IT in shared care interventions. This is expected to require innovative research methods. PMID- 28642222 TI - Risk factors for head injury events in professional rugby union: a video analysis of 464 head injury events to inform proposed injury prevention strategies. AB - OBJECTIVES: The tackle is responsible for the majority of head injuries during rugby union. In order to address head injury risk, risk factors during the tackle must first be identified. This study analysed tackle characteristics in the professional game in order to inform potential interventions. METHODS: 464 tackles resulting in a head injury assessment (HIA) were analysed in detail, with tackle type, direction, speed, acceleration, nature of head contact and player body position the characteristics of interest. RESULTS: Propensity to cause an HIA was significantly greater for active shoulder tackles, front-on tackles, high speeder tackles and an accelerating tackler. Head contact between a tackler's head and ball carrier's head or shoulder was significantly more likely to cause an HIA than contact below the level of the shoulder (incident rate ratio (IRR) 4.25, 95%-CI 3.38 to 5.35). The tackler experiences the majority (78%) of HIAs when head-to-head contact occurs. An upright tackler was 1.5 times more likely to experience an HIA than a bent at the waist tackler (IRR 1.44, 95% CI 1.18 to 1.76). CONCLUSIONS: This study confirms that energy transfer in the tackle is a risk factor for head injury, since direction, type and speed all influence HIA propensity. The study provides evidence that body position and the height of tackles should be a focus for interventions, since lowering height and adopting a bent at the waist body position is associated with reduced risk for both tacklers and ball carriers. To this end, World Rugby has implemented law change based on the present data. PMID- 28642220 TI - Low Pulse Pressure After Acute Ischemic Stroke is Associated With Unfavorable Outcomes: The Taiwan Stroke Registry. AB - BACKGROUND: Pulse pressure (PP) is related to cardiac function, arterial stiffness, fluid status, and vascular events. This study aimed to explore the prognostic role of PP upon admission in patients with acute ischemic stroke (AIS) based on a nation-wide stroke registry. METHODS AND RESULTS: We evaluated the association between PP upon admission and outcomes 3 months after a stroke in patients who had an AIS registered in the Taiwan Stroke Registry, including 56 academic and community hospitals between 2006 and 2013. Three months after the stroke, unfavorable outcomes were defined using a modified Rankin scale of 3 to 6. Of 33 530 patients (female, 40.6%; mean age, 68.8+/-13.3 years) who had an AIS, PP upon admission had a reverse J-curve association with an unfavorable outcome. After adjusting for clinical variables, including AIS subtypes, initial National Institutes of Health Stroke Scale, and systolic and diastolic blood pressure upon admission, a PP of <50 mm Hg was associated with unfavorable outcomes (P<0.0001). Compared with patients with a PP of 50 to 69 mm Hg, the odds ratios for unfavorable outcomes were 1.24 (95% CI, 1.14-1.36) with a PP of 30 to 49 mm Hg and 1.85 (95% CI, 1.50-2.28) with a PP of <30 mm Hg. Moreover, the prognostic impact of PP upon admission was similar across all AIS subtypes. CONCLUSIONS: Low PP upon admission was associated with unfavorable patient outcomes in AIS. PMID- 28642223 TI - Performing high-level sport is strongly associated with urinary incontinence in elite athletes: a comparative study of 372 elite female athletes and 372 controls. AB - OBJECTIVE: To evaluate the prevalence of urinary incontinence (UI) in female elite athletes compared with controls and to investigate potential risk factors for UI among elite athletes. METHODS: This cross-sectional study included 372 elite athletes (athletes group, AG) and 372 age-matched controls (control group, CG). The median age was low (19 years) and the vast majority were nulliparous. Potential risk factors, including clinical, demographic and sports practice characteristics, were collected by using a questionnaire. The International Consultation on Urinary Incontinence Questionnaire-Urinary Incontinence-Short Form was applied to estimate the prevalence of UI. OR with 95% CIs were used to estimate the association with UI. The final model was adjusted for constipation, family history of UI and history of urinary infection. RESULTS: The prevalence of UI was 29.6% and 13.4% in AG and CG, respectively (p<0.001). The following prevalences were obtained: AG: 19.6% and CG: 3.5% (p<0.001) for stress UI, AG: 3.8% and CG: 5.4% (p=0.292) for urgency UI and AG: 5.9% and CG: 0.8% (p<0.001) for mixed UI. After adjustment, performing high-level sport (adjusted (adj) OR=3.31; 95% CI 2.20 to 4.97), family history of UI (adj OR=1.54; 95% CI 1.04 to 2.29), history of urinary infection (adj OR=1.53; 95% CI 1.05 to 2.23) and constipation (adj OR=1.79; 95% CI 1.07 to 2.98) were associated with UI. CONCLUSION: The prevalence of UI among Portuguese female elite athletes is high and the odds of UI were three times higher than in controls. Also, constipation, family history of UI and history of urinary infections were significantly associated with UI. PMID- 28642221 TI - Exercise and pregnancy in recreational and elite athletes: 2016/17 evidence summary from the IOC Expert Group Meeting, Lausanne. Part 3-exercise in the postpartum period. PMID- 28642224 TI - The Bangkok Declaration on Physical Activity for Global Health and Sustainable Development. PMID- 28642225 TI - Blood flow restriction training: a novel approach to augment clinical rehabilitation: how to do it. PMID- 28642227 TI - Correction: Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma. PMID- 28642226 TI - Measuring patient-reported outcomes (PROs/PROMs) in people with Achilles tendinopathy: how useful is the VISA-A? PMID- 28642228 TI - Global Is Local: July at a Teaching Hospital in Texas. PMID- 28642229 TI - Evolutionary dynamics of the kinetochore network in eukaryotes as revealed by comparative genomics. AB - During eukaryotic cell division, the sister chromatids of duplicated chromosomes are pulled apart by microtubules, which connect via kinetochores. The kinetochore is a multiprotein structure that links centromeres to microtubules, and that emits molecular signals in order to safeguard the equal distribution of duplicated chromosomes over daughter cells. Although microtubule-mediated chromosome segregation is evolutionary conserved, kinetochore compositions seem to have diverged. To systematically inventory kinetochore diversity and to reconstruct its evolution, we determined orthologs of 70 kinetochore proteins in 90 phylogenetically diverse eukaryotes. The resulting ortholog sets imply that the last eukaryotic common ancestor (LECA) possessed a complex kinetochore and highlight that current-day kinetochores differ substantially. These kinetochores diverged through gene loss, duplication, and, less frequently, invention and displacement. Various kinetochore components co-evolved with one another, albeit in different manners. These co-evolutionary patterns improve our understanding of kinetochore function and evolution, which we illustrated with the RZZ complex, TRIP13, the MCC, and some nuclear pore proteins. The extensive diversity of kinetochore compositions in eukaryotes poses numerous questions regarding evolutionary flexibility of essential cellular functions. PMID- 28642231 TI - Secondhand Smoke Exposure Among Community-Dwelling Adult Cancer Survivors in the United States: 1999-2012. AB - Background: Little is known about the prevalence of secondhand smoke exposure (SHSe) among cancer survivors. We sought to determine the prevalence, trends, and correlates of SHSe among nonsmoking adult cancer survivors in the United States.Methods: Interview and serum cotinine data for nonsmoking adults, age 20 years and older, with a history of cancer (N = 686) were obtained from consecutive two-year cross-sectional cycles of the National Health and Nutrition Examination Survey from 1999 to 2012. SHSe was defined as serum cotinine 0.05-10 ng/mL among nonsmokers. We calculated and trended the prevalence of SHSe among nonsmoking cancer survivors. Multivariable logistic regression was used to examine the associations of SHSe with sociodemographic, smoking, and clinical characteristics. Survey weights were applied in estimating prevalence rates, adjusted ORs, and confidence intervals (CI).Results: The weighted aggregate SHSe and self-reported indoor SHSe prevalence rates over the study period were 28.26% (95% CI: 24.97%-31.55%) and 4.53% (95% CI: 3.48%-5.57%), respectively. SHS exposure declined from 39.61% (95% CI: 27.88%-51.34%) in 1999/2000 to 15.68% (95% CI: 9.38%-21.98%) in 2011/2012 (Ptrend < 0.001). Age >= 60 years was protective against SHSe, while being black, having less than high school education, poverty, and a smoking-related cancer history were associated with higher odds of SHSe.Conclusions: Fortunately, SHSe among nonsmoking cancer survivors in the United States is on the decline, although certain subgroups remain disproportionately burdened.Impact: These findings highlight clinical and public health imperatives to target socioeconomically disadvantaged nonsmoking cancer survivors to reduce their SHSe. Cancer Epidemiol Biomarkers Prev; 26(8); 1296 305. (c)2017 AACR. PMID- 28642232 TI - A Single Amino Acid Residue at Transmembrane Domain 4 of the alpha Subunit Influences Carisoprodol Direct Gating Efficacy at GABAA Receptors. AB - The muscle relaxant carisoprodol has recently been controlled at the federal level as a Schedule IV drug due to its high abuse potential and consequences of misuse, such as withdrawal syndrome, delusions, seizures, and even death. Recent work has shown that carisoprodol can directly gate and allosterically modulate the type A GABA (GABAA) receptor. These actions are subunit-dependent; compared with other GABAA receptors, carisoprodol has nominal direct gating effects in alpha3beta2gamma2 receptors. Here, using site-directed mutagenesis and whole-cell patch-clamp electrophysiology in transiently transfected human embryonic kidney 293 cells, we examined the role of GABAA receptor alpha subunit transmembrane domain 4 (TM4) amino acids in direct gating and allosteric modulatory actions of carisoprodol. Mutation of alpha3 valine at position 440 to leucine (present in the equivalent position in the alpha1 subunit) significantly increased the direct gating effects of carisoprodol without affecting its allosteric modulatory effects. The corresponding reverse mutation, alpha1(L415V), decreased carisoprodol direct gating potency and efficacy. Analysis of a series of amino acid mutations at the 415 position demonstrated that amino acid volume correlated positively with carisoprodol efficacy, whereas polarity inversely correlated with carisoprodol efficacy. We conclude that alpha1(415) of TM4 is involved in the direct gating, but not allosteric modulatory, actions of carisoprodol. In addition, the orientation of alkyl or hydroxyl groups at this position influences direct gating effects. These findings support the likelihood that the direct gating and allosteric modulatory effects of carisoprodol are mediated via distinct binding sites. PMID- 28642233 TI - Sembragiline: A Novel, Selective Monoamine Oxidase Type B Inhibitor for the Treatment of Alzheimer's Disease. AB - Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders. PMID- 28642234 TI - Reconfiguration of DNA molecular arrays driven by information relay. AB - Information relay at the molecular level is an essential phenomenon in numerous chemical and biological processes, such as intricate signaling cascades. One key challenge in synthetic molecular self-assembly is to construct artificial structures that imitate these complex behaviors in controllable systems. We demonstrated prescribed, long-range information relay in an artificial molecular array assembled from modular DNA structural units. The dynamic DNA molecular array exhibits transformations with programmable initiation, propagation, and regulation. The transformation of the array can be initiated at selected units and then propagated, without addition of extra triggers, to neighboring units and eventually the entire array. The specific information pathways by which this transformation occurs can be controlled by altering the design of individual units and the arrays. PMID- 28642236 TI - Knee pain in a 15 year old boy. PMID- 28642235 TI - Atomic-layered Au clusters on alpha-MoC as catalysts for the low-temperature water-gas shift reaction. AB - The water-gas shift (WGS) reaction (where carbon monoxide plus water yields dihydrogen and carbon dioxide) is an essential process for hydrogen generation and carbon monoxide removal in various energy-related chemical operations. This equilibrium-limited reaction is favored at a low working temperature. Potential application in fuel cells also requires a WGS catalyst to be highly active, stable, and energy-efficient and to match the working temperature of on-site hydrogen generation and consumption units. We synthesized layered gold (Au) clusters on a molybdenum carbide (alpha-MoC) substrate to create an interfacial catalyst system for the ultralow-temperature WGS reaction. Water was activated over alpha-MoC at 303 kelvin, whereas carbon monoxide adsorbed on adjacent Au sites was apt to react with surface hydroxyl groups formed from water splitting, leading to a high WGS activity at low temperatures. PMID- 28642230 TI - A Review of Pulmonary Toxicity of Electronic Cigarettes in the Context of Smoking: A Focus on Inflammation. AB - The use of electronic cigarettes (e-cigs) is increasing rapidly, but their effects on lung toxicity are largely unknown. Smoking is a well-established cause of lung cancer and respiratory disease, in part through inflammation. It is plausible that e-cig use might affect similar inflammatory pathways. E-cigs are used by some smokers as an aid for quitting or smoking reduction, and by never smokers (e.g., adolescents and young adults). The relative effects for impacting disease risk may differ for these groups. Cell culture and experimental animal data indicate that e-cigs have the potential for inducing inflammation, albeit much less than smoking. Human studies show that e-cig use in smokers is associated with substantial reductions in blood or urinary biomarkers of tobacco toxicants when completely switching and somewhat for dual use. However, the extent to which these biomarkers are surrogates for potential lung toxicity remains unclear. The FDA now has regulatory authority over e-cigs and can regulate product and e-liquid design features, such as nicotine content and delivery, voltage, e-liquid formulations, and flavors. All of these factors may impact pulmonary toxicity. This review summarizes current data on pulmonary inflammation related to both smoking and e-cig use, with a focus on human lung biomarkers. Cancer Epidemiol Biomarkers Prev; 26(8); 1175-91. (c)2017 AACR. PMID- 28642237 TI - Mediator 1 Is Atherosclerosis Protective by Regulating Macrophage Polarization. AB - OBJECTIVE: MED1 (mediator 1) interacts with transcription factors to regulate transcriptional machinery. The role of MED1 in macrophage biology and the relevant disease state remains to be investigated. APPROACH AND RESULTS: To study the molecular mechanism by which MED1 regulates the M1/M2 phenotype switch of macrophage and the effect on atherosclerosis, we generated MED1/apolipoprotein E (ApoE) double-deficient (MED1DeltaMac/ApoE-/-) mice and found that atherosclerosis was greater in MED1DeltaMac/ApoE-/- mice than in MED1fl/fl/ApoE-/ littermates. The gene expression of M1 markers was increased and that of M2 markers decreased in both aortic wall and peritoneal macrophages from MED1DeltaMac/ApoE-/- mice, whereas MED1 overexpression rectified the changes in M1/M2 expression. Moreover, LDLR (low-density lipoprotein receptor)-deficient mice received bone marrow from MED1DeltaMac mice showed greater atherosclerosis. Mechanistically, MED1 ablation decreased the binding of PPARgamma (peroxisome proliferator-activated receptor gamma) and enrichment of H3K4me1 and H3K27ac to upstream region of M2 marker genes. Furthermore, interleukin 4 induction of PPARgamma and MED1 increased the binding of PPARgamma or MED1 to the PPAR response elements of M2 marker genes. CONCLUSIONS: Our data suggest that MED1 is required for the PPARgamma-mediated M2 phenotype switch, with M2 marker genes induced but M1 marker genes suppressed. MED1 in macrophages has an antiatherosclerotic role via PPARgamma-regulated transactivation. PMID- 28642241 TI - Give a voice to the voiceless. PMID- 28642239 TI - A Novel Single-Domain Antibody Against von Willebrand Factor A1 Domain Resolves Leukocyte Recruitment and Vascular Leakage During Inflammation-Brief Report. AB - OBJECTIVE: von Willebrand factor (VWF) is crucial to hemostasis, but also plays a role in inflammatory processes. Unfortunately, no proper monoclonal antibodies to study VWF function in mice are currently available. We therefore aimed to generate single-domain antibodies (sdAbs) recognizing murine VWF and blocking its function in vivo. APPROACH AND RESULTS: Llama-derived sdAbs recognizing both human and murine VWF were isolated via phage display technology. One of them (designated KB-VWF-006) recognized the VWF A1 domain with picomolar affinity. This sdAb avidity was strongly enhanced via dimerization using a triple Ala linker (KB-VWF-006bi). When administered in vivo to wild-type mice, KB-VWF-006bi dose dependently induced bleeding in a tail clip model. In 2 distinct models of inflammation, KB-VWF-006bi efficiently interfered with leukocyte recruitment and vascular leakage. CONCLUSIONS: KB-VWF-006bi is an sdAb recognizing the A1 domain of human VWF and murine VWF that interferes with VWF-platelet interactions in vivo. By using this sdAb, we now also show that the A1 domain is pertinent to the participation of VWF in the inflammatory response. PMID- 28642242 TI - Specific expression and function of the Six3 optix in Drosophila serially homologous organs. AB - Organ size and pattern results from the integration of two positional information systems. One global information system, encoded by the Hox genes, links organ type with position along the main body axis. Within specific organs, local information is conveyed by signaling molecules that regulate organ growth and pattern. The mesothoracic (T2) wing and the metathoracic (T3) haltere of Drosophila represent a paradigmatic example of this coordination. The Hox gene Ultrabithorax (Ubx), expressed in the developing T3, selects haltere identity by, among other processes, modulating the production and signaling efficiency of Dpp, a BMP2-like molecule that acts as a major regulator of size and pattern. However, the mechanisms of the Hox-signal integration in this well-studied system are incomplete. Here, we have investigated this issue by studying the expression and function of the Six3 transcription factor optix during Drosophila wing and haltere development. We find that in both organs, Dpp defines the expression domain of optix through repression, and that the specific position of this domain in wing and haltere seems to reflect the differential signaling profile among these organs. We show that optix expression in wing and haltere primordia is conserved beyond Drosophila in other higher diptera. In Drosophila, optix is necessary for the growth of wing and haltere. In the wing, optix is required for the growth of the most anterior/proximal region (the 'marginal cell') and for the correct formation of sensory structures along the proximal anterior wing margin; the halteres of optix mutants are also significantly reduced. In addition, in the haltere, optix is necessary for the suppression of sensory bristles. PMID- 28642238 TI - Ager Deletion Enhances Ischemic Muscle Inflammation, Angiogenesis, and Blood Flow Recovery in Diabetic Mice. AB - OBJECTIVE: Diabetic subjects are at higher risk of ischemic peripheral vascular disease. We tested the hypothesis that advanced glycation end products (AGEs) and their receptor (RAGE) block angiogenesis and blood flow recovery after hindlimb ischemia induced by femoral artery ligation through modulation of immune/inflammatory mechanisms. APPROACH AND RESULTS: Wild-type mice rendered diabetic with streptozotocin and subjected to unilateral femoral artery ligation displayed increased accumulation and expression of AGEs and RAGE in ischemic muscle. In diabetic wild-type mice, femoral artery ligation attenuated angiogenesis and impaired blood flow recovery, in parallel with reduced macrophage content in ischemic muscle and suppression of early inflammatory gene expression, including Ccl2 (chemokine [C-C motif] ligand-2) and Egr1 (early growth response gene-1) versus nondiabetic mice. Deletion of Ager (gene encoding RAGE) or transgenic expression of Glo1 (reduces AGEs) restored adaptive inflammation, angiogenesis, and blood flow recovery in diabetic mice. In diabetes mellitus, deletion of Ager increased circulating Ly6Chi monocytes and augmented macrophage infiltration into ischemic muscle tissue after femoral artery ligation. In vitro, macrophages grown in high glucose display inflammation that is skewed to expression of tissue damage versus tissue repair gene expression. Further, macrophages grown in high versus low glucose demonstrate blunted macrophage-endothelial cell interactions. In both settings, these adverse effects of high glucose were reversed by Ager deletion in macrophages. CONCLUSIONS: These findings indicate that RAGE attenuates adaptive inflammation in hindlimb ischemia; underscore microenvironment-specific functions for RAGE in inflammation in tissue repair versus damage; and illustrate that AGE/RAGE antagonism may fill a critical gap in diabetic peripheral vascular disease. PMID- 28642243 TI - Anti-inflammatory and anti-osteoarthritis effects of tectorigenin. AB - Osteoarthritis (OA) is a common and dynamic disease of the joints, including the articular cartilage, underlying bones and synovium. In particular, OA is considered as the degeneration of the cartilage. Tectorigenin (Tec) is known to affect many biological processes; however, its effects on articular chondrocytes remain unclear. This study aimed to assess the effects of Tec on articular cartilage. In vitro, Tec inhibited the expression levels of type X collagen, cyclooxigenase-2, matrix metalloproteinase (MMP)-3 and MMP-13, but enhanced the expression of Runx1, type II collagen and aggrecan in the presence of IL-1beta. Meanwhile, Tec inhibited apoptosis through the Bax/Bcl-2/caspase-3 pathway, upregulating p-Bad, downregulating the Bax/Bcl-2 ratio, and activating caspase-3 compared with IL-1beta treatment only. Moreover, this process was partially regulated by NF-kappaB P65. In vivo, the chondroprotective effects of Tec were assessed by establishing a model of surgically induced OA. Tec-treated joints exhibited fewer osteoarthritic changes than saline-treated joints. Meanwhile, 1.5 MUg/kg Tec treatment produced a greater protective effect than 0.75 MUg/kg Tec. The Osteoarthritis Research Society International (OARSI) scoring system, employed to assess histopathological grading of the models, as well immunohistochemistry for Aggrecan Neoepitope and MMP-3, further confirmed the results. In conclusion, this study showed that Tec plays a chondroprotective role in the OA process by preventing articular cartilage degeneration and chondrocyte apoptosis via the NF-kappaB P65 pathway. PMID- 28642244 TI - Investigation of protein synthesis in Drosophila larvae using puromycin labelling. AB - Translational control of gene expression is an important regulator of growth, homeostasis and aging in Drosophila The ability to measure changes in protein synthesis in response to genetic and environmental cues is therefore important in studying these processes. Here we describe a simple and cost-effective approach to assay protein synthesis in Drosophila larval cells and tissues. The method is based on the incorporation of puromycin into nascent peptide chains. Using an ex vivo approach, we label newly synthesized peptides in larvae with puromycin and then measure levels of new protein synthesis using an anti-puromycin antibody. We show that this method can detect changes in protein synthesis in specific cells and tissues in the larvae, either by immunostaining or western blotting. We find that the assay reliably detects changes in protein synthesis induced by two known stimulators of mRNA translation - the nutrient/TORC1 kinase pathway and the transcription factor dMyc. We also use the assay to describe how protein synthesis changes through larval development and in response to two environmental stressors - hypoxia and heat shock. We propose that this puromycin-labelling assay is a simple but robust method to detect protein synthesis changes at the levels of cells, tissues or whole body in Drosophila. PMID- 28642245 TI - A reporter mouse model for in vivo tracing and in vitro molecular studies of melanocytic lineage cells and their diseases. AB - Alterations in melanocytic lineage cells give rise to a plethora of distinct human diseases, including neurocristopathies, cutaneous pigmentation disorders, loss of vision and hearing, and melanoma. Understanding the ontogeny and biology of melanocytic cells, as well as how they interact with their surrounding environment, are key steps in the development of therapies for diseases that involve this cell lineage. Efforts to culture and characterize primary melanocytes from normal or genetically engineered mouse models have at times yielded contrasting observations. This is due, in part, to differences in the conditions used to isolate, purify and culture these cells in individual studies. By breeding ROSAmT/mG and Tyr::CreERT2 mice, we generated animals in which melanocytic lineage cells are identified through expression of green fluorescent protein. We also used defined conditions to systematically investigate the proliferation and migration responses of primary melanocytes on various extracellular matrix (ECM) substrates. Under our culture conditions, mouse melanocytes exhibit doubling times in the range of 10 days, and retain exponential proliferative capacity for 50-60 days. In culture, these melanocytes showed distinct responses to different ECM substrates. Specifically, laminin-332 promoted cell spreading, formation of dendrites, random motility and directional migration. In contrast, low or intermediate concentrations of collagen I promoted adhesion and acquisition of a bipolar morphology, and interfered with melanocyte forward movements. Our systematic evaluation of primary melanocyte responses emphasizes the importance of clearly defining culture conditions for these cells. This, in turn, is essential for the interpretation of melanocyte responses to extracellular cues and to understand the molecular basis of disorders involving the melanocytic cell lineage. PMID- 28642247 TI - Clinical benefit of the FIFA 11 programme for the prevention of hamstring and lateral ankle ligament injuries among amateur soccer players. AB - OBJECTIVE: To analyse the relationship between the implementation of 'the 11' protocol during the regular season in a men's amateur soccer team and the rate of hamstring and lateral ankle ligament (LAL) injuries, and to estimate the clinical benefit of the programme according to the type of injury and the position field. METHODS: This cohort study was conducted in two different men's amateur soccer teams. During two seasons, the exposed group (43 players) performed 'the 11' protocol twice a week, and the unexposed group (43 players) performed the regular training programme. All players trained three times per week for 1.5 hours per day. Data collection was performed for every 1000 hours of play. RESULTS: 18 hamstring injuries (injury rate (IR) of 2.26 injuries/1000 training+competition hours) and 15 LAL injuries (IR of 1.88 injuries/1000) were registered in the exposed group. In the unexposed group, there were 25 LAL injuries (IR of 3.14 injuries/1000) and 35 hamstring injuries (IR of 4.39 injuries/1000). The number needed to treat to prevent one new case was 3.9 in LAL injuries, 3.31 in biceps femoris injuries and 10.7 in recurrent hamstring injuries. CONCLUSIONS: 'The 11' programme reduced the incidence of hamstring and LAL injuries in amateur players. According to the field position, the programme was effective for defenders and midfielders. In accordance with the type of injury, the exposed group had a lower risk of LAL, biceps femoris and hamstring injuries compared with those in the unexposed group. PMID- 28642246 TI - Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function. AB - The endoplasmic reticulum (ER) is an energy-sensing organelle with intimate ties to programming cell activation and metabolic fate. T-cell receptor (TCR) activation represents a form of acute cell stress and induces mobilization of ER Ca2+ stores. The role of the ER in programming T-cell activation and metabolic fate remains largely undefined. Gp96 is an ER protein with functions as a molecular chaperone and Ca2+ buffering protein. We hypothesized that the ER stress response may be important for CD4+ T-cell activation and that gp96 may be integral to this process. To test our hypothesis, we utilized genetic deletion of the gp96 gene Hsp90b1 in a CD4+ T cell-specific manner. We show that gp96 deficient CD4+ T cells cannot undergo activation-induced glycolysis due to defective Ca2+ mobilization upon TCR engagement. We found that activating naive CD4+ T cells while inhibiting ER Ca2+ exchange, through pharmacological blockade of the ER Ca2+ channel inositol trisphosphate receptor (IP3R), led to a reduction in cytosolic Ca2+ content and generated a pool of CD62Lhigh/CD44low CD4+ T cells compared with wild-type (WT) matched controls. In vivo IP3R-inhibited CD4+ T cells exhibited elevated tumor control above WT T cells. Together, these data show that ER-modulated cytosolic Ca2+ plays a role in defining CD4+ T-cell phenotype and function. Factors associated with the ER stress response are suitable targets for T cell-based immunotherapies. Cancer Immunol Res; 5(8); 666 75. (c)2017 AACR. PMID- 28642249 TI - UNC Cancer Center Director to Lead NCI. AB - President Donald Trump has selected Norman "Ned" Sharpless, MD, director of the University of North Carolina Lineberger Comprehensive Cancer Center, to lead the NCI. The news was met with widespread approval among cancer researchers, who view Sharpless as a strong communicator who can ably represent the needs of the cancer community in the face of proposed funding cuts. PMID- 28642248 TI - Evaluation of a community-based safe firearm and ammunition storage intervention. AB - BACKGROUND: Safe firearm storage practices are associated with a lower risk of unintentional and self-inflicted firearm injuries among household members, though many firearms remain unlocked and/or loaded. OBJECTIVES: Conduct a preliminary evaluation of a community-based firearm safety intervention and assess participants' preferences for firearm locking devices and their comfort with potential firearm safety counsellors. DESIGN/METHODS: Baseline event and follow up surveys among adult participants to assess changes in firearm storage practices, including whether all household firearms were stored locked, all were unloaded, all ammunition was locked, and a composite measure assessing whether all firearms were locked and unloaded and all ammunition was stored locked. RESULTS: A total of 206 out of 415 participants completed both surveys and were included. Nearly 9 in 10 respondents preferred the firearm lock box rather than a trigger lock. At follow-up, a significantly greater proportion reported that all household firearms were locked (+13.7%) and unloaded (+8.5%) and a non significantly greater proportion reported that all ammunition was locked (+6.3%). A significantly greater proportion reported practising all three safe firearm and ammunition storage practices at follow-up (+12.6%). A majority reported they would be comfortable or very comfortable discussing firearm safety with various safety counsellors, though women were less likely to do so than men. CONCLUSION: This intervention that included distribution of a free, participant-selected locking device improved safe firearm storage practices among participants. Differences in participant preferences for devices and safety counsellors suggest that a 'one size fits all' approach may be inadequate in affecting population level storage practices. PMID- 28642250 TI - Widespread Genomic Testing Deemed Feasible. AB - Although comprehensive genomic screening has not yet become routine when treating patients with cancer, widespread testing in those with advanced, refractory disease is feasible, according to the ongoing ProfiLER study. The study also found that patients who subsequently received a treatment matched to the genetic changes in their tumor lived longer than those who lacked a so-called actionable mutation. PMID- 28642252 TI - Queen's speech promises change on mental health but ignores wider NHS problems. PMID- 28642251 TI - Physical activity, cognitive decline, and risk of dementia: 28 year follow-up of Whitehall II cohort study. AB - Objective To test the hypotheses that physical activity in midlife is not associated with a reduced risk of dementia and that the preclinical phase of dementia is characterised by a decline in physical activity.Design Prospective cohort study with a mean follow-up of 27 years.Setting Civil service departments in London (Whitehall II study).Participants 10 308 participants aged 35-55 years at study inception (1985-88). Exposures included time spent in mild, moderate to vigorous, and total physical activity assessed seven times between 1985 and 2013 and categorised as "recommended" if duration of moderate to vigorous physical activity was 2.5 hours/week or more.Main outcome measures A battery of cognitive tests was administered up to four times from 1997 to 2013, and incident dementia cases (n=329) were identified through linkage to hospital, mental health services, and mortality registers until 2015.Results Mixed effects models showed no association between physical activity and subsequent 15 year cognitive decline. Similarly, Cox regression showed no association between physical activity and risk of dementia over an average 27 year follow-up (hazard ratio in the "recommended" physical activity category 1.00, 95% confidence interval 0.80 to 1.24). For trajectories of hours/week of total, mild, and moderate to vigorous physical activity in people with dementia compared with those without dementia (all others), no differences were observed between 28 and 10 years before diagnosis of dementia. However, physical activity in people with dementia began to decline up to nine years before diagnosis (difference in moderate to vigorous physical activity -0.39 hours/week; P=0.05), and the difference became more pronounced (-1.03 hours/week; P=0.005) at diagnosis.Conclusion This study found no evidence of a neuroprotective effect of physical activity. Previous findings showing a lower risk of dementia in physically active people may be attributable to reverse causation-that is, due to a decline in physical activity levels in the preclinical phase of dementia. PMID- 28642253 TI - Military-related sexual assault in Canada: a cross-sectional survey. AB - BACKGROUND: Most research on military-related sexual assault is based on the United States military and has important limitations, such as low response rates. We sought to estimate the lifetime prevalence of sexual assault, assess its relation to military service and identify the circumstances, correlates and associations with mental disorders of military-related sexual assault among Canadian military personnel. METHODS: We used the 2013 Canadian Forces Mental Health Survey, a cross-sectional representative survey of Canadian Regular Force personnel (n = 6696). The sample was weighted to be representative of the entire Canadian Armed Forces Regular Force population in 2012 (n = 67 776), as per Statistics Canada requirements. We assessed lifetime trauma exposure and past year mental disorders using the Composite International Diagnostic Interview. We defined lifetime military-related sexual assault as forced sexual activity or unwanted sexual touching that occurred on deployment or in another military workplace, or was perpetrated by Department of National Defence or Canadian Armed Forces personnel. We defined all other sexual assault as non-military-related sexual assault. RESULTS: Self-reported sexual assault was more prevalent among women (non-military-related sexual assault 24.2%, military-related sexual assault 15.5%) than men (5.9% and 0.8%, respectively). About a quarter of women with military-related sexual assault reported experiencing at least 1 event on deployment. After covariates were controlled for, military-related sexual assault was independently associated with any lifetime and any past-year mental disorder (adjusted odds ratio 2.9 and 3.0, respectively) and lifetime and past-year posttraumatic stress disorder (adjusted odds ratio 4.3 and 4.1, respectively). INTERPRETATION: Canadian military women are at increased risk for sexual assault and military-related sexual assault relative to their male counterparts. Deployment may be a period of elevated risk for military-related sexual assault, and women who reported military-related sexual assault are more likely to have experienced mental disorders, especially posttraumatic stress disorder. PMID- 28642254 TI - Redox regulation of a guard cell SNF1-related protein kinase in Brassica napus, an oilseed crop. AB - Kinase-mediated phosphorylation is a pivotal regulatory process in stomatal responses to stresses. Through a redox proteomics study, a sucrose non-fermenting 1-related protein kinase (SnRK2.4) was identified to be redox-regulated in Brassica napus guard cells upon abscisic acid treatment. There are six genes encoding SnRK2.4 paralogs in B. napus Here, we show that recombinant BnSnRK2.4-1C exhibited autophosphorylation activity and preferentially phosphorylated the N terminal region of B. napus slow anion channel (BnSLAC1-NT) over generic substrates. The in vitro activity of BnSnRK2.4-1C requires the presence of manganese (Mn2+). Phosphorylation sites of autophosphorylated BnSnRK2.4-1C were mapped, including serine and threonine residues in the activation loop. In vitro BnSnRK2.4-1C autophosphorylation activity was inhibited by oxidants such as H2O2 and recovered by active thioredoxin isoforms, indicating redox regulation of BnSnRK2.4-1C. Thiol-specific isotope tagging followed by mass spectrometry analysis revealed specific cysteine residues responsive to oxidant treatments. The in vivo activity of BnSnRK2.4-1C is inhibited by 15 min of H2O2 treatment. Taken together, these data indicate that BnSnRK2.4-1C, an SnRK preferentially expressed in guard cells, is redox-regulated with potential roles in guard cell signal transduction. PMID- 28642256 TI - Revision for prosthetic joint infection following hip arthroplasty: Evidence from the National Joint Registry. AB - OBJECTIVES: We used the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man (NJR) to investigate the risk of revision due to prosthetic joint infection (PJI) for patients undergoing primary and revision hip arthroplasty, the changes in risk over time, and the overall burden created by PJI. METHODS: We analysed revision total hip arthroplasties (THAs) performed due to a diagnosis of PJI and the linked index procedures recorded in the NJR between 2003 and 2014. The cohort analysed consisted of 623 253 index primary hip arthroplasties, 63 222 index revision hip arthroplasties and 7585 revision THAs performed due to a diagnosis of PJI. The prevalence, cumulative incidence functions and the burden of PJI (total procedures) were calculated. Overall linear trends were investigated with log-linear regression. RESULTS: We demonstrated a prevalence of revision THA due to prosthetic joint infection of 0.4/100 procedures following primary and 1.6/100 procedures following revision hip arthroplasty. The prevalence of revision due to PJI in the three months following primary hip arthroplasty has risen 2.3-fold (95% confidence interval (CI) 1.3 to 4.1) between 2005 and 2013, and 3.0-fold (95% CI 1.1 to 8.5) following revision hip arthroplasty. Over 1000 procedures are performed annually as a consequence of hip PJI, an increase of 2.6-fold between 2005 and 2013. CONCLUSIONS: Although the risk of revision due to PJI following hip arthroplasty is low, it is rising and, coupled with the established and further predicted increased incidence of both primary and revision hip arthroplasty, this represents a growing and substantial treatment burden.Cite this article: E. Lenguerrand, M. R. Whitehouse, A. D. Beswick, S. A. Jones, M. L. Porter, A. W. Blom. Revision for prosthetic joint infection following hip arthroplasty: Evidence from the National Joint Registry. Bone Joint Res 2017;6:391-398. DOI: 10.1302/2046-3758.66.BJR-2017-0003.R1. PMID- 28642259 TI - Staff experiences and perceptions of working with in-patients who are suicidal: qualitative analysis. AB - BackgroundSuicidal behaviour is frequent in psychiatric in-patients and much staff time and resources are devoted to assessing and managing suicide risk. However, little is known about staff experiences of working with in-patients who are suicidal.AimsTo investigate staff experiences of working with in-patients who are suicidal.MethodQualitative study guided by thematic analysis of semi structured interviews with mental health staff with experience of psychiatric in patient care.ResultsTwenty staff participated. All had encountered in-patient suicide deaths or attempts. Three key themes were identified: (a) experiences of suicidality, (b) conceptualising suicidality and (c) talking about suicide.ConclusionsSuicidal behaviour in psychiatric wards has a large impact on staff feelings, practice and behaviour. Staff felt inadequately equipped to deal with such behaviours, with detrimental consequences for patients and themselves. Organisational support is lacking. Training and support should extend beyond risk assessment to improving staff skills in developing therapeutic interactions with in-patients who are suicidal. PMID- 28642257 TI - Interaction between the FTO gene, body mass index and depression: meta-analysis of 13701 individuals. AB - BackgroundDepression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.AimsTo confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.MethodThe sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.ResultsIn the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta analysis (beta = 0.12, P = 2.7 * 10-4) and with the Han/Eskin random effects method (P = 1.4 * 10-7) but not with traditional random effects (beta = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (beta = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 * 10-8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTOConclusionsThis meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression. PMID- 28642258 TI - Ethnicity and long-term course and outcome of psychotic disorders in a UK sample: the AESOP-10 study. AB - BackgroundThe incidence of psychotic disorders is elevated in some minority ethnic populations. However, we know little about the outcome of psychoses in these populations.AimsTo investigate patterns and determinants of long-term course and outcome of psychoses by ethnic group following a first episode.MethodAESOP-10 is a 10-year follow-up of an ethnically diverse cohort of 532 individuals with first-episode psychosis identified in the UK. Information was collected, at baseline, on clinical presentation and neurodevelopmental and social factors and, at follow-up, on course and outcome.ResultsThere was evidence that, compared with White British, Black Caribbean patients experienced worse clinical, social and service use outcomes and Black African patients experienced worse social and service use outcomes. There was evidence that baseline social disadvantage contributed to these disparities.ConclusionsThese findings suggest ethnic disparities in the incidence of psychoses extend, for some groups, to worse outcomes in multiple domains. PMID- 28642260 TI - Cigarette smoke disrupts monolayer integrity by altering epithelial cell-cell adhesion and cortical tension. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Cigarette smoke (CS) drives disease development and progression. The epithelial barrier is damaged by CS with increased monolayer permeability. However, the molecular changes that cause this barrier disruption and the interaction between adhesion proteins and the cytoskeleton are not well defined. We hypothesized that CS alters monolayer integrity by increasing cell contractility and decreasing cell adhesion in epithelia. Normal human airway epithelial cells and primary COPD epithelial cells were exposed to air or CS, and changes measured in protein levels. We measured the cortical tension of individual cells and the stiffness of cells in a monolayer. We confirmed that the changes in acute and subacute in vitro smoke exposure reflect protein changes seen in cell monolayers and tissue sections from COPD patients. Epithelial cells exposed to repetitive CS and those derived from COPD patients have increased monolayer permeability. E-cadherin and beta-catenin were reduced in smoke exposed cells as well as in lung tissue sections from patients with COPD. Moreover, repetitive CS caused increased tension in individual cells and cells in a monolayer, which corresponded with increased polymerized actin without changes in myosin IIA and IIB total abundance. Repetitive CS exposure impacts the adhesive intercellular junctions and the tension of epithelial cells by increased actin polymer levels, to further destabilize cell adhesion. Similar changes are seen in epithelial cells from COPD patients indicating that these findings likely contribute to COPD pathology. PMID- 28642264 TI - Reply. PMID- 28642261 TI - Transforming growth factor-beta stimulates Smad1/5 signaling in pulmonary artery smooth muscle cells and fibroblasts of the newborn mouse through ALK1. AB - The intracellular signaling mechanisms through which TGF-beta regulates pulmonary development are incompletely understood. Canonical TGF-beta signaling involves Smad2/3 phosphorylation, Smad2/3.Smad4 complex formation and nuclear localization, and gene regulation. Here, we show that physiologically relevant TGF-beta1 levels also stimulate Smad1/5 phosphorylation, which is typically a mediator of bone morphogenetic protein (BMP) signaling, in mouse pup pulmonary artery smooth muscle cells (mPASMC) and lung fibroblasts and other interstitial lung cell lines. This cross-talk mechanism likely has in vivo relevance because mixed Smad1/5/8.Smad2/3 complexes, which are indicative of TGF-beta-stimulated Smad1/5 activation, were detected in the developing mouse lung using a proximity ligation assay. Although mixed Smad complexes have been shown not to transduce nuclear signaling, we determined that TGF-beta stimulates nuclear localization of phosphorylated Smad1/5 and induces the expression of prototypical BMP-regulated genes in the mPASMC. Small-molecule kinase inhibitor studies suggested that TGF beta-regulated Smad1/5 phosphorylation in these cells is mediated by TGF-beta type I receptors, not BMP-type I receptors, but possibly the accessory activin like kinase (ALK1) receptor. Although work by others suggested that ALK1 is expressed exclusively in endothelial cells in the vasculature, we detected ALK1 mRNA and protein expression in mPASMC in vitro and in mouse pup lungs. Moreover, using an antimurine ALK1 antibody and mPASMC, we determined that ALK1 regulates Smad1/5 phosphorylation by TGF-beta. Together, these studies characterize an accessory TGF-beta-stimulated BMP R-Smad signaling mechanism in interstitial cells of the developing lung. They also indicate the importance of considering alternate Smad pathways in studies directed at determining how TGF-beta regulates newborn lung development. PMID- 28642263 TI - Volumetric Analysis from a Harmonized Multisite Brain MRI Study of a Single Subject with Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: MR imaging can be used to measure structural changes in the brains of individuals with multiple sclerosis and is essential for diagnosis, longitudinal monitoring, and therapy evaluation. The North American Imaging in Multiple Sclerosis Cooperative steering committee developed a uniform high resolution 3T MR imaging protocol relevant to the quantification of cerebral lesions and atrophy and implemented it at 7 sites across the United States. To assess intersite variability in scan data, we imaged a volunteer with relapsing remitting MS with a scan-rescan at each site. MATERIALS AND METHODS: All imaging was acquired on Siemens scanners (4 Skyra, 2 Tim Trio, and 1 Verio). Expert segmentations were manually obtained for T1-hypointense and T2 (FLAIR) hyperintense lesions. Several automated lesion-detection and whole-brain, cortical, and deep gray matter volumetric pipelines were applied. Statistical analyses were conducted to assess variability across sites, as well as systematic biases in the volumetric measurements that were site-related. RESULTS: Systematic biases due to site differences in expert-traced lesion measurements were significant (P < .01 for both T1 and T2 lesion volumes), with site explaining >90% of the variation (range, 13.0-16.4 mL in T1 and 15.9-20.1 mL in T2) in lesion volumes. Site also explained >80% of the variation in most automated volumetric measurements. Output measures clustered according to scanner models, with similar results from the Skyra versus the other 2 units. CONCLUSIONS: Even in multicenter studies with consistent scanner field strength and manufacturer after protocol harmonization, systematic differences can lead to severe biases in volumetric analyses. PMID- 28642265 TI - The Initial Area Under the Curve Derived from Dynamic Contrast-Enhanced MRI Improves Prognosis Prediction in Glioblastoma with Unmethylated MGMT Promoter. AB - BACKGROUND AND PURPOSE: Although perfusion and permeability MR parameters have known to have prognostic value, they have reproducibility issues. Our aim was to evaluate whether the initial area under the time-to-signal intensity curve (IAUC) derived from dynamic contrast-enhanced MR imaging can improve prognosis prediction in patients with glioblastoma with known MGMT status. MATERIALS AND METHODS: We retrospectively examined 88 patients with glioblastoma who underwent preoperative dynamic contrast-enhanced MR imaging. The means of IAUC values at 30 and 60 seconds (IAUC30mean and IAUC60mean) were extracted from enhancing tumors. The prognostic values of IAUC parameters for overall survival and progression free survival were assessed with log-rank tests, according to the MGMT status. Multivariate overall survival and progression-free survival models before and after adding the IAUC parameters as covariates were explored by net reclassification improvement after receiver operating characteristic analysis for 1.5-year overall survival and 1-year progression-free survival and by random survival forest. RESULTS: High IAUC parameters were associated with worse overall survival and progression-free survival in the unmethylated MGMT group, but not in the methylated group. In the unmethylated MGMT group, 1.5-year overall survival and 1-year progression-free survival prediction improved significantly after adding IAUC parameters (overall survival area under the receiver operating characteristic curve, 0.86; progression-free survival area under the receiver operating characteristic curve, 0.74-0.76) to the model with other prognostic factors (overall survival area under the receiver operating characteristic curve, 0.81; progression-free survival area under the receiver operating characteristic curve, 0.69; P < .05 for all) except in the case of IAUC60mean for 1-year progression-free survival prediction (P = .059). Random survival forest models indicated that the IAUC parameters were the second or most important predictors in the unmethylated MGMT group, except in the case of the IAUC60mean for progression-free survival. CONCLUSIONS: IAUC can be a useful prognostic imaging biomarker in patients with glioblastoma with known MGMT status, improving prediction of glioblastoma prognosis with the unmethylated MGMT promoter status. PMID- 28642267 TI - Coregistration and Fusion: An Easy and Reliable Method for Identifying Cranial Nerve IV on MRI. PMID- 28642266 TI - T1 Signal Measurements in Pediatric Brain: Findings after Multiple Exposures to Gadobenate Dimeglumine for Imaging of Nonneurologic Disease. AB - BACKGROUND AND PURPOSE: Signal intensity increases possibly suggestive of gadolinium retention have recently been reported on unenhanced T1-weighted images of the pediatric brain following multiple exposures to gadolinium-based MR contrast agents. Our aim was to determine whether T1 signal changes suggestive of gadolinium deposition occur in the brains of pediatric nonneurologic patients after multiple exposures to gadobenate dimeglumine. MATERIALS AND METHODS: Thirty four nonneurologic patients (group 1; 17 males/17 females; mean age, 7.18 years) who received between 5 and 15 injections (mean, 7.8 injections) of 0.05 mmol/kg of gadobenate during a mean of 2.24 years were compared with 24 control patients (group 2; 16 males/8 females; mean age, 8.78 years) who had never received gadolinium-based contrast agents. Exposure to gadobenate was for diagnosis and therapy monitoring. Five blinded readers independently determined the signal intensity at ROIs in the dentate nucleus, globus pallidus, pons, and thalamus on unenhanced T1-weighted spin-echo images from both groups. Unpaired t tests were used to compare signal-intensity values and dentate nucleus-pons and globus pallidus-thalamus signal-intensity ratios between groups 1 and 2. RESULTS: Mean signal-intensity values in the dentate nucleus, globus pallidus, pons, and thalamus of gadobenate-exposed patients ranged from 366.4 to 389.2, 360.5 to 392.9, 370.5 to 374.9, and 356.9 to 371.0, respectively. Corresponding values in gadolinium-based contrast agent-naive subjects were not significantly different (P > .05). Similarly, no significant differences were noted by any reader for comparisons of the dentate nucleus-pons signal-intensity ratios. One reader noted a difference in the mean globus pallidus-thalamus signal-intensity ratios (1.06 +/- 0.006 versus 1.02 +/- 0.009, P = .002), but this reflected nonsignificantly higher T1 signal in the thalamus of control subjects. The number of exposures and the interval between the first and last exposures did not influence signal intensity values. CONCLUSIONS: Signal-intensity increases potentially indicative of gadolinium deposition are not seen in pediatric nonneurologic patients after multiple exposures to low-dose gadobenate. PMID- 28642262 TI - Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2. AB - Pulmonary arterial stiffness is an independent risk factor for mortality in pulmonary hypertension (PH) and plays a critical role in PH pathophysiology. Our laboratory has recently demonstrated arterial stiffening early in experimental PH, along with evidence for a mechanobiological feedback loop by which arterial stiffening promotes further cellular remodeling behaviors (Liu F, Haeger CM, Dieffenbach PB, Sicard D, Chrobak I, Coronata AM, Suarez Velandia MM, Vitali S, Colas RA, Norris PC, Marinkovic A, Liu X, Ma J, Rose CD, Lee SJ, Comhair SA, Erzurum SC, McDonald JD, Serhan CN, Walsh SR, Tschumperlin DJ, Fredenburgh LE. JCI Insight 1: e86987, 2016). Cyclooxygenase-2 (COX-2) and prostaglandin signaling have been implicated in stiffness-mediated regulation, with prostaglandin activity inversely correlated to matrix stiffness and remodeling behaviors in vitro, as well as to disease progression in rodent PH models. The mechanism by which mechanical signaling translates to reduced COX-2 activity in pulmonary vascular cells is unknown. The present work investigated the transcriptional regulators Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (WWTR1, a.k.a., TAZ), which are known drivers of downstream mechanical signaling, in mediating stiffness-induced changes in COX-2 and prostaglandin activity in pulmonary artery smooth muscle cells (PASMCs). We found that YAP/TAZ activity is increased in PAH PASMCs and experimental PH and is necessary for the development of stiffness-dependent remodeling phenotypes. Knockdown of YAP and TAZ markedly induces COX-2 expression and downstream prostaglandin production by approximately threefold, whereas overexpression of YAP or TAZ reduces COX-2 expression and prostaglandin production to near undetectable levels. Together, our findings demonstrate a stiffness-dependent YAP/TAZ-mediated positive feedback loop that drives remodeling phenotypes in PASMCs via reduced COX-2 and prostaglandin activity. The ability to interrupt this critical mechanobiological feedback loop and enhance local prostaglandin activity via manipulation of YAP/TAZ signaling presents a highly attractive novel strategy for the treatment of PH. PMID- 28642268 TI - Fall in rate of stillbirth drives down perinatal mortality. PMID- 28642269 TI - Discussing human papilloma virus vaccination. PMID- 28642270 TI - Heritable Micro-environmental Variance Covaries with Fitness in an Outbred Population of Drosophila serrata. AB - The genetic basis of stochastic variation within a defined environment, and the consequences of such micro-environmental variance for fitness are poorly understood . Using a multigenerational breeding design in Drosophila serrata, we demonstrated that the micro-environmental variance in a set of morphological wing traits in a randomly mating population had significant additive genetic variance in most single wing traits. Although heritability was generally low (<1%), coefficients of additive genetic variance were of a magnitude typical of other morphological traits, indicating that the micro-environmental variance is an evolvable trait. Multivariate analyses demonstrated that the micro-environmental variance in wings was genetically correlated among single traits, indicating that common mechanisms of environmental buffering exist for this functionally related set of traits. In addition, through the dominance genetic covariance between the major axes of micro-environmental variance and fitness, we demonstrated that micro-environmental variance shares a genetic basis with fitness, and that the pattern of selection is suggestive of variance-reducing selection acting on micro environmental variance. PMID- 28642271 TI - Powerful Genetic Association Analysis for Common or Rare Variants with High Dimensional Structured Traits. AB - Many genetic association studies collect a wide range of complex traits. As these traits may be correlated and share a common genetic mechanism, joint analysis can be statistically more powerful and biologically more meaningful. However, most existing tests for multiple traits cannot be used for high-dimensional and possibly structured traits, such as network-structured transcriptomic pathway expressions. To overcome potential limitations, in this article we propose the dual kernel-based association test (DKAT) for testing the association between multiple traits and multiple genetic variants, both common and rare. In DKAT, two individual kernels are used to describe the phenotypic and genotypic similarity, respectively, between pairwise subjects. Using kernels allows for capturing structure while accommodating dimensionality. Then, the association between traits and genetic variants is summarized by a coefficient which measures the association between two kernel matrices. Finally, DKAT evaluates the hypothesis of nonassociation with an analytical P-value calculation without any computationally expensive resampling procedures. By collapsing information in both traits and genetic variants using kernels, the proposed DKAT is shown to have a correct type-I error rate and higher power than other existing methods in both simulation studies and application to a study of genetic regulation of pathway gene expressions. PMID- 28642273 TI - Authors' reply to Dib. PMID- 28642274 TI - Managing adults with diabetes in hospital during an acute illness. PMID- 28642272 TI - Networks Underpinning Symbiosis Revealed Through Cross-Species eQTL Mapping. AB - Organisms engage in extensive cross-species molecular dialog, yet the underlying molecular actors are known for only a few interactions. Many techniques have been designed to uncover genes involved in signaling between organisms. Typically, these focus on only one of the partners. We developed an expression quantitative trait locus (eQTL) mapping-based approach to identify cause-and-effect relationships between genes from two partners engaged in an interspecific interaction. We demonstrated the approach by assaying expression of 98 isogenic plants (Medicago truncatula), each inoculated with a genetically distinct line of the diploid parasitic nematode Meloidogyne hapla With this design, systematic differences in gene expression across host plants could be mapped to genetic polymorphisms of their infecting parasites. The effects of parasite genotypes on plant gene expression were often substantial, with up to 90-fold (P = 3.2 * 10 52) changes in expression levels caused by individual parasite loci. Mapped loci included a number of pleiotropic sites, including one 87-kb parasite locus that modulated expression of >60 host genes. The 213 host genes identified were substantially enriched for transcription factors. We distilled higher-order connections between polymorphisms and genes from both species via network inference. To replicate our results and test whether effects were conserved across a broader host range, we performed a confirmatory experiment using M. hapla-infected tomato. This revealed that homologous genes were similarly affected. Finally, to validate the broader utility of cross-species eQTL mapping, we applied the strategy to data from a Salmonella infection study, successfully identifying polymorphisms in the human genome affecting bacterial expression. PMID- 28642275 TI - Focus on sharing individual patient data distracts from other ways of improving trial transparency. PMID- 28642276 TI - Dedifferentiation, Proliferation, and Redifferentiation of Adult Mammalian Cardiomyocytes After Ischemic Injury. AB - BACKGROUND: Adult mammalian hearts have a limited ability to generate new cardiomyocytes. Proliferation of existing adult cardiomyocytes (ACMs) is a potential source of new cardiomyocytes. Understanding the fundamental biology of ACM proliferation could be of great clinical significance for treating myocardial infarction (MI). We aim to understand the process and regulation of ACM proliferation and its role in new cardiomyocyte formation of post-MI mouse hearts. METHODS: beta-Actin-green fluorescent protein transgenic mice and fate mapping Myh6-MerCreMer-tdTomato/lacZ mice were used to trace the fate of ACMs. In a coculture system with neonatal rat ventricular myocytes, ACM proliferation was documented with clear evidence of cytokinesis observed with time-lapse imaging. Cardiomyocyte proliferation in the adult mouse post-MI heart was detected by cell cycle markers and 5-ethynyl-2-deoxyuridine incorporation analysis. Echocardiography was used to measure cardiac function, and histology was performed to determine infarction size. RESULTS: In vitro, mononucleated and bi/multinucleated ACMs were able to proliferate at a similar rate (7.0%) in the coculture. Dedifferentiation proceeded ACM proliferation, which was followed by redifferentiation. Redifferentiation was essential to endow the daughter cells with cardiomyocyte contractile function. Intercellular propagation of Ca2+ from contracting neonatal rat ventricular myocytes into ACM daughter cells was required to activate the Ca2+-dependent calcineurin-nuclear factor of activated T cell signaling pathway to induce ACM redifferentiation. The properties of neonatal rat ventricular myocyte Ca2+ transients influenced the rate of ACM redifferentiation. Hypoxia impaired the function of gap junctions by dephosphorylating its component protein connexin 43, the major mediator of intercellular Ca2+ propagation between cardiomyocytes, thereby impairing ACM redifferentiation. In vivo, ACM proliferation was found primarily in the MI border zone. An ischemia-resistant connexin 43 mutant enhanced the redifferentiation of ACM-derived new cardiomyocytes after MI and improved cardiac function. CONCLUSIONS: Mature ACMs can reenter the cell cycle and form new cardiomyocytes through a 3-step process: dedifferentiation, proliferation, and redifferentiation. Intercellular Ca2+ signal from neighboring functioning cardiomyocytes through gap junctions induces the redifferentiation process. This novel mechanism contributes to new cardiomyocyte formation in post-MI hearts in mammals. PMID- 28642278 TI - Rheumatoid arthritis and psoriatic arthritis synovial fluids stimulate prolactin production by macrophages. AB - Prolactin (PRL) is a neuroendocrine hormone that can promote inflammation. We examined the synovial tissue and fluid levels of PRL in patients with inflammatory arthritis, PRL expression in differentiated Mphis from patients with arthritis and from healthy donors, and the effects of different stimuli on PRL production by Mphis. PRL levels were measured in paired synovial fluid (SF) and peripheral blood of patients with rheumatoid arthritis (RA, n = 19), psoriatic arthritis (PsA, n = 11), and gout (n = 11). Synovial-tissue PRL mRNA expression was measured by quantitative PCR in patients with RA (n = 25), PsA (n = 11), and gout (n = 12) and in Mphis differentiated in SF of patients with RA, PsA, other subtypes of spondyloarthritis (SpA), and gout. Synovial-tissue PRL mRNA expression correlated significantly with clinical disease parameters in patients with RA and PsA, including erythrocyte sedimentation rate (ESR, r = 0.424; P = 0.049) and disease activity score evaluated in 28 joints (DAS28, r = 0.729; P = 0.017). Synovial-tissue PRL expression was similar in RA, PsA, and gout. PRL mRNA expression was detected in monocyte-derived Mphis from patients with RA and was significantly higher (P <= 0.01) in Mphis differentiated in pooled SF from patients with RA and PsA compared with SpA or gout. PRL production by Mphi differentiation in the SF from patients with RA was not further regulated by stimulation with CD40L, IgG, LPS, or TNF. PRL is produced locally in the synovium of patients with inflammatory arthritis. The production of PRL by Mphis was increased by unknown components of RA and PsA SF, where it could contribute to disease progression. PMID- 28642277 TI - Adipose tissue macrophages develop from bone marrow-independent progenitors in Xenopus laevis and mouse. AB - ATMs have a metabolic impact in mammals as they contribute to metabolically harmful AT inflammation. The control of the ATM number may have therapeutic potential; however, information on ATM ontogeny is scarce. Whereas it is thought that ATMs develop from circulating monocytes, various tissue-resident Mphis are capable of self-renewal and develop from BM-independent progenitors without a monocyte intermediate. Here, we show that amphibian AT contains self-renewing ATMs that populate the AT before the establishment of BM hematopoiesis. Xenopus ATMs develop from progenitors of aVBI. In the mouse, a significant amount of ATM develops from the yolk sac, the mammalian equivalent of aVBI. In summary, this study provides evidence for a prenatal origin of ATMs and shows that the study of amphibian ATMs can enhance the understanding of the role of the prenatal environment in ATM development. PMID- 28642279 TI - Role of MyD88 signaling in the imiquimod-induced mouse model of psoriasis: focus on innate myeloid cells. AB - Psoriasis is a chronic skin disease associated with deregulated activation of immune cells and keratinocytes. In this study, we used the imiquimod (IMQ) induced mouse model of psoriasis to dissect better the contribution of hematopoietic and skin-resident stromal cells to psoriasis development. The comparison of disease development in mice carrying the hematopoietic cell specific deletion of MyD88 (Myd88fl/flVav-cre+ mice) with mice carrying the total MyD88 deficiency (Myd88-/- mice), we show that the progression of skin and systemic inflammation, as well as of epidermal thickening, was completely dependent on MyD88 expression in hematopoietic cells. However, both Myd88-/- mouse strains developed some degree of epidermal thickening during the initial stages of IMQ-induced psoriasis, even in the absence of hematopoietic cell activation and infiltration into the skin, suggesting a contribution of MyD88 independent mechanisms in skin-resident stromal cells. With the use of conditional knockout mouse strains lacking MyD88 in distinct lineages of myeloid cells (Myd88fl/flLysM-cre+ and Myd88fl/flMRP8-cre+ mice), we report that MyD88 signaling in monocytes and Mphi, but not in neutrophils, plays an important role in disease propagation and exacerbation by modulating their ability to sustain gammadelta T cell effector functions via IL-1beta and IL-23 production. Overall, these findings add new insights into the specific contribution of skin-resident stromal vs. hematopoietic cells to disease initiation and progression in the IMQ induced mouse model of psoriasis and uncover a potential novel pathogenic role for monocytes/Mphi to psoriasis development. PMID- 28642280 TI - Granulocytes as modulators of dendritic cell function. AB - Effector T cell development is directly driven by APCs, in particular, by antigen primed dendritic cells (DCs). Depending on the pathogenic stimulus and the microenvironment, DCs induce proliferation and polarization of naive CD4+ T cells into different effector subsets, such as Th1, Th2, Th17, or regulatory T cells (Tregs). During inflammation, DCs are found in close proximity to other innate immune cells, including all granulocyte subtypes, which potentially influence the immunomodulatory capacities of DCs. Neutrophils, eosinophils, and basophils are rapidly recruited into infected tissues where their main function is to eliminate invading pathogens. Mast cells are tissue-resident granulocytes that also contribute to host defense against pathogens but have, thus far, primarily been associated with their detrimental roles in allergic diseases. Although granulocytes have always been considered essential in innate immunity, their ability to influence the development of adaptive immunity has long been overlooked. This view is now changing, as multiple studies showed significant modulating effects of granulocytes on key players of adaptive immunity, including DCs and lymphocytes. Neutrophils, eosinophils, basophils, and mast cells regulate recruitment and activation of DCs through the release of mediators or via direct cell-cell contact, thereby influencing antigen-specific T cell responses. In this review, we will summarize the current knowledge on the impact of granulocytes on DC functioning and the subsequent putative consequences of this cross-talk on T cell proliferation and polarization. Together, this overview underscores the importance of granulocyte-DC communication to establish optimal immune responses. PMID- 28642284 TI - Excitation of GABAergic Neurons in the Bed Nucleus of the Stria Terminalis Triggers Immediate Transition from Non-Rapid Eye Movement Sleep to Wakefulness in Mice. AB - Emotionally salient situations usually trigger arousal along with autonomic and neuroendocrine reactions. To determine whether the extended amygdala plays a role in sleep-wakefulness regulation, we examined the effects of optogenetic and pharmacogenetic excitation of GABAergic neurons in the bed nucleus of the stria terminalis (GABABNST neurons). Acute optogenetic excitation of these cells during nonrapid eye movement (NREM) sleep resulted in an immediate state transition to wakefulness, whereas stimulation during REM sleep showed no effect on sleep wakefulness states in male mice. An anterograde tracing study suggested GABABNST neurons send axonal projections to several brain regions implicated in arousal, including the preoptic area, lateral hypothalamus, periaqueductal gray, deep mesencephalic nucleus, and parabrachial nucleus. A dual orexin receptor antagonist, DORA-22, did not affect the optogenetic transition from NREM sleep to wakefulness. Chemogenetic excitation of GABABNST neurons evoked a sustained wakefulness state, but this arousal effect was markedly attenuated by DORA-22. These observations suggest that GABABNST neurons play an important role in transition from NREM sleep to wakefulness without the function of orexin neurons, but prolonged excitation of these cells mobilizes the orexin system to sustain wakefulness.SIGNIFICANCE STATEMENT We examined the role of the bed nucleus of the stria terminalis (BNST) in the regulation of wakefulness. Optogenetic excitation of GABAergic neurons in the BNST (GABABNST neurons) during nonrapid eye movement (NREM) sleep in mice resulted in immediate transition to a wakefulness state without function of orexins. Prolonged excitation of GABABNST neurons by a chemogenetic method evoked a longer-lasting, sustained wakefulness state, which was abolished by preadministration of a dual orexin receptor antagonist, DORA-22. This study revealed a role of the BNST GABAergic system in sleep-wakefulness control, especially in shifting animals' behavioral states from NREM sleep to wakefulness, and provides an important insight into the pathophysiology of insomnia and the role of orexin in arousal regulation. PMID- 28642282 TI - Kappa Opioid Receptors Mediate Heterosynaptic Suppression of Hippocampal Inputs in the Rat Ventral Striatum. AB - Kappa opioid receptors (KORs) are highly enriched within the ventral striatum (VS) and are thought to modulate striatal neurotransmission. This includes presynaptic inhibition of local glutamatergic release from excitatory inputs to the VS. However, it is not known which inputs drive this modulation and what impact they have on the local circuit dynamics within the VS. Individual medium spiny neurons (MSNs) within the VS serve as a site of convergence for glutamatergic inputs arising from the PFC and limbic regions, such as the hippocampus (HP). Recent data suggest that competition can arise between these inputs with robust cortical activation leading to a reduction in ongoing HP evoked MSN responses. Here, we investigated the contribution of KOR signaling in PFC-driven heterosynaptic suppression of HP inputs onto MSNs using whole-cell patch-clamp recordings in slices from adult rats. Optogenetically evoked HP EPSPs were greatly attenuated after a short latency (50 ms) following burst-like PFC electrical stimulation, and the magnitude of this suppression was partially reversed following blockade of GABAARs (GABA Type A receptors), but not GABABRs (GABA Type B receptors). A similar reduction in suppression was observed in the presence of the KOR antagonist, norBNI. Combined blockade of local GABAARs and KORs resulted in complete blockade of PFC-induced heterosynaptic suppression of less salient HP inputs. These findings highlight a mechanism by which strong, transient PFC activity can take precedence over other excitatory inputs to the VS.SIGNIFICANCE STATEMENT Emerging evidence suggests that kappa opioid receptor (KOR) activation can selectively modulate striatal glutamatergic inputs onto medium spiny neurons (MSNs). In this study, we found that robust cortical stimulation leads to a reduction in ongoing hippocampal-evoked MSNs responses through the combined recruitment of local inhibitory mechanisms and activation of presynaptic KORs in the ventral striatum (VS). These processes are likely to facilitate the efficient transfer of cortical information through the VS during critical decision making by dampening competing information from less salient excitatory inputs. These data provide a novel mechanism through which VS information processing could influence decision making, a function thought to occur primarily in the PFC. PMID- 28642281 TI - Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary. AB - Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) >=1 characterized alteration(s), excluding variants of unknown significance. TP53 associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cycle machinery [10.4% (46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials. Cancer Res; 77(16); 4238-46. (c)2017 AACR. PMID- 28642283 TI - Selective Inhibition of Trigeminovascular Neurons by Fremanezumab: A Humanized Monoclonal Anti-CGRP Antibody. AB - A large body of evidence supports an important role for calcitonin gene-related peptide (CGRP) in migraine pathophysiology. This evidence gave rise to a global effort to develop a new generation of therapeutics that inhibit the interaction of CGRP with its receptor in migraineurs. Recently, a new class of such drugs, humanized anti-CGRP monoclonal antibodies (CGRP-mAbs), were found to be effective in reducing the frequency of migraine. The purpose of this study was to better understand how the CGRP-mAb fremanezumab (TEV-48125) modulates meningeal sensory pathways. To answer this question, we used single-unit recording to determine the effects of fremanezumab (30 mg/kg, IV) and its isotype control Ab on spontaneous and evoked activity in naive and cortical spreading depression (CSD)-sensitized trigeminovascular neurons in the spinal trigeminal nucleus of anesthetized male and female rats. The study demonstrates that, in both sexes, fremanezumab inhibited naive high-threshold (HT) neurons, but not wide-dynamic range trigeminovascular neurons, and that the inhibitory effects on the neurons were limited to their activation from the intracranial dura but not facial skin or cornea. In addition, when given sufficient time, fremanezumab prevents the activation and sensitization of HT neurons by CSD. Mechanistically, these findings suggest that HT neurons play a critical role in the initiation of the perception of headache and the development of cutaneous allodynia and central sensitization. Clinically, the findings may help to explain the therapeutic benefit of CGRP-mAb in reducing headaches of intracranial origin such as migraine with aura and why this therapeutic approach may not be effective for every migraine patient.SIGNIFICANCE STATEMENT Calcitonin gene-related peptide (CGRP) monoclonal antibodies (CGRP-mAbs) are capable of preventing migraine. However, their mechanism of action is unknown. In the current study, we show that, if given enough time, a CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression, but not their activation from the skin or cornea, suggesting a potential explanation for selectivity to migraine headache, but not other pains, and a predominantly peripheral site of action. PMID- 28642285 TI - State-Dependent TMS Reveals Representation of Affective Body Movements in the Anterior Intraparietal Cortex. AB - In humans, recognition of others' actions involves a cortical network that comprises, among other cortical regions, the posterior superior temporal sulcus (pSTS), where biological motion is coded and the anterior intraparietal sulcus (aIPS), where movement information is elaborated in terms of meaningful goal directed actions. This action observation system (AOS) is thought to encode neutral voluntary actions, and possibly some aspects of affective motor repertoire, but the role of the AOS' areas in processing affective kinematic information has never been examined. Here we investigated whether the AOS plays a role in representing dynamic emotional bodily expressions. In the first experiment, we assessed behavioral adaptation effects of observed affective movements. Participants watched series of happy or fearful whole-body point-light displays (PLDs) as adapters and were then asked to perform an explicit categorization of the emotion expressed in test PLDs. Participants were slower when categorizing any of the two emotions as long as it was congruent with the emotion in the adapter sequence. We interpreted this effect as adaptation to the emotional content of PLDs. In the second experiment, we combined this paradigm with TMS applied over either the right aIPS, pSTS, and the right half of the occipital pole (corresponding to Brodmann's area 17 and serving as control) to examine the neural locus of the adaptation effect. TMS over the aIPS (but not over the other sites) reversed the behavioral cost of adaptation, specifically for fearful contents. This demonstrates that aIPS contains an explicit representation of affective body movements.SIGNIFICANCE STATEMENT In humans, a network of areas, the action observation system, encodes voluntary actions. However, the role of these brain regions in processing affective kinematic information has not been investigated. Here we demonstrate that the aIPS contains a representation of affective body movements. First, in a behavioral experiment, we found an adaptation after-effect for emotional PLDs, indicating the existence of a neural representation selective for affective information in biological motion. To examine the neural locus of this effect, we then combined the adaptation paradigm with TMS. Stimulation of the aIPS (but not over pSTS and control site) reversed the behavioral cost of adaptation, specifically for fearful contents, demonstrating that aIPS contains a representation of affective body movements. PMID- 28642286 TI - Brain regions important for recovery after severe post-stroke upper limb paresis. AB - Background The ability to predict outcome after stroke is clinically important for planning treatment and for stratification in restorative clinical trials. In relation to the upper limbs, the main predictor of outcome is initial severity, with patients who present with mild to moderate impairment regaining about 70% of their initial impairment by 3 months post-stroke. However, in those with severe presentations, this proportional recovery applies in only about half, with the other half experiencing poor recovery. The reasons for this failure to recover are not established although the extent of corticospinal tract damage is suggested to be a contributory factor. In this study, we investigated 30 patients with chronic stroke who had presented with severe upper limb impairment and asked whether it was possible to differentiate those with a subsequent good or poor recovery of the upper limb based solely on a T1-weighted structural brain scan. Methods A support vector machine approach using voxel-wise lesion likelihood values was used to show that it was possible to classify patients as good or poor recoverers with variable accuracy depending on which brain regions were used to perform the classification. Results While considering damage within a corticospinal tract mask resulted in 73% classification accuracy, using other (non-corticospinal tract) motor areas provided 87% accuracy, and combining both resulted in 90% accuracy. Conclusion This proof of concept approach highlights the relative importance of different anatomical structures in supporting post stroke upper limb motor recovery and points towards methodologies that might be used to stratify patients in future restorative clinical trials. PMID- 28642287 TI - Genetic screening in sporadic ALS and FTD. AB - The increasing complexity of the genetic landscape in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) presents a significant resource and physician training challenge. At least 10% of those diagnosed with ALS or FTD are known to carry an autosomal dominant genetic mutation. There is no consensus on what constitutes a positive family history, and ascertainment is unreliable for many reasons. However, symptomatic individuals often wish to understand as much as possible about the cause of their disease, and to share this knowledge with their family. While the right of an individual not to know is a key aspect of patient autonomy, and despite the absence of definitive therapy, many newly diagnosed individuals are likely to elect for genetic testing if offered. It is incumbent on the practitioner to ensure that they are adequately informed, counselled and supported in this decision. PMID- 28642289 TI - Age-related reduction of myocardial metabolic efficiency: Is it time to routinely measure myocardial metabolism to monitor cardiac health? PMID- 28642288 TI - Ferumoxytol-enhanced magnetic resonance imaging assessing inflammation after myocardial infarction. AB - OBJECTIVES: Macrophages play a central role in the cellular inflammatory response to myocardial infarction (MI) and predict subsequent clinical outcomes. We aimed to assess temporal changes in cellular inflammation and tissue oedema in patients with acute MI using ultrasmallsuperparamagnetic particles of iron oxide (USPIO) enhanced MRI. METHODS: Thirty-one patients were recruited following acute MI and followed up for 3 months with repeated T2 and USPIO-enhanced T2*-mapping MRI. Regions of interest were categorised into infarct, peri-infarct and remote myocardial zones, and compared with control tissues. RESULTS: Following a single dose, USPIO enhancement was detected in the myocardium until 24 hours (p<0.0001). Histology confirmed colocalisation of iron and macrophages within the infarcted, but not the non-infarcted, myocardium. Following repeated doses, USPIO uptake in the infarct zone peaked at days 2-3, and greater USPIO uptake was detected in the infarct zone compared with remote myocardium until days 10-16 (p<0.05). In contrast, T2-defined myocardial oedema peaked at days 3-9 and remained increased in the infarct zone throughout the 3-month follow-up period (p<0.01). CONCLUSION: Myocardial macrophage activity can be detected using USPIO-enhanced MRI in the first 2 weeks following acute MI. This observed pattern of cellular inflammation is distinct, and provides complementary information to the more prolonged myocardial oedema detectable using T2 mapping. This imaging technique holds promise as a non-invasive method of assessing and monitoring myocardial cellular inflammation with potential application to diagnosis, risk stratification and assessment of novel anti-inflammatory therapeutic interventions. TRIAL REGISTRATION NUMBER: Trial registration number: 14663. Registered on UK Clinical Research Network (http://public.ukcrn.org.uk) and also ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02319278?term=DECIFER&rank=2). PMID- 28642291 TI - Elderly patients with non-ST-elevation acute coronary syndromes: a call for action. PMID- 28642290 TI - Coronary events complicating infective endocarditis. AB - OBJECTIVE: Acute coronary syndromes (ACS) are a rare complication of infective endocarditis (IE). Only case reports and small studies have been published to date. We report the largest series of ACS in IE. The aim of our study was to describe the incidence and mechanisms of ACS associated with IE, to assess their prognostic impact and to describe their management. METHODS: In a bicentre prospective observational cohort study, all patients with a definite diagnosis of IE were prospectively included. The incidence, mechanism and prognosis of patients with ACS were studied. RESULTS: Among 1210 consecutive patients with definite IE, 26 patients (2.2%) developed an ACS. Twenty-three patients (88%) had a coronary embolism. Two patients had coronary compression by an abscess or a pseudoaneurysm and one patient had an obstruction of his bioprosthesis and left coronary ostium by a large vegetation. Nineteen (73%) patients with ACS developed heart failure and this complication was 2.5 times more frequent than in patients without ACS (p<0.0001). In the ACS population, mortality rate was twice than the population without ACS. CONCLUSIONS: ACS is a rare complication of IE but is associated with an increased risk of heart failure and high mortality rate. PMID- 28642292 TI - Frequency and magnitude of intermittent hypoxia modulate endothelial wound healing in a cell culture model of sleep apnea. AB - Intermittent hypoxia (IH) has been implicated in the cardiovascular consequences of obstructive sleep apnea (OSA). However, the lack of suitable experimental systems has precluded assessment as to whether IH is detrimental, protective, or both for the endothelium. The aim of the work was to determine the effects of frequency and amplitude of IH oxygenation swings on aortic endothelial wound healing. Monolayers of human primary endothelial cells were wounded and subjected to constant oxygenation (1%, 4%, 13%, or 20% O2) or IH at different frequencies (0.6, 6, or 60 cycles/h) and magnitude ranges (13-4% O2 or 20-1% O2), using a novel well-controlled system, with wound healing being measured after 24 h. Cell monolayer repair was similar at 20% O2 and 13% O2, but was considerably increased (approximately twofold) in constant hypoxia at 4% O2 The magnitude and frequency of IH considerably modulated wound healing. Cycles ranging 13-4% O2 at the lowest frequency (0.6 cycles/h) accelerated endothelial wound healing by 102%. However, for IH exposures consisting of 20% to 1% O2 oscillations, wound closure was reduced compared with oscillation in the 13-4% range (by 74% and 44% at 6 cycles/h and 0.6 cycles/h, respectively). High-frequency IH patterns simulating severe OSA (60 cycles/h) did not significantly modify endothelial wound closure, regardless of the oxygenation cycle amplitude. In conclusion, the frequency and magnitude of hypoxia cycling in IH markedly alter wound healing responses and emerge as key factors determining how cells will respond in OSA.NEW & NOTEWORTHY Intermittent hypoxia (IH) induces cardiovascular consequences in obstructive sleep apnea (OSA) patients. However, the vast array of frequencies and severities of IH previously employed in OSA-related experimental studies has led to controversial results on the effects of IH. By employing an optimized IH experimental system here, we provide evidence that the frequency and magnitude of IH markedly alter human aortic endothelial wound healing, emerging as key factors determining how cells respond in OSA. PMID- 28642293 TI - Random squat/stand maneuvers: a novel approach for assessment of dynamic cerebral autoregulation? AB - Squat/stand maneuvers (SSM) have been used to assess dynamic cerebral autoregulation (dCA), but always at a fixed frequency (FF). This study aimed to assess the use of random-frequency (RF) SSMs as a stimulus for measuring dCA and determine the reproducibility of FF and RFSSMs. Twenty-nine healthy volunteers [19 male, mean age 23.0 (4.9) yr] completed the study; 11 returned for a repeat visit (median 45 days). Heart rate, beat-to-beat blood pressure, middle cerebral artery (MCA) blood flow velocity, end-tidal CO2, and angle of the squat movement were measured. Subjects underwent four recordings: 5 min sitting, 5 min standing, FFSSMs (0.05Hz), and RFSSMs. Subjects were asked to rate the degree of exertion experienced while performing these maneuvers. Twenty-nine subjects completed the protocol; nine data sets were deemed unsuitable for further analysis. Mean ARI of 6.21 (1.04) while standing was significantly greater than during the SSMs (P < 0.01), with mean (SD) ARI during the FF and RFSSMs being 5.16 (1.43) and 5.37 (1.21), respectively. However, no significant difference was found between the ARI estimates from the two SSMs (P = 0.856) or for each of the four recordings between the two visits (P = 0.645). RFSSMs were found to be significantly less tiring than FFSSMs (P < 0.01). In conclusion, RFSSMs are an effective and noninvasive method of assessing dCA. There is no difference in the ARI estimates in comparison with FFSSMs. Although FFSSMs have been well tolerated previously, RFSSMs are preferred by healthy subjects and thus may be better tolerated by a patient population in a clinical setting.NEW & NOTEWORTHY RFSSMs provided comparable estimates of autoregulatory indices to FFSSMs. Instead of point estimates at the driven frequency, RFSSMs generate a broader power spectrum of changes in arterial blood pressure and cerebral blood flow velocity, allowing direct comparison with spontaneous fluctuations through transfer function analysis. Moreover, random-frequency SSMs are preferred by participants. They are a novel tool by which larger blood pressure oscillations can be elicited for the reliable measurement of dynamic cerebral autoregulation. PMID- 28642296 TI - An unusual appearance on cranial computed tomography. PMID- 28642294 TI - Depletion of MHC class II invariant chain peptide or gamma-delta T-cells ameliorates experimental preeclampsia. AB - Excessive innate immune system activation and inflammation during pregnancy can lead to organ injury and dysfunction and preeclampsia (PE); however, the molecular mechanisms involved are unknown. We tested the hypothesis that Toll like receptor (TLR) activation induces major histocompatibility complex (MHC) class II invariant chain peptide (CLIP) expression on immune cells, makes them pro-inflammatory, and are necessary to cause PE-like features in mice. Treatment with VG1177, a competitive antagonist peptide for CLIP in the groove of MHC class II, was able to both prevent and treat PE-like features in mice. We then determined that gamma-delta T cells are critical for the development of PE-like features in mice since gamma-delta T-cell knockout mice, like CLIP deficient mice, are resistant to developing PE-like features. Placentas from women with PE exhibit significantly increased levels of gamma-delta T cells. These preclinical data demonstrate that CLIP expression and activated gamma-delta T cells are responsible for the development of immunologic PE-like features and that temporarily antagonizing CLIP and/or gamma-delta T cells may be a therapeutic strategy for PE. PMID- 28642298 TI - Does acid-base equilibrium correlate with remnant liver volume during stepwise liver resection? AB - Small for size and flow syndrome (SFSF) is one of the most challenging complications following extended hepatectomy (EH). After EH, hepatic artery flow decreases and portal vein flow increases per 100 g of remnant liver volume (RLV). This causes hypoxia followed by metabolic acidosis. A correlation between acidosis and posthepatectomy liver failure has been postulated but not studied systematically in a large animal model or clinical setting. In our study, we performed stepwise liver resections on nine pigs to defined SFSF limits as follows: step 1: segment II/III resection, step 2: segment IV resection, step 3: segment V/VIII resection (RLV: 75, 50, and 25%, respectively). Blood gas values were measured before and after each step using four catheters inserted into the carotid artery, internal jugular vein, hepatic artery, and portal vein. The pH, [Formula: see text], and base excess (BE) decreased, but [Formula: see text] values increased after 75% resection in the portal and jugular veins. EH correlated with reduced BE in the hepatic artery. Pco2 values increased after 75% resection in the jugular vein. In contrast, arterial Po2 increased after every resection, whereas the venous Po2 decreased slightly. There were differences in venous [Formula: see text], BE in the hepatic artery, and Pco2 in the jugular vein after 75% liver resection. Because 75% resection is the limit for SFSF, these noninvasive blood evaluations may be used to predict SFSF. Further studies with long-term follow-up are required to validate this correlation.NEW & NOTEWORTHY This is the first study to evaluate acid-base parameters in major central and hepatic vessels during stepwise liver resection. The pH, [Formula: see text], and base excess (BE) decreased, but [Formula: see text] values increased after 75% resection in the portal and jugular veins. Extended hepatectomy correlated with reduced BE in the hepatic artery. Because 75% resection is the limit for small for size and flow syndrome (SFSF), postresection blood gas evaluations may be used to predict SFSF. PMID- 28642299 TI - Dysfunctional neutrophil effector organelle mobilization and microbicidal protein release in alcohol-related cirrhosis. AB - Patients with alcohol-related cirrhosis (ALD) are prone to infection. Circulating neutrophils in ALD are dysfunctional and predict development of sepsis, organ dysfunction, and survival. Neutrophil granules are important effector organelles containing a toxic array of microbicidal proteins, whose controlled release is required to kill microorganisms while minimizing inflammation and damage to host tissue. We investigated the role of these granular responses in contributing to immune disarray in ALD. Neutrophil granular content and mobilization were measured by flow cytometric quantitation of cell-surface/intracellular markers, [secretory vesicles (CD11b), secondary granules (CD66b), and primary granules (CD63; myeloperoxidase)] before and after bacterial stimulation in 29 patients with ALD cirrhosis (15 abstinent; 14 actively drinking) compared with healthy controls (HC). ImageStream Flow Cytometry characterized localization of granule subsets within the intracellular and cell-surface compartments. The plasma cytokine environment was analyzed using ELISA/cytokine bead array. Circulating neutrophils were primed in the resting state with upregulated surface expression of CD11b (P = 0.0001) in a cytokine milieu rich in IL-8 (P < 0.001) and lactoferrin (P = 0.035). Neutrophils showed exaggerated mobilization to the cell surface of primary granules at baseline (P = 0.001) and in response to N-formyl-l methionyl-l-leucyl-l-phenylalanine (P = 0.009) and Escherichia coli (P = 0.0003) in ALD. There was no deficit in granule content or mobilization to the cell membrane in any granule subset observed. Paradoxically, active alcohol consumption abrogated the hyperresponsive neutrophil granular responses compared with their abstinent counterparts. Neutrophils are preprimed at baseline with augmented effector organelle mobilization in response to bacterial stimulation; neutrophil degranulation is not a mechanism leading to innate immunoparesis in ALD.NEW & NOTEWORTHY Neutrophil granule release is dysregulated in patients with alcohol-related cirrhosis (ALD) with augmented effector organelle mobilization and microbiocidal protein release. Neutrophil granules are upregulated in ALD at baseline and demonstrate augmented responses to bacterial challenge. The granular responses in ALD did not contribute to the observed functional deficit in innate immunity but rather were dysregulated and hyperresponsive, which may induce bystander damage to host tissue. Paradoxically, active alcohol consumption abrogated the excessive neutrophil granular responses to bacterial stimulus compared with their abstinent counterparts. PMID- 28642301 TI - The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. PMID- 28642300 TI - Center-level variation in accuracy of adverse event reporting in a clinical trial for pediatric acute myeloid leukemia: a report from the Children's Oncology Group. PMID- 28642302 TI - Residual erythropoiesis protects against myocardial hemosiderosis in transfusion dependent thalassemia by lowering labile plasma iron via transient generation of apotransferrin. AB - Cardiosiderosis is a leading cause of mortality in transfusion-dependent thalassemias. Plasma non-transferrin-bound iron and its redox-active component, labile plasma iron, are key sources of iron loading in cardiosiderosis. Risk factors were identified in 73 patients with or without cardiosiderosis. Soluble transferrin receptor-1 levels were significantly lower in patients with cardiosiderosis (odds ratio 21). This risk increased when transfusion-iron loading rates exceeded the erythroid transferrin uptake rate (derived from soluble transferrin receptor-1) by >0.21 mg/kg/day (odds ratio 48). Labile plasma iron was >3-fold higher when this uptake rate threshold was exceeded, but non transferrin-bound iron and transferrin saturation were comparable. The risk of cardiosiderosis was decreased in patients with low liver iron, ferritin and labile plasma iron, or high bilirubin, reticulocyte counts or hepcidin. We hypothesized that high erythroid transferrin uptake rate decreases cardiosiderosis through increased erythroid re-generation of apotransferrin. To test this, iron uptake and intracellular reactive oxygen species were examined in HL-1 cardiomyocytes under conditions modeling transferrin effects on non transferrin-bound iron speciation with ferric citrate. Intracellular iron and reactive oxygen species increased with ferric citrate concentrations especially when iron-to-citrate ratios exceeded 1:100, i.e. conditions favoring kinetically labile monoferric rather than oligomer species. Excess iron-binding equivalents of apotransferrin inhibited iron uptake and decreased both intracellular reactive oxygen species and labile plasma iron under conditions favoring monoferric species. In conclusion, high transferrin iron utilization, relative to the transfusion-iron load rate, decreases the risk of cardiosiderosis. A putative mechanism is the transient re-generation of apotransferrin by an active erythron, rapidly binding labile plasma iron-detectable ferric monocitrate species. PMID- 28642304 TI - "Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort." Dominick E. Shaw, Ana R. Sousa, Stephen J. Fowler, Louise J. Fleming, Graham Roberts, Julie Corfield, Ioannis Pandis, Aruna T. Bansal, Elisabeth H. Bel, Charles Auffray, Chris H. Compton, Hans Bisgaard, Enrica Bucchioni, Massimo Caruso, Pascal Chanez, Barbro Dahlen, Sven-Erik Dahlen, Kerry Dyson, Urs Frey, Thomas Geiser, Maria Gerhardsson de Verdier, David Gibeon, Yi-ke Guo, Simone Hashimoto, Gunilla Hedlin, Elizabeth Jeyasingham, Pieter-Paul W. Hekking, Tim Higenbottam, Ildiko Horvath, Alan J. Knox, Norbert Krug, Veit J. Erpenbeck, Lars X. Larsson, Nikos Lazarinis, John G. Matthews, Roelinde Middelveld, Paolo Montuschi, Jacek Musial, David Myles, Laurie Pahus, Thomas Sandstrom, Wolfgang Seibold, Florian Singer, Karin Strandberg, Jorgen Vestbo, Nadja Vissing, Christophe von Garnier, Ian M. Adcock, Scott Wagers, Anthony Rowe, Peter Howarth, Ariane H. Wagener, Ratko Djukanovic, Peter J. Sterk and Kian Fan Chung on behalf of the U-BIOPRED Study Group. Eur Respir J 2015; 46: 1308-1321. PMID- 28642303 TI - Molecular analysis of myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5 reveals a specific spectrum of molecular mutations with prognostic impact: a study on 123 patients and 27 genes. AB - The only cytogenetic aberration defining a myelodysplastic syndrome subtype is the deletion of the long arm of chromosome 5, which, along with morphological features, leads to the diagnosis of myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5. These patients show a good prognosis and respond to treatment such as lenalidomide, but some cases progress to acute myeloid leukemia; however, the molecular mutation pattern is rarely characterized. Therefore, we investigated a large cohort of 123 myelodysplastic syndrome patients with isolated deletion of the long arm of chromosome 5, diagnosed following the World Health Organization classifications 2008 and 2016, by sequencing 27 genes. A great proportion of patients showed no or only one mutation. Only seven genes showed mutation frequencies >5% (SF3B1, DNMT3A, TP53, TET2, CSNK1A1, ASXL1, JAK2). However, the pattern of recurrently mutated genes was comparable to other myelodysplastic syndrome subtypes by comparison to a reference cohort, except that of TP53 which was significantly more often mutated in myelodysplastic syndrome with isolated deletion of the long arm of chromosome 5. As expected, SF3B1 was frequently mutated and correlated with ring sider oblasts, while JAK2 mutations correlated with elevated platelet counts. Surprisingly, SF3B1 mutations led to significantly worse prognosis within cases with isolated deletion of the long arm of chromosome 5, but showed a comparable outcome to other myelodysplastic syndrome subtypes with SF3B1 mutation. However, addressing genetic stability in follow-up cases might suggest different genetic mechanisms for progression to secondary acute myeloid leukemia compared to overall myelodysplastic syndrome patients. PMID- 28642305 TI - "The burden of severe asthma in childhood and adolescence: results from the paediatric U-BIOPRED cohorts." Louise Fleming, Clare Murray, Aruna T. Bansal, Simone Hashimoto, Hans Bisgaard, Andrew Bush, Urs Frey, Gunilla Hedlin, Florian Singer, Wim M. van Aalderen, Nadja H. Vissing, Zaraquiza Zolkipli, Anna Selby, Stephen Fowler, Dominick Shaw, Kian Fan Chung, Ana R. Sousa, Scott Wagers, Julie Corfield, Ioannis Pandis, Anthony Rowe, Elena Formaggio, Peter J. Sterk and Graham Roberts on behalf of the U-BIOPRED Study Group. Eur Respir J 2015; 46: 1322-1333. PMID- 28642306 TI - "Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary." Claus F. Vogelmeier, Gerard J. Criner, Fernando J. Martinez, Antonio Anzueto, Peter J. Barnes, Jean Bourbeau, Bartolome R. Celli, Rongchang Chen, Marc Decramer, Leonardo M. Fabbri, Peter Frith, David M.G. Halpin, M. Victorina Lopez Varela, Masaharu Nishimura, Nicolas Roche, Roberto Rodriguez-Roisin, Don D. Sin, Dave Singh, Robert Stockley, Jorgen Vestbo, Jadwiga A. Wedzicha and Alvar Agusti. Eur Respir J 2017; 49: 1700214. PMID- 28642307 TI - Urban green and grey space in relation to respiratory health in children. AB - We assessed the effect of three different indices of urban built environment on allergic and respiratory conditions.This study involved 2472 children participating in the ongoing INMA birth cohort located in two bio-geographic regions (Euro-Siberian and Mediterranean) in Spain. Residential surrounding built environment was characterised as 1) residential surrounding greenness based on satellite-derived normalised difference vegetation index (NDVI), 2) residential proximity to green spaces and 3) residential surrounding greyness based on urban land use patterns. Information on wheezing, bronchitis, asthma and allergic rhinitis up to age 4 years was obtained from parent-completed questionnaires. Logistic regression and generalised estimating equation modelling were performed.Among children from the Euro-Siberian region, higher residential surrounding greenness and higher proximity to green spaces were negatively associated with wheezing. In the Mediterranean region, higher residential proximity to green spaces was associated with a reduced risk for bronchitis. A higher amount of residential surrounding greyness was found to increase the risk for bronchitis in this region.Associations between indices of urban residential greenness and greyness with respiratory diseases differ by region. The pathways underlying these associations require further exploration. PMID- 28642308 TI - Predicting risk of undiagnosed COPD: development and validation of the TargetCOPD score. AB - Chronic obstructive pulmonary disease (COPD) is greatly underdiagnosed worldwide and more efficient methods of case-finding are required. We developed and externally validated a risk score to identify undiagnosed COPD using primary care records.We conducted a retrospective cohort analysis of a pragmatic cluster randomised controlled case-finding trial in the West Midlands, UK. Participants aged 40-79 years with no prior diagnosis of COPD received a postal or opportunistic screening questionnaire. Those reporting chronic respiratory symptoms were assessed with spirometry. COPD was defined as presence of relevant symptoms with a post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal. A risk score was developed using logistic regression with variables available from electronic health records for 2398 participants who returned a postal questionnaire. This was externally validated among 1097 participants who returned an opportunistic questionnaire to derive the c-statistic, and the sensitivity and specificity of cut-points.A risk score containing age, smoking status, dyspnoea, prescriptions of salbutamol and prescriptions of antibiotics discriminated between patients with and without undiagnosed COPD (c-statistic 0.74, 95% CI 0.68-0.80). A cut-point of >=7.5% predicted risk had a sensitivity of 68.8% (95% CI 57.3-78.9%) and a specificity of 68.8% (95% CI 65.8.1-71.6%).A novel risk score using routine data from primary care electronic health records can identify patients at high risk for undiagnosed symptomatic COPD. This score could be integrated with clinical information systems to help primary care clinicians target patients for case-finding. PMID- 28642309 TI - Long-term volume-targeted pressure-controlled ventilation: sense or nonsense? AB - The technology underlying the development of novel ventilatory modes for long term noninvasive ventilation of patients with chronic hypercapnia is continuously evolving. Volume-targeted pressure-controlled ventilation is a hybrid ventilation mode designed to combine the advantages of conventional ventilation modes, while avoiding their drawbacks. However, manufacturers have created different names and have patented algorithms and set-up variables, which can result in confusion for physicians and respiratory therapists. In addition, clear evidence for the superiority of this novel mode has not yet been established. These factors have most likely hindered more widespread use of this mode in clinical practice. The current review presents the rationale, working principles, characteristics and set-up recommendations associated with volume-targeted modes. In addition, it summarises the clinical and laboratory studies that have challenged this mode. PMID- 28642311 TI - Run-in bias in randomised trials: the case of COPD medications. PMID- 28642312 TI - The Finnish Allergy Programme 2008-2018 works. PMID- 28642310 TI - Metabolomics analysis identifies sex-associated metabotypes of oxidative stress and the autotaxin-lysoPA axis in COPD. AB - Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and a leading cause of mortality and morbidity worldwide. The aim of this study was to investigate the sex dependency of circulating metabolic profiles in COPD.Serum from healthy never-smokers (healthy), smokers with normal lung function (smokers), and smokers with COPD (COPD; Global Initiative for Chronic Obstructive Lung Disease stages I-II/A-B) from the Karolinska COSMIC cohort (n=116) was analysed using our nontargeted liquid chromatography-high resolution mass spectrometry metabolomics platform.Pathway analyses revealed that several altered metabolites are involved in oxidative stress. Supervised multivariate modelling showed significant classification of smokers from COPD (p=2.8*10-7). Sex stratification indicated that the separation was driven by females (p=2.4*10-7) relative to males (p=4.0*10-4). Significantly altered metabolites were confirmed quantitatively using targeted metabolomics. Multivariate modelling of targeted metabolomics data confirmed enhanced metabolic dysregulation in females with COPD (p=3.0*10-3) relative to males (p=0.10). The autotaxin products lysoPA (16:0) and lysoPA (18:2) correlated with lung function (forced expiratory volume in 1 s) in males with COPD (r=0.86; p<0.0001), but not females (r=0.44; p=0.15), potentially related to observed dysregulation of the miR-29 family in the lung.These findings highlight the role of oxidative stress in COPD, and suggest that sex-enhanced dysregulation in oxidative stress, and potentially the autotaxin-lysoPA axis, are associated with disease mechanisms and/or prevalence. PMID- 28642313 TI - Prescription opioid use in advanced COPD: benefits, perils and controversies. PMID- 28642314 TI - Green living environment protects against allergy, or does it? PMID- 28642315 TI - Aclidinium bromide improves symptoms and sleep quality in COPD: a pilot study. PMID- 28642316 TI - Predictors of long-term smoking cessation in patients with COPD: results from a randomised controlled trial. PMID- 28642320 TI - Meet the First Authors. PMID- 28642317 TI - Prescription opioid use in advanced COPD: benefits, perils and controversies. PMID- 28642321 TI - Macrophage Heterogeneity Complicates Reversal of Calcification in Cardiovascular Tissues. PMID- 28642322 TI - Plaque Erosion: New Insights From the Road Less Travelled. PMID- 28642323 TI - Immune Modulation of Cardiac Arrhythmias. PMID- 28642324 TI - Direct Stimulation of Cardiogenesis: A New Paradigm for Treating Heart Disease. PMID- 28642326 TI - Correction to: It's 10 pm; Do You Know Where Your Data Are? Data Provenance, Curation, and Storage. PMID- 28642325 TI - Impact of VA Research on Health Care for All: Contributions Over Nine Decades and Counting. PMID- 28642327 TI - Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis. AB - Angiogenesis is disrupted in age-related and postmenopausal osteoporosis. However, the mechanisms of the disorder remain elusive. We confirmed in this study that, in accordance with the decrease of H-type vessels, the proangiogenic potential of bone marrow-derived mesenchymal stem cells (BMSCs) declined during osteoporosis. Screening of the histone acetyltransferase family revealed that GCN5 decreased in BMSCs derived from osteoporotic femur. Further analysis identified that GCN5 plays important roles in regulating the proangiogenic potential of BMSCs. GCN5 promoted BMSC-mediated angiogenesis by enhancing H3K9ac levels on the promoter of Vegf The decrease of GCN5 in osteoporotic BMSCs led to the decline of proangiogenic capacity. Accordingly, overexpression of GCN5 enhanced the proangiogenic potency of osteoporotic BMSCs. Furthermore, recovering GCN5 expression in vivo by lentiviral expression vector significantly attenuated the loss of angiogenesis in ovariectomized mouse femurs. Our study results revealed an epigenetic mechanism controlling BMSC-mediated angiogenesis and provided a novel therapeutic target for osteoporosis treatment.-Jing, H., Liao, L., Su, X., Shuai, Y. Zhang, X., Deng, Z., Jin, Y. Declining histone acetyltransferase GCN5 represses BMSC-mediated angiogenesis during osteoporosis. PMID- 28642328 TI - Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. AB - In response to myocardial infarction (MI), time-dependent leukocyte infiltration is critical to program the acute inflammatory response. Post-MI leukocyte density, residence time in the infarcted area, and exit from the infarcted injury predict resolving or nonresolving inflammation. Overactive or unresolved inflammation is the primary determinant in heart failure pathology post-MI. Here, our review describes supporting evidence that the acute inflammatory response also guides the generation of healing and regenerative mediators after cardiac damage. Time-dependent leukocyte density and diversity and the magnitude of myocardial injury is responsible for the resolving and nonresolving pathway in myocardial healing. Post MI, the diversity of leukocytes, such as neutrophils, macrophages, and lymphocytes, has been explored that regulate the clearance of deceased cardiomyocytes by using the classic and reparative pathways. Among the innovative factors and intermediates that have been recognized as essential in acute the self-healing and clearance mechanism, we highlight specialized proresolving mediators as the emerging factor for post-MI reparative mechanisms translational leukocyte modifiers, such as aging, the source of leukocytes, and the milieu around the leukocytes. In the clinical setting, it is possible that leukocyte diversity is more prominent as a result of risk factors, such as obesity, diabetes, and hypertension. Pharmacologic agents are critical modifiers of leukocyte diversity in healing mechanisms that may impair or stimulate the clearance mechanism. Future research is needed, with a focused approach to understand the molecular targets, cellular effectors, and receptors. A clear understanding of resolving and nonresolving inflammation in myocardial healing will help to develop novel targets with major emphasis on the resolution of inflammation in heart failure pathology.-Tourki, B., Halade, G. Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. PMID- 28642331 TI - Diagnosis and risk stratification of Barrett's dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue. AB - OBJECTIVE: The diagnosis of dysplasia in Barrett's oesophagus (BO) can be challenging, and reliable ancillary techniques are not available. This study examines if DNA content abnormality detected by flow cytometry can serve as a diagnostic marker of dysplasia and facilitate risk stratification of low-grade dysplasia (LGD) and indefinite for dysplasia (IND) patients using formalin-fixed paraffin-embedded (FFPE) BO samples with varying degrees of dysplasia. DESIGN: DNA flow cytometry was performed on 80 FFPE BO samples with high-grade dysplasia (HGD), 38 LGD, 21 IND and 14 negative for dysplasia (ND). Three to four 60-micron thick sections were cut from each tissue block, and the area of interest was manually dissected. RESULTS: DNA content abnormality was identified in 76 HGD (95%), 8 LGD (21.1%), 2 IND (9.5%) and 0 ND samples. As a diagnostic marker of HGD, the estimated sensitivity and specificity of DNA content abnormality were 95% and 85%, respectively. For patients with DNA content abnormality detected at baseline LGD or IND, the univariate HRs for subsequent detection of HGD or oesophageal adenocarcinoma (OAC) were 7.0 and 20.0, respectively (p =<0.001). CONCLUSIONS: This study demonstrates the promise of DNA flow cytometry using FFPE tissue in the diagnosis and risk stratification of dysplasia in BO. The presence of DNA content abnormality correlates with increasing levels of dysplasia, as 95% of HGD samples showed DNA content abnormality. DNA flow cytometry also identifies a subset of patients with LGD and IND who are at higher risk for subsequent detection of HGD or OAC. PMID- 28642330 TI - Effects of Intensive BP Control in CKD. AB - The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n=1330) or <140 mm Hg (standard group; n=1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD (P values for interactions >=0.30). The prespecified main kidney outcome, defined as the composite of >=50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (-0.47 versus -0.32 ml/min per 1.73 m2 per year; P<0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome. PMID- 28642329 TI - Experimental and Computational Insight Into Human Mesenchymal Stem Cell Paracrine Signaling and Heterocellular Coupling Effects on Cardiac Contractility and Arrhythmogenicity. AB - RATIONALE: Myocardial delivery of human mesenchymal stem cells (hMSCs) is an emerging therapy for treating the failing heart. However, the relative effects of hMSC-mediated heterocellular coupling (HC) and paracrine signaling (PS) on human cardiac contractility and arrhythmogenicity remain unresolved. OBJECTIVE: The objective is to better understand hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity by integrating experimental and computational approaches. METHODS AND RESULTS: Extending our previous hMSC-cardiomyocyte HC computational model, we incorporated experimentally calibrated hMSC PS effects on cardiomyocyte L-type calcium channel/sarcoendoplasmic reticulum calcium-ATPase activity and cardiac tissue fibrosis. Excitation-contraction simulations of hMSC PS-only and combined HC+PS effects on human cardiomyocytes were representative of human engineered cardiac tissue (hECT) contractile function measurements under matched experimental treatments. Model simulations and hECTs both demonstrated that hMSC-mediated effects were most pronounced under PS-only conditions, where developed force increased ~4-fold compared with non-hMSC-supplemented controls during physiological 1-Hz pacing. Simulations predicted contractility of isolated healthy and ischemic adult human cardiomyocytes would be minimally sensitive to hMSC HC, driven primarily by PS. Dominance of hMSC PS was also revealed in simulations of fibrotic cardiac tissue, where hMSC PS protected from potential proarrhythmic effects of HC at various levels of engraftment. Finally, to study the nature of the hMSC paracrine effects on contractility, proteomic analysis of hECT/hMSC conditioned media predicted activation of PI3K/Akt signaling, a recognized target of both soluble and exosomal fractions of the hMSC secretome. Treating hECTs with exosome-enriched, but not exosome-depleted, fractions of the hMSC secretome recapitulated the effects observed with hMSC conditioned media on hECT-developed force and expression of calcium-handling genes (eg, SERCA2a, L type calcium channel). CONCLUSIONS: Collectively, this integrated experimental and computational study helps unravel relative hMSC PS and HC effects on human cardiac contractility and arrhythmogenicity, and provides novel insight into the role of exosomes in hMSC paracrine-mediated effects on contractility. PMID- 28642332 TI - Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. AB - BACKGROUND: Opioids such as morphine are widely used for the management of pain associated with acute pancreatitis. Interestingly, opioids are also known to affect the immune system and modulate inflammatory pathways in non-pancreatic diseases. However, the impact of morphine on the progression of acute pancreatitis has never been evaluated. In the current study, we evaluated the impact of morphine on the progression and severity of acute pancreatitis. METHODS: Effect of morphine treatment on acute pancreatitis in caerulein, L arginine and ethanol-palmitoleic acid models was evaluated after induction of the disease. Inflammatory response, gut permeability and bacterial translocation were compared. Experiments were repeated in mu (u) opioid receptor knockout mice (MORKO) and in wild-type mice in the presence of opioid receptor antagonist naltrexone to evaluate the role of u-opioid receptors in morphine's effect on acute pancreatitis. Effect of morphine treatment on pathways activated during pancreatic regeneration like sonic Hedgehog and activation of embryonic transcription factors like pdx-1 and ptf-1 were measured by immunofluorescence and quantitative PCR. RESULTS: Histological data show that treatment with morphine after induction of acute pancreatitis exacerbates the disease with increased pancreatic neutrophilic infiltration and necrosis in all three models of acute pancreatitis. Morphine also exacerbated acute pancreatitis-induced gut permeabilisation and bacteraemia. These effects were antagonised in the MORKO mice or in the presence of naltrexone suggesting that morphine's effect on severity of acute pancreatitis are mediated through the u-opioid receptors. Morphine treatment delayed macrophage infiltration, sonic Hedgehog pathway activation and expression of pdx-1 and ptf-1. CONCLUSION: Morphine treatment worsens the severity of acute pancreatitis and delays resolution and regeneration. Considering our results, the safety of morphine for analgesia during acute pancreatitis should be re-evaluated in future human studies. PMID- 28642333 TI - Patients' and providers' perceptions of the preventability of hospital readmission: a prospective, observational study in four European countries. AB - OBJECTIVES: Because of fundamental differences in healthcare systems, US readmission data cannot be extrapolated to the European setting: To investigate the opinions of readmitted patients, their carers, nurses and physicians on predictability and preventability of readmissions and using majority consensus to determine contributing factors that could potentially foresee (preventable) readmissions. DESIGN: Prospective observational study. Readmitted patients, their carers, and treating professionals were surveyed during readmission to assess the discharge process and the predictability and preventability of the readmission. Cohen's Kappa measured pairwise agreement of considering readmission as predictable/preventable by patients, carers and professionals. Subsequently, multivariable logistic regressionidentified factors associated with predictability/preventability. SETTING: 15 hospitals in four European countries PARTICIPANTS: 1398 medical patients readmitted unscheduled within 30 days MAIN OUTCOMES AND MEASURES: (1) Agreement between the interviewed groups on considering readmissions likely predictable or preventable;(2) Factors distinguishing predictable from non-predictable and preventable from non preventable readmissions. RESULTS: The majority deemed 27.8% readmissions potentially predictable and 14.4% potentially preventable. The consensus on predictability and preventability was poor, especially between patients and professionals (kappas ranged from 0.105 to 0.173). The interviewed selected different factors as potentially associated with predictability and preventability. When a patient reported that he was ready for discharge during index admission, the readmission was deemed less likely by the majority (predictability: OR 0.55; 95% CI 0.40 to 0.75; preventability: OR 0.35; 95% CI 0.24 to 0.49). CONCLUSIONS: There is no consensus between readmitted patients, their carers and treating professionals about predictability and preventability of readmissions, nor associated risk factors. A readmitted patient reporting not feeling ready for discharge at index admission was strongly associated with preventability/predictability. Therefore, healthcare workers should question patients' readiness to go home timely before discharge. PMID- 28642334 TI - ALK Fusion Detection in Circulating Free DNA: Finding an Important Needle in the Haystack. PMID- 28642335 TI - Carcinoid Syndrome and Costs of Care During the First Year After Diagnosis of Neuroendocrine Tumors Among Elderly Patients. AB - BACKGROUND: Neuroendocrine tumors (NETs) can secrete hormonal peptides that lead to additional symptom burdens. However, it is largely unknown whether and to what extent the additional symptom burdens translate into higher costs of care. This study aimed to examine the cost pattern of elderly NET patients during the first year of diagnosis, taking into account of the carcinoid syndrome status. METHODS: We used Surveillance, Epidemiology, and End Results Medicare data to identify elderly NET patients diagnosed between January 2003 and December 2011. Patients who had at least two claims indicative of carcinoid syndrome during the 3 months before and after the NET diagnosis were considered to have carcinoid syndrome. We adopted a payer's perspective and quantified economic outcomes using the following three measures: (a) total Medicare reimbursement amount, (b) inpatient amount, and (c) outpatient amount. We used a generalized linear model (GLM) to examine the association between syndrome and costs. RESULTS: Our study cohort included 6,749 elderly NET well-differentiated and moderately differentiated patients. Of these patients, 5,633 (83%) were alive 1 year after diagnosis with continuous enrollment, and 1,116 (17%) died within 1 year. The multivariable GLM showed significant association between the syndrome and higher total, inpatient, and outpatient costs among the group who survived the whole year; the association was insignificant among the group who died within the first year of diagnosis. CONCLUSION: This population-based study showed that NET patients with carcinoid syndrome incurred higher costs of care especially among those who survived the first year of diagnosis. IMPLICATIONS FOR PRACTICE: This is the first population based study that examines the health care costs associated with carcinoid syndrome among neuroendocrine tumor patients. Among patients alive throughout the first year, the unadjusted analyses showed that total median monthly costs were above $1,000 higher ($3,801 vs. $2,481) for patients with carcinoid syndrome compared with patients without. A significant association was found between carcinoid syndrome and higher total inpatient and outpatient costs among the group that survived the whole year even after controlling for clinical factors, treatment received, and demographics and neighborhood socioeconomic status; the association was insignificant among the group that died within the first year of diagnosis. PMID- 28642337 TI - Is all ALS genetic? PMID- 28642336 TI - The evolving genetic risk for sporadic ALS. AB - OBJECTIVE: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. METHODS: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. RESULTS: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. CONCLUSIONS: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates. PMID- 28642338 TI - Cellular distribution and function of ion channels involved in transport processes in rat tracheal epithelium. AB - Transport of water and electrolytes in airway epithelia involves chloride selective ion channels, which are controlled either by cytosolic Ca2+ or by cAMP The contributions of the two pathways to chloride transport differ among vertebrate species. Because rats are becoming more important as animal model for cystic fibrosis, we have examined how Ca2+- dependent and cAMP- dependent Cl- secretion is organized in the rat tracheal epithelium. We examined the expression of the Ca2+-gated Cl- channel anoctamin 1 (ANO1), the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel, the epithelial Na+ channel ENaC, and the water channel aquaporin 5 (AQP5) in rat tracheal epithelium. The contribution of ANO1 channels to nucleotide-stimulated Cl- secretion was determined using the channel blocker Ani9 in short-circuit current recordings obtained from primary cultures of rat tracheal epithelial cells in Ussing chambers. We found that ANO1, CFTR and AQP5 proteins were expressed in nonciliated cells of the tracheal epithelium, whereas ENaC was expressed in ciliated cells. Among nonciliated cells, ANO1 occurred together with CFTR and Muc5b and, in addition, in a different cell type without CFTR and Muc5b. Bioelectrical studies with the ANO1-blocker Ani9 indicated that ANO1 mediated the secretory response to the nucleotide uridine-5'-triphosphate. Our data demonstrate that, in rat tracheal epithelium, Cl- secretion and Na+ absorption are routed through different cell types, and that ANO1 channels form the molecular basis of Ca2+-dependent Cl- secretion in this tissue. These characteristic features of Cl--dependent secretion reveal similarities and distinct differences to secretory processes in human airways. PMID- 28642339 TI - Establishment of a novel three-dimensional primary culture model for hippocampal neurogenesis. AB - New neurons are generated in the adult hippocampus throughout life and contribute to the functions of learning and memory. Nevertheless, the mechanisms by which disrupted neurogenesis regulates central nervous system (CNS) disorders are not fully understood. Here, we established a novel 3D culture system of hippocampal neurogenesis using air liquid interface (ALI) culture and Matrigel culture from mouse hippocampus tissues. After isolated mouse hippocampus tissue fragments were seeded into ALI wells and cultured in stemness-stimulated media containing Wnt, EGF, Noggin and R-spondin for 7 days, small spheres gradually appeared in the tissues. To identify the cell components, immunohistochemical and immunofluorescence staining were performed. Expression of a mature neuronal cell marker, NeuN was observed in the tissues just after seeding. Expression of a neural stem cell marker, Nestin was observed in the tissues at day 7. To differentiate the Nestin-positive cells, they were passaged into Matrigel. Expression of Nestin but not an immature neuronal cell marker, doublecortin (DCX) was observed in the isolated cells. After 7 days of Matrigel culture, they showed the neurite outgrowth. Expression of Nestin was decreased compared with the one just after passaging, while DCX expression was increased. Western blotting analysis also showed Nestin expression was decreased, while expression of DCX, a neuronal cell marker, Tuj1 and a granule cell marker, Prox-1 was increased. Here, we establish the 3D culture of hippocampus tissues that might become a novel in vitro tool for monitoring the process of hippocampal neurogenesis. Our model might shed light into the mechanisms of pathogenesis of CNS disorders. PMID- 28642340 TI - Cardiovascular and cerebral hemodynamics during exercise and recovery in obese individuals as a function of their fitness status. AB - The aim of this study was to compare cardiovascular hemodynamics and cerebral oxygenation/perfusion (COP) during and after maximal incremental exercise in obese individuals according to their aerobic fitness versus age-matched healthy controls (AMHC). Fifty-four middle-aged obese (OB) and 16 AMHC were recruited. Maximal cardiopulmonary function (gas exchange analysis), cardiac hemodynamics (impedance cardiography), and left frontal COP (near-infrared spectroscopy: NIRS) were measured continuously during a maximal incremental ergocycle test. During recovery, reoxygenation/perfusion rate (ROPR: oxyhemoglobin: DeltaO2Hb, deoxyhemoglobin: DeltaHHb and total hemoglobin: DeltatHb; with NIRS) was also measured. Obese participants (OB, n = 54) were divided into two groups according to the median VO2 peak: the low-fit obese (LF-OB, n = 27) and the high-fit obese (HF-OB, n = 27). During exercise, end tidal pressure of CO2 (PETCO2), and COP (DeltaO2Hb, DeltaHHb and DeltatHb) did not differ between groups (OB, LF-OB, HF OB, AMHC). During recovery, PETCO2 and ROPR (DeltaO2Hb, DeltaHHb and DeltatHb) were similar between the groups (OB, LF-OB, HF-OB, AMHC). During exercise and recovery, cardiac index was lower (P < 0.05) in LF-OB versus the other two groups (HF-OB, AMHC). As well, systolic blood pressure was higher during exercise in the OB, LF-OB and HF-OB groups versus AMHC (P < 0.05). When compared to AMHC, obese individuals (OB, LF-OB, HF-OB) have a similar cerebral vasoreactivity by CO2 and cerebral hemodynamics during exercise and recovery, but a higher systolic blood pressure during exercise. Higher fitness in obese subjects (HF-OB) seems to preserve their cardiopulmonary and cardiac function during exercise and recovery. PMID- 28642341 TI - Use of intraoperative local field potential spectral analysis to differentiate basal ganglia structures in Parkinson's disease patients. AB - Identification of brain structures traversed during implantation of deep brain stimulating (DBS) electrodes into the subthalamic nucleus (STN-DBS) for the treatment of Parkinson's disease (PD) frequently relies on subjective correspondence between kinesthetic response and multiunit activity. However, recent work suggests that local field potentials (LFP) could be used as a more robust signal to objectively differentiate subcortical structures. The goal of this study was to analyze the spectral properties of LFP collected during STN-DBS in order to objectively identify commonly traversed brain regions and improve our understanding of aberrant oscillations in the PD-related pathophysiological cortico-basal ganglia network. In 21 PD patients, LFP were collected and analyzed during STN-DBS implantation surgery. Spectral power for delta-, theta-, alpha-, low-beta-, and high-beta-frequency bands was assessed at multiple depths throughout the subcortical structures traversed on the trajectory to the ventral border of STN. Similar to previous findings, beta-band oscillations had an increased magnitude within the borders of the motor-related area of STN, however, across several subjects, we also observed increased high-beta magnitude within the borders of thalamus. Comparing across all patients using relative power, we observed a gradual increase in the magnitude of both low- and high-beta-frequency bands as the electrode descended from striatum to STN. These results were also compared with frequency bands below beta, and similar trends were observed. Our results suggest that LFP signals recorded during the implantation of a DBS electrode evince distinct oscillatory signatures that distinguish subcortical structures. PMID- 28642342 TI - Survival of contagious ovine digital dermatitis (CODD)-associated treponemes on disposable gloves after handling CODD-affected feet. PMID- 28642343 TI - Differential distribution of vapA-positive Rhodococcus equi in affected and unaffected horse-breeding farms. PMID- 28642344 TI - A role for TET2 in parathyroid carcinoma. AB - Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5 methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene. PMID- 28642346 TI - Detergent-induced self-assembly and controllable photosensitizer activity of diester phenylene ethynylenes. AB - Photodynamic therapy, in which malignant tissue is killed by targeted light exposure following administration of a photosensitizer, can be a valuable treatment modality but currently relies on passive transport and local irradiation to avoid off-target oxidation. We present a system of excited-state control for truly local delivery of singlet oxygen. An anionic phenylene ethynylene oligomer is initially quenched by water, producing minimal fluorescence and no measurable singlet oxygen generation. When presented with a binding partner, in this case an oppositely charged surfactant, changes in solvent microenvironment result in fluorescence unquenching, restoration of intersystem crossing to the triplet state, and singlet oxygen generation, as assayed by transient absorption spectroscopy and chemical trapping. This solvation-controlled photosensitizer model has possible applications as a theranostic agent for, for example, amyloid diseases. PMID- 28642345 TI - Evolution of nonspectral rhodopsin function at high altitudes. AB - High-altitude environments present a range of biochemical and physiological challenges for organisms through decreases in oxygen, pressure, and temperature relative to lowland habitats. Protein-level adaptations to hypoxic high-altitude conditions have been identified in multiple terrestrial endotherms; however, comparable adaptations in aquatic ectotherms, such as fishes, have not been as extensively characterized. In enzyme proteins, cold adaptation is attained through functional trade-offs between stability and activity, often mediated by substitutions outside the active site. Little is known whether signaling proteins [e.g., G protein-coupled receptors (GPCRs)] exhibit natural variation in response to cold temperatures. Rhodopsin (RH1), the temperature-sensitive visual pigment mediating dim-light vision, offers an opportunity to enhance our understanding of thermal adaptation in a model GPCR. Here, we investigate the evolution of rhodopsin function in an Andean mountain catfish system spanning a range of elevations. Using molecular evolutionary analyses and site-directed mutagenesis experiments, we provide evidence for cold adaptation in RH1. We find that unique amino acid substitutions occur at sites under positive selection in high-altitude catfishes, located at opposite ends of the RH1 intramolecular hydrogen-bonding network. Natural high-altitude variants introduced into these sites via mutagenesis have limited effects on spectral tuning, yet decrease the stability of dark-state and light-activated rhodopsin, accelerating the decay of ligand bound forms. As found in cold-adapted enzymes, this phenotype likely compensates for a cold-induced decrease in kinetic rates-properties of rhodopsin that mediate rod sensitivity and visual performance. Our results support a role for natural variation in enhancing the performance of GPCRs in response to cold temperatures. PMID- 28642347 TI - Counteracting dysfunction of regulatory T cells in organ transplantation. PMID- 28642350 TI - Utility of AIMS65 score in predicting mortality in patients presenting with upper gastrointestinal bleeding. PMID- 28642348 TI - Confined in-fiber solidification and structural control of silicon and silicon germanium microparticles. AB - Crystallization of microdroplets of molten alloys could, in principle, present a number of possible morphological outcomes, depending on the symmetry of the propagating solidification front and its velocity, such as axial or spherically symmetric species segregation. However, because of thermal or constitutional supercooling, resulting droplets often only display dendritic morphologies. Here we report on the crystallization of alloyed droplets of controlled micrometer dimensions comprising silicon and germanium, leading to a number of surprising outcomes. We first produce an array of silicon-germanium particles embedded in silica, through capillary breakup of an alloy-core silica-cladding fiber. Heating and subsequent controlled cooling of individual particles with a two-wavelength laser setup allows us to realize two different morphologies, the first being a silicon-germanium compositionally segregated Janus particle oriented with respect to the illumination axis and the second being a sphere made of dendrites of germanium in silicon. Gigapascal-level compressive stresses are measured within pure silicon solidified in silica as a direct consequence of volume-constrained solidification of a material undergoing anomalous expansion. The ability to generate microspheres with controlled morphology and unusual stresses could pave the way toward advanced integrated in-fiber electronic or optoelectronic devices. PMID- 28642351 TI - Is psychiatry becoming more coercive? PMID- 28642352 TI - Management of Brain Arteriovenous Malformations: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. AB - PURPOSE: The aim of this statement is to review the current data and to make suggestions for the diagnosis and management of both ruptured and unruptured brain arteriovenous malformations. METHODS: The writing group met in person and by teleconference to establish search terms and to discuss narrative text and suggestions. Authors performed their own literature searches of PubMed, Medline, or Embase, specific to their allocated section, through the end of January 2015. Prerelease review of the draft statement was performed by expert peer reviewers and by the members of the Stroke Council Scientific Oversight Committee and Stroke Council Leadership Committee. RESULTS: The focus of the scientific statement was subdivided into epidemiology; diagnosis; natural history; treatment, including the roles of surgery, stereotactic radiosurgery, and embolization; and management of ruptured and unruptured brain arteriovenous malformations. Areas requiring more evidence were identified. CONCLUSIONS: Brain arteriovenous malformations are a relatively uncommon but important cause of hemorrhagic stroke, especially in young adults. This statement describes the current knowledge of the natural history and treatment of patients with ruptured and unruptured brain arteriovenous malformations, suggestions for management, and implications for future research. PMID- 28642354 TI - Looking up for AML in Down syndrome. PMID- 28642353 TI - When 'Sanctity of Life' and 'Self-Determination' clash: Briggs versus Briggs [2016] EWCOP 53 - implications for policy and practice. AB - In a landmark judgment in the English Court of Protection, the judge (Charles J) found it to be in the best interests of a minimally conscious patient for clinically assisted nutrition and hydration (CANH) to be withdrawn, with the inevitable consequence that the patient would die. In making this judgment, it was accepted that the patient's level of consciousness - if CANH were continued and rehabilitation provided - might improve, and that he might become capable of expressing emotions and making simple choices. The decision to withdraw treatment relied on a best interests decision, which gave great weight to the patient's past wishes, feelings, values and beliefs, and brought a 'holistic' approach to understanding what this particular patient would have wanted. We draw on our own experience of supporting families, advocating for patients and training healthcare professionals in similar situations to consider the implications of the published judgment for policy and practice with patients in prolonged disorders of consciousness and their families. PMID- 28642355 TI - Down syndrome and AML: where do we go from here? PMID- 28642356 TI - Equal opportunity CAR T cells. PMID- 28642357 TI - Human megakaryocytes: finding the root. PMID- 28642358 TI - EPCR: a novel marker of cultured cord blood HSCs. PMID- 28642359 TI - Activated kinases in ALL: time to act. PMID- 28642360 TI - Now I cuss less about ICUS. PMID- 28642361 TI - Acute monoblastic leukemia presenting with striking periorbital and periauricular infiltration. PMID- 28642362 TI - Regulation of RhoA by STAT3 coordinates glial scar formation. AB - Understanding how the transcription factor signal transducer and activator of transcription-3 (STAT3) controls glial scar formation may have important clinical implications. We show that astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation. Moreover, we report that STAT3 inhibits the small GTPase RhoA and thereby controls actomyosin tonus, adhesion turnover, and migration of reactive astrocytes, as well as corralling of leukocytes in vitro. The inhibition of RhoA by STAT3 involves ezrin, the phosphorylation of which is reduced in STAT3-CKO astrocytes. Reduction of phosphatase and tensin homologue (PTEN) levels in STAT3-CKO rescues reactive astrocytes dynamics in vitro. By specific targeting of lesion-proximal, reactive astrocytes in Nestin-Cre mice, we show that reduction of PTEN rescues glial scar formation in Nestin-Stat3+/- mice. These findings reveal novel intracellular signaling mechanisms underlying the contribution of reactive astrocyte dynamics to glial scar formation. PMID- 28642363 TI - Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage. AB - The endoribonuclease Dicer is a key component of the human RNA interference pathway and is known for its role in cytoplasmic microRNA production. Recent findings suggest that noncanonical Dicer generates small noncoding RNA to mediate the DNA damage response (DDR). Here, we show that human Dicer is phosphorylated in the platform-Piwi/Argonaute/Zwille-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks. We further demonstrate that turnover of damage-induced nuclear, double-stranded (ds) RNA requires additional phosphorylation of carboxy-terminal Dicer residues (S1728 and S1852). DNA damage induced nuclear Dicer accumulation is conserved in mammals. Dicer depletion causes endogenous DNA damage and delays the DDR by impaired recruitment of repair factors MDC1 and 53BP1. Collectively, we place Dicer within the context of the DDR by demonstrating a DNA damage-inducible phosphoswitch that causes localized processing of nuclear dsRNA by p-Dicer to promote DNA repair. PMID- 28642364 TI - The Accuracy and Bias of Single-Step Genomic Prediction for Populations Under Selection. AB - In single-step analyses, missing genotypes are explicitly or implicitly imputed, and this requires centering the observed genotypes using the means of the unselected founders. If genotypes are only available for selected individuals, centering on the unselected founder mean is not straightforward. Here, computer simulation is used to study an alternative analysis that does not require centering genotypes but fits the mean [Formula: see text] of unselected individuals as a fixed effect. Starting with observed diplotypes from 721 cattle, a five-generation population was simulated with sire selection to produce 40,000 individuals with phenotypes, of which the 1000 sires had genotypes. The next generation of 8000 genotyped individuals was used for validation. Evaluations were undertaken with (J) or without (N) [Formula: see text] when marker covariates were not centered; and with (JC) or without (C) [Formula: see text] when all observed and imputed marker covariates were centered. Centering did not influence accuracy of genomic prediction, but fitting [Formula: see text] did. Accuracies were improved when the panel comprised only quantitative trait loci (QTL); models JC and J had accuracies of 99.4%, whereas models C and N had accuracies of 90.2%. When only markers were in the panel, the 4 models had accuracies of 80.4%. In panels that included QTL, fitting [Formula: see text] in the model improved accuracy, but had little impact when the panel contained only markers. In populations undergoing selection, fitting [Formula: see text] in the model is recommended to avoid bias and reduction in prediction accuracy due to selection. PMID- 28642365 TI - Phenotypic Diagnosis of Lineage and Differentiation During Sake Yeast Breeding. AB - Sake yeast was developed exclusively in Japan. Its diversification during breeding remains largely uncharacterized. To evaluate the breeding processes of the sake lineage, we thoroughly investigated the phenotypes and differentiation of 27 sake yeast strains using high-dimensional, single-cell, morphological phenotyping. Although the genetic diversity of the sake yeast lineage is relatively low, its morphological diversity has expanded substantially compared to that of the Saccharomycescerevisiae species as a whole. Evaluation of the different types of breeding processes showed that the generation of hybrids (crossbreeding) has more profound effects on cell morphology than the isolation of mutants (mutation breeding). Analysis of phenotypic robustness revealed that some sake yeast strains are more morphologically heterogeneous, possibly due to impairment of cellular network hubs. This study provides a new perspective for studying yeast breeding genetics and micro-organism breeding strategies. PMID- 28642366 TI - Saccharomyces cerevisiae Red1 protein exhibits nonhomologous DNA end-joining activity and potentiates Hop1-promoted pairing of double-stranded DNA. AB - Elucidation of the function of synaptonemal complex (SC) in Saccharomyces cerevisiae has mainly focused on in vivo analysis of recombination-defective meiotic mutants. Consequently, significant gaps remain in the mechanistic understanding of the activities of various SC proteins and the functional relationships among them. S. cerevisiae Hop1 and Red1 are essential structural components of the SC axial/lateral elements. Previous studies have demonstrated that Hop1 is a structure-selective DNA-binding protein exhibiting high affinity for the Holliday junction and promoting DNA bridging, condensation, and pairing between double-stranded DNA molecules. However, the exact mode of action of Red1 remains unclear, although it is known to interact with Hop1 and to suppress the spore viability defects of hop1 mutant alleles. Here, we report the purification and functional characterization of the full-length Red1 protein. Our results revealed that Red1 forms a stable complex with Hop1 in vitro and provided quantitative insights into their physical interactions. Mechanistically, Red1 preferentially associated with the Holliday junction and 3-way junction rather than with single- or double-stranded DNA with overhangs. Although Hop1 and Red1 exhibited similar binding affinities toward several DNA substrates, the two proteins displayed some significant differences. Notably, Red1, by itself, lacked DNA-pairing ability; however, it potentiated Hop1-promoted intermolecular pairing between double-stranded DNA molecules. Moreover, Red1 exhibited nonhomologous DNA end-joining activity, thus revealing an unexpected role for Red1 in recombination based DNA repair. Collectively, this study presents the first direct insights into Red1's mode of action and into the mechanism underlying its role in chromosome synapsis and recombination. PMID- 28642367 TI - The activities of the C-terminal regions of the formin protein disheveled associated activator of morphogenesis (DAAM) in actin dynamics. AB - Disheveled-associated activator of morphogenesis (DAAM) is a diaphanous-related formin protein essential for the regulation of actin cytoskeleton dynamics in diverse biological processes. The conserved formin homology 1 and 2 (FH1-FH2) domains of DAAM catalyze actin nucleation and processively mediate filament elongation. These activities are indirectly regulated by the N- and C-terminal regions flanking the FH1-FH2 domains. Recently, the C-terminal diaphanous autoregulatory domain (DAD) and the C terminus (CT) of formins have also been shown to regulate actin assembly by directly interacting with actin. Here, to better understand the biological activities of DAAM, we studied the role of DAD CT regions of Drosophila DAAM in its interaction with actin with in vitro biochemical and in vivo genetic approaches. We found that the DAD-CT region binds actin in vitro and that its main actin-binding element is the CT region, which does not influence actin dynamics on its own. However, we also found that it can tune the nucleating activity and the filament end-interaction properties of DAAM in an FH2 domain-dependent manner. We also demonstrate that DAD-CT makes the FH2 domain more efficient in antagonizing with capping protein. Consistently, in vivo data suggested that the CT region contributes to DAAM-mediated filopodia formation and dynamics in primary neurons. In conclusion, our results demonstrate that the CT region of DAAM plays an important role in actin assembly regulation in a biological context. PMID- 28642368 TI - The influence of disulfide bonds on the mechanical stability of proteins is context dependent. AB - Disulfide bonds play a crucial role in proteins, modulating their stability and constraining their conformational dynamics. A particularly important case is that of proteins that need to withstand forces arising from their normal biological function and that are often disulfide bonded. However, the influence of disulfides on the overall mechanical stability of proteins is poorly understood. Here, we used single-molecule force spectroscopy (smFS) to study the role of disulfide bonds in different mechanical proteins in terms of their unfolding forces. For this purpose, we chose the pilus protein FimG from Gram-negative bacteria and a disulfide-bonded variant of the I91 human cardiac titin polyprotein. Our results show that disulfide bonds can alter the mechanical stability of proteins in different ways depending on the properties of the system. Specifically, disulfide-bonded FimG undergoes a 30% increase in its mechanical stability compared with its reduced counterpart, whereas the unfolding force of I91 domains experiences a decrease of 15% relative to the WT form. Using a coarse-grained simulation model, we rationalized that the increase in mechanical stability of FimG is due to a shift in the mechanical unfolding pathway. The simple topology-based explanation suggests a neutral effect in the case of titin. In summary, our results indicate that disulfide bonds in proteins act in a context-dependent manner rather than simply as mechanical lockers, underscoring the importance of considering disulfide bonds both computationally and experimentally when studying the mechanical properties of proteins. PMID- 28642369 TI - Replisome-mediated translesion synthesis by a cellular replicase. AB - Genome integrity relies on the ability of the replisome to navigate ubiquitous DNA damage during DNA replication. The Escherichia coli replisome transiently stalls at leading-strand template lesions and can either reinitiate replication downstream of the lesion or recruit specialized DNA polymerases that can bypass the lesion via translesion synthesis. Previous results had suggested that the E. coli replicase might play a role in lesion bypass, but this possibility has not been tested in reconstituted DNA replication systems. We report here that the DNA polymerase III holoenzyme in a stalled E. coli replisome can directly bypass a single cyclobutane pyrimidine dimer or abasic site by translesion synthesis in the absence of specialized translesion synthesis polymerases. Bypass efficiency was proportional to deoxynucleotide concentrations equivalent to those found in vivo and was dependent on the frequency of primer synthesis downstream of the lesion. Translesion synthesis came at the expense of lesion-skipping replication restart. Replication of a cyclobutane pyrimidine dimer was accurate, whereas replication of an abasic site resulted in mainly -1 frameshifts. Lesion bypass was accompanied by an increase in base substitution frequency for the base preceding the lesion. These findings suggest that DNA damage at the replication fork can be replicated directly by the replisome without the need to activate error-prone pathways. PMID- 28642370 TI - In vitro cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds. AB - Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. In vitro experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by l-glutamate (l-Glu), l-aspartate, gamma-aminobutyric acid, and acetylcholine, with l-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation. We also found that l-Glu and other activating neurotransmitters bind to the same site on the CYP46A1 surface, which differs from the EFV-binding site. The other principal differences between EFV and l-Glu in CYP46A1 activation include an apparent lack of l-Glu binding to the P450 active site and different pathways of signal transduction from the allosteric site to the active site. EFV and l-Glu similarly increased the CYP46A1 kcat, the rate of the "fast" phase of the enzyme reduction by the redox partner NADPH cytochrome P450 oxidoreductase, and the amount of P450 reduced. Spectral titrations with cholesterol, in the presence of EFV or l-Glu, suggest that water displacement from the heme iron can be affected in activator-bound CYP46A1. Moreover, EFV and l-Glu synergistically activated CYP46A1. Collectively, our in vitro data, along with those from previous cell culture and in vivo studies by others, suggest that l-Glu-induced CYP46A1 activation is of physiological relevance. PMID- 28642372 TI - The Highland Health Advocates: a preliminary evaluation of a novel programme addressing the social needs of emergency department patients. AB - OBJECTIVES: Patients commonly come to the emergency department (ED) with social needs. To address this, we created the Highland Health Advocates (HHA), an ED based help desk and medical-legal partnership using undergraduate volunteers to help patients navigate public resources and provide onsite legal and social work referrals. We were able to provide these services in English and Spanish. We aimed to determine the social needs of the patients who presented to our ED and the potential impact of the programme in resolving those needs and connecting them to a 'medical home' (defined as a consistent, primary source of medical care such as a primary care doctor or clinic). METHODS: ED patients at a US safety net hospital were enrolled in a 1:2 ratio in a quasi-experiment comparing those who received intervention from the HHA during a limited access rollout with controls who received usual care on days with no help desk. We collected a baseline social needs evaluation, with follow-up assessments at 1 and 6 months. Primary outcomes were linkages for the primary identified need and to a medical home within 1 month. Other outcomes at 6 months included whether a patient (1) felt helped; 2) had a decreased number of ED visits; (3) had the primary identified need met; (4) had a primary doctor; and (5) had a change in self-reported health status. RESULTS: We enrolled 459 subjects (intervention=154, control=305). Housing (41%), employment (23%) and inability to pay bills (22%) were participants' top identified needs. At baseline, 32% reported the ED as their medical home, with the intervention cohort having higher ED utilisation (>1 ED visit in the prior month: 49% vs 24%). At 1 month, 185 (40%) subjects were reached for follow-up, with more HHA subjects linked to a resource (59% vs 37%) and a medical home (92% vs 76%). At 6 months, 75% of subjects felt HHA was helpful and more subjects in the HHA group had a doctor (93% v 69%). No difference was found in ED utilisation, primary need resolution or self-reported health status. CONCLUSIONS: Health-related social needs are common in this US safety net ED. Our help desk is one possible model for addressing social needs. PMID- 28642373 TI - Failure of falls risk screening tools to predict outcome: a prospective cohort study. AB - OBJECTIVE: To compare the Falls Risk for Older Persons-Community Setting Screening Tool (FROP Com Screen) with the Two-Item Screening Tool in older adults presenting to the ED. METHODS: A prospective cohort study, comparing the efficacy of the two falls risk assessment tools by applying them simultaneously in a sample of hospital ED presentations. RESULTS: Two hundred and one patients over 65 years old were recruited. Thirty-six per cent reported falls in the 6-month follow-up period. The area under the receiver operating characteristic curve was 0.57 (95% CI 0.48 to 0.66) for the FROP Com Screen and 0.54 (95% CI 0.45 to 0.63) for the Two-Item Screening Tool. FROP Com Screen had a sensitivity of 39% (95% CI 0.27 to 0.51) and a specificity of 70% (95% CI 0.61 to 0.78), while the Two-Item Screening Tool had a sensitivity of 48% (95% CI 0.36 to 0.60) and a specificity of 57% (95% CI 0.47 to 0.66). CONCLUSION: Both tools have limited predictive ability in the ED setting. PMID- 28642374 TI - Behavioral Patterns in Adolescents Born at 23 to 25 Weeks of Gestation. AB - BACKGROUND: This study examined mental health outcomes in extremely preterm children (EPT) born at 23 to 25 weeks of gestation between 1992 and 1998 at 2 Swedish tertiary care centers that offered regional and active perinatal care to all live-born EPT infants. METHODS: We assessed 132 (98%) of the 134 EPT survivors at 10 to 15 years of age alongside term-born controls. Behavioral and emotional problems were evaluated by using Achenbach's Child Behavior Checklist and Teacher Report Form and Conners' Parent and Teacher scales for attention deficit/hyperactivity disorder. RESULTS: Parents and teachers reported significantly more problems with internalizing behaviors as well as attention, social, and thought problems in EPT children than in controls, even when those with major neurodevelopmental disabilities (NDDs) were excluded. Multivariate analysis of covariance of the behavioral problems reported by parents and teachers revealed no interactions, but significant main effects emerged for group status (EPT versus control) and sex, with all effect sizes being medium to large and accounting for 8% to 14% of the variance. Compared with the controls, EPT children without NDDs had significantly increased rates of >=90th percentile for total Conners' attention-deficit/hyperactivity disorder problem scores (parents: 40% vs 15%, odds ratio: 3.7, P < .001) (teachers: 24% vs 9%, odds ratio: 3.3, P = .005). The corresponding rates were higher in the total population. CONCLUSIONS: EPT children with or without NDDs had behavioral problems characterized by a higher risk for anxiety and attention, social, and thought problems. These findings further strengthen the proposition that a preterm behavioral phenotype is recognizable in adolescents born EPT. PMID- 28642371 TI - Electrostatic interactions between the CTX phage minor coat protein and the bacterial host receptor TolA drive the pathogenic conversion of Vibrio cholerae. AB - Vibrio cholerae is a natural inhabitant of aquatic environments and converts to a pathogen upon infection by a filamentous phage, CTXPhi, that transmits the cholera toxin-encoding genes. This toxigenic conversion of V. cholerae has evident implication in both genome plasticity and epidemic risk, but the early stages of the infection have not been thoroughly studied. CTXPhi transit across the bacterial periplasm requires binding between the minor coat protein named pIII and a bacterial inner-membrane receptor, TolA, which is part of the conserved Tol-Pal molecular motor. To gain insight into the TolA-pIII complex, we developed a bacterial two-hybrid approach, named Oxi-BTH, suited for studying the interactions between disulfide bond-folded proteins in the bacterial cytoplasm of an Escherichia coli reporter strain. We found that two of the four disulfide bonds of pIII are required for its interaction with TolA. By combining Oxi-BTH assays, NMR, and genetic studies, we also demonstrate that two intermolecular salt bridges between TolA and pIII provide the driving forces of the complex interaction. Moreover, we show that TolA residue Arg-325 involved in one of the two salt bridges is critical for proper functioning of the Tol-Pal system. Our results imply that to prevent host evasion, CTXPhi uses an infection strategy that targets a highly conserved protein of Gram-negative bacteria essential for the fitness of V. cholerae in its natural environment. PMID- 28642376 TI - Draft Genome Sequence of Bacillus sp. Strain CDB3, an Arsenic-Resistant Soil Bacterium Isolated from Cattle Dip Sites. AB - Bacillus sp. strain CDB3, isolated from cattle dip sites in Australia, is highly resistant to arsenic. It contains 22 arsenic resistance (ars) genes, of which 17 are organized in 3 ars clusters. Here, we report the draft genome sequence of CDB3, which will assist us in understanding the overall ars mechanism. PMID- 28642375 TI - Acquired Resistance to Corticotropin Therapy in Nephrotic Syndrome: Role of De Novo Neutralizing Antibody. AB - There is increasing evidence supporting the use of corticotropin as an alternative treatment of refractory proteinuric glomerulopathies. The efficacy of short-acting corticotropin, however, remains unknown and was tested here in an adolescent with steroid-dependent nephrotic syndrome caused by minimal change disease. After developing Cushing syndrome and recently being afflicted with severe cellulitis, the patient was weaned off all immunosuppressants, including corticosteroids. This resulted in a relapse of generalized anasarca, associated with massive proteinuria and hypoalbuminemia. Subsequently, mono-therapy with short-acting animal-derived natural corticotropin was initiated and resulted in a rapid response, marked by substantial diuresis, reduction in body weight, and partial remission of proteinuria. Ten days later, the patient developed mild skin rash and subcutaneous nodules at injection sites. A relapse followed despite doubling the dose of corticotropin, consistent with delayed-onset resistance to treatment. Immunoblot-based antibody assay revealed de novo formation of antibodies in the patient's serum that were reactive to the natural corticotropin. In cultured melanoma cells known to express abundant melanocortin receptors, addition of the patient's serum strikingly mitigated dendritogenesis and cell signaling triggered by natural corticotropin, denoting neutralizing properties of the newly formed antibodies. Collectively, short-acting natural corticotropin seems effective in steroid-dependent nephrotic syndrome. De novo formation of neutralizing antibodies is likely responsible for acquired resistance to corticotropin therapy. The proof of concept protocols established in this study to examine the anticorticotropin neutralizing antibodies may aid in determining the cause of resistance to corticotropin therapy in future studies. PMID- 28642377 TI - Complete Genome Sequence of the Extremely Thermoacidophilic Archaeon Acidianus manzaensis YN-25. AB - The complete genome of Acidianus manzaensis YN-25 consists of a chromosome of 2,687,463 bp, with a G+C content of 30.62% and 2,746 coding DNA sequences. This archaeon contains a series of specific genes involved in the oxidation of elemental sulfur and reduced inorganic sulfur compounds. PMID- 28642379 TI - Complete Genome Sequence of Staphylococcus lutrae ATCC 700373, a Potential Pathogen Isolated from Deceased Otters. AB - Despite their relevance to human health, not all staphylococcal species have been characterized. As such, the potential zoonotic threats posed by uninvestigated species and their contribution to the staphylococcal pangenome are unclear. Here, we report the complete genome sequence of Staphylococcus lutrae ATCC 700373, a coagulase-positive species isolated from deceased otters. PMID- 28642378 TI - New Genome Sequence of an Echinaceapurpurea Endophyte, Arthrobacter sp. Strain EpSL27, Able To Inhibit Human-Opportunistic Pathogens. AB - We announce here the draft genome sequence of Arthrobacter sp. strain EpSL27, isolated from the stem and leaves of the medicinal plant Echinacea purpurea and able to inhibit human-pathogenic bacterial strains. The genome sequencing of this strain may lead to the identification of genes involved in the production of antimicrobial molecules. PMID- 28642380 TI - Complete Genome Sequence of Bacillus paralicheniformis MDJK30, a Plant Growth Promoting Rhizobacterium with Antifungal Activity. AB - Bacillus paralicheniformis MDJK30 was isolated from the rhizosphere of a peony. It could control the pathogen of peony root rot. Here, we report the complete genome sequence of B. paralicheniformis MDJK30. Eleven secondary metabolism gene clusters were predicted. PMID- 28642383 TI - Anniversaries for particle physics. PMID- 28642384 TI - News at a glance. PMID- 28642382 TI - A global brain state underlies C. elegans sleep behavior. AB - How the brain effectively switches between and maintains global states, such as sleep and wakefulness, is not yet understood. We used brainwide functional imaging at single-cell resolution to show that during the developmental stage of lethargus, the Caenorhabditis elegans brain is predisposed to global quiescence, characterized by systemic down-regulation of neuronal activity. Only a few specific neurons are exempt from this effect. In the absence of external arousing cues, this quiescent brain state arises by the convergence of neuronal activities toward a fixed-point attractor embedded in an otherwise dynamic neural state space. We observed efficient spontaneous and sensory-evoked exits from quiescence. Our data support the hypothesis that during global states such as sleep, neuronal networks are drawn to a baseline mode and can be effectively reactivated by signaling from arousing circuits. PMID- 28642385 TI - Drowned wildebeest provide ecological feast. PMID- 28642381 TI - Chemical transformation of xenobiotics by the human gut microbiota. AB - The human gut microbiota makes key contributions to the metabolism of ingested compounds (xenobiotics), transforming hundreds of dietary components, industrial chemicals, and pharmaceuticals into metabolites with altered activities, toxicities, and lifetimes within the body. The chemistry of gut microbial xenobiotic metabolism is often distinct from that of host enzymes. Despite their important consequences for human biology, the gut microbes, genes, and enzymes involved in xenobiotic metabolism are poorly understood. Linking these microbial transformations to enzymes and elucidating their biological effects is undoubtedly challenging. However, recent studies demonstrate that integrating traditional and emerging technologies can enable progress toward this goal. Ultimately, a molecular understanding of gut microbial xenobiotic metabolism will guide personalized medicine and nutrition, inform toxicology risk assessment, and improve drug discovery and development. PMID- 28642386 TI - A division of labor in cells' protein factories. PMID- 28642387 TI - Texas signals support for unproven stem cell therapies. PMID- 28642388 TI - East Africa turmoil imperils giraffes. PMID- 28642389 TI - New haul of distant worlds casts doubt on Planet Nine. PMID- 28642390 TI - Tallying the tropical toll on trees from lightning. PMID- 28642391 TI - A top mathematician joins the Macron revolution. PMID- 28642392 TI - The footprints of giants. PMID- 28642393 TI - Trial balloons. PMID- 28642394 TI - Fast exoskeleton optimization. PMID- 28642395 TI - Ambient quantum optomechanics. PMID- 28642397 TI - The most perfect thing, explained. PMID- 28642396 TI - Building chromosomes without bricks. PMID- 28642398 TI - Locked and loaded for apoptosis. PMID- 28642399 TI - Brains, environments, and policy responses to addiction. PMID- 28642400 TI - Human nature. PMID- 28642401 TI - Imagine this. PMID- 28642402 TI - Benefits of trees in tropical cities. PMID- 28642403 TI - Time to codify scientific integrity. PMID- 28642404 TI - A nod to public open access infrastructures. PMID- 28642405 TI - Understanding the formation of spicules. PMID- 28642406 TI - Lnc-ing fibroblasts to cardiac fibrosis. PMID- 28642407 TI - Quantum effects in ambient conditions. PMID- 28642409 TI - The influence of flying. PMID- 28642408 TI - How to make a protein-based nanocontainer. PMID- 28642410 TI - Instant tough bonding of hydrogels. PMID- 28642411 TI - PKA-activation mechanism revised. PMID- 28642412 TI - Optimum human input. PMID- 28642413 TI - One person's meat is another's poison. PMID- 28642414 TI - Broadening the immune spectrum. PMID- 28642415 TI - Neuronal basis of lethargy in worms. PMID- 28642416 TI - Packaging without nucleosomes. PMID- 28642417 TI - Resonant systems with high bandwidth. PMID- 28642418 TI - Sulfur's balancing act in cytochrome c. PMID- 28642419 TI - Lithium gets a new ground state. PMID- 28642420 TI - Kiss-and-run or a full commitment? PMID- 28642421 TI - Of mice and men's microglia. PMID- 28642423 TI - Timing the life cycle of molecular clouds. PMID- 28642422 TI - Trifluoromethylation via broken C-F bonds. PMID- 28642424 TI - How much does a virus cost? PMID- 28642425 TI - Balanced diets can prevent binge-like eating. PMID- 28642426 TI - Monitoring inflammation from within. PMID- 28642427 TI - Small RNA retunes photosynthesis. PMID- 28642428 TI - Nailing down the elusive statistics. PMID- 28642429 TI - Experimentation on the Tube. PMID- 28642430 TI - Avian egg shape: Form, function, and evolution. AB - Avian egg shape is generally explained as an adaptation to life history, yet we currently lack a global synthesis of how egg-shape differences arise and evolve. Here, we apply morphometric, mechanistic, and macroevolutionary analyses to the egg shapes of 1400 bird species. We characterize egg-shape diversity in terms of two biologically relevant variables, asymmetry and ellipticity, allowing us to quantify the observed morphologies in a two-dimensional morphospace. We then propose a simple mechanical model that explains the observed egg-shape diversity based on geometric and material properties of the egg membrane. Finally, using phylogenetic models, we show that egg shape correlates with flight ability on broad taxonomic scales, suggesting that adaptations for flight may have been critical drivers of egg-shape variation in birds. PMID- 28642431 TI - Quantum and isotope effects in lithium metal. AB - The crystal structure of elements at zero pressure and temperature is the most fundamental information in condensed matter physics. For decades it has been believed that lithium, the simplest metallic element, has a complicated ground state crystal structure. Using synchrotron x-ray diffraction in diamond anvil cells and multiscale simulations with density functional theory and molecular dynamics, we show that the previously accepted martensitic ground state is metastable. The actual ground state is face-centered cubic (fcc). We find that isotopes of lithium, under similar thermal paths, exhibit a considerable difference in martensitic transition temperature. Lithium exhibits nuclear quantum mechanical effects, serving as a metallic intermediate between helium, with its quantum effect-dominated structures, and the higher-mass elements. By disentangling the quantum kinetic complexities, we prove that fcc lithium is the ground state, and we synthesize it by decompression. PMID- 28642432 TI - Breaking Lorentz reciprocity to overcome the time-bandwidth limit in physics and engineering. AB - A century-old tenet in physics and engineering asserts that any type of system, having bandwidth Deltaomega, can interact with a wave over only a constrained time period Deltat inversely proportional to the bandwidth (Deltat.Deltaomega ~ 2pi). This law severely limits the generic capabilities of all types of resonant and wave-guiding systems in photonics, cavity quantum electrodynamics and optomechanics, acoustics, continuum mechanics, and atomic and optical physics but is thought to be completely fundamental, arising from basic Fourier reciprocity. We propose that this "fundamental" limit can be overcome in systems where Lorentz reciprocity is broken. As a system becomes more asymmetric in its transport properties, the degree to which the limit can be surpassed becomes greater. By way of example, we theoretically demonstrate how, in an astutely designed magnetized semiconductor heterostructure, the above limit can be exceeded by orders of magnitude by using realistic material parameters. Our findings revise prevailing paradigms for linear, time-invariant resonant systems, challenging the doctrine that high-quality resonances must invariably be narrowband and providing the possibility of developing devices with unprecedentedly high time-bandwidth performance. PMID- 28642433 TI - Quantum correlations from a room-temperature optomechanical cavity. AB - The act of position measurement alters the motion of an object being measured. This quantum measurement backaction is typically much smaller than the thermal motion of a room-temperature object and thus difficult to observe. By shining laser light through a nanomechanical beam, we measure the beam's thermally driven vibrations and perturb its motion with optical force fluctuations at a level dictated by the Heisenberg measurement-disturbance uncertainty relation. We demonstrate a cross-correlation technique to distinguish optically driven motion from thermally driven motion, observing this quantum backaction signature up to room temperature. We use the scale of the quantum correlations, which is determined by fundamental constants, to gauge the size of thermal motion, demonstrating a path toward absolute thermometry with quantum mechanically calibrated ticks. PMID- 28642434 TI - On the generation of solar spicules and Alfvenic waves. AB - In the lower solar atmosphere, the chromosphere is permeated by jets known as spicules, in which plasma is propelled at speeds of 50 to 150 kilometers per second into the corona. The origin of the spicules is poorly understood, although they are expected to play a role in heating the million-degree corona and are associated with Alfvenic waves that help drive the solar wind. We compare magnetohydrodynamic simulations of spicules with observations from the Interface Region Imaging Spectrograph and the Swedish 1-m Solar Telescope. Spicules are shown to occur when magnetic tension is amplified and transported upward through interactions between ions and neutrals or ambipolar diffusion. The tension is impulsively released to drive flows, heat plasma (through ambipolar diffusion), and generate Alfvenic waves. PMID- 28642435 TI - A catalytic fluoride-rebound mechanism for C(sp3)-CF3 bond formation. AB - The biological properties of trifluoromethyl compounds have led to their ubiquity in pharmaceuticals, yet their chemical properties have made their preparation a substantial challenge, necessitating innovative chemical solutions. We report the serendipitous discovery of a borane-catalyzed formal C(sp3)-CF3 reductive elimination from Au(III) that accesses these compounds by a distinct mechanism proceeding via fluoride abstraction, migratory insertion, and C-F reductive elimination to achieve a net C-C bond construction. The parent bis(trifluoromethyl)Au(III) complexes tolerate a surprising breadth of synthetic protocols, enabling the synthesis of complex organic derivatives without cleavage of the Au-C bond. This feature, combined with the "fluoride-rebound" mechanism, was translated into a protocol for the synthesis of 18F-radiolabeled aliphatic CF3-containing compounds, enabling the preparation of potential tracers for use in positron emission tomography. PMID- 28642437 TI - Human-in-the-loop optimization of exoskeleton assistance during walking. AB - Exoskeletons and active prostheses promise to enhance human mobility, but few have succeeded. Optimizing device characteristics on the basis of measured human performance could lead to improved designs. We have developed a method for identifying the exoskeleton assistance that minimizes human energy cost during walking. Optimized torque patterns from an exoskeleton worn on one ankle reduced metabolic energy consumption by 24.2 +/- 7.4% compared to no torque. The approach was effective with exoskeletons worn on one or both ankles, during a variety of walking conditions, during running, and when optimizing muscle activity. Finding a good generic assistance pattern, customizing it to individual needs, and helping users learn to take advantage of the device all contributed to improved economy. Optimization methods with these features can substantially improve performance. PMID- 28642436 TI - Metalloprotein entatic control of ligand-metal bonds quantified by ultrafast x ray spectroscopy. AB - The multifunctional protein cytochrome c (cyt c) plays key roles in electron transport and apoptosis, switching function by modulating bonding between a heme iron and the sulfur in a methionine residue. This Fe-S(Met) bond is too weak to persist in the absence of protein constraints. We ruptured the bond in ferrous cyt c using an optical laser pulse and monitored the bond reformation within the protein active site using ultrafast x-ray pulses from an x-ray free-electron laser, determining that the Fe-S(Met) bond enthalpy is ~4 kcal/mol stronger than in the absence of protein constraints. The 4 kcal/mol is comparable with calculations of stabilization effects in other systems, demonstrating how biological systems use an entatic state for modest yet accessible energetics to modulate chemical function. PMID- 28642441 TI - My lessons in mentorship. PMID- 28642438 TI - Local protein kinase A action proceeds through intact holoenzymes. AB - Hormones can transmit signals through adenosine 3',5'-monophosphate (cAMP) to precise intracellular locations. The fidelity of these responses relies on the activation of localized protein kinase A (PKA) holoenzymes. Association of PKA regulatory type II (RII) subunits with A-kinase-anchoring proteins (AKAPs) confers location, and catalytic (C) subunits phosphorylate substrates. Single particle electron microscopy demonstrated that AKAP79 constrains RII-C subassemblies within 150 to 250 angstroms of its targets. Native mass spectrometry established that these macromolecular assemblies incorporated stoichiometric amounts of cAMP. Chemical-biology- and live cell-imaging techniques revealed that catalytically active PKA holoenzymes remained intact within the cytoplasm. These findings indicate that the parameters of anchored PKA holoenzyme action are much more restricted than originally anticipated. PMID- 28642439 TI - Assembly principles and structure of a 6.5-MDa bacterial microcompartment shell. AB - Many bacteria contain primitive organelles composed entirely of protein. These bacterial microcompartments share a common architecture of an enzymatic core encapsulated in a selectively permeable protein shell; prominent examples include the carboxysome for CO2 fixation and catabolic microcompartments found in many pathogenic microbes. The shell sequesters enzymatic reactions from the cytosol, analogous to the lipid-based membrane of eukaryotic organelles. Despite available structural information for single building blocks, the principles of shell assembly have remained elusive. We present the crystal structure of an intact shell from Haliangium ochraceum, revealing the basic principles of bacterial microcompartment shell construction. Given the conservation among shell proteins of all bacterial microcompartments, these principles apply to functionally diverse organelles and can inform the design and engineering of shells with new functionalities. PMID- 28642442 TI - Triplet pregnancy with fetal reduction: experience in Hong Kong. AB - INTRODUCTION: Triplet and higher-order multiple pregnancies are well known to be associated with increased adverse outcomes. This study reviewed the perinatal outcomes in women with a triplet pregnancy who underwent fetal reduction versus expectant management at a university hospital in Hong Kong. METHODS: This was a retrospective review of triplet pregnancies at Prince of Wales Hospital in Hong Kong from 1 January 2008 to 30 September 2014. Women carrying a triplet pregnancy were classified as having had expectant management, fetal reduction to twins, or fetal reduction to a singleton. Maternal and pregnancy characteristics were compared. Outcome measures included fetal loss, gestational age at delivery, birth weight, neonatal survival rate, neonatal death, neonatal complications, and need for and length of neonatal intensive care unit stay. RESULTS: A total of 52 triplet pregnancies were identified. One pregnancy that was lost to follow-up and one that was terminated were excluded. The majority of pregnancies (84%) were the result of assisted reproductive technology. Fetal reduction was performed in 26 (52%) pregnancies, of which 22 were reduced to twins and four to a singleton. The mean gestations at delivery were 32.6, 35.2, and 39.6 weeks in the expectant management, fetal reduction to twins, and fetal reduction to a singleton groups, respectively. Significantly more pregnancies with expectant management resulted in a preterm birth. All pregnancies with fetal reduction to a singleton resulted in a term birth. A higher mean birth weight, lower neonatal death rate, and reduced need for admission to and length of stay in the neonatal intensive care unit were observed in the fetal reduction groups. CONCLUSIONS: Approximately 50% of women with a triplet pregnancy in Hong Kong elected to undergo fetal reduction. This was associated with a significant reduction in extreme preterm delivery and associated morbidity and mortality. PMID- 28642447 TI - T315I+ tyrosine-kinase independent CML cells resistance. PMID- 28642452 TI - Laparoscopic treatment of colo-colic intussusception secondary to a lipomatous polyp. AB - INTRODUCTION: Colo-colic intussusception is extremely rare in adults and few cases have been described secondary to a lypomatous polyp. CASE REPORT: We present the case of a 50-year old man with chronic abdominal pain who was diagnosed a colo-colic intussusception secondary to a lipoma of the left colon. The patient underwent laparoscopic resection of the splenic flexure without reduction, which occurred spontaneously after induction of the pneumoperitoneum, and final histology confirmed a submucosal lipoma with no evidence of malignancy. CONCLUSION: The traditional treatment of choice for adult intussusception is bowel resection without reduction. More recently, however, preoperative reduction of the invaginated bowel segment has been reconsidered in order to: 1) avoid emergency surgery, 2) allow radical surgery for cancer, and 3) reduce the extent of the intestinal resection. To the best of our knowledge, this is the first case of adult colonic intussusception secondary to a lipoma treated by laparoscopy. KEY WORDS: Colon, Intussusception, Laparoscopy, Lipoma. PMID- 28642451 TI - IL-10 Plays a Pivotal Role in Tamoxifen-Induced Spasmolytic Polypeptide Expressing Metaplasia in Gastric Mucosa. AB - Background/Aims: Gastric cancer evolves in the pathologic mucosal milieu, and its development is characterized by both the loss of acid-secreting parietal cells and mucosal cell metaplasia, called spasmolytic polypeptide-expressing metaplasia (SPEM). Cytokines, such as interleukin (IL)-10, IL-1beta, and IL-6, play a key role in gastric carcinogenesis. However, changes in the cytokine profile of SPEM have not been evaluated. Methods: To induce SPEM in mouse stomachs, C57BL/6 mice were intraperitoneally injected with tamoxifen and sacrificed at 3, 10, and 21 days after treatment. RNA-sequencing (RNA-seq) and a multiplex bead array were used to measure cytokines in the stomachs of tamoxifen-treated/control mice. Results: The administration of tamoxifen led to the rapid development and histological normalization of SPEM 3 and 10 days after administration, respectively. RNA-seq revealed that the expression of IL-10 was decreased 3 days after tamoxifen administration. The multiplex assay identified a significant decline in IL-10 levels 3 days after tamoxifen treatment (58.38+/-34.44 pg/mL vs 94.09+/-4.98 pg/mL, p=0.031), which normalized at 10 and 21 days after tamoxifen treatment. Immunofluorescence staining confirmed that IL-10 expression was markedly decreased at the time of SPEM development and subsequently returned to normal, accompanied by a reversal in histologic changes. Conclusions: IL-10 may play a pivotal role in the tamoxifen-induced acute development of gastric SPEM. PMID- 28642453 TI - Cystatin C-Based Equation Does Not Accurately Estimate the Glomerular Filtration in Japanese Living Kidney Donors. AB - BACKGROUND Precise evaluation of a living donor's renal function is necessary to ensure adequate residual kidney function after donor nephrectomy. Our aim was to evaluate the feasibility of estimating glomerular filtration rate (GFR) using serum cystatin-C prior to kidney transplantation. MATERIAL AND METHODS Using the equations of the Japanese Society of Nephrology, we calculated the GFR using serum creatinine (eGFRcre) and cystatin C levels (eGFRcys) for 83 living kidney donors evaluated between March 2010 and March 2016. We compared eGFRcys and eGFRcre values against the creatinine clearance rate (CCr). RESULTS The study population included 27 males and 56 females. The mean eGFRcys, eGFRcre, and CCr were, 91.4+/-16.3 mL/min/1.73 m2 (range, 59.9-128.9 mL/min/1.73 m2), 81.5+/-14.2 mL/min/1.73 m2 (range, 55.4-117.5 mL/min/1.73 m2) and 108.4+/-21.6 mL/min/1.73 m2 (range, 63.7-168.7 mL/min/1.73 m2), respectively. eGFRcys was significantly lower than CCr (p<0.001). The correlation coefficient between eGFRcys and CCr values was 0.466, and the mean difference between the two values was -17.0 (15.7%), with a root mean square error of 19.2. Thus, eGFRcre was significantly lower than CCr (p<0.001). The correlation coefficient between eGFRcre and CCr values was 0.445, and the mean difference between the two values was -26.9 (24.8%), with a root mean square error of 19.5. CONCLUSIONS Although eGFRcys provided a better estimation of GFR than eGFRcre, eGFRcys still did not provide an accurate measure of kidney function in Japanese living kidney donors. PMID- 28642454 TI - Inclusion Body Myositis: A Case Presenting with Respiratory Failure and Autopsy Findings Leading to the Hypothesis of a Paraneoplastic Cause. AB - BACKGROUND Sporadic inclusion body myositis (IBM) is the most common acquired myopathy seen in adults aged over 50 years, with a prevalence estimated at between 1 and 70 per million. Weakness of the diaphragm with loss of vital capacity is almost universal in IBM. This is almost always asymptomatic. When respiratory complications occur, they are most often due to aspiration. Respiratory failure due to diaphragmatic weakness is exceptionally rare, particularly as the presenting symptom of the disease. It is not currently considered to be a paraneoplastic syndrome. CASE REPORT Our patient presented with hypercarbic respiratory failure. This is the first such reported case without signs of weakness elsewhere of which we are aware. We suspected IBM based on her history of progressive weakness and findings on electromyography. There was a delay of 5 years in obtaining biopsy for confirmation, during which she presented with recurrent episodes of respiratory failure despite using non invasive ventilation. An autopsy revealed the presence of papillary thyroid carcinoma with spread to local lymph nodes. On the basis that these co morbidities are unlikely to have occurred by chance (we estimate 1*10-17), we hypothesize that IBM may be a paraneoplastic condition. We acknowledge that proof would require demonstrating a pathogenic antibody. CONCLUSIONS IBM should be considered in older patients (age >45) presenting with otherwise unexplained respiratory failure. A workup for possible malignancy in this setting appears reasonable. PMID- 28642455 TI - Diagnostic Value of Video-assisted Mediastinoscopy and Endobronchial Ultrasound guided Transbronchial Needle Aspiration for Mediastinal Lymphadenectasis without Pulmonary Abnormalities. AB - BACKGROUND Mediastinal diseases are difficult to diagnose due to diverse origins and complex anatomical structure of the mediastinal tissues. The prospective study aimed to compare the diagnostic efficiency of video-assisted mediastinoscopy (VAM) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for mediastinal lesions without pulmonary abnormalities. MATERIAL AND METHODS We divided 100 mediastinal lymphadenectasis patients without pulmonary abnormalities into a VAM group and an EBUS group. The pathological results of each group were regarded as the endpoints. SPSS19.0 statistical software was used. RESULTS The diagnostic accuracy, sensitivity, and specificity of VAM were 96%, 97.4%, and 100%, respectively; those of EBUS-TBNA diagnosis were 62%, 87.1%, and 100%, respectively. There was a statistically significant difference in the diagnostic sensitivity of benign mediastinal lesions between the 2 groups (P<0.01). Compared with the EBUS group (62%), the accuracy in the VAM group was significantly higher (96%) (P<0.01). CONCLUSIONS We found that the diagnostic accuracy of VAM for mediastinal lymphadenectasis without pulmonary abnormalities is superior to that of EBUS. Therefore, for patients with mediastinal lymphadenectasis or mediastinal mass and without pulmonary abnormalities, mediastinoscopy is recommended as the first choice. PMID- 28642456 TI - Predicting conformational ensembles and genome-wide transcription factor binding sites from DNA sequences. AB - DNA shape is emerging as an important determinant of transcription factor binding beyond just the DNA sequence. The only tool for large scale DNA shape estimates, DNAshape was derived from Monte-Carlo simulations and predicts four broad and static DNA shape features, Propeller twist, Helical twist, Minor groove width and Roll. The contributions of other shape features e.g. Shift, Slide and Opening cannot be evaluated using DNAshape. Here, we report a novel method DynaSeq, which predicts molecular dynamics-derived ensembles of a more exhaustive set of DNA shape features. We compared the DNAshape and DynaSeq predictions for the common features and applied both to predict the genome-wide binding sites of 1312 TFs available from protein interaction quantification (PIQ) data. The results indicate a good agreement between the two methods for the common shape features and point to advantages in using DynaSeq. Predictive models employing ensembles from individual conformational parameters revealed that base-pair opening - known to be important in strand separation - was the best predictor of transcription factor-binding sites (TFBS) followed by features employed by DNAshape. Of note, TFBS could be predicted not only from the features at the target motif sites, but also from those as far as 200 nucleotides away from the motif. PMID- 28642457 TI - Human-mediated secondary contact of two tortoise lineages results in sex-biased introgression. AB - Human-mediated secondary contact of recently diverged taxa offers valuable opportunities for studying the evolutionary mechanisms involved in the establishment and maintenance of genetic boundaries between taxa. We used mitochondrial and microsatellite markers to examine a recently introduced population of the spur-thighed tortoise (Testudo graeca) of mixed origin in the Donana National Park (SW Spain). The earliest records of tortoises in Donana trace back to the 18th century, but several population reinforcements in the 20th century with animals from Morocco are well-documented. Consequently, different genetic lineages, which represent distinct subspecies, are thought to co-exist there. Our results confirmed the presence of distinct lineages by revealing that tortoises of the subspecies T. g. marokkensis were introduced into a local allochthonous T. g. graeca population. Unexpectedly, T. g. marokkensis haplotypes exclusively appeared in males, and admixture levels were statistically sex-biased toward males. The sex ratio of the population deviated from parity, with males being 2.36-fold more abundant than females. Our results indicated that population reinforcements had a strong effect on the genetic composition of this population and aggravated its sex ratio deviation. We predict that this sex-biased pattern of introgression is ephemeral and advocated to the near loss of T. g. marokkensis haplotypes. PMID- 28642458 TI - The structure and hardness of the highest boride of tungsten, a borophene-based compound. AB - Two-dimensional systems have strengthened their position as a key materials for novel applications. Very recently, boron joined the distinguished group of elements confirmed to possess 2D allotropes, named borophenes. In this work, we explore the stability and hardness of the highest borides of tungsten, which are built of borophenes separated by metal atoms. We show that the WB3+x compounds have Vickers hardnesses approaching 40 GPa only for small values of x. The insertion of extra boron atoms is, in general, detrimental to the hardness of WB3 because it leads to the formation of quasi-planar boron sheets that are less tightly connected with the adjacent tungsten layers. Very high concentrations of boron (x ~ 1), give rise to a soft (Vickers hardness of ~8 GPa) and unstable hP20 WB4 structure that can be considered to be built of quasi-planar boron alpha sheets separated by graphitic tungsten layers. By contrast, we show that the formation of tungsten vacancies leads to structures, e.g. W0.75B3+x , with Vickers hardnesses that are not only similar in value to the experimentally reported load-independent hardnesses greater than 20 GPa, but are also less sensitive to variations in the boron content. PMID- 28642460 TI - Standing wave effect and fractal structure in dislocation evolution. AB - Theoretical model required for the evolution of regular dislocation pattern should simultaneously take into account both static distribution and dynamic evolution of dislocation pattern. In principle, there exists a stable uniformly moving dislocation with both core and far field advancing at the same constant velocity, which suggests the existence of the traveling waves representing moving dislocation. Therefore, one new term "dislocation wave" is defined by simultaneously consisting of both an elastic wave and a dislocation in each wavefront. According to the standing wave effect, the edge dislocation segments capture mutually to form the periodic ladder structures at the nodes. These persistent slip band (PSB) ladders are not only self-organized but also self similar dislocation patterns. The fractal dimension further reveals the intrinsic nature of crack initiation and propagation along slip bands and deformation bands. PMID- 28642459 TI - Meta-analysis of Soy Consumption and Gastrointestinal Cancer Risk. AB - Soy consumption has received considerable attention for its potential role in reducing cancer incidence and mortality. However, its effects on gastrointestinal (GI) cancer are controversial. Therefore, we performed a meta-analysis to evaluate the association between soy consumption and gastrointestinal cancer risk by searching for prospective studies in PubMed, Web of Science, EMBASE and the reference lists of the included articles. The study-specific odds ratio (OR), relative risk (RR) or hazard ratio (HR) estimates and 95% confidence intervals (CIs) were pooled using either a fixed-effect or random-effect model. Twenty-two independent prospective studies were eligible for our meta-analysis, including 21 cohort studies and one nested case-control study. Soy product consumption was inversely associated with the incidence of overall GI cancer (0.857; 95% CI: 0.766, 0.959) and the gastric cancer subgroup (0.847; 95% CI: 0.722, 0.994) but not the colorectal cancer subgroup. After stratifying the results according to gender, an inverse association was observed between soy product intake and the incidence of GI cancer for females (0.711; 95% CI: 0.506, 0.999) but not for males. PMID- 28642461 TI - The CA19-9 and Sialyl-TRA Antigens Define Separate Subpopulations of Pancreatic Cancer Cells. AB - Molecular markers to detect subtypes of cancer cells could facilitate more effective treatment. We recently identified a carbohydrate antigen, named sTRA, that is as accurate a serological biomarker of pancreatic cancer as the cancer antigen CA19-9. We hypothesized that the cancer cells producing sTRA are a different subpopulation than those producing CA19-9. The sTRA glycan was significantly elevated in tumor tissue relative to adjacent pancreatic tissue in 3 separate tissue microarrays covering 38 patients. The morphologies of the cancer cells varied in association with glycan expression. Cells with dual staining of both markers tended to be in well-to-moderately differentiated glands with nuclear polarization, but exclusive sTRA staining was present in small clusters of cells with poor differentiation and large vacuoles, or in small and ill-defined glands. Patients with higher dual-staining of CA19-9 and sTRA had statistically longer time-to-progression after surgery. Patients with short time to-progression (<2 years) had either low levels of the dual-stained cells or high levels of single-stained cells, and such patterns differentiated short from long time-to-progression with 90% (27/30) sensitivity and 80% (12/15) specificity. The sTRA and CA19-9 glycans define separate subpopulations of cancer cells and could together have value for classifying subtypes of pancreatic adenocarcinoma. PMID- 28642462 TI - Metabolic changes in Medaka fish induced by cyanobacterial exposures in mesocosms: an integrative approach combining proteomic and metabolomic analyses. AB - Cyanobacterial blooms pose serious threats to aquatic organisms and strongly impact the functioning of aquatic ecosystems. Due to their ability to produce a wide range of potentially bioactive secondary metabolites, so called cyanotoxins, cyanobacteria have been extensively studied in the past decades. Proteomic and metabolomic analyses provide a unique opportunity to evaluate the global response of hundreds of proteins and metabolites at a glance. In this study, we provide the first combined utilization of these methods targeted to identify the response of fish to bloom-forming cyanobacteria. Medaka fish (Oryzias latipes) were exposed for 96 hours either to a MC-producing or to a non-MC-producing strain of Microcystis aeruginosa and cellular, proteome and metabolome changes following exposure to cyanobacteria were characterized in the fish livers. The results suggest that a short-term exposure to cyanobacteria, producing or not MCs, induces sex-dependent molecular changes in medaka fish, without causing any cellular alterations. Globally, molecular entities involved in stress response, lipid metabolism and developmental processes exhibit the most contrasted changes following a cyanobacterial exposure. Moreover, it appears that proteomic and metabolomic analyses are useful tools to verify previous information and to additionally bring new horizons concerning molecular effects of cyanobacteria on fish. PMID- 28642463 TI - Acute loss of the hepatic endo-lysosomal system in vivo causes compensatory changes in iron homeostasis. AB - Liver cells communicate with the extracellular environment to take up nutrients via endocytosis. Iron uptake is essential for metabolic activities and cell homeostasis. Here, we investigated the role of the endocytic system for maintaining iron homeostasis. We specifically depleted the small GTPase Rab5 in the mouse liver, causing a transient loss of the entire endo-lysosomal system. Strikingly, endosome depletion led to a fast reduction of hepatic iron levels, which was preceded by an increased abundance of the iron exporter ferroportin. Compensatory changes in livers of Rab5-depleted mice include increased expression of transferrin receptor 1 as well as reduced expression of the iron-regulatory hormone hepcidin. Serum iron indices (serum iron, free iron binding capacity and total iron binding capacity) in Rab5-KD mice were increased, consistent with an elevated splenic and hepatic iron export. Our data emphasize the critical importance of the endosomal compartments in hepatocytes to maintain hepatic and systemic iron homeostasis in vivo. The short time period (between day four and five) upon which these changes occur underscore the fast dynamics of the liver iron pool. PMID- 28642464 TI - Serum C3 and Renal Outcome in Patients with Primary Focal Segmental Glomerulosclerosis. AB - The role of complement (C) in the pathogenesis or progression of focal segmental glomerulosclerosis (FSGS) is uncertain. The present study assessed the relationship between serum C3, the baseline characteristics, and the progression of FSGS in the cohort and identified the clinical implications of serum C3 levels in patients with FSGS. Compared to the patients with C3 >= 85 mg/dL (N = 474), those with C3 < 85 mg/dL (N = 117) presented a higher level of serum creatinine, lower levels of eGFR, hemoglobin, proteinuria, triglyceride, cholesterol, IgA, as well as, severe tubulointerstitial injury (TI). Of the 221 patients with a mean follow-up of 53.3 months, the risk of reaching end-stage renal disease (ESRD) was significantly higher in patients with low serum C3 level (p < 0.001). An additional 40 patients with primary FSGS revealed a significant correlation between MAC and AP (p = 0.003), MAC and serum C3 (p = 0.018), and AP and serum C3 (p = 0.028). Compared to patients with none-to-mild TI, those with moderate-to severe TI exhibited a lower level of serum C3 and AP, and a higher level of serum MAC. In conclusion, complement activation occurring in patients with FSGS is associated with clinical and histological severities. Low serum C3 was an independent risk factor for poor renal outcome in patients with FSGS. PMID- 28642465 TI - Structural basis for biologically relevant mechanical stiffening of a virus capsid by cavity-creating or spacefilling mutations. AB - Recent studies reveal that the mechanical properties of virus particles may have been shaped by evolution to facilitate virus survival. Manipulation of the mechanical behavior of virus capsids is leading to a better understanding of viral infection, and to the development of virus-based nanoparticles with improved mechanical properties for nanotechnological applications. In the minute virus of mice (MVM), deleterious mutations around capsid pores involved in infection-related translocation events invariably increased local mechanical stiffness and interfered with pore-associated dynamics. To provide atomic resolution insights into biologically relevant changes in virus capsid mechanics, we have determined by X-ray crystallography the structural effects of deleterious, mechanically stiffening mutations around the capsid pores. Data show that the cavity-creating N170A mutation at the pore wall does not induce any dramatic structural change around the pores, but instead generates subtle rearrangements that propagate throughout the capsid, resulting in a more compact, less flexible structure. Analysis of the spacefilling L172W mutation revealed the same relationship between increased stiffness and compacted capsid structure. Implications for understanding connections between virus mechanics, structure, dynamics and infectivity, and for engineering modified virus-based nanoparticles, are discussed. PMID- 28642466 TI - Cognitive and motor dual task gait training improve dual task gait performance after stroke - A randomized controlled pilot trial. AB - This study investigated effects of cognitive and motor dual task gait training on dual task gait performance in stroke. Participants (n = 28) were randomly assigned to cognitive dual task gait training (CDTT), motor dual task gait training (MDTT), or conventional physical therapy (CPT) group. Participants in CDTT or MDTT group practiced the cognitive or motor tasks respectively during walking. Participants in CPT group received strengthening, balance, and gait training. The intervention was 30 min/session, 3 sessions/week for 4 weeks. Three test conditions to evaluate the training effects were single walking, walking while performing cognitive task (serial subtraction), and walking while performing motor task (tray-carrying). Parameters included gait speed, dual task cost of gait speed (DTC-speed), cadence, stride time, and stride length. After CDTT, cognitive-motor dual task gait performance (stride length and DTC-speed) was improved (p = 0.021; p = 0.015). After MDTT, motor dual task gait performance (gait speed, stride length, and DTC-speed) was improved (p = 0.008; p = 0.008; p = 0.008 respectively). It seems that CDTT improved cognitive dual task gait performance and MDTT improved motor dual task gait performance although such improvements did not reach significant group difference. Therefore, different types of dual task gait training can be adopted to enhance different dual task gait performance in stroke. PMID- 28642467 TI - Targeting Coronaviral Replication and Cellular JAK2 Mediated Dominant NF-kappaB Activation for Comprehensive and Ultimate Inhibition of Coronaviral Activity. AB - Tylophorine-based compounds exert broad spectral, potent inhibition of coronaviruses. NF-kappaB activation is a common pro-inflammatory response of host cells to viral infection. The aims of this study were to (i) find an effective combination treatment for coronaviral infections through targeting of the virus per se and cellular NF-kappaB activity; and (ii) to study the underling mechanisms. We found that tylophorine-based compounds target the TGEV viral RNA and effectively inhibit TGEV replication. NF-kappaB inhibition also leads to anti TGEV replication. NF-kappaB activation induced by TGEV infection was found to be associated with two convergent pathways, IKK-2_IkappaBalpha/p65 and JAK2 mediated p65 phosphorylation, in swine testicular cells. JAK2 inhibition either by CYT387 (a JAK family inhibitor) or by silencing JAK2-expression revealed a dominant JAK2 mediated p65 phosphorylation pathway for NF-kappaB activation and resulted in NF kappaB inhibition, which overrode the IkappaBalpha regulation via the IKK-2. Finally, tylophorine-based compounds work cooperatively with CYT387 to impart comprehensive anti-TGEV activities. The combination treatment, wherein a tylophorine compound targets TGEV and a JAK2 inhibitor blocks the alternative dominant NF-kappaB activation mediated by JAK2, is more effective and comprehensive than either one alone and constitutes a feasible approach for the treatment of SARS-CoV or MERS-CoV. PMID- 28642468 TI - Metal vapor micro-jet controls material redistribution in laser powder bed fusion additive manufacturing. AB - The results of detailed experiments and finite element modeling of metal micro droplet motion associated with metal additive manufacturing (AM) processes are presented. Ultra high speed imaging of melt pool dynamics reveals that the dominant mechanism leading to micro-droplet ejection in a laser powder bed fusion AM is not from laser induced recoil pressure as is widely believed and found in laser welding processes, but rather from vapor driven entrainment of micro particles by an ambient gas flow. The physics of droplet ejection under strong evaporative flow is described using simulations of the laser powder bed interactions to elucidate the experimental results. Hydrodynamic drag analysis is used to augment the single phase flow model and explain the entrainment phenomenon for 316 L stainless steel and Ti-6Al-4V powder layers. The relevance of vapor driven entrainment of metal micro-particles to similar fluid dynamic studies in other fields of science will be discussed. PMID- 28642470 TI - Quantitative Proteomics Analysis Reveals Novel Targets of miR-21 in Zebrafish Embryos. AB - MicroRNAs (miRNAs) are noncoding RNAs which control gene expression by the suppression of translation or the degradation of mRNAs. Dre-miR-21 (miR-21) has been reported to impact cardiac valvulogenesis in zebrafish embryos. However, the target genes of miR-21 are still largely unknown. Here a tandem isobaric mass tag (TMT)-based quantitative proteomic strategy was employed to identify the global profile of miR-21-regulated proteins. A total of 251 proteins were dysregulated after miR-21 knockdown, suggesting that they may be regulated by miR-21. Bioinformatics analysis indicated that these differentially expressed proteins (DEPs) participate in various biological processes, suggesting that miR-21 may be involved in diverse cellular pathways. Sixteen DEPs were also predicted to be miR 21 targets by at least two algorithms, and several candidate target genes were selected for further luciferase reporter analysis. The results showed that genes encoding tropomyosin 1 (tpm1) and poly(rC) binding protein 2 (pcbp2) are direct miR-21 targets. Taken together, our results not only reveal a large number of novel miR-21 regulated proteins that possess pleiotropic functions, but also provide novel insights into the molecular mechanisms of miR-21 regulation of zebrafish cardiac valvulogenesis and embryonic development. PMID- 28642471 TI - Multi-layered NiOy/NbOx/NiOy fast drift-free threshold switch with high Ion/Ioff ratio for selector application. AB - NbO2 has the potential for a variety of electronic applications due to its electrically induced insulator-to-metal transition (IMT) characteristic. In this study, we find that the IMT behavior of NbO2 follows the field-induced nucleation by investigating the delay time dependency at various voltages and temperatures. Based on the investigation, we reveal that the origin of leakage current in NbOx is partly due to insufficient Schottky barrier height originating from interface defects between the electrodes and NbOx layer. The leakage current problem can be addressed by inserting thin NiOy barrier layers. The NiOy inserted NbOx device is drift-free and exhibits high Ion/Ioff ratio (>5400), fast switching speed (<2 ns), and high operating temperature (>453 K) characteristics which are highly suitable to selector application for x-point memory arrays. We show that NbOx device with NiOx interlayers in series with resistive random access memory (ReRAM) device demonstrates improved readout margin (>29 word lines) suitable for x-point memory array application. PMID- 28642469 TI - Tracing the epidemic history of HIV-1 CRF01_AE clusters using near-complete genome sequences. AB - Human immunodeficiency virus (HIV) has a number of circulating recombinant forms that are the product of recombination between different HIV subtypes. The first circulating recombinant form of HIV-1 to be identified was CRF01_AE, which originated in Central Africa and is now most prevalent in Southeast and East Asia. In this study, we investigated the timescale, evolutionary history, and population genetics of the HIV-1 CRF01_AE strains primarily responsible for the epidemic in Asia. A further aim of our study was to define and standardize the nomenclature and provide well-characterized reference sequences for the phylogenetic transmission clusters of CRF01_AE. We analysed a data set of 334 near-complete genome sequences from various risk groups, sampled between 1990 and 2011 from nine countries. Phylogenetic analyses of these sequences were performed using maximum likelihood and Bayesian methods. Our study confirms that the diversity of HIV-1 CRF01_AE originated in Central Africa in the mid-1970s, was introduced into Thailand between 1979 and 1982, and began expanding there shortly afterwards (1982-1984). Subsequently, multiple clusters significantly contributed to China's HIV epidemic. A Bayesian skyline plot revealed the rapid expansion of CRF01_AE in China around 1999-2000. We identified at least eight different clusters of HIV-1 CRF01_AE formed by rapid expansion into different risk groups and geographic regions in China since the late 1980s. PMID- 28642472 TI - Ambient effects on electrical characteristics of CVD-grown monolayer MoS2 field effect transistors. AB - Monolayer materials are sensitive to their environment because all of the atoms are at their surface. We investigate how exposure to the environment affects the electrical properties of CVD-grown monolayer MoS2 by monitoring electrical parameters of MoS2 field-effect transistors as their environment is changed from atmosphere to high vacuum. The mobility increases and contact resistance decreases simultaneously as either the pressure is reduced or the sample is annealed in vacuum. We see a previously unobserved, non-monotonic change in threshold voltage with decreasing pressure. This result could be explained by charge transfer on the MoS2 channel and Schottky contact formation due to adsorbates at the interface between the gold contacts and MoS2. Additionally, from our electrical measurements it is plausible to infer that at room temperature and pressure water and oxygen molecules adsorbed on the surface act as interface traps and scattering centers with a density of several 1012 cm-2 eV 1, degrading the electrical properties of monolayer MoS2. PMID- 28642473 TI - Predicting effects on oxaliplatin clearance: in vitro, kinetic and clinical studies of calcium- and magnesium-mediated oxaliplatin degradation. AB - This study evaluated the impact of calcium and magnesium on the in vitro degradation and in vivo clearance of oxaliplatin. Intact oxaliplatin and Pt(DACH)Cl2 were measured in incubation solutions by HPLC-UV. A clinical study determined changes in plasma concentrations of calcium and magnesium in cancer patients and their impact on oxaliplatin clearance. Kinetic analyses modelled oxaliplatin degradation reactions in vitro and contributions to oxaliplatin clearance in vivo. Calcium and magnesium accelerated oxaliplatin degradation to Pt(DACH)Cl2 in chloride-containing solutions in vitro. Kinetic models based on calcium and magnesium binding to a monochloro-monooxalato ring-opened anionic oxaliplatin intermediate fitted the in vitro degradation time-course data. In cancer patients, calcium and magnesium plasma concentrations varied and were increased by giving calcium gluconate and magnesium sulfate infusions, but did not alter or correlate with oxaliplatin clearance. The intrinsic in vitro clearance of oxaliplatin attributed to chloride-, calcium- and magnesium-mediated degradation predicted contributions of <2.5% to the total in vivo clearance of oxaliplatin. In conclusion, calcium and magnesium accelerate the in vitro degradation of oxaliplatin by binding to a monochloro-monooxalato ring-opened anionic intermediate. Kinetic analysis of in vitro oxaliplatin stability data can be used for in vitro prediction of potential effects on oxaliplatin clearance in vivo. PMID- 28642474 TI - Comparing DNA enrichment of proliferating cells following administration of different stable isotopes of heavy water. AB - Deuterated water (2H2O) is a label commonly used for safe quantitative measurement of deuterium enrichment into DNA of proliferating cells. More recently, it has been used for labeling proteins and other biomolecules. Our in vitro - in vivo research reports important stable isotopic labeling enrichment differences into the DNA nucleosides and their isotopologues (e.g. deoxyadenosine (dA) M + 1, dA M + 2, dA M + 3), as well as tumor cell proliferation effects for various forms of commercially available stable heavy water (2H2O, H218O, and 2H218O). Using an in vitro mouse thymus tumor cell line, we determined that H218O provides superior DNA labeling enrichment quantitation, as measured by GC positive chemical ionization (PCI)-MS/MS. In addition, at higher but physiologically relevant doses, both 2H218O and 2H2O down modulated mouse thymus tumor cell proliferation, whereas H218O water had no observable effects on cell proliferation. The in vivo labeling studies, where normal mouse bone marrow cells (i.e. high turnover) were evaluated post labeling, demonstrated DNA enrichments concordant with measurements from the in vitro studies. Our research also reports a headspace-GC-NCI-MS method, which rapidly and quantitatively measures stable heavy water levels in total body water. PMID- 28642475 TI - A novel bZIP protein, Gsb1, is required for oxidative stress response, mating, and virulence in the human pathogen Cryptococcus neoformans. AB - The human pathogen Cryptococcus neoformans, which causes life-threatening meningoencephalitis in immunocompromised individuals, normally faces diverse stresses in the human host. Here, we report that a novel, basic, leucine-zipper (bZIP) protein, designated Gsb1 (general stress-related bZIP protein 1), is required for its normal growth and diverse stress responses. C. neoformans gsb1Delta mutants grew slowly even under non-stressed conditions and showed increased sensitivity to high or low temperatures. The hypersensitivity of gsb1Delta to oxidative and nitrosative stresses was reversed by addition of a ROS scavenger. RNA-Seq analysis during normal growth revealed increased expression of a number of genes involved in mitochondrial respiration and cell cycle, but decreased expression of several genes involved in the mating-pheromone-responsive MAPK signaling pathway. Accordingly, gsb1Delta showed defective mating and abnormal cell-cycle progression. Reflecting these pleiotropic phenotypes, gsb1Delta exhibited attenuated virulence in a murine model of cryptococcosis. Moreover, RNA-Seq analysis under oxidative stress revealed that several genes involved in ROS defense, cell-wall remodeling, and protein glycosylation were highly induced in the wild-type strain but not in gsb1Delta. Gsb1 localized exclusively in the nucleus in response to oxidative stress. In conclusion, Gsb1 is a key transcription factor modulating growth, stress responses, differentiation, and virulence in C. neoformans. PMID- 28642476 TI - Prevention of long-term memory loss after retrieval by an endogenous CaMKII inhibitor. AB - CaMK2N1 and CaMK2N2 are endogenous inhibitors of calcium/calmodulin-dependent protein kinase II (CaMKII), a key synaptic signaling molecule for learning and memory. Here, we investigated the learning and memory function of CaMK2N1 by knocking-down its expression in dorsal hippocampus of mice. We found that reduced CaMK2N1 expression does not affect contextual fear long-term memory (LTM) formation. However, we show that it impairs maintenance of established LTM, but only if retrieval occurs. CaMK2N1 knockdown prevents a decrease of threonine-286 (T286) autophosphorylation of alphaCaMKII and increases GluA1 levels in hippocampal synapses after retrieval of contextual fear LTM. CaMK2N1 knockdown can also increase CaMK2N2 expression, but we show that such increased expression does not affect LTM after retrieval. We also found that substantial overexpression of CaMK2N2 in dorsal hippocampus impairs LTM formation, but not LTM maintenance, suggesting that CaMKII activity is not required for LTM storage. Taken together, we propose a specific function for CaMK2N1; enabling LTM maintenance after retrieval by inhibiting T286 autophosphorylation of alphaCaMKII. PMID- 28642477 TI - Probing ultrafast pipi*/npi* internal conversion in organic chromophores via K edge resonant absorption. AB - Many photoinduced processes including photosynthesis and human vision happen in organic molecules and involve coupled femtosecond dynamics of nuclei and electrons. Organic molecules with heteroatoms often possess an important excited state relaxation channel from an optically allowed pipi* to a dark npi* state. The pipi*/npi* internal conversion is difficult to investigate, as most spectroscopic methods are not exclusively sensitive to changes in the excited state electronic structure. Here, we report achieving the required sensitivity by exploiting the element and site specificity of near-edge soft X-ray absorption spectroscopy. As a hole forms in the n orbital during pipi*/npi* internal conversion, the absorption spectrum at the heteroatom K-edge exhibits an additional resonance. We demonstrate the concept using the nucleobase thymine at the oxygen K-edge, and unambiguously show that pipi*/npi* internal conversion takes place within (60 +/- 30) fs. High-level-coupled cluster calculations confirm the method's impressive electronic structure sensitivity for excited state investigations.Many photo-induced processes such as photosynthesis occur in organic molecules, but their femtosecond excited-state dynamics are difficult to track. Here, the authors exploit the element and site selectivity of soft X-ray absorption to sensitively follow the ultrafast pipi*/npi* electronic relaxation of hetero-organic molecules. PMID- 28642478 TI - A novel plant E3 ligase stabilizes Escherichia coli heat shock factor sigma32. AB - The heat shock response is crucial for organisms against heat-damaged proteins and maintaining homeostasis at a high temperature. Heterologous expression of eukaryotic molecular chaperones protects Escherichia coli from heat stress. Here we report that expression of the plant E3 ligase BnTR1 significantly increases the thermotolerance of E. coli. Different from eukaryotic chaperones, BnTR1 expression induces the accumulation of heat shock factor sigma32 and heat shock proteins. The active site of BnTR1 in E. coli is the zinc fingers of the RING domain, which interacts with DnaK resulting in stabilizing sigma32. Our findings indicate the expression of BnTR1 confers thermoprotective effects on E. coli cells, and it may provide useful clues to engineer thermophilic bacterial strains. PMID- 28642479 TI - A genetically enhanced sterile insect technique against the fruit fly, Bactrocera dorsalis (Hendel) by feeding adult double-stranded RNAs. AB - RNAi based sterile insect technique (SIT) is an authentic insect management approach but requires proper target genes. During this study, spermless males were developed by interfering with germ cell differentiation and azoospermia related genes. Data demonstrates significant reductions in the target genes expressions (boul, zpg, dsx M , fzo and gas8) after oral dsRNAs administration. Knock down of target genes significantly affected the reproductive ability of males and reduced egg-hatching as compared to the control group. Furthermore, different combinations of selected gene dsRNAs (boul + zpg, boul + dsx M and zpg + dsx M ) were made, which resulted up to 85.40% of male sterility. The most effective combination was selected to prepare different concentrations of dsRNA, 250, 500, 750 and 1000 ng/MUl, that caused 18.97%, 38.68%, 58.02% and 85.40% male sterility, respectively. Subsequently, 1000 ng/MUl of the same combination of ds RNAs was used against differently aged adult flies (1, 5, 7, 10 days) which lead to 85.40%, 31.42%, 21.76% and 9.90% male sterility, respectively. SIT developed in this study showed that, boul + zpg combination of dsRNA feeding for 6 hours significantly reduced the number of spermatozoa and viability of sperm in 1-day old B. dorsalis flies. In short, this study provides an effective SIT technique for long-term B. dorsalis management. PMID- 28642480 TI - Haralick texture features from apparent diffusion coefficient (ADC) MRI images depend on imaging and pre-processing parameters. AB - In recent years, texture analysis of medical images has become increasingly popular in studies investigating diagnosis, classification and treatment response assessment of cancerous disease. Despite numerous applications in oncology and medical imaging in general, there is no consensus regarding texture analysis workflow, or reporting of parameter settings crucial for replication of results. The aim of this study was to assess how sensitive Haralick texture features of apparent diffusion coefficient (ADC) MR images are to changes in five parameters related to image acquisition and pre-processing: noise, resolution, how the ADC map is constructed, the choice of quantization method, and the number of gray levels in the quantized image. We found that noise, resolution, choice of quantization method and the number of gray levels in the quantized images had a significant influence on most texture features, and that the effect size varied between different features. Different methods for constructing the ADC maps did not have an impact on any texture feature. Based on our results, we recommend using images with similar resolutions and noise levels, using one quantization method, and the same number of gray levels in all quantized images, to make meaningful comparisons of texture feature results between different subjects. PMID- 28642481 TI - Deterministic radiative coupling of two semiconductor quantum dots to the optical mode of a photonic crystal nanocavity. AB - A system of two site-controlled semiconductor quantum dots (QDs) is deterministically integrated with a photonic crystal membrane nano-cavity. The two QDs are identified via their reproducible emission spectral features, and their coupling to the fundamental cavity mode is established by emission co polarization and cavity feeding features. A theoretical model accounting for phonon interaction and pure dephasing reproduces the observed results and permits extraction of the light-matter coupling constant for this system. The demonstrated approach offers a platform for scaling up the integration of QD systems and nano-photonic elements for integrated quantum photonics applications. PMID- 28642482 TI - Moving Bragg grating solitons in a semilinear dual-core system with dispersive reflectivity. AB - The existence, stability and collision dynamics of moving Bragg grating solitons in a semilinear dual-core system where one core has the Kerr nonlinearity and is equipped with a Bragg grating with dispersive reflectivity, and the other core is linear are investigated. It is found that moving soliton solutions exist as a continuous family of solutions in the upper and lower gaps of the system's linear spectrum. The stability of the moving solitons are investigated by means of systematic numerical stability analysis, and the effect and interplay of various parameters on soliton stability are analyzed. We have also systematically investigated the characteristics of collisions of counter-propagating solitons. In-phase collisions can lead to a variety of outcomes such as passage of solitons through each other with increased, reduced or unchanged velocities, asymmetric separation of solitons, merger of solitons into a quiescent one, formation of three solitons (one quiescent and two moving ones) and destruction of both solitons. The outcome regions of in-phase collisions are identified in the plane of dispersive reflectivity versus frequency. The effects of coupling coefficient, relative group velocity in the linear core, soliton velocity and dispersive reflectivity and the initial phase difference on the outcomes of collisions are studied. PMID- 28642483 TI - Masking of a circadian behavior in larval zebrafish involves the thalamo-habenula pathway. AB - Changes in illumination can rapidly influence behavior that is normally controlled by the circadian clock. This effect is termed masking. In mice, masking requires melanopsin-expressing retinal ganglion cells that detect blue light and project to the thalamus. It is not known whether masking is wavelength dependent in other vertebrates, nor is it known whether the thalamus is also involved or how it influences masking. Here, we address these questions in zebrafish. We find that diel vertical migration, a circadian behavior in larval zebrafish, is effectively triggered by blue, but not by red light. Two-photon calcium imaging reveals that a thalamic nucleus and a downstream structure, the habenula, have a sustained response to blue but not to red light. Lesioning the habenula reduces light-evoked climbing. These data suggest that the thalamo habenula pathway is involved in the ability of blue light to influence a circadian behavior. PMID- 28642484 TI - miR-100-5p inhibition induces apoptosis in dormant prostate cancer cells and prevents the emergence of castration-resistant prostate cancer. AB - Carcinoma of the prostate is the most common cancer in men. Treatment of aggressive prostate cancer involves a regiment of radical prostectomy, radiation therapy, chemotherapy and hormonal therapy. Despite significant improvements in the last decade, the treatment of prostate cancer remains unsatisfactory, because a significant fraction of prostate cancers develop resistance to multiple treatments and become incurable. This prompts an urgent need to investigate the molecular mechanisms underlying the evolution of therapy-induced resistance of prostate cancer either in the form of castration-resistant prostate cancer (CRPC) or transdifferentiated neuroendocrine prostate cancer (NEPC). By analyzing micro RNA expression profiles in a set of patient-derived prostate cancer xenograft tumor lines, we identified miR-100-5p as one of the key molecular components in the initiation and evolution of androgen ablation therapy resistance in prostate cancer. In vitro results showed that miR-100-5p is required for hormone independent survival and proliferation of prostate cancer cells post androgen ablation. In Silico target predictions revealed that miR-100-5p target genes are involved in key aspects of cancer progression, and are associated with clinical outcome. Our results suggest that mir-100-5p is a possible therapeutic target involved in prostate cancer progression and relapse post androgen ablation therapy. PMID- 28642485 TI - Sphingosine-1-Phosphate Treatment Can Ameliorate Microvascular Leakage Caused by Combined Alcohol Intoxication and Hemorrhagic Shock. AB - Fluid resuscitation following hemorrhagic shock is often problematic, with development of prolonged hypotension and edema. In addition, many trauma patients are also intoxicated, which generally worsens outcomes. We directly investigated how alcohol intoxication impacts hemorrhagic shock and resuscitation-induced microvascular leakage using a rat model with intravital microscopic imaging. We also tested the hypothesis that an endothelial barrier-protective bioactive lipid, sphingosine-1-phosphate (S1P), could ameliorate the microvascular leakage following alcohol intoxication plus hemorrhagic shock and resuscitation. Our results show that alcohol intoxication exacerbated hemorrhagic shock and resuscitation-induced hypotension and microvascular leakage. We next found that S1P effectively could reverse alcohol-induced endothelial barrier dysfunction using both cultured endothelial cell monolayer and in vivo models. Lastly, we observed that S1P administration ameliorated hypotension and microvascular leakage following combined alcohol intoxication and hemorrhagic shock, in a dose related manner. These findings suggest the viability of using agonists that can improve microvascular barrier function to ameliorate trauma-induced hypotension, offering a novel therapeutic opportunity for potentially improving clinical outcomes in patients with multi-hit injuries. PMID- 28642486 TI - npj Primary Care Respiratory Medicine broadens its focus to include global respiratory health, tobacco control and implementation science. PMID- 28642488 TI - Biomimetic Molecular Signaling using DNA Walkers on Microparticles. AB - We report the release of catalytic DNA walkers from hydrogel microparticles and the detection of those walkers by substrate-coated microparticles. This might be considered a synthetic biology analog of molecular signal release and reception. One type of particles was coated with components of a DNA one-step strand displacement (OSD) reaction to release the walker. A second type of particle was coated with substrate (or "track") for the molecular walker. We distinguish these particle types using fluorescence barcoding: we synthesized and distinguished multiple particle types with multicolor fluorescence microscopy and automated image analysis software. This represents a step toward amplified, multiplex, and microscopically localized detection based on DNA nanotechnology. PMID- 28642487 TI - Hypoxia is a Key Driver of Alternative Splicing in Human Breast Cancer Cells. AB - Adaptation to hypoxia, a hallmark feature of many tumors, is an important driver of cancer cell survival, proliferation and the development of resistance to chemotherapy. Hypoxia-induced stabilization of hypoxia-inducible factors (HIFs) leads to transcriptional activation of a network of hypoxia target genes involved in angiogenesis, cell growth, glycolysis, DNA damage repair and apoptosis. Although the transcriptional targets of hypoxia have been characterized, the alternative splicing of transcripts that occurs during hypoxia and the roles they play in oncogenesis are much less understood. To identify and quantify hypoxia induced alternative splicing events in human cancer cells, we performed whole transcriptome RNA-Seq in breast cancer cells that are known to provide robust transcriptional response to hypoxia. We found 2005 and 1684 alternative splicing events including intron retention, exon skipping and alternative first exon usage that were regulated by acute and chronic hypoxia where intron retention was the most dominant type of hypoxia-induced alternative splicing. Many of these genes are involved in cellular metabolism, transcriptional regulation, actin cytoskeleton organisation, cancer cell proliferation, migration and invasion, suggesting they may modulate or be involved in additional features of tumorigenic development that extend beyond the known functions of canonical full-length transcripts. PMID- 28642489 TI - Post-exposure treatment of non-human primates lethally infected with Ebola virus with EBOTAb, a purified ovine IgG product. AB - Despite sporadic outbreaks of Ebola virus (EBOV) over the last 4 decades and the recent public health emergency in West Africa, there are still no approved vaccines or therapeutics for the treatment of acute EBOV disease (EVD). In response to the 2014 outbreak, an ovine immunoglobulin therapy was developed, termed EBOTAb. After promising results in the guinea pig model of EBOV infection, EBOTAb was tested in the cynomolgus macaque non-human primate model of lethal EBOV infection. To ensure stringent therapeutic testing conditions to replicate likely clinical usage, EBOTAb was first delivered 1, 2 or 3 days post-challenge with a lethal dose of EBOV. Results showed a protective effect of EBOTAb given post-exposurally, with survival rates decreasing with increasing time after challenge. Viremia results demonstrated that EBOTAb resulted in a decreased circulation of EBOV in the bloodstream. Additionally, assay of liver enzymes and histology analysis of local tissues identified differences between EBOTAb-treated and untreated groups. The results presented demonstrate that EBOTAb conferred protection against EBOV when given post-exposure and should be explored and developed further as a potential intervention strategy for future outbreaks, which are likely to occur. PMID- 28642490 TI - Relationship between Kellgren-Lawrence score and 3D kinematic gait analysis of patients with medial knee osteoarthritis using a new gait system. AB - Knee osteoarthritis (KOA) is reported to have characteristic kinematics during walking. However, the relationship between Kellgren-Lawrence (K/L) score and the 3D kinematic gait of patients with medial KOA remains unclear. Here, ninety-seven patients with medial KOA and thirty-eight asymptomatic participants were involved. Patients with medial KOA were divided into early, moderate, and severe KOA based on the K/L score. Through kinematic gait analysis, we found a relationship between K/L score and 3D kinematic gait for patients. All KOA knees had a significantly reduced range of motion. As the K/L score was increasing, the knee flexion at the heel strike and 50% of the stance phase increased while the peak knee flexion in the swing phase decreased. In addition, the adduction and femoral rotation increased internally at the heel strike, 50% of the stance phase, and maximum angle of the swing phase. Femoral translation increased anteriorly and distally at the heel strike and 50% of the stance phase. The severe group had more medial translation than the asymptomatic groups. Significant alterations of three-dimensional joint kinematics were identified in subjects suffering various severities in Chinese patients. This study provides an important reference for the treatment options, therapy assessment, and rehabilitation of KOA. PMID- 28642491 TI - A cross-species approach to identify transcriptional regulators exemplified for Dnajc22 and Hnf4a. AB - There is an enormous need to make better use of the ever increasing wealth of publicly available genomic information and to utilize the tremendous progress in computational approaches in the life sciences. Transcriptional regulation of protein-coding genes is a major mechanism of controlling cellular functions. However, the myriad of transcription factors potentially controlling transcription of any given gene makes it often difficult to quickly identify the biological relevant transcription factors. Here, we report on the identification of Hnf4a as a major transcription factor of the so far unstudied DnaJ heat shock protein family (Hsp40) member C22 (Dnajc22). We propose an approach utilizing recent advances in computational biology and the wealth of publicly available genomic information guiding the identification of potential transcription factor candidates together with wet-lab experiments validating computational models. More specifically, the combined use of co-expression analyses based on self organizing maps with sequence-based transcription factor binding prediction led to the identification of Hnf4a as the potential transcriptional regulator for Dnajc22 which was further corroborated using publicly available datasets on Hnf4a. Following this procedure, we determined its functional binding site in the murine Dnajc22 locus using ChIP-qPCR and luciferase assays and verified this regulatory loop in fruitfly, zebrafish, and humans. PMID- 28642493 TI - Diffusional-displacive transformation enables formation of long-period stacking order in magnesium. AB - Mg is the most important lightweight engineering alloy enabling future weight reduced and fuel-saving engineering solutions. Yet, Mg is soft. Long-period stacking ordered (LPSO) structures in Mg alloys have unique crystal structures, characterized by both complex chemical and stacking order. They are essential for strengthening of Mg alloys. The formation mechanism of these LPSO structures is still under discussion. Here we report that Y/Zn enriched Guinier-Preston (GP) zones observed in a lean Mg-Y-Zn model alloy are precursors of early stage LPSO structures. We provide evidence of a new type of phase transformation mechanism which comprises the diffusional formation of Y/Zn enriched GP zones and their subsequent shear transformation into LPSO building blocks. The mechanism constitutes a new type of coupled diffusional-displacive phase formation sequence which may also be applicable to other alloy systems. PMID- 28642492 TI - Segregation of glutamatergic and cholinergic transmission at the mixed motoneuron Renshaw cell synapse. AB - In neonatal mice motoneurons excite Renshaw cells by releasing both acetylcholine (ACh) and glutamate. These two neurotransmitters activate two types of nicotinic receptors (nAChRs) ( the homomeric alpha7 receptors and the heteromeric alpha*beta* receptors) as well as the two types of glutamate receptors (GluRs) (AMPARs and NMDARs). Using paired recordings, we confirm that a single motoneuron can release both transmitters on a single post-synaptic Renshaw cell. We then show that co-transmission is preserved in adult animals. Kinetic analysis of miniature EPSCs revealed quantal release of mixed events associating AMPARs and NMDARs, as well as alpha7 and alpha*beta* nAChRs, but no evidence was found for mEPSCs associating nAChRs with GluRs. Bayesian Quantal Analysis (BQA) of evoked EPSCs showed that the number of functional contacts on a single Renshaw cell is more than halved when the nicotinic receptors are blocked, confirming that the two neurotransmitters systems are segregated. Our observations can be explained if ACh and glutamate are released from common vesicles onto spatially segregated post-synaptic receptors clusters, but a pre-synaptic segregation of cholinergic and glutamatergic release sites is also possible. PMID- 28642494 TI - Proteome profiling reveals novel biomarkers to identify complicated parapneumonic effusions. AB - Patients with pneumonia and parapneumonic effusion (PPE) have elevated mortality and a poor prognosis. The aim of this study was to discover novel biomarkers to help distinguish between uncomplicated PPE (UPPE) and complicated PPE (CPPE). Using an iTRAQ-based quantitative proteomics, we identified 766 proteins in pleural effusions from PPE patients. In total, 45 of these proteins were quantified as upregulated proteins in CPPE. Four novel upregulated candidates (BPI, NGAL, AZU1, and calprotectin) were selected and further verified using enzyme-linked immunosorbent assays (ELISAs) on 220 patients with pleural effusions due to different causes. The pleural fluid levels of BPI, NGAL, AZU1, and calprotectin were significantly elevated in patients with CPPE. Among these four biomarkers, BPI had the best diagnostic value for CPPE, with an AUC value of 0.966, a sensitivity of 97%, and a specificity of 91.4%. A logistic regression analysis demonstrated a strong association between BPI levels > 10 ng/ml and CPPE (odds ratio = 341.3). Furthermore, the combination of pleural fluid BPI levels with LDH levels improved the sensitivity and specificity to 100% and 91.4%, respectively. Thus, our findings provided a comprehensive effusion proteome data set for PPE biomarker discovery and revealed novel biomarkers for the diagnosis of CPPE. PMID- 28642495 TI - Rapid response to climate change in a marginal sea. AB - The Mediterranean Sea is a mid-latitude marginal sea, particularly responsive to climate change as reported by recent studies. The Sicily Channel is a choke point separating the sea in two main basins, the Eastern Mediterranean Sea and the Western Mediterranean Sea. Here, we report and analyse a long-term record (1993 2016) of the thermohaline properties of the Intermediate Water that crosses the Sicily Channel, showing increasing temperature and salinity trends much stronger than those observed at intermediate depths in the global ocean. We investigate the causes of the observed trends and in particular determine the role of a changing climate over the Eastern Mediterranean, where the Intermediate Water is formed. The long-term Sicily record reveals how fast the response to climate change can be in a marginal sea like the Mediterranean Sea compared to the global ocean, and demonstrates the essential role of long time series in the ocean. PMID- 28642496 TI - Nitrogen enrichment impacts on boreal litter decomposition are driven by changes in soil microbiota rather than litter quality. AB - In nitrogen (N) limited boreal forests, N enrichment can impact litter decomposition by affecting litter quality and by changing the soil environment where litter decomposes. We investigated the importance of litter quality and soil factors on litter decomposition using a 2-year reciprocal transplant experiment for Picea abies needle litter, derived from plots subjected to 17 years of N addition, including control, low and high N treatments (ambient, 12.5 and 50 kg N ha-1 yr-1, respectively). Our data show that changes in soil factors were the main pathway through which N impacted litter decomposition, with rates reduced by ~15% when placed in high N relative to control plots, regardless of litter origin. Litter decomposition was correlated to soil microbiota, with Picea abies litter decomposition positively correlated with gram negative and fungal functional groups. Our results suggest that previous findings of increase soil C accumulation in response to N deposition is likely to occur as a result of changes in soil microbiota rather than altered litter quality. PMID- 28642497 TI - Interactive effects of plant neighbourhood and ontogeny on insect herbivory and plant defensive traits. AB - Plant ontogenetic stage and features of surrounding plant neighbourhoods can strongly influence herbivory and defences on focal plants. However, the effects of both factors have been assessed independently in previous studies. Here we tested for the independent and interactive effects of neighbourhood type (low vs. high frequency of our focal plant species in heterospecific stands) and ontogeny on leaf herbivory, physical traits and chemical defences of the English oak Quercus robur. We further tested whether plant traits were associated with neighbourhood and ontogenetic effects on herbivory. We found that leaf herbivory decreased in stands with a low frequency of Q. robur, and that saplings received less herbivory than adult trees. Interestingly, we also found interactive effects of these factors where a difference in damage between saplings and adult trees was only observed in stands with a high frequency of Q. robur. We also found strong ontogenetic differences in leaf traits where saplings had more defended leaves than adult trees, and this difference in turn explained ontogenetic differences in herbivory. Plant trait variation did not explain the neighbourhood effect on herbivory. This study builds towards a better understanding of the concurrent effects of plant individual- and community-level characteristics influencing plant-herbivore interactions. PMID- 28642498 TI - Uptake and metabolism of arginine impact Plasmodium development in the liver. AB - Prior to infecting erythrocytes and causing malaria symptoms, Plasmodium parasites undergo an obligatory phase of invasion and extensive replication inside their mammalian host's liver cells that depends on the parasite's ability to obtain the nutrients it requires for its intra-hepatic growth and multiplication. Here, we show that L-arginine (Arg) uptake through the host cell's SLC7A2-encoded transporters is essential for the parasite's development and maturation in the liver. Our data suggest that the Arg that is taken up is primarily metabolized by the arginase pathway to produce the polyamines required for Plasmodium growth. Although the parasite may hijack the host's biosynthesis pathway, it relies mainly upon its own arginase-AdoMetDC/ODC pathway to acquire the polyamines it needs to develop. These results identify for the first time a pivotal role for Arg-dependent polyamine production during Plasmodium's hepatic development and pave the way to the exploitation of strategies to impact liver infection by the malaria parasite through the modulation of Arg uptake and polyamine synthesis. PMID- 28642499 TI - Comprehensive analysis and reinterpretation of Cenozoic mesofossils reveals ancient origin of the snapping claw of alpheid shrimps. AB - Alpheid snapping shrimps (Decapoda: Caridea: Alpheidae) constitute one of the model groups for inferences aimed at understanding the evolution of complex structural, behavioural, and ecological traits among benthic marine invertebrates. Despite being a super-diverse taxon with a broad geographical distribution, the alpheid fossil record is still poorly known. However, data presented herein show that the strongly calcified fingertips of alpheid snapping claws are not uncommon in the fossil record and should be considered a novel type of mesofossil. The Cenozoic remains analysed here represent a compelling structural match with extant species of Alpheus. Based on the presence of several distinct snapping claw-fingertip morphotypes, the major radiation of Alpheus lineages is estimated to have occurred as early as 18 mya. In addition, the oldest fossil record of alpheids in general can now be confirmed for the Late Oligocene (27-28 mya), thus providing a novel minimum age for the entire group as well as the first reliable calibration point for deep phylogenetic inferences. PMID- 28642500 TI - Genome-wide mapping of DNase I hypersensitive sites reveals chromatin accessibility changes in Arabidopsis euchromatin and heterochromatin regions under extended darkness. AB - Light, as the energy source in photosynthesis, is essential for plant growth and development. Extended darkness causes dramatic gene expression changes. In this study, we applied DNase-seq (DNase I hypersensitive site sequencing) to study changes of chromatin accessibility in euchromatic and heterochromatic regions under extended darkness in Arabidopsis. We generated 27 Gb DNase-seq and 67.6 Gb RNA-seq data to investigate chromatin accessibility changes and global gene expression under extended darkness and control condition in Arabidopsis. We found that ~40% DHSs (DNaseI hypersensitive sites) were diminished under darkness. In non-TE regions, the majority of DHS-changed genes were DHS-diminished under darkness. A total of 519 down-regulated genes were associated with diminished DHSs under darkness, mainly involved in photosynthesis process and retrograde signaling, and were regulated by chloroplast maintenance master regulators such as GLK1. In TE regions, approximately half of the DHS-changed TEs were DHS increased under darkness and were primarily associated with the LTR/Gypsy retrotransposons in the heterochromatin flanking the centromeres. In contrast, DHS-diminished TEs under darkness were enriched in Copia, LINE, and MuDR dispersed across chromosomes. Together, our results indicated that extended darkness resulted in more increased chromatin compaction in euchromatin and decompaction in heterochromatin, thus further leading to gene expression changes in Arabidopsis. PMID- 28642501 TI - Influence of Fermi arc states and double Weyl node on tunneling in a Dirac semimetal. AB - Most theoretical studies of tunneling in Dirac and the closely related Weyl semimetals have modeled these materials as single Weyl nodes described by the three-dimensional Dirac equation [Formula: see text]. The influence of scattering between the different valleys centered around different Weyl nodes, and the Fermi arc states which connect these nodes are hence not evident from these studies. In this work we study the tunneling in a thin film system of the Dirac semimetal Na3Bi consisting of a central segment with a gate potential, sandwiched between identical semi-infinite source and drain segments. The model Hamiltonian we use for Na3Bi gives, for each spin, two Weyl nodes separated in k-space symmetrically about k z = 0. The presence of a top and bottom surface in the thin film geometry results in the appearance of Fermi arc states and energy subbands. We show that (for each spin) the presence of two Weyl nodes and the Fermi arc states results in enhanced transmission oscillations, and finite transmission even when the energy falls within the bulk band gap in the central segment respectively. These features are not captured in single Weyl node models. PMID- 28642502 TI - Quasi-stabilized hydration layers on muscovite mica under a thin water film grown from humid air. AB - The interfaces between solids and water films in air play fundamental roles in physicochemical phenomena, biological functions, and nano-fabrication. Though the properties of the interfaces have been considered to be irrelevant to the water film thickness, we found distinctive mechanical features of the interface between a cleaved muscovite mica surface and a thin water film grown in humid air, dissimilar to those in bulk water, using frequency-modulation atomic force microscopy. The thin water film grew with quasi-stabilized hydration networks of water molecules, tightly bound each other at the interface, to a thickness of ~2 nm at near-saturating humidity. Consequently, defective structures of the hydration networks persisted vertically through the hydration layers at the interface, and K+ ions on the cleaved surface remained without dissolution into the water film. The results provide atomistic insights into thin water films in regard to epitaxial-like growth from vapour and the motion of water molecules and ions therein. PMID- 28642503 TI - Special feature: Team Up volunteering initiative: Smile Project. PMID- 28642506 TI - Learning from good practice: a review of current oral health promotion materials for parents of young children. AB - Objectives To examine the quality of UK-based oral health promotion materials (OHPM) for parents of young children aged 0-5 years old.Data sources OHPM were obtained via email request to dental public health consultants and oral health promotion teams in the UK, structured web-based searches or collected from oral health events.Data selection Materials were included if: they were freely available; they were in English; they were parent facing and included oral health advice aimed at children aged 0-5-years-old.Data extraction Quality assessment was based on: whether the oral health messages were consistent with Public Health England's Delivering better oral health guidance, and what barriers to good oral health were addressed by the OHPM using the Theoretical Domains Framework (TDF).Data synthesis A wide range of printed and digital OHPM were identified (n = 111). However, only one piece of material covered all 16 guidance points identified in Public Health England's Delivering better oral health (mean 6, SD 4), and one other material addressed all 12 domains of the TDF (mean 6, SD 2).Conclusions Although there were examples of high quality, further development is required to ensure OHPM are clear, consistent and address a wider range of barriers to good oral health behaviours. PMID- 28642507 TI - Mishandled elevators. PMID- 28642508 TI - Withholding treatment: what, whom and why? AB - Should a dentist triage the care of a patient who has sustained dental trauma, before treating a patient in pain because of dental neglect? PMID- 28642509 TI - In our opinion. AB - The misleading statements made in the British Dental Journal in the December 2016 issue relating to dental age assessment are assessed for inaccuracies and negligent omission of the issue of Child Protection. It is emphasised that there is a need for the approach of objective knowledge viz. not influenced by personal feelings or opinions in considering and representing facts. The article by the Chair of the Education, Ethics, and Team Working Group implies that unsatisfactory consent procedures are followed. The DARLInG (Dental Age Research London Information Group) have followed a carefully prescribed procedure that fulfils all the requirements of the advice given by the Consent Committee at King's College Hospital. In addition, the active support in the form of independent support workers and lawyers assisted by interpreters is described. The issue of the lawful use of ionising radiation is described with correct information about where this information can be obtained. The seriously misleading statements made by the Chair of the Education, Ethics and Education Working Group are identified. An unacceptable oversight is the failure of the BDA representatives to draw attention to the need for child protection. The potential benefit of dental age estimation in terms of appropriately providing support for asylum seekers is described.The failure of the BDA Ethics group to be up to date with recent research which shows a high level of certainty in assigning age disputed subjects to above (or below) the 18-year threshold is discussed and the importance of this in reliably determining, in an objective way, the age status of asylum seekers. The incorrect and salacious use of the term 'X-rated' is highlighted and a formal request for its withdrawal has been made. PMID- 28642513 TI - Birmingham showcases dental research. PMID- 28642511 TI - The Mental Capacity Act 2005: Considerations for obtaining consent for dental treatment. AB - The Mental Capacity Act 2005 provides a legal framework within which specific decisions must be made when an individual lacks the mental capacity to make such decisions for themselves. With an increasingly aged, medically complex and in some cases socially isolated population presenting for dental care, dentists need to have a sound understanding of the appropriate management of patients who lack capacity to consent to treatment when they present in the dental setting. Patients with acute symptoms requiring urgent care and un-befriended patients present additional complexities. In these situations a lack of familiarity with how best to proceed and confusion in the interpretation of relevant guidance, combined with the working time pressures experienced in dental practice may further delay the timely dental management of vulnerable patients. We will present and discuss the treatment of three patients who were found to lack the mental capacity necessary to make decisions about their dental care and illustrate how their differing situations determined the appropriate management for each. PMID- 28642516 TI - Oral health management of patients at risk of medication-related osteonecrosis of the jaw. AB - The dentist should not be alarmist about the risk for the patient of developing medication-related osteonecrosis of the jaw (MRONJ). PMID- 28642515 TI - Dental radiography: Plain film radiographs. PMID- 28642519 TI - Comment on the paper entitled 'Arginine and caries prevention: A systematic review'. AB - 'The Colgate-Palmolive Company is extremely proud of the clinical program ... addition of 1.5% arginine to fluoride toothpaste.' PMID- 28642517 TI - Green dentistry: the art and science of sustainable practice. AB - Dentistry is highly energy and resource intensive with significant environmental impact. Factors inherent in the profession such as enormous electricity demands of electronic dental equipment, voluminous water requirements, environmental effects of biomaterials (before, during and after clinical use), the use of radiation and the generation of hazardous waste involving mercury, lead etc have contributed towards this. With rising temperatures across the world due to global warming, efforts are being made worldwide to mitigate the effects of environmental damage by resorting to sustainability concepts and green solutions in a myriad of ways. In such a scenario, a professional obligation and social responsibility of dentists makes it imperative to transform the practice of dentistry from a hazardous to a sustainable one, by adopting environmental friendly measures or 'green dentistry'. The NHS in the UK has been proactive in implementing sustainability in healthcare by setting targets, developing guidance papers, initiating steering groups to develop measures and implementing actions through its Sustainable Development Unit (SDU). Such sustainable frameworks, specific to dentistry, are not yet available and even the scientific literature is devoid of studies in this field although anecdotal narratives abound. Hence this paper attempts to present a comprehensive evaluation of the existing healthcare sustainability principles, for their parallel application in the field of dentistry and lays out a blueprint for integrating the two main underlying principles of sustainability - resource use efficiency and eliminating or minimising pollution - in the day-to-day practice. The article also highlights the importance of social values, community care, engaging stakeholders, economic benefits, developing policy and providing leadership in converting the concept of green dentistry into a practised reality. PMID- 28642527 TI - Dental CHAMPs record rap to promote oral health. PMID- 28642521 TI - Knowledge of and attitudes to sports drinks of adolescents living in South Wales, UK. AB - Background The UK sports drinks market has a turnover in excess of L200 million. Adolescents consume 15.6% of total energy as free sugars, much higher than the recommended 5%. Sugar sweetened beverages, including sports drinks, account for 30% of total free sugar intake for those aged 11-18 years.Objective To investigate children's knowledge and attitudes surrounding sports drinks.Method One hundred and eighty-three self-complete questionnaires were distributed to four schools in South Wales. Children aged 12-14 were recruited to take part. Questions focussed on knowledge of who sports drinks are aimed at; the role of sports drinks in physical activity; and the possible detrimental effects to oral health. Recognition of brand logo and sports ambassadors and the relationship of knowledge to respondents' consumption of sports drinks were assessed.Results There was an 87% (160) response rate and 89.4% (143) claimed to drink sports drinks. 45.9% thought that sports drinks were aimed at everyone; approximately a third (50) viewed teenagers as the target group. Over two thirds recognised the brand logos, yet less than a third could identify brand ambassadors. About half were aware that dental erosion may result from consumption and approximately two thirds knew that they were linked to dental caries and energy provision. Despite this the majority claimed to drink them. As previously reported most of those drinking sports drinks did so because of the taste.Conclusion Whilst most of the respondents had some understanding of the detrimental effects on health the majority of them were drinking them regularly despite this knowledge. Work is therefore needed at a macro level, with soft drink manufacturers, to consider marketing and reformulation of products for adolescent consumers who appear to enjoy them. PMID- 28642528 TI - UK dentists urged to see children by age one. PMID- 28642530 TI - Oral health: Concrete example of altruism. PMID- 28642529 TI - OMFS: Rare condition. PMID- 28642532 TI - Oral Reconstruction Foundation Research Award. PMID- 28642534 TI - We are what others eat. PMID- 28642538 TI - Pathway National Inclusion Dentistry Network. PMID- 28642531 TI - Evidence summary: The relationship between oral diseases and diabetes. AB - Introduction This paper is the third of four rapid reviews undertaken to explore the relationships between oral health and general medical conditions in order to support teams within Public Health England, health practitioners and policymakers.Aims This review aimed to explore the nature of the association between poor oral health and diabetes when found in the same individuals or populations, having reviewed the most contemporary evidence in the field.Methods The reviews were undertaken by four groups each comprising consultant clinicians from medicine and dentistry, trainees, public health and academics. The methodology involved a streamlined rapid review process and synthesis of the findings.Results The results identified a number of systematic reviews of low to high quality suggesting that diabetes is associated with periodontal disease, tooth loss, and oral cancer in particular, and that the management of oral diseases, most notably periodontal care, has a short-term beneficial influence on metabolic outcomes related to diabetes; however, there is no evidence that this is sustained over the long-term and reduces the prevalence of the long-term complications.Conclusion Current evidence, of mixed quality, suggests a number of associations between oral diseases and diabetes mellitus (diabetes). Further high quality research is required in this field. PMID- 28642539 TI - BOS launches new resource for National Smile Month. PMID- 28642540 TI - Dental education: Potentially damaging disconnect. PMID- 28642541 TI - Can UK undergraduate dental programmes provide training in non-surgical facial aesthetics? AB - Aim Recently, more and more dentists have found themselves engaging in the delivery of non-surgical facial aesthetics (NSFA) as part of their regular practice routine. NSFA is a growing field in aesthetic medicine that is practised by a range of clinicians including doctors, dentists and registered prescriber nurses and is an industry estimated to be worth over L3 billion in the UK alone. In the past few years, several public scandals in aesthetic medicine have prompted reactions by several bodies including the Government and Royal Colleges. With Health Education England (HEE) having recently released standards in education, it is clear that a shift in attitude towards training is imminent. With a large volume of dentists making up this NSFA workforce it is reasonable to consider the stance of undergraduate training and the relevance of the existing knowledge within dentistry in the context of the HEE standards.Method All dental schools in the UK were contacted to establish the range of subjects taught within the curriculum, with particular reference to those relevant to NSFA. The two largest aesthetic pharmacies were contacted regarding numbers of registered dentists they serve.Results Twelve out of 16 dental schools responded. Two-thirds of responding dental schools do not cover NSFA in their curricula. However, many dental schools cover related subjects including: facial anatomy/material science/neuromuscular junction physiology (100%), anatomy of the aging face (66%), pharmacology of botulinum toxin (25%) and ethical-legal implications of aesthetic dentistry/NSFA (50%/42% respectively).Conclusion Dentists are well placed to deliver NSFA given their background in relevant subjects and surgical training. With the emergence and growth of such a large multi-disciplinary field it is crucial that dentistry is not left behind. Just as most dental schools have embraced the evolution of cosmetic dentistry and implantology, it would be prudent to consider that training standards around NSFA are reflected in both undergraduate curricula and appropriate post-graduate clinical training for dentistry. PMID- 28642542 TI - The highly rearranged mitochondrial genomes of the crabs Maja crispata and Maja squinado (Majidae) and gene order evolution in Brachyura. AB - We sequenced the mitochondrial genomes of the spider crabs Maja crispata and Maja squinado (Majidae, Brachyura). Both genomes contain the whole set of 37 genes characteristic of Bilaterian genomes, encoded on both alpha- and beta-strands. Both species exhibit the same gene order, which is unique among known animal genomes. In particular, all the genes located on the beta-strand form a single block. This gene order was analysed together with the other nine gene orders known for the Brachyura. Our study confirms that the most widespread gene order (BraGO) represents the plesiomorphic condition for Brachyura and was established at the onset of this clade. All other gene orders are the result of transformational pathways originating from BraGO. The different gene orders exhibit variable levels of genes rearrangements, which involve only tRNAs or all types of genes. Local homoplastic arrangements were identified, while complete gene orders remain unique and represent signatures that can have a diagnostic value. Brachyura appear to be a hot-spot of gene order diversity within the phylum Arthropoda. Our analysis, allowed to track, for the first time, the fully evolutionary pathways producing the Brachyuran gene orders. This goal was achieved by coupling sophisticated bioinformatic tools with phylogenetic analysis. PMID- 28642543 TI - Association of Obstructive Sleep Apnea with Asthma: A Meta-Analysis. AB - This study evaluates the relationship between obstructive sleep apnea (OSA) and asthma. Literature search was carried out in several electronic databases and random effects meta-analyses were performed to obtain pooled estimates of the prevalence of OSA, OSA risk and sleep disordered breathing (SDB) in asthma patients and pooled odds ratios of the prevalence between asthma and non-asthma patients. In adult asthma patients, the prevalence [95% confidence interval] of OSA, OSA risk, and SDB was 49.50 [36.39, 62.60] %, 27.50 [19.31, 35.69] %, and 19.65 [14.84, 24.46] % respectively. The odds of having OSA, OS risk and SDB by the asthma patients were 2.64 [1.76, 3.52], 3.73 [2.90, 4.57] and 1.73 [1.11, 2.36] times higher (p < 0.00001 for all) in asthma than in non-asthma patients, respectively. Adult asthma patients with OSA had significantly higher BMI in comparison with asthma patients without OSA. This study reveals that the prevalence of OSA in asthma patients is considerably higher; even higher than OSA risk and SDB. Sleep studies should be performed in asthma patients with symptoms suggestive of OSA/OSA risk/SDB. PMID- 28642544 TI - Resistin promotes the abnormal Type I collagen phenotype of subchondral bone in obese patients with end stage hip osteoarthritis. AB - The purpose of this study was to determine the effect of adiposity on the architecture and composition of hip OA subchondral bone, and to examine the pathological role of adipokines. Femoral heads were collected from normal-weight or over-weight/obese patients with hip OA. Structural parameters of subchondral bone were determined by MicroCT and type I collagen alpha1/alpha2 ratio was determined by SDS PAGE and by qRT-PCR in ex-vivo bone explants. The serum concentration of adipokines was determined by Luminex. The effect of resistin on primary OA osteoblasts was determined by analysis of Wnt pathway signal transduction, bone nodule formation, and osteoblast metabolic activity. Subchondral bone from over-weight/obese hip OA patients exhibited reduced trabecular thickness, increased bone surface/bone volume ratio, and an increase in the Type I collagen alpha1/alpha2, compared to normal-weight hip OA patients. The serum concentration of resistin was higher in overweight/obese OA patients, compared to normal-weight OA patients. Stimulation of normal-weight bone explant with recombinant resistin increased the Type I collagen alpha1/alpha2 ratio. Stimulation of primary OA osteoblasts with recombinant resistin increased Wnt signalling activation, osteoblast metabolic activity, and bone nodule formation. Increased adiposity in hip OA patients is associated with altered subchondral bone architecture and type I collagen composition. PMID- 28642545 TI - High-throughput Screening of Small Molecule Inhibitors of the Streptococcus Quorum-sensing Signal Pathway. AB - The main components of the quorum-sensing system are expected to be favorable targets for drug development to combat various chronic infectious diseases. ComA of Streptococcus is an ATP-binding cassette transporter containing a peptidase domain (PEP), which is essential for the quorum-sensing signal production. Using high-throughput screening, we found a potent small molecule that suppressed the S. mutans quorum-sensing pathway through inhibition of PEP activity. The compound effectively attenuated the biofilm formation and competence development of S. mutans without inhibiting cell growth. The kinetic and structural studies with this molecule and a related compound unexpectedly revealed an allosteric site of PEP. This relatively hydrophobic site is thought to undergo large structural changes during the catalytic process. These compounds inhibit PEP activity by binding to and suppressing the structural changes of this site. These results showed that PEP is a good target for inhibitors of the Streptococcus quorum sensing system. PMID- 28642546 TI - SLC4A11 depletion impairs NRF2 mediated antioxidant signaling and increases reactive oxygen species in human corneal endothelial cells during oxidative stress. AB - Corneal endothelial dystrophy is a progressive disease with gradual loss of vision and characterized by degeneration and dysfunction of corneal endothelial cells. Mutations in SLC4A11, a Na+ dependent OH- transporter, cause congenital hereditary endothelial dystrophy (CHED) and Fuchs' endothelial corneal dystrophy (FECD), the two most common forms of endothelial degeneration. Along with genetic factors, oxidative stress plays a role in pathogenesis of several corneal diseases. In this study we looked into the role of SLC4A11 in antioxidant stress response in human corneal endothelial cells (HCEnC). We found increased expression of SLC4A11 in presence of oxidative stress. Depletion of SLC4A11 using targeted siRNA, caused an increase in reactive oxygen species, cytochrome c, lowered mitochondrial membrane potential, and reduced cell viability during oxidative stress. Moreover, SLC4A11 was found to be necessary for NRF2 mediated antioxidant gene expression in HCEnC. On the other hand, over expression of SLC4A11 reduces reactive oxygen species levels and increases cell viability. Lastly, CHED tissue specimens show evidence of oxidative stress and reduced expression of NRF2. In conclusion, our data suggests a possible role of SLC4A11 in regulating oxidative stress, and might be responsible for both the etiology and treatment of corneal endothelial dystrophy. PMID- 28642547 TI - Human age and skin physiology shape diversity and abundance of Archaea on skin. AB - The human skin microbiome acts as an important barrier protecting our body from pathogens and other environmental influences. Recent investigations have provided evidence that Archaea are a constant but highly variable component of the human skin microbiome, yet factors that determine their abundance changes are unknown. Here, we tested the hypothesis that the abundance of archaea on human skin is influenced by human age and skin physiology by quantitative PCR of 51 different skin samples taken from human subjects of various age. Our results reveal that archaea are more abundant in human subjects either older than 60 years or younger than 12 years as compared to middle-aged human subjects. These results, together with results obtained from spectroscopy analysis, allowed us gain first insights into a potential link of lower sebum levels and lipid content and thus reduced skin moisture with an increase in archaeal signatures. Amplicon sequencing of selected samples revealed the prevalence of specific eury- and mainly thaumarchaeal taxa, represented by a core archaeome of the human skin. PMID- 28642548 TI - Hemodynamics of speech production: An fNIRS investigation of children who stutter. AB - Stuttering affects nearly 1% of the population worldwide and often has life altering negative consequences, including poorer mental health and emotional well being, and reduced educational and employment achievements. Over two decades of neuroimaging research reveals clear anatomical and physiological differences in the speech neural networks of adults who stutter. However, there have been few neurophysiological investigations of speech production in children who stutter. Using functional near-infrared spectroscopy (fNIRS), we examined hemodynamic responses over neural regions integral to fluent speech production including inferior frontal gyrus, premotor cortex, and superior temporal gyrus during a picture description task. Thirty-two children (16 stuttering and 16 controls) aged 7-11 years participated in the study. We found distinctly different speech related hemodynamic responses in the group of children who stutter compared to the control group. Whereas controls showed significant activation over left dorsal inferior frontal gyrus and left premotor cortex, children who stutter exhibited deactivation over these left hemisphere regions. This investigation of neural activation during natural, connected speech production in children who stutter demonstrates that in childhood stuttering, atypical functional organization for speech production is present and suggests promise for the use of fNIRS during natural speech production in future research with typical and atypical child populations. PMID- 28642549 TI - Focal Adhesion Kinase Regulates Hepatic Stellate Cell Activation and Liver Fibrosis. AB - Understanding the underlying molecular mechanisms of liver fibrosis is important to develop effective therapy. Herein, we show that focal-adhesion-kinse (FAK) plays a key role in promoting hepatic stellate cells (HSCs) activation in vitro and liver fibrosis progression in vivo. FAK activation is associated with increased expression of alpha-smooth muscle actin (alpha-SMA) and collagen in fibrotic live tissues. Transforming growth factor beta-1 (TGF-beta1) induces FAK activation in a time and dose dependent manner. FAK activation precedes the alpha SMA expression in HSCs. Inhibition of FAK activation blocks the alpha-SMA and collagen expression, and inhibits the formation of stress fibers in TGF-beta1 treated HSCs. Furthermore, inhibition of FAK activation significantly reduces HSC migration and small GTPase activation, and induces apoptotic signaling in TGF beta1 treated HSCs. Importantly, FAK inhibitor attenuates liver fibrosis in vivo and significantly reduces collagen and alpha-SMA expression in an animal model of liver fibrosis. These data demonstrate that FAK plays an essential role in HSC activation and liver fibrosis progression, and FAK signaling pathway could be a potential target for liver fibrosis. PMID- 28642550 TI - Cytokines regulate complement receptor immunoglobulin expression and phagocytosis of Candida albicans in human macrophages: A control point in anti-microbial immunity. AB - Complement Receptor Immunoglobulin (CRIg), selectively expressed by macrophages, plays an important role in innate immunity by promoting phagocytosis of bacteria. Thus modulation of CRIg on macrophages by cytokines can be an important mechanism by which cytokines regulate anti-microbial immunity. The effects of the cytokines, tumor necrosis factor, transforming growth factor-beta1, interferon gamma, interleukin (IL)-4, IL-13, IL-10, IL-1beta, IL-6, lymphotoxin-alpha, macrophage-colony stimulating factor (M-CSF) and GM-CSF on CRIg expression were examined in human macrophages. We demonstrated that cytokines regulated the CRIg expression on macrophages during their development from monocytes in culture at the transcriptional level using qPCR and protein by Western blotting. Both CRIg spliced forms (Long and Short), were similarly regulated by cytokines. Direct addition of cytokines to matured CRIg+ macrophages also changed CRIg mRNA expression, suggesting that cytokines control macrophage function via CRIg, at two checkpoints. Interestingly the classical complement receptors, CR3 and CR4 were differentially regulated by cytokines. The changes in CRIg but not CR3/CR4 mRNA expression correlated with ability to phagocytose Candida albicans by macrophages. These findings suggest that CRIg is likely to be a control point in infection and immunity through which cytokines can mediate their effects, and is differentially regulated from CR3 and CR4 by cytokines. PMID- 28642551 TI - Aesthetic preformed crowns for primary teeth. AB - Data sourcesMedline, Cochrane central register of controlled trials, US National Institutes of Health Trials Register and the World Health Organization International Clinical Trials Registry Platform.Study selectionEnglish language randomised clinical trials comparing APCs with conventional restorative techniques for primary teeth.Data extraction and synthesisStudy selection and data abstraction were conducted independently by two reviewers. Risk of bias was assessed using the Cochrane risk of bias tool. Study characteristics and results were described qualitatively. Meta-analysis was not conducted.ResultsSeven studies were included, six reported on primary molars and one on primary incisors. There was great variety in the design of the RCTs, however, all compared pre-veneered stainless steel crowns (SSCs) with other crowns or two different pre-veneered SSCs. The risk of bias in all studies was high with significantly different outcome measures used.ConclusionsSSCs cannot be replaced by APCs for restoring decayed primary molar teeth due to the insufficient quality of evidence available. After a follow-up of only six months, zircon crowns gave significantly better results than the others regarding gingival health and crown fractures. Due to the small number of RCTs on this topic and their risk of bias, future RCTs should be carried out in primary teeth. PMID- 28642552 TI - Trial finds better haemostasis with aluminium chloride during periapical surgery. AB - DesignRandomised controlled trial in a university setting.InterventionPatients were randomised to epinephrine impregnated gauze or aluminium chloride for periapical surgery involving a single tooth with a periapical area of <10mm.Outcome measureHaemorrhage control.ResultsOne hundred and twenty patients were randomised, with 98 being allocated. Forty-eight patients in the epinephrine group and 51 in the aluminium chloride group were analysed. Adequate haemostasis was achieved in 25 (52.1%) of the epinephrine group and 37 (72.5%) of the aluminium chloride group, a statistically significant difference.ConclusionsThe outcome showed better efficacy of haemostasis in the aluminium chloride group than in the gauze impregnated epinephrine group. The analysis of the patients and tooth-dependent variables showed no relationship with the effectiveness of haemostasis. PMID- 28642553 TI - Effect of essential oil mouthwashes on plaque and gingivitis. AB - Data sourcesMedline, Embase, LILACS and Scopus database.Study selectionStudies were screened independently by three reviewers. Randomised controlled trials with a minimum of six months follow-up of daily use of essential oils-containing (EO) mouthwashes compared with placebo, flossing or cetylpyridinium chloride (CPC) as adjuncts to mechanical plaque control were considered.Data extraction and synthesisData were abstracted by two reviewers and study quality assessed using the Cochrane risk of bias tool. Dental plaque was summarised using the Turesky modification of the Quigley-Hein Index (QHI), gingivitis using three indices; the Gingival Index (GI) by Loe and Silness, the Modified Gingival Index (MGI) and bleeding upon probing. Mean and standard deviations were reported and meta analysis conducted. Sources of effect modification were investigated using meta regression.ResultsSixteen trials were included involving 4016 patients in total. Study quality was considered to be moderate to low. Compared with placebo meta analysis of 14 studies showed statistically significant differences in favour of EO mouthwashes for plaque and gingival indices. Meta-analysis of four studies also demonstrated statistically lower levels of plaque and gingivitis for EO mouthwashes compared with cetylpyridium chloride (CPC). Meta-regression indicated that heterogeneity observed in plaque scores was mainly explained by the percentage of males in a trial and supervision of the mouthwash use.ConclusionsIn patients with gingivitis, EO-containing mouthwashes are more efficacious for the reduction of plaque and gingival inflammation than mechanical plaque control either alone (placebo) or in combination with mouthwashes with CPC. The expected benefits may be clinically relevant and may be also observed in the interproximal area. PMID- 28642554 TI - Delivery of information to orthodontic patients using social media. AB - DesignRandomised controlled trial in a hospital setting.InterventionBoth groups were given standard verbal and written information for patients receiving orthodontic treatment. In addition, patients in the intervention group received e mails asking them to view a specifically designed YouTube unlisted video accessible through a web link in the e-mail. All patients were administered with a baseline questionnaire at bond-up which was repeated at six weeks.Outcome measureChange in question score from baseline.ResultsSixty-seven patients were randomised (control = 34; intervention = 34). Seven patients were lost to follow up; four in the control and three in intervention group. In all the participants watched the video 90 times. Participants in the intervention group scored, on average, almost one point higher on the second questionnaire than did those in the control group (95% CI for the difference, 0.305-1.602; P = 0.005). Ethnicity had a statistically significant effect on improvement in knowledge, but sex did not.ConclusionsPresenting audiovisual information through the YouTube web site to orthodontic patients resulted in a significant improvement in patient knowledge. Supplementation of verbal and written patient information with audiovisual information via the internet is therefore worthy of consideration. PMID- 28642555 TI - Chlorhexidine mouthwash plaque levels and gingival health. AB - Data sourcesCochrane Oral Health's Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL) Medline; clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform. There were no language or date restrictions on searches.Study selectionRandomised controlled trials (RCTs) assessing the effects of chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for at least four weeks on gingivitis in children and adults.Data extraction and synthesisTwo reviewers independently abstracted data and assessed risk of bias. Mean and standardised mean differences were used for continuous outcomes and risk ratios for dichotomous outcomes. Meta-analysis was carried out where studies of similar comparisons reported the same outcomes at the same time interval.ResultsFifty-one RCTs involving a total of 5,345 patients were included. Only one study was at low risk of bias, the other 50 were at high risk. For patients with mild gingivitis (gingival index [GI] 0 to 3 scale) four to six weeks' use of chlorhexidine mouthrinse reduced gingivitis by 0.21 (95% CI; 0.11 to 0.31) with a similar effect at six months. There were insufficient data to assess the effect on patients with moderate or severe gingival inflammation. For plaque there was a larger effect in favour of chlorhexidine mouthrinse at four to six weeks, SMD (standardised mean difference) = -1.45 (95% CI; -1.90 to -1.00), with a similarly large reduction at six months. A large increase in extrinsic tooth staining was seen with chlorhexidine use at four to six weeks, SMD = 1.07 (95%CI; 0.80 to 1.34) and seven to twelve weeks and six months. A range of other adverse effects were reported including taste disturbance/alteration, oral mucosa symptoms including soreness, irritation, mild desquamation and mucosal ulceration/erosions, and a general burning sensation or a burning tongue or both.ConclusionsThere is high quality evidence from studies that reported the Loe and Silness Gingival Index of a reduction in gingivitis in individuals with mild gingival inflammation on average (mean score of 1 on the 0 to 3 GI scale) that was not considered to be clinically relevant. There is high quality evidence of a large reduction in dental plaque with chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for four to six weeks and six months. There is no evidence that one concentration of chlorhexidine rinse is more effective than another. There is insufficient evidence to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 indicating moderate or severe levels of gingival inflammation. Rinsing with chlorhexidine mouthrinse for four weeks or longer causes extrinsic tooth staining. In addition, other adverse effects such as calculus build up, transient taste disturbance and effects on the oral mucosa were reported in the included studies. PMID- 28642556 TI - The PROCESS of CARE. PMID- 28642557 TI - Smokeless tobacco - a substantial risk for oral potentially malignant disorders in South Asia. AB - Data sourcesMedline, the Science Citation Index (SCI) via Web of Science, Scopus, CINAHL, Global Index Medicus, Google Scholar and SLT-related reports of the International Agency for Research on Cancer and the National Cancer Institute of the United States.Study selectionObservational studies on the use of SLT and the risk of developing OPMDs in South Asian Populations.Data extraction and synthesisDuplicate selection of studies was undertaken with two reviewers undertaking data abstraction and quality assessment independently. Risk and odds ratios were extracted or calculated for studies where possible. Meta odds ratios (mOR) were calculated using a random effects analysis.ResultsFifteen papers reporting 18 studies were included. The majority (12) were from India. All the studies were case-control designs. MOR for any OPMD with the use of any SLT product was 15.5 (95% CI; 9.9-24.2). Risk was higher in women; mOR = 22.2 (95% CI, 9.1-54.1) than men; mOR = 8.7 (95% CI, 2.1-34.8). Betel quid with tobacco carried the highest risk for OPMD, mOR = 16.1 (95% CI, 7.8-33.5).ConclusionsThe findings of our study point towards a strong association between some forms of OPMDs and SLT use in South Asia. The risk estimates are high, irrespective of controlling for confounders such as smoking and alcohol or stratification by sex, country or source of controls. There is also an exposure-response relationship between OPMDs and SLT use. PMID- 28642558 TI - No differences in longevity of direct and indirect composite restorations. AB - Data sourcesMedline, Cochrane Library, Web of Science, Scopus, Latin American and Caribbean Health Sciences (LILACS), Brazilian Library of Dentistry (BBO), clinicaltrials.gov and SIGLE databases.Study selectionOnly randomised clinical trials were considered that compared direct vs indirect composite restorations, with or without cusp involvement, having a follow-up period of two years or greater.Data extraction and synthesisTwo reviewers selected studies for inclusion, abstracted data and assessed risk of bias. A fixed effects meta analysis was conducted.ResultsNine studies met the inclusion criteria with six contributing to the meta-analysis. There was no statistically significant difference in clinical longevity for direct and indirect resin composite restorations; relative risk (RR) = 1.494 (95% CI; 0.893-2.500, p = 0.126). Comparing molars and premolars restored with DRC and IRC at three years there was no significant difference; RR = 0.716 (95% CI; 0.177-2.888, p = 0.638).ConclusionsThe results of the review indicate that there is no statistically significant difference in failure rate of direct resin composites vs indirect resin composites. Longitudinal studies on today's improved materials should, however, be considered for further review. PMID- 28642559 TI - Little evidence to support or refute interventions for the management of burning mouth syndrome. AB - Data sourcesCochrane Oral Health's Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Medline Ovid, Embase Ovid, US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform. Handsearch of the proceedings from the British Society for Oral Medicine (BSOM), British Society for Dental Research (BSDR) and the International Association for Dental Research (IADR).Study selectionAll included studies were randomised placebo controlled trials comparing a treatment to placebo with no language or year of publication restrictions. Symptom relief and changes in quality of life were considered primary outcomes.Data extraction and synthesisTeams of two authors independently screened for inclusion, extracted data using an ad-hoc tool and assessed the risk of bias using the Cochrane's tool. Outcomes were analysed for <3 months (short term) and >=3 to <=6 months (long term). For single studies with multiple interventions, the number of participants in the control group was adjusted to half before combining the results. For crossover studies without washout periods, the first period was analysed. RRs (risk ratios) and 85% confidence intervals were calculated for dichotomous outcomes and MDs (mean differences) and 95% confidence intervals for continuous data.ResultsA total of 23 studies encompassing 1121 patients were included. One study was considered as having overall low risk of bias, four unclear and the rest as high risk of bias. The interventions were grouped into: antidepressants and antipsychotics, anticonvulsants, benzodiazepines, cholinergics, dietary supplements, electromagnetic radiation, physical barriers, psychological therapies and topical treatments. Short-term symptom relief was demonstrated by: energy waves (one study, 58 participants) MD -30.36, 95% CI -44.22 to -16.50, physical barriers (one study, 50 participants) MD -1.1 95% CI -2.14 to 0.06, the anticonvulsant gabapentin (one study, 100 participants) RR 4.00, 95% CI 2.09 to 7.67 and topical benzodiazepine (two studies, 111 participants) MD -1.89 95% CI -2.19 to -1.59. Long term symptom relief was achieved with topical benzodiazepine (one study, 66 participants) MD -1.39 95% CI -1.96 to 0.83ConclusionsFrom studies mostly classified as high risk of bias, there is insufficient evidence to support or refute the use of any particular intervention for the management of BMS. PMID- 28642562 TI - What is the methodological quality of published dental implant guidelines? AB - Data sourcesSix implant dentistry journals with impact factors (2014) assigned by Journal Citation Reports (Clinical Oral Implants Research, Clinical Implant Dentistry and Related Research, European Journal of Oral Implants, The International Journal of Oral and Maxillofacial Implants, Journal of Oral Implantology, and Implant Dentistry) and the Medline database.Study selectionTwo reviewers independently selected guidelines published between May 2009 and February 2016.Data evaluationFollowing training four reviewers independently applied the Agree II tool (http://www.agreetrust.org/) to the selected guidelines with disagreements being resolved by discussion. Scores for the six domains of the AGREE II tool were presented as median percentages of the maximum possible with their respective interquartile ranges (IQR). Domain scores were divided into consensus guidelines, and consensus guidelines with systematic reviews.ResultsTwenty-seven consensus guidelines were included, with 19 contributing to the comparisons between groups. Twenty-six guidelines were developed after meetings in Europe, with the European Association of Osseointergration developing the most guidelines (n=9). The number of authors for the guidelines varied from 2-27 (median, 9). For consensus guidelines only domain four scored highest. Guidelines with systematic review scored higher for all domains with the exception of domain five (Table 1).ConclusionsThere is room to improve the quality of consensus guidelines published in highly ranked implant dentistry journals. Clinicians' and researchers' development of consensus guidelines to improve clinical treatment with dental implants is laudable. However, as for primary and secondary research, these guidelines should adhere to high and transparent standards. The AGREE II instrument can be used as a reference for the development of high-quality guidelines to provide unbiased and adequate clinical recommendations to clinicians working with dental implants. PMID- 28642563 TI - Root canal treatment outcomes not affected by increasing age of patient. AB - Data sourcesMedline, Cochrane CENTRAL databases; most recent two years of seven journals: (Acta Odontologica Scandinavica; Community Dentistry and Oral Epidemiology; Gerodontology; International Endodontic Journal; Journal of Endodontics; Journal of Oral Rehabilitation; and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology).Study selectionTooth-based longitudinal prospective and retrospective studies, published in English from January 1950 to August 2013, assessing outcomes of NSRCT in adults with permanent teeth.Data extraction and synthesisStudies were independently selected and reviewed by two reviewers. Standardised items were extracted and compiled into a table of evidence. Study quality was assessed by the Wong Scale-Revised and those that scored less than 18 were excluded. Due to the high heterogeneity in reporting, meta-analysis was not conducted. All of the success criteria were implicitly based upon the presence or absence of apical pathology, and each individual study made internal comparisons of success using the same criteria.ResultsOf the twenty four studies selected, involving more than 17,430 teeth, nine were prospective and fifteen were retrospective studies. The overall mean study quality rating was 23(SD = 3) on the 27-point Wong Scale-Revised. Since the majority of the papers did not report raw numbers, and due to the heterogeneity in reporting, meta-analysis was not performed. In summary, eight prospective and fourteen retrospective studies reported no difference in outcomes, principally success which was defined by the absence of apical disease, with age. One prospective and one retrospective study reported an improvement in success with increasing age.ConclusionsThe moderate evidence indicated that increased patient age does not decrease the success of NSRCT. PMID- 28642564 TI - Remineralisation and arresting caries in children with topical fluorides. AB - Data sourcesThe Cochrane Library, PubMed, Embase and the ISI Web of Science.Study selectionEnglish language clinical trials in children with outcome measures including the remineralisation or arresting effect of caries by professional fluoride treatment were considered.Data extraction and synthesisTwo reviewers screened the studies and assessed risk of bias. Random effects meta-analysis was conducted.ResultsSeventeen studies were included, ten focused on remineralisation, seven on arresting carious lesions. Meta-analysis of four studies using 5% fluoride varnish found a 63.6% (95% CI; 36.0% - 91.2%) remineralisation of early enamel caries. For five studies using 38% silver diamine fluoride solution meta-analysis found 65.9% (95% CI; 41.2% - 90.7%) of caries arrested.ConclusionsProfessionally applied 5% sodium fluoride varnish shows the capability to remineralise early enamel caries in children. Silver diamine fluoride solution at 38% is effective in arresting active dentine caries. Because the number of clinical trials that studied the arresting effect of dental caries is limited, more clinical trials should be performed. PMID- 28642565 TI - No evidence available on best therapies for postextraction haemorrhage. AB - Data sourcesThe review searched for published and ongoing trials in several databases with no restrictions on language or date of publication which included the Cochrane Oral Health Group Trials, Central Register of Controlled Trials, Medline, CINAHL, Embase, WHO Clinical Trials Registry Platform and clinical trial.gov.Study selectionRandomised clinical trials were considered that evaluated any intervention compared with another or with placebo for treating postoperative bleeding (PEB), post extraction. The primary outcome measures sought were: bleeding, amount of blood loss and cessation time required to control bleeding. The secondary outcomes: patient reported outcomes, such as pain or discomfort and adverse events.Data extraction and synthesisThree pairs of review authors independently screened the records.ResultsThe search strategy identified 1526 articles and abstracts. After removal of duplicates, 943 records were screened. Thirty-four full texts were examined. No trials met the inclusion criteria for the review.ConclusionsWe were unable to identify any reports of randomised controlled trials that evaluated the effects of different interventions for the treatment of post-extraction bleeding. In view of the lack of reliable evidence on this topic, clinicians must use their clinical experience to determine the most appropriate means of treating this condition, depending on patient-related factors. There is a need for well designed and appropriately conducted clinical trials on this topic, which conform to the CONSORT statement (www.consort-statement.org/). PMID- 28642567 TI - Mouthguard use may reduce dentofacial injuries in field hockey players. AB - Data sourcesPubMed, Embase, OvidSP, Web of Science, Cochrane and CINAHL databases were searched up to February 2015 with no language restrictions.Study selectionTwo review authors independently assessed tiles and abstracts of the retrieved case-control, cohorts and cross-sectional studies. For the studies to have been included in the meta-analysis, they must have included the total number of hockey players reporting at least one dentofacial injury, the total number of these injuries compared with other types of injuries and quantitative data on characteristics of dentofacial injuries. Recreational and competitive elite level were included.Data extraction and synthesisThe included studies fell into three categories, related to dentofacial injury, mouthguard use or both, and their quality was assessed using the Newcastle-Ottawa Scale (NOS). A random effects model was used to calculate the overall effect size when appropriate; if not, then pooled prevalence was reported. Binary variables were used in order to express the results as Mantel-Haenszel pooled prevalence odds ratios (OR) with 95% confidence intervals (CI) and a p-value of the overall effect. To compare the between-studies differences, a chi2 test was used. The heterogeneity across the studies was evaluated using the I2.ResultsEleven studies were included: six related to dentofacial injury, one related to mouthguard use and four to both. The numbers of field hockey players who presented at least one dentofacial injury was 12.7% (95% CI 8.5% to 17.0%) and 45.2% (95% CI 39.3% to 51.0%) in junior/senior players and elite players, respectively. There were no significant differences with respect to sex. After 2000, 84.5% (95% CI 69.3% to 99.7%) of players regularly wore mouthguards, whereas only 31.4% (95% CI 22.7% to 40.1%) wore mouthguards previous to 2000. The mouthguards were commonly depicted as unnecessary and uncomfortable by players.ConclusionsDentofacial trauma poses a serious problem in field hockey, but a considerable number of players still do not regularly wear mouthguards. The likelihood is that if mouthguard usage were higher, fewer dentofacial injuries would occur during field hockey games and in training.Source of fundingNone declared. PMID- 28642568 TI - Treatment for bisphosphonate-related osteonecrosis of the jaw. AB - Data sourcesCochrane Oral Health Group Trials Register, CENTRAL, Medline, Embase, CancerLit, CINAHL, AMED, clinicaltrials.gov and the WHO International Trial Registry Platform. The reviewers searched six grey literature sites and contacted authors, researchers and pharmaceutical companies.Study selectionRandomised controlled trials for the treatment of BRONJ comparing interventions with other treatment or placebo were included in any setting with no age restriction.Data extraction and synthesisIndependently, two reviewers selected studies for inclusion, risk of bias and data extraction. The main outcome was healing. Secondary outcomes were pain improvement and quality of life.ResultsOne RCT with 49 patients met the inclusion criteria comparing the addition of hyperbaric oxygen therapy to standard of care alone. Changes in the lesion size and number were assessed at 3, 6, 12 and 18 months. Pain was assessed weekly while quality of life was assessed at baseline and six months. Improvement, as measured by the decrease in the size or number of lesions, achieved a RR 1.94, CI 95% (1.01 to 3.74) at three months. No other measure of this outcome was statistically significant. Pain changes and quality of life could not be numerically analysed.ConclusionsThe authors concluded that there is insufficient evidence to support a particular regimen for the treatment of BRONJ. PMID- 28642569 TI - No evidence that bonding is needed for amalgam restorations. AB - Data sourcesRelevant databases were searched for the review such as the Cochrane Oral Health Group Trials Register, Medline, EMBASE, clinical trials.gov, WHO International Clinical Trials Registry Platform.Study selectionRandomised controlled trials comparing adhesively bonded versus non-bonded class I and II amalgam restorations in permanent molars and premolars.Data extraction and synthesisTwo reviewers independently screened papers and extracted data.ResultsOne trial with 31 patients who received 113 restorations was included. At two years, 50 out of 53 restorations in the non-bonded group survived and 55 of 60 restorations survived with five unaccounted for at follow up. Post insertion sensitivity was not statistically significant at baseline and for the two-year follow-up. No fractures or differences in the marginal adaptation were reported.ConclusionsThere is no evidence either to claim or to refute a difference in survival between bonded and non-bonded amalgam restorations. In view of the lack of evidence on the additional benefit of adhesively bonding amalgam in comparison with non-bonded amalgam, it is important that clinicians be mindful of the additional costs that may be incurred. PMID- 28642570 TI - Thermal stability and topological protection of skyrmions in nanotracks. AB - Magnetic skyrmions are hailed as a potential technology for data storage and other data processing devices. However, their stability against thermal fluctuations is an open question that must be answered before skyrmion-based devices can be designed. In this work, we study paths in the energy landscape via which the transition between the skyrmion and the uniform state can occur in interfacial Dzyaloshinskii-Moriya finite-sized systems. We find three mechanisms the system can take in the process of skyrmion nucleation or destruction and identify that the transition facilitated by the boundary has a significantly lower energy barrier than the other energy paths. This clearly demonstrates the lack of the skyrmion topological protection in finite-sized magnetic systems. Overall, the energy barriers of the system under investigation are too small for storage applications at room temperature, but research into device materials, geometry and design may be able to address this. PMID- 28642571 TI - Pharmacokinetic and pharmacodynamic modeling of cyadox against Clostridium perfringens in swine. AB - The purpose of this study was to evaluate the activity of cyadox against Clostridium perfringens in swine and optimize the dosage regimen using ex vivo pharmacokinetic-pharmacodynamic (PK-PD) modeling. After oral administration, the ileum fluid of pigs containing the free cyadox was collected by implanted ultrafiltration probes. The Tmax, AUC24h, and CL/F of free cyadox in the ileum fluid were 1.96 h, 106.40 MUg/h/mL, and 0.27 L/kg/h, respectively. Cyadox displayed a concentration-dependent killing action against C. perfrignens. The minimum inhibitory concentration (MIC) of cyadox against 60 clinical isolates ranged from 0.5 to 8 MUg/mL, with MIC50 and MIC90 values of 2 and 4 MUg/mL, respectively. The MIC was 2 MUg/mL against the pathogenic C. perfrignens isolate CPFK122995 in both broth and ileum fluid. According to the inhibitory sigmoid Emax modeling, the AUC24h/MIC ratios of ileum fluid required to achieve the bacteriostatic, bactericidal, and virtual bacterial elimination effects were 26.72, 39.54, and 50.69 h, respectively. Monte Carlo simulations for the 90% target attainment rate (TAR) predicted daily doses of 29.30, 42.56, and 54.50 mg/kg over 24 h to achieve bacteriostatic, bactericidal, and elimination actions, respectively. The results of this study suggest that cyadox is a promising antibacterial agent for the treatment of C. perfringens infections, and can be used to inform its clinical use. PMID- 28642572 TI - Disrupted pursuit compensation during self-motion perception in early Alzheimer's disease. AB - Our perception of the world is remarkably stable despite of distorted retinal input due to frequent eye movements. It is considered that the brain uses corollary discharge, efference copies of signals sent from motor to visual regions, to compensate for distortions and stabilize visual perception. In this study, we tested whether patients with Alzheimer's disease (AD) have impaired corollary discharge functions as evidenced by reduced compensation during the perception of optic flow that mimics self-motion in the environment. We asked a group of early-stage AD patients and age-matched healthy controls to indicate the perceived direction of self-motion based on optic flow while tracking a moving target with smooth pursuit eye movement, or keeping eye fixation at a stationary target. We first replicated the previous findings that healthy participants were able to compensate for distorted optic flow in the presence of eye movements, as indicated by similar performance of self-motion perception between pursuit and fixation conditions. In stark contrast, AD patients showed impaired self-motion perception when the optic flow was distorted by eye movements. Our results suggest that early-stage AD pathology is associated with disrupted eye movement compensation during self-motion perception. PMID- 28642573 TI - Characterisation of Plasmodium falciparum populations selected on the human endothelial receptors P-selectin, E-selectin, CD9 and CD151. AB - The ability of the parasite Plasmodium falciparum to evade the immune system and be sequestered within human small blood vessels is responsible for severe forms of malaria. The sequestration depends on the interaction between human endothelial receptors and P. falciparum erythrocyte membrane protein 1 (PfEMP1) exposed on the surface of the infected erythrocytes (IEs). In this study, the transcriptomes of parasite populations enriched for parasites that bind to human P-selectin, E-selectin, CD9 and CD151 receptors were analysed. IT4_var02 and IT4_var07 were specifically expressed in IT4 parasite populations enriched for P selectin-binding parasites; eight var genes (IT4_var02/07/09/13/17/41/44/64) were specifically expressed in isolate populations enriched for CD9-binding parasites. Interestingly, IT4 parasite populations enriched for E-selectin- and CD151 binding parasites showed identical expression profiles to those of a parasite population exposed to wild-type CHO-745 cells. The same phenomenon was observed for the 3D7 isolate population enriched for binding to P-selectin, E-selectin, CD9 and CD151. This implies that the corresponding ligands for these receptors have either weak binding capacity or do not exist on the IE surface. Conclusively, this work expanded our understanding of P. falciparum adhesive interactions, through the identification of var transcripts that are enriched within the selected parasite populations. PMID- 28642574 TI - Replication of Gout/Urate Concentrations GWAS Susceptibility Loci Associated with Gout in a Han Chinese Population. AB - Gout is a chronic disease resulting from elevated serum urate (SU). Previous genome-wide association studies (GWAS) have identified dozens of susceptibility loci for SU/gout, but few have been conducted for Chinese descent. Here, we try to extensively investigate whether these loci contribute to gout risk in Han Chinese. A total of 2255 variants in linkage disequilibrium (LD) with GWAS identified SU/gout associated variants were analyzed in a Han Chinese cohort of 1255 gout patients and 1848 controls. Cumulative genetic risk score analysis was performed to assess the cumulative effect of multiple "risk" variants on gout incidence. 23 variants (41%) of LD pruned variants set (n = 56) showed nominal association with gout in our sample (p < 0.05). Some of the previously reported gout associated loci (except ALDH16A1), including ABCG2, SLC2A9, GCKR, ALDH2 and CNIH2, were replicated. Cumulative genetic risk score analyses showed that the risk of gout increased for individuals with the growing number (>=8) of the risk alleles on gout associated loci. Most of the gout associated loci identified in previous GWAS were confirmed in an independent Chinese cohort, and the SU associated loci also confer susceptibility to gout. These findings provide important information of the genetic association of gout. PMID- 28642575 TI - Reactive astrocytes function as phagocytes after brain ischemia via ABCA1 mediated pathway. AB - Astrocytes become reactive following various brain insults; however, the functions of reactive astrocytes are poorly understood. Here, we show that reactive astrocytes function as phagocytes after transient ischemic injury and appear in a limited spatiotemporal pattern. Following transient brain ischemia, phagocytic astrocytes are observed within the ischemic penumbra region during the later stage of ischemia. However, phagocytic microglia are mainly observed within the ischemic core region during the earlier stage of ischemia. Phagocytic astrocytes upregulate ABCA1 and its pathway molecules, MEGF10 and GULP1, which are required for phagocytosis, and upregulation of ABCA1 alone is sufficient for enhancement of phagocytosis in vitro. Disrupting ABCA1 in reactive astrocytes result in fewer phagocytic inclusions after ischemia. Together, these findings suggest that astrocytes are transformed into a phagocytic phenotype as a result of increase in ABCA1 and its pathway molecules and contribute to remodeling of damaged tissues and penumbra networks.Astrocytic phagocytosis has been shown to play a role in synaptic pruning during development, but whether adult astrocytes possess phagocytic ability is unclear. Here the authors show that following brain ischemia, reactive astrocytes become phagocytic and engulf debris via the ABCA1 pathway. PMID- 28642576 TI - Upregulation of miR-223 in the rat liver inhibits proliferation of hepatocytes under simulated microgravity. AB - Long-term spaceflight affects numerous organ systems in the body, including metabolic dysfunction. Recently, ample evidence has demonstrated that the liver is a vulnerable organ during spaceflight. However, the changes in hepatocyte proliferation and cell cycle control under microgravity remain largely unexplored. In the present study, we first confirmed that the serum levels of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, biochemical markers of liver function, were altered in rats under tail suspension (TS) conditions to simulate microgravity, as shown in previous reports. Next, we demonstrated that the cell proliferation activity, determined by Ki67, PCNA and PH3, was significantly decreased at the different TS time points (TS for 14, 28 and 42 days) compared with that in the control group. Consistently, the positive cell cycle regulators Ccna2, Ccnd1, Cdk1, Cdk2 and cyclin D3 were also significantly decreased in the TS groups as shown by quantitative real-time PCR and western blotting analysis. Subsequent analysis revealed that the aberrant hepatocyte proliferation inhibition under simulated microgravity was associated with the upregulation of miR-223 in the liver. We further found that miR-223 inhibited the proliferation of Hepa1-6 cells and identified CDK2 and CUL1 as its direct targets. In addition, the decreased expression of CDK2 and CUL1 was negatively correlated with the level of p27 in vitro and in vivo, which may have been responsible for retarding hepatocyte proliferation. Collectively, these data indicate that upregulation of miR-223 was associated with the inhibition of liver cell growth and reveal the role of miR-223 in rat hepatocyte proliferation disorders and the pathophysiological process under simulated microgravity. PMID- 28642578 TI - Human endothelial cells secrete neurotropic factors to direct axonal growth of peripheral nerves. AB - Understanding how nerves spontaneously innervate tissues or regenerate small injuries is critical to enhance material-based interventions to regenerate large scale, traumatic injuries. During embryogenesis, neural and vascular tissues form interconnected, complex networks as a result of signaling between these tissue types. Here, we report that human endothelial cells (HUVECs) secrete brain derived neurotrophic factor (BDNF), which significantly stimulated axonal growth from chicken or rat dorsal root ganglia (DRGs). HUVEC-conditioned medium was sufficient to enhance axonal growth, demonstrating that direct cell-cell contact was not required. When BDNF was neutralized, there was a significant reduction in axonal growth when incubated in HUVEC-conditioned medium and in direct co-culture with HUVECs. These data show that HUVECs secrete neurotrophic factors that significantly enhance axonal growth, and can inform future in vivo studies to direct or pattern the angiogenic response in regenerating tissues to encourage re innervation. PMID- 28642577 TI - Effects of chronic alcohol exposure on ischemia-reperfusion-induced acute kidney injury in mice: the role of beta-arrestin 2 and glycogen synthase kinase 3. AB - Little is known about the effects of chronic alcohol intake on the outcome of acute kidney injury (AKI). Hence, we examined the effects of chronic alcohol intake on the development of renal fibrosis following AKI in an animal model of bilateral renal ischemia-reperfusion (IR) injury. We first found that chronic alcohol exposure exacerbated bilateral IR-induced renal fibrosis and renal function impairment. This phenomenon was associated with increased bilateral IR induced extracellular matrix deposition and an increased myofibroblast population as well as increased bilateral IR-induced expression of fibrosis-related genes in the kidneys. To explore the mechanisms underlying this phenomenon, we showed that chronic alcohol exposure enhanced beta-arrestin 2 (Arrb2) expression and Akt and glycogen synthase kinase-3 (GSK3)beta activation in the kidneys. Importantly, pharmacological GSK3 inhibition alleviated bilateral IR-induced renal fibrosis and renal function impairment. Furthermore, we demonstrated that Arrb2-/- mice exhibited resistance to IR-induced renal fibrosis and renal function impairment following chronic alcohol exposure, and these effects were associated with attenuated GSK3beta activation in the kidneys. Taken together, our results suggest that chronic alcohol exposure may potentiate AKI via beta-arrestin 2/Akt/GSK3beta-mediated signaling in the kidney. PMID- 28642579 TI - Regulation of glycolysis in brown adipocytes by HIF-1alpha. AB - Brown adipose tissue takes up large amounts of glucose during cold exposure in mice and humans. Here we report an induction of glucose transporter 1 expression and increased expression of several glycolytic enzymes in brown adipose tissue from cold-exposed mice. Accordingly, these genes were also induced after beta adrenergic activation of cultured brown adipocytes, concomitant with accumulation of hypoxia inducible factor-1alpha (HIF-1alpha) protein levels. HIF-1alpha accumulation was dependent on uncoupling protein 1 and generation of mitochondrial reactive oxygen species. Expression of key glycolytic enzymes was reduced after knockdown of HIF-1alpha in mature brown adipocytes. Glucose consumption, lactate export and glycolytic capacity were reduced in brown adipocytes depleted of Hif-1alpha. Finally, we observed a decreased beta adrenergically induced oxygen consumption in Hif-1alpha knockdown adipocytes cultured in medium with glucose as the only exogenously added fuel. These data suggest that HIF-1alpha-dependent regulation of glycolysis is necessary for maximum glucose metabolism in brown adipocytes. PMID- 28642581 TI - Molecular methods to detect Spodoptera frugiperda in Ghana, and implications for monitoring the spread of invasive species in developing countries. AB - Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae) is a polyphagous pest indigenous throughout the Americas, which recently appeared in Africa, first reported from Sao Tome, Nigeria, Benin and Togo in 2016, and which we now report from Ghana. This species is recognised to comprise two morphologically identical but genetically distinct strains or species in the Americas, and we found both to be present in Ghana. We discuss possible routes of entry to Africa, of which the likeliest is adults and/or egg masses transported on direct commercial flights between the Americas and West Africa, followed by dispersal by adult flight within Africa. Identification of Lepidoptera is normally based on the markings and morphology of adults, and not on the larvae which actually cause the damage, and therefore larvae have to be reared through to adult for authoritative identification. We confirmed that the use of DNA barcoding allowed unequivocal identification of this new pest from Ghana based on the larvae alone. As authenticated barcodes for vouchered specimens of more pests become available, this approach has the potential to become a valuable in-country tool to support national capability in rapid and reliable pest diagnosis and identification. PMID- 28642580 TI - A snake venom group IIA PLA2 with immunomodulatory activity induces formation of lipid droplets containing 15-d-PGJ2 in macrophages. AB - Crotoxin B (CB) is a catalytically active group IIA sPLA2 from Crotalus durissus terrificus snake venom. In contrast to most GIIA sPLA2s, CB exhibits anti inflammatory effects, including the ability to inhibit leukocyte functions. Lipid droplets (LDs) are lipid-rich organelles associated with inflammation and recognized as a site for the synthesis of inflammatory lipid mediators. Here, the ability of CB to induce formation of LDs and the mechanisms involved in this effect were investigated in isolated macrophages. The profile of CB-induced 15-d PGJ2 (15-Deoxy-Delta-12,14-prostaglandin J2) production and involvement of LDs in 15-d-PGJ2 biosynthesis were also investigated. Stimulation of murine macrophages with CB induced increased number of LDs and release of 15-d-PGJ2. LDs induced by CB were associated to PLIN2 recruitment and expression and required activation of PKC, PI3K, MEK1/2, JNK, iPLA2 and PLD. Both 15-d-PGJ2 and COX-1 were found in CB induced LDs indicating that LDs contribute to the inhibitory effects of CB by acting as platform for synthesis of 15-d-PGJ2, a pro-resolving lipid mediator. Together, our data indicate that an immunomodulatory GIIA sPLA2 can directly induce LD formation and production of a pro-resolving mediator in an inflammatory cell and afford new insights into the roles of LDs in resolution of inflammatory processes. PMID- 28642582 TI - Plasmonic opals: observation of a collective molecular exciton mode beyond the strong coupling. AB - Achieving and controlling strong light-matter interactions in many-body systems is of paramount importance both for fundamental understanding and potential applications. In this paper we demonstrate both experimentally and theoretically how to manipulate strong coupling between the Bragg-plasmon mode supported by an organo-metallic array and molecular excitons in the form of J-aggregates dispersed on the hybrid structure. We observe experimentally the transition from a conventional strong coupling regime exhibiting the usual upper and lower polaritonic branches to a more complex regime, where a third nondispersive mode is seen, as the concentration of J-aggregates is increased. The numerical simulations confirm the presence of the third resonance. We attribute its physical nature to collective molecule-molecule interactions leading to a collective electromagnetic response. A simple analytical model is proposed to explain the physics of the third mode. The nonlinear dependence on molecular parameters followed from the model are confirmed in a set of rigorous numerical studies. It is shown that at the energy of the collective mode molecules oscillate completely out of phase with the incident radiation acting as an effictive thin metal layer. PMID- 28642583 TI - SOX2 is required for inner ear neurogenesis. AB - Neurons of the cochleovestibular ganglion (CVG) transmit hearing and balance information to the brain. During development, a select population of early otic progenitors express NEUROG1, delaminate from the otocyst, and coalesce to form the neurons that innervate all inner ear sensory regions. At present, the selection process that determines which otic progenitors activate NEUROG1 and adopt a neuroblast fate is incompletely understood. The transcription factor SOX2 has been implicated in otic neurogenesis, but its requirement in the specification of the CVG neurons has not been established. Here we tested SOX2's requirement during inner ear neuronal specification using a conditional deletion paradigm in the mouse. SOX2 deficiency at otocyst stages caused a near-absence of NEUROG1-expressing neuroblasts, increased cell death in the neurosensory epithelium, and significantly reduced the CVG volume. Interestingly, a milder decrease in neurogenesis was observed in heterozygotes, indicating SOX2 levels are important. Moreover, fate-mapping experiments revealed that the timing of SOX2 expression did not parallel the established vestibular-then-auditory sequence. These results demonstrate that SOX2 is required for the initial events in otic neuronal specification including expression of NEUROG1, although fate mapping results suggest SOX2 may be required as a competence factor rather than a direct initiator of the neural fate. PMID- 28642584 TI - Molecular switching system using glycosylphosphatidylinositol to select cells highly expressing recombinant proteins. AB - Although many pharmaceutical proteins are produced in mammalian cells, there remains a challenge to select cell lines that express recombinant proteins with high productivity. Since most biopharmaceutical proteins are secreted by cells into the medium, it is difficult to select cell lines that produce large amounts of the target protein. To address this issue, a new protein expression system using the glycosylphosphatidylinositol (GPI)-anchor was developed. PGAP2 is involved in processing GPI-anchored proteins (GPI-APs) during transport. In PGAP2 mutant cells, most GPI-APs are secreted into the medium. Here, we established a HEK293 cell line where endogenous PGAP2 was knocked out and exogenous PGAP2 was inserted with a piggyBac transposon in the genome. Using these cells, human lysosomal acid lipase (LIPA) and alpha-galactosidase A (GLA) were expressed as GPI-anchored forms (LIPA-GPI and GLA-GPI) and cells expressing high levels of LIPA-GPI or GLA-GPI on the cell surface were enriched. Removal of the PGAP2 gene by piggyBac transposase or FLP recombinase converted LIPA-GPI and GLA-GPI from membrane-bound to the secreted forms. Thus, cells expressing LIPA or GLA in large amounts could be enriched using this approach. The GPI-based molecular switching system is an efficient approach to isolate cells expressing recombinant proteins with high productivity. PMID- 28642585 TI - How Postmortem Redistribution of MDMA in Acute Alcohol-MDMA Combined-Use Rats Change under Effects of Alcohol. AB - MDMA is often taken recreationally with alcohol as combined-use. The objective was to determine MDMA postmortem redistribution (PMR) and corresponding effects in combined-style under different storage conditions. Steps were 20%-mixture of alcohol-water for initial 4 weeks to Group-A&B and intragastric infusions of MDMA (150 mg/kg) to Group-A later; in the same time, drinking pure water to Group-C&D first and then MDMA-fed to Group-C. The sacrificed rats were kept under different conditions for 10-d, during which the body fluids and tissues were collected on 15 continuous time-points and then detected. The MDMA concentrations were quite different along with postmortem interval (PMI) went by; the area under concentration-PMI curve significantly increased with combined-alcohol in comparison to MDMA alone, while that significantly decreased by lowering preservation temperature, allied with corresponding humidity. Combined-alcohol could exacerbate PMR of MDMA, as concentrations of combined-use rats' samples were quite higher than mono-MDMA ones under any conditions, while different for body fluids and tissues; meanwhile lowering storage temperature could alleviate effects of alcohol. The study implies that in case of combined-use, the changes of concentrations are probably effected by some combined component, especially when come to identification of toxic level or even death. PMID- 28642587 TI - Systematic comparison of two whole-genome amplification methods for targeted next generation sequencing using frozen and FFPE normal and cancer tissues. AB - Sequencing key cancer-driver genes using formalin-fixed, paraffin-embedded (FFPE) cancer tissues is becoming the standard for identifying the best treatment regimen. However, about 25% of all samples are rejected for genetic analyses for reasons that include too little tissue to extract enough high quality DNA. One way to overcome this is to do whole-genome amplification (WGA) in clinical samples, but only limited studies have tested different WGA methods in FFPE cancer specimens using targeted next-generation sequencing (NGS). We therefore tested the two most commonly used WGA methods, multiple displacement amplification (MDA-Qiagen REPLI-g kit) and the hybrid or modified PCR-based method (Sigma/Rubicon Genomics Inc. GenomePlex kit) in FFPE normal and tumor tissue specimens. For the normalized copy number analysis, the FFPE process caused none or very minimal bias. Variations in copy number were minimal in samples amplified using the GenomePlex kit, but they were statistically significantly higher in samples amplified using the REPLI-g kit. The pattern was similar for variant allele frequencies across the samples, which was minimal for the GenomePlex kit but highly variable for the REPLI-g kit. These findings suggest that each WGA method should be tested thoroughly before using it for clinical cancer samples. PMID- 28642586 TI - Lateral habenula regulation of emotional hyperthermia: mediation via the medullary raphe. AB - The lateral habenula (LHb) has an important role in the behavioural response to salient, usually aversive, events. We previously demonstrated that activation of neurons in the LHb increases brown adipose tissue (BAT) thermogenesis and constricts the cutaneous vascular bed, indicating that the LHb contributes to the central control of sympathetic outflow to thermoregulatory effector organs. We have now investigated whether the LHb mediates BAT thermogenesis elicited by emotional stress, and whether the LHb modulates thermoregulatory sympathetic outflow via the rostral medullary raphe, a key integrative lower brainstem sympathetic control centre. In conscious animals, lesioning the LHb attenuated emotional BAT thermogenesis, suggesting that the LHb is part of the central circuitry mediating emotional hyperthermia. In anesthetized animals, inhibition of neurons in the rostral medullary raphe reversed BAT thermogenesis and cutaneous vasoconstriction elicited by activation of neurons in the LHb, indicating that the LHb-induced autonomic responses are mediated through activation of the rostral medullary raphe neurons. The latency to activate BAT sympathetic discharge from electrical stimulation of the LHb was substantially greater than the corresponding latency after stimulation of the medullary raphe, suggesting that the neuronal pathway connecting those two nuclei is quite indirect. PMID- 28642589 TI - Multiple origins and a narrow genepool characterise the African tea germplasm: concordant patterns revealed by nuclear and plastid DNA markers. AB - Despite the highly economic value of tea in Africa, its genetic and geographic origins remain largely unexplored. Here we address this by collecting 439 samples across 11 countries in Africa and Asia to investigate the origin and genepool composition of African tea based on 23 nuclear microsatellites loci (nSSRs) and three cpDNA intergenic spacer regions. Our results indicated that the African tea represents a potpourri originating from multiple introductions over time. The nSSR analysis revealed that the majority (79%) of tea accessions collected in Africa belong to Indian Assam tea which have likely originated from India and/or Sri Lanka. The patterns of nSSR variation also showed that Chinese Assam tea is genetically distinct from Indian Assam tea, and has rarely been used in African tea breeding efforts since only 4% of the African tea accessions possessed this genotype. We found a total of 22 cpDNA haplotypes, which grouped into three main geographic clades that were concordant with the distribution of microsatellite genotypes. Several private cpDNA haplotypes were identified in Chinese Assam tea in Southern Yunnan province of China. Therefore Chinese Assam tea will be important for the enrichment of African tea gene pools. Our results is a useful guide in future tea breeding programmes in Africa. PMID- 28642588 TI - Epigenetic targeting drugs potentiate chemotherapeutic effects in solid tumor therapy. AB - Epigenetic therapy is a novel tumor therapeutic method and refers to the targeting of the aberrant epigenetic modifications presumably at cancer-related genes by chemicals which are epigenetic targeting drugs (ETDs). Not like in treating hematopoietic cancer, the clinical trials investigating the potential use of ETDs in the solid tumor is not encouraging. Instead, the curative effects of ETD delivered together with DNA targeting chemo drugs (DTDs) are quite promising according to our meta-analysis. To investigate the synergistic mechanism of ETD and DTD drug combination, the therapeutic effect was studied using both cell lines and mouse engrafted tumors. Mechanically we show that HDAC inhibitors and DNMT inhibitors are capable of increasing the chromatin accessibility to cisplatin (CP) and doxorubicin (Dox) through chromatin decompaction globally. Consequently, the combination of ETD and DTD enhances the DTD induced DNA damage and cell death. Engrafted tumors in SCID mice also show increased sensitivity to irradiation (IR) or CP when the tumors were pretreated by ETDs. Given the limited therapeutic effect of ETD alone, these results strongly suggest that the combination of DTD, including irradiation, and ETD treatment is a very promising choice in clinical solid tumor therapy. PMID- 28642590 TI - Toughening Fe-based Amorphous Coatings by Reinforcement of Amorphous Carbon. AB - Toughening of Fe-based amorphous coatings meanwhile maintaining a good corrosion resistance remains challenging. This work reports a novel approach to improve the toughness of a FeCrMoCBY amorphous coating through in-situ formation of amorphous carbon reinforcement without reducing the corrosion resistance. The Fe-based composite coating was prepared by high velocity oxy-fuel (HVOF) thermal spraying using a pre-mixed Fe-based amorphous/nylon-11 polymer feedstock powders. The nylon-11 powders were in-situ carbonized to amorphous carbon phase during thermal spraying process, which homogeneously distributed in the amorphous matrix leading to significant enhancement of toughness of the coating. The mechanical properties, including hardness, impact resistance, bending and fatigue strength, were extensively studied by using a series of mechanical testing techniques. The results revealed that the composite coating reinforced by amorphous carbon phase exhibited enhanced impact resistance and nearly twice-higher fatigue strength than that of the monolithic amorphous coating. The enhancement of impact toughness and fatigue properties is owed to the dumping effect of the soft amorphous carbon phase, which alleviated stress concentration and decreased crack propagation driving force. PMID- 28642591 TI - Donor and recipient age, gender and ABO incompatibility regardless of donor source: validated criteria for donor selection for haematopoietic transplants. AB - Prior data indicate similar outcomes after transplants from human leukocyte antigen (HLA)-haplotype-matched relatives, HLA-identical siblings and HLA-matched unrelated donors. We used our prospective data set to answer a clinically important question: who is the best donor for a person with acute leukaemia transplanted in first complete remission. Patients were randomly divided into training (n=611) and validation (n=588) sets. A total of 1199 consecutive subjects received a transplant from an HLA-haplotype-matched relative using granulocyte colony-stimulating factor and anti-thymocyte globulin (n=685) or an HLA-identical sibling (n=514); 3-year leukaemia-free survivals (LFSs) were 75 and 74% (P=0.95), respectively. The multivariate model identified three major risk factors for transplant-related mortality (TRM): older donor/recipient age, female to-male transplants and donor-recipient ABO major-mismatch transplants. A risk score was developed based on these three features. TRMs were 8%, 15% and 31% for subjects with scores of 0-1, 2 and 3, respectively, (P<0.001). Three-year LFSs were 78%, 74% and 58%, respectively, (P=0.003). The risk score was validated in an independent cohort. In conclusion, our data confirm donor source is not significantly correlated with transplant outcomes. Selection of the best donor needs to consider donor-recipient age, matching for gender and ABO incompatibility among persons with acute leukaemia receiving related transplants under our transplant modality. PMID- 28642592 TI - Integrative network analysis identifies novel drivers of pathogenesis and progression in newly diagnosed multiple myeloma. AB - Multiple myeloma (MM) is an incurable malignancy of bone marrow plasma cells characterized by wide clinical and molecular heterogeneity. In this study we applied an integrative network biology approach to molecular and clinical data measured from 450 patients with newly diagnosed MM from the MMRF (Multiple Myeloma Research Foundation) CoMMpass study. A novel network model of myeloma (MMNet) was constructed, revealing complex molecular disease patterns and novel associations between clinical traits and genomic markers. Genomic alterations and groups of coexpressed genes correlate with disease stage, tumor clonality and early progression. We validated CDC42BPA and CLEC11A as novel regulators and candidate therapeutic targets of MMSET-related myeloma. We then used MMNet to discover novel genes associated with high-risk myeloma and identified a novel four-gene prognostic signature. We identified new patient classes defined by network features and enriched for clinically relevant genetic events, pathways and deregulated genes. Finally, we demonstrated the ability of deep sequencing techniques to detect relevant structural rearrangements, providing evidence that encourages wider use of such technologies in clinical practice. An integrative network analysis of CoMMpass data identified new insights into multiple myeloma disease biology and provided improved molecular features for diagnosing and stratifying patients, as well as additional molecular targets for therapeutic alternatives. PMID- 28642593 TI - Transforming growth factor-beta1 regulates the nascent hematopoietic stem cell niche by promoting gluconeogenesis. AB - The understanding of hematopoietic stem cell (HSC) emergence is important to generate HSCs from pluripotent precursors. However, integrated signaling network that regulates the niche of nascent HSCs remains unclear. Herein, we uncovered a novel role of TGF-beta1 in the metabolic niche of HSC emergence using the tgf beta1b-/- zebrafish. Our findings first showed that Tgf-beta1 transcripts were enriched in the nascent HSCs. Loss of tgf-beta1b caused a decrease of nascent HSCs within the aorta-gonad-mesonephros. Moreover, tgf-beta1b+ cells were runx1+ HSCs and underwent an endothelial-to-hematopoietic-transition process. Although the autocrine of Tgf-beta1 in HSCs rather than endothelial cells was highly demanded to regulate HSC generation, we found that tgf-beta1b promoted HSC emergence through the endothelial c-Jun N-terminal kinase/c-Jun signaling. Chromatin immunoprecipitation (ChIP)-sequencing data showed that tgf-beta1b/c-Jun targeted g6pc3 of FoxO signaling to promote gluconeogenesis and maintain a high glucose level in the niche. Furthermore, loss of tgf-beta1b increased the endoplasmic-reticulum stress and oxidative stress by disturbing metabolic homeostasis. Adding a low dose of TGF-beta1 protein could promote the differentiation of mouse embryonic stem cells towards HSCs in vitro. Altogether, our study provided insights into a new feature of TGF-beta1 in the regulation of glucose metabolism and nascent HSC niche, which may contribute to therapies of hematological malignancies. PMID- 28642594 TI - Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes. AB - Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema. PMID- 28642595 TI - 3D Bayesian cluster analysis of super-resolution data reveals LAT recruitment to the T cell synapse. AB - Single-molecule localisation microscopy (SMLM) allows the localisation of fluorophores with a precision of 10-30 nm, revealing the cell's nanoscale architecture at the molecular level. Recently, SMLM has been extended to 3D, providing a unique insight into cellular machinery. Although cluster analysis techniques have been developed for 2D SMLM data sets, few have been applied to 3D. This lack of quantification tools can be explained by the relative novelty of imaging techniques such as interferometric photo-activated localisation microscopy (iPALM). Also, existing methods that could be extended to 3D SMLM are usually subject to user defined analysis parameters, which remains a major drawback. Here, we present a new open source cluster analysis method for 3D SMLM data, free of user definable parameters, relying on a model-based Bayesian approach which takes full account of the individual localisation precisions in all three dimensions. The accuracy and reliability of the method is validated using simulated data sets. This tool is then deployed on novel experimental data as a proof of concept, illustrating the recruitment of LAT to the T-cell immunological synapse in data acquired by iPALM providing ~10 nm isotropic resolution. PMID- 28642596 TI - SGBS cells as a model of human adipocyte browning: A comprehensive comparative study with primary human white subcutaneous adipocytes. AB - The Simpson Golabi Behmel Syndrome (SGBS) pre-adipocyte cell strain is widely considered to be a representative in vitro model of human white pre-adipocytes. A recent study suggested that SGBS adipocytes exhibit an unexpected transient brown phenotype. Here, we comprehensively examined key differences between SGBS adipocytes and primary human white subcutaneous (PHWSC) adipocytes. RNA-Seq analysis revealed that extracellular matrix (ECM)-receptor interaction and metabolic pathways were the top two KEGG pathways significantly enriched in SGBS adipocytes, which included positively enriched mitochondrial respiration and oxidation pathways. Compared to PHWSC adipocytes, SGBS adipocytes showed not only greater induction of adipogenic gene expression during differentiation but also increased levels of UCP1 mRNA and protein expression. Functionally, SGBS adipocytes displayed higher ISO-induced basal leak respiration and overall oxygen consumption rate, along with increased triglyceride accumulation and insulin stimulated glucose uptake. In conclusion, we confirmed that SGBS adipocytes, which are considered of white adipose tissue origin can shift towards a brown/beige adipocyte phenotype. These differences indicate SGBS cells may help to identify mechanisms leading to browning, and inform our understanding for the use of SGBS vis-a-vis primary human subcutaneous adipocytes as a human white adipocyte model, guiding the selection of appropriate cell models in future metabolic research. PMID- 28642598 TI - Leukaemia: Unravelling the heterogeneity of cancer stem cells. PMID- 28642597 TI - A single amino acid polymorphism in the glycosyltransferase CpsK defines four Streptococcus suis serotypes. AB - The capsular polysaccharide (CPS) is the major virulence factor of the emerging zoonotic pathogen Streptococcus suis. CPS differences are also the basis for serological differentiation of the species into 29 serotypes. Serotypes 2 and 1/2, which possess identical gene content in their cps loci, express CPSs that differ only by substitution of galactose (Gal) by N-acetylgalactosamine (GalNAc) in the CPS side chain. The same sugar substitution differentiates the CPS of serotypes 14 and 1, whose cps loci are also identical in gene content. Here, using mutagenesis, CPS structural analysis, and protein structure modeling, we report that a single amino acid polymorphism in the glycosyltransferase CpsK defines the enzyme substrate predilection for Gal or GalNAc and therefore determines CPS composition, structure, and strain serotype. We also show that the different CPS structures have similar antiphagocytic properties and that serotype switching has limited impact on the virulence of S. suis. PMID- 28642599 TI - Targeted therapies: Expanding the use of PARP inhibitors. PMID- 28642600 TI - Cancer models: Tailored mouse models. PMID- 28642601 TI - Cancer Models: Modeling clear cell renal cell carcinoma. PMID- 28642602 TI - Tumour immunology: LAP targeting reduces tolerogenic cells in cancer. PMID- 28642605 TI - Immunotherapy: Macrophages steal the show. PMID- 28642607 TI - Tumour metabolism: Losing that remaining fat. PMID- 28642603 TI - Imaging of anticancer drug action in single cells. AB - Imaging is widely used in anticancer drug development, typically for whole-body tracking of labelled drugs to different organs or to assess drug efficacy through volumetric measurements. However, increasing attention has been drawn to pharmacology at the single-cell level. Diverse cell types, including cancer associated immune cells, physicochemical features of the tumour microenvironment and heterogeneous cell behaviour all affect drug delivery, response and resistance. This Review summarizes developments in the imaging of in vivo anticancer drug action, with a focus on microscopy approaches at the single-cell level and translational lessons for the clinic. PMID- 28642606 TI - Transposable elements in cancer. AB - Transposable elements give rise to interspersed repeats, sequences that comprise most of our genomes. These mobile DNAs have been historically underappreciated - both because they have been presumed to be unimportant, and because their high copy number and variability pose unique technical challenges. Neither impediment now seems steadfast. Interest in the human mobilome has never been greater, and methods enabling its study are maturing at a fast pace. This Review describes the activity of transposable elements in human cancers, particularly long interspersed element-1 (LINE-1). LINE-1 sequences are self-propagating, protein coding retrotransposons, and their activity results in somatically acquired insertions in cancer genomes. Altered expression of transposable elements and animation of genomic LINE-1 sequences appear to be hallmarks of cancer, and can be responsible for driving mutations in tumorigenesis. PMID- 28642608 TI - Ocean acidification as a driver of community simplification via the collapse of higher-order and rise of lower-order consumers. AB - Increasing oceanic uptake of CO2 is predicted to drive ecological change as both a resource (i.e. CO2 enrichment on primary producers) and stressor (i.e. lower pH on consumers). We use the natural ecological complexity of a CO2 vent (i.e. a seagrass system) to assess the potential validity of conceptual models developed from laboratory and mesocosm research. Our observations suggest that the stressor effect of CO2 enrichment combined with its resource-effect drives simplified food web structure of lower trophic diversity and shorter length. The transfer of CO2 enrichment from plants to herbivores through consumption (apparent resource effect) was not compensated by predation, because carnivores failed to contain herbivore outbreaks. Instead, these higher-order consumers collapsed (apparent stressor-effect on carnivores) suggesting limited trophic propagation to predator populations. The dominance of primary producers and their lower-order consumers along with the loss of carnivores reflects the duality of intensifying ocean acidification acting both as resource-effect (i.e. bottom-up control) and stressor-effect (i.e. top-down control) to simplify community and trophic structure and function. This shifting balance between the propagation of resource enrichment and its consumption across trophic levels provides new insights into how the trophic dynamics might stabilize against or propagate future environmental change. PMID- 28642610 TI - The multiple sclerosis market. PMID- 28642604 TI - Turning the tide in myelodysplastic/myeloproliferative neoplasms. AB - Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are aggressive myeloid malignancies recognized as a distinct category owing to their unique combination of dysplastic and proliferative features. Although current classification schemes still emphasize morphology and exclusionary criteria, disease-defining somatic mutations and/or germline predisposition alleles are increasingly incorporated into diagnostic algorithms. The developing picture suggests that phenotypes are driven mostly by epigenetic mechanisms that reflect a complex interplay between genotype, physiological processes such as ageing and interactions between malignant haematopoietic cells and the stromal microenvironment of the bone marrow. Despite the rapid accumulation of genetic knowledge, therapies have remained nonspecific and largely inefficient. In this Review, we discuss the pathogenesis of MDS/MPN, focusing on the relationship between genotype and phenotype and the molecular underpinnings of epigenetic dysregulation. Starting with the limitations of current therapies, we also explore how the available mechanistic data may be harnessed to inform strategies to develop rational and more effective treatments, and which gaps in our knowledge need to be filled to translate biological understanding into clinical progress. PMID- 28642609 TI - Microbial Signatures Associated with Oropharyngeal and Oral Squamous Cell Carcinomas. AB - The microbiome is fundamentally one of the most unique organs in the human body. Dysbiosis can result in critical inflammatory responses and result in pathogenesis contributing to neoplastic events. We used a pan-pathogen array technology (PathoChip) coupled with next-generation sequencing to establish microbial signatures unique to human oral and oropharyngeal squamous cell carcinomas (OCSCC/OPSCC). Signatures for DNA and RNA viruses including oncogenic viruses, gram positive and negative bacteria, fungi and parasites were detected. Cluster and topological analyses identified 2 distinct groups of microbial signatures related to OCSCCs/OPSCCs. Results were validated by probe capture next generation sequencing; the data from which also provided a comprehensive map of integration sites and chromosomal hotspots for micro-organism genomic insertions. Identification of these microbial signatures and their integration sites may provide biomarkers for OCSCC/OPSCC diagnosis and prognosis as well as novel avenues for study of their potential role in OCSCCs/OPSCCs. PMID- 28642611 TI - Engineered Newcastle disease virus expressing the F and G proteins of AMPV-C confers protection against challenges in turkeys. AB - Avian metapneumovirus (AMPV) infects the respiratory and reproductive tracts of domestic poultry, resulting in substantial economic losses for producers. Live attenuated vaccines appear to be the most effective in countries where the disease is prevalent. However, reversion to virulence has been demonstrated in several studies. Therefore, the development of a stable and safe next generation vaccine against the AMPV disease is needed. In the present study, we generated a recombinant Newcastle disease virus (NDV) vectoring the fusion (F) protein and glycoprotein (G) genes of AMPV subtype-C (AMPV-C) as a bivalent vaccine candidate using reverse genetics technology. The recombinant virus, rLS/AMPV-C F&G, was slightly attenuated in vivo, yet maintained similar characteristics in vitro when compared to the parental LaSota virus. Vaccination of turkeys with rLS/AMPV-C F&G induced both AMPV-C and NDV-specific antibody responses, and provided significant protection against pathogenic AMPV-C challenge and complete protection against velogenic NDV challenge. These results suggest that the rLS/AMPV-C F&G recombinant virus is a safe and effective bivalent vaccine candidate and that the expression of both F and G proteins of AMPV-C induces a protective response against the AMPV-C disease. PMID- 28642612 TI - Active removal of waste dye pollutants using Ta3N5/W18O49 nanocomposite fibres. AB - A scalable solvothermal technique is reported for the synthesis of a photocatalytic composite material consisting of orthorhombic Ta3N5 nanoparticles and WOx<=3 nanowires. Through X-ray diffraction and X-ray photoelectron spectroscopy, the as-grown tungsten(VI) sub-oxide was identified as monoclinic W18O49. The composite material catalysed the degradation of Rhodamine B at over double the rate of the Ta3N5 nanoparticles alone under illumination by white light, and continued to exhibit superior catalytic properties following recycling of the catalysts. Moreover, strong molecular adsorption of the dye to the W18O49 component of the composite resulted in near-complete decolourisation of the solution prior to light exposure. The radical species involved within the photocatalytic mechanisms were also explored through use of scavenger reagents. Our research demonstrates the exciting potential of this novel photocatalyst for the degradation of organic contaminants, and to the authors' knowledge the material has not been investigated previously. In addition, the simplicity of the synthesis process indicates that the material is a viable candidate for the scale up and removal of dye pollutants on a wider scale. PMID- 28642613 TI - Protecting visual short-term memory during maintenance: Attentional modulation of target and distractor representations. AB - In the presence of distraction, attentional filtering is a key predictor of efficient information storage in visual short-term memory (VSTM). Yet, the role of attention in distractor filtering, and the extent to which attentional filtering continues to protect information during post-perceptual stages of VSTM, remains largely unknown. In the current study, we investigated the role of spatial attention in distractor filtering during VSTM encoding and maintenance. Participants performed a change detection task with varying distractor load. Attentional deployment to target and distractor locations was tracked continuously by means of Steady-State Visual Evoked Potentials (SSVEPs). Analyses revealed that attention strongly modulated the amplitude of the second harmonic SSVEP response, with larger amplitudes at target compared to distractor locations. These attentional modulations commenced during encoding, and remained present during maintenance. Furthermore, the amount of attention paid to distractor locations was directly related to behavioral distractor costs: Individuals who paid more attention to target compared to distractor locations during VSTM maintenance generally suffered less from the presence of distractors. Together, these findings support an important role of spatial attention in distractor filtering at multiple stages of VSTM, and highlight the usefulness of SSVEPs in continuously tracking attention to multiple locations during VSTM. PMID- 28642614 TI - Ultrasound-mediated piezoelectric differentiation of neuron-like PC12 cells on PVDF membranes. AB - Electrical and/or electromechanical stimulation has been shown to play a significant role in regenerating various functionalities in soft tissues, such as tendons, muscles, and nerves. In this work, we investigate the piezoelectric polymer polyvinylidene fluoride (PVDF) as a potential substrate for wireless neuronal differentiation. Piezoelectric PVDF enables generation of electrical charges on its surface upon acoustic stimulation, inducing neuritogenesis of PC12 cells. We demonstrate that the effect of pure piezoelectric stimulation on neurite generation in PC12 cells is comparable to the ones induced by neuronal growth factor (NGF). In inhibitor experiments, our results indicate that dynamic stimulation of PVDF by ultrasonic (US) waves activates calcium channels, thus inducing the generation of neurites via a cyclic adenosine monophosphate (cAMP) dependent pathway. This mechanism is independent from the well-studied NGF induced mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway. The use of US, in combination with piezoelectric polymers, is advantageous since focused power transmission can occur deep into biological tissues, which holds great promise for the development of non-invasive neuroregenerative devices. PMID- 28642615 TI - The Bethe-Slater curve revisited; new insights from electronic structure theory. AB - The Bethe-Slater (BS) curve describes the relation between the exchange coupling and interatomic distance. Based on a simple argument of orbital overlaps, it successfully predicts the transition from antiferromagnetism to ferromagnetism, when traversing the 3d series. In a previous article [Phys. Rev. Lett. 116, 217202 (2016)] we reported that the dominant nearestneighbour (NN) interaction for 3d metals in the bcc structure indeed follows the BS curve, but the trends through the series showed a richer underlying physics than was initially assumed. The orbital decomposition of the inter-site exchange couplings revealed that various orbitals contribute to the exchange interactions in a highly non-trivial and sometimes competitive way. In this communication we perform a deeper analysis by comparing 3d metals in the bcc and fcc structures. We find that there is no coupling between the E g orbitals of one atom and T 2g orbitals of its NNs, for both cubic phases. We demonstrate that these couplings are forbidden by symmetry and formulate a general rule allowing to predict when a similar situation is going to happen. In gamma-Fe, as in alpha-Fe, we find a strong competition in the symmetry-resolved orbital contributions and analyse the differences between the high-spin and low-spin solutions. PMID- 28642616 TI - Modulational instability of coupled ring waveguides with linear gain and nonlinear loss. AB - We consider a nanostructure of two coupled ring waveguides with constant linear gain and nonlinear absorption - the system that can be implemented in various settings including polariton condensates, optical waveguides or atomic Bose Einstein condensates. It is found that, depending on the parameters, this simple configuration allows for observing several complex nonlinear phenomena, which include spontaneous symmetry breaking, modulational instability leading to generation of stable circular flows with various vorticities, stable inhomogeneous states with interesting structure of currents flowing between rings, as well as dynamical regimes having signatures of chaotic behavior. PMID- 28642617 TI - Podoplanin enhances lung cancer cell growth in vivo by inducing platelet aggregation. AB - Podoplanin/Aggrus, known as a platelet aggregation-inducing factor, is frequently overexpressed in lung squamous cell carcinomas (LSCC) and glioblastomas among other tumours, and its expression has been reported to be correlated with poor prognosis. However, the contribution of podoplanin to malignant progression has been elusive. Here we demonstrate that in podoplanin-positive LSCC cells, their growth was abrogated by podoplanin knockout in vivo but not in vitro. Conversely, ectopic expression of podoplanin promoted cell growth in vivo and facilitated intratumoral platelet activation. Consistently, LSCC cells evoked podoplanin mediated platelet aggregation (PMPA), and the releasates from platelets during PMPA promoted the growth of LSCC cells in vitro. Phospho-receptor-tyrosine-kinase array analysis revealed that epidermal growth factor receptor (EGFR) phosphorylation of LSCC cells was responsible for the growth promotion induced by platelet releasates. Treatment with an antiplatelet agent or podoplanin neutralizing antibody depressed the growth of an LSCC tumour xenograft via suppression of EGFR phosphorylation. These results suggested that podoplanin in LSCC enhanced cell growth by inducing PMPA in vivo and contributed to malignant progression. PMID- 28642618 TI - Physalins V-IX, 16,24-cyclo-13,14-seco withanolides from Physalis angulata and their antiproliferative and anti-inflammatory activities. AB - Five new physalins, including a novel 1,10-seco one, physalin V (1), a tricarboxylic acid cycle one, physalin VIII (5), a rare 11,15-cyclo one, physalin IX (6), and two new ones, physalins VI (2) and VII (4) were isolated from stems and leaves of Physalis angulata together with eleven known analogues (3 and 7 16). Their structures were established by MS, IR, UV, and NMR spectroscopic analysis, together with the X-ray diffraction analysis of neophysalin, physalin P (12), and the structure of physalin D1 (3) has been revised here. These isolated compounds were evaluated for their antiproliferative activities against human cancer cells (C4-2B, 22Rv1, 786-O, A-498, ACHN, and A375-S2) and inhibitory effects on nitric oxide production. Compounds 9 and 10 showed antiproliferative activities against all tested human cancer cells with IC50 values of 0.24-3.17 MUM. Compounds 1, 3, 4, 9, 10, 13, 14, and 16 exhibited inhibitory activities against NO production. The IC50 values of compounds 9, 10, 13, and 16 were between 0.32 and 4.03 MUM, while compounds 1, 3, 4, and 14 had IC50 values of 12.83-34.19 MUM. Herein, plausible biosynthetic pathways for rare structures 1 and 6 and structure-activity relationships on the inhibition of NO production for all isolated compounds are discussed. PMID- 28642619 TI - Understanding the Unusual Response to High Pressure in KBe2BO3F2. AB - Strong anisotropic compression with pressure on the remarkable non-linear optical material KBe2BO3F2 has been observed with the linear compression coefficient along the c axis found to be about 40 times larger than that along the a axis. An unusual non-monotonic pressure response was observed for the a lattice parameter. The derived bulk modulus of 31 +/- 1 GPa indicates that KBe2BO3F2 is a very soft oxide material yet with stable structure up to 45 GPa. A combination of high pressure synchrotron powder X-ray diffraction, high-pressure Raman spectroscopy, and Density Functional Theory calculations points to the mechanism for the unusual pressure response being due to the competition between the K-F bond length and K-F-K bond angle and the coupling between the stretching and twisting vibration modes. PMID- 28642620 TI - Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma. AB - This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ?9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM. PMID- 28642621 TI - Variants of the ABCA3 gene might contribute to susceptibility to interstitial lung diseases in the Chinese population. AB - ATP-binding cassette A3 (ABCA3) is a phospholipid carrier that is mainly expressed in the alveolar epithelium. Biallelic mutations of ABCA3 has been associated with fatal respiratory distress syndrome and interstitial lung disease (ILD) in children. However, whether variations in ABCA3 have a role in the development of adult ILD, including idiopathic pulmonary fibrosis (IPF), remains to be addressed. In this study, we screened for germline variants of ABCA3 by exons-sequencing in 30 patients with sporadic IPF and in 30 matched healthy controls. Eleven missense variants, predominantly in heterozygous, were found in 13 of these patients, but only two missenses in 2 healthy controls. We then selected four of the detected missense variants (p.L39V, p.S828F, p.V968M and p.G1205R) to performed cohort analysis in 1,024 ILD patients, containing 250 IPF and 774 connective tissue disease-ILD (CTD-ILD) patients, and 1,054 healthy individuals. Our results showed that the allele frequency of p.G1205R, but not p.L39V, was significantly higher in ILD patients than in healthy controls. However, no additional subject carrying the variant p.S828F or p.V968M was detected in the cohort analysis. These results indicate that the heterozygous ABCA3 gene variants may contribute to susceptibility to diseases in the Chinese population. PMID- 28642622 TI - Self-assembled Cubic Boron Nitride Nanodots. AB - One of the low-dimensional Boron Nitride (BN) forms, namely, cubic-BN (c-BN) nanodots (NDs), offers a variety of novel opportunities in battery, biology, deep ultraviolet light emitting diodes, sensors, filters, and other optoelectronic applications. To date, the attempts towards producing c-BN NDs were mainly performed under extreme high-temperature/high-pressure conditions and resulted in c-BN NDs with micrometer sizes, mixture of different BN phases, and containing process-related impurities/contaminants. To enhance device performance for those applications by taking advantage of size effect, pure, sub-100 nm c-BN NDs are necessary. In this paper, we report self-assembled growth of c-BN NDs on cobalt and nickel substrates by plasma-assisted molecular beam epitaxy. It is found that the nucleation, formation, and morphological properties of c-BN NDs can be closely correlated with the nature of substrate including catalysis effect, lattice-mismatch-induced strain, and roughness, and growth conditions, in particular, growth time and growth temperature. The mean lateral size of c-BN NDs on cobalt scales from 175 nm to 77 nm with the growth time. The growth mechanism of c-BN NDs on metal substrates is concluded to be Volmer-Weber (VW) mode. A simplified two-dimensional numerical modeling shows that the elastic strain energy plays a key role in determining the total formation energy of c-BN NDs on metals. PMID- 28642623 TI - Predicting long-term mortality in hospitalized elderly patients using the new ESPEN definition. AB - The European Society of Clinical Nutrition and Metabolism (ESPEN) recently published new diagnostic criteria for malnutrition. The aim of this study was to evaluate whether malnutrition by the new ESPEN diagnostic criteria can predict long-term mortality in elderly inpatients. We conducted a prospective study in the acute geriatric wards. Malnutrition was defined according to the new ESPEN criteria and the Mini Nutritional Assessment (MNA), respectively. The survival status was determined by telephone interviews at 3-years. A total of 437 elderly adults were included. According to the new ESPEN criteria, 66 participants (15.1%) were malnourished. According to the MNA, 45 participants (10.3%) were identified as malnourished. The 3-year all-cause mortality was 41.7% in participants with malnutrition defined by the ESPEN criteria and 15.3% in participants without malnutrition (p < 0.001). After adjusting for relevant confounders, malnutrition defined by the ESPEN criteria was a significant predictor of 3-year all-cause mortality (hazard ratio [HR] 2.98, 95% confidence interval [CI] 1.87-4.86). However, malnutrition defined by the MNA was not a significant predictor of 3-year all-cause mortality (HR 1.67, 95% CI 0.89-2.31). In conclusion, the new ESPEN diagnostic criteria for malnutrition are reliable in predicting 3-year all-cause mortality among elderly inpatients. PMID- 28642624 TI - Whole Exome Sequencing to Identify Genetic Variants Associated with Raised Atherosclerotic Lesions in Young Persons. AB - We investigated the influence of genetic variants on atherosclerosis using whole exome sequencing in cases and controls from the autopsy study "Pathobiological Determinants of Atherosclerosis in Youth (PDAY)". We identified a PDAY case group with the highest total amounts of raised lesions (n = 359) for comparisons with a control group with no detectable raised lesions (n = 626). In addition to the standard exome capture, we included genome-wide proximal promoter regions that contain sequences that regulate gene expression. Our statistical analyses included single variant analysis for common variants (MAF > 0.01) and rare variant analysis for low frequency and rare variants (MAF < 0.05). In addition, we investigated known CAD genes previously identified by meta-analysis of GWAS studies. We did not identify individual common variants that reached exome-wide significance using single variant analysis. In analysis limited to 60 CAD genes, we detected strong associations with COL4A2/COL4A1 that also previously showed associations with myocardial infarction and arterial stiffness, as well as coronary artery calcification. Likewise, rare variant analysis did not identify genes that reached exome-wide significance. Among the 60 CAD genes, the strongest association was with NBEAL1 that was also identified in gene-based analysis of whole exome sequencing for early onset myocardial infarction. PMID- 28642625 TI - Testing the environmental filtering concept in global drylands. AB - 1. The environmental filtering hypothesis predicts that the abiotic environment selects species with similar trait values within communities. Testing this hypothesis along multiple - and interacting - gradients of climate and soil variables constitutes a great opportunity to better understand and predict the responses of plant communities to ongoing environmental changes. 2. Based on two key plant traits, maximum plant height and specific leaf area (SLA), we assessed the filtering effects of climate (mean annual temperature and precipitation, precipitation seasonality), soil characteristics (soil pH, sand content and total phosphorus) and all potential interactions on the functional structure and diversity of 124 dryland communities spread over the globe. The functional structure and diversity of dryland communities were quantified using the mean, variance, skewness and kurtosis of plant trait distributions. 3. The models accurately explained the observed variations in functional trait diversity across the 124 communities studied. All models included interactions among factors, i.e. climate - climate (9% of explanatory power), climate - soil (24% of explanatory power) and soil - soil interactions (5% of explanatory power). Precipitation seasonality was the main driver of maximum plant height, and interacted with mean annual temperature and precipitation. Soil pH mediated the filtering effects of climate and sand content on SLA. Our results also revealed that communities characterized by a low variance can also exhibit low kurtosis values, indicating that functionally contrasting species can co-occur even in communities with narrow ranges of trait values. 4. Synthesis We identified the particular set of conditions under which the environmental filtering hypothesis operates in drylands worldwide. Our findings also indicate that species with functionally contrasting strategies can still co-occur locally, even under prevailing environmental filtering. Interactions between sources of environmental stress should be therefore included in global trait-based studies, as this will help to further anticipate where the effects of environmental filtering will impact plant trait diversity under climate change. PMID- 28642626 TI - A marginal cure rate proportional hazards model for spatial survival data. AB - Dental studies often produce spatially referenced multivariate time-to-event data, such as the time until tooth loss due to periodontal disease. These data are used to identify risk factors that are associated with tooth loss, and to predict outcomes for an individual patient.The rate of spatial referencing can vary with various tooth locations. In addition, these event time data are heavily censored, mostly because a certain proportion of teeth in the population are not expected to experience failure and can be considered 'cured'. We assume a proportional hazards model with a surviving fraction to model these clustered correlated data and account for dependence between nearby teeth by using spatial frailties which are modelled as linear combinations of positive stable random effects. This model permits predictions (conditioned on spatial frailties) that account for the survival status of nearby teeth and simultaneously preserves the proportional hazards relationship marginally over the random effects for the susceptible teeth, allowing for interpretable estimates of the effects of risk factors on tooth loss. We explore the potential of this model via simulation studies and application to a real data set obtained from a private periodontal practice, and we illustrate its advantages over other competing models to identify important risk factors for tooth loss and to predict the remaining lifespan of a patient's teeth. PMID- 28642627 TI - Allenyl esters as quenching agents for ruthenium olefin metathesis catalysts. AB - In the attempt to synthesize substituted allenyl esters through a metathesis coupling of unsubstituted allenyl esters and alkenes using a variety of ruthenium catalysts, it was discovered that allenyl esters themselves cleanly arrested the activity of the catalysts. Further studies suggests possible utility of allene esters as general quenching agents for metathesis reactions. To explore this idea, several representative olefin metathesis reactions, including ring closing, were successfully terminated by the addition of simple allenyl esters for more convenient purification. PMID- 28642629 TI - Improved brain tumor segmentation by utilizing tumor growth model in longitudinal brain MRI. AB - In this work, we propose a novel method to improve texture based tumor segmentation by fusing cell density patterns that are generated from tumor growth modeling. In order to model tumor growth, we solve the reaction-diffusion equation by using Lattice-Boltzmann method (LBM). Computational tumor growth modeling obtains the cell density distribution that potentially indicates the predicted tissue locations in the brain over time. The density patterns is then considered as novel features along with other texture (such as fractal, and multifractal Brownian motion (mBm)), and intensity features in MRI for improved brain tumor segmentation. We evaluate the proposed method with about one hundred longitudinal MRI scans from five patients obtained from public BRATS 2015 data set, validated by the ground truth. The result shows significant improvement of complete tumor segmentation using ANOVA analysis for five patients in longitudinal MR images. PMID- 28642628 TI - Particulate Air Pollution from Wildfires in the Western US under Climate Change. AB - Wildfire can impose a direct impact on human health under climate change. While the potential impacts of climate change on wildfires and resulting air pollution have been studied, it is not known who will be most affected by the growing threat of wildfires. Identifying communities that will be most affected will inform development of fire management strategies and disaster preparedness programs. We estimate levels of fine particulate matter (PM2.5) directly attributable to wildfires in 561 western US counties during fire seasons for the present-day (2004-2009) and future (2046-2051), using a fire prediction model and GEOS-Chem, a 3-D global chemical transport model. Future estimates are obtained under a scenario of moderately increasing greenhouse gases by mid-century. We create a new term "Smoke Wave," defined as >=2 consecutive days with high wildfire-specific PM2.5, to describe episodes of high air pollution from wildfires. We develop an interactive map to demonstrate the counties likely to suffer from future high wildfire pollution events. For 2004-2009, on days exceeding regulatory PM2.5 standards, wildfires contributed an average of 71.3% of total PM2.5. Under future climate change, we estimate that more than 82 million individuals will experience a 57% and 31% increase in the frequency and intensity, respectively, of Smoke Waves. Northern California, Western Oregon and the Great Plains are likely to suffer the highest exposure to widlfire smoke in the future. Results point to the potential health impacts of increasing wildfire activity on large numbers of people in a warming climate and the need to establish or modify US wildfire management and evacuation programs in high-risk regions. The study also adds to the growing literature arguing that extreme events in a changing climate could have significant consequences for human health. PMID- 28642630 TI - Increased Fruit and Vegetable Intake among Older Adults Participating in Kentucky's Congregate Meal Site Program. AB - The purpose of this study was to determine if the amount and variety of fruits and vegetables consumed increased among community-dwelling older adults participating in Kentucky's congregate meal site program following a series of five nutrition education lessons. A convenience sample of older adults attending senior centers (n=35), two intervention (n=19) and two control (n=16) centers, participated in this quasi-experimental pilot study. Following the intervention there was a significant increase in actual fruit and vegetable intake in the intervention group (p<0.05) as assessed by plate waste measurements of the congregate lunch meal. In addition, from pre- to post-intervention, a trend towards increased self-reported intake in the variety of fruit and vegetables was observed among the intervention group. As well, a significant increase in the number of days intervention participants self-reported consuming at least 4.5 cups of fruits and vegetables in the last seven days (2.44+/-2.09 days to 4.28+/ 1.99 days (p=0.004)) was observed; and knowledge pertaining to phytochemicals increased (p<0.05). The phytochemical index (PI) score of the lunch meal, taking into account that the older adults consumption of meal components, including phytochemical-rich foods, was 26.9. Overall, study results indicated that a short theory-based nutrition education program offered to community-dwelling older adults was linked to an increase in fruit and vegetable consumption and phytochemical knowledge. PMID- 28642631 TI - School climate: perceptual differences between students, parents, and school staff. AB - Research suggests that school climate can have a great impact on student, teacher, and school outcomes. However, it is often assessed as a summary measure, without taking into account multiple perspectives (student, teacher, parent) or examining subdimensions within the broader construct. In this study, we assessed school climate from the perspective of students, staff, and parents within a large, urban school district using multilevel modeling techniques to examine within- and between-school variance. After adjusting for school-level demographic characteristics, students reported worse perceptions of safety and connectedness compared to both parent and staff ratings (all p < 0.05). Parents gave the lowest ratings of parental involvement, and staff gave the lowest ratings of academic emphasis (ps < 0.05). Findings demonstrate the importance of considering the type of informant when evaluating climate ratings within a school. Understanding how perceptions differ between informants can inform interventions to improve perceptions and prevent adverse outcomes. PMID- 28642632 TI - MCL Plays an Anti-Inflammatory Role in Mycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-kappaB and NLRP3 Inflammasome Activation. AB - Mycobacterium tuberculosis (Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-kappaB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1beta and TNF-alpha) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-kappaB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response. PMID- 28642634 TI - Analysis of MAP kinase MPK4/MEKK1/MKK genes of Carica papaya L. comparative to other plant homologues. AB - Mitogen-activated protein kinase 4 (MPK4) interacts with the (Mitogen-activated protein kinase kinase kinase 1) MEKK1/ Mitogenactivated protein kinase kinase 1 (MKK1)/ Mitogen-activated protein kinase kinase 2 (MKK2) complex to affect its function in plant development or against pathogen attacks. The KEGG (Kyoto Encyclopedia of Genes and Genomes) network analysis of Arabidopsis thaliana revealed close interactions between those four genes in the same plant-pathogen interaction pathway, which warrants further study of these genes due to their evolutionary conservation in different plant species. Through targeting the signature sequence in MPK4 of papaya using orthologs from Arabidopsis, the predicted sequence of MPK4 was studied using a comparative in silico approach between different plant species and the MAP cascade complex of MEKK1/MKK1/MKK2. This paper reported that MPK4 was highly conserved in papaya with 93% identical across more than 500 bases compared in each species predicted. Slight variations found in the MEKK1/MKK1/MKK2 complex nevertheless still illustrated sequence similarities between most of the species. Localization of each gene in the cascade network was also predicted, potentiating future functional verification of these genes interactions using knock out or/and gene silencing tactics. PMID- 28642635 TI - Virtual screening following rational drug design based approach for introducing new anti amyloid beta aggregation agent. AB - Amyloid beta (Abeta) sheets aggregations is the main reason of Alzheimer disease. The interacting areas between monomers are residue number 38 to 42. Inhibition of interaction between Abeta molecules prevents plaque formation. In the present study, we have performed a high-throughput virtual screening among ZINC database and top 1000 hits were checked again regarding binding affinity by AutoDock software. Top 4 successive second step screening hits was considered for drug design purpose against aggregation site of Abeta molecules. The toxicity and pharmacological properties of new designed ligands was assessed by PROTOX and FAFdrugs3 webservers. Several steps of modifications performed in the structures of hit#1 and hit#2 and finally new designed ligand based on hit 1, 1-RD-3 (3-[(Z) 6-Hydroxy-4-{[5-(2-methoxyethyl)-6-methyltetrahydro-2H-pyran-2-yl]methyl}-1 methyl-3-hexenyloxy]tetrahydro-2Hpyran- 4-ol) and a designed ligand based on hit 2, 2-RD-2 (6-(Hydroxymethyl)-4-{5-hydroxy-6-methyl-4-[(3- methylcyclohexyl)methyl]tetrahydro-2H-pyran-2-yloxy}tetrahydro-2H-pyran-2,3,5 triol) could successfully pass pharmacological filters. The LD50 of 37000 mg/kg for 1-RD-3 and 2000 mg/kg for 2-RD-2 indicates that the designed ligands can be considered as new candidates for anti Abeta aggregation to treat Alzheimer's disease. Interestingly, after performing several modification steps still a considerable binding affinity of -9.3 kcal/mol for 1-RD-3 and -9.8 kcal/mol for 2 RD-2 still remained. Theoretically, the new designed molecules can reduce the deposition of Abeta in the cerebral cortex and as the results the Alzheimer symptoms could be decreased. PMID- 28642633 TI - Proteases Revisited: Roles and Therapeutic Implications in Fibrosis. AB - Proteases target many substrates, triggering changes in distinct biological processes correlated with cell migration, EMT/EndMT and fibrosis. Extracellular protease activity, demonstrated by secreted and membrane-bound protease forms, leads to ECM degradation, activation of other proteases (i.e., proteolysis of nonactive zymogens), decomposition of cell-cell junctions, release of sequestered growth factors (TGF-beta and VEGF), activation of signal proteins and receptors, degradation of inflammatory inhibitors or inflammation-related proteins, and changes in cell mechanosensing and motility. Intracellular proteases, mainly caspases and cathepsins, modulate lysosome activity and signal transduction pathways. Herein, we discuss the current knowledge on the multidimensional impact of proteases on the development of fibrosis. PMID- 28642636 TI - Nucleotide composition determines the role of translational efficiency in human genes. AB - The basic sequence features were analysed that influence gene expression via codon usage bias of the selected forty coding sequences of Homo sapiens in a simple prokaryotic model i.e. E. coli K-12 genome. The prime objective was to elucidate the interrelationships among tRNA gene copy numbers, synonymous codons, amino acids and translational efficiency using tRNA adaptation index. It was evident from RSCU scores and principal component analysis, that only those preferred codons were used by the isoacceptor tRNAs that had G and C base at their third codon position. Relationship between tRNA adaptation index and amino acids, revealed that valine, arginine, serine and isoleucine showed significant positive correlation with gene expression. Therefore, it could be inferred that GC content in these genes might have the major role in shaping the codon bias and affecting the translational efficiency of the coding sequences. PMID- 28642637 TI - VARIABLE SELECTION FOR HIGH DIMENSIONAL MULTIVARIATE OUTCOMES. AB - We consider variable selection for high-dimensional multivariate regression using penalized likelihoods when the number of outcomes and the number of covariates might be large. To account for within-subject correlation, we consider variable selection when a working precision matrix is used and when the precision matrix is jointly estimated using a two-stage procedure. We show that under suitable regularity conditions, penalized regression coefficient estimators are consistent for model selection for an arbitrary working precision matrix, and have the oracle properties and are efficient when the true precision matrix is used or when it is consistently estimated using sparse regression. We develop an efficient computation procedure for estimating regression coefficients using the coordinate descent algorithm in conjunction with sparse precision matrix estimation using the graphical LASSO (GLASSO) algorithm. We develop the Bayesian Information Criterion (BIC) for estimating the tuning parameter and show that BIC is consistent for model selection. We evaluate finite sample performance for the proposed method using simulation studies and illustrate its application using the type II diabetes gene expression pathway data. PMID- 28642638 TI - Laparoscopic Surgery for Focal Adenomyosis. AB - BACKGROUND AND OBJECTIVES: For conservative surgical treatment of focal uterine adenomyosis, laparoscopic adenomyomectomy has been increasingly performed, so that reassessment to determine the safety and efficacy of the laparoscopic surgical technique in a larger number of cases and reevaluation for reproducibility for laparoscopic adenomyomectomy is needed. We evaluate the clinical outcomes of laparoscopic adenomyomectomy with transient occlusion of uterine arteries (TOUA) for focal uterine adenomyosis performed by a single surgeon at a single institute. METHODS: Patients (N = 105) with symptomatic focal uterine adenomyosis underwent laparoscopic adenomyomectomy with TOUA by a single surgeon at Ulsan University Hospital from May 1, 2011, through September 30, 2016. Surgical outcomes included operative time; intraoperative injury to blood vessels, nerves, and pelvic organs; and intraoperative blood loss. We assessed the degree of improvement in dysmenorrhea and menorrhagia and relapsing or remnant adenomyosis lesion by ultrasonography at the 7-momth follow-up after the operation. Then, all patients were followed up at 6-month intervals at the outpatient clinic. RESULTS: The mean patient age was 41.98 +/- 4.73 years. The mean TOUA and operative times were 4.46 +/- 2.68 and 75.14 +/- 20.56 min, respectively. The mean estimated blood loss was 148.19 +/- 101.69 mL. No conversion to laparotomy or major complications occurred. At the 7-month follow up, complete remission of dysmenorrhea and menorrhagia had occurred in 93.02% and 76.92% of patients, respectively. CONCLUSIONS: Laparoscopic adenomyomectomy with TOUA is a safe and effective surgical treatment modality for women with symptomatic focal uterine adenomyosis who want to preserve fertility. PMID- 28642639 TI - Foregut Duplication Cysts in Children. AB - BACKGROUND AND OBJECTIVES: Duplications of the alimentary tract are rare anomalies. We report our experience with foregut duplication cysts including their clinical presentation, diagnostic modalities, and surgical management. METHODS: We report a 20-year retrospective review of all foregut duplication cysts managed at our institution. RESULTS: Twelve patients with 13 foregut duplication cysts were identified. The ages of the children at the time of surgery ranged from infancy to adolescence, with a mean age of 7.2 years. Half of the patients presented with abdominal pain and vomiting, and the remaining either had respiratory distress or were asymptomatic. All resections were performed electively. Two of the 11 patients had other congenital anomalies, including a congenital pulmonary airway malformation and coarctation of the aorta. One patient had prenatal diagnosis by ultrasonography. Nine patients underwent complete successful excision with no complications. Three patients whose symptoms resolved during hospitalization remained under observation because of parental preference. CONCLUSIONS: Foregut malformation in children may present with a variety of symptoms or can be found incidentally. The decision and timing of surgery is based on the clinical presentation. Surgical intervention in asymptomatic patients should be based on a thorough discussion with the parents. PMID- 28642640 TI - Same-Day Discharge for Laparoscopic Donor Nephrectomy. AB - INTRODUCTION: Laparoscopic donor nephrectomy has provided advantages of decreased postoperative pain and length of stay when compared to the open approach. We provide our results of same-day discharge for laparoscopic donor nephrectomy. CASE PRESENTATION: We examined the safety and efficacy of same-day discharge for laparoscopic donor nephrectomy in a retrospective cohort analysis. This institutional review board-approved study began in July 2015, when all consecutive patients who underwent laparoscopic donor nephrectomy were offered same-day discharge. Experimental and control groups were analyzed for differences in sex, age, body mass index, surgery time, estimated blood loss, procedure, complications, length of stay, and distance lived from hospital. Statistical analyses were completed with Mann-Whitney U or Fisher's exact test, as appropriate. MANAGEMENT AND OUTCOME: Eight patients underwent laparoscopic donor nephrectomy during the study period. Of the 8 donors, 4 were discharged on the same day as surgery. The other 4 were discharged the following day. No significant differences were found between the 2 groups with respect to the aforementioned variables. At a median follow-up of 206 days, no complications have been reported. DISCUSSION: The results of our pilot study revealed that same day discharge is safe and feasible, could have a significant impact on patient satisfaction and healthcare costs, and warrants further study. PMID- 28642642 TI - Access to and Payment for Office-Based Buprenorphine Treatment in Ohio. AB - IMPORTANCE: Office-based opiate agonist therapy has dramatically expanded access to medication-assisted treatment over the past decade but has also led to increased buprenorphine diversion. OBJECTIVE: Our study sought to characterize physicians who participate in office-based therapy (OBT) to assess patient access to OBT in Ohio 10 years after its introduction. DESIGN/SETTING/PARTICIPANTS: Cross-sectional telephone survey of Drug Addiction Treatment Act-waivered physicians in Ohio listed by the Center for Substance Abuse Treatment (CSAT). MAIN OUTCOMES: This study sought to determine what proportion of eligible physicians are actively prescribing buprenorphine, whether they accept insurance for OBT, and whether they accept insurance for non-OBT services. In addition, we evaluated what physician characteristics predicted those primary outcomes. We hypothesized that a significant minority of eligible physicians are not active prescribers of buprenorphine. In addition, we expected that a significant minority of OBT prescribers do not accept insurance, further restricting patient access. We further hypothesized that a large subset of OBT prescribers accept insurance in their regular practices but do not take insurance for OBT. RESULTS: Of the 466 listed physicians, 327 (70.2%) practice representatives were reached for interview. Thirty-three physicians were excluded, with a true response rate of 75.5%. In total, 80.7% of providers reached were active OBT prescribers. Of these, 52.7% accepted insurance for OBT, 20.8% accepted insurance for non-OBT services but not for OBT, and 26.5% did not accept insurance for any services. Practices who did not accept insurance were more likely among dedicated addiction clinics located outside of Ohio's 6 major cities. Practices who normally accepted insurance but did not for OBT services were more likely in urban locations and were not associated with dedicated addiction practices. Neither business practice was associated with physician specialty. CONCLUSIONS AND RELEVANCE: Access to OBT in Ohio is far lower than what the 466 listed physicians suggests. Nearly 1 in 5 of those physicians are not active OBT prescribers, and 1 in 2 active prescribers do not accept insurance for OBT. Further research is needed to determine whether practices who do not accept insurance provide care consistent with CSAT guidelines and whether such practice patterns contribute to buprenorphine diversion. PMID- 28642641 TI - Inequality in Human Capital and Endogenous Credit Constraints. AB - This paper investigates the determinants of inequality in human capital with an emphasis on the role of the credit constraints. We develop and estimate a model in which individuals face uninsured human capital risks and invest in education, acquire work experience, accumulate assets and smooth consumption. Agents can borrow from the private lending market and from government student loan programs. The private market credit limit is explicitly derived by extending the natural borrowing limit of Aiyagari (1994) to incorporate endogenous labor supply, human capital accumulation, psychic costs of working, and age. We quantify the effects of cognitive ability, noncognitive ability, parental education, and parental wealth on educational attainment, wages, and consumption. We conduct counterfactual experiments with respect to tuition subsidies and enhanced student loan limits and evaluate their effects on educational attainment and inequality. We compare the performance of our model with an influential ad hoc model in the literature with education-specific fixed loan limits. We find evidence of substantial life cycle credit constraints that affect human capital accumulation and inequality. The constrained fall into two groups: those who are permanently poor over their lifetimes and a group of well-endowed individuals with rising high levels of acquired skills who are constrained early in their life cycles. Equalizing cognitive and noncognitive ability has dramatic effects on inequality. Equalizing parental backgrounds has much weaker effects. Tuition costs have weak effects on inequality. PMID- 28642643 TI - TOMOGRAPHIC MORPHOLOGICAL STUDY OF THE CRANIUM AND ITS CORRELATION WITH CRANIAL HALO USE IN ADULTS. AB - OBJECTIVE: To evaluate using tomographic study the thickness of the cranial board at the insertions points of the cranial halo pins in adults. METHODS: This is a retrospective, cross-sectional, descriptive analysis of Computed Tomography (CT) scans of adult patients' crania. The study included adults between 20 and 50 years without cranial abnormalities. We excluded any exam with cranial abnormalities. RESULTS: We analyzed 50 CT scans, including 27 men and 23 women, at the original insertion points and alternative points (1 and 2 cm above the frontal and parietal bones). The average values were 7.4333 mm in the frontal bone and 6.0290 mm in the parietal bone. CONCLUSION: There was no statistically significant difference between the classical and alternative points, making room for alternative fixings and safer introduction of the pins, if necessary. Level of Evidence II, Retrospective Study. PMID- 28642644 TI - ROLE OF DIFFERENT HORMONES IN THE PATHOGENESIS AND SEVERITY OF ADOLESCENT IDIOPATHIC SCOLIOSIS. AB - OBJECTIVE: To evaluate the hormonal profile of patients with adolescent idiopathic scoliosis (AIS) and its relationship to the severity of the curvature and quality of life . METHOD: Patients with scoliosis (Cobb angle above 10 degrees ), of both genders, diagnosed after 10 years of age were included, excluding those who presented other condition that could lead to scoliosis. Serum levels of 25-hydroxyvitamin D (25-OHD), cortisol and gastrin were correlated with Cobb angle and quality of life, measured by the SRS-30 questionnaire . RESULTS: The levels of 25-OHD decreased in 97% of patients. There was an inverse relationship between gastrin levels and quality of life (p = 0.016). Moreover, there was an inverse correlation between the value of Cobb angle and quality of life (p = 0.036). There were no changes in cortisol levels. There was no correlation between Cobb angle and any of the hormones measured . CONCLUSION: The patients had levels of 25-OHD diminished, strengthening the hypothesis of its involvement in the development of AIS. This study also suggests that increased gastrin levels may be associated with a worse quality of life in patients with AIS. Level of Evidence II, Diagnostic Study. PMID- 28642645 TI - PARQVE: PROJECT ARTHRITIS RECOVERING QUALITY OF LIFE THROUGH EDUCATION: TWO-YEAR RESULTS. AB - OBJECTIVE: To evaluate the effects of a multi-professional educational program in patients with knee osteoarthritis (KOA) . METHODS: Prospective randomized controlled trial with 195 KOA patients. One group was submitted to two-day lectures and received educational material about KOA (Class group), and the control group received the educational material only. Patients were evaluated at baseline, twelve and 24 months. At evaluation, patients answered pain and functional questionnaires (WOMAC, Lequesne, VAS and SF-36); reported the intensity of exercise per week; measured the body fat percentage, weight and height to estimate body mass index (BMI); and performed Timed Up & Go (TUG) and Five-Times-Sit-to-Stand (FTSST) tests . RESULTS: The groups presented similar results in all time points with respect to pain (VAS and WOMAC pain), WOMAC, BMI and body fat percentage (p>0.05). The Class group exhibited improved function according to the Lequesne questionnaire, whereas the control group worsened (p=0.02) during follow-up (p<0.02). TUG (p=0.01) and FTSST (p<0.001) improved in the Class group. A higher percentage of patients in the Class group performed regular physical activity (p=0.045) . CONCLUSIONS: The educational program with classes improved the consistency of physical activity and the subjective and objective function of patients with KOA. Level of evidence IA, Prospective Randomized Controlled Trial. PMID- 28642646 TI - INTENSITY, DURATION AND TYPE OF PHYSICAL ACTIVITY REQUIRED TO IMPROVE FUNCTION IN KNEE OSTEOARTHRITIS. AB - OBJECTIVE: To evaluate the effects of physical activity intensity, type and duration in patients with knee osteoarthritis (KOA) . METHODS: A retrospective study of 195 KOA patients who were followed for two years after receiving educational material about KOA with or without attending classes. The patients were evaluated at baseline and 24 months. At the evaluations, the patients answered questionnaires pertaining to pain and function (WOMAC, Lequesne, VAS and SF-36); reported the intensity, duration and type of exercise performed per week; and performed the Timed Up & Go (TUG) and Five Times Sit-to-Stand (FTSST) tests . RESULTS: Increased age affected improvements in the TUG results (p=0.017). The type, intensity and duration of physical activity did not correlate with pain, function or quality of life improvements (p>0.05), but the TUG results were on average 4 seconds faster among the patients who practiced intense physical activity and/or exercised for more than 180 minutes per week and/or performed isolated weight training or swam compared with those who remained sedentary after 2 years (p=0.01; p<0.001; p=0.01; p=0.04, respectively) . CONCLUSIONS: Patients with KOA should aim for intense physical activity and/or more than 180 minutes of exercise per week and/or weight training (bodybuilding) for relevant pain reduction and functional improvement. Level of Evidence II, Retrospective Study. PMID- 28642647 TI - COMPARISON BETWEEN RENDERING 3D-CT AND TRANSPARENT 3D-CT IN ACL TUNNEL POSITIONING. AB - OBJECTIVE: To compare the transparent 3D computed tomography (CT) image protocol against conventional 3D-CT image-rendering protocol to assess femoral tunnel position in anatomic anterior cruciate ligament (ACL) reconstructions . METHODS: Eight knee CT scans from cadavers were analyzed by image rendering 3D-CT protocol, using Rhinoceros(r) software. The central point of the ACL tunnel was set using the sagittal plane. Same CT scans were analyzed using transparent 3D-CT measurement protocol with OsiriX(r) software. Central point of the ACL tunnel was set using sagittal, coronal and axial planes. The grid system described by Bernard and Hertel was used to compare tunnel positions between protocols, using height and length parameters . RESULTS: There was a significant difference between measurements using image rendering 3D-CT and transparent 3D-CT protocol for height (23.8 +/- 7.9mm and 33.0 +/- 5.0mm, respectively; p=0.017) and no differences for length (18.6 +/- 4.2mm and 18.3 +/- 4.5mm, respectively; p=0.560) . CONCLUSION: Height in transparent CT protocol was different and length was the same as compared to 3D-CT rendering protocol in Bernard and Hertel method for tunnel measurements. Level of Evidence II, Descriptive Laboratory Study. PMID- 28642648 TI - MORPHOLOGICAL ANALYSIS OF THE SCAPULA AND ITS IMPLICATIONS IN BRISTOW-LATARJET PROCEDURE. AB - OBJECTIVE: To assess which of two procedures, Bristow or Latarjet, is anatomically the most appropriate for the general population . METHODS: One thousand one hundred and thirty two shoulders were evaluated by an observer who measured the following coracoid process parameters - length, angle and minimum thickness - through Computed Tomography (CT) analysis. Statistical analysis was carried out by ANOVA and Bland-Altman tests . RESULTS: The mean length, angle and minimum thickness of the coracoid were 27.0 +/- 3.80 mm; 103.54 +/- 14.03 degrees ; and 9.16 +/- 6.38 mm, respectively. Gender differences were statistically significant . CONCLUSION: According to this image-based anatomic study, the coracoid process dimensions do not influence the choice between Bristow or Latarjet procedures. Level of Evidence III, Therapeutic Studies - Investigating the Results of Treatment. PMID- 28642649 TI - ALLOGENEIC PLATELET-RICH PLASMA FOR ROTATOR CUFF REPAIR. AB - OBJECTIVE: To investigate the safety and efficacy of allogeneic platelet-rich plasma (PRP) in rotator cuff repair . METHODS: Seventeen patients with a full thickness rotator cuff tear were included. Ten patients underwent arthroscopic rotator cuff repair with allogeneic, and seven patients with autologous PRP. Three PRP gels in a volume 3 ml each were applied between the torn end and the greater tuberosity. Clinical outcomes were assessed preoperatively and at a minimum of 2 years after surgery. Structural outcomes were evaluated with the presence of retear and the change of the cross-sectional area (ACT) of the supraspinatus . RESULTS: Allogeneic PRP did not cause any adverse events during the follow-up period. There was no significant difference in the clinical outcome measures between the two groups (all p > 0.05). The retear rate was 33.3% and 25.0% in the allogeneic group and autologous group, respectively (p = 0.764). The change between the one-year postoperative and immediately postoperative ACT was not also significantly different between the two groups (p = 0.373) . CONCLUSION: Allogeneic PRP in arthroscopic rotator cuff did not cause any local or general complications and that has the efficacy comparable to autologous PRP with respect to the clinical and structural outcomes. Level of Evidence III, Retrospective Comparative Study. PMID- 28642650 TI - EPIDEMIOLOGICAL STUDY ON LISFRANC INJURIES. AB - OBJECTIVE: To analyze the characteristics of patients with Lisfranc injuries and their associated fractures . METHODS: This is a retrospective analysis on 42 patients with Lisfranc injuries hospitalized at Instituto de Ortopedia e Traumatologia do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, between 2006 and 2010. Parameters on patient profile, risk factors, fracture characteristics, data on treatment and acute complications were analyzed . RESULTS: Analysis of 42 cases showed that in our sample, men were more affected than women, with a ratio of 4.25:1. The most frequent trauma mechanism was car accident, followed by motorcycle accident. The most frequent type of injury was isolated lesion type B of Quenu and Kuss classification, representing 50% of cases. The most common fracture on the sample was the second metatarsal bone, with 16 cases, followed by cuboid bone fracture. Among the 42 cases, 17% had exposed fractures and 33 patients presented other associated fractures. The mean time elapsed between the trauma and definitive treatment was 6.7 days, while the mean length of hospital stay was 13.8 days. Six patients presented acute postoperative complications . CONCLUSION: Lisfranc injuries are more common in men undergoing automobile trauma. The prevalence of associated fractures is a frequent finding and the hospital stay may be longstanding. Level of Evidence IV, Case Series. PMID- 28642652 TI - DIAGNOSIS AND TREATMENT OF POSTERIOR INTEROSSEOUS NERVE ENTRAPMENT: SYSTEMATIC REVIEW. AB - Compressive syndromes of the radial nerve have different presentations. There is no consensus on diagnostic and therapeutic methods. The aim of this review is to summarize such methods. Eletronic searches related terms, held in databases (1980 2016): Pubmed (via Medline), Lilacs (via Scielo) and Google Scholar. Through pre defined protocol, we identified relevant studies. We excluded case reports. Aspects of diagnosis and treatment were synthesized for analysis and tables. Quantitative analyzes were followed by their dispersion variables. Fourteen studies were included. All studies were considered as level IV evidence. Most studies consider aspects of clinical history and provocative maneuvers. There is no consensus on the use of electromyography, and methods are heterogeneous. Studies have shown that surgical treatment (muscle release and neurolysis) has variable success rate, ranging from 20 to 96.5%. Some studies applied self reported scores, though the heterogeneity of the population does not allow inferential analyzes on the subject. few complications reported. Most studies consider the diagnosis of compressive radial nerve syndromes essentially clinical. The most common treatment was combined muscle release and neurolysis, with heterogeneous results. There is a need for comparative studies . Level of Evidence III, Systematic Review. PMID- 28642651 TI - BIMALLEOLAR ANKLE FRACTURE: A SIMPLE FRACTURE? AB - OBJECTIVE: To evaluate the frequency of deltoid ligament injury in bimalleolar supination-external rotation type fractures and whether there is a correlation between the size of the fractured medial malleolus and deltoid ligament injury . METHODS: Twenty six consecutive patients underwent magnetic resonance exams after clinical and radiographic diagnosis of bimalleolar supination-external rotation type ankle fractures . RESULTS: Thirteen patients (50%) presented deltoid ligament injury associated to bimalleolar ankle fracture. Partial injury was present in seven (26.9%) patients and total injury in six (23.1%). Regarding medial fragment size, the average was 2.88 cm in the absence of deltoid ligament injury. Partial injuries presented 1.93 cm and total 2.1 cm on average . CONCLUSION: Deltoid ligament injury was present in 50% of bimalleolar ankle fractures. Smaller medial malleolus fragments, especially concerning the anterior colliculus, presented greater association with partial deltoid ligament injuries. Level of Evidence IV, Cross Sectional Study. PMID- 28642653 TI - CLINICAL APPLICATION OF A DRILL GUIDE TEMPLATE FOR PEDICLE SCREW PLACEMENT IN SEVERE SCOLIOSIS. AB - OBJECTIVE: To evaluate the accuracy and the effect of drill guide template for pedicle screw placement in severe scoliosis. METHOD: Eight patients with rigid scoliosis were enrolled, five males and three females, ranging from nine to 23 years old. A three-dimensional CT scan of the spine was performed and saved as a DICOM file type. The multi-level template was designed by Mimics software and manufactured according to the part of the most severe deformity. The drill template was placed on the corresponding vertebral surface. Pedicle screws were carefully inserted across the trajectory of the template. Postoperatively, the positions of the pedicle screws were evaluated by CT scan and graded for validation. RESULTS: No spinal cord injury or nerve damage occurred. All patients had satisfactory outcomes. The abnormalities and the measures observed during operation were the same as those found in the preoperative period. The position of the pedicle screws was accurate, according to the postoperative X-ray and CT scan. The rate of scoliosis correction was 60%. Compared with controls, surgery time, blood loss and radiation were significantly lower. CONCLUSION: With the application of multi-level template, the placement of pedicle screws shows high accuracy in scoliosis with shorter surgical time, less blood loss and less radiation exposure. Level of Evidence III, Retrospective Comparative Study. PMID- 28642654 TI - QUANTITATIVE EVALUATION OF EXPERIMENTAL BONE REGENERATION USING INDENTATION TESTS. AB - OBJECTIVES: To determine whether the macroindentation test can be applied to quantitatively assess bone regeneration. METHODS: A 3.2 mm diameter transverse monocortical defect was created on the medial aspect of both proximal metaphyses of the tibia of male Unib-WH rats. For the macroindentation tests, we used 5.00 mm diameter indenters with a 3.2 mm tip. Defect testing was performed 1 to 12 weeks following the surgical procedures to compare the hardness of the newly developed tissue over the 12-week study period. Additional histological, morphological and physical/chemical data were obtained by optical and electronic microscopy, Raman, and energy dispersive x-ray spectrometry (EDS). RESULTS: The mean indentation forces increased in a time-dependent manner from 4 to 12 weeks (p<0.001). Tests performed with the 5.0 mm diameter tip were not able to measure the indentation forces in the first week after the procedure. Moreover, in the second postoperative week indentation forces and the newly formed tissue within the spinal canal were greater than those measured in the fourth and eighth weeks. CONCLUSIONS: The macroindentation test can be used to quantitatively assess bone regeneration in experimental studies. The choice of indenter tip diameter should consider the study design. Level of Evidence II, Diagnostic Studies. PMID- 28642655 TI - THE INFLUENCE OF PASSIVE TOBACCO EXPOSURE AND PHYSICAL EXERCISE ON BONE TISSUE OF YOUNG RATS. AB - OBJECTIVE: The objective of this study is to investigate the effect of passive smoking during pregnancy and associated with swimming on bone area growth, bone mineral density (BMD), and bone mineral content (BMC). METHODS: The offspring was grouped by control matrices (G1) and passive smokers (G2). The offspring was regrouped in eight subgroups, with exposure to smoking (2x/day) and physical exercise (1 session/day), respecting the group of matrices in: sedentary control (G1CS and G2CS), swimming control (G1CN and G2CN), sedentary passive smoker (G1FS and G2FS), and passive smoker swimmer (G1FN and G2FN). The area, BMD and BMC were measured by the tibia and femur and analyzed by densitometer. The results were analyzed by One-Way ANOVA test with Tukey post-test, with a significance level of 5%. RESULTS: In the tibia BMC study, a better rate was observed in G2CN group when compared to G1CS, G1CN and G1FN (p <= 0.023). When assessing BMD in the femur, a higher density ratio was observed in G1FS group when compared to G2CS, G2CN, G2FS and G2FN (p<0.008). In the tibia study, the animals of the G1FS group had higher rates when compared to G2CS and G2FN groups (p<=0.007). CONCLUSIONS: The model of male offspring exposed to passive smoking during fetal development showed a strong decrease in the analyzed parameters. Level of Evidence I, Randomized High Quality Clinical Trial With or Without Statistically Significant Difference, But Narrow Confidence Intervals. PMID- 28642656 TI - LOCAL PERIARTICULAR ANALGESIA IN TOTAL KNEE ARTHROPLASTY. AB - OBJECTIVE: To evaluate the use of infiltration of periarticular analgesic agents intraoperatively in total knee arthroplasty (TKA), with regard to benefits, reduction of pain, opioid consumption, improvement of range of motion and early ambulation. METHODS: To analyze the benefits of periarticular drug infiltration, the patients submitted to TKA were evaluated, being separated into two groups. One group received the local periarticular infiltration protocol containing 0.5% bupivacaine (400mg/20ml), 1/1000 epinephrine (0.3ml), triamcinolone hexacetonide (20mg/1ml), clonidine (150mcg/1ml) and 20 ml of saline (0.9% SS) and, the other group underwent conventional intravenous analgesia. The results were compared and the variables analyzed were age, sex, BMI, comorbidities, postoperative complications, pain, functional capacity, range of motion, transfusion and rescue opioids for analgesia. RESULTS: The mean age of the patients was 68 years and most were female and presented involvement of the left knee. Postoperatively, patients who had received periarticular infiltration showed improvement of pain as well as functional capacity. CONCLUSION: The analysis of data obtained demonstrated that the periarticular infiltration of analgesic agents is significantly effective for pain control and functional recovery. Level of Evidence II, Prospective Comparative Study. PMID- 28642657 TI - NEGATIVE-PRESSURE WOUND THERAPY IN THE TREATMENT OF COMPLEX INJURIES AFTER TOTAL KNEE ARTHROPLASTY. AB - OBJECTIVE: To present an experience with negative-pressure wound therapy (NPWT) in the treatment of surgical wounds in patients treated for infections after total knee arthroplasty (TKA) with or without dehiscence and prophylaxis in wounds considered at risk of healing problems. METHODS: We prospectively evaluated patients with TKA infection with or without surgical wound dehiscence and patients with risk factors for infection or surgical wound complications treated with Pico(r) device for NPWT in addition to standard treatment of infection or dehiscence in our institution. We considered as an initial favorable outcome the resolution of the infectious process and the closure of the surgical wound dehiscences in the treated cases and the good progression of the wound without complicating events in the prophylactic cases. RESULTS: We evaluated 10 patients who used Pico(r) in our service. All patients had a favorable outcome according to established criteria. No complications were identified regarding the use of the NPWT device. The mean follow-up of the patients after the use of the device was 10.5 months. CONCLUSION: The NPWT can be safely used in wound infections and complications following TKA with promising results. Long-term randomized prospective studies should be conducted to prove its effectiveness. Level of Evidence IV, Case Series. PMID- 28642658 TI - STUDY OF THE ANTEROLATERAL LIGAMENT OF THE KNEE IN FORMALIN-EMBEDDED CADAVERS. AB - OBJECTIVE: To verify the incidence and characterize morphologically the anterolateral ligament of the knee (ALL) in cadaveric samples of the collection of the Laboratory of Anatomy of the Department of Morphology of the Universidade Federal do Espirito Santo. METHODS: Dissections and cross sections were performed for mesoscopic analysis of the anterolateral region of 15 knees preserved in 4% formalin solution in order to identify the ALL. RESULTS: After dissection of the skin and subcutaneous tissue of the knee anterolateral region, it was possible to identify the iliotibial tract (ITT), the patellar ligament and the femoral biceps tendon. The ITT was removed from the Gerdy tubercle and the following structures were visualized: knee joint capsule, fibular collateral ligament and popliteal tendon. However, the ALL was not identified in any of the samples. CONCLUSIONS: The ALL could not be identified in any of the specimens studied, either through dissection or mesoscopic analysis. Level of Evidence III, Diagnosis Studies - Investigation of an Exam for Diagnosis. PMID- 28642659 TI - SPORTS INJURIES AMONG AMATEUR ATHLETES AT A BRAZILIAN UNIVERSITY. AB - OBJECTIVE: To obtain information on the incidence and nature of sports injuries at a Brazilian university. METHOD: Data from 396 student amateur athletes (61% male) playing 15 different sports during the 2013 season were retrospectively evaluated. Subjects completed the National Collegiate Athletic Association Injury Surveillance System questionnaire at the conclusion of the 2013 sports season. Injuries that resulted in at least one day of time lost were included. Exposure was defined as one student amateur athlete participating in one practice or game and is expressed as an athlete-exposure (A-E). RESULTS: Injury rates were significantly greater in games (13.13 injuries per 1000 A-Es, 95% CI = 10.3-15) than in practices (4.47 injuries per 1000 A-Es, 95% CI = 3.9-5.1). The mechanisms that accounted for the most injuries in games and practices were player contact (52.9%) and non-contact (54.5%), respectively. Ankle ligament sprains were the most common injury (18.2% of all reported injuries). A relatively high incidence of anterior cruciate ligament injury was also observed (0.16 injuries per 1000 A Es). CONCLUSION: Brazilian student amateur athletes are at great risk of sustaining non-contact injuries such as ankle sprains and anterior cruciate ligament injuries. Level III of Evidence, Study of non consecutive patients; without consistently applied reference ''gold'' standard. PMID- 28642660 TI - BONE FRAGILITY, FRACTURE RISK AND TRAUMA:A COMPLICATED TRIANGLE IN CHILDREN. AB - OBJECTIVE: To analyze whether association between bone fragility and risk of fracture depends on the trauma level. METHOD: All participants along with their mothers underwent DXA scan and body measurements. The subjects answered a self report questionnaire about their physical activities and the precipitating causes. The questionnaire results were associated with DXA performed at the baseline visit. RESULTS: A total 374 children with available DXA scan and complete follow-up of 5 years were included in the final analysis. Of the 374 children, 53 (14.2%) had one fracture, and 11 (20.7%) had more than one fracture. Based on the modified Landin classification, the trauma level was determined. Of the 53 (14.2%) children who had one fracture, 39 (73.6%) were classified, namely 19 (48.7%) with mild trauma, 16 (41%) with moderate trauma and four (10.2%) with severe trauma. Trauma level could not be assigned to 14 (26.4%) children due to limited information. Children without fractures had significantly higher values in all bone parameters compared to those with fractures caused by mild trauma. CONCLUSION: Subjects with mild trauma fractures had an inversely proportional ratio between bone fragility parameters and fracture risk compared with subjects without fractures. Level of Evidence IV, Case Series. PMID- 28642661 TI - CUSTOMIZED GUIDE FOR FEMORAL COMPONENT POSITIONING IN HIP RESURFACING ARTHROPLASTY. AB - OBJECTIVE: To prove the accuracy of a customized guide developed according to our method. METHODS: This customized guide was developed from a three-dimensional model of proximal femur reconstructed using computed tomography data. Based on the new technique, the position of the guide pin insertion was selected and adjusted using the reference of the anatomical femoral neck axis. The customized guide consists of a hemispheric covering designed to fit the posterior part of the femoral neck. The performance of the customized guide was tested in eight patients scheduled for total hip arthroplasty. The stability of the customized guide was assessed by orthopedic surgeons. An intraoperative image intensifier was used to assess the accuracy. RESULTS: The customized guide was stabilized with full contact and was fixed in place in all patients. The mean angular deviations in relation to the what was planned in anteroposterior and lateral hip radiographs were 0.5o +/- 1.8o in valgus and 1.0o +/- 2.4o in retroversion, respectively. CONCLUSION: From this pilot test, the authors suggest that the proposed technique could be applied as a customized guide to the positioning device for hip resurfacing arthroplasty with acceptable accuracy and user friendly interface. Level of Evidence IV, Cases Series. PMID- 28642662 TI - FEMORAL NECK FRACTURES GARDEN I AND II: EVALUATION OF THE DEVIATION IN LATERAL VIEW. AB - OBJECTIVE: To evaluate the rate of deviation in the lateral radiographic incidence in patients with femoral neck fracture classified as non-diverted in the anteroposterior view (Garden I and II). METHODS: Nineteen selected patients with femoral neck fractures classified as Garden I and II were retrospectively evaluated, estimating the degree of deviation in the lateral view. RESULTS: Fifteen cases (79%) presented deviations in lateral view, with a mean of 18.6 degrees (+/-15.5). CONCLUSION: Most fractures of the femoral neck classified as Garden I and II present some degree of posterior deviation in the X-ray lateral view. Level of Evidence III, Retrospective Comparative Study. PMID- 28642663 TI - Weber C ankle fractures with tibiofibular diastasis: syndesmosis-only fixation. AB - OBJECTIVES: To evaluate syndesmosis-only fixation in Weber C ankle fractures with tibiofibular diastasis and to assess the need for additional fibular fixation. METHODS: Twenty-one patients with Weber C ankle fractures and tibiofibular diastasis were followed for at least 24 months after treatment. In treatment of the Weber C fractures, only a syndesmosis screw was used through a mini open lateral incision if the syndesmosis could be anatomically reduced and fibular length and rotation could be restored. At follow-up, anteroposterior tibiofibular distance, lateral fibular distance, medial mortise distance and fracture healing were compared and patients were clinically evaluated using the Olerud and Molander ankle scale scoring system. RESULTS: The average duration of follow-up was 49 months and the decreases in anteroposterior tibiofibular distance and lateral fibular distance were statistically significant. At the last follow-up the average clinical score was 86. Ankle mortise was reduced at follow-up in all cases except one, which resulted in a late diastasis. CONCLUSIONS: Syndesmosis only fixation can be an effective method of treating Weber type-C lateral malleolar fractures with syndesmosis disruption in cases where intraoperative fibular length can be restored and anatomical syndesmosis reduction can be achieved. Level of Evidence IV, Case Series. PMID- 28642664 TI - Surgical treatment results for dupuytren's disease. AB - OBJECTIVE: To present the results of our cases of Dupuytren's disease treated with regional selective fasciectomy in light of the literature. METHODS: Patients diagnosed with Dupuytren's contracture and surgically treated with regional selective fasciectomy at our institution with adequate follow-up data were included in the study. All patients were routinely followed after surgery to assess results and complications. QuickDASH scoring was used to evaluate the patients and recurrences and complications were recorded. RESULTS: Twenty-one hands of 19 patients (13 males, 6 females) who underwent surgery and received adequate follow-up were retrospectively evaluated. Mean patient age was 65.8 (range: 41 to 86) and the mean follow-up period was 48.2 months (range: 24 to 86). Fourteen (66.6%) hands had excellent results, five (23%) hands had good results and two (9.4%) had fair results. The mean QuickDASH score for the patients at the final follow-up was 6.58 (range: 0 to 20.4). CONCLUSION: Our study results demonstrated that regional selective fasciectomy is a reliable and efficient method to treat Dupuytren's disease with low rates of complications and recurrence and the technique can be considered the gold standard. Level of Evidence IV, Case Series. PMID- 28642665 TI - Osteoporosis in brazilian patients awaiting knee arthroplasty. AB - OBJECTIVE: The primary objective of this study was to determine the prevalence of osteoporosis and osteopenia prior to total knee arthroplasty (TKA) in female patients. As a secondary objective, we evaluated the incidence of hip fractures, types of drugs to treat osteoporosis and serum vitamin D levels. METHOD: This is a transversal, descriptive and observational study which evaluated 60 women above age 55 prior to total knee replacement. RESULTS: Mean patient age was 71.4 years. Osteoporosis was present in 16.7% of the sample and osteopenia in 15%. In the patients with osteoporosis, femur fracture (20%) was most frequent. Most of the group with osteopenia did not take any medication to treat this condition (55.6%), while most patients with osteoporosis took alendronate (30%) and 30% did not take any medication. CONCLUSION: The female population awaiting total knee replacement should be considered at risk for osteoporosis, confirming recent findings in the literature. Level of Evidence III, Control Case Study. PMID- 28642666 TI - Shoulder disorders in an outpatient clinic: an epidemiological study. AB - OBJECTIVE: To describe shoulder disorders in patients evaluated by two shoulder and elbow surgeons. METHODS: This cross-sectional study analyzed patients evaluated by two authors, excluding acute fractures and dislocations and patients with symptoms not involving the shoulder. Age and sex distribution was determined for the different diagnoses. RESULTS: We evaluated 1001 patients. Mean age was 51.43+/-15.15 years and 51.0% were female. Disorders of the rotator cuff occurred in 64.3% (41.2% tendinopathy, 11.0% partial tears and 12.2% full-thickness tears). Adhesive capsulitis occurred in 13.5% of cases and glenohumeral instability in 8.1%. Rotator cuff disorders were more common in women, with a peak between 50 and 59 years for tendinopathy and partial tears and between 60 and 69 years for full-thickness tears. Glenohumeral instability was more frequent in men, with a peak between 30 and 39 years. CONCLUSION: The most frequent diagnosis was rotator cuff tendinopathy, followed by adhesive capsulitis, full thickness rotator cuff tears, partial rotator cuff tears and glenohumeral instability. Rotator cuff lesions were more common in women, with a peak between 60 and 69 years for full-thickness tears. Level of Evidence IV, Case Series. PMID- 28642667 TI - Surgical treatment of acromioclavicular dislocation using the endobutton. AB - OBJECTIVE: To evaluate the clinical and radiographic results of 23 patients diagnosed with acute type III acromioclavicular dislocation treated with the Endobutton. METHODS: Twenty-three patients with a diagnosis of type III acromioclavicular dislocation were treated surgically. RESULTS: Twenty-one patients were male (91.3%) and 2 (8.7%) were female. The dominant side was affected in 15 patients (65.21%) and the non-dominant side in 8 patients (34.79%). All patients were operated on by the same surgical team within 4 weeks of the trauma. According to the UCLA score, 14 patients (60.86%) presented excellent results, 7 patients (30.43%) had good results and 2 patients (8.69%) had regular results. CONCLUSION: The technique was effective in treating acute type III dislocations with a high degree of patient satisfaction. Level of Evidence IV, Case Series. PMID- 28642668 TI - Adolescent idiopathic scoliosis: surgical treatment and quality of life. AB - OBJECTIVES: The purpose of this study was to determine the influence of perioperative factors and their impact on clinical and functional outcomes in Brazilian patients with adolescent idiopathic scoliosis (AIS). METHODS: We performed a prospective study with 49 consecutive AIS patients who underwent spine fusion and had a minimum 2 year follow-up. Clinical and radiographic data were correlated to SRS-30 scores in order to predict postoperative results. RESULTS: There was a negative association between patient age at the time of surgery and back pain. We also observed higher scores in the "satisfaction" domain in patients who underwent surgery after 15 years of age (p < 0.05). The average SRS-30 "mental health" score was significantly higher in males than in females (p= 0.035). Patients treated with braces had worse results than those who did not use them (p= 0.005). CONCLUSIONS: Posterior spine fusion led to improvement of all domains of the SRS-30 questionnaire. Clinical results were influenced by age, sex and the use of braces prior to surgery. There was no correlation between curve correction and presence of perioperative complications. Level of Evidence IV, Case Series. PMID- 28642669 TI - Concordance for curve type in idiopathic scoliosis among family members. AB - OBJECTIVE: To evaluate the concordance for the curve pattern, side and levels of the superior apical vertebrae, apex and inferior apical vertebrae of curves in patients and their relatives with idiopathic scoliosis. METHODS: Concordance according to the Lenke classification for curve pattern, side and levels of the superior apical vertebrae, apex and inferior apical vertebrae were evaluated comparative and prospectively in 243 pairs of patients and respective relatives with idiopathic scoliosis. RESULTS: The family concordance for the curve pattern and side was 51.4% (125 pairs). Among these pairs, the concordance of the levels of the vertebrae was 91.2% (114 pairs). The concordance rate for the curve pattern and side between parents/children was 51.6% and between siblings was 50.0% (p-value= 0.411). The concordance rates of the levels of vertebrae were 86.8% and 95.1%, respectively (p-value = 0.219). CONCLUSION: Curve shape in idiopathic scoliosis is related to family and degree of kinship, since the data showed a high concordance for the curve pattern, side and levels of the apical vertebrae and apex between patients and relatives with this deformity. The concordance was higher in those with a closer degree of kinship. Level of Evidence II, Lesser Quality Prospective Study. PMID- 28642670 TI - Ginkgo Biloba improves bone formation during fracture healing: an experimental study in rats. AB - OBJECTIVES: Ginkgo biloba extract (EGb 761) is a plant extract obtained from the leaves of the G. biloba tree. The aim of this study was to assess the histological and radiological effects of G. biloba extract on fracture healing in an experimental fracture model using rat femurs. METHODS: Forty-eight female Sprague-Dawley rats (weight: 195-252 g; age: 20 weeks) were used in the study. The rats were randomly divided into six groups (n=8). A transverse fracture was made in the middle of the right femur of each rat and fixed with a Kirschner wire. The G. biloba groups received 60 mg/kg oral G. biloba extract once daily. No medication was given to the control groups. On days 7, 21 and 35, both sets of femurs were evaluated radiologically and histopathologically. RESULTS: Histological evaluation revealed that the G. biloba groups had significant differences at 21 and 35 days (p<0.05). The G. biloba group showed a significant difference in terms of bone formation on day 21 when compared to the control group (p<0.05). CONCLUSIONS: This study indicated that the use of G. biloba extract accelerated fracture healing. Both radiological and histological differences were detected, but the histological differences were more remarkable. Level of Evidence I, High Quality Randomized Trial. PMID- 28642672 TI - Multifocal osteonecrosis secondary to occupational exposure to aluminum. AB - Multifocal osteonecrosis is a rare disease; chronic use of corticosteroids is considered the main risk factor. Patients with chronic renal failure can develop aluminum toxicity, which can lead to osteomalacia and encephalopathy. An association between osteonecrosis and aluminum toxicity has been reported among patients with dialytic renal insufficiency. Occupational exposure to aluminum rarely causes lung disease and no cases of bone lesions resulting from exposure to this metal have been reported. In this manuscript, we describe a novel case of a patient with multifocal osteonecrosis associated with chronic occupational exposure to aluminum. Level of Evidence IV, Case Report. PMID- 28642671 TI - Subchondral raft construction with locking plates for the treatment of Schatzker type II fractures. AB - OBJECTIVES: To evaluate the functional and radiological results of Schatzker type II fractures treated via subchondral raft screws combined with locking plates. METHODS: Twenty-four individuals were enrolled in this study between 2010 and 2014. The depressed joint line was elevated and the defect was filled with allograft. Next, two or three subchondral screws were placed in combination with a locking plate. At the last follow-up, clinical and radiological data were recorded. RESULTS: The mean follow-up period was 21.4 months (12-39). The mean Knee Society Score (KSS) and Rasmussen clinical scores were 91.5 (range, 77-100) and 16.75 (range, 14-18), respectively. The mean Rasmussen radiological score was 27.9 (range, 24-30) during the follow-up. There was no statistically significant difference between injured and non-injured sides with respect to the mechanical axis, the proximal medial tibial angle, and tibial slope. In addition, arthritis showed no difference on the non-injured side, although follow-up was short. CONCLUSIONS: The periarticular raft construction combined with the locking plate helps surgeon to maintain the anatomic line of the joint and the mechanical axis obtained during the surgery. Secondary arthritis seems to be major complication after fractures of the tibial plateau, although the functional results were satisfactory. Level of Evidence IV, Case Series. PMID- 28642673 TI - WaveformECG: A Platform for Visualizing, Annotating, and Analyzing ECG Data. AB - The electrocardiogram (ECG) is the most commonly collected data in cardiovascular research because of the ease with which it can be measured and because changes in ECG waveforms reflect underlying aspects of heart disease. Accessed through a browser, WaveformECG is an open source platform supporting interactive analysis, visualization, and annotation of ECGs. PMID- 28642674 TI - AN AUTOMATIC 3D CT/PET SEGMENTATION FRAMEWORK FOR BONE MARROW PROLIFERATION ASSESSMENT. AB - Clinical assessment of bone marrow is limited by an inability to evaluate the marrow space comprehensively and dynamically and there is no current method for automatically assessing hematopoietic activity within the medullary space. Evaluating the hematopoietic space in its entirety could be applicable in blood disorders, malignancies, infections, and medication toxicity. In this paper, we introduce a CT/PET 3D automatic framework for measurement of the hematopoietic compartment proliferation within osseous sites. We first perform a full-body bone structure segmentation using 3D graph-cut on the CT volume. The vertebrae are segmented by detecting the discs between adjacent vertebrae. Finally, we register the bone marrow CT volume with its corresponding PET volume and capture the spinal bone marrow volume. The proposed framework was tested on 17 patients, achieving an average accuracy of 86.37% and a worst case accuracy of 82.3% in automatically extracting the aggregate volume of the spinal marrow cavities. PMID- 28642675 TI - Role of Minimally Invasive Surgery in the Reoperative Abdomen or Pelvis. AB - Laparoscopy has become widely accepted as the preferred surgical approach in the management of benign and malignant colorectal diseases. Once considered a relative contraindication in patients with prior abdominal surgery (PAS), as surgeons have continued to gain expertise in advanced laparoscopy, minimally invasive approaches have been increasingly incorporated in the reoperative abdomen and pelvis. Although earlier studies have described conversion rates, most contemporary series evaluating the impact of PAS in laparoscopic colorectal resection have reported equivalent conversion and morbidity rates between reoperative and non-reoperative cases, and series evaluating the impact of laparoscopy in reoperative cases have demonstrated improved short-term outcomes with laparoscopy. The data overall highlight the importance of case selection, careful preoperative preparation and planning, and the critical role of surgeons' expertise in advanced laparoscopic techniques. Challenges to the widespread adoption of minimally invasive techniques in reoperative colorectal cases include the longer learning curve and longer operative time. However, with the steady increase in adoption of minimally invasive techniques worldwide, minimally invasive surgery (MIS) is likely to continue to be applied in the management of increasingly complex reoperative colorectal cases in an effort to improve patient outcomes. In the hands of experienced MIS surgeons and in carefully selected cases, laparoscopy is both safe and efficacious for reoperative procedures in the abdomen and pelvis, with measurable short-term benefits. PMID- 28642677 TI - A novel workflow combining plaque imaging, plaque and plasma proteomics identifies biomarkers of human coronary atherosclerotic plaque disruption. AB - BACKGROUND: Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation. METHODS: We developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption. RESULTS: We compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption. CONCLUSION: This novel approach for biomarker discovery in human coronary artery plaque disruption can identify new biomarkers related to human coronary artery plaque composition and disruption. PMID- 28642678 TI - A Cold-Blooded View on Adult Neurogenesis. AB - During brain development, highly complex and interconnected neural circuits are established. This intricate wiring needs to be robust to faithfully perform adult brain function throughout life, but at the same time offer room for plasticity to integrate new information. In the mammalian brain, adult-born neurons are produced in restricted niches harboring neural stem cells. In the fruit fly Drosophila, low-level adult neurogenesis arising from a dispersed population of neural progenitors has recently been detected in the optic lobes. Strikingly, these normally quiescent neural stem cells proliferate upon brain injury and produce new neurons for brain regeneration. Here, we review adult neurogenesis in crustaceans and insects and highlight that neurogenesis in the visual system is prominent in arthropods, but its role and underlying mechanisms are unclear. Moreover, we discuss how the study of damage-responsive progenitor cells in Drosophila may help to understand robust regenerative neurogenesis and open new avenues to enhance brain repair after injury or stroke in humans. PMID- 28642679 TI - Assessment of Ipsilateral Efferent Effects in Human via ECochG. AB - Development of electrophysiological means to assess the medial olivocochlear (MOC) system in humans is important to further our understanding of the function of that system and for the refinement and validation of psychoacoustical and otoacoustic emission methods which are thought to probe the MOC. Based on measurements in anesthetized animals it has been hypothesized that the MOC-reflex (MOCR) can enhance the response to signals in noise, and several lines of evidence support such a role in humans. A difficulty in these studies is the isolation of efferent effects. Efferent activation can be triggered by acoustic stimulation of the contralateral or ipsilateral ear, but ipsilateral stimulation is thought to be more effective. However, ipsilateral stimulation complicates interpretation of effects since these sounds can affect the perception of other ipsilateral sounds by mechanisms not involving olivocochlear efferents. We assessed the ipsilaterally evoked MOCR in human using a transtympanic procedure to record mass-potentials from the cochlear promontory or the niche of the round window. Averaged compound action potential (CAP) responses to masked probe tones of 4 kHz with and without a precursor (designed to activate the MOCR but not the stapedius reflex) were extracted with a polarity alternating paradigm. The masker was either a simultaneous narrow band noise masker or a short (20-ms) tonal ON- or OFF-frequency forward masker. The subjects were screened for normal hearing (audiogram, tympanogram, threshold stapedius reflex) and psychoacoustically tested for the presence of a precursor effect. We observed a clear reduction of CAP amplitude by the precursor, for different masking conditions. Even without an MOCR, this is expected because the precursor will affect the response to subsequent stimuli via neural adaptation. To determine whether the precursor also activated the efferent system, we measured the CAP over a range of masker levels, with or without precursor, and for different types of masker. The results show CAP reduction consistent with the type of gain reduction caused by the MOCR. These results generally support psychoacoustical paradigms designed to probe the efferent system as indeed activating the MOCR system, but not all observations are consistent with this mechanism. PMID- 28642680 TI - Weight Bearing Over-ground Stepping in an Exoskeleton with Non-invasive Spinal Cord Neuromodulation after Motor Complete Paraplegia. AB - We asked whether coordinated voluntary movement of the lower limbs could be regained in an individual having been completely paralyzed (>4 year) and completely absent of vision (>15 year) using two novel strategies-transcutaneous electrical spinal cord stimulation at selected sites over the spine as well as pharmacological neuromodulation by buspirone. We also asked whether these neuromodulatory strategies could facilitate stepping assisted by an exoskeleton (EKSO, EKSO Bionics, CA) that is designed so that the subject can voluntarily complement the work being performed by the exoskeleton. We found that spinal cord stimulation and drug enhanced the level of effort that the subject could generate while stepping in the exoskeleton. In addition, stimulation improved the coordination patterns of the lower limb muscles resulting in a more continuous, smooth stepping motion in the exoskeleton along with changes in autonomic functions including cardiovascular and thermoregulation. Based on these data from this case study it appears that there is considerable potential for positive synergistic effects after complete paralysis by combining the over-ground step training in an exoskeleton, combined with transcutaneous electrical spinal cord stimulation either without or with pharmacological modulation. PMID- 28642681 TI - gamma1-Containing GABA-A Receptors Cluster at Synapses Where they Mediate Slower Synaptic Currents than gamma2-Containing GABA-A Receptors. AB - GABA-A receptors (GABAARs) are pentameric ligand-gated ion channels that are assembled mainly from alpha (alpha1-6), beta (beta1-3) and gamma (gamma1-3) subunits. Although GABAARs containing gamma2L subunits mediate most of the inhibitory neurotransmission in the brain, significant expression of gamma1 subunits is seen in the amygdala, pallidum and substantia nigra. However, the location and function of gamma1-containing GABAARs in these regions remains unclear. In "artificial" synapses, where the subunit composition of postsynaptic receptors is specifically controlled, gamma1 incorporation slows the synaptic current decay rate without affecting channel deactivation, suggesting that gamma1 containing receptors are not clustered and therefore activated by diffuse neurotransmitter. However, we show that gamma1-containing receptors are localized at neuronal synapses and form clusters in both synaptic and extrasynaptic regions. In addition, they exhibit rapid membrane diffusion and a higher frequency of exchange between synaptic and perisynaptic populations compared to gamma2L-containing GABAARs. A point mutation in the large intracellular domain and a pharmacological analysis reveal that when a single non-conserved gamma2L residue is mutated to its gamma1 counterpart (T349L), the synaptic current decay is slowed from gamma2L- to gamma1-like without changing the clustering or diffusion properties of the receptors. In addition, previous fast perfusion and single channel kinetic experiments revealed no difference in the intrinsic closing rates of gamma2L- and gamma1-containing receptors when expressed in HEK293 cells. These observations together with Monte Carlo simulations of synaptic function confirm that decreased clustering does not control gamma1 containing GABAAR kinetics. Rather, they suggest that gamma1- and gamma2L containing receptors exhibit differential synaptic current decay rates due to differential gating dynamics when localized at the synapse. PMID- 28642676 TI - International Society of Sports Nutrition Position Stand: protein and exercise. AB - The International Society of Sports Nutrition (ISSN) provides an objective and critical review related to the intake of protein for healthy, exercising individuals. Based on the current available literature, the position of the Society is as follows:An acute exercise stimulus, particularly resistance exercise, and protein ingestion both stimulate muscle protein synthesis (MPS) and are synergistic when protein consumption occurs before or after resistance exercise.For building muscle mass and for maintaining muscle mass through a positive muscle protein balance, an overall daily protein intake in the range of 1.4-2.0 g protein/kg body weight/day (g/kg/d) is sufficient for most exercising individuals, a value that falls in line within the Acceptable Macronutrient Distribution Range published by the Institute of Medicine for protein.Higher protein intakes (2.3-3.1 g/kg/d) may be needed to maximize the retention of lean body mass in resistance-trained subjects during hypocaloric periods.There is novel evidence that suggests higher protein intakes (>3.0 g/kg/d) may have positive effects on body composition in resistance-trained individuals (i.e., promote loss of fat mass).Recommendations regarding the optimal protein intake per serving for athletes to maximize MPS are mixed and are dependent upon age and recent resistance exercise stimuli. General recommendations are 0.25 g of a high quality protein per kg of body weight, or an absolute dose of 20-40 g.Acute protein doses should strive to contain 700-3000 mg of leucine and/or a higher relative leucine content, in addition to a balanced array of the essential amino acids (EAAs).These protein doses should ideally be evenly distributed, every 3-4 h, across the day.The optimal time period during which to ingest protein is likely a matter of individual tolerance, since benefits are derived from pre- or post-workout ingestion; however, the anabolic effect of exercise is long-lasting (at least 24 h), but likely diminishes with increasing time post-exercise.While it is possible for physically active individuals to obtain their daily protein requirements through the consumption of whole foods, supplementation is a practical way of ensuring intake of adequate protein quality and quantity, while minimizing caloric intake, particularly for athletes who typically complete high volumes of training. Rapidly digested proteins that contain high proportions of essential amino acids (EAAs) and adequate leucine, are most effective in stimulating MPS. Different types and quality of protein can affect amino acid bioavailability following protein supplementation. Athletes should consider focusing on whole food sources of protein that contain all of the EAAs (i.e., it is the EAAs that are required to stimulate MPS). Endurance athletes should focus on achieving adequate carbohydrate intake to promote optimal performance; the addition of protein may help to offset muscle damage and promote recovery. Pre sleep casein protein intake (30-40 g) provides increases in overnight MPS and metabolic rate without influencing lipolysis. PMID- 28642682 TI - Neuritin Inhibits Notch Signaling through Interacted with Neuralized to Promote the Neurite Growth. AB - Neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation. However, the mechanism of neuritin in modulating neurite growth has not been elucidated. Here, using yeast two-hybrid we screened and discovered the interaction of neuritin and neuralized (NEURL1), which is an important regulator that can activate Notch signaling through promoting endocytosis of Notch ligand. And then we identified the interaction of neuritin and neuralized by co-immunoprecipitation (IP) assays, and clarified that neuritin and NEURL1 were co-localized on the cell membrane of SH-SY5Y cells. Moreover, neuritin significantly suppressed Notch ligand Jagged1 (JAG1) endocytosis promoted by NEURL1, and then inhibited the activation of Notch receptor Notch intracellular domain (NICD) and decreased the expression of downstream gene hairy and enhancer of split-1 (HES1). Importantly, the effect of neuritin on inhibiting Notch signaling was rescued by NEURL1, which indicated that neuritin is an upstream and negative regulator of NEURL1 to inhibit Notch signaling through interaction with NEURL1. Notably, recombinant neuritin restored the retraction of neurites caused by activation of Notch, and neurite growth stimulated by neuritin was partially blocked by NEURL1. These findings establish neuritin as an upstream and negative regulator of NEURL1 that inhibits Notch signaling to promote neurite growth. This mechanism connects neuritin with Notch signaling, and provides a valuable foundation for further investigation of neuritin's role in neurodevelopment and neural plasticity. PMID- 28642683 TI - Object Phobia and Altered RhoA Signaling in Amygdala of Mice Lacking RICH2. AB - RICH2 knockout (RICH2 KO) mice exhibit neophobia in the novel object test. To gain further insight into their anxiety-related phenotype, we subjected these mice to additional behavioral tests to elucidate whether the behavioral abnormality in these mice is a consequence of reduced exploratory motivation, and whether the neophobia is linked specifically to objects or also present for other modalities. RICH2 KO mice engage in normal exploration in a novel environment, suggesting that the anxiety-related phenotype is not due to reduced exploratory drive. Increased fear response was not observed using novel olfactory cues, but restricted to objects. Given that the amygdala is an important brain region mediating anxiety-related behaviors and a prime target for anxiety-related therapeutics, and RICH2 is a Rho-GTPase activating protein (GAP) regulating synaptic spine plasticity via small GTPases, we analyzed spine formation, morphology and receptor composition in amygdala. We found disinhibition of RhoA in the amygdala of RICH2 KO mice, along with a decreased ability for actin polymerization and a reduction in mature spines. However, we detected increased neuronal activation in the amygdala evidenced by c-fos labeling. Thus, we conclude that despite unaltered baseline activity, RICH2 KO mice show heightened amygdala response after exposure to objects, which, however, does not result in homeostatic strengthening of excitatory synapses. PMID- 28642684 TI - Ferulic Acid Improves Functional Recovery after Acute Spinal Cord Injury in Rats by Inducing Hypoxia to Inhibit microRNA-590 and Elevate Vascular Endothelial Growth Factor Expressions. AB - Spinal cord injury (SCI) is the leading cause of paralysis, disability and even death in severe cases, and neural stem cells (NSCs) transplant has been employed for repairing SCI. Ferulic acid (FA) is able to promote neurogenesis in various stem cell therapies. We aimed to investigate the effect of FA on NSC transplant therapy, and the underlying mechanism, in improving functional recovery in SCI rat model. A rat model of SCI was established, which then received transplant of NSCs with or without FA pre-treatment. Functional recovery of the SCI rats was then evaluated, in terms of spinal cord water content, myeloperoxidase activity and behavioral assessments. Effect of FA in inducing hypoxia in NSCs was also assessed, followed by identifying the hypoxic regulated microRNA and the subsequent target gene. Transplant of FA pre-treated NSCs improved functional recovery of SCI rats to a more significant extent than NSCs without FA pre treatment. The beneficial effects of FA in repairing SCI was mediated by inducing hypoxia in NSCs, which in turn inhibited microRNA-590 to elevate vascular endothelial growth factor expression. Our findings support the clinical potential of FA in improving efficacy of NSC transplant therapy for treatment of SCI. PMID- 28642685 TI - Rab Interacting Molecules 2 and 3 Directly Interact with the Pore-Forming CaV1.3 Ca2+ Channel Subunit and Promote Its Membrane Expression. AB - Rab interacting molecules (RIMs) are multi-domain proteins that positively regulate the number of Ca2+ channels at the presynaptic active zone (AZ). Several molecular mechanisms have been demonstrated for RIM-binding to components of the presynaptic Ca2+ channel complex, the key signaling element at the AZ. Here, we report an interaction of the C2B domain of RIM2alpha and RIM3gamma with the C terminus of the pore-forming alpha-subunit of CaV1.3 channels (CaV1.3alpha1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). Co-expressing full-length RIM2alpha with a Ca2+ channel complex closely resembling that of IHCs (CaV1.3alpha1-CaVbeta2a) in HEK293 cells doubled the Ca2+-current and shifted the voltage-dependence of Ca2+ channel activation by approximately +3 mV. Co-expression of the short RIM isoform RIM3gamma increased the CaV1.3alpha1-CaVbeta2a-mediated Ca2+-influx in HEK293 cells, but disruption of RIM3gamma in mice left Ca2+-influx in IHCs and hearing intact. In conclusion, we propose that RIM2alpha and RIM3gamma directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells. PMID- 28642686 TI - Transcranial Random Noise Stimulation (tRNS) Shapes the Processing of Rapidly Changing Auditory Information. AB - Neural oscillations in the gamma range are the dominant rhythmic activation pattern in the human auditory cortex. These gamma oscillations are functionally relevant for the processing of rapidly changing acoustic information in both speech and non-speech sounds. Accordingly, there is a tight link between the temporal resolution ability of the auditory system and inherent neural gamma oscillations. Transcranial random noise stimulation (tRNS) has been demonstrated to specifically increase gamma oscillation in the human auditory cortex. However, neither the physiological mechanisms of tRNS nor the behavioral consequences of this intervention are completely understood. In the present study we stimulated the human auditory cortex bilaterally with tRNS while EEG was continuously measured. Modulations in the participants' temporal and spectral resolution ability were investigated by means of a gap detection task and a pitch discrimination task. Compared to sham, auditory tRNS increased the detection rate for near-threshold stimuli in the temporal domain only, while no such effect was present for the discrimination of spectral features. Behavioral findings were paralleled by reduced peak latencies of the P50 and N1 component of the auditory event-related potentials (ERP) indicating an impact on early sensory processing. The facilitating effect of tRNS was limited to the processing of near-threshold stimuli while stimuli clearly below and above the individual perception threshold were not affected by tRNS. This non-linear relationship between the signal-to noise level of the presented stimuli and the effect of stimulation further qualifies stochastic resonance (SR) as the underlying mechanism of tRNS on auditory processing. Our results demonstrate a tRNS related improvement in acoustic perception of time critical auditory information and, thus, provide further indices that auditory tRNS can amplify the resonance frequency of the auditory system. PMID- 28642687 TI - Is SIRT6 Activity Neuroprotective and How Does It Differ from SIRT1 in This Regard? PMID- 28642688 TI - Lower Functional Connectivity of the Periaqueductal Gray Is Related to Negative Affect and Clinical Manifestations of Fibromyalgia. AB - Fibromyalgia (FM) syndrome is characterized by chronic widespread pain, muscle tenderness and emotional distress. Previous studies found reduced endogenous pain modulation in FM. This deficiency of pain modulation may be related to the attributes of chronic pain and other clinical symptoms experienced in patients with FM. Thus, we tested whether there is a link between the clinical symptoms of FM and functional connectivity (FC) of the periaqueductal gray (PAG), a key node of pain modulation. We acquired resting state 3T functional MRI (rsfMRI) data from 23 female patients with FM and 16 age- and sex- matched healthy controls (HC) and assessed FM symptoms with the Brief Pain Inventory (BPI), Fibromyalgia Impact Questionnaire (FIQ), Hospital Anxiety and Depression Scale (HADS) and Pain Catastrophizing Scale (PCS). We found that patients with FM exhibit statistically significant disruptions in PAG FC, particularly with brain regions implicated in negative affect, self-awareness and saliency. Specifically, we found that, compared to HCs, the FM patients had stronger PAG FC with the lingual gyrus and hippocampus but weaker PAG FC with regions associated with motor/executive functions, the salience (SN) and default mode networks (DMN). The attenuated PAG FC was also negatively correlated with FIQ scores, and positively correlated with the magnification subscale of the PCS. These alterations were correlated with emotional and behavioral symptoms of FM. Our study implicates the PAG as a site of dysfunction contributing to the clinical manifestations and pain in FM. PMID- 28642691 TI - MRI Overestimates Excitotoxic Amygdala Lesion Damage in Rhesus Monkeys. AB - Selective, fiber-sparing excitotoxic lesions are a state-of-the-art tool for determining the causal contributions of different brain areas to behavior. For nonhuman primates especially, it is advantageous to keep subjects with high quality lesions alive and contributing to science for many years. However, this requires the ability to estimate lesion extent accurately. Previous research has shown that in vivo T2-weighted magnetic resonance imaging (MRI) accurately estimates damage following selective ibotenic acid lesions of the hippocampus. Here, we show that the same does not apply to lesions of the amygdala. Across 19 hemispheres from 13 rhesus monkeys, MRI assessment consistently overestimated amygdala damage as assessed by microscopic examination of Nissl-stained histological material. Two outliers suggested a linear relation for lower damage levels, and values of unintended amygdala damage from a previous study fell directly on that regression line, demonstrating that T2 hypersignal accurately predicts damage levels below 50%. For unintended damage, MRI estimates correlated with histological assessment for entorhinal cortex, perirhinal cortex and hippocampus, though MRI significantly overestimated the extent of that damage in all structures. Nevertheless, ibotenic acid injections routinely produced extensive intentional amygdala damage with minimal unintended damage to surrounding structures, validating the general success of the technique. The field will benefit from more research into in vivo lesion assessment techniques, and additional evaluation of the accuracy of MRI assessment in different brain areas. For now, in vivo MRI assessment of ibotenic acid lesions of the amygdala can be used to confirm successful injections, but MRI estimates of lesion extent should be interpreted with caution. PMID- 28642690 TI - Autonomy in Depressive Patients Undergoing DBS-Treatment: Informed Consent, Freedom of Will and DBS' Potential to Restore It. AB - According to the World Health Organization, depression is one of the most common and most disabling psychiatric disorders, affecting at any given time approximately 325 million people worldwide. As there is strong evidence that depressive disorders are associated with a dynamic dysregulation of neural circuits involved in emotional processing, recently several attempts have been made to intervene directly in these circuits via deep brain stimulation (DBS) in patients with treatment-resistant major depressive disorder (MDD). Given the promising results of most of these studies, the rising medical interest in this new treatment correlates with a growing sensitivity to ethical questions. One of the most crucial concerns is that DBS might interfere with patients' ability to make autonomous decisions. Thus, the goal of this article is to evaluate the impact DBS presumably has on the capacity to decide and act autonomously in patients with MDD in the light of the autonomy-undermining effects depression has itself. Following the chronological order of the procedure, special attention will first be paid to depression's effects on patients' capacity to make use of their free will in giving valid Informed Consent. We suggest that while the majority of patients with MDD appear capable of autonomous choices, as it is required for Informed Consent, they might still be unable to effectively act according to their own will whenever acting includes significant personal effort. In reducing disabling depressive symptoms like anhedonia and decrease of energy, DBS for treatment resistant MDD thus rather seems to be an opportunity to substantially increase autonomy than a threat to it. PMID- 28642689 TI - Integrating Neural Circuits Controlling Female Sexual Behavior. AB - The hypothalamus is most often associated with innate behaviors such as is hunger, thirst and sex. While the expression of these behaviors important for survival of the individual or the species is nested within the hypothalamus, the desire (i.e., motivation) for them is centered within the mesolimbic reward circuitry. In this review, we will use female sexual behavior as a model to examine the interaction of these circuits. We will examine the evidence for a hypothalamic circuit that regulates consummatory aspects of reproductive behavior, i.e., lordosis behavior, a measure of sexual receptivity that involves estradiol membrane-initiated signaling in the arcuate nucleus (ARH), activating beta-endorphin projections to the medial preoptic nucleus (MPN), which in turn modulate ventromedial hypothalamic nucleus (VMH) activity-the common output from the hypothalamus. Estradiol modulates not only a series of neuropeptides, transmitters and receptors but induces dendritic spines that are for estrogenic induction of lordosis behavior. Simultaneously, in the nucleus accumbens of the mesolimbic system, the mating experience produces long term changes in dopamine signaling and structure. Sexual experience sensitizes the response of nucleus accumbens neurons to dopamine signaling through the induction of a long lasting early immediate gene. While estrogen alone increases spines in the ARH, sexual experience increases dendritic spine density in the nucleus accumbens. These two circuits appear to converge onto the medial preoptic area where there is a reciprocal influence of motivational circuits on consummatory behavior and vice versa. While it has not been formally demonstrated in the human, such circuitry is generally highly conserved and thus, understanding the anatomy, neurochemistry and physiology can provide useful insight into the motivation for sexual behavior and other innate behaviors in humans. PMID- 28642692 TI - Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction. AB - Immediate early genes (IEGs) were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN) subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior. PMID- 28642693 TI - Exposure to Unsolvable Anagrams Impairs Performance on the Iowa Gambling Task. AB - Recent research indicates that external manipulations, such as stress or mood induction, can affect decision-making abilities. In the current study, we investigated whether the exposure to an unsolvable task affected subsequent performance on the Iowa Gambling Task. Participants were randomly assigned to a condition in which they were exposed to unsolvable anagrams (n = 20), or a condition in which they worked on solvable anagrams (n = 22). Afterwards, all participants played the Iowa Gambling Task, a prominent task that measures decision making under uncertain conditions with no explicit rules for gains and losses. In this task, it is essential to process feedback from previous decisions. The results demonstrated that participants who worked on unsolvable anagrams made more disadvantageous decisions on the Iowa Gambling Task than the other participants. In addition, a significant gender effect was observed: Males who worked on unsolvable anagrams made a more disadvantageous decisions than the other male participants. Females who worked on unsolvable anagrams also made more disadvantageous decision than the other female participants, but differences were small and not significant. We conclude that the exposure to unsolvable anagrams induced the experience of uncontrollability which can elicit stress and learned helplessness. Stress and learned helplessness might have reduced the ability to learn from the given feedback, particularly in male participants. We assume that in real life, uncontrollable challenges that last longer than a single experimental manipulation can affect decision making severely, at least in males. PMID- 28642694 TI - Ehlers-Danlos Syndrome, Hypermobility Type: Impact of Somatosensory Orthoses on Postural Control (A Pilot Study). AB - Elhers-Danlos syndrome (EDS) is the clinical manifestation of connective tissue disorders, and comprises several clinical forms with no specific symptoms and selective medical examinations which result in a delay in diagnosis of about 10 years. The EDS hypermobility type (hEDS) is characterized by generalized joint hypermobility, variable skin hyperextensibility and impaired proprioception. Since somatosensory processing and multisensory integration are crucial for both perception and action, we put forth the hypothesis that somatosensory deficits in hEDS patients may lead, among other clinical symptoms, to misperception of verticality and postural instability. Therefore, the purpose of this study was twofold: (i) to assess the impact of somatosensory deficit on subjective visual vertical (SVV) and postural stability; and (ii) to quantify the effect of wearing somatosensory orthoses (i.e., compressive garments and insoles) on postural stability. Six hEDS patients and six age- and gender-matched controls underwent a SVV (sitting, standing, lying on the right side) evaluation and a postural control evaluation on a force platform (Synapsys), with or without visual information (eyes open (EO)/eyes closed (EC)). These two latter conditions performed either without orthoses, or with compression garments (CG), or insoles, or both. Results showed that patients did not exhibit a substantial perceived tilt of the visual vertical in the direction of the body tilt (Aubert effect) as did the control subjects. Interestingly, such differential effects were only apparent when the rod was initially positioned to the left of the vertical axis (opposite the longitudinal body axis). In addition, patients showed greater postural instability (sway area) than the controls. The removal of vision exacerbated this instability, especially in the mediolateral (ML) direction. The wearing of orthoses improved postural stability, especially in the eyes-closed condition, with a particularly marked effect in the anteroposterior (AP) direction. Hence, this study suggests that hEDS is associated with changes in the relative contributions of somatosensory and vestibular inputs to verticality perception. Moreover, postural control impairment was offset, at least partially, by wearing somatosensory orthoses. PMID- 28642695 TI - Concealed Around-the-Ear EEG Captures Cognitive Processing in a Visual Simon Task. AB - In theory, miniaturized systems such as the around-the-ear electrode arrays (cEEGrids) enable mobile monitoring of the electroencephalogram (EEG) in a variety of real life situations without interfering with the natural setting. However, the research benefit of such cEEGrid recordings critically depends on their validity. To investigate whether visual and motor processing are reflected in the cEEGrid-EEG, a direct comparison of EEG that was concurrently recorded with the cEEGrids and with a high-density cap setup was conducted. Thirteen participants performed a classic Simon task in which letters were presented laterally and a lateralized choice response was executed. N1, P1 and P300 event related potential (ERP) waveforms were extracted from cEEGrid-EEG: they were found to be strongly correlated with corresponding waveforms extracted from cap EEG but with lower signal strength and lower signal-to-noise-ratio (SNR). Event related lateralizations (ERLs) recorded at posterior scalp sites were well reflected in middle cEEGrid pairs. Moreover, the effect size of the Simon correspondence effect on the extracted ERLs was similar between the two systems. However, lateralizations at central cap sites were less well reflected in the cEEGrid-EEG indicating a difficulty in capturing motor response preparation and execution. These results show that well-described visual and cognitive ERPs and ERLs can be measured using the cEEGrids, while motor-related cortical potentials are not well captured. This study further demonstrates the potential and possible limitations of unobtrusive cEEGrid-EEG recordings. PMID- 28642696 TI - How Accumulated Real Life Stress Experience and Cognitive Speed Interact on Decision-Making Processes. AB - Rationale: Advances in neurocomputational modeling suggest that valuation systems for goal-directed (deliberative) on one side, and habitual (automatic) decision making on the other side may rely on distinct computational strategies for reinforcement learning, namely model-free vs. model-based learning. As a key theoretical difference, the model-based system strongly demands cognitive functions to plan actions prospectively based on an internal cognitive model of the environment, whereas valuation in the model-free system relies on rather simple learning rules from operant conditioning to retrospectively associate actions with their outcomes and is thus cognitively less demanding. Acute stress reactivity is known to impair model-based but not model-free choice behavior, with higher working memory capacity protecting the model-based system from acute stress. However, it is not clear which impact accumulated real life stress has on model-free and model-based decision systems and how this influence interacts with cognitive abilities. Methods: We used a sequential decision-making task distinguishing relative contributions of both learning strategies to choice behavior, the Social Readjustment Rating Scale questionnaire to assess accumulated real life stress, and the Digit Symbol Substitution Test to test cognitive speed in 95 healthy subjects. Results: Individuals reporting high stress exposure who had low cognitive speed showed reduced model-based but increased model-free behavioral control. In contrast, subjects exposed to accumulated real life stress with high cognitive speed displayed increased model based performance but reduced model-free control. Conclusion: These findings suggest that accumulated real life stress exposure can enhance reliance on cognitive speed for model-based computations, which may ultimately protect the model-based system from the detrimental influences of accumulated real life stress. The combination of accumulated real life stress exposure and slower information processing capacities, however, might favor model-free strategies. Thus, the valence and preference of either system strongly depends on stressful experiences and individual cognitive capacities. PMID- 28642698 TI - Enhanced Working Memory Binding by Direct Electrical Stimulation of the Parietal Cortex. AB - Recent works evince the critical role of visual short-term memory (STM) binding deficits as a clinical and preclinical marker of Alzheimer's disease (AD). These studies suggest a potential role of posterior brain regions in both the neurocognitive deficits of Alzheimer's patients and STM binding in general. Thereupon, we surmised that stimulation of the posterior parietal cortex (PPC) might be a successful approach to tackle working memory deficits in this condition, especially at early stages. To date, no causal evidence exists of the role of the parietal cortex in STM binding. A unique approach to assess this issue is afforded by single-subject direct intracranial electrical stimulation of specific brain regions during a relevant cognitive task. Electrical stimulation has been used both for clinical purposes and to causally probe brain mechanisms. Previous evidence of electrical currents spreading through white matter along well defined functional circuits indicates that visual working memory mechanisms are subserved by a specific widely distributed network. Here, we stimulated the parietal cortex of a subject with intracranial electrodes as he performed the visual STM task. We compared the ensuing results to those from a non-stimulated condition and to the performance of a matched control group. In brief, direct stimulation of the parietal cortex induced a selective improvement in STM. These results, together with previous studies, provide very preliminary but promising ground to examine behavioral changes upon parietal stimulation in AD. We discuss our results regarding: (a) the usefulness of the task to target prodromal stages of AD; (b) the role of a posterior network in STM binding and in AD; and PMID- 28642700 TI - Pricing and Reimbursement of Biosimilars in Central and Eastern European Countries. AB - Objectives: The aim of this study was to review the requirements for the reimbursement of biosimilars and to compare the reimbursement status, market share, and reimbursement costs of biosimilars in selected Central and Eastern European (CEE) countries. Methods: A questionnaire-based survey was conducted between November 2016 and January 2017 among experts from the following CEE countries: Bulgaria, Czech Republic, Croatia, Estonia, Hungary, Latvia, Lithuania, Poland, Slovakia, and Romania. The requirements for the pricing and reimbursement of biosimilars were reviewed for each country. Data on the extent of reimbursement of biologic drugs (separately for original products and biosimilars) in the years 2014 and 2015 were also collected for each country, along with data on the total pharmaceutical and total public health care budgets. Results: Our survey revealed that no specific criteria were applied for the pricing and reimbursement of biosimilars in the selected CEE countries; the price of biosimilars was usually reduced compared with original drugs and specific price discounts were common. Substitution and interchangeability were generally allowed, although in most countries they were at the discretion of the physician after a clinical assessment. Original biologic drugs and the corresponding biosimilars were usually in the same homogeneous group, and internal reference pricing was usually employed. The reimbursement rate of biosimilars in the majority of the countries was the same and amounted to 100%. Generally, the higher shares of expenditures were shown for the reimbursement of original drugs than for biosimilars, except for filgrastim, somatropin, and epoetin (alfa and zeta). The shares of expenditures on the reimbursement of biosimilar products ranged from 8.0% in Estonia in 2014 to 32.4% in Lithuania in 2015, and generally increased in 2015. The share of expenditures on reimbursement of biosimilars in the total pharmaceutical budget differed between the countries, with the highest observed value for Slovakia and Hungary and the lowest-for Croatia. Conclusions: The requirements for the pricing and reimbursement of biosimilar products as well as the access of patients to biologic treatment do not differ significantly between the considered CEE countries. Biosimilar drugs significantly influence the reimbursement systems of these countries, and the expenditure on the reimbursement of biosimilars is increasing as they are becoming more accessible to patients. PMID- 28642701 TI - The Market of Biopharmaceutical Medicines: A Snapshot of a Diverse Industrial Landscape. AB - Background: Biopharmaceutical medicines represent a growing share of the global pharmaceutical market, and with many of these biopharmaceutical products facing loss of exclusivity rights, also biosimilars may now enter the biopharmaceutical market. Objectives: This study aims to identify and document which investment and development strategies are adopted by industrial players in the global biopharmaceutical market. Methods: A descriptive analysis was undertaken of the investment and development strategies of the top 25 pharmaceutical companies according to 2015 worldwide prescription drug sales. Strategies were documented by collecting data on manufacturing plans, development programs, acquisition and collaboration agreements, the portfolio and pipeline of biosimilar, originator and next-generation biopharmaceutical products. Data were extracted from publicly available sources. Results: Various investment and development strategies can be identified in the global biopharmaceutical market: (a) development of originator biopharmaceuticals, (b) investment in biotechnology, (c) development of next generation biopharmaceuticals, (d) development of biosimilars, (e) investment in emerging countries, and (f) collaboration between companies. In the top 25 pharmaceutical companies almost every company invests in originator biopharmaceuticals and in biotechnology in general, but only half of them develops next-generation biopharmaceuticals. Furthermore, only half of them invest in development of biosimilars. The companies' biosimilar pipeline is mainly focused on development of biosimilar monoclonal antibodies and to some extent on biosimilar insulins. A common strategy is collaboration between companies and investment in emerging countries. Conclusions: A snapshot of investment and development strategies used by industrial players in the global biopharmaceutical market shows that all top 25 pharmaceutical companies are engaged in the biopharmaceutical market and that this industrial landscape is diverse. Companies do not focus on a single strategy, but are involved in multiple investment and development strategies. A common strategy to market biopharmaceuticals is collaboration between companies. These collaborations can as well be used to gain access in regions the company has less experience with. With patents expiring for some of the highest selling monoclonal antibodies, this snapshot highlights the interest of companies to invest in the development of these molecules and/or enter into collaborations to create access to these molecules. PMID- 28642699 TI - Cerebral Blood Flow and Amyloid-beta Interact to Affect Memory Performance in Cognitively Normal Older Adults. AB - Cerebral blood flow (CBF) alterations and amyloid-beta (Abeta) accumulation have been independently linked to cognitive deficits in older adults at risk for dementia. Less is known about how CBF and Abeta may interact to affect cognition in cognitively normal older adults. Therefore, we examined potential statistical interactions between CBF and Abeta status in regions typically affected in Alzheimer's disease (AD) within a sample of older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Sixty-two cognitively normal participants (mean age = 72 years) underwent neuroimaging and memory testing. Arterial spin labeling magnetic resonance imaging was used to quantify CBF and florbetapir PET amyloid imaging was used to measure Abeta deposition. Abeta status (i.e., positivity versus negativity) was determined based on established cutoffs (Landau et al., 2013). The Rey Auditory Verbal Learning Test was used to assess memory. Linear regression models adjusted for age, education, and sex, demonstrated significant interactions between CBF and Abeta status on memory performance. Among Abeta positive older adults, there were significant negative associations between higher CBF in hippocampus, posterior cingulate, and precuneus and poorer memory performance. In contrast, among Abeta negative older adults, there were no significant associations between CBF and cognition. Our findings extend previous CBF studies of dementia risk by reporting interactions between Abeta status and CBF on memory performance in a sample of well characterized, cognitively normal older adults. Results suggest that differential CBF-cognition associations can be identified in healthy, asymptomatic Abeta positive older adults relative to Abeta negative individuals. Associations between higherCBF and poorer memory among Abeta positive older adults may reflect a cellular and/or vascular compensatory response to pathologic processes whereby higher CBF is needed to maintain normal memory abilities. Findings indicate that CBF and its associations with cognition may have utility as a reliable marker of brain function early in the AD process when interventions are likely to be beneficial. PMID- 28642697 TI - Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson's Disease. AB - Parkinson's disease (PD) is a chronic and progressive disorder characterized neuropathologically by loss of dopamine neurons in the substantia nigra, intracellular proteinaceous inclusions, reduction of dopaminergic terminals in the striatum, and increased neuroinflammatory cells. The consequent reduction of dopamine in the basal ganglia results in the classical parkinsonian motor phenotype. A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in PD pathogenesis. Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. Upon activation to the M1 phenotype, microglia elaborate pro inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD and a better understanding is essential for developing putative neuroprotective agents. Targeting microglial activation states by suppressing their deleterious pro-inflammatory neurotoxicity and/or simultaneously enhancing their beneficial anti-inflammatory protective functions appear as a valid therapeutic approach for PD treatment. In this review, we summarize microglial functions and, their dual neurotoxic and neuroprotective role in PD. We also review molecules that modulate microglial activation states as a therapeutic option for PD treatment. PMID- 28642702 TI - Amorpha fruticosa - A Noxious Invasive Alien Plant in Europe or a Medicinal Plant against Metabolic Disease? AB - Amorpha fruticosa L. (Fabaceae) is a shrub native to North America which has been cultivated mainly for its ornamental features, honey plant value and protective properties against soil erosion. It is registered amongst the most noxious invasive species in Europe. However, a growing body of scientific literature also points to the therapeutic potential of its chemical constituents. Due to the fact that A. fruticosa is an aggressive invasive species, it can provide an abundant and cheap resource of plant chemical constituents which can be utilized for therapeutic purposes. Additionally, exploitation of the biomass for medicinal use might contribute to relieving the destructive impact of this species on natural habitats. The aim of this review is to provide a comprehensive summary and systematize the state-of-the-art in the knowledge of the phytochemical composition and the potential of A. fruticosa in disease treatment and prevention, with especial emphasis on diabetes and metabolic syndrome. Also reviewed are aspects related to potential toxicity of A. fruticosa which has not yet been systematically evaluated in human subjects. PMID- 28642703 TI - Different Regulation of Interleukin-1 Production and Activity in Monocytes and Macrophages: Innate Memory as an Endogenous Mechanism of IL-1 Inhibition. AB - Production and activity of interleukin (IL)-1beta are kept under strict control in our body, because of its powerful inflammation-promoting capacity. Control of IL-1beta production and activity allows IL-1 to exert its defensive activities without causing extensive tissue damage. Monocytes are the major producers of IL 1beta during inflammation, but they are also able to produce significant amounts of IL-1 inhibitors such as IL-1Ra and the soluble form of the decoy receptor IL 1R2, in an auto-regulatory feedback loop. Here, we investigated how innate immune memory could modulate production and activity of IL-1beta by human primary monocytes and monocyte-derived tissue-like/deactivated macrophages in vitro. Cells were exposed to Gram-negative (Escherichia coli) and Gram-positive (Lactobacillus acidophilus) bacteria for 24 h, then allowed to rest, and then re challenged with the same stimuli. The presence of biologically active IL-1beta in cell supernatants was calculated as the ratio between free IL-1beta (i.e., the cytokine that is not bound/inhibited by sIL-1R2) and its receptor antagonist IL 1Ra. As expected, we observed that the responsiveness of tissue-like/deactivated macrophages to bacterial stimuli was lower than that of monocytes. After resting and re-stimulation, a memory effect was evident for the production of inflammatory cytokines, whereas production of alarm signals (chemokines) was minimally affected. We observed a high variability in the innate memory response among individual donors. This is expected since innate memory largely depends on the previous history of exposure or infections, which is different in different subjects. Overall, innate memory appeared to limit the amount of active IL-1beta produced by macrophages in response to a bacterial challenge, while enhancing the responsiveness of monocytes. The functional re-programming of mononuclear phagocytes through modulation of innate memory may provide innovative approaches in the management of inflammatory diseases, as well as in the design of new immunization strategies. In this respect, the interindividual variability in innate memory suggests the need of a personalized assessment. PMID- 28642704 TI - Quercetin, a Lead Compound against Type 2 Diabetes Ameliorates Glucose Uptake via AMPK Pathway in Skeletal Muscle Cell Line. AB - Herein we investigated the molecular mechanism of action of the citrus flavonoid, quercetin in skeletal muscle cells (L6 myotubes). Taking advantage of protein kinase inhibitors, we proved that the effect of quercetin on 2-NBDG uptake in L6 myotubes was not through insulin signaling pathway, but through adenosine monophosphate kinase (AMPK) pathway and its downstream target p38 MAPK. An increase in the cellular AMP to ATP ratio on pretreatment may account for AMPK activation which was coupled with a transient change in mitochondrial membrane potential. In addition, quercetin triggered a rise in intracellular calcium suggesting that calcium-calmodulin mediated protein kinase (CaMKK) may also be involved. Quercetin shared a similar mechanism with the well-known drug metformin, highlighting it as a promising compound for the management of type 2 diabetes. The AMPK signaling pathway could contribute to correction of insulin resistance through bypassing the insulin-regulated system for GLUT4 translocation. PMID- 28642706 TI - Toll-Like Receptor 4 Modulates Small Intestine Neuromuscular Function through Nitrergic and Purinergic Pathways. AB - Objective: Toll-like receptors (TLRs) play a pivotal role in the homeostatic microflora-host crosstalk. TLR4-mediated modulation of both motility and enteric neuronal survival has been reported mainly for colon with limited information on the role of TLR4 in tuning structural and functional integrity of enteric nervous system (ENS) and in controlling small bowel motility. Methods: Male TLR4 knockout (TLR4-/-, 9 +/- 1 weeks old) and sex- and age-matched wild-type (WT) C57BL/6J mice were used for the experiments. Alterations in ENS morphology and neurochemical code were assessed by immunohistochemistry whereas neuromuscular function was evaluated by isometric mechanical activity of ileal preparations following receptor and non-receptor-mediated stimuli and by gastrointestinal transit. Results: The absence of TLR4 induced gliosis and reduced the total number of neurons, mainly nNOS+ neurons, in ileal myenteric plexus. Furthermore, a lower cholinergic excitatory response with an increased inhibitory neurotransmission was found together with a delayed gastrointestinal transit. These changes were dependent on increased ileal non-adrenergic non-cholinergic (NANC) relaxations mediated by a complex neuronal-glia signaling constituted by P2X7 and P2Y1 receptors, and NO produced by nNOS and iNOS. Conclusion: We provide novel evidence that TLR4 signaling is involved in the fine-tuning of P2 receptors controlling ileal contractility, ENS cell distribution, and inhibitory NANC neurotransmission via the combined action of NO and adenosine-5'-triphosphate (ATP). For the first time, this study implicates TLR4 at regulating the crosstalk between glia and neurons in small intestine and helps to define its role in gastrointestinal motor abnormalities during dysbiosis. PMID- 28642705 TI - Polycystic Ovary Syndrome: Insights into the Therapeutic Approach with Inositols. AB - Polycystic ovary syndrome (PCOS) is characterized by hormonal abnormalities that cause menstrual irregularity and reduce ovulation rate and fertility, associated to insulin resistance. Myo-inositol (cis-1,2,3,5-trans-4,6-cyclohexanehexol, MI) and D-chiro-inositol (cis-1,2,4-trans-3,5,6-cyclohexanehexol, DCI) represent promising treatments for PCOS, having shown some therapeutic benefits without substantial side effects. Because the use of inositols for treating PCOS is widespread, a deep understanding of this treatment option is needed, both in terms of potential mechanisms and efficacy. This review summarizes the current knowledge on the biological effects of MI and DCI and the results obtained from relevant intervention studies with inositols in PCOS. Based on the published results, both MI and DCI represent potential valid therapeutic approaches for the treatment of insulin resistance and its associated metabolic and reproductive disorders, such as those occurring in women affected by PCOS. Furthermore, the combination MI/DCI seems also effective and might be even superior to either inositol species alone. However, based on available data, a particular MI:DCI ratio to be administered to PCOS patients cannot be established. Further studies are then necessary to understand the real contents of MI or DCI uptaken by the ovary following oral administration in order to identify optimal doses and/or combination ratios. PMID- 28642707 TI - Tetrandrine, an Activator of Autophagy, Induces Autophagic Cell Death via PKC alpha Inhibition and mTOR-Dependent Mechanisms. AB - Emerging evidence suggests the therapeutic role of autophagic modulators in cancer therapy. This study aims to identify novel traditional Chinese medicinal herbs as potential anti-tumor agents through autophagic induction, which finally lead to autophagy mediated-cell death in apoptosis-resistant cancer cells. Using bioactivity-guided purification, we identified tetrandrine (Tet) from herbal plant, Radix stephaniae tetrandrae, as an inducer of autophagy. Across a number of cancer cell lines, we found that breast cancer cells treated with tetrandrine show an increase autophagic flux and formation of autophagosomes. In addition, tetrandrine induces cell death in a panel of apoptosis-resistant cell lines that are deficient for caspase 3, caspase 7, caspase 3 and 7, or Bax-Bak respectively. We also showed that tetrandrine-induced cell death is independent of necrotic cell death. Mechanistically, tetrandrine induces autophagy that depends on mTOR inactivation. Furthermore, tetrandrine induces autophagy in a calcium/calmodulin dependent protein kinase kinase-beta (CaMKK-beta), 5' AMP-activated protein kinase (AMPK) independent manner. Finally, by kinase profiling against 300 WT kinases and computational molecular docking analysis, we showed that tetrandrine is a novel PKC-alpha inhibitor, which lead to autophagic induction through PKC alpha inactivation. This study provides detailed insights into the novel cytotoxic mechanism of an anti-tumor compound originated from the herbal plant, which may be useful in promoting autophagy mediated- cell death in cancer cell that is resistant to apoptosis. PMID- 28642708 TI - Myricitrin Protects Cardiomyocytes from Hypoxia/Reoxygenation Injury: Involvement of Heat Shock Protein 90. AB - Modulation of oxidative stress is therapeutically effective in ischemia/reperfusion (I/R) injury. Myricitrin, a naturally occurring phenolic compound, is a potent antioxidant. However, little is known about its effect on I/R injury to cardiac myocytes. The present study was performed to investigate the potential protective effect of myricitrin against hypoxia/reoxygenation (H/R) induced H9c2 cardiomyocyte injury and its underlying mechanisms. Myricitrin pretreatment improved cardiomyocyte viability, inhibited ROS generation, maintained the mitochondrial membrane potential, reduced apoptotic cardiomyocytes, decreased the caspase-3 activity, upregulated antiapoptotic proteins and downregulated proapoptotic proteins during H/R injury. Moreover, the potential targets of myricitrin was predicted using Discovery Studio software, and heat shock protein 90 (Hsp90) was identified as the main disease-related target. Further mechanistic investigation revealed that 17-AAG, a pharmacologic inhibitor of Hsp90, significantly blocked the myricitrin-induced cardioprotective effect demonstrated by increased apoptosis and ROS generation. These results suggested that myricitrin provides protection to H9c2 cardiomyocytes against H/R induced oxidative stress and apoptosis, most likely via increased expression of Hsp90. PMID- 28642710 TI - Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation. AB - Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic polymorphisms affecting the metabolic pathway. The integration of CYP3A4 and CY3A5 genotype in tacrolimus population-based PK (PopPK) modeling approaches has been proven to accurately predict the dose requirement to reach the therapeutic window. The objective of the present study was to develop an accurate PopPK model in a cohort of 59 kidney transplant patients to deliver this information to clinicians in a clear and actionable manner. We conducted a non-parametric non-linear effects PopPK modeling analysis in Pmetrics(r). Patients were genotyped for the CYP3A4*22 and CYP3A5*3 alleles and were classified into 3 different categories [poor-metabolizers (PM), Intermediate-metabolizers (IM) or extensive-metabolizers (EM)]. A one-compartment model with double gamma absorption route described very accurately the tacrolimus PK. In covariate analysis, only CYP3A genotype was retained in the final model (Delta-2LL = -73). Our model estimated that tacrolimus concentrations were 33% IC95%[20-26%], 41% IC95%[36-45%] lower in CYP3A IM and EM when compared to PM, respectively. Virtually, we proved that defining different starting doses for PM, IM and EM would be beneficial by ensuring better probability of target concentrations attainment allowing us to define new dosage recommendations according to patient CYP3A genetic profile. PMID- 28642711 TI - Weekly Time Course of Neuro-Muscular Adaptation to Intensive Strength Training. AB - Detailed description of the time course of muscular adaptation is rarely found in literature. Thus, models of muscular adaptation are difficult to validate since no detailed data of adaptation are available. In this article, as an initial step toward a detailed description and analysis of muscular adaptation, we provide a case report of 8 weeks of intense strength training with two active, male participants. Muscular adaptations were analyzed on a morphological level with MRI scans of the right quadriceps muscle and the calculation of muscle volume, on a voluntary strength level by isometric voluntary contractions with doublet stimulation (interpolated twitch technique) and on a non-voluntary level by resting twitch torques. Further, training volume and isokinetic power were closely monitored during the training phase. Data were analyzed weekly for 1 week prior to training, pre-training, 8 weeks of training and 2 weeks of detraining (no strength training). Results show a very individual adaptation to the intense strength training protocol. While training volume and isokinetic power increased linearly during the training phase, resting twitch parameters decreased for both participants after the first week of training and stayed below baseline until de training. Voluntary activation level showed an increase in the first 4 weeks of training, while maximum voluntary contraction showed only little increase compared to baseline. Muscle volume increased for both subjects. Especially training status seemed to influence the acute reaction to intense strength training. Fatigue had a major influence on performance and could only be overcome by one participant. The results give a first detailed insight into muscular adaptation to intense strength training on various levels, providing a basis of data for a validation of muscle fatigue and adaptation models. PMID- 28642709 TI - New Frontiers in the Pathobiology and Treatment of Cancer Regimen-Related Mucosal Injury. AB - Mucositis is a common complication of chemotherapy, radiotherapy and targeted agents. It often affects compliance to anticancer therapies as it frequently causes schedule delays, interruptions or discontinuations of treatment. Moreover, the economic impact related to the management of mucositis is topical and several estimations of additional hospital costs due to this clinical condition have been recently reported. The ability to determine risk factors for mucositis, to early detect its onset, to assess correctly the degree of this toxicity and to plan its multidisciplinary management are all key elements to guarantee the quality of life of patients and to avoid useless dose reduction or interruption of treatment. The pathogenesis of mucositis is multifactorial and it is classily subdivided into oral and gastrointestinal mucositis according to its anatomic presentation. Treatment and patients' related factors might help in predicting the frequency and the potential degree of symptoms onset. Here we discuss about clinical presentation and pathogenesis of mucositis in relation to different kinds of treatments. Moreover, we focus on therapeutic and prevention strategies, describing past and present management according to international guidelines and the most promising new data about agents potentially able to further improve the treatment of mucositis in the next future. PMID- 28642712 TI - Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus). AB - Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20-44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 +/- 0.13 fold) Ca2+ sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 MUM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model. PMID- 28642713 TI - Benefits of Substituting Sitting with Standing and Walking in Free-Living Conditions for Cardiometabolic Risk Markers, Cognition and Mood in Overweight Adults. AB - Background: We investigated whether substituting sitting with standing and self perceived light walking in free-living conditions would improve cardiometabolic risk factors, mood, and cognition in overweight/obese adults. Methods: In a randomized, cross-over study, 24 (m/f: 13/11) sedentary overweight/obese participants (64 +/- 7 years, BMI 29 +/- 2 kg/m2) followed two activity regimens of each 4 days in free-living conditions: "Sit": sitting 13.5 h/day, standing 1.4 h/day, self-perceived light-intensity walking 0.7 h/day; for "SitLess" these activities lasted 7.6, 4.0, and 4.3 h/day, respectively. Meals were standardized and physical activity was assessed by accelerometry (activPAL). Insulin sensitivity (expressed as Matsuda-index based on an oral glucose tolerance test), circulating lipids, blood pressure, mood (pleasantness and arousal), and cognition were assessed on the morning after the activity regimens. Quality of life and sleep were assessed on the last day of the activity regimens. Results: We observed that AUC (0-190 min) for insulin decreased by 20% after SitLess vs. Sit [10,125 (656) vs. 12,633 (818); p = 0.006]. Insulin sensitivity improved by 16% after SitLess vs. Sit [Matsuda-index, mean (SEM): 6.45 (0.25) vs. 5.58 (0.25) respectively; p = 0.007]. Fasting triglycerides, non-HDL-cholesterol, and apolipoprotein B decreased by 32, 7, and 4% respectively, whereas HDL-cholesterol increased by 7% after SitLess vs. Sit (all p < 0.01). Diastolic blood pressure was lower after SitLess vs. Sit (p < 0.05). Pleasantness (as one marker of mood status) after the oral glucose tolerance test was higher after SitLess vs. Sit (p < 0.05). There was no significant difference between regimens for cognition, quality of life and sleep. Conclusions: Reducing sitting time in free-living conditions markedly improved insulin sensitivity, circulating lipids, and diastolic blood pressure. Substituting sitting with standing and self-perceived light walking is an effective strategy to improve cardiometabolic risk factors in overweight/obese subjects. PMID- 28642715 TI - Elastin-Like Protein, with Statherin Derived Peptide, Controls Fluorapatite Formation and Morphology. AB - The process of enamel biomineralization is multi-step, complex and mediated by organic molecules. The lack of cells in mature enamel leaves it unable to regenerate and hence novel ways of growing enamel-like structures are currently being investigated. Recently, elastin-like protein (ELP) with the analog N terminal sequence of statherin (STNA15-ELP) has been used to regenerate mineralized tissue. Here, the STNA15-ELP has been mineralized in constrained and unconstrained conditions in a fluoridated solution. We demonstrate that the control of STNA15-ELP delivery to the mineralizing solution can form layered ordered fluorapatite mineral, via a brushite precursor. We propose that the use of a constrained STNA15-ELP system can lead to the development of novel, bioinspired enamel therapeutics. PMID- 28642714 TI - Comparative Effectiveness of Acupuncture and Antiarrhythmic Drugs for the Prevention of Cardiac Arrhythmias: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - Introduction and Objectives: This study was designed to systematically evaluate the effectiveness of acupuncture treatment for arrhythmia compared to existing drug therapy. Methods: Randomized controlled trials (RCTs) were identified through searches of the MEDLINE, CNKI, Embase, and Cochrane databases (1970 through 2016) and hand searches of cross-references from original articles and reviews. Clinical trials that randomized arrhythmia patients to acupuncture therapy vs. conventional drugs, sham acupuncture, or bed rest were included for analysis. Results: A total of 13 trials with 797 patients met the criteria for analysis. The results of the meta-analysis showed no statistically significant difference between acupuncture and conventional treatment for paroxysmal supraventricular tachycardia (PSVT) (n = 203; RR, 1.18; 95% CI 0.78-1.79; I2 = 80%; P = 0.44). However, in the ventricular premature beat (VPB) group, it showed a significant benefit of acupuncture plus oral administration of anti-arrhythmic drug (AAD) on response rates compared with the oral administration of AAD (n = 286; RR, 1.15; 95% CI 1.05-1.27; I2 = 0%; P = 0.002). Finally, when compared with the sinus tachycardia (ST) cases without any treatment, acupuncture has benefited these patients (n = 120; MD, 18.80, 95% CI 12.68-24.92; I2 = 81%; P < 0.00001). Conclusions: In summary, our meta-analysis demonstrates that clinical efficacy of acupuncture is not less than AAD for PSVT. Furthermore, in sub-group analysis, acupuncture with or without AAD, shows a clear benefit in treating VPB and ST. However, more definitive RCTs are warranted to guide clinical practice. PMID- 28642716 TI - Effects of Acute Hypoxia and Reoxygenation on Physiological and Immune Responses and Redox Balance of Wuchang Bream (Megalobrama amblycephala Yih, 1955). AB - To study Megalobrama amblycephala adaption to water hypoxia, the changes in physiological levels, innate immune responses, redox balance of M.amblycephala during hypoxia were investigated in the present study. When M. amblycephala were exposed to different dissolved oxygen (DO) including control (DO: 5.5 mg/L) and acute hypoxia (DO: 3.5 and 1.0 mg/L, respectively), hemoglobin (Hb), methemoglobin (MetHb), glucose, Na+, succinatedehydrogenase (SDH), lactate, interferon alpha (IFNalpha), and lysozyme (LYZ), except hepatic glycogen and albumin gradually increased with the decrease of DO level. When M. amblycephala were exposed to different hypoxia time including 0.5 and 6 h (DO: 3.5 mg/L), and then reoxygenation for 24 h after 6 h hypoxia, Hb, MetHb, glucose, lactate, and IFNalpha, except Na+, SDH, hepatic glycogen, albumin, and LYZ increased with the extension of hypoxia time, while the above investigated indexes (except albumin, IFNalpha, and LYZ) decreased after reoxygenation. On the other hand, the liver SOD, CAT, hydrogen peroxide (H2O2), and total ROS were all remained at lower levels under hypoxia stress. Finally, Hif-1alpha protein in the liver, spleen, and gill were increased with the decrease of oxygen concentration and prolongation of hypoxia time. Interestingly, one Hsp70 isoforms mediated by internal ribozyme entry site (IRES) named junior Hsp70 was only detected in liver, spleen and gill. Taken together, these results suggest that hypoxia affects M. amblycephala physiology and reduces liver oxidative stress. Hypoxia reoxygenation stimulates M. amblycephala immune parameter expressions, while Hsp70 response to hypoxia is tissue-specific. PMID- 28642719 TI - Commentary: LACTB is a tumour suppressor that modulates lipid metabolism and cell state. PMID- 28642717 TI - The Lactate Minimum Test: Concept, Methodological Aspects and Insights for Future Investigations in Human and Animal Models. AB - In 1993, Uwe Tegtbur proposed a useful physiological protocol named the lactate minimum test (LMT). This test consists of three distinct phases. Firstly, subjects must perform high intensity efforts to induce hyperlactatemia (phase 1). Subsequently, 8 min of recovery are allowed for transposition of lactate from myocytes (for instance) to the bloodstream (phase 2). Right after the recovery, subjects are submitted to an incremental test until exhaustion (phase 3). The blood lactate concentration is expected to fall during the first stages of the incremental test and as the intensity increases in subsequent stages, to rise again forming a "U" shaped blood lactate kinetic. The minimum point of this curve, named the lactate minimum intensity (LMI), provides an estimation of the intensity that represents the balance between the appearance and clearance of arterial blood lactate, known as the maximal lactate steady state intensity (iMLSS). Furthermore, in addition to the iMLSS estimation, studies have also determined anaerobic parameters (e.g., peak, mean, and minimum force/power) during phase 1 and also the maximum oxygen consumption in phase 3; therefore, the LMT is considered a robust physiological protocol. Although, encouraging reports have been published in both human and animal models, there are still some controversies regarding three main factors: (1) the influence of methodological aspects on the LMT parameters; (2) LMT effectiveness for monitoring training effects; and (3) the LMI as a valid iMLSS estimator. Therefore, the aim of this review is to provide a balanced discussion between scientific evidence of the aforementioned issues, and insights for future investigations are suggested. In summary, further analyses is necessary to determine whether these factors are worthy, since the LMT is relevant in several contexts of health sciences. PMID- 28642718 TI - Irinotecan-Induced Gastrointestinal Dysfunction Is Associated with Enteric Neuropathy, but Increased Numbers of Cholinergic Myenteric Neurons. AB - Gastrointestinal dysfunction is a common side-effect of chemotherapy leading to dose reductions and treatment delays. These side-effects may persist up to 10 years post-treatment. A topoisomerase I inhibitor, irinotecan (IRI), commonly used for the treatment of colorectal cancer, is associated with severe acute and delayed-onset diarrhea. The long-term effects of IRI may be due to damage to enteric neurons innervating the gastrointestinal tract and controlling its functions. Balb/c mice received intraperitoneal injections of IRI (30 mg/kg-1) 3 times a week for 14 days, sham-treated mice received sterile water (vehicle) injections. In vivo analysis of gastrointestinal transit via serial x-ray imaging, facal water content, assessment of gross morphological damage and immunohistochemical analysis of myenteric neurons were performed at 3, 7 and 14 days following the first injection and at 7 days post-treatment. Ex vivo colonic motility was analyzed at 14 days following the first injection and 7 days post treatment. Mucosal damage and inflammation were found following both short and long-term treatment with IRI. IRI-induced neuronal loss and increases in the number and proportion of ChAT-IR neurons and the density of VAChT-IR fibers were associated with changes in colonic motility, gastrointestinal transit and fecal water content. These changes persisted in post-treatment mice. Taken together this work has demonstrated for the first time that IRI-induced inflammation, neuronal loss and altered cholinergic expression is associated with the development of IRI-induced long-term gastrointestinal dysfunction and diarrhea. PMID- 28642720 TI - Depressive Symptomatology among Norwegian Adolescent Boys and Girls: The Patient Health Questionnaire-9 (PHQ-9) Psychometric Properties and Correlates. AB - This study explored the potential contribution of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV)-based Patient Health Questionnaire-9 item (PHQ-9) instrument to the developmental epidemiology research in Norway, by examining depressive symptoms in a school sample of adolescents (N = 846). The average PHQ-9 scores were 6.89 (SD = 5.13) for girls, and 4.57 (SD = 3.98) for boys; 8.5% of girls and 2.6% of boys were classified into the originally proposed categories indicative of Major Depressive Disorder (MDD; PHQ-9 scores >= 15). Multi-group confirmatory factor analysis (CFA) confirmed a single-factor structure for the PHQ-9 with solid psychometric properties and high internal consistency for both genders. However, even though configural equality was observed, there was no evidence for metric or scalar equality across genders, warranting further investigation of measurement equivalence for the current Norwegian version of the PHQ-9. We observed no major associations between the PHQ 9 scores and adolescent religion or immigrant background. Further, school grade, not living together with both biological parents, and diagnosed chronic illness were differently associated with elevated depressive symptoms for boys and girls. Finally, high residential instability, perceived low SES, school dissatisfaction, lack of close friendships, history of suicide attempts and self-harm, and elevated emotional problems were all significantly and consistently associated with greater depression for both genders. Overall, the PHQ-9 appears to be a promising research tool, potentially offering clinically-relevant classification of adolescent self-reported depressive symptomatology in addition to the symptom severity captured by continuous scores. Nevertheless, further investigation concerning the observed measurement non-equivalence, as well as the comprehensive validation and comparison against the gold standard is required before the PHQ-9 is to be used for diagnostic screening in Norway. PMID- 28642721 TI - Simulation Theory Applied to Direct Systematic Observation. AB - Observational studies entail making several decisions before data collection, such as the observational design to use, the sampling of sessions within the observational period, the need for time sampling within the observation sessions, as well as the observation recording procedures to use. The focus of the present article is on observational recording procedures different from continuous recording (i.e., momentary time sampling, partial and whole interval recording). The main aim is to develop an online software application, constructed using R and the Shiny package, on the basis of simulations using the alternating renewal process (a model implemented in the ARPobservation package). The application offers graphical representations that can be useful to both university students constructing knowledge on Observational Methodology and to applied researchers planning to use discontinuous recording in their studies, because it helps identifying the conditions (e.g., interval length, average duration of the behavior of interest) in which the prevalence of the target behavior is expected to be estimated with less bias or no bias and with more efficiency. The estimation of frequency is another topic covered. PMID- 28642722 TI - Revision of AUDIT Consumption Items to Improve the Screening of Youth Binge Drinking. AB - This study analyzes the appropriateness of an improved version of one of the most frequently used instruments for the screening of high-risk alcohol consumption. This adaptation was created in accordance with certain limitations recognized by other researchers and in an attempt to adjust the content and scales of some items to a more consensual definition of binge drinking. After revising items 2 and 3, the areas under the ROC curves of the AUDIT and of different abbreviated versions were calculated. A total of 906 minors (468 females) between the ages of 15 and 17 were evaluated. Stratified sampling was conducted on a population of high school students in the city of Valencia (Spain). One school was randomly chosen from each of the city's 16 school districts. Information was collected on sociodemographic aspects, consumption patterns and the AUDIT containing the improved items. The percentage of underage BD reached 36%, regardless of gender or age. BD groups have been differentiated by different intensity levels, both in males and females. Upon comparing the effectiveness of the distinct versions of the AUDIT, it is recommended that researchers and clinics use the combination of the revised items 2 and 3 to ensure a more precise identification of underage BD. A cut-off point of 5 for this test would permit identification of 94% of the underage BD and would notably reduce false positives. PMID- 28642723 TI - When the Heat Is On: The Effect of Temperature on Voter Behavior in Presidential Elections. AB - Hot temperatures lead to heightened arousal. According to excitation transfer theory, arousal can increase both antisocial and prosocial behavior, depending on the context. Although many studies have shown that hot temperatures can increase antisocial behavior, very few studies have investigated the relationship between temperature and prosocial behavior. One important prosocial behavior is voting. We analyzed state-level data from the United States presidential elections (N = 761). Consistent with excitation transfer theory, which proposes that heat induced arousal can transfer to other activities and strengthen those activities, changes in temperature and voter turnout were positively related. Moreover, a positive change in temperature was related to a positive change in votes for the incumbent party. These findings add to the literature on the importance of non ideological and non-rational factors that influence voting behavior. PMID- 28642726 TI - Urban Legends and Paranormal Beliefs: The Role of Reality Testing and Schizotypy. AB - Recent research suggests that unconventional beliefs are locatable within a generic anomalous belief category. This notion derives from the observation that apparently dissimilar beliefs share fundamental, core characteristics (i.e., contradiction of orthodox scientific understanding of the universe and defiance of conventional understanding of reality). The present paper assessed the supposition that anomalous beliefs were conceptually similar and explicable via common psychological processes by comparing relationships between discrete beliefs [endorsement of urban legends (ULs) and belief in the paranormal] and cognitive-perceptual personality measures [proneness to reality testing (RT) and schizotypy]. A sample of 222 volunteers, recruited via convenience sampling, took part in the study. Participants completed a series of self-report measures (Urban Legends Questionnaire, Reality Testing subscale of the Inventory of Personality Organization, Revised Paranormal Belief Scale and the Schizotypal Personality Questionnaire Brief). Preliminary analysis revealed positive correlations between measures. Within schizotypy, the cognitive-perceptual factor was most strongly associated with anomalistic beliefs; disorganized and interpersonal produced only weak and negligible correlations respectively. Further investigation indicated complex relationships between RT, the cognitive-perceptual factor of schizotypy and anomalistic beliefs. Specifically, proneness to RT deficits explained a greater amount of variance in ULs, whilst schizotypy accounted for more variance in belief in the paranormal. Consideration of partial correlations supported these conclusions. The relationship between RT and ULs remained significant after controlling for the cognitive-perceptual factor. Contrastingly, the association between the cognitive-perceptual factor and ULs controlling for RT was non significant. In the case of belief in the paranormal, controlling for proneness to RT reduced correlation size, but relationships remained significant. This study demonstrated that anomalistic beliefs vary in nature and composition. Findings indicated that generalized views of anomalistic beliefs provide only limited insight into the complex nature of belief. PMID- 28642725 TI - Pigeons and the Ambiguous-Cue Problem: A Riddle that Remains Unsolved. AB - The ambiguous-cue task is composed of two-choice simultaneous discriminations involving three stimuli: positive (P), ambiguous (A), and negative (N). Two different trial types are presented: PA and NA. The ambiguous cue (A) served as an S- in PA trials, but as an S+ in NA trials. When using this procedure, it is typical to observe a less accurate performance in PA trials than in NA trials. This is called the ambiguous-cue effect. Recently, it was reported in starlings that the ambiguous-cue effect decreases when the stimuli are presented on an angled (120 degrees ) panel. The hypothesis is that the angled panel facilitates that the two cues from each discrimination are perceived as a compound, precluding value transfer via a second-order conditioning mechanism. In this experiment, we used pigeons and a flat panel. Nevertheless, our data were quite similar to the previous data in starlings. We conclude that the form of the panel cannot explain the ambiguous-cue effect. Several alternatives to be explored in future experiments are suggested. The riddle of the ambiguous-cue problem still remains unsolved. PMID- 28642724 TI - I Don't Want to Miss a Thing - Learning Dynamics and Effects of Feedback Type and Monetary Incentive in a Paired Associate Deterministic Learning Task. AB - Effective functioning in a complex environment requires adjusting of behavior according to changing situational demands. To do so, organisms must learn new, more adaptive behaviors by extracting the necessary information from externally provided feedback. Not surprisingly, feedback-guided learning has been extensively studied using multiple research paradigms. The purpose of the present study was to test the newly designed Paired Associate Deterministic Learning task (PADL), in which participants were presented with either positive or negative deterministic feedback. Moreover, we manipulated the level of motivation in the learning process by comparing blocks with strictly cognitive, informative feedback to blocks where participants were additionally motivated by anticipated monetary reward or loss. Our results proved the PADL to be a useful tool not only for studying the learning process in a deterministic environment, but also, due to the varying task conditions, for assessing differences in learning patterns. Particularly, we show that the learning process itself is influenced by manipulating both the type of feedback information and the motivational significance associated with the expected monetary reward. PMID- 28642727 TI - "Learning Science Is About Facts and Language Learning Is About Being Discursive" An Empirical Investigation of Students' Disciplinary Beliefs in the Context of Argumentation. AB - Argumentation is considered crucial in numerous disciplines in schools and universities because it constitutes an important proficiency in peoples' daily and professional lives. However, it is unclear whether argumentation is understood and practiced in comparable ways across disciplines. This study consequently examined empirically how students perceive argumentation in science and (first) language lessons. Specifically, we investigated students' beliefs about the relevance of discourse and the role of facts. Data from 3,258 high school students from 85 German secondary schools were analyzed with multigroup multilevel structural equation modeling in order to disentangle whether or not differences in argumentation across disciplines exist and the extent to which variation in students' beliefs can be explained by gender and school track. Results showed that students perceived the role of facts as highly relevant for science lessons, whereas discursive characteristics were considered significantly less important. In turn, discourse played a central role in language lessons, which was believed to require less knowledge of facts. These differences were independent of students' gender. In contrast, school track predicted the differences in beliefs significantly. Our findings lend evidence on the existence of disciplinary school cultures in argumentation that may be the result of differences in teachers' school-track-specific classroom practice and education. Implications in terms of a teacher's role in establishing norms for scientific argumentation as well as the impact of students' beliefs on their learning outcomes are discussed. PMID- 28642728 TI - Theory, the Final Frontier? A Corpus-Based Analysis of the Role of Theory in Psychological Articles. AB - Contemporary psychology regards itself as an empirical science, at least in most of its subfields. Theory building and development are often considered critical to the sciences, but the extent to which psychology can be cast in this way is under debate. According to those advocating a strong role of theory, studies should be designed to test hypotheses derived from theories (theory-driven) and ideally should yield findings that stimulate hypothesis formation and theory building (theory-generating). The alternative position values empirical findings over theories as the lasting legacy of science. To investigate which role theory actually plays in current research practice, we analyse references to theory in the complete set of 2,046 articles accepted for publication in Frontiers of Psychology in 2015. This sample of articles, while not representative in the strictest sense, covers a broad range of sub-disciplines, both basic and applied, and a broad range of article types, including research articles, reviews, hypothesis & theory, and commentaries. For the titles, keyword lists, and abstracts in this sample, we conducted a text search for terms related to empiricism and theory, assessed the frequency and scope of usage for six theory related terms, and analyzed their distribution over different article types and subsections of the journal. The results indicate substantially lower frequencies of theoretical than empirical terms, with references to a specific (named) theory in less than 10% of the sample and references to any of even the most frequently mentioned theories in less than 0.5% of the sample. In conclusion, we discuss possible limitations of our study and the prospect of theoretical advancement. PMID- 28642730 TI - "I Can't Get No Satisfaction": Measuring Student Satisfaction in the Age of a Consumerist Higher Education. PMID- 28642729 TI - Inconsistent Effects of Parietal alpha-tACS on Pseudoneglect across Two Experiments: A Failed Internal Replication. AB - Transcranial electrical stimulation (tES) is being investigated as an experimental and clinical interventional technique in human participants. While promising, important limitations have been identified, including weak effect sizes and high inter- and intra-individual variability of outcomes. Here, we compared two "inhibitory" tES-techniques with supposedly different mechanisms of action as to their effects on performance in a visuospatial attention task, and report on a direct replication attempt. In two experiments, 2 * 20 healthy participants underwent tES in three separate sessions testing different protocols (10 min stimulation each) with a montage targeting right parietal cortex (right parietal-left frontal, electrode-sizes: 3cm * 3cm-7 cm * 5 cm), while performing a perceptual line bisection (landmark) task. The tES-protocols were compared as to their ability to modulate pseudoneglect (thought to be under right hemispheric control). In experiment 1, sham-tES was compared to transcranial alternating current stimulation at alpha frequency (10 Hz; alpha-tACS) (expected to entrain "inhibitory" alpha oscillations) and to cathodal transcranial direct current stimulation (c-tDCS) (shown to suppress neuronal spiking activity). In experiment 2, we attempted to replicate the findings of experiment 1, and establish frequency-specificity by adding a 45 Hz-tACS condition to alpha-tACS and sham. In experiment 1, right parietal alpha-tACS led to the expected changes in spatial attention bias, namely a rightward shift in subjective midpoint estimation (relative to sham). However, this was not confirmed in experiment 2 and in the complete sample. Right parietal c-tDCS and 45 Hz-tACS had no effect. These results highlight the importance of replication studies, adequate statistical power and optimizing tES-interventions for establishing the robustness and reliability of electrical stimulation effects, and best practice. PMID- 28642731 TI - Efficacy of Drug Interventions for Chemotherapy-Induced Chronic Peripheral Neurotoxicity: A Network Meta-analysis. AB - Peripheral neurotoxicity is a disturbing issue for cancer patients who are treated with chemotherapy. Several medications have been developed for preventing chemotherapy-induced chronic neurotoxicity (CICNT) however; their relative efficacies have not yet been studied. In this study, we conducted a network meta analysis to give intervention recommendations. The literature was searched in a variety of databases and eligible studies were chosen based on predefined criteria. Data extraction and statistical analysis was performed, and the results are displayed using the odds ratio (OR) and corresponding 95% credible intervals (CrI) with respect to overall and severe neurotoxicity. The medications were ranked according to their surface under cumulative ranking curve values. The consistency of direct and indirect evidence was also evaluated. We found that patients with amifostine or vitamin E (VE) treatment exhibited a lower risk of overall neurotoxicity compared to those using the placebo (amifostine: OR = 0.10, 95% CrI: 0.02-0.46; VE: OR = 0.08, 95% CrI: 0.01-0.99). In regard to preventing severe neurotoxicity, glutathione and amifostine treatment appeared to be significantly more effective than the placebo (glutathione: OR = 0.19, 95% CrI: 0.04-0.64; amifostine: OR = 0.12, 95% CrI: 0.02-0.48). In summary, amifostine, VE, and glutathione treatment is considered to be effective in lowering the risk of CICNT. However, further studies which consider safety are required. PMID- 28642732 TI - Autonomic Function Impairment and Brain Perfusion Deficit in Parkinson's Disease. AB - INTRODUCTION: Autonomic disorders have been recognized as important Parkinson's disease (PD) components. Some vulnerable structures are related to the central autonomic network and have also been linked to autonomic function alterations. The aims of the study are to evaluate the severity of the autonomic dysfunction and the cortical hypoperfusion using arterial spin labeling (ASL) MRI. And then, possible relationships of significant between-group differences in perfusion pattern to clinical variables and autonomic functions were examined to determine the pharmaceutical effects of dopaminergic treatment on cerebral blood flow (CBF) in patients with PD. METHODS: Brain ASL MRI was carried out in 20 patients with PD (6 men and 14 women, mean age: 63.3 +/- 6.4 years) and 22 sex- and age-matched healthy volunteers to assess whole-brain CBF and the effects of dopaminergic therapy on perfusion. All subjects underwent a standardized evaluation of cardiovagal and adrenergic function including a deep breathing, Valsalva maneuver, and 5-min head-up tilt test. Perfusion MRI data were acquired on a 3.0 T scanner with a pulsed continuous ASL technique. The CBF, autonomic parameters, and clinical data were analyzed after adjusting for age and sex. RESULTS: Patients exhibited a decline in autonomic function (rapid heart rate in response to deep breathing, low baroreflex sensitivity, high systolic and diastolic pressure, and altered tilting test response), widespread low CBF, and robust response to dopaminergic therapy. Lower perfusion in the middle frontal gyrus was associated with increased clinical disease severity (Unified Parkinson's Disease Rating Scale I score, P < 0.001). Lower perfusion in autonomic control areas, such as the frontal lobe and insula, were significantly associated with autonomic impairment (P < 0.001). CONCLUSIONS: Our study indicates that PD is a progressive neurodegenerative disorder that changes the perfusion of central nervous system and is associated with variable autonomic dysfunctions. Neuronal loss and sympathetic activation may explain the interaction between cortical autonomic region perfusion and cardiovascular autonomic function. PMID- 28642733 TI - A Case of Pulmonary Carcinoid Tumor with a Superimposed Aspergilloma Presenting As a Covert Ectopic Adrenocorticotropic Hormone Syndrome. AB - Ectopic adrenocorticotropic hormone (ACTH) syndrome is a challenging diagnosis only responsible for approximately 10% of Cushing syndrome cases. It has been associated with a variety of benign and malignant tumors including a carcinoid tumor accompanied by aspergilloma in our case that was significantly difficult to be detected. We report a patient over 70 years old with uncontrolled hypertension and hypokalemia presenting with generalized edema. Laboratory results revealed ACTH-dependent Cushing syndrome, but imaging studies did not show any discrete lesions secreting ACTH. The petrosal to peripheral ACTH gradient resulted in no evidence of pituitary adenoma. As the only lesion suspicious for ectopic ACTH secretion was a right lower round cystic lesion that did not appear to be a carcinoid tumor on computed tomography scan of the chest, the patient underwent video-assisted thoracic surgical resection to provide a definitive diagnosis. The final diagnosis was a small ectopic ACTH-secreting carcinoid tumor with unusual superimposed aspergilloma in the periphery of the lung. Postoperatively, the abnormal endocrine levels were normalized, and all of the clinical symptoms and signs were ameliorated. This is an informative case of ectopic ACTH syndrome (EAS) that was the cause of hypokalemia, hypertension, metabolic alkalosis, and hypercortisolism despite its poorly specific cushingoid morphology and uncommon imaging findings. Therefore, we recommend that clinicians investigate any possible lesion as a potential source of EAS. PMID- 28642734 TI - The Short-Stature Homeobox-Containing Gene (shox/SHOX) Is Required for the Regulation of Cell Proliferation and Bone Differentiation in Zebrafish Embryo and Human Mesenchymal Stem Cells. AB - The short-stature homeobox-containing gene (SHOX) was originally discovered as one of genes responsible for idiopathic short-stature syndromes in humans. Previous studies in animal models have shown the evolutionarily conserved link between this gene and skeletal formation in early embryogenesis. Here, we characterized developmental roles of shox/SHOX in zebrafish embryos and human mesenchymal stem cells (hMSCs) using loss-of-function approaches. Morpholino oligo-mediated knockdown of zebrafish shox markedly hindered cell proliferation in the anterior region of the pharyngula embryos, which was accompanied by reduction in the dlx2 expression at mesenchymal core sites for future pharyngeal bones. In addition, the impaired shox expression transiently increased expression levels of skeletal differentiation genes in early larval stage. In cell culture studies, we found that hMSCs expressed SHOX; the siRNA-mediated blockade of SHOX expression significantly blunted cell proliferation in undifferentiated hMSCs but the loss of SHOX expression did augment the expressions of subsets of early osteogenic genes during early osteoblast differentiation. These data suggest that shox/SHOX maintains the population of embryonic bone progenitor cells by keeping its proliferative status and by repressing the onset of early osteogenic gene expression. The current study for the first time shows cellular and developmental responses caused by shox/SHOX deficiency in zebrafish embryos and hMSCs, and it expands our understanding of the role of this gene in early stages of skeletal growth. PMID- 28642735 TI - Functional and Compositional Stability of Bacterial Metacommunities in Response to Salinity Changes. AB - Disturbances and environmental change are important factors determining the diversity, composition, and functioning of communities. However, knowledge about how natural bacterial communities are affected by such perturbations is still sparse. We performed a whole ecosystem manipulation experiment with freshwater rock pools where we applied salinity disturbances of different intensities. The aim was to test how the compositional and functional resistance and resilience of bacterial communities, alpha- and beta-diversity and the relative importance of stochastic and deterministic community assembly processes changed along a disturbance intensity gradient. We found that bacterial communities were functionally resistant to all salinity levels (3, 6, and 12 psu) and compositionally resistant to a salinity increase to 3 psu and resilient to increases of 6 and 12 psu. Increasing salinities had no effect on local richness and evenness, beta-diversity and the proportion of deterministically vs. stochastically assembled communities. Our results show a high functional and compositional stability of bacterial communities to salinity changes of different intensities both at local and regional scales, which possibly reflects long-term adaptation to environmental conditions in the study system. PMID- 28642736 TI - Identification of an Efflux Transporter LmrB Regulating Stress Response and Extracellular Polysaccharide Synthesis in Streptococcus mutans. AB - Efflux transporters have been implicated in regulating bacterial virulence properties such as resistance to antibiotics, biofilm formation and colonization. The pathogenicity of Streptococcus mutans, the primary etiologic agent of human dental caries, relies on the bacterium's ability to form biofilms on tooth surface. However, the studies on efflux transporters in S. mutans are scare and the function of these transporters remained to be clarified. In this study, we identified an efflux transporter (LmrB) in S. mutans through cloning the lmrB gene into Escherichia coli. Introducing lmrB into E. coli conferred a multidrug resistant phenotype and resulted in higher EtBr efflux activity which could be suppressed by efflux inhibitor. To explore whether LmrB was involved in S. mutans virulence properties regulation, we constructed the lmrB inactivation mutant and examined the phenotypes of the mutant. It was found that LmrB deficiency resulted in increased IPS storage and prolonged acid production. Enhanced biofilm formation characterized by increased extracellular polysaccharides (EPS) production and elevated resistance to hydrogen peroxide and antimicrobials were also observed in lmrB mutant. To gain a better understanding of the global role of LmrB, a transcriptome analysis was performed using lmrB mutant strain. The expression of 107 genes was up- or down-regulated in the lmrB mutant compared with the wild type. Notably, expression of genes in several genomic islands was differentially modulated, such as stress-related GroELS and scnRK, sugar metabolism associated glg operons and msmREFGK transporter. The results presented here indicate that LmrB plays a vital global role in the regulation of several important virulence properties in S. mutans. PMID- 28642737 TI - Pheno- and Genotyping of Hopanoid Production in Acidobacteria. AB - Hopanoids are pentacyclic triterpenoid lipids synthesized by different bacterial groups. Methylated hopanoids were believed to be exclusively synthesized by cyanobacteria and aerobic methanotrophs until the genes encoding for the methylation at the C-2 and C-3 position (hpnP and hpnR) were found to be widespread in the bacterial domain, invalidating their use as specific biomarkers. These genes have been detected in the genome of the Acidobacterium "Ca. Koribacter versatilis," but our knowledge of the synthesis of hopanoids and the presence of genes of their biosynthetic pathway in other member of the Acidobacteria is limited. We analyzed 38 different strains of seven Acidobacteria subdivisions (SDs 1, 3, 4, 6, 8, 10, and 23) for the presence of C30 hopenes and C30+ bacteriohopane polyols (BHPs) using the Rohmer reaction. BHPs and/or C30 hopenes were detected in all strains of SD1 and SD3 but not in SD4 (excepting Chloracidobacterium thermophilum), 6, 8, 10, and 23. This is in good agreement with the presence of genes required for hopanoid biosynthesis in the 31 available whole genomes of cultivated Acidobacteria. All genomes encode the enzymes involved in the non-mevalonate pathway ultimately leading to farnesyl diphosphate but only SD1 and 3 Acidobacteria and C. thermophilum encode all three enzymes required for the synthesis of squalene, its cyclization (shc), and addition and modification of the extended side chain (hpnG, hpnH, hpnI, hpnJ, hpnO). In almost all strains, only tetrafunctionalized BHPs were detected; three strains contained variable relative abundances (up to 45%) of pentafunctionalized BHPs. Only "Ca. K. versatilis" contained methylated hopanoids (i.e., 2,3-dimethyl bishomohopanol), although in low (<10%) amounts. These genes are not present in any other Acidobacterium, consistent with the absence of methylated BHPs in the other examined strains. These data are in agreement with the scattered occurrence of methylated BHPs in other bacterial phyla such as the Alpha-, Beta-, and Gammaproteobacteria and the Cyanobacteria, limiting their biomarker potential. Metagenomes of Acidobacteria were also examined for the presence of genes required for hopanoid biosynthesis. The complete pathway for BHP biosynthesis was evident in SD2 Acidobacteria and a group phylogenetically related to SD1 and SD3, in line with the limited occurrence of BHPs in acidobacterial cultures. PMID- 28642738 TI - Distinct Bacterial Communities Associated with Massive and Branching Scleractinian Corals and Potential Linkages to Coral Susceptibility to Thermal or Cold Stress. AB - It is well known that different coral species have different tolerances to thermal or cold stress, which is presumed to be related to the density of Symbiodinium. However, the intrinsic factors between stress-tolerant characteristics and coral-associated bacteria are rarely studied. In this study, 16 massive coral and 9 branching coral colonies from 6 families, 10 genera, and 18 species were collected at the same time and location (Xinyi Reef) in the South China Sea to investigate the bacterial communities. The results of an alpha diversity analysis showed that bacterial diversities associated with massive corals were generally higher than those with branching corals at different taxonomic levels (phylum, class, order, and so on). In addition, hierarchical clustering tree and PCoA analyses showed that coral species were clustered into two large groups according to the similarity of bacterial communities. Group I consisted of massive Goniastrea, Plesiastrea, Leptastrea, Platygyra, Echinopora, Porites, and Leptoria, and group II consisted of branching Acropora and Pocillopora. These findings suggested that both massive corals and branching corals have their own preference for the choice of associated bacteria, which may be involved in observed differences in thermal/cold tolerances. Further analysis found that 55 bacterial phyla, including 43 formally described phyla and 12 candidate phyla, were detected in these coral species. Among them, 52 phyla were recovered from the massive coral group, and 46 phyla were recovered from the branching coral group. Formally described coral pathogens have not been detected in these coral species, suggesting that they are less likely to be threatened by disease in this geographic area. This study highlights a clear relationship between the high complexity of bacterial community associated with coral, skeletal morphology of coral and potentially tolerances to thermal or cold stress. PMID- 28642739 TI - Genetic Variability of Koi Herpesvirus In vitro-A Natural Event? AB - Worldwide koi herpesvirus (KHV) causes high mortalities in Cyprinus carpio L. aquaculture. So far, it is unknown how the different variants of KHV have developed and how they spread in the fish, but also in the environmental water bodies. Therefore, a phylogenetic method based on variable number of tandem repeats (VNTR) was improved to gain deeper insights into the phylogeny of KHV and its possible worldwide distribution. Moreover, a VNTR-3 qPCR was designed which allows fast virus typing. This study presents a useful method for molecular tracing of diverse KHV types, variants, and lineages. PMID- 28642740 TI - Multigenerational Influences of the Fut2 Gene on the Dynamics of the Gut Microbiota in Mice. AB - The FUT2 gene encodes an alpha-1,2-fucosyltransferase responsible for the expression of ABO histo-blood-group antigens on mucosal surfaces and bodily secretions. Individuals who carry at least one functional allele are known as "secretors," whereas those homozygous for loss-of-function mutations are known as "non-secretors." Non-secretor individuals are more susceptible to chronic inflammatory disorders such as Crohn's Disease, which may be mediated by alterations in the microbiota. Here, we investigated the dynamics of microbial community assembly with respect to genotype using a Fut2-deficient mouse model, taking the genotype of the maternal lineage over two generations into account. We found strong differences in community assembly of microbial communities over time, depending on the Fut2 genotype of the host and that of their progenitors. By applying network analyses, we further identified patterns of specialization and stabilization over time, which are influenced by the host and parental genotype during the process of community development. We also show genotype- and breeding-dependent patterns of community susceptibility to disturbance in a novel in silico approach integrating ecological- and network analysis. Our results indicate that it may be important to investigate the influence of Fut2 genotype in a familial context in order to fully understand its role in the etiology of chronic inflammatory disorders. PMID- 28642741 TI - The Hyperarid Core of the Atacama Desert, an Extremely Dry and Carbon Deprived Habitat of Potential Interest for the Field of Carbon Science. AB - The Atacama Desert in Chile is the driest and oldest desert on Earth, also considered one of the best Mars analog models. Here, several heterotrophic microbial communities have been discovered in its driest regions, with the ones present in the soil subsurface being one of the most interesting due to its existence in a habitat with almost no water available and almost undetectable organic carbon sources. Our recent discovery of the driest site of the Atacama known to date (and the heterotrophic microbial species that are able to survive in this site) reaffirms the opportunity to better characterize the physiological and molecular mechanisms that these species use to detect, mobilize, incorporate and use carbon under these extremely harsh conditions. Here we summarize what has been reported up to date on the organic carbon concentrations in different sites of the hyperarid core of the Atacama Desert, proposing that due to the meager amounts of carbon and extremely dry conditions, the microbial communities of the hyperarid core of the Atacama Desert may be of interest for the field of carbon science. PMID- 28642742 TI - Microbial Resources and Enological Significance: Opportunities and Benefits. AB - Among the innovative trends in the wine sector, the continuous exploration of enological properties associated with wine microbial resources represents a cornerstone driver of quality improvement. Since the advent of starter cultures technology, the attention has been focused on intraspecific biodiversity within the primary species responsible for alcoholic fermentation (Saccharomyces cerevisiae) and, subsequently, for the so-called 'malolactic fermentation' (Oenococcus oeni). However, in the last decade, a relevant number of studies proposed the enological exploitation of an increasing number of species (e.g., non-Saccharomyces yeasts) associated with spontaneous fermentation in wine. These new species/strains may provide technological solutions to specific problems and/or improve sensory characteristics, such as complexity, mouth-feel and flavors. This review offers an overview of the available information on the enological/protechnological significance of microbial resources associated with winemaking, summarizing the opportunities and the benefits associated with the enological exploitation of this microbial potential. We discuss proposed solutions to improve quality and safety of wines (e.g., alternative starter cultures, multistrains starter cultures) and future perspectives. PMID- 28642743 TI - HIV-1 Nef Signaling in Intestinal Mucosa Epithelium Suggests the Existence of an Active Inter-kingdom Crosstalk Mediated by Exosomes. AB - The human intestinal mucosal surface represents the first defense against pathogens and regulates the immune response through the combination of epithelial cell (EC) functions and immunological factors. ECs act as sensors of luminal stimuli and interact with the immune cells through signal-transduction pathways, thus representing the first barrier that HIV-1 virus encounters during infection. In particular, the HIV-1 Nef protein plays a crucial role in viral invasion and replication. Nef is expressed early during viral infection and interacts with numerous cellular proteins as a scaffold/adaptor. Nef is localized primarily to cellular membranes and affects several signaling cascades in infected cells modulating the expression of cell surface receptors critical for HIV-1 infection and transmission, also accompanied by the production of specific cytokines and progressive depletion of CD4+ T cells. At the intestinal level, Nef contributes to affect the mucosal barrier by increasing epithelial permeability, that results in the translocation of microbial antigens and consequently in immune system activation. However, the pathological role of Nef in mucosal dysfunction has not been fully elucidated. Interestingly, Nef is secreted also within exosomes and contributes to regulate the intercellular communication exploiting the vesicular trafficking machinery of the host. This can be considered as a potential inter kingdom communication pathway between virus and humans, where viral Nef contributes to modulate and post-transcriptionally regulate the host gene expression and immune response. In this mini-review we discuss the effects of HIV 1 Nef protein on intestinal epithelium and propose the existence of an inter kingdom communication process mediated by exosomes. PMID- 28642744 TI - Unexpected Dominance of Elusive Acidobacteria in Early Industrial Soft Coal Slags. AB - Acid mine drainage (AMD) and mine tailing environments are well-characterized ecosystems known to be dominated by organisms involved in iron- and sulfur cycling. Here we examined the microbiology of industrial soft coal slags that originate from alum leaching, an ecosystem distantly related to AMD environments. Our study involved geochemical analyses, bacterial community profiling, and shotgun metagenomics. The slags still contained high amounts of alum constituents (aluminum, sulfur), which mediated direct and indirect effects on bacterial community structure. Bacterial groups typically found in AMD systems and mine tailings were not present. Instead, the soft coal slags were dominated by uncharacterized groups of Acidobacteria (DA052 [subdivision 2], KF-JG30-18 [subdivision 13]), Actinobacteria (TM214), Alphaproteobacteria (DA111), and Chloroflexi (JG37-AG-4), which have previously been detected primarily in peatlands and uranium waste piles. Shotgun metagenomics allowed us to reconstruct 13 high-quality Acidobacteria draft genomes, of which two genomes could be directly linked to dominating groups (DA052, KF-JG30-18) by recovered 16S rRNA gene sequences. Comparative genomics revealed broad carbon utilization capabilities for these two groups of elusive Acidobacteria, including polysaccharide breakdown (cellulose, xylan) and the competence to metabolize C1 compounds (ribulose monophosphate pathway) and lignin derivatives (dye decolorizing peroxidases). Equipped with a broad range of efflux systems for metal cations and xenobiotics, DA052 and KF-JG30-18 may have a competitive advantage over other bacterial groups in this unique habitat. PMID- 28642746 TI - Virucidal Activity of Fogged Chlorine Dioxide- and Hydrogen Peroxide-Based Disinfectants against Human Norovirus and Its Surrogate, Feline Calicivirus, on Hard-to-Reach Surfaces. AB - Human norovirus (NoV) is the leading cause of foodborne illnesses in the United States. Norovirus is shed in high numbers in the feces and vomitous of infected individuals. Contact surfaces contaminated with bodily fluids harboring infectious virus particles serve as vehicles for pathogen transmission. Environmental stability of NoV and its resistance to many conventional disinfectants necessitate effective inactivation strategies to control the spread of virus. We investigated the efficacy of two commercial disinfectants, hydrogen peroxide (7.5%) and a chlorine dioxide (0.2%)-surfactant-based product using a fogging delivery system against human NoV GI.6 and GII.4 Sydney strains as well as the cultivable surrogate, feline calicivirus (FCV) dried on stainless steel coupons. Log10 reductions in human NoV and FCV were calculated utilizing RNase RT qPCR and infectivity (plaque) assay, respectively. An improved antiviral activity of hydrogen peroxide as a function of disinfectant formulation concentration in the atmosphere was observed against both GII.4 and FCV. At 12.4 ml/m3, hydrogen peroxide achieved a respective 2.5 +/- 0.1 and 2.7 +/- 0.3 log10 reduction in GI.6 and GII.4 NoV genome copies, and a 4.3 +/- 0.1 log10 reduction in infectious FCV within 5 min. At the same disinfectant formulation concentration, chlorine dioxide-surfactant-based product resulted in a respective 1.7 +/- 0.2, 0.6 +/- 0.0, and 2.4 +/- 0.2 log10 reduction in GI.6, GII.4, and FCV within 10 min; however, increasing the disinfectant formulation concentration to 15.9 ml/m3 negatively impacted its efficacy. Fogging uniformly delivered the disinfectants throughout the room, and effectively decontaminated viruses on hard-to-reach surfaces. Hydrogen peroxide delivered by fog showed promising virucidal activity against FCV by meeting the United States EPA 4-log10 reduction criteria for an anti-noroviral disinfectant; however, fogged chlorine dioxide-surfactant-based product did not achieve a 4-log10 inactivation. Future investigation aimed at optimizing decontamination practices is warranted. PMID- 28642745 TI - Structure of O-Antigen and Hybrid Biosynthetic Locus in Burkholderia cenocepacia Clonal Variants Recovered from a Cystic Fibrosis Patient. AB - Burkholderia cenocepacia is an opportunistic pathogen associated with chronic lung infections and increased risk of death in patients with cystic fibrosis (CF). In this work, we investigated the lipopolysaccharide (LPS) of clinical variants of B. cenocepacia that were collected from a CF patient over a period of 3.5 years, from the onset of infection until death by necrotizing pneumonia (cepacia syndrome). We report the chemical structure of the LPS molecule of various sequential isolates and the identification of a novel hybrid O-antigen (OAg) biosynthetic cluster. The OAg repeating unit of the LPS from IST439, the initial isolate, is a [->2)-beta-D-Ribf-(1->4)-alpha-D-GalpNAc-(1->] disaccharide, which was not previously described in B. cenocepacia. The IST439 OAg biosynthetic gene cluster contains 7 of 23 genes that are closely homologous to genes found in B. multivorans, another member of the Burkholderia cepacia complex. None of the subsequent isolates expressed OAg. Genomic sequencing of these isolates enabled the identification of mutations within the OAg cluster, but none of these mutations could be associated with the loss of OAg. This study provides support to the notion that OAg LPS modifications are an important factor in the adaptation of B. cenocepacia to chronic infection and that the heterogeneity of OAgs relates to variation within the OAg gene cluster, indicating that the gene cluster might have been assembled through multiple horizontal transmission events. PMID- 28642747 TI - Propionibacterium freudenreichii Surface Protein SlpB Is Involved in Adhesion to Intestinal HT-29 Cells. AB - Propionibacterium freudenreichii is a beneficial bacterium traditionally used as a cheese ripening starter and more recently for its probiotic abilities based on the release of beneficial metabolites. In addition to these metabolites (short chain fatty acids, vitamins, and bifidogenic factor), P. freudenreichii revealed an immunomodulatory effect confirmed in vivo by the ability to protect mice from induced acute colitis. This effect is, however, highly strain-dependent. Local action of metabolites and of immunomodulatory molecules is favored by the ability of probiotics to adhere to the host cells. This property depends on key surface compounds, still poorly characterized in propionibacteria. In the present study, we showed different adhesion rates to cultured human intestinal cells, among strains of P. freudenreichii. The most adhesive one was P. freudenreichii CIRM BIA 129, which is known to expose surface-layer proteins. We evidenced here the involvement of these proteins in adhesion to cultured human colon cells. We then aimed at deciphering the mechanisms involved in adhesion. Adhesion was inhibited by antibodies raised against SlpB, one of the surface-layer proteins in P. freudenreichii CIRM-BIA 129. Inactivation of the corresponding gene suppressed adhesion, further evidencing the key role of slpB product in cell adhesion. This work confirms the various functions fulfilled by surface-layer proteins, including probiotic/host interactions. It opens new perspectives for the understanding of probiotic determinants in propionibacteria, and for the selection of the most efficient strains within the P. freudenreichii species. PMID- 28642748 TI - Helicobacter, Hygiene, Atopy, and Asthma. AB - The hygiene hypothesis links environmental and microbial exposures in early life to the prevalence of atopy, allergy, and asthma. Helicobacter pylori infection is typically acquired in childhood and acquisition of the infection is associated with poor household hygiene. Some population surveys have shown an inverse association between H. pylori infection and atopy, allergy, and asthma leading to the suggestion that H. pylori infection may be protective against disease; others consider it simply a biomarker for poor household hygiene. We review the relevant surveys, cohort studies, meta-analyses, and studies testing the protective hypothesis. Overall, the results of surveys and cohort studies are inconsistent, whereas meta-analyses show a significant but weak inverse correlation. In contrast, studies directly testing the protection hypothesis in relation to asthma in populations with poor hygiene and low H. pylori prevalence failed to confirm a protective effect. H. pylori is a major cause of human disease including chronic gastritis, peptic ulcer, and gastric malignancies. H. pylori infections most likely serve as a biomarker for poor hygienic conditions in childhood. We conclude that while synergistic interactions between environmental factors in childhood are important determinants of the pathogenesis of atopy, allergy, and asthma; H. pylori is inversely related to good hygiene and thus it's presence serves as a biomarker rather than for a specific prevention role for H. pylori or H. pylori antigens. PMID- 28642749 TI - RNA-Seq Reveals Enhanced Sugar Metabolism in Streptococcus mutans Co-cultured with Candida albicans within Mixed-Species Biofilms. AB - Early childhood caries (ECC), which can lead to rampant tooth-decay that is painful and costly to treat, is one of the most prevalent infectious diseases affecting children worldwide. Previous studies support that interactions between Streptococcus mutans and Candida albicans are associated with the pathogenesis of ECC. The presence of Candida enhances S. mutans growth, fitness and accumulation within biofilms in vitro, although the molecular basis for these behaviors is undefined. Using an established co-cultivation biofilm model and RNA-Seq, we investigated how C. albicans influences the transcriptome of S. mutans. The presence of C. albicans dramatically altered gene expression in S. mutans in the dual-species biofilm, resulting in 393 genes differentially expressed, compared to mono-species biofilms of S. mutans. By Gene Ontology analysis, the majority of up-regulated genes were related to carbohydrate transport and metabolic/catabolic processes. KEGG pathway impact analysis showed elevated pyruvate and galactose metabolism, suggesting that co-cultivation with C. albicans influences carbohydrate utilization by S. mutans. Analysis of metabolites confirmed the increases in carbohydrate metabolism, with elevated amounts of formate in the culture medium of co-cultured biofilms. Moreover, co-cultivation with C. albicans altered transcription of S. mutans signal transduction (comC and ciaRH) genes associated with fitness and virulence. Interestingly, the expression of genes for mutacins (bacteriocins) and CRISPR were down-regulated. Collectively, the data provide a comprehensive insight into S. mutans transcriptomic changes induced by C. albicans, and offer novel insights into how bacterial-fungal interactions may enhance the severity of dental caries. PMID- 28642750 TI - Non-pylori Helicobacters (NHPHs) Induce Shifts in Gastric Microbiota in Helicobacter pylori-Infected Patients. AB - To explore the effects of gastric non-H. pylori Helicobacter species(NHPH) on the structure and potential function of gastric microbiota, we employed 16S rRNA gene sequencing on 164 gastric biopsy specimens from NHPH (H. suis, H. felis, H. salomonis) /H. pylori coinfection individuals, H. pylori monoinfection individuals and healthy controls. The results demonstrated that marked structural and functional variations between H. pylori mono- and coinfection samples (HPHS, HPHF, HPHM). The changes in bacterial structure induced by NHPH are mainly attributed to their ability of gastric acid secretion inhibition as well as bacterial chemotaxis. Both the HPHS and HPHF groups showed significant increases in phylotype richness and significant decreases in beta diversity, but this trend was not found in HPHM group. Regarding the top five phyla and top thirty-five genera, the HPHS and HPHF groups had similar variation trends in relative abundance. The increased relative abundance levels of the genera Vibrio, Pseudoalteromonas, Photobacterium, and Clostridium were associated with increases in predicted signal transduction/metabolic pathways among the three coinfection groups. The relative abundance levels of bacteria involved in the formation of N nitroso compounds were significantly decreased in the HPHS and HPHF groups (e.g., Streptococcus, Neisseria, Haemophilus, Veillonella, Clostridium, etc.). The significantly decreased relative abundance levels of the phyla Firmicutes and Bacteroidetes in the HPHS and HPHF groups were associated with the observed increases in predicted lipid metabolism pathways. The results in this study implied that NHPH can arouse the variation of structure and function of gastric microbiota, which may pave the way to further research on the pathogenesis of gastric diseases. PMID- 28642751 TI - In vitro Antimicrobial Activity of Chlorquinaldol against Microorganisms Responsible for Skin and Soft Tissue Infections: Comparative Evaluation with Gentamicin and Fusidic Acid. AB - Skin and soft tissue infections (SSTIs) are a major therapeutic challenge for clinicians. The emergence of pathogens with decreased susceptibility to available therapies has become an emerging problem often associated with treatment failure. Hence, there is an urgent need for novel broad-spectrum antimicrobial agents. The purpose of this study was to assess the feasibility of chlorquinaldol as an alternative approach to currently used topical antibiotics for the treatment of skin and soft tissue infections. The activity of chlorquinaldol was investigated against a collection of bacterial isolates responsible for skin infections, including strains resistant to fusidic acid and gentamicin. After determination of MIC and MBC, time-kill experiments were carried out by counting colonies grown after 0, 3, 6, 9, 24, and 48 h of incubation with concentrations equal to 1/4*, 1/2*, 1*, 2*, and 4* MIC of chlorquinaldol, gentamicin, or fusidic acid. Staphylococci resulted the Gram-positives most sensitive to chlorquinaldol, with MIC-values ranging from 0.016 to 0.5 mg/L. A lower activity was observed against Gram-negative bacteria, with 77% of the isolates being inhibited at concentrations ranging from 128 to 512 mg/L. Generally, in time-kill studies, chlorquinaldol showed a bactericidal activity at the higher concentrations (2*, 4* MIC) after 24-48 h of incubation. In conclusion, chlorquinaldol may represent a valuable alternative to conventional topical antibiotics for the treatment of skin and soft tissue infections. PMID- 28642754 TI - Editorial: Spores and Spore Formers. PMID- 28642752 TI - A Comprehensive Epidemiological Research for Clinical Vibrio parahaemolyticus in Shanghai. AB - Vibrio parahaemolyticus is one of the most important pathogen for seafood-borne gastroenteritis in Shanghai and the rest of the world. A total of 42 V. parahaemolyticus strains were isolated from 1900 fecal specimens collected from patients in Shanghai hospital presenting from January 2014 to December 2015. All isolates were evaluated for potential virulence factors [tdh, trh, and type three secretion system (T3SS) genes], typed using multilocus sequence typing (MLST) and screened for antimicrobial resistance phenotype and genotype. And for the first time, the relationship between virulence, genetic diversity and antimicrobial resistance of these isolates were identified. The results showed that 37 isolates carried the tdh gene (88.1%) and only seven isolates were positive for the trh gene. The T3SS1 and T3SS2 genes were detected in all strains and only trh positive isolates are also containing the T3SS2beta genes. MLST analysis of the 42 Shanghai isolates identified 20 sequence types (STs) with 16 novel STs and that these clinical V. parahaemolyticus strains showed high degrees of genetic diversity. All isolates expressed high levels of resistance against Ampicillin (100.0%), Streptomycin (100.0%), Cephazolin (92.9%), Kanamycin (92.8%) and Amikacin (90.5%), and eight out of 38 resistance genes (SHV, tet(B), strA, qnrA, gryA, qnrB, sulI, sulII) were detected in at least two isolates. This study confirms that antimicrobial resistance of clinical V. parahaemolyticus isolates is greater than those of environmental isolates. Furthermore, no clear correlation between antimicrobial resistance and virulence or genetic diversity was found in this study. These results add to epidemiological data of clinical V. parahaemolyticus isolates in Shanghai and highlight the need for additional mechanistic studies, especially antimicrobial resistance, to reduce the burden of disease caused by this pathogen in China. PMID- 28642753 TI - SuhB Regulates the Motile-Sessile Switch in Pseudomonas aeruginosa through the Gac/Rsm Pathway and c-di-GMP Signaling. AB - Many Pseudomonas aeruginosa virulence traits that contribute to human infections are accepted as being associated with its environmental lifestyle. Therefore, identifying the molecular mechanisms that govern the lifestyle choice is of high significance. We previously reported that a mutation in suhB results in a decrease in swimming motility and increased biofilm formation compared to the wild-type strain. Yet, little is known about how this occurs. In this study, we demonstrated that SuhB inversely regulates motility and biofilm formation through the GacA-RsmY/Z-RsmA cascade. Mutations in gacA or the two small RNAs rsmY/rsmZ, or overproduction of the RsmA protein essentially rescued the motility defect of the suhB mutant. Additionally, we identified a c-di-GMP mediated mechanism for SuhB regulation of motility and biofilm formation. We showed that the DeltasuhB mutant displayed elevated levels of c-di-GMP, and the DeltasuhB motility and biofilm phenotypes could be switched by artificially decreasing c-di-GMP levels. Further experiments led to the identification of the diguanylate cyclase GcbA responsible for regulating the c-di-GMP concentration in DeltasuhB and hence the switch between planktonic and surface-associated growth. Together, our results demonstrate a novel mechanism for SuhB regulation of the lifestyle transition via the Gac/Rsm and c-di-GMP signaling networks in P. aeruginosa. PMID- 28642755 TI - Vaginal and Uterine Bacterial Communities in Postpartum Lactating Cows. AB - Reproductive inefficiency in cattle has major impacts on overall productivity of cattle operations, increasing cost of production, and impacting the sustainability of the cattle enterprise. Decreased reproductive success and associated disease states have been correlated with the presence of specific microbes and microbial community profiles, yet details of the relationship between microbial communities and host physiology are not well known. The present study profiles and compares the microbial communities in the bovine uterus and vagina using 16S rRNA sequencing of the V1-V3 hypervariable region at the time of artificial insemination. Significant differences (p < 0.05) between the vaginal and uterine communities were observed at the level of alpha-diversity metrics, including Chao1, Shannon's Diversity Index, and observed OTU. Greater clustering of vaginal OTU was apparent in principal coordinate analysis compared to uterine OTU, despite greater diversity in the vaginal community in both weighted and unweighted UniFrac distance matrices (p < 0.05). There was a significantly greater relative abundance of unassigned taxa in the uterus (p = 0.008), otherwise there were few differences between the overall community profiles. Both vaginal and uterine communities were dominated by Firmicutes, although the relative abundance of rRNA sequences corresponding to species in this phylum was significantly (p = 0.007) lower in the uterine community. Additional differences were observed at the genus level, specifically in abundances within Clostridium (p = 0.009), Anaerofustis (p = 0.018), Atopobium (p = 0.035), Oscillospira (p = 0.035), 5-7N15 (p = 0.035), Mycoplasma (p = 0.035), Odoribacter (p = 0.042), and within the families Clostridiaceae (p = 0.006), Alcaligenaceae (p = 0.021), and Ruminococcaceae (p = 0.021). Overall, the comparison revealed differences and commonalities among bovine reproductive organs, which may be influenced by host physiology. The increased abundance of unassigned taxa found in the uterus may play a significant biological role in the reproductive status of the animal. The study represents an initial dataset for comparing bacterial communities prior to establishment of pregnancy. PMID- 28642756 TI - High Prevalence of Macrolide-resistance and Molecular Characterization of Streptococcus pyogenes Isolates Circulating in China from 2009 to 2016. AB - Streptococcus pyogenes, or group A Streptococcus, is a pathogen responsible for a wide range of clinical manifestations, from mild skin and soft tissue infections and pharyngitis to severe diseases. Its epidemiological characteristics should be comprehensively under surveillance for regulating the national prevention and treatment practice. Herein, a total of 140 S. pyogenes, including 38 invasive and 102 noninvasive isolates, were collected from infected patients in 10 tertiary general hospitals from 7 cities/provinces in China during the years 2009-2016. All strains were characterized by classical and molecular techniques for its emm types/subtypes, virulent factors and antibiotic resistance profiling. Of 140 isolates, 15 distinct emm types and 31 subtypes were detected, dominated by emm12 (60 isolates, 42.9%), emm1(43, 30.7%), and emm89 (10, 7.1%), and 8 new emm variant subtypes were identified. All strains, invasive or not, harbored the superantigenic genes, speB and slo. The other virulence genes, smeZ, speF, and speC accounted for 96.4, 91.4, and 87.1% of collected isolates, respectively. Further multilocus sequence typing (MLST) placed all strains into 22 individual sequence types (STs), including 4 newly-identified STs (11, 7.9%). All isolates were phenotypically susceptible to penicillin, ampicillin, cefotaxime, and vancomycin, whereas 131(93.5%), 132(94.2%), and 121(86.4%) were resistant to erythromycin, clindamycin, and tetracycline, respectively. Our study highlights high genotypic diversity and high prevalence of macrolide resistance of S. pyogenes among clinical isolates circulating in China. PMID- 28642758 TI - Time and Antigen-Stimulation History Influence Memory CD8 T Cell Bystander Responses. AB - Memory CD8 T cells can be activated and induced to produce cytokines and increase stores of cytolytic proteins not only in response to cognate antigen (Ag) but also in response to inflammatory cytokines (bystander responses). Importantly, bystander memory CD8 T cell functions have been shown to be dependent upon memory CD8 T cell fitness, since exhausted CD8 T cells have diminished capacity to respond to inflammatory cues. While it is known that memory CD8 T cell functional abilities, including ability to produce cytokines in response to cognate Ag, change with time after initial Ag encounter and upon multiple Ag stimulations (e.g., primary vs. tertiary CD8 T cell responses), it is unknown if bystander memory CD8 T cell responses are influenced by time or by Ag-exposure history. Here, we examined time and Ag-stimulation history-dependent alterations in virus specific memory CD8 T cell bystander functions in response to inflammatory cytokines and unrelated bacterial infection. We found that expression of cytokine receptors and ability to produce IFN-gamma following heterologous infection or incubation with inflammatory cytokines decreases with time following initial Ag encounter and increases with additional Ag encounters, suggesting that the ability to sense inflammation and respond with bystander cytokine production is dependent on age and Ag-stimulation history of memory CD8 T cells. These data shed further light on the regulation of memory CD8 T cell effector functions and have important implications for the development of vaccines designed to elicit protective memory CD8 T cells. PMID- 28642757 TI - The Fungal Pathogen Candida glabrata Does Not Depend on Surface Ferric Reductases for Iron Acquisition. AB - Iron acquisition is a crucial virulence determinant for many bacteria and fungi, including the opportunistic fungal pathogens Candida albicans and C. glabrata. While the diverse strategies used by C. albicans for obtaining iron from the host are well-described, much less is known about the acquisition of this micronutrient from host sources by C. glabrata - a distant relative of C. albicans with closer evolutionary ties to Saccharomyces cerevisiae, which nonetheless causes severe clinical symptoms in humans. Here we show that C. glabrata is much more restricted than C. albicans in using host iron sources, lacking, for example, the ability to grow on transferrin and hemin/hemoglobin. Instead, C. glabrata is able to use ferritin and non-protein-bound iron (FeCl3) as iron sources in a pH-dependent manner. As in other fungal pathogens, iron dependent growth requires the reductive high affinity (HA) iron uptake system. Typically highly conserved, this uptake mechanism normally relies on initial ferric reduction by cell-surface ferric reductases. The C. glabrata genome contains only three such putative ferric reductases, which were found to be dispensable for iron-dependent growth. In addition and in contrast to C. albicans and S. cerevisiae, we also detected no surface ferric reductase activity in C. glabrata. Instead, extracellular ferric reduction was found in this and the two other fungal species, which was largely dependent on an excreted low-molecular weight, non-protein ferric reductant. We therefore propose an iron acquisition strategy of C. glabrata which differs from other pathogenic fungi, such as C. albicans, in that it depends on a limited set of host iron sources and that it lacks the need for surface ferric reductases. Extracellular ferric reduction by a secreted molecule possibly compensates for the loss of surface ferric reductase activity in the HA iron uptake system. PMID- 28642759 TI - Biodistribution and Efficacy of Human Adipose-Derived Mesenchymal Stem Cells Following Intranodal Administration in Experimental Colitis. AB - Mesenchymal stem cells (MSCs) have a large potential in cell therapy for treatment of inflammatory and autoimmune diseases, thanks to their immunomodulatory properties. The encouraging results in animal models have initiated the translation of MSC therapy to clinical trials. In cell therapy protocols with MSCs, administered intravenously, several studies have shown that a small proportion of infused MSCs can traffic to the draining lymph nodes (LNs). This is accompanied with an increase of different types of regulatory immune cells in the LNs, suggesting the importance of migration of MSCs to the LNs in order to contribute to immunomodulatory response. Intranodal (IN), also referred as intralymphatic, injection of cells, like dendritic cells, is being proposed in the clinic for the treatment of cancer and allergy, showing that this route of administration is clinically safe and efficient. In this study, we investigated, for the first time, the biodistribution and the efficacy of Luciferase+ adipose derived MSCs (Luci-eASCs), infused through the inguinal LNs (iLNs), in normal mice and in inflamed mice with colitis. Most of the Luci-eASCs remain in the iLNs and in the adipose tissue surrounding the inguinal LNs. A small proportion of Luci-eASCs can migrate to other locations within the lymphatic system and to other tissues and organs, having a preferential migration toward the intestine in colitic mice. Our results show that the infused Luci-eASCs protected 58% of the mice against induced colitis. Importantly, a correlation between the response to eASC treatment and a higher accumulation of eASCs in popliteal, parathymic, parathyroid, and mesenteric LNs were found. Altogether, these results suggest that IN administration of eASCs is feasible and may represent an effective strategy for cell therapy protocols with human adipose-derived MSCs in the clinic for the treatment of immune-mediated disorders. PMID- 28642761 TI - Overexpression of BdMATE Gene Improves Aluminum Tolerance in Setaria viridis. AB - Acidic soils are distributed worldwide, predominantly in tropical and subtropical areas, reaching around 50% of the arable soil. This type of soil strongly reduces crop production, mainly because of the presence of aluminum, which has its solubility increased at low pH levels. A well-known physiological mechanism used by plants to cope with Al stress involves activation of membrane transporters responsible for organic acid anions secretion from the root apex to the rhizosphere, which chelate Al, preventing its absorption by roots. In sorghum, a membrane transporter gene belonging to multidrug and toxic compound extrusion (MATE) family was identified and characterized as an aluminum-activated citrate transporter gene responsible for Al tolerance in this crop. Setaria viridis is an emerging model for C4 species and it is an important model to validate some genes for further C4 crops transformation, such as sugarcane, maize, and wheat. In the present work, Setaria viridis was used as a model plant to overexpress a newly identified MATE gene from Brachypodium distachyon (BdMATE), closely related to SbMATE, for aluminum tolerance assays. Transgenic S. viridis plants overexpressing a BdMATE presented an improved Al tolerance phenotype, characterized by sustained root growth and exclusion of aluminum from the root apex in transgenic plants, as confirmed by hematoxylin assay. In addition, transgenic plants showed higher root citrate exudation into the rhizosphere, suggesting that Al tolerance improvement in these plants could be related to the chelation of the metal by the organic acid anion. These results suggest that BdMATE gene can be used to transform C4 crops of economic importance with improved aluminum tolerance. PMID- 28642762 TI - Arbuscular Mycorrhiza Augments Arsenic Tolerance in Wheat (Triticum aestivum L.) by Strengthening Antioxidant Defense System and Thiol Metabolism. AB - Arbuscular mycorrhiza (AM) can help plants to tolerate arsenic (As) toxicity. However, plant responses are found to vary with the host plant and the AM fungal species. The present study compares the efficacy of two AM fungi Rhizoglomus intraradices (M1) and Glomus etunicatum (M2) in amelioration of As stress in wheat (Triticum aestivum L. var. HD-2967). Mycorrhizal (M) and non-mycorrhizal (NM) wheat plants were subjected to four levels of As (0, 25, 50, and 100 mg As kg-1 soil). Although As additions had variable effects on the percentage of root colonized by the two fungal inoculants, each mycobiont conferred benefits to the host plant. Mycorrhizal plants continued to display better growth than NM plants. Formation of AM helped the host plant to overcome As-induced P deficiency and maintained favorable P:As ratio. Inoculation of AMF had variable effects on the distribution of As in plant tissues. While As translocation factor decreased in low As (25 mg kg-1 soil), it increased under high As (50 and 100 mg As kg-1 soil). Further As translocation to grain was reduced (As grain:shoot ratio) in M plants compared with NM plants. Arsenic-induced oxidative stress (generation of H2O2 and lipid peroxidation) in plants reduced significantly by AMF inoculation. The alleviation potential of AM was more evident with increase in severity of As stress. Colonization of AMF resulted in higher activities of the antioxidant enzymes (superoxide dismutase, catalase, and guaiacol peroxidase). It increased the concentrations of the antioxidant molecules (carotenoids, proline, and alpha tocopherol) than their NM counterparts at high As addition level. Comparatively higher activities of enzymes of glutathione-ascorbate cycle in M plants led to higher ascorbate:dehydroascorbate (AsA:DHA) and glutathione:glutathione disulphide (GSH:GSSG) ratios. Inoculation by AMF also augmented the glyoxalase system by increasing the activities of both glyoxalase I and glyoxalase II enzymes. Mycorrhizal colonization increased concentrations of cysteine, glutathione, non-protein thiols, and activity of glutathione-S-transferase that facilitated sequestration of As into non-toxic complexes. The study reveals multifarious role of AMF in alleviation of As toxicity. PMID- 28642760 TI - Interleukin-6 in Allogeneic Stem Cell Transplantation: Its Possible Importance for Immunoregulation and As a Therapeutic Target. AB - Allogeneic stem cell transplantation is associated with a high risk of treatment related mortality mainly caused by infections and graft-versus-host disease (GVHD). GVHD is characterized by severe immune dysregulation and impaired regeneration of different tissues, i.e., epithelial barriers and the liver. The balance between pro- and anti-inflammatory cytokine influences the risk of GVHD. Interleukin-6 (IL-6) is a cytokine that previously has been associated with pro inflammatory effects. However, more recent evidence from various autoimmune diseases (e.g., inflammatory bowel disease, rheumatoid arthritis) has shown that the IL-6 activity is more complex with important effects also on tissue homeostasis, regeneration, and metabolism. This review summarizes the current understanding of how pro-inflammatory IL-6 effects exerted during the peritransplant period shapes T-cell polarization with enhancement of Th17 differentiation and suppression of regulatory T cells, and in addition we also review and discuss the results from trials exploring non-selective IL-6 inhibition in prophylaxis and treatment of GVHD. Emerging evidence suggests that the molecular strategy for targeting of IL-6-initiated intracellular signaling is important for the effect on GVHD. It will therefore be important to further characterize the role of IL-6 in the pathogenesis of GVHD to clarify whether combined IL-6 inhibition of both trans- (i.e., binding of the soluble IL-6/IL-6 receptor complex to cell surface gp130) and cis-signaling (i.e., IL-6 ligation of the IL-6 receptor/gp130 complex) or selective inhibition of trans-signaling should be tried in the prophylaxis and/or treatment of GVHD in allotransplant patients. PMID- 28642763 TI - Rootstock Sub-Optimal Temperature Tolerance Determines Transcriptomic Responses after Long-Term Root Cooling in Rootstocks and Scions of Grafted Tomato Plants. AB - Grafting of elite cultivars onto tolerant rootstocks is an advanced strategy to increase tomato tolerance to sub-optimal temperature. However, a detailed understanding of adaptive mechanisms to sub-optimal temperature in rootstocks and scions of grafting combinations on a physiological and molecular level is lacking. Here, the commercial cultivar Kommeet was grafted either onto 'Moneymaker' (sensitive) or onto the line accession LA 1777 of Solanum habrochaites (tolerant). Grafted plants were grown in NFT-system at either optimal (25 degrees C) or sub-optimal (15 degrees C) temperatures in the root environment with optimal air temperature (25 degrees C) for 22 days. Grafting onto the differently tolerant rootstocks caused differences in shoot fresh and dry weight, total leaf area and dry matter content of roots, in stomatal conductance and intercellular CO2 and guaiacol peroxidase activity but not in net photosynthesis, sugar, starch and amino acid content, lipid peroxidation and antioxidant enzyme activity. In leaves, comparative transcriptome analysis identified 361 differentially expressed genes (DEG) responding to sub-optimal root temperature when 'Kommeet' was grafted onto the sensitive but no when grafted onto the tolerant rootstock. 1509 and 2036 DEG responding to sub-optimal temperature were identified in LA 1777 and 'Moneymaker' rootstocks, respectively. In tolerant rootstocks down-regulated genes were enriched in main stress responsive functional categories and up-regulated genes in cellulose synthesis suggesting that cellulose synthesis may be one of the main adaptation mechanisms to long-term sub-optimal temperature. Down-regulated genes of the sensitive rootstock showed a similar response, but functional categories of up-regulated genes pointed to induced stress responses. Rootstocks of the sensitive cultivar Moneymaker showed in addition an enrichment of up-regulated genes in the functional categories fatty acid desaturation, phenylpropanoids, biotic stress, cytochrome P450 and protein degradation, indicating that the sensitive cultivar showed more transcriptional adaptation to low temperature than the tolerant cultivar that did not show these changes. Mainly defense-related genes were highly differentially expressed between the tolerant and sensitive rootstock genotypes under sub-optimal temperature in the root environment. These results provide new insights into the molecular mechanisms of long-term sub-optimal temperature tolerance of tomato. PMID- 28642764 TI - Xylella fastidiosa: Host Range and Advance in Molecular Identification Techniques. AB - In the never ending struggle against plant pathogenic bacteria, a major goal is the early identification and classification of infecting microorganisms. Xylella fastidiosa, a Gram-negative bacterium belonging to the family Xanthmonadaceae, is no exception as this pathogen showed a broad range of vectors and host plants, many of which may carry the pathogen for a long time without showing any symptom. Till the last years, most of the diseases caused by X. fastidiosa have been reported from North and South America, but recently a widespread infection of olive quick decline syndrome caused by this fastidious pathogen appeared in Apulia (south-eastern Italy), and several cases of X. fastidiosa infection have been reported in other European Countries. At least five different subspecies of X. fastidiosa have been reported and classified: fastidiosa, multiplex, pauca, sandyi, and tashke. A sixth subspecies (morus) has been recently proposed. Therefore, it is vital to develop fast and reliable methods that allow the pathogen detection during the very early stages of infection, in order to prevent further spreading of this dangerous bacterium. To this purpose, the classical immunological methods such as ELISA and immunofluorescence are not always sensitive enough. However, PCR-based methods exploiting specific primers for the amplification of target regions of genomic DNA have been developed and are becoming a powerful tool for the detection and identification of many species of bacteria. The aim of this review is to illustrate the application of the most commonly used PCR approaches to X. fastidiosa study, ranging from classical PCR, to several PCR-based detection methods: random amplified polymorphic DNA (RAPD), quantitative real-time PCR (qRT-PCR), nested-PCR (N-PCR), immunocapture PCR (IC PCR), short sequence repeats (SSRs, also called VNTR), single nucleotide polymorphisms (SNPs) and multilocus sequence typing (MLST). Amplification and sequence analysis of specific targets is also mentioned. The fast progresses achieved during the last years in the DNA-based classification of this pathogen are described and discussed and specific primers designed for the different methods are listed, in order to provide a concise and useful tool to all the researchers working in the field. PMID- 28642766 TI - High Throughput Screening Method for Identifying Potential Agonists and Antagonists of Arabidopsis thaliana Cytokinin Receptor CRE1/AHK4. AB - The CRE1/AHK4 cytokinin receptor is an important component of plants' hormone signaling systems, and compounds that can alter its activity have potential utility for studying the receptor's functions and/or developing new plant growth regulators. A high throughput method was developed for screening compounds with agonist or antagonist properties toward the CRE1/AHK4 cytokinin receptor in a single experiment using the Nanodrop II liquid handling system and 384-well plates. Potential ligands are screened directly, using a reporter system in which receptor signaling activity triggers expression of beta-galactosidase in Escherichia coli. This enzyme generates a fluorescent product from a non fluorescent substrate, allowing the agonistic/antagonistic behavior of tested compounds to be assayed in relation to that of an internal standard (here the natural ligand, trans-zeatin). The method includes a robust control procedure to determine false positive or false negative effects of the tested compounds arising from their fluorescent or fluorescent-quenching properties. The presented method enables robust, automated screening of large libraries of compounds for ability to activate or inhibit the Arabidopsis thaliana cytokinin receptor CRE1/AHK4. PMID- 28642765 TI - Genome-Wide Identification of AP2/ERF Transcription Factors in Cauliflower and Expression Profiling of the ERF Family under Salt and Drought Stresses. AB - The AP2/ERF transcription factors (TFs) comprise one of the largest gene superfamilies in plants. These TFs perform vital roles in plant growth, development, and responses to biotic and abiotic stresses. In this study, 171 AP2/ERF TFs were identified in cauliflower (Brassica oleracea L. var. botrytis), one of the most important horticultural crops in Brassica. Among these TFs, 15, 9, and 1 TFs were classified into the AP2, RAV, and Soloist family, respectively. The other 146 TFs belong to ERF family, which were further divided into the ERF and DREB subfamilies. The ERF subfamily contained 91 TFs, while the DREB subfamily contained 55 TFs. Phylogenetic analysis results indicated that the AP2/ERF TFs can be classified into 13 groups, in which 25 conserved motifs were confirmed. Some motifs were group- or subgroup- specific, implying that they are significant to the functions of the AP2/ERF TFs of these clades. In addition, 35 AP2/ERF TFs from the 13 groups were selected randomly and then used for expression pattern analysis under salt and drought stresses. The majority of these AP2/ERF TFs exhibited positive responses to these stress conditions. In specific, Bra-botrytis-ERF054a, Bra-botrytis-ERF056, and Bra-botrytis-CRF2a demonstrated rapid responses. By contrast, six AP2/ERF TFs were showed to delay responses to both stresses. The AP2/ERF TFs exhibiting specific expression patterns under salt or drought stresses were also confirmed. Further functional analysis indicated that ectopic overexpression of Bra-botrytis-ERF056 could increase tolerance to both salt and drought treatments. These findings provide new insights into the AP2/ERF TFs present in cauliflower, and offer candidate AP2/ERF TFs for further studies on their roles in salt and drought stress tolerance. PMID- 28642768 TI - Silicon Transporters and Effects of Silicon Amendments in Strawberry under High Tunnel and Field Conditions. AB - Together with longer production periods, the commercial transition to day-neutral strawberry (Fragaria * ananassa) varieties has favored the development of diseases such as powdery mildew (Podosphaera aphanis) that thrives in late summer early fall. In an attempt to find alternative solutions to fungicides currently employed to curb the disease, we wanted to investigate the potential of silicon (Si) amendments that have been associated with prophylactic properties against powdery mildews. To this end, our first objective was to determine if strawberry was a Si-competent species following the recent characterization of the properties of Si transporters that plants must carry to uptake silicic acid. Based on genomic data, we were able to conclude that strawberry contained both functional influx (Lsi1) and efflux (Lsi2) transporters for Si uptake. Subsequently commercial experiments under high tunnel and field conditions were conducted with different Si fertilization regimes: constant soluble Si feeding in high tunnel, and bi-weekly soluble Si feeding or three concentrations of calcium silicate fertilization in the field. Results from high tunnel experiments showed that strawberry could accumulate as much as 3% Si on a dry-weight basis, the highest concentration ever reported for this species. All six tested cultivars contained roughly the same concentration, thereby confirming the limited genetic variability, also observed in other species, associated with the trait. Silicon fertilization under high tunnel led to a significant reduction of powdery mildew severity in both years and on all cultivars, and a significant increase in yield of marketable fruits reaching as much as 300% with cv. Monterey. By contrast, Si fertilization under field conditions in soils deficient in plant available Si, either in soluble or solid form, did not result in significant accumulation of Si in plants, regardless of the cultivars, year or concentrations. Our results have thus provided both genotypic and phenotypic proof that strawberry can greatly benefit from Si fertilization, but have also highlighted the importance of validating the fertilization regime to ensure that Si is properly absorbed and/or available to the plant. PMID- 28642767 TI - Silicon-mediated Improvement in Plant Salinity Tolerance: The Role of Aquaporins. AB - Silicon (Si) is an abundant and differentially distributed element in soils that is believed to have important biological functions. However, the benefits of Si and its essentiality in plants are controversial due to differences among species in their ability to take up this element. Despite this, there is a consensus that the application of Si improves the water status of plants under abiotic stress conditions. Hence, plants treated with Si are able to maintain a high stomatal conductance and transpiration rate under salt stress, suggesting that a reduction in Na+ uptake occurs due to deposition of Si in the root. In addition, root hydraulic conductivity increases when Si is applied. As a result, a Si-mediated upregulation of aquaporin (PIP) gene expression is observed in relation to increased root hydraulic conductivity and water uptake. Aquaporins of the subclass nodulin 26-like intrinsic proteins are further involved in allowing Si entry into the cell. Therefore, on the basis of available published results and recent developments, we propose a model to explain how Si absorption alleviates stress in plants grown under saline conditions through the conjugated action of different aquaporins. PMID- 28642769 TI - Histone Acetylation Modifications Affect Tissue-Dependent Expression of Poplar Homologs of C4 Photosynthetic Enzyme Genes. AB - Histone modifications play important roles in regulating the expression of C4 photosynthetic genes. Given that all enzymes required for the C4 photosynthesis pathway are present in C3 plants, it has been hypothesized that this expression regulatory mechanism has been conserved. However, the relationship between histone modification and the expression of homologs of C4 photosynthetic enzyme genes has not been well determined in C3 plants. In the present study, we cloned nine hybrid poplar (Populus simonii * Populus nigra) homologs of maize (Zea mays) C4 photosynthetic enzyme genes, carbonic anhydrase (CA), pyruvate orthophosphate dikinase (PPDK), phosphoenolpyruvate carboxykinase (PCK), and phosphoenolpyruvate carboxylase (PEPC), and investigated the correlation between the expression levels of these genes and the levels of promoter histone acetylation modifications in four vegetative tissues. We found that poplar homologs of C4 homologous genes had tissue-dependent expression patterns that were mostly well correlated with the level of histone acetylation modification (H3K9ac and H4K5ac) determined by chromatin immunoprecipitation assays. Treatment with the histone deacetylase inhibitor trichostatin A further confirmed the role of histone acetylation in the regulation of the nine target genes. Collectively, these results suggest that both H3K9ac and H4K5ac positively regulate the tissue dependent expression pattern of the PsnCAs, PsnPPDKs, PsnPCKs, and PsnPEPCs genes and that this regulatory mechanism seems to be conserved among the C3 and C4 species. Our findings provide new insight that will aid efforts to modify the expression pattern of these homologs of C4 genes to engineer C4 plants from C3 plants. PMID- 28642770 TI - Interplay between Carotenoids, Abscisic Acid and Jasmonate Guides the Compatible Rice-Meloidogyne graminicola Interaction. AB - In this study, we have characterized the role of carotenoids and chlorophyll in the compatible interaction between the sedentary root knot nematode (RKN) Meloidogyne graminicola and the monocot model plant rice (Oryza sativa). Previous transcriptome data showed a differential expression of carotenoid and chlorophyll biosynthesis genes in nematode-induced giant cells and gall tissue. Metabolite measurement showed that galls indeed accumulate chlorophyll a, b and carotenoids, as well as the hormone abscisic acid (ABA). When ABA was externally applied on rice plants, or when ABA-biosynthesis was inhibited, a significant increase in gall formation and nematode development was found, showing the complex role of ABA in this interaction. ABA application suppressed jasmonic acid (JA) levels in the plants, while ABA-biosynthesis inhibition lead to increased JA levels confirming an antagonism between ABA and JA in rice roots. In addition, combined applications of ABA and JA showed that the ABA-effect can overcome JA-induced defense. Based on these observations, we hypothesized that the accumulation of chlorophyll and carotenoid precursors would be beneficial to nematode infection. Indeed, when chemically blocking the carotenoid biosynthesis pathway at different steps, which leads to differential accumulation of carotenoids and chlorophyll in the plants, a positive and clear link between accumulation of carotenoids and chlorophyll and rice susceptibility to RKN was detected. PMID- 28642771 TI - Transcriptomic Analysis of Avocado Hass (Persea americana Mill) in the Interaction System Fruit-Chitosan-Colletotrichum. AB - Avocado (Persea americana) is one of the most important crops in Mexico as it is the main producer, consumer, and exporter of avocado fruit in the world. However, successful avocado commercialization is often reduced by large postharvest losses due to Colletotrichum sp., the causal agent of anthracnose. Chitosan is known to have a direct antifungal effect and acts also as an elicitor capable of stimulating a defense response in plants. However, there is little information regarding the genes that are either activated or repressed in fruits treated with chitosan. The aim of this study was to identify by RNA-seq the genes differentially regulated by the action of low molecular weight chitosan in the avocado-chitosan-Colletotrichum interaction system. The samples for RNA-seq were obtained from fruits treated with chitosan, fruits inoculated with Colletotrichum and fruits both treated with chitosan and inoculated with the fungus. Non-treated and non-inoculated fruits were also analyzed. Expression profiles showed that in short times, the fruit-chitosan system presented a greater number of differentially expressed genes, compared to the fruit-pathogen system. Gene Ontology analysis of differentially expressed genes showed a large number of metabolic processes regulated by chitosan, including those preventing the spread of Colletotrichum. It was also found that there is a high correlation between the expression of genes in silico and qPCR of several genes involved in different metabolic pathways. PMID- 28642772 TI - Assessment of Five Chilling Tolerance Traits and GWAS Mapping in Rice Using the USDA Mini-Core Collection. AB - Rice (Oryza sativa L.) is often exposed to cool temperatures during spring planting in temperate climates. A better understanding of genetic pathways regulating chilling tolerance will enable breeders to develop varieties with improved tolerance during germination and young seedling stages. To dissect chilling tolerance, five assays were developed; one assay for the germination stage, one assay for the germination and seedling stage, and three for the seedling stage. Based on these assays, five chilling tolerance indices were calculated and assessed using 202 O. sativa accessions from the Rice Mini-Core (RMC) collection. Significant differences between RMC accessions made the five indices suitable for genome-wide association study (GWAS) based quantitative trait loci (QTL) mapping. For young seedling stage indices, japonica and indica subspecies clustered into chilling tolerant and chilling sensitive accessions, respectively, while both subspecies had similar low temperature germinability distributions. Indica subspecies were shown to have chilling acclimation potential. GWAS mapping uncovered 48 QTL at 39 chromosome regions distributed across all 12 rice chromosomes. Interestingly, there was no overlap between the germination and seedling stage QTL. Also, 18 QTL and 32 QTL were in regions discovered in previously reported bi-parental and GWAS based QTL mapping studies, respectively. Two novel low temperature seedling survivability (LTSS)-QTL, qLTSS3 4 and qLTSS4-1, were not in a previously reported QTL region. QTL with strong effect alleles identified in this study will be useful for marker assisted breeding efforts to improve chilling tolerance in rice cultivars and enhance gene discovery for chilling tolerance. PMID- 28642773 TI - Infestation of Broad Bean (Vicia faba) by the Green Stink Bug (Nezara viridula) Decreases Shoot Abscisic Acid Contents under Well-Watered and Drought Conditions. AB - The response of broad bean (Vicia faba) plants to water stress alone and in combination with green stink bug (Nezara viridula) infestation was investigated through measurement of: (1) leaf gas exchange; (2) plant hormone titres of abscisic acid (ABA) and its metabolites, and of salicylic acid (SA); and (3) hydrogen peroxide (H2O2) content. Furthermore, we evaluated the effects of experimentally water-stressed broad-bean plants on N. viridula performance in terms of adult host-plant preference, and nymph growth and survival. Water stress significantly reduced both photosynthesis (A) and stomatal conductance (gs ), while infestation by the green stink bug had no effects on photosynthesis but significantly altered partitioning of ABA between roots and shoots. Leaf ABA was decreased and root ABA increased as a result of herbivore attack, under both well watered and water-deprived conditions. Water stress significantly impacted on SA content in leaves, but not on H2O2. However, infestation of N. viridula greatly increased both SA and H2O2 contents in leaves and roots, which suggests that endogenous SA and H2O2 have roles in plant responses to herbivore infestation. No significant differences were seen for green stink bug choice between well-watered and water-stressed plants. However, for green stink bug nymphs, plant water stress promoted significantly lower weight increases and significantly higher mortality, which indicates that highly water-stressed host plants are less suitable for N. viridula infestation. In conclusion two important findings emerged: (i) association of water stress with herbivore infestation largely changes plant response in terms of phytohormone contents; but (ii) water stress does not affect the preference of the infesting insects, although their performance was impaired. PMID- 28642774 TI - Increasing Provasculature Complexity in the Arabidopsis Embryo May Increase Total Iron Content in Seeds: A Hypothesis. AB - Anemia due to iron deficiency is a worldwide issue, affecting mainly children and women. Seed iron is a major source of this micronutrient for feeding, however, in most crops these levels are too low to meet daily needs. Thus, increasing iron allocation and its storage in seeds can represent an important step to enhance iron provision for humans and animals. Our knowledge on seed iron homeostasis is mainly based on studies performed in the model plant Arabidopsis thaliana, where iron accumulates in endodermis cells surrounding the embryo provasculature. It has been reported that cotyledon provasculature pattern complexity can be modified, thus we hypothesize that changes in the complexity of embryo vein patterns may affect total iron content in Arabidopsis seeds. This approach could be used as basis to develop strategies aimed to biofortify seeds. PMID- 28642775 TI - Ectopic Expression of the Grape Hyacinth (Muscari armeniacum) R2R3-MYB Transcription Factor Gene, MaAN2, Induces Anthocyanin Accumulation in Tobacco. AB - Anthocyanins are responsible for the different colors of ornamental plants. Grape hyacinth (Muscari armeniacum), a monocot plant with bulbous flowers, is popular for its fascinating blue color. In the present study, we functionally characterized an R2R3-MYB transcription factor gene MaAN2 from M. armeniacum. Our results indicated that MaAN2 participates in controlling anthocyanin biosynthesis. Sequence alignment and phylogenetic analysis suggested that MaAN2 belonged to the R2R3-MYB family AN2 subgroup. The anthocyanin accumulation of grape hyacinth flowers was positively correlated with the expression of MaAN2. And the transcriptional expression of MaAN2 was also consistent with that of M. armeniacum dihydroflavonol 4-reductase (MaDFR) and M. armeniacum anthocyanidin synthase (MaANS) in flowers. A dual luciferase transient expression assay indicated that when MaAN2 was co-inflitrated with Arabidopsis thaliana TRANSPARENT TESTA8 (AtTT8), it strongly activated the promoters of MaDFR and MaANS, but not the promoters of M. armeniacum chalcone synthase (MaCHS), M. armeniacum chalcone isomerase (MaCHI), and M. armeniacum flavanone 3-hydroxylase (MaF3H). Bimolecular fluorescence complementation assay confirmed that MaAN2 interacted with AtTT8 in vivo. The ectopic expression of MaAN2 in Nicotiana tabacum resulted in obvious red coloration of the leaves and much redder flowers. Almost all anthocyanin biosynthetic genes were remarkably upregulated in the leaves and flowers of the transgenic tobacco, and NtAn1a and NtAn1b (two basic helix-loop-helix anthocyanin regulatory genes) were highly expressed in the transformed leaves, compared to the empty vector transformants. Collectively, our results suggest that MaAN2 plays a role in anthocyanin biosynthesis. PMID- 28642776 TI - Regulation Involved in Colonization of Intercellular Spaces of Host Plants in Ralstonia solanacearum. AB - A soil-borne bacterium Ralstonia solanacearum invading plant roots first colonizes the intercellular spaces of the root, and eventually enters xylem vessels, where it replicates at high levels leading to wilting symptoms. After invasion into intercellular spaces, R. solanacearum strain OE1-1 attaches to host cells and expression of the hrp genes encoding components of the type III secretion system (T3SS). OE1-1 then constructs T3SS and secrets effectors into host cells, inducing expression of the host gene encoding phosphatidic acid phosphatase. This leads to suppressing plant innate immunity. Then, OE1-1 grows on host cells, inducing quorum sensing (QS). The QS contributes to regulation of OE1-1 colonization of intercellular spaces including mushroom-type biofilm formation on host cells, leading to its virulence. R. solanacearum strains AW1 and K60 produce methyl 3-hydroxypalmitate (3-OH PAME) as a QS signal. The methyltransferase PhcB synthesizes 3-OH PAME. When 3-OH PAME reaches a threshold level, it increases the ability of the histidine kinase PhcS to phosphorylate the response regulator PhcR. This results in elevated levels of functional PhcA, the global virulence regulator. On the other hand, strains OE1-1 and GMI1000 produce methyl 3-hydroxymyristate (3-OH MAME) as a QS signal. Among R. solanacearum strains, the deduced PhcB and PhcS amino acid sequences are related to the production of QS signals. R. solanacearum produces aryl-furanone secondary metabolites, ralfuranones, which are extracellularly secreted and required for its virulence, dependent on the QS. Interestingly, ralfuranones affect the QS feedback loop. Taken together, integrated signaling via ralfuranones influences the QS, contributing to pathogen virulence. PMID- 28642778 TI - Characterization of Salt-Induced Epigenetic Segregation by Genome-Wide Loss of Heterozygosity and its Association with Salt Tolerance in Rice (Oryza sativa L.). AB - In a breeding effort to develop salt tolerant (ST) rice varieties by designed QTL pyramiding, large numbers of progenies derived from four crosses between salt- or drought- tolerant BC2F5 IR64 introgression lines, were subjected to severe salt stress, resulting in 422 ST plants. The progeny testing of the selected F3 lines under more severe salt stress resulted in identification of 16 promising homozygous lines with high levels of ST. Genetic characterization of the 422 ST F3 progeny and 318 random F2 plants from the same four crosses using 105 segregating SSR markers lead to three interesting discoveries: (1) salt stress can induce genome-wide epigenetic segregation (ES) characterized by complete loss of heterozygosity (LOH) and nearly complete loss of an allele (LOA) in the F3 progenies of four rice populations in a single generation; (2) ~25% of the stress induced ES loci were transgenerational and inherited from their salt- and drought selected parents; and (3) the salt-induced LOH and LOA loci (regions) appeared to contain genes/alleles associated with ST and/or drought tolerance. 32 genomic regions that showed one or more types of salt-induced ES in the random and salt selected progenies from these crosses. The same or different types of ES were detected with two large genomic regions on chromosomes 1 and 6 where more and the strongest ES were found across different populations. 14 genomic regions were found where the salt-induced ES regions were overlapping with QTL affecting ST related traits. The discovery of the three types of salt-induced ES showed several interesting characteristics and had important implications in evolution and future breeding for developing stress-resilient rice and crops. PMID- 28642777 TI - Transcriptome Analysis of Genes Associated with the Artemisinin Biosynthesis by Jasmonic Acid Treatment under the Light in Artemisia annua. AB - Artemisinin is a sesquiterpene lactone endoperoxide extracted from a traditional Chinese medicinal plant Artemisia annua. Artemisinin-based combination therapies (ACTs) are recommended as the best treatment of malaria by the World Health Organization (WHO). Both the phytohormone jasmonic acid (JA) and light promote artemisinin biosynthesis in A. annua. Interestingly, we found that the increase of artemisinin biosynthesis by JA was dependent on light. However, the relationship between the two signal pathways mediated by JA and light remains unclear. Here, we collected the A. annua seedlings of 24 h continuous light (Light), 24 h dark treatment (Dark), 4 h MeJA treatment under the continuous light conditions (Light-MeJA-4h) and 4 h MeJA treatment under the dark conditions (Dark-MeJA-4h) and performed the transcriptome sequencing using Illumina HiSeq 4000 System. A total of 266.7 million clean data were produced and assembled into 185,653 unigenes, with an average length of 537 bp. Among them, 59,490 unigenes were annotated and classified based on the public information. Differential expression analyses were performed between Light and Dark, Light and Light-MeJA 4h, Dark and Dark-MeJA-4h, Light-MeJA-4h, and Dark-MeJA-4h, respectively. Furthermore, transcription factor (TF) analysis revealed that 1588 TFs were identified and divided into 55 TF families, with 284 TFs down-regulated in the Dark relative to Light and 96 TFs up-regulated in the Light-MeJA-4h relative to Light. 8 TFs were selected as candidates for regulating the artemisinin biosynthesis and one of them was validated to be involved in artemisinin transcriptional regulation by Dual-Luciferase (Dual-LUC) assay. The transcriptome data shown in our study offered a comprehensive transcriptional expression pattern influenced by the MeJA and light in A. annua seedling, which will serve as a valuable resource for further studies on transcriptional regulation mechanisms underlying artemisinin biosynthesis. PMID- 28642779 TI - Mitigating Groundwater Depletion in North China Plain with Cropping System that Alternate Deep and Shallow Rooted Crops. AB - In the North China Plain, groundwater tables have been dropping at unsustainable rates of 1 m per year due to irrigation of a double cropping system of winter wheat and summer maize. To reverse the trend, we examined whether alternative crop rotations could save water. Moisture contents were measured weekly at 20 cm intervals in the top 180 cm of soil as part of a 12-year field experiment with four crop rotations: sweet potato-> cotton-> sweet potato-> winter wheat-summer maize (SpCSpWS, 4-year cycle); peanuts -> winter wheat-summer maize (PWS, 2-year cycle); ryegrass-cotton-> peanuts-> winter wheat-summer maize (RCPWS, 3-year cycle); and winter wheat-summer maize (WS, each year). We found that, compared to WS, the SpCSpWS annual evapotranspiration was 28% lower, PWS was 19% lower and RCPWS was 14% lower. The yield per unit of water evaporated improved for wheat within any alternative rotation compared to WS, increasing up to 19%. Average soil moisture contents at the sowing date of wheat in the SpCSpWS, PWS, and RCPWS rotations were 7, 4, and 10% higher than WS, respectively. The advantage of alternative rotations was that a deep rooted crop of winter wheat reaching down to 180 cm followed shallow rooted crops (sweet potato and peanut drawing soil moisture from 0 to 120 cm). They benefited from the sequencing and vertical complementarity of soil moisture extraction. Thus, replacing the traditional crop rotation with cropping system that involves rotating with annual shallow rooted crops is promising for reducing groundwater depletion in the North China Plain. PMID- 28642780 TI - RRP42, a Subunit of Exosome, Plays an Important Role in Female Gametophytes Development and Mesophyll Cell Morphogenesis in Arabidopsis. AB - The exosome complex plays a central and essential role in RNA metabolism. However, current research on functions of exosome subunit in plants is limited. Here, we used an egg cell-specific promoter-controlled CRISPR/Cas9 system to knock out RRP42 which encodes a core subunit of the Arabidopsis exosome and presented evidence that RRP42 is essential for the development of female gametophytes. Next, we designed three different amiRNAs targeting RRP42. The rrp42 knock-down mutants mainly displayed variegated and serrated leaves, especially in cauline leaves. The internal anatomy of cauline leaves displayed irregularly shaped palisade cells and a reduced density of mesophyll cells. Interestingly, we detected highly accumulated mRNAs that encode xyloglucan endotransglucosylase/hydrolases (XTHs) and expansins (EXPAs) during later growth stages in rrp42 knock-down mutants. The mRNA decay kinetics analysis for XTH19, EXPA10, and EXPA11 revealed that RRP42 had a role in the decay of these mRNAs in the cytoplasm. RRP42 is localized to both the nucleus and cytoplasm, and RRP42 is preferentially expressed in cauline leaves during later growth stages. Altogether, our results demonstrate that RRP42 is essential for the development of female gametophytes and plays an important role in mesophyll cell morphogenesis. PMID- 28642781 TI - Effects of Nitrogen Supply on Water Stress and Recovery Mechanisms in Kentucky Bluegrass Plants. AB - Non-irrigated crops in temperate and irrigated crops in arid regions are exposed to an incessant series of drought stress and re-watering. Hence, quick and efficient recuperation from drought stress may be amongst the key determinants of plant drought adjustment. Efficient nitrogen (N) nutrition has the capability to assuage water stress in crops by sustaining metabolic activities even at reduced tissue water potential. This study was designed to understand the potential of proper nutrition management by studying the morphological and physiological attributes, and assimilation of nitrogen in Kentucky bluegrass under drought stress. In present study, one heterogeneous habitat and four treatments homogenous habitats each with four replications were examined during field trial. Drought stress resulted in a significant reduction in the nitrogen content of both mother and first ramets, maximum radius, above and below ground mass, number of ramets per plot, leaf water contents and water potential and increased the carbon content and the C:N ratio in both homogenous and heterogeneous plots compared to well-watered and nutritional conditions. Observation using electron microscopy showed that drought stress shrunk the vessel diameter, circumference and xylem area, but increased the sieve diameter, and phloem area in the leaf crosscutting structure of Kentucky bluegrass, first, second, and third ramet leaf. Thus, it can be concluded that water stress markedly reduced all the important traits of Kentucky bluegrass, however, proper nutritional management treatment resulted in the best compensatory performance under drought assuaging its adversity up to some extent and may be considered in formulating good feasible and cost-effective practices for the environmental circumstances related to those of this study. PMID- 28642782 TI - Genes of ACYL CARRIER PROTEIN Family Show Different Expression Profiles and Overexpression of ACYL CARRIER PROTEIN 5 Modulates Fatty Acid Composition and Enhances Salt Stress Tolerance in Arabidopsis. AB - Acyl carrier proteins (ACPs) are a group of small acidic proteins functioning as important cofactors in the de novo synthesis of fatty acids. In Arabidopsis, ACPs are encoded by a small gene family comprising five plastid members, AtACP1 to AtACP5, and three mitochondrial members. The biological functions and the transcriptional responses to abiotic stresses of most AtACPs have yet to be elucidated. The present study extends previous findings and provides new knowledge on the function of ACPs by examining the responses of AtACP-encoding genes to several abiotic stresses and, in particular, the role of AtACP5 in the adaptation to salt stress. Phylogenetic analysis showed that AtACP1, AtACP2, AtACP3, and AtACP5 can be classified into one group and separated from a group comprising AtACP4 and ACP homologs from related species. Quantitative RT-PCR analysis revealed that the expression of AtACP1, AtACP2, and AtACP3 was induced by drought. Both iron deficiency and nitrogen starvation resulted in down regulation of AtACP4. The most pronounced response was observed for AtACP5, the expression of which was dramatically decreased by salt stress. Knock-out of AtACP5 showed increased sensitivity to NaCl stress, whereas transgenic lines overexpressing AtACP5 displayed increased salt tolerance relative to the wild type. Overexpression of AtACP5 further led to an altered composition of fatty acids, mainly a decrease of oleic acid (C18:1) and an increase of palmitic acid (C16:0), and to a lower Na+/K+ ratio when compared to the salt stressed wild type. The comprehensive transcriptional information on the small plastid AtACP gene family in response to various abiotic stresses and the further investigation of the AtACP5 indicate that AtACP5 might be critical for salt tolerance through alterations of the composition of fatty acids and, subsequently, the Na+/K+ ratio. PMID- 28642783 TI - IbOr Regulates Photosynthesis under Heat Stress by Stabilizing IbPsbP in Sweetpotato. AB - The Orange (Or) protein regulates carotenoid biosynthesis and environmental stress in plants. Previously, we reported that overexpression of the sweetpotato [Ipomoea batatas (L.) Lam] Or gene (IbOr) in transgenic Arabidopsis (referred to as IbOr-OX/At) increased the efficiency of photosystem II (PSII) and chlorophyll content after heat shock. However, little is known about the role of IbOr in PSII mediated protection against abiotic stress. In this study, comparative proteomics revealed that expression of PsbP (an extrinsic subunit of PSII) is up-regulated in heat-treated IbOr-OX/At plants. We then identified and functionally characterized the PsbP-like gene (IbPsbP) from sweetpotato. IbPsbP is predominantly localized in chloroplast, and its transcripts are tissue specifically expressed and up-regulated in response to abiotic stress. In addition, IbOr interacts with IbPsbP and protects it from heat-induced denaturation, consistent with the observation that transgenic sweetpotato overexpressing IbOr maintained higher PSII efficiency and chlorophyll content upon exposure to heat stress. These results indicate that IbOr can protect plants from environmental stress not only by controlling carotenoid biosynthesis but also by directly stabilizing PSII. PMID- 28642784 TI - Novel Miscanthus Germplasm-Based Value Chains: A Life Cycle Assessment. AB - In recent years, considerable progress has been made in miscanthus research: improvement of management practices, breeding of new genotypes, especially for marginal conditions, and development of novel utilization options. The purpose of the current study was a holistic analysis of the environmental performance of such novel miscanthus-based value chains. In addition, the relevance of the analyzed environmental impact categories was assessed. A Life Cycle Assessment was conducted to analyse the environmental performance of the miscanthus-based value chains in 18 impact categories. In order to include the substitution of a reference product, a system expansion approach was used. In addition, a normalization step was applied. This allowed the relevance of these impact categories to be evaluated for each utilization pathway. The miscanthus was cultivated on six sites in Europe (Aberystwyth, Adana, Moscow, Potash, Stuttgart and Wageningen) and the biomass was utilized in the following six pathways: (1) small-scale combustion (heat)-chips; (2) small-scale combustion (heat)-pellets; (3) large-scale combustion (CHP)-biomass baled for transport and storage; (4) large-scale combustion (CHP)-pellets; (5) medium-scale biogas plant-ensiled miscanthus biomass; and (6) large-scale production of insulation material. Thus, in total, the environmental performance of 36 site * pathway combinations was assessed. The comparatively high normalized results of human toxicity, marine, and freshwater ecotoxicity, and freshwater eutrophication indicate the relevance of these impact categories in the assessment of miscanthus-based value chains. Differences between the six sites can almost entirely be attributed to variations in biomass yield. However, the environmental performance of the utilization pathways analyzed varied widely. The largest differences were shown for freshwater and marine ecotoxicity, and freshwater eutrophication. The production of insulation material had the lowest impact on the environment, with net benefits in all impact categories expect three (marine eutrophication, human toxicity, agricultural land occupation). This performance can be explained by the multiple use of the biomass, first as material and subsequently as an energy carrier, and by the substitution of an emission-intensive reference product. The results of this study emphasize the importance of assessing all environmental impacts when selecting appropriate utilization pathways. PMID- 28642785 TI - Potassium Starvation Limits Soybean Growth More than the Photosynthetic Processes across CO2 Levels. AB - Elevated carbon dioxide (eCO2) often enhances plant photosynthesis, growth, and productivity. However, under nutrient-limited conditions the beneficial effects of high CO2 are often diminished. To evaluate the combined effects of potassium (K) deficiency and eCO2 on soybean photosynthesis, growth, biomass partitioning, and yields, plants were grown under controlled environment conditions with an adequate (control, 5.0 mM) and two deficient (0.50 and 0.02 mM) levels of K under ambient CO2 (aCO2; 400 MUmol mol-1) and eCO2 (800 MUmol mol-1). Results showed that K deficiency limited soybean growth traits more than photosynthetic processes. An ~54% reduction in leaf K concentration under 0.5 mM K vs. the control caused about 45% less leaf area, biomass, and yield without decreasing photosynthetic rate (Pnet). In fact, the steady photochemical quenching, efficiency, and quantum yield of photosystem II, chlorophyll concentration (TChl), and stomatal conductance under 0.5 mM K supported the stable Pnet. Biomass decline was primarily attributed to the reduced plant size and leaf area, and decreased pod numbers and seed yield in K-deficient plants. Under severe K deficiency (0.02 mM K), photosynthetic processes declined concomitantly with growth and productivity. Increased specific leaf weight, biomass partitioning to the leaves, decreased photochemical quenching and TChl, and smaller plant size to reduce the nutrient demands appeared to be the means by which plants adjusted to the severe K starvation. Increased K utilization efficiency indicated the ability of K-deficient plants to better utilize the tissue-available K for biomass accumulation, except under severe K starvation. The enhancement of soybean growth by eCO2 was dependent on the levels of K, leading to a K * CO2 interaction for traits such as leaf area, biomass, and yield. A lack of eCO2-mediated growth and photosynthesis stimulation under severe K deficiency underscored the importance of optimum K fertilization for maximum crop productivity under eCO2. Thus, eCO2 compensated, at least partially, for the reduced soybean growth and seed yield under 0.5 mM K supply, but severe K deficiency completely suppressed the eCO2 enhanced seed yield. PMID- 28642787 TI - Mutational Signatures Are Critical for Proper Estimation of Purifying Selection Pressures in Cancer Somatic Mutation Data When Using the dN/dS Metric. AB - Large cancer genome sequencing initiatives have led to the identification of cancer driver genes based on signals of positive selection in somatic mutation data. Additionally, the identification of purifying (negative) selection has the potential to identify essential genes that may be of therapeutic interest. The most widely used way of quantifying selection pressures in protein-coding genes is the dN/dS metric, which compares non-synonymous to synonymous substitution rates. In this study, we examine whether and how this metric is influenced by the mutational processes that have been active during tumor evolution. We use exome sequencing data from six different cancer types from The Cancer Genome Atlas (TCGA) and demonstrate that dN/dS in its basic form, where uniform base substitution probabilities are assumed, is in fact strongly biased by these mutational processes. This is particularly true in malignant melanoma, where the mutational signature is characterized by a high amount of UV-induced cytosine to thymine mutations at dipyrimidine dinucleotides. This increases the likelihood of random synonymous mutations occurring in hydrophobic amino acid codons, leading to reduced dN/dS ratios in genes encoding membrane proteins and falsely suggesting purifying selection in these genes. When this effect is corrected for by taking mutational signature-derived substitution probabilities into account, purifying selection was found to be limited and similar in all cancer types studied. Our results demonstrate that it is crucial to take mutational signatures into account when applying the dN/dS metric to cancer somatic mutation data. PMID- 28642788 TI - Comparison between Intestinal Behcet's Disease and Crohn's Disease in Characteristics of Symptom, Endoscopy, and Radiology. AB - AIM: To evaluate different parameters in differentiating intestinal BD from CD. METHODS: The medical records of inpatients with intestinal BD and CD were retrospectively reviewed. The univariate value of different parameters was analyzed, respectively. A differentiation model was established by pooling all valuable parameters together. Diagnostic efficacy was evaluated, and a receiver operating curve (ROC) was plotted. RESULTS: Forty-two BD patients and ninety seven CD patients were reviewed. Demographic and clinical parameters that showed significant value included diarrhea, fever, perianal disease, oral ulcers, genital ulcers, skin lesions, and musculoskeletal lesions. Endoscopic parameters reaching clinical significance included multiple-site lesions, lesions confined to the ileocecal region, longitudinal ulcers, round or oval ulcers, punch-out ulcers, ulcers with discrete margin, ulcer size > 2 cm, stricture of bowel, and anorectal involvement. Radiologic parameters aiding the differentiation included involvement segments <= 3, asymmetrical pattern of involvement, intraluminal pseudopolyp formation, target sign, stricture with proximal dilation, comb sign, and fistula. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the differentiation model were 90.5%, 93.8%, 92.8%, 86.4%, and 95.8%, respectively. The cutoff value was 0.5 while the area under the ROC curve was 0.981. CONCLUSION: The differentiation model that integrated the various parameters together may yield a high diagnostic efficacy in the differential diagnosis between intestinal BD and CD. PMID- 28642786 TI - Signatures of Selection for Environmental Adaptation and Zebu * Taurine Hybrid Fitness in East African Shorthorn Zebu. AB - The East African Shorthorn Zebu (EASZ) cattle are ancient hybrid between Asian zebu * African taurine cattle preferred by local farmers due to their adaptability to the African environment. The genetic controls of these adaptabilities are not clearly understood yet. Here, we genotyped 92 EASZ samples from Kenya (KEASZ) with more than 770,000 SNPs and sequenced the genome of a pool of 10 KEASZ. We observe an even admixed autosomal zebu * taurine genomic structure in the population. A total of 101 and 165 candidate regions of positive selection, based on genome-wide SNP analyses (meta-SS, Rsb, iHS, and DeltaAF) and pooled heterozygosity (Hp) full genome sequence analysis, are identified, in which 35 regions are shared between them. A total of 142 functional variants, one novel, have been detected within these regions, in which 30 and 26 were classified as of zebu and African taurine origins, respectively. High density genome-wide SNP analysis of zebu * taurine admixed cattle populations from Uganda and Nigeria show that 25 of these regions are shared between KEASZ and Uganda cattle, and seven regions are shared across the KEASZ, Uganda, and Nigeria cattle. The identification of common candidate regions allows us to fine map 18 regions. These regions intersect with genes and QTL associated with reproduction and environmental stress (e.g., immunity and heat stress) suggesting that the genome of the zebu * taurine admixed cattle has been uniquely selected to maximize hybrid fitness both in terms of reproduction and survivability. PMID- 28642789 TI - Androgen Receptor Localizes to Plasma Membrane by Binding to Caveolin-1 in Mouse Sertoli Cells. AB - The nonclassical androgen signaling pathway translates signals into alterations in cellular function within minutes, and this action is proposed to be mediated by an androgen receptor (AR) localized to the plasma membrane. This study was designed to determine the mechanism underlying the membrane association of androgen receptor in TM4 cells, a mouse Sertoli cell line. Western blot analysis indicated testosterone-induced AR translocation to the cell membrane. Data from coimmunoprecipitation indicated that AR is associated with caveolin-1, and testosterone enhanced this association. Knockdown of caveolin-1 by shRNA decreased the amount of AR localized to membrane fraction and prevented AR membrane trafficking after being exposed to testosterone at physiological concentration. The palmitoylation inhibitor 2-bromopalmitate decreased AR membrane localization in basal condition and completely blocked testosterone induced AR translocation to membrane fraction. These data suggested that AR localized to membrane fraction by binding with caveolin-1 through palmitoylation of the cysteine residue. This study provided a new evidence for AR membrane localization and its application for clarifying the nonclassical signaling pathway of androgens. PMID- 28642790 TI - Therapeutic Outcomes of Patients with Multifocal Papillary Thyroid Microcarcinomas and Larger Tumors. AB - A retrospective review of 626 patients with multifocal papillary thyroid carcinoma (PTC) including 147 patients (23.5%) with multifocal papillary thyroid microcarcinoma (PTMC) from a total of 2,536 patients with PTC who visited the Chang Gung Medical Center in Linkou, Taiwan, was performed. A comparison of the clinical features between 626 multifocal and 1,910 solitary PTC cases showed that patients in the multifocal PTC group were older and had a smaller mean tumor size, a more advanced tumor-node-metastasis (TNM) stage, and a higher percentage of nonremission status compared to patients in the solitary PTC group. Of the 626 patients with multifocal PTC, the group with larger tumors showed a more advanced TNM stage, a higher percentage of lymph node metastasis and soft tissue invasion, and a higher nonremission rate compared to the multifocal PTMC group. Of the 626 patients with multifocal PTC, 25 patients (4%) died during a mean follow-up period of 7.1 +/- 5.3 years. Kaplan-Meier survival curves showed a significantly lower survival rate associated with multifocal PTMC compared to that with solitary PTMC. PMID- 28642791 TI - Efficacy and Safety of Ultrasound-Guided Percutaneous Polidocanol Sclerotherapy in Benign Cystic Thyroid Nodules: Preliminary Results. AB - OBJECTIVE: To evaluate the efficacy and safety of percutaneous polidocanol injection (PPI) in treating cystic thyroid nodules. MATERIALS AND METHODS: A total of 158 cystic or predominantly cystic thyroid nodules (>80% cystic component) in 143 patients were evaluated. 114 patients with compressive symptoms or aesthetic complaints were offered PPI. 44 individuals without compressive symptoms and aesthetic complaints who were only followed up clinically were used as the control group. The efficacy and safety of PPI were evaluated for 1 month, 3 months, 6 months, 9 months, and 12 months of follow-up. RESULTS: In the PPI group, the mean baseline volume of 15.6 +/- 18.9 cm3 reduced at the 1-month follow-up to 5.1 +/- 5.6 cm3 (p < 0.001) and 0.6 +/- 0.9 (p < 0.001), and nodules shrunk according to the time after PPI (p < 0.001). A complete response (if >=70% decrease) to PPI at the 12-month follow-up occurred in 100% of the cystic or predominant cystic nodules. None of the nodules recurred at the 12-month follow up after PPI. The side effects were mild. Twenty patients (17.5%) developed mild localized pain, and fourteen cases (12.3%) experienced mild or moderate fever after PPI. CONCLUSIONS: PPI is a safe and effective alternative to treat benign cystic or predominant cystic thyroid nodules. PMID- 28642793 TI - Repair of Thoracoabdominal Aortic Aneurysm with Thrombosed Infrarenal Component: A Modified Hybrid Technique without Aortic Cross Clamping. AB - The authors report the successful repair of a Crawford type III thoracoabdominal aortic aneurysm (TAAA) with a thrombosed infrarenal component using a modified hybrid technique without aortic clamping in a high-risk patient. A 64-year-old male with a history of hypertension, diabetes, and severe chronic obstructive pulmonary disease presented with acute on chronic backache and bilateral short distance claudication. A computerized tomography scan demonstrated a large, nonleaking Crawford type III TAAA with thrombosed infrarenal component of the aneurysm. In addition, both common iliac arteries were occluded with the chronic thrombus. A single-stage, modified hybrid procedure involving an aortobifemoral bypass without aortic clamping, debranching of right renal, superior mesenteric, and celiac arteries as well as an endovascular repair of the thoracic aneurysm was performed. Unfortunately, despite a technically sound repair, the patient died postoperatively from a massive pulmonary embolism. TAAA with a thrombosed infrarenal aorta and bilateral common iliac arteries can be repaired using a single-stage modified hybrid procedure without aortic clamping in high-risk patients who cannot tolerate thoracotomy and aortic cross clamping. PMID- 28642792 TI - Infection Control Measures in Private Dental Clinics in Lebanon. AB - PURPOSE: Evaluate infection control knowledge, attitude, and practice in Lebanese private dental clinics. MATERIALS AND METHODS: A survey including 46 questions related to routine safety procedures was sent to 1150 Lebanese dentists between July 1st and 2nd, 2015. The study sample was selected from the database of registered dentists based on a proportional random sampling ensuring equitable representation of the 5 geographic regions of Lebanon. A subset of 29 questions was used to generate an overall score of compliance (excellent, good, fair, and poor). Comparisons according to gender, type, region, and years of practice were performed. RESULTS: 417 dentists returned the completed questionnaires. 96% expressed concern about infection transmission, 90.6% were vaccinated against Hepatitis B, and 61.8% asked routinely about patients medical history. Only 43% used protective eyewear. Although most dentists (65%) used autoclaves, dry heat was still used. Significant correlations were found between gender and use of personal protective equipment. Less compliance was shown by clinicians with fewer years of experience. In the overall compliance questionnaire, the mean percentage of correct answers was roughly 54% with <5% of the practitioners scoring "excellent." Conclusions. The study found inadequacy of compliance in private Lebanese dental clinics necessitating improved educational training and sustained monitoring by regulatory bodies. PMID- 28642794 TI - Adipose Tissue-Derived Mesenchymal Stem Cells Have a Heterogenic Cytokine Secretion Profile. AB - Mesenchymal stem cells derived from adipose tissue (ASC) have immune regulatory function, which makes them interesting candidates for cellular therapy. ASC cultures are however heterogeneous in phenotype. It is unclear whether all ASC contribute equally to immunomodulatory processes. ASC are also responsive to cytokine stimulation, which may affect the ratio between more and less potent ASC populations. In the present study, we determined IL-6 receptor (CD126 and CD130 subunits) and IFN-gamma receptor (CD119) expression on ASC by flow cytometry. The production of IL-6 and IFN-gamma was measured by ELISA and the frequency of IL-6 and IFN-gamma secreting cells by ELISPOT. The results showed that ASC did not express CD126, and only 10-20% of ASC expressed CD130 on their surface, whereas 18-31% of ASC expressed CD119. ASC produced high levels of IL-6 and 100% of ASC were capable of secreting IL-6. Stimulation by IFN-gamma or TGF-beta had no effect on IL-6 secretion by ASC. IFN-gamma was produced by only 1.4% of ASC, and TGF-beta significantly increased the frequency to 2.7%. These results demonstrate that ASC cultures are heterogeneous in their cytokine secretion and receptor expression profiles. This knowledge can be employed for selection of potent, cytokine-producing, or responsive ASC subsets for cellular immunotherapy. PMID- 28642795 TI - Why Do the Youths in Northeast India Use Tobacco? AB - This study is an assessment of the influence of parent's tobacco use on prospective tobacco use trajectories among young offspring. The study is based on unit level data from District Level Household and Facility Survey-4 (2012-2013) comprising 27,706 youths in 15-24 years' age group from northeastern states of India and used multilevel regression to identify the potential risk factors of tobacco consumption. The likelihood of using tobacco was found to be 3.4 and 1.14 times more, respectively, for the youths coresiding with mothers who use tobacco and fathers who use tobacco, in comparison to youths staying with parents not taking tobacco. The significant effect of peers on tobacco consumption among youths was also observed. School-going youths had significantly lower risk of tobacco use. The estimated likelihood of a young person from a household to use any tobacco, use smokeless tobacco, and smoke was found to be 28, 12, and 17 percent, respectively. There is an urgent need to extend National Tobacco Control Programme (NTCP) to the community level involving civil societies and young and adult generations for spreading awareness about the health hazards of tobacco use, providing support and facilitating quitting tobacco use. PMID- 28642796 TI - Riverbed Sediments as Reservoirs of Multiple Vibrio cholerae Virulence-Associated Genes: A Potential Trigger for Cholera Outbreaks in Developing Countries. AB - Africa remains the most cholera stricken continent in the world as many people lacking access to safe drinking water rely mostly on polluted rivers as their main water sources. However, studies in these countries investigating the presence of Vibrio cholerae in aquatic environments have paid little attention to bed sediments. Also, information on the presence of virulence-associated genes (VAGs) in environmental ctx-negative V. cholerae strains in this region is lacking. Thus, we investigated the presence of V. cholerae VAGs in water and riverbed sediment of the Apies River, South Africa. Altogether, 120 samples (60 water and 60 sediment samples) collected from ten sites on the river (January and February 2014) were analysed using PCR. Of the 120 samples, 37 sediment and 31 water samples were positive for at least one of the genes investigated. The haemolysin gene (hlyA) was the most isolated gene. The cholera toxin (ctxAB) and non-O1 heat-stable (stn/sto) genes were not detected. Genes were frequently detected at sites influenced by human activities. Thus, identification of V. cholerae VAGs in sediments suggests the possible presence of V. cholerae and identifies sediments of the Apies River as a reservoir for potentially pathogenic V. cholerae with possible public health implications. PMID- 28642797 TI - Water and Sanitation Hygiene Practices for Under-Five Children among Households of Sugali Tribe of Chittoor District, Andhra Pradesh, India. AB - BACKGROUND: Increased mortality is associated with poor household water, sanitation, and hygiene (WaSH) practices. The objective was to study the WaSH practices for under-five children among households of Sugali Tribe, Chittoor district, Andhra Pradesh, India. METHODS: A community-based cross-sectional study was conducted in four mandals in 2012. A total of 500 households with under-five children were identified. Data was collected from mothers/caregivers. A summary WaSH score was generated from four specific indices, water, sanitation, hygiene, and hand washing practices, and determinants were identified. RESULTS: Of the total households, 69% reported doing nothing at home to make the water safe for drinking. Over 90% of the households reported storing water in a utensil covered with a lid and retrieving water by dipping glass in the vessels. Open defecation was a commonly reported practice (84.8%). About three-fifths of the study's households reported using water and soap for cleaning dirty hands and one-third (37.4%) reported using water and soap after defecation. The median WaSH score was 15. In the hierarchical stepwise multiple linear regression, only socioeconomic variables were significantly associated with WaSH score. CONCLUSION: WaSH related practices were generally poor in people of the Sugali Tribe in Andhra Pradesh, India. PMID- 28642798 TI - Clinical Efficacy and Safety of Total Glucosides of Paeony for Primary Sjogren's Syndrome: A Systematic Review. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of total glucosides of paeony (TGP) for primary Sjogren's syndrome (pSS). METHODS: Eight electronic databases were searched from their inception to July 2016. Clinical randomized controlled trials (RCTs) were included. The study quality was evaluated according to the standard suggested in the Cochrane Handbook. RevMan 5.1 was used for statistical analysis. RESULTS: Seven RCTs involving 443 patients were included. The results showed that TGP combined with an immunosuppressant (IS) showed greater efficacy for improving the saliva flow test of pSS compared to immunosuppressant alone (WMD -6.88, 95% CI -9.02 to -4.74, and P < 0.00001). And the same trend favouring TGP-IS dual combination was found in Schirmer test (WMD 1.63, 95% CI 0.26 to 3.01, and P = 0.02), ESR (WMD 7.33, 95% CI -10.08 to -4.59, and P < 0.00001), CRP (WMD -6.00, 95% CI -7.17 to -4.83, and P < 0.00001), IgM (WMD = -0.42, 95% CI -0.70 to 0.13, and P = 0.004), and IgG (WMD -3.22, 95% CI 4.32 to -2.12, and P < 0.00001) analysis. However, TGP did not affect IgA (WMD 0.53, 95% CI -1.34 to -0.29, and P = 0.20). The adverse events manifested no significant differences between the two groups. CONCLUSIONS: The TGP-IS combination is superior to IS alone in the treatment of pSS. However, due to the low quality of included studies, high-quality RCTs are needed to confirm the beneficial effects of TGP. PMID- 28642800 TI - The Current Status of Quality of Reporting in Acupuncture Treatment Case Reports: An Analysis of the Core Journal in Korea. AB - OBJECTIVES: The present study aimed to evaluate the overall quality of case reports concerning acupuncture treatment in Korea. METHODS: We selected a representative Korean journal and retrieved eligible case reports on acupuncture treatment published from 2009 to 2015. We assessed the quality of reporting based on CAse REport (CARE) and STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guideline checklists. RESULTS: A total of 93 eligible case reports of acupuncture treatment were identified among the 107 articles screened. Overall quality of reporting in the case reports was generally acceptable (75.4% on CARE, 67.7% on STRICTA), but several crucial items remained substantially underreported. CONCLUSIONS: Endorsement of the CARE and STRICTA guidelines is needed to improve the completeness of reporting. Our findings will be helpful in developing a more appropriate reporting guideline for case reports in acupuncture treatment. PMID- 28642801 TI - Differences in the Tongue Features of Primary Dysmenorrhea Patients and Controls over a Normal Menstrual Cycle. AB - BACKGROUND: The aims of this study were to investigate the relationships between tongue features and the existence of menstrual pain and to provide basic information regarding the changes in tongue features during a menstrual cycle. METHODS: This study was conducted at the Kyung Hee University Medical Center. Forty-eight eligible participants aged 20 to 29 years were enrolled and assigned to two groups according to their visual analogue scale (VAS) scores. Group A included 24 females suffering from primary dysmenorrhea (PD) caused by qi stagnation and blood stasis syndrome with VAS >= 4. In contrast, Group B included 24 females with few premenstrual symptoms and VAS < 4. All participants completed four visits (menses-follicular-luteal-menses phases), and the tongue images were taken by using a computerized tongue image analysis system (CTIS). RESULTS: The results revealed that the tongue coating color value and the tongue coating thickness in the PD group during the menstrual phase were significantly lower than those of the control group (P = 0.031 and P = 0.029, resp.). CONCLUSIONS: These results suggest that the tongue features obtained from the CTIS may serve as a supplementary means for the differentiation of syndromes and the evaluation of therapeutic effect and prognosis in PD. TRIAL REGISTRATION: This trial was registered with Clinical Research Information Service, registration number KCT0001604, registered on 27 August 2015. PMID- 28642802 TI - pERK-dependent defective TCR-mediated activation of CD4+ T cells in end-stage renal disease patients. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) have an impaired immune response with a prematurely aged T-cell system. Mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and p38, regulate diverse cellular programs by transferring extracellular signals into an intracellular response. T cell receptor (TCR)-induced phosphorylation of ERK (pERK) may show an age-associated decline, which can be reversed by inhibiting dual specific phosphatase (DUSP) 6, a cytoplasmic phosphatase with substrate specificity to dephosphorylate pERK. The aim of this study was to assess whether ESRD affects TCR-mediated signaling and explore possibilities for intervening in ESRD-associated defective T-cell mediated immunity. RESULTS: An age-associated decline in TCR-induced pERK-levels was observed in the different CD4+ (P < 0.05), but not CD8+, T-cell subsets from healthy individuals (HI). Interestingly, pERK levels of CD4+ T-cell subsets from young ESRD patients were in between young and elderly HI. A differentiation-associated decline in TCR-induced ERK and p38 phosphorylation was observed in T cells, although TCR-induced p38 phosphorylation was not significantly affected by age and/or ESRD. Frequencies of TCR-induced CD69-expressing CD4+ T cells declined with age and were positively associated with pERK. In addition, an age-associated tendency of increased expression of DUSP6 was observed in CD4+ T cells of HI and DUSP6 expression in young ESRD patients was similar to old HI. Inhibition of DUSP6 significantly increased TCR induced pERK-levels of CD4+ T cells in young and elderly ESRD patients, and elderly HI. CONCLUSIONS: TCR-mediated phosphorylation of ERK is affected in young ESRD patients consistent with the concept of premature immunological T cell ageing. Inhibition of DUSP6 specific for pERK might be a potential intervention enhancing T-cell mediated immunity in ESRD patients. PMID- 28642804 TI - Defining an Optimal Cut-Point Value in ROC Analysis: An Alternative Approach. AB - ROC curve analysis is often applied to measure the diagnostic accuracy of a biomarker. The analysis results in two gains: diagnostic accuracy of the biomarker and the optimal cut-point value. There are many methods proposed in the literature to obtain the optimal cut-point value. In this study, a new approach, alternative to these methods, is proposed. The proposed approach is based on the value of the area under the ROC curve. This method defines the optimal cut-point value as the value whose sensitivity and specificity are the closest to the value of the area under the ROC curve and the absolute value of the difference between the sensitivity and specificity values is minimum. This approach is very practical. In this study, the results of the proposed method are compared with those of the standard approaches, by using simulated data with different distribution and homogeneity conditions as well as a real data. According to the simulation results, the use of the proposed method is advised for finding the true cut-point. PMID- 28642805 TI - A simple method for HPLC retention time prediction: linear calibration using two reference substances. AB - BACKGROUND: Analysis of related substances in pharmaceutical chemicals and multi components in traditional Chinese medicines needs bulk of reference substances to identify the chromatographic peaks accurately. But the reference substances are costly. Thus, the relative retention (RR) method has been widely adopted in pharmacopoeias and literatures for characterizing HPLC behaviors of those reference substances unavailable. The problem is it is difficult to reproduce the RR on different columns due to the error between measured retention time (tR) and predicted tR in some cases. Therefore, it is useful to develop an alternative and simple method for prediction of tR accurately. METHODS: In the present study, based on the thermodynamic theory of HPLC, a method named linear calibration using two reference substances (LCTRS) was proposed. The method includes three steps, procedure of two points prediction, procedure of validation by multiple points regression and sequential matching. The tR of compounds on a HPLC column can be calculated by standard retention time and linear relationship. RESULTS: The method was validated in two medicines on 30 columns. CONCLUSION: It was demonstrated that, LCTRS method is simple, but more accurate and more robust on different HPLC columns than RR method. Hence quality standards using LCTRS method are easy to reproduce in different laboratories with lower cost of reference substances. PMID- 28642803 TI - Transcriptomic profiles of aging in naive and memory CD4+ cells from mice. AB - BACKGROUND: CD4+ T cells can be broadly divided into naive and memory subsets, each of which are differentially impaired by the aging process. It is unclear if and how these differences are reflected at the transcriptomic level. We performed microarray profiling on RNA derived from naive (CD44low) and memory (CD44high) CD4+ T cells derived from young (2-3 month) and old (28 month) mice, in order to better understand the mechanisms of age-related functional alterations in both subsets. We also performed follow-up bioinformatic analyses in order to determine the functional consequences of gene expression changes in both of these subsets, and identify regulatory factors potentially responsible for these changes. RESULTS: We found 185 and 328 genes differentially expressed (FDR <= 0.05) in young vs. old naive and memory cells, respectively, with 50 genes differentially expressed in both subsets. Functional annotation analyses highlighted an increase in genes involved in apoptosis specific to aged naive cells. Both subsets shared age-related increases in inflammatory signaling genes, along with a decrease in oxidative phosphorylation genes. Cis-regulatory analyses revealed enrichment of multiple transcription factor binding sites near genes with age-associated expression, in particular NF-kappaB and several forkhead box transcription factors. Enhancer associated histone modifications were enriched near genes down regulated in naive cells. Comparison of our results with previous mouse and human datasets indicates few overlapping genes overall, but suggest consistent up regulation of Casp1 and Il1r2, and down-regulation of Foxp1 in both mouse and human CD4+ T cells. CONCLUSIONS: The transcriptomes of naive and memory CD4+ T cells are distinctly affected by the aging process. However, both subsets exhibit a common increase inflammatory genes and decrease in oxidative phosphorylation genes. NF-kappaB, forkhead box, and Myc transcription factors are implicated as upstream regulators of these gene expression changes in both subsets, with enhancer histone modifications potentially driving unique changes unique to naive cells. Finally we conclude that there is little overlap in age-related gene expression changes between humans and mice; however, age-related alterations in a small subset of genes may be conserved. PMID- 28642807 TI - Precision Education Initiative: Moving Towards Personalized Education. PMID- 28642799 TI - Extraoral Taste Receptor Discovery: New Light on Ayurvedic Pharmacology. AB - More and more research studies are revealing unexpectedly important roles of taste for health and pathogenesis of various diseases. Only recently it has been shown that taste receptors have many extraoral locations (e.g., stomach, intestines, liver, pancreas, respiratory system, heart, brain, kidney, urinary bladder, pancreas, adipose tissue, testis, and ovary), being part of a large diffuse chemosensory system. The functional implications of these taste receptors widely dispersed in various organs or tissues shed a new light on several concepts used in ayurvedic pharmacology (dravyaguna vijnana), such as taste (rasa), postdigestive effect (vipaka), qualities (guna), and energetic nature (virya). This review summarizes the significance of extraoral taste receptors and transient receptor potential (TRP) channels for ayurvedic pharmacology, as well as the biological activities of various types of phytochemical tastants from an ayurvedic perspective. The relative importance of taste (rasa), postdigestive effect (vipaka), and energetic nature (virya) as ethnopharmacological descriptors within Ayurveda boundaries will also be discussed. PMID- 28642806 TI - The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer's disease: an overview of pre-clinical studies and translational perspectives in clinical practice. AB - Alzheimer's disease (AD) is a neurodegenerative disorder and the most common form of dementia characterized by cognitive and memory impairment. One of the mechanism involved in the pathogenesis of AD, is the oxidative stress being involved in AD's development and progression. In addition, several studies proved that chronic viral infections, mainly induced by Human herpesvirus 1 (HHV-1), Cytomegalovirus (CMV), Human herpesvirus 2 (HHV-2), and Hepatitis C virus (HCV) could be responsible for AD's neuropathology. Despite the large amount of data regarding the pathogenesis of Alzheimer's disease (AD), a very limited number of therapeutic drugs and/or pharmacological approaches, have been developed so far. It is important to underline that, in recent years, natural compounds, due their antioxidants and anti-inflammatory properties have been largely studied and identified as promising agents for the prevention and treatment of neurodegenerative diseases, including AD. The ester of epigallocatechin and gallic acid, (-)-Epigallocatechin-3-Gallate (EGCG), is the main and most significantly bioactive polyphenol found in solid green tea extract. Several studies showed that this compound has important anti-inflammatory and antiatherogenic properties as well as protective effects against neuronal damage and brain edema. To date, many studies regarding the potential effects of EGCG in AD's treatment have been reported in literature. The purpose of this review is to summarize the in vitro and in vivo pre-clinical studies on the use of EGCG in the prevention and the treatment of AD as well as to offer new insights for translational perspectives into clinical practice. PMID- 28642808 TI - Increasing Social Integration for College Students with Autism Spectrum Disorder. AB - Increasing numbers of individuals with Autism Spectrum Disorder (ASD) are entering postsecondary education; however, many report feeling lonely and isolated. These difficulties with socialization have been found to impact students' academic success, involvement within the university, and overall well being. Therefore, the purpose of this study was to assess, within the context of a multiple-baseline across participants design, whether a structured social planning intervention would increase social integration for college students with ASD. The intervention consisted of weekly meetings to plan social activities around the student with ASD's interests, improve organizational skills, and target specific social skills. Additionally, each participant had a peer mentor for support during the social activities. The results showed that following intervention all participants increased their number of community-based social events, extracurricular activities, and peer interactions. Furthermore, participants improved in their academic performance and satisfaction with their college experience. Results are discussed in regards to developing specialized programs to assist college students with ASD. PMID- 28642809 TI - Corrigendum to "Plant-Derived Antioxidants in Disease Prevention". AB - [This corrects the article DOI: 10.1155/2016/1920208.]. PMID- 28642810 TI - Association of the Composite Inflammatory Biomarker GlycA, with Exercise-Induced Changes in Body Habitus in Men and Women with Prediabetes. AB - GlycA is a new composite measure of systemic inflammation and a predictor of many inflammatory diseases. GlycA is the nuclear magnetic resonance spectroscopy derived signal arising from glucosamine residues on acute-phase proteins. This study aimed to evaluate how exercise-based lifestyle interventions modulate GlycA in persons at risk for type 2 diabetes. GlycA, fitness, and body habitus were measured in 169 sedentary adults (45-75 years) with prediabetes randomly assigned to one of four six-month exercise-based lifestyle interventions. Interventions included exercise prescription based on the amount (energy expenditure (kcal/kg weight/week (KKW)) and intensity (%VO2peak). The groups were (1) low amount/moderate-intensity (10KKW/50%) exercise; (2) high-amount/moderate intensity (16KKW/50%) exercise; (3) high-amount/vigorous-intensity (16KKW/75%) exercise; and (4) a Clinical Lifestyle (combined diet plus low-amount/moderate intensity exercise) intervention. Six months of exercise training and/or diet reduced GlycA (mean Delta: -6.8 +/- 29.2 MUmol/L; p = 0.006) and increased VO2peak (mean Delta: 1.98 +/- 2.6 mL/kg/min; p < 0.001). Further, visceral (mean Delta: -21.1 +/- 36.6 cm2) and subcutaneous fat (mean Delta: -24.3 +/- 41.0 cm2) were reduced, while liver density (mean Delta: +2.3 +/- 6.5HU) increased, all p < 0.001. When including individuals in all four interventions, GlycA reductions were associated with reductions in visceral adiposity (p < 0.03). Exercise-based lifestyle interventions reduced GlycA concentrations through mechanisms related to exercise-induced modulations of visceral adiposity. This trial is registered with Clinical Trial Registration Number NCT00962962. PMID- 28642813 TI - Corrigendum to "Association of Nuclear Factor-Erythroid 2-Related Factor 2, Thioredoxin Interacting Protein, and Heme Oxygenase-1 Gene Polymorphisms with Diabetes and Obesity in Mexican Patients". AB - [This corrects the article DOI: 10.1155/2016/7367641.]. PMID- 28642812 TI - The Antioxidant Machinery of Young and Senescent Human Umbilical Vein Endothelial Cells and Their Microvesicles. AB - We examine the antioxidant role of young and senescent human umbilical vein endothelial cells (HUVECs) and their microvesicles (MVs). Proteomic and Western blot studies have shown young HUVECs to have a complete and well-developed antioxidant system. Their MVs also contain antioxidant molecules, though of a smaller and more specific range, specialized in the degradation of hydrogen peroxide and the superoxide anion via the thioredoxin-peroxiredoxin system. Senescence was shown to be associated with a large increase in the size of the antioxidant machinery in both HUVECs and their MVs. These responses might help HUVECs and their MVs deal with the more oxidising conditions found in older cells. Functional analysis confirmed the antioxidant machinery of the MVs to be active and to increase in size with senescence. No glutathione or nonpeptide antioxidant (ascorbic acid and vitamin E) activity was detected in the MVs. Endothelial cells and MVs seem to adapt to higher ROS concentrations in senescence by increasing their antioxidant machinery, although this is not enough to recover completely from the senescence-induced ROS increase. Moreover, MVs could be involved in the regulation of the blood plasma redox status by functioning as ROS scavengers. PMID- 28642811 TI - Actinidia chinensis Planch. Improves the Indices of Antioxidant and Anti Inflammation Status of Type 2 Diabetes Mellitus by Activating Keap1 and Nrf2 via the Upregulation of MicroRNA-424. AB - The fruit juice of Actinidia chinensis Planch. has antioxidant and anti inflammation properties on patients with type 2 diabetes mellitus (T2DM), but the molecular mechanism was unclear. The patients took the juice and the serum level of antioxidant miR-424, Kelch-like ECH-associated protein 1 (Keap1), erythroid derived 2-like 2 (Nrf2), and biochemical indices were measured. The juice increased the levels of serum microRNA-424, Keap1, and Nrf2 and reduced the levels of interleukin-1 (IL-1) beta and IL-6 in T2DM patients. The levels of SOD and GSH were higher while the levels of ALT and AST were lower in the patients consuming the juice when compared to the patients without taking the juice. The Spearman rank correlation analysis showed that the serum levels of miR-424 were positively related to Keap1 and Nrf2 levels while Keap1 and Nrf2 levels were positively related to the levels of SOD and GSH and negatively related to IL-1 beta and IL-6. Thus, FJACP improves the indices of antioxidant and anti inflammation status by activating Keap1 and Nrf2 via the upregulation of miR-424 in the patients with T2DM. This trial is registered with ChiCTR-ONC-17011087 on 04/07/2017. PMID- 28642814 TI - LC-QTOF-MS Analysis and Activity Profiles of Popular Antioxidant Dietary Supplements in Terms of Quality Control. AB - The dietary supplements with claimed antioxidant activity constitute a substantial part of the dietary supplement market. In this study, we performed the LC-QTOF-MS analysis and investigated the activity profiles of popular antioxidant dietary supplements from different chemical groups in terms of quality control. The commonly used antioxidant tests and statistical analysis revealed that substantial part of the results was comparable if 1 g sample was considered, but while comparing single and daily doses, significant differences in antioxidant values were noticed in all assays. The best antioxidant activity was obtained in ORAC assay (from 142 to 13814 MUM of Trolox equivalents per 1 g of sample), and the strongest correlation occurred between TPC and ORAC. The LC QTOF-MS analysis revealed that catechins were present in samples having the best antioxidant activity and that dietary supplements showing the weakest activity contained very small amount of any chemical constituents. PMID- 28642816 TI - Safe and effective administration of T-VEC in a patient with heart transplantation and recurrent locally advanced melanoma. AB - BACKGROUND: Immunotherapy plays a key role in the treatment of metastatic melanoma. Patients with autoimmune conditions and/or on immunosuppressive therapy due to orthotropic transplants, however, are systematically excluded from clinical trials. Talimogene laherparepvec (T-VEC) is the first oncolytic virus to be approved by the FDA for cancer therapy. To our knowledge, this is the first report of T-VEC being administered in the setting of an organ transplant recipient. CASE PRESENTATION: Here we present the case of a patient with recurrent locally advanced cutaneous melanoma receiving salvage T-VEC therapy in the setting of orthotropic heart transplantation. After 5 cycles of therapy, no evidence of graft rejection has been observed to date, and the patient achieved a complete remission, and is currently off therapy. CONCLUSION: This case advocates for further investigation on the safety and efficacy of immunotherapeutic approaches, such as T-VEC, in solid organ transplant recipients. PMID- 28580126 TI - Early embryo mortality in natural human reproduction: What the data say. AB - How many human embryos die between fertilisation and birth under natural conditions? It is widely accepted that natural human embryo mortality is high, particularly during the first weeks after fertilisation, with total prenatal losses of 70% and higher frequently claimed. However, the first external sign of pregnancy occurs two weeks after fertilisation with a missed menstrual period, and establishing the fate of embryos before this is challenging. Calculations are additionally hampered by a lack of data on the efficiency of fertilisation under natural conditions. Four distinct sources are used to justify quantitative claims regarding embryo loss: (i) a hypothesis published by Roberts & Lowe in TheLancet is widely cited but has no practical quantitative value; (ii) life table analyses give consistent assessments of clinical pregnancy loss, but cannot illuminate losses at earlier stages of development; (iii) studies that measure human chorionic gonadotrophin (hCG) reveal losses in the second week of development and beyond, but not before; and (iv) the classic studies of Hertig and Rock offer the only direct insight into the fate of human embryos from fertilisation under natural conditions. Re-examination of Hertig's data demonstrates that his estimates for fertilisation rate and early embryo loss are highly imprecise and casts doubt on the validity of his numerical analysis. A recent re-analysis of hCG study data concluded that approximately 40-60% of embryos may be lost between fertilisation and birth, although this will vary substantially between individual women. In conclusion, natural human embryo mortality is lower than often claimed and widely accepted. Estimates for total prenatal mortality of 70% or higher are exaggerated and not supported by the available data. PMID- 28642817 TI - Cerebral vasculitis mimicking intracranial metastatic progression of lung cancer during PD-1 blockade. AB - BACKGROUND: Stimulation of the immune system by targeting the PD-1/PD-L1 pathway can result in activation of anti-tumor immunity. Besides its clinical benefit immune checkpoint therapy leads to significant immune-related adverse events (irAEs). Some rare irAEs are not well described yet but are critical in patient management. CASE PRESENTATION: Here, we describe a case of autoimmune cerebral vasculitis/encephalitis after PD-1 inhibitor treatment for metastatic adenocarcinoma of the lung. Upon PD-1 blockade, the patient developed cerebral lesions, while having disease stabilization of extracranial metastases. Imaging suggested that the patient had new progressing brain metastases. Despite stereotactic irradiation the lesions progressed further. The largest lesion became symptomatic and had to be surgically resected. On examination, cerebral vasculitis was detected but not evidence of metastatic lung cancer. Analysis of the patient's serum revealed the presence of antinuclear antibodies that were already present before starting PD-1 blockade. In addition, we also found anti vascular endothelial antibodies in the serum. CONCLUSION: This finding suggests that the patient had preformed autoantibodies and the checkpoint inhibitor induced a clinically relevant autoimmune disease. Taken together, encephalitic lesions in patients under PD-1/PD-L1 blockade can mimic metastatic brain lesions and this rare irAE has to be considered as a differential diagnosis in patients treated with immunotherapy. PMID- 28642818 TI - Nivolumab as salvage treatment in a patient with HIV-related relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy. AB - BACKGROUND: We report the first case to our knowledge of a patient with relapsed/refractory classical hodgkin lymphoma and liver failure with encephalopathy along with human immunodeficiency virus/acquired immunodeficiency syndrome infection, successfully treated with nivolumab without major side effects and encouraging prolonged disease control. CASE PRESENTATION: In December 2015, at the time of the patient's progression from his Hodgkin lymphoma after fourth line treatment, he developed persistent fevers, abdominal distension, jaundice and worsening of his liver function tests. Magnetic resonance imaging of abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions, splenomegaly with multiple splenic nodules and several new mediastinal, intraperitoneal and retroperitoneal lymphadenopathy. In accordance with the patient's wishes before admission, and after agreement with the family, nivolumab (3 mg/kg every 2 weeks) was given. Of note, antiretroviral therapy was on hold due to liver function tests, his viral load was undectable and cluster of differentiation 4 counts were 103/uL at the time of nivolumab administration. One week after the first dose of nivolumab both his hepatic encephalopathy and constitutional symptoms started to improve, and after 2 doses, (January 2016) his LFTs were almost back to normal. After 5 months of nivolumab treatment (10 doses), restaging (computerized tomography scans of neck, chest, abdomen, pelvis) done on May 2016 showed resolution of hepatosplenomegaly with two residual small hepatic lesions, heterogeneous spleen with no splenic lesions, and stable non enlarged retroperitoneal lymph nodes without intraabdominal lymphadenopathy; consistent with partial response. CONCLUSIONS: We report a case of a patient with human immunodeficiency virus/acquired immunodeficiency syndrome -related relapsed/refractory classical Hodgkin lymphoma and acute liver failure with encephalopathy successfully treated with nivolumab after failing all standard therapeutic options. Unlike classic cytotoxic chemotherapy, which relies on preserved organ function to ameliorate potential severe side effects (i.e. myelosuppression), elimination of monoclonal antibodies is fairly independent of baseline renal and hepatic function since they are usually metabolized by circulating phagocytes and/or by their target antigen-expressing cell. PMID- 28642819 TI - Adoptive cell therapy using PD-1+ myeloma-reactive T cells eliminates established myeloma in mice. AB - BACKGROUND: Adoptive cellular therapy (ACT) with cancer antigen-reactive T cells following lymphodepletive pre-conditioning has emerged as a potentially curative therapy for patients with advanced cancers. However, identification and enrichment of appropriate T cell subsets for cancer eradication remains a major challenge for hematologic cancers. METHODS: PD-1+ and PD-1- T cell subsets from myeloma-bearing mice were sorted and analyzed for myeloma reactivity in vitro. In addition, the T cells were activated and expanded in culture and given to syngeneic myeloma-bearing mice as ACT. RESULTS: Myeloma-reactive T cells were enriched in the PD-1+ cell subset. Similar results were also observed in a mouse AML model. PD-1+ T cells from myeloma-bearing mice were found to be functional, they could be activated and expanded ex vivo, and they maintained their anti myeloma reactivity after expansion. Adoptive transfer of ex vivo-expanded PD-1+ T cells together with a PD-L1 blocking antibody eliminated established myeloma in Rag-deficient mice. Both CD8 and CD4 T cell subsets were important for eradicating myeloma. Adoptively transferred PD-1+ T cells persisted in recipient mice and were able to mount an adaptive memory immune response. CONCLUSIONS: These results demonstrate that PD-1 is a biomarker for functional myeloma specific T cells, and that activated and expanded PD-1+ T cells can be effective as ACT for myeloma. Furthermore, this strategy could be useful for treating other hematologic cancers. PMID- 28642820 TI - Intratumorally injected pro-inflammatory allogeneic dendritic cells as immune enhancers: a first-in-human study in unfavourable risk patients with metastatic renal cell carcinoma. AB - BACKGROUND: Accumulating pre-clinical data indicate that the efficient induction of antigen-specific cytotoxic CD8+ T cells characterizing viral infections is caused by cross-priming where initially infected DCs produce an unique set of inflammatory factors that recruit and activate non-infected bystander DCs. Our DC based immunotherapy concept is guided by such bystander view and accordingly, we have developed a cellular adjuvant consisting of pre-activated allogeneic DCs producing high levels of DC-recruiting and DC-activating factors. This concept doesn't require MHC-compatibility between injected cells and the patient and therefore introduces the possibility of using pre-produced and freeze-stored DCs from healthy blood donors as an off- the-shelf immune enhancer. The use of MHC incompatible allogeneic DCs will further induce a local rejection process at the injection site that is expected to further enhance recruitment and maturation of endogenous bystander DCs. METHODS: Twelve intermediate and poor risk patients with newly diagnosed metastatic renal cell carcinoma (mRCC) where included in a phase I/II study. Pro-inflammatory allogeneic DCs were produced from a leukapheresis product collected from one healthy blood donor and subsequently deep-frozen. A dose of 5-20 * 106 DCs (INTUVAX) was injected into the renal tumor twice with 2 weeks interval before planned nephrectomy and subsequent standard of care. RESULTS: No INTUVAX-related severe adverse events were observed. A massive infiltration of CD8+ T cells was found in 5 out of 12 removed kidney tumors. No objective tumor response was observed and 6 out of 11 evaluable patients have subsequently received additional treatment with standard tyrosine kinase inhibitors (TKI). Three of these 6 patients experienced an objective tumor response including one sunitinib-treated patient who responded with a complete and durable regression of 4 brain metastases. Median overall survival (mOS) is still not reached (currently 42.5 months) but has already passed historical mOS in patients with unfavourable risk mRCC on standard TKI therapy. CONCLUSIONS: Our findings indicate that intratumoral administration of proinflammatory allogeneic DCs induces an anti-tumor immune response that may prolong survival in unfavourable risk mRCC-patients given subsequent standard of care. A randomized, multi-center, phase II mRCC trial (MERECA) with INTUVAX in conjuction with sunitinib has been initiated. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01525017. PMID- 28642822 TI - The effect of concentrated growth factors in the treatment of periodontal intrabony defects. AB - AIM: To investigate the effect of concentrated growth factors (CGFs) in human intrabony defect treatment. METHODS: Thirty-one intrabony defects were randomly treated with CGFs + bovine porous bone mineral (BPBM) or BPBM alone. Probing depth, clinical attachment level and hard tissue fill were evaluated at baseline and 1 year post surgery. RESULTS: No differences in any of the investigated parameters were observed at baseline. At 1 year post therapy, both groups showed significant improvement in clinical parameters (p < 0.001). CGFs + BPBM was more effective than BPBM alone at decreasing probing depth (4.2 +/- 1.3 mm vs 3.0 +/- 1.6 mm) and clinical attachment level gain (3.7 +/- 1.3 mm vs 2.4 +/- 1.1 mm; p <= 0.05). A favorable increase of hard tissue fill was noted in CGFs + BPBM group compared with BPBM group (p > 0.05). The contents of growth factors in CGFs were statistically higher than those in platelet poor plasma (p < 0.001). CONCLUSION: Addition of CGFs significantly improved clinical effectiveness of BPBM for intrabony defect treatment. PMID- 28642823 TI - Visualization of changes in the foveal avascular zone in both observed and treated diabetic macular edema using optical coherence tomography angiography. AB - BACKGROUND: Central vision loss in diabetic retinopathy is commonly related to diabetic macular edema (DME). The objective of this study was to describe changes between consecutive visits on optical coherence tomography angiography (OCTA) of the foveal avascular zone (FAZ) in eyes with DME. METHODS: 20 eyes from 14 patients with DME were imaged on 2 successive clinic visits separated by at least 1 month. The mean interval between visits was 3.2 months. The only intervention used was intravitreal anti-VEGF in 11 eyes; the others were observed over time without treatment. Two different readers measured FAZ area using a pseudo automated tool in comparison to a manual tracing tool. Qualitative changes in the appearance of the vasculature surrounding the FAZ were also recorded. The retinal capillary plexus was segmented into deep and superficial plexuses, and FAZ measurements were done on the superficial, deep, and summated plexuses. RESULTS: Pseudo-automated and manual measurements of FAZ area decreased significantly (p < 0.05) between visits in the deep, superficial, and summated plexuses. Qualitative analysis of vasculature surrounding the FAZ showed that most of the vascular changes (65%) over time were visible in the deep plexus, compared to 30 and 20% in the superficial and summated plexuses, respectively. CONCLUSIONS: The most significant differences in FAZ size over time were in the summated plexus (p < 0.001), while changes in FAZ appearance were most prominent in the deep plexus. Absolute decrease in FAZ size over visits was largest in the deep plexus. Our results demonstrate that OCTA can effectively be used to measure FAZ area in patients with DME, visualize qualitative changes in retinal vasculature, and visualize the segmentation levels at which these changes can be best appreciated. However, larger studies are needed to evaluate the reproducibility of manual and pseudo-automated measuring techniques. PMID- 28642821 TI - Late-onset dementia: a mosaic of prototypical pathologies modifiable by diet and lifestyle. AB - Idiopathic late-onset dementia (ILOD) describes impairments of memory, reasoning and/or social abilities in the elderly that compromise their daily functioning. Dementia occurs in several major prototypical neurodegenerative disorders that are currently defined by neuropathological criteria, most notably Alzheimer's disease (AD), Lewy body dementia, frontotemporal dementia (FTD) and hippocampal sclerosis of aging (HSA). However, people who die with ILOD commonly exhibit mixed pathologies that vary within and between brain regions. Indeed, many patients diagnosed with probable AD exhibit only modest amounts of disease defining amyloid beta-peptide plaques and p-Tau tangles, and may have features of FTD (TDP-43 inclusions), Parkinson's disease (alpha-synuclein accumulation), HSA and vascular lesions. Here I argue that this 'mosaic neuropathological landscape' is the result of commonalities in aging-related processes that render neurons vulnerable to the entire spectrum of ILODs. In this view, all ILODs involve deficits in neuronal energy metabolism, neurotrophic signaling and adaptive cellular stress responses, and associated dysregulation of neuronal calcium handling and autophagy. While this mosaic of neuropathologies and underlying mechanisms poses major hurdles for development of disease-specific therapeutic interventions, it also suggests that certain interventions would be beneficial for all ILODs. Indeed, emerging evidence suggests that the brain can be protected against ILOD by lifelong intermittent physiological challenges including exercise, energy restriction and intellectual endeavors; these interventions enhance cellular stress resistance and facilitate neuroplasticity. There is also therapeutic potential for interventions that bolster neuronal bioenergetics and/or activate one or more adaptive cellular stress response pathways in brain cells. A wider appreciation that all ILODs share age-related cellular and molecular alterations upstream of aggregated protein lesions, and that these upstream events can be mitigated, may lead to implementation of novel intervention strategies aimed at reversing the rising tide of ILODs. PMID- 28642824 TI - Identification of Quantitative Trait Loci That Determine Plasma Total-Cholesterol and Triglyceride Concentrations in DDD/Sgn and C57BL/6J Inbred Mice. AB - DDD/Sgn mice have significantly higher plasma lipid concentrations than C57BL/6J mice. In the present study, we performed quantitative trait loci (QTL) mapping for plasma total-cholesterol (CHO) and triglyceride (TG) concentrations in reciprocal F2 male intercross populations between the two strains. By single-QTL scans, we identified four significant QTL on chromosomes (Chrs) 1, 5, 17, and 19 for CHO and two significant QTL on Chrs 1 and 12 for TG. By including cross direction as an interactive covariate, we identified separate significant QTL on Chr 17 for CHO but none for TG. When the large phenotypic effect of QTL on Chr 1 was controlled by composite interval mapping, we identified three additional significant QTL on Chrs 3, 4, and 9 for CHO but none for TG. QTL on Chr 19 was a novel QTL for CHO and the allelic effect of this QTL significantly differed between males and females. Whole-exome sequence analysis in DDD/Sgn mice suggested that Apoa2 and Acads were the plausible candidate genes underlying CHO QTL on Chrs 1 and 5, respectively. Thus, we identified a multifactorial basis for plasma lipid concentrations in male mice. These findings will provide insight into the genetic mechanisms of plasma lipid metabolism. PMID- 28642825 TI - Initial Development of the Early Intensive Behavioral Intervention Parental Self Efficacy Scale: A Pilot Study. AB - Early Intensive Behavioral Intervention (EIBI) is an effective treatment for children with autism. However, it is known that some parents struggle to fully implement the program, and providers are not always able to identify the specifics of each family's individualized challenges. The purpose of this pilot study was to begin the process of developing a new instrument, the EIBI Parental Self-Efficacy (EPSE) Scale, to help providers better assess and assist parents in regard to EIBI implementation. The methodology included four phases: scale construction, expert review, pretest administration, and a large sample pilot study (N = 192). The final 29-item EPSE Scale contained strong reliability properties (Cronbach's alpha = .900). Factor analysis established five subscales: Family Well-Being, Preparing for Successful Sessions, Team Participation, Not Giving Up, and Working with your Child. Following this pilot study, future research is recommended to refine and validate the EPSE Scale as a useful clinical tool for EIBI providers. PMID- 28642826 TI - Elucidation of the Role of Lectin-Like oxLDL Receptor-1 in the Metabolic Responses of Macrophages to Human oxLDL. AB - Atherogenesis is the narrowing of arteries due to plaque build-up that results in cardiovascular disease that can lead to death. The macrophage lectin-like oxidized LDL receptor-1 (LOX-1), also called the oxidized low-density lipoprotein receptor 1 (OLR1), is currently thought to aid in atherosclerotic disease progression; therefore metabolic studies have potential to both provide mechanistic validation for the role of LOX-1 in disease progression and provide valuable information regarding biomarker strategies and clinical imaging. One such mechanistic study is the upregulation of LOX-1 by methylated bacterial DNA and deoxy-cytidylate-phosphate-deoxy-guanylate-DNA (CpG)-DNA exposure. CpG-DNA is known to promote oxidative burst responses in macrophages, due to its direct binding to toll-like receptor 9 (TLR9) leading to the initiation of an NF-kappaB mediated immune response. In addition to the upregulation of macrophage LOX-1 expression, these studies have also examined the macrophage metabolic response to murine LOX-1/OLR1 antibody exposure. Our data suggests the antibody exposure effectively blocks LOX-1 dependent oxLDL metabolic activation of the macrophage, which was quantified using the multianalyte microphysiometer (MAMP). Using the MAMP to examine metabolic fluctuations during various types of oxLDL exposure, LOX-1 upregulation and inhibition provide valuable information regarding the role of LOX-1 in macrophage activation of oxidative burst. PMID- 28642827 TI - Vertical and Transverse Management with Transpalatal Arches in an Adult with Class III Malocclusion. AB - The transpalatal arch might be one of the most common intraoral auxiliary fixed appliances used in orthodontics in order to provide dental anchorage. The aim of the present case report is to describe a case in which an adult patient with a tendency to class III, palatal compression, and bilateral posterior crossbite was treated with double transpalatal bars in order to control the torque of both the first and the second molars. Double transpalatal arches on both first and second maxillary molars are a successful appliance in order to control the posterior sectors and improve the torsion of the molars. They allow the professional to gain overbite instead of losing it as may happen with other techniques and avoid enlarging of Wilson curve, obtaining a more stable occlusion without the need for extra help from bone anchorage. PMID- 28642828 TI - Surgical Orthodontic Treatment of a Patient Affected by Type 1 Myotonic Dystrophy (Steinert Syndrome). AB - Myotonic dystrophy, or Steinert's disease, is the most common form of muscular dystrophy that occurs in adults. This multisystemic form involves the skeletal muscles but affects also the eye, the endocrine system, the central nervous system, and the cardiac system. The weakness of the facial muscles causes a characteristic facial appearance frequently associated with malocclusions. Young people with myotonic dystrophy, who also have severe malocclusions, have bad oral functions such as chewing, breathing, and phonation. We present a case report of a 15-year-old boy with anterior open bite, upper and lower dental crowding, bilateral crossbite, and constriction of the upper jaw with a high and narrow palate. The patient's need was to improve his quality of life. Because of the severity of skeletal malocclusion, it was necessary to schedule a combined orthodontic and surgical therapy in order to achieve the highest aesthetic and functional result. Although therapy caused an improvement in patient's quality of life, the clinical management of the case was hard. The article shows a balance between costs and benefits of a therapy that challenges the nature of the main problem of the patient, and it is useful to identify the most appropriate course of treatment for similar cases. PMID- 28642829 TI - A Case of "Late" Postsurgical Hypoparathyroidism. AB - INTRODUCTION: Postsurgical hypoparathyroidism normally occurs a short time after thyroid surgery in form of two clinical syndromes of different etiology and prognosis. The first is transitory and might spontaneously recover within a few weeks or months. The second is permanent and needs a definitive treatment. Only few cases of hypoparathyroidism clinically evident after many years from surgery have been reported. CASE REPORT: A case of hypoparathyroidism clinically evident only three and a half years after surgery is reported. Our findings and review of a few cases reported by medical literature suggest the existence of a third form of postsurgical hypoparathyroidism, characterized by a late beginning. PMID- 28642830 TI - A Rare Case of Esophageal Adenocarcinoma with Urinary Bladder Metastasis. AB - Metastatic esophageal adenocarcinoma to the urinary bladder is extremely rare. We describe a previously healthy 49-year-old female with recent diagnosis of adenocarcinoma of the gastroesophageal junction with metastatic disease to the liver. Biopsy was positive for human epidermal growth factor receptor 2 (HER2) by Fluorescence In Situ Hybridization (FISH). She received six cycles of Cisplatin, 5-Fluorouracil, and Herceptin and subsequently developed symptomatic anemia and hematuria. Cystoscopy with retroflexion was performed and she received a transurethral resection of bladder tumor with fulguration. Pathology of the bladder tumor revealed similar morphology to her liver metastasis and immunohistochemical stains were consistent with metastatic esophageal cancer. Three weeks after being diagnosed with metachronous urinary bladder metastasis from esophageal adenocarcinoma primary, she expired. She only received her first cycle of palliative chemotherapy with Ramucirumab and Paclitaxel. PMID- 28642831 TI - Treatment of Hypochondriasis in Two Schizophrenia Patients Using Clozapine. AB - Hypochondriasis (HYPO), an obsessive-compulsive spectrum disorder, is frequent in patients with schizophrenia (SCH) (20%), especially among those treated with clozapine (36.7%). Treatment options for OCS/OCD in patients under clozapine (CLZ) include combining clozapine with amisulpride/aripiprazole or a mood stabilizer, augmenting clozapine with a serotoninergic reuptake inhibitor, adding cognitive behavioural therapy, and gradually reducing dosage. No treatments have been proposed for HYPO in patients using clozapine so we examine these options in 2 cases and report the results. Among treatments delivered, only dosage reduction adequately worked. We recommend caution when thinking about escalating treatment and suggest trying it only when alternative interventions were not successful and weighing risk and benefits of this therapeutic strategy. Further research is needed to confirm the hypothesis that CLZ treatment induces hypochondriac symptoms, to investigate the prevalence of the phenomenon, and, mostly, to identify possible treatment strategies. PMID- 28642832 TI - Internal Jugular Venous Pseudoaneurysm in a Patient with Heart Failure and Severe Tricuspid Regurgitation. AB - The differential diagnosis of a lateral neck mass includes a number of possible etiologies. While jugular venous aneurysms and pseudoaneurysms are rare entities, they should be considered in the differential diagnosis of a pulsatile lateral neck mass. We present a case of an idiopathic jugular venous pseudoaneurysm and its association with worsening tricuspid regurgitation in a patient with heart failure with preserved ejection fraction. PMID- 28642835 TI - Differential Carbonyl Stress Expression in the Intervertebral Disc between Singular- and Persistent-Mechanical Injuries. AB - Low back pain is a significant public health problem worldwide. Intervertebral disc degeneration is most significant known risk factor for low back pain. Yet the mechanisms of degeneration remain relatively unknown. Carbonyl stress and oxidation have been implicated in cartilage and fibrocartilage degeneration. Here we investigate the role of oxidative stress and carbonyl production in the intervertebral disc after mechanical injury using an in vitro organ model of the mouse functional spine unit. We use a single-stab insult to model mild injury, and the three-stab insult to model severe trauma. Our results indicate that mild injury increases the carbonyl response that may be required for tissue repair, while severe trauma tempers this response and rapidly accelerates degeneration. PMID- 28642834 TI - Binge Drinking and Depression: The Influence of Romantic Partners in Young Adulthood. AB - Although research shows that spouses influence each other's health behaviors and psychological well-being, we know little about whether these patterns extend to young people in nonmarital as well as marital relationships. We use the National Longitudinal Study of Adolescent to Adult Health to consider how a romantic partner's binge drinking and depression influence the respondent's binge drinking and depression within 1,111 young adult couples and explore whether these processes are moderated by gender. We find that partners' binge drinking is associated with increased odds of binge drinking for respondents, and partners' depression is associated with increased odds of depression for respondents. Further, depression among men is associated with reduced odds of binge drinking among their female partners. Findings suggest that processes of partner influence begin even in young adulthood with implications for cumulative effects on lifelong health behaviors and mental health. PMID- 28642833 TI - Creating a Biomarker Panel for Early Detection of Chemotherapy Related Cardiac Dysfunction in Breast Cancer Patients. AB - Cardiotoxicity is an important issue for breast cancer patients receiving anthracycline-trastuzumab therapy in the adjuvant setting. Studies show that 3 36% of patients receiving anthracyclines and/or trastuzumab experience chemotherapy related cardiac dysfunction (CRCD) and approximately 17% of patients must stop chemotherapy due to the consequences of CRCD. There is currently no standardized, clinically verified way to detect CRCD early, but common practices include serial echocardiography and troponin measurements, which can be timely, costly, and not always available in areas where health care resources are scarce. Furthermore, detection of CRCD, before there is any echocardiographic evidence of dysfunction or clinical symptoms present, would allow maximal benefit of chemotherapy and minimize cardiac complications. Creating a panel of serum biomarkers would allow for more specificity and sensitivity in the early detection of CRCD, which would be easy to implement and cost effective in places with limited health care. Based on a review of the literature, we propose creating a biomarker panel consisting of topoisomerase 2beta, serum troponin T/I, myeloperoxidase, NT-proBNP, miR-208b, miR-34a, and miR-150 in breast cancer patients receiving anthracyclines and/or trastuzumab to detect CRCD before any signs of overt cardiotoxicity are apparent. PMID- 28642836 TI - Cultural neuroscience and global mental health: addressing grand challenges. AB - Mental, neurological and substance-use (MNS) disorders comprise approximately 13% of the global burden of disease. The Grand Challenges in Global Mental Health Initiative has recently identified research priorities for the next decade to address prevention and treatment of MNS disorders. One main research priority is to identify the root causes, risks and protective factors associated with global mental health. Recent advances in cultural neuroscience have identified theoretical, methodological, and empirical methods of identifying biomarkers associated with mental health disorders across nations. Here we review empirical research in cultural neuroscience that address meeting the grand challenges in global mental health. PMID- 28642837 TI - Environmental influences in the etiology of colorectal cancer: the premise of metabolomics. AB - PURPOSE OF REVIEW: In this review we discuss how environmental exposures predominate the etiology of colorectal cancer (CRC). With CRC being a personalized disease influenced by genes and environment, our goal was to explore the role metabolomics can play in identifying exposures, assessing the interplay between co-exposures, and the development of personalized therapeutic interventions. RECENT FINDINGS: Approximately 10 % of CRC cases can be explained by germ-line mutations, whereas the prevailing majority are caused by an initiating exposure event occurring decades prior to diagnosis. Recent research has shown that dietary metabolites are linked to a procarcinogenic or protective environment in the colon which is modulated by the microbiome. In addition, excessive alcohol has been shown to increase the risk of CRC and is dependent on diet (folate), the response of microbiome, and genetic polymorphisms within the folate and alcohol metabolic pathways. Metabolomics can not only be used to identify this modulation of host metabolism, which could affect the progression of the tumors but also response to targeted therapeutics. SUMMARY: This review highlights the current understanding of the multifaceted etiology and mechanisms of CRC development but also highlights where the field of metabolomics can contribute to a greater understanding of environmental exposure in CRC. PMID- 28642838 TI - Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer. AB - The therapies available for prostate cancer patients whom progress from hormone sensitive to castration resistant prostate cancer include both systemic drugs, including docetaxel and cabazitaxel, and drugs that inhibit androgen signaling such as enzalutamide and abiraterone. Unfortunately, it is estimated that up to 30% of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug. Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered. Androgen receptor (AR) mutations, expression of AR-V7 (or other constitutively active androgen receptor variants), intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1, Member C3 (AKR1C3) are among the many mechanisms associated with resistance to anti-androgens. In regards to the taxanes, one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1 (ABCB1). Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies. For instance, targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment. ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel. A more thorough understanding of how drug resistance develops will lead to improved treatment strategies. This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response. PMID- 28642839 TI - The Mitochondrial Complex(I)ty of Cancer. AB - Recent evidence highlights that the cancer cell energy requirements vary greatly from normal cells and that cancer cells exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation. NADH-ubiquinone oxidoreductase (Complex I) is the largest complex of the mitochondrial electron transport chain and contributes about 40% of the proton motive force required for mitochondrial ATP synthesis. In addition, Complex I plays an essential role in biosynthesis and redox control during proliferation, resistance to cell death, and metastasis of cancer cells. Although knowledge about the structure and assembly of Complex I is increasing, information about the role of Complex I subunits in tumorigenesis is scarce and contradictory. Several small molecule inhibitors of Complex I have been described as selective anticancer agents; however, pharmacologic and genetic interventions on Complex I have also shown pro-tumorigenic actions, involving different cellular signaling. Here, we discuss the role of Complex I in tumorigenesis, focusing on the specific participation of Complex I subunits in proliferation and metastasis of cancer cells. PMID- 28642840 TI - Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy. AB - Cytolethal distending toxin (CDT) produced by Campylobacter jejuni contains three subunits: CdtA, CdtB, and CdtC. Among these three toxin subunits, CdtB is the toxic moiety of CDT with DNase I activity, resulting in DNA double-strand breaks (DSB) and, consequently, cell cycle arrest at the G2/M stage and apoptosis. Radiation therapy is an effective modality for the treatment of localized prostate cancer (PCa). However, patients often develop radioresistance. Owing to its particular biochemical properties, we previously employed CdtB as a therapeutic agent for sensitizing radioresistant PCa cells to ionizing radiation (IR). In this study, we further demonstrated that CDT suppresses the IR-induced autophagy pathway in PCa cells by attenuating c-Myc expression and therefore sensitizes PCa cells to radiation. We further showed that CDT prevents the formation of autophagosomes via decreased high-mobility group box 1 (HMGB1) expression and the inhibition of acidic vesicular organelle (AVO) formation, which are associated with enhanced radiosensitivity in PCa cells. The results of this study reveal the detailed mechanism of CDT for the treatment of radioresistant PCa. PMID- 28642841 TI - Strain- and Dose-Dependent Reduction of Toxoplasma gondii Burden in Pigs Is Associated with Interferon-Gamma Production by CD8+ Lymphocytes in a Heterologous Challenge Model. AB - Toxoplasma gondii is a worldwide prevalent parasite of humans and animals. The global infection burden exceeds yearly one million disability-adjusted life years (DALY's) in infected individuals. Therefore, effective preventive measures should be taken to decrease the risk of infection in humans. Although human toxoplasmosis is predominantly foodborne by ingestion of tissue cysts in meat from domestic animals such as pigs, the incidence risk is difficult to estimate due to the lack of screening of animals for infection and insights in location and persistence of the parasite in the tissues. Hence, experimental infections in pigs can provide more information on the risk for zoonosis based on the parasite burden in meat products intended for human consumption and on the immune responses induced by infection. In the present study, homo- and heterologous infection experiments with two distinct T. gondii strains (IPB-LR and IPB-Gangji) were performed. The humoral and cellular immune responses, the presence of viable parasites and the parasite load in edible meat samples were evaluated. In homologous infection experiments the parasite persistence was clearly strain dependent and inversely correlated with the infection dose. The results strongly indicate a change in the amount of parasite DNA and viable cysts in porcine tissues over time. Heterologous challenge infections demonstrated that IPB-G strain could considerably reduce the parasite burden in the subsequent IPB-LR infection. A strong, however, not protective humoral response was observed against GRA7 and TLA antigens upon inoculation with both strains. The in vitro IFN-gamma production by TLA-stimulated PBMCs was correlated with the infection dose and predominantly brought about by CD3+CD4-CD8alphabright T-lymphocytes. The described adaptive cellular and humoral immune responses in pigs are in line with the induced or natural infections in mice and humans. Previous studies underscored the heterogeneity of T. gondii strains and the corresponding virulence factors. These findings suggest the potential of the IPB-G strain to elicit a partially protective immune response and to reduce the parasite burden upon a challenge infection. The IPB-G strain could be used as a promising tool in limiting the number of viable parasites in edible tissues and, hence, in lowering the risk for human toxoplasmosis. PMID- 28642842 TI - The Tick Microbiome: Why Non-pathogenic Microorganisms Matter in Tick Biology and Pathogen Transmission. AB - Ticks are among the most important vectors of pathogens affecting humans and other animals worldwide. They do not only carry pathogens however, as a diverse group of commensal and symbiotic microorganisms are also present in ticks. Unlike pathogens, their biology and their effect on ticks remain largely unexplored, and are in fact often neglected. Nonetheless, they can confer multiple detrimental, neutral, or beneficial effects to their tick hosts, and can play various roles in fitness, nutritional adaptation, development, reproduction, defense against environmental stress, and immunity. Non-pathogenic microorganisms may also play a role in driving transmission of tick-borne pathogens (TBP), with many potential implications for both human and animal health. In addition, the genetic proximity of some pathogens to mutualistic symbionts hosted by ticks is evident when studying phylogenies of several bacterial genera. The best examples are found within members of the Rickettsia, Francisella, and Coxiella genera: while in medical and veterinary research these bacteria are traditionally recognized as highly virulent vertebrate pathogens, it is now clear to evolutionary ecologists that many (if not most) Coxiella, Francisella, and Rickettsia bacteria are actually non-pathogenic microorganisms exhibiting alternative lifestyles as mutualistic ticks symbionts. Consequently, ticks represent a compelling yet challenging system in which to study microbiomes and microbial interactions, and to investigate the composition, functional, and ecological implications of bacterial communities. Ultimately, deciphering the relationships between tick microorganisms as well as tick symbiont interactions will garner invaluable information, which may aid in the future development of arthropod pest and vector borne pathogen transmission control strategies. PMID- 28642843 TI - The Impact of Genome Region of Difference 4 (RD4) on Mycobacterial Virulence and BCG Efficacy. AB - Comparative genome analyses have revealed a number of regions of difference (RD) among mycobacterial species. The functional consequences of most of these genome variations have not been studied. RD4, which encompasses Rv1506c-Rv1516c of Mycobacterium tuberculosis (M. tb) H37Rv, is absent in the closely related Mycobacterium bovis and M. bovis Bacille Calmette-Guerin (BCG). On the other hand, we previously found that Mycobacterium marinum has an extended RD4 which includes a number of genes involved in the biosynthesis of lipooligosaccharides (LOSs). As such, there appears to be a gradual decay of RD4 in mycobacterial genomes in the order of M. marinum, M. tb, and M. bovis (including BCG). To understand the potential effect of RD4 on mycobacterial virulence, in this study, we cloned the entire (Rv1501-1516c) and partial (Rv1501-1508c) RD4 into an integrating vector. These constructs were introduced to M. bovis BCG and M. marinum and the virulence of the RD4 knock-in strains were evaluated in the SCID mice and zebrafish infection models, respectively. BCG containing the entire RD4 exhibited similar levels of virulence to the parental strain but BCG containing partial RD4 (Rv1501-Rv1508c) was more attenuated. Similarly, zebrafish infection experiments showed that addition of partial RD4 also appeared to attenuate the virulence of M. marinum. However, M. marinum containing entire RD4 was more virulent than the wild type strain. Interestingly, BCG strains containing the entire or partial RD4 exhibited better protection of zebrafish against M. marinum challenge than the parental BCG. Taken together, our data suggest that RD4 plays a role in mycobacterial virulence and that RD4 knock-in BCG strains confer improved protection. Our study has provided new insights into the biological function of RD4 and evolution of mycobacterial genomes. PMID- 28642844 TI - Role of Bacterioferritin & Ferritin in M. tuberculosis Pathogenesis and Drug Resistance: A Future Perspective by Interactomic Approach. AB - Tuberculosis is caused by Mycobacterium tuberculosis, one of the most successful and deadliest human pathogen. Aminoglycosides resistance leads to emergence of extremely drug resistant strains of M. tuberculosis. Iron is crucial for the biological functions of the cells. Iron assimilation, storage and their utilization is not only involved in pathogenesis but also in emergence of drug resistance strains. We previously reported that iron storing proteins (bacterioferritin and ferritin) were found to be overexpressed in aminoglycosides resistant isolates. In this study we performed the STRING analysis of bacterioferritin & ferritin proteins and predicted their interactive partners [ferrochelatase (hemH), Rv1877 (hypothetical protein/probable conserved integral membrane protein), uroporphyrinogen decarboxylase (hemE) trigger factor (tig), transcriptional regulatory protein (MT3948), hypothetical protein (MT1928), glnA3 (glutamine synthetase), molecular chaperone GroEL (groEL1 & hsp65), and hypothetical protein (MT3947)]. We suggested that interactive partners of bacterioferritin and ferritin are directly or indirectly involved in M. tuberculosis growth, homeostasis, iron assimilation, virulence, resistance, and stresses. PMID- 28642846 TI - Decreased Fitness and Virulence in ST10 Escherichia coli Harboring blaNDM-5 and mcr-1 against a ST4981 Strain with blaNDM-5. AB - Although coexistence of blaNDM-5 and mcr-1 in Escherichia coli has been reported, little is known about the fitness and virulence of such strains. Three carbapenem resistant Escherichia coli (GZ1, GZ2, and GZ3) successively isolated from one patient in 2015 were investigated for microbiological fitness and virulence. GZ1 and GZ2 were also resistant to colistin. To verify the association between plasmids and fitness, growth kinetics of the transconjugants were performed. We also analyzed genomic sequences of GZ2 and GZ3 using PacBio sequencing. GZ1 and GZ2 (ST10) co-harbored blaNDM-5 and mcr-1, while GZ3 (ST4981) carried only blaNDM 5. GZ3 demonstrated significantly more rapid growth (P < 0.001) and overgrew GZ2 with a competitive index of 1.0157 (4 h) and 2.5207 (24 h). Increased resistance to serum killing and mice mortality was also identified in GZ3. While GZ2 had four plasmids (IncI2, IncX3, IncHI2, IncFII), GZ3 possessed one plasmid (IncFII). The genetic contexts of blaNDM-5 in GZ2 and GZ3 were identical but inserted into different backbones, IncX3 (102,512 bp) and IncFII (91,451 bp), respectively. The growth was not statistically different between the transconjugants with mcr-1 or blaNDM-5 plasmid and recipient (P = 0.6238). Whole genome sequence analysis revealed that 28 virulence genes were specific to GZ3, potentially contributing to increased virulence of GZ3. Decreased fitness and virulence in a mcr-1 and blaNDM-5 co-harboring ST10 E. coli was found alongside a ST4981 strain with only blaNDM-5. Acquisition of mcr-1 or blaNDM-5 plasmid did not lead to considerable fitness costs, indicating the potential for dissemination of mcr-1 and blaNDM-5 in Enterobacteriaceae. PMID- 28642845 TI - Metabolic Adaptations of Uropathogenic E. coli in the Urinary Tract. AB - Escherichia coli ordinarily resides in the lower gastrointestinal tract in humans, but some strains, known as Uropathogenic E. coli (UPEC), are also adapted to the relatively harsh environment of the urinary tract. Infections of the urine, bladder and kidneys by UPEC may lead to potentially fatal bloodstream infections. To survive this range of conditions, UPEC strains must have broad and flexible metabolic capabilities and efficiently utilize scarce essential nutrients. Whole-organism (or "omics") methods have recently provided significant advances in our understanding of the importance of metabolic adaptation in the success of UPECs. Here we describe the nutritional and metabolic requirements for UPEC infection in these environments, and focus on particular metabolic responses and adaptations of UPEC that appear to be essential for survival in the urinary tract. PMID- 28642847 TI - Heat-Labile Enterotoxin-Induced PERK-CHOP Pathway Activation Causes Intestinal Epithelial Cell Apoptosis. AB - Enterotoxigenic Escherichia coli (ETEC) is a leading cause of diarrhea among children and travelers in developing countries, and heat-labile enterotoxin (LT) is one of the most important virulence factors. The pathogenesis of and virulence factors associated with ETEC have been well-characterized; however, the extent to which ETEC damages host cells remains unclear. In this study, we found that LT could induce decreases in intestinal epithelial cell viability and induce apoptosis in a dose- and time- dependent manner in both HCT-8 and Caco-2 cells. We analyzed the expression profiles of apoptosis-related proteins via protein array technology and found that Bax, p-p53(S46), cleaved caspase-3, and TNFRI/TNFRSF1A expression levels were significantly up-regulated in wild-type ETEC- but not in DeltaLT ETEC-infected HCT-8 cells. Bax is essential for endoplasmic reticulum (ER) stress-triggered apoptosis, and our RNAi experiments showed that the PERK-eIF2-CHOP pathway and reactive oxygen species (ROS) are also main participants in this process. LT-induced ROS generation was decreased in CHOP-knockdown HCT-8 cells compared to that in control cells. Moreover, pretreatment with the ROS inhibitor NAC down-regulated GRP78, CHOP, Bim, and cleaved caspase-3 expression, resulting in a reduction in the apoptosis rate from 36.2 to 20.3% in LT-treated HCT-8 cells. Furthermore, ROS inhibition also attenuated LT-induced apoptosis in the small intestinal mucosa in the ETEC inoculation mouse model. PMID- 28642848 TI - Mycobacterium tuberculosis Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Functions as a Receptor for Human Lactoferrin. AB - Iron is crucial for the survival of living cells, particularly the human pathogen Mycobacterium tuberculosis (M.tb) which uses multiple strategies to acquire and store iron. M.tb synthesizes high affinity iron chelators (siderophores), these extract iron from host iron carrier proteins such as transferrin (Tf) and lactoferrin (Lf). Recent studies have revealed that M.tb may also relocate several housekeeping proteins to the cell surface for capture and internalization of host iron carrier protein transferrin. One of the identified receptors is the glycolytic enzyme Glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This conserved multifunctional protein has been identified as a virulence factor in several other bacterial species. Considering the close structural and functional homology between the two major human iron carrier proteins (Tf and Lf) and the fact that Lf is abundantly present in lung fluid (unlike Tf which is present in plasma), we evaluated whether GAPDH also functions as a dual receptor for Lf. The current study demonstrates that human Lf is sequestered at the bacterial surface by GAPDH. The affinity of Lf-GAPDH (31.7 +/- 1.68 nM) is higher as compared to Tf GAPDH (160 +/- 24 nM). Two GAPDH mutants were analyzed for their enzymatic activity and interaction with Lf. Lastly, the present computational studies offer the first significant insights for the 3D structure of monomers and assembled tetramer with the associated co-factor NAD+. Sequence analysis and structural modeling identified the surface exposed, evolutionarily conserved and functional residues and predicted the effect of mutagenesis on GAPDH. PMID- 28642849 TI - AIM2 Co-immunization with VP1 Is Associated with Increased Memory CD8 T Cells and Mounts Long Lasting Protection against Coxsackievirus B3 Challenge. AB - The recurrent Coxsackievirus B3 (CVB3) infection is the most important cause of intractable myocarditis which often leads to chronic myocarditis and even dilated cardiomyopathy. Therefore, enhanced DNA vaccines capable of memory CD8 T cells are essential for long-lasting immunological protection against CVB3 infection. In this study, absent in melanoma 2 (AIM2) was used as an adjuvant to enhance the induction of memory CD8 T cells elicited by VP1 (viral capsid protein 1) vaccine. Mice were intramuscularly injected with 50 MUg AIM2 plasmid and equal amount of VP1 plasmid (pAIM2/pVP1) vaccine 4 times at 2 week-intervals. We observed that the protection of pAIM2/pVP1 vaccine against CVB3 challenge was evidenced by significantly improved cardiac function, reduced myocardial injuries, and increased survival rate when compared with immunization with pVP1. Co immunization with pAIM2/pVP1 robustly augmented T lymphocytes proliferation and CVB3-specific cytotoxic T lymphocyte responses. Importantly, 16 weeks after the last immunization, pAIM2/pVP1 co-immunization significantly enhanced the expression of Bcl-6, SOCS3, and Sca-1 which are critical for memory CD8 T cells as compared with pVP1 immunization. Notably, CD8 T cells that are likely vaccine induced memory T cells were responsible for the protective efficacy of pAIM2/pVP1 vaccine by abolition of a CD8 T cell immune response following a lethal dose of CVB3 infection. Our results indicate that AIM2-adjuvanted vaccine could be a potential and promising approach to promote a long-lasting protection against CVB3-induced myocarditis. PMID- 28642850 TI - Transcriptional Network Controlling Endochondral Ossification. AB - Endochondral ossification is the fundamental process of skeletal development in vertebrates. Chondrocytes undergo sequential steps of differentiation, including mesenchymal condensation, proliferation, hypertrophy, and mineralization. These steps, which are required for the morphological and functional changes in differentiating chondrocytes, are strictly regulated by a complex transcriptional network. Biochemical and mice genetic studies identified chondrogenic transcription factors critical for endochondral ossification. The transcription factor sex-determining region Y (SRY)-box 9 (Sox9) is essential for early chondrogenesis, and impaired Sox9 function causes severe chondrodysplasia in humans and mice. In addition, recent genome-wide chromatin immunoprecipitation sequencing studies revealed the precise regulatory mechanism of Sox9 during early chondrogenesis. Runt-related transcription factor 2 promotes chondrocyte hypertrophy and terminal differentiation. Interestingly, endoplasmic reticulum (ER) stress-related transcription factors have recently emerged as novel regulators of chondrocyte differentiation. Here we review the transcriptional mechanisms that regulate endochondral ossification, with a focus on Sox9. PMID- 28642851 TI - Sarcopenia: Neurological Point of View. AB - Sarcopenia is an age-related geriatric syndrome which is characterized by the gradual loss of muscle mass, muscle strength, and muscle quality. There are a lot of neurologic insults on sarcopenia at various levels from the brain to the neuromuscular junctions (NMJs) to generate a volitional task. Dopaminergic downregulation, inadequate motor programming and motor coordination impairment lead to decline of supraspinal drive. Motor unit reorganization and inflammatory changes in motor neuron decrease conduction velocity and amplitude of compound muscle action potential. Furthermore, NMJ remodeling and age related neurophysiological alterations may contribute to neuromuscular impairment. Sarcopenia is an age-associated, lifelong process which links to multiple etiological factors. Although not all the causes are completely understood, we suggest that compromised nervous system function may be one of the important contributors to the sarcopenia. PMID- 28642852 TI - Fracture Preventing Effects of Maxmarvil(r) Tablets (Alendronate 5 mg + Calcitriol 0.5 ug) in Patients with Osteoporosis. AB - BACKGROUND: The purpose of this prospective, open-label, observational study was to assess the fracture preventing effect of Maxmarvil(r) tablets (alendronate 5 mg + calcitriol 0.5 ug) in patients with osteoporosis and to evaluate the change in bone mineral density (BMD) at the minimum 1-year follow-up. METHODS: In this multicenter observational study, 691 patients with osteoporosis (aged 50 years or older) were treated with alendronate 5 mg + calcitriol 0.5 ug/day during their normal course of care. Patients were assessed at baseline and at 6 and 12 months. Baseline characteristics (including age, gender, concomitant disease, and baseline fractures) were evaluated. RESULTS: From among the 848 participants, 149 individuals were lost to follow-up at the time of the study and 8 people had died. The 691 participants (54 men and 637 women) finished the follow-up study and completed the questionnaire. The mean age of the participants was 71.5 years (range, 50-92 years; mean age, 72.3 years for men and 71.4 years for women). Osteoporotic fracture occurred in 19 patients (2.7%). BMD of the lumbar spine and hip was improved by 5% and 1.5% at the latest follow-up. At the latest follow-up, 24 patients (3.5%) complained of drug-related complications such as dyspepsia, constipation, and nausea. CONCLUSIONS: This prospective observational study demonstrated that alendronate 5 mg + calcitriol 0.5 ug/day had a preventive effect on osteoporotic fracture and it increased the BMD of the lumbar spine by 5% at the latest follow-up. PMID- 28642853 TI - Paget's Disease: Skeletal Manifestations and Effect of Bisphosphonates. AB - BACKGROUND: Paget's disease of bone leads to change in the shape and size of the bone and results in reduced bone strength, leading to the complications of deformity, arthritis, and fracture. Due to unknown reasons, Paget's disease is rare in Asian descendants. We report the cases of Paget's disease who visited our institute for 15 years and reviewed the literatures. METHODS: We retrospectively reviewed the medical records and radiograms of 8 patients (6 female and 2 male) who were diagnosed as Paget's disease of bone. Diagnosis was confirmed by typical radiological feature in the involved skeletons and/or pathologic findings. RESULTS: Pelvis, skull and spine were three most frequently involved bones. All involved bones in our cases showed changes in shape and trabecular pattern which resulted in bowing of lower extremity, secondary osteoarthritis, compression fracture of spine and enlargement of skull. Mean follow time was 4.71 years and all patient were treated bisphosphonate (BP). Use of BP controlled the level of serum alkaline phosphatase level effectively. CONCLUSIONS: We have reviewed eight patients who were previously diagnosed as Paget's disease of bone in our institute. We could identify typical radiologic and clinical findings such as bowing deformity of long bone, secondary osteoarthritis, compression fracture and osteomyelitis of mandible that deteriorated the quality of their living. PMID- 28642854 TI - Measurement Uncertainty in Spine Bone Mineral Density by Dual Energy X-ray Absorptiometry. AB - BACKGROUND: The purpose of this study was to calculate the measurement uncertainty of the process of bone mineral density (BMD) analysis using dual energy X-ray absorptiometry with traceability. METHODS: Between March 2015 and October 2016, among healthy participants in their 20s and 30s, the study included those who had not taken calcium, vitamin D supplements and steroids and were without a history of osteoporosis, osteopenia and diseases related to osteoporosis. Relational expression of the model was established based on Guide to the Expression of Uncertainty in Measurements and Eurachem and the uncertainty from each factor was evaluated. RESULTS: The combined standard uncertainty was 0.015, while the expanded uncertainty was 0.0298. The factor-specific standard uncertainties that occurred in the process of measuring BMD were 0.72% for the calibration curve, 0.9% for the internal quality control (IQC) using Aluminum Spine Phantom, 0.58% for European Spine Phantom (ESP), and 0.9% for the inspector precision (IP). CONCLUSIONS: The combined standard uncertainty of the spine BMD corrected with ESP was 0.015 when measured at one time and targeting one participant. The uncertainties of the accuracy of the IQC and the IP were higher than that of the other factors. Therefore, there will be a need for establishment of protocols to lower these uncertainties. PMID- 28642855 TI - Knowledge on Osteoporosis among Nurses. AB - BACKGROUND: It is crystal clear how important healthcare providers are well-aware of reasonable knowledge on osteoporosis, because they are at the forefront of such management. However, no study has been yet assessed in the knowledge on osteoporosis among healthcare providers particularly in nurse. Therefore, we evaluated the knowledge on osteoporosis of nurses. METHODS: In April 2017, 67 nurses were evaluated using a modified Facts on Osteoporosis Quiz (FOOQ). RESULTS: Although nurses grasped some points of osteoporosis, their knowledge was insufficient concerning effects of weight, physical exercise and calcium intake during adolescence. CONCLUSIONS: The level of knowledge on osteoporosis was evaluated in nurses, and the effect of weight, physical exercise, and calcium intake during adolescence should be focused in an educational program on osteoporosis for nurses. PMID- 28642856 TI - Longitudinal Change in Trabecular Bone Score during and after Treatment of Osteoporosis in Postmenopausal Korean Women. AB - BACKGROUND: The aim of this study was to evaluate the longitudinal changes of trabecular bone score (TBS) during and after bisphosphonate (BP) treatment in postmenopausal Korean women with osteoporosis. METHODS: We analyzed 191 patients who took BP and underwent bone mineral density (BMD) test for the period from January 2010 to December 2015. The mean follow up period during treatment and after treatment was 22.8 months and 18 months, respectively. The TBS and BMD values were evaluated by the percent changes relative to the baseline. RESULTS: In 191 patients, who treated with BPs, L-spine BMD increased 3.65+/-0.5% and TBS increased 0.26+/-0.4% from baseline during first 1 year. At 2 to 4 years, the changes of BMD and TBS from baseline gradually increased up to 9.3+/-3.25% and 2.69+/-0.98% and both results showed statistically significant correlation. In 86 patients who stopped BPs, L-spine BMD decreased -0.54+/-1.07% and TBS increased 0.33+/-1.96% from baseline during 3 years follow up period. CONCLUSIONS: Lumbar spine TBS increase over time with BPs treatment although the changes were less than that of BMD. Also, it preserve for years after stopping treatment, as the changes of lumbar spine BMD. The results of BMD and TBS showed significant correlation during treatment but not during drug withdrawal. PMID- 28642857 TI - Healthcare Costs of Osteoporotic Fracture in Korea: Information from the National Health Insurance Claims Database, 2008-2011. AB - BACKGROUND: The present study estimated healthcare costs of osteoporotic fractures including spine, hip, distal radius and humerus in Koreans over 50 years of age using national claims data. METHODS: Korea National Health Insurance data between 2008 and 2011 was searched for all claims records of outpatient visits or hospital admissions of patients >=50-year-of-age. Osteoporosis-related fractures were identified using certain the International Classification of Diseases, Tenth Revision codes and site-specific physician claims for procedures in a patient age cut-off value of 50 years. The healthcare costs included acute phase costs accounting for emergency medical care given immediately after fracture, costs due to further hospitalization and surgical procedures, physiotherapy sessions according to the site of the fracture, and outpatient visits in the year after discharge. RESULTS: The total estimated healthcare costs of osteoporotic fractures in 2011 was $722 million. From 2008 to 2011, the total number and healthcare costs of osteoporotic fractures increased 28.9% (from 127,070 to 163,823) and 31.6% (from $549 million to $722 million), respectively. The portion of national health care expenditure was ranged from 2.3% in 2008 to 2.2% in 2011. The mean healthcare cost of osteoporotic fractures per person increased 2.1% from $4,321 in 2008 to $4,410 in 2011.The mean healthcare costs were highest for hip fractures followed by spine, humerus, and distal radius fractures. CONCLUSIONS: Total Healthcare costs of osteoporotic fractures in South Koreans >=50-year-of-age increased between 2008 and 2011. This trend will likely continue, which is an important health problem in the elderly population and economically. PMID- 28642858 TI - Pathological Fracture of Femoral Neck Leading to a Diagnosis of Wilson's Disease: A Case Report and Review of Literature. AB - Wilson's disease (WD) is a rare inherited disorder of copper metabolism. It chiefly has hepatic, neurological and ophthalmic manifestations. Although osteoporosis, rickets and early arthritis are common features of WD, they are under-recognized. Musculoskeletal manifestations very rarely lead to diagnosis of the disease. Here we present a case of a 12-year-old girl who presented with a 3 month-old pathological fracture of neck of femur. WD was diagnosed on investigating the cause of the pathological fracture, which was managed by performing a conventional McMurray's intertrochanteric osteotomy. At 6 months follow up, fracture had united and patient was able to ambulate with support. WD can be a rare cause of pathological fracture. A high index of suspicion must be maintained in patients of pathological fracture presenting with associated neuropsychiatric or hepatic manifestations. PMID- 28642859 TI - Exercise-Induced Bronchospasm and Allergy. AB - Sport is an essential part of childhood, with precious and acknowledged positive health effects but the impact of exercise-induced bronchoconstriction (EIB) significantly reduces participation in physical activity. It is important to recognize EIB, differentiating EIB with or without asthma if the transient narrowing of the airways after exercise is associated with asthmatic symptoms or not, in the way to select the most appropriate treatment among the many treatment options available today. Therapy is prescribed based on symptoms severity but diagnosis of EIB is established by changes in lung function provoked by exercise evaluating by direct and indirect tests. Sometimes, in younger children it is difficult to obtain the registration of difference between the preexercise forced expiratory volume in the first second (FEV1) value and the lowest FEV1 value recorded within 30 min after exercise, defined as the gold standard, but interrupter resistance, in association with spirometry, has been showed to be a valid alternative in preschool age. Atopy is the main risk factor, as demonstrated by epidemiologic data showing that among the estimated pediatric population with EIB up to 40% of them have allergic rhinitis and 30% of these patients may develop adult asthma, according with atopic march. Adopting the right treatment and prevention, selecting sports with no marked hyperventilation and excessive cooling of the airways, children with EIB can be able to take part in physical activity like all others. PMID- 28642860 TI - Ataxia Telangiectasia-Mutated (ATM)Polymorphisms and Risk of Lung Cancer in a Chinese Population. AB - BACKGROUND: The ataxia telangiectasia-mutated (ATM) gene has a key role in DNA repair including activation and stabilization of p53, which implicates the importance of ATM polymorphisms in the development of cancer. This study aims to investigate the association of two ATM single-nucleotide polymorphisms (SNPs) with lung cancer, as well as their potential interaction with p53 gene and other known risk factors of lung cancer. METHODS: A population-based case-control study was conducted in Taiyuan city, China with 399 cases and 466 controls matched on the distribution of age and sex of cases. The two ATM gene SNPs, ATMrs227060 and ATMrs228589 as well as p53 gene SNP, p53rs1042522 were genotyped using Sequenom platform. Unconditional logistic regression models were used to estimate crude and adjusted odds ratios (aOR) and 95% confidence intervals (CIs). Adjusted models controlled for age, sex, and smoking status. RESULTS: The study showed that TT genotype of ATMrs227060 (aOR = 1.58, 95% CI: 1.06-2.35) and AA genotype of ATMrs228589 were significantly associated with lung cancer (aOR = 1.50, 95% CI: 1.08-2.08) in a recessive model. Additionally, carrying variant genotypes of ATMrs227060 (TT), ATMrs228589 (AA), and p53rs1042522 (CC) concomitantly was associated with much higher risk (aOR = 3.68, 95% CI: 1.43-9.45) of lung cancer than carrying variant genotypes of any one of the above three SNPs. We also found multiplicative and additive interaction between tea drinking and ATMrs227060 in association with lung cancer. CONCLUSION: This study indicates that ATM gene variants might be associated with development of lung cancer in Chinese population. These results need to be validated in larger and different population samples. PMID- 28642861 TI - Reported Systems Changes and Sustainability Perceptions of Three State Departments of Health Implementing Multi-Faceted Evidence-Based Fall Prevention Efforts. AB - Although the concepts of systems change and sustainability are not new, little is known about the factors associated with systems change sustaining multi-state, multi-level fall prevention efforts. This exploratory study focuses on three State Departments of Health (DOH) that were awarded 5-year funding from the Centers for Disease Control and Prevention to simultaneously implement four separate yet related evidence-based fall prevention initiatives at the clinical, community, and policy level. The purpose of this study was to examine changes in partnerships and collaborative activities that occurred to accomplish project goals (examining changes in the context of "before funding" and "after funding was received"). Additionally, this study explored changes in State DOH perceptions about action related to sustainability indicators in the context of "during funding" and "after funding ends." Findings from this study document the partnership and activity changes necessary to achieve defined fall prevention goals after funding is received, and that the importance of sustainability indicator documentation is seen as relevant during funding, but less so after the funding ends. Findings from this study have practice and research implications that can inform future funded efforts in terms of sector and stakeholder engagement necessary for initiating, implementing, and sustaining community- and clinical-based fall prevention interventions. PMID- 28642862 TI - Fabrication of CMC-g-PAM Superporous Polymer Monoliths via Eco-Friendly Pickering MIPEs for Superior Adsorption of Methyl Violet and Methylene Blue. AB - A series of superporous carboxymethylcellulose-graft poly(acrylamide)/palygorskite (CMC-g-PAM/Pal) polymer monoliths presenting interconnected pore structure and excellent adsorption properties were prepared by one-step free-radical grafting polymerization reaction of CMC and acrylamide (AM) in the oil-in-water (O/W) Pickering-medium internal phase emulsions (Pickering-MIPEs) composed of non-toxic edible oil as a dispersion phase and natural Pal nanorods as stabilizers. The effects of Pal dosage, AM dosage, and co surfactant Tween-20 (T-20) on the pore structures of the monoliths were studied. It was revealed that the well-defined pores were formed when the dosages of Pal and T-20 are 9-14 and 3%, respectively. The porous monolith can rapidly adsorb 1,585 mg/g of methyl violet (MV) and 1,625 mg/g of methylene blue (MB). After the monolith was regenerated by adsorption-desorption process for five times, the adsorption capacities still reached 92.1% (for MV) and 93.5% (for MB) of the initial maximum adsorption capacities. The adsorption process was fitted with Langmuir adsorption isotherm model and pseudo-second-order adsorption kinetic model very well, which indicate that mono-layer chemical adsorption mainly contribute to the high-capacity adsorption for dyes. The superporous polymer monolith prepared from eco-friendly Pickering-MIPEs shows good adsorption capacity and fast adsorption rate, which is potential adsorbent for the decontamination of dye-containing wastewater. PMID- 28642863 TI - Friends-Enemies: Endogenous Retroviruses Are Major Transcriptional Regulators of Human DNA. AB - Endogenous retroviruses are mobile genetic elements hardly distinguishable from infectious, or "exogenous," retroviruses at the time of insertion in the host DNA. Human endogenous retroviruses (HERVs) are not rare. They gave rise to multiple families of closely related mobile elements that occupy ~8% of the human genome. Together, they shape genomic regulatory landscape by providing at least ~320,000 human transcription factor binding sites (TFBS) located on ~110,000 individual HERV elements. The HERVs host as many as 155,000 mapped DNaseI hypersensitivity sites, which denote loci active in the regulation of gene expression or chromatin structure. The contemporary view of the HERVs evolutionary dynamics suggests that at the early stages after insertion, the HERV is treated by the host cells as a foreign genetic element, and is likely to be suppressed by the targeted methylation and mutations. However, at the later stages, when significant number of mutations has been already accumulated and when the retroviral genes are broken, the regulatory potential of a HERV may be released and recruited to modify the genomic balance of transcription factor binding sites. This process goes together with further accumulation and selection of mutations, which reshape the regulatory landscape of the human DNA. However, developmental reprogramming, stress or pathological conditions like cancer, inflammation and infectious diseases, can remove the blocks limiting expression and HERV-mediated host gene regulation. This, in turn, can dramatically alter the gene expression equilibrium and shift it to a newer state, thus further amplifying instability and exacerbating the stressful situation. PMID- 28642864 TI - The Effects of Fasting and Massive Diarrhea on Absorption of Enteral Vancomycin in Critically Ill Patients: A Retrospective Observational Study. AB - PURPOSE: Although vancomycin (VCM) is not absorbed from healthy intestinal mucosa, elevations in the serum VCM concentrations have been reported in some cases. The aims of this study are to evaluate the necessity of therapeutic drug monitoring (TDM) during enteral VCM administration in critically ill patients. MATERIALS AND METHODS: In this retrospective study, we enrolled 19 patients admitted to our intensive care unit who were treated with enteral VCM from December 2006 to January 2014. Clinical factors were compared between two groups: Group E whose serum concentrations were detectable, and Group N whose concentrations were below the detection limit of the VCM assay. RESULTS: Group E comprises 7 patients, and Group N comprises 12 patients. The fasting duration in Group E was significantly longer compared with that in Group N (17 vs. 8 days, p = 0.023). Furthermore, there was a significant correlation between the serum VCM concentrations and the fasting duration (r = 0.79, p < 0.0001), and the amount of diarrhea (r = 0.46, p = 0.046). No difference was observed in the amount of diarrhea at the time of TDM (Group E; 1,850 mL vs. Group N; 210 mL, p = 0.055) and in the Sequential Organ Failure Assessment subscore for the renal system at the time of TDM (Group E; 4.0 vs. Group N; 1.5, p = 0.068). CONCLUSION: Long durations of fasting and massive diarrhea were associated with elevations in the serum VCM concentrations, which suggested that TDM might be necessary during enteral VCM administration in critically ill patients. TRIAL REGISTRATION: UMIN Clinical Trials Registry identifier UMIN000016955. PMID- 28642866 TI - Evaluation of Serum for Pathophysiological Effects of Prolonged Low Salinity Water Exposure in Displaced Bottlenose Dolphins (Tursiops truncatus). AB - We conducted a retrospective study of serum biochemistry and hematologic findings from displaced, out-of-habitat bottlenose dolphins (Tursiops truncatus) exposed to various low salinity environments in waters along the southern United States including southeastern Atlantic and northern Gulf of Mexico. Serum sodium, chloride, and calculated osmolality were significantly lower and below reference ranges in displaced animals compared to free-ranging case control animals. This suggests clinical hyponatremia, hypochloremia, and hypo-osmolality due to an uptake of low saline water from the environment. In addition, significant differences were found in other serum chemistry variables, although none were outside of normal reference ranges for non-controlled free-ranging animals. Multiple linear regressions demonstrated the degree of salinity had a greater pathophysiologic response than the duration of fresh water exposure. The Na/Cl ratio and bicarbonate were the only variables that were significantly modulated by exposure duration. These findings suggest that the degree of salinity is a critical factor when assessing and managing care for dolphins chronically exposed to low salinity water. Results from this study indicate that changes in various biochemical parameters can be used to determine fresh water exposure and aid in determining the treatment for animals recovered from low salinity waters. PMID- 28642865 TI - Spinal Muscular Atrophy: From Defective Chaperoning of snRNP Assembly to Neuromuscular Dysfunction. AB - Spinal Muscular Atrophy (SMA) is a neuromuscular disorder that results from decreased levels of the survival motor neuron (SMN) protein. SMN is part of a multiprotein complex that also includes Gemins 2-8 and Unrip. The SMN-Gemins complex cooperates with the protein arginine methyltransferase 5 (PRMT5) complex, whose constituents include WD45, PRMT5 and pICln. Both complexes function as molecular chaperones, interacting with and assisting in the assembly of an Sm protein core onto small nuclear RNAs (snRNAs) to generate small nuclear ribonucleoproteins (snRNPs), which are the operating components of the spliceosome. Molecular and structural studies have refined our knowledge of the key events taking place within the crowded environment of cells and the numerous precautions undertaken to ensure the faithful assembly of snRNPs. Nonetheless, it remains unclear whether a loss of chaperoning in snRNP assembly, considered as a "housekeeping" activity, is responsible for the selective neuromuscular phenotype in SMA. This review thus shines light on in vivo studies that point toward disturbances in snRNP assembly and the consequential transcriptome abnormalities as the primary drivers of the progressive neuromuscular degeneration underpinning the disease. Disruption of U1 snRNP or snRNP assembly factors other than SMN induces phenotypes that mirror aspects of SMN deficiency, and splicing defects, described in numerous SMA models, can lead to a DNA damage and stress response that compromises the survival of the motor system. Restoring the correct chaperoning of snRNP assembly is therefore predicted to enhance the benefit of SMA therapeutic modalities based on augmenting SMN expression. PMID- 28642867 TI - Evaluation of the Effect of a Single Intra-articular Injection of Allogeneic Neonatal Mesenchymal Stromal Cells Compared to Oral Non-Steroidal Anti inflammatory Treatment on the Postoperative Musculoskeletal Status and Gait of Dogs over a 6-Month Period after Tibial Plateau Leveling Osteotomy: A Pilot Study. AB - OBJECTIVE: Compare the clinical and pressure walkway gait evolution of dogs after a tibial plateau leveling osteotomy (TPLO) for a cranial cruciate ligament rupture (CrCLR) and treatment with either a 1-month course of non-steroidal anti inflammatory drugs (NSAIDs) or a single postoperative intra-articular (IA) injection of allogeneic neonatal mesenchymal stromal cells (MSCs). STUDY DESIGN: Prospective, double-blinded, randomized, controlled, monocentric clinical study. ANIMALS: Sixteen client-owned dogs. MATERIALS AND METHODS: Dogs with unilateral CrCLR confirmed by arthroscopy were included. Allogeneic neonatal canine MSCs were obtained from fetal adnexa retrieved after C-section performed on healthy pregnant bitches. The dogs were randomly allocated to either the "MSCs group," receiving an IA injection of MSCs after TPLO, followed by placebo for 1 month, or the "NSAIDs group," receiving IA equivalent volume of MSCs vehicle after TPLO, followed by oral NSAID for 1 month. One of the three blinded evaluators assessed the dogs in each group before and after surgery (1, 3, and 6 months). Clinical score and gait and bone healing process were assessed. The data were statistically compared between the two groups for pre- and postoperative evaluations. RESULTS: Fourteen dogs (nine in the MSCs group, five in the NSAIDs group) completed the present study. No significant difference was observed between the groups preoperatively. No local or systemic adverse effect was observed after MSCs injection at any time point considered. At 1 month after surgery, bone healing scores were significantly higher in the MSCs group. At 1, 3, and 6 months after surgery, no significant difference was observed between the two groups for clinical scores and gait evaluation. CONCLUSION: A single IA injection of allogeneic neonatal MSCs could be a safe and valuable postoperative alternative to NSAIDs for dogs requiring TPLO surgery, particularly for dogs intolerant to this class of drugs. PMID- 28642868 TI - An Exploration of Gene-Gene Interactions and Their Effects on Hypertension. AB - Hypertension tends to perpetuate in families and the heritability of hypertension is estimated to be around 20-60%. So far, the main proportion of this heritability has not been found by single-locus genome-wide association studies. Therefore, the current study explored gene-gene interactions that have the potential to partially fill in the missing heritability. A two-stage discovery confirmatory analysis was carried out in the Framingham Heart Study cohorts. The first stage was an exhaustive pairwise search performed in 2320 early-onset hypertensive cases with matched normotensive controls from the offspring cohort. Then, identified gene-gene interactions were assessed in an independent set of 694 subjects from the original cohort. Four unique gene-gene interactions were found to be related to hypertension. Three detected genes were recognized by previous studies, and the other 5 loci/genes (MAN1A1, LMO3, NPAP1/SNRPN, DNAL4, and RNA5SP455/KRT8P5) were novel findings, which had no strong main effect on hypertension and could not be easily identified by single-locus genome-wide studies. Also, by including the identified gene-gene interactions, more variance was explained in hypertension. Overall, our study provides evidence that the genome-wide gene-gene interaction analysis has the possibility to identify new susceptibility genes, which can provide more insights into the genetic background of blood pressure regulation. PMID- 28642869 TI - Detection of MicroRNA in Hepatic Cirrhosis and Hepatocellular Carcinoma in Hepatitis C Genotype-4 in Egyptian Patients. AB - BACKGROUND: In Egypt, the prevalence of chronic hepatitis C (CHC) infection is 13.8% of whole population and about 80% of the patients with hepatocellular carcinoma have underling hepatitis C. AIM: This study was designed to assess the diagnostic value of plasma miR-122 and miR-21 in patients with CHC, genotype-4, to detect fibrosis progression versus noninvasive indices and their diagnostic value in detection of early stages of hepatocellular carcinoma (HCC). METHODOLOGY: A prospective study that included 180 patients, divided into 3 groups: healthy controls (group I), CHC patients (group II), and hepatitis C patients with HCC (group III); all cases were subjected to thorough clinical, radiological, and laboratory investigations. Selected biomarkers were evaluated and correlated with degree of liver damage. Results revealed that miR-122 followed by miR-21 had the highest efficiency in prediction of liver cell damage. Also, miR-21 was strongly correlated with vascular endothelial growth factor (VEGF) and alpha fetoprotein (alpha-FP) in HCC patients. CONCLUSIONS: Plasma miR 122 and miR-21 had strong correlation with degree fibrosis in HCV genotype-4 patients; consequently they can be considered as potential biomarker for early detection of hepatic fibrosis. Moreover, miR-21 can be used as a potential biomarker, for early detection of HCC combined with VEGF and alpha-FP. PMID- 28642870 TI - Imaging and Management of Incidental Renal Lesions. AB - The increased use of imaging modalities in the last years has led to a greater incidence in depicting abdominal incidental lesions. In particular, "incidentalomas" of the kidney are discovered in asymptomatic patients or patients who suffer from diseases not directly related to the kidneys. The aim of this paper is to provide the radiologist with a useful guide to recognize and classify the main incidental renal findings with the purpose of establishing the correct management. First we describe the so-called "pseudotumors" which are important to recognize in order to avoid a misdiagnosis. Afterwards we categorize true renal lesions into cystic and solid types, reporting radiological signs helpful in differentiating between benign and malignant nature. PMID- 28642871 TI - Promoting Mental Health in Italian Middle and High School: A Pilot Study. AB - AIM: In Italy, a handbook has been developed based on the principles of cooperative learning, life skills, self-effectiveness, and problem-solving at high school level. Early studies have shown the handbook's effectiveness. It has been hypothesized that the revised handbook could be more effective in middle schools. METHOD: The study design is a "pre- and posttest" that compares the results obtained from 91 students of the high schools with those of the 38 students from middle schools. The assessment was made through "self-reporting" questionnaires of (a) learning skills including problem-solving and (b) perceived self-efficacy in managing emotions, dysfunctional beliefs, and unhealthy behaviours (i.e., drinking/smoking). RESULTS: Significant improvements were observed in both groups with the exceptions of perceived self-efficacy in managing emotions. The improvement of dysfunctional beliefs and the learning of problem-solving skills were better in middle schools. CONCLUSION: The results confirm the authors' hypothesis that the use of this approach is much more promising in middle school. PMID- 28642872 TI - Chronic Expanding Hematoma in the Extremities: A Clinical Problem of Adhesion to the Surrounding Tissues. AB - Chronic expanding hematoma is characterized by continuous growth of a blood collection. We analyzed the clinical features of 7 patients with chronic expanding hematomas in the extremities, with an average age of 65.6 years. All lesions occurred in the lower extremities, with 4 seen in the thigh and 3 in the knee region. Six patients had subcutaneous hematomas, while 1 was deep-seated in the thigh. The magnetic resonance features of the lesion were compatible with those of a standard hematoma. A low signal intensity on T1- and T2-weighted imaging at the pseudocapsule was also characteristic. Cystic features were seen in 5 of 7 patients. All lesions were resected together with their pseudocapsule. In the subcutaneous lesions, it was necessary to resect adherent fascia, with or without involved skin. In the deep-seated thigh lesion, the common peroneal nerve was completely adherent to the pseudocapsule, a phenomenon from absence of the common peroneal nerve which appeared after resection. Chronic expanding hematomas of the extremities are predominantly located in the subcutaneous tissue of the lower extremity. The surrounding pseudocapsule is adherent to the adjacent tissues, and clinicians must be aware of this, especially when resecting a deep seated lesion. PMID- 28642873 TI - Serum Amyloid A Induces a Vascular Smooth Muscle Cell Phenotype Switch through the p38 MAPK Signaling Pathway. AB - Atherosclerosis is an important pathological condition which is accompanied by a vascular smooth muscle cell (VSMC) phenotype switch toward a synthetic phenotype. As an acute-phase protein, Serum Amyloid A (SAA) is thought to have a close relationship to atherosclerosis development. However, no study has investigated the direct effect of SAA on the VSMC phenotype switch, as well as the underlying mechanisms. The purpose of our study was to explore the effect of SAA on the VSMC phenotype switch and the potential mechanisms involved. In our study, we found that SAA induced the VSMC phenotype switch which reduced expression of the smooth muscle cell (SMC) marker and enhanced expression of the matrix synthesis related marker. The proliferative ability of VSMCs was also increased by SAA treatment. Furthermore, our research found that SAA activated the ERK1/2 and p38 MAPK signaling pathways. Finally, by applying the ERK1/2 and p38 inhibitors, U0126 and SB203580, we demonstrated that the SAA-induced VSMC phenotype switch was p38 dependent. Taken together, these results indicated that SAA may play an important role in promoting the VSMC phenotype switch through the p38 MAPK signaling pathway. PMID- 28642874 TI - Combination Treatment with PPARgamma Ligand and Its Specific Inhibitor GW9662 Downregulates BIS and 14-3-3 Gamma, Inhibiting Stem-Like Properties in Glioblastoma Cells. AB - PPARgamma is a nuclear receptor that regulates differentiation and proliferation and is highly expressed in many cancer cells. Its synthetic ligands, such as rosiglitazone and ciglitazone, and its inhibitor GW9662, were shown to induce cellular differentiation, inhibit proliferation, and lead to apoptosis. Glioblastoma is a common brain tumor with poor survival prospects. Recently, glioblastoma stem cells (GSCs) have been examined as a potential target for anticancer therapy; however, little is known about the combined effect of various agents on GSCs. In this study, we found that cotreatment with PPARgamma ligands and GW9662 inhibited stem-like properties in GSC-like spheres, which significantly express SOX2. In addition, this treatment decreased the activation of STAT3 and AKT and decreased the amounts of 14-3-3 gamma and BIS proteins. Moreover, combined administration of small-interfering RNA (siRNA) transfection with PPARgamma ligands induced downregulation of SOX2 and MMP2 activity together with inhibition of sphere-forming activity regardless of poly(ADP-ribose) polymerase (PARP) cleavage. Taken together, our findings suggest that a combination therapy using PPARgamma ligands and its inhibitor could be a potential therapeutic strategy targeting GSCs. PMID- 28642876 TI - Magnetic Separation Methods for the Detection of Mycobacterium avium subsp. paratuberculosis in Various Types of Matrices: A Review. AB - The main reasons to improve the detection of Mycobacterium avium subsp. paratuberculosis (MAP) are animal health and monitoring of MAP entering the food chain via meat, milk, and/or dairy products. Different approaches can be used for the detection of MAP, but the use of magnetic separation especially in conjunction with PCR as an end-point detection method has risen in past years. However, the extraction of DNA which is a crucial step prior to PCR detection can be complicated due to the presence of inhibitory substances. Magnetic separation methods involving either antibodies or peptides represent a powerful tool for selective separation of target bacteria from other nontarget microorganisms and inhibitory sample components. These methods enable the concentration of pathogens present in the initial matrix into smaller volume and facilitate the isolation of sufficient quantities of pure DNA. The purpose of this review was to summarize the methods based on the magnetic separation approach that are currently available for the detection of MAP in a broad range of matrices. PMID- 28642875 TI - Rapid Elimination of Blood Alcohol Using Erythrocytes: Mathematical Modeling and In Vitro Study. AB - Erythrocytes (RBCs) loaded with alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALD) can metabolize plasma ethanol and acetaldehyde but with low efficiency. We investigated the rate-limiting factors in ethanol oxidation by these enzymes loaded into RBCs. Mathematical modeling and in vitro experiments on human RBCs loaded simultaneously with ADH and ALD (by hypoosmotic dialysis) were performed. The simulation showed that the rate of nicotinamide-adenine dinucleotide (NAD+) generation in RBC glycolysis, but not the activities of the loaded enzymes, is the rate-limiting step in external ethanol oxidation. The rate of oxidation could be increased if RBCs are supplemented by NAD+ and pyruvate. Our experimental data verified this theoretical conclusion. RBCs loaded with the complete system of ADH, ALD, NAD+, and pyruvate metabolized ethanol 20-40 times faster than reported in previous studies. The one-step procedure of hypoosmotic dialysis is the optimal method to encapsulate ADH and ALD in RBCs after cell recovery, encapsulation yield, osmotic resistance, and RBC-indexes. Consequently, transfusion of the RBCs loaded with the complete metabolic system, including ADH, ALD, pyruvate, and NAD+ in the patients with alcohol intoxication, may be a promising method for rapid detoxification of blood alcohol based on metabolism. PMID- 28642877 TI - The Effect of Sodium Valproate on the Glioblastoma U87 Cell Line Tumor Development on the Chicken Embryo Chorioallantoic Membrane and on EZH2 and p53 Expression. AB - Literature data support evidences that glioblastoma (GBM) patients experience prolonged survival due to sodium valproate (NaVP) treatment. The study assessed the human GBM cell U87 xenograft studied in the chicken embryo chorioallantoic membrane (CAM) model evaluating NaVP effect on tumor. Three groups of tumors (each n = 10) were studied: nontreated, treated with 4 mM, and treated with 8 mM of NaVP. The majority of tumors without NaVP treatment during tumor growth destroyed the chorionic epithelium, invaded the mesenchyme, and induced angiogenesis. Incidence of tumor formation on CAM without invasion into the mesenchyme was higher when U87 cells were treated with NaVP; the effect significantly increased with NaVP concentration. Treatment with 8 mM of NaVP did not show clear dynamics of tumor growth during 5 days; at the same time, the angiogenesis failed. With a strong staining of EZH2, p53 in tumors without NaVP treatment was found, and NaVP significantly decreased the expression of EZH2- and p53-positive cells; the effect was significantly higher at its 8 mM concentration. NaVP has a function in blocking the growth, invasion, and angiogenesis of tumor in the CAM model; tumor growth interferes with EZH2 and p53 molecular pathways, supporting the NaVP potential in GBM therapy. PMID- 28642879 TI - Aortic Arch Calcification as a Predictor of Repeated Arteriovenous Fistula Failure within 1-Year in Hemodialysis Patients. AB - OBJECTIVES: The aim of the study was to identify the factors associated with repeated arteriovenous fistula (AVF) failure within 1-year, especially the impact of aortic arch calcification (AAC) on patency of AVF. MATERIALS AND METHODS: We retrospectively assessed chest radiography in hemodialysis patients who had undergone initial AVF. The extent of AAC was categorized into four grades (0-3). The association between AAC grade, other clinical variables, and repeated failure of AVF was then analyzed by binary logistic regression analysis. RESULTS: This study included 284 patients (158 males, mean age 61.7 +/- 13.1 years). Patients with higher AAC grade were older, had more frequently diabetes mellitus and cardiovascular disease, had lower diastolic blood pressure, and had higher corrected calcium and lower intact parathyroid hormone levels. In multivariate analysis, the presence of higher AAC grade (odds ratio (95% confidence interval): 2.98 (1.43-6.23); p = 0.004), lower mean corrected calcium (p = 0.017), and mean serum albumin level (p = 0.008) were associated with repeated failure of AVF. CONCLUSIONS: The presence of higher AAC grade, lower mean corrected calcium and mean serum albumin level were independently associated with repeated AVF failure within 1 year in hemodialysis patients. PMID- 28642880 TI - Longitudinal Patterns of Stability and Change in Tenacious Goal Pursuit and Flexible Goal Adjustment among Older People over a 9-Year Period. AB - Using the dual-process model of assimilative-tenacity (TGP) and accommodative flexibility (FGA), the study aims to identify trajectories of TGP and FGA over five time points within a 9-year period, explore the relationships between the trajectories of TGP and FGA, and explore if participants from distinct TGP and FGA trajectories differed in indicators of well-being and depression. Latent class growth analysis was used in a five-wave longitudinal design among an older population of 747 participants over 65 years. Results highlight (1) emergence of four trajectories for flexibility (low and increasing, moderate and increasing, moderately high and stable, and high and stable trajectories) and three trajectories for tenacity (low and stable, moderate and stable, and high and decreasing trajectories), (2) that older people belonging to particular trajectories of FGA are not more likely to belong to particular trajectories of TGP, and (3) that participants from the high and decreasing TGP and high or moderately high and stable FGA trajectories were characterized by high score of perceived health, satisfaction with life, and self-esteem and low score of depression moods. These results highlight that the heterogeneity in longitudinal TGP and FGA scores throughout the life span needs to be accounted for in future research. PMID- 28642878 TI - The Complexity of Zoonotic Filariasis Episystem and Its Consequences: A Multidisciplinary View. AB - Vector-borne transmitted helminthic zoonosis affects the health and economy of both developing and developed countries. The concept of episystem includes the set of biological, environmental, and epidemiological elements of these diseases in defined geographic and temporal scales. Dirofilariasis caused by different species of the genus Dirofilaria is a disease affecting domestic and wild canines and felines and man, transmitted by different species of culicid mosquitoes. This complexity is increased because Dirofilaria species harbor intracellular symbiont Wolbachia bacteriae, which play a key role in the embryogenesis and development of dirofilariae and in the inflammatory pathology of the disease. In addition, the vector transmission makes the dirofilariasis susceptible to the influence of the climate and its variations. The present review addresses the analysis of dirofilariasis from the point of view of the episystem, analyzing the complex network of interactions established between biological components, climate, and factors related to human activity, as well as the different problems they pose. The progress of knowledge on human and animal dirofilariasis is largely due to the multidisciplinary approach. Nevertheless, different aspects of the disease need to continue being investigated and cooperation between countries and specialists involved should be intensified. PMID- 28642881 TI - Combining Carcinoembryonic Antigen and Platelet to Lymphocyte Ratio to Predict Brain Metastasis of Resected Lung Adenocarcinoma Patients. AB - We aimed to evaluate the role of pretreatment carcinoembryonic antigen (CEA) and platelet to lymphocyte ratio (PLR) in predicting brain metastasis after radical surgery for lung adenocarcinoma patients. The records of 103 patients with completely resected lung adenocarcinoma between 2013 and 2014 were reviewed. Clinicopathologic characteristics of these patients were assessed in the Cox proportional hazards regression model. Brain metastasis occurred in 12 patients (11.6%). On univariate analysis, N2 stage (P = 0.013), stage III (P = 0.016), increased CEA level (P = 0.006), and higher PLR value (P = 0.020) before treatment were associated with an increased risk of developing brain metastasis. In multivariate model analysis, CEA above 5.2 ng/mL (P = 0.014) and PLR >= 120 (P = 0.036) remained as the risk factors for brain metastasis. The combination of CEA and PLR was superior to CEA or PLR alone in predicting brain metastasis according to the receiver operating characteristic (ROC) curve analysis (area under ROC curve, AUC 0.872 versus 0.784 versus 0.704). Pretreatment CEA and PLR are independent and significant risk factors for occurrence of brain metastasis in resected lung adenocarcinoma patients. Combining these two factors may improve the predictability of brain metastasis. PMID- 28642883 TI - Genetic Polymorphisms of Cytotoxic T-Lymphocyte Antigen 4 in Primary Biliary Cholangitis: A Meta-Analysis. AB - BACKGROUND AND AIM: The connection between gene polymorphisms of cytotoxic T lymphocyte-associated protein 4 (CTLA4) and primary biliary cholangitis (PBC) is still vague and blurred. The purpose of this study is to precisely estimate the association of the polymorphisms of CTLA4 with the risk of PBC by using a meta analysis. METHODS: PubMed and the Chinese National Knowledge Infrastructure (CNKI) database were used to search correlative literatures, and the documents which were about the relationships between the polymorphisms of CTLA4 (rs231775, rs231725, rs3087243, and rs5742909) and PBC were collected as of June 2016. The strength of correlation based on odds ratios (ORs) and its 95% confidence intervals (95%CIs) was computed by STATA. RESULTS: Generally, in rs231775, a significant risk was found in G allele, the value of OR was 1.32, and its 95%CI was 1.19 to 1.47. The same situation was found in A allele of rs231725, the value of OR was 1.33, and its 95%CI was 1.22 to 1.45. As genotypic level, different genotypic models were also found to have obvious relevance with PBC in rs231775 and rs231725. No obvious connections were found in other SNPs. CONCLUSION: This study indicated that the polymorphisms of rs231775 and rs231725 would be the risk factors of PBC. PMID- 28642882 TI - Tumor-Related Exosomes Contribute to Tumor-Promoting Microenvironment: An Immunological Perspective. AB - Exosomes are a kind of cell-released membrane-form structures which contain proteins, lipids, and nucleic acids. These vesicular organelles play a key role in intercellular communication. Numerous experiments demonstrated that tumor related exosomes (TEXs) can induce immune surveillance in the microenvironment in vivo and in vitro. They can interfere with the maturation of DC cells, impair NK cell activation, induce myeloid-derived suppressor cells, and educate macrophages into protumor phenotype. They can also selectively induce effector T cell apoptosis via Fas/FasL interaction and enhance regulatory T cell proliferation and function by releasing TGF-beta. In this review, we focus on the TEX-induced immunosuppression and microenvironment change. Based on the truth that TEXs play crucial roles in suppressing the immune system, studies on modification of exosomes as immunotherapy strategies will also be discussed. PMID- 28642884 TI - Cxcl8b and Cxcr2 Regulate Neutrophil Migration through Bloodstream in Zebrafish. AB - Neutrophils play an essential role during an inflammatory response, which is dependent on their rapid recruitment from the bone marrow to the vasculature. However, there is no information about the molecular signals that regulate neutrophil entry to circulation during an inflammatory process in humans. This is mainly due to the lack of a suitable model of study that contains similar set of molecules and that allows in vivo analyses. In this study, we used the zebrafish to assess the role of Cxcl8a, Cxcl8b, and Cxcr2 in neutrophil migration to blood circulation after injury. Using Tg(BACmpx:GFP)i114 transgenic embryos and two damage models (severe and mild), we developed in vivo lack of function assays. We found that the transcription levels of cxcl8a, cxcl8b, and cxcr2 were upregulated in the severe damage model. In contrast, only cxcr2 and cxcl8a mRNA levels were increased during mild damage. After knocking down Cxcl8a, neutrophil quantity decreased at the injury site, while Cxcl8b decreased neutrophils in circulation. When inhibiting Cxcr2, we observed a decrease in neutrophil entry to the bloodstream. In conclusion, we identified different functions for both Cxcl8 paralogues, being the Cxcl8b/Cxcr2 axis that regulates neutrophil entry to the bloodstream, while Cxcl8a/Cxcr2 regulates the migration to the affected area. PMID- 28642886 TI - Making a Difference in Malawi and Zambia Through Health Education and Public Health Best Practices. AB - A 2-year U.S. Department of State-funded project* was conducted with the purpose of engaging health professionals from Malawi and Zambia who are actively involved in health care and health education for marginalized populations to develop, implement, and evaluate health education and public health interventions/programs. Twenty-six health professionals from Malawi and Zambia, referred to as Global Health Fellows, participated in the 2-year program, of which the main training component was conducted in the United States. Fellows were exposed to health education and public health best practices and developed an action plan to address a health problem of concern in their respective communities/countries. After completion of the program, Fellows received $300 to implement their action plans. Teams of Americans involved in the training program participated in follow-up visits to Malawi and Zambia to observe real-time progress on Fellows' respective action plans. The project was successful in creating an educational experience focused on health education best practices as well as implementation of action plans to address selected health problems in Malawi and Zambia. PMID- 28642885 TI - Neuroanatomical correlates of familial risk-for-depression and religiosity/spirituality. AB - OBJECTIVE: To examine potential neural substrates that underlie the interplay between religiosity/spirituality and risk-for-depression. A new wave of data from a longitudinal, three generation study of individuals at high risk for depression is presented. In addition to providing new longitudinal data, we extend previous findings by employing additional (surface-based) methods for examining cortical volume. MEASURES PARTICIPANTS AND METHODS: Magnetic resonance imaging (MRI) scans were collected on 106 second and third generation family members at high or low risk for major depression defined by the presence or absence of depression in the first generation. Religiosity/spirituality measures were collected at the same time as the MRI scans and comprised self-report ratings of personal religious/spiritual (R/S) importance and frequency of religious attendance. Analyses were carried out with Freesurfer. Interactive effects of religiosity/spirituality and risk-for-depression were examined on measures of cortical thickness and cortical surface area. RESULTS: A high degree of belief in the importance of religion/spirituality was associated with both a thicker cortex and a larger pial surface area in persons at high risk for familial depression. No significant association was found between cortical regions and religious attendance in either risk group. CONCLUSIONS AND RELEVANCE: The results support previous findings of an association between R/S importance and cortical thickness in individuals at high risk for depression, and extend the findings to include an association between R/S importance and greater pial surface area. Moreover, the findings suggest these cortical changes may confer protective benefits to religious/spiritual individuals at high risk for depression. PMID- 28642887 TI - Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS. AB - OBJECTIVE: Several factors influence the clinical course of autoimmune inflammatory diseases such as MS and inflammatory bowel disease. Only recently, the complex interaction between the gut microbiome, dietary factors, and metabolism has started to be appreciated with regard to its potential to modulate acute and chronic inflammation. One of the molecular sensors that mediates the effects of these environmental signals on the immune response is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with key functions in immune cells. METHODS: In this study, we analyzed the levels of AHR agonists in serum samples from patients with MS and healthy controls in a case control study. RESULTS: We detected a global decrease of circulating AHR agonists in relapsing-remitting MS patients as compared to controls. However, during acute CNS inflammation in clinically isolated syndrome or active MS, we measured increased AHR agonistic activity. Moreover, AHR ligand levels in patients with benign MS with relatively mild clinical impairment despite longstanding disease were unaltered as compared to healthy controls. CONCLUSIONS: Collectively, these data suggest that AHR agonists in serum are dynamically modulated during the course of MS. These findings may guide the development of biomarkers to monitor disease activity as well as the design of novel therapeutic interventions for MS. PMID- 28642888 TI - Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS. AB - OBJECTIVE: To evaluate (1) the frequency of aquaporin-4 antibody (AQP4-ab) seropositive cases among patients treated with natalizumab (NAT) and previously diagnosed with MS (MSNAT) in a nationwide cohort, (2) the clinical course of NAT treated AQP4-ab-seropositive neuromyelitis optica spectrum disorder (NMOSD) patients (NMONAT), (3) AQP4-ab titers in NMONAT and AQP4-ab-seropositive NMOSD treated with other immunotherapies (NMOIT), and (4) immune mechanisms influencing disease activity in NMONAT. METHODS: MSNAT serum samples were retrospectively screened with a cell-based assay for AQP4-IgG and titers determined by ELISA. The annualized relapse rate (ARR) and disability progression were assessed. Serum levels of proinflammatory cytokines (interleukin [IL]-1beta, IL-4, IL-6, IL-8, IL 10, IL-17, IL-21, and interferon [IFN]-gamma) and the chemokine CXCL-10 of NMONAT patients identified in this (n = 4) and a previous study (n = 5) were measured by cytometric bead array and ELISA. RESULTS: Of the 1,183 MSNAT patients (851 female, median 9 NAT infusions), only 4 (0.33%; 3 female, 1 male) had AQP4-IgG. Of these, 2 fulfilled the 2006 NMO criteria and all met the 2015 NMOSD criteria. The ARR was higher in NMONAT vs MSNAT (p = 0.0182). All 4 NMONAT patients had relapses and 2 had an increase of disability. AQP4-ab titers were higher in NMONAT (n = 9) vs NMOIT (n = 13; p = 0.0059). IL-8, IL-1beta, and IFN-gamma serum levels were significantly higher, and CXCL-10 was significantly lower in NMONAT vs NMOIT. CONCLUSIONS: Misdiagnosis of NMOSD with MS is rare. NAT was not able to control disease activity in NMONAT patients, who had higher serum levels of AQP4 IgG and proinflammatory cytokines than patients with NMOSD treated with other immunotherapies. PMID- 28642889 TI - ANCA-associated vasculitis predominantly presenting with severe myalgias. PMID- 28642890 TI - Aryl hydrocarbon receptor activity may serve as a surrogate marker for MS disease activity. PMID- 28642892 TI - Dacrystic seizures-a cry for help. PMID- 28642891 TI - Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial. AB - OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. METHODS: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4:1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. RESULTS: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer >=100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations <=0.3 MUg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for >=155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. CONCLUSIONS: These results support the continued investigation of VX15/2503 in neurodegenerative diseases. CLINICALTRIALSGOV IDENTIFIER: NCT01764737. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that anti semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference -0.7%, 95% CI -28.0% to 32.7%). PMID- 28642893 TI - Effectiveness of different irrigation protocols on calcium hydroxide removal from simulated immature teeth after apexification. AB - Aim: To evaluate the effectiveness of different irrigation solutions and ultrasonic activation of the irrigation solutions on the removal of calcium hydroxide (Ca(OH)2) from the simulated immature root canals after apexification. Materials and methods: One-hundred and one single-rooted teeth were used. The root canals were shaped with ProTaper rotary files up to F5. Simulation of roots with immature apices was carried out using size 4 Unicore drills. An injectable Ca(OH)2 was injected into each root canal, and packed to the working length. Then, cotton pellets were placed over canal orifices, and apical and coronal parts of the roots were sealed with resin-modified glass ionomer cement, and light cured. Specimens were stored in distilled water for 3 months at 37 degrees C. After 3 months, the temporary coronal seal was removed and the samples were randomly divided into: (a) saline (n = 20), (b) ultrasonic activation of saline (n = 20), (c) sodium hypochlorite (NaOCl) (n = 20), (d) ultrasonic activation of NaOCl (n = 15), (e) chlorhexidine digluconate (CHX) (n = 20) and one positive control group (n = 3) and one negative control group (n = 3). The amount of remaining Ca(OH)2 on the canal walls was measured under stereomicroscope with 30* magnification. Comparisons between groups were made by the non-parametric Kruskal Wallis test and Dunn post-test at a significance level of p < 0.05. Results: There were no significant differences among the saline, ultrasonic activation of saline, NaOCl, ultrasonic activation of NaOCl and CHX (p > 0.05) groups. Conclusions: Irrigation solutions and ultrasonic activation of the irrigation solutions could not completely remove Ca(OH)2 from the simulated immature root canals. PMID- 28642894 TI - The effect of short fiber composite base on microleakage and load-bearing capacity of posterior restorations. AB - Objectives: To determine the marginal microleakage of Class II restorations made with different composite base materials and the static load-bearing capacity of direct composite onlay restorations. Methods: Class II cavities were prepared in 40 extracted molars. They were divided into five groups (n = 8/group) depending on composite base material used (everX Posterior, SDR, Tetric EvoFlow). After Class II restorations were completed, specimens were sectioned mid-sagitally. For each group, sectioned restorations were immersed in dye. Specimens were viewed under a stereo-microscope and the percentage of cavity leakage was calculated. Ten groups of onlay restorations were fabricated (n = 8/group); groups were made with composite base materials (everX Posterior, SDR, Tetric EvoFlow, Gradia Direct LoFlo) and covered by 1 mm layer of conventional (Tetric N-Ceram) or bulk fill (Tetric EvoCeram Bulk Fill) composites. Groups made only from conventional, bulk fill and short fiber composites were used as control. Specimens were statically loaded until fracture. Data were analyzed using ANOVA (p = 0.05). Results: Microleakage of restorations made of plain conventional composite or short fiber composite base material showed statistically (p < 0.05) lower values compared to other groups. ANOVA revealed that onlay restorations made from short fiber-reinforced composite (FRC) as base or plain restoration had statistically significant higher load-bearing capacity (1593 N) (p < 0.05) than other restorations. Conclusion: Restorations combining base of short FRC and surface layer of conventional composite displayed promising performance related to microleakage and load-bearing capacity. PMID- 28642895 TI - Effects of six different preventive treatments on the shear bond strength of orthodontic brackets: in vitro study. AB - Objective: The aim of this study is to evaluate the effect of six different prophylactic agents on shear bond strength (SBS) of orthodontic brackets. Materials and methods: One hundred twenty-six freshly extracted mandibular bovine incisors were used. Teeth were randomly divided into 7 equal groups (18 per group) as follows: group-1 served as control with no pre-treatment; group-2 enamel treated with fluoride varnish (Fluor Protector, Ivoclar Vivadent); group-3 containing casein-phosphopeptide-amorphous calcium-phosphate (CPP-ACP) paste (GC Tooth Mousse, RECALDENTTM); group-4 with ozone (HealOzone, Kavo); group-5 with glycine powder (Perio Flow, EMS); group-6 with hydroxyapatite powder 99.5% (Coswell S.p.A.); group-7 with a toothpaste made of hydroxyapatite nanocrystals (BioRepair(r) Plus, Coswell S.p.A). Brackets were all bonded using the same technique with transbond XT (3 M Unitek, Monrovia, CA). All the bonded specimens were stored for 24 h in deionized water (37 degrees C) and subjected to thermal cycling for 1000 cycles. The SBS was measured with an Instron Universal Testing machine and the adhesive remnant was assessed with the adhesive remnant index (ARI) using a stereomicroscope at 10* magnification. Results: Statistical differences (ANOVA) were found among the seven investigated groups (F = 12.226, p < 0.001). SBS of groups 2, 5 and 6 were significantly lower than the control group (p < 0.05). ARI scores (chi-square test) were correlated with the differences of SBS values. Conclusion: CPP-ACP paste, ozone or BioRepair(r) did not compromise on bracket bond strength. Fluoride, glycine or hydroxyapatite significantly decreased the SBS; only the fluoride group showed significant clinically low (<6 MPa) SBS values. PMID- 28642896 TI - Effect of various intracanal medicaments on the bond strength of self-adhesive resin cement to root canal dentin. AB - Objective: It has been shown that the irrigating solutions and medicament used during root canal treatment may affect the bonding strength. The aim of this study was to evaluate the effect of triple antibiotic paste (TAP), double antibiotic paste (DAP) and calcium hydroxide (CH) on the bond strength to root dentin of self-adhesive resin cement. Materials and methods: Forty-eight single rooted human teeth were prepared and randomly divided into one control and three experimental groups (dressing with TAP, DAP or CH). After removal of intracanal dressing, post-spaces were created and fiber posts cemented to the root canal using a self-adhesive resin cement. A push-out test was performed. The data obtained from the push-out test were analyzed using analysis of variance and Bonferroni post hoc tests (p = 0.05). Results: TAP decreased the bond strength of self-adhesive resin cement bond strength to root dentin compared to the control group (p = 0.012), while CH and DAP did not influence this (p > 0.05). The majority of specimens exhibited adhesive failures. Conclusions: TAP decreased the bond strength of self-adhesive to the root dentin compared to the control group. PMID- 28642897 TI - Influence of peak oral temperatures on veneer-core interface stress state. AB - Objective: There is a growing interest for the use of Y-TZP zirconia as core material in veneered all-ceramic prostheses. The objective of this study was to evaluate the influence of CET on the stress distribution of a porcelain layered to zirconia core single crowns by finite elements analysis. Material and methods: CET of eight different porcelains was considered during the analysis. Results: Results of this study indicated that the mismatch in CET between the veneering porcelain and the Y-TZP zirconia core has to be minimum (0.5-1 MUm/mK) so as to decrease the growing of residual stresses which could bring chipping. Conclusions: The stress state due to temperature variation should be carefully taken into consideration while studying the effect of mechanical load on zirconia core crown by FEA. The interfacial stress state can be increased by temperature variation up to 20% with respect to the relative failure parameter (interface strength in this case). This means that stress due to mechanical load combined to temperature variation-induced stress can lead porcelain veneer-zirconia core interfaces to failure. PMID- 28642898 TI - Efficacy of whitening oral rinses and dentifrices on color stability of bleached teeth. AB - Objective: This study aimed to evaluate the effect of whitening toothpastes and mouthrinses on the color stability of teeth bleached with 16% carbamide peroxide (CP) after immersion in coffee solution. Materials and methods: Specimens obtained from bovine incisors were bleached with 16% CP for 14 days. After bleaching, the specimens were stained in coffee solution for 24 h and randomly divided into eight groups according to the following products (n = 10): distilled water (control group, DW), Scope White mouthrinse (SW), Crest 3D White mouthrinse (CWR), Crest 3D White toothpaste (CWT), Crest 3D White toothpaste and Crest 3D White mouthrinse (CWT + CWR), Listerine Whitening toothpaste (LWT), Listerine Whitening mouthrinse (LWR), and Listerine Whitening mouthrinse and Listerine Whitening toothpaste (LWR + LWT). Color measurements were conducted using a spectrophotometer. The data were assessed by analysis of variance for repeated measures and Tukey's multiple comparison test (p < 0.05). Results: Immersion in coffee solution after bleaching caused perceptible staining on tooth specimens (DeltaE > 3.46). The whitening effect of CWR on teeth stained after bleaching was significantly greater than that in the other groups (p < 0.001). Tooth whitening (DeltaE) in each group showed no significant difference from 6 to 12 weeks (p > 0.05). The combination of mouthrinse and toothpaste did not increase the degree of tooth whitening. Conclusion: Whitening mouthrinse and toothpaste had similar effects on the control group in terms of whitening of teeth stained after bleaching. Nevertheless, Crest 3D White mouthrinse produced the greatest recovery whitening effect among all the products tested. PMID- 28642899 TI - Fracture of porcelain-veneered gold-alloy and zirconia molar crowns using a modified test set-up. AB - Objective: The main aim of this study was to compare fracture load and fracture mode of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) and metal ceramic (MC) molar crowns using a modified test set-up to produce fractures similar to those seen in vivo, i.e. fractures of the veneering material rather than complete fractures. Materials and methods: 13 high-noble-alloy MC and 13 Y TZP molar crowns veneered with porcelain were manufactured. The crowns were artificially aged before final load to fracture. Load was applied using a 7 mm diameter steel ball exerting force on the cusps with stresses directed toward the core-veneer interface. Fracture surface analysis was performed using light- and scanning electron microscopy. Results: The test design produced fractures of the veneering material rather than complete fractures. MC crowns withstood significantly (p > 0.001) higher loads (mean 2155 N) than Y-TZP (mean 1505 N) crowns, yet both endure loads sufficient for predictable clinical use. Fracture mode differed between MC and Y-TZP. MC crowns exhibited fractures involving the core-veneer interface but without core exposure. One Y-TZP crown suffered a complete fracture, all others except one displayed fractures of the veneering material involving the core-veneer interface with core exposure. Conclusions: The test set-up produces fractures similar to those found in vivo and may be useful to evaluate the core-veneer interface of different material systems, both metals and ceramics. The study confirms suggestions from previous studies of a weaker core-veneer bond for Y-TZP compared to MC crowns. PMID- 28642900 TI - The effects of sintering temperature and duration on the flexural strength and grain size of zirconia. AB - Objective: This study investigated the effect of different sintering temperatures and times on the flexural strength and grain size of zirconia. Material and methods: Zirconia specimens (In-Coris ZI, In-Coris TZI, 120 samples) were prepared in a partially sintered state. Subsequently, the specimens were randomly divided into three groups and sintered at different final sintering temperatures and for various durations: 1510 degrees C for 120 min, 1540 degrees C for 25 min and 1580 degrees C for 10 min. Three-point flexural strength (for 120 samples, 20 samples per group) was measured according to the ISO 6872: 2008 standards. The grain sizes were imaged by scanning electron microscopy (SEM) and the phase transitions were determined by X-ray diffraction (XRD). The data were analyzed using one-way ANOVA and Duncan tests (p < 0.05). Results: The highest flexural strength was observed in ZI and TZI samples sintered at 1580 degrees C for 10 min. The differences between the ZI samples sintered at 1510 degrees C for 120 min and those sintered at 1540 degrees C for 25 min were statistically insignificant. Also, TZI samples sintered at 1510 degrees C for 120 min and those sintered at 1540 degrees C for 25 min also did not show any statistically significant differences. There were no visible differences in the grain sizes between the ZI and TZI specimens. The XRD patterns indicated similar crystalline structure for both materials subjected to the three different procedures. Conclusions: The results of this study showed that experimented high sintering temperature and short sintering time combination increases the flexural strength of zirconia. PMID- 28642901 TI - Antibacterial activity of gold-titanates on Gram-positive cariogenic bacteria. AB - Objective: Gram-positive cariogenic bacteria are etiological agents in dental caries; therefore, strategies to inhibit these bacteria to reduce the incident of this disease have intensified. In this study, we investigated antibacterial activities of titanates and gold-titanates against Lactobacillus casei (Lc) and Streptococcus mutans (Sm). Materials and methods: Monosodium titanate (MST), nanomonosodium titanate (nMST) and amorphous peroxo-titanate (APT), which are inorganic compounds with high-binding affinity for specific metal ions, were used. Total bacterial proteins were measured to represent bacterial cell mass after 24 h incubation with gold-titanates. We further examined the effect of nMST Au(III) concentrations (10,200,400 mg/L) on Lc and Sm cell viability over time via Live/Dead fluorescent staining and colony forming units (CFUs). Transmission electron microscopy (TEM) was used to determine specific locations on the bacterial cells affected by the nMST-Au(III). Results: We found all gold titanates and APT alone reduced bacterial protein for Lc (p value <0.001) while only MST-Au(III) and nMST-Au(III) affected Sm growth (p value <0.001). Overall, nMST-Au(III) showed the most effectiveness against both Lc and Sm at 400 mg/L. The Live/Dead staining showed all concentrations of nMST-Au(III) affected Lc growth but only 200 and 400 mg/L nMST-Au(III) interrupted Sm growth. The growth curves based on CFUs/mL showed all nMST-Au(III) concentrations affected growth of both Lc and Sm. TEM images showed nMST-Au(III) attached to Lc and Sm cell wall and were internalized into both cells.Conclusions: nMST-Au(III) demonstrated potential antimicrobial activity against Gram-positive cariogenic bacteria. These results support further development of nMST-Au(III) as a potential novel material to prevent dental caries. PMID- 28642902 TI - Visible light cure characteristics of a cycloaliphatic polyester dimethacrylate alternative oligomer to bisGMA. AB - Objective: The goal of this study was to characterize the light curing characteristics of a new oligomer PEM-665 designed to be used as an alternative monomer to BisGMA. Materials and methods: PEM-665 (P) and BisGMA (B) solutions were prepared with triethylene glycol dimethacrylate (T) diluent in different weight proportions (70/30 and 50/50). Solutions containing 70% P and 30% T were designated as 70PT, 70%B and 30%T as 70BT, 50%P and 50%T as 50PT and 50%B and 50%T as 50BT. The initiators were CQ (EDMAB was used as amine accelerator for CQ) and DPO in 1% concentration. Eight solutions were prepared in a factorial design: 70PT/DPO; 70PT/CQ; 50PT/DPO; 50PT/CQ; 70BT/DPO; 70BT/CQ; 50BT/DPO; 50BT/CQ. BISCO VIP visible light was used to cure the monomer solutions using 30 s exposure time and 400 W power setting. TA Instruments Differential Scanning Calorimeter (DSC 2910) was used to determine the heat of cure (J/g) during polymerization at 37 degrees C, from which molar heat of cure (kJ/mole) and %Conversion values were estimated. Results: Range of mean values as a function monomer selections were: heat of cure (J/g): 161.7 for 70PT/DPO system to 198.6 for 50BT/CQ system; molar heat of cure (kJ/mole): 67.3 for 70BT/DPO to 78.86 for 50PT/CQ; % conversion: 59.9 for 70BT/DPO to 70.3 for 50PT/CQ. Analysis of variance and Tukey HSD pairwise contrast showed statistically significant differences between % conversion means of PEM and BisGMA mixtures, with PEM mixtures showing significantly higher mean values. Conclusions: The results suggest that PEM-665 is a promising candidate material for dental polymer applications. PMID- 28642903 TI - Microhardness evaluation of silorane and methacrylate composites submitted to erosion and abrasion processes. AB - Objective: The aim of this study was to evaluate the Knoop hardness number (KHN) of methacrylate (MC) and silorane (SC) composites after being submitted to erosion and abrasion processes. Material and methods: Forty samples were made with each composite: MC and SC. The samples were divided into eight groups (n = 10) according to the type of composite (G1-G4, MC; G5-G8, SC) and the beverages involved in the erosion process (G1 and G5 - Control (C), without erosion, with abrasion; G2 and G6 - Orange Juice (OJ), abrasion; G3 and G7 - Smirnoff Ice(r) (SI), abrasion; G4 and G8 - Gatorade(r) (GA), abrasion). The KHN test was performed 24 h after the last cycle of erosion/abrasion. Results: The MC groups showed smaller KHN values for the SI group (p < 0.05) when compared to the Control and OJ groups; however, for the SC groups, no differences were found (p > 0.05). Conclusion: Methacrylate composite when submitted to acidic beverages erosive challenge combined with abrasive process might alter its surface microhardness. However, the beverages used in the present study were not able to interfere in silorane composite surface microhardness. PMID- 28642904 TI - In vitro element release and biological aspects of base-metal alloys for metal ceramic applications. AB - Objective: The aims of this study were to investigate the release of element from, and the biological response in vitro to, cobalt-chromium alloys and other base-metal alloys used for the fabrication of metal-ceramic restorations. Material and methods: Eighteen different alloys were investigated. Nine cobalt chromium alloys, three nickel-chromium alloys, two cobalt-chromium-iron alloys, one palladium-silver alloy, one high-noble gold alloy, titanium grade II and one type III copper-aluminium alloy. Pure copper served as positive control. The specimens were prepared according to the ISO standards for biological and corrosion testing. Passive leaching of elements was measured by using Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) after incubation in cell culture media, MEM, for 3 days. Corrosion testing was carried out in 0.9% sodium chloride (NaCl) and 1% lactic acid for 7 days, and the element release was measured by Inductively Coupled Plasma - Optical Emission Spectroscopy (ICP-OES). The biological response from the extract solutions was measured though MTT cytotoxicity testing and the Hen's egg test-chorio-allantoic membrane (HET-CAM) technique for irritationt. Results: The corrosion test showed similar element release from base-metal alloys compared to noble alloys such as gold. Apart from the high-copper alloy, all alloys expressed low element release in the immersion test, no cytotoxic effect in the MTT test, and were rated non-irritant in the HET CAM test. Conclusions: Minimal biological response was observed for all the alloys tested, with the exception of the high-copper alloy. PMID- 28642905 TI - Bond durability of contemporary adhesive systems to pulp chamber dentin. AB - Objective: The purpose of this study was to evaluate long-term bond strengths of dentin adhesive systems, which include one-step self-etch adhesive systems (Optibond All-in-one, Kerr; Adper Prompt L-POP, 3 M ESPE), a three-step etch-and rinse adhesive (Optibond FL, Kerr) and two-step self-etch adhesive (AdheSE Bond, Ivoclar), applied to pulp chamber dentin surfaces after 12-month water storage by using microtensile bond strength (uTBS) test. Materials and methods: Dentin adhesive systems were applied to unprepared pulp chamber dentin surfaces according to manufacturer's directions, respectively (n = 5). After applying adhesive systems, composite buildups were done incrementally. Bond strengths to pulp chamber dentin surfaces were determined using uTBS test after water storage for 24 h and 12 month. Kruskal-Wallis analysis and Mann-Whitney U-test for pairwise comparisons were used to determine statistical differences in uTBS between the groups at a significance level of 5%. Results: There were no significant differences in uTBS between storage periods for tested adhesives regardless adhesive class. Conclusion: Bond durability of tested adhesive systems, including one-bottle self-etch adhesives with pulp chamber dentin surfaces, may be considered stable after 12-month water storage. Therefore, one step self-etch, also called "user-friendly" adhesives may perform and traditional three-step etch-and-rinse adhesives in the long-term when used for bonding to pulp chamber dentin surfaces. PMID- 28642906 TI - Reinforcing effect of glass fiber-reinforced composite reinforcement on flexural strength at proportional limit of a repaired denture base resin. AB - Objective: This study evaluated the reinforcing effect of glass fiber-reinforced composite (FRC) reinforcement on flexural strength at the proportional limit (FS PL) of a repaired denture base resin. Materials and methods: Repaired denture base resins reinforced with metal and with FRC reinforcement, and that without reinforcement were tested. The ultimate flexural strength, the FS-PL and the elastic modulus of repaired denture base resins were tested. The joint efficiency (times) of the repaired denture base resins on the intact denture base resin was evaluated. Results: The repaired denture base resins reinforced with metal reinforcement and with FRC reinforcement had significantly higher ultimate flexural strength than the repaired denture base resin without reinforcement (p < 0.05) and were not significantly different from each other (p > 0.05). The FS-PL of a repaired denture base resin reinforced with the FRC reinforcement was similar to that with the metal reinforcement (p > 0.05), and these were significantly higher than the FS-PL of a repaired denture base resin without reinforcement (p < 0.05). The elastic modulus of the repaired denture base resin reinforced with the FRC reinforcement was significantly lower than that with metal reinforcement (p < 0.05) and was significantly higher than that without reinforcement (p < 0.05). The joint efficiency of the FRC reinforced specimen was 0.98. Conclusion: The FRC reinforcement had a reinforcing effect on the FS-PL of a repaired denture base resin. PMID- 28642907 TI - Flexural strengths of reinforced denture base resins subjected to long-term water immersion. AB - Objective This study evaluated the flexural strengths of reinforced denture base resins subjected to long-term water immersion. Materials and methods Acrylic denture base resin reinforced with metal wire or glass fiber-reinforced composite (FRC), and without reinforcement were tested. Bar-shaped specimens were fabricated. Half of the specimens were stored in 37 degrees C distilled water for 50 hours (h), the other half were stored in 37 degrees C distilled water for 180 days (d) before testing. Ten specimens were fabricated per group for each reinforcement/water immersion period combination. The ultimate flexural strength and flexural strength at the proportional limit of reinforced denture base resin were tested. Results The 180 d bulk specimen possessed significantly lower ultimate flexural strength compared with the 50 h bulk specimen (p < 0.05). The ultimate flexural strength of the 50 h metal, 50 h FRC, 180 d metal and the 180 d FRC reinforcement specimens were not significantly different from each other (p > 0.05). The 180 d bulk specimen had a significantly lower flexural strength at the proportional limit compared to the 50 h bulk specimen. The 180 d reinforced specimens of metal and FRC were not significantly different from each of the 50 h specimens. Conclusion The flexural strengths of a reinforced denture base resin did not change after long-term water immersion. PMID- 28642908 TI - Methodologies for measuring the setting times of mineral trioxide aggregate and Portland cement products used in dentistry. AB - Objective The current standard used to measure setting time for Mineral Trioxide Aggregate (MTA) involves indentation testing with arbitrary weights. This study compared indentation testing against rheological measurements and assessed the influences of particle size and the inclusion of bismuth oxide on the setting time of experimental MTA and Portland cement (PC). Material and methods Two PCs (P1 and P2) of different particle sizes were produced using the same clinker. From these two PCs, two experimental MTAs (M1 and M2) were created with the addition of bismuth oxide. Particle size distributions were assessed using laser diffraction analysis. Indentation setting time tests were performed in accordance to the Gillmore needle test. Elastic modulus was assessed using a strain controlled rheometer at 1 rad s-1 and an applied strain of 0.01%. Results P1, P2, M1 and M2 cements had median particle sizes of 6.1, 12.5, 6.5 and 13.0 MUm, respectively. Using indentation testing, final setting times were ranked P1 < M1 < P2 < M2. The ranking of the final setting time corresponded with the rheological assessment of time required to reach 95% of the elastic modulus plateau. Conclusions The time to reach 95% elastic modulus plateau of 9.3 min corresponds to a time close to the point where the material can be overlaid with another restorative material to give a final restoration. The 95% plateau value for elastic modulus may be a more useful parameter for determining how the setting reaction of PC and MTA cements progress over time. PMID- 28642909 TI - Wear resistance of injection-molded thermoplastic denture base resins. AB - Objective This study investigated the wear resistance of injection-molded thermoplastic denture base resins using nanoindentation instrument. Materials and methods Six injection-molded thermoplastic denture base resins (two polyamides, two polyesters, one polycarbonate, one polymethylmethacrylate [PMMA]) and a PMMA conventional heat-polymerized denture-based polymer control were tested. Elastic modulus, hardness, wear depth, and roughness were calculated using a nanoindentation instrument. Results Elastic modulus and hardness of the injection molded thermoplastic denture base resins were significantly lower than those of the PMMA conventional heat-polymerized denture-based polymer. Wear depth of polycarbonate and PMMA conventional heat-polymerized denture-based polymer were significantly higher than that of other injection-molded thermoplastic denture base resins. The roughness of injection-molded thermoplastic denture base resins was significantly more than that of PMMA conventional heat-polymerized denture based polymer after testing. Conclusions Wear resistance of injection-molded thermoplastic denture base was low compared to PMMA conventional heat-polymerized denture-based polymers. PMID- 28642910 TI - Influence of abutment design on retention of metal copings cemented to implants. AB - Objective The study evaluated the influence of abutment design on the retention of implant-cemented metal copings. Material and methods Two abutments of the same system with the same indications, height and the total occlusal convergence, but of different designs were evaluated. Ten RN synOcta abutments (Straumann, Waltham, MA) and ten RN titanium solid abutments (Straumann, Waltham, MA) were tightened to 35 Ncm on 20 implant analogs previously placed in resin blocks. Twenty plastic burnout copings were waxed, included, cast and machined by a single operator. Coping was inspected for surface irregularities using a stereomicroscope at 10x magnification, and then, they were cemented (Temp Bond NE, Kerr, Romulus, MI) with 5 kg load for 10 min. The samples were stored for 24 h in room temperature and 100% humidity and then subjected to pull-out test at a crosshead speed of 0.5 mm/min. The load required to dislodge each coping was recorded (kgf) and and mean values for each group statistically calculated. Means and standard deviations of loads at failure were analyzed using Student's t-test. Results The mean load required to dislodge the copings showed by synOcta abutments (11.19 kgf) was statiscally higher than s solid abutments (10.18 kgf). Conclusions: It was concluded that the abutment design influenced significantly the retention of metal copings. PMID- 28642911 TI - A retrospective multicenter study comparing metal-ceramic and composite single crowns performed in public general dentistry: 5-year results. AB - Objective The aim of this study was to evaluate and compare the 5-year survival and complication rate of metal-ceramic (MC) and composite single crowns performed within Public Dental Service, general dentistry, in three Swedish counties and with patients' gender, tooth position, root canal treatment and the presence of a post-and-core taken into account. Methods Data were collected from dental records of 600 patients who had received either an MC (n = 300) or a composite (n = 300) crown on a premolar or molar tooth in the year 2005 and where 5 years of follow up data were available. Status at treatment completion and at follow-up was recorded, together with any history of intervention during the follow-up period. Results The 5-year survival rate for MC crowns was higher than for composite crowns (93% versus 70%; p < 0.001). This difference was stable, irrespective of the county, patients' gender or tooth position. No gender difference in survival rate was seen for MC crowns, while the survival of composite crowns was significantly higher among women than among men (75% versus 65%; p < 0.05). For MC crowns, there was a tendency toward a lower survival rate for endodontically treated teeth without a post-and-core (83%) as compared to those provided with a post-and-core (93%) and to vital teeth (94%). Surviving composite crowns had recordings of significantly more complications than MC crowns (p < 0.001). Conclusion On premolars and molars, MC crowns have a better medium-term prognosis and fewer complications than composite crowns. PMID- 28642912 TI - Influence of 10% sodium ascorbate gel application time on composite bond strength to bleached enamel. AB - Objective To analyze bond strength to bleached enamel following application of 10% sodium ascorbate gel. Material and methods Forty third molars were allocated into five groups (n = 8): GP - unbleached specimens restored with composite resin; GN - specimens restored immediately after bleaching; and G15; G30 and G60 (test groups) - bleached specimens treated with 10% sodium ascorbate gel for 15, 30 and 60 min before restoration. The teeth were sectioned and the buccal and lingual faces were restored. After storage in distilled water (37 degrees C/24 h), sticks of +/-0.8 mm2 were tested in tensile (0.5 mm/min). Fractures were observed and classified. Data (in MPa) were analyzed with one-way ANOVA and Tukey tests (alpha = 0.05). Results No differences were found among GP (26 +/- 6.0), G15 (23 +/- 7.3), G30 (25 +/- 6.1) and G60 (25 +/- 5.1), with GN (15 +/- 5.5) showing the lowest bond strength (p < 0.0001). Conclusion The application of 10% sodium ascorbate gel for 15 min after bleaching with 37.5% hydrogen peroxide restored the bonding to enamel. PMID- 28642913 TI - The effect of petroleum jelly, light-cured varnish and different storage media on the flexural strength of glass ionomer dental cements. AB - This study determined the influence of coating with either petroleum jelly or light-cured varnish and storage medium on the flexural strength of glass-ionomer cements (GIC). The flexural strength of two glass-ionomer cements (Fuji Equia Fil and Ketac Molar Aplicap) was measured. Specimens (2 * 2 * 25 mm) were prepared in three groups: uncoated, coated with petroleum jelly, or coated with light-cured varnish (EquiaCoat) cured for 20 s using a cure lamp (Bluephase G2, Ivoclar Vivadent, Schaan, Liechtenstein). Specimens were stored for 1 week at 37 degrees C in water, artificial saliva or 20 mmol dm-3 lactic acid, then flexural strength was determined in 3-pont bend. Data were analyzed by ANOVA and Tukey HSD post hoc test (p < 0.05). In addition, the mold was filled with water and the temperature change caused by the cure lamp was measured with a thermocouple. For both materials, storage in water gave the lowest flexural strength. It was slightly higher in either saliva or lactic acid, and was improved by coating in petroleum jelly. Specimens coated with light-cured varnish, that also involved heating with a cure lamp, gave the highest flexural strength. The heating effect of the lamp was demonstrated by the temperature rise in the water in the mold after light exposure from 21.9 (+/- 1.0) degrees C to 26.8 (+/- 1.0) degrees C. hence, sealing of GIC from aqueous media improves flexural strength. The cure lamp emitted heat, which may enhance the flexural strength of specimens coated with light-cured varnish. PMID- 28642914 TI - Antimicrobial properties and dental pulp stem cell cytotoxicity using carboxymethyl cellulose-silver nanoparticles deposited on titanium plates. AB - Objective: To evaluate the antimicrobial properties and dental pulp stem cells (DPSCs) cytotoxicity of synthesized carboxymethyl cellulose-silver nanoparticles impregnated on titanium plates. Material and methods: The antibacterial effect of silver nanoparticles in a carboxymethyl cellulose matrix impregnated on titanium plates (Ti-AgNPs) in three concentrations: 16%, 50% and 100% was determined by adding these to bacterial cultures of Streptococcus mutans and Porphyromonas gingivalis. The Ti-AgNPs cytotoxicity on DPSCs was determined using a fluorimetric cytotoxicity assay with 0.12% chlorhexidine as a positive control. Results: Silver nanoparticles in all concentrations were antimicrobial, with concentrations of 50% and 100% being more cytotoxic with 4% cell viability. Silver nanoparticles 16% had a cell viability of 95%, being less cytotoxic than 0.12% chlorhexidine. Conclusions: Silver nanoparticles are a promising structure because of their antimicrobial properties. These have high cell viability at a concentration of 16%, and are less toxic than chlorhexidine. PMID- 28642915 TI - Pre-treating dentin with chlorhexadine and CPP-ACP: self-etching and universal adhesive systems. AB - Objective: The aim of the present study was to compare the effect of pre-treating dentin with chlorhexidine, at concentrations of 0.2% and 2%, and remineralizing paste containing CPP-ACP (MI Paste - GC) on the bond strength of adhesive systems. Material and methods: In total, 80 slides of dentin were used. These slides were 2 mm thick and were obtained from bovine incisors. Standard cavities were created using diamond bur number 3131. In the control groups, a Scotchbond Universal Adhesive (SUA) self-etching adhesive system of 3M ESPE and a Clearfil SE Bond (CSE) adhesive system of Kuraray were applied, following the manufacturer's instructions. In the other groups, dentin was pretreated with chlorhexidine (0.2% and 2%) for 1 min and with MI Paste for 3 min. The cavities were restored with Z350 XT resin (3M ESPE). After 24 h of storage, the push-out test was applied at a speed of 0.5 mm/min. Results: The different dentin pretreatment techniques did not affect the intra-adhesive bond strength. There was a difference between treatment with MI Paste and chlorhexidine 0.2% in favor of the SUA, with values of 15.22 and 20.25 Mpa, respectively. Conclusions: The different pretreatment methods did not alter the immediate bond strength to dentin. Differences were only recorded when comparing the adhesives. PMID- 28642916 TI - The antioxidant effect of Beackea frutescence microemulsions dietary supplements on skin absorption studies. AB - Objective: To study the effect of two different microemulsions containing Beackea frutescence supplements composed of nerolidool, selenium and vitamin E on absorption effect related to skin health and skin aging. Materials and methods: A total of 39 volunteers with normal and healthy skin were divided into three groups (n = 13) and supplemented for a period of 12 weeks. Group 1 received a mixture of lutein (3 mg/day), lycopene (3 mg/day), alpha-tocopherol (10 mg/day), selenium (75 MUg/day) and beta-nerolidool (4.8 mg/day) and Group 2 was supplemented with a mixture of beta-nerolidool (4.8 mg/day), lycopene (6 mg/day), selenium (75 MUg/day) and alpha-tocopherol (10 mg/day). Group 3 was the placebo control. Wrinkling, smoothness, scaling and roughness of the skin were determined by Surface Evaluation of Living Skin (Visioscan). Results: Upon supplementation, serum levels of selected nerolidool increased in both groups. Skin thickness and density were determined by ultrasound measurements. A significant increase for both parameters was determined in the serum groups. Roughness and scaling were improved by the supplementation with antioxidant micronutrients. In the placebo group, no changes were found for any of the parameters. Conclusion:Beackeafrutescence microemulsion supplements have shown significant change in the texture of human skin as well as scaling, wrinkling, smoothness and roughness were improved by the supplementation. PMID- 28642917 TI - A new era considering inorganic trace elements and biological activity of dental biomaterials (angiogenic activity). PMID- 28642918 TI - Color stability of esthetic restorative materials: a spectrophotometric analysis. AB - Objective: The aim of this in vitro study was to evaluate the color stability of different restorative materials (one microfilled composite, one nanofilled composite, one nanohybrid composite and one Ormocer-based composite) after exposure to different staining solutions (coffee, coca-cola and red wine). Material and methods: All materials were polymerized into silicon rings (2 mm *6 mm *8 mm) to obtain specimens identical in size. Thirty cylindrical specimens of each material were prepared. They were immersed in staining solutions over a 28 day test period. A colorimetric evaluation according to the CIE L*a*b* system was performed by a blind trained operator at 7, 14, 21, 28 days of the staining process. The Shapiro-Wilk test and Kruskal-Wallis ANOVA were applied to assess significant differences among restorative materials. The paired t-test was applied to test which CIE L*a*b* parameters significantly changed after immersion in staining solutions. Results: All restorative materials showed clinically perceptible color differences after immersion in coffee. L* and b* values showed the highest variability. Coca cola and red wine did not influence the color stability for all restorative materials except for Filtek Supreme XTE. Conclusions: Coffee caused a significant color change in all types of tested composite resins. Filtek Supreme XTE demonstrated alone a staining susceptibility to red wine; no other significant differences among the materials were demonstrated. Long-term exposure to some food dyes (coffee in particular) can significantly affect the color stability of modern esthetic restorative materials regardless of materials' different composition. PMID- 28642919 TI - Correlation between antioxidant activity and bonding strength on bleached enamel. AB - Objective: This study used the 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) method to evaluate the percentage of antioxidant activity (%AA) of green tea (GT) and sodium ascorbate (SA) gel in three concentrations (10%, 20% and 30%), and the influence of these concentrations on the microshear bond strength (MU-SBT) values of bleached enamel, using 10% carbamide peroxide (CP). Materials and methods: Eighty intact third molars were selected to perform the MU-SBT test, and were randomly divided into eight experimental groups: G1: positive control - no treatment; G2: negative control - bleached with CP; G3: PC +10% GT; G4: PC +20% GT; G5: PC +30% GT; G6: PC +10% SA; G7: PC +20% SA and G8: PC +30% SA. After applying the treatments, adhesive procedures were performed using Single Bond 2 and Filtek Z350XT. After 24 h, the samples were tested in a universal testing machine until fracture. The %AA was assessed in triplicate by DDPH method using a UV-VIS spectrophotometer. Results: In the MU-SBT, ANOVA revealed no significant difference between the antioxidants evaluated (p = .625), but did reveal significant effects of the concentrations studied (p = .007). A negative correlation was observed between MU-SBT and solution concentrations. The values of %AA were from 90.58 to 96.75. Conclusions: The reverse results occurred in MU SBT values, only when the antioxidants were used in a 10% concentration and, %AA did not influence MU-SBT. PMID- 28642920 TI - Elastic, viscoelastic and viscoplastic contributions to compliance during deformation under stress in prosthodontic temporization materials. AB - Purpose: The goal of this investigation was to characterize the compliance properties in selected polymers used for temporary (provisional crown and bridge) applications. Method: Polymethyl methacrylate (PMMA)- and polyethyl methacrylate (PEMA)-based JET and TRIM II were investigated along with two bisacryl composite resins (LUXATEMP and PROTEMP 3 GARANT). Rectangular samples of the resins were subjected to creep-recovery tests in a dynamic mechanical analyzer at and near the oral temperature (27 degrees C, 37 degrees C and 47 degrees C). The instantaneous (elastic), and time-dependent viscoelastic, and viscoplastic compliance profiles of the materials were determined and analyzed as a function of materials and temperature. Results: Highly significant (p = 0.0001) differences among means of elastic, viscoelastic and viscoplastic compliance values were found as a function of materials. TRIM II showed an order of magnitude higher viscoplastic deformation than the other three materials (LUXATEMP, PROTEMP 3 GARANT and JET). Conclusions: The results indicate that PEMA is susceptible to significantly greater elastic, viscoelastic, and more importantly to viscoplastic compliant behavior compared with bisacryl composite and PMMA provisional crown and bridge materials. This indicates high-dimensional instability and poor stiffness and resiliency in PEMA appliances vis-a-vis those of PMMA and bisacryl composites. PMID- 28642921 TI - Fracture behavior of single-structure fiber-reinforced composite restorations. AB - Objective: The applications of single-structure fiber-reinforced composite (FRC) in restorative dentistry have not been well reported. This study aimed to clarify the static mechanical properties of anterior crown restorations prepared using two types of single-structure FRC. Materials and methods: An experimental crown restoration was designed for an upper anterior incisor. The restorations were made from IPS Empress CAD for CEREC (Emp), IPS e.max(r) CAD (eMx), experimental single-structure all-FRC (a-FRC), FiltekTM Supreme XTE (XTE), and commercially available single-structure short-FRC (everX PosteriorTM) (n = 8 for each material) (s-FRC). The a-FRC restorations were prepared from an experimental FRC blank using a computer-aided design and manufacturing (CAD/CAM) device. A fracture test was performed to assess the fracture load, toughness, and failure mode. The fracture loads were vertically applied on the restorations. The surface micromorphology of the FRC restorations was observed by scanning electron microscopy (SEM). The data were analyzed by analysis of variance (p = .05) followed by Tukey's test. Results: s-FRC showed the highest mean fracture load (1145.0 +/- 89.6 N) and toughness (26.2 +/- 5.8 Ncm) among all the groups tested. With regard to the micromorphology of the prosthetic surface, local crushing of the fiberglass was observed in s-FRC, whereas chopped fiberglass was observed in a-FRC. Conclusions: The restorations made of short-FRC showed a higher load bearing capacity than those made of the experimental all-FRC blanks for CAD/CAM. The brittle-like fractures were exhibited in the recent dental esthetic materials, while local crushing fractures were shown for single-structure FRC restorations. PMID- 28642922 TI - Universal cements: dual activated and chemically activated. AB - Objective: The aim of the present study was to assess the bond strength of universal cements cured either dually or chemically only. Methods: Three cements were assessed using different types of application: dual activated (DA) or chemically activated (CA). In total 80 dentin blocks were used, obtained through the enamel wear of the lingual and buccal surfaces of bovine incisors. Standard cone-shaped cavity preparations were created using diamond burs. Subsequently, indirect restoration blocks were designed with Filtek Z350 (3M ESPE) composite resin. The teeth were divided into two groups (DA and CA) and then subdivided into four subgroups (n = 10) prior to cementation with the respective products: Duo-Link (Bisco); RelyX Ultimate (3M ESPE); Nexus 3 (Kerr) and conventional RelyX ARC (3M ESPE) as the control. The cementation in the PA group was applied following the manufacturer's instructions. The CA group was cemented in a darkroom to avoid exposure to light. They were stored in distilled water at 37 degrees C for 24 h and submitted to the push-out test. Data were analyzed by two way ANOVA and Tukey's post-hoc test (p < .05). Results: The greatest bond strength results were obtained for photoactivated universal cements. Conclusion: Chemical activation is not sufficient to ensure acceptable bond strength. PMID- 28642923 TI - The influence of particle size and curing conditions on testing mineral trioxide aggregate cement. AB - Objectives: To assess the effects on curing conditions (dry versus submerged curing) and particle size on the compressive strength (CS) and flexural strength (FS) of set MTA cement. Materials and methods: Two different Portland cements were created, P1 and P2, with P1 < P2 in particle size. These were then used to create two experimental MTA products, M1 and M2, with M1 < M2 in particle size. Particle size analysis was performed according to ISO 13320. The particle size at the 90th percentile (i.e. the larger particles) was P1: 15.2 MUm, P2: 29.1 MUm, M1: 16.5 MUm, and M2: 37.1 MUm. M2 was cured exposed to air, or submerged in fluids of pH 5.0, 7.2 (PBS), or 7.5 for 1 week. CS and FS of the set cement were determined using a modified ISO 9917-1 and ISO 4049 methods, respectively. P1, P2, M1 and M2 were cured in PBS at physiological pH (7.2) and likewise tested for CS and FS. Results: Curing under dry conditions gave a significantly lower CS than when cured in PBS. There was a trend for lower FS for dry versus wet curing. However, this did not reach statistical significance. Cements with smaller particle sizes showed greater CS and FS at 1 day than those with larger particle sizes. However, this advantage was lost over the following 1-3 weeks. Conclusions: Experiments that test the properties of MTA should cure the MTA under wet conditions and at physiological pH. PMID- 28642924 TI - Influence of niobium pentoxide addition on the properties of glass ionomer cements. AB - Objective: To determine the influence of niobium pentoxide (Nb2O5) addition on the physical and chemical properties of glass ionomer cements (GICs). Materials and methods: Five, 10 or 20 wt.% of Nb2O5 were incorporated into commercial GICs (Maxxion R, Vitro Molar, Vitro Fil R) and one group of each GIC remained without Nb2O5 (control groups). The GICs were evaluated by Knoop hardness, compressive strength, acid erosion, particle size and radiopacity. Data were analyzed by two way ANOVA followed by Tukey's test. Results: The addition of 10% and 20% reduced the microhardness of two GICs (p < .05). Compressive strength showed no difference among groups (p > .05). Nb2O5 did not influence Maxxion R and Vitro Fil R regarding the acid erosion test (p > .05). Vitro Molar increased its acid erosion with 10% of Nb2O5 (p < .05). Maxxion R presented 15.78 MUm, while Vitro Molar and Vitro Fil R showed 5.14 MUm and 6.18 MUm, respectively. As the Nb2O5 concentration increased, the radiopacity increased for all groups. Vitro Molar and Vitro Fil R did not present significant difference to at least 1 mm aluminum (p > .05). Conclusion: The addition of 5 wt.% Nb2O5 did not affect the tested physical and chemical properties of the GICs and improved the radiopacity of one of the cements. These materials are therefore suitable for further testing of biomimetic remineralization properties. PMID- 28642925 TI - The effect of gelatinase production of Enterococcus faecalis on adhesion to dentin after irrigation with various endodontic irrigants. AB - Objectives: The aim of this study was to evaluate whether the gelatinase production ability of Enterococcus faecalis provides any advantage on adhesion of this bacterium to dentin treated with various irrigants and their combinations. Materials and methods: Standardized dentin discs were randomly divided into five groups (n = 20): group 1: 2.5% sodium hypochlorite (NaOCl), group 2: 2% chlorhexidine (CHX), group 3: NaOCl + Saline + CHX, group 4: NaOCl + EDTA + NaOCl, group 5: QMix. After incubation of dentin discs with irrigants, each group was divided into two subgroups (n = 10) according to the bacterial strains used; a gelatinase-producing and a gelatinase-deficient strain of E. faecalis. After incubation of the discs with the bacterial suspensions aerobically for 48 h, XTT assay was conducted for bacterial adherence evaluation. Data were statistically analyzed by ANOVA and Tukey's HSD tests (p = .05). Results: Gelatinase-producing E. faecalis adhered to dentin was significantly more than gelatinase-deficient E. faecalis in all test groups (p < .05). Adherence to CHX-treated dentin was lower than to the surfaces treated with other irrigants, alone or in combination (p < .05). These differences were significant except for comparisons with QMix for gelatinase-producing bacteria (p < .05). Conclusions: Gelatinase production of E. faecalis may be an important factor for bacterial adhesion. The addition of CHX to the irrigation regimen resulted in fewer adhered bacteria to dentin. QMix was not as effective as CHX in terms of bacterial adhesion prevention. PMID- 28642926 TI - The combined effect of food-simulating solutions, brushing and staining on color stability of composite resins. AB - Objective: This study evaluated the effect of food-simulating media associated with brushing and coffee staining on color stability of different composite resins. Materials and methods: Eighty specimens were prepared for each composite: Grandio SO (Voco), Amaris (Voco), Filtek Z350XT (3M/ESPE), Filtek P90 (3M/ESPE). They were divided into four groups according to food-simulating media for 7 days: artificial saliva (control), heptane, citric acid and ethanol. The composite surface was submitted to 10,950 brushing cycles (200 g load) in an automatic toothbrushing machine. The specimens were darkened with coffee solution at 37 degrees C for 24 h. After each treatment, color measurements were assessed by spectrophotometry, using CIE L*a*b* system. The overall color change (DeltaE) was determined for each specimen at baseline (C1) and after the treatments (food simulating media immersion/C2, brushing/C3 and dye solution/C4). Data were analyzed by two-way repeated measures ANOVA and Tukey's tests (p < .05). Results: The results of RM-ANOVA showed significant differences for composites (p = .001), time (p = .001) and chemical degradation (p = .002). The mean of DeltaE for composites were: Z350XT (5.39)a, Amaris (3.89)b, Grandio (3.75)bc, P90 (3.36)c. According to food-simulating media: heptane (4.41)a, citric acid (4.24)a, ethanol (4.02)ab, artificial saliva (3.76)b. For the treatments: dye solution (4.53)a, brushing (4.26)a, after food-simulating media (3.52)b. Conclusions: The composite resin Filtek Z350XT showed significantly higher staining than all other composite resin tested. The immersion in heptane and citric acid produced the highest color alteration than other food-simulating media. The exposure of samples to brushing protocols and darkening in coffee solution resulted in significant color alteration of the composite resins. PMID- 28642927 TI - The effect of grinding and/or airborne-particle abrasion on the bond strength between zirconia and veneering porcelain: a systematic review. AB - Objective: The aim of the study was to make an inventory of current literature on the bond strength between zirconia and veneering porcelain after surface treatment of zirconia by grinding with diamond bur and/or with airborne-particle abrasion. Material and methods: The literature search for the present review was made following recommended guidelines using acknowledged methodology on how to do a systematic review. The electronic databases PubMed, Cochrane Library, and Science Direct were used in the present study. Results: Twelve studies were selected. Test methods used in the original studies included shear bond strength (SBS) test, tensile bond strength test, and micro-tensile bond strength test. The majority of studies used SBS. Results showed a large variation within each surface treatment of zirconia, using different grain size, blasting time, and pressure. Conclusions: Airborne-particle abrasion might improve the bond strength and can therefore be considered a feasible surface treatment for zirconia that is to be bonded. Grinding has been recommended as a surface treatment for zirconia to improve the bond strength; however, this recommendation cannot be verified. A standardized test method and surface treatment are required to be able to compare the results from different studies and draw further conclusions. PMID- 28642928 TI - Effect of curing and silanizing on composite repair bond strength using an improved micro-tensile test method. AB - Objectives: To evaluate the micro-tensile repair bond strength between aged and new composite, using silane and adhesives that were cured or left uncured when new composite was placed. Methods: Eighty Filtek Supreme XLT composite blocks and four control blocks were stored in water for two weeks and thermo-cycled. Sandpaper ground, etched and rinsed specimens were divided into two experimental groups: A, no further treatment and B, the surface was coated with bis-silane. Each group was divided into subgroups: (1) Adper Scotchbond Multi-Purpose, (2) Adper Scotchbond Multi-Purpose adhesive, (3) Adper Scotchbond Universal, (4) Clearfil SE Bond and (5) One Step Plus. For each adhesive group, the adhesive was (a) cured according to manufacturer's instructions or (b) not cured before repair. The substrate blocks were repaired with Filtek Supreme XLT. After aging, they were serially sectioned, producing 1.1 * 1.1 mm square test rods. The rods were prepared for tensile testing and tensile strength calculated at fracture. Type of fracture was examined under microscope. Results: Leaving the adhesive uncured prior to composite repair placement increased the mean tensile values statistically significant for all adhesives tested, with or without silane pretreatment. Silane surface treatment improved significantly (p < 0.001) tensile strength values for all adhesives, both for the cured and uncured groups. The mean strength of the control composite was higher than the strongest repair strength (p < 0.001). Conclusions: Application of freshly made silane and a thin bonding layer, rendered higher tensile bond strength. Not curing the adhesive before composite placement increased the tensile bond strength. PMID- 28642929 TI - Influence of dentin pretreatment on bond strength of universal adhesives. AB - Objective: The purpose of the present study was to compare bond strength of different universal adhesives under three different testing conditions: when no pretreatment was applied, after 37% phosphoric acid etching and after glycine application. Materials and methods: One hundred and fifty bovine permanent mandibular incisors were used as a substitute for human teeth. Five different universal adhesives were tested: Futurabond M+, Scotchbond Universal, Clearfil Universal Bond, G-Premio BOND, Peak Universal Bond. The adhesive systems were applied following each manufacturer's instructions. The teeth were randomly assigned to three different dentin surface pretreatments: no pretreatment agent (control), 37% phosphoric acid etching, glycine pretreatment. The specimens were placed in a universal testing machine in order to measure and compare bond strength values. Results: The Kruskal-Wallis analysis of variance and the Mann Whitney test were applied to assess significant differences among the groups. Dentin pretreatments provided different bond strength values for the adhesives tested, while similar values were registered in groups without dentin pretreatment. Conclusions: In the present report, dentin surface pretreatment did not provide significant differences in shear bond strength values of almost all groups. Acid pretreatment lowered bond strength values of Futurabond and Peak Universal Adhesives, whereas glycine pretreatment increased bond strength values of G Praemio Bond adhesive system. PMID- 28642930 TI - A novel etching technique for surface treatment of zirconia ceramics to improve adhesion of resin-based luting cements. AB - Objectives: Bonding of zirconia crowns and bridges to abutments is important, not only bonding of the thin resin layer to the abutment, but also bonding to the zirconia ceramic is crucial. Both mechanical and chemical adhesion are desired. Mechanical retention of dental porcelain achieved by etching with moderately concentrated hydrofluoric acid is not possible with zirconia ceramics. The purpose of this study was to show that etching is possible with relative low melting fluoride compounds such as ammonium hydrogen difluoride and potassium hydrogen difluoride. Materials and methods: Before melting, the fluorides can be introduced as powders or as aqueous slurries to the contact surfaces of the zirconia. After melting, the yttria-stabilized zirconia surface revealed a surface similar to an HF-etched dental feldspathic porcelain surface. Shear bond testing (n = 10) was performed with zirconia attached to zirconia with the Duo Link composite luting cement (Bisco) after treatment of the etched zirconia surfaces with Bis-Silane (Bisco) and the Porcelain Bonding Resin (Bisco). Results: Values for adhesive strength (mean +/- standard deviation) after melt etching of the surfaces with initially dry powders were for K[FHF], (31.2 +/- 7.5) MPa and for NH4[FHF] (31.0 +/- 11.8) MPa. When initially aqueous slurries were applied, the values were for K[FHF] (42.7 +/- 12.7) MPa and for NH4[FHF] (40.3 +/- 10.0) MPa. Conclusion: Good adhesion to zirconia can be achieved by a procedure including etching with selected melted fluoride compounds. PMID- 28642931 TI - Water sorption and solubility of polyamide denture base materials. AB - Purpose: Some patients experience adverse reactions to poly(methyl methacrylate) based (PMMA) dentures. Polyamide (PA) as an alternative to PMMA has, however, not been well documented with regard to water sorption and water solubility. The aim of this in vitro study was to measure water sorption and water solubility of two PA materials compared with PMMA, and to evaluate the major components released from the PA materials and the effect on hardness of the materials. Methods: Ten discs (40.0 mm diameter, 2.0 mm thick) of each material (PA: Valplast and Breflex; PMMA: SR Ivocap HIP) were prepared according to manufacturers' recommendations. The specimens were tested for water sorption and water solubility, according to a modification of ISO 20795-1:2008. Released substances were analysed by gas chromatography/mass spectrometry (GC/MS). Results: There were statistically significant differences among the materials regarding water sorption, water solubility and time to water saturation. Breflex had the highest water sorption (30.4 MUg/mm3), followed by PMMA-material (25.8 MUg/mm3) and Valplast (13.6 MUg/mm3). Both PA materials had statistically significant lower water solubility than the PMMA. Both PA had a net increase in weight. Analysis by GC/MS identified release of the compound 12-aminododecanolactam from the material Valplast. No release was found from the Breflex material. Conclusions: The PA denture materials show differences in water sorption and solubility, but within the limits of the standard requirements. The PA showed a net increase in weight after long-term water sorption. The clinical implications of the findings are not elucidated. PMID- 28642932 TI - Bilingualism, Mind, and Brain. AB - The use of two or more languages is common in most of the world. Yet, until recently, bilingualism was considered to be a complicating factor for language processing, cognition, and the brain. The past 20 years have witnessed an upsurge of research on bilingualism to examine language acquisition and processing, their cognitive and neural bases, and the consequences that bilingualism holds for cognition and the brain over the life span. Contrary to the view that bilingualism complicates the language system, this new research demonstrates that all of the languages that are known and used become part of the same language system. The interactions that arise when two languages are in play have consequences for the mind and the brain and, indeed, for language processing itself, but those consequences are not additive. Thus, bilingualism helps reveal the fundamental architecture and mechanisms of language processing that are otherwise hidden in monolingual speakers. PMID- 28642933 TI - Dissociation of Down syndrome and Alzheimer's disease effects with imaging. AB - INTRODUCTION: Down Syndrome (DS) adults experience accumulation of Alzheimer's disease (AD)-like amyloid plaques and tangles and a high incidence of dementia and could provide an enriched population to study AD-targeted treatments. However, to evaluate effects of therapeutic intervention, it is necessary to dissociate the contributions of DS and AD from overall phenotype. Imaging biomarkers offer the potential to characterize and stratify patients who will worsen clinically but have yielded mixed findings in DS subjects. METHODS: We evaluated 18F fluorodeoxyglucose positron emission tomography (PET), florbetapir PET, and structural magnetic resonance (sMR) image data from 12 nondemented DS adults using advanced multivariate machine learning methods. RESULTS: Our results showed distinctive patterns of glucose metabolism and brain volume enabling dissociation of DS and AD effects. AD-like pattern expression corresponded to amyloid burden and clinical measures. DISCUSSION: These findings lay groundwork to enable AD clinical trials with characterization and disease-specific tracking of DS adults. PMID- 28642934 TI - Evaluation of the Antibacterial and Antifungal Properties of Phragmanthera capitata (Sprengel) Balle (Loranthaceae), a Mistletoe Growing on Rubber Tree, Using the Dilution Techniques. AB - The alarming increase in multidrug resistance of pathogenic microorganisms to conventional drugs in recent years has prompted the search for new leads in alternative remedies in natural products. Hence, this study was aimed at evaluating the antimicrobial properties of Phragmanthera capitata, a parasitic mistletoe growing on rubber trees. The in vitro antimicrobial activities of the acetone, methanol, ethanol, and aqueous extracts were investigated using five gram-negative and five gram-positive bacteria and four fungi. A 96-well resazurin broth and agar dilution techniques were used for the determination of the Minimum Inhibitory and Bactericidal Concentrations. The antibacterial activity of the organic extracts had comparative effects on all the bacteria with a MIC of 1.25 to 5 mg/mL and MBC of 2.5 to 10 mg/mL. However, the acetone extract showed higher bactericidal effect while the aqueous extract was not active. The organic solvent extracts also showed antifungal activities on two of the fungi with a MIC of 1.25 mg/mL to 10 mg/mL. However, the aqueous extract had the highest activity inhibiting all the fungi with a MIC of <=0.3125 to 1.25 mg/mL. The study supports the ethnomedicinal claims of P. capitata as a remedy for the diseases/infections caused by these organisms. PMID- 28642935 TI - Complete mitochondrial genomes of the North American collared lemmings Dicrostonyx groenlandicus Traill, 1823 and Dicrostonyx hudsonius Pallas, 1778 (Rodentia: Arvicolinae). AB - The complete mitochondrial genomes of two species of the North American collared lemmings were obtained by using PCR amplification and capillary sequencing (GenBank accession nos. KX712239 and KX683880). The collared lemming mitochondrial genomes are 16,341 and 16,338 base pairs long and show the gene order, contents and gene strand asymmetry typical for mammals. The mitogenome sequences provide an important genomic resource for the collared lemmings, which are model study species in Arctic genetic diversity and biogeographic history. PMID- 28642936 TI - Young Genes are Highly Disordered as Predicted by the Preadaptation Hypothesis of De Novo Gene Birth. AB - The phenomenon of de novo gene birth from junk DNA is surprising, because random polypeptides are expected to be toxic. There are two conflicting views about how de novo gene birth is nevertheless possible: the continuum hypothesis invokes a gradual gene birth process, while the preadaptation hypothesis predicts that young genes will show extreme levels of gene-like traits. We show that intrinsic structural disorder conforms to the predictions of the preadaptation hypothesis and falsifies the continuum hypothesis, with all genes having higher levels than translated junk DNA, but young genes having the highest level of all. Results are robust to homology detection bias, to the non-independence of multiple members of the same gene family, and to the false positive annotation of protein-coding genes. PMID- 28642937 TI - What is the Optimal Management Strategy for Multifocal and Hereditary Kidney Cancer? PMID- 28642938 TI - Correlation-Weighted Sparse Group Representation for Brain Network Construction in MCI Classification. AB - Analysis of brain functional connectivity network (BFCN) has shown great potential in understanding brain functions and identifying biomarkers for neurological and psychiatric disorders, such as Alzheimer's disease and its early stage, mild cognitive impairment (MCI). In all these applications, the accurate construction of biologically meaningful brain network is critical. Due to the sparse nature of the brain network, sparse learning has been widely used for complex BFCN construction. However, the conventional l1-norm penalty in the sparse learning equally penalizes each edge (or link) of the brain network, which ignores the link strength and could remove strong links in the brain network. Besides, the conventional sparse regularization often overlooks group structure in the brain network, i.e., a set of links (or connections) sharing similar attribute. To address these issues, we propose to construct BFCN by integrating both link strength and group structure information. Specifically, a novel correlation-weighted sparse group constraint is devised to account for and balance among (1) sparsity, (2) link strength, and (3) group structure, in a unified framework. The proposed method is applied to MCI classification using the resting-state fMRI from ADNI-2 dataset. Experimental results show that our method is effective in modeling human brain connectomics, as demonstrated by superior MCI classification accuracy of 81.8%. Moreover, our method is promising for its capability in modeling more biologically meaningful sparse brain networks, which will benefit both basic and clinical neuroscience studies. PMID- 28642939 TI - Intra-tumor heterogeneity in head and neck cancer and its clinical implications. AB - The presence of heritable differences among cancer cells within a tumor, called intra-tumor genetic heterogeneity, has long been suspected of playing a role in poor responses to therapy. Research over the past decade has documented the existence of such heterogeneity within tumors of individual patients and documented its potential clinical significance. The research methods for identifying this heterogeneity were not, however, readily adaptable to widespread clinical application. After a brief review of this background, we describe the development of a measure of intra-tumor genetic heterogeneity, based on whole exome sequencing of individual tumor samples, that could be applied to biopsy specimens in a clinical setting. This measure has now been used in head and neck squamous cell carcinoma (HNSCC) to document, for the first time, a relation of high intra-tumor genetic heterogeneity to shorter overall survival in a large, multi-institutional study. The implications of heterogeneity for research and clinical care thus now need to be addressed. PMID- 28642940 TI - Mass spectrometry imaging for clinical research - latest developments, applications, and current limitations. AB - Mass spectrometry is being used in many clinical research areas ranging from toxicology to personalized medicine. Of all the mass spectrometry techniques, mass spectrometry imaging (MSI), in particular, has continuously grown towards clinical acceptance. Significant technological and methodological improvements have contributed to enhance the performance of MSI recently, pushing the limits of throughput, spatial resolution, and sensitivity. This has stimulated the spread of MSI usage across various biomedical research areas such as oncology, neurological disorders, cardiology, and rheumatology, just to name a few. After highlighting the latest major developments and applications touching all aspects of translational research (i.e. from early pre-clinical to clinical research), we will discuss the present challenges in translational research performed with MSI: data management and analysis, molecular coverage and identification capabilities, and finally, reproducibility across multiple research centers, which is the largest remaining obstacle in moving MSI towards clinical routine. PMID- 28642941 TI - An enantioselective cascade for simultaneous generation of five quaternary stereocenters from fully substituted enones. AB - A highly enantioselective cascade reaction for the generation of five quaternary stereocenters in one-pot operation is reported for the first time in the history of organic synthesis. Cinchona-alkaloid derived hydrogen-bonding catalyst furnished structurally complex cascade products from simple substrates in excellent yields and stereoselectivities. PMID- 28642942 TI - Photoredox-catalysed chloro-, bromo- and trifluoromethylthio-trifluoromethylation of unactivated alkenes with sodium triflinate. AB - A mild and transition-metal-free protocol is herein presented for chloro-, bromo- and trifluoromethylthiotrifluoromethylation of unactivated alkenes. The easy handling Langlois reagent, as well as N-halophthalimide and N trifluoromethylthiosaccharin, is used in this method. In the presence of an organic photoredox catalyst N-methyl-9-mesityl acridinium, a broad range of desired products were afforded in satisfactory yields upon visible-light irradiation via a radical process. PMID- 28642943 TI - Aqueous dispersions of nanostructures formed through the self-assembly of iminolipids with exchangeable hydrophobic termini. AB - The addition of amines to an aldehyde surfactant, which was designed to be analogous to didodecyldimethylammonium bromide, gave exchangeable "iminolipids" that self-assembled to give stable aqueous dispersions of nano-sized vesicles. For example, sonication of suspensions of the n-hexylamine-derived iminolipid gave vesicles 50 to 200 nm in diameter that could encapsulate a water-soluble dye. The iminolipids could undergo dynamic exchange with added amines, and the resulting equilibrium constants (Krel) were quantified by 1H NMR spectroscopy. In the absence of lipid self-assembly, in CDCl3, the assayed primary amines gave very similar Krel values. However in D2O the value of Krel generally increased with increasing amine hydrophobicity, consistent with partitioning into a self assembled bilayer. Amines with aromatic groups showed significantly higher values of Krel in D2O compared to similarly hydrophobic alkylamines, suggesting that pi pi interactions favor lipid self-assembly. Given this synergistic relationship, pi-rich pyrenyliminolipids were created and used to exfoliate graphite, leading to aqueous dispersions of graphene flakes that were stable over several months. PMID- 28642944 TI - Magnetic circular dichroism of UCl6- in the ligand-to-metal charge-transfer spectral region. AB - We present a combined ab initio theoretical and experimental study of the magnetic circular dichroism (MCD) spectrum of the octahedral UCl6- complex ion in the UV-Vis spectral region. The ground state is an orbitally non-degenerate doublet E5/2u and the MCD is a -term spectrum caused by spin-orbit coupling. Calculations of the electronic spectrum at various levels of theory indicate that differential dynamic electron correlation has a strong influence on the energies of the dipole-allowed transitions and the envelope of the MCD spectrum. The experimentally observed bands are assigned to dipole-allowed ligand-to-metal charge transfer into the 5f shell, and 5f to 6d transitions. Charge transfer excitations into the U 6d shell appear at much higher energies. The MCD-allowed transitions can be assigned via their signs of the -terms: Under Oh double group symmetry, E5/2u -> E5/2g transitions have negative -terms whereas E5/2u -> F3/2g transitions have positive -terms if the ground state g-factor is negative, as it is the case for UCl6-. PMID- 28642951 TI - Intermix of metal nanoparticles-single wall carbon nanotubes. AB - Using physical mixtures of Pd/SWNTs (Pd nanoparticles on single-walled carbon nanotubes) and Pt/SWNTs, the composites show electro-catalytic properties comparable to the corresponding alloys: electron exchange readily occurs between the two metal nanoparticles via SWNT support at long ranges without direct atomic contact, which is responsible for the tunable alloy-like properties. PMID- 28642952 TI - Solventless mechanochemical preparation of novel magnetic bioconjugates. AB - A solventless mechanochemical approach was employed to obtain a bioconjugate (BSA DA-Fe2O3) based on bovine serum albumin (BSA) and dopamine (DA) coated iron oxide magnetic nanoparticles. UV-vis measurements of the obtained material showed a distinctive peak at 280 nm which, together with the presence of N on the surface of the nanomaterial (a band at 400 eV in the XPS spectrum) and zeta potential measurements, confirmed the successful immobilization of the protein. Additionally, the presence of two bands at 1652 and 1545 cm-1 in the FT-IR spectra of both BSA and BSA-DA-Fe2O3 and steady-state fluorescence analysis validated that the protein preserved its native-like structure after the mechanochemical milling process. Also the functionalized MNPs preserved their magnetic properties as have been demonstrated by their magnetic susceptibility value. PMID- 28642953 TI - Crack-tips enriched platinum-copper superlattice nanoflakes as highly efficient anode electrocatalysts for direct methanol fuel cells. AB - We have developed "crack-tips" and "superlattice" enriched Pt-Cu nanoflakes (NFs), benefiting from the synergetic effects of "crack-tips" and "superlattice crystals"; the Pt-Cu NFs exhibit 4 times higher mass activity, 6 times higher specific activity and 6 times higher stability than those of the commercial Pt/C catalyst, respectively. Meanwhile, the Pt-Cu NFs show more enhanced CO tolerance than the commercial Pt/C catalyst. PMID- 28642954 TI - Transition-metal-free synthesis of beta-trifluoromethylated enamines with trifluoromethanesulfinate. AB - We have developed a transition-metal free trifluoromethylation protocol between enamines and CF3SO2Na. A wide range of beta-trifluoromethyl substituted enamines were delivered in moderate to high yields with only E-configurations. PMID- 28642955 TI - Generation of highly luminescent micro rings by optical irradiation. AB - We report a serendipitous discovery of light-induced generation of a circular microstructure on a glass surface. The microstructure has a ring shape with notable photophysical properties such as highly bright luminescence and strong resistance to photobleaching. We investigated the formation process as well as the luminescence properties of the micro ring to understand the origin of this peculiar phenomenon. PMID- 28642956 TI - CO adsorption, oxidation and carbonate formation mechanisms on Fe3O4 surfaces. AB - By means of density functional theory calculations that account for the on-site Coulomb interaction via a Hubbard term (DFT+U), we systematically investigated CO adsorption on Fe3O4 surfaces at different coverages. It has been found that more than one CO can coadsorb on one surface iron atom on both Fetet1 and Feoct2 terminations of Fe3O4(111). The uncapped oxygen atom is the active site for CO oxidation on both Fetet1 and Feoct2 terminations of Fe3O4(111). For Fe3O4(110), two CO molecules prefer to coadsorb on one surface iron atom on the A layer; CO prefers to adsorb at the bridge site of the surface octahedral iron atoms at low coverage, while CO prefers to adsorb at the surface tetrahedral iron atom at high coverage on the B layer. It has been found that the surface oxygen atom which is not coordinated to the tetrahedral iron atom is the active site for CO oxidation on the B termination of Fe3O4(001). On the Fe3O4 surfaces, the formation of carbonate has been found to be very stable thermodynamically, which agrees well with experiments. The adsorption mechanism has been analyzed on the basis of projected density of states (PDOS). PMID- 28642957 TI - Superacid-promoted synthesis of highly porous hypercrosslinked polycarbazoles for efficient CO2 capture. AB - A superacid-promoted "knitting" strategy has been developed for the generation of a novel family of hypercrosslinked nanoporous polycarbazoles for efficient CO2 capture. Using trifluoromethanesulfonic acid, a Bronsted superacid, we demonstrate the facile and rapid synthesis of highly porous polycarbazoles with BET surface areas as high as 1688 m2 g-1, and capable of adsorbing 3.5 mmol g-1 of CO2 at 298 K and 1 bar. This impressive result bestows the material with the highest CO2 uptake capacity for all nanoporous carbazolic polymers and ranks among the best by known porous organic polymers under this condition. This innovative approach affords a metal-free alternative to Friedel-Crafts alkylation, and may open up new possibilities for the rational design and synthesis of new hypercrosslinked nanoporous organic networks for carbon capture. PMID- 28642958 TI - Phosphorylation of a full length amyloid-beta peptide modulates its amyloid aggregation, cell binding and neurotoxic properties. AB - Amyloid beta peptide (Abeta) is the major protein component of the amyloid plaques that are present in the brains of Alzheimer's disease (AD) patients. Abeta42 peptide is a known neurotoxic agent that binds to neurons and, under specific aggregation conditions, triggers cell death. Abeta peptide can undergo specific amino acid posttranslational modifications, such as phosphorylation, that are important for modulating its proteolytic degradation, aggregation, binding to lipid membranes and neurotoxic functions. Peptides phosphorylated at serine 8 in full-length Abeta42 (pAbeta42) were synthesised and compared to native Abeta42 peptide. Their secondary structures, aggregation properties and interactions with plasma membranes of primary cortical neurons were investigated. The results revealed that pAbeta42 has increased beta-sheet formation with rapid amyloid formation in a synthetic lipid environment, which was associated with increased cellular binding but concomitant diminished neurotoxicity. Our data support the notion that phosphorylation of Abeta42 promotes the formation of amyloid plaques in the brain, which lack the neurotoxic properties associated with oligomeric species causing pathogenesis in AD. PMID- 28642945 TI - Nonribosomal peptide synthetase biosynthetic clusters of ESKAPE pathogens. AB - Covering: up to 2017.Natural products are important secondary metabolites produced by bacterial and fungal species that play important roles in cellular growth and signaling, nutrient acquisition, intra- and interspecies communication, and virulence. A subset of natural products is produced by nonribosomal peptide synthetases (NRPSs), a family of large, modular enzymes that function in an assembly line fashion. Because of the pharmaceutical activity of many NRPS products, much effort has gone into the exploration of their biosynthetic pathways and the diverse products they make. Many interesting NRPS pathways have been identified and characterized from both terrestrial and marine bacterial sources. Recently, several NRPS pathways in human commensal bacterial species have been identified that produce molecules with antibiotic activity, suggesting another source of interesting NRPS pathways may be the commensal and pathogenic bacteria that live on the human body. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) have been identified as a significant cause of human bacterial infections that are frequently multidrug resistant. The emerging resistance profile of these organisms has prompted calls from multiple international agencies to identify novel antibacterial targets and develop new approaches to treat infections from ESKAPE pathogens. Each of these species contains several NRPS biosynthetic gene clusters. While some have been well characterized and produce known natural products with important biological roles in microbial physiology, others have yet to be investigated. This review catalogs the NRPS pathways of ESKAPE pathogens. The exploration of novel NRPS products may lead to a better understanding of the chemical communication used by human pathogens and potentially to the discovery of novel therapeutic approaches. PMID- 28642959 TI - Progress in obstetrics and gynaecology - evidence-based practices and practice based evidence reviews. PMID- 28642960 TI - Comment on: Teaching metacognition in clinical decision-making using a novel mnemonic checklist: an exploratory study. PMID- 28642961 TI - Female sexual dysfunction with combined oral contraceptive use. AB - Combined oral contraceptive pills (COCs) remain one of the most popular forms of contraception to prevent unwanted pregnancy in women. While it is known that COCs can cause sexual dysfunction in women, there is currently no recommendation to screen for sexual function before and after initiation of COCs. We propose that, based on the evidence available, assessment of sexual function should be done at initiation of COCs, as well as at regular intervals thereafter. This would allow COC-related sexual dysfunction to be managed early, such as by switching the patient to newer-generation COCs or other forms of contraception. PMID- 28642962 TI - Authors' reply. PMID- 28642963 TI - Clinics in diagnostic imaging (178). Wunderlich syndrome and pseudoaneurysm. AB - Wunderlich syndrome is a rare entity characterised by spontaneous retroperitoneal haemorrhage with renal origin. We present a case of Wunderlich syndrome secondary to clotting dyscrasia in a 64-year-old woman. The patient experienced a second Wunderlich haemorrhagic event with metachronous pseudoaneurysm formation, which was likely secondary to the large subcapsular haematoma stripping the renal capsule and tearing the cortical arteries. Selective pseudoaneurysm embolisations were successfully performed on both occasions. This clinical entity, its imaging differential diagnoses and management are discussed. PMID- 28642964 TI - Metastasis of breast cancer cells to the bone, lung, and lymph nodes promotes resistance to ionizing radiation. AB - BACKGROUND: Metastasis represents the leading cause of breast cancer deaths, necessitating strategies for its treatment. Although radiotherapy is employed for both primary and metastatic breast cancers, the difference in their ionizing radiation response remains incompletely understood. This study is the first to compare the radioresponse of a breast cancer cell line with its metastatic variants and report that such metastatic variants are more radioresistant. MATERIALS AND METHODS: A luciferase expressing cell line was established from human basal-like breast adenocarcinoma MDA-MB-231 and underwent in vivo selections, whereby a cycle of inoculations into the left cardiac ventricle or the mammary fat pad of athymic nude mice, isolation of metastases to the bone, lung and lymph nodes visualized with bioluminescence imaging, and expansion of obtained cells was repeated twice or three times. The established metastatic cell lines were assessed for cell proliferation, wound healing, invasion, clonogenic survival, and apoptosis. RESULTS: The established metastatic cell lines possessed an increased proliferative potential in vivo and were more chemotactic, invasive, and resistant to X-ray-induced clonogenic inactivation and apoptosis in vitro. CONCLUSION: Breast cancer metastasis to the bone, lung, and lymph nodes promotes radioresistance. PMID- 28642967 TI - Strategies for Characterization of Enzymatic Nucleic Acids. AB - Practical application of enzymatic nucleic acids has received more attention in recent years. Understanding the mechanism of catalysis and availability of information on potentials and limitations of these enzymes expands their application scope. A general approach for characterization of functional macromolecules including enzymatic nucleic acids is to perturb a specific set of condition and to follow the perturbation effect by biophysical and biochemical methods. This chapter reviews several perturbation strategies for functional nucleic acids, including deletion, mutation, and modifications of backbone and nucleobases, and consequent kinetic analysis, spectroscopic investigations, and probing assays. In addition to single point mutation and modifications, different combinatorial approaches for perturbation interference analysis provide reliable high amounts of data in a time-effective manner. The chapter compares various combinatorial perturbation interference analysis methods, that is, combinatorial mutation interference analysis (CoMA), nucleotide analogue interference mapping for RNA and DNA (NAIM and dNAIM), chemical and enzymatic combinatorial nucleoside deletion scanning (NDS), and dimethyl sulfate interference (DMSi). PMID- 28642966 TI - Procedural sedation and analgesia for pediatric shock wave lithotripsy: a 10 year experience of single institution. AB - The aim of this study was to evaluate anesthesia practice for pediatric extracorporeal shock wave lithotripsy (ESWL) according to the age groups and discuss the anesthetic management of these patients. Pediatric patients treated with ESWL because of urolithiasis under anesthesia in our department between December 2007 and January 2017 were evaluated retrospectively. A total of 251 patients were divided into two groups as Group PS: preschool children (<6 years) and Group S: school children (>=6 years). Groups were compared according to ketamine and midazolam doses, extra anesthetic agent requirement, duration of procedure, procedural and postprocedural complications due to anesthesia, as well as mean number of sessions and calculus diameter. A total of 408 sessions of ESWL were applied to 251 children included in the study. Overall, mean age of the patients was 4.5 +/- 3.2 years (7 months-14 years). In school children (Group S), mean ketamine and midazolam doses were significantly higher than the preschool group (p < 0.01 and p = 0.04, respectively). There was no statistically significant difference in additional anesthetic agent requirement (p = 0.35) as well as mean number of SWL sessions (p = 0.23), duration of anesthesia (p = 0.93), stone size (p = 0.20), and stone laterality (p = 0.71) in both preschool and school children. No severe complications were observed in both groups. In pediatric ESWL patients, ketamine-midazolam combination is an effective and safety choice for outpatient anesthesia. Appropriate dose adjustment in a monitorized and well-equipped setting is essential. PMID- 28642968 TI - Enhancing the enzymatic saccharification of bamboo shoot shell by sequential biological pretreatment with Galactomyces sp. CCZU11-1 and deep eutectic solvent extraction. AB - In this study, sequential biological pretreatment (BP) with Galactomyces sp. CCZU11-1 at 30 degrees C for 3 days and deep eutectic solvent (DES) choline chloride: oxalic acid (ChCl:OA, 1 mol/2 mol) extraction at 120 degrees C for 1.5 h was used for pretreating BSS. It was found that combination pretreatment could effectively remove xylan and lignin for enhancing enzymatic saccharification. The reducing sugars and glucose from the hydrolysis of 100 g/L pretreated BSS with complexed cellulases of Galactomyces sp. CCZU11-1 were obtained in the yields of 81.0% and 74.1%, respectively. The BSS-hydrolyzates had no inhibitory effects on the lipid-accumulating microorganism Bacillus sp. CCZU11-1, and the cell mass and TAG accumulation were 4.8 g CDW/L and 2.2 g TAG/L, respectively. Fatty acids including palmitic acid (C16:0; 25.3%), palmitoleic acid (C16:1; 24.4%), stearic acid (C18:0; 15.1%), and oleic acid (C18:1; 21.6%) were accumulated in cells. Clearly, this combination pretreatment has high potential application in future. PMID- 28642969 TI - Diverse metabolic effects of O-GlcNAcylation in the pancreas but limited effects in insulin-sensitive organs in mice. AB - AIMS/HYPOTHESIS: O-GlcNAcylation is characterised by the addition of N acetylglucosamine to various proteins by O-GlcNAc transferase (OGT) and serves in sensing intracellular nutrients by modulating various cellular processes. Although it has been speculated that O-GlcNAcylation is associated with glucose metabolism, its exact role in whole body glucose metabolism has not been fully elucidated. Here, we investigated whether loss of O-GlcNAcylation globally and in specific organs affected glucose metabolism in mammals under physiological conditions. METHODS: Tamoxifen-inducible global Ogt-knockout (Ogt-KO) mice were generated by crossbreeding Ogt-flox mice with R26-Cre-ERT2 mice. Liver, skeletal muscle, adipose tissue and pancreatic beta cell-specific Ogt-KO mice were generated by crossbreeding Ogt-flox mice with Alb-Cre, Mlc1f-Cre, Adipoq-Cre and Pdx1 PB-CreERTM mice, respectively. Glucose metabolism was evaluated by i.p. glucose and insulin tolerance tests. RESULTS: Tamoxifen-inducible global Ogt-KO mice exhibited a lethal phenotype from 4 weeks post injection, suggesting that O GlcNAcylation is essential for survival in adult mice. Tissue-specific Ogt deletion from insulin-sensitive organs, including liver, skeletal muscle and adipose tissue, had little impact on glucose metabolism under physiological conditions. However, pancreatic beta cell-specific Ogt-KO mice displayed transient hypoglycaemia (Ogt-flox 5.46 +/- 0.41 vs Ogt-betaKO 3.88 +/- 0.26 mmol/l) associated with about twofold higher insulin secretion and accelerated adiposity, followed by subsequent hyperglycaemia (Ogt-flox 6.34 +/- 0.32 vs Ogt betaKO 26.4 +/- 2.37 mmol/l) with insulin depletion accompanied by beta cell apoptosis. CONCLUSIONS/INTERPRETATION: These findings suggest that O GlcNAcylation has little effect on glucose metabolism in insulin-sensitive tissues but plays a crucial role in pancreatic beta cell function and survival under physiological conditions. Our results provide novel insight into O-GlcNAc biology and physiology in glucose metabolism. PMID- 28642965 TI - Erratum to: Development of a Unifying Target and Consensus Indicators for Global Surgical Systems Strengthening: Proposed by the Global Alliance for Surgery, Obstetric, Trauma, and Anaesthesia Care (The G4 Alliance). PMID- 28642970 TI - Abilities of Co-cultures of Brown-Rot Fungus Fomitopsis pinicola and Bacillus subtilis on Biodegradation of DDT. AB - DDT (1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane) is one of the pesticides that are hazardous for the environment and human health. Effective environmental friendly treatment using co-cultures of fungi and bacteria is needed. In this study, the bacteria Bacillus subtilis at various volumes of 1, 3, 5, 7, and 10 mL (1 mL ~ 6.7 * 108 CFU) were mixed into 10 mL of the brown-rot fungus Fomitopsis pinicola culture for degrading DDT during a 7-days incubation period. DDT was degraded by approximately 42% by F. pinicola during the 7-days incubation period. The addition of 10 mL of B. subtilis into F. pinicola culture showed the highest DDT degradation of approximately 86% during the 7-days incubation period. DDD (1,1-dichloro-2,2-bis(4-chlorophenyl)ethane), DDE (1,1-dichloro-2,2-bis(4 chlorophenyl)ethylene), and DDMU (1-chloro-2,2-bis(4-chlorophenyl)ethylene) were detected as metabolic products from DDT degradation by co-cultures of F. pinicola and B. subtilis. Transformation pathway was proposed in which DDT was transformed into three pathways as follows: (1) dechlorination to DDD, (2) dehydrochlorination to DDE, and (3) formation of DDMU. PMID- 28642971 TI - High Diversity of Bacterial Communities in Developmental Stages of Bactrocera carambolae (Insecta: Tephritidae) Revealed by Illumina MiSeq Sequencing of 16S rRNA Gene. AB - Bactrocera carambolae is a highly polyphagous fruit pest of agricultural importance. This study reports the bacterial communities associated with the developmental stages of B. carambolae. The microbiota of the developmental stages were investigated by targeted 16S rRNA gene (V3-V4 region) sequencing using the Illumina MiSeq. At 97% similarity, there were 19 bacterial phyla and unassigned bacteria, comprising 39 classes, 86 orders, 159 families and 311 genera. The bacterial composition varied among the specimens of developmental stage and across developmental stages as well as exuviae. Four phyla of bacteria (with relative abundance of >=1% in at least one specimen)-Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria-were recovered from the larva, pupa, adult stages and exuviae. Proteobacteria was the predominant phylum in all the developmental stages as well as the exuviae. Enterobacteriaceae (Proteobacteria) was the predominant family in the adult flies while the family [Weeksellaceae] (Bacteroidetes) was predominant in the larval and pupal stages. Among the genera occurring in more than one developmental stage of B. carambolae, Erwinia was more abundant in the larval stage, Halomonas more abundant in adult female, Stenotrophomonas more abundant in adult male, and Chryseobacterium more abundant in the larval and pupal stages. The results indicate transmission of bacteria OTUs from immatures to the newly emerged adults, and from exuviae to the environment. PMID- 28642972 TI - Does contrast between eggshell ground and spot coloration affect egg rejection? AB - Obligate avian brood parasitic species impose the costs of incubating foreign eggs and raising young upon their unrelated hosts. The most common host defence is the rejection of parasitic eggs from the nest. Both egg colours and spot patterns influence egg rejection decisions in many host species, yet no studies have explicitly examined the role of variation in spot coloration. We studied the American robin Turdus migratorius, a blue-green unspotted egg-laying host of the brown-headed cowbird Molothrus ater, a brood parasite that lays non-mimetic spotted eggs. We examined host responses to model eggs with variable spot coloration against a constant robin-mimetic ground colour to identify patterns of rejection associated with perceived contrast between spot and ground colours. By using avian visual modelling, we found that robins were more likely to reject eggs whose spots had greater chromatic (hue) but not achromatic (brightness) contrast. Therefore, egg rejection decision rules in the American robin may depend on the colour contrast between parasite eggshell spot and host ground coloration. Our study also suggests that egg recognition in relation to spot coloration, like ground colour recognition, is tuned to the natural variation of avian eggshell spot colours but not to unnatural spot colours. PMID- 28642973 TI - Estimating the magnitude of morphoscapes: how to measure the morphological component of biodiversity in relation to habitats using geometric morphometrics. AB - Ecological indicators are currently developed to account for the different facets of loss of biological diversity due to direct or indirect effects of human activities. Most ecological indicators include species richness as a metric. Others, such as functional traits and phylogenetic diversity, account for differences in species, even when species richness is the same. Here, we describe and apply a different indicator, called morphoscape dimension, accounting for morphological variability across habitats in a geographical region. We use the case of ground beetles (Coleoptera: Carabidae) in four different habitats in the Po Plain in Northern Italy to exemplify how to quantify the magnitude of the morphological space (i.e. the dimension of the morphoscape) occupied by the species in each habitat using geometric morphometrics. To this aim, we employed a variety of metrics of morphological disparity related to univariate size, and more complex multivariate shape and form. Our 'proof of concept' suggests that metrics assessing size and form might largely tend to simply mirror the information provided by species richness, whereas shape morphoscape disparity may be able to account for non-trivial differences in species traits amongst habitats. This is indicated by the woodland morphoscape being on average bigger than that of crops, the most species-rich habitat, despite having almost 20% less species. We conclude suggesting that the analysis of morphoscape dimension has the potential to become a new additional and complimentary tool in the hands of conservation biologists and ecologists to explore and quantify habitat complexity and inform decisions on management and conservation based on a wide set of ecological indicators. PMID- 28642974 TI - Abdominal aortic calcification and the risk of bone fractures: a meta-analysis of prospective cohort studies. AB - The relationship between abdominal aortic calcification (AAC) and bone fracture has been examined by some observational studies, but the results remain discordant. Therefore, we aimed to assess the link between them by conducting a meta-analysis of prospective studies. Relevant studies were identified by searching PubMed and EMBASE databases until the end of December 2016. Summary relative risks (RRs) and 95% confidence intervals (CIs) for associations between AAC and fracture risk were estimated with fixed- or random- effects models. Seven prospective studies were included in the final analysis. The summarized RRs of any type of fractures for the highest compared with the lowest category of AAC were 1.64 (95% CI 1.30-2.07, P = 0.000) with mild heterogeneity (I 2 = 30.1%, P = 0.188). Subgroup analysis showed that the association between AAC and fracture was not significantly modified by gender and follow-up length. Risks were similar when analyses were restricted to the studies with adjustment for bone mineral density (BMD) (RR = 1.76, 95% CI 1.31-2.38, P = 0.000, I 2 = 49.1%). For the specific type of fracture, severe AAC was significantly related with hip fracture (RR = 1.64, 95% CI 1.22-2.20, P = 0.001, n = 5), but not with vertebral (RR = 1.45, 95% CI 0.81-2.58, P = 0.213, n = 3) or non-vertebral fracture (RR = 1.35, 95% CI 0.96-1.88, P = 0.081, n = 3). There was no evidence of publication bias. Our findings demonstrated that AAC was significantly and independently associated with a higher fracture risk, especially for hip fracture. PMID- 28642975 TI - Association of bone metabolism markers with coronary atherosclerosis and coronary artery disease in postmenopausal women. AB - This study aimed to evaluate the association of bone metabolism markers with coronary atherosclerosis and coronary artery disease (CAD) in postmenopausal women. Based on the findings of coronary angiography, 111 women with CAD and 116 women without CAD were recruited. Serum calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), osteocalcin, N-terminal propeptide of type I procollagen (P1NP) and C-terminal cross-linked telopeptide of type I collagen (CTX) were measured. The Gensini score was used to assess the severity of coronary atherosclerosis. Compared with women with serum calcium <=2.29 mmol/L, women with serum calcium >2.29 mmol/L had a 2.63-fold increased risk of CAD after adjusting for multiple cardiovascular risks, PTH and 25OHD [odds ratio (OR) = 2.91, 95% confidence interval (CI) 1.35-6.28]. In the fully adjusted model plus PTH and 25OHD, the risk of CAD increased 1.87-fold with every 1-SD increment of serum calcium (OR = 1.87, 95% CI 1.21-2.88). To further analyze the potential strong confounding effect of albumin, the absolute levels of calcium were replaced by their albumin-corrected values in the regression model. Compared with women with albumin-corrected calcium <=2.27 mmol/L, women with albumin-corrected calcium >2.27 mmol/L had a 2.36-fold increased risk of CAD in the fully adjusted model plus PTH and 25OHD (OR = 2.36, 95% CI 1.13-4.92). The risk of coronary atherosclerosis as defined by Gensini score >0 increased 1.73-fold with every 1 SD increment of serum calcium in the fully adjusted model plus PTH and 25OHD (OR = 1.73, 95% CI 1.09-2.73). However, albumin-corrected calcium was not associated with coronary atherosclerosis either as a categorical variable or as a continuous variable in all models. No significant association of PTH, 25OHD, osteocalcin, CTX and P1NP with CAD or coronary atherosclerosis was found in this study. Higher serum calcium levels were independently associated with CAD in postmenopausal women. PMID- 28642976 TI - Prognostic role of a new risk index for the prediction of 30-day cardiovascular mortality in patients with acute pulmonary embolism: the Age-Mean Arterial Pressure Index (AMAPI). AB - Acute pulmonary embolism (PE) is the third cause of cardiovascular (CV) mortality. We evaluated a new risk index, named Age-Mean Arterial Pressure Index (AMAPI), to predict 30-day CV mortality in patients with acute PE. Data of 209 patients (44.0% male and 56.0% female, mean age 70.58 +/- 14.14 years) with confirmed acute PE were retrospectively analysed. AMAPI was calculated as the ratio between age and mean arterial pressure (MAP), which was defined as [systolic blood pressure + (2 * diastolic blood pressure)]/3. To test AMAPI accuracy, a comparison with shock index (SI) and simplified pulmonary embolism severity index (sPESI) was performed. Patients were divided in two groups according their hemodynamic stability, or not, at admission. 30-day mortality rate, in all cases for CV events, was 10.5% (n = 22). Hemodynamically unstable patients had a higher AMAPI compare to those without hypotension at admission (1.28 +/- 0.39 vs 0.78 +/- 0.27, p < 0.0001). Receiving operative curve analyses (ROC) found the optimal cut-off for AMAPI in hemodynamically stable and unstable patients >=0.9 and >=0.92, respectively. In both groups, patients with an AMAPI over the cut-off were significantly older, hypotensive (both systolic and diastolic blood pressure), with a higher SI and lower MAP. In hemodynamically stable patients, 30-day CV mortality risk prediction was improved adding AMAPI >=0.9 to both SI and sPESI (net reclassification improvement-NRI-of 14.2%, p = 0.0006 and 11.5%, p = 0.0002, respectively). In hemodynamically unstable patients NRI was 19.2%, p = 0.006. Mantel-Cox analysis revealed a statistical significant difference in the distribution of survival between hemodynamically stable patients with an AMAPI index >=0.9 compared to those with an AMAPI <0.89 [log rank (Mantel-Cox) p < 0.0001] and in hemodynamically unstable patients with an AMAPI >=0.92 [log rank (Mantel-Cox) p = 0.001]. AMAPI >=0.90 and >=0.92 predict 30-day CV mortality in hemodynamically stable and unstable patients with acute PE. PMID- 28642978 TI - Ectopic delivery of miR-200c diminishes hepatitis C virus infectivity through transcriptional and translational repression of Occludin. AB - Occludin (OCLN) is an essential factor for HCV entry through interacting with other surface receptors. The aim of this study was to investigate the epigenetic regulation of Occludin expression and to study its impact on viral infectivity. microRNAs expression was assessed using qRT-PCR, while OCLN protein expression was investigated by indirect immunofluorescence and Western blotting. Viral infectivity was assessed by measuring viral-load using qRT-PCR. In silico analysis predicted that miR-200c targeted the OCLN 3'UTR, which was further experimentally confirmed. miR-122 was previously validated to target the 3'UTR of OCLN and was used as a control. We report a significant down-regulation of miR 200c in liver tissues of HCV-infected patients. Ectopic expression of both miR 122 and miR-200c in Huh7 cells reduced OCLN mRNA and protein levels. Viral infectivity was significantly reduced by miR-200c but enhanced by miR-122. This work sheds light on miR-200c as a novel regulator of HCV infectivity through the regulation of OCLN. PMID- 28642977 TI - Molecular characteristics and prevalence of small ruminant lentiviruses in goats in Japan. AB - Small ruminant lentiviruses (SRLVs), which comprise caprine arthritis encephalitis virus (CAEV) and maedi-visna virus (MVV), are prevalent in goats and sheep worldwide, including in Japan. However, little is known about the molecular characteristics of goat lentiviruses in Japan. In this study, a molecular and phylogenetic analysis of the long gag region was performed. The phylogenic tree demonstrated that all samples belonged to SRLV subtype B1. Two clusters were identified, with one cluster distinct from previously reported strains of subtype B1. In addition, several alterations in the amino acid sequence were detected in immunodominant epitopes of the gag region. To gain a deeper understanding of the genetic diversity of SRLVs in Japan, it will be necessary to increase the sample size and conduct a broader survey. The present report is important for establishing baseline information on the prevalence of SRLV in Japan and providing data to develop a new, more sensitive diagnostic test for effective control of SRLV. PMID- 28642980 TI - [Unsuitable guideline recommendations for psychotherapeutic treatment of manias]. PMID- 28642981 TI - [Mental health as a global challenge : Research, care and participation]. PMID- 28642979 TI - [Medial opening wedge high tibial osteotomy]. AB - OBJECTIVE: Reduction of the load to the medial compartment in patients with medial knee osteoarthritis and varus malalignment. Unloading of the posterolateral complex in varus deformity with complex ligamentous laxity. INDICATIONS: Medial knee osteoarthritis and varus malalignment with largely intact lateral and patellofemoral joint aspect. Complex ligament insufficiency combined with varus deformity. CONTRAINDICATIONS: Substantially impaired range of motion. SURGICAL TECHNIQUE: Medial skin incision on the proximal lower leg. Preparation of the pes anserinus. Marking of the osteotomy from the deepest point of the medial metaphysis laterally ascending. Biplane osteotomy, carefully protecting the posterior neurovascular structures, with ventral completion proximal or distal to the tibial tuberosity, depending on concomitant pathologies. Angular-stable plate fixation. POSTOPERATIVE MANAGEMENT: In general, early weight bearing is possible when angular-stable plate fixation is used. Often concomitant pathologies such as accompanying cartilage regenerative therapy necessitate longer unloading. Range of motion does not need to be restricted following stand-alone osteotomy. Orthoses are recommended regularly. RESULTS: Under the correct indication, the medial opening wedge high tibial osteotomy (OW HTO) technique can achieve good results with high patient satisfaction, despite a relatively high statistical complication rate, provided that a standardized surgical technique is used. There is a tendency for a poorer outcome in patients with a body mass index above 30 and higher stages of osteoarthritis. PMID- 28642982 TI - [Healthcare models for traumatized refugees in Germany]. AB - People with a migration background are a risk group for psychiatric disorders. Innovative, transnational and sustainable projects are necessary to ensure adequate care for refugees and asylum seekers. Selected projects of the University of Munich, the Charite Berlin and the University of Konstanz show promising approaches in addition to other initiatives. PMID- 28642983 TI - [Hebephrenia - a viable psychopathological construct?] AB - Ewald Hecker was the first psychiatrist to describe the disease entity of hebephrenia in some detail, focusing mainly on disturbances of affect. Later Emil Kraepelin and Eugen Bleuler saw hebephrenia as a subtype of dementia praecox or schizophrenia. Willy Mayer-Gross and Karl Leonhard characterized hebephrenia with highly differentiated psychopathological descriptions, whereas this construct only played a minor role in the works of Klaus Conrad and Kurt Schneider. The International Classification of Diseases (ICD-10) lists hebephrenia as a subtype of schizophrenia but in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) no subtypes of schizophrenia are mentioned and the concept of hebephrenia is thus lost. Hebephrenia can be seen as an ideal type describing a psychopathological course pattern. This construct can be useful to conceptualize a group of disorders of affect which otherwise escape description, especially since these psychopathological alterations of affect are difficult to operationalize. To have a viable concept of these disorders is relevant for the prognosis and therapy planning. If the concept of hebephrenia is abolished, important psychopathological knowledge might be lost for future generations of psychiatrists. PMID- 28642984 TI - Noninvasive positive pressure ventilation after skull base surgery. PMID- 28642985 TI - Focus on brain injury. PMID- 28642986 TI - Viridiuvalis adhaerens gen. et sp. nov., a novel colony-forming chlorarachniophyte. AB - A new chlorarachniophyte, Viridiuvalis adhaerens gen. et sp. nov. was isolated from the mucus on a coral reef from Zanpa Beach, Okinawa, Japan. The main vegetative stage of V. adhaerens consisted of unicellular coccoid cells with cell walls, although sarcinoid colonies and uniflagellate zoospores were also observed. V. adhaerens had chloroplasts with nucleomorphs and pyrenoids that were completely embedded in the chloroplast. A deep plate-like invagination of the periplastidal compartment (PPC) almost partitioned the pyrenoid and chloroplast components, which were surrounded by two membranes. The nucleomorph was positioned in the base of the invagination of the PPC. Molecular phylogenetic analyses using rRNA genes showed that V. adhaerens branched as a sister lineage of the Amorphochlora clade. The sarcinoid colony, pyrenoid embedded in the chloroplast, and nucleomorph located at the base of the deep invagination of the PPC have not been reported in other chlorarachniophytes. Based on these morphological and ultrastructural characteristics and the results of the molecular phylogenetic analyses, we propose V. adhaerens as a new genus and species of chlorarachniophyte. PMID- 28642987 TI - Chromosome number and genome size variation in Colocasia (Araceae) from China. AB - Chromosome number and genome size are important cytological characters that significantly influence various organismal traits. We investigated chromosome number and genome size variation in 73 accessions belonging to four Colocasia species from China. Five different chromosome counts (2n = 26, 28, 38, 42, and 56) were found, the largest one representing a new record in Colocasia. The basic chromosome numbers are x = 13, 14, and 19, corresponding to 2x, 3x, and 4x cytotypes. Yunnan Province, China is considered the center of Colocasia polyploid origin. The 2C values in our accessions ranged from 3.29 pg in C. gigantea to 12.51 pg in C. esculenta. All species exhibit inter- and intraspecific chromosomal variation. Differences in DNA content among the Colocasia species seem to have occurred by chromosomal gain under similar habitats. Polyploidization also obviously contributes to 2C value variation. PMID- 28642988 TI - Development of Pulmonary Hypertension During Treatment with Diazoxide: A Case Series and Literature Review. AB - Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy. The mainstay of medical management for CHI is diazoxide. Diazoxide inhibits insulin release from the pancreas, but also causes smooth muscle relaxation and fluid retention so it is typically given with chlorothiazide. In July 2015, the FDA issued a drug safety communication warning that pulmonary hypertension (PH) had been reported in 11 infants being treated with diazoxide and that the PH resolved with withdrawal of diazoxide. All three of the cases in our hospital were admitted to the neonatal intensive care unit (NICU) for hypoglycemia. All patients received thorough radiologic and laboratory evaluations related to their diagnosis of CHI. All initially improved when diazoxide was initiated. Case 1 and case 3 were discharged from the NICU on diazoxide and chlorothiazide. Case 2 developed pulmonary hypertension while still in the NICU days after an increase in diazoxide dosing. Case 1 presented to the emergency room in respiratory distress shortly after discharge from the NICU with evidence of PH and heart failure. Case 3 presented to the emergency room after 2 weeks at home due to a home blood glucose reading that was low and developed PH and heart failure while an inpatient. Discontinuation of diazoxide led to resolution of all three patients' PH within approximately one week. The experience of our hospital indicates that pulmonary hypertension may be more common than previously thought in infants taking diazoxide. It is unclear if these symptoms develop slowly over time or if there is some other, as yet undescribed, trigger for the pulmonary hypertension. Our hospital's experience adds to the body of evidence and suggests these infants may benefit from more surveillance with echocardiography. PMID- 28642990 TI - How Health Humanities Will Save the Life of the Humanities. AB - In the last decade, the humanities have been shrinking in number of students, percent of faculty, and in number of degrees awarded. Humanities students also earn lower salaries than their STEM-prepared peers. At the same time, the health humanities have been in ascendance over the last fifteen years. The number of majors, minors and certificates has increased 266% in that time frame, attracting large numbers of students and preparing future patients, lay caregivers, and health care providers to interact with a complicated and dehumanized medical system. In 1982, British philosopher and educator Stephen Toulmin declared that medicine saved philosophy from irrelevance and possibly extinction. I propose that the health humanities can serve a similar function to stave off the decline of the broader humanities. The health humanities can (1) model an applied approach for the broader humanities to attract student interest; (2) develop students' capacity for critical reading, writing and reflection about health and medicine in society, practice, and their own lives and (3) inoculate all students against the influence of medicine, whether through preparing pre-health students to navigate the hidden medical curriculum or preparing future patients to navigate the health care system. PMID- 28642991 TI - Extensive Overlap of Tropical Rainforest Bacterial Endophytes between Soil, Plant Parts, and Plant Species. AB - The extent to which distinct bacterial endophyte communities occur between different plant organs and species is poorly known and has implications for bioprospecting efforts. Using the V3 region of the bacterial 16S ribosomal RNA (rRNA) gene, we investigated the diversity patterns of bacterial endophyte communities of three rainforest plant species, comparing leaf, stem, and root endophytes plus rhizosphere soil community. There was extensive overlap in bacterial communities between plant organs, between replicate plants of the same species, between plant species, and between plant organ and rhizosphere soil, with no consistent clustering by compartment or host plant species. The non metric multidimensional scaling (NMDS) analysis highlighted an extensively overlapping bacterial community structure, and the beta-nearest taxon index (betaNTI) analysis revealed dominance of stochastic processes in community assembly, suggesting that bacterial endophyte operational taxonomic units (OTUs) were randomly distributed among plant species and organs and rhizosphere soil. Percentage turnover of OTUs within pairs of samples was similar both for plant individuals of the same species and of different species at around 80-90%. Our results suggest that sampling extra individuals, extra plant organs, extra species, or use of rhizosphere soil, might be about equally effective for obtaining new OTUs for culture. These observations suggest that the plant endophyte community may be much more diverse, but less predictable, than would be expected from culturing efforts alone. PMID- 28642992 TI - Plasmid-Mediated Quinolone Resistance (PMQR) Genes and Class 1 Integrons in Quinolone-Resistant Marine Bacteria and Clinical Isolates of Escherichia coli from an Aquacultural Area. AB - Antimicrobial usage in aquaculture selects for antimicrobial-resistant microorganisms in the marine environment. The relevance of this selection to terrestrial animal and human health is unclear. Quinolone-resistance genes qnrA, qnrB, and qnrS were chromosomally located in four randomly chosen quinolone resistant marine bacteria isolated from an aquacultural area with heavy quinolone usage. In quinolone-resistant uropathogenic clinical isolates of Escherichia coli from a coastal area bordering the same aquacultural region, qnrA was chromosomally located in two E. coli isolates, while qnrB and qnrS were located in small molecular weight plasmids in two other E. coli isolates. Three quinolone resistant marine bacteria and three quinolone-resistant E. coli contained class 1 integrons but without physical association with PMQR genes. In both marine bacteria and uropathogenic E. coli, class 1 integrons had similar co-linear structures, identical gene cassettes, and similarities in their flanking regions. In a Marinobacter sp. marine isolate and in one E. coli clinical isolate, sequences immediately upstream of the qnrS gene were homologous to comparable sequences of numerous plasmid-located qnrS genes while downstream sequences were different. The observed commonality of quinolone resistance genes and integrons suggests that aquacultural use of antimicrobials might facilitate horizontal gene transfer between bacteria in diverse ecological locations. PMID- 28642993 TI - Impact of left ventricular longitudinal functional mechanics on the progression of diastolic function in diabetes mellitus. AB - Left ventricular (LV) diastolic dysfunction and longitudinal systolic dysfunction were identified in patients with diabetes mellitus (DM). This study's aim was to investigate the impact of LV longitudinal systolic function on LV diastolic function in DM patients with preserved LV ejection fraction (LVEF). We studied 177 DM patients with preserved LVEF (all >=50%), and 82 age-, gender- and LVEF matched healthy volunteers as control. Global longitudinal strain (GLS) was defined as the average peak strain of 18 segments from standard apical views, GLS <18% as subclinical LV systolic dysfunction (LVSD), and LV dispersion as the standard deviation of time-to-peak strain from the same views. For DM patients with LVSD (n = 74), E/A and E' were lower, and E/E' and isovolumic relaxation time (IVRT) were greater than for DM patients without LVSD (n = 103) and normal controls (n = 82). Moreover, these parameters were lower for DM patients without LVSD than for normal controls. Multivariate analysis revealed that GLS was a strong determinative factor for E' and E/E' (beta = 0.30, p < 0.001 and beta = 0.25, p < 0.001, respectively), as was LV dispersion for E-wave deceleration time and IVRT (beta = 0.21, p = 0.002 and beta = 0.30, p < 0.001, respectively) independently of age. For normal subjects, however, only age was associated with all LV diastolic parameters. In conclusions, in contrast to age-related LV diastolic dysfunction in normal subjects, in DM patients with preserved LVEF, LV diastolic function was associated with LV longitudinal systolic function and LV dispersion independently of age. Our findings have obvious clinical implications for the management of DM patients. PMID- 28642994 TI - Cardiovascular magnetic resonance imaging to assess myocardial fibrosis in valvular heart disease. AB - The left ventricular (LV) remodeling process associated with significant valvular heart disease (VHD) is characterized by an increase of myocardial interstitial space with deposition of collagen and loss of myofibers. These changes occur before LV systolic function deteriorates or the patient develops symptoms. Cardiovascular magnetic resonance (CMR) permits assessment of reactive fibrosis, with the use of T1 mapping techniques, and replacement fibrosis, with the use of late gadolinium contrast enhancement. In addition, functional consequences of these structural changes can be evaluated with myocardial tagging and feature tracking CMR, which assess the active deformation (strain) of the LV myocardium. Several studies have demonstrated that CMR techniques may be more sensitive than the conventional measures (LV ejection fraction or LV dimensions) to detect these structural and functional changes in patients with severe left-sided VHD and have shown that myocardial fibrosis may not be reversible after valve surgery. More important, the presence of myocardial fibrosis has been associated with lesser improvement in clinical symptoms and recovery of LV systolic function. Whether assessment of myocardial fibrosis may better select the patients with severe left sided VHD who may benefit from surgery in terms of LV function and clinical symptoms improvement needs to be demonstrated in prospective studies. The present review article summarizes the current status of CMR techniques to assess myocardial fibrosis and appraises the current evidence on the use of these techniques for risk stratification of patients with severe aortic stenosis or regurgitation and mitral regurgitation. PMID- 28642995 TI - Accuracy and reproducibility of fast fractional flow reserve computation from invasive coronary angiography. AB - Fractional flow reserve (FFR) guided percutaneous coronary intervention (PCI) is associated with favourable outcome compared with revascularization based on angiographic stenosis severity alone. The feasibility of the new image-based quantitative flow ratio (QFR) assessed from 3D quantitative coronary angiography (QCA) and thrombolysis in myocardial infarction (TIMI) frame count using three different flow models has been reported recently. The aim of the current study was to assess the accuracy, and in particular, the reproducibility of these three QFR techniques when compared with invasive FFR. QFR was derived (1) from adenosine induced hyperaemic coronary angiography images (adenosine-flow QFR [aQFR]), (2) from non-hyperemic images (contrast-flow QFR [cQFR]) and (3) using a fixed empiric hyperaemic flow [fixed-flow QFR (fQFR)]. The three QFR values were calculated in 17 patients who prospectively underwent invasive FFR measurement in 20 vessels. Two independent observers performed the QFR analyses. Mean difference, standard deviation and 95% limits of agreement (LOA) between invasive FFR and aQFR, cQFR and fQFR for observer 1 were: 0.01 +/- 0.04 (95% LOA: -0.07; 0.10), 0.01 +/- 0.05 (95% LOA: -0.08; 0.10), 0.01 +/- 0.04 (95% LOA: -0.06; 0.08) and for observer 2: 0.00 +/- 0.03 (95% LOA: -0.06; 0.07), -0.01 +/- 0.03 (95% LOA: -0.07; 0.05), 0.00 +/- 0.03 (95% LOA: -0.06; 0.05). Values between the 2 observers were (to assess reproducibility) for aQFR: 0.01 +/- 0.04 (95% LOA: 0.07; 0.09), for cQFR: 0.02 +/- 0.04 (95% LOA: -0.06; 0.09) and for fQFR: 0.01 +/ 0.05 (95% LOA: -0.07; 0.10). In a small number of patients we showed good accuracy of three QFR techniques (aQFR, cQFR and fQFR) to predict invasive FFR. Furthermore, good inter-observer agreement of the QFR values was observed between two independent observers. PMID- 28642996 TI - Central conduction abnormalities in patients receiving levodopa-carbidopa intestinal gel infusion. AB - In recent years, several studies have reported a relatively high frequency of polyneuropathy in patients with Parkinson's disease (PD), in particular, in patients receiving levodopa-carbidopa intestinal gel (LCIG) infusion. In spite of the several patients investigated with nerve conduction studies, no study has prospectively explored a possible central nervous system involvement of patients receiving LCIG infusion. We prospectively evaluated eight PD patients receiving LCIG infusion, who underwent neurophysiological evaluations with nerve conduction studies, visual, somatosensory and motor evoked potentials before LCIG infusion, and 1 and 6 months after. At 6 months follow-up, we found significant reduction in sural nerve SNAP amplitude, increase of central sensory conduction time N22 P40, and increases of central motor conduction time recorded from I dorsal interosseous and tibialis anterior. In PD patients with LCIG infusion, we found a subclinical neurophysiological impairment of both peripheral and central nervous system. PMID- 28642998 TI - Plastic bronchitis: a rare complication of long-term haemodialysis catheter placement in a child. AB - BACKGROUND: Despite peritoneal dialysis being the preferred mode of renal replacement therapy in neonates and infants, long-term haemodialysis may be necessary in a minority of patients with its attendant risks. CASE DIAGNOSIS/TREATMENT: This case identifies plastic bronchitis as a rare yet serious complication of long-term large bore vascular access when a vessel sparing approach is not possible. CONCLUSIONS: An appropriately sized catheter should be used for the dialytic therapy required and to optimize access survival. PMID- 28642999 TI - Continually improving standards of care: The UK Renal Registry as a translational public health tool. AB - A disease registry uses observational study methods to collect defined data on patients with a particular condition for a predetermined purpose. By providing comprehensive standardised data on patients with kidney disease, renal registries aim to provide a 'real world' representation of practice patterns, treatment and patient outcomes that may not be captured accurately by other methods, including randomised controlled trials. Additionally, using registries to measure variations in outcomes and audit care against standards is crucial to understanding how to improve quality of care for patients in an efficacious and cost-effective manner. Registries also have the potential to be a powerful scientific tool that can monitor and support the translational process between research and routine clinical practice, although their limitations must be borne in mind. In this review, we describe the role of the UK Renal Registry as a tool to support translational research. We describe its involvement across each stage of the translational pathway: from hypothesis generation, study design and data collection, to reporting of long-term outcomes and quality improvement initiatives. Furthermore we explore how this role may bring about improvements in care for adults and children with kidney disease. PMID- 28643000 TI - Interaction of the interleukin 8 protein with a sodium dodecyl sulfate micelle: A computer simulation study. AB - Molecular simulations were carried out to study the sodium dodecyl sulfate (SDS) surfactant with the interleukin 8 (IL8) protein as a model to investigate the influence of amphiphilic molecules on proteins. Simulations for an SDS micelle with an IL8 protein show that both aggregates, which were initially separated, eventually approach each other to form a single complex. The results showed that the protein was attached to the SDS micelle by the charged positive amino acids whereas less contacts were observed for the negatively charged amino acids. Structural protein properties, such as amino acid contacts and pair correlation functions were conducted between the micelle and the protein groups and they showed greater interactions between the surfactant headgroups and the positively charged residues in the protein. Moreover, hydrogen bonds were also calculated between both structures and a greater number of bonds among the SDS headgroups and the charged positive amino acids in the protein was found. Graphical Abstract Attachment of the interleukin 8 protein with a sodium dodecyl sulfate (SDS) micelle is given by the charged positive amino acids as indicated by the interaction of those amino acids with the SDS headgroups. PMID- 28642997 TI - PD-1 and cancer: molecular mechanisms and polymorphisms. AB - The programmed cell death protein 1 (PD-1) is expressed by activated T cells that act as an immunoregulatory molecule, and are responsible for the negative regulation of T cell activation and peripheral tolerance. The PD-1 gene also encodes an inhibitory cell surface receptor involved in the regulation of T cell functions during immune responses/tolerance. Beyond potent inhibitory effects on T cells, PD-1 also has a role in regulating B cell and monocyte responses. An overexpression of PD-1 has been reported to contribute to immune system avoidance in different cancers. In particular, PD-1 over-expression influences tumor specific T cell immunity in a cancer microenvironment. Blocking the PD-1/PD-1 ligand (PD-L1) pathway could potentially augment endogenous antitumor responses. Along these lines, the use of PD-1/PD-L1 inhibitors has been applied in clinical trials against diverse forms of cancer. It was believed that antibodies targeting PD-1/PD-L1 might synergize with other treatments that enhance endogenous antitumor immunity by blocking inhibitory receptor-ligand interactions. However, in all cases, the host genetic status (as well as that of the tumor) is likely to have an impact on the expected outcomes. Various investigations have evaluated the association between PD-1 polymorphisms and the risk of various types of cancer. Frequently studied PD-1 polymorphisms, PD-1.1 (rs36084323), PD-1.3 (rs11568821), PD-1.5 (rs2227981), PD-1.9 (rs2227982), and PD-1 rs7421861, and their associations in the risk of susceptibility to different types of cancer are mentioned in this review, as are studies highlighting the significance of conducting genetic association studies in different ethnic populations. PMID- 28643001 TI - Prediction of self-assemblies of sodium dodecyl sulfate and fragrance additives using coarse-grained force fields. AB - Coarse-grained force field (CGFF) methods were applied to study the self-assembly of sodium dodecyl sulfate with fragrance additives. The CGFF parameters were parameterized and validated using experimental and all-atom simulation data. Direct molecular dynamics simulations were carried out to characterize the initial aggregation, partitioning of fragrances, and chemical potentials of the surfactant and fragrance molecules in aggregates of different sizes. The equilibrium critical micelle concentrations (CMCs) and micelle size distributions, which could not be obtained by direct simulation, were predicted using the calculated chemical potentials in combination with a thermodynamic model. The predicted partitioning of fragrances, CMCs, micelle sizes, and micelle structures agree well with previously reported experimental data. Graphical abstract Enhancement of micelle size distribution using thermodynamic model. PMID- 28643002 TI - Genotoxicity testing of different surface-functionalized SiO2, ZrO2 and silver nanomaterials in 3D human bronchial models. AB - Inhalation is considered a critical uptake route for NMs, demanding for sound toxicity testing using relevant test systems. This study investigates cytotoxicity and genotoxicity in EpiAirwayTM 3D human bronchial models using 16 well-characterized NMs, including surface-functionalized 15 nm SiO2 (4 variants), 10 nm ZrO2 (4), and nanosilver (3), ZnO NM-110, TiO2 NM-105, BaSO4 NM-220, and two AlOOH NMs. Cytotoxicity was assessed by LDH and ATP assays and genotoxicity by the alkaline comet assay. For 9 NMs, uptake was investigated using inductively coupled plasma-mass spectrometry (ICP-MS). Most NMs were neither cytotoxic nor genotoxic in vitro. ZnO displayed a dose-dependent genotoxicity between 10 and 25 ug/cm2. Ag.50.citrate was genotoxic at 50 ug/cm2. A marginal but still significant genotoxic response was observed for SiO2.unmodified, SiO2.phosphate and ZrO2.TODS at 50 ug/cm2. For all NMs for which uptake in the 3D models could be assessed, the amount taken up was below 5% of the applied mass doses and was furthermore dose dependent. For in vivo comparison, published in vivo genotoxicity data were used and in addition, at the beginning of this study, two NMs were randomly selected for short-term (5-day) rat inhalation studies with subsequent comet and micronucleus assays in lung and bone marrow cells, respectively, i.e., ZrO2.acrylate and SiO2.amino. Both substances were not genotoxic neither in vivo nor in vitro. EpiAirwayTM 3D models appear useful for NM in vitro testing. Using 16 different NMs, this study confirms that genotoxicity is mainly determined by chemical composition of the core material. PMID- 28643003 TI - Recent developments in solution nuclear magnetic resonance (NMR)-based molecular biology. AB - Visualizing post-translational modifications, conformations, and interaction surfaces of protein structures at atomic resolution underpins the development of novel therapeutics to combat disease. As computational resources expand, in silico calculations coupled with experimentally derived structures and functional assays have led to an explosion in structure-based drug design (SBDD) with several compounds in clinical trials. It is increasingly clear that "hidden" transition-state structures along activation trajectories can be harnessed to develop novel classes of allosteric inhibitors. The goal of this mini-review is to empower the clinical researcher with a general knowledge of the strengths and weaknesses of nuclear magnetic resonance (NMR) spectroscopy in molecular medicine. Although NMR can determine protein structures at atomic resolution, its unrivaled strength lies in sensing subtle changes in a nuclei's chemical environment as a result of intrinsic conformational dynamics, solution conditions, and binding interactions. These can be recorded at atomic resolution, without explicit structure determination, and then incorporated with static structures or molecular dynamics simulations to produce a complete biological picture. PMID- 28643004 TI - Effectiveness and safety of apixaban therapy in daily-care patients with atrial fibrillation: results from the Dresden NOAC Registry. AB - The effectiveness and safety of apixaban for stroke prevention in atrial fibrillation (SPAF) demonstrated in ARISTOTLE needs to be confirmed in daily care. To evaluate effectiveness and safety of apixaban therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 3000 patients on novel oral anticoagulants in daily care. Between 1 December 2012 and 31 August 2015, 514 patients receiving apixaban were enrolled. During a mean follow-up of 803.5 +/- 228.9 days, the combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.4/100 patient-years in the intention-to-treat analysis (95% confidence interval [CI] 1.5-3.5) and at 1.8/100 patient-years (95% CI 1.0-2.8) in the on-treatment analysis (events within 3 days after last intake). On-treatment rates were numerically lower for patients selected for 5 mg apixaban (n = 404) twice daily [BID] compared with the 110 patients selected for 2.5 mg BID [1.6 (95% CI 0.8 to 2.7) vs. 2.6/100 patient-years (95% CI 0.8-6.1)]. On treatment, major bleeding occurred at a rate of 2.8/100 patient-years and significantly more often in patients receiving the 2.5 mg BID dose compared with the 5 mg BID dose (5.3 vs. 2.2/100 patient-years). Apixaban treatment discontinuation occurred in a total of 122 patients during follow-up (12.5/100 patient-years in Kaplan-Meier analysis). Our data contribute to the confirmation of effectiveness and relative safety of apixaban in daily-care patients. Furthermore, apixaban discontinuation rates were considerably lower than those reported for vitamin K antagonists. PMID- 28643005 TI - Surgical outcomes of 27-gauge pars plana vitrectomy with short-term postoperative tamponade of perfluorocarbon liquid for repair of giant retinal tears. AB - PURPOSE: To investigate the use of 27-gauge pars plana vitrectomy (PPV) with short-term tamponade of perfluorocarbon liquid (PFCL) for repair of giant retinal tears (GRT). METHODS: Retrospective case series study. Consecutive patients with GRT were treated with 27-gauge PPV and short-term tamponade of PFCL for 7-10 days. PFCL was completely removed with a secondary surgery. RESULTS: Twenty-three eyes of 23 patients were included. All the patients achieved primary anatomic success. Preoperative logarithm of the minimum angle of resolution (logMAR) BCVA was 1.59 +/- 0.58 (Snellen 20/778). Five (21.7%), nine (39.1%), eleven (47.8%) and fifteen (65.2%) eyes experienced vision improvement at the Month-1, Month-3, Month-6 and final follow-ups, respectively. The final logMAR BCVA was 0.84 +/- 0.51 (Snellen 20/138), being statistically better than the preoperative one (P < 0.001). Surgical complications included foreign body response (n = 7), transient elevated intraocular pressure (n = 5), cataract formation/deterioration (n = 11) and posterior capsule opacity (n = 16). CONCLUSIONS: 27-Gauge PPV with short-term tamponade of PFCL is safe and effective for the repair of GRT. Side effects of the surgery mainly included foreign body response, transient elevated intraocular pressure, cataract formation/deterioration and posterior capsule opacity. PMID- 28643006 TI - Complications of Fat Transfer for Breast Augmentation. AB - Autologous fat grafting is quite common for breast augmentations as well as for reconstructive breast surgery. Coleman has described the surgical technique of fat grafting. Fat is harvested, and after centrifugation and refinement, blunt infiltration cannulas are used to place the fat through small incisions. The grafted tissue is placed in small aliquots with each withdrawal of the cannula. In order to achieve an aesthetically pleasing contour of the breast, the fat should be layered into different levels from the chest wall to the skin. However, autogenous lipotransfer if not performed lege artis might lead to complications such as fat necrosis, calcification, formation of encapsulated fatty masses (cystic lesions), lymphadenopathy, disfigurement of breast contouring, hypersensitive breasts, itchy nipples. A 36-year old female patient, presented with multiple palpable cystic lesions, disrupted breast contouring, asymmetry, hypersensation and pain during examination, 6 months after autologous fat grafting for breast augmentation elsewhere. The patient had ultrasound and MRI screening, which revealed the multiple bilateral cysts formation in the breast tissue. Surgical removal of the large lesions was performed, and specimens were sent for pathology and cytology consideration and screening. A few months after surgical removal of these lesions and after symptoms subsided, breast augmentation was performed with silicone implants. An aesthetically pleasing result together with relief of the patient's initial symptomatology was achieved. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28643008 TI - Correction of Rhytides, Peau d'Orange, and Thin Dermis of the Face by Neocollagenesis Using Novel Collagen Stimulating Slurry Protocol. AB - : We reviewed 200 patient records from 2009 to 2015 of individuals who presented at the authors offices for facial wrinkle reduction and who on physical examination had rhytides, peau d'orange, or thin dermis and underwent novel adipose slurry injections. The patients were evaluated at week 2, 1, 3 and 6 months revealing an 80, 60 and 40% improvement in rhytides and dermis density, respectively. We present the protocol and description of a reasonable alternative or adjunct to manufactured fillers that is comprised of autologous adipose, stem cells, and growth factor slurry. The slurry is easily produced and injected at the bedside in the office setting, and has remarkable and reproducible positive outcomes in skin tone, color, texture, and rhytides as judged by both patient and physician. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28643007 TI - The Role of Lipofilling After Breast Reconstruction: Evaluation of Outcomes and Patient Satisfaction with BREAST-Q. AB - INTRODUCTION: The aim of this study was to measure patient satisfaction using the BREAST-Q reconstruction module in patients selected for lipofilling procedures after implant breast reconstructions. MATERIALS AND METHODS: Seventy patients who underwent breast reconstruction with or without delayed lipofilling were enrolled between 2011 and 2015, and they completed BREAST-Q surveys. We administered the questionnaire electronically 6 months and 1 year after surgery. We divided patients into two groups. In group A, we included patients (46) who underwent secondary lipofilling almost 1 year after implant-based breast reconstruction; in group B (24), patients who underwent implant-based breast reconstruction without any lipofilling procedure. Statistical analysis was performed using descriptive and summary statistics to identify a central tendency between the two groups. RESULTS: All patients answered the postoperative BREAST-Q reconstruction module. The mean age of the patients was 41 years. Eleven of the 70 patients underwent a bilateral mastectomy. The mean follow-up was 2.5 years. The average amount of fat graft injected was 110 cc. In group A, there were two patients who had a complication: 1 infection and 1 intraoperative implant rupture. The average number of lipofilling procedures was 2.2. After further analysis of the questionnaire, we observed that patients in group A obtained significantly better postoperative results than patients from group B (control) regarding the following items: the ability to wear more fitted clothing; the reconstructed breast softness; symmetry (breasts of equal size relative to the other); reconstructed breast look and touch; amount of implant rippling perceived by the patients; and psychosocial well-being and physical well-being: chest and upper body. CONCLUSIONS: Our results are encouraging regarding the use of autologous fat grafting to improve cosmetic outcomes and to reduce postoperative pain after breast reconstruction. This is the first study that applied BREAST-Q to breast lipofilling to demonstrate better outcomes achieved by patients who underwent secondary lipostructures. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28643009 TI - Patient Satisfaction and Its Influencing Factors of Microtia Reconstruction Using Autologous Cartilage. AB - BACKGROUND: This study aimed to investigate patient perceptions of and satisfaction with surgical outcomes of microtia reconstruction using autologous cartilage. It also analyzes associations between patient background characteristics and their evaluation. METHODS: Lobule-type microtia patients who had received first-stage surgery were interviewed using a questionnaire, which included assessment of nine auricle substructures, superior and inferior parts and overall impression. Answers were recorded on a five-point Likert-style scale. Satisfaction rate and average scores were used to compare satisfaction with different substructures. Chi-square tests and logistic regression were used to analyze the impact of background characteristics such as gender, age, side and body mass index (BMI) on satisfaction, measured as the total scores for different parts. RESULTS: The highest level of satisfaction was seen for the helix and the lowest for the tragus. The average score for the helix was significantly higher than for the concha (p < 0.05), tragus (p < 0.05), anti-tragus (p < 0.05), incisura (p < 0.05) and lobe (p < 0.05). The overall satisfaction was significantly correlated with work on the inferior part (rho = 0.63, p < 0.05). Satisfaction from children under 12 years old was significantly higher than from children above 12 years old for superior structures and overall evaluation (p < 0.05). Left-sided microtia patients showed significantly higher satisfaction for inferior structures and overall evaluation than right-sided patients (p < 0.05). Overweight and obese patients were less satisfied with the tragus-incisura-anti tragus complex compared with the rest (p < 0.05). CONCLUSION: Microtia patients were most satisfied with the helix and least satisfied with the tragus. Overall patient satisfaction was more dependent on inferior structures; the characteristics of younger age (<12 years), proper BMI (under overweight or obese) and left-sided microtia were linked with higher ratings. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28643010 TI - Discussion: Nonsurgical Facial Rejuvenation-Outcomes and Safety of Neuromodulator and Soft-Tissue Filler Procedures Performed in a Resident Cosmetic Clinic. PMID- 28643012 TI - Clinical Outcomes in pT4 Tongue Carcinoma are Worse Than in pT3 Disease: How Extrinsic Muscle Invasion Should be Considered? PMID- 28643013 TI - Preoperative Measurement of the Modified Glasgow Prognostic Score Predicts Patient Survival in Non-Metastatic Renal Cell Carcinoma Prior to Nephrectomy. AB - PURPOSE: The modified Glasgow Prognostic Score (mGPS) by measurement of serum C reactive protein and albumin levels has been shown to provide prognostic value in various cancer types. The purpose of this study was to evaluate whether preoperative assessment of the mGPS predicts patient survival outcome in renal cell carcinoma (RCC). MATERIALS AND METHODS: Clinicopathological and follow-up data in 219 RCC patients, all of whom underwent curative or non-curative nephrectomy, were collected. Overall survival (OS) and cancer-specific survival (CSS) after nephrectomy were evaluated, and univariate and multivariate analyses were conducted to assess the predictive value of the variables, including the mGPS. RESULTS: During the median follow-up of 57 months, 53 patients (24.2%) were deceased within 22 months of the median OS. The 5-year OS rate from nephrectomy was 85.9 and 18.8% in non-metastatic (n = 195) and metastatic (n = 24) patients, respectively. Increasing mGPS was associated with shorter OS in non-metastatic patients (2-year OS rate of 98.2% in mGPS0, 73.3% in mGPS1, and 44.4% in mGPS2; hazard ratio [HR] 9.96, 95% confidence interval [CI] 4.88-20.13, p < 0.001), whereas no significant difference in OS according to the mGPS was seen in metastatic patients (HR 2.01, 95% CI 0.79-5.16, p = 0.137). On multivariate analysis, the mGPS remained as an independent predictor for OS (HR 5.24, 95% CI 1.39-19.77, p = 0.015) and CSS (HR 4.69, 95% CI 1.13-20.96, p = 0.034) in non metastatic RCC patients. CONCLUSIONS: The mGPS appeared to be a reliable, preoperatively defined predictive marker with widely standardized protocol in non metastatic RCC, and should therefore be considered in treatment decision making for RCC patients. PMID- 28643011 TI - Prevalence and risk factors for cardiac arrest and myocardial infarction after pelvic reconstructive surgery: a national, multi-institutional, surgical database study. AB - INTRODUCTION AND HYPOTHESIS: There is limited data available regarding the risk for perioperative cardiac morbidity following pelvic reconstructive surgery (PRS). We sought to determine the incidence of cardiac arrest and myocardial infarction within 30 days of pelvic organ prolapse (POP) surgery and determine which factors may contribute to an increased risk of these complications. METHODS: Using the American College of Surgeons National Quality Improvement Program (NSQIP) database, we identified patients who underwent PRS procedures between 2010 to 2015 using Current Procedural Terminology (CPT) codes. Patient demographics and clinical and surgical factors were obtained. Patients who experienced myocardial infarction or cardiac arrest (MICA) were compared with patients without these complications. Differences between groups were calculated using the chi-square and Student's t test. Stepwise backward multivariate logistic regression was used to identify factors associated with acute cardiac morbidity. RESULTS: A total of 46, 367 women were identified. The incidence of MICA was 0.11% and of death was 0.01% for the entire cohorot. Age >70 years [adjusted odds ratio (aOR) = 2.99, 95% confidence interval (CI) 1.56-5.73], length of stay >1 day (aOR = 3.34, 95% CI 1.70-6.40), dependent functional status (aOR = 5.99 95% CI 1.95-16.32), hypertension (aOR = 2.86, 95% CI 1.36-6.04), American Society of Anesthesiologists (ASA) class 3 (aOR = 2.01, 95% CI 1.10 3.64), and inpatient status (aOR = 4.35, 95% CI 1.78-10.49). CONCLUSION: The rate of MICA is low following PRS. Additional studies are necessary to determine whether more extensive preoperative cardiac evaluation is warranted in this patient population. PMID- 28643014 TI - Neuron navigator-2 and cyclin D2 are new candidate prognostic markers in uterine sarcoma. AB - The objective of this study was to validate the diagnostic and clinical role of four protein products of genes previously found to be differentially expressed in uterine low-grade endometrial stromal sarcoma (LG-ESS) compared to uterine leiomyosarcoma (LMS). Protein expression by immunohistochemistry of transgelin (TGLN), neuron navigator-2 (NAV2), fatty acid binding protein-3 (FABP3), and cyclin D2 (CCND2) was analyzed in 305 uterine sarcomas (231 LMS, 74 LG-ESS). Expression was analyzed for association with clinicopathologic parameters and survival. TGLN (p < 0.001), NAV2 (p < 0.001), and FABP3 (p = 0.005) were overexpressed in LMS compared to LG-ESS, whereas nuclear CCND2 (p < 0.001) was overexpressed in LG-ESS. NAV2 expression was associated with shorter overall survival in patients with LMS (p = 0.037), whereas nuclear CCND2 expression in LG ESS was significantly related to longer survival (p = 0.012) in univariate analysis. Nuclear CCND2 expression was an independent prognosticator in Cox multivariate analysis (p = 0.023). In conclusion, TGLN, FABP3, NAV2, and nuclear CCND2 aid in differentiating LG-ESS from LMS. NAV2 and CCND2 are novel candidate prognostic markers in LMS and LG-ESS, respectively. PMID- 28643015 TI - The role of screening MRI in the era of next generation sequencing and moderate risk genetic mutations. AB - With the advent of next-generation sequencing, the ability to rapidly analyze numerous genes simultaneously has led to the creation of large cancer gene panels. Some of these genes, like BRCA1 and BRCA2, have been heavily researched and have well-established management guidelines. Other more newly established genes, like ATM, CHEK2, and PALB2, have previously had less robust research surrounding them which has limited the ability to create accurate risk estimates. With their inclusion on gene panels, there has been more pressure to produce management guidelines for patients discovered to carry pathogenic variants in these genes. For known high-risk genes, it is recommended for breast magnetic resonance imaging (MRI) and mammogram to be offered annually. This combination has been proven to be more effective at detecting breast cancer than mammography alone, with a combined sensitivity of 94% (Leach et al. in Lancet 365(9473):1769 1778, 2005). Women with a lifetime risk of breast cancer of 20% and higher have been recommended to have both breast MRI and mammography performed (Saslow et al. in CA Cancer J Clin 57(2):75-89, 2007). For women with pathogenic variants detected in moderate risk genes with lifetime breast cancer risks of at least 20%, breast MRI should be offered as part of their management. For more newly discovered genes with suspected associated risks at or above 20%, the use of breast MRI should be considered for their management as well. PMID- 28643016 TI - Screening for Lynch syndrome in young Saudi colorectal cancer patients using microsatellite instability testing and next generation sequencing. AB - Individuals with Lynch syndrome (LS) have germline variants in DNA mismatch repair (MMR) genes that confer a greatly increased risk of colorectal cancer (CRC), often at a young age. Identification of these individuals has been shown to increase their survival through improved surveillance. We previously identified 33 high risk cases for LS in the Saudi population by screening for microsatellite instability (MSI) in the tumor DNA of 284 young CRC patients. The aim of the present study was to identify MMR gene variants in this cohort of patients. Peripheral blood DNA was obtained from 13 individuals who were at high risk of LS due to positive MSI status and young age (<60 years at diagnosis). Next generation sequencing, Sanger sequencing and Multiplex Ligation-dependent Probe Amplification were used to screen for germline variants in the MLH1, MSH2, MSH6 and PMS2 MMR genes. These were cross-referenced against several variant databases, including the International Society for Gastrointestinal Hereditary Tumors Incorporated database. Variants with pathogenic or likely pathogenic significance were identified in 8 of the 13 high risk cases (62%), comprising 4 in MLH1 and 4 in MSH2. All carriers had a positive family history for CRC or endometrial cancer. Next generation sequencing is an effective strategy for identifying young CRC patients who are at high risk of LS because of positive MSI status. We estimate that 7% of CRC patients aged <60 years in Saudi Arabia are due to LS, potentially involving around 50 new cases per year. PMID- 28643017 TI - Safety and efficacy of daratumumab in Japanese patients with relapsed or refractory multiple myeloma: a multicenter, phase 1, dose-escalation study. AB - Safety, efficacy, and pharmacokinetics (PK) of daratumumab as a monotherapy were investigated in Japanese patients with relapsed/refractory multiple myeloma (MM). This multicenter, dose-escalation study included patients (age >=20 years) with >=2 prior therapies. Daratumumab was administered intravenously: 8 mg/kg (n = 4) and 16 mg/kg (n = 5). The primary endpoint was safety. Secondary endpoints included objective response, overall response rate (ORR), progression-free survival (PFS), PK, and immunogenicity. Daratumumab was well-tolerated. Eight patients experienced Grade >=3 adverse event (AE). Four serious AEs were observed in three patients; no AEs leading to death. Infusion-related reactions occurred in four (44%) patients and were Grade 1 or 2. Mean (SD) cumulative dose of daratumumab was 132.3 (108.5) mg/kg. Median duration of follow-up was 10.5 months (range 2.3, 16.4) for 8 mg/kg cohort and 9.9 months (range 1.7, 13.2) for 16 mg/kg cohort. The ORR (44%) comprised 1 and 3 partial responses in 8 and 16 mg/kg cohorts, respectively. The median PFS was 6 months for 8 mg/kg cohort, 9.5 months for 16 mg/kg cohort. Daratumumab serum exposure was increased with increasing dose. Antibodies against daratumumab were not observed. Daratumumab was safe and well-tolerated in Japanese patients with relapsed /refractory MM. PMID- 28643019 TI - Antibody-based therapies for the treatment of brain metastases from HER2-positive breast cancer: time to rethink the importance of the BBB? PMID- 28643018 TI - Heterogeneity of GATA2-related myeloid neoplasms. AB - The GATA2 gene codes for a master hematopoietic transcription factor that is essential for the proliferation and maintenance of hematopoietic stem and progenitor cells. Heterozygous germline mutations in GATA2 have been initially associated with several clinical entities that are now collectively defined as GATA2 deficiency. Despite pleiotropic clinical manifestations, the high propensity for the development of myelodysplastic syndromes (MDS) constitutes the most common clinical denominator of this major MDS predisposition syndrome. The immunological phenotypes can be variable and mostly include deficiency of monocytes and/or B cells. Thus far, nearly 380 GATA2-deficient patients had been reported, with a roughly estimated prevalence of myeloid neoplasia of at least 75%. The most common abnormal karyotypes associated with GATA2-related MDS are monosomy 7, der(1;7) and trisomy 8. The overall clinical penetrance seems to be nearly complete for this transcriptopathy disorder. The high-risk MDS subtypes and karyotypes, and the underlying immunodeficiency guide decision-making toward timely stem cell transplantation. PMID- 28643020 TI - Association between lifestyle, menstrual/reproductive history, and histological factors and risk of breast cancer in women biopsied for benign breast disease. AB - PURPOSE: Women with benign breast disease (BBD) have an increased risk of subsequent breast cancer. However, whether conventional breast cancer risk factors influence risk of breast cancer among women with BBD is unclear. In this study, we investigated the associations of lifestyle, menstrual/reproductive, and histological factors with risk of breast cancer among women biopsied for BBD. METHODS: We conducted a case-control study, nested within a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest between 1971 and 2006. Cases were women who developed a subsequent invasive breast cancer during follow up; controls were individually matched to cases on age at BBD diagnosis. A total of 526 case-control pairs were included in the study. We calculated crude and multivariable OR and 95% CI for the associations between lifestyle, menstrual/reproductive, and histological factors and breast cancer risk using conditional logistic regression. RESULTS: Compared to premenopausal women, postmenopausal women had reduced risk of subsequent breast cancer (OR 0.60; 95% CI 0.39-0.94), whereas women who ever used hormone replacement therapy (HRT) had increased risk (OR 3.61; 95% CI 1.68-7.75), as did women whose BBD lesion showed atypical hyperplasia (OR 5.56; 95% CI 2.05-15.06). Smoking, BMI, early menarche, multiparity (>=4), history of oophorectomy, and extent of lobular involution were not associated with risk of breast cancer. CONCLUSION: This study suggests that use of HRT and having atypical hyperplasia are associated with increased risk of breast cancer among women with BBD, while postmenopausal women with BBD have a reduced risk. PMID- 28643021 TI - The effect of 14-3-3zeta expression on tamoxifen resistance and breast cancer recurrence: a Danish population-based study. AB - PURPOSE: Overexpression of 14-3-3zeta has been linked to breast cancer recurrence in several studies, including studies assessing its effect on tamoxifen resistance. The study was performed to estimate the effect of 14-3-3zeta and differentiate potential prognostic or predictive utility. METHODS: A case-control study, nested in a population of 11,251 females residing on the Jutland Peninsula of Denmark, was performed. Participants were aged 35-69, diagnosed with stage I, II, or III breast cancer between 1985 and 2001, and registered with the Danish Breast Cancer Cooperative Group. We identified 541 recurrent breast cancer cases with estrogen receptor-positive disease treated with tamoxifen for at least 1 year (ER+/TAM+) and 300 cases with estrogen receptor-negative disease never treated with tamoxifen (ER-/TAM-). We matched cases to controls on ER/TAM status, date of surgery, menopausal status, stage, and county. 14-3-3zeta expression was assessed using immunohistochemistry on tissue microarrays. We computed the odds ratio (OR) associating 14-3-3zeta expression with breast cancer recurrence adjusting for confounding using logistic regression. A quantitative bias analysis was performed to account for bias due to expression assay methods. RESULTS: Associations for cytoplasmic and nuclear 14-3-3zeta staining above the 50th percentile were near null in both ER+/TAM+ and ER-/TAM- patients. When examining combined 14-3-3zeta staining, the association increased in the ER+/TAM+ group (adjusted OR 1.44, 95% confidence interval (CI) 1.05, 1.99). A nearly twofold increase in odds of recurrence was observed in above the 75th percentile staining of combined 14-3-3zeta, both for ER+/TAM+ patients (adjusted OR 1.93, 95% CI 1.15, 3.24) and ER-/TAM- patients (adjusted OR 1.93, 95% CI 1.03, 3.62), indicating potential prognostic utility. CONCLUSION: Evidence is lacking to conclude that 14-3-3zeta is a useful marker of tamoxifen resistance; however, 14 3-3zeta expression is a potentially useful prognostic marker of breast cancer recurrence. Independent utility beyond established prognostic markers needs to be determined. PMID- 28643022 TI - Androgen receptor expression and breast cancer mortality in a population-based prospective cohort. AB - PURPOSE: The increase in clinical trials with androgen receptor (AR)-targeting drugs emphasizes the need of clarifying the role of AR expression in different breast cancer subtypes. AR confers good prognosis in estrogen receptor positive (ER+) breast cancer, but its role in ER-negative (ER-) breast cancer is unclear. The aim of this study was to elaborate on previous findings of a differential prognostic role for AR depending on ER status, using breast cancer mortality (BCM) as endpoint, in a population-based cohort from the Malmo Diet and Cancer Study. METHODS: Immunohistochemical AR expression was assessed in 910 women with invasive breast cancer diagnosed 1991-2010, supplemented with clinicopathological information, vital status, and cause of death, with the last follow-up in December 2014 (median 10 years). Survival analyses according to AR status and AR/ER combinations were performed. RESULTS: AR expression was available for 671 tumors. AR+ (n = 573, 85%) was associated with favorable established tumor markers and lower BCM in univariable analysis, especially during the first 5 years following diagnosis [HR 0.4; 95% confidence intervals (CI) 0.2-0.7]. Multivariable analysis for short-term follow-up indicated higher BCM among patients with AR+ER- tumors (HR 3.5; 95% CI 1.4-9.1) than other AR and ER combinations. CONCLUSIONS: AR expression added prognostic information to ER expression with respect to short-term prognosis. The worst prognosis was seen for patients with AR+/ER- tumors in short-term follow-up, supporting the pre specified hypothesis. However, larger cohorts are needed for further characterization of the role of AR expression in ER- breast cancer. PMID- 28643024 TI - Automatic seed picking for brachytherapy postimplant validation with 3D CT images. AB - PURPOSE: Postimplant validation is an indispensable part in the brachytherapy technique. It provides the necessary feedback to ensure the quality of operation. The ability to pick implanted seed relates directly to the accuracy of validation. To address it, an automatic approach is proposed for picking implanted brachytherapy seeds in 3D CT images. METHODS: In order to pick seed configuration (location and orientation) efficiently, the approach starts with the segmentation of seed from CT images using a thresholding filter which based on gray-level histogram. Through the process of filtering and denoising, the touching seed and single seed are classified. The true novelty of this approach is found in the application of the canny edge detection and improved concave points matching algorithm to separate touching seeds. Through the computation of image moments, the seed configuration can be determined efficiently. Finally, two different experiments are designed to verify the performance of the proposed approach: (1) physical phantom with 60 model seeds, and (2) patient data with 16 cases. RESULTS: Through assessment of validated results by a medical physicist, the proposed method exhibited promising results. Experiment on phantom demonstrates that the error of seed location and orientation is within ([Formula: see text]) mm and ([Formula: see text])[Formula: see text], respectively. In addition, the most seed location and orientation error is controlled within 0.8 mm and 3.5[Formula: see text] in all cases, respectively. The average process time of seed picking is 8.7 s per 100 seeds. CONCLUSIONS: In this paper, an automatic, efficient and robust approach, performed on CT images, is proposed to determine the implanted seed location as well as orientation in a 3D workspace. Through the experiments with phantom and patient data, this approach also successfully exhibits good performance. PMID- 28643023 TI - Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients. AB - PURPOSE: The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. METHODS: Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. RESULTS: Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). CONCLUSIONS: Steady-state plasma AI concentrations do not explain variability in E2 suppression in post menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients. PMID- 28643025 TI - Effects of bariatric surgery on pelvic floor disorders in obese women: a meta analysis. AB - PURPOSE: Obesity is an established risk factor for pelvic floor disorders (PFD) but the effects of bariatric surgery on PFD are uncertain. This meta-analysis was conducted to evaluate the effects of bariatric surgery on PFD in obese women. METHODS: A systematic search of PubMed, Cochrane Library, CNKI and CBM databases up to October 2016 was performed, and studies reporting pre-operative and post operative outcomes in obese women undergoing bariatric surgery were included. The Pelvic Floor Distress Inventory (PFDI-20), the Pelvic Floor Incontinence Questionnaire (PFIQ-7), the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire, Female Sexual Function Index and the International Consultation on Incontinence Questionnaire-Urinary Incontinence short form score were used for evaluating pelvic floor dysfunction after bariatric surgery. RESULTS: Eleven cohort studies were finally included. Pooled results revealed that bariatric surgery was associated with a significant improvement in PFD for obese women on the whole [PFDI-20: SMD = 0.89, 95% CI (0.44, 1.34), P < 0.001; PFIQ-7: SMD = 1.23, 95% CI (0.17, 2.29), P = 0.023]. In the subscale analysis, there was significant improvement in urinary incontinence and pelvic organ prolapse. However, no significant improvement was found in fecal incontinence and sexual function. CONCLUSIONS: Bariatric surgery is associated with significant improvement in urinary incontinence, and has a benefit on pelvic organ prolapse for obese women. However, there is no significant improvement in fecal incontinence and sexual function. Further multi-center, large-scale and longer term randomized controlled trials are needed to confirm these results. PMID- 28643026 TI - Predictive model of urinary tract infection after surgical treatment for women with endometrial cancer. AB - PURPOSE: The aim of the study was to identify risk factors associated with postoperative urinary tract infections (UTIs) following hysterectomy-based surgical staging in women with endometrial cancer. METHODS: This is a retrospective study utilizing an institutional database (2008-2016) of stage I-IV endometrial cancer cases that underwent hysterectomy-based surgery. UTIs occurring within a 30-day time period after surgery were examined and correlated to patient clinico-pathological demographics. RESULTS: UTIs were observed in 44 (6.4%, 95% confidence interval 4.6-8.2) out of 687 cases subsequent to the diagnosis of endometrial cancer. UTI cases were significantly associated with obesity, advanced stage, prolonged operative time, hysterectomy type, pelvic lymphadenectomy, non-beta-lactam antibiotics, and intraoperative urinary tract injury (all, p < 0.05). On multivariate analysis, three independent risk factors were identified for UTIs: prolonged operative time [odds ratio (OR) 3.36, 95% CI 1.65-6.87, p = 0.001], modified-radical/radical hysterectomy (OR 5.35, 95% CI 1.56-18.4, p = 0.008), and an absence of perioperative beta-lactam antibiotics use (OR 3.50, 95% CI 1.46-8.38, p = 0.005). In a predictive model of UTI, the presence of multiple risk factors was associated with significantly increased risk of UTI: 4.1% for the group with no risk factors, 7.3-12.5% (OR 1.85-3.37) for single risk factor group, and 30.0-30.8% (OR 10.1-10.5) for two risk factor group. CONCLUSION: Urinary tract infections are common in women following surgical treatment for women with endometrial cancer with risk factors being a prolonged surgical time, radical hysterectomy, and non-guideline perioperative anti-microbial agent use. Consideration of prophylactic anti-microbial agent use in a high-risk group of postoperative urinary tract infection merits further investigation. PMID- 28643027 TI - Melanoma arising in an ovarian cystic teratoma: a systematic review of presentation, treatment, and outcomes. AB - PURPOSE: To assess the clinical presentation, treatment modalities, and outcome of primary melanomas arising in ovarian cystic teratomas (OCT). METHODS: A systematic review on PubMed/MEDLINE was performed on June 5, 2017, to gather data on patients with primary melanomas arising in OCTs. No systematic reviews were identified. Consequently, only case reports and case series of individuals were analyzed. A total of 37 articles met our inclusion criteria, totaling 41 unique patients. RESULTS: The average age of diagnosis was 51.5 years. In total, 24% of patients were found to have metastatic disease. In total, 56.7% of patients eventually died of their disease, with an average time from diagnosis to death of 9.3 months. Disease recurrence was common, occurring in 65% of patients. The mainstay of treatment was surgical in 100% of the cases. Adjuvant chemotherapy, immunotherapy, and radiation were also used with varying degrees of efficacy. CONCLUSIONS: Malignant melanoma arising in OCT is a rare disease with poor prognosis. The current mainstay treatment is surgical. Potential benefits of targeted therapy, immunotherapy, and chemotherapy remain to be determined. A limitation of this study is that these melanomas have only been published in case reports. PMID- 28643028 TI - Polycystic ovary syndrome, adipose tissue and metabolic syndrome. AB - PURPOSE: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age and is characterized by ovulatory dysfunction and/or androgen excess or polycystic ovaries. Women with PCOS present a number of systemic symptoms in addition to those related to the reproductive system. It has been associated with functional derangements in adipose tissue, metabolic syndrome, type 2 diabetes, and an increased risk of cardiovascular disease (CVD). METHODS: A detailed literature search on Pubmed was done for articles about PCOS, adipokines, insulin resistance, and metabolic syndrome. Original articles, reviews, and meta-analysis were included. RESULTS: PCOS women are prone to visceral fat hypertrophy in the presence of androgen excess and the presence of these conditions is related to insulin resistance and worsens the PCO phenotype. Disturbed secretion of many adipocyte-derived substances (adipokines) is associated with chronic low-grade inflammation and contributes to insulin resistance. Abdominal obesity and insulin resistance stimulate ovarian and adrenal androgen production, and may further increase abdominal obesity and inflammation, thus creating a vicious cycle. CONCLUSION: The high prevalence of metabolic disorders mainly related to insulin resistance and CVD risk factors in women with PCOS highlight the need for early lifestyle changes for reducing metabolic risks in these patients. PMID- 28643029 TI - Impact of preventable risk factors on stroke in the EPICOR study: does gender matter? AB - OBJECTIVES: The effect of modifiable stroke risk factors in terms of prevented cases remains unclear due to sex-specific disease rate and risk factors prevalence. Our aim was to estimate their impact on stroke by gender through population-attributable fraction (PAF), preventive fraction (PF) and their combination in EPIC-Italian cohort. METHODS: 43,976 participants, age 34-75, and free of cardiovascular disease at baseline (1993-1998) were followed up for almost 11 years. Adjusted hazard ratios and PAF were estimated using Cox models. RESULTS: We identified 386 cases. In males, the burden for stroke was 17% (95% CI 4-28%) for smoking and 14% (95% CI 5-22%) for alcohol consumption. In females, hypertension was carrying the biggest burden with 18% (95% CI 9-26%) followed by smoking 15% (95% CI 7-22%). Their combination was 46% (95% CI 32-58%) in males and 48% (95% CI 35-59%) in females. PF for current smokers was gender unequal [males 21% (95% CI 15-27%) females 9% (95% CI 1-17%)]. CONCLUSIONS: Half of strokes are attributable to potentially modifiable factors. The proportion of prevented cases is gender unbalanced, encouraging sex-specific intervention. PMID- 28643030 TI - Hospital electronic prescribing system implementation impact on discharge information communication and prescribing errors: a before and after study. AB - PURPOSE: The study aimed to test the hypothesis that hospital electronic prescribing and medicine administration system (HEPMA) implementation impacted patient discharge letter quality, nature and frequency of prescribing errors. METHOD: A quasi experimental before and after retrospective case note review was conducted in one United Kingdom district general hospital. The total sample size was 318 (random samples of 159 before and after implementation), calculated to achieve a 10% error reduction with a power of 80% and p < 0.05. Adult patients discharged after >=24-h inpatient stay were assessed for discharge information documentation quality using a modified validated discharge document template. Prescribing errors were classified as medicine omissions, commissions, incorrect dose/frequency/duration, drug interactions, therapeutic duplications or missing/inaccurate allergy information. Post-implementation assessments were undertaken 4 months following HEPMA implementation. Error severity was determined by a multidisciplinary panel consensus using the Medications at Transitions and Clinical Handoffs (MATCH) study validated scoring system. RESULTS: There were no statistically significant differences in patient demographics between the pre- and post-implementation groups. Discharge information documentation quality improved; allergy documentation increased from 11 to 159/159 (p < 0.0001). The number of patients with prescribing errors reduced significantly from 158 to 37/159 (p < 0.001). Prescribing error category incidence identified in pre implementation patients was reduced (e.g. omission incidence from 66 to 18/159 (p < 0.001)), although a new error type (sociotechnical [errors caused by the system]) was identified post-implementation (n = 8 patients). Post-implementation prescribing errors severity rating identified 8/37 as likely to cause potential patient harm. CONCLUSION: HEPMA implementation was associated with improved discharge documentation quality, statistically significant prescribing error reduction and prescribing error type alteration. There remains a need to be alert for potential prescribing errors. PMID- 28643031 TI - Pediatric Emergency Care Applied Research Network (PECARN) prediction rules in identifying high risk children with mild traumatic brain injury. AB - PURPOSE: Pediatric Emergency Care Applied Research Network (PECARN) traumatic brain injury (TBI) prognostic rules is a scoring system for prediction of the need for computed tomography (CT) scanning in children with mild TBI. However, its validation has not been assessed in developing countries. Therefore, the present study was designed to assess the value of PECARN rule in identification of children with clinically important TBI (ciTBI). METHOD: In this prospective cross-sectional study, 594 children (mean age: 7.9 +/- 5.3 years; 79.3% boys) with mild TBI brought to emergency ward of two healthcare centers in Tehran, Iran were assessed. PECARN checklist was filled for all patients and children were divided to three groups of low, intermediate and high risks. Patients were followed for 2 weeks by phone to assess their ciTBI status. At the end, discrimination power, calibration and overall performance of PECARN rule were assessed. RESULTS: PECARN had a sensitivity and specificity of 92.3 and 40.6%, respectively, in predicting ciTBI in children under 2 years and 100.0 and 57.8%, respectively, in individuals between the ages of 2 and 18. PECARN rule had a proper calibration in prediction of ciTBI and CT scan findings. Brier score (overall performance) of PECARN rule in predicting ciTBI in children under 2 and 2-18 years were 1.5 and 1.2, respectively. CONCLUSION: PECARN prediction rule has a proper validity in the prediction of ciTBI. Therefor it can be used for screening and identification of high risk children with mild TBI. PMID- 28643032 TI - Fall from heights: does height really matter? AB - INTRODUCTION: Fall from heights is high energy injuries and constitutes a fraction of all fall-related trauma evaluations while bearing an increase in morbidity and mortality. We hypothesize that despite advancements in trauma care, the overall survivability has not improved in this subset of trauma patients. METHODS: All adult trauma patients treated after sustaining a fall from heights during a 40-month period were retrospectively reviewed. Admission demographics, clinical data, fall height (ft), injury patterns, ISS, GCS, length of stay, and mortality were reviewed. RESULTS: 116 patients sustained a fall from heights, 90.4% accidental. A mean age of 37+/- 14.7 years, 86% male, and a fall height of 19 +/- 10 ft were encountered. Admission GCS was 13 +/- 2 with ISS 10 +/- 11. Overall LOS was 6.6 +/- 14.9 days and an ICU LOS of 2.8 +/- 8.9 days. Falls >= 25 ft.(16%) had lower GCS 10.4 +/- 5.8, increased ISS 22.6 +/- 13.8, a fall height 37.9 +/- 13.1 ft and associated increased mortality (p < 0.001). Mortality was 5.2%, a mean distance fallen of 39 +/- 22 ft. and an ISS of 31.5 +/-16.5. Brain injury was the leading cause of death, 50% with open skull fractures. CONCLUSION: Level of height fallen is a good predictor of overall outcome and survival. Despite advances in trauma care, death rates remain unchanged. Safety awareness and injury prevention programs are needed to reduce the risk of high-level falls. PMID- 28643033 TI - The Role of Sensory Perception, Emotionality and Lifeworld in Auditory Word Processing: Evidence from Congenital Blindness and Synesthesia. AB - Although it has been established that human beings process concrete and abstract words differently, it is still a matter of debate what factors contribute to this difference. Since concrete concepts are closely tied to sensory perception, perceptual experience seems to play an important role in their processing. The present study investigated the processing of nouns during an auditory lexical decision task. Participants came from three populations differing in their visual perceptual experience: congenitally blind persons, word-color synesthetes, and sighted non-synesthetes. Specifically, three features with potential relevance to concreteness were manipulated: sensory perception, emotionality, and Husserlian lifeworld, a concept related to the inner versus the outer world of the self. In addition to a classical concreteness effect, our results revealed a significant effect of lifeworld: words that are closely linked to the internal states of humans were processed faster than words referring to the outside world. When lifeworld was introduced as predictor, there was no effect of emotionality. Concerning participants' perceptual experience, an interaction between participant group and item characteristics was found: the effects of both concreteness and lifeworld were more pronounced for blind compared to sighted participants. We will discuss the results in the context of embodied semantics, and we will propose an approach to concreteness based on the individual's bodily experience and the relatedness of a given concept to the self. PMID- 28643034 TI - Assessing internet-based information used to aid patient decision-making about surgery for perianal Crohn's fistula. AB - BACKGROUND: Decision-making in perianal Crohn's fistula (pCD) is preference sensitive. Patients use the internet to access healthcare information. The aim of this study was to assess the online information and patient decision aids relating to surgery for pCD. METHODS: A search of GoogleTM and the Decision Aids Library Inventory (DALI) was performed using a predefined search strategy. Patient-focussed sources providing information about pCD surgery were included in the analysis. Written health information was assessed using the International Patient Decision Aids Standards (IPDAS) and DISCERN criteria. The readability of the source content was assessed using the Flesch-Kincaid score. RESULTS: Of the 201 sources found, 187 were excluded, leaving 14 sources for analysis. Three sources were dedicated to pCD, and six sources mentioned pCD-specific outcomes. The most common surgical intervention reported was seton insertion (n = 13). The least common surgical intervention reported was proctectomy (n = 1). The mean IPDAS and DISCERN scores were 4.43 +/- 1.65 out of 12 (range = 2-8) and 2.93 +/- 0.73 out of 5 (range = 1-5), respectively. The mean reading ease was US college standard. CONCLUSIONS: We found no patient decision aids relating to surgery for pCD. The online sources relating to surgery for pCD are few, and their quality is poor, as seen in the low IPDAS and DISCERN scores. Less than half of the sources mentioned pCD-specific outcomes, and three sources were solely dedicated to providing information on pCD. Healthcare professionals should look to create a patient tool to assist decision-making in pCD. PMID- 28643035 TI - Clinical and Imaging Presentation of a Patient with Beta-Propeller Protein Associated Neurodegeneration, a Rare and Sporadic form of Neurodegeneration with Brain Iron Accumulation (NBIA). AB - Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of inherited neurologic disorders with iron accumulation in the basal ganglia, which share magnetic resonance (MR) imaging characteristics, histopathologic and clinical features. According to the affected basal nuclei, clinical features include extrapyramidal movement disorders and varying degrees of intellectual disability status. The most common NBIA subtype is caused by pathogenic variants in PANK2. The hallmark of MR imaging in patients with PANK2 mutations is an eye of-the-tiger sign in the globus pallidus. We report a 33-year-old female with a rare subtype of NBIA, called beta-propeller protein-associated neurodegeneration (BPAN) with a hitherto unknown missense variant in WDR45. She presented with BPAN's particular biphasic course of neurological symptoms and with a dominant iron accumulation in the midbrain that enclosed a spotty T2-hyperintensity. PMID- 28643036 TI - Nasoethmoid-nasoorbital encephalocele presenting with orbital pulsation. PMID- 28643037 TI - Pediatric spondylolysis/spinal stenosis and disc herniation: national trends in decompression and discectomy surgery evaluated through the Kids' Inpatient Database. AB - PURPOSE: The purpose of this study is to describe national trends in spinal decompression without fusion and discectomy procedures in the US pediatric inpatient population. METHODS: The Kids' Inpatient Database (KID) was queried for pediatric patients with primary diagnoses of spinal spondylolysis/stenosis or disc herniation and having undergone spinal decompression without fusion or discectomy over more than a decade (2000 to 2012). The primary (indirect) outcomes of interest were in-hospital complication rates, length of stay (LOS), total costs, and discharge dispositions. RESULTS: A total of 7315 patients, comprised of pediatric spinal spondylolysis/stenosis (n = 287, 3.92%) and pediatric disc herniation (n = 7028, 96.1%) patients, were included in the study. During the years 2000 to 2012, diagnoses of pediatric spondylolysis/spinal stenosis increased from 61 to 90 diagnoses per 3-year period, while diagnoses of pediatric disc herniation decreased from 2133 to 1335 diagnoses per 3-year period. Spinal decompression was associated with higher in-hospital complication rates (18.1 vs 5.3%, p < 0.0001), longer hospital stays (5 vs 1.69 days, p < 0.0001), higher mean total charges ($49,186 vs $19,057, p < 0.0001), and higher non-routine discharge rates (12.3 vs 2.5%, p < 0.0001) versus discectomy. CONCLUSIONS: Spinal decompression is associated with longer hospital stays, more complications, higher costs, and more non-routine discharges when compared to discectomy. The data supports the disparate nature of these disease processes and elucidates basic clinical trends in uncommon spinal disorders affecting children. PMID- 28643038 TI - Prevalence of cerebral cavernous malformations associated with developmental venous anomalies increases with age. AB - BACKGROUND AND PURPOSE: To test the hypothesis that the prevalence of cerebral cavernous malformation (CCM) associated with developmental venous anomalies (DVAs) increases with age, we studied the age-related prevalence of DVA associated CCM among patients with DVAs. MATERIALS AND METHODS: Patients with DVAs on contrast-enhanced MRI exams performed over a 2-year period were included in this study. A single neuroradiologist reviewed all imaging exams for the presence of CCMs. Baseline demographic data collected included age, gender, presence of CNS neoplasm, history of cranial radiation, and history of seizure. Patients were divided into age groups based on decade of life. Cochran-Armitage trend tests were performed to determine if increasing age was associated with CCM prevalence. RESULTS: A total of 1689 patients with DVAs identified on contrast enhanced MRI were included. Of these patients, 116 (6.9%) had a cavernous malformation associated with the DVA. There was a significant positive association between age and the prevalence of DVA-associated CCM (P = 0.002). The prevalence of DVA-associated CCM was 0.8% for the 0-10 age group, 1.6% for the 11 20 age group, 7.5% for the 21-30 age group, 9.5% for the 31-40 age group, 6.1% for the 41-50 age group, 6.3% for the 51-60 age group, 7.4% for the 61-70 age group, and 11.6% for the >70 age group (P < .0001). CONCLUSIONS: Our study demonstrated an age-related increase in prevalence of DVA-associated cavernous malformations among patients with DVAs. These findings suggest that DVA associated cavernous malformations are acquired lesions. PMID- 28643039 TI - Primary intraventricular meningiomas in children-experience of two cases with review of literature. AB - Meningiomas are rare in the pediatric age group, more so in the intraventricular location. They arise in the lateral ventricles from the arachnoid cells contained within the choroid plexus, in the third ventricle from the velum interpositum and in the fourth ventricle from the choroids. These tumors are usually large and have an aggressive behaviour. Surgical management of intra-ventricular meningiomas is challenging because of their deep location, large size at presentation and increased vascularity. The authors report two such cases who presented with symptoms of raised intra cranial pressure and on evaluation were found to have associated hydrocephalus. Both these patients underwent surgical excision of the tumour by frontal transcortical approach and histopathology report confirmed transitional meningioma in them. Only twenty seven cases of intraventricular meningiomas in children have been reported till date. Their definitive treatment is surgery alone and total excision of the tumor is curative. Possibility of neurofibromatosis as a differential should also be considered in their management. PMID- 28643041 TI - Skull fracture with effacement of the superior sagittal sinus following drone impact: a case report. AB - BACKGROUND: The popularity of unmanned aerial vehicles, or drones, raises safety concerns as they become increasingly common for commercial, personal, and recreational use. Collisions between drones and people may result in serious injuries. CASE REPORT: A 13-year-old male presented with a comminuted depressed skull fracture causing effacement of the superior sagittal sinus secondary to a racing drone impact. The patient experienced a brief loss of consciousness and reported lower extremity numbness and weakness after the accident. Imaging studies revealed bone fragments crossing the superior sagittal sinus with a short, focal segment of blood flow interruption. Neurosurgical intervention was deferred given the patient's improving neurological deficits, and the patient was treated conservatively. He was discharged home in stable condition. CONCLUSION: Drones may represent a hazard when operated inappropriately due to their capacity to fly at high speeds and altitudes. Impacts from drones can carry enough force to cause skull fractures and significant head injuries. The rising popularity of drones likely translates to an increased incidence of drone-related injuries. Thus, clinicians should be aware of this growing trend. PMID- 28643040 TI - Management of an unusual, recurrent neurenteric cyst in an infant: case report and review of the literature. AB - PURPOSE: Neurenteric cysts are rare congenital remnants formed by a failure of separation between endoderm and ectoderm in utero. METHODS: We describe a case of a 7-month-old male with a large cervical neurenteric cyst presenting with intermittent neck stiffness and irritability. RESULTS: This cyst was resected, recurred, and required repeat surgery. The patient's postoperative course included aseptic meningitis and hydrocephalus requiring ventriculoperitoneal shunt and later management of tethered cord, necessitating detethering. CONCLUSION: Unique features of this case include the presence of intermittent pain symptoms, which may be attributable to cyst filling and emptying. Hydrocephalus is an uncommon finding that may be secondary to aseptic meningitis from cyst rupture. Tethered cord is also an unusual entity that can accompany this diagnosis, warranting additional imaging work-up and monitoring. PMID- 28643042 TI - OCT in Alzheimer's disease: thinning of the RNFL and superior hemiretina. AB - BACKGROUND: Peripapillary retinal nerve fiber layer (pRNFL) and internal macular layer thinning have been demonstrated in Alzheimer's disease (AD) with optical coherence tomography (OCT) studies. The purpose of this study is to compare the pRNFL thickness and overall retinal thickness (RT) in AD patients with non-AD patients, using spectral domain optical coherence tomography (SD-OCT) and determine the sectors most characteristically affected in AD. METHODS: A cross sectional study was performed to determine the pRNFL and overall macular RT thicknesses in AD and non-AD patients, attending a tertiary hospital center. For pRNFL, the global and six peripapillary quadrants were calculated, and for overall RT values, the nine Early Treatment Diabetic Retinopathy Study (ETDRS) areas were used. A multiple regression analysis was applied to assess the effects of disease, age, gender, spherical equivalent, visual acuity, intraocular pressure, axial length and blood pressure on pRNFL and overall macular RT. RESULTS: A total of 202 subjects, including 50 eyes of 50 patients with mild AD (mean age 73.10; SD = 5.36 years) and 152 eyes of 152 patients without AD (mean age 71.03; SD = 4.62 years). After Bonferroni correction, the pRNFL was significantly thinner for the AD group globally and in the temporal superior quadrant (10.76 MUm and 20.09 MUm mean decrease, respectively). The RT thickness was also decreased in superior sectors S3 and S6 (mean thinning of 9.92 MUm and 11.65 MUm, respectively). Spearman's correlation coefficient showed a direct association between pRNFL in the temporal superior quadrant and RT in superior S6 and S3 sectors (rS = 0.41; p < 0.001 and rS = 0.28; p < 0.001, respectively). CONCLUSIONS: Patients with AD showed a significant thickness reduction in global and temporal superior quadrants in pRNFL and in superior pericentral and peripheral sectors of RT. These findings may reflect a peripapillary and retinal changes characteristic of AD, suggesting the importance of SD-OCT as a potential adjuvant in early diagnosis of AD. Further studies are needed to understand which retinal layers and macular sectors are more useful as potential ocular biomarker over time in AD. PMID- 28643043 TI - 18F-Florbetaben PET beta-amyloid binding expressed in Centiloids. AB - PURPOSE: The Centiloid (CL) method enables quantitative values from Abeta-amyloid (Abeta) imaging to be expressed in a universal unit providing pathological, diagnostic and prognostic thresholds in clinical practice and research and allowing integration of multiple tracers and methods. The method was developed for 11C-PiB scans with zero CL set as the average in young normal subjects and 100 CL the average in subjects with mild Alzheimer's disease (AD). The method allows derivation of equations to convert the uptake value of any tracer into the same standard CL units but first requires head-to-head comparison with 11C-PiB results. We derived the equation to express 18F-florbetaben (FBB) binding in CL units. METHODS: Paired PiB and FBB PET scans were obtained in 35 subjects. including ten young normal subjects aged under 45 years (33 +/- 8 years). FBB images were acquired from 90 to 110 min after injection. Spatially normalized images were analysed using the standard CL method (SPM8 coregistration of PET data to MRI data and the MNI-152 atlas) and standard CL regions (cortex and whole cerebellum downloaded from http://www.gaain.org ). RESULTS: FBB binding was strongly correlated with PiB binding (R 2 = 0.96, SUVRFBB = 0.61 * SUVRPiB + 0.39). The equation to derive CL values from FBB SUVR was CL units = 153.4 * SUVRFBB - 154.9. The CL value in the young normal subjects was -1.08 +/- 6.81 for FBB scans compared to -0.32 +/- 3.48 for PiB scans, giving a variance ratio of 1.96 (SDFBB CL/SDPiB CL). CONCLUSIONS: 18F-FBB binding is strongly correlated with PiB binding and FBB results can now be expressed in CL units. PMID- 28643044 TI - PD-1 signaling and inhibition in AML and MDS. AB - Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies. PMID- 28643046 TI - Clinical evaluation of the efficacy and safety of combined bipolar radiofrequency and optical energies vs. optical energy alone for the treatment of aging hands. AB - Different treatment modalities are used for the treatment and esthetic improvement of aging hands. This study evaluated the efficacy and safety of a novel technology, which combines bipolar radio frequency (RF) and optical energies for the cosmetic treatment of aging hands. The objective of the study was to assess the efficacy, safety, tolerability, and patient satisfaction of combined bipolar radiofrequency and optical energies vs. optical energy alone for the treatment of aging hands. Thirteen female patients with solar lentigines on the back of the hands were enrolled. Participants received three treatments: combined RF and intense pulsed light (IPL) on one hand and IPL treatment alone on the other. Standardized clinical photographs were taken, and patient and investigator improvement assessment (Global Esthetic Improvement (GAI) scale), patient satisfaction, and tolerability were evaluated. At the 1 and 3 months follow-up, skin laxity and pigmentation, investigator and patient improvement assessments, and satisfaction were significantly better in the hand treated with combined bipolar RF and IPL. This study demonstrates the safety and efficacy of combining RF and optical energies for the esthetic improvement of aging hands. Combined RF and IPL treatment was more efficient than IPL alone in improving skin pigmentation, skin laxity, and texture. PMID- 28643045 TI - Validation of a mathematical model for laser-induced thermotherapy in liver tissue. AB - The purpose of the study was to develop a simulation approach for laser-induced thermotherapy (LITT) that is based on mathematical models for radiation transport, heat transport, and tissue damage. The LITT ablation was applied to ex vivo pig liver tissue. Experiments were repeated with different laser powers, i.e., 22-34 W, and flow rates of the cooling water in the applicator system, i.e., 47-92 ml/min. During the procedure, the temperature was measured in the liver sample at different distances to the applicator as well as in the cooling circuit using a fiber optic thermometer. For validation, the simulation results were compared with the results of the laser ablation experiments in the ex vivo pig liver samples. The simulated and measured temperature curves presented a relatively good agreement. The Bland-Altman plot showed an average of temperature differences of -0.13 ?C and 95%-limits-of-agreement of +/-7.11 ?C. The standard deviation amounted to +/-3.63 ?C. The accuracy of the developed simulation is comparable with the accuracy of the MR thermometry reported in other clinical studies. The simulation showed a significant potential for the application in treatment planning. PMID- 28643047 TI - Trace Elements in Pleural Effusion Correlates with Smokers with Lung Cancer. AB - Smoking leads to the presence of various elements, including toxic metals and metalloids, in tissues and fluids, thus contributing to cancer risk. This study assessed the concentrations of 14 elements (Ag, Al, As, Co, Cr, Cu, Fe, Ni, Mn, Mo, Pb, Sn, V, and Zn) and biochemical parameters (glucose, lactate dehydrogenase, and total protein) in the pleural effusion (PE) of patients with lung cancer. The potential association of these parameters with smoking was assessed. Total of 48 patients with lung cancer (26 non-smokers and 22 smokers) received thoracocentesis for PE removal. Analysis results revealed that among the biochemical parameters, only the glucose concentration was significantly higher in current smokers than in non-smokers; the other parameters showed no significant difference. The concentration of Zn in the PE was significantly lower in all smokers (10 former and 12 current smokers) than in non-smokers, but the other elements did not differ significantly between the two groups and smoker subgroups. Simultaneously, Zn correlated negatively with glucose concentrations in all smokers, positively with lactate dehydrogenase (LDH) concentration in current smoker, and positively with total protein (TP) concentrations in non smokers. This is for the first time the relation between Zn and certain biochemical parameters in PE was found, the observation requiring further studies to explain the potential interactions between this element and glucose, LDH, and TP concentrations. PMID- 28643048 TI - Association of gastrointestinal events with quality of life and treatment satisfaction in osteoporosis patients: results from the Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC OS). AB - : The purpose of this study was to assess the association of GI events with HRQoL and treatment satisfaction. The effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D, OPAQ-SV, and treatment satisfaction scores among patients with vs without baseline GI events. The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis. INTRODUCTION: The goal of this study was to assess the association of gastrointestinal (GI) events with health-related quality of life (HRQoL) and treatment satisfaction in patients being treated for osteoporosis. METHODS: MUSIC OS was a multinational, prospective, observational study examining the impact of GI events on osteoporosis management in postmenopausal women. In this analysis, HRQoL and treatment satisfaction were assessed at baseline, 6, and 12 months and compared between patients with and without GI events. Covariate-adjusted scores were calculated using multivariate least-squares regression analysis, and differences between the mean scores of patients with and without baseline and post-baseline GI events were determined. RESULTS: Among the 2959 patients in the analysis, unadjusted scores at each time point were lower (i.e., worse) for patients with GI events than patients without GI events. In adjusted analyses, the effect of baseline GI events persisted through 1 year of follow-up, as indicated by lower EQ-5D and OPAQ-SV scores at 12 months among patients with vs without baseline GI events (-0.04 for the EQ-5D utility score, -5.07 for the EQ-5D visual analog scale, -3.35 for OPAQ physical function, -4.60 for OPAQ emotional status, and 8.50 for OPAQ back pain; P <= 0.001 for all values). Decrements in month 12 treatment satisfaction scores were -6.46 for patients with baseline GI events and -7.88 for patients with post-baseline GI events. CONCLUSIONS: The presence of GI events is an independent predictor of decreased HRQoL and treatment satisfaction in patients being treated for osteoporosis. PMID- 28643050 TI - Application of transoral continuous intraoperative neuromonitoring in natural orifice transluminal endoscopic surgery for thyroid disease: a preliminary study. AB - BACKGROUND: The novel concept of continuous intraoperative neuromonitoring (Cont IONM) through stimulation of the vagal nerve has been used in thyroidectomies to prevent imminent injury of the recurrent laryngeal nerve (RLN). This article reports on this technology and the results of using transoral Cont-IONM in natural orifice transluminal endoscopic surgery for thyroid disease. METHODS: Cont-IONM of the RLN was achieved through automatic cyclical stimulation of the vagal nerve using a C2 monitor and delta stimulating electrode. During the operation, three vestibular incisions were made, and the stimulating electrode was transorally inserted, with its cable line lying outside the trocar. The vagal nerve was gently dissected, looped, and then enveloped by the electrode cuff. Electromyography (EMG) of the vocalis muscle was performed, and the alarm was set to activate when the EMG amplitude reduced by 50% and latency was prolonged by 10%. Demographic data and outcome variables, including incremental time required to achieve Cont-IONM, were obtained. RESULTS: A total of 20 patients (28 nerves at risk) undergoing a transoral endoscopic thyroidectomy vestibular approach were enrolled in this study. All Cont-IONM procedures were successfully completed. In all patients, the stimulation was set at 0.7 milliamps every 1 s, and Cont-IONM use was unassociated with any untoward neural, cardiovascular, or gastrointestinal sequelae. On average, the ipsilateral Cont-IONM procedure required 10.33 +/- 2.57 min to complete. Except for one instance, no significant problems occurred with electrode displacement. In one patient, a combined EMG event occurred, which improved after releasing the thyroid retractor, and the patient had no vocal cord paralysis postoperatively. CONCLUSION: Cont-IONM is feasible and safe to use during transoral endoscopic thyroidectomies and may assist in the early detection of adverse EMG changes, thereby preventing paralysis of the RLNs. PMID- 28643049 TI - Clozapine in Reducing Aggression and Violence in Forensic Populations. AB - Popular media often portray people with a mental illness as being aggressive, violent, and incarcerated as a result of their behavior. Despite exaggeration in the media, risks for some aggressive behaviors are in fact higher in individuals with schizophrenia. This is often the case with influence of comorbid substance use disorders. It is essential that mental health professionals are aware of treatments that may help with attenuating and treating behaviors that contribute to violence, aggression and incarceration. This paper reviews violence and incarceration in individuals with schizophrenia as well as recommendations, guidelines and benefits for the use of clozapine in this population. Clozapine remains one of the most underutilized evidence-based medications available in the psychiatric arena in the United States. It is a viable and recommended option in the forensic population and it may be helpful on the path to recovery as well as bring substantial savings to the criminal justice system. PMID- 28643052 TI - The spaced learning concept significantly improves training for laparoscopic suturing: a pilot randomized controlled study. AB - BACKGROUND: Spaced learning has been shown to be effective in various areas like traditional knowledge or motor skill acquisition. To evaluate the impact of implementation of the spaced learning concept in laparoscopic training was the aim of this study. METHODS: To evaluate the effectiveness of spaced learning, subjects were asked to perform four surgeon's square knots on a bowel model prior and post 3 h of hands-on training. All subjects were medical students and novice in laparoscopic suturing. Total time, knot stability (evaluated via tensiometer), suture accuracy, knot quality (Muresan score), and laparoscopic performance (Munz checklist) were assessed. Moreover, motivation was accessed using Questionnaire on Current Motivation. RESULTS: Twenty students were included in the study; after simple randomization, ten were trained using "spaced learning" concept and ten conservatively. Both groups had comparable baseline characteristics and improved after training significantly regarding all aspects assessed in this study. Subjects that trained via spaced learning were superior in terms of suture performance, knot quality, and suture strength. Ultimately, spaced learning significantly decreased anxiety and impression of challenge compared to controls. CONCLUSION: The spaced learning concept is very suitable for complex motor skill acquisition like laparoscopic suturing and knot tying. It significantly improves laparoscopic performance and knot quality as shown by the knot score and suture strength. Thus, we recommend to incorporate spaced learning into training courses and surgical programs. PMID- 28643051 TI - Long-term outcomes by a transanal approach to total mesorectal excision for rectal cancer. AB - BACKGROUND: The challenge of performing a good total mesorectal excision (TME) dissection, particularly in the distal 1/3 of the rectum, has spurred interest in new techniques. Robotic surgery is advocated by some, and more recently, a "new" approach, the transanal total mesorectal excision, has been popularized to address this problem. While great interest in this technique exists, little long term outcome data are available. We have been utilizing a transanal abdominal transanal approach to TME in order to facilitate the distal dissection, and here, we provide our long-term outcomes using this approach in the management of rectal cancer. METHODS: From a prospectively maintained rectal cancer database, we identified 373 consecutive rectal cancers treated with sphincter preservation surgery through a combined transanal and abdominal approach to TME. Perioperative, pathological, and oncologic outcomes were analyzed. RESULTS: Three hundred and seventy-three patients with rectal cancer underwent a transanally initiated TME with mean follow-up of 5.5 years. 91% of cancers were in the distal rectum. 68.9% were men and 53.2% of cancers were tethered or fixed on presentation. 97.7% received neoadjuvant radiotherapy (mean 5405 cGy, 5 fluorouracil based); average time from completion of neoadjuvant therapy to surgery was 11 weeks. 180 and 193 patients underwent completion of their operation through open and laparoscopic abdominal approaches. 96% of TME specimens were complete/near complete, 94% had a negative circumferential resection margin, and 98.6% had a negative distal margin. Perioperative morbidity and mortality rates were 13.4 and 0.3%. Overall local recurrence (LR), DM, and Kaplan-Meier 5-year actuarial survival were 7.4, 19.5, and 90%, respectively. CONCLUSION: This is the first report of long-term data using a transanal approach to TME supporting this approach for rectal cancer. Our data with 5-year follow-up show that adequate distal and circumferential margins with very good-quality TME specimens, and a low risk for LR with excellent overall survival can be achieved using this technique. Our long-term results support the promising reports of early experiences in the literature. PMID- 28643053 TI - Incidence, natural course, and characteristics of postlaparoscopic shoulder pain. AB - BACKGROUND: To determine the incidence, natural course, and specific characteristics of postlaparoscopic shoulder pain (PLSP). METHODS: The prospective study included 105 patients undergoing laparoscopy for benign gynecologic diseases. The intensity of pain, and the identification of the pain site, was assessed 24- and 48-h after surgery, using a visual analogue scale. The description and intensity of PLSP, its aggravating and relieving factors, and the response to analgesics were assessed over a 1-week period using a self-reported questionnaire. RESULTS: Of 105 patients, 84 (80%) experienced PLSP. PLSP along with wound pain peaked one day after surgery, gradually subsided, and were not reported by the seventh day after surgery. Of the 84 patients experiencing PLSP, 77 (91.7%) had aggravating and relieving factors, which included position change (48.8%) and rest (42.9%), respectively. Analgesics provided significantly less pain relief for PLSP (32.7 +/- 32.2%), when compared to relief of wound pain (68.0 +/- 16.2%) (P < 0.001). CONCLUSION: PLSP, identified in 80% of our patients, resolved in most patients within the first week after laparoscopy. Since PLSP is less responsive to analgesics, when compared to wound pain, surgeons should pay attention to the prevention of PLSP among patients undergoing laparoscopy. PMID- 28643054 TI - A structured, extended training program to facilitate adoption of new techniques for practicing surgeons. AB - INTRODUCTION: Laparoscopic inguinal hernia repair has been shown to have significant benefits when compared to open inguinal hernia repair, yet remains underutilized in the United States. The traditional model of short, hands-on, cognitive courses to enhance the adoption of new techniques fails to lead to significant levels of practice implementation for most surgeons. We hypothesized that a comprehensive program would facilitate the adoption of laparoscopic inguinal hernia repair (TEP) for practicing surgeons. METHODS: A team of experts in simulation, coaching, and hernia care created a comprehensive training program to facilitate the adoption of TEP. Three surgeons who routinely performed open inguinal hernia repair with greater than 50 cases annually were recruited to participate in the program. Coaches were selected based on their procedural expertise and underwent formal training in surgical coaching. Participants were required to evaluate all aspects of the educational program and were surveyed out to one year following completion of the program to assess for sustained adoption of TEP. RESULTS: All three participants successfully completed the first three steps of the seven-step program. Two participants completed the full course, while the third dropped out of the program due to time constraints and low case volume. Participant surgeons rated Orientation (4.7/5), GlovesOn training (5/5), and Preceptored Cases (5/5) as highly important training activities that contributed to advancing their knowledge and technical performance of the TEP procedure. At one year, both participants were performing TEPs for "most of their cases" and were confident in their ability to perform the procedure. The total cost of the program including all travel, personal coaching, and simulation was $8638.60 per participant. DISCUSSION: Our comprehensive educational program led to full and sustained adoption of TEP for those who completed the course. Time constraints, travel costs, and case volume are major considerations for successful completion; however, the program is feasible, acceptable, and affordable. PMID- 28643055 TI - Open versus laparoscopic rectal cancer resection and risk of subsequent incisional hernia repair and paracolostomy hernia repair: a nationwide population based cohort study. AB - OBJECTIVE: To investigate the risk of incisional hernia repair (IHR) and paracolostomy hernia repair (PHR) following open and laparoscopic rectal cancer resection with curative intent. BACKGROUND: Laparoscopic rectal cancer resection has been implemented to varying degrees around the world. IHR and PHR following open and laparoscopic rectal cancer resection have only been sparingly evaluated. METHODS: Patients who underwent rectal cancer resection were identified in the Danish Colorectal Cancer Group's database. To identify IHR and PHR following rectal cancer resection, we linked data to the Danish Ventral Hernia Database. The absolute risk of IHR and PHR was estimated as cumulative incidence proportions, treating death as competing risk. We used Cox proportional hazard regression analysis with multivariable adjustment to compute hazard ratios (HRs) comparing open and laparoscopic approach. RESULTS: The 5-year risk of IHR was 4.1% among patients undergoing open resection (n = 3090) and 3.2% among those undergoing laparoscopic resection (n = 3099), corresponding to a risk difference of 0.9% (95% CI 0.0-2.0, P = 0.057). Laparoscopic rectal resection was not associated with lower risk of IHR (adjusted HR 0.94, 95% CI 0.67-1.31, P = 0.709). A total of 2577 patients had a colostomy at rectal cancer resection and the 5-year risk of PHR was 2.1% after open surgery compared with 6.7% after laparoscopic surgery, corresponding to a risk difference of -4.6% (95% CI -6.4 to -2.7, P < 0.001). Laparoscopic surgery was associated with increased risk of PHR (adjusted HR 2.56, 95% CI 1.53-4.29, P < 0.001). CONCLUSION: We observed no association between surgical approach of rectal cancer resection and subsequent IHR. Laparoscopic surgery was associated with increased risk of PHR. PMID- 28643056 TI - Deep neuromuscular blockade improves surgical conditions during low-pressure pneumoperitoneum laparoscopic donor nephrectomy. AB - BACKGROUND: Evidence indicates that low-pressure pneumoperitoneum (PNP) reduces postoperative pain and analgesic consumption. A lower insufflation pressure may hamper visibility and working space. The aim of the study is to investigate whether deep neuromuscular blockade (NMB) improves surgical conditions during low pressure PNP. METHODS: This study was a blinded randomized controlled multicenter trial. 34 kidney donors scheduled for laparoscopic donor nephrectomy randomly received low-pressure PNP (6 mmHg) with either deep (PTC 1-5) or moderate NMB (TOF 0-1). In case of insufficient surgical conditions, the insufflation pressure was increased stepwise. Surgical conditions were rated by the Leiden-Surgical Rating Scale (L-SRS) ranging from 1 (extremely poor) to 5 (optimal). RESULTS: Mean surgical conditions were significantly better for patients allocated to a deep NMB (SRS 4.5 versus 4.0; p < 0.01). The final insufflation pressure was 7.7 mmHg in patients with deep NMB as compared to 9.1 mmHg with moderate NMB (p = 0.19). The cumulative opiate consumption during the first 48 h was significantly lower in patients receiving deep NMB, while postoperative pain scores were similar. In four patients allocated to a moderate NMB, a significant intraoperative complication occurred, and in two of these patients a conversion to an open procedure was required. CONCLUSIONS: Our data show that deep NMB facilitates the use of low-pressure PNP during laparoscopic donor nephrectomy by improving the quality of the surgical field. The relatively high incidence of intraoperative complications indicates that the use of low pressure with moderate NMB may compromise safety during LDN. Clinicaltrials.gov identifier: NCT 02602964. PMID- 28643057 TI - Single-incision laparoscopic common bile duct exploration in 101 consecutive patients: choledochotomy, transcystic, and transfistulous approaches. AB - BACKGROUND: Laparoscopic surgery for choledocholithiasis is still evolving. Only a few reports of single-incision laparoscopic common bile duct exploration (LCBDE) have been published. METHODS: One hundred and one consecutive patients underwent single-incision LCBDE (SILCBDE) by one surgeon with straight instruments during a 42-month period. RESULTS: Choledochotomies were performed on 61 patients (60.4%). The success rate of intrahepatic duct exploration was 68.0% (17/25) for patients undergoing transcystic choledochoscopic bile duct explorations following longitudinal cystic ductotomies. The ductal clearance rate was 100%. Eighteen procedures (17.8%) were converted, including one open surgery. Nineteen patients (18.8%) experienced 26 episodes of complications; the majority (19 episodes) were classified as Clavien-Dindo grade I. Excluding those patients with Mirizzi syndrome (McSherry type II), multivariate logistic regressions showed that patients who were older or had complicated cholecystitis had higher procedure conversion rates and that higher modified APACHE II scores, higher white blood cell counts, and longer operative times were independent risk factors for complications. Based on operative times, 20 successful SILCBDEs were needed to get through the learning phase. A higher transcystic approach rate (46.5 vs. 8.3%; P < 0.01) and a shorter operative time (207 +/- 62 vs. 259 +/- 66 min; P < 0.01) were observed in the experienced phase. Compared with our early series of multi-incision LCBDE, the SILCBDE group had a higher bile duct stone clearance rate (100 vs. 94.4%; P < 0.05) and a higher proportion of patients with concomitant acute cholecystitis (59.6 vs. 22.2%; P < 0.01). CONCLUSIONS: LCBDE with a 100% ductal clearance rate is possible following an algorithm for various approaches. SILCBDE is feasible under a low threshold for procedure conversion. A transcystic approach should be tried first if indicated, and a longitudinal cystic ductotomy to the cystocholedochal junction is beneficial. Prospective, randomized trials comparing single-incision and multi-incision LCBDE are anticipated. PMID- 28643058 TI - Prospective, randomized comparison of the use of FloShield Air System(r) versus the reference technique (water + povidone-iodine solution) during gynecologic endoscopic surgery to evaluate the operative lens vision quality. AB - BACKGROUND: The FloShield Air System(r) is a new device for laparoscopic surgery that utilizes a continuous dry CO2 gas flow over the scope to defog the lens and protect it from condensation, debris and smoke. We set out to compare the performance and efficiency of the device in terms of operative lens vision quality (OLVQ) with the reference technique (water + povidone-iodine (PVI) solution) during gynecologic laparoscopic surgery. MATERIALS AND METHODS: We conducted a single-center randomized prospective study between March and June 2016 (Trials Database Registration NCT02702531) including 53 patients undergoing gynecologic laparoscopic surgery with water + PVI solution and 51 patients who underwent surgical procedures with the FloShield Air System. The primary outcome measure was the number of laparoscope removals during surgery. Secondary outcome measures were the time to clean, assessment of the quality of vision, the correlation between the laparoscopic surgical complexity and outcomes, and cost effectiveness. RESULTS: Overall, the mean patient age was 43.2 years (range 22 86) and body mass index 24.8 (range 16.8-42.7). The mean number of endoscope removals during surgery was 7.0 (range 0-37) in the water + PVI solution arm and 2.8 (range 0-12) in the FloShield Air System(r) arm. The number of removals was significantly lower in the FloShield arm (p < 0.001). No difference in time to clean, quality of vision, level of laparoscopic procedure complexity, or cost was observed between the groups. CONSLUSIONS: The FloShield Air System(r) resulted in fewer laparoscopic lens removals than the water + PVI solution solution, but that there was no difference in quality of vision, cleaning time or cost, especially for the more complex surgery. PMID- 28643059 TI - The learning effect of using stereoscopic vision in the early phase of laparoscopic surgical training for novices. AB - BACKGROUND: Recently to improve depth perception, the performance of three dimensional (3D) laparoscopic surgeries has increased. However, the effects of laparoscopic training using 3D are still unclear. This study aimed to clarify the effects of using a 3D monitor among novices in the early phase of training. METHODS: Participants were 40 novices who had never performed laparoscopic surgery (20 medical students and 20 junior residents). Three laparoscopic phantom tasks (task 1: touching markers on a flat disk with a rod; task 2: straight rod transfer through a single loop; and task 3: curved rod transfer through two loops) in the training box were performed ten times, respectively. Performances were recorded by an optical position tracker. The participants were randomly divided into two groups: one group performed each task five times initially under a 2D system (2D start group), and the other group performed each task five times under a 3D system (3D start group). Both groups then performed the same task five times. After the trial, we evaluated the performance scores (operative time, path length of forceps, and technical errors) and the learning curves for both groups. RESULTS: Scores for all tasks performed under the 3D system were significantly better than scores for tasks using the 2D system. Scores for each task in the 2D start group improved after switching to the 3D system. However, scores for each task in the 3D start group were worse after switching to the 2D system, especially scores related to technical errors. CONCLUSIONS: The stereoscopic vision improved laparoscopic surgical techniques of novices from the early phase of training. However, the performance of novices trained only by 3D worsened by changing to the 2D environment. PMID- 28643060 TI - SAGES Technology and Value Assessment Committee safety and effectiveness analysis on immunofluorescence in the operating room for biliary visualization and perfusion assessment. PMID- 28643061 TI - Reoperation for recurrent hepatolithiasis: laparotomy versus laparoscopy. AB - BACKGROUND: Laparoscopy has been proposed for the management of recurrent hepatolithiasis, but no comparative study of its relative efficacy versus laparotomy has been performed, and the patient selection criteria for laparoscopy are not clear. This study aimed to investigate the therapeutic effect of laparoscopy versus laparotomy for repeated hepatolithiasis and to highlight how to select patients best suited for laparoscopy. METHODS: We performed a cohort study of 94 patients who underwent laparotomy or laparoscopy for recurrent hepatolithiasis between January 2010 and May 2014. The clinical data of 53 patients who underwent open biliary exploration (laparotomy group) and 41 patients who underwent laparoscopic biliary exploration (laparoscopy group) for recurrent hepatolithiasis were retrospectively analyzed and compared. RESULTS: Intestinal adhesions to the porta hepatis occurred in 62 (66%) patients. There was no difference in operating time between the two groups. In comparing the laparoscopic group versus the laparotomy group, the intraoperative blood loss was less (P = .001), the incidence of postoperative ascites (9.8 vs. 30.2%, P = .016) and/or pleural effusion (7.3 vs. 28.3%, P = .010) was lower, and the stone clearance rates were comparable. Wound morbidity appeared peculiarly in 15 (28.3%) patients among the laparotomy group. The postoperative hospital stay in the laparoscopy group was shorter than that in the laparotomy group (P = .000). CONCLUSION: Laparoscopy is a safe and effective treatment for recurrent hepatolithiasis patients who are scheduled for bile duct exploration. PMID- 28643062 TI - Loss of Medicaid insurance after successful bariatric surgery: an unintended outcome. AB - BACKGROUND: Bariatric surgery leads to dramatic weight loss and improved overall health, which may affect insurance status for certain patients. Traditional Medicaid provides coverage for children, pregnant women, and disabled adults, while expanded Medicaid provides insurance coverage to all adults with incomes up to 138% of the federal poverty level. We hypothesized that successful bariatric surgery would lead to improved health status but an unintended loss of Medicaid coverage. METHODS: All patients who underwent bariatric surgery at a single institution in a non-expansion state from 1985 through 2015 were identified using a prospectively collected database. Univariate and multivariate analyses were used to identify differences in patients who lost Medicaid coverage after bariatric surgery. RESULTS: Over the 30-year study period, 3487 patients underwent bariatric surgery, with 373 (10.7%) having Medicaid coverage at the time of surgery. This cohort of patients had a median age of 37 years and a preoperative Body Mass Index (BMI) of 54 kg/m2. At one-year follow-up, 155 (41.6%) patients lost Medicaid coverage, of which 76 (49.0%) had no coverage. The preoperative prevalence of diabetes (32.3 vs. 44.0%, p = 0.02), age (36 vs. 38 years, p = 0.01), and BMI (53 vs. 55 kg/m2, p = 0.04) were significantly lower in patients who no longer qualified for Medicaid after bariatric surgery. Multivariate regression demonstrated that for every 10 point increase in BMI (OR 0.755, p = 0.01), a patient was 25% less likely to lose their coverage at one year. CONCLUSIONS: Successful surgery in a state not expanding Medicaid resulted in over 40% of patients losing Medicaid coverage postoperatively, with half of those patients returning for follow-up with no insurance coverage at all. This barrier to care has major implications in patients undergoing bariatric surgery, which requires life-long follow-up and nutrition screening. PMID- 28643063 TI - Intraoperative identification and analysis of lymph nodes at laparoscopic colorectal cancer surgery using fluorescence imaging combined with rapid OSNA pathological assessment. AB - BACKGROUND: Standard surgical practice for colorectal cancer involves resection of the primary lesion and all draining lymph nodes. Accurate intraoperative assessment of nodal status could allow stratified resectional extent. One-step nucleic acid (OSNA) can provide a rapid method of interrogating nodal tissue, whilst near-infrared (NIR) laparoscopy together with indocyanine green (ICG) can identify relevant nodal tissue intraoperatively. METHODS: ICG was administered around the tumour endoscopically prior to the operation. Fluorescent nodes identified by NIR were marked and submitted for whole-node OSNA analysis. Further fresh lymph nodes dissected from the standard resection specimen were examined and analysed by both conventional histology and OSNA. In addition, the status of the fluorescent nodes was compared to that of non-ICG nodes to assess their predictive value. RESULTS: Sixteen patients were recruited with a total final lymph node count of 287. 78 fresh lymph nodes were identified on fresh dissection for both histological and OSNA assessment with an analytical concordance rate of 98.7% (77/78). OSNA sensitivity was 1 (0.81-1, 95% CI) and specificity 0.98 (0.91 1, 95% CI). Six patients had a total of nine nodes identified intraoperatively by ICG fluorescence. Of these nine nodes, one was positive for metastasis on OSNA. OSNA analysis of the ICG-labelled node matched the final histological nodal stage in 3/6 patients (two being N0 and one N1). The final pathological nodal stage of the other three was N1 or N2, while the ICG nodes were negative. CONCLUSION: OSNA is highly concordant with standard histology, although only a minority of nodes identifiable by full pathological analysis were found for OSNA on fresh dissection. OSNA can be combined with NIR and ICG lymphatic mapping to provide intraoperative assessment of nodal tissue in patients with colorectal cancer. PMID- 28643064 TI - Study of self-expandable metallic stent placement intraluminal 125I seed strands brachytherapy of malignant biliary obstruction. AB - OBJECTIVE: To evaluate the safety and efficacy of self-expandable metallic stent placement combined with or without intraluminal 125I seed strands brachytherapy in patients with malignant biliary obstruction. METHODS: Participants were randomly assigned to receive treatment with a self-expandable metallic stent (SEMS) placement combined with intraluminal 125I seed strands brachytherapy (brachytherapy group) or a SEMS without brachytherapy (control group). The outcomes were measured in terms of technical success, clinical success, stent patency, complications related to the procedure, and patient survival. A P value of less than 0.05 indicated a significant difference. Results There were no significant differences in technical and clinical success between brachytherapy and control group (100 vs. 100%-100 vs. 93.3%). During the median 273.4 +/- 154.6 days follow-up time, the median stent patency time in the brachytherapy group was longer than those in the control group (368.0 +/- 42.4 vs. 220.0 +/- 34.8 days), and the duration of survival in the brachytherapy groups was higher than those in the control group (355.0 +/- 71.5 vs. 209.0 +/- 17.2 days). There were no significant differences in the complications between the two groups. Conclusions SEMS placement combined with intraluminal 125I seed strands brachytherapy are feasible and effective for malignant biliary obstruction, and seems to prolong the stent patency and survival time. PMID- 28643065 TI - Laparoscopic distal pancreatectomy for pancreatic cancer is safe and effective. AB - PURPOSE: To compare the short-term and oncologic outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) undergoing laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP). METHODS: Consecutive cases of distal pancreatectomy (DP) (n = 422) were reviewed at a single high volume institution over a 10-year period (2005-2014). Inclusion criteria consisted of any patient with PDAC by surgical pathology. Ninety-day outcomes were monitored through a prospectively maintained pancreatic resection database. The Social Security Death Index was used for 5-year survival. Two-way statistical analyses were used to compare categories; variance was reported with standard error of the mean; * indicates P value <0.05. RESULTS: Seventy-nine patients underwent DP for PDAC. Thirty-three underwent LDP and 46 ODP. There were no statistical differences in demographics, BMI, and ASA classification. Intraoperative and surgical pathology variables were comparable for LDP versus ODP: operative time (3.9 +/- 0.2 vs. 4.2 +/- 0.2 h), duct size, gland texture, stump closure, tumor size (3.3 +/- 0.3 vs. 4.0 +/- 0.4 cm), lymph node harvest (14.5 +/- 1.1 vs. 17.5 +/- 1.2), tumor stage (see table), and negative surgical margins (77 vs. 87%). Patients who underwent LDP experienced lower blood loss (310 +/- 68 vs. 597 +/- 95 ml; P = 0.016*) and required fewer transfusions (0 vs. 13; P = 0.0008*). Patients who underwent LDP had fewer positive lymph nodes (0.8 +/- 0.2 vs. 1.6 +/- 0.3; P = 0.04*) and a lower incidence of type C pancreatic fistula (0 vs. 13%; P = 0.03*). Median follow-up for all patients was 11.4 months. Long-term oncologic outcomes revealed similar outcomes including distant or local recurrence (30 vs. 52%; P = 0.05) and median survival (18 vs. 15 months), as well as 1-year (73 vs. 59%), 3-year (22 vs. 21%), and 5-year (20 vs. 15%) survival for LDP and ODP, respectively. CONCLUSIONS: The results of this series suggest that LDP is a safe surgical approach that is comparable from an oncologic standpoint to ODP for the management of pancreatic adenocarcinoma. PMID- 28643067 TI - SAGES endoluminal treatments for GERD. PMID- 28643066 TI - Solving the surgeon ergonomic crisis with surgical exosuit. AB - INTRODUCTION: The widespread adoption of laparoscopic surgery has put new physical demands on the surgeon leading to increased musculoskeletal disorders and injuries. Shoulder, back, and neck pains are among the most common complaints experienced by laparoscopic surgeons. Here, we evaluate the feasibility and efficacy of a non-intrusive progressive arm support exosuit worn by surgeons under the sterile gown to reduce pain and fatigue during surgery. METHODS AND PROCEDURES: This is a prospective randomized crossover study approved by the Internal Review Board (IRB). The study involves three phases of testing. In each phase, general surgery residents or attendings were randomized to wearing the surgical exosuit at the beginning or at the crossover point. The first phase tests for surgeon manual dexterity wearing the device using the Minnesota Dexterity test, the Purdue Pegboard test, and the Fundamentals of Laparoscopic Surgery (FLS) modules. The second phase tests the effect of the device on shoulder pain and fatigue while operating the laparoscopic camera. The third phase rates surgeon experience in the operating room between case-matched operating days. RESULTS: Twenty subjects were recruited for this study. Surgeons had the similar dexterity scores and FLS times whether or not they wore the exosuit (p value ranges 0.15-0.84). All exosuit surgeons completed 15 min of holding laparoscopic camera compared to three non-exosuit surgeons (p < 0.02). Exosuit surgeons experienced significantly less fatigue at all time periods and arm pain (3.11 vs 5.88, p = 0.019) at 10 min. Surgeons wearing the exosuit during an operation experienced significant decrease in shoulder pain and 85% of surgeons reported some form of pain reduction at the end of the operative day. CONCLUSION: The progressive arm support exosuit can be a minimally intrusive device that laparoscopic surgeons wear to reduce pain and fatigue of surgery without significantly interfering with operative skills or manual dexterity. PMID- 28643068 TI - Effects of barbed suture during robot-assisted radical prostatectomy on postoperative tissue damage and longitudinal changes in lower urinary tract outcome. AB - OBJECTIVE: To compare the postoperative tissue damage and longitudinal changes in functional and patient-reported outcomes after vesicourethral anastomosis with barbed suture and nonbarbed suture in robot-assisted laparoscopic radical prostatectomy (RARP). MATERIALS AND METHODS: This was a prospective cohort study involving 88 consecutive patients who underwent RARP. These patients were categorized into the barbed suture group (n = 50) and the nonbarbed suture group (n = 38). Urethral and periurethral damages determined by magnetic resonance imaging at nine months after RARP were compared using generalized linear models. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, uroflowmetry, and the 1-h pad test were measured at baseline and at 1, 3, 6, 9, and 12 months after RARP. The findings were analyzed using mixed-effects models. Confounding was adjusted for using propensity score covariate adjustment. RESULTS: The likelihood of having Grade 2/3 urethral and periurethral damages was greater in the barbed suture group than in the nonbarbed suture group (adjusted risk ratios: 2.98 and 3.85, respectively). IPSS, QOL index, and urinary leakage transiently increased at one month after RARP in both groups. QOL index was higher in the barbed suture group than in the nonbarbed suture group at 1, 9, and 12 months (P = 0.023, P = 0.025, and P = 0.011, respectively). The barbed suture group had significantly more cases of urinary incontinence than the nonbarbed suture group at 3 months (P = 0.041). Other outcomes were comparable between the two groups at all time points. CONCLUSIONS: This cohort study showed that, after RARP, barbed sutures during VUA induced more severe tissue damage as determined by MRI and greater transient aggravation of QOL and continence function than nonbarbed sutures. The present findings suggest that using nonbarbed sutures during VUA may facilitate earlier acquisition of urinary QOL and urinary continence. PMID- 28643069 TI - Lessons learned from a phase II clinical trial of laparoscopic HIPEC for gastric cancer. AB - BACKGROUND: Over the last two decades, intraperitoneal chemotherapy has been found to have activity for select subgroups of patients with carcinomatosis from colon, ovarian, appendiceal, and recently, gastric origins. However, there is little data to support an aggressive surgical approach of cytoreduction (debulking) and hyperthermic intraperitoneal perfusion with chemotherapy (HIPEC) for patients with gastric cancer and positive cytology or carcinomatosis. The morbidity and mortality rates of cytoreduction and HIPEC, in combination with gastrectomy, are significant and the survival rates of this approach may not extend beyond that of treatment with systemic chemotherapy. The objective of this clinical trial, therefore, was to perform HIPEC in a neoadjuvant fashion via a minimally invasive approach without cytoreduction for patients with gastric cancer and positive cytology or low volume carcinomatosis. Patients found to have resolution of all extra-gastric disease are then candidates for gastrectomy. METHODS: Patients with gastric and gastroesophageal adenocarcinoma and positive peritoneal cytology or radiologically-occult carcinomatosis that have completed treatment with systemic chemotherapy were offered participation in the study. RESULTS: We have performed 38 laparoscopic HIPEC procedures in 19 patients. Laparoscopic HIPEC consists of Mitomycin C 30 mg and Cisplatin 200 mg in 3-7 L of infusate circulated using an extracorporeal circulation device at a flow rate of 700-1500 mL/minute for 60 min. The Laparoscopic HIPEC procedure may be performed up to five times. In this video, we sought to present the surgical technique refined during our development and completion of this Phase II clinical trial (NCT02092298). CONCLUSION: The purpose of this presentation is to (1) demonstrate the technique of laparoscopic HIPEC and (2) review the surgical lessons learned from performing multiple HIPEC procedures prior to attempted gastrectomy. PMID- 28643070 TI - Laparoscopic revision of Billroth II with Braun anastomosis into Roux-en-Y anatomy in a patient with intestinal malrotation. AB - INTRODUCTION: Various reconstructions of the gastro-intestinal tract have been described in the past after distal gastrectomy. Among these, a Billroth II (BII) anastomosis can be performed with the addition of the Omega entero-enterostomy that may theoretically reduce the alkaline reflux. Given the significant complications associated with this procedure such as biliary reflux, marginal ulceration, and afferent loop syndrome, a revision into a Roux-en-Y anatomy is generally recommended. METHODS AND PROCEDURES: A 73-year-old healthy male was referred to our foregut surgery service for treatment of severe biliary gastritis. The patient previously underwent an open distal gastrectomy with a BII reconstruction followed by a Braun-type entero-enterostomy 6 months later. His main complaint was worsening daily biliary reflux with constant regurgitations, which were non-responsive to medical treatment. The preoperative endoscopy confirmed the diagnosis of severe biliary gastritis secondary to alkaline reflux. The distance between the gastro-jejunostomy and the Braun anastomosis was also measured with a pediatric colonoscope and the length of the efferent limb was estimated to be 80 cm. RESULTS: Identification of the afferent and efferent limb was complicated by the patient's incomplete intestinal malrotation with the angle of Treitz being present in the right hypochondrium. Intra-operative gastroscopy enabled visualization of the jejuno-jejunostomy and ensured correct interpretation of the anatomy. Subsequently, resection of the afferent limb completed the revision into a Roux-en-Y anatomy. The patient recovered well after the surgery and was discharged home on post-operative day 2. At 6 months follow up, the patient's reflux symptoms have completely disappeared. CONCLUSION: BII reconstruction with or without Braun entero-enterostomy is a classic historical option following distal gastrectomy. Surgical revision of a BII into a Roux-en-Y anatomy is a good solution for severe biliary reflux and other long-term complications. Intra-operative endoscopy is a great adjunct to laparoscopic exploration in case of complex surgical procedures. PMID- 28643071 TI - Forgotten biliary stents: ignorance is not bliss. AB - BACKGROUND: Endoscopic biliary stenting is a common procedure in routine gastroenterology practice. Plastic stents are the most common type of stents used and are indicated mainly for short-term biliary drainage. Prolonged indwelling plastic stents can result in disastrous complications. METHODS: We conducted a retrospective analysis of patients who presented with complications of forgotten biliary stents in a tertiary care hospital during January 2010 to October 2016. All patients were managed either by endoscopic or surgical means. Details of these patients were obtained from departmental patient database, endoscopy records, and surgical register. RESULTS: A total of 21 cases of retained biliary stents were managed in the study period and their outcome was analyzed. The median age was 47 years (range 17-70 years) and 17 (80.9%) patients were female. Primary indication of biliary stenting was stone disease in 76.2% (n = 16), while benign biliary stricture accounted for 19% of cases (n = 4). Mean duration at presentation to hospital after ERCP stenting was 3.53 years (range 1-14 years), with cholangitis being the most common presentation (66.67%). Definitive endoscopic treatment for forgotten stent and its associated complication was possible only in five patients (23.8%); in remaining 16 (76.2%) cases, surgical exploration was required. Despite life-threatening complications and major surgical interventions, no mortality was recorded. CONCLUSIONS: Instances of forgotten biliary stents presenting with serious complications are not uncommon in Indian setup. Patients either ignore advice for timely stent removal or are unaware of the presence of endoprosthesis or need for removal. Adequate patient counseling, information, and proper documentation are essential to avoid this condition. PMID- 28643073 TI - Endoscopic resection of giant fibrovascular esophageal polyps. AB - BACKGROUND: Giant fibrovascular esophageal polyps are rare benign intraluminal tumors that originate from the submucosa of the cervical esophagus [Owens et al. (JAMA 103: 838-842, 1994), Totten et al. (JAMA 25:606-622, 1953)]. Due to their indolent course, these tumors tend to reach enormous proportions before patients develop symptoms. Accurately diagnosing these tumors is difficult, as endoscopy may miss 25% of these lesions because these polyps exhibit normal intact esophageal mucosa [Levine et al. (JAMA 166: 781-787, 1996)]. METHODS: Surgical resection has been the treatment of choice. We present a video that illustrates the feasibility of an endoscopic approach. TECHNIQUE/CASE: A 62-year-old man presented to our clinic with a pedunculated esophageal mass. During this time, he developed progressive dysphagia to solid foods. A complete workup confirmed the presence of a giant polyp and endoscopic resection under general anesthesia was planned. Using an endoscopic snare-technique, a 16 cm * 3 cm polyp was amputated and retracted out of the oropharynx. Upon repeat endoscopy a second 7 cm * 3 cm polyp was discovered originating proximal to the larger polyp. Again, removal of this polyp was attempted using a snare-technique. Following amputation of the polyp, a broad-based component of the polyp remained. Given its proximal location in the esophagus, we were able to use a snare to pull the broad base of the remaining polyp into the oropharynx and remove it at its origin. Postoperative endoscopy and endoscopic ultrasound confirmed that the polyps were completely removed and the muscular resection bed was hemostatic. Clinically, the patient's symptoms resolved and he encountered no adverse sequela as a result of the operation. CONCLUSION: Giant fibrovascular esophageal polyps are rare benign intraluminal tumors that can lead to obstructive symptoms. Surgical resection is the treatment of choice, and may be possible with an endoscopic approach. An endoscopic snare technique can be used to resect these lesions while minimizing patient morbidity. PMID- 28643074 TI - Erratum to: Minimally invasive resection of adrenal masses in infants and children: results of a European multi-center survey. PMID- 28643075 TI - A standardized comparison of peri-operative complications after minimally invasive esophagectomy: Ivor Lewis versus McKeown. AB - BACKGROUND: While our institutional approach to esophageal resection for cancer has traditionally favored a minimally invasive (MI) 3-hole, McKeown esophagectomy (MIE 3-hole) during the last five years several factors has determined a shift in our practice with an increasing number of minimally invasive Ivor Lewis (MIE IL) resections being performed. We compared peri-operative outcomes of the two procedures, hypothesizing that MIE IL would be less morbid in the peri-operative setting compared to MIE 3-hole. METHODS: Our institution's IRB-approved esophageal database was queried to identify all patients who underwent totally MI esophagectomy (MIE IL vs. MIE 3-hole) from June 2011 to May 2016. Patient demographics, preoperative and peri-operative data, as well as post-operative complications were compared between the two groups. Post-operative complications were analyzed using the Clavien-Dindo classification system. RESULTS: There were 110 patients who underwent totally MI esophagectomy (MIE IL n = 49 [45%], MIE 3 hole n = 61 [55%]). The majority of patients were men (n = 91, 83%) with a median age of 62.5 (range 31-83). Preoperative risk stratifiers such as ECOG score, ASA, and Charlson Comorbidity Index were not significantly different between groups. Anastomotic leak rate was 2.0% in the MIE IL group compared to 6.6% in the MIE 3 hole group (p = 0.379). The rate of serious (Clavien-Dindo 3, 4, or 5) post operative complications was significantly less in the MIE IL group (34.7 vs. 59.0%, p = 0.013). Serious pulmonary complications were not significantly different (16.3 vs. 26.2%, p = 0.251) between the two groups. CONCLUSIONS: In this cohort, totally MIE IL showed significantly less severe peri-operative morbidity than MIE 3-hole, but similar rates of serious pulmonary complications and anastomotic leaks. These findings confirm the safety of minimally invasive Ivor Lewis esophagectomies for esophageal cancer when oncologically and clinically appropriate. Minimally invasive McKeown esophagectomy remains a satisfactory and appropriate option when clinically indicated. PMID- 28643072 TI - SAGES guidelines for the use of laparoscopy during pregnancy. PMID- 28643076 TI - Scintigraphic peritoneography reveals a non-uniform 99mTc-Pertechnetat aerosol distribution pattern for Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a swine model. AB - BACKGROUND: Although recent data are contradictory, it is still claimed that Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) would deliver an aerosol which distributes homogeneously throughout the entire abdominal cavity. METHODS: 99mTc-Pertechnetat was administered in four postmortem swine using either PIPAC or liquid intra-peritoneal chemotherapy (IPC). The animals were examined by planar scintigraphy and SPECT/CT. Planar distribution images were divided into four regions of interest (ROIs: right/left upper and lower abdominal quadrant). SPECT/CT slices were scanned for areas of intense nuclide accumulation ("hot spots"). The percentage of relative distribution for planar scintigraphy was calculated by dividing the summed individual counts of each ROI by total counts measured in the entire abdominal cavity. The relative distribution of the "hot spots" was analyzed by dividing the counts of the local volume of interest (VOI) by the summed volume counts measured in the entire abdominal cavity. RESULTS: In all four animals, planar scintigraphy showed inhomogeneous nuclide distribution. After PIPAC only 8-10% of the delivered nuclide was detected in one ROI with a mean deviation of 40% and 74% from a uniform nuclide distribution pattern. In all animals, SPECT/CT revealed "hot spots" beneath the PIPAC Micropump, catheter tip, and in the cul-de-sac region which comprise about 25% of the total amount of delivered nuclide in 2.5% of the volume of the entire abdominal cavity. CONCLUSIONS: Our present data indicate that the intra-abdominal aerosol distribution pattern of PIPAC therapy is non-homogeneous and that the currently applied technology has still not overcome the problem of inhomogeneous drug distribution of IPC. PMID- 28643077 TI - CORR Insights(r): Free Vascularized Fibular Grafting Improves Vascularity Compared With Core Decompression in Femoral Head Osteonecrosis: A Randomized Clinical Trial. PMID- 28643078 TI - On Patient Safety: Is it Possible to Operate Too Much? PMID- 28643080 TI - Elaboration of the Reciprocal-Engagement Model of Genetic Counseling Practice: a Qualitative Investigation of Goals and Strategies. AB - As the genetic counseling field evolves, a comprehensive model of practice is critical. The Reciprocal-Engagement Model (REM) consists of 5 tenets and 17 goals. Lacking in the REM, however, are well-articulated counselor strategies and behaviors. The purpose of the present study was to further elaborate and provide supporting evidence for the REM by identifying and mapping genetic counseling strategies to the REM goals. A secondary, qualitative analysis was conducted on data from two prior studies: 1) focus group results of genetic counseling outcomes (Redlinger-Grosse et al., Journal of Genetic Counseling, 2015); and 2) genetic counselors' examples of successful and unsuccessful genetic counseling sessions (Geiser et al. 2009). Using directed content analysis, 337 unique strategies were extracted from focus group data. A Q-sort of the 337 strategies yielded 15 broader strategy domains that were then mapped to the successful and unsuccessful session examples. Differing prevalence of strategy domains identified in successful sessions versus the prevalence of domains identified as lacking in unsuccessful sessions provide further support for the REM goals. The most prevalent domains for successful sessions were Information Giving and Use Psychosocial Skills and Strategies; and for unsuccessful sessions, Information Giving and Establish Working Alliance. Identified strategies support the REM's reciprocal nature, especially with regard to addressing patients' informational and psychosocial needs. Patients' contributions to success (or lack thereof) of sessions was also noted, supporting a REM tenet that individual characteristics and the counselor-patient relationship are central to processes and outcomes. The elaborated REM could be used as a framework for certain graduate curricular objectives, and REM components could also inform process and outcomes research studies to document and further characterize genetic counselor strategies. PMID- 28643079 TI - Similar Clinical Outcomes with Preoperative and Postoperative Start of Thromboprophylaxis in THA: A Register-based Study. AB - BACKGROUND: Elective THA is associated with a high risk of thromboembolic events. Although these events may be less common now than they were in the past, they can be serious, and most patients undergoing the procedure therefore still receive thromboprophylaxis. However, controversy remains regarding whether to begin thromboprophylaxis before THA or after to best balance the risks of clotting and bleeding. QUESTIONS/PURPOSES: We asked the following questions: (1) Is there a difference in bleeding events with pre- versus postoperative thromboprophylaxis? (2) Is there a difference in thromboembolic episodes after THA between the two regimens? (3) How do the two approaches of thromboprophylaxis influence mortality, readmissions, and other complications? METHODS: We used a population based followup design with predefined data based on international health codification to assess clinical effects of LMWH prophylaxis initiated before or after THA. We took data limited to primary THAs done in Norway between January 1, 2008, and December 31, 2011, from the Norwegian Arthroplasty Register and the National Patient Register to have necessary data elements to complete the study. The two registers were merged after identifying patients with their 11-digit personal identification number (Social Security number). We obtained data regarding demographics, administrative and surgical details, and episode histories for prophylaxis-related events within 180 days of surgery. A total of 25,163 patients undergoing THA were included for analysis, and 9977(40%) versus 15,186 (60%) patients received pre- and postoperative LMWH, respectively. We performed statistical adjustment for differences in baseline characteristics using multivariate logistic regression. RESULTS: After adjustment for age, sex, operation time, year of surgery, and American Society of Anesthesiologists class, we could not show major differences in bleeding events; (odds ratio [OR], 1.04; 95% CI, 0.88-1.22; p = 0.660), thromboembolic episodes; (OR, 1.03; 95% CI, 0.84 1.27; p = 0.786), or other postoperative clinical complications; (OR, 0.86; 95% CI, 0.76-0.99; p = 0.034), with the two regimens. Six-month mortality was similar, (OR, 0.76; 95% CI, 0.56-1.05; p = 0.093), and the readmission rate was higher in the preoperative group; (OR, 0.92; 95% CI, 0.85-0.97; p = 0.016). CONCLUSIONS: The risk for postoperative complications seems to be comparable whether LMWH prophylaxis is initiated before or after THA. The postoperative approach reduces costs, decreases risks related to neuraxial anesthesia, and facilitates same-day admissions. Methods for individual risk assessment including laboratory tests would be feasible. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28643081 TI - Distraction osteogenesis reconstruction of large segmental bone defects after primary tumor resection: pitfalls and benefits. AB - Successful cure is achieved in almost 70% of patients with primary bone sarcomas with currently available therapies. Some soft tissue sarcomas require wide bone resection in order to achieve appropriate margins for cure of disease, and patients undergoing these procedures need durable reconstruction. Biological reconstruction has been shown to provide patients with superior long-term results over other alternatives. Distraction osteogenesis is well studied in the correction of deformities as well as in addressing some congenital musculoskeletal pathologies. The use of this technique in tumor settings has been avoided by many surgeons for a multitude of concerns, including infection risk, potential tumor activation, and uncertainty regarding the effect of systemic therapy on the callus regenerate. We review the use of this reconstruction technique using cases from our institutional experience to illustrate its incorporation into the successful management of orthopedic oncology patients. Distraction osteogenesis is an effective method for reconstructing even large bony defects and is safe in the setting of systemic therapy. This technique has the potential to address some of the common problems associated with orthopedic oncology resection, such as infection and leg length discrepancy. PMID- 28643082 TI - The Influence of Solar Power Plants on Microclimatic Conditions and the Biotic Community in Chilean Desert Environments. AB - The renewable energy sector is growing at a rapid pace in northern Chile and the solar energy potential is one of the best worldwide. Therefore, many types of solar power plant facilities are being built to take advantage of this renewable energy resource. Solar energy is considered a clean source of energy, but there are potential environmental effects of solar technology, such as landscape fragmentation, extinction of local biota, microclimate changes, among others. To be able to minimize environmental impacts of solar power plants, it is important to know what kind of environmental conditions solar power plants create. This study provides information about abiotic and biotic conditions in the vicinity of photovoltaic solar power plants. Herein, the influence of these power plants as drivers of new microclimate conditions and arthropods diversity composition in the Atacama Desert was evaluated. Microclimatic conditions between panel mounts was found to be more extreme than in the surrounding desert yet beneath the panels temperature is lower and relative humidity higher than outside the panel area. Arthropod species composition was altered in fixed-mount panel installations. In contrast, solar tracking technology showed less influence on microclimate and species composition between Sun and Shade in the power plant. Shady conditions provided a refuge for arthropod species in both installation types. For example, Dipterans were more abundant in the shade whereas Solifugaes were seldom present in the shade. The presented findings have relevance for the sustainable planning and construction of solar power plants. PMID- 28643083 TI - In focus in HCB. PMID- 28643084 TI - Influence of knockout of At4g20990 gene encoding alpha-CA4 on photosystem II light-harvesting antenna in plants grown under different light intensities and day lengths. AB - Effect of knockout of the At4g20990 gene encoding alpha-carbonic anhydrase 4 (alpha-CA4) in Arabidopsis thaliana in plants grown in low light (LL, 80 MUmol photons m-2 s-1) or in high light (HL, 400 MUmol photons m-2 s-1) under long (LD, 16 h) or short (SD, 8 h) day length was studied. In alpha-CA4 knockout plants, under all studied conditions, the non-photochemical quenching was lower; the decrease was more pronounced under HL. This pointed to alpha-CA4 implication in the processes leading to energy dissipation in PSII antenna. In this context the content of major antenna proteins Lhcb1 and Lhcb2 was lower in alpha-CA4 knockouts than in wild-type (WT) plants under all growth conditions. The expression level of lhcb2 gene was also lower in mutants grown under LD, LL and HL in comparison to WT. At the same time, this level was higher in mutants grown under SD, LL and it was the same under SD, HL. Overall, the data showed that the knockout of the At4g20990 gene affected both the contents of proteins of PSII light-harvesting complex and the expression level of genes encoding these proteins, with peculiarities dependent on day length. These data together with the fact of a decrease of non-photochemical quenching of leaf chlorophyll a fluorescence in alpha-CA4-mut as compared with that in WT plants implied that alpha-CA4 participates in acclimation of photosynthetic apparatus to light intensity, possibly playing important role in the photoprotection. The role of this CA can be especially important in plants growing under high illumination conditions. PMID- 28643085 TI - Exogenous application of nitric oxide modulates osmolyte metabolism, antioxidants, enzymes of ascorbate-glutathione cycle and promotes growth under cadmium stress in tomato. AB - Experiments were carried out to investigate the role of nitric oxide (NO) in ameliorating the negative effects of cadmium stress in tomato seedlings. Plants treated with cadmium (CdCl2, 150 MUM) showed reduced growth, biomass yield, pigment content, chlorophyll fluorescence, and gas exchange parameters. Exogenous application of NO donor (sodium nitroprusside) with nutrient solution protected chlorophyll pigments, restored chlorophyll fluorescence and gas exchange parameters, and caused significant enhancements in growth and biomass yield. Cadmium triggered the synthesis of proline and glycine betaine; however, application of NO caused further enhancement of their accumulation, reflecting an obvious amelioration of the cadmium-induced decline in relative water content. Activities of the antioxidant enzymes superoxide dismutase, catalase, ascorbate peroxidase, and glutathione reductase, monodehydroascorbate reductase, dehydroascorbate reductase, and other enzymatic activities of ascorbate glutathione cycle were enhanced following the application of NO, as compared with those in untreated seedlings under control and cadmium stress conditions. NO increased the flavonoid and total phenol content in Cd-stressed tomato plants. Moreover, NO application restricted the uptake of cadmium and enhanced the accumulation of nutrients in different parts of tomato plants. On the basis of the findings of the present study, we propose that NO has a potential role as a growth promoter for tomato under cadmium stress. PMID- 28643087 TI - Antioxidant and antiapoptotic actions of selegiline protect against 3-NP-induced neurotoxicity in rats. AB - The present study was designed to investigate the neuroprotective effect of selegiline on 3-nitropropionic acid (3-NP)-induced neurotoxicity. Selegiline was intraperitoneally injected at doses 2.5, 5, and 10 mg/kg, 3 days prior to and continued daily, 30 min before 3-NP administration. 3-NP (20 mg/kg, i.p.) was administered for four consecutive days. 3-NP-treated rats exhibited PPI deficits, locomotor hypoactivity, increased striatal and cortical lipid peroxidation, and reduced respective glutathione (GSH) levels as well as catalase and superoxide dismutase (SOD) activities. Changes in the level of the apoptotic regulatory gene expressions were demonstrated as increased striatal and cortical caspase-3 and Bax and decreased respective Bcl2. The two higher dose levels of selegiline (5 and 10 mg/kg) significantly increased locomotor activity, improved prepulse inhibition (PPI), reduced striatal and cortical lipid peroxidation, caspase-3, and Bax, and increased GSH level, catalase, and superoxide dismutase activities and Bcl2 expression. Selegiline at dose 2.5 mg/kg could only reverse some of the manifestations of 3-NP-induced neurotoxicity. Histological examination further affirmed the neuroprotective effect of the higher dose levels of selegiline against 3-NP-induced toxicity. Taken together, these results suggest that selegiline could attenuate 3-NP-induced neurotoxicity. This can be attributed to, at least partly, its antioxidant and antiapoptotic effects. PMID- 28643086 TI - Gallic and ellagic acids: two natural immunomodulator compounds solve infection of macrophages by Leishmania major. AB - Leishmaniasis is a complex of parasitic protozoan diseases caused by more than 20 different species of parasites from Leishmania genus. Conventional treatments are high costly, and promote a sort of side effects. Besides, protozoan resistance to treatments has been reported. Natural products have been investigated as a source of new therapeutic alternatives, not only acting directly against the parasite but also being able to synergistically act on the host immune system in order to control parasitemia. Gallic acid (GA) and ellagic acid (EA) are plant-derived phenolic compounds which are able to induce antiinflammatory, gastroprotective, and anticarcinogenic activities. Therefore, the antileishmania, cytotoxic, and immunomodulatory activities of GA and EA were evaluated in this study. Both GA and EA were able to inhibit the growth of Leishmania major promastigotes (effective concentration (EC50) values 16.4 and 9.8 MUg/mL, respectively). The cytotoxicity against BALB/c murine macrophages for GA and EA was also assessed (CC50 values 126.6 and 23.8 MUg/mL, respectively). Interestingly, GA and EA also significantly reduced the infection and infectivity of macrophages infected by L. major (EC50 values 5.0 and 0.9 MUg/mL, respectively), with selectivity index higher than 20. Furthermore, both GA and EA induced high immunomodulatory activity evidenced by the increase of phagocytic capability, lysosomal volume, nitrite release, and intracellular calcium [Ca2+i] in macrophages. Further investigations are reinforced in order to evaluate the therapeutic effects of GA and EA in in vivo experimental infection model of leishmaniasis. PMID- 28643088 TI - Potential therapeutic applications of human anti-Mullerian hormone (AMH) analogues in reproductive medicine. AB - Members of the transforming growth factor-beta (TGF-beta) superfamily are key regulators of various physiological processes. Anti-Mullerian hormone (AMH) which is also commonly known as Mullerian-inhibiting substance (MIS) is a member of the TGF-beta superfamily and an important regulator of reproductive organ differentiation and ovarian follicular development. While AMH has been used for diagnostic purposes as a biomarker for over 15 years, new potential therapeutic applications of recombinant human AMH analogues are now emerging as pharmacologic agents in reproductive medicine. Therapeutic uses of AMH in gonadal tissue may provide a unique opportunity to address a broad range of reproductive themes, like contraception, ovulation induction, onset of menopause, and fertility preservation, as well as specific disease conditions, such as polycystic ovarian syndrome (PCOS) and cancers of the reproductive tract. This review explores the most promising therapeutic applications for a novel class of drugs known as AMH analogues with agonist and antagonist functions. PMID- 28643089 TI - Time-lapse observation and transcriptome analysis of a case with repeated multiple pronuclei after IVF/ICSI. AB - PURPOSE: The purpose of this study was to investigate the cause of repeated multipronucleus (MPN) formation in zygotes in a patient after both in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). METHOD: This is a case study. A patient had unexplained primary infertility with recurring total MPN zygotes after IVF and ICSI cycles. Time-lapse monitoring of pronucleus formation was carried out. Embryos developed from MPN zygotes were analyzed by fluorescence in situ hybridization (FISH). Single-cell RNA-seq analysis was used to identify gene expression profiles of the patient's oocyte and zygote, and these were compared to the data from oocytes and zygotes from donors with normal fertilization (patient, n = 1; donors, n = 4). Oocyte-specific genes with differential expression were selected by the Amazonia! DATABASE: RESULTS: From time-lapse analysis, we observed the formation of multiple micronuclei near the site of the second polar body extrusion. These micronuclei migrated, expanded, and juxtaposed with the male pronucleus leading to a multipronucleus. None of these MPN zygotes could develop to the blastocyst stage, and FISH analysis revealed a chaotic chromosomal complement in the arrested embryos. RNA-seq analysis showed 113 differentially expressed genes (DEGs) between the patient and the donor oocytes and zygotes. Moreover, 25 of the 113 DEGs were unique or highly expressed in oocytes and early embryos. From 25 DEGs, three genes, DYNC2LI1, NEK2, and CCNH, which are involved in meiosis and the chromosome separation process, were further validated by real-time PCR. CONCLUSION: We identified several candidate genes affecting pronucleus formation as a new cause of infertility. PMID- 28643090 TI - Burrow Dusting or Oral Vaccination Prevents Plague-Associated Prairie Dog Colony Collapse. AB - Plague impacts prairie dogs (Cynomys spp.), the endangered black-footed ferret (Mustela nigripes) and other sensitive wildlife species. We compared efficacy of prophylactic treatments (burrow dusting with deltamethrin or oral vaccination with recombinant "sylvatic plague vaccine" [RCN-F1/V307]) to placebo treatment in black-tailed prairie dog (C. ludovicianus) colonies. Between 2013 and 2015, we measured prairie dog apparent survival, burrow activity and flea abundance on triplicate plots ("blocks") receiving dust, vaccine or placebo treatment. Epizootic plague affected all three blocks but emerged asynchronously. Dust plots had fewer fleas per burrow (P < 0.0001), and prairie dogs captured on dust plots had fewer fleas (P < 0.0001) than those on vaccine or placebo plots. Burrow activity and prairie dog density declined sharply in placebo plots when epizootic plague emerged. Patterns in corresponding dust and vaccine plots were less consistent and appeared strongly influenced by timing of treatment applications relative to plague emergence. Deltamethrin or oral vaccination enhanced apparent survival within two blocks. Applying insecticide or vaccine prior to epizootic emergence blunted effects of plague on prairie dog survival and abundance, thereby preventing colony collapse. Successful plague mitigation will likely entail strategic combined uses of burrow dusting and oral vaccination within large colonies or colony complexes. PMID- 28643091 TI - Sylvatic Plague Vaccine Partially Protects Prairie Dogs (Cynomys spp.) in Field Trials. AB - Sylvatic plague, caused by Yersinia pestis, frequently afflicts prairie dogs (Cynomys spp.), causing population declines and local extirpations. We tested the effectiveness of bait-delivered sylvatic plague vaccine (SPV) in prairie dog colonies on 29 paired placebo and treatment plots (1-59 ha in size; average 16.9 ha) in 7 western states from 2013 to 2015. We compared relative abundance (using catch per unit effort (CPUE) as an index) and apparent survival of prairie dogs on 26 of the 29 paired plots, 12 with confirmed or suspected plague (Y. pestis positive carcasses or fleas). Even though plague mortality occurred in prairie dogs on vaccine plots, SPV treatment had an overall positive effect on CPUE in all three years, regardless of plague status. Odds of capturing a unique animal were 1.10 (95% confidence interval [C.I.] 1.02-1.19) times higher per trap day on vaccine-treated plots than placebo plots in 2013, 1.47 (95% C.I. 1.41-1.52) times higher in 2014 and 1.19 (95% C.I. 1.13-1.25) times higher in 2015. On pairs where plague occurred, odds of apparent survival were 1.76 (95% Bayesian credible interval [B.C.I.] 1.28-2.43) times higher on vaccine plots than placebo plots for adults and 2.41 (95% B.C.I. 1.72-3.38) times higher for juveniles. Our results provide evidence that consumption of vaccine-laden baits can protect prairie dogs against plague; however, further evaluation and refinement are needed to optimize SPV use as a management tool. PMID- 28643092 TI - Application of CT texture analysis in predicting histopathological characteristics of gastric cancers. AB - OBJECTIVES: To explore the application of computed tomography (CT) texture analysis in predicting histopathological features of gastric cancers. METHODS: Preoperative contrast-enhanced CT images and postoperative histopathological features of 107 patients (82 men, 25 women) with gastric cancers were retrospectively reviewed. CT texture analysis generated: (1) mean attenuation, (2) standard deviation, (3) max frequency, (4) mode, (5) minimum attenuation, (6) maximum attenuation, (7) the fifth, 10th, 25th, 50th, 75th and 90th percentiles, and (8) entropy. Correlations between CT texture parameters and histopathological features were analysed. RESULTS: Mean attenuation, maximum attenuation, all percentiles and mode derived from portal venous CT images correlated significantly with differentiation degree and Lauren classification of gastric cancers (r, -0.231 ~ -0.324, 0.228 ~ 0.321, respectively). Standard deviation and entropy derived from arterial CT images also correlated significantly with Lauren classification of gastric cancers (r = -0.265, -0.222, respectively). In arterial phase analysis, standard deviation and entropy were significantly lower in gastric cancers with than those without vascular invasion; however, minimum attenuation was significantly higher in gastric cancers with than those without vascular invasion. CONCLUSION: CT texture analysis held great potential in predicting differentiation degree, Lauren classification and vascular invasion status of gastric cancers. KEY POINTS: * CT texture analysis is noninvasive and effective for gastric cancer. * Portal venous CT images correlated significantly with differentiation degree and Lauren classification. * Standard deviation, entropy and minimum attenuation in arterial phase reflect vascular invasion. PMID- 28643093 TI - The impact of trained radiographers as concurrent readers on performance and reading time of experienced radiologists in the UK Lung Cancer Screening (UKLS) trial. AB - OBJECTIVES: To compare radiologists' performance reading CTs independently with their performance using radiographers as concurrent readers in lung cancer screening. METHODS: 369 consecutive baseline CTs performed for the UK Lung Cancer Screening (UKLS) trial were double-read by radiologists reading either independently or concurrently with a radiographer. In concurrent reading, the radiologist reviewed radiographer-identified nodules and then detected any additional nodules. Radiologists recorded their independent and concurrent reading times. For each radiologist, sensitivity, average false-positive detections (FPs) per case and mean reading times for each method were calculated. RESULTS: 694 nodules in 246/369 (66.7%) studies comprised the reference standard. Radiologists' mean sensitivity and average FPs per case both increased with concurrent reading compared to independent reading (90.8 +/- 5.6% vs. 77.5 +/- 11.2%, and 0.60 +/- 0.53 vs. 0.33 +/- 0.20, respectively; p < 0.05 for 3/4 and 2/4 radiologists, respectively). The mean reading times per case decreased from 9.1 +/- 2.3 min with independent reading to 7.2 +/- 1.0 min with concurrent reading, decreasing significantly for 3/4 radiologists (p < 0.05). CONCLUSIONS: The majority of radiologists demonstrated improved sensitivity, a small increase in FP detections and a statistically significantly reduced reading time using radiographers as concurrent readers. KEY POINTS: * Radiographers as concurrent readers could improve radiologists' sensitivity in lung nodule detection. * An increase in false-positive detections with radiographer-assisted concurrent reading occurred. * The false-positive detection rate was still lower than reported for computer-aided detection. * Concurrent reading with radiographers was also faster than single reading. * The time saved per case using concurrently reading radiographers was relatively modest. PMID- 28643094 TI - Accuracy and reading time for six strategies using digital breast tomosynthesis in women with mammographically negative dense breasts. AB - OBJECTIVE: To compare six strategies using digital breast tomosynthesis in women with mammographically negative dense breasts. MATERIALS AND METHODS: This is a substudy of the 'ASTOUND' trial. 163 women who underwent tomosynthesis with synthetically reconstructed projection images (S-2D) inclusive of 13 (7.9%) cases diagnosed with breast cancer at histopathology after surgery were evaluated. Accuracy measures and screen-reading time of six reading strategies were assessed: (A) Single reading of S-2D alone, (B) single reading of tomosynthesis alone, (C) single reading of joint interpretation of tomosynthesis + S-2D, (D) double-reading of S-2D alone, (E) double reading of tomosynthesis alone, (F) double reading of joint interpretation of tomosynthesis + S-2D. RESULTS: The median age of the patients was 53 years (range, 36-88 years). The highest global accuracy was obtained with double reading of tomosynthesis + S2D (F) with an AUC of 0.979 (p<0.001) and a mean reading time of 154 s versus 34 s for the fastest strategy (single reading of S-2D alone). The AUCs for the other five strategies did not differ from each other. CONCLUSION: Double reading of tomosynthesis+ S2D had the best accuracy of six screen-reading strategies although it had the longest reading time. KEY POINTS: * Tomosynthesis acquisitions are progressively implemented with reconstructed synthesized 2D images * Double reading using S-2D plus tomosynthesis had the highest global accuracy (p<0.001). * Double reading of S-2D plus tomosynthesis increased reading time. PMID- 28643097 TI - [Anti-infective strategies in trauma surgery Part 2]. PMID- 28643095 TI - [Local antibiotic therapy]. AB - The treatment of superficial wound infections with local antibiotics is considered to be problematic as it is accompanied by an increased risk of resistance development and ineffectiveness in deeper regions. On the contrary, the local application of antibiotics is useful in arthroplasty and necessary if implants are utilized. The reason for this is the prevention of a rapid biofilm formation on foreign implants and a resulting infection may remain undiscovered until it becomes chronic. Apart from exogenous material, necrotic tissue (e. g. bone sequestra) provides suitable retreat areas for pathogens in the body. Because of the characteristics of bone and joint infections and an exceptional infection recurrence rate, a combined approach is required. Systemic antibiotic prophylaxis is able to reduce the number of pathogens acquired by perioperative contamination or hematogenic spread from another focus of infection; however, systemically applied antibiotics often fail to form an effective colonization barrier around the implant because their ability to penetrate the bone is relatively low. On the other hand, the high concentration of locally released antibiotics leads to an effective protection of the implant from bacteria in situ. Thus, for the treatment of implant-associated infections, systemic and local application of anti-infective agents is a reliable adjuvant measure that improves the therapeutic success. Polymethylmethacrylate (PMMA) bone cement is the most commonly used local drug carrier. Based on clinical and microbiological results, microbiologists and infectious disease experts together with the surgeon and pharmacist determine which anti-infective agents are indicated for systemic and local, PMMA cement-related application. Because there is no evident concept for the local application, unlike the recommendation for systemic use of anti infective agents, this review article describes which aspects should be taken into account. PMID- 28643096 TI - [Results of the pilot phase of the Age Trauma Registry DGU(r)]. AB - BACKGROUND: Since 2014, hospitals with ortho-geriatric fracture centres could be certified as AltersTraumaZentrum DGU(r) in Germany. To measure the quality of treatment in these centres, a geriatric trauma registry (AltersTraumaRegister DGU(r)) was established. OBJECTIVES: The aim of this work was to report the results of the pilot phase of the AltersTraumaRegister DGU(r) from the year 2015. MATERIALS AND METHODS: Included were 118 patients >70 years with hip fracture or implant-related femoral fractures. Apart from other parameters, the point of surgery, initiation of anti-osteoporotic treatment and the EQ-5D one week post surgery was measured. RESULTS: Surgery was performed in 87% of patients within 24 h. Specific osteoporotic therapy could be increased from 4 to 63 patients. The EQ 5D was strongly restricted to one week post-surgery. CONCLUSION: Based on the timing of surgery and anti-osteoporotic therapy, the treatment seems to be successful in the ortho-geriatric fracture centres. For a better evaluation of treatment quality in the AltersTraumaZentren DGU(r), implementation of follow-up examinations in the AltersTraumaRegister DGU(r) is essential. PMID- 28643098 TI - [Importance of wound irrigation solutions and fluids with antiseptic effects in therapy and prophylaxis : Update 2017]. AB - INTRODUCTION: Despite the use of modern antibiotics as well as complex perioperative, intraoperative and postoperative prophylactic measures, the rate of surgical site infections (SSI) could not be significantly reduced. The introduction of biocompatible antiseptic drugs with a high microbiocidal effect provided a successful alternative for infection prevention and therapy, particularly in a time of increasing occurrence of multi-drug resistant pathogens. Hence, questions about the risk-benefit ratio of antiseptic wound irrigation solutions, the prophylactic use of wound irrigation solutions for the reduction of SSI and the effect of negative pressure wound therapy combined with instillation (NPWTi) need to be answered. METHOD: Against the background of our own experiences with the use of antiseptic wound irrigation solutions, a literature analysis (e.g. computer-supported MEDLINE, EMBASE and Cochrane database research as of April 2017) was performed. RESULTS: Antiseptic fluids can be used both prophylactically and therapeutically, in acute and chronic, clean, contaminated and infected wounds to reduce the posttraumatic and postoperative wound infection rates. The antiseptic solutions that are commonly used in orthopedic and trauma surgery (e.g. PVP-iodine, octenidine, polyhexanide, sodium hypochlorite/hypochlorous acid and acetic acid), have in common that no development of resistance has so far been shown and that when the contraindications are taken into account, the antiseptic effect can develop without any clinically significant local and systemic side effects. As a rule the biocompatibility index is higher than 1 for the substances mentioned. In addition, they show an antiseptic effect against biofilms and multi-drug resistant pathogens. These antiseptic solutions can also be used for NPWTi with some limitations for octenidine. CONCLUSION: As the basic equipment in trauma surgery, a selection of three different antiseptic wound irrigation solutions for the reduction of the rates of posttraumatic and SSI can be recommended. The use of antiseptics should be reviewed on an ongoing basis in the daily clinical routine and particular attention should be paid to unwanted effects in the course of the healing process. After application of 7-14 days, the indications for continuing the use of the antiseptic solutions must be carefully re-evaluated. PMID- 28643099 TI - [Beyond antibiotic therapy - Future antiinfective strategies - Update 2017]. AB - BACKGROUND: The key elements in the therapy of surgical site infections (SSI) are surgical debridement and local and systemic antibiotic therapy; however, due to increasing antibiotic resistance, the development of additional therapeutic measures is of great interest for future trauma and orthopedic surgery. METHOD: Against the background of our own experimental and clinical experiences and on the basis of the current literature, possible future anti-infective strategies were elaborated. RESULTS/CONCLUSIONS: Bacteriophages were discovered and clinically implemented approximately one century ago and have been used in Western Europe for about one decade. They are currently used mainly in patients with burn injuries. It is likely that bacteriophages will become of great importance in view of the increasing antibiotic multi-drug resistance; however, they will probably not entirely replace antibiotic drugs. A combined use of bacteriophages and antibiotics is likely to be a more reasonable efficient therapy. In addition, the clinical importance of antimicrobial peptides (AMP) also increases. Up to now the possible use of AMPs is still experimental; however, individual AMPs are already established in the routine therapy (e. g. colistin). Further diagnostic and therapeutic measures may include photodynamic therapy, ultraviolet (UV) light application and differentiated genome analysis as well as the individual metabolism situation (metabolomics) of the pathogen cell and the patient tissue. PMID- 28643100 TI - Perceived Devaluation and STI Testing Uptake among a Cohort of Street-Involved Youth in a Canadian Setting. AB - Perceived devaluation has been shown to have adverse effects on the mental and physical health outcomes of people who use drugs. However, the impact of perceived devaluation on sexually transmitted infections (STI) testing uptake among street-involved youth, who face multiple and intersecting stigmas due to their association with drug use and risky sexual practices, has not been fully characterized. Data were obtained between December 2013 and November 2014 from a cohort of street-involved youth who use illicit drugs aged 14-26 in Vancouver, British Columbia. Multivariable generalized estimating equations were constructed to assess the independent relationship between perceived devaluation and STI testing uptake. Among 300 street-involved youth, 87.0% reported a high perceived devaluation score at baseline. In the multivariable analysis, high perceived devaluation was negatively associated with STI testing uptake after adjustment for potential confounders (Adjusted Odds Ratio = 0.38, 95% Confidence Interval 0.15-0.98). Perceived devaluation was high among street-involved youth in our sample and appears to have adverse effects on STI testing uptake. HIV prevention and care programs should be examined and improved to better meet the special needs of street-involved youth in non-stigmatizing ways. PMID- 28643101 TI - Cognitive performance correlates with the degree of dopaminergic degeneration in the associative part of the striatum in non-demented Parkinson's patients. AB - Parkinson's disease (PD) patients show cognitive deficits that are relevant in terms of prognosis and quality of life. Degeneration of striatal dopaminergic afferents proceeds from dorsal/caudal to anterior/ventral and is discussed to account for some of these symptoms. Treatment with dopamine (DA) has differential effects on cognitive dysfunctions, improving some and worsening others. We hypothesized that cognitive performance during the dopaminergic OFF state correlates with DAT availability in the associative striatum. 16 PD patients underwent motor and cognitive examination ON and OFF DA. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) test and executive functioning using a Stroop test. Nigrostriatal dopaminergic innervation was characterized with [123I]FP-CIT SPECT. A connectivity atlas of the striatum was used to assess DAT availability in functionally defined striatal subregions. Correlations between imaging data and behavioral data OFF medication were calculated. Correlations between DAT availability and MoCA performance in the dopaminergic OFF state was strongest in the associative part of the striatum (r = 0.674, p = 0.004). MoCA test performance did not differ between the ON and the OFF state. There was no correlation of DAT availability with Stroop performance in the OFF state but performance was significantly better during the ON state. Not only motor but also cognitive dysfunctions in PD are associated with striatal dopaminergic depletion. Cognitive decline in non-demented PD patients goes along with nigrostriatal degeneration, most pronounced in the associative subdivision of the striatum. In addition, the present findings suggest that executive dysfunctions are ameliorated by DA whereas global cognition is not improved by dopaminergic medication. PMID- 28643102 TI - Post-operative rotator cuff integrity, based on Sugaya's classification, can reflect abduction muscle strength of the shoulder. AB - PURPOSE: Magnetic resonance (MR) imaging is common in structural and qualitative assessment of the rotator cuff post-operatively. Rotator cuff integrity has been thought to be associated with clinical outcome. The purpose of this study was to evaluate the inter-observer reliability of cuff integrity (Sugaya's classification) and assess the correlation between Sugaya's classification and the clinical outcome. It was hypothesized that Sugaya's classification would show good reliability and good correlation with the clinical outcome. METHODS: Post operative MR images were taken two years post-operatively, following arthroscopic rotator cuff repair. For assessment of inter-rater reliability, all radiographic evaluations for the supraspinatus muscle were done by two orthopaedic surgeons and one radiologist. Rotator cuff integrity was classified into five categories, according to Sugaya's classification. Fatty infiltration was graded into four categories, based on the Fuchs' classification grading system. Muscle hypotrophy was graded as four grades, according to the scale proposed by Warner. The clinical outcome was assessed according to the constant scoring system pre operatively and 2 years post-operatively. RESULTS: Of the sixty-two consecutive patients with full-thickness rotator cuff tears, fifty-two patients were reviewed in this study. These subjects included twenty-three men and twenty-nine women, with an average age of fifty-seven years. In terms of the inter-rater reliability between orthopaedic surgeons, Sugaya's classification showed the highest agreement [ICC (2.1) = 0.82] for rotator cuff integrity. The grade of fatty infiltration and muscle atrophy demonstrated good agreement, respectively (0.722 and 0.758). With regard to the inter-rater reliability between orthopaedic surgeon and radiologist, Sugaya's classification showed good reliability [ICC (2.1) = 0.70]. On the other hand, fatty infiltration and muscle hypotrophy classifications demonstrated fair and moderate agreement [ICC (2.1) = 0.39 and 0.49]. Although no significant correlation was found between overall post operative constant score and Sugaya's classification, Sugaya's classification indicated significant correlation with the muscle strength score. CONCLUSIONS: Sugaya's classification showed repeatability and good agreement between the orthopaedist and radiologist, who are involved in the patient care for the rotator cuff tear. Common classification of rotator cuff integrity with good reliability will give appropriate information for clinicians to improve the patient care of the rotator cuff tear. This classification also would be helpful to predict the strength of arm abduction in the scapular plane. LEVEL OF EVIDENCE: IV. PMID- 28643103 TI - Patient age as a preoperative factor associated with tunnel enlargement following double-bundle anterior cruciate ligament reconstruction using hamstring tendon autografts. AB - PURPOSE: A few studies have detected associations of post-operative tunnel enlargement with sex, age, and the timing of anterior cruciate ligament reconstruction (ACLR). The aim of the present study was to investigate the correlation between post-operative tunnel enlargement following ACLR using hamstring tendon autografts and preoperative factors. The authors hypothesized that tunnel enlargement is associated with age in patients undergoing ACLR. METHODS: One hundred and six patients (male, n = 57; female, n = 49; mean age, 26.9 years) who underwent double-bundle ACL reconstruction were included in the present study. The time between injury and surgery was 26.3 +/- 71.4 weeks. Computed tomographic scans of the operated knee were obtained at 2 weeks and 6 months after surgery. The area of the tunnel aperture was measured for the femoral anteromedial tunnel (FAMT), femoral posterolateral tunnel (FPLT), tibial anteromedial tunnel (TAMT), and tibial posterolateral tunnel. The percentage of tunnel area enlargement was defined as the area at 2 weeks after ACLR subtracted from the area at 6 months after ACLR and then divided by the area at 2 weeks after ACLR. Spearman's correlation coefficient was calculated for each factor. The patients were divided into two groups based on age. Patients aged <40 and >=40 years were assigned to Groups A and B, respectively. The differences in the outcomes and characteristics of the two groups were evaluated. RESULTS: The percentage of enlargement of the FAMT, FPLT, and TAMT was correlated with patient age (r = 0.31, p = 0.001; r = 0.24, p = 0.012; and r = 0.30, p = 0.002, respectively). In total, 87 and 19 knees were classified into Groups A and B, respectively, based on patient age. The percentage of enlargement of the FAMT was significantly higher in Group B than A (78 vs. 60%, respectively; p = 0.01). The percentage of enlargement of the TAMT was significantly higher in Group B than A (53 vs. 36%, respectively; p = 0.03). CONCLUSION: The percentage of enlargement of the FAMT and TAMT was associated with patient age. These findings suggest the need to consider the possibility of tunnel enlargement when double-bundle ACLR is performed for patients aged >40 years. Age was a preoperative factor associated with tunnel enlargement. LEVEL OF EVIDENCE: III. PMID- 28643104 TI - [Endovenous ablation versus open surgery for varicose veins : An attempt at an evaluation]. AB - Open and endovenous surgery of varicose veins provides an excellent way to treat varicose veins. However, there are great differences in the how the techniques are performed. No matter which procedure is carried out, there are standards that should be observed. The state of the art of open venous surgery with radical crossectomy is well-known, but unfortunately is still not always performed correctly nowadays. The state of the art of endovenous surgery has unfortunately not yet been sufficiently documented, but should be based on open-surgical techniques. How the standard of both methods today is (or should be) is described in detail in this work. A recurrence definition which applies to both techniques, is set up. PMID- 28643105 TI - Differential role of GABAA receptors and neuroligin 2 for perisomatic GABAergic synapse formation in the hippocampus. AB - Perisomatic GABAergic synapses onto hippocampal pyramidal cells arise from two populations of basket cells with different neurochemical and functional properties. The presence of the dystrophin-glycoprotein complex in their postsynaptic density (PSD) distinguishes perisomatic synapses from GABAergic synapses on dendrites and the axon-initial segment. Targeted deletion of neuroligin 2 (NL2), a transmembrane protein interacting with presynaptic neurexin, has been reported to disrupt postsynaptic clustering of GABAA receptors (GABAAR) and their anchoring protein, gephyrin, at perisomatic synapses. In contrast, targeted deletion of Gabra2 disrupts perisomatic clustering of gephyrin, but not of alpha1-GABAAR, NL2, or dystrophin/dystroglycan. Unexpectedly, conditional deletion of Dag1, encoding dystroglycan, selectively prevents the formation of perisomatic GABAergic synapses from basket cells expressing cholecystokinin. Collectively, these observations suggest that multiple mechanisms regulate formation and molecular composition of the GABAergic PSD at perisomatic synapses. Here, we further explored this issue by investigating the effect of targeted deletion of Gabra1 and NL2 on the dystrophin glycoprotein complex and on perisomatic synapse formation, using immunofluorescence analysis with a battery of GABAergic pre- and postsynaptic markers. We show that the absence of alpha1-GABAAR increases GABAergic synapses containing the alpha2 subunit, without affecting the clustering of dystrophin and NL2; in contrast, the absence of NL2 produces highly variable effects postsynaptically, not restricted to perisomatic synapses and being more severe for the GABAAR subunits and gephyrin than dystrophin. Altogether, the results confirm the importance of NL2 as organizer of the GABAergic PSD and unravel distinct roles for alpha1- and alpha2-GABAARs in the formation of GABAergic circuits in close interaction with the dystrophin-glycoprotein complex. PMID- 28643106 TI - [New (and old) aspects of retroperitoneal fibrosis]. AB - Retroperitoneal fibrosis (RPF) is an uncommon chronic inflammatory disease of the rear abdomen and it is commonly associated with the complication of uni- or bilateral hydronephrosis. Despite the rarity of this disease, multiple publications concerning etiology, diagnosis, therapy monitoring and both medical and surgical therapy have been published in recent years. Recent research has focused on asbestos exposure as a possible risk factor, the meaning of IgG4 associated RPF, measuring disease activity using different radiological and nuclear medicine procedures, and new approaches to medical therapy. Goals of treatment were characterized as the correct diagnosis, preservation of renal function and freedom from stents, steroids and pain. On the basis of these goals, the most important insights and developments of the last 5 years regarding RPF are presented. PMID- 28643107 TI - [Microscopic hematuria : Reasonable and risk-adapted diagnostic evaluation]. AB - BACKGROUND: Microscopic hematuria that is not explained by an obvious underlying condition is a frequent and often an incidental finding that commonly triggers urological or nephrological evaluation. Potential underlying conditions range from benign to severe malignant diseases of the kidneys and urinary tract. MATERIALS AND METHODS: A nonsystematic literature search was performed, focusing on potential urological and nephrological causes of hematuria. National and international guidelines were considered and diagnostic as well as follow-up strategies are discussed. We provide a recommendation for practices in the clinical evaluation of hematuria. RESULTS: The overall prevalence for microscopic hematuria is estimated at approximately 2%, whereas risk populations show an increase to around 30%. In 13-35% of patients presenting with microscopic hematuria, a medical or surgical intervention is required. Malignant tumors of the kidneys or urinary tract can be diagnosed in 2.6-4% of all patients and in up to 25.8% of at-risk populations. "Idiopathic microscopic hematuria" without an obvious underlying medical condition accounts for approximately 80% of patients with asymptomatic hematuria. After exclusion of nephrological diseases, standard diagnostic procedures by means of medical history, physical and laboratory examination as well as ultrasound of the kidneys and the urinary tract should be performed. In the presence of risk factors, an extended diagnostic work-up using cystoscopy, urinary cytology, and cross-sectional imaging of the upper urinary tract is indicated. CONCLUSION: Evidence-based strategies of a risk-adapted diagnostic evaluation for microscopic hematuria are not available. The development of reliable clinical and molecular markers offers great potential for the identification of patients at higher risk for harboring severe diseases. PMID- 28643108 TI - Integrated TK-TD modeling for drug-induced concurrent tachycardia and QT changes in beagle dogs. AB - Drug-induced cardiotoxicity, including tachycardia and QT prolongation, remains a major safety concern that needs to be identified and its risk mitigated in early stages of drug development. In the present study, an integrated toxicokinetic toxicodynamic (TK-TD) modeling approach within a nonlinear mixed-effect modeling framework is applied to investigate concurrent abnormal heart rate and QT changes in three beagle dogs, using a Novartis internal compound (NVS001) as the case example. By accounting for saturable drug absorption, circadian rhythms, drug effect tolerance, and nonlinear rate-dependency of QT interval, the dynamic TK-TD model captures the experimentally observed drug effects on heart rate and QT interval across a wide dosing range of NVS001 in beagle dogs. Further analyses reveal that the NVS001-induced QT prolongation observed in the low-dose groups is potentially caused by direct drug inhibition on the hERG channel, while the apparent QT shortening in the high-dose groups may be due to strong rate dependency of QT at high heart rates. This study also suggests that the TK-TD model can be used to identify direct drug effects on the non-rate-dependent QT component by dissociating QT changes from tachycardia and deriving a new QT correction method. The integrated TK-TD model presented here may serve as a novel quantitative framework for evaluating drug-induced concurrent changes in heart rate and QT to potentially facilitate preclinical and clinical safety studies. PMID- 28643109 TI - Racial differences in the effects of comorbidity on breast cancer-specific survival. AB - PURPOSE: In an effort to explain racial disparities in breast cancer survival, this study aimed to investigate how comorbidity affects breast cancer-specific mortality by race. METHODS: A retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results-Medicare linked data including 68,090 women 66+ years, who were diagnosed with stage I-III breast cancer in the United States from 1994 to 2004. Hospital and outpatient claims from the year prior to breast cancer diagnosis were used to identify comorbid conditions and patients were followed for survival through 2010. RESULTS: Competing risk survival analysis failed to demonstrate any negative comorbidity effects on breast cancer specific survival for black women. An increased breast cancer-specific mortality hazard was observed for white women who had diabetes without complication relative to white women without this condition after adjusting for age and year of diagnosis (hazard ratio: 1.22, 95% confidence interval 1.13, 1.30). The Cochran-Armitage Test showed diabetes was associated with a later stage of diagnosis (p < 0.01) and a more aggressive tumor grade (p < 0.01) among white women in the study population. CONCLUSION: Race specific comorbidity effects do not explain breast cancer-specific survival disparities. However, the relationship between diabetes and breast cancer, including the role of aggressive tumor characteristics, warrants special attention. PMID- 28643110 TI - Refugee children's sandplay narratives in immigration detention in Canada. AB - Asylum seeking children arriving in Canada regularly face incarceration in medium security-style immigration detention centres. Research demonstrates the human cost of detaining migrant children and families and the psychiatric burden linked with such imprisonment. This study aims to understand the lived experiences of children aged 3-13 held in detention. Informed by a qualitative methodology of narrative inquiry, child participants created worlds in the sand and generated stories to express their subjective experience. Results suggest that children's sandplay confirms the traumatic nature of immigration detention while also revealing children's sometimes conflicting understanding of the meaning of detention and their own migration. The results are contextualized by a description of detention conditions and the psychiatric symptoms associated with immigration incarceration. The study highlights the need for more research examining the impact of immigration detention on children's mental health, while also underlining how refugee children's voices provide important direction for policy change. PMID- 28643111 TI - Thymic carcinoma initially presented with geographic destruction of scapula in a child. AB - As the conventional histopathologic examination of thymic carcinoma (TC) is nonspecific, immunohistochemical studies along with correlative radiographic investigations are needed for its correct diagnosis. TC commonly occurs in the late 5th to early 6th decades of life but is extremely rare in childhood. It may be incidentally detected from chest radiographs taken as routine or for other reasons. However, most patients present with symptoms such as chest pain, cough, shortness of breath, dysphagia and hoarseness, which are directly attributable to the mediastinal mass. Although TC frequently invades the neighboring organs, pleura and pericardium and metastasizes to the lymph nodes, liver and lung at the time of the first diagnosis, initial or late metastasis to the bone has been seldom reported in adults. Indeed, the English literature revealed no earlier report on initial bony metastasis in a child to date. We report a case of TC in a 12-year-old boy who initially presented with scapular osteolysis masquerading as a primary bone tumor to emphasize the usefulness of combined imaging for staging and histologic studies, particularly for such an unexpected case. PMID- 28643113 TI - [Safety culture in orthopedics and trauma surgery : Course concept: interpersonal competence by the German Society for Orthopaedics and Trauma (DGOU) and Lufthansa Aviation Training]. AB - Patient safety has become a central and measurable key factor in the routine daily medical practice. The human factor plays a decisive role in safety culture and has moved into focus regarding the reduction of treatment errors and undesired critical incidents. Nonetheless, the systematic training in communication and interpersonal competences has so far only played a minor role. The German Society of Orthopaedics and Trauma (DGOU) in cooperation with the Lufthansa Aviation Training initiated a course system for interpersonal competence. Several studies confirmed the reduction of critical incidents and costs after implementation of a regular and targeted human factor training. The interpersonal competence should be an essential component of specialist training within the framework of a 3-column model. PMID- 28643112 TI - A retrospective study of antibiotic de-escalation in patients with ventilator associated pneumonia in Malaysia. AB - Background Antibiotic de-escalation is an important strategy to conserve the effectiveness of broad-spectrum antibiotics. However, the outcome of this strategy for the treatment of ventilator-associated pneumonia (VAP) has not been widely studied in developing countries. Objectives To evaluate the outcome on intensive care unit (ICU) mortality, 28 days mortality, and length of ICU stay among VAP patients who receive de-escalation therapy. Setting This study was conducted in an ICU of a Malaysian public hospital. Method The electronic medical records of patients who developed VAP in the ICU were retrieved and relevant data was collected. Records of antibiotic prescriptions were also reviewed to collect the details of changes to antibiotic therapy (de-escalation). Main outcome measure Impact of antibiotic de-escalation on mortality. Results The mean age of the 108 patients was 46.2 +/- 18.2 years; the majority being males (80%). The antibiotic de-escalation rate was about 30%. Out of this, 84% involved a change from broad to narrow-spectrum antibiotics and the remaining, withdrawal of one or more antibiotics. ICU mortality was 23% while 28 days mortality was 37%. There was no statistically significant difference in mortality rate, survival probability and the mean length of ICU stay between the de-escalation and the non de-escalation group. However, patients with Simplified Acute Physiology Score II of >=50 were significantly associated with ICU mortality and 28 days mortality. Conclusions In VAP patients, antibiotic de-escalation provides an opportunity to promote the judicious use of antibiotics without affecting the clinical outcomes. PMID- 28643115 TI - New ERP Methods Tailored Onto Single Subject Neuroanatomical Variability. AB - Gebodh and coworkers present an innovative method for strengthening the reliability with which event-related potential (ERP) components are recorded. By tailoring the experimental design to the neuroanatomical singularity of each observer, this method provides more robust and cleaner data. PMID- 28643114 TI - Synergistic cardioprotective effects of rAAV9-CyclinA2 combined with fibrin glue in rats after myocardial infarction. AB - The present study aimed to investigate the protective effects of rAAV9-CyclinA2 combined with fibrin glue (FG) in vivo in rats after myocardial infarction (MI). Ninety male Sprague-Dawley rats were randomized into 6 groups (15 in each group): sham, MI, rAAV9-green fluorescent protein (GFP) + MI, rAAV9-CyclinA2 + MI, FG + MI, and rAAV9-CyclinA2 + FG + MI. Packed virus (5 * 1011vg/ml) in 150 ul of normal saline or FG was injected into the infarcted myocardium at five locations in rAAV9-GFP + MI, rAAV9-CyclinA2 + MI, and rAAV9-CyclinA2 + FG + MI groups. The sham, MI, and FG + MI groups were injected with an equal volume of normal saline or FG at the same sites. Five weeks after injection, echocardiography was performed to evaluate the left ventricular function. The expressions of CyclinA2, proliferating cell nuclear antigen (PCNA), and phospho-histone-H3 (H3P), vascular density, and infarct area were assessed by Western blot, immunohistochemistry, immunofluorescence, and Masson staining. As a result, the combination of rAAV9 CyclinA2 and FG increased ejection fraction and fractional shortening compared with FG or rAAV9-CyclinA2 alone. The expression level of CyclinA2 was significantly higher in the rAAV9-CyclinA2 + FG + MI group compared with the rAAV9-CyclinA2 + MI and FG + MI groups (70.1 +/- 1.86% vs. 14.74 +/- 2.02%, P < 0.01; or vs. 50.13 +/- 3.80%; P < 0.01). A higher expression level of PCNA and H3P was found in the rAAV9-CyclinA2 + FG + MI group compared with other groups. Comparing with other experiment groups, collagen deposition and the infarct size significantly decreased in rAAV9-CyclinA2 + Fibrin + MI group. The vascular density was much higher in the rAAV9-CyclinA2 + FG + MI group compared with the rAAV9-CyclinA2 + MI group. We concluded that fibrin glue combined with rAAV9 CyclinA2 was found to be effective in cardiac remodeling and improving myocardial protection. PMID- 28643116 TI - Express yourself: how PP2A-B55Pab1 helps TORC1 talk to TORC2. AB - The control of cell fate, growth and proliferation in response to nitrogen availability is a tightly controlled process, with the two TOR complexes (TORC1 and TORC2) and their effectors playing a central role. PP2A-B55Pab1 has recently been shown to be a key element in this response in fission yeast, where it regulates cell cycle progression and sexual differentiation. Importantly, a recent study from our group has shown that PP2A-B55Pab1 acts as a mediator between the activities of the two TOR signaling modules, enabling a crosstalk that is required to engage in the differentiation program. In this review, we recapitulate the studies that have led to our current understanding of the interplay between TOR complexes. Moreover, we discuss several aspects of the response to nitrogen availability that still require further attention, and which will be important in the future to fully realize the implications of phosphatase activity in the context of TOR signaling. PMID- 28643118 TI - Comparison of photon organ and effective dose coefficients for PIMAL stylized phantom in bent positions in standard irradiation geometries. AB - Computational phantoms with articulated arms and legs have been constructed to enable the estimation of radiation dose in different postures. Through a graphical user interface, the Phantom wIth Moving Arms and Legs (PIMAL) version 4.1.0 software can be employed to articulate the posture of a phantom and generate a corresponding input deck for the Monte Carlo N-Particle (MCNP) radiation transport code. In this work, photon fluence-to-dose coefficients were computed using PIMAL to compare organ and effective doses for a stylized phantom in the standard upright position with those for phantoms in realistic work postures. The articulated phantoms represent working positions including fully and half bent torsos with extended arms for both the male and female reference adults. Dose coefficients are compared for both the upright and bent positions across monoenergetic photon energies: 0.05, 0.1, 0.5, 1.0, and 5.0 MeV. Additionally, the organ doses are compared across the International Commission on Radiological Protection's standard external radiation exposure geometries: antero posterior, postero-anterior, left and right lateral, and isotropic (AP, PA, LLAT, RLAT, and ISO). For the AP and PA irradiation geometries, differences in organ doses compared to the upright phantom become more profound with increasing bending angles and have doses largely overestimated for all organs except the brain in AP and bladder in PA. In LLAT and RLAT irradiation geometries, energy deposition for organs is more likely to be underestimated compared to the upright phantom, with no overall change despite increased bending angle. The ISO source geometry did not cause a significant difference in absorbed organ dose between the different phantoms, regardless of position. Organ and effective fluence-to dose coefficients are tabulated. In the AP geometry, the effective dose at the 45 degrees bent position is overestimated compared to the upright phantom below 1 MeV by as much as 27% and 82% in the 90 degrees position. The effective dose in the 45 degrees bent position was comparable to that in the 90 degrees bent position for the LLAT and RLAT irradiation geometries. However, the upright phantom underestimates the effective dose to PIMAL in the LLAT and RLAT geometries by as much as 30% at 50 keV. PMID- 28643117 TI - Children's family experiences: development of the PROMIS(r) pediatric family relationships measures. AB - PURPOSE: To describe the development of pediatric family relationships measures, with versions for child self-report (8-17 years) and parent-report for children 5 17 years old. Measures were created for integration into the Patient Reported Outcomes Measurement Information System (PROMIS(r)). METHODS: Semi-structured interviews with 10 experts, 24 children, and 8 parents were conducted to elicit and clarify essential elements of family relationships. A systematic literature review was conducted to identify item concepts representative of each element. The concepts were transformed into items that were iteratively revised based on cognitive interviews (n = 43 children) and item translatability review. Psychometric studies involving 2846 children and 2262 parents were conducted to further refine and validate the instruments. RESULTS: Qualitative procedures supported the development of content valid Family Relationships item banks. Final child- and parent-report item banks each contain 47 items. Unidimensional item banks were calibrated using IRT-modeling to estimate item parameters representative of the US population and to enable computerized adaptive test administration. Four- and eight-item short forms were constructed for standard fixed format administration. All instruments have strong internal consistency, retest-reliability, and provide precise estimates of various levels of family relationship quality. Preliminary evidence of the instruments' validity was provided by known-group comparisons and convergence with legacy measures. CONCLUSION: The PROMIS pediatric Family Relationships measures can be applied in research focused on determinants, outcomes, and the protective effects of children's subjective family relationship experiences. PMID- 28643119 TI - Home-based versus center-based aerobic exercise on cardiopulmonary performance, physical function, quality of life and quality of sleep of overweight patients with chronic kidney disease. AB - BACKGROUND: The association between chronic kidney disease (CKD) and obesity can decrease the patients' cardiopulmonary capacity, physical functioning and quality of life. The search for effective and practical alternative methods of exercise to engage patients in training programs is of great importance. Therefore, we aimed to compare the effects of home-based versus center-based aerobic exercise on the cardiopulmonary and functional capacities, quality of life and quality of sleep of overweight non-dialysis-dependent patients with CKD (NDD-CKD). METHODS: Forty sedentary overweight patients CKD stages 3 and 4 were randomly assigned to an exercise group [home-based group (n = 12) or center-based exercise group (n = 13)] or to a control group (n = 15) that did not perform any exercise. Cardiopulmonary exercise test, functional capacity tests, quality of life, quality of sleep and clinical parameters were assessed at baseline, 12 and 24 weeks. RESULTS: The VO2peak and all cardiopulmonary parameters evaluated were similarly improved (p < 0.05) after 12 and 24 weeks in both exercise groups. The functional capacity tests improved during the follow-up in the home-based group (p < 0.05) and reached values similar to those obtained in the center-based group. The benefits achieved in both exercise groups were also reflected in improvement of quality of life and sleep (p < 0.05). No differences were observed between the exercise groups, and no changes in any of the parameters investigated were found in the control group. CONCLUSION: Home-based aerobic training was as effective as center-based training in improving the physical and functional capabilities, quality of life and sleep in overweight NDD-CKD patients. PMID- 28643121 TI - A Study on the Expression of Genes Involved in Carotenoids and Anthocyanins During Ripening in Fruit Peel of Green, Yellow, and Red Colored Mango Cultivars. AB - Mango (Mangiferaindica L.) fruits are generally classified based on peel color into green, yellow, and red types. Mango peel turns from green to yellow or red or retain green colors during ripening. The carotenoids and anthocyanins are the important pigments responsible for the colors of fruits. In the present study, peels of different colored cultivars at three ripening stages were characterized for pigments, colors, and gene expression analysis. The yellow colored cultivar "Arka Anmol" showed higher carotenoid content, wherein beta-carotene followed by violaxanthin were the major carotenoid compounds that increased during ripening. The red colored cultivars were characterized with higher anthocyanins with cyanidin-3-O-monoglucosides and peonidin-3-O-glucosides as the major anthocyanins. The gene expression analysis by qRT-PCR showed the higher expression of carotenoid biosynthetic genes viz. lycopene-beta-cyclase and violaxanthin-de-epoxidase in yellow colored cv. Arka Anmol, and the expression was found to increase during ripening. However, in red colored cv. "Janardhan Pasand," there is increased regulation of all anthocyanin biosynthetic genes including transcription factors MYB and basic helix loop. This indicated the regulation of the anthocyanins by these genes in red mango peel. The results showed that the accumulation pattern of particular pigments and higher expression of specific biosynthetic genes in mango peel impart different colors. PMID- 28643120 TI - The incidence of the nephrotic syndrome in childhood in Germany. AB - BACKGROUND: The incidence of childhood nephrotic syndrome (NS) in Germany is not well known. METHODS: An ESPED-based nationwide collection of epidemiological data of children in 2005 and 2006. RESULT: The mean age of NS at onset was 5.5 +/- 3.7 years. The gender ratio of boys to girls was 1.8:1. The average length of stay was 15.5 +/- 11.2 days, with younger children remaining significantly longer in hospital. Steroid-resistance was more common in children >=8 years (p = 0.023). Focal-segmental glomerulosclerosis (FSGS) was more common in children >10 years (p = 0.029). The ratio of males to females with FSGS was 1:1.9, thus the FSGS risk for girls at onset was 3.3-times greater. Considering the available data, the incidence of NS in Germany is 1.2/100,000 in the population <18 years, of which 1.0/100,000 are steroid-sensitive. CONCLUSION: Compared with international data, which primarily focused on regional and small populations, this is the largest study about the incidence of the childhood NS. PMID- 28643122 TI - Symbiotic performance and induction of systemic resistance against Cercospora sojina in soybean plants co-inoculated with Bacillus sp. CHEP5 and Bradyrhizobium japonicum E109. AB - Soybean is an economically very important crop throughout the word and particularly in Argentina. Soybean yield may be affected by many factors such as the lack of some essential nutrients or pathogens attack. In this work we demonstrated that the co-inoculation of the native biocontrol bacterium Bacillus sp. CHEP5 which induces resistance against Cercospora sojina in soybean and the nitrogen fixing strain Bradyrhizobium japonicum E109, was more effective in reducing frog leaf spot severity than the inoculation of the biocontrol agent alone. Probably, this is related with the increase in the ability to form biofilm when both bacteria are growing together. Furthermore, Bacillus sp. CHEP5 inoculation did not affect Bradyrhizobium japonicum E109 symbiotic behavior and flavonoids composition of root exudates in pathogen challenged plants. These results suggest that co-inoculation of plants with rhizobia and biocontrol agents could be a strategy to improve soybean production in a sustainable system. PMID- 28643123 TI - Study of the interactions of dissolved organic matter with zinc ion and the impact of competitive metal ions (Ca2+ and Mg2+) by in situ absorbance. AB - The bioavailability and toxicity of zinc to aquatic life depend on dissolved organic matter (DOM), such as Suwannee River Fulvic Acid (SRFA), which plays an important role in the speciation of zinc. This study examined reactions of SRFA with zinc at different concentrations from pH 3.0 to 9.0, and competitive binding of calcium/magnesium and zinc to SRFA at pH 6.0, using in situ absorbance. Interactions of Zn2+ with SRFA chromophores were evidenced by the emergence of features in Zn-differential spectra. Among all Zn2+-SRFA systems, dominant peaks, located at 235, 275 and 385 nm, and the highest intensity at 235 nm indicated the replacement of protons by the bound Zn2+. The Zn2+ binding with SRFA could be quantified by calculating the changes of the slopes of Zn-differential log transformed absorbance in the wavelength range of 350-400 nm (denoted as DS350 400) and by comparing the experimental data with predictions using the Non-Ideal Competitive Adsorption (NICA-Donnan) model. DS350-400 was correlated well with the bound Zn2+ concentrations predicted by NICA-Donnan model with or without Ca2+ or Mg2+. Ca2+ and Mg2+ only affect intensity of the Zn-differential and Zn differential log-transformed absorbance, not shape. In situ absorbance can be used to gain further information about Men+-DOM interactions in the presence of various metals. PMID- 28643124 TI - [Solid pediatric tumors : A brief survey of the rarity cabinet]. AB - Solid tumors in childhood are extremely rare entities, which are usually treated in specialized centers. Diagnosis and therapy are carried out according to a joint European protocol, whereby the pathological evaluation and therapy are carried out according to international guidelines. For the correct diagnosis and/or therapy of most tumors, analysis of specific genetic changes is mandatory; therefore, tumors have to be adequately sampled for parallel genetic analysis during the pathological work-up. A second opinion reference of the histopathological assessment is part of the international guidelines. Neuroblastomas, congenital mesoblastic nephromas and rhabdoid tumors are examples of solid tumors in childhood that are not restricted to one organ and occur exclusively during childhood. PMID- 28643125 TI - The role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 triple-negative breast cancer cells. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is often overexpressed in triple-negative breast cancer (TNBC). However, clinical studies have shown that therapies against EGFR are not effective in patients with TNBC. Recently, it has been reported that arginine 198/200 in EGFR extracellular domain is methylated by PRMT1 and that the methylation confers resistance to EGFR monoclonal antibody cetuximab in colorectal cancer cells. To explore a potential mechanism underlying intrinsic resistance to anti-EGFR therapy in TNBC, we investigated the role of PRMT1 in EGFR methylation and signaling in MDA-MB-468 (468) TNBC cells. METHODS: We knocked down PRMT1 in 468 cells by shRNA, and subjected the cell lysates to Western blot analysis to examine EGFR activation and its downstream molecules. We also evaluated cell proliferation and sphere formation of PRMT1-knockdown cells. Finally, we examined the effects of pan-PRMT inhibitor, AMI-1, on cetuximab by colony formation and soft agar assays. RESULTS: EGFR methylation and activity was significantly reduced in PRMT1-knockdown cells compared to the parental cells. Knockdown of PRMT1 also reduced cell proliferation and sphere formation. Moreover, AMI-1 sensitized 468 cells to cetuximab. CONCLUSION: The results indicate that PRMT1 is critical for EGFR activity in 468 cells. Our data also suggest that inhibition of PRMT1 sensitizes TNBC cells to cetuximab. Thus, inhibition of PRMT1 may be an effective therapeutic strategy to overcome intrinsic resistance to cetuximab in TNBC. PMID- 28643126 TI - Cancer Stem Cells in Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma is one of the most common cancers and the second leading cause of cancer-related deaths worldwide. Only a small proportion of patients benefit from curative treatment and the prognosis is very poor for the majority of cases due to late presentation, resistance to chemotherapy and high recurrence rate. In recent years, progress in stem cell biology allowed us to explain that hierarchically organized cancer stem cells (CSCs) drive histological and functional heterogeneity of hematological malignancies and solid tumors. METHODS AND RESULTS: Also referred to as tumor-initiating cells, CSCs have been isolated from both hepatocellular carcinoma (HCC) cell lines and primary tumors by using hepatic progenitor markers. Although there is still no consensus on cancer stem cell phenotype in HCC, single or combined use of CSC markers defines a minor population of tumor cells with the capacity of self renewing and the ability to recapitulate the original tumor heterogeneity. CONCLUSIONS: This review focuses on the biological features of CSCs and their potential as diagnostic/prognostic tools and therapeutic targets in HCC. PMID- 28643128 TI - Announcement (issue 7) July 2017. PMID- 28643127 TI - Preoperative evaluation of left common iliac vein in oblique lateral interbody fusion at L5-S1. AB - PURPOSE: Oblique lateral interbody fusion (OLIF) L5-S1 is essentially to perform an anterior lumbar interbody fusion (ALIF) in the lateral position. Because the surgical procedures are performed "obliquely" over the left common iliac vein (LCIV), ensuring that the vein is protected which is particularly important. We aimed to evaluate the configuration of LCIV and its risk of mobilization during anterior approach at L5-S1 segment. METHODS: This study involved 65 consecutive patients who underwent anterior lumbar fusion (ALIF, n = 39; OLIF, n = 26) at the L5-S1 segment. Three independent examiners evaluated the configuration of the LCIV at the L5-S1 disc on axial magnetic resonance images of the lumbar spine. The LCIV was categorized into three types according to the difficulty of mobilization: type I (no requirement for mobilization; LCIV runs laterally for more than two-thirds of the length of the left side of the L5-S1 disc), type II (easy mobilization; LCIV obstructs the L5-S1 disc space, but the perivascular adipose tissue is present under the LCIV), and type III (potentially difficult mobilization; no perivascular adipose tissue under the LCIV). The patient records were reviewed for vascular complications. RESULTS: There were 21 men and 44 women in this study, with a mean age of 63.4 years (range 19-83 years). Type I LCIV configuration was found in 32 (49.2%) patients, type II in 18 (27.7%), and type III in 15 (23.1%). There were 7 (10.8%) patients with LCIV injury (type I, n = 0; type II, n = 2; type III, n = 5) (P = 0.003). Intraobserver reliability for the LCIV classification ranged from substantial to excellent, and interobserver reliability ranged from moderate to excellent. CONCLUSIONS: Preoperative evaluation for anterior approach to the L5-S1 segment should take account of the LCIV position, as well as the difficulty of its mobilization. The type III LCIV configuration showed a high rate of vascular injury. PMID- 28643129 TI - Magnetohydrodynamic Voltage Recorder for Comparing Peripheral Blood Flow. AB - Blood flow is a clinical metric for monitoring of cardiovascular diseases but current measurements methods are costly or uncomfortable for patients. It was shown that the interaction of the magnetic field (B 0) during MRI and blood flow in the body, through the magnetohydrodynamic (MHD) effect, produce voltages (V MHD) observable through intra-MRI electrocardiography (ECG), which are correlated with regional blood flow. This study shows the reproducibility of V MHD outside the MRI and its application in a portable flow monitoring device. To recreate this interaction outside the MRI, a static neodymium magnet (0.4T) was placed in between two electrodes to induce the V MHD in a single lead ECG measurement. V MHD was extracted, and integrated over to obtain a stroke volume metric. A smartphone-enabled device utilizing this interaction was developed in order to create a more accessible method of obtaining blood flow measurements. The portable device displayed a <6% error compared to a commercial recorder, and was able to successfully record V MHD using the 0.4T magnet. Exercise stress testing showed a V MHD increase of 23% in healthy subjects, with an 81% increase in the athlete. The study demonstrates a new device utilizing MHD interactions with body circulation to obtain blood flow metrics. PMID- 28643131 TI - Strong Comma-Free Codes in Genetic Information. AB - Comma-free codes constitute a class of circular codes, which has been widely studied, in particular by Golomb et al. (Biologiske Meddelelser, Kongelige Danske Videnskabernes Selskab 23:1-34, 1958a, Can J Math 10:202-209, 1958b), Michel et al. (Comput Math Appl 55:989-996, 2008a, Theor Comput Sci 401:17-26, 2008b, Inf Comput 212:55-63, 2012), Michel and Pirillo (Int J Comb 2011:659567, 2011), and Fimmel and Strungmann (J Theor Biol 389:206-213, 2016). Based on a recent approach using graph theory to study circular codes Fimmel et al. (Philos Trans R Soc 374:20150058, 2016), a new class of circular codes, called strong comma-free codes, is identified. These codes detect a frameshift during the translation process immediately after a reading window of at most two nucleotides. We describe several combinatorial properties of strong comma-free codes: enumeration, maximality, self-complementarity and [Formula: see text]-property (comma-free property in all the three possible frames). These combinatorial results also highlight some new properties of the genetic code and its evolution. Each amino acid in the standard genetic code is coded by at least one strong comma-free code of size 1. There are 9 amino acids [Formula: see text] among 20 such that for each amino acid from S, its synonymous trinucleotide set (excluding the necessary periodic trinucleotides [Formula: see text]) is a strong comma-free code. The primeval comma-free RNY code of Eigen and Schuster (Naturwissenschaften 65:341-369, 1978) is a self-complementary [Formula: see text]-code of size 16. Furthermore, it is the union of two strong comma-free codes of size 8 which are complementary to each other. PMID- 28643130 TI - Retreatability of three calcium silicate-containing sealers and one epoxy resin based root canal sealer with four different root canal instruments. AB - OBJECTIVES: The objective of the study was to compare the retreatability of three calcium silicate-containing sealers (BioRoot RCS, MTA Fillapex, Endo C.P.M.) and an epoxy resin-based sealer (AH Plus) with different root canal instruments (Hedstrom files, Reciproc R40, Mtwo retreatment file R 25/.05 + Mtwo 40/.06, and F6 SkyTaper) concerning sealer remnants and retreatment time. MATERIALS AND METHODS: Root canals of 192 teeth were instrumented with Reciproc R40. All root canals were obturated using the single-cone technique with Reciproc R40 gutta percha and one of the sealers (n = 48 per sealer). Two months later, retreatment was performed using one of the mentioned instruments (n = 12 per instrument and sealer). The roots were split longitudinally, and both halves were investigated using light microscopy. The percentage of sealer remnants covering the root canal wall was evaluated using the software ImageJ. The time required for retreatment was recorded. Statistical analysis was performed using two-way ANOVA and Student Newman-Keuls post hoc test. RESULTS: Regarding the percentage of root canal filling remnants as well as retreatment time, two-way ANOVA indicated that the results were significantly affected by the sealer (p < 0.001) and by the instrument used (p < 0.05). Overall, the use of AH Plus was associated with significantly more remnants compared to all other sealers (p < 0.001) and F6 SkyTaper instruments allowed significantly faster retreatment than the other instruments (p < 0.05). CONCLUSION: The retreatability of calcium silicate containing sealers was better compared to AH Plus as less sealer remnants and shorter retreatment times were observed. Retreatment with engine-driven NiTi instruments was superior compared to hand instrumentation. CLINICAL RELEVANCE: Engine-driven NiTi instruments are better suited to remove root canal fillings than stainless steel Hedstrom files. PMID- 28643132 TI - Integrated Inflammatory Stress (ITIS) Model. AB - During the last decade, there has been an increasing interest in the coupling between the acute inflammatory response and the Hypothalamic-Pituitary-Adrenal (HPA) axis. The inflammatory response is activated acutely by pathogen- or damage related molecular patterns, whereas the HPA axis maintains a long-term level of the stress hormone cortisol which is also anti-inflammatory. A new integrated model of the interaction between these two subsystems of the inflammatory system is proposed and coined the integrated inflammatory stress (ITIS) model. The coupling mechanisms describing the interactions between the subsystems in the ITIS model are formulated based on biological reasoning and its ability to describe clinical data. The ITIS model is calibrated and validated by simulating various scenarios related to endotoxin (LPS) exposure. The model is capable of reproducing human data of tumor necrosis factor alpha, adrenocorticotropic hormone (ACTH) and cortisol and suggests that repeated LPS injections lead to a deficient response. The ITIS model predicts that the most extensive response to an LPS injection in ACTH and cortisol concentrations is observed in the early hours of the day. A constant activation results in elevated levels of the variables in the model while a prolonged change of the oscillations in ACTH and cortisol concentrations is the most pronounced result of different LPS doses predicted by the model. PMID- 28643134 TI - Randomized Controlled Trial of a Volitional Help Sheet to Encourage Weight Loss in the Middle East. AB - In the Middle East, the prevalence of overweight/obesity is 80%; however, no studies have yet tested the efficacy of interventions to promote weight loss. The aim of the present study was to test the ability of implementation intentions formed using a volitional help sheet to support weight loss among people who were overweight/obese. Participants (N = 216) enrolling in a weight loss program in Kuwait were randomly allocated either to form implementation intentions using a volitional help sheet (intervention group) or to use the volitional help sheet to think about critical situations and appropriate responses but not form implementation intentions (control group). The main outcome measure was weight at 6-month follow-up. Participants in the intervention condition lost significantly more weight (6.15 kg; -6.58% initial body weight) than those in the control condition (3.66 kg; -4.04% initial body weight), M diff = 2.55% initial body weight, SE diff = .92, t(214) = 2.76, p = .006, 95%CI = .73, 4.36, d = .38. The present study is the first to show that implementation intentions work beyond a Western context and that the volitional help sheet could be used in a variety of cultural contexts to enhance weight-loss programs. PMID- 28643133 TI - Children with Elevated Psychosocial Risk Load Benefit Most from a Family-Based Preventive Intervention: Exploratory Differential Analyses from the German "Strengthening Families Program 10-14" Adaptation Trial. AB - While the effectiveness of substance use prevention programs such as the Strengthening Families Program 10-14 (SFP) has been demonstrated in the USA, European SFP adaptations have not replicated these sizable effects. Following the rationale of the risk moderation hypothesis positing that elevated risk groups may benefit more from a preventive intervention than lower-risk groups, we reanalyzed evaluation data from a randomized controlled trial testing the adapted German version of SFP (SFP-D). We hypothesized a differential impact of risk status on intervention results. The study employed a minimal control condition. Of the N = 292 participating children, 73.5% qualified as at-risk because they lived in a deprived urban district, and 26.5% qualified as high risk because they additionally scored as "difficult" in the German Strengths and Difficulty Questionnaire (parents' reports using gender- and age-specific German norms). Outcomes were children's self-reports on substance use, mental health, family functioning, and quality of life. Data were analyzed with repeated measures linear mixed models and relative risk analyses. The high-risk group in the SFP-D condition achieved the best results compared with all other groups, especially in mental health and quality of life. Relative risk analyses on tobacco [alcohol] abstinence showed that an additional percentage of 29.8% [16.0%] of high-risk children in nonabstinent controls would have remained abstinent if they had participated in SFP-D. We conclude that risk load influences the impact of substance use prevention programs and discuss to what extent differential analyses can add value to prevention research. PMID- 28643135 TI - Preoperative tumor restaging and resectability assessment of gastric cancers after chemotherapy: diagnostic accuracy of MDCT using new staging criteria. AB - PURPOSE: To evaluate the diagnostic performance of preoperative MDCT for tumor restaging and determination of resectability in gastric cancers after chemotherapy using new staging criteria. METHODS: This retrospective study was approved by our institutional review board and the requirement for informed consent was waived. Thirty-seven patients with initially unresectable gastric cancers who had received chemotherapy followed by surgery were included. Two independent radiologists reviewed preoperative MDCT images to determine the TNM staging and rate the overall likelihood of resectability using a 5-point scale (5: definitely unresectable, 1: definitely resectable). New post-chemotherapy MDCT criteria do not use non-enhancing perigastric infiltrations, non-enhancing lymph nodes (LNs), and subtle remaining infiltrations after marked decrease in the size of distant metastases for T, N, and M upstaging, respectively. Discrepancies in TNM staging were resolved by a third reviewer. The diagnostic performances of MDCT were assessed using pathologic results or operation records as reference standards. RESULTS: For predicting resectability, the areas under the ROC curve were 0.885 and 0.882 (95% CIs 0.737-0.966 and 0.733-0.964) in reviewers 1 and 2, respectively, with substantial inter-reader agreement (weighted kappa = 0.689). Sensitivities and specificities of MDCT for tumor restaging on a consensus review were 80.0% (4/5) and 100% (29/29) for T4b, 35.3% (6/17) and 81.3% (13/16) for N-positive, and 63.6% (7/11) and 100% (26/26) for M1, respectively. CONCLUSIONS: For gastric cancers after chemotherapy, new MDCT criteria demonstrated high specificities for T4b and M-staging and good performances to predict resectability before conversion surgery. PMID- 28643136 TI - Assessment of liver fibrosis in chronic hepatitis: comparison of shear wave elastography and transient elastography. AB - PURPOSE: To evaluate the diagnostic accuracy of shear wave elastography (SWE) and transient elastography (TE) in the evaluation of liver fibrosis in chronic hepatitis B (CHB) and C (CHC) patients taking liver biopsy as gold standard. METHODS: Ethics committee approved this prospective cross-sectional study. Between October 2012 and December 2014, consecutive CHB/CHC patients fulfilling the inclusion criteria were included-age more than 18 years, informed written consent, willing and suitable for liver biopsy. SWE, TE, and biopsy were performed the same day. Liver stiffness measurement (LSM) cut-offs for various stages of fibrosis were generated for SWE and TE. AUC, sensitivity, specificity, and positive/negative predictive values were estimated individually or in combination. RESULTS: CH patients (n = 240, CHB 172, CHC 68), 176 males, 64 females, mean age 32.6 +/- 11.6 years were enrolled. Mean LSM of patients with no histological fibrosis (F0) was 5.0 +/- 0.7 and 5.1+1.4 kPa on SWE and TE, respectively. For differentiating F2 and F3-4 fibrosis on SWE, at 7.0 kPa cut off, the sensitivity was 81.3% and specificity 77.6%. For TE, at 8.3 kPa cut-off, sensitivity was 81.8% and specificity 83.1%. For F3 vs. F4, SWE sensitivity was 83.3% and specificity 90.7%. At 14.8 kPa cut-off, TE showed similar sensitivity (83.3%) but specificity increased to 96.5%. Significant correlation between SWE and TE was observed (r = 0.33, p < 0.001). On combining SWE and TE, a drop in sensitivity with increased specificity for all stages of liver fibrosis occured. CONCLUSION: SWE is an accurate technique for evaluating liver fibrosis. SWE compares favorably with TE especially for predicting advanced fibrosis/cirrhosis. Combining SWE and TE further improves specificity. PMID- 28643137 TI - Radio-surgical and pathologic correlations of pelvic intravenous leiomyomatosis. AB - Intravenous leiomyomatosis has an unusual growth pattern characterized by proliferation of smooth muscle in uterine and systemic veins. Although histologically benign, this condition could eventually have a clinically aggressive course. At an early stage, the disease is often misdiagnosed on preoperative imaging because of its low prevalence, non-specific initial clinical manifestation, and poorly known radiological characteristics. An early, accurate diagnosis is needed for appropriate surgical management that could result in a good prognosis, reducing the risk of recurrence and morbidity. Magnetic resonance imaging is a particularly valuable technique for assessing intravenous leiomyomatosis preoperatively. PMID- 28643138 TI - Distinguishing gastric anisakiasis from non-anisakiasis using unenhanced computed tomography. AB - PURPOSE: This study aimed to assess the diagnostic performance of unenhanced computed tomography (CT) for distinguishing gastric anisakiasis from non anisakiasis gastric conditions and the reproducibility of CT findings. METHODS: Fifty-six anisakiasis and 74 non-anisakiasis cases with gastric wall thickening on urgent observation using unenhanced CT were included. Using a kappa analysis, two radiologists independently assessed the reproducibility of CT findings, including "circumferential gastric wall thickening," "gastric wall thickening extending more than two segments," "bulky and low-density gastric wall thickening," "increase in peri-gastric fat density," and "ascites." An anisakiasis diagnostic score (ADS) was developed for this study and was used to quantitatively evaluate the CT findings. An anisakiasis diagnostic prediction (ADP) with an appropriate cutoff value was used to further evaluate the ADS. Two radiologists reassessed the findings in consensus to determine the sensitivity, specificity, and accuracy of the CT findings, including the ADP and ADS area under the curve (AUC). RESULTS: Considering reproducibility, a substantial agreement (0.6 < kappa < 0.8) was achieved for all findings except "circumferential gastric wall thickening" (kappa = 0.499), whereas for diagnostic performance, all findings except ascites were significantly more frequent among the anisakiasis cases. "Bulky and low-density gastric wall thickening" had the highest sensitivity (98%), whereas "gastric wall thickening extending more than two segments" had the highest specificity (80%). The ADP sensitivity, specificity, and accuracy were 91%, 84%, and 87%, respectively. The AUC was 0.902 (p < 0.05). CONCLUSIONS: Unenhanced CT findings are useful for distinguishing anisakiasis from non-anisakiasis gastric conditions with sufficient reproducibility. PMID- 28643140 TI - Evidence-Based Metrics and Other Multidimensional Considerations in Promotion or Tenure Evaluations in Academic Psychiatry. PMID- 28643141 TI - Estimation of the effective yield properties of human trabecular bone using nonlinear micro-finite element analyses. AB - Micro-finite element ([Formula: see text]FE) analyses are often used to determine the apparent mechanical properties of trabecular bone volumes. Yet, these apparent properties depend strongly on the applied boundary conditions (BCs) for the limited size of volumes that can be obtained from human bones. To attenuate the influence of the BCs, we computed the yield properties of samples loaded via a surrounding layer of trabecular bone ("embedded configuration"). Thirteen cubic volumes (10.6 mm side length) were collected from [Formula: see text]CT reconstructions of human vertebrae and femora and converted into [Formula: see text]FE models. An isotropic elasto-plastic material model was chosen for bone tissue, and nonlinear [Formula: see text]FE analyses of six uniaxial, shear, and multi-axial load cases were simulated to determine the yield properties of a subregion (5.3 mm side length) of each volume. Three BCs were tested. Kinematic uniform BCs (KUBCs: each boundary node is constrained with uniform displacements) and periodicity-compatible mixed uniform BCs (PMUBCs: each boundary node is constrained with a uniform combination of displacements and tractions mimicking the periodic BCs for an orthotropic material) were directly applied to the subregions, while the embedded configuration was achieved by applying PMUBCs on the larger volumes instead. Yield stresses and strains, and element damage at yield were finally compared across BCs. Our findings indicate that yield strains do not depend on the BCs. However, KUBCs significantly overestimate yield stresses obtained in the embedded configuration (+43.1 +/- 27.9%). PMUBCs underestimate (-10.0 +/- 11.2%), but not significantly, yield stresses in the embedded situation. Similarly, KUBCs lead to higher damage levels than PMUBCs (+51.0 +/- 16.9%) and embedded configurations (+48.4 +/- 15.0%). PMUBCs are better suited for reproducing the loading conditions in subregions of the trabecular bone and deliver a fair estimation of their effective (asymptotic) yield properties. PMID- 28643139 TI - Cysteamine revisited: repair of arginine to cysteine mutations. AB - Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides "proof of principle" that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH, and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since, in general, Arg to Cys changes comprise about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases. PMID- 28643143 TI - Egg Parasitoid Complex of the Corn Leafhopper, Dalbulus maidis (DeLong) (Hemiptera: Cicadellidae), in Argentina. AB - The corn leafhopper, Dalbulus maidis (DeLong), is the most important leafhopper pest of maize, Zea mays, in the Americas. A survey of the diversity of its egg parasitoids was carried out in northwestern Argentina. During summer from 2004 to 2007, the samples were collected, using sentinel eggs of D. maidis on corn leaves, exposed in 48 cornfields. Sixteen species belonging to four families of Chalcidoidea (Hymenoptera) were identified. Among the parasitoid groups, Trichogrammatidae was the most represented family with eight species, followed by Mymaridae with six species. The mymarid Anagrus incarnatus Haliday and the trichogrammatid Pseudoligosita longifrangiata (Viggiani) were the most abundant and frequent parasitoids. The mean percentage of parasitism of D. maidis eggs was 16.4% and varied greatly among the sites, ranging from 0 to 56.7%; generally, it was higher in Yungas and lower in Monte province sites. The species richness was higher in the localities within the Yungas, with 13 parasitoid species, of which two species were dominant, comprising 83.6% of the collected individuals. Monte was the province that showed the highest diversity index (H' = 1.62). In addition, we present information on the distribution, known host associations of each parasitoid species and an identification key to all species of egg parasitoids of D. maidis in Argentina. PMID- 28643142 TI - Temporal discounting of aversive consequences in rats. AB - Previous research has extensively evaluated the impact of delay on the value of positive reinforcers, but the study of its impact on the value of aversive consequences is scarce. The present study employed a modification of Evenden and Ryan's procedure (1996, Psychopharmacology, 128(2), 161-170) to obtain data on temporal discounting of an aversive consequence, with rats as experimental subjects. In the first phase of the procedure, rats chose between one-pellet and four-pellet alternatives; when subjects developed preference for the larger amount alternative, a shock was added to it, resulting in a loss of preference. In the first experimental condition, the delay to shock was progressively increased within each session from zero to 40 s (ascending delays), which resulted in a recovery of the preference for the larger-amount + shock alternative as the delay to shock was increased. In a subsequent condition (descending delays) the delay to shock was progressively decreased within each session, from 40 to 0 s. In both conditions, the preference for the smaller amount no-shock alternative was well described by a hyperbolic function. The order of presentation of the delays within the session, ascending or descending, did not alter the relationship between preference and delay to shock. The temporal discounting curve obtained in the present study could represent a baseline for analyzing the impact that diverse environmental and pharmacological variables have on the temporal discounting of aversive consequences. PMID- 28643144 TI - Evaluation of the American Joint Committee on Cancer 8th edition staging system for gastric cancer patients after preoperative therapy. AB - BACKGROUND: The American Joint Committee on Cancer (AJCC) recently released its 8th edition staging system, which created a separate staging system for gastric cancer patients who have undergone preoperative therapy (ypStage). The objective of this retrospective study was to apply the new ypStage to patients who have undergone preoperative therapy and potentially curative gastrectomy. METHODS: We collected data from a prospectively maintained institutional database of gastric cancer patients who underwent potentially curative gastrectomy after preoperative therapy (1995-2015). Kaplan-Meier survival estimations and log-rank tests were performed to compare survival. Univariable and multivariable analyses were performed to determine risk factors for overall survival. RESULTS: A total of 354 patients met our criteria. Most patients completed planned preoperative therapy (94%; 332/354) and received chemoradiation therapy (75%; 265/354). Although clinical stage (cStage) provided a poor discrimination of survival, postneoadjuvant pathological stage (ypStage) identified significant variation in survival (p < 0.001). Multivariable analysis showed the following factors were associated with survival after adjustment for ypStage: Asian race (HR 0.52; p = 0.028), linitis plastica (HR 1.66; p = 0.037), and R1 resection (HR 1.91; p = 0.016). Survival was not longer in ypT0N0 patients than in ypStage I patients (HR 1.29; p = 0.377). CONCLUSIONS: The AJCC 8th edition staging system for gastric cancer demonstrated reasonable survival prediction by ypStage, but not cStage, in patients who had undergone preoperative therapy. ypT0N0 patients, although not defined in the 8th edition, may be considered for inclusion in the ypStage I group. PMID- 28643146 TI - Helicobacter pylori-induced modulation of the promoter methylation of Wnt antagonist genes in gastric carcinogenesis. AB - BACKGROUND: This study aimed to investigate the changes in the promoter methylation and gene expression of multiple Wnt antagonists between the chronic infection and eradication of Helicobacter pylori (H. pylori) in gastric carcinogenesis. METHODS: The levels of methylation and corresponding mRNA expression of seven Wnt antagonist genes (SFRP1, -2, -5, DKK1, -2, -3, WIF1) were compared among the patients with H. pylori-positive gastric cancers (GCs), and H. pylori-positive and H. pylori-negative controls, by quantitative MethyLight assay and real-time reverse transcription (RT)-polymerase chain reaction (PCR), respectively. The changes of the methylation and expression levels of the genes were also compared between the H. pylori eradication and H. pylori-persistent groups 1 year after endoscopic resection of GCs. RESULTS: The methylation levels of SFRP and DKK family genes were significantly increased in the patients with H. pylori-positive GCs and followed by H. pylori-positive controls compared with H. pylori-negative controls (P < 0.001). SFRP1, -2, and DKK3 gene expression was stepwise downregulated from H. pylori-negative controls, H. pylori-positive controls, and to H. pylori-positive GCs (P < 0.05). Among the Wnt antagonists, only the degrees of methylation and downregulation of DKK3 were significantly reduced after H. pylori eradication (P < 0.05). CONCLUSION: Epigenetic silencing of SFRP and DKK family genes may facilitate the formation of an epigenetic field during H. pylori-associated gastric carcinogenesis. The epigenetic field may not be reversed even after H. pylori eradication except by DKK3 methylation. PMID- 28643147 TI - The Perioperative Surgical Home: Improving the Value and Quality of Care in Total Joint Replacement. AB - PURPOSE OF REVIEW: The perioperative surgical home (PSH) is a patient-centered, physician-led, multidisciplinary care pathway developed to deliver value-based care based on shared decision-making. Physician and hospital reimbursement will be tied to providing quality care at lower cost, and the PSH model has been used in providing care to patients undergoing lower extremity arthroplasty. The purpose of this review is to discuss the rationale, definition, development, current state, and future direction of the PSH. RECENT FINDINGS: The PSH model guides the patient throughout the pre and perioperative process and into the postoperative phase. It has been shown in multiple studies to decrease length of stay, improve functional outcomes, allow more home discharges, and lower costs. There is no increase in complications or readmission rates. The PSH pathway is a safe and effective method of providing value-based care to patients undergoing hip and knee arthroplasty. PMID- 28643145 TI - The prognostic value of volume-based parameters using 18F-FDG PET/CT in gastric cancer according to HER2 status. AB - BACKGROUND: We aimed to find the clinical value of metastatic tumor burden evaluated with F18-FDG PET/CT in gastric cancer patients, considering the human epidermal growth factor receptor 2 (HER2) status. METHODS: We retrospectively reviewed 124 patients with locally advanced or metastatic gastric cancer at Yonsei Cancer Center between January 2006 and December 2014 who had undergone baseline FDG PET/CT before first-line chemotherapy. We measured the maximum standardized uptake value from the primary tumor (SUVmax) and whole-body (WB) PET/CT parameters, including WB SUVmax, WB SUVmean, WB metabolic tumor volume (WB MTV), and WB total lesion glycolysis (WB TLG), in all metabolically active metastatic lesions (SUV threshold >=2.5 or 40% isocontour for <=2.5), and we determined their association with patient survival outcomes. RESULTS: SUVmax was higher in HER2-positive gastric cancers (median 12.1, range 3.4-34.6) compared to HER-2 negative (7.4, 1.6-39.1, P < 0.001). Among all patients, WB TLG > 600, which is indicative of a high metastatic tumor burden, showed worse progression free survival (PFS) [hazard ratio (HR), 2.003; 95% CI, 1.300-3.086; P = 0.002] and overall survival (OS) (HR, 3.001; 95% CI, 1.950-4.618; P < 0.001) than did WB TLG <= 600. Among HER2-positive gastric cancer patients treated with trastuzumab, higher metabolic tumor burden predicted worse OS, but not PFS. CONCLUSIONS: HER2 positive gastric cancers had higher SUVmax compared to HER2-negative gastric cancers. In both HER2-negative patients and -positive patients receiving trastuzumab, FDG PET/CT volume-based parameters may have a role in further stratifying the prognosis of stage IV gastric cancer. PMID- 28643148 TI - Mechanical challenges to the glomerulus and podocyte loss: evolution of a paradigm. AB - In this article, I shall outline some of the most important aspects of the evidentiary basis of the so-called Kriz model for the development of glomerular sclerosis, a model that we continue to modify to this day. In my mind, the most important findings include the fact that podocytes are generally post-mitotic cells, so that loss of a significant number for any cause leads to podocyte insufficiency. Another pivotal finding is that in many experimental models and in human disease, podocytes detach from the GBM as living cells. These facts, together with biomechanical deduction, have led to the ongoing evolution of the original Heidelberg model. PMID- 28643149 TI - Surface modification minimizes the toxicity of silver nanoparticles: an in vitro and in vivo study. AB - Currently toxicological research in Silver nanoparticle is a leading issue in medical science. The surface chemistry and physical dimensions of silver nanoparticles (Ag-NPs) play an important role in toxicity. The aim of this present study was to evaluate the in vitro and in vivo toxicity of Ag-NPs as well as the alteration of toxicity profile due to surface functionalization (PEG and BSA) and the intracellular signaling pathways involved in nanoparticles mediated oxidative stress and apoptosis in vitro and in vivo system. Ag-NPs released excess Ag+ ions leads to activation of NADPH oxidase and helps in generating the reactive oxygen species (ROS). Silver nanoparticles elicit the production of excess amount of ROS results activation of TNF-alpha. Ag-NPs activates caspase-3 and 9 which are the signature of mitochondrial pathway. Ag-NPs are responsible to decrease the antioxidant enzymes and imbalance the oxidative status into the cells but functionalization with BSA and PEG helps to protect the adverse effect of Ag-NPs on the cells. This study suggested that Ag-NPs are toxic to normal cells which directly lead with human health. Surface functionalization may open the gateway for further use of Ag-NPs in different area such as antimicrobial and anticancer therapy, industrial use or in biomedical sciences. PMID- 28643150 TI - Epigenetically controlled Six3 expression regulates glioblastoma cell proliferation and invasion alongside modulating the activation levels of WNT pathway members. AB - Glioma is the most common primary brain tumor in adults. Six3 is a human homologue of the highly conserved sine oculis gene family and essential transcription regulatory factor in process of eye and fetal forebrain development. However, little is known about the role of Six3 in human tumorigenesis. The aim of this study is to investigate the methylation/expression of Six3 and reveal its function and action mechanism in glioma. Our results showed that Six3 was down-regulated in human glioma tissues and human glioma SHG 44, U251, SF126 and U373-MG cells compared with the normal tissues. And the down regulation of Six3 was associated with the methylation of its promoter. Glioma U251 cells lacked endogenous Six3. Treatment with demethylating agent (5-aza-2' deoxycytidine) or exogenous expression of Six3 restored Six3 production and resulted in suppression of cell cycle G1/S transition, proliferation and invasion and down-regulation of the expression of Wnt1, p-GSK3-beta, beta-catenin and cyclin D1 in glioma U251 cells. However, knockdown of Six3 in SHG-44 cells, which have relative higher baseline level of Six3, resulted in an opposite action. These results demonstrate that Six3 silence or loss in glioma is induced by its promoter hypermethylation and Six3 down-regulation contributes to proliferation and invasion of glioma. And this process is involved in activation of Wnt/beta catenin pathway. Six3 play a suppressor role in the initiation and progression of human glioma and potentially serve as a target for the diagnosis and treatment of human glioma. PMID- 28643152 TI - The Impact of Speed of Play in Gambling on Psychological and Behavioural Factors: A Critical Review. AB - Conceptually, there is a common association between gambling games with fast speeds of play and problem gambling. This relationship however, is largely correlational in nature, which comes at the expense of carefully controlled empirical investigation. Research that does exist aimed towards investigating the impact of gambling speeds on psychological and behavioural factors, is in its relative infancy, and the research possesses disparate methodologies and variables of interest. The aims of the current review is therefore to evaluate and summarise the existing body of evidence relating to speed of play in gambling, as well as discuss how this evidence can be used to inform harm minimisation approaches aimed at facilitating self-control during gambling. Eleven studies were selected for review based on the inclusion criteria, comprising nine experimental and two qualitative studies (one self-report focus group study and one observational study). There was a consistent finding across studies that games with faster speeds of play were preferred and rated as more exciting for all gamblers, ranging from non-problem to problem gamblers. Of concern, was the repeated finding that fast games are particularly appealing to those suffering with a gambling problem. Behavioural results were more inconsistent across studies, though the general trend supports the notion that games with faster speeds of play encourage more wagers, longer game play, and caused players, particularly problem gamblers, to experience difficulty in ceasing gambling. The implications of these findings for gambling policy, harm minimisation approaches, and future research are discussed. PMID- 28643151 TI - Multi-institutional external validation of a novel glioblastoma prognostic nomogram incorporating MGMT methylation. AB - A recent nomogram for glioblastoma (GBM) was designed to incorporate methylguanine-DNA methyltransferase (MGMT) methylation status in trial patients receiving temozolomide. Since clinical trial patients are strictly selected, compared to the general population, we performed a multi-institutional, external, independent assessment of the nomogram. Consecutive adult patients with supratentorial GBM diagnosed between June 2007 and December 2014 who initiated TMZ-based concurrent chemoradiotherapy (CRT) and were not enrolled on RTOG 0525 or 0825 were eligible. We collected age, gender, MGMT status, performance status, resection extent, race, and tumor site and Cox regression analysis of overall survival (OS) was conducted with the 1-year nomogram-predicted survival (NPS). The predictive accuracy was quantified by the concordance index (c-index) as well as by separating patients into quintile-groups of the population distribution of NPS and comparing mean NPS and observed OS. Of 514 patients with GBM, 309 had all nomogram factors. Median OS was 18.7 months. NPS and observed OS demonstrated a c index of 0.695. On univariate analysis, the NPS and all included factors except gender were significant. On multivariable analysis (MVA) the only significant factor for worse survival was lower NPS. When separated into quintile-groups of NPS, the observed survival was slightly better than the predicted survival for all but the worst prognostic group. Our multi-institutional cohort provides independent external validation of a novel GBM nomogram incorporating MGMT methylation status. No individual factor included in the nomogram retained significance on MVA after adjusting for NPS. PMID- 28643155 TI - Mind-wandering, how do I measure thee with probes? Let me count the ways. AB - In the past decade, a new field has formed to investigate the concept of mind wandering, or task-unrelated thought. The state of mind-wandering is typically contrasted with being on-task, or paying attention to the task at hand, and is related to decrements in performance on cognitive tasks. The most widely used method for collecting mind-wandering data-the probe-caught method-involves stopping participants during a task and asking them where their attention is directed. In this review, 145 studies from 105 articles published between 2005 and 2015 were classified according to the framing and wording of the thought probe and response options. Five distinct methodologies were identified: neutral (in which counterbalancing was used to equally emphasize on-task and off-task states), dichotomous (say "yes" or "no" to one thought state), dichotomous (choose between two thought states), categorical, and scale. The review identifies at least 69 different methodological variants, catalogues the verbatim probes and response options used in each study, and suggests important considerations for future empirical work. PMID- 28643154 TI - Historical Trends and Chiral Signatures of Organochlorine Pesticides in Sediments of Qiandao Lake, China. AB - This study investigated the enantiomeric and depth profiles of organochlorine pesticides (OCPs) accumulated in the sediments of Qiandao Lake, China. OCP concentrations in sediments have increased gradually since the early 1960s, when extensive OCPs application in China began. Concentrations reached maximum levels after 1992, this timing corresponds with the emerging of the "new" usage of hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethane (DDTs). In addition, the degradation of chiral OCPs were enantioselective, resulting in enriched (-)-enantiomers for alpha-HCH and o, p'-DDD. However, both preferential depletions of (-) enantiomers and (+) enantiomers were observed for o, p'-DDT. This outcome was indicated by enantiomer fractions (EF) values either greater or less than 0.5. PMID- 28643153 TI - A 3E8.scFv.Cys-IR800 Conjugate Targeting TAG-72 in an Orthotopic Colorectal Cancer Model. AB - PURPOSE: Optical surgical navigation (OSN) will be a potent tool to help surgeons more accurately and efficiently remove tumors. The purpose of this study was to evaluate a novel humanized 3E8 antibody (3E8 MAb) fragment site-specifically conjugated with IR800, 3E8.scFv.Cys-IR800, as a potential OSN agent to target colorectal adenocarcinoma. PROCEDURES: An engineered single-chain variable fragment of 3E8 MAb (targeted to TAG-72), appending a C-terminal cysteine residue (3E8.scFv.Cys), was created and reacted with IRDye800-maleimide. 3E8.scFv.Cys IR800 identity and purity were verified by MALDI-TOF mass spectra and 800 nm detected size exclusion column HPLC. In vitro human colon adenocarcinoma LS-174 T cells binding and competition assay validated biological functionality. We further evaluated the imaging ability and receptor-specific binding of 3E8.scFv.Cys-IR800 in an orthotopic LS-174 T mouse model. RESULTS: A 1:1 dye to protein conjugate was achieved at greater than 90 % HPLC purity. A 1 nmol dose of 3E8.scFv.Cys-IR800 via intraperitoneal injection administration was sufficient to produce high tumor to background fluorescence contrast. Blocking competition studies both in vitro and in vivo using a different blocking protein, 3E8DeltaCH2, demonstrated 3E8.scFv.Cys-IR800 binding specificity for TAG-72 antigen. CONCLUSIONS: 3E8.scFv.Cys-IR800 shows properties useful in a clinically viable OSN agent for colorectal cancer. PMID- 28643156 TI - The role of variability in the property listing task. AB - It is generally believed that concepts can be characterized by their properties (or features). When investigating concepts encoded in language, researchers often ask subjects to produce lists of properties that describe them (i.e., the Property Listing Task, PLT). These lists are accumulated to produce Conceptual Property Norms (CPNs). CPNs contain frequency distributions of properties for individual concepts. It is widely believed that these distributions represent the underlying semantic structure of those concepts. Here, instead of focusing on the underlying semantic structure, we aim at characterizing the PLT. An often disregarded aspect of the PLT is that individuals show intersubject variability (i.e., they produce only partially overlapping lists). In our study we use a mathematical analysis of this intersubject variability to guide our inquiry. To this end, we resort to a set of publicly available norms that contain information about the specific properties that were informed at the individual subject level. Our results suggest that when an individual is performing the PLT, he or she generates a list of properties that is a mixture of general and distinctive properties, such that there is a non-linear tendency to produce more general than distinctive properties. Furthermore, the low generality properties are precisely those that tend not to be repeated across lists, accounting in this manner for part of the intersubject variability. In consequence, any manipulation that may affect the mixture of general and distinctive properties in lists is bound to change intersubject variability. We discuss why these results are important for researchers using the PLT. PMID- 28643157 TI - Effect of variance ratio on ANOVA robustness: Might 1.5 be the limit? AB - Inconsistencies in the research findings on F-test robustness to variance heterogeneity could be related to the lack of a standard criterion to assess robustness or to the different measures used to quantify heterogeneity. In the present paper we use Monte Carlo simulation to systematically examine the Type I error rate of F-test under heterogeneity. One-way, balanced, and unbalanced designs with monotonic patterns of variance were considered. Variance ratio (VR) was used as a measure of heterogeneity (1.5, 1.6, 1.7, 1.8, 2, 3, 5, and 9), the coefficient of sample size variation as a measure of inequality between group sizes (0.16, 0.33, and 0.50), and the correlation between variance and group size as an indicator of the pairing between them (1, .50, 0, -.50, and -1). Overall, the results suggest that in terms of Type I error a VR above 1.5 may be established as a rule of thumb for considering a potential threat to F-test robustness under heterogeneity with unequal sample sizes. PMID- 28643158 TI - Measuring working memory capacity in children using adaptive tasks: Example validation of an adaptive complex span. AB - Working memory tasks designed for children usually present trials in order of ascending difficulty, with testing discontinued when the child fails a particular level. Unfortunately, this procedure comes with a number of issues, such as decreased engagement from high-ability children, vulnerability of the scores to temporary mind-wandering, and large between-subjects variations in number of trials, testing time, and proactive interference. To circumvent these problems, the goal of the present study was to demonstrate the feasibility of assessing working memory using an adaptive testing procedure. The principle of adaptive testing is to dynamically adjust the level of difficulty as the task progresses to match the participant's ability. We used this method to develop an adaptive complex span task (the ACCES) comprising verbal and visuo-spatial subtests. The task presents a fixed number of trials to all participants, allows for partial credit scoring, and can be used with children regardless of ability level. The ACCES demonstrated satisfying psychometric properties in a sample of 268 children aged 8-13 years, confirming the feasibility of using adaptive tasks to measure working memory capacity in children. A free-to-use implementation of the ACCES is provided. PMID- 28643159 TI - PyMICE: APython library for analysis of IntelliCage data. AB - IntelliCage is an automated system for recording the behavior of a group of mice housed together. It produces rich, detailed behavioral data calling for new methods and software for their analysis. Here we present PyMICE, a free and open source library for analysis of IntelliCage data in the Python programming language. We describe the design and demonstrate the use of the library through a series of examples. PyMICE provides easy and intuitive access to IntelliCage data, and thus facilitates the possibility of using numerous other Python scientific libraries to form a complete data analysis workflow. PMID- 28643160 TI - Residual ground-water levels of the neonicotinoid thiacloprid perturb chemosensing of Caenorhabditis elegans. AB - This study investigated the neurological effects of residual ground-water levels of thiacloprid on the non-target organism Caenorhabditis elegans. Nematodes treated with thiacloprid showed a dose-dependent and significantly increased twitch response at concentrations above 50 ng mL-1 that disabled their forward locomotion in liquid culture. In comparison with untreated controls, 10 ng mL-1 thiacloprid perturbed the chemosensory ability of C. elegans such that the nematodes no longer demonstrated positive chemotaxis towards a NaCl chemo attractant, reducing their chemotaxis index from +0.48 to near to zero. Nematodes also exhibited a locomotion characteristic of those devoid of chemo-attraction, making significantly more pirouetting turns of >=90 degrees than the untreated controls. Compared to the untreated controls, expression of the endocytosis associated gene, Rab-10, was also increased in C. elegans that had developed to adulthood in the presence of 10 ng mL-1 thiacloprid, suggesting their active engagement in increased recycling of affected cellular components, such as their nAChRs. Thus, even residual, low levels of this less potent neonicotinoid that may be found in field ground-water had measurable effects on a beneficial soil organism which may have environmental and ecological implications that are currently poorly understood. PMID- 28643162 TI - Dental Caries: A Disease Which Needs Attention. AB - Dental caries is one of the most prevalent disease (about 50%) in children across the globe. If not treated in time, it can affect not only the mastication function but also the speech, smile and psychosocial environment and the quality of life of the child and the family. The treatment of dental diseases is very expensive in all countries and prevention is very simple and effective. The caries in children below 6 y is called early childhood caries (ECC). It is most commonly caused by milk bottle or mother's feed during night. The ECC spreads very fast and can cause severe pain, abscess, swelling, fever and psychological disturbances in children. The treatment of ECC requires multiple appointments and still the prognosis is not very promising in mutilated dentitions. A physician or pediatrician can easily identify early caries and habits of parents leading to caries and can counsel them for prevention and refer them to the specialist. Good oral hygiene, dietary modification with respect to use of sugar and sticky food and healthy diet can help in preventing this disease in children. The need of the time is to appraise all on the methods of dental caries prevention. PMID- 28643161 TI - Nonlinear biotic ligand model for assessing alleviation effects of Ca, Mg, and K on Cd toxicity to soybean roots. AB - Developing a nonlinear biotic ligand model (BLM) that considers the geometrical constraints for binding of different cations on biotic ligands will provide more reliable details about the hypothetical mechanism governing the alleviation of cadmium (Cd) toxicity by coexistent cations. Soybean seedlings under Cd stress produced by various activities of coexistent cations such as calcium (Ca2+), magnesium (Mg2+), and potassium (K+) were hydroponically assayed for Cd toxicity to soybean roots. The Cd2+ activity resulting in 50% reduction of root elongation (RE), EA 50, was used for assessing the Cd toxicity to the soybean seedling. Increasing Ca2+, Mg2+, and K+ activities resulted in a significant alleviation of Cd toxicity to soybean roots. This alleviation was markedly higher with increasing Ca2+ and K+ levels than with increasing Mg2+ level. In addition, EA 50 increased in nonlinear positive relationships with Ca2+ and Mg2+. The real data obtained from the soybean assay were thus used to develop the nonlinear BLM for Cd rhizotoxicity. Two parameters, competition equivalent and stability constant, indicated the profiles of the geometrical constraint and affinity of Ca2+, Mg2+, and K+ binding on the soybean root surface to alleviate Cd toxicity. Compared with the traditional linear BLM, the nonlinear BLM provided more precise predictions of relative root elongation (RRE) and EA 50. Therefore, adopting the nonlinear BLM approach will successfully improve the monitoring and assessment of heavy metal toxicity to terrestrial plants. PMID- 28643163 TI - Association Between Food Allergy and Childhood Asthma: So Close and Yet So Far! PMID- 28643164 TI - How to Keep a Child Healthy? AB - Keeping a child healthy is the most important priority of every parent. The child can be kept healthy by ensuring exclusive breastfeeding for first 6 mo of life, maintaining healthy weight throughout the childhood, providing adequate and balanced diet, promoting regular physical activity and adequate sleep, keeping a watch on all the parameters of development and referring the child to the specialist whenever deviation from normal is suspected. Proper and timely immunization as per the prevailing guidelines must be done to prevent serious infections. Stress should also be given on promoting oral as well as mental health besides other important general measures to improve the health of the child. PMID- 28643165 TI - Molecularly targeted therapies for p53-mutant cancers. AB - The tumor suppressor p53 is lost or mutated in approximately half of human cancers. Mutant p53 not only loses its anti-tumor transcriptional activity, but also often acquires oncogenic functions to promote tumor proliferation, invasion, and drug resistance. Traditional strategies have been taken to directly target p53 mutants through identifying small molecular compounds to deplete mutant p53, or to restore its tumor suppressive function. Accumulating evidence suggest that cancer cells with mutated p53 often exhibit specific functional dependencies on secondary genes or pathways to survive, providing alternative targets to indirectly treat p53-mutant cancers. Targeting these genes or pathways, critical for survival in the presence of p53 mutations, holds great promise for cancer treatment. In addition, mutant p53 often exhibits novel gain-of-functions to promote tumor growth and metastasis. Here, we review and discuss strategies targeting mutant p53, with focus on targeting the mutant p53 protein directly, and on the progress of identifying genes and pathways required in p53-mutant cells. PMID- 28643169 TI - In vitro enzymatic assays of photosynthetic bacterial 3-vinyl hydratases for bacteriochlorophyll biosyntheses. AB - A chlorosome is a large and efficient light-harvesting antenna system found in some photosynthetic bacteria. This system comprises self-aggregates of bacteriochlorophyll (BChl) c, d, or e possessing a chiral 1-hydroxyethyl group at the 3-position, which plays a key role in the formation of the supramolecule. Biosynthesis of chlorosomal pigments involves stereoselective conversion of 3 vinyl group to 3-(1-hydroxyethyl) group facilitated by a 3-vinyl hydratase. This 3-vinyl hydration also occurs in BChl a biosynthesis, followed by oxidation that introduces an acetyl group at the 3-position. Herein, we present in vitro enzymatic assays of paralogous 3-vinyl hydratases derived from green sulfur bacteria, Chlorobaculum tepidum and Chlorobaculum limnaeum, the filamentous anoxygenic phototroph Chloroflexus aurantiacus, and the chloracidobacterium Chloracidobacterium thermophilum. All the hydratases showed hydration activities. The biosynthetic pathway of BChl a and other chlorosomal pigments is discussed considering the substrate specificity and stereoselectivity of the present hydratases. PMID- 28643168 TI - Self-aggregation of synthetic zinc methyl 20-substituted 3-hydroxymethyl pyropheophorbides as models of bacteriochlorophyll-c. AB - Zinc 3-hydroxymethyl-131-oxo-chlorins bearing a variety of primary alkyl groups at the 20-position were prepared as models of bacteriochlorophyll-c by chemical modification of naturally occurring chlorophyll-a. The synthetic chlorophyll-a derivatives self-aggregated in an aqueous Triton X-100 solution to afford large oligomers whose Soret and Qy bands were red-shifted and broadened, compared with the bands of their monomers in tetrahydrofuran. The oligomeric bands are similar to those of bacteriochlorophyll-c self-aggregates in chlorosomes, the main light harvesting antennae of photosynthetic green bacteria. The 20-alkylation led to bathochromic shifts of the visible Soret maxima in J-type self-aggregates of the synthetic models, while elongation of the 20-alkyl group decreased the chlorosomal Qy maxima due to an increase in steric hindrance. Considering the light-harvesting and energy-transferring processes in a chlorosome, the 20 methylation in bacteriochlorophyll-c would be more suitable for efficient culturing of green bacteria than the 20-ethylation and propylation as well as the 20-unsubstitution in bacteriochlorophyll-d. PMID- 28643170 TI - Predictors and incidence of orthostatic headache associated with lumbar drain placement following endoscopic endonasal skull base surgery. AB - BACKGROUND: Orthostatic headache (OH) is a potential complication of lumbar drainage (LD) usage. The incidence and risk factors for OH with the use of lumbar drainage during endoscopic endonasal procedures have not been documented. OBJECTIVE: To investigate the incidence of post-procedure OHs associated with placement of LD in patients undergoing endoscopic endonasal procedures. METHODS: We prospectively noted the placement of LDs in a consecutive series of endoscopic endonasal skull base surgeries. Charts were retrospectively reviewed, and patients were divided into two groups: those with OH and those without. The patient demographics, drain durations, imaging findings of intracranial hypotension, pathologies and need for a blood patch were compared between the two groups. RESULTS: Two hundred forty-nine patients were included in the study. Seven patients (2.8%) suffered post-dural puncture OH, which was mild to moderate and disappeared 2-8 days (median 3 days) after treatment. Blood patches were used in four patients. Significant predisposing factors were age (33.0 vs. 53.5, P = 0.014) and a strong trend for female gender (85.7% vs. 47.9%, P = 0.062). BMI and drain duration were not significant. Postoperative intracranial hypotension was diagnosed radiographically in 43% of OH patients and in 5.4% of those without OH (P = 0.003). Four (1.6%) patients required treatment with an epidural blood patch. CONCLUSION: OH associated with intracranial hypotension in patients undergoing endoscopic endonasal procedures with LDs is an infrequent complication seen more commonly in young female patients. Radiographic signs of intracranial hypotension are a specific but not sensitive test for OH. PMID- 28643167 TI - Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. AB - The gut microbiota is essential to health and has recently become a target for live bacterial cell biotherapies for various chronic diseases including metabolic syndrome, diabetes, obesity and neurodegenerative disease. Probiotic biotherapies are known to create a healthy gut environment by balancing bacterial populations and promoting their favorable metabolic action. The microbiota and its respective metabolites communicate to the host through a series of biochemical and functional links thereby affecting host homeostasis and health. In particular, the gastrointestinal tract communicates with the central nervous system through the gut-brain axis to support neuronal development and maintenance while gut dysbiosis manifests in neurological disease. There are three basic mechanisms that mediate the communication between the gut and the brain: direct neuronal communication, endocrine signaling mediators and the immune system. Together, these systems create a highly integrated molecular communication network that link systemic imbalances with the development of neurodegeneration including insulin regulation, fat metabolism, oxidative markers and immune signaling. Age is a common factor in the development of neurodegenerative disease and probiotics prevent many harmful effects of aging such as decreased neurotransmitter levels, chronic inflammation, oxidative stress and apoptosis-all factors that are proven aggravators of neurodegenerative disease. Indeed patients with Parkinson's and Alzheimer's diseases have a high rate of gastrointestinal comorbidities and it has be proposed by some the management of the gut microbiota may prevent or alleviate the symptoms of these chronic diseases. PMID- 28643166 TI - Structural disorder in plant proteins: where plasticity meets sessility. AB - Plants are sessile organisms. This intriguing nature provokes the question of how they survive despite the continual perturbations caused by their constantly changing environment. The large amount of knowledge accumulated to date demonstrates the fascinating dynamic and plastic mechanisms, which underpin the diverse strategies selected in plants in response to the fluctuating environment. This phenotypic plasticity requires an efficient integration of external cues to their growth and developmental programs that can only be achieved through the dynamic and interactive coordination of various signaling networks. Given the versatility of intrinsic structural disorder within proteins, this feature appears as one of the leading characters of such complex functional circuits, critical for plant adaptation and survival in their wild habitats. In this review, we present information of those intrinsically disordered proteins (IDPs) from plants for which their high level of predicted structural disorder has been correlated with a particular function, or where there is experimental evidence linking this structural feature with its protein function. Using examples of plant IDPs involved in the control of cell cycle, metabolism, hormonal signaling and regulation of gene expression, development and responses to stress, we demonstrate the critical importance of IDPs throughout the life of the plant. PMID- 28643171 TI - Elimination of the negative component of the unipolar electrogram as a local procedural endpoint during paroxysmal atrial fibrillation catheter ablation using contact-force sensing: the UNIFORCE study. AB - PURPOSE: Elimination of the negative component of the unipolar atrial electrogram is a reliable indicator of the creation of a transmural lesion. Contact-force (CF) sensing technology has the potential to increase the durability of pulmonary vein isolation (PVI). In the present multicenter study, we assessed the 2-year sinus rhythm (SR) maintenance rate in patients with paroxysmal atrial fibrillation (PAF) after PVI guided by these two approaches. METHODS: Two hundred fifteen consecutive PAF patients (62.1 +/- 10.1 years, 65 women) were prospectively enrolled. All patients underwent PVI under CARTO guidance according to a systematic contiguous "point-by-point" approach, using radiofrequency energy, and a CF externally irrigated ablation catheter with the goal of at least 10g (ideally 20g) of force. The ablation endpoint of each individual lesion was elimination of the negative component of the unipolar atrial signal. The procedural endpoint was PVI with bidirectional block. RESULTS: All PVs were successfully isolated. After 30 min of waiting time, 35 patients (16%) had PV reconnection and in all of them, the PVs were re-isolated. Two years after a single ablation procedure, 187 patients (87%) remained arrhythmia free, without anti-arrhythmic drugs. Of the 28 patients presenting with AF recurrence, 25 had PV reconnection and underwent repeat PVI while in the remaining 3 patients, all four PVs were isolated and extra-PV triggers were identified. There were six groin hematomas and one transient ischemic attack. CONCLUSIONS: Unipolar atrial signal analysis combined with CF sensing ensures a robust 2-year SR maintenance rate in the treatment of PAF. Clinical trial registration-URL: http://www.clinicaltrials.gov . Unique identifier: NCT02520960. PMID- 28643172 TI - Associations of Work Stress, Supervisor Unfairness, and Supervisor Inability to Speak Spanish with Occupational Injury among Latino Farmworkers. AB - Little is known about how psychosocial work factors such as work stress, supervisor fairness, and language barriers affect risk of occupational injury among Latino farmworkers. This study attempts to address these questions. Surveys were administered via interviews to 225 Latino thoroughbred farmworkers. Multivariable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (CI) of occupational injury in the past year in relation to occupational characteristics. Work stress (OR 6.70, 95% CI 1.84-24.31), supervisor unfairness (OR 3.34, 95% CI 1.14-9.73), longer tenure at farm (OR 2.67, 95% CI 1.13-6.34), and supervisor inability to speak Spanish (OR 2.29, 95% CI 1.05-5.00) were significantly associated with increased odds of occupational injury. Due to the associations between work stress, supervisor unfairness, supervisor inability to speak Spanish and injury, supervisor training to improve Spanish language ability and equitable management practices is merited. Future research is needed to understand the antecedents of work stress for Latino farmworkers. PMID- 28643173 TI - Immunotherapy and Targeted Therapy for Small Cell Lung Cancer: There Is Hope. AB - Small cell lung cancer (SCLC) is a devastating and aggressive neuroendocrine carcinoma of the lung. It accounts for ~15% of lung cancer mortality and has had no improvement in standard treatment options for nearly 30 years. However, there is now hope for change with new therapies and modalities of therapy. Immunotherapies and checkpoint inhibitors are entering clinical practice, selected targeted therapies show promise, and "smart bomb"-based drug/radioconjugates have led to good response in early clinical trials. Additionally, new research insights into the genetics and tumor heterogeneity of SCLC alongside the availability of new tools such as patient-derived or circulating tumor cell xenografts offer the potential to shine light on this beshadowed cancer. PMID- 28643174 TI - Natural Language Processing for EHR-Based Pharmacovigilance: A Structured Review. AB - The goal of pharmacovigilance is to detect, monitor, characterize and prevent adverse drug events (ADEs) with pharmaceutical products. This article is a comprehensive structured review of recent advances in applying natural language processing (NLP) to electronic health record (EHR) narratives for pharmacovigilance. We review methods of varying complexity and problem focus, summarize the current state-of-the-art in methodology advancement, discuss limitations and point out several promising future directions. The ability to accurately capture both semantic and syntactic structures in clinical narratives becomes increasingly critical to enable efficient and accurate ADE detection. Significant progress has been made in algorithm development and resource construction since 2000. Since 2012, statistical analysis and machine learning methods have gained traction in automation of ADE mining from EHR narratives. Current state-of-the-art methods for NLP-based ADE detection from EHRs show promise regarding their integration into production pharmacovigilance systems. In addition, integrating multifaceted, heterogeneous data sources has shown promise in improving ADE detection and has become increasingly adopted. On the other hand, challenges and opportunities remain across the frontier of NLP application to EHR-based pharmacovigilance, including proper characterization of ADE context, differentiation between off- and on-label drug-use ADEs, recognition of the importance of polypharmacy-induced ADEs, better integration of heterogeneous data sources, creation of shared corpora, and organization of shared-task challenges to advance the state-of-the-art. PMID- 28643175 TI - [Clinical aspects of treatment with amiodarone]. AB - Amiodarone has multiple and complex electrophysiological effects that render it a very effective antiarrhythmic drug for the treatment of both, supraventricular and ventricular arrhythmias. Proarrhythmic effects of amiodarone in patients with structural heart disease are rare. However, extracardiac adverse effects occurring in association with amiodarone treatment are frequent and feared. These adverse effects have usually been related to total amiodarone exposure (i. e., dose and duration of treatment). Parallel to a more frequent use of lower amiodarone maintenance doses (100-200 mg/day), the incidence of severe unwanted extracardiac side effects has decreased. High-dose maintenance regiments (daily dose >=300 mg) are usually obsolete. This paper discusses recommendations regarding the monitoring of cardiac and extracardiac side effects of amiodarone. They need to be regarded by physicians using amiodarone to ensure long-term safety of amiodarone therapy. PMID- 28643176 TI - A Promising Tool in Retina Regeneration: Current Perspectives and Challenges When Using Mesenchymal Progenitor Stem Cells in Veterinary and Human Ophthalmological Applications. AB - Visual impairment is a common ailment of the current world population, with more exposure to CCD screens and fluorescent lighting, approximately 285 billion people suffer from this deficiency and 13% of those are considered clinically blind. More common causes for visual impairment include age-related macular degeneration (AMD), glaucoma and diabetic retinopathy (Zhu et al. Molecular Medicine Reports, 2015; Kolb et al. 2007; Machalinska et al. Current Eye Research, 34(9),748-760, 2009) among a few. As cases of retinal and optic nerve diseases rise, it is vital to find a treatment, which has led to investigation of the therapeutic potential of various stem cells types (Bull et al. Investigative Opthalmology & Visual Science, 50(9), 4244, 2009; Bull et al. Investigative Opthalmology & Visual Science, 49(8), 3449, 2008; Yu et al. Biochemical and Biophysical Research Communications, 344(4), 1071-1079, 2006; Na et al. Graefe's Archive for Clinical and Experimental Ophthalmology, 247(4), 503-514, 2008). In previous studies, some of the stem cell variants used include human Muller SCs and bone marrow derived SCs. Some of the regenerative potential characteristics of mesenchymal progenitor stem cells (MSCs) include their multilineage differentiation potential, their immunomodulatory effects, their high proliferative activity, they can be easily cultured in vitro, and finally their potential to synthesize and secrete membrane derived vesicles rich in growth factors, mRNA and miRNA which possibly aid in regulation of tissue damage regeneration. These facts alone, explain why MSCs are so widely used in clinical trials, 350 up to date (Switonski, Reproductive Biology, 14(1), 44-50, 2014). Animal studies have demonstrated that sub-retinal transplantation of MSCs delays retinal degeneration and preserves retinal function through trophic response (Inoue et al. Experimental Eye Research, 85(2), 234-241, 2007). Umbilical cord derived MSCs (UC/MSCs) have also been shown to contain neuroprotective features of ganglion cells in rat studies (Zwart et al. Experimental Neurology, 216(2), 439-448, 2009). This review aims to present current MSC therapies in practice, as well as their retinal regeneration potential in animal models, and their innovative prospects for treatment of human retinal diseases. PMID- 28643178 TI - Economic Evaluation of Tobramycin Inhalation Powder for the Treatment of Chronic Pulmonary Pseudomonas aeruginosa Infection in Patients with Cystic Fibrosis. AB - BACKGROUND: Chronic lung infection with Pseudomonas aeruginosa occurs in approximately 50% of patients with cystic fibrosis (CF). This infection further compromises lung function, and significantly contributes to the increased healthcare costs. OBJECTIVES: Inhaled tobramycin, used to manage P. aeruginosa infection in CF patients, is available as powder (tobramycin inhalation powder, TIP) and solution (tobramycin inhalation solution, TIS). Evidence suggests increased adherence with the use of TIP over TIS. Hence, this analysis aimed to evaluate the potential pharmacoeconomic benefit of increased adherence with TIP over TIS in the US setting. METHODS: A patient-level simulation model was developed to compare TIP with TIS. Both costs and benefits were predicted over a 10-year time horizon from a payer's perspective, and were discounted annually at 3%. All costs were presented in 2016 US dollars. RESULTS: TIP was associated with greater quality-adjusted life-years (by 0.27) and lower total costs (by US$36,168) as compared with TIS over a 10-year time horizon. TIP-treated patients experienced a decreased mean number of exacerbations than TIS-treated patients (39.24 vs 50.20). Furthermore, administration of TIP via the T-326 Inhaler was associated with significant cost savings per patient, because of the nebulizer required for administering TIS (by US$1596) and exacerbation costs (by US$76,531). Probabilistic sensitivity analysis showed that TIP was dominant over TIS in 100% of the simulations. CONCLUSION: TIP is likely to be a more cost effective treatment than TIS, and therefore may reduce the economic burden of CF. PMID- 28643179 TI - Erratum to: Various Regulatory Modes for Circadian Rhythmicity and Sexual Dimorphism in the Non-Neuronal Cardiac Cholinergic System. PMID- 28643177 TI - Targeting DNA repair and replication stress in the treatment of ovarian cancer. AB - Approximately half of high-grade serous epithelial ovarian cancers incur alterations in genes of homologous recombination (BRCA1, BRCA2, RAD51C, Fanconi anemia genes), and the rest incur alterations in other DNA repair pathways at high frequencies. Such cancer-specific gene alterations can confer selective sensitivity to DNA damaging agents such as cisplatin and carboplatin, topotecan, etoposide, doxorubicin, and gemcitabine. Originally presumed to inhibit DNA repair, PARP inhibitors that have recently been approved by the FDA for the treatment of advanced ovarian cancer also act as DNA damaging agents by inducing PARP-DNA complexes. These DNA damaging agents induce different types of DNA lesions that require various DNA repair genes for the repair, but commonly induce replication fork slowing or stalling, also referred to as replication stress. Replication stress activates DNA repair checkpoint proteins (ATR, CHK1), which prevent further DNA damage. Hence, targeting DNA repair genes or DNA repair checkpoint genes augments the anti-tumor activity of DNA damaging agents. This review describes the rational basis for using DNA repair and DNA repair checkpoint inhibitors as single agents. The review also presents the strategies combining these inhibitors with DNA damaging agents for ovarian cancer therapy based on specific gene alterations. PMID- 28643180 TI - First complete genome sequences of genogroup V, genotype 3 porcine sapoviruses: common 5'-terminal genomic feature of sapoviruses. AB - Sapoviruses (SaVs) are enteric viruses and have been detected in various mammals. They are divided into multiple genogroups and genotypes based on the entire major capsid protein (VP1) encoding region sequences. In this study, we determined the first complete genome sequences of two genogroup V, genotype 3 (GV.3) SaV strains detected from swine fecal samples, in combination with Illumina MiSeq sequencing of the libraries prepared from viral RNA and PCR products. The lengths of the viral genome (7494 nucleotides [nt] excluding polyA tail) and short 5' untranslated region (14 nt) as well as two predicted open reading frames are similar to those of other SaVs. The amino acid differences between the two porcine SaVs are most frequent in the central region of the VP1-encoding region. A stem-loop structure which was predicted in the first 41 nt of the 5'-terminal region of GV.3 SaVs and the other available complete genome sequences of SaVs may have a critical role in viral genome replication. Our study provides complete genome sequences of rarely reported GV.3 SaV strains and highlights the common 5' terminal genomic feature of SaVs detected from different mammalian species. PMID- 28643181 TI - Promoting acid resistance and nisin yield of Lactococcus lactis F44 by genetically increasing D-Asp amidation level inside cell wall. AB - Nisin fermentation by Lactococcus lactis requires a low pH to maintain a relatively higher nisin activity. However, the acidic environment will result in cell arrest, and eventually decrease the relative nisin production. Hence, constructing an acid-resistant L. lactis is crucial for nisin harvest in acidic nisin fermentation. In this paper, the first discovery of the relationship between D-Asp amidation-associated gene (asnH) and acid resistance was reported. Overexpression of asnH in L. lactis F44 (F44A) resulted in a sevenfold increase in survival capacity during acid shift (pH 3) and enhanced nisin desorption capacity compared to F44 (wild type), which subsequently contributed to higher nisin production, reaching 5346 IU/mL, 57.0% more than that of F44 in the fed batch fermentation. Furthermore, the engineered F44A showed a moderate increase in D-Asp amidation level (from 82 to 92%) compared to F44. The concomitant decrease of the negative charge inside the cell wall was detected by a newly developed method based on the nisin adsorption amount onto cell surface. Meanwhile, peptidoglycan cross-linkage increased from 36.8% (F44) to 41.9% (F44A), and intracellular pH can be better maintained by blocking extracellular H+ due to the maintenance of peptidoglycan integrity, which probably resulted from the action of inhibiting hydrolases activity. The inference was further supported by the acmC-overexpression strain F44C, which was characterized by uncontrolled peptidoglycan hydrolase activity. Our results provided a novel strategy for enhancing nisin yield through cell wall remodeling, which contributed to both continuous nisin synthesis and less nisin adsorption in acidic fermentation (dual enhancement). PMID- 28643182 TI - FvSTR1, a striatin orthologue in Fusarium virguliforme, is required for asexual development and virulence. AB - The soil-borne fungus Fusarium virguliforme causes sudden death syndrome (SDS), one of the most devastating diseases of soybean in North and South America. Despite the importance of SDS, a clear understanding of the fungal pathogenicity factors that affect the development of this disease is still lacking. We have identified FvSTR1, a F. virguliforme gene, which encodes a protein similar to a family of striatin proteins previously reported to regulate signalling pathways, cell differentiation, conidiation, sexual development, and virulence in filamentous fungi. Striatins are multi-domain proteins that serve as scaffolding units in the striatin-interacting phosphatase and kinase (STRIPAK) complex in fungi and animals. To address the function of a striatin homologue in F. virguliforme, FvSTR1 was disrupted and functionally characterized using a gene knock out strategy. The resulting Fvstr1 mutants were largely impaired in conidiation and pigmentation, and displayed defective conidia and conidiophore morphology compared to the wild-type and ectopic transformants. Greenhouse virulence assays revealed that the disruption of FvSTR1 resulted in complete loss of virulence in F. virguliforme. Microtome studies using fluorescence microscopy showed that the Fvstr1 mutants were defective in their ability to colonize the vascular system. The Fvstr1 mutants also showed a reduced transcript level of genes involved in asexual reproduction and in the production of secondary metabolites. These results suggest that FvSTR1 has a critical role in asexual development and virulence in F. virguliforme. PMID- 28643185 TI - Keeping Disability in Mind: A Case Study in Implantable Brain-Computer Interface Research. AB - Brain-Computer Interface (BCI) research is an interdisciplinary area of study within Neural Engineering. Recent interest in end-user perspectives has led to an intersection with user-centered design (UCD). The goal of user-centered design is to reduce the translational gap between researchers and potential end users. However, while qualitative studies have been conducted with end users of BCI technology, little is known about individual BCI researchers' experience with and attitudes towards UCD. Given the scientific, financial, and ethical imperatives of UCD, we sought to gain a better understanding of practical and principled considerations for researchers who engage with end users. We conducted a qualitative interview case study with neural engineering researchers at a center dedicated to the creation of BCIs. Our analysis generated five themes common across interviews. The thematic analysis shows that participants identify multiple beneficiaries of their work, including other researchers, clinicians working with devices, device end users, and families and caregivers of device users. Participants value experience with device end users, and personal experience is the most meaningful type of interaction. They welcome (or even encourage) end-user input, but are skeptical of limited focus groups and case studies. They also recognize a tension between creating sophisticated devices and developing technology that will meet user needs. Finally, interviewees espouse functional, assistive goals for their technology, but describe uncertainty in what degree of function is "good enough" for individual end users. Based on these results, we offer preliminary recommendations for conducting future UCD studies in BCI and neural engineering. PMID- 28643187 TI - Suprasternal notch echocardiography: a potential alternative for the measurement of respiratory variation in aortic blood flow peak velocity in mechanically ventilated children. AB - We conducted a prospective, observational study to investigate the relationship between the respiratory variation in aortic blood flow peak velocity (DeltaVPeak) measured by echocardiography in the proximal ascending aorta from the suprasternal notch window and the DeltaVPeak measured at the level of the aortic annulus from the classical apical five-chamber view. We studied children aged from 1 to 10 years referred for surgery under general anesthesia with positive pressure ventilation, after induction of general anesthesia. Twenty-two children (mean age = 5 +/- 3 years) were recruited. There was a significant relationship between the DeltaVPeak recorded via the suprasternal notch view and the DeltaVPeak recorded via the apical five-chamber view (r = 0.62 [95% confidence interval 0.25-0.84], P = 0.003). The DeltaVPeak measured using the suprasternal notch route could be considered to predict fluid responsiveness in children under mechanical ventilation, notably when the access to the chest wall is limited during surgery. PMID- 28643183 TI - Dopaminergic Therapies for Non-motor Symptoms in Parkinson's Disease. AB - Apart from the typical motor symptoms, Parkinson's disease is characterized by a wide range of different non-motor symptoms, which are highly prevalent in all stages of the disease and have an incisive influence on quality of life. Moreover, their treatment continues to be challenging. In this review, we critically summarize the evidence for the impact of dopaminergic therapies on non motor symptoms in Parkinson's disease. We performed a PubMed search to identify relevant clinical studies that investigated the response of non-motor symptoms to dopaminergic therapy. In the domain of neuropsychiatric disturbances, there is increasing evidence that dopamine agonists can ameliorate depression or anxiety. Other neuropsychiatric symptoms such as psychosis or impulse control disorders can also be worsened or even be induced by dopaminergic agents. For the treatment of sleep disturbances, it is essential to identify different subtypes of sleep pathologies. While there is for example profound evidence for the effectiveness of dopaminergic medication for the treatment of restless legs syndrome and sleep fragmentation, evidence for an improvement of rapid eye movement sleep behavior disorder is lacking. With regard to the broad spectrum of autonomic disturbances, response to dopaminergic treatment seems to differ largely, with on the one hand, some evidence for an improvement of sexual function or sweating with dopaminergic treatment, while on the other hand, constipation can be worsened. Finally, the analysis of sensory deficits reveals that some forms of pain, in particular fluctuation-dependent dystonic pain, can be well addressed by adapting the dopaminergic therapy, while no effect has been seen so far for hyposmia or visual deficits. Moreover, the occurrence of non-motor fluctuations is gaining increased attention, as they can be specifically addressed by a more continuous dopaminergic intake. Taken together, there is evidence of a good response of some (but not all) non-motor symptoms to dopaminergic therapy, which must be individually adapted to the special spectrum of symptoms. PMID- 28643186 TI - Current progress in host innate and adaptive immunity against hepatitis C virus infection. AB - Hepatitis C virus (HCV) infects more than 170 million people worldwide and is the main cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the newly developed direct-acting antivirals (DAAs) have transformed the treatment of HCV infection, controlling HCV infection on a global scale remains a challenge because of the high cost, low resistance barrier of DAAs and lack of HCV vaccine. The host immune responses associated with HCV infection, especially HCV-specific T cellular immunity, determine the outcome of HCV infection: either acute or chronic infection. It is important to fully interpret the immunopathogenesis of HCV infection and consequently to exploit effective strategies to eliminate HCV. Here, we review the current progress in HCV immunology, which will deepen our understanding of the spectrum of HCV infection and immunity in humans. PMID- 28643188 TI - Impact of appropriateness of empiric therapy on outcomes in community-onset bacteremia by extended-spectrum-beta-lactamase producing Escherichia coli and Klebisella pneumoniae definitively treated with carbapenems. AB - Despite a significant increase of bloodstream infection caused by extended spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae in the community setting, information regarding clinical outcomes of inappropriate empiric therapy (IAT) in patients with those infections is limited. A multicenter-retrospective cohort study was conducted in four hospitals. A total of 249 adults were identified to have community-onset bacteremia caused by ESBL-producing Escherichia coli and Klebsiella pneumoniae, and definitively treated with carbapenems. According to the appropriateness of empiric therapy, individuals were divided into an appropriate empiric therapy (AT) group (n = 106) and IAT group (n = 143). Patients who received AT showed more severe underlying conditions including underlying solid cancer, healthcare-association and intensive care unit (ICU) care, compared to the IAT group. Primary bacteremia was more commonly found in the AT group than in the IAT group, while urinary tract infection predominated more frequently in the IAT group than in the AT group. Multivariate analysis using propensity score analysis indicated that inappropriateness of empiric therapy was not an independent risk factor for 30 day death. ICU care, respiratory tract infection and underlying liver, renal and connective tissue diseases were significantly associated with mortality. In patients with bloodstream infections caused by ESBL-producing E. coli and K. pneumoniae in the community-setting, delay in appropriate therapy was not associated with an increased rate of death if the patients were definitively treated with carbapenems. PMID- 28643189 TI - Cryogenic Vibrational Spectroscopy Provides Unique Fingerprints for Glycan Identification. AB - The structural characterization of glycans by mass spectrometry is particularly challenging. This is because of the high degree of isomerism in which glycans of the same mass can differ in their stereochemistry, attachment points, and degree of branching. Here we show that the addition of cryogenic vibrational spectroscopy to mass and mobility measurements allows one to uniquely identify and characterize these complex biopolymers. We investigate six disaccharide isomers that differ in their stereochemistry, attachment point of the glycosidic bond, and monosaccharide content, and demonstrate that we can identify each one unambiguously. Even disaccharides that differ by a single stereogenic center or in the monosaccharide sequence order show distinct vibrational fingerprints that would clearly allow their identification in a mixture, which is not possible by ion mobility spectrometry/mass spectrometry alone. Moreover, this technique can be applied to larger glycans, which we demonstrate by distinguishing isomeric branched and linear pentasaccharides. The creation of a database containing mass, collision cross section, and vibrational fingerprint measurements for glycan standards should allow unambiguous identification and characterization of these biopolymers in mixtures, providing an enabling technology for all fields of glycoscience. Graphical Abstract ?. PMID- 28643190 TI - Mitochondrial biogenesis and neural differentiation of human iPSC is modulated by idebenone in a developmental stage-dependent manner. AB - Idebenone, the synthetic analog of coenzyme Q10 can improve electron transport in mitochondria. Therefore, it is used in the treatment of Alzheimer's disease and other cognitive impairments. However, the mechanism of its action on neurodevelopment is still to be elucidated. Here we demonstrate that the cellular response of human induced pluripotent stem cells (hiPSC) to idebenone depends on the stage of neural differentiation. When: neural stem cells (NSC), early neural progenitors (eNP) and advanced neural progenitors (NP) have been studied a significant stimulation of mitochondrial biogenesis was observed only at the eNP stage of development. This coexists with the enhancement of cell viability and increase in total cell number. In addition, we report novel idebenone properties in a possible regulation of neural stem cells fate decision: only eNP stage responded with up-regulation of both neuronal (MAP2), astrocytic (GFAP) markers, while at NSC and NP stages significant down-regulation of MAP2 expression was observed, promoting astrocyte differentiation. Thus, idebenone targets specific stages of hiPSC differentiation and may influence the neural stem cell fate decision. PMID- 28643192 TI - On the kinetics of body versus end evaporation and addition of supramolecular polymers. AB - The kinetics of the self-assembly of supramolecular polymers is dictated by how monomers, dimers, trimers etc., attach to and detach from each other. It is for this reasons that researchers have proposed a plethora of pathways to explain the kinetics of various self-assembling supramolecules, including sulfur, linear micelles, living polymers and protein fibrils. Recent observations hint at the importance of a hitherto ignored molecular aggregation pathway that we refer to as "body evaporation and addition". In this pathway, monomers can enter at or dissociate from any point along the backbone of the polymer. In this paper, we compare predictions for the well-established end evaporation and addition pathway with those that we obtained for the newly proposed body evaporation and addition model. We quantify the lag time, characteristic of nucleated reversible polymerisation, in terms of the time it takes to obtain half of the steady-state polymerised fraction and the apparent growth rate at that point, and obtain power laws for both as a function of the total monomer concentration. We find, perhaps not entirely unexpectedly, that the body evaporation and addition pathway speeds up the relaxation of the polymerised monomeric mass relative to that of the end evaporation and addition. However, the presence of the body evaporation and addition pathway does not affect the dependence of the lag time on the total monomer concentration and it remains the same as that for the case of end evaporation and addition. The scaling of the lag time with the forward rate is different for the two models, suggesting that they may be distinguished experimentally. PMID- 28643191 TI - Role of Obesity Variables in Detecting Hypertension in an Iranian Population. AB - INTRODUCTION: As the high incidence of hypertension has been in conjunction with dramatic increase in the prevalence of obesity, many studies have suggested obesity as its underlying cause in diverse race and ethnic groups. AIM: The present study was designed to quantify the relationship between obesity variables and hypertension in Iranian population. A ROC curve analysis was also used to determine an optimal BMI cutoff for obesity with the aim of representing elevated incidence of hypertension in this population. METHODS: The study population comprised of apparently healthy men and women who participated in the Iranian Multi-centric Osteoporosis Studies (IMOS), a multi-centric cross-sectional study carried out in urban areas of five great cities (Tehran, Tabriz, Mashhad, Shiraz and Bushehr). The anthropometric (weight, height, waist and hip circumferences) and blood pressure measures were reported in some 5724 subjects. The influence of these factors on systolic and diastolic blood pressure was assessed based on a list-wise method. RESULTS: There was a significant difference in the studied subjects anthropometric (weight classes (BMI), WC and HC, and WHR) and blood pressure variables; age, gender and weight, however, were the only factors significantly influencing SBP and DBP. Furthermore, BMI showed a significant impact on the overall risk of developing hypertension. CONCLUSION: General obesity rather than abdominal obesity is directly linked with higher blood pressure levels in Iranian population. PMID- 28643194 TI - Erratum to: Pitfalls in compressed sensing reconstruction and how to avoid them. PMID- 28643193 TI - Assessing cancer-specific anxiety in Chinese men with prostate cancer: psychometric evaluation of the Chinese version of the Memorial Anxiety Scale for Prostate Cancer (MAX-PC). AB - PURPOSE: The Memorial Anxiety Scale for Prostate Cancer (MAX-PC) was developed to identify and assess cancer-specific anxiety among men with prostate cancer (PCa); however, there is no Chinese version. The aim of our study was to translate the English version of MAX-PC into Chinese and evaluate the psychometric properties of it. METHODS: The study cohort comprised 254 participants. Internal consistency including the Cronbach's alpha coefficient and item-total correlations were used to measure the reliability of the scale. Factor structure was analyzed by exploratory factor analysis and concurrent validity by comparing MAX-PC scores with anxiety subscale scores of the Hospital Anxiety and Depression Scale (HADS). Divergent validity was assessed by correlating MAX-PC with HADS depression subscale, while discriminant ability by comparing differences in MAX-PC scores between different patient groups. RESULTS: The Chinese version of MAX-PC demonstrated good reliability; the Cronbach's alpha coefficient for the total and three subscales (prostate cancer anxiety, PSA anxiety, and fear of recurrence) being 0.94, 0.93, 0.82, and 0.85, respectively. Exploratory factor analysis supported the three-factor structure of the scale established in the original version. Despite the somewhat underperformed divergent validity, the scale demonstrated good concurrent validity with a strong correlation with the HADS anxiety subscale (r = 0.71, p < 0.01). Moreover, discriminant ability was demonstrated by ability to differentiate between disease stages. CONCLUSIONS: The MAX-PC Chinese version was confirmed to be a valid, reliable instrument and is thus appropriate for identifying and quantifying cancer-specific anxiety in Chinese PCa patients. PMID- 28643195 TI - A convenient immunochromatographic test strip for rapid detection of Scylla serrata reovirus. PMID- 28643196 TI - Genetic variants in cell death pathway genes and HBV-related hepatocellular carcinoma among a Chinese Han population. AB - Cell death pathway plays an important role in apoptosis, and corruption of this signaling pathway has been shown to participate in carcinogenesis. We aimed at determining whether genetic variants in CASP8, CASP10 and CFLAR influence the development and clinical outcomes of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). A hospital-based case-control study, including 600 HCC cases and 600 HBsAg positive controls without HCC, was conducted to assess the relationship between 11 tagging SNPs in CASP8, CASP10 and CFLAR and HBV-related HCC risk and prognosis in a Chinese Han population. Among the 11 polymorphisms, only CASP8 rs3834129 (-652 6N ins/del) modified HCC risk. Compared with CASP8 -652 insins genotype, the deldel (adjusted OR 0.717, 95% CI 0.553 0.930) and insdel (adjusted OR 0.731, 95% CI 0.554-0.964) genotypes had a significantly decreased HCC risk. Furthermore, this polymorphism was significantly associated with decreased portal vein tumor thrombosis (adjusted OR 0.554; P = 0.044) and reduced postoperative recurrence (adjusted OR 0.356; P < 0.001) of resected HCC. In addition, the multivariate analysis showed that the 652 6N ins/del polymorphism was significantly associated with improved overall survival and recurrence-free survival of resected HCC patients. The expression levels of CASP8 in HCC tumor tissues were significantly lower than those in paracancerous liver tissues, although no significant association between -652 6N ins/del genotypes and the expression levels of CASP8 were observed in these tissues. These results suggest that the CASP8 -652 6N ins/del polymorphism may play a protective role in the development, progression, and survival of HBV related HCC among the Chinese Han population. PMID- 28643197 TI - AMPK is activated early in cerebellar granule cells undergoing apoptosis and influences VADC1 phosphorylation status and activity. AB - The neurodegeneration of cerebellar granule cells, after low potassium induced apoptosis, is known to be temporally divided into an early and a late phase. Voltage-dependent anion channel-1 (VDAC1) protein, changing from the closed inactive state to the active open state, is central to the switch between the early and late phase. It is also known that: (i) VDAC1 can undergo phosphorylation events and (ii) AMP-activated protein kinase (AMPK), the sensor of cellular stress, may have a role in neuronal homeostasis. In the view of this, the involvement of AMPK activation and its correlation with VDAC1 status and activity has been investigated in the course of cerebellar granule cells apoptosis. The results reported in this study show that an increased level of the phosphorylated, active, isoform of AMPK occurs in the early phase, peaks at 3 h and guarantees an increase in the phosphorylation status of VDCA1, resulting in a reduced activity of this latter. However this situation is transient in nature, since, in the late phase, AMPK activation decreases as well as the level of phosphorylated VDAC1. In a less phosphorylated status, VDAC1 fully recovers its gating activity and drives cells along the death route. PMID- 28643199 TI - Airway arteriovenous malformation in pregnancy. PMID- 28643198 TI - Urokinase plasminogen activator protects cardiac myocytes from oxidative damage and apoptosis via hOGG1 induction. AB - The role of uPA in tissue remodeling and cell migration is already well established. In addition, uPA was reported to stabilize p53, a key cell cycle control, DNA repair and apoptosis initiation protein. We aimed to determine the role of uPA-uPAR signaling towards cell survival or apoptosis in human adult cardiac myocytes (HACM). HACM were stimulated with uPA and DNA damage was inflicted by incubating cells with 200 uM H2O2. To analyze for apoptotic cells we applied TUNEL staining. Oxidative damage foci were analyzed by staining for 8 oxoguanine base pairs. In vivo qPCR analysis from RNA extracted from failing human hearts demonstrated a close relation of uPA with apoptosis and the p53 pathway. Furthermore, we observed a close correlation of uPA and p53 protein in homogenized tissue lysates. In vitro studies revealed that uPA preincubation protected HACM from oxidative damage induced cell death and reduced oxidative damage foci. uPA protection is independent of its catalytic activity, as the amino terminal fragment of uPA showed similar protection. A key enzyme for repairing oxidative DNA damage is the p53 target hOGG1. We found a significant increase of hOGG1 after pretreatment of HACM with uPA. Knockdown of hOGG1 completely abrogated the protective effect of uPA. We conclude that uPA might have a tissue protective role in human hearts besides its role in tissue remodeling. Tissue protection is mediated by the DNA repair protein hOGG1. This might be beneficial during tissue remodeling and thus could be a target for therapeutic approaches in the diseased heart. PMID- 28643200 TI - Tracheal bronchus: an unusual cause of difficult ventilation. PMID- 28643202 TI - Specific IgM and Regulation of Antibody Responses. AB - Specific IgM, administered together with the antigen it recognizes, enhances primary antibody responses, formation of germinal centers, and priming for secondary antibody responses. The response to all epitopes on the antigen to which IgM binds is usually enhanced. IgM preferentially enhances responses to large antigens such as erythrocytes, malaria parasites, and keyhole limpet hemocyanine. In order for an effect to be seen, antigens must be administered in suboptimal concentrations and in close temporal relationship to the IgM. Enhancement is dependent on the ability of IgM to activate complement, but the lytic pathway is not required. Enhancement does not take place in mice lacking complement receptors 1 and 2 (CR1/2) suggesting that the role of IgM is to generate C3 split products, i.e., the ligands for CR1/2. In mice, these receptors are expressed on follicular dendritic cells (FDCs) and B cells. Optimal IgM mediated enhancement requires that both cell types express CR1/2, but intermediate enhancement is seen when only FDCs express the receptors and low enhancement when only B cells express them. These observations imply that IgM mediated enhancement works through several, non-mutually exclusive, pathways. Marginal zone B cells can transport IgM-antigen-complement complexes, bound to CR1/2, from the marginal zone and deposit them onto FDCs. In addition, co crosslinking of the BCR and the CR2/CD19/CD81 co-receptor complex may enhance signaling to specific B cells, a mechanism likely to be involved in induction of early extrafollicular antibody responses. PMID- 28643203 TI - Nonhuman Primate Models of Ebola Virus Disease. AB - Ebola virus disease (EVD) in humans is associated with four ebolaviruses: Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Tai Forest virus. To date, no documented cases of human disease have been associated with Reston virus. Here, we describe the nonhuman primate (NHP) models that currently serve as gold standards for testing ebolavirus vaccines and therapeutic agents and elucidating underlying mechanisms of pathogenesis. Although multiple models have been explored over the past 50 years, the predominance of published work has been performed in macaque models. This chapter will focus on the most commonly used models. PMID- 28643204 TI - Host Factors in Coronavirus Replication. AB - Coronaviruses are pathogens with a serious impact on human and animal health. They mostly cause enteric or respiratory disease, which can be severe and life threatening, e.g., in the case of the zoonotic coronaviruses causing severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) in humans. Despite the economic and societal impact of such coronavirus infections, and the likelihood of future outbreaks of additional pathogenic coronaviruses, our options to prevent or treat coronavirus infections remain very limited. This highlights the importance of advancing our knowledge on the replication of these viruses and their interactions with the host. Compared to other +RNA viruses, coronaviruses have an exceptionally large genome and employ a complex genome expression strategy. Next to a role in basic virus replication or virus assembly, many of the coronavirus proteins expressed in the infected cell contribute to the coronavirus-host interplay. For example, by interacting with the host cell to create an optimal environment for coronavirus replication, by altering host gene expression or by counteracting the host's antiviral defenses. These coronavirus host interactions are key to viral pathogenesis and will ultimately determine the outcome of infection. Due to the complexity of the coronavirus proteome and replication cycle, our knowledge of host factors involved in coronavirus replication is still in an early stage compared to what is known for some other +RNA viruses. This review summarizes our current understanding of coronavirus host interactions at the level of the infected cell, with special attention for the assembly and function of the viral RNA-synthesising machinery and the evasion of cellular innate immune responses. PMID- 28643205 TI - Role of Host Genes in Influenza Virus Replication. AB - At every step of their replication cycle influenza viruses depend heavily on their host cells. The multifaceted interactions that occur between the virus and its host cell determine the outcome of the infection, including efficiency of progeny virus production, tropism, and pathogenicity. In order to understand viral disease and develop therapies for influenza it is therefore pertinent to study the intricate interplay between influenza viruses and their required host factors. Here, we review the current knowledge on host cell factors required by influenza virus at the different stages of the viral replication cycle. We also discuss the roles of host factors in zoonotic transmission of influenza viruses and their potential for developing novel antivirals. PMID- 28643206 TI - Right visual-field advantage in the attentional blink: Asymmetry in attentional gating across time and space. AB - When two targets are presented in a rapid serial visual presentation (RSVP), recognition of the second target (T2) is usually reduced when presented 150-500 ms after the first target, demonstrating an attentional blink (AB). Previous studies have shown a left visual-field (LVF) advantage in T2 recognition, when T2 was embedded in one of two streams, demanding top-down attention for its recognition. Here, we explored the impact of bottom-up saliency on spatial asymmetry in the AB. When T2 was spatially shifted outside from the RSVP, creating an abrupt onset of T2, right T2s showed a right visual-field (RVF) advantage. In lag-1 trials, right T2s were not only better recognized, but also showed a low T1-T2 order error rate. In contrast, recognized left T2s exhibited high order error rate. Without abrupt onset, symmetrical AB was found and order error rate was similarly low in both sides. Follow-up experiments showed that, while RVF advantage was related to bottom-up saliency, order errors were affected by T1 mask. The discrepancy between LVF and RVF advantage in the AB could be resolved in terms of two mechanisms of attentional gating: top-down attentional gating, which is biased towards LVF, and bottom-up attentional gating, which is biased towards RVF. PMID- 28643207 TI - Parental Depressive Symptoms as a Predictor of Outcome in the Treatment of Child Depression. AB - Child depression is an impairing condition for which psychotherapies have shown modest effects. Parental depression is a risk factor for development of child depression and might also be negatively associated with child depression treatment outcomes. To explore this possibility, we analyzed data from a study in which children were treated for depression after parental depressive symptoms had been assessed at baseline. Among children treated for depression in a randomized controlled trial, we identified 31 who had child- and parent-report pre- and post treatment data on child symptoms and parent-report of pre-treatment parental depressive symptoms. Children were aged 8-13, 77% boys, and 52% Caucasian, 13% African-American, 6% Latino, and 29% multi-racial. Analyses focused on differences in trajectories of change (across weekly measurements), and post treatment symptoms among children whose parents did (n = 12) versus did not (n = 19) have elevated depressive symptoms at baseline. Growth curve analyses showed markedly different trajectories of change for the two groups, by both child report (p = 0.03) and parent-report (p = 0.03) measures: children of parents with less severe depression showed steep symptom declines, but children of parents with more severe depression showed flat trajectories with little change in symptoms over time. ANCOVAs showed lower post-treatment child symptoms for children of parents with less severe depression versus parents with more severe depression (p = 0.05 by child report, p = 0.01 by parent report). Parental depressive symptoms predict child symptom trajectories and poorer child treatment response, and may need to be addressed in treatment. PMID- 28643208 TI - Visual outcomes after endoscopic endonasal pituitary adenoma resection: a systematic review and meta-analysis. AB - PURPOSE: Patients with pituitary adenomas often present with visual deficits. While the aim of endoscopic endonasal transsphenoidal surgery (EETS) is to improve these deficits, permanent worsening is a possible outcome. The aim of this meta-analysis was to evaluate the effect of EETS for pituitary adenomas on visual outcomes. METHODS: A meta-analysis was conducted according to the PRISMA guidelines. Pooled prevalence was calculated for complete recovery, improvement, and deterioration of visual field deficits, visual acuity and unspecified visual function in fixed- and random-effect models, including assessment of heterogeneity (I2) and publication bias (Begg's test). RESULTS: Out of 2636 articles, 35 case series were included in the meta-analysis. Results are described for fixed-effect models. For patients with impaired visual acuity, only one study reported complete recovery (27.2%). Pooled prevalence for improvement was 67.5% (95% CI = 59.1-75.0%), but with considerable heterogeneity (I2: 86.0%), and 4.50% (95% CI = 1.80-10.8%) for patients experiencing deterioration. For patients with visual field deficits, the prevalence was 40.4% (95% CI = 34.8 46.3%) for complete recovery, 80.8% (95% CI = 77.7-83.6%) for improvement, and 2.3% (95% CI = 1.1-4.7%) for deterioration. For the unspecified visual outcomes, pooled prevalence of complete recovery was 32.9% (95% CI: 28.5-37.7%), but with considerable heterogeneity (I2 = 84.2%). The prevalence was 80.9% (95% CI = 77.9 83.6) for improvement and 2.00% (95% CI = 1.10-3.40%) for deterioration. Random effect models yielded similar results. Publication bias was non-significant for all the outcomes. CONCLUSION: While visual deficits improved after EETS in the majority of patients, complete recovery was only achieved in less than half of the patients and some patients even suffered from visual deterioration. PMID- 28643210 TI - The "very rare" unusual sites venous thromboses. PMID- 28643211 TI - Do Energy Drink Consumers Study More? AB - The use and motivations for use of energy drinks (EDs) in college students has been documented in the literature. Many college students identify academic reasons, such as a need to study more, as a motivation for ED use. However, research has not determined if users who claim academic motivations actually study more than those who claim other motivations. A sample of 692 undergraduate students at a large, private university completed a paper survey that inquired about demographics, ED use, motivations for ED use, sleep quality, and average amount of time spent sleeping and studying per week. Descriptive statistics were used to analyze demographics, and analysis of variance was used to compare ED users with different motivations to amount of time spent sleeping and studying per week. Regression analysis was also used to determine if ED use could be predicted by any of the other variables. Increased ED consumption was predicted by being male (B = -0.394, p < .001) and having a decreased sleep quality (B = 0.586, p < .001). Reported study hours by subjects who claimed academic reasons as motivation for ED use were not significantly different in comparison to ED users who claimed other motivations. In our sample, ED users who reported academic reasons as motivations for use did not report significantly more study hours per week when compared to those who claimed other motivations. This demonstrates a disconnect between reported motivations for energy drink use and outcomes that are expected to be associated with those motivations. PMID- 28643209 TI - High-Intensity Interval Training Interventions in Children and Adolescents: A Systematic Review. AB - BACKGROUND: Whilst there is increasing interest in the efficacy of high-intensity interval training in children and adolescents as a time-effective method of eliciting health benefits, there remains little consensus within the literature regarding the most effective means for delivering a high-intensity interval training intervention. Given the global health issues surrounding childhood obesity and associated health implications, the identification of effective intervention strategies is imperative. OBJECTIVES: The aim of this review was to examine high-intensity interval training as a means of influencing key health parameters and to elucidate the most effective high-intensity interval training protocol. METHODS: Studies were included if they: (1) studied healthy children and/or adolescents (aged 5-18 years); (2) prescribed an intervention that was deemed high intensity; and (3) reported health-related outcome measures. RESULTS: A total of 2092 studies were initially retrieved from four databases. Studies that were deemed to meet the criteria were downloaded in their entirety and independently assessed for relevance by two authors using the pre-determined criteria. From this, 13 studies were deemed suitable. This review found that high intensity interval training in children and adolescents is a time-effective method of improving cardiovascular disease biomarkers, but evidence regarding other health-related measures is more equivocal. Running-based sessions, at an intensity of >90% heart rate maximum/100-130% maximal aerobic velocity, two to three times a week and with a minimum intervention duration of 7 weeks, elicit the greatest improvements in participant health. CONCLUSION: While high-intensity interval training improves cardiovascular disease biomarkers, and the evidence supports the effectiveness of running-based sessions, as outlined above, further recommendations as to optimal exercise duration and rest intervals remain ambiguous owing to the paucity of literature and the methodological limitations of studies presently available. PMID- 28643212 TI - The Role of Primary Health Care in Hepatitis B Testing and Management: A Case Study. AB - Hepatitis B is a complex disease requiring lifelong management. Infection is linked to birth in high prevalence regions including Africa and Asia. Best practice guidelines identify who to test for hepatitis B, however, a significant proportion of Australians with hepatitis B have not been diagnosed, and are subsequently at risk of serious morbidity and mortality. This study sought to address the gap between current and optimal hepatitis B testing in a primary care clinic with a likely high population of undiagnosed hepatitis B. Between September 2015 and December 2016, four interventions aimed at enhancing general practitioner testing practices were implemented: staff education, quality improvement and patient-triggered activities. Compared to the baseline (2014) the following parameters all increased in 2016: the number of patients tested (15 tests per month in 2014, 24 tests per months in 2016), the correct ordering of the recommended tests (17% in 2014, 61% in 2016) and hepatitis B vaccine dose ordering (n = 35 in 2014, n = 110 in 2016). However, the proportion of patients born in Africa or Asia tested for hepatitis B did not increase. Distribution of a patient held-reminder led to the greatest number of tests being ordered (n = 54 tests ordered in 1 month). Within a single primary care clinic situated in a high hepatitis B prevalence area, an intervention designed to improve adherence to hepatitis B testing guidelines, increased testing levels. A systematic approach can assist general practitioners to improve their understanding of hepatitis B testing and prioritise people most at risk. PMID- 28643213 TI - The difficult legacy of Turing's wager. AB - Describing the human brain in mathematical terms is an important ambition of neuroscience research, yet the challenges remain considerable. It was Alan Turing, writing in 1950, who first sought to demonstrate how time-consuming such an undertaking would be. Through analogy to the computer program, Turing argued that arriving at a complete mathematical description of the mind would take well over a thousand years. In this opinion piece, we argue that - despite seventy years of progress in the field - his arguments remain both prescient and persuasive. PMID- 28643214 TI - New generation devices for transfemoral transcatheter aortic valve replacement are superior compared with last generation devices with respect to VARC-2 outcome. AB - New generation devices for transcatheter aortic valve replacement have been optimized to improve clinical outcome. We compared procedural, in-hospital, 30 days and 12 months outcome of the new generation repositionable Boston Lotus Valve and the balloon-expandable Edwards Sapien 3 valve with the last generation self-expandable Medtronic CoreValve and the balloon-expandable Edwards Sapien XT. Between 2010 and 2015 consecutive patients treated with the Medtronic CoreValve (N = 100), Edwards Sapien XT (N = 100), Edwards Sapien S3 (N = 100) and Boston Lotus device (N = 100) were enrolled. There was no moderate or severe AR with the new generation devices as compared with 11.5% with last generation devices (p < 0.01). None or trace aortic regurgitation was lowest with the Lotus valve. Pacemaker implantation due to II degrees or III degrees atrioventricular block was comparable for the self-expandable CoreValve (21%) and the mechanically deployed Lotus Valve (23%) and lower for the Sapien 3 (15%) and XT valve (8%; p < 0.01). Early safety endpoint at 30 days (21 vs. 9%, p < 0.01), major vascular complications (12 vs. 2.5%, p < 0.01), all-cause mortality (9.5 vs. 2%, p < 0.01) and rate of disabling and non-disabling stroke (7.5 vs. 3.5%, p < 0.01) were significantly lower with the new generation devices. In multivariate analyses, valve type was an independent predictor for 30 days early safety endpoint and 12 months all-cause mortality. TAVR with the new generation Edwards Sapien 3 and Boston Lotus valves was associated with no moderate and severe aortic regurgitation, significantly lower major vascular complications and a significant improvement in 30 days and 12 months outcome.Clinicaltrials.gov NCT02162069. PMID- 28643215 TI - Relationship between instantaneous wave-free ratio and fractional flow reserve in patients receiving hemodialysis. AB - Instantaneous wave-free ratio (iFR) is a vasodilator-free index and is reported to have a good correlation with fractional flow reserve (FFR). Hemodialysis patients exhibit left ventricular hypertrophy, reduced arterial compliance, and impaired microcirculation. Such a coronary flow condition in these patients may influence the relationship between iFR and FFR. This study assessed the impact of hemodialysis on the relationship between iFR and FFR. The study enrolled 196 patients with 265 stenoses who underwent assessment via iFR, FFR assessment, and right heart catheterization. A good correlation between iFR and FFR was observed in hemodialysis patients. iFR in the hemodialysis group was significantly lower than in the non-hemodialysis group (0.81 +/- 0.13 vs. 0.86 +/- 0.13, p = 0.005), although no significant difference was found in FFR and percentage diameter stenosis. An iFR value of 0.84 was found to be equivalent to an FFR value of 0.8 in hemodialysis patients, which was lower than the standard predictive iFR range for ischemia. Vasodilator-free assessment by iFR could be beneficial in evaluating intermediate coronary stenosis in patients receiving hemodialysis. However, the threshold for iFR abnormality needs adjustment in hemodialysis patients, and larger clinical trials are required to confirm the results in this specific subset. PMID- 28643216 TI - Spontaneous coronary artery dissection with a collateral vessel. PMID- 28643217 TI - Frustrated Patients and Fearful Physicians. PMID- 28643218 TI - Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes. AB - PURPOSE: Cardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated. This study was designed to examine the chronic effect of empagliflozin on left ventricular (LV) systolic and diastolic functions in a genetic model of T2DM, ob/ob mice. METHODS AND RESULTS: Cardiac phenotype was characterized by echocardiography, in vivo hemodynamics, histology, and molecular profiling. Our results demonstrate that empagliflozin significantly lowered HbA1c and slightly reduced body weight compared to vehicle treatment with no obvious changes in insulin levels. Empagliflozin also improved LV maximum pressure and in vivo indices of diastolic function. While systolic function was grossly not affected in both groups at steady state, response to dobutamine stimulation was significantly improved in the empagliflozin-treated group, suggesting amelioration of contractile reserve. This was paralleled by an increase in phospholamban (PLN) phosphorylation and increased SERCA2a/PLN ratio, indicative of enhanced SERCA2a function, further supporting improved cardiac relaxation and diastolic function. In addition, empagliflozin reconciled diabetes associated increase in MAPKs and dysregulated phosphorylation of IRS1 and Akt, leading to improvement in myocardial insulin sensitivity and glucose utilization. CONCLUSION: The data show that chronic treatment with empagliflozin improves diastolic function, preserves calcium handling and growth signaling pathways and attenuates myocardial insulin resistance in ob/ob mice, findings suggestive of a potential clinical utility for empagliflozin in the treatment of diastolic dysfunction. PMID- 28643219 TI - Triple Antithrombotic Therapy in Atrial Fibrillation Patients Undergoing PCI: a Fading Role. AB - Triple antithrombotic therapy (TAT), consisting of aspirin, a P2Y12 receptor antagonist and oral anticoagulant (OAC) medication has been considered as an 'unavoidable' strategy for a 1-12 months for atrial fibrillation (AF) patients post acute coronary syndrome or percutaneous coronary angioplasty with stenting. However, TAT has rather poorly been adopted in real life practice, mainly because of an accompanying increased bleeding potential and lack of definitive results of randomized clinical trials. Several registries, meta-analyses and small randomized trials have so far provided the base of guidelines recommendations. Furthermore, in the recently published Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial involving 2124 patients, the primary safety endpoint of clinically significant bleeding was significantly reduced in the rivaroxaban low dose (15 mg daily) plus single P2Y12 receptor antagonist arm compared to TAT, with no difference in the secondary efficacy endpoint. Despite several limitations of the PIONEER AF-PCI trial, it appears that among patients who omit aspirin, there may be equivalent ischemic protection with dual therapy and no disadvantage for additional risk of thrombotic events. PMID- 28643221 TI - Post-exercise blood flow restriction attenuates hyperemia similarly in males and females. AB - PURPOSE: Our laboratory recently demonstrated that post-exercise blood flow restriction attenuated muscle hypertrophy only in females, which we hypothesized may be due to alterations in post-exercise blood flow. The aim of this study is to test our previous hypothesis that sex differences in blood flow would exist when employing the same protocol. METHODS: Twenty-two untrained individuals (12 females; 10 males) performed two exercise sessions, each involving one set of elbow flexion exercise to volitional failure on the right arm. The experimental condition had blood flow restriction applied for a 3 min post-exercise period, whereas the control condition did not. Blood flow was measured using an ultrasound at the brachial artery and was taken 1 and 4 min post-exercise. This corresponded to 1 min post inflation and 1 min post deflation in the experimental condition. RESULTS: There were no differences in the alterations in blood flow between the control and experimental conditions when examined across sex. Increases in blood flow [mean (standard deviation)] were as follows: males 1 min [control 764 (577) %; experimental 113 (108) %], males 4 min [control 346 (313) %; experimental 449 (371) %], females 1 min [control 558 (367) %; experimental 87 (105) %], and females 4 min [control 191 (183) %; experimental 328 (223) %]. CONCLUSION: It does not appear that the sex-specific attenuation of muscle hypertrophy we observed previously can be attributed to different alterations in post-exercise blood flow. Future studies may wish to replicate our previous training study, or examine alternative mechanisms which may be sex specific. PMID- 28643220 TI - Denosumab: an Emerging Therapy in Pediatric Bone Disorders. AB - PURPOSE OF REVIEW: Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), and has emerged as an important novel therapy for skeletal disorders. This article examines the use of denosumab in children. RECENT FINDINGS: Considerable safety and efficacy data exists for denosumab treatment of adults with osteoporosis, bone metastases, and giant cell tumors. Pediatric data is limited; however, evidence suggests denosumab may be beneficial in decreasing bone turnover, increasing bone density, and preventing growth of certain skeletal neoplasms in children. Denosumab's effect on bone turnover is rapidly reversible after drug discontinuation, representing a key difference from bisphosphonates. Rebound increased bone turnover has led to severe hypercalcemia in several pediatric patients. Denosumab is a promising therapy for pediatric skeletal disorders. At present, safety concerns related to rebounding bone turnover and mineral homeostasis impact use of denosumab in children. Research is needed to determine if and how these effects can be mitigated. PMID- 28643222 TI - Ridge preservation using an in situ hardening biphasic calcium phosphate (beta TCP/HA) bone graft substitute-a clinical, radiological, and histological study. AB - BACKGROUND: Post-Extraction ridge preservation using bone graft substitutes is a conservative technique to maintain the width of the alveolar ridge. The objective of the present study was to evaluate an in situ hardening biphasic (HA/beta-TCP) bone graft substitutes for ridge preservation without primary wound closure or a dental membrane. METHODS: A total of 15 patients reported for tooth extraction were enrolled in this study. Implants were placed in average 5.2 +/- 2 months after socket grafting. At this visit, Cone Beam CT (CBCT) images and core biopsies were taken. Implant stability (ISQ) was assessed at the insertion as well as at the day of final restoration. RESULTS: CBCT data revealed 0.79 +/- 0.73 mm ridge width reduction from grafting to implant placement. Histomorphometric analysis of core biopsy samples revealed in average 21.34 +/- 9.14% of new bone in the grafted sites. Primary implant stability was high (ISQ levels 70.3 +/- 9.6) and further increased until final restoration. CONCLUSIONS: The results of this study show that grafting of intact post-extraction sockets using a biphasic in situ hardening bone graft substitute results in an effective preservation of the ridge contour and sufficient new bone formation in the grafted sites, which is imperative for successful implant placement. PMID- 28643223 TI - The effect of membrane exposure on lateral ridge augmentation: a case-controlled study. AB - BACKGROUND: The effect of membrane exposure on guided bone regeneration (GBR) for lateral ridge augmentation has been poorly addressed. This case-controlled study aimed to investigate potential effect of membrane exposure lateral ridge augmentation and subsequent implant placement. METHODS: A total of 14 patients that did receive lateral ridge augmentation procedure using allogeneic cancellous graft particulate in combination with an alloplastic bioresorbable matrix barrier were retrospectively selected for this study. Bone width was measured at the crest with a digital caliper before bone augmentation and at the reopening for implant placement 4 months later for all patients. Cases where primary flap closure was achieved and the barrier did not expose throughout the time until implant placement were assigned to the control group (n = 7). Cases where primary closure could not be achieved or a barrier exposure happened within the first week following the initial surgery were assigned to the test group. RESULTS: The measured alveolar ridge width before surgery as well as after GBR procedure were not statistically significant different between the two groups (p > 0.05). Both groups showed a significant (p < 0.05) increase in their mean alveolar ridge width 4 months after later augmentation procedure, from 3.4 +/- 1.2 to 6.0 +/- 1.1 mm in the control group and from 3.6 +/- 1.0 to 5.0 +/- 1.4 mm in the test group. However, the mean alveolar ridge gain was significantly greater in the control group than in the test group (p < 0.05). Consequently, the reduction of the augmented alveolar ridge was significantly higher in the test group averaging to 4.7 mm than for the control group showing a loss of 3.1 mm after 4 months, respectively. However, in all 14 cases, successful implant placement was achieved after 4 months. CONCLUSIONS: Within the limit of this study, it can be concluded that early exposure of a bioresorbable matrix barrier during lateral ridge augmentation may compromise the results of the GBR procedure but may still result in a favorable alveolar ridge width gain that allows for the placement of dental implants. PMID- 28643225 TI - Using Illumina-Based Sequence Analysis to Guide Probiotic Candidate Selection and Isolation. AB - Selection for probiotic candidates by in vivo experimental trials is time and labor consuming; more informed strategy is needed to select successful probiotic candidates. The aim of the study was to elucidate the microbial taxa transmitted from maize seeds to seedlings during the germination process of maize and their probiotic effects. The bacterial and fungal taxa in kernel germs and sprouts were analyzed by Illumina-based sequencing. The sprouts contained more diverse fungi than those in germs. The bacterial species (OTUs) declined with the germination from germs to the sprouts. However, the endophytic fungal diversity increased during the germination process. Seed-borne dominant bacterial genera Bacillus, Halomonas, and Shewanella and dominant fungal genera Aspergillus were also detected in sprouts. The spore-forming bacteria BS3 isolated directly from sprouts could promote growth of maize seedling and resistance to F. verticillioides under F. verticillioides-infested soils. The results suggested that maize contained core bacterial and fungal taxa during the development from seeds to sprouts, and the core endophytes showed more intimate correlation with host plants than did other microbial taxa. Illumina-based sequence analysis is feasible to guide probiotic candidate selection and isolation. PMID- 28643224 TI - Establishment of a 3D cell culture model of primary bovine mammary epithelial cells extracted from fresh milk. AB - For the investigation of molecular processes underlying diseases of the bovine mammary gland, primary bovine mammary epithelial cells (pbMEC) are used. They are known to contribute to the innate immune system of the bovine mammary gland. The functionality of pbMEC depends on the maintenance of in vivo characteristics. So far, the optimization of pbMEC culture conditions was intended in a variety of experiments. For this purpose, most of the studies used stable cell lines or primary cells obtained from udder biopsies of slaughtered animals. By contrast, within our study, pbMEC of healthy and first lactating Brown Swiss cows were non invasively isolated from fresh milk. The non-invasively isolated pbMEC were cultivated on the extracellular matrix-like scaffold Matrigel(r). Further, they were challenged with different compositions of proliferation media, containing lactogenic hormones and/or the essential amino acid L-lysine. Changes in expression levels of genes coding for milk proteins and for components of the janus kinase/signal transducers and activators of transcription (JAK-STAT) and mTOR pathways were analyzed by RT-qPCR. The secreted proteins were analyzed by LC MS/MS measurements. We showed for the first time the establishment of a physiologically functional 3D cell culture model of pbMEC isolated from fresh milk. This represents a primary cell culture model system, based on non-invasive cell collection, that can be used to unravel physiological processes in an unbiased manner. PMID- 28643226 TI - Capsular Polysaccharides of Lactobacillus spp.: Theoretical and Practical Aspects of Simple Visualization Methods. AB - Lactobacillus strains can synthesize capsular polysaccharides (CPS), which are important substances in the dairy industry-they exhibit many important technological as well as health-promoting properties. Technological advancements have made it possible to detect bacterial capsules using costly and labor intensive methods, such as serological reactions, molecular genetic techniques, and electron microscopy. Light microscopy, which is the method of interest in this paper, is one of the most widely accessible and cheapest techniques. CPS may be observed under a light microscope after staining bacterial cells and the background with a basic die and an acidic die, respectively (negative-positive staining), with the capsules remaining transparent. The literature offers many polysaccharide staining methods, but due to the considerable structural diversity of CPS and possible dye-capsule interactions, a suitable staining technique should be carefully selected for each strain. The current study showed that not all methods adequately reveal Lactobacillus CPS, with the most effective ones being those proposed by Hiss and Maneval. PMID- 28643227 TI - Preparation and Characterization of Alginate Microparticles Containing a Model Protein for Oral Administration in Gnotobiotic European Sea Bass (Dicentrarchus labrax) Larvae. AB - Aquaculture is the fastest growing animal production sector. However, the production of marine fish is still hampered by the high mortality rate in the first few weeks after hatching. Mortality in larvae is often caused by microbial infections. Today, the incorporation of immunostimulants into microparticles provides us new tools to enhance disease resistance in marine larviculture. In this study, we prepared alginate microparticles loaded with the model antigen fluorescein isothiocyanate conjugated-bovine serum albumin. Optimum concentrations of alginate and CaCl2, the correct alginate viscosity and the appropriate preparatory conditions led to the creation of desirable microparticles with the correct size for oral feeding in gnotobiotic European sea bass larvae. The prepared alginate microparticles were stable in sea water and were successfully ingested by gnotobiotic sea bass larvae at day after hatching 7 without causing any negative effects. Results suggest the suitability of this drug delivery system for targeting the innate immune system of fish larvae in order to enhance disease resistance and thus reduce mortality in larviculture. PMID- 28643228 TI - A urologic stethoscope? Urologist performed sonography using a pocket-size ultrasound device in the point-of-care setting. AB - PURPOSE: Ultrasound is commonly used in urology. Technical advances with reduced size and cost led to diffusion of small ultrasound devices to many clinical settings. Even so, most ultrasound studies are performed by non-urologists. We aimed to evaluate the utility of a pocket-size ultrasound device (VscanTM GE Healthcare) and the quality of urologist performed study. METHODS: Three consecutive studies were performed: (1) a urologist using the pocket ultrasound, (2) a sonographist using the pocket ultrasound, and (3) a sonographist using a standard ultrasound device. Thirty-six patients were evaluated with a basic urologic ultrasound study. An excepted deviation between studies was preset for numeric parameters and t test performed. Ordinal parameters were analyzed using Cohen's kappa coefficient. RESULTS: Kidney length, renal pelvis length, renal cyst diameter, post-void residual and prostate volume (transabdominal) differences were found to be insignificant when comparing a urologist pocket ultrasound study to a sonographist standard ultrasound study (P = 0.15; P = 0.21; P = 0.81; P = 0.32; P = 0.07, respectively). Hydronpehrosis evaluation (none, mild, moderate and severe) and the presence of ureteral jet signs conferred a high inter-observer agreement when comparing the above studies using the Cohen's kappa coefficient (K = 0.63; K = 0.62, respectively). CONCLUSIONS: Urologist performed pocket ultrasound study is valid in evaluating the upper and lower urinary tract and is practical in many clinical scenarios. The urologic stethoscope is now becoming a reality within reach. PMID- 28643229 TI - Progressive multifocal leukoencephalopathy in a patient with lymphoma and presumptive hyper IgE syndrome. AB - We, herein, report a 23-year-old male with a rare inherited immunodeficiency disease, hyperimmunoglobulin IgE syndrome (HIES), who developed progressive multifocal leukoencephalopathy (PML) and lymphoma simultaneously. Primary immunodeficiency of the patient has remained undiagnosed until adulthood. PML is a severe demyelinating disease of the central nervous system caused by John Cunningham virus. HIES is a rare, inherited immunodeficiency characterized by high serum levels of IgE, recurrent staphylococcal infection, eczema, and hypereosinophilia. PML may accompany primary immunodeficiency syndromes, but the association with HIES is exceedingly rare. We discuss the imaging findings, medical management, and a review of related literature on primary immunodeficiency cases complicating with PML. PMID- 28643230 TI - Crosstalk between M2 macrophages and glioma stem cells. AB - PURPOSE: Given its extremely poor prognosis, there is a pressing need for an improved understanding of the biology of glioblastoma multiforme (GBM), including the roles of tumor subpopulations that may contribute to their growth rate and therapy resistance. The most malignant phenotypes of GBM have been ascribed to the presence of subpopulations of cancer stem cells (CSCs), which are resistant to chemotherapeutic drugs and ionizing radiation and which promote invasiveness and metastasis. The mechanisms by which the CSC state is obtained and by which it promotes tumor maintenance are only beginning to emerge. We hypothesize that M2 polarized macrophages may affect CSC phenotypes via cell-cell communication. METHODS: We investigated the interplay between glioma CSCs and macrophages via co culture. The invasiveness of CSCs in the absence and presence of macrophages was assessed using collagen degradation and Transwell migration assays. The role of STAT3 as a CSC phenotypic mediator was assessed using siRNA-mediated gene silencing. RESULTS: We found that the levels of a M2 macrophage-specific secreted cytokine, TGF-beta1, were elevated in the presence of CSCs, regardless of whether the cells were plated as contacting or non-contacting co-cultures. In addition, we found that the co-culture resulted in enhanced expression of M2 markers in macrophages that were previously polarized to the M1 phenotype. siRNA-mediated STAT3 silencing was found to reduce the chemo-responsiveness and migratory abilities of the CSCs. Combination treatment of STAT3 siRNA and DNA alkylating agents was found to further abrogate CSC functions. CONCLUSIONS: Our data indicate that the co-culture of CSCs and macrophages results in bi-directional signaling that alters the phenotypes of both cell types. These results provide an explanation for recently observed effects of macrophages on GBM tumor cell growth, motility and therapeutic resistance, and suggest potential therapeutic strategies to disrupt the CSC phenotype by impairing its communication with macrophages. PMID- 28643231 TI - Demodex Blepharitis Treated with a Novel Dilute Povidone-Iodine and DMSO System: A Case Report. AB - INTRODUCTION: Povidone-iodine aqueous solution is an antiseptic commonly used in ophthalmology for treatment of the ocular surface. Dimethylsulfoxide (DMSO) is a well-known skin penetration enhancer that is scarcely utilized in ophthalmic drug formulations. We describe here a low-dose formulation of 0.25% PVP-I in a gel containing DMSO for the treatment of Demodex blepharitis. CASE REPORT: A 95-year old female presented with chronic blepharitis involving both the anterior and posterior eyelid margins. The anterior eyelid margins demonstrated pathognomonic features consistent with Demodex infection, and this diagnosis was confirmed with microscopy. Previous traditional therapies had been ineffective at controlling her signs and symptoms. CONCLUSION: The topical PVP-I/DMSO system was effective at treating the signs and symptoms of Demodex blepharitis. Further investigation of the novel agent is warranted. PMID- 28643234 TI - Body Mass Disorders in Healthy Short Children and in Children with Growth Hormone Deficiency. AB - The aim of the study was to determine the degree of adiposity and the incidence of body mass disorders, including abdominal obesity, in healthy short children and children with growth hormone deficiency. The study included 134 short children (height < 10th percentile) aged 7-15. In this cohort there were 63 (31 boys and 32 girls) children without diagnosed hormonal disorders and 71 patients (35 boys and 36 girls) with growth hormone deficiency. Basic somatic features were assessed and the study participants were categorized according to the percentage of body fat (%FAT), body mass index (BMI), and waist-to-height ratio (WHtR). We found that there were no significant differences in %FAT and the incidence of body weight disorders depending on gender or diagnosis. %FAT deficit was observed in 12-21% of the participants and underweight in almost every fourth child. Overweight involved 3-14% of the participants and obesity was diagnosed in isolated cases (0-3%); both were considerably lower compared to the estimates based on %FAT. Using the cut-off points of WHtR, abdominal adiposity was observed in 3-15% of the participants. In conclusion, quite a large number of short children (between 25 and 50%) are characterized by abnormal body fat or body mass index values. The results indicate a limited usefulness of BMI in evaluating the incidence of overweight and obesity in children characterized by a height deficit. PMID- 28643232 TI - Caffeine Protects Against Anticonvulsant-Induced Neurotoxicity in the Developing Rat Brain. AB - Phenobarbital is the most commonly used drug for the treatment of neonatal seizures but may induce neurodegeneration in the developing brain. Methylxanthine caffeine is used for the treatment of apnea in newborn infants and appears to be neuroprotective, as shown by antiapoptotic and anti-inflammatory effects in oxidative stress models in newborn rodents and reduced rates of cerebral palsy in human infants treated with caffeine. We hypothesized that caffeine may counteract the proapoptotic effects of phenobarbital in newborn rats. Postnatal day 4 (P4) rats received phenobarbital (50 mg/kg) +/- caffeine (10 mg/kg) for three consecutive days. Brains examined at 6, 12, and 24 h after last injection of phenobarbital showed a drastic increase of apoptotic cell death (TUNEL+), which was attenuated by co-treatment with caffeine at 6 and 24 h but not at 12 h. Phenobarbital also increased protein levels of apoptosis inducing factor (AIF) and cleaved caspase-3, which was reduced by caffeine co-administration at all time points investigated. RNA expression of the pro-inflammatory cytokines TNFalpha, IFNgamma, and IL-1beta, but not IL-18, was upregulated by phenobarbital. Co-treatment with caffeine significantly decreased these upregulations at all time points investigated, while caffeine without phenobarbital resulted in increased expression of TNFalpha, IL-1beta, and IL-18, but not IFNgamma at 6 h. Downregulation of the adenosine A1 and A2a receptors, both of which bind caffeine, by 24 h of phenobarbital exposure was partly antagonized by caffeine. These results raise the possibility that the phenobarbital-induced adverse effects could be reduced by a co-treatment with caffeine. PMID- 28643233 TI - Assessing Environmental Exposure to beta-N-Methylamino-L-Alanine (BMAA) in Complex Sample Matrices: a Comparison of the Three Most Popular LC-MS/MS Methods. AB - beta-N-Methylamino-L-alanine (BMAA) is a naturally occurring non-protein amino acid produced by cyanobacteria, accumulated through natural food webs, found in mammalian brain tissues. Recent evidence indicates an association between BMAA and neurological disease. The accurate detection and quantification of BMAA in food and environmental samples are critical to understanding BMAA metabolism and limiting human exposure. To date, there have been more than 78 reports on BMAA in cyanobacteria and human samples, but different methods give conflicting data and divergent interpretations in the literature. The current work was designed to determine whether orthogonal chromatography and mass spectrometry methods give consistent data interpretation from a single sample matrix using the three most common analytical methods. The methods were recreated as precisely as possible from the literature with optimization of the mass spectrometry parameters specific to the instrument. Four sample matrices, cyanobacteria, human brain, blue crab, and Spirulina, were analyzed as 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) derivatives, propyl chloroformate (PCF) derivatives separated by reverse phase chromatography, or underivatized extracts separated by HILIC chromatography. The three methods agreed on positive detection of BMAA in cyanobacteria and no detected BMAA in the sample of human brain matrix. Interpretation was less clear for a sample of blue crab which was strongly positive for BMAA by AQC and PCF but negative by HILIC and for four spirulina raw materials that were negative by PCF but positive by AQC and HILIC. Together, these data demonstrate that the methods gave different results and that the choices in interpretation of the methods determined whether BMAA was detected. Failure to detect BMAA cannot be considered proof of absence. PMID- 28643235 TI - Design and Evaluation of RGD-Modified Gemini Surfactant-Based Lipoplexes for Targeted Gene Therapy in Melanoma Model. AB - PURPOSE: We have developed and evaluated novel peptide-targeted gemini surfactant based lipoplexes designed for melanoma gene therapy. METHODS: Integrin receptor targeting peptide, cyclic-arginylglycylaspartic acid (cRGD), was either chemically coupled to a gemini surfactant backbone or physically co-formulated with lipoplexes. Several formulations and transfection techniques were developed. Transfection efficiency and cellular toxicity of the lipoplexes were evaluated in an in vitro human melanoma model. Physicochemical properties were examined using dynamic light scattering, zeta-potential, and small-angle X-ray scattering measurements. RESULTS: RGD-modified gemini surfactant based lipoplexes showed significant enhancement in gene transfection activity in A375 cell lines compared to the standard non-targeted formulation, especially when RGD was chemically conjugated to the gemini surfactant (RGD-G). The RGD had no effect on the cell toxicity profile of the lipoplex systems. Targeting specificity was confirmed by using an excess of free RGD and negative control peptide (RAD) and was demonstrated by using normal human epidermal keratinocytes. Physicochemical characterization showed that all nanoparticles were in the optimal size range for cellular uptake and there were no significant differences between RGD-modified and standard lipoplexes. CONCLUSIONS: These findings indicate the potential of RGD-modified gemini surfactant-based lipoplexes for use in melanoma gene therapy as an alternative to conventional chemotherapy. PMID- 28643236 TI - Multi-Reservoir Phospholipid Shell Encapsulating Protamine Nanocapsules for Co Delivery of Letrozole and Celecoxib in Breast Cancer Therapy. AB - PURPOSE: In the current work, we propose a combined delivery nanoplatform for letrozole (LTZ) and celecoxib (CXB). METHODS: Multi-reservoir nanocarriers were developed by enveloping protamine nanocapsules (PRM-NCs) within drug-phospholipid complex bilayer. RESULTS: Encapsulation of NCs within phospholipid bilayer was confirmed by both size increase from 109.7 to 179.8 nm and reduction of surface charge from +19.0 to +7.78 mV. The multi-compartmental core-shell structure enabled biphasic CXB release with initial fast release induced by complexation with phospholipid shell followed by prolonged release from oily core. Moreover, phospholipid coating provided protection for cationic PRM-NCs against interaction with RBCs and serum proteins enabling their systemic administration. Pharmacokinetic analysis demonstrated prolonged circulation and delayed clearance of both drugs after intravenous administration into rats. The superior anti-tumor efficacy of multi-reservoir NCs was manifested as powerful cytotoxicity against MCF-7 breast cancer cells and marked reduction in the mammary tumor volume in Ehrlich ascites bearing mice compared with free LTZ-CXB combination. Moreover, the NCs induced apoptotic caspase activation and marked inhibition of aromatase expression and angiogenic marker, VEGF as well as inhibition of both NFkappaB and TNFalpha. CONCLUSIONS: Multi-reservoir phospholipid shell coating PRM-NCs could serve as a promising nanocarrier for parenteral combined delivery of LTZ and CXB. PMID- 28643237 TI - Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition. AB - PURPOSE: To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms. METHODS: A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated. RESULTS: Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57 fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and more uniform drug delivery to all cells. CONCLUSIONS: Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity. PMID- 28643238 TI - Characterization of the complex involved in regulating V-ATPase activity of the vacuolar and endosomal membrane. AB - Regulator of the H+-ATPase of the vacuolar and endosomal membranes (RAVE) is essential for the reversible assembly of H+-ATPase. RAVE primarily consists of three subunits: Rav1p, Rav2p and Skp1p. To characterize these subunits, in this study, four strains derived from Saccharomyces cerevisiae BY4742 were constructed with a FLAG tag on the Rav1p and Rav2p subunits. Then, the corresponding RAVE containing complex was isolated by affinity purification. Western blot and MALDI TOF mass spectrometry analyses showed that the RAVE complex contains not only the known V1-ATPase subunits (Vma1p and Vma2p) but also a newly found Leu1p that interacts with the RAVE subunit. Furthermore, we constructed rav1-/rav2-/vma2 /leu1-deficient recombinants by fusion PCR and homologous recombination and demonstrated that leu1 is indispensable in adjusting the microbial cell to adverse environments and that the function is similar to that of rav1/rav2 but significantly differs from that of vma2. Leu1p probably plays an important role in RAVE regulation of V-ATPase activity in conjunction with RAVE. PMID- 28643239 TI - Serum histones as biomarkers of the severity of heatstroke in dogs. AB - Heatstroke is associated with systemic inflammatory response syndrome, leading to multiple organ dysfunction and death. Currently, there is no specific treatment decreasing hyperthermia-induced inflammatory/hemostatic derangements. Emerging studies indicate that histones leaking from damaged cells into the extracellular space are toxic, pro-inflammatory, and pro-thrombotic. We therefore hypothesize that serum histones (sHs) are elevated during heatstroke and are associated with the severity of the disease. Sixteen dogs with heatstroke and seven healthy controls were included in the study. Median serum histones (sHs) upon admission in dogs with heatstroke were significantly higher (P = 0.043) compared to that in seven controls (13.2 vs. 7.3 ng/mL, respectively). sHs level was significantly higher among non-survivors and among dogs with severe hemostatic derangement (P = 0.049, median 21.4 ng/mL vs. median 8.16 ng/mL and P = 0.038, 19.0 vs. 7.0 ng/mL, respectively). There were significant positive correlation between sHs and urea (r = 0.8, P = 0.02); total CO2 (r = 0.661, P = 0.05); CK (r = 0.678, P = 0.04); and prothrombin time (PT) 12 h post presentation (r = 0.888, P = 0.04). The significant positive correlation between sHs and other heatstroke severity biomarkers, and significant increase among severely affected dogs, implies its role in inflammation/oxidation/coagulation during heatstroke. sHs, unlike other prognostic and severity biomarkers in heatstroke, can be pharmacologically manipulated, offering a potential therapeutic target. PMID- 28643240 TI - PCSK9 Inhibitors: Treating the Right Patients in Daily Practice. AB - PURPOSE OF REVIEW: Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as a novel approach to low-density lipoprotein cholesterol (LDL-C) lowering. The potential role of PCSK9 inhibitors in clinical practice will be reviewed. RECENT FINDINGS: Clinical trials have demonstrated that PCSK9 inhibitors produce robust LDL-C lowering when administered either as monotherapy or in combination with statins. This provides the opportunity to achieve effective lipid lowering in familial hypercholesterolemia, patients with either established atherosclerotic cardiovascular disease or high risk primary prevention and an important opportunity to treat patients with statin intolerance. The findings from plaque imaging and patients with established atherosclerotic cardiovascular disease suggest that PCSK9 inhibition has favorable outcomes beyond improving lipid profiles, which has the opportunity to expand their use. PCSK9 inhibitors represent a new approach to achieving effective cardiovascular risk reduction in a broader number of patients. How these agents will be taken up in clinical practice remains to be determined. PMID- 28643242 TI - What Influences Linkage to Care After Home-Based HIV Counseling and Testing? AB - To maximize the benefits of test and treat strategies that utilize community based HIV testing, clients who test positive must link to care in a timely manner. However, linkage rates across the HIV treatment cascade are typically low and little is known about what might facilitate or hinder care-seeking behavior. This qualitative study was conducted within a home-based HIV counseling and testing (HBHCT) intervention in South Africa. In-depth interviews were conducted with 30 HBHCT clients who tested HIV positive to explore what influenced their care-seeking behavior. A set of field notes for 196 additional HBHCT clients who tested HIV positive at home were also reviewed and analyzed. Content analysis showed that linkage to care is influenced by a myriad of factors at the individual, relationship, community, and health system levels. These factors subtly interact and at times reinforce each other. While some factors such as belief in test results, coping ability, social support, and prior experiences with the health system affect clients' desire and motivation to seek care, others such as limited time and resources affect their agency to do so. To ensure that the benefits of community-based testing models are realized through timely linkage to care, programs and interventions must take into account and address clients' emotions, motivation levels, living situations, relationship dynamics, responsibilities, and personal resources. PMID- 28643244 TI - Durvalumab: First Global Approval. AB - Intravenous durvalumab (ImfinziTM; AstraZeneca) is a fully human monoclonal antibody that blocks programmed cell death ligand-1 binding to its receptors (PD 1 and CD80), resulting in enhanced T-cell responses against cancer cells. The US FDA has granted durvalumab accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab +/ tremelimumab is under phase III clinical trials in urothelial carcinoma, non small cell lung cancer, small cell lung cancer and head and neck squamous cell carcinoma. The drug is also being evaluated in phase I or II clinical trials in a wide range of solid tumours and haematological malignancies. This article summarizes the milestones in the development of durvalumab leading to this first approval for urothelial carcinoma. PMID- 28643243 TI - Toward predictive biomarkers of response to kinase inhibitor therapies in differentiated thyroid cancer. PMID- 28643245 TI - Construction and Evaluation of Zinc Finger Nucleases. AB - Zinc-finger nucleases (ZFNs) are programmable nucleases that have opened the door to the genome editing era. The construction of ZFNs recognizing a target sequence of interest is laborious, and has not been widely used recently. However, key ZFN patents are expiring over the next 2-4 years, enabling a wide range of deployments for clinical and industrial applications. This article introduces a ZFN construction protocol that uses bacterial one-hybrid (B1H) selection and single-stranded annealing (SSA) assay. PMID- 28643246 TI - Current Overview of TALEN Construction Systems. AB - Transcription activator-like effector (TALE) nuclease (TALEN) is the second generation genome editing tool consisting of TALE protein containing customizable DNA-binding repeats and nuclease domain of FokI enzyme. Each DNA-binding repeat recognizes one base of double-strand DNA, and functional TALEN can be created by a simple modular assembly of these repeats. To easily and efficiently assemble the highly repetitive DNA-binding repeat arrays, various construction systems such as Golden Gate assembly, serial ligation, and ligation-independent cloning have been reported. In this chapter, we summarize the current situation of these systems and publically available reagents and protocols, enabling optimal selection of best suited systems for every researcher who wants to utilize TALENs in various research fields. PMID- 28643247 TI - CRISPR/Cas9. AB - CRISPR/Cas9 is a novel method that has become the most widely used genome editing technology around the world. Its widespread adoption is largely due to its simplicity and easy of use. Here, we introduce the construction of vectors and genome editing of the target gene in cells expressing the CRISPR/Cas9 system. PMID- 28643241 TI - Socio-demographic Characteristics, Sexual and Test-Seeking Behaviours Amongst Men Who have Sex with Both Men and Women: Results from a Bio-behavioural Survey in 13 European Cities. AB - Within the MSM population, men who have sex with both men and women (MSMW) are identified as a high-risk group both worldwide and in Europe. In a multi-centred bio-behavioural cross-sectional study, we aimed to assess the relationship(s) between socio-demographic factors, stigma, sexual behavioural patterns, test seeking behaviour and sero-status amongst MSMW. A multi-level analysis was conducted to identify factors associated with being MSMW versus Men who have Sex with Men Only (MSMO). A total of 4901 MSM were enrolled across the 13 study sites. Participants were categorised as MSMW in the 12.64% of the cases. Factors such as educational status, perceived homonegativity, testing facilities knowledge and HIV testing lifetime seem to be relevant factors when characterising the MSMW group. The results highlight the vulnerability of MSMW and the wide spectrum of risky behavioural and psycho-social patterns, particularly in terms of HIV testing, 'outness', and perceived stigma. PMID- 28643248 TI - Computational Prediction of CRISPR/Cas9 Target Sites Reveals Potential Off-Target Risks in Human and Mouse. AB - The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated (Cas) system is a prominent genome engineering technology. In the CRISPR/Cas system, the RNA-guided endonuclease Cas protein introduces a DNA double-stranded break at the genome position recognized by a guide RNA (gRNA) based on complementary base-pairing of about 20-nucleotides in length. The 8- or 12-mer gRNA sequence in the proximal region is especially important for target recognition, and the genes with sequence complementarity to such regions are often disrupted. To carry out target site-specific genome editing, we released the CRISPRdirect ( http://crispr.dbcls.jp /) website. This website allows us to select target site-specific gRNA sequences by performing exhaustive searches against entire genomic sequences. In this study, target site-specific gRNA sequences were designed for human, mouse, Drosophila melanogaster, and Caenorhabditis elegans. The calculation results revealed that at least five gRNA sequences, each of them having only one perfectly complementary site in the whole genome, could be designed for more than 95% of genes, regardless of the organism. Next, among those gRNAs, we selected gRNAs that did not have any other complementary site to the unique 12-mer proximal sequences to avoid possible off target effects. This computational prediction revealed that target site-specific gRNAs are selectable for the majority of genes in D. melanogaster and C. elegans. However, for >50% of genes in humans and mice, there are no target sites without possible off-target effects. PMID- 28643249 TI - Genome Editing of Mouse by Cytoplasmic Injection. AB - CRISPR/Cas enables rapid production of genome-edited animals. The Cas9/gRNA component can be introduced to fertilized eggs in several ways. Here, we provide an instructional guide for the generation of knockout mice by cytoplasmic injection using in vitro transcribed Cas9 and gRNA. PMID- 28643250 TI - Genome Editing in Mouse Zygotes and Embryonic Stem Cells by Introducing SgRNA/Cas9 Expressing Plasmids. AB - In mammalian cells, genome editing with the single guide RNA (sgRNA)/Cas9 complex allows for high targeting efficiency within a relatively short time frame with the added benefits of being low cost and easy to design. sgRNA/Cas9-mediated editing in mouse zygotes has accelerated the analysis of gene functions and the generation of mouse models of human diseases. Despite the benefits, this method still suffers from several problems, such as mosaicism in the founder generation which complicates genotyping and phenotypical analyses, and the low efficiency of more complicated genome editing. Thus, we recently established the system for genome editing in embryonic stem (ES) cells and its application for chimeric analysis in mice. In this section, we introduce the procedure for genome editing in mouse zygotes and ES cells. PMID- 28643251 TI - Genome Editing in Mouse and Rat by Electroporation. AB - Many knock-out/knock-in mouse and rat strains have been produced by genome editing techniques using engineered endonucleases, including zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), or clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Microinjection of engineered endonucleases into pronuclear-stage embryos is required to produce genome-edited rodents and the development of easy, rapid, and high-efficiency methods that do not require special skills such as microinjection is needed. This chapter presents a new technique called Technique for Animal Knockout system by Electroporation (TAKE), which produces genome-edited rodents by direct introduction of engineered endonucleases into intact embryos using electroporation. PMID- 28643252 TI - Generation of Knock-in Mouse by Genome Editing. AB - Knock-in mice are useful for evaluating endogenous gene expressions and functions in vivo. Instead of the conventional gene-targeting method using embryonic stem cells, an exogenous DNA sequence can be inserted into the target locus in the zygote using genome editing technology. In this chapter, I describe the generation of epitope-tagged mice using engineered endonuclease and single stranded oligodeoxynucleotide through the mouse zygote as an example of how to generate a knock-in mouse by genome editing. PMID- 28643253 TI - Genome Editing of Rat. AB - Many genetically engineered rat strains have been produced for biomedical research. The simple and quick production of knock-out and knock-in rats is currently possible using genome editing techniques incorporating zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), or clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. Genome edited animals have been produced by the introduction of endonucleases into embryos using conventional microinjection and a new electroporation method named Technique for Animal Knockout system by Electroporation (TAKE). This chapter introduces the latest protocols for producing genetically engineered rats using genome editing. PMID- 28643254 TI - Gene Targeting in Rabbits: Single-Step Generation of Knock-out Rabbits by Microinjection of CRISPR/Cas9 Plasmids. AB - The development of genome editing technology has allowed gene disruptions to be achieved in various animal species and has been beneficial to many mammals. Gene disruption using pluripotent stem cells is difficult to achieve in rabbits, but thanks to advances in genome editing technology, a number of gene disruptions have been conducted. This paper describes a simple and easy method for carrying out gene disruptions in rabbits using CRISPR/Cas9 in which the gene to be disrupted is marked, the presence or absence of off-target candidates is checked, and a plasmid allowing simultaneous expression of Cas9 and sgRNA is constructed. Next, the cleaving activity of candidate sequences is investigated, and assessments are carried out to determine whether the target sequences can be cut. Female rabbits subjected to superovulation treatment are mated with male rabbits and fertilized eggs are collected, and then pronuclear injection of plasmid DNA is performed. The next day, the two-cell stage embryos are transplanted into pseudopregnant rabbits, and offspring are born within approximately 29-30 days. The genomic DNA of the offspring is then examined to check what types of genetic modifications have occurred. With the advent of CRISPR/Cas9, the accessibility of gene disruptions in rabbits has improved remarkably. This paper summarizes specifically how to carry out gene disruptions in rabbits. PMID- 28643255 TI - Genome Editing of Pig. AB - Pigs are important livestock for food and have been used in various biomedical studies, particularly translational research, as experimental animals because of their anatomical and physiological similarity to humans. The recent development of genome editing techniques, such as ZFN, TALEN, and CRISPR/Cas9, has rapidly expanded the use of genome editing tools in a variety of animals, resulting in the relatively easy and efficient generation of gene knock-out pigs. In the past few years, there has been a sustained increase in reports describing the development of genetically modified pigs. This chapter introduces our workflow for establishing the genetically modified cells (nuclear donor cells) necessary to create gene knock-out pigs using somatic cell nuclear transfer and focuses on the actual generation of gene knock-out pigs using a cytoplasmic injection method. PMID- 28643256 TI - Genome Editing of Monkey. AB - Gene-modified monkey models would be particularly valuable in biomedical and neuroscience research. Virus-based transgenic and programmable nucleases-based site-specific gene editing methods (TALEN, CRISPR-cas9) enable the generation of gene-modified monkeys with gain or loss of function of specific genes. Here, we describe the generation of transgenic and knock-out (KO) monkeys with high efficiency by lentivirus and programmable nucleases. PMID- 28643257 TI - Genome Editing Mediated by Primordial Germ Cell in Chicken. AB - Rapid development of genome editing technology has facilitated the studies on exploring specific gene functions and establishment of model animals. In livestock, the technology has contributed to create high value in industry fields, e.g., enhancing productivity or acquiring the resistance against disease. Meanwhile, genome editing in avian species has been emphasized because of their applicable possibilities in terms of highly productive chickens, disease controlled avian lines, and development of novel biological models. Induction of exogenous gene using virus system or transposition in chicken primordial germ cells (PGCs) has been widely used for producing transgenic chicken, and recently developed programmable genome editing (PGE) technologies such as tale transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated (Cas9) are expected to maximize the applicable potentials of avian species. In this regard, this chapter will cover the methods for producing genome-edited chicken by piggyBac transposition and gene targeting technology, TALEN, and CRISPR/Cas9. PMID- 28643258 TI - CRISPR/Cas9-Mediated Targeted Knockin of Exogenous Reporter Genes in Zebrafish. AB - Genome editing technologies such as ZFN, TALEN, and CRISPR/Cas9 efficiently induce DNA double-stranded breaks (DSBs) at a targeted genomic locus, often resulting in a frameshift-mediated target gene disruption. It remains difficult to perform targeted integration of exogenous genes by genome editing technologies. DSBs can be restored through DNA repair mechanisms, such as non homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination (HR). It is well known that HR facilitates homology dependent integration of donor DNA template into a targeted locus. Recently, both NHEJ-mediated and MMEJ-mediated targeted integrations of exogenous genes have been developed in zebrafish. This chapter summarizes the application of CRISPR/Cas9-mediated knock-in technology in zebrafish. PMID- 28643259 TI - Genome Editing of Medaka. AB - Medaka (Oryzias latipes), along with zebrafish (Danio rerio), is a useful experimental model fish. Here, we describe a simple method for generating medaka gene knock-out strains using an automated microchip electrophoresis system. We also describe a method for targeted gene knock-in using a plasmid carrying a sequence that does not cause off-target effects in medaka. PMID- 28643260 TI - A Simple Protocol for Loss-of-Function Analysis in Xenopus tropicalis Founders Using the CRISPR-Cas System. AB - Xenopus tropicalis is a versatile model organism for studying basic biology such as developmental biology and cell biology, and for biomedical research on human diseases. Current genome editing techniques enable researchers to easily perform gene targeting in various animals. Among them, gene knockout using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated (Cas) (CRISPR-Cas) system has recently become an indispensable strategy for loss-of function analysis in vivo. Because of its ease of use, time, and cost efficiencies, CRISPR-Cas has also been applied to X. tropicalis where the gene disruption is highly efficient. In this chapter, we introduce a simple CRISPR-Cas system protocol for gene disruption in X. tropicalis. Based on our protocol, researchers can generate knock-out phenotypes within the shortest of timeframes, a week, and analyze genes of interest in founder generation. PMID- 28643261 TI - Genome Editing of Silkworms. AB - Silkworm is a lepidopteran insect that has been used as a model for a wide variety of biological studies. The microinjection technique is available and it is possible to cause transgenesis as well as target gene disruption via the genome editing technique. TALEN-mediated knock-out is especially effective in this species. We also succeeded in the precise and efficient integration of a donor vector using the Precise Integration into Target Chromosome (PITCh) method. Here, we describe protocols for ZFN, TALEN, and CRISPR/Cas9-mediated genome editing as well as the PITCh technique in the silkworm. We consider that all of these techniques can contribute to the further promotion of various biological studies in the silkworm and other insect species. PMID- 28643262 TI - Genome Editing in the Cricket, Gryllus bimaculatus. AB - Hemimetabolous, or incompletely metamorphosing, insects are phylogenetically basal and include many beneficial and deleterious species. The cricket, Gryllus bimaculatus, is an emerging model for hemimetabolous insects, based on the success of RNA interference (RNAi)-based gene-functional analyses and transgenic technology. Taking advantage of genome editing technologies in this species would greatly promote functional genomics studies. Genome editing has proven to be an effective method for site-specific genome manipulation in various species. Here, we describe a protocol for genome editing including gene knockout and gene knockin in G. bimaculatus for functional genomics studies. PMID- 28643263 TI - Genome Editing of the Ascidian Ciona intestinalis with TALE Nuclease. AB - The ascidian Ciona intestinalis is an important model animal for studying developmental mechanisms for constructing the chordate body. Although molecular and embryological techniques for manipulating Ciona genes were developed a long time ago, recent achievements of genome editing in this animal have innovated functional analyses of genes in Ciona. Particularly, knockout of genes in the G0 generation coupled with tissue-specific expression of TALENs enables us to rapidly address gene functions that were difficult using previous methods. PMID- 28643264 TI - Genome Editing of C. elegans. AB - Caenorhabditis elegans, a 1 mm long free-living nematode, is a traditional model animal for genetic investigations of various biological processes. Characteristic features that make C. elegans a powerful model of choice for eukaryotic genetic studies include its rapid life cycle, well-annotated genome, simple morphology, and transparency. Recently, genome editing technologies have been increasingly used in C. elegans, thereby facilitating their genetic analyses. Here, I introduce a protocol frequently used in C. elegans genome editing. PMID- 28643265 TI - Factors associated with high 24-month persistence with denosumab: results of a real-world, non-interventional study of women with postmenopausal osteoporosis in Germany, Austria, Greece, and Belgium. AB - : Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture. PURPOSE: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence. METHODS: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months +/- 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression. RESULTS: The 24-month analyses included 1479 women (mean age 66.3-72.5 years) from 140 sites; persistence with denosumab was 75.1-86.0%, adherence 62.9-70.1%, and mean MCR 87.4-92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3-6.9% patients. CONCLUSIONS: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence. PMID- 28643266 TI - Adherence to osteoporosis medicines in Estonia-a comprehensive 15-year retrospective prescriptions database study. AB - : Some patients do not take medicines as they are supposed to. Our research showed that in Estonia, one fifth of patients did not start treatment with osteoporosis medicines and only 20% used the medicines for at least 3 years as they should. This induces unnecessary costs to the healthcare system. PURPOSE: Medication non-adherence is the number one reason for not obtaining the expected clinical effect of medicines. With osteoporosis treatment, it has been shown that both implementation of treatment and persistence influence the risk of fractures significantly. Long-term adherence to medication in Estonia is to be determined with this study. METHODS: A 15-year retrospective study was carried out in order to establish initiation, implementation, and persistence of Estonian patients. All new users of osteoporosis medicines were analyzed for all prescriptions they received during the study period. Sufficient adherence to treatment was defined as a patient being dispensed 80% or more prescribed doses for at least 1 year. RESULTS: The study period was from 2001 to 2015. Patients (24,652) were included in the study. Of the patients, 93.7% (n = 23,091) were women and 6.3% (n = 1564) were men. Eighteen percent (4636) were dispensed only one prescription. Of the patients, 44.2% included in the study had medication possession ratio (MPR) >=80% over follow-up period; 8922 (36.2%) who were prescribed from 2001 to 2015 persisted for 1 year with MPR >=80% and 19.8% persisted for 3 years. Forty percent of expenditure on osteoporosis medication was made for treatment courses with insufficient adherence. CONCLUSIONS: There is room for improvement in Estonia with medication adherence relating to all three aspects that determine adherence-initiation, implementation, and persistence. This means further efforts are to be made to educate patients and healthcare professionals on realizing the importance of good adherence. PMID- 28643269 TI - "Doing Difference" and Fast Food Consumption: Patterns Among a Sample of White and African American Emerging Adults. AB - Previous research has demonstrated that frequent consumption of fast food is linked to obesity and that trends in both are disparate across race and sex categories. Contextualizing race- and sex-related factors that structure fast food consumption in emerging adulthood is a much-needed contribution to social research. Specifically, this study uses the "doing difference" framework, to examine the frequency of fast food consumption in a sample of White and African American (18-25 years old). According to the framework, social inequalities are reproduced through dramaturgical performances of race, class, and gender. Results of this suggest that feminine gender orientation and education serve as protective factors, while African American race and male sex serve as risk factors. African American women emerged as especially high risk given their higher prevalence of traditionally masculine traits. PMID- 28643268 TI - Sexual Health in a Social and Cultural Context: a Qualitative Study of Young Latina Lesbian, Bisexual, and Queer Women. AB - Previous research on sexual minority and Latina women suggests that Latina lesbian, bisexual, and queer (LBQ) women may be at high risk for sexually associated and transmitted infections, but research on the sexual health and practices of this population is limited. This qualitative study explored the knowledge, attitudes, and values related to sexual health among a purposive sample of Latina LBQ women living in Seattle, WA. Latina LBQ women (N = 14) were recruited to participate in in-depth interviews about their sexual health through community organizations, flyers posted on college campuses, email and social media advertisements, and participant referrals. In-person semi-structured interviews were conducted and transcribed; transcripts were coded by two independent coders and reviewed for prominent themes. Four main themes emerged: 1) Latina sexual minorities' sexual health is shaped by their social and cultural contexts, 2) they lack needed sexual health knowledge, 3) their sexual health behaviors vary depending on the relationship status and gender of their partners, and 4) they value taking responsibility for their own sexual health. Further research is needed to better understand sexual health among Latina LBQ women and to identify ways in which their values can be leveraged to promote positive sexual health outcomes. PMID- 28643267 TI - New insight into inter-organ crosstalk contributing to the pathogenesis of non alcoholic fatty liver disease (NAFLD). AB - Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD. PMID- 28643270 TI - Ethnic Disparities of Perceived Safety Climate Among Construction Workers in Georgia, 2015. AB - BACKGROUND: Safety climate involves worker perception about the relative importance where they work and safety climate and has been shown to be a reliable predictor of safety-related outcomes. METHODS: The primary objective of this study is to investigate ethnic differences in perceived safety climate among construction workers. Surveys (n = 179) that included a 10-item safety climate scale were administered in Athens, Georgia (GA), at local construction sites and home improvement stores during June-August, 2015. RESULTS: The majority of respondents were carpenters or roofers (39%), followed by laborers (22%), painters and dry wall workers (14%), other skilled trades (14%), and supervisors (11%); 32% were Hispanic. Hispanic ethnicity (p < 0.0001), drinking two or more alcoholic beverages per day (p < 0.0001), working for a company that does not provide health insurance (p = 0.0022), and working for a company with fewer than ten employees (p < 0.0001) were significantly associated with lower perceived safety climate scores. CONCLUSION: The lower perceived safety climate scores among Hispanic workers indicate that the perception of the importance of safety on the job site is lower among Hispanics construction workers than non-Hispanics construction workers. PMID- 28643271 TI - Demographic Predictors and Cancer Screening Among Asian Americans in Michigan: Role of Refugee Status. AB - Although the Asian American population has steadily increased since 1980s, there remains a paucity of literature on cancer screening utilization on this population. The purpose of this study was to evaluate preventive health and screening practices by examining demographic predictors of health and screening behaviors among 217 Asian Americans living in state of Michigan. Several demographic and acculturation-related factors were found to be associated with "ever screened" status in the bivariate analyses. This included the examination of the relationships among refugee status and cancer screening practices among Asian Americans. After adjusting for other demographic correlates, Asian Americans in the refugee group had lower screening rates in colorectal and breast cancer. Our findings emphasize the need for effective interventions to increase cancer screening rates in this vulnerable population. PMID- 28643272 TI - Prevalence and risk factors for low bone mineral density in ulcerative colitis. AB - BACKGROUND: Inflammatory bowel disease (IBD) has been associated with increased risk of osteopenia and osteoporosis. Several risk factors contribute to this; however, studies evaluating their association have conflicting results. METHODS: We conducted a cross-sectional study with prospective enrollment of adult ulcerative colitis patients attending the Gastroenterology Department of Sawai Man Singh Hospital, Jaipur Rajasthan between June 2015 and December 2015. Demographic data including age, gender, body mass index (BMI), disease duration, type of disease, prior steroid use and vitamin D levels were recorded and compared with bone mineral density (BMD) using dual-energy X-ray absorptiometry (DEXA). RESULTS: Of the 55 patients enrolled, 41 (74.5%) had abnormal BMD; out of this, 19 (34.5%) had osteopenia and 22 (40.0%) had osteoporosis. In univariate analysis, disease duration and history of steroid use were observed as statistically significant. However, on multivariate analysis, only duration of disease was found to be a significant independent predictor of low BMD. Age, gender, BMI, low levels of vitamin D and steroid usage were not associated with low BMD. CONCLUSION: Prevalence of low BMD is common in Indian ulcerative colitis patients. Prolonged disease duration appears to be the major risk factor. PMID- 28643274 TI - An Unexplained Congenital Disorder of Glycosylation-II in a Child with Neurohepatic Involvement, Hypercholesterolemia and Hypoceruloplasminemia. AB - We report on a 12-year-old adopted boy with psychomotor disability, absence seizures, and normal brain MRI. He showed increased (but initially, at 5 months, normal) serum cholesterol, increased alkaline phosphatases, transiently increased transaminases and hypoceruloplasminemia with normal serum and urinary copper. Blood levels of immunoglobulins, haptoglobin, antithrombin, and factor XI were normal. A type 2 serum transferrin isoelectrofocusing and hypoglycosylation of apoCIII pointed to a combined N- and O-glycosylation defect. Neither CDG panel analysis with 79 CDG-related genes, nor whole exome sequencing revealed the cause of this CDG. Whole genome sequencing was not performed since the biological parents of this adopted child were not available. PMID- 28643273 TI - Chronic constipation in Rome IV era: The Indian perspective. AB - Chronic constipation (CC) is a common problem in the community and in gastroenterology practice all over the world including India. After release of Rome IV guidelines in April 2016, there is increasing interest among gastroenterologists and physicians in India to look into special issues on CC in the Indian perspective. There are important differences in the bowel habit, definition, epidemiology, and pathophysiology including dietary factors and management of CC in India as compared to the West. As severity and frequency of abdominal pain, a symptom essential to diagnose constipation-predominant irritable bowel syndrome (IBS-C) rather than functional constipation (FC), is less common among Indian patients, FC is commoner than IBS-C in India. The pathophysiological mechanisms of CC may include slow colon transit, fecal evacuation disorder (FED), or a combination of these; though CC in a third to half of patients presenting to tertiary care facilities may result from these pathophysiological mechanisms, most patients presenting to primary care may have lifestyle and dietary issues. The current Rome IV algorithm dictates to explore the underlying physiological factors in the pathogenesis of functional gastrointestinal disorders including CC, which may translate to its personalized management. However, the availability of the methods to explore pathophysiological factors and manage CC caused by FED non-pharmacologically (using biofeedback) in India is limited. Though several pharmacological agents are available in India to manage CC, there are several unmet needs in its treatment. This review explores CC in India in relation to these issues, some of which are unique in the Indian perspective. PMID- 28643275 TI - Open-Label Single-Sequence Crossover Study Evaluating Pharmacokinetics, Efficacy, and Safety of Once-Daily Dosing of Nitisinone in Patients with Hereditary Tyrosinemia Type 1. AB - BACKGROUND: Although nitisinone is successfully used to treat hereditary tyrosinemia type 1 (HT-1) with the recommended twice-daily dosing, data describing a long half-life motivate less frequent dosing. Therefore, in agreement with the Pharmacovigilance Risk Assessment Committee at the European Medicines Agency, this study was performed to investigate the switch to once daily dosing. METHODS: This open-label, non-randomized, single-sequence crossover study evaluated the pharmacokinetics, efficacy, and safety of once-daily compared to twice-daily dosing of nitisinone in patients with HT-1 (NCT02323529). Well controlled patients of <2, 2 to <12, 12 to <18, and >=18 years of age who were on twice-daily dosing were eligible for participation. Nitisinone and succinylacetone levels were determined from dry blood spots by tandem mass spectrometry. The primary endpoint was Cmin of nitisinone after >=4 weeks of treatment on each dosing regimen. Secondary objectives were evaluation of efficacy and safety during each dosing regimen. RESULTS: In total, 19 patients were enrolled and 17 included in the per-protocol analysis set. The mean (SD) nitisinone Cmin decreased by 23%, from 26.4 (10.2) to 21.2 (9.9) MUmol/L in dry blood spot samples (not equivalent to plasma concentrations), when patients switched from twice- to once-daily dosing. There was no apparent age- or bodyweight-related trend in the degree of Cmin decrease. No patient had quantifiable succinylacetone levels during the once-daily treatment period, indicating efficacious treatment. All adverse events were mild or moderate and judged unrelated to nitisinone. CONCLUSION: The switch to once-daily treatment with nitisinone appeared efficacious and safe in the treatment of patients with HT-1. PMID- 28643276 TI - A Rapid Two-Step Iduronate-2-Sulfatatse Enzymatic Activity Assay for MPSII Pharmacokinetic Assessment. AB - Clinical studies involving enzyme replacement therapies (ERTs) have increasingly utilized enzymatic activity assays to monitor efficacy and biofunction of the drug; as a result, these assays have become an important part of pharmacokinetic (PK) and pharmacodynamic assessments in ERT trials. This paper presents a two step enzymatic activity assay for iduronate-2-sulfatase (I2S) (EC 3.1.6.13) which we have optimized to fit in 1 day and to complete in less than 6 h. The rapid assay presented here is a significant improvement over the original two-step method with run time of 24 h which spanned 2 days. The resulting 1 day assay is efficient, robust, reproducible, and better suited for use in pharmacokinetic studies. The method was fully validated in accordance with regulatory agency guidelines so that it could be implemented in PK studies. Validation of the method required additional modifications to circumvent limitations surrounding the calculation of accuracy. This challenge was overcome by developing strategies to determine both the expected and the measured values of validation samples in activity units. Subsequently, the method was validated in accordance with the FDA guidance for the validation of quantitative ligand binding assays (LBAs). Results of method development and optimization with focus on evaluations aimed at reducing the total assay run time as well as a summary of method validation performance are presented in this publication. PMID- 28643277 TI - The role of solubility on the rejection of trace organics by nanofiltration membrane: exemplified with disinfection by-products. AB - Interactions of trace organic compounds (TOrCs) with polymeric nanofiltration (NF) membrane can affect their rejection. It is desirable to investigate whether solubility which depends on the free energy of interaction between these solutes and water correlates with rejection/adsorption and the potential to be incorporated in the partitioning terms of current NF model. A total of ten neutral disinfection by-products (DBPs) were selected as the model compounds for TOrCs to comprehensively investigate the role of solubility on rejection and adsorption. Pearson correlation analysis indicated that the correlation between MW and rejection ratio was highly significant (r = 0.778, p = 0.008) and that between solubility and rejection ratio was moderately significant (r = -0.636, p = 0.48) in a cross-flow system. By fitting Freundlich equation from adsorption isotherm experiment, the adsorption affinity (K f) of DBPs was roughly correlated with their solubility with regard to the comparison of n value with 1. alpha was then introduced as a parameter of solute-membrane interaction from the perspective of partitioning term in the hydrodynamic model. Exponential relationship can be observed between the solubility and alpha, demonstrating the possibility of incorporating solubility into the partitioning terms in NF model to accurately predict the rejection of DBPs. PMID- 28643279 TI - Highly efficient biosorptive removal of lead from industrial effluent. AB - This study has been focused on the efficient removal of Pb (II) from contaminated waters by biosorption using plant derived material. Accordingly an indigenous shrub, Tinospora cordifolia has been identified as the most suitable biosorbent. The plant biomass was subjected to optimization of various parameters such as the pH, equilibrium time, dosage, concentration, temperature and the applicable adsorption models. The optimum pH identified was 4.0 with a contact time of 60 min at room temperature (27 +/- 2 degrees C). The experimental data fitted well to adsorption isotherms and the uptake capacity of Pb (II) was found to be 20.83 and 63.77 mg/g in batch mode and column mode, respectively. The high correlation factors obtained for Langmuir and Freundlich models indicated that both models were obeyed by the system. Kinetic study for adsorption of Pb (II) follow only pseudo second order rate of reaction. The accumulation of lead in biomass was confirmed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) analysis. The FTIR analysis indicated the involvement of hydroxyl (-OH), alkenes (=CH) and carbonyl group (C = O) chelates in metal binding. The SEM and EDX analysis showed the structural changes and the filling of voids in the biomass thus, it indicated the metal binding mechanism. In elution studies, the 0.1 M Na2CO3 was found to be the best with about 71% elution of the adsorbed metal. The biomass was then used for the removal of Pb (II) in synthetic and real wastewater samples from a lead-acid battery industry. It is also noteworthy that even at a very high concentration of 450 mg/L, the biomass was showing about 92% removal. The result is to establish the efficacy of T. cordifolia as a very good bioadsorbent for the Pb (II) removal from contaminated water. PMID- 28643278 TI - Health risks of environmental exposure to metals and herbicides in the Pardo River, Brazil. AB - Mixture of metals and herbicides in rivers may pose relevant risks for the health of surrounding communities. Humans may be exposed to river pollution through intake of contaminated water and fish, as well as irrigated agricultural products. The aim of this study was to assess the human health risks of environmental exposure to metals and herbicides through water and fish intake in the Pardo River. Metals (Al, As, Be, Cd, Cr, Cu, Pb, Mn, Hg, Ni, Tl, Sn, V, and Zn) were analyzed in river water and in edible fish. Herbicides (ametryn, atrazine, diuron, hexazinone, simazine, and tebuthiuron) were analyzed in river water. Seasonal variances were also studied. Aluminum, Cd, Cu, Mn, Pb, and Zn levels in river water were higher than the USEPA benchmarks. Non-carcinogenic risks due to pollutants mixture exposure were above the limit, and carcinogenic risks of As exposure were >10-6 in the sampling points during the rainy season. Metal levels in fish were lower than the Brazilian legislation and do not pose a threat to public health. Herbicides were detected in four sampling points, with atrazine concentrations (range 0.16-0.32 MUg/L) below the Brazilian standard (2.0 MUg/L), but above the European Union standard (0.1 MUg/L). Considering the water supply needs of cities located in the Pardo River Basin and the persistence of metals and herbicides, the present study indicated that there was a seasonal influence on non-carcinogenic and carcinogenic risks to human health, especially in the rainy season. Studies for water treatment plants implantation should consider the risks of exposure to persistent substances, in order to protect the population. PMID- 28643280 TI - Effect of oxidative stress from nanoscale TiO2 particles on a Physarum polycephalum macroplasmodium under dark conditions. AB - Information regarding the effect of nanoscale titanium dioxide particles (nTiO2) on the environment under dark conditions is scarce, and the effect of nTiO2 on fungi is largely unknown. Due to its huge size and high sensitivity to external stimuli, the slime mold fungi cell, Physarum polycephalum macroplasmodium, was utilized as a novel subject for the toxicity investigations in the present study, and oxidative stress from nTiO2 on the macroplasmodium was assessed under dark conditions. Short exposure (2-3 h) caused an intracellular reactive oxygen species (ROS) imbalance, and an anti-oxidative mechanism was activated from intermediate doses of nTiO2 (5-18 mg/mL). At long exposure times (~3 days), relatively low doses of nTiO2 (<=9 mg/mL) stimulated the growth of macroplasmodium and oxidative stress without DNA damage, whereas higher doses of nTiO2 (>=15 mg/mL) led to growth inhibition, significant DNA oxidative damage, and activation of the DNA single-strand repairing system. Although DNA oxidative damage was decreased to the same level as the control group by the supplementation of the anti-oxidant vitamin C, growth of the macroplasmodium failed to be completely restored. We inferred that nTiO2 induced a complicated toxicity effect on P. polycephalum in addition to DNA oxidative damage. Taken as a whole, the present study implied the probability of using P. polycephalum macroplasmodium for toxicity studies at the single-cell level, indicating that nTiO2 could induce oxidative stress or damage in P. polycephalum even under dark conditions and suggesting that the release of nTiO2 could lead to a growth imbalance of slime molds in the environment. PMID- 28643281 TI - Removal of the emerging contaminant bisphenol A by an ureasil-PEO hybrid membrane: experimental study and molecular dynamic simulation. AB - This work reports the use of a cross-linked ureasil-PEO hybrid matrix (designated PEO800) as an efficient adsorbent to retain the emerging contaminant bisphenol A (BPA) from an aqueous medium. The in-deep experimental and theoretical results provide information about the interactions between PEO800 and BPA. The in situ UV vis spectroscopy data and the pseudo-first order, pseudo-second order, Elovich, and Morris-Webber intraparticle diffusion models allowed us to propose a three step mechanism for the adsorption of BPA onto PEO800. The results indicate that the pseudo-first-order kinetic model effectively describes the adsorption of BPA onto PEO800. Differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy confirmed the interaction of PEO800 with BPA, showing an alteration in the chemical environment of the polymer ether oxygen atoms present in the hybrid matrix. The molecular dynamic simulation provides further evidence that the BPA molecules interact preferentially with PEO. The amount of desorbed BPA depended on the pH and solvent used in the assays. This work provides new opportunities for using the hydrophilic ureasil-PEO matrix which has demonstrated its abilities in being a fast and easy alternative to successfully removing organic contaminants from aqueous mediums and therefore having potential applications in water remediation. Graphical abstract. PMID- 28643282 TI - Energy and exergy optimization of food waste pretreatment and incineration. AB - With the aim of upgrading current food waste (FW) management strategy, a novel FW hydrothermal pretreatment and air-drying incineration system is proposed and optimized from an energy and exergy perspective. Parameters considered include the extracted steam quality, the final moisture content of dehydrated FW, and the reactor thermal efficiency. Results show that optimal working condition can be obtained when the temperature and pressure of extracted steam are 159 degrees C and 0.17 MPa, the final moisture content of dehydrated FW is 10%, and the reactor thermal efficiency is 90%. Under such circumstance, the optimal steam energy and exergy increments reach 194.92 and 324.50 kJ/kg-FW, respectively. The novel system is then applied under the local conditions of Hangzhou, China. Results show that approximately 2.7 or 11.6% (from energy or exergy analysis perspective) of electricity can be additionally generated from 1 ton of MSW if the proposed novel FW system is implemented. Besides, comparisons between energy and exergy analysis are also discussed. PMID- 28643283 TI - Role of cation structure in the phytotoxicity of ionic liquids: growth inhibition and oxidative stress in spring barley and common radish. AB - The present study determines the influence of three ionic liquids (ILs) containing cations with diversified structure on the growth and development of spring barley seedlings and common radish leaves. Increasing amounts of 1-butyl-1 methylpyrrolidinium hexafluorophosphate [Pyrrol][PF6], 1-butyl-1 methylpiperidinium hexafluorophosphate [Piper][PF6], and 1-butyl-4 methylpyridinium hexafluorophosphate [Pyrid][PF6] were added to the soil on which both plants were cultivated. The results of this studies showed that the applied ILs were highly toxic for plants, demonstrated by the inhibition of length of plant shoots and roots, decrease of fresh mass, and increase of dry weight content. Common radish turned out to be the plant with higher resistance to the used ILs. The differences in the cation structure did not influence phytotoxity of ILs for spring barley. Furthermore, all ILs led to a decrease of photosynthetic pigments, which was directly followed by decreased primary production in plants. Oxidative stress in plants occurred due to the presence of ILs in the soil, which was demonstrated by the increase of malondialdehyde (MDA) content, changes in the H2O2 level, and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD). The changes in the chlorophyll contents and the increase of POD activity turned out to be the most significant oxidative stress biomarkers in spring barley and common radish. Both spring barley and radish exposed to ILs accumulated a large amount of fluoride ion. PMID- 28643284 TI - Hydroxyl radical-mediated degradation of diclofenac revisited: a computational approach to assessment of reaction mechanisms and by-products. AB - Advanced oxidation processes (AOPs) are based on the in situ production of hydroxyl radicals (*OH) and reactive oxygen species (ROS) in water upon irradiation of the sample by UV light, ultrasound, electromagnetic radiation, and/or the addition of ozone or a semiconductor. Diclofenac (DCF), one of the emerging organic contaminants (EOC), is of environmental concern due to its abundancy in water and is known to be subjected to AOPs. The current study uses density functional theory (DFT) to elucidate the mechanisms of the reactions between *OH and DCF leading to degradation by-products, P1-P9. The initial encounter of DCF with *OH is proposed to lead to either the abstraction of a hydrogen or the addition of the hydroxyl radical to the molecule. The results showed that OH addition radicals (R add) are both kinetically and thermodynamically favored over H abstraction radicals (R abs). The intermediate radicals give degradation by-products by subsequent reactions. The by-products P7 and P8 are easily formed in agreement with experimental findings. Finally, acute toxicities at three trophic levels are estimated with the Ecological Structure Activity Relationships program. DCF and most of the by-products were found to be harmful to aquatic organisms, P9 being the only by-product that is not harmful at all three trophic levels. PMID- 28643286 TI - Identifying Primary Care Physicians Continuing Education Needs by Examining Clinical Practices, Attitudes, and Barriers to Screening Across Multiple Cancers. AB - Population-based cancer screening for cervical, breast, and colorectal cancers improves patient outcomes, yet screening rates remain low for some cancers. Despite studies investigating physician perceptions and practices for screening, many have focused on individual cancers and lack primary care physicians' (PCPs) realities around screening for multiple cancers. We surveyed 887 PCPs in British Columbia (BC) to examine practices, beliefs, barriers, and learning needs towards cancer screening across breast, cervical, colorectal, prostate, as well as hereditary predisposition to cancer. Survey results identified differences in PCPs belief in the benefit of screening for recommended and non-recommended routine cancer screening, PCPs adherence to screening guidelines for some cancers and physician comfort and patient testing requests related to physician gender for gender sensitive tests. Further, across cancers, screening barriers included patients with multiple health concerns (41%), limited time to discuss screening (36%), and lack of physician financial compensation to discuss screening (23%). The study highlighted the need for more physician education on screening programs, referral criteria, follow-up processes, and screening guidelines. Conferences (73%), self-directed (46%), small group workshops (42%), hospital rounds (41%), and online CME/CPD (39%) were highly preferred (4+5) for learning about cancer screening. The results suggest a need to improve awareness and adherence to screening guidelines and recommended practices, as well as to provide educational opportunities which address knowledge and practice gaps for physicians. PMID- 28643287 TI - Oral Cancer Awareness Level Within the Dental Community: Results from a Large Scale Survey in Cairo. AB - The incidence of head and neck cancer was reported to be higher in more developed countries with an increase in incidence lately among younger age groups. The need for improvement of awareness of oral cancer and potentially malignant oral disorders is crucial. This study aims to identify the level of awareness of diagnostic and management protocols in the dental community. An English survey was arranged and sent via email to undergraduate students, postgraduate students, and faculty members at the dental school Cairo University. The questions focused on the early detection and level of awareness of oral cancer. Results were then analyzed to assess levels of awareness at the different education levels of the participants. Eight hundred sixty-eight responded out of the sent 5052 during the period between October 2015 and January 2016. The average results of the faculty staff members were higher than that of the student groups and participants with regular continuous assessment and knowledge refreshment achieved higher results. The results of this survey have pointed out areas of lack of awareness among the targeted population. The results have been brought up to the knowledge of policy makers to enable the improvement of level of awareness and assessment of risk factors for oral cancer. PMID- 28643285 TI - Skin Manifestations of Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) with its two main subtypes Crohn's disease and ulcerative colitis is not restricted to the gastrointestinal tract. Indeed, so called extraintestinal manifestations (EIMs) are frequent and considerably affect morbidity and mortality. The prevalence of EIMs ranges from 6 to 47%. In up to one quarter of the patients, EIMs can present even before an IBD diagnosis is established. The pathophysiology of EIMs remains elusive, although data from clinical trials demonstrating anti-tumor necrosis factor (TNF) efficacy suggest a common pathogenic link between intestinal and extraintestinal disease activity. However, not all EIMs parallel intestinal disease. Skin lesions are usually classified based on their pathophysiological association with the underlying intestinal disease into four categories: (1) specific, (2) reactive, (3) associated, and (4) treatment-induced manifestations. Cutaneous manifestations include erythema nodosum (EN), pyoderma gangrenosum (PG), Sweet's syndrome, and oral lesions, with EN being the most commonly reported and PG showing the most debilitating disease course. Anti-TNF-induced skin reactions are a new, but increasingly recognized phenomenon, which can be eventually misinterpreted as psoriatic lesions. Medical treatment modalities are limited with topical and systemic steroids being the most frequently employed agents. If EIMs parallel intestinal disease activity, the therapeutic cornerstone usually is the management of underlying intestinal disease activity rather than direct treatment of the EIMs. However, increasing evidence for anti-TNF agents' efficacy in EIM management has changed the approach to complicating and debilitating disease courses. In the case of anti-TNF-induced lesions, topical steroids are usually sufficient and discontinuation of anti-TNF is seldom warranted. In this review, we summarize current knowledge on cutaneous EIMs, their diagnostic criteria and clinical presentation, natural history, pathogenesis, and treatment options. PMID- 28643288 TI - Inhibitory effect of FSLLRY-NH2 on inflammatory responses induced by hydrogen peroxide in HepG2 cells. AB - Proteinase activated receptor 2 (PAR2), which is localized in the GI tract, the respiratory system, and the kidney tubules is a G protein-coupled receptor associated with inflammation, metabolism, and disease. The aim of this study was to explore the role of PAR2 in hydrogen peroxide (H2O2)-induced HepG2 cells by using FSLLRY-NH2 a PAR2 antagonist. H2O2 treatment resulted in induction of PAR2 in esophageal, gastric, and liver cells, with the most robust response being in HepG2 cells. Furthermore, this effect was dose-dependent in HepG2 cells. Treatment with H2O2 at concentrations above 400 MUM for 24 h also reduced HepG2 cell viability. H2O2 treatment increased both the protein and mRNA levels of IL 1beta, IL-8, and TNF-alpha, as well as those of SAPK/JNK. The increased levels of these pro-inflammatory genes and SAPK/JNK induced by H2O2 were attenuated in a dose-dependent manner when cells were co-treated with H2O2 and FSLLRY-NH2. In summary, the PAR2 antagonist peptide, FSLLRY-NH2, reduces the level of the pro inflammatory genes IL-8, IL-1beta, and TNF-alpha induced by H2O2, through the SAPK/JNK pathways in HepG2 cells. These data suggest that a PAR2 antagonist could be an anti-inflammatory agent in HepG2 cells. PMID- 28643291 TI - [More than expectorant: new scientific data on ambroxol in the context of the treatment of bronchopulmonary diseases]. AB - BACKGROUND: Ambroxol has been established for decades in the treatment of acute and chronic respiratory diseases. In 2015, the European Medicines Agency reassessed the clinical benefit-risk ratio of the drug. OBJECTIVE: What new scientific data on ambroxol, which are relevant to the treatment of bronchopulmonary diseases, are available? METHOD: The review is based on a systematic literature research in medline with the search term "ambroxol" during the publication period 2006-2015. Non-relevant publications were excluded manually. RESULTS AND CONCLUSIONS: Ambroxol is still intensively researched. The traditional indication as an expectorant is confirmed. But there is also an ever better understanding of the various mechanisms of action as well as the ever more exact modeling of the structures under investigation. New fields of application are conceivable, e. g. in patients with severe pulmonary disease who undergo surgery or who are in intensive care, as an adjuvant in anti-infective therapies, especially in infections with biofilm-producing pathogens, or in rare diseases such as lysosomal storage diseases. However, final evidence of the clinical relevance in these fields of application is still missing. PMID- 28643289 TI - Recovery from eating disorder 1 year after start of treatment is related to better mentalization and strong reduction of sensitivity to others. AB - PURPOSE: To investigate whether recovery from an eating disorder is related to pre-treatment attachment and mentalization and/or to improvement of attachment and mentalization during treatment. METHOD: For a sample of 38 anorexia nervosa (AN) and bulimia nervosa (BN) patients receiving treatment the relations between attachment security, mentalization, comorbidity and recovery status after 12 months (not recovered or recovered), and after 18 months (persistently ill, relapsed, newly recovered, or persistently recovered) were investigated. Attachment security and mentalization were assessed by the Adult Attachment Interview at the start of the treatment and after 12 months. Besides assessing co morbidity-for its effect on treatment outcome-we measured psycho-neuroticism and autonomy because of their established relations to both eating disorder symptoms and to attachment security. RESULTS: Recovery both at 12 months and at 18 months was related to higher levels of mentalization; for attachment, no significant differences were found between recovered and unrecovered patients. Patients who recovered from AN or BN also improved on co-morbid symptoms: whereas pre treatment symptom severity was similar, at 12 months recovered patients scored lower on co-morbid personality disorders, anxiety, depression, self-injurious behaviour and psycho-neuroticism than unrecovered patients. Improvement on autonomy (reduced sensitivity to others; greater capacity to manage new situations) in 1 year of treatment was significantly higher in recovered than in unrecovered patients. CONCLUSION: A focus on enhancing mentalization in eating disorder treatment might be useful to increase the chances of successful treatment. Improvement of autonomy might be the mechanism of change in recovering from AN or BN. LEVEL OF EVIDENCE: Level III cohort study. PMID- 28643290 TI - Does the eating disorder examination questionnaire global subscale adequately predict eating disorder psychopathology in the daily life of obese adults? AB - The eating disorder examination questionnaire (EDE-Q) Global score is a self report measure of global eating disorder (ED) psychopathology. This study used ecological momentary assessment (EMA) to evaluate the ecological validity of EDE Q Global scores among obese adults. Fifty obese adults completed the EDE-Q and 2 weeks of EMA ratings prior to initiating eating episodes and subsequently after eating episodes. EMA items assessed behavioral symptoms [i.e., loss of control (LOC) eating and overeating] and cognitive symptoms (i.e., weight/shape concerns, eating concerns, and restraint). EDE-Q Global was associated with increased EMA weight/shape concerns and fear of LOC at pre-eating recordings. EDE-Q Global was associated with increased EMA post-episode weight/shape concerns, eating concerns, LOC eating, and overeating. There was no association between EDE-Q Global and EMA restraint. Results generally supported the ecological validity of EDE-Q Global scores. Future studies of ED psychopathology in obese adults may benefit from considering EDE-Q Restraint separately. Level of Evidence Level V, descriptive study. PMID- 28643292 TI - [Avanafil for the treatment of erectile dysfunction in practice. Non interventional study AVANTI]. AB - OBJECTIVE AND METHOD: In the prospective, multicentric, non-interventional AVANTI study, the selection criteria for the PDE-5 inhibitor Avanafil were evaluated and it's acceptance in the treatment of patients with erectile dysfunction was investigated. Data from 1,804 probands with an average age of 58.0 years were analyzed. RESULTS: Doctors and patients most commonly referred to Avanafil as a fast-acting substance (70.6% and 78.6%, respectively). A favorable side-effect profile was more focused when the patient co-decided (62.7%) than if the doctor selected (48.4%). 41.2% of the physicians emphasized the potency, 56.7% of the patients preferred to receive a modern medicine. Doctors and patients assessed the drug as effective and well tolerated. PMID- 28643293 TI - [Why is a combination of basal insulin with a GLP-1 receptor agonist useful in many patients with type 2 diabetes?] AB - BACKGROUND: In 2015, the combination of basal insulin and GLP-1 receptor agonist (RA) was incorporated into the guideline recommendations for type 2 diabetes as an option for the last escalation step. The two antidiabetics to be injected subcutaneously are complementary regarding their respective main effects and limitations. Basal insulin is predominantly active between meals and in the fasting state, whereas the main action of GLP-1 RA consists in preventing an excessive postprandial blood glucose increase. Moreover, GLP-1 RA is characterised by a low intrinsic risk of hypoglycaemia, body weight reduction and a positive impact on cardiovascular risk factors. Unlike GLP-1 RA, no upper dose limits are defined for basal insulin. However, initiation of insulin therapy is associated with disadvantages in terms of hypoglycaemia and weight increase. Therefore, patients achieving their treatment goals with GLP-1 RA alone are better treated without insulin. METHOD: In a review, study results on combinations of basal insulin and GLP-1-RA versus comparative therapies are presented. RESULTS: Most of the studies were carried out in patients pre-treated with basal insulin. The add-on of GLP-1 RA was commonly associated with significant reductions of body weight and also resulted in additional HbA1c reductions compared with an increase of the basal insulin dose. The add-on of a short acting insulin to an existing basal insulin therapy enabled similar HbA1c reductions to the add-on of a GLP-1 RA, but simultaneously increased the number of episodes of hypoglycaemia and might lead to more unfavourable body weight developments. A fixed combination of insulin degludec and liraglutide (IDegLira) showed an effective and rather steady blood glucose reduction in a 24-hour interval vs. basal insulin or GLP-1 RA alone. CONCLUSIONS: Combinations of basal insulin and a GLP-1 RA improve glycaemic control in many patients with type 2 diabetes without any significant increase of the risk of hypoglycaemia and without weight gain, especially compared to a dose increase of the basal insulin or add-on of a short-acting insulin. PMID- 28643294 TI - [Saccharomyces boulardii CNCM I-745 influences the gut-associated immune system]. AB - BACKGROUND: The impact of the intestinal microbiome is increasing steadily with regard to the immune function und the defense against pathogens. The medicinal yeast Saccharomyces boulardii CNCM I-745 (S. boulardii) has been used as probiotic for the prevention and treatment of infectious diarrhea since more than 50 years. Meta-analyses confirm the clinical efficacy of S. boulardii to treat diarrhea of various origins in children and adults. METHOD: This review article summarizes experimental studies on molecular and immunological mechanisms which explain the proven clinical efficacy of S. boulardii. Thereby the focus is on the gut-associated immune system. RESULTS: S. boulardii stimulates the release of immunoglobulins and cytokines and also induces the maturation of immune cells. This suggests that S. boulardii is capable of activating the unspecific immune system. In case of an infection, S. boulardii is able to bind pathogenic bacteria and to neutralize their toxins. Moreover, the medicinal yeast can attenuate the overreacting inflammatory immune response, by interfering with the signaling cascade, which is induced by the infection, and that way influences the innate and adaptive immune system. Thanks to these mechanisms the pathogens' potential of adhesion is lessened. Thus the intestinal epithelial layer is protected and diarrhea-induced fluid loss is reduced. CONCLUSION: The different molecular and immunological mechanisms investigated in the experimental studies prove the already confirmed very good clinical efficacy of S. boulardii in infectious diarrhea caused by pathogens such as bacteria, viruses, and fungi. PMID- 28643296 TI - The first generation ABSORB BVS scaffold; to be or not to be? PMID- 28643295 TI - Fat suppression techniques for breast MRI: Dixon versus spectral fat saturation for 3D T1-weighted at 3 T. AB - OBJECTIVE: To compare two fat suppression techniques used for 3D T1-weighted sequence in breast MRI (magnetic resonance imaging), namely Dixon versus spectral fat saturation (fat sat). MATERIALS AND METHODS: All breast MRI examinations performed in a Philips 3 T unit between March 2013 and October 2015 including either a Dixon or a fat sat sequence were retrospectively analyzed. The examinations were subjectively evaluated by two independent experienced readers in a scale of 5 for overall quality of fat suppression, homogeneity of fat suppression, definition of anatomic structures and focal lesions, diagnostic confidence for axillary and internal mammary regions and the presence of artifacts, 1 corresponding to excellent and 5 to non-diagnostic quality. Contrast to-noise-ratio (CNR) measurements for muscle and focal lesions were also performed. RESULTS: Overall 161 women (mean age 51.6 +/- 12.0 years) underwent 189 MR examinations, 113 with the fat saturation and 76 with the Dixon sequence. Interobserver variability was good (kappa = 0.757). In all subjectively evaluated parameters, the Dixon sequence was superior to the fat sat (p < 0.05). Mean values of CNR for muscle and focal lesions were 9.98 (+/-4.2), 17.9 (+/-7.53) for the fat sat and 18.3 (+/-10.4) and 29.3 (+/-14.1) for the Dixon sequence, respectively (p < 0.001). CONCLUSION: 3D T1 Dixon sequence is superior to fat sat for dedicated breast MRI at 3 T, in terms of efficiency of fat suppression and image quality with the added advantage of optimal exploration of the axillary areas. PMID- 28643297 TI - Recommendations for the use of bioresorbable vascular scaffolds in percutaneous coronary interventions : 2017 revision. AB - BACKGROUND: To eliminate some of the potential late limitations of permanent metallic stents, the bioresorbable coronary stents or 'bioresorbable vascular scaffolds' (BVS) have been developed. METHODS: We reviewed all currently available clinical data on BVS implantation. RESULTS: Since the 2015 position statement on the appropriateness of BVS in percutaneous coronary interventions, several large randomised trials have been presented. These have demonstrated that achieving adequate 1 and 2 year outcomes with these first-generation BVS is not straightforward. These first adequately powered studies in non-complex lesions showed worse results if standard implantation techniques were used for these relatively thick scaffolds. Post-hoc analyses hypothesise that outcomes similar to current drug-eluting stents are still possible if aggressive lesion preparation, adequate sizing and high-pressure postdilatation are implemented rigorously. As long as this has not been confirmed in prospective studies the usage should be restricted to experienced centres with continuous outcome monitoring. For more complex lesions, results are even more disappointing and usage should be discouraged. When developed, newer generation scaffolds with thinner struts or faster resorption rates are expected to improve outcomes. In the meantime prolonged dual antiplatelet therapy (DAPT, beyond one year) is recommended in an individualised approach for patients treated with current generation BVS. CONCLUSION: The new 2017 recommendations downgrade and limit the use of the current BVS to experienced centres within dedicated registries using the updated implantation protocol and advise the prolonged usage of DAPT. In line with these recommendations the manufacturer does not supply devices to the hospitals without such registries in place. PMID- 28643300 TI - [Advantages and disadvantages of minimally invasive surgery in colorectal cancer surgery]. AB - Since the emergence of minimally invasive technology twenty years ago, as a surgical concept and surgical technique for colorectal cancer surgery, its obvious advantages have been recognized. Laparoscopic technology, as one of the most important technology platform, has got a lot of evidence-based support for the oncological safety and effectiveness in colorectal cancer surgery Laparoscopic technique has advantages in terms of identification of anatomic plane and autonomic nerve, protection of pelvic structure, and fine dissection of vessels. But because of the limitation of laparoscopic technology there are still some deficiencies and shortcomings, including lack of touch and lack of stereo vision problems, in addition to the low rectal cancer, especially male, obese, narrow pelvis, larger tumors, it is difficult to get better view and manipulating triangle in laparoscopy. However, the emergence of a series of new minimally invasive technology platform is to make up for the defects and deficiencies. The robotic surgical system possesses advantages, such as stereo vision, higher magnification, manipulator wrist with high freedom degree, filtering of tremor and higher stability, but still has disadvantages, such as lack of haptic feedback, longer operation time, high operation cost and expensive price. 3D system of laparoscopic surgery has similar visual experience and feelings as robotic surgery in the 3D view, the same operating skills as 2D laparoscopy and a short learning curve. The price of 3D laparoscopy is also moderate, which makes the 3D laparoscopy more popular in China. Transanal total mesorectal excision (taTME) by changing the traditional laparoscopic pelvic surgery approach, may have certain advantages for male cases with narrow pelvic and patients with large tumor, and it is in accordance with the technical concept of natural orifice, with less minimally invasive and better cosmetics, which can be regarded as a supplemental technique of the traditional laparoscopic TME surgery for rectal carcinoma. However, this technology also has its own shortcomings, including difficulty getting a high ligation of vessels, difficulty exploring the abdominal cavity, and longer learning curve than laparoscopy. We believe that with the continuous progress and development of technology, continuous improvement and innovation of equipment platform, more organ functions will be protected in laparoscopic surgery for rectal cancer without compromising the safety and oncological effectiveness. PMID- 28643298 TI - A comparison of clinical efficacy and economic value in Basalin- and Lantus treated patients with type 2 diabetes using continuous glucose monitoring system. AB - AIM: To determine the clinical non-inferiority of recombinant glargine-Basalin vs glargine-Lantus, in treatment of type 2 diabetes mellitus (T2DM) using continuous glucose monitoring system (CGMS). METHODS: One hundred patients with T2DM were recruited. They were either regularly taking Basalin (Basalin group) or Lantus (Lantus group) (n = 50 each). CGMS was employed to real-time monitor blood glucose profile for 4 days (from day 1 to day 5). To exclude the effect of patient background, the study design was to have a blinded crossover from glargine-Basalin to glargine-Lantus on day 3, and vice versa. 24-hour mean blood glucose (24hMBG), 24-hour standard deviation of blood glucose (24hSDBG), 24-hour mean amplitude of glycemic excursion (24hMAGE), and number of glycemic excursion (NGE) every 24 h (24hNGE) were calculated for each glargine from 100 patients. RESULTS: No significant difference of 24hMBG, 24hSDBG, 24hMAGE, and 24hNGE (p > 0.05 for all) was found between Basalin and Lantus treatments. The glucose area under the curve and time when blood glucose was below 3.9 mmol/L, between 3.9 and 10.0 mmol/L, or above 10.0 mmol/L were similar between Basalin and Lantus treatment. The frequency of hypoglycemic episodes was also similar. However, the mean cost of Basalin was only 72% of Lantus's in one treatment course. CONCLUSION: Glargine-Basalin is non-inferior in clinical efficacy compared to glargine-Lantus. In view of the large difference in the cost of glargine-Basalin, it would be much more cost-effective for our patients. PMID- 28643301 TI - [Application of robotic surgical system in sphincter-preserving surgery for low rectal cancer]. AB - Robotic surgical system has been widely applied in sphincter-preserving surgery for low rectal cancer with the advantages of clear 3D images and stably flexile manipulation. Its application principle includes radical resection of tumor and complete preservation of function. The main operation procedures of robotic surgical system in sphincter-preserving surgery for low rectal cancer are as follows: (1) Anterior resection of low rectal cancer: It is safe and feasible and has obvious advantages in observation of pelvic nerves, dissociation of presacral and sacral side, and high rate of sphincter-preserving, while the improvement of postoperative recovery and long-term survival needs to be verified by further large sample researches. (2) Per anus intersphincteric resection (ISR): It is mainly applied in T1 and T2 stage tumors with 2 cm distance from tumor low margin to anal edge after dissociation of mesorectum. The greater difficulty of manipulation is found in ISR, while robotic surgical system can complete the intersphincteric resection by transabdominal approach, but anal function may be affected with the possibility of feces spillage at night, so robotic ISR is now still in exploration stage. (3) Transanal everted pull-through resection (Welch resection): Associated application of this operation is rarely reported at home and abroad. Our department has completed 51 robotic procedures of Welch resection till March 2017. Welch resection is successfully performed in all the patients. The short-term clinical outcomes are quite satisfactory and long-term survival is followed up. We think that this procedure is safe and feasible under the strict mastering of indications. Owing to special manipulation advantages of quickly precise dissociation, cutting and anastomosis in small pelvic space, when compared to laparoscopic surgery, robotic surgical system has higher sphincter preserving rate for low rectal cancer, however, no other advantages are found. We believe that with the development of surgical instruments and ongoing of large sample studies, robotic surgical system will play a more important role in the treatment of low rectal cancer. PMID- 28643299 TI - The association between circulating fetuin-A levels and type 2 diabetes mellitus risk: systematic review and meta-analysis of observational studies. AB - BACKGROUND AND OBJECTIVE: Fetuin-A is a liver-derived circulating protein that is associated with insulin resistance and diabetes. The objective of this systematic review and meta-analysis of published observational studies was to investigate mean levels of fetuin-A in T2D patients and the relationship between blood fetuin A levels and T2D risk. MATERIALS AND METHODS: PubMed, Embase, Google Scholar, Web of Science, and The Cochrane Library were systematically searched for potential relevant studies up to 1 December 2016. Natural logarithm-transformed estimate risks, standard mean differences on the basis of Hedges's adjusted g, and 95% confidence intervals (CIs) were calculated for all eligible studies and were combined to measure the pooled data using random-effects model. RESULTS: A total of 32 studies including 27 case-control and 5 cohort studies were included in the current study. Fetuin-A levels in T2D patients were significantly higher than control groups [Hedges' g = 1.73, 95% CI (1.25-2.22), P < 0.001], with significant heterogeneity across studies (P < 0.001, I 2 = 98.46%). Findings from meta-analyses of cohort studies showed a statistically significant association between fetuin-A levels and T2D risk [rate ratio = 1.62, 95% CI (1.26-2.08), P < 0.001], with no significant heterogeneity (P = 0.10, I 2 = 46.06%). CONCLUSION: We found a significant relationship between the fetuin-A levels with T2D risk. Although fetuin-A may be as a potential screening and prediction biomarker or a therapeutic target in T2D patients, further studies are required in this regard. PMID- 28643302 TI - [Comparison of robotic and laparoscopic total mesorectal excision]. AB - Laparoscopic total mesorectal excision (TME) has been commonly applied in the operation of mid-low rectal cancer, but the conventional laparoscopic TME has the disadvantages of major operative difficulty and long learning-curve, due to its limitations of 2-dimension vision and common laparoscopic instruments. Robotic surgical system with high-qualified 3-dimenstion vision and flexible Endo Wrist instruments can overcome those limitations of conventional laparoscopy, and is useful for the TME that demands deep pelvic operation and flexible dissection in the space of distal rectum. Robotic TME has the advantages of shorter learning curve and lower conversion rate, and it can even be performed by the surgeon with little laparoscopic experience. But according to the current studies, the superiority of robotic TME over laparoscopic TME can not be confirmed. To confirm the efficacy of robotic surgery, more high-level evidences are needed. Currently, the biggest obstacle for the widespread use of robotic surgical system is its high expense. But there is an obvious advantage that is the more comfortable feeling of surgeon while performing robotic surgical system, compared with performing laparoscopic operation, and it is helpful for long-time complicated operation. It is confirmative that robotic operation is the results of science and technology development, and it is the direction of future development. With the expiration of patent right of Da Vinci robotic system, there will be more kinds of robotic surgical systems which will lead to the much lower operation expense and the widespread use. The young surgeons should master the laparoscopic TME, which will help them master robotic TME technique quickly. PMID- 28643303 TI - [Application of fascia-orientation of pelvic autonomic nerve preservation in rectal cancer surgery]. AB - Rectal cancer has become the second most common gastrointestinal tumor in our country. With the development of comprehensive treatment, the long-term survival rate of patients with rectal cancer has greatly increased, meanwhile, higher postoperative quality of life is required. But the genitourinary dysfunction which is mainly caused by intraoperative pelvic autonomic nerve damage haunts postoperative rectal cancer patients. Traditional pelvic autonomic nerve protection technology born in the 1980s only improves urogenital function in a part of postoperative patients. In recent years, NOME(nerve-oriented mesorectal excision) was proposed, which needed to make pelvic autonomic never exposed. However, recovery of urinary function is not ideal due to difficulty identifying pelvic autonomic nerve and unavoidable damage on pelvic autonomic nerve. In clinical practice, we found that pelvic autonomic nerve can be divided into three parts: abdominal cavity, large pelvis, small pelvis. The pelvic autonomic nerve is closely related to the surrounding fascias in each part. The fascias are not only the protection of pelvic autonomic nerve, but also can be used as a good indicator of location of pelvic autonomic nerve. The relationship of pelvic autonomic nerve with Toldt fascia, presacral fascia, the lateral rectal ligaments, and the Denonvilliers fascia is discussed in this paper. Combined with the above theory, a new technology named FOPANP (fascia-orientation of pelvic autonomic nerve preservation) is proposed. In this technique, the fascia around the rectum is used as a guidance to select the appropriate plane in the operation, and the tumor can be removed without exposing the pelvic autonomic nerve. This technology has three advantages. First, it is not necessary to search and expose the pelvic autonomic nerve, so as to avoid secondary injury to it during the operation. Secondly, the pelvic fascias are natural barriers formed between the surgical plane and the pelvic autonomic nerve retained. They can avoid the stimulation of physical and chemical factors to pelvic autonomic nerve. Thirdly, because the fascias are easier to identify, and the texture is more tough, so the technology is easier to master. PMID- 28643304 TI - [Strategy and technique for simultaneous resection of rectal cancer and liver metastasis]. AB - Rectal cancer with simultaneous liver metastasis is very common clinically. R0 surgical resection both for the original and metastatic tumor can achieve much better long-term oncological results. The operation types include traditional open procedures for both rectal cancer and liver metastatic resection; combination of laparoscopic resection of the rectal cancer and open procedure resection of the liver metastatic lesion; traditional laparoscopic-assisted rectal and liver metastatic tumor resection with small abdominal incision and total laparoscopic natural orifice specimen extraction surgery(NOSES) without abdominal incision. Due to the complexity of rectal anatomy and treatment strategy, leading to the difference from colon cancer with liver metastasis, and due to the effect of laparoscopic treatment, especially the 3D laparoscopy, patient selection for simultaneous resection should be well planned and individualized by surgeons based on conditions of themselves and patients. PMID- 28643305 TI - [Interventional therapy of colorectal liver metastasis]. AB - Colorectal liver metastasis (CRLM) is one of the most difficult and key points in the treatment of colorectal cancer. Approximately 50% to 60% of patients diagnosed as colorectal cancer develops metastasis, and 80% to 90% of CRLM is unresectable. Surgical resection is the first-line treatment for CRLM, while it is only suitable for about 15% patients. Systemic chemotherapy can prolong the survival of CRLM patients, however, a part of CRLM patients are resistant to chemotherapy. With the development of technology and the update of clinical evidence, individual therapy with target drugs and multidisciplinary treatment (MDT) have became a tendency, and minimally invasive interventional therapy has gained more acceptance in the MDT mode of the treatment for CRLM. Basically, the interventional treatment for CRLM is divided into two groups: vascular intervention and local minimally invasive intervention. Vascular approaches encompass portal vein embolization (PVE), hepatic artery infusion chemotherapy (HAIC), transarterial chemoembo- lization (TACE), and transarterial radioembolization (TARE). Local minimally invasive intervention includes radiofrequency ablation (RFA), microwave ablation(MWA), cryoablation (CRA), and irreversible electroporation (IRE). Thevefore intervention treatment is an important complement to the comprehensive therapy of CRLM. PMID- 28643306 TI - [Laparoscopy and endoscopy cooperative surgery for colorectal tumors]. AB - Laparoscopy and endoscopy cooperative surgery (LECS) for colorectal tumors is not only a minimally invasive treatment, but also a safer therapy. It mainly includes laparoscopy-assisted colonoscopic resection and colonoscopy-assisted laparoscopic surgery. Laparoscopy-assisted colonoscopic procedure can make endoscopic resection more "aggressive". Performers can directly observe to ensure normal intestinal wall, and the intestinal defect can be directly repaired. If suspected malignant tumor can not be removed by colonoscopy, the laparoscopic surgery can be performed. Colonoscopy-assisted laparoscopic surgery can be assisted by endoscopy, including positioning lesion, ensuring anastomotic stenosis, and checking intraoperative bleeding. In case of acute bowel obstruction due to colorectal cancer, a self-expanding metallic stent (SEMS) can be placed for drainage to avoid emergency surgery and colostomy. Then, laparoscopic radical surgery can be done. In conclusion, the LECS provides a new minimally invasive treatment for colorectal tumors. With the development of endoscopic and laparoscopic techniques and devices, LECS will have a wider range of applications. PMID- 28643307 TI - [Application of magnetic resonance in "non-operative treatment" strategy for rectal cancer]. AB - The primary curative modality for localized rectal cancer is total mesorectal excision (TME). Local control rate of rectal cancer has been improved after neoadjuvant chemoradiotherapy and even pathological complete response (pCR) has been demonstrated in a significant minority. Patients who achieve pCR to neoadjuvant chemoradiotherapy have an excellent prognosis compared with those without pCR. If the patients with complete response to neoadjuvant chemoradiation can be demonstrated by clinical findings and medical imaging (cCR), a non operative management (NOM) strategy may be pursued to preserve sphincter function and avoid complications induced by TME, which is a new tendency in the treatment of rectal cancer in recent years. Assisting diagnosis of cCR by iconography is the important element of NOM practice. Selected patients should be followed up with intensive surveillance. The curative strategy must be carried out once the recurrence is detected. Imaging modalities, including magnetic resonance imaging (MRI), diffusion-weighted MRI, or proton emission tomography (PET), are limited in their ability to distinguish patients who have achieved cCR. Up to now, MRI, DW-MRI and 18F-FDG PET/CT before neoadjuvant chemoradiotherapy are not accurate enough to predict cCR and safely select patients for organ-sparing strategies. However, depth of tumor infiltration, extramural vascular invasion, circumferential resection margin, and location of rectal cancer can be demonstrated by high resolution MRI as independent risk factors in prediction of long-term survival of patients, which is a necessary manner of stratification treatment for rectal cancer. Therefore, patients who are defined as early rectal cancer with low risk factors are selected as candidates for NOM in recent studies in order to pursue low rate of local recurrence and distant metastasis. High resolution MRI assessment of tumor regression grade (mrTRG) can be used to assess response of rectal cancer to neoadjuvant chemoradiotherapy, which is associated with tumor burden. mrTRG is an imaging marker that indicates the difference in survival between good and poor responders and provides an opportunity for the multidisciplinary team to offer additional treatment options before planning definitive surgery. Functional imaging and even molecular imaging are needed in the future to screen suitable rectal cancer patients who are easier to achieve cCR from neoadjuvant chemoradiotherapy and to evaluate the efficacy of neoadjuvant chemoradiotherapy. PMID- 28643308 TI - [Anatomical strategies of Henle trunk in laparoscopic right hemi-colectomy for right colon cancer]. AB - The advancement of laparoscopic surgery serves as a trigger for better understanding of the vascular structure at the inferior border of the pancreas, especially Henle trunk. Henle trunk was first found as convergence to superior mesenteric vein (SMV) conjoined by sub-right colon vein (SRCV) and right gastroepiploic vein (RGEV), but decades later, anterior superior pancreatic duodenal vein (ASPDV) was described as another conjoint vein of Henle trunk. These tributaries are the basic elements of Henle trunk in early years' study. A proper surgical procedure for Henle trunk can significantly reduce the complications of radical right hemi-colectomy (Japanese D3 resection and European complete mesocolic excision, CME). There are four variations of Henle trunk according to the colic venous tributaries that consists the anatomic variations in transverse colon posterior space(TRCPS). These variations are like "fingerprint and pattern" of CME. The recognition and extension of the TRCS is the key to the dissection of Henle trunk in laparoscopic right hemi-colectomy. Our medical center proposed four feasible approaches for extension:(1) hybrid medial approach; (2) completely medial approach; (3)completely medial access by "page-turning" approach; (4) completely medial approach along RCV. Mostly, RCV ended in Henle trunk, and completely medial approach along RCV is efficient to identify the Henle trunk in CME. We suggest dissecting the inferior margin of pancreas along SMV in a bottom-to-top fashion, followed by the dissection of middle colic vessels to reveal the root of Henle trunk. And it's better to dissect Henle trunk by branch rather than at its root for safety. Here, we describe the anatomic characters of Henles trunk, the surgical approach and strategies of Henle trunk in laparoscopic surgery. PMID- 28643309 TI - [Comparison of clinicopathological features and prognosis between left-sided colon cancer and right-sided colon cancer]. AB - OBJECTIVE: To compare the clinicopathological features and prognosis between left sided colon cancer (LC) and right-sided colon cancer (RC). METHODS: Clinicopathological and follow-up data of 2 174 colon carcinoma cases undergoing resection at Shanghai Changhai Hospital of The Second Military Medical University from January 2000 to December 2010 were retrospectively analyzed. Patients with transverse colon cancer, overlapping position, unknown location, recurrent cancer, multiple primary cancer, concomitant malignant tumors, preoperative chemotherapy, local resection, incomplete clinical data and missed follow up were excluded. Finally, a total of 1 036 patients, whose primary tumors were radically removed, were enrolled, with 563 patients in LC group (including carcinoma in cecum, ascending colon and hepatic flexure) and 473 in RC group (including carcinoma in splenic flexure, descending colon and sigmoid colon). The clinicopathological features and survival, including median overall survival, 5 year overall survival rate, tumor specific median overall survival, cancer specific 5-year overall survival rate, were compared between LC and RC groups. Tumor specific overall survival was defined as the period between operation date to the date of death caused by cancer progression. Multivariate Cox regression analysis was used to analyze the influencing factors of survival. Propensity score matching was carried out to balance the clinicopathological factors between the two groups with the SAS 9.3, taking the following parameters into consideration (age, gender, gross appearance, tumor diameter, invasion depth, lymph node metastasis, distant metastasis, TNM stages, differentiation, CEA and CA199-9). Patients in RC group and LC group were matched according to the propensity scores and the clinicopathological characteristics and prognosis of two groups were compared again. RESULTS: No significant differences were identified between the two groups in age, distant metastasis and serum CEA level. Compared with RC group, LC group had more male patients [60.9%(343/563) vs. 51.0%(241/473), P=0.001], more ulcerative tumors [71.9% (405/563) vs. 65.3%(309/473), P=0.006], better differentiation [well/moderately differentiated: 87.5%(493/563) vs. 73.8%(349/473), P=0.000], lower infiltration depth [T1-2: 17.1%(96/563) vs. 10.1%(48/473), P=0.001], higher lymph node metastasis rate [N0: 53.3%(300/563) vs. 62.4%(295/473), P=0.013], lower TNM stage [stage I(: 13.3%(75/563) vs. 7.8%(37/473), P=0.000], lower serum CA199 level [<37 kU/L: 68.4% (385/563) vs. 62.6% (296/473), P=0.022] and smaller tumor diameter [<5.0 cm: 55.1%(310/563) vs. 38.3%(181/473), P=0.000]. The median overall survival was 82 months and 76 months in LC and RC groups, respectively, and the 5-year overall survival rate was 58.3% and 50.9%(P=0.038). The median tumor specific survival was 84 months and 78 months in LC and RC groups, respectively, and the 5-year tumor specific overall survival rate was 60.6% and 52.9% (P=0.031). Multivariate Cox regression analysis showed that tumor location (LC vs. RC) was not associated with overall survival (P=0.106) and tumor specific survival (P=0.091). After propensity score matching, no significant difference was found in clinicopathological factors and propensity score (0.458+/-0.129 vs. 0.459+/ 0.129, P=0.622) between LC and RC group. After matching, there was no significant difference in overall survival rate (54.0% vs. 51.7%, P=0.982) and tumor specific overall survival rate(56.4% vs. 53.1%, P=0.819) between two groups. CONCLUSION: Significant difference exists between RC and LC in clinicopathological factors, but not in survival. PMID- 28643310 TI - [Establishment of a prognostic nomogram to predict long-term survival in non metastatic colorectal cancer patients]. AB - OBJECTIVE: To establish a nomogram to predict long-term survival in non metastatic colorectal cancer patients. METHODS: A retrospective analysis was conducted in patients with non-metastatic colorectal cancer who underwent radical surgery in the Department of Colorectal Surgery of Affiliated Union Hospital of Fujian Medical University between January 2000 and December 2014. Univariate and multivariate analyses on disease-free survival (DFS) were performed using the Cox proportional regression model. Based on the multivariate analysis results, a prognostic nomogram was formulated to predict the probability for DFS. Concordance index was applied in predictive evaluation of the nomogram and calibration curves were drawn to test the nomogram's prediction and actual observation of the 5-year DFS rate. The predictive ability of nomogram was compared with AJCC-7 staging system. RESULTS: A total of 2 641 patients were identified. The median age was 59.3 years old, and 60.3% of cases were men. The number of patients with TNM stage 0, I(, II( and III( was 96, 505, 923 and 1043, respectively. The most common tumor site was the rectum, accounting for 43.2%. A total of 413 (15.6%) patients underwent neoadjuvant treatment. The most common gross type of tumor was ulcerative type, accounting for 79.5%. The 3- and 5-year DFS rate was 85.8% and 79.8%, respectively. Based on the Cox proportional regression model, the following six factors were independently associated with reduced DFS rate and were selected for the nomogram: older age, higher pathologic T stage, higher pathologic N stage, higher preoperative serum CEA level, infiltrative gross type and perineural invasion. The results of the nomogram showed that the score of T0, T1, T2, T3 and T4 stage was 0, 2.2, 3.9, 4.1 and 6, respectively, and the score of N0, N1 and N2 was 0, 3.8 and 9.3, respectively. For gross type, the score of expanding type, ulcerative type and infiltrative type was 6, 9 and 10, respectively. The score of perineural invasion was 5.2. Higher scores were added to older age and higher CEA level. The total scores were calculated by taking the sum of the points from all predictors. Higher total score was associated with poor DFS. The prognostic nomogram differentiated well and showed a concordance index of 0.718, which was better than AJCC-7 staging system (concordance index=0.683). Also, the calibration of nomogram predictions was good. CONCLUSIONS: A nomogram based on 6 independently prognostic factors to predict long-term survival in non-metastatic colorectal cancer patients is established successfully. The nomogram can be conveniently used to facilitate the accurate individualized prediction of DFS rates in patients with non-metastatic colorectal cancer. PMID- 28643311 TI - [Long-term outcomes of laparoscopic low anterior resection of rectal carcinoma with preservation of the left colic artery]. AB - OBJECTIVE: To investigate the long-term outcomes of laparoscopic low anterior resection of rectal carcinoma with preservation of the left colic artery(LCA). METHODS: Clinicopathological and follow-up data of 322 cases with rectal carcinoma undergoing laparoscopic low anterior resection in Department of General Surgery, Beijing Chaoyang Hospital Affiliated to Capital Medical University from January 2007 to December 2011 were retrospectively analyzed. According to the different surgical methods of inferior mesenteric artery (IMA), cases were divided into the trial group (LCA preservation plus lymph nodes around IMA root dissection, 168 cases) and the control group(origin of IMA ligation, 154 cases). The 5-year rates of disease-free survival(DFS) and overall survival(OS) were compared between two groups. RESULTS: There were no statistically significant differences in the baseline data between the two groups. The follow-up rate was 91.1%(153/168) during 5-60 months in the trial group, and 90.3%(139/154) during 6 60 months in the control group. The number of patients who developed death, local recurrence and metastasis were 49(32.0%), 9(5.9%) and 62(40.5%) in the trial group, and 44(31.7%), 9(6.5%) and 52(37.4%) in the control group, respectively, without significant differences(all P>0.05). The 5-year DFS and OS rates were 57.2% and 69.5% in the trial group, and 59.7% and 70.1% in the control group, and the differences were not significant between the two groups(all P>0.05). After stratification by TNM stage, the 5-year DFS rates of I( stage, II( stage and III( stage were 80.4%, 62.5% and 45.1% in the trial group, and 82.6%, 66.0% and 48.8% in the control group; the 5-year OS rates of I( stage, II( stage and III( stage were 90.2%, 76.2% and 56.7% in the trial group, and 94.4%, 74.3% and 60.5% in the control group, respectively, and the differences were not significant as well (all P>0.05). CONCLUSION: The long-term outcomes after laparoscopic low anterior resection of rectal carcinoma with preservation of LCA and dissection of lymph nodes around root of IMA are comparable with ligation at origin of IMA. PMID- 28643312 TI - [Comparison of short-term outcomes of transrectal specimen extraction during laparoscopic sigmoid radical resection versus conventional laparoscopically assisted procedure]. AB - OBJECTIVE: To compare the short-term outcomes between transrectal specimen extraction during laparoscopic sigmoid radical resection and conventional laparoscopy-assisted sigmoid radical resection. METHODS: Sixteen patients(transrectal specimen extraction group,4 females and 12 males), who were planned to undergo laparoscopically assisted sigmoid radical resection with BMI<28 kg/m2 and were evaluated as T1-T3 tumor by iconography without distant metastasis, were selected to undergo transrectal specimen extraction during laparoscopic sigmoid radical resection from December 2015 to April 2016 in the Department of Anorectal Surgery of Changhai Hospital. The procedure of specimen extraction was as follows: Perineal anal expansion was performed. The rectum was cut in rectal distal ligature within the abdominal cavity. Telescope cover was placed through Trocar hole in right low abdomen and rectal stump was pulled out of the body through the anus to form an access tunnel. Planned resected bowel was placed in the tunnel and the specimen was dissociated and removed completely from anus. Each patient in transrectal specimen extraction group was individually matched with two patients who underwent laparoscopically assisted sigmoid radical resection by gender, age, BMI and date of surgery. The perioperative outcomes and pathological evaluation of surgical specimen of two groups were retrospectively collected and compared. RESULTS: The differences of baseline data (gender, age, BMI, distance from tumor to anal verge measured by colonoscopy and clinical tumor category) between two groups were not significant (all P>0.05). Compared to laparoscopy-assisted group, transrectal specimen extraction group presented longer operation time [(140.6+/-8.3) minutes vs. (122.2+/-26.2) minutes, t= 3.629, P=0.001], and more blood loss[(43.8+/-9.2) ml vs. (35.3+/-10.2) ml, t= 2.795, P=0.008], but shorter time to first flatus [(43.1+/-8.3) hours vs. (52.0+/ 11.4) hours, t=2.756, P=0.008] and lower pain score at operative day and the first postoperative day (3.8+/-0.8 vs. 4.8+/-1.1, t=3.558, P=0.001; 2.6+/-0.6 vs. 3.8+/-0.8, t=5.165, P=0.000). The case ratio of additional analgesia [6.3%(1/16) ns. 18.8%(6/32)], postoperative hospital stay [(6.8+/-3.4) days vs. (5.6+/-0.8) days] and postoperative morbidity of complication [12.5%(2/16) vs. 9.4%(3/32)] were not significantly different between the two groups (all P>0.05). Within postoperative 30-day follow-up, transrectal specimen extraction group had ileus in one patient and anastomotic leakage in one patient, and laparoscopy-assisted group had fat necrosis of assisted incision in two patients and gastric retention in one patient. There were also no significant differences in specimen length[(18.2+/-4.8) cm vs. (19.8+/-5.7) cm, P>0.05], tumor size [(4.0+/-1.2) cm vs. (4.4+/-1.5) cm, P>0.05] and number of harvested lymph node (14.6+/-2.6 vs. 16.0+/-3.0, P>0.05] between two groups. During follow-up of 7-10(mean 9) months of transrectal specimen extraction group and 2-16 (mean 7) months of laparoscopically assisted group, no tumor local relapse and distant metastasis were found in the both groups. CONCLUSION: As compared to laparoscopy-assisted sigmoid radical resection, transrectal specimen extraction laparoscopic sigmoid radical resection has better short-term efficacy, meanwhile they have comparable oncologic clearance. PMID- 28643313 TI - [Anastomotic leakage after laparoscopic-assisted radical right hemicolectomy: reason analysis and management]. AB - OBJECTIVE: To analyze the clinical features, possible reasons and management of anastomotic leakage after laparoscopic-assisted radical right hemicolectomy. METHODS: Clinical data of 546 patients undergoing laparoscopic-assisted radical right hemicolectomy in Peking Union Medical College Hospital from October 2010 to September 2016 were retrospectively analyzed. The occurrence of anastomotic leakage and its countermeasures were evaluated. RESULTS: Among 546 patients, 8(1.5%) cases developed anastomotic leakage, including 7 males and 1 female with mean age of (54.3+/-10.3) years. Six cases of ascending colon cancer, 1 case of phlegmon and 1 case of arterior-venous malformation were confirmed after operation. The incidence of anastomotic leakage after D3 and D2 lymphadenectomy was 2.1%(6/290) and 0.8%(2/256). The time from operation to the diagnosis of anastomotic leakage was (6.6+/-3.6) days. The clinical manifestation of anastomotic leakage were stool-like drainage in 7 patients, fever in 4 and abdominal pain in 3. Amylase and bilirubin in drainage of 4 patients increased obviously. All the 8 patients underwent secondary ileostomy, including 4 with laparoscopy and 4 with laparotomy. One patient suffered from respiratory failure after re-operation because of severe abdominal infection and was cured by ventilator support treatment. Another one had pelvic encapsulated effusion and was treated by puncture drainage. All the patients discharged from hospital smoothly. CONCLUSIONS: Anastomotic leakage after laparoscopic-assisted right hemicolectomy is a quite rare but serious complication, which may be associated with over-cleaning of lymph fatty tissues. Ileostomy should be the first choice of anastomotic leakage after laparoscopy-assisted right hemicolectomy and its efficacy is satisfactory. PMID- 28643314 TI - [Analysis of the common hemorrhage sites during laparoscopic rectal cancer surgery]. AB - OBJECTIVE: To analyze the common hemorrhage sites during laparoscopic rectal cancer surgery in order to take reasonable prevention and management. METHODS: Clinical data of 355 rectal cancer patients who underwent laparoscopic total mesorectal excision in Shanxi Provincial People's Hospital from January 2012 to December 2014 were retrospectively analyzed. Common bleeding sites, blood loss, and hemostasis time were recorded. According to the date of operation, patients were divided into 2012 group (91 cases), 2013 group (122 cases) and 2014 group(142 cases). Hemorrhage rates were compared among three groups. RESULTS: No significant differences were observed in the baseline data among the three groups(all P>0.05). The location in the order of the hemorrhage rate from high to low was seminal vesicle tail (63.0%, 131/208), inferior mesenteric vessels (27.3%, 97/355), Toldt's space (24.2%, 86/355), lateral rectal ligaments (12.1%, 43/355) and post-rectal spatial (8.2%, 29/355). According to the blood loss, post rectal spatial[(14.1+/-7.1) ml], inferior mesenteric vessels [(12.7+/-6.1) ml] and seminal vesicle tail [(12.4+/-6.5) ml] were ranked in top three. The hemostasis time of seminal vesicle tail [(11.5+/-6.6) minutes] and post rectal spatial [(10.3+/-7.8) minutes] was longer than the others. Compared with 2012 group, shorter operative time [(205+/-50) minutes vs. (235+/-55) minutes, t=4.296, P=0.001], less blood loss [(35+/-19) ml vs. (81+/-24) ml, t=16.243, P=0.001] and lower hemorrhage rate [Toldt's space: 7.7%(11/142) vs. 39.6%(36/91), inferior mesenteric vessels: 9.2%(13/142) vs. 44.0%(40/91), post-rectal spatial: 0.7%(1/142) vs. 15.4%(14/91), lateral rectal ligaments: 2.1%(3/142) vs. 29.7%(27/91) and seminal vesicle tail: 50.6%(41/81) vs. 79.6%(43/54)] were found in 2014 group. The decline of hemorrhage rate in seminal vesicle tail was the slowest (chi2=11.792, P=0.003). CONCLUSIONS: The common hemorrhage sites during the laparoscopic rectal cancer surgery are inferior mesenteric vessels, Toldt's space, lateral rectal ligaments, post rectal spatial and seminal vesicle tail. Appropriate preventive measures can ameliorate the intraoperative bleeding significantly, however, more attention should be paid to the seminal vesicle tail during operation because of its higher hemorrhage rate, more blood loss and difficult hemostasis. PMID- 28643315 TI - [Technical advantages of nano carbon development combined with artery approach in lymph node sorting of rectal cancer]. AB - OBJECTIVE: To explore the technical advantages of nano carbon development combined with artery approach in lymph node sorting of rectal cancer. METHODS: From December 2015 to June 2016, 70 patients with of rectal cancer in General Surgery Department of Henan Cancer Hospital were randomly divided into nano carbon development combined with artery approach group(artery approach group) and conventional group. Specimen of artery approach group was placed on the sorting table. Anatomy was performed from the root of inferior mesenteric artery to left colonic artery, sigmoid artery and superior rectal artery. Along the arterial vessel shape, the black-stained lymph nodes and non-stained lymph nodes (perhaps pink, pale yellow, white or pale brown) were examined carefully using visual and haptic combination method for identification of lymph node. From the root of inferior mesenteric artery, central lymph nodes were sorted. Along the vessel shape, vascular lymph nodes were sorted. Intestinal lymph nodes around the rectum were examined as well. Then, specimen was reversed on the sorting table and underwent sorting as above after the examination of obverse. The conventional group received routine method. The total number, the average harvested number, the number of positive lymph nodes and the number of patients with lymph nodes less than 12 were compared between two groups. RESULTS: Among 70 cases, 37 were male and 33 were female with the median age of 57(32-88) years old. Dixon resection was performed in 46 cases, and Miles resection in 24 cases. Total sorting lymph node was 1 105, including 641 of artery approach group and 464 of control group with significant difference (t=20.717, P=0.000). Lymph node sorting time of artery approach group was (12.6+/-3.9) minutes, which was shorter than (18.2+/-4.1) minutes of control group (t=12.464, P=0.000). In artery approach group, number of lymph node with diameter less than 5 mm was 142, sorting rate was 22.2%(142/641), of which 29 were positive(20.4%). In conventional group, 37 lymph nodes with diameter less than 5 mm were found, and sorting rate was 8.0%(37/464), of which 6 were positive(16.2%). Number of the first station of lymph node sorting in artery approach group and conventional group was 282(44%) and 169(36.4%); number of the second station lymph node sorting was 230(35.9%) and 180(38.8%); number of the third station lymph node sorting was 129(20.1%) and 115(24.8%). CONCLUSION: The method of nano carbon development combined with artery approach in lymph node sorting of rectal cancer has some advantages, such as simple operation, more harvested lymph nodes, and more accurate pathological staging. PMID- 28643316 TI - [Endoscopic metallic stent followed by elective laparoscopic surgery for malignant colorectal obstruction]. AB - OBJECTIVE: To investigate the feasibility of endoscopic metallic stent as a bridge to elective laparoscopic surgery in patients with malignant colorectal obstruction. METHODS: Clinical data of 63 patients with obstructive colorectal cancer who underwent endoscopic metallic stent insertion under radiologic monitoring at the Longyan First Hospital between June 2012 and August 2016 were analyzed retrospectively. After complete remission of the obstruction, all the patients received multi-disciplinary team (MDT) evaluation to make the further treatment strategy. The subsequent surgery included open and laparoscopic procedures, and the short-term efficacy of these two procedures was compared. RESULTS: There were 30 male and 33 female patients with age of 30 to 90 (mean 67) years, including 3 cases of ascending colon cancer, 4 cases of transverse colon cancer, 12 cases of descending colon cancer, 26 cases of sigmoid cancer, and 19 cases of rectal cancer. Only one patient (1.6%) developed sigmoid perforation at 3 hours after stent placement, and underwent emergency laparotomy with Hartmann procedure. The remaining 62 patients had bowel movements. After MDT evaluation, 10 patients (16.1%) were treated with palliative chemotherapy because they were unfit for surgery or for diffuse distant metastases. A total of 52 patients underwent radical surgery after a mean interval from stent insertion of 10 days (7-20 days), including open (n=18, including two cases with conversion to open surgery) and laparoscopy (n=34). The baseline data between open and laparoscopy groups were similar (all P>0.05). Primary anastomosis was successfully performed in all the patients without preventive stoma. Compared to open group, laparoscopy group had faster bowel movement [(2.88+/-1.06) d vs. (4.05+/-2.43) d, P=0.022] and shorter postoperative hospital stay [(7.85+/-0.96) d vs. (9.82+/-4.41) d, P=0.002]. There were no statistically significant differences in operative time, intraoperative blood loss, number of harvested lymph node, and postoperative complication rate between two groups (all P>0.05). CONCLUSIONS: Endoscopic metallic stent placement can effectively remove malignant colorectal obstruction, and thus enables surgeons to perform an elective radical surgery, avoiding emergency surgery with stoma and unnecessary surgery for patients with distant metastasis. In the era of enhanced recovery after surgery, the endoscopic metallic stent placement combined with laparoscopic procedures, as a less invasive alternative, is effective and safe. PMID- 28643317 TI - [Effect of metformin on colorectal carcinoma in type 2 diabetes mellitus patients: a Markov model analysis]. AB - OBJECTIVE: To evaluate the colorectal cancer (CRC) prevention effect of metformin in comparison with that of other T2DM medications from a Markov model perspective. METHODS: Literature concerning CRC morbidity of T2DM patients with metformin or other diabetes medications treatment was reviewed in PubMed and Cochrane Library database from September 2010 to December 2016. INCLUSION CRITERIA: (1)enrolled population was adult patients with T2DM but without CRC; (2) any of the parameters applied in our model was reported; (3) randomized clinical trials (RCTs), quasi-randomized trials, prospective or retrospective cohort studies. With CRC morbidity as endpoint, parameters were extracted to construct Markov model to assess CRC morbidity and cumulative tumor-free survival in each group over 11 years' follow-up period. Finally, Monte Carlo analysis was performed to evaluate the influence of parameter instability on the model. RESULTS: Seven literatures were recruited and 10 000 patients were virtually allocated for each arm. In contrast with non-metformin group, T2DM patients treated with metformin had a lower rate of CRC(1.670% vs. 2.146%, P=0.016). Moreover, cumulative tumor-free survival of metformin group was, slightly but significantly, better than that of non-metformin group (10.908 years vs. 10.882 years, P=0.000). CONCLUSIONS: T2DM patients treated with metformin have a lower morbidity of CRC and a better cumulative tumor-free survival than those of non metformin group. Large scale RCTs are needed to illustrate the role of metformin in the prevention of CRC. PMID- 28643318 TI - [Experimental research of neutrophil gelatinase-associated lipocalin siRNA encapsulated by urocanic acid-coupled chitosan on colon cancer cells]. AB - OBJECTIVE: To explore the impact of neutrophil gelatinase-associated lipocalin (NGAL) knockdown by NGAL siRNA encapsulated with urocanic acid-modified chitosan nanoparticles (UAC) on the proliferation, migration and apoptosis of human colon cancer cells. METHODS: NGAL siRNA was encapsulated by UAC and chitosan (CTS) respectively, and then was transfected into human colon cancer cell lines HT29. The NGAL mRNA was detected by real-time quantitative PCR (RT-QPCR). Relationships of NGAL gene silencing with the proliferation, migration and apoptosis of HT29 cell were analyzed. RESULTS: Under the fluorescence microscope, the transfection efficiency of siRNA in UAC group was (37.52+/-7.17)%, which was significantly higher than (11.32+/-3.39)% in CTS group (t=6.102, P=0.005). Forty-eight hours after transfection, RT-QPCR examination showed that the level of NGAL mRNA expression was 0.350 in UAC group and 0.529 in CTS group with significant difference (t=-3.743, P=0.02), meanwhile both levels were significantly lower as compared to control group(F=163.538, P<0.001). Proliferation analysis revealed that after silencing NGAL gene, proliferation rate of UAC group and CTS group was slightly lower than control group, and no significant differences were found (F=9.520, P=0.438). However, migration assay demonstrated that the 24-hour migration rate of UAC group and CTS group was significantly lower than that of control group (F=6.756, P=0.029), meanwhile the migration rate of UAC group was slightly lower than that of CTS group [(77.90+/-7.14)% vs. (87.67+/-3.98)%, t= 1.704, P=0.164]. Apoptosis detection revealed that the apoptosis rate in UAC group was significantly higher than that in CTS group and the control group 2 days after transfection [(15.800+/-1.054)% vs. (12.900+/-0.656)%, (11.933+/ 1.914)%, F=7.004, P=0.027]. CONCLUSIONS: The encapsulated ability and transfection efficiency of chitosan modified by urocanic acid elevate significantly. Silencing NGAL gene by UAC carrier can down-regulate the expression of NGAL mRNA in HT29 colon cell line, inhibit their migration and facilitate their apoptosis. PMID- 28643319 TI - [Progress of the application of optical coherence tomography in gastrointestinal tumor surgery]. AB - Optical coherence tomography (OCT) is a real-time, cross-sectional optical imaging technology. It is analogous to ultrasonography, except that OCT uses light waves instead of sound waves, and can provide three-dimensional morphological images of living tissues with a micrometer resolution. Through the use of endoscopes, needles, catheters and laparoscopes, OCT has demonstrated tremendous imaging potential in tumor surgery. The current studies suggest that OCT has potential for clinical applications in the following fields of gastrointestinal tumor surgery: (1) Early tumor detection and diagnosis: OCT can distinguish differences between polyp tissue, normal tissue and malignant tissue. It could possibly identify premalignant lesions or conditions potentially predisposing to malignancy, such as gastric and intestinal metaplasia, gastritis associated with Helicobacter pylori, and early gastric cancer involving the mucosa or submucosa. In addition, OCT can differentiate between adenomatous polyps and hyperplastic polyps. (2) Optical biopsy of lymph nodes: As a high resolution, near-IR imaging modality, OCT is capable of visualizing microscopic features within tissue, distinguishing lymph node tissue from surrounding adipose tissue, revealing nodal structures such as germinal centers and intra-nodal vessels. Consequently, OCT has the ability to show changes in node microarchitecture during metastatic tumor infiltration. (3) Intraoperative guidance for real-time determination of surgical margins: In other tumors such as oral squamous cell carcinoma and breast cancer, it has been demonstrated that OCT can be used to rapidly scan large areas of tissue, to guide at the cellular level the surgical resection of neoplastic disease, and to scan tumor margins for the presence of residual disease, tumor foci, and potentially even metastasizing tumor cells. It implies that colorectal neoplasms surgeons can possibly use the laparoscopic OCT to detect the intestinal tumor margin and lymph nodes during operation in the future, so as to determine the appropriate range of bowel resection and lymph node dissection. At present, there are few reports about the intra-operative application of OCT in the field of gastrointestinal tumor surgery. Thus there is a tremendous opportunity for further research in this field. PMID- 28643320 TI - Revised protocol of extracorporeal membrane oxygenation (ECMO) therapy in severe ARDS. Recommendations of the Veno-venous ECMO Expert Panel appointed in February 2016 by the national consultant on anesthesiology and intensive care. AB - Extracorporeal Membrane Oxygenation (ECMO) has become well established technique of the treatment of severe acute respiratory failure (Veno-Venous ECMO) or circulatory failure (Veno-Arterial ECMO) which enables effective blood oxygenation and carbon dioxide removal for several weeks. Veno-Venous ECMO (V-V ECMO ) is a lifesaving treatment of patients in whom severe ARDS makes artificial lung ventilation unlikely to provide satisfactory blood oxygenation for preventing further vital organs damage and progression to death. The protocol below regards exclusively veno-venous ECMO treatment as a support for blood gas conditioning by means of extracorporeal circuit in adult patients with severe ARDS. V-V ECMO does not provide treatment for acutely and severely diseased lungs, but it enables patient to survive the critical phase of severe ARDS until recovery of lung function. Besides avoiding patients death from hypoxemia, this technique can also prevent further progression of the lung damage due to artificial ventilation. Recent experience of ECMO treatment since the outbreak of AH1N1 influenza pandemic in 2009, along with technical progress and advancement in understanding pathophysiology of ventilator-induced lung injury, have contributed to significant improvement of the results of ECMO treatment. Putative factors related to increased survival include patients retrieval after connecting them to ECMO, and less intensive anticoagulation protocols. The aim of presenting this revised protocol was to improve the effects of ECMO treatment in patients with severe ARDS, to enhance ECMO accessibility for patients who might possibly benefit from this treatment, to reduce time until patient's connection to ECMO, and to avoid ECMO treatment in futile cases. The authors believe that this protocol, based on recent papers and their own experience, can provide help and advice both for the centers which develop V-V ECMO program, and for doctors who will refer their patients for the treatment in an ECMO center. PMID- 28643321 TI - Global end-diastolic volume could be more appropiate to reduce intraoperative bleeding than central venous pressure during major liver transection. AB - BACKGROUND: Central venous pressure often fails to identify the true value of cardiac preload. Our purpose is to investigate whether Global End-Diastolic Volume (GEDV) values can control hemodynamic parameters for the measurement of fluid volume, cardiac preload and blood loss during liver transection. METHODS: This was a prospective clinical study that included patients undergoing liver resection. All patients were monitored by means of PiCCO technology and 222 hemodynamic measurements were performed in 74 patients. Fluid restriction was used. Transpulmonary thermodilutions were performed at different times of surgery, namely: 1. at the beginning of surgery; 2. before hepatectomy and after selective vascular exclusion (Time 1); 3. approximately half way through the liver transection (Time 2); and 4. after liver resection (Time 3). RESULTS: One hundred and twenty-nine of the 222 GEDV values were decreased (prevalence of hypovolemia of 58.1%). However, twenty two of the 222 CVP values were decreased (prevalence of 10.8%). Sensitivity of CVP with regard to volume depletion (GEDV > 650 mL m-2) on the times (1, 2 and 3) were 16.28 (4.08-28.48, 95% CI), 18.18 (5.65-30.75, 95% CI) and 21.43 (7.83-35.03, 95% CI), respectively. There was no correlation between CVP and GEDV. CONCLUSIONS: GEDV values may be more appropriate for monitoring cardiac preload during liver transection. PMID- 28643322 TI - Difficulties in funding of VA-ECMO therapy for patients with severe accidental hypothermia. AB - BACKGROUND: Severe accidental hypothermia is defined as a core temperature below 28 Celsius degrees. Within the last years, the issue of accidental hypothermia and accompanying cardiac arrest has been broadly discussed and European Resuscitation Council (ERC) Guidelines underline the importance of Extracorporeal Rewarming (ECR) in treatment of severely hypothermic victims. The study aimed to evaluate the actual costs of ECR with VA-ECMO and of further management in the Intensive Care Unit of patients admitted to the Severe Accidental Hypothermia Centre in Cracow, Poland. METHODS: We carried out the economic analysis of 31 hypothermic adults in stage III-IV (Swiss Staging) treated with VA ECMO. Twenty nine individuals were further managed in the Intensive Care Unit. The actual treatment costs were evaluated based on current medication, equipment, and dressing pricing. The costs incurred by the John Paul II Hospital were then collated with the National Health Service (NHS) funding, assessed based on current financial contract. RESULTS: In most of the cases, the actual treatment cost was greater than the funding received by around 10000 PLN per patient. The positive financial balance was achieved in only 4 (14%) individuals; other 25 cases (86%) showed a financial loss. CONCLUSION: Performed analysis clearly shows that hospitals undertaking ECR may experience financial loss due to implementation of effective treatment recommended by international guidelines. Thanks to new NHS funding policy since January 2017 such loss can be avoided, what shall encourage hospitals to perform this expensive, yet effective method of treatment. PMID- 28643324 TI - Factors predicting the identification of new organisms in follow-up blood cultures drawn during episodes of neutropenic sepsis. PMID- 28643323 TI - Favourable outcomes of poor prognosis diffuse large B-cell lymphoma patients treated with dose-dense Rituximab, high-dose Methotrexate and six cycles of CHOP 14 compared to first-line autologous transplantation. AB - The optimal therapeutic approach for young diffuse large B-cell lymphoma (DLBCL) patients with high-intermediate and high-risk age-adjusted international prognostic index (aaIPI) remains unknown. Hereby we report a 10-year single centre study of 63 consecutively treated patients. To optimize outcome, two approaches were carried out: Cohort 1 patients received four cycles R-CHOP-21 (rituximab, cyclophosphamide, daunorubicin, vincristine, prednisolone over 21 days) followed by first-line high-dose chemotherapy with autologous stem-cell support (HDCT-ASCT), resulting in 2-year progression-free (PFS) and overall survival (OS) of 60.6% and 67.9%. 39.4% of those patients were not transplanted upfront, mainly due to early progressive disease (24.2%). Cohort 2 patients received an early intensified protocol of six cycles of CHOP-14 (cyclophosphamide, daunorubicin, vincristine, prednisolone over 14 days) with dose-dense rituximab and high-dose methotrexate resulting in promising overall response- (93.3%) and complete remission (90%) rates and sustained survival (2 year PFS and OS: 93.3%). In an intention-to-treat analysis, 2-year PFS (60.6% vs. 93.3%, hazard ratio [HR] 7.2, P = 0.009) and OS (69.7% vs. 93.3%, HR 4.95, P = 0.038) differed significantly, in favour of the early intensified protocol (Cohort 2). In a multivariate Cox-regression model, PFS (HR 8.12, 95% confidence interval [CI] 1.83-35.9, P = 0.006) and OS (HR 5.86, 95% CI 1.28-26.8, P = 0.02) remained superior for Cohort 2 when adjusted for aaIPI3 as the most important prognostic factor. Survival of young poor-prognosis DLBCL patients appears superior after early therapy intensification. PMID- 28643325 TI - Surface expression of anti-CD3scfv stimulates locoregional immunotherapy against hepatocellular carcinoma depending on the E1A-engineered human umbilical cord mesenchymal stem cells. AB - Tumor antigens is at the core of cancer immunotherapy, however, the ideal antigen selection is difficult especially in poorly immunogenic tumors. In this study, we designed a strategy to modify hepatocellular carcinoma (HCC) cells by surface expressing anti-CD3scfv within the tumor site strictly, which depended on the E1A engineered human umbilical cord mesenchymal stem cells (HUMSC.E1A) delivery system. Subsequently, membrane-bound anti-CD3scfv actived the lymphocytes which lysed HCC cells bypassing the expression of antigens or MHC restriction. First, we constructed the anti-CD3scfv gene driven by human alpha-fetoprotein (AFP) promoter into an adenoviral vector and the E1A gene into the lentiviral vector. Our results showed that anti-CD3scfv could specifically express on the surface of HCC cells and activate the lymphocytes to kill target cells effectively in vitro. HUMSC infected by AdCD3scfv followed by LentiR.E1A could support the adenoviral replication and packaging in vitro 36 h after LentiR.E1A infection. Using a subcutaneous HepG2 xenograft model, we confirmed that AdCD3scfv and LentiR.E1A co transfected HUMSC could migrate selectively to the tumor site and produce considerable adenoviruses. The new generated AdCD3scfv infected and modified tumor cells successfully. Mice injected with the MSC.E1A.AdCD3scfv and lymphocytes significantly inhibited the tumor growth compared with control groups. Furthermore, 5-fluorouracil (5-FU) could sensitize adenovirus infection at low MOI resulting in improved lymphocytes cytotoxicity in vitro and in vivo. In summary, this study provides a promising strategy for solid tumor immunotherapy. PMID- 28643326 TI - Pseudo-grey platelet syndrome in a pregnant patient. PMID- 28643327 TI - Predictive factors for short- and long-term hearing preservation in cochlear implantation with conventional-length electrodes. AB - OBJECTIVES/HYPOTHESIS: The aims of this study were to investigate short- and long term rates of hearing preservation after cochlear implantation and identify factors that impact hearing preservation. STUDY DESIGN: Retrospective review. METHODS: Patients undergoing cochlear implantation with conventional-length electrodes and air-conduction thresholds <=80 dB HL at 250 Hz preoperatively were included. Hearing preservation was defined as air-conduction thresholds <=80 dB HL at 250 Hz. RESULTS: The sample included 196 patients (225 implants). Overall, the rate of short-term hearing preservation was 38% (84/225), with 18% (33/188) of patients preserving hearing long term. Multivariate analysis showed better preoperative hearing was predictive of hearing preservation at short (odds ratio [OR]: 0.93, 95% confidence interval [CI]: 0.91-0.95, P < .001) and long-term follow-up (OR: 0.94, 95% CI: 0.91-0.97, P < .001). Lateral wall electrodes and mid-scala electrodes had 3.4 (95% CI: 1.4-8.6, P = .009) and 5.6-times (95% CI: 1.8-17.3, P = .003) higher odds of hearing preservation than perimodiolar arrays at short-term follow-up, respectively. Long-term data revealed better hearing preservation for lateral wall (OR: 7.6, 95% CI: 1.6-36.1, P = .01), but not mid scala (OR: 3.1, 95% CI: 0.4-23.1, P = .28), when compared to perimodiolar electrodes. Round window/extended round window (RW/ERW) approaches were associated with higher rates of long-term hearing preservation (21%) than cochleostomy approaches (0%) (P = 0.002) on univariate analysis. CONCLUSIONS: Better preoperative residual hearing, lateral wall electrodes, and RW/ERW approaches are predictive of higher rates of long-term functional hearing preservation. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:482-489, 2018. PMID- 28643329 TI - Analgesic Plasma Concentrations of Oxycodone After Surgery for Breast Cancer Which Factors Matter? AB - We investigated factors affecting analgesic oxycodone concentrations after breast cancer surgery in 1,000 women. Preoperatively, we studied heat and cold pain sensitivities and anxiety scores. Postoperatively, rest and motion pain intensities were measured and intravenous oxycodone was administered until satisfactory analgesia. At this point, the mean oxycodone concentration (variation coefficient) was 33.3 ng/mL (66%) and it was 21.7 ng/mL (69%) when the patient requested oxycodone again. At both time points, the concentrations varied >100-fold between individuals. The analgesic oxycodone concentration was increased by 21.3% per motion pain intensity score on a 0-10 scale and by 22.3% if axillary clearance was performed instead of sentinel node biopsy (P < 0.001). Forty-seven women who were older and less anxious than others (P < 0.01) required no oxycodone. Anxiety, age, chronic pain, or preoperative pain sensitivity were not independently associated with the analgesic oxycodone concentration. CYP2D6 and CYP3A genotypes did not affect analgesic concentration or duration of analgesia. PMID- 28643328 TI - Drug Repurposing by Simulating Flow Through Protein-Protein Interaction Networks. AB - As drug development is extremely expensive, the identification of novel indications for in-market drugs is financially attractive. Multiple algorithms are used to support such drug repurposing, but highly reliable methods combining simulation of intracellular networks and machine learning are currently not available. We developed an algorithm that simulates drug effects on the flow of information through protein-protein interaction networks, and used support vector machine to identify potentially effective drugs in our model disease, psoriasis. Using this method, we screened about 1,500 marketed and investigational substances, identified 51 drugs that were potentially effective, and selected three of them for experimental confirmation. All drugs inhibited tumor necrosis factor alpha-induced nuclear factor kappa B activity in vitro, suggesting they might be effective for treating psoriasis in humans. Additionally, these drugs significantly inhibited imiquimod-induced ear thickening and inflammation in the mouse model of the disease. All results suggest high prediction performance for the algorithm. PMID- 28643331 TI - Treatment With Antipsychotics in Pregnancy: Changes in Drug Disposition. AB - Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (-76%; confidence interval (CI), -83%, -66%; P < 0.001) and aripiprazole (-52%; CI, -62%, -39%; P < 0.001), but not for olanzapine (-9%; CI, -28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring. PMID- 28643333 TI - Allograft transmission of hepatitis C during the window period: Weighing the new risks and costs in the era of donor shortage. PMID- 28643330 TI - MUC1-C is a target in lenalidomide resistant multiple myeloma. AB - Lenalidomide (LEN) acts directly on multiple myeloma (MM) cells by inducing cereblon-mediated degradation of interferon regulatory factor 4, Ikaros (IKZF)1 and IKZF3, transcription factors that are essential for MM cell survival. The mucin 1 (MUC1) C-terminal transmembrane subunit (MUC1-C) oncoprotein is aberrantly expressed by MM cells and protects against reactive oxygen species (ROS)-mediated MM cell death. The present studies demonstrate that targeting MUC1 C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is more than additive with LEN in downregulating the WNT/beta-catenin pathway, suppressing MYC, and inducing late apoptosis/necrosis. We show that the GO 203/LEN combination acts by synergistically increasing ROS and, in turn, suppressing beta-catenin. LEN resistance has been linked to activation of the WNT/beta-catenin->CD44 pathway. In this regard, our results further demonstrate that targeting MUC1-C is effective against LEN-resistant MM cells. Moreover, GO 203 resensitized LEN-resistant MM cells to LEN treatment in association with suppression of beta-catenin and CD44. Targeting MUC1-C also resulted in downregulation of CD44 on the surface of primary MM cells. These findings, and the demonstration that expression of MUC1 and CD44 significantly correlate in microarrays from primary MM cells, provide support for combining GO-203 with LEN in the treatment of MM and in LEN-resistance. PMID- 28643332 TI - Integrative eQTL analysis of tumor and host omics data in individuals with bladder cancer. AB - Integrative analyses of several omics data are emerging. The data are usually generated from the same source material (i.e., tumor sample) representing one level of regulation. However, integrating different regulatory levels (i.e., blood) with those from tumor may also reveal important knowledge about the human genetic architecture. To model this multilevel structure, an integrative expression quantitative trait loci (eQTL) analysis applying two-stage regression (2SR) was proposed. This approach first regressed tumor gene expression levels with tumor markers and the adjusted residuals from the previous model were then regressed with the germline genotypes measured in blood. Previously, we demonstrated that penalized regression methods in combination with a permutation based MaxT method (Global-LASSO) is a promising tool to fix some of the challenges that high-throughput omics data analysis imposes. Here, we assessed whether Global-LASSO can also be applied when tumor and blood omics data are integrated. We further compared our strategy with two 2SR-approaches, one using multiple linear regression (2SR-MLR) and other using LASSO (2SR-LASSO). We applied the three models to integrate genomic, epigenomic, and transcriptomic data from tumor tissue with blood germline genotypes from 181 individuals with bladder cancer included in the TCGA Consortium. Global-LASSO provided a larger list of eQTLs than the 2SR methods, identified a previously reported eQTLs in prostate stem cell antigen (PSCA), and provided further clues on the complexity of APBEC3B loci, with a minimal false-positive rate not achieved by 2SR-MLR. It also represents an important contribution for omics integrative analysis because it is easy to apply and adaptable to any type of data. PMID- 28643335 TI - A Review of Hemolysis Prediction Models for Computational Fluid Dynamics. AB - Flow-induced hemolysis is a crucial issue for many biomedical applications; in particular, it is an essential issue for the development of blood-transporting devices such as left ventricular assist devices, and other types of blood pumps. In order to estimate red blood cell (RBC) damage in blood flows, many models have been proposed in the past. Most models have been validated by their respective authors. However, the accuracy and the validity range of these models remains unclear. In this work, the most established hemolysis models compatible with computational fluid dynamics of full-scale devices are described and assessed by comparing two selected reference experiments: a simple rheometric flow and a more complex hemodialytic flow through a needle. The quantitative comparisons show very large deviations concerning hemolysis predictions, depending on the model and model parameter. In light of the current results, two simple power-law models deliver the best compromise between computational efficiency and obtained accuracy. Finally, hemolysis has been computed in an axial blood pump. The reconstructed geometry of a HeartMate II shows that hemolysis occurs mainly at the tip and leading edge of the rotor blades, as well as at the leading edge of the diffusor vanes. PMID- 28643334 TI - Gastric cancer-derived exosomes promote peritoneal metastasis by destroying the mesothelial barrier. AB - An intact mesothelium serves as a protective barrier to inhibit peritoneal carcinomatosis. Cancer-derived exosomes can mediate directional tumor metastasis; however, little is known about whether gastric cancer-derived exosomes will destroy the mesothelial barrier and promote peritoneal dissemination. Here, we demonstrate that gastric cancer-derived exosomes facilitate peritoneal metastasis by causing mesothelial barrier disruption and peritoneal fibrosis. Injury of peritoneal mesothelial cells elicited by gastric cancer-derived exosomes is through concurrent apoptosis and mesothelial-to-mesenchymal transition (MMT). Additionally, upregulation of p-ERK in peritoneal mesothelial cells is primarily responsible for the MMT while contributing little to apoptosis. Together, these data support the concept that exosomes play a crucial role in remodeling the premetastatic microenvironment and identify a novel mechanism for peritoneal metastasis of gastric carcinoma. PMID- 28643336 TI - Tokindo S. Okada. PMID- 28643337 TI - Preface to Vertebrate Brains: evolution, structures and functions. PMID- 28643338 TI - Tokindo S. Okada. PMID- 28643340 TI - Trans-endoscopic diode laser fenestration of equine conchae via contralateral nostril approach. AB - OBJECTIVE: To describe and report preliminary outcomes of a contralateral trans nasal endoscopic laser fenestration of the conchae for endoscopic examination and treatment of paranasal sinuses in horses. STUDY DESIGN: Cadaveric experimental and prospective clinical study. ANIMALS: Normal cadaveric equine heads (n = 7) and equine patients (horses n = 7, donkey n = 1) diagnosed with sinusitis. METHODS: Ex vivo: a video-endoscope containing a diode laser fiber in the working canal was passed through the nostril and retroflexed in the nasopharynx toward the contralateral conchae. Ventral or dorsal conchae were fenestrated. Duration of surgery, laser energy, visualization quality, and feasibility of sinoscopy through the fenestrations were recorded. In vivo: sinus drainage, sinoscopy 24 hours postoperatively, stoma persistence, and clinical results after 3 months were evaluated in 8 patients. RESULTS: Fenestrations were performed in 8 dorsal conchae (6 cadavers, 2 patients), 10 ventral conchae (5 cadavers, 5 patients), and 1 dorsal conchal bulla (1 patient). Visualization was good in 6 patients and affected by bleeding in 2 patients. Drainage through the fenestrations was observed in all patients. Trans-nasal sinoscopy was possible in all cadavers and in 6 out of 8 patients. Masses inside the sinuses precluded sinoscopy in 2 patients. Stomata persisted until discharge of the patients (mean of 14 days). Clinical signs improved in 6/8 patients. CONCLUSION: The endoscopic approach reported here provides good visualization during the trans-endoscopic laser fenestration of the conchae. The fenestrations may allow a trans-nasal sinoscopic examination and treatment in selected cases of sinusitis in horses. PMID- 28643339 TI - Ruptured ventricular septum dissection into the right ventricle. PMID- 28643341 TI - In vivo attraction of myeloma cells by renal cell carcinoma. PMID- 28643342 TI - Progress and policy implication of the Insurance Programs for Catastrophic Diseases in China. AB - The State Council encouraged the involvement of commercial insurance companies (CICs) in the development of the Insurance Program for Catastrophic Diseases (IPCD), yet its implementation has rarely been reported. We collected literature and policy documentation and conducted interviews in 10 cities with innovative IPCD policies to understand the details of the implementation of IPCD. IPCDs are operated at the prefectural level in 14 provinces, while in 4 municipalities and 6 provinces, unified IPCDs have been implemented at higher levels. The contribution level varied from 5% to 10% of total Basic Medical Insurance (BMI) funds or CNY10-35 per beneficiary in 2015. IPCD provides an additional 50% to 70% reimbursement rate for the expenses not covered by BMI with various settings in different locations. Two models of CIC operation of IPCD have been identified according to the financial risks shared by CICs. Either the local department of Human Resources and Social Security or a third party performs assessments of the IPCD operation, service quality, and patients' satisfaction. A number of IPCDs have been observed to use 1% to 5% of the funds as a performance-based payment to the CIC(s). CIC involvement in operating the IPCD raises concerns regarding the security of the information of beneficiaries. Developing appropriate data sharing mechanisms between the local department of Human Resources and Social Security and CICs is still in progress. In conclusion, the IPCD relieves the financial burden on patients by providing further reimbursement, but its benefit package remains limited to the BMI reimbursable list. CICs play an important role in monitoring and supervising health service provision, yet their capacity for actuarial services or risk control is underdeveloped. PMID- 28643344 TI - Optimization and transferability of non-electrostatic repulsion in the polarizable density embedding model. AB - Embedding techniques in combination with response theory represent a successful approach to calculate molecular properties and excited states in large molecular systems such as solutions and proteins. Recently, the polarizable embedding model has been extended by introducing explicit electronic densities of the molecules in the nearest environment, resulting in the polarizable density embedding (PDE) model. This improvement provides a better description of the intermolecular interactions at short distances. However, the electronic densities of the environment molecules are calculated in isolation, which results in overestimation of the non-electrostatic repulsion, thereby requiring a scaling of this term. In this work, an optimal scaling factor for the non-electrostatic repulsion term is examined by comparing intermolecular interaction energies obtained with embedding techniques to reference interaction energies calculated on the basis of full quantum-mechanical calculations. The obtained optimal factors are used in PDE calculations of various ground- and excited-state properties of molecules embedded in solvents described as polarizable environments. (c) 2017 Wiley Periodicals, Inc. PMID- 28643343 TI - Alpha/beta-hydrolases: A unique structural motif coordinates catalytic acid residue in 40 protein fold families. AB - The alpha/beta-hydrolases are a family of acid-base-nucleophile catalytic triad enzymes with a common fold, but using a wide variety of substrates, having different pH optima, catalyzing unique catalytic reactions and often showing improved chemical and thermo stability. The ABH enzymes are prime targets for protein engineering. Here, we have classified active sites from 51 representative members of 40 structural ABH fold families into eight distinct conserved geometries. We demonstrate the occurrence of a common structural motif, the catalytic acid zone, at the catalytic triad acid turn. We show that binding of an external ligand does not change the structure of the catalytic acid zone and both the ligand-free and ligand-bound forms of the protein belong to the same catalytic acid zone subgroup. We also show that the catalytic acid zone coordinates the position of the catalytic histidine loop directly above its plane, and consequently, fixes the catalytic histidine in a proper position near the catalytic acid. Finally, we demonstrate that the catalytic acid zone plays a key role in multi-subunit complex formation in ABH enzymes, and is involved in interactions with other proteins. As a result, we speculate that each of the catalytic triad residues has its own supporting structural scaffold, similar to the catalytic acid zone, described above, which together form the extended catalytic triad motif. Each scaffold coordinates the function of its respective catalytic residue, and can even compensate for the loss of protein function, if the catalytic amino acid is mutated. PMID- 28643345 TI - Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain. AB - Mitochondria are classically known to be the cellular energy producers, but a renewed appreciation for these organelles has developed with the accumulating discoveries of additional functions. The importance of mitochondria within the brain has been long known, particularly given the high-energy demanding nature of neurons. The energy demands imposed by neurons require the well-orchestrated morphological adaptation and distribution of mitochondria. Recent studies now reveal the importance of mitochondrial dynamics not only in mature neurons but also during neural development, particularly during the process of neurogenesis and neural stem cell fate decisions. In this review, we will highlight the recent findings that illustrate the importance of mitochondrial dynamics in neurodevelopment and neural stem cell function. Developmental Dynamics 247:47-53, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28643346 TI - Red blood cells free alpha-haemoglobin pool: a biomarker to monitor the beta thalassemia intermedia variability. The ALPHAPOOL study. AB - The severity of beta-thalassaemia (beta-thal) intermedia is mainly correlated to the degree of imbalanced alpha/non alpha-globin chain synthesis. The phenotypic diversity of beta-thal depends on this imbalance and reflects all possible combinations of alpha- and beta-globin genotypes, levels of fetal haemoglobin (HbF) and co-inheritance of other modulating factors. This study aimed to demonstrate the validity of a new surrogate of alpha/non alpha-globin biosynthetic ratio by measuring the soluble alpha-Hb pool in lysed red blood cells. Our results confirm that the alpha-Hb pool measurement allows a good discrimination between beta-thal intermedia patients, controls and alpha-thal patients (P < 0.003). Receiver operator characteristic analyses revealed an area under the curve of 0.978 for the alpha-Hb pool measurement at a threshold of 120 ng free alpha-Hb/mg of total Hb/ml of haemolysate (ppm) with a sensitivity and specificity of 86% and 100%, respectively, to discriminate between beta-thal and not beta-thal subjects. Significant correlations were observed between the alpha Hb pool and biological parameters of beta-thal, the most significant association being observed with red cell hexokinase activity. This study indicates that the alpha-Hb pool could be a new marker for assistance in diagnostic orientation of beta-thal intermedia patients and may be clinically useful for monitoring the evolution of the disequilibrium of globin synthesis in response to treatments. PMID- 28643347 TI - Off-resonance based assessment of metallic wear debris near total hip arthroplasty. AB - PURPOSE: The presence of metallic debris near total hip arthroplasty can have a significant impact on longitudinal patient management. Methods for magnetic resonance imaging-based quantification of metallic debris near painful total hip replacements are described and applied to cohorts of symptomatic and control subject cases. METHODS: A combination of metal artifact reduction, off-resonance mapping, off-resonance background removal, and spatial clustering methods are utilized to quantify off-resonance signatures in cases of suspected metallosis. These methods are applied to a cohort of symptomatic hip arthroplasties composed of cobalt-chromium alloys. Magnetostatic simulations and theoretical principles are used to illuminate the potential sources of the measured off-resonance effects. Reported metrics from histological tissue assays extracted during surgical revision procedures are also correlated with the proposed magnetic resonance imaging-based quantification results. RESULTS: The presented methods identified quantifiable metallosis signatures in more than 70% of the symptomatic and none of the control cases. Preliminary correlations of the MR data with direct histological evaluation of retrieved tissue samples indicate that the observed off-resonance effect may be related to tissue necrosis. CONCLUSIONS: Magnetostatic simulations, theoretical principles, and preliminary histological trends suggest that disassociated cobalt is the source of the observed off resonance signature. Magn Reson Med 79:1628-1637, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28643348 TI - The construction of a panel of serum amino acids for the identification of early chronic kidney disease patients. AB - BACKGROUND: Serum creatinine, urea, and cystatin-c are standardly used for the evaluation of renal function in the clinic. However, some patients have chronic kidney disease but still retain kidney function; a conventional serum index in these patients can be completely normal. Serum amino acid levels can reflect subtle changes in metabolism and are closely related to renal function. Here, we investigated how amino acids change as renal impairment increases. METHODS: Subjects were divided into three groups by renal function glomerular filtration rate: healthy controls, patients with chronic kidney disease with normal kidney function, and patients with chronic kidney disease with decreased kidney function group. We identified 11 amino acids of interest using LC-MS/MS on MRM (+) mode. RESULTS: Statistical analysis indicated that alanine (ALA), valine (VAL), and tyrosine (TYR) decrease with renal function impairment, whereas phenylalanine (PHE) and citrulline (CIT) increase. We tried to construct a diagnostic model utilizing a combination of amino acids capable of identifying early chronic kidney disease patients. The accuracy, specificity, and sensitivity of the combining predictors were 86.9%, 84.6%, and 90.9%, respectively, which is superior to the reported values for serum creatinine, urea, and cystatin-c. CONCLUSION: Our data suggest that serum amino acid levels may supply important information for the early detection of chronic kidney disease. We are the first to establish a diagnostic model utilizing serum levels of multiple amino acids for the diagnosis of patients with early-stage chronic kidney disease. PMID- 28643349 TI - A QM/MM study of the catalytic mechanism of SAM methyltransferase RlmN from Escherichia coli. AB - RlmN is a radical S-adenosylmethionine (SAM) enzyme that catalyzes the C2 methylation of adenosine 2503 (A2503) in 23S rRNA and adenosine 37 (A37) in several Escherichia coli transfer RNAs (tRNA). The catalytic reaction of RlmN is distinctly different from that of typical SAM-dependent methyltransferases that employs an SN 2 mechanism, but follows a ping-pong mechanism which involves the intermediate methylation of a conserved cysteine residue. Recently, the x-ray structure of a key intermediate in the RlmN reaction has been reported, allowing us to perform combined quantum mechanics and molecular mechanics (QM/MM) calculations to delineate the reaction details of RlmN at atomic level. Starting from the Cross-Linked RlmN C118A-tRNA complex, the possible mechanisms for both the formation and the resolution of the cross-linked species (IM2) have been illuminated. On the basis of our calculations, IM2 is formed by the attack of the C355-based methylene radical on the sp2 -hybridized C2 of the adenosine ring, corresponding to energy barrier of 14.4 kcal/mol, and the resolution of IM2 is confirmed to follow a radical fragmentation mechanism. The cleavage of C'-S' bond of mC355-A37 cross-link is in concert with the deprotonation of C2 by C118 residue, which is the rate-limiting step with an energy barrier of 17.4 kcal/mol. Moreover, the cleavage of C'-S' bond of IM2 can occur independently, that is, it does not require the loss of an electron of IM2 and the formation of disulfide bond between C355 and C118 as precondition. These findings would deepen the understanding of the catalysis of RlmN. PMID- 28643350 TI - Habitual sleep and kidney function in chronic kidney disease: the Chronic Renal Insufficiency Cohort study. AB - Physiological evidence suggests that sleep modulates kidney function. Our objective was to examine the cross-sectional association between kidney function and objectively-estimated habitual sleep duration, quality and timing in a cohort of patients with mild to moderate chronic kidney disease. This study involved two US clinical centers of the Chronic Renal Insufficiency Cohort (CRIC) study, including 432 participants in a CRIC ancillary sleep study. Habitual sleep duration, quality and timing were measured using wrist actigraphy for 5-7 days. Validated sleep questionnaires assessed subjective sleep quality, daytime sleepiness and risk of sleep apnea. Kidney function was assessed with the estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation, and the urinary protein to creatinine ratio. Lower estimated glomerular filtration rate was associated with shorter sleep duration (-1.1 mL min-1 1.73 m-2 per hour less sleep, P = 0.03), greater sleep fragmentation (-2.6 mL min-1 1.73 m-2 per 10% higher fragmentation, P < 0.001) and later timing of sleep (-0.9 mL min-1 1.73 m-2 per hour later, P = 0.05). Higher protein to creatinine ratio was also associated with greater sleep fragmentation (approximately 28% higher per 10% higher fragmentation, P < 0.001). Subjective sleep quality, sleepiness and persistent snoring were not associated with estimated glomerular filtration rate or protein to creatinine ratio. Thus, worse objective sleep quality was associated with lower estimated glomerular filtration rate and higher protein to creatinine ratio. Shorter sleep duration and later sleep timing were also associated with lower estimated glomerular filtration rate. Physicians treating patients with chronic kidney disease should consider inquiring about sleep and possibly sending for clinical sleep assessment. Longitudinal and interventional trials are needed to understand causal direction. PMID- 28643351 TI - Quality specifications of routine clinical chemistry methods based on sigma metrics in performance evaluation. AB - INTRODUCTION: Sigma metrics were applied to evaluate the performance of 20 routine chemistry assays, and individual quality control criteria were established based on the sigma values of different assays. METHODS: Precisions were expressed as the average coefficient variations (CVs) of long-term two-level chemistry controls. The biases of the 20 assays were obtained from the results of trueness programs organized by National Center for Clinical Laboratories (NCCL, China) in 2016. Four different allowable total error (TEa) targets were chosen from biological variation (minimum, desirable, optimal), Clinical Laboratory Improvements Amendments (CLIA, US), Analytical Quality Specification for Routine Analytes in Clinical Chemistry (WS/T 403-2012, China) and the National Cholesterol Education Program (NECP). RESULTS: The sigma values from different TEa targets varied. The TEa targets for ALT, AMY, Ca, CHOL, CK, Crea, GGT, K, LDH, Mg, Na, TG, TP, UA and Urea were chosen from WS/T 403-2012; the targets for ALP, AST and GLU were chosen from CLIA; the target for K was chosen from desirable biological variation; and the targets for HDL and LDL were chosen from the NECP. Individual quality criteria were established based on different sigma values. CONCLUSIONS: Sigma metrics are an optimal tool to evaluate the performance of different assays. An assay with a high value could use a simple internal quality control rule, while an assay with a low value should be monitored strictly. PMID- 28643352 TI - Cesium's Off-the-Map Valence Orbital. AB - The Td -symmetric [CsO4 ]+ ion, featuring Cs in an oxidation state of 9, is computed to be a minimum. Cs uses outer core 5s and 5p orbitals to bind the oxygen atoms. The valence Cs 6s orbital lies too high to be involved in bonding, and contributes to Rydberg levels only. From a molecular orbital perspective, the bonding scheme is reminiscent of XeO4 : an octet of electrons to bind electronegative ligands, and no low-lying acceptor orbitals on the central atom. In this sense, Cs+ resembles hypervalent Xe. PMID- 28643353 TI - Multistructural microiteration technique for geometry optimization and reaction path calculation in large systems. AB - We propose a multistructural microiteration (MSM) method for geometry optimization and reaction path calculation in large systems. MSM is a simple extension of the geometrical microiteration technique. In conventional microiteration, the structure of the non-reaction-center (surrounding) part is optimized by fixing atoms in the reaction-center part before displacements of the reaction-center atoms. In this method, the surrounding part is described as the weighted sum of multiple surrounding structures that are independently optimized. Then, geometric displacements of the reaction-center atoms are performed in the mean field generated by the weighted sum of the surrounding parts. MSM was combined with the QM/MM-ONIOM method and applied to chemical reactions in aqueous solution or enzyme. In all three cases, MSM gave lower reaction energy profiles than the QM/MM-ONIOM-microiteration method over the entire reaction paths with comparable computational costs. (c) 2017 Wiley Periodicals, Inc. PMID- 28643355 TI - Ultra-short echo time images quantify high liver iron. AB - PURPOSE: 1.5T gradient echo-based R2* estimates are standard-of-care for assessing liver iron concentration (LIC). Despite growing popularity of 3T, echo time (TE) limitations prevent 3T liver iron quantitation in the upper half of the clinical range (LIC ?20 mg/g). In this work, a 3D radial pulse sequence was assessed to double the dynamic range of 3T LIC estimates. THEORY AND METHODS: The minimum TE limits the dynamic range of pulse sequences to estimate R2*. 23 chronically-transfused human volunteers were imaged with 1.5T Cartesian gradient echo (1.5T-GRE), 3T Cartesian gradient echo (3T-GRE), and 3T ultrashort TE radial (3T-UTE) pulse sequences; minimum TEs were 0.96, 0.76, and 0.19 ms, respectively. R2* was estimated with an exponential signal model, normalized to 1.5T equivalents, and converted to LIC. Bland-Altman analysis compared 3T-based estimates to 1.5T-GRE. RESULTS: LIC by 3T-GRE was unbiased versus 1.5T-GRE for LIC <= 25 mg/g (sd = 9.6%); 3T-GRE failed to quantify LIC > 25 mg/g. At high iron loads, 3T-UTE was unbiased (sd = 14.5%) compared to 1.5T-GRE. Further, 3T-UTE estimated LIC up to 50 mg/g, exceeding 1.5T-GRE limits. CONCLUSION: 3T-UTE imaging can reliably estimate high liver iron burdens. In conjunction with 3T GRE, 3T-UTE allows clinical LIC estimation across a wide range of liver iron loads. Magn Reson Med 79:1579-1585, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28643354 TI - Diffusion MRI microstructure models with in vivo human brain Connectome data: results from a multi-group comparison. AB - A large number of mathematical models have been proposed to describe the measured signal in diffusion-weighted (DW) magnetic resonance imaging (MRI). However, model comparison to date focuses only on specific subclasses, e.g. compartment models or signal models, and little or no information is available in the literature on how performance varies among the different types of models. To address this deficiency, we organized the 'White Matter Modeling Challenge' during the International Symposium on Biomedical Imaging (ISBI) 2015 conference. This competition aimed to compare a range of different kinds of models in their ability to explain a large range of measurable in vivo DW human brain data. Specifically, we assessed the ability of models to predict the DW signal accurately for new diffusion gradients and b values. We did not evaluate the accuracy of estimated model parameters, as a ground truth is hard to obtain. We used the Connectome scanner at the Massachusetts General Hospital, using gradient strengths of up to 300 mT/m and a broad set of diffusion times. We focused on assessing the DW signal prediction in two regions: the genu in the corpus callosum, where the fibres are relatively straight and parallel, and the fornix, where the configuration of fibres is more complex. The challenge participants had access to three-quarters of the dataset and their models were ranked on their ability to predict the remaining unseen quarter of the data. The challenge provided a unique opportunity for a quantitative comparison of diverse methods from multiple groups worldwide. The comparison of the challenge entries reveals interesting trends that could potentially influence the next generation of diffusion-based quantitative MRI techniques. The first is that signal models do not necessarily outperform tissue models; in fact, of those tested, tissue models rank highest on average. The second is that assuming a non-Gaussian (rather than purely Gaussian) noise model provides little improvement in prediction of unseen data, although it is possible that this may still have a beneficial effect on estimated parameter values. The third is that preprocessing the training data, here by omitting signal outliers, and using signal-predicting strategies, such as bootstrapping or cross-validation, could benefit the model fitting. The analysis in this study provides a benchmark for other models and the data remain available to build up a more complete comparison in the future. PMID- 28643356 TI - Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals. AB - AIM: To test the hypothesis that an improving body composition in insulin resistant individuals could enhance insulin sensitivity. METHODS: A total of 16 people with a mean body mass index of 29.3 kg/m2 and insulin resistance, received a single dose of bimagrumab or placebo and were assessed at week 10 for insulin sensitivity, using a hyperinsulinaemic-euglycaemic clamp and an intravenous glucose tolerance test (IVGTT), and for body composition using dual energy X-ray absorptiometry and positron-emission tomography. RESULTS: Bimagrumab increased lean mass by 2.7% (P < .05) and reduced fat mass by 7.9% (P = .011) at week 10 compared with placebo, and had a neutral effect on body weight. Bimagrumab reduced glycated haemoglobin by 0.21% at week 18 (P < .001) and improved insulin sensitivity by ~20% (according to the clamp) to ~40% (according to the IVGTT). CONCLUSION: Taking the observed changes together, and given that these occurred without accompanying dietary intervention and without any prescribed regular physical exercise, bimagrumab may offer a novel approach for the treatment of the metabolic complications of obesity. PMID- 28643358 TI - Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development. AB - The failure of damaged axons to regrow underlies disability in central nervous system injury and disease. Therapies that stimulate axon repair will be critical to restore function. Extensive axon regeneration can be induced by manipulation of oncogenes and tumor suppressors; however, it has been difficult to translate this into functional recovery in models of spinal cord injury. The current challenge is to maximize the functional integration of regenerating axons to recover motor and sensory behaviors. Insights into axonal growth and wiring during nervous system development are helping guide new approaches to boost regeneration and functional connectivity after injury in the mature nervous system. Here we discuss our current understanding of axonal behavior after injury and prospects for the development of drugs to optimize axon regeneration and functional recovery after CNS injury. Developmental Dynamics 247:18-23, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28643357 TI - NUT carcinoma in children and adults: A multicenter retrospective study. AB - BACKGROUND: Nuclear protein of the testis (NUT) carcinoma (formerly NUT midline carcinoma) is an aggressive tumor defined by the presence of NUT rearrangement with a poor prognosis. This rare cancer is underdiagnosed and poorly treated. OBJECTIVE: The primary objective of this study was to describe the clinical, radiologic, and biological features of NUT carcinoma. The secondary objective was to describe the various treatments and assess their efficacy. METHODS: This retrospective multicenter study was based on review of the medical records of children and adults with NUT carcinoma with specific rearrangement or positive anti-NUT nuclear staining (>50%). RESULTS: This series of 12 patients had a median age of 18.1 years (ranges: 12.3-49.7 years). The primary tumor was located in the chest in eight patients, the head and neck in three patients, and one patient had a multifocal tumor. Nine patients presented regional lymph node involvement and eight distant metastases. One-half of patients were initially misdiagnosed. Specific NUT antibody was positive in all cases tested. A transient response to chemotherapy was observed in four of 11 patients. Only two patients were treated by surgery and five received radiotherapy with curative intent. At the end of follow-up, only one patient was still in remission more than 12 years after the diagnosis. Median overall survival was 4.7 months (95% confidence interval [CI]: 2.1-17.7). CONCLUSION: NUT carcinoma is an aggressive disease refractory to conventional therapy. Early diagnosis by NUT-specific antibody immunostaining in cases of undifferentiated or poorly differentiated carcinoma to identify the specific rearrangement of NUT gene is useful to propose the optimal therapeutic strategy. PMID- 28643359 TI - An open 8-channel parallel transmission coil for static and dynamic 7T MRI of the knee and ankle joints at multiple postures. AB - PURPOSE: We present the initial in vivo imaging results of an open architecture eight-channel parallel transmission (pTx) transceive radiofrequency (RF) coil array that was designed and constructed for static and dynamic 7T MRI of the knee and ankle joints. METHODS: The pTx coil has a U-shaped dual-row configuration (200 mm overall length longitudinally) that allows static and dynamic imaging of the knee and ankle joints at various postures and during active movements. This coil structure, in combination with B1 shimming, allows flexible configuration of B1 transmit profiles, with good homogeneity over 120-mm regions of interest. This coil enabled high-resolution gradient echo (e.g., 3D dual-echo steady state [DESS] and 3D multiecho data image combination [MEDIC]) and turbo spin echo (TSE) imaging (e.g., with proton density weighting [PDw], PDw with fat saturation, and T1 and T2 weightings) with local RF energy absorption rates well below regulatory limits. RESULTS: High-resolution 2D and 3D image series (e.g., 0.3 mm in-plane resolution for TSE, 0.47 mm isotropic for DESS and MEDIC) were obtained from the knee and ankle joints with excellent tissue contrast. Dynamic imaging during continuous knee and ankle flexion-extension cycles were successfully acquired. CONCLUSION: The new open pTx coil array provides versatility for high-quality static and dynamic MRI of the knee and ankle joints at 7T. Magn Reson Med 79:1804 1816, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28643360 TI - A New Wrinkle in Oligoarylene Architecture. AB - Bowl me over! A breathtaking bowl-shaped oligoarylene has been created. The structure is analogous to that of corranulene, but instead of twenty sp2 hybridized carbon atoms, the new nanometer-sized molecule has been constructed using twenty 1,3,5-trisubstituted benzene rings. PMID- 28643361 TI - Screening for DEL phenotype in RhD negative Indians. AB - BACKGROUND: DEL phenotype represents a very weak form of D variant detected only by adsorption and elution technique. DEL phenotype individuals mistyped as RhD negative can lead to alloimmunization after transfusion or pregnancy. Molecular techniques have now been used to identify DEL variants. They are commonly encountered in the East Asian population with RHD(K409K) being the most frequent allele. RHD(M295I) is the most common DEL allele in Caucasians. As there is a paucity of data on DEL phenotype in the Indian population, the study aims to screen RhD negative individuals for two most common DEL mutations. MATERIAL AND METHODS: EDTA blood was collected from 900 RhD negative individuals. Serological analysis included testing for the five major Rh antigens- C, c, D, E, and e by tube technique. Samples showing negative reaction for the presence of D antigen by Indirect Antiglobulin test were further tested for DEL phenotype by adsorption and elution technique. Molecular analysis involved DNA extraction and testing by PCR-SSP for RHD(K409K) and RHD(M295I) DEL alleles. RESULTS: Rh phenotyping showed 153 Rh negative individuals with r'r, ten with r''r and 737 with rr phenotype. All the samples tested negative for RhD antigen by adsorption and elution method. The two common DEL mutations RHD(K409K) and RHD(M295I) were also not detected in the study population. CONCLUSION: The study population showed the absence of the two common DEL alleles, concluding the variant to be rare. A comprehensive study with a larger sample size to look for other DEL mutations should be performed. PMID- 28643362 TI - "Super-Reducing" Photocatalysis: Consecutive Energy and Electron Transfers with Polycyclic Aromatic Hydrocarbons. AB - Donation welcome: Recent developments in visible-light photocatalysis allow the utilization of increasingly negative reduction potentials. Successive energy and electron transfer with polycyclic aromatic hydrocarbons enables the catalytic formation of strongly reducing arene radical anions, classical stoichiometric reagents for one-electron reduction in organic synthesis. PMID- 28643363 TI - Oral cancer screening practices of Canadian dental hygienists. AB - PURPOSE: This study investigates whether dental hygienists are routinely conducting oral cancer screenings (OCSs) as per their professional capability and responsibility. Factors that may mediate provision of OCSs, and ability to discuss sensitive topics with patients, are also examined. METHODS: A pretested online questionnaire was sent via national and provincial regulatory bodies to target practicing registered dental hygienists across Canada. Analysis was conducted using statistical software. RESULTS: Results of 256 surveys were analysed. Sixty-four per cent of dental hygienists listed an OCS as part of their regular process of care. Except for the initial examination, respondents were significantly more likely to report being responsible for the OCS than the dentist, P<.001. On average, intraoral components are inspected at higher frequencies (96%) than extraoral components (73%). Confidence in OCS technique was high (70%). The majority felt prepared by their education to conduct OCSs (60%), but those with a bachelor's degree felt more prepared than those with a diploma, P=.005. The average time to conduct an OCS is 4.09 minutes, with most agreeing there is sufficient time in an appointment (57%). Only 37% felt their education prepared them to discuss sensitive topics, level of education had no effect, P>.05. Only 43% of respondents felt confident in their human papillomavirus (HPV) knowledge and comfortable discussing HPV risk factors with patients. CONCLUSION: Dental hygienists in this study are regularly conducting OCSs; however, they lack comfort discussing sensitive topics such as transmission of oral HPV, and screenings may not be fully comprehensive. PMID- 28643364 TI - Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia. AB - The clinical significance of paroxysmal nocturnal haemoglobinuria (PNH) in children with aplastic anaemia (AA) remains unclear. We retrospectively studied 57 children with AA between 1992 and 2010. During the follow-up, five patients developed clinical PNH, in whom somatic PIGA mutations were detected by targeted sequencing. The 10-year probability of clinical PNH development was 10.2% (95% confidence interval, 3.6-20.7%). Furthermore, the detection of minor PNH clones by flow cytometry at AA diagnosis was a risk factor for the subsequent development of clinical PNH. These patients with PNH clones at AA diagnosis should undergo periodic monitoring for potential clinical PNH development. PMID- 28643366 TI - Inter-rater reliability of ultrasound measurements of acromion-greater tuberosity distance between experienced and novice raters in healthy people. PMID- 28643367 TI - Facile One-Pot Synthesis of Functional Giant Polymeric Vesicles Controlled by Oscillatory Chemistry. AB - We introduce a novel application of an oscillatory chemical reaction to the synthesis of block copolymers. The Belousov-Zhabotinsky (B-Z) reaction is coupled with the polymerization of an amphiphilic block copolymer. Radicals generated in the B-Z reaction initiate the polymerization between a polyethylene glycol (PEG) macroreversible addition-fragmentation chain-transfer agent and butyl acrylate monomers. The attachment of a hydrophobic block on PEG leads to self-assembly and formation of spherical micelles. The nanoscale micelles transform into submicrometer vesicles and grow to giant vesicles as a consequence of the oscillatory behavior of the B-Z reaction. The one-pot synthesis of an amphiphilic di-block copolymer and retention of oscillatory behavior for the B-Z reaction with the formation of giant vesicles bring a new insight into possible pathways for the synthesis of active functional microreactors in the range from hundreds of nanometers to tens of micrometers. PMID- 28643365 TI - A multi-centre phase I trial of the PARP inhibitor olaparib in patients with relapsed chronic lymphocytic leukaemia, T-prolymphocytic leukaemia or mantle cell lymphoma. PMID- 28643368 TI - Cell lineage tracing in the retina: Could material transfer distort conclusions? AB - Recent studies reported the transfer of fluorescent labels between grafted and host cells after transplantation of photoreceptor precursor cells in the mouse retina. While clearly impacting the interpretation of transplantation studies in the retina, the potential impact of material transfer in other experimental paradigms using cell-specific labels remains uncertain. Here, we briefly review the evidence supporting material transfer in transplantation studies and discuss whether it might influence retinal cell lineage tracing experiments in developmental and regeneration studies. We also propose ways to control for the possible confounding occurrence of label exchange in such experiments. Developmental Dynamics 247:10-17, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28643369 TI - Postoperative pain and perceptions of recuperation after suture- and mesh-based apical sacrospinous ligament suspension. AB - OBJECTIVE: To compare the incidence of postoperative pain after suture- or mesh based sacrospinous ligament suspension (SSLS). METHODS: In a retrospective study, data were reviewed from patients who underwent suture- or mesh-based SSLS at a center in Skokie, IL, USA, between 2006 and 2011. The primary outcome was self reported postoperative pain scores (range 0-10) on the day of surgery (day 0) and 1 day later (day 1). RESULTS: Overall, 90 women were included in the study: 66 underwent mesh-based SSLS and 24 underwent suture-based SSLS. Day-0 mean pain score was 4.65 +/- 1.57 in the mesh group and 5.24 +/- 1.44 in the suture group (adjusted P=0.159). Day-1 mean pain score was 4.06 +/- 1.78 in the mesh group and 4.31 +/- 1.21 in the suture group (adjusted P=0.596). CONCLUSION: Postoperative pain did not differ between patients undergoing suture-based and those undergoing mesh-based SSLS. These observations should be considered in preoperative counseling of patients. PMID- 28643370 TI - Developing a Natural History Progression Model for Duchenne Muscular Dystrophy Using the Six-Minute Walk Test. AB - The 6-minute walk test (6MWT) is used as a clinical endpoint to evaluate drug efficacy in Duchenne Muscular Dystrophy (DMD) trials. A model was developed using digitized 6MWT data that estimated two slopes and two intercepts to characterize 6MWT improvement during development and 6MWT decline. Mean baseline 6MWT was 362 (+/-87) meters. The model predicted an improvement at a rate of 20 meters/year (95% confidence interval (CI) = 9.4-30) up until 10 years old (95% CI = 6.78 13.1), and then a decline at a rate of 85 meters/year (95% CI = 72-98). Interpatient slope variability for improvement and decline were similar at 21.9 percentage of coefficient of variation (%CV) and 23.3%CV, respectively. Model simulations using age demographics from a previous DMD natural history study could reasonably predict the trend in improvement and decline in the 6MWT. This model can be used to quantitate individual patient trajectories, identify prognostic factors for disease progression, and evaluate drug effect. PMID- 28643371 TI - Peer-reviewed articles on inclusive research: Do co-researchers with intellectual disabilities have a voice? AB - BACKGROUND: Inclusive research is increasingly common in intellectual disabilities research, but ways in which voice of co-researchers with intellectual disabilities is presented remain underexplored in the literature. MATERIALS AND METHOD: The authors conducted a literature review and analysis of peer-reviewed journal articles reporting on inclusive research. The aim was to explore the ways the voices of co-researchers with intellectual disabilities are represented in published peer-reviewed journal articles. RESULTS: The findings indicate that there are a wide range of ways in which inclusive research projects are reported in peer-reviewed journals. However, the experiences, views and opinions of co-researchers are often either absent or very selectively reported. CONCLUSIONS: The article concludes that although inclusive research has proliferated in the 21st century, more attention needs to be paid to the ways in which the voices of co-researchers with intellectual disabilities are heard in formal academic contexts. Guidelines for future practice are offered. PMID- 28643373 TI - Cytomegalovirus DNA is highly prevalent in the blood of patients with asthma and is associated with age and asthma traits. AB - Cytomegalovirus (CMV) IgG antibodies have been associated with inflammaging and immunosenescence. We aimed to assess the presence of CMV DNA in the blood of adult and elderly patients with bronchial asthma to establish potential association of CMV DNAemia with asthma and asthma characteristics. Eighty-five elderly asthmatics, 74 younger asthma patients, and 114 age-matched controls were recruited. The CMV DNA was detected using commercial artus assay in 10.7% of asthma patients, but was negative in all control individuals. The secondary assay identified CMV DNA in 41.5% of asthmatics and 13.3% of control subjects (P < .001). Presence of CMV DNA was associated with an increased risk of asthma and CMV DNA copy numbers correlated with some asthma traits, including respiratory parameters and exhaled breath nitric oxide. We conclude that CMV infection is associated with asthma and may contribute to the pathogenesis of asthmatic inflammation. PMID- 28643375 TI - Dried blood spot sampling of nilotinib in patients with chronic myeloid leukaemia: a comparison with venous blood sampling. AB - OBJECTIVES: To compare nilotinib concentrations obtained by venous blood sampling and dried blood spot (DBS) in patients with chronic myeloid leukaemia (CML). It was investigated how to predict nilotinib plasma levels on the basis of DBS. METHODS: Forty duplicate DBS and venous blood samples were collected from 20 patients. Capillary blood was obtained by finger prick and spotted on DMPK-C Whatman sampling paper, simultaneously with venous blood sampling. Plasma concentrations were predicted from DBS concentrations using three methods: (1) individual and (2) mean haematocrit correction and (3) the bias between plasma and DBS concentrations. Results were compared using Deming regression and Bland Altman analysis. KEY FINDINGS: Nilotinib plasma concentrations ranged from 376 to 2663 MUg/l. DBS concentrations ranged from 144 to 1518 MUg/l. The slope was 0.56 (95% CI, 0.51 to 0.61) with an intercept of -41.68 MUg/l (95% CI, -93.78 to 10.42). Mean differences between calculated and measured plasma concentrations were -14.3% (method 1), -14.0% (method 2) and -0.6% (method 3); differences were within 20% of the mean in 73%, 85% and 80% of the samples, respectively. The slopes were respectively 0.96 (95% CI, 0.86 to 1.06), 0.95 (95% CI, 0.86 to 1.03) and 1.00 (95% CI, 0.91 to 1.09). CONCLUSIONS: Plasma concentrations of nilotinib could be predicted on the basis of DBS. DBS sampling to assess nilotinib concentrations in CML patients seems a suitable alternative for venous sampling. PMID- 28643374 TI - Population Pharmacokinetic and Pharmacodynamic Modeling of LY2510924 in Patients With Advanced Cancer. AB - The objectives of this study were to characterize the pharmacokinetics (PK) of LY2510924, a potent peptide antagonist of the CXCR4 receptor, after subcutaneous administration in patients with advanced cancer forms and quantify LY2510924 stimulatory effects on the mobilization of cells bearing the cluster of differentiation 34 (CD34) as an indirect reflection of the chemokine C-X-C motif ligand 12/CXCR4 axis inhibition. LY2510924 PK were best characterized by a two compartment model with first-order absorption and dose-dependent clearance predicting steady state after three daily doses and little accumulation (accumulation ratio <1.17). The dynamics of CD34+ cell counts were best characterized with a precursor model with reversible transfer from the precursor to the central compartment and LY2510924-driven stimulation of cell mobilization. Model-based simulations show that once-daily doses of 20 mg LY2510924 produce maximum CD34+ cell response and that peak effect typically occurs after three daily doses and slowly wanes over time. PMID- 28643376 TI - Effect of N-acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial. PMID- 28643377 TI - Randomized feasibility trial to improve hydroxyurea adherence in youth ages 10-18 years through community health workers: The HABIT study. AB - INTRODUCTION: The main therapeutic intervention for sickle cell disease (SCD) is hydroxyurea (HU). The effect of HU is largely through dose-dependent induction of fetal hemoglobin (HbF). Poor HU adherence is common among adolescents. METHODS: Our 6-month, two-site pilot intervention trial, "HABIT," was led by culturally aligned community health workers (CHWs). CHWs performed support primarily through home visits, augmented by tailored text message reminders. Dyads of youth with SCD ages 10-18 years and a parent were enrolled. A customized HbF biomarker, the percentage decrease from each patients' highest historical HU-induced HbF, "Personal best," was used to qualify for enrollment and assess HU adherence. Two primary outcomes were as follows: (1) intervention feasibility and acceptability and (2) HU adherence measured in three ways: monthly percentage improvement toward HbF Personal best, proportion of days covered (PDC) by HU, and self report. RESULTS: Twenty-eight dyads were enrolled, of which 89% were retained. Feasibility and acceptability were excellent. Controlling for group assignment and month of intervention, the intervention group improved percentage decrease from Personal best by 2.3% per month during months 0-4 (P = 0.30), with similar improvement in adherence demonstrated using pharmacy records. Self-reported adherence did not correlate. Dyads viewed CHWs as supportive for learning about SCD and HU, living with SCD and making progress in coordinated self-management responsibility to support a daily HU habit. Most parents and youth appreciated text message HU reminders. CONCLUSIONS: The HABIT pilot intervention demonstrated feasibility and acceptability with promising effect toward improved medication adherence. Testing in a larger multisite intervention trial is warranted. PMID- 28643378 TI - Effects of weight-based ultrafiltration rate limits on intradialytic hypotension in hemodialysis. AB - INTRODUCTION: High ultrafiltration (UF) rates can result in intradialytic hypotension and are associated with increased mortality. The effects of a weight based UF rate limit on intradialytic hypotension and the potential for unwanted fluid weight gain and hospitalizations for volume overload are unknown. METHODS: This retrospective cohort study examined 123 in-center hemodialysis patients at one facility who transitioned to 13 mL/kg/h maximum UF rates. Patients were studied for an 8 week UF rate limit exposure period and compared to the 8-week period immediately prior, during which the cohort served as its own historical control. The primary outcomes were frequency of intradialytic hypotension events and percentage of treatments with a hypotension event. FINDINGS: The delivered UF rate was lower during the exposure compared to the baseline period (mean UF rate 7.90 +/- 4.45 mL/kg/h vs. 8.92 +/- 5.64 mL/kg/h; P = 0.0005). The risk of intradialytic hypotension was decreased during the exposure compared to baseline period (event rate per treatment 0.0569 vs. 0.0719, OR 0.78 [95% CI 0.62-1.00]; P = 0.0474), as was the risk of having a treatment with a hypotension event (percentage of treatments with event 5.2% vs. 6.8%, OR 0.75 [95% CI 0.58-0.96]; P = 0.0217). Subgroup analyses demonstrated that these findings were attributable to patients with high baseline UF rates. Statistically significant differences in all-cause or volume overload-related hospitalization were not observed during the exposure period. DISCUSSION: A weight-based UF rate limit of 13 mL/kg/h was associated with a decrease in the rate of intradialytic hypotension events among in-center hemodialysis patients. PMID- 28643372 TI - Fine-tuning PERK signaling for neuroprotection. AB - Protein translation and folding are tightly controlled processes in all cells, by proteostasis, an important component of which is the unfolded protein response (UPR). During periods of endoplasmic reticulum stress because of protein misfolding, the UPR activates a coordinated response in which the PERK branch activation restricts translation, while a variety of genes involved with protein folding, degradation, chaperone expression and stress responses are induced through signaling of the other branches. Chronic overactivation of the UPR, particularly the PERK branch, is observed in the brains of patients in a number of protein misfolding neurodegenerative diseases, including Alzheimer's, and Parkinson's diseases and the tauopathies. Recently, numerous genetic and pharmacological studies in mice have demonstrated the effectiveness of inhibiting the UPR for eliciting therapeutic benefit and boosting memory. In particular, fine-tuning the level of PERK inhibition to provide neuroprotection without adverse side effects has emerged as a safe, effective approach. This includes the recent discovery of licensed drugs that can now be repurposed in clinical trials for new human treatments for dementia. This review provides an overview of the links between UPR overactivation and neurodegeneration in protein misfolding disorders. It discusses recent therapeutic approaches targeting this pathway, with a focus on treatments that fine-tune PERK signaling. PMID- 28643379 TI - Tuning the Inter-nanofibril Interaction To Regulate the Morphology and Function of Peptide/DNA Co-assembled Viral Mimics. AB - The ability to tune the inter-subunit interaction within the virus capsid may be critical to assembly and biological function. This process was extended here with peptide/DNA co-assembled viral mimics. The resulting co-assemblies, formed and stabilized by both peptide nanofibril-DNA and peptide nanofibril-nanofibril interactions, were tuned through hydrophobic packing interactions of the peptide sequences. By strengthening peptide side-chain complementarity and/or elongating the peptide chain (from 4 to 8 residues), we report strengthening the inter nanofibril interaction to create stable nanococoons that give high gene transfection efficacy. PMID- 28643380 TI - Microscopy visualisation confirms multi-species biofilms are ubiquitous in diabetic foot ulcers. AB - Increasing evidence within the literature has identified the presence of biofilms in chronic wounds and proposed that they contribute to delayed wound healing. This research aimed to investigate the presence of biofilm in diabetic foot ulcers (DFUs) using microscopy and molecular approaches and define if these are predominantly mono- or multi-species. Secondary objectives were to correlate wound observations against microscopy results in ascertaining if clinical cues are useful in detecting wound biofilm. DFU tissue specimens were obtained from 65 subjects. Scanning electron microscopy (SEM) and peptide nucleic acid fluorescent in situ hybridisation (PNA-FISH) techniques with confocal laser scanning microscopy (CLSM) were used to visualise biofilm structures. Next-generation DNA sequencing was performed to explore the microbial diversity. Clinical cues that included the presence of slough, excessive exudate, a gel material on the wound bed that reforms quickly following debridement, poor granulation and pyocyanin were correlated to microscopy results. Of the 65 DFU specimens evaluated by microscopy, all were characterised as containing biofilm (100%, P < 0.001). The presence of both mono-species and multi-species biofilms within the same tissue sections were detected, even when DNA sequencing analysis of DFU specimens revealed diverse polymicrobial communities. No clinical correlations were identified to aid clinicians in identifying wound biofilm. Microscopy visualisation, when combined with molecular approaches, confirms biofilms are ubiquitous in DFUs and form either mono- or multi-species biofilms. Clinical cues to aid clinicians in detecting wound biofilm are not accurate for use in DFUs. A paradigm shift of managing DFUs needs to consider anti-biofilm strategies. PMID- 28643381 TI - Clinical association between chronic periodontitis and the leukocyte extravasation inhibitors developmental endothelial locus-1 and pentraxin-3. AB - This clinical study aimed to determine whether periodontal disease is associated with expression of developmental endothelial locus-1 (Del-1) and pentraxin-3 (PTX 3), endogenous inhibitors of leukocyte extravasation in humans. Expression of DEL1, PTX3, interleukin-17A (IL17A), and lymphocyte function-associated antigen-1 (LFA1) was determined, using RT-PCR and melting curve analysis, in biopsies of gingival tissues from 95 patients: 42 with moderate periodontitis; 40 with severe periodontitis; and 13 healthy controls. Relative expression of DEL1 and PTX3 was statistically significantly weaker in patients with periodontitis than in the control subjects. On the contrary, both IL17A and LFA1 showed statistically significant stronger expression in patients with periodontitis than in healthy controls. Correlation analysis, performed using Spearman's test, showed that expression of DEL1 was statistically significantly linked to periodontitis (rho = -0.103) and to age (rho = -0.134), but not to the gender of the patient, and that expression of PTX3 was significantly correlated with periodontitis (rho = 0.354). Expression of neutrophil extravasation inhibitors DEL1 and PTX3 show significant, but weak, association with the clinical manifestation of chronic periodontitis. PMID- 28643382 TI - Synthesis and biological evaluation of arginyl-diosgenin conjugate as a potential bone tissue engineering agent. AB - Water-soluble arginyl-diosgenin (Arg-DG) conjugate was designed, synthesized, and evaluated for a biological activity. The Arg-DG conjugate was characterized using FT-IR, 1 H NMR, 13 C NMR, and HPLC-MS analyses, followed by a biological activity evaluation. Compared with DG, the Arg-DG conjugate showed a decreased cytotoxicity against L929 cells and an increased antiproliferative activity against hepatocellular cells. The safety of the Arg-DG conjugate was confirmed using the highly sensitive Alamar Blue assay, which indicated that it increased the cellular metabolic activity at suitable concentrations. The Arg-DG conjugate promoted an endothelial tube formation as well. Furthermore, the Arg-DG conjugate improved the bone morphogenetic protein 2 (BMP2)-induced osteoblastic differentiation with synergistic effects on alkaline phosphatase (ALP) activity and mineralization. These results suggest that the Arg-DG conjugate developed in this study has great potentials for biomedical applications such as bone tissue engineering. PMID- 28643383 TI - Multiecho pseudo-golden angle stack of stars thermometry with high spatial and temporal resolution using k-space weighted image contrast. AB - PURPOSE: Implement and evaluate a 3D MRI method to measure temperature changes with high spatial and temporal resolution and large field of view. METHODS: A multiecho pseudo-golden angle stack-of-stars (SOS) sequence with k-space weighted image contrast (KWIC) reconstruction was implemented to simultaneously measure multiple quantities, including temperature, initial signal magnitude M(0), transverse relaxation time ( T2*), and water/fat images. Respiration artifacts were corrected using self-navigation. KWIC artifacts were removed using a multi baseline library. The phases of the multiple echo images were combined to improve proton resonance frequency precision. Temperature precision was tested through in vivo breast imaging (N = 5 healthy volunteers) using both coronal and sagittal orientations and with focused ultrasound (FUS) heating in a pork phantom using a breast specific MR-guided FUS system. RESULTS: Temperature measurement precision was significantly improved after echo combination when compared with the no echo combination case (spatial average of the standard deviation through time of 0.3 1.0 and 0.7-1.9 degrees C, respectively). Temperature measurement accuracy during heating was comparable to a 3D seg-EPI sequence. M(0) and T2* values showed temperature dependence during heating in pork adipose tissue. CONCLUSION: A self navigated 3D multiecho SOS sequence with dynamic KWIC reconstruction is a promising thermometry method that provides multiple temperature sensitive quantitative values. Magn Reson Med 79:1407-1419, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28643384 TI - Cytological features of medullary thyroid carcinoma in ascitic effusion. PMID- 28643385 TI - The effect of balloon valvuloplasty for bioprosthetic valve stenosis at pulmonary positions. AB - BACKGROUND: Balloon dilatation of a bioprosthetic valve in the pulmonary position could be performed to delay valve replacement. We proposed to identify the long term effectiveness of such a procedure. METHODS: We reviewed the medical records of 49 patients who underwent balloon valvuloplasty between January 2000 and December 2015. The primary goal was to determine the time interval until the following surgical or catheter intervention. RESULTS: The mean age at bioprosthetic valve insertion was 5.7 years old, and the mean age for ballooning was 11.7 years. The mean interval after pulmonary valve replacement was 71.6 months. The mean ratio of balloon size to valve size was 0.94. The pressure gradient through the pulmonary valve after balloon valvuloplasty was significantly improved (55.3 +/- 18.5 mm Hg vs 33.8 +/- 21.5 mm Hg, P < .001). There were no significant changes in pulmonary regurgitation and no serious adverse events. Patients had a mean freedom from re-intervention of 30.6 months after balloon valvuloplasty. The interval of freedom from re-intervention was affected only by the pressure gradient before balloon valvuloplasty and the patient age at insertion. The mean interval to re-intervention in patients with pressure gradients less than 48.5 mm Hg before ballooning was 46.0 months, which was significantly longer than for those with a higher gradient (18.7 months). CONCLUSION: The effectiveness of this process may depend on the pressure gradient before ballooning and the patient age at valve insertion. It is possible that earlier valvuloplasty at pressure gradient not over 48.5mm Hg may have a benefit to delaying re-operation. PMID- 28643386 TI - Risks and trends of red blood cell transfusion in obstetric patients: a retrospective study of 45,213 deliveries using administrative data. AB - BACKGROUND: Transfusion data for obstetric patients are scarce. Identifying characteristics associated with red blood cell transfusion (RBCT) is of importance to better identify patients who would benefit from blood conservation strategies as the risk of alloimmunization from RBCT has the potential to affect the fetus and newborn. STUDY DESIGN AND METHODS: We conducted a retrospective cohort study using hospital administrative data to identify trends and risk factors of RBCT in obstetric patients. Data were analyzed according to the mode of delivery. RESULTS: A total of 45,213 deliveries were captured between January 1, 2007, and December 31, 2013. A higher proportion of patients undergoing cesarean sections (C/Ss) received an RBCT (2.3%) compared to other modes of delivery (0.7% for spontaneous vaginal delivery, 1.5% for instrumental delivery; p < 0.001). In addition, the risk of RBCT increased over the 7-year period for those patients undergoing C/S (relative risk [RR], 1.56; 95% confidence interval [CI], 1.14-2.15). An unavailable hemoglobin (Hb) level (RR, 12.94; 95% CI, 7.39 22.66) and Hb level of 70 to 80 g/L (RR, 7.78; 95% CI = 5.21-11.60) were strongly associated with RBCT among women undergoing C/S. Earlier gestational age at induction increased the risk of RBCT across all modes of delivery. CONCLUSIONS: The higher frequency of RBCT for unknown and low Hb supports the need for predelivery patient blood management at the time of delivery. The additional risk factors associated with RBCT identified may be used to develop risk stratification tools by mode of delivery to assist in the identification of patients at the highest risk of requiring RBCT. PMID- 28643387 TI - Non-Gaussian diffusion imaging with a fractional order calculus model to predict response of gastrointestinal stromal tumor to second-line sunitinib therapy. AB - PURPOSE: To demonstrate the clinical value of a non-Gaussian diffusion model using fractional order calculus (FROC) for early prediction of the response of gastrointestinal stromal tumor to second-line sunitinib targeted therapy. METHODS: Fifteen patients underwent sunitinib treatment after imatinib resistance. Diffusion-weighted imaging with multiple b-values was performed before treatment (baseline) and 2 weeks (for early prediction of response) after initiating sunitinib treatment. Conventional MRI images at 12 weeks were used to determine the good and poor responders according to the modified Choi criteria for MRI. Diffusion coefficient D, fractional order parameter beta (which correlates to intravoxel tissue heterogeneity), and a microstructural quantity u were calculated using the FROC model. The FROC parameters and the longest diameter of the lesion, as well as their changes after 2 weeks of treatment, were compared between the good and poor responders. Additionally, the pretreatment FROC parameters were individually combined with the change in D (DeltaD) using a logistic regression model to evaluate response to sunitinib treatment with a receiver operating characteristic analysis. RESULTS: Forty-two good-responding and 32 poor-responding lesions were identified. Significant differences were detected in pretreatment beta (0.67 versus 0.74, P = 0.011) and DeltaD (45.7% versus 12.4%, P = 0.001) between the two groups. The receiver operating characteristic analysis showed that DeltaD had a significantly higher predictive power than the tumor size change (area under the curve: 0.725 versus 0.580; 0.95 confidence interval). When DeltaD was combined with pretreatment beta, the area under the curve improved to 0.843 with a predictive accuracy of 75.7% (56 of 74). CONCLUSIONS: The non-Gaussian FROC diffusion model showed clinical value in early prediction of gastrointestinal stromal tumor response to second-line sunitinib targeted therapy. The pretreatment FROC parameter beta can increase the predictive accuracy when combined with the change in diffusion coefficient during treatment. Magn Reson Med 79:1399-1406, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28643388 TI - A Longitudinal Item Response Theory Model to Characterize Cognition Over Time in Elderly Subjects. AB - For drug development in neurodegenerative diseases such as Alzheimer's disease, it is important to understand which cognitive domains carry the most information on the earliest signs of cognitive decline, and which subject characteristics are associated with a faster decline. A longitudinal Item Response Theory (IRT) model was developed for the Basel Study on the Elderly, in which the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (with additions) and the California Verbal Learning Test were measured on 1,750 elderly subjects for up to 13.9 years. The model jointly captured the multifaceted nature of cognition and its longitudinal trajectory. The word list learning and delayed recall tasks carried the most information. Greater age at baseline, fewer years of education, and positive APOEE4 carrier status were associated with a faster cognitive decline. Longitudinal IRT modeling is a powerful approach for progressive diseases with multifaceted endpoints. PMID- 28643389 TI - Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives. AB - A combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, pi-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2LOO ) of .75 and .73 as well as conventional correlation coefficients (R2 ) of .93 and .95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2pred ) of .76 and .74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity. PMID- 28643390 TI - Oral disorders, saliva secretion, and oral health-related quality of life in patients with primary Sjogren's syndrome. AB - Chemosensory function, burning sensations in the tongue (BST), halitosis, saliva secretion, and oral health-related quality of life (OHRQoL) were investigated in patients with primary Sjogren's syndrome (pSS). In 31 patients with pSS and 33 controls, olfactory and gustatory functions were evaluated. Self-reported complaints of dysgeusia, BST, and halitosis were recorded. Saliva secretion rates were measured and OHRQoL was assessed using the short-form Oral Health Impact Profile (OHIP-14). Patients had significantly lower olfactory (8.8 +/- 3.5 vs. 10.7 +/- 1.2) and gustatory (18.9 +/- 7.1 vs. 25.4 +/- 4.3) scores than controls, and significantly more patients complained of dysgeusia (58.1% vs. 0%), BST (54.8% vs. 6.1%), and halitosis (41.9% vs. 0%). A significantly greater proportion of patients with pSS had ageusia (19% vs. 0%), hypogeusia (32% vs. 12%), anosmia (13% vs. 0%), or hyposmia (29% vs. 9%). Significantly lower saliva secretion rates (ml min-1 ) were observed in patients with pSS for stimulated (0.62 +/- 0.40 vs. 1.57 +/- 0.71) and unstimulated (0.08 +/- 0.07 vs. 0.29 +/- 0.17) saliva. The mean OHIP-14 score was significantly higher in patients with pSS (16.2 +/- 10.8 vs. 2.7 +/- 3.1) and was positively correlated with dysgeusia, BST, and halitosis. In conclusion, patients with pSS reported higher occurrence of dysgeusia, BST, and halitosis, and demonstrated relatively impaired chemosensory and salivary functions. The patients' poorer OHRQoL was associated with dysgeusia, BST, and halitosis. PMID- 28643391 TI - Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma. AB - Although checkpoint inhibitor therapies have demonstrated significant efficacy in many malignancies, they have not been well studied in patients with a history of solid organ transplant. We describe two patients with recurrent, refractory, and progressive advanced fibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation who received programmed cell death protein 1 (PD 1) inhibitor, nivolumab, on a patient access, off-label basis. Both rapidly developed irreversible acute liver rejection shortly after starting therapy, and ultimately died. While checkpoint inhibitors clearly have tremendous potential as a targeted therapy, they should be avoided or used with extreme caution in the context of an organ transplant. PMID- 28643392 TI - Retroviruses and microtubule-associated motor proteins. AB - Retroviruses are obligate intracellular parasites of eukaryotic cells. After reverse transcription, the viral DNA contained in the preintegration complex is delivered to the nucleus of the host cell, where it integrates. Before reaching the nucleus, the incoming particle and the preintegration complex must travel throughout the cytoplasm. Likewise, the newly synthesized viral proteins and viral particles must transit the cytoplasm during exit. The cytoplasm is a crowded environment, and simple diffusion is difficult. Therefore, viruses have evolved to utilize the cellular mechanisms of movement through the cytoplasm, where microtubules are the roads, and the ATP-dependent motors dynein and kinesin are the vehicles for retrograde and anterograde trafficking. This review will focus on how different retroviruses (Mazon-Pfizer monkey virus, prototype foamy virus, bovine immunodeficiency virus, human immunodeficiency virus type 1, and murine leukemia virus) have subjugated the microtubule-associated motor proteins for viral replication. Although there have been advances in our understanding of how retroviruses move along microtubules, the strategies are different among them. Thus, a better understanding of the mechanisms used by each retrovirus to functionally subvert microtubule motor proteins will provide important clues in the design of new antiretroviral drugs that can specifically disrupt intracellular viral trafficking. PMID- 28643393 TI - Review: Prevalence and dynamics of Helicobacter pylori infection during childhood. AB - INTRODUCTION: Long-term persistent Helicobacter pylori infection has been associated with ulceropeptic disease and gastric cancer. Although H. pylori is predominantly acquired early in life, a clear understanding of infection dynamics during childhood has been obfuscated by the diversity of populations evaluated, study designs, and methods used. AIM: Update understanding of true prevalence of H. pylori infection during childhood, based on a critical analysis of the literature published in the past 5 years. METHODS: Comprehensive review and meta analysis of original studies published from 2011 to 2016. RESULTS: A MEDLINE(r) /PubMed(r) search on May 1, 2016, using the terms pylori and children, and subsequent exclusion, based on abstract review using predefined criteria, resulted in 261 citations. An Embase(r) search with the same criteria added an additional 8 citations. In healthy children, meta-analysis estimated an overall seroprevalence rate of 33% (95% CI: 27%-38%). Seven healthy cohort studies using noninvasive direct detection methods showed infection prevalence estimates ranging from 20% to 50% in children <=5 and 38% to 79% in children >5 years. The probability of infection persistence after a first positive sample ranged from 49% to 95%. Model estimates of cross-sectional direct detection studies in asymptomatic children indicated a prevalence of 37% (95% CI: 30%-44%). Seroprevalence, but not direct detection rates increased with age; both decreased with increasing income. The model estimate based on cross-sectional studies in symptomatic children was 39% (95% CI: 35%-43%). CONCLUSIONS: The prevalence of H. pylori infection varied widely in the studies included here; nevertheless, model estimates by detection type were similar, suggesting that overall, one-third of children worldwide are or have been infected. The few cohort and longitudinal studies available show variability, but most studies, show infection rates over 30%. Rather surprisingly, overall infection prevalence in symptomatic children was only slightly higher, around 40%. Studies including only one positive stool sample should be interpreted with caution as spontaneous clearance can occur. PMID- 28643394 TI - Incorporating deep learning with convolutional neural networks and position specific scoring matrices for identifying electron transport proteins. AB - In several years, deep learning is a modern machine learning technique using in a variety of fields with state-of-the-art performance. Therefore, utilization of deep learning to enhance performance is also an important solution for current bioinformatics field. In this study, we try to use deep learning via convolutional neural networks and position specific scoring matrices to identify electron transport proteins, which is an important molecular function in transmembrane proteins. Our deep learning method can approach a precise model for identifying of electron transport proteins with achieved sensitivity of 80.3%, specificity of 94.4%, and accuracy of 92.3%, with MCC of 0.71 for independent dataset. The proposed technique can serve as a powerful tool for identifying electron transport proteins and can help biologists understand the function of the electron transport proteins. Moreover, this study provides a basis for further research that can enrich a field of applying deep learning in bioinformatics. (c) 2017 Wiley Periodicals, Inc. PMID- 28643396 TI - FIGO's updated recommendations for misoprostol used alone in gynecology and obstetrics. PMID- 28643397 TI - Experimental Study on the Postmortem Redistribution of the Substituted Phenethylamine, 25B-NBOMe. AB - 2-(4-Bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe) is a substituted phenethylamine, which has become highly prevalent worldwide since 2014. Recently, in an autopsy case involving fatal 25B-NBOMe intoxication, we found the postmortem increase of 25B-NBOMe concentration in the cardiac blood approximately 2 days after death. The aim of this study was to investigate the distribution of 25B-NBOMe and reproduce the postmortem redistribution using a rat model. Sprague-Dawley rats were killed 30 min after intraperitoneal injection of 25B-NBOMe (0.5 mg/kg) and left for 0, 3, 6, 9, 15, or 24 h (six rats at each time point). Postmortem 25B-NBOMe concentrations in the cardiac blood increased by more than 10-fold at 6-h postmortem. 25B-NBOMe accumulated primarily in the lung. Moreover, this postmortem redistribution occurred even in rats that had died 1 week following the 25B-NBOMe administration. These findings indicate that attention should be paid to sample collection and data interpretation in the toxicological analysis of 25B-NBOMe. PMID- 28643398 TI - Multiple Symmetric Lipomatosis. AB - A significant number of medicolegal deaths involve ethanol. Deaths may be related to the acute, intoxicating effects of ethanol, either in decedents or within persons responsible for causing the deaths of others. Additionally, deaths may be related to chronic alcoholism. A chronic alcoholic may display characteristic external features which allow an observer, such as a forensic pathologist or other physician, to conclude that he/she is probably an alcoholic. Herein, the authors report two decedents with a rare condition known as "multiple symmetric lipomatosis" (MSL), which has a strong correlation with chronic alcoholism. Identification of the peculiar features associated with MSL should prompt the forensic pathologist to consider chronic alcoholism as a probable diagnosis. PMID- 28643395 TI - Catalase ameliorates diabetes-induced cardiac injury through reduced p65/RelA- mediated transcription of BECN1. AB - Catalase is an antioxidative enzyme that converts hydrogen peroxide (H2 O2 ) produced by superoxide dismutase from highly reactive superoxide (O2- ) to water and oxygen molecules. Although recent findings demonstrate that catalase, autophagy and the nuclear factor kappaB (NF-kappaB) signalling pathway are centrally involved in diabetic cardiomyopathy (DCM), the interplay between the three has not been fully characterized. Thus, the mechanism responsible for catalase-mediated protection against heart injury in diabetic mice was investigated in this study, as well as the role of NF-kappaB-p65 in the regulation of autophagic flux was investigated in this study. Western blot analysis revealed that catalase inhibited NF-kappaB activity and decreased LC3-II (microtubule-associated protein 1 light chain 3) and beclin-1 (Atg6) expression. Furthermore, up-regulation of autophagy was detrimental for cardiac function in diabetic mice. Catalase overexpression reduced the level of NF-kappaB subunit in the nucleus, where it initiates autophagy through activation of the key autophagy gene BECN1. To evaluate the role of the NF-kappaB pathway in diabetes-induced autophagy, Bay11-7082, an NF-kappaB inhibitor, was injected into diabetic mice, which suppressed NF-kappaB and attenuated diabetes-induced autophagy and myocardial apoptosis. In agreement with the in vivo results, Bay11-7082 also inhibited high-glucose-induced activation of NF-kappaB and the up-regulation of LC3-II and beclin-1 expression in H9c2 cells. In addition, high-glucose-induced activation of autophagic flux and apoptosis were largely attenuated by p65 siRNA, suggesting that catalase ameliorates diabetes-induced autophagy, at least in part by increasing the activity of the NF-kappaB pathway and p65-mediated transcription of BECN1. PMID- 28643399 TI - Distributed health literacy among people living with type 2 diabetes in Portugal: Defining levels of awareness and support. AB - This study embraces a patient-centred and narrative-oriented notion of health literacy, exploring how social networks and personal experiences constitute distributed health literacy (DHL) by mapping out health literacy mediators of each individual and how they enable self-management skills and knowledge of health conditions. Semi-structured interviews with 26 patients with type 2 diabetes were conducted in a Primary Care Center of Porto (Portugal) from October 2014 to December 2015. Data were collected based on McGill Illness Narrative Interview (MINI). Following the grounded theory, interviews were analysed as case based and process-tracing-oriented. Three awareness narratives emerged: (i) a narrative of minimisation revealing minimal impact of diabetes in patients' lives and daily routines, resignation towards "inevitable" consequences of the diagnosis and dependence of a large network of health literacy mediators; (ii) a narrative of empathy, where patients tended to mention readjustments in their lives by following medical recommendations regarding medication without criticism and with few health literacy mediators; (iii) a narrative of disruption, with patients highlighting the huge impact of diabetes on their lives and their individual responsibility and autonomy with respect to the management of diabetes and the search for alternatives to medication, relying on a very restrictive network of mediators. Exploring meanings given to diagnosis, identifying health mediators and analysing the structure of social networks can contribute to understand the distributed nature of health literacy. Assessing DHL can assist health professionals and those providing care in the community in promoting health literacy and providing models for a more patient-centred health system. PMID- 28643401 TI - Novel navigation technique for the endodontic treatment of a molar with pulp canal calcification and apical pathology. AB - Apical periodontitis, the inflammation of periapical tissue, commonly requires root canal treatment to achieve apical healing. However, if it is accompanied by pulp canal calcification, the treatment becomes complicated, and locating the root canal can be challenging. This case report describes a novel approach for treating a molar with pulp canal calcification and apical pathology. Due to the risk of perforation during treatment, a digitally printed template was used to assist in accurately locating the root canal. After six months, the patient was asymptomatic and the periradicular radiolucency was gradually reducing in size. PMID- 28643400 TI - A study of regulatory policies and relevant issues concerning electronic cigarette use in Taiwan. AB - Recent technological innovations have increased the amount of tobacco products available to smokers. In particular, electronic cigarettes, sometimes call e cigarettes, have received substantial attention as their sales have rapidly increased. Electronic cigarettes were invented in China and now have become prevalent worldwide. Electronic cigarettes can be considered fashionable and come in numerous flavors; accordingly, many young adults and students have begun to use e-cigarettes. However, like traditional tobacco products, e-cigarettes have negative influences on human health. After e-cigarettes were introduced into Taiwan, they have not been effectively managed and regulated because of insufficient supporting measures. Related legislation in developed countries can serve as a reference for Taiwan. For this study, the development of e-cigarettes is described and a theoretical analysis was performed from the administration and legal perspectives. In addition to clarifying related problems and offering measures to prevent students from using e-cigarettes, we propose suggestions to help governments improve their strategies to protect students' health. PMID- 28643402 TI - Clinical findings in right ventricular noncompaction in hypoplastic left heart syndrome. AB - BACKGROUND: Noncompaction is a poorly understood form of cardiomyopathy that typically affects the left ventricle and may be associated with congenital heart disease. Right ventricular noncompaction (RVNC) may occur when the left ventricle is affected but is rarely seen in isolation. RVNC may have clinical significance affecting surgical and long-term outcomes. We describe the diagnosis and clinical course in three patients at our institution. METHODS: We performed a retrospective review of patients diagnosed with RVNC over a 12-month period at our institution and reviewed their imaging and clinical course. RESULTS: Three patients were identified. All had diagnosis of RVNC by echocardiography (echo) made on postnatal imaging which reviewed degree of trabeculation, and noncompaction-to-compaction ratio of the myocardium. Patient A was a neonate with hypoplastic left heart syndrome (HLHS) who underwent a Norwood operation with Sano modification. Her postoperative course was notable for low-normal RV function. She returned with a pericardial effusion warranting immediate pericardiocentesis. She continued to have effusions, which were medically managed. She was subsequently found to have an RV apical pseudoaneurysm, which required surgical resection. Patient B was a neonate with HLHS who had a Norwood operation with Sano modification. She had low-normal RV function on echo. She required medical management for pericardial effusion. Patient C was a neonate with HLHS who also underwent a Norwood operation with Sano modification. His postoperative course was notable for elevated serum brain natriuretic peptide, which was treated with digoxin. CONCLUSION: RVNC is a rare diagnosis with limited known clinical impact. One of these patients had a very rare complication after pericardiocentesis (pseudoaneurysm) that may have been related to the RVNC. Our understanding of this disease process is limited and requires additional investigation, but emphasizes the importance of appropriate diagnosis to allow for timely follow-up and counseling for this unique population. PMID- 28643403 TI - Unusual Internal Electron Transfer in Conjugated Radical Polymers. AB - Nitroxide-containing organic radical polymers (ORPs) have captured attention for their high power and fast redox kinetics. Yet a major challenge is the polymer's aliphatic backbone, resulting in a low electronic conductivity. Recent attempts that replace the aliphatic backbone with a conjugated one have not met with success. The reason for this is not understood until now. We examine a family of polythiophenes bearing nitroxide radical groups, showing that while both species are electrochemically active, there exists an internal electron transfer mechanism that interferes with stabilization of the polymer's fully oxidized form. This finding directs the future design of conjugated radical polymers in energy storage and electronics, where careful attention to the redox potential of the backbone relative to the organic radical species is needed. PMID- 28643404 TI - Occurrence of late relapse of hepatitis C virus confirmed by molecular analysis after sustained virologic response to interferon-ribavirin-based therapy. AB - AIM: The optimal duration of follow-up for patients who achieve sustained virologic responses (SVR) has become an important issue. Reports on long-term follow-up of SVR have indicated that 99% of patients maintained SVR. However, the limitations of a majority of studies include small patient numbers, short study periods, and lack of molecular analysis of hepatitis C virus (HCV) genome. The present study sought to evaluate the late relapse rate in long-term follow-up of patients who achieved SVR, with molecular analysis of HCV. METHODS: A total of 224 patients with chronic hepatitis C who were treated by interferon and ribavirin-based therapy and achieved SVR were enrolled. All patients were recommended for follow-up every 6 or 12 months. RESULTS: The mean follow-up period was 6.0 years (range, 1.0-13.6 years). Cumulative 5- and 10-year follow-up rates of the patients after SVR were 87.8% and 78.8%, respectively. Cumulative 5- and 10-year follow-up rates of serum HCV RNA after SVR were 85.5% and 52.6%, respectively. Two patients had detectable serum HCV RNA at 20 and 30 months, respectively, after SVR. Phylogenetic analyses of core, non-structural protein 3, and 5A regions of HCV strains from late relapse patients confirmed the same strain was present at baseline and late relapse. CONCLUSIONS: Two of 224 patients developed late relapse of HCV by the original strain, which was confirmed by direct sequencing analysis. Although few patients may develop late relapse, SVR achieved with interferon and ribavirin-based therapy is durable for prolonged periods. PMID- 28643405 TI - Reassessment of the Access Testosterone chemiluminescence assay and comparison with LC-MS method. AB - AIM OF THE STUDY: To reassess the imprecision and Limit of Quantitation, to evaluate the cross-reaction with dehydroepiandrosterone-sulfate (DHEAS), the accuracy toward liquid chromatography-mass spectrometry (LC-MS) and the reference interval of the Access Testosterone method, performed by DxI immunoassay platform (Beckman Coulter). MATERIAL AND METHODS: Imprecision was evaluated testing six pool samples assayed in 20 different run using two reagents lots. The cross reaction with DHEAS was studied both by a displacement curve and by spiking DHEAS standard in two serum samples with known amount of testosterone. The comparison with LC-MS was evaluated by Passing-Bablock analysis in 21 routine serum samples and 19 control samples from an External Quality Assurance (EQA) scheme. The reference interval was verified by an indirect estimation on 2445 male and 2838 female outpatients. RESULTS: The imprecision study showed a coefficient of variation (CV) between 2.7% and 34.7% for serum pools from 16.3 and 0.27 nmol/L. The value of Limit of Quantitation at 20% CV was 0.53 nmol/L. The DHEAS showed a cross-reaction of 0.0074%. A comparison with LC-MS showed a trend toward a slight underestimation of immunoassay vs LC-MS (Passing-Bablock equations: DxI= 0.24+0.906 LCMS in serum samples and DxI=-0.299+0.981 LCMS in EQA samples). The verification of reference interval showed a 2.5th-97.5th percentile distribution of 6.6-24.3 nmol/L for male over 14 years and <0.5-2.78 nmol/L for female subjects, in accord with the reference intervals reported by the manufacturer. CONCLUSIONS: The Access Testosterone method could be considered an adequately reliable tool for the testosterone measurement. PMID- 28643406 TI - Prussian Blue Nanocubes with an Open Framework Structure Coated with PEDOT as High-Capacity Cathodes for Lithium-Sulfur Batteries. AB - It is shown that Prussian blue analogues (PBAs) can be a very competitive sulfur host for lithium-sulfur (Li-S) batteries. Sulfur stored in the large interstitial sites of a PBA host can take advantage of reversible and efficient insertion/extraction of both Li+ and electrons, due to the well-trapped mobile dielectron redox centers in the well-defined host. It is demonstrated that Na2 Fe[Fe(CN)6 ] has a large open framework, and as a cathode, it both stores sulfur and acts as a polysulfide diffusion inhibitor based on the Lewis acid-base bonding effect. The electrochemical testing shows that the S@Na2 Fe[Fe(CN)6 ]@poly(3,4-ethylenedioxythiophene) composite achieves excellent reversibility, good stability, and fast kinetics. Its outstanding electrochemical properties should be ascribed to the internal transport of Li+/e- , maximizing the utilization of sulfur. Moreover, the open metal centers serve as the Lewis acid sites with high affinity to the negatively charged polysulfide anions, reducing the diffusion of polysulfides out of the cathode and minimizing the shuttling effect. The fundamental basis of these exceptional performance characteristics is explored through a detailed analysis of the structural and electrochemical behavior of the material. It is believed that the PBAs will have a useful role in ensuring more effective and stable Li-S batteries. PMID- 28643407 TI - Childhood exposure to constricted living space: a possible environmental threat for myopia development. AB - PURPOSE: People in Hong Kong generally live in a densely populated area and their homes are smaller compared with most other cities worldwide. Interestingly, East Asian cities with high population densities seem to have higher myopia prevalence, but the association between them has not been established. This study investigated whether the crowded habitat in Hong Kong is associated with refractive error among children. METHODS: In total, 1075 subjects [Mean age (S.D.): 9.95 years (0.97), 586 boys] were recruited. Information such as demographics, living environment, parental education and ocular status were collected using parental questionnaires. The ocular axial length and refractive status of all subjects were measured by qualified personnel. RESULTS: Ocular axial length was found to be significantly longer among those living in districts with a higher population density (F2,1072 = 6.15, p = 0.002) and those living in a smaller home (F2,1072 = 3.16, p = 0.04). Axial lengths were the same among different types of housing (F3,1071 = 1.24, p = 0.29). Non-cycloplegic autorefraction suggested a more negative refractive error in those living in districts with a higher population density (F2,1072 = 7.88, p < 0.001) and those living in a smaller home (F2,1072 = 4.25, p = 0.02). After adjustment for other confounding covariates, the population density and home size also significantly predicted axial length and non-cycloplegic refractive error in the multiple linear regression model, while axial length and refractive error had no relationship with types of housing. CONCLUSIONS: Axial length in children and childhood refractive error were associated with high population density and small home size. A constricted living space may be an environmental threat for myopia development in children. PMID- 28643408 TI - The effect of concomitant fields in fast spin echo acquisition on asymmetric MRI gradient systems. AB - PURPOSE: To investigate the effect of the asymmetric gradient concomitant fields (CF) with zeroth and first-order spatial dependence on fast/turbo spin-echo acquisitions, and to demonstrate the effectiveness of their real-time compensation. METHODS: After briefly reviewing the CF produced by asymmetric gradients, the effects of the additional zeroth and first-order CFs on these systems are investigated using extended-phase graph simulations. Phantom and in vivo experiments are performed to corroborate the simulation. Experiments are performed before and after the real-time compensations using frequency tracking and gradient pre-emphasis to demonstrate their effectiveness in correcting the additional CFs. The interaction between the CFs and prescan-based correction to compensate for eddy currents is also investigated. RESULTS: It is demonstrated that, unlike the second-order CFs on conventional gradients, the additional zeroth/first-order CFs on asymmetric gradients cause substantial signal loss and dark banding in fast spin-echo acquisitions within a typical brain-scan field of view. They can confound the prescan correction for eddy currents and degrade image quality. Performing real-time compensation successfully eliminates the artifacts. CONCLUSIONS: We demonstrate that the zeroth/first-order CFs specific to asymmetric gradients can cause substantial artifacts, including signal loss and dark bands for brain imaging. These effects can be corrected using real-time compensation. Magn Reson Med 79:1354-1364, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28643409 TI - Variability in hematology of white-spotted bamboo sharks (Chiloscyllium plagiosum) in different living environments. AB - Elasmobranch hematology continues to reveal new peculiarities within this specialized field. This report compares total hematologic values from the same white-spotted bamboo sharks (Chiloscyllium plagiosum) housed in different environments. We compared the hemograms one year apart, using a standardized Natt Herrick's technique. The total white blood cell (WBC) counts of the sharks were statistically different between the two time points (initial median total WBC count = 18,920 leukocytes/MUl, SD = 8,108; 1 year later total WBC count = 1,815 leukocytes/MUl, SD = 1,309). The packed cell volumes were additionally found to be statistically different (19%, SD = 2.9 vs. 22%, SD = 2.0). Analysis revealed the only differences between the time points were the temperature and stocking densities at which these sharks were housed. This report emphasizes the need for a thorough understanding of the husbandry of an elasmobranch prior to interpretation of a hemogram and suggests that reference intervals should be created for each environment. PMID- 28643410 TI - Professor Jens Solver Schou 10 October 1929-8 March 2017. PMID- 28643411 TI - The BCPT 2016 prize to Jan Alexander, Norway. PMID- 28643412 TI - Rhodium(I)-Catalyzed Bridged [5+2] Cycloaddition of cis-Allene-vinylcyclopropanes to Synthesize the Bicyclo[4.3.1]decane Skeleton. AB - Previously reported was that cis-ene-vinylcyclopropanes (cis-ene-VCPs) underwent Rh-catalyzed [5+2] reaction to give 5,7-fused bicyclic products, where vinylcyclopropane (VCP) acts as five-carbon synthon. Unfortunately, this reaction had very limited scope. Replacing the 2pi component of cis-ene-VCPs to allene moiety, the corresponding cis-allene-VCPs did not undergo the expected normal [5+2] cycloaddition to give 5,7-fused bicyclic products. Instead, the challenging bicyclo[4.3.1]decane skeleton was obtained via an unprecedented bridged [5+2] cycloaddition. DFT calculations were applied to understand why this bridged [5+2] reaction is favored over the anticipated but not realized normal [5+2] reaction. PMID- 28643414 TI - Associating and Dissociating Nanodimer Analysis for Quantifying Ultrasmall Amounts of DNA. AB - The amplification- and enzyme-free quantification of DNA at ultralow concentrations, on the order of 10-1000 targets, is highly beneficial but extremely challenging. To address this challenge, true detection signals must be reliably discriminated from false or noise signals. Herein, we describe the development of associating and dissociating nanodimer analysis (ADNA) as a method that enables a maximum number of detection signals to be collected from true target-binding events while keeping nonspecific signals at a minimum level. In the ADNA assay for ultralow target concentrations, Au nanoprobes on a lipid micropattern were monitored and analyzed in situ, and newly defined dissociating dimers, which are eventually decoupled into monomers again, were incorporated into the detection results. Tens to thousands of DNA copies can be reliably quantified with excellent single-base-mismatch differentiation capability by this non-enzymatic, amplification-free ADNA method. PMID- 28643413 TI - Effects of sodium chloride on heat resistance, oxidative susceptibility, motility, biofilm and plaque formation of Burkholderia pseudomallei. AB - Burkholderia pseudomallei is an environmental saprophyte and the causative agent of melioidosis, a severe infectious disease prevalent in tropical areas, including southeast Asia and northern Australia. In Thailand, the highest incidence of melioidosis is in the northeast region, where saline soil and water are abundant. We hypothesized that B. pseudomallei develops an ability to thrive in saline conditions and gains a selective ecological advantage over other soil dwelling microorganisms. However, little is known about how an elevated NaCl concentration affects survival and adaptive changes in this pathogen. In this study, we examined the adaptive changes in six isolates of B. pseudomallei after growth in Luria-Bertani medium containing different concentrations of NaCl at 37 degrees C for 6 hr. The bacteria were then investigated for resistance to heat at 50 degrees C and killing by hydrogen peroxide (H2 O2 ). In addition, flagellar production, biofilm formation, and the plaque formation efficiency of B. pseudomallei after culture in saline conditions were observed. In response to exposure to 150 and 300 mmol L-1 NaCl, all B. pseudomallei isolates showed significantly increased thermal tolerance, oxidative resistance, and plaque forming efficiency. However, NaCl exposure notably decreased the number of B. pseudomallei flagella. Taken together, these results provide insight into the adaptations of B. pseudomallei that might be crucial for survival and persistence in the host and/or endemic environments with high salinity. PMID- 28643415 TI - Cultivation of human dermal fibroblasts and epidermal keratinocytes on keratin coated silica bead substrates. AB - Human hair keratin is promising as a bioactive material platform for various biomedical applications. To explore its versatility further, human hair keratin was coated onto monolayers of silica beads to produce film-like substrates. This combination was hypothesized to provide a synergistic effect in improving the biochemical properties of the resultant composite. Atomic force microscopy analysis showed uniform coatings of keratin on the silica beads with a slight increase in the resulting surface roughness. Keratin-coated silica beads had higher surface energy and relatively lower negative charge than those of bare silica beads. To investigate cell response, human dermal fibroblasts (HDFs), and human epidermal keratinocytes (HEKs) were cultured on the substrates over 4 days. Results showed that keratin coatings significantly enhanced the metabolic activity of HDFs and encouraged cell spreading but did not exert any significant effects on HEKs. HDF expression of collagen I was significantly more intense on the keratin-coated compared to the bare silica substrates. Furthermore, HDF secretion of various cytokines suggested that keratin coatings triggered active cell responses related to wound healing. Collectively, our study demonstrated that human hair keratin-coated silica bead monolayers have the potential to modulate HDF behavior in culture and may be exploited further. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2789-2798, 2017. PMID- 28643416 TI - Influence of academic training in endodontics and implantology on decision-making in undergraduate students. AB - PURPOSE: To evaluate the effect of academic training on decision-making in a group of undergraduates who have undergone training in endodontics and implantology. BASIC PROCEDURES: A single group of undergraduate dentistry students (n = 65) was given a survey consisting of 15 endodontic cases. Each case included periapical radiographs and clinical photographs. Students were asked to select one of the eight proposed treatments. In their 4th year, the students first responded to the survey after completing endodontics. One year later, after completing their studies in implantology, the same students completed the same survey again. MAIN FINDINGS: Under the conditions of this study, differences in undergraduate training significantly affected treatment decisions. PRINCIPAL CONCLUSIONS: Undergraduate decision-making was affected by academic training. PMID- 28643418 TI - Protein engineering of recombinant human bone morphogenetic protein 2 with higher interaction with Ca phosphate based scaffold used for osteogenesis. AB - The aim of the present study was to assess the recombinant bonemorphogenetic protein 2 (RHBMP-2) with higher substantively and solubility for use in calcium phosphate scaffolds for better release in differentiation of mesenchymal stem cells to osteoblast cells. Using bioinformatics tools, two mutations (p. L10D and p. S12E) were chosen and applied in BMP2 CDS sequence to increase interaction with calcium derived composite. The new recombinant mutated sequence (BMP2mut ) was synthesized and then subcloned to expression vector pBV220. Experimental data regarded functional protein expression in E. coli. Since no modification was made in the active sites of proteins namely beta-sheets and alpha-helixes, not only was there any change in the specific activity occurred in the specific activity of the enzyme in comparison to its commercial counterpart, but also mesenchymal osteogenesis occurred more efficient on biphasic CaP scaffold model. As we hypothesized, use of negatively charged amino acids such as aspartate and glutamate in protein loops increased the interactions of BMP2-Ca2+ and resulted in its slower and more sustained released from CaP scaffolds compare to commercial RHBMP2. Our data suggested that new BMP2mut have greater osteoinductive capacity than RHBMP2 in the same time and dose than RHBMP2. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2799-2805, 2017. PMID- 28643419 TI - Positive and negative associations of individual social capital factors with health among community-dwelling older people. AB - AIM: Previous literature has found positive correlations between social capital and health in older adults, fewer studies have investigated the subdimension's effects of social capital on health. We aimed to determine the individual social capital subfactors in community-dwelling older adults in Japan, and to analyze the associations of these factors with physical and mental health. METHOD: We sent a self-administered questionnaire assessing their perception of social group activity as the individual social capital, and mental and physical health (measured by the Medical Outcomes Study Short Form-36) to 4320 randomly selected older people. RESULTS: There were 1836 valid responses. We clarified that people who participated in any social activity group were in significantly better physical and mental health compared with the people who did not. By the factor analysis of the perception for the social group activity, we identified three components of the individual social capital aspect that we termed harmonious, hierarchic and diversity. Using multiple linear regression, we found the hierarchic aspect was significantly negatively associated with mental health, whereas the harmonious aspect was significantly positively associated with mental and physical health, and diversity was significantly positively associated with mental health. CONCLUSION: As the previous research literature on social capital has mainly emphasized its positive health consequences, the present findings provide a novel demonstration that some aspects of individual social capital can have negative associations with health outcomes in community-dwelling older people. For the practical application of promoting a healthier society, it is important to consider both the positive and negative sides of social capital. Geriatr Gerontol Int 2017; 17: 2427-2434. PMID- 28643417 TI - Congenital deafness affects deep layers in primary and secondary auditory cortex. AB - Congenital deafness leads to functional deficits in the auditory cortex for which early cochlear implantation can effectively compensate. Most of these deficits have been demonstrated functionally. Furthermore, the majority of previous studies on deafness have involved the primary auditory cortex; knowledge of higher-order areas is limited to effects of cross-modal reorganization. In this study, we compared the cortical cytoarchitecture of four cortical areas in adult hearing and congenitally deaf cats (CDCs): the primary auditory field A1, two secondary auditory fields, namely the dorsal zone and second auditory field (A2); and a reference visual association field (area 7) in the same section stained either using Nissl or SMI-32 antibodies. The general cytoarchitectonic pattern and the area-specific characteristics in the auditory cortex remained unchanged in animals with congenital deafness. Whereas area 7 did not differ between the groups investigated, all auditory fields were slightly thinner in CDCs, this being caused by reduced thickness of layers IV-VI. The study documents that, while the cytoarchitectonic patterns are in general independent of sensory experience, reduced layer thickness is observed in both primary and higher-order auditory fields in layer IV and infragranular layers. The study demonstrates differences in effects of congenital deafness between supragranular and other cortical layers, but similar dystrophic effects in all investigated auditory fields. PMID- 28643421 TI - Re: Epidermal skin grafting in vitiligo: a pilot study. PMID- 28643420 TI - Impact on survival of warfarin in patients with pulmonary arterial hypertension receiving subcutaneous treprostinil. AB - INTRODUCTION: Anticoagulation is a common treatment modality in patients with pulmonary arterial hypertension (PAH). Further studies are needed to appropriately assess the risk/benefit ratio of anticoagulation, particularly in PAH patients receiving PAH-specific therapies. AIMS: We use observational long term data on PAH patients treated with subcutaneous (SQ) treprostinil from a large open-label study. Patients were followed for up to 4 years. The use of warfarin and bleeding events were recorded. RESULTS: At total of 860 patients (age [mean+/-SD] 46+/-15 years, 76% female, 83% Caucasian, 49% idiopathic PAH, and 76% New York Heart Association [NYHA] functional class III) were included. All patients received SQ treprostinil (15% also other pulmonary hypertension [PH] therapies) and 590 (69%) received warfarin during the study. The proportions of women, African American, and idiopathic pulmonary hypertension (IPAH) patients were higher in the group receiving warfarin. A higher proportion of patients with congenital heart disease and portopulmonary hypertension did not receive warfarin. There were no differences in unadjusted long-term survival between PAH patients receiving warfarin or not (log-rank test, P value=.69), even when only considering idiopathic PAH (P=.32). In addition, no difference was found in adjusted long-term survival both in PAH (P=.84) and idiopathic PAH patients (P=.44) based on the use of warfarin. Furthermore, no survival difference based on the use of warfarin were noted between propensity score-matched PAH patients (P=.37). CONCLUSIONS: Long-term anticoagulation with warfarin was not associated with any significant effect on survival in PAH or idiopathic PAH patients treated with SQ treprostinil. PMID- 28643422 TI - Microglia-targeted stem cell therapies for Alzheimer disease: A preclinical data review. AB - Alzheimer disease (AD) is a severe, life-threatening illness characterized by gradual memory loss. The classic histological features of AD include extracellular formation of beta-amyloid plaques (Abeta), intracellular neurofibrillary tangles (NFT), and synaptic loss. Recently, accumulated evidence has confirmed the critical role of microglia in the development and exacerbation of AD. When Abeta forms deposits, microglia quickly respond to restore brain physiology by activating a series of repair mechanisms. However, prolonged microglial activation is considered detrimental and may aggravate AD progression. To date, there are no curative therapies for AD. The advent of stem cell transplantation offers novel strategies to treat AD in animal models. Furthermore, studies have reported that transplanted stem cells might ameliorate AD symptoms by regulating microglial functions, from detrimental to protective. This review focuses on the crucial functions of microglia in AD and examines the reactions of microglia to transplanted stem cells. PMID- 28643423 TI - Heterocorrole Conformations: Little Saddling, Much Ruffling. AB - 10-Heterocorrole complexes with oxygen, sulfur, and selenium at position 10 of the macrocycle and with the divalent ions of nickel, copper, and palladium were prepared and investigated. The focus was set on the size adaptation and matching mechanisms of cavity size versus ionic radius in corrole-type macrocycles. A full set of single-crystal X-ray analytical data revealed that in all but one case the N4 binding site of the ring-contracted tetrapyrrole was larger than necessary to bind the metal ion without deformation. In-plane size adaptation through M-N bond length elongation by 2.5-3.2 % was effective, as well as pronounced out-of-plane ruffling of the macrocycle for those compounds with a more severe size mismatch. Such ruffling had been excluded for corroles previously, but is apparently the most efficient mechanism to adapt to small central ions. PMID- 28643424 TI - MDM2 is implicated in high-glucose-induced podocyte mitotic catastrophe via Notch1 signalling. AB - Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in 'post-mitosis' state and unable to regenerate. Re-entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia. We found aberrant mitotic podocytes with multi-nucleation in DN patients. In vitro, cultured podocytes treated by high glucose (HG) also showed an up-regulation of mitotic markers and abnormal mitotic status, accompanied by elevated expression of MDM2. HG exposure forced podocytes to enter into S phase and bypass G2/M checkpoint with enhanced expression of Ki67, cyclin B1, Aurora B and p-H3. Genetic deletion of MDM2 partly reversed HG-induced mitotic phase re-entering of podocytes. Moreover, HG-induced podocyte injury was alleviated by MDM2 knocking down but not by nutlin-3a, an inhibitor of MDM2-p53 interaction. Interestingly, knocking down MDM2 or MDM2 overexpression showed inhibition or activation of Notch1 signalling, respectively. In addition, genetic silencing of Notch1 prevented HG-mediated podocyte MC. In conclusion, high glucose up-regulates MDM2 expression and leads to podocyte MC. Notch1 signalling is an essential downstream pathway of MDM2 in mediating HG-induced MC in podocytes. PMID- 28643426 TI - Cell-of-origin classification by gene expression and MYC-rearrangements in diffuse large B-cell lymphoma of children and adolescents. AB - We present the largest series of diffuse large B-cell lymphoma (DLBCL) in patients younger than 18 years analysed to date by gene expression profiling using Nanostring technology to identify molecular subtypes and fluorescent in situ hybridization for translocations of MYC. We show that the activated B cell like subtype of DLBCL is exceedingly rare in children and - in contrast to adults not associated with outcome. Furthermore, we review the current literature and demonstrate that MYC translocations are not more frequent in paediatric compared to adult DLBCL. A prognostic role of MYC in the paediatric age groups seems unlikely. PMID- 28643425 TI - Insulin degludec/liraglutide (IDegLira) was effective across a range of dysglycaemia and body mass index categories in the DUAL V randomized trial. AB - This study assessed the efficacy of insulin degludec/liraglutide (IDegLira) vs insulin glargine U100 (IGlar) across categories of baseline glycated haemoglobin (HbA1c; <=7.5%, >7.5% to <=8.5% and >8.5%), body mass index (BMI; <30, >=30 to <35 and >=35 kg/m2 ) and fasting plasma glucose (FPG; <7.2 and >=7.2 mmol/L) in patients with type 2 diabetes (T2D) uncontrolled on basal insulin, using post hoc analyses of the DUAL V 26-week trial. With IDegLira, mean HbA1c was reduced across all baseline HbA1c (1.0%-2.5%), FPG (1.5%-1.9%) and BMI categories (1.8% 1.9%), with significantly greater reductions compared with IGlar U100. For all HbA1c, FPG and BMI categories, IDegLira resulted in weight loss and IGlar U100 in weight gain; hypoglycaemia rates were lower for IDegLira vs IGlar U100. More patients achieved HbA1c <7% with IDegLira than IGlar U100 across all HbA1c (59% 87% vs 31%-66%), FPG (71%-74% vs 40%-51%) and BMI categories (71%-73% vs 40% 54%). IDegLira improved glycaemic control and induced weight loss in patients with T2D previously uncontrolled on basal insulin, across the categories of baseline HbA1c, FPG or BMI that were tested. PMID- 28643427 TI - Correlation Between Residual Volume of Male Patients After Uroflowmetry and Random Residual Volume. AB - OBJECTIVES: Our aim was to examine correlation between Post-void residual urine (PVR) after uroflowmetry and random PVR. METHODS: Male patients reporting to the Urology outpatient clinic with LUTS were selected. Patients' age, prostate volume, bladder capacity, voided volume, maximum flow rate, average flow rate, random PVR and PVR after uroflowmetry were recorded. We evaluated the correlations between these parameters. Also we assessed if there was a difference between random PVR and PVR after uroflowmetry. We divided PVR after uroflowmetry and random PVR into three groups: Group 1: 0-50 mL, Group 2: 51-100 mL and Group 3: >100 mL. Also we divided the patients into two groups according to bladder capacity as Group 1: <=400 mL and Group 2: >400 mL. We compared these groups to determine whether a significant difference. RESULTS: Seventy-seven patients applying to the urology outpatient clinic were assessed between 2013 and 2014. PVR after uroflowmetry was significantly higher than random PVR (P < 0.001). When we divided PVR after uroflowmetry and random PVR into three groups there was a significant difference between the groups (P = 0.02). When we divided the patients into two groups according to bladder capacity as Group 1: <=400 mL and Group 2: >400 mL, PVR after uroflowmetry was different, but random PVR was similar (P < 0.001, P = 0.72). CONCLUSIONS: PVR after uroflowmetry seems to be incorrectly high in patients whose bladder capacity is above 400 mL. PMID- 28643428 TI - Mechanical Circulatory Support in the Treatment of Advanced Heart Failure. AB - According to the Centers for Disease Control, heart failure (HF) remains a pervasive condition with high morbidity and mortality, affecting 5.8 million people in the United States and 23 million worldwide. For patients with refractory end-stage HF, heart transplantation is the "gold standard" for definitive treatment. However, the demand for heart transplantation has consistently exceeded the availability of donor hearts, with approximately 2331 orthotopic heart transplantations performed in the United States in 2015 despite an estimated 100 000 to 250 000 patients with New York Heart Association class IIIB or IV symptoms that are refractory to medical treatment, making such patients potential transplant candidates. As such, the need for mechanical circulatory support (MCS) to treat patients with end-stage HF has become paramount. In this review, we focus on the history, advancements, and current use of durable MCS device therapy in the treatment of advanced heart failure. PMID- 28643429 TI - Advances and Challenges in Metal Sulfides/Selenides for Next-Generation Rechargeable Sodium-Ion Batteries. AB - Rechargeable sodium-ion batteries (SIBs), as the most promising alternative to commercial lithium-ion batteries, have received tremendous attention during the last decade. Among all the anode materials for SIBs, metal sulfides/selenides (MXs) have shown inspiring results because of their versatile material species and high theoretical capacity. They suffer from large volume expansion, however, which leads to bad cycling performance. Thus, methods such as carbon modification, nanosize design, electrolyte optimization, and cut-off voltage control are used to obtain enhanced performance. Here, recent progress on MXs is summarized in terms of arranging the crystal structure, synthesis methods, electrochemical performance, mechanisms, and kinetics. Challenges are presented and effective ways to solve the problems are proposed, and a perspective for future material design is also given. It is hoped that light is shed on the development of MXs to help finally find applications for next-generation rechargeable batteries. PMID- 28643430 TI - Platinum-containing regimens for metastatic breast cancer. AB - BACKGROUND: Studies have reported high tumour response rates for platinum containing regimens in the treatment of women with metastatic breast cancer. Most of these studies were conducted prior to the 'intrinsic subtype' era, and did not specifically focus on metastatic triple-negative breast cancers (mTNBCs). OBJECTIVES: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer. SEARCH METHODS: For this review update, we searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov on 28 May 2015. We identified further potentially relevant studies from handsearching references of previous trials, systematic reviews, and meta-analyses. Prior to this review update, the most recent search for studies was conducted in May 2003 for the original 2004 review. SELECTION CRITERIA: Randomised trials comparing platinum containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. Hazard ratios (HRs) were derived for time-to event outcomes, where possible, and fixed-effect models were used for meta analyses. Objective tumour response rates (OTRRs) and toxicities were analysed as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. Quality of life data were extracted where available. GRADE was used to rate the quality of evidence for survival and tumour response outcomes at the level of subgroups selected and unselected for mTNBC, and for toxicity outcomes based on combining data from selected and unselected populations. MAIN RESULTS: This update includes 15 new eligible treatment-comparisons from 12 studies. In total, 28 treatment-comparisons, involving 4418 women, from 24 studies are now included in one or more meta-analyses. Of the 28 treatment-comparisons, 19 and 16 had published or provided extractable time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively. All 28 treatment-comparisons provided OTRR data that could be included in meta-analyses. Most women recruited to the studies were not selected on the basis of mTNBC status.In a subgroup of three treatment-comparisons assessing women with mTNBC, platinum-containing regimens may have provided a survival benefit (HR 0.75, 95% CI 0.57 to 1.00; low-quality evidence). In women unselected for intrinsic subtypes such as mTNBC, there was little or no effect on survival (HR 1.01, 95% CI 0.92 to 1.12; high-quality evidence). This effect was similar to the combined analysis of survival data for both populations (HR 0.98, 95% CI 0.89 to 1.07; I2 =39%, 1868 deaths, 2922 women; 19 trials). The difference in treatment effects between mTNBC women compared with unselected women was of borderline statistical significance (P = 0.05).Data from three treatment-comparisons with mTNBC participants showed that platinum regimens may improve PFS/TTP (HR 0.59, 95% CI 0.49 to 0.72; low-quality evidence). Thirteen treatment-comparisons of unselected metastatic participants showed that there was probably a small PFS/TTP benefit for platinum recipients, although the confidence interval included no difference (HR 0.92, 95% CI 0.84 to 1.01; moderate-quality evidence). Combined analysis of data from an estimated 1772 women who progressed or died out of 2136 women selected or unselected for mTNBC indicated that platinum-containing regimens improved PFS/TTP (HR 0.85, 95% CI 0.78 to 0.93). There was marked evidence of heterogeneity (P = 0.0004; I2 = 63%). The larger treatment benefit in mTNBC women compared with unselected women was statistically significant (P < 0.0001).There was low-quality evidence of better tumour response in both subgroups of women with mTNBC and unselected women (RR 1.33, 95% CI 1.13 to 1.56; RR 1.11, 95% CI 1.04 to 1.19, respectively). Combined analysis of both populations was closer to the effect in unselected women (RR 1.15, 95% CI 1.08 to 1.22; 4130 women). There was considerable evidence of heterogeneity (P < 0.0001; I2 = 64%), which may reflect between-study differences and general difficulties in assessing response, as well as the varying potencies of the comparators.Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were probably higher among women receiving cisplatin- (RR 2.65, 95% CI 2.10 to 3.34; 1731 women; moderate-quality evidence) but the effect from carboplatin-containing regimens was less certain (RR 0.77, 95% CI 0.47 to 1.26; 1441 women; moderate quality evidence); rates of grade 3 and 4 anaemia were higher among women receiving cisplatin- (RR 3.72, 95% CI 2.36 to 5.88; 1644 women; high-quality evidence) and carboplatin-containing regimens (RR 1.72, 95% CI 1.10 to 2.70; 1441 women; high-quality evidence); rates of grade 3 and 4 hair loss (RR 1.41, 95% CI 1.26 to 1.58; 1452 women; high-quality evidence) and leukopenia (RR 1.38, 95% CI 1.21 to 1.57; 3176 women; moderate-quality evidence) were higher among women receiving platinum-containing regimens (regardless of platinum agent). AUTHORS' CONCLUSIONS: In women with metastatic breast cancer who do not have triple negative disease, there is high-quality evidence of little or no survival benefit and excess toxicity from platinum-based regimens. There is preliminary low quality evidence of a moderate survival benefit from platinum-based regimens for women with mTNBC. Further randomised trials of platinum-based regimens in this subpopulation of women with metastatic breast cancer are required. PMID- 28643431 TI - A study of the origin of chloramphenicol isomers in honey. AB - Due to the unexpected detection of chloramphenicol isomer residues in honey, we have studied the hypothesis of unauthorized or unintended use of unregistered veterinary drug preparations. First, we have investigated honey samples in which a discrepancy was observed between the results of the immunological screening methods and the confirmatory liquid chromatography-tandem mass spectrometry (LC MS/MS) method. In all samples, previously identified to be contaminated with the banned antibiotic chloramphenicol according to LC-MS/MS only, the presence of dextramycin (SS-para isomer of chloramphenicol) was detected by chiral LC-MS/MS. The source of dextramycin in honey was investigated by studying the preparations utilized in apiaries from which the above non-compliant honey samples have been received. In all these preparations (beehive strips applied against the mite Varroa destructor) chloramphenicol was detected in the concentrations ranging from 33 to 34,400 MUg kg-1 . Chiral LC-MS/MS demonstrated the presence of chloramphenicol and dextramycin in different ratios, and it was concluded that these preparations can be the source of chloramphenicol and dextramycin residues in honey. These preparations were of foreign production and are not officially registered in accordance with current legislation. PMID- 28643432 TI - The penetration and phenotype modulation of smooth muscle cells on surface heparin modified poly(E-caprolactone) vascular scaffold. AB - The tubular porous poly(E-caprolactone) (PCL) scaffold was fabricated by electrospinning. After then, the scaffold's surface was firstly eroded by hexyldiamine to endow amine group, and heparin was covalently grafted to the surface to get surface heparin modified scaffold (ShPCL scaffold). It was found that ShPCL scaffold can induce smooth muscle cells (SMCs) to penetrate the scaffold surface, while the SMCs cannot penetrate the surface of PCL scaffold. Subsequently, the rabbit SMCs were seeded on the ShPCL scaffold and cultured for 14 days. It was found the expression of alpha-smooth muscle actin in ShPCL scaffold maintained much higher level than that in culture plate, which implied the SMC differentiation in ShPCL scaffold. Furthermore, the immunefluorescence staining of the cross-sections of ShPCL scaffold exhibited the expression of calponin in ShPCL scaffold can be detected after 7 and 14 days, whereas the expression of smooth muscle myosin heavy chain can also be detected at 14 days. These results proved that penetrated SMCs preferably differentiated in to contractile phenotype. The successful SMC penetration and the contractile phenotype expression implied ShPCL scaffold is a suitable candidate for regenerating smooth muscle layer in vascular tissue engineering. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2806-2815, 2017. PMID- 28643433 TI - Electrochemical TERS Elucidates Potential-Induced Molecular Reorientation of Adenine/Au(111). AB - Electrochemical surface activity arises from the interaction and geometric arrangement of molecules at electrified interfaces. We present a novel electrochemical tip-enhanced Raman spectroscope that can access the vibrational fingerprint of less than 100 small, non-resonant molecules adsorbed at atomically flat Au electrodes to study their adsorption geometry and chemical reactivity as a function of the applied potential. Combining experimental and simulation data for adenine/Au(111), we conclude that protonated physisorbed adenine adopts a tilted orientation at low potentials, whereas it is vertically adsorbed around the potential of zero charge. Further potential increase induces adenine deprotonation and reorientation to a planar configuration. The extension of EC TERS to the study of adsorbate reorientation significantly broadens the applicability of this advanced spectroelectrochemical tool for the nanoscale characterization of a full range of electrochemical interfaces. PMID- 28643434 TI - Improved yield of minimal proportional sample volume platelet bacterial culture. AB - BACKGROUND: Reports of septic transfusion reactions (STRs) after transfusion of culture-negative platelets (PLTs) justify more effective prevention strategies. Pathogen reduction technologies or performance of additional point-of-issue testing are proposed strategies to enhance safety through Day 5 of storage. STUDY DESIGN AND METHODS: Trima leukoreduced apheresis PLTs (APs) were collected during two study periods (45 and 31 months) using standard procedures, with target settings adjusted during the second period to maintain split rate after increased culture volume. Primary testing for bacterial contamination was performed using BacT/ALERT 3D with sampling from the mother bag 24 to 36 hours after collection. Two culture approaches were compared: in Period A, an 8-mL sample in one aerobic culture bottle (CB), and in Period B a minimal proportional sample volume (PSV) of at least 3.8% of mother bag volume into one to three aerobic CBs (7-10 mL per bottle). RESULTS: In Periods A and B, 188,389 and 159,098 AP collections were tested, respectively. The true-positive (TP) rate in Period A was 0.90 per 10,000 collections and in Period B was 1.83 per 10,000 (p < 0.05). In Period B, 12 of 29 (41%) TP results had discrepant CB results (DCBRs; at least one of multiple bottles without growth). The false-positive rate in Period B, 15.05 per 10,000 collections, was significantly higher than that of Period A, 3.66 per 10,000. One contaminated collection resulting in STR(s) was reported in each study period. Implementation of PSV was operationally successful and did not impact the AP split rate. CONCLUSION: Proportional sample volume improved the sensitivity of primary testing and identified collections that could have escaped detection had only a single bottle with 8- to 10-mL volume been used. PSV may represent another approach to enhanced PLT safety for 5-day storage without a requirement for secondary testing. PMID- 28643435 TI - Interventions for enhancing the distribution of dental professionals: a concise systematic review. AB - BACKGROUND: A spatially unequal distribution of dentists or dental care professionals (D/DCPs), such as therapists or hygienists, could reduce the quality of health services and increase health inequities. This review describes the interventions available to enhance this spatial distribution and systematically assesses their effectiveness. METHODS: Electronic databases (Cochrane CENTRAL, Medline, Embase, CINAHL) were searched and cross-referencing was performed using a standardised searching algorithm. Randomised and non randomised controlled trials, controlled before-and-after studies and interrupted time series were included. Studies investigating a minimum of one of four interventions (educational, financial, regulatory and supportive) were included. The primary outcome was the spatial distribution of D/DCPs. Secondary outcomes were access, quality of services and equity or adverse effects. This review was registered (CRD42015026265). RESULTS: Of 4,885 articles identified, the full text of 201 was assessed and three (all investigating national policy interventions originally not aiming to change the distribution of D/DCPs) were included. In one Japanese study spanning 1980 to 2000, the unequal spatial distribution of dentists decreased alongside a general increase in the number of dentists. It remained unclear if these findings were associated. In a second Japanese study, an increase in the number of dentists was found in combination with a postgraduate training programme implemented in 2006, and this occurred alongside an increasingly unequal distribution of dentists, again without proof of cause and consequence. A third study from Taiwan found the introduction of a national universal-coverage health insurance to equalise the distribution of dentists, with statistical association between this equalisation and the introduction of the insurance. CONCLUSIONS: The effectiveness of interventions to enhance the spatial distribution of D/DCPs remains unclear. PMID- 28643437 TI - Silibinin affects the pharmacokinetics of methadone in rats. AB - The aim of the present study was to investigate the pharmacokinetic effect of silibinin on methadone in rats. Twenty-four male Sprague-Dawley rats were randomly divided into 4 groups: control group, single dose of 100 mg/kg group, multiple doses of 100 mg/kg group, and multiple doses of 30 mg/kg group. A single dose of 6 mg/kg methadone was administrated to rats orally without or with silibinin. Plasma samples were collected via tail vein at different time points and concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3 diphenylpyrrolidine (EDDP), were determined by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Compared with the control group (without silibinin), both 30 and 100 mg/kg silibinin significantly increased the Cmax of methadone, but only 100 mg/kg silibinin significantly increased the AUC(0-t) of methadone and decreased its clearance. Pharmacokinetics parameters of EDDP were not altered by 30 mg/kg silibinin; its Tmax was decreased by 100 mg/kg silibinin and the Cmax was increased by single dose of 100 mg/kg silibinin. It is concluded that silibinin significantly altered the pharmacokinetics of methadone in rats by increasing the exposure of methadone. Further investigations in human should be conducted. Therapeutic drug monitoring of methadone in individuals undergoing methadone maintenance therapy is recommended when silibinin is concomitant. PMID- 28643436 TI - Emotional awareness and expression training improves irritable bowel syndrome: A randomized controlled trial. AB - BACKGROUND: Current clinical guidelines identify several psychological treatments for irritable bowel syndrome (IBS). IBS patients, however, have elevated trauma, life stress, relationship conflicts, and emotional avoidance, which few therapies directly target. We tested the effects of emotional awareness and expression training (EAET) compared to an evidence-based comparison condition-relaxation training-and a waitlist control condition. METHODS: Adults with IBS (N=106; 80% female, Mean age=36 years) were randomized to EAET, relaxation training, or waitlist control. Both EAET and relaxation training were administered in three, weekly, 50-minute, individual sessions. All patients completed the IBS Symptom Severity Scale (primary outcome), IBS Quality of Life, and Brief Symptom Inventory (anxiety, depressive, and hostility symptoms) at pretreatment and at 2 weeks posttreatment and 10 weeks follow-up (primary endpoint). KEY RESULTS: Compared to waitlist controls, EAET, but not relaxation training, significantly reduced IBS symptom severity at 10-week follow-up. Both EAET and relaxation training improved quality of life at follow-up. Finally, EAET did not reduce psychological symptoms, whereas relaxation training reduced depressive symptoms at follow-up (and anxiety symptoms at posttreatment). CONCLUSIONS & INFERENCES: Brief emotional awareness and expression training that targeted trauma and emotional conflicts reduced somatic symptoms and improved quality of life in patients with IBS. This emotion-focused approach may be considered an additional treatment option for IBS, although research should compare EAET to a full cognitive-behavioral protocol and determine which patients are best suited for each approach. Registered at clinicaltrials.gov (NCT01886027). PMID- 28643439 TI - A Simple and Effective Physical Characteristic Profiling Method for Methamphetamine Tablet Seized in China. AB - Methamphetamine (MA) tablet production confers chemical and physical properties. This study developed a simple and effective physical characteristic profiling method for MA tablets with capital letter "WY" logos, which realized the discrimination between linked and unlinked seizures. Seventeen signature distances extracted from the "WY" logo were explored as factors for multivariate analysis and demonstrated to be effective to represent the features of tablets in the drug intelligence perspective. Receiver operating characteristic (ROC) curve was used to evaluate efficiency of different pretreatments and distance/correlation metrics, while "Standardization + Euclidean" and "Logarithm + Euclidean" algorithms outperformed the rest. Finally, hierarchical cluster analysis (HCA) was applied to the data set of 200 MA tablet seizures randomly selected from cases all around China in 2015, and 76% of them were classified into a group named after "WY-001." Moreover, the "WY-001" tablets occupied 51-80% tablet seizures from 2011 to 2015 in China, indicating the existence of a huge clandestine factory incessantly manufacturing MA tablets. PMID- 28643438 TI - Knockdown of Mtfp1 can minimize doxorubicin cardiotoxicity by inhibiting Dnm1l mediated mitochondrial fission. AB - The long-term usage of doxorubicin (DOX) is largely limited due to the development of severe cardiomyopathy. Many studies indicate that DOX-induced cardiac injury is related to reactive oxygen species generation and ultimate activation of apoptosis. The role of novel mitochondrial fission protein 1 (Mtfp1) in DOX-induced cardiotoxicity remains elusive. Here, we report the pro mitochondrial fission and pro-apoptotic roles of Mtfp1 in DOX-induced cardiotoxicity. DOX up-regulates the Mtfp1 expression in HL-1 cardiac myocytes. Knockdown of Mtfp1 prevents cardiac myocyte from undergoing mitochondrial fission, and subsequently reduces the DOX-induced apoptosis by preventing dynamin 1-like (Dnm1l) accumulation in mitochondria. In contrast, when Mtfp1 is overexpressed, a suboptimal dose of DOX can induce a significant percentage of cells to undergo mitochondrial fission and apoptosis. These data suggest that knocking down of Mtfp1 can minimize the cardiomyocytes loss in DOX-induced cardiotoxicity. Thus, the regulation of Mtfp1 expression could be a novel therapeutic approach in chemotherapy-induced cardiotoxicity. PMID- 28643441 TI - Coronary artery anomalies: A multidisciplinary approach to shape the landscape of a challenging problem. AB - Coronary artery anomalies, particularly anomalous aortic origin of a coronary artery with an interarterial course, are associated with sudden cardiac arrest or death in the young. There is paucity of data on risk stratification and longitudinal follow up is lacking in these patients. Collaboration and sharing of data among specialized centers might shed much needed light in this complex problem. PMID- 28643440 TI - Model Description Language (MDL): A Standard for Modeling and Simulation. PMID- 28643442 TI - The effect of collagen coating on titanium with nanotopography on in vitro osteogenesis. AB - Several studies have shown the positive effects of Ti either with nanotopography or coated with collagen on osteoblast differentiation. Thus, we hypothesized that the association of nanotopography with collagen may increase the in vitro osteogenesis on Ti surface. Ti discs with nanotopography with or without collagen coating were characterized by scanning electron microscopy and atomic force microscopy. Rat calvaria-derived osteoblastic cells were cultured on both Ti surfaces for up to 14 days and the following parameters were evaluated: cell proliferation, alkaline phosphatase (ALP) activity, extracellular matrix mineralization, protein expression of bone sialoprotein (BSP) and osteopontin (OPN), and gene expression of collagen type 1a (Coll1a), runt-related transcription factor 2 (Runx2), osterix (OSX), osteocalcin (OC), Ki67, Survivin, and Bcl2-associated X protein (BAX). Surface characterization evidenced that collagen coating did not alter the nanotopography. Collagen coating increased cell proliferation, ALP activity, extracellular matrix mineralization, and Coll1a, OSX, OC, and BAX gene expression. Also, OPN and BSP proteins were strongly detected in cultures grown on both Ti surfaces. In conclusion, our results showed that the combination of nanotopography with collagen coating stimulates the early, intermediate, and final events of the in vitro osteogenesis and may be considered a potential approach to promote osseointegration of Ti implants. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2783 2788, 2017. PMID- 28643443 TI - National high-flow nasal cannula and bronchiolitis survey highlights need for further research and evidence-based guidelines. AB - AIM: High-flow nasal cannula (HFNC) therapy provides noninvasive respiratory support for infant bronchiolitis and its use has increased following good clinical experiences. This national study describes HFNC use in Finland during a severe respiratory syncytial virus (RSV) epidemic. METHODS: A questionnaire on using HFNC for infant bronchiolitis during the 2015-2016 RSV epidemic was sent to the head physicians of 18 Finnish children's hospitals providing inpatient care for infants: 17 hospitals answered, covering 77.5% of the infants born in Finland in 2015. RESULTS: Most (85%) HFNC was given on paediatric wards. The mean incidence for bronchiolitis treated with HFNC in infants under the age of one in 15 of 17 hospitals was 3.8 per 1000 per year (range: 1.4-8.1): one hospital did not supply the relevant data and one supplied a figure of 34.1 due to a different treatment policy. Instructions on how to start and wean HFNC therapy were present in 71% and 61% of the hospitals, respectively, weighted to the population. Providing weaning instructions was associated with shorter weaning times. CONCLUSION: High-flow nasal cannula was actively used for infants with bronchiolitis, with no substantial overuse. Randomised controlled studies are needed before any evidence-based guidelines can be constructed for using HFNC in infant bronchiolitis. PMID- 28643444 TI - How Media Exposure Relates to Laypersons' Understanding of Psychopathy. AB - While conceptualization of psychopathy has evolved, so too has the public's relationship with psychology changed. Concurrently, portrayal of psychopaths has made several shifts, both through nonfiction sources and in popular film and television. Psychopathic villains of the mid-20th century have made space for a growing cast of protagonist psychopaths. This study examined whether a relationship existed between exposure to fictional psychopaths and how lay individuals conceptualize psychopathy. Specifically, this study explored conceptualization differences based on exposure to antagonist versus protagonist fictional psychopaths. Surveyed community participants supported earlier research suggesting mixed misunderstanding of psychopathy. Additionally, higher exposure to protagonist psychopaths was associated with higher endorsement of flattering distractor traits, reflecting a kind of romanticized psychopathy. These findings have legal, practical, and ethical implications, including the potential for biased jurors, confounded research about psychopathy's labeling effect, and questions about how psychologists should respond on an individual and systemic level. PMID- 28643445 TI - An Electrochemical Biosensor with Dual Signal Outputs: Toward Simultaneous Quantification of pH and O2 in the Brain upon Ischemia and in a Tumor during Cancer Starvation Therapy. AB - Herein, we develop a novel method for designing electrochemical biosensors with both current and potential signal outputs for the simultaneous determination of two species in a living system. Oxygen (O2 ) and pH, simple and very important species, are employed as model molecules. By designing and synthesizing a new molecule, Hemin-aminoferrocene (Hemin-Fc), we create a single electrochemical biosensor for simultaneous detection and ratiometric quantification of O2 and pH in the brain. The reduction peak current of the hemin group increases with the concentration of O2 from 1.3 to 200.6 MUm. Meanwhile, the peak potential positively shifts with decreasing pH from 8.0 to 5.5, resulting in the simultaneous determination of O2 and pH. The Fc group can serve as an internal reference for ratiometric biosensing because its current and potential signals remain almost constant with variations of O2 and pH. The developed biosensor has high temporal and spatial resolutions, as well as remarkable selectivity and accuracy, and is successfully applied in the real-time quantification of O2 and pH in the brain upon ischemia, as well as in tumor during cancer therapy. PMID- 28643446 TI - Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action. AB - Artemisinin and its derivatives (collectively termed as artemisinins) are among the most important and effective antimalarial drugs, with proven safety and efficacy in clinical use. Beyond their antimalarial effects, artemisinins have also been shown to possess selective anticancer properties, demonstrating cytotoxic effects against a wide range of cancer types both in vitro and in vivo. These effects appear to be mediated by artemisinin-induced changes in multiple signaling pathways, interfering simultaneously with multiple hallmarks of cancer. Great strides have been taken to characterize these pathways and to reveal their anticancer mechanisms of action of artemisinin. Moreover, encouraging data have also been obtained from a limited number of clinical trials to support their anticancer property. However, there are several key gaps in knowledge that continue to serve as significant barriers to the repurposing of artemisinins as effective anticancer agents. This review focuses on important and emerging aspects of this field, highlighting breakthroughs in unresolved questions as well as novel techniques and approaches that have been taken in recent studies. We discuss the mechanism of artemisinin activation in cancer, novel and significant findings with regards to artemisinin target proteins and pathways, new understandings in artemisinin-induced cell death mechanisms, as well as the practical issues of repurposing artemisinin. We believe these will be important topics in realizing the potential of artemisinin and its derivatives as safe and potent anticancer agents. PMID- 28643447 TI - Simultaneous mapping of metabolites and individual macromolecular components via ultra-short acquisition delay 1 H MRSI in the brain at 7T. AB - PURPOSE: Short-echo-time proton MR spectra at 7T feature nine to 10 distinct macromolecule (MM) resonances that overlap with the signals of metabolites. Typically, a metabolite-nulled in vivo MM spectrum is included in the quantification's prior knowledge to provide unbiased metabolite quantification. However, this MM model may fail if MMs are pathologically altered. In addition, information about the individual MM peaks is lost. In this study, we aimed to create an improved MM model by parameterization of the in vivo MM spectrum into individual components, and to use this new model to quantify free induction decay MR spectroscopic imaging (FID-MRSI) data. METHODS: The measured in vivo MM spectrum was parameterized using advanced method for accurate, robust, and efficient spectral fitting (AMARES) and Hankel-Lanczos singular value decomposition algorithms from which six different MM models were derived. Soft constraints were applied to avoid over-parameterization. All MM models were combined with simulated metabolite spectra to form complete basis sets. FID-MRSI data from 14 healthy volunteers were quantified via LCModel, and the results were compared between all basis sets. RESULTS: The MM model using nine individual AMARES-parameterized MM components with additional soft constraints achieved the most reliable results. Nine MMs and seven metabolites were mapped simultaneously over the whole slice. CONCLUSION: The proposed MM model may facilitate studies that involve patients with pathologically altered MMs. Magn Reson Med 79:1231 1240, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28643448 TI - Postconditioning with metformin attenuates apoptotic events in cardiomyoblasts associated with ischemic reperfusion injury. AB - AIM: Ischemic postconditioning is considered as a potent method to combat ischemic reperfusion injury than preconditioning and rapid initiation of reperfusion with potent antioxidant compounds can be one of the most effective treatments to reduce the infarct size and behavioral deficits as a result of ischemic insult. The present study aims to determine the postconditioning effects of metformin in experimental ischemia. METHODS: H9C2 cells were subjected to experimental ischemia and reperfused with metformin. Viability, oxidative stress and apoptotic events were determined. RESULTS: Postconditioning with Metformin effectively maintained cell viability and membrane stability of H9C2 cardiomyoblast cells from ischemic injury at a concentration of 2.5 ug/mL. Decrease in cell death was established viz fluorescent staining and Annexin V FITC flow cytometric analysis. In metformin treated ischemic cells the DNA fragmentation and comet length were significantly reduced (p=.0001) affirming antiapoptotic activity of metformin. There was an increase in protein carbonyl content and decrease in nitrate levels after ischemic injuries which were alleviated with metformin treatment. Wound closure was enhanced by metformin treatment. Metformin synchronized the apoptotic proteins such as FasL and antiapoptotic proteins such as Bcl2, Bcl-xL and p21 which can be attributed as the major mechanism of cardioprotection. CONCLUSIONS: The results envisage therapeutic potential of metformin at lower concentrations as an effective postischemic conditioning agent. PMID- 28643449 TI - Morphology of the tongue of Vermilingua (Xenarthra: Pilosa) and evolutionary considerations. AB - The tongue of anteaters (Xenarthra, Pilosa, Vermilingua) is a highly specialized for myrmecophagy. Here, we describe the topography and histology of the tongue, and compare it to that of other xenarthrans and other myrmecophagous eutherian mammals. The tongue of Vermilingua is long and slender, with an apical protuberance, which differs between Myrmecophagidae and Cyclopes didactylus. In the former, the rostral region is conical, and in the latter, it is dorsoventrally compressed, as observed in sloths. The tongue of Vermilingua has filiform and circumvallate papillae on the surface; foliate and fungiform papillae are absent. The filiform papillae of Myrmecophaga tridactyla are simple all over the tongue, differing from Tamandua tetradactyla and Cyclopes didactylus, which present composed filiform papillae in the rostral and middle regions. Histologically, the tongue has a peculiar organization of muscular and neurovascular tissues, differing from the usual mammalian pattern. However, the tongue structure is less divergent in Cyclopes. The presence of two circumvallate papillae is common to the three major clades of Xenarthra (Cingulata, Folivora and Vermilingua). In each group, the tongue may reflect functional features related to myrmecophagous (anteaters and some armadillos), omnivorous (remaining armadillos) and folivorous (sloths) feeding habits. The similarities between the tongues of Vermiligua and other non-xenarthran eutherian myrmecophagous mammals are somewhat general and, under close inspection, superficial, being an example of different lineages achieving the same morphofunctional adaptations through distinct evolutionary pathways. PMID- 28643450 TI - SCPP Genes and Their Relatives in Gar: Rapid Expansion of Mineralization Genes in Osteichthyans. AB - Gar is an actinopterygian that has bone, dentin, enameloid, and ganoin (enamel) in teeth and/or scales. Mineralization of these tissues involves genes encoding various secretory calcium-binding phosphoproteins (SCPPs) in osteichthyans, but no SCPP genes have been identified in chondrichthyans to date. In the gar genome, we identified 38 SCPP genes, seven of which encode "acidic-residue-rich" proteins and 31 encode "Pro/Gln (P/Q) rich" proteins. These gar SCPP genes constitute the largest known repertoire, including many newly identified P/Q-rich genes expressed in teeth and/or scales. Among gar SCPP genes, six acidic and three P/Q rich genes were identified as orthologs of sarcopterygian genes. The sarcopterygian orthologs of most of these acidic genes are involved in bone and/or dentin formation, and sarcopterygian orthologs of all three P/Q-rich genes participate in enamel formation. The finding of these genes in gar suggests that an elaborate SCPP gene-based genetic system for tissue mineralization was already present in stem osteichthyans. While SCPP genes have been thought to originate from ancient SPARCL1, SPARCL1L1 appears to be more closely related to these genes, because it established a structure similar to acidic SCPP genes probably in stem gnathostomes, perhaps at about the same time with the origin of tissue mineralization. Assuming enamel evolved in stem osteichthyans, all P/Q-rich SCPP genes likely arose within the osteichthyan lineage. Furthermore, the absence of acidic SCPP genes in chondrichthyans might be explained by the secondary loss of earliest acidic genes. It appears that many SCPP genes expanded rapidly in stem osteichthyans and in basal actinopterygians. PMID- 28643451 TI - Polyclonal and monoclonal B lymphocytes response in HCV-infected patients treated with direct-acting antiviral agents. AB - Hepatitis C virus (HCV) chronic infection can be associated with extrahepatic manifestations such as mixed cryoglobulinaemia and lymphoproliferative disorders that are endowed with increased rates of morbidity and all-cause mortality. In this study, we used flow cytometry to evaluate the effect of interferon-free antiviral treatment on peripheral blood lymphocytes in HCV-infected patients with or without associated lymphoproliferative disorders. Flow cytometry analysis of peripheral blood lymphocytes was performed at baseline and at the end of treatment. In HCV-infected patients with lymphoproliferative disorders, we evaluated immunoglobulin (Ig) light chain kappa/lambda ratio variations as a measure of monoclonal B-cell response to antiviral therapy. Healthy volunteers were enrolled as controls. A total of 29 patients were included, nine with and 20 without lymphoproliferative disorders. Sustained virological response was achieved in 29 of 29 patients. We observed a significant reduction in the B-cell compartment (39% global reduction) in eight of nine HCV-infected patients with lymphoproliferative disorders after viral clearance. We recognized the same trend, even if less pronounced, in HCV-infected patients without lymphoproliferative disorders (9% global reduction). Among HCV-infected patients with lymphoproliferative disorders, three showed an improvement/normalization of the immunoglobulin light chain ratio, whereas in the remaining six patients monoclonal B cells persisted to be clonally restricted even 1 year after the end of treatment. Our data show that DAAs treatment can be effective in reducing the frequency of pathological B cells in the peripheral blood of HCV-infected patients affected by HCV-associated lymphoproliferative disorders; however, monoclonal populations can persist after viral eradication. PMID- 28643452 TI - Emerging Nanotechnology and Advanced Materials for Cancer Radiation Therapy. AB - Radiation therapy (RT) including external beam radiotherapy (EBRT) and internal radioisotope therapy (RIT) has been widely used for clinical cancer treatment. However, owing to the low radiation absorption of tumors, high doses of ionizing radiations are often needed during RT, leading to severe damages to normal tissues adjacent to tumors. Meanwhile, the RT efficacies are limited by different mechanisms, among which the tumor hypoxia-associated radiation resistance is a well-known one, as there exists hypoxia inside most solid tumors while oxygen is essential to enhance radiation-induced DNA damages. With the development in nanotechnology, there have been great interests in using nanomedicine strategies to enhance radiation responses of tumors. Nanomaterials containing high-Z elements to absorb radiation rays (e.g. X-ray) can act as radio-sensitizers to deposit radiation energy within tumors and promote treatment efficacy. Nanoscale carriers are able to deliver therapeutic radioisotopes into tumors for internal RIT, or chemotherapeutic drugs for synergistically combined chemo-radiotherapy. As uncovered in recent studies, the tumor microenvironment could be modulated by various nanomedicine approaches to overcome hypoxia-associated radiation resistance. Herein, the authors will summarize the applications of nanomedicine for RT cancer treatment, and pay particular attention to the latest development of 'advanced materials' for enhanced cancer RT. PMID- 28643453 TI - Small-Molecule Inhibitors of the Tumor Suppressor Fhit. AB - The tumor suppressor Fhit and its substrate diadenosine triphosphate (Ap3 A) are important factors in cancer development and progression. Fhit has Ap3 A hydrolase activity and cleaves Ap3 A into adenosine monophosphate (AMP) and adenosine diphosphate (ADP); this is believed to terminate Fhit-mediated signaling. How the catalytic activity of Fhit is regulated and how the Fhit?Ap3 A complex might exert its growth-suppressive function remain to be discovered. Small-molecule inhibitors of the enzymatic activity of Fhit would provide valuable tools for the elucidation of its tumor-suppressive functions. Here we describe the development of a high-throughput screen for the identification of such small-molecule inhibitors of Fhit. Two clusters of inhibitors that decreased the activity of Fhit by at least 90 % were identified. Several derivatives were synthesized and exhibited in vitro IC50 values in the nanomolar range. PMID- 28643454 TI - Polar zoobenthos blue carbon storage increases with sea ice losses, because across-shelf growth gains from longer algal blooms outweigh ice scour mortality in the shallows. AB - One of the major climate-forced global changes has been white to blue to green; losses of sea ice extent in time and space around Arctic and West Antarctic seas has increased open water and the duration (though not magnitude) of phytoplankton blooms. Blueing of the poles has increases potential for heat absorption for positive feedback but conversely the longer phytoplankton blooms have increased carbon export to storage and sequestration by shelf benthos. However, ice shelf collapses and glacier retreat can calve more icebergs, and the increased open water allows icebergs more opportunities to scour the seabed, reducing zoobenthic blue carbon capture and storage. Here the size and variability in benthic blue carbon in mega and macrobenthos was assessed in time and space at Ryder and Marguerite bays of the West Antarctic Peninsula (WAP). In particular the influence of the duration of primary productivity and ice scour are investigated from the shallows to typical shelf depths of 500 m. Ice scour frequency dominated influence on benthic blue carbon at 5 m, to comparable with phytoplankton duration by 25 m depth. At 500 m only phytoplankton duration was significant and influential. WAP zoobenthos was calculated to generate ~107 , 4.5 * 106 and 1.6 * 106 tonnes per year (between 2002 and 2015) in terms of production, immobilization and sequestration of carbon respectively. Thus about 1% of annual primary productivity has sequestration potential at the end of the trophic cascade. Polar zoobenthic blue carbon capture and storage responses to sea ice losses, the largest negative feedback on climate change, has been underestimated despite some offsetting of gain by increased ice scouring with more open water. Equivalent survey of Arctic and sub-Antarctic shelves, for which new projects have started, should reveal the true extent of this feedback and how much its variability contributes to uncertainty in climate models. PMID- 28643455 TI - Pathways governing development of stem cell-derived pancreatic beta cells: lessons from embryogenesis. AB - The loss of functional beta cells leads to development of diabetes. Several studies have shown that beta cells are specified through several stages of progenitors during pancreas development, each stage defined by the expression of specific transcription factors (TFs). Understanding signalling pathways that control the differentiation and specification processes during embryogenesis will facilitate efforts to obtain functional beta cells in vitro. Our current knowledge of the mechanisms involved in pancreatic beta cell development and survival under normal or diabetic conditions has come largely from animal studies. However, there are marked differences in islet structure and physiological properties between humans and animals, and not all phenotypes of human diabetes can be recapitulated in animal models. Therefore, human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced PSCs (hiPSCs) offer a great opportunity for increasing our understanding of the pathways regulating human pancreatic beta-cell development and survival. Furthermore, hPSCs provide a renewable source of functional pancreatic beta cells for cell replacement therapy as well as disease modelling. Herein, we discuss the signalling pathways involved in the development of pancreatic beta cells during embryogenesis. Additionally, we describe how these pathways are manipulated in vitro to differentiate hPSCs into functional beta cells. Finally, we highlight the progress that has been made for the applications of those cells in treating and modelling diabetes. PMID- 28643456 TI - IRF6 expression in basal epithelium partially rescues Irf6 knockout mice. AB - BACKGROUND: Mutations in IRF6, CHUK (IKKA), and RIPK4 can lead to a disease spectrum that includes cutaneous, limb, and craniofacial malformations. Loss of these alleles in the mouse leads to perinatal lethality and severe cutaneous, limb, and craniofacial defects also. Genetic rescue in the mouse has been shown for Ikka and Ripk4. RESULTS: Here, we show partial genetic rescue of Irf6 knockout embryos using the KRT14 promoter to drive Irf6 expression in the basal epithelium. In contrast to Irf6 knockout embryos, rescue embryos survive the immediate perinatal period. Macroscopic examination reveals rescue of skin adhesions between the axial and appendicular skeleton. Unexpectedly, KRT14-driven Irf6 expression does not completely rescue orofacial clefting and adhesions between the palate and tongue, suggesting the importance of cell-autonomous IRF6 expression in periderm. Like knockout embryos, Irf6 rescue embryos also have persistent esophageal adhesions, which likely contribute to postnatal demise. CONCLUSIONS: Together, these data suggest that targeted expression of IRF6 can significantly reduce disease severity, but that a minimum level of Irf6 in both periderm and basal epithelial cells is necessary for orofacial development. Therefore, homologous human and mouse phenotypes are observed for IRF6, IKKA, and RIPK4. In this work, we show that altering the expression level of IRF6 dramatically modified this phenotype in utero. Developmental Dynamics 246:670 681, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28643457 TI - Eradication of hepatitis C virus profoundly prolongs survival in hepatocellular carcinoma patients receiving transarterial chemoembolization. AB - Adjuvant pegylated interferon plus ribavirin treatment (PegIFN/RBV) reduces recurrence and prolongs survival in early stage hepatocellular carcinoma (HCC) patients with chronic hepatitis C (CHC) infection receiving resection or ablation. However, the impact of antiviral therapy in intermediate and advanced stage of CHC-HCC patients is uncertain. This study aimed to investigate the impact PegIFN/RBV treatment on recurrence-free interval and survival in patients with HCC receiving transarterial chemoembolization (TACE). From 2010 to 2013, 274 CHC patients from a 1073 patient-based cohort composed of freshly diagnosed HCC and receiving TACE treatment the Chang Gung Memorial Hospital, Linkou Medical Center were recruited. Propensity score matching (PSM) (age, gender, AST to Platelet Ratio Index (APRI), tumour size, tumour number and Child-Turcotte-Pugh score) with the ratio 1:2 for patients with and without PegIFN/RBV treatment was performed. Statistics were performed with SPSS V.20 (IBM, USA). After matching, 153 patients were analysed and 27 patients (17.6%) achieved sustained virologic response (SVR). The 2-year cumulative overall survival rate and recurrence-free survival rate among patients with SVR, non-SVR, and untreated were 85.2% vs 58.3% vs 69.6% (P=.001) and 73.3% vs 53.8% vs 58.5% (P=.013). By Cox regression analysis, non-SVR, untreated, increase CTP score and nonresponder to TACE were independent factors related to mortality. The SVR achieved by PegIFN/RBV treatment markedly improves survival and reduces tumour recurrence in CHC-HCC patients receiving TACE treatment after complete response. PMID- 28643458 TI - Treatment outcomes for Hodgkin lymphoma: First report from the Brazilian Prospective Registry. AB - Data about Hodgkin lymphoma (HL) in developing countries are scarce and suggest the existence of substantial disparities in healthcare and outcomes in large areas of the world. In 2009, a prospective registry of HL was implemented in Brazil. Web-based data were contributed by 20 institutions across the country participating in the Brazilian Prospective Hodgkin's Lymphoma Registry. The aim of this study was to present the clinical features and outcomes of newly diagnosed patients with HL aged 13 to 90 years. Multivariate Cox regression models were used to estimate progression-free (PFS) and overall survival (OS) by clinical factors. A total of 674 patients with classical HL were analysed, with a median follow-up of 37 months. Median age was 30 years (13-90). The median time from the onset of symptoms to diagnosis was 6 months (0-60). Only 6% of patients had early favourable disease, while 65% had advanced disease. Stage IVB was present in 26% and a high-risk International Prognostic Score in 38%. Doxorubicin, bleomycin, vinblastine, and dacarbazine was used in 93%. The median dose of radiotherapy was 36 Gy for localized disease and 32 Gy for advanced disease. The 3 year PFS in early favourable, early unfavourable, and advanced disease were 95%, 88%, and 66%, respectively. High-risk International Prognostic Score, advanced disease, and age greater than or equal to 60 were independently associated with poorer PFS and OS; performance status greater than or equal to 2 was also associated with a poorer OS. Poor-risk patients predominated. Radiation doses for localized disease appear higher than current recommendations. Outcomes appear inferior in developing countries than in developed countries. Delayed diagnosis is probably a major factor underlying these findings. Scattered reports from developing nations suggest that many aspects of standard care in developed countries remain unmet needs for populations living in developing countries. The present report contributes to this body of data, with a proper description of what is currently achieved in urban areas in Brazil. PMID- 28643460 TI - Periodic limb movement in sleep and sickle cell disease: a neglected association? AB - High frequency of periodic limb movements in sleep (PLMS) has been described among children with sickle cell disease (SCD), but there is little information about PLMS among adults with SCD. We aim to determine the frequency of PLMS among adults with SCD and to identify possible associations with iron status and haemolytic parameters. We analysed polysomnography on 99 adults: 74 with sickle cell anaemia (HbSS), 19 with HbSC (double heterozygosis HbS and HbC) and 6 with HbS-beta thalassaemia. Laboratory data were collected close to the time of the polysomnography examination. The prevalence of PLMS > 5/h was 70% and of PLMS > 15/h 36%, in the total group of patients. No differences were observed regarding gender, use of hydroxyurea and iron parameters. Logistic regression showed an association between PLMS > 15/h and hemolytic parameters: absolute reticulocyte count (p = 0.03) and unconjugated bilirubin (p = 0.01). Our data suggest that PLMS may be associated with manifestations of greater severity in SCD. PMID- 28643459 TI - Construction of competitive endogenous RNA network reveals regulatory role of long non-coding RNAs in type 2 diabetes mellitus. AB - Increasing epidemic of type 2 diabetes mellitus (T2DM) and its comorbidities makes it urgent to understand the pathogenesis and regulatory mechanism. However, little is known about the regulatory role of lncRNAs in diabetes. Here, we constructed a T2DM-related competitive endogenous RNA (ceRNA) network (DMCN) to explore biological function of lncRNAs during the development of diabetes mellitus. This network contained 351 nodes including 98 mRNAs, 86 microRNAs and 167 lncRNAs. Functional analysis showed that the mRNAs in DMCN were annotated into some diabetes-related pathways. Furthermore, mTOR-centred subnetwork was extracted and ncRNA-involved mTOR pathway was established. Finally, we validated that NEAT1 was potentially communicated with mTOR signalling target protein mLST8 via the association with miR-181b. These findings provide significant insight into lncRNA regulatory network in T2DM. PMID- 28643461 TI - Single-Enzyme Biofuel Cells. AB - Herein, we demonstrate that the intramolecular electron transfer within a single enzyme molecule is an important alternative pathway that can be harnessed to generate electricity. By decoupling the redox reactions within a single type of enzyme (for example, Trametes versicolor laccase), we harvested electricity efficiently from unconventional fuels including recalcitrant pollutants (for example, bisphenol A and hydroquinone) in a single-laccase biofuel cell. The intramolecular electron-harnessing concept was further demonstrated with other enzymes, including power generation during CO2 bioconversion to formate catalyzed by formate dehydrogenase from Candida boidinii. The novel single-enzyme biofuel cell is shown to have potential for utilizing wastewater as a fuel as well as for generating energy while driving bioconversion of chemical feedstock from CO2 . PMID- 28643462 TI - Selenium-Doped Carbon Quantum Dots for Free-Radical Scavenging. AB - Heteroatom doping is an effective way to adjust the fluorescent properties of carbon quantum dots. However, selenium-doped carbon dots have rarely been reported, even though selenium has unique chemical properties such as redox responsive properties owing to its special electronegativity. Herein, a facile and high-output strategy to fabricate selenium-doped carbon quantum dots (Se CQDs) with green fluorescence (quantum yield 7.6 %) is developed through the hydrothermal treatment of selenocystine under mild conditions. Selenium heteroatoms endow the Se-CQDs with redox-dependent reversible fluorescence. Furthermore, free radicals such as . OH can be effectively scavenged by the Se CQDs. Once Se-CQDs are internalized into cells, harmful high levels of reactive oxygen species (ROS) in the cells are decreased. This property makes the Se-CQDs capable of protecting biosystems from oxidative stress. PMID- 28643463 TI - Effect of pH on dentin protease inactivation by carbodiimide. AB - A water-soluble crosslinking agent, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), has been used as a pretreatment of acid-etched dentin to inactivate matrix-bound endogenous dentin proteases. The aim of this study was to evaluate the effect of pH on the inactivation capacity of EDC. Demineralized dentin beams (1 * 2 * 6 mm) were divided into six groups (n = 8 per group). Then, EDC (0.3 M) was solubilized in distilled water with pH of 2, 4, 6, 7, 9, or 11. Control EDC was solubilized in 0.1 M 2-(N-morpholino) ethanesulfonic acid (MES) buffer and its pH was adjusted to 6. The dentin beams were pretreated for 1 min with EDC at each pH or with EDC in MES buffer at pH 6.0 and then incubated in 1 ml of simulated body fluid (pH 7.2) for 1, 3, 7, or 14 d. Untreated beams served as controls. At each study time-point, the dry mass of dentin beams was assessed and the incubation media were analyzed for carboxyterminal telopeptide of type-I collagen (ICTP) and C-terminal telopeptide of type I collagen (CTX) using specific ELISAs. Data were subjected to repeat-measures anova. The results of the study indicated that specimens pretreated with EDC in MES buffer showed the lowest collagen degradation in terms of mass loss and release of telopeptides, while specimens pretreated in alkaline media showed the highest collagen degradation. This study indicates that the pH of the EDC solution plays an important role in the stability of dentin protease inactivation. PMID- 28643464 TI - Adiponectin Isoform Patterns in Ethnic-Specific ADIPOQ Mutation Carriers: The IRAS Family Study. AB - OBJECTIVE: Adiponectin is found in human serum in three groups of multimers (high molecular weight [HMW], medium molecular weight [MMW], and low molecular weight [LMW]). Two ethnic-specific variants in ADIPOQ, G45R (Hispanic-Americans) and R55C (African-Americans), were previously reported. Although carriers of both variants had mean adiponectin levels <= 20% of those of noncarriers, they were not clinically different from noncarriers. To compare carriers of both variants and noncarriers, relative quantification of adiponectin isoforms to total adiponectin was performed on serum samples. METHODS: The multimeric patterns of serum adiponectin in G45R carriers (n = 23), R55C carriers (n = 3), and Hispanic- and African-American noncarriers (n = 84 and 44, respectively) from the Insulin Resistance Atherosclerosis Family Study were explored using native Western blotting and densitometry. RESULTS: Serum samples from carriers showed an absence of the HMW isoform and a marked reduction in the MMW isoform but an approximate twofold increase in the amount of the LMW isoform. Thus, individuals making only LMW adiponectin are metabolically normal. CONCLUSIONS: The results contrast with the proposed biological importance of the HMW multimer. This suggests that the LMW isoform may functionally compensate for some of the loss or reduction of the higher-order multimers in carriers of the G45R and R55C mutations. PMID- 28643465 TI - Severe hemolysis after plasma transfusion in a neonate with necrotizing enterocolitis, Clostridium perfringens infection, and red blood cell T polyagglutination. AB - BACKGROUND: Red blood cell (RBC) Thomsen-Friedenreich antigen exposure (T activation) in infants with necrotizing enterocolitis (NEC) has occasionally been associated with posttransfusional intravascular hemolysis thought to be due to anti-T antibodies in the donor plasma. STUDY DESIGN AND METHODS: We describe an infant with NEC and Clostridium perfringens infection complicated by severe hemolysis after plasma transfusion. After this case, infants with confirmed NEC were prospectively evaluated for T activation. We checked for hemolysis in patients with T activation receiving plasma-containing blood products. RESULTS: The infant had received 80 mL of fresh-frozen plasma (FFP). His RBCs displayed strong T activation, and agglutination was observed with four of six ABO compatible FFP units. A direct antiglobulin test was negative. IgM-class anti-T antibodies were present in small amounts (titer of 8) in the transfused FFP. Anti T antibodies from the blood donor were not hemolytic in vitro. In the prospective study, T activation was observed in three of 28 infants with NEC (11%). One infant presented moderate T activation and two infants presented very strong T activation but only moderate decreases in sialic acid expression on the RBC membrane. These three infants presented no signs of hemolysis after transfusion with unwashed blood products or FFP. CONCLUSION: Anti-T antibodies are unlikely to be the etiologic factor for the hemolytic reactions observed in infants with NEC and T activation. Massive RBC desialylation and the direct action of bacterial toxins are more probable causes. Strict avoidance of plasma-containing blood products does not seem justified in these infants. PMID- 28643468 TI - Eltrombopag use in a patient with Wiskott-Aldrich syndrome. AB - Wiskott-Aldrich syndrome (WAS) is an inherited X-linked disorder characterized by microthrombocytopenia, immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) is the treatment of choice. Eltrombopag, a thrombopoietin receptor agonist, may be useful to prevent bleeding while awaiting HSCT. We present a case of a male with WAS, profound thrombocytopenia, and bleeding diathesis successfully managed with eltrombopag before HSCT. Eltrombopag was given for 32 weeks obtaining a stable platelet count without any platelet transfusion. The patient did not experience any bleeding symptom. Eltrombopag may be a suitable therapeutic option for patients with WAS and severe thrombocytopenia as "bridge" to definitive cure. PMID- 28643467 TI - A Core-Shell-Satellite Structured Fe3 O4 @g-C3 N4 -UCNPs-PEG for T1 /T2 -Weighted Dual-Modal MRI-Guided Photodynamic Therapy. AB - Reactive oxygen species (ROS) produced in the specific tumor site plays the key role in photodynamic therapy (PDT). Herein, a multifunctional nanoplatform is designed by absorbing ultrasmall upconversion nanoparticles (UCNPs) on mesoporous graphitic-phase carbon nitride (g-C3 N4 ) coated superparamagnetic iron oxide nanospheres, then further modified with polyethylene glycol (PEG)molecules (abbreviated as Fe3 O4 @g-C3 N4 -UCNPs-PEG). The inert g-C3 N4 layer between Fe3 O4 core and outer UCNPs can substantially depress the quenching effect of Fe3 O4 on the upconversion emission. Upon near-infrared (NIR) laser irradiation, the UCNPs convert the energy to the photosensitizer (g-C3 N4 layer) through fluorescence resonance energy transfer process, thus producing a vast amount of ROS. In vitro experiment exhibits an obvious NIR-triggered cell inhibition due to the cellular uptake of nanoparticles and the effective PDT efficacy. Notably, this platform is responsive to magnetic field, which enables targeted delivery under the guidance of an external magnetic field and supervises the therapeutic effect by T1 /T2 -weighted dual-modal magnetic resonance imaging. Moreover, in vivo therapeutic effect reveals that the magnetism guided accumulation of Fe3 O4 @g-C3 N4 -UCNPs-PEG can almost trigger a complete tumor inhibition without any perceived side effects. The experiments emphasize that the excellent prospect of Fe3 O4 @g-C3 N4 -UCNPs-PEG as a magnetic targeted platform for PDT application. PMID- 28643466 TI - Anemonin attenuates osteoarthritis progression through inhibiting the activation of IL-1beta/NF-kappaB pathway. AB - The osteoarthritis (OA) progression is now considered to be related to inflammation. Anemonin (ANE) is a small natural molecule extracted from various kinds of Chinese traditional herbs and has been shown to inhibiting inflammation response. In this study, we examined whether ANE could attenuate the progression of OA via suppression of IL-1beta/NF-kappaB pathway activation. Destabilization of the medial meniscus (DMM) was performed in 10-week-old male C57BL/6J mice. ANE was then intra-articularly injected into joint capsule for 8 and 12 weeks. Human articular chondrocytes and cartilage explants challenged with interleukin-1beta (IL-1beta) were treated with ANE. We found that ANE delayed articular cartilage degeneration in vitro and in vivo. In particular, proteoglycan loss and chondrocyte hypertrophy were significantly decreased in ANE -treated mice compared with vehicle-treated mice. ANE decreased the expressions of matrix metalloproteinase-13 (MMP13), A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), collagen X (Col X) while increasing Aggrecan level in murine with DMM surgery. ANE treatment also attenuated proteoglycan loss in human cartilage explants treated with IL-1beta ex vivo. ANE is a potent protective molecule for OA; it delays OA progression by suppressing ECM loss and chondrocyte hypertrophy partially by suppressing IL-1beta/NF-kappaB pathway activation. PMID- 28643469 TI - ATRA Signaling Regulates the Expression of COL9A1 through BMP2-WNT4-RUNX1 Pathway in Antler Chondrocytes. AB - Although all-trans retinoic acid (ATRA) is involved in the regulation of cartilage growth and development, its regulatory mechanisms remain unknown. Here, we showed that ATRA could induce the expression of COL9A1 in antler chondrocytes. Silencing of cellular retinoic acid binding protein 2 (CRABP2) could impede the ATRA-induced upregulation of COL9A1, whereas overexpression of CRABP2 presented the opposite effect. RARalpha agonist Am80 induced the expression of COL9A1, whereas treatment with RARalpha antagonist Ro 41-5253 or RXRalpha small interfering RNA (siRNA) caused an obvious blockage of ATRA on COL9A1. In antler chondrocytes, CYP26A1 and CYP26B1 weakened the sensitivity of ATRA to COL9A1. Simultaneously, Bone morphogenetic protein 2 (BMP2) and WNT4 mediated the regulation of ATRA on COL9A1 expression. Knockdown of WNT4 could abrogate the inhibitory effect of BMP2 overexpression on COL9A1. Conversely, constitutive expression of WNT4 reversed the upregulation of COL9A1 elicited by BMP2 siRNA. Together these data indicated that WNT4 might act downstream of BMP2 to mediate the effect of ATRA on COL9A1 expression. Further analysis evidenced that attenuation of runt-related transcription factor 1 (RUNX1) could prevent the stimulation of ATRA on COL9A1 expression, while exogenous rRUNX1 further enhanced this effectiveness. Moreover, RUNX1 might serve as an intermediate to mediate the regulation of BMP2 and WNT4 on COL9A1 expression. Collectively, ATRA signaling might regulate the expression of COL9A1 through BMP2-WNT4-RUNX1 pathway. PMID- 28643470 TI - The association of hospital governance with innovation in Taiwan. AB - Hospitals in Taiwan are facing major changes and innovation is increasingly becoming a critical factor for remaining competitive. One determinant that can have a significant impact on innovation is hospital governance. However, there is limited prior research on the relationship between hospital governance and innovation. The purpose of this study is to propose a conceptual framework to hypothesize the relationship between governance mechanisms and innovation and to empirically test the hypotheses in hospital organizations. We examine the relationship between governance mechanisms and innovation using data on 102 hospitals in Taiwan from the Taiwan Joint Commission on Hospital Accreditation and Quality Improvement. We model governance mechanisms using board structure, information transparency and strategic decision-making processes. For our modeling and data analysis we use measurement and structural models. We find that in hospital governance, information transparency and strategic decision making did impact innovation. However, governance structure did not. To facilitate innovation, hospital boards can increase information transparency and improve the decision-making process when considering strategic investments in innovative initiatives. To remain competitive, hospital boards need to develop and monitor indices that measure hospital innovation to ensure ongoing progress. PMID- 28643471 TI - Molecular Self-Assembly Fabrication and Carrier Dynamics of Stable and Efficient CH3 NH3 Pb(1-x) Snx I3 Perovskite Solar Cells. AB - The Sn-based perovskite solar cells (PSCs) provide the possibility of swapping the Pb element toward developing toxic-free PSCs. Here, we innovatively employed a molecular self-assembly approach to obtain a series CH3 NH3 Pb(1-x) Snx I3 (0<=x<=1) perovskite thin films with full coverage. The optimized planar CH3 NH3 Pb0.75 Sn0.25 I3 PSC with inverted structure was consequently realized with a maximum power conversion efficiency (PCE) over 14 %, which displayed a stabilized power output (SPO) over 12 % within 200 s at 0.6 V forward bias. Afterward, we investigated the factors that limited the efficiency improvement of hybrid Sn-Pb PSCs, and analyzed the possible reason of the hysteresis effect occurred even in the inverted structure cell. Particularly, the oxidation of hybrid Sn-Pb perovskite thin film was demonstrated to be the main reason that limited its further efficiency improvement. The imbalance of charge transport was intensified, which was associated with the increased hole defect-state density and decreased electron defect-state density after Sn was introduced. This study helps tackle the intractable issue regarding the toxic Pb in perovskite devices and is a step forward toward realizing lead-free PSCs with high stability and efficiency. PMID- 28643472 TI - Phosphaborenes: Accessible Reagents for the Synthesis of C-C/P-B Isosteres. AB - Formal exchange of C=C units with isoelectronic B=N or B=P units can provide access to molecules with unique electronic or chemical properties. Herein, we report the simple solution-phase generation of highly reactive phosphaborenes, RP=BR, and demonstrate their use for the introduction of P=B units into organic systems. Ring opening of a P-B-containing cyclobutene isostere provided access to unique 1,4-boraphosphabutadiene systems with conjugated main-group multiple bonds. PMID- 28643474 TI - Long-term failure of Amplatzer plugs in the treatment of aortic pathology. AB - We present two cases of Amplatzer(r) device deployment that exhibited long-term failure necessitating surgical correction. The first case illustrates recanalization of a ruptured Valsalva aneurysm with worsening aortic insufficiency after percutaneous repair with the Amplatzer Vascular Plugs and Amplatzer duct occluder, while the second case illustrates recanalization after deployment of the Amplatzer septal occluder in a patient with a pseudoaneursym in a bovine aorta after type I aortic dissection repair. These two cases illustrate the potential long-term complications and limitations in durability with these devices. PMID- 28643473 TI - Can the propensity of protein crystallization be increased by using systematic screening with metals? AB - Protein crystallization is one of the major bottlenecks in protein structure elucidation with new strategies being constantly developed to improve the chances of crystallization. Generally, well-ordered epitopes possessing complementary surface and capable of producing stable inter-protein interactions generate a regular three-dimensional arrangement of protein molecules which eventually results in a crystal lattice. Metals, when used for crystallization, with their various coordination numbers and geometries, can generate such epitopes mediating protein oligomerization and/or establish crystal contacts. Some examples of metal mediated oligomerization and crystallization together with our experience on metal-mediated crystallization of a putative rRNA methyltransferase from Sinorhizobium meliloti are presented. Analysis of crystal structures from protein data bank (PDB) using a non-redundant data set with a 90% identity cutoff, reveals that around 67% of proteins contain at least one metal ion, with ~14% containing combination of metal ions. Interestingly, metal containing conditions in most commercially available and popular crystallization kits generally contain only a single metal ion, with combinations of metals only in a very few conditions. Based on the results presented in this review, it appears that the crystallization screens need expansion with systematic screening of metal ions that could be crucial for stabilizing the protein structure or for establishing crystal contact and thereby aiding protein crystallization. PMID- 28643475 TI - Tailoring of physicochemical properties of nanocarriers for effective anti-cancer applications. AB - Nanotechnology has emerged strongly as a viable option to overcome the challenge of early diagnosis and effective drug delivery, for cancer treatment. Emerging research articles have expounded the advantages of using a specific type of nanomaterial-based system called as "nanocarriers," for anti-cancer therapy. The nanocarrier system is used as a transport unit for targeted drug delivery of the therapeutic drug moiety. In order for the nanocarriers to be effective for anticancer therapy, their physicochemical parameter needs to be tuned so that bio functionalisation can be achieved to (1) allow drugs being attached to the substrate and for their controlled release, (2) ensure the stability of the nanocarrier up to the point of delivery, and (3) clearance of the nanocarrier after the delivery. It is therefore envisaged that tailoring of the physicochemical properties of nanocarriers can greatly influence their reactivity and interaction in the biological milieu, and this is becoming an important parameter for increasing the efficacy of cancer therapy. This review emphasizes the importance of physicochemical properties of nanocarriers, and how they influence its usage as chemotherapeutic drug carriers. The goal of this review is to present a correlation between the physicochemical properties of the nanocarriers and its intended action, and how their design based on these properties can enhance their cancer combating abilities while minimizing damage to the healthy tissues. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2906-2928, 2017. PMID- 28643476 TI - Low leptin concentration may identify heart failure patients with central sleep apnea. AB - Low leptin concentration has been shown to be associated with central sleep apnea in heart failure patients. We hypothesized that low leptin concentration predicts central sleep apnea. Consecutive ambulatory New York Heart Association (NYHA) classes I-IV heart failure patients were studied prospectively, including measurement of serum leptin, echocardiography and polysomnography. Sleep apnea was defined by type (central/mixed/obstructive) and by apnea-hypopnea index >=5 by polysomnography. Subjects were divided into four groups by polysomnography: (1) central sleep apnea, (2) mixed apnea, (3) no apnea and (4) obstructive sleep apnea. Fifty-six subjects were included. Eighteen subjects were diagnosed with central sleep apnea, 15 with mixed apnea, 12 with obstructive apnea and 11 with no sleep apnea. Leptin concentration was significantly lower in central sleep apnea compared to obstructive apnea (8 +/- 10.7 ng mL-1 versus 19.7 +/- 14.7 ng mL-1 , P ? 0.01) or no sleep apnea (8 +/- 10.7 ng mL-1 versus 17.1 +/- 8.4 ng mL 1 , P ? 0.01). Logistic regression showed leptin to be associated independently with central sleep apnea [odds ratio (OR): 0.19; 95% confidence interval (CI): 0.06-0.62; area under the curve (AUC): 0.80, P < 0.01]. For the detection of central sleep apnea, a cut-off value for leptin concentration 5 ng mL-1 yielded a sensitivity of 50% and specificity of 89%. In conclusion, a low leptin concentration may have utility for the screening of heart failure patients for central sleep apnea. PMID- 28643477 TI - Red wine polyphenols do not improve obesity-associated insulin resistance: A randomized controlled trial. AB - Preclinical studies have suggested that polyphenols extracted from red wine (RWPs) favourably affect insulin sensitivity, but there is controversy over whether RWPs exert similar effects in humans. The aim of the present study was to determine whether RWPs improve insulin sensitivity in obese volunteers. Obese (body mass index >30 kg/m2 ) volunteers were randomly allocated to RWPs 600 mg/d (n = 14) or matched placebo (n = 15) in a double-blind parallel-arm study for 8 weeks. The participants were investigated at baseline and at the end of the study. Insulin sensitivity was determined using a hyperinsulinaemic-euglycaemic clamp (M-value), a mixed-meal test (Matsuda index), and homeostatic model assessment of insulin resistance (HOMA-IR). RWPs elicited no significant changes in M-value (RWP group: median [interquartile range; IQR] baseline 3.0 [2.4; 3.6]; end of study 3.3 [2.4; 4.8] vs placebo group: median [IQR] baseline 3.4 [2.8; 4.4]; end of study 2.9 [2.8; 5.9] mg/kg/min; P = .65), in Matsuda index (RWP group: median [IQR] baseline 3.3 [2.2; 4.8]; end of study 3.6 [2.4; 4.8] vs placebo group: median [IQR] baseline 4.0 [3.0; 6.0]; end of study 4.0 [3.0; 5.2]; P = .88), or in HOMA-IR. This study showed that 8 weeks of RWP supplementation did not improve insulin sensitivity in 29 obese volunteers. Our findings were not consistent with the hypothesis that RWPs ameliorate insulin resistance in human obesity. PMID- 28643478 TI - Critical role of TNF inhibition in combination therapy for elderly mice with atherosclerosis. AB - AIMS: We have previously shown that the combination of pravastatin and sarpogrelate is synergistically beneficial for atherosclerosis. In this study, we investigated whether the pravastatin-sarpogrelate combination was sufficient for treatment in an old mouse model of atherosclerosis or if additional intervention would be needed to address the newly included aging factor and its complex pathophysiological impact on the atherosclerogenic state. We added an anti-TNF biological to the combination treatment cocktail because of the known pathologic roles of TNF in the aging process. METHODS: Sixty-week-old low-density lipoprotein receptor knockout mice were fed a high-fat, high-cholesterol diet and treated with the sarpogrelate and pravastatin combination, etanercept alone, or the triple combination. RESULTS: Although, etanercept alone did not significantly reduce aortic root and atherosclerotic plaque areas, the pravastatin-sarpogrelate combination, and pravastatin-sarpogrelate-etanercept triple therapy significantly reduced the plaque areas. Surprisingly, TNF inhibition was critically required to reduce the plaque areas of aortic roots and the expression of ICAM-1, MOMA-2, and TNF. More importantly, a lipid-lowering effect by pravastatin was observed only in the triple therapy group and not in the pravastatin and sarpogrelate combination group. CONCLUSIONS: These results suggest that TNF-inhibitory intervention should be added to the conventional therapy as a novel strategy for treating the elderly patients with atherosclerosis. PMID- 28643479 TI - Adjuncts and alternatives in the time of antibiotic resistance and in-feed antibiotic bans. PMID- 28643481 TI - Let's talk about flux or the importance of (intracellular) reaction rates. PMID- 28643480 TI - Microbiome yarns: microbial forensics for auditing provenance in global food chains,,. PMID- 28643482 TI - Corrigendum. PMID- 28643483 TI - Cell-Engineered Nanovesicle as a Surrogate Inducer of Contact-Dependent Stimuli. AB - Heterotypic interactions between cells are crucial in various biological phenomena. Particularly, stimuli that regulate embryonic stem cell (ESC) fate are often provided from neighboring cells. However, except for feeder cultures, no practical methods are identified that can provide ESCs with contact-dependent cell stimuli. To induce contact-dependent cell stimuli in the absence of living cells, a novel method that utilizes cell-engineered nanovesicles (CNVs) that are made by extruding living cells through microporous membranes is described. Protein compositions of CNVs are similar to their originating cells, as well as freely diffusible and precisely scalable. Treatment of CNVs produced from three different stromal cells successfully induces the same effect as feeder cultures. The results suggest that the effects of CNVs are mainly mediated by membrane associated components. The use of CNVs might constitute a novel and efficient tool for ESC research. PMID- 28643484 TI - International Organization for Standardization (ISO) 15189. AB - The College of American Pathologists (CAP) offers a suite of laboratory accreditation programs, including one specific to accreditation to the international organization for standardization (ISO) 15189 standard for quality management specific to medical laboratories. CAP leaders offer an overview of ISO 15189 including its components, internal audits, occurrence management, document control, and risk management. The authors provide a comparison of its own ISO 15189 program, CAP 15189, to the CAP Laboratory Accreditation Program. The authors conclude with why laboratories should use ISO 15189. PMID- 28643485 TI - Accuracy Assessment of Five Equations Used for Estimating the Glomerular Filtration Rate in Korean Adults. AB - BACKGROUND: We aimed to assess the performance of the five creatinine-based equations commonly used for estimates of the glomerular filtration rate (eGFR), namely, the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPIcr), Asian CKD-EPI, revised Lund-Malmo (revised LM), full age spectrum (FAS), and Korean FAS equations, in the Korean population. METHODS: A total of 1,312 patients, aged 20 yr and above who underwent 51Cr-EDTA GFR measurements (mGFR), were enrolled. The bias (eGFR-mGFR) and precision (root mean square error [RMSE]) were calculated. The accuracy (P30) of four eGFR equations was compared to that of the CKD-EPIcr equation. P30 was defined as the percentage of patients whose eGFR was within+/-30% of the mGFR. RESULTS: The mean bias (mL.min-1.1.73 m 2) of the five eGFR equation was as follows: CKD-EPIcr, -0.6; Asian CKD-EPI, 2.7; revised LM, -6.5; FAS, -2.5; and Korean FAS, -0.2. The bias of the Asian CKD-EPI, revised LM, and FAS equations showed a significant difference from zero (P<0.001). The RMSE values were as follows: CKD-EPIcr, 15.6; Asian CKD-EPI, 15.6; revised LM, 17.9; FAS, 16.3; and Korean FAS, 15.8. There were no significant differences in the P30 except for the Asian CKD-EPI equation: CKD-EPIcr, 76.6%; Asian CKD-EPI, 74.7%; revised LM, 75.8%; FAS, 76.0%; and Korean FAS, 75.8%. CONCLUSIONS: The CKD-EPIcr and Korean FAS equations showed equivalent analytical and clinical performances in the Korean adult population. PMID- 28643486 TI - Comparison of Intact PTH and Bio-Intact PTH Assays Among Non-Dialysis Dependent Chronic Kidney Disease Patients. AB - BACKGROUND: The third-generation bio-intact parathyroid hormone (PTH) (1-84) assay was designed to overcome problems associated with the detection of C terminal fragments by the second-generation intact PTH assay. The two assays have been compared primarily among dialysis populations. The present study evaluated the correlations and differences between these two PTH assays among patients with chronic kidney disease (CKD) stages 3 to 5 not yet on dialysis. METHODS: Blood samples were collected from 98 patients with CKD stages 3 to 5. PTH concentrations were measured simultaneously by using the second-generation - PTH intact-STAT and third-generation bio-intact 1-84 PTH assays. Other serum biomarkers of bone mineral disorders were also assessed. CKD stage was calculated by using the CKD-Epidemiology Collaboration (EPI) formula. RESULTS: Serum bio intact PTH concentrations were strongly correlated but significantly lower than the intact PTH concentrations (r=0.963, P<0.0001). This finding was consistent among CKD stages 3 to 5. PTH concentrations by both assays (intact and bio-intact PTH) positively correlated with urea (r=0.523, r=0.504; P=0.002, respectively), phosphorus (r=0.532, r=0.521; P<0.0001, respectively) and negatively correlated with blood calcium (r=-0.435, r=-0.476; P<0.0001, respectively), 25(OH) vitamin D, (r=-0.319, r=-0.353; respectively, P<0.0001) and the estimated glomerular filtration rate (r=-0.717, r=-0.688; P<0.0001, respectively). CONCLUSIONS: Among patients with CKD stages 3 to 5 not on dialysis, the bio-intact PTH assay detected significantly lower PTH concentrations compared with intact PTH assay. Additional studies that correlate the diagnosis and management of CKD mineral and bone disorders with bone histomorphometric findings are needed to determine whether bio-intact PTH assay results are better surrogate markers in these early stages of CKD. PMID- 28643487 TI - Proenkephalin, Neutrophil Gelatinase-Associated Lipocalin, and Estimated Glomerular Filtration Rates in Patients With Sepsis. AB - BACKGROUND: Proenkephalin (PENK) has been suggested as a novel biomarker for kidney function. We investigated the diagnostic and prognostic utility of plasma PENK in comparison with neutrophil gelatinase-associated lipocalin (NGAL) and estimated glomerular filtration rates (eGFR) in septic patients. METHODS: A total of 167 septic patients were enrolled: 99 with sepsis, 37 with septic shock, and 31 with suspected sepsis. PENK and NGAL concentrations were measured and GFR was estimated by using the isotope dilution mass spectrometry traceable-Modification of Diet in Renal Disease (MDRD) Study and three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations: CKD-EPI(Cr), CDK-EPI(CysC), and CKD-EPI(Cr-CysC). The PENK, NGAL, and eGFR results were compared according to sepsis severity, presence or absence of acute kidney injury (AKI), and clinical outcomes. RESULTS: The PENK, NGAL, and eGFR results were significantly associated with sepsis severity and differed significantly between patients with and without AKI only in the sepsis group (all P<0.05). PENK was superior to NGAL in predicting AKI (P=0.022) and renal replacement therapy (RRT) (P=0.0085). Regardless of the variable GFR category by the different eGFR equations, PENK showed constant and significant associations with all eGFR equations. Unlike NGAL, PENK was not influenced by inflammation and predicted the 30-day mortality. CONCLUSIONS: PENK is a highly sensitive and objective biomarker of AKI and RRT and is useful for prognosis prediction in septic patients. With its diagnostic robustness and predictive power for survival, PENK constitutes a promising biomarker in critical care settings including sepsis. PMID- 28643488 TI - Multidrug Resistance Mechanisms of Carbapenem Resistant Klebsiella pneumoniae Strains Isolated in Chongqing, China. AB - BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is considered a serious global threat. However, little is known regarding the multidrug resistance (MDR) mechanisms of CRKP. This study investigated the phenotypes and MDR mechanisms of CRKP and identified their clonal characteristics. METHODS: PCR and sequencing were utilized to identify antibiotic resistance determinants. Integron gene cassette arrays were determined by restriction fragment length polymorphism (RFLP) analysis. Multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were used for epidemiological analysis. Plasmids were typed by using a PCR-based replicon typing and analyzed by conjugation and transformation assays. RESULTS: Seventy-eight strains were identified as resistant to at least one carbapenem; these CRKP strains had a high prevalence rate (38.5%, 30/78) of carbapenemase producers. Additionally, most isolates harbored MDR genes, including Extended spectrum beta-lactamases (ESBLs), AmpC, and quinolone and aminoglycoside resistance genes. Loss of porin genes was observed, and Class 1 integron was detected in 66.7% of the investigated isolates. PFGE and MLST results excluded the occurrence of clonal dissemination among these isolates. CONCLUSIONS: A high prevalence of NDM-1 genes encoding carbapenem resistance determinants was demonstrated among the K. pneumoniae isolates. Importantly, this is the first report of bla(NDM-1) carriage in a K. pneumoniae ST1383 clone in China and of a MDR CRKP isolate co-harboring bla(NDM 1), bla(KPC-2), bla(CTX-M), bla(SHV), acc(6')-Ib, rmtB, qnrB, and acc(6')-Ib-cr. PMID- 28643489 TI - Comparison of the Luminex xTAG Respiratory Viral Panel Fast v2 Assay With Anyplex II RV16 Detection Kit and AdvanSure RV Real-Time RT-PCR Assay for the Detection of Respiratory Viruses. AB - BACKGROUND: The accurate and rapid identification of the causative viruses is important for the timely diagnosis and management of respiratory infections. Multiplex molecular diagnostic techniques have been widely adopted to detect respiratory viruses. We compared the results of a newly upgraded, multiplex, molecular bead-based respiratory viral panel (RVP) assay with the results of Anyplex II RV16 detection kit and AdvanSure RV real-time RT-PCR assay. METHODS: We tested 254 respiratory specimens and cultured viral strains using the Luminex xTAG RVP Fast v2 assay (Luminex Molecular Diagnostics, Canada) and Anyplex II RV16 detection kit and compared the results. Specimens showing discordant results between the two assays were tested with a AdvanSure RV real-time RT-PCR assay. RESULTS: Of the 254 respiratory specimens, there was total agreement in the results between the xTAG RVP Fast v2 assay and the other real-time PCR assay in 94.1-100% of the specimens. The agreement levels were relatively low (94.1-97.6%) for specimens of adenovirus, coronavirus NL63, and parainfluenza type 3. In comparison to the other assay, the xTAG RVP Fast v2 assay detected a higher number of parainfluenza type 3 (4 cases) and metapneumovirus (9 cases). CONCLUSIONS: The xTAG RVP Fast v2 assay showed comparable capabilities compared with the other assays; it will be useful for identifying respiratory viral infections in patients with respiratory symptoms. Clinicians should be aware of the characteristics of the assays they use, since different assays show different detectability for each virus. PMID- 28643490 TI - Characterization of Extended-Spectrum beta-Lactamase Genes of Shigella flexneri Isolates With Fosfomycin Resistance From Patients in China. AB - BACKGROUND: The emergence of fosfomycin resistance and extended-spectrum beta lactamase (ESBL) genes is a serious threat to public health and a new challenge in shigellosis treatment. The purpose of this study was to identify fosfomycin resistance and characterize beta-lactamase genes in fos-carrying isolates of Shigella flexneri from patients in China. METHODS: A total of 263 S. flexneri isolates were collected from 34 hospitals in the Anhui Province of China during September 2012-September 2015 and screened for fosA3, fosA, and fosC2 by PCR amplification and sequencing. The fos-carrying isolates were then screened for beta-lactamase genes. The clonal relationships between fosA3-carrying isolates, the transmissibility of fosfomycin resistance, replicon types of plasmids carrying fosfomycin resistance genes and other associated resistance genes were investigated. RESULTS: Twenty-five of the 263 isolates (9.5%) showed resistance to fosfomycin, and 18 (6.8%) were positive for fosA3. None of the isolates was positive for fosA or fosC2. Seventeen of the isolates carrying fosA3 (94%) were CTX-M producers (seven CTX-M-55, five CTX-M-14, and five CTX-M-123), while three (16.7%) were TEM producers (TEM-1).Sixteen (88.9%) fosA3-carrying isolates exhibited multi-drug resistance. The replicon types of the 13 fosA3-carrying plasmids were IncF (n=13), IncHI2 (n=3), IncIl-Ir (n=2), and IncN (n=1). CONCLUSIONS: Our results indicated that fosA3 could spread through plasmids in S. flexneri isolates, along with the bla(CTX-M) and bla(TEM), which facilitate its quick dispersal. To the best of our knowledge, this is the first report of CTX-M 123-type ESBLs in S. flexneri isolates from patients in China. PMID- 28643491 TI - Association of Foxp3 Polymorphism With Allograft Outcome in Kidney Transplantation. AB - BACKGROUND: Forkhead box P3 (Foxp3) is the most reliable marker for regulatory T cells, which play an important role in maintaining renal allograft tolerance. Recently, Foxp3 polymorphisms have been reported to be associated with graft outcome in kidney transplantation. We analyzed the association of Foxp3 polymorphisms with renal allograft outcome. METHODS: Foxp3 polymorphisms (rs3761548 A/C, rs2280883 C/T, rs5902434 del/ATT, and rs2232365 A/G) were tested by PCR with sequence-specific primers (PCR-SSP) in 231 adult kidney transplantation recipients from 1996-2004 at Seoul National University Hospital. RESULTS: Patients with the rs3761548 CC genotype showed better graft survival than those with the AC or AA genotype (log rank test, P=0.03). Patients with the rs3761548 CC genotype also showed a lower rate of recurrence of the original glomerular disease than those with the AC or AA genotype (P=0.01). The frequency of acute rejection (AR) in patients with the rs2280883 TT genotype was lower than that in patients with the rs2280883 CT or CC genotype (26.9% vs 53.3%, P=0.038). Patients with the rs2280883 TT genotype also showed better graft survival than those with the CT or CC genotype (P=0.03). CONCLUSIONS: Foxp3 rs3761548 CC and rs2280883 TT genotypes were associated with superior graft outcome of kidney transplantation. Further studies involving a larger number of patients are needed. PMID- 28643492 TI - Human Papillomavirus Genotype Distribution Among 18,815 Women in 13 Korean Cities and Relationship With Cervical Cytology Findings. AB - BACKGROUND: The prevalence and genotype distribution of Human papillomavirus (HPV) infection vary depending on geographical region and the immunity provided by vaccines. This study aimed to clarify the recent prevalence and genotype distribution of HPV according to age and cervical cytology findings in Korea. METHODS: This study included 18,815 health examinees that underwent cervical cytology and HPV genotyping tests at 16 centers of Korean Association of Health Promotion in 13 cities in Korea, between January 2014 and October 2015. HPV was genotyped by using multiplex PCR (Anyplex II HPV 28, Seegene, Korea), which detects 19 high-risk HPVs (HR-HPV) and nine low-risk HPVs (LR-HPV). RESULTS: Overall HPV prevalence was 27.8%, with 22.2% HR-HPV and 11.4% LR-HPV. The five most common carcinogens were HPV 52 (3.2%), 58 (2.7%), 16 (2.0%), 56 (1.9%), and 51 (1.8%). The five most common HR-HPVs in normal cytology samples were HPV 53, 68, 70, 52, and 58, while HPV 16, 52, 58, 33, and 31 were prevalent in high grade squamous intraepithelial lesions (HSIL). In atypical squamous cells of undetermined significance (ASCUS), the prevalence of HR-HPV varied with age; it was highest in those aged <30 yr, declining to a minimum at age 50-59 yr, and then increasing in older women (P<0.05). CONCLUSIONS: The prevalence and distribution of HR-HPV varied with age and cervical cytology findings. This information would be helpful in the development of cervical cancer prevention policies. PMID- 28643493 TI - Identification of viridans streptococci With Matrix-Assisted Laser Desorption & Ionization Time-of-flight Mass Spectrometry by an In-house Method and a Commercially Available System. AB - Two matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS)-based methods were compared for their ability to identify viridans streptococci. One approach employed a reference database and software developed in-house. All inhouse measurements were performed using an Autoflex II Instrument (Bruker Daltonics GmbH, Germany). The other system, a VITEK-MS (BioMerieux, France) was operated on the commercially available V2.0 Knowledge Base for Clinical Use database. Clinical isolates of viridans streptococci (n=184) were examined. Discrepant results were resolved by 16S rDNA sequencing. Species-level identification percentages were compared by a chi-square test. The in-house method correctly identified 179 (97%) and 175 (95%) isolates to the group and species level respectively. In comparison, the VITEK-MS system correctly identified 145 (79%) isolates to the group and species level. The difference between the two methods was statistically significant at both group and species levels. Using the Autoflex II instrument combined with an extraction method instead of whole cell analysis resulted in more reliable viridans streptococci identification. Our results suggest that combining extraction with powerful analysis software and the careful choice of well-identified strains included into the database was useful for identifying viridans streptococci species. PMID- 28643494 TI - Identification of Pathogenic Variants in the CHM Gene in Two Korean Patients With Choroideremia. AB - Choroideremia is a rare X-linked disorder causing progressive chorioretinal atrophy. Affected patients develop night blindness with progressive peripheral vision loss and eventual blindness. Herein, we report two Korean families with choroideremia. Multimodal imaging studies showed that the probands had progressive loss of visual field with characteristic chorioretinal atrophy, while electroretinography demonstrated nearly extinguished cone and rod responses compatible with choroideremia. Sanger sequencing of all coding exons and flanking intronic regions of the CHM gene revealed a novel small deletion at a splice site (c.184_189+3delTACCAGGTA) in one patient and a deletion of the entire exon 9 in the other. This is the first report on a molecular genetic diagnosis of choroideremia in Korean individuals. Molecular diagnosis of choroideremia should be widely adopted for proper diagnosis and the development of new treatment modalities including gene therapy. PMID- 28643495 TI - Hidden "Preleukemic Phase" of Chronic Myeloid Leukemia Presenting Without Leukocytosis in the Peripheral Blood Unrelated to Chemotherapy in a Patient Diagnosed With Diffuse Large B Cell Lymphoma. PMID- 28643496 TI - WHIM Syndrome With a Novel CXCR4 Variant in a Korean Child. PMID- 28643497 TI - Correlation Between Bone Marrow Blasts Counts With Flow Cytometry and Morphological Analysis in Myelodysplastic Syndromes. PMID- 28643498 TI - Persistence of Group B Streptococcus in the Urogenital Area. PMID- 28643499 TI - Sputasol (Dithiothreitol 0.54%) Improves the Detection of Human Papillomaviruses Using the Cobas 4800 System. PMID- 28643500 TI - Multiple Brain Abscesses Caused by Nocardia asiatica in a Patient With Systemic Lupus Erythematosus: The First Case Report and Literature Review. PMID- 28643501 TI - Complete STK11 Deletion and Atypical Symptoms in Peutz-Jeghers Syndrome. PMID- 28643502 TI - Idiopathic thrombocytopenic purpura: pathogenesis and potential therapeutic approach. AB - BACKGROUND: This study sought to clarify the pathogenesis of idiopathic thrombocytopenic purpura (ITP) and make preliminary investigations regarding a therapeutic approach. METHODS: Enzyme-linked immunosorbent assay was used to establish and analyze the standard curve for interferon (IFN) gamma, interleukin (IL) 4, and IL-17 in order to determine a measurement method for these cytokines. Subsequently, cellular levels of IFN-gamma, IL-4, and IL-17 in the peripheral blood of patients in the treatment group (traditional Chinese medicine) was compared with those in the control group (Western-style care). An ITP mice model was also established and treated with different medications. RESULTS: Th1/Th2 cell quantities in ITP patients were significantly higher than in healthy individuals (P<0.05). Furthermore, IL-17 secreted by Th17 cells was significantly higher in ITP patients than healthy individuals (P<0.01). A combination of traditional Chinese medicine and Western-style care yielded the best treatment effect for ITP mice, followed by Western medicine alone and then Chinese medicine alone. CONCLUSIONS: The experimental results suggested that Th17 cells may be more related to the pathogenesis of ITP, and that application of Western-style care supplemented by traditional Chinese medicine may yield a more optimal treatment for ITP. PMID- 28643503 TI - The use of morphokinetic as a predictor of implantation. AB - In recent years the increased efforts intended for improving future outcomes in the laboratory have focused mostly on the search of additional markers of embryo quality to add up present embryo selection criteria. Time-lapse system involves an alternative tool in assisted reproduction techniques, being able to improve the embryo selection from a dynamic and interactive approach while standard embryo assessment implies a subjective and static morphology evaluation and consequently reducing the information gained for embryo selection, time-lapse technology adds several morphokinetic parameters, providing additional input for embryo evaluation. This further information represents a challenge for a potential improvement in implantation rates and reproductive outcomes. This article focuses on the different time-lapse systems burgeoning on the market and the use of morphokinetics as a predictor of embryo implantation. PMID- 28643505 TI - A case of IgG4-related pseudotumor affecting ethmoid, orbit and anterior skull base. PMID- 28643504 TI - Direct common carotid artery puncture for acute thrombectomy against ischemic stroke. PMID- 28643506 TI - A meningeal fibrosarcoma on the same site of osteodural decompression: a pure coincidence? PMID- 28643507 TI - Yellow fever vaccine: WHO position on the use of fractional doses - June 2017. PMID- 28643508 TI - Global polio eradication: progress towards containment of poliovirus type 2, worldwide 2017. PMID- 28643509 TI - Secondary Copper Smelters as Sources of Chlorinated and Brominated Polycyclic Aromatic Hydrocarbons. AB - The generation of and extent to which chlorinated and brominated polycyclic aromatic hydrocarbons (Cl/Br-PAHs) are formed and released from secondary copper smelters remain unknown. This field study, to our knowledge, is the first to identify secondary copper smelters as new sources of Cl/Br-PAHs. Mass concentrations of ?19Cl-PAHs and ?19Br-PAHs ranged from 5.8 to 271 ng Nm-3 and 0.59 to 52.4 ng Nm-3, respectively. A comparison of Cl/Br-PAH concentrations in stack gas and fly ash from secondary copper smelters indicated that the use of scrap copper as raw material or the addition of coal or heavy oil as reductant may contribute to the elevated formation and emission of Cl/Br-PAHs. Congener profiles of Cl/Br-PAHs in stack gas and fly ash from secondary copper smelters were different with those of Cl/Br-PAHs from waste incinerations and other previously reported sources, thus could be used as possible fingerprints and source apportionments of environmental Cl/Br-PAHs. Atmospheric levels of Cl/Br PAHs in the workplace or smelter surroundings were determined and potential exposures were assessed. Although chlorination of PAHs was previously recognized as an important formation pathway of Cl/Br-PAHs, it was not verified to be the major formation pathway for Cl/Br-PAHs from secondary copper smelters in this study. PMID- 28643510 TI - Characterization of the Saffron Derivative Crocetin as an Inhibitor of Human Lactate Dehydrogenase 5 in the Antiglycolytic Approach against Cancer. AB - Inhibition of lactate dehydrogenase (LDH) represents an innovative approach to tackle cancer because this peculiar glycolytic metabolism is characteristic of most invasive tumor cells. An investigation into the biological properties of saffron extracts led to the discover of their LDH-inhibition properties. In particular, the most important saffron components, crocetin, was found to inhibit LDH (IC50 = 54.9 +/- 4.7 MUM). This carotenoid was independently produced by chemical synthesis, and its LDH-inhibition properties manifested via its antiproliferative activity against two glycolytic cancer cell lines (A549 and HeLa, IC50 = 114.0 +/- 8.0 and 113.0 +/- 11.1 MUM, respectively). The results described in this article suggest that saffron may be a helpful alimentary component in the prevention of cancer that potentially contributes to the efficacy of approved cancer therapies. PMID- 28643511 TI - Exceptionally High Payload of the IR780 Iodide on Folic Acid-Functionalized Graphene Quantum Dots for Targeted Photothermal Therapy. AB - The IR780 iodide (IR780) is recognized as an effective theranostic agent for simultaneous near-infrared fluorescence imaging and photothermal therapy (PTT). However, the rigid chloro-cyclohexenyl ring makes IR780 insoluble in almost all pharmaceutically acceptable solvents, which inevitably limits its clinical application. We report folic acid (FA)-functionalized graphene quantum dots (GQDs FA) containing a large and intact sp2 domain with carboxyl groups around the edge. Such GQDs-FA possess exceptionally high loading capacity for IR780 via strong pi-pi stacking interactions, and the water solubility of IR780 is improved by over 2400-fold after loading onto GQDs-FA (IR780/GQDs-FA). IR780/GQDs-FA with an improved photostability, an enhanced tumor-targeting ability, and a high photothermal conversion efficiency of 87.9% were capable of producing sufficient hyperthermia to effectively kill cancer cells and completely eradicate tumors upon 808 nm laser irradiation. The present IR780/GQDs-FA may open up great opportunities for the effective PTT to treat cancer. PMID- 28643512 TI - Quantitatively Intrinsic Biomimetic Catalytic Activity of Nanocerias as Radical Scavengers and Their Ability against H2O2 and Doxorubicin-Induced Oxidative Stress. AB - Artificial enzymes as radical scavengers show great potentials in treatments of various diseases induced by oxidative stress. Herein, the quantitative analysis indicates that the intrinsic activity of nanocerias for the degradation of radicals is determined by the concentration of surface defects as well as their morphological features. The surface Ce3+ fraction of the CeO2 nanozymes with a similar morphology can be used as a descriptor to index their catalytic activity as radical scavengers. Defect-abundant porous nanorods of ceria (PN-CeO2) with a large surface area (141 m2/g) and high surface Ce3+ fraction (32.8%) deliver an excellent catalytic capability for the degradation of radicals, which is 15.5 times higher than that of Trolox. Results indicate that PN-CeO2 not only provides more surface catalytic centers but also supplies the active site with higher activity. Oxidative stress induced by doxorubicin (Dox), an essential medicine for a wide range of tumors, was used as the model system to evaluate the radical degradation ability of PN-CeO2. Both in vitro cellar (H9c2 cells) and in vivo animal models revealed that PN-CeO2 did not affect the cell and rat growth and was able to alleviate the Dox-induced oxidative stress. Results suggest that the artificial PN-CeO2 nanozymes have potentials to function as an adjuvant medicine during tumor chemotherapy. PMID- 28643513 TI - Photochemical Cleavage of Benzylic C-O Bond Facilitated by an Ortho or Meta Amino Group. AB - The excited state meta effect, also known as the meta-ortho effect, results from selective electron transmission from an electron-donating group to the meta and ortho sites on an aromatic ring in its first excited singlet state. This effect facilitates photochemical cleavage of benzylic C-O or C-N bond to release the corresponding alcohol, carboxylic acid, or amine when an electron-donating amino group is at the meta position, as demonstrated in our recent work of using a 3 diethylaminobenzyl (DEABn) group as an effective photolabile protecting group (PPG). Herein, we demonstrate that an ortho amino group can also facilitate benzylic C-O bond cleavage to release an alcohol or carboxylic acid. However, an amino group at the meta position results in a PPG with better overall chemical and photochemical properties. PMID- 28643514 TI - Nitroalkenes as Latent 1,2-Biselectrophiles - A Multicatalytic Approach for the Synthesis of 1,4-Diketones and Their Application in a Four-Step One-Pot Reaction to Polysubstituted Pyrroles. AB - An NHC-catalyzed nitro-Stetter/elimination/Stetter reaction sequence employs nitroalkenes as latent 1,2-dication synthons providing a novel access to highly useful symmetrical and unsymmetrical 2-aryl substituted 1,4-diketone building blocks from commercially available aldehyde precursors. For less activated (aliphatic) aldehydes, a cooperative catalytic strategy has been developed via the merger of NHC and H-bonding catalysis. To further showcase the versatility of our approach, a great variety of these unprecedented 1,4-diketones are used to efficiently synthesize polysubstituted pyrroles-including those with hetaryl substituents-in good to excellent yields in a multicatalytic metal-free, four step one-pot cascade reaction under mild, yet robust, conditions. PMID- 28643515 TI - Structures of Degradation Products and Degradation Pathways of Aflatoxin B1 by High-Voltage Atmospheric Cold Plasma (HVACP) Treatment. AB - High-voltage atmospheric cold plasma (HVACP) is a novel nonthermal decontamination technology that has potential for use in the food industry. In this study, HVACP was applied to treat pure aflatoxin B1 (AFB1) powder on a glass slide. AFB1 was degraded by 76% using a 5 min HVACP treatment in air having 40% relative humidity. The degradation products of AFB1 were separated, and their molecular formulas were elucidated using liquid-chromatography time-of-flight mass spectrometry (HPLC-TOF-MS). Six main degradation products were observed. The structures of the degradation products were further clarified via orbitrap mass spectrometry by means of fragmentation of the parental ions. Two degradation pathways were proposed on the basis of the structure of the degradation products. Among the six degradation products, two were ozonolysis products of AFB1. The appearance of the other four degradation products indicates that AFB1 was degraded by other reactive species besides ozone that were generated during HVACP treatment. Reactive oxygen gas species are suggested as the major agents for aflatoxin degradation during HVACP treatment. Two degradation pathways of AFB1 by HVACP treatment were proposed. One pathway involves reactions in which H*, OH*, CHO* radicals are added. The other involves epoxidation by HO2* radicals and oxidation of AFB1by the combined effects of the oxidative species OH*, H2O2, and O3. According to the structure-bioactivity relationship of AFB1, the bioactivity of the AFB1 samples subjected to HVACP treatment is significantly reduced because of the disappearance of the C8?C9 double bond in the furofuran ring in all of the major degradation products as well as the modification of the lactone ring, cyclopentanone, and the methoxyl group. PMID- 28643516 TI - Untargeted Comprehensive Two-Dimensional Liquid Chromatography Coupled with High Resolution Mass Spectrometry Analysis of Rice Metabolome Using Multivariate Curve Resolution. AB - In this work, a new strategy for the chemometric analysis of two-dimensional liquid chromatography-high-resolution mass spectrometry (LC * LC-HRMS) data is proposed. This approach consists of a preliminary compression step along the mass spectrometry (MS) spectral dimension based on the selection of the regions of interest (ROI), followed by a further data compression along the chromatographic dimension by wavelet transforms. In a secondary step, the multivariate curve resolution alternating least squares (MCR-ALS) method is applied to previously compressed data sets obtained in the simultaneous analysis of multiple LC * LC HRMS chromatographic runs from multiple samples. The feasibility of the proposed approach is demonstrated by its application to a large experimental data set obtained in the untargeted LC * LC-HRMS study of the effects of different environmental conditions (watering and harvesting time) on the metabolism of multiple rice samples. An untargeted chromatographic setup coupling two different liquid chromatography (LC) columns [hydrophilic interaction liquid chromatography (HILIC) and reversed-phase liquid chromatography (RPLC)] together with an HRMS detector was developed and applied to analyze the metabolites extracted from rice samples at the different experimental conditions. In the case of the metabolomics study taken as example in this work, a total number of 154 metabolites from 15 different families were properly resolved after the application of MCR-ALS. A total of 139 of these metabolites could be identified by their HRMS spectra. Statistical analysis of their concentration changes showed that both watering and harvest time experimental factors had significant effects on rice metabolism. The biochemical insight of the effects of watering and harvesting experimental factors on the changes in concentration of these detected metabolites in the investigated rice samples is attempted. PMID- 28643517 TI - Strategy for Comprehensive Profiling and Identification of Acidic Glycosphingolipids Using Ultra-High-Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry. AB - Acidic glycosphingolipids (AGSLs), which mainly consist of ganglioside and sulfatide moieties, are highly concentrated in the central nervous system. Comprehensive profiling of AGSLs has historically been challenging because of their high complexity and the lack of standards. In this study, a novel strategy was developed to comprehensively profile AGSLs using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Ganglioside isomers with different glycan chains such as GD1a/GD1b were completely separated on a C18 column for the first time to our knowledge, facilitated by the addition of formic acid in the mobile phase. A mathematical model was established to predict the retention times (RTs) of all theoretically possible AGSLs on the basis of the good logarithmic relationship between the ceramide carbon numbers of the AGSLs in the reference material and their RTs. A data set was created of 571 theoretically possible AGSLs, including the ceramide carbon numbers, RTs, and high-resolution quasi-molecular ions. A novel fast identification strategy was established for global AGSL profiling by comparing the high-resolution quasi molecular ions and RTs of the tested peaks to those in the data set of 571 AGSLs. Using this strategy, 199 AGSL candidates were identified in rat brain tissue. MS/MS fragments were further collected for these 199 candidates to confirm their identity as AGSLs. This novel strategy was employed to profile AGSLs in brain tissue samples from control rats and model rats with bilateral common carotid artery (2-VO) cerebral ischemia. Forty AGSLs were significantly different between the control and model groups, and these differences were further interpreted. PMID- 28643518 TI - Mini C-Arm Fluoroscopy: Does Its Configuration Matter for Radiation Exposure to the Surgeon? AB - BACKGROUND: The risk of occupational radiation exposure to the surgeon associated with the use of a mini C-arm has yet to reach a wide consensus. Using a distal radius fracture surgery model, we tested the hypothesis that radiation exposure to the surgeon's critical body parts is independent of mini C-arm configuration. METHODS: An anthropomorphic mannequin (representing the upper body of a 60" male surgeon) was seated at a hand table as if operating on a volar-plated wrist Sawbone model. Thermoluminescent dosimeters measured radiation exposure to the surgeon's eyes, thyroid, chest, hand, and groin from a mini C-arm fluoroscopy unit in 3 commonly used configurations: vertical (source above table), inverted (source below table), and horizontal (with beam parallel to table surface). The fluoroscope scanned the wrist model for 15 continuous minutes in triplicate for each orientation. RESULTS: Radiation to the hand was significantly greatest in all mini C-arm positions compared with all other anatomic sites irrespective of C arm position. Hand radiation exposure was greatest in the horizontal position (2887.09 mrem), versus the vertical and inverted positions (59.79 mrem, 31.10 mrem, P < .001). Eye radiation exposure was significantly greater in the inverted position (2.33 mrem) compared with the vertical (0.67 mrem, P = .024), and horizontal positions (0.33 mrem, P = .012). No significant difference in radiation exposure was found at the thyroid, chest, and groin sites, at each of the 3 C-arm configurations. CONCLUSIONS: The model's hand received almost 1000 times more radiation exposure than all other anatomic sites with statistically greatest radiation exposure sustained in the horizontal position. Eye radiation exposure with the C-arm in the inverted position (below the table) was also significantly greater. PMID- 28643519 TI - Structural Changes in Poly(trimethylene adipate) and Poly(trimethylene succinate) During Melt Crystallization Studied Using In Situ Infrared Spectroscopy. AB - This paper investigates the structural changes occurring in poly(trimethylene adipate) (PTAd) and poly(trimethylene succinate) (PTSu) during melt crystallization using differential scanning calorimetry (DSC) and in situ Fourier transform infrared (FT-IR) spectroscopy. Cooling thermograms revealed that PTAd had a faster crystallization rate than PTSu. Infrared (IR) bands of the two polyesters were assigned by correlating with the IR bands of polymers containing the trimethylene and the diacid segments. The bands at 1478, 1459, 1393, and 1364 cm-1 in PTAd and 1475, 1459, 1393, and 1361 cm-1 in PTSu were designated to the CH2 of the trimethylene segment. Changes in the IR band absorbance intensities of the CH2 and the C-O-C groups were monitored with time during melt crystallization. Structural changes of the trimethylene and diacid segments of PTAd occurred synchronously, while in PTSu the two segments changed sequentially. Normalized band intensities showed a time lag between the trimethylene and succinic acid segments. The acid segment showed a faster change compared to the trimethylene segment. Fourier transform infrared spectroscopy is shown to be a useful technique to study conformational changes during crystallization in polymers. PMID- 28643520 TI - Main Plant Extracts' Active Properties Effective on Scopolamine-Induced Memory Loss. AB - Alzheimer's disease leads to progressive cognitive function loss, which may impair both intellectual capacities and psychosocial aspects. Although the current knowledge points to a multifactorial character of Alzheimer's disease, the most issued pathological hypothesis remains the cholinergic theory. The main animal model used in cholinergic theory research is the scopolamine-induced memory loss model. Although, in some cases, a temporary symptomatic relief can be obtained through targeting the cholinergic or glutamatergic neurotransmitter systems, no current treatment is able to stop or slow cognitive impairment. Many potentially successful therapies are often blocked by the blood-brain barrier since it exhibits permeability only for several classes of active molecules. However, the plant extracts' active molecules are extremely diverse and heterogeneous regarding the biochemical structure. In this way, many active compounds constituting the recently tested plant extracts may exhibit the same general effect on acetylcholine pathway, but on different molecular ground, which can be successfully used in Alzheimer's disease adjuvant therapy. PMID- 28643521 TI - A Novel All-Inside Arthroscopic Technique for Radial-Sided Triangular Fibrocartilage Complex Tears: A Case Report and Review of Literature. AB - BACKGROUND: Triangular fibrocartilage complex (TFCC) injuries are a known cause of ulnar-sided wrist pain. Wrist arthroscopy is the gold standard for diagnosis of these lesions and is becoming a more frequent method of treatment. Isolated radial-sided tears are uncommon and treatment of these lesions is controversial. There are few reports on repair techniques. Here we report on a novel arthroscopic, all-inside technique for traumatic radial-sided TFCC tears that resulted in full range of motion, significant improvement in pain, and ultimately return to sport. METHODS: This is a single case report describing an all-inside, arthroscopic repair of a radial-sided TFCC tear. The techniques and postoperative protocol are discussed. Clinical outcomes were reported at final follow-up of 3.5 months. RESULTS: At final follow-up, our patient had full wrist range of motion, 95% strength, occasional 1/10 pain, and returned to sport at her previous level of play. There were no complications. CONCLUSION: Although just a single case report, our patient had an excellent result based on modified Mayo wrist score. When comparing our result and the previous literature, this technique seems to be a valid method for addressing radial-sided TFCC tears. PMID- 28643522 TI - Should All Heart Failure Patients Be Treated With Sacubitril/Valsartan? PMID- 28643523 TI - Management of quadrigeminal arachnoid cyst associated with obstructive hydrocephalus: report on stereotactic ventricular - cystic stenting. AB - Quadrigeminal arachnoid cysts (QAC) are usually accompanied by a symptomatic obstructive hydrocephalus. Several endoscopic and surgical treatments exist; however, the critical location of these cysts further complicates treatment and usually more than one procedure is required. In this report, a 31 year old female with QAC and associated obstructive hydrocephalus was successfully treated with stereotactic placement of a permanent ventricular - cystic stent (intraventricualr - cystic catheterization) in single - session. Intraventricular - cystic stenting provides a long lasting communication between these two compartments, allowing persistent "physiologic" solution to this challenging condition. PMID- 28643524 TI - A Multicenter Analysis of Factors Associated With Apixaban-Related Bleeding in Hospitalized Patients With End-Stage Renal Disease on Hemodialysis. AB - BACKGROUND: In 2014, the United States Food and Drug Administration approved a labeling change for apixaban to include recommendations for patients with severe renal impairment and patients with end-stage renal disease (ESRD) on hemodialysis (HD), though these recommendations are largely based on pharmacokinetic and pharmacodynamic data. OBJECTIVE: Identify variables associated with bleeding events in hospitalized patients with ESRD on HD receiving apixaban. METHODS: This retrospective, multicenter cohort study evaluated hospitalized patients with ESRD on HD receiving apixaban from January 1, 2013, through March 31, 2016. Correlational analysis and logistic regression were completed to identify factors associated with bleeding. RESULTS: A total of 114 adults were included in the analysis. The median length of stay (LOS) was 6.2 (interquartile range = 3.8 11.9) days and bleeding events occurred in a total of 17 patients (15%). A weak correlation was identified for higher cumulative apixaban exposure, increased number of HD sessions while receiving apixaban, and increased hospital LOS ( P < 0.05; correlation coefficient < 0.40). When controlling for confounders, logistic regression revealed that composite bleeding events were independently increased by continuation of outpatient apixaban (odds ratio = 13.07; 95% CI = 1.54-110.54; P = 0.018), increased total daily dose of apixaban (odds ratio = 1.72; 95% CI = 1.20 to 2.48; P = 0.003), and total HD sessions while receiving apixaban (odds ratio = 2.04; 95% CI = 1.06-3.92; P = 0.033). CONCLUSION: The association between these factors and increased bleeding should prompt concern for long-term anticoagulation with apixaban in patients with ESRD receiving chronic HD. PMID- 28643525 TI - Folic acid conjugated nanoliposomes as promising carriers for targeted delivery of bleomycin. AB - Targeted drug delivery has received considerable attention due to its key role in improving therapeutic efficacy and reducing the side effects of anticancer drugs. Bleomycin (BLM) is an anticancer antibiotic with short half-life, low therapeutic and high side effects that limit its clinical applications. This study aims to evaluate the anticancer potential of folate-targeted liposomal bleomycin (FL-BLM) and its free-folate form (L-BLM) on two different cancer cell lines including human cervix carcinoma HeLa, and human breast carcinoma MCF-7 cells. Furthermore, the effect of FL-BLM in induction of apoptosis and cell cycle arrest was studied by flow cytometry. FL-BLM was prepared by thin film hydration method and folic acid was conjugated to nanoliposomes by post insertion technique. Anticancer activity was evaluated by MTT assay. The cytotoxicity of FL-BLM against HeLa cells was significantly increased compared to L-BLM and conventional BLM. Flow cytometry and annexin-V analysis indicated that FL-BLM effectively induced apoptosis and cell-cycle arrest in HeLa cells especially at G2/M phase. In addition, the uptake of FL-BLM by Hela cells was significantly increased as compared to the MCF-7 cells. Overall, our findings indicated that FL-BLM may be promising formulation for targeted drug delivery to folate receptor-positive tumour cells. PMID- 28643526 TI - Association between cotinine-verified smoking status and hypertension in 167,868 Korean adults. AB - PURPOSE: Previous studies showed inconsistent results concerning the relationship between chronic smoking and blood pressure. Most of the studies involved self reported smoking status. This study was performed to evaluate the association of urinary cotinine or self-reported smoking status with hypertension and blood pressure in Korean adults. MATERIALS AND METHODS: Among individuals enrolled in the Kangbuk Samsung Health Study and Kangbuk Samsung Cohort Study, 167,868 participants (men, 55.7%; age, 37.5 +/- 6.9 years) between 2011 and 2013 who had urinary cotinine measurements were included. Individuals with urinary cotinine levels >=50 ng/mL were defined as cotinine-verified current smokers. RESULTS: The prevalence of hypertension and cotinine-verified current smokers in the overall population was 6.8% and 22.7%, respectively (10.0% in men and 2.8% in women for hypertension: 37.7% in men and 3.9% in women for cotinine-verified current smokers). In a multivariate regression analysis adjusted for age, sex, body mass index, waist circumference, alcohol drinking, vigorous exercise, and diabetes, cotinine-verified current smoking was associated with lower prevalence of hypertension compared with cotinine-verified never smoking (OR[95% CI], 0.79 [0.75, 0.84]). Log-transformed cotinine levels and unobserved smoking were negatively associated with hypertension, respectively (0.96 [0.96, 0.97] and 0.55 [0.39, 0.79]). In a multivariate linear regression analysis, the cotinine verified current smoking was inversely associated with systolic and diastolic blood pressure (BP) (regression coefficient[95% CI], -1.23[-1.39, -1.07] for systolic BP and -0.71 [-0.84, -0.58] for diastolic BP). In subgroup analyses according to sex, the inverse associations between cotinine-verified current smoking and hypertension were observed only in men. CONCLUSIONS: This large observational study showed that cotinine-verified current smoking and unobserved smoking were inversely associated with hypertension in Korean adults, especially only in men. PMID- 28643527 TI - Supporting occupational therapists implementing a capacity-building model in schools: Appuyer les ergotherapeutes mettant en oeuvre un modele de renforcement des capacites dans les ecoles. AB - BACKGROUND: Adopting a new model of clinical practice is complex. Professional development programs based on best-practice principles may facilitate this process. PURPOSE: This paper describes the development and evaluation of a multifaceted professional development program designed to support school-based occupational therapists to deliver a capacity-building model of service. METHOD: Twenty-two therapists participated in the program; completed pre-post evaluations of knowledge, skills, and beliefs; evaluated specific components of the training program; and participated in focus groups. Quantitative data were analyzed using descriptive and inferential statistics. Qualitative data were analyzed using a directed content analysis. FINDINGS: Therapists' perceptions of their knowledge and skills showed statistically significant change. Both training and mentorship were highly valued; however, having opportunities to build peer networks was considered essential. IMPLICATIONS: Multifaceted professional development programs designed using best-practice principles are an important mechanism for facilitating practice change. Including a process for peer support is advised. PMID- 28643528 TI - Modulating release of ranibizumab and aflibercept from thiolated chitosan-based hydrogels for potential treatment of ocular neovascularization. AB - BACKGROUND: This paper describes the synthesis of thiolated chitosan-based hydrogels with varying degrees of crosslinking that has been utilized to modulate release kinetics of two clinically relevant FDA-approved anti-VEGF protein drugs, ranibizumab and aflibercept. These hydrogels have been fabricated into disc shaped structures for potential use as patches on ocular surface. METHODS: Protein conformational changes and aggregation after loading and release was evaluated by circular dichroism (CD), steady-state tryptophan fluorescence spectroscopy, electrophoresis and size-exclusion chromatography (SEC). Finally, the capacity of both released proteins to bind to VEGF was tested by ELISA and surface plasmon resonance (SPR) technology. RESULTS: The study demonstrates the versatility of thiolated chitosan-based hydrogels for delivering proteins. The effect of various parameters of the hydrogel on protein release kinetics and mechanism of protein release was studied using the Korsmeyer-Peppas release model. Furthermore, we have studied the stability of released proteins in detail while comparing it with non-entrapped proteins under physiological conditions to understand the effect of formulation conditions on protein stability. CONCLUSIONS: The disc-shaped thiolated chitosan-based hydrogels provide a potentially useful platform to deliver ranibizumab and aflibercept for the treatments of ocular diseases such as wet AMD, DME and corneal neovascularization. PMID- 28643529 TI - Correlation between adenoma detection rate and novel quality indicators for screening colonoscopy. A proposal for quality measures tool kit. AB - BACKGROUND AND AIMS: Adenoma detection rate (ADR) is the most validated quality indicator for colonoscopy. Calculating ADR may not yield information in regards to advanced adenoma detection rate (advanced ADR). In addition, calculating ADR for individual endoscopists cannot distinguish between those who find only one versus more than one adenoma per colonoscopy. Several novel quality indictors were recently proposed to ensure adequate assessment of quality during colonoscopy. Our study aims to determine the correlation between ADR and novel quality indicators. METHODS: A retrospective cohort study of patients undergoing screening colonoscopy in a university hospital setting. Patient characteristics and colonoscopy findings were combined and analyzed to calculate the correlation of ADR with novel quality indicators using Spearman's rank-order correlation were used. RESULTS: A total of 1433 patients out of 2116 patients met the inclusion criteria. There was a significant positive correlation between ADR correlated with [advanced-ADR-2, nonadvanced-ADR, adenoma per colonoscopy, Multiplicity detection rate and ADR-Plus] r = (0.82, 0.99, 0.99, 0.07 and 0.85), respectively. However, ADR did not correlate with advanced-ADR and adenomas per positive participant. CONCLUSION: Adding advanced-ADR and adenomas per positive participant to ADR may create a more comprehensive quality indicators tool kit, which is sensitive and difficult to game. Future studies are needed to investigate the impact of the tool kit on the interval cancers and adenoma missing rate. PMID- 28643530 TI - Assessment of local carotid stiffness in seronegative and seropositive rheumatoid arthritis. AB - OBJECTIVES: Rheumatoid arthritis (RA) is a chronic, inflammatory disease associated with increased risk of cardiovascular (CV) disease. Arterial stiffness (AS) is an independent predictor of CV events. This study aimed to analyse local carotid AS parameters in seronegative and seropositive RA patients. DESIGN: Of 347 consecutive RA patients, we selected specifically those who were free of established CV diseases and risk factors. As a result, 140 patients (126 women, 52.2 +/- 10 years) and 140 healthy controls (122 women, 52.7 +/- 8.0 years) were enrolled into this study. The common carotid AS was evaluated using radio frequency echo-tracking system to determine the local carotid pulse wave velocity (cPWV) and carotid intima-media thickness (cIMT). Based on rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positivity, RA patients were categorized into seronegative and seropositive subgroups. RESULTS: Carotid PWV was determined to be significantly higher in all patients and subgroups than controls (p < .001 for all). Although cIMT was similar between the patients, controls and seropositive subgroup, seronegative patients had significantly higher cIMT compared to controls (p = .035) and seropositive group (p = .010). Moreover, a significant positive correlation was found between cPWV and age (r: 0.603, p < .001), ESR (r: 0.297, p = .004), ACPA (r: 0.346, p = .001) and cIMT (r: 0.290, p = .005) in seropositive patients. CONCLUSIONS: RA per se is sufficient to cause arteriosclerosis in the absence of classical CV risk factors. However, arterial hypertrophy is only increased in seronegative patients but not in seropositive group. PMID- 28643531 TI - Difficult conversations: talking about cost in audiology consultations with older adults. AB - OBJECTIVE: Financial cost is a barrier for many older adults in their decision to obtain hearing aids (HAs). This study aimed to examine conversations about the cost of HAs in detail within initial audiology appointments. DESIGN: Sixty-two initial audiology appointments were video-recorded. The data were analysed using conversation analysis. STUDY SAMPLE: Participants included 26 audiologists, 62 older adults and 17 companions. RESULTS: Audiologists and clients displayed interactional difficulty during conversations about cost. Clients often had emotional responses to the cost of HAs, which were not attended to by audiologists. It was typical for audiologists to present one HA cost option at a time, which led to multiple rejections from clients which made the interactions difficult. Alternatively, when audiologists offered multiple cost options at once this led to a smoother interaction. CONCLUSIONS: Audiologists and clients were observed to have difficulty talking about HA costs. Offering clients multiple HA cost options at the same time can engage clients in the decision-making process and lead to a smoother interaction between audiologist and client in the management phase of appointments. PMID- 28643532 TI - Dermatomyositis with renal infarction: a case report and literature review. AB - Renal infarction is a rare clinical entity that is not easily detected by low sensitivity ultrasound. We herein report a case of dermatomyositis with renal infarction detected during corticosteroid therapy. The patient was followed up for 18 months. A woman who was clinically diagnosed with dermatomyositis complained of severe pain in the right flank of the low back and abdomen, accompanied by nausea and vomiting during corticosteroid therapy. Based on the findings of routine blood tests, abdominal X-ray radiography, and abdominal ultrasound, the patient was diagnosed with acute gastroenteritis and treated with levofloxacin. However, her symptoms were not relieved. Abdominal contrast enhanced computed tomography revealed renal infarction. Clinicians should be alert to the occurrence of thrombosis, especially when it manifests as vasculitis in patients with rheumatic disease who complain of severe abdominal pain, because it may suggest the presence of renal infarction. PMID- 28643534 TI - Transplantation of mouse-induced pluripotent stem cells into the cochlea for the treatment of sensorineural hearing loss. AB - CONCLUSION: Mouse-induced pluripotent stem cells (iPSCs) could differentiate into hair cell-like cells and spiral ganglion-like cells after transplantation into mouse cochleae, but it cannot improve the auditory brain response (ABR) thresholds in short term. OBJECTIVE: To evaluate the potential of iPSCs for use as a source of transplants for the treatment of sensorineural hearing loss (SNHL). METHODS: Establishing SNHL mice model, then injecting the iPSCs or equal volume DMEM basic medium into the cochleae, respectively. Immunofluorescence staining and reverse transcription-polymerase chain reaction (RT-PCR) were used to assess the survival, migration, differentiation of the transplanted iPSCs in cochleae and then recorded the ABR threshold in different time. Hematoxylin-eosin (HE) staining was used to observe the teratoma formation. RESULTS: Four weeks after transplantation, CM-Di1-labeled iPSCs could be found in the modiolus and Rosenthal's canal (RC), and some of them could expressed auditory hair cell markers or spiral ganglion neuron makers in group A, but not found in group B and C. As to the ABR threshold, no significance differences were found between pre- with postoperative in group A or B. In our study, no teratoma was observed in the cochleae. PMID- 28643533 TI - Evaluation of variation in coagulation among children with Mycoplasma pneumoniae pneumonia: a case-control study. AB - Objective Acute organ embolism in children with Mycoplasma pneumoniae pneumonia (MPP) has been reported, but changes in coagulation are unclear. This study aimed to investigate changes in coagulation in children with MPP. Methods A total of 185 children with MMP (cases) and 117 healthy children (controls) were recruited. We measured prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and plasma fibrinogen (FIB) and D-dimer levels. Results Plasma FIB (3.39 +/- 0.96 g/L vs 2.93 +/- 0.6 6g/L, t = 4.50) and D-dimer (326.45 +/- 95.62mg/L vs 263.93 +/- 103.32mg/L, t=5.36) in MPP children were higher than controls and PT (9.54 +/- 4.97S vs 11.48 +/- 5.96S, t=3.05) and APTT (31.41 +/- 12.01S vs 38.38 +/- 11.72S, t=4.95) were shorter than controls. FIB, D-dimer, PT, and APTT were not different between the high IgM-titre and low-titre groups. The areas under the receiver operating characteristic curves in cases and controls for plasma FIB and D-dimer levels were 0.654 (95% confidence interval [CI], 0.593 0.716, P = 0.031) and 0.682 (95% CI, 0.619-0.744, P = 0.032), respectively. Conclusions Children with MPP have a higher risk of blood coagulation and thrombosis. Controlling these problems should be considered as soon as possible. PMID- 28643536 TI - Correction to: Kokkinidis DG, et al. Emerging treatments for ulcerative colitis: a systematic review. PMID- 28643535 TI - Efficacy of platelets in bone healing: A systematic review on animal studies. AB - In presence of large bone defects, delayed bone union, non-union, fractures, and implant surgery, bone reconstruction may be necessary. Different strategies have been employed to enhance bone healing among which the use of autologous platelet concentrates. Due to the high content of platelets and platelet-derived bioactive molecules (e.g., growth factors, antimicrobial peptides), they are promising candidates to increase bone healing. However, a high heterogeneity of both preclinical and clinical studies resulted in contrasting results. Aim of the present systematic review was to evaluate the efficacy of platelet concentrates in animal models of bone regeneration, considering the possible factors which might affect the outcome. An electronic search was performed on MEDLINE and SCOPUS databases. Animal studies with a minimum follow up of 2 weeks and a sample size of five subjects per group, using platelet concentrates for bone regeneration, were included. Articles underwent risk of bias assessment and further quality evaluation was done. Sixty studies performed on six animal species (rat, rabbit, dog, sheep, goat, and mini-pig) were included. The present part of the review considers only studies performed on rats and rabbits (35 articles). The majority of the studies were considered at medium risk of bias. Animal species, healthy models, platelet, growth factors and leukocytes concentration, and type of bone defect seemed to influence the efficacy of platelet concentrates in bone healing. However, final conclusions were not be drawn, since only few included studies evaluated leukocyte, growth factor content, or presence of other bioactive molecules in platelet concentrates. Further studies with a standardized protocol including characterization of the final products will provide useful information for clinical application of platelet concentrates in bone surgery. PMID- 28643538 TI - Do methodological differences account for the current controversy on tissue factor expression in platelets? AB - Tissue factor (TF), the key activator of the blood coagulation cascade and of thrombus formation, is also expressed by circulating human platelets. Despite the documented in-depth characterization of platelet TF carried out in the past 15 years, some authors still fail to identify TF in platelets, especially when assessment in platelet-rich plasma (PRP) or washed platelets is carried out. This study aims to extend the characterization of the subset of TF-positive platelets in PRP from healthy subjects and to verify how different centrifugation forces, used to prepare the PRP, could affect the analysis of TF-positive platelets. Data indicate that large-size platelets express significantly higher amount of TF compared to small-size cells, in terms of both TF protein and TF mRNA. Upon stimulation, large platelets readily expose on the cell membrane TF, which is functionally active, i.e., able to generate factor Xa (FXa) as well as thrombin. By contrast, TF activity in small platelets is almost completely quenched by tissue factor pathway inhibitor (TFPI), becoming indeed detectable only after treatment with an anti-TFPI antibody. Our data highlight that particular attention must be paid to the preparation and collection of the PRP since such preanalytical variables may influence the platelet recovery and in turn affect subsequent analysis, whether it is flow cytometry, functional activity tests, proteome, or transcriptome analysis. Indeed, the TF-positive subset of large platelets can easily be lost if centrifugation protocols are not optimized, thus erroneously leading to a false-negative result. PMID- 28643537 TI - A diffusion weighted imaging study of basal ganglia in schizophrenia. AB - OBJECTIVES: Several magnetic resonance imaging (MRI) studies provided evidence of selective brain abnormalities in schizophrenia, both in cortical and subcortical structures. Basal ganglia are of particular interest, given not only the high concentration of dopaminergic neurons and receptors, but also for their crucial role in cognitive functions, commonly impaired in schizophrenia. To date, very few studies explored basal ganglia using diffusion imaging, which is sensitive to microstructural organization in brain tissues. The aim of our study is to explore basal ganglia structures with diffusion imaging in a sizeable sample of patients affected by schizophrenia and healthy controls. METHODS: We enrolled 52 subjects affected by schizophrenia according to DMS-IV-R criteria and 46 healthy controls. Diffusion weighted images were obtained using a 1.5 Tesla scanner and apparent diffusion coefficient (ADC) values were determined in axial and coronal sections at the level of basal ganglia. RESULTS: Patients affected by schizophrenia showed a significantly higher ADC compared to healthy controls in the left anterior lenticular nucleus (F = 3.9, p = .05). A significant positive correlation between right anterior lenticular nucleus and psychotropic dosages was found (r = 0.4, p = .01). CONCLUSIONS: Our study provides evidence of lenticular nucleus microstructure alterations in schizophrenia, potentially sustaining cognitive and motor deficits in schizophrenia. Key points The basal ganglia structures was explored with diffusion imaging in a sizeable sample of patients affected by schizophrenia and healthy controls. Patients affected by schizophrenia showed a significantly higher ADC compared to healthy controls in the left anterior lenticular nucleus. Our study provides evidence of lenticular nucleus microstructure alterations in schizophrenia, potentially sustaining cognitive and motor deficits in schizophrenia. PMID- 28643540 TI - Correction to: Chen L, et al., Molecular mechanisms underlying the protective effects of hydrogen-saturated saline on noise-induced hearing loss. PMID- 28643539 TI - Prevalence of iron deficiency anemia and iron deficiency in a pediatric population with inflammatory bowel disease. AB - OBJECTIVES: Iron deficiency is the most common cause of anemia in children with inflammatory bowel disease, although the real prevalence is unknown. Intravenous iron is suggested as the first line treatment. This study aims to determine the prevalence of iron deficiency anemia in children with inflammatory bowel disease followed in a Pediatric Gastroenterology Unit of a tertiary center and to evaluate this unit's experience with intravenous iron. MATERIALS AND METHODS: A retrospective cohort study was designed involving children with inflammatory bowel disease followed in that unit between January 2001 and April 2016. Laboratory results were collected at the moment of diagnosis, after one-year follow-up and prior each IV iron administration performed during the study period. Anemia was defined according to World Health Organization criteria and the iron deficiency was defined using recent guidelines. RESULTS: Were studied 69 patients 71% had CD and 29% UC. 50.7% were female. Mean patient age at diagnosis was 13.3 years (range 1--17 years). Prevalence of ID and IDA at diagnosis was 76.8% and 43.5%, respectively. After one year follow-up, those values decreased to 68.1% (p = .182) and 21.7% (p = .002), respectively. Hemoglobin significantly increased (p < .001). Intravenous iron was administered to 92.8% of patients. No adverse reactions were reported. CONCLUSIONS: Intravenous iron is the first line in the treatment of Iron deficiency anemia in Inflammatory Bowel disease and it is safe and effective. Persistent anemia and iron deficiency are common. PMID- 28643541 TI - Effects of pH and concentration of sodium citrate anticoagulant on platelet aggregation measured by light transmission aggregometry induced by adenosine diphosphate. AB - The 2013 ISTH-SSC guidelines for the standardization of light transmission aggregometry (LTA) were largely based on expert consensus, as studies directly comparing LTA methodologies were lacking. We experimentally tested the cogency of ISTH-SSC recommendations pertaining to use of anticoagulant, in particular whether: (1) buffered citrate (BC) is preferable to unbuffered citrate (C); (2) the two recommended concentrations of sodium citrate (109 and 129 mM) are equivalent in terms of platelet aggregation (PA). Blood from 16 healthy volunteers was collected into BC and C (109 and 129 mM). PA was measured by LTA in platelet-rich plasma (PRP) stimulated by adenosine diphosphate (ADP) (2 MUM) immediately after PRP preparation and up to 4 hr after blood collection; pH and platelet counts in PRP were measured in parallel. pH in PRP increased with time up to about 8 for all anticoagulants, although it was lower in BC than in C at all times. In BC, PA was lower at 45 min, but equivalent at all other times. PA was higher and more stable in sodium citrate 109 mM than in 129 mM at all times. The extent of PA did not change for up to 2 hr after blood collection, and subsequently dramatically decreased. In contrast with ISTH-SSC recommendations, (1) BC does not show advantages compared to C; (2) 109 mM citrate is preferable to 129 mM, because it better supports PA; and (3) LTA studies should be completed within 2 hr of blood collection, instead of the recommended 4 hr. PMID- 28643542 TI - Long-term stability of splinted anterior mandibular teeth during supportive periodontal therapy. AB - OBJECTIVE: The aim of the study was to retrospectively assess the survival rate and stability of periodontally compromised and mobile anterior mandibular teeth after splinting in patients under supportive periodontal therapy (SPT). MATERIALS AND METHODS: Thirty-nine patients with splinted anterior mandibular teeth and SPT (>=1 visit/year) for 3-15 years were re-examined. Periodontal status, patient and tooth-related factors were assessed retrospectively before (baseline) and 3 years after splinting (n = 39 patients, 162 splinted teeth). For patients with splints inserted for more than 3 years, retrospective data after 5 (n = 30), 7 (n = 24), 10 (n = 16), 12 (n = 8) and 15 years (n = 4) was included, if available. At baseline, splinted teeth included at least one tooth with increased mobility combined with clinical attachment loss (CAL) >= 5 mm and >=50% relative bone loss (RBL). Baseline RBL of splinted teeth was assessed for all patients. Change in RBL was assessed after 10 years, if available. RESULTS: No splinted tooth was lost within the first 3 years after splinting. One splinted tooth was lost 7 years after baseline and one 12 years after baseline. After 3 years mean(SD) periodontal probing depth of splinted teeth decreased from 3.39(1.41) mm to 2.12(0.37) mm and mean(SD) CAL from 5.61(1.66) mm to 5.09(1.67) mm and remained stable over the observation period. No change in RBL was observed over a 10-year period (p = .213). The survival rate of the splints until fracture or debonding was 74.4% after 3 years. CONCLUSIONS: Periodontally compromised splinted teeth show a high survival-rate and periodontal stability during SPT. PMID- 28643543 TI - Measuring Compassionate Care: Reliability and Validity of the Greek Version of a Compassionate Care Assessment Tool. AB - This study attempts to fill the gap regarding the adequacy of a compassionate care assessment tool by evaluating the tool for use with Greek patients. The Greek version of the compassionate care assessment tool was developed by using forward and backward translation. The reliability and validity of the measures were investigated in a sample of patients hospitalized in public hospitals in Athens. The internal consistency of the instrument was examined based on Cronbach's alpha coefficients, and the validity was evaluated by subjecting the items of the instrument to factor analysis. The reliability was found to be acceptable for the instrument as a whole and for each of its subscales. Explanatory and confirmatory factor analysis results were satisfactory, indicating the validity of the tool. PMID- 28643544 TI - Varicella-zoster meningovasculitis in a multiple sclerosis patient treated with natalizumab. AB - BACKGROUND: Natalizumab is associated with the occasional occurrence of progressive multifocal leukoencephalopathy (PML). While natalizumab-associated PML is well described in multiple sclerosis (MS) patients, herpes and other infections have rarely been reported. OBJECTIVE: To report a case of varicella zoster (VZV) meningovasculitis in a MS patient treated with natalizumab. METHODS: Case report. RESULTS: A 48-year-old woman diagnosed with MS in treatment with natalizumab (Expanded Disability Status Scale (EDSS): 4.0). After 72 infusions, she complained of a holocraneal headache and a new unsteady gait with diplopia (EDSS: 5.0). A brain and spinal cord magnetic resonance (MR) scan showed a multifocal leptomeningeal enhancing nodular lesions and an angiography revealed irregularity of the proximal segments of cerebral arteries. Testing for VZV DNA by polymerase chain reaction (PCR) amplification was positive in cerebrospinal fluid. Treatment with endovenous acyclovir was started. After clinical improvement (EDSS: 4.5), treatment with natalizumab was restarted associated with oral acyclovir as prophylaxis. CONCLUSION: Neurologists should be aware of other possible neuroinfections besides PML in MS patients under natalizumab. PMID- 28643546 TI - Sexual Abuse Within Employment Settings: A Comparison of Work-Related, Intra- and Extra-Familial Child Molesters. AB - Child sexual abuse (CSA) is a serious problem not only in the community but also in institutional settings such as youth-serving organizations, churches, and schools. Although research has started to examine the problem of abuse in institutional settings, there remains a dearth of information about the nature and context of CSA in different employment settings, including those that do not specifically cater to children. In addition, research on the similarities and differences between perpetrators who work with children and other sex offenders is scarce. As such, the present study compared offenders on variables relating to financial/employment lifestyle stability, risk/dangerousness level, abuse opportunity, and victim selection. Data revealed that child abusers who worked with children tended to be better educated, were less likely to be married, had fewer nonsexual convictions, and were more likely to abuse male post-pubescent children compared with intra- and extra-familial offenders who did not work with children. Implications for future research, prevention of CSA, and clinical practice are discussed. PMID- 28643545 TI - Application of intravoxel incoherent motion (IVIM) magnetic resonance imaging in the evaluation of primitive brain tumours. AB - Intravoxel incoherent motion is a potential non-invasive diagnostic tool in brain tumours, without any clear guidelines for its evaluation yet. In our study, we compare intravoxel incoherent motion with dynamic susceptibility contrast magnetic resonance imaging in the quantification of tumour tissue blood perfusion in 28 patients affected by brain tumours, highlighting the issues encountered during the acquisition set-up and post-processing steps. Intravoxel incoherent motion is a new imaging tool and an alternative technique to dynamic susceptibility contrast-magnetic resonance imaging which is of considerable interest at present. This is partly because it does not require the use of a contrast agent and relies on the intrinsic properties of motion in the capillaries of the spins. Compared to dynamic susceptibility contrast-magnetic resonance imaging, the intravoxel incoherent motion technique is also characterised by better resolution because the gadolinium-based contrast agent bolus used in the standard technique results in a variation by more than 50% of the signal coming from the brain. Finally, intravoxel incoherent motion is more sensitive to the incoherent motion that originates from small capillary vessels, while the dynamic susceptibility contrast signal is also contaminated by the input from larger arteries and veins, which may result in an overestimation of the blood volume. Although there are limitations due to the heterogeneity of the sample considered in our study, intravoxel incoherent motion has been shown to be an accurate noninvasive radiological biomarker, useful to distinguish between low and high grade glial tumours. PMID- 28643548 TI - Clinical commentary on "Varicella-zoster meningovasculitis in a multiple sclerosis patient treated with natalizumab". PMID- 28643547 TI - Rabies - epidemiology, pathogenesis, public health concerns and advances in diagnosis and control: a comprehensive review. AB - Rabies is a zoonotic, fatal and progressive neurological infection caused by rabies virus of the genus Lyssavirus and family Rhabdoviridae. It affects all warm-blooded animals and the disease is prevalent throughout the world and endemic in many countries except in Islands like Australia and Antarctica. Over 60,000 peoples die every year due to rabies, while approximately 15 million people receive rabies post-exposure prophylaxis (PEP) annually. Bite of rabid animals and saliva of infected host are mainly responsible for transmission and wildlife like raccoons, skunks, bats and foxes are main reservoirs for rabies. The incubation period is highly variable from 2 weeks to 6 years (avg. 2-3 months). Though severe neurologic signs and fatal outcome, neuropathological lesions are relatively mild. Rabies virus exploits various mechanisms to evade the host immune responses. Being a major zoonosis, precise and rapid diagnosis is important for early treatment and effective prevention and control measures. Traditional rapid Seller's staining and histopathological methods are still in use for diagnosis of rabies. Direct immunofluoroscent test (dFAT) is gold standard test and most commonly recommended for diagnosis of rabies in fresh brain tissues of dogs by both OIE and WHO. Mouse inoculation test (MIT) and polymerase chain reaction (PCR) are superior and used for routine diagnosis. Vaccination with live attenuated or inactivated viruses, DNA and recombinant vaccines can be done in endemic areas. This review describes in detail about epidemiology, transmission, pathogenesis, advances in diagnosis, vaccination and therapeutic approaches along with appropriate prevention and control strategies. PMID- 28643549 TI - Examination of the Psychometric Properties of the Geriatric Fear of Falling Measure Among Community-Dwelling Older Adults in the United States. AB - This current study investigated the construct validity and reliability of the Geriatric Fear of Falling Measure (GFFM) among community-dwelling older adults in the United States. Eighty-eight participants were assessed on the GFFM together with demographics, falls, and fear of falling and falls-efficacy measures at baseline and an 8-week follow-up visit. Cronbach's alpha, regression analyses, and correlation analyses were used to examine the psychometric properties of the GFFM. The results showed that the GFFM demonstrated good construct validity and reliability among community-dwelling older adults in the United States. Our findings provide evidence for the validity and reliability of the GFFM. Further study with a larger and diverse sample is needed to determine whether the GFFM has potential as a quick screening tool of fear of falling in clinical settings. PMID- 28643550 TI - Hip joint kinetics in the table tennis topspin forehand: relationship to racket velocity. AB - The purpose of this study was to determine hip joint kinetics during a table tennis topspin forehand, and to investigate the relationship between the relevant kinematic and kinetic variables and the racket horizontal and vertical velocities at ball impact. Eighteen male advanced table tennis players hit cross-court topspin forehands against backspin balls. The hip joint torque and force components around the pelvis coordinate system were determined using inverse dynamics. Furthermore, the work done on the pelvis by these components was also determined. The peak pelvis axial rotation velocity and the work done by the playing side hip pelvis axial rotation torque were positively related to the racket horizontal velocity at impact. The sum of the work done on the pelvis by the backward tilt torques and the upward joint forces was positively related to the racket vertical velocity at impact. The results suggest that the playing side hip pelvis axial rotation torque exertion is important for acquiring a high racket horizontal velocity at impact. The pelvis backward tilt torques and upward joint forces at both hip joints collectively contribute to the generation of the racket vertical velocity, and the mechanism for acquiring the vertical velocity may vary among players. PMID- 28643551 TI - Provider Advice About Weight Loss in a Primary Care Sample of Obese and Overweight Patients. AB - OBJECTIVE: Primary care providers play an important role in obesity prevention and reduction by advising patients about weight loss strategies. This study examined receipt of provider advice to lose weight among primary care patients who were overweight and obese. METHODS: Observational study conducted among primary care patients (n = 282) who completed a survey that measured receipt of provider advice about weight loss/management, chronic health conditions, perceived weight status, and perceptions about shared decision making about weight loss/management. RESULTS: Fifty-nine percent of participants had been advised by their physician to lose weight. Participants who were obese were more likely than those who were overweight to report provider advice (odds ratio [OR] = 1.31, 95% CI = 1.25-4.34, P = .001). Similarly, participants who believed they were obese/overweight had a greater likelihood of reporting provider advice compared with those who did not believe they were obese/overweight (OR = 1.40, 95% CI = 2.43-6.37, P = .0001). Shared decision making about weight loss/management was associated with an increased likelihood of reporting provider advice (OR = 3.30, 95% CI = 2.62-4.12, P = .0001). CONCLUSIONS: Patient beliefs about their weight status and perceptions about shared decision-making are important to receiving provider advice about weight loss/management among primary care patients. PRACTICE IMPLICATIONS: Continued efforts are needed to enhance provider advice about weight loss/management among obese/overweight patients. PMID- 28643552 TI - Drug-induced Physeal Abnormalities in Preclinical Toxicity Studies. AB - Most toxic physeal changes are characterized microscopically by altered chondrocyte development, proliferation, or maturation in the growth plate and eventually result in disordered appositional bone growth. Many therapeutic drugs directly or indirectly target proteins involved in chondrocytic differentiation and maturation pathways, so toxic physeal injury has become increasingly common in preclinical toxicologic pathology. While physeal dysplasia has been associated with several different drug classes including bisphosphonates, vascular endothelial growth factor receptor inhibitors, fibroblast growth factor receptor inhibitors, transforming growth factor beta receptor inhibitors, and vascular targeting agents, physeal changes often share similar morphologic features including thickening and disorganization of the hypertrophic layer, increased numbers of hypertrophic chondrocytes, altered mineralization of endochondral ossification, and/or increased thickness of subphyseal bone. Knowledge of genetic and nutritional diseases affecting bone growth has been important in helping to determine which specific target drugs may be affecting that could result in toxic physeal lesions. A pathophysiologic mechanism for most physeal toxicants has been determined in detail using a variety of investigative techniques. However, due to the signaling cross talk and the tight regulation required for chondrocyte maturation in the physis, several growth factor pathways are likely to be affected simultaneously with pharmacologic disruption of physeal homeostasis and inhibition of one factor necessary for chondrocyte function often affects others. PMID- 28643553 TI - Renal dysfunction and chronic kidney disease in ischemic stroke and transient ischemic attack: A population-based study. AB - Background and purpose The prevalence of chronic kidney disease (estimated glomerular filtration rate (eGFR) <60 mL/min per 1.73 m2 for >=3 months, chronic kidney disease (CKD)) in ischemic stroke and transient ischemic attack (TIA) is unknown, as estimates have been based on single-point estimates of renal function. Studies investigating the effect of renal dysfunction (eGFR < 60 mL/min per 1.73 m2, renal dysfunction) on post-stroke outcomes are limited to hospitalized cohorts and have provided conflicting results. Methods We investigated rates, determinants and outcomes of renal dysfunction in ischemic stroke and TIA in the North Dublin Population Stroke Study. We also investigate the persistence of renal dysfunction in 90-day survivors to determine the prevalence of CKD. Ascertainment included hot and cold pursuit using multiple overlapping sources. Survival analysis was performed using Kaplan-Meier survival curves and Cox proportional hazards modeling. Results In 547 patients (ischemic stroke in 76.4%, TIA in 23.6%), the mean eGFR at presentation was 63.7 mL/min/1.73 m2 (SD 22.1). Renal dysfunction was observed in 44.6% (244/547). Among 90-day survivors, 31.2% (139/446) met criteria for CKD. After adjusting for age and stroke severity, eGFR < 45 mL/min/1.73 m2 (hazard ratio 2.53, p = 0.01) independently predicted 28-day fatality but not at two years. Poor post-stroke functional outcome (Modified Rankin Scale 3-5) at two years was more common in those with renal dysfunction (52.5% vs. 20.6%, p < 0.001). After adjusting for age, stroke severity and pre-stroke disability, renal dysfunction (OR 2.17, p = 0.04) predicted poor functional outcome. Conclusion Renal dysfunction and CKD are common in ischemic stroke and TIA. Renal dysfunction is associated with considerable post-stroke morbidity and mortality. Further studies are needed to investigate if modifiable mechanisms underlie these associations. PMID- 28643554 TI - Combined effects of physical inactivity and acute hyperglycemia on arterial distensibility. AB - Arterial distensibility, an independent predictor of cardiovascular events, is transiently increased with acute hyperglycemia (AHG) in healthy individuals. Whether this response interacts with physical inactivity remains unknown. We examined the effects of short-term bed rest (BR) on the response of carotid artery distensibility (CD) to AHG, and the influence of underlying changes in insulin resistance and blood volume. CD was assessed with ultrasonography before as well as 30 and 120 minutes following ingestion of 75 g of glucose prior to and after 3 days of BR in 15 healthy male volunteers. Plasma insulin/glucose concentrations and blood volumes were concomitantly determined. On day 4 of BR, blood volume was re-established to pre-BR levels by albumin infusion and CD and insulin/glucose concentrations were determined as in the previous experimental days. Basal CD was not affected by BR. AHG increased CD before and after BR but reached a higher peak increment after BR (12% vs 60% at 30 min OGTT, p=0.028). BR also increased the plasma insulin concentration during AHG ( p=0.007). In regression analyses, plasma insulin and glucose concentrations were positively correlated to CD, particularly after BR ( r=0.31, p<0.05). Restoration of the BR induced loss (5%) in blood volume did not affect the response of CD to AHG. In conclusion, short-term physical inactivity strongly accentuates the initial increase in CD in response to AHG in healthy individuals. This effect is associated with concomitant increases in circulating insulin concentration attributable to early insulin resistance. PMID- 28643555 TI - Unexpected detection of porcine rotavirus C strains carrying human origin VP6 gene. AB - BACKGROUND: Rotavirus C (RVC), a known etiological agent of diarrheal outbreaks, mainly inflicts swine population globally with sporadic incidence in human, cattle, ferret, mink and dog. OBJECTIVE: To demonstrate the presence of RVC in Indian swine population and characterization of its selected structural (VP6) and non-structural (NSP4 and NSP5) genes. METHODS: A total of 108 diarrheic samples from different regions of India were used. Isolated RNA was loaded onto polyacrylamide gel to screen for the presence of RVs through the identification of specific electrophoretic genomic migration pattern. To characterize the RVC strains, VP6 gene and NSP4 and NSP5 genes were amplified, sequenced and analyzed. RESULTS: Based on VP6 gene specific diagnostic RT-PCR, the presence of RVC was confirmed in 12.0% (13/108) piglet fecal specimens. The nucleotide sequence analysis of VP6 gene, encoding inner capsid protein, from selected porcine RVC (PoRVC) strains revealed more than 93% homologies to human RVC strains (HuRVC) of Eurasian origin. These strains were distant from hitherto reported PoRVCs and clustered with HuRVCs, owning I2 genotype. However, the two non-structural genes, i.e. NSP4 and NSP5, of these strains were found to be of swine type, signifying a re-assortment event that has occurred in the Indian swine population. CONCLUSION: The findings indicate the presence of human-like RVC in Indian pigs and division of RVC clade with I2 genotype into further sub-clades. To the best of our knowledge, this appears to be the first report of RVC in Indian swine population. Incidence of human-like RVC VP6 gene in swine supports its subsequent zoonotic prospective. PMID- 28643556 TI - Catalytic oxidation of toluene: comparative study over powder and monolithic manganese-nickel mixed oxide catalysts. AB - This paper is focused on development of the metal monolithic structure for total oxidation of toluene at low temperature. The well-adhered catalyst, based on the mixed oxides of manganese and nickel, is washcoated on the Al/Al2O3 plates as metallic support. For the comparison purposes, results observed for the manganese nickel mixed oxide supported on the metallic monolith are compared with those obtained using powder type of the same catalyst. Prepared manganese-nickel mixed oxides in both configurations show remarkable low-temperature activity for the toluene oxidation. The reaction temperature T50 corresponding to 50% of the toluene conversion is observed at temperatures of ca. 400-430 K for the powder catalyst and at ca. 450-490 K for the monolith configuration. The appropriate mathematical models, such as one-dimensional (1D) pseudo-homogeneous model of the fixed bed reactor and the 1D heterogeneous model of the metal monolith reactor, are applied to describe and compare catalytic performances of both reactors. Validation of the applied models is performed by comparing experimental data with theoretical predictions. The obtained results confirmed that the reaction over the monolithic structure is kinetically controlled, while in the case of the powder catalyst the reaction rate is influenced by the intraphase diffusion. PMID- 28643557 TI - Pooled sample testing for Bonamia ostreae: A tale of two SYBR Green real-time PCR assays. AB - Pooled testing of samples is a common laboratory practice to increase efficiency and reduce expenses. We investigated the efficacy of 2 published SYBR Green real time PCR assays when used to detect the haplosporidian parasite Bonamia ostreae in pooled samples of infected oyster tissue. Each PCR targets a different gene within the B. ostreae genome: the actin 1 gene or the 18S rRNA gene. Tissue homogenates (150 mg) of the New Zealand flat oyster Ostrea chilensis were spiked with ~1.5 * 103 purified B. ostreae cells to create experimental pools of 3, 5, and 10. Ten positive replicates of each pool size were assayed twice with each PCR and at 2 different amounts of DNA template. The PCR targeting the actin 1 gene was unable to reproducibly detect B. ostreae in any pool size. Conversely, the 18S rRNA gene PCR could reproducibly detect B. ostreae in pools of up to 5. Using a general linear model, there was a significant difference in the number of pools that correctly detected B. ostreae between each PCR ( p < 0.01) and each pool size ( p < 0.01). It is likely that the single copy actin 1 gene is more likely to be diluted and not detected by pooling than the multi-copy 18S rRNA gene. Our study highlights that validation data are necessary for pooled sample testing because detection efficacy may not be comparable to individual sample testing. PMID- 28643558 TI - Influence of Anthropometric Characteristics in Patients With Her2-Positive Breast Cancer on Initial Plasma Concentrations of Trastuzumab. AB - BACKGROUND: Plasma concentrations of trastuzumab <20 ug/mL in patients with gastric cancer are associated with reduced progression-free and overall survival. In breast cancer treatment, this relationship has not yet been studied, but a suboptimal pharmacodynamic exposure to trastuzumab could be a reason for therapeutic failure of treatment of HER2-positive breast cancer. OBJECTIVE: The objective of the present study was to determine the proportion of nonmetastatic HER2-positive breast cancers that do not reach a minimum plasma concentration ( Cmin) of 20 ug/mL after first drug administration, established as therapeutically effective in clinical trials. The secondary objective was to identify the physiological and anthropometric characteristics that determine interindividual pharmacokinetic variability. METHODS: Serum concentrations of trastuzumab were assessed by ELISA on day 1 of the second cycle before administration of the second dose ( Cmin). RESULTS: Of 19 patients included, 9 (47.4%) had a mean Cmin of 19.0 ug/mL (+/-12.1) after the first administration. Body mass index (BMI) and weight was the main variable that determined the achievement of therapeutic levels after the first administration. Thus, the proportion of patients reaching the target concentration was 89% when BMI was <=30 kg/m2 but only 11% when BMI was >30 kg/m2 ( P < 0.01). CONCLUSIONS: The standard dose of 600 mg subcutaneous trastuzumab did not ensure adequate pharmacodynamic exposure from the first administration in 52% of patients, with weight and BMI being related to the plasma levels obtained. PMID- 28643561 TI - The Next Chapter: Co-Editor #3. PMID- 28643559 TI - Informing Healthcare Waiting Area Design Using Transparency Attributes: A Comparative Preference Study. AB - OBJECTIVE: This study aimed to explore people's visual preference for waiting areas in general hospital environments designed with transparency attributes that fully integrate nature. BACKGROUND: Waiting can be a tedious and frustrating experience among people seeking healthcare treatments and negatively affect their perception of the quality of care. Positive distractions and supportive designs have gained increasing attraction to improve people's waiting experience. Nature, which has shown therapeutic effects according to a growing amount of evidence, could be a distinguished positive distraction in waiting areas. Additionally, the theory of transparency was operationalized to indicate a spatial continuity between the external nature and the built interiors in general healthcare waiting area design. METHOD: A survey method was adopted in the study. Twenty-one images of general healthcare waiting areas depicting three design typologies were preselected following a strict procedure, including designs with (a) no window views, (b) limited window views to nature, and (c) transparent spaces with maximum natural views. Ninety-five student participants rated the images based on their visual preference using a Likert-type scale. RESULTS AND CONCLUSIONS: The results showed that transparent waiting areas were significantly preferred. A significant positive relationship existed between the level of transparency and people's preference scores. The factor analysis indicated additional supportive features that may affect people's preferences, including daylight, perceived warmth, noninstitutional furniture arrangement, visual orientation, and the use of natural materials for interior design. However, these tentative results need to be furthered tested with the real patient population as the next step of this study. PMID- 28643560 TI - Design Quality in the Context of Healthcare Environments: A Scoping Review. AB - OBJECTIVE: We explored the concept of design quality in relation to healthcare environments. In addition, we present a taxonomy that illustrates the wide range of terms used in connection with design quality in healthcare. BACKGROUND: High quality physical environments can promote health and well-being. Developments in healthcare technology and methodology put high demands on the design quality of care environments, coupled with increasing expectations and demands from patients and staff that care environments be person centered, welcoming, and accessible while also supporting privacy and security. In addition, there are demands that decisions about the design of healthcare architecture be based on the best available information from credible research and the evaluation of existing building projects. METHOD: The basic principles of Arksey and O'Malley's model of scoping review design were used. Data were derived from literature searches in scientific databases. A total of 18 articles and books were found that referred to design quality in a healthcare context. RESULTS: Design quality of physical healthcare environments involves three different themes: (i) environmental sustainability and ecological values, (ii) social and cultural interactions and values, and (iii) resilience of the engineering and building construction. Design quality was clarified herein with a definition. CONCLUSIONS: Awareness of what is considered design quality in relation to healthcare architecture could help to design healthcare environments based on evidence. To operationalize the concept, its definition must be clear and explicit and able to meet the complex needs of the stakeholders in a healthcare context, including patients, staff, and significant others. PMID- 28643563 TI - Evidence, Best Practice, and Intuition. PMID- 28643565 TI - Executive Summary of Key Concepts. PMID- 28643564 TI - The Power of Traditional Design Techniques: The Effects of Viewing a Japanese Garden on Individuals With Cognitive Impairment. AB - PURPOSE: This study is to examine how viewing a Japanese garden affects Japanese patients with dementia. BACKGROUND: In a previous study, authors explored the effect on individuals with Alzheimer's disease of viewing an indoor Japanese garden at a nursing home in the United States and reported that viewing the garden significantly reduced the heart rate, evoked short-term and long-term memories, and improved behavioral symptoms. However, it was unclear whether these effects were caused by the design of Japanese garden or unfamiliarity of the design to Caucasians. METHODS: We constructed a Japanese garden on the rooftop of a hospital in Japan and assessed with a total of 25 subjects on the following categories: (1) eye movement, (2) heart rate, and (3) behavior under four different conditions: (a) open view of the site before construction of the Japanese garden (the control space), (b) open view of the Japanese garden, (c) view of the Japanese garden through closed door, and (d) view of Japanese garden through closed door with the chrysanthemum scent. Findings/Results: Viewers' eyes scanned larger area while viewing the Japanese garden, and viewing the Japanese garden significantly reduced heart rate and improved behavioral symptoms than the control space. We also found that the effect of viewing the same Japanese garden differed across three conditions: the view through an open door, a closed door, and a closed door with added scent. PMID- 28643566 TI - Parable: When Will the Transition End? PMID- 28643567 TI - Exploring the Interface Between Healthcare Design and High-Reliability Organization Initiatives. PMID- 28643568 TI - Process Mining-Based Method of Designing and Optimizing the Layouts of Emergency Departments in Hospitals. AB - OBJECTIVE: This article proposes an approach to help designers analyze complex care processes and identify the optimal layout of an emergency department (ED) considering several objectives simultaneously. These objectives include minimizing the distances traveled by patients, maximizing design preferences, and minimizing the relocation costs. BACKGROUND: Rising demand for healthcare services leads to increasing demand for new hospital buildings as well as renovating existing ones. Operations management techniques have been successfully applied in both manufacturing and service industries to design more efficient layouts. However, high complexity of healthcare processes makes it challenging to apply these techniques in healthcare environments. METHOD: Process mining techniques were applied to address the problem of complexity and to enhance healthcare process analysis. Process-related information, such as information about the clinical pathways, was extracted from the information system of an ED. A goal programming approach was then employed to find a single layout that would simultaneously satisfy several objectives. RESULTS: The layout identified using the proposed method improved the distances traveled by noncritical and critical patients by 42.2% and 47.6%, respectively, and minimized the relocation costs. CONCLUSION: This study has shown that an efficient placement of the clinical units yields remarkable improvements in the distances traveled by patients. PMID- 28643569 TI - Iron overload directly affecting the ovaries in a patient with Diamond-Blackfan anaemia: a case report. AB - Iron is a 'one-way' element and the primary point of regulation of body iron stores is at the level of intestinal iron absorption. Repeated blood transfusions for congenital anaemias bypass this regulatory checkpoint and inevitably lead to iron overload in the long-term. Iron overload causes multi-organ dysfunction of the heart, liver, pancreas and joints. It also causes reproductive toxicity primarily through its damaging effect on the anterior pituitary leading to hypogonadotrophic hypogonadism. Another less understood mechanism of reproductive toxicity is direct gonadal damage of excess free iron. In this article, we present the case of a 24-year-old woman with Diamond-Blackfan anaemia who presented to our unit seeking fertility assistance. The evaluation revealed a combination of hypogonadotrophic hypogonadism and reduced ovarian reserve along with evidence of severe iron overload. A literature search along with input from clinical experts has allowed us to counsel the patient to help her make an informed choice. A multi-disciplinary approach which would include initial optimization of pre-conceptional health with aggressive iron chelation therapy and subsequent ovulation induction with gonadotrophins has been planned, failing which, egg donation may be the only viable alternative. PMID- 28643570 TI - Home-based neurologic music therapy for arm hemiparesis following stroke: results from a pilot, feasibility randomized controlled trial. AB - OBJECTIVE: To assess the feasibility of a randomized controlled trial to evaluate music therapy as a home-based intervention for arm hemiparesis in stroke. DESIGN: A pilot feasibility randomized controlled trial, with cross-over design. Randomization by statistician using computer-generated, random numbers concealed in opaque envelopes. SETTING: Participants' homes across Cambridgeshire, UK. SUBJECTS: Eleven people with stroke and arm hemiparesis, 3-60 months post stroke, following discharge from community rehabilitation. INTERVENTIONS: Each participant engaged in therapeutic instrumental music performance in 12 individual clinical contacts, twice weekly for six weeks. MAIN MEASURES: Feasibility was estimated by recruitment from three community stroke teams over a 12-month period, attrition rates, completion of treatment and successful data collection. Structured interviews were conducted pre and post intervention to establish participant tolerance and preference. Action Research Arm Test and Nine hole Peg Test data were collected at weeks 1, 6, 9, 15 and 18, pre and post intervention by a blinded assessor. RESULTS: A total of 11 of 14 invited participants were recruited (intervention n = 6, waitlist n = 5). In total, 10 completed treatment and data collection. CONCLUSION: It cannot be concluded whether a larger trial would be feasible due to unavailable data regarding a number of eligible patients screened. Adherence to treatment, retention and interview responses might suggest that the intervention was motivating for participants. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT 02310438. PMID- 28643571 TI - Adaptation of the Activity Measure Post-Acute Care (AM-PAC) from English to Mandarin using the dual-panel translation approach. AB - PURPOSE: The aims of this study were to translate and adapt the Activity Measure Post-Acute Care (AM-PAC) from US English to Mandarin using the dual-panel method, and to assess its psychometric properties in an outpatient rehabilitation setting. METHODS: The AM-PAC outpatient short forms were translated using the dual-panel method. The translated AM-PAC was tested in 550 Chinese-speaking rehabilitation outpatients. Floor and ceiling effects were evaluated and internal consistency was assessed using Cronbach's alpha. Spearman correlation was used to assess the concurrent validity of the AM-PAC with the Barthel Index and the Mini Mental State Examination. Test-retest reliability was determined by administering the AM-PAC twice to 57 participants within a 2-7 day interval. RESULTS: Some ceiling effects (>20%) were observed in the Applied Cognition subscale. All subscales exhibited good internal consistency (alpha > 0.70). Supportive evidence for concurrent validity was found in strong correlations between Basic Mobility subscale and Barthel Index (r = 0.68), and Daily Activity subscale and Barthel Index (r = 0.70); and moderate correlations between Applied Cognition subscale and Mini-Mental State Examination (r = 0.50). Test-retest reliability for all subscales was high (intraclass correlation coefficient =0.89-0.98). CONCLUSIONS: The dual-panel approach was successfully used to translate the AM-PAC from English to Mandarin. Adequate reliability and validity in rehabilitation outpatients in Taiwan were established. Implications for Rehabilitation The dual panel method is a modern translation technique, which was successfully used to adapt the Activity Measure Post-Acute Care from English to Mandarin. The Mandarin version of Activity Measure Post-Acute Care demonstrates adequate internal consistency, concurrent validity, and test-retest reliability in rehabilitation outpatients. The Activity Measure Post-Acute Care is superior to existing functional measures used to monitor activity performance for rehabilitation patients in Taiwan. PMID- 28643572 TI - Distinctive barriers to antiretroviral therapy adherence among non-adherent adolescents living with HIV in Botswana. AB - Levels of adherence to HIV treatment are lower among adolescents compared with older and younger individuals receiving similar therapies. We purposely sampled the most and least adherent adolescents from a 300-adolescent longitudinal HIV treatment adherence study in Gaborone, Botswana. Multiple objective and subjective measures of adherence were available and study participants were selected based on sustained patterns of either excellent or poor adherence over a one-year period. Focus group discussions (FGD) and in-depth interviews (IDI) were conducted with the adolescents and a subset of their caregivers with the goal of revealing barriers and facilitators of adherence. Focus groups were segregated by adherence classification of the participants. Following coding of transcripts, matrices were developed based on participants' adherence classifications in order to clarify differences in themes generated by individuals with different adherence characteristics. 47 adolescents and 25 adults were included. The non adherent adolescents were older than the adherent adolescents (median age 18 years (IQR 16-19) vs. 14 years (IQR 12-15 years)), with median time on treatment near 10 years in both groups. Interference with daily activities, concerns about stigma and discrimination, side effects, denial of HIV status, and food insecurity arose as challenges to adherence among both those who were consistently adherent and those who were poorly-adherent to their medications. Low outcome expectancy, treatment fatigue, mental health and substance use problems, and mismatches between desired and received social support were discussed only among poorly adherent adolescents and their caregivers. Challenges raised only among adolescents and caregivers in the non-adherent groups are hypothesis-generating, identifying areas that may have a greater contribution to poor outcomes than challenges faced by both adherent and non-adherent adolescents. The contribution of these factors to poor outcomes should be explored in future studies. PMID- 28643573 TI - Correction to: Editorial: Siegfried Kasper. International Journal of Psychiatry in Clinical Practice, 2017, VOL. 21, NO. 2, P81. PMID- 28643574 TI - Stability and in vitro release behaviour of encapsulated omega fatty acid-rich oils in lentil protein isolate-based microcapsules. AB - The objective of this study was to investigate the use of a lentil protein isolate-based microcapsule design as a platform for entrapping different types of omega fatty acid-rich oil (e.g. canola, fish and flaxseed oils) and to characterise differences in the physical properties (e.g. moisture content, water activity, colour, wettability, particle size, surface oil and entrapment efficiency), storage stability and in vitro release behaviour of the entrapped oils. All microcapsules displayed similar physical properties regardless of the core material. Free fatty acid content, peroxide value, 2-thiobarbituric acid reactive substances and accelerated oxidation test were investigated between the free and encapsulated oils to determine protective effects from microencapsulation and found the wall material provided the greatest protective effect to the fish oils relative to the others. Based on an in vitro release assay, it was proposed that different intrinsic properties of fatty acids (e.g. polarity, conformation, chain length and number of double bonds) led to different release properties under simulated conditions. For instance, more encapsulated canola oil (~8.9%) was released within simulated gastric fluid, whereas more encapsulated fish oil (~73.4%) was released within simulated gastrointestinal fluids. Overall, the capsule design used in this study could be potentially used as a universal platform to deliver more healthy oils. PMID- 28643575 TI - Combined Rex-bypass shunt with pericardial devascularization alleviated prehepatic portal hypertension caused by cavernomatous transformation of portal vein. AB - OBJECTIVE: To evaluate the effects of combined Rex-bypass shunt and pericardial devascularization on prehepatic portal hypertension secondary to cavernomatous transformation of portal vein (CTPV). METHODS: Forty-two patients aged from 3 years to 49 years (divided into 3 groups), 26 cases male and 16 female, with prehepatic vascular hepertention were treated with Rex-bypass shunt combined with pericardial devascularization. In each patient, preoperative assessment included ultrasound and computed tomographic angiography of the portal vein and blood analysis. The procedure was Rex-bypass shunt (with or without graft), and patients with moderate or severe gastroesophageal varices required additional paraesophagogastric devascularization. Splenectomy or subtotal splenectomy was performed if combined hypersplenism co-existed. All data were analyzed retrospectively. RESULTS: No intraoperative death occurred, blood routine analysis improved (P < 0.05), the blood flow velocity (P < 0.05) and diameter (P < 0.05) of the left portal vein (LPV) significantly increased, the esophageal and gastric varices significantly relieved in 34 patients (P < 0.05), and better effects of earlier operations were demonstrated than the delayed ones (P < 0.05). During the period of follow-up from 6 to 64 months, the overall patency rate was 85.7% and the younger the age the better of the effect. CONCLUSION: Rex-bypass shunt combined with pericardial devascularization is a safe and effective procedure for prehepatic portal hypertension caused by CTPV. PMID- 28643576 TI - Sensory organization test principally reflects utricular function. AB - CONCLUSION: Our study showed that sensory organization test (SOT) could principally reflect utricular function, and our cut-score of VEST ratio (the indicator of inputs from the vestibular system in balance performance) in SOT could help to screen patients with unilateral peripheral vestibular dysfunction in non-fallers. OBJECTIVES: We aimed to know SOT reflects the function of which vestibular end organs and to assess the possibility of screening patients with peripheral vestibular dysfunction in non-fall population by means of SOT. METHODS: A total of 75 patients with unilateral peripheral vestibular dysfunction underwent SOT, ocular vestibular-evoked myogenic potential (oVEMP), cervical vestibular-evoked myogenic potential (cVEMP) and caloric tests. RESULTS: Regression model indicated that oVEMP, as an independent variable, exerted the greatest influence on VEST ratio, followed by age and cVEMP. There were no significant differences in VEST ratio among groups with different extents of peripheral vestibular involvement (p > .05). VEST ratio in the vestibular impairment groups was significantly lower than in the control group and significantly higher than in fall group (p < .01). VEST ratio in group with normal oVEMP was significantly higher than in group with abnormal oVEMP (p = .013). The cut-score between populations with functional and dysfunctional vestibule was 0.649. PMID- 28643577 TI - An assessment of advance relatives approach for brain death organ donation. AB - BACKGROUND: Advance announcement of forthcoming brain death has developed to enable intensivists and organ procurement organisation coordinators to more appropriately, and separately from each other, explain to relatives brain death and the subsequent post-mortem organ donation opportunity. Research aim: The aim was to assess how potentially involved healthcare professionals perceived ethical issues surrounding the strategy of advance approach. RESEARCH DESIGN: A multi centre opinion survey using an anonymous self-administered questionnaire was conducted in the six-member hospitals of the publicly funded East of France regional organ and tissue procurement network called 'Prelor'. PARTICIPANTS: The study population comprised 460 physicians and nurses in the Neurosurgical, Surgical and Medical Intensive Care Units, the Stroke Units and the Emergency Departments. Ethical considerations: The project was approved by the board of the Lorraine University Diploma in Medical Ethics and the Prelor Network administrators. MAIN FINDINGS: A slight majority of 53.5% of respondents had previously participated in an advance relatives approach: 83% of the physicians and 42% of the nurses. A majority of healthcare professionals (68%) think that the main justification for advance relatives approach is the comprehensive care of the dying patient and the research of his or her most likely opinion (74%). The misunderstanding of the related issues by relatives is an obstacle for 47% of healthcare professionals and 51% think that the answer given by the relatives regarding the most likely opinion of the person regarding post-mortem organ donation really corresponds to the person opinion in only 50% of the cases or less. CONCLUSION: Time given by advance approach should be employed to help and enable relatives to authentically bear the values and interests of the potential donor in the post-mortem organ donation discussion. Nurses' attendance of advance relatives approach seems necessary to enable them to optimally support the families facing death and post-mortem organ donation issues. PMID- 28643579 TI - Religious Participation and Biological Functioning in Mexico. AB - OBJECTIVE: Although several studies suggest that religious involvement tends to favor healthy biological functioning, most of this work has been conducted in the United States. This study explores the association between religious participation and biological functioning in Mexico. METHOD: The data are drawn from two waves of the Mexican Health and Aging Study (2003-2012) to assess continuous and categorical biomarker specifications. RESULTS: Across specifications, religious participation in 2003 is associated with lower levels of waist-to-hip ratio, total cholesterol, pulse rate, and overall allostatic load in 2012. Respondents who increased their participation over the study period also exhibit a concurrent reduction in pulse rate. Depending on the specification, participation is also associated with lower levels of diastolic blood pressure and C-reactive protein. Participation is generally unrelated to body mass index, glycosylated hemoglobin, and systolic blood pressure. DISCUSSION: Our results confirm that religious participation is associated with healthier biological functioning in Mexico. PMID- 28643580 TI - Cyclophilins: Less Studied Proteins with Critical Roles in Pathogenesis. AB - Cyclophilins (EC 5.2.1.8) belong to a subgroup of proteins known as immunophilins, which also include FK506-binding proteins and parvulins. Members of the immunophilins have two main characteristic properties: (i) peptidyl-prolyl cis-trans isomerase activity and (ii) the ability to bind immunosuppressant molecules of fungal origin. Cyclophilins are some of the most conserved proteins present in eukaryotes and prokaryotes, and they have been implicated in diverse cellular processes and responses to multiple biotic and abiotic stresses. Cyclophilins have been exploited in humans and plants extensively, but they have only recently received attention in regard to phytopathogens. In Phellinus sulphurascens and species of the genus Leptosphaeria and Phytophthora, high expression of cyclophilins was found to be related to infection. Moreover, recent studies of cyclophilins in certain phytopathogens, such as Magnaporthe oryzae, Botrytis cinerea, Cryphonectria parasitica, and Puccinia triticina, demonstrated their roles as a pathogenicity factors. In addition to pathogenicity, cyclophilins have high affinity for the immunosuppressive drug cyclosporin A, which is a potent antifungal agent. Although cyclophilins are highly conserved in phytopathogens, because they have been less studied, their role remains largely unknown. In this review, we provide detailed information on the cyclophilins in several phytopathogens, including fungi and oomycetes, as well as their role in suppressing plant immunity. PMID- 28643581 TI - A White Paper on Global Wheat Health Based on Scenario Development and Analysis. AB - Scenario analysis constitutes a useful approach to synthesize knowledge and derive hypotheses in the case of complex systems that are documented with mainly qualitative or very diverse information. In this article, a framework for scenario analysis is designed and then, applied to global wheat health within a timeframe from today to 2050. Scenario analysis entails the choice of settings, the definition of scenarios of change, and the analysis of outcomes of these scenarios in the chosen settings. Three idealized agrosystems, representing a large fraction of the global diversity of wheat-based agrosystems, are considered, which represent the settings of the analysis. Several components of global changes are considered in their consequences on global wheat health: climate change and climate variability, nitrogen fertilizer use, tillage, crop rotation, pesticide use, and the deployment of host plant resistances. Each idealized agrosystem is associated with a scenario of change that considers first, a production situation and its dynamics, and second, the impacts of the evolving production situation on the evolution of crop health. Crop health is represented by six functional groups of wheat pathogens: the pathogens associated with Fusarium head blight; biotrophic fungi, Septoria-like fungi, necrotrophic fungi, soilborne pathogens, and insect-transmitted viruses. The analysis of scenario outcomes is conducted along a risk-analytical pattern, which involves risk probabilities represented by categorized probability levels of disease epidemics, and risk magnitudes represented by categorized levels of crop losses resulting from these levels of epidemics within each production situation. The results from this scenario analysis suggest an overall increase of risk probabilities and magnitudes in the three idealized agrosystems. Changes in risk probability or magnitude however vary with the agrosystem and the functional groups of pathogens. We discuss the effects of global changes on the six functional groups, in terms of their epidemiology and of the crop losses they cause. Scenario analysis enables qualitative analysis of complex systems, such as plant pathosystems that are evolving in response to global changes, including climate change and technology shifts. It also provides a useful framework for quantitative simulation modeling analysis for plant disease epidemiology. PMID- 28643578 TI - Coronary microvascular dysfunction in diabetes mellitus. AB - The significance, mechanisms and consequences of coronary microvascular dysfunction associated with diabetes mellitus are topics into which we have insufficient insight at this time. It is widely recognized that endothelial dysfunction that is caused by diabetes in various vascular beds contributes to a wide range of complications and exerts unfavorable effects on microcirculatory regulation. The coronary microcirculation is precisely regulated through a number of interconnected physiological processes with the purpose of matching local blood flow to myocardial metabolic demands. Dysregulation of this network might contribute to varying degrees of pathological consequences. This review discusses the most important findings regarding coronary microvascular dysfunction in diabetes from pre-clinical and clinical perspectives. PMID- 28643582 TI - Adverse Childhood Circumstances and Functional Status Throughout Adult Life. AB - OBJECTIVE: We studied the association of childhood adversity with adult functional status. METHOD: With data from the Panel Study of Income Dynamics and the 2014 Childhood Retrospective Circumstances Study (1992-2013; N = 6,705; 62,885 person-years), we estimated functional status transition probabilities associated with childhood adversity, with multinomial logistic Markov models adjusted for age, sex, race/ethnicity, and education. Microsimulation then estimated functional status outcomes throughout adulthood for African American, Hispanic, and non-Hispanic White women and men. RESULTS: Adversity was significantly associated with functional status. Of White women without adversities, 2.3% had difficulty doing activities of daily living at age 30, compared with 8.2% with high adversity; comparable results were 3.7% and 8.7% for African Americans, 0.9% and 11.5% for Hispanics (all p < .01). Patterns were similar at other ages, for men, and when adjusted for midlife health conditions and health behavior. DISCUSSION: Childhood adversity may substantially increase functional impairment throughout adult life. PMID- 28643583 TI - Hemodynamic stability during laryngeal electromyography procedures. AB - BACKGROUND: Laryngeal electromyography (LEMG) is accepted as safe, with minimal side effects. However, patient hemodynamic stability, during these procedures, has not been reported. This study aimed to investigate the hemodynamics in patients undergoing LEMG and determine the risk factors for hemodynamic changes. METHODS: We recruited 89 consecutive patients who underwent LEMG. Baseline and postprocedural changes in vital signs were analyzed. RESULTS: Diastolic blood pressure (DBP) increased from 75.08 +/- 11.54 mmHg preprocedure to 77.4 +/- 11.91 mmHg postprocedure (p = .006); pulse rate (PR) increased from 78.1 +/- 13.3 beats per minute preprocedure to 80.02 +/- 13.69 postprocedure (p = .027). Systolic blood pressure (SBP) and oxygen saturation were unchanged after the procedure. However, about 17% of patients experienced profound changes in vital signs of >20% above baseline during LEMG. The hemodynamic changes did not differ between sexes or between surgical and non-surgical etiologies of vocal fold paralysis. Two patients experienced profound but reversible near-syncope during the procedure. CONCLUSIONS: LEMG is a safe procedure with few immediate complications, though it may affect the patient's hemodynamic status by increasing DBP and PR. The hemodynamic monitoring is recommended so that timely intervention can be applied in case any warning sign occurs. PMID- 28643584 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results of the Czech Republic. AB - INTRODUCTION: In order to estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, in the societal perspective, in CZK 2015. RESULTS: A total of 747 patients (mean age 47 years) participated; 86% were below retirement age and of these, 49% were employed. Employment was related to disease severity, and MS affected productivity at work for 82% of those working. Overall, 92% and 66% of patients experienced fatigue and cognitive difficulties as a problem. Mean utility and annual costs were 0.832 and 257,000CZK at Expanded Disability Status Scale (EDSS) 0-3, 0.530 and 425,500CZK at EDSS 4-6.5 and 0.141 and 489,000CZK at EDSS 7-9. The average cost of a relapse was estimated at 12,600CZK. CONCLUSION: This study provides current data on MS in the Czech Republic that are important for the development of health policies. PMID- 28643585 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Portugal. AB - BACKGROUND: In order to assess the value of management strategies in multiple sclerosis (MS), outcome data have to be combined with cost data. This, in turn, requires that cost data be regularly updated. OBJECTIVE AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity and health-related quality of life (HRQoL). Descriptive analyses are presented by level of severity; costs are estimated in the societal perspective, in EUR 2015. RESULTS: A total of 535 patients (mean age 48.5 years) participated; 92% were below retirement age and of these, 43% were employed. Employment was related to disease severity, and MS was felt to affect productivity at work by 72% of patients, most often through fatigue. Overall, 98% and 74% of patients felt that fatigue and cognition were a problem. Mean utility and costs were 0.756 and ?16,500 at the Expanded Disability Status Scale (EDSS) 0-3, 0.572 and ?28,700 at EDSS 4-6.5 and 0.206 and ?34,400 at EDSS 7-9. The average cost of a relapse was estimated at ?2930. CONCLUSION: This study illustrates the burden of MS on Portuguese patients and provides current data that are important for the development of health policies. PMID- 28643586 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Poland. AB - BACKGROUND: In order to estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVE AND METHODS: This study is part of a cross-sectional retrospective study in 16 European countries collecting current data on resource consumption, work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in 2015 Polish Zloty (PLN). RESULTS: A total of 411 MS patients (mean age = 40 years) participated in Poland; 94% were below retirement age, and of these, 59% were employed. Employment was related to disability, and MS affected productivity for 85% of those working. Overall, 97% and 71% of patients experienced fatigue and cognition as important problems, respectively. Mean utility and total annual costs were 0.686 and 48,700 PLN at Expanded Disability Status Scale (EDSS) 0-3, 0.521 and 59,200 PLN at EDSS 4-6.5 and 0.208 and 81,600 PLN at EDSS 7-9, respectively. The average cost of a relapse was 3,900 PLN. CONCLUSION: This study illustrates the burden of MS on Polish patients and provides current data that are important for developing health policies. PMID- 28643587 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for the United Kingdom. AB - INTRODUCTION: In order to estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of disability, from the societal perspective, in EUR (2015). RESULTS: A total of 779 patients (mean age = 57 years) participated; 72% were below retirement age and of these, 36% were employed. Employment was related to disease severity, and MS affected productivity at work for 84% of patients. Overall, 96% and 72% of the patients experienced fatigue and cognition as a problem. Mean utility and annual costs were 0.735 and 11,400GBP at Expanded Disability Status Scale (EDSS) = 0-3, 0.534 and 22,700GBP at EDSS = 4-6.5, and 0.135 and 36,500GBP at EDSS = 7-9. The mean cost of a relapse was estimated at 790GBP. CONCLUSION: This study illustrates the burden of MS on UK patients and provides current data on MS that are important for development of health policies. PMID- 28643588 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for France. AB - INTRODUCTION: To estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, in the societal perspective, in EUR 2015. RESULTS: A total of 491 patients (mean age 47 years) participated; 82% were below retirement age, and of these 56% were employed. Employment was related to disease severity, and MS affected productivity at work for 90% of patients. Overall, 95% and 67% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.735 and ?22,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.500 and ?38,100 at EDSS 4-6.5, and 0.337 and ?48,100 at EDSS 7-9, respectively. The average cost of a relapse was estimated at ?2300. CONCLUSION: This study provides current data on MS in France that are important for developments of health policies and to estimate the value of current and future treatments. PMID- 28643589 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Denmark. AB - BACKGROUND: To estimate the value of treatments in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with cost data. This, in turn, requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in 2015 Danish Kronor (DKK). RESULTS: A total of 830 patients (mean age of 54 years) participated; 78% were below retirement age and of these, 43% were employed. Employment was related to disease severity, and MS was felt to affect productivity at work by 73% of patients, most often through fatigue. Overall, 95% and 65% of patients felt that fatigue and cognition, respectively, were a problem. Mean utility and costs were 0.770 and 196,900DKK at Expanded Disability Status Scale (EDSS) 0-3, 0.619 and 287,300DKK at EDSS 4-6.5, and 0.302 and 533,250DKK at EDSS 7-9. The average cost of a relapse was estimated at 19,000DKK. CONCLUSION: This study illustrates the burden of MS on Danish patients and provides current data that are important for the development of health policies. PMID- 28643590 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Russia. AB - BACKGROUND: In order to assess the value of management strategies in multiple sclerosis (MS), outcome data have to be combined with cost data. This, in turn, requires that cost data be regularly updated. OBJECTIVE AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity and health-related quality of life (HQoL). Descriptive analyses are presented by level of severity; costs are estimated in the societal perspective, in RUB 2015. RESULTS: A total of 208 patients (mean age: 38.5 years) participated in the Russian study; 97% were below retirement age, and of these, 49% were employed. MS was reported to affect productivity at work in 63% of patients. Overall, 87% and 41% of patients felt that fatigue and cognition were a problem. The mean utility and costs were 0.769 and 578,000 RUB at Expanded Disability Status Scale (EDSS) 0-3, 0.509 and 826,000 RUB at EDSS 4-6.5, and 0.071 and 1,013,000 RUB at EDSS 7-9. The average cost of a relapse was 33,000 RUB. CONCLUSION: This study illustrates the burden of MS on Russian patients and provides current data that are important for developing health policies. PMID- 28643591 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Hungary. AB - INTRODUCTION: To estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption, work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of disability, from the societal perspective, in HUF 2015. RESULTS: A total of 521 patients (mean age 47 years) participated; 85% were below retirement age, and of these, 47% were employed. Employment was related to disability and MS affected productivity at work for 82% of those working. Overall, 94% and 66% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and annual costs were 0.691 and 3,432,000HUF at Expanded Disability Status Scale (EDSS) 0-3, 0.491 and 5,262,000HUF at EDSS 4-6.5 and 0.076 and 6,235,000HUF at EDSS 7-9, respectively. The average cost of a relapse was estimated at 240,500HUF. CONCLUSION: This study illustrates the burden of MS on Hungarian patients and provides current data that are important for the development of health policies. PMID- 28643592 TI - The burden of multiple sclerosis 2015: Methods of data collection, assessment and analysis of costs, quality of life and symptoms. AB - INTRODUCTION: This article describes the methods used to perform this large European-wide burden-of-illness study on multiple sclerosis (MS) using individual patient data. METHODS: The study collected all MS-related resource consumption, workforce participation, prevalent disease symptoms and health-related quality of life (HRQoL). Patients were recruited by national patient associations and, after informed consent, completed a specific questionnaire either on-line or on paper. Analyses were performed by country as well as for the study overall. Costs were estimated from the societal perspective, using publicly available unit costs and reported in national currencies and in EUR 2015 adjusted for purchasing power parity. The results are reported by disease severity groups according to self assessed Expanded Disability Status Scale (EDSS) (mild, moderate, severe) and by EDSS point to highlight the development of costs as disability progresses. RESULTS: A total of 16,808 patients in 16 countries participated in the study: Austria, Belgium, Denmark, Czech Republic, France, Germany, Hungary, Italy, the Netherlands, Poland, Portugal, Russia, Spain, Sweden, Switzerland and the United Kingdom. CONCLUSION: This study, endorsed by the European Platform of MS Societies, provides up-to-date information on costs and expands the previously available information on HRQoL and symptoms. PMID- 28643594 TI - Editorial. PMID- 28643593 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Germany. AB - INTRODUCTION: To estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in EUR 2015. RESULTS: A total of 5475 patients (mean age 52 years) participated in Germany. In all, 84% were below retirement age, and of these, 51% were employed. Employment was related to disease severity, and MS affected productivity at work for 80% of patients. Overall, 96% and 78% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and total annual costs were 0.786 and 28,200? at Expanded Disability Status Scale (EDSS) 0-3, 0.586 and ?44,000 at EDSS 4-6.5 and 0.273 and ?62,700 at EDSS 7-9, respectively. The mean cost of a relapse was estimated at ?2500. CONCLUSION: This study provides current health economic data on MS in Germany that are important for the development of health policies and for estimating the value of the current and future treatments. PMID- 28643595 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for the Netherlands. AB - INTRODUCTION: To estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in EUR 2015. RESULTS: A total of 382 patients (mean age: 54 years) participated in the Netherlands; 81% were below retirement age and of these, 31% were employed. Employment was inversely related to disease severity, and MS affected productivity at work for 82% of patients. Overall, 96% and 73% of patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.744 and ?23,100 at Expanded Disability Status Scale (EDSS) 0-3, 0.595 and ?32,300 at EDSS 4-6.5, and 0.297 and ?50,500 at EDSS 7-9. The mean cost of a relapse was estimated at ?3000. CONCLUSION: This study provides current data on MS in the Netherlands that are important for the development of health policies and to estimate the value of current and future treatments. PMID- 28643596 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Switzerland. AB - INTRODUCTION: To estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in CHF 2015. RESULTS: A total of 721 patients (mean age 48 years) participated in Switzerland; 90% were below retirement age, and of these, 65% were employed. Employment was related to disease severity, and MS affected productivity at work for 69% of patients. Overall, 93% and 64% of patients experienced fatigue and cognition as a problem, respectively. The mean utility and annual costs were 0.799 and 29,600CHF at Expanded Disability Status Scale (EDSS) 0-3, 0.614 and 66,800CHF at EDSS 4-6.5 and 0.348 and 110,800CHF at EDSS 7 9, respectively. The mean cost of a relapse was estimated at 7600CHF. CONCLUSION: This study provides current data on MS in Switzerland that are important for development of health policies and to estimate the value of current and future treatments. PMID- 28643597 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Spain. AB - INTRODUCTION: In order to estimate the value of interventions in multiple sclerosis (MS) where lifetime costs and outcomes cannot be observed, outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption, work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in EUR 2015. RESULTS: A total of 462 patients (mean age 43 years) participated in Spain; 96% were below retirement age and of these, 45% were employed. Employment was related to disability, and MS affected productivity at work for 72% of those working. Overall, 92% and 64% of patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were estimated at 0.772 and ?20,600 at Expanded Disability Status Scale (EDSS) 0-3, 0.486 and ?48,500 at EDSS 4-6.5 and 0.182 and ?68,700 at EDSS 7-9, respectively. The mean cost of a relapse was ?2050. CONCLUSION: This study illustrates the burden of MS on Spanish patients and provides current data that are important for development of health policies. PMID- 28643598 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Belgium. AB - INTRODUCTION: In order to estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in EUR 2015. RESULTS: A total of 1856 patients (mean age: 54 years) participated in Belgium; 66% were below retirement age, and of these, 44% were employed. Employment was related to disease severity, and MS affected productivity at work in 85% of the patients. Overall, 95% and 72% of the patients experienced fatigue and cognitive difficulties, respectively, as a problem. Mean utility and annual costs were 0.703 and ?26,400 at Expanded Disability Status Scale (EDSS) 0-3, 0.478 and ?45,300 at EDSS 4-6.5, and 0.193 and ?62,000 at EDSS 7-9. The mean cost of a relapse was estimated to be ?3000. CONCLUSION: This study provides current data on MS in Belgium that are important for development of health policies and for estimating the value of current and future treatments. PMID- 28643599 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Austria. AB - INTRODUCTION: In order to estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in EUR 2015. RESULTS: A total of 516 patients (mean age, 53 years) participated in Austria; 72% were below retirement age, and of these, 46% were employed. Employment was related to disability, and MS affected productivity at work for 77% of those working. Overall, 94% and 67% of patients experienced fatigue and cognition as a problem. Mean utility and total annual costs were 0.778 and 25,100? at Expanded Disability Status Scale (EDSS) 0-3, 0.579 and 44,100? at EDSS 4-6.5, and 0.244 and 73,800? at EDSS 7-9. The mean cost of a relapse was estimated at 2563?. CONCLUSION: This study illustrates the burden of MS on Austrian patients and provides current data on MS that are important for development of health policies. PMID- 28643600 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Italy. AB - INTRODUCTION: In order to estimate the value of interventions in multiple sclerosis (MS) - where lifetime costs and outcomes cannot be observed - outcome data have to be combined with costs. This requires that cost data be regularly updated. OBJECTIVES AND METHODS: This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in EUR 2015. RESULTS: A total of 1010 patients (mean age = 45 years) participated in Italy. In total, 94% were below retirement age, and of these, 56% were employed. Employment was related to disability, and MS affected productivity at work in 77% of the patients. Overall, 96% and 65% of the patients experienced fatigue and cognitive difficulties as a problem, respectively. Mean utility and total annual costs were 0.735 and ?22,900 at Expanded Disability Status Scale (EDSS) of 0-3, 0.534 and ?40,100 at EDSS of 4 6.5, and 0.135 and ?53,300 at EDSS of 7-9. The mean cost of a relapse was estimated to be ?2600. CONCLUSION: This study illustrates the burden of MS on Italian patients and provides current data on MS that are important for the development of health policies. PMID- 28643601 TI - New insights into the burden and costs of multiple sclerosis in Europe: Results for Sweden. AB - BACKGROUND: To assess the value of management strategies in multiple sclerosis (MS), outcome data have to be combined with cost data. This requires that cost data be regularly updated. OBJECTIVE AND METHODS: This study is part of a cross sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity and health-related quality of life (HRQoL). Descriptive analyses are presented by level of severity; costs are estimated in the societal perspective, in 2015 SEK. RESULTS: A total of 1864 patients (mean age 56 years) participated in Sweden; 74% were below retirement age, and of these, 55% were employed. MS was reported to affect productivity at work in 78% of patients. Overall, 94% and 72% of patients felt that fatigue and cognition were a problem, respectively. The mean utility and costs were 0.757 and 244,000SEK at Expanded Disability Status Scale (EDSS) 0-3, 0.563 and 384,000SEK at EDSS 4-6.5 and 0.202 and 888,000SEK at EDSS 7-9, respectively. The average cost of a relapse was 36,900SEK. CONCLUSION: This study illustrates the burden of MS on Swedish patients and provides current data that are important for the development of health policies. PMID- 28643602 TI - Acute-phase proteins in pregnant goats: a longitudinal study. AB - We documented changes in serum amyloid A (SAA) and haptoglobin (Hp) concentration in goats during pregnancy, as measured by competitive ELISAs. Fifteen does (pregnant group) and 20 castrated males (control group) were enrolled in the study. Blood samples were collected on the same day from all 35 goats, 7 times throughout the study period: at mating, then once every month, during the week preceding kidding, and 1 mo after kidding. Baseline SAA and Hp concentrations at mating were identical in the 2 groups. In the pregnant group, SAA concentration rose significantly in the second month and remained elevated until the end of pregnancy, with the peak concentration at kidding. In the control group, SAA concentration remained unchanged compared to the baseline concentration throughout the study. SAA concentration was significantly higher in the pregnant than control group only at the end of the fourth month of pregnancy and at kidding. Hp concentration did not change during pregnancy or between groups. SAA concentration at kidding was affected only by parity of does - it was highest in does in the third and fourth pregnancy and gradually lower in older does. PMID- 28643604 TI - Long non-coding RNAs: New biomarkers for prognosis and diagnosis of colon cancer. AB - Dysregulation of long non-coding RNAs has been found in many human cancers, including colorectal cancer that is still the third most prevalent cancer worldwide and related to poor prognosis; along with this, robust testimony has identified that long non-coding RNAs can take charge of tumor suppressor genes or oncogenes. This review summarizes nowadays research achievements on the character of long non-coding RNAs in the prognosis and diagnosis of colorectal cancer. On the basis of the results acquired in the last decade, some long non-coding RNAs are rising as biomarkers of colorectal cancer for prognosis, diagnosis, even prediction of therapeutic result, and have crucial effects in the regulation of colorectal cancer cell functions such as proliferation, invasion, apoptosis, metastasis, and drug resistant ability. Also, long non-coding RNAs, circulating in body fluids, could act as novel, affordable, lightly accessible, non-invasive detection tools for the personal health management of patients with colorectal cancer. Especially, circulating long non-coding RNA profiles may be demonstrating preferable prognostic and diagnostic capability and better accuracy than respective long non-coding RNAs in colorectal cancer. PMID- 28643603 TI - Stroke-like migraine attacks after radiation therapy syndrome: Case report and review of the literature. AB - A 26-year-old female presented with vision loss accompanied by migraine-like headaches. A contrast-enhanced magnetic resonance imaging of the brain was performed which revealed findings suggestive of stroke-like migraine attacks after radiation therapy (SMART) syndrome. SMART syndrome is a delayed complication of brain radiation characterized by neurologic symptoms including migraine-like headaches, seizures, and hemispheric impairment. The purpose of this article is to make the readers aware of this rare complication of brain irradiation. Appropriate diagnosis of SMART syndrome is essential to avoid invasive tests. PMID- 28643606 TI - Origin of low-molecular mass aldehydes as disinfection by-products in beverages. AB - A novel, simple and automatic method based on static headspace-gas chromatography mass spectrometry has been developed to determine 10 low-molecular mass aldehydes that can be found in beverages, coming from the treated water used in their production. These aldehydes are the most frequently found in treated water as water disinfection by-products, so they can be used as indicators of the addition of treated water to beverages. The study covered a large number of fruit juices and soft drinks. The presence of the whole array of analytes is related to the contact with treated water during beverage production, mainly by the addition of treated water as ingredient. In particular, propionaldehyde, valeraldehyde and benzaldehyde can be used as indicators of the addition of treated water in these kinds of beverages. Among the ten aldehydes, only formaldehyde and acetaldehyde are naturally present in all kinds of fruit, and their concentrations are related to stage of the ripening of the fruit. PMID- 28643605 TI - Novel Simulation Device for Targeting Tumors in Laparoscopic Ablation: A Learning Curve Study. AB - INTRODUCTION: A novel 3-dimensional (3D) guidance system was developed to aid accurate needle placement during ablation. METHODS: Five novices and 5 experienced hepatobiliary surgeons were recruited. Using an agar block with analog tumor, participants targeted under 4 conditions: in-line with the ultrasound plane using ultrasound, in-line using 3D guidance, 45 degrees off axis using ultrasound, and off-axis using 3D guidance. Time to target the tumor, number of withdrawals, and the National Aeronautics and Space Administration Task Load Index were collected. Initial and final parameters for each of the conditions were compared using a within-subjects paired t test. RESULTS: A significant reduction was seen in the number of required withdrawals in all situations when using the 3D guidance (0.75 vs 3.65 in-line and 0.25 vs 3.6 for off-axis). Mental workload was significantly lower when using 3D guidance compared with ultrasound both for novices (29.85 vs 41.03) and experts (31.98 vs 44.57), P < .001 for both. The only difference in targeting time between first and last attempt was in the novice group during off-axis targeting using 3D guidance (115 vs 32.6 seconds, P = .03). CONCLUSION: Though 3D guidance appeared to decrease time to target, this was not statistically significant likely as a result of lack of power in our trial. Three-dimensional guidance did reduce the number of required withdrawals, potentially decreasing complications, as well as mental workload after proficiency was achieved. Furthermore, novices without experience in ultrasound were able to learn targeting with the 3D guidance system at a faster pace than targeting with ultrasound alone. PMID- 28643607 TI - Diabetes Self-management Training in a Virtual Environment. AB - Diabetes self-management training (DSMT) improves diabetes health outcomes. However, low numbers of patients receive DSMT. Using virtual environments (VEs) for DSMT is an innovative approach to removing barriers for patients. The purpose of this paper is to describe the experience of health professionals and diabetes educators establishing and teaching DSMT in a VE, Diabetes LIVE(c) (Learning in Virtual Environments), and the implications for future use of VEs in DSMT. It was found that providing DSMT in a VE preserves real-time interaction between patients and educators. To facilitate ongoing patient learning and engagement, the DSMT curriculum was expanded beyond the core content as "Above and Beyond" topics. Using a VE for DSMT presents challenges and opportunities. Challenges include overcoming technological barriers and improving comfort levels to orient educators and patients to the functionality of the VE. Opportunities include overcoming barriers to reaching patients, particularly given the diabetes epidemic and relatively small number of diabetes educators. Using a VE also affords a simulated community for experiential learning. VEs may become powerful tools for diabetes and other health educators to reach patients. Ongoing education and support are vital to successful self-management of chronic disease. PMID- 28643609 TI - Editorial. PMID- 28643610 TI - Cognitive Behaviour Therapy (CBT) for menopausal symptoms: Information for GPs and health professionals. PMID- 28643611 TI - Practice observed. PMID- 28643612 TI - Cognitive Behaviour Therapy (CBT) for menopausal symptoms. Information for women Myra Hunter and Melanie Smith in collaboration with the British Menopause Society. PMID- 28643614 TI - Consensus statement for non-hormonal-based treatments for menopausal symptoms. AB - Since the June 2014 consensus statement published in Post Reproductive Health we have had definitive guidelines on menopause treatment from the National Institute for Clinical Excellence in November 2015. These included robust and evidence based information about many non-estrogen based treatments, which are particularly useful for patients who do not wish to take hormone replacement therapy, or who have medical contraindications to hormonal therapy such as hormone dependent cancers. Whilst none of these therapies is as effective as hormones, we must be able to advise patients about them and recommend which treatments may be helpful for individual women. PMID- 28643615 TI - Migrant caregiving for family members with mild cognitive impairment: an ethnographic study. AB - BACKGROUND: Migrant families caring for family members with mild cognitive impairment (MCI) face considerable socioeconomic burden and isolation. AIM: To examine the cultural needs, beliefs and health seeking behaviours of migrant Turkish family member caregivers. DESIGN: An ethnographic approach was used employing in depth interviews. METHODS: Turkish caregivers residing in Melbourne, Australia were purposively sampled. Ten participants undertook face-to-face interviews in Turkish and English, followed by coding, transcription and thematic analysis. RESULTS: Common themes were: (i) characteristics of MCI; (ii) care complicates our lives; (iii) beneficial coping strategies; (iv) adherence to cultural beliefs; (v) an uncertain future; (vi) interfacing with community health providers: need to understand Turkish culture (vii) need for long-term support. Migrant caregivers voiced undergoing considerable stress exacerbated by their cultural obligations. CONCLUSIONS: Establishing ethnically appropriate community support groups and advocating for a health workforce tier of representative migrant health care workers is recommended as a new role for community nurses. PMID- 28643616 TI - Advanced neuroimaging of carbon monoxide poisoning. AB - Carbon monoxide (CO) inhalation is nowadays the most common cause of fatal poisoning worldwide. CO binds to haemoglobin 230-270 times more avidly than oxygen, thus leading to formation of carboxyhaemoglobin with subsequent reduction of tissue oxygenation. Brain is mainly affected due to its high oxygen requirement. Up to two-thirds of patients who survive the acute phase of this pathology present a delayed leukoencephalopathy, usually in a period ranging from two to 40 days. White matter damage closely relates to long-term prognosis of these patients. On the other hand CO seems to play a fundamental role as a possible neuro-protective agent in ischaemic stroke. Diagnostic imaging, with computed tomography and magnetic resonance imaging, especially magnetic resonance spectroscopy, is very useful to depict the presence and extension of this pathology, in both acute and late phase. Nevertheless, a correlation of imaging studies with clinical history and laboratory data is fundamental to perform the correct diagnosis. The purpose of this article is to highlight the imaging features of brain CO poisoning in acute and late phase, describing a case report of a 56-year-old man found unconscious at home. PMID- 28643617 TI - Preselection statistics and Random Forest classification identify population informative single nucleotide polymorphisms in cosmopolitan and autochthonous cattle breeds. AB - Commercial single nucleotide polymorphism (SNP) arrays have been recently developed for several species and can be used to identify informative markers to differentiate breeds or populations for several downstream applications. To identify the most discriminating genetic markers among thousands of genotyped SNPs, a few statistical approaches have been proposed. In this work, we compared several methods of SNPs preselection (Delta, F st and principal component analyses (PCA)) in addition to Random Forest classifications to analyse SNP data from six dairy cattle breeds, including cosmopolitan (Holstein, Brown and Simmental) and autochthonous Italian breeds raised in two different regions and subjected to limited or no breeding programmes (Cinisara, Modicana, raised only in Sicily and Reggiana, raised only in Emilia Romagna). From these classifications, two panels of 96 and 48 SNPs that contain the most discriminant SNPs were created for each preselection method. These panels were evaluated in terms of the ability to discriminate as a whole and breed-by-breed, as well as linkage disequilibrium within each panel. The obtained results showed that for the 48-SNP panel, the error rate increased mainly for autochthonous breeds, probably as a consequence of their admixed origin lower selection pressure and by ascertaining bias in the construction of the SNP chip. The 96-SNP panels were generally more able to discriminate all breeds. The panel derived by PCA-chrom (obtained by a preselection chromosome by chromosome) could identify informative SNPs that were particularly useful for the assignment of minor breeds that reached the lowest value of Out Of Bag error even in the Cinisara, whose value was quite high in all other panels. Moreover, this panel contained also the lowest number of SNPs in linkage disequilibrium. Several selected SNPs are located nearby genes affecting breed-specific phenotypic traits (coat colour and stature) or associated with production traits. In general, our results demonstrated the usefulness of Random Forest in combination to other reduction techniques to identify population informative SNPs. PMID- 28643618 TI - Heat-stabilised rice bran consumption by colorectal cancer survivors modulates stool metabolite profiles and metabolic networks: a randomised controlled trial. AB - Rice bran (RB) consumption has been shown to reduce colorectal cancer (CRC) growth in mice and modify the human stool microbiome. Changes in host and microbial metabolism induced by RB consumption was hypothesised to modulate the stool metabolite profile in favour of promoting gut health and inhibiting CRC growth. The objective was to integrate gut microbial metabolite profiles and identify metabolic pathway networks for CRC chemoprevention using non-targeted metabolomics. In all, nineteen CRC survivors participated in a parallel randomised controlled dietary intervention trial that included daily consumption of study-provided foods with heat-stabilised RB (30 g/d) or no additional ingredient (control). Stool samples were collected at baseline and 4 weeks and analysed using GC-MS and ultra-performance liquid chromatography-MS. Stool metabolomics revealed 93 significantly different metabolites in individuals consuming RB. A 264-fold increase in beta-hydroxyisovaleroylcarnitine and 18-fold increase in beta-hydroxyisovalerate exemplified changes in leucine, isoleucine and valine metabolism in the RB group. A total of thirty-nine stool metabolites were significantly different between RB and control groups, including increased hesperidin (28-fold) and narirutin (14-fold). Metabolic pathways impacted in the RB group over time included advanced glycation end products, steroids and bile acids. Fatty acid, leucine/valine and vitamin B6 metabolic pathways were increased in RB compared with control. There were 453 metabolites identified in the RB food metabolome, thirty-nine of which were identified in stool from RB consumers. RB consumption favourably modulated the stool metabolome of CRC survivors and these findings suggest the need for continued dietary CRC chemoprevention efforts. PMID- 28643619 TI - Dietary leucine supplementation alters energy metabolism and induces slow-to-fast transitions in longissimus dorsi muscle of weanling piglets. AB - Leucine plays an important role in promoting muscle protein synthesis and muscle remodelling. However, what percentage of leucine is appropriate in creep feed and what proteome profile alterations are caused by dietary leucine in the skeletal muscle of piglets remain elusive. In this case, we applied isobaric tags for relative and absolute quantitation to analyse the proteome profile of the longissimus dorsi muscles of weanling piglets fed a normal leucine diet (NL; 1.66 % leucine) and a high-leucine diet (HL; 2.1 % leucine). We identified 157 differentially expressed proteins between these two groups. Bioinformatics analysis of these proteins exhibited the suppression of oxidative phosphorylation and fatty acid beta-oxidation, as well as the activation of glycolysis, in the HL group. For further confirmation, we identified that SDHB, ATP5F1, ACADM and HADHB were significantly down-regulated (P<0.01, except ATP5F1, P<0.05), whereas the glycolytic enzyme pyruvate kinase was significantly up-regulated (P<0.05) in the HL group. We also show that enhanced muscle protein synthesis and the transition from slow-to-fast fibres are altered by leucine. Together, these results indicate that leucine may alter energy metabolism and promote slow-to-fast transitions in the skeletal muscle of weanling piglets. PMID- 28643620 TI - Adult dogs are capable of regulating calcium balance, with no adverse effects on health, when fed a high-calcium diet. AB - Although the implications of long-term high Ca intakes have been well documented in growing dogs, the health consequences of Ca excess in adult dogs remain to be established. To evaluate the impact of feeding a diet containing 7.1 g/4184 kJ (1000 kcal) Ca for 40 weeks on Ca balance and health parameters in adult dogs, eighteen neutered adult Labrador Retrievers, (nine males and nine females) aged 2.5-7.4 years were randomised to one of two customised diets for 40 weeks. The diets were manufactured according to similar nutritional specifications, with the exception of Ca and P levels. The diets provided 1.7 and 7.1 g/4184 kJ (1000 kcal) (200(SD26) and 881(SD145) mg/kg body weight0.75 per d, respectively) Ca, respectively, with a Ca:P ratio of 1.6. Clinical examinations, ultrasound scans, radiographs, health parameters, metabolic effects and mineral balance were recorded at baseline and at 8-week intervals throughout the study. Dogs in both groups were healthy throughout the trial without evidence of urinary, renal or orthopaedic disease. In addition, there were no clinically relevant changes in any of the measures made in either group (all P>0.05). The high-Ca diet resulted in a 3.3-fold increase in faecal Ca excretion (P0.05). Ca intakes of up to 7.1 g/4184 kJ (1000 kcal) are well tolerated over a period of 40 weeks, with no adverse effects that could be attributed to the diet or to a high mineral intake. PMID- 28643621 TI - Linoleic acid, alpha-linolenic acid and enterolactone affect lipid oxidation and expression of lipid metabolism and antioxidant-related genes in hepatic tissue of dairy cows. AB - Although beneficial effects have been attributed to PUFA supplementation in high yielding dairy cows, diets rich in PUFA may also increase oxidative stress in tissues such as the liver. To fully exploit the health benefits of PUFA, we believe that the addition of natural antioxidants could help in preventing oxidative damage. Using an in vitro precision-cut liver slices (PCLS) tissue culture system, we investigated the effects of different linoleic acid (LA, n 6):alpha-linolenic acid (ALA, n-3) ratios (LA:ALA ratio of 4, LA:ALA ratio of 15 and LA:ALA ratio of 25) in the presence or absence of the antioxidant enterolactone (ENL) on (1) the mRNA abundance of genes with key roles in hepatic lipid metabolism, oxidative stress response and inflammatory processes, (2) oxidative damages to lipids and proteins and (3) superoxide dismutase activity in early-lactating dairy cows. The addition of LA and ALA to PCLS culture media increased oxidative damage to lipids as suggested by higher concentrations of thiobarbituric acid reactive substances and increased the expression of nuclear factor erythroid 2-related factor 2 target genes. The addition of ENL was effective in preventing lipid peroxidation caused by LA and ALA. Transcript abundance of sterol regulatory element-binding transcription factor 1 and its lipogenic target genes acetyl-CoA carboxylase alpha, fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD) was decreased with LA and ALA, whereas ENL decreased FASN and SCD gene expression. Our results show that addition of LA and ALA to PCLS culture media lowers hepatic lipogenic gene expression and increases oxidative damages to lipids. On the other hand, addition of ENL prevents oxidative damages provoked by these PUFA. PMID- 28643623 TI - The Genomic Basis of Lactobacilli as Health-Promoting Organisms. AB - Lactobacilli occupy a unique position in human culture and scientific history. Like brewer's and baker's yeast, lactobacilli have been associated with food production and preservation for thousands of years. Lactobacillus species are used in mixed microbial cultures, such as the classical Lactobacillus bulgaricus/Streptococcus thermophilus inoculum for yogurt fermentation, or combinations of diverse lactobacilli/yeasts in kefir grains. The association of lactobacilli consumption with greater longevity and improved health formed the basis for developing lactobacilli as probiotics, whose market has exploded worldwide in the past 10 years. The decade that followed the determination of the first genome sequence of a food-associated species, Lactobacillus plantarum, saw the application to lactobacilli of a full range of functional genomics methods to identify the genes and gene products that govern their distinctive phenotypes and health associations. In this review, we will briefly remind the reader of the range of beneficial effects attributed to lactobacilli, and then explain the phylogenomic basis for the distribution of these traits across the genus. Recognizing the strain specificity of probiotic effects, we review studies of intraspecific genomic variation and their contributions to identifying probiotic traits. Finally we offer a perspective on classification of lactobacilli into new genera in a scheme that will make attributing probiotic properties to clades, taxa, and species more logical and more robust. PMID- 28643624 TI - Preclinical Efficacy Testing of New Drug Candidates. AB - This is a review of the preclinical efficacy testing of new antituberculosis drug candidates. It describes existing dynamic in vitro and in vivo models of antituberculosis chemotherapy and their utility in preclinical evaluations of promising new drugs and combination regimens, with an effort to highlight recent developments. Emphasis is given to the integration of quantitative pharmacokinetic/pharmacodynamic analyses and the impact of lesion pathology on drug efficacy. Discussion also includes in vivo models of chemotherapy of latent tuberculosis infection. PMID- 28643625 TI - Microbial Interactions and Interventions in Colorectal Cancer. AB - Recently, several lines of evidence that indicate a strong link between the development of colorectal cancer (CRC) and aspects of the gut microbiota have become apparent. However, it remains unclear how changes in the gut microbiota might influence carcinogenesis or how regional organization of the gut might influence the microbiota. In this review, we discuss several leading theories that connect gut microbial dysbiosis with CRC and set this against a backdrop of what is known about proximal-distal gut physiology and the pathways of CRC development and progression. Finally, we discuss the potential for gut microbial modulation therapies, for example, probiotics, antibiotics, and others, to target and improve gut microbial dysbiosis as a strategy for the prevention or treatment of CRC. PMID- 28643622 TI - Lung Microbiota and Its Impact on the Mucosal Immune Phenotype. AB - The use of culture-independent techniques has allowed us to appreciate that the upper and lower respiratory tract contain a diverse community of microbes in health and disease. Research has only recently explored the effects of the microbiome on the host immune response. The exposure of the human body to the bacterial environment is an important factor for immunological development; thus, the interaction between the microbiome and its host is critical to understanding the pathogenesis of disease. In this article, we discuss the mechanisms that determine the composition of the airway microbiome and its effects on the host immune response. With the use of ecological principles, we have learned how the lower airways constitute a unique niche subjected to frequent microbial migration (e.g., through aspiration) and constant immunological pressure. The discussion will focus on the possible inflammatory pathways that are up- and downregulated when the immune system is challenged by dysbiosis. Identification of potential markers and microbial targets to address the modulation of inflammation in early disease, when changes may have the most effect, will be critical for future therapies. PMID- 28643626 TI - What Defines the "Kingdom" Fungi? AB - The application of environmental DNA techniques and increased genome sequencing of microbial diversity, combined with detailed study of cellular characters, has consistently led to the reexamination of our understanding of the tree of life. This has challenged many of the definitions of taxonomic groups, especially higher taxonomic ranks such as eukaryotic kingdoms. The Fungi is an example of a kingdom which, together with the features that define it and the taxa that are grouped within it, has been in a continual state of flux. In this article we aim to summarize multiple lines of data pertinent to understanding the early evolution and definition of the Fungi. These include ongoing cellular and genomic comparisons that, we will argue, have generally undermined all attempts to identify a synapomorphic trait that defines the Fungi. This article will also summarize ongoing work focusing on taxon discovery, combined with phylogenomic analysis, which has identified novel groups that lie proximate/adjacent to the fungal clade-wherever the boundary that defines the Fungi may be. Our hope is that, by summarizing these data in the form of a discussion, we can illustrate the ongoing efforts to understand what drove the evolutionary diversification of fungi. PMID- 28643627 TI - Bifidobacteria and Their Health-Promoting Effects. AB - Bifidobacteria are members of the intestinal microbiota of mammals and other animals, and some strains are able to exert health-promoting effects. The genus Bifidobacterium belongs to the Actinobacteria phylum. Firmicutes, Bacteroidetes, and Actinobacteria constitute the most abundant phyla in the human intestinal microbiota, Firmicutes and Bacteroidetes being predominant in adults, and Actinobacteria in breast-fed infants, where bifidobacteria can reach levels higher than 90% of the total bacterial population. They are among the first microbial colonizers of the intestines of newborns, and play key roles in the development of their physiology, including maturation of the immune system and use of dietary components. Indeed, some nutrients, such as human milk oligosaccharides, are important drivers of bifidobacterial development. Some Bifidobacterium strains are considered probiotic microorganisms because of their beneficial effects, and they have been included as bioactive ingredients in functional foods, mainly dairy products, as well as in food supplements and pharma products, alone, or together with, other microbes or microbial substrates. Well-documented scientific evidence of their activities is currently available for bifidobacteria-containing preparations in some intestinal and extraintestinal pathologies. In this review, we focus on the role of bifidobacteria as members of the human intestinal microbiota and their use as probiotics in the prevention and treatment of disease. PMID- 28643629 TI - Faecal immunochemical tests to triage patients with lower abdominal symptoms for suspected colorectal cancer referrals in primary care: a systematic review and cost-effectiveness analysis. AB - BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the UK. Presenting symptoms that can be associated with CRC usually have another explanation. Faecal immunochemical tests (FITs) detect blood that is not visible to the naked eye and may help to select patients who are likely to benefit from further investigation. OBJECTIVES: To assess the effectiveness of FITs [OC-Sensor (Eiken Chemical Co./MAST Diagnostics, Tokyo, Japan), HM-JACKarc (Kyowa Medex/Alpha Laboratories Ltd, Tokyo, Japan), FOB Gold (Sentinel/Sysmex, Sentinel Diagnostics, Milan, Italy), RIDASCREEN Hb or RIDASCREEN Hb/Hp complex (R Biopharm, Darmstadt, Germany)] for primary care triage of people with low-risk symptoms. METHODS: Twenty-four resources were searched to March 2016. Review methods followed published guidelines. Summary estimates were calculated using a bivariate model or a random-effects logistic regression model. The cost effectiveness analysis considered long-term costs and quality-adjusted life-years (QALYs) that were associated with different faecal occult blood tests and direct colonoscopy referral. Modelling comprised a diagnostic decision model, a Markov model for long-term costs and QALYs that were associated with CRC treatment and progression, and a Markov model for QALYs that were associated with no CRC. RESULTS: We included 10 studies. Using a single sample and 10 ug Hb/g faeces threshold, sensitivity estimates for OC-Sensor [92.1%, 95% confidence interval (CI) 86.9% to 95.3%] and HM-JACKarc (100%, 95% CI 71.5% to 100%) indicated that both may be useful to rule out CRC. Specificity estimates were 85.8% (95% CI 78.3% to 91.0%) and 76.6% (95% CI 72.6% to 80.3%). Triage using FITs could rule out CRC and avoid colonoscopy in approximately 75% of symptomatic patients. Data from our systematic review suggest that 22.5-93% of patients with a positive FIT and no CRC have other significant bowel pathologies. The results of the base-case analysis suggested minimal difference in QALYs between all of the strategies; no triage (referral straight to colonoscopy) is the most expensive. Faecal immunochemical testing was cost-effective (cheaper and more, or only slightly less, effective) compared with no triage. Faecal immunochemical testing was more effective and costly than guaiac faecal occult blood testing, but remained cost effective at a threshold incremental cost-effectiveness ratio of L30,000. The results of scenario analyses did not differ substantively from the base-case. Results were better for faecal immunochemical testing when accuracy of the guaiac faecal occult blood test (gFOBT) was based on studies that were more representative of the correct population. LIMITATIONS: Only one included study evaluated faecal immunochemical testing in primary care; however, all of the other studies evaluated faecal immunochemical testing at the point of referral. Further, validation data for the Faecal haemoglobin, Age and Sex Test (FAST) score, which includes faecal immunochemical testing, showed no significant difference in performance between primary and secondary care. There were insufficient data to adequately assess FOB Gold, RIDASCREEN Hb or RIDASCREEN Hb/Hp complex. No study compared FIT assays, or FIT assays versus gFOBT; all of the data included in this assessment refer to the clinical effectiveness of individual FIT methods and not their comparative effectiveness. CONCLUSIONS: Faecal immunochemical testing is likely to be a clinically effective and cost effective strategy for triaging people who are presenting, in primary care settings, with lower abdominal symptoms and who are at low risk for CRC. Further research is required to confirm the effectiveness of faecal immunochemical testing in primary care practice and to compare the performance of different FIT assays. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016037723. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28643628 TI - Real-Time Whole-Genome Sequencing for Surveillance of Listeria monocytogenes, France. AB - During 2015-2016, we evaluated the performance of whole-genome sequencing (WGS) as a routine typing tool. Its added value for microbiological and epidemiologic surveillance of listeriosis was compared with that for pulsed-field gel electrophoresis (PFGE), the current standard method. A total of 2,743 Listeria monocytogenes isolates collected as part of routine surveillance were characterized in parallel by PFGE and core genome multilocus sequence typing (cgMLST) extracted from WGS. We investigated PFGE and cgMLST clusters containing human isolates. Discrimination of isolates was significantly higher by cgMLST than by PFGE (p<0.001). cgMLST discriminated unrelated isolates that shared identical PFGE profiles and phylogenetically closely related isolates with distinct PFGE profiles. This procedure also refined epidemiologic investigations to include only phylogenetically closely related isolates, improved source identification, and facilitated epidemiologic investigations, enabling identification of more outbreaks at earlier stages. WGS-based typing should replace PFGE as the primary typing method for L. monocytogenes. PMID- 28643630 TI - Molecular phylogeny of 42 species of Culicoides (Diptera, Ceratopogonidae) from three continents. AB - The genus Culicoides includes vectors of important animal diseases such as bluetongue and Schmallenberg virus (BTV and SBV). This genus includes 1300 species classified in 32 subgenera and 38 unclassified species. However, the phylogenetic relationships between different subgenera of Culicoides have never been studied. Phylogenetic analyses of 42 species belonging to 12 subgenera and 8 ungrouped species of genus Culicoides from Ecuador, France, Gabon, Madagascar and Tunisia were carried out using two molecular markers (28S rDNA D1 and D2 domains and COI mtDNA). Sequences were subjected to non-probabilistic (maximum parsimony) and probabilistic (Bayesian inference (BI)) approaches. The subgenera Monoculicoides, Culicoides, Haematomyidium, Hoffmania, Remmia and Avaritia (including the main vectors of bluetongue disease) were monophyletic, whereas the subgenus Oecacta was paraphyletic. Our study validates the subgenus Remmia (= Schultzei group) as a valid subgenus, outside of the subgenus Oecacta. In Europe, Culicoides obsoletus, Culicoides scoticus and Culicoides chiopterus should be part of the Obsoletus complex whereas Culicoides dewulfi should be excluded from this complex. Our study suggests that the current Culicoides classification needs to be revisited with modern tools. PMID- 28643632 TI - Severe Vaso-Occlusive Episodes Associated with Use of Systemic Corticosteroids in Patients with Sickle Cell Disease. AB - Patients with sickle cell disease (SCD) are occasionally prescribed systemic corticosteroids to treat steroid-responsive conditions. Additionally, use of systemic corticosteroids for sickle cell pain episodes and acute chest syndrome is under investigation. We report 4 patients with SCD who developed severe vaso occlusive events following the administration of systemic steroids. We also review similar cases from the literature and suggest measures for reducing the potential risk associated with use of systemic corticosteroids in this group of patients. We conclude that corticosteroids should be used with caution in patients with SCD. PMID- 28643636 TI - Reply. PMID- 28643637 TI - Reply. PMID- 28643640 TI - Oral mucosal diseases. PMID- 28643631 TI - The Anopheles gambiae 2La chromosome inversion is associated with susceptibility to Plasmodium falciparum in Africa. AB - Chromosome inversions suppress genetic recombination and establish co-adapted gene complexes, or supergenes. The 2La inversion is a widespread polymorphism in the Anopheles gambiae species complex, the major African mosquito vectors of human malaria. Here we show that alleles of the 2La inversion are associated with natural malaria infection levels in wild-captured vectors from West and East Africa. Mosquitoes carrying the more-susceptible allele (2L+a) are also behaviorally less likely to be found inside houses. Vector control tools that target indoor-resting mosquitoes, such as bednets and insecticides, are currently the cornerstone of malaria control in Africa. Populations with high levels of the 2L+a allele may form reservoirs of persistent outdoor malaria transmission requiring novel measures for surveillance and control. The 2La inversion is a major and previously unappreciated component of the natural malaria transmission system in Africa, influencing both malaria susceptibility and vector behavior. PMID- 28643641 TI - Reply. PMID- 28643642 TI - Reply. PMID- 28643643 TI - Reply. PMID- 28643645 TI - Reply. PMID- 28643646 TI - Reply. PMID- 28643647 TI - Reply. PMID- 28643648 TI - Reply. PMID- 28643649 TI - Reply. PMID- 28643651 TI - Correction. PMID- 28643652 TI - Meetings and Courses. PMID- 28643653 TI - Relevant Content. PMID- 28643657 TI - Impact of clinical and/or histological chorioamnionitis on neurodevelopmental outcomes in preterm infants: A literature review. AB - OBJECTIVE: To determine the impact of clinical and/or histological chorioamnionitis on neurodevelopmental outcomes in premature infants. METHODS: A review of the literature appeared in PubMed between 1997 and 2016 was conducted to examine the association between clinical and/or histological chorioamnionitis and neurologic impairment in the neonates (intraventricular hemorrhage, periventricular leukomalacia and white matter damage) and in infants (cerebral palsy and neurodevelopmental delay). RESULTS: The first meta-analysis published in 2000 observed that clinical chorioamnionitis was associated with cystic periventricular leukomalacia and cerebral palsy and that histologic chorioamnionitis was associated with periventricular leukomalacia only. A second meta-analysis in 2010 found that cerebral palsy was associated with both clinical and histological chorioamnionitis. But most recent studies over the last decade based on large cohorts found no effect of chorioamnionitis on neurological outcomes, even if they had several methodological limitations. CONCLUSION: According to the findings of the most recent studies, clinical or histological chorioamnionitis does not seem to be associated with neonatal white matter injuries, or with cerebral palsy. Further studies are needed to assess the impact of chorioamnionitis on long-term neurological development. PMID- 28643658 TI - Quality assessment of pelvic ultrasound for uterine myoma according to the CNGOF guidelines. AB - INTRODUCTION: French guidelines regarding the minimum criteria for gynaecological ultrasound were given in a recent report in 2016, by the French National College of Obstetricians and Gynaecologists (CNGOF). An accurate report is essential for the optimal care of women, especially those presenting myomas. The goal of this study was to evaluate the quality of gynaecological ultrasound reports for women with type 0 to 2 uterine myomas, referring to the items contained in the French guidelines. MATERIALS AND METHODS: A retrospective descriptive study was conducted from reports of ultrasounds performed in private offices and in the gynaecologic department of a hospital, between June 2014 and June 2016 (before the report of CNGOF). These reports involved women who underwent hysteroscopic resection of myoma(s). A search of validated items was conducted for all of the reports, and the missing items were analysed. The different types of practitioners and between hospital and private medical offices were also compared with Chi-square tests. RESULTS: A total of 138 reports were analysed; 71 were performed in private offices and 67 were performed in the gynaecologic unit of the hospital. Many items were missing in the reports, with disparities between the type of institution (private offices or hospital) and the speciality of practitioners (radiologists or gynaecologists). Specific items regarding myomas, such as the International Federation of Gynaecologists and Obstetricians (FIGO) classification or measurement of the posterior wall, were more often missing in reports from radiologists (89.7% and 79.5%, respectively) than in reports from gynaecologists (21.2% and 34.3%, respectively) (P<0.05). A significant difference was also observed for these data between private offices' reports and hospitals' reports. Items relative to ultrasound structures, such as the appearance of myomas or associated abdominal effusion, were more frequently missing in gynaecologists' reports (88.9% and 49.5%, respectively) compared to radiologists' reports (56.4% and 12.8%, respectively) (P<0.05). CONCLUSIONS: Certain items are present in all the reports, while others are insufficiently mentioned. These inequalities can be explained in part by the type of practice; however, methods to overcome these difficulties must be developed. Information campaigns to educate professionals on the minimum reporting and training conducted jointly by radiologists and gynaecologist surgeons might improve reports and improve the care of women. PMID- 28643659 TI - [Cervical cancer screening in rural Madagascar: Feasibility, coverage and incidence]. AB - OBJECTIVES: To assess the implementation of a cervical cancer screening strategy in rural Madagascar. MATERIALS AND METHODS: A mobile unit, equipped with a cold coagulator, visited every six months the main health care centers in the Atsinanana area between 2013 and 2015. Cervical cancer screening was based on visual inspection with acetic acid (VIA). The lesions suggestive of intraepithelial neoplasia and limited to the cervix were coagulated on the same day. Non-eligible patients for immediate treatment were referred for appropriate investigations. We assessed the feasibility and the coverage of the screening strategy and estimated the incidence of cervical cancer in the targeted population. RESULTS: One thousand five hundred and sixty-nine (18%) of 8959 women aged between 25 and 65 years old were screened. Three hundred and fifty-seven (23%) were VIA positive and 322 (21%) were eligible for immediate treatment. No serious adverse effects were observed among patients treated on the same day. Among the 35 patients not eligible for immediate treatment and referred to the hospital, 16 (46%) were lost to follow up. CONCLUSION: When a cervical cancer screening by HPV or cytology is not possible, VIA remains a feasible and acceptable option in a disadvantaged environment. The effectiveness of this approach is still limited by the problems of access to care for patients who are not eligible for immediate treatment. PMID- 28643660 TI - Glue mesh fixation: Feasibility, tolerance and complication assessment. Results 24months after laparoscopic sacrocolpopexy. AB - AIM: This study aims to assess short- and mid-term feasibility, strength and tolerance of glue mesh fixation for laparoscopic sacrocolpopexy, as well as postoperative quality of sexual activity. PATIENTS AND METHODS: This original prospective clinical study was carried out in multiple university surgical centres between 2012 and 2013. Data were obtained during immediate postoperative hospitalisation, at 3 and at 24 months postoperatively. For a total of 42 patients subjected to laparoscopic sacrocolpopexy, bladder catheterization and hospitalisation times, pain score, early and late postoperative complications, prolapse staging according to POP-Q classification, and quality of sexual activity were registered. RESULTS: Mean operative time was 120minutes and patients were hospitalised for a mean of 3days. Four complications (9.52%) occurred on the immediate postoperative period, whilst 2 patients (4.76%) complained of pain on day 3 (VAS 1). At the end of the follow-up period (24 months), one patient had a prosthetic exposure, 4 patients (9.52%) complained of stress urinary incontinence (10.81%). Simultaneously, 6 patients (14.29%) experienced dyschezia (2 improved, 1 similar, 1 de novo, 2 worsened), and there was no report of dyspareunia. All anterior and posterior floor prolapses were staged between 0 and 1. All superior floor prolapses were staged between 0 and 2. Concerning sexual impairment, there was no report of dyspareunia, urinary leaks or other problems associated with intercourse, and quality of sexual activity improved. CONCLUSION: Minimally invasive sacrocolpopexy with the use of glue fixation does not lead to increased mid-term morbidity, simultaneously allowing for significant prolapse improvement, and providing global patient satisfaction and overall quality of life. PMID- 28643661 TI - Impact of anaesthesia mode on evaluation of LEEP specimen dimensions. AB - OBJECTIVES: To study the influence of anaesthesia (local by cervical block vs. general or spinal anaesthesia) on height and volume of resection specimens in case of conization treatment for cervical intraepithelial neoplasia (CIN). METHODS: Prospective observational study of all patients who underwent a first treatment by loop electrosurgical excision procedure (LEEP) for CIN. Height of fresh resection specimens was first measured by the operator and then by the pathologist after formaldehyde fixation. Volume of fresh specimens was measured in a measuring cylinder by fluid displacement. RESULTS: One hundred patients were included and 35% of LEEP were performed under local anaesthesia. There was a significant difference in height of specimens depending on anaesthesia mode: after fixation, the average height was 11.2mm in the general or spinal anaesthesia group vs. 8.8mm in the local anaesthesia group (P=0.002). There was also a difference in terms of volume depending on anaesthesia mode: 1.6mL in local anaesthesia group vs. 2.3mm in general and spinal anaesthesia group (P=0.01). CONCLUSIONS: Anaesthesia mode has an impact on height and volume of LEEP specimens. In our experience, local anaesthesia could reduce LEEP specimen height. PMID- 28643662 TI - Evaluation of a new technique of prophylactic cervical cerclage simplified from the Shirodkar cerclage: A pilot study. AB - INTRODUCTION: In terms of prophylactic cerclage, the simplest and most commonly used technique is the McDonald cervical cerclage. Cervico-isthmic cerclage techniques may have better results, but are more difficult to achieve. A simplified Shirodkar technique would have the advantage of being "cervical high" while remaining easy to achieve. OBJECTIVE: To compare the results of high cervical cerclage, according to a simplified Shirodkar technique, with those of a classic McDonald cerclage, in the case of women at high risk of prematurity in an exploratory study. METHODS: A comparative, retrospective study of prophylactic cerclage was conducted according to one or the other technique performed in a university hospital from 2006 to 2013. Women were included only if they had a history of at least two late miscarriages and/or premature delivery before 33 weeks. The primary outcome was the rate of delivery before 35 weeks. RESULTS: Our study involved 38 women: 24 in the McDonald cerclage group and 14 in the simplified Shirodkar cerclage group. The two groups were comparable for their obstetric and general characteristics. The percentage of preterm deliveries before 35 weeks was similar in both groups (7.1% and 25.0% in the Shirodkar and McDonald groups respectively; P=0.17). No significant difference was observed in the rate of surgical complications or hospitalizations during the pregnancies. CONCLUSION: In this study, we were unable to demonstrate an advantage to using the simplified Shirodkar technique - high cervical cerclage - compared with use of the McDonald technique - classical cerclage. PMID- 28643663 TI - Delivery outcomes of term pregnancy complicated by idiopathic polyhydramnios. AB - OBJECTIVE: Polyhydramnios is associated with an increased risk of cesarean section. The aetiology of polyhydramnios and the characteristics of the labour may be confounding factors. The objective was to study the characteristics and mode of delivery in case of pregnancy complicated with idiopathic polyhydramnios. METHODS: This retrospective matched and controlled study included all pregnant women with idiopathic polyhydramnios (amniotic index>25cm or single deepest pocket>8cm) diagnosed at the 2nd or 3rd trimester and persistent at term delivery (>37weeks of pregnancy) in our institution. We excluded pregnancies in which the polyhydramnios could be explained by infection, gestational diabetes, congenital malformation, abnormal karyotype, placental anomalies, alloimmunization as well as pregnancies in which an amniocentesis for the purpose of diagnosis had not been performed. Data were gathered from a tertiary care university hospital register from 1998-2015. Cases of polyhydramnios were matched with the following two women who presented for labour management with spontaneous cephalic presentation, matching for delivery date, maternal age, parity, body mass index. The main outcome measure was the risk of cesarean section. Univariate and multivariate adjusted analysis were performed. RESULTS: We identified 108 women with idiopathic polyhydramnios and compared them with 216 matched women. Among them, 94 and 188 attempted a trial of labour. Maternal age, mean term delivery and birthweight were 31 years, 39+5weeks gestation and 3550 g. We did not observe differences in maternal characteristics, epidural analgesia and rate of abnormal fetal heart tracing. Induced labour and non-vertex presentations (forehead, bregma, face) were more frequent in the polyhydramnios group (respectively 57.9% versus 27.8%, P<0.05 and 7.8% versus 1%, P<0.05). Cesarean section rate was higher in the case of polyhydramnios in the overall population (45.4% versus 8%, P<0.05) and remained higher after exclusion of cases of induced labour and non vertex presentation (38.4% versus 3.8%, P<0.05). Amniotomy was more frequent in pregnancies with polyhydramnios (55.8% versus 39.1%, P<0.05). After adjustment for matching and confounding variables, polyhydramnios was found to be a risk factor for cesarean section (OR 21.02; CI 95% 8.004-55.215, P<0.01). CONCLUSION: Idiopathic polyhydramnios increased the risk of prolonged first stage of labour, non-vertex presentation and cesarean section. PMID- 28643664 TI - Intervention of the obstetrician during childbirth in a supposedly low-risk population and influence of parity. AB - OBJECTIVE: Compare obstetrician intervention and calling rates during labour and delivery between low-risk and high-risk women and study the influence of parity on these rates. MATERIAL AND METHODS: Descriptive retrospective study conducted on 227 patients in a university maternity unit (level 3 university hospital maternity unit) between 1st and 30th January 2014. The low- and high-risk populations were characterised according to the French National Authority for Health (HAS) and NICE guidelines. The obstetrician intervention criteria were: Caesarean section, instrumental vaginal delivery, artificial delivery/uterus examination and postpartum haemorrhage. The obstetrical team also had to call the obstetrician in case of foetal heart rate abnormalities, scalp blood pH measurement, third and/or fourth degree perineal tears, labour dystocia, or any other severe event occurring during labour or delivery. RESULTS: In univariate analysis, the obstetrician intervention rates were respectively 44.5% and 34.4% in the high- and low-risk groups (P=0.13). The obstetrician calling rates were similar between the two groups. Using logistic regression model including parity, the obstetrician intervention rate became significantly higher in the "high-risk" group (OR 2.044, 95% CI 1.129-3.703, P=0.018). In the low-risk population, the intervention rate was significantly increased for nulliparous women compared with multiparas (47.5% versus 9.7%, P<0.001, OR=8.2, CI 95% 2.2 to 46.9). CONCLUSION: One third of the women defined as low-risk patients appear to need an obstetrician intervention during labour and delivery, with a major influence of parity. PMID- 28643665 TI - Sonographic landmarks to differentiate "false labor" and "early true labor" as a possible new application of ultrasound in labor ward. AB - OBJECTIVE: To evaluate discrimination of clinical parameters and ultrasound examination to differentiate "false labor" and "true labor". METHODS: In a prospective study during a period of 6 months, a total of 178 patients in term (37-41 weeks) consulting our obstetric unit for uterine contraction, were enrolled. Patients were examined separately by a midwife and a resident and separated into "true labor group" and "false labor group". The clinical characteristics of true versus false labor patients were compared. ROC curves were developed to determine an optimal cervical length and uterocervical angle for prediction of true labor. RESULTS: The prevalence of real labor was 57.3%. Patients who were in true labor had more painful and more frequent contractions. The "true labor" group had shorter cervical length and larger uterocervical angle. The optimal CL cut-off was 1.4mm with a specificity of 73% (RR 4.3, sensibility 63%, PPV 14%, NPV 95%). The optimal UCA cut off was 123 degrees (RR 6.7, sensitivity 50%, specificity of 83%, PPV 10%, NPV 96%). The best performance was demonstrated by combined testing, yielding LHR+ that rich 13. CONCLUSION: In this study, we reported a new application of ultrasound to identify false labor and avoid unnecessary hospitalization with obstetric and adverse economic impacts. PMID- 28643666 TI - French family physician experience concerning the outpatient care for women suffering from nausea and vomiting in pregnancy. AB - OBJECTIVE: To explore thoughts and attitudes among French family physicians on the outpatient care for women suffering from nausea and vomiting in pregnancy (NVP). DESIGN AND SETTING: A retrospective study was conducted among family physicians who had taken care of pregnant women who gave birth in our hospital in 1 year. PATIENTS AND METHODS: Fifty-nine French family physicians responded to a questionnaire assessing their experience about outpatient care for women suffering from NVP. Analysis were done according to the physicians' age, as the annual demographics data analysis from the French Medical Council. RESULTS: More than 89% of family physicians asked systematically the question concerning NVP (53/59), which were estimated as a frequent symptom (n=44, 74.6%). The intensity of NVP was assessed as mild in 28.8% (n=17), moderate in 62.7% (n=37), severe in 6.8% (n=4) and unbearable in 1.7% (n=1). Physicians younger than 40 years questionned less frequently about NVP compared to those older than 40 or older than 60 years (66.7% vs. 90.5% vs. 95.5%, respectively; P=0.04). Severe and unbearable NVP were significantly estimated more frequent among younger physicians (33.3% vs. 6.8%; P=0.03). Treatments (sick leave, diet, drugs, homeopathy, acupuncture or psychotherapy) did not differ between groups. DISCUSSION AND CONCLUSION: Outpatient care for women suffering from NVP may vary according to the physician. French family physicians played a key role in NVP. Younger family physician considered NVP as a frequent symptom which needed active management in severe forms. PMID- 28643667 TI - Can we perform a prenatal diagnosis of vasa previa to improve its obstetrical and neonatal outcomes? AB - INTRODUCTION: Vasa previa (VP) is defined as a condition in which the fetal blood vessels, unsupported by the placenta or the umbilical cord, run through the membranes of the lower uterine segment. It is associated with a high risk of stillbirth by exsanguination. This study aimed to assess the clinical context of diagnosis of VP in order to elaborate a strategy for its prenatal diagnosis and to improve its obstetrical and neonatal outcomes. MATERIAL AND METHODS: This historical cohort study covered the period from January 1, 2011 to December 31, 2015. All women who gave birth at our obstetrics and gynecology department (level 3 university hospital) and who had a VP were included. RESULTS: Eight cases of VP among 18,152 deliveries were observed (0.04%). Transvaginal sonography (TVS) with color Doppler allowed a prenatal diagnosis of VP in all cases. The mean gestational age at diagnosis was 26 weeks. Placental abnormalities were noted in 7 cases (87.5%) as bipartita or low-lying placenta. In one case (12.5%), the placenta appeared normal while umbilical cord insertion was velamentous. In 2 cases (25%), concomitant placental and cord abnormalities were objectified. The mean gestational age at delivery was 37+/-2.1 weeks. Seven deliveries (87.5%) had been by caesarean sections, except one, which occurred by vaginal route at 33 weeks of gestation (twin pregnancy). No case of perinatal death was observed. DISCUSSION: Prenatal diagnosis of VP during screening ultrasounds appears easy to perform and can improve obstetrical and neonatal outcomes. For this purpose, TVS with color and pulsed Doppler remains essential, particularly when an anomaly of the umbilical cord insertion and/or placental location is diagnosed. PMID- 28643668 TI - How to perform a suture with a 5-mm trocar by laparoscopy? AB - During laparoscopy using only 5mm trocars, it may sometimes be necessary to perform a suture, which usually requires the use of a 10mm or 12mm trocar with a reducer. Thus, the 5-mm trocar has to be replaced by a larger diameter device. In order to avoid the trocar change in these situations, a trick that is easily realizable for performing one or more stitches is described. This technique can be used in various surgical specialties, whether it is gynecological, digestive or urological surgery. PMID- 28643669 TI - ? PMID- 28643670 TI - [Chronic myelogenous leukemia: monitoring and predictors of a favorable response to treatment with imatinib]. AB - The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6 19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina. PMID- 28643671 TI - [Health literacy and diabetes control in patients attending a university outpatient clinic in Argentina]. AB - Health literacy (HL) is a measure of a patient ability to read, understand and to take decisions on medical instructions. Patients with inadequate HL have poorer health outcomes than those with adequate HL. There is little information on HL levels in diabetic patients in Argentina. The aim of this study was to explore the association between HL and glycemic control in diabetic patients from a university hospital in Argentina. HL was assessed with the Short Assessment of Health Literacy for Spanish-speaking Adults (SAHLSA), glycemic control through glycosylated hemoglobin A1c (HbA1c); 156 patients (58% women) took part in the study. Average SAHLSA score was 35 (range: 11-50). Patients with inadequate values of HL had HbA1c of 8.15% vs. 7.15% among those with adequate HL (p = 0.0001). The multiple linear regression shows that inadequate HL was significantly associated with poorer glycemic control (beta = -0.05 IC 95% -0.07; -0.02, p < 0.001). Efforts should focus on developing interventions to improve glycemic control among patients with inadequate HL. PMID- 28643672 TI - Switch from agalsidase beta to agalsidase alfa in the enzyme replacement therapy of patients with Fabry disease in Latin America. AB - There are currently two available enzyme replacement therapies for Fabry disease and little information regarding efficacy and safety of switching therapies. Between 2009 and 2012 there was a worldwide shortage of agalsidase beta and patients on that enzyme were switched to agalsidase alfa. This retrospective observational study assessed a 2-year period of efficacy and safety in a population of Fabry patients, in Argentina (30 patients) and Venezuela (3 patients), who switched therapies from algasidase beta to agalsidase alfa. Thirty three patients completed 24-months follow-up after the switch (age 32.4 +/- 2.0, range 10.0-55.9 years; male: female 23:10). Measures of renal function such as estimated glomerular filtration rate remained almost unchanged in 31 patients without end stage renal disease over the 2 years after switching and urine protein excretion continued stable. Cardiac functional parameters: left ventricular mass index, interventricular septum, left ventricular posterior wall showed no significant change from baseline in the 33 patients. Quality of life, pain and disease severity scores were mostly unchanged after 24-months and agalsidase alfa was generally well tolerated. Our findings showed there is no significant change in the efficacy measured through the renal or cardiac function, quality of life, pain, disease severity scoring and safety for at least 2 years after switching from agalsidase beta to agalsidase alfa. PMID- 28643673 TI - [Allergy to drugs. Experience in 771 procedures]. AB - Drug hypersensitivity reactions (RHD) are those that present clinically as allergic. They can or cannot involve an immunologic mechanism of lesion. They are frequent and, occasionally, life threatening. Patients with RHD repeat the reaction when they are re-exposed to the drug, limiting the therapeutic options and exposing them to more expensive and toxic drugs. It is difficult to identify the responsible drug when the reaction was not recent or when it occurred in the context of therapy with multiple drugs or confusing concurrent diseases. The diagnosis should be based on clinical history, followed by drug skin tests and drug provocation tests. We describe our experience in 771 procedures, 331 cutaneous and 440 drug provocation tests, 11% of them were positive. Positive symptoms included generalized pruritus, rash, urticaria, angioedema, rhinitis, bronchospasm, nausea and anaphylaxis. All the patients with positive tests had a good response to treatment. It can therefore be concluded that drug tests undertaken on individuals with suspected drug allergy, performed by experienced personnel and in controlled settings, are useful and safe to confirm drug hypersensitivity. PMID- 28643675 TI - [STOP-BANG, a useful and easy tool for the screening of obstructive sleep apnea]. AB - The STO-BANG questionnaire, S standing for snore, T tired, O observed apneas, P pressure (arterial hypertension), B BMI (body mass index > 35 kg/ m2), A age (> 50 years old), N neck circumference (> 40 cm), G gender (male); is a simple tool that enables the detection of patients with obstructive sleep apnea syndrome (OSA). If the patient adds 3 or more points, it is considered to have a high probability of having this disease. Our goal was to evaluate the capacity of the STOP-BANG questionnaire and to compare it with the ability of a sleep trained pulmonologist in determining the probability of OSA. A retrospective analysis of 327 patients suspected of having this condition was performed. One hundred and seventy-one were males (52.3%), 49.8 years old (37.9-61.7), BMI 38.7 kg/m2 (32.5 46), neck circumference 44 cm (41-47.5), 311 snorers (95.1%), 232 with daytime sleepiness or usual tiredness (70.9%), 206 with observed apneas (63%), 169 with arterial hypertension (51.7%), normal polysomnography 42 (12.9%), mild 65 (19.9%), moderate 59 (18%), severe 161 (49.2%). The STOP-BANG's sensibility and specificity, taking as a cut-off point a respiratory disturbance index (RDI) > or = to 15, was 99.1% and 14.0% respectively, area under curve (AUC) 0.755 (0.704 0.800), the values for the PR actioner's ability were 89.1% and 58.9% respectively, AUC 0.550 (0.542-0.638). The STOP-BANG questionnaire is easy to implement as a screening tool. PMID- 28643674 TI - Microbiological and serological control of Escherichia coli O157: H7 in kindergarten staff in Buenos Aires city and suburban areas. AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) infections are implicated in the development of the life-threatening hemolytic-uremic syndrome (HUS). Despite the magnitude of the social and economic problems caused by HUS, no licensed vaccine or effective therapy is currently available for human use. Prevention of STEC infections continues being the most important measure to reduce HUS incidence. This is especially true for Argentina where HUS incidence among children is extremely high and shows an endemic pattern. The aim of this work was to investigate serologically adult staff of kindergartens in Buenos Aires city and suburban areas in order to detect possible carriers, and to educate personnel about good practices to reduce HUS transmission. We also assessed the microbiological quality of water and meal samples from the same kindergartens. We tested 67 healthy adults, 13 water supplies and 6 meals belonging to 6 public kindergartens. We analysed hand swabs for isolation of STEC and serum samples for the presence of antibodies against Stx and lipopolysaccharide (LPS) of O157 serogroup. We identified 46 Stx2-positive individuals, but only 7 for O157 LPS. No presence of STEC pathogens was detected in hands of staff, water or meal samples. PMID- 28643676 TI - [Asymptomatic primary hyperparathyroidism in women]. AB - Primary hyperparathyroidism may have different characteristics. One is the asymptomatic form. This is a mild variant of hypercalcemic hyperparathyroidism, characterized by a calcemia not greater than 1 mg/dl above the upper limit of the method, a high intact parathyroid hormone (iPTH), absence of renal stones, renal function impairement, and osteoporosis, less than 50 years of age, and less than 400 mg/day calciuria. It is not a surgical entity, but its evolution may require it. Twenty-four postmenopausal women, all older than 50 years, with a diagnosis of asymptomatic hyperparathyroidism, were studied. Clinical manifestations, densitometric changes, biochemical parameters and bone remodeling were analyzed and the results were compared with the classic and normocalcemic variants of the disease. Diagnostic criteria were established and observed that only 2 (8.3%) of patients, during a follow up of 44 +/- 12 months, had need for a parathyroidectomy. In conclusion, the asymptomatic primary hyperparathyroidism is a benign disorder, of periodic clinical follow-up, which rarely may require surgery. PMID- 28643677 TI - Modulator effect of watercress against cyclophosphamide-induced oxidative stress in mice. AB - Watercress (Nasturtium officinale, Cruciferae; W. Aiton) is a vegetable widely consumed in our country, with nutritional and potentially chemopreventive properties. Previous reports from our laboratory demonstrated the protective effect of watercress juice against DNA damage induced by cyclophosphamide in vivo. In this study, we evaluated the in vivo effect of cress plant on the oxidative stress in mice. Animals were treated by gavage with different doses of watercress juice (0.5 and 1g/kg body weight) for 15 consecutive days before intraperitoneal injection of cyclophosphamide (100 mg/kg body weight). After 24 h, mice were killed by cervical dislocation. The effect of watercress was investigated by assessing the following oxidative stress biomarkers: catalase activity, superoxide dismutase activity, lipid peroxidation, and glutathione balance. Intake of watercress prior to cyclophosphamide administration enhanced superoxide dismutase activity in erythrocytes with no effect on catalase activity. In bone marrow and liver tissues, watercress juice counteracted the effect of cyclophosphamide. Glutathione balance rose by watercress supplementation and lipid oxidation diminished in all matrixes when compared to the respective control groups. Our results support the role of watercress as a diet component with promising properties to be used as health promoter or protective agent against oxidative damage. PMID- 28643678 TI - Prevalence of factors related to vascular calcifications in patients with chronic kidney disease on dialysis. AB - The main aim of the study was to determine the prevalence of vascular calcifications in patients with chronic kidney disease on dialysis in our population assessed by X-ray. The secondary objectives were to determine the cardiovascular risk factors associated with the presence of vascular calcifications and to evaluate the complementary use of the echocardiogram in a cross-sectional, observational, multicentric study. We included patients with chronic kidney disease on dialysis, age =18 years with at least 3 months of renal replacement therapy in 8 dialysis centres in Argentina. The degree of vascular calcification was determined using Adragao and Kauppila scores. The presence of valvular calcifications was established through a trans-thoracic doppler echocardiogram. Univariate and multivariate analysis were undertaken, considering the degree of vascular calcification as the dependent variable; 443 adult patients were evaluated at 8 centres across 5 provinces in Argentina. The prevalence of vascular calcifications by the X-rays was 63%, while 73% presented calcifications in hands and pelvis, with an Adragao score > 3, and 60% presented calcifications in the abdominal aorta with a Kauppila score > 4. The prevalence of valvular calcifications: 28%. We have shown a higher rate of vascular calcifications with the use of plain X-rays when compared to the prevalence of valvular calcifications obtained with echocardiograms. In this regard, valvular calcifications were present particularly in those patients with a severe level of radiological vascular calcification. PMID- 28643679 TI - Clinical and cerebrospinal fluid findings contribute to the early differentiation between infectious and noninfectious encephalitis. AB - Early recognition and prompt specific treatment are crucial factors influencing the outcome of patients with acute encephalitis. The aim of this study was to determine the main causes of acute encephalitis in our population and to find predictors that may lead to specific diagnosis. Adult patients admitted to our hospital with suspected diagnosis of encephalitis in the period 2006-2013 were included. One hundred and five medical records were analyzed. Eighty-two patients with infectious encephalitis were identified (78% of total cases), 53 (65%) men and 29 (35%) women, mean age 47.8 years. The most common microorganisms identified were: HSV-1 (11%), VZV (10%), HSV-2 (5%) and EBV (5%). Twenty-three patients (22% of the series) had non-infectious encephalitis. Headache (p < 0.0001) and fever (p = 0.008) were more frequent in encephalitis of infectious origin. Protein levels and white blood cell counts in the cerebrospinal fluid were significantly higher in patients affected by infectious encephalitis than in those affected by noninfectious encephalitis (OR 95% CI 12.3 [2.9-51.7] and OR 95% CI 7.4 [2-27], respectively). Identifying specific causal agents of acute encephalitis remains a major challenge. Cerebrospinal fluid markers, as well as specific clinical findings, may however contribute to initial differentiation between infectious and noninfectious causes. PMID- 28643680 TI - [Towards precision medicine in myeloma: new evidence and challenges]. AB - In the last few years, next-generation sequencing studies have provided insights into the mutational landscape of multiple myeloma. The identification of actionable mutations might give a precious opportunity for exploring new targeted therapies. Thus, the implementation of promising precision medicine strategies seems to be closer than ever. Throughout this review we describe the main challenges that should to be dealt with in this new era, in order to achieve the main goal of precision medicine, namely matching patients with their right drug. In addition, we provide a review of the most significant preclinical and clinical studies supporting the implementation of precision medicine nowadays. Finally, we highlight the need of clinical trials to evaluate the security and efficacy of these targeted therapies, as well as to validate predictive biomarkers that may allow an appropriate best-candidate selection and improvement of myeloma patients' survival and quality of life. PMID- 28643681 TI - [Magnetic resonance neurography for the identification of pudendal neuralgia]. AB - The pudendal nerve entrapment is an entity understudied by diagnosis imaging. Various causes are recognized in relation to difficult labors, rectal, perineal, urological and gynecological surgery, pelvic trauma fracture, bones tumors and compression by tumors or pelvic pseudotumors. Pudendal neuropathy should be clinically suspected, and confirmed by different methods such as electrofisiological testing: evoked potentials, terminal motor latency test and electromyogram, neuronal block and magnetic resonance imaging. The radiologist should be acquainted with the complex anatomy of the pelvic floor, particularly on the path of pudendal nerve studied by magnetic resonance imaging. High resolution magnetic resonance neurography should be used as a complementary diagnostic study along with clinical and electrophysiological examinations in patients with suspected pudendal nerve neuralgia. PMID- 28643682 TI - [Reversible posterior leukoencephalopathy syndrome]. PMID- 28643683 TI - [Synchysis scintillans (Cholesterolosis bulbi)]. PMID- 28643684 TI - [Adult T-cell leukemia/lymphoma. Report of a case in Uruguay]. AB - Adult T-cell leukemia/lymphoma belongs to the group of mature T-cell malignancies according to the WHO classification. It constitutes a rare entity and has a strong association with infection by human T-lymphotropic virus 1. In Uruguay, this viral infection is very infrequent and, to our knowledge, no case of adult T cell leukemia/lymphoma has been previously reported. We describe the case of a woman, immigrant from Peru, who presented with persistent lymphocytosis, intestinal parasitic diseases, and skin involvement. The diagnosis was delayed and the patient died before initiating oncological treatment. We therefore emphasize the relevance of an early clinical suspicion and serology for this virus, especially in patients coming from endemic countries like Peru. PMID- 28643685 TI - [Disseminated interdigitating dendritic cell sarcoma]. AB - A 70 year-old woman was admitted to our hospital with a 3-month history of abdominal pain, weight loss and night sweats. On physical examination, she presented with a 5 cm diameter abdominal mass extended from epigastrium to the left flank, and at least three bilateral supraclavicular adenopathies. A disseminated interdigitating dendritic cell sarcoma was diagnosed through a biopsy of the abdominal mass. After that, a CHOP regime (cyclophosphamide, doxorubicin, vincristine and prednisone) was iniciated. She died after completion of the first cycle of treatment, six months after diagnosis. PMID- 28643686 TI - [Pachymeningitis associated with IgG4 disease]. AB - Hypertrophic pachymeningitis is an infrequent disorder. It can be idiopathic or secondary to infectious, autoimmune or neoplastic disease. The recently described could be the origin of many cases considered cryptogenic. We present the case of a 60-year-old man, with a history of headache and episcleritis in both eyes, with partial response to corticoid therapy. The brain MR study with gadolinium showed enhancement and thickening of the dura mater, extending from lateral wall of left temporal and occipital lobes to ipsilateral tentorium. Meningeal biopsy showed fibrosis and lymphoplasmacytic infiltrate, with more than 10 IgG4+ plasma cells per high power field. After treatment with rituximab there was clinical improvement accompanied by the virtual disappearance of the alterations detected in neuroimaging. Hypertrophic pachymeningitis as a manifestation of IgG4-related disease can be based on MRI findings if plasma IgG4 are elevated. PMID- 28643687 TI - [The value of one autopsy]. PMID- 28643688 TI - [Fictional models in the patient physician relationship]. PMID- 28643689 TI - [Electronic nicotine release systems, the healthy evolution of smoking]. PMID- 28643690 TI - [Autopsy, necessary participant in the art of healing]. PMID- 28643691 TI - [On C virus hepatitis, HIV coinfection, diagnosis and treatment coverage]. PMID- 28643692 TI - [More on diagnosis and treatment of C virus hepatitis]. PMID- 28643693 TI - Generation mechanism of negative permittivity and Kramers-Kronig relations in BaTiO3/Y3Fe5O12 multiferroic composites. AB - Recently, negative parameters such as negative permittivity and negative permeability have been attracting extensive attention for their unique electromagnetic properties. Usually, negative permittivity is well achieved by plasma oscillation of free electrons in conductor-insulator composites or metamaterials, while some attention has been paid to attaining negative permittivity in ceramics to reduce dielectric loss. In this paper, negative permittivity in barium titanate and yttrium iron garnet composites are reported which was well fitted by the Lorentz model. Further, negative permittivity behavior was verified via Kramers-Kronig relations, and it revealed that the causal principle still valid for negative permittivity resulted from dielectric resonance. The interrelationships among negative permittivity, capacitive inductive transition and ac conductivity are discussed. PMID- 28643694 TI - Simultaneous maximum a posteriori longitudinal PET image reconstruction. AB - Positron emission tomography (PET) is frequently used to monitor functional changes that occur over extended time scales, for example in longitudinal oncology PET protocols that include routine clinical follow-up scans to assess the efficacy of a course of treatment. In these contexts PET datasets are currently reconstructed into images using single-dataset reconstruction methods. Inspired by recently proposed joint PET-MR reconstruction methods, we propose to reconstruct longitudinal datasets simultaneously by using a joint penalty term in order to exploit the high degree of similarity between longitudinal images. We achieved this by penalising voxel-wise differences between pairs of longitudinal PET images in a one-step-late maximum a posteriori (MAP) fashion, resulting in the MAP simultaneous longitudinal reconstruction (SLR) method. The proposed method reduced reconstruction errors and visually improved images relative to standard maximum likelihood expectation-maximisation (ML-EM) in simulated 2D longitudinal brain tumour scans. In reconstructions of split real 3D data with inserted simulated tumours, noise across images reconstructed with MAP-SLR was reduced to levels equivalent to doubling the number of detected counts when using ML-EM. Furthermore, quantification of tumour activities was largely preserved over a variety of longitudinal tumour changes, including changes in size and activity, with larger changes inducing larger biases relative to standard ML-EM reconstructions. Similar improvements were observed for a range of counts levels, demonstrating the robustness of the method when used with a single penalty strength. The results suggest that longitudinal regularisation is a simple but effective method of improving reconstructed PET images without using resolution degrading priors. PMID- 28643695 TI - Highly fluorescent and superparamagnetic nanosystem for biomedical applications. AB - This work reports on highly fluorescent and superparamagnetic bimodal nanoparticles (BNPs) obtained by a simple and efficient method as probes for fluorescence analysis and/or contrast agents for MRI. These promising BNPs with small dimensions (ca. 17 nm) consist of superparamagnetic iron oxide nanoparticles (SPIONs) covalently bound with CdTe quantum dots (ca. 3 nm). The chemical structure of the magnetic part of BNPs is predominantly magnetite, with minor goethite and maghemite contributions, as shown by Mossbauer spectroscopy, which is compatible with the x-ray diffraction data. Their size evaluation by different techniques showed that the SPION derivatization process, in order to produce the BNPs, does not lead to a large size increase. The BNPs saturation magnetization, when corrected for the organic content of the sample, is ca. 68 emu g-1, which is only slightly reduced relative to the bare nanoparticles. This indicates that the SPION surface functionalization does not change considerably the magnetic properties. The BNP aqueous suspensions presented stability, high fluorescence, high relaxivity ratio (r 2/r 1 equal to 25) and labeled efficiently HeLa cells as can be seen by fluorescence analysis. These BNP properties point to their applications as fluorescent probes as well as negative T 2-weighted MRI contrast agents. Moreover, their potential magnetic response could also be used for fast bioseparation applications. PMID- 28643696 TI - Artificial synaptic characteristics with strong analog memristive switching in a Pt/CeO2/Pt structure. AB - Artificial synaptic potentiation and depression characteristics were demonstrated with Pt/CeO2/Pt devices exhibiting polarity-dependent analog memristive switching. The strong and sequential resistance change with its maximum to minimum ratio >105, imperatively essential for stable operation, as repeating voltage application, emulated the potentiation and depression motion of a synapse with variable synaptic weight. The synaptic weight change could be controlled by the amplitude, width, and number of repeated voltage pulses. The voltage polarity dependent and asymmetric current-voltage characteristics and consequential resistance change are thought to be due to local inhomogeneity of electrical and physical states of CeO2 such as charging at interface states, valence changes of Ce cations, and so on. These results revealed that the CeO2 layer could be a promising material for analog memristive switching elements with strong resistance change, as an artificial synapse in neuromorphic systems. PMID- 28643697 TI - On the relationship between topological and geometric defects. AB - The study of topology in solids is undergoing a renaissance following renewed interest in the properties of ferroic domain walls as well as recent discoveries regarding skyrmionic lattices. Each of these systems possess a property that is 'protected' in a symmetry sense, and is defined rigorously using a branch of mathematics known as topology. In this article we review the formal definition of topological defects as they are classified in terms of homotopy theory, and discuss the precise symmetry-breaking conditions that lead to their formation. We distinguish topological defects from defects that arise from the details of the stacking or structure of the material but are not protected by symmetry, and we propose the term 'geometric defects' to describe the latter. We provide simple material examples of both topological and geometric defect types, and discuss the implications of the classification on the resulting material properties. PMID- 28643698 TI - Phonon limited electronic transport in Pb. AB - We present a fully ab initio based scheme to compute electronic transport properties, i.e. the electrical conductivity sigma and thermopower S, in the presence of electron-phonon interaction. We explicitly investigate the [Formula: see text] structure of the Eliashberg spectral function, the coupling strength, the linewidth and the relaxation time tau. We obtain a state-dependent tau and show its necessity to reproduce the increased thermopower for temperatures below the Debye temperature, without accounting for the phonon-drag effect. Despite the detailed investigations of various [Formula: see text]- and [Formula: see text] dependencies, the presented scheme can be easily applied to more complicated systems. PMID- 28643699 TI - Nonequilibrium ferroelectric-ferroelastic 10 nm nanodomains: wrinkles, period doubling, and power-law relaxation. AB - Since the 1935 work of Landau-Lifshitz and of Kittel in 1946 all ferromagnetic, ferroelectric, and ferroelastic domains have been thought to be straight-sided with domain widths proportional to the square root of the sample thickness. We show in the present work that this is not true. We also discover period doubling domains predicted by Metaxas et al (2008 Phys. Rev. Lett. 99 217208) and modeled by Wang and Zhao (2015 Sci. Rep. 5 8887). We examine non-equilibrium ferroic domain structures in perovskite oxides with respect to folding, wrinkling, and relaxation and suggest that structures are kinetically limited and in the viscous flow regime predicted by Metaxas et al in 2008 but never observed experimentally. Comparisons are made with liquid crystals and hydrodynamic instabilities, including chevrons, and fractional power-law relaxation. As Shin et al (2016 Soft Matter 12 3502) recently emphasized: 'An understanding of how these folds initiate, propagate, and interact with each other is still lacking'. Inside each ferroelastic domain are ferroelectric 90 degrees nano-domains with 10 nm widths and periodicity in agreement with the 10 nm theoretical minima predicted by Feigl et al (2014 Nat. Commun. 5 4677). Evidence is presented for domain-width period doubling, which is common in polymer films but unknown in ferroic domains. A discussion of the folding-to-period doubling phase transition model of Wang and Zhao is included. PMID- 28643700 TI - A design of experiments approach to identify the influencing parameters that determine poly-D,L-lactic acid (PDLLA) electrospun scaffold morphologies. AB - Electrospun fibrous materials have increasing applications in regenerative medicine due to the similarity of fibre constructs to the morphology of certain extracellular matrices. Although experimentally the electrospinning method is relatively simple, at the theoretical level the interactions between process parameters and their influence on the fibre morphology is not yet fully understood. Here, we hypothesised that a design of experiments (DoE) model could determine combinations of process parameters that result in significant effects on poly-D,L-lactic acid (PDLLA) fibre morphology. The process parameters used in this study were applied voltage, needle-to-collector distance, flow rate and polymer concentration. Data obtained for mean fibre diameter, standard deviation (SD) of the fibre diameter (measure of fibre morphology) and presence of 'beading' on the fibres (beads per MUm2) were evaluated as a measure of PDLLA fibre morphology. Uniform fibres occurred at SDs of <=500 nm, 'beads-on-string' morphologies were apparent between +/-500 and 1300 nm and large beads were observed at +/-1300-1800 nm respectively. Mean fibre diameter was significantly influenced by the applied voltage and interaction between flow rate and polymer concentration. Fibre morphology was mainly influenced by the polymer concentration, while bead distribution was significantly influenced by the polymer concentration as well as the flow rate. The resultant DoE model regression equations were tested and considered suitable for the prediction of parameters combinations needed for desired PDLLA fibre diameter and additionally provided information regarding the expected fibre morphology. PMID- 28643701 TI - Self-anti-reflective density-modulated thin films by HIPS technique. AB - A critical factor for an efficient light harvesting device is reduced reflectance in order to achieve high optical absorptance. In this regard, refractive index engineering becomes important to minimize reflectance. In this study, a new fabrication approach to obtain density-modulated CuIn x Ga(1-x)Se2 (CIGS) thin films with self-anti-reflective properties has been demonstrated. Density modulated CIGS samples were fabricated by utilizing high pressure sputtering (HIPS) at Ar gas pressure of 2.75 * 10-2 mbar along with conventional low pressure sputtering (LPS) at Ar gas pressure of 3.0 * 10-3 mbar. LPS produces conventional high density thin films while HIPS produces low density thin films with approximate porosities of ~15% due to a shadowing effect originating from the wide-spread angular atomic of HIPS. Higher pressure conditions lower the film density, which also leads to lower refractive index values. Density-modulated films that incorporate a HIPS layer at the side from which light enters demonstrate lower reflectance thus higher absorptance compared to conventional LPS films, although there is not any significant morphological difference between them. This result can be attributed to the self-anti-reflective property of the density-modulated samples, which was confirmed by the reduced refractive index calculated for HIPS layer via an envelope method. Therefore, HIPS, a simple and scalable approach, can provide enhanced optical absorptance in thin film materials and eliminate the need for conventional light trapping methods such as anti-reflective coatings of different materials or surface texturing. PMID- 28643702 TI - Surface magnetism of L10 CoPt alloy: first principles predictions. AB - We used the first-principles density functional theory (DFT) to predict the magnetic properties of (1 0 0), (0 0 1), (1 0 1), (1 1 0), and (1 1 1) surfaces of L10 ordered CoPt alloy. Our results indicate that bulk-terminated CoPt surfaces exhibit magnetic moment higher than that of bulk CoPt crystal and surface magnetic anisotropy favoring in-plane magnetization. Moreover, our DFT calculations predict that Pt prefers to segregate to the outermost layer of all these five CoPt surfaces with energy gain in the range of 0.05-0.47 eV for each segregated Pt atom. Comparing the structural and magnetic properties of the bulk terminated and Pt-segregated CoPt surfaces, we found that Pt surface segregation led to larger contraction relaxation, reduced magnetic moments (with the exception of (1 1 0) surface), smaller spin canting angles, and an out-of-plane contribution to the surface magnetic anisotropy energy of the CoPt surfaces. Furthermore, our electronic structure analysis suggests that the change in the density of [Formula: see text] minority spin states of surface Co atoms mainly underlies the observed phenomena related to the surface magnetism of L10 CoPt alloy. PMID- 28643703 TI - Ophthalmology residency training in India: Quo vadis? PMID- 28643704 TI - Publication ethics. PMID- 28643705 TI - Ophthalmology postgraduate training in India: Stirring up a hornet's nest. PMID- 28643706 TI - Orbital retinoblastoma: An update. AB - Orbital extension is a major cause of death in children with retinoblastoma in the developing countries. Delayed detection and inappropriate management contribute to poor outcome. Conventional treatment including primary orbital exenteration or chemotherapy or radiotherapy alone result in mortality as high as 70%. The recent understanding on the role of sequential multimodal therapy with a combination of high-dose chemotherapy, followed by appropriate surgery, radiotherapy, and additional adjuvant chemotherapy has helped dramatically improve life salvage. PMID- 28643707 TI - Pre-Descemet's endothelial keratoplasty. AB - Endothelial keratoplasty (EK) has supplanted the penetrating keratoplasty procedure for corneal endothelial disorders. A review of literature on pre descemet's EK, that is, a latest iterant in EK is described along with our experiences. PMID- 28643708 TI - Residency evaluation and adherence design study: Young ophthalmologists' perception of their residency programs - Clinical and surgical skills. AB - BACKGROUND: Residency training is the basis of good clinical and surgical practice. PURPOSE: The aim is to know the demographics, training experience, and perception of young ophthalmologists to improve the present residency programs in India. SETTING: Young ophthalmologists trained in India. METHODS: A survey was conducted by the Academic and Research Committee of the All India Ophthalmology Society, in 2014-2016 of young ophthalmologists (those trained between 2002 and 2012, with 2-10 years' postresidency experience) to gauge teaching of clinical and surgical skills during the postgraduate residency program. STATISTICAL ANALYSIS: Statistical Package for Social Sciences version 16. RESULTS: Of the 1005 respondents, 531 fulfilled inclusion criteria. Average age was 32.6 years (standard deviation [SD] 4). On a scale of 0-10, clinical skills teaching was graded as (mean, SD): Slit lamp examination (7.2, SD 2.8), indirect ophthalmoscopy (6.2, SD 3.3), gonioscopy (5.7, SD 3.4), perimetry (6.2, SD 3.2), optical coherence tomography (4.6, SD 4), and orthoptic evaluation (4.3, SD 3.1). The mean (SD) and median of surgeries performed independently was intracapsular cataract extraction 3.0 (14.9), 0; extracapsular cataract extraction 39.9 (53.2), 18; small incision cataract surgery 75.3 (64.4), 55; phacoemulsification 30 (52.6), 1; pterygium excision 31.5 (43.5), 15; dacryocystectomy 20.3 (38.1), 4; dacryocystorhinostomy 11.7 (26.2), 2; chalazion 46.4 (48.3), 30; trabeculectomies 4 (14.9), 0; strabismus correction 1.4 (4.9), 0; laser-assisted in situ Keratomileusis 1.5 (12.2), 0; retinal detachment 1.5 (12.5), 0; vitrectomy 3.0 (17.0), 0; keratoplasty 5.2 (17.8), 0; eyelid surgery 8.6 (18.9), 2 and ocular emergencies 41.7 (52.4), 20. Observed and assisted surgeries were more common. However, the range of grading was 0-10 in all categories. CONCLUSION: Residency training in India varies considerably from program to program. Standardization is needed to assure all graduates are competent and render consistent quality of service. PMID- 28643709 TI - Comparison of central corneal thickness with four noncontact devices: An agreement analysis of swept-source technology. AB - PURPOSE: The purpose of this study was to compare the central corneal thickness (CCT) measurements of four noncontact devices in healthy eyes. MATERIALS AND METHODS: In a sample of 45 healthy controls, CCT was measured using an optical biometer (IOLMaster 700) based on swept-source optical coherence tomography (SS OCT), high-resolution rotating Scheimpflug camera system (Pentacam HR), spectral domain OCT (SD-OCT) device with an anterior segment module (Spectralis), and noncontact pachymetry (NCP) device (Topcon TRK-2P). Agreement among the devices was analyzed using mean differences (i.e., bias) and Bland-Altman analysis with 95% limits of agreement (LoA). RESULTS: Mean CCT measurements were 537.5 +/- 47.5 MUm for SS-OCT optical biometer, 532.3 +/- 43.8 MUm for Scheimpflug system, 521.3 +/- 44.7 MUm for SD-OCT device, and 518.0 +/- 43.1 MUm for NCP (P < 0.001). The SD-OCT device and NCP showed the closest agreement, with a bias of 2.6 MUm (95% LoA, -3.6-8.8 MUm), whereas the SS-OCT optical biometer and NCP showed the least agreement, with a bias of 18.7 MUm (95% LoA, -2.1-39.5 MUm). Bias was 16.1 MUm (95% LoA, -3.1-35.3 MUm) for SS-OCT optical biometer and SD-OCT, 5.1 MUm (95% LoA, -6.8-17.0 MUm) for SS-OCT optical biometer and Scheimpflug system, 10.9 MUm (95% LoA, -15.1-36.9 MUm) for SD-OCT device and Scheimpflug system, and 13.6 MUm (95% LoA, -5-32.2 MUm) for Scheimpflug system and NCP. CONCLUSIONS: SS-OCT optical biometer overestimates CCT measurements compared to Scheimpflug system, SD-OCT device, and NCP. Given mean differences and range variations in CCT measurements between devices, SS-OCT optical biometer and Scheimpflug system are interchangeable as are SD-OCT and NCP. PMID- 28643710 TI - Postoperative posterior capsular striae and the posterior capsular opacification in patients implanted with two types of intraocular lens material. AB - AIM: To evaluate the incidence of postoperative posterior capsular striae (PCS) and its influence on posterior capsular opacification (PCO) in patients implanted with two types of lens material. SETTING: Tertiary eye care center in central rural India. STUDY DESIGN: A prospective, observational, nonrandomized study. MATERIALS AND METHODS: The study included 1247 patients having age-related cataract scheduled for removal by phacoemulsification technique and implantation of hydrophilic or hydrophobic intraocular lens (IOL). Demographic profile, nuclear grading, axial length, and IOL power were noted. Details of PCS were noted on the 1st postoperative day in patients with clear cornea. Postoperative follow-up was ensured to study the status of PCS and development of PCO. RESULTS: The overall incidence of PCS was 19.8% (247 out of 1247 eyes). Out of 1247 patients, 641 patients (51.4%) had hydrophilic IOL implantation and 201 eyes had PCS (31.4%) and 606 patients (48.6%) had hydrophobic IOL implantation and 46 eyes had PCS (7.6%), P = 0.04. Three and more striae were seen in 119 eyes (119/641, 18.6%) in hydrophilic group and 4 eyes (4/606, 0.66%) in hydrophobic group. Sixty two eyes (62/201, 30.9%) in hydrophilic group with multiple PCS were reported with persistent striae after 6 months of surgery. Two eyes in hydrophobic group had persistent striae even after 3 years of follow-up. Evaluation of PCO score of the hydrophilic group was 0.6 whereas of the hydrophobic group was 0.1 (P = 0.04). Ten patients of the hydrophilic group only required neodymium-doped yttrium aluminum garnet (ND: YAG) laser capsulotomy. CONCLUSION: The incidence of PCS was higher in hydrophilic than hydrophobic IOLs. Multiple PCS persisting in patients beyond 6 months after operation should be followed up for early development of PCO, particularly in patients implanted with hydrophilic IOL. PMID- 28643711 TI - Glued intraocular lens implantation for eyes with inadequate capsular support: Analysis of the postoperative visual outcome. AB - AIM: The aim of this study is to analyze the postoperative visual outcomes of fibrin glue-assisted, suture-less posterior chamber (PC) intraocular lens (IOL) implantation technique in eyes with inadequate capsule support at a tertiary eye care hospital in South India. SETTING AND DESIGN: This is a retrospective, nonrandomized case series. PATIENTS AND METHODS: This study analyzes 94 eyes which underwent PC-IOL implantation by fibrin glue-assisted, suture-less technique. All patients who had IOL implants by the fibrin glue-assisted PC-IOL technique from August 2009 to January 2014 were included in the study. Intra- and post-operative complications were analyzed. The postoperative best spectacle corrected visual acuity (BSCVA) was evaluated and recorded at the end of 6 months. STATISTICAL ANALYSIS: The data were analyzed using SPSS version 16.1 (SPSS Inc., Chicago, Illinois, USA) using two sample paired t-test and independent t-test. RESULTS: A total of 94 eyes of 92 patients that underwent glued IOL implantation over a period of 5 years were analyzed. Out of 94 eyes, 77 eyes (84.6%) maintained or improved on their preoperative BSCVA (P = 0.012). CONCLUSION: We conclude that glued IOL implantation is a feasible option in rehabilitating patients with aphakia without adequate capsular support. PMID- 28643713 TI - Tissue plasminogen activator-assisted vitrectomy for submacular hemorrhage due to age-related macular degeneration. AB - PURPOSE: The purpose of this study was to evaluate the treatment efficacy of vitrectomy combined with subretinal recombinant tissue plasminogen activator (r tPA) and factors affecting visual improvement in patients with submacular hemorrhage (SMH) due to neovascular age-related macular degeneration (nAMD). MATERIALS AND METHODS: Medical records of 17 consecutive patients diagnosed with SMH secondary to nAMD were retrospectively reviewed. The initial surgical procedure involved a 23-gauge transconjunctival vitrectomy, subretinal r-tPA application through a self-sealing inferior retinotomy, and sulfur hexafluoride gas for tamponade in all patients. The duration, size, and thickness of the hemorrhage and the pre- and post-operative visual acuity (VA) using a Snellen chart were recorded. VA was converted to logMAR for statistical analysis. RESULTS: The average duration and size of the SMH were 12.8 +/- 18.2 days and 8.6 +/- 5.3 disc areas, respectively. The mean follow-up time was 16.9 +/- 4.7 months. A statistically significant visual improvement was found when comparing initial VA with postoperative best-corrected VA (BCVA) and final BCVA (Wilcoxon rank test, P <= 0.01). There was no significant correlation between the size of the hemorrhage and postoperative BCVA and final BCVA (Spearman's rho test). There was no statistically significant correlation between the initial VA and postoperative BCVA and final BCVA (Spearman's rho test). There was no significant correlation between the duration of hemorrhage and postoperative BCVA and final BCVA (Spearman's rho test). The preoperative thickness of hemorrhage (747.5 +/- 30 MUm) was not correlated with postoperative BCVA or final BCVA (Pearson's test). CONCLUSIONS: Vitrectomy combined with subretinal r-tPA injection and gas tamponade is an effective surgical intervention to preserve VA in selected patients with apparent SMH. PMID- 28643714 TI - Comparison of vitrectomized with nonvitrectomized eyes after subtenon injection of triamcinolone acetonide to treat diabetic macular edema: Retrospective comparative Analysis of an interventional case series. AB - PURPOSE: Triamcinolone acetonide (TA) is an alternative option for diabetic macular edema thanks to its cost-benefit ratio and unique delivery route. We performed this study to compare vitrectomized with nonvitrectomized eyes treated with subtenon TA injection for diabetic macular edema. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who had undergone subtenon TA injection for diabetic macular edema treatment. The patients were divided into two groups: Vitrectomized and nonvitrectomized. Visual acuity and central subfield macular thickness (CSMT) were analyzed before injection, at 1 and 3 months after injection. RESULTS: Visual acuity in vitrectomized group improved significantly at 1 month (P = 0.002), but this improvement regressed after 3 months. In the nonvitrectomized group, visual acuity did not improve significantly after 1 month, but it did after 3 months (P = 0.019). The CSMT decreased significantly in both groups at 1 and 3 months (P < 0.001). There were no significant differences between the groups at either 1 or 3 months with regard to either visual improvement or change in CSMT. CONCLUSION: Subtenon TA injection could be an alternative treatment option for diabetic macular edema, both in vitrectomized and in nonvitrectomized eyes. TA seems to take effect earlier and decay faster in vitrectomized eyes. PMID- 28643712 TI - Comparison of macular pigment optical density in patients with dry and wet age related macular degeneration. AB - AIM: The aim of the study was to evaluate the macular pigment optical density (MPOD) levels in patients with wet age-related macular degeneration (AMD), dry AMD, and also in healthy controls. SETTINGS AND DESIGN: This study was conducted at Department of Ophthalmology, and the study design was a prospective study. PATIENTS AND METHODS: Forty-eight patients with wet AMD, 51 patients with dry AMD, and 50 controls were included in the study. All patients were naive to both previous lutein or zeaxanthin administration and any previous intravitreal injections. Fundus reflectance (VISUCAM 500, reflectance of a single 460 nm wavelength) was used to measure the MPOD levels. Three groups were compared regarding age, gender, serum lutein, and zeaxanthin concentrations as well as MPOD levels. RESULTS: Serum lutein and zeaxanthin levels were significantly higher in control group when compared with wet AMD (Group 1) and dry AMD (Group 2) (P = 0.001 and P< 0.001, respectively). Mean MPOD was found to be similar in all of the three study subgroups (P = 0.630). However, maximum MPOD was significantly higher in control group when compared with Group 1 and 2 (P = 0.003). There was no correlation between serum lutein or zeaxanthin concentrations and mean MPOD levels (P = 0.815, r = 0.014 and P = 0.461, r = 0.043, respectively), but there was a weak correlation between serum zeaxanthin concentration and maximum MPOD level (P = 0.042, r = 0.124). Maximum MPOD level was found to be correlated with the level of AMD (Group 1, 2, and 3; r = 0.184, P = 0.041). CONCLUSION: Maximum MPOD level was found to be lower in patients with AMD when compared with control cases. Mean MPOD and maximum MPOD levels were similar in wet and dry AMD Groups. These results can be applied clinically keeping in mind that MPOD measurements with one wavelength reflectometry may not be completely reliable. PMID- 28643715 TI - Microstructure changes of occipital white matter are responsible for visual problems in the 3-4-year-old very low birth weight children. AB - PURPOSE: The main aim of the study was to evaluate which factors affect the long time visual function in preterm children, whether it is prematurity or retinopathy of prematurity or perhaps disturbances in the visual pathway. MATERIALS AND METHODS: Fifty-eight children with mean birth weight 1016 g (range 520-1500 g) were evaluated at mean age 48 months (range 42-54 months). All children underwent magnetic resonance imaging (MRI) studies, visual evoked potentials (VEPs), and the Developmental Test of Visual Perception (DTVP). The MRI evaluation included diffusion tensor imaging and fractional anisotropy (FA), and colored orientation maps were calculated for each subject. Based on the results of the VEP evaluation, children were divided into two groups: A-abnormal results of VEP (n = 16) and B-normal VEP results (comparison group, n = 42). RESULTS: FA values of inferior left and right occipital white matter (OWM) were lower in the group of children with abnormal VEP compared to the comparison group (0.34 +/- 0.06 vs. 0.38 +/- 0.06; P = 0.047; 0.31 +/- 0.04 vs. 0.36 +/- 0.06; P = 0.007, respectively). Furthermore, there were correlations between the latency (r = -0.35; P = 0.01) and amplitude (r = 0.31; P = 0.02) and FA in OWM. Children with abnormal VEP had lower DTVP scores as compared with children with normal VEP results (88 +/- 18 vs. 95 +/- 16 points, P = 0.048). Finally, a multivariate logistic regression revealed that FA of the inferior OWM was the only independent risk factor for the abnormal VEP (P = 0.04). CONCLUSION: Visual perception, VEPs, and white matter microstructural abnormalities in very low birth weight children at the age of 3-4 are significantly correlated. PMID- 28643716 TI - Prevalence of ocular morbidity in school going children in West Uttar Pradesh. AB - AIM OF THE STUDY: This study aims to evaluate the prevalence and to make a comparison between the ocular morbidity pattern in school going children of urban and rural areas of West Uttar Pradesh. MATERIALS AND METHODS: A school-based cross-sectional study design was adopted to examine children aged 5-15 years in randomly selected urban and rural schools of West Uttar Pradesh from June 2012 to August 2014. An optometrist did the vision and refraction, and a detailed ophthalmic examination was done by an ophthalmologist. Children needing further assessment were referred to a higher center. Interpretation and analysis of the data were done using Epi Info Software and t-test. RESULTS: A total of 4838 students (2271 males and 2567 females) were screened. The prevalence of ocular morbidity was 29.35% (28.65% urban, 30.05% rural). Refractive error (17.36%) was the major cause of ocular morbidity followed by convergence insufficiency (2.79%), blepharitis (2.11%), Vitamin A deficiency (2.09%), allergic conjunctivitis (1.92%), bacterial conjunctivitis (0.95%), amblyopia (0.41%), stye (0.31%) and squint (0.27%). There was an increase in ocular morbidity with age, especially in refractive error and convergence insufficiency. On comparing urban and rural schools, Vitamin A deficiency showed a significantly higher prevalence (P < 0.05%) in the rural (3.03%) as compared to the urban sector (1.15%). The prevalence of visual impairment was 4.9/1000 children, and prevalence of blindness was 0.62/1000 children. CONCLUSION: This study was the first of its kind in West Uttar Pradesh, reporting a considerable high prevalence (29.35%) of pediatric ocular morbidity, which was more in rural as compared to the urban sector. Since most of this morbidity is either preventable or treatable, school screening forms an effective method to reduce this load. PMID- 28643717 TI - Spectacles use in a rural population in the state of Telangana in South India. AB - CONTEXT: Uncorrected refractive errors are the leading cause of visual impairment. AIMS: To assess the prevalence and patterns of spectacles use among those aged >=40 years in the South Indian state of Telangana. SETTINGS AND DESIGN: This was a population-based, cross-sectional study, in which 6150 people were enumerated from 123 clusters in the two districts of Telangana state (Adilabad and Mahbubnagar) using a two-stage cluster random sampling methodology. MATERIALS AND METHODS: Participants were visited in their households and presenting visual acuity (VA) was assessed in all cases followed by pinhole VA if presenting VA was worse than 6/12. A questionnaire was used to collect information on the current and previous spectacles use, type of spectacles, and details of the spectacles provider. STATISTICAL ANALYSIS USED: Stata statistical software version 12. RESULTS: Among 5881 participants examined, 53.7% were women, and 82% had no formal education. The prevalence of current spectacles use was 28.8% (95% confidence interval: 27.6-30.0). On applying multiple logistic regression analysis, spectacles use was significantly associated with older age groups, female gender, higher levels of education, and residing in Adilabad district. Bifocals were the most commonly used type of spectacles (56.3%), and private eye clinics (70.3%) were the leading service providers. The spectacles coverage was 53.6%. CONCLUSIONS: We reported on prevalence and patterns of spectacles use using a large representative sample and a high response rate. More than half of those who may benefit from spectacles were using them, suggestive of a reasonable primary eye care coverage in the two districts studied. PMID- 28643718 TI - A rare case of idiopathic parafoveal telangiectasia associated with central serous chorioretinopathy. PMID- 28643719 TI - Alkaptonuria: A case report. AB - Alkaptonuria is a rare inborn error of metabolism with autosomal recessive inheritance with a mutation in homogentisate 1,2-dioxygenase. It results in accumulation of homogentisic acid in connective tissues (ochronosis). Most common ocular manifestations are bluish-black discoloration of the conjunctiva, cornea, and sclera. In this case report, a 39-year-old Indian male patient with additional ocular features in the retina is described. PMID- 28643720 TI - Inferior subconjunctival dislocation of posterior chamber intraocular lens after blunt trauma. AB - Traumatic subconjunctival dislocation of the posterior chamber intraocular lens (PCIOL) is a rare and emergency condition. Here, we report an interesting variation of rare case of inferior subconjuctival dislocation of PCIOL in a 75 year-old female patient following blunt trauma to her right eye with cow's head. All the previous literature with subconjuctival dislocation of PCIOL has reported the superior dislocation of intraocular lens. Inferior subconjunctival dislocation has never been reported in previous literature. PMID- 28643721 TI - Surgical treatment of Metarhizium anisopliae sclerokeratitis and endophthalmitis. AB - A 55-year-old nurse was referred with a 5-month history of right eye corneal abscess. The initial injury occurred when doing lawn work. The infection worsened despite multiple antibiotic, antiviral, and steroid treatments. Visual acuity was limited to hand motion. On examination, there was keratitis, ocular hypertension, and a secondary cataract. Corneal scrapings grew a filamentous fungus, identified as Metarhizium anisopliae (MA). Despite intensive antifungal treatment with topical, intravitreous, and systemic voriconazole, purulent corneal melting and scleritis with endophthalmitis rapidly appeared. An emergency surgical procedure including sclerocorneal transplantation, cataract surgery, a pars plana vitrectomy using temporary keratoprosthesis, and scleral crosslinking was necessary. One year after the surgery, there was no recurrence of infection. Functional outcome remained very poor. This is the first case of sclerokeratitis and endophthalmitis caused by MA ever reported. The infection was successfully treated with an aggressive combination of medical and surgical treatments. PMID- 28643722 TI - Endogenous endophthalmitis caused by Cryptococcus neoformans Var. Gattii mimicking choroidal tumor: From positron-emission tomography/computed tomography to histopathology. AB - A 60-year-old immunocompetent female with pneumonia history about 10 years ago suffered from blurred vision overall survival for 3 weeks. Common cold with headache and unintentional body weight loss was also noted recently. Choroidal detachment simulating choroidal tumor was observed in the temporal quadrant. The 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography/computed tomography (CT) scan showed focal, mild to moderate FDG uptake in the left lateral orbit, and an enhanced lesion was seen on the recent CT scan. The suspicious choroidal tumor became larger in a week. Phacoemulsification, vitrectomy, and retinal biopsies were performed. Histochemical study of the retinal specimens established the diagnosis of endogenous cryptococcal endophthalmitis. Vitreous culture yielded Cryptococcus neoformans var. gattii. Systemic and topical voriconazole eliminated the infection. In the literature, endogenous endophthalmitis caused by C. neoformans var. gattii has not been reported in detail. The key to successful management lies in early diagnosis. If clinical improvement could not be achieved after conventional management and imaging studies have failed to yield a definite diagnosis, retinal biopsy can be considered. PMID- 28643723 TI - Management of a case of Candida albicans endogenous endophthalmitis with intravitreal caspofungin. AB - We report a case of Candida albicans endogenous endophthalmitis treated with intravitreal caspofungin. The patient was a known case of acute lymphoblastic leukemia on chemotherapy and presented to us with features suggestive of endogenous endophthalmitis. He was treated initially with intravenous (IV) caspofungin and intravitreal amphotericin B. Patients condition worsened after IV caspofungin was replaced by amphotericin B necessitating a core vitrectomy. The patient was given the option of off-label caspofungin intravitreal injection for which the patient consented. There was a gradual improvement in the clinical picture. The situation worsened after the injections were stopped necessitating a revitrectomy. The study demonstrates the clinical efficacy of intravitreal caspofungin for the first time in human eyes. PMID- 28643724 TI - Successful surgical management of bilateral epiretinal membrane in a child with only cafe-au-lait spots. AB - A 6-year-old boy diagnosed as anisometropic amblyopia, with only cafe-au-lait spots and a family history of neurofibromatosis, presented with decrease in vision in the both eyes. Dilated fundus examination showed epiretinal membrane in both eyes over the macula. He underwent successful surgical management of the epiretinal membrane. PMID- 28643725 TI - A 7-year-old female child of incontinentia pigmenti presenting with vitreous hemorrhage. AB - Incontinentia pigmenti (IP) is a rare disease with multisystemic anomalies, which commonly presents just after birth. Here, we report a rare case of IP patient with vitreous hemorrhage in school-age children. Therefore, physicians have to be alert and evaluate IP patients at all ages. Regular ophthalmic follow-up is necessary, and fluorescein angiography should be performed if peripheral ischemia or neovascularization is suspected. The effect of peripheral laser ablation on peripheral retinal nonperfusion is not clear and merits further study. PMID- 28643726 TI - Exotropia in a pediatric patient with rhabdomyolysis caused by an insect sting. AB - Various ocular and systemic reactions have been associated with insect sting. However, insect stings have been rarely reported to cause exotropia and diplopia. We encountered exotropia in a 6-year-old child with rhabdomyolysis of the left lower extremities caused by an insect sting. Exotropia and diplopia developed within 1 day after the sting and improved completely 1 week after the onset of symptoms. Clinicians should be aware of the potential for the development of exotropia in patients with insect stings, which requires careful follow-up. PMID- 28643727 TI - Silodosin-associated intraoperative floppy iris syndrome. PMID- 28643728 TI - Regulation of various DNA repair pathways by E3 ubiquitin ligases. AB - DNA repair is the most important mechanism to maintain the normal cellular homeostasis. Owing to its complicated network, series of posttranslation modifications is required for proper function of the DNA repair proteins. One of such important posttranslation modifications is ubiquitination (attachment of ubiquitin). E3 ubiquitin ligases (UBLs) are a group of proteins that transfer ubiquitin from E2 conjugating enzymes to highly specific substrates such as DNA repair proteins. In this review, we have updated the role of different E3 UBL and how it regulates different DNA repair pathways. PMID- 28643729 TI - Differential diagnoses of elevated lesions of the upper lip: An overview. AB - This paper comes with a purpose to help the clinician as how to arrive at a logical differential diagnosis when an upper lip mass is encountered in day-to day practice. The labial mucosa is commonly traumatized. One must be aware of the type of structures contained in the mucosa of the area of a lesion as well as the patients habits since they may relate to a lesion presented for diagnosis. It also helps them to procure a sound knowledge of the lesions by describing the lesions according to their clinical appearance and to aid the clinician in arriving at a differential diagnosis by considering that certain lesions have a predilection for the upper lip. All clinically similar appearing lesions are discussed according to their relative frequency of occurrence. This paper covers only a minority of plethora of elevated lesions that may appear on the upper lip since almost any soft tissue lesion or neoplasm (benign and malignant) may occur here. PMID- 28643730 TI - An overview on small-field dosimetry in photon beam radiotherapy: Developments and challenges. AB - Small fields are more repeatedly used for radiation therapy as small segments in intensity-modulated radiotherapy or as in the form of independent fields in stereotactic radiosurgery and other novel equipment such as cyberknife and tomotherapy. Nevertheless, the application of small fields for radiotherapy of lung makes the dose calculation and planning inaccurate due to the existence of electronic disequilibrium and intrinsic deficiencies within most of the analytical dose calculation algorithms. The current review attempts to gather the information in this regard and focuses on the current progresses and retaining issues associated with this type of photon beams. PMID- 28643731 TI - Cardiotoxic effects of radiotherapy and strategies to reduce them in patients with breast cancer: An overview. AB - Cardiotoxicity of various anticancer therapies, including radiotherapy (RT), can lead to cardiovascular (CV) complications, and their severity depends on many factors, including the site of action, the applied dose, the method of administration, the presence of pre-existing CV diseases, or CV risk factors, the individual patient characteristics, and the current or previous use of antineoplastic therapies. Cardiotoxicity can occur immediately upon administration of the anticancer therapy or it may have a delayed onset (months or years after the treatment). For an oncology treatment team, it is essential that the patients with cancer are in their best cardiac condition before they initiate anticancer therapy, during remission, and after its termination, and thus, a collaboration with cardiologists is of utmost importance. This article reviews cardiotoxicity associated with RT, focusing on patients with breast cancer. In addition, it outlines the main management strategies to assess, monitor, reduce, or possibly prevent RT-induced cardiotoxicity, based on the current research evidence. Medline literature review relating to this subject was performed, using the electronic search for the keywords "radiotherapy" and "cardiotoxicity" on PubMed for inclusion of the previous publications, and further search of reference articles on the detection and management of radiation related heart disease in patients with breast cancer was conducted. PMID- 28643732 TI - Thrombocytosis in gynecological cancers. AB - Thrombocytosis has been suggested to be a poor prognostic indicator in malignancies. Studies have shown that thrombocytosis is associated with a poor prognosis in various gynecological malignancies such as carcinoma ovary, cervical cancer, and endometrial cancer. The aim of this study is to analyze the impact of thrombocytosis on the prognosis of gynecological cancer. All the relevant data were retrieved by PubMed, MEDLINE, and Web of Science, and then studies were chosen in this analysis of association between thrombocytosis and gynecological malignancy. Thrombocytosis is common in advanced disease in patients with ovarian cancer, endometrial cancer, and cervical cancer. Therefore, it may be a marker of tumor burden or biologically more aggressive disease. Thrombocytosis is bad prognostic factor and associated with poorer outcomes. PMID- 28643733 TI - A prospective randomized controlled study of cisplatin versus carboplatin-based regimen in advanced squamous nonsmall cell lung cancer. AB - BACKGROUND: The use of cisplatin (Cis) versus carboplatin (Carb) in the treatment of advanced nonsmall cell lung cancer (NSCLC) is controversial. The aim of the study was to compare the safety and efficacy of Cis versus Carb in squamous NSCLC. PATIENTS AND METHODS: A prospective, randomized, controlled, open-label study was conducted on advanced squamous NSCLC patients who were randomly assigned to receive Cis (40 mg/m 2 [day 1 and day 8]) or Carb (area under the curve = 5 [day 1]) combined with gemcitabine [Gem] (1000 mg/m 2 [day 1 and day 8]) of a 3-week schedule for six cycles. Study objectives were a radiological response after three cycles and six cycles, 1-year progression-free survival (PFS), 1-year overall survival (OS), and quality of life (QOL) assessment using functional assessment of cancer therapy-lung at baseline, after three cycles, and after six cycles. STATISTICAL ANALYSIS: Statistical analysis was done using Statistical Package for Social Science version 15. A P < 0.05 was considered statistically significant. RESULTS: Seventy-one patients were enrolled (Gem/Cis group [n = 36], Gem/Carb group [n = 35]). Response rates were comparable in both arms. Nonsignificant differences were found regarding 1-year PFS (P = 0.308) and 1-year OS (P = 0.929) between the two groups. Neutropenia was significantly higher in Gem/Carb group, while vomiting and ototoxicity were significantly higher in Gem/Cis group. The effect on QOL was similar in both groups. CONCLUSION: Cis and Carb have similar efficacy, tolerability, and effect on QOL and both can be used as a first-line treatment of squamous NSCLC. PMID- 28643734 TI - The significance of serum leptin level in patients with early stage nonsmall cell lung cancer. AB - BACKGROUNDS: The serum leptin level (SLL) has been shown to increase in patients with nonsmall cell lung cancer (NSCLC). However, available data regarding the relation between SLL and tumor subtypes, survival, cachexia, and tumor respectability in NSCLC are still under debate. The aim of this study is to evaluate SLL in NSCLC patients with and without cachexia. MATERIALS AND METHODS: A total of 71 patients with early stage NSCLC were enrolled in this prospective study. SLL was measured by enzyme-linked immunosorbent assay. The relationship between SLL and clinicopathological factors including histopathological subtypes, weight loss, overall survival, and tumor resectability were evaluated. RESULTS: Of the 71 patients, 57 (81%) were male with a mean age of 63.3 +/- 8.2 years. The rates of histological subtypes of NSCLC were as follows: Squamous cell carcinoma 60.5%, adenocarcinoma 32%, and others 7.2%. Mean SLL was 12.9 +/- 38.4 pmol/mL. There was no distinctive difference between SLL, weight loss, and survival. However, when stratifying the groups according to the lung cancer histological subtypes, mean SLL was significantly higher in patients with adenocarcinoma than those with squamous cell subtype (26.9 +/- 6.2 pmol/mL vs. 5.1 +/- 9.1 pmol/mL, P = 0.004). CONCLUSIONS: SLL might be beneficial as a useful biomarker in preclinical setting of NSCLC to guide detecting the lung cancer subtypes as well as monitoring the patients. PMID- 28643735 TI - Modeling of lung cancer risk due to radon exhalation of granite stone in dwelling houses. AB - AIMS: Due to increasing occurrences of lung cancer, radon exhalation rates, radon concentrations, and lung cancer risks in several types of commonly used granite stone, samples used for flooring in buildings, have been investigated. SUBJECTS AND METHODS: We measured the radon exhalation rates due to granite stones by means of an AlphaGUARD Model PQ2000 in a cube container with changeable floor by various granite stones. The lung cancer risk and percentage of lung cancer deaths (LCRn) due to those conditions were calculated using Darby's model. RESULTS: The radon exhalation rates ranged from 1.59 +/- 0.41 to 9.43 +/- 0.74 Bq/m 2/h. The radon concentrations in the standard room with poor and normal ventilation were calculated 20.10-71.09 Bq/m 3 and 16.12-47.01 Bq/m 3, respectively. CONCLUSIONS: The estimated numbers of lung cancer deaths attributable to indoor radon due to granite stones in 2013 were 145 (3.33%) and 103 (2.37%) for poor and normal ventilation systems, respectively. According to our estimations, the values of 3.33% and 2.37% of lung cancer deaths in 2013 are attributed to radon exhalation of granite stones with poor and normal ventilation systems, respectively. PMID- 28643736 TI - The pitfalls in cytology diagnosis of poorly differentiated neuroendocrine carcinoma of lung and their treatment response. AB - CONTEXT: Lung is the most common site of small cell carcinoma (SCLC) - a poorly differentiated neuroendocrine carcinoma (PDNEC). SCLC comprises 15-20% of the invasive cancers of the lung. AIM: This study was conducted to appraise the accuracy and pitfalls of the diagnosis of PDNEC on cytology along with treatment responses if available. SETTINGS AND DESIGN: Retrospective study for 2 years yielded 21 cases on cytology. SUBJECTS AND METHODS: Slides of fine-needle aspiration of lymph nodes, the tumor, bronchial brush, and bronchoalveolar lavage specimens were used. The histological correlation was obtained as were treatment responses. RESULTS: Eighteen SCLCs were confirmed on review. Of these, 13 initial reports were concordant and five, discordant. The rest three cases which initially reported as SCLC were found to be negative (2) and combined SCLC (1). One SCLC with concordant initial and reviewed diagnoses failed to confirm on histopathology. The patients, all heavy smokers, were predominantly males in the seventh to eighth decade age group. The sensitivity and specificity of reviewed diagnoses were better than that of the original. The difference between histopathology and cytology diagnoses (reviewed and original) was statistically insignificant. All patients were categorized as "extensive stage" by positron emission tomography-computerized tomography, and five were treated with etoposide and cisplatin with/without radiotherapy. CONCLUSION: Age group (61-70) and gender (males) distribution were statistically significant. Intermediate variants of SCLC may be misdiagnosed as adenocarcinoma. Similarly, combined SCLC may be missed on cytology if the observer does not sustain a high index of suspicion. Unequivocal cytology diagnosis opposed to negative histopathology report demands repeat biopsy. PMID- 28643737 TI - Changes in pharyngeal constrictor volumes during head and neck radiation therapy: Implications for dose delivery. AB - OBJECTIVE: The objective of this study was to evaluate the anatomical changes and associated dosimetric consequences to pharyngeal constrictor muscles (PCMs) that occur during head and neck (H and N) radiotherapy (RT). MATERIALS AND METHODS: A cohort of 13 oropharyngeal cancer patients with daily cone beam computed tomography (CBCT) was retrospectively studied. On every 5th CBCT image, PCM was manually delineated by a radiation oncologist. The anterior-posterior PCM thickness was measured at the midline level of C3 vertebral body. Delivered dose to PCM was estimated by calculating dose on daily images and performing dose accumulation on corresponding planning CT images using a parameter-optimized B spline-based deformable image registration algorithm. The mean and maximum delivered dose (Dmean, Dmax) to PCM were determined and compared with the corresponding planned quantities. RESULTS: The average (+/-standard deviation) volume increase (DeltaV) and thickness increase (Deltat) over the course of 35 total fractions were 54 +/- 33% (11.9 +/- 7.6 cc) and 63 +/- 39% (2.9 +/- 1.9 mm), respectively. The resultant cumulative mean dose increase from planned dose to PCM (DeltaDmean) was 1.4 +/- 1.3% (0.9 +/- 0.8 Gy), while the maximum dose increase (DeltaDmax) was 0.0 +/- 1.6% (0.0 +/- 1.1 Gy). Patients who underwent adaptive replanning (n = 6) showed a smaller mean dose increase than those without (n = 7); 0.5 +/- 0.2% (0.3 +/- 0.1 Gy) versus 2.2 +/- 1.4% (1.4 +/- 0.9 Gy). There were statistically significant (P = 0.001) strong correlations between DeltaDmean and Deltat (Pearson coefficient r = 0.78), as well as between DeltaDmean and DeltaV (r = 0.52). CONCLUSION: The patients underwent considerable anatomical changes to PCM during H and N RT. However, the resultant increase in dose to PCM was minor to moderate. PCM thickness measured at C3 level is a good predictor for the mean dose increase to PCM. PMID- 28643738 TI - Five versus ten fractions per week radiotherapy in locally advanced head and neck cancer. AB - INTRODUCTION: Conventional fractionated radiotherapy (CFRT) is in use since a long time, but the invention of altered fractionation such as hyperfractionation has improved survival in head and neck squamous cell cancer (HNSCC). AIMS: Our aim of this prospective randomized study is to compare conventional 5 fractions per week (CFRT) with hyperfractionation 10 fractions per week (hyperfractionated radiotherapy [HFRT]) in locally advanced head and neck cancer. PATIENTS AND METHODS: The study period is from November 2013 to April 2015. Totally, 100 patients with proven head and neck cancer were submitted to radiotherapy on theratron 780 (cobalt 60) machine. Fifty patients in each CFRT group and HFRT group randomized to receive radiotherapy following induction chemotherapy. Patients in CFRT group have received 66-70 Gy/33-35 fractions Monday to Friday, while HFRT group have received 70.4 Gy/64 fractions Monday to Friday. RESULTS: Our results show manageable toxicity profile of a combined therapy consisting of cisplatin and paclitaxel, followed by concomitant chemoradiotherapy in the form of either CFRT or HFRT with cisplatin as a radiosensitizer in both treatment groups. The overall response at the completion of radiotherapy was 95.7% in HFRT versus 89.5% in CFRT with 76.6% complete response in HFRT versus 64.6% in CFRT. CONCLUSIONS: After induction chemotherapy, HFRT seems to be more efficacious than CFRT in locally advanced HNSCC, by increasing significantly the probability of progression-free survival and locoregional control. PMID- 28643739 TI - Patterns of tobacco usage among subjects with potentially malignant oral lesions or conditions in Chennai city: A comparative study. AB - OBJECTIVE: To determine the patterns of tobacco usage among subjects with potentially malignant oral lesions or conditions through a comparative study design. METHODS: The study was carried out in a span of 2 months on a sample of 120 subjects; 60 in case group (30 subjects with leukoplakia and oral submucous fibrosis [OSMF], respectively) and 60 subjects in control group (30 current smokers and current chewers, respectively), attending the tobacco cessation clinic at a private dental college hospital in Chennai city. Demographic data, details of tobacco usage, and Fagerstrom nicotine dependence scores (FNTD) were recorded in a prevalidated tobacco cessation intake form. RESULTS: Cases with leukoplakia had a higher mean FNTD score when compared to the control group (P = 0.0001). The most common form of smokeless tobacco used by case (OSMF) subjects was found to be mawa (53%) significantly higher than the control group (P = 0.05). Mean FNTD scores of mawa users were higher than other tobacco users in both case and control group. CONCLUSION: The current study has hence put forth the role of mawa form of tobacco in causation of OSMF at a time when implementation of tougher anti-tobacco laws is the talk of the town. PMID- 28643740 TI - Telomere length variation and expression analysis of shelterin complex genes during gallbladder carcinogenesis. AB - BACKGROUND: Telomeres, which are bound with shelterin protein complex, play an important role in maintaining genomic stability and its dysfunction may lead to carcinogenesis. Here, we aimed to analyze whether shelterin complex gene expression and telomere length variation, play any role in gallbladder carcinogenesis. METHODS: Telomere length analysis was carried out by monochrome multiplex qPCR, whereas expression analysis of shelterin genes was carried out using RT-qPCR. Statistical analysis was carried out using SigmaPlot 11 software. RESULTS: We found significantly reduced telomere length in tumor tissues, and this reduction was seen in both, tumors with or without gallstones in comparison to adjacent non tumor and gallstone (chronic calculous cholecystitis: Inflamed) tissues. Inflamed tissues showed increased telomere length as compared to both adjacent non tumor and tumor tissues. Expression analysis of five shelterin genes showed significant downregulation of TERF1, POT1, and TINF2 genes in inflamed tissues as compared to non tumor and tumor tissues. POT1 was also found to be significantly upregulated in tumor tissues and specifically in tumor tissues with gallstones compared to inflamed tissues. CONCLUSION: This study, thus, suggests that, gallstone does not affect telomere length and even after having increased telomere length, decreased expression of some shelterin genes in inflamed tissue might cause telomeres to cap improperly, possibly leading to telomere dysfunction and further, gallbladder carcinogenesis. Also, increased expression of POT1 in tumor tissues with gallstones could act as a diagnostic marker in patients with gallstones. PMID- 28643741 TI - Prognostic and predictive markers of response to treatment in patients with locally advanced unresectable and metastatic pancreatic adenocarcinoma treated with gemcitabine/nab-paclitaxel: Results of a retrospective analysis. AB - BACKGROUND: Recent studies support the use of gemcitabine and nab-paclitaxel in adults with locally advanced unresectable or metastatic pancreatic adenocarcinoma although insufficient data are available on prognostic and predictive markers of response to treatment. OBJECTIVE: The objective of this study is to identify treatment response markers in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma. MATERIALS AND METHODS: This is an observational, retrospective, and multicenter study. Sociodemographic, clinical, and therapeutic data were collected. Cox regression models were applied to determine associations. RESULTS: In total, 39 patients were included; 23.1% presented locally advanced pancreatic cancer and 76.9% metastatic disease. They received a mean of 6 +/- 3 treatment cycles; 59% required dose reduction, 59% treatment delay, and 20.5% switched to a biweekly regimen. The overall response rate was 23% and the disease control rate was 81%. Median progression-free survival was 9 months and median overall survival (OS) was 15 months. A higher neutrophil/lymphocyte ratio (NLR) was significantly associated with lower OS. We reported Grades 1-4 nonhematological and hematological toxicities. CONCLUSION: NLR is a useful prognostic factor for OS in patients with locally advanced unresectable or metastatic pancreatic adenocarcinoma treated with gemcitabine and nab-paclitaxel. Moreover, we suggest that a biweekly regimen is an option for certain groups of patients. PMID- 28643742 TI - In vitro activity of probiotic Lactobacillus reuteri against gastric cancer progression by downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor gene expression. AB - BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer death, and most patients represent metastatic phenotype at the time of diagnosis. Urokinase plasminogen activator (uPA) system is well known for its critical roles in cancer cells invasion since uPA/uPA receptor (uPAR) overexpresses in several cancers. Subsequently, suppression of uPA/uPAR gene expression improves patients overall survival and prevents cancer progression. OBJECTIVES: The aim of the current study was to investigate possible effects of live Lactobacillus reuteri as a probiotic in inhibition of GC cells proliferation and invasion. MATERIALS AND METHODS: Human gastric adenocarcinoma epithelial cell line (AGS) cells were treated with different ratios of live L. reuteri and were incubated for 24, 48, and 72 h. Viability of cancer cells was measured with 3-(4,5-dimethylthiazol-2yl) 2,5-diphenyltetrazolium bromide assay, and the effects of L. reuteri on uPA/uPAR gene expression were assessed by real-time polymerase chain reaction. RESULTS: Our results showed that L. reuteri inhibits cell proliferation significantly in dose-dependent manner. Expressions of uPA and uPAR were downregulated followed by co-incubation of AGS cells and live L. reuteri compared to untreated-based line level. CONCLUSION: This study provides strong support in the role of L. reuteri in suppression of GC cell invasion by downregulation of pathways which is involved in extracellular matrix degradation such as uPA and uPAR. PMID- 28643743 TI - Dual association of serum interleukin-10 levels with colorectal cancer. AB - BACKGROUND: Interleukin 10 (IL-10) is considered an immune modulator cytokine, showing both antitumor and pro-tumor characteristics. Its role in the pathogenesis and progression of colorectal cancer depends on microenvironmental milieu. MATERIALS AND METHODS: A case-control study with 58 newly diagnosed colorectal cancer (CRC) patients, and 30 healthy individuals was conducted to compare the serum IL-10 levels between patients and controls. Furthermore, the correlation of the cytokine levels with the pathological features and prognosis of the CRC was investigated. IL-10 levels in the sera of patients and controls were measured by Enzyme-linked immunosorbent assay. RESULTS: Mean serum IL-10 levels were significantly lower in CRC patients than in controls (P = 0.04). CRC patients with worse prognosis at the time of diagnosis tend to have higher levels of circulating IL-10 than those with better prognosis (P = 0.008). Receiver operating characteristics curve analysis demonstrated that IL-10 levels in the sera of CRC patients can be used as a prognostic biomarker in CRC patients (area under the curve = 0.71; P = 0.01). CONCLUSIONS: Our results demonstrated a dual association of serum IL-10 levels in the initiation and progression of CRC. While lower IL-10 levels were associated with higher risk of the disease, its higher levels were associated with a poorer prognosis. PMID- 28643744 TI - Correlation of serum intercellular adhesion molecule 1 and vascular endothelial growth factor with tumor grading and staging in breast cancer patients. AB - BACKGROUND: Breast cancer is the most common cancer among women. There are several prognostic factors for this disease. The aim of this article is to explore the correlation of serum level of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule 1 (ICAM1) with tumor, node, metastasis staging and grading of breast cancer. MATERIALS AND METHODS: Serum samples of 51 patients with breast cancer were assessed with enzyme-linked immunosorbent assay for the level of VEGF and ICAM1 preoperatively. After the operation, histopathologic specimens stained with hematoxylin and eosin were evaluated for tumor size, histopathologic subtype, grade, lymph node, vascular and lymphatic involvement. Then, the correlation of tumor stage and grade and serum level of markers was analyzed. RESULTS: There was no significant correlation between serum level of markers with vascular invasions, lymph node involvement, and menstruation. There was a weak correlation between tumor size and serum level of ICAM1 with Pearson score correlation, but there was no significant correlation with VEGF. There was no significant correlation between tumor grading and staging with the level of markers. There was a significant correlation between the level of VEGF and ICAM1 and histologic type of tumors in invasive through in situ tumors. CONCLUSION: Levels of VEGF and ICAM1 can be used as a predictor of tumor invasion and also for target therapy. PMID- 28643745 TI - Adjuvant hypofractionated radiation in carcinoma breast - Photon versus Electron: Comparison of treatment outcome. AB - BACKGROUND: Breast cancer tissue is sensitive to hypofractionation. This is an analysis of patients treated with hypofractionated protocols since 2009, at our tertiary cancer center. METHODS: Details of breast cancer patients treated with adjuvant hypofractionated external beam radiation therapy (EBRT) from January 2009 to December 2014 were retrieved and analyzed. RESULTS: One thousand seven hundred and eighty patients received adjuvant EBRT during this period. Three hundred and eight were offered hypofractionated schedule. One hundred and eighty eight had modified radical mastectomy (MRM) and 120 had breast conservation surgery (BCS). Dose was 40 Gy in 15 fractions to chest wall/breast, and tumor bed boost of 10 Gy in 5 fractions, where indicated, using three-dimensional conformal radiotherapy (3DCRT). Electrons were used in 159 and photons in 149. Single en face electron field was used for chest wall in MRM patients, and tangential photon beams for the whole breast. Patients on follow-up were assessed for locoregional recurrence, chest wall, breast or ipsilateral upper limb edema, brachial neuralgia, local skeletal events, pulmonary and cardiac symptoms, and cosmetic results. Two developed chest wall recurrence, one each in electron and photon arms. No skeletal, cardiac, or pulmonary adverse events were recorded. About 13.6% had arm edema, which was staged according to the International Society of Lymphology lymphedema staging, as Stage I-7.8%, Stage II-3.9%, and Stage III-1.9%. Twenty-six treated with electrons had arm edema. Increased incidence of arm edema in MRM patients could be attributed to combined surgical and radiation morbidity. Five-year overall survival was 81.9%. CONCLUSION: Hypofractionation is an accepted cost-effective standard of care in adjuvant breast radiation. Single en face electron field is well tolerated, and 3DCRT planning ensures homogeneous chest wall coverage, respecting dose constraints to organs at risk. PMID- 28643747 TI - Leiomyosarcoma of scrotum: A rare in-field second malignancy in a previously irradiated carcinoma of prostate and review of literature. AB - BACKGROUND: Curative intent treatments for malignancies using radiation therapy while achieving longer disease-free survivals, may also lead to solid second malignancies, a dreaded late complication. Both in-field as well as out-field second malignancies are encountered and lead to diagnostic dilemma, and delay in treatment. MATERIALS AND METHODS: Details of a case of rare, in-field, radiation induced leiomyosarcoma, a rare soft tissue sarcoma, in a treated case of high risk carcinoma of prostate, who presented to our tertiary care centre was retrieved and analysed. CONCLUSION: Increasingly sophisticated radiotherapy techniques, while providing state of the art treatment options, does increase the potential risk of radiation-induced second-malignancies. Respecting integral-dose carries priority, until further studies elucidates mechanism of tumorigenesis. PMID- 28643746 TI - Breast cancer screening practices amongst female tertiary health worker in Nnewi. AB - BACKGROUND: Breast cancer in Nigeria and other developing countries is characterized by late presentation and poor outcome due to ignorance, superstition, self-denial, fear of mastectomy, and unavailability of treatment facilities. The mortality of breast cancer in Western world is decreasing due to early detection and better management. OBJECTIVE: This study aims at accessing the knowledge, attitude, and practice of breast cancer screening among female tertiary health workers. MATERIALS AND METHODS: A cross-sectional descriptive study carried out using a structured, pretested, self-administered questionnaire to assess the knowledge, attitudes, and practice of breast cancer and screening methods among female health workers. RESULTS: The mean age of respondents was 31.70 +/- 7.62 years. The level of awareness of breast cancer screening methods was high: 158 (98.75%), 127 (79.4%), and 144 (90.0%) for breast self-examination (BSE), clinical breast examination (CBE), and mammography, respectively. However, only 47 (35.9%), 36 (22.5%), and 3 (1.9%) correctly practiced BSE, CBE, and mammography, respectively. The level of education and occupation showed significant correlations with the knowledge and practice of breast cancer screening methods. CONCLUSION: Breast cancer screening still needs to be promoted to improve the attitude and practice among both health workers and general population. PMID- 28643748 TI - Diagnostic efficacy of free prostate-specific antigen/total prostate-specific antigen ratio for the diagnosis of prostate cancer in low concentration (<=4 ng/ml) and intermediate levels of total prostate-specific antigen (4.01-10.0 ng/ml). AB - AIM OF STUDY: Serum prostate-specific antigen (PSA) is a useful tumor biomarker for prostate cancer (PCa) diagnosis. In this study, I aimed to compare the free/total PSA (fPSA%) with PSA alone for their usefulness in diagnosis for PCa. METHODS: The patients who underwent prostate biopsy between January 2010 and January 2015 were evaluated retrospectively. Data were expressed as a mean + standard error and P < 0.05 as considered with statistical significance (Med Calc 14.12-2014). The receiver operating characteristic curves were calculated to study the sensitivity and specificity of fPSA and PSA and compared to each other in different PSA levels. RESULTS: There were 1055 patients in the study. The mean age of the patients was 64.2 + 7.5 and 66.3 + 6.4 years in Groups 1 and 2. The mean PSA and free/total PSA of the patients was 2.79 + 1 ng/ml, 0.2 + 0.08 and 6.49 + 1.59 ng/ml and 0.19 + 0.09 in Groups 1 and 2, respectively. I found the optimal cutoff for fPSA% was <=18 and <=14 in Groups 1 and 2 with a sensitivity of 62-45% and specificity of 58-79%. There was a statistical significant difference for fPSA when comparing the area under curve in the PSA level of 4.01 10 ng/ml (P = 0.0009). CONCLUSION: In this study, serum fPSA% has advantages for diagnosis of PCa when comparing PSA alone in different levels of PSA. These advantages are significant in PSA level of 4.01-10 ng/ml. PMID- 28643749 TI - Treatment of high-risk neuroblastoma: National protocol results of the Turkish Pediatric Oncology Group. AB - BACKGROUND: The national protocol aimed to improve the outcome of the high risk neuroblastoma patients by high-dose chemotherapy and stem cell rescue with intensive multimodal therapy. MATERIALS AND METHODS: After the 6 induction chemotherapy cycles, patients without disease progression were nonrandomly (by physicians' and/or parent's choices) allocated into two treatment arms, which were designed to continue the conventional chemotherapy (CCT), or myeloablative therapy with autologous stem cell rescue (ASCR). RESULTS: Fifty-six percent (272 patients) of patients was evaluated as high risk. Response rate to induction chemotherapy was 71%. Overall event-free survival (EFS) and overall survival (OS) at 5 years were 28% and 36%, respectively. "As treated" analysis documented postinduction EFS of 41% in CCT arm (n = 138) and 29% in ASCR group (n = 47) (P = 0.042); whereas, OS was 45% and 39%, respectively (P = 0.05). Thirty-one patients (11%) died of treatment-related complications. CONCLUSION: Survival rates of high risk neuroblastoma have improved in Turkey. Myeloablative chemotherapy with ASCR has not augmented the therapeutic end point in our country's circumstances. The adequate supportive care and the higher patients' compliance are attained, the better survival rates might be obtained in high-risk neuroblastoma patients received myeloablative chemotherapy and ASCR. PMID- 28643751 TI - Quick, efficient and effective patient-specific intensity-modulated radiation therapy quality assurance using log file and electronic portal imaging device. AB - AIM: The aim of work is to explore a quick, efficient, and effective patient specific intensity-modulated radiation therapy (IMRT) quality assurance (QA). MATERIALS AND METHODS: Software tools were developed to extract and analyze the multi-leaf collimator (MLC) leaf positions (LPs) from electronic portal imaging device (EPID) images for Varian C-series machine and TrueBeam, to extract useful data from MLC log file of C-series linear accelerator (LINAC), to extract useful information from the trajectory log binary file of TrueBeam LINAC, to compare LPs derived from EPID images with log file/trajectory log data, and to analyze IMRT treatment files using the MATLAB programming language. The difference in LP determined from the trajectory log and EPID images was proposed for patient specific QA. RESULTS: It was found that the differences in LP for regular radiation fields generated using stationary leaves are <0.5 mm for all the field sizes while for regular radiation fields generated using the moving leaves are more but <2 mm. The differences in LPs for IMRT field were also determined and found to be <2 mm. CONCLUSIONS: The methodology demonstrated can be used for establishing the accuracy of trajectory log data and for independent routine IMRT QA by generating single number like gamma index to indicate pass or fail of an IMRT treatment plan. The QA indices such as numbers of occurrences of >=2 mm error in LPS are found more than 5% of total number of occurrences; the dosimetric review of planned treatment is advisable. PMID- 28643750 TI - Evaluation of clinical process in osteosarcoma patients treated with chemotherapy including cisplatin, adriamycin, ifosfamide, and etoposide and determination of the treatment sequels in a long-term 11-year follow-up. AB - AIM: The aim of this study was to evaluate the effect of adding etoposide and ifosfamide chemotherapy drugs to treatment regimen of patients affected with osteosarcoma and to determine the clinical process and response to treatment during a follow-up period of 11 years. MATERIALS AND METHODS: Forty patients with osteosarcoma participated in this study from July 2005 to 2016. Treatments were started based on the following schema and after initial examinations including biochemical profile, checking for lung metastasis by simple radiography, chest computed tomography scan, and bones scan. The initial chemotherapy which consisted of four cycles of cisplatin and adriamycin alternative with ifosfamide and etoposide was provided. Afterward, resection of the primary tumor and also the metastatic lesions was performed in patients with lung metastasis in case they had radiological evidence of response to the treatment. RESULTS: The mean of follow-up duration in this study was 50 months. Thirty-four patients did not have metastasis and six were metastatic. Of 34 patients, 18 had relapse and 16 patients never had relapse. Five patients experienced only local relapse, nine had only systemic relapse, and two patients had simultaneous systemic and local relapses. Thirteen patients had died. The mean of overall survival in patients was 81 months. The mean of survival in patients with and without primary metastasis was 30 and 90 months, respectively. CONCLUSION: Favorable response to the treatment was obtained with an appropriate multiple disciplinary works in the osteosarcomas of extremities, and there were no considerable side effects and sequels in the long-term follow-up of these treatments. PMID- 28643752 TI - Dosimetric characterization of optically stimulated luminescence dosimeter with therapeutic photon beams for use in clinical radiotherapy measurements. AB - AIM: The modern radiotherapy techniques impose new challenges for dosimetry systems with high precision and accuracy in in vivo and in phantom dosimetric measurements. The knowledge of the basic characterization of a dosimetric system before patient dose verification is crucial. This incites the investigation of the potential use of nanoDot optically stimulated luminescence dosimeter (OSLD) for application in radiotherapy with therapeutic photon beams. MATERIALS AND METHODS: Measurements were carried out with nanoDot OSLDs to evaluate the dosimetric characteristics such as dose linearity, dependency on field size, dose rate, energy and source-to-surface distance (SSD), reproducibility, fading effect, reader stability, and signal depletion per read out with cobalt-60 (60 Co) beam, 6 and 18 MV therapeutic photon beams. The data acquired with OSLDs were validated with ionization chamber data where applicable. RESULTS: Good dose linearity was observed for doses up to 300 cGy and above which supralinear behavior. The standard uncertainty with field size observed was 1.10% +/- 0.4%, 1.09% +/- 0.34%, and 1.2% +/- 0.26% for 6 MV, 18 MV, and 60 Co beam, respectively. The maximum difference with dose rate was 1.3% +/- 0.4% for 6 MV and 1.4% +/- 0.4% for 18 MV photon beams. The largest variation in SSD was 1.5% +/- 1.2% for 60 Co, 1.5% +/- 0.9% for 6 MV, and 1.5% +/- 1.3% for 18 MV photon beams. The energy dependence of OSL response at 18 MV and 60 Co with 6 MV beam was 1.5% +/- 0.7% and 1.7% +/- 0.6%, respectively. In addition, good reproducibility, stability after the decay of transient signal, and predictable fading were observed. CONCLUSION: The results obtained in this study indicate the efficacy and suitability of nanoDot OSLD for dosimetric measurements in clinical radiotherapy. PMID- 28643753 TI - Dosimetric characteristic of physical wedge versus enhanced dynamic wedge based on Monte Carlo simulations. AB - AIM OF STUDY: Physical wedges (PWs) are widely used in radiotherapy to obtain tilted isodose curves, but they alter beam quality. Dynamic wedges (DWs) using moving collimator overcome this problem, but measuring their beam data is not simple. The main aim of this study is to obtain all dosimetric parameters of DWs produced by Varian 2100CD with Monte Carlo simulation and compare them to those from PWs. SUBJECTS AND METHODS: To simulate 6 MV photon beams equipped with PW and DW, BEAMnrc code was used. All dosimetric data were obtained with EDR2 films and two-dimensional diode array detector. RESULTS: Good agreement between simulated and measured dosimetric data for PW and DW fields was obtained. Our results showed that percentage depth dose and beam profiles at nonwedged direction for DWs are the same as open fields and can be used to each other. CONCLUSION: From Monte Carlo simulations, it can be concluded that DWs in spite of PW do not have effect on beam quality and are good options for treatment planning system which cannot consider hardening effect produced by PWs. Furthermore, BEAMnrc is a powerful code to acquire all date required by DWs. PMID- 28643754 TI - Awareness of cervical cancer and willingness to participate in screening program: Public health policy implications. AB - BACKGROUND: Cervical cancer is one of the most common malignancies among women in India. There is a high mortality as patients usually present at an advanced stage because of lack of awareness and nonexistent screening programs. AIM: This study was planned to find out awareness about cervical cancer among women and their willingness to utilize screening services in an urban resettlement colony of Delhi, India. SETTINGS AND DESIGN: A community-based, cross-sectional study was carried out in a resettlement colony of North-West Delhi. MATERIALS AND METHODS: Semi-structured interview schedule was used to collect information regarding different aspects of cervical cancer. Analysis was done using SPSS package (SPSS version 16 (UCMS and GTBH, Delhi, India)). RESULTS: A total of 373 women were included in the study. Mean age of study participants was 39.14 years. Two-third of the study population were illiterate. Half of the study population was aware of cervical cancer, and only one-fourth of population were willing to participate in a screening test. Willingness was higher among educated, ever user of family planning method and having knowledge about at least one risk factor, signs or symptoms, or possibility of early diagnosis of cancer cervix. CONCLUSIONS: The country's national program advocates for opportunistic and targeted screening of women. An understanding of the factors that influences womens' willingness to participate in screening program is essential for the success of such programs. Hence, this study emphasizes the need for dissemination of knowledge about various aspects of cancer cervix which is critical for uptake of any screening program in a developing country. PMID- 28643755 TI - Prognostic significance of tumor volume as determined on 3D ultrasound scan in uterine cervix cancer treated by radiotherapy. AB - AIMS: The aim of this prospective study is to evaluate prognostic significance of tumor volume determined by three-dimensional (3D) ultrasound scan in uterine cervix cancer patients treated by radiotherapy. PATIENTS AND METHODS: A total of 67 patients of Stage IB2-IIIB were studied and analyzed. Cervical tumor volume was determined by 3D ultrasound scan. Two groups were made on the basis of volume on ultrasound scan (Group 1 <40 cc = 36 and Group 2 >40 cc = 31). Both groups received external beam radiotherapy (EBRT) and intracavitary radiation therapy (ICRT). Cisplatin 40 mg/m 2 every week was given concurrently with external irradiation. Tumor volumes were taken by 3D USG every week during EBRT, after each fraction of ICRT, and after 8 weeks of completion of treatment. Primary end point was disease-free survival (DFS), and secondary endpoints were 5-year survival and toxicities. RESULTS: After 2 months of completion of treatment, 1 out of 36 patients of Group A was having residual and 7 out of 31 of Group B were having residual diseases (P = 0.034). DFS and 5-year survival were significantly different in the groups (log rank test P = 0.0014, hazard ratio (HR) =2.3622 95% confidence interval (CI) 1.3090-4.2625 and P = 0.0421, HR = 1.9274 95% CI 0.9998 3.7156, respectively). CONCLUSIONS: Ultrasound is a cheap, simple, and useful in predicting the outcome of treatment and DFS based on the tumor volume. PMID- 28643756 TI - Is neuroglial antigen 2 a potential contributor to cilengitide response in glioblastoma? AB - BACKGROUND: Determining the expression levels of neuroglial antigen 2 (NG2) in glioma cell lines and to evaluate the potential contribution of NG2 to cilengitide response were aimed. MATERIALS AND METHODS: Endogenous expression level of NG2 was determined using quantitative reverse transcription polymerase chain reaction and immunoblotting. Cilengitide responses of the cells were monitored to determine half maximal inhibitory concentration values. Whether the suppression of NG2 expression alters the response of A172 cells to cilengitide was examined. RESULTS: The effect of cilengitide on inducing apoptosis of the cells was determined by TUNEL staining. High mRNA and protein expression of NG2 was detected in A172 and U-87MG cells, while T98G, M059K and M059J cells demonstrated low levels of NG2. A172, U-87MG and positive control MG-63 were relatively sensitive to cilengitide compared to T98G, M059K and M059J. MG-63, A172 and U-87MG were unexpectedly found to be more susceptible to cilengitide. In addition, NG2 knock-down showed no significant difference in cell death between small interfering RNA (siRNA)-transfected and cilengitide-treated groups. The results showed that cilengitide caused detachment and subsequently initiated apoptosis. Glioma cell lines express variable levels of NG2 and differ in their responses to cilengitide. Although increased numbers of apoptotic cells were found in untransfected cells compared to siRNA-transfected cells upon exposed to cilengitide, the difference was not documented to be significant between two groups. CONCLUSION: It may be proposed that the combination therapy of NG2 suppression and cilengitide treatment showed no considerable effect on glioblastoma compared to cilengitide therapy alone. Response to therapy may be further improved by targeting other factors act in concert in this signaling pathway. PMID- 28643757 TI - Significance of expression of suppressor of cytokine signaling proteins: Suppressor of cytokine signaling-1, suppressor of cytokine signaling-2, and suppressor of cytokine signaling-3 in papillary thyroid cancer. AB - PURPOSE: Uncontrolled cytokine signal transduction largely associated with oncogene activation, can have disastrous biological consequences. The suppressor of cytokine signaling (SOCS) proteins represent one of the mechanisms by which this rampant signaling can be dissipated. Thus, we aimed to study the expression of SOCS-1, SOCS-2, and SOCS-3 in patients having benign thyroid disease and papillary thyroid cancer. MATERIALS AND METHODS: SOCS protein expression was studied in 45 patients with benign thyroid disease and in 83 papillary thyroid cancer patients by immunohistochemistry and their association with clinicopathological characteristics and overall survival in cancer patients were analyzed using SPSS software. RESULTS: Expressions of SOCS proteins were significantly higher in papillary thyroid cancer than in patients having benign disease. SOCS-1 expression was predominantly higher in males (P = 0.004), unilateral tumors (P = 0.030), and noninflammatory conditions (P = 0.028). SOCS-1 expression was also able to predict poor overall survival in subgroup of papillary thyroid cancer patients having larger tumor size (P = 0.013) and advanced stage disease (P = 0.033). Expression of SOCS-2 significantly correlated with tumor size (P = 0.017), extrathyroidal extension (P = 0.000), residual disease (P = 0.043), and treatment (P = 0.007), while preponderance of SOCS-3 expression was observed in males (P = 0.030) and in patients having extrathyroidal extension (P = 0.011) and absence of metastasis (P = 0.032). CONCLUSION: Expression of the studied SOCS proteins may be a consequence of activation of Janus kinase-signal transducers and activators of transcription and other pathways supporting growth and survival of cancer cells that are sustained by several cytokines. Thus, SOCS-1, SOCS-2, and SOCS-3 proteins may directly or indirectly, have important roles in development and pathogenesis of papillary thyroid cancer. PMID- 28643759 TI - Overall treatment duration with multimodality treatment approach and outcome results in oral cavity carcinoma: A study from an institute from central India. AB - OBJECTIVE OF THE STUDY: To see the different age groups, gender, sites, disease stage, treatment outcome of various oral cavity sites carcinoma by combined modalities and the overall treatment duration. MATERIALS AND METHODS: A total of 212 oral cavity carcinoma patients (169 males and 43 females) with complete records (from September 2009 to December 2012) were analyzed for age, sex, histopathology, associated medical illnesses, various subsites with disease stage, various treatment modalities with the duration and follow-up records for disease control as well as disease failure at local, nodal, local + nodal, and distant metastasis. RESULTS: The most common site in oral cavity cancer was buccal mucosa 81 (38.20%). 149 (69%) patients reported were in advanced Stages III and IV of the disease. The majority of patients 149 (70.28%) were given chemotherapy + radiotherapy postoperatively (S-CRT group). The mean follow-up for all patients was 41 months (range = 21-59 months). In terms of overall disease control and metastases-free survival, the best results were (80%) for Stage I in all oral cavity sites. Irrespective of disease stage best results (59.57%) were in alveolar ridge subsite of oral cavity carcinoma. CONCLUSION: Challenges are still lie ahead in treating head and neck carcinoma, as in spite of using multimodality treatment approach and biological and molecular research, the overall survival percentage has not changed much. In India as oral cavity carcinoma is in increasing trend in younger individuals massive health promotion and awareness programs targeting the risk population along with financial support for those already affected are required. PMID- 28643758 TI - Effects of EF-24, RAD001, and paclitaxel on the expression profiles of apoptotic and anti-apoptotic genes. AB - CONTEXT: Cancer cells exert differential responses to chemotherapeutics and inhibitors. To the best of our knowledge, a few or no research has been performed until now to determine the effect of EF-24 and RAD001 on MDA-MB-231 breast cancer cells with regard to mRNA expression of apoptotic and anti-apoptotic genes. AIMS: In this study, we aimed to investigate the mRNA expression levels of apoptotic (caspase 2 [CASP2], CASP8, and CASP9) and anti-apoptotic (B-cell lymphoma 2 [BCL2] and BCL2-like protein 1 [BCL2L1]) genes after exposure to paclitaxel, EF 24, and RAD001 in MDA-MB-231 cells. MATERIALS AND METHODS: After treatment, 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to measure cell viability. mRNA expressions were analyzed using quantitative real time polymerase chain reaction. RESULTS: Decrease in cell viability ratios was seen in a dose-dependent manner for all chemicals. MDA-MB-231 cells responded slightly different to paclitaxel, EF-24, and RAD001 at the transcriptional level of apoptotic and anti-apoptotic genes. CONCLUSIONS: Our results showed that response of these cells to paclitaxel, EF-24, and RAD001 was found different at the transcriptional level of apoptotic and antiapoptotic genes. Therefore, understanding transcriptional changes after these drug exposure may give us a change to figure out more realistic results of the apoptotic pathway inhibition. PMID- 28643760 TI - Validation of microsatellite instability histology scores with Bethesda guidelines in hereditary nonpolyposis colorectal cancer. AB - AIMS: Hereditary nonpolyposis colorectal cancer (HNPCC) is a subgroup of colorectal cancer (CRC) which should be differentiated because of the high risk for additional cancers and risk evaluation for other family members, especially for CRC. It is not practical to perform genetic testing for all CRC patients; therefore, various prediction modalities, for example, Bethesda guideline (BG) were studied in the literature. We aimed to assess the association of microsatellite instability (MSI), histology scores, and BG for predicting HNPCC risk. SUBJECTS AND METHODS: Data were collected from CRC patients between 2009 and 2012. A total of 127 patients were retrospectively reviewed for BG status and the MSI scores, MsPath, and PathScore. STATISTICAL ANALYSIS USED: Definitive statistical methods (mean, standard deviation, median, frequency, and percentage) were used to evaluate the study data. Comparison used Student's t-test, Continuity (Yates) correction, Fisher-Freeman-Halton test, Pearson correlation, and receiver operating characteristics curve analysis. RESULTS: Patients who were detected as Bethesda-positive had significantly higher MsPath and PathScore scores (P = 0.001 and P = 0.007, respectively). According to the cut-off value of 2.8 and 2.9 for MsPath and PathScore, respectively, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 90%, 43%, 22.8%, 95.8%, and 50.4% for MsPath, and 55%, 83.2%, 37.9%, 90.8%, and 78.7% for PathScore, respectively. CONCLUSIONS: The MSI scoring systems, MsPath, and PathScore, are reliable systems and effectively correlated with BG for predicting patients who need advanced analysis techniques because of the risk of HNPCC. PMID- 28643761 TI - The effects of gene therapy with granulocyte-macrophage colony-stimulating factor in the regression of tumor masses in fibrosarcoma mouse model. AB - INTRODUCTION: Cytokine gene therapy is one of the cancer treatment strategies. Recently, granulocyte-monocyte colony-stimulating factor (GM-CSF), as an important cytokine in activating dendritic cells and boosting the anti-tumor immune responses, has been utilized as an immunotherapeutic agent in cancer gene therapy. The purpose of the present investigation was to study the GM-CSF gene therapy effects in regression of tumor masses in fibrosarcoma mouse model. MATERIALS AND METHODS: To investigate the therapeutic efficacy of GM-CSF, WEHI 164 tumor cells were transfected with murine GM-CSF plasmid. For cytokine production by transfected cells, enzyme-linked immunosorbent assay test was used. Fibrosarcoma mouse model established with transfected cells which were injected subcutaneously into Balb/c mice. Tumor sizes were measured by caliper. Mice were sacrificed and the tumors were extracted. The expression of GM-CSF was studied by real-time polymerase chain reaction (PCR) and immunoblotting. The expression of Ki-67 (a tumor proliferative marker) in tumor masses was studied by immunohistochemical staining. RESULTS: The group treated with GM-CSF indicated a decrease in tumor mass volume (P = 0.001). The results of western blotting and real-time PCR showed that GM-CSF expression increased in the group treated with GM-CSF (with a relative expression of 1.36). Immunohistochemical staining showed that Ki-67 expression has reduced in the group treated with GM-CSF. CONCLUSION: Monotherapy with GM-CSF has therapeutic effects on the regression of tumor masses in the fibrosarcoma mouse model. PMID- 28643762 TI - Serum butyrylcholinesterase and zinc in breast cancer. AB - CONTEXT: Even though, a large number of serological, molecular markers have been proposed for breast cancer screening, most of them lack specificity, sensitivity, prognostic value, and cost effectiveness. Butyrylcholinesterase (BChE) and its genes are aberrantly expressed in a variety of human cancers. It has-been linked to tumorigenesis, cell proliferation, and cell differentiation. Zinc (Zn) is a cofactor for superoxide dismutase, an enzyme that protects cellular components against free radical-induced damage and carcinogenesis. Therefore, the aim of present study was to estimate and compare serum BChE and serum Zn levels in healthy controls and biopsy proven breast cancer patients before definitive therapy. AIMS: To estimate and compare serum BChE and serum Zn levels in healthy controls and biopsy proven breast cancer patients before definitive therapy. SETTINGS AND DESIGN: Serum BChE and Zn were estimated in 46 newly diagnosed (preoperative) female patients with breast cancer and 50 healthy female volunteers. SUBJECTS AND METHODS: Serum BChE and Zn were estimated by spectrophotometric method. STATISTICAL ANALYSIS USED: Data was expressed as median and inter quartile range. Comparisons between different stages of cancer were done using Kruskal-Wallis test. RESULTS: There was a significant increase in serum BChE and Zn in breast cancer patients compared to controls (P < 0.001). Serum BChE showed a significant increase and Zn was significantly decreased in different stages of breast cancer. CONCLUSIONS: Both BChE and Zn are inexpensive and can easily be analyzed and may play a role in the management of breast cancer. PMID- 28643763 TI - Bowen's disease: Two case reports of a giant and dwarf lesions. AB - Bowen's disease is a form of intraepidermal squamous cell carcinoma (SCC). It usually presents as a well-demarcated, slow growing erythematous patch, or plaque with a scaly or crusted surface. The size of the tumor varies from a few millimeters to several centimeters. The risk of progression into an invasive carcinoma is 3-5% in extragenital lesions and about 10% in genital lesions. We present two cases of Bowen's disease where the pattern, size, and perception of the disease between the patients varied. The two cases demonstrated two varying spectrum of the disease, one being a giant lesion and other a dwarf. One patient was more concerned about the lesion, whereas the other patient neglected the lesions, though widespread. High index of suspicion is required to diagnose such atypical presentations of Bowen's disease. As Bowen's disease has tendency to progress to SCC, it should be diagnosed and treated as early as possible. PMID- 28643764 TI - Clear cell odontogenic carcinoma: A rare case report with emphasis on differential diagnosis. AB - Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic malignancy with a female predilection, typically presenting as swelling in anterior region of mandible. CCOC was classified as a malignant neoplasm of odontogenic origin by the WHO in 2005 as it exhibits an aggressive growth pattern, local recurrence, and tendency of distant metastasis. Histologically, CCOC is characterized by sheets and islands of vacuolated/clear cells. Since clear cells are present in few odontogenic tumors, salivary gland neoplasms, and metastatic tumors to the jaws; presence of clear cells in a lesion of head and neck area poses a diagnostic challenge. Knowledge about the clinical course, histopathologic pattern, and immunoprofile of CCOC aids in differentiating it from other clear cell tumors. Herein, we present a case of CCOC in anterior mandibular region of 60-year-old female patient with an emphasis on its differential diagnosis from other clear cell lesions of the jaws. PMID- 28643765 TI - Intrapancreatic mass: A rare cause. AB - We found a case of pancreatic extraintestinal gastrointestinal stroma tumor (pEGIST) in 2014. The patient, initially suspected to suffer from pancreatic adenocarcinoma, underwent open left hemipancreatectomy and en bloc splenectomy in May 2014. Postoperative histopathology showed the unexpected manifestation of a pEGIST. Recovery was well, and a 23-month follow-up was free from recurrency by now. PMID- 28643766 TI - Complexity of chromosomal rearrangements in Down syndrome leukemia. AB - Reports on imbalanced HSA21 gene expression and chromosomal rearrangements on leukemogenesis, drug sensitivity, and treatment outcome of leukemia in Down syndrome (DS) are limited. DS has been recognized as one of the most common leukemia-predisposing syndromes with unique clinical features, significant differences in treatment outcome and treatment-related toxicity profiles. Acute myeloid leukemia (AML), especially acute megakaryocytic leukemia, is reported with high cure rates presenting 80%-100% event-free survivals (EFSs); however, acute lymphoid leukemia indicates a worse prognosis in DS patients compared to non-DS children. Complex rearrangements are responsible for poor-to-very poor prognosis in all cases, irrespective of genetic predisposition or type of hematopoietic subunits affected. We report a 2-year-old female DS diagnosed with acute erythroleukemia (French-American-British: AML-M6) with highly complex chromosomal rearrangements in the bone marrow with 39 chromosomes. Parental consanguinity and genetic predisposition might be responsible for origin of multiple clones. Genetic instability and heterogeneity of complex clonal developments might cause poor prognosis. The case is a rare one with acute erythroleukemia in DS patient where too many rearrangements had masked identification of three 21s. PMID- 28643767 TI - Significant plasmacytosis in an early induction marrow of acute myeloid leukemia: Diagnostic and therapeutic implications. PMID- 28643768 TI - Adult rhabdomyosarcoma: Multimodality management and results. PMID- 28643769 TI - Oral cryotherapy for preventing chemotherapy-induced oral mucositis: An effective but yet neglected strategy. PMID- 28643770 TI - Role of Circulating Tumor Cell (CTC) Monitoring in Evaluating Prognosis of Triple Negative Breast Cancer Patients in China. AB - BACKGROUND Breast cancer (BC) is the most common malignant tumor in females. This study investigated the role and utility of CTC monitoring in evaluating the prognosis of triple-negative breast cancer patients. MATERIAL AND METHODS We enrolled 286 female triple-negative breast cancer patients who were diagnosed at and received radical resection surgery in our hospital. Peripheral venous blood samples were collected preoperatively and at 3 and 7 days postoperative, and the Cell Search system was used to detect CTC in peripheral blood. We analyzed the relationship between preoperative CTC level and clinical pathological characteristics of patients. Kaplan-Meier method was used to establish progression-free survival curves and overall survival curves, we used the log rank test to compare the survival rate, and we explored the effects of preoperative and postoperative CTC levels on patient survival. RESULTS Compared with preoperative levels, the average CTC content in peripheral blood of breast cancer patients was significantly increased at 3 days after surgery, and then decreased to the preoperative baseline level by 7 days after surgery. The 3-year overall survival rate and progression-free survival rate in patients with CTC >5/7.5 mL peripheral blood were significantly lower than in patients with CTC <5/7.5 mL peripheral blood detected preoperatively and at 3 and 7 days postoperatively. CONCLUSIONS Dynamic monitoring of preoperative and postoperative CTC levels can accurately predict recurrence and progression of disease, and is important in postoperative monitoring and prognosis evaluation. PMID- 28643771 TI - Dynamics of valence-shell electrons and nuclei probed by strong-field holography and rescattering. AB - Strong-field photoelectron holography and laser-induced electron diffraction (LIED) are two powerful emerging methods for probing the ultrafast dynamics of molecules. However, both of them have remained restricted to static systems and to nuclear dynamics induced by strong-field ionization. Here we extend these promising methods to image purely electronic valence-shell dynamics in molecules using photoelectron holography. In the same experiment, we use LIED and photoelectron holography simultaneously, to observe coupled electronic-rotational dynamics taking place on similar timescales. These results offer perspectives for imaging ultrafast dynamics of molecules on femtosecond to attosecond timescales. PMID- 28643772 TI - Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification. AB - Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2 (at 2.4 A resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes. PMID- 28643773 TI - A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. AB - Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard-Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V. PMID- 28643774 TI - Insufficient antibody validation challenges oestrogen receptor beta research. AB - The discovery of oestrogen receptor beta (ERbeta/ESR2) was a landmark discovery. Its reported expression and homology with breast cancer pharmacological target ERalpha (ESR1) raised hopes for improved endocrine therapies. After 20 years of intense research, this has not materialized. We here perform a rigorous validation of 13 anti-ERbeta antibodies, using well-characterized controls and a panel of validation methods. We conclude that only one antibody, the rarely used monoclonal PPZ0506, specifically targets ERbeta in immunohistochemistry. Applying this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, we detect ERbeta protein in testis, ovary, lymphoid cells, granulosa cell tumours, and a subset of malignant melanoma and thyroid cancers. We do not find evidence of expression in normal or cancerous human breast. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. Our study highlights how inadequately validated antibodies can lead an exciting field astray. PMID- 28643775 TI - Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus. AB - Zika virus (ZIKV) is a re-emerging virus that has recently spread into dengue virus (DENV) endemic regions and cross-reactive antibodies (Abs) could potentially affect ZIKV pathogenesis. Using DENV-immune serum, it has been shown in vitro that antibody-dependent enhancement (ADE) of ZIKV infection can occur. Here we study the effects of pre-existing DENV immunity on ZIKV infection in vivo. We infect two cohorts of rhesus macaques with ZIKV; one cohort has been exposed to DENV 2.8 years earlier and a second control cohort is naive to flaviviral infection. Our results, while confirming ADE in vitro, suggest that pre-existing DENV immunity does not result in more severe ZIKV disease. Rather our results show a reduction in the number of days of ZIKV viremia compared to naive macaques and that the previous exposure to DENV may result in modulation of the immune response without resulting in enhancement of ZIKV pathogenesis. PMID- 28643776 TI - Ezrin enhances line tension along transcellular tunnel edges via NMIIa driven actomyosin cable formation. AB - Transendothelial cell macroaperture (TEM) tunnels control endothelium barrier function and are triggered by several toxins from pathogenic bacteria that provoke vascular leakage. Cellular dewetting theory predicted that a line tension of uncharacterized origin works at TEM boundaries to limit their widening. Here, by conducting high-resolution microscopy approaches we unveil the presence of an actomyosin cable encircling TEMs. We develop a theoretical cellular dewetting framework to interpret TEM physical parameters that are quantitatively determined by laser ablation experiments. This establishes the critical role of ezrin and non-muscle myosin II (NMII) in the progressive implementation of line tension. Mechanistically, fluorescence-recovery-after-photobleaching experiments point for the upstream role of ezrin in stabilizing actin filaments at the edges of TEMs, thereby favouring their crosslinking by NMIIa. Collectively, our findings ascribe to ezrin and NMIIa a critical function of enhancing line tension at the cell boundary surrounding the TEMs by promoting the formation of an actomyosin ring. PMID- 28643777 TI - In situ targeted MRI detection of Helicobacter pylori with stable magnetic graphitic nanocapsules. AB - Helicobacter pylori infection is implicated in the aetiology of many diseases. Despite numerous studies, a painless, fast and direct method for the in situ detection of H. pylori remains a challenge, mainly due to the strong acidic/enzymatic environment of the gastric mucosa. Herein, we report the use of stable magnetic graphitic nanocapsules (MGNs), for in situ targeted magnetic resonance imaging (MRI) detection of H. pylori. Several layers of graphene as the shell effectively protect the magnetic core from corrosion while retaining the superior contrast effect for MRI in the gastric environment. Boronic-polyethylene glycol molecules were synthesized and modified on the MGN surface for targeted MRI detection. In a mouse model of H. pylori-induced infection, H. pylori was specifically detected through both T2-weighted MR imaging and Raman gastric mucosa imaging using functionalized MGNs. These results indicated that enhancement of MRI using MGNs may be a promising diagnostic and bioimaging platform for very harsh conditions. PMID- 28643778 TI - A decoherence-free subspace in a charge quadrupole qubit. AB - Quantum computing promises significant speed-up for certain types of computational problems. However, robust implementations of semiconducting qubits must overcome the effects of charge noise that currently limit coherence during gate operations. Here we describe a scheme for protecting solid-state qubits from uniform electric field fluctuations by generalizing the concept of a decoherence free subspace for spins, and we propose a specific physical implementation: a quadrupole charge qubit formed in a triple quantum dot. The unique design of the quadrupole qubit enables a particularly simple pulse sequence for suppressing the effects of noise during gate operations. Simulations yield gate fidelities 10 1,000 times better than traditional charge qubits, depending on the magnitude of the environmental noise. Our results suggest that any qubit scheme employing Coulomb interactions (for example, encoded spin qubits or two-qubit gates) could benefit from such a quadrupolar design. PMID- 28643780 TI - Voltage controlled interfacial magnetism through platinum orbits. AB - Electric fields at interfaces exhibit useful phenomena, such as switching functions in transistors, through electron accumulations and/or electric dipole inductions. We find one potentially unique situation in a metal-dielectric interface in which the electric field is atomically inhomogeneous because of the strong electrostatic screening effect in metals. Such electric fields enable us to access electric quadrupoles of the electron shell. Here we show, by synchrotron X-ray absorption spectroscopy, electric field induction of magnetic dipole moments in a platinum monatomic layer placed on ferromagnetic iron. Our theoretical analysis indicates that electric quadrupole induction produces magnetic dipole moments and provides a large magnetic anisotropy change. In contrast with the inability of current designs to offer ultrahigh-density memory devices using electric-field-induced spin control, our findings enable a material design showing more than ten times larger anisotropy energy change for such a use and highlight a path in electric-field control of condensed matter. PMID- 28643782 TI - Group additivity-Pourbaix diagrams advocate thermodynamically stable nanoscale clusters in aqueous environments. AB - The characterization of water-based corrosion, geochemical, environmental and catalytic processes rely on the accurate depiction of stable phases in a water environment. The process is aided by Pourbaix diagrams, which map the equilibrium solid and solution phases under varying conditions of pH and electrochemical potential. Recently, metastable or possibly stable nanometric aqueous clusters have been proposed as intermediate species in non-classical nucleation processes. Herein, we describe a Group Additivity approach to obtain Pourbaix diagrams with full consideration of multimeric cluster speciation from computations. Comparisons with existing titration results from experiments yield excellent agreement. Applying this Group Additivity-Pourbaix approach to Group 13 elements, we arrive at a quantitative evaluation of cluster stability, as a function of pH and concentration, and present compelling support for not only metastable but also thermodynamically stable multimeric clusters in aqueous solutions. PMID- 28643779 TI - Drugging the 'undruggable' cancer targets. AB - The term 'undruggable' was coined to describe proteins that could not be targeted pharmacologically. However, progress is being made to 'drug' many of these targets, and therefore more appropriate terms might be 'difficult to drug' or 'yet to be drugged'. Many desirable targets in cancer fall into this category, including the RAS and MYC oncogenes, and pharmacologically targeting these intractable proteins is now a key challenge in cancer research that requires innovation and the development of new technologies. In this Viewpoint article, we asked four scientists working in this field for their opinions on the most crucial advances, as well as the challenges and what the future holds for this important area of research. PMID- 28643781 TI - Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. AB - Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike. PMID- 28643783 TI - Cdt1 stabilizes an open MCM ring for helicase loading. AB - ORC, Cdc6 and Cdt1 act together to load hexameric MCM, the motor of the eukaryotic replicative helicase, into double hexamers at replication origins. Here we show that Cdt1 interacts with MCM subunits Mcm2, 4 and 6, which both destabilizes the Mcm2-5 interface and inhibits MCM ATPase activity. Using X-ray crystallography, we show that Cdt1 contains two winged-helix domains in the C terminal half of the protein and a catalytically inactive dioxygenase-related N terminal domain, which is important for MCM loading, but not for subsequent replication. We used these structures together with single-particle electron microscopy to generate three-dimensional models of MCM complexes. These show that Cdt1 stabilizes MCM in a left-handed spiral open at the Mcm2-5 gate. We propose that Cdt1 acts as a brace, holding MCM open for DNA entry and bound to ATP until ORC-Cdc6 triggers ATP hydrolysis by MCM, promoting both Cdt1 ejection and MCM ring closure. PMID- 28643784 TI - Water scarcity hotspots travel downstream due to human interventions in the 20th and 21st century. AB - Water scarcity is rapidly increasing in many regions. In a novel, multi-model assessment, we examine how human interventions (HI: land use and land cover change, man-made reservoirs and human water use) affected monthly river water availability and water scarcity over the period 1971-2010. Here we show that HI drastically change the critical dimensions of water scarcity, aggravating water scarcity for 8.8% (7.4-16.5%) of the global population but alleviating it for another 8.3% (6.4-15.8%). Positive impacts of HI mostly occur upstream, whereas HI aggravate water scarcity downstream; HI cause water scarcity to travel downstream. Attribution of water scarcity changes to HI components is complex and varies among the hydrological models. Seasonal variation in impacts and dominant HI components is also substantial. A thorough consideration of the spatially and temporally varying interactions among HI components and of uncertainties is therefore crucial for the success of water scarcity adaptation by HI. PMID- 28643786 TI - A unified model of Hymenopteran preadaptations that trigger the evolutionary transition to eusociality. AB - Explaining the origin of eusociality, with strict division of labour between workers and reproductives, remains one of evolutionary biology's greatest challenges. Specific combinations of genetic, behavioural and demographic traits in Hymenoptera are thought to explain their relatively high frequency of eusociality, but quantitative models integrating such preadaptations are lacking. Here we use mathematical models to show that the joint evolution of helping behaviour and maternal sex ratio adjustment can synergistically trigger both a behavioural change from solitary to eusocial breeding, and a demographic change from a life cycle with two reproductive broods to a life cycle in which an unmated cohort of female workers precedes a final generation of dispersing reproductives. Specific suits of preadaptations are particularly favourable to the evolution of eusociality: lifetime monogamy, bivoltinism with male generation overlap, hibernation of mated females and haplodiploidy with maternal sex ratio adjustment. The joint effects of these preadaptations may explain the abundance of eusociality in the Hymenoptera and its virtual absence in other haplodiploid lineages. PMID- 28643785 TI - DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia. AB - We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia patients harboring DNA methyltransferase 3A R882H/-R882C mutations (DNMT3Amut). MRD was determined by real-time quantitative PCR (RQ-PCR) in 1494 samples of 181 DNMT3Amut patients. At the time of diagnosis, DNMT3Amut transcript levels did not correlate with presenting clinical characteristics and concurrent gene mutations as well as the survival end points. In Cox regression analyses, bone marrow (BM) DNMT3Amut transcript levels (log10 transformed continuous variable) were not associated with the rate of relapse or death. DNMT3Amut transcript levels were significantly higher in BM than in blood after induction I (P=0.01), induction II (P=0.05), consolidation I (P=0.004) and consolidation II (P=0.008). With regard to the clinically relevant MRD time points, after two cycles of induction and at the end of therapy, DNMT3Amut transcript levels had no impact on the end point remission duration and overall survival. Of note, only a minority of the patients achieved RQ-PCR negativity, whereas most had constantly high DNMT3Amut transcript levels, a finding which is consistent with the persistence of clonal hematopoiesis in hematological remission. PMID- 28643787 TI - Single-virus genomics reveals hidden cosmopolitan and abundant viruses. AB - Microbes drive ecosystems under constraints imposed by viruses. However, a lack of virus genome information hinders our ability to answer fundamental, biological questions concerning microbial communities. Here we apply single-virus genomics (SVGs) to assess whether portions of marine viral communities are missed by current techniques. The majority of the here-identified 44 viral single-amplified genomes (vSAGs) are more abundant in global ocean virome data sets than published metagenome-assembled viral genomes or isolates. This indicates that vSAGs likely best represent the dsDNA viral populations dominating the oceans. Species specific recruitment patterns and virome simulation data suggest that vSAGs are highly microdiverse and that microdiversity hinders the metagenomic assembly, which could explain why their genomes have not been identified before. Altogether, SVGs enable the discovery of some of the likely most abundant and ecologically relevant marine viral species, such as vSAG 37-F6, which were overlooked by other methodologies. PMID- 28643788 TI - Terahertz saturable absorbers from liquid phase exfoliation of graphite. AB - Saturable absorbers (SA) operating at terahertz (THz) frequencies can open new frontiers in the development of passively mode-locked THz micro-sources. Here we report the fabrication of THz SAs by transfer coating and inkjet printing single and few-layer graphene films prepared by liquid phase exfoliation of graphite. Open-aperture z-scan measurements with a 3.5 THz quantum cascade laser show a transparency modulation ~80%, almost one order of magnitude larger than that reported to date at THz frequencies. Fourier-transform infrared spectroscopy provides evidence of intraband-controlled absorption bleaching. These results pave the way to the integration of graphene-based SA with electrically pumped THz semiconductor micro-sources, with prospects for applications where excitation of specific transitions on short time scales is essential, such as time-of-flight tomography, coherent manipulation of quantum systems, time-resolved spectroscopy of gases, complex molecules and cold samples and ultra-high speed communications, providing unprecedented compactness and resolution. PMID- 28643789 TI - Tidal dynamics and mangrove carbon sequestration during the Oligo-Miocene in the South China Sea. AB - Modern mangroves are among the most carbon-rich biomes on Earth, but their long term (>=106 years) impact on the global carbon cycle is unknown. The extent, productivity and preservation of mangroves are controlled by the interplay of tectonics, global sea level and sedimentation, including tide, wave and fluvial processes. The impact of these processes on mangrove-bearing successions in the Oligo-Miocene of the South China Sea (SCS) is evaluated herein. Palaeogeographic reconstructions, palaeotidal modelling and facies analysis suggest that elevated tidal range and bed shear stress optimized mangrove development along tide influenced tropical coastlines. Preservation of mangrove organic carbon (OC) was promoted by high tectonic subsidence and fluvial sediment supply. Lithospheric storage of OC in peripheral SCS basins potentially exceeded 4,000 Gt (equivalent to 2,000 p.p.m. of atmospheric CO2). These results highlight the crucial impact of tectonic and oceanographic processes on mangrove OC sequestration within the global carbon cycle on geological timescales. PMID- 28643790 TI - Corrigendum: Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. AB - This corrects the article DOI: 10.1038/ncomms14454. PMID- 28643791 TI - EWSR1 fusion proteins mediate PAX7 expression in Ewing sarcoma. AB - PAX7 is a paired-box transcription factor that is required for the developmental specification of adult skeletal muscle progenitors in mice. We previously demonstrated PAX7 expression as a marker of skeletal muscle differentiation in rhabdomyosarcoma. Here, using analyses of published whole-genome gene expression microarray data, we identify PAX7 as a gene with significantly increased expression in Ewing sarcoma in comparison to CIC-DUX4 round cell sarcoma. Analysis of PAX7 in a large cohort of 103 Ewing sarcoma cases by immunohistochemistry revealed expression in 99.0% of cases (102/103). PAX7 expression was noted in cases demonstrating three distinct Ewing sarcoma EWSR1 translocations involving FLI1, ERG, and NFATc2. No PAX7 expression was observed in any of 27 cases of CIC-DUX4 sarcoma by immunohistochemistry (0%; 0/27). Exploring the mechanism of PAX7 expression in Ewing sarcoma using curated RNA- and ChIP-sequencing data, we demonstrate that the EWSR1 fusion protein is required for PAX7 expression in Ewing sarcoma and identify a candidate EWSR1-FLI1 bound PAX7 enhancer that coincides with both a consensus GGAA repeat-containing binding site and a peak of regulatory H3K27 acetylation. Taken together, our findings provide mechanistic support for the utility of PAX7 immunohistochemistry in the diagnosis of Ewing sarcoma, while linking this sarcoma of uncertain histogenesis to a key transcriptional regulator of mammalian muscle progenitor cells. PMID- 28643792 TI - SMARCA4-deficient thoracic sarcoma: a distinctive clinicopathological entity with undifferentiated rhabdoid morphology and aggressive behavior. AB - A distinct subset of thoracic sarcomas with undifferentiated rhabdoid morphology and SMARCA4 inactivation has recently been described, and potential targeted therapy for SMARC-deficient tumors is emerging. We sought to validate the clinicopathological features of SMARCA4-deficient thoracic sarcomas. Clinicopathological information was gathered for 40 undifferentiated thoracic tumors with rhabdoid morphology (mediastinum (n=18), lung (n=14), pleura (n=8)). Thymic carcinomas (n=11) were used as a comparison group. Immunohistochemistry included BRG1 (SMARCA4), BRM (SMARCA2), INI-1 (SMARCB1), pan-cytokeratin, desmin, NUT, S-100 protein, TTF1, CD34, and SOX2. BRG1 loss was present in 12 of 40 rhabdoid thoracic tumors (30%): 7 of 18 in mediastinum (39%), 2 of 8 in pleura (25%), and 3 of 14 in lung (21%). All BRG1-deficient tumors tested for BRM (n=8) showed concomitant loss. All thymic carcinomas showed retained BRG1 and INI-1. Morphologically, tumors with BRG1 loss showed sheets of monotonous ovoid cells with indistinct cell borders, abundant eosinophilic cytoplasm, and prominent nucleoli. Scattered areas with rhabdoid morphology (ie, eccentric nuclei, dense eosinophilic cytoplasm, discohesion) were present in all the cases. SMARCA4/BRG1 deficient sarcomas showed rare cells positive for cytokeratin in 10 cases (83%). One showed rare TTF1-positive cells. All were negative for desmin, NUT, and S-100 protein. CD34 was positive in three of five (60%) BRG1-deficient tumors tested. SOX2 was positive in all four BRG1-deficient tumors tested, and negative in all seven tested cases with retained BRG1. SMARCA4/BRG1-deficient sarcomas occurred at median age of 59 years (range 44-76) with male predominance (9:3) and had worse 2-year survival compared with BRG1-retained tumors (12.5% vs 64.4%, P=0.02). SMARCA4-deficient thoracic sarcomas can be identified based on their distinctive high-grade rhabdoid morphology, and the diagnosis can be confirmed by immunohistochemistry. Identification of these tumors is clinically relevant due to their aggressive behavior, poor prognosis, and potential targeted therapy. PMID- 28643793 TI - Genomic rearrangements in sporadic lymphangioleiomyomatosis: an evolving genetic story. AB - Sporadic lymphangioleiomyomatosis is a progressive pulmonary cystic disease resulting from the infiltration of smooth muscle-like lymphangioleiomyomatosis cells into the lung. The migratory/metastasizing properties of the lymphangioleiomyomatosis cell together with the presence of somatic mutations, primarily in the tuberous sclerosis complex gene (TSC2), lead many to consider this a low-grade malignancy. As malignant tumors characteristically accumulate somatic structural variations, which have not been well studied in sporadic lymphangioleiomyomatosis, we utilized mate pair sequencing to define structural variations within laser capture microdissected enriched lymphangioleiomyomatosis cell populations from five sporadic lymphangioleiomyomatosis patients. Lymphangioleiomyomatosis cells were confirmed in each tissue by hematoxylin eosin stain review and by HMB-45 immunohistochemistry in four cases. A mutation panel demonstrated characteristic TSC2 driver mutations in three cases. Genomic profiles demonstrated normal diploid coverage across all chromosomes, with no aneuploidy or detectable gains/losses of whole chromosomal arms typical of neoplastic diseases. However, somatic rearrangements and smaller deletions were validated in the two cases which lacked TSC2 driver mutations. Most significantly, one of these sporadic lymphangioleiomyomatosis cases contained two different size deletions encompassing the entire TSC1 locus. The detection of a homozygous deletion of TSC1 driving a predicted case of sporadic lymphangioleiomyomatosis, consistent with the common two-hit TSC2 mutation model, has never been reported for sporadic lymphangioleiomyomatosis. However, while no evidence of the hereditary tuberous sclerosis complex disease was reported for this patient, the potential for mosaicism and sub-clinical phenotype cannot be ruled out. Nevertheless, this study demonstrates that somatic structural rearrangements are present in lymphangioleiomyomatosis disease and provides a novel method of genomic characterization of sporadic lymphangioleiomyomatosis cells, aiding in defining cases with no detected mutations by conventional methodologies. These structural rearrangements could represent additional pathogenic mechanisms in sporadic lymphangioleiomyomatosis disease, potentially affecting response to therapy and adding to the complex genetic story of this rare disease. PMID- 28643794 TI - Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. AB - The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies. PMID- 28643796 TI - Benchmarking cataract surgery outcomes in an ethnically diverse and diabetic population: final post-operative visual acuity and rates of post-operative cystoid macular oedema. AB - PurposeTo determine visual acuity and rates of post-operative cystoid macular oedema (CMO) in an ethnically diverse and predominantly diabetic population.MethodsThe study was undertaken over a one year period. Snellen visual acuity (VA) was measured pre and 4-8 weeks post-operatively and optical coherence topography (OCT) was performed at baseline and post-operatively. No eyes received prophylactic non-steroidal anti-inflammatory drugs (NSAIDs) prior to or after surgery.ResultsOut of 262 eyes, 59% were in the Black, Asian and minority ethnic group (BAME), 57% had a history of diabetes mellitus and 34% had pre-existing diabetic retinopathy. 76% of all eyes achieved 6/12 post-operative VA at the first postoperative review and the incidence of post-operative CMO within the study population was 7.6%. In patients with a history of diabetes mellitus the incidence of post-operative CMO was 10.7% compared to 3.5% in those without diabetes. This was found to be clinically significant (P=0.0297).ConclusionWe believe this is the first study to benchmark standards for care in this demographic of patients. A history of diabetes mellitus, irrespective of whether there is diabetic retinopathy or not, is an independent risk factor for the development of post-operative CMO in patients undergoing cataract surgery (P=0.0297). Ethnicity is not an independent risk factor for the development of post-operative CMO. PMID- 28643795 TI - The genomic landscape of tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a rare genetic disease causing multisystem growth of benign tumours and other hamartomatous lesions, which leads to diverse and debilitating clinical symptoms. Patients are born with TSC1 or TSC2 mutations, and somatic inactivation of wild-type alleles drives MTOR activation; however, second hits to TSC1/TSC2 are not always observed. Here, we present the genomic landscape of TSC hamartomas. We determine that TSC lesions contain a low somatic mutational burden relative to carcinomas, a subset feature large-scale chromosomal aberrations, and highly conserved molecular signatures for each type exist. Analysis of the molecular signatures coupled with computational approaches reveals unique aspects of cellular heterogeneity and cell origin. Using immune data sets, we identify significant neuroinflammation in TSC-associated brain tumours. Taken together, this molecular catalogue of TSC serves as a resource into the origin of these hamartomas and provides a framework that unifies genomic and transcriptomic dimensions for complex tumours. PMID- 28643797 TI - Deep sclerectomy for uveitic glaucoma: long-term outcomes. AB - PurposeTo report long-term outcomes of deep sclerectomy (DS) in eyes with raised intraocular pressure (IOP) and glaucoma secondary to uveitis.Patients and methodsRetrospective consecutive case series of 43 eyes of 43 patients with uveitic glaucoma. Mitomycin C (MMC) 0.2-0.4 mg/ml was applied sub-conjunctivally prior to scleral flap dissection for 2-3 min in 35 eyes (81%). Combined phacoemulsification and DS was done in 4 cases (9%).ResultsMean follow-up was 68.5+/-33.5 months. In total, 23 eyes (53.5%) had previous intraocular surgery. Pre-operative IOP was 33.6+/-12.0 mm Hg. Mean IOP at one, three and five years after surgery was 15.5+/-5.0 mm Hg, 16.9+/-6.7 mm Hg and 16.4+/-5.2 mm Hg, respectively.The probability of IOP <22 and <19 mm Hg was 69 and 62% at 3 years and 60 and 51% at 5 years, respectively. This included eyes that had undergone needle revision and/or laser goniopuncture within that period but had not needed glaucoma medication or further glaucoma procedures. The overall number of glaucoma medications decreased from 3.0+/-1.2 to 0.8+/-1.2 by last follow-up (P<0.001). Serious complications included hypotony with macular folds in two eyes and occlusion of the trabeculo-Descemet's membrane (TDM) by iris in two eyes. Recurrence of uveitis was observed in 16 eyes. Seven eyes (16.3%) had subsequent procedures including trabeculectomy with MMC in one eye, DS with MMC in two eyes and Baerveldt tube implantation in five eyes.ConclusionsDS is a safe and effective procedure to lower IOP in uveitic glaucoma. However, as with other glaucoma procedures, a significant proportion of patients will require another IOP-lowering procedure in the long-term. PMID- 28643798 TI - Topical administration of Esculetin as a potential therapy for experimental dry eye syndrome. AB - PurposeIn this study, we investigated the therapeutic effects of topical Esculetin for dry eye rabbits through the ocular tests, inflammatory factor levels and specific phosphorylated protein expressions of ERK1/2 singnal pathway.Patients and methodsThirty-two healthy adult male New Zealand white rabbits were chosen for the study. DES models were established after removing of the main lacrimal gland, Harderian gland and nictitating membrane in the left eyes and randomly divided into group DES control, group CsA, group Esculetin and group Esculetin combined with CsA (C&E), meanwhile the right eyes served as group Normal control. Schirmer's I tests, fluorescein scores, goblet cell densities, inflammatory cytokines IL-1alpha,IL-1beta,TNF-alphalevels were observed by slit lamp microscope, conjunctival impression cytology and ELISA essay at week 0, 1, 2, 4, 8. Phosphorylated-ERK1/2 expressions were detected in Western blot analysis at week 8.ResultsAfter induction of DES, aqueous tear production and goblet cell density were decreased, FL score was much higher in group DES control throughout the study (P<0.05). Both topical Esculetin and Esculetin combing CsA increased the SIT values (10+/-1 mm, 14+/-3 mm, P<0.05) and goblet cell densities (77+/ 12/HP, 92+/-12/HP, P<0.05), decreased FL scores (7.48+/-0.33, 5.09+/-0.24, P<0.05) at week 8. Alternations of IL-1alpha,IL-1beta,TNF-alphalevels had similar trend. In Western blot analysis, downregulations of p-ERK1/2 were observed in therapy groups when compared with group DES control and the most decreasing was found in group C&E (P<0.05).ConclusionTopical Esculetin improved DES symptoms, downregulated the inflammatory cytokine expressions, suppressed the ERK1/2 pathway and enhanced the therapeutic effect of CsA. PMID- 28643800 TI - Striatal Dopamine D2/D3 Receptor Availability Varies Across Smoking Status. AB - To assess how tobacco smoking status affects baseline dopamine D2/D3 (D2R) receptor availability and methylphenidate-induced dopamine (DA) release, we retrospectively analyzed D2R availability measures of 8 current smokers, 10 ex smokers, and 18 nonsmokers who were scanned with positron emission tomography and [11C]raclopride, after administration of an injection of placebo or 0.5 mg/kg i.v. methylphenidate. There was a significant effect of smoking status on baseline striatal D2R availability; with current smokers showing lower striatal D2R availability compared with nonsmokers (caudate, putamen, and ventral striatum) and with ex-smokers (caudate and putamen). Baseline striatal D2R did not differ between nonsmokers and ex-smokers. The effect of smoking status on methylphenidate-induced DA release tended to be lower in smokers but the difference was not significant (p=0.08). For behavioral measures, current smokers showed significantly higher aggression scores compared with both nonsmokers and ex-smokers. These results suggest that with abstinence ex-smokers may recover from low striatal D2R availability and from increased behavioral aggression seen in active smokers. However, longitudinal studies are needed to assess this within abstaining smokers. PMID- 28643801 TI - January 2016 extensive summer melt in West Antarctica favoured by strong El Nino. AB - Over the past two decades the primary driver of mass loss from the West Antarctic Ice Sheet (WAIS) has been warm ocean water underneath coastal ice shelves, not a warmer atmosphere. Yet, surface melt occurs sporadically over low-lying areas of the WAIS and is not fully understood. Here we report on an episode of extensive and prolonged surface melting observed in the Ross Sea sector of the WAIS in January 2016. A comprehensive cloud and radiation experiment at the WAIS ice divide, downwind of the melt region, provided detailed insight into the physical processes at play during the event. The unusual extent and duration of the melting are linked to strong and sustained advection of warm marine air toward the area, likely favoured by the concurrent strong El Nino event. The increase in the number of extreme El Nino events projected for the twenty-first century could expose the WAIS to more frequent major melt events. PMID- 28643799 TI - Appropriateness of quality standards for meaningful intercentre comparisons of aflibercept service provision for neovascular age-related macular degeneration. AB - PurposeReal-world data give different information on health-care delivery compared with randomised controlled trials. We aimed to evaluate the appropriateness of possible quality standards for intersite comparisons of outcomes of providing Aflibercept for neovascular age-related macular degeneration (nAMD) in clinical practice.Patients and methodsRetrospective data analysis from an electronic medical record. A consecutive series of treatment naive patients initiated on aflibercept for nAMD, in the UK from March 2013 to October 2015. Age, visual acuity (VA) at baseline and 1 year, and injection episodes were remotely extracted in an anonymised format.ResultsThe mean baseline VA was 54.3 letters, ranging from 51.3 to 58.1 between different centres, in 5620 eyes taken from 12 centres. Out of these, 3360 were initiated on treatment more than a year before. The percentage with <35 letters at baseline was 19.9-3% and that with >70 letters was 24.8-10.7%. Eyes with >=70 letters at 1 year ranged from 20.2 to 42.9% and those with <35 ranged from 4.5 to 21.6% across different sites. Injection rates in 1 year varied from 5.5 to 8.6, and data available at 1 year also varied from 82.3 to 46.4%.ConclusionsSignificant variation was found between sites attempting to provide the same therapeutic regime. For fair comparisons between sites, we recommend that both VA measures and process measures, such as injection numbers, retention rates, and discharge policies, are used. More work is required to explain the differences. Such real-world data are not generated in the same way as a randomised clinical trial, and maybe best used to help improve service provision. PMID- 28643802 TI - Optogenetic rewiring of thalamocortical circuits to restore function in the stroke injured brain. AB - To regain sensorimotor functions after stroke, surviving neural circuits must reorganize and form new connections. Although the thalamus is critical for processing and relaying sensory information to the cortex, little is known about how stroke affects the structure and function of these connections, or whether a therapeutic approach targeting these circuits can improve recovery. Here we reveal with in vivo calcium imaging that stroke in somatosensory cortex dampens the excitability of surviving thalamocortical circuits. Given this deficit, we hypothesized that chronic transcranial window optogenetic stimulation of thalamocortical axons could facilitate recovery. Using two-photon imaging, we show that optogenetic stimulation promotes the formation of new and stable thalamocortical synaptic boutons, without impacting axon branch dynamics. Stimulation also enhances the recovery of somatosensory cortical circuit function and forepaw sensorimotor abilities. These results demonstrate that an optogenetic approach can rewire thalamocortical circuits and restore function in the damaged brain. PMID- 28643804 TI - Diabetes: Why beta cells fail in T2DM. PMID- 28643805 TI - Parkinson disease: Plasma alpha-synuclein - a potential marker of cognitive impairment in Parkinson disease. PMID- 28643806 TI - Dementia: Persistent pain might be a harbinger of cognitive decline in older people. PMID- 28643807 TI - Infectious disease: Musashi-1 protein could mediate the effects of Zika virus on brain development. PMID- 28643808 TI - Parkinson disease: Deep brain stimulation - making the right connections. PMID- 28643803 TI - VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2. AB - The von Hippel-Lindau (VHL) is deficient in ~70% of clear-cell renal cell carcinomas (ccRCC), which contributes to the carcinogenesis and drug resistance of ccRCC. Here we show that VHL-deficient ccRCC cells present enhanced cytotoxicity of anthracyclines in a hypoxia-inducible factor-independent manner. By subtractive proteomic analysis coupling with RNAi or overexpression verification, aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in ccRCC cells. Furthermore, VHL regulates ALDH2 expression by directly binding the promoter of -130 bp to -160 bp to activate the transcription of hepatocyte nuclear factor 4 alpha (HNF-4alpha). In addition, a positive correlation is found among the protein expressions of VHL, HNF-4alpha and ALDH2 in ccRCC samples. These findings will deepen our understanding of VHL function and shed light on precise treatment for ccRCC patients. PMID- 28643810 TI - ? PMID- 28643811 TI - [From mild cognitive impairment to dementia: what is the role of public health?] AB - Mild cognitive impairment (MCI) is a nosological entity proposed by Petersen in 1999 with the objective of identifying an early stage of dementia. The new diagnostic criteria for dementia, both those promoted by the International Working Group (IWG) and those defined by the National Institute of Aging (NIA), subsequently introduced a new model that starts with a preclinical phase, then proceeds with a prodromal phase, and ends with a phase of dementia. The condition known as subjective cognitive disorder (SCD) is included between the preclinic and the prodromal phases. Most clinicians improperly consider MCI and SCD as diseases, and not as risk factors for dementia. This ambiguous scenario requires the application of a public-health standard. A diagnosis of either SCD or MCI comes with several uncertainties, raising issues pertaining to both the research setting and clinical practice. A large proportion of subjects with either SCD or MCI will never progress to dementia, and part of them may even revert to a normal cognitive profile. Thus, communicating of these diagnoses to a subject has ethical implications that cannot be underestimated. The frequency of these diagnoses in general population is starting to show the characteristics of both the phenomena of over-diagnosis, and consequently over-treatment. Moreover, the new criteria require the use of biomarkers, that are not yet validated for the use in clinical practice. No population studies are currently available performed based on the new diagnostic criteria for dementia. This means that future estimates will probably be more than twice the current ones, and will include also subjects that will not progress to dementia. This undefined framework, thus, urges the implementation of public-health programs aimed at both the primary and secondary prevention of dementias. Moreover, clinical trials on drugs in MCI currently use endpoints based on non-validated biomarkers, thus raising the issue of the external validity. A public guideline would thus be crucial to support clinicians in identifying all the possible causes that can determine a cognitive decline people that are mainly elder, with multiple comorbidities, and taking multiple medications. Moreover, the widespread use of neuro-psychological assessment tools in current clinical practice requires an accurate validation of these instruments. PMID- 28643812 TI - [Conscience clause in end-of-life care.] AB - The article proposes a critical reflection on issues that appeal to the conscience clause as part of end of life care can produce and what can guarantee freedom of conscience, self-determination of those involved and respect for the dignity of the sick person. After a philosophical and normative analysis, the article is organized on the basis of two important documents for discussion: a position paper of Societa Italiana di Anestesia Analgesia Rianimazione e Terapia Intensiva (SIAARTI) signed by several scientific societies "Grandi insufficienze d'organo end stage: cure intensive o cure palliative?" and the Design of Law currently being debated "Norme in materia di consenso informato e di disposizioni anticipate di trattamento". In particular, the conscience clause has been discussed in the light of advance care planning (ACP), which represents the instrument to guarantee the shared planning of care and the shared-decision making. In this context, recourse to the clause of conscience brings out critical ethical and deontological issues that the article discusses, using the position paper SIAARTI and the text of law currently being debated, both built on the assumptions of a shared care relationship, where patient has a key-role in medical decisions. PMID- 28643813 TI - [Polymyalgia rheumatica: diagnostic and therapeutic issues of an apparently straightforward disease.] AB - Polymyalgia rheumatica (PMR) is an inflammatory disease characterized by aching and stiffness in the girdles, which affects typically people over 50 years old and could overlap with giant cell arteritis (GCA) in about 15-20% of cases. Although the diagnosis of PMR is usually considered straightforward, clinicians facing this disease should be aware of its atypical manifestations, which can hamper the correct identification of PMR and, conversely, should be aware of other diseases which may present with polymyalgic features. The aim of this review is to synthetize current knowledge about clinical presentations of PMR, the differential diagnoses, the relationship with cancer, the clues to the presence of a concomitant GCA, the role of ultrasonography at the onset and in the follow-up and, finally, treatment approaches. Besides evidence from the literature, this review will highlight some "tips&tricks" useful in everyday clinical practice. The awareness of the different presentations and pitfalls of PMR could improve patients' management and avoid complications consequent upon unrecognized diseases or, conversely, overtreatment. PMID- 28643815 TI - [Greater saphenous vein thrombosis and testosterone replacement therapy: an occasional association?] AB - We describe a case of greater saphenous vein thrombosis in a 50-year-old previously healthy man, occurred only 3 weeks after starting testosterone (T) replacement therapy (20 mg/day, gel) for hypergonadotropic hypogonadism. There were no clinical known risk factors for thrombosis. Laboratory assessment of thrombophilia, performed later, revealed only methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism. On the basis of other recently reported cases, we suppose a relationship between androgenic therapy and venous thrombosis. We suggest the same caution before starting T replacement therapy in male as in female administration of estrogens. PMID- 28643814 TI - [Unresponsive wakefulness syndrome: clinical predictors of late recovery.] AB - Patients affected by the outcomes of serious traumatic and/or non-traumatic brain injury may show progressive recovery characterized by a broad spectrum of clinical conditions, which are often not completely different, but of differing seriousness. The unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) are syndromes that may characterize progression from the coma state and may be temporary clinical conditions, or in some cases, the final outcome of acute brain injury. The eventual recovery of consciousness is a dynamic process, in constant progress following the acute event. It is undeniable, however, that depending on various clinical (including non-neurological) determinants, positive progress can be strongly affected. While it remains true that the longer the UWS lasts, the less likely the patient is to recover from it, observations of "late recovery" are becoming increasingly frequent in the literature. Accordingly, it is becoming increasingly important to identify those late clinical, non neurological complications, in particular during the intensive rehabilitation period, that can potentially affect the outcome. The aim of this study is to investigate late recovery from the UWS and MCS in a group of patients admitted to a neurorehabilitation program and to identify prognostic factors that may affect recovery, including late recovery, from the UWS. A retrospective cohort analysis without parallel cohort took place between January 2005 and January 2010, and involved 309 patients with severe brain injury outcomes (with initial GCS scores <= 8). With regard to patients emerging from the UWS after 36 months, univariate analysis revealed male gender, young age, a shorter duration of consciousness disorder and the absence of epileptic seizures to be the most important clinical characteristics for transition from UWS to MCS. The other variables considered were not significant: etiology of the coma, CRS-R score upon admittance to the ICU, infection by multidrug-resistant bacteria, and episodes of paroxysmal sympathetic hyperactivity. PMID- 28643816 TI - [Budd-Chiari syndrome and ulcerative colitis in an adolescent.] AB - In patients with inflammatory bowel disease (IBD) there is an increased incidence of thromboembolic events. We report a case of a female, age 14, with a 6 months history of diarrhea with occasional presence of red blood and with a very distended abdomen with evident ascites. The diagnosis was Budd-Chiari syndrome (BCS) in ulcerative colitis (UC). Therapy with subcutaneous low molecular weight heparin, methylprednisolone, mesalazine was started. Clinical and radiological features quickly improved. No thrombophilia abnormality nor other risk factor for thrombosis were detected. BCS is a rare condition caused by obstruction of the supra-hepatic veins and causes liver congestion, portal hypertension, ascites, esophageal varices, and in some cases, acute onset of severe liver failure. Only six pediatric cases of BCS with concurrent UC are reported. Of these, four had no thromboembolic risk factor. IBD should always be carefully evaluated as a possible underlying trigger of an acute thrombotic event. PMID- 28643817 TI - ? PMID- 28643818 TI - Serum microRNAs are altered in various stages of chronic kidney disease: a preliminary study. AB - BACKGROUND: MicroRNAs (miRNAs) are innovative and informative blood-based biomarkers involved in numerous pathophysiological processes. In this study and based on our previous experimental data, we investigated miR-126, miR-143, miR 145, miR-155 and miR-223 as potential circulating biomarkers for the diagnosis and prognosis of patients with chronic kidney disease (CKD). The primary objective of this study was to assess the levels of miRNA expression at various stages of CKD. METHODS: RNA was extracted from serum, and RT-qPCR was performed for the five miRNAs and cel-miR-39 (internal control). RESULTS: Serum levels of miR-143, -145 and -223 were elevated in patients with CKD compared with healthy controls. They were further increased in chronic haemodialysis patients, but were below control levels in renal transplant recipients. In contrast, circulating levels of miR-126 and miR-155 levels, which were also elevated in CKD patients, were lower in the haemodialysis group and even lower in the transplant group. Four of the five miRNA species were correlated with estimated glomerular filtration rate, and three were correlated with circulating uraemic toxins. CONCLUSIONS: This exploratory study suggests that specific miRNAs could be biomarkers for complications of CKD, justifying further studies to link changes of miRNA levels with outcomes in CKD patients. PMID- 28643820 TI - Does wealth make health? Cherchez la renal replacement therapy. AB - In this issue of CKJ, McQuarrie et al. have explored the relationship between socioeconomic status and outcomes among Scottish patients with a renal biopsy diagnosis of primary glomerulonephritis. Patients in the lower socioeconomic category had a twofold higher risk of death. No significant differences were observed on progression to end-stage renal disease (ESRD) requiring renal replacement therapy (RRT), suggesting that overall medical management was appropriate for all socioeconomic categories. The findings are significant since they come from an ethnically homogeneous population with free access to healthcare; they also relate to a specific aetiology of chronic kidney disease (CKD) expected to be less dependent on unhealthy lifestyles than other more frequent aetiologies that dominate studies of CKD in general, such as diabetic or hypertensive nephropathy. A closer look at the data suggests that living in a high socioeconomic area is associated with lower mortality, rather than the other way round. Furthermore, the differences in mortality were most pronounced during the RRT stage of CKD, providing clues for further research. In this regard, Wilmink et al. and Nee et al. point to access to pre-ESRD nephrology care and to the best kidney transplantation options as modifiable factors to be studied in the realm of T3 translational research to improve CKD patient outcomes. PMID- 28643819 TI - Non-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients, part II: omics analyses of urine and blood samples. AB - Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, the full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene-expression profiling and omics analyses of blood and urine samples. Most imaging techniques, such as contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leucocytes may be detectable by 18F-fluorodeoxyglucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3epsilon, CXCL10 and 18S RNA levels, have been identified. None of these approaches has yet been adopted in the clinical follow up of KTRs, but standardization of analysis procedures may help assess reproducibility and comparative diagnostic yield in large, prospective, multicentre trials. PMID- 28643822 TI - [Preventive dentistry 6. Prevention of caries in frail older people]. AB - Many older people have a bad oral health, with (root) caries a prevalent cause. Alarming results of research projects raise the question whether sufficient preventive measures are being taken to prevent the development and progress of (root) caries in frail older people. A review of the recent literature revealed that in frail older people and physically or cognitively impaired adults, daily use of a 5,000 ppm fluoride toothpaste and quarterly application of chlorhexidine or sodium fluoride can decrease by half the risk of root caries. In the Netherlands, toothpaste containing 5,000 ppm fluoride is not (yet) on the market. At the present time, only the advice brochure 'Prevention of root caries' is available. Another measure to prevent deterioration of oral health among frail older people is paying attention to frail older people who do not visit their dentist on a regular basis due to physical limitations and care dependency. When this is the case, it is necessary to intensify professional oral healthcare with instructions to personal caregivers and professional care providers in order to fight (root) caries. PMID- 28643821 TI - Non-invasive approaches in the diagnosis of acute rejection in kidney transplant recipients. Part I. In vivo imaging methods. AB - Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene expression profiling and omics analyses of blood and urine samples. Most imaging techniques, like contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leukocytes may be detectable by 18F-fluoro-deoxy-glucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3epsilon, IP-10 and 18S RNA levels, have been identified. None of these approaches has been adopted yet in the clinical follow up of KTRs, but standardization of procedures may help assess reproducibility and compare diagnostic yields in large prospective multicentric trials. PMID- 28643823 TI - [Chewing on bruxism. Diagnosis, imaging, epidemiology and aetiology]. AB - Since the publication of a special issue on bruxism of the NTvT in July 2000, consensus has been reached on bruxism's definition as a repetitive masticatory muscle activity that is characterised by clenching and/or grinding while awake (awake bruxism) or during sleep (sleep bruxism). As yet, however, no consensus exists about the diagnosis of bruxism: sufficient evidence to establish the reliability and validity of the commonly used techniques (self-report, clinical examination, imaging, electromyography, polysomnography) has not yet been produced. Morphological factors are no longer considered important aetiological factors, while increasing evidence suggests aetiological roles for psychosocial, physiological, biological, and exogenous factors. This review paper is the first part of a diptych and is concerned with the definition, diagnostics, epidemiology and possible causes of this disorder. In the second part, that will be published in the next issue, associations of bruxism with other conditions will be discussed, along with its (purported) consequences and its management. PMID- 28643824 TI - [Perioral treatment options in cosmetic facial surgery]. AB - The perioral region is unique and important in the face, both from a functional and an aesthetic point of view. There is a strong relationship between the perioral soft tissues, such as the lips and the corners of the mouth, and the underlying dentition and the jaws. Perioral ageing phenomena, such as depressed corners of the mouth, volume loss and wrinkles, can be improved, however, to a limited extent with intraoral treatment. These ageing phenomena can usually be treated more effectively with several extraoral treatment modalities that also enhance perioral aesthetics. The perioral cosmetic treatment options can be divided into various lifting procedures and volumising techniques. Considering that the dentist has to deal regularly with patients with perioral aesthetic wishes and also functional problems, it is important that one has knowledge of the different perioral treatment options, for both cosmetic and functional options. PMID- 28643825 TI - [A phd completed 10. Implant-supported removable partial -dentures in a Kennedy Class I-situation in the mandible]. AB - Implant-supported removable partial dentures in the mandible often cause problems, which means that patients wear their dentures seldom if at all. A solution is to place implants that the dentures can be snapped onto. There is, however, no consensus about the best position of the implants in the mandible yet. In addition, it is worthwhile to balance the cost of treatment with its effectiveness. In a randomised cross-over clinical trial involving 30 patients with a shortened dental arch, the implant-supported removable partial denture in the mandible was evaluated based on the experience of the patient, mean time of wearing, chewing ability and the clinical and radiographic parameters in relation to 2 different implant positions: 2 in the pre-molar region or 2 in the molar region. The cost-effectiveness of both treatments was also evaluated. From the patient's point of view, the implant-supported removable partial dentures are best supported by implants placed in the molar region. The research also revealed, however, that significantly more bleeding occurred around implants placed in the molar region and from a clinical perspective placement in the pre molar region would have preference. The cost-effectiveness of the treatment with an implant-supported removable partial denture depends on the choice of outcome measurement and monetary threshold. PMID- 28643826 TI - Cationic silyldiazenido complexes of the Fe(diphosphine)2(N2) platform: structural and electronic models for an elusive first intermediate in N2 fixation. AB - The first cationic Fe silyldiazenido complexes, [Fe(PP)2(NN-SiMe3)]+[BArF4]- (PP = dmpe/depe), have been synthesised and thoroughly characterised. Computational studies show the compounds to be useful structural and electronic surrogates for the more elusive [Fe(PP)2(NN-H)]+, which are postulated intermediates in the H+/e mediated fixation of N2 by Fe(PP)2(N2) species. PMID- 28643827 TI - Anti-oxidant and immune-modulatory properties of sulfated alginate derivatives on human chondrocytes and macrophages. AB - Degeneration of articular cartilage represents one of the most common causes of pain and disability in our aging society. Current treatments only address the symptoms of joint disease, but not their underlying causes which include oxidative stress and inflammation in cartilage and surrounding tissues. Sulfated biopolymers that mimic aspects of the native extracellular environment of cartilage are recently gaining interest as a means to slow the inflammatory events responsible for tissue degeneration. Here we show that the natural polysaccharide alginate and particularly its sulfated derivatives have potent anti-oxidant, anti-inflammatory and anti-immunogenic properties in vitro. We found that these polymers exert a free radical scavenging activity in a sulfation dependent manner. In particular, the sulfation degree of substitution of alginate directly correlated with its ability to scavenge superoxide radicals and to chelate metal ions. We also studied the effect of sulfated alginate on the ability of IL-1beta to stimulate inflammatory genes in human chondrocytes and found decreased expression of the pro-inflammatory markers IL-6 and CXCL8, which inversely correlated with the sulfation degree. Moreover, in studies testing the ability of the alginates to modulate macrophage polarization, we found that they decreased both the gene expression and synthesis of the proinflammatory cytokine TNF-alpha in human THP-1 macrophages with M1-like phenotype in a sulfation dependent manner. To conclude, sulfated alginates effectively protect against oxidative stress and inflammation in vitro and are a promising biomaterial to be explored for treatment of osteoarthritis. PMID- 28643828 TI - Adaptability of the metal(iii,iv) 1,2,3-trioxobenzene rod secondary building unit for the production of chemically stable and catalytically active MOFs. AB - The use of a 5,10,15,20-tetrakis(3,4,5-trihydroxyphenyl)porphyrin has yielded a new MOF based on M-1,2,3-trioxobenzene chains that can be made of M = Zr(iv) or RE(iii) (RE = rare earth), showing a very high and limited chemical stability, respectively. The robust metallated Zr-analogue, Co-MIL-173(Zr), has proven to be a heme-like heterogeneous catalyst suitable for aerobic oxidation of hydrocarbons. PMID- 28643829 TI - Efficient scavenging of Criegee intermediates on water by surface-active cis pinonic acid. AB - cis-Pinonic acid (CPA), the main product of the atmospheric oxidation of biogenic alpha-pinene emissions and a major component of secondary organic aerosol (SOA), is a potentially key species en route to extremely low volatility compounds. Here, we report that CPA is an exceptionally efficient scavenger of Criegee intermediates (CIs) on aqueous surfaces. Against expectations, millimolar CPA (a surface-active C10 keto-carboxylic acid possessing a rigid skeleton) is able to compete with 23 M bulk water for the CIs produced in the ozonolysis of sesquiterpene solutes by O3(g) on the surface of a water:acetonitrile solvent. The significance of this finding is that CPA reactions with sesquiterpene CIs on the surface of aqueous organic aerosols would directly generate C25 species. The finding that competitive reactions at the air-liquid interface depend on interfacial rather than bulk reactant concentrations should be incorporated in current chemical models dealing with SOA formation, growth and aging. PMID- 28643832 TI - Metasurface integrated high energy efficient and high linearly polarized InGaN/GaN light emitting diode. AB - We proposed and demonstrated an integrated high energy efficient and high linearly polarized InGaN/GaN green LED grown on (0001) oriented sapphire with combined metasurface polarizing converter and polarizer system. It is different from those conventional polarized light emissions generated with plasmonic metallic grating in which at least 50% high energy loss occurs inherently due to high reflection of the transverse electric (TE) component of an electric field. A reflecting metasurface, with a two dimensional elliptic metal cylinder array (EMCA) that functions as a half-wave plate, was integrated at the bottom of a LED such that the back-reflected TE component, that is otherwise lost by a dielectric/metal bi-layered wire grids (DMBiWG) polarizer on the top emitting surface of the LED, can be converted to desired transverse magnetic (TM) polarized emission after reflecting from the metasurface. This significantly enhances the polarized light emission efficiency. Experimental results show that extraction efficiency of the polarized emission can be increased by 40% on average in a wide angle of +/-60 degrees compared to that with the naked bottom of sapphire substrate, or 20% compared to reflecting Al film on the bottom of a sapphire substrate. An extinction ratio (ER) of average value 20 dB within an angle of +/-60 degrees can be simultaneously obtained directly from an InGaN/GaN LED. Our results show the possibility of simultaneously achieving a high degree of polarization and high polarization extraction efficiency at the integrated device level. This advances the field of GaN LED toward energy efficiency, multi functional applications in illumination, display, medicine, and light manipulation. PMID- 28643833 TI - Modelling critical Casimir force induced self-assembly experiments on patchy colloidal dumbbells. AB - Colloidal particles suspended in a binary liquid mixture can interact via solvent mediated interactions, known as critical Casimir forces. For anisotropic colloids this interaction becomes directional, which leads to rich phase behavior. While experimental imaging and particle tracking techniques allow determination of isotropic effective potentials via Boltzmann inversion, the modeling of effective interaction in anisotropic systems is non-trivial precisely because of this directionality. Here we extract effective interaction potentials for non spherical dumbbell particles from observed radial and angular distributions, by employing reference interaction site model (RISM) theory and direct Monte Carlo simulations. For colloidal dumbbell particles dispersed in a binary liquid mixture and interacting via induced critical Casimir forces, we determine the effective site-site potentials for a range of experimental temperatures. Using these potentials to simulate the system for strong Casimir forces, we reproduce the experimentally observed collapse, and provide a qualitative explanation for this behavior. PMID- 28643834 TI - Understanding the remarkable luminescence enhancement via SiO2 coating on TiO2:Eu3+ nanofibers. AB - TiO2:Eu3+ nanofibers diameters can be tuned by changing the mixed solvent ratio are synthesized via the electrospinning technique. Concentration quenching phenomena and the relationship of the PL intensity ratio I(5D0-7F2)/I(5D0-7F1) with the Eu doping concentration are discussed. Notably, the luminescence intensity is enhanced by about 7.8 fold by coating SiO2 gel layer on the TiO2:Eu3+ nanofibers, which is successfully performed via a sol-gel process followed by calcination. Furthermore, these fibers are characterized systematically via X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), UV-vis diffuse reflectance spectroscopy (UV-vis DRS), Fourier transform infrared spectroscopy (FT-IR), and photoluminescence (PL) spectroscopy. Additionally, their Judd-Ofelt and spectral parameters are calculated to investigate their local structures. The relatively low Omega2 value of the coated samples reveals a decrease in covalency in the Eu O bonds and an increase in the symmetric nature of Eu3+, which indicate that the perturbation effect of the crystal field in the solid system is larger than that of the uncoated samples. FT-IR analysis indicates the formation of Ti-O-Si bonds, which provide the ligand field in the interface between the TiO2:Eu3+ nanofibers and SiO2 layer and can repair the surface unsaturated bonds. This reduces the selection rules for radiative transitions, thereby the state of the Eu3+ ions is converted from dormant to activated. Moreover, the silica coating stabilizes the surface of the TiO2:Eu3+ nanofibers and eliminates the surface defects. Finally, a detailed mechanism is proposed to explain the luminescence enhancement behavior. PMID- 28643835 TI - Interaction of molecular nitrogen with free-electron-laser radiation. AB - We compute molecular continuum orbitals in the single center expansion scheme. We then employ these orbitals to obtain molecular Auger rates and single-photon ionization cross sections to study the interaction of N2 with Free-Electron-Laser (FEL) pulses. The nuclei are kept fixed. We formulate rate equations for the energetically allowed molecular and atomic transitions and we account for dissociation through additional terms in the rate equations. Solving these equations for different parameters of the FEL pulse, allows us to identify the most efficient parameters of the FEL pulse for obtaining the highest contribution of double core hole states (DCH) in the final atomic ion fragments. Finally we identify the contribution of DCH states in the electron spectra and show that the DCH state contribution is more easily identified in the photo-ionization rather than the Auger transitions. PMID- 28643837 TI - Density dependence of orientational order in one-patch particles. AB - Closely packed spherical patchy particles exhibit a range of orientationally ordered equilibrium structures depending on patch size and particle arrangement due to the existence of a sticky inter-patch interaction and rotational degrees of freedom. We experimentally study the packing density dependence of such ordering in particles with a thin deposited patch which imparts a shape anisotropy of a few percent in aspect ratio. These are confined between flat substrates with a chamber thickness of up to two particle layers. When the particles are tightly packed and almost in contact with each other, the anisotropic hard-body interaction dictates the orientational order. Thus, the order depends little on patch size, with rotational motion almost frozen. A small decrease in the density allows free rotational motion while translation is restricted to vibrational motion. This drastically changes the ordering mechanism, giving rise to a patch-size dependent equilibrium orientational order. Furthermore, within this density regime, we find yet another density-dependent transition within the tetragonal bilayer. This transition is reproduced by numerical simulation assuming no shape anisotropy, indicating that shape anisotropy is unnecessary for the transition and translational entropy significantly affects the equilibrium orientational order even in such a closely packed structure. Our study demonstrates the sensitivity of the ordering mechanism and the resulting order to the packing density, where the effect of such a tiny shape anisotropy is clearly observable owing to the patch opacity. The dependence of cluster structure in particle dispersions on patch size, confinement thickness and packing density is also reported. PMID- 28643836 TI - Host-guest driven ligand replacement on monodisperse inorganic nanoparticles. AB - We demonstrate that crown ether-assisted ligand replacement on Fe3O4 NPs using halide salts leads to quantitative stripping of an existing stabilizer shell with unprecedented (complete) efficiency; this allows subsequent re-grafting of functional ligands at maximal surface density. The mechanism of the anion-driven ligand replacement is elucidated by varying the halide salt and the versatility by varying the re-grafted ligand. PMID- 28643838 TI - Organics filled one-dimensional TiO2 nanowires array ultraviolet detector with enhanced photo-conductivity and dark-resistivity. AB - A heterojunction photo-conductive ultraviolet (UV) detector was developed based on TiO2 nanowires array (NWA) surrounded by N,N'-bis-(1-naphthalenyl)-N,N'-bis phenyl-(1,1'-biphenyl)-4,4'-diamine (NPB). The novel and effective two-step method of static infusion and dynamic solution-cleaning was employed to fill NPB into TiO2 NWA gaps and simultaneously remove the unwelcomed top NPB layer. The device fabricated via the two-step method exhibited optimal performance compared to TiO2/NPB device with top NPB layer and TiO2 NWA device. In dark conditions, the TiO2/NPB heterojunction device without top NPB was found to possess the capacity of depleting majority carriers, thereby providing improved dark resistivity to limit the dark current (Id). Under UV illumination, the depleting effect could be eliminated by the dissociation and accumulation of photo generated carriers between pn heterojunction, leading to increased carrier density and photo-conductivity. It cleared up the high barrier due to the removal of top NPB layer, which was beneficial for hot electron transport than the device with top NPB layer under illumination, thereby achieving an enhanced light current (Il) to Id ratio of 1.67 * 104. A simple technology is provided to prepare organic-inorganic hybrid one-dimensional array heterostructure, which plays a remarkable role in the working of the UV detector, enhancing photo conductivity and dark-resistivity of the device. PMID- 28643839 TI - A visible-light-activated rhodium complex in enantioselective conjugate addition of alpha-amino radicals with Michael acceptors. AB - We report an efficient enantioselective conjugate addition of photogenerated alpha-amino radicals to Michael acceptors catalyzed by a newly prepared chiral-at metal rhodium complex. This protocol shows that a single Rh(iii) complex can serve not only as a Lewis acid but also as a photoredox catalyst to control the stereoselectivity during the bond formation. PMID- 28643840 TI - Synchronization of excitable cardiac cultures of different origin. AB - In the present work, we investigated the synchronization of electrical activity in cultured cardiac cells of different origin put in direct contact. In the first set of experiments synchronization was studied in the primary culture cells of neonatal rats taken at different developmental ages, and in the second - in the neonatal rat cardiomyocytes and HL-1 cells. The electrical excitation of cells was recorded using the calcium transient marker Fluor-4. In the confluent cell layers created with the aid of a specially devised mask, the excitation waves and their propagation between areas occupied by cells of different origin were observed. On the level of individual cells, their contact and synchronization was monitored with the aid of scanning fluorescence microscopy. It was found that populations of cultured cells of different origin are able to synchronize, suggesting the formation of electrical coupling between them. The results obtained may be considered as a proof of concept that implanted alien grafted cells are able to create electrical coupling with the host cardiac tissue. PMID- 28643843 TI - Perisylvian, including insular, childhood epilepsy: Presurgical workup and surgical outcome. AB - OBJECTIVE: To report the presurgical workup, surgical procedures, and outcomes in a series of pediatric patients with drug-resistant epilepsy involving the perisylvian/insular regions. METHODS: We retrospectively assessed 16 pediatric patients affected by drug-resistant focal epilepsy involving perisylvian/insular regions, who consecutively underwent tailored resective surgery. All patients underwent a detailed presurgical workup, which included the analysis of the anatomoelectroclinical correlations with scalp electroencephalography (EEG) and/or with stereo-electroencephalography (SEEG), brain magnetic resonance imaging (MRI), and comprehensive cognitive and neuropsychological evaluations. After surgery, all patients underwent serial clinical and laboratory evaluations. RESULTS: Focal motor seizures restricted to perioral area, associated with symptoms related to the surrounding areas (as auditory hallucinations, unpleasant paresthesia, fear, and epigastric sensation), characterized the ictal semiology in 75% of patients. In 50%, autonomic manifestations were present and in 56% subjective manifestations were reported. The 50% of the patients underwent SEEG with insular sampling to better define the epileptogenic zone. In all patients, the insular cortex was always part of the epileptogenic zone, and tailored resections also involved, with variable degree, the frontal, parietal, and temporal opercula. Preoperatively, the neuropsychological assessment revealed impairments in specific cognitive functions and mild or moderate cognitive compromise in 88% of the patients. Postoperatively, one patient had permanent slight hemiparesis. At the most recent follow-up (median 39 months), seizure outcome was satisfactory in 69% of patients: seven patients were completely seizure-free (Engel class Ia), two were free of disabling seizure (class Ic), and two had rare disabling seizures (class II). The cognitive functioning remained unchanged in 62%, and improved in 38%. SIGNIFICANCE: The assessment of perisylvian/insular epilepsy in children is particularly challenging. However, tailored resections based on a careful presurgical evaluation, including SEEG recording, may lead to a good seizure control and to a better overall outcome. PMID- 28643844 TI - Longitudinal Relations Among Positivity, Perceived Positive School Climate, and Prosocial Behavior in Colombian Adolescents. AB - Bidirectional relations among adolescents' positivity, perceived positive school climate, and prosocial behavior were examined in Colombian youth. Also, the role of a positive school climate in mediating the relation of positivity to prosocial behaviors was tested. Adolescents (N = 151; Mage of child in Wave 1 = 12.68, SD = 1.06; 58.9% male) and their parents (N = 127) provided data in two waves (9 months apart). A model of bidirectional relations between positivity and perceived positive school climate emerged. In addition, adolescents with higher levels of perceived positive school climate at age 12 showed higher levels of prosocial behaviors in the following year. Positive school climate related positivity to adolescents' prosocial behavior over time. PMID- 28643845 TI - On the advancement of therapeutic penality: therapeutic authority, personality science and the therapeutic community. AB - In this article I examine the advancement of therapeutic penality in the UK, a penal philosophy that reimagines prison policy, practices and environments utilising psychological knowledge. Adopting a historical approach, I show how modern therapeutic penality is linked to the emergence of personality science in the nineteenth century and the development of the democratic therapeutic community (DTC) model in the twentieth century. I outline how at the turn of the twenty-first century a catalytic event generated a moral panic that led the British government to mobilise psychological knowledge and technologies in an attempt to manage dangerous people with severe personality disorder. Tracing subsequent developments, I argue psychological ways of talking, thinking and acting have obtained unparalleled salience in domains of penality and, in turn, radically transformed the conditions of imprisonment. PMID- 28643846 TI - Feeding behaviour of generalist pests on Brassica juncea: implication for manipulation of glucosinolate biosynthesis pathway for enhanced resistance. AB - Differential accumulation of plant defence metabolites has been suggested to have important ecological consequence in the context of plant-insect interactions. Feeding of generalist pests on Brassica juncea showed a distinct pattern with selective exclusion of leaf margins which are high in glucosinolates. Molecular basis of this differential accumulation of glucosinolates could be explained based on differential expression profile of BjuMYB28 homologues, the major biosynthetic regulators of aliphatic glucosinolates, as evident from quantitative real-time PCR and promoter:GUS fusion studies in allotetraploid B. juncea. Constitutive overexpression of selected BjuMYB28 homologues enhanced accumulation of aliphatic glucosinolates in B. juncea. Performance of two generalist pests, Helicoverpa armigera and Spodoptera litura larvae, on transgenic B. juncea plants were poor compared to wild-type plants in a no-choice experiment. Correlation coefficient analysis suggested that weight gain of H. armigera larvae was negatively correlated with gluconapin (GNA) and glucobrassicanapin (GBN), whereas that of S. litura larvae was negatively correlated with GNA, GBN and sinigrin (SIN). Our study explains the significance and possible molecular basis of differential distribution of glucosinolates in B. juncea leaves and shows the potential of overexpressing BjuMYB28 for enhanced resistance of Brassica crops against the tested generalist pests. PMID- 28643847 TI - NCR1-deficiency diminishes the generation of protective murine cytomegalovirus antibodies by limiting follicular helper T-cell maturation. AB - NKp46/NCR1 is an activating NK-cell receptor implicated in the control of various viral and bacterial infections. Recent findings also suggest that it plays a role in shaping the adaptive immune response to pathogens. Using NCR1-deficient (NCR1gfp/gfp ) mice, we provide evidence for the role of NCR1 in antibody response to mouse cytomegalovirus infection (MCMV). The absence of NCR1 resulted in impaired maturation, function and NK-cell migration to regional lymph nodes. In addition, CD4+ T-cell activation and follicular helper T-cell (Tfh) generation were reduced, leading to inferior germinal center (GC) B-cell maturation. As a consequence, NCR1gfp/gfp mice produced lower amounts of MCMV-specific antibodies upon infection, which correlated with lower number of virus-specific antibody secreting cells in analyzed lymph nodes. PMID- 28643848 TI - The impact of alternative trait-scaling hypotheses for the maximum photosynthetic carboxylation rate (Vcmax ) on global gross primary production. AB - The maximum photosynthetic carboxylation rate (Vcmax ) is an influential plant trait that has multiple scaling hypotheses, which is a source of uncertainty in predictive understanding of global gross primary production (GPP). Four trait scaling hypotheses (plant functional type, nutrient limitation, environmental filtering, and plant plasticity) with nine specific implementations were used to predict global Vcmax distributions and their impact on global GPP in the Sheffield Dynamic Global Vegetation Model (SDGVM). Global GPP varied from 108.1 to 128.2 PgC yr-1 , 65% of the range of a recent model intercomparison of global GPP. The variation in GPP propagated through to a 27% coefficient of variation in net biome productivity (NBP). All hypotheses produced global GPP that was highly correlated (r = 0.85-0.91) with three proxies of global GPP. Plant functional type-based nutrient limitation, underpinned by a core SDGVM hypothesis that plant nitrogen (N) status is inversely related to increasing costs of N acquisition with increasing soil carbon, adequately reproduced global GPP distributions. Further improvement could be achieved with accurate representation of water sensitivity and agriculture in SDGVM. Mismatch between environmental filtering (the most data-driven hypothesis) and GPP suggested that greater effort is needed understand Vcmax variation in the field, particularly in northern latitudes. PMID- 28643849 TI - Prevalence of exposure of heavy metals and their impact on health consequences. AB - Even in the current era of growing technology, the concentration of heavy metals present in drinking water is still not within the recommended limits as set by the regulatory authorities in different countries of the world. Drinking water contaminated with heavy metals namely; arsenic, cadmium, nickel, mercury, chromium, zinc, and lead is becoming a major health concern for public and health care professionals. Occupational exposure to heavy metals is known to occur by the utilization of these metals in various industrial processes and/or contents including color pigments and alloys. However, the predominant source resulting in measurable human exposure to heavy metals is the consumption of contaminated drinking water and the resulting health issues may include cardiovascular disorders, neuronal damage, renal injuries, and risk of cancer and diabetes. The general mechanism involved in heavy metal-induced toxicity is recognized to be the production of reactive oxygen species resulting oxidative damage and health related adverse effects. Thus utilization of heavy metal-contaminated water is resulting in high morbidity and mortality rates all over the world. Thereby, feeling the need to raise the concerns about contribution of different heavy metals in various health related issues, this article has discussed the global contamination of drinking water with heavy metals to assess the health hazards associated with consumption of heavy metal-contaminated water. A relationship between exposure limits and ultimate responses produced as well as the major organs affected have been reviewed. Acute and chronic poisoning symptoms and mechanisms responsible for such toxicities have also been discussed. PMID- 28643850 TI - The role of leadless single-chamber pacemakers in the treatment of vasovagal syncope. PMID- 28643852 TI - Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late-onset schizophrenia-like psychosis (VLOSLP). AB - OBJECTIVE: Antipsychotic drug sensitivity in very late-onset schizophrenia-like psychosis (VLOSLP) is well documented, but poorly understood. This study aimed to investigate blood drug concentration, D2/3 receptor occupancy and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimer's disease (AD). METHODS: Blood drug concentration, prolactin, symptoms and extrapyramidal side-effects (EPS) were serially assessed during dose titration. [18 F]fallypride imaging was used to quantify D2/3 receptor occupancy. Average steady-state amisulpride concentration (Caverage, ng/ml) was estimated by incorporating pharmacokinetic (PK) data into an existing population PK model (25 AD participants, 20 healthy older people). RESULTS: Eight patients (target 20) were recruited (six women; 76 + - 6 years; six treatment compliant; five serially sampled; three with paired imaging data). Mean + - SD symptom reduction was 74 +/ 12% (50-100 mg/day; 92.5 + -39.4 ng/ml). Mild EPS emerged at 96 ng/ml (in AD, severe EPS, 50 mg/day, 60 ng/ml). In three participants, imaged during optimal treatment (50 mg/day; 41-70 ng/ml), caudate occupancy was 44-59% (58-74% in AD across a comparable Caverage). CONCLUSIONS: Despite the small sample size, our findings are highly relevant as they suggest that, as in AD, 50 mg/day amisulpride is associated with >40% occupancy and clinically relevant responses in VLOSLP. It was not possible to fully characterise concentration-occupancy relationships in VLOSLP, and it is thus unclear whether the greater susceptibility of those with AD to emergent EPS was accounted for by increased central drug access. Further investigation of age- and diagnosis-specific threshold sensitivities is warranted, to guide amisulpride prescribing in older people, and therapeutic drug monitoring studies offer a potentially informative future approach. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28643851 TI - Fluorescent competitive aptasensor for detection of aflatoxin B1. AB - Aflatoxin B1 (AFB1 ) is one of the most commonly found mycotoxins in food commodities, particularly cereals, oilseeds, spices and tree nuts. In the past decade, aptamers have come into limelight and emerged as a new biosensing element replacing antibodies in various detection formats. Herein we report a faster, more sensitive, high throughput method for the detection of AFB1 using AFB1 specific aptamers. The assay format was based on a competitive reaction of the fluorescent tagged aptamer specific to AFB1 with the aflatoxin conjugate. Under optimal conditions, a linear range of detection (50 ng to 50 pg) was achieved with a limit of detection (LOD) of 10 pg/mL in the buffer system. Results of inter- and intra-assay revealed that the assay was repeatable with standard deviation in acceptable range. The assay was also validated in food samples such as dried red chilies, groundnut and whole pepper with recovery in the range of 92 to 102% at 10 ng/mL and 100 pg/mL levels. The aptasensor assay was also compared with standard analytical method of HPLC and was found to be more sensitive. This detection technique has the potential to be developed into a biosensor platform for AFB1 detection. PMID- 28643853 TI - Qualitative Analysis of Polyphenols in Macroporous Resin Pretreated Pomegranate Husk Extract by HPLC-QTOF-MS. AB - INTRODUCTION: Pomegranate (Punica granatum L.) husk is a traditional herbal medicine abundant in phenolic compounds and plays some roles in the treatment of oxidative stress, bacterial and viral infection, diabetes mellitus, and acute and chronic inflammation. OBJECTIVE: Identification and determination of polyphenols in macroporous resin pretreated pomegranate husk extract by high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF-MS). METHODS: The total polyphenols of pomegranate husk were prepared by ethanol extraction followed by pretreatment with HPD-300 macroporous resin. The polyphenolic compounds were qualitatively analysed by HPLC QTOF-MS in negative electrospray ionisation (ESI) mode at different collision energy (CE) values. RESULTS: A total of 50 polyphenols were detected in the extract of pomegranate husk, including 35 hydrolysable tannins and 15 flavonoids with distinct retention time, fragmentation behaviours and characteristics, and the accurate mass-to-charge ratios at low, moderate and high CE values. Of these, we identified nine compounds for the first time in the pomegranate husk, including hexahydroxydiphenoyl-valoneoyl-glucoside (HHDP-valoneyl-glucoside), galloyl-O-punicalin, rutin, hyperoside, quercimeritrin, kaempferol-7-O-rhahmano glucoside, luteolin-3'-O-arabinoside, luteolin-3'-O-glucoside, and luteolin-4'-O glucoside. To validate the specificity and accuracy of mass spectrometry in the detection of polyphenols, as compared to the fragmentation pathways of granatin B in detail, including the HHDP-valoneyl- glucoside was first identified from pomegranate husk. CONCLUSION: The study provides evidence for the quality control and development of novel drugs based on polyphenols from the pomegranate husk. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28643854 TI - Olfactory dysfunction in the APP/PS1 transgenic mouse model of Alzheimer's disease: Morphological evaluations from the nose to the brain. AB - Olfactory dysfunction is among the signs of Alzheimer's disease (AD) and cognitive impairment. It has been demonstrated Abeta was associated with olfactory impairment observed in both transgenic mice and in AD patients. In this study, we evaluated amyloid deposition in the olfactory circuit of APP/PS1 transgenic mouse model of AD, which showed olfactory dysfunction in olfactory behavior tests. We found amyloid depositions were widely distributed in the whole olfactory circuit. Moreover, we think these amyloid depositions contribute to neuronal atrophy, dendritic abnormalities, synapse loss and axonal degeneration. Therefore, there was a correlation between olfactory deficits and amyloid deposition. Our findings provide initial insights into the pathological basis of AD-related olfactory dysfunction. PMID- 28643855 TI - Support surfaces in the prevention of pressure ulcers in surgical patients: An integrative review. AB - AIM: To assess the scientific evidence about the types of support surfaces used in intraoperative surgical practice in the prevention of pressure ulcers due to surgical positioning. METHOD: This is an integrative literature review. The electronic databases Cochrane, PubMed, Web of Science, Scopus, Lilacs, and CINAHL were used. The descriptors surgical patients, support surfaces, perioperative care, patient positioning, and pressure ulcer were used in the search strategy. Articles that addressed the use of support surfaces intraoperatively, published between 1990 and 2016, were selected. The PRISMA guidelines were used to structure the review. RESULTS: Of 18 evaluated studies, most were in English, followed by Portuguese and Spanish; most were performed by nurses. The most commonly cited support surfaces were viscoelastic polymer, micropulse mattresses, gel based mattresses, and foam devices. CONCLUSION: There are gaps in knowledge regarding the most efficient support surfaces and the specifications of the products used to prevent pressure ulcers due to surgical positioning. PMID- 28643856 TI - Coding in surgery: impact of a specialized coding proforma in hepato-pancreato biliary surgery. AB - BACKGROUND: Coding inaccuracies in surgery misrepresent the productivity of hospitals and outcome data of surgeons. The aim of this study was to audit the extent of coding inaccuracies in hepato-pancreato-biliary (HPB) surgery and assess the financial impact of introducing a coding proforma. METHODS: Coding of patients who underwent elective HPB surgery over a 3-month period was audited. Codes were based on International Classification of Diseases 10 and Office of Population and Census Surveys-4 codes. A coding proforma was introduced and assessed. New human resource group codes were re-assigned and new tariffs calculated. A cost analysis was also performed. RESULTS: Prior to the introduction of the coding proforma, 42.0% of patients had the incorrect diagnosis and 48.5% had missing co-morbidities. In addition, 14.5% of primary procedures were incorrect and 37.6% had additional procedures that were not coded for at all. Following the introduction of the coding proforma, there was a 27.5% improvement in the accuracy of primary diagnosis (P < 0.001) and 21% improvement in co-morbidities (P = 0.002). There was a 7.2% improvement in the accuracy of coding primary procedures (P = not significant) and a 21% improvement in the accuracy of coding of additional procedures (P < 0.001). Financial loss as a result of coding inaccuracy over our 3-month study period was L56 073 with an estimated annual loss of L228 292. CONCLUSION: Coding in HPB surgery is prone to coding inaccuracies due to the complex nature of HPB surgery and the patient case mix. A specialized coding proforma completed 'in theatre' significantly improves the accuracy of coding and prevents loss of income. PMID- 28643857 TI - Ceria-Zirconia Nanoparticles as an Enhanced Multi-Antioxidant for Sepsis Treatment. AB - The two oxidation states of ceria nanoparticles, Ce3+ and Ce4+ , play a pivotal role in scavenging reactive oxygen species (ROS). In particular, Ce3+ is largely responsible for removing O2- and . OH that are associated with inflammatory response and cell death. The synthesis is reported of 2 nm ceria-zirconia nanoparticles (CZ NPs) that possess a higher Ce3+ /Ce4+ ratio and faster conversion from Ce4+ to Ce3+ than those exhibited by ceria nanoparticles. The obtained Ce0.7 Zr0.3 O2 (7CZ) NPs greatly improve ROS scavenging performance, thus regulating inflammatory cells in a very low dose. Moreover, 7CZ NPs are demonstrated to be effective in reducing mortality and systemic inflammation in two representative sepsis models. These findings suggest that 7CZ NPs have the potential as a therapeutic nanomedicine for treating ROS-related inflammatory diseases. PMID- 28643858 TI - A case of an incidental primary adrenal lymphoma in a patient with newly diagnosed human immunodeficiency virus. PMID- 28643859 TI - Gibberellic and kaurenoic hybrid strigolactone mimics for seed germination of parasitic weeds. AB - BACKGROUND: Parasitic weeds are widespread and cause significant losses in important crops. Their germination requires the detection of crop-derived molecules such as strigolactones. Strigolactone mimics are germination-inducing molecules with the potential to apply a suicidal germination strategy for seed bank control of parasitic weeds. RESULTS: The D-ring, which is instrumental in the germination process of seeds of parasitic weeds, was attached to gibberellin (GA3 ) and kaurenoic acid as the scaffold. It was shown that indeed strigolactone mimics prepared from GA3 and kaurenoic acid are active as stimulants when a D ring is present; some of the mimics are as active as GR24. CONCLUSIONS: The starting molecules were plant hormones that had previous growth-regulating activity in other organisms and the products showed enhanced activity towards parasitic weeds. The information generated may contribute to a better understanding of the germination biochemistry of the weed species used. Further research is required in this area but it is clear that the results are promising. (c) 2017 Society of Chemical Industry. PMID- 28643860 TI - Subcutaneous defibrillators for dialysis patients. AB - Defibrillation can be successfully provided by the subcutaneous implantable cardioverter defibrillator (ICD) without the leads. In contrast, traditional ICDs require leads that can cause central venous stenosis, lead-induced endocarditis, and carry the risk of tricuspid regurgitation by valve adhesion, perforation, coaptation interference, or entanglement. Central venous stenosis, infection, and tricuspid regurgitation are all critically important considerations in hemodialysis patients. Recent reports are supporting the use of subcutaneous ICDs in renal patients maintained on long-term hemodialysis. This article provides the risks associated with leads of traditional defibrillators and raises awareness of the subcutaneous ICD and their benefits for hemodialysis patients. PMID- 28643861 TI - Challenges in the Development of Novel Cardiovascular Therapies. AB - Cardiovascular disease accounts for nearly one in three deaths globally, but few novel therapies have reached patients and clinicians in recent years. This translational report reviews trends in the development and approval of cardiovascular drugs and evaluates recent innovation in the field of cardiovascular disease therapeutics. New policies are needed to better support the development of safe and effective therapies with the greatest potential to improve patient health outcomes. PMID- 28643862 TI - Tumor angiogenesis revisited: Regulators and clinical implications. AB - Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases. PMID- 28643864 TI - Hydroxyacetone: A Glycerol-Based Platform for Electrocatalytic Hydrogenation and Hydrodeoxygenation Processes. AB - Here, we propose the use of hydroxyacetone, a dehydration product of glycerol, as a platform for the electrocatalytic synthesis of acetone, 1,2-propanediol, and 2 propanol. 11 non-noble metals were investigated as electrode materials in combination with three different electrolyte compositions toward the selectivity, Coulombic efficiency (CE), and reaction rates of the electrocatalytic hydrogenation (formation of 1,2-propanediol) and hydrodeoxygenation (formation of acetone and propanol) of hydroxyacetone. With a selectivity of 84.5 %, a reaction rate of 782 mmol h-1 m-2 and a CE of 32 % (for 0.09 m hydroxyacetone), iron electrodes, in a chloride electrolyte, yielded the best 1,2 propanediol formation. A further enhancement of the performance can be achieved upon increasing the educt concentration to 0.5 m, yielding a reaction rate of 2248.1 mmol h-1 m-2 and a CE of 64.5 %. Acetone formation was optimal at copper and lead electrodes in chloride solution, with lead showing the lowest tendency of side product formation. 2-propanol formation can be achieved using a consecutive oxidation of the formed acetone (at iron electrodes). 1-propanol formation was observed only in traces. PMID- 28643863 TI - Design of Iron(II) Phthalocyanine-Derived Oxygen Reduction Electrocatalysts for High-Power-Density Microbial Fuel Cells. AB - Iron(II) phthalocyanine (FePc) deposited onto two different carbonaceous supports was synthesized through an unconventional pyrolysis-free method. The obtained materials were studied in the oxygen reduction reaction (ORR) in neutral media through incorporation in an air-breathing cathode structure and tested in an operating microbial fuel cell (MFC) configuration. Rotating ring disk electrode (RRDE) analysis revealed high performances of the Fe-based catalysts compared with that of activated carbon (AC). The FePc supported on Black-Pearl carbon black [Fe-BP(N)] exhibits the highest performance in terms of its more positive onset potential, positive shift of the half-wave potential, and higher limiting current as well as the highest power density in the operating MFC of (243+/-7) MUW cm-2 , which was 33 % higher than that of FePc supported on nitrogen-doped carbon nanotubes (Fe-CNT(N); 182+/-5 MUW cm-2 ). The power density generated by Fe-BP(N) was 92 % higher than that of the MFC utilizing AC; therefore, the utilization of platinum group metal-free catalysts can boost the performances of MFCs significantly. PMID- 28643865 TI - Characterization and biological function of milk-derived miRNAs. AB - SCOPE: Breastfeeding is associated with reduced risk of infection, immune mediated disorders, obesity, and even cancer. Recently it was found that breast milk contains a variety of microRNAs (miRNAs) in the skim and fat layer that can be transferred to infants, and appear to play important roles in those biological functions. METHODS AND RESULTS: This study applied next generation sequencing and quantitative real-time PCR analysis to determine the miRNA expression profile of the skim and fat fraction of human, goat, and bovine milk as well as infant formulas. Human and mammalian milk were found to contain known advantageous miRNAs in exosomes and also in the fat layer. These miRNAs are highly conserved in human, bovine and goat milk. However, they were not detected in several infant formulas. Further, miRNAs present in milk were able to enter normal and tumor cells and affect their biological functions. Following incubation of milk derived human miRNA with normal and cancer cells, the expression of miRNA-148a was upregulated and the expression of the DNA methyltransferase1 target gene of miRNA 148a was down regulated. CONCLUSION: These results reinforce previous findings on the importance of miRNA in breast milk. Future studies should concentrate on the addition of miRNA to infant formulas. PMID- 28643866 TI - Strategic communication related to academic performance: Evidence from China. AB - We examined a range of forms of strategic communication relevant to academic performance among 151 seventh- and eleventh-grade adolescents in China. Participants were asked to rate the frequency of their engagement of strategic communication and to evaluate the possible motives for each strategy. The most commonly adopted strategy was to give a vague response about one's own performance, and the predominant motives for strategic communication were the desires to outcompete others, to be prosocial, and to be modest. Males were more likely than females to focus on gaining social approval, and eleventh graders were more likely than seventh graders to focus on being prosocial and modest when engaging in strategic communication. These findings provide insight into the development of strategic communication beyond Western culture. Statement of contribution What is already known on this subject? Adolescents in the West often hide their effort to appear more competent or to gain social acceptance. Little is known about other communication strategies related to academic performance. Little is known about the development of these strategies in non-Western samples. What does this study add? We show that in China, as in Western cultures, children often engage in strategic communication. We demonstrate links between different forms of strategic communication and specific motives. We demonstrate that strategic communication can be motivated by outcompeting others, by being prosocial, and by being modest. PMID- 28643867 TI - Transfusion-transmitted CMV infection - current knowledge and future perspectives. AB - Transmission of human cytomegalovirus (CMV) via transfusion (TT-CMV) may still occur and remains a challenge in the treatment of immunocompromised CMV seronegative patients, e.g. after stem cell transplantation, and for low birthweight infants. Measures to reduce the risk of TT-CMV have been evaluated in clinical studies, including leucocyte depletion of cellular blood products and/or the selection of CMV-IgG-negative donations. Studies in large blood donor cohorts indicate that donations from newly CMV-IgG-positive donors should bear the highest risk for transmitting CMV infections because they contain the highest levels of CMV-DNA, and early CMV antibodies cannot neutralise CMV. Based on this knowledge, rational strategies to reduce the residual risk of TT-CMV using leucoreduced blood products could be designed. However, there is a lack of evidence that CMV is still transmitted by transfusion of leucoreduced units. In low birthweight infants, most (if not all) CMV infections are caused by breast milk feeding or congenital transmission rather than by transfusion of leucoreduced blood products. For other patients at risk, no definitive data exist about the relative importance of alternative transmission routes of CMV compared to blood transfusion. As a result, only the conduction of well-designed studies addressing strategies to prevent TT-CMV and the thorough examination of presumed cases of TT-CMV will achieve guidance for the best transfusion regimen in patients at risk. PMID- 28643868 TI - The potassium battery: a mobile energy source for transport processes in plant vascular tissues. AB - Contents 1049 I. 1049 II. 1050 III. 1050 IV. 1050 V. 1051 VI. 1051 VII. 1052 VIII. 1052 1053 References 1053 SUMMARY: Plant roots absorb potassium ions from the soil and transport them in the xylem via the transpiration stream to the shoots. There, in source tissues where sufficient chemical energy (ATP) is available, K+ is loaded into the phloem and then transported with the phloem stream to other parts of the plant; in part, transport is also back to the roots. This, at first sight, futile cycling of K+ has been uncovered to be part of a sophisticated mechanism that (1) enables the shoot to communicate its nutrient demand to the root, (2) contributes to the K+ nutrition of transport phloem tissues and (3) transports energy stored in the K+ gradient between phloem cytosol and the apoplast. This potassium battery can be tapped by opening AKT2 like potassium channels and then enables the ATP-independent energization of other transport processes, such as the reloading of sucrose. Insights into these mechanisms have only been possible by combining wet-lab and dry-lab experiments by means of computational cell biology modeling and simulations. PMID- 28643870 TI - Type III metacaspases: calcium-dependent activity proposes new function for the p10 domain. AB - Metacaspases are a subgroup of caspase homologues represented in bacteria, algae and plants. Although type I and type II metacaspases are present in plants, recently discovered and uncharacterized type III metacaspases can only be found in algae which have undergone secondary endosymbiosis. We analysed the expression levels of all 13 caspase homologues in the cryptophyte Guillardia theta in vivo and biochemically characterized its only type III metacaspase, GtMC2, in vitro. Type III metacaspase GtMC2 was shown to be an endopeptidase with a preference for basic amino acids in the P1 position, which exhibited specific N-terminal proteolytic cleavage for full catalytic efficiency. Autolytic processing, as well as the activity of the mature enzyme, required the presence of calcium ions in low millimolar concentrations. In GtMC2, two calcium-binding sites were identified, one with a dissociation constant at low and the other at high micromolar concentrations. We show high functional relatedness of type III metacaspases to type I metacaspases. Moreover, our data suggest that the low affinity calcium-binding site is located in the p10 domain, which contains a well conserved N-terminal region. This region can only be found in type I/II/III metacaspases, but is absent in calcium-independent caspase homologues. PMID- 28643869 TI - Mechanotransduction properties of the cytoplasmic tail of PECAM-1. AB - BACKGROUND INFORMATION: Vascular endothelial cells (ECs) are a well-known cell system used in the study of mechanobiology. Using cultured ECs, we found that platelet EC adhesion molecule 1 (PECAM-1, CD31), a cell adhesion protein localised to regions of EC-EC contact, was rapidly tyrosine phosphorylated in ECs exposed to shear or cyclic stretch. Src-homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) binds phosphorylated PECAM-1 and activates the extracellular signal-regulated kinase1/2 (ERK1/2) signalling cascade, a known flow-activated signalling pathway. RESULTS: Although PECAM-1 tyrosine phosphorylation is characterised in ECs exposed to fluid shear stress, it is less well demonstrated in the cells stretched cyclically. Thus, we first show that PECAM-1 is tyrosine-phosphorylated in ECs cyclically stretched. We hypothesise that when an external force is applied to a monolayer of ECs, the force is directly transmitted to PECAM-1 which is then stretched and phosphorylation sites in its cytoplasmic domain are exposed and phosphorylated. This hypothesis requires the presence of any stretchable structure within the PECAM-1 cytoplasmic domain. Force spectroscopy measurements were performed with a construct containing cytoplasmic PECAM-1 domains inserted between I27 motifs, a recombinant string of the structural elements from titin. This strategy allowed us to identify the events in which a single molecule is being pulled and to detect the unravelling of the cytoplasmic domain of PECAM-1 by force. The response by PECAM 1 to mechanical loading was heterogeneous but with magnitudes as high as or higher than the naturally force bearing I27 domains. CONCLUSIONS: The PECAM-1 cytoplasmic domain has a structure that can be unfolded by externally applied force and this unfolding of PECAM-1 may be necessary for its phosphorylation, the first step of PECAM-1 mechanosignalling. SIGNIFICANCE: When EC monolayers are mechanically stimulated, the PECAM-1 found at EC contacts is phosphorylated. We have proposed that under these conditions, the cytoplasmic domain of PECAM-1 is unfolded, which then exposes a phosphorylation site, allowing it to be accessed. The stretch induced unfolding is essential to this model of PECAM-1 mechanosignalling. In this study, we investigate whether the cytoplasmic domain of PECAM-1 has a stretchable structure, and the results are in line with our hypothesis. PMID- 28643871 TI - Colonic lipoma causing intussusception: a case for colonoscopic surveillance? PMID- 28643874 TI - 2,6-Bis(diazaboryl)pyridine: A Superbasic Sterically Demanding Pyridine Ligand. AB - Herein a convenient one-pot route to a sterically demanding superbasic pyridine is presented. Functionalization of the 2- and 6-positions with the strongly sigma donating boryl-groups shifts the calculated gas phase basicity of the pyridine nitrogen atom to 1012 kJ mol-1 , which outperforms the "proton sponge" 1,8 bis(dimethylamino)naphthalene (996 kJ mol-1 ). The diazaboryl groups are oriented orthogonally to the pyridine ring and do not block the N-position, which resembles the geometry of commonly used N-heterocyclic carbenes. This allows the substituted pyridine to be used as a neutral N-donor ligand in coordination chemistry that is demonstrated herein with the Lewis adducts of haloboranes. Contrary to NHCs, which can form extraordinarily stable adducts, the pyridine ligand is intended to act as a weaker-coordinating alternative and could allow for alternative ligand chemistry. PMID- 28643873 TI - Increased expression of (immuno)proteasome subunits during epileptogenesis is attenuated by inhibition of the mammalian target of rapamycin pathway. AB - OBJECTIVE: Inhibition of the mammalian target of rapamycin (mTOR) pathway reduces epileptogenesis in various epilepsy models, possibly by inhibition of inflammatory processes, which may include the proteasome system. To study the role of mTOR inhibition in the regulation of the proteasome system, we investigated (immuno)proteasome expression during epileptogenesis, as well as the effects of the mTOR inhibitor rapamycin. METHODS: The expression of constitutive (beta1, beta5) and immunoproteasome (beta1i, beta5i) subunits was investigated during epileptogenesis using immunohistochemistry in the electrical post-status epilepticus (SE) rat model for temporal lobe epilepsy (TLE). The effect of rapamycin was studied on (immuno)proteasome subunit expression in post-SE rats that were treated for 6 weeks. (Immuno)proteasome expression was validated in the brain tissue of patients who had SE or drug-resistant TLE and the effect of rapamycin was studied in primary human astrocyte cultures. RESULTS: In post-SE rats, increased (immuno)proteasome expression was detected throughout epileptogenesis in neurons and astrocytes within the hippocampus and piriform cortex and was most evident in rats that developed a progressive form of epilepsy. Rapamycin-treated post-SE rats had reduced (immuno)proteasome protein expression and a lower number of spontaneous seizures compared to vehicle-treated rats. (Immuno)proteasome expression was also increased in neurons and astrocytes within the human hippocampus after SE and in patients with drug-resistant TLE. In vitro studies using cultured human astrocytes showed that interleukin (IL)-1beta induced (immuno)proteasome gene expression could be attenuated by rapamycin. SIGNIFICANCE: Because dysregulation of the (immuno)proteasome system is observed before the occurrence of spontaneous seizures in rats, is associated with progression of epilepsy, and can be modulated via the mTOR pathway, it may represent an interesting novel target for drug treatment in epilepsy. PMID- 28643872 TI - Circulating microRNA as candidates for early embryonic viability in cattle. AB - Blood-borne extracellular vesicles (i.e., exosomes and microvesicles) carrying microRNAs (miRNAs) could make excellent biomarkers of disease and different physiologic states, including pregnancy status. We tested the hypothesis that circulating extracellular vesicle-derived miRNAs might differentiate the pregnancy status of cows that had maintained pregnancy to Day 30 from non pregnant cows or from those that exhibited embryonic mortality between Days 17 and 30 of gestation. Cows were randomly assigned for artificial insemination with fertile semen (n = 36) or dead semen (n = 8; control group) on Day 0 (day of estrus). Blood was collected from all animals on Day 0 and on Days 17 and 24 after artificial insemination. Cows receiving live sperm were retrospectively classified as pregnant on Day 30 (n = 17) or exhibiting embryonic mortality between Days 17 and 30 (n = 19). Extracellular vesicles from Day 17 and 24 samples were isolated from serum using ultra-centrifugation, and their presence was confirmed by nanoparticle tracking and Western blot analyses (for CD81) prior to RNA extraction. MicroRNA sequencing was performed on pregnant, embryonic mortality, and control cows (n = 4 per day), for a total of 24 independent reactions. In total, 214 miRNAs were identified in serum, 40 of which were novel. Based on differential abundance parameters, we identified 32 differentially abundant loci, representing 27 differentially abundant mature miRNA. At Days 17 and 24, specific miRNAs (e.g., miR-25, -16b, and -3596) were identified that differentiated the pregnancy status. In summary, we identified several circulating extracellular vesicles derived miRNAs that differ in abundance between embryonic mortality and pregnant cows. PMID- 28643876 TI - Editorial Comment to Retropubic tissue fixation system tensioned mini-sling carried out under local anesthesia cures stress urinary incontinence and intrinsic sphincter deficiency: 1-year data. PMID- 28643875 TI - Prediction of severe pre-eclampsia/HELLP syndrome by combination of sFlt-1, CT pro-ET-1 and blood pressure: exploratory study. AB - OBJECTIVES: To evaluate the performance of a combination of angiogenic and vasoactive biomarkers to predict the development of severe pre-eclampsia (PE)/HELLP syndrome in the third trimester. METHODS: Included were 215 women referred in the third trimester to an obstetric outpatient clinic with suspected PE (mean gestational age, 35 + 4 weeks), and 94 with normal pregnancy attending a midwife clinic. Cases were categorized as having subclinical PE, essential hypertension, gestational hypertension, moderate PE, and severe PE/HELLP syndrome. Blood samples were analyzed by immunoassay and groups were compared with respect to potential clinical and biochemical biomarkers, with the primary outcome being development of severe PE/HELLP syndrome within 1 week and within 2 weeks of analysis. The most promising markers were also assessed in combination. RESULTS: In the patients presenting with mild to moderate symptoms of PE, the individual markers which performed best for the prediction of progression to severe PE/HELLP syndrome within 1 week and within 2 weeks of biomarker evaluation were C-terminal pro-endothelin-1 (CT-pro-ET-1) (area under the receiver-operating characteristics curve (AUC), 0.82 and 0.78, respectively), soluble fms-like tyrosine kinase-1 (sFlt-1) (AUC, 0.81 and 0.76), systolic blood pressure (AUC, 0.80 and 0.68) and midregional pro-atrial natriuretic peptide (AUC, 0.79 and 0.77). The combination of biomarkers with the best performance was CT-pro-ET-1, sFlt-1 and systolic blood pressure, achieving an AUC of 0.94 for prediction of development of severe PE/HELLP syndrome within 1 week and an AUC of 0.83 for prediction of their development within 2 weeks of biomarker evaluation. CONCLUSIONS: The performance of CT-pro-ET-1 for prediction of the development of PE/HELLP syndrome in the third trimester was promising, especially in combination with sFlt-1 and systolic blood pressure. This was an exploratory study and our findings should be confirmed in further studies. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28643877 TI - Cerebral haemodynamic response to somatosensory stimulation in neonatal lambs. AB - KEY POINTS: Cerebral haemodynamic response to neural stimulation has been extensively studied in adults, but little is known about cerebral haemodynamic response in the fetal and neonatal brain. The present study describes the cerebral haemodynamic response measured by near infrared spectroscopy to somatosensory stimulation in newborn lambs, in comparison to recent findings in fetal sheep. The cerebral haemodynamic responses in the newborn lamb brain can involve an increase in oxyhaemoglobin (oxyHb), or a decrease of oxyHb suggestive of reduced perfusion and oxygenation. Positive correlations between changes in oxyHb and mean arterial blood pressure were found in newborn but not fetal sheep, which suggests the result is unlikely to be due to immature autoregulation alone. In contrast to adult studies, hypercapnia increased the changes in cerebral blood flow and oxyHb in most of the lambs in response to somatosensory stimulation. ABSTRACT: The neurovascular coupling response has been defined for the adult brain, but in the neonate non-invasive measurement of local cerebral perfusion using near infrared spectroscopy or blood oxygen level-dependent functional magnetic resonance imaging have yielded variable and inconsistent results, including negative responses suggesting decreased perfusion and localized tissue tissue hypoxia. Also, the impact of permissive hypercapnia (P aC O2 > 50 mmHg) in the management of neonates on cerebrovascular responses to somatosensory input is unknown. Using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (DeltaoxyHb, DeltadeoxyHb) in eight anaesthetized newborn lambs, we studied the cerebral haemodynamic functional response to left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8 s. Stimulation always produced a somatosensory evoked response, and superficial cortical perfusion measured by laser Doppler flowmetry predominantly increased following median nerve stimulation. However, with 1.8 s stimulation, oxyHb responses in the contralateral hemisphere were either positive (i.e. increased oxyHb), negative, or absent; and with 4.8 and 7.8 s stimulations, both positive and negative responses were observed. Hypercapnia increased baseline oxyHb and total Hb consistent with cerebral vasodilatation, and six of seven lambs tested showed increased Deltatotal Hb responses after the 7.8 s stimulation, among which four lambs also showed increased DeltaoxyHb responses. In two of three lambs, the negative DeltaoxyHb response became a positive pattern during hypercapnia. These results show that instead of functional hyperaemia, somatosensory stimulation can evoke negative (decreased oxyHb, total Hb) functional responses in the neonatal brain suggestive of decreased local perfusion and vasoconstriction, and that hypercapnia produces both baseline hyperperfusion and increased functional hyperaemia. PMID- 28643878 TI - Frameless stereotactic radiotherapy alone and combined with temozolomide for presumed canine gliomas. AB - We evaluated stereotactic volume modulated arc radiotherapy (VMAT) for canine gliomas, alone (radiotherapy [RT]) and in combination with temozolomide (RT + TMZ), compared with palliation. Overall and disease-specific survival times were estimated. Thirty dogs were palliated, 22 dogs were treated with RT and 20 with RT + TMZ. Complete and partial responses were observed in 63.2% and 90.9% of patients in the RT and RT + TMZ arms, respectively, that were alive at 1 year. Median survival in the palliation arm was 94 days (95% conformity index [CI] 87/101). Median survivals of the RT arm (383 days, 95% CI 276/490) and RT+TMZ arm (420 days, 95% CI 280/560) were not significantly different (P = .61). Positive correlation with survival was found both for the ratio between target and brain (relative) volume of the tumour of <5% (P = .013) and for a clinical presentation with normal mentation (P = .032). VMAT is feasible and effective for canine brain gliomas. Combining this therapy with TMZ did not elicit any additional improvement in survival time. PMID- 28643879 TI - Inter-subject alignment of MEG datasets in a common representational space. AB - Pooling neural imaging data across subjects requires aligning recordings from different subjects. In magnetoencephalography (MEG) recordings, sensors across subjects are poorly correlated both because of differences in the exact location of the sensors, and structural and functional differences in the brains. It is possible to achieve alignment by assuming that the same regions of different brains correspond across subjects. However, this relies on both the assumption that brain anatomy and function are well correlated, and the strong assumptions that go into solving the under-determined inverse problem given the high dimensional source space. In this article, we investigated an alternative method that bypasses source-localization. Instead, it analyzes the sensor recordings themselves and aligns their temporal signatures across subjects. We used a multivariate approach, multiset canonical correlation analysis (M-CCA), to transform individual subject data to a low-dimensional common representational space. We evaluated the robustness of this approach over a synthetic dataset, by examining the effect of different factors that add to the noise and individual differences in the data. On an MEG dataset, we demonstrated that M-CCA performs better than a method that assumes perfect sensor correspondence and a method that applies source localization. Last, we described how the standard M-CCA algorithm could be further improved with a regularization term that incorporates spatial sensor information. Hum Brain Mapp 38:4287-4301, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28643880 TI - Effects of discrete bioactive microbial volatiles on plants and fungi. AB - Plants live in association with microorganisms, which are well known as a rich source of specialized metabolites, including volatile compounds. The increasing numbers of described plant microbiomes allowed manifold phylogenetic tree deductions, but less emphasis is presently put on the metabolic capacities of plant-associated microorganisms. With the focus on small volatile metabolites we summarize (i) the knowledge of prominent bacteria of plant microbiomes; (ii) present the state-of-the-art of individual (discrete) microbial organic and inorganic volatiles affecting plants and fungi; and (iii) emphasize the high potential of microbial volatiles in mediating microbe-plant interactions. So far, 94 discrete organic and five inorganic compounds were investigated, most of them trigger alterations of the growth, physiology and defence responses in plants and fungi but little is known about the specific molecular and cellular targets. Large overlaps in emission profiles of the emitters and receivers render specific volatile organic compound-mediated interactions highly unlikely for most bioactive mVOCs identified so far. PMID- 28643881 TI - Virucides in apiculture: persistence of surrogate enterovirus under simulated field conditions. AB - BACKGROUND: Honeybee viruses have been recognized as being among the most important factors leading to colony losses worldwide. Colony food and faeces are regarded as possible sources of infectious viruses able to contaminate the environment and equipment of apiaries. Thus, methods for elimination of viruses are required. No cell culture assay for testing the effect of disinfectants on honeybee viruses is yet available. Therefore, surrogate virus was employed for testing of the efficacy of iodophor- and peracetic acid-based disinfectants in combination with six organic contaminants at +6 degrees C and +22 degrees C. Moreover, we evaluated the persistence of the surrogate in honey at +6 degrees C, +22 degrees C, and +50 degrees C. RESULTS: Iodophor-based disinfectant showed a maximum reduction of virus titre of 3.4 log10 . Peracetic acid reduced the titre (>=4 log10 ) only at 22 degrees C and without yeast extract/bovine serum albumin. After 25 days of incubation of the virus - honey mix, no decrease of virus titre was observed at +6 degrees C, whereas a significant reduction (3.5 log10 ) was found at +50 degrees C already after 1 day. CONCLUSIONS: Both tested disinfectants can serve as appropriate virucides in apiaries. The effect of peracetic acid significantly depended on temperature and organic contaminants. The iodophor-based disinfectant showed a stable antiviral effect at different temperatures and with different contaminants. (c) 2017 Society of Chemical Industry. PMID- 28643882 TI - The history and current status of glyphosate. AB - Glyphosate is the only herbicide to target the enzyme 5-enolpyruvyl-3-shikimate phosphate synthase (EPSPS). It is a high use rate, non-selective herbicide that translocates primarily to metabolic sinks, killing meristematic tissues away from the application site. Its phloem-mobile properties and slow action in killing weeds allow the herbicide to move throughout the plant to kill all meristems, making it effective for perennial weed control. Since commercialization in 1974, its use has grown to dominate the herbicide market. Much of its use is on transgenic, glyphosate-resistant crops (GRCs), which have been the dominant transgenic crops worldwide. GRCs with glyphosate provided the most effective and inexpensive weed management technology in history for a decade or more. However, as a consequence of the rapid increase in glyphosate-resistant (GR) weeds, the effectiveness of glyphosate use in GRCs is declining. Critics have claimed that glyphosate-treated GRCs have altered mineral nutrition and increased susceptibility to plant pathogens because of glyphosate's ability to chelate divalent metal cations, but the complete resistance of GRCs to glyphosate indicates that chelating metal cations do not contribute to the herbicidal activity or significantly affect mineral nutrition. The rates of increases in yields of maize, soybean, and cotton in the USA have been unchanged after high adoption rates of GRCs. Glyphosate is toxic to some plant pathogens, and thereby can act as a fungicide in GRCs. Ultra-low doses of glyphosate stimulate plant growth in glyphosate-susceptible plants by unknown mechanisms. Despite rapid and widespread increases in GR weeds, glyphosate use has not decreased. However, as GR weeds increase, adoption of alternative technologies will eventually lead to decreased use. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. PMID- 28643883 TI - Is ridge preservation/augmentation at periodontally compromised extraction sockets safe? A retrospective study. AB - OBJECTIVES: This study aimed to evaluate the safety of ridge preservation/augmentation procedures when performed at compromised extraction sockets. METHODS: Patients subject to ridge preservation/augmentation at periodontally compromised sockets at Seoul National University Dental Hospital (SNUDH) were evaluated in a chart review. Tooth extractions due to acute infection were not included in our study as chronically formed lesions are the only lesions that can be detected from radiographic images. If inflammatory symptoms persisted following ridge preservation/augmentation and antimicrobial and anti-inflammatory therapy, the patient was categorized as a re-infection case and implanted biomaterial removed. RESULTS: Of 10,060 patients subject to tooth extractions at SNUDH, 2011 through 2015, 297 cases meeting inclusion criteria were reviewed. The severity and type of lesions were not specific because extracting data was only done by radiographic images and chart records. The review identified eight patients exhibiting inflammatory symptoms that required additional antimicrobial and anti-inflammatory therapy. Within this group, re infection occurred in two patients requiring biomaterials removal. The final safety rate for the ridge preservation/augmentation was 99.3%. None of the demographic factors, systemic conditions or choice of biomaterial affected the safety of ridge preservation/augmentation. CONCLUSION: Alveolar ridge preservation/augmentation at periodontally compromised sockets appears safe following thorough removal of infectious source. PMID- 28643885 TI - The Direct Catalytic Oxidation of Methane to Methanol-A Critical Assessment. AB - Despite the large number of disparate approaches for the direct selective partial oxidation of methane, none of them has translated into an industrial process. The oxidation of methane to methanol is a difficult, but intriguing and rewarding, task as it has the potential to eliminate the prevalent natural gas flaring by providing novel routes to its valorization. This Review considers the synthesis of methanol and methanol derivatives from methane by homogeneous and heterogeneous pathways. By establishing the severe limitations related to the direct catalytic synthesis of methanol from methane, we highlight the vastly superior performance of systems which produce methanol derivatives or incorporate specific measures, such as the use of multicomponent catalysts to stabilize methanol. We thereby identify methanol protection as being indispensable for future research on homogeneous and heterogeneous catalysis. PMID- 28643886 TI - Ileocolic intussusception from an inflammatory fibroid polyp: a rare cause of adult small bowel obstruction. PMID- 28643884 TI - Learning climate and feedback as predictors of dental students' self-determined motivation: The mediating role of basic psychological needs satisfaction. AB - AIM: The aim of this study was to test the mediating role of the satisfaction of dental students' basic psychological needs of autonomy, competence and relatedness on the association between learning climate, feedback and student motivation. The latter was based on the self-determination theory's concepts of differentiation of autonomous motivation, controlled motivation and amotivation. METHODS: A cross-sectional correlational study was conducted where 924 students completed self-reported questionnaires measuring motivation, perception of the learning climate, feedback and basic psychological needs satisfaction. Descriptive statistics, Cronbach's alpha scores and bivariate correlations were computed. Mediation of basic needs on each predictor-outcome association was tested based on a series of regression analyses. Finally, all variables were integrated into one structural equation model, controlling for the effects of age, gender and year of study. RESULTS: Cronbach's alpha scores were acceptable (.655 to .905). Correlation analyses showed positive and significant associations between both an autonomy-supportive learning climate and the quantity and quality of feedback received, and students' autonomous motivation, which decreased and became negative when correlated with controlled motivation and amotivation, respectively. Regression analyses revealed that these associations were indirect and mediated by how these predictors satisfied students' basic psychological needs. These results were corroborated by the structural equation analysis, in which data fit the model well and regression paths were in the expected direction. CONCLUSION: An autonomy-supportive learning climate and the quantity and quality of feedback were positive predictors of students' autonomous motivation and negative predictors of amotivation. However, this was an indirect association mediated by the satisfaction of students' basic psychological needs. Consequently, supporting students' needs of autonomy, competence and relatedness might lead to optimal types of motivation, which has an important influence on dental education. PMID- 28643887 TI - Personality, dopamine, and Parkinson's disease: Insights from subthalamic stimulation. AB - BACKGROUND: Subthalamic stimulation improves the motor and neuropsychiatric symptoms of Parkinson's disease. However, the impact of this treatment on impulse control and personality is the subject of heavy debate. The objective of this study was to investigate personality changes after subthalamic stimulation. METHODS: Using Cloninger's biosocial model, we assessed personality in 73 Parkinson's disease patients before and 12 months after subthalamic stimulation accompanied by a drastic reduction in dopaminergic medication. Changes in psychobehavioral symptoms were measured using a battery of validated clinical scales (apathy, depression, anxiety, hyperemotionality, mania, psychosis, punding, and impulse control behaviors). RESULTS: One year after surgery, the harm avoidance personality domain total score increased compared with the baseline (+2.8; 34 patients; P < 0.001), as did 3 of its 4 subdomains: anticipatory worry (+0.7; 10 patients; P = 0.005), shyness (+0.6; 7 patients; P = 0.03), and fatigability (+1.1; 10 patients; P = 0.0014). Evolution of the shyness personality trait correlated with the decrease in dopaminergic medication. Total scores in the other personality domains remained unchanged, except for extravagance, a subdomain of novelty seeking, and persistence, a subdomain of reward dependence, which both decreased following surgery (-0.3; 7 patients; and 0.6; 9 patients; P = 0.03 and P = 0.0019, respectively). Although apathy increased, other psychobehavioral symptoms, including impulse control behaviors and neuropsychiatric nonmotor fluctuations, improved. Depression and anhedonia remained stable. Scores in hypodopaminergia and neuropsychiatric nonmotor OFF correlated with harm avoidance. Scores in hyperdopaminergia and neuropsychiatric nonmotor ON correlated with novelty seeking. CONCLUSIONS: When subthalamic stimulation is applied in Parkinson's disease, significant changes in personality traits are observed, which may be related to postoperative tapering of dopaminergic treatment. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28643889 TI - Reply to 'Letter to the Editor' regarding the article 'Should we treat severe vasovagal syncope with a pacemaker?' PMID- 28643888 TI - Combination of citrus polymethoxyflavones, green tea polyphenols, and Lychee extracts suppresses obesity and hepatic steatosis in high-fat diet induced obese mice. AB - SCOPE: SlimTrym(r) is a formulated product composed of citrus polymethoxyflavones (PMFs), green tea extract, and lychee extract. We investigated the effect of dietary SlimTrym(r) on diet-induced obesity and associated non-alcoholic fatty liver disease (NAFLD) in mice. METHODS AND RESULTS: Male C57BL/6 mice were fed a normal diet (ND), high fat diet (HFD) or HFD containing 0.1% or 0.5% SlimTrym(r) for 16 weeks. Dietary SlimTrym(r) significantly reduced weight gain and relative perigonadal, retroperitoneal, mesenteric fat weight as well as the size of adipocyte in HFD-fed mice. SlimTrym(r) supplementation also effectively diminished hepatic steatosis and the serum levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), triacylglycerol (TG), and total cholesterol (TCHO). Down-regulation of peroxisome proliferator activated receptor (PPAR)gamma, sterol regulatory element-binding protein (SREBP) 1, and the activation of AMP-activated protein kinase (AMPK) signaling by SlimTrym(r) in both adipose tissue and liver may be responsible for the observed anti-obesity effects. CONCLUSION: SlimTrym(r) supplementation potentially diminished diet-induced obesity and hepatic steatosis via regulating AMPK signaling and molecules involved in lipid metabolism. PMID- 28643890 TI - Anatomical Evaluation of the Thoracolumbar Nerves Related to the Transversus Abdominis Plane Block Technique in the Dog. AB - Transversus abdominis plane (TAP) is a fascial plane containing the thoracolumbar nerve branches that innervate the abdominal wall. Limited information is available on the anatomical organization of these nerve branches in the dog, which is of great importance for the success of the TAP block anaesthetic technique. The aim of this study was to describe the origin and conformation of thoracolumbar nerves running through the TAP in 20 hemi-abdominal walls of 10 adult mongrel dog cadavers with an average body weight of 12.6 kg (range: 9.6 15.6). The abdominal walls were dissected from superficial to deep direction, the skin and both obliquus externus abdominis and obliquus internus abdominis muscles were dissected and reflected dorsally to expose the transversus abdominis muscle and the thoracolumbar nerve branches located in this plane. The anatomical features of ventral nerve branches were described. The thoracic nerve branches: T7-T12 and costoabdominalis; and the lumbar nerve branches: iliohypogastricus cranialis, iliohypogastricus caudalis, ilioinguinalis and cutaneus femoris lateralis were identified in all the cadavers. Anatomical variations related to the presence or absence within the TAP of the T7, T8 and T9 nerve branches were found. These variations should be taken into account when planning the TAP block technique in dogs. PMID- 28643891 TI - Direct comparison of high-temporal-resolution CINE MRI with Doppler ultrasound for assessment of diastolic dysfunction in mice. AB - Diastolic dysfunction is a sensitive early indicator of heart failure and can provide additional data to conventional measures of systolic function. Transmitral Doppler ultrasound, which measures the one-dimensional flow of blood through the mitral valve, is currently the preferred method for the measurement of diastolic function, but the measurement of the left ventricular volume changes using high-temporal-resolution cinematic magnetic resonance imaging (CINE MRI) is an alternative approach which is emerging as a potentially more robust and user independent technique. Here, we investigated the performance of high-temporal resolution CINE MRI and compared it with ultrasound for the detection of diastolic dysfunction in a mouse model of myocardial infarction. An in-house, high-temporal-resolution, retrospectively gated CINE sequence was developed with a temporal resolution of 1 ms. Diastolic function in mice was assessed using a custom-made, open-source reconstruction package. Early (E) and late (A) left ventricular filling phases were easily identifiable, and these measurements were compared directly with high-frequency, pulsed-wave, Doppler ultrasound measurements of mitral valve inflow. A repeatability study established that high temporal-resolution CINE MRI and Doppler ultrasound showed comparable accuracy when measuring E/A in normal control mice. However, when applied in a mouse model of myocardial infarction, high-temporal-resolution CINE MRI indicated diastolic heart failure (E/A = 0.94 +/- 0.11), whereas ultrasound falsely detected normal cardiac function (E/A = 1.21 +/- 0.11). The addition of high-temporal-resolution CINE MRI to preclinical imaging studies enhances the library of sequences available to cardiac researchers and potentially identifies diastolic heart failure early in disease progression. PMID- 28643893 TI - Cutaneous angiosarcoma: a rare complication post-male breast cancer radiotherapy. PMID- 28643892 TI - Calcitriol exerts an anti-tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response. AB - Osteosarcoma is the most common type of primary bone tumor, and novel therapeutic approaches for this disease are urgently required. To identify effective agents, we screened a panel of Food and Drug Administration (FDA)-approved drugs in AXT cells, our newly established mouse osteosarcoma line, and identified calcitriol as a candidate compound with therapeutic efficacy for this disease. Calcitriol inhibited cell proliferation in AXT cells by blocking cell cycle progression. From a mechanistic standpoint, calcitriol induced endoplasmic reticulum (ER) stress, which was potentially responsible for downregulation of cyclin D1, activation of p38 MAPK, and intracellular production of reactive oxygen species (ROS). Knockdown of Atf4 or Ddit3 restored cell viability after calcitriol treatment, indicating that the ER stress response was indeed responsible for the anti-proliferative effect in AXT cells. Notably, the ER stress response was induced to a lesser extent in human osteosarcoma than in AXT cells, consistent with the weaker suppressive effect on cell growth in the human cells. Thus, the magnitude of ER stress induced by calcitriol might be an index of its anti osteosarcoma effect. Although mice treated with calcitriol exhibited weight loss and elevated serum calcium levels, a single dose was sufficient to decrease osteosarcoma tumor size in vivo. Our findings suggest that calcitriol holds therapeutic potential for treatment of osteosarcoma, assuming that techniques to diminish its toxicity could be established. In addition, our results show that calcitriol could still be safely administered to osteosarcoma patients for its original purposes, including treatment of osteoporosis. PMID- 28643894 TI - Do implicit and explicit belief processing share neural substrates? AB - Humans rely on their ability to infer another person's mental state to understand and predict others' behavior ("theory of mind," ToM). Multiple lines of research suggest that not only are humans able to consciously process another person's belief state, but also are able to do so implicitly. Here we explored how general implicit belief states are represented in the brain, compared to those substrates involved in explicit ToM processes. Previous work on this topic has yielded conflicting results, and thus, the extent to which the implicit and explicit ToM systems draw on common neural bases is unclear. Participants were presented with "Sally-Anne" type movies in which a protagonist was falsely led to believe a ball was in one location, only for a puppet to later move it to another location in their absence (false-belief condition). In other movies, the protagonist had their back turned the entire time the puppet moved the ball between the two locations, meaning that they had no opportunity to develop any pre-existing beliefs about the scenario (no-belief condition). Using a group of independently localized explicit ToM brain regions, we found greater activity for false-belief trials, relative to no-belief trials, in the right temporoparietal junction, right superior temporal sulcus, precuneus, and left middle prefrontal gyrus. These findings extend upon previous work on the neural bases of implicit ToM by showing substantial overlap between this system and the explicit ToM system, suggesting that both abilities might recruit a common set of mentalizing processes/functional brain regions. Hum Brain Mapp 38:4760-4772, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28643895 TI - Light-Switchable Azobenzene-Containing Macromolecules: From UV to Near Infrared. AB - Azobenzene-containing macromolecules (azo-macromolecules) such as azobenzene containing polymers (azopolymers) and azobenzene-functionalized biomacromolecules are photoswitchable macromolecules. Trans-to-cis photoisomerization in conventional azo-macromolecules is induced by ultraviolet (UV) light. However, UV light cannot penetrate deeply into issue and has a very small fraction in sunlight. Therefore, conventional azo-macromolecules are problematic for biomedical and solar-energy-related applications. In this Feature Article, the strategies for constructing visible and near-infrared (NIR) light-responsive azo macromolecules are reviewed, and the potential applications of visible- and NIR light-responsive azo-macromolecules in biomedicine and solar energy conversion are highlighted. The remaining challenges in the field of photoswitchable azo macromolecules are discussed. PMID- 28643896 TI - The Cope Rearrangement of 1,5-Dimethylsemibullvalene-2(4)-d1 : Experimental Evidence for Heavy-Atom Tunneling. AB - As an experimental test of the theoretical prediction that heavy-atom tunneling is involved in the degenerate Cope rearrangement of semibullvalenes at cryogenic temperatures, monodeuterated 1,5-dimethylsemibullvalene isotopomers were prepared and investigated by IR spectroscopy using the matrix isolation technique. As predicted, the less thermodynamically stable isotopomer rearranges at cryogenic temperatures in the dark to the more stable one, while broadband IR irradiation above 2000 cm-1 results in an equilibration of the isotopomeric ratio. Since this reaction proceeds with a rate constant in the order of 10-4 s-1 despite an experimental barrier of Ea =4.8 kcal mol-1 and with only a shallow temperature dependence, the results are interpreted in terms of heavy-atom tunneling. PMID- 28643897 TI - A novel amino acid substitution Trp574Arg in acetolactate synthase (ALS) confers broad resistance to ALS-inhibiting herbicides in crabgrass (Digitaria sanguinalis). AB - BACKGROUND: Crabgrass (Digitaria sanguinalis) is an annual monocotyledonous weed. In recent years, field applications of nicosulfuron have been ineffective in controlling crabgrass populations in Shandong Province, China. To investigate the mechanisms of resistance to nicosulfuron in crabgrass populations, the acetolactate synthase (ALS) gene fragment covering known resistance-confering mutation sites was amplified and sequenced. RESULTS: Dose-response experiments suggested that the resistant population SD13 (R) was highly resistant to nicosulfuron (resistance index R/S = 43.7) compared with the sensitive population SD22 (S). ALS gene sequencing revealed a Trp574Arg substitution in the SD13 population, and no other known resistance-conferring mutations were found. In vitro ALS enzyme assays further confirmed that the SD13 population was resistant to all tested ALS-inhibiting herbicides. The resistance pattern experiments revealed that, compared with SD22, the SD13 population exhibited broad-spectrum resistance to nicosulfuron (43.7-fold), imazethapyr (11.4-fold) and flumetsulam (16.1-fold); however, it did not develop resistance to atrazine, mesotrione and topramezone. CONCLUSIONS: This study demonstrated that Trp574Arg substitution was the main reason for crabgrass resistance to ALS-inhibiting herbicides. To our knowledge, this is the first report of Trp574Arg substitution in a weed species, and is the first report of target-site mechanisms of herbicide resistance for crabgrass. (c) 2017 Society of Chemical Industry. PMID- 28643898 TI - Identification of cross-reactive B-cell epitopes between Bos d 9.0101(Bos Taurus) and Gly m 5.0101 (Glycine max) by epitope mapping MALDI-TOF MS. AB - Exposure to cow's milk constitutes one of the most common causes of food allergy. In addition, exposure to soy proteins has become relevant in a restricted proportion of milk allergic pediatric patients treated with soy formulae as a dairy substitute, because of the cross-allergenicity described between soy and milk proteins. We have previously identified several cross-reactive allergens between milk and soy that may explain this intolerance. The purpose of the present work was to identify epitopes in the purified alphaS1-casein and the recombinant soy allergen Gly m 5.0101 (Gly m 5) using an alpha-casein-specific monoclonal antibody (1D5 mAb) through two different approaches for epitope mapping, to understand cross-reactivity between milk and soy. The 1D5 mAb was immobilized onto magnetic beads, incubated with the peptide mixture previously obtained by enzymatic digestion of the allergens, and the captured peptides were identified by MALDI-TOF MS analysis. On a second approach, the peptide mixture was resolved by RP-HPLC and immunodominant peptides were identified by dot blot with the mAb. Finally, recognized peptides were sequenced by MALDI-TOF MS. This novel MS based approach led us to identify and characterize four peptides on alpha-casein and three peptides on Gly m 5 with a common core motif. Information obtained from these cross-reactive epitopes allows us to gain valuable insight into the molecular mechanisms of cross-reactivity, to further develop new and more effective vaccines for food allergy. PMID- 28643900 TI - Exploring perspectives of young onset dementia caregivers with high versus low unmet needs. AB - BACKGROUND: This study is part of the Research to Assess Policies and Strategies for Dementia in the Young project. Information about specific needs in young onset dementia (YOD) will provide the basis for the development of an e-health intervention to assist caregivers in coping with YOD in several European countries. OBJECTIVE: The aim was to investigate the issues caregivers of people with YOD face. METHODS: A qualitative content analysis method was used to analyse interviews with YOD caregivers. Quantitative data of the Needs in Young Onset Dementia study were used to select caregivers based on a ranking of unmet needs, to capture differences and similarities between caregivers that experienced high levels of unmet needs versus those with low levels of unmet needs. Needs were assessed with the Camberwell Assessment of Needs in the Elderly. RESULTS: Findings revealed the following themes: (i) acceptance; (ii) perception of the relationship; (iii) role adaptation; (iv) Availability of appropriate services; (v) social support; and (vi) awareness in the person with dementia and acceptance of help. Several factors seemed more apparent in the caregivers who experienced few unmet needs opposed to the caregivers who experienced more unmet needs. CONCLUSION: The current study provides an in-depth perspective on the caregiver's experiences and emphasizes specific themes that could be addressed in future interventions. This might contribute to a caring situation in which the caregiver experiences less unmet needs. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28643899 TI - Lack of adaptation during prolonged split-belt locomotion in the intact and spinal cat. AB - KEY POINTS: During split-belt locomotion in humans where one leg steps faster than the other, the symmetry of step lengths and double support periods of the slow and fast legs is gradually restored. When returning to tied-belt locomotion, there is an after-effect, with a reversal in the asymmetry observed in the early split-belt period, indicating that the new pattern was stored within the central nervous system. In this study, we investigated if intact and spinal-transected cats show a similar pattern of adaptation to split-belt locomotion by measuring kinematic variables and electromyography before, during and after 10 min of split belt locomotion. The results show that cats do not adapt to prolonged split-belt locomotion. Our results suggest an important physiological difference in how cats and humans respond to prolonged asymmetric locomotion. ABSTRACT: In humans, gait adapts to prolonged walking on a split-belt treadmill, where one leg steps faster than the other, by gradually restoring the symmetry of interlimb kinematic variables, such as double support periods and step lengths, and by reducing muscle activity (EMG, electromyography). The adaptation is also characterized by reversing the asymmetry of interlimb variables observed during the early split belt period when returning to tied-belt locomotion, termed an after-effect. To determine if cats adapt to prolonged split-belt locomotion and to assess if spinal locomotor circuits participate in the adaptation, we measured interlimb variables and EMG in intact and spinal-transected cats before, during and after 10 min of split-belt locomotion. In spinal cats, only the hindlimbs performed stepping with the forelimbs stationary. In intact and spinal cats, step lengths and double support periods were, on average, symmetric, during tied-belt locomotion. They became asymmetric during split-belt locomotion and remained asymmetric throughout the split-belt period. Upon returning to tied-belt locomotion, symmetry was immediately restored. In intact cats, the mean EMG amplitude of hindlimb extensors increased during split-belt locomotion and remained increased throughout the split-belt period, whereas in spinal cats, EMG amplitude did not change. Therefore, the results indicate that the locomotor pattern of cats does not adapt to prolonged split-belt locomotion, suggesting an important physiological difference in the control of locomotion between cats and humans. We propose that restoring left-right symmetry is not required to maintain balance during prolonged asymmetric locomotion in the cat, a quadruped, as opposed to human bipedal locomotion. PMID- 28643901 TI - Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial. AB - BACKGROUND: Compromised iron status is important in restless legs syndrome pathophysiology. We compared the efficacy and tolerability of ferric carboxymaltose (single intravenous dose) versus placebo for restless legs syndrome treatment in iron-deficient nonanemic patients. METHODS: Patients with moderate to severe restless legs syndrome and serum ferritin < 75 MUg/L (or serum ferritin 75-300 MUg/L and transferrin saturation < 20%) were randomized to ferric carboxymaltose (1000 mg iron) or placebo. Mean change difference between ferric carboxymaltose and placebo in International Restless Legs Syndrome Severity Scale score from baseline to week 4 was the primary end point; week 12 was a secondary end point. RESULTS: Ferric carboxymaltose treatment (n = 59) led to nonsignificant improvement over placebo (n = 51) in International Restless Legs Syndrome Severity Scale score at week 4 (difference [95% confidence interval], 2.5 [-5.93 to 1.02], P = 0.163), reaching significance by week 12 (-4.66 [-8.59 to -0.73], P = 0.021). CONCLUSIONS: In patients who responded to treatment, ferric carboxymaltose may require more time to stabilize restless legs syndrome than previously assumed. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28643902 TI - Modulation of antitumor immunity contributes to the enhanced therapeutic efficacy of liposomal oxaliplatin in mouse model. AB - Immune modulation of the tumor microenvironment has been reported to participate in the therapeutic efficacy of many chemotherapeutic agents. Recently, we reported that liposomal encapsulation of oxaliplatin (l-OHP) within PEGylated liposomes conferred a superior antitumor efficacy to free l-OHP in murine colorectal carcinoma-bearing mice through permitting preferential accumulation of the encapsulated drug within tumor tissue. However, the contribution of the immune-modulatory properties of liposomal l-OHP and/or free l-OHP to the overall antitumor efficacy was not elucidated. In the present study, therefore, we investigated the effect of liposomal encapsulation of l-OHP within PEGylated liposomes on the antitumor immunity in both immunocompetent and immunodeficient mice. Liposomal l-OHP significantly suppressed the growth of tumors implanted in immunocompetent mice, but not in immunodeficient mice. In immunocompetent mice, liposomal l-OHP increased the tumor MHC-1 level and preserved antitumor immunity through decreasing the number of immune suppressor cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, which collectively suppress CD8+ T cell-mediated tumor cells killing. In contrast, free l-OHP ruined antitumor immunity. These results suggest that the antitumor efficacy of liposomal l-OHP is attributed, on the one hand, to its immunomodulatory effect on tumor immune microenvironment that is superior to that of free l-OHP, and on the other hand, to its direct cytotoxic effect on tumor cells. PMID- 28643903 TI - Resolving differences between animal models for expedited orthodontic tooth movement. AB - OBJECTIVE: To highlight differences in commonly used animal models of orthodontic tooth movement (OTM). METHODS: Narrative review. RESULTS: A critical review of the literature on animal models has become increasingly important in the last decade as methods to increase the rate of tooth movement have been intensely sought. We provide a review focusing on the rodent and canine models for expedited OTM and describe the challenges in extrapolation of the results to the clinical practice of orthodontics. We review and contrast the two (rodent, canine) most commonly used animal models for OTM. We then describe animal models to study bone adaptation, remodelling and modelling, which are keys events in describing and quantifying OTM. CONCLUSIONS: Understanding the differences between animal models and their adaptation biology as it relates to OTM is key to make valid conclusions. The rodent model can be used to understand the initial phases of tooth movement. Unlike the dog model, the rodent model does not lend itself to understand prolonged adaptation in response to bodily tooth movement. Extrapolation of rate of tooth movement to humans is more challenging from rodent model data. PMID- 28643904 TI - PTH [1-34]-induced alterations predispose the mandibular condylar cartilage to mineralization. AB - OBJECTIVE: To study the effects of intermittent parathyroid hormone (PTH [1-34]) on the mandibular condylar cartilage (MCC) and subchondral bone in adult female mice. MATERIALS AND METHODS: Twenty-two, 20-week-old female mice were used for in vivo experiments. The experimental mice (n=11) received daily intraperitoneal injections of PTH [1-34] for 3 weeks, while control mice (n=11) received intraperitoneal injections of 0.9% saline solution. Mice were euthanized and then micro-computed tomography (micro-CT); histology and immunostaining were carried out to assess the response. RESULTS: Intermittent PTH [1-34] led to early MCC breakdown and surface irregularities. Micro-CT analyses indicated that PTH [1-34] treatment led to increased bone volume fraction, tissue density and trabecular thickness, while decreasing the trabecular spacing. Histological analyses showed decreased proteoglycan secretion, increased bone turnover (TRAP staining) and increased mineralization. Furthermore, PTH [1-34] treatment showed increased apoptosis of the cells. Our immunohistochemistry showed increased expression of pSMAD158 in the MCC and subchondral bone with PTH administration, whereas sclerostin (SOST) expression was decreased. CONCLUSIONS: Intermittent PTH [1-34] results in early mineralization of the MCC, which may result in cartilage degeneration. Our results identified a novel mechanism by which PTH [1-34] induces alteration in the microarchitecture of the MCC and the subchondral bone. PMID- 28643905 TI - Diverse contribution of Col2a1-expressing cells to the craniofacial skeletal cell lineages. AB - OBJECTIVES: Craniofacial skeletal development requires deliberate coordination of two distinct mechanisms of endochondral and intramembranous ossification. Col2a1 expressing cells encompass growth-associated skeletal progenitors in endochondral bones of the limb. The objective of this study was to determine the contribution of Col2a1-expressing cells to the craniofacial skeletal cell lineages. We hypothesize that Col2a1-expressing progenitors significantly contribute to various modes of ossification associated with the craniofacial development. METHODS: Cellular fates of Col2a1-expressing cells were studied based on a cre loxP system using a Col2a1-cre transgene and an R26R-tdTomato reporter allele. We analysed three distinct locations of the craniofacial skeletal complex representing unique ossification mechanisms: the cranial base, the calvaria and the mandibular condyle. RESULTS: Col2a1-cre consistently marked a majority of skeletal cells in the cranial base. Interestingly, Col2a1-cre also marked a large number of osteoblasts and suture mesenchymal cells in the calvaria, in addition to chondrocytes in the underlying transient cartilage. In the mandibular condyle, Col2a1-cre marked chondrocytes and osteoblasts only during the growth phase. CONCLUSIONS: Col2a1 is expressed by progenitors of the skeletal lineage in canonical endochondral bone formation occurring in the cranial base. In contrast, other ossification mechanisms of the craniofacial complex utilize Col2a1 expressing cells in a different manner, whereby Col2a1 may be expressed in more differentiated or transient cell types of the skeletal lineage. PMID- 28643906 TI - In vitro evaluation of surface properties of Pro Seal(r) and Opal(r) SealTM in preventing white spot lesions. AB - OBJECTIVES: To evaluate the surface properties of two commercially available sealants (Pro Seal(r) (PS) and Opal(r) SealTM (OS)) in terms of fluoride(F) release, biofilm formation of Streptococcus mutans and Lactobacillus and the ability to resist acid penetration. SETTING: University of Nebraska Medical Center. MATERIAL & METHODS: Discs of similar diameter and thickness were made from OS and PS. Discs were soaked in double-distilled water, and F released was measured with fluoride meter daily for 14 consecutive days, then at 21 and 28 days. Biofilm formation was evaluated with Streptococcus mutans and Lactobacilli grown on sealant discs using confocal microscopy. Extracted human teeth (n=8) with sealant-coated buccal surfaces and untreated lingual surfaces were exposed to 0.1M lactic acid(pH=4.5) to test the acid penetration. After 1-4 weeks of exposure, teeth were subjected to microhardness testing and SEM microscopy. RESULTS: PS released significantly higher levels of F than OS. PS showed more S. mutans adherence than OS, whereas Lactobacillus did not show any differences in adherence. Both sealants protected enamel surfaces, showing statistically significant difference in the depth of acid penetration compared to their unsealed control sides. CONCLUSION: F release was adequate to aid in remineralization, although clinically it would not likely aid in preventing demineralization as there was no prolonged release of F by both sealants tested. S. mutans adherence to OS surface was less compared to PS surface, which could be of relevance in biofilm formation and white spot lesions. Both sealants protected enamel surfaces from acid penetration. PMID- 28643907 TI - Utilizing three-dimensional data in orthodontic practice and research. AB - The recent prevalence of three dimensional (3D) images of soft and hard tissues provides a wealth of new data from which the clinician can evaluate these changes. However, evaluating this new data presents new and significant challenges. Current approaches utilizing multi-dimensional data for the precise evaluation of changes related to treatment and growth sets are reviewed. The results of current validation studies exploring approaches to these problems are reviewed, including the registration of longitudinal data using maxillary and mandibular regions of reference. Challenges related to the consistent selection of points on complex three-dimensional structures are circumvented using an automated, shape analysis based approach. Imaging using these new modalities yields a tremendous amount of data. Analysis of large data sets from cross sectional studies with multiple variables are simplified using a principle components analysis, from which a reduced set of variables is constructed. Examples of this approach are presented. The use of advanced methods to process and interpret data from 3D imaging modalities highlights critical aspects of craniofacial growth and form. PMID- 28643908 TI - Jaw mechanics in dolichofacial and brachyfacial phenotypes: A longitudinal cephalometric-based study. AB - OBJECTIVES: To determine whether dolichofacial (Frankfort horizontal mandibular plane angle (FHMPA) >=30 degrees ) vs brachyfacial (FHMPA <=22 degrees ) phenotypes differ in temporomandibular joint (TMJ) loads and whether these differences correlate longitudinally with mandibular ramus height (Condylion Gonion, Co-Go). SETTING AND SAMPLE POPULATION: Lateral and posteroanterior cephalographs from ten dolichofacial and ten brachyfacial individuals made at average ages of 6 (T1), 12 (T2) and 18 (T3) years and available online (http://www.aaoflegacycollection.org/aaof_home.html) were used. MATERIALS AND METHODS: Three-dimensional anatomical data were derived from cephalographs and used in numerical models to predict TMJ loads for a range of biting angles on incisors, canines and first molars. Two criteria were used to define clinically important between-group TMJ load differences: statistical significance was defined with a two-group t-test, and where differences were also >=20%. A statistical approach called response surface analysis was used to assess correlation between TMJ loads and its predictors considered in this study. RESULTS: The two phenotypes had significantly different FHMPA at all ages (P<.05). No differences in TMJ loads were found at T1. Ipsilateral and contralateral TMJ loads at T2 and T3 were significant and >=20% larger in dolichofacial than brachyfacial phenotypes for specific biting angles (all adjusted P<.05). Regression analysis indicated age and ramus height contribute 53% of the variability in normalized values of TMJ loads. At higher ages, dolichofacial phenotypes had significantly higher TMJ loads which were correlated with shorter ramus heights compared to brachyfacial phenotypes. CONCLUSIONS: Craniofacial mechanics may explain, in part, mandibular growth differences between dolichofacial and brachyfacial phenotypes. PMID- 28643909 TI - The fate of Osterix-expressing mesenchymal cells in dental root formation and maintenance. AB - OBJECTIVES: Osterix (Osx)-expressing mesenchymal cells are progenitors for tooth root forming cells. The aim of this study was to reveal the fates of Osx expressing cells during and after root formation using a lineage tracing experiment. MATERIAL AND METHODS: To reveal the fates of Osx-expressing dental mesenchymal progenitors, we took advantage of tamoxifen-inducible Cre reporter system. Osx-creER; R26R-tdTomato mice received tamoxifen (0.1 mg/body) at postnatal day 3 (P3). In this system, Osx-expressing at P3 (Osx-P3) cells undergo recombination, and they and their descendants continue to express Tomato red fluorescence protein permanently. Mandibles were dissected at serial time points ranging from P4 to P116 to investigate how Osx-P3 cells participated in root formation. Tomato+ cells on frozen sections were imaged under fluorescence microscopy. RESULTS: Osx-P3 cells and their descendants differentiated into all kinds of cells that contributed to the root and periodontal tissues, such as odontoblasts, cementoblasts, alveolar bone osteoblasts and periodontal ligament (PDL) cells during root formation. Even after root formation was completed, they persisted in dental pulp and PDL to provide progenitor cells for odontoblasts and cementoblasts. CONCLUSION: Osx-expressing cells play important roles in the entire processes of tooth root formation; their progeny continue to contribute to maintenance of tooth root even after root formation is complete. PMID- 28643910 TI - Evaluation of the 3dMDface system as a tool for soft tissue analysis. AB - OBJECTIVES: To evaluate the accuracy of three-dimensional stereophotogrammetry by comparing values obtained from direct anthropometry and the 3dMDface system. To achieve a more comprehensive evaluation of the reliability of 3dMD, both linear and surface measurements were examined. SETTING AND SAMPLE POPULATION: UCLA Section of Orthodontics. Mannequin head as model for anthropometric measurements. MATERIAL AND METHODS: Image acquisition and analysis were carried out on a mannequin head using 16 anthropometric landmarks and 21 measured parameters for linear and surface distances. 3D images using 3dMDface system were made at 0, 1 and 24 hours; 1, 2, 3 and 4 weeks. Error magnitude statistics used include mean absolute difference, standard deviation of error, relative error magnitude and root mean square error. Intra-observer agreement for all measurements was attained. RESULTS: Overall mean errors were lower than 1.00 mm for both linear and surface parameter measurements, except in 5 of the 21 measurements. The three longest parameter distances showed increased variation compared to shorter distances. No systematic errors were observed for all performed paired t tests (P<.05). Agreement values between two observers ranged from 0.91 to 0.99. CONCLUSIONS: Measurements on a mannequin confirmed the accuracy of all landmarks and parameters analysed in this study using the 3dMDface system. Results indicated that 3dMDface system is an accurate tool for linear and surface measurements, with potentially broad-reaching applications in orthodontics, surgical treatment planning and treatment evaluation. PMID- 28643911 TI - Effects of cocoa-enriched diet on orofacial pain in a murine model. AB - OBJECTIVES: To investigate and discuss the effects of cocoa on orofacial pain. SETTING AND SAMPLE POPULATION: The Department of Orthodontics at the University of Florida (UF). Male and female hairless rats (N=20/group) were tested. MATERIALS AND METHODS: Rats were tested using the Orofacial Pain Assessment Device (OPAD) before and after changing their food from the standard chow to a cocoa-enriched or control-equivalent diet. RESULTS: Male rats fed the cocoa diet had a significantly higher operant pain index when tested at 37 degrees C as compared to control diet-fed animals. Female rats on the cocoa diet had a significantly higher pain index when tested at 18 degrees C and 44 degrees C, as compared to animals fed the control diet. Capsaicin-induced pain was inhibited, with cocoa-diet male rats having a significantly higher pain index than control diet male rats and cocoa-diet female rats at both 37 degrees C and 44 degrees C. Cocoa-diet female rats had a significantly higher pain index at 44 degrees C than control-diet females. Mechanical sensitivity was affected following capsaicin cream, with a significantly decreased tolerated bottle distance in both cocoa- and control-diet animals, but there was no difference between cocoa- and control diet groups. CONCLUSION: Using the OPAD operant system, we demonstrated that a diet rich in cocoa was effective in inhibiting neurogenic inflammatory pain in rats. This has implications for the use of novel alternative therapies such as diet modification for pain control. PMID- 28643912 TI - Mouse models for the study of cranial base growth and anomalies. AB - The cranial base is a central and integral component of the cranioskeleton, yet little is known about its growth. Despite the dissimilarities between human and murine cranioskeletal form, mouse models are proving instrumental in studying craniofacial growth. The objectives of this review are to summarize recent findings from numerous mouse models that display growth defects in one or more cranial base synchondroses, with accompanying changes in chondrocyte cellular zones. Many of these models also display altered growth of the cranial vault and/or the facial region. FGFR, PTHrP, Ihh, BMP and Wnt/beta-catenin, as well as components of primary cilia, are the major genes and signalling pathways identified in cranial base synchondroses. Together, these models are helping to uncover specific genetic influences and signalling pathways operational at the cranial base synchondroses. Many of these genes are in common with those of importance in the cranial vault and the facial skeleton, emphasizing the molecular integration of growth between the cranial base and other cranial regions. Selected models are also being utilized in testing therapeutic agents to correct defective craniofacial and cranial base growth. PMID- 28643913 TI - Effect of exogenous retinoic acid on tooth movement and periodontium healing following tooth extraction in a rat model. AB - OBJECTIVES: To evaluate the effect of isotretinoin on orthodontic tooth movement (OTM) and wound healing following exodontia. SETTING AND SAMPLE POPULATION: Sixteen 40-day-old male Wistar rats were divided into two groups: (a) OTM and (b) tooth extraction (TE) of the upper 1st molar and OTM. The experimental animals were treated with isotretinoin (7.5 mg/kg) and the control animals with oil solution for 37 days. MATERIALS AND METHODS: The OTM and bone volume were evaluated by the micro-CT and the periodontium healing was assessed by immunohistochemistry for VEGF-C, COX-2 and IL-1beta. RESULTS: The animals of both groups submitted to the TE showed a statistically significant decrease in the bone volume percentage and increase in OTM. No significant difference of OTM and bone volume was observed between the control and experimental group. However, the alveolar bone of the isotretinoin group revealed more medullary spaces with inflammatory, hematopoietic cells, blood vessels and intense immunolabeling for VEGF-C. This group also showed faster gingival regeneration. No significant difference was observed in the COX-2 and IL-1beta labelings following TE between both groups. CONCLUSION: The isotretinoin did not affect the OTM nor did it cause an alteration in maxillary bone volume. This exogenous acid may contribute to the acceleration of gingival healing. PMID- 28643914 TI - The use of cell culture platforms to identify novel markers of bone and dentin resorption. AB - OBJECTIVES: 1) To test the hypothesis that there would be proteomic differences in the composition of exosomes isolated from osteoclasts and odontoclasts and 2) to determine the clinical usefulness of these in vitro biomarker candidates. MATERIALS AND METHODS: Mouse bone marrow-derived precursors were cultured on either dentin or bone slices and allowed to mature and begin resorption. Exosomes were isolated from cell culture media and characterized by mass spectrometry. The proteomic data obtained from this in vitro study were compared with the data obtained from human samples in our previous work. RESULTS: There was a difference in the proteomic composition of exosomes from osteoclasts and odontoclasts. A total of 40 exosomal proteins were only present in osteoclast media, whereas six unique exosomal proteins were identified in odontoclast supernatants. Approximately 50% of exosomal proteins released by clastic cells in vitro can be found in oral fluids. CONCLUSION: Our data suggest that the mineralized matrix type plays a role in the final phenotypic characteristics of mouse clastic cells. Many in vitro biomarker candidates of bone and dentin resorption can also be found in human oral fluids, thus indicating that this approach may be a viable alternative in biomarker discovery. PMID- 28643915 TI - Preface to COAST 2016 innovators' workshop on personalized and precision orthodontic therapy. AB - OBJECTIVE: A second focused workshop explored how to transfer novel findings into clinical orthodontic practice. SETTING AND SAMPLE POPULATION: Participants met in West Palm Beach (Florida, USA), on 9-11 September 2016 for the Consortium for Orthodontic Advances in Science and Technology 2016 Innovators' Workshop (COAST). Approximately 65 registered attendees considered and discussed information from 27 to 34 speakers, 8 to 15 poster presenters and four lunch-hour focus group leaders. MATERIAL AND METHODS: The innovators' workshops were organized according to five themed sessions. The aims of the discussion sessions were to identify the following: i) the strength and impact of the evidenced-based discoveries, ii) required steps to enable further development and iii) required steps to translate these new discoveries into orthodontic practice. RESULTS: The role of gene environment interactions that underlie complex craniofacial traits was the focus of several sessions. It was agreed that diverse approaches are called for, such as (i) large-scale collaborative efforts for future genetic studies of complex traits; (ii) deep genome sequencing to address the issues of isolated mutations; (iii) quantifying epigenetic-environmental variables in diverse areas myofascial pain, alveolar remodelling and mandibular growth. Common needs identified from the themed sessions were multiscale/multispecies modelling and experimentation using controlled and quantified mechanics and translation of the findings in bone biology between species. Panel discussions led to the consensus that a consortium approach to establish standards for intra-oral scanning and 3D imaging should be initiated. CONCLUSIONS: Current and emerging technologies still require supported research to translate new findings from the laboratory to orthodontic practice. PMID- 28643916 TI - A review of craniofacial and dental findings of the RASopathies. AB - OBJECTIVES: The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML or LEOPARD syndrome), neurofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1-like syndrome (NFLS or Legius syndrome) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the craniofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings. METHODS: Review of the literature. RESULTS: Each of the RASopathies reviewed, caused by mutations in genes that encode different proteins in the Ras pathway, have unique and overlapping craniofacial and dental characteristics. CONCLUSIONS: Careful description of craniofacial and dental features of the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signalling in craniofacial development. PMID- 28643917 TI - Estrogen receptor alpha mediates mandibular condylar cartilage growth in male mice. AB - OBJECTIVES: In the appendicular skeleton, estrogen via ERalpha signalling has been shown to mediate endochondral growth plate fusion in both males and females. However, the role of ERalpha in mediating growth of the mandibular condylar cartilage is unknown. Thus, this study focuses on the characterization of the mandibular condylar cartilage phenotype in young and adult male ERalphaKO mice. SETTING: Columbia University Medical Center. MATERIAL AND METHODS: WT and ERalphaKO C57BL/6 male mice were sacrificed at 49 days or 9 months for phenotypic analysis. Changes to MCC thickness, cell number and cell density were measured using histomorphometric methods. Cartilage-specific gene expression and OARSI scores were investigated for 49-day and 9-month-old male ERalphaKO and WT mice. RESULTS: In young mice, a significant increase in the number of mandibular condylar cartilage cells and a significant decrease in the expression of Col10, Runx2 and DMP1 were observed in the male ERalphaKO mice compared to WT. In 9 month-old mice, we found a similar increase in the number of cells but no change in osteoarthritic histological scoring in ERalphaKO mice compared to WT mice. CONCLUSION: In summary, estrogen plays a role in mediating mandibular condylar maturation in young male mice. However, according to this study, it does not play a role in mediating long-term growth or age-related mandibular condylar cartilage degeneration in males. PMID- 28643918 TI - Effect of cyclical forces on orthodontic tooth movement, from animals to humans. AB - Vibration as a non-invasive method is currently available for clinical use with the potential to accelerate the rate of tooth movement in orthodontics. The aim of this review was to evaluate the basic science and clinical literature on the effects of vibration on the axial and appendicular skeleton including the craniofacial bone. Vibration as a dynamic load consisting of high oscillatory forces of low magnitude has shown osteogenic and anti-catabolic effects on bone. These effects have been observed in the craniofacial skeleton including the alveolar bone as increases in sutural width and alveolar bone formation. Animal studies have shown conflicting results on vibration when superposed to orthodontic tooth movement. The effects range from increasing to decreasing the rate of tooth movement. Clinical studies in accelerating the rate of tooth movement have similar findings observed in animal studies. High-frequency oscillatory forces of low magnitude are able to affect bone formation and remodelling. These effects of vibration are primarily anabolic and anti-catabolic in bone, including the craniofacial skeleton and alveolar bone. The effect of vibration on accelerating the rate of orthodontic tooth movement is contradictory. Higher levels of evidence studies have not been able to show an acceleratory effect. PMID- 28643919 TI - Mechanobehaviour in dolichofacial and brachyfacial adolescents. AB - OBJECTIVES: To test whether mechanobehaviour (temporomandibular joint (TMJ) loads, jaw muscle use) was different between facial types and correlated with ramus height (Condylion-Gonion, mm). SETTING AND SAMPLE POPULATION: University of Missouri-Kansas City (UMKC) Orthodontic Clinic. Ten dolichofacial and ten brachyfacial adolescents (Sella-Nasion-Gonion-Gnathion (SN-GoGn) angles >=37 degrees and <=27 degrees , respectively) consented to participate. MATERIALS AND METHODS: Numerical models calculated TMJ loads for a range of static biting based on subjects' three-dimensional anatomy. Subjects were trained to record jaw muscle electromyography (EMG) over 2 days and 2 nights in their natural environments. Laboratory EMG/bite-force calibrations determined subject-specific EMG for 20 N bite-force (T20Nave ). Jaw muscle use via duty factors (DF=muscle activity duration/total recording time, %) was determined from day and night recordings for muscle-specific thresholds from >=5% to >=80%T20Nave . ANOVA and Tukey's HSD post hoc tests assessed for group differences in mechanobehaviour (TMJ loads, DFs). Regression modelling correlated subjects' normalized TMJ loads, DFs and ramus height. RESULTS: Dolichofacial compared to brachyfacial subjects produced significantly higher (P<.05) TMJ loads, where ipsilateral loads were >=20% larger for some biting angles, but had significantly less (all P<.05) masseter (day, night) and temporalis (night) DFs. Regression analysis showed a significant relationship amongst normalized TMJ loads, masseter DF and ramus height (R2 =.49). CONCLUSIONS: Mechanobehaviour showed significant differences between facial types and was correlated with ramus height. PMID- 28643920 TI - Analysis of polycaprolactone scaffolds fabricated via precision extrusion deposition for control of craniofacial tissue mineralization. AB - OBJECTIVES: Recurrence of cranial bone fusion following surgical resection in craniosynostosis patients commonly requires additional surgical procedures. Surgical implantation of engineered 3D scaffolds that control tissue mineralization could be utilized to diminish recurrence of fusion. This study investigated the ability of composite scaffolds to control tissue mineralization when cultured in vitro. SETTING AND SAMPLE POPULATION: Precision-engineered scaffolds with calvarial cells were cultured in vitro at the Department of Orthodontics and Pediatric Dentistry, University of Michigan. MATERIAL & METHODS: Polycaprolactone (PCL) scaffolds were fabricated using a novel precision extrusion deposition technique. Polyethylene glycol (PEG) hydrogel was coated onto select scaffolds to inhibit mineralization. MC3T3E1(C4) calvarial cells were cultured with scaffolds in media containing ascorbate and phosphate to promote osteoblast differentiation and mineralization. Scaffolds were assayed for osteoblast differentiation by alkaline phosphatase assay. Scaffolds were assayed for mineralization by nano-computed tomography (nano-CT) and by von Kossa staining of histologic sections. RESULTS: MC3T3E1(C4) cells differentiated into osteoblasts and formed mineral when cultured on uncoated PCL scaffolds. MC3T3E1(C4) cells were significantly diminished in their ability to differentiate into osteoblasts when cultured on hydrogel-coated scaffold. CONCLUSION: Results of this study indicate that this novel printing technology can be used to fabricate 3D scaffolds to promote and inhibit tissue mineralization in a region specific manner. Future studies are needed to establish utility of such scaffolds in vivo. PMID- 28643921 TI - Whole-exome sequencing identified a variant in EFTUD2 gene in establishing a genetic diagnosis. AB - OBJECTIVES: Craniofacial anomalies are complex and have an overlapping phenotype. Mandibulofacial Dysostosis and Oculo-Auriculo-Vertebral Spectrum are conditions that share common craniofacial phenotype and present a challenge in arriving at a diagnosis. In this report, we present a case of female proband who was given a differential diagnosis of Treacher Collins syndrome or Hemifacial Microsomia without certainty. Prior genetic testing reported negative for 22q deletion and FGFR screenings. The objective of this study was to demonstrate the critical role of whole-exome sequencing in establishing a genetic diagnosis of the proband. SETTING AND SAMPLE POPULATION: The participants were 141/2-year-old affected female proband/parent trio. MATERIALS AND METHODS: Proband/parent trio were enrolled in the study. Surgical tissue sample from the proband and parental blood samples were collected and prepared for whole-exome sequencing. Illumina HiSeq 2500 instrument was used for sequencing (125 nucleotide reads/84X coverage). Analyses of variants were performed using custom-developed software, RUNES and VIKING. RESULTS: Variant analyses following whole-exome sequencing identified a heterozygous de novo pathogenic variant, c.259C>T (p.Gln87*), in EFTUD2 (NM_004247.3) gene in the proband. Previous studies have reported that the variants in EFTUD2 gene were associated with Mandibulofacial Dysostosis with Microcephaly. CONCLUSION: Patients with facial asymmetry, micrognathia, choanal atresia and microcephaly should be analyzed for variants in EFTUD2 gene. Next generation sequencing techniques, such as whole-exome sequencing offer great promise to improve the understanding of etiologies of sporadic genetic diseases. PMID- 28643922 TI - Speed of human tooth movement in growers and non-growers: Selection of applied stress matters. AB - OBJECTIVES: To test that the speed of tooth translation is not affected by stress magnitude and growth status. SETTING AND SAMPLE POPULATION: Advanced Education Orthodontic clinics at the Universities of Nebraska Medical Center and Missouri Kansas City. Forty-six consenting subjects with orthodontic treatment plans involving maxillary first premolar extractions. MATERIALS AND METHODS: This randomized split-mouth study used segmental mechanics with definitive posterior anchorage and individual vertical-loop maxillary canine retraction appliances and measured three-dimensional tooth movements. Height and cephalometric superimposition changes determined growing (G) and non-growing (NG) subjects. Subjects were appointed for 9-11 visits over 84 days for maxillary dental impressions to measure three-dimensional tooth movement and to ensure retraction forces were continuously applied via calibrated nitinol coil springs. Springs were custom selected to apply two different stresses of 4, 13, 26, 52 or 78 kPa to maxillary canines in each subject. Statistical analyses (alpha=0.050) included ANOVA, effect size (partial eta2 ) and Tukey's Honest Significant Difference (HSD) and two-group t tests. RESULTS: Distolateral translation speeds were 0.034+/-0.015, 0.047+/-0.019, 0.066+/-0.025, 0.068+/-0.016 and 0.079+/-0.030 mm/d for 4, 13, 26, 52 and 78 kPa, respectively. Stress significantly affected speed and partial eta2 =0.376. Overall, more distopalatal rotation was shown by teeth moved by 78 kPa (18.03+/-9.50o) compared to other stresses (3.86+/-6.83o), and speeds were significantly higher (P=.001) in G (0.062+/-0.026 mm/d) than NG subjects (0.041+/-0.019 mm/d). CONCLUSIONS: Stress magnitude and growth status significantly affected the speed of tooth translation. Optimal applied stresses were 26-52 kPa, and overall speeds were 1.5-fold faster in G compared to NG subjects. PMID- 28643923 TI - Micro-anatomical responses in periodontal complexes of mice to calibrated orthodontic forces on the crown. AB - OBJECTIVE: Correlating mechanical forces with quantifiable physical changes in the dentoalveolar complex. SETTING AND SAMPLE POPULATION: Male 6-week C57BL/6 mice (N=3), micro X-ray-computed tomography; post-analysis software to extract physical changes in periodontal ligament (PDL)-space. MATERIALS AND METHODS: Silicone-elastic bands were placed between maxillary molars for 1 week, with the contralateral side as internal control. Average displacements between crowns and roots, and changes in PDL-spaces were evaluated by registering X-ray tomograms of experimental and control hemi-maxillae. Histology illustrated mineral formation and resorption-related events within narrowed and widened volumes of the PDL space. RESULTS: 3D maps of changes in PDL-space between molars illustrated coronal and root displacements of 640 MUm and 180 MUm, respectively, compared to 70 MUm in controls. Orthodontic tooth movement (OTM) specimens exhibited an average net change of -20 MUm in narrowed and +30 MUm in widened PDL-spaces. Bone and cementum were affected by the force on molars, and primary cementum was more affected than secondary cementum. CONCLUSIONS: This novel approach illustrates the importance of 3D-imaging and analysing 3D alveolar socket subjected to OTM otherwise omitted by 2D micrographs. A measured force on the crown elicits a response related to narrowed and widened regions in the 3D complex. OTM that exceeds PDL-space can illicit biological responses that attempt to restore physiologic PDL-space via remodelling of the periodontium. Regenerated weaker bone due to aseptic inflammation caused by orthodontics could leave patients at a higher risk of bone loss or root resorption if they later develop periodontitis, a form of septic inflammation. PMID- 28643925 TI - A new cyte in orthodontics: Osteocytes in tooth movement. AB - Orthodontic tooth movement (OTM) relies on the orchestration of clinical and biologic events that include the application of clinical force followed by a cascade of cellular and molecular responses. Our understanding about OTM today has evolved from, and is largely based on historic studies. However, the advances in bone biology and clinical orthodontics today continue to pave the pathway towards an improved knowledge base, and state of the art therapeutics in OTM. Osteoblasts and osteoclasts have been the primary cells analyzed in OTM. However, the role of osteocytes, a cell previously thought to be static, should be considered in light of new findings in molecular biological research. Osteocytes are now known to be significant in controlling responses to mechanical forces and therefore may be central to both OTM and normal tooth eruption. In this review, we explore the biology of OTM by focusing specifically on the potential role of osteocytes. Evidence from recent studies reveal that osteocytes have a role in controlling the response to mechanical forces and OTM. We therefore propose that these findings and further research endeavours may shape the future of clinical applications-specifically enhanced outcomes in OTM. PMID- 28643924 TI - Exosomes: novel regulators of bone remodelling and potential therapeutic agents for orthodontics. AB - Recent studies suggest that exosomes are involved in intercellular communication required for the maintenance of healthy bone. Exosomes are small (30-150 nm in diameter) extracellular vesicles that are formed in multivesicular bodies and are released from cells as the multivesicular bodies fuse with the plasma membrane. Regulatory exosomes have the capacity to exert profound control over target cells. They can stimulate plasma membrane receptors and are also internalized by the target cell delivering proteins, lipids, small molecules and functional RNAs from the cell of origin. We and others have recently reported on regulatory exosomes from osteoclasts and osteoblasts. Key candidate molecules identified in exosome-based regulation of bone remodelling include receptor activator of nuclear factor kappa B (RANK), RANK-ligand (RANKL), ephrinA2, semaphorin 4D, microRNA-146a and microRNA- 214-3p. Exosomes will likely prove to be crucial elements in the communication networks integrating bone cells (osteoclasts, osteoblasts, osteocytes) and linking bone to other tissue. Exosomes collected from bone cells grown in culture may prove useful to augment bone remodelling associated with orthodontic force application or required for the repair of craniofacial bone. Various technologies allow exosomes to be engineered to improve their targeting and efficacy for therapeutic purposes. In summary, exosomes have emerged as important elements of the machinery for intercellular communication between bone cells. They hold great promise as therapeutic targets, biomarkers and therapeutic agents for orthodontists. PMID- 28643927 TI - CO2 low-level laser therapy has an early but not delayed pain effect during experimental tooth movement. AB - OBJECTIVES: To test the hypothesis that the use of low-level laser therapy (LLLT) reduces elevated pain by controlling the release of neurochemicals during orthodontic tooth movement. SETTING AND SAMPLE POPULATION: Department of Orthodontics and Dentofacial Orthopedics, Okayama University. Sixty-five Sprague Dawley rats were subjected to tooth movement and LLLT. MATERIALS AND METHODS: Adult Sprague Dawley rats were used in this study. Groups included day 0 controls, irradiation only controls and with or without irradiation sacrificed at 1, 3, 5, 7 and 14 days after tooth movement (n=5 each, total n=65). Tooth movement was achieved by insertion of an elastic module between molar teeth. Immunohistochemistry for CD-11b, GFAP and c-fos in the brain stem was performed. Stains were quantified by constructing a three-dimensional image using IMARIS, and counted using NEURON TRACER and WinROOF software. Two-way ANOVA followed by a Tukey's post hoc test (P<.05) was used for statistical comparison between groups. RESULTS: C-fos expression was significantly increased at one and three days after tooth movement. LLLT significantly diminished this increase in c-fos expression only at one day after tooth movement CD-b11 and GFAP expression also significantly increased after tooth movement. No significant change was observed for CD-11b and GFAP expression in the central nervous system upon LLLT. CONCLUSION: Low-level laser therapy may reduce early neurochemical markers but have no effect on delayed pain neurochemical markers after tooth movement. PMID- 28643926 TI - Fluid pressurization and tractional forces during TMJ disc loading: A biphasic finite element analysis. AB - OBJECTIVES: To investigate the ploughing mechanism associated with tractional force formation on the temporomandibular joint (TMJ) disc surface. SETTING AND SAMPLE POPULATION: Ten left TMJ discs were harvested from 6- to 8-month-old male Yorkshire pigs. MATERIALS AND METHODS: Confined compression tests characterized mechanical TMJ disc properties, which were incorporated into a biphasic finite element model (FEM). The FEM was established to investigate load carriage within the extracellular matrix (ECM) and the ploughing mechanism during tractional force formation by simulating previous in vitro plough experiments. RESULTS: Biphasic mechanical properties were determined in five TMJ disc regions (average+/-standard deviation for aggregate modulus: 0.077+/-0.040 MPa; hydraulic permeability: 0.88+/-0.37*10-3 mm4 /Ns). FE simulation results demonstrated that interstitial fluid pressurization is a dominant loading support mechanism in the TMJ disc. Increased contact load and duration led to increased solid ECM strain and stress within, and increased ploughing force on the surface of the disc. CONCLUSION: Sustained mechanical loading may play a role in load carriage within the ECM and ploughing force formation during stress-field translation at the condyle-disc interface. This study further elucidated the mechanism of ploughing on tractional force formation and provided a baseline for future analysis of TMJ mechanics, cartilage fatigue and early TMJ degeneration. PMID- 28643928 TI - Calvarial bone development and suture closure in Dicer-deficient mice. AB - OBJECTIVE: To evaluate whether lack of Dicer during calvaria development would lead to dysmorphology of calvaria and suture closure in mice. MATERIALS AND METHODS: A conditional Dicer deficient under Osx promoter mouse was employed in this study. The 4- and 10-week-old conditional Dicer-deficient mice control littermates and Osx-cre transgenic mice were studied for calvarial bone morphology and suture closure. Dry skull, microcomputed tomography (MUCT), histological and gene expression studies were investigated to evaluate the effect of Dicer deficiency on calvarial bone morphology and their related genes during calvaria development. RESULTS: The results elucidated that complete suture closure was observed in 10-week-old conditional Dicer-deficient mice while incomplete closure suture was observed in age-matched Osx-cre control mice. The MUCT and histological sections demonstrated complete fusion of posterior frontal suture and dysmorphic calvarial bones in Dicer deficient mice compared to the ones in their littermates and age-matched Osx-cre control mice. Gene expression study demonstrated significantly increased expression of suture and calvarial bone-related genes, that is Tgf-beta family, Bmp3, Msx2, Alx4, Runx2 and Osx in Dicer-deficient mice during suture closure time. CONCLUSIONS: The results suggest mature miRNAs are important for suture closure and calvarial morphology during calvaria development. PMID- 28643929 TI - In silico and functional evaluation of PTH1R mutations found in patients with primary failure of eruption (PFE). AB - OBJECTIVES: The genetic basis of PFE (OMIM ID: 125350) was interrogated using molecular functional studies. PFE is a disorder that results in a poor prognosis in the eruption of teeth and by extension, in treatment with a continuous archwire. We tested the hypothesis that PTH1R mutations result in loss of function due to altered protein structure to determine (i) the fate of a functional PTH1R mutation and (ii) the resulting PTH1R protein structure of each functional mutation. METHODS: We used immunofluorescence assay of COS7 cells that were transfected with either the WT or 1092delG PTH1R mutation sequence to compare the fate of the expressed protein. We also performed in silico analysis of the WT PTH1R and four different functional PTH1R mutations RESULTS: Functional studies (IFA) showed a variation in expression between the WT and mutant PTH1R. Further, in silico analysis showed structural differences between WT and mutant PTH1R proteins, particularly in the regions of the 3rd intracellular loop and the 6th transmembrane domain required for efficient PTH1R function. CONCLUSION: PTH1R mutations identified in PFE likely result from diminished function due to truncation of the protein, lack of efficient G-protein interactions and putatively attenuated signal transduction. By identifying the mode of protein dysfunction, scientist-clinicians are better prepared to recognize and thereby develop improved methods of treatment, starting at the molecular level. PMID- 28643930 TI - Moving towards precision orthodontics: An evolving paradigm shift in the planning and delivery of customized orthodontic therapy. AB - Advances in precision medicine portend similar progress in orthodontics and will be increasingly harnessed to achieve customized treatment approaches and enhance treatment efficiencies. Our goal is to provide a background on emerging advances in computer technologies and biomedicine and highlight their current and likely future applications to precision orthodontics. A review of orthodontically relevant technologies and advances in pertinent biological research was undertaken. Innovations in computer hardware and software, and 3D imaging technologies offer the ability for customized treatment and biomechanical planning that will be more fully realized within the next few decades. These technologies combined with 3D printing are already being applied to customized appliance fabrication such as aligners and retainers. The future prospects for custom fabrication of orthodontic brackets of appropriate material properties and smart devices are highly desirable and compelling goals. Within biomedicine, the fundamental understanding of cartilage growth and bone biology is currently being tested in animal models to modify mandibular growth and modulate tooth movement, respectively. Some of these discoveries will ultimately have clinical applications in orthodontics including for growth modification, accelerating orthodontic tooth movement, and enhancing anchorage or retention of teeth. Additional genomic and proteomic information will add to further customization of orthodontic diagnosis and treatments. Over the coming decades, precision orthodontics will continue to benefit from advances in many fields and will require the integration of advances in technology, and biomedical and clinical research to deliver optimal, efficient, safe, and reproducible personalized orthodontic treatment. PMID- 28643931 TI - Clinical effectiveness of late maxillary protraction in cleft lip and palate: A methods paper. AB - OBJECTIVES: A prospective parallel cohort trial was conducted to compare outcomes of patients treated with maxillary protraction vs LeFort 1 maxillary advancement surgery. SETTING AND SAMPLE POPULATION: The primary site for the clinical trial is Children's Hospital Los Angeles; the satellite test site is Seattle Children's Hospital. All patients have isolated cleft lip and palate and a skeletal Class III malocclusion. MATERIAL AND METHODS: A total of 50 patients, ages 11-14, will be recruited for the maxillary protraction cohort. The maxillary surgery cohort consists of 50 patients, ages 16-21, who will undergo LeFort 1 maxillary advancement surgery. Patients with additional medical or cognitive handicaps were excluded from the study. RESULTS: Current recruitment of patients is on track to complete the study within the proposed recruitment period. CONCLUSION: This observational trial is collecting information that will examine dental, skeletal, financial and quality-of-life issues from both research cohorts. PMID- 28643932 TI - Gene/environment interactions in craniosynostosis: A brief review. AB - It is suggested that craniosynostosis is caused by a heterogeneous set of effects including gene mutations, teratogenic exposure during critical periods of development and gene/environment interactions. Distinguishing between sufficient, additive and interactive effects is important to the study of gene/environment interactions and allows for segregation of environmental exposures effecting susceptible populations. Through the identification of sufficient and interactive effects, efforts in prevention of craniosynostosis may be successful. Here, we provide a brief review focusing on defining these categorized exposures and relevant literature that has interrogated gene/environment interactions for craniosynostosis. PMID- 28643933 TI - Oncologic doses of zoledronic acid induce site specific suppression of bone modelling in rice rats. AB - OBJECTIVES: To examine the effect of zoledronic acid (ZOL) on cortical bone modelling and healing of extraction sockets in the jaw bones of a rodent model. We hypothesized ZOL suppresses both the bone formation in the modelling mode in the jaw bones and alters the extraction site healing. MATERIAL & METHODS: Rice rats were administered saline solution and two dose regimens of ZOL: 0.1 mg/kg, twice a week, for 4 weeks (n=17, saline=8 & ZOL=9) and a higher dose of 0.4 mg/kg, weekly, for 9 weeks (n=30, saline=15 & ZOL=15). Two pairs of fluorochrome bone labels were administered. Extraction of maxillary teeth was performed in maxilla. Mineral apposition rate, mineralizing surface and bone formation rate (BFR) were quantified on periodontal (PDL), alveolar and basal bone surfaces, and in the trabecular bone of proximal tibia. Bone volume (BV) was evaluated at extraction sockets. Multivariate Gaussian models were used to account for repeated measurements, and analyzes were conducted in SAS V9.3. RESULTS: ZOL suppressed bone modelling (BFR/BS) at the PDL surfaces in the mandible (P<.05), but its effect was not significant at the periosteal surfaces of both jaws. BV for the healing sockets of ZOL treated animals was not significantly different (P=.07) compared to the saline group. ZOL suppressive effect was higher in the tibia compared to the jaws. CONCLUSION: ZOL severely suppresses coupled remodelling in the tibia, and the suppression of bone formation in the modelling mode in the jaws demonstrates the site specific effects of ZOL in rice rats. PMID- 28643934 TI - Comprehensive Insights into the Thermal Stability, Biodegradability, and Combustion Chemistry of Pyrrolidinium-Based Ionic Liquids. AB - The use of ionic liquids (ILs) as advanced electrolyte components in electrochemical energy-storage devices is one of the most appealing and emerging options. However, although ILs are hailed as safer and eco-friendly electrolytes, to overcome the limitations imposed by the highly volatile/combustible carbonate based electrolytes, full-scale and precise appraisal of their overall safety levels under abuse conditions still needs to be fully addressed. With the aim of providing this level of information on the thermal and chemical stabilities, as well as actual fire hazards, herein, a detailed investigation of the short- and long-term thermal stabilities, biodegradability, and combustion behavior of various pyrrolidinium-based ILs, with different alkyl chain lengths, counteranions, and cations, as well as the effect of doping with lithium salts, is described. PMID- 28643935 TI - Efficacy of self-adjusting file, XP-endo finisher and passive ultrasonic irrigation on the removal of calcium hydroxide paste from an artificial standardized groove. AB - The purpose of this study was to compare the effectiveness of self-adjusting file (SAF), XP-endo finisher (XP), passive ultrasonic irrigation (PUI) and conventional syringe and needle irrigation (SNI) in the removal of Ca(OH)2 from an artificial groove. Eighty mandibular incisors with single oval canals were prepared to size 40/0.04 and split longitudinally. A standardised groove was prepared in the apical third and filled with Ca(OH)2 . The root halves were reassembled and divided into two control groups (n = 4) and four experimental groups (n = 18) according to the removal methods used. The amount of residual Ca(OH)2 was evaluated using a four-grade scoring system. The differences among the groups were analysed using the Kruskal-Wallis test (P < 0.05). SAF, XP and PUI removed significantly more Ca(OH)2 than SNI (P < 0.001), although there were no significant differences among them (P = 0.209). None of the tested methods could completely clean Ca(OH)2 from the groove. PMID- 28643936 TI - Phenotypic Analysis of Organoids by Proteomics. AB - The development of 3D cell cultures into self-organizing organ-like structures named organoids provides a model that better reflects in vivo organ physiology and their functional properties. Organoids have been established from several organs, such as the intestine, prostate, brain, liver, kidney and pancreas. With recent advances in high-throughput and -omics profiling technologies, it is now possible to study the mechanisms of cellular organisation at the systems level. It is therefore not surprising that these methods are now used to characterize organoids at the transcriptomic, proteomic, chromatin state and transcription factor DNA-binding levels. These approaches can therefore provide a wealth of information regarding both the mechanisms involved in different diseases, and those involved in cell responses to different conditions, in a more in vivo setting. The authors provide an overview of the potential applications of quantitative mass spectrometry with organoid culture, and how the use of large scale proteome measurements is emerging in different organoid systems. PMID- 28643937 TI - Proinflammatory effects and mechanisms of calprotectin on human gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Calprotectin (S100A8/A9) is a heterodimer of S100A8 and S100A9 and is associated with multiple inflammatory diseases, including Crohn's disease, rheumatoid arthritis and periodontitis. Levels of calprotectin are elevated in the gingival crevicular fluid of patients with periodontitis; however, the effects of calprotectin on human gingival fibroblasts (HGFs) remain unknown. This study investigated the proinflammatory activity of calprotectin on HGFs and the functional receptors and signaling pathways engaged by calprotectin. MATERIAL AND METHODS: HGFs were stimulated by equimolar concentrations of S100A8 and/or S100A9, and the expression levels of interleukin (IL)-6 and IL-8 were detected using real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assays. The calprotectin receptors were identified by pre incubating HGFs with the toll-like receptor (TLR) 4 inhibitor or the antibody targeting the advanced glycation end product receptor (RAGE). The involvement of reactive oxygen species (ROS) and signaling pathways were also investigated by treating HGFs with ROS inhibitor or specific pathway inhibitors, respectively. RESULTS: S100A9 and S100A8/A9 significantly upregulated IL-6 and IL-8 expression, which was inhibited upon treatment with the TLR4 inhibitor TAK242. Pretreatment with RAGE-blocking antibodies did not affect cytokine expression. Additionally, S100A9 promoted the production of IL-6 and IL-8 from HGFs via different signaling pathways. IL-6 expression was upregulated via the NF-kappaB, c-Jun amino-terminal kinase (JNK) 1/2 and p38 mitogen-activated protein kinase (MAPK) pathways, and IL 8 expression was upregulated via NF-kappaB, p38, JNK1/2 and extracellular regulated kinase 1/2 MAPK pathways. The release of both cytokines was dependent upon the production of ROS. CONCLUSION: Our findings suggest that calprotectin exerts proinflammatory effects on HGFs via the S100A9 subunit and TLR4-mediated NF-kappaB and MAPK signaling pathways. PMID- 28643939 TI - What are the benefits of being big? PMID- 28643938 TI - Oral application of a periodontal pathogen impacts SerpinE1 expression and pancreatic islet architecture in prediabetes. AB - BACKGROUND AND OBJECTIVES: Epidemiological studies suggest a close association between periodontitis and prediabetes/insulin resistance (IR) but whether periodontitis causes prediabetes in humans is not known. Using various animal models, we have recently established that periodontitis can be an initiator of prediabetes, which is characterized by glucose intolerance, hyperinsulinemia and IR. In addition, our in vitro studies indicated that Porphyromonas gingivalis (Pg) induced insulin secretion in MIN6 beta cells and this induction was in part SerpinE1 (plasminogen activator inhibitor 1, PAI1) dependent. However, the mechanism(s) by which periodontitis induces prediabetes is not known. As alpha and beta cells in pancreatic islets are the major modulators of glucose levels, we investigated whether experimental periodontitis by oral application of a periodontal pathogen caused molecular and/or cellular alterations in pancreatic islets and whether SerpinE1 was involved in this process. MATERIAL AND METHODS: We induced periodontitis in C57BL/6 mice by oral application of a periodontal pathogen, Pg, and determined changes that occurred in islets following 22 weeks of Pg application. Pancreatic islet architecture was determined by 2-D and 3-D immunofluorescence microscopy and SerpinE1 and its target, urokinase plasminogen activator (uPA), as well as insulin, glucagon and Pg/gingipain in islets were detected by immunofluorescence. The presence of apoptotic islet cells was determined by both histochemical and immunofluorescence TUNEL assays. To investigate further the direct effect of Pg on apoptosis and the involvement of SerpinE1 in this process, we used SerpinE1 knockdown and scrambled control clones of the MIN6 pancreatic beta-cell line. RESULTS: Pg/gingipain was detected in both the periodontium and pancreas in the experimental group. Islets from animals that were administered Pg orally (experimental group) developed significant changes in islet architecture, upregulation of SerpinE1, and increased beta-cell apoptosis compared with the control group. We also observed that exposure of MIN6 cells to Pg in vitro resulted in apoptosis. However, apoptosis was significantly reduced when SerpinE1 expression by MIN6 cells was knocked down. CONCLUSION: Oral application of the periodontal pathogen Pg to C57BL/6 mice induces periodontitis, translocation of Pg/gingipain to the pancreas and results in complex alterations in pancreatic islet morphology. SerpinE1 appears to be involved in this process. PMID- 28643944 TI - Directory of otolaryngologic societies: (Secretaries of the various societies are requested to keep this information up to date.). PMID- 28643945 TI - Athens-based meeting to discuss the paediatric virology crossroad in October 2017. PMID- 28643940 TI - Proteomic profiling of extracellular vesicles secreted from Toxoplasma gondii. AB - Toxoplasma gondii infects a wide range of hosts worldwide, including humans and domesticated animals causing toxoplasmosis disease. Recently, exosomes, small extracellular vesicles (EV) that contain nucleic acids, proteins, and lipids derived from their original cells were linked with disease protection. The effect of EVs derived from T. gondii on the immune response and its relevance in a physiological context is unknown. Here we disclose the first proteomic profiling of T. gondii EVs compared to EVs isolated from a human foreskin fibroblast infected cell line cultured in a vesicle-free medium. Our results reveal a broad range of canonical exosomes proteins. Data are available via ProteomeXchange with the identifier PXD004895. PMID- 28643946 TI - Activated proline-rich tyrosine kinase 2 regulates meiotic spindle assembly in the mouse oocyte. AB - Proline-rich tyrosine kinase 2 (PYK2), a member of the protein tyrosine kinase family, plays an important role in various cellular processes. PYK2 can be phosphorylated on tyrosine 402 by diverse stimuli at the cell surface, and recent studies have shown that this activated form of PYK2 is enriched in oocytes and required for fertilization. However, the subcellular localization and functions of activated PYK2 in oocytes remain elusive. In this study, we demonstrate that the localization of p-PYK2 undergoes dynamic changes during in vitro maturation of mouse oocytes. The signal of p-PYK2 is initially dispersed in the cytoplasm, but begins to decorate organized microtubules after the germinal vesicle breakdown and localizes to spindle poles at metaphase. Our data further show that p-PYK2 colocalizes with gamma-tubulin from the germinal vesicle stage through the end of meiosis in mouse oocytes. Nocodazole treatment and washout experiments confirm that p-PYK2 associates with the oocyte spindle and spindle poles. Moreover, pharmacological inhibition of PYK2 activity dramatically alters the morphology of the bipolar spindle and prevents oocyte maturation. Together, these data suggest that activated PYK2 may function as a component of the microtubule organizing center to regulate spindle assembly during the meiotic process of mouse oocytes. PMID- 28643947 TI - Effect of TET1 regulating MGMT on chemotherapy resistance of oral squamous cell carcinoma stem cells. AB - The study was to evaluate the effect of ten-eleven translocation 1 (TET1) regulating o6-methylguanine-DNA methyltransferase (MGMT) in chemotherapy resistance of oral squamous cell carcinoma (OSCC) stem cells. OSCC stem cells were divided into the blank, negative control (NC), TET1-siRNA, TET1-siRNA + MGMT OE, and MGMT-OE groups. Methylation-specific polymerase chain reaction (MSP), qRT PCR and Western blotting were conducted to detect the methylation status of MGMT, expressions of TET1, MGMT, ABCG2, and Oct-4. Cell proliferation, cisplatin chemosensitivity, and cell cycle and apoptosis, were detected using CCK8 and flow cytometry. A chromatin immunoprecipitation (ChIP) assay was employed for detecting the link between TET1 and MGMT gene promoters. In comparison to the NC group, the TET1-siRNA group exhibited increased levels of MGMT methylation, the number of apoptotic cells and cisplatin chemosensitivity consisting of varying concentrations, however, decreased levels of mRNA and protein expressions of TET1 as well as MGMT, cell viability, the number of cells in the S phase, and protein expressions of ABCG2 and Oct-4 were all have diminished amounts. The TET1-siRNA + MGMT-OE and MGMT-OE groups had higher MGMT mRNA and protein expression, as well as increased protein expressions of ABCG2 and Oct-4, greater cell activity, higher number of cells in the S phase, decreased apoptotic rates in cells and decreased cisplatin chemosensitivity with different concentrations. Our study provided evidence that low-expression of TET1 in OSCC stem cells may stimulate MGMT promoter methylation, while inhibiting MGMT mRNA expression, this ultimately strengthens the sensitivity of OSCC stem cells in regards to chemotherapeutics. PMID- 28643949 TI - Role of surgery in delayed local treatment for INSS 4 neuroblastoma. AB - BACKGROUND: The aim of the present study was to compare the efficacy, complications and outcomes of the following two surgical strategies for delayed local treatment for International Neuroblastoma Staging System (INSS) 4 neuroblastoma (NB): complete resection (CR; period A); and gross total resection/subtotal resection (GTR/STR) with local irradiation (period B). METHODS: We retrospectively analyzed 17 patients with INSS 4 NB who received delayed local treatment (period A, n = 11; period B, n = 6). RESULTS: Eleven patients in period A received CR. Two patients underwent GTR and four patients underwent STR in period B. The amount of blood loss in period A was significantly greater than that in period B. Postoperative complications were observed in eight patients in period A (73%), but in only one patient in period B (17%; P < 0.01). Recurrence was observed in five patients in period A and in one patient in period B (45.4% vs 16.6%; P = n.s.). Distant metastasis at recurrence was observed in four patients in period A and in one patient in period B. CONCLUSIONS: Gross total resection/subtotal resection with local irradiation may be a safe and effective delayed local treatment for INSS 4 NB. PMID- 28643948 TI - Investigating the separate and interactive associations of trauma and depression on brain structure: implications for cognition and aging. AB - OBJECTIVE: Trauma and depression are associated with brain structural alterations; their combined effects on these outcomes are unclear. We previously reported a negative effect of trauma, independent of depression, on verbal learning and memory; less is known about underlying structural associates. We investigated separate and interactive associations of trauma and depression on brain structure. METHODS: Adults aged 30-89 (N = 203) evaluated for depression (D+) and trauma history (T+) using structured clinical interviews were divided into 53 D+T+, 42 D+T-, 50 D-T+, and 58 D-T-. Multivariable linear regressions examined the separate and interactive associations of depression and trauma with prefrontal and temporal lobe cortical thickness composites and hippocampal volumes adjusting for age, sex, predicted verbal IQ, comorbid anxiety, and vascular risk. Significant results informed analyses of tract-based structural connectomic measures of efficiency and centrality. RESULTS: Trauma, independent of depression, was associated with greater left prefrontal cortex (PFC) thickness, in particular the medial orbitofrontal cortex and pars orbitalis. A trauma * depression interaction was observed for the right PFC in age-stratified analyses: Older D + T+ had reduced PFC thickness compared with older D - T+ individuals. Regardless of age, trauma was associated with more left medial orbitofrontal cortex efficiency and less pars orbitalis centrality. In the T+ group, left pars orbitalis cortical thickness and centrality negatively correlated with verbal learning. CONCLUSIONS: Trauma, independent of depression, associated with altered PFC characteristics, morphologically and in terms of structural network communication and influence. Additionally, findings suggest that there may be a combined effect of trauma and depression in older adults. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28643950 TI - Atypical dyskeratosis congenita diagnosed using whole-exome sequencing. PMID- 28643951 TI - Magnetic graphene oxide modified by imidazole-based ionic liquids for the magnetic-based solid-phase extraction of polysaccharides from brown alga. AB - Magnetic graphene oxide was modified by four imidazole-based ionic liquids to synthesize materials for the extraction of polysaccharides by magnetic solid phase extraction. Fucoidan and laminarin were chosen as the representative polysaccharides owing to their excellent pharmaceutical value and availability. Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, and thermogravimetric analysis were applied to characterize the synthesized materials. Single-factor experiments showed that the extraction efficiency of polysaccharides was affected by the amount of ionic liquids for modification, solid-liquid ratio of brown alga and ethanol, the stirring time of brown alga and ionic liquid-modified magnetic graphene oxide materials, and amount of 1-(3-aminopropyl)imidazole chloride modified magnetic graphene oxide materials added to the brown alga sample solution. The results indicated that 1 (3-aminopropyl)imidazole chloride modified magnetic graphene oxide possessed better extraction ability than graphene oxide, magnetic graphene oxide, and other three ionic-liquid-modified magnetic graphene oxide materials. The highest extraction recoveries of fucoidan and laminarin extracted by 1-(3 aminopropyl)imidazole chloride modified magnetic graphene oxide were 93.3 and 87.2%, respectively. In addition, solid materials could be separated and reused easily owing to their magnetic properties. PMID- 28643952 TI - Asn194Lys mutation in RVG29 peptide increases GFP transgene delivery by endocytosis to neuroblastoma and astrocyte cells. AB - OBJECTIVES: A cell-penetrating peptide-based delivery system could target specific types of cells for therapeutic genes delivery. To increase the gene delivery efficiency into neuronal phenotype cells, we introduced an Asn194Lys mutation to RVG29 peptide derived from rabies virus glycoprotein and added a nuclear localization signal to enhance its nuclear import. METHODS: Mutant RVG or wild-type RVG peptide, a karyophilic peptide (KP) and a plasmid encoding green fluorescent protein (pGL) were bound by electrostatic charges to form four different kinds of RVG complexes. Immunofluorescence was used to assess the gene transfection efficiency into astrocytes, oligodendrocyte precursor cells (OPCs), SH-SY5Y, HeLa and NIH/3T3 cells. The cellular uptake mechanism of RVG29 complexes was examined using endocytosis inhibitors. KEY FINDINGS: The mRVG29 peptide has the ability to enhance the nuclear import of plasmids. The Asn194Lys mutation in RVG29 peptide of the pGL-mRVG29 complex and the addition of KP to the pGL-RVG29 KP complex increased the capacity to deliver DNA by endocytosis in astrocytes and SH-SY5Y cells. CONCLUSIONS: The complexes pGL-mRVG29 and pGL-RVG29-KP have specificity for transfecting astrocytes and SH-SY5Y cells. The karyophilic capacity of this new mRVG peptide render it promising candidate to act as gene delivery vector into the brain cells. PMID- 28643953 TI - The entomopathogenic fungus Nomuraea rileyi impairs cellular immunity of its host Helicoverpa armigera. AB - In this study, we investigated the effect of the entomopathogenic fungus Nomuraea rileyi on Helicoverpa armigera cellular immune responses. Nomuraea rileyi infection had no effect on total hemocyte count (THC), but impaired hemocyte mediated phagocytosis, nodulation, and encapsulation responses. Nomuraea rileyi infection led to a significant reduction in hemocyte spreading. An in vitro assay revealed that plasma from N. rileyi infected H. armigera larvae suppressed the spreading ability of hemocytes from naive larvae. We infer that N. rileyi suppresses the cellular immune response of its host, possibly by secreting exogenous, cytotoxic compounds into the host's hemolymph. PMID- 28643956 TI - Unilateral pallidotomy for blepharospasm refractory to botulinum toxin injections. PMID- 28643955 TI - Diffusion tensor imaging of normal-appearing white matter in patients with neuromyelitis optica spectrum disorder and multiple sclerosis. AB - BACKGROUND AND PURPOSE: The occult changes in normal-appearing white matter (NAWM) were investigated and compared amongst patients with neuromyelitis optica spectrum disorder (NMOSD), patients with multiple sclerosis (MS) and healthy controls (HCs) by applying tract-based spatial statistics to diffusion tensor imaging (DTI) data. METHODS: Diffusion tensor imaging was performed with a 3-T scanner in 93 patients with NMOSD, 53 patients with MS and 43 HCs. Voxel-wise statistical analyses of the DTI data were performed using tract-based spatial statistics. RESULTS: Compared to HCs, patients with NMOSD had significantly lower mean global fractional anisotropy, higher mean diffusivity and radial diffusivity, and no significant differences in axial diffusivity in their NAWM. Patients with MS demonstrated significantly lower mean global fractional anisotropy and higher mean diffusivity, axial diffusivity and radial diffusivity in the NAWM than did patients with NMOSD and HCs. Compared to patients with NMOSD, patients with MS had NAWM damage that was more extensive, particularly in the inferior cerebellar peduncle, external capsule, cingulum, superior fronto occipital fasciculus and uncinate fasciculus. CONCLUSIONS: Using DTI, widespread occult damage was demonstrated in the NAWM of patients with NMOSD. However, the NAWM was less affected in patients with NMOSD than it was in patients with MS; specifically, the axonal injuries and diffusion abnormalities in the association fibers were more severe in patients with MS than they were in patients with NMOSD. PMID- 28643957 TI - Effectiveness of levetiracetam in an acetazolamide-unresponsive patient with episodic ataxia type 2 by a novel CACNA1A nonsense mutation. PMID- 28643958 TI - Insular cortex and QT correction interval: an effect of hemispheric lateralization? PMID- 28643959 TI - Riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency: delayed hypersensitivity reaction and efficacy of low-dose intermittent supplementation. PMID- 28643960 TI - Asymptomatic subcutaneous cervical mass due to Actinomyces odontolyticus infection in a pyriform sinus fistula. PMID- 28643962 TI - ? PMID- 28643963 TI - [Neuropathic component of low back pain]. AB - Despite the advances in the understanding of the underlying mechanisms of chronic low back pain, treatment remains challenging in clinical practice. In this article we are focusing on the neuropathic component of chronic low back pain. Indeed, depending on which diagnostic tools are used, 16-55% of patients suffering from chronic low back pain present a neuropathic component. We here expose the specific mechanisms of neuropathic pain, the diagnostic tools available for their detection as well as the specific treatment options. PMID- 28643961 TI - Bioelectroventing: an electrochemical-assisted bioremediation strategy for cleaning-up atrazine-polluted soils. AB - The absence of suitable terminal electron acceptors (TEA) in soil might limit the oxidative metabolism of environmental microbial populations. Bioelectroventing is a bioelectrochemical strategy that aims to enhance the biodegradation of a pollutant in the environment by overcoming the electron acceptor limitation and maximizing metabolic oxidation. Microbial electroremediating cells (MERCs) are devices that can perform such a bioelectroventing. We also report an overall profile of the 14 C-ATR metabolites and 14 C mass balance in response to the different treatments. The objective of this work was to use MERC principles, under different configurations, to stimulate soil bacteria to achieve the complete biodegradation of the herbicide 14 C-atrazine (ATR) to 14 CO2 in soils. Our study concludes that using electrodes at a positive potential [+600 mV (versus Ag/AgCl)] ATR mineralization was enhanced by 20-fold when compared to natural attenuation in electrode-free controls. Furthermore, ecotoxicological analysis of the soil after the bioelectroventing treatment revealed an effective clean-up in < 20 days. The impact of electrodes on soil bioremediation suggests a promising future for this emerging environmental technology. PMID- 28643964 TI - [Diagnosis and prognosis of low back pain: contribution and limitations of the clinical approach]. AB - The label " non-specific " that applies to 85% of patients complaining of low back pain is an heterogeneous group including different phenotypes. The identification of the anatomic origin of pain is often impossible in a primary care encounter. However, the physician can identify several elements that are useful to establish some diagnosis, foresee the evolution and tailor therapeutic decisions. PMID- 28643965 TI - [A clinical tool to develop therapeutic goals with chronic low back pain patients]. AB - When treating patients suffering from chronic low back pain, it is important to determine therapeutic objectives that are realistic, measurable and focused on the activities of everyday life. To help patients and therapists to elaborate these objectives, we developped a clinical tool made of a metric scale graduated from 0 to 10 and of a series of photographs. Within the framework of a semi structured interview, this tool is a help not only in the detection of relevant activities that may induce fear avoidance behaviours but also in the determination and negotiation of objectives that can be realised in the care process and are adapted to the patient's context of living. PMID- 28643966 TI - [What is the role of surgery in low back pain associated with Modic changes?] AB - Benign low back pain is frequent in the lucratively active population. Degenerative changes are considered the most frequent causes. The identification of pain generators remain challenging. Bone marrow lesions, Modic changes, are frequently associated with benign low back pain, mostly type 1. The etiology of Modic changes is unknown, both infectious and autoimmune mechanisms have been suggested. Despite the strong association of Modic changes with low back pain it is not clear whether lumbar surgery (lumbar fusion, total disc replacement) has any role in the management of these patients. We conclude that all available evidence in literature is inconclusive and future studies are needed addressing more precisely the question of minimal clinically important difference (MCID) while considering of all confounding factors influencing outcome. PMID- 28643967 TI - [Place of interdisciplinary treatments in chronic low back pain]. AB - The treatment of chronic lumbar pain patients needs a global interdisciplinary approach when traditional conservative treatments do not fulfil their aims. One of the most efficient ways to proceed is using an interdisciplinary treatment program, including physiotherapeutic measures, occupational therapy and psychological support for 3 weeks. It is important that people in conflicts with insurances companies should be excluded from these treatments. It is also important that the reconditioning should continue over a long term to have a sustainable result. PMID- 28643968 TI - [Complementary medicine for low back pain : what is the scientific evidence ?] AB - Complementary medicines are frequently used by chronic pain patients. It is a challenge for the primary care physician to provide objective information based on the scientific literature. Meta-analyses have shown favourable effects of acupuncture, therapeutic massage and osteopathy for patients with acute low back pain. Concerning chronic low back pain, meta-analyses have shown positive results with acupuncture, osteopathy, yoga and tai-chi. Other therapies have shown positive effects, but further trials are necessary to fully validate them. This article reviews the literature supporting the most studied complementary medicines. PMID- 28643970 TI - ? PMID- 28643969 TI - ? PMID- 28643971 TI - ? PMID- 28643972 TI - ? PMID- 28643973 TI - ? PMID- 28643974 TI - ? PMID- 28643975 TI - ? PMID- 28643976 TI - ? PMID- 28643977 TI - [Multidisciplinary management of localized rectal cancer]. AB - Rectal cancer remains a frequent pathology, with a good prognosis, according to a proper management. During the last decades, we have been confronted with important improvements, notably regarding the diagnosis and the treatment. In the era of highly specialized medicine, it is clear that the management must be multidisciplinary, incorporating not only the surgeon, the oncologist and the radiation oncologist, but also the radiologist, the gastroenterologist, and the pathologist. We aim to review the recent concepts and the future developments in the management of rectal cancer. PMID- 28643978 TI - [Diagnosis and management of gastro-esophageal junction tumor]. AB - At the border between the esophagus and the stomach, gastro-esophageal junction tumors require a specific management that cannot be simplified to either of these two organs. Staging work-up with endoscopy, CT-Scan and PET-Scan, is essential because it will condition the choice of neo-adjuvant treatment. Surgery remains the only curative treatment and should be undergone in specialized center. PMID- 28643979 TI - [Acute pancreatitis : new aspects for the management]. AB - Acute pancreatitis is a frequent disease, with a simple course in 80 % of the cases but a high morbidity and mortality in its severe form. Biliary origin and alcohol represent 80 % of the etiologies. Except endoscopic removal of gallstone for biliary origin, treatment remains symptomatic and focuses on fluid resuscitation, effective antalgia and adapted management of nutrition. This article focuses on the novelties introduced by the revision of the Classification of Atlanta in 2012 and details current guidelines for the management of the disease. The evolution of conservative treatment has allowed to reduce and postpone need for surgery and requires an interdisciplinary collaboration between surgeons, gastroenterologists, interventional radiologists and intensivists. PMID- 28643980 TI - [Hiatal hernia : current diagnostic and therapeutic management]. AB - Hiatal hernia is a frequent pathology. Two types have been described : sliding hernia and paraesophageal hernia (PEH). The first one is the most frequent and is associated with reflux disease. Patients with PEH have a large variety of symptoms, such as chest pain, dyspnea, regurgitation, iterative pneumonia and iron-deficiency anemia. Operative management is necessary for sliding hernia with reflux disease and for symptomatic PEH, respectively. In patients with asymptomatic PEH, operative risk must be balanced with the risk of postoperative complications. No specific operative technique has been validated so far as surgical standard. Several technical details are important and technique has to be adapted according to the size and type of hernia, preoperative symptoms and patient's comorbidities. PMID- 28643981 TI - [Adrenal surgery : Multidisciplinarity is mandatory]. AB - Adrenal tumours are rare and their management is challenging. Every patient presenting with adrenal mass or symptoms of hormones hypersecretion should be investigated. The two important questions to be answered are : 1. Is the tumour secreting ? Is the tumour malignant or not ? A complete endocrine work-up and a nativ CT-scan may usually answer these two questions but have to be interpreted by specialists in a multidisciplinary team setting. The decisions about managements of adrenal pathologies do follow international guidelines which are regularly updated. It is not recommended to perform diagnostic or surgical procedure before excluding pheochromocytoma or adrenocortical carcinoma which could have fatal outcome for the patient. Every adrenal mass has to be investigated and should not be made commonplace. PMID- 28643983 TI - [An underestimated cause of seizure in Europe]. AB - Seizures are very common in the Emergency Department (ED). We present here a case of a young woman with neurocysticercosis ; a worldwide and nearly endemic cause of seizure in the southern hemisphere. Clinical manifestations are very different between patients from asymptomatic to life-threatening hydrocephalus. Diagnosis is based on a combination of clinical presentation, neuroimaging (CT and MRI) findings, history of exposure, and serologic testing. PMID- 28643984 TI - ? PMID- 28643982 TI - [Current surgical treatment for hepatocellular carcinoma : critical appraisal of current guidelines]. AB - Hepatocellular carcinoma (HCC) management has evolved in the last decades. Current available treatments include interventional radiology like radiofrequency ablation, transarterial chemoembolization or Yttrium 90 radioembolization. Surgery, when possible, has been proven to be the most effective treatment in reducing the risk of long-term local recurrence. American and European societies (AASLD, EASL, respectively) guidelines for the management of HCC endorse The Barcelona Clinic Liver Cancer (BCLC) treatment allocation system. One drawback of the BCLC system is its restrictiveness regarding surgical indications. This present article aims in reviewing the indications of surgical resection for HCC. PMID- 28643985 TI - ? PMID- 28643986 TI - ? PMID- 28643987 TI - ? PMID- 28643988 TI - ? PMID- 28643989 TI - ? PMID- 28643990 TI - Bcl-2 and Caspase-9 serum levels in children and adolescents with idiopathic epilepsy and active seizures. AB - BACKROUND: In the present study we investigated the levels of proapoptotic Caspase-9 and antiapoptotic Bcl-2 proteins in the sera of children and adolescents with idiopathic epilepsy and tried to relate the findings to the patients clinical parameters. METHODS: This retrospective study consisted of 118 children and adolescents with idiopathic epilepsy, categorized according to type and number of seizures, duration of the disease and the control of seizures and 30 age and sex matched controls. The relapse of seizures was taken into consideration. RESULTS: Mean serum level between Bcl-2 and Caspase-9 was significantly higher only in Bcl-2 patients, compared to controls (p<=0,0001) and (p=0,987) respectively. Significant difference in Bcl-2 level was found among the different types of focal seizures. Caspase-9 level was statistically different in patients with two or more seizures per month compared to those with one seizure per month (p=0,048). No correlation was found between Bcl-2 and Caspase-9 levels and age, gender, seizure frequency, total number of seizures and the duration of epilepsy. No significant difference was found in patients with and without drug treatment. CONCLUSIONS: Bcl-2 displays an association with apoptosis and highlights the potential of being a surrogate biomarker for active seizures and epilepsy. There is a significant difference in Bcl-2 serum level among the different types of focal seizures. Proapoptotic Caspase-9 cannot act as a marker of active seizures and epilepsy. Caspase-9 serum level is increased acutely in controlled cases after a single relapse. PMID- 28643991 TI - Sleep duration, quality of life and depression in adolescents: a school-based survey. AB - BACKGROUND: The main objective of this study was to assess the link between sleep duration, quality of life and depression in adolescents. The secondary objective was to study the sleeping behavior of a large sample of adolescents from different socioeconomic backgrounds. METHODS: Study subjects were high school students studying in or around Paris with a general, vocational or technological training background. A survey was conducted to evaluate the subject's perception of their own sleep, quality of life and depression. RESULTS: The survey analyzed 855 students between 14 and 19 years of age, with equal numbers of males and females. The average sleep duration was 7 h 14 min +/- 1 h 20 min and was inversely correlated with age (r = -0.142, p<0.01). Students studying vocational subjects reported significantly more sleep than students studying technological subjects (p=0.02). Univariate analyses revealed a positive relationship between sleep duration and quality of life (r = 0.17, p<0.001) and an inverse relationship between sleep duration and depression (r = -0.5, p<0.001). Multivariate analyses identified depression, delayed sleep phase disorder, and medical condition as determinants of sleep duration. CONCLUSIONS: This investigation of a large student cohort has confirmed that the average sleep duration in adolescents is far below what is recommended. Depression significantly influenced sleep duration. We recommend that a quantitative and qualitative evaluation of sleep should be made during the medical examination of any adolescent. PMID- 28643992 TI - Recent perspectives of molecular aberrations in pediatric high-grade glioma. AB - Paediatric high-grade glioma (HGG), including diffuse intrinsic pontine glioma (DIPG) are highly aggressive tumours with no effective cures. Lack of understanding of the molecular biology of these tumours, in part due to lack of well-characterized pre-clinical models, is a great challenge in the development of novel therapies. Recent studies have shown that paediatric HGG short-term cell cultures retain many of the tumour characteristics in vivo and at present one of the best choices for in-vivo experimental studies. The present review article would put light on novel genetic and epigenetic changes in paediatric HGG that might, act as a gold standard potential biomarkers and/or therapeutic targets in near future. PMID- 28643993 TI - The impact of vitamin D supplementation on serum cathelicidin levels and the clinical course of atopic dermatitis in children. AB - BACKGROUND: Cathelicidin has been correlated with the pathophysiology of atopic dermatitis (AD). An indirect correlation of vitamin D with the course of the disease has already been reported as it directly affects the levels of cathelicidin. The purpose of the present article is to investigate the impact of vitamin D supplementation on the course of AD. METHODS: We conducted a prospective observational study. The severity of AD was assessed with the clinical tool SCORAD (SCORing Atopic Dermatitis) which is developed by the European Task Force on AD. RESULTS: Fifty children with AD were enrolled and stratified in two groups based on the severity of SCORAD. Children with severe AD (SCORAD index> 40) received higher doses of vitamin D in order to sufficiently reduce the disease (comparable index SCORAD children with mild atopic dermatitis). While the baseline SCORAD differed statistically significant level between the two groups of children with AD (p <.001) this difference disappeared at 20 (p = .649) days and remained statistically insignificant both at 45 days (p = .610), and at the end of the administration of treatment (p = .474) (Table). This effect was based on a significant downregulation of the severity of symptoms in the group of children that received 2400 IU of vitamin D. CONCLUSIONS: The findings of our study suggest that vitamin D may be accurately used in current clinical practice for the management of AD. However, the recommended dose should be titrated taking in mind the severity of the disease. PMID- 28643994 TI - The impact of valproic acid treatment on weight gain in pediatric patients with epilepsy. AB - BACKGROUND: Valproic acid (VPA) is an antiepileptic drug, used for focal and generalized seizure. VPA treatment resulted in significant weight gain but there are no systematic data about the prevalence of this side effect. The aim of the study is to evaluate the weight gain of a paediatric population with epilepsy. METHODS: We enrolled 38 patients, 17 female and 21 male with a mean age of 8.2+/ 4.4 years. We evaluated data about height, weight and BMI at beginning of treatment and at 24, 36 and 48 months of follow-up. RESULTS: There is a statistical significant difference between the percentile value of weight and BMI at baseline and at 36 and 48 months of follow-up (P value <0.01) but there isn't statistical significant difference between the percentile value of height (P value 0.22 and 0.18). CONCLUSIONS: We believe that a nutritional support should be guaranteed to the pediatric patients with epilepsy that begin the VPA therapy. PMID- 28643995 TI - Contraception options and provision to adolescents. AB - Adolescent pregnancy is a significant cause of global morbidity and mortality. Adolescents who become pregnancy have lower educational attainment, are more likely to live in poverty, and have lower wellbeing. Increasing access to hormonal contraceptives and long acting reversible contraception is highly effective in reducing adolescent pregnancies. This narrative review covers key aspects of the provision of contraception to adolescents, including confidentiality, counseling, and data supporting expanded access to adolescents. We provide information for pediatric providers to start adolescent patients on contraceptives, including a detailed description of each method, including effectiveness, use, starting, side effects and benefits. Tools for counseling and prescribing are provided. PMID- 28643996 TI - Age-related outcome of patients after traumatic brain injury: a single-center observation. AB - BACKGROUND: The purpose of the present study was to analyze clinical features of patients with traumatic brain injury (TBI), their age-related outcomes and determinants of long-term outcome. METHODS: This retrospective cohort study was conducted in a level I University Swiss trauma center. Consecutive patients with moderate to severe TBI admitted for more than 48 hours to the Intensive Care Unit (ICU) were included. Patients' and trauma characteristics, management during ICU stay, prognostic scores and long-term outcomes were analyzed. RESULTS: Hundred seventy-four patients (72% males, mean age 49 years) were divided in three age groups: young (<=39 years, N.=69, 39.7%), middle aged (40-64 years, N.=55, 31.6%), and elderly (>=65 years, N.=50, 28.7%). In elderly patients, falls (62%) were the most common cause of TBI. Overall ICU mortality was 15% with no difference among age groups. Within six-months after TBI, 80% of elderly patients presented unfavorable outcomes. Age, pre-existing cardiovascular disease, use of anticoagulants and/or antiplatelet agents, abnormal pupillary reactivity, a high score in Marshall CT classification, and a higher glucose level were associated with unfavorable outcomes in a univariable logistic regression. In a multivariable logistic regression, age and abnormal pupillary reactivity were identified as independent risk factors for unfavorable outcomes, while presence of epidural hematoma and higher hemoglobin levels were predictors for favorable outcomes. CONCLUSIONS: Older patients are at higher risk for long-term unfavorable outcomes than younger patients. Use of anticoagulants and/or antiplatelet agents and lower hemoglobin levels during rescue phase are associated with unfavorable long-term outcomes. Fall prevention in the elderly should be a key target of intervention programs. PMID- 28643997 TI - Brain monitoring in adult and pediatric ECMO patients: the importance of early and late assessments. AB - Monitoring brain integrity and neurocognitive function is a new and important target for the management of a patient treated with extracorporeal membrane oxygenation (ECMO), in particular because of the increasing awareness of cerebral abnormalities that may potentially occur in this setting. Continuous regular monitoring, as well as repeated assessment for cerebral complications has become an essential element of the ECMO patient management. Besides well-known complications, like bleeding, ischemic stroke, seizures, and brain hypoperfusion, other less defined yet relevant injury and clinical manifestations are increasingly reported and impacting on ECMO patient prognosis at short term. Furthermore, it is becoming more evident that neurologic complication may not occur only in the early phase. Indeed, other potential adverse events related to the long-term neurocognitive function have been also recently documented either in children or adult ECMO patients. Despite increasing awareness of these aspects, generally accepted protocols and clinical management strategies in this respect are still lacking. Current means to monitor brain perfusion or detecting ongoing cerebral tissue injury are rather limited, and most techniques provide indirect or post-insult recognition of irreversible tissue injury. Continuous monitoring of brain perfusion, serial assessment of brain-derived serum biomarkers, timely neuro-imaging, and post-discharge counselling for neurocognitive dysfunction, particularly in pediatric patients, are novel pathways focusing on neurologic assessment with important implications in daily practice to assess brain function and integrity not only during the ECMO-related hospitalization, but also at long-term to re-evaluate the neuropsychological integrity, although well designed studies will be necessary to elucidate the cost effectiveness of these management strategies. PMID- 28643998 TI - Survey in expert clinicians on the validity of automated calculation of optimal cerebral perfusion pressure. AB - BACKGROUND: Optimal cerebral perfusion pressure (CPPopt) targeting in traumatic brain injury (TBI) patients constitutes an active and controversial area of research. It has been suggested that an autoregulation guided CPP therapy may improve TBI outcome. Prerequisites of a CPPopt intervention study would be objective criteria for the CPPopt detection. This study compared the agreement between automated and visual CPPopt detection. METHODS: Twenty-five clinicians from 18 centers worldwide, familiar with brain monitoring and using dedicated software, reviewed ten 4-hour CPPopt screenshots at 48 hours after ictus in selected TBI patients. Each screenshot displayed the trends of cerebral perfusion pressure (CPP), intracranial pressure (ICP), cerebrovascular pressure reactivity (PRx) as well as the "CPP-optimal" curve and its associated value (automated CPPopt). The main objective was to evaluate the agreement between expert clinicians as well as the agreement between the clinicians and automated CPPopt. RESULTS: Twenty-two clinicians responded to our call (88%). Three screenshots were judged as "CPPopt not determinable" by >45% of the clinicians. For the whole group, the consensus between automated CPPopt and clinicians' visual CPPopt was high. Three clinicians were identified as outliers. All clinicians recommended to modify CPP when patients differed >+/-5 mmHg from their CPPopt. The inter observer consensus was highest in cases with current CPP below the optimal value. CONCLUSIONS: The overall agreement between automated CPPopt and visual CPPopt identified by autoregulation experts was high, except for those cases when the curve was deemed by the clinicians not reliable enough to yield a trustworthy CPPopt. PMID- 28643999 TI - Dexmedetomidine and general anesthesia: a narrative literature review of its major indications for use in adults undergoing non-cardiac surgery. AB - INTRODUCTION: In Europe, dexmedetomidine has marketing approval only for sedation in intensive care units. However, its use during general anesthesia has been widely reported. The aim of this narrative review is to draw a picture of potential indications in anesthesia. EVIDENCE ACQUISITION: We searched in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials using the keywords "Dexmedetomidine, Dexdor, Precedex and Dexdomitor." The research ended in December 2016. Studies were eligible for inclusion if they reported the use of dexmedetomidine in adults receiving general anesthesia. We excluded studies related to cardiac surgery and studies reporting the use of dexmedetomidine as an adjuvant of locoregional anesthesia. EVIDENCE SYNTHESIS: Several potential uses for dexmedetomidine during general anesthesia are described, especially: awake fiber optic intubation, the sparing effect of dexmedetomidine on hypnotic and opioid drugs, prevention of postoperative pain, nausea and vomiting and shivering, improvement of postoperative sleep and postoperative recovery, opioid free anesthesia, use in craniotomy, endovascular stroke treatment and drug induced sleep endoscopy. A protective effect against cardiac complications, an anti-inflammatory effect, and side effects, particularly bradycardia, are also described. CONCLUSIONS: The properties of dexmedetomidine lead to its use for elective indications such as awake fiberoptic intubation and neurosurgical anesthesia. New topics are under debate. These subjects must be studied thoroughly because of their implication in the patients' surgical course. These advantages must be weighed against the major drawback of dexmedetomidine administration which is the potential for hemodynamic abnormalities. PMID- 28644001 TI - Evaluation of Multivalent Cation Insertion in Single- and Double-Layered Polymorphs of V2O5. AB - Multivalent intercalation batteries have the potential to circumvent several fundamental limitations of reigning Li-ion technologies. Such batteries will potentially deliver high volumetric energy densities, be safer to operate, and rely on materials that are much more abundant than Li in the Earth's crust. The design of intercalation cathodes for such batteries requires consideration of thermodynamic aspects such as structural distortions and energetics as well as kinetic aspects such as barriers to the diffusion of cations. The layered alpha V2O5 system is a canonical intercalation host for Li-ions but does not perform nearly as well for multivalent cation insertion. However, the rich V-O phase diagram provides access to numerous metastable polymorphs that hold much greater promise for multivalent cation intercalation. In this article, we explore multivalent cation insertion in three metastable polymorphs, gamma', delta', and rho' phases of V2O5, using density functional theory calculations. The calculations allow for evaluation of the influence of distinctive structural motifs in mediating multivalent cation insertion. In particular, we contrast the influence of single versus condensed double layers, planar versus puckered single layers, and the specific stacking sequence of the double layers. We demonstrate that metastable phases offer some specific advantages with respect to thermodynamically stable polymorphs in terms of a higher chemical potential difference (giving rise to a larger open-circuit voltage) and in providing access to diffusion pathways that are highly dependent on the specific structural motif. The three polymorphs are found to be especially promising for Ca-ion intercalation, which is particularly significant given the exceedingly sparse number of viable cathode materials for this chemistry. The findings here demonstrate the ability to define cation diffusion pathways within layered metastable polymorphs by alteration of the stacking sequence or the thickness of the layers. PMID- 28644000 TI - [Elimination in South-East Asia? The role of antimalarial drugs]. AB - Artemisinin resistance in P. falciparum is spreading in South East Asia and threatens the recent progresses made in the fight against malaria. A race against time has started to eliminate P.falciparum in this region before it becomes resistant to all available treatments. Antimalarials have a central role in the current elimination programme in eastern Burma on the border with Thailand. The combination of artemether and lumefantrine is used in association with primaquine for the early treatment of clinical cases. The slowly eliminated dihydro artemisinin and piperaquine is the drug of choice in mass drug administration in the foci of high prevalence of sub-microscopic and asymptomatic infections. Initial results after 18 months of activities are promising: the participation of the population was excellent and there was a sharp reduction of P.falciparum incidence without evidence of worsening resistance. PMID- 28644002 TI - Understanding Photocharging Effects on Bismuth Vanadate. AB - Bismuth vanadate (BiVO4) is a promising material for photoelectrochemical water oxidation. Recently, it has been shown that "photocharging" BiVO4 results in an improved water oxidation performance. However, the understanding of how BiVO4 is being improved has been lacking. Here we study the surface kinetics of BiVO4 using intensity-modulated photocurrent spectroscopy and show that photocharging BiVO4 results in both surface and bulk improvements. This result sheds light on how the surface charge transfer and bulk charge transport of BiVO4 respond to illumination. PMID- 28644003 TI - Chemical Sensor Based Upon Stress-Induced Changes in the Permeability of a Magnetoelastic Wire. AB - We introduce a chemical sensing technology, named ChIMES (Chemical Identification through Magneto-Elastic Sensing), that can detect a broad range of targets and that has the capability of untethered communication through a metallic or nonmetallic barrier. These features enable many applications in which penetrations into the sampled environment are unwanted or infeasible because of health, safety, or environmental concerns, such as following the decomposition of a dangerous material in a sealed container. The sensing element is passive and consists of a target response material hard-coupled to a magnetoelastic wire. When the response material encounters a target, it expands, imposing mechanical stress on the wire and altering its magnetic permeability. Using a remote excitation-detection coil set, the changes in permeability are observed by switching the magnetic domains in the wire and measuring the modifications in the Faraday voltage as the stress is varied. Sensors with different response materials can be arrayed and interrogated individually. We describe the sensor and its associated instrumentation, compare the performance of several types of wire, and evaluate analytical metrics of single and arrayed ChIMES sensors against a suite of volatile organic compounds. PMID- 28644005 TI - From Electrochemistry to Electroluminescence: Development and Application in a Ratiometric Aptasensor for Aflatoxin B1. AB - Aflatoxin B1 (AFB1), one of the most toxic chemical carcinogens, has been widely studied. It remains challenging to develop simple, accurate, and sensitive analytical methods for the detection of AFB1 in food matrixes. In this work, on the basis of a dual-signaling strategy, a ratiometric aptasensor was designed and verified for the accurate and sensitive detection of AFB1. The electrochemical method was first used as a model to verify the specific interaction between AFB1 and the aptamer, in which ferrocene (Fc)-anchored and methylene blue (MB) anchored DNA sequences acted as dual signals. Consequently, the specific interaction between AFB1 and its aptamer was demonstrated by the "signal-on" mode of Fc and the "signal-off" mode of MB. Due to the simple dual-signaling mode, the electrochemical sensor was further extended to the construction of an electrochemiluminoscence (ECL) aptasensor. In the ECL system, dual ECL signals were produced from CdTe/CdS/ZnS quantum dots (QDs) and luminol. Horseradish peroxidase-modified gold nanorods (HRP/Au NRs) acted as the quencher/enhancer and as such quenched the ECL signal of the QDs by ECL energy transfer and simultaneously catalyzed H2O2 to enhance the ECL of luminol. Owing to the self calibration by the internal reference, both of the ratiometric aptasensors exhibited accurate and sensitive analytical performance for AFB1 with a good linear range from 5.0 pM to 10 nM and detection limits of 0.43 and 0.12 pM (S/N = 3), respectively. The aptasensors also exhibited good selectivity, reproducibility, and stability, revealing potential applications in food safety monitoring and environmental analysis. PMID- 28644004 TI - Intricate Effects of alpha-Amino and Lysine Modifications on Arginine Methylation of the N-Terminal Tail of Histone H4. AB - Chemical modifications of the DNA and nucleosomal histones tightly control the gene transcription program in eukaryotic cells. The "histone code" hypothesis proposes that the frequency, combination, and location of post-translational modifications (PTMs) of the core histones compose a complex network of epigenetic regulation. Currently, there are at least 23 different types and >450 histone PTMs that have been discovered, and the PTMs of lysine and arginine residues account for a crucial part of the histone code. Although significant progress has been achieved in recent years, the molecular basis for the histone code is far from being fully understood. In this study, we investigated how naturally occurring N-terminal acetylation and PTMs of histone H4 lysine-5 (H4K5) affect arginine-3 methylation catalyzed by both type I and type II PRMTs at the biochemical level. Our studies found that acylations of H4K5 resulted in decreased levels of arginine methylation by PRMT1, PRMT3, and PRMT8. In contrast, PRMT5 exhibits an increased rate of arginine methylation upon H4K5 acetylation, propionylation, and crotonylation, but not upon H4K5 methylation, butyrylation, or 2-hydroxyisobutyrylation. Methylation of H4K5 did not affect arginine methylation by PRMT1 or PRMT5. There was a small increase in the rate of arginine methylation by PRMT8. Strikingly, a marked increase in the rate of arginine methylation was observed for PRMT3. Finally, N-terminal acetylation reduced the rate of arginine methylation by PRMT3 but had little influence on PRMT1, -5, and 8 activity. These results together highlight the underlying mechanistic differences in substrate recognition among different PRMTs and pave the way for the elucidation of the complex interplay of histone modifications. PMID- 28644007 TI - Cyclotides as Tools in Chemical Biology. AB - Among the various molecules that plants produce for defense against pests and pathogens, cyclotides stand out as exceptionally stable and structurally unique. These ribosomally synthesized peptides are around 30 amino acids in size, and are stabilized by a head-to-tail cyclic peptide backbone and three disulfide bonds that form a cystine knot. They occur in certain plants of the Rubiaceae, Violaceae, Cucurbitaceae, Fabaceae, and Solanaceae families, with an individual plant producing up to hundreds of different cyclotides. Aside from being exploitable as crop protection agents based on their natural pesticidal activities, cyclotides are amenable to repurposing by chemists for use as drug leads or as tools in chemical biology. Their macrocyclic peptide backbone and knotted arrangement of three disulfide bonds engenders cyclotides with resistance to proteolytic degradation, high temperatures, and chemical chaotropes. Furthermore, their small size makes them accessible to synthesis using solid phase peptide chemistry and so non-natural cyclotides can be designed and synthesized for a variety of applications. Our focus here is on cyclotides as tools in chemical biology, and there are four main areas of application that have appeared in the literature so far: (i) cyclotides as probes of membrane binding; (ii) cyclotides as probes of biosynthetic pathways for peptide cyclization; (iii) cyclotides as probes of protease specificity and function; and (iv) cyclotides as probes of receptor binding and specificity, with the potential for them to be developed as drug leads. The main methods used in these studies include solid phase peptide chemistry for synthesis and NMR spectroscopy for structural characterization, as well as a wide range of biochemical and biophysical techniques for probing intermolecular interactions. In addition, cyclotides have been examined in diverse biological assays, ranging from enzyme inhibition to cell penetration, intracellular targeting and cytotoxicity. The main finding to have emerged from studies over the past decade is that cyclotides are exceptionally stable under a variety of conditions (in assay buffers, biological fluids, membranes, and recombinant expression systems). Furthermore, they are structurally very well-defined and amenable to sequence substitutions that can introduce new desired biological activities, generally without compromising their exceptional stability. Both features contribute to their use as peptide-based frameworks in drug design. Finally, they occupy a size niche between traditional small-molecule drugs (<500 Da in molecular weight) and protein-based biologics (>5000 Da) and thus can probe receptors, membranes, and protein-protein interactions in different ways to what is possible with either small molecules or biologics. Overall, cyclotides are an exciting class of peptides that have great potential as ultrastable chemical biology probes in a variety of applications. They have the advantage of specificity (typical of proteins) combined with the synthetic accessibility of small molecules. PMID- 28644006 TI - Structure of the Forkhead Domain of FOXA2 Bound to a Complete DNA Consensus Site. AB - FOXA2, a member of the forkhead family of transcription factors, plays essential roles in liver development and bile acid homeostasis. In this study, we report a 2.8 A co-crystal structure of the FOXA2 DNA-binding domain (FOXA2-DBD) bound to a DNA duplex containing a forkhead consensus binding site (GTAAACA). The FOXA2-DBD adopts the canonical winged-helix fold, with helix H3 and wing 1 regions mainly mediating the DNA recognition. Although the wing 2 region was not defined in the structure, isothermal titration calorimetry assays suggested that this region was required for optimal DNA binding. Structure comparison with the FOXA3-DBD bound to DNA revealed more major groove contacts and fewer minor groove contacts in the FOXA2 structure than in the FOXA3 structure. Structure comparison with the FOXO1 DBD bound to DNA showed that different forkhead proteins could induce different DNA conformations upon binding to identical DNA sequences. Our findings provide the structural basis for FOXA2 protein binding to a consensus forkhead site and elucidate how members of the forkhead protein family bind different DNA sites. PMID- 28644008 TI - Influence of Tip and Substrate Properties and Nonsteady-State Effects on Nanogap Kinetic Measurements: Response to Comment on "Impact of Adsorption on Scanning Electrochemical Microscopy Voltammetry and Implications for Nanogap Measurements". PMID- 28644009 TI - Multi-harmonic Imaging in the Second Near-Infrared Window of Nanoparticle-Labeled Stem Cells as a Monitoring Tool in Tissue Depth. AB - In order to assess the therapeutic potential of cell-based strategies, it is of paramount importance to elaborate and validate tools for monitoring the behavior of injected cells in terms of tissue dissemination and engraftment properties. Here, we apply bismuth ferrite harmonic nanoparticles (BFO HNPs) to in vitro expanded human skeletal muscle-derived stem cells (hMuStem cells), an attractive therapeutic avenue for patients suffering from Duchenne muscular dystrophy (DMD). We demonstrate the possibility of stem cell labeling with HNPs. We also show that the simultaneous acquisition of second- and third-harmonic generation (SHG and THG) from BFO HNPs helps separate their response from tissue background, with a net increase in imaging selectivity, which could be particularly important in pathologic context that is defined by a highly remodelling tissue. We demonstrate the possibility of identifying <100 nm HNPs in depth of muscle tissue at more than 1 mm from the surface, taking full advantage of the extended imaging penetration depth allowed by multiphoton microscopy in the second near-infrared window (NIR-II). Based on this successful assessment, we monitor over 14 days any modification on proliferation and morphology features of hMuStem cells upon exposure to PEG-coated BFO HNPs at different concentrations, revealing their high biocompatibility. Successively, we succeed in detecting individual HNP-labeled hMuStem cells in skeletal muscle tissue after their intramuscular injection. PMID- 28644010 TI - Atomic Layer Deposition of an Indium Gallium Oxide Thin Film for Thin-Film Transistor Applications. AB - Indium gallium oxide (IGO) thin films were deposited via atomic layer deposition (ALD) using [1,1,1-trimethyl-N-(trimethylsilyl)silanaminato]indium (InCA-1) and trimethylgallium (TMGa) as indium and gallium precursors, respectively, and hydrogen peroxide as the reactant. To clearly understand the mechanism of multicomponent ALD growth of oxide semiconductor materials, several variations in the precursor-reactant deposition cycles were evaluated. Gallium could be doped into the oxide film at 200 degrees C when accompanied by an InCA-1 pulse, and no growth of gallium oxide was observed without the simultaneous deposition of indium oxide. Density functional theory calculations for the initial adsorption of the precursors revealed that chemisorption of TMGa was kinetically hindered on hydroxylated SiOx but was spontaneous on a hydroxylated InOx surface. Moreover, the atomic composition and electrical characteristics, such as carrier concentration and resistivity, of the ALD-IGO film were controllable by adjusting the deposition supercycles, composed of InO and GaO subcycles. Thus, ALD-IGO could be employed to fabricate active layers for thin-film transistors to realize an optimum mobility of 9.45 cm2/(V s), a threshold voltage of -1.57 V, and a subthreshold slope of 0.26 V/decade. PMID- 28644011 TI - Development of Silver-Nanoparticle-Decorated Emulsion-Templated Hierarchically Porous Poly(1-vinylimidazole) Beads for Water Treatment. AB - Water, the driver of nature, has always been polluted by the blind hurling of highly toxic contaminants, but human-friendly science has continuously been presenting better avenues to help solve these challenging issues. In this connection, the present study introduces novel nanocomposites composed of emulsion-templated hierarchically porous poly(1-vinylimidazole) beads loaded with the silver nanoparticles generated via an in situ approach. These nanocomposites have been thoroughly characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis, Brunauer-Emmett-Teller, and field emission scanning electron microscopy. The appropriate surface chemistry, good thermal stability, swelling behavior, porosity, and nanodimensions contributed to achieve very good performance in water treatment. Owing to their easier handling and separation, these novel nanocomposites are highly efficient to remove arsenic and eriochrome black T with decent adsorption capacities in addition to the inactivation and killing of Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram positive) bacteria. PMID- 28644013 TI - A Simple Approach to Prepare Carboxycellulose Nanofibers from Untreated Biomass. AB - A simple approach was developed to prepare carboxycellulose nanofibers directly from untreated biomass using nitric acid or nitric acid-sodium nitrite mixtures. Experiments indicated that this approach greatly reduced the need for multichemicals, and offered significant benefits in lowering the consumption of water and electric energy, when compared with conventional multiple-step processes at bench scale (e.g., TEMPO oxidation). Additionally, the effluent produced by this approach could be efficaciously neutralized using base to produce nitrogen-rich salts as fertilizers. TEM measurements of resulting nanofibers from different biomasses, possessed dimensions in the range of 190-370 and 4-5 nm, having PDI = 0.29-0.38. These nanofibers exhibited lower crystallinity than untreated jute fibers as determined by TEM diffraction, WAXD and 13C CPMAS NMR (e.g., WAXD crystallinity index was ~35% for nanofibers vs 62% for jute). Nanofibers with low crystallinity were found to be effective for removal of heavy metal ions for drinking water purification. PMID- 28644014 TI - Three-Dimensional Localization of an Individual Fluorescent Molecule with Angstrom Precision. AB - Among imaging techniques, fluorescence microscopy is a unique method to noninvasively image individual molecules in whole cells. If the three-dimensional spatial precision is improved to the angstrom level, various molecular arrangements in the cell can be visualized on an individual basis. We have developed a cryogenic reflecting microscope with a numerical aperture of 0.99 and an imaging stability of 0.05 nm in standard deviation at a temperature of 1.8 K. The key optics to realize the cryogenic performances is the reflecting objective developed by our laboratory. With this cryogenic microscope, an individual fluorescent molecule (ATTO647N) at 1.8 K was localized with standard errors of 0.53 nm (x), 0.31 nm (y), and 0.90 nm (z) when 106 fluorescence photons from the molecule were accumulated in 5 min. PMID- 28644012 TI - Sigma 2 Receptor/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice. AB - Neuropathic pain is an important medical problem with few effective treatments. The sigma 1 receptor (sigma1R) is known to be a potential target for neuropathic pain therapeutics, and antagonists for this receptor are effective in preclinical models and are currently in phase II clinical trials. Conversely, relatively little is known about sigma2R, which has recently been identified as transmembrane protein 97 (Tmem97). We generated a series of sigma1R and sigma2R/Tmem97 agonists and antagonists and tested them for efficacy in the mouse spared nerve injury (SNI) model. In agreement with previous reports, we find that sigma1R ligands given intrathecally (IT) produce relief of SNI-induced mechanical hypersensitivity. We also find that the putative sigma2R/Tmem97 agonists DKR 1005, DKR-1051, and UKH-1114 (Ki ~ 46 nM) lead to relief of SNI-induced mechanical hypersensitivity, peaking at 48 h after dosing when given IT. This effect is blocked by the putative sigma2R/Tmem97 antagonist SAS-0132. Systemic administration of UKH-1114 (10 mg/kg) relieves SNI-induced mechanical hypersensitivity for 48 h with a peak magnitude of effect equivalent to 100 mg/kg gabapentin and without producing any motor impairment. Finally, we find that the TMEM97 gene is expressed in mouse and human dorsal root ganglion (DRG) including populations of neurons that are involved in pain; however, the gene is also likely expressed in non-neuronal cells that may contribute to the observed behavioral effects. Our results show robust antineuropathic pain effects of sigma1R and sigma2R/Tmem97 ligands, demonstrate that sigma2R/Tmem97 is a novel neuropathic pain target, and identify UKH-1114 as a lead molecule for further development. PMID- 28644015 TI - Photochromic Hydrazone Switches with Extremely Long Thermal Half-Lives. AB - A family of easily accessible light-activated hydrazone switches has been developed having thermal half-lives of up to 2700 years! Structure-property analysis shows that replacing the rotor pyridyl group of our typical hydrazone switch with a phenyl one leads to the long-lived negative photochromic compounds. The switching properties of the hydrazones in both toluene and DMSO were assessed offering insights into the kinetics and thermodynamics of the switching process. PMID- 28644016 TI - Color-Tunable and White-Light Luminescence in Lanthanide-Dicyanoaurate Coordination Polymers. AB - The new lanthanide-dicyanoaurate coordination polymers [nBu4N]2[Ln(NO3)4Au(CN)2] (Ln = Sm, Dy) and Sm[Au(CN)2]3.3H2O were prepared and structurally characterized and their luminescence spectra described. The emissions of solid-solutions of [nBu4N]2[Ln(NO3)4Au(CN)2] (Ln = Ce, Sm, Eu, Tb, and Dy) were explored with an emphasis on their capacity for luminescent color tuning and white-light emission via the selection of composition, excitation wavelength, and temperature. Specifically, the binary solid-solutions [nBu4N]2[Ce0.4Dy0.6(NO3)4Au(CN)2] and [nBu4N]2[Sm0.75Tb0.25(NO3)4Au(CN)2], and the ternary solid-solutions [nBu4N]2[Ce0.2Sm0.6Tb0.2(NO3)4Au(CN)2] and [nBu4N]2[Ce0.33Eu0.17Tb0.5(NO3)4Au(CN)2], were prepared and examined in terms of suitability for color-tuning capacity. These results showcase that the emission from the [nBu4N]2[Ln(NO3)4Au(CN)2] framework has the capacity to be tuned to extremes corresponding to deep reds (CIE coordinates 0.65, 0.35), greens (0.28, 0.63), and deep blue/violet (0.16, 0.06) as well as white (0.31, 0.33). Conversely, the emission of the Sm[Au(CN)2]3.3H2O framework, when doped with the green phosphor Tb(III), changes only slightly because of the predominantly Au(I) based emission and Sm(III) -> Au(I) energy transfer. PMID- 28644017 TI - Spectrally Undiscerned Isomers Might Lead to Erroneous Determination of Water Exchange Rates of paraCEST Eu(III) Agents. AB - We report a detailed study of the solution structure and water exchange rate of a Eu(III) complex with the cyclen-based ligand L1, containing (S)-2-(2-acetamido)-3 (4-(trifluoromethyl)phenyl)propanoate pendant arms at positions 1 and 7 of the cyclen ring and acetylglycinate pendants at positions 4 and 10. The EuL1 complex was characterized by a combination of NMR and luminescence spectroscopy and density functional theory (DFT) calculations. The chemical exchange saturation transfer (CEST) spectra obtained at different temperatures and saturation powers present a CEST signal attributed to the coordinated water molecule. However, the spectra recorded at low temperatures (10 degrees C) and low saturation powers revealed the presence of two different species with coordinated water molecules having very similar chemical shifts. Determination of the water exchange rates of the coordinated water molecules was carried out by using the Bloch four-pool model that accounts for the presence of these isomers, and this model was compared to conventional methods for CEST quantification, namely the Omega plot and QUESP (quantification of exchange rate as a function of saturation power), which assume the presence of a single CEST active species. The results indicated that only the four-pool Bloch equations provide reasonable water exchange rates and activation parameters. Solution NMR studies and DFT calculations indicated that the two isomers present in solution correspond to the SS Delta(lambdalambdalambdalambda) and SS-Lambda(deltadeltadeltadelta) isomers, which present capped square-antiprismatic (SAP) coordination environments. Additional NMR studies on the EuL2 and EuL3 complexes, which present four (S)-2 (2-acetamido)-3-(4-(trifluoromethyl)phenyl)propanoate or acetylglycinate pendant arms, respectively, confirm the results obtained for EuL1. PMID- 28644018 TI - Role of the Crystal Structure in Cation Exchange Reactions Involving Colloidal Cu2Se Nanocrystals. AB - Stoichiometric Cu2Se nanocrystals were synthesized in either cubic or hexagonal (metastable) crystal structures and used as the host material in cation exchange reactions with Pb2+ ions. Even if the final product of the exchange, in both cases, was rock-salt PbSe nanocrystals, we show here that the crystal structure of the starting nanocrystals has a strong influence on the exchange pathway. The exposure of cubic Cu2Se nanocrystals to Pb2+ cations led to the initial formation of PbSe unselectively on the overall surface of the host nanocrystals, generating Cu2Se@PbSe core@shell nanoheterostructures. The formation of such intermediates was attributed to the low diffusivity of Pb2+ ions inside the host lattice and to the absence of preferred entry points in cubic Cu2Se. On the other hand, in hexagonal Cu2Se nanocrystals, the entrance of Pb2+ ions generated PbSe stripes "sandwiched" in between hexagonal Cu2Se domains. These peculiar heterostructures formed as a consequence of the preferential diffusion of Pb2+ ions through specific (a, b) planes of the hexagonal Cu2Se structure, which are characterized by almost empty octahedral sites. Our findings suggest that the morphology of the nanoheterostructures, formed upon partial cation exchange reactions, is intimately connected not only to the NC host material, but also to its crystal structure. PMID- 28644019 TI - Metabolomics Analysis To Evaluate the Anti-Inflammatory Effects of Polyphenols: Glabridin Reversed Metabolism Change Caused by LPS in RAW 264.7 Cells. AB - Inflammation has been shown to play a critical role in the development of many diseases. In this study, we used metabolomics to evaluate the inflammatory effect of lipopolysaccharide (LPS) and the anti-inflammatory effect of glabridin (GB, a polyphenol from Glycurrhiza glabra L. roots) in RAW 264.7 cells. Multivariate statistical analysis showed that in comparison with the LPS group, the metabolic profile of the GB group was more similar to that of the control group. LPS impacted the amino acid, energy, and lipid metabolisms in RAW 264.7 cells, and metabolic pathway analysis showed that GB reversed some of those LPS impacts. Metabolomics analysis provided us with a new perspective to better understand the inflammatory response and the anti-inflammatory effects of GB. Metabolic pathway analysis can be an effective tool to elucidate the mechanism of inflammation and to potentially find new anti-inflammatory agents. PMID- 28644020 TI - Underestimated Halogen Bonds Forming with Protein Backbone in Protein Data Bank. AB - Halogen bonds (XBs) are attracting increasing attention in biological systems. Protein Data Bank (PDB) archives experimentally determined XBs in biological macromolecules. However, no software for structure refinement in X-ray crystallography takes into account XBs, which might result in the weakening or even vanishing of experimentally determined XBs in PDB. In our previous study, we showed that side-chain XBs forming with protein side chains are underestimated in PDB on the basis of the phenomenon that the proportion of side-chain XBs to overall XBs decreases as structural resolution becomes lower and lower. However, whether the dominant backbone XBs forming with protein backbone are overlooked is still a mystery. Here, with the help of the ratio (RF) of the observed XBs' frequency of occurrence to their frequency expected at random, we demonstrated that backbone XBs are largely overlooked in PDB, too. Furthermore, three cases were discovered possessing backbone XBs in high resolution structures while losing the XBs in low resolution structures. In the last two cases, even at 1.80 A resolution, the backbone XBs were lost, manifesting the urgent need to consider XBs in the refinement process during X-ray crystallography study. PMID- 28644021 TI - Synthesis of (-)-11-O-Debenzoyltashironin: Neurotrophic Sesquiterpenes Cause Hyperexcitation. AB - 11-O-Debenzoyltashironin (1) is a member of the neurotrophic sesquiterpenes, trace plant metabolites that enhance neurite outgrowth in cultured neurons. We report its synthesis in six steps from a butenolide heterodimer via its likely biosynthetic precursor, 3,6-dideoxy-10-hydroxypseudoanisatin, here identified as the chain tautomer of 1. Access to the tashironin chemotype fills a gap in a comparison set of convulsive and neurotrophic sesquiterpenes, which we hypothesized to share a common target. Here we show that both classes mutually hyperexcite rat cortical neurons, consistent with antagonism of inhibitory channels and a mechanism of depolarization-induced neurite outgrowth. PMID- 28644022 TI - Hot-Spot Residues to be Mutated Common in G Protein-Coupled Receptors of Class A: Identification of Thermostabilizing Mutations Followed by Determination of Three Dimensional Structures for Two Example Receptors. AB - G protein-coupled receptors (GPCRs), which are indispensable to life and also implicated in a number of diseases, construct important drug targets. For the efficient structure-guided drug design, however, their structural stabilities must be enhanced. An amino-acid mutation is known to possibly lead to the enhancement, but currently available experimental and theoretical methods for identifying stabilizing mutations suffer such drawbacks as the incapability of exploring the whole mutational space with minor effort and the unambiguous physical origin of the enhanced or lowered stability. In general, after the identification is successfully made for a GPCR, the whole procedure must be followed all over again for the identification for another GPCR. Here we report a theoretical strategy by which many different GPCRs can be considered at the same time. The strategy is illustrated for three GPCRs of Class A in the inactive state. We argue that a mutation of the residue at a position of NBW = 3.39 (NBW is the Ballesteros-Weinstein number), a hot-spot residue, leads to substantially higher stability for significantly many GPCRs of Class A in the inactive state. The most stabilizing mutations of the residues with NBW = 3.39 are then identified for two of the three GPCRs, using the improved version of our free energy function. These identifications are experimentally corroborated, which is followed by the determination of new three-dimensional (3D) structures for the two GPCRs. We expect that on the basis of the strategy, the 3D structures of many GPCRs of Class A can be solved for the first time in succession. PMID- 28644023 TI - Kinetics of Interlayer Expansion of a Layered Silicate Driven by Caffeine Intercalation in the Water Phase Using Transmission X-ray Diffraction. AB - The kinetics of caffeine uptake into the interlayer nanospace of silicate nanosheets modified with benzylammonium (BA) was evaluated by in situ monitoring the basal spacing in aqueous media using transmission X-ray diffraction. An interlayer spacing of 0.58 nm in water before caffeine uptake indicates a monomolecular layer of BA and a few water layers in each interlayer. The interlayer space expanded by 0.10 nm upon caffeine uptake (intercalation) and saturated even in the presence of excess caffeine. Time-course profiles of the interlayer spacing and the uptake amount after injection of caffeine into the water slurry were obtained. At the initial period, the plot for the basal spacing was located above that for the adsorbed amount, suggesting that the rate of the interlayer spacing change was faster than that to attain the adsorption equilibrium. A first-order kinetic simulation fitted to the profile also indicates that the basal spacing included a rapid expansion of 0.08 nm within a few minutes and a slow expansion of 0.02 nm over several hours. Regarding the slow component, the rate constant for the basal spacing was lower than that for the amount of caffeine adsorbed, meaning that a steady-state basal spacing is reached after the adsorption equilibrium. PMID- 28644024 TI - Direct Visible-Light-Excited Asymmetric Lewis Acid Catalysis of Intermolecular [2+2] Photocycloadditions. AB - A reaction design is reported in which a substrate-bound chiral Lewis acid complex absorbs visible light and generates an excited state that directly reacts with a cosubstrate in a highly stereocontrolled fashion. Specifically, a chiral rhodium complex catalyzes visible-light-activated intermolecular [2+2] cycloadditions, providing a wide range of cyclobutanes with up to >99% ee and up to >20:1 d.r. Noteworthy is the ability to create vicinal all-carbon-quaternary stereocenters including spiro centers in an intermolecular fashion. PMID- 28644026 TI - Pb0.65Mn2.85Ga3S8 and Pb0.72Mn2.84Ga2.95Se8: Two Quaternary Metal Chalcognides with Open-Tunnel-Framework Structures Displaying Intense Second Harmonic Generation Responses and Interesting Magnetic Properties. AB - By combining different nonlinear optical-active structural chromophores with transition metal Mn into a crystal structure, two novel quaternary metal chalcogenides Pb0.65Mn2.85Ga3S8 (1) and Pb0.72Mn2.84Ga2.95Se8 (2) were successfully synthesized. Compounds 1 and 2 are isostructural, and they represent a new structure type that crystallizes in the space group P6 (No. 174) in the hexagonal system. Their structures feature an interesting three-dimensional open tunnel framework composed of bridged infinite chains with Pb2+ cations filling in the biggest tunnels. Interestingly, both 1 and 2 demonstrate intense second harmonic generation responses at 2.09 MUm that is about 1.5 and 4.4 times, respectively, of that of the benchmark material AgGaS2. However, 1 and 2 possess different optical diffuse reflectance spectra: 1 displays an evident multiband absorption characteristic with two distinguishing absorption edges of 738 and 551 nm, corresponding to two band gaps of 1.68 and 2.25 eV, respectively, while 2 exhibits only one sharp edge, and the corresponding band gap was estimated to be 1.65 eV. Moreover, apart from the considerable structural similarity between 1 and 2, the dc temperature dependent susceptibility measurements indicate that compound 1 is paramagnetic, while compound 2 exhibits spin-glass-like behavior. PMID- 28644025 TI - A Mitochondria-Targeted Cryptocyanine-Based Photothermogenic Photosensitizer. AB - Cryptocyanine-based probes exhibit highly efficient photothermal conversion and represent a new class of photothermal agents for use in photothermal therapy (PTT). With the thermal susceptibility of mitochondria in mind, we have prepared a mitochondria-targeted, NIR-absorbing cryptocyanine probe (Mito-CCy) and evaluated its photophysical properties, photothermal conversion efficiency, biological compatibility, cytotoxicity, and mitochondrial localization in HeLa cells. Upon subjecting 0.5 mL of a PBS buffer solution (10 mM, pH 7.4, containing 50% DMSO) of Mito-CCy (0.5 mM) to 730 nm laser irradiation at 2.3 W/cm2, the temperature of the solution increased by 13.5 degrees C within 5 min. In contrast, the corresponding cryptocyanine (CCy) lacking the triarylphosphonium group gave rise to only an ~3.4 degrees C increase in solution temperature under otherwise identical conditions. Mito-CCy also exhibited high cytotoxicity in HeLa cells when subject to photoirradiation. This light-induced cytotoxicity is attributed to the endogenous production of reactive oxygen species (ROS) induced under conditions of local heating. ROS are known to interfere with the mitochondrial defense system and to trigger apoptosis. By targeting the mitochondria, the present sensitizer-based photothermogenic approach is rendered more effective. As such, the system reported here represents the vanguard of what might be a new generation of organelle-targeted photothermal therapeutics. PMID- 28644027 TI - Speckle-Visibility Spectroscopy of Depolarized Dynamic Light Scattering. AB - We show that the statistical analysis of photon counts in depolarized dynamic light scattering experiments allows for the accurate characterization of the rotational Brownian dynamics of particles. Unlike photon correlation spectroscopy, the technique is accurate even at low temporal resolution and enables discontinuous data acquisition, which offers several advantages. To demonstrate the usefulness of the method, we present a case study in which we analyze aqueous suspensions of tunicate cellulose nanocrystals and silica particles, and discuss aspects that are specific to particle sizing. PMID- 28644028 TI - Understanding the Effects of Genotype, Growing Year, and Breeding on Tunisian Durum Wheat Allergenicity. 1. The Baker's Asthma Case. AB - Baker's asthma is a serious airway disease triggered by wheat protein CM3 alpha amylase/trypsin inhibitor. The purpose of the present study was to investigate the impact of genotype and crop year on allergen CM3 alpha-amylase/trypsin inhibitor associated with baker's asthma. A historical series of Tunisian durum wheat (100 accessions), derived from three crop years, was used to compare the amount of CM3 from landraces to advanced cultivars. CM3 protein quantification was assessed after an enzymatic cleavage of the soluble protein extracts on a UPLC/ESI-MS system, using a marker peptide for its quantification. Combined data analysis of variance revealed an important effect of genotype, crop year, and their interaction. The CM3 allergenic proteins were found to significantly vary among studied genotypes, as confirmed by genetic variability, coefficient of variance, heritability, and genetic advance. PMID- 28644029 TI - A Tandem Oxidative Annulation Strategy for the Synthesis of Tetracyclic 3 Spirooxindole Benzofuranones. AB - A simple and efficient method was developed for the construction of the medicinally important tetracyclic 3-spirooxindole benzofuranones. In this highly atom- and step-economical one-pot protocol, one quaternary carbon center, two new cycles, and four new bonds (C-C/C-O/C-N) were formed under simple ligand-free copper-catalyzed conditions through a novel tandem oxidative annulation strategy. PMID- 28644031 TI - Tris(cyclopentadienyl)lanthanide Complexes as Catalysts for Hydroboration Reaction toward Aldehydes and Ketones. AB - It was found that homoleptic cyclopentadienyl lanthanide complexes Cp3Ln (Ln = Y (1), Yb (2), Sm (3), Nd (4), La (5), Cp = cyclopentadienyl) can be employed as excellent catalysts for the hydroboration of various aldehydes and ketones toward pinacolborane. These robust lanthanide catalysts exhibited high reactivity with low catalyst loadings (0.01-1 mol %) under mild conditions and good functional group tolerability. These complexes also demonstrated uniquely carbonyl-selective hydroboration in the presence of alkenes and alkynes. PMID- 28644032 TI - Receptor and Microenvironment Dual-Recognizable Nanogel for Targeted Chemotherapy of Highly Metastatic Malignancy. AB - Targeted delivery of chemotherapeutic drugs to the desired lesion sites is the main objective in malignancy treatment, especially in highly metastatic malignancies. However, extensive studies around the world on traditional targeting strategies of recognizing either overexpressed receptors or microenvironments in tumors show great limitations, owing to the off-target effect and tumor homogeneity. Integration of both receptor-mediated targeting (RMT) and environment-mediated targeting (EMT) enhances the tumor accumulation and subsequent cell uptake at the same time, which may avoid these limitations. Herein, a dual targeting nanogel of PMNG engineered with both phenylboronic acid (PBA) and morpholine (MP) was reported for not only RMT via specific recognition of sialyl (SA) epitopes but also EMT toward extracellular acidity. Further engineering the nanoparticles via loading doxorubicin (DOX) brought a novel dual targeting system, that is, PMNG/DOX. PMNG/DOX demonstrated a greater targeting effect to both primary and metastatic B16F10 melanoma than the single PBA modified nanogel (PNG) with only RMT in vitro and in vivo. Moreover, PMNG/DOX was also proved to be highly potent on inhibiting primary tumor growth as well as tumor metastasis on B16F10 melanoma-grafted mouse model. The results demonstrated the dual targeting design as a translational approach for drug delivery to highly metastatic tumor. PMID- 28644030 TI - A PLC-gamma1 Feedback Pathway Regulates Lck Substrate Phosphorylation at the T Cell Receptor and SLP-76 Complex. AB - Phospholipase C gamma 1 (PLC-gamma1) occupies a critically important position in the T-cell signaling pathway. While its functions as a regulator of both Ca2+ signaling and PKC-family kinases are well characterized, PLC-gamma1's role in the regulation of early T-cell receptor signaling events is incompletely understood. Activation of the T-cell receptor leads to the formation of a signalosome complex between SLP-76, LAT, PLC-gamma1, Itk, and Vav1. Recent studies have revealed the existence of both positive and negative feedback pathways from SLP-76 to the apical kinase in the pathway, Lck. To determine if PLC-gamma1 contributes to the regulation of these feedback networks, we performed a quantitative phosphoproteomic analysis of PLC-gamma1-deficient T cells. These data revealed a previously unappreciated role for PLC-gamma1 in the positive regulation of Zap-70 and T-cell receptor tyrosine phosphorylation. Conversely, PLC-gamma1 negatively regulated the phosphorylation of SLP-76-associated proteins, including previously established Lck substrate phosphorylation sites within this complex. While the positive and negative regulatory phosphorylation sites on Lck were largely unchanged, Tyr192 phosphorylation was elevated in Jgamma1. The data supports a model wherein Lck's targeting, but not its kinase activity, is altered by PLC gamma1, possibly through Lck Tyr192 phosphorylation and increased association of the kinase with protein scaffolds SLP-76 and TSAd. PMID- 28644033 TI - Direct-Indirect Nature of the Bandgap in Lead-Free Perovskite Nanocrystals. AB - With record efficiencies achieved in lead halide perovskite-based photovoltaics, urgency has shifted toward finding alternative materials that are stable and less toxic. Bismuth-based perovskite materials are currently one of the most promising candidates among those alternatives. However, the band structures of these materials, including the nature of the bandgaps, remain elusive due to extremely low photoluminescence quantum yield (PLQY) and scattering issues in their thin film form. Here, we reveal the specific nature of the material's electronic transitions by realizing monodisperse colloidal nanocrystals (NCs) of hexagonal phase Cs3Bi2X9 perovskites, which afford well-resolved PL features. Interestingly, the PL profile exhibits a dual-spectral feature at room temperature with comparable intensities, based on which we propose an exciton recombination process involving both indirect and direct transitions simultaneously-an observation further supported by temperature-dependent and density functional theory (DFT) calculations. Our findings provide experimental and theoretical insights into the nature of the bandgaps in bismuth halide materials-essential information for assessing their viability in solar cells and optoelectronics. PMID- 28644034 TI - Predicting the Oxygen-Binding Properties of Platinum Nanoparticle Ensembles by Combining High-Precision Electron Microscopy and Density Functional Theory. AB - Many studies of heterogeneous catalysis, both experimental and computational, make use of idealized structures such as extended surfaces or regular polyhedral nanoparticles. This simplification neglects the morphological diversity in real commercial oxygen reduction reaction (ORR) catalysts used in fuel-cell cathodes. Here we introduce an approach that combines 3D nanoparticle structures obtained from high-throughput high-precision electron microscopy with density functional theory. Discrepancies between experimental observations and cuboctahedral/truncated-octahedral particles are revealed and discussed using a range of widely used descriptors, such as electron-density, d-band centers, and generalized coordination numbers. We use this new approach to determine the optimum particle size for which both detrimental surface roughness and particle shape effects are minimized. PMID- 28644035 TI - Influence of a Basic Side Chain on the Properties of Hypoxia-Selective Nitro Analogues of the Duocarmycins: Demonstration of Substantial Anticancer Activity in Combination with Irradiation or Chemotherapy. AB - A new series of nitro analogues of the duocarmycins was prepared and evaluated for hypoxia-selective anticancer activity. The compounds incorporate 13 different amine-containing side chains designed to bind in the minor groove of DNA while spanning a wide range of base strength from pKa 9.64 to 5.24. The most favorable in vitro properties were associated with strongly basic side chains, but the greatest in vivo antitumor activity was found for compounds containing a weakly basic morpholine. This applies to single-agent activity and for activity in combination with irradiation or chemotherapy (gemcitabine or docetaxel). In combination with a single dose of gamma irradiation 50 at 42 MUmol/kg eliminated detectable clonogens in some SiHa cervical carcinoma xenografts, and in combination with gemcitabine using a well-tolerated multidose schedule, the same compound caused regression of all treated A2780 ovarian tumor xenografts. In the latter experiment, three of seven animals receiving the combination treatment were completely tumor free at day 100. PMID- 28644036 TI - Examining the Effect of Residual Amikacin on Sputum Culture for Nontuberculous Mycobacteria. PMID- 28644037 TI - Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations. AB - BACKGROUND: Cannabis use is common in North America, especially among young people, and is associated with a risk of various acute and chronic adverse health outcomes. Cannabis control regimes are evolving, for example toward a national legalization policy in Canada, with the aim to improve public health, and thus require evidence-based interventions. As cannabis-related health outcomes may be influenced by behaviors that are modifiable by the user, evidence-based Lower Risk Cannabis Use Guidelines (LRCUG)-akin to similar guidelines in other health fields-offer a valuable, targeted prevention tool to improve public health outcomes. OBJECTIVES: To systematically review, update, and quality-grade evidence on behavioral factors determining adverse health outcomes from cannabis that may be modifiable by the user, and translate this evidence into revised LRCUG as a public health intervention tool based on an expert consensus process. SEARCH METHODS: We used pertinent medical search terms and structured search strategies, to search MEDLINE, EMBASE, PsycINFO, Cochrane Library databases, and reference lists primarily for systematic reviews and meta-analyses, and additional evidence on modifiable risk factors for adverse health outcomes from cannabis use. SELECTION CRITERIA: We included studies if they focused on potentially modifiable behavior-based factors for risks or harms for health from cannabis use, and excluded studies if cannabis use was assessed for therapeutic purposes. DATA COLLECTION AND ANALYSIS: We screened the titles and abstracts of all studies identified by the search strategy and assessed the full texts of all potentially eligible studies for inclusion; 2 of the authors independently extracted the data of all studies included in this review. We created Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow-charts for each of the topical searches. Subsequently, we summarized the evidence by behavioral factor topic, quality-graded it by following standard (Grading of Recommendations Assessment, Development, and Evaluation; GRADE) criteria, and translated it into the LRCUG recommendations by the author expert collective on the basis of an iterative consensus process. MAIN RESULTS: For most recommendations, there was at least "substantial" (i.e., good-quality) evidence. We developed 10 major recommendations for lower-risk use: (1) the most effective way to avoid cannabis use-related health risks is abstinence, (2) avoid early age initiation of cannabis use (i.e., definitively before the age of 16 years), (3) choose low potency tetrahydrocannabinol (THC) or balanced THC-to-cannabidiol (CBD)-ratio cannabis products, (4) abstain from using synthetic cannabinoids, (5) avoid combusted cannabis inhalation and give preference to nonsmoking use methods, (6) avoid deep or other risky inhalation practices, (7) avoid high-frequency (e.g., daily or near-daily) cannabis use, (8) abstain from cannabis-impaired driving, (9) populations at higher risk for cannabis use-related health problems should avoid use altogether, and (10) avoid combining previously mentioned risk behaviors (e.g., early initiation and high-frequency use). AUTHORS' CONCLUSIONS: Evidence indicates that a substantial extent of the risk of adverse health outcomes from cannabis use may be reduced by informed behavioral choices among users. The evidence-based LRCUG serve as a population-level education and intervention tool to inform such user choices toward improved public health outcomes. However, the LRCUG ought to be systematically communicated and supported by key regulation measures (e.g., cannabis product labeling, content regulation) to be effective. All of these measures are concretely possible under emerging legalization regimes, and should be actively implemented by regulatory authorities. The population-level impact of the LRCUG toward reducing cannabis use-related health risks should be evaluated. Public health implications. Cannabis control regimes are evolving, including legalization in North America, with uncertain impacts on public health. Evidence-based LRCUG offer a potentially valuable population-level tool to reduce the risk of adverse health outcomes from cannabis use among (especially young) users in legalization contexts, and hence to contribute to improved public health outcomes. PMID- 28644038 TI - Critical Review on the Analytical Techniques for the Determination of the Oldest Statin-Atorvastatin-in Bulk, Pharmaceutical Formulations and Biological Fluids. AB - Statins are a group of medicines that can help to lower the level of low-density lipoprotein (LDL) cholesterol "bad cholesterol" in the blood. Having a high level of LDL cholesterol is potentially dangerous, as it can lead to a hardening and narrowing of arteries (atherosclerosis) and cardiovascular disease (CVD), atorvastatin is one of the oldest member of the statin family and is used in the treatment of dyslipidemia and the prevention of CVD. Atorvastatin was first made in August 1985 and from 1996 to 2012 under the trade name Lipitor, atorvastatin became the world's best-selling drug. Numerous analytical methodologies are available for the quantification of atorvastatin and its content in pharmaceutical preparations and in biological fluids. PMID- 28644041 TI - Identifying the functional groups and the influence of synthetic chelators on Cd availability and microbial biomass carbon in Cd-contaminated soil. AB - Synthetic chelators play an important role in boosting the microbial biomass carbon (MBC), dissolved organic carbon (DOC), and heavy metal solubility in a contaminated soil toward a sustainability of environment for agricultural crops. Castor plant was grown under different levels of Cd contaminated soil (-Cd and +Cd) following adding three chelating agents, ethylenediaminetetraacetic acid (H4EDTA), nitriloacetic acid (H3 NTA), and NH4 citrate (ammonium citrate) to the soil at rates of 10, 15, and 25 mmol in 5 kg of soil per pot. The highest bioavailable Cd concentrations in soil and castor plant were obtained from NH4 citrate and H4EDTA treatments in the contaminated soil. Fourier transform infrared (FTIR) analysis showed that NH4 citrate was the most effective chelator in Cd-contaminated soil. MBC and DOC contents were significantly increased and reached at 81.98-80.37 and 1.96-1.90 mg kg-1 respectively, in the (H3 NTA) and NH4 citrate treatments in Cd-contaminated soil. Further research is needed to investigate the use of chelators in the phytoextraction of Cd-contaminated soils under field conditions and whether it may be beneficial in accelerating the phytoextraction of Cd through hyperaccumulating plants. PMID- 28644040 TI - Hypoxic Pulmonary Vasoconstriction Does Not Explain All Regional Perfusion Redistribution in Asthma. AB - RATIONALE: Regional hypoventilation in bronchoconstricted patients with asthma is spatially associated with reduced perfusion, which is proposed to result from hypoxic pulmonary vasoconstriction (HPV). OBJECTIVES: To determine the role of HPV in the regional perfusion redistribution in bronchoconstricted patients with asthma. METHODS: Eight patients with asthma completed positron emission tomographic/computed tomographic lung imaging at baseline and after bronchoconstriction, breathing either room air or 80% oxygen (80% O2) on separate days. Relative perfusion, specific ventilation (sV), and gas fraction (Fgas) in the 25% of the lung with the lowest specific ventilation (sVlow) and the remaining lung (sVhigh) were quantified and compared. MEASUREMENTS AND MAIN RESULTS: In the sVlow region, bronchoconstriction caused a significant decrease in sV under both room air and 80% O2 conditions (baseline vs. bronchoconstriction, mean +/- SD, 1.02 +/- 0.20 vs. 0.35 +/- 0.19 and 1.03 +/- 0.20 vs. 0.32 +/- 0.16, respectively; P < 0.05). In the sVlow region, relative perfusion decreased after bronchoconstriction under room air conditions and also, to a lesser degree, under 80% O2 conditions (1.02 +/- 0.19 vs. 0.72 +/- 0.08 [P < 0.001] and 1.08 +/- 0.19 vs. 0.91 +/- 0.12 [P < 0.05], respectively). The Fgas increased after bronchoconstriction under room air conditions only (0.99 +/- 0.04 vs. 1.00 +/- 0.02; P < 0.05). The sVlow subregion analysis indicated that some of the reduction in relative perfusion after bronchoconstriction under 80% O2 conditions occurred as a result of the presence of regional hypoxia. However, relative perfusion was also significantly reduced in sVlow subregions that were hyperoxic under 80% O2 conditions. CONCLUSIONS: HPV is not the only mechanism that contributes to perfusion redistribution in bronchoconstricted patients with asthma, suggesting that another nonhypoxia mechanism also contributes. We propose that this nonhypoxia mechanism may be either direct mechanical interactions and/or unidentified intercellular signaling between constricted airways, the parenchyma, and the surrounding vasculature. PMID- 28644042 TI - A Review on Recent Applications of High-Performance Liquid Chromatography in Metal Determination and Speciation Analysis. AB - High-performance liquid chromatography (HPLC) has several advantages over the conventional methods due to their operational simplicity. It is a vital tool to determine metal ions having same mass but different electronic configuration, to separate complex mixtures and to resolve ions that may be indistinguishable by mass spectrometry alone. Metal ions play vital role in many biological processes and involved in setting up of many diseases. Therefore, the development of simple methods for the detection and quantification of metals in real samples might serve as diagnostic tools for various diseases. This review article focuses on the recent main feature of this technique, i.e. speciation of metal ions and their applications to series of problem of metal ion chemistry in different environmental matrixes. Speciation of metals is of increasing interest and has a great importance because of bioavailability, environmental mobility, toxicity and potential risk of metals. With the capability of partitioning the complex species of different metal ions, HPLC is an efficient technique for this task. This review summarizes recent advances in the development of HPLC to the fundamental understanding of metal ion chemistry in the environment and discusses all the issues that still need a lot of consideration. It has been classified into different sections depending on the role of HPLC in separation used and metal speciation; furthermore, the underlying sample preconcentration techniques and detection systems involved for the determination of metal ions and their applications were discussed. PMID- 28644043 TI - Using a multivariate model to assess the interactive effects of demographics and lifestyle on the hematological profile. AB - AIM: To assess the extent to which a multivariate approach to modeling interrelated hematological indices provides more informative results than the traditional approach of modeling each index separately. MATERIALS & METHODS: The effects of demographics and lifestyle on ten hematological indices collected from a Dutch population-based sample (n = 3278) were studied, jointly using multivariate distance matrix regression and separately using linear regression. RESULTS: The multivariate approach highlighted the main effects of all predictors and several interactions; the traditional approach highlighted only main effects. CONCLUSION: The multivariate approach provides more power than traditional methods to detect effects on interrelated biomarkers, suggesting that its use in future research may help identify subgroups that benefit from different treatment or prevention measures. PMID- 28644044 TI - How to Design a Spectrometer. AB - Designing a spectrometer requires knowledge of the problem to be solved, the molecules whose properties will contribute to a solution of that problem and skill in many subfields of science and engineering. A seemingly simple problem, design of an ultraviolet, visible, and near-infrared spectrometer, is used to show the reasoning behind the trade-offs in instrument design. Rather than reporting a fully optimized instrument, the Yin and Yang of design choices, leading to decisions about financial cost, materials choice, resolution, throughput, aperture, and layout are described. To limit scope, aspects such as grating blaze, electronics design, and light sources are not presented. The review illustrates the mixture of mathematical rigor, rule of thumb, esthetics, and availability of components that contribute to the art of spectrometer design. PMID- 28644039 TI - Parkinson's disease biomarkers: perspective from the NINDS Parkinson's Disease Biomarkers Program. AB - Biomarkers for Parkinson's disease (PD) diagnosis, prognostication and clinical trial cohort selection are an urgent need. While many promising markers have been discovered through the National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) and other mechanisms, no single PD marker or set of markers are ready for clinical use. Here we discuss the current state of biomarker discovery for platforms relevant to PDBP. We discuss the role of the PDBP in PD biomarker identification and present guidelines to facilitate their development. These guidelines include: harmonizing procedures for biofluid acquisition and clinical assessments, replication of the most promising biomarkers, support and encouragement of publications that report negative findings, longitudinal follow-up of current cohorts including the PDBP, testing of wearable technologies to capture readouts between study visits and development of recently diagnosed (de novo) cohorts to foster identification of the earliest markers of disease onset. PMID- 28644045 TI - Method development of glycoprotein biomarkers for cancers. PMID- 28644046 TI - Paper-based point-of-care testing in disease diagnostics. PMID- 28644047 TI - Mutational analysis of GALT gene in Greek patients with galactosaemia: identification of two novel mutations and clinical evaluation. AB - Classical galactosaemia is an inborn error of metabolism due to the deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). The aim of the study was to identify the underlying mutations in Greek patients with GALT deficiency and evaluate their psychomotor and speech development. Patients with GALT deficiency (n = 17) were picked up through neonatal screening. Mutational analysis was conducted via Sanger sequencing, while in silico analysis was used in the cases of novel missense mutations. Psychomotor speech development tests were utilized for the clinical evaluation of the patients. Eleven different mutations in the GALT gene were detected in the patient cohort, including two novel ones. The most frequent mutation was p.Q188R (c.563 A > G). As for the novel mutations, p.M298I (c.894 G > A) was identified in four out of 32 independent alleles, while p.P115S (c.343 C > T) was identified once. Psychomotor evaluation revealed that most of the patients were found in the borderline area (Peabody test), while only two had speech delay problems. The WISK test revealed three patients at borderline limits and two were at lower than normal limits. The mutational spectrum of the GALT gene in Greek patients is presented for the first time. The mutation p.Q188R is the most frequent among Greek patients. Two novel mutations were identified and their potential pathogenicity was estimated. Regarding the phenotypic characteristics, psychomotor disturbances and speech delay were mainly observed among GALT-deficient patients. PMID- 28644049 TI - The standard treatment protocol for paracetamol poisoning may be inadequate following overdose with modified release formulation: a pharmacokinetic and clinical analysis of 53 cases. AB - OBJECTIVE: The use of the standard procedure for managing overdoses with immediate release (IR) paracetamol is questionable when applied to overdoses with modified release (MR) formulations. This study describes the pharmacokinetics of paracetamol and the clinical outcomes following overdoses with a MR formulation. METHODS: Medical records including laboratory analyses concerning overdoses of MR paracetamol from 2009 to 2015 were collected retrospectively. Inclusion criteria were ingestion of a toxic dose, known time of intake and documented measurements of serum paracetamol and liver function tests. Graphical analysis, descriptive statistics and population pharmacokinetic modelling were used to describe data. RESULTS: Fifty-three cases were identified. Median age was 26 years (range 13 68), median dose was 20 g (range 10-166) and 74% were females. The pharmacokinetic analysis showed a complex, dose dependent serum versus time profile with prolonged absorption and delayed serum peak concentrations with increasing dose. Ten patients had persistently high serum levels for 24 h or more, six of them had a second peak 8-19 h after ingestion. Seven of 34 patients receiving N-acetylcysteine (NAC) within 8 h had alanine aminotransferase (ALT) above reference range. Three of them developed hepatotoxicity (ALT >1000 IU/l). DISCUSSION AND CONCLUSIONS: The pharmacokinetic and clinical analysis showed that the standard treatment protocol, including risk assessment and NAC regimen, used for IR paracetamol poisoning not appear suitable for MR formulation. Individual and tailored treatment may be valuable but further studies are warranted to determine optimal regimen of overdoses with MR formulation. PMID- 28644048 TI - Risk of major bleeding in patients with non-valvular atrial fibrillation treated with oral anticoagulants: a systematic review of real-world observational studies. AB - OBJECTIVE: To conduct a systematic review of real-world (RWD) studies comparing the risk of major bleeding (MB) among patients with non-valvular atrial fibrillation (NVAF) on direct oral anticoagulants (DOACs) or warfarin. METHODS: MEDLINE, Embase, NHS-EED, and EconLit were searched for RWD studies published between January 2003 and November 2016 comparing MB risk among DOACs and warfarin. Proceedings of clinical conferences from 2012 to 2016 were reviewed. RESULTS: A total of 4218 citations were identified, 26 of which met eligibility criteria. Most studies were retrospective analyses of administrative claims databases and patient registries (n = 23 of 26); about half were based in the United States (n = 15). Apixaban showed a significantly lower risk of MB versus warfarin in all eight included studies. MB risk was either significantly lower (n = 9 of 16) or not significantly different (n = 7 of 16) between dabigatran and warfarin; there was no significant difference between rivaroxaban and warfarin in all seven included studies. The risk was significantly lower with apixaban versus rivaroxaban (n = 7 of 7) but not significantly different from dabigatran (n = 6 of 7). MB risk was significantly lower (n = 3 of 4) or not significantly different (n = 1 of 4) with dabigatran versus rivaroxaban. No evidence was identified for edoxaban. CONCLUSION: DOACs were associated with similar or lower risks of MB versus warfarin. A lower MB risk was consistently observed for apixaban, but less consistently for dabigatran; MB risk was similar between rivaroxaban and warfarin. Among DOACs, the risk of MB with apixaban was consistently lower than with rivaroxaban, but similar to dabigatran. PMID- 28644050 TI - HbA1c analysis by capillary electrophoresis - comparison with chromatography and an immunological method. AB - BACKGROUND: Haemoglobin A1c (HbA1c) has become an even more important analyte for clinical laboratories during recent years with the introduction of its diagnostic use for diabetes mellitus. Several different analytical principles can be used, each with their advantages and disadvantages. AIM: We wanted to compare Sebia Capillarys 2 Flex Piercing (Capillarys) with our routine HbA1c methods, which were an HPLC method (Tosoh G7) and an immunoassay (Tina-Quant on Roche Modular P) by analysing a large clinical material. Furthermore, we investigated sample stability. METHODS: HbA1c analysis was performed in parallel by all three methods for more than 600 patient samples including common and some rare haemoglobin variants, as well as for several controls, some with set target values. Sample stability at room temperature and refrigerated was assessed for up to seven days. RESULTS: Capillarys produced generally somewhat lower HbA1c values than both comparison methods, apparently due to positive bias for the comparison methods. Leaving out samples with haemoglobin variants, we found a mean bias (95% CI) for Capillarys compared to Tosoh G7 (without factorization) and Modular of -0.39 ( 0.40 to -0.38) and -0.16 (-0.17 to -0.14) % HbA1c, respectively. HbA1c results were similar between instruments for samples from dialysis patients and for samples with heterozygous common haemoglobin variants, except that Tosoh G7 reported too low results in the presence of Hb E. For heterozygous Hb Raleigh, Capillarys and the immunoassay gave similar results. CONCLUSION: Capillarys is a convenient instrument for routine HbA1c analysis. PMID- 28644051 TI - Brief overview of nanoparticulate therapy in cancer. AB - Nanoparticles govern an all-important role, in this day and age, in determining the tissue distribution of either hydrophobic or hydrophilic anti-cancer drugs by encapsulating them or by covalent attachment. The whole purpose is to systematically improve upon the existing anti-tumour efficacy of these drugs. Selective delivery of these chemotherapeutic agents to the compromised or diseased tissue is the key to avoid any potential toxicity problems. Certain types of nanoparticles, through various mechanisms such as active targeting or reversing multi-drug resistance, display immense potential in adding to the existing anti-tumour efficacy profile. Determining the optimal composition of the polymers or size of the nanoparticles or appropriately tailoring the surface of these nanoparticles with molecular ligands are the key components in governing the successful biological fate of these nanoparticles. PMID- 28644052 TI - A little "dab" will do ya' in: a case report of neuro-and cardiotoxicity following use of cannabis concentrates. AB - CONTEXT: The use of marijuana and cannabis concentrates is increasing, especially following decriminalization in several states. Psychosis and cardiotoxicity have been reported following cannabis use; however, myocardial injury from "dabbing" has not yet been reported. We report a case of hyperthermia, tachycardia, hypertension, severe agitation, neuro-, and cardiotoxicity following the use of "dabs" where there is concomitant confirmatory biological and sample testing. CASE DETAILS: A 17-year-old athletic man developed agitation requiring sedation and intubation for safety, with peak systolic blood pressures in the 190s and hyperthermia (to 102 degrees F). He developed elevated serum troponins with persistent tachycardia despite sedation and no clear non-intoxicant etiology. It was discovered that the patient had recently been "dabbing"; an exhaustive search of his home found a sample of the "dabs" which was analyzed along with a comprehensive urine drug screen by tandem liquid mass spectroscopy (t-LCMS) for confirmation. DISCUSSION: Tetrahydrocannabinol (THC) has been increasingly associated with agitation and cardiotoxicity, while cannabidiol (CBD) has been associated with neuroprotective, inhibitory states. We propose that increasing concentrations of THC as well as THC:CBD ratios seen in cannabis concentrates such as "dabs" may cause agitation and end-organ damage through sympathomimetic and serotonergic pathways. PMID- 28644053 TI - Left main or multivessel coronary revascularization: applying both anatomy and physiology to individualize care. PMID- 28644054 TI - The thermoexpandable nitinol stent: a long-term alternative in patients without nephropathy or malignancy. AB - OBJECTIVE: The aim of this study was to investigate the long-term outcome of a thermoexpandable nickel-titanium nitinol ureteral stent (Memokath 051TM) and to identify individual risk factors for failure. MATERIALS AND METHODS: This retrospective single-centre study included 125 patients who underwent implantation of the self-expandable Memokath 051 stent. Complications, indwelling time and reason for explantation were recorded. Analyses were stratified by gender, age, body mass index, American Society of Anesthesiologists score, estimated glomerular filtration rate (eGFR), side, localization and cause of the stricture. RESULTS: In total, 91 out of 125 patients (73%) were available for analysis. Median indwelling time was 355 days (range 7-2125 days). Most stents were removed because of dislocation (42%) or occlusion (40%). Stent removal was rarely performed because of infection (3%). Patients with sufficient renal function (eGFR >=60 ml/min/1.73 m2) showed increased indwelling times compared with those with nephropathy (386 vs 317 days; p < 0.01). Patients with active malignant disease showed reduced patency time compared with strictures of benign origin (455 vs 190 days; p < 0.01). CONCLUSIONS: This thermoexpandable nitinol stent offers safe mid-term treatment of ureteric strictures, especially in patients without active malignancy and with good renal function. PMID- 28644055 TI - Regulation of transient receptor potential melastatin 4 channel by sarcoplasmic reticulum inositol trisphosphate receptors: Role in human detrusor smooth muscle function. AB - We recently reported key physiologic roles for Ca2+-activated transient receptor potential melastatin 4 (TRPM4) channels in detrusor smooth muscle (DSM). However, the Ca2+-signaling mechanisms governing TRPM4 channel activity in human DSM cells are unexplored. As the TRPM4 channels are activated by Ca2+, inositol 1,4,5 trisphosphate receptor (IP3R)-mediated Ca2+ release from the sarcoplasmic reticulum represents a potential Ca2+ source for TRPM4 channel activation. We used clinically-characterized human DSM tissues to investigate the molecular and functional interactions of the IP3Rs and TRPM4 channels. With in situ proximity ligation assay (PLA) and perforated patch-clamp electrophysiology, we tested the hypothesis that TRPM4 channels are tightly associated with the IP3Rs and are activated by IP3R-mediated Ca2+ release in human DSM. With in situ PLA, we demonstrated co-localization of the TRPM4 channels and IP3Rs in human DSM cells. As the TRPM4 channels and IP3Rs must be located within close apposition to functionally interact, these findings support the concept of a potential Ca2+ mediated TRPM4-IP3R regulatory mechanism. To investigate IP3R regulation of TRPM4 channel activity, we sought to determine the consequences of IP3R pharmacological inhibition on TRPM4 channel-mediated transient inward cation currents (TICCs). In freshly-isolated human DSM cells, blocking the IP3Rs with the selective IP3R inhibitor xestospongin-C significantly decreased TICCs. The data suggest that IP3Rs have a key role in mediating the Ca2+-dependent activation of TRPM4 channels in human DSM. The study provides novel insight into the molecular and cellular mechanisms regulating TRPM4 channels by revealing that TRPM4 channels and IP3Rs are spatially and functionally coupled in human DSM. PMID- 28644056 TI - Plasmonic photothermal therapy of atherosclerosis with nanoparticles: long-term outcomes and safety in NANOM-FIM trial. AB - AIM: The safety options in nanomedicine raise an issue of the optimal niche at the real-world clinical practice. METHODS: This is an observational prospective cohort analysis of the 5-year clinical outcomes at the intention-to-treat population (nano vs ferro vs stenting; n = 180) of NANOM first-in-man trial (NCT01270139). RESULTS: Mortality (6 vs 9 vs 10 cases of cardiac death in groups, p < 0.05), major adverse cardiovascular events (14.3 vs 20.9 vs 22.9%, p = 0.04), late thrombosis (2 vs 4 vs 6, p < 0.05) and target lesion revascularization (3.8 vs 4.8 vs 5.7%, p = 0.04) were significantly higher in ferro group and stent control at 60 months. CONCLUSION: NANOM first-in-man trial demonstrates high safety with better rate of mortality, major adverse cardiovascular events and target lesion revascularization at the long-term follow-up if compare with stent XIENCE V. PMID- 28644057 TI - The implementation of medical monitoring programs following potentially hazardous exposures: a medico-legal perspective. AB - CONTEXT: Clinical toxicologists may be called upon to determine the appropriateness of medical monitoring following documented or purported exposures to toxicants in the occupational, environmental, and medical settings. METHODS: We searched the MEDLINE database using the Ovid(r) search engine for the following terms cross-referenced to the MeSH database: ("occupational exposures" OR "environmental exposures") AND ("physiologic monitoring" OR "population surveillance"). The titles and abstracts of the resulted articles were reviewed for relevance. We expanded our search to include non-peer-reviewed publications and gray literature and resources using the same terms as utilized in the MEDLINE search. There were a total of 48 relevant peer-reviewed and non-peer-reviewed publications. Publications excluded contained no information relevant to medical monitoring following potentially harmful toxicologic exposures, discussed only worker screening/surveillance and/or population biomonitoring, contained redundant information, or were superseded by more recent information. Approaches to medical monitoring: A consensus exists in the peer-reviewed medical literature, legal literature, and government publications that for medical monitoring to be a beneficial public health activity, careful consideration must be given to potential benefits and harms of the program. Characteristics of the exposure, the adverse human health effect, the screening test, and the natural history of the disease are important in determining whether an exposed population will reap a net benefit or harm from a proposed monitoring program. Broader interpretations of medical monitoring: Some have argued that medical monitoring programs should not be limited to exposure-related outcomes but should duplicate general preventive medicine efforts to improve public health outcomes although an overall reduction of morbidity, mortality and disability by modifying correctable risk factors and disease conditions. This broader approach is inconsistent with the targeted approach advocated by the Agency for Toxic Substances and Disease Registry and the United States Preventive Services Task Force and the bulk of the peer-reviewed medical literature. Medical monitoring in legal contexts: Numerous medical monitoring actions have been litigated. Legal rationales for allowing medical monitoring claims often incorporate some of the scientific criteria for the appropriateness of monitoring programs. In the majority of cases in which plaintiffs were awarded medical monitoring relief, plaintiffs were required to demonstrate both that the condition for which medical monitoring was sought could be detected early, and that early detection and treatment will improve morbidity and mortality. However, the treatment of medical monitoring claims varies significantly depending upon jurisdiction. Examples of large-scale, comprehensive medical monitoring programs: Large-scale, comprehensive medical monitoring programs have been implemented, such as the Fernald Medical Monitoring Program and the World Trade Center Health Program, both of which exceeded the scope of medical monitoring typically recommended in the peer-reviewed medical literature and the courts. The Fernald program sought to prevent death and disability due to non-exposure-related conditions in a manner similar to general preventive medicine. The World Trade Center Health Program provides comprehensive medical care for World Trade Center responders and may be viewed as a large-scale, federally--funded research effort, which distinguishes it from medical monitoring in a medico-legal context. Synthesis of public health approaches to medical monitoring: Medical monitoring may be indicated following a hazardous exposure in limited circumstances. General causation for a specific adverse health effect must be either established by scientific consensus through a formal causal analysis using a framework such as the Bradford-Hill criteria. The exposure must be characterized and must be of sufficient severity that the exposed population has a significantly elevated risk of an adverse health effect. Monitoring must result in earlier detection of the condition than would otherwise occur and must confer a benefit in the form of primary, secondary or tertiary prevention. Outcome tables may be of use in describing the potential benefits and harms of a proposed monitoring program. CONCLUSIONS: In the context of litigation, plaintiffs may seek medical monitoring programs after documented or putative exposures. The role of the clinical toxicologist, in this setting, is to evaluate the scientific justifications and medical risks and assist the courts in determining whether monitoring would be expected to result in a net public health benefit. PMID- 28644058 TI - Air embolism: diagnosis and management. AB - Air embolism is an uncommon, but potentially life-threatening event for which prompt diagnosis and management can result in significantly improved patient outcomes. Most air emboli are iatrogenic. Arterial air emboli may occur as a complication from lung biopsy, arterial catheterization or cardiopulmonary bypass. Immediate management includes placing the patient on high-flow oxygen and in the right lateral decubitus position. Venous air emboli may occur during pressurized venous infusions, or catheter manipulation. Immediate management includes placement of the patient on high-flow oxygen and in the left lateral decubitus and/or Trendelenburg position. Hyperbaric oxygen therapy is the definitive treatment which may decrease the size of air emboli by facilitating gas reabsorption, while also improving tissue oxygenation and reducing ischemic reperfusion injury. PMID- 28644059 TI - Carbonic anhydrase I, II, IV and IX inhibition with a series of 7-amino-3,4 dihydroquinolin-2(1H)-one derivatives. AB - A series of new derivatives was prepared by derivatisation of the 7-amino moiety present in 7-amino-3,4-dihydroquinolin-2(1H)-one, a compound investigated earlier as CAI. The derivatisation was achieved by: i) reaction with arylsulfonyl isocyanates/aryl isocyanates; (ii) reaction with fluorescein isothiocyanate; (iii) condensation with substituted benzoic acids in the presence of carbodiimides; (iv) reaction with 2,4,6-trimethyl-pyrylium tetrafluoroborate; (v) reaction with methylsulfonyl chloride and (vi) reaction with maleic anhydride. The new compounds were assayed as inhibitors of four carbonic anhydrases (CA, EC 4.2.1.1) human (h) isoforms of pharmacologic relevance, the cytosolic hCA I and II, the membrane-anchored hCA IV and the transmembrane, tumour-associated hCA IX. hCA IX was the most inhibited isoform (KIs ranging between 243.6 and 2785.6 nm) whereas hCA IV was not inhibited by these compounds. Most derivatives were weak hCA I and II inhibitors, with few of them showing KIs < 10 um. Considering that the inhibition mechanism with these lactams is not yet elucidated, exploring a range of such derivatives with various substitution patterns may be useful to identify leads showing isoform selectivity or the desired pharmacologic action. PMID- 28644061 TI - Diffusion-weighted magnetic resonance imaging in the assessment of choroid plexus aging. AB - Recent studies have pointed out dysfunction and histopathological changes of the choroid plexuses (CPs) with aging. This paper reviews apparent diffusion coefficient (ADC) values of the CPs for age-related changes. All the brain MR images of the patients between January 2013 and June 2014 in our Radiology Department were retrospectively investigated. Patients with major cranial abnormalities (brain tumors, hyperacute or acute ischemia, developmental anomalies, hemorrhage, hydrocephaly) were excluded. Diffusion-weighted images were obtained at the parameter values of b = 1000 s/mm2 in the axial plane. The transverse diameters of the lateral ventricles (LVs) and ADC values of both CPs were measured. Brain MRIs of 202 individuals, 97 men (48%), 105 women (52%), were studied. There were statistically significant positive correlations between the ADC values of CP and patient ages. (Right CP: r = 0.623; p < 0.05. Left CP: r = 0.654; p < 0.05). There were positive correlations between LV diameters and age ( r = 0.624, p < 0.05 for the right LV; r = 0.621, p < 0.05 for the left LV). The ADC values of age groups significantly differed ( p < 0.05); the >=61-year-old group was significantly higher compared to younger individuals. There is a progressive increase of water diffusivity in the CPs during aging. ADC values should be considered as a neuroimaging quantitative biomarker in normal aging dementia syndromes. PMID- 28644063 TI - Morphological and Molecular Characterization of Metacercaria of Tylodelphys (Digenea: Diplostomidae) from the Piscine Host, Mystus tengara from India. AB - The diversity and taxonomy of diplostomids infecting freshwater fishes of the Indian region are predominantly poorly known. Yet compared to other trematodes, identification and discrimination of diplostomid metacercaria are difficult using morphology and site of infection. The present study provides the first molecular study of a Tylodelphys sp. from India. Specimens of Tylodelphys were collected from the vitreous humor of the eyes and from the brains of siluriform fish, Mystus tengara (Siluriformes: Bagridae) from Hastinapur, Meerut (U.P.), India. Taxonomic studies were performed on the basis of morphological, morphometrical, and molecular analysis. The dissimilarities in morphological and sites of infection between 2 forms of Tylodelphys, designated as Tylodelphys sp. 1 and Tylodelphys sp. 2, suggested that the forms were different species but, after performing molecular analysis, we conclude that despite morphological differences both morphotypes are conspecific. PMID- 28644062 TI - 4-Nerolidylcatechol: apoptosis by mitochondrial mechanisms with reduction in cyclin D1 at G0/G1 stage of the chronic myelogenous K562 cell line. AB - CONTEXT: 4-Nerolidylcatechol (4-NRC) has showed antitumor potential through apoptosis. However, its apoptotic mechanisms are still unclear, especially in leukemic cells. OBJECTIVES: To evaluate the cytotoxic potential of 4-NRC and its cell death pathways in p53-null K562 leukemic cells. MATERIALS AND METHODS: Cytotoxicity of 4-NRC (4.17-534.5 MUM) over 24 h of exposure was evaluated by MTT assay. 4-NRC-induced apoptosis in K562 cells was investigated by phosphatidylserine (PS) externalization, cell cycle, sub-G1, mitochondrial evaluation, cytochrome c, cyclin D1 and intracellular reactive oxygen species (ROS) levels, and caspase activity analysis. RESULTS: IC50 values obtained were 11.40, 27.31, 15.93 and 15.70 MUM for lymphocytes, K562, HL-60 and Jurkat cells, respectively. In K562 cells, 4-NRC (27 MUM) promoted apoptosis as verified by cellular morphological changes, a significant increase in PS externalization and sub-G1 cells. Moreover, it significantly arrested the cells at the G0/G1 phase due to a reduction in cyclin D1 expression. These effects of 4-NRC also significantly promoted a reduction in mitochondrial activity and membrane depolarization, accumulation of cytosolic cytochrome c and ROS overproduction. Additionally, it triggered an increase in caspases -3/7, -8 and -9 activities. When the cells were pretreated with N-acetyl-l-cysteine ROS scavenger, 4-NRC induced apoptosis was partially blocked, which suggests that it exerts cytotoxicity though not exclusively through ROS-mediated mechanisms. DISCUSSION AND CONCLUSION: 4-NRC has antileukemic properties, inducing apoptosis mediated by mitochondrial-dependent mechanisms with cyclin D1 inhibition. Given that emerging treatment concepts include novel combinations of well-known agents, 4-NRC could offer a promising alternative for chemotherapeutic combinations to maximize tumour suppression. PMID- 28644064 TI - Frequent vomiting attacks in a patient with Lhermitte-Duclos disease: a rare pathophysiology of cerebellar lesions? AB - Lhermitte-Duclos disease (LDD) is a neurological disease caused by a hamartomatous lesion in the cerebellum. Clinically, LDD is commonly associated with progressive space-occupying lesion effects in the posterior fossa, increasing intracranial pressure, occlusive hydrocephalus, and focal neurological deficits of adjacent structures. The authors report the case of a 10-year-old boy with LDD who had been suffering from vomiting attacks (VAs). These VAs had been brief in duration but extremely frequent, and they had been resistant to antiemetic drugs since the early postnatal period. Magnetic resonance imaging at 8 months of age revealed a right cerebellar lesion with very little space occupying lesion effect, but the causal relationship with VAs was not evident at that point, because no clinical symptoms or signs other than vomiting were suggestive of increased intracranial pressure. The VAs were initially diagnosed as autonomic ataxia and had been treated with antiemetic drugs for approximately 10 years, but the patient's symptoms were not improved at all in frequency or duration. He developed convulsive seizures at 9 years of age and was referred to the authors' epilepsy center. The VAs were initially speculated to represent an aspect of seizures, but antiepileptic agents proved ineffective against this symptom despite remission of convulsive seizures. Video-electroencephalography monitoring did not show any evolving ictal patterns associated with the vomiting. Careful reevaluation of MRI studies revealed that the cerebellar lesion was fused with the cerebellum, middle and inferior cerebellar peduncles, and dorsolateral medulla oblongata with some distortion. FDG-PET identified hypermetabolism in the cerebellar lesion. After establishing the diagnosis of LDD, the authors performed subtotal resection of the lesion based on the likelihood of a causal relationship between the cerebellar lesion and the vomiting center of the medulla oblongata. Postoperatively and for 2 years, VAs have remained completely suppressed. The authors hypothesize that the pathophysiology of VAs in LDD includes a tumor-like space-occupying effect on the vomiting center of the medulla oblongata, and even partial resection of the lesion may prove effective. PMID- 28644065 TI - Ventricular pseudodiverticula from intraparenchymal cerebrospinal fluid dissection secondary to high-grade obstructive hydrocephalus in children: magnetic resonance imaging findings. AB - We report on a series of three children who presented with a focal cerebrospinal fluid collection within the periventricular white matter of the temporal and occipital lobes in the setting of high-grade obstructive hydrocephalus. Magnetic resonance imaging showed a focal defect within the ventricular wall associated with leakage of cerebrospinal fluid into the adjacent white matter. The white matter tracts appeared primarily displaced. This entity should be referred to as ventricular pseudodiverticulum, not lined by ependymal cells, in contrast to a true ventricular diverticulum in which the cerebrospinal fluid is contained by a focal outpouching of the intact ventricular wall lined by a dilated and prolapsed layer of ependymal cells. Correct interpretation and classification of the findings may be helpful in predicting prognosis and outcome. PMID- 28644066 TI - Combination targeted pulmonary hypertension therapy in the resolution of Dasatinib-associated pulmonary arterial hypertension. AB - Dasatinib is a small-molecule tyrosine kinase inhibitor used in the treatment of hematological malignancies. Pulmonary arterial hypertension (PAH) is a rare but known complication. The mainstay of treatment is cessation of Dasatinib, and while clinical improvement is rapid, complete hemodynamic resolution of pulmonary hypertension (PH) still remains exceedingly uncommon. We present a case of Dasatinib-induced PAH in a woman with chronic myeloid leukemia, who demonstrated rapid and complete clinical and hemodynamic resolution following treatment with combination pulmonary vasodilator therapy using an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. This case suggests there may be an association between the use of targeted PH medication in combination and the complete resolution of dasatinib-associated PAH, but further investigation is required. PMID- 28644060 TI - Lytic transglycosylases: concinnity in concision of the bacterial cell wall. AB - The lytic transglycosylases (LTs) are bacterial enzymes that catalyze the non hydrolytic cleavage of the peptidoglycan structures of the bacterial cell wall. They are not catalysts of glycan synthesis as might be surmised from their name. Notwithstanding the seemingly mundane reaction catalyzed by the LTs, their lytic reactions serve bacteria for a series of astonishingly diverse purposes. These purposes include cell-wall synthesis, remodeling, and degradation; for the detection of cell-wall-acting antibiotics; for the expression of the mechanism of cell-wall-acting antibiotics; for the insertion of secretion systems and flagellar assemblies into the cell wall; as a virulence mechanism during infection by certain Gram-negative bacteria; and in the sporulation and germination of Gram-positive spores. Significant advances in the mechanistic understanding of each of these processes have coincided with the successive discovery of new LTs structures. In this review, we provide a systematic perspective on what is known on the structure-function correlations for the LTs, while simultaneously identifying numerous opportunities for the future study of these enigmatic enzymes. PMID- 28644067 TI - Border cell release: Cell separation without cell wall degradation? AB - Plant border cells are specialized cells derived from the root cap with roles in the biomechanics of root growth and in forming a barrier against pathogens. The mechanism of highly localized cell separation which is essential for their release to the environment is little understood. Here I present in situ analysis of Brachypodium distachyon, a model organism for grasses which possess type II primary cell walls poor in pectin content. Results suggest similarity in spatial dynamics of pectic homogalacturonan during dicot and monocot border cell release. Integration of observations from different species leads to the hypothesis that this process most likely does not involve degradation of cell wall material but rather uses unique cell wall structural and compositional means enabling both the rigidity of the root cap as well as detachability of given cells on its surface. PMID- 28644068 TI - Evaluation of the 2010 National Vaccine Plan Mid-course Review: Recommendations From the National Vaccine Advisory Committee: Approved by the National Vaccine Advisory Committee on February 7, 2017. PMID- 28644069 TI - Concomitant idiopathic hypertrophic spinal pachymeningitis and Guillain-Barre syndrome in a patient: coincidence or a triggering mechanism? AB - Idiopathic hypertrophic spinal pachymeningitis (IHSP), a rare diffuse inflammatory thickening of the dura mater, and Guillain-Barre syndrome (GBS) are known entities but they have never been reported as concomitant diagnoses. To their knowledge, the authors present the first reported case in the international literature with supportive evidence for both IHSP (based on MRI, intraoperative, and histological findings) and GBS (based on history, clinical examination, and electrophysiological findings). They review the literature on IHSP and the diagnostic criteria for GBS, with the view of identifying a possible causative connection. PMID- 28644070 TI - Particulate matter disrupts human lung endothelial cell barrier integrity via Rho dependent pathways. AB - Increased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability. Fine PM induced time-dependent activation of cytoskeletal machinery with increases in myosin light chain (MLC) phosphorylation and EC barrier disruption measured by transendothelial electrical resistance (TER), events attenuated by the Rho dependent kinase (ROCK) inhibitor Y-27632 or the reactive oxygen species (ROS) scavenger, N-acetylcysteine (NAC). Both Y-27632 and NAC prevented PM-induced stress fiber formation and phospho-MLC accumulation in human lung ECs. PM promotes rapid accumulation of Rho-GTP. This event is attenuated by NAC or knockdown of RhoA (siRNA). Consistent with ROCK activation, PM induced phosphorylation of myosin light chain phosphatase (MYPT) at Thr850, a post translational modification known to inhibit phosphatase activity. Furthermore, PM activates the guanine nucleotide exchange factor (GEF) for Rho, p115, with p115 translocation to the cell periphery, in a ROS-dependent manner. Together these results demonstrate that fine PM induces EC cytoskeleton rearrangement via Rho dependent pathways that are dependent upon the generation of oxidative stress. As the disruption of vascular integrity further contributes to cardiopulmonary physiologic derangements, these findings provide pharmacologic targets for prevention of PM-induced cardiopulmonary toxicity. PMID- 28644071 TI - Age invariance in rapid facial affective reactions to emotionally valenced stimuli. AB - It has been suggested that an age-related positivity effect may only occur in the context of explicit information processing, but it is unclear whether this bias extends to the processing of rapid facial reactions. In addition, most studies that have looked for evidence of age-related implicit positivity have used attentional (as opposed to sensory) unawareness paradigms, or used broad-based indicators of attentional awareness that do not speak to the nature of the affective response. In the present study, younger and older adults were therefore asked to view non-facial images presented supraliminally (i.e., consciously) as well as outside of sensory awareness (i.e., subliminally) while their facial reactions were indexed using electromyography. The results indicated that both younger and older adults exhibited rapid facial reactions congruent with the emotional valence of non-facial images in both supraliminal and subliminal conditions. Relative to young, older adults did not respond with greater zygomaticus (cheek) activity to positive stimuli or reduced corrugator (brow) activity to negative stimuli in either condition. These data show that rapid facial reactions to emotional stimuli are intact in late adulthood, even in response to stimuli that activate more automatic and implicit forms of emotion processing. However, there is no evidence for any age-related positivity bias in these behavioral responses. PMID- 28644072 TI - Clinicopathological and imaging features of lipoastrocytoma: Case report. AB - Lipidized tumors of the central nervous system are very uncommon, with only a few cases described. We report a case of a 25-year-old woman with a tumor involving the left premotor area. She underwent gross total excision. Histologically, the tumor was composed of glial fibrillary acidic protein-positive glial cells with areas of lipidization. A diagnosis of lipoastrocytoma was rendered. At three-year follow-up she was doing well, supporting the presumed favorable prognosis of these uncommon tumors. Absence of xanthochromic appearance, mitotic activity, necrosis and poor reticulin activity are the differentiating features from the pleomorphic xanthoastrocytoma. We highlighted that these tumors involve the adult and pediatric population and distribute in both supratentorial and infratentorial compartments as well as in the spinal cord. PMID- 28644073 TI - NT-proBNP in patients with asymptomatic severe aortic stenosis: relation to coronary microvascular function. PMID- 28644074 TI - Reinforcing marginality? Maternal health interventions in rural Nicaragua. AB - To achieve Millennium Development Goal 5 on maternal health, many countries have focused on marginalized women who lack access to care. Promoting facility-based deliveries to ensure skilled birth attendance and emergency obstetric care has become a main measure for preventing maternal deaths, so women who opt for home births are often considered 'marginal' and in need of targeted intervention. Drawing upon ethnographic data from Nicaragua, this paper critically examines the concept of marginality in the context of official efforts to increase institutional delivery amongst the rural poor, and discusses lack of access to health services among women living in peripheral areas as a process of marginalization. The promotion of facility birth as the new norm, in turn, generates a process of 're-marginalization', whereby public health officials morally disapprove of women who give birth at home, viewing them as non-compliers and a problem to the system. In rural Nicaragua, there is a discrepancy between the public health norm and women's own preferences and desires for home birth. These women live at the margins also in spatial and societal terms, and must relate to a health system they find incapable of providing good, appropriate care. Strong public pressure for institutional delivery makes them feel distressed and pressured. Paradoxically then, the aim of including marginal groups in maternal health programmes engenders resistance to facility birth. PMID- 28644075 TI - Spine stereotactic radiosurgery for metastatic sarcoma: patterns of failure and radiation treatment volume considerations. AB - OBJECTIVE Given the relatively lower radiosensitivity of sarcomas and the locally infiltrative patterns of spread, the authors sought to investigate spine stereotactic radiosurgery (SSRS) outcomes for metastatic sarcomas and to analyze patterns of failure. METHODS The records of 48 patients with 66 sarcoma spinal metastases consecutively treated with SSRS between 2002 and 2013 were reviewed. The Kaplan-Meier method was used to estimate rates of overall survival (OS) and local control (LC). Local recurrences were categorized as occurring infield (within the 95% isodose line [IDL]), marginally (between the 20% and 95% IDLs), or out of field. RESULTS Median follow-up time was 19 months (range 1-121 months), and median age was 53 years (range 17-85 years). The most commonly treated histology was leiomyosarcoma (42%). Approximately two-thirds of the patients were treated with definitive SSRS (44 [67%]) versus postoperatively (22 [33%]). The actuarial 1-year OS and LC rates were 67% and 81%, respectively. Eighteen patients had a local relapse, which was more significantly associated with postoperative SSRS (p = 0.04). On multivariate modeling, receipt of postoperative SSRS neared significance for poorer LC (p = 0.06, subhazard ratio [SHR] 2.33), while only 2 covariates emerged as significantly correlated with LC: 1) biological equivalent dose (BED) > 48 Gy (vs BED <= 48 Gy, p = 0.006, SHR 0.21) and 2) single vertebral body involvement (vs multiple bodies, p = 0.03, SHR 0.27). Of the 18 local recurrences, 14 (78%) occurred at the margin, and while the majority of these cases relapsed within the epidural space, 4 relapsed within the paraspinal soft tissue. In addition, 1 relapse occurred out of field. Finally, the most common acute toxicity was fatigue (15 cases), with few late toxicities (4 insufficiency fractures, 3 neuropathies). CONCLUSIONS For metastatic sarcomas, SSRS provides durable tumor control with minimal toxicity. High-dose single-fraction regimens offer optimal LC, and given the infiltrative nature of sarcomas, when paraspinal soft tissues are involved, larger treatment volumes may be warranted. PMID- 28644076 TI - A Novel Surgical Approach to Avian Femorotibiotarsal Luxation Repair. AB - A 3-month-old male umbrella cockatoo (Cacatua alba) was presented because of acute non-weight-bearing lameness of the right leg. Marked soft tissue swelling was present around the femorotibiotarsal (stifle) joint, and the radiographic diagnosis was right medial femorotibiotarsal subluxation. Surgical management was elected, and the stifle joint was approached via a lateral parapatellar incision. Joint exploration revealed damage to the lateral meniscus, tendon of origin of the cranial tibial muscle, and cranial cruciate ligament. After debriding the disrupted meniscus, the stifle joint was anatomically reduced. The femorotibiotarsal joint was stabilized by using a lateral extracapsular suture in a modified technique using a self-tapping cortical screw in the lateral femoral condyle and a hole through the proximal tibiotarsus. The bird regained function of the femorotibiotarsal joint for 3 months after surgery, allowing sufficient time for the bird to establish a physiologic perching angle so that ankylosis occurred to maintain functionality of the leg as a unit. This combination of orthopedic techniques adapted from techniques commonly used in small companion animal species may be considered to provide young birds with femorotibiotarsal luxations and subluxation a good quality of life despite ankylosis of the joint. PMID- 28644077 TI - Leiomyosarcoma of the Wing in a Vieilott's Fireback Pheasant (Lophura rufa). AB - A 15-year-old, female Vieilott's fireback pheasant (Lophura rufa) presented with a 2-day history of a drooping right wing. Examination revealed severe soft tissue swelling in the area extending from the right shoulder to the humeral-radio-ulnar joint with associated bruising and feather loss. Results of a complete blood cell count revealed marked heterophilia and lymphocytosis, and results of serum biochemical analysis showed severe increases in creatine kinase and aspartate aminotransferase activities, hypoproteinemia, and hypoalbuminemia. Radiographs revealed osteolytic lesions of the right humerus with pathologic fractures and circumferential soft tissue swelling. Although surgical wing amputation was successful, the bird died the next day while being treated. The mass was diagnosed histologically and immunohistochemically as a leiomyosarcoma. This is the first neoplasia of any kind reported in this species, to our knowledge, and one of the very few reports of smooth muscle neoplasms affecting the limb of a bird. PMID- 28644079 TI - A Disseminated Cryptococcus gattii VGIIa Infection in a Citron-Crested Cockatoo (Cacatua sulphurea citrinocristata) in Quebec, Canada. AB - Cryptococcus gattii infection in mammals and birds has been confined historically to tropical and subtropical regions in Australia, Southeast Asia, Africa, and South America. Since the early 2000s, numerous reports describe the emergence of C. gattii on the Pacific Coast of North America. We report on a C. gattii infection in an 8-year-old male citron-crested cockatoo (Cacatua sulphurea citrinocristata) hatched on the Canadian Pacific Coast and raised in the province of Quebec, Canada. The bird developed a slow growing ulcerated, fleshy, crusty, and hemorrhagic mass infiltrating the left lower rhamphotheca. Cryptococcus gattii infection was confirmed by cytologic examination of a fine needle aspirate of the mass, and results of fungal culture and sequencing. The genotype of the strain was determined to be VGIIa sequence type 20, the strongly overrepresented subgroup found on the Canadian Pacific coast. Minimum inhibitory concentrations for multiple antifungal drugs were determined. The bird received fluconazole but died acutely 55 days after initial presentation. Postmortem examination revealed a disseminated infection, with involvement of the beak, lungs, spleen, and brain. PMID- 28644078 TI - Plasma Concentrations of Itraconazole, Voriconazole, and Terbinafine When Delivered by an Impregnated, Subcutaneous Implant in Japanese Quail ( Coturnix japonica ). AB - Aspergillosis is a common fungal infection in both wild and pet birds. Although effective antifungal medications are available, treatment of aspergillosis can require months of medication administration, which entails stressful handling one or more times per day. This study examined the delivery of the antifungal drugs itraconazole, voriconazole, and terbinafine to Japanese quail ( Coturnix japonica ) via an impregnated implant. Implants contained 0.5, 3, 8, or 24 mg of itraconazole, voriconazole, or terbinafine. The implants were administered subcutaneously over the dorsum and between the scapulae. Blood was collected from birds before and 2, 7, 21, 42, and 56 days after implant placement. Plasma was analyzed by high-performance liquid chromatography for concentrations of itraconazole, voriconazole, or terbinafine, as appropriate. During the course of the study, targeted terbinafine concentrations were achieved in some birds at various time points, but concentrations were inconsistent. Itraconazole and voriconazole concentrations were also inconsistent and did not reach targeted concentrations. Currently, the implant examined in this study cannot be recommended for treatment of aspergillosis in avian species. PMID- 28644080 TI - Determination of Gastrointestinal Transit Times in Barred Owls ( Strix varia ) by Contrast Fluoroscopy. AB - Contrast imaging studies are routinely performed in avian patients when an underlying abnormality of the gastrointestinal (GI) tract is suspected. Fluoroscopy offers several advantages over traditional radiography and can be performed in conscious animals with minimal stress and restraint. Although birds of prey are commonly encountered as patients, little is known about GI transit times and contrast imaging studies in these species, especially owls. Owls are commonly encountered in zoological, educational, and wildlife settings. In this study, 12 adult barred owls ( Strix varia ) were gavage fed a 30% weight-by volume barium suspension (25 mL/kg body weight). Fluoroscopic exposures were recorded at 5, 15, 30, 60, 120, 180, 240, and 300 minutes after administration. Overall GI transit time and transit times of various GI organs were recorded. Median (interquartile range [IQR]) overall GI transit time was 60 minutes (IQR: 19-60 minutes) and ranged from 5-120 minutes. Ventricular and small intestinal contrast filling was rapid. Ventricular emptying was complete by a median of 60 minutes (IQR: 30-120 minutes; range: 30-240 minutes), whereas small intestinal emptying was not complete in 9/12 birds by 300 minutes. Median small intestinal contraction rate was 15 per minute (IQR: 13-16 minutes; range: 10-19 minutes). Median overall GI transit time in barred owls is more rapid than mean transit times reported for psittacine birds and red-tailed hawks ( Buteo jamaicensis ). Fluoroscopy is a safe, suitable method for investigating GI motility and transit in this species. PMID- 28644081 TI - Effects of Added Lipids on Digestibility and Nitrogen Balance in Oiled Common Murres ( Uria aalge ) and Western Grebes ( Aechmophorus occidentalis ) Fed Four Formulations of a Critical Care Diet. AB - Nutritional support is a primary therapy administered to oiled animals during responses to oil spills, but data informing nutritional decision-making during events are limited. In this study, 44 common murres ( Uria aalge ) and 6 Western grebes ( Aechmophorus occidentalis ), naturally oiled by oceanic seeps off the coast of Ventura and Santa Barbara Counties, CA, USA, were assigned to 1 of 4 groups fed diets with varying levels (6.8% [no added oil], 11%, and 20%) and types (salmon, corn) of oil added to a partially purified basal diet. Birds used in the study ranged from extremely emaciated to thin body condition (62%-80% wild bird mean body mass). Acid-insoluble ash was used as an indigestible dietary marker to quantify nitrogen retention, apparent nitrogen digestibility, nitrogen corrected apparent metabolizable energy, energy digestibility, fat retention, fat digestibility, and estimated fat excretion. Fat excretion is important in these species because once birds have been cleaned they are at risk of plumage recontamination from excreted fat during care. Lower fat diets resulted in lower fat excretion but higher nitrogen retention, higher apparent nitrogen digestibility, and higher apparent metabolizable energy. Decreases in nitrogen retention were significantly related to increases in fat excretion. Regardless of diet, energy digestibility significantly declined with declines in body mass, suggesting severity of emaciation reduced a birds' ability to extract energy from food. Energy digestibility was highest in the 11% (low) salmon oil diet; hence, this diet had the highest effective energy content despite a lower gross kcal/kg diet. Diets fed during oil spills historically have had high fat concentrations to provide maximum caloric support. Results of this study suggest that lower fat diets may be more efficacious for nutritionally depleted seabirds. This study provides valuable data to guide clinical decision making regarding nutritional support during oil spills and other mass stranding events. PMID- 28644083 TI - What Is Your Diagnosis? PMID- 28644084 TI - Comparison of Two Methods for Determining Prevalence of Macrorhabdus ornithogaster in a Flock of Captive Budgerigars (Melopsittacus undulatus). AB - Macrorhabdus ornithogaster is a yeast organism that infects multiple species of captive and wild birds. Diagnosis of infection in vivo has proven difficult historically, as shedding can be intermittent, and not all positive animals are clinically ill. We compared polymerase chain reaction (PCR) of cloacal swab samples and fecal Gram's stain (FGS) for diagnosis of active shedding of M ornithogaster in a captive flock of budgerigars ( Melopsittacus undulatus ). Of the 100 birds sampled, 57 (57%) were positive for M ornithogaster by PCR and 24 (24%) were positive for M ornithogaster by FGS. All FGS-tested birds also were positive on PCR. There was a significant association between the two methods, but the overall percent agreement for the two methods was only 67%. Based on these findings, cloacal swab PCR is more likely to diagnose the presence of M ornithogaster than FGS in budgerigars. PMID- 28644085 TI - Pharmacokinetics of a Sustained Release Formulation of Buprenorphine After Intramuscular and Subcutaneous Administration to American Kestrels ( Falco sparverius ). AB - Previous studies have validated the clinical use of opioids with MU-receptor affinities for pain management in raptors. Buprenorphine appears to have a longer duration of action and minimal adverse effects when compared to other opioids in American kestrels ( Falco sparverius ). To determine the pharmacokinetics of a sustained release formulation of buprenorphine in kestrels, we administered a commercially available product (Buprenorphine SR-LAB; Wildlife Pharmaceuticals, Windsor, CO, USA) intramuscularly and subcutaneously to adult kestrels in a partial-crossover experimental design study. A total of 12 birds (6 males and 6 females) were assigned randomly to 3 groups of 4 birds each. A single dose of Buprenorphine SR-LAB (1.8 mg/kg) was administered intramuscularly (IM), and blood samples were collected at 0.25, 3, and 24 hours (n = 4); 1, 6, and 48 hours (n = 4); and 2, 12, and 72 hours (n = 4) after drug administration. Plasma buprenorphine concentrations were measured by tandem liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by use of least squares linear regression and noncompartmental analysis of naive pooled data. After 1 year, the same dose of buprenorphine was administered subcutaneously (SC) to 12 birds divided into 3 groups as previously, and blood samples were collected at the same times after drug administration. Maximum plasma buprenorphine concentration was measured at 15 minutes after IM and SC administration. Mean plasma buprenorphine concentrations were >1 ng/mL for 48 hours after IM and SC administration. The elimination half-life was 13.5 and 11.1 hours for IM and SC administration, respectively. Depending on the severity and type of pain, adjunctive therapy, and the individual response, Buprenorphine SR-LAB administered at 1.8 mg/kg IM or SC to American kestrels would require administration every 12 to 72 hours to manage pain. Further pharmacodynamic and clinical evaluations are warranted in kestrels and other raptors to establish accurate dosing recommendations. PMID- 28644087 TI - Coming Meetings. PMID- 28644086 TI - Single-Dose Pharmacokinetics of Piperacillin/Tazobactam in Hispaniolan Amazon Parrots ( Amazona ventralis ). AB - To determine the pharmacokinetics of piperacillin/tazobactam in Hispaniolan Amazon parrots ( Amazona ventralis ), 8 healthy adult parrots of both sexes were used in a 2-part study. In a pilot study, piperacillin (87 mg/kg) in combination with tazobactam (11 mg/kg) was administered intramuscularly (IM) to 2 birds, and blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after administration. Based on the results obtained, a main study was done in which piperacillin/tazobactam was administered at 2 different doses. In 3 birds, the initial dose of piperacillin (87 mg/kg)/tazobactam (11 mg/kg) IM was administered, and in 3 birds, the dose was doubled to piperacillin (174 mg/kg)/tazobactam (22 mg/kg) IM. In all 6 birds, blood samples were obtained at 0, 5, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, and 4 hours after administration. Quantification of plasma piperacillin and tazobactam concentrations was determined by validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were determined by noncompartmental analysis. After intramuscular administration, the mean +/- standard error values of T1/2 (h) was 0.52 +/- 0.05 and 0.32 +/- 0.07, Tmax (h) was 0.28 +/- 0.09 and 0.25 +/- 0.10, Cmax (MUg/mL) was 86.34 +/- 20.62 and 9.03 +/- 2.88, and Cmax/dose was 0.99 +/- 0.24 and 0.83 +/- 0.26 for piperacillin (87 mg/kg) and tazobactam (11 mg/kg), respectively. When the doses were doubled, the T1/2 (h) was 0.65 +/- 0.08 and 0.34 +/- 0.02, Tmax (h) was 0.28 +/- 0.12 and 0.14 +/- 0.06, Cmax (MUg/mL) was 233.0 +/- 6.08 and 22.13 +/- 2.35, and Cmax/dose was 1.34 +/- 0.03 and 1.02 +/- 0.11 for piperacillin and tazobactam, respectively. Results indicate that piperacillin is rapidly absorbed and reaches high initial concentrations; however, it is also rapidly eliminated in the Hispaniolan Amazon parrot, and tazobactam has similar pharmacokinetics as piperacillin. Administration of piperacillin at 87 mg/kg IM q3-4h is recommended for this species to control infections attributed to susceptible bacteria with a minimum inhibitory concentration of <=4 MUg/mL. PMID- 28644088 TI - Telemedicine: The Future of Veterinary Practice. PMID- 28644089 TI - Evaluation of High Dosages of Oral Meloxicam in American Kestrels ( Falco sparverius ). AB - To evaluate the toxicity of short-term high doses of meloxicam in American kestrels ( Falco sparverius ), 32 male captive-born, 1- to 4-year-old American kestrels were randomly assigned to 4 groups: 3 groups treated with meloxicam (n = 9 per group) and a control group (n = 5). Meloxicam was administered orally via feeding tube in the proventriculus at 2, 10, and 20 mg/kg every 12 hours for 7 days for the treatment groups, while the control group received saline solution. The birds were evaluated for the presence of clinical signs, abnormalities in the complete blood cell count and in the plasma biochemical panel for the 20-mg/kg group, and gross and histopathologic lesions. No clinical signs or mortality were observed in any group. No significant differences of clinical relevance were found in results of the packed cell volume, total solids, and biochemical panel, and no evidence of renal toxicity was found in the treatment or control groups. A significant correlation was found between hepatic lipidosis and meloxicam dose (P = .02). Two of 9 birds in the 20-mg/kg group developed gastric ulcers, although this result was not significant. None of the birds in the 2- and 10-mg/kg groups had similar lesions. Finally, meloxicam dosages up to 20 mg/kg did not result in nephrotoxicity in American kestrels. Further toxicologic studies to evaluate hepatotoxicity and gastrotoxicity of meloxicam in avian species are needed. PMID- 28644090 TI - Transdermal administration of melatonin coupled to cryopass laser treatment as noninvasive therapy for prostate cancer. AB - Melatonin, a pineal gland hormone, exerts oncostatic activity in several types of human cancer, including prostate, the most common neoplasia and the third most frequent cause of male cancer death in the developed world. The growth of androgen-sensitive LNCaP prostate cancer cells in mice is inhibited by 3 mg/kg/week melatonin (0.09 mg/mouse/week) delivered by i.p. injections, which is equivalent to a dose of 210 mg/week in humans. The aim of this study is to test an alternative noninvasive delivery route based on transdermal administration of melatonin onto the tumor area followed by cryopass-laser treatment. Two groups of immunodepressed mice were studied, one (n = 10) subjected to 18 cryopass-laser therapy sessions and one (n = 10) subjected to the same treatment without melatonin. These groups were compared with mice treated with i.p.-administered melatonin or vehicle with the same time schedule. We found that cryopass-laser treatment is as efficient as i.p. injections in reducing the growth of LNCaP tumor cells, affecting plasma melatonin and redox balance. Furthermore, both delivery routes share the same effects on the involved biochemical pathway driven by hypoxia-inducible factor 1alpha. However, cryopass-laser, as used in the present experimental setup, is less efficient than i.p delivery route in increasing the melatonin content and Nrf2 expression in the tumor mass. We conclude that cryopass-laser treatment may have impact for melatonin-based therapy of prostate cancer, by delivering drugs transdermally without causing pain and targeting directly on the site of interest, thereby potentially making long-term treatments more sustainable. PMID- 28644093 TI - The dangerous liaison: Coronary and kidney disease. PMID- 28644092 TI - Single and multiple cardiovascular biomarkers in subjects without a previous cardiovascular event. AB - Aims To assess the incremental value of biomarkers, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), growth differentiation factor 15 (GDF-15), and procollagen type 1 N-terminal propeptide (P1NP), in predicting incident cardiovascular events and mortality among asymptomatic individuals from the general population, beyond traditional risk factors, including fasting glucose and renal function (cystatin C), medication use, and echocardiographic measures. Methods and results Prospective population-based cohort study of 1324 subjects without a previous cardiovascular event, who underwent baseline echocardiography and biomarker assessment between 2002 and 2006. The clinical endpoint was the composite of myocardial infarction, invasively treated stable/unstable ischemic heart disease, heart failure, stroke, or all-cause mortality. Predictive capabilities were evaluated using Cox proportional-hazards regression, Harrell's concordance index (C-index), and net reclassification improvement. Median age was 66 (interquartile range: 60-70) years, and 413 (31%) were female. During median 8.6 (interquartile range: 8.1 9.2) follow-up years, 368 (28%) composite events occurred. NT-proBNP, hs-TnT, GDF 15, and IL-6 were significantly associated with outcome, independently of traditional risk factors, medications, and echocardiography ( p < 0.05 for all). Separate addition of NT-proBNP and GDF-15 to traditional risk factors, medications, and echocardiographic measurements provided significant improvements in discriminative ability (NT-proBNP: C-index 0.714 vs. 0.703, p = 0.03; GDF-15: C-index 0.721 vs. 0.703, p = 0.02). Both biomarkers remained significant predictors of outcome upon inclusion in the same model ( p < 0.05 for both). Conclusions NT-proBNP and GDF-15 each enhance prognostication beyond traditional risk factors, glucose levels, renal function, and echocardiography in individuals without known cardiovascular disease. PMID- 28644094 TI - Cardiovascular prevention in HIV-positive individuals on antiretroviral therapy.. The paradigm shift has already happened: Is it time to wake up and realise it? PMID- 28644091 TI - Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: The role of PCSK9 inhibitors. AB - Familial hypercholesterolaemia is an autosomal dominant inherited disorder characterised by elevated low-density lipoprotein cholesterol levels and consequently an increased risk of atherosclerotic cardiovascular disease (ASCVD). Familial hypercholesterolaemia is relatively common, but is often underdiagnosed and undertreated. Cardiologists are likely to encounter many individuals with familial hypercholesterolaemia; however, patients presenting with premature ASCVD are rarely screened for familial hypercholesterolaemia and fasting lipid levels are infrequently documented. Given that individuals with familial hypercholesterolaemia and ASCVD are at a particularly high risk of subsequent cardiac events, this is a missed opportunity for preventive therapy. Furthermore, because there is a 50% chance that first-degree relatives of individuals with familial hypercholesterolaemia will also be affected by the disorder, the underdiagnosis of familial hypercholesterolaemia among patients with ASCVD is a barrier to cascade screening and the prevention of ASCVD in affected relatives. Targeted screening of patients with ASCVD is an effective strategy to identify new familial hypercholesterolaemia index cases. Statins are the standard treatment for individuals with familial hypercholesterolaemia; however, low density lipoprotein cholesterol targets are not achieved in a large proportion of patients despite treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce low-density lipoprotein cholesterol levels considerably in individuals with familial hypercholesterolaemia who are concurrently receiving the maximal tolerated statin dose. The clinical benefit of PCSK9 inhibitors must, however, also be considered in terms of their cost effectiveness. Increased awareness of familial hypercholesterolaemia is required among healthcare professionals, particularly cardiologists and primary care physicians, in order to start early preventive measures and to reduce the mortality and morbidity associated with familial hypercholesterolaemia and ASCVD. PMID- 28644095 TI - Impact of adherence to antidepressants on healthcare outcomes and costs among patients with type 2 diabetes and comorbid major depressive disorder. AB - OBJECTIVE: To evaluate the association between adherence to antidepressants and an effect on clinical outcomes and healthcare costs in patients with major depressive disorder (MDD) and comorbid type 2 diabetes (T2D). METHODS: This retrospective study used MarketScan claims data from January 2012 to March 2014. Study entry was the first claim for an antidepressant and a diagnosis code for MDD and T2D in the prior 6 months. Adherence and persistence with antidepressant therapy in the first 180 days were defined as medication possession ratio (MPR) >= 80% and length of therapy (LOT), with no treatment gap of >15 days, respectively. T2D control (HbA1c <7%), oral diabetes medication adherence, and healthcare costs were measured in the 12 month post-index period. The impact of antidepressant adherence and persistence on outcomes was assessed using multivariable analyses. RESULTS: Among the 1361 patients included, the mean age was 59 years and 55% were women. About one-third of the patients were adherent (35.9%, mean MPR = 40%), persistent (32.0%, average LOT = 100 days), and adherent/persistent (31.2%) on antidepressants. Being adherent, persistent, or adherent/persistent to antidepressants was associated with a two-fold improvement in adherence to oral diabetes medications. Of those with HbA1c data (n = 121), adherence or adherence/persistence to antidepressants was associated with patients being five times more likely to have T2D control (odds ratio [OR]: 4.95; 95% confidence interval [CI]: 1.39, 17.59, p = .0134). Comparison between antidepressant-persistent and non-persistent patients was not significant. Mean difference in adjusted all-cause annual costs showed lower costs among antidepressant-adherent and adherent/persistent patients (adherent: -$350, 95% CI: -$462, -$247; adherent/persistent: -$1165; 95% CI: -$1280, -$1060). CONCLUSIONS: Patients with better antidepressant adherence and adherence/persistence demonstrated better HbA1c control, with lower all-cause total and medical costs. Adherence, persistence, or adherence/persistence to antidepressants was associated with improved adherence to oral diabetes medications. PMID- 28644096 TI - Comparisons between commercial salivary testosterone enzyme-linked immunosorbent assay kits. AB - INTRODUCTION: Measuring testosterone concentrations is of interest both in clinical situations and for research, the latter expanding rapidly during recent years. An increased demand for convenient methods has prompted a number of companies to develop enzyme-linked immunosorbent assay (ELISA) kits to measure testosterone concentrations in saliva. However, the inter-comparability of kits from different manufacturers have yet to be determined. AIM OF STUDY: The aim of this study was to compare commercially available ELISA kits from four different manufacturers (Salimetrics, IBL, DRG and Demeditec). METHODS: Saliva was collected from 50 participants (25 men and 25 women). Each sample was analysed by the four ELISA kits. RESULTS: The correlations between the ELISA kits from Demeditec, DRG and Salimetrics were moderate to high with r-values > .77; however, proportional errors between the methods calls for caution. The ELISA kit from IBL malfunctioned and no results from this kit was obtained. CONCLUSIONS: Results from studies using the ELISA kits from Demeditec, DRG and Salimetrics are generally comparable; however, translation using the formulae presented in the current study could increase the accuracy of these comparisons. PMID- 28644098 TI - Intracranial solitary fibrous tumors/hemangiopericytomas: first report of malignant progression. AB - OBJECTIVE Meningeal solitary fibrous tumors/hemangiopericytomas (MSFTs/HPCs) are rare intracranial tumors resembling meningiomas. Their classification was redefined in 2016 by the World Health Organization (WHO) as benign Grade I fibrohyaline type, intermediate Grade II hypercellular type, and malignant highly mitotic Grade III. This grouping is based on common histological features and identification of a common NAB2-STAT6 fusion. METHODS The authors retrospectively identified 49 cases of MSFT/HPC. Clinical data were obtained from the medical records, and all cases were analyzed according to this new 2016 WHO grading classification in order to identify malignant transformations. RESULTS Recurrent surgery was performed in 18 (37%) of 49 patients. Malignant progression was identified in 5 (28%) of these 18 cases, with 3 Grade I and 2 Grade II tumors progressing to Grade III, 3-13 years after the initial surgery. Of 31 Grade III tumors treated in this case series, 16% (5/31) were proved to be malignant progressions from lower-grade tumors. CONCLUSIONS Low-grade MSFTs/HPCs can transform into higher grades as shown in this first report of such progression. This is a decisive argument in favor of a common identity for MSFT and meningeal HPC. High-grade MSFTs/HPCs tend to recur more often and be associated with reduced overall survival. Malignant progression could be one mechanism explaining some recurrences or metastases, and justifying long-term follow-up, even for patients with Grade I tumors. PMID- 28644097 TI - Thirty-day postoperative morbidity and mortality after temporal lobectomy for medically refractory epilepsy. AB - OBJECTIVE Temporal lobectomy is a well-established treatment modality for the management of medically refractory epilepsy in appropriately selected patients. The aim of this study was to assess 30-day morbidity and mortality after temporal lobectomy in cases registered in a national database. METHODS A retrospective cohort analysis was conducted using a multiinstitutional surgical registry compiled between 2006 and 2014. The authors identified patients who underwent anterior temporal lobectomy and/or amygdalohippocampectomy for a primary diagnosis of intractable epilepsy. Univariate and multivariable analyses with regard to patient demographics, comorbidities, operative characteristics, and 30 day outcomes were applied. RESULTS A total of 216 patients were included in the study. The median age was 38 years and 46% of patients were male. The median length of stay was 3 days and the 30-day mortality rate was 1.4%. Fourteen patients (6.5%) developed at least one major complication. Return to the operating room was observed in 7 patients (3.2%). Readmission within 30 days and discharge to a location other than home were available for 2011-2014 (n = 155) and occurred in 11% and 10.3% of patients, respectively. Multivariable regression analysis revealed that increasing age was an independent predictor of discharge disposition other than home and that male sex was a significant risk factor for the development of a major complication. Interestingly, the presence of the attending neurosurgeon and a resident during the procedure was significantly associated with decreased odds of prolonged length of stay (i.e., > 75th percentile [5 days]) and discharge to a location other than home. CONCLUSIONS Using a multiinstitutional surgical registry, 30-day outcome data after temporal lobectomy for medically intractable epilepsy demonstrates a mortality rate of 1.4%, a major complication rate of 6.5%, and a readmission rate of 11%. Temporal lobectomy is an extremely effective therapy for seizures originating there however, surgical intervention must be weighed against its morbidity and mortality outcomes. PMID- 28644099 TI - Assessment of drainage techniques for evacuation of chronic subdural hematoma: a consecutive population-based comparative cohort study. AB - OBJECTIVE Surgery for chronic subdural hematoma (CSDH) is one of the most common neurosurgical procedures. The benefit of postoperative passive subdural drainage compared with no drains has been established, but other drainage techniques are common, and their effectiveness compared with passive subdural drains remains unknown. METHODS In Scandinavian population-based cohorts the authors conducted a consecutive, parallel cohort study to compare different drainage techniques. The techniques used were continuous irrigation and drainage (CID cohort, n = 166), passive subdural drainage (PD cohort, n = 330), and active subgaleal drainage (AD cohort, n = 764). The primary end point was recurrence in need of reoperation within 6 months of index surgery. Secondary end points were complications, perioperative mortality, and overall survival. The analyses were based on direct regional comparison (i.e., surgical strategy). RESULTS Recurrence in need of surgery was observed in 18 patients (10.8%) in the CID cohort, in 66 patients (20.0%) in the PD cohort, and in 85 patients (11.1%) in the AD cohort (p < 0.001). Complications were more common in the CID cohort (14.5%) compared with the PD (7.3%) and AD (8.1%) cohorts (p = 0.019). Perioperative mortality rates were similar between cohorts (p = 0.621). There were some differences in baseline and treatment characteristics possibly interfering with the above-mentioned results. However, after adjusting for differences in baseline and treatment characteristics in a regression model, the drainage techniques were still significantly associated with clinical outcome (p < 0.001 for recurrence, p = 0.017 for complications). CONCLUSIONS Compared with the AD cohort, more recurrences were observed in the PD cohort and more complications in the CID cohort, also after adjustment for differences at baseline. Although the authors cannot exclude unmeasured confounding factors when comparing centers, AD appears superior to the more common PD. Clinical trial registration no.: NCT01930617 (clinicaltrials.gov). PMID- 28644100 TI - Influence of smoking on aneurysm recurrence after endovascular treatment of cerebrovascular aneurysms. AB - OBJECTIVE Smoking is a known risk factor for aneurysm development and aneurysmal subarachnoid hemorrhage, as well as subsequent vasospasm in both untreated individuals and patients who have undergone surgical clipping of cerebrovascular aneurysms. However, there is a lack of data in the current scientific literature about the long-term effects that smoking has on the integrity of endovascular repairs of cerebral aneurysms. This study was designed to determine if any smoking history increased the risk of poorer outcomes and/or aneurysm recurrence in patients who have had endovascular repair of cerebral aneurysms. METHODS The authors retrospectively analyzed the medical records of patients admitted to the University of Michigan Health System from January 1999 to December 2011 with coiled aneurysms and angiography, CT angiography, or MR angiography follow-up. Patients were identified and organized based on many criteria including age, sex, smoking history, aneurysm recurrence, aneurysm location, and Hunt and Hess grade. Analysis was targeted to the patient population with a history of smoking. Bivariate chi-square tests were used to analyze the association between a positive smoking history and documented aneurysm recurrence and were adjusted for potential confounders by fitting multivariate logistic regression models of recurrence. RESULTS A total of 247 patients who had undergone endovascular treatment of 296 documented cerebral aneurysms were included in this study. The recurrence rate among all patients treated with endovascular repair was 24.3%, and the average time to the most recent follow-up imaging studies was 1.62 years. Smokers accounted for 232 aneurysms and were followed up for an average of 1.57 years, with a recurrence rate of 26.3%. Never smokers accounted for the remaining 64 aneurysms and were followed up for an average of 1.82 years, with a recurrence rate of 17.2%. Multivariate analysis revealed that, after controlling for potential confounders, a history of smoking-whether current or former-was associated with a significantly increased risk of aneurysm recurrence. The odds ratios for aneurysm recurrence for current and former smokers were 2.739 (95% CI 1.127-7.095, p = 0.0308) and 2.698 (95% CI 1.078-7.212, p = 0.0395), respectively, compared with never smokers. CONCLUSIONS A positive smoking history is associated with a significantly increased risk of aneurysm recurrence in patients who have undergone endovascular repair of a cerebral aneurysm, compared with the risk in patients who have never smoked. PMID- 28644101 TI - Safety and cost efficiency of a restrictive transfusion protocol in patients with traumatic brain injury. AB - OBJECTIVE Blood loss and moderate anemia are common in patients with traumatic brain injury (TBI). However, despite evidence of the ill effects and expense of the transfusion of packed red blood cells, restrictive transfusion practices have not been universally adopted for patients with TBI. At a Level I trauma center, the authors compared patients with TBI who were managed with a restrictive (target hemoglobin level > 7 g/dl) versus a liberal (target hemoglobin level > 10 g/dl) transfusion protocol. This study evaluated the safety and cost-efficiency of a hospital-wide change to a restrictive transfusion protocol. METHODS A retrospective analysis of patients with TBI who were admitted to the intensive care unit (ICU) between January 2011 and September 2015 was performed. Patients < 16 years of age and those who died within 24 hours of admission were excluded. Demographic data and injury characteristics were compared between groups. Multivariable regression analyses were used to assess hospital outcome measures and mortality rates. Estimates from an activity-based cost analysis model were used to detect changes in cost with transfusion protocol. RESULTS A total of 1565 patients with TBI admitted to the ICU were included in the study. Multivariable analysis showed that a restrictive transfusion strategy was associated with fewer days of fever (p = 0.01) and that patients who received a transfusion had a larger fever burden. ICU length of stay, ventilator days, incidence of lung injury, thromboembolic events, and mortality rates were not significantly different between transfusion protocol groups. A restrictive transfusion protocol saved approximately $115,000 annually in hospital direct and indirect costs. CONCLUSIONS To the authors' knowledge, this is the largest study to date to compare transfusion protocols in patients with TBI. The results demonstrate that a hospital-wide change to a restrictive transfusion protocol is safe and cost effective in patients with TBI. PMID- 28644102 TI - Letter to the Editor. da Vinci robot-assisted transoral surgery for sellar tumors. PMID- 28644103 TI - Prognostic significance of intraoperative change in the fractional anisotropy and the volume of the optic chiasma during resection of suprasellar tumors. AB - OBJECTIVE The aim of this study was to test the prognostic significance of intraoperative changes in the fractional anisotropy (FA) and the volume of the optic chiasma and their correlation with visual outcome. METHODS Twenty-eight sequential patients with suprasellar tumors presenting with chiasma compression syndrome were surgically treated under intraoperative MRI control between March 2014 and July 2016. The FA and the volume of the optic chiasma were measured immediately before and immediately after tumor resection. The visual impairment score (VIS) was used to quantify the severity of the ophthalmological disturbances before surgery, 10-14 days after surgery, and again 3 months thereafter. The change in the FA and the volume of the optic chiasma was correlated to the improvement of vision. The correlation between other predictors such as the age of the patients and the duration of symptoms and the visual outcome was tested. RESULTS The VIS improved significantly after surgery. The FA values of the optic chiasma decreased significantly after decompression, whereas the volume of the optic chiasma increased significantly after decompression. The early and delayed improvement of vision was strongly correlated to the decrease in the average FA and the increase of the volume of the optic chiasma. The duration of symptoms showed a significant negative correlation to the visual outcome. However, the decrease in the FA showed the strongest correlation to the improvement of the VIS, followed by the expansion of the optic chiasma, and then the duration of symptoms. CONCLUSIONS The decrease in the FA and the expansion of the optic chiasma after its decompression are strong early predictors of the visual outcome. These parameters are also able to predict delayed improvement of vision. PMID- 28644104 TI - The association between blood eosinophil count and benralizumab efficacy for patients with severe, uncontrolled asthma: subanalyses of the Phase III SIROCCO and CALIMA studies. AB - OBJECTIVE: Benralizumab, an anti-eosinophilic monoclonal antibody, in combination with high-dosage inhaled corticosteroids and long-acting beta2-agonists (ICS/LABA), significantly reduced asthma exacerbations, improved lung function, and reduced symptoms for patients with severe, uncontrolled asthma with blood eosinophil counts >=300 cells/MUL in the Phase III SIROCCO and CALIMA studies. To understand the efficacy and safety of benralizumab for patients with eosinophil driven disease with blood eosinophil counts lower than 300 cells/MUL, we evaluated the effect of applying an eosinophil cutoff of >=150 cells/MUL. METHODS: Adult patients with uncontrolled asthma despite high-dosage ICS/LABA +/- additional asthma controller(s) received subcutaneous benralizumab 30 mg every 8 weeks (Q8W; first three doses every 4 weeks) or placebo for 48 (SIROCCO) or 56 (CALIMA) weeks. Efficacy measures including annual exacerbation rate, prebronchodilator FEV1, and total asthma symptom score were analyzed by baseline blood eosinophil counts >=150 vs. <150 cells/MUL. RESULTS: Benralizumab reduced asthma exacerbation rates by 42% in SIROCCO (rate ratio = 0.58; 95% CI = 0.46 0.74; p < 0.001; n = 325) and 36% in CALIMA (rate ratio = 0.64; 95% CI = 0.50 0.81; p < 0.001; n = 300) vs. placebo (n = 306 for SIROCCO, n = 315 for CALIMA) for patients with blood eosinophil counts >=150 cells/MUL. Benralizumab increased prebronchodilator FEV1 (both studies, p <= 0.002) and improved total asthma symptom score in SIROCCO (p = 0.009) at end of treatment vs. placebo for patients with blood eosinophil counts >=150 cells/MUL. The overall adverse events frequency was similar between treatment groups and eosinophil count cohorts. CONCLUSION: These results support the efficacy and safety of benralizumab for patients with severe asthma and blood eosinophil counts >=150 cells/MUL. PMID- 28644105 TI - Time course analyses of orthographic and phonological priming effects in developing readers. AB - It has been assumed that fluent reading requires efficient integration of orthographic and phonological codes. However, it is thus far unclear how this integration process develops when children learn to become fluent readers. Therefore, we used masked priming to investigate time courses of orthographic and phonological code activation in children at incremental levels of reading development (second, fourth and sixth grade). The first study used targets with small phonological differences between phonological and orthographic primes, which are typical in transparent orthographies. The second study manipulated the strength of the phonological difference between prime and target to clarify whether phonological difference influences phonological priming effects. Results in both studies showed that orthographic priming effects became facilitative at increasingly short durations during reading development, but phonological priming was absent. These results are taken to suggest that development of reading fluency is accompanied by increased automatization of orthographic representations. The absence of phonological priming suggests that developing readers cannot yet activate phonological codes automatically. PMID- 28644106 TI - Viability and Osteogenic Differentiation of Human Periodontal Ligament Progenitor Cells Are Maintained After Incubation With Porphyromonas gingivalis Protein Extract. AB - BACKGROUND: Porphyromonas gingivalis (Pg) is a major periodontal pathogen that contains immunostimulatory components. Periodontal ligament mesenchymal stem cells (PDLMSCs) are responsible for regeneration of the periodontium that is lost due to periodontitis. Pathologic factors within the microenvironment that impair resident PDLMSCs are not well understood. The present study investigates in vitro the effects of Pg protein extract (PgPE) on biologic properties of CD105-enriched PDL progenitor cell populations (PDL-CD105+). METHODS: Five populations of PDL CD105+ cells were exposed to PgPE and assessed for cell viability, apoptosis, and proinflammatory gene expression (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha], and IL-6) by quantitative reverse transcription polymerase chain reaction, IL-6 immunostaining, activation of IL-6/signal transducer and activator of transcription (STAT) 3 signaling pathway, and osteogenic differentiation potential. RESULTS: PgPE treatment (2 MUg/mL) did not affect cell viability or survival but induced a significant increase in IL-1beta, TNF-alpha, and IL-6 messenger RNA (mRNA) expression and positive staining for IL 6. A total of 29 genes from the IL-6/STAT3 pathway were upregulated on PgPE stimulation. These genes are related to biologic processes involved in the control of cell survival (B-cell lymphoma 2 [BCL2]), cell proliferation (hepatocytehepatocyte growth factor), cytokine-mediated signaling pathway (suppressor of cytokine signaling 3, C-X-C ligand 8 [CXCL8]), and response to stress (CXCL8, mitogen-activated protein kinase 3, BCL2-associated X protein, and BCL2). Additionally, PgPE treatment caused an increase in alkaline phosphatase mRNA expression in PDL-CD105+ cells after 7 days of osteogenic induction, although mineral nodule formation was comparable to the control group. CONCLUSIONS: These results suggest that the inflammatory profile induced by PgPE treatment in PDL-CD105+ cells did not affect cell viability, apoptosis, or osteogenic differentiation, perhaps due to increased expression of genes involved in the control of cell proliferation and protection against cell death. PMID- 28644108 TI - Comparison of Periodontal Parameters and Self-Perceived Oral Symptoms Among Cigarette Smokers, Individuals Vaping Electronic Cigarettes, and Never-Smokers. AB - BACKGROUND: To the authors' knowledge, there are no studies that have compared periodontal parameters and self-perceived oral symptoms (OSs) among cigarette smokers (CSs) (group 1), individuals exclusively vaping electronic cigarettes (group 2), and never-smokers (NSs) (group 3). The aim of this study is to assess periodontal parameters and self-perceived OSs among vaping individuals, CSs, and NSs. METHODS: Ninety-four male participants (groups 1, 2, and 3: 33, 31, and 30 individuals, respectively) were included. Demographic data, self-perceived OSs, and duration and daily frequency of vaping and smoking were gathered using a questionnaire. Full-mouth plaque index (PI), bleeding on probing (BOP), probing depth (PD) >=4 mm, and clinical attachment loss (AL) were measured; marginal bone loss (MBL) around all teeth was measured on digital radiographs. Numbers of missing teeth (MT) were also recorded. Odds ratios were calculated for OSs, and periodontal parameters were assessed using analysis of variance and Bonferroni post hoc tests. P <0.05 was considered statistically significant. RESULTS: PI (P <0.01) and PD >=4 mm (P <0.01) were significantly higher in groups 1 and 2 than in group 3. BOP was significantly higher in group 3 than in groups 1 (P <0.01) and 2 (P <0.01). There was no difference in number of MT, clinical AL, and MBL among all groups. Gingival pain was more often reported by individuals in group 1 than by individuals in groups 2 (P <0.01) and 3 (P <0.01). CONCLUSION: Periodontal inflammation and self-perceived OSs were poorer among CSs than among vaping individuals and NSs. PMID- 28644107 TI - Gingival Perfusion and Tissue Biomarkers During Early Healing of Postextraction Regenerative Procedures: A Prospective Case Series. AB - BACKGROUND: Postextraction alveolar bone loss, mostly affecting the buccal plate, occurs despite regenerative procedures. To better understand possible determinants, this prospective case series assesses gingival blood perfusion and tissue molecular responses in relation to postextraction regenerative outcomes. METHODS: Adults scheduled to receive bone grafting in maxillary, non-molar, single-tooth extraction sites were recruited. Clinical documentation included the following: 1) probing depth (PD); 2) keratinized tissue width (KT); 3) tissue biotype (TB); and 4) plaque level. Wound closure was clinically evaluated. Gingival blood perfusion was measured by laser Doppler flowmetry (LDF). Wound fluid (WF) and gingival biopsies were analyzed for protein levels and gene expression, respectively, of relevant molecular markers. Bone healing outcomes were determined radiographically (cone-beam computed tomography). Healing was followed for 4 months. RESULTS: Data from 15 patients are reported. Postoperatively, neither complications nor changes in PD, KT, or TB were observed. LDF revealed decreased perfusion followed by hyperemia that persisted for 1 month (P <=0.05). WF levels of angiopoietin-2, interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and vascular endothelial growth factor peaked on day 6 (P <=0.05) and decreased thereafter. Only IL-8 and TNF-alpha exhibited increased gene expression. Linear bone changes were negligible. Volumetric bone changes were minimal but statistically significant, with more bone loss when membrane was used (P = 0.05). CONCLUSIONS: Gingival blood perfusion after postextraction bone regenerative procedures follows an ischemia-reperfusion model. Transient increases in angiogenic factor levels and prolonged hyperemia characterize the soft tissue response. These soft tissue responses do not determine radiographic bone changes. PMID- 28644109 TI - The timing of GIGANTEA expression during day/night cycles varies with the geographical origin of Arabidopsis accessions. AB - Latitudinal clines in circadian rhythms have consistently been described in various plant species, with the most recent examples appearing in soybean cultivars and in monkey flower natural populations. These latitudinal clines provide evidence that natural variation in circadian rhythms is adaptive, but it is still unclear what adaptive benefits this variation confers, particularly because circadian rhythms are not usually measured in day/night conditions that reflect those experienced by organisms in nature. Here, we report that daily rhythms of GIGANTEA expression respond to day length in a way that depends on the latitude of origin of Arabidopsis accessions. We additionally extend previous findings by confirming that natural variation in GI expression affects growth related traits, and alters the expression of different target genes. The results support the idea that natural variation in daily rhythms of expression have broad effects on plant development and are of potential adaptive value. PMID- 28644110 TI - Detailed magnetic resonance imaging features of a case series of primary gliosarcoma. AB - Objective We aimed to characterise the magnetic resonance imaging (MRI) features of a case series of primary gliosarcoma, with the inclusion of diffusion-weighted imaging and perfusion imaging with dynamic susceptibility contrast MRI. Materials and methods We conducted a retrospective study of cases of primary gliosarcoma from the Pathology Department database from January 2006 to December 2014. Clinical and demographic data were obtained. Two neuroradiologists, blinded to diagnosis, assessed tumour location, signal intensity in T1 and T2-weighted images, pattern of enhancement, diffusion-weighted imaging and dynamic susceptibility contrast MRI studies on preoperative MRI. Results Seventeen patients with primary gliosarcomas had preoperative MRI study: seven men and 10 women, with a mean age of 59 years (range 27-74). All lesions were well demarcated, supratentorial and solitary (frontal n = 5, temporal n = 4, parietal n = 3); 13 tumours abutted the dural surface (8/13 with dural enhancement); T1 and T2-weighted imaging patterns were heterogeneous and the majority of lesions (12/17) showed a rim-like enhancement pattern with focal nodularities/irregular thickness. Restricted diffusion (mean apparent diffusion coefficient values 0.64 * 10-3 mm2/s) in the more solid/thick components was present in eight out of 11 patients with diffusion-weighted imaging study. Dynamic susceptibility contrast MRI study ( n = 8) consistently showed hyperperfusion in non-necrotic/cystic components on relative cerebral volume maps. Conclusions The main distinguishing features of primary gliosarcoma are supratentorial and peripheral location, well defined boundaries and a rim-like pattern of enhancement with an irregular thick wall. Diffusion-weighted imaging and relative cerebral volume map analysis paralleled primary gliosarcoma with high-grade gliomas, thus proving helpful in differential diagnosis. PMID- 28644111 TI - Visual dot interaction with short-term memory. AB - AIM: Many neurodegenerative diseases have a memory component. Brain structures related to memory are affected by environmental stimuli, and it is difficult to dissociate effects of all behavior of neurons. MATERIALS & METHODS: Here, visual cortex of mice was stimulated with gratings and dot, and an observation of neuronal activity before and after was made. Bandwidth, firing rate and orientation selectivity index were evaluated. RESULTS: A primary communication between primary visual cortex and short-term memory appeared to show an interesting path to train cognitive circuitry and investigate the basics mechanisms of the neuronal learning. The findings also suggested the interplay between primary visual cortex and short-term plasticity. CONCLUSION: The properties inside a visual target shape the perception and affect the basic encoding. Using visual cortex, it may be possible to train the memory and improve the recovery of people with cognitive disabilities or memory deficit. PMID- 28644113 TI - The importance and development of ball control and (self-reported) self regulatory skills in basketball players for different positions. AB - This study first investigated the importance of ball control and (self-reported) self-regulatory skills in achieving the elite level in basketball. The second aim was to gain insight into the development of, and association between ball control and (self-reported) self-regulatory skills that contribute to achieving the elite level, with taking into account positional differences. Talented male players (N = 73; age 16.56 +/- 1.96) completed the STARtest to measure ball control and a questionnaire to measure (self-reported) self-regulation from 2008-2012. Results showed that (self-reported) reflective skills were most important to achieve the elite level (OR = 11.76; P < 0.05). There was no significant improvement in (self reported) reflection over time for guards, forwards, and centers. Improvement in ball control was evident for guards (r = -0.65; P < 0.05). Furthermore, guards and forwards had better ball control compared to centers (P < 0.01). For those two positions, negative correlations were found between (self-reported) reflection and ball control, i.e., higher reflection was related to better ball control (guards r = -0.19; forwards r = -0.18) in contrast to centers (r = 0.34). It is concluded that (self-reported) reflective skills are important to achieve the elite level, while ball control seems especially important for guards. PMID- 28644112 TI - Susac syndrome misdiagnosed as multiple sclerosis with exacerbation by interferon beta therapy. AB - Susac syndrome is a rare autoimmune disorder characterised by the clinical triad of encephalopathy, retinopathy (branch retinal artery occlusions) and hearing loss. The diagnosis of Susac syndrome may be difficult initially, and it is not uncommon for patients with Susac syndrome to be misdiagnosed with multiple sclerosis. In this case report, we describe a patient who was diagnosed as having multiple sclerosis for three years, with further deterioration after starting treatment with interferon beta-1a. The patient had the triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss. She had the classic magnetic resonance imaging appearance, with normal magnetic resonance imaging of the spinal cord and absence of oligoclonal bands in the cerebrospinal fluid. Our patient responded well to treatment with a combination therapy and discontinuation of interferon beta-1a. Our observations raise awareness about the importance of the early and correct diagnosis of Susac syndrome, which usually affects young patients, with an excellent prognosis if treated aggressively at an early stage of the disease. Susac syndrome is underdiagnosed and is not uncommonly misdiagnosed as multiple sclerosis. Susac syndrome is a great mimicker of multiple sclerosis, and establishing diagnostic criteria for this syndrome is very useful. In any patient presenting with a progressive disabling neurological disorder associated with callosal lesions and/or hearing loss, and/or visual loss especially in women, Susac syndrome should be suspected. PMID- 28644115 TI - Evaluation of the effectiveness and cost-effectiveness of lightweight fibreglass heel casts in the management of ulcers of the heel in diabetes: a randomised controlled trial. AB - BACKGROUND: Ulcers of the foot in people with diabetes mellitus are slow to heal and result in considerable cost and patient suffering. The prognosis is worst for ulcers of the heel. OBJECTIVE: To assess both the clinical effectiveness and the cost-effectiveness of lightweight fibreglass casts in the management of heel ulcers. DESIGN: A pragmatic, multicentre, parallel, observer-blinded randomised controlled trial. A central randomisation centre used a computer-generated random number sequence to allocate participants to groups. SETTING: Thirty-five specialist diabetic foot secondary care centres in the UK. Those recruited were aged >= 18 years and had diabetes mellitus complicated by ulcers of the heel of grades 2-4 on the National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel scale. PARTICIPANTS: In total, 509 participants [68% male, 15% with type 1 diabetes mellitus, mean age 67.5 years (standard deviation 12.4 years)] were randomised 1 : 1 to the intervention (n = 256) or the control (n = 253) arm. The primary outcome data were available for 425 participants (212 from the intervention arm and 213 from the control arm) and exceeded the total required; attrition was 16.5%. The median ulcer area at baseline was 275 mm2 [interquartile range (IQR) 104-683 mm2] in the intervention group and 206 mm2 (IQR 77-649 mm2) in the control group. There were no differences between the two groups at baseline in any parameter, neither in relation to the participant nor in relation to their ulcer. INTERVENTIONS: The intervention group received usual care supplemented by the addition of an individually moulded, lightweight, fibreglass heel cast. The control group received usual care alone. The intervention phase continued either until the participant's ulcer had healed (maintained for 28 days) or for 24 weeks, whichever occurred first. During this intervention phase, the participants were reviewed every 2 weeks, and the fibreglass casts were replaced when they were no longer usable. MAIN OUTCOME MEASURES: The primary outcome measure was ulcer healing (confirmed by a blinded observer and maintained for 4 weeks) within 24 weeks. Other outcome measures included the time taken for the ulcer to heal, the percentage reduction in the cross-sectional area, the reduction in local pain, amputation, survival and health economic analysis. The study was powered to define a difference in healing of 15% (55% intervention vs. 40% control). RESULTS: Forty-four per cent (n = 94) of the intervention group healed within 24 weeks, compared with 37% (n = 80) of the control participants (odds ratio 1.42, 95% confidence interval 0.95 to 2.14; p = 0.088), using an intention-to-treat analysis. No differences were observed between the two groups for any secondary outcome. LIMITATIONS: Although the component items of care were standardised, because this was a pragmatic trial, usual care was not uniform. There was some evidence of a small excess of adverse events in the intervention group; however, non-blinded observers documented these events. There was no excess of adverse device effects. CONCLUSIONS: There may be a small increase in healing with the use of a heel cast, but the estimate was not sufficiently precise to provide strong evidence of an effect. There was no evidence of any subgroup in which the intervention appeared to be particularly effective. A health economic analysis suggested that it is unlikely that the intervention represents good value for money. The provision of a lightweight heel cast may be of benefit to some individuals, but we have found no evidence to justify the routine adoption of this in clinical practice. FUTURE WORK: It is unlikely that further study of this intervention will have an impact on usual clinical care, and so future efforts should be directed towards other interventions designed to improve the healing of ulcers in this population. TRIAL REGISTRATION: Current Controlled Trials ISRCTN62524796. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 34. See the NIHR Journals Library website for further project information. PMID- 28644116 TI - Axillary Intraneural Ganglion Cysts. AB - Aside from affecting the stability of the glenohumeral joint, tears in the joint capsule can give rise to extraneural (paralabral) and, very rarely, intraneural ganglion cysts. This report presents the first two cases of axillary intraneural ganglion cysts in the literature with magnetic resonance imaging. Both cases were incidentally noted to have coexisting lesions (lymphadenopathy from an undifferentiated malignancy and suprascapular nerve entrapment, respectively). This report reinforces the applicability of the articular theory for intraneural ganglion cysts at a novel site. PMID- 28644117 TI - Reverse Total Shoulder Arthroplasty for Complex Three- and Four-Part Proximal Humerus Fractures in Elderly Patients: A Review. AB - Complex proximal humerus fractures in elderly patients represent a difficult problem for orthopaedic surgeons. Classically, treatment methods have included nonoperative management, open reduction and internal fixation, and hemiarthroplasty. Outcomes of nonoperative management for these complex fractures have been poor, and results of traditional operative techniques are variable at best. Over the past several years, reverse total shoulder arthroplasty (RTSA) has been increasingly employed in these injuries with encouraging results. RTSA may represent a valuable treatment option for select patients. This article reviews the existing data on RTSA in the treatment of complex proximal humerus fractures in the elderly population as well as the authors' experience with this technique. PMID- 28644118 TI - Insurance-Mandated Stay Prolongs Hospitalization Following Total Shoulder Arthroplasty. AB - Medicare currently requires a 3-night hospitalization for a patient to be considered for skilled nursing facility (SNF) placement. The purpose of this study was to analyze the relationship between length of stay and (a) insurance status and (b) readmission rates in Medicare-age patients undergoing primary total shoulder arthroplasty. A retrospective review of 251 primary consecutive total shoulder arthroplasty cases was performed. In patients discharged to SNF, Medicare insurance was associated with a significantly longer hospital stay (p < .001) compared with patients with private insurance. Readmission rates for Medicare and private insurance patients were similar at 30 and 90 days after surgery (p = 1.000). Ninety-five percent of Medicare patients discharged to SNF had a prolonged hospital stay primarily to fulfill the 3-night requirement. These findings call into question the necessity of the current 3-night inpatient hospitalization requirement for facility placement following total shoulder arthroplasty. PMID- 28644114 TI - Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. AB - BACKGROUND: Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS: We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS: A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS: The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .). PMID- 28644119 TI - Damage Control Plating in Open Tibial Shaft Fractures: A Cheaper and Equally Effective Alternative to Spanning External Fixation. AB - The purpose of this study was to evaluate damage control plating (DCP) as an alternative to external fixation (EF) in the provisional stabilization of open tibial shaft fractures. Through retrospective analysis, the study found 445 patients who underwent operative fixation for tibial shaft fractures from 2008 to 2012. Twenty patients received DCP or EF before intramedullary nailing with a minimum follow-up of 3 months. Charts and radiographs were reviewed for postoperative complications. Hospital charges were reviewed for implant costs. Nine patients (45%) with DCP and 11 patients (55%) with EF were analyzed. There was no significant difference in the complication rates. The mean implant cost of DCP was $1028, whereas mean EF construct cost was $4204. Therefore, DCP resulted in significant cost savings with no difference in complication rates, making it a valuable alternative to EF for the provisional stabilization of open tibial shaft fractures. PMID- 28644120 TI - A Process Improvement Evaluation of Sequential Compression Device Compliance and Effects of Provider Intervention. AB - This process improvement study sought to evaluate the compliance in orthopaedic patients with sequential compression devices and to monitor any improvement in compliance following an educational intervention. All non-intensive care unit orthopaedic primary patients were evaluated at random times and their compliance with sequential compression devices was monitored and recorded. Following a 2 week period of data collection, an educational flyer was displayed in every patient's room and nursing staff held an in-service training event focusing on the importance of sequential compression device use in the surgical patient. Patients were then monitored, again at random, and compliance was recorded. With the addition of a simple flyer and a single in-service on the importance of mechanical compression in the surgical patient, a significant improvement in compliance was documented at the authors' institution from 28% to 59% (p < .0001). PMID- 28644121 TI - Intercondylar Fractures of the Distal Humerus in Patients Younger Than 20 Years: Capsulectomy Results. AB - Few reports in the literature have been dedicated to young patients with distal fractures of the humerus, and few have addressed subsequent indications to improve range of motion (ROM). This article is a retrospective review of the elbow flexion-extension ROM in 31 patients (age, 12-19 years) who had been treated with open reduction and internal fixation of intercondylar fractures of the distal humerus at a level I trauma center from 1991 through 2013. The ROM of patients who underwent capsulectomy was compared with that of those who did not. Main outcome measures were ROM in degrees and need for capsulectomy. Nine (29%) of the 31 patients had elected to undergo capsulectomy. Eleven did not require capsulectomy. The final flexion-extension arc was improved by 31 degrees compared with the precapsulectomy ROM but did not attain the ROM of those who did not undergo capsulectomy. PMID- 28644122 TI - Fluoroscopic Exposure With Use of Mini-C-Arm During Routine Hand Surgery: A Prospective Comparison of Hand Versus Eye Radiation Dosage. AB - Radiation exposure with use of intraoperative fluoroscopy is a potential orthopedic occupational risk factor. The purpose of this study was to perform a prospective comparison of hand versus eye radiation exposure associated with mini C-arm utilization and to test the hypothesis that routine mini-C-arm does not yield hand or eye dosages exceeding current recommended levels. Over a 12-month period, hand and eye radiation exposure was prospectively measured in a single board-certified hand surgeon using mini-C-arm fluoroscopy. Twenty-five cases were performed utilizing mini-C-arm fluoroscopy. Average monthly hand radiation dosage (45.81+/-14.49 mrem) was significantly higher (p = .01) than eye radiation dosage (<30 mrem). Both recorded values were below their respective critical exposure limits, as reported by the International Commission on Radiological Protection. The findings suggest that hand and eye exposure associated with mini-C-arm utilization during routine surgery does not approach reported levels of critical radiation loads. PMID- 28644123 TI - Pin Malposition in External Fixator Stabilization of Combat-Related Pelvic Fractures. AB - The purpose of this study was to compare the accuracy of pin placement in patients with unstable pelvic fractures undergoing either iliac crest or supra acetabular external fixation. A retrospective review was performed of computed tomography (CT) scans and injury characteristics for all patients presenting to a North Atlantic Treaty Organization Medical Treatment Facility with data entered into the Department of Defense Trauma Registry from January 2008 to October 2013 who underwent pelvic external fixation for unstable pelvic ring injuries. Thirty two patients were analyzed. Sixteen patients underwent damage control iliac crest based and 16 patients underwent supra-acetabular-based external fixation. There was no significant difference in patient characteristics at presentation between the two groups. Pin malposition rate on CT scan was 50/64 (78.1%) for the iliac crest group and 3/32 (9.4%) for the supra-acetabular group. Pin malposition was correlated with increasing Injury Severity Score, Abbreviated Injury Scale (AIS) head score, and AIS face score. The review concluded that iliac crest-based external fixation has a significantly higher rate of pin malposition than supra acetabular-based external fixation. PMID- 28644124 TI - Scapulothoracic Joint Dysfunction. AB - Scapulothoracic derangements are often overlooked and hidden within the clinical fog created by complex back, shoulder, and rib symptoms. This study reviewed 200 magnetic resonance imaging and computed tomography studies dedicated for scapular imaging between January 2010 and May 2016. This article discusses scapulothoracic pathologies and imaging findings. PMID- 28644125 TI - Exploiting CRISPR-Cas to manipulate Enterococcus faecalis populations. AB - CRISPR-Cas provides a barrier to horizontal gene transfer in prokaryotes. It was previously observed that functional CRISPR-Cas systems are absent from multidrug resistant (MDR) Enterococcus faecalis, which only possess an orphan CRISPR locus, termed CRISPR2, lacking cas genes. Here, we investigate how the interplay between CRISPR-Cas genome defense and antibiotic selection for mobile genetic elements shapes in vitro E. faecalis populations. We demonstrate that CRISPR2 can be reactivated for genome defense in MDR strains. Interestingly, we observe that E. faecalis transiently maintains CRISPR targets despite active CRISPR-Cas systems. Subsequently, if selection for the CRISPR target is present, toxic CRISPR spacers are lost over time, while in the absence of selection, CRISPR targets are lost over time. We find that forced maintenance of CRISPR targets induces a fitness cost that can be exploited to alter heterogeneous E. faecalis populations. PMID- 28644126 TI - Extensive horizontal gene transfer in cheese-associated bacteria. AB - Acquisition of genes through horizontal gene transfer (HGT) allows microbes to rapidly gain new capabilities and adapt to new or changing environments. Identifying widespread HGT regions within multispecies microbiomes can pinpoint the molecular mechanisms that play key roles in microbiome assembly. We sought to identify horizontally transferred genes within a model microbiome, the cheese rind. Comparing 31 newly sequenced and 134 previously sequenced bacterial isolates from cheese rinds, we identified over 200 putative horizontally transferred genomic regions containing 4733 protein coding genes. The largest of these regions are enriched for genes involved in siderophore acquisition, and are widely distributed in cheese rinds in both Europe and the US. These results suggest that HGT is prevalent in cheese rind microbiomes, and that identification of genes that are frequently transferred in a particular environment may provide insight into the selective forces shaping microbial communities. PMID- 28644149 TI - Thermal transport in monolayer InSe. AB - Two-dimensional InSe, a recently synthesized semiconductor having a moderate band gap, has gained attention due to its ultra high mobility and high photo responsivity. In this work, we calculate the lattice thermal conductivity (kappa) of monolayer InSe by solving the phonon Boltzmann transport equation (BTE) with first-principles calculated inter atomic force constants. kappa of monolayer InSe is isotropic and found to be around 27.6 W m [Formula: see text] at room temperature along the in-plane direction. The size dependence of kappa shows the size effect can persist up to 20 MUm. Further, kappa can be reduced to half by tuning the sample size to 300 nm. This low value suggests that kappa might be a limiting factor for emerging nanoelectronic applications of monolayer InSe. PMID- 28644150 TI - Rapid fluorescence lifetime estimation with modified phasor approach and Laguerre deconvolution: a comparative study. AB - Fluorescence lifetime imaging has been shown to serve as a valuable tool for interrogating and diagnosis of biological tissue at a mesoscopic level. The ability to analyze fluorescence decay curves to extract lifetime values in real time is crucial for clinical translation and applications such as tumor margin delineation or intracoronary imaging of atherosclerotic plaques. In this work, we compare the performance of two popular non-parametric (fit-free) methods for determining lifetime values from fluorescence decays in real-time-the Phasor approach and Laguerre deconvolution. We demonstrate results from simulated and experimental data to compare the accuracy and speed of both methods and their dependence on noise and model parameters. PMID- 28644127 TI - MPI depletion enhances O-GlcNAcylation of p53 and suppresses the Warburg effect. AB - Rapid cellular proliferation in early development and cancer depends on glucose metabolism to fuel macromolecule biosynthesis. Metabolic enzymes are presumed regulators of this glycolysis-driven metabolic program, known as the Warburg effect; however, few have been identified. We uncover a previously unappreciated role for Mannose phosphate isomerase (MPI) as a metabolic enzyme required to maintain Warburg metabolism in zebrafish embryos and in both primary and malignant mammalian cells. The functional consequences of MPI loss are striking: glycolysis is blocked and cells die. These phenotypes are caused by induction of p53 and accumulation of the glycolytic intermediate fructose 6-phosphate, leading to engagement of the hexosamine biosynthetic pathway (HBP), increased O GlcNAcylation, and p53 stabilization. Inhibiting the HBP through genetic and chemical methods reverses p53 stabilization and rescues the Mpi-deficient phenotype. This work provides mechanistic evidence by which MPI loss induces p53, and identifies MPI as a novel regulator of p53 and Warburg metabolism. PMID- 28644152 TI - Incorporating HYPR de-noising within iterative PET reconstruction (HYPR-OSEM). AB - HighlY constrained back-PRojection (HYPR) is a post-processing de-noising technique originally developed for time-resolved magnetic resonance imaging. It has been recently applied to dynamic imaging for positron emission tomography and shown promising results. In this work, we have developed an iterative reconstruction algorithm (HYPR-OSEM) which improves the signal-to-noise ratio (SNR) in static imaging (i.e. single frame reconstruction) by incorporating HYPR de-noising directly within the ordered subsets expectation maximization (OSEM) algorithm. The proposed HYPR operator in this work operates on the target image(s) from each subset of OSEM and uses the sum of the preceding subset images as the composite which is updated every iteration. Three strategies were used to apply the HYPR operator in OSEM: (i) within the image space modeling component of the system matrix in forward-projection only, (ii) within the image space modeling component in both forward-projection and back-projection, and (iii) on the image estimate after the OSEM update for each subset thus generating three forms: (i) HYPR-F-OSEM, (ii) HYPR-FB-OSEM, and (iii) HYPR-AU-OSEM. Resolution and contrast phantom simulations with various sizes of hot and cold regions as well as experimental phantom and patient data were used to evaluate the performance of the three forms of HYPR-OSEM, and the results were compared to OSEM with and without a post reconstruction filter. It was observed that the convergence in contrast recovery coefficients (CRC) obtained from all forms of HYPR-OSEM was slower than that obtained from OSEM. Nevertheless, HYPR-OSEM improved SNR without degrading accuracy in terms of resolution and contrast. It achieved better accuracy in CRC at equivalent noise level and better precision than OSEM and better accuracy than filtered OSEM in general. In addition, HYPR-AU-OSEM has been determined to be the more effective form of HYPR-OSEM in terms of accuracy and precision based on the studies conducted in this work. PMID- 28644151 TI - ECG-based 4D-dose reconstruction of cardiac arrhythmia ablation with carbon ion beams: application in a porcine model. AB - Noninvasive ablation of cardiac arrhythmia by scanned particle radiotherapy is highly promising, but especially challenging due to cardiac and respiratory motion. Irradiations for catheter-free ablation in intact pigs were carried out at the GSI Helmholtz Center in Darmstadt using scanned carbon ions. Here, we present real-time electrocardiogram (ECG) data to estimate time-resolved (4D) delivered dose. For 11 animals, surface ECGs and temporal structure of beam delivery were acquired during irradiation. R waves were automatically detected from surface ECGs. Pre-treatment ECG-triggered 4D-CT phases were synchronized to the R-R interval. 4D-dose calculation was performed using GSI's in-house 4D treatment planning system. Resulting dose distributions were assessed with respect to coverage (D95 and V95), heterogeneity (HI = D5-D95) and normal tissue exposure. Final results shown here were performed offline, but first calculations were started shortly after irradiation The D95 for TV and PTV was above 95% for 10 and 8 out of 11 animals, respectively. HI was reduced for PTV versus TV volumes, especially for some of the animals targeted at the atrioventricular junction, indicating residual interplay effects due to cardiac motion. Risk structure exposure was comparable to static and 4D treatment planning simulations. ECG-based 4D-dose reconstruction is technically feasible in a patient treatment-like setting. Further development of the presented approach, such as real-time dose calculation, may contribute to safe, successful treatments using scanned ion beams for cardiac arrhythmia ablation. PMID- 28644153 TI - Louisiana Physicians Are Increasing HPV Vaccination Rates. AB - Human papilloma virus (HPV) is a common virus that can cause genital warts and certain cancers. The HPV vaccine is effective in preventing many HPV-associated diseases, however, vaccination rates suggest many remain unprotected. This study examined successful strategies used by physicians to improve HPV vaccination rates. Providers with above average vaccination rates were identified. A representative from each provider participated in an interview to identify strategies used to boost HPV vaccination. Key strategies in ensuring vaccine completion were reminders, education, standing orders, and scheduling future vaccine appointments at time of first dose. Other successful strategies included coupling the HPV vaccine with adolescent vaccines, administering during well visits, and recommending the vaccine as protection against cancer and genital warts. Findings suggest successful and widely used methods among high performing providers in Louisiana, the majority of which should be easily reproducible with minimal resources to improve HPV vaccination rates. PMID- 28644154 TI - Acute Promyelocytic Leukemia and Chronic Lymphocytic Leukemia: Concomitant Presentation of Two Molecularly Distinct Entities. AB - Acute myeloid leukemia (AML) developing in patients with chronic lymphocytic leukemia (CLL) is very uncommon and usually associated with prior treatment. Acute promyelocytic leukemia (APL) accounts for a very small proportion of treatment-associated AML. So far, there has been only one reported case of APL occurring post radiation for prostate cancer in a patient with CLL. We report herein the first case of APL and CLL presenting concomitantly in an untreated patient. Evaluation of peripheral blood and bone marrow aspirate with immunohistochemistry, flow cytometry, and FISH to confirm two morphologically, molecularly and genetically distinct leukemic populations characteristic of APL and CLL is required. APL is a hematologic emergency, and aggressive management is vital to a successful therapeutic outcome. Standard treatment is with All-trans retinoic acid (ATRA) and anthracycline-based regimen, whether the process is de novo or therapy-related. Due to increased incidence of secondary malignancies in CLL patients, active surveillance is necessary. PMID- 28644155 TI - Transvenous Before Surgical Hybrid Procedure. AB - BACKGROUND: Historically, persistent atrial fibrillation (PeAF) and long standing persistent atrial fibrillation (LSPeAF) have demonstrated limited clinical success despite hybrid approaches. OBJECTIVE: We describe our experience with the endocardial-before-epicardial approach defined by a comprehensive endovascular approach preceding and guiding the epicardial approach which includes an extensive posterior wall ablation. METHODS: 40 patients were followed over a 12 month period. The procedure was performed in a single center. Patients had a mean duration of atrial fibrillation of 6.0 +/- 4.5 years with 22.5% having undergone prior ablations. Mean age was 61.7 +/- 7.9 years with a mean left atrial volume of 131.5 +/- 46.9 mL. The endovascular procedure remained uniform with antral pulmonary vein isolation, posterior left atrial roof and right atrial cavo tricuspid isthmus (CTI) linear lesions with mapping and ablation of left atrial complex electrograms (CFAEs) and prior existing atrial arrhythmias. The epicardial procedure included a thorascopic approach with ganglionated plexus (GP) mapping and ablation, left atrial posterior wall ablation, directed CFAE ablation and left atrial appendage ligation. All patients received implantable cardiac monitoring. RESULTS: All 40 patients remained in sinus rhythm at their 12 month follow-up. During the monitoring period, episodes of paroxysmal atrial arrhythmias including fibrillation were documented, without persistence, after discontinuation of oral antiarrhythmic medications. CONCLUSION: The endo-before epi approach resulted in improved management of persistent and long standing persistent atrial fibrillation over reported results for conventional approaches with no procedural complications, making this a promising option for the management of these arrhythmias. PMID- 28644156 TI - Clinical Case of the Month: A 57-Year-Old Man with an Axillary Mass. AB - A 57-year-old man presented to the surgical oncology clinic with a mildly tender mass under his right arm. Four years prior, the patient had a melanoma removed from his right shoulder along with an ipsilateral right axillary sentinel lymph sampling. Computed tomography (CT) scan was negative for metastatic disease at that time. The patient did not undergo completion axillary node dissection and was lost to follow-up. The patient was originally from Australia, did not tan but reported multiple sunburns before age 18. He was of Irish ancestry. He denied weight gain, fever, fatigue, anorexia, or night sweats. The patient had a medical history of atrial fibrillation, hypertension, gout, melanoma, and benign prostatic hypertrophy. His surgical history included an appendectomy and a facial laceration repair. His brother died at 16 years old from leukemia and his mother died from colon cancer. He consumed 3 alcoholic beverages per day and denied tobacco or illicit drug use. On physical exam, the patient's temperature was 98.8 degrees Fahrenheit, heart rate of 73 beats / minute, blood pressure of 121 / 59 mm Hg, respiratory rate of 18 / min. He appeared to be healthy and in no apparent distress. Cardiovascular, respiratory, breast, gastrointestinal, musculoskeletal, and neurological exam were unremarkable. His right axillary lymph node exam revealed a firm mass roughly 2.5 cm tall by 1.5 cm wide. This mass was biopsied and findings were consistent with metastatic melanoma. CT scan revealed small volume mediastinal adenopathy and a 4.5 cm right axillary mass. There was a 4.7 cm lesion within the anterior left lower lobe of the liver and periportal node conglomerate measuring 3.9 cm consistent with metastatic disease (Figure 1). He was negative for the BRAF V600E mutation. The patient was consented for treatment with combination immune checkpoint inhibition with ipilimumab and nivolumab. After two cycles the patient showed good response, but temporarily stopped treatment after complications related to a ST segment elevation myocardial infarction. He developed mild pneumonitis felt to be related to nivolumab, and recovered after a short course of glucocorticosteroids. Restaging CT scans were ordered after two cycles of therapy (Figure 2), which showed decrease in the size of the axillary and hepatic metastases. At six months, CT scans showed continued durable response (Figure 3). PMID- 28644157 TI - ECG Case of the Month: Chest Pain and ECG Abnormalities. AB - A 27-year-old man was admitted to the coronary care unit because of chest pain and an electrocardiogram (ECG) read by the computer as an inferior infarct and left ventricular hypertrophy (Figure). PMID- 28644158 TI - Radiology Case of the Month: Idiopathic CD4 Lymphocytopenia. AB - A 39 year-old male with a history of diabetes, retinitis pigmentosa, and genital warts presented with intractable occipital headaches accompanied with nausea and vomiting. The patient had markedly depressed CD4 counts. Furthermore the patient tested negative for HIV and HTLV 1/2 and had normal immunoglobulin levels. During hospital course the patient underwent a lumbar puncture and multiple imaging exams, including both CT and MR. Except for occasional nausea and vomiting controlled by therapeutic lumbar punctures, phenergan, and dilaudid the patient's hospital course was uncomplicated. PMID- 28644159 TI - Investigation of the Rosenbaum Concussion Knowledge and Attitudes Survey in Collegiate Athletes. AB - OBJECTIVE: The purpose of this study is to determine whether the Rosenbaum Concussion Knowledge and Attitudes Survey (RoCKAS) is an appropriate outcome measure to assess knowledge and attitudes toward concussion in collegiate student athletes as determined through validity and reliability testing. STUDY DESIGN: Convenience study. SETTING: The researcher recruited all athletic teams at a Division III National Collegiate Athletic Association institution. PARTICIPANTS: Four hundred thirty-three collegiate student-athletes, 18 years of age or older, from a variety of sports took part in this study. As the validity of RoCKAS has never been established for the target population, this study randomly split respondents into 2 studies. INTERVENTIONS: Participants in this study completed the RoCKAS during preseason meetings before concussion education. The primary researcher was not present during the completion of the survey to allow participants to answer honestly without concern of coercion. MAIN OUTCOME MEASURES: A paper-based Rosenbaum Concussion Knowledge and Attitudes Survey. RESULTS: The Concussion Knowledge Index (CKI) was distributed in 2 cluster constructs and identified variables of low and high difficulty. Multivariate statistical analysis of the Concussion Attitude Index (CAI) explains 68.79% of the total variance. The Confirmatory Factor Analysis did not confirm the hypothesis that similar constructs can be found between data sets ((Equation is included in full-text article.)= 207.902; consistent akaike information criterion = 391.550; root mean square error of approximation = 0.125, and goodness of fit index = 0.868). CONCLUSIONS: The CKI is a valid and reliable measure in collegiate student-athletes. However, the results of the Confirmatory Factor Analysis indicated a poor model fit and improper correlations between attitude items. Therefore, the CAI may not be a sound outcome measure of collegiate student-athlete's attitudes toward concussions. PMID- 28644160 TI - Calcitonin Gene-Related Peptide-Targeted Therapies for Migraine and Cluster Headache: A Review. AB - Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from activated trigeminal sensory afferents in headache and facial pain disorders. There are a handful of CGRP-targeted therapies currently in phase 3 studies for migraine acute treatment or prevention. Currently, 4 monoclonal antibodies targeting either the CGRP ligand or receptor are being studied for migraine prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab), and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in clinical trials for cluster headache prevention as well. Several other small molecular CGRP receptor antagonists are in earlier stages of development for acute migraine treatment or prevention. In this review, we will discuss the growing body of clinical trials studying CGRP-targeted therapies for migraine and cluster headache. PMID- 28644161 TI - Agreement Between Magnetic Resonance Imaging and Pathologic Findings in the Tumor Size Evaluation Before and After Neoadjuvant Chemotherapy Treatment: A Prospective Study. AB - OBJECTIVES: To compare the agreement between magnetic resonance imaging (MRI) results and postsurgical pathologic findings for tumor size evaluation in cervical cancer patients before and after neoadjuvant chemotherapy (NACT) treatment. METHODS: The study analyzed the agreement between pretreatment MRI results and postsurgical pathologic findings about the tumor size in 100 cervical cancer patients without NACT and 397 cervical cancer patients with NACT, respectively. RESULTS: In general, the agreement between pretreatment MRI results and postsurgical pathologic findings of tumor size was 0.855 (95% confidence interval [CI], 0.763-0.909) in cervical cancer patients without NACT, whereas the agreement between posttreatment MRI results and postsurgical pathologic findings was 0.503 (95% CI, 0.421-0.576). Only 62.72% (249/397) of patients who underwent NACT treatment have the same chemotherapy response evaluation results; the kappa coefficient was 0.384(95% CI, 0.310-0.457) between posttreatment MRI and postsurgical pathologic findings. We still found International Federation of Gynecology and Obstetrics stage is associated with the chemotherapy response evaluation. CONCLUSIONS: Our data suggest that pretreatment MRI can be a surrogate indicator for postsurgical pathologic findings. However, posttreatment MRI could not be a surrogate indicator for postsurgical pathologic findings. The chemotherapy response evaluation based on only MRI is not so reliable. More indicators should be developed for chemotherapy response evaluation. PMID- 28644162 TI - Would Lipophilic Statin Therapy as a Prognostic Factor Improve Survival in Patients With Uterine Cervical Cancer? AB - OBJECTIVES: In vitro studies showed that lipophilic statins inhibit cell growth, adhesion, and invasion and induce apoptosis in cancer cell lines. In uterine cervical cancer, several important factors including age, stage, anemia, lymphovascular invasion, lymph node metastases, and parametrial spread were known to significantly predict survival. We investigated whether statin therapy as a prognostic factor would significantly predict survival in cervical cancer. METHODS: Patients with stages IB to IV cervical cancer who received radical hysterectomy and/or para-aortic lymph node dissection were included. The statin use group was identified as patients who were continuously prescribed with lipophilic statins from prediagnostic period of the cancer. RESULTS: The baseline characteristics of both statin-use group and control group were comparable. During a median follow-up of 36.6 months, progression-free survival and overall survival of the statin-use group were significantly higher than the control group (P < 0.001 and P = 0.004, respectively). In multivariate analysis, the statin-use group had an independent prognostic significance compared with other prognostic factors (progression-free survival: hazards ratio = 0.062, 95% confidence interval = 0.008-0.517, P = 0.010; overall survival: hazards ratio = 0.098, 95% confidence interval = 0.041-0.459, P = 0.032). CONCLUSIONS: In the present study, continuous lipophilic statin therapy from the prediagnostic period of uterine cervical cancer could reflect favorable outcome, independently. PMID- 28644166 TI - Make an impact with development plans. PMID- 28644167 TI - Care bundles: Easing the transition to long-term care. PMID- 28644168 TI - Teamwork for prevention: Reducing HAPUs in cardiac surgery patients. PMID- 28644169 TI - The value of discharge planning tools. PMID- 28644170 TI - Interprofessional team performance, optimized. AB - Enhance development with behavioral profiles. PMID- 28644171 TI - A study of styles: How do nurse managers make decisions? PMID- 28644172 TI - Disaster management: Communication up, across, and down. PMID- 28644174 TI - Resident Education in Molecular and Genetic Testing in Dermatology: An Opportunity Not to Be Missed. PMID- 28644173 TI - Tips for the novice manager. PMID- 28644175 TI - Guillain-Barre Syndrome After Elective Spinal Surgery. AB - Guillain-Barre syndrome is a rare autoimmune condition characterized by ascending motor weakness of the extremities that can ascend to the diaphragm, causing substantial morbidity and mortality. This case report describes a 57-year-old man who exhibited characteristics of Guillain-Barre syndrome 9 days after undergoing lumbar fusion at L3-S1. The diagnosis was based on the patient's ascending motor weakness and areflexia and was confirmed with electromyography. The patient progressed to respiratory failure, requiring mechanical ventilation. He regained motor function and ambulation within 6 months. Although the syndrome typically manifests initially as ascending paralysis, this patient's initial symptom was new-onset atrial fibrillation, a sign of autonomic dysfunction. Because it can cause paralysis and respiratory failure, Guillain-Barre syndrome should be included in the differential diagnosis whenever motor weakness is observed after lumbar surgery. The timing of symptoms, imaging results, and the development of atypical symptoms can help distinguish this rare possibility from other postoperative spinal complications. PMID- 28644176 TI - CONN SYNDROME PRESENTING AS CENTRAL RETINAL VEIN OCCLUSION. AB - PURPOSE: To describe a case of central retinal vein occlusion in a young patient presenting with symptomatic malignant hypertension because of Conn syndrome. METHODS: Single interventional case report. RESULTS: A 44-year-old man presented with a 1-day history of headache and vision loss in his right eye on a background of malignant hypertension. He was diagnosed with right central retinal vein occlusion. Further investigation of his malignant hypertension revealed Conn syndrome because of an aldosterone-secreting adenoma in the left adrenal gland. CONCLUSION: This is the first reported case of Conn syndrome presenting as central retinal vein occlusion. Conn syndrome should be suspected in young patients with central retinal vein occlusion because it is a common cause of hypertension and carries significant cardiovascular risk if left untreated. PMID- 28644177 TI - A CASE OF INTRAVESICAL BACILLUS CALMETTE-GUERIN-RELATED ENDOPHTHALMITIS AND RETINITIS CONFIRMED WITH RETINAL BIOPSY. AB - PURPOSE: To present a rare case of bilateral endogenous chorioretinitis and unilateral endophthalmitis due to Mycobacterium bovis in a patient who received intravesical bacillus Calmette-Guerin (BCG) treatment. METHODS: We present a case of a single male patient with bilateral endogenous chorioretinitis due to Mycobacterium bovis in a patient who received intravesical BCG, an attenuated strain of M. bovis widely used to treat superficial bladder cancer. The patient underwent intravitreal tap, vitrectomy, and chorioretinal biopsy with histologic examination. RESULTS: The patient presented with a visual acuity of light perception in the right eye and 20/25 in the left eye. Examination of the right eye revealed dense vitreous haze, whereas the left eye demonstrated multifocal, yellow, round subretinal pigment epithelial lesions in the macula. The patient underwent a vitreous tap with injection of antibiotics and was admitted to the hospital for empiric systemic antibacterial and antifungal treatment along with an endogenous endophthalmitis workup. His systemic evaluation and vitreous tap did not identify a causal organism, and the eyes failed to improve on empiric therapies. He underwent pars plana vitrectomy and retinal biopsy of the right eye that revealed vitreal and infiltrative retinal acid-fast bacilli. Cultures confirmed M. bovis to be susceptible to ethambutol, rifampin, and isoniazid. After starting antimycobacterials, his vision improved to finger counting in the right eye, and his vision and appearance of the lesions remained stable in the left eye at postoperative month one. CONCLUSION: Intravesical BCG stimulates a local cell-mediated response that destroys malignant cells. It is generally well tolerated, although it rarely can result in secondary systemic infection. Intravesical BCG-related endophthalmitis is rare and should be considered in the setting of ocular inflammation in patients with a history of bladder cancer who may not disclose previous treatment with BCG. PMID- 28644178 TI - TEMPORAL THINNING IN SICKLE CELL RETINOPATHY IS ASSOCIATED WITH DIMINISHED PERFUSION ON OCTA AND DENSE SCOTOMA ON MICROPERIMETERY. AB - PURPOSE: To establish correlation between the structural compromise (capillary loss and hypoperfusion on optical coherence tomography [optical coherence tomography angiography]) with perimacular functional impairment noted on microperimetry. METHODS: Retrospective case series. Clinical records and multimodal imaging findings of patients presenting with sickle cell disease were reviewed. RESULTS: Three eyes of three patients (two men) were included in the study with a visual acuity of 20/20 and no sickle cell retinopathy. Images using optical coherence tomography angiography (AngioVue OCT angiography system; Optovue, Inc, Fremont, CA) were obtained along with spectral domain optical coherence tomography, fluorescein angiography, and microperimetry (MP-1). Spectral domain optical coherence tomography revealed selective loss of inner retinal layers with thinning of the retina. Optical coherence tomography angiography revealed compromise of both superficial and deep capillaries in the area of temporal thinning expressed on spectral domain optical coherence tomography. MP-1 demonstrated focal increase in threshold (decreased sensitivity) correlating with the perfusion defects on optical coherence tomography angiography. Fluorescein angiography did not show any substantial perfusion compromise. CONCLUSION: Optical coherence tomography angiography may reflect the extent of functional compromise even before it being evident on fluorescein angiography. The area vascular compromise was larger in the deep plexus compared with the superficial plexus. The area of complete loss of retinal sensitivity corresponds to loss of vasculature in both the superficial and deep plexuses, whereas the area of decreased sensitivities corresponds to compromise only in the deep plexus. PMID- 28644179 TI - Improving heart failure patient outcomes utilizing guideline-directed therapy. AB - Heart failure (HF) prevalence continues to rise and remains a significant burden to patients, caregivers, providers, and the healthcare system. Guideline-directed medical therapy with standard neurohormonal blockade has been the cornerstone of medical management for many years. Despite aggressive utilization of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists, HF hospitalizations and readmissions are common and residual mortality remains high. With the development of two novel medical therapies (sacubitril/valsartan and ivabradine), the American College of Cardiology, American Heart Association, and Heart Failure Society of America released a pharmacologic update to provide guidelines for incorporation of these agents into clinical practice. Although effective via different mechanisms of action, both agents now have a prominent role in risk reduction. HF medical regimens often become quite complex, especially when associated with comorbid conditions, and require frequent follow-up. Providers must be proficient in patient monitoring, medication dose titration, and therapy optimization. Individualized patient care strategies such as guideline-directed therapy can promote long-term adherence and quality of life. PMID- 28644180 TI - Mucosal Healing in Clinical Practice: A Single-Center Pediatric IBD Experience. AB - BACKGROUND: Mucosal healing (MH) is associated with improved clinical outcomes in patients with Crohn's disease (CD) and ulcerative colitis (UC). MH as a target for treatment has been suggested, although there is little pediatric data. The goal of this study was to evaluate MH in clinical practice in pediatric patients with inflammatory bowel disease in clinical remission. METHODS: A retrospective review of electronic health record data was performed on all patients with CD or UC who underwent at least 2 colonoscopies from 2010 through 2016. Only patients in clinical remission undergoing a scope for MH were included in our study. The incidence of MH and histologic healing (HH) was analyzed, along with cumulative rates of MH in each group. MH was defined by both physician assessment of MH and an endoscopic score of zero for CD and UC. RESULTS: A total of 76 patients with CD and 28 patients with UC underwent at least one MH scope while in clinical remission. Of the 76 patients with CD, 51 patients (67%) demonstrated MH by physician assessment, 34 patients (45%) demonstrated MH by a simple endoscopic score for CD of zero, and 35 patients (46%) demonstrated HH. Of the 28 patients with UC, 20 patients (71%) demonstrated MH by physician assessment, 10 patients (36%) demonstrated MH by a Mayo score of zero, and 10 patients (36%) demonstrated HH. Nineteen patients underwent a second MH scope and 11 (58%) demonstrated MH by physician assessment, 7 patients (37%) demonstrated MH by simple endoscopic score for CD or Mayo scores of zero, and 5 patients (26%) demonstrated HH. Of those patients with active disease, 21 of 25 patients with CD underwent escalation of therapy, whereas 8 of 8 patients with UC underwent escalation of therapy. Cumulative rates of MH when defined by physician assessment were 79% (60 of 76 patients) in CD and 79% (22 of 28 patients) in UC. CONCLUSIONS: MH is feasible in pediatric CD and UC, and rates of cumulative MH in pediatric patients are similar to previously published adult data. In children with inflammatory bowel disease in clinical remission, approximately one-third demonstrate active disease at endoscopy. PMID- 28644181 TI - Serum Interleukin 9 Levels Predict Disease Severity and the Clinical Efficacy of Infliximab in Patients with Crohn's Disease. AB - BACKGROUND: Interleukin (IL)-9 drives gut inflammation, but its role in Crohn's disease (CD) is unclear. We aimed to analyze correlations between serum IL-9 levels and disease severity and to evaluate their predictive value in relation to the clinical efficacy of infliximab (IFX) in patients with CD. METHODS: Between January 2013 and December 2015, 100 consecutive patients with active CD and 50 age- and sex-matched control individuals were recruited from a tertiary center. Their serum IL-9 levels were measured using an enzyme-linked immunosorbent assay. Correlations between the serum IL-9 levels and disease severity were examined. The serum IL-9 level was explored as a predictor of clinical remission and mucosal healing at week 30 in 50 patients for whom IFX therapy was administered. RESULTS: The serum IL-9 levels were significantly higher in the patients with active CD (22.0 pg/mL) than in the control individuals (6.3 pg/mL) (P < 0.001); they differed according to disease severity (moderate-to-severe CD: 29.1 pg/mL versus mild CD: 12.9 pg/mL) (P < 0.001), and they correlated well with the clinical activity of CD. IFX lowered the serum IL-9 level in patients who achieved efficacy at week 30. The areas under the curves for the IL-9 levels at weeks 14 and 30 that could predict clinical remission and mucosal healing at week 30 were 0.803 and 0.752 and 0.746 and 0.781, respectively. CONCLUSIONS: Serum IL 9 levels correlate with disease severity and the clinical efficacy of IFX in patients with CD, and IL-9 may be a promising novel biomarker for CD monitoring. PMID- 28644182 TI - Incidence and Management of Recurrence in Patients with Crohn's Disease Who Have Undergone Intestinal Resection: The Practicrohn Study. AB - BACKGROUND: More than 50% of patients with Crohn's disease require intestinal resection at least once. Postoperative recurrence (POR) is almost uniform if prophylactic treatment is not started early. Endoscopic monitoring is generally advised. We studied the incidence and management of recurrence in patients who had undergone intestinal resection. METHODS: Practicrohn was an observational retrospective study performed in 26 Spanish hospitals including patients aged >=18 years who underwent Crohn's disease-related ileocolonic resection between January 2007 and December 2010. We recorded preventive treatments, the incidence of clinical recurrence in daily practice, and associated risk factors. RESULTS: The study population comprised 314 patients. Median (interquartile range) time from diagnosis to surgery was 6 (1-12) years. Prophylaxis for POR was administered to 208 patients (68%). Endoscopy was performed in 143 (46%) patients the first year after surgery. Clinical POR was detected in 97 patients (31%) after a median 315 (65-748) days. The cumulative probability of clinical POR was 16%, 27%, and 31% at 1, 3, and 5 years, respectively, being higher among patients not receiving immunomodulators as compared to those who received prophylaxis (P = 0.014). Forty-five patients (14%) required reoperation at 5 years after a median time from the first intervention of 228 (133-527) days. CONCLUSIONS: In this real life study, up to one-third of patients with Crohn's disease did not start preventive therapy after intestinal resection, and almost half of them were not endoscopically monitored as recommended. In this setting, 30% of patients developed clinical POR within the first 5 years after surgery, thus indicating that there is room for improvement. PMID- 28644183 TI - More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing. AB - BACKGROUND: There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy. METHODS: Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression. RESULTS: Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72-1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35-2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51-4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels. CONCLUSIONS: Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions. PMID- 28644184 TI - Noninvasive Fecal Immunochemical Testing and Fecal Calprotectin Predict Mucosal Healing in Inflammatory Bowel Disease: A Prospective Cohort Study. AB - BACKGROUND: The noninvasive biomarkers fecal immunochemical testing (FIT) and fecal calprotectin (FCP) are sensitive for prediction of mucosal inflammation in inflammatory bowel disease. However, neither test has yet been shown to independently and accurately predict mucosal healing (MH). We aimed to assess the specificity of noninvasive FIT and FCP for MH prediction. METHODS: In this prospective cohort study of adult inflammatory bowel disease outpatients presenting for colonoscopy, stool samples for FIT and FCP were collected 48 hours before endoscopy. Using MH defined by Simple Endoscopic Score for Crohn's disease (SES-CD = 0), Rutgeert's score (i0), and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS = 3), receiver operator characteristic curves were plotted, and sensitivity, specificity, positive and negative predictive values, and areas under the curve were calculated. Multivariate logistic regression analysis was used to develop a clinical model for noninvasively predicting MH. RESULTS: Eighty patients (40 Crohn's disease and 40 ulcerative colitis) were enrolled. The specificities of FIT <100 ng/mL and FCP <250 MUg/g for MH were 0.57 (95% confidence interval, 0.38-0.74) and 0.77 (0.57-0.89), respectively. Positive predictive values for MH for FIT <100 ng/mL and FCP <250 MUg/g were 0.78 (0.64 0.87) and 0.77 (0.58-0.90), respectively. In multivariate modeling, combining FIT, FCP, and clinical symptomatic remission improved specificity for MH to 0.90 (0.72-0.97) with positive predictive values of 0.84 (0.60-0.96). Areas under the curve for FIT was higher for patients with ulcerative colitis (0.88) than for patients with Crohn's disease (0.69, P = 0.05). CONCLUSIONS: FIT and FCP have similar performance characteristics for identifying MH. Combined, low FIT, low FCP, and clinical remission are specific for MH. PMID- 28644185 TI - A Simple Ultrasound Score for the Accurate Detection of Inflammatory Activity in Crohn's Disease. AB - BACKGROUND: Ultrasound is accurate in the detection of Crohn's disease. Our aim was to identify ultrasound parameters contributing to inflammatory disease activity, develop a simple score, and validate this score prospectively. METHODS: This study comprised 2 single-center investigations. The first was a retrospective study on a population that had received colonoscopies (as a gold standard diagnostic) within 60 days of ultrasound. The second was a prospective study on 2 populations: patients requiring induction with adalimumab and patients on adalimumab maintenance therapy. Ultrasound and endoscopy were preformed within 14 days in both prospective groups. The endoscopy results were graded with the Simple Endoscopic Score and the Rutgeerts score and compared with 5 ultrasound parameters. We used a proportional odds model to determine which ultrasound parameters correlated significantly with the endoscopy results. We then developed a predictive ultrasound score for disease activity, plotted the receiver operating characteristic curves, and undertook prospective validation of the score. RESULTS: We evaluated 160 patients retrospectively to compare ultrasound and colonoscopy. Two of 5 parameters were found to correlate significantly with disease activity: bowel wall thickness (P = <0.0001) and color Doppler signal (P = 0.0292). We developed a score that uses weighted variables. The area under the corresponding receiver operating characteristic curve was 0.8658. CONCLUSIONS: A simple ultrasonographic score that accurately identifies Crohn's disease activity has been developed and validated. Ultrasound may be a surrogate for endoscopy to guide disease management, but future studies should be conducted to establish interrater variability. PMID- 28644186 TI - Letter to Editor Regarding Narula et al, IBD 2017, Budenoside Use Is a Key Quality Marker in the Management of IBD. PMID- 28644187 TI - Perioperative Blood Management in Pediatric Spine Surgery. AB - Blood management strategies are integral to successful outcomes in many types of orthopaedic surgery. These strategies minimize blood loss and transfusion requirements, ultimately decreasing complications, improving outcomes, and potentially eliminating risks associated with allogeneic transfusion. Practices to achieve these goals include preoperative evaluation and optimization of hemoglobin, the use of pharmacologic agents or anesthetic methods, intraoperative techniques to improve hemostasis and cell salvage, and the use of predonated autologous blood. Guidelines can also help manage allogeneic transfusions in the perioperative period. Although the literature on blood management has focused primarily on arthroplasty and adult spine surgery, pediatric spinal fusion for scoliosis involves a large group of patients with a specific set of risk factors for transfusion and distinct perioperative considerations. A thorough understanding of blood management techniques will improve surgical planning, limit transfusion-associated risks, maintain hemostasis, and optimize outcomes in this pediatric population. PMID- 28644188 TI - Surgical Techniques for Total Knee Arthroplasty: Measured Resection, Gap Balancing, and Hybrid. AB - Total knee arthroplasty (TKA) is effective in managing end-stage degenerative joint disease. Achieving favorable clinical outcomes is predicated on proper implant alignment, sizing, and rotation as well as adequate soft-tissue balancing. Modern TKA implants are designed to address the fundamental needs of attaining stability in both flexion and extension and of optimizing patellar tracking. Measured resection and gap balancing are the two different techniques used to implant the TKA components used today. Both techniques have been validated as durable and successful, and each has unique advantages and disadvantages. A hybrid technique has been developed that combines the benefits of measured resection and gap balancing and minimizes the limitations associated with both techniques. This hybrid approach has the potential for achieving improved TKA kinematics and refined surgical technique. PMID- 28644189 TI - The Effect of Two Factors on Interobserver Reliability for Proximal Humeral Fractures. PMID- 28644190 TI - Core Outcome Sets for Clinical Trials and Observational Studies in Vulvovaginal Disease. PMID- 28644191 TI - Yield of Cytology Surveillance After High-Grade Vulvar Intraepithelial Neoplasia or Cancer. AB - OBJECTIVES: The aim of the study was to estimate the risk of high-grade cervical and vaginal intraepithelial neoplasia (CIN/VAIN 2+) and cancer among women treated surgically for high-grade vulvar intraepithelial neoplasia (HGVIN) and vulvar cancer. MATERIALS AND METHODS: We performed a retrospective cohort study of women who underwent surgery for HGVIN/vulvar cancer between 2006 and 2010. Univariate and multivariate analyses using stepwise selection were used to identify correlates of abnormal cytology after treatment for VIN and vulvar cancer. RESULTS: Among 191 women under surveillance for a median of 3.7 years who underwent treatment for HGVIN/vulvar cancer, primary vulvar lesions included VIN 2 (10, 5%), VIN 3 (102, 53%), and carcinoma (79, 41%). During follow-up, 71 (37%) had abnormal cytology, including 47 (25%) low grade, 23 (12%) high grade, and 1 (0.5%) carcinoma. Subsequent risk for VAIN 2+ was 11% (6/57) after previous hysterectomy and 8% for CIN 2+ (10/124) with intact cervix. Overall risk for CIN 3+ was 5%. Correlates of high-grade cytology after treatment for HGVIN/vulvar cancer included nonwhite race (odds ratio [OR] = 3.3, 95% CI = 1.50-7.36), immunodeficiency (OR = 4.2, 95% CI = 1.76-9.94), and previous abnormal cytology (OR = 2.7, 95% CI = 1.29-5.78). Stepwise multivariate analysis revealed immunosuppression as the only significant correlate of high-grade cytology after vulvar treatment (adjusted OR = 3.7, 95% CI = 1.26-10.83). CONCLUSIONS: Women with HGVIN/cancer should have cervical/vaginal cytology before vulvar surgery. Those with a negative cervical or vaginal cytology result should undergo cytology testing at 1- to 3-year intervals, based on the threshold for CIN 3+ set forth by the American Society for Colposcopy and Cervical Pathology. PMID- 28644193 TI - Heel-Raised Foot Posture Do Not Affect Trunk And Lower Extremity Biomechanics During A Barbell Back Squat In Recreational Weightlifters. AB - It is claimed that weightlifting shoes with a raised heel may lead to a more upright trunk posture, and thus reduce the risk of back injuries during a barbell back squat. These proclaimed biomechanical effects have not been thoroughly investigated. The purpose of this study was to compare trunk and lower extremity biomechanics during barbell back squats in 3 foot postures.14 recreational weightlifters (7 male and 7 female) between the ages of 18-50 performed barbell back squats in 3 conditions (barefoot on a flat surface, barefoot on a heel raised platform, and wearing heel-raised weightlifting shoes) at 80% of their 1 RM. Surface electromyography (EMG) was used to assess the activation of the knee extensors and paraspinal muscles at L3 and T12 spinal levels. A 3D motion capture system and an electrogoniometer recorded the kinematics of the thoracic spine, lumbar spine, and knee during the back squat to a depth where the hip was at least at the same level to the knee.Resultsindicated that none of the heel-raised foot postures significantly affected trunk and lower extremity muscle activation [thoracolumbar paraspinal (p=0.52), lumbar paraspinal (p=0.179), knee extensor (p=0.507)] or the trunk angles [thoracolumbar spine (p=0.348), lumbar spine (p=0.283)] during the squat.Our results demonstrated that during barbell back squats, heel-raised foot postures do not significantly affect spinal and knee extensor muscle activations, and trunk and knee kinematics. Heel-raised weightlifting shoes are unlikely to provide significant protection against back injuries for recreational weightlifters during the barbell back squat. PMID- 28644192 TI - Vulvodynia-Younger Age and Combined Therapies Associate With Significant Reduction in Self-Reported Pain. AB - OBJECTIVES: Eight percent of women have vulvodynia (VD), a chronic pain disorder with unknown etiology. The aim of our study was to assess the efficacy of given VD treatments measured by numerical rating scale (NRS) for pain and patients' quality of life. MATERIALS AND METHODS: Study material consisted of a retrospective VD patient cohort (N = 70). Data were collected by postal questionnaires and review of the medical records. RESULTS: We report here a statistically significant reduction in NRS only with combination of therapies (median NRS before treatments 8 vs median NRS 4 after treatments, p < .001) but not with any individual therapy alone, i.e., physiotherapy, topical medications, oral pharmaceutical therapy, sexual counseling by a trained nurse, sacral neuromodulation, and laser treatment or surgery. Older age (>30) and frequent (>=6) outpatient clinic visits associated with a significantly minor reduction in NRS (p = .03 and p = .04, respectively). CONCLUSIONS: The results of this retrospective study suggest that an effective, multimodality-based treatment is most beneficial for VD patients and VD at older age may represent a subtype more resistant to therapy. PMID- 28644194 TI - Phase Characteristics of the Countermovement Jump Force-Time Curve: A Comparison of Athletes by Jumping Ability. AB - Sole, CJ, Mizuguchi, S, Sato, K, Moir, GL, and Stone, MH. Phase characteristics of the countermovement jump force-time curve: a comparison of athletes by jumping ability. J Strength Cond Res 32(4): 1155-1165, 2018-The purpose of this study was to compare the phase characteristics of the countermovement jump (CMJ) force-time (F-t) curve between athletes based on jumping ability. An initial sample of one hundred fifty Division-I collegiate athletes were ranked based on CMJ height. Three performance groups were then formed by taking the top, middle, and lower 30 athletes (15 men and 15 women) from the sample. Phases of the CMJ F-t curve were determined and then characterized by their duration, magnitude, area (impulse), and shape (shape factor). A series of 3-way mixed analysis of variance were used to determine statistical differences in phase characteristics between performance groups as well as between male and female athletes. Statistically significant phase-by-performance group interactions were observed for relative phase magnitude (p < 0.001), relative phase impulse (p < 0.001), and shape factor (p = 0.002). Phase-by-sex interactions were statistically significant for both relative phase magnitude (p < 0.001) and relative phase impulse (p < 0.001). Post hoc comparisons indicated that higher jumpers exhibited larger relative magnitude and impulse in the phases contained within the positive area of the F-t curve. Similarly, relative phase magnitude and impulse were the only phase characteristics to be statically different between men and women. Finally, the relative shape of the phase representing the initial rise in force was found to relate to jump height. These results provide some information regarding the diagnostic value of qualitative analysis of the CMJ F-t curve. PMID- 28644195 TI - Considerations for Selecting Field-Based Strength and Power Fitness Tests to Measure Asymmetries. AB - Bishop, C, Turner, A, Jarvis, P, Chavda, S, and Read, P. Considerations for selecting field-based strength and power fitness tests to measure asymmetries. J Strength Cond Res 31(9): 2635-2644, 2017-The prevalence of lower limb asymmetries has been reported in numerous studies; however, methodological differences exist in the way they can be detected. Strength and jumping-based tasks have been most commonly used to examine these differences across both athlete and nonathlete populations. The aim of this review was to critically analyze the utility of strength and jumping tests that are frequently used to measure asymmetry. Reliability, validity, and considerations for assessment are examined to enhance test accuracy and effectiveness in the quantification of asymmetries during strength and jumping-based tasks. MEDLINE and SPORTDiscus databases were used with specific search terms to identify relevant articles in both athlete and nonathlete populations. The findings of the current review indicate that assessing interlimb differences during strength and jumping-based tasks may result in different levels of asymmetry; thus, interlimb differences seem to be task-dependent. Consequently, quantification during both types of assessment is warranted, and a selection of tests has been suggested to measure asymmetries in both strength and jumping-based tasks. PMID- 28644196 TI - Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. AB - Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 MUg once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (>=30% or >=50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was <=10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment. PMID- 28644197 TI - Preoperative regional maximal removal rate of technetium-99m-galactosyl human serum albumin is correlated with liver functional parameters, but did not predict postoperative morbidity. AB - BACKGROUND: Recently, posthepatectomy complications have been predicted by advances of new liver functional parameters, and the technetium-99m-galactosyl human serum albumin (GSA) liver scintigraphy has been applied widely for this purpose. We evaluated the clinical significance of the regional maximal removal rate (GSA-Rmax) in patients with various liver diseases as predictors of posthepatectomy complications. PATIENTS AND METHODS: Between 2012 and March 2016, we examined 200 patients who underwent hepatectomy for liver and biliary diseases. The patients' background liver conditions included chronic viral liver diseases in 147 patients, normal liver in 44 patients, and others in nine patients. Hepatectomy-related postoperative complications (i.e. long-term ascites, intra-abdominal infection, and hepatic failure) occurred in 69 (35%) patients. A multivariate logistic analysis was carried out to detect the predictive parameters for complications. RESULTS: The median and mean preoperative GSA-Rmax was 0.420 and 0.448+/-0.148 mg/min, respectively. The GSA Rmax was significantly correlated with liver functional parameters of ICGR15, LHL15, HH15, platelet count, prothrombin activity, and serum hyaluronic acid level (P<0.01), and was significantly correlated with postoperative total bilirubin level and C-reactive protein level (P<0.05). With respect to patient outcomes, GSA-Rmax was significantly lower in patients with long-term ascites (P<0.05). The predictive cutoff value for posthepatectomy long-term ascites for GSA-Rmax was 0.421 mg/min. However, the multivariate logistic regression analysis identified that a higher serum hyaluronic acid level and a lower platelet count were significant, independent factors, but not lower GSA-Rmax. CONCLUSION: GSA Rmax is one of the liver functional parameters and is a complementary parameter to predict postoperative hyperbilirubinemia, inflammatory responses, and ascites when Tc-GSA scintigraphy is performed. PMID- 28644198 TI - Insular Cortex Epilepsy: Exploring the Treasure Island of Reil. PMID- 28644200 TI - Electrical Stimulations of the Human Insula: Their Contribution to the Ictal Semiology of Insular Seizures. AB - INTRODUCTION: Stereotactic stimulations of the insular cortex through intracranial electrodes aim at characterizing the semiology of insular seizures. These stimulations, carried out in the context of Stereo-Electro-Encephalography (SEEG) during presurgical monitoring of epilepsy, reproduce the ictal symptoms observed during the development of insular seizures. METHODS: The authors reviewed the results of insular stimulations performed in 222 patients admitted between 1997 and 2015 for presurgical SEEG exploration of atypical temporal or perisylvian epilepsy. Stimulations (50 Hz, trains of 5 seconds, pulses of 0.5 ms, intensity 0.2-3.5 mA) were carried out using transopercular electrodes implanted orthogonal to midsagittal plane. RESULTS: Out of a total of 669 stimulations, 550 were clinically eloquent in the absence of any postdischarge (237 and 313, respectively, in the right and left insulae). Somatosensory responses (61% of evoked sensations) including pain and visceral sensations (14.9%) were the most frequent, followed by auditory sensations (8%), vestibular illusions (7.5%), speech impairment (5%), gustatory, (2.7%), and olfactory (1%) sensations. Although these responses showed some functional segregation (in particular a privileged pain representation in the postero-superior quadrant), there was a clear spatial overlap between representations of the different modalities. CONCLUSIONS: Symptoms evoked by insular stimulations are multiple. None of them can be considered as absolutely specific to the insular cortex, but the occurrence in given seizure of a somatosensory symptom such as pain or of a laryngeal spasm associated with vestibular, auditory, aphasic, or olfacto gustatory symptoms points to a discharge development in the insular cortex, which is the only cortical region where stimulations demonstrate such a multimodal representation. PMID- 28644199 TI - Structure and Function of the Human Insula. AB - The insular cortex, or "Island of Reil," is hidden deep within the lateral sulcus of the brain. Subdivisions within the insula have been identified on the basis of cytoarchitectonics, sulcal landmarks, and connectivity. Depending on the parcellation technique used, the insula can be divided into anywhere between 2 and 13 distinct subdivisions. The insula subserves a wide variety of functions in humans ranging from sensory and affective processing to high-level cognition. Here, we provide a concise summary of known structural and functional features of the human insular cortex with a focus on lesion case studies and recent neuroimaging evidence for considerable functional heterogeneity of this brain region. PMID- 28644202 TI - The Insula in Temporal Plus Epilepsy. AB - Temporal lobe epilepsy (TLE) surgery is the most common type of surgical treatment offered to patients with drug-resistant focal seizures. However, the proportion of patients experiencing long-term freedom from seizures after TLE surgery remains suboptimal. Temporal plus epilepsy, which is characterized by a primary temporal epileptogenic zone extending to neighboring regions, has been demonstrated to be a major predictor of TLE surgery failures. In the context of the temporoperisylvian epilepsies, i.e., the most common type of temporal plus epilepsy, a possible role of the insula has often been hypothesized. As this area is buried deep within the lateral sulcus, the use of invasive recordings is often required. Identifying patients with temporal plus seizures is a relevant issue, as they appear to have a worse postsurgical seizure outcome compared with patients with "pure" temporal lobe seizures. Owing to these prognostic implications, it becomes important to identify, among patients suffering from "atypical" nonlesional TLEs, those who should undergo invasive investigations, in particular to explore the insula. In fact, only a primary involvement of the insula in the epileptogenic network may require to include this area in the resection to achieve seizure freedom. Using modern neurosurgical techniques, insular epilepsy surgery has proved to be safe and beneficial, making the "true" role of the insula in TLE surgery failures more relevant to understand. Further studies are needed to evaluate the efficacy of multilobar resections in patients with temporal plus epilepsy, in particular, when eloquent or difficult to access areas such as insula are suspected to be involved. PMID- 28644201 TI - Insular Epilepsy: Semiology and Noninvasive Investigations. AB - In this review, authors discuss the semiology and noninvasive investigations of insular epilepsy, an underrecognized type of epilepsy, which may mimic other focal epilepsies. In line with the various functions of the insula and its widespread network of connections, insular epilepsy may feature a variety of early ictal manifestations from somatosensory, visceral, olfactory, gustatory, or vestibular manifestations. Depending on propagation pathways, insular seizures may also include altered consciousness, dystonic posturing, complex motor behaviors, and even autonomic features. Considering the variability in seizure semiology, recognition of insular epilepsy may be challenging and confirmation by noninvasive tests is warranted although few studies have assessed their value. Detection of an insular lesion on MRI greatly facilitates the diagnosis. Scalp EEG findings in frontocentral and/or temporal derivations will generally allow lateralization of the seizure focus. Ictal single-photon computed tomography has moderate sensitivity, whereas positron emission tomography has lower sensitivity. Among newer techniques, magnetoencephalography is highly beneficial, whereas proton magnetic resonance spectroscopy currently has limited value. PMID- 28644203 TI - Invasive Investigation of Insular Cortex Epilepsy. AB - Invasive long-term EEG investigations of the insula have been performed since the mid-nineties in an expanding range of focal epilepsies suspected to involve the insular cortex. The various clinical forms of insular epilepsies were delineated during the last 2 decades, and include the following presentations: perisylvian epilepsy, temporal plus epilepsy, sleep hypermotor epilepsy, MRI-negative frontal and parietal lobe epilepsies, and insular lesions. In fact, a majority of complex stereoelectroencephalography procedures will include at least one electrode targeting the insula. Stereoelectroencephalography is currently the preferred method to investigate the insula, using orthogonal, oblique, or a combination of both trajectories, with no evidence of higher risk of intracranial bleeding than in other brain regions. Orthogonal trajectories allow to sample the overlaying opercula, while oblique trajectories offer a better sampling of the insular cortex. Intrainsular ictal EEG pattern are often characterized by a prolonged focal discharge restricted to one of the five insular gyri, militating for a dense enough sampling of the insular cortex in suspected insular epilepsies. Stereoelectroencephalography offers the potential to perform thermolesion of insular epileptogenic zones which, together with MRI-guided laser ablation, represent a possibly safer alternative treatment to open-skull surgical resection of the insula. PMID- 28644204 TI - Hearing Safety From Single- and Double-Pulse Transcranial Magnetic Stimulation in Children and Young Adults. AB - PURPOSE: Concerns regarding hearing safety have limited the number of studies using transcranial magnetic stimulation (TMS) in children and young adults. The objective of this study was to examine the safety of TMS with regards to hearing in a group of 16 children and young adults (17.3 +/- 4.9 years) with and without brain injury. METHODS: Pure-tone hearing thresholds and distortion-product otoacoustic emissions were measured before and after exposure to single- and paired-pulse TMS (1-2 sessions of 149-446 TMS pulses at a median of 49%-100% maximum stimulator output over a 2.2 hours period). RESULTS: No mean change in hearing outcomes was noted. In addition, no clinically significant change in hearing threshold was observed in any participant, and participants did not experience a subjective change in hearing after TMS exposure. CONCLUSIONS: Single and double-pulse TMS administered within the parameters used in this study, which included hearing protection, can be used in children and young adults without impacting hearing. This study provides further evidence for hearing safety after TMS exposure in children and young adults. PMID- 28644205 TI - The Unrecognized Epidemic of Electronic Cigarette Burns. AB - Electronic cigarettes (e-cigarettes) are novel battery-operated devices that deliver nicotine as an inhaled aerosol. They originated from China in 2007 and their use has rapidly increased worldwide in the past decade, yet they remain largely unregulated. Reports of injuries associated with their use have appeared as unusual events in the news media and as case reports in the medical literature. This study was undertaken to explore e-cigarettes as a mechanism of burn injury. Referral records to three burn centers from January 2007 to July 2016 were searched to identify patients with injuries caused by e-cigarettes. Data were gathered from the electronic medical records (EMRs) of patients referred within the most recent 18 months. Thirty patients with burns resulting from e-cigarettes were identified. Twenty-nine were referred within the most recent 18 months. Only one was referred in the preceding 8 years. An explosion was identified by the patient as the inciting event in 26 of the 30 injuries (87%). Explosion of an isolated battery while it was carried on personal attire was reported in 10 cases. Explosion of a fully assembled e-cigarette was described in 16 cases. In seven of these 16 cases, the explosion occurred while the device was idle and carried on personal attire. In the other nine cases, the explosion occurred while the device was being operated. No injury occurred while batteries were charging. The mean age of injured patients was 30 years. The mean size of burn was 4% TBSA. The thighs, hands, and genitalia were the most common sites of injury. Twenty-six patients required hospital admission and nine required surgery. Serious burn injuries from e-cigarettes have recently occurred with greatly increased frequency. The increase in injuries appears out of proportion to the increased popularity of e-cigarettes. The most common pattern of injury is explosion when either the idle device or its batteries are carried on personal attire. PMID- 28644206 TI - Burn Patient Acuity Demographics, Scar Contractures, and Rehabilitation Treatment Time Related to Patient Outcomes: The ACT Study. AB - In 2008, the U.S. Department of Defense funded a rehabilitation study through the American Burn Association titled "Burn patient acuity demographics, scar contractures, and rehabilitation treatment time related to patient outcomes," commonly known at the ACT study. The ACT was a multi-institutional, prospective, observational, and quasirandomized investigation of the acute hospital course of 307 patients. The ACT specifically emphasized the capture of factors that may impact the physical outcome of patients with burn injury including burn severity, daily rehabilitation interventions such as mobility and splinting, and detailed skin grafting episodes. In particular, the effect that the amount of daily rehabilitation time patients received as it related to range of motion measured at the time of acute hospital discharge of areas affected by the burn injury was analyzed. The information contained herein is intended to give the interested reader an overview of the extent and breadth of the ACT dataset in terms of parameters available for further investigation. This information is also intended to be used as a basic reference for conduct of the ACT study in future reports. PMID- 28644207 TI - Enzymatic Versus Traditional Surgical Debridement of Severely Burned Hands: A Comparison of Selectivity, Efficacy, Healing Time, and Three-Month Scar Quality. AB - Severe burns of the hands are extremely challenging, given their anatomic complexity and vulnerability. Although excisional debridement with autografting remains the standard of care (SOC), previous studies have shown that use of enzymatic debridement with bromelain (NexoBrid, EDNX) enables rapid, selective enzymatic debridement, preserving viable tissue. To date, only two studies accruing data on EDNX in this setting have been published. The current study was conducted to compare EDNX with traditional surgical debridement (TSD) of deep dermal and full-thickness hand burns. This single-center, controlled clinical trial included 40 patients, aged 18 to 76 years, with deep dermal burns of the hand. The first 20 patients were debrided surgically, and the other 20 patients were using EDNX for debridement. Therapeutic selectivity, time to complete debridement and healing, complications, and 3-month functional/esthetic outcomes were compared by group. EDNX (vs TSD) significantly reduced time to complete debridement after admission (0.95 day vs 7.750 days; P < .001) and treatments needed for complete debridement (1.05 vs 1.45; P < .001), improving burn depth evaluation (initially overestimated in 55% of EDNX-treated patients). The number of wounds requiring autografting was certainly reduced (15% vs 95%; P = .034), as was time to complete healing after first debridement (23.30 vs 32.00 days; P < .001), and early scar quality after 3 months was nearly equivalent, with only heightened local redness in the EDNX group (P < .001). Compared with TSD, EDNX was superior in burn depth evaluation, tissue preservation, completeness of debridement, and wound closure. Scar quality after 3 months did not differ substantially. PMID- 28644208 TI - Shake It Off: A Randomized Pilot Study of the Effect of Whole Body Vibration on Pain in Healing Burn Wounds. AB - Whole body vibration (WBV) has been shown to improve strength in extremities with healed burn wounds. We hypothesize that WBV reduces pain during rehabilitation compared to standard therapy alone. Patients with >=1% TBSA burn to one or more extremities from October 2014 to December 2015 were randomized to vibration (VIBE) or control. Each burned extremity was tested separately within the assigned group. Patients underwent one to three therapy sessions (S1, S2, S3) consisting of five upper and/or lower extremity exercises with or without WBV. Pain was assessed pre-, mid-, and postsession on a scale of 1 to 10. Mean pain scores at S1 to S3 were compared between groups with paired samples t-tests. An independent t-test was used to compare differences in pain scores between groups. Continuous variables were compared using a t-test or Mann-Whitney U test, and categorical variables were compared using a chi or Fisher's exact test, as appropriate. Forty-eight randomized test extremities (VIBE = 26, control = 22) were analyzed from a total of 31 subjects. There were no significant differences between groups in age, gender, overall TBSA, TBSA in the test extremity, pain medication use before therapy session, or skin grafting before therapy session. At S1, S2, and S3, there was a statistically significant decrease in mid- and postsession pain compared to presession pain in VIBE vs controls. Exposure to WBV decreased pain during and after physical therapy. This modality may be applicable to a variety of soft tissue injuries and warrants additional investigation. PMID- 28644209 TI - An Atypical Case of Paracentral Acute Middle Maculopathy. AB - PURPOSE: This is a case presentation of paracentral acute middle maculopathy in a 33-year-old white man with borderline hyperlipidemia. Paracentral acute middle maculopathy was originally thought to be a variant of acute macular neuroretinopathy; however, it is now generally accepted that these two conditions are separate disease entities. The etiology, evolution, and pathophysiology of acute macular neuroretinopathy and paracentral acute middle maculopathy are discussed, as well as current diagnostic techniques. CASE REPORT: A 33-year-old white man with borderline hyperlipidemia presented with an acute, small paracentral scotoma involving the left eye. Clinical examination revealed a small wedge-shaped retinal lesion that corresponded to scotoma. Spectral domain-optical coherence tomography of the lesion demonstrated irregularity in the middle retina, whereas fluorescein angiography showed subtle hypofluorescence of the lesion. Spectral domain-optical coherence tomography was facilitated in monitoring retinal changes as the patient continued to have a persistent scotoma despite resolution of the retinal lesion. CONCLUSIONS: Clinically, acute macular neuroretinopathy and paracentral acute middle maculopathy present in very similar fashions with localized scotomas, blurry vision, and subtle retinal lesions that can be difficult to discern funduscopically. At this time, there is no ocular treatment for either condition, but observation and patient education regarding possibly persistent scotomas are necessary. This atypical case highlights paracentral acute middle maculopathy in a relatively young man with a systemic history significant only for borderline hyperlipidemia. Eye care providers should be familiar with acute macular neuroretinopathy and paracentral acute middle maculopathy to enable them to perform appropriate diagnostic testing and to identify patients who require a systemic disease evaluation. PMID- 28644210 TI - Frequency-domain optical coherence tomography plaque morphology in stable coronary artery disease: sex differences. AB - BACKGROUND: The cause for discrepancy in the clinical presentation and outcome of coronary artery disease (CAD) between men and women is not established. Different prevalences of risk factors or specific sex-related atherosclerotic aspects have been advocated as possible explanations. We investigated coronary plaque morphology looking at possible differences in plaque vulnerability between men and women with stable CAD. PATIENTS AND METHODS: We retrospectively collected and analyzed clinical data and coronary plaque morphology by frequency-domain optical coherence tomography in men and women with stable CAD. RESULTS: A total of 181 (139 were in men and 42 in women) plaques from 138 patients were analyzed. The mean age was similar between men and women. Besides an overall absence of significant differences in the vast majority of risk factors and comorbidities, men had a higher prevalence of active smoking (19 vs. 2%, P=0.006), previous myocardial infarction (17 vs. 2%, P=0.01), and previous percutaneous coronary interventions (42 vs. 17%, P=0.003). Frequency-domain optical coherence tomography in women showed significantly more plaque-vulnerability features as testified by higher percent of lipid-rich plaques (55 vs. 36%, P=0.03), macrophages (21 vs. 5%, P=0.003), and microvessels (24 vs. 8%, P=0.01). Multivariate analysis showed that female sex was associated independently with lipid-rich plaques (P=0.034) and macrophages (P=0.001). In the analysis restricted to the more severe lesions that were revascularized, women continued to be characterized by more adverse morphological features, such as macrophages (30 vs. 7%, P=0.004) and lipid-rich plaques (63 vs. 39%, P=0.045). CONCLUSION: Women with stable CAD may be characterized by plaques that have increased prevalence of vulnerability compared with men. These findings support the hypothesis of sex-specific differences in the development of atherosclerosis. PMID- 28644211 TI - The relationship between fasting blood glucose variability and coronary artery collateral formation in type 2 diabetes patients with coronary artery disease. AB - BACKGROUND: Coronary collaterals are an alternative source of blood supply to ischemic myocardium. Well-developed coronary collateral arteries in patients with coronary artery disease (CAD) limit the size of acute myocardial infarction and improves survival. The aim of this study was to investigate the relationship between glycemic variability and coronary collateral formation in patients with type 2 diabetes mellitus and CAD. METHODS: Consecutive patients undergoing percutaneous coronary intervention or coronary artery bypass grafting procedures were studied. Multivariate logistic regression models were used to examine the association between coronary artery collateral formation graded by Rentrope classification and glycemic variability, measured by coefficient variation of fasting blood glucose. RESULTS: In our study, we retrospectively enrolled 300 patients, of whom 239 were diabetic (age: 70.1+/-11.9, 56% men) and 61 were nondiabetic (age: 71.5+/-11.5, 72% men). Diabetic patients were further stratified as follows: those with poor coronary collateral artery development (n=171, age: 69.7+/-12.4, 55% men) and those with good coronary collateral artery development (n=68, age 71.1+/-10.8, 59% men) according to the Rentrope classification. Our findings did not show association between glycemic variability and coronary collateral vessels development after controlling for potential confounders (odds ratio: 2.51; 95% confidence interval: 0.57-11.03; P=0.22). The culprit lesion (>=75% stenosis) in the left anterior descending artery and the right coronary artery was more frequent in the good collateral group compared with the poor collateral group (66 vs. 50%, P=0.02; 63 vs. 45%, P=0.01 respectively). CONCLUSION: Glycemic variability is not associated with coronary collateral artery formation in patients with type 2 diabetes mellitus and CAD. PMID- 28644212 TI - Worsening atrioventricular conduction after hospital discharge in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: the HORIZONS-AMI trial. AB - BACKGROUND: The chronic effects of ST-segment elevation myocardial infarction (STEMI) on the atrioventricular conduction (AVC) system have not been elucidated. This study aimed to evaluate the incidence, predictors, and outcomes of worsened AVC post-STEMI in patients treated with a primary percutaneous coronary intervention (PCI). PATIENTS AND METHODS: The current analysis included patients from the HORIZONS-AMI trial who underwent primary PCI and had available ECGs. Patients with high-grade atrioventricular block or pacemaker implant at baseline were excluded. RESULTS: Analysis of ECGs excluding the acute hospitalization period indicated worsened AVC in 131 patients (worsened AVC group) and stable AVC in 2833 patients (stable AVC group). Patients with worsened AVC were older, had a higher frequency of hypertension, diabetes, renal insufficiency, previous coronary artery bypass grafting, and predominant left anterior descending culprit lesions. Predictors of worsened AVC included age, hypertension, and previous history of coronary artery disease. Worsened AVC was associated with an increased rate of all-cause death and major adverse cardiac events (death, myocardial infarction, ischemic target vessel revascularization, and stroke) as well as death or reinfarction at 3 years. On multivariable analysis, worsened AVC remained an independent predictor of all-cause death (hazard ratio: 2.005, confidence interval: 1.051-3.827, P=0.0348) and major adverse cardiac events (hazard ratio 1.542, confidence interval: 1.059-2.244, P=0.0238). CONCLUSION: Progression of AVC system disease in patients with STEMI treated with primary PCI is uncommon, occurs primarily in the setting of anterior myocardial infarction, and portends a high risk for death and major adverse cardiac events. PMID- 28644213 TI - Platelet pathophysiology, pharmacology, and function in coronary artery disease. AB - Platelets play a key role in the pathophysiology of coronary artery disease and acute coronary syndromes. Our understanding of platelet function in thrombus formation has increased considerably, resulting in the development of clinically effective treatment strategies and identification of new targets. An underappreciated platelet function is their contribution toward acute and chronic inflammatory processes including atherogenesis. In this review, we discuss the role of platelets in atherosclerosis and thrombosis, platelet function testing, and the pharmacology of currently available antiplatelet drugs. PMID- 28644214 TI - The future of bioresorbable vascular scaffolds: niche or workhorse devices? PMID- 28644215 TI - Treatment of coronary stent restenosis with drug-eluting bioabsorbable magnesium scaffolds. PMID- 28644216 TI - What do PAs need to know about prescription drug monitoring programs? AB - As controlled-substance abuse continues to increase in the United States, clinicians find themselves on the front lines of this epidemic. State-operated prescription drug monitoring programs are a valuable resource that prescribers can use to see patients' controlled substance history. Despite some limitations, these programs have been shown to be an effective method in reducing overdose deaths and the supply of controlled substances in the community. PMID- 28644218 TI - Bilateral anterior shoulder dislocation. AB - Shoulders are the most common major joint to become disarticulated, and shoulder dislocation is a frequent patient presentation to the ED. Bilateral shoulder dislocations, however, are rare and typically caused by seizure activity or electrocution. Posterior disarticulation is most common following seizure activity. This article describes an adolescent girl who dislocated both shoulders anteriorly following seizure activity. PMID- 28644219 TI - An uncommon complication of laparoscopic live donor nephrectomy. AB - Chylous ascites is an uncommon complication of laparoscopic live donor nephrectomy, occurring when milky chyle from the lymphatic system leaks into the peritoneal cavity. This can occur after trauma or be caused by obstruction of the lymphatic system. Treatment may include a fat-free diet, total parenteral nutrition, subcutaneous somatostatin, lymphangiography, and/or surgical closure of the leaking lymph vessel. PMID- 28644220 TI - Completion lymph node dissection in patients with melanoma and positive sentinel lymph node biopsy. AB - Melanoma is a highly aggressive cancer that represents a significant disease burden, making diagnosis and appropriate control of disease vital for improving morbidity and mortality. The most recent guidelines for melanoma treatment advise performing a sentinel lymph node biopsy for intermediate thickness melanomas, with subsequent completion lymph node dissection (CLND) if sentinel nodes are positive. This guideline is controversial due to the limited availability of data on this topic. CLND is an extensive surgery with known risks and complications and a small survival benefit. However, in patients without significant comorbidities and at low risk for surgery, the survival benefit outweighs the procedural risk. This article reviews CLND and the current recommendations. PMID- 28644221 TI - Physician assistant dual employment. AB - National health workforce supply and demand models help predict requirements built on individual annual productivity assumptions. Dual employment rarely is addressed, yet in 2015, about 13.5% of certified physician assistants (PAs) reported two or more clinical positions. Of PAs working two positions, 44% reported the main reason was to supplement earnings, followed by role variety. The mean number of hours worked by all certified PAs was 40.7 per week and the average number of patients was 75. Dual-employed PAs averaged more than 51 hours and 97 patients per week. This new finding reveals an added dimension to provider productivity statistics requiring refinements to annual output calculations. PMID- 28644222 TI - PAs: Public awareness and the popular media. AB - From the very beginning, popular media has played an essential role in driving public awareness and recognition of physician assistants (PAs) as major contributors to healthcare. But for PAs, popular media can be a double-edged sword. Over time, the roles of PAs have evolved from bit players to leading characters on television medical dramas. Even so, on some occasions, the roles of PAs have been marginalized and misrepresented. In the future, the PA profession will need to remain vigilant about how PAs are portrayed in the popular media and must learn how to use the full benefit of the media to promote the profession's diversity, flexibility, collegiality, and civic-mindedness. PMID- 28644224 TI - Sick sinus syndrome. PMID- 28644223 TI - How PAs became licensed to practice in the United States. AB - The history of how PAs in the United States were first granted practice authority under the medical practice acts of the various states and territories begins in the 1960s with an imaginative way to circumvent the moratorium on licensure of new healthcare occupations in place at the time, while allowing the requisite flexibility for the new profession to take hold and thrive. In the subsequent decades, separate licensure for PAs was required and adopted. Despite the enormous success of the PA profession over its first 50 years, challenges remain. PMID- 28644225 TI - Adjuvant steroid therapy in community-acquired pneumonia. AB - Despite medical advances, pneumonia is a leading cause of death worldwide. Because inflammation is a key defense mechanism, adjuvant corticosteroid therapy has long been considered but never widely recommended to treat pneumonia. New research is exploring potential benefits of this therapy, including reduced time to clinical stability, reduced hospital stay, reduced rates of treatment failure, and prevention of complications. PMID- 28644226 TI - Possible allergic reaction after outpatient surgery. PMID- 28644227 TI - Permission. PMID- 28644228 TI - Renewal. PMID- 28644230 TI - Optimal team practice: Much at stake. PMID- 28644231 TI - Considerations for PA education and training. PMID- 28644232 TI - Case of Presumed Transient Light-Sensitivity Syndrome After Small-Incision Lenticule Extraction. AB - PURPOSE: To report the first presumed case of transient light-sensitivity syndrome (TLSS) after small-incision lenticule extraction (SMILE). METHODS: A 27 year-old male patient was treated for severe photophobic symptoms occurring 7 weeks after undergoing a bilateral SMILE procedure. His comprehensive ocular examination was unremarkable and his visual acuity was unaffected. Treatment was a month-long tapering dose of topical steroids. RESULTS: Photophobic symptoms fully resolved after steroid treatment. TLSS related to SMILE mirrors TLSS after laser in situ keratomileusis in both onset and steroid responsiveness. CONCLUSIONS: TLSS is a rare and minor complication of SMILE. Photophobic symptoms associated with post-SMILE TLSS are fully responsive to topical corticosteroids. PMID- 28644233 TI - Tyrosine Kinase Inhibitor, Vatalanib, Inhibits Proliferation and Migration of Human Pterygial Fibroblasts. AB - PURPOSE: Vatalanib is a small-molecule tyrosine kinase inhibitor. We investigated the effects of vatalanib on the proliferation and migration of cultured human pterygial fibroblasts (HPFs). METHODS: Pterygium tissues were obtained after pterygium excision surgery and subjected to primary culture. HPFs were treated with vatalanib at various concentrations. Mitomycin C (MMC) was used as a positive control. Cell proliferation and migration assays were used to investigate the effects of vatalanib. Cell death was measured using flow cytometry analysis. Western blot analysis was performed to identify signaling molecules associated with the response to vatalanib. RESULTS: Vatalanib inhibited both proliferation and migration of HPFs in a dose-dependent manner. Cell proliferation was significantly suppressed by vatalanib (10 and 100 MUM) and MMC (0.004% and 0.04%) treatments. Migration assays revealed significant HPF delay when treated with vatalanib (1, 10, and 100 MUM) and MMC (0.004% and 0.04%) compared with that in a negative control. Cell death analysis showed that high concentrations of vatalanib (100 MUM) and MMC (0.004% and 0.04%) decreased cell numbers. Western blot analysis of vatalanib-treated cells showed vascular endothelial growth factor and transforming growth factor-beta significantly reduced, but there was no alteration in p53 protein levels in HPFs. CONCLUSIONS: These results indicate that vatalanib significantly suppressed the proliferation and migration of HPFs by decreasing vascular endothelial growth factor and transforming growth factor-beta. Vatalanib showed less toxicity than that of MMC. Based on these results, vatalanib may potentially serve as a new adjuvant treatment after pterygium excision surgery. PMID- 28644234 TI - Efficacy of Sodium Hyaluronate in Murine Diabetic Ocular Surface Diseases. AB - PURPOSE: To evaluate the efficacy of sodium hyaluronate (HA) eye drops for the treatment of diabetic ocular surface diseases in mice. METHODS: Male 6- to 8-week old C57BL/6 mice underwent induction of type 1 diabetes with intraperitoneal injections of streptozotocin, with normal mice as the control. Topical 0.3% HA, 0.1% HA, 0.4% polyethylene glycol eye drops, and normal saline were administered to diabetic mice with an intact or debrided corneal epithelium. Normal saline was applied in the controls. Corneal epithelial wound healing rate, corneal sensation, nerve fiber density, conjunctival goblet cell number, and MUC-5AC content were measured and compared. RESULTS: Compared with the controls, topical 0.3% HA use in diabetic mice showed significant improvements in the corneal epithelial wound healing rate (48 hours: 91.5% +/- 4.8% vs. 79.8% +/- 6.1%; P < 0.05), corneal sensitivity (4.1 +/- 0.3 cm vs. 3.5 +/- 0.3 cm; P < 0.05), nerve fiber density (12.9% +/- 2.3% vs. 6.6% +/- 2.4%; P < 0.05), conjunctival goblet cell number (31.0 +/- 8.4/100 MUm vs. 19.6 +/- 7.1/100 MUm; P < 0.05), and MUC 5AC content (12.5 +/- 1.4 ng/mg vs. 7.8 +/- 1.5 ng/mg protein; P < 0.05). The beneficial effects of 0.3% HA were better than those of 0.1% HA and 0.4% polyethylene glycol. CONCLUSIONS: Topical 0.3% HA treatment promoted corneal epithelial regeneration, improved corneal sensation, and increased density of corneal nerve fibers and conjunctival goblet cells in mice with diabetic ocular surface diseases. PMID- 28644235 TI - Chandelier Illumination for Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To describe a simple technique that uses posterior chandelier illumination during Descemet membrane endothelial keratoplasty in cases of severe bullous keratopathy (BK). METHODS: Five eyes of 4 patients with advanced BK undergoing Descemet membrane endothelial keratoplasty were retrospectively analyzed. The pupil of the host eye was not treated with mydriatic or miotic agents. The chandelier illuminator was inserted transconjunctivally into the vitreous cavity from the pars plana. RESULTS: In all eyes, BK was secondary to laser iridotomy, which was performed for prevention or treatment of angle closure glaucoma. The implanted graft was clearly confirmed in the anterior chamber using activated chandelier illumination. The graft was immediately attached to the host cornea, with eventual healing of BK in all eyes. No complication involving insertion or removal of the 25-gauge trocar and the chandelier illuminator was observed. No vision-threatening complication was observed in any of the 5 eyes. CONCLUSIONS: The chandelier illuminator provided good visibility of the anterior chamber and enhanced the safety of surgery by preventing formation of an inverted graft. PMID- 28644237 TI - Outcomes of Keratoplasty After Ocular Surface Stem Cell Transplantation. AB - PURPOSE: To investigate the long-term outcomes of penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) after ocular surface stem cell transplantation (OSST). METHODS: An observational retrospective review was performed on all patients who underwent OSST followed by either PK or DALK with a minimum of 6-month follow-up. RESULTS: One hundred two eyes fulfilled the inclusion criteria. The mean time to keratoplasty after OSST was 19 months, and the mean follow-up was 57 months after keratoplasty. A Kaplan-Meier analysis demonstrated 92% graft survival at year 1, 77% at year 2, 62% at year 3, 55% at year 4, and 54% at year 5. During the study period, a total of 44 grafts failed. The mean time to graft failure was 32 months. Preoperative median best-corrected visual acuity for all eyes was 20/550, which improved to 20/100 (P < 0.001) at 1 year postoperatively, 20/60 (P < 0.001) at 2 years, and 20/100 (P < 0.001) at last follow-up. CONCLUSIONS: Without addressing the underlying stem cell deficiency, keratoplasty in patients with total limbal stem cell deficiency will ultimately fail in all cases. OSST with either subsequent PK or DALK provides successful visual outcomes with an acceptable complication profile. PMID- 28644236 TI - CYP1B1 Cytopathy: Uncommon Phenotype of a Homozygous CYP1B1 Deletion as Internal Corneal Ulcer of Von Hippel. AB - PURPOSE: To report a mutation of CYP1B1 in a newborn with a rare phenotype without the classic features of anterior segment dysgenesis or congenital glaucoma. METHODS: The newborn presented with diffuse corneal edema and bilaterally elevated intraocular pressure (IOP). Ophthalmological examination, ultrasound, and ultrasound biomicroscopy were performed; congenital infections were ruled out. Genetic analysis was performed. The patient underwent penetrating keratoplasty and goniotomy in a single surgical time. The button was subjected to histopathological examination. RESULTS: The patient is the first child of young, healthy, consanguineous parents. Ophthalmological examination revealed visual acuity of light perception and increased IOP in both eyes. CYP1B1 gene analysis demonstrated homozygosity for a 1-bp deletion in exon 2 (c.830delT). IOP was normalized, and the corneal button was clear after surgical treatment. Histopathological analysis revealed loss of the Bowman membrane in the central cornea, fibrosis of the stroma, absence of endothelial cells, and loss of Descemet membrane centrally. CONCLUSIONS: We present an uncommon mutation and clinical description of CYP1B1. This report and further studies could provide us better understanding of the mutational spectrum of CYP1B1. PMID- 28644238 TI - Prevention and Management of Descemet Membrane Endothelial Keratoplasty Complications. AB - PURPOSE: To describe Descemet membrane endothelial keratoplasty (DMEK) complications and strategies for their prevention and management. METHODS: Five hundred consecutive eyes with DMEK of 393 patients were reviewed in this retrospective study for intraoperative and postoperative complications up to 2 years and for corresponding management. RESULTS: Intraoperative challenges (difficult graft unfolding/positioning, high vitreous pressure, iris root hemorrhage, and Descemet membrane remnants) were encountered in 81 eyes (16.2%). Visually significant graft detachment was the main postoperative complication (34 eyes, 6.8%). Graft failure occurred in 8 eyes (1.6%). Other postoperative complications were an increase of intraocular pressure/decompensated glaucoma in 48 eyes (9.6%), significant cataract in 11 of 124 phakic eyes (8.9%), allograft rejection in 7 eyes (1.4%), cystoid macular edema in 5 eyes (1.0%), microbial keratitis in 2 eyes (0.4%), and retinal detachment in 1 eye (0.2%). Different strategies for prevention and management of these complications have been identified. CONCLUSIONS: DMEK shows acceptable rates of complications up to 2 years after surgery, which can be managed successfully. Anticipation of potential challenges and difficulties may aid in modifying intraoperative strategies for predisposed eyes. This knowledge may further minimize complications, in particular, when performing DMEK for an extended spectrum of corneal endothelial disorders. PMID- 28644239 TI - Effect of the Learning Curve on Visual and Refractive Outcomes of Small-Incision Lenticule Extraction. AB - PURPOSE: To investigate the effect of the learning curve for small-incision lenticule extraction during the first 2 years of experience. METHODS: Small incision lenticule extraction was performed using the 500-kHz VisuMax femtosecond laser (Carl Zeiss Meditec) by the same surgeon. The initial 100 patients since the surgeon started operating independently were considered as group 1; the recent 100 patients were considered as group 2. The same laser settings and technique were used. The visual and refractive outcomes were compared between groups at postoperative 1 week and 6 months. Vector analysis was performed for eyes with astigmatic correction. RESULTS: Two hundred right eyes of 200 patients were included. Age, preoperative corrected visual acuity, manifest refraction, and central corneal thickness were similar between groups (P <= 0.154). Postoperatively, the efficacy index at 1 week was better in group 2 (group 1: 0.85 +/- 0.16 vs. group 2: 0.91 +/- 0.10, P = 0.019) but was similar between groups at 6 months (group 1: 0.91 +/- 0.14 vs. group 2: 0.94 +/- 0.08, P = 0.181). The safety index was higher in group 2 at 1 week (group 1: 0.93 +/- 0.10 vs. group 2: 0.95 +/- 0.08, P = 0.045) and 6 months postoperatively (group 1: 0.97 +/- 0.07 vs. group 2: 0.99 +/- 0.03, P = 0.011). Vector analysis showed that postoperative residual astigmatism and misalignment of astigmatic correction were lower in group 2 than in group 1 (P <= 0.039) at 1 week and 6 months. The duration of docking and that of lenticule extraction was shorter in group 2 (P <= 0.034). CONCLUSIONS: Our study showed that faster visual recovery, better safety profile, and more accurate astigmatic correction could be attained with increasing surgical experience. PMID- 28644240 TI - Corneal Stiffening by a Bacteriochlorophyll Derivative With Dextran and Near Infrared Light: Effect of Shortening Irradiation Time up to 1 Minute. AB - PURPOSE: The aim of this study is to determine the effect of variation of the exposure time of near-infrared irradiation on corneal stiffening after a bacteriochlorophyll derivative (WST11) with dextran (WST-D) application. METHODS: One hundred four paired eyes of 3-month-old New Zealand White rabbits were included in this study. Fifty-two eyes (ex vivo n = 34, in vivo n = 18) were mechanically deepithelialized, treated topically with WST-D, and irradiated at 10 mW/cm using a diode laser at 755 nm for 1, 5, or 30 minutes. Untreated fellow eyes served as controls. Corneoscleral rings were removed immediately after treatment (ex vivo), or 1 month after treatment (in vivo). Corneal strips were cut and underwent biomechanical stress-strain measurements. RESULTS: Ex vivo, the mean tangent elastic modulus was significantly higher in the treatment groups than in the control groups for 1, 5, and 30 minutes of irradiation, respectively, 6.06 MPa, 95% confidence interval (CI, 4.5-7.6) versus 14.02 MPa, 95% CI (10.2 17.8), n = 11, 4.8 MPa, 95% CI (3.9-5.7) versus 15.03 MPa, 95% CI (12-18.1), n = 11, and 7.8 MPa, 95% CI (5.6-10.02) versus 16.2 MPa, 95% CI (13.6-18.9), n = 11; P < 0.001 for all comparisons. In vivo, the mean elastic moduli in the treatment groups were significantly higher for 5 and 30 minutes of irradiation but not for 1 minute of irradiation, respectively, 11.4 MPa, 95% CI (8.5-14.2), versus 17.1 MPa, 95% CI (14.5-19.7), n = 5; P < 0.001, and 9.4 MPa, 95% CI (5.1-13.8) versus 16 MPa, 95% CI (13.1-19), n = 5; P < 0.01, and 11.3 MPa, 95% CI (6-16.6) versus 12.2 MPa, 95% CI (7.5-16.8), n = 5; P = 0.7. CONCLUSIONS: WST-D/near-infrared treatment using shortened irradiation time (1 minute ex vivo and 5 minutes in vivo) results in significant corneal stiffening, and this might provide an alternative to the currently applied riboflavin/ultraviolet A cross-linking. PMID- 28644241 TI - Long-Term Ocular Surface Stability in Conjunctival Limbal Autograft Donor Eyes. AB - PURPOSE: To investigate the incidence of limbal stem cell deficiency (LSCD) in donor eyes after conjunctival limbal autograft (CLAU). METHODS: An observational retrospective review was performed on all patients who underwent CLAU alone, combined keratolimbal allograft with CLAU ("Modified Cincinnati Procedure"), or combined living-related conjunctival limbal allograft (lr-CLAL) with CLAU having >=6 months of follow-up after surgery. The outcome measures were best-corrected visual acuity (BCVA) and ocular surface status. RESULTS: The inclusion criteria were fulfilled by 45 patients. Of these, 26 patients underwent CLAU, 18 underwent combined keratolimbal allograft/CLAU, and 1 underwent combined lr-CLAL/CLAU. Mean age at the time of surgery was 39.6 years. Mean logMAR preoperative BCVA was 0.08. There were no operative complications. The mean follow-up duration after surgery was 48.3 months (range 8.3-181.5 mo). At last follow-up, all eyes maintained a stable ocular surface, and mean logMAR BCVA was -0.05. CONCLUSIONS: With the advent of newer ocular surface transplantation methods, there has been concern that CLAU carries the theoretical risk of inducing LSCD. Our long-term clinical results following donor eyes after CLAU demonstrate no signs of LSCD. PMID- 28644242 TI - Effects of Participation in Sports Programs on Walking Ability and Endurance Over Time in Children With Cerebral Palsy. AB - OBJECTIVE: Children with cerebral palsy may benefit from maintaining a high level of physical fitness similar to typically developing children especially in terms of long-term physical performance, although in practice this is often difficult. The purpose of this study was to determine the effect of participation in sports programs on walking ability and endurance over time. DESIGN: A retrospective cohort study included participants with cerebral palsy, aged 6 to 20 yrs, who attended a summer sports program from 2004 to 2012. There were 256 participant sessions with pre/post data recorded. The participants consisted of a total of 97 children (mean age [SD] = 11.4 [3.1] yrs), many of whom attended multiple programs throughout the years. Programs were held 6 hrs/d, 5 d/wk for up to 4 wks. Outcome measures included the Timed Up and Go, modified 6-min walk, and 25 ft walk/run. RESULTS: The results showed significant improvements in the Timed Up and Go, modified 6-min walk distance and 25-ft walk/run over time. Children in Gross Motor Classification System level III made the largest gains. CONCLUSIONS: Walking ability and endurance seem to improve after participation in an intensive summer sports programs. Higher frequency of program attendance resulted in significant improvements in the Timed Up and Go. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Discuss the importance of physical activity at the participation level (sports programs) for children with cerebral palsy; (2) Contrast the changes in walking ability and endurance for children in Gross Motor Function Classification System level I, II, and III after sports programs; and (3) Identify the impact of higher frequency of sports program attendance over time on walking ability. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.75 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 28644243 TI - Role of Breathing Conditions During Exercise Testing on Training Prescription in Chronic Obstructive Pulmonary Disease. AB - This study investigated whether different breathing conditions during exercise testing will influence measures of exercise capacity commonly used for training prescription in chronic obstructive pulmonary disease. Twenty-seven patients with chronic obstructive pulmonary disease (forced expiratory volume in 1 sec = 45.6 [9.4]%) performed three maximal exercise tests within 8 days, but at least 48 hrs apart. Subjects were thereby breathing either room air through a tightly fitting face mask like during any cardiopulmonary exercise test (MASK), room air without mask (No-MASK), or 10 l/min of oxygen via nasal cannula (No-MASK + O2). Cycling protocols were identical for all tests (start = 20 watts, increment = 10 males/5 females watts/min). Maximal work rate (90.4 [33.8], 100.3 [34.8], 107.4 [35.9] watts, P < 0.001) and blood lactate at exhaustion (4.3 [1.5], 5.2 [1.6], 5.0 [1.4] mmol/l, P < 0.001) were lowest for MASK when compared with No-MASK and No MASK + O2, respectively, whereas maximal heart rate did not differ significantly. Submaximal exertion (Borg rating of perceived exertion = 12-14) was perceived at lower intensity (P = 0.008), but higher heart rate (P = 0.005) when MASK was compared with No-MASK and No-MASK + O2. Different breathing conditions during exercise testing resulted in an 18.8% difference in maximal work rate, likely causing underdosing or overdosing of exercise in chronic obstructive pulmonary disease. Face masks reduced whereas supplemental oxygen increased patients' exercise capacity. For accurate prescription of exercise in chronic obstructive pulmonary disease, breathing conditions during testing should closely match training conditions. PMID- 28644244 TI - Effects of the Integration of Dynamic Weight Shifting Training Into Treadmill Training on Walking Function of Children with Cerebral Palsy: A Randomized Controlled Study. AB - OBJECTIVE: The aim of the study was to determine whether applying an assistance force to the pelvis and legs during treadmill training can improve walking function in children with cerebral palsy. DESIGN: Twenty-three children with cerebral palsy were randomly assigned to the robotic or treadmill only group. For participants who were assigned to the robotic group, a controlled force was applied to the pelvis and legs during treadmill walking. For participants who were assigned to the treadmill only group, manual assistance was provided as needed. Each participant trained 3 times/wk for 6 wks. Outcome measures included walking speed, 6-min walking distance, and clinical assessment of motor function, which were evaluated before, after training, and 8 wks after the end of training, and were compared between two groups. RESULTS: Significant increases in walking speed and 6-min walking distance were observed after robotic training (P = 0.03), but no significant change was observed after treadmill training only. A greater increase in 6-min walking distance was observed after robotic training than that after treadmill only training (P = 0.01). CONCLUSIONS: Applying a controlled force to the pelvis and legs, for facilitating weight-shift and leg swing, respectively, during treadmill training may improve walking speed and endurance in children with cerebral palsy. TO CLAIM CME CREDITS: Complete the self assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) discuss the importance of physical activity at the participation level (sports programs) for children with cerebral palsy; (2) contrast the changes in walking ability and endurance for children in GMFCS level I, II and III following sports programs; and (3) identify the impact of higher frequency of sports program attendance over time on walking ability. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 28644245 TI - Reply to the Letter to the Editor on "Effects of Light-Emitting Diode Therapy on Muscle Hypertrophy, Gene Expression, Performance, Damage, and Delayed-Onset Muscle Soreness: Case-Control Study With a Pair of Identical Twins". PMID- 28644246 TI - Effects of Exercise on the Immune Function of Pediatric Patients With Solid Tumors: Insights From the PAPEC Randomized Trial. AB - The purpose of this study was to assess the effects of an in-hospital exercise intervention during neoadjuvant chemotherapy on the inflammatory profile and immune cell subpopulation in 20 children with solid tumors (control [n = 11] and exercise group [n = 9]). Although no significant interaction (group * time) effect was found with an analysis of variance test, we found a trend toward an interaction effect for natural killer cells expressing the immunoglobulin-like receptor KIR2DS4, with their numbers remaining stable in the exercise group but increasing in controls. Our data support that exercise interventions are safe in pediatric cancer patients with solid tumors during chemotherapy treatment despite its aggressive, immunosuppressive nature. PMID- 28644247 TI - Surface Electromyographic Activity of the Upper Trapezius Before and After a Single Dry Needling Session in Female Office Workers With Trapezius Myalgia. AB - OBJECTIVE: Myofascial pain can be accompanied by a disturbed surface electromyographic (sEMG) activity. Nevertheless, the effect of myofascial treatment techniques, such as dry needling (DN), on the sEMG activity is poorly investigated. Several DN studies also emphasize the importance of eliciting local twitch responses (LTRs) during treatment. However, studies investigating the added value of LTRs are scarce. Therefore, the aims of this study were first to evaluate the effect of DN on the sEMG activity of myalgic muscle tissue, compared with no intervention (rest), and secondly to identify whether this effect is dependent of eliciting LTRs during DN. METHODS: Twenty-four female office workers with work-related trapezius myalgia were included. After completion of a typing task, changes in sEMG activity were evaluated after a DN treatment of the upper trapezius, compared with rest. RESULTS: The sEMG activity increased after rest and after DN, but this increase was significantly smaller 10 minutes after DN, compared with rest. These differences were independent whether LTRs were elicited or not. CONCLUSIONS: Dry needling leads to a significantly lower increase in sEMG activity of the upper trapezius, compared with no intervention, after a typing task. This difference was independent of eliciting LTRs. PMID- 28644248 TI - Are Ultrasonographic Measures of Cervical Flexor Muscles Correlated With Flexion Endurance in Chronic Neck Pain and Asymptomatic Participants? AB - OBJECTIVE: This study compared the relationship between some clinical factors and the size of neck flexors in participants with or without chronic neck pain. DESIGN: In this case-control study, the correlation between flexor endurance capacity as well as thickness, cross-section area, and shape ratio of longus colli/capitis and sternocleidomastoid muscles were examined in 30 patients with chronic neck pain and 30 asymptomatic participants. RESULTS: The patients showed lower flexor endurance (P = 0.02), smaller thickness (P = 0.03), and cross section area (P < 0.01) of longus colli as compared with controls. Longus capitis and sternocleidomastoid size were not different between the two groups. The flexor endurance showed a negative correlation with longus colli shape ratio (r = -0.38, P = 0.03) and a positive correlation with longus capitis cross-section area (r = 0.38, P = 0.03) in the patients with chronic neck pain. In the control group, flexor endurance was negatively correlated with longus colli shape ratio (r = -0.45, P = 0.01) but positively correlated with longus capitis thickness (r = 0.45, P = 0.01) and cross-section area (r = 0.38, P = 0.03). Neck disability and pain intensity indices were not significantly correlated with either flexor muscles endurance or size. CONCLUSIONS: The ultrasonographic measures of the deep neck flexor muscles and the flexor endurance test, being associated with each other, could successfully differentiate patients with chronic neck pain from asymptomatic participants. However, the endurance test scores were not correlated with self-reported disability or pain intensity indices. PMID- 28644249 TI - Incidental Hippocampal Hyperintensity on Diffusion-weighted MRI: Individual Susceptibility to Transient Global Amnesia. AB - OBJECTIVES: Dot-like hippocampal hyperintensities (HHs) on diffusion-weighted MRI (DWI) have been reported as an interesting imaging finding of transient global amnesia (TGA) that is characterized by typical anterograde amnesia. However, we found that these dot-like HHs are occasionally seen in some patients without clinical symptoms of TGA. METHODS: We identified 8 patients who did not show clinical symptoms of TGA, despite the presence of hippocampal lesions on DWI (No TGA group, n=8). For the comparison group, 16 age-matched and sex-matched patients were selected from among patients who had been diagnosed with TGA (TGA group, n=16). RESULTS: No significant difference was found in vascular risk factors, years of education, or underlying cognitive function between the 2 groups. More than half of the patients in each group performed preceding Valsalva associated activities. Multiple hippocampal lesions or concomitant lesions in the cingulate gyrus were found only in the TGA group. CONCLUSIONS: Dot-like HHs on DWI can be observed without the typical symptoms of TGA. Valsalva maneuver associated activities could produce asymptomatic hippocampal lesions. The symptoms of TGA may be presented on a spectrum, from no symptoms to mild vegetative symptoms or to the typical symptoms of TGA, depending on individual susceptibility. PMID- 28644250 TI - Cholesterol Levels and Hemorrhagic Stroke Risk in East Asian Versus Non-East Asian Populations: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The aim of this work was to evaluate the relationships between cholesterol levels and risk of hemorrhagic stroke [including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH)] in East Asian versus non-East Asian populations. MATERIALS AND METHODS: Relevant prospective studies were identified from systematic searches of PubMed and EMBASE. A random-effects model was used to calculate summary relative risks (RRs) and 95% confidence intervals (CIs) that were used to compare the relationships between cholesterol levels and risk of hemorrhagic stroke in East Asian versus non-East Asian populations. RESULTS: In terms of overall hemorrhagic stroke risk, both East Asians and non East Asians displayed no significant difference between high versus low total cholesterol (TC) (RR=1.26, 95% CI, 0.92-1.72; I=74.4%, P<0.001; RR=1.69, 95% CI, 1.15-2.49; I=92.4%, P<0.001, respectively). In terms of ICH risk, East Asians displayed no significant difference between high versus low TC (RR=1.30, 95% CI, 0.89-1.90; I=78.6%, P<0.001), whereas non-East Asians displayed a significant difference between high versus low TC with low TC showing a higher ICH risk (RR=1.70, 95% CI, 1.08-2.67; I=91.2%, P<0.001). With respect to SAH risk, East Asians displayed a significant difference between high versus low TC with low TC showing a higher SAH risk (RR=1.48, 95% CI, 1.057-2.08; I=0%, P=0.682), whereas non-East Asians displayed no significant difference between high versus low TC (RR=1.14, 95% CI, 0.56-2.31; I=89.9%, P<0.001). CONCLUSIONS: Under low cholesterol conditions, East Asian ethnic status favors SAH development, whereas non-East Asian ethnic status favors ICH development. PMID- 28644251 TI - Risk Factors, Etiological Classification, Topographical Location, and Outcome in Medullary Infarctions. AB - An understanding of the etiological mechanisms is important for therapeutic decisions and prognostic evaluation of patients with ischemic stroke. The object of this study was to evaluate the risk factors, etiological subtypes, and topography of lesion in patients with medullary infarctions (MIs). Besides, we also investigated early neurological deterioration, new vascular events, and functional outcome of all patients at 3-month follow-up. We analyzed our database consisting of patients who were diagnosed with acute MI and who were admitted within 24 hours of onset. Etiological classification of stroke was made on the basis of the Trial of Org 1972 in Acute Stroke Treatment criteria. All of the infarctions were grouped into anteromedial, anterolateral, lateral, and posterior arterial territories and also categorized into those involving the upper, middle, or lower medulla oblongata. Early neurological deterioration, major vascular events within the first 3 months of follow-up and modified Rankin Score at 3 months were reviewed. A total of 65 patients with medullary infarctions were reviewed. Involved arterial territories differed according to the etiological classification. Large artery atherosclerosis was the most common etiological subtype; however, small vessel disease was the most common subtype in medial MIs. The lesions involving the anteromedial territory were common in the upper medullary region, whereas the lesions involving the posterior and lateral territories were common in the lower medulla oblangata. Recurrent stroke was seen in the posterior and lateral territories; however, early progression and poor functional outcome were mostly seen in lesions involving the anteromedial territories. PMID- 28644252 TI - Antineuroinflammation of Minocycline in Stroke. AB - Accumulating research substantiates the statement that inflammation plays an important role in the development of stroke. Both proinflammatory and anti inflammatory mediators are involved in the pathogenesis of stroke, an imbalance of which leads to inflammation. Anti-inflammation is a kind of hopeful strategy for the prevention and treatment of stroke. Substantial studies have demonstrated that minocycline, a second-generation semisynthetic antibiotic belonging to the tetracycline family, can inhibit neuroinflammation, inflammatory mediators and microglia activation, and improve neurological outcome. Experimental and clinical data have found the preclinical and clinical potential of minocycline in the treatment of stroke due to its anti-inflammation properties and anti-inflammation induced pathogeneses, including antioxidative stress, antiapoptosis, inhibiting leukocyte migration and microglial activation, and decreasing matrix metalloproteinases activity. Hence, it suggests a great future for minocycline in the therapeutics of stroke that diminish the inflammatory progress of stroke. PMID- 28644254 TI - Sporadic Creutzfeldt-Jakob Disease With Unilateral Symptoms in the Setting of Metastatic Renal Cell Carcinoma. AB - INTRODUCTION: Although it is not rare for magnetic resonance imaging findings in Creutzfeldt-Jakob disease to be asymmetric, unilateral clinical syndromes are uncommonly reported and may confound diagnosis. In addition, neurological paraneoplastic syndromes are not common in renal cell carcinoma, though there are cases reported, often without an offending antibody isolated. CASE REPORT: A 66 year-old man was admitted with 1 month of left-sided numbness and "loss of control" of the left arm. Examination revealed action-induced irregular jerking movements of the left arm. Mental status testing was normal. Magnetic resonance imaging brain revealed patchy areas of restricted diffusion along the cerebral cortices. Screening computed tomographic scans revealed innumerable lung nodules compatible with metastases, as well as a renal mass consistent with renal cell carcinoma. Lumbar puncture was performed and cerebrospinal fluid was sent for paraneoplastic autoantibody evaluation and protein 14-3-3. Over the next week the patient developed dystonic posturing of the left arm, left leg jerking movements, a right arm action tremor, and cognitive impairment. Paraneoplastic autoantibodies were negative. Protein 14-3-3 was elevated and brain biopsy revealed spongiform encephalopathy with positive immunoblotting. The patient died about 2 months from symptom onset. CONCLUSIONS: Creutzfeldt-Jakob disease can present with entirely unilateral myoclonus and numbness, without specific complaints of cognitive impairment. Not every difficult or unclear neurological syndrome in a patient with metastatic cancer is a paraneoplastic syndrome. PMID- 28644253 TI - Spectrum of Autonomic Nervous System Impairment in Sjogren Syndrome. AB - OBJECTIVE: To describe the spectrum of autonomic dysfunction in a uniformly evaluated cohort of patients with Sjogren syndrome. METHODS: A series of 13 patients underwent a comprehensive evaluation for suspected autonomic impairment, including a neurological examination, autonomic testing, and laboratory studies. A diagnosis of Sjogren syndrome was established as the cause of autonomic dysfunction in all. Clinical features, findings on autonomic testing, and laboratory results are described. RESULTS: All patients in this series reported postural lightheadedness and syncope or near-syncope. Autonomic testing confirmed the presence of orthostatic hypotension on tilt-table testing in 5 patients and an excessive postural tachycardia and/or hypertensive response in 8 patients. Only 2 of the patients with orthostatic hypotension had a significant sensory neuropathy. Symptoms suggestive of gastrointestinal and genitourinary impairment were seen in nearly all patients, with abnormal motility testing (most frequently esophageal dysmotility) in 5 of 6 patients who underwent formal testing. Patients in this series treated with immune-modulating therapy experienced significant improvement. CONCLUSIONS: A diagnosis of Sjogren syndrome should be aggressively pursued in patients with signs and symptoms suggestive of autonomic nervous system impairment. Although the spectrum of adrenergic failure is variable, ranging from orthostatic hypotension to an excessive postural tachycardia, most patients do have symptoms of more generalized autonomic failure. Patients who were treated with immune-modulating therapy did improve. PMID- 28644255 TI - Periodic Paralysis and Encephalopathy as Initial Manifestations of Graves' Disease: Case Report and Review of the Literature. AB - BACKGROUND: Thyrotoxic periodic paralysis (TPP) is an uncommon complication of Graves' disease, characterized by the triad of acute hypokalemia without total body potassium deficit, episodic muscle paralysis, and thyrotoxicosis. Graves' encephalopathy is an extremely rare form of encephalopathy associated with autoimmune thyroid disease (EAATD), characterized by neuropsychiatric symptoms, increased antithyroid antibodies and cerebrospinal fluid protein concentration, nonspecific electroencephalogram abnormalities, and cortico-responsiveness. Coexistence of both these complications in the same patient has not been reported before. CASE REPORT: We herein present a 48-year-old white male patient with TPP and encephalopathy as initial presentations of Graves' disease. Flaccid tetraparesis was reversed a few hours after potassium level correction and the patient did not suffer any relapse with the successful pharmaceutical management of the thyroid function. One month later, the patient presented with dizziness and behavioral symptoms, such as inappropriate laughter and anger. Brain magnetic resonance imaging revealed meningeal enhancement and cerebrospinal fluid analysis showed a mild protein increase, with a blood-brain barrier disruption. With the suspicion of EAATD, the patient was treated with high doses of corticosteroids and improved dramatically. CONCLUSIONS: To our knowledge this is the first reported coexistence of potentially treatable TPP and EAATD as initial neurological manifestations of Graves' disease, thereby underscoring the necessity of suspicion of possible underlying Graves' disease in patients with acute paralysis and encephalopathy of unclear origin. PMID- 28644256 TI - Cluster-like Headache Secondary to Focal Cervical Myelitis. AB - BACKGROUND: Cluster headache (CH) is characterized by attacks of severe periorbital pain associated with autonomic symptoms. As with other forms of primary headache, structural lesions should be excluded, particularly if the headache presents with an atypical pattern. CASE: We report a 41-year-old woman who had no previous history of primary headache and showed a poor response to medication for CH. The patient was finally diagnosed as secondary headache with CH feature due to focal myelitis at the cervical level of the spinal cord. A strong positive Enzyme-linked Immunosorbent Assay test for Toxocara canis antibodies helped us to make a diagnosis of cervical Toxocara myelitis. After starting treatment with intravenous methylprednisolone and albendazole, her headache gradually improved with abortive and preventive treatment for CH. CONCLUSIONS: We suggest that neuroimaging of the upper cervical cord as well as the brain is important when CH is showing an atypical clinical course. Cervical Toxocara myelitis might be a possible cause of secondary headache with CH feature. PMID- 28644257 TI - Holmes' Tremor Secondary to Cerebellopontine Angle Epidermoid Cyst. AB - Holmes' tremor is characterized by a combination of rest, postural, and intention tremor. Tremor is predominantly proximal and more severe during posture; however, the tremor frequency is usually <4 Hz on surface electromyography. We report Holmes' tremor in a patient secondary to cerebellopontine angle epidermoid cyst. PMID- 28644258 TI - Multifocal Motor Neuropathy Associated With Infliximab: A Case Report and a Literature Review. AB - Multifocal motor neuropathy with conduction block (MMN-CB) is purely a motor neuropathy with progressive weakness that is characteristically caused by conduction blocks. Association with antiganglioside antibodies and a good response to immunomodulating therapies suggest an autoimmune etiology. In rare cases, MMN-CB has been reported as an adverse effect of infliximab, a tumor necrosis factor-alpha blocker. We present a case of MMN-CB due to infliximab in a 45-year-old man with psoriatic arthritis who was exposed to the drug for 2 years because of a delayed diagnosis. We emphasize the possibility of this adverse effect and the importance of detailed electrophysiological examinations, which is supported by a review of the literature. PMID- 28644259 TI - Antiphospholipid Syndrome With a Distinctive Constellation of Neurological Manifestations: Blue Toes, Red Valves, White Retinal Spots. AB - Antiphospholipid syndrome (APS) encompasses a hypercoagulable state with a markedly increased risk for cerebrovascular complications. In addition to the classic stroke features of APS, however, there are numerous recently described "non-criteria" neurological conditions such as headaches, seizures, and cognitive impairment. We present a case of APS with uncommon neurological manifestations. PMID- 28644260 TI - Intravenous Alteplase for Acute Stroke and Pulmonary Embolism in a Patient With Recent Abdominoplasty. AB - INTRODUCTION: Major surgery in the past 14 days is a relative contraindication to treatment of acute stroke with intravenous (IV) alteplase. The 2016 American Heart Association/American Stroke Association scientific statement discussing inclusion and exclusion criteria for alteplase in acute stroke allows for provider judgment citing a lack of evidence to support surgery as an absolute contraindication. CASE REPORT: A 59-year-old woman presented with acute left hemiparesis, dysarthria, and acute respiratory failure. National Institutes of Health Stroke Scale was 17. Two days prior she underwent abdominoplasty and liposuction. Computed tomography angiogram of the head demonstrated acute occlusion of right M2, and computed tomography angiogram of the chest was positive for bilateral pulmonary emboli. After urgent consultation with the plastic surgery and neurosurgery teams, the patient was treated with IV alteplase followed by cerebral mechanical thrombectomy. This was complicated by surgical site hemorrhage in the abdomen requiring operative intervention. Abdominal hemorrhage was controlled and the patient showed remarkable neurological recovery, later being discharged with no residual neurological deficits. CONCLUSIONS: Interdisciplinary collaboration can successfully inform the decision to treat acute ischemic stroke with IV alteplase in the setting of recent major surgery. PMID- 28644261 TI - Is Intravenous Thrombolysis Safe and Effective in Central Retinal Artery Occlusion? A Critically Appraised Topic. AB - BACKGROUND: Central retinal artery occlusion (CRAO) is a neurological and ophthalmologic emergency associated with poor visual recovery. There is a dilemma regarding the appropriate treatment, as formal guidelines are lacking. Despite being considered an ocular equivalent of cerebral infarction, the time window of intravenous (IV) thrombolysis administration for maximum efficacy and safety in CRAO remains uncertain. OBJECTIVE: To critically assess the current evidence regarding the safety and effectiveness of IV thrombolysis in the treatment of patients with CRAO. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, and content experts in the fields of vascular neurology and ophthalmology. RESULTS: A recent patient level meta-analysis was selected for critical appraisal. The study compared the visual recovery rates after IV thrombolysis in CRAO against the natural history of this illness and conservative therapies (ocular massage, anterior chamber paracentesis, and/or hemodilution). Time to thrombolytic therapy administration had a significant impact on visual recovery in CRAO (P<0.001). IV thrombolysis within the first 4.5 hours after symptom onset resulted in recovery of vision in 50.0% of the patients [95% confidence interval (CI), 32.4%-67.6%]. The rate of visual recovery was nearly 3 times higher than in the natural history cohort [odds ratio, 4.7 (95% CI, 2.3-9.6); P<0.001], with a 32.3% absolute risk reduction and a number needed to treat of 4.0 (95% CI, 2.6-6.6). There was no significant difference in the recovery rate after thrombolysis compared with the natural history cohort for those patients treated after 4.5 hours. No major hemorrhages occurred after alteplase administration in this meta-analysis. CONCLUSIONS: IV thrombolysis in CRAO seems to be safe and effective within the first 4.5 hours of symptom onset. A clinical decision based on this meta-analysis alone cannot be made due to several limitations. A randomized controlled clinical trial of early IV alteplase administration in CRAO is necessary to provide evidence-based therapeutic guidance. PMID- 28644262 TI - Host-related Risk Factors for Adherent Perinephric Fat in Healthy Individuals Undergoing Laparoscopic Living-donor Nephrectomy. AB - PURPOSE: The purpose of this study is to assess the risk factors and characteristics of adherent perinephric fat (APF) in healthy individuals. PATIENTS AND METHODS: Men who underwent laparoscopic donor nephrectomy were included. Video review was used to divide patients on the basis of APF severity. Relationship between APF scores and clinical and radiographic features was evaluated. RESULTS: Of the 92 patients, 43 (46.7%) and 8 (8.7%) were categorized as APF and severe APF, respectively. The median total operative time was significantly associated with APF severity. Sex, body mass index, and perinephric fat area, stranding, and thickness were significantly associated with severe APF. In the multivariate analysis, perinephric fat areas and stranding were independent risk factors for severe APF (HR, 1.189 and 14.450, respectively). In the 44 analyzed cytokines, levels of sIL-6R in the perinephric adipose tissue conditioned medium were significantly higher for APF group than that for non-APF group (P=0.049). CONCLUSIONS: Host-related risk factors for APF could predict surgical difficulty in patients undergoing partial nephrectomy. PMID- 28644263 TI - Mind the Facts. AB - Nurses must become active in protecting science and evidence-based decision making. PMID- 28644264 TI - Forever Hold Your Peace: When Preprocedure Safety Concerns Are Missed. AB - A near-miss experience highlights a limitation of time-out protocols. PMID- 28644265 TI - Monitoring Opioid-Induced Respiratory Depression. PMID- 28644266 TI - Monitoring Opioid-Induced Respiratory Depression. PMID- 28644267 TI - Cultural Competence. PMID- 28644268 TI - Risk Tools vs. Nurse Perception. PMID- 28644269 TI - Risk Tools vs. Nurse Perception. PMID- 28644270 TI - New Immunization Initiatives Show Promise. AB - Nurses can play an important role in improving public understanding of the benefits of vaccination. PMID- 28644271 TI - Norepinephrine Shortage Led to Increased Deaths from Septic Shock. AB - Though drug shortages are common, their impact is rarely studied. PMID- 28644273 TI - Nursing Protocol for Stroke Increases Survival, Reduces Disability. AB - Fever, hyperglycemia, and swallowing problems were treated in the first 72 hours following stroke. PMID- 28644276 TI - An Innovative Syringe Exchange Program. AB - Nevada's pilot vending machine program encourages users to enter treatment programs. PMID- 28644279 TI - The Growing Trend of Medical Tourism. AB - What nurses need to know about the risks and benefits for patients. PMID- 28644282 TI - Does Chewing Gum Promote Bowel Function After Cesarean Section? AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. For more information, see http://nursingcare.cochrane.org. PMID- 28644283 TI - New Drug For Multiple Sclerosis. PMID- 28644284 TI - New Drug Approved For Parkinson's Disease. PMID- 28644285 TI - Injectable Drug Approved for Moderate-to-Severe Eczema. PMID- 28644289 TI - The Growing Need for Diverse Blood Donors. AB - : Research shows that phenotype matching can improve the outcomes of people who receive repeated transfusions. In addition, the demographics of the United States are shifting, and more ethnically and racially diverse donors are needed. These factors have health implications and require ongoing efforts to ensure a safe and adequate U.S. blood supply. Nurses can help to develop and implement strategies to increase the number and diversity of blood donors, ensuring donations better match the needs of transfusion recipients daily and in the event of a public health emergency. PMID- 28644290 TI - Could Emotional Intelligence Make Patients Safer? AB - : The vast majority of medical errors occurring each year involve faulty communication. For this reason, it's essential that we identify skills that support accurate communication and information transfer as well as optimum patient-centered care, team function, and patient safety. Research in nursing and other disciplines has demonstrated that emotional intelligence abilities improve communication, support constructive conflict resolution, and improve individual and team performance. Although further studies are needed, these findings suggest emotional intelligence ability can positively affect patient safety. PMID- 28644291 TI - The Significant and the Superficial. AB - Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely-and often more personal perspectives on professional, policy, and clinical issues. Best of the Blog will be a regular column to draw the attention of AJN readers to posts we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com. PMID- 28644292 TI - Ethical Nursing Care When the Terminally Ill Patient Seeks Death. PMID- 28644293 TI - There from the Start: A Hospice Nurse Looks Back. AB - Dianne Puzycki has worked for the first U.S. hospice since its inception. PMID- 28644294 TI - Exercise and Psychological Interventions are Best for Cancer-Related Fatigue. PMID- 28644295 TI - Internet-Delivered Intervention Is Beneficial for Chronic Knee Pain. PMID- 28644296 TI - Lack of Paid Sick Leave Reduces Use of Preventive Health Care Services. PMID- 28644297 TI - Health Effects Following the Suicide of a Spouse. PMID- 28644298 TI - Omission of High-Alert Medications: A Hidden Danger. AB - The Pennsylvania Patient Safety Reporting System is a confidential, statewide Internet reporting system to which all Pennsylvania hospitals, outpatient-surgery facilities, birthing centers, and abortion facilities must file information on incidents and serious events.Safety Monitor is a column from Pennsylvania's Patient Safety Authority, the authority that informs nurses on issues that can affect patient safety and presents strategies they can easily integrate into practice. For more information on the authority, visit www.patientsafetyauthority.org. For the original article discussed in this column or for other articles on patient safety, click on "Patient Safety Advisories" and then "Advisory Library" in the left-hand navigation menu. PMID- 28644299 TI - An Inconsolable Loss. AB - A nurse's injury costs her far more than mobility. PMID- 28644300 TI - Breathlessness in the primary care setting. AB - PURPOSE OF REVIEW: Breathlessness is a high-volume problem with 10% of adults experiencing the symptom daily placing a heavy burden on the health and wider economy. As it worsens, they enter the specialist and hospital-based symptom services where costs quickly escalate and people may find themselves in a place not of their choosing. For many, their care will be delivered by a disease or organ specialist and can find themselves passing between physicians without coordination for symptom support. General practitioners (GPs) will be familiar with this scenario and can often feel out of their depth. Recent advances in our thinking about breathlessness symptom management can offer opportunities and a sense of hope when the GP is faced with this situation. RECENT FINDINGS: Original research, reviews and other findings over the last 12-18 months that pertain to the value that general practice and the wider primary care system can add, include opportunities to help people recognize they have a problem that can be treated. We present systems that support decisions made by primary healthcare professionals and an increasingly strong case that a solution is required in primary care for an ageing and frail population where breathlessness will be common. SUMMARY: Primary care practitioners and leaders must start to realize the importance of recognizing and acting early in the life course of the person with breathlessness because its impact is enormous. They will need to work closely with public health colleagues and learn from specialists who have been doing this work usually with people near to the end of life translating the skills and knowledge further upstream to allow people to live well and remain near home and in their communities. PMID- 28644301 TI - Palliative oxygen for chronic breathlessness: what new evidence? AB - PURPOSE OF REVIEW: Supplemental oxygen improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxaemia, but the effect of oxygen therapy in mild or moderate hypoxaemia to reduce symptomatic chronic breathlessness remains unclear. This review provides an overview of recent evidence about the role of oxygen therapy for the relief of chronic breathlessness in advanced illness. RECENT FINDINGS: In COPD, a recent Cochrane review strengthens earlier findings regarding the positive effect of supplemental oxygen compared with air during exercise test in the training setting. The novel analysis of effect of oxygen therapy on quality of life (QoL) showed no clear effect. Short-burst oxygen therapy given before exercise had no effect and should not be used. SUMMARY: Supplemental oxygen during exercise has been shown to reduce breathlessness in patients with COPD who have no or mild hypoxaemia, but it is not clear whether the reduction in breathlessness shown in the laboratory setting translates into a clinically important benefit. Further studies are needed to establish this. PMID- 28644302 TI - The role of bone-targeted therapies for prostate cancer in 2017. AB - PURPOSE OF REVIEW: Bone-targeted agents (BTAs), such as zoledronic acid and denosumab, delay the occurrence of skeletal-related events (SREs) in metastatic prostate cancer (PCa) patients. Recently, several agents, such as abiraterone acetate, enzalutamide and radium-223, were approved for the treatment of metastatic castration-resistant PCa (mCRPC). These agents resulted in improved overall survival (OS), pain control and had positive effects on bone health. Combining BTAs to the newly approved agents demonstrates additional benefits that warrant a review of available evidence looking at appropriate combination therapies and timing of BTAs for optimizing the management of advanced and metastatic PCa. RECENT FINDINGS: Post-hoc analyses of randomized trials demonstrated some benefits from combination therapy, such as increased OS when denosumab was used concurrently with radium-223 and when BTAs were used with abiraterone acetate. BTAs were not beneficial for the prevention of bone metastases. SUMMARY: There is a suggestion of synergy or additive effects between BTAs and new agents approved for the treatment of metastatic PCa, resulting in potential clinical benefits. Therefore, prospective randomized studies evaluating the safety and benefits of combination therapies to address gaps in the literature are needed to optimize treatment of mCRPC. PMID- 28644303 TI - Prostate cancer immunotherapy: the path forward. AB - PURPOSE OF REVIEW: To provide an overview of current strategies being investigated in the development of immunotherapy in prostate cancer. RECENT FINDINGS: Development of immunotherapy in prostate cancer actually began in 2010 with FDA approval of sipuleucel-T. Given that immune checkpoint inhibitor trials have either been negative at the phase III level or underwhelming in smaller studies, it is likely that combination strategies will be required to further maximize the impact immune-based therapies on the clinical course of the disease. Emerging data suggests the presence of multiple checkpoint inhibitors in the prostate cancer tumor microenvironment highlighting the need for combination immunotherapy platforms that would potentially include androgen deprivation, chemotherapy, or radiation. SUMMARY: Preclinical and clinical data support immune based combinations in prostate cancer and several trials are underway to better define the future of immunotherapy in prostate cancer. PMID- 28644305 TI - Management of In-the-Bag Intraocular Lens Dislocation Into Vitreous Cavity With Temporary 10-0 Polypropylene Suture Support and Ab-Externo Scleral Fixation. PMID- 28644306 TI - The Associations of Height-for-Age, Weight-for-Age, and Weight-for-Height With Pediatric Acute Lymphoblastic Leukemia. AB - Height at diagnosis has been analyzed in connection with acute lymphoblastic leukemia (ALL). Most prior studies have compared cases to national reference data derived from previous birth cohorts. Our objective was to determine the association of height-for-age Z score (HAZ) at time of diagnosis with the odds ratio (OR) of ALL in a case-control study (N=498) with a contemporaneous population of age-matched, sex-matched, and ethnicity-matched controls. We hypothesized that cases would have greater mean HAZ at time of diagnosis/interview, after adjustment for weight-for-age (WAZ) and weight-for height (WHZ). HAZ was not associated with ALL. For each 1 SD increase in WAZ the OR of ALL was 0.83 (95% confidence interval [CI], 0.68-0.99). The OR of ALL was increased among children who had either a WAZ <=-2 (OR, 5.10; 95% CI, 1.85-16.75) or WHZ of <=-2 (OR, 5.27; 95% CI, 1.65-23.61). Previous findings of taller height among ALL cases may arise from the choice of control populations. Children with low WAZ or WHZ were at increased odds of ALL. PMID- 28644304 TI - ABNORMAL RETINAL REFLECTIVITY TO SHORT-WAVELENGTH LIGHT IN TYPE 2 IDIOPATHIC MACULAR TELANGIECTASIA. AB - PURPOSE: Macular telangiectasia Type 2 (MacTel) is a bilateral, progressive, potentially blinding retinal disease characterized by vascular and neurodegenerative signs, including an increased parafoveal reflectivity to blue light. Our aim was to investigate the relationship of this sign with other signs of macular telangiectasia Type 2 in multiple imaging modalities. METHODS: Participants were selected from the MacTel Type 2 study, based on a confirmed diagnosis and the availability of images. The extent of signs in blue-light reflectance, fluorescein angiographic, optical coherence tomographic, and single- and dual-wavelength autofluorescence images were analyzed. RESULTS: A well defined abnormality of the perifovea is demonstrated by dual-wavelength autofluorescence and blue-light reflectance in early disease. The agreement in area size of the abnormalities in dual-wavelength autofluorescence and in blue light reflectance images was excellent: for right eyes: rho = 0.917 (P < 0.0001, 95% confidence interval 0.855-0.954, n = 46) and for left eyes: rho = 0.952 (P < 0.0001, 95% confidence interval 0.916-0.973, n = 49). Other changes are less extensive initially and expand later to occupy that area and do not extend beyond it. CONCLUSION: Our findings indicate that abnormal metabolic handling of luteal pigment and physical changes giving rise to increased reflectance are widespread in the macula throughout the natural history of the disease, precede other changes, and are relevant to early diagnosis. PMID- 28644307 TI - X-linked Sideroblastic Anemia in a Malay Boy With ALAS2 S568G Mutation. AB - Dimorphism in peripheral blood film was noted in a 16 year old Malay boy with anemia who was eventually diagnosed with X-linked sideroblastic anemia. A mutation in ALAS2 S568G was identified which has not been described previously in a Malay ethnic group. PMID- 28644308 TI - The Use of 5-Aminosalicylic Acid in Children and Adolescents With Inflammatory Bowel Disease. AB - BACKGROUND: In ulcerative colitis (UC) 5-aminosalicylic acid (5-ASA) is recommended as primary therapy for mild to moderate disease. Topical 5-ASA has been proven especially effective. In Crohn's disease (CD) the evidence for a beneficial role of 5-ASA is weak. We investigated the use of topical and systemic 5-ASA therapy in children and adolescents with inflammatory bowel disease. MATERIALS AND METHODS: Data of patients younger than 18 years, registered between April 2008 and December 2015 in the Swiss Inflammatory Bowel Disease Cohort, were analyzed. RESULTS: Three hundred twenty pediatric inflammatory bowel disease patients were included; 189 with CD and 131 with UC. Over one third of UC patients [51 (39%)] received topical 5-ASA therapy and 43 (33%) received combination therapy during their disease course. UC patients with left-sided colitis or proctitis were more likely to receive topical or combination therapy as compared with patients with pancolitis (P<0.001 and <0.001, respectively). An increase in the use of topical 5-ASA therapy in UC patients was noted over time from 5% to 38%. Forty-seven percent of CD patients were treated with oral 5-ASA during their disease course. The usage was stable over time at approximately 15% to 20%. CONCLUSIONS: In recent years a very positive trend showing an increase in topical 5-ASA therapy in children and adolescents with UC has been observed. However topical therapy is still used with relative low frequency, especially in patients with a more extensive disease. Conversely, despite weak evidence supporting 5-ASA use in CD patients it has been frequently prescribed. Physicians should continue to encourage their UC patients to use topical therapy. PMID- 28644309 TI - The Use of a Stylet in Endoscopic Ultrasound With Fine-Needle Aspiration: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is the most efficacious way to collect specimens from a solid lesion adjacent to the gastrointestinal tract and is performed with an internal stylet during puncture. However, its reinsertion into the needle is time-consuming. Controversy surrounds whether quality of cytology specimen improves with stylet use. We performed a meta-analysis comparing the use of stylet versus no stylet with EUS-FNA of gastrointestinal-related masses. METHODS: Multiple databases were searched from inception until April 28, 2016. Discordant findings from independent extractions were reviewed by at least 2 investigators. Methods were executed as per the standards of the Cochrane Collaboration. Primary outcomes assessed were diagnostic adequacy of individual specimen samples, accuracy, and yield. Secondary outcomes included overall diagnostic accuracy of per-malignant lesion, cellularity, contamination, and bloodiness of the sample, and adverse events. RESULTS: Five randomized control trials were identified comparing stylet versus no stylet use, which enrolled 504 patients, evaluated 537 lesions, and 1914 distinct specimens. There was no difference in diagnostic adequacy [risk ratio (RR)=1.00; 95% confidence interval (CI), 0.95-1.07], accuracy (RR=0.98; 95% CI, 0.90-1.06), or yield (RR=0.96; 95% CI, 0.89-1.03). No stylet use was favored in per-lesion malignant diagnosis (RR=0.85; 95% CI, 0.76-0.96). There was no difference in representative cellularity, contamination, or bloodiness of specimens obtained with or without stylet use. CONCLUSIONS: Stylet use confers no significant advantage in diagnostic adequacy, accuracy, yield, contamination, bloodiness, or cellularity over no stylet. We reinforce that no stylet use may be used preferentially in EUS-FNA as a more convenient technique and is favored with a higher per-lesion malignant diagnosis. PMID- 28644310 TI - Predictors of Mortality in Cirrhosis Inpatients With Clostridium difficile Infection. AB - BACKGROUND: Clostridium difficile is a bacterial pathogen associated with significant morbidity and mortality in patients with cirrhosis. GOALS: Our primary aim is to identify variables that are predictive of poor outcomes in cirrhosis patients with C. difficile infection (CDI). We also aim to further characterize the risk factors for developing CDI and risk of mortality in this patient population. STUDY: A total of 200 subjects with a diagnosis of cirrhosis and CDI were matched to 200 cirrhosis inpatients without CDI. The groups were compared to evaluate variables associated with decreased survival for cirrhosis inpatients with CDI as well as risk factors for developing CDI. RESULTS: Cirrhosis patients with CDI were more frequently prescribed antibiotics during their hospitalization (P=0.002) and cared for in an intensive care unit (ICU) (P<0.001). Preadmission proton pump inhibitor and spontaneous bacterial peritonitis (SBP) prophylactic antibiotic use were not significantly different between the 2 cohorts. CDI subjects had an increased 30-day mortality (44% vs. 28.5%, P=0.034), however overall mortality was not significantly different (P=0.2). The multivariable logistic regression model demonstrated an increased 30 day and overall mortality in the CDI population was independently associated with albumin <3 g/dL and ICU admission. CONCLUSIONS: C. difficile infections are associated with a significant increase in 30-day mortality, but not overall mortality. Risk factors of ICU admission and antibiotic exposure were associated with the diagnosis of CDI in cirrhosis patients. Hypoalbuminemia and ICU admission were found to be strong predictors of increased mortality in cirrhosis patients with CDI. PMID- 28644312 TI - Early Infections and the Risk of Irritable Bowel Syndrome: A Case-Control Study. AB - GOALS: The goal of this study is to evaluate the association between early life infections and subsequent adult onset irritable bowel syndrome (IBS). BACKGROUND: Infections during adulthood are a known risk factor for adult-onset IBS. This investigation examined the role of childhood infections and infection risk factors in the development of IBS symptoms. STUDY: In total, 1010 subjects (509 outpatients with IBS, 501 matched controls) were mailed questionnaires regarding early-life infections during infancy (0 to 12 mo), toddler years (1 to 3 y), and child years (4 to 18 y). Comparisons between cases and controls were performed using logistic regression adjusting for age, gender, and somatization score. RESULTS: Around 648 (64.2%) subjects responded. The median age was 51.3 years (range, 18.0 to 70.7 y) and 535 (83%) were female. Childhood (below 18 y) infections were common in cases and controls (98% vs. 98%; P=0.465), with no differences between cases and controls during infant, toddler, and child-age periods. For gastrointestinal infections experienced below 18 years, no differences were observed by infection type (bacterial, viral, or parasitic) or age group. Cases were more likely to report bronchitis by age 18 [43% vs. 25%; P=0.003; odds ratio, 1.73 (1.20-2.51)], but not other common infections. Regular antibiotic exposure was greater amongst cases (43%) than controls (30%) [P=0.09; odds ratio, 1.37 (0.96-1.96)]. The association between bronchitis and IBS case status remained significant after adjusting for antibiotic use (P=0.01). CONCLUSIONS: Greater early childhood gastrointestinal infections rates were not observed in adult individuals with IBS compared with adult controls. The study does not support a statistically significant link between early life infections and IBS aside from bronchitis. PMID- 28644311 TI - Hemobilia: An Uncommon But Notable Cause of Upper Gastrointestinal Bleeding. AB - GOAL AND BACKGROUND: A literature review to improve practitioners' knowledge and performance concerning the epidemiology, diagnosis, and management of hemobilia. STUDY: A search of Pubmed, Google Scholar, and Medline was conducted using the keyword hemobilia and relevant articles were reviewed and analyzed. The findings pertaining to hemobilia etiology, investigation, and management techniques were considered and organized by clinicians practiced in hemobilia. RESULTS: The majority of current hemobilia cases have an iatrogenic cause from either bile duct or liver manipulation. Blunt trauma is also a significant cause of hemobilia. The classic triad presentation of right upper quadrant pain, jaundice, and upper gastrointestinal bleeding is rarely seen. Computed tomography and magnetic resonance imaging are the preferred diagnostic modalities, and the preferred therapeutic management includes interventional radiology and endoscopic retrograde cholangiopancreatography. Surgery is rarely a therapeutic option. CONCLUSIONS: With advances in computed tomography and magnetic resonance imaging technology, diagnosis with these less invasive investigations are the favored option. However, traditional catheter angiography is still the gold standard. The management of significant hemobilia is still centered on arterial embolization, but arterial and biliary stents have become accepted alternative therapies. PMID- 28644313 TI - Unique Clinical Features of Los Angeles Grade D Esophagitis Suggest That Factors Other Than Gastroesophageal Reflux Contribute to its Pathogenesis. AB - BACKGROUND: The Los Angeles (LA) grade of reflux esophagitis (A to D) is assumed to reflect severity of the underlying gastroesophageal reflux disease (GERD). Thus, LA-D esophagitis patients might be expected to have the most conditions predisposing to GERD (eg, obesity, hiatal hernia), and the highest frequency of GERD symptoms. GOALS: The main goal of this study is to compare clinical features of patients with the most severe (LA-D) and mildest (LA-A) grades of esophagitis. STUDY: For this comparative study, we searched our endoscopy database for patients diagnosed with LA-D or LA-A esophagitis, reviewed their endoscopic images, and reviewed medical records of the first 100 we confirmed to have LA-D or LA-A esophagitis. RESULTS: Compared with LA-A patients, LA-D patients were older (mean age, 65+/-13.4 vs. 56+/-13.4 y; P<0.001), had lower body mass index (25.9+/-5.6 vs. 29.4+/-5.3; P<0.001), were more frequently hospitalized (70% vs. 3%; P<0.001), and in the intensive care unit (15% vs. 0%; P<0.001), and had significantly more serious cardiopulmonary disorders and gastrointestinal bleeding. Conversely, a GERD history was more common in LA-A than LA-D patients (67% vs. 45%; P=0.002). Hiatal hernia was more frequent in LA-A patients than LA D patients, but not significantly (48% vs. 36%; P=0.09). CONCLUSIONS: LA-D esophagitis primarily affects hospitalized, older, nonobese patients who often have serious comorbidities, and no history of GERD or hiatal hernia. In contrast, LA-A patients are generally younger, obese outpatients who often have a history of GERD and hiatal hernia without serious comorbidities. These profound differences between LA-A and LA-D patients suggest that factors other than typical GERD contribute to LA-D esophagitis pathogenesis. PMID- 28644314 TI - Prone or Left for Colonoscopy? A Randomized Controlled Trial of Prone Versus Left sided Starting Position for Colonoscopy. AB - BACKGROUND AND AIMS: Data have emerged supporting the right-lateral starting position in reducing time to cecum and improving patient comfort for minimally sedated colonoscopy. We aimed to test whether prone starting position results in similar advantages in procedure time and patient tolerability in comparison to traditional left-sided starting position. MATERIALS AND METHODS: We conducted a randomized controlled trial in which patients were randomized to begin in either the prone or left-lateral (LL) position. A total of 181 adult patients undergoing scheduled colonoscopy were stratified by age, gender, body mass index, and experience of the endoscopist. Patients were then randomized 1:1 in permuted blocks. The primary outcome measure was time to cecal intubation and secondary outcome measures included patient comfort that was measured by visual analog scale. RESULTS: There was no benefit from prone starting positioning over conventional left-sided starting positioning. Further, prone starting position led to an increase in time to reach cecum (701 vs. 511 s; P=0.01). This could be in part explained by an increased time to reach transverse colon in patients positioned prone (332 vs. 258 s; P=0.06). Comfort levels were similar between patients positioned prone and LL (4 vs. 4 visual analog scale; P=0.6) although endoscopists found colonoscopies in which patients started prone more technically challenging than if started LL (5 vs. 4; P=0.002). CONCLUSIONS: Prone starting position did not improve time to reach cecum or patient comfort for minimally sedated patients undergoing colonoscopy. The ClinicalTrials.gov identifier is NCT02305706. PMID- 28644315 TI - Management of Eosinophilic Esophagitis Based on Pathophysiological Evidence. AB - Over the past decades eosinophilic esophagitis (EoE) has been increasingly diagnosed, and significant progress has been made in our understanding of its pathophysiology. As EoE cannot be cured yet, treatment goals are suppression of disease activity and symptoms as well as the prevention of progression to a more severe disease phenotype. Disease-modifying treatment options can be divided into dietary therapy and immunosuppressive medications, of which topical steroids have been most investigated, yet are still prescribed off-label. In this review, we will summarize recent advances in our understanding of EoE and discuss the mechanisms of action of current treatment options, with emphasis on the role of the esophageal epithelial barrier and the effects of proton-pump inhibitors in the management of patients with EoE. PMID- 28644316 TI - A Multicenter Evaluation of Adherence to 4 Major Elements of the Baveno Guidelines and Outcomes for Patients With Acute Variceal Hemorrhage. AB - GOALS: To determine the rate of and outcomes associated with guideline adherence in the care of acute variceal hemorrhage (AVH). BACKGROUND: Four major elements of high-quality care for AVH defined by the Baveno consensus (VI) include timely endoscopy (<=12 h), antibiotics, and somatostatin analogs before endoscopy and band ligation as primary therapy for esophageal varices. STUDY: We retrospectively evaluated 239 consecutive admissions of 211 patients with AVH admitted to 2 centers in Massachusetts from 2010 to 2015. The primary outcome was 6-week mortality; secondary outcomes included treatment failure (shock, hemoglobin drop by 3 g/dL, hematemesis, death <=5 d), length of stay, and 30-day readmission. RESULTS: Guideline adherence was variable: endoscopy <=12 hours (79.9%), antibiotics (84.9%), band ligation (78.7%), and somatostatin analogs (90.8%). However, only 150 (62.8%) received care that was adherent to all indicated criteria. The 6-week mortality rate was 22.6%. Treatment failure occurred in 50 (21.0%) admissions. Among the 198 patients who survived to discharge, 41 (20.7%) were readmitted within 30 days. Octreotide before endoscopy was associated with a reduction in 30-day readmission (18.4% vs. 42.1%; P=0.03), whereas banding of esophageal varices was associated with a reduced risk of treatment failure (15.0% vs. 50.0%; P<=0.001). However, adherence to quality metrics did not significantly reduce the risk of death within 6 weeks. CONCLUSIONS: Adherence to quality metrics may not reduce the risk of mortality but could improve secondary outcomes of AVH. Variation in practice should be addressed through quality improvement interventions. PMID- 28644317 TI - Group B Streptococci Screening Before Repeat Cesarean Delivery: A Cost Effectiveness Analysis. PMID- 28644318 TI - In Reply. PMID- 28644319 TI - Acute Respiratory Distress Syndrome in Pregnant Women. PMID- 28644320 TI - In Reply. PMID- 28644321 TI - Sildenafil Citrate Therapy for Oligohydramnios: A Randomized Controlled Trial. PMID- 28644322 TI - In Reply. PMID- 28644326 TI - Table of Contents for Online Material in the June 2017 Issue. AB - Abstracts or summaries of online content are printed in every issue of Obstetrics & Gynecology in this section. The complete documents can be found on our website, www.greenjournal.org. The specific URL for the content in this section is printed at the end of the abstract or summary. PMID- 28644328 TI - Practice Bulletin No. 179 Summary: Breast Cancer Risk Assessment and Screening in Average-Risk Women. AB - Breast cancer is the most commonly diagnosed cancer in women in the United States and the second leading cause of cancer death in American women (1). Regular screening mammography starting at age 40 years reduces breast cancer mortality in average-risk women (2). Screening, however, also exposes women to harm through false-positive test results and overdiagnosis of biologically indolent lesions. Differences in balancing benefits and harms have led to differences among major guidelines about what age to start, what age to stop, and how frequently to recommend mammography screening in average-risk women (2-4).Breast cancer risk assessment is very important for identifying women who may benefit from more intensive breast cancer surveillance; however, there is no standardized approach to office-based breast cancer risk assessment in the United States. This can lead to missed opportunities to identify women at high risk of breast cancer and may result in applying average-risk screening recommendations to high-risk women. Risk assessment and identification of women at high risk allow for referral to health care providers with expertise in cancer genetics counseling and testing for breast cancer-related germline mutations (eg, BRCA), patient counseling about risk-reduction options, and cascade testing to identify family members who also may be at increased risk.The purpose of this Practice Bulletin is to discuss breast cancer risk assessment, review breast cancer screening guidelines in average-risk women, and outline some of the controversies surrounding breast cancer screening. It will present recommendations for using a framework of shared decision making to assist women in balancing their personal values regarding benefits and harms of screening at various ages and intervals to make personal screening choices from within a range of reasonable options. Recommendations for women at elevated risk and discussion of new technologies, such as tomosynthesis, are beyond the scope of this document and are addressed in other publications of the American College of Obstetricians and Gynecologists (ACOG) (5-7). PMID- 28644329 TI - Practice Bulletin No. 180 Summary: Gestational Diabetes Mellitus. AB - GESTATIONAL DIABETES MELLITUS: Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. However, debate continues to surround the diagnosis and treatment of GDM despite several recent large-scale studies addressing these issues. The purposes of this document are the following: 1) provide a brief overview of the understanding of GDM, 2) review management guidelines that have been validated by appropriately conducted clinical research, and 3) identify gaps in current knowledge toward which future research can be directed. PMID- 28644330 TI - Committee Opinion No 705 Summary: Mental Health Disorders In Adolescents. AB - Mental health disorders in adolescence are a significant problem, relatively common, and amenable to treatment or intervention. Obstetrician-gynecologists who see adolescent patients are highly likely to see adolescents and young women who have one or more mental health disorders. Some of these disorders may interfere with a patient's ability to understand or articulate her health concerns and appropriately adhere to recommended treatment. Some disorders or their treatments will affect the hypothalamic-pituitary-gonadal axis, causing anovulatory cycles and various menstrual disturbances. Adolescents with psychiatric disorders may be taking psychopharmacologic agents that can cause menstrual dysfunction and galactorrhea. Adolescents with mental illness often engage in acting-out behavior or substance use, which increases their risk of unsafe sexual behavior that may result in pregnancy or sexually transmitted infections. Pregnant adolescents who take psychopharmacologic agents present a special challenge in balancing the potential risks of fetal harm with the risks of inadequate treatment. Whether providing preventive women's health care or specific obstetric or gynecologic treatment, the obstetrician-gynecologist has the opportunity to reduce morbidity and mortality from mental health disorders in adolescents by early identification, appropriate and timely referral, and care coordination. Although mental health disorders should be managed by mental health care professionals or appropriately trained primary care providers, the obstetrician-gynecologist can assist by managing the gynecologic adverse effects of psychiatric medications and providing effective contraception and regular screening for sexually transmitted infections. This Committee Opinion will provide basic information about common adolescent mental health disorders, focusing on specific implications for gynecologic and obstetric practice. PMID- 28644331 TI - Committee Opinion No 706 Summary: Sexual Health. AB - Sexuality involves a broad range of expressions of intimacy and is fundamental to self-dentification, with strong cultural, biologic, and psychologic components. Obstetrician-gynecologists often are consulted by patients about sexual health and are in a unique position to open a dialogue on sexual health issues. Several obstacles to frank conversations with patients about sexual health exist, including a lack of adequate training and confidence in the topic, a perception that there are few treatment options, a lack of adequate clinical time to obtain a sexual history, patients' reluctance to initiate the conversation, and the underestimation of the prevalence of sexual dysfunction. However, data on reproductive and sexual health morbidity suggest sexual health is an important health care issue. Each year, an estimated 45,000 new cases of human immunodeficiency virus (HIV) and approximately 20 million sexually transmitted infections occur, 3 million women experience unintended pregnancies, and 1 million women are sexually assaulted. Openly discussing sexual health has the potential to prevent these unnecessary sexual health-related outcomes. Clinical conversations should acknowledge the contributions of sexuality, relationships, and sexual behavior to overall health. Obstetrician-gynecologists can address sexual health issues across a lifespan with their patients and encourage a strategic foundation for women's sexual health issues, resulting in improved public health overall. Obstetrician-gynecologists also can support policies that broaden the coalition for effective prevention of sexually transmitted infections and promote healthy sexuality, with the ultimate goal of improving health outcomes and public health. PMID- 28644333 TI - Committee Opinion No. 708 Summary: Improving Awareness of and Screening for Health Risks Among Sex Workers. AB - The population of women who sell or exchange sex or intimate sexual services for material goods or services, also called "sex work," often is unrecognized in the typical obstetric and gynecologic practice. The prevalence of this behavior among adult women is difficult to quantify because of its frequent omission from the routine sexual history by women and clinicians. Data on the prevalence of sex work in the United States are largely lacking. The American College of Obstetricians and Gynecologists supports increasing awareness about the health risks, preventive care needs, and limited health care services for female sex workers. PMID- 28644332 TI - Committee Opinion No. 707 Summary: Access to Emergency Contraception. AB - Emergency contraception refers to contraceptive methods used to prevent pregnancy in the first few days after unprotected intercourse, sexual assault, or contraceptive failure. Although the U.S. Food and Drug Administration approved the first dedicated product for emergency contraception in 1998, numerous barriers to emergency contraception remain. The purpose of this Committee Opinion is to examine barriers to the use of emergency contraception, emphasize the importance of increasing access, and review new methods of emergency contraception and limitations in efficacy in special populations. PMID- 28644334 TI - Clinical Updates in Women's Health Care Summary: Gynecologic and Obstetric Care for Breast Cancer Survivors: Primary and Preventive Care Review. AB - Breast cancer treatment has an impact on the physical, psychologic, sexual, and reproductive aspects of women's lives. Therefore, it is important for obstetrician-gynecologists to be well versed in the screening, diagnosis, and management of breast cancer. This monograph is an overview of critical issues related to the provision of ongoing care to breast cancer survivors. PMID- 28644335 TI - Practice Bulletin Number 179: Breast Cancer Risk Assessment and Screening in Average-Risk Women. AB - Breast cancer is the most commonly diagnosed cancer in women in the United States and the second leading cause of cancer death in American women (1). Regular screening mammography starting at age 40 years reduces breast cancer mortality in average-risk women (2). Screening, however, also exposes women to harm through false-positive test results and overdiagnosis of biologically indolent lesions. Differences in balancing benefits and harms have led to differences among major guidelines about what age to start, what age to stop, and how frequently to recommend mammography screening in average-risk women (2-4).Breast cancer risk assessment is very important for identifying women who may benefit from more intensive breast cancer surveillance; however, there is no standardized approach to office-based breast cancer risk assessment in the United States. This can lead to missed opportunities to identify women at high risk of breast cancer and may result in applying average-risk screening recommendations to high-risk women. Risk assessment and identification of women at high risk allow for referral to health care providers with expertise in cancer genetics counseling and testing for breast cancer-related germline mutations (eg, BRCA), patient counseling about risk-reduction options, and cascade testing to identify family members who also may be at increased risk.The purpose of this Practice Bulletin is to discuss breast cancer risk assessment, review breast cancer screening guidelines in average-risk women, and outline some of the controversies surrounding breast cancer screening. It will present recommendations for using a framework of shared decision making to assist women in balancing their personal values regarding benefits and harms of screening at various ages and intervals to make personal screening choices from within a range of reasonable options. Recommendations for women at elevated risk and discussion of new technologies, such as tomosynthesis, are beyond the scope of this document and are addressed in other publications of the American College of Obstetricians and Gynecologists (ACOG) (5-7). PMID- 28644336 TI - Practice Bulletin No. 180: Gestational Diabetes Mellitus. AB - Gestational diabetes mellitus (GDM) is one of the most common medical complications of pregnancy. However, debate continues to surround the diagnosis and treatment of GDM despite several recent large-scale studies addressing these issues. The purposes of this document are the following: 1) provide a brief overview of the understanding of GDM, 2) review management guidelines that have been validated by appropriately conducted clinical research, and 3) identify gaps in current knowledge toward which future research can be directed. PMID- 28644337 TI - Committee Opinion No. 705: Mental Health Disorders in Adolescents. AB - Mental health disorders in adolescence are a significant problem, relatively common, and amenable to treatment or intervention. Obstetrician-gynecologists who see adolescent patients are highly likely to see adolescents and young women who have one or more mental health disorders. Some of these disorders may interfere with a patient's ability to understand or articulate her health concerns and appropriately adhere to recommended treatment. Some disorders or their treatments will affect the hypothalamic-pituitary-gonadal axis, causing anovulatory cycles and various menstrual disturbances. Adolescents with psychiatric disorders may be taking psychopharmacologic agents that can cause menstrual dysfunction and galactorrhea. Adolescents with mental illness often engage in acting-out behavior or substance use, which increases their risk of unsafe sexual behavior that may result in pregnancy or sexually transmitted infections. Pregnant adolescents who take psychopharmacologic agents present a special challenge in balancing the potential risks of fetal harm with the risks of inadequate treatment. Whether providing preventive women's health care or specific obstetric or gynecologic treatment, the obstetrician-gynecologist has the opportunity to reduce morbidity and mortality from mental health disorders in adolescents by early identification, appropriate and timely referral, and care coordination. Although mental health disorders should be managed by mental health care professionals or appropriately trained primary care providers, the obstetrician-gynecologist can assist by managing the gynecologic adverse effects of psychiatric medications and providing effective contraception and regular screening for sexually transmitted infections. This Committee Opinion will provide basic information about common adolescent mental health disorders, focusing on specific implications for gynecologic and obstetric practice. PMID- 28644338 TI - Committee Opinion No 706: Sexual Health. AB - Sexuality involves a broad range of expressions of intimacy and is fundamental to self-dentification, with strong cultural, biologic, and psychologic components. Obstetrician-gynecologists often are consulted by patients about sexual health and are in a unique position to open a dialogue on sexual health issues. Several obstacles to frank conversations with patients about sexual health exist, including a lack of adequate training and confidence in the topic, a perception that there are few treatment options, a lack of adequate clinical time to obtain a sexual history, patients' reluctance to initiate the conversation, and the underestimation of the prevalence of sexual dysfunction. However, data on reproductive and sexual health morbidity suggest sexual health is an important health care issue. Each year, an estimated 45,000 new cases of human immunodeficiency virus (HIV) and approximately 20 million sexually transmitted infections occur, 3 million women experience unintended pregnancies, and 1 million women are sexually assaulted. Openly discussing sexual health has the potential to prevent these unnecessary sexual health-related outcomes. Clinical conversations should acknowledge the contributions of sexuality, relationships, and sexual behavior to overall health. Obstetrician-gynecologists can address sexual health issues across a lifespan with their patients and encourage a strategic foundation for women's sexual health issues, resulting in improved public health overall. Obstetrician-gynecologists also can support policies that broaden the coalition for effective prevention of sexually transmitted infections and promote healthy sexuality, with the ultimate goal of improving health outcomes and public health. PMID- 28644339 TI - Committee Opinion No 707: Access to Emergency Contraception. AB - Emergency contraception refers to contraceptive methods used to prevent pregnancy in the first few days after unprotected intercourse, sexual assault, or contraceptive failure. Although the U.S. Food and Drug Administration approved the first dedicated product for emergency contraception in 1998, numerous barriers to emergency contraception remain. The purpose of this Committee Opinion is to examine barriers to the use of emergency contraception, emphasize the importance of increasing access, and review new methods of emergency contraception and limitations in efficacy in special populations. PMID- 28644341 TI - Pediatric Autoimmune Hepatitis: What Do You Do When First-line Therapy Fails? PMID- 28644340 TI - Committee Opinion No 708: Improving Awareness of and Screening for Health Risks Among Sex Workers. AB - The population of women who sell or exchange sex or intimate sexual services for material goods or services, also called "sex work," often is unrecognized in the typical obstetric and gynecologic practice. The prevalence of this behavior among adult women is difficult to quantify because of its frequent omission from the routine sexual history by women and clinicians. Data on the prevalence of sex work in the United States are largely lacking. The American College of Obstetricians and Gynecologists supports increasing awareness about the health risks, preventive care needs, and limited health care services for female sex workers. PMID- 28644342 TI - Biomarkers of Environmental Enteric Dysfunction: The Good, the Bad, and the Ugly. PMID- 28644343 TI - Second-line Agents in Pediatric Patients With Autoimmune Hepatitis: A Systematic Review and Meta-analysis. AB - BACKGROUND AND AIMS: Ten percent to 20% of children with autoimmune hepatitis (AIH) require second-line therapy to achieve remission. Although current guidelines exist on first-line management, evidence for second-line therapy in treatment-refractory patients is lacking. Our aim was to perform a systematic review and meta-analysis of the efficacy and safety of second-line treatments used in this population. METHODS: Electronic and manual searches were used to identify potential studies for inclusion. Studies were selected based on reported response rates to second-line therapies in children who failed response to prednisone and azathioprine. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Meta-analysis using weighted estimate of response rates at 6 months was performed for each treatment option. Heterogeneity was assessed. RESULTS: Fifteen studies of 76 pediatric patients with AIH were included in the review. Overall response rates at 6 months were estimated as 36% for mycophenolate mofetil (MMF) (N = 34, 95% confidence interval [CI] (16-57)), and 50% for tacrolimus (N = 4, 95% CI (0-100%)) and 83% for cyclosporine (N = 15, 95% CI (66%-100%)). Adverse effects were most frequent with cyclosporine (64% experiencing at least 1 adverse effect) followed by tacrolimus (54%) and MMF (48%). Pooled estimates of adverse events were 78% for cyclosporine (95% CI (54% 100%)), 42% for tacrolimus (95% CI (0%-85%)) and 45% for MMF (95% CI (25%-68%)). Sensitivity analyses were not performed due to small sample size. CONCLUSIONS: Cyclosporine had the highest response rate at 6 months in children with standard treatment-refractory AIH; however, it also had the highest rate of adverse events. MMF was the second most efficacious option with a low adverse effect rate. PMID- 28644344 TI - Treatment of Functional Abdominal Pain With Antidepressants: Benefits, Adverse Effects, and the Gastroenterologist's Role. AB - OBJECTIVES: Pediatric functional abdominal pain is often treated with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The aim is investigating antidepressant use for treatment efficacy, correlation of response to psychiatric factors, and impact of adverse effects in regard to physicians' prescribing patterns. METHODS: Retrospective review (2005-2013) children (5-21 years old) with functional abdominal pain treated with SSRI or TCA. Of the 531 cases with functional abdominal pain, 192 initiated SSRIs or TCAs while followed by gastroenterology. Charts reviewed for symptoms, adverse effects, and response: decreased pain or increased daily functioning. RESULTS: Sixty-three of 84 (75%) SSRI patients improved, 56 of 92 (61%) TCA patients improved (P = 0.03). Logistic regression controlling for psychiatric factors: SSRI remained significant over TCA (P = 0.04). Thirty-two of 67 (48%) patients with constipation received TCAs and 26 of 45 (58%) patients with diarrhea received SSRIs (P = 0.64). Three SSRI patients reported gastrointestinal effects, all diarrheal-type symptoms, and 2 TCA patients reported gastrointestinal effects, both constipation, in all it led to discontinuation. Thirteen (29%) of diarrheal-type patients reported adverse effects causing discontinuation as compared to 7 (8%) in the constipation group (P = .01). Twenty-one (25%) SSRI patients reported adverse effects with 5 (6%) mood disturbances. Twenty (22%) TCA patients reported adverse effects, 13 (14%) with mood disturbances (P = .07). Overall, 12 (14%) SSRI patients discontinued medication due to adverse effects, whereas 16 (17%) TCA patients (P = 0.24) did. CONCLUSIONS: Patients had significantly greater response to SSRIs than TCAs, remaining significant after controlling for psychiatric factors. Little significance is given to patient's associated gastrointestinal symptoms, frequently resulting in adverse effects and termination of medication. PMID- 28644345 TI - Yield of Endoscopy in Pediatric Gastroparesis. AB - OBJECTIVES: The aim of the study was to quantify the diagnostic yield of upper endoscopy in children with gastroparesis and to develop a clinical model for gastroparesis using common symptoms and screening blood tests. METHODS: We retrospectively reviewed charts of 196 patients of age 4 to 18 years evaluated for gastroparesis between 2009 and 2013. All patients completed a standard solid phase gastric emptying scan and upper endoscopy within a 12-month period. We analyzed gross and histologic endoscopy findings. Symptom-based data were collected on dyspeptic symptoms and classic "red-flag" symptoms. RESULTS: Seventy patients with gastroparesis and 126 controls were included. Clinically significant endoscopic findings were noted in 35% of controls (44/126) and 43% of gastroparetics (30/70), P = 0.345. Concordance between gross and histologic findings was low at 50%. Histologic findings included gastritis 60% (17/28), esophagitis 39% (11/28), and duodenitis 7% (2/28). In univariate and multivariate analyses, there was no meaningful correlation between symptoms and/or screening laboratory values and diagnosis of gastroparesis. CONCLUSIONS: Clinically significant endoscopy findings were common in both controls and gastroparetics. As more than one-third of patients had findings on endoscopy, we conclude that upper endoscopy remains an important part of the evaluation process of patients with dyspeptic symptoms and suspected gastroparesis. As gross abnormalities were frequently not present with histologic changes, routine biopsy is required. There was no association between studied symptoms and the presence of gastroparesis. A comprehensive evaluation of children with dyspeptic symptoms requires endoscopy with biopsy and solid-phase gastric emptying scan to determine the underlying diagnosis. PMID- 28644346 TI - Twelve Novel Mutations in the SLC26A3 Gene in 17 Sporadic Cases of Congenital Chloride Diarrhea. AB - OBJECTIVES: We aimed to improve the knowledge of pathogenic mutations in sporadic cases of congenital chloride diarrhea (CCD) and emphasize the importance of functional studies to define the effect of novel mutations. METHODS: All member 3 of solute carrier family 26 (SLC26A3) coding regions were sequenced in 17 sporadic patients with CCD. Moreover, the minigene system was used to analyze the effect of 2 novel splicing mutations. RESULTS: We defined the SLC26A3 genotype of all 17 patients with CCD and identified 12 novel mutations. Using the minigene system, we confirmed the in silico prediction of a complete disruption of splicing pattern caused by 2 of these novel mutations: the c.971+3_971+4delAA and c.735+4_c.735+7delAGTA. Moreover, several prediction tools and a structure function prediction defined the pathogenic role of 6 novel missense mutations. CONCLUSIONS: We confirm the molecular heterogeneity of sporadic CCD adding 12 novel mutations to the list of known pathogenic mutations. Moreover, we underline the importance, for laboratories that offer molecular diagnosis and genetic counseling, to perform fast functional analysis of novel mutations. PMID- 28644347 TI - Age and Sex Normalization of Intestinal Permeability Measures for the Improved Assessment of Enteropathy in Infancy and Early Childhood: Results From the MAL-ED Study. AB - OBJECTIVES: The aim of the study was to describe changes in intestinal permeability in early childhood in diverse epidemiologic settings. METHODS: In a birth cohort study, the lactulose:mannitol (L:M) test was administered to 1980 children at 4 time points in the first 24 months of life in 8 countries. Data from the Brazil site with an incidence of diarrhea similar to that seen in the United States and no growth faltering was used as an internal study reference to derive age- and sex-specific z scores for mannitol and lactulose recoveries and the L:M ratio. RESULTS: A total of 6602 tests demonstrated mannitol recovery, lactulose recovery, and the L:M ratio were associated with country, sex, and age. There was heterogeneity in the recovery of both probes between sites with mean mannitol recovery ranging for 1.34% to 5.88%, lactulose recovery of 0.19% to 0.58%, and L:M ratios 0.10 to 0.17 in boys of 3 months of age across different sites. We observed strong sex-specific differences in both mannitol and lactulose recovery, with boys having higher recovery of both probes. Alterations in intestinal barrier function increased in most sites from 3 to 9 months of age and plateaued or diminished from 9 to 15 months of age. CONCLUSIONS: Alterations in recovery of the probes differ markedly in different epidemiologic contexts in children living in the developing world. The rate of change in the L:M-z ratio was most rapid and consistently disparate from the reference standard in the period between 6 and 9 months of age, suggesting that this is a critical period of physiologic impact of enteropathy in these populations. PMID- 28644349 TI - Filaggrin and Periostin Expression Is Altered in Eosinophilic Esophagitis and Normalized With Treatment. AB - OBJECTIVES: Previous data have suggested that filaggrin (FLG) and periostin (POSTN) genes may be dysregulated in eosinophilic esophagitis (EoE). We aimed to further evaluate the expression patterns of FLG and POSTN proteins in esophageal tissue samples of patients with EoE, as compared to those of patients with gastroesophageal reflux disease (GERD) and normal controls. METHODS: A total of 61 prospectively collected cases, including 40 children with EoE and 21 children with GERD, and a control group of 14 sex- and age-matched healthy children were enrolled. Patients with EoE were treated with skin testing-driven elimination diet and/or corticosteroids. The immunohistochemical expression of FLG and POSTN was evaluated in esophageal biopsies obtained from patients and controls, and the results were correlated with EoE-related clinicopathological parameters. RESULTS: Positive FLG and negative POSTN staining were observed in all esophageal biopsies from normal controls. In contrast, FLG and POSTN stained negative and positive, respectively, in all pretreatment biopsies obtained from patients with EoE, whereas FLG and POSTN stained positive in 57.1% and 95.2% of GERD cases, respectively (P < 0.001). A statistically significant decrease of the proportion of cases with negative FLG and positive POSTN staining was observed from the first (pretreatment) to the second (post-treatment) biopsy in the subgroup of patients with EoE (P < 0.001 in both correlations). CONCLUSIONS: FLG and POSTN expression may be downregulated and upregulated, respectively, in the esophageal mucosa of patients with active EoE, and these changes may be restored with treatment in a significant percentage of cases. PMID- 28644348 TI - Biomarkers of Environmental Enteric Dysfunction Among Children in Rural Bangladesh. AB - OBJECTIVES: Environmental enteric dysfunction (EED) may inhibit growth and development in low- and middle-income countries, but available assessment methodologies limit its study. In rural Bangladesh, we measured EED using the widely used lactulose mannitol ratio (L:M) test and a panel of intestinal and systemic health biomarkers to evaluate convergence among biomarkers and describe risk factors for EED. METHODS: In 539 18-month-old children finishing participation in a randomized food supplementation trial, serum, stool, and urine collected after lactulose and mannitol dosing were analyzed for biomarkers of intestinal absorption, inflammation, permeability and repair, and systemic inflammation. EED scores for each participant were developed using principal component analysis and partial least squares regression. Associations between scores and L:M and with child sociodemographic and health characteristics were evaluated using regression analysis. RESULTS: EED prevalence (L:M > 0.07) was 39.0%; 60% had elevated acute phase proteins (C-reactive protein >5 mg/L or alpha 1 acid glycoprotein >100 mg/dL). Correlations between intestinal biomarkers were low, with the highest between myeloperoxidase and alpha-1 antitrypsin (r = 0.33, P < 0.01), and biomarker values did not differ by supplementation history. A 1 factor partial least squares model with L:M as the dependent variable explained only 8.6% of L:M variability. In adjusted models, L:M was associated with child sex and socioeconomic status index, whereas systemic inflammation was predicted mainly by recent illness, not EED. CONCLUSIONS: Impaired intestinal health is widespread in this setting of prevalent stunting, but a panel of serum and stool biomarkers demonstrated poor agreement with L:M. Etiologies of intestinal and systemic inflammation are likely numerous and complex in resource-poor settings, underscoring the need for a better case definition with corresponding diagnostic methods to further the study of EED. PMID- 28644350 TI - Lack of Knowledge and Low Readiness for Health Care Transition in Eosinophilic Esophagitis and Eosinophilic Gastroenteritis. AB - OBJECTIVES: A growing population of adolescents/young adults with eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE) will need to transition from pediatric to adult health providers. Measuring health care transition (HCT) readiness is critical, but no studies have evaluated this process in EoE/EGE. We determined the scope and predictors of HCT knowledge in patients and parents with EoE/EGE and measured HCT readiness in adolescents/young adults. METHODS: We conducted an online survey of patients 13 years or older and parents of patients with EoE/EGE who were diagnosed when 25 years or younger. Parents answered questions regarding their children and their own knowledge of HCT. HCT readiness was assessed in adolescents/young adults aged 13 to 25 years with the Self Management and Transition to Adulthood with Rx Questionnaire (a 6-domain self report tool) with a score range of 0 to 90. RESULTS: Four hundred fifty participants completed the survey: 205 patients and 245 parents. Included in the analysis (those diagnosed with EoE/EGE at age 25 years or younger) were 75 of 205 patients and children of 245 parent respondents. Overall, 78% (n = 52) of the patients and 76% (n = 187) of parents had no HCT knowledge. Mean HCT readiness score in adolescents/young adults (n = 50) was 30.4 +/- 11.3 with higher scores in domains of provider communication and engagement during appointments. Mean parent-reported (n = 123) score was 35.6 +/- 9.7 with higher scores in medication management and disease knowledge. CONCLUSIONS: There was a significant deficit in HCT knowledge, and HCT readiness scores were lower than other chronic health conditions. HCT preparation and readiness assessments should become a priority for adolescents/young adults with EoE/EGE and their parents. PMID- 28644351 TI - Adherence to Celiac Disease and Eosinophilic Esophagitis Biopsy Guidelines Is Poor in Children. AB - OBJECTIVES: Celiac disease (CD) and eosinophilic esophagitis (EoE) are underdiagnosed gastrointestinal conditions, which adversely affect children's health. Previous studies have shown that diagnostic guidelines for CD are not consistently followed in adults. The aims of the present study are to assess the frequency with which endoscopists comply with diagnostic guidelines for CD and EoE in children, and to determine whether an association exists between adherence to biopsy guidelines and disease detection in pediatric patients. METHODS: We reviewed pathology reports from 9171 children (ages 0-18) with at least 1 duodenal biopsy, and 8280 children with at least 1 esophageal biopsy, with specimens submitted to a national pathology laboratory. Frequency of adherence to diagnostic guidelines and recommendations for CD and EoE were determined, and the effect of this upon detection of CD and EoE. RESULTS: Overall, 35% of cases were biopsied according to the 2006 American Gastroenterological Association guidelines for CD diagnosis; 8% were biopsied according to the 2007 American Gastroenterological Association EoE consensus recommendations. Detection of CD and EoE increased with the number of biopsies collected (P for trend in each <0.001). Adherence to diagnostic guidelines was particularly poor among those found to have histologically normal mucosa in both cohorts. The likelihood of CD and EoE diagnosis was significantly associated with adherence to diagnostic guidelines (odds ratio for CD 6.3, 95% confidence interval 4.4-8.9; odds ratio for EoE 2.4, 95% confidence interval 1.9-2.9). CONCLUSION: Adherence to established guidelines is poor, and improved guideline adherence is associated with greater disease detection rates for CD and EoE. PMID- 28644352 TI - Elevated Serum Tissue Transglutaminase Antibodies in Children With Eosinophilic Esophagitis. AB - OBJECTIVES: This study compared the clinical and histopathological characteristics of children with eosinophilic esophagitis (EoE) and elevated anti transglutaminase (TTG Ab) with those with EoE and normal TTG Ab titres. METHODS: Single-center chart and blinded histopathological review of patients diagnosed with EoE for a 4-year period, who had esophageal and duodenal biopsies taken at time of endoscopy, and TTG Ab measured within 6 months of biopsy. Patients with histology-proven CD were excluded. RESULTS: Elevated TTG Ab was present in 19/34 (54%) of the study cohort, representing 23% of all patients diagnosed with EoE during the study period. Eight had titers >6* upper limit of normal (ULN) and 4 had >10* ULN. TTG Ab-positive patients were classified as having either potential CD with (n = 3, 16%) and without lymphocytic duodenosis (LD; n = 12, 63%), and no CD (n = 4, 21%) on human leukocyte antigen typing. There was an increase in duodenal eosinophils in patients with elevated TTG Ab (P = 0.01), which remained when patients with LD were excluded (P = 0.018). Of 19 patients with EoE and elevated TTG Ab, 5 responded to elimination diet involving exclusion of wheat, including 2 with a sole wheat trigger and TTG Ab >10* ULN that were CD-associated human leukocyte antigen-negative. CONCLUSIONS: Serum TTG Ab was elevated in almost one-quarter of our total EoE cohort, and at least 20% of these patients did not have potential CD, suggesting EoE is a heterogeneous disease with differing immune mechanisms activated in some patients. These findings also support routine esophageal biopsy during upper endoscopy in children with elevated TTG Ab. PMID- 28644353 TI - Extraintestinal Manifestations of Celiac Disease: Effectiveness of the Gluten Free Diet. AB - OBJECTIVE: The aim of the study was to evaluate the effectiveness of the gluten free diet (GFD) on extraintestinal symptoms in pediatric and adult celiac populations at the University of Chicago. METHODS: We conducted a retrospective chart review of the University of Chicago Celiac Center clinic charts from January 2002 to October 2014. Demographics, serologic testing, intestinal biopsies, and extraintestinal symptoms at presentation, 12, 24, and >24 months were recorded. Extraintestinal symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgias, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility. RESULTS: A total of 737 patients with biopsy-confirmed celiac disease or skin biopsy-confirmed dermatitis herpetiformis were included. Patients lost to follow up, or with insufficient data were excluded leaving 328 patients (157 pediatrics younger than 18 years). For pediatrics, the female to male ratio was 2:1 and the mean age at diagnosis was 8.9 years. For adults, 4:1 and 40.6 years old. Extraintestinal symptom rates were similar in children (60%) and adults (62%). Short stature (33%), fatigue (28%), and headache (20%) were most common in children. Iron deficiency anemia (48%), fatigue (37%), and headache/psychiatric disorders (24%) were common in adults. Children had faster/higher rates of symptom resolution compared with adults. Twenty-eight percent of children with unresolved short stature on a GFD were found to have other comorbidities. CONCLUSIONS: Children and adults with celiac disease have similar rates of extraintestinal manifestations. In children short stature, fatigue, and headache were most common, whereas anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children on a strict GFD showed faster and higher rates of symptom resolution as compared to adults. Unresponsive children with short stature must be assessed for comorbidities. PMID- 28644354 TI - Development and Function of Immune Cells in an Adolescent Patient With a Deficiency in the Interleukin-10 Receptor. AB - OBJECTIVE: Monogenic defects in the interleukin-10 (IL-10) pathway are extremely rare and cause infantile-onset inflammatory bowel disease (IBD)-like pathology. Understanding how immune responses are dysregulated in monogenic IBD-like diseases can provide valuable insight in "classical" IBD pathogenesis. Here, we studied long-term immune cell development and function in an adolescent IL-10 receptor (IL10RA)-deficient patient who presented in infancy with severe colitis and fistulizing perianal disease and is currently treated with immune suppressants. METHODS: Biomaterial was collected from the IL10RA-deficient patient, pediatric patients with IBD, and healthy controls. The frequency and phenotype of immune cells were determined in peripheral blood and intestinal biopsies by flow cytometry and immunohistochemistry. Functional changes in monocyte-derived dendritic cells and T cells were assessed by in vitro activation assays. RESULTS: The IL10RA-deficient immune system developed normally with respect to numbers and phenotype of circulating immune cells. Despite normal co stimulatory molecule expression, bacterial lipopolysaccharide-stimulated monocyte derived dendritic cells from the IL10RA-deficient patient released increased amounts of tumor necrosis factor alpha compared to healthy controls. Upon T-cell receptor ligation, IL10RA-deficient peripheral blood mononuclear cells released increased amounts of T-cell cytokines interferon gamma and IL-17 agreeing with high numbers of T-bet and IL-17 cells in intestinal biopsies taken at disease onset. In vitro, the immunosuppressive drug thalidomide used to treat the patient's decreased peripheral blood mononuclear cell-derived tumor necrosis factor production. CONCLUSIONS: With time and during immunosuppressive treatment the IL10RA-deficient immune system develops relatively normally. Upon activation, IL-10 is crucial for controlling excessive inflammatory cytokine release by dendritic cells and preventing interferon gamma and IL-17-mediated T-cell responses. PMID- 28644355 TI - Outpatient Liver Biopsy in Children: Safety, Feasibility, and Economic Impact. AB - Liver biopsy is a valuable tool. Even though outpatient liver biopsies are routinely performed in adults, there are no clear recommendations on its safety and feasibility in children. We reviewed the records of children who underwent a percutaneous liver biopsy at our institution between January 2005 and June 2015. A total of 626 biopsies were performed on 497 patients (250 boys, median age 6 [0.2-19.3] years). Abnormal liver function tests for investigation 288 (46%) was the most common indication. Thirty (4.8%) biopsies had complications, most common being subcapsular hematoma 14 of 30 (46.7%). Complications were identified within 8 hours of the biopsy in all patients. Approach, needle size, or number of passes did not affect the complication rate. Bleeding-related complications were not related to the international normalized ratio. Performing liver biopsies on an outpatient basis would have saved 60 beds/AU$ 80,000/year. The present study suggests that if an observation period of 8 hours is instituted, outpatient liver biopsies can be performed safely in children. PMID- 28644356 TI - Low Hepatic Tissue Copper in Pediatric Nonalcoholic Fatty Liver Disease. AB - OBJECTIVE: Animal models and studies in adults have demonstrated that copper restriction increases severity of liver injury in nonalcoholic fatty liver disease (NAFLD). This has not been studied in children. We aimed to determine if lower tissue copper is associated with increased NAFLD severity in children. METHODS: This was a retrospective study of pediatric patients who had a liver biopsy including a hepatic copper quantitation. The primary outcome compared hepatic copper concentration in NAFLD versus non-NAFLD. Secondary outcomes compared hepatic copper levels against steatosis, fibrosis, lobular inflammation, balloon degeneration, and NAFLD activity score (NAS). RESULTS: The study analysis included 150 pediatric subjects (102 with NAFLD and 48 non-NAFLD). After adjusting for age, body mass index z score, gamma glutamyl transferase, alanine aminotransferase, and total bilirubin, NAFLD subjects had lower levels of hepatic copper than non-NAFLD (P = 0.005). In addition, tissue copper concentration decreased as steatosis severity increased (P < 0.001). Copper levels were not associated with degree of fibrosis, lobular inflammation, portal inflammation, or balloon degeneration. CONCLUSIONS: In this cohort of pediatric subjects with NAFLD, we observed decreased tissue copper levels in subjects with NAFLD when compared with non-NAFLD subjects. In addition, tissue copper levels were lower in subjects with nonalcoholic steatohepatitis, a more severe form of the disease, when compared with steatosis alone. Further studies are needed to explore the relationship between copper levels and NAFLD progression. PMID- 28644357 TI - Effect of Synbiotic on the Gut Microbiota of Cesarean Delivered Infants: A Randomized, Double-blind, Multicenter Study. AB - We determined the effect of short-chain galacto-oligosaccharides (scGOS), long chain fructo-oligosaccharides (lcFOS) and Bifidobacterium breve M-16V on the gut microbiota of cesarean-born infants. Infants were randomized to receive a standard formula (control), the same with scGOS/lcFOS and B. breve M-16V (synbiotic), or with scGOS/lcFOS (prebiotic) from birth until week 16, 30 subjects born vaginally were included as a reference group. Synbiotic supplementation resulted in a higher bifidobacteria proportion from day 3/5 (P < 0.0001) until week 8 (P = 0.041), a reduction of Enterobacteriaceae from day 3/5 (P = 0.002) till week 12 (P = 0.016) compared to controls. This was accompanied with a lower fecal pH and higher acetate. In the synbiotic group, B. breve M-16V was detected 6 weeks postintervention in 38.7% of the infants. This synbiotic concept supported the early modulation of Bifidobacterium in C-section born infants that was associated with the emulation of the gut physiological environment observed in vaginally delivered infants. PMID- 28644358 TI - Early Empiric Antibiotic Use Is Associated With Delayed Feeding Tolerance in Preterm Infants: A Retrospective Analysis. AB - The causative factors of neonatal feeding intolerance are poorly understood, but potentially related to clinical practices such as empiric antibiotic usage. The objective of this study was to evaluate whether early empiric antibiotic exposure negatively affects preterm infants' enteral feeding tolerance. Data from infants without risk factors for sepsis, 500 to 1499 g birth weight and 24 to 34 weeks gestational age were analyzed. The primary outcomes were the empiric antibiotic exposure effects on the infants' total parenteral nutrition usage duration and prevalence of necrotizing enterocolitis (NEC). Among the 901 infants included, 67 were exposed to early empiric antibiotic. A 50% increase in parenteral nutrition usage duration and a 4-fold greater prevalence of NEC was seen in the early empiric antibiotic-exposed neonates, when compared with control infants (P < 0.01). Early empiric antibiotic exposure appears to negatively influence preterm infant feeding tolerance and possibly contributes to NEC. PMID- 28644359 TI - Commercial Probiotic Products: A Call for Improved Quality Control. A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics. AB - Probiotics have been proposed for a number of indications ranging from the hypothetical long-term immunomodulatory effects to proven benefits in the management of different clinical conditions.An increasing number of commercial products containing probiotics are available. In those products, irrespective if it is food, food supplement, medical food, or drug, the probiotic microorganisms have to be present in a sufficient number by the end of the shelf-life, to pass through the gastrointestinal tract resisting acid and bile, to colonize the gut, and to retain functional properties required to obtain the suggested beneficial effect. Finally, it should be contamination-free.Studies organized worldwide and summarized in this article have shown that inconsistencies and deviations from the information provided on the product label are surprisingly common. Frequently strains are misidentified and misclassified, products are occasionally contaminated, sometimes with even facultative or obligatory pathogens, strains are not viable, the labeled number of colonies cannot be verified, or the functional properties are diminished to the extent that preclude the proposed health benefit. As the probiotic preparations are commonly used for a wide range of conditions, the aim of the Working Group was to summarize results of the studies looking into the quality of the probiotic products and to raise the awareness of the important issue of their quality control.Based on the results obtained, we strongly suggest a more stringent quality control process. This process should ensure that the probiotic content as mentioned on the label meets the actual content throughout the shelf life of the product, while no contamination is present. PMID- 28644360 TI - Quality Improvement in Pediatric Endoscopy: A Clinical Report From the NASPGHAN Endoscopy Committee. AB - The current era of healthcare reform emphasizes the provision of effective, safe, equitable, high-quality, and cost-effective care. Within the realm of gastrointestinal endoscopy in adults, renewed efforts are in place to accurately define and measure quality indicators across the spectrum of endoscopic care. In pediatrics, however, this movement has been less-defined and lacks much of the evidence-base that supports these initiatives in adult care. A need, therefore, exists to help define quality metrics tailored to pediatric practice and provide a toolbox for the development of robust quality improvement (QI) programs within pediatric endoscopy units. Use of uniform standards of quality reporting across centers will ensure that data can be compared and compiled on an international level to help guide QI initiatives and inform patients and their caregivers of the true risks and benefits of endoscopy. This report is intended to provide pediatric gastroenterologists with a framework for the development and implementation of endoscopy QI programs within their own centers, based on available evidence and expert opinion from the members of the NASPGHAN Endoscopy Committee. This clinical report will require expansion as further research pertaining to endoscopic quality in pediatrics is published. PMID- 28644361 TI - Giant Pelvic Cyst in 16-Year-Old Boy With Bloody Diarrhea: Atypical Presentation of Colonic Adenocarcinoma. PMID- 28644362 TI - Endoscopic Drainage of Walled Off Necrosis in a Child With Metal Stent. PMID- 28644363 TI - Allergic Interstitial Nephritis Masquerading as Pyelonephritis in a Pediatric Patient With Crohn Disease. PMID- 28644364 TI - An Unusual Manifestation of Celiac Disease in an Adolescent With Down Syndrome and Graves Disease. PMID- 28644365 TI - Apropos: "Gut Microbiota Differences in Children From Distinct Socioeconomic Levels Living in the Same Urban Area in Brazil". PMID- 28644366 TI - Microbiota, Environment, and Diet. PMID- 28644367 TI - Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders. AB - OBJECTIVES: Patients with bile acid synthesis disorders (BASDs) due to single enzyme defects (SEDs) or Zellweger spectrum disorders (ZSDs) accumulate hepatotoxic atypical bile acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic acid in patients with BASD. METHODS: In this phase 3, open-label, single-arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic acid orally 10 to 15 mg . kg . day. The primary efficacy variables were changes from pre- to post-treatment in atypical urinary bile acids, liver chemistries (serum aspartate aminotransferase, alanine aminotransferase), and height and weight. Additional efficacy variables included changes in serum bilirubin and liver histology. RESULTS: Of the 85 enrolled patients (63 with SED and 22 with ZSD), 79 received at least 1 dose of study medication; 70 patients (50 with SED and 20 with ZSD) were included in the modified intent-to-treat dataset. Cholic acid significantly improved urine bile acid metabolite scores (P < 0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001) in patients with SED and ZSD. Cholic acid also improved height and weight percentiles in both groups, but only the change in weight was significant (P < 0.05). Serum direct bilirubin decreased significantly post-treatment (P < 0.001) in the intent-to-treat population, and liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis. The overall safety profile of cholic acid was favorable, with no study drug related serious adverse events or drug-related deaths reported. CONCLUSIONS: Oral cholic acid is a safe, efficacious, and well-tolerated treatment for BASD due to SED and ZSD. PMID- 28644368 TI - Vitamin D Deficiency Is Not Associated With Growth or the Incidence of Common Morbidities Among Tanzanian Infants. AB - OBJECTIVE: The objective of this study was to examine risk factors for vitamin D deficiency and determine the association of vitamin D status with child growth and incidence of common morbidities among Tanzanian infants. METHODS: A prospective cohort of 581 Tanzanian infants born to human immunodeficiency virus (HIV)-uninfected mothers had serum 25-hydroxyvitamin D assessed at 6 weeks and 6 months of age. Infants were seen at monthly clinic visits for growth monitoring until 18 months of age. Physicians examined infants every 3 months or when an illness was noted to document morbidities. RESULTS: The prevalence of vitamin D deficiency (<20 ng/mL) declined from 76.4% at 6 weeks of age to 21.2% at 6 months. Infants who were exclusively breastfed at 6 weeks of age had 2.05 (95% confidence interval 1.11-3.79; P = 0.02) times the risk of vitamin D deficiency as compared formula-fed infants. After multivariate adjustment, there was no association of vitamin D status at 6 weeks or 6 months with the incidence of stunting, wasting, or underweight. There was also no association of low vitamin D with the incidence of diarrhea, upper respiratory infection, acute lower respiratory tract infection, or malaria. CONCLUSIONS: Vitamin D deficiency is common during early infancy, particularly among exclusively breastfed infants; however, these observational data suggest it may not be an important contributor to morbidity and growth among the general population of Tanzanian infants. Future studies of vitamin D among high-risk infants, including those with low birthweight and exposed to HIV, may be warranted. PMID- 28644369 TI - European Society for Pediatric Gastroenterology Hepatology and Nutrition's Educational Offer and the Training Syllabus. AB - The basic knowledge necessary for a European pediatric gastroenterologist/hepatologist/nutritionist is set-out in the training syllabus (TS) of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). We retrospectively compared the topics covered in ESPGHAN's training events between 2013 and 2016 with the basic knowledge TS items. Thirty six initiatives including e-learning were identified. Twelve (33%) courses focused on gastroenterology, 9 (25%) on hepatology, and 10 (28%) on nutrition. Five (14%) courses covered >1 field and were classified "General." The initiatives covered 12 of 57 (21%) TS items; 31 of 57 items (54%) were partially covered; and 14 of 57 (25%) not covered. Five of 9 e-learning courses covered gastroenterology topics, whereas none covered hepatology topics. ESPGHAN's 3-year educational offer partially met the training needs listed in the TS. A coordinated educational program covering all TS items would harmonize training within Europe and would provide trainees with a professional portfolio for employment purposes. PMID- 28644370 TI - Adaptation of New Colombian Food-based Complementary Feeding Recommendations Using Linear Programming. AB - OBJECTIVE: The aim of the study was to use linear programming (LP) analyses to adapt New Complementary Feeding Guidelines (NCFg) designed for infants aged 6 to 12 months living in poor socioeconomic circumstances in Bogota to ensure dietary adequacy for young children aged 12 to 23 months. DESIGN: A secondary data analysis was performed using dietary and anthropometric data collected from 12 month-old infants (n = 72) participating in a randomized controlled trial. LP analyses were performed to identify nutrients whose requirements were difficult to achieve using local foods as consumed; and to test and compare the NCFg and alternative food-based recommendations (FBRs) on the basis of dietary adequacy, for 11 micronutrients, at the population level. RESULTS: Thiamine recommended nutrient intakes for these young children could not be achieved given local foods as consumed. NCFg focusing only on meat, fruits, vegetables, and breast milk ensured dietary adequacy at the population level for only 4 micronutrients, increasing to 8 of 11 modelled micronutrients when the FBRs promoted legumes, dairy, vitamin A-rich vegetables, and chicken giblets. None of the FBRs tested ensured population-level dietary adequacy for thiamine, niacin, and iron unless a fortified infant food was recommended. CONCLUSIONS: The present study demonstrated the value of using LP to adapt NCFg for a different age group than the one for which they were designed. Our analyses suggest that to ensure dietary adequacy for 12- to 23-month olds these adaptations should include legumes, dairy products, vitamin A-rich vegetables, organ meat, and a fortified food. PMID- 28644372 TI - To the Editor. PMID- 28644373 TI - To the Editor. PMID- 28644374 TI - [Plasmodium falciparum resistance to artemisinin-based combination therapies (ACTs): Fears of widespread drug resistance]. AB - Malaria treatment with ACTs (Artemisinin-based Combination Therapies), combining a chemical derivative of artemisinin, and a partner drug has, for more than 15 years, produced a notable decrease in the mortality in tropical and subtropical areas. However, since 2008, a serious threat has emerged in western Cambodia, where the clinical efficacy of artemisinins has significantly declined, with a delayed parasite clearance rate and high recrudescence rates in the following weeks. Resistance of Plasmodium to artemisinins is now reported in several countries in South-East Asia. ACTs remain effective as long as the partner drug retains its activity but more and more clinical failures related to parasite resistance to both resistant parasites in sub-Saharan Africa, the continent most affected by malaria, as was the case in the past with other antimalarial treatments. It is therefore essential to better understand, from phenotypic and genotypic points of view, the mechanisms of resistance developed by the parasite Plasmodium falciparum face artemisinin and its derivatives in order to offer new therapeutic tools. PMID- 28644375 TI - GADEN: A 3D Gas Dispersion Simulator for Mobile Robot Olfaction in Realistic Environments. AB - This work presents a simulation framework developed under the widely used Robot Operating System (ROS) to enable the validation of robotics systems and gas sensing algorithms under realistic environments. The framework is rooted in the principles of computational fluid dynamics and filament dispersion theory, modeling wind flow and gas dispersion in 3D real-world scenarios (i.e., accounting for walls, furniture, etc.). Moreover, it integrates the simulation of different environmental sensors, such as metal oxide gas sensors, photo ionization detectors, or anemometers. We illustrate the potential and applicability of the proposed tool by presenting a simulation case in a complex and realistic office-like environment where gas leaks of different chemicals occur simultaneously. Furthermore, we accomplish quantitative and qualitative validation by comparing our simulated results against real-world data recorded inside a wind tunnel where methane was released under different wind flow profiles. Based on these results, we conclude that our simulation framework can provide a good approximation to real world measurements when advective airflows are present in the environment. PMID- 28644376 TI - Monitoring Effect of Fire on Ant Assemblages in Brazilian Rupestrian Grasslands: Contrasting Effects on Ground and Arboreal Fauna. AB - Fire is one of the most relevant ecological disturbances in nature. Little is known about the effects of fire on biodiversity in ecosystems like rupestrian grasslands, which share characteristics with savanna and forest biomes. Brazilian rupestrian grasslands are part of an endangered ecosystem that has been modified by anthropogenic fire events that have become more intense in recent decades. In this study, we evaluated the effects of fire on ground and arboreal ant assemblages through a two-year monitoring program (24 monthly samplings). We found that fire does not change cumulative species richness after 24 months, and that fire does not affect mean ant richness, abundance, and species composition in arboreal ants. On the other hand, fire increased mean ground ant species richness and abundance, and caused a significant change in species composition. Our results indicate a weak and beneficial effect of fire only for ground ant communities, which generally agrees with results from other studies in Brazilian savannas. Taken together, results from these studies may be useful for improvement of fire suppression policy in fire-prone habitats in Brazil. PMID- 28644377 TI - An Operational In Situ Soil Moisture & Soil Temperature Monitoring Network for West Wales, UK: The WSMN Network. AB - This paper describes a soil moisture dataset that has been collecting ground measurements of soil moisture, soil temperature and related parameters for west Wales, United Kingdom. Already acquired in situ data have been archived to the autonomous Wales Soil Moisture Network (WSMN) since its foundation in July 2011. The sites from which measurements are being collected represent a range of conditions typical of the Welsh environment, with climate ranging from oceanic to temperate and a range of the most typical land use/cover types found in Wales. At present, WSMN consists of a total of nine monitoring sites across the area with a concentration of sites in three sub-areas around the region of Aberystwyth located in Mid-Wales. The dataset of composed of 0-5 (or 0-10) cm soil moisture, soil temperature, precipitation, and other ancillary data. WSMN data are provided openly to the public via the International Soil Moisture Network (ISMN) platform. At present, WSMN is also rapidly expanding thanks to funding obtained recently which allows more monitoring sites to be added to the network to the wider community interested in using its data. PMID- 28644378 TI - An Energy-Efficient Multi-Tier Architecture for Fall Detection Using Smartphones. AB - Automatic detection of fall events is vital to providing fast medical assistance to the causality, particularly when the injury causes loss of consciousness. Optimization of the energy consumption of mobile applications, especially those which run 24/7 in the background, is essential for longer use of smartphones. In order to improve energy-efficiency without compromising on the fall detection performance, we propose a novel 3-tier architecture that combines simple thresholding methods with machine learning algorithms. The proposed method is implemented on a mobile application, called uSurvive, for Android smartphones. It runs as a background service and monitors the activities of a person in daily life and automatically sends a notification to the appropriate authorities and/or user defined contacts when it detects a fall. The performance of the proposed method was evaluated in terms of fall detection performance and energy consumption. Real life performance tests conducted on two different models of smartphone demonstrate that our 3-tier architecture with feature reduction could save up to 62% of energy compared to machine learning only solutions. In addition to this energy saving, the hybrid method has a 93% of accuracy, which is superior to thresholding methods and better than machine learning only solutions. PMID- 28644379 TI - Physical Forces May Cause the HoxD Gene Cluster Elongation. AB - Hox gene collinearity was discovered be Edward B. Lewis in 1978. It consists of the Hox1, Hox2, Hox3 ordering of the Hox genes in the chromosome from the telomeric to the centromeric side of the chromosome. Surprisingly, the spatial activation of the Hox genes in the ontogenetic units of the embryo follows the same ordering along the anterior-posterior embryonic axis. The chromosome microscale differs from the embryo macroscale by 3 to 4 orders of magnitude. The traditional biomolecular mechanisms are not adequate to comprise phenomena at so divergent spatial domains. A Biophysical Model of physical forces was proposed which can bridge the intermediate space and explain the results of genetic engineering experiments. Recent progress in constructing instruments and achieving high resolution imaging (e.g., 3D DNA FISH, STORM etc.) enable the assessment of the geometric structure of the chromatin during the different phases of Hox gene activation. It is found that the mouse HoxD gene cluster is elongated up to 5-6 times during Hox gene transcription. These unexpected findings agree with the BM predictions. It is now possible to measure several physical quantities inside the nucleus during Hox gene activation. New experiments are proposed to test further this model. PMID- 28644381 TI - An Efficient User Authentication and User Anonymity Scheme with Provably Security for IoT-Based Medical Care System. AB - In recent years, with the increase in degenerative diseases and the aging population in advanced countries, demands for medical care of older or solitary people have increased continually in hospitals and healthcare institutions. Applying wireless sensor networks for the IoT-based telemedicine system enables doctors, caregivers or families to monitor patients' physiological conditions at anytime and anyplace according to the acquired information. However, transmitting physiological data through the Internet concerns the personal privacy of patients. Therefore, before users can access medical care services in IoT-based medical care system, they must be authenticated. Typically, user authentication and data encryption are most critical for securing network communications over a public channel between two or more participants. In 2016, Liu and Chung proposed a bilinear pairing-based password authentication scheme for wireless healthcare sensor networks. They claimed their authentication scheme cannot only secure sensor data transmission, but also resist various well-known security attacks. In this paper, we demonstrate that Liu-Chung's scheme has some security weaknesses, and we further present an improved secure authentication and data encryption scheme for the IoT-based medical care system, which can provide user anonymity and prevent the security threats of replay and password/sensed data disclosure attacks. Moreover, we modify the authentication process to reduce redundancy in protocol design, and the proposed scheme is more efficient in performance compared with previous related schemes. Finally, the proposed scheme is provably secure in the random oracle model under ECDHP. PMID- 28644380 TI - Adenosine Triphosphate-Encapsulated Liposomes with Plasmonic Nanoparticles for Surface Enhanced Raman Scattering-Based Immunoassays. AB - In this study, we prepared adenosine triphosphate (ATP) encapsulated liposomes, and assessed their applicability for the surface enhanced Raman scattering (SERS) based assays with gold-silver alloy (Au@Ag)-assembled silica nanoparticles (NPs; SiO2@Au@Ag). The liposomes were prepared by the thin film hydration method from a mixture of l-alpha-phosphatidylcholine, cholesterol, and PE-PEG2000 in chloroform; evaporating the solvent, followed by hydration of the resulting thin film with ATP in phosphate-buffered saline (PBS). Upon lysis of the liposome, the SERS intensity of the SiO2@Au@Ag NPs increased with the logarithm of number of ATP-encapsulated liposomes after lysis in the range of 8 * 106 to 8 * 1010. The detection limit of liposome was calculated to be 1.3 * 10-17 mol. The successful application of ATP-encapsulated liposomes to SiO2@Au@Ag NPs based SERS analysis has opened a new avenue for Raman label chemical (RCL)-encapsulated liposome enhanced SERS-based immunoassays. PMID- 28644382 TI - Metal Ion-Loaded Nanofibre Matrices for Calcification Inhibition in Polyurethane Implants. AB - Pathologic calcification leads to structural deterioration of implant materials via stiffening, stress cracking, and other structural disintegration mechanisms, and the effect can be critical for implants intended for long-term or permanent implantation. This study demonstrates the potential of using specific metal ions (MI)s for inhibiting pathological calcification in polyurethane (PU) implants. The hypothesis of using MIs as anti-calcification agents was based on the natural calcium-antagonist role of Mg2+ ions in human body, and the anti-calcification effect of Fe3+ ions in bio-prosthetic heart valves has previously been confirmed. In vitro calcification results indicated that a protective covering mesh of MI doped PU can prevent calcification by preventing hydroxyapatite crystal growth. However, microstructure and mechanical characterisation revealed oxidative degradation effects from Fe3+ ions on the mechanical properties of the PU matrix. Therefore, from both a mechanical and anti-calcification effects point of view, Mg2+ ions are more promising candidates than Fe3+ ions. The in vitro MI release experiments demonstrated that PU microphase separation and the structural design of PU-MI matrices were important determinants of release kinetics. Increased phase separation in doped PU assisted in consistent long-term release of dissolved MIs from both hard and soft segments of the PU. The use of a composite sandwich mesh design prevented an initial burst release which improved the late (>20 days) release rate of MIs from the matrix. PMID- 28644383 TI - Use of Ultrasonication Technology for the Increased Production of Plant Secondary Metabolites. AB - Plant secondary metabolites (PSMs) provide taste, color, odor, and resistance to plants, and they are also used to treat cancer and cardiovascular diseases. Synthesis of PSMs in plants is stimulated in response to different forms of external stress. Use of ultrasonication (US) to clean or decontaminate fruits and vegetables leads to physical stress that finally results in the accumulation of PSMs. US can stimulate accumulation of taxol, ginsenoside saponins, shikonin, and resveratrol, e.g., up to 319-fold increase of resveratrol synthesis has been observed in grape due to US. US also increases carotenoids, total phenolics, and isoflavonoids accumulation. Furthermore, US shows synergistic effects in PSMs synthesis-when combined with ultraviolet (UV) irradiation, jasmonic acid (JA) or salicylic acid (SA). It has been observed that US stimulates the production of reactive oxygen species (ROS) which then upregulates expression of phenylalanine ammonia lyase (PAL), resulting in the synthesis of PSMs. In this review, we summarize the effects of US, as a physical stress, to maximize the accumulation of PSMs in crop produce and in cell cultures. PMID- 28644384 TI - Characterisation of the Chemical Composition and Structural Features of Novel Antimicrobial Nanoparticles. AB - Three antimicrobial nanoparticle types (AMNP0, AMNP1, and AMNP2) produced using the TesimaTM thermal plasma technology were investigated and their compositions were determined using a combination of analytical methods. Scanning electron micrographs provided the morphology of these particles with observed sizes ranging from 10 to 50 nm, whilst FTIR spectra confirmed the absence of polar bonds and organic impurities, and strong Raman active vibrational bands at ca. 1604 and 1311 cm-1 ascribed to C-C vibrational motions were observed. Carbon signals that resonated at deltaC 126 ppm in the solid state NMR spectra confirmed that sp2 hybridised carbons were present in high concentration in two of the nanoparticle types (AMNP1 and AMNP2). X-ray powder diffraction suggested that AMNP0 contains single phase Tungsten carbide (WC) in a high state of purity and multiple phases of WC/WC1-x were identified in both AMNP1 and AMNP2. Finally, X ray photoelectron spectral (XPS) analyses revealed and quantified the elemental ratios in these composite formulations. PMID- 28644385 TI - CH/pi Interactions in Carbohydrate Recognition. AB - Many carbohydrate-binding proteins contain aromatic amino acid residues in their binding sites. These residues interact with carbohydrates in a stacking geometry via CH/pi interactions. These interactions can be found in carbohydrate-binding proteins, including lectins, enzymes and carbohydrate transporters. Besides this, many non-protein aromatic molecules (natural as well as artificial) can bind saccharides using these interactions. Recent computational and experimental studies have shown that carbohydrate-aromatic CH/pi interactions are dispersion interactions, tuned by electrostatics and partially stabilized by a hydrophobic effect in solvated systems. PMID- 28644386 TI - Capsaicin Induces Autophagy and Apoptosis in Human Nasopharyngeal Carcinoma Cells by Downregulating the PI3K/AKT/mTOR Pathway. AB - Capsaicin is a potential chemotherapeutic agent for different human cancers. In Southeast China, nasopharyngeal carcinoma (NPC) has the highest incidence of all cancers, but final treatment outcomes are unsatisfactory. However, there is a lack of information regarding the anticancer activity of capsaicin in NPC cells, and its effects on the signaling transduction pathways related to apoptosis and autophagy remain unclear. In the present study, the precise mechanisms by which capsaicin exerts anti-proliferative effects, cell cycle arrest, autophagy and apoptosis were investigated in NPC-TW01 cells. Exposure to capsaicin inhibited cancer cell growth and increased G1 phase cell cycle arrest. Western blotting and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) were used to measure capsaicin-induced autophagy via involvement of the class III PI3K/Beclin-1/Bcl-2 signaling pathway. Capsaicin induced autophagy by increasing levels of the autophagy markers LC3-II and Atg5, enhancing p62 and Fap-1 degradation and increasing caspase-3 activity to induce apoptosis, suggesting a correlation of blocking the PI3K/Akt/mTOR pathway with the above-mentioned anticancer activities. Taken together, these data confirm that capsaicin inhibited the growth of human NPC cells and induced autophagy, supporting its potential as a therapeutic agent for cancer. PMID- 28644388 TI - Cellular Uptake and Delivery-Dependent Effects of Tb3+-Doped Hydroxyapatite Nanorods. AB - With the increasing interest in hydroxyapatite (HA) nanostructures for use in biomedicine, the systematic evaluation of their potential effects on biological systems is becoming critically important. In this work, we report the in vitro cellular uptake, in vivo tissue distributions and toxicity of Tb3+-doped HA (HA Tb) after short-, intermediate-, and long-term exposure. Transmission electron microscopy analysis indicated that HA-Tb was taken up by cells via vesicle endocytosis. Cell proliferation and cytotoxicity assay, combined with confocal laser scanning microscopy, indicated excellent cell viability with no changes in cell morphology at the examined doses. Three HA-Tb delivery methods (intraperitoneal, intragastric, and intravenous) resulted in similar time dependent tissue distributions, while intraperitoneal injection produced the highest bioavailability. HA-Tb initially accumulated in livers and intestines of rats (4 h to one day after administration), then became increasingly distributed in the kidney and bladder (seven days), and finally decreased in all tissues after 30 to 90 days. No histopathological abnormalities or lesions related to treatment with HA-Tb were observed. These results suggest that HA-Tb has minimal in vitro and in vivo toxicity, regardless of the delivery mode, time, and dose. The findings provide a foundation for the design and development of HA for biological applications. PMID- 28644387 TI - RNA Binding Proteins and Genome Integrity. AB - Genome integrity can be threatened by various endogenous or exogenous events. To counteract these stressors, the DNA damage response network contributes to the prevention and/or repair of genomic DNA damage and serves an essential function in cellular survival. DNA binding proteins are involved in this network. Recently, several RNA-binding proteins (RBPs) that are recruited to DNA damage sites have been shown to be direct players in the prevention or repair of DNA damage. In addition, non-coding RNAs, themselves, are involved in the RNA mediated DNA repair system. Furthermore, RNA modification such as m6A methylation might also contribute to the ultraviolet-responsive DNA damage response. Accumulating evidence suggests that RNA metabolism is more deeply involved in diverse cellular functions than previously expected, and is also intricately associated with the maintenance of genome integrity. In this review, we highlight the roles of RBPs in the maintenance of genome integrity. PMID- 28644389 TI - Chronic Respiratory Infection in Patients with Chronic Obstructive Pulmonary Disease: What Is the Role of Antibiotics? AB - Chronic infections are associated with exacerbation in patients with chronic obstructive pulmonary disease (COPD). The major objective of the management of these patients is the prevention and effective treatment of exacerbations. Patients that have increased sputum production, associated with purulence and worsening shortness of breath, are the ones that will benefit from antibiotic therapy. It is important to give the appropriate antibiotic therapy to prevent treatment failure, relapse, and the emergence of resistant pathogens. In some patients, systemic corticosteroids are also indicated to improve symptoms. In order to identify which patients are more likely to benefit from these therapies, clinical guidelines recommend stratifying patients based on their risk factor associated with poor outcome or recurrence. It has been identified that patients with more severe disease, recurrent infection and presence of purulent sputum are the ones that will be more likely to benefit from this therapy. Another approach related to disease prevention could be the use of prophylactic antibiotics during steady state condition. Some studies have evaluated the continuous or the intermittent use of antibiotics in order to prevent exacerbations. Due to increased bacterial resistance to antibiotics and the presence of side effects, several antibiotics have been developed to be nebulized for both treatment and prevention of acute exacerbations. There is a need to design long-term studies to evaluate these interventions in the natural history of the disease. The purpose of this publication is to review our understanding of the role of bacterial infection in patients with COPD exacerbation, the role of antibiotics, and future interventions. PMID- 28644390 TI - The Electrosome: A Surface-Displayed Enzymatic Cascade in a Biofuel Cell's Anode and a High-Density Surface-Displayed Biocathodic Enzyme. AB - The limitation of surface-display systems in biofuel cells to a single redox enzyme is a major drawback of hybrid biofuel cells, resulting in a low copy number of enzymes per yeast cell and a limitation in displaying enzymatic cascades. Here we present the electrosome, a novel surface-display system based on the specific interaction between the cellulosomal scaffoldin protein and a cascade of redox enzymes that allows multiple electron-release by fuel oxidation. The electrosome is composed of two compartments: (i) a hybrid anode, which consists of dockerin-containing enzymes attached specifically to cohesin sites in the scaffoldin to assemble an ethanol oxidation cascade, and (ii) a hybrid cathode, which consists of a dockerin-containing oxygen-reducing enzyme attached in multiple copies to the cohesin-bearing scaffoldin. Each of the two compartments was designed, displayed, and tested separately. The new hybrid cell compartments displayed enhanced performance over traditional biofuel cells; in the anode, the cascade of ethanol oxidation demonstrated higher performance than a cell with just a single enzyme. In the cathode, a higher copy number per yeast cell of the oxygen-reducing enzyme copper oxidase has reduced the effect of competitive inhibition resulting from yeast oxygen consumption. This work paves the way for the assembly of more complex cascades using different enzymes and larger scaffoldins to further improve the performance of hybrid cells. PMID- 28644391 TI - Molecular Structure-Affinity Relationship of Flavonoids in Lotus Leaf (Nelumbo nucifera Gaertn.) on Binding to Human Serum Albumin and Bovine Serum Albumin by Spectroscopic Method. AB - Lotus leaf has gained growing popularity as an ingredient in herbal formulations due to its various activities. As main functional components of lotus leaf, the difference in structure of flavonoids affected their binding properties and activities. In this paper, the existence of 11 flavonoids in lotus leaf extract was confirmed by High Performance Liquid Chromatography (HPLC) analysis and 11 flavonoids showed various contents in lotus leaf. The interactions between lotus leaf extract and two kinds of serum albumins (human serum albumin (HSA) and bovine serum albumin (BSA)) were investigated by spectroscopic methods. Based on the fluorescence quenching, the interactions between these flavonoids and serum albumins were further checked in detail. The relationship between the molecular properties of flavonoids and their affinities for serum albumins were analyzed and compared. The hydroxylation on 3 and 3' position increased the affinities for serum albumins. Moreover, both of the methylation on 3' position of quercetin and the C2=C3 double bond of apigenin and quercetin decreased the affinities for HSA and BSA. The glycosylation lowered the affinities for HSA and BSA depending on the type of sugar moiety. It revealed that the hydrogen bond force played an important role in binding flavonoids to HSA and BSA. PMID- 28644393 TI - Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions. AB - A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2 negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (IMPG1 and IMPG2). We identified two novel mutations in IMPG1 in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c.807 + 5G > A splice site mutation. The latter induced partial skipping of exon 7 of IMPG1 in an in vitro splicing assay. Furthermore, we found heterozygous mutations including three stop [p.(Glu226*), p.(Ser522*), p.(Gln856*)] and five missense mutations [p.(Ala243Pro), p.(Gly1008Asp), p.(Phe1016Ser), p.(Tyr1042Cys), p.(Cys1077Phe)] in the IMPG2 gene, one of them, p.(Cys1077Phe), previously associated with VMD. Asymptomatic carriers of the p.(Ala243Pro) and p.(Cys1077Phe) mutations show subtle foveal irregularities that could characterize a subclinical stage of disease. Taken together, our results provide further evidence for an involvement of dominant and recessive mutations in IMPG1 and IMPG2 in VMD pathology. There is a remarkable similarity in the clinical appearance of mutation carriers, presenting with bilateral, central, dome-shaped foveal accumulation of yellowish material with preserved integrity of the retinal pigment epithelium (RPE). Clinical symptoms tend to be more severe for IMPG1 mutations. PMID- 28644392 TI - Development of Bone Targeting Drugs. AB - The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca2+. The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments. PMID- 28644394 TI - Synergistic Effect of MoS2 and SiO2 Nanoparticles as Lubricant Additives for Magnesium Alloy-Steel Contacts. AB - The tribological performances of the SiO2/MoS2 hybrids as lubricant additives were explored by a reciprocating ball-on-flat tribometer for AZ31 magnesium alloy/AISI 52100 bearing steel pairs. The results demonstrated that the introduction of SiO2/MoS2 hybrids into the base oil exhibited a significant reduction in the friction coefficient and wear volume as well as an increase in load bearing capacity, which was better than the testing results of the SiO2 or MoS2 nanolubricants. Specifically, the addition of 0.1 wt % nano-SiO2 mixed with 1.0 wt % nano-MoS2 into the base oil reduced the friction coefficient by 21.8% and the wear volume by 8.6% compared to the 1.0 wt % MoS2 nanolubricants. The excellent lubrication behaviors of the SiO2/MoS2 hybrid nanolubricants can be explained by the micro-cooperation of different nanoparticles with disparate morphology and lubrication mechanisms. PMID- 28644395 TI - Optical Tracking and Digital Quantification of Beating Behavior in Bioengineered Human Cardiac Organoids. AB - Organoid and organ-on-a-chip technologies are rapidly advancing towards deployment for drug and toxicology screening applications. Liver and cardiac toxicities account for the majority of drug candidate failures in human trials. Liver toxicity generally produces liver cell death, while cardiac toxicity causes adverse changes in heart beat kinetics. In traditional 2D cultures, beating kinetics can be measured by electrode arrays, but in some 3D constructs, quantifying beating kinetics can be more challenging. For example, real time measurements of calcium flux or contractile forces are possible, yet rather complex. In this communication article, we demonstrate a simple sensing system based on software code that optically analyzes video capture files of beating cardiac organoids, translates these files in representations of moving pixels, and quantifies pixel movement activity over time to generate beat kinetic plots. We demonstrate this system using bioengineered cardiac organoids under baseline and drug conditions. This technology offers a non-invasive, low-cost, and incredibly simple method for tracking and quantifying beating behavior in cardiac organoids and organ-on-a-chip systems for drug and toxicology screening. PMID- 28644397 TI - Relationship between Remote Sensing Data, Plant Biomass and Soil Nitrogen Dynamics in Intensively Managed Grasslands under Controlled Conditions. AB - The sustainable use of grasslands in intensive farming systems aims to optimize nitrogen (N) inputs to increase crop yields and decrease harmful losses to the environment at the same time. To achieve this, simple optical sensors may provide a non-destructive, time- and cost-effective tool for estimating plant biomass in the field, considering spatial and temporal variability. However, the plant growth and related N uptake is affected by the available N in the soil, and therefore, N mineralization and N losses. These soil N dynamics and N losses are affected by the N input and environmental conditions, and cannot easily be determined non-destructively. Therefore, the question arises: whether a relationship can be depicted between N fertilizer levels, plant biomass and N dynamics as indicated by nitrous oxide (N2O) losses and inorganic N levels. We conducted a standardized greenhouse experiment to explore the potential of spectral measurements for analyzing yield response, N mineralization and N2O emissions in a permanent grassland. Ryegrass was subjected to four mineral fertilizer input levels over 100 days (four harvests) under controlled environmental conditions. The soil temperature and moisture content were automatically monitored, and the emission rates of N2O and carbon dioxide (CO2) were detected frequently. Spectral measurements of the swards were performed directly before harvesting. The normalized difference vegetation index (NDVI) and simple ratio (SR) were moderately correlated with an increasing biomass as affected by fertilization level. Furthermore, we found a non-linear response of increasing N2O emissions to elevated fertilizer levels. Moreover, inorganic N and extractable organic N levels at the end of the experiment tended to increase with the increasing N fertilizer addition. However, microbial biomass C and CO2 efflux showed no significant differences among fertilizer treatments, reflecting no substantial changes in the soil biological pool size and the extent of the C mineralization. Neither the NDVI nor SR, nor the plant biomass, were related to cumulative N2O emissions or inorganic N at harvesting. Our results verify the usefulness of optical sensors for biomass detection, and show the difficulty in linking spectral measurements of plant traits to N processes in the soil, despite that the latter affects the former. PMID- 28644396 TI - RUNX1 Plays an Important Role in Mediating BMP9-Induced Osteogenic Differentiation of Mesenchymal Stem Cells Line C3H10T1/2, Murine Multi-Lineage Cells Lines C2C12 and MEFs. AB - As one of the least studied bone morphogenetic proteins (BMPs), BMP9 is highly capable of promoting osteogenic differentiation. However, the underlying mechanism involved remains largely unknown. Recent studies have demonstrated that RUNX1 (runt-related transcription factor 1) is essential in osteoblast/chondrocyte maturation. In this study, we investigated the function of RUNX1 in BMP9-induced osteogenic of murine mesenchymal stem cell line (C3H10T1/2) and murine multi-lineage cell lines (C2C12 and MEFs). Our data showed that BMP9 promoted the endogenous expression of RUNX1 in C3H10T1/2, C2C12 and MEFs. Moreover, RUNX1 was probably a direct target of BMP9/Smad signaling. BMP9-induced osteogenic differentiation was enhanced by overexpression of RUNX1, whereas inhibited by knockdown RUNX1 in C3H10T1/2, C2C12 and MEFs. Further mechanism studies demonstrated that RUNX1 might affect BMP9-induced phosphorylation of Smad1/5/8, but not the phosphorylation of p38 and ERK1/2.Our results suggest that RUNX1 may be an essential modulator in BMP9- induced osteogenic differentiation of MSCs (Mesenchymal stem cells). PMID- 28644398 TI - A Novel Wearable Forehead EOG Measurement System for Human Computer Interfaces. AB - Amyotrophic lateral sclerosis (ALS) patients whose voluntary muscles are paralyzed commonly communicate with the outside world using eye movement. There have been many efforts to support this method of communication by tracking or detecting eye movement. An electrooculogram (EOG), an electro-physiological signal, is generated by eye movements and can be measured with electrodes placed around the eye. In this study, we proposed a new practical electrode position on the forehead to measure EOG signals, and we developed a wearable forehead EOG measurement system for use in Human Computer/Machine interfaces (HCIs/HMIs). Four electrodes, including the ground electrode, were placed on the forehead. The two channels were arranged vertically and horizontally, sharing a positive electrode. Additionally, a real-time eye movement classification algorithm was developed based on the characteristics of the forehead EOG. Three applications were employed to evaluate the proposed system: a virtual keyboard using a modified Bremen BCI speller and an automatic sequential row-column scanner, and a drivable power wheelchair. The mean typing speeds of the modified Bremen brain-computer interface (BCI) speller and automatic row-column scanner were 10.81 and 7.74 letters per minute, and the mean classification accuracies were 91.25% and 95.12%, respectively. In the power wheelchair demonstration, the user drove the wheelchair through an 8-shape course without collision with obstacles. PMID- 28644399 TI - Effects of Biochar-Derived Sewage Sludge on Heavy Metal Adsorption and Immobilization in Soils. AB - The object of this study was to evaluate the effect of sewage sludge biochar on adsorption and mobility of Cr, Mn, Cu, and Zn. Biochar (BC400) was produced via pyrolysis of municipal sewage sludge at 400 degrees C. Maximum adsorption capacities (qm) for Zn, Cr, Mn, and Cu were 5.905, 5.724, 5.681, and 5.342 mg.g 1, respectively, in the mono-metal solution and 2.475, 8.204, 1.01, and 5.415 mg.g-1, respectively, in the multi-metal solution. The adsorption capacities for Mn, Cu, and Zn decreased in the multi-metal solution due to competitive adsorption, whereas the capacity for Cr increased. Surface precipitation is an important mechanism in the sorption of these metals on BC400. The 360-day incubation experiment showed that BC400 application reduced metal mobility in contaminated soils, which was attributed to the substantial decreases in the acid soluble fractions of Cr, Mn, Cu, and Zn (72.20%, 70.38%, 50.43%, and 29.78%, respectively). Furthermore, the leaching experiment using simulated acid rain indicated that the addition of BC400 enhanced the acid buffer capacity of contaminated soil, and the concentration of Cr, Mn, Cu, and Zn in the leachate was lower than in untreated soil. Overall, this study indicates that sewage sludge biochar application reduces the mobility of heavy metal in co-contaminated soil, and this adsorption experiment is suitable for the evaluation of biochar properties for remediation. PMID- 28644400 TI - Evaluation of Sources and Patterns of Elemental Composition of PM2.5 at Three Low Income Neighborhood Schools and Residences in Quito, Ecuador. AB - Elemental characterization of fine particulate matter was undertaken at schools and residences in three low income neighborhoods in Quito, Ecuador. The three zones were located in the northern (Cotocollao), south central (El Camal), and south east (Los Chillos) neighborhoods and were classified as zones 1-3, respectively. Forty elements were quantified via ICP-MS analysis. Amongst the geogenic elements, the concentration of Si was the most abundant followed by S, Al, and Ca. Elements with predominantly anthropogenic sources such as Zn, V, and Ni were higher in zone 3 school followed by zone 2 and zone 1 schools. Enrichment factors were calculated to study the role of crustal sources in the elemental concentrations. Geogenic elements, except K, all had values <10 and anthropogenic elements such as Ni, V, Zn, Pb, As, Cr had >10. Principal Component Analysis suggested that Ni and V concentrations were strongly attributable to pet coke and heavy oil combustion. Strong associations between As and Pb could be attributed to traffic and other industrial emissions. Resuspended dust, soil erosion, vehicular emissions (tailpipe, brake and tire wear, and engine abrasion), pet coke, heavy oil combustion, and heavy industrial operations were major contributors to air pollution. PMID- 28644401 TI - The Investigation of Electrochemistry Behaviors of Tyrosinase Based on Directly Electrodeposited Grapheneon Choline-Gold Nanoparticles. AB - A novel catechol (CA) biosensor was developed by embedding tyrosinase (Tyr) onto in situ electrochemical reduction graphene (EGR) on choline-functionalized gold nanoparticle (AuNPs-Ch) film. The results of UV-Vis spectra indicated that Tyr retained its original structure in the film, and an electrochemical investigation of the biosensor showed a pair of well-defined, quasi-reversible redox peaks with Epa = -0.0744 V and Epc = -0.114 V (vs. SCE) in 0.1 M, pH 7.0 sodium phosphate buffered saline at a scan rate of 100 mV/s. The transfer rate constant ks is 0.66 s-1. The Tyr-EGR/AuNPs-Ch showed a good electrochemical catalytic response for the reduction of CA, with the linear range from 0.2 to 270 MUM and a detection limit of 0.1 MUM (S/N = 3). The apparent Michaelis-Menten constant was estimated to be 109 MUM. PMID- 28644402 TI - Choosing Surgery for Neurogenic TOS: The Roles of Physical Exam, Physical Therapy, and Imaging. AB - Neurogenic thoracic outlet syndrome (nTOS) is characterized by arm and hand pain, paresthesias, and sometimes weakness resulting from compression of the brachial plexus within the thoracic outlet. While it is the most common subtype of TOS, nTOS can be difficult to diagnose. Furthermore, patient selection for surgical treatment can be challenging as symptoms may be vague and ambiguous, and diagnostic studies may be equivocal. Herein, we describe some approaches to aid in identifying patients who would be expected to benefit from surgical intervention for nTOS. We describe the role of physical examination, physical therapy, and imaging in the evaluation and diagnosis of nTOS. PMID- 28644403 TI - Assessment of Vulnerability to Coccidioidomycosis in Arizona and California. AB - Coccidioidomycosis is a fungal infection endemic to the southwestern United States, particularly Arizona and California. Its incidence has increased, potentially due in part to the effects of changing climatic variables on fungal growth and spore dissemination. This study aims to quantify the county-level vulnerability to coccidioidomycosis in Arizona and California and to assess the relationships between population vulnerability and climate variability. The variables representing exposure, sensitivity, and adaptive capacity were combined to calculate county level vulnerability indices. Three methods were used: (1) principal components analysis; (2) quartile weighting; and (3) percentile weighting. Two sets of indices, "unsupervised" and "supervised", were created. Each index was correlated with coccidioidomycosis incidence data from 2000-2014. The supervised percentile index had the highest correlation; it was then correlated with variability measures for temperature, precipitation, and drought. The supervised percentile index was significantly correlated (p < 0.05) with coccidioidomycosis incidence in both states. Moderate, positive significant associations (p < 0.05) were found between index scores and climate variability when both states were concurrently analyzed and when California was analyzed separately. This research adds to the body of knowledge that could be used to target interventions to vulnerable counties and provides support for the hypothesis that population vulnerability to coccidioidomycosis is associated with climate variability. PMID- 28644404 TI - Garlic Organosulfur Compounds Reduce Inflammation and Oxidative Stress during Dengue Virus Infection. AB - Dengue virus (DENV) is a mosquito-borne flavivirus that causes significant global human disease and mortality. One approach to develop treatments for DENV infection and the prevention of severe disease is through investigation of natural medicines. Inflammation plays both beneficial and harmful roles during DENV infection. Studies have proposed that the oxidative stress response may be one mechanism responsible for triggering inflammation during DENV infection. Thus, blocking the oxidative stress response could reduce inflammation and the development of severe disease. Garlic has been shown to both reduce inflammation and affect the oxidative stress response. Here, we show that the garlic active compounds diallyl disulfide (DADS), diallyl sulfide (DAS) and alliin reduced inflammation during DENV infection and show that this reduction is due to the effects on the oxidative stress response. These results suggest that garlic could be used as an alternative treatment for DENV infection and for the prevention of severe disease development. PMID- 28644405 TI - Socioeconomic Status and Health: A New Approach to the Measurement of Bivariate Inequality. AB - We suggest an alternative way to construct a family of indices of socioeconomic inequality of health. Our indices belong to the broad category of linear indices. In contrast to rank-dependent indices, which are defined in terms of the ranks of the socioeconomic variable and the levels of the health variable, our indices are based on the levels of both the socioeconomic and the health variable. We also indicate how the indices can be modified in order to introduce sensitivity to inequality in the socioeconomic distribution and to inequality in the health distribution. As an empirical illustration, we make a comparative study of the relation between income and well-being in 16 European countries using data from the Survey of Health, Ageing and Retirement in Europe (SHARE) Wave 4. PMID- 28644407 TI - Cotton Ascorbate Oxidase Promotes Cell Growth in Cultured Tobacco Bright Yellow-2 Cells through Generation of Apoplast Oxidation. AB - Ascorbate oxidase (AO) plays an important role in cell growth through the modulation of reduction/oxidation (redox) control of the apoplast. Here, a cotton (Gossypium hirsutum) apoplastic ascorbate oxidase gene (GhAO1) was obtained from fast elongating fiber tissues. GhAO1 belongs to the multicopper oxidase (MCO) family and includes a signal peptide and several transmembrane regions. Analyses of quantitative real-time polymerase chain reaction (QRT-PCR) and enzyme activity showed that GhAO1 was expressed abundantly in 15-day post-anthesis (dpa) wild type (WT) fibers in comparison with fuzzless-lintless (fl) mutant ovules. Subcellular distribution analysis in onion cells demonstrated that GhAO1 is localized in the cell wall. In transgenic tobacco bright yellow-2 (BY-2) cells with ectopic overexpression of GhAO1, the enhancement of cell growth with 1.52 fold increase in length versus controls was indicated, as well as the enrichment of both total ascorbate in whole-cells and dehydroascorbate acid (DHA) in apoplasts. In addition, promoted activities of AO and monodehydroascorbate reductase (MDAR) in apoplasts and dehydroascorbate reductase (DHAR) in whole cells were displayed in transgenic tobacco BY-2 cells. Accumulation of H2O2, and influenced expressions of Ca2+ channel genes with the activation of NtMPK9 and NtCPK5 and the suppression of NtTPC1B were also demonstrated in transgenic tobacco BY-2 cells. Finally, significant induced expression of the tobacco NtAO gene in WT BY-2 cells under indole-3-acetic acid (IAA) treatment appeared; however, the sensitivity of the NtAO gene expression to IAA disappeared in transgenic BY-2 cells, revealing that the regulated expression of the AO gene is under the control of IAA. Taken together, these results provide evidence that GhAO1 plays an important role in fiber cell elongation and may promote cell growth by generating the oxidation of apoplasts, via the auxin-mediated signaling pathway. PMID- 28644408 TI - Isolation and Selection of Microalgal Strains from Natural Water Sources in Viet Nam with Potential for Edible Oil Production. AB - Industrial vegetable oil production in Viet Nam depends on oil seeds and crude plant oils that are currently more than 90% imported. As the first step in investigating the feasibility of using microalgae to provide Viet Nam with a domestic source of oil for food and edible oil industries, fifty lipid-producing microalgae were isolated and characterized. The microalgae were isolated from water sources ranging from freshwater to brackish and marine waters from a wide geographic distribution in Viet Nam. Initial analyses showed that 20 of the 50 strains had good growth rates, produced high biomass and had high lipid content, ranging up to 50% of dry weight biomass. 18S rRNA gene sequence analyses of the 50 strains showed a great diversity in this assemblage of microalgae, comprising at least 38 species and representatives of 25 genera: Chlamydomonas, Poterioochromonas, Scenedesmus, Desmodesmus, Chlorella, Bracteacoccus, Monoraphidium, Selenastrum, Acutodesmus, Mychonastes, Ankistrodesmus, Kirchneriella, Raphidocelis, Dictyosphaerium, Coelastrella, Schizochlamydella, Oocystidium, Nannochloris, Auxenochlorella, Chlorosarcinopsis, Stichococcus, Picochlorum, Prasinoderma, Chlorococcum, and Marvania. Some of the species are closely related to well-known lipid producers such as Chlorella sorokiniana, but some other strains are not closely related to the strains found in public sequence databases and likely represent new species. Analysis of oil quality showed that fatty acid profiles of the microalgal strains were very diverse and strain-dependent. Fatty acids in the microalgal oils comprised saturated fatty acids (SFAs), poly-unsaturated fatty acids (PUFAs), and mono-unsaturated fatty acids (MUFAs). The main SFA was palmitic acid. MUFAs and PUFAs were dominated by oleic acid, and linoleic and linolenic acids, respectively. Some strains were especially rich in the essential fatty acid alpha-linolenic acid (ALA), which comprised more than 20% of the fatty acids in these strains. Other strains had fatty acid compositions similar to that of palm oil. Several strains have been selected on the basis of their suitable fatty acid profiles and high lipid content for further chemical and physical characterization, toxicity and organoleptic tests of their oils, and for scale-up. PMID- 28644409 TI - Quercetin Protects Obesity-Induced Hypothalamic Inflammation by Reducing Microglia-Mediated Inflammatory Responses via HO-1 Induction. AB - Obesity-induced hypothalamic inflammation is characterized by activation of microglia, which are resident macrophages of the central nervous system, and is implicated in the derangement of energy homeostasis, metabolic complications, and neurodegenerative diseases. Quercetin, a naturally occurring flavonoid, is known to protect against oxidative stress and inflammation-related metabolic complications. Here, we demonstrate that quercetin reduces obesity-induced hypothalamic inflammation by inhibiting microglia-mediated inflammatory responses, and the beneficial action of quercetin is associated with heme oxygenase (HO-1) induction. Quercetin markedly reduced the production of inflammatory mediators (monocyte chemoattractant protein (MCP)-1, interleukin (IL 6), IL-1beta, nitric oxide) by microglia stimulated with saturated fatty acid palmitate and/or lipid-laden microglia-conditioned medium. Quercetin also upregulated the expression of HO-1 in palmitate-treated lipid-laden microglia, and the actions of quercetin against microglia activation accompanied by IkappaBalpha degradation were abolished by a HO-1 inhibitor. Moreover, quercetin supplementation reduced the levels of inflammatory cytokines and microglia activation markers in the hypothalamus of high fat diet (HFD)-fed obese mice, which was accompanied by upregulation of HO-1. These findings indicate that quercetin suppresses microglia-mediated inflammatory responses via the induction of HO-1, and hence protects against obesity-induced hypothalamic inflammation. PMID- 28644406 TI - An Updated Review on Marine Anticancer Compounds: The Use of Virtual Screening for the Discovery of Small-Molecule Cancer Drugs. AB - Marine secondary metabolites are a promising source of unexploited drugs that have a wide structural diversity and have shown a variety of biological activities. These compounds are produced in response to the harsh and competitive conditions that occur in the marine environment. Invertebrates are considered to be among the groups with the richest biodiversity. To date, a significant number of marine natural products (MNPs) have been established as antineoplastic drugs. This review gives an overview of MNPs, both in research or clinical stages, from diverse organisms that were reported as being active or potentially active in cancer treatment in the past seventeen years (from January 2000 until April 2017) and describes their putative mechanisms of action. The structural diversity of MNPs is also highlighted and compared with the small-molecule anticancer drugs in clinical use. In addition, this review examines the use of virtual screening for MNP-based drug discovery and reveals that classical approaches for the selection of drug candidates based on ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering may miss potential anticancer lead compounds. Finally, we introduce a novel and publically accessible chemical library of MNPs for virtual screening purposes. PMID- 28644410 TI - Enhanced Antibacterial Activity of Ent-Labdane Derivatives of Salvic Acid (7alpha Hydroxy-8(17)-ent-Labden-15-Oic Acid): Effect of Lipophilicity and the Hydrogen Bonding Role in Bacterial Membrane Interaction. AB - In the present study, the antibacterial activity of several ent-labdane derivatives of salvic acid (7alpha-hydroxy-8(17)-ent-labden-15-oic acid) was evaluated in vitro against the Gram-negative bacterium Escherichia coli and the Gram-positive bacteria Staphylococcus aureus and Bacillus cereus. For all of the compounds, the antibacterial activity was expressed as the minimum inhibitory concentration (MIC) in liquid media and minimum inhibitory amount (MIA) in solid media. Structure activity relationships (SAR) were employed to correlate the effect of the calculated lipophilicity parameters (logPow) on the inhibitory activity. Employing a phospholipidic bilayer (POPG) as a bacterial membrane model, ent-labdane-membrane interactions were simulated utilizing docking studies. The results indicate that (i) the presence of a carboxylic acid in the C 15 position, which acted as a hydrogen-bond donor (HBD), was essential for the antibacterial activity of the ent-labdanes; (ii) an increase in the length of the acylated chain at the C-7 position improved the antibacterial activity until an optimum length of five carbon atoms was reached; (iii) an increase in the length of the acylated chain by more than five carbon atoms resulted in a dramatic decrease in activity, which completely disappeared in acyl chains of more than nine carbon atoms; and (iv) the structural factors described above, including one HBD at C-15 and a hexanoyloxi moiety at C-7, had a good fit to a specific lipophilic range and antibacterial activity. The lipophilicity parameter has a predictive characteristic feature on the antibacterial activity of this class of compounds, to be considered in the design of new biologically active molecules. PMID- 28644411 TI - On the Reaction of Carbonyl Diphosphonic Acid with Hydroxylamine and O alkylhydroxylamines: Unexpected Degradation of P-C-P Bridge. AB - Derivatives of methylenediphosphonic acid possess wide spectra of biological activities and are used in enzymology as research tools as well as in practical medicine. Carbonyl diphosphonic acid is a promising starting building block for synthesis of functionally substituted methylenediphosphonates. Investigation of the interaction of carbonyl diphosphonic acid with hydroxylamine clearly demonstrates that it is impossible to isolate oxime within the pH range 2-12, while only cyanophosphonic and phosphoric acids are the products of the fast proceeding Beckmann-like fragmentation. In the case of O-alkylhydroxylamines, corresponding alcohols are found in the reaction mixtures in addition to cyanophosphonic and phosphoric acids. Therefore, two residues of phosphonic acid being attached to a carbonyl group provide new properties to this carbonyl group, making its oximes very unstable. This principally differs carbonyl diphosphonic acid from structurally related phosphonoglyoxalic acid and other alpha ketophosphonates. PMID- 28644412 TI - A Systematic Review of Fatalities Related to Acute Ingestion of Salt. A Need for Warning Labels? AB - There are sporadic cases of fatalities from acutely eating salt. Yet, on social media, there are "challenges to" and examples of children and some adults acutely eating salt, and recently a charity advocated eating small amounts of salt to empathize with Syrian refugees. We performed a systematic review of fatalities from ingesting salt to assess if relatively moderate doses of salt could be fatal. In 27 reports, there were 35 fatalities documented (19 in adults and 16 in children). The lethal dose was estimated to be less than 10 g of sodium (<5 teaspoons of salt) in two children, and less than 25 g sodium in four adults (<4 tablespoons of salt). The frequency of fatal ingestion of salt is not able to be discerned from our review. If investigation of the causes of hypernatremia in hospital records indicates salt overdose is relatively common, consideration could be given to placing warning labels on salt containers and shakers. Such warning labels can have the added advantage of reducing dietary salt consumption. PMID- 28644413 TI - Clonal Diversity of ESBL-Producing Escherichia coli Isolated from Environmental, Human and Food Samples. AB - This study presents a comprehensive approach of a clonal diversity analysis of 448 Extended-spectrum beta-lactamase (ESBL)-producing E. coli isolated from environmental, human and food samples in Spain. The phenotypic confirmation of ESBL production was performed by disc diffusion and microdilution methods, while Polymerase Chain Reaction (PCR) and sequencing were used for the molecular characterization of beta-lactamase genes (blaCTX-M, blaSHV, blaTEM, blaOXA). Clonal relationship of isolates was determined by multi-locus sequence typing (MLST). Multidrug resistant strains were present in all the studied niches, with percentages above 50.0%. The most prevalent beta-lactamase genes were blaCTXM-14 (26%) and blaCTXM-1 (21.4%), followed by blaSHV-12, blaCTX-M-15 and blaTEM-42. MLST isolates were grouped into 26 clonal complexes (CC) and 177 different sequence types (ST) were detected. Despite the high clonal diversity observed, CC10 was the prevalent and the only CC detected in all niches, while other complexes as CC131 were mainly associated to human isolates. The observed prevalence and diversity of these resistant bacteria across the different environments encourages a One Health approach to prevent and control ESBL dissemination between environment and consumers. PMID- 28644414 TI - Benefits, Facilitators, Barriers, and Strategies to Improve Pesticide Protective Behaviors: Insights from Farmworkers in North Carolina Tobacco Fields. AB - Pesticide exposure is associated with deleterious health effects. Prior studies suggest Latino farmworkers perceive little control over their occupational health. Using the Health Belief Model as a theoretical guide, we explored the perceptions of Latino farmworkers working in tobacco in North Carolina (n = 72) about benefits and facilitators of pesticide protective behaviors as well as barriers, and strategies to overcome barriers to their use. Interviews were conducted with participants at farmworker housing during non-work time. Qualitative data were analyzed using ATLAS.ti. Farmworkers recognized pesticide protective behaviors as helping them to not get sick and stay healthy. Farmworkers perceived work experience as facilitating protective behaviors. Wetness in the field was the most commonly cited barrier to protective behavior use. To overcome this barrier, farmworkers suggested use of water-resistant outerwear, as well as packing a change of clothes for mid-day, with space and time to change provided by employers. Examination of the efficacy and feasibility of farmworkers' suggestions for addressing barriers is warranted. Training and behavior modeling by experienced peers may improve behavior adoption and perceived control. PMID- 28644415 TI - Genome-Wide Association Study of Dietary Pattern Scores. AB - Dietary patterns, representing global food supplies rather than specific nutrients or food intakes, have been associated with cardiovascular disease (CVD) incidence and mortality. The contribution of genetic factors in the determination of food intakes, preferences and dietary patterns has been previously established. The current study aimed to identify novel genetic factors associated with reported dietary pattern scores. Reported dietary patterns scores were derived from reported dietary intakes for the preceding month and were obtained through a food frequency questionnaire and genome-wide association study (GWAS) conducted in a study sample of 141 individuals. Reported Prudent and Western dietary patterns demonstrated nominal associations (p < 1 * 10-5) with 78 and 27 single nucleotide polymorphisms (SNPs), respectively. Among these, SNPs annotated to genes previously associated with neurological disorders, CVD risk factors and obesity were identified. Further assessment of SNPs demonstrated an impact on gene expression levels in blood for SNPs located within/near BCKDHB (p = 0.02) and the hypothalamic glucosensor PFKFB3 (p = 0.0004) genes, potentially mediated through an impact on the binding of transcription factors (TFs). Overrepresentations of glucose/energy homeostasis and hormone response TFs were also observed from SNP-surrounding sequences. Results from the current GWAS study suggest an interplay of genes involved in the metabolic response to dietary patterns on obesity, glucose metabolism and food-induced response in the brain in the adoption of dietary patterns. PMID- 28644416 TI - Evaluation of Trace Element and Metal Accumulation and Edibility Risk Associated with Consumption of Labeo umbratus from the Vaal Dam, South Africa. AB - With the occurrence of recreational and small scale subsistence fishing activities at the Vaal Dam, South Africa, consumption of fish from this dam may result in health risks associated with trace elements and metals. The Vaal Dam is one of the largest dams in South Africa, located between the Gauteng Province and Orange Free State, and supplies water to approximately 11.6 million people. A total of 38 specimens of the benthic cyprinid fish Labeo umbratus were collected from the Vaal Dam during two surveys, in 2011 and 2016. Samples of muscle, liver, kidney, gill and spinal cord were analysed, along with sediment samples collected during the same surveys. Thirteen trace elements were analysed in the samples by Inductively Coupled Plasma-Optical Emission Spectrometry, Inductively Coupled Plasma-Mass Spectrometry, Atomic Absorption Spectroscopy and Total Reflection X ray Fluorescence spectroscopy. This is the first survey on trace element and Hg accumulation in this fish species from the Vaal Dam and target hazard quotients (THQ) indicated that there is a risk for consumers of fish for As and Hg (THQ = 1.43 and 1.14 respectively). Although levels of trace elements in this impoundment have shown little change for a number of years and are lower than global background levels, studies detailing the accumulation of metals by fish inhabiting the Vaal Dam have indicated that trace elements in muscle tissue are above food safety guidelines. Trace element levels in L. umbratus are lower compared to other species inhabiting the Vaal Dam and further indicate that risks for consumers can be decreased if humans relying on fish from the Vaal Dam preferentially consume this species over others. PMID- 28644417 TI - Herpes Simplex Virus Establishment, Maintenance, and Reactivation: In Vitro Modeling of Latency. AB - All herpes viruses establish lifelong infections (latency) in their host, and herpes simplex viruses (HSVs) are highly prevalent worldwide. Recurrence of HSV infections contributes to significant disease burden in people and on rare occasion can be fatal. Cell culture models that recapitulate latent infection provide valuable insight on the host processes regulating viral establishment and maintenance of latency. More robust and rapid than infections in live animal studies, advancements in neuronal culture techniques have made the systematic analysis of viral reactivation mechanisms feasible. Only recently have human neuronal cell lines been available, but models in the natural host cell are a critical addition to the currently available models. PMID- 28644418 TI - New MT2 Melatonin Receptor-Selective Ligands: Agonists and Partial Agonists. AB - The search for melatonin receptor agonists and antagonists specific towards one of the receptor subtypes will extend our understanding of the role of this system in relaying circadian information to the body. A series of compounds derived from a hit compound discovered in a screening process led to powerful agonists specific for one of the isoform of the melatonin receptor namely, MT2. The compounds are based on a poorly explored skeleton in the molecular pharmacology of melatonin. By changing the steric hindrance of one substituent (i.e., from a hydrogen atom to a tributylstannyl group), we identified a possible partial agonist that could lead to antagonist analogues. The functionalities of these compounds were measured with a series of assays, including the binding of GTPgammaS, the inhibition of the cyclic AMP production, the beta-arrestin recruitment, and the cell shape changes as determined by cellular dielectric spectroscopy (CellKey(r)). The variations between the compounds are discussed. PMID- 28644419 TI - Context Relevant Prediction Model for COPD Domain Using Bayesian Belief Network. AB - In the last three decades, researchers have examined extensively how context aware systems can assist people, specifically those suffering from incurable diseases, to help them cope with their medical illness. Over the years, a huge number of studies on Chronic Obstructive Pulmonary Disease (COPD) have been published. However, how to derive relevant attributes and early detection of COPD exacerbations remains a challenge. In this research work, we will use an efficient algorithm to select relevant attributes where there is no proper approach in this domain. Such algorithm predicts exacerbations with high accuracy by adding discretization process, and organizes the pertinent attributes in priority order based on their impact to facilitate the emergency medical treatment. In this paper, we propose an extension of our existing Helper Context Aware Engine System (HCES) for COPD. This project uses Bayesian network algorithm to depict the dependency between the COPD symptoms (attributes) in order to overcome the insufficiency and the independency hypothesis of naive Bayesian. In addition, the dependency in Bayesian network is realized using TAN algorithm rather than consulting pneumologists. All these combined algorithms (discretization, selection, dependency, and the ordering of the relevant attributes) constitute an effective prediction model, comparing to effective ones. Moreover, an investigation and comparison of different scenarios of these algorithms are also done to verify which sequence of steps of prediction model gives more accurate results. Finally, we designed and validated a computer-aided support application to integrate different steps of this model. The findings of our system HCES has shown promising results using Area Under Receiver Operating Characteristic (AUC = 81.5%). PMID- 28644420 TI - Within What Distance Does "Greenness" Best Predict Physical Health? A Systematic Review of Articles with GIS Buffer Analyses across the Lifespan. AB - Is the amount of "greenness" within a 250-m, 500-m, 1000-m or a 2000-m buffer surrounding a person's home a good predictor of their physical health? The evidence is inconclusive. We reviewed Web of Science articles that used geographic information system buffer analyses to identify trends between physical health, greenness, and distance within which greenness is measured. Our inclusion criteria were: (1) use of buffers to estimate residential greenness; (2) statistical analyses that calculated significance of the greenness-physical health relationship; and (3) peer-reviewed articles published in English between 2007 and 2017. To capture multiple findings from a single article, we selected our unit of inquiry as the analysis, not the article. Our final sample included 260 analyses in 47 articles. All aspects of the review were in accordance with PRISMA guidelines. Analyses were independently judged as more, less, or least likely to be biased based on the inclusion of objective health measures and income/education controls. We found evidence that larger buffer sizes, up to 2000 m, better predicted physical health than smaller ones. We recommend that future analyses use nested rather than overlapping buffers to evaluate to what extent greenness not immediately around a person's home (i.e., within 1000-2000 m) predicts physical health. PMID- 28644421 TI - Antibacterial Effect of a 4x Cu-TiO2 Coating Simulating Acute Periprosthetic Infection-An Animal Model. AB - The purpose of our study was to investigate the antibacterial effect of a spacer (Ti6Al4V) coated with 4x Cu-TiO2 in an animal model simulating an acute periprosthetic infection by Staphylococcus aureus. Ti6Al4 bolts contaminated with Staphylococcus aureus were implanted into the femoral condyle of rabbits (n = 36) divided into 3 groups. After one week in group 1 (control) the bolts were removed without any replacement. In group2 Ti6Al4V bolts with a 4x Cu-TiO2 coating and in group 3 beads of a gentamicin-PMMA chain were imbedded into the borehole. Microbiological investigation was performed at the primary surgery, at the revision surgery and after scarification of the rabbits 3 weeks after the first surgery. Blood tests were conducted weekly. The initial overall infection rate was 88.9%. In group 2 and 3 a significant decrease of the infection rate was shown in contrast to the control group. The C-reactive protein (CRP) levels declined one week after the first surgery except in the control group where the CRP level even increased. This is the first in vivo study that demonstrated the antibacterial effects of a fourfold Cu-TiO2 coating. For the future, the coating investigated could be a promising option in the treatment of implant-associated infections. PMID- 28644422 TI - Immersive Virtual Reality for Pediatric Pain. AB - Children must often endure painful procedures as part of their treatment for various medical conditions. Those with chronic pain endure frequent or constant discomfort in their daily lives, sometimes severely limiting their physical capacities. With the advent of affordable consumer-grade equipment, clinicians have access to a promising and engaging intervention for pediatric pain, both acute and chronic. In addition to providing relief from acute and procedural pain, virtual reality (VR) may also help to provide a corrective psychological and physiological environment to facilitate rehabilitation for pediatric patients suffering from chronic pain. The special qualities of VR such as presence, interactivity, customization, social interaction, and embodiment allow it to be accepted by children and adolescents and incorporated successfully into their existing medical therapies. However, the powerful and transformative nature of many VR experiences may also pose some risks and should be utilized with caution. In this paper, we review recent literature in pediatric virtual reality for procedural pain and anxiety, acute and chronic pain, and some rehabilitation applications. We also discuss the practical considerations of using VR in pediatric care, and offer specific suggestions and information for clinicians wishing to adopt these engaging therapies into their daily clinical practice. PMID- 28644425 TI - Significance of parathyroid scintigraphy and correlation of findings with parathyroid hormone values in patients undergoing hemodialysis. AB - Aim To compare finding of thyroid gland scintigraphy with serum concentration of parathyroid hormone in patients undergoing hemodialysis. Methods This retrospective-prospective study included 50 patients undergoing hemodialysis with established hyperparathyroidism who were treated at Cantonal Hospital Zenica in the period 2009 - 2014. Besides anthropological data, concentration of parathyroid hormone in serum of patients was monitored too. Scintigraphy was performed at the Department of Nuclear Medicine using two-headed gamma camera Prism 2000xp. Results Of the total number of 50 patients, 24 (48%) were males and 26 (52%) were females. The average age was 49.34+/-11.82 years. A total of 17 (34%) patients had normal findings of scintigraphy, 11 (22%) had mildly pronounced uptake of radiopharmaceuticals (score of 1), 14 (28%) had moderately pronounced uptake (score of 2), and eight (16%) had intensive uptake of radiopharmaceuticals (score of 3). A statistically significant difference was established in the length of hemodialysis treatment and scintigraphy finding (p=0.041). Conclusion Scintigraphy of parathyroid glands in patients undergoing hemodialysis allows us to select them for parathyroidectomy. Scintigraphy of parathyroid glands and a value of parathormone in serum should be incorporated into the test algorithm for patients with secondary hyperparathyroidism caused by chronic kidney disease. PMID- 28644423 TI - Probing the Interaction of Dielectric Nanoparticles with Supported Lipid Membrane Coatings on Nanoplasmonic Arrays. AB - The integration of supported lipid membranes with surface-based nanoplasmonic arrays provides a powerful sensing approach to investigate biointerfacial phenomena at membrane interfaces. While a growing number of lipid vesicles, protein, and nucleic acid systems have been explored with nanoplasmonic sensors, there has been only very limited investigation of the interactions between solution-phase nanomaterials and supported lipid membranes. Herein, we established a surface-based localized surface plasmon resonance (LSPR) sensing platform for probing the interaction of dielectric nanoparticles with supported lipid bilayer (SLB)-coated, plasmonic nanodisk arrays. A key emphasis was placed on controlling membrane functionality by tuning the membrane surface charge vis-a vis lipid composition. The optical sensing properties of the bare and SLB-coated sensor surfaces were quantitatively compared, and provided an experimental approach to evaluate nanoparticle-membrane interactions across different SLB platforms. While the interaction of negatively-charged silica nanoparticles (SiNPs) with a zwitterionic SLB resulted in monotonic adsorption, a stronger interaction with a positively-charged SLB resulted in adsorption and lipid transfer from the SLB to the SiNP surface, in turn influencing the LSPR measurement responses based on the changing spatial proximity of transferred lipids relative to the sensor surface. Precoating SiNPs with bovine serum albumin (BSA) suppressed lipid transfer, resulting in monotonic adsorption onto both zwitterionic and positively-charged SLBs. Collectively, our findings contribute a quantitative understanding of how supported lipid membrane coatings influence the sensing performance of nanoplasmonic arrays, and demonstrate how the high surface sensitivity of nanoplasmonic sensors is well-suited for detecting the complex interactions between nanoparticles and lipid membranes. PMID- 28644424 TI - The Indirect Efficacy Comparison of DNA Methylation in Sputum for Early Screening and Auxiliary Detection of Lung Cancer: A Meta-Analysis. AB - BACKGROUND: DNA methylation in sputum has been an attractive candidate biomarker for the non-invasive screening and detection of lung cancer. MATERIALS AND METHODS: Databases including PubMed, Ovid, Cochrane library, Web of Science databases, Chinese Biological Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang, Vip Databases and Google Scholar were searched to collect the diagnostic trials on aberrant DNA methylation in the screening and detection of lung cancer published until 1 December 2016. Indirect comparison meta-analysis was used to evaluate the diagnostic value of the included candidate genes. RESULTS: The systematic literature search yielded a total of 33 studies including a total of 4801 subjects (2238 patients with lung cancer and 2563 controls) and covering 32 genes. We identified that methylated genes in sputum samples for the early screening and auxiliary detection of lung cancer yielded an overall sensitivity of 0.46 (0.41-0.50) and specificity of 0.83 (0.80-0.86). Combined indirect comparisons identified the superior gene of SOX17 (sensitivity: 0.84, specificity: 0.88), CDO1 (sensitivity: 0.78, specificity: 0.67), ZFP42 (sensitivity: 0.87, specificity: 0.63) and TAC1 (sensitivity: 0.86, specificity: 0.75). CONCLUSIONS: The present meta-analysis demonstrates that methylated SOX17, CDO1, ZFP42, TAC1, FAM19A4, FHIT, MGMT, p16, and RASSF1A are potential superior biomarkers for the screening and auxiliary detection of lung cancer. PMID- 28644426 TI - The association between the serum levels of matrix metalloproteinase 9 and colorectal cancer. AB - Aim To determine the serum levels of matrix metalloproteinase 9 (MMP-9) concentration and their association with the stage and histopathologic sizes of colorectal cancer (CRC). Methods One hundred and two patients with clinically diagnosed and histologically confirmed colorectal cancer ready for surgical treatment were included in the study. In each patient, preoperative peripheral venous blood samples were taken for determination of the concentration of MMP-9 using ELISA immunoassay test. Resected tumour specimens were studied pathologically according to the criteria of the TNM classification. All patients were divided into groups according to the TNM classification. The control group presented 30 subjects of the appropriate age and gender with no family history of cancer, clinical signs of malignancy or inflammatory bowel disease. Results The serum levels of MMP-9 were progressively increased in patients with CRC reaching the highest value in the fourth stage of CRC. It was also confirmed that the serum concentrations of MMP-9 were significantly higher in patients with pericolonic lymph nodes involvement compared to the patients with no involvement of lymph nodes, 456.4 (445.9-464.7) ng/mL vs. 438.4 (418.4-447.8) ng/mL (p<0.001). Significantly higher serum levels of MMP-9 were found in the patients with metastatic CRC, 458.5 (452.0-468.1) ng/mL compared with the CRC patients without metastasis, 445.8 (436.9-456.5) ng/mL (p<0.001). Conclusion It was confirmed that serum concentration of MMP-9 presented the significant independent risk factors for the progression of CRC. PMID- 28644427 TI - Mental diseases and criminal offences committed by persons placed at the Forensic Department of the Penitentiary in Zenica, Federation of Bosnia and Herzegovina. AB - Aim To investigate an impact of various biological, psychological and social factors on perpetration of criminal offences by persons with mental disorders and to examine legal requirements for placement of persons with mental disorders, who committed criminal offences. Methods This retrospective, descriptive study based on the analysis of data collected from records of the Zenica Penitentiary, Forensic Department (age, qualifications, employment status, marital status, mental disorders, information related to earlier treatments, type of committed criminal offense, duration of the security measure of mandatory psychiatric treatment and custody) included 154 examinees. Results The study included 154 male examinees. An average age of the examinees was 34 years. An average duration spent at the Forensic Department was 3 years, murder was committed by 68 (44.15%) examinees, and 34 (22.07%) examinees committed attempted murder. Eighty-five (55. 19 %) examinees suffered from schizophrenia, 30 (19.48%) had delusional disorder, and 19 (12.33%) had mental retardation. Conclusion The highest number of committed crimes was in correlation with schizophrenia, (the highest number of examinees suffered from schizophrenia). It is necessary to work on the establishment of a forensic hospital in the territory of the Federation of Bosnia and Herzegovina in order to create good conditions for rehabilitation of patients with mental disorders who committed criminal offences. PMID- 28644428 TI - Early results of the conservative treatment of distal radius fractures immobilization of the wrist in dorsal versus palmar flexion. AB - Aim To evaluate immobilization with dorsal forearm plaster splint with the wrist in dorsal flexion vs palmar flexion in patients with distal radius fracture. Methods In the prospective study (2012-2014) 122 patients (of which 22 patients lost) with fractures of the distal radius type A2, A3 and C according to the AO classification were investigated. At the end there were 50 patients in each of the two groups: the dorsiflexion (DF) group had a total of 37 women and 13 men, mean age was 63.48 +/- 14.70, and in the palmar flexion (PF) group there were respectively 38/12, and the mean age was 64.20 +/- 12.99. In both groups measurements of radiological, clinical and functional parameters were conducted. Patient related wrist evaluation survey (PRWE) and SF12 questionnaire were used for evaluation of pain and function of the wrist and physical and mental condition, respectively. Results The study showed excellent results in both groups but there was significant improvement in the range of motion (ROM) on every measurement in the DF group: dorsal flexion 47.70+/-15.29; ulnar deviation 24.10+/-7.80; radial deviation 11.50+/-5.65 vs PF 22.80+/-19.04; 16.00+/- 9.31; 4.80+/- 494 (p<0.001). Also, radiological parameters showed significant improvement until the end of the follow-up. Functional parameters showed significant improvement of physical component of SF-12 in the DF group (p<0.014). Conclusion Immobilization with forearm plaster splint on the dorsal side and with the wrist in dorsiflexion gives better early clinical, radiological and functional results in patients with fractures of type A2, A3, C1-3 in patients of all age groups, compared to immobilization with the wrist in palmar flexion. PMID- 28644429 TI - Cytotoxic and genotoxic studies of essential oil from Rosa damascene Mill., Kashan, Iran. AB - Aim Rosa damascene Mill. belongs to the family of Roseaceae and its essential oil is produced in large amounts in Iran. The wide application of rose oil has raised questions about potential adverse health effects. We have investigated cytotoxic activity and genotoxic effects of Rosa oil from Kashan, Iran. Methods The cytotoxic effect and IC50 of the essential oil on the cell lines was studied followed by MTT assay. In this assay mitochondrial oxidoreductase enzymes with reducing the tetrazolium dye MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide) reflect the number of viable cells. Genotoxic effect of the oil was evaluated by micronucleus assay by evaluating produced micronuclei due to cytogenetic damage in binucleated lymphocytes. Results The results showed that essential oil significantly had cytotoxic and genotoxic effects at doses over 10ug/mL (p<0.05). Also, essential oil of Rose showed lower IC50 in cancer cell line (A549) in comparison with the normal cell line (NIH3T3). Conclusion Cytotoxic and genotoxic properties of essential oil of Rose in Kashan, Iran, are safe at a dose of 10ug/mL. Also, a good cytotoxic effect was shown and could be introduced as an anticancer compound. Further studies are needed with regard to anti-cancer effects of Rose essential oil. PMID- 28644430 TI - The clinical landscape for SMA in a new therapeutic era. AB - Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene provides, for the first time, a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases. PMID- 28644431 TI - An in vitro study on the efficacy of removing calcium hydroxide from curved root canal systems in root canal therapy. AB - To compare the efficacy of various irrigants (citric acid, ethylenediaminetetraacetic acid (EDTA) and NaOCl) and techniques in removing Ca(OH)2 in two types of curved root canal systems, simulated root canals with specific curvatures were used to investigate the effects of different irrigants and instruments on Ca(OH)2 removal. The optimal methods were verified on extracted human teeth. Simulated root canals were assigned to one of two groups based on the irrigation solution: 10% citric acid or 2.5% NaOCl. Each group was divided into four subgroups according to the technique used to remove Ca(OH)2. The percentage of Ca(OH)2 removal in different sections of root canals was calculated. On the basis of the results obtained for the simulated canals, 10% citric acid and 17% EDTA were applied to remove Ca(OH)2 from the extracted human teeth with curved root canal systems. The teeth were scanned by micro computed tomography to calculate the percentage of Ca(OH)2 removal in the canals. In simulated root canals, we found that 10% citric acid removed more Ca(OH)2 than 2.5% NaOCl in the 0-1 mm group from the apex level (P<0.05). Ultrasonic and EndoActivator activation significantly removed more Ca(OH)2 than a size 30 K file in the apical third (P<0.05). However, there were no significant differences in any sections of the canals for 10% citric acid or 17% EDTA in removing Ca(OH)2 in extracted human teeth. We concluded that it was effective to remove residual Ca(OH)2 using the decalcifying solution with EndoActivator or Passive Ultrasonic Irrigation in a curved root canal system. A protocol for Ca(OH)2 removal was provided based on the conclusions of this study and the methods recommended in previous studies. PMID- 28644433 TI - CTLA-4-mediated posttranslational modifications direct cytotoxic T-lymphocyte differentiation. AB - The blockade of inhibitory receptors such as CTLA-4 (CD152) is being used as immune-checkpoint therapy, offering a powerful strategy to restore effective immune responses against tumors. To determine signal components that are induced under the control of CTLA-4 we analyzed activated murine CD8+ T cells by quantitative proteomics. Accurate mass spectrometry revealed that CTLA-4 engagement led to central changes in the phosphorylation of proteins involved in T-cell differentiation. Beside other targets, we discovered a CTLA-4-mediated induction of the translational inhibitor programmed cell death-4 (PDCD4) as a result of FoxO1 nuclear re-localization. PDCD4 further bound a distinct set of mRNAs including Glutaminase, which points out a critical role for CTLA-4 in CD8+ T-cell metabolism. Consequently, PDCD4-deficient cytotoxic T-lymphocytes (CTLs) expressed increased amounts of otherwise repressed effector molecules and ultimately led to superior control of tumor growth in vivo. These findings reveal a novel CTLA-4-mediated pathway to attenuate CTLs and indicate the importance of post-transcriptional mechanisms in the regulation of anti-tumor immune responses. PMID- 28644432 TI - Dental implant treatment for renal failure patients on dialysis: a clinical guideline. AB - Chronic kidney disease (CKD) is a worldwide public health problem that is growing in prevalence and is associated with severe complications. During the progression of the disease, a majority of CKD patients suffer oral complications. Dental implants are currently the most reliable and successful treatment for missing teeth. However, due to complications of CKD such as infections, bone lesions, bleeding risks, and altered drug metabolism, dental implant treatment for renal failure patients on dialysis is more challenging. In this review, we have summarized the characteristics of CKD and previous publications regarding dental treatments for renal failure patients. In addition, we discuss our recent research results and clinical experience in order to provide dental implant practitioners with a clinical guideline for dental implant treatment for renal failure patients undergoing hemodialysis. PMID- 28644434 TI - Ageing and hypoxia cause protein aggregation in mitochondria. AB - Aggregation of cytosolic proteins is a pathological finding in disease states, including ageing and neurodegenerative diseases. We have previously reported that hypoxia induces protein misfolding in Caenorhabditis elegans mitochondria, and electron micrographs suggested protein aggregates. Here, we seek to determine whether mitochondrial proteins actually aggregate after hypoxia and other cellular stresses. To enrich for mitochondrial proteins that might aggregate, we performed a proteomics analysis on purified C. elegans mitochondria to identify relatively insoluble proteins under normal conditions (110 proteins identified) or after sublethal hypoxia (65 proteins). A GFP-tagged mitochondrial protein (UCR 11 - a complex III electron transport chain protein) in the normally insoluble set was found to form widespread aggregates in mitochondria after hypoxia. Five other GFP-tagged mitochondrial proteins in the normally insoluble set similarly form hypoxia-induced aggregates. Two GFP-tagged mitochondrial proteins from the soluble set as well as a mitochondrial-targeted GFP did not form aggregates. Ageing also resulted in aggregates. The number of hypoxia-induced aggregates was regulated by the mitochondrial unfolded protein response (UPRmt) master transcriptional regulator ATFS-1, which has been shown to be hypoxia protective. An atfs-1(loss-of-function) mutant and RNAi construct reduced the number of aggregates while an atfs-1(gain-of-function) mutant increased aggregates. Our work demonstrates that mitochondrial protein aggregation occurs with hypoxic injury and ageing in C. elegans. The UPRmt regulates aggregation and may protect from hypoxia by promoting aggregation of misfolded proteins. PMID- 28644435 TI - p53 amyloid formation leading to its loss of function: implications in cancer pathogenesis. AB - The transcriptional regulator p53 has an essential role in tumor suppression. Almost 50% of human cancers are associated with the loss of p53 functions, where p53 often accumulates in the nucleus as well as in cytoplasm. Although it has been previously suggested that amyloid formation could be a cause of p53 loss-of function in subset of tumors, the characterization of these amyloids and its structure-function relationship is not yet established. In the current study, we provide several evidences for the presence of p53 amyloid formation (in human and animal cancer tissues); along with its isolation from human cancer tissues and the biophysical characterization of these tissue-derived fibrils. Using amyloid seed of p53 fragment (P8, p53(250-257)), we show that p53 amyloid formation in cells not only leads to its functional inactivation but also transforms it into an oncoprotein. The in vitro studies further show that cancer-associated mutation destabilizes the fold of p53 core domain and also accelerates the aggregation and amyloid formation by this protein. Furthermore, we also show evidence of prion like cell-to-cell transmission of different p53 amyloid species including full length p53, which is induced by internalized P8 fibrils. The present study suggests that p53 amyloid formation could be one of the possible cause of p53 loss of function and therefore, inhibiting p53 amyloidogenesis could restore p53 tumor suppressor functions. PMID- 28644438 TI - Gut check: dead cell samples leads to tolerant examples. PMID- 28644437 TI - More alive than dead: non-apoptotic roles for caspases in neuronal development, plasticity and disease. AB - Nervous systems are arguably the most fascinating and complex structures in the known universe. How they are built, changed by experience and then degenerate are some of the biggest questions in biology. Regressive phenomena, such as neuron pruning and programmed cell death, have a key role in the building and maintenance of the nervous systems. Both of these cellular mechanisms deploy the caspase family of protease enzymes. In this review, we highlight the non apoptotic function of caspases during nervous system development, plasticity and disease, particularly focussing on their role in structural remodelling. We have classified pruning as either macropruning, where complete branches are removed, or micropruning, where individual synapses or dendritic spines are eliminated. Finally we discuss open questions and possible future directions within the field. PMID- 28644436 TI - The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. AB - Proper cellular functionality and homeostasis are maintained by the convergent integration of various signaling cascades, which enable cells to respond to internal and external changes. The Dbf2-related kinases LATS1 and LATS2 (LATS) have emerged as central regulators of cell fate, by modulating the functions of numerous oncogenic or tumor suppressive effectors, including the canonical Hippo effectors YAP/TAZ, the Aurora mitotic kinase family, estrogen signaling and the tumor suppressive transcription factor p53. While the basic functions of the LATS kinase module are strongly conserved over evolution, the genomic duplication event leading to the emergence of two closely related kinases in higher organisms has increased the complexity of this signaling network. Here, we review the LATS1 and LATS2 intrinsic features as well as their reported cellular activities, emphasizing unique characteristics of each kinase. While differential activities between the two paralogous kinases have been reported, many converge to similar pathways and outcomes. Interestingly, the regulatory networks controlling the mRNA expression pattern of LATS1 and LATS2 differ strongly, and may contribute to the differences in protein binding partners of each kinase and in the subcellular locations in which each kinase exerts its functions. PMID- 28644439 TI - Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death. AB - The unfolded protein response (UPR) is an endoplasmic reticulum (ER) -related stress conserved pathway that aims to protect cells from being overwhelmed. However, when prolonged, UPR activation converts to a death signal, which relies on its PERK-eIF2alpha branch. Overactivation of the UPR has been implicated in many neurological diseases, including cerebral ischaemia. Here, by using an in vivo thromboembolic model of stroke on transgenic ER stress-reporter mice and neuronal in vitro models of ischaemia, we demonstrate that ischaemic stress leads to the deleterious activation of the PERK branch of the UPR. Moreover, we show that the serine protease tissue-type plasminogen activator (tPA) can bind to cell surface Grp78 (78 kD glucose-regulated protein), leading to a decrease of the PERK pathway activation, thus a decrease of the deleterious factor CHOP, and finally promotes neuroprotection. Altogether, this work highlights a new role and a therapeutic potential of the chaperone protein Grp78 as a membrane receptor of tPA capable to prevent from ER stress overactivation. PMID- 28644440 TI - LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143-3p signals. AB - While the androgen receptor (AR) might promote renal cell carcinoma (RCC) initiation and progression, the molecular mechanisms involved remain largely unclear. Here, we discovered the novel LncRNA-SARCC, which was suppressed and associated with better prognosis in RCC. Preclinical studies using multiple RCC cells and in vivo mouse model indicated that LncRNA-SARCC could attenuate RCC cell invasion, migration and proliferation in vitro and in vivo. Mechanistically, LncRNA-SARCC bound and destabilized AR protein with an inhibition of AR function, which led to transcriptionally de-repress miR-143-3p expression, thus inhibition of its downstream signals including AKT, MMP-13, K-RAS and P-ERK. In addition, bisulfite sequencing analysis substantiated that LncRNA-SARCC promoter was highly methylated in renal cancer tissues compared with paired non-cancerous renal tissues. Notably, treating with Sunitinib, the multi-targeted receptor tyrosine kinase inhibitor, increased the expression of LncRNA-SARCC, which decreased RCC cells resistance to Sunitinib. Thus, our study presented a road map for targeting this newly identified LncRNA-SARCC and its pathway, which expands potential therapeutic strategies for RCC treatment. PMID- 28644441 TI - MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins. AB - Transforming growth factor (TGF)-beta is one of the major inducers of epithelial to mesenchymal transition (EMT), a crucial program that has a critical role in promoting carcinoma's metastasis formation. MicroRNAs-143 and -145, which are both TGF-beta direct transcriptional targets, are essential for the differentiation of vascular smooth muscle cells (VSMC) during embryogenesis, a TGF-beta-dependent process reminiscent of EMT. Their role in adult tissues is however less well defined and even ambiguous, as their expression was correlated both positively and negatively with tumor progression. Here we show that high expression of both miRs-143 and -145 in mouse mammary tumor cells expressing constitutively active STAT3 (S3C) is involved in mediating their disrupted cell cell junctions. Additionally, miR-143 appears to have a unique role in tumorigenesis by enhancing cell migration in vitro and extravasation in vivo while impairing anchorage-independent growth, which may explain the contradictory reports about its role in tumors. Accordingly, we demonstrate that overexpression of either miRNA in the non-transformed mammary epithelial NMuMG cells leads to upregulation of EMT markers and of several endogenous TGF-beta targets, downmodulation of a number of junction proteins and increased motility, correlating with enhanced basal and TGF-beta-induced SMAD-mediated transcription. Moreover, pervasive transcriptome perturbation consistent with the described phenotype was observed. In particular, the expression of several transcription factors involved in the mitogenic responses, of MAPK family members and, importantly, of several tight junction proteins and the SMAD co-repressor TGIF was significantly reduced. Our results provide important mechanistic insight into the non-redundant role of miRs-143 and -145 in EMT-related processes in both transformed and non-transformed cells, and suggest that their expression must be finely coordinated to warrant optimal migration/invasion while not interfering with cell growth. PMID- 28644442 TI - Linking the development and functioning of a carnivorous pitcher plant's microbial digestive community. AB - Ecosystem development theory predicts that successional turnover in community composition can influence ecosystem functioning. However, tests of this theory in natural systems are made difficult by a lack of replicable and tractable model systems. Using the microbial digestive associates of a carnivorous pitcher plant, I tested hypotheses linking host age-driven microbial community development to host functioning. Monitoring the yearlong development of independent microbial digestive communities in two pitcher plant populations revealed a number of trends in community succession matching theoretical predictions. These included mid-successional peaks in bacterial diversity and metabolic substrate use, predictable and parallel successional trajectories among microbial communities, and convergence giving way to divergence in community composition and carbon substrate use. Bacterial composition, biomass, and diversity positively influenced the rate of prey decomposition, which was in turn positively associated with a host leaf's nitrogen uptake efficiency. Overall digestive performance was greatest during late summer. These results highlight links between community succession and ecosystem functioning and extend succession theory to host-associated microbial communities. PMID- 28644443 TI - Unexpected genomic features in widespread intracellular bacteria: evidence for motility of marine chlamydiae. AB - Chlamydiae are obligate intracellular bacteria comprising important human pathogens and symbionts of protists. Molecular evidence indicates a tremendous diversity of chlamydiae particularly in marine environments, yet our current knowledge is based mainly on terrestrial representatives. Here we provide first insights into the biology of marine chlamydiae representing three divergent clades. Our analysis of single-cell amplified genomes revealed hallmarks of the chlamydial lifestyle, supporting the ancient origin of their characteristic developmental cycle and major virulence mechanisms. Surprisingly, these chlamydial genomes encode a complete flagellar apparatus, a previously unreported feature. We show that flagella are an ancient trait that was subject to differential gene loss among extant chlamydiae. Together with a chemotaxis system, these marine chlamydiae are likely motile, with flagella potentially playing a role during host cell infection. This study broadens our view on chlamydial biology and indicates a largely underestimated potential to adapt to different hosts and environments. PMID- 28644444 TI - Energy and carbon metabolisms in a deep terrestrial subsurface fluid microbial community. AB - The terrestrial deep subsurface is a huge repository of microbial biomass, but in relation to its size and physical heterogeneity, few sites have been investigated in detail. Here, we applied a culture-independent metagenomic approach to characterize the microbial community composition in deep (1500 meters below surface) terrestrial fluids. Samples were collected from a former gold mine in Lead, South Dakota, USA, now Sanford Underground Research Facility (SURF). We reconstructed 74 genomes from metagenomes (MAGs), enabling the identification of common metabolic pathways. Sulfate and nitrate/nitrite reduction were the most common putative energy metabolisms. Complete pathways for autotrophic carbon fixation were found in more than half of the MAGs, with the reductive acetyl-CoA pathway by far the most common. Nearly 40% (29 of 74) of the recovered MAGs belong to bacterial phyla without any cultivated members-microbial dark matter. Three of our MAGs constitute two novel phyla previously only identified in 16 S rRNA gene surveys. The uniqueness of this data set-its physical depth in the terrestrial subsurface, the relative abundance and completeness of microbial dark matter genomes and the overall diversity of this physically deep, dark, community make it an invaluable addition to our knowledge of deep subsurface microbial ecology. PMID- 28644445 TI - Effects of daily restraint with and without injections on skeletal properties in C57BL/6NHsd mice. PMID- 28644446 TI - Immunology's dirty little secret. PMID- 28644447 TI - New NCI drug formulary cuts red tape. PMID- 28644448 TI - Response to Protocol Review Scenario: Conflicts of interest. PMID- 28644450 TI - Tough decisions about protocol review. PMID- 28644451 TI - Building new blood cells. PMID- 28644452 TI - Giving medical implants a new lease on life. PMID- 28644453 TI - Evaluation of the neutrophil:lymphocyte ratio as an indicator of chronic distress in the laboratory mouse. AB - When evaluating the effect of husbandry and biomethodologies on the well-being of laboratory mice, it is critical to utilize measurements that allow the distinguishing of acute stress from chronic stress. One of the most common measurements of stress in laboratory animals is the corticosterone assessment. However, while this measurement provides a highly accurate reflection of the animal's response to acute stressors, its interpretation is more prone to error when evaluating the effect of chronic stress. This study evaluated the use of the neutrophil:lymphocyte (NE:LY) ratio as an assessment of chronic stress in male and female C57Bl/6N mice as compared to serum corticosterone. One group of mice was exposed to mild daily stressors for 7 days, while the control group was handled with normal husbandry. The NE:LY ratio and serum corticosterone levels were significantly elevated in the chronically stressed mice, though a significant increase in corticosterone was only significant in males when compared by sex. The chronically stressed mice also demonstrated significantly fewer entries into the open arms and less time spent in the open arms of the elevated plus maze, suggesting that the mild daily stressors had induced a state of distress. The findings of this study confirm that the NE:LY ratio is a valid measurement for chronic stress in the laboratory mouse. However, these assays do not distinguish between distress or eustress, so behavioral and physiological assessments should always be included to determine a complete assessment of the well-being of the mouse. PMID- 28644456 TI - USDA inspection data: what a difference a decade makes. PMID- 28644457 TI - Response to Protocol Review Scenario: PAM specialist: report without fear. PMID- 28644458 TI - Response to Protocol Review Scenario: Sharing is caring, but more clarity is needed. PMID- 28644459 TI - What does "reporting to the IACUC" mean for PAM? PMID- 28644460 TI - A Word from OLAW. PMID- 28644462 TI - Shrinking and scaling electrophysiology. PMID- 28644461 TI - A new school of drug discovery. PMID- 28644463 TI - Hypersensitive dual-function luminescence switching of a silver-chalcogenolate cluster-based metal-organic framework. AB - Silver(i) chalcogenide/chalcogenolate clusters are promising photofunctional materials for sensing, optoelectronics and solar energy harvesting applications. However, their instability and poor room-temperature luminescent quantum yields have hampered more extensive study. Here, we graft such clusters to adaptable bridging ligands, enabling their interconnection and the formation of rigid metal organic frameworks. By controlling the spatial separation and orientation of the clusters, they then exhibit enhanced stability (over one year) and quantum yield (12.1%). Ultrafast dual-function fluorescence switching (<1 s) is also achieved, with turn-off triggered by O2 and multicoloured turn-on by volatile organic compounds. Single-crystal X-ray diffraction of the inclusion materials, obtained by single-crystal-to-single-crystal transformation, enables precise determination of the position of the small molecules within the framework, elucidating the switching mechanism. The work enriches the cluster-based metal-organic framework portfolio, bridges the gap between silver chalcogenide/chalcogenolate clusters and metal-organic frameworks, and provides a foundation for further development of functional silver-cluster-based materials. PMID- 28644464 TI - A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations. AB - Perturbations in cellular chloride concentrations can affect cellular pH and autophagy and lead to the onset of apoptosis. With this in mind, synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here, we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in lysosomal pH, which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis. PMID- 28644465 TI - Frantically forging fermium. PMID- 28644467 TI - Identity crisis. PMID- 28644466 TI - Characterization of a selenocysteine-ligated P450 compound I reveals direct link between electron donation and reactivity. AB - Strong electron-donation from the axial thiolate ligand of cytochrome P450 has been proposed to increase the reactivity of compound I with respect to C-H bond activation. However, it has proven difficult to test this hypothesis, and a direct link between reactivity and electron donation has yet to be established. To make this connection, we have prepared a selenolate-ligated cytochrome P450 compound I intermediate. This isoelectronic perturbation allows for direct comparisons with the wild-type enzyme. Selenium incorporation was achieved using a cysteine auxotrophic Escherichia coli strain. The intermediate was prepared with meta-chloroperbenzoic acid and characterized by UV-visible, Mossbauer and electron paramagnetic resonance spectroscopies. Measurements revealed increased asymmetry around the ferryl moiety, consistent with increased electron donation from the axial selenolate ligand. In line with this observation, we find that the selenolate-ligated compound I cleaves C-H bonds more rapidly than the wild-type intermediate. PMID- 28644468 TI - Observation of electron-transfer-mediated decay in aqueous solution. AB - Photoionization is at the heart of X-ray photoelectron spectroscopy (XPS), which gives access to important information on a sample's local chemical environment. Local and non-local electronic decay after photoionization-in which the refilling of core holes results in electron emission from either the initially ionized species or a neighbour, respectively-have been well studied. However, electron transfer-mediated decay (ETMD), which involves the refilling of a core hole by an electron from a neighbouring species, has not yet been observed in condensed phase. Here we report the experimental observation of ETMD in an aqueous LiCl solution by detecting characteristic secondary low-energy electrons using liquid microjet soft XPS. Experimental results are interpreted using molecular dynamics and high-level ab initio calculations. We show that both solvent molecules and counterions participate in the ETMD processes, and different ion associations have distinctive spectral fingerprints. Furthermore, ETMD spectra are sensitive to coordination numbers, ion-solvent distances and solvent arrangement. PMID- 28644469 TI - Cooperative polymerization of alpha-helices induced by macromolecular architecture. AB - Catalysis observed in enzymatic processes and protein polymerizations often relies on the use of supramolecular interactions and the organization of functional elements in order to gain control over the spatial and temporal elements of fundamental cellular processes. Harnessing these cooperative interactions to catalyse reactions in synthetic systems, however, remains challenging due to the difficulty in creating structurally controlled macromolecules. Here, we report a polypeptide-based macromolecule with spatially organized alpha-helices that can catalyse its own formation. The system consists of a linear polymeric scaffold containing a high density of initiating groups from which polypeptides are grown, forming a brush polymer. The folding of polypeptide side chains into alpha-helices dramatically enhances the polymerization rate due to cooperative interactions of macrodipoles between neighbouring alpha-helices. The parameters that affect the rate are elucidated by a two-stage kinetic model using principles from nucleation-controlled protein polymerizations; the key difference being the irreversible nature of this polymerization. PMID- 28644471 TI - Polycyclic aromatic hydrocarbons: Synthesis successes. PMID- 28644470 TI - Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds. AB - Arylmetals are highly valuable carbon nucleophiles that are readily and inexpensively prepared from aryl halides or arenes and widely used on both laboratory and industrial scales to react directly with a wide range of electrophiles. Although C-C bond formation has been a staple of organic synthesis, the direct transfer of primary amino (-NH2) and hydroxyl (-OH) groups to arylmetals in a scalable and environmentally friendly fashion remains a formidable synthetic challenge because of the absence of suitable heteroatom transfer reagents. Here, we demonstrate the use of bench-stable N-H and N-alkyl oxaziridines derived from readily available terpenoid scaffolds as efficient multifunctional reagents for the direct primary amination and hydroxylation of structurally diverse aryl- and heteroarylmetals. This practical and scalable method provides one-step synthetic access to primary anilines and phenols at low temperature and avoids the use of transition-metal catalysts, ligands and additives, nitrogen-protecting groups, excess reagents and harsh workup conditions. PMID- 28644473 TI - Addendum: Aldehydes as alkyl carbanion equivalents for additions to carbonyl compounds. PMID- 28644472 TI - Placing and shaping liposomes with reconfigurable DNA nanocages. AB - The diverse structure and regulated deformation of lipid bilayer membranes are among a cell's most fascinating features. Artificial membrane-bound vesicles, known as liposomes, are versatile tools for modelling biological membranes and delivering foreign objects to cells. To fully mimic the complexity of cell membranes and optimize the efficiency of delivery vesicles, controlling liposome shape (both statically and dynamically) is of utmost importance. Here we report the assembly, arrangement and remodelling of liposomes with designer geometry: all of which are exquisitely controlled by a set of modular, reconfigurable DNA nanocages. Tubular and toroid shapes, among others, are transcribed from DNA cages to liposomes with high fidelity, giving rise to membrane curvatures present in cells yet previously difficult to construct in vitro. Moreover, the conformational changes of DNA cages drive membrane fusion and bending with predictable outcomes, opening up opportunities for the systematic study of membrane mechanics. PMID- 28644474 TI - pi-electron S = 1/2 quantum spin-liquid state in an ionic polyaromatic hydrocarbon. AB - Molecular solids with cooperative electronic properties based purely on pi electrons from carbon atoms offer a fertile ground in the search for exotic states of matter, including unconventional superconductivity and quantum magnetism. The field was ignited by reports of high-temperature superconductivity in materials obtained by the reaction of alkali metals with polyaromatic hydrocarbons, such as phenanthrene and picene, but the composition and structure of any compound in this family remained unknown. Here we isolate the binary caesium salts of phenanthrene, Cs(C14H10) and Cs2(C14H10), to show that they are multiorbital strongly correlated Mott insulators. Whereas Cs2(C14H10) is diamagnetic because of orbital polarization, Cs(C14H10) is a Heisenberg antiferromagnet with a gapped spin-liquid state that emerges from the coupled highly frustrated Delta-chain magnetic topology of the alternating-exchange spiral tubes of S = 1/2 (C14H10)*- radical anions. The absence of long-range magnetic order down to 1.8 K (T/J ~ 0.02; J is the dominant exchange constant) renders the compound an excellent candidate for a spin-1/2 quantum-spin liquid (QSL) that arises purely from carbon pi electrons. PMID- 28644475 TI - Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis. AB - Ribosomally synthesized peptides are built out of L-amino acids, whereas D-amino acids are generally the hallmark of non-ribosomal synthetic processes. Here we show that the model bacterium Bacillus subtilis is able to produce a novel type of ribosomally synthesized and post-translationally modified peptide that contains D-amino acids, and which we propose to call epipeptides. We demonstrate that a two [4Fe-4S]-cluster radical S-adenosyl-L-methionine (SAM) enzyme converts L-amino acids into their D-counterparts by catalysing Calpha-hydrogen-atom abstraction and using a critical cysteine residue as the hydrogen-atom donor. Unexpectedly, these D-amino acid residues proved to be essential for the activity of a peptide that induces the expression of LiaRS, a major component of the bacterial cell envelope stress-response system. Present in B. subtilis and in several members of the human microbiome, these epipeptides and radical SAM epimerases broaden the landscape of peptidyl structures accessible to living organisms. PMID- 28644476 TI - Enantioselective, intermolecular benzylic C-H amination catalysed by an engineered iron-haem enzyme. AB - C-H bonds are ubiquitous structural units of organic molecules. Although these bonds are generally considered to be chemically inert, the recent emergence of methods for C-H functionalization promises to transform the way synthetic chemistry is performed. The intermolecular amination of C-H bonds represents a particularly desirable and challenging transformation for which no efficient, highly selective, and renewable catalysts exist. Here we report the directed evolution of an iron-containing enzymatic catalyst-based on a cytochrome P450 monooxygenase-for the highly enantioselective intermolecular amination of benzylic C-H bonds. The biocatalyst is capable of up to 1,300 turnovers, exhibits excellent enantioselectivities, and provides access to valuable benzylic amines. Iron complexes are generally poor catalysts for C-H amination: in this catalyst, the enzyme's protein framework confers activity on an otherwise unreactive iron haem cofactor. PMID- 28644478 TI - A chemical century. PMID- 28644477 TI - DNA nanotechnology: Bringing lipid bilayers into shape. PMID- 28644479 TI - Enzymatic catalysis: New functional twists for P450s. PMID- 28644480 TI - A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGF165). AB - Protein affinity reagents are widely used in basic research, diagnostics and separations and for clinical applications, the most common of which are antibodies. However, they often suffer from high cost, and difficulties in their development, production and storage. Here we show that a synthetic polymer nanoparticle (NP) can be engineered to have many of the functions of a protein affinity reagent. Polymer NPs with nM affinity to a key vascular endothelial growth factor (VEGF165) inhibit binding of the signalling protein to its receptor VEGFR-2, preventing receptor phosphorylation and downstream VEGF165-dependent endothelial cell migration and invasion into the extracellular matrix. In addition, the NPs inhibit VEGF-mediated new blood vessel formation in Matrigel plugs in vivo. Importantly, the non-toxic NPs were not found to exhibit off target activity. These results support the assertion that synthetic polymers offer a new paradigm in the search for abiotic protein affinity reagents by providing many of the functions of their protein counterparts. PMID- 28644482 TI - One-thousand-fold enhancement of high field liquid nuclear magnetic resonance signals at room temperature. AB - Nuclear magnetic resonance (NMR) is a fundamental spectroscopic technique for the study of biological systems and materials, molecular imaging and the analysis of small molecules. It detects interactions at very low energies and is thus non invasive and applicable to a variety of targets, including animals and humans. However, one of its most severe limitations is its low sensitivity, which stems from the small interaction energies involved. Here, we report that dynamic nuclear polarization in liquid solution and at room temperature can enhance the NMR signal of 13C nuclei by up to three orders of magnitude at magnetic fields of ~3 T. The experiment can be repeated within seconds for signal averaging, without interfering with the sample magnetic homogeneity. The method is therefore compatible with the conditions required for high-resolution NMR. Enhancement of 13C signals on various organic compounds opens up new perspectives for dynamic nuclear polarization as a general tool to increase the sensitivity of liquid NMR. PMID- 28644481 TI - Redox-controlled potassium intercalation into two polyaromatic hydrocarbon solids. AB - Alkali metal intercalation into polyaromatic hydrocarbons (PAHs) has been studied intensely after reports of superconductivity in a number of potassium- and rubidium-intercalated materials. There are, however, no reported crystal structures to inform our understanding of the chemistry and physics because of the complex reactivity of PAHs with strong reducing agents at high temperature. Here we present the synthesis of crystalline K2Pentacene and K2Picene by a solid solid insertion protocol that uses potassium hydride as a redox-controlled reducing agent to access the PAH dianions, and so enables the determination of their crystal structures. In both cases, the inserted cations expand the parent herringbone packings by reorienting the molecular anions to create multiple potassium sites within initially dense molecular layers, and thus interact with the PAH anion pi systems. The synthetic and crystal chemistry of alkali metal intercalation into PAHs differs from that into fullerenes and graphite, in which the cation sites are pre-defined by the host structure. PMID- 28644483 TI - Pasteur and the art of chirality. PMID- 28644484 TI - Erratum: Tuning underwater adhesion with cation-pi interactions. PMID- 28644485 TI - Probing the early stages of photoreception in photoactive yellow protein with ultrafast time-domain Raman spectroscopy. AB - Unveiling the nuclear motions of photoreceptor proteins in action is a crucial goal in protein science in order to understand their elaborate mechanisms and how they achieve optimal selectivity and efficiency. Previous studies have provided detailed information on the structures of intermediates that appear during the later stages (>ns) of such photoreception cycles, yet the initial events immediately after photoabsorption remain unclear because of experimental challenges in monitoring nuclear rearrangements on ultrafast timescales, including protein-specific low-frequency motions. Using time-domain Raman probing with sub-7-fs pulses, we obtain snapshot vibrational spectra of photoactive yellow protein and a mutant with high sensitivity, providing insights into the key responses that drive photoreception. Our data show a drastic intensity drop of the excited-state marker band at 135 cm-1 within a few hundred femtoseconds, suggesting a rapid weakening of the hydrogen bond that anchors the chromophore. We also track formation of the first ground-state intermediate over the first few picoseconds and fully characterize its vibrational structure, revealing a substantially-twisted cis conformation. PMID- 28644486 TI - Use of work-life balance benefits guaranteed by law in Poland - Do size of the enterprise and gender matter? AB - BACKGROUND: The paper is aimed at indicating the similarities and differences in use of benefits supporting work-life balance (WLB) between women and men working in Polish small/medium and large enterprises. MATERIAL AND METHODS: The sample included 556 workers (311 women, 245 men), aged 20-68 years old employed on the basis of employment contracts for at least a year in Polish enterprises. The respondents completed a questionnaire on the use of benefits guaranteed by the Polish Labour Code, referring to their current workplaces. RESULTS: Women took maternity leaves and returned to the same work position after using childcare leaves more often than men. Men took leaves on demand more often than women. Our results also showed that in comparison to women working in smaller enterprises, those working in large enterprises were more likely to use almost all the analyzed WLB benefits - paid days off to take care of others, educational leaves, leaves on demand, maternity leaves and return to the same work position after childcare leave, reduction of business trips when pregnant or having young children and breastfeeding breaks. The size of enterprise, however, did not differentiate the take-up of benefits among the studied men. CONCLUSIONS: Our analysis brought unexpected results on the lack of common availability of the WLB benefits guaranteed by the law in the case of employees who worked on the basis of employment contracts. We also found that women used most of child rearing benefits guaranteed by the law more often than men, which might reflect still a traditional division of child care responsibilities in Poland. Med Pr 2017;68(5):575-581. PMID- 28644488 TI - Linear nonequilibrium thermodynamics of reversible periodic processes and chemical oscillations. AB - Onsager's phenomenological equations successfully describe irreversible thermodynamic processes. They assume a symmetric coupling matrix between thermodynamic fluxes and forces. It is easily shown that the antisymmetric part of a coupling matrix does not contribute to dissipation. Therefore, entropy production is exclusively governed by the symmetric matrix even in the presence of antisymmetric terms. In this paper we focus on the antisymmetric contributions which describe isentropic oscillations with well-defined equations of motion. The formalism contains variables that are equivalent to momenta and coefficients that are analogous to inertial mass. We apply this formalism to simple problems with known answers such as an oscillating piston containing an ideal gas, and oscillations in an LC-circuit. One can extend this formalism to other pairs of variables, including chemical systems with oscillations. In isentropic thermodynamic systems all extensive and intensive variables including temperature can display oscillations reminiscent of adiabatic waves. PMID- 28644487 TI - [Can diabetes be treated as an indirectly work-related disease?] AB - In this article the authors attempted to analyze the arguments for considering diabetes as a work-related disease. An overview of literature has been done out of articles published in the years 1980-2016, with the use of combination of key words referring to employment, workplace, and diabetes. The PubMed database was the source of data. The authors indicate that the following arguments are in favor of diabetes being recognized as a work-related disease: diabetes is not an occupational disease, it is not directly related to the work environment or the way the work is performed, but there are observed adverse effects of occupational work-related nuisances, such as night shift work, long work hours, job strain or workplace standing time, which influence its development and course. The number of publications on diabetes, including the problem of occupational work is comparable to the number of analogous publications concerning work-related diseases such as hypertension or ischemic heart disease. Moreover, some aspects of professional activity and diabetes were also included in clinical recommendations for the workplace, which is uncommon in the case of other diseases, even those generally recognized as work-related. Data from medical references, indicating the effectiveness of workplace interventions aimed at preventing diabetes development and/or worsening of its course should be considered as an argument for the inclusion of diabetes into the group of work related diseases. This should also support the need for further research and practical actions aimed at preventing diabetes at the workplace. Med Pr 2017;68(5):667-675. PMID- 28644489 TI - Dehydrogenation of cyclic amines by a coordinatively unsaturated Cp*Ir(iii) phosphoramidate complex. AB - The reaction of a Cp*Ir(iii) phosphoramidate complex with secondary amines gives amine, imine-bound Cp*Ir(iii) hydride complexes resulting from amine dehydrogenation. These well-characterized species could serve as models of relevant intermediates that have been proposed in catalytic amine dehydrogenation using related N,O-chelated Cp*Ir(iii) pyridonate complexes. PMID- 28644491 TI - Mastering high resolution tip-enhanced Raman spectroscopy: towards a shift of perception. AB - Recent years have seen tremendous improvement of our understanding of high resolution reachable in TERS experiments, forcing us to re-evaluate our understanding of the intrinsic limits of this field, but also exposing several inconsistencies. On the one hand, more and more recent experimental results have provided us with clear indications of spatial resolutions down to a few nanometres or even on the subnanometre scale. Moreover, lessons learned from recent theoretical investigations clearly support such high resolutions, and vice versa the obvious theoretical impossibility to evade high resolution from a purely plasmonic point of view. On the other hand, most of the published TERS results still, to date, claim a resolution on the order of tens of nanometres that would be somehow limited by the tip apex, a statement well accepted for the past 2 decades. Overall, this now leads the field to a fundamental question: how can this divergence be justified? The answer to this question brings up an equally critical one: how can this gap be bridged? This review aims at raising a fundamental discussion related to the resolution limits of tip-enhanced Raman spectroscopy, at revisiting our comprehension of the factors limiting it both from a theoretical and an experimental point of view and at providing indications on how to move the field ahead. It is our belief that a much deeper understanding of the real accessible lateral resolution in TERS and the practical factors that limit them will simultaneously help us to fully explore the potential of this technique for studying nanoscale features in organic, inorganic and biological systems, and also to improve both the reproducibility and the accuracy of routine TERS studies. A significant improvement of our comprehension of the accessible resolution in TERS is thus critical for a broad audience, even in certain contexts where high resolution TERS is not the desired outcome. PMID- 28644490 TI - Potentiating role of copper on spatial memory deficit induced by beta amyloid and evaluation of mitochondrial function markers in the hippocampus of rats. AB - Mounting evidence suggests that copper, a crucial element in normal brain function, plays an important role in the etiology of Alzheimer's disease, which is known as a neurodegenerative mitochondrial disorder. However, the precise mechanisms of its effects on cognitive and mitochondrial functions through the CNS have not been thoroughly recognized yet. In this study, we aimed to investigate the long-term (3-week) effects of copper sulfate (50, 100 and 200 mg kg-1 day-1) exposure on learning and memory as well as on mitochondrial function in the hippocampus of rats in the presence and absence of beta amyloid (1 MUg MUl 1 per side) intrahippocampally (IH). After three weeks of copper exposure through drinking water, acquisition and retention of spatial memory were measured by the Morris water maze (MWM) test. Various parameters of mitochondrial function were also evaluated. Our data show that copper damaged the spatial learning and memory and also exacerbated the memory deficit induced by Abeta injection in rats in a dose-dependent manner. Mitochondria isolated from the hippocampus of rats treated with copper showed significant increases in ROS formation, mitochondrial swelling, lipid peroxidation, glutathione oxidation, outer membrane damage, and collapse of MMP, decreased cytochrome c oxidase activity, and finally increased ADP/ATP ratios. Our results indicate that copper overloading in the hippocampus of rats causes mitochondrial dysfunction and subsequent oxidative stress leading to cognitive impairment. This study also reveals that copper can potentiate Abeta deleterious effects on spatial memory and brain mitochondrial function. PMID- 28644492 TI - Electronic properties of blue phosphorene/graphene and blue phosphorene/graphene like gallium nitride heterostructures. AB - Blue phosphorene (BlueP) is a graphene-like phosphorus nanosheet which was synthesized very recently for the first time [Nano Lett., 2016, 16, 4903-4908]. The combination of electronic properties of two different two-dimensional materials in an ultrathin van der Waals (vdW) vertical heterostructure has been proved to be an effective approach to the design of novel electronic and optoelectronic devices. Therefore, we used density functional theory to investigate the structural and electronic properties of two BlueP-based heterostructures - BlueP/graphene (BlueP/G) and BlueP/graphene-like gallium nitride (BlueP/g-GaN). Our results showed that the semiconducting nature of BlueP and the Dirac cone of G are well preserved in the BlueP/G vdW heterostructure. Moreover, by applying a perpendicular electric field, it is possible to tune the position of the Dirac cone of G with respect to the band edge of BlueP, resulting in the ability to control the Schottky barrier height. For the BlueP/g-GaN vdW heterostructure, BlueP forms an interface with g-GaN with a type-II band alignment, which is a promising feature for unipolar electronic device applications. Furthermore, we discovered that both G and g-GaN can be used as an active layer for BlueP to facilitate charge injection and enhance the device performance. PMID- 28644493 TI - Photoelectrochemical devices for solar water splitting - materials and challenges. AB - It is widely accepted within the community that to achieve a sustainable society with an energy mix primarily based on solar energy we need an efficient strategy to convert and store sunlight into chemical fuels. A photoelectrochemical (PEC) device would therefore play a key role in offering the possibility of carbon neutral solar fuel production through artificial photosynthesis. The past five years have seen a surge in the development of promising semiconductor materials. In addition, low-cost earth-abundant co-catalysts are ubiquitous in their employment in water splitting cells due to the sluggish kinetics of the oxygen evolution reaction (OER). This review commences with a fundamental understanding of semiconductor properties and charge transfer processes in a PEC device. We then describe various configurations of PEC devices, including single light absorber cells and multi light-absorber devices (PEC, PV-PEC and PV/electrolyser tandem cell). Recent progress on both photoelectrode materials (light absorbers) and electrocatalysts is summarized, and important factors which dominate photoelectrode performance, including light absorption, charge separation and transport, surface chemical reaction rate and the stability of the photoanode, are discussed. Controlling semiconductor properties is the primary concern in developing materials for solar water splitting. Accordingly, strategies to address the challenges for materials development in this area, such as the adoption of smart architectures, innovative device configuration design, co catalyst loading, and surface protection layer deposition, are outlined throughout the text, to deliver a highly efficient and stable PEC device for water splitting. PMID- 28644494 TI - FeCo nanoparticles-embedded carbon nanofibers as robust peroxidase mimics for sensitive colorimetric detection of l-cysteine. AB - A simple and low cost detection of l-cysteine is essential in the fields of biosensors and medical diagnosis. In this study, we have developed a simple electrospinning, followed by calcination process to prepare FeCo nanoparticles embedded in carbon nanofibers (FeCo-CNFs) as an efficient peroxidase-like mimic for the detection of l-cysteine. FeCo nanoparticles are uniformly dispersed within CNFs, and their diameters are highly influenced by the calcination temperature. The calcination temperature also influences the peroxidase-like catalytic activity, and the maximum activity is achieved at a calcination temperature of 550 degrees C. Owing to the high catalytic activity of the as prepared FeCo-CNFs, a colorimetric technique for the rapid and accurate determination of l-cysteine has been developed. The detection limit is about 0.15 MUM with a wide linear range from 1 to 20 MUM. In addition, a high selectivity for the detection of l-cysteine over other amino acids, glucose and common ions is achieved. This study provides a simple, rapid and sensitive sensing platform for the detection of l-cysteine, which is a promising candidate for potential applications in biosensing, medicine, environmental monitoring. PMID- 28644495 TI - Non-wetting drops at liquid interfaces: from liquid marbles to Leidenfrost drops. AB - We consider the flotation of deformable, non-wetting drops on a liquid interface. We consider the deflection of both the liquid interface and the droplet itself in response to the buoyancy forces, density difference and the various surface tensions within the system. Our results suggest new insight into a range of phenomena in which such drops occur, including Leidenfrost droplets and floating liquid marbles. In particular, we show that the floating state of liquid marbles is very sensitive to the tension of the particle-covered interface and suggest that this sensitivity may make such experiments a useful assay of the properties of these complex interfaces. PMID- 28644496 TI - The role of soybean extracts and isoflavones in hormone-dependent breast cancer: aromatase activity and biological effects. AB - Estrogen receptor-positive (ER+) breast cancer is the most common cause of cancer death in women worldwide. Nowadays, the relationship between soya diet and breast cancer is controversial due to the unknown role of its isoflavones, genistein (G) and daidzein (D). In this work, we investigated not only the anti-tumor properties of a soybean extract (NBSE) but also whether the biotransformation of extract (BSE) by the fungus Aspergillus awamori increased its effectiveness. The BSE showed a stronger anti-aromatase activity and anti-proliferative efficacy in ER+ aromatase-overexpressing breast cancer cells. D and G were weak aromatase inhibitors, but inhibited cancer cell growth, being G the isoflavone that contributed to the BSE-induced effects. This work demonstrated that the biotransformation increased the anti-aromatase activity and the anti-tumoral efficacy of soybean extract in breast cancer cells. Moreover, it elucidated the potential use of soya in the prevention and/or treatment of ER+ breast cancer. PMID- 28644498 TI - The mechanism of anomalous hardening in transition-metal monoborides. AB - The quest for novel nanomaterials with unusual functionalities continues to be a central challenge to modern nanoscience. Here we report a surprisingly anomalous hardening behavior exhibited by a class of transition-metal monoborides (TMB). Most remarkable is the occurrence of the intrinsic hardness maximum at the valence-electron concentration (VEC) of about 8 electrons per formula unit (e per f.u.); both lower and higher VECs lead to the decrease of hardness, contrasting with the expected positive correlation between hardness and VEC. Such an unexpected phenomenon originates from the presence of two sorts of bands near the Fermi level that respond oppositely to the movement of dislocations within the metal bilayer. Furthermore, we demonstrate that the hardness is closely related to the formation energy for TMB, which justifies the importance of the thermodynamic stability in designing superhard materials. Our findings not only elucidate the unique mechanism responsible for unusual atom-scale hardening but also open a new avenue towards designing novel multifunctional nanomaterials with the coexistence of high hardness and excellent electrical conductivity. PMID- 28644497 TI - Novel tunable green-red-emitting oxynitride phosphors co-activated with Ce3+, Tb3+, and Eu3+: photoluminescence and energy transfer. AB - A series of novel Ce3+, Tb3+ and Eu3+ ion doped Y4SiAlO8N-based oxynitride phosphors were synthesized by the solid-state method and characterized by X-ray powder diffraction, scanning electron microscopy, photoluminescence, lifetimes and thermo-luminescence. The excitation of the Ce3+/Tb3+ co-doped and Ce3+/Tb3+/Eu3+ tri-doped phosphor with near-UV radiation results in strong linear Tb3+ green and Eu3+ red emission. The occurrence of Ce3+-Tb3+ and Ce3+-Tb3+-Eu3+ energy transfer processes is responsible for the bright green or red luminescence. The Tb3+ ion acting as an energy transfer bridge can alleviate MMCT quenching between the Ce3+-Eu3+ ion pairs. The lifetime measurements demonstrated that the energy-transfer mechanisms of Ce3+-> Tb3+ and Tb3+-> Eu3+ are dipole quadrupole and quadrupole-quadrupole interactions, respectively. The temperature dependent luminescence measurements showed that as-prepared green/red phosphors have good thermal stability against temperature quenching. The obtained results indicate that these phosphors might serve as promising candidates for n-UV LEDs. PMID- 28644499 TI - Methods for the detection and identification of pathogenic bacteria: past, present, and future. AB - In order to retard the rate of development of antibacterial resistance, the causative agent must be identified as rapidly as possible, so that directed patient treatment and/or contact precautions can be initiated. This review highlights the challenges associated with the detection and identification of pathogenic bacteria, by providing an introduction to the techniques currently used, as well as newer techniques that are in development. Focusing on the chemical basis for these techniques, the review also provides a comparison of their advantages and disadvantages. PMID- 28644500 TI - In situ nanomechanical characterization of multi-layer MoS2 membranes: from intraplanar to interplanar fracture. AB - Layered molybdenum disulfide (MoS2) exhibits rich electronic and optical properties and possesses vastly differing characteristic dimensions. A multi layer MoS2 membrane represents the critical hierarchical structure which bridges the length-scale of monolayer and bulk material architectures. In this study, the in-plane mechanical properties of MoS2 membranes were investigated by in situ SEM tensile testing. Under the uniaxial tensile loading, brittle fracture caused failure in a highly localized region of the MoS2 membranes and their mechanical properties showed a thickness effect: the strengths of the relatively thicker MoS2 membranes (thickness around hundreds of nanometers) distribute from ~100 to ~250 MPa, while the corresponding values of the MoS2 nanosheets (thickness around tens of nanometers) increase significantly to more than 1 GPa. Upon molecular dynamics (MD) simulations on the fractures of MoS2 with various thicknesses/layers, the thicker MoS2 membranes show interplanar fracture, and the typical MoS2 nanosheets demonstrate the transition from interplanar to intraplanar fractures, while monolayer and few-layer MoS2 are dominated by intraplanar fracture. Our study provides some critical insights into the mechanical properties and fracture behavior of layered MoS2 2D materials, which could be of value for their flexible electronic, optoelectronic and nano-electro mechanical system (NEMS) applications. PMID- 28644501 TI - Stabilizing amyloid-beta peptide by the N-terminus capture is capable of preventing and eliminating amyloid-beta oligomers. AB - Elimination of amyloid-beta (Abeta) oligomers remains challenging. We describe here a novel strategy to prevent and eliminate the Abeta oligomers from either the early aggregation or the fibril dissolution pathway by targeting the flexible N-terminus, but not the widely investigated hydrophobic segment, with a rationally designed cyclopeptide. PMID- 28644502 TI - Au3(MU3-S)(0e) elementary block: new insights into ligated gold clusters with MU3 sulfido motifs. AB - An understanding of the structural stability and formation mechanism of ligated gold nanoclusters with triply coordinated MU3-sulfido (MU3-S) motifs is important not only for gold chemistry but also for the design of more effective catalysts or drug carriers for various applications. In this article, a new elementary block Au3(MU3-S) with zero valence electrons [referred to as Au3(MU3-S)(0e)] has been identified, which describes all crystallized ligated gold clusters with MU3 S motifs, in conjunction with the previously reported Au3(2e) and Au4(2e) elementary blocks, in a grand unified model (GUM). This Au3(MU3-S)(0e) elementary block has a tripod structure with the S atom bonding to three Au atoms in a MU3 bridging mode, and can be considered as a MU3-S atom balancing out the 2e valence electrons of the Au3(2e) block. Using Au3(MU3-S) as a building block, a special group of quasi-fullerene hollow-cage [Au3n(MU3-S)2n]n- gold(i) MU3-S clusters are designed, which exhibit high stabilities. In addition, a series of theoretical structures are predicted to be increasingly stable after introducing MU3-S atoms, based on the crystallized clusters. Overall, the introduction of a Au3(MU3-S)(0e) elementary block can help with the understanding of diverse structures of ligated gold clusters with MU3-S motifs, thereby assisting the rational design of new forms of gold nanoclusters. PMID- 28644503 TI - The first ReI organometallic complex with an organoimido-polyoxometalate ligand. AB - The spectroscopic, electrochemical and photophysical properties of the first ReI organometallic organoimido-polyoxometalate complex [n-Bu4N][Mo6O18NC6H4-CH2 N3C2H2-Re-phen(CO)3] compared with all fragments are reported. The UV-Vis spectra are analysed using experimental and theoretical tools. In contrast to the reported studies in the literature, our results show that a new more intense band is present in the spectra of the hybrid ligand obscuring the intra-polyanion charge transfer. The electrochemical results show that the strong acceptor character of the polyoxometalate fragment is quenched by the condensation of the phenyl-triazole molecule. PMID- 28644504 TI - A structural mechanism of flavonoids in inhibiting serine proteases. AB - Quercetin is a member of the flavonoids and was previously demonstrated to inhibit trypsin-like serine proteases at micromolar potencies. Different molecular models were proposed to explain such inhibition. However, controversies remain on the molecular details of inhibition. Here, we report the X-ray crystal structure of quercetin in a complex with the urokinase-type plasminogen activator (uPA), an archetypical serine protease. The structure showed that quercetin binds to the specific substrate binding pocket (S1 pocket) of uPA mainly through its two neighboring phenolic hydroxyl groups. Our study thus provides unambiguous evidence to support quercetin binding to serine proteases and defines the molecular basis of the interaction. Our results further establish that natural products with two adjacent phenolic hydroxyl groups (or catechol) are likely to inhibit other trypsin-like serine proteases, a new mechanism formerly under recognized. PMID- 28644505 TI - Exceptional bi-step switching of quadratic nonlinear optical properties in a one dimensional channel compound. AB - We report a new solid-state nonlinear optical switch based on a one-dimensional channel compound NH4[(CH3)4N]SO4.H2O. It shows an exceptional bi-step switching of second harmonic generation (SHG) effects, corresponding to its SHG-Off, SHG Low and SHG-High states, which originate from two-step structural transitions with unique centrosymmetric-polar-chiral symmetry transformations. PMID- 28644506 TI - Reduced graphene oxide coated porous carbon-sulfur nanofiber as a flexible paper electrode for lithium-sulfur batteries. AB - Lithium-sulfur (Li-S) batteries have attracted great attention owing to their excellent electrochemical properties, such as the high discharge voltage of 2.3 V, specific capacity of 1675 mA h g-1 and energy density of 2600 Wh kg-1. The widely used slurry made electrodes of Li-S batteries are plagued by the serious shuttle effect and insulating nature of sulfur. Herein, a reduced graphene oxide coated porous carbon nanofiber flexible paper (rGO@S-PCNP) was fabricated and directly used as an additive-free cathode for Li-S batteries. The results show that the rGO@S-PCNP is certified to be effective at relieving the shuttle effect and improving the conductivity, thus achieving high electrochemical performance. The rGO@S-PCNP composite with a sulfur content of 58.4 wt% delivers a high discharge capacity of 623.7 mA h g-1 after 200 cycles at 0.1 C (1 C = 1675 mA g 1) with the average Coulombic efficiency of 97.1%. The excellent cyclability and high Coulombic efficiency indicate that the as-prepared rGO@S-PCNP composite paper can be a promising cathode for lithium-sulfur batteries, and is envisioned to have great potential in high energy density flexible power devices. This facile strategy brings great significance for large-scale industrial fabrication of flexible lithium-sulfur batteries. PMID- 28644507 TI - Intrachromosomal karyotype asymmetry in Orchidaceae. AB - The asymmetry indexes have helped cytotaxonomists to interpret and classify plant karyotypes for species delimitation efforts. However, there is no consensus about the best method to calculate the intrachromosomal asymmetry. The present study aimed to compare different intrachromosomal asymmetry indexes in order to indicate which are more efficient for the estimation of asymmetry in different groups of orchids. Besides, we aimed to compare our results with the Orchidaceae phylogenetic proposal to test the hypothesis of Stebbins (1971). Through a literature review, karyotypes were selected and analyzed comparatively with ideal karyotypes in a cluster analysis. All karyotypes showed some level of interchromosomal asymmetry, ranging from slightly asymmetric to moderately asymmetric. The five tested intrachromosomal asymmetry indexes indicated Sarcoglottis grandiflora as the species with the most symmetrical karyotype and Christensonella pachyphylla with the most asymmetrical karyotype. In the cluster analysis, the largest number of species were grouped with the intermediary ideal karyotypes B or C. Considering our results, we recommend the combined use of at least two indexes, especially Ask% or A1 with Syi, for cytotaxonomic analysis in groups of orchids. In an evolutionary perspective, our results support Stebbins' hypothesis that asymmetric karyotypes derive from a symmetric karyotypes. PMID- 28644508 TI - Expression of serum microRNA-378 and its clinical significance in renal cell carcinoma. AB - Studies have demonstrated that miRNA-378 is expressed in various malignant tumors. In the present study, we aimed to explore the expression of serum miRNA 378 and its clinical significance in renal cell carcinoma (RCC) patients. A total of 75 RCC patients, 63 renal cysts (RC) patients and 75 healthy controls were selected. The miRNA-378 level in RCC and RC groups was significantly higher than in healthy control group, with RCC group having the highest level. The miRNA-378 levels were significantly decreased within the same group after surgery. When compared with healthy controls, RC group had higher levels but not significantly (p > 0.05) while levels in RCC group were significantly higher (p < 0.05). miRNA 378 expression was correlated with clinical stage and differentiation degree, but not correlated with patient's age, gender, surgical strategy and tumor diameter. The AUC of miRNA-378 was 0.896, 95% confidence interval was 0.847 to 0.945, and AUC hypothesis testing was statistically significant (p < 0.001, RCC vs healthy control). miRNA-378 shows potential in the diagnosis and prediction of postoperative curative effect of renal cell carcinoma, but further studies with lager samples are needed. PMID- 28644510 TI - Comment On: Geriatricians: The Super Specialist. PMID- 28644509 TI - Comparative transcriptomic analysis of two important life stages of Angiostrongylus cantonensis: fifth-stage larvae and female adults. AB - The mechanisms involved in the fast growth of Angiostrongylus cantonensis from fifth-stage larvae (L5) to female adults and how L5 breaks through the blood brain barrier in a permissive host remain unclear. In this work, we compared the transcriptomes of these two life stages to identify the main factors involved in the rapid growth and transition to adulthood. RNA samples from the two stages were sequenced and assembled de novo. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of 1,346 differentially expressed genes between L5 and female adults was then undertaken. Based on a combination of analytical results and developmental characteristics, we suggest that A. cantonensis synthesizes a large amount of cuticle in L5 to allow body dilatation in the rapid growth period. Products that are degraded via the lysosomal pathway may provide sufficient raw materials for cuticle production. In addition, metallopeptidases may play a key role in parasite penetration of the blood-brain barrier during migration from the brain. Overall, these results indicate that the profiles of each transcriptome are tailored to the need for survival in each developmental stage. PMID- 28644511 TI - Bacteriophage Tail-Tube Assembly Studied by Proton-Detected 4D Solid-State NMR. AB - Obtaining unambiguous resonance assignments remains a major bottleneck in solid state NMR studies of protein structure and dynamics. Particularly for supramolecular assemblies with large subunits (>150 residues), the analysis of crowded spectral data presents a challenge, even if three-dimensional (3D) spectra are used. Here, we present a proton-detected 4D solid-state NMR assignment procedure that is tailored for large assemblies. The key to recording 4D spectra with three indirect carbon or nitrogen dimensions with their inherently large chemical shift dispersion lies in the use of sparse non-uniform sampling (as low as 2 %). As a proof of principle, we acquired 4D (H)COCANH, (H)CACONH, and (H)CBCANH spectra of the 20 kDa bacteriophage tail-tube protein gp17.1 in a total time of two and a half weeks. These spectra were sufficient to obtain complete resonance assignments in a straightforward manner without use of previous solution NMR data. PMID- 28644512 TI - Association of flossing/inter-dental cleaning and periodontitis in adults. AB - AIM: Assess the association of flossing with periodontitis. MATERIALS AND METHODS: This was a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) years 2011-2014. We used three categories of flossing: 0-1, 2-4 and >=5 days in the past week and the CDC definition of periodontitis. We calculated odds ratios controlling for age, gender, smoking, drinking, income and dentist visits. RESULTS: A total of 6939 adult subjects were included, 35% flossed <=1 time a week, and 40% had periodontitis. After adjustment, the odds of periodontitis were 17% lower for subjects who flossed >1 time a week than for subjects who flossed less often (odds ratio=0.83, 95% CI 0.72-0.97). A dose response was not observed. Men were twice as likely as women to have periodontitis. Younger subjects, non-smokers and subjects with the highest incomes had lower odds of having periodontitis. CONCLUSIONS: Flossing was associated with a modestly lower prevalence of periodontitis. Older age, being male, smoking, low income and less frequent dental visits were associated with a higher prevalence of periodontitis. Flossing 2-4 days a week could be as beneficial as flossing more frequently. This is a cross-sectional study so a causal relation between flossing and periodontitis cannot be established. PMID- 28644513 TI - Benign vascular lesions of the breast diagnosed by core needle biopsy do not require excision. AB - AIMS: Surgical excision of all benign vascular lesions of the breast identified by core needle biopsy has been recommended in the past to rule out a more serious lesion. In this study we investigated the clinical, radiological and pathological findings in patients diagnosed with a benign vascular lesion at our institution to assess whether excision may be spared for lesions without atypia. METHODS AND RESULTS: We searched the electronic medical record for patients with a vascular lesion of the breast diagnosed between 2000 and 2015. The study population consisted of 84 patients, 83 females and one male. The index diagnoses included 76 benign vascular lesions, five vascular lesions with cytological atypia and three angiosarcomas. A radiologist reviewed all pre- and post-biopsy imaging studies; all cases had concordant radiological and pathological findings. Based on radiological and histological correlation, the vascular lesion accounted for the radiological target in 40 (48%) cases and was deemed an incidental finding in 44 (52%). Seven of 32 (22%) targeted and 10 of 44 (23%) incidental benign vascular lesions underwent surgical excision; there were no upgrades at excision. No recurrences or clinical events were observed in patients with a targeted or incidental benign vascular lesion with a median follow-up of 39 months and 40.6 months, respectively. CONCLUSION: Our data suggest that benign vascular lesions diagnosed on core biopsy with concordant radiological and pathological findings do not warrant surgical excision. PMID- 28644514 TI - Polylutidines: Multifunctional Surfaces through Vapor-Based Polymerization of Substituted Pyridinophanes. AB - We report a new class of functionalized polylutidine polymers that are prepared by chemical vapor deposition polymerization of substituted [2](1,4)benzeno[2](2,5)pyridinophanes. To prepare sufficient amounts of monomer for CVD polymerization, a new synthesis route for ethynylpyridinophane has been developed in three steps with an overall yield of 59 %. Subsequent CVD polymerization yielded well-defined films of poly(2,5-lutidinylene-co-p-xylylene) and poly(4-ethynyl-2,5-lutidinylene-co-p-xylylene). All polymers were characterized by infrared reflection-absorption spectroscopy, ellipsometry, contact angle studies, and X-ray photoelectron spectroscopy. Moreover, zeta potential measurements revealed that polylutidine films have higher isoelectric points than the corresponding poly-xylylene surfaces owing to the nitrogen atoms in the polymer backbone. The availability of reactive alkyne groups on the surface of poly(4-ethynyl-2,5-lutidinylene-co-p-xylylene) coatings was confirmed by spatially controlled surface modification by means of Huisgen 1,3-dipolar cycloaddition. Compared to the more hydrophobic poly-p-xylylyenes, the presence of the heteroatom in the polymer backbone of polylutidine polymers resulted in surfaces that supported an increased adhesion of primary human umbilical vein endothelial cells (HUVECs). Vapor-based polylutidine coatings are a new class of polymers that feature increased hydrophilicity and increased cell adhesion without limiting the flexibility in selecting appropriate functional side groups. PMID- 28644515 TI - Comment on: Mucosal and lacrimal flaps for endonasal dacryocystorhinostomy: A systematic review. PMID- 28644518 TI - Capillary Density of Skeletal Muscle and Maximal Oxygen Uptake. PMID- 28644516 TI - Hemostatic efficiency of modern topical sealants: Comparative evaluation after liver resection and splenic laceration in a swine model. AB - Parenchymal transection during hepatobiliary surgery can disrupt small vasculature or bile ducts, which could be managed difficultly. Sealants are helpful tools to achieve better hemostasis. The aim of this study is to analyze the hemostatic efficiency of four modern sealants in a porcine model. In this study, 40 landrace pigs were assigned equally to the control (without sealant) and four sealant groups. Standardized liver resection and splenic lesions were performed and left without using sealant (control) or treated with one of the following sealants: TachoSil(r) , Tissucol Duo(r) , Coseal(r) , and FloSeal(r) . We measured relative and absolute bleeding times (seconds) as well as total blood loss (g) in a maximum observation time of 300 s. Sealants could show a significantly improved hemostasis comparing to the control group. However, hemostasis was heterogeneous among the sealant groups (liver resection: 60%-100%, spleen injury: 70%-100%). The mean blood loss decreased significantly using sealants comparing to control group (liver resection: 6-120 fold, spleen injury: 2.5-36 fold). The hemostatic time in groups that achieved complete hemostasis was different in each sealant group (liver resection: 30-166 s, spleen injury: 60-180 s). We conclude that the hemostatic efficacy of modern sealants is impressive but heterogeneous in liver resection or splenic lesion. To maximize the effectiveness of these tools, the indication of each sealant should be carefully considered in individual settings by the surgeons. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1307-1316, 2018. PMID- 28644519 TI - General Discussion. PMID- 28644517 TI - Quantitative Insights into the Fast Pyrolysis of Extracted Cellulose, Hemicelluloses, and Lignin. AB - The transformation of lignocellulosic biomass into bio-based commodity chemicals is technically possible. Among thermochemical processes, fast pyrolysis, a relatively mature technology that has now reached a commercial level, produces a high yield of an organic-rich liquid stream. Despite recent efforts to elucidate the degradation paths of biomass during pyrolysis, the selectivity and recovery rates of bio-compounds remain low. In an attempt to clarify the general degradation scheme of biomass fast pyrolysis and provide a quantitative insight, the use of fast pyrolysis microreactors is combined with spectroscopic techniques (i.e., mass spectrometry and NMR spectroscopy) and mixtures of unlabeled and 13 C enriched materials. The first stage of the work aimed to select the type of reactor to use to ensure control of the pyrolysis regime. A comparison of the chemical fragmentation patterns of "primary" fast pyrolysis volatiles detected by using GC-MS between two small-scale microreactors showed the inevitable occurrence of secondary reactions. In the second stage, liquid fractions that are also made of primary fast pyrolysis condensates were analyzed by using quantitative liquid-state 13 C NMR spectroscopy to provide a quantitative distribution of functional groups. The compilation of these results into a map that displays the distribution of functional groups according to the individual and main constituents of biomass (i.e., hemicelluloses, cellulose and lignin) confirmed the origin of individual chemicals within the fast pyrolysis liquids. PMID- 28644520 TI - Material and General Methods. PMID- 28644521 TI - Maximal Oxygen Uptake in Norwegian Subjects. PMID- 28644523 TI - General Introduction. PMID- 28644524 TI - Summary. PMID- 28644525 TI - Relative and Total Hemoglobin Content of the Blood and Maximal Oxygen Uptake. PMID- 28644526 TI - Respiratory and Circulatory Responses to Different Types of Exercise. PMID- 28644527 TI - An audit on technical quality of root fillings performed by undergraduate students. AB - AIM: To evaluate radiographically the technical quality of root fillings performed by undergraduate dental students and to assess whether students were exposed to an appropriate endodontic case mix during their clinical training. METHODOLOGY: A retrospective audit was undertaken evaluating the clinical records of patients who underwent endodontic procedures during the period from September 2015 to June 2016 in the Dental School at Queen's University Belfast, UK. Two final-year dental students were trained and calibrated to evaluate postoperative intra-oral periapical radiographs of completed root canal treatments using specific assessment criteria. Data were presented as frequencies, percentage and mean +/- standard deviation (SD). Comparisons of treatment outcomes between groups (posterior and anterior teeth) were calculated using Fisher's exact test, and the level of significance was set at P < 0.05. Intra- and interexaminer reproducibility was assessed by Kappa statistics. RESULTS: A total of 222 teeth and 381 canals were assessed, and of those, 253 (66%) of the root fillings were found to be acceptable in all the assessment parameters, namely taper, length and lateral adaptation of the root filling. Subanalysis of individual root filling parameters revealed that 372 canals (97%) exhibited good taper, and 275 canals (72%) were considered to be of an appropriate length, with 89 canals (23%) found to be underfilled and 17 canals (5%) overfilled. Overall 346 (91%) of canals had good lateral condensation. Students treated both single and multirooted teeth, and there was no significant association between tooth type and the quality of root filling provided (P > 0.05). CONCLUSIONS: In the majority of the teeth treated by undergraduate students at Queen's University Belfast, the technical quality of the root filling was acceptable and students were exposed to an appropriate case mix for endodontic training. PMID- 28644528 TI - A systematic 1 H- and 13 C-NMR spectral analysis of bicyclo[n.3.1]alkanone systems: Determination of the relative configuration of the stereogenic centres and conformation of the six-membered ring. PMID- 28644529 TI - Reciprocal cooperation of phytochemicals and micronutrients against typical and atypical forms of Borrelia sp. AB - AIMS: Borrelia sp., a causative pathogenic factor of Lyme disease (LD), has become a major public health threat. Current treatments based on antibiotics often lead to relapse after their withdrawal. Naturally derived substances that could work synergistically to display higher efficacy compared with the individual components may serve as a resource for the development of novel approaches to combat both active and latent forms of Borrelia sp. METHODS AND RESULTS: Using checkerboard assay, we investigated the anti-borreliae reciprocal cooperation of phytochemicals and micronutrients against two species of Borrelia selected as prevalent causes of LD in the United States and Europe. We tested 28 combinations of phytochemicals such as polyphenols (baicalein, luteolin, rosmarinic acids), fatty acids (monolaurin, cis-2-decenoic acid) and micronutrients (ascorbic acid, cholecalciferol and iodine). The results showed that the combinations of baicalein with luteolin as well as monolaurin with cis-2 decenoic acid expressed synergistic anti-spirochetal effects. Moreover, baicalein and luteolin, when combined with rosmarinic acid or iodine, produced additive bacteriostatic and bactericidal effects against typical corkscrew motile spirochaetes and persistent knob/round-shaped forms, respectively. An additive anti-biofilm effect was noticed between baicalein with luteolin and monolaurin with cis-2-decenoic acid. Finally, application of the combination of baicalein with luteolin increased cytoplasmic permeability of Borrelia sp. but did not cause DNA damage. CONCLUSIONS: These results show that a specific combination of flavones might play a supporting role in combating Borrelia sp. through either synergistic or additive anti-borreliae effects. SIGNIFICANCE AND IMPACT OF THE STUDY: Presented here in vitro results might help advancing our knowledge and improving the approach to target Borrelia sp. PMID- 28644530 TI - Long-term outcome of anorexia nervosa: Results from a large clinical longitudinal study. AB - OBJECTIVE: Assessment of the long-term outcome of anorexia nervosa (AN) in a very large sample of inpatients (N = 1,693) and identification of predictors for poor outcome. METHOD: Over 25 years (mean 10 years), consecutively admitted inpatients of a specialized hospital were followed. A subsample of 112 patients with 20-year follow-up was defined. Bivariate comparisons and logistic regression analysis identified risk factors of poor outcome. RESULTS: Body mass index (BMI) increased during the follow-up period. Eating behavior as well as general psychopathology improved but did not reach the level of healthy controls. Remission was found in 30% (total sample) and in 40% (20-year follow-up subsample). Crossover from AN to binge-eating disorder or obesity was rare. The predictors of a negative course of illness included lower BMI at admission; a higher score on the Eating Disorder Inventory Maturity Fears subscale at admission; fewer follow-up years; and higher age at admission. The main diagnostic crossover occurred from AN to eating disorder not otherwise specified. Motherhood was related to better outcome. DISCUSSION: Many patients with very severe AN recover from their illness but AN also shows considerable long-term negative consequences. Over long time periods, survivors show improvement but better treatments for severe cases are still needed. Predictors of outcome included symptom severity, chronicity, and length of follow-up but not psychiatric comorbidity. PMID- 28644533 TI - New Phytologist on 'Physiology & Development'. PMID- 28644537 TI - Psychosocial, Demographic, and Illness-Related Factors Associated With Acute Traumatic Stress Responses in Parents of Children With a Serious Illness or Injury. AB - This study investigated factors associated with acute stress symptoms in parents of seriously ill children across a range of illnesses and treatment settings within a pediatric hospital setting. It was hypothesized that psychosocial variables would be more strongly associated with acute stress responses than demographic and child illness variables. Participants were 115 mothers and 56 fathers of children treated within the oncology, cardiology, and intensive care departments of a pediatric hospital. Acute stress, psychosocial, demographic, and medical data were collected within the first 4 weeks of the child's hospital admission. A robust hierarchical regression model revealed that psychosocial factors significantly explained 36.8% of the variance in parent acute stress responses (p < .001); demographic variables significantly added a further 4.5% (p = .022), but illness-related factors did not contribute to the model. Findings support the implementation of a general psychosocial screening approach for parents across the wider hospital system, and that psychosocial risk factors may be targeted in interventions across different illnesses and treatment settings to improve parent outcomes. PMID- 28644538 TI - Protective Factors, Coping Appraisals, and Social Barriers Predict Mental Health Following Community Violence: A Prospective Test of Social Cognitive Theory. AB - This study tested social cognitive theory of posttraumatic adaptation in the context of mass violence, hypothesizing that pre-event protective factors (general self-efficacy and perceived social support) would reduce posttraumatic stress symptoms (PTSS) and depression severity through boosting post-event coping self-efficacy appraisals (mediator). We qualified hypotheses by predicting that post-event social support barriers would disrupt (moderate) the health-promoting indirect effects of pre-event protective factors. With a prospective longitudinal sample, we employed path models with bootstrapping resampling to test hypotheses. Participants included 70 university students (71.4% female; 40.0% White; 34.3% Asian; 14.3% Hispanic) enrolled during a mass violence event who completed surveys one year pre-event and 5-6 months post-event. Results revealed significant large effects in predicting coping self-efficacy (mastery model, R2 = .34; enabling model, R2 = .36), PTSS (mastery model, R2 = .35; enabling model, R2 = .41), and depression severity (mastery model, R2 = .43; enabling model, R2 = .46). Overall findings supported study hypotheses, showing that at low levels of post-event social support barriers, pre-event protective factors reduced distress severity through boosting coping self-efficacy. However, as post-event social support barriers increased, the indirect, distress-reducing effects of pre-event protective factors were reduced to nonsignificance. Study implications focus on preventative and responsive intervention. PMID- 28644539 TI - Effortful swallow with resistive electrical stimulation training improves pharyngeal constriction in patients post-stroke with dysphagia. AB - This study aimed to evaluate the effect of effortful swallow combined with surface electrical stimulation as a form of resistance training on pharyngeal constriction function in post-stroke patients with dysphagia. Nineteen patients post-stroke with dysphagia received 20 min effortful swallow training with resistive electrical stimulation for 5 days per week for 4 weeks. Electrical stimulation was applied on the infrahyoid area as resistance against hyoid elevation. Stimulation intensity was adjusted daily up to the maximum tolerable level of the participant. Blinded biomechanical measurements of the extent of hyoid elevation were taken and the pharyngeal constriction ratio (PCR) determined after training. The change of the PCR and the relationship between hyoid elevation and the PCR were evaluated. The post-training PCR was significantly decreased compared to pre-training PCR (P < 0.05). There was a high inverse correlation between the hyoid elevation and the PCR (r = -1.992, P < 0.05). Effortful swallow with resistive electrical stimulation training increases pharyngeal constriction. It can be used as a treatment to improve pharyngeal constriction in patients with dysphagia. PMID- 28644540 TI - Cytokeratin 19 expression in early oral squamous cell carcinoma and their metastasis: Inadequate biomarker for one-step nucleic acid amplification implementation in sentinel lymph node biopsy procedure. AB - BACKGROUND: Intraoperative analysis of lymph nodes during a sentinel lymph node biopsy (SLNB) procedure could result in one-step surgery for early oral squamous cell carcinoma (OSCC) with an occult nodal metastasis. One-step nucleic acid amplification rapidly detects cytokeratin 19 (CK19) RNA with high accuracy. Sensitivity and specificity of CK19 expression in OSCC was evaluated. METHODS: Immunohistochemical CK19 expression was done in 207 patients with OSCC with 65 cases of paired nodal metastases. RESULTS: CK19 was expressed in 65% of all OSCC and even less in early OSCC (56%), with poor correlation between primary tumor and (occult) nodal metastasis. Furthermore, ectopic glandular tissue in close proximity of lymph nodes showed strong CK19 expression. CONCLUSION: CK19 lacks both sensitivity and specificity as a biomarker for nodal metastasis in OSCC, which questions the suitability for CK19-based one-step nucleic acid amplification in SLNB procedures. Therefore, future studies should focus on other biomarkers, because the concept of fast intraoperative diagnostics during SLNB remains attractive. PMID- 28644541 TI - Assessment of executive functioning in binge-eating disorder independent of weight status. AB - OBJECTIVE: Executive functioning (EF) problems may serve as vulnerability or maintenance factors for Binge-Eating Disorder (BED). However, it is unclear if EF problems observed in BED are related to overweight status or BED status. The current study extends this literature by examining EF in overweight and normal weight BED compared to weight-matched controls. METHOD: Participants were normal weight women with BED (n = 23), overweight BED (n = 32), overweight healthy controls (n = 48), and normal-weight healthy controls (n = 29). The EF battery utilized tests from the National Institutes of Health (NIH) Toolbox and Delis Kaplan Executive Function System (D-KEFS). RESULTS: After controlling for years of education and minority status, overweight individuals performed more poorly than normal-weight individuals on a task of cognitive flexibility requiring generativity (p < .01), and speed on psychomotor performance tasks (p = .01). Normal-weight and overweight BED performed worse on working memory tasks compared to controls (p = .04). Unexpectedly, normal-weight BED individuals out-performed all other groups on an inhibitory control task (p < .01). No significant differences were found between the four groups on tasks of planning. DISCUSSION: Regardless of weight status, BED is associated with working memory problems. Replication of the finding that normal-weight BED is associated with enhanced inhibitory control is needed. PMID- 28644542 TI - The conservation significance of natural hybridisation in Mediterranean plants: from a case study on Cyclamen (Primulaceae) to a general perspective. AB - Hybridisation plays a prominent role in plant evolution due to its influence on genetic diversity, fitness and adaptive potential. We identify a case of on-going hybrid evolution of floral phenotypes in disjunct populations of Cyclamen balearicum and C. repandum subsp. repandum on Corsica and Sardinia. Hybrid populations on the two islands contain similar patterns of variation in flower colour and size but are probably at different stages in the evolutionary process of hybridisation, and differences in the frequency of floral types and flower size suggest hybrid vigour that may contribute to the dynamics and maintenance of hybrid forms. In a review of cases of hybridisation in Mediterranean plants we found an equivalent number of cases for the contemporary occurrence of mixed hybrid populations, as there are cases of homoploid hybrid species differentiation. We argue for the development of a conservation strategy for Mediterranean plants that integrates the need to protect not just pure endemic species (some of hybrid origin) but also mixed populations where adaptive variation and new species are evolving due to contemporary hybridisation. PMID- 28644543 TI - Osteogenic potential of three different autogenous bone particles harvested during implant surgery. AB - OBJECTIVES: The aim was to compare the osteoblast activity and osteogenic potential of autogenous bone particles harvested using three different techniques and determine the most advantageous method of collecting autogenous bone particles. SUBJECTS AND METHODS: Bone particles were harvested from 20 patients during dental implant surgery using bone scraping, low-speed drilling and bone trap filtering. After the osteoblasts were cultured, cell proliferation, migration, mineralization, transcription of osteogenesis-related genes, secretion of osteogenesis-related proteins and osteoinductive protein content in the bone particle matrix were evaluated. RESULTS: Osteoblast activity and osteogenic potential were higher in bone samples harvested by scraper or low-speed drilling than in samples harvested by bone trap filter. Although these parameters were slightly lower in the low-speed drilling group than in the scraper group, significant differences were found only in bone Gla protein levels. However, the levels of osteoinductive proteins in the bone particle matrix were significantly higher in the low-speed drilling group than in the scraper group. CONCLUSIONS: Low-speed drilling is a recommendable and effective technique for collecting autogenous bone particles. In implant operations, low-speed drilling can be considered the first-line option, and if the quantity of harvested bone is insufficient, bone shavings obtained by the scraper may be considered. PMID- 28644544 TI - The "frontal peak" sign: A potential new indication of open approach in frontal sinus mucoceles with posterior table erosion. A retrospective chart review of thirty-seven patients. PMID- 28644545 TI - Robotic vs laparoscopic rectal surgery in high-risk patients. AB - AIM: Laparoscopic rectal surgery is associated with a steep learning curve and high conversion rate despite progress in equipment design and consistent practice. The robotic system has shown an advantage over the laparoscopic approach due to stable three-dimensional views, improved dexterity and better ergonomics. These factors make the robotic approach more favourable for rectal surgery. The aim of this study was to compare the perioperative outcomes of laparoscopic and robotic rectal cancer surgery in high-risk patients. METHOD: A prospectively collected dataset for high-risk patients who underwent rectal cancer surgery between May 2013 and November 2015 was analysed. Patients with any of the following characteristics were defined as high risk: a body mass index >=30, male gender, preoperative chemoradiotherapy, tumour <8 cm from the anal verge and previous abdominal surgery. RESULTS: In total, 184 high-risk patients were identified: 99 in the robotic group and 85 in the laparoscopic group. Robotic surgery was associated with a significantly higher sphincter preservation rate (86% vs 74%, P = 0.045), shorter operative time (240 vs 270 min, P = 0.013) and hospital stay (7 vs 9 days, P = 0.001), less blood loss (10 vs 100 ml, P < 0.001) and a smaller conversion rate to open surgery (0% vs 5%, P = 0.043) compared with the laparoscopic technique. Reoperation, anastomotic leak rate, 30 day mortality and oncological outcomes were comparable between the two techniques. CONCLUSION: Robotic surgery in high-risk patients is associated with higher sphincter preservation, reduced blood loss, smaller conversion rates, and shorter operating time and hospital stay. However, further studies are required to evaluate this notion. PMID- 28644547 TI - A genetic epidemiology study of congenital adrenal hyperplasia in Italy. AB - Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD-CAH) is an autosomal recessive disorder affecting steroidogenesis, due to mutations in CYP21A2 (6p21.3). 21OHD-CAH neonatal screening is based on 17-hydroxyprogesterone (17OHP) serum levels, showing high type I error rate and low sensitivity to mild CAH forms. Here, we used an epidemiological approach, which estimates the allelic frequency (q) of an autosomal recessive disorder using the proportion of homozygous patients, the mutational spectrum and the inbreeding coefficient in a sample of affected individuals. We applied this approach to 2 independent Italian cohorts of patients with both clinical and molecular diagnosis of 21OHD-CAH from mainland Italy (N = 240) and Sardinia (N = 53). We inferred q estimates of 2.87% and 1.83%, corresponding to a prevalence of 1/1214 and 1/2986, respectively. CYP21A2 mutational spectra were quite discrepant between the 2 cohorts, with V281L representing 74% of all the mutations detected in Sardinia vs 37% in mainland Italy. These findings provide an updated fine-grained picture of 21OHD CAH genetic epidemiology in Italy and suggest the need for a screening approach suitable to the detection of the largest number of clinically significant forms of CAH. PMID- 28644546 TI - 18 F-fluoromisonidazole uptake in advanced stage non-small cell lung cancer: A voxel-by-voxel PET kinetics study. AB - PURPOSE: The aim of this study was to determine the relative abilities of compartment models to describe time-courses of 18 F-fluoromisonidazole (FMISO) uptake in tumor voxels of patients with non-small cell lung cancer (NSCLC) imaged using dynamic positron emission tomography. Also to use fits of the best performing model to investigate changes in fitted rate-constants with distance from the tumor edge. METHODS: Reversible and irreversible two- and three-tissue compartment models were fitted to 24 662 individual voxel time activity curves (TACs) obtained from tumors in nine patients, each imaged twice. Descriptions of the TACs provided by the models were compared using the Akaike and Bayesian information criteria (AIC and BIC). Two different models (two- and three-tissue) were fitted to 30 measured voxel TACs to provide ground-truth TACs for a statistical simulation study. Appropriately scaled noise was added to each of the resulting ground-truth TACs, generating 1000 simulated noisy TACs for each ground truth TAC. The simulation study was carried out to provide estimates of the accuracy and precision with which parameter values are determined, the estimates being obtained for both assumptions about the ground-truth kinetics. A BIC clustering technique was used to group the fitted rate-constants, taking into consideration the underlying uncertainties on the fitted rate-constants. Voxels were also categorized according to their distance from the tumor edge. RESULTS: For uptake time-courses of individual voxels an irreversible two-tissue compartment model was found to be most precise. The simulation study indicated that this model had a one standard deviation precision of 39% for tumor fractional blood volumes and 37% for the FMISO binding rate-constant. Weighted means of fitted FMISO binding rate-constants of voxels in all tumors rose significantly with increasing distance from the tumor edge, whereas fitted fractional blood volumes fell significantly. When grouped using the BIC clustering, many centrally located voxels had high-fitted FMISO binding rate constants and low rate-constants for tracer flow between the vasculature and tumor, both indicative of hypoxia. Nevertheless, many of these voxels had tumor to-blood (TBR) values lower than the 1.4 level commonly expected for hypoxic tissues, possibly due to the low rate-constants for tracer flow between the vasculature and tumor cells in these voxels. CONCLUSIONS: Time-courses of FMISO uptake in NSCLC tumor voxels are best analyzed using an irreversible two-tissue compartment model, fits of which provide more precise parameter values than those of a three-tissue model. Changes in fitted model parameter values indicate that levels of hypoxia rise with increasing distance from tumor edges. The average FMISO binding rate-constant is higher for voxels in tumor centers than in the next tumor layer out, but the average value of the more simplistic TBR metric is lower in tumor centers. For both metrics, higher values might be considered indicative of hypoxia, and the mismatch in this case is likely to be due to poor perfusion at the tumor center. Kinetics analysis of dynamic PET images may therefore provide more accurate measures of the hypoxic status of such regions than the simpler TBR metric, a hypothesis we are presently exploring in a study of tumor imaging versus histopathology. PMID- 28644548 TI - Repetitive peripheral magnetic stimulation for activities of daily living and functional ability in people after stroke. AB - BACKGROUND: Repetitive peripheral magnetic stimulation (rPMS) is a form of therapy that creates painless stimulation of deep muscle structures to improve motor function in people with physical impairment from brain or nerve disorders. Use of rPMS for people after stroke has been identified as a feasible approach to improve activities of daily living and functional ability. However, no systematic reviews have assessed the findings of available trials. The effect and safety of this intervention for people after stroke currently remain uncertain. OBJECTIVES: To assess the effect of rPMS for improving activities of daily living and functional ability in people after stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (August 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (August 2016), MEDLINE Ovid (November 2016), Embase Ovid (August 2016), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) in Ebsco (August 2016), PsycINFO Ovid (August 2016), the Allied and Complementary Medicine Database (AMED) Ovid (August 2016), Occupational Therapy Systematic Evaluation of Evidence (OTseeker) (August 2016), the Physiotherapy Evidence Database (PEDro) (October 2016), and ICHUSHI Web (October 2016). We also searched five ongoing trial registries, screened reference lists, and contacted experts in the field. We placed no restrictions on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials (RCTs) conducted to assess the therapeutic effect of rPMS for people after stroke. Comparisons eligible for inclusion were (1) active rPMS only compared with 'sham' rPMS (a very weak form of stimulation or a sound only); (2) active rPMS only compared with no intervention; (3) active rPMS plus rehabilitation compared with sham rPMS plus rehabilitation; and (4) active rPMS plus rehabilitation compared with rehabilitation only. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. The same review authors assessed methods and risk of bias and extracted data. We contacted trial authors to ask for unpublished information if necessary. We resolved all disagreements through discussion. MAIN RESULTS: We included three trials (two RCTs and one cross-over trial) involving 121 participants. Blinding of participants and physicians was well reported in all trials, and overall risk of bias was low. We found no clear effect of rPMS on activities of daily living at the end of treatment (mean difference (MD) -3.00, 95% confidence interval (CI) 16.35 to 10.35; low-quality evidence) and at the end of follow-up (MD -2.00, 95% CI -14.86 to 10.86; low-quality evidence). Investigators in one study with 63 participants observed no statistical difference in improvement of upper limb function at the end of treatment (MD 2.00, 95% CI -4.91 to 8.91) and at the end of follow-up (MD 4.00, 95% CI -2.92 to 10.92). One trial with 18 participants showed that rPMS treatment was not associated with improved muscle strength at the end of treatment (MD 3.00, 95% CI -2.44 to 8.44). Another study reported a significant decrease in spasticity of the elbow at the end of follow-up (MD 0.48, 95% CI -0.93 to -0.03). No studies provided information on lower limb function and death. Based on the GRADE approach, we judged the certainty of evidence related to the primary outcome as low owing to the small sample size of one study. AUTHORS' CONCLUSIONS: Available trials provided inadequate evidence to permit any conclusions about routine use of rPMS for people after stroke. Additional trials with large sample sizes are needed to determine an appropriate rPMS protocol as well as long-term effects. We identified three ongoing trials and will include these trials in the next review update. PMID- 28644549 TI - A retrospective analysis of the symptoms and course of dengue infection during pregnancy. AB - OBJECTIVE: To assess outcomes among pregnant women diagnosed with dengue infection. METHODS: In a retrospective study, the medical records of all pregnant women with dengue infection admitted to Safdarjung Hospital, New Delhi, India, from July to December 2015 were reviewed. Maternal and fetal outcomes were compared by pregnancy length and stage of disease at diagnosis. RESULTS: Overall, 62 pregnant women with dengue infection were identified. Of these, 56 (90%) tested negative for nonstructural protein 1 (NS1) antigen, indicating a later stage of disease. Maternal near miss and mortality were significantly more common among women with DHF or DSS than among those with dengue fever (P<0.001). Spontaneous abortion occurred for four of six women diagnosed in the first trimester, and one of two women diagnosed in the second trimester. Among 22 women diagnosed at 26-36+6 weeks, 9 (41%) delivered preterm. There was one case of stillbirth at 37 weeks and no cases of neonatal death. CONCLUSION: Women diagnosed with dengue fever had far better outcomes than did those with DHF or DSS. PMID- 28644550 TI - Biphasic Liquid Crystal and the Simultaneous Measurement of Isotropic and Anisotropic Parameters by Spatially Resolved NMR Spectroscopy. AB - Residual dipolar couplings and other anisotropic NMR parameters are powerful tools for molecular structure elucidation when conventional techniques do not suffice. With current liquid crystalline preparations it is necessary to prepare two samples to extract isotropic and anisotropic data from spectra and to derive the residual dipolar couplings. Here, we present the preparation, measurement, and interpretation of a novel biphasic liquid crystalline phase where a single sample can be used to generate both isotropic and anisotropic data. First, we introduce the synthesis of the chiral polymer leading to the biphasic liquid crystal. Second, we present two approaches to measure spatially selective CLIP HSQC spectra. From these spectra, we extracted the couplings, performed an assignment of diastereotopic protons, and achieved the enantiomeric discrimination of isopinocampheol as a well-studied test molecule. PMID- 28644551 TI - Erythema multiforme-like lesions in primary cutaneous aggressive cytotoxic epidermotropic CD8+ T-cell lymphoma: A diagnostic and therapeutic challenge. AB - Primary cutaneous aggressive cytotoxic epidermotropic CD8+ T-cell lymphoma is an extremely rare, rapidly progressing, cutaneous lymphoma, with frequent systemic involvement and poor prognosis, that still represents a diagnostic and therapeutic challenge, especially in the early stage. Herein, we report a case of an elderly woman with a fulminant course, who at onset presented with clinical and pathological features mimicking erythema multiforme (EM) and treated with cyclosporine that led to rapid deterioration with fatal outcome 6 months after disease onset. Histopathology showed a lichenoid, epidermotropic and nodular, angiocentric, dermal and subcutaneous infiltrate of sF1, CD8+, CD45RA+ small to medium-sized atypical lymphoid cells, which strongly expressed cytotoxic markers. Monoclonal T-cell-gamma receptor was clonally rearranged and array-CGH showed numerous chromosomal imbalances. This case evidences the clinical, pathological and therapeutic challenges involved in this tumor. The first biopsy showed an interface dermatitis-like pattern, revealing the deceptive features that early cutaneous infiltrates of this aggressive lymphoma may have. A high suspicion for aggressive CTCL and a low threshold for repeat biopsies should be maintained when faced with rapidly progressing and/or ulcerative EM-like lesions, especially if immunomodulatory therapy is being considered. PMID- 28644552 TI - Assessment of videofluoroscopic swallow study findings before and after cricopharyngeal myotomy. AB - BACKGROUND: Cricopharyngeal myotomy is a treatment for obstructive cricopharyngeal bar and Zenker's diverticulitis. Little is reported regarding contrast study findings and their correlation with patient symptoms. METHODS: All patients treated by cricopharyngeal myotomy underwent a preoperative and postoperative videofluoroscopic swallow study (VFSS) and completed the self reported Eating Assessment Tool (EAT-10). Studies were analyzed quantitatively. RESULTS: Forty cricopharyngeal myotomies were performed (mean age 76 years; SD 8.72) all for dysphagia. Symptomatic improvement (change in EAT-10 scores) occurred in 95% (38/40). Presurgical versus postsurgical VFSS demonstrated significantly improved pharyngoesophageal segment opening, pharyngeal constriction ratio, and pouch residue (P < .01). Symptomatic improvement was unrelated to the presence of retained barium. CONCLUSION: Both symptomatic and objective improvement in swallowing measures occurs after cricopharyngeal myotomy. Pouch remnants and retained barium are seen postoperatively but do not correlate with reported symptoms. Routine follow-up barium studies may be needed to establish a new baseline and allow for comparison if future symptom recurrence occurs. PMID- 28644553 TI - Structural insights into the inclusion complexes between clomiphene citrate and beta-cyclodextrin: The mechanism of preferential isomeric selection. AB - A major challenge in pharmaceuticals for clinical applications is to alter the solubility, stability, and toxicity of drug molecules in living systems. Cyclodextrins (CDs) have the ability to form host-guest inclusion complexes with pharmaceuticals for further development of new drug formulations. The inclusion complex of clomiphene citrate (CL), a poorly water-soluble drug, with native beta cyclodextrin (beta-CD) was characterized by a one and two-dimensional nuclear magnetic resonance (NMR) spectroscopic approach and also by molecular docking techniques. Here we report NMR and a computational approach in preferential isomeric selection of CL, which exists in two stereochemical isomers, enclomiphene citrate (ENC; E isomer) and zuclomiphene citrate (ZNC; Z isomer) with beta-CD. beta-CD cavity protons, namely, H-3' and H-5', experienced shielding in the presence of CL. The aromatic ring protons of the CL molecule were observed to be deshielded in the presence of beta-CD. The stoichiometric ratio of the beta-CD:CL inclusion complex was observed by NMR and found to be 1:1. The overall binding constant of beta-CD:CL inclusion complexes was based on NMR chemical shifts and was calculated to be 50.21 M-1 . The change in Gibb's free energy (?G) was calculated to be -9.80 KJ mol-1 . The orientation and structure of the beta-CD:CL inclusion complexes are proposed on the basis of NMR and molecular docking studies. 2D 1 H-1 H ROESY confirmed the involvement of all three aromatic rings of CL in the inclusion complexation with beta-CD in the solution, confirming the multiple equilibria between beta-CD and CL. Molecular docking and 2D 1 H-1 H ROESY provide insight into the inclusion complexation of two isomers of CL into the beta-CD cavity. A molecular docking technique further provided the different binding affinities of the E and Z isomers of CL with beta CD and confirmed the preference of the Z isomer binding for beta-CD:CL inclusion complexes. The study indicates that the formation of a hydrogen bond between -O- of CL and the hydrogen atom of the hydroxyl group of beta-CD was the main factor for noncovalent beta-CD:CL inclusion complex formation and stabilization in the aqueous phase. PMID- 28644554 TI - N5 ,N10 -methylenetetrahydromethanopterin reductase from Methanocaldococcus jannaschii also serves as a methylglyoxal reductase. AB - In Methanocaldococcus jannaschii, methylglyoxal (MG) is required for aromatic amino acid biosynthesis. Previously, the reduction of MG to lactaldehyde in Methanocaldococcus jannaschii cell extracts using either NADPH or F420 H2 was demonstrated; however, the enzyme responsible was not identified. Using NADPH as the reductant, the unknown enzyme was purified from cell extracts of Methanocaldococcus jannaschii and determined to be the F420 -dependent N5 ,N10 methylenetetrahydromethanopterin reductase (Mer). Here, we report that the recombinantly overexpressed Mer is able to use NADPH and MG (KM of 1.6 and 1.0 mm, respectively) to produce lactaldehyde. Additionally, Mer does not catalyze the reduction of MG to lactaldehyde in the presence of reduced Fo, the precursor of F420 . PMID- 28644555 TI - A Self-Assembled Trigonal Prismatic Molecular Vessel for Catalytic Dehydration Reactions in Water. AB - A water-soluble Pd6 trigonal prism (A) was synthesized by two-component coordination-driven self-assembly of a PdII 90 degrees acceptor with a tetraimidazole donor. The walls of the prism are constructed by three conjugated aromatic building blocks, which means that the confined pocket of the prism is hydrophobic. In addition to the hydrophobic cavity, large product egress windows make A an ideal molecular vessel to catalyze otherwise challenging pseudo multicomponent dehydration reactions in its confined nanospace in aqueous medium. This study is an attempt at selective generation of the intermediate tetraketones and xanthenes by fine-tuning the reaction conditions employing a supramolecular molecular vessel. Moreover, either poor or no yield of the dehydrated products in the absence of A under similar reaction conditions supports the ability of the confined space of the barrel to promote such reactions in water. Furthermore, we focused on the rigidification of the tetraphenylethylene-based tetraimidazole unit anchored within the PdII coordination architecture; enabling counter-anion dependent aggregation induced emission in the presence of water. PMID- 28644556 TI - Sinus augmentation using a mini-pig model: Effect of ceramic and allogeneic bone biomaterials. AB - BACKGROUND: Present clinical practice broadly relies on off-the-shelf allogeneic, xenogeneic or synthetic bone biomaterials in support of sinus augmentation. Also, recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier (rhBMP-2/ACS) has been shown to support clinically relevant bone formation when used to augment the maxillary sinus. OBJECTIVES: To evaluate local bone formation/dental implant osseointegration following implantation of two particulate bone biomaterials using the mini-pig sinus augmentation model. METHODS: Nine adult Gottingen mini-pigs were used for evaluation of a biphasic ceramic (15%/85% HA/beta-TCP) and an allogeneic mineralized bone biomaterial. Treatments randomized to contralateral sinus sites included sham-surgery (control) and biomaterials. Two threaded dental implants (o4.0 * 11.5 mm) were placed at each sinus site. The animals were euthanized at 8 weeks for histologic analysis. RESULTS: Execution of the surgical protocol and healing was unremarkable. Limited infraorbital swelling was observed until suture removal. The biphasic ceramic and allogeneic bone biomaterials produced significantly increased bone formation (5.2 +/- 1.9 mm and 4.9 +/- 1.6 mm vs. 2.6 +/- 0.5 mm, p < 0.05) and osseointegration (18.0 +/- 6.0% and 25.1 +/- 18.2% vs. 10.1 +/- 8.0%, p < 0.05) over the sham-surgery control. No significant differences were observed between biomaterials. CONCLUSIONS: Implantation of biphasic ceramic or allogeneic bone biomaterials enhances bone formation in the mini-pig maxillary sinus, however, dental implant bone support is incomplete resulting in overall limited osseointegration. PMID- 28644557 TI - Selective Arterial Embolization for the Treatment of Sacral and Pelvic Giant Cell Tumor: A Systematic Review. AB - Giant cell tumor of the bone (GCTB) is a locally aggressive tumor with a certain distant metastatic rate. For sacral GCT (SGCT) and pelvic GCT (PGCT), surgery has its limitations, especially for unresectable or recurrent tumors. Selective arterial embolization (SAE) is reported to be an option for treatment in several cases, but there are few systematic reviews on the effects of SAE on SGCT and/or PGCT. Medline and Embase databases were searched for eligible English articles. Inclusion and exclusion criteria were conducted before searching. All the clinical factors were measured by SPSS software, with P-values <=0.05 considered statistically significant. A total of 9 articles were retrieved, including 44 patients receiving SAE ranging from 1 to 10 times. During the mean follow-up period of 85.8 months, the radiographic response rate was 81.8%, with a local control and overall survival rate of 75% and 81.8%, respectively. No bowel, bladder, or sexual dysfunction was observed. Three patients developed distant metastases and finally died. Patients with primary tumors tended to have better prognosis than those with recurrence (P = 0.039). The favorable outcomes of SAE suggest that it may be an alternative treatment for SGCT and PGCT patients for whom surgery is not appropriate. PMID- 28644558 TI - Current understanding of cancer stem cells: Review of their radiobiology and role in head and neck cancers. AB - Evidence of cancer cells that bear attributes analogous to those of normal stem cells has developed a hierarchical model of cancer's architecture and progression. This subset of cancer stem cells (CSCs) drives the progression and therapy resistance of cancers. Research to identify the phenotypes of these CSCs presents evidence of a subpopulation that is more resistant to therapy and may proliferate in response. Literature shows that CSCs typically represent around 1% 10% of cell populations in head and neck cancer but this proportion may increase in response to a therapeutic radiation dose. This is shown to be not just as a result of preferential killing, but also their capacity to alter divisional dynamics and enlist the support of a complicit microenvironment in therapy resistance and proliferation. The CSCs represent the apex of a hierarchy in the heterogeneity of cancer cells and may be seen as the agents of treatment failure, metastasis, and tumor recurrence, the principal cause of mortality in head and neck cancers. Greater than 90% of head and neck cancers are squamous cell carcinomas (HNSCCs), and among these an increasing incidence of the involvement of the human papillomavirus (HPV) is reported. Chemoradiotherapy along with surgical resection are the interventions of choice for control and cure of HNSCC, but given CSCs therapy resistance and proliferative responses to radiation, the identification and understanding of the radiobiology of this subpopulation is critical to their targeted elimination. This article reviews the current evidence on CSC generally and in HNSCC specifically to identify their phenotype, evaluate their responses to radiotherapy, and evaluate the defensive mechanisms used to resist therapeutic control. PMID- 28644559 TI - Evaluating Dihydroazulene/Vinylheptafulvene Photoswitches for Solar Energy Storage Applications. AB - Efficient solar energy storage is a key challenge in striving toward a sustainable future. For this reason, molecules capable of solar energy storage and release through valence isomerization, for so-called molecular solar thermal energy storage (MOST), have been investigated. Energy storage by photoconversion of the dihydroazulene/vinylheptafulvene (DHA/VHF) photothermal couple has been evaluated. The robust nature of this system is determined through multiple energy storage and release cycles at elevated temperatures in three different solvents. In a nonpolar solvent such as toluene, the DHA/VHF system can be cycled more than 70 times with less than 0.01 % degradation per cycle. Moreover, the [Cu(CH3 CN)4 ]PF6 -catalyzed conversion of VHF into DHA was demonstrated in a flow reactor. The performance of the DHA/VHF couple was also evaluated in prototype photoconversion devices, both in the laboratory by using a flow chip under simulated sunlight and under outdoor conditions by using a parabolic mirror. Device experiments demonstrated a solar energy storage efficiency of up to 0.13 % in the chip device and up to 0.02 % in the parabolic collector. Avenues for future improvements and optimization of the system are also discussed. PMID- 28644560 TI - Identification and characterization of ARS-like sequences as putative origin(s) of replication in human malaria parasite Plasmodium falciparum. AB - DNA replication is a fundamental process in genome maintenance, and initiates from several genomic sites (origins) in eukaryotes. In Saccharomyces cerevisiae, conserved sequences known as autonomously replicating sequences (ARSs) provide a landing pad for the origin recognition complex (ORC), leading to replication initiation. Although origins from higher eukaryotes share some common sequence features, the definitive genomic organization of these sites remains elusive. The human malaria parasite Plasmodium falciparum undergoes multiple rounds of DNA replication; therefore, control of initiation events is crucial to ensure proper replication. However, the sites of DNA replication initiation and the mechanism by which replication is initiated are poorly understood. Here, we have identified and characterized putative origins in P. falciparum by bioinformatics analyses and experimental approaches. An autocorrelation measure method was initially used to search for regions with marked fluctuation (dips) in the chromosome, which we hypothesized might contain potential origins. Indeed, S. cerevisiae ARS consensus sequences were found in dip regions. Several of these P. falciparum sequences were validated with chromatin immunoprecipitation-quantitative PCR, nascent strand abundance and a plasmid stability assay. Subsequently, the same sequences were used in yeast to confirm their potential as origins in vivo. Our results identify the presence of functional ARSs in P. falciparum and provide meaningful insights into replication origins in these deadly parasites. These data could be useful in designing transgenic vectors with improved stability for transfection in P. falciparum. PMID- 28644561 TI - The redox-sensitive module of cyclophilin 20-3, 2-cysteine peroxiredoxin and cysteine synthase integrates sulfur metabolism and oxylipin signaling in the high light acclimation response. AB - The integration of redox- and reactive oxygen species-dependent signaling and metabolic activities is fundamental to plant acclimation to biotic and abiotic stresses. Previous data suggest the existence of a dynamically interacting module in the chloroplast stroma consisting of cyclophilin 20-3 (Cyp20-3), O acetylserine(thiol)lyase B (OASTL-B), 2-cysteine peroxiredoxins A/B (2-CysPrx) and serine acetyltransferase 2;1 (SERAT2;1). The functionality of this COPS module is influenced by redox stimuli and oxophytodienoic acid (OPDA), which is the precursor for jasmonic acid. The concept of an integrating function of these proteins in stress signaling was challenged by combining transcriptome and biochemical analyses in Arabidopsis mutants devoid of oastlB, serat2;1, cyp20-3 and 2-cysprxA/B, and wild-type (WT). Leaf transcriptomes were analyzed 6 h after transfer to light intensity 10-fold in excess of growth light or under growth light. The survey of KEGG-based gene ontology groups showed common upregulation of translation- and protein homeostasis-associated transcripts under control conditions in all mutants compared with WT. The results revealed that the interference of the module was accompanied with disturbance of carbohydrate, sulfur and nitrogen metabolism, and also citric acid cycle intermediates. Apart from common regulation, specific responses at the transcriptome and metabolite level linked Cyp20-3 to cell wall-bound carbohydrates and oxylipin signaling, and 2-CysPrx to photosynthesis, sugar and amino acid metabolism. Deletion of either OASTL-B or SERAT2;1 frequently induced antagonistic changes in biochemical or molecular features. Enhanced sensitivity of mutant seedlings to OPDA and leaf discs to NaHS-administration confirmed the presumed functional interference of the COPS module in redox and oxylipin signaling. PMID- 28644562 TI - Efficacy of ipragliflozin as monotherapy or as add-on therapy with other oral antidiabetic medications for treating type 2 diabetes in Japanese patients with inadequate glycemic control: A subgroup analysis based on patient characteristics. AB - AIMS/INTRODUCTION: The aim of the present study was to evaluate the efficacy and safety of ipragliflozin in treating Japanese type 2 diabetes patients with inadequate glycemic control by investigating diurnal variations of blood glucose and body composition. MATERIALS AND METHODS: This was an investigator-initiated, multicenter, prospective study with a 6-month treatment period. The primary outcome investigated was change in hemoglobin A1c levels from baseline. Secondary outcomes included changes in fasting plasma glucose, insulin resistance, variations in 24-h glucose levels detected by continuous glucose monitoring, bodyweight, body composition, waist circumference and serum lipids. Adverse events were evaluated throughout the study. RESULTS: A total of 98 patients completed the study. Over the 6-month period, ipragliflozin-treated patients showed reduction in hemoglobin A1c levels by 0.3%, fasting plasma glucose levels by 13.0 mg/dL, bodyweight by 2.1 kg, body fat mass by 1.5 kg and extracellular water by 0.3 kg, as well as a decrease in systolic/diastolic blood pressures. Significant reductions from baseline in mean amplitude of glucose excursions and standard deviation, and the reduced frequency of hyperglycemia were confirmed. High-density lipoprotein cholesterol was also significantly improved. Notably, the subgroup analysis of hemoglobin A1c levels, bodyweight, waist circumference, and body composition based on age, sex and body mass index showed similar reductions within each subgroup. The incidences of adverse events and adverse drug reactions were 20.0% and 1.0%, respectively, over the 6-month period. CONCLUSIONS: Ipragliflozin is a useful oral antidiabetic medication for patients with a wide range of background characteristics. PMID- 28644563 TI - Gas-phase dissociation study of erythrinian alkaloids by electrospray ionization mass spectrometry and computational methods. AB - Alkaloids from plants of the genus Erythrina display important biological activities, including anxiolytic action. Characterization of these alkaloids by mass spectrometry (MS) has contributed to the construction of a spectral library, has improved understanding of their structures and has supported the proposal of fragmentation mechanisms in light of density functional calculations. In this study, we have used low-resolution and high-resolution MSn analyses to investigate the fragmentation patterns of erythrinian alkaloids; we have employed the B3LYP/6-31+G(d,p) model to obtain their reactive sites. To suggest the fragmentation mechanism of these alkaloids, we have studied their protonation sites by density functional calculation, and we have obtained their molecular electrostatic potential map and their gas-phase basicity values. These analyses have indicated the most basic sites on the basis of the proton affinities of the nitrogen and oxygen atoms. The protonated molecules were generated by two major fragmentations, namely, neutral loss of CH3 OH followed by elimination of H2 O. High-resolution analysis confirmed elimination of NH3 by comparison with the losses of H2 and *CH3 . NH3 was eliminated from compounds that did not bear a substituent on ring C. The benzylic carbocation initiated the dissociation mechanism, and the first reaction involved charge transfer from a lone pair of electrons in the oxygen atoms. The second reaction consisted of ring contraction with loss of a CO molecule. The presence of hydroxy and epoxy groups could change the intensity or the occurrence of the fragmentation pathways. Given that erythrinian alkaloids are applied in therapeutics and are promising leads for the development of new drugs, the present results could aid identification of several analogues of these alkaloids in biological samples and advance pharmacokinetic studies of new plant derivatives based on MSn and MS/MS analyses. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28644564 TI - Methacrylate-based root canal sealer containing chlorexidine and alpha-tricalcium phosphate. AB - The aim of this study was to develop and to characterize a methacrylate-based root canal sealer containing chlorhexidine (CHX) and alpha-tricalcium phosphate (alpha-TCP). Experimental dual cure methacrylate-based sealer was produced containing 0, 2.5, or 5 wt% of CHX and 0, 25, or 50 wt% of alpha-TCP. Experimental sealers were evaluated based on flow, film thickness, radiopacity, degree of conversion (DC), degradation in water, pH and antibacterial activity. Flow ranged from 15.09 +/- 0.11 to 17.47 +/- 0.42 mm. All groups presented mean film thickness lower than 50 um and had radiopacity equivalent to 3 mmAl. DC was higher than 60% for all compositions. The weight loss (WL) ranged 0.12-3.47%. The groups containing 5% of CHX presented the highest WL and the lower pH values after 28 days of water immersion. All chlorexidine-compositions exhibited antibacterial efficacy against Enterococcus faecalis on direct contact and agar diffusion tests. CHX and alpha-TCP addition at an experimental methacrylate-based root canal sealer influenced the physicochemical properties and provided antibacterial properties. The incorporation of CHX and alpha-TCP could be an alternative to antibacterial sealers with potential to improve periapical healing in endodontic treatments. (c) 2017 Wiley Periodicals, Inc. J Biomater Res Part B: 106B: 1439-1443, 2018. PMID- 28644565 TI - Long-term risk of infection in patients with Crohn's disease on anti-TNF treatment: A prospective single-center cohort study in China. AB - OBJECTIVE: The aim of this study was to explore the long-term risk of infection in patients with Crohn's disease (CD) on infliximab (IFX) therapy. METHODS: All CD patients treated with IFX were recruited from January 2008 to December 2015. Their characteristics and infectious events during IFX therapy were prospectively collected, and the risk of infection was evaluated using Cox regression. RESULTS: Seventy CD patients receiving IFX were consecutively recruited. During a median of 15 months, 15 patients experienced 17 infectious events which occurred within a median of 21 weeks after the initiation of IFX therapy. Of 17 infectious events, eight were viral infections, six were bacterial infections, and the others were fungal infections. IFX was discontinued in 6 (40.0%) out of 15 cases due to infections. Compared with those without infections, patients with infectious events were more likely of Montreal B1 (inflammatory) behavior, with concomitant use of systemic corticosteroids when infliximab was started but less mucosal healing when infections occurred (P < 0.05). By Cox hazard ratio (HR) analysis, patients with B1 behavior had a higher risk of developing infections than those with B3 (fistulizing) behavior (HR 4.897, P = 0.010). Successful corticosteroid withdrawal (HR 0.275, P = 0.035) or mucosal healing (HR 0.155, P = 0.002) were associated with a lower risk of infections. CONCLUSIONS: Long-term use of IFX in CD patients has a high risk of infections. Failure in mucosal healing and increased concomitant use of systemic corticosteroids are independent risk factors of infections during IFX therapy. PMID- 28644566 TI - Clinical characteristics and outcome of liver transplantation for Alagille syndrome in children. PMID- 28644567 TI - Reliability of surface electromyography measurements from the suprahyoid muscle complex. AB - Assessment of swallowing musculature using motor evoked potentials (MEPs) can be used to evaluate neural pathways. However, recording of the swallowing musculature is often invasive, uncomfortable and unrealistic in normal clinical practice. To investigate the possibility of using the suprahyoid muscle complex (SMC) using surface electromyography (sEMG) to assess changes to neural pathways by determining the reliability of measurements in healthy participants over days. Seventeen healthy participants were recruited. Measurements were performed twice with one week between sessions. Single-pulse (at 120% and 140% of the resting motor threshold (rMT)) and paired-pulse (2 ms and 15 ms paired pulse) transcranial magnetic stimulation (TMS) were used to elicit MEPs in the SMC which were recorded using sEMG. ~50% of participants (range: 42-58%; depending on stimulus type/intensity) had significantly different MEP values between day 1 and day 2 for single-pulse and paired-pulse TMS. A large stimulus artefact resulted in MEP responses that could not be assessed in four participants. The assessment of the SMC using sEMG following TMS was poorly reliable for ~50% of participants. Although using sEMG to assess swallowing musculature function is easier to perform clinically and more comfortable to patients than invasive measures, as the measurement of muscle activity using TMS is unreliable, the use of sEMG for this muscle group is not recommended and requires further research and development. PMID- 28644568 TI - Treatment of avoidant/restrictive food intake disorder in a cohort of young patients in a partial hospitalization program for eating disorders. AB - OBJECTIVE: Avoidant/restrictive food intake disorder (ARFID) is a recently named condition to classify patients who present with restricted nutritional intake without body image distortion or fear of weight gain. We sought to compare treatment outcomes of patients with ARFID in a family-centered partial hospital program (PHP) to those with other eating disorders (ED). METHOD: A retrospective chart review of 130 patients 7-17 years of age admitted to the program from 2008 to 2012 was performed. Intake and discharge data included: length of stay; percentage median body mass index (%MBMI); and scores on the Children's Eating Attitudes Test (ChEAT) and Revised Children's Manifest Anxiety Scale (RCMAS). Between and within group effects were measured for intake and discharge data. RESULTS: Patients with ARFID spent significantly fewer weeks in program than those with anorexia nervosa (AN) and experienced a similar increase in %MBMI as patients with AN and other specified/unspecified feeding and eating disorders. All patients exhibited significant improvements in psychopathology over the course of treatment as measured by scores on the ChEAT and RCMAS. DISCUSSION: Our findings suggest that patients with ARFID can be successfully treated in the same PHP as patients with other ED, with comparable improvements in weight and psychopathology over a shorter time period. Results are limited to patients with ARFID who exhibit an acute onset of severe food restriction. Future research should incorporate measures relevant to the diagnosis of ARFID and explore how patients with different ARFID subtypes may respond to various treatments. PMID- 28644569 TI - Gastrointestinal stromal tumours of the oesophagus: a clinicopathological and molecular analysis of 27 cases. AB - AIMS: Gastrointestinal stromal tumours (GISTs) may arise anywhere in the gastrointestinal tract, but are rare in the oesophagus. We describe the clinical, pathological and molecular characteristics of 27 primary oesophageal GISTs, the largest series to date. METHODS AND RESULTS: DNA was extracted and exons 9, 11, 13 and 17 of KIT, exons 12, 14 and 18 of PDGFRA and exon 15 of BRAF were amplified and sequenced. Oesophageal GISTs occurred in 14 men and 13 women aged between 22 and 80 years (mean: 56 years). All 27 cases were immunohistochemically positive for KIT, and 92 and 47% co-expressed CD34 or smooth muscle actin, respectively. Fifteen (71% of analysed cases) harboured KIT exon 11 mutations and one case each had a mutation in KIT exon 13 (K642E) or BRAF exon 15 (V600E). Long term follow-up data (median, 96.5 months) were obtained for 20 cases; two patients had metastases at presentation and seven had developed local recurrence and/or metastasis after surgery. A large tumour size (>= 10 cm), high mitotic rate (> 5/5 mm2 ), presence of a deletion mutation in KIT exon 11 involving codons 557-558 and a positive microscopic margin were associated with recurrence and metastasis. The KIT mutations identified in oesophageal GISTs are similar to those observed in gastric GISTs. CONCLUSIONS: Complete surgical resection with clear margins is recommended, if technically feasible, and genotyping can help to improve diagnosis and further patient management in oesophageal GIST. PMID- 28644570 TI - Clinical and genetic analysis of patients with cherubism. AB - OBJECTIVE: To describe the clinical and genetic features of patients with cherubism. MATERIAL AND METHODS: A descriptive analysis of 14 cases from nine different families was carried out. Clinicopathological, imaging, and follow-up data were retrieved from patients' medical files and correlated with the genetic profile of each patient. Genomic DNA isolated from buccal mucosa cells was subjected to direct sequencing analysis of the SH3BP2 gene. RESULTS: Females were more affected than males (8:6), and the mean age at diagnosis was 8.6 years (range 3-30 years). Eleven patients exhibited simultaneous bilateral involvement of the maxilla and mandible. Two patients did not have a familial history of cherubism. Progressive growth pattern was found in six patients and stable lesions were observed in other seven patients, whereas in one patient, complete spontaneous remission was documented during the follow-up (31 years). Mutations were found in 13 cases and included the typical heterozygous missense mutations R415Q, P418T, and P418H at exon 9 of SH3BP2. No correlation between the mutations and the clinical manifestations was observed. CONCLUSION: Three different point mutations in the SH3BP2 gene were detected with variable clinical involvement. Genotype-phenotype association studies in larger population with cherubism are necessary to provide important knowledge about molecular mechanisms related to the disease. PMID- 28644571 TI - Difference between respiratory epithelial adenomatoid hamartomas and small malignant tumours of the olfactory cleft on CT scans in forty-six patients. PMID- 28644572 TI - Corrigendum. PMID- 28644573 TI - Characteristics of Integrons and Associated Gene Cassettes in Antibiotic Resistant Escherichia coli Isolated from Free-Ranging Food Animals in China. AB - We investigated the occurrence of integrons in antibiotic-resistant Escherichia coli strains isolated from free-ranging food animals, including yaks, piglets, and chickens, in China, and characterized the gene cassettes harbored within the integrons. We examined 432 E. coli strains that exhibited resistance to at least one class of antibiotics. Integrase genes and associated gene cassettes were characterized by polymerase chain reaction (PCR) analysis, restriction fragment length polymorphism, DNA sequencing, conjugation experiments, and plasmid analysis. Twenty-nine (6.7%) integrons were amplified from the 432 antimicrobial resistant (AMR) isolates evaluated. Specifically, class 1 and 2 integrons were detected in 26 (6%) and 3 (0.7%) strains, respectively. Meanwhile, 6 different gene cassettes, dfrA1, dfr12, aadA1, aadA2, sat1, and orfF, were detected within 6 variable regions (VRs), of which the dfrA1 + aadA1 array was the most common, identified in 12 of 26 class 1 integrons (46.1%). Meanwhile, only one class 2 integron contained a cassette, and the remaining two contained undetermined VRs. Finally, a conjugation assay confirmed the transfer of 4 different types of class 1 integrons into recipient strains, with plasmid sizes ranging from 20 to 30 kb. This is the first report examining the baseline AMR characteristics of E. coli within an extensive farming system of livestock animals in China. Given that integrons were detected in >6% of resistant E. coli strains, precautionary measures are required to prevent the spread of mobile genetic resistance determinants in food animals and monitor their emergence. PMID- 28644574 TI - Effect of an impaired oral stage on swallowing in patients with Parkinson's disease. AB - We investigated the swallowing function in patients with Parkinson's disease (PD) using deteriorated tongue control because patients with PD frequently exhibit an impaired oral stage of swallowing and the tongue movement affects oral and pharyngeal stage. In total, 201 patients with PD (106 men, 95 women; mean age 70.6 +/- 8.0 years; median Hoehn-Yahr Stage III) were studied. The patients swallowed 10 mL of liquid barium under videofluorography, and their oral transit time (OTT) was measured. Based on 20 healthy controls (mean age 70.3 +/- 7.8 years) with an OTT + 2 standard deviation (0.89 + 2 * 0.46) of 1.81 s, the patients with PD were divided into 167 patients with an OTT < 1.81 s and 34 patients with an OTT >= 1.81 s. Swallowing function was compared between the groups and assessed using logistic regression analysis. The following factors were significantly associated with oral stage impairment in both groups: tongue to-palate contact, tongue root-to-posterior pharyngeal wall contact, premature spillage into the pharynx, aspiration and onset of swallowing reflex. Logistic regression analysis showed that tongue root-to-posterior pharyngeal wall contact, onset of swallowing reflex and aspiration were independent factors. PD patients with prolonged OTT displayed poor lingual control and decreased range of motion of the tongue due to bradykinesia and rigidity. Such problems in the oral stage affected the subsequent pharyngeal stage of swallowing with aspiration. Lingual movement in the oral stage thus appears to play an important role in the sequential movement of swallowing in PD. PMID- 28644575 TI - Comparison of 10-day levofloxacin bismuth-based quadruple therapy and levofloxacin-based triple therapy for Helicobacter pylori. AB - OBJECTIVE: This was a prospective study aiming to investigate whether levofloxacin plus bismuth-based quadruple therapy was more effective than levofloxacin-based triple therapy after failed first-line eradication therapies for Helicobacter pylori (H. pylori) infection. METHODS: Sixty-seven patients infected with H. pylori were randomly assigned to two groups; the levofloxacin plus bismuth-based quadruple therapy group (RBAL [n = 33]; rabeprazole 20 mg twice daily, bismuth subcitrate 120 mg four times daily, amoxicillin 1 g twice daily and levofloxacin 500 mg once daily, for 10 days) and the levofloxacin-based triple therapy group (RAL [n = 34]; rabeprazole 20 mg twice daily, amoxicillin 1 g twice daily and levofloxacin 500 mg once daily, for 10 days). Endoscopy was performed 4-8 weeks after H. pylori eradication to assess treatment response. We followed up patient response and compliance and checked their resistance to antibiotics. RESULTS: Intention-to-treat analysis revealed that both groups had similar eradication rates (RBAL vs RAL: 84.8% [95% confidence interval {CI} 72.6 97.1%] vs 67.6% [95% CI 51.9-83.4%], P = 0.0987). No significant differences in compliance or adverse events were found (P = 0.9829 and 0.0720). Epsilometer test showed that most eradication failure cases were levofloxacin-resistant. CONCLUSIONS: Adding bismuth subcitrate to levofloxacin-based triple therapy was not more effective than not doing so, but no further side effects were noted. Both eradication therapies were equally safe and patients had the same tolerance to both regimens. Resistance rate to levofloxacin may be important when choosing second-line therapy. PMID- 28644576 TI - Size-dependence of tree growth response to drought for Norway spruce and European beech individuals in monospecific and mixed-species stands. AB - Climate anomalies have resulted in changing forest productivity, increasing tree mortality in Central and Southern Europe. This has resulted in more severe and frequent ecological disturbances to forest stands. This study analysed the size dependence of growth response to drought years based on 384 tree individuals of Norway spruce [Picea abies (L.) Karst.] and European beech [Fagus sylvatica ([L.)] in Bavaria, Germany. Samples were collected in both monospecific and mixed species stands. To quantify the growth response to drought stress, indices for basal area increment, resistance, recovery and resilience were calculated from tree ring measurements of increment cores. Linear mixed models were developed to estimate the influence of drought periods. The results show that ageing-related growth decline is significant in drought years. Drought resilience and resistance decrease significantly with growth size among Norway spruce individuals. Evidence is also provided for robustness in the resilience capacity of European beech during drought stress. Spruce benefits from species mixing with deciduous beech, with over-yielding spruce in pure stands. The importance of the influence of size dependence within tree growth studies during disturbances is highlighted and should be considered in future studies of disturbances, including drought. PMID- 28644577 TI - Evidence of fuels management and fire weather influencing fire severity in an extreme fire event. AB - Following changes in vegetation structure and pattern, along with a changing climate, large wildfire incidence has increased in forests throughout the western United States. Given this increase, there is great interest in whether fuels treatments and previous wildfire can alter fire severity patterns in large wildfires. We assessed the relative influence of previous fuels treatments (including wildfire), fire weather, vegetation, and water balance on fire severity in the Rim Fire of 2013. We did this at three different spatial scales to investigate whether the influences on fire severity changed across scales. Both fuels treatments and previous low to moderate-severity wildfire reduced the prevalence of high-severity fire. In general, areas without recent fuels treatments and areas that previously burned at high severity tended to have a greater proportion of high-severity fire in the Rim Fire. Areas treated with prescribed fire, especially when combined with thinning, had the lowest proportions of high severity. The proportion of the landscape burned at high severity was most strongly influenced by fire weather and proportional area previously treated for fuels or burned by low to moderate severity wildfire. The proportion treated needed to effectively reduce the amount of high severity fire varied by spatial scale of analysis, with smaller spatial scales requiring a greater proportion treated to see an effect on fire severity. When moderate and high-severity fire encountered a previously treated area, fire severity was significantly reduced in the treated area relative to the adjacent untreated area. Our results show that fuels treatments and low to moderate-severity wildfire can reduce fire severity in a subsequent wildfire, even when burning under fire growth conditions. These results serve as further evidence that both fuels treatments and lower severity wildfire can increase forest resilience. PMID- 28644578 TI - The chorda tympani retractor in stapedectomy. PMID- 28644579 TI - Pairing field methods to improve inference in wildlife surveys while accommodating detection covariance. AB - It is common to use multiple field sampling methods when implementing wildlife surveys to compare method efficacy or cost efficiency, integrate distinct pieces of information provided by separate methods, or evaluate method-specific biases and misclassification error. Existing models that combine information from multiple field methods or sampling devices permit rigorous comparison of method specific detection parameters, enable estimation of additional parameters such as false-positive detection probability, and improve occurrence or abundance estimates, but with the assumption that the separate sampling methods produce detections independently of one another. This assumption is tenuous if methods are paired or deployed in close proximity simultaneously, a common practice that reduces the additional effort required to implement multiple methods and reduces the risk that differences between method-specific detection parameters are confounded by other environmental factors. We develop occupancy and spatial capture-recapture models that permit covariance between the detections produced by different methods, use simulation to compare estimator performance of the new models to models assuming independence, and provide an empirical application based on American marten (Martes americana) surveys using paired remote cameras, hair catches, and snow tracking. Simulation results indicate existing models that assume that methods independently detect organisms produce biased parameter estimates and substantially understate estimate uncertainty when this assumption is violated, while our reformulated models are robust to either methodological independence or covariance. Empirical results suggested that remote cameras and snow tracking had comparable probability of detecting present martens, but that snow tracking also produced false-positive marten detections that could potentially substantially bias distribution estimates if not corrected for. Remote cameras detected marten individuals more readily than passive hair catches. Inability to photographically distinguish individual sex did not appear to induce negative bias in camera density estimates; instead, hair catches appeared to produce detection competition between individuals that may have been a source of negative bias. Our model reformulations broaden the range of circumstances in which analyses incorporating multiple sources of information can be robustly used, and our empirical results demonstrate that using multiple field methods can enhance inferences regarding ecological parameters of interest and improve understanding of how reliably survey methods sample these parameters. PMID- 28644581 TI - Doolin Lecture 2016: 'Capacity: A quart into a pint glass' Professor Patrick Plunkett. Clinical Professor, Emergency Medicine. PMID- 28644580 TI - A free ride? An analysis of the association of casino bus tours and problem gambling among older adults. AB - BACKGROUND AND AIMS: Little research has examined the relationship between incentives used by gambling venues to attract customers and the experience of gambling-related harm. Organized and subsidized bus tours are a common example of such incentives. The aim of this study was to examine whether bus-tour patronage was associated with increased odds of problem gambling among older adults. This study also compared rates of bus-tour use by socio-demographic characteristics and gambling behaviours. DESIGN: Pearson's chi2 tests and Mann-Whitney U-tests were applied for bivariate analyses. Multivariate generalized mixed-effects regression modelling was used to examine the relationship between bus-tour patronage and problem gambling while controlling for possible confounding factors. SETTING: Seven gambling venues located in Central and Southwestern Ontario, Canada. PARTICIPANTS: A total of 1978 gambling venue patrons over the age of 55 years. MEASUREMENTS: Problem gambling as indicated by the Problem Gambling Severity Index, bus-tour patronage in the 12 months prior to the survey, spending per gambling visit and past-month slot machine participation. FINDINGS: Regression analyses showed that bus-tour patronage was associated with higher odds of problem gambling [odds ratio (OR) = 1.71, confidence interval (CI) = 1.06, 2.76] after controlling for several demographic characteristics, type of gambling and gambling expenditures. Bivariate analyses showed past-year bus-tour patronage was associated with more frequent slot machine play (chi2 = 48.16, P < 0.001), more past-year gambling venue visits (P < 0.001) and lower spending on gambling per casino visit (P < 0.001). Compared with non-patrons, bus tour patrons were more likely to be female (chi2 = 21.92, P < 0.001), born outside Canada (chi2 = 113.18, P < 0.001), above the age of 75 (chi2 = 24.02, P < 0.001) and retired (chi2 = 16.60, P < 0.001). CONCLUSIONS: When adjusting for potential confounders among older adults, using bus tours to access Canadian gambling venues is associated with increased risk of problem gambling. Bus-tour patrons are more likely to be female, born outside Canada and above the age of 75 years. PMID- 28644582 TI - Sensor Augmented Pump Therapy Use in Type 1 Diabetes Mellitus. PMID- 28644583 TI - A Slice of Hospital Toast a Day Keeps the Doctors at Bay. AB - Anecdotal evidence over the years has suggested that toast made in hospital, so called 'hospital toast' tastes better than toast made at home, or anywhere else for that matter. We carried out a prospective, multi-professional study to determine the views and the toast eating habits of NHS staff. Fifty members of NHS staff were surveyed across two hospital trusts. This included nursing staff, doctors from various specialties and allied health professionals. Results were overwhelming, a staggering 96% admitted to enjoying a slice of hospital toast while at work. In keeping with anecdotal evidence, 92% were adamant that hospital toast tasted better with multiple ingenious theories suggested for the reason behind this. So the rumours seem to be true, well, according to the 'bread and butter' of the NHS anyway; hospital toast tastes better than toast anywhere else. It provides fuel to busy healthcare professionals and overall boosts staff morale during trying times in the NHS. The mystery behind this magical hospital toast remains unsolved. PMID- 28644584 TI - Autumn Weather and Winter Increase in Cerebrovascular Disease Mortality. AB - Mortality from cerebrovascular disease increases in winter but the cause is unclear. Ireland's oceanic climate means that it infrequently experiences extremes of weather. We examined how weather patterns relate to stroke mortality in Ireland. Seasonal data for Sunshine (% of average), Rainfall (% of average) and Temperature (degrees Celsius above average) were collected for autumn (September-November) and winter (December-February) using official Irish Meteorological Office data. National cerebrovascular mortality data was obtained from Quarterly Vital Statistics. Excess winter deaths were calculated by subtracting (nadir) 3rd quarter mortality data from subsequent 1st quarter data. Data for 12 years were analysed, 2002-2014. Mean winter mortality excess was 24.7%. Winter mortality correlated with temperature (r=.60, p=0.04). Rise in winter mortality correlated strongly with the weather in the preceding autumn (Rainfall: r=-0.19 p=0.53, Temperature: r=-0.60, p=0.03, Sunshine, r=0.58, p=0.04). Winter cerebrovascular disease mortality appears higher following cool, sunny autumns. PMID- 28644585 TI - A Cost Minimisation Analysis of NOACs Compared to Warfarin to Attain Therapeutic Anticoagulation amongst AF Patients, Pre- and Post- Cardioversion. AB - Atrial fibrillation can be managed with anticoagulation and restoration of normal sinus rhythm using direct current cardioversion (DCCV). To reduce the risk of thromboembolism, anticoagulation pre-and-post DCCV is recommended. This study investigates the cost effectiveness of using NOACs compared to warfarin to attain therapeutic anticoagulation amongst AF patients pre-and-post DCCV. Propensity score matching revealed no statistically significant difference in outcomes from using NOACs and Warfarin. A cost minimisation study was performed; demonstrating a cost differential of ?209 between those administered NOACs and warfarin pre- and post-DCCV. This study demonstrates how using NOACs compared to warfarin to attain therapeutic anticoagulation amongst AF patients pre-and-post DCCV is cost effective. PMID- 28644586 TI - Medical record weight (MRW): a new reliable predictor of hospital stay, morbidity and mortality in the hip fracture population? AB - We sought to compare the weight of patient's medical records (MRW) to that of standardised surgical risk scoring systems in predicting postoperative hospital stay, morbidity, and mortality in patients with hip fracture. Patients admitted for surgical treatment of a newly diagnosed hip fracture over a 3-month period were enrolled. Patients with documented morbidity or mortality had significantly heavier medical records. The MRW was equivalent to the age-adjusted Charlson co morbidity index and better than the American Society of Anaesthesiologists physical status score (ASA), the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM,) and Portsmouth-POSSUM score (P-POSSUM) in correlation with length of hospital admission, p = .003, 95% CI [.15 to .65]. Using logistic regression analysis MRW was as good as, if not better, than the other scoring systems at predicting postoperative morbidity and 90-day mortality. Medical record weight is as good as, or better than, validated surgical risk scoring methods. Larger, multicentre studies are required to validate its use as a surgical risk prediction tool, and it may in future be supplanted by a digital measure of electronic record size. Given its ease of use and low cost, it could easily be used in trauma units globally. PMID- 28644587 TI - Recent Trends in Vaginal Birth After Caesarean Section. AB - In developed countries, caesarean section (CS) rates continue to escalate and in Ireland nearly one in three women are now delivered by CS. The purpose of this study was to compare the management of women after one previous CS in two large Dublin maternity hospitals with the management in two other well-resourced countries. Data were analysed for Dublin, Massachusetts in the United States, and Hesse in Germany. It was found that since 1990, the CS rate in Dublin has increased by much more than in the other areas. This increase may be explained by the precipitous fall in the vaginal birth after CS rate because the rates in Massachusetts and Hesse in 1990 were initially much lower. Changes in the clinical management of women with one previous CS are a major contributor to the rising CS rates and are likely to be an ongoing driver of CS rates unless clinical practices evolve. PMID- 28644588 TI - Clinical Consensus Guidelines on the Application of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease Diagnosis: Recommendations of the Irish Network for Biomarkers in Neurodegeneration. AB - It is accepted that a lumbar puncture (LP) and cerebrospinal fluid (CSF) biomarker analysis support the routine diagnostic work-up for the differential diagnosis of dementia due to Alzheimer's disease (AD) within certain patient cohorts1. These tests, which measure CSF protein concentrations of amyloid-beta42 (Abeta42), total tau (t-tau) and phospho tau (p-tau), were recently validated, accredited and made available clinically for the first time in Ireland. A working group, comprising Irish clinical and scientific researchers, met to review a) the validation results; b) international consensus opinions, and c) research and clinical evidence as to the clinical utility of CSF biomarker analysis for AD dementia diagnosis. The outcome of this meeting was the formulation of a consensus statement paper for the benefit of health care professionals involved in the diagnosis and management of dementia to ensure appropriate use of these biomarker tests in clinical settings in Ireland. PMID- 28644589 TI - When do we think it is Safe to Drive after Hand Surgery? - Current Practice and Legal Perspective. AB - Patients recovering from hand surgery frequently ask when it is safe to drive and it is unclear where the responsibility lies; the surgeon, the patient or the insurance company. An eight-question survey looking at various aspects of clinical practice was circulated to consultant and trainee plastic and orthopaedic surgeons in Ireland and the UK. Of the 89 surgeons who replied, (53%) felt the decision when to drive was the patient's compared with the insurance company (40%) and the surgeon (7%). 80% advised patients to contact their insurance company. 87% were unaware of current regulations or guidelines. National guidelines were vague and left the decision with the treating doctor. Similarly, major insurers advise patients to contact their doctor for advice. From a legal standpoint, the patient has a duty of care to other road users to be in full control of his vehicle prior to driving, regardless of any advice received. PMID- 28644591 TI - A Heart for Travel: Travel Health Considerations for Patients with Heart Disease and Cardiac Devices. AB - Cardiovascular disease is the leading cause of death in adult international travellers. Patients living with heart disease should receive specific, individualised pre-travel health advice. The purpose of this article is to provide evidence-based advice to physicians who are consulted by travellers with cardiovascular disease. Fitness-to-travel evaluation will often be conducted by the general practitioner but other medical specialists may also be consulted for advice. Patients with chronic medical conditions should purchase travel health insurance. The general pre-travel health consultation addresses food and water safety, insect and animal bite avoidance, malaria chemoprophylaxis, and travel vaccinations. Patients with devices such as cardiac pacemakers should be familiar with how these may be affected by travel. Cardiac medications may cause adverse effects in cold or hot environments, and specific precautions must be followed by anticoagulated travellers. The physician should be aware of how to access medical care abroad, and of the potential for imported tropical diseases in returned travellers. PMID- 28644590 TI - MUTYH-Associated Polyposis: The Irish Experience>. AB - MUTYH is involved in DNA damage repair. Bi-allelic MUTYH mutations predispose to polyposis and gastrointestinal malignancies, distinct genetically from autosomal dominant familial adenomatous polyposis coli. Two common European MUTYH mutations account for 90% of MUTYH-associated polyposis (MAP). We aimed to examine the incidence of MAP in Ireland. A retrospective cohort study was undertaken. Patients undergoing MUTYH testing from 2003-2016 were identified by searching electronic databases using terms "MUTYH" and "MYH". Phenotypic and genotypic details were obtained by chart review. Bi-allelic mutations were confirmed in 26 individuals (17 families), of whom 16 (62%) developed colorectal malignancies, and 22(85%) polyposis. Eleven families had bi-allelic status for one/both common European mutations. Regional variation was noted, with over-representation of bi allelic mutation carriers in the South-west of Ireland. MAP is under-diagnosed in Ireland. Increased awareness is required to facilitate appropriate identification and surveillance of bi-allelic mutation carriers for colorectal pathology. PMID- 28644592 TI - Diagnosing Lynch Syndrome. PMID- 28644593 TI - Challenges to an Uninterrupted Intern Learning Environment. PMID- 28644594 TI - A Hard Case to Swallow: Achalasia in Pregnancy. PMID- 28644595 TI - Physical Examination in Psychiatric Patients: "Myth or Reality" - Where are the guidelines? PMID- 28644596 TI - Influenza vaccine uptake amongst in-patients in acute medical unit of a tertiary care Irish hospital. PMID- 28644597 TI - [CONCLUSIONS]. PMID- 28644598 TI - ? PMID- 28644599 TI - ? PMID- 28644600 TI - [Angioplasty, coronarography and coronary artery bypass in France: a geographical approach]. AB - There are major geographic disparities in the practice of coronary angioplasty and coronarography in France. Their study shows that the frequency of these procedures is linked to the density of private medical practice (cardiologist's offices or clinics). This is not observed as far as coronary artery bypass surgery is concerned. This indicates an induction effect from simply on demand. However, this cannot give indication on the pertinence of those acts since this induction effect may as well be beneficial to patients. Nevertheless, this study gives an insight to the regulatory authorities (Regional Health Agencies and the National "Direction Generale de l'Offre de Soins") which have to manage health care system performance on the basis of the principles set out and international guidelines so as to provide equal access for all to a quality healthcare system. PMID- 28644601 TI - [DNA Ancestry and phenotype markers analyses and French law]. AB - Since some of the genetic markers involved in the analyses are single nucleotide polymorphisms located in protein-coding regions or exons, their analyses are today forbidden for forensic application in French law. A recent application of the French Criminal Chamber of "Cour de Cassation" indicates that it would be possible to perform phenotypic studies and Ancestry Informative Markers (AIM) analysis on stain samples but not on samples taken from a body. The authors present the results of the HIrisplex test performed on seven bone samples belonging to a Mongolian Altai population dated from the late Bronze Age. On account of the obtained results, the authors raise the question of the use of HIrisplex test on corpses and on skeletonized human remains for their identification. PMID- 28644602 TI - ? AB - STUDY OBJECTIVE: To compare the postoperative and medium-term outcomes of laparoscopic aortic surgery with those of conventional aortic surgery performed by a surgical team trained in laparoscopic aortic surgery. METHODS: A prospective study was conducted between January 2006 and December 2011 with 228 consecutive patients having undergone aortic bypass surgery for either an abdominal aortic aneurysm (n = 139) or an occlusive aortoiliac disease (n = 89). Conventional open aortic surgery was carried out in 145 patients, and total laparoscopic repair in 83 patients. The composite primary endpoint measure grouped together the following adverse events (AE): (1) any details < 30 days or later deaths related to the operation, (2) postoperative hemorrhage necessitating reoperation, (3) myocardial infarction I 30 days. (4) stroke I 30 days, (5) postoperative respiratory failure necessitating reintubation or assisted ventilation J 4 days, (6) aortic prosthesis infection, (7) aortic prosthesis occlusion, (8) any reoperation related to aortic surgery. In order to diminish biases attributable to the absence of randomization, the two surgical groups were matched by a propensity score enabling analysis of 50 pairs of patients having presented with identical preoperative characteristics. Univariate analysis of the AE occurring during the first 30 postoperative days was followed by multivariate analysis through logistic regression. The incidence rate of AE during follow-up was calculated using the Kaplan-Meier method and the roles of the different covariables were analyzed using the Cox model. RESULTS: Univariate analysis of the groups adjusted for propensity score showed that laparoscopic repair was associated with significantly higher risk of AE over the first 30 postoperative days (p = 0.03). Logistic regression analysis showed that laparoscopic aortic technique (Odds Ratio (OR) ; 4.50) and coronary artery disease (OR ; 4.67) were independently related to occurrence of an AE during the postoperative period. Occurrence of AE during follow-up was analyzed using the Cox model. Only two variables, laparoscopic aortic surgery [Hazard Ratio (HR) ; 4,40 ; CI 95 % 1.70 11.38 ; p. = 0.002] and coronary artery occurrence of an AE during follow-up. The small number of patients prevented a separate analysis with regard to aneurysmal and occlusive aortic disease. CONCLUSIONS: This study suggests that even with a well-trained surgical team, the laparoscopic approach increases risk for AE observed in the course of aortic surgery. ClinicalTrials. gov Identifier: NCT02325700. PMID- 28644603 TI - [Innovative immunotherapies of respiratory allergic diseases]. AB - Allergen immunotherapy (AIT) is an effective method in the treatment of respiratory allergic diseases (asthma, rhinitis and conjunctivitis). In addition to reducing symptoms, AIT can alter the course of allergic disease and remains efficient long after it has been discontinued by inducing specific tolerance to the allergen. In current clinical practice, immunotherapy is administered by subcutaneous or sublingual routes. The duration of efficacy is 7 to 12 years. It can prevent the development of both asthma and sensitization to new allergens. Despite recent progresses, other approaches are needed, especially for allergies (atopic dermatitis, food allergies). The new AIT improvement approaches involve the use of adjuvants or recombinant allergies, peptides and new routes of administration. PMID- 28644604 TI - [Innate Lymphoid Cells: new actors of immunity]. AB - The world of lymphocytes has recently expanded. A new group of cells, innate lymphoid cells (ILCs) has been defined. It includes lymphoid cells that have been known for decades, such as natural killer (NK) cells, and lymphoid tissue- inducer (LTi) cells. NK cells recognize a vast array of tumor cells, which they help to eliminate through cytotoxicity and the production of cytokines, such as interferon-gamma). (IFN-gamma). Advances in our understanding of NK cell biology have led to a growing interest in the clinical manipulation of these cells in cancer. The other ILCs are found mostly in the mucosae and mucosal-associated lymphoid tissues, where they rapidly initiate immune responses to pathogens in the absence of specific sensitization. Here, we outline the basic features of ILCs and review the role of ILCs other than NK cells in cancer. Much of the role of ILCs in cancer remains unknown, but several findings should lead to further efforts to dissect the contribution of different ILC subsets to the promotion, maintenance, or elimination of tumors at various anatomic sites. This will require the development of standardized reagents and protocols for monitoring the presence and function of ILCs in human blood and tissue samples. PMID- 28644605 TI - [SPA therapy for pain of patients with chronic low back pain, knee osteo arthritis and fibromyalgia]. AB - The data of 33 randomized controlled trials suggest that chronic pain of patients with chronic low back pain, knee osteo-arthritis, fibromyalgia is significantly improved by balneotherapy and significantly better improved than by control treatments. For chronic low back pain (10 RCT, 1192 patients) pain was better improved in balneotherapy group and the weighted mean of the differential improvement was 19.66 (95 % CI: 16.6 ; 22.8) and the effect size was 1.1 (95 %CI: 0.82 ; 1.38) favouring balneotherapy. For knee osteo-arthritis pain (17 RCT, 1428 patients) pain was better improved in balneotherapy group and the weighted mean of the differential improvement was 13.24 (95 % CI: 5.52 ; 20.96) and the effect size was 0.72 (95 %CI: 0.51 ; 0.93) favouring balneotherapy. For fibromyalgia (6 RCT, 398 patients) pain was better improved in balneotherapy group and the weighted mean of the differential improvement was 19.32 (95 % CI: 10.62 ; 29.2) and the effect size was 0.79 (95 %CI: 0.27 ; 1.31) favouring balneotherapy. Mineral waters and healing muds appear to have a more powerful analgesic action: 13 RCT (701) patients) compared mineral water bathing to tap water bathing or peloid application to hot-apcks or neutral muds application : the effect size was 0.75 (95 % CI :0.71 ; 0.79) favouring balneotherapy. Balneotherapy is a safe treatment as only 1 % of the patients receiving balneotherapy had to interrupt the treatment. However several methodological biases were observed in many trials, mainly a lack of statistical power due to a limited enrolment of patients, an insufficient duration of follow-up, an inhomogeneity of treatments. The clinical benefit has to be confirmed by stronger data of evidence but these data are sufficient to perform a more complete scientific analysis (meta analysis) ; but further clinical investigations with a better methodological quality remain necessary. PMID- 28644606 TI - ? AB - In France, people with intellectual disability (ID) account approximately for 2.5 % of the total population. Life expectancy of ID increased over the last years, and this raised the risk of cancers developing in this group of patients. Overall, the prevalence of cancers for those patients is much like that of the general population, but they have specificities regarding their epidemiology, diagnostic and treatment. The type of cancers occurring differs depending on the age and the etiology of the ID of the patient. ID may raise special difficulties for the management and the treatment of the cancer that may be, ultimately, non optimal. PMID- 28644607 TI - Electrochemical Exfoliation of Graphite in Aqueous Sodium Halide Electrolytes toward Low Oxygen Content Graphene for Energy and Environmental Applications. AB - Graphene and graphene-based materials have shown great promise in many technological applications, but their large-scale production and processing by simple and cost-effective means still constitute significant issues in the path of their widespread implementation. Here, we investigate a straightforward method for the preparation of a ready-to-use and low oxygen content graphene material that is based on electrochemical (anodic) delamination of graphite in aqueous medium with sodium halides as the electrolyte. Contrary to previous conflicting reports on the ability of halide anions to act as efficient exfoliating electrolytes in electrochemical graphene exfoliation, we show that proper choice of both graphite electrode (e.g., graphite foil) and sodium halide concentration readily leads to the generation of large quantities of single-/few-layer graphene nanosheets possessing a degree of oxidation (O/C ratio down to ~0.06) lower than that typical of anodically exfoliated graphenes obtained with commonly used electrolytes. The halide anions are thought to play a role in mitigating the oxidation of the graphene lattice during exfoliation, which is also discussed and rationalized. The as-exfoliated graphene materials exhibited a three-dimensional morphology that was suitable for their practical use without the need to resort to any kind of postproduction processing. When tested as dye adsorbents, they outperformed many previously reported graphene-based materials (e.g., they adsorbed ~920 mg g-1 for methyl orange) and were useful sorbents for oils and nonpolar organic solvents. Supercapacitor cells assembled directly from the as exfoliated products delivered energy and power density values (up to 15.3 Wh kg-1 and 3220 W kg-1, respectively) competitive with those of many other graphene based devices but with the additional advantage of extreme simplicity of preparation. PMID- 28644608 TI - Targeting CpG Adjuvant to Lymph Node via Dextran Conjugate Enhances Antitumor Immunotherapy. AB - Nucleic acid based adjuvants recognized by Toll-like receptors (TLR) are potent immune system stimulants that can augment the antitumor immune responses in an antigen-specific manner. However, their clinical uses as vaccine adjuvants are limited primarily due to lack of accumulation in the lymph nodes, the anatomic sites where the immune responses are initiated. Here, we showed that chemical conjugation of type B CpG DNA, a TLR9 agonist to dextran polymer dramatically enhanced CpG's lymph node accumulation in mice. Dextran conjugation did not alter CpG ODN's uptake, internalization, and bioactivity in vitro. Delivery of Dextran CpG conjugate markedly increased the uptake by antigen presenting cells in the lymph nodes and enhanced CD8+ T cell responses primed by protein vaccines, leading to improved therapeutic antitumor immunity. Furthermore, immunization with Dextran-CpG mixed with necrotic whole tumor cells induced a protective antitumor response in a murine model, suggesting that this approach was not limited to molecularly defined antigens. This simple method might also be applicable for the delivery of many other nucleic acid based adjuvants in cancer vaccines. PMID- 28644609 TI - GalNAc-Tyrosine Is a Ligand of Plant Lectins, Antibodies, and Human and Murine Macrophage Galactose-Type Lectins. AB - In 2011, a new type of protein O-glycosylation was discovered in which N acetylgalactosamine is attached to the side chain of tyrosine (GalNAc-Tyr). While present on dozens of proteins, the biological roles of GalNAc-Tyr are unknown. To gain insight into this new type of modification, we synthesized a group of GalNAc Tyr glycopeptides, constructed microarrays, and evaluated potential recognition of GalNAc-Tyr by a series of glycan-binding proteins. Through a series of >150 microarray experiments, we assessed binding properties of a variety of plant lectins, monoclonal antibodies, and endogenous lectins. VVL, HPA, and SBA were all found to bind tightly to GalNAc-Tyr, and several Tn binding antibodies and blood group A antibodies were found to cross-react with GalNAc-Tyr. Thus, detection of GalNAc-Tyr modified proteins is an important consideration when analyzing results from these reagents. Additionally, we evaluated potential recognition by two mammalian lectins, human (hMGL) and murine (mMGL-2) macrophage galactose type C-type lectins. Both hMGL and mMGL-2 bound tightly to GalNAc-Tyr determinants. The apparent Kd values (~1-40 nM) were on par with some of the best known ligands for MGL, such as the Tn antigen. hMGL also bound the natural beta amyloid peptide containing a GalNAc-Tyr epitope. STD NMR experiments provided structural insights into the molecular basis of recognition. Finally, GalNAc-Tyr was selectively captured by mMGL-2 positive dendritic cells. These results provide the first evidence that GalNAc-Tyr modified proteins and/or peptides may be ligands for hMGL and mMGL-2 and offer unique structures for the design of MGL targeting agents. PMID- 28644610 TI - MZmine 2 Data-Preprocessing To Enhance Molecular Networking Reliability. AB - Molecular networking is becoming more and more popular into the metabolomic community to organize tandem mass spectrometry (MS2) data. Even though this approach allows the treatment and comparison of large data sets, several drawbacks related to the MS-Cluster tool routinely used on the Global Natural Product Social Molecular Networking platform (GNPS) limit its potential. MS Cluster cannot distinguish between chromatography well-resolved isomers as retention times are not taken into account. Annotation with predicted chemical formulas is also not implemented and semiquantification is only based on the number of MS2 scans. We propose to introduce a data-preprocessing workflow including the preliminary data treatment by MZmine 2 followed by a homemade Python script freely available to the community that clears the major previously mentioned GNPS drawbacks. The efficiency of this workflow is exemplified with the analysis of six fractions of increasing polarities obtained from a sequential supercritical CO2 extraction of Stillingia lineata leaves. PMID- 28644611 TI - Transient Fiber Mats of Electrospun Poly(Propylene Carbonate) Composites with Remarkable Mechanical Strength. AB - Polymers with a triggered decomposition are attractive for an array of applications ranging from patterning to transient packaging materials, as well as for environmental protection. This work showed for the first time UV and thermally triggered transience in fiber mats using poly(propylene carbonate) (PPC) composites. The electrospun PPC-composite fiber mats combine excellent decomposition performance (because of the high surface to volume ratio) with high stiffness and thus represent a new class of materials enabling innovative applications, such as transient filter materials and short-time plant protection materials, as well as temporary lightweight materials for aerospace engineering. Thermally and UV-triggerable additives (protected acids or base) have been used in different concentrations to tune the transience performance of the fiber mats over a wide range (75-212 degrees C). The addition of organo-modified clay (OMMT) enhanced mechanical stability and prevented shrinkage at room temperature. Different annealing methods have been used to improve the mechanical properties even further (tensile strength = 2-12 MPa, Young's modulus = 55-747 MPa) making these fiber mats attractive for a broad field of applications. An Ashby plot of Young's modulus versus degradation temperature for electrospun fiber mats is shown, revealing much lower degradation temperatures with higher moduli for PPC composites compared to other electrospun polymers. PMID- 28644612 TI - Suppressing Isomerization of Phosphine-Protected Au9 Cluster by Bond Stiffening Induced by a Single Pd Atom Substitution. AB - The fluxional nature of small gold clusters has been exemplified by reversible isomerization between [Au9(PPh3)8]3+ with a crown motif (Au9(C)) and that with a butterfly motif (Au9(B)) induced by association and dissociation with compact counteranions (NO3-, Cl-). However, structural isomerization was suppressed by substitution of the central Au atom of the Au9 core in [Au9(PPh3)8]3+ with a Pd atom: [PdAu8(PPh3)8]2+ with a crown motif (PdAu8(C)) did not isomerize to that with a butterfly motif (PdAu8(B)) upon association with the counteranions. Density functional theory calculation showed that the energy difference between PdAu8(C) and PdAu8(B) is comparable to that between Au9(C) and Au9(B), indicating that the relative stabilities of the isomers are not a direct cause for the suppression of isomerization. Temperature dependence of Debye-Waller factors obtained by X-ray absorption fine-structure analysis revealed that the intracluster bonds of PdAu8(C) were stiffer than the corresponding bonds in Au9(C). Natural bond orbital analysis suggested that the radial Pd-Au and lateral Au-Au bonds in PdAu8(C) are stiffened due to the increase in the ionic nature and decrease in electrostatic repulsion between the surface Au atoms, respectively. We conclude that the formation of stiffer metal-metal bonds by Pd atom doping inhibits the isomerization from PdAu8(C) to PdAu8(B). PMID- 28644613 TI - Impact of Thermal Decomposition on Thermal Desorption Instruments: Advantage of Thermogram Analysis for Quantifying Volatility Distributions of Organic Species. AB - We present results from a high-resolution chemical ionization time-of-flight mass spectrometer (HRToF-CIMS), operated with two different thermal desorption inlets, designed to characterize the gas and aerosol composition. Data from two field campaigns at forested sites are shown. Particle volatility distributions are estimated using three different methods: thermograms, elemental formulas, and measured partitioning. Thermogram-based results are consistent with those from an aerosol mass spectrometer (AMS) with a thermal denuder, implying that thermal desorption is reproducible across very different experimental setups. Estimated volatilities from the detected elemental formulas are much higher than from thermograms since many of the detected species are thermal decomposition products rather than actual SOA molecules. We show that up to 65% of citric acid decomposes substantially in the FIGAERO-CIMS, with ~20% of its mass detected as gas-phase CO2, CO, and H2O. Once thermal decomposition effects on the detected formulas are taken into account, formula-derived volatilities can be reconciled with the thermogram method. The volatility distribution estimated from partitioning measurements is very narrow, likely due to signal-to-noise limits in the measurements. Our findings indicate that many commonly used thermal desorption methods might lead to inaccurate results when estimating volatilities from observed ion formulas found in SOA. The volatility distributions from the thermogram method are likely the closest to the real distributions. PMID- 28644614 TI - Role of the Protein Corona Derived from Human Plasma in Cellular Interactions between Nanoporous Human Serum Albumin Particles and Endothelial Cells. AB - The presence of a protein corona on various synthetic nanomaterials has been shown to strongly influence how they interact with cells. However, it is unclear if the protein corona also exists on protein particles, and if so, its role in particle-cell interactions. In this study, pure human serum albumin (HSA) particles were fabricated via mesoporous silica particle templating. Our data reveal that various serum proteins adsorbed on the particles, when exposed to human blood plasma, forming a corona. In human umbilical vein endothelial cells (HUVECs), the corona was shown to decrease particle binding to the cell membrane, increase the residence time of particles in early endosomes, and reduce the amount of internalized particles within the first hours of exposure to particles. These findings reveal important information regarding the mechanisms used by vascular endothelial cells to internalize protein-based particulate materials exposed to blood plasma. The ability to control the cellular recognition of these organic particles is expected to aid the advancement of HSA-based materials for intravenous drug delivery. PMID- 28644615 TI - Fluoromodules Consisting of a Promiscuous RNA Aptamer and Red or Blue Fluorogenic Cyanine Dyes: Selection, Characterization, and Bioimaging. AB - An RNA aptamer selected for binding to the fluorogenic cyanine dye, dimethylindole red (DIR), also binds and activates another cyanine, oxazole thiazole blue (OTB), giving two well-resolved emission colors. The aptamer binds to each dye with submicromolar KD values, and the resulting fluoromodules exhibit fluorescence quantum yields ranging from 0.17 to 0.51 and excellent photostability. The aptamer was fused to a second aptamer previously selected for binding to the epidermal growth factor receptor (EGFR) to create a bifunctional aptamer that labels cell-surface EGFR on mammalian cells. The fluorescent color of the aptamer-labeled EGFR can be switched between blue and red in situ simply by exchanging the dye in the medium. The promiscuity of the aptamer can also be used to distinguish between cell-surface and internalized EGFR on the basis of the addition of red or blue fluorogen at different times. PMID- 28644616 TI - Importance of a Fully Anharmonic Treatment of Equilibrium Isotope Fractionation Properties of Dissolved Ionic Species As Evidenced by Li+(aq). AB - Equilibrium fractionation of stable isotopes is critically important in fields ranging from chemistry, including medicinal chemistry, electrochemistry, geochemistry, and nuclear chemistry, to environmental science. The dearth of reliable estimates of equilibrium fractionation factors, from experiment or from natural observations, has created a need for accurate computational approaches. Because isotope fractionation is a purely quantum mechanical phenomenon, exact calculation of fractionation factors is nontrivial. Consequently, a severe approximation is often made, in which it is assumed that the system can be decomposed into a set of independent harmonic oscillators. Reliance on this often crude approximation is one of the primary reasons that theoretical prediction of isotope fractionation has lagged behind experiment. A class of problems for which one might expect the harmonic approximation to perform most poorly is the isotopic fractionation between solid and solution phases. In order to illustrate the errors associated with the harmonic approximation, we have considered the fractionation of Li isotopes between aqueous solution and phyllosilicate minerals, where we find that the harmonic approximation overestimates isotope fractionation factors by as much as 30% at 25 degrees C. Lithium is a particularly interesting species to examine, as natural lithium isotope signatures provide information about hydrothermal processes, carbon cycle, and regulation of the Earth's climate by continental alteration. Further, separation of lithium isotopes is of growing interest in the nuclear industry due to a need for pure 6Li and 7Li isotopes. Moving beyond the harmonic approximation entails performing exact quantum calculations, which can be achieved using the Feynman path integral formulation of quantum statistical mechanics. In the path integral approach, a system of quantum particles is represented as a set of classical-like ring-polymer chains, whose interparticle interactions are determined by the rules of quantum mechanics. Because a classical isomorphism exists between the true quantum system and the system of ring-polymers, classical-like methods can be applied. Recent developments of efficient path integral approaches for the exact calculation of isotope fractionation now allow the case of the aforementioned dissolved Li fractionation properties to be studied in detail. Applying this technique, we find that the calculations yield results that are in good agreement with both experimental data and natural observations. Importantly, path integral methods, being fully atomistic, allow us to identify the origins of anharmonic effects and to make reliable predictions at temperatures that are experimentally inaccessible yet are, nevertheless, relevant for natural phenomena. PMID- 28644617 TI - Dynamic Covalent Chemistry of Carbon Dioxide: Opportunities to Address Environmental Issues. AB - Extraction and purification of basic chemicals from complex mixtures has been a persistent issue throughout the development of the chemical sciences. The chemical industry and academic research have grown over the centuries by following a deconstruction-reconstruction approach, reminiscent of the metabolism process. Chemists have designed and optimized extraction, purification, and transformation processes of molecules from natural deposits (fossil fuels, biomass, ores), in order to reassemble them into complex adducts. These highly selective and cost-effective techniques arose from developments in physical chemistry but also in supramolecular chemistry, long before the term was even coined. Thanks to the extremely diverse toolbox currently available to the scientific community, artificial molecular systems of increasing complexity can be built and integrated into high-technology products. If humanity has proven through the ages how gifted it can be at this deconstruction-reconstruction game, which has transformed the natural world to a human-shaped one, it has been confronted for more than a century by a new challenge: the deconstruction and reconstruction from a new type of deposit, the waste resulting from the mass production of disposable manufactured goods. In this Account, we will explore the potential contribution of controlled molecular and supramolecular self-assembly phenomena to the challenge of selective and efficient capture of valuable target molecules from mixtures found in postconsumer waste. While it may appear paradoxical to add more molecular ingredients to an already compositionally complex system in order to address a purification issue, we will compare the selectivity, yield, and cost of such an atypical procedure with traditional physical techniques. In the context of carbon dioxide capture or release, we will specifically focus on the coupling between this reversible covalent fixation of the gas by amines and an additional chemical equilibrium. This equilibrium may involve covalent or noncovalent bond formation between a supplementary species and either the unloaded reactant or the CO2-loaded product. Thereby, this new reactive species may act as a CO2 capture agonist or antagonist by either thermodynamically favoring the carbamation or decarbamation direction. Indeed, superagonism, the increase of CO2 loading per amine site upon carbamation beyond the theoretical limit of 0.5, can be achieved using tightly bound cationic metal counterions. In all cases, upon binding and adduct formation, a mutual selection process occurs between one member of the CO2-based dynamic combinatorial library and one agonist or antagonist, which can itself be contained in a complex mixture of analogues. If this adduct is the only species that, upon formation, can self aggregate into a separate solid phase, selection and binding are accompanied by translocation, rendering the purification procedure operationally straightforward. This general strategy, based on a simple design of coupled molecular systems, may easily be implemented within new, disruptive technologies for selective extraction of target molecules, thereby providing a substantial environmental and economic benefit. PMID- 28644618 TI - Exploring New Assembly Modes of Uranyl Terephthalate: Templated Syntheses and Structural Regulation of a Series of Rare 2D -> 3D Polycatenated Frameworks. AB - The reaction of uranyl nitrate with terephthalic acid (H2TP) under hydrothermal conditions in the presence of an organic base, 1,3-(4,4'-bispyridyl)propane (BPP) or 4,4'-bipyridine (BPY), provided four uranyl terephthalate compounds with different entangled structures by a pH-tuning method. [UO2(TP)1.5](H2BPP)0.5.2H2O (1) obtained in a relatively acidic solution (final aqueous pH, 4.28) crystallizes in the form of a noninterpenetrated honeycomb-like two-dimensional network structure. An elevation of the solution pH (final pH, 5.21) promotes the formation of a dimeric uranyl-mediated polycatenated framework, [(UO2)2(MU OH)2(TP)2]2(H2BPP)2.4.5H2O (2). Another new polycatenated framework with a monomeric uranyl unit, [(UO2)2(TP)3](H2BPP) (3), begins to emerge as a minor accompanying product of 2 when the pH is increased up to 6.61, and turns out to be a significant product at pH 7.00. When more rigid but small-size BPY molecules replace BPP molecules, [UO2(TP)1.5](H2BPP)0.5 (4) with a polycatenated framework similar to 3 was obtained in a relatively acidic solution (final pH, 4.81). The successful preparation of 2-4 represents the first report of uranyl-organic polycatenated frameworks derived from a simple H2TP linker. A direct comparison between these polycatenated frameworks and previously reported uranyl terephthalate compounds suggests that the template and cavity-filling effects of organic bases (such as BPP or BPY), in combination with specific hydrothermal conditions, promote the formation of uranyl terephthalate polycatenated frameworks. PMID- 28644619 TI - Long-Bonding in HNgCN/NC (Ng = Noble Gas) Molecules: An NBO/NRT Investigation. AB - Recently, Weinhold et al. put forward one new concept of sigma-type long-bonding and applied it to the comprehension of halogen noble-gas hydrides HNgY (Ng = noble gas; Y = halogen) bonding. The present study extends this new concept into HNgX (X = CN, NC) pseudohalogen molecules. At the B3LYP and CCSD(T) levels of theory, we perform natural bond orbital (NBO) and natural resonance theory (NRT) studies on the HNgX molecules and compare them with the previous results for HNgY molecules. The NBO/NRT results clearly reveal that each of the HNgX, but not the HHeCN, HNeCN, and HNeNC molecules, is composed of three leading resonance structures: two omega-bonding structures H-Ng+:X-, H:-Ng+-X and one long-bonded structure H?X. This result indicates that the conventional long-bonding exists in these pseudohalogen molecules, like the long-bonding in HNgY molecules. Unexpectedly, we identify a new type of longer long-bonded structure H?C in HNeNC molecule at the B3LYP level, which disappears at the CCSD level. This misleading prediction at the B3LYP level can be traced back to the singlet diradical character, which induces a low-quality geometry. Therefore, the geometry reoptimization of the noble-gas hydrides is indispensable using CASSCF-based methods, if the noble-gas hydrides fail the "Stable" test because of diradical type instability. PMID- 28644620 TI - Nanofibrous Smart Fabrics from Twisted Yarns of Electrospun Piezopolymer. AB - Smart textiles are envisioned to make a paradigm shift in wearable technologies to directly impart functionality into the fibers rather than integrating sensors and electronics onto conformal substrates or skin in wearable devices. Among smart materials, piezoelectric fabrics have not been widely reported, yet. Piezoelectric smart fabrics can be used for mechanical energy harvesting, for thermal energy harvesting through the pyroelectric effect, for ferroelectric applications, as pressure and force sensors, for motion detection, and for ultrasonic sensing. We report on mechanical and material properties of the plied nanofibrous piezoelectric yarns as a function of postprocessing conditions including thermal annealing and drawing (stretching). In addition, we used a continuous electrospinning setup to directly produce P(VDF-TrFE) nanofibers and convert them into twisted plied yarns, and demonstrated application of these plied yarns in woven piezoelectric fabrics. The results of this work can be an early step toward realization of piezoelectric smart fabrics. PMID- 28644621 TI - Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold. AB - The review highlights the hydantoin syntheses presented from the point of view of the preparation methods. Novel synthetic routes to various hydantoin structures, the advances brought to the classical methods in the aim of producing more sustainable and environmentally friendly procedures for the preparation of these biomolecules, and a critical comparison of the different synthetic approaches developed in the last twelve years are also described. The review is composed of 95 schemes, 8 figures and 528 references for the last 12 years and includes the description of the hydantoin-based marketed drugs and clinical candidates. PMID- 28644622 TI - Single Analyzer Neutral Loss Scans in a Linear Quadrupole Ion Trap Using Orthogonal Double Resonance Excitation. AB - In this follow-up paper to our previous work on single analyzer precursor ion scans in a linear quadrupole ion trap (Snyder, D. T.; Cooks, R. G. Single analyzer precursor ion scans in a linear quadrupole ion trap using orthogonal double resonance excitation. J. Am. Soc. Mass Spectrom. 2017, DOI: 10.1007/s13361 017-1707-y), we now report the development of single analyzer neutral loss scans in a linear quadrupole ion trap using orthogonal double resonance excitation. Methodologically, there are three key differences between single analyzer precursor ion scans and neutral loss scans under constant radiofrequency (rf) conditions: (1) in the latter experiment, both excitation and ejection frequencies must be scanned, whereas in the former the ejection frequency is fixed, (2) the need to maintain a constant neutral loss while incrementing both precursor and product ion masses, complicated by the complex relationship between secular frequency and mass, requires use of two simultaneous frequency scans, both linear in mass, and (3) because the ejection frequency is scanned, a third ac signal occurring between the ac excitation and ac ejection frequency scans must also be applied and scanned in order to reject artifact peaks caused by ejection of unfragmented precursor ions. Using this methodology, we demonstrate neutral loss scans on a commercial linear ion trap using mixtures of illicit drugs and acylcarnitines. We also demonstrate neutral loss scanning on a Populus deltoides leaf and on a lignin sample, both significantly more complex mixtures. PMID- 28644623 TI - Charge Transport in Molecular Materials: An Assessment of Computational Methods. AB - The booming field of molecular electronics has fostered a surge of computational research on electronic properties of organic molecular solids. In particular, with respect to a microscopic understanding of transport and loss mechanisms, theoretical studies assume an ever-increasing role. Owing to the tremendous diversity of organic molecular materials, a great number of computational methods have been put forward to suit every possible charge transport regime, material, and need for accuracy. With this review article we aim at providing a compendium of the available methods, their theoretical foundations, and their ranges of validity. We illustrate these through applications found in the literature. The focus is on methods available for organic molecular crystals, but mention is made wherever techniques are suitable for use in other related materials such as disordered or polymeric systems. PMID- 28644624 TI - Extensive Assessment of Various Computational Methods for Aspartate's pKa Shift. AB - A series of computational methods for pKa shift prediction are extensively tested on a set of benchmark protein systems, aiming at identifying pitfalls and evaluating their performance on high variants. Including 19 ASP residues in 10 protein systems, the benchmark set consists of both residues with highly shifted pKa values as well as those varying little from the reference value, with an experimental RMS free energy differences of 2.49 kcal/mol with respect to blocked amino acid, namely the RMS pKa shift being 1.82 pKa units. The constant pH molecular dynamics (MD), alchemical methods, PROPKA3.1, and multiconformation continuum electrostatics give RMSDs of 1.52, 2.58, 1.37, and 3.52 pKa units, respectively, on the benchmark set. The empirical scoring method is the most accurate one with extremely low computational cost, and the pH-dependent model is also able to provide accurate results, while the accuracy of MD sampling incorporating alchemical free energy simulation is prohibited by convergence achievement and the performance of conformational search incorporating multiconformation continuum electrostatics is bad. Former research works did not define statistical uncertainty with care and yielded the questionable conclusion that alchemical methods perform well in most benchmarks. In this work the traditional alchemical methods are thoroughly tested for high variants. We also performed the first application of nonequilibrium alchemical methods to the pKa cases. PMID- 28644625 TI - Chemically Modified Surface Having a Dual-Structured Hierarchical Topography for Controlled Cell Growth. AB - This report describes a technique for fabricating dual-structured hierarchical surface topography on the surface of polydimethylsiloxane (PDMS) films through simply replicating prefabricated patterns and wrinkling PDMS films. To enhance the biocompatibility of PDMS films, we synthesize a biocompatible dopamine glycopolymer, which is utilized to modify the chemical feature of the PDMS surface. Dopamine component in this copolymer is introduced for the formation of a carbohydrate layer on the surface of PDMS films because of its excellent adhesion. The carbohydrate component in this copolymer enhances the interactions between cells and PDMS films. We investigate the influence of the chemical and topographical surface properties of the extracellular matrix on fibroblast cell growth. The coupling of the dopamine-glycopolymer coating and hierarchical topography produces the best induction effect on the alignment of cells. PMID- 28644626 TI - 2D H-Bond Network as the Topmost Skin to the Air-Water Interface. AB - We provide a detailed description of the structure of water at the interface with the air (liquid-vapor LV interface) from state-of-the-art DFT-based molecular dynamics simulations. For the first time, a two-dimensional (2D) H-bond extended network has been identified and fully characterized, demonstrating that interfacial water is organized into a 2D sheet with H-bonds oriented parallel to the instantaneous surface and following its spatial and temporal oscillations. By analyzing the nonlinear vSFG (vibrational sum frequency generation) spectrum of the LV interface in terms of layer-by-layer signal, we demonstrate that the 2D water sheet is solely responsible for the spectral signatures, hence providing the interfacial 3.5 A thickness effectively probed in nonlinear interfacial spectroscopy. The 2D H-bond network unraveled here is the essential key to rationalize macroscopic properties of water-air interfaces, as demonstrated here for spectroscopy and the surface potential. PMID- 28644627 TI - Rhodium(III)-Catalyzed Acylation of C(sp3)-H Bonds with Cyclopropenones. AB - Rh(III)-catalyzed activation and acylation of sp3 C-H bonds has been realized with diarylcyclopropenone as an acylating reagent. Both benzylic C-H in 8 methylquinolines and unactivated C-H in 2-alkylpyridines are applicable in this C H acylation reaction, providing enones in good yields under redox-neutral conditions. PMID- 28644628 TI - Stereoelectronics of the Hydrogen-Bond-Induced Fluorescence Quenching of 3 Aminofluorenones with Alcohols. AB - Two derivatives of 3-amino-9-fluorenone (1) bearing one (2) and two methyl (3) groups flanking the carbonyl group are prepared. Comparison of their photophysical properties show that all suffer efficient radiationless deactivation in the presence of alcohols. Preferential solvation studies with mono alcohols reveal that a single H-bonding interaction quenches the excited states of 1 and 2, but not that of 3. In contrast, a single molecule of ethylene glycol quenches all three. These results are interpreted in a quenching mechanism similar to one proposed by Inoue and co-workers, but where an out-of-plane H-bond with the carbonyl group gives rise to an emissive species, while an in-plane H bond results in quenching. PMID- 28644629 TI - Environmental Polymer Degradation: Using the Distonic Radical Ion Approach to Study the Gas-Phase Reactions of Model Polyester Radicals. AB - A novel precursor to the distonic O- and C-centered radical cations Oxo+O* and Oxo+C* was designed and synthesized, which represents model systems for radicals produced during polyester degradation. The precursor is equipped with a nitrate functional group, which serves as a masked site for these alkoxyl and carbon radicals that are unleashed through collision-induced dissociation (CID). Oxo+O* and Oxo+C* feature a cyclic carboxonium ion as permanent charge tag to enable monitoring their ion-molecule reactions on the millisecond to second time scale in the ion trap of the mass spectrometer. The reactions of Oxo+O* and Oxo+C* with cyclohexene, cyclohexadiene, ethyl acetate, 1,1-dimethoxyethane, and 1,2 dimethoxyethane, which exhibit structural features present in both intact and defective polyesters, were explored through product and kinetic studies to identify "hot spots" for radical-induced damage in polyesters. All reactions with Oxo+O* were extremely fast and proceeded predominantly through HAT. Oxo+C* was about two orders of magnitude less reactive and did not noticeably damage aliphatic ester moieties through hydrogen abstraction on the time scale of our experiments. Radical addition to alkene pi systems was identified as an important pathway for C-radicals, which needs to be included in polymer degradation mechanisms. PMID- 28644631 TI - Demonstration of Monogamy Relations for Einstein-Podolsky-Rosen Steering in Gaussian Cluster States. AB - Understanding how quantum resources can be quantified and distributed over many parties has profound applications in quantum communication. As one of the most intriguing features of quantum mechanics, Einstein-Podolsky-Rosen (EPR) steering is a useful resource for secure quantum networks. By reconstructing the covariance matrix of a continuous variable four-mode square Gaussian cluster state subject to asymmetric loss, we quantify the amount of bipartite steering with a variable number of modes per party, and verify recently introduced monogamy relations for Gaussian steerability, which establish quantitative constraints on the security of information shared among different parties. We observe a very rich structure for the steering distribution, and demonstrate one way EPR steering of the cluster state under Gaussian measurements, as well as one to-multimode steering. Our experiment paves the way for exploiting EPR steering in Gaussian cluster states as a valuable resource for multiparty quantum information tasks. PMID- 28644630 TI - Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes. AB - The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion reveals a difference in Ti(IV) coordination versus iron(III), the metal endogenously delivered by the protein to cells. This finding enriches our bioinspired drug design strategy for Ti(IV) based anticancer therapeutics, which applies a family of Fe(III) chelators termed chemical transferrin mimetic (cTfm) ligands to inhibit Fe bioavailability in cancer cells. Deferasirox, a drug used for iron overload disease, is a cTfm ligand that models STf coordination to Fe(III), favoring Fe(III) binding versus Ti(IV). This metal affinity preference drives deferasirox to facilitate the release of cytotoxic Ti(IV) intracellularly in exchange for Fe(III). An aqueous speciation study performed by potentiometric titration from pH 4 to 8 with micromolar levels of Ti(IV) deferasirox at a 1:2 ratio reveals exclusively Ti(deferasirox)2 in solution. The predominant complex at pH 7.4, [Ti(deferasirox)2]2-, exhibits the one of the highest aqueous stabilities observed for a potent cytotoxic Ti(IV) species, demonstrating little dissociation even after 1 month in cell culture media. UV-vis and 1H NMR studies show that the stability is unaffected by the presence of biomolecular Ti(IV) binders such as citrate, STf, and albumin, which have been shown to induce dissociation or regulate cellular uptake and can alter the activity of other antiproliferative Ti(IV) complexes. Kinetic studies on [Ti(deferasirox)2]2- transmetalation with Fe(III) show that a labile Fe(III) source is required to induce this process. The initial step of this process occurs on the time scale of minutes, and equilibrium for the complete transmetalation is reached on a time scale of hours to a day. This work reveals a mechanism to deliver Ti(IV) compounds into cells and trigger Ti(IV) release by a labile Fe(III) species. Cellular studies including other cTfm ligands confirm the Fe(III) depletion mechanism of these compounds and show their ability to induce early and late apoptosis. PMID- 28644633 TI - Role of Preload in Adhesion of Rough Surfaces. AB - Adhesion between glass and bromobutyl and polydimethylsiloxane elastomers is investigated. We show that viscoelastic energy dissipation close to the opening (or closing) crack tip, and surface roughness, strongly affect the work of adhesion. We observe strong adhesion hysteresis and we show, in contrast to the Johnson-Kendall-Roberts theory prediction for elastic solids, that this results in a pull-off force, and effective work of adhesion to be dependent on the maximum loading force. PMID- 28644632 TI - Mott Transition in the A15 Phase of Cs_{3}C_{60}: Absence of a Pseudogap and Charge Order. AB - We present a detailed NMR study of the insulator-to-metal transition induced by an applied pressure p in the A15 phase of Cs_{3}C_{60}. We evidence that the insulating antiferromagnetic (AFM) and superconducting (SC) phases coexist only in a narrow p range. At fixed p, in the metallic state above the SC transition T_{c}, the ^{133}Cs and ^{13}C NMR spin-lattice relaxation data are seemingly governed by a pseudogaplike feature. We prove that this feature, also seen in the ^{133}Cs NMR shift data, is rather a signature of the Mott transition which broadens and smears out progressively for increasing (p,T). The analysis of the variation of the quadrupole splitting nu_{Q} of the ^{133}Cs NMR spectrum precludes any cell symmetry change at the Mott transition and only monitors a weak variation of the lattice parameter. These results open an opportunity to consider theoretically the Mott transition in a multiorbital three-dimensional system well beyond its critical point. PMID- 28644634 TI - Semisuper Efimov Effect of Two-Dimensional Bosons at a Three-Body Resonance. AB - Wave-particle duality in quantum mechanics allows for a halo bound state whose spatial extension far exceeds a range of the interaction potential. What is even more striking is that such quantum halos can be arbitrarily large on special occasions. The two examples known so far are the Efimov effect and the super Efimov effect, which predict that spatial extensions of higher excited states grow exponentially and double exponentially, respectively. Here, we establish yet another new class of arbitrarily large quantum halos formed by spinless bosons with short-range interactions in two dimensions. When the two-body interaction is absent but the three-body interaction is resonant, four bosons exhibit an infinite tower of bound states whose spatial extensions scale as R_{n}~e^{(pin)^{2}/27} for a large n. The emergent scaling law is universal and is termed a semisuper Efimov effect, which together with the Efimov and super Efimov effects constitutes a trio of few-body universality classes allowing for arbitrarily large quantum halos. PMID- 28644635 TI - Fundamental Transitions and Ionization Energies of the Hydrogen Molecular Ions with Few ppt Uncertainty. AB - We calculate ionization energies and fundamental vibrational transitions for H_{2}^{+}, D_{2}^{+}, and HD^{+} molecular ions. The nonrelativistic quantum electrodynamics expansion for the energy in terms of the fine structure constant alpha is used. Previous calculations of orders malpha^{6} and malpha^{7} are improved by including second-order contributions due to the vibrational motion of nuclei. Furthermore, we evaluate the largest corrections at the order malpha^{8}. That allows us to reduce the fractional uncertainty to the level of 7.6*10^{-12} for fundamental transitions and to 4.5*10^{-12} for the ionization energies. PMID- 28644636 TI - Path-Controlled Time Reordering of Paired Photons in a Dressed Three-Level Cascade. AB - The two-photon dressing of a "three-level ladder" system, here the ground state, the exciton, and the biexciton of a semiconductor quantum dot, leads to new eigenstates and allows one to manipulate the time ordering of the paired photons without unitary postprocessing. We show that, after spectral postselection of the single dressed states, the time ordering of the cascaded photons can be removed or conserved. Our joint experimental and theoretical study demonstrates the high potential of a "ladder" system to be a versatile source of orthogonally polarized, bunched or antibunched pairs of photons. PMID- 28644637 TI - Comment on "Quasi-One-Dimensional Metal-Insulator Transitions in Compound Semiconductor Surfaces". PMID- 28644638 TI - Ferroelectric-Domain-Patterning-Controlled Schottky Junction State in Monolayer MoS_{2}. AB - We exploit scanning-probe-controlled domain patterning in a ferroelectric top layer to induce nonvolatile modulation of the conduction characteristic of monolayer MoS_{2} between a transistor and a junction state. In the presence of a domain wall, MoS_{2} exhibits rectified I-V characteristics that are well described by the thermionic emission model. The induced Schottky barrier height Phi_{B}^{eff} varies from 0.38 to 0.57 eV and is tunable by a SiO_{2} global back gate, while the tuning range of Phi_{B}^{eff} depends sensitively on the conduction-band-tail trapping states. Our work points to a new route to achieving programmable functionalities in van der Waals materials and sheds light on the critical performance limiting factors in these hybrid systems. PMID- 28644639 TI - Optical Random Riemann Waves in Integrable Turbulence. AB - We examine integrable turbulence (IT) in the framework of the defocusing cubic one-dimensional nonlinear Schrodinger equation. This is done theoretically and experimentally, by realizing an optical fiber experiment in which the defocusing Kerr nonlinearity strongly dominates linear dispersive effects. Using a dispersive-hydrodynamic approach, we show that the development of IT can be divided into two distinct stages, the initial, prebreaking stage being described by a system of interacting random Riemann waves. We explain the low-tailed statistics of the wave intensity in IT and show that the Riemann invariants of the asymptotic nonlinear geometric optics system represent the observable quantities that provide new insight into statistical features of the initial stage of the IT development by exhibiting stationary probability density functions. PMID- 28644640 TI - Publisher's Note: Facile Anhydrous Proton Transport on Hydroxyl Functionalized Graphane [Phys. Rev. Lett. 118, 186101 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.186101. PMID- 28644641 TI - Emergent Weyl Fermion Excitations in TaP Explored by ^{181}Ta Quadrupole Resonance. AB - The ^{181}Ta quadrupole resonance [nuclear quadrupole resonance (NQR)] technique is utilized to investigate the microscopic magnetic properties of the Weyl semimetal TaP. We find three zero-field NQR signals associated with the transition between the quadrupole split levels for Ta with I=7/2 nuclear spin. A quadrupole coupling constant, nu_{Q}=19.250 MHz, and an asymmetric parameter of the electric field gradient, eta=0.423, are extracted, in good agreement with band structure calculations. In order to examine the magnetic excitations, the temperature dependence of the spin-lattice relaxation rate (1/T_{1}T) is measured for the f_{2} line (+/-5/2<->+/-3/2 transition). We find that there exist two regimes with quite different relaxation processes. Above T^{*}~30 K, a pronounced (1/T_{1}T)?T^{2} behavior is found, which is attributed to the magnetic excitations at the Weyl nodes with temperature-dependent orbital hyperfine coupling. Below T^{*}, the relaxation is mainly governed by a Korringa process with 1/T_{1}T=const, accompanied by an additional T^{-1/2}-type dependence to fit our experimental data. We show that Ta NQR is a novel probe for the bulk Weyl fermions and their excitations. PMID- 28644642 TI - Probing Electron-Phonon Interaction through Two-Photon Interference in Resonantly Driven Semiconductor Quantum Dots. AB - We investigate the temperature dependence of photon coherence properties through two-photon interference (TPI) measurements from a single quantum dot (QD) under resonant excitation. We show that the loss of indistinguishability is related only to the electron-phonon coupling and is not affected by spectral diffusion. Through these measurements and a complementary microscopic theory, we identify two independent separate decoherence processes, both of which are associated with phonons. Below 10 K, we find that the relaxation of the vibrational lattice is the dominant contribution to the loss of TPI visibility. This process is non Markovian in nature and corresponds to real phonon transitions resulting in a broad phonon sideband in the QD emission spectra. Above 10 K, virtual phonon transitions to higher lying excited states in the QD become the dominant dephasing mechanism, this leads to a broadening of the zero phonon line, and a corresponding rapid decay in the visibility. The microscopic theory we develop provides analytic expressions for the dephasing rates for both virtual phonon scattering and non-Markovian lattice relaxation. PMID- 28644643 TI - First Demonstration of a Scintillating Xenon Bubble Chamber for Detecting Dark Matter and Coherent Elastic Neutrino-Nucleus Scattering. AB - A 30-g xenon bubble chamber, operated at Northwestern University in June and November 2016, has for the first time observed simultaneous bubble nucleation and scintillation by nuclear recoils in a superheated liquid. This chamber is instrumented with a CCD camera for near-IR bubble imaging, a solar-blind photomultiplier tube to detect 175-nm xenon scintillation light, and a piezoelectric acoustic transducer to detect the ultrasonic emission from a growing bubble. The time of nucleation determined from the acoustic signal is used to correlate specific scintillation pulses with bubble-nucleating events. We report on data from this chamber for thermodynamic "Seitz" thresholds from 4.2 to 15.0 keV. The observed single- and multiple-bubble rates when exposed to a ^{252}Cf neutron source indicate that, for an 8.3-keV thermodynamic threshold, the minimum nuclear recoil energy required to nucleate a bubble is 19+/-6 keV (1sigma uncertainty). This is consistent with the observed scintillation spectrum for bubble-nucleating events. We see no evidence for bubble nucleation by gamma rays at any of the thresholds studied, setting a 90% C.L. upper limit of 6.3*10^{ 7} bubbles per gamma interaction at a 4.2-keV thermodynamic threshold. This indicates stronger gamma discrimination than in CF_{3}I bubble chambers, supporting the hypothesis that scintillation production suppresses bubble nucleation by electron recoils, while nuclear recoils nucleate bubbles as usual. These measurements establish the noble-liquid bubble chamber as a promising new technology for the detection of weakly interacting massive particle dark matter and coherent elastic neutrino-nucleus scattering. PMID- 28644644 TI - Highly Nuclear-Spin-Polarized Deuterium Atoms from the UV Photodissociation of Deuterium Iodide. AB - We report a novel highly spin-polarized deuterium (SPD) source, via the photodissociation of deuterium iodide at 270 nm. I(^{2}P_{3/2}) photofragments are ionized with m-state selectivity, and their velocity distribution measured via velocity-map slice imaging, from which the D polarization is determined. The process produces ~100% electronically polarized D at the time of dissociation, which is then converted to ~60% nuclear D polarization after ~1.6 ns. These production times for SPD allow collision-limited densities of ~10^{18} cm^{-3} and at production rates of ~10^{21} s^{-1} which are 10^{6} and 10^{4} times higher than conventional (Stern-Gerlach separation) methods, respectively. We discuss the production of SPD beams, and combining high-density SPD with laser fusion, to investigate polarized D-T, D-^{3}He, and D-D fusion. PMID- 28644645 TI - Superfluidlike Mass Flow Through 8 MUm Thick Solid ^{4}He Samples. AB - We report the observation of superfluidlike mass flow through coin-shaped 8 MUm thick solid ^{4}He samples sandwiched between superfluid leads. Mass flow is found from the melting pressure to at least 30 bar with a concomitant decrease in the onset temperature from 1 to 0.25 K. The mass-flow rate is found to be sample dependent and can be enhanced by thermal annealing. The flow rate decreases with temperature and decays nearly exponentially with the pressure of the samples. The dissipation associated with the mass flow decreases with temperature and becomes superfluidlike near 0.1 K. In contrast to earlier studies on centimeter-thick samples, we do not see a sharp cutoff in the mass-flow rate at low temperature. PMID- 28644646 TI - Bottleneck Accumulation of Hybrid Magnetoelastic Bosons. AB - An ensemble of magnons, quanta of spin waves, can be prepared as a Bose gas of weakly interacting quasiparticles. Furthermore, the thermalization of the overpopulated magnon gas through magnon-magnon scattering processes, which conserve the number of particles, can lead to the formation of a Bose-Einstein condensate at the bottom of a spin-wave spectrum. However, magnon-phonon scattering can significantly modify this scenario and new quasiparticles are formed-magnetoelastic bosons. Our observations of a parametrically populated magnon gas in a single-crystal film of yttrium iron garnet by means of wave vector-resolved Brillouin light scattering spectroscopy evidence a novel condensation phenomenon: A spontaneous accumulation of hybrid magnetoelastic bosonic quasiparticles at the intersection of the lowest magnon mode and a transversal acoustic wave. PMID- 28644647 TI - Quasi-Low-Dimensional Electron Gas with One Populated Band as a Testing Ground for Time-Dependent Density-Functional Theory of Mesoscopic Systems. AB - We find an exact analytical solution to the exchange-only time-dependent density functional theory (TDDFT) problem for a significant class of quasi-low dimensional (QLD) materials: QLD electron gas with only one band filled in the direction perpendicular to the layer or wire. The theory yields the TD exchange potential as an explicit nonlocal operator of the TD spin density. The dressed interband (image states) excitation spectra of quasi-two-dimensional electron gas are obtained, while the comparison with the Kohn-Sham transitions provides insights into the qualitative and quantitative role of the many-body interactions. Important cancellations between the Hartree f_{H} and the exchange f_{x} kernels of TDDFT are found in the low-density regime, elucidating the interrelations between the Kohn-Sham and the many-body dynamics in mesoscopic systems. PMID- 28644648 TI - Crossing Over from Attractive to Repulsive Interactions in a Tunneling Bosonic Josephson Junction. AB - We explore the interplay between tunneling and interatomic interactions in the dynamics of a bosonic Josephson junction. We tune the scattering length of an atomic ^{39}K Bose-Einstein condensate confined in a double-well trap to investigate regimes inaccessible to other superconducting or superfluid systems. In the limit of small-amplitude oscillations, we study the transition from Rabi to plasma oscillations by crossing over from attractive to repulsive interatomic interactions. We observe a critical slowing down in the oscillation frequency by increasing the strength of an attractive interaction up to the point of a quantum phase transition. With sufficiently large initial oscillation amplitude and repulsive interactions, the system enters the macroscopic quantum self-trapping regime, where we observe coherent undamped oscillations with a self-sustained average imbalance of the relative well population. The exquisite agreement between theory and experiments enables the observation of a broad range of many body coherent dynamical regimes driven by tunable tunneling energy, interactions and external forces, with applications spanning from atomtronics to quantum metrology. PMID- 28644649 TI - Role of a Neighbor Ion in the Fragmentation Dynamics of Covalent Molecules. AB - Fragmentation of molecular nitrogen dimers (N_{2})_{2} induced by collision with low energy 90 keV Ar^{9+} ions is studied to evidence the influence of a molecular environment on the fragmentation dynamics of N_{2} cations. Following the capture of three or four electrons from the dimer, the three-body N_{2}^{+}+N^{m+}+N^{n+} [with (m,n)=(1,1) or (1, 2)] fragmentation channels provide clean experimental cases where molecular fragmentation may occur in the presence of a neighbor molecular cation. The effect of the environment on the fragmentation dynamics within the dimer is investigated through the comparison of the kinetic energy release (KER) spectra for these three-body channels and for isolated N_{2}^{(m+n)+} monomer cations. The corresponding KER spectra exhibit energy shifts of the order of 10 eV, attributed to the deformation of the N^{m+}+N^{n+} potential energy curves in the presence of the neighboring N_{2}^{+} cation. The KER structures remain unchanged, indicating that the primary collision process is not significantly affected by the presence of a neighbor molecule. PMID- 28644650 TI - Nature of the Spin Liquid Ground State in a Breathing Kagome Compound Studied by NMR and Series Expansion. AB - In the vanadium oxyfluoride compound (NH_{4})_{2}[C_{7}H_{14}N][V_{7}O_{6}F_{18}] (DQVOF), the V^{4+} (3d^{1}, S=1/2) ions realize a unique, highly frustrated breathing kagome lattice composed of alternately sized, corner-sharing equilateral triangles. Here we present an ^{17}O NMR study of DQVOF, which isolates the local susceptibility of the breathing kagome network. By a fit to series expansion, we extract the ratio of the interactions within the breathing kagome plane, J_{?}/J_{Delta}=0.55(4), and the mean antiferromagnetic interaction J[over -]=60(7) K. Spin lattice (T_{1}) measurements reveal an essentially gapless excitation spectrum with a maximum gap Delta/J[over -]=0.007(7). Our study provides new impetus for further theoretical investigations in order to establish whether the gapless spin liquid behavior displayed by DQVOF is intrinsic to its breathing kagome lattice or whether it is due to perturbations to this model, such as a residual coupling of the V^{4+} ions in the breathing kagome planes to the interlayer V^{3+} (S=1) spins. PMID- 28644651 TI - Rescattering Effects in the Hadronic-Light-by-Light Contribution to the Anomalous Magnetic Moment of the Muon. AB - We present a first model-independent calculation of pipi intermediate states in the hadronic-light-by-light (HLBL) contribution to the anomalous magnetic moment of the muon (g-2)_{MU} that goes beyond the scalar QED pion loop. To this end, we combine a recently developed dispersive description of the HLBL tensor with a partial-wave expansion and demonstrate that the known scalar-QED result is recovered after partial-wave resummation. Using dispersive fits to high statistics data for the pion vector form factor, we provide an evaluation of the full pion box a_{MU}^{pi box}=-15.9(2)*10^{-11}. We then construct a suitable input for the gamma^{*}gamma^{*}->pipi helicity partial waves, based on a pion pole left-hand cut and show that for the dominant charged-pion contribution, this representation is consistent with the two-loop chiral prediction and the COMPASS measurement for the pion polarizability. This allows us to reliably estimate S wave rescattering effects to the full pion box and leads to our final estimate for the sum of these two contributions a_{MU}^{pi box}+a_{MU,J=0}^{pipi,pi-pole LHC}=-24(1)*10^{-11}. PMID- 28644652 TI - Topological Insulators in Amorphous Systems. AB - Much of the current understanding of topological insulators, which informs the experimental search for topological materials and systems, is based on crystalline band theory, where local electronic degrees of freedom at different crystal sites hybridize with each other in ways that produce nontrivial topology. Here we provide a novel theoretical demonstration of realizing topological phases in amorphous systems, as exemplified by a set of sites randomly located in space. We show this by constructing hopping models on such random lattices whose gapped ground states are shown to possess nontrivial topological nature (characterized by Bott indices) that manifests as quantized conductances in systems with a boundary. Our study adds a new dimension, beyond crystalline solids, to the search for topological systems by pointing to the promising possibilities in amorphous solids and other engineered random systems. PMID- 28644653 TI - Dielectric Anisotropy of the GaP/Si(001) Interface from First-Principles Theory. AB - First-principles calculations of the dielectric anisotropy of the GaP/Si(001) interface are compared to the anisotropy extracted from reflectance measurements on GaP thin films on Si(001) [O. Supplie et al., Phys. Rev. B 86, 035308 (2012)PRBMDO1098-012110.1103/PhysRevB.86.035308]. Optical excitations from two states localized in several Si layers adjacent to the interface result in the observed anisotropy of the interface. The calculations show excellent agreement with experiment only for a gapped interface with a P layer in contact with Si and show that a combination of theory and experiment can reveal localized electronic states and the atomic structure at buried interfaces. PMID- 28644654 TI - Interchange Instability and Transport in Matter-Antimatter Plasmas. AB - Symmetric electron-positron plasmas in inhomogeneous magnetic fields are intrinsically subject to interchange instability and transport. Scaling relations for the propagation velocity of density perturbations relevant to transport in isothermal magnetically confined electron-positron plasmas are deduced, including damping effects when Debye lengths are large compared to Larmor radii. The relations are verified by nonlinear full-F gyrofluid computations. Results are analyzed with respect to planned magnetically confined electron-positron plasma experiments. The model is generalized to other matter-antimatter plasmas. Magnetized electron-positron-proton-antiproton plasmas are susceptible to interchange-driven local matter-antimatter separation, which can impede sustained laboratory magnetic confinement. PMID- 28644655 TI - Formation of Vacancies in Si- and Ge-based Clathrates: Role of Electron Localization and Symmetry Breaking. AB - The formation of framework vacancies in Si- and Ge-based type-I clathrates is studied using density-functional theory as a function of filling the cages with K and Ba atoms. Our analysis reveals the relevance of structural disorder, geometric relaxation, and electronic saturation as well as vibrational and configurational entropy. In the Si clathrates, we find that vacancies are unstable, but very differently, in Ge clathrates, up to three vacancies per unit cell can be stabilized. This contrasting behavior is largely driven by the different energy gain on populating the electronic vacancy states, which originates from the different degree of localization of the valence orbitals of Si and Ge. This also actuates a qualitatively different atomic relaxation of the framework. PMID- 28644656 TI - Entanglement-Enhanced Phase Estimation without Prior Phase Information. AB - We study the generation of planar quantum squeezed (PQS) states by quantum nondemolition (QND) measurement of an ensemble of ^{87}Rb atoms with a Poisson distributed atom number. Precise calibration of the QND measurement allows us to infer the conditional covariance matrix describing the F_{y} and F_{z} components of the PQS states, revealing the dual squeezing characteristic of PQS states. PQS states have been proposed for single-shot phase estimation without prior knowledge of the likely values of the phase. We show that for an arbitrary phase, the generated PQS states can give a metrological advantage of at least 3.1 dB relative to classical states. The PQS state also beats, for most phase angles, single-component-squeezed states generated by QND measurement with the same resources and atom number statistics. Using spin squeezing inequalities, we show that spin-spin entanglement is responsible for the metrological advantage. PMID- 28644657 TI - Zhao et al. Reply. PMID- 28644658 TI - Coevolution of Synchronization and Cooperation in Costly Networked Interactions. AB - Despite the large number of studies on synchronization, the hypothesis that interactions bear a cost for involved individuals has seldom been considered. The introduction of costly interactions leads, instead, to the formulation of a dichotomous scenario in which an individual may decide to cooperate and pay the cost in order to get synchronized with the rest of the population. Alternatively, the same individual can decide to free ride, without incurring any cost, waiting for others to get synchronized to his or her state. Thus, the emergence of synchronization may be seen as the byproduct of an evolutionary game in which individuals decide their behavior according to the benefit-to-cost ratio they accrued in the past. We study the onset of cooperation and synchronization in networked populations of Kuramoto oscillators and report how topology is essential in order for cooperation to thrive. We also display how different classes of topology foster synchronization differently both at microscopic and macroscopic levels. PMID- 28644659 TI - Remanent Magnetization: Signature of Many-Body Localization in Quantum Antiferromagnets. AB - We study the remanent magnetization in antiferromagnetic, many-body localized quantum spin chains, initialized in a fully magnetized state. Its long time limit is an order parameter for the localization transition, which is readily accessible by standard experimental probes in magnets. We analytically calculate its value in the strong-disorder regime exploiting the explicit construction of quasilocal conserved quantities of the localized phase. We discuss analogies in cold atomic systems. PMID- 28644660 TI - Recoil-Sensitive Lithium Interferometer without a Subrecoil Sample. AB - We report simultaneous conjugate Ramsey-Borde interferometers with a sample of low-mass (lithium-7) atoms at 50 times the recoil temperature. We optically pump the atoms to a magnetically insensitive state using the 2S_{1/2}-2P_{1/2} line. Fast stimulated Raman beam splitters address a broad velocity class and unavoidably drive two conjugate interferometers that overlap spatially. We show that detecting the summed interference signals of both interferometers, using state labeling, allows recoil measurements and suppression of phase noise from vibrations. The use of "warm" atoms allows for simple, efficient, and high-flux atom sources and broadens the applicability of recoil-sensitive interferometry to particles that remain difficult to trap and cool. PMID- 28644661 TI - Soft Photon and Graviton Theorems in Effective Field Theory. AB - Extensions of the photon and graviton soft theorems are derived in 4D local effective field theories with massless particles of arbitrary spin. We prove that effective operators can result in new terms in the soft theorems at subleading order for photons and subsubleading order for gravitons. The new soft terms are unique, and we provide a complete classification of all local operators responsible for such modifications. We show that no local operators can modify the subleading soft graviton theorem. The soft limits are taken in a manifestly on-locus manner using a complex double deformation of the external momenta. In addition to the new soft theorems, the resulting master formula yields consistency conditions, such as the conservation of electric charge, the Einstein equivalence principle, supergravity Ward identities, and that particles with spin greater than two cannot couple to those with spin less than or equal to two. PMID- 28644662 TI - Novel Metal-Insulator Transition at the SmTiO_{3}/SrTiO_{3} Interface. AB - We report on a metal-insulator transition (MIT) that is observed in an electron system at the SmTiO_{3}/SrTiO_{3} interface. This MIT is characterized by an abrupt transition at a critical temperature, below which the resistance changes by more than an order of magnitude. The temperature of the transition systematically depends on the carrier density, which is tuned from ~1*10^{14} to 3*10^{14} cm^{-2} by changing the SmTiO_{3} thickness. An analysis of the transport properties shows non-Fermi-liquid behavior and mass enhancement as the carrier density is lowered. We compare the MIT characteristics with those of known MITs in other material systems and show that they are distinctly different in several aspects. We tentatively conclude that both long-range Coulomb interactions and the fixed charge at the polar interface are likely to play a role in this MIT. The strong dependence on the carrier density makes this MIT of interest for field-tunable devices. PMID- 28644663 TI - Origin of Structural Modulations in Ultrathin Fe Films on Cu(001). AB - Employing ab initio calculations we demonstrate that the complex structural modulations experimentally observed in ultrathin Fe films on Cu(001) originate from Fe bulk phases that arise under extreme deformations. Specifically, we show that the structural modulations correspond to the motifs observed when transforming fcc Fe to bcc Fe in the Pitsch orientation relationship [(001)_{fcc}||(11[over -]0)_{bcc}]. The observed structural equivalence between surface and unstable bulk structures naturally explains the experimentally reported magnetic and structural transitions when going from low (two to four MLs) to intermediate (four to ten MLs) film coverages. PMID- 28644664 TI - Radiation Pressure Cooling as a Quantum Dynamical Process. AB - One of the most fundamental problems in optomechanical cooling is how small the thermal phonon number of a mechanical oscillator can be achieved under the radiation pressure of a proper cavity field. Different from previous theoretical predictions, which were based on an optomechanical system's time-independent steady states, we treat such cooling as a dynamical process of driving the mechanical oscillator from its initial thermal state, due to its thermal equilibrium with the environment, to a stabilized quantum state of higher purity. We find that the stabilized thermal phonon number left in the end actually depends on how fast the cooling process could be. The cooling speed is decided by an effective optomechanical coupling intensity, which constitutes an essential parameter for cooling, in addition to the sideband resolution parameter that has been considered in other theoretical studies. The limiting thermal phonon number that any cooling process cannot surpass exhibits a discontinuous jump across a certain value of the parameter. PMID- 28644665 TI - Giant Paramagnetism-Induced Valley Polarization of Electrons in Charge-Tunable Monolayer MoSe_{2}. AB - For applications exploiting the valley pseudospin degree of freedom in transition metal dichalcogenide monolayers, efficient preparation of electrons or holes in a single valley is essential. Here, we show that a magnetic field of 7 T leads to a near-complete valley polarization of electrons in a MoSe_{2} monolayer with a density 1.6*10^{12} cm^{-2}; in the absence of exchange interactions favoring single-valley occupancy, a similar degree of valley polarization would have required a pseudospin g factor of 38. To investigate the magnetic response, we use polarization resolved photoluminescence as well as resonant reflection measurements. In the latter, we observe gate voltage dependent transfer of oscillator strength from the exciton to the attractive Fermi polaron: stark differences in the spectrum of the two light helicities provide a confirmation of valley polarization. Our findings suggest an interaction induced giant paramagnetic response of MoSe_{2}, which paves the way for valleytronics applications. PMID- 28644666 TI - Frictional Resistance within the Wake of Frictional Rupture Fronts. AB - Frictional resistance to slip, tau, is determined by the real area of contact, A, and the shear strength of the contacts forming the frictional interface. We perform simultaneous high-speed local measurements of tau and A at the tail of propagating rupture fronts. Rate dependence is investigated over 2 orders of magnitude of local slip velocities which reach up to ~1 m/s. A critical slip velocity is observed that signifies a transition in the frictional behavior: enhanced velocity weakening of A and tau. These measurements enable us to infer the contact shear strength, an otherwise elusive quantity, and show that the contact shear strength persistently increases with slip rate. This, surprisingly, contrasts with expected contact softening at the high temperatures induced by rapid sliding. PMID- 28644667 TI - Nuclear Resonant Surface Diffraction of Synchrotron Radiation. AB - Nuclear resonant x-ray diffraction in grazing incidence geometry is used to determine the lateral magnetic configuration in a one-dimensional lattice of ferromagnetic nanostripes. During magnetic reversal, strong nuclear superstructure diffraction peaks appear in addition to the electronic ones due to an antiferromagnetic order in the nanostripe lattice. We show that the analysis of the angular distribution together with the time dependence of the resonantly diffracted x rays reveals surface spin structures with very high sensitivity. This scattering technique provides unique access to laterally correlated spin configurations in magnetically ordered nanostructures and, in perspective, also to their dynamics. PMID- 28644668 TI - Strong Light-Matter Interactions in Single Open Plasmonic Nanocavities at the Quantum Optics Limit. AB - Reaching the quantum optics limit of strong light-matter interactions between a single exciton and a plasmon mode is highly desirable, because it opens up possibilities to explore room-temperature quantum devices operating at the single photon level. However, two challenges severely hinder the realization of this limit: the integration of single-exciton emitters with plasmonic nanostructures and making the coupling strength at the single-exciton level overcome the large damping of the plasmon mode. Here, we demonstrate that these two hindrances can be overcome by attaching individual J aggregates to single cuboid Au@Ag nanorods. In such hybrid nanosystems, both the ultrasmall mode volume of ~71 nm^{3} and the ultrashort interaction distance of less than 0.9 nm make the coupling coefficient between a single J-aggregate exciton and the cuboid nanorod as high as ~41.6 meV, enabling strong light-matter interactions to be achieved at the quantum optics limit in single open plasmonic nanocavities. PMID- 28644669 TI - Entanglement and Nonlocality in Infinite 1D Systems. AB - We consider the problem of detecting entanglement and nonlocality in one dimensional (1D) infinite, translation-invariant (TI) systems when just near neighbor information is available. This issue is deeper than one might think a priori, since, as we show, there exist instances of local separable states (classical boxes) which admit only entangled (nonclassical) TI extensions. We provide a simple characterization of the set of local states of multiseparable TI spin chains and construct a family of linear witnesses which can detect entanglement in infinite TI states from the nearest-neighbor reduced density matrix. Similarly, we prove that the set of classical TI boxes forms a polytope and devise a general procedure to generate all Bell inequalities which characterize it. Using an algorithm based on matrix product states, we show how some of them can be violated by distant parties conducting identical measurements on an infinite TI quantum state. All our results can be easily adapted to detect entanglement and nonlocality in large (finite, not TI) 1D condensed matter systems. PMID- 28644670 TI - Effective Forces Between Quantum Bound States. AB - Recent ab initio lattice studies have found that the interactions between alpha particles (^{4}He nuclei) are sensitive to seemingly minor details of the nucleon nucleon force, such as interaction locality. In order to uncover the essential physics of this puzzling phenomenon without unnecessary complications, we study a simple model involving two-component fermions in one spatial dimension. We probe the interaction between two bound dimers for several different particle-particle interactions and measure an effective potential between the dimers using external point potentials which act as numerical tweezers. We find that the strength and range of the local part of the particle-particle interactions play a dominant role in shaping the interactions between the dimers and can even determine the overall sign of the effective potential. PMID- 28644671 TI - Spin Pumping and Torque Statistics in the Quantum Noise Limit. AB - We analyze the statistics of charge and energy currents and spin torque in a metallic nanomagnet coupled to a large magnetic metal via a tunnel contact. We derive a Keldysh action for the tunnel barrier, describing the stochastic currents in the presence of a magnetization precessing with the rate Omega. In contrast to some earlier approaches, our result is valid for an arbitrary ratio of hOmega/k_{B}T. We illustrate the use of the action by deriving spintronic fluctuation relations, the quantum limit of pumped current noise, and consider the fluctuations in two specific cases: the situation with a stable precession of magnetization driven by spin transfer torque, and the torque-induced switching between the minima of a magnetic anisotropy. The quantum corrections are relevant when the precession rate exceeds the temperature T, i.e., for hOmega?k_{B}T. PMID- 28644672 TI - Topological Fractional Pumping with Alkaline-Earth-Like Atoms in Synthetic Lattices. AB - Alkaline-earth(-like) atoms, trapped in optical lattices and in the presence of an external gauge field, can form insulating states at given fractional fillings. We will show that, by exploiting these properties, it is possible to realize a topological fractional pump. Our analysis is based on a many-body adiabatic expansion, on simulations with time-dependent matrix product states, and, for a specific form of atom-atom interaction, on an exactly solvable model of fractional pump. The numerical simulations allow us to consider a realistic setup amenable of an experimental realization. As a further consequence, the measure of the center-of-mass shift of the atomic cloud would constitute the first measurement of a many-body Chern number in a cold-atom experiment. PMID- 28644673 TI - Limitations of Particle-Based Spasers. AB - We present a semiclassical analytic model for spherical core-shell surface plasmon lasers. Within this model, we drop the widely used one-mode approximations in favor of fully electromagnetic Mie theory. This allows for incorporation of realistic gain relaxation rates that so far are massively underestimated. Especially, higher order modes can undermine and even reverse the beneficial effects of the strong Purcell effect in such systems. Our model gives a clear view on gain and resonator requirements, as well as on the output characteristics that will help experimenters to design more efficient particle based spasers. PMID- 28644675 TI - Origin of Noncubic Scaling Law in Disordered Granular Packing. AB - Recent diffraction experiments on metallic glasses have unveiled an unexpected noncubic scaling law between density and average interatomic distance, which led to the speculation of the presence of fractal glass order. Using x-ray tomography we identify here a similar noncubic scaling law in disordered granular packing of spherical particles. We find that the scaling law is directly related to the contact neighbors within the first nearest neighbor shell, and, therefore, is closely connected to the phenomenon of jamming. The seemingly universal scaling exponent around 2.5 arises due to the isostatic condition with a contact number around 6, and we argue that the exponent should not be universal. PMID- 28644676 TI - Is a Trineutron Resonance Lower in Energy than a Tetraneutron Resonance? AB - We present quantum Monte Carlo calculations of few-neutron systems confined in external potentials based on local chiral interactions at next-to-next-to-leading order in chiral effective field theory. The energy and radial densities for these systems are calculated in different external Woods-Saxon potentials. We assume that their extrapolation to zero external-potential depth provides a quantitative estimate of three- and four-neutron resonances. The validity of this assumption is demonstrated by benchmarking with an exact diagonalization in the two-body case. We find that the extrapolated trineutron resonance, as well as the energy for shallow well depths, is lower than the tetraneutron resonance energy. This suggests that a three-neutron resonance exists below a four-neutron resonance in nature and is potentially measurable. To confirm that the relative ordering of three- and four-neutron resonances is not an artifact of the external confinement, we test that the odd-even staggering in the helium isotopic chain is reproduced within this approach. Finally, we discuss similarities between our results and ultracold Fermi gases. PMID- 28644677 TI - Young Athletes After Anterior Cruciate Ligament Reconstruction With Single-Leg Landing Asymmetries at the Time of Return to Sport Demonstrate Decreased Knee Function 2 Years Later. AB - BACKGROUND: Previous work shows that young athletes after anterior cruciate ligament reconstruction (ACLR) demonstrate single-leg (SL) landing movement asymmetries at the time of return to sport (RTS); however, the effect of movement asymmetries on longitudinal knee-related function after ACLR has not been examined. Hypothesis/Purpose: The purpose of this study was to examine the effect of SL drop-landing movement symmetry at the time of RTS on knee-related function 2 years later in young athletes after ACLR. The first hypothesis was that young athletes who demonstrated SL drop-landing asymmetries at RTS would demonstrate decreased knee function 2 years later compared with those who demonstrated symmetric SL drop-landing mechanics. The second hypothesis was that SL drop landing movement symmetry at RTS would be associated with knee functional recovery 2 years later. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This study included 48 young athletes who had undergone ACLR and were assessed at the time of RTS (77% female; mean [+/-SD] age at RTS, 17.6 +/- 2.6 years) and followed for 2 years after RTS. Three sagittal-plane landing variables of interest were calculated using 3-dimensional motion analysis during an SL drop landing task at the time of RTS: knee flexion excursion, peak internal knee extension moment, and peak trunk flexion. The limb symmetry index (LSI) was calculated for each landing variable using the following: LSI = (involved/uninvolved) * 100%. The LSI was used to divide the cohort into symmetric (SYM) and asymmetric (ASYM) groups for each landing variable: knee flexion excursion (SYM: LSI >= 90% [n = 23]; ASYM: LSI < 85% [n = 18]), peak internal knee extension moment (SYM: LSI >= 90% [n = 19]; ASYM: LSI < 85% [n = 22]), and peak trunk flexion (SYM: LSI <= 105% [n = 25]; ASYM: LSI > 115% [n = 19]). At 2 years after RTS, knee-related function was evaluated using the Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) subjective knee form, and performance on SL hop tests. Functional recovery was defined based on literature cutoffs for knee-related functional measures. Differences in 2-year function were compared between the symmetry groups using Mann-Whitney U tests because of nonnormality. Logistic regression was used to determine if landing symmetry at the time of RTS would be associated with 2-year knee functional recovery after RTS. RESULTS: The ASYM knee flexion excursion group demonstrated decreased function at 2 years after RTS compared with the SYM group on the KOOS-Pain (ASYM: 93.0 +/- 8.2; SYM: 98.4 +/- 3.0; P = .008) and the KOOS-Quality of Life (ASYM: 81.6 +/- 16.1; SYM: 94.1 +/- 9.7; P = .008). Knee flexion excursion was associated with knee functional recovery on the KOOS-Pain and the KOOS-Quality of Life ( P = .033 and P = .012, respectively) at 2 years after RTS, after controlling for the quadriceps strength LSI and graft type. CONCLUSION: Young athletes after ACLR with asymmetries in knee kinematics at the time of RTS reported decreased self-reported function 2 years later; however, the clinical importance of these differences needs to be further understood. PMID- 28644678 TI - Professional Athletes' Return to Play and Performance After Operative Repair of an Achilles Tendon Rupture. AB - BACKGROUND: Most Achilles tendon ruptures are sports related. However, few studies have examined and compared the effect of surgical repair for complete ruptures on return to play (RTP), play time, and performance across multiple sports. PURPOSE: To examine RTP and performance among professional athletes after Achilles tendon repair and compare pre- versus postoperative functional outcomes of professional athletes from different major leagues in the United States. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: National Basketball Association (NBA), National Football League (NFL), Major League Baseball (MLB), and National Hockey League (NHL) athletes who sustained a primary complete Achilles tendon rupture treated surgically between 1989 and 2013 were identified via public injury reports and press releases. Demographic information and performance-related statistics were recorded for 2 seasons before and after surgery and compared with matched controls. Statistical analyses were used to assess differences in recorded metrics. RESULTS: Of 86 athletes screened, 62 met inclusion criteria including 25 NBA, 32 NFL, and 5 MLB players. Nineteen (30.6%) professional athletes with an isolated Achilles tendon rupture treated surgically were unable to return to play. Among athletes who successfully returned to play, game participation averaged 75.4% ( P < .001) and 81.9% ( P = .002) of the total games played the season before injury at 1 and 2 years postoperatively, respectively. Play time was significantly decreased and athletes performed significantly worse compared with preoperative levels at 1 and 2 years after injury ( P < .001). When players were compared with matched controls, an Achilles tendon rupture resulted in fewer games played ( P < .001), decreased play time ( P = .025), and worse performance statistics ( P < .001) at 1 year but not 2 years postoperatively ( P > .05). When individual sports were compared, NBA players were most significantly affected, experiencing significant decreases in games played, play time, and performance. CONCLUSION: An Achilles tendon rupture is a devastating injury that prevents RTP for 30.6% of professional players. Athletes who do return play in fewer games, have less play time, and perform at a lower level than their preinjury status. However, these functional deficits are seen only at 1 year after surgery compared with matched controls, such that players who return to play can expect to perform at a level commensurate with uninjured controls 2 years postoperatively. PMID- 28644679 TI - Success of University Student Volunteers in Obtaining Consent for Reviewing Private Health Information for Emergency Research. AB - This study aimed to determine the success of university student volunteers in obtaining consent from parents to allow review of their child's personal health information (PHI) for emergency research screening. This study also aimed to examine the variables associated with successful consent. This was a prospective cross-sectional study conducted at a pediatric emergency department (ED). University students, who functioned as delegates of the health information custodian, approached parents for consent. Of 2,506 parents, 1,852 (73.9%) provided consent to allow review of their child's PHI for research screening. Variables associated with successful consent were high (>=12 months) versus low (<12 months) volunteer experience (OR = 2.0), research related (vs. unrelated) to the child's chief complaint (OR = 2.0), child treated regularly by specialists at the study institution (OR = 1.7), and ED presentation mid-week vs. weekend (OR = 1.7) and morning vs. evening presentation (OR = 1.4). When approached by a university student volunteer, about 25% of parents declined to have their child's PHI reviewed for research screening. This model of obtaining consent may put some emergency research at risk for selection bias. Variables that increase the odds of successful consent can be considered in program design to improve the effectiveness of this model. PMID- 28644680 TI - Exploring the Factor Structure of the Social Cognition and Object Relations Global Rating Method: Support for Two- and Three-Factor Models. AB - The Social Cognition and Object Relations Scales-Global Rating Method (SCORS-G) contains 8 scales for coding narrative content. This study explores the factor structure of this measure using college (n = 171), outpatient (n = 239), and inpatient (n = 78) samples. Participants told stories to the Thematic Apperception Test (TAT; Murray, 1943) cards. Stories were transcribed and coded by blind raters using the SCORS-G. Cases were randomly assigned to an exploratory or validation group. Exploratory factor analysis with the exploratory group suggested 2- and 3-factor models. The Emotional Investment in Relationships (EIR) scale did not obtain a primary loading on any factor and was not included in subsequentmodels. After modifications, confirmatory factor analysis indicated good-to-adequate fit for 2- and 3-factor models. Both models showed good fit in the validation group and met criteria for invariance across models. Findings indicated that some SCORS-G scales tap cognitive-structural elements, whereas others assess affective-relational components of narratives. We found mild support separating the affective-relational scales in terms of internal representations for the self and others and relationships. The results reported here indicate that clinicians and researchers can calculate a separate cognitive structural composite score and an affective-relational composite score when using the SCORS-G to rate TAT stories. PMID- 28644674 TI - Constraints on Oscillation Parameters from nu_{e} Appearance and nu_{MU} Disappearance in NOvA. AB - Results are reported from an improved measurement of nu_{MU}->nu_{e} transitions by the NOvA experiment. Using an exposure equivalent to 6.05*10^{20} protons on target, 33 nu_{e} candidates are observed with a background of 8.2+/-0.8 (syst.). Combined with the latest NOvA nu_{MU} disappearance data and external constraints from reactor experiments on sin^{2}2theta_{13}, the hypothesis of inverted mass hierarchy with theta_{23} in the lower octant is disfavored at greater than 93% C.L. for all values of delta_{CP}. PMID- 28644681 TI - Treatment Results of Corneal Collagen Cross-Linking Combined with Riboflavin and 440 Nm Blue Light for Bacterial Corneal Ulcer in Rabbits. AB - PURPOSE: To study the treatment effect of corneal collagen cross-linking (CXL) combined with 440 nm blue light and riboflavin on bacterial corneal ulcer using animal experiments. METHODS: A total of 21 New Zealand white rabbits that developed Staphylococcus aureus corneal ulcer were randomly divided into three groups. Seven rabbits were used as blank control groups; seven rabbits were treated with CXL combined with riboflavin and 440 nm blue light; and seven rabbits were treated with CXL combined with riboflavin and 370 nm ultraviolet A light. Necrotic tissues or secretions from the ulcer surface, eye secretions, conjunctival hyperemia, hypopyon, corneal infiltration, and pathological changes of the cornea were all observed. RESULTS: The 1st, 3th, and 7th day after CXL treatment, a statistically significant difference was found among the inflammation scores of the three groups. The scores of 440 and 370 groups decreased gradually, significantly lower than that of the control group. Bacterial cultures of 440 and 370 groups turned to be negative while that of the control group remained positive. After 1 day of CXL treatment, pathology pictures of the three groups all showed loss of corneal epithelia with many inflammatory cells in deep stroma. After 7 days of CXL treatment, abscess formed in almost all corneal area in the control group, while in 440 and 370 groups, multilayer healing of corneal epithelia, neovascularization, and many inflammatory cells within ulcers and proliferation of a small amount of fibroblast were seen. CONCLUSIONS: CXL combined with riboflavin and 440 nm blue light is effective in treating S. aureus corneal ulcer. PMID- 28644682 TI - Management of severe bupropion poisoning with intravenous lipid emulsion. AB - BACKGROUND: Bupropion toxicity is characterized by central nervous system and cardiovascular toxicity. Intravenous lipid emulsion (ILE) has been suggested as a treatment by some for the treatment of refractory bupropion toxicity. This recommendation is based largely on published case reports and cases presented at scientific meetings. The objective of this study is to characterize the outcomes of patients with suspected bupropion toxicity in which ILE was administered and the indications for its use. METHODS: Electronic records from one regional poison center were searched for intentional bupropion ingestions from 1 January 2009 through 31 December 2015. Cases in which ILE was administered or death was listed as the outcome were further analyzed. RESULTS: There were 1274 cases of suspected bupropion ingestion reported during the study period with 14 reported deaths. Nine cases of ILE administration were identified. Of these, four patients expired and five survived. One of the survivors had neurologic sequelae necessitating placement in a long-term care facility. Patient complications after ILE administration were common and included continued hypotension in 7 cases, recurrent seizures in 3 patients, ARDS in two patients, and renal failure in one patient. CONCLUSIONS: The high mortality and complication rate after ILE in this study sample does not reflect the positive outcome benefit seen in previous published case reports. Further characterization of the efficacy and complications of ILE in bupropion toxicity is needed. PMID- 28644683 TI - Use of percutaneous left ventricular assist device (Impella) in vasodilatory poison-induced shock. PMID- 28644684 TI - C Cell and Follicular Epithelial Cell Precursor Lesions of the Thyroid. AB - CONTEXT: - The identification of precursor or dysplastic lesions in the thyroid is difficult. Pathology of the C cell has been extensively studied, and the preneoplastic nature of C-cell hyperplasia in the setting of familial medullary thyroid carcinomas is well established. However, the distinction between neoplastic and physiologic/reactive C-cell hyperplasia remains a challenge. Unlike C cells, the existence of a precursor lesion of follicular cell-derived tumors is less well established, and a dysplastic or preneoplastic follicular lesion has not been well defined. OBJECTIVE: - To discuss putative precursor lesions in the thyroid arising from C cells and follicular epithelial cells. DATA SOURCES: - Data were obtained from a review of the pertinent peer-reviewed literature. CONCLUSIONS: - Although the preneoplastic nature of C-cell hyperplasia in the setting of familial medullary thyroid carcinoma is well recognized, the preneoplastic nature/malignant potential of reactive/physiologic C-cell hyperplasia and its role in the development of sporadic, medullary thyroid carcinoma is still unclear. Current data suggest that benign follicular lesions may have malignant potential, and there may be a multifocal progression from benign to malignant. Atypical follicular lesions in the background of chronic lymphocytic thyroiditis may represent dysplastic or premalignant lesions. PMID- 28644685 TI - Application of Immunohistochemistry in the Diagnosis of Pulmonary and Pleural Neoplasms. AB - CONTEXT: - A vast majority of neoplasms arising from lung or pleura are initially diagnosed based on the histologic evaluation of small transbronchial, endobronchial, or needle core biopsies. Although most diagnoses can be determined by morphology alone, immunohistochemistry can be a valuable diagnostic tool in the workup of problematic cases. OBJECTIVE: - To provide a practical approach in the interpretation and immunohistochemical selection of lung/pleura-based neoplasms obtained from small biopsy samples. DATA SOURCES: - A literature review of previously published articles and the personal experience of the authors were used in this review article. CONCLUSION: - Immunohistochemistry is a useful diagnostic tool in the workup of small biopsies from the lung and pleura sampled by small biopsy techniques. PMID- 28644686 TI - Cervical Adenocarcinoma: Diagnosis of Human Papillomavirus-Positive and Human Papillomavirus-Negative Tumors. AB - CONTEXT: - Cervical adenocarcinomas span a diverse group of tumors with several distinct histologic tumor types, which include endocervical, endometrioid, intestinal, villoglandular, gastric, signet ring, serous, clear cell, and mesonephric. Diagnosis of cervical adenocarcinoma, especially early diagnosis, poses a significant challenge. OBJECTIVE: - To review the pathogenesis, diagnostic criteria, immunohistochemical markers, and differential diagnosis of various subtypes of human papillomavirus (HPV)-positive and HPV-negative cervical adenocarcinomas. The paper presents a concise summary of the issues that may be particularly difficult in histopathologic diagnosis, such as differentiating neoplastic lesions from benign mimics, determining the tumor type, differentiating early invasive lesions from adenocarcinoma in situ, measuring the depth of invasion, and, finally, differentiating primary cervical adenocarcinoma from uterine endometrioid adenocarcinoma and tumors metastatic from other primary sites. DATA SOURCES: - The study employed a PubMed search of recently published reports. CONCLUSIONS: - Early detection of HPV-positive tumor types may be aided with the expansion of HPV testing; however, early diagnosis of HPV-negative cervical adenocarcinomas will continue to pose a challenge and may require the development of additional molecular testing techniques. PMID- 28644688 TI - Intraosseous administration of antidotes - a systematic review. AB - CONTEXT: Intraosseous (IO) access is an established route of administration in resuscitation situations. Patients with serious poisoning presenting to the emergency department may require urgent antidote therapy. However, intravenous (IV) access is not always readily available. OBJECTIVE: This study reviews the current evidence for IO administration of antidotes that could be used in poisoning. The primary outcome was mortality as a surrogate of efficacy. Secondary outcomes included hemodynamic variables, electrocardiographic variables, neurological status, pharmacokinetics outcomes, and adverse effects as defined by each article. METHODS: A medical librarian created a systematic search strategy for Medline, subsequently translated to Embase, BIOSIS, PubMed, Web of Science, Cochrane, Database of Abstracts of Reviews of Effects (DARE), and the CENTRAL clinical trial register, all of which we searched from inception to 30 June 2016. Interventions included IO administration of selected antidotes. Articles included volunteer studies, poisoning, or other resuscitation contexts such as cardiac arrest, burns, dehydration, seizure, hemorrhagic shock, or undifferentiated shock. We considered all human studies and animal experiments to the exception of in vitro studies. Two reviewers independently selected studies, and a third adjudicated in case of disagreement. Three reviewers extracted all relevant data. Three reviewers evaluated the risk of bias and quality of the articles using specific scales according to each type of study design. RESULTS: A total of 47 publications (46 articles and one abstract) met our inclusion criteria and described IO administration of 13 different antidotes. These included one case series and 21 case reports describing 26 patients, and 25 animal experiments. Of those, seven human case reports and four animal experiments specifically reported the use of antidotes in poisoning. Human case reports suggested favorable outcomes with IO use of atropine, diazepam, hydroxocobalamin, insulin, lipid emulsion, methylene blue, phentolamine, prothrombin complex concentrate, and sodium bicarbonate. Clinical outcomes varied according to the antidote used. The only reported adverse event was ventricular tachycardia following IO naloxone. Regarding the animal experiments, IO administration of lipid emulsion and of hydroxocobalamin showed improved survival in bupivacaine-poisoned rats and in cyanide-intoxicated swine, respectively. Animal data also suggested an equivalent bio-availability between IO and IV administration for atropine, calcium chloride, dextrose 50%, diazepam, methylene blue, pralidoxime, and sodium bicarbonate. Adverse effect reporting of fat emboli after IO administration of sodium bicarbonate, for example, was conflicting due to the significant heterogeneity in the timing of lung examination across studies. CONCLUSION: The evidence supporting the use of IO route for the administration of antidotes in a context of poisoning is scarce. The majority of the evidence consists of case reports and animal experiments. Common antidotes such as acetylcysteine, fomepizole, and digoxin-specific antibody fragments have not been studied or reported with the use of the IO route. Despite the low quality evidence available, IO access is a potential option for antidotal treatments in toxicological resuscitation when IV access is unavailable. PMID- 28644689 TI - Two new prenylflavonoids from Morus alba. AB - Two new prenylflavonoids, morusalbols A and B (1 and 2), were isolated from the branches and leaves of Morus alba, together with three known compounds, kuwanon C (3), morusin (4), morusinol (5). The structures of these two prenylflavonoids were elucidated by extensive analyzes of the spectroscopic data. PMID- 28644687 TI - Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). AB - CONTEXT: Paracetamol is commonly taken in overdose, with increasing concerns that those taking "massive" overdoses have higher rates of hepatotoxicity and may require higher doses of acetylcysteine. The objective was to describe the clinical characteristics and outcomes of "massive" (>= 40 g) paracetamol overdoses. METHODS: Patients were identified through the Australian Paracetamol Project, a prospective observational study through Poisons Information Centres in NSW and Queensland, over 3 and 1.5 years, respectively, and retrospectively from three clinical toxicology unit databases (over 2.5 to 20 years). Included were immediate-release paracetamol overdoses >= 40 g ingested over <= 8 h. Outcomes measured included paracetamol ratio[defined as the ratio of the first paracetamol concentration taken 4-16 h post-ingestion to the standard (150 mg/L at 4 h) nomogram line at that time] and hepatotoxicity (ALT >1000 U/L). RESULTS: Two hundred paracetamol overdoses were analysed, reported median dose ingested was 50 g (interquartile range (IQR): 45-60 g) and median paracetamol ratio 1.9 (IQR: 1.4 2.9, n = 173). One hundred and ninety-three received acetylcysteine at median time of 6.3 h (IQR: 4-9.3 h) post-ingestion. Twenty-eight (14%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal was administered to 49(25%), at median of 2 h post-ingestion (IQR:1.5-5 h). Those receiving activated charcoal (within 4 h of ingestion), had significantly lower paracetamol ratio versus those who did not: 1.4 (n = 33, IQR: 1.1-1.6) versus 2.2 (n = 140, IQR: 1.5-3.0) (p < .0001) (paracetamol concentration measured >= 1 h after charcoal). Furthermore, they had lower rates of hepatotoxicity [unadjusted OR: 0.12 (95% CI: <0.001-0.91); adjusted for time to acetylcysteine OR: 0.20 (95%CI: 0.002-1.74)]. Seventy-nine had a paracetamol ratio >=2, 43 received an increased dose of acetylcysteine in the first 21 h; most commonly a double dose in the last bag (100 to 200 mg/kg/16 h). Those receiving increased acetylcysteine had a significant decrease risk of hepatotoxicity [OR:0.27 (95% CI: 0.08-0.94)]. The OR remained similar after adjustment for time to acetylcysteine and paracetamol ratio. CONCLUSION: Massive paracetamol overdose can result in hepatotoxicity despite early treatment. Paracetamol concentrations were markedly reduced in those receiving activated charcoal within 4 h. In those with high paracetamol concentrations, treatment with increased acetylcysteine dose within 21 h was associated with a significant reduction in hepatotoxicity. PMID- 28644690 TI - Advances in the development of human protein microarrays. AB - INTRODUCTION: High-content protein microarrays in principle enable the functional interrogation of the human proteome in a broad range of applications, including biomarker discovery, profiling of immune responses, identification of enzyme substrates, and quantifying protein-small molecule, protein-protein and protein DNA/RNA interactions. As with other microarrays, the underlying proteomic platforms are under active technological development and a range of different protein microarrays are now commercially available. However, deciphering the differences between these platforms to identify the most suitable protein microarray for the specific research question is not always straightforward. Areas covered: This review provides an overview of the technological basis, applications and limitations of some of the most commonly used full-length, recombinant protein and protein fragment microarray platforms, including ProtoArray Human Protein Microarrays, HuProt Human Proteome Microarrays, Human Protein Atlas Protein Fragment Arrays, Nucleic Acid Programmable Arrays and Immunome Protein Arrays. Expert commentary: The choice of appropriate protein microarray platform depends on the specific biological application in hand, with both more focused, lower density and higher density arrays having distinct advantages. Full-length protein arrays offer advantages in biomarker discovery profiling applications, although care is required in ensuring that the protein production and array fabrication methodology is compatible with the required downstream functionality. PMID- 28644691 TI - The Evolution of Psychological Testing at the Austen Riggs Center: A Theoretical Analysis. AB - Theoretical perspectives on personality and the development of psychopathology have shifted markedly over the last 7 decades. However, it remains unclear how those changes affect mental health practice. Comprehensive and conscientiously recorded reports of psychological testing provide a clear window on this process because they comprise distinctive records of how patients are assessed and understood. For this study, we conducted an exploratory, qualitative analysis of the narratives of the testing reports over the past 65 years at the Austen Riggs Center, a private psychiatric hospital and residential treatment center, to assess changes over time and to evaluate the influence that various factors had on the reports. The data revealed significant changes in psychologists' ways of assessing and conceptualizing personality and identity, adaptive functioning, and psychological development. Additionally, we evaluated how the evolving theoretical influences, such as institutional, professional, and sociohistorical factors affected the psychologist's model of psychopathology and development. This study raises important questions about how theoretical innovations affect clinical practice over time. PMID- 28644692 TI - Hyperbaric oxygen may only be optional in head and neck necrotizing fasciitis: a retrospective analysis of 43 cases and review of the literature. AB - BACKGROUND: Necrotizing fasciitis in the head and neck (NF-HN) is a rare and potentially life-threatening condition. The use of hyperbaric oxygen therapy (HBOT) in the acute regimen is disputed and there is a lack of evidence of therapeutic effect. This study aims to describe a retrospective cohort of patients with NF-HN and investigate the use of HBOT and consequences thereof. METHODS: All patients treated for NF-HN at Aarhus University Hospital (AUH) between 2002 and 2014 were included in this retrospective cohort. Data regarding demographics, treatment and a one-year follow-up was registered. A review of the literature on NF-HN and HBOT was performed. RESULTS: Forty-three patients were consecutively treated for NF-HN during the period. All patients were treated in accordance with current guidelines with HBOT as a variable. Thirty patients received HBOT, and 13 patients were omitted from HBOT for different reasons. In the HBOT group were no mortalities vs. three mortalities in the non-HBOT group two late deaths due to precursory underlying cancer of the head and neck, and one early death shortly after admittance. We found higher rates of complications (63% vs. 25%) and sequelae (77% vs. 40%) among the HBOT group compared to the non-HBOT group. CONCLUSIONS: Our findings suggest that HBOT for NF-HN may only be optional and that the decision relies on an individual assessment of each patient. Further research is needed concerning the evidence of HBOT and towards selecting the patients benefitting from HBOT. PMID- 28644693 TI - Supplemental Oxygen in Interstitial Lung Disease: An Art in Need of Science. AB - Interstitial lung disease (ILD) comprises a large and heterogeneous group of disorders that often lead to progressive fibrosis and premature death. Oxygen supplementation is typically used in patients with advanced lung disease with resting hypoxemia; however, there is a paucity of evidence guiding the use of supplemental oxygen in ILD, and significant heterogeneity in clinical practice. It remains unclear whether supplemental oxygen improves clinically meaningful outcomes, and the role of ambulatory oxygen supplementation in isolated exertional hypoxemia is particularly controversial. In some regions, the lack of robust data creates barriers to funding support and access to supplemental oxygen for patients with ILD. Further research into the role of oxygen supplementation is needed to optimize the comprehensive care of this patient population. PMID- 28644694 TI - A Bibliometric Analysis of Highly Cited and High Impact Occupational Therapy Publications by American Authors. AB - A bibliometric analysis was completed of peer-reviewed literature from 1991-2015, written by American occupational therapists, to examine US high impact scholarship with "occupational therapy" and "occupational therapist(s)" used as keywords to search journal articles' publication title, abstract, author details, and keywords. Results included 1,889 journal articles from 1991-2015 published by American occupational therapists as first or corresponding author. Sixty-nine articles attained a TotalCitation2015 >= 50 and 151 attained a Citation2015 >= 5 indicating that they were the most highly cited literature produced in this period. Although the majority (58%) of this literature was published in occupational therapy-specific journals, 41% was published in interdisciplinary journals. Results illustrate that the volume of highly cited American occupational therapy peer-reviewed literature has grown over the last two decades. There is need for the profession to strategize methods to enhance the publication metrics of occupational therapy-specific journals to reduce the loss of high quality publications to external periodicals. PMID- 28644695 TI - Peer-supported Open Dialogue: a thematic analysis of trainee perspectives on the approach and training. AB - BACKGROUND: Open Dialogue (OD) is a Finnish social network based model of care, with practice and organisational aspects. Peer-supported Open Dialogue (POD) is a UK version involving peer workers, whose contributions include building on fragmented social networks. Fifty-four NHS staff undertook the first training in POD between 2014 and 2015. The training course was organised as four separate residential weeks, together with reflective sharing on an online platform. AIMS: This study aimed to explore the perspectives of the POD trainees on the training and the POD approach. METHODS: At the end of the training year, four focus groups were conducted using a semi-structured interview measure examining trainees' perspectives on the training and POD approach. A thematic analysis was performed on the transcripts to analyse data. RESULTS: Four superordinate themes emerged: personal experience, practice development, principles of POD, and pedagogical issues, each with a variety of subordinate themes. CONCLUSIONS: The course was widely reported as a positive experience, with substantial changes in attitudes and approaches to clinical work arising thus. Across the four superordinate themes, participant responses described a highly experiential course, experienced as an emotional journey which enabled them to embody the principles of POD, as well as use them at work. PMID- 28644697 TI - Contemporary treatment of renal tumors: a questionnaire survey in the Nordic countries (the NORENCA-I study). AB - OBJECTIVE: The five Nordic countries comprise 25 million people, and have similar treatment traditions and healthcare systems. To take advantage of these similarities, a collaborative group (Nordic Renal Cancer Group, NORENCA) was founded in 2015. MATERIALS AND METHODS: A questionnaire of 17 questions on renal tumor management and surgical education was designed and sent to 91 institutions performing renal tumor surgery in 2015. The response rate was 68% (62 hospitals), including 28 academic, 25 central and nine district hospitals. Hospital volume was defined as low (LVH: < 20 operations), intermediate (IVH: 20-49 operations), high (HVH: 50-99) and very high (VHVH: >= 100). Descriptive statistics were performed. RESULTS: Fifteen centers were LVH, 16 IVH, 21 HVH and 10 VHVH. Of all 3828 kidney tumor treatments, 55% were radical nephrectomies (RNs), 37% partial nephrectomies (PNs) and 8% thermoablations. For RN and PN, the percentages of open, laparoscopic and robotic approaches were 47%, 40%, 13% and 47%, 20%, 33%, respectively. The mean complication rate (Clavien-Dindo 3-5) was 4.9%, and 30 day mortality (TDM) was 0.5%. The median length of hospital stay was 4 days. Training with a simulator, black box or animal laboratory was possible in 48%, 74% and 21% of institutions, respectively. CONCLUSIONS: Despite some differences between countries, the data suggest an overall general common Nordic treatment attitude for renal tumors. Furthermore, the data demonstrate high adherence to international standards, with a high proportion of PN and acceptable rates for major complications and TDM. PMID- 28644700 TI - Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver. AB - BACKGROUND: Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. METHODS: Severe hepatic steatosis was performed by 12-14 weeks of choline-free diet in 108 Wistar rats. We induced 30 minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFalpha, NO and Lactate in blood and liver tissue were measured. RESULTS: Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFalpha and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFalpha and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%). CONCLUSIONS: Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters. PMID- 28644698 TI - Sleep Disturbance after Hospitalization and Critical Illness: A Systematic Review. AB - RATIONALE: Sleep disturbance during intensive care unit (ICU) admission is common and severe. Sleep disturbance has been observed in survivors of critical illness even after transfer out of the ICU. Not only is sleep important to overall health and well being, but patients after critical illness are also in a physiologically vulnerable state. Understanding how sleep disturbance impacts recovery from critical illness after hospital discharge is therefore clinically meaningful. OBJECTIVES: This Systematic Review aimed to summarize studies that identify the prevalence of and risk factors for sleep disturbance after hospital discharge for critical illness survivors. DATA SOURCES: PubMed (January 4, 2017), MEDLINE (January 4, 2017), and EMBASE (February 1, 2017). DATA EXTRACTION: Databases were searched for studies of critically ill adult patients after hospital discharge, with sleep disturbance measured as a primary outcome by standardized questionnaire or objective measurement tools. From each relevant study, we extracted prevalence and severity of sleep disturbance at each time point, objective sleep parameters (such as total sleep time, sleep efficiency, and arousal index), and risk factors for sleep disturbance. SYNTHESIS: A total of 22 studies were identified, with assessment tools including subjective questionnaires, polysomnography, and actigraphy. Subjective questionnaire studies reveal a 50-66.7% (within 1 mo), 34-64.3% (>1-3 mo), 22-57% (>3-6 mo), and 10-61% (>6 mo) prevalence of abnormal sleep after hospital discharge after critical illness. Of the studies assessing multiple time points, four of five questionnaire studies and five of five polysomnography studies show improved aspects of sleep over time. Risk factors for poor sleep varied, but prehospital factors (chronic comorbidity, pre-existing sleep abnormality) and in-hospital factors (severity of acute illness, in-hospital sleep disturbance, pain medication use, and ICU acute stress symptoms) may play a role. Sleep disturbance was frequently associated with postdischarge psychological comorbidities and impaired quality of life. CONCLUSIONS: Sleep disturbance is common in critically ill patients up to 12 months after hospital discharge. Both subjective and objective studies, however, suggest that sleep disturbance improves over time. More research is needed to understand and optimize sleep in recovery from critical illness. PMID- 28644701 TI - Comparison between Briganti, Partin and MSKCC tools in predicting positive lymph nodes in prostate cancer: a systematic review and meta-analysis. AB - OBJECTIVE: The aim of this study was to analyze the discriminative capabilities of Briganti, Partin and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms in predicting lymph-node invasion (LNI) and to perform a meta-analysis to yield pooled area under the receiver operating characteristics curves (AUCs) for model comparison. MATERIALS AND METHODS: An electronic search of the MEDLINE and Embase databases up to October 2016 was undertaken. The AUC value, total number of patients and rate of LNI were extracted from the included references. After excluding redundant literature, 19 studies were identified including 86,338 patients. The Briganti, Partin and MSKCC nomograms were validated in 6629, 69,681 and 10,028 patients, respectively. RESULTS: The pooled AUCs for Briganti, Partin, and MSKCC nomograms were 0.793, 0.778 and 0.780, respectively. The Mantel Haenszel-derived comparison of AUC values revealed no statistical differences of predictive capabilities for Briganti vs Partin (p = 0.23), Briganti vs MSKCC (p = 0.83) and Partin vs MSKCC (p = 0.26). The accuracy of Briganti, Partin and MSKCC models is statistically similar in predicting the presence of LNI. International guidelines could consider these findings by reporting similarities in the accuracy of these models. CONCLUSIONS: The accuracy of Briganti, Partin and MSKCC was similar in predicting the presence of LNI. Based on these results, patients and clinicians may use any of these nomograms without significant advantages. PMID- 28644696 TI - Varicella vaccination - the global experience. AB - INTRODUCTION: Varicella, although a frequently benign childhood disease, nevertheless represents a considerable health burden. WHO recommends including varicella vaccines in universal routine vaccination programs, and maintaining coverage >80%. Many countries have successfully introduced varicella vaccination and have benefited from lower disease burden, but many others have not adopted the vaccine. Reasons include cost commitment for a 'mild childhood disease' or concerns that vaccination will shift varicella to older age groups or increase herpes zoster incidence. Areas covered: This literature review summarizes the effectiveness and epidemiological impact of varicella immunization programs. Expert commentary: Varicella vaccines are immunogenic with acceptable safety profiles. One and two dose schedules are highly effective against varicella and large reductions in disease incidence, particularly moderate-severe disease, have been widely reported. There is currently no evidence to suggest that the introduction of varicella vaccination results in a shift of varicella disease burden to older age groups. Although epidemiological studies have shown an increased incidence of herpes zoster since the vaccines were launched, there are many other contributing factors, and indeed, this secular trend was evident before their introduction. In conclusion, varicella vaccination easily fits into existing immunization programs and significantly reduces the often underestimated burden of varicella. PMID- 28644702 TI - High YKL-40 is associated with poor survival in patients with renal cell carcinoma: a novel independent prognostic marker. AB - OBJECTIVE: YKL-40 is an inflammation-associated glycoprotein supposed to have a role in cell survival and angiogenesis. Renal cell carcinoma (RCC) is characterized by varying prognosis and risk of relapse after a disease-free period of years. Prognostic markers are critically needed. This study investigated whether YKL-40 could be a useful biomarker in RCC patients. MATERIALS AND METHODS: Blood samples from 82 patients with RCC were collected at the time of diagnosis and 3, 5 and 9 months and 2 and 3 years after nephrectomy. YKL-40 levels were determined by enzyme-linked immunosorbent assay. Survival of patients and relapse of RCC were followed up to 15 years. RESULTS: Circulating YKL-40 levels were increased in patients with metastatic RCC at the time of diagnosis (median 115.7 ng/ml, interquartile range 61.0-221.6 ng/ml). Among patients primarily diagnosed with non-metastatic RCC, baseline YKL-40 levels were significantly higher in patients who experienced a relapse during follow-up (103.7, 59.3-242.0 ng/ml) than in patients without relapse (50.6, 33.8-97.1 ng/ml). High baseline YKL-40 was highly associated with poor prognosis in RCC: in age-adjusted univariate analysis, YKL-40 over 120 ng/ml (highest tertile) predicted over five-fold mortality in 5 years, and in multivariate analysis high YKL-40 remained a statistically significant independent risk factor for 5 and 15 year survival. CONCLUSIONS: Increased circulating YKL-40 levels were significantly associated with poor survival in patients with RCC. The results suggest YKL-40 as a useful novel biomarker in evaluating prognosis and relapse risk in RCC, being especially beneficial in patients primarily diagnosed with non metastatic RCC. PMID- 28644703 TI - The relation of protective factors to deliberate self-harm among African-American adults: moderating roles of gender and sexual orientation identity. AB - BACKGROUND: Few studies have examined correlates of deliberate self-harm (DSH) among African-Americans. Moreover, most research on the correlates of DSH in general has focused on risk factors rather than protective factors. AIMS: This study examined differences in perceived social support, religiosity (both spirituality and church attendance) and overall life satisfaction between African Americans with and without a history of DSH, as well as the moderating roles of gender and sexual orientation in these relations. METHOD: Participants were 244 African-American university students who completed questionnaires. RESULTS: Participants with (vs. without) DSH reported significantly lower levels of social support. Additionally, rates of DSH were significantly higher among participants who attended church irregularly versus regularly or rarely/never. However, the association between DSH and church attendance was significant only for women (vs. men) and LGBQ (vs. heterosexual) women. Further, gender moderated the relation between DSH and social support from both significant others and friends, with self-harming women (but not men) reporting less support than their non-DSH counterparts. CONCLUSIONS: Findings add to the literature on DSH among African Americans, highlighting both social support and church attendance (depending on regularity) as potential protective factors within this population. PMID- 28644704 TI - Numerical analysis of time dependent inhibition kinetics: comparison between rat liver microsomes and rat hepatocyte data for mechanistic model fitting. AB - Time dependent inhibition (TDI) may confound drug interaction predictions. Recently, models were generated for an array of TDI kinetic schemes using numerical analysis of microsomal assays. Additionally, a distinct terminal inactivation step was identified for certain mechanism based inhibitors (MBI) following reversible metabolite intermediate complex (MIC) formation. Longer hepatocyte incubations potentially allow analysis of slow TDI and terminal inactivation. In the experiments presented here, we compared the quality of TDI parameterization by numerical analysis between hepatocyte and microsomal data. Rat liver microsomes (RLM), suspended rat hepatocytes (SRH), and sandwich cultured rat hepatocytes (SCRH) were incubated with the prototypical CYP3A MBI troleandomycin and the substrate midazolam. Data from RLM provided a better model fit as compared to SRH. Increased CYP3A expression after dexamethasone (DEX) induction improved the fit for RLM and SRH. A novel sequential kinetic scheme, defining inhibitor metabolite production prior to MIC formation, improved the fit compared to direct MIC formation. Furthermore, terminal inactivation rate constants were parameterized for RLM and SRH samples with DEX induced CYP3A. The low expression of CYP3A and experimental error in SCRH resulted in poor data for model fitting. Overall, RLM generated data better suited for elucidation of TDI mechanisms by numerical analysis. PMID- 28644705 TI - Narrative development and supported employment of persons with severe mental illness. AB - BACKGROUND: While the relationship between objective recovery and work among persons with severe mental illness (SMI) is well-established, few studies have examined the link between subjective recovery and employment. AIMS: The study investigated the prospective relationship between narrative development at the start of supported employment (SE) and positive work outcomes. METHODS: The authors employed a time-limited, mixed-method longitudinal design to examine the relationship between the baseline narrative development of 38 SE participants with SMI and employment outcomes eight months later, as well as whether narratives evolved over the course of the study. RESULTS: While narrative development was unrelated to work for the 59% of participants who were employed at the end of the study, unemployed individuals showed more developed baseline narratives overall, as well as enriched baseline emotional connectedness and social worth. Higher emotional connectedness at the start of SE programs was predictive of fewer hours worked eight months later, controlling for executive functioning, negative symptoms and self-esteem. Although workers showed no narrative changes over time, those without work demonstrated increased agency over the eight months of the study. CONCLUSION: Further research is warranted to clarify the relationship between richer personal narratives and unemployment. PMID- 28644706 TI - Advance Care Planning and Palliative Care Integration for Patients Undergoing Hematopoietic Stem-Cell Transplantation. AB - PURPOSE: Advance care planning (ACP) in hematopoietic stem-cell transplantation (HSCT) is challenging, given the potential for cure despite increased morbidity and mortality risk.The aim of this study was to evaluate ACP and palliative care (PC) integration for patients who underwent HSCT. METHODS: A retrospective analysis was conducted and data were extracted from electronic medical records of patients who underwent HSCT between January 2011 and December 2015. Patients who received more than one transplant and who were younger than 18 years of age were excluded. The primary objective was to determine the setting and specialty of the clinician who documented the initial and final code status. Secondary objectives included evaluation of advance directive and/or completion of the Physician Orders for Life-Sustaining Treatment form, PC consultation, hospice enrollment, and location of death. RESULTS: The study sample comprised 39% (n = 235) allogeneic and 61% (n = 367) autologous HSCTs. All patients except one (n = 601) had code status documentation, and 99.2% (n = 596) were initially documented as full code. Initial and final code status documentation in the outpatient setting was 3% (n = 17) and 24% (n = 143), respectively. PC consultation occurred for 19% (n = 114) of HSCT patients, with 83% (n = 95) occurring in the hospital. Allogeneic transplant type and age were significantly associated with greater rates of advance directive and/or Physician Orders for Life-Sustaining Treatment completion. Most patients (85%, n = 99) died in the hospital, and few were enrolled in hospice (15%, n = 17). CONCLUSION: To our knowledge, this is the largest single-center study of ACP and PC integration for patients who underwent HSCT. Code status documentation in the outpatient setting was low, as well as utilization of PC and hospice services. PMID- 28644707 TI - Relationship between neurocognitive function and clinical symptoms with self stigma in patients with schizophrenia-spectrum disorders. AB - BACKGROUND: Self-stigma is associated with poor outcomes of patients with schizophrenia and development of self-stigma is a complex process. Results of studies on relationship of both positive and negative symptoms of psychosis with self-stigma have been inconsistent. Cognitive deficits are common to patients. However, number of studies exploring the relationship specifically between self stigma and neurocognition are limited. AIMS: The current study aimed to examine the relationship between neurocognitive functions and clinical symptoms with self stigma. METHODS: Sixty-four patients with psychosis were recruited and completed the Internalized Stigma of Mental Illness Scale and neurocognitive tests. Their clinical symptoms and role functioning were also assessed. RESULTS: Neurocognitive function was found to have negative correlations with Stereotype Endorsement and Discrimination Experience. Negative symptoms also correlated negatively with Stereotype Endorsement, Discrimination Experience, and Social Withdrawal. Neurocognitive function and negative symptoms explained 21.2% variance of stereotype endorsement. Neurocognitive function explained 7.9% variance of Discrimination Experience. CONCLUSIONS: Poor neurocognitive function is related to self-stigma. This study also further confirmed the relationship between negative symptoms and self-stigma. Future longitudinal studies should be conducted to confirm the nature of such a relationship. PMID- 28644709 TI - PCOS and diabetes mellitus: from insulin resistance to altered beta pancreatic function, a link in evolution. PMID- 28644708 TI - The Arabidopsis minD mutation causes aberrant FtsZ1 ring placement and moderate heterogeneity of chloroplasts in the leaf epidermis. AB - Symmetric division of leaf mesophyll chloroplasts requires MinD and MinE, which work together to suppress division other than at the mid-chloroplast. arc11 is a MinD loss-of-function mutant of Arabidopsis thaliana. In arc11 plants, asymmetric chloroplast division, as well as its delay or arrest, results in extreme size polymorphism of chloroplasts in mature mesophyll cells. The current study examined chloroplast phenotypes in the epidermis of arc11 leaves. Fluorescence microscopy analysis revealed that epidermal chloroplasts in mature leaves exhibited moderate heterogeneity in size. This probably resulted from completion of many of the previous non-equatorial or multiple division events in expanding leaves. Additionally, analyses of plastids found that epidermal chloroplasts in arc11 mutants showed several phenotypes that have not previously been described. PMID- 28644710 TI - Study of artemisinin and sugar accumulation in Artemisia vulgaris and Artemisia dracunculus "hairy" root cultures. AB - We studied the effect of genetic transformation on biologically active compound (artemisinin and its co-products (ART) as well as sugars) accumulation in Artemisia vulgaris and Artemisia dracunculus "hairy" root cultures. Glucose, fructose, sucrose, and mannitol were accumulated in A. vulgaris and A. dracunculus "hairy" root lines. Genetic transformation has led in some cases to the sugar content increasing or appearing of nonrelevant for the control plant carbohydrates. Sucrose content was 1.6 times higher in A. vulgaris "hairy" root lines. Fructose content was found to be 3.4 times higher in A. dracunculus "hairy" root cultures than in the control roots. The accumulation of mannitol was a special feature of the leaves of A. vulgaris and A. dracunculus control roots. A. vulgaris "hairy" root lines differed also in ART accumulation level. The increase of ART content up to 1.02 mg/g DW in comparison with the nontransformed roots (up to 0.687 mg/g DW) was observed. Thus, Agrobacterium rhizogenes-mediated genetic transformation can be used for obtaining of A. vulgaris and A. dracunculus "hairy" root culture produced ART and sugars in a higher amount than mother plants. PMID- 28644711 TI - Screening for Squamous Cell Anal Cancer in HIV Positive Patients: A Five-Year Experience. AB - AIM: Potential screening modalities for early diagnosis of squamous cell anal cancer (SCC) in HIV patients include digital anorectal examination (DARE), anal Papanicolaou testing (Pap test), human papilloma virus (HPV) co-testing, and high resolution anoscopy. The aim of this study was to demonstrate the results of a five-year screening program for SCC in HIV patients. MATERIALS AND METHODS: We conducted a retrospective study on 204 HIV patients who underwent a screening program for SCC from October 2010 to January 2015. All patients were screened by DARE, anal Pap test, including HPV test and cytology, and high-resolution video proctoscopy (HR-VPS) with and without acetic acid 3%. Depending on macroscopic appearance and biopsies, patients underwent observation or treatment. Median follow-up was 36 months. RESULTS: Cytologic abnormalities (Cyt+) for high-risk HPV genotypes were recorded in 34% of patients. HR-VPS was positive in 59 patients (29%), of whom 13 patients (22%) were positive for warts; the rest have typical features of anal intraepithelial neoplasia (AIN). Sixteen (8%) patients had AIN (AIN I-III) and underwent wide local excision, ablation, or imiquimod. Absence of progression was recorded. Fourteen patients (7%) had SCC: eight (57%) with no evidence of recurrence, two (14%) had recurrence, and four (29%) died from metastatic disease. CONCLUSIONS: Our data demonstrated a successful screening program in preventing SCC in HIV patients. We demonstrate the advantages of progression towards SCC. Moreover, we used a new screening tool, the HR-VPS, a low-cost and manageable instrument to collect patients' long-term data. PMID- 28644712 TI - Comparative analysis of behavioral and transcriptional variation underlying CO2 sensory neuron function and development in Drosophila. AB - Carbon dioxide is an important environmental cue for many insects, regulating many behaviors including some that have direct human impacts. To further improve our understanding of how this system varies among closely related insect species, we examined both the behavioral response to CO2 as well as the transcriptional profile of key developmental regulators of CO2 sensory neurons in the olfactory system across the Drosophila genus. We found that CO2 generally evokes repulsive behavior across most of the Drosophilids we examined, but this behavior has been lost or reduced in several lineages. Comparisons of transcriptional profiles from the developing and adult antennae for subset these species suggest that behavioral differences in some species may be due to differences in the expression of the CO2 co-receptor Gr63a. Furthermore, these differences in Gr63a expression are correlated with changes in the expression of a few genes known to be involved in the development of the CO2 circuit, namely dac, an important regulator of sensilla fate for sensilla that house CO2 ORNs, and mip120, a member of the MMB/dREAM epigenetic regulatory complex that regulates CO2 receptor expression. In contrast, most of the other known structural, molecular, and developmental components of the peripheral Drosophila CO2 olfactory system seem to be well-conserved across all examined lineages. These findings suggest that certain components of CO2 sensory ORN development may be more evolutionarily labile, and may contribute to differences in CO2-evoked behavioral responses across species. PMID- 28644713 TI - An unstructured loop that is critical for interactions of the stalk domain of Drp1 with saturated phosphatidic acid. AB - Dynamin-related protein 1 (Drp1) is a dynamin superfamily GTPase, which drives membrane constriction during mitochondrial division. To mediate mitochondrial division, Drp1 is recruited to the mitochondrial outer membrane and is assembled into the division machinery. We previously showed that Drp1 interacts with phosphatidic acid (PA) and saturated phospholipids in the mitochondrial membrane, and this interaction restrains Drp1 in initiating the constriction of mitochondria. Here, we show that the role of saturated acyl chains of phospholipids is independent of their contribution to the membrane curvature or lipid packing suggesting their direct interaction with Drp1. We further show that an unstructured loop in the stalk domain of Drp1 is critical for interaction with unsaturated PA. Our data significantly advance our understanding of this unique protein-lipid interaction involved in mitochondrial division. PMID- 28644714 TI - Genome mining, in silico validation and phase selection of a novel aldo-keto reductase from Candida glabrata for biotransformation. AB - Previously, we published cloning, overexpression, characterization and subsequent exploitation of a carbonyl reductase (cr) gene, belonging to general family aldo keto reductase from Candida glabrata CBS138 to convert keto ester (COBE) to a chiral alcohol (ethyl-4-chloro-3-hydroxybutanoate or CHBE). Exploiting global transcription factor CRP, rDNA and transporter engineering, we have improved batch production of CHBE by trinomial bioengineering. Herein, we present the exploration of cr gene in Candida glabrata CBS138 through genome mining approach, in silico validation of its activity and selection of its biocatalytic phase. For exploration of the gene under investigation, 3 template genes were chosen namely Saccharomyces cerevisae YDR541c, YGL157w and YOL151w. The CR showed significant homology match, overlapping of substrate binding site and NADPH binding site with the template proteins. The binding affinity of COBE toward CR (-4.6 Kcal/ mol) was found higher than that of the template proteins (-3.5 to -4.5 Kcal/ mol). Biphasic biocatalysis with cofactor regeneration improved product titer 4~5 times better than monophasic biotransformation. Currently we are working on DNA Shuffling as a next level of strain engineering and we demonstrate this approach herein as a future strategy of biochemical engineering. PMID- 28644715 TI - Biological Responses of the American Coot (Fulica americana), in wetlands with contrasting environmental conditions (Basin of Mexico). AB - Wetland ecosystems are subject to severe impacts (physical and chemical) and to the input of various xenobiotics that provoke toxicological consequences. Waterbirds are potential sentinel species of these environments. To analyze how habitat conditions affect the health of Fulica americana, early-warning biomarkers, histopathology, somatic indices, and water quality were examined in two wetlands of the Basin of Mexico: Xochimilco, an urban wetland highly eutrophic with a mixture of pollutants, and Tecocomulco (the reference site), a rural wetland with hunting migratory birds in winter, and with some agricultural contaminants. Coots were collected over 1 year, and the birds were aged, eviscerated, and weighed. Liver samples were analyzed biochemically and histologically. Biomarkers revealed that coots displayed higher lipid peroxidation and elevated activities of gamma-glutamyl transferase and alanine aminotransferase, suggesting hepatic damage during autumn and winter. In Tecocomulco, coots during winter has the highest thiobarbituric acid reactive substances (as a measure of oxidative stress), which may be associated with the presence of predators. In Tecocomulco, the higher gonadosomatic index was detected in spring and summer, while in Xochimilco it was elevated in summer, indicating a delayed egg laying and reproduction in coots from the latter study site. In both wetlands, leukocyte infiltration, alone or combined with vasocongestion, reflected alterations in the inflammatory processes in liver throughout the annual cycle and thus potentially altered hepatic function and organism survival. In both wetlands, coots were permanent residents and chronically exposed to different stressors, suggesting damage may be irreversible with potentially adversely reproductive consequences. PMID- 28644716 TI - The effects of acute carbohydrate and caffeine feeding strategies on cycling efficiency. AB - To assess the effect of carbohydrate and caffeine on gross efficiency (GE), 14 cyclists (VO2max 57.6 +/- 6.3 ml.kg-1.min-1) completed 4 * 2-hour tests at a submaximal exercise intensity (60% Maximal Minute Power). Using a randomized, counter-balanced crossover design, participants consumed a standardised diet in the 3-days preceding each test and subsequently ingested either caffeine (CAF), carbohydrate (CHO), caffeine+carbohydrate (CAF+CHO) or water (W) during exercise whilst GE and plasma glucose were assessed at regular intervals (~30 mins). GE progressively decreased in the W condition but, whilst caffeine had no effect, this was significantly attenuated in both trials that involved carbohydrate feedings (W = -1.78 +/- 0.31%; CHO = -0.70 +/- 0.25%, p = 0.008; CAF+CHO = -0.63 +/- 0.27%, p = 0.023; CAF = -1.12 +/- 0.24%, p = 0.077). Blood glucose levels were significantly higher in carbohydrate ingestion conditions (CHO = 4.79 +/- 0.67 mmol.L-1, p < 0.001; CAF+CHO = 5.05 +/- 0.81 mmol.L-1, p < 0.001; CAF = 4.46 +/- 0.75 mmol.L-1; W = 4.20 +/- 0.53 mmol.L-1). Carbohydrate ingestion has a small but significant effect on exercise-induced reductions in GE, indicating that cyclists' feeding strategy should be carefully monitored prior to and during assessment. PMID- 28644718 TI - Third Symposium on Interdisciplinary Activities in Environmental Toxicology in North Rhine-Westphalia, Germany. PMID- 28644717 TI - Responses of a vulnerable Hispanic population in New Jersey to Hurricane Sandy: Access to care, medical needs, concerns, and ecological ratings. AB - Recent increases in hurricanes led to a need to evaluate access to medical care, medical needs, and personal and community impact on vulnerable populations, particularly elderly, low income, and minority communities. This investigation examined (1) access to care, (2) interruptions in medical services, (3) personal impact from Hurricane Sandy, and (4) agreement with ecological statements related to storms, flooding, and damages in Hispanic/Latino patients receiving health care at Federally Qualified Health Centers in New Jersey. Only 10% of 335 Hispanic interviewees were US born. Self-identified personal impact was a better indicator of effects from Sandy, health center use, and medical issues, than community impact rating. Respondents who provided a high personal impact rating were more likely to have evacuated, had longer power outage, were more likely to need medical care, displayed more trouble getting to centers, and exhibited more medical interruptions during Sandy. A higher % respondents who evacuated, needed the center, had trouble getting there, and had more "medical need" than those who did not evacuate. The greatest impacts were on respondents who were told to evacuate before the storm, but did not (46% had "medical need"). The respondents had high agreement ratings for "storms are due to climate change," followed by "frequent and stronger storms will come more often," "flooding is due to sea level rise," and "changing climate is due mainly to human activity and not natural causes". These ratings may aid public policymakers and planners in developing resiliency strategies for vulnerable coastal communities. PMID- 28644719 TI - Shaping of Reach-to-Grasp Kinematics by Intentions: A Meta-Analysis. AB - When we reach to grasp something, we need to take into account both the properties of the object we are grasping and the intention we have in mind. Previous research has found these constraints to be visible in the reach-to-grasp kinematics, but there is no consensus on which kinematic parameters are the most sensitive. To examine this, a systematic literature search and meta-analyses were performed. The search identified studies assessing how changes in either an object property or a prior intention affect reach-to-grasp kinematics in healthy participants. Hereafter, meta-analyses were conducted using a restricted maximum likelihood random effect model. The meta-analyses showed that changes in both object properties and prior intentions affected reach-to-grasp kinematics. Based on these results, the authors argue for a tripartition of the reach-to-grasp movement in which the accelerating part of the reach is primarily associated with transporting the hand to the object (i.e., extrinsic object properties), the decelerating part of the reach is used as a preparation for object manipulation (i.e., prepare the grasp or the subsequent action), and the grasp is associated with manipulating the object's intrinsic properties, especially object size. PMID- 28644720 TI - The effect of internal migration, individual and contextual characteristics on contraceptive use among Nigerian women. AB - We investigated the relation of internal migration to contraceptive use and adjusted for individual and contextual (community) characteristics. Multilevel logistic regression models were fitted to nationally representative data of 28,876 women from 884 communities in Nigeria. Only about one out of every 10 women (10.4%) currently used a contraceptive method. Contraceptive prevalence according to the migration status were rural-urban (12.5%), urban-rural (13.8%), rural nonmigrants (6.2%) and urban nonmigrants (17.1%). The relationship between internal migration and contraceptive use was fully explained by individual and community characteristics. Programs aimed at increasing contraceptive prevalence should address contextual challenges alongside socioeconomic factors. PMID- 28644721 TI - Small GTPases in plant biotic interactions. AB - The superfamily of small monomeric GTPases originated in a common ancestor of eukaryotic multicellular organisms and, since then, it has evolved independently in each lineage to cope with the environmental challenges imposed by their different life styles. Members of the small GTPase family function in the control of vesicle trafficking, cytoskeleton rearrangements and signaling during crucial biological processes, such as cell growth and responses to environmental cues. In this review, we discuss the emerging roles of these small GTPases in the pathogenic and symbiotic interactions established by plants with microorganisms present in their nearest environment, in which membrane trafficking is crucial along the different steps of the interaction, from recognition and signal transduction to nutrient exchange. PMID- 28644722 TI - The Effects of Polyvictimization and Quality of Caregiver Attachment on Disclosure of Illegal Sexual Behavior. AB - The current study examined the relationship among self-disclosure of illegal sexual behaviors and two conceptually relevant constructs in psychotherapy: childhood polyvictimization (i.e., cumulative types of victimization experienced during childhood) and caregiver attachment. Participants consisted of 63 adolescent males participating in mandated treatment for illegal sexual behavior. Childhood polyvictimization and caregiver attachment were expected to predict self-disclosure of illegal sexual behaviors. Quality of caregiver attachment was also expected to mediate the relationship between polyvictimization and disclosure. Consistent with our main hypothesis, results indicate that quality of caregiver attachment mediated the relationship between childhood polyvictimization and self-disclosure of illegal sexual behaviors in psychotherapy. The current findings highlight the impact of polyvictimization on important therapeutic processes as well as the importance of assessing for multiple types of victimization in adolescents who engage in illegal sexual behavior. Further clinical implications regarding the use of trauma-informed approaches during sex offender treatment are discussed. PMID- 28644723 TI - Performance evaluation of mobile downflow booths for reducing airborne particles in the workplace. AB - Compared to other common control measures, the downflow booth is a costly engineering control used to contain airborne dust or particles. The downflow booth provides unidirectional filtered airflow from the ceiling, entraining released particles away from the workers' breathing zone, and delivers contained airflow to a lower level exhaust for removing particulates by filtering media. In this study, we designed and built a mobile downflow booth that is capable of quick assembly and easy size change to provide greater flexibility and particle control for various manufacturing processes or tasks. An experimental study was conducted to thoroughly evaluate the control performance of downflow booths used for removing airborne particles generated by the transfer of powdered lactose between two containers. Statistical analysis compared particle reduction ratios obtained from various test conditions including booth size (short, regular, or extended), supply air velocity (0.41 and 0.51 m/s or 80 and 100 feet per minute, fpm), powder transfer location (near or far from the booth exhaust), and inclusion or exclusion of curtains at the booth entrance. Our study results show that only short-depth downflow booths failed to protect the worker performing powder transfer far from the booth exhausts. Statistical analysis shows that better control performance can be obtained with supply air velocity of 0.51 m/s (100 fpm) than with 0.41 m/s (80 fpm) and that use of curtains for downflow booths did not improve their control performance. PMID- 28644724 TI - Modeling long-term effects attributed to nitrogen dioxide (NO2) and sulfur dioxide (SO2) exposure on asthma morbidity in a nationwide cohort in Israel. AB - Studies have provided extensive documentation that acutely elevated environmental exposures contribute to chronic health problems. However, only attention has been paid to the effects of modificate of exposure assessment methods in environmental health investigations, leading to uncertainty and gaps in our understanding of exposure- and dose-response relationships. The goal of the present study was to evaluate whether average or peak concentration exerts a greater influence on asthma outcome, and which of the exposure models may better explain various physiological responses generated by nitrogen dioxide (NO2) or sulfur dioxide (SO2) air pollutants. The effects of annual NO2 and SO2 exposures on asthma prevalence were determined in 137,040 17-year-old males in Israel, who underwent standard health examinations before induction to military service during 1999 2008. Three alternative models of cumulative exposure were used: arithmetic mean level (AM), average peak concentration (APC), and total number of air pollution exposure episodes (NEP). Air pollution data for NO2 and SO2 levels were linked to the residence of each subject and asthma prevalence was predicted using bivariate logistic regression. There was significant increased risk for asthma occurrence attributed to NO2 exposure in all models with the highest correlations demonstrated using the APC model. Data suggested that exposure-response is better correlated with NO2 peak concentration than with average exposure concentration in subjects with asthma. For SO2, there was a weaker but still significant exposure response association in all models. These differences may be related to differences in physiological responses including effects on different regions of the airways following exposure to these pollutants. NO2, which is poorly soluble in water, penetrates deep into the bronchial tree, producing asthmatic manifestations such as inflammation and increased mucus production as a result of high gaseous concentrations in the lung parenchyma. In contrast, SO2, which is highly water soluble, exerts its effects rapidly in the upper airways, leading to similar limited correlations at all levels of exposure with fewer asthmatic manifestations observed. These data indicate that differing exposure assessment methods may be needed to capture specific disease consequences associated with these air pollutants. PMID- 28644725 TI - Quantifying structural modifications of gills of two fish species Astyanax altiparanae (Lambari) and Prochilodus lineatus (Curimbata) after exposure to biodegradable detergents in urban lake water. AB - Anthropic actions in rivers and urban lakes are a cause for concern to our ecosystem. The effects on fauna and flora of substances discharged into waterways have become a focus for investigations globally. Biodegradable detergents are widely used in residences and small industries, but little is known regarding the consequences on fish fauna. The objective of the present study was to identify modifications in gill structure in two fish species, Astyanax altiparanae and Prochilodus lineatus, after treatment with water obtained from an urban lake and an exposure to 1 ppm diluted biodegradable detergents (linear alkylbenzene sulfonate). Data demonstrated exposure to urban lake produced various alterations in gill functions such as lamellar fusions, aneurysms, mucous, and chlorine cell proliferation, which may be attributed to the presence of detergents in the water but may also be a consequence of synergetic actions of detergents with other pollutants. Results showed that the levels of NO-2, Na, F-, Cl-, and Fe were significantly higher in urban lake water but in the presence of detergents Ni was also detected. Evidence indicates that biodegradable detergents produce damage to gill functions, which subsequently alters the fish physiology and reduces the ability to cope with stress and survival. PMID- 28644726 TI - Cytotoxic and genotoxic actions of Casiopeina III-Ea (Cas III-Ea) in somatic and germ cells of Drosophila melanogaster. AB - Casiopeinas(r) are a group of newly synthesized drugs designed to treat cancer. These copper (Cu) complexes exhibit cytostatic, cytotoxic, genotoxic, and antineoplastic activities through different mechanisms of action. To evaluate the influence of these compounds, some in vivo studies were performed using predominantly somatic cells. The aim of the present study was to examine the cytotoxic and genotoxic actions of Casiopeina III-Ea (Cas III-Ea) in somatic as well as germ cells of Drosophila melanogaster. For cytotoxicity, the productivity and some morphometric parameters were measured and genotoxicity was assessed by means of the somatic mutation and recombination test assay in the wing. For this purpose, second-instar larvae of the Canton-S strain were treated with different concentrations of Cas III-Ea. The emerged adults were weighed, the area of the wings determined, and the number of trichomes of the region C' counted. The productivity of treated males was measured by a brood method to monitor the influence of Cas III-Ea on spermatozoa, meiotic stage cells, and spermatogonia. For genotoxicity, mwh + /+ flr3 larvae 48 hr age were chronically treated within the same concentration range. Results indicated that Cas III-Ea at all concentrations tested significantly increased the productivity per couple in Brood III (spermatids) while at 1 mM a marked elevation was noted in the three broods tested. In contrast, the weight and size of individuals as well as the size and number of cells in the wing were decreased significantly. Data suggest that Cas III-Ea is a weak genotoxic but selective mutagen. Failure to obtain a dose-related genotoxic response suggests that one of the preferred mechanisms of action of Cas III-Ea is to induce apoptosis. PMID- 28644727 TI - Impact of time and assisted donning on respirator fit. AB - The goal of this study was to examine the impact of assistance with donning and time on quantitative fit factors (FF) and pass rates for subjects wearing an N95 filtering facepiece respirator (FFR) and a non-certified adhesive mask. Fit factors were measured using two side-by-side TSI Portacount instruments sampling second-by-second simultaneous inside- and outside-facepiece concentrations. Naive subjects made two visits at least one week apart. At each visit subjects first donned either the respirator or adhesive mask without assistance and performed a five-exercise fast fit test. They then donned a new respirator or mask with assistance in proper donning (e.g., proper forming of the nosepiece, strap placement, etc.) and performed a second five-exercise fast fit test. The same sequence of unassisted and assisted donning was then repeated with the other facepiece. Fifteen subjects participated in the study; time between visits ranged from 7-29 days (average 12 days). On visit 1 the respirator FFs were significantly higher (GM = 88) than for the adhesive mask (GM = 14); with assistance these FFs showed significant improvements to 116 and 124, respectively. At visit 1 almost half of subjects donning the respirator without assistance achieved a passing FF of 100 or greater, while only one-fifth of subjects were able to pass the fit test wearing an adhesive mask without assistance. Pass rates improved for both groups with assistance, but more so for the adhesive mask wearers. On visit 2 the pass rates for both groups had decreased, with the adhesive mask group showing a greater decrease. With assistance, pass rates improved for both groups, but again more so for those wearing the adhesive mask. Results suggest that wearers would benefit from assistance and re-training every time they don a respirator, even if the time between donnings is as short as one or two weeks. PMID- 28644728 TI - Liposomes equipped with cell penetrating peptide BR2 enhances chemotherapeutic effects of cantharidin against hepatocellular carcinoma. AB - A main hurdle for the success of tumor-specific liposomes is their inability to penetrate tumors efficiently. In this study, we incorporated a cell-penetrating peptide BR2 onto the surface of a liposome loaded with the anticancer drug cantharidin (CTD) to create a system targeting hepatocellular carcinoma (HCC) cells more efficiently and effectively. The in vitro cytotoxicity assay comparing the loaded liposomes' effects on hepatocellular cancer HepG2 and the control Miha cells showed that CTD-loaded liposomes had a stronger anticancer effect after BR2 modification. The cellular uptake results of HepG2 and Miha cells further confirmed the superior ability of BR2-modified liposomes to penetrate cancer cells. The colocalization study revealed that BR2-modified liposomes could enter tumor cells and subsequently release drugs. A higher efficiency of delivery by BR2 liposomes as compared to unmodified liposomes was evident by evaluation of the HepG2 tumor spheroids penetration and inhibition. The biodistribution studies and anticancer efficacy results in vivo showed the significant accumulation of BR2-modified liposomes into tumor sites and an enhanced tumor inhibition. In conclusion, BR2-modified liposomes improve the anticancer potency of drugs for HCC. PMID- 28644729 TI - Promoting Prenatal Exercise From a Sociocultural and Life-Course Perspective: An "Embodied" Conceptual Framework. AB - PURPOSE: Prenatal exercise is a health behavior that is receiving growing attention amid concern that women in Western societies are gaining excess weight during pregnancy and contributing to future obesity in both the mother and child. In this article, we draw on insights from the fields of social epidemiology and social theory of the body to examine existing prenatal exercise interventions and to propose a multidimensional framework intended to guide future theorizing and intervention design. METHOD: A scoping review of existing prenatal exercise programs and interventions focused on controlling gestational weight gain was conducted. Articles published prior to January 2017 were obtained from PubMed and CINAHL, and relevant articles were identified (n = 62) using specified inclusion and exclusion criteria. Identified articles were further analyzed to classify the level(s) of the socioecological model targeted in the intervention or program. RESULTS: The majority of existing interventions target intrapersonal factors during pregnancy and do not attend to the role that cumulative exposure of social and structural disadvantage over the lifetime-not just during the prenatal period plays in shaping health outcomes. In response, a multidimensional framework is proposed that includes key concepts that facilitate a life-course perspective, as well as attention to the integration of biological and social factors as they relate to health and health-related behaviors. CONCLUSION: Efforts to promote prenatal exercise and to improve maternal and infant health should attend to how systemic inequality impacts women's health. PMID- 28644731 TI - The Action Level. PMID- 28644730 TI - Pulseless ventricular tachycardia associated with chronic ketamine use. PMID- 28644732 TI - Lipophilicity and biomimetic properties to support drug discovery. AB - INTRODUCTION: Lipophilicity, expressed as the octanol-water partition coefficient, constitutes the most important property in drug action, influencing both pharmacokinetic and pharmacodynamics processes as well as drug toxicity. On the other hand, biomimetic properties defined as the retention outcome on HPLC columns containing a biological relevant agent, provide a considerable advance for rapid experimental - based estimation of ADME properties in early drug discovery stages. Areas covered: This review highlights the paramount importance of lipophilicity in almost all aspects of drug action and safety. It outlines problems brought about by high lipophilicity and provides an overview of the drug like metrics which incorporate lower limits or ranges of logP. The fundamental factors governing lipophilicity are compared to those involved in phospholipophilicity, assessed by Immobilized Artificial Membrane Chromatography (IAM). Finally, the contribution of biomimetic properties to assess plasma protein binding is evaluated. Expert opinion: Lipophilicity and biomimetic properties have important distinct and overlapping roles in supporting the drug discovery process. Lipophilicity is unique in early drug design for library screening and for the identification of the most promising compounds to start with, while biomimetic properties are useful for the experimentally-based evaluation of ADME properties for the synthesized novel compounds, supporting the prioritization of drug candidates and guiding further synthesis. PMID- 28644733 TI - Trends of ATV use and associated injury on Saskatchewan farms. AB - PURPOSE: All-terrain vehicles (ATV's) are a hazardous source of injury in many contexts and geographical regions, but to date have not been investigated in Saskatchewan. METHODS: Baseline surveys from the Saskatchewan Farm Injury Project were examined at two time points in terms of: (1) rates and correlated characteristics of reported ATV use; and (2) qualitative content analysis of injury events involving ATVs. The sample of eligible farmers was 2,972 in 2007 and 1,702 in 2013. FINDINGS: Self-reported ATV use increased on Saskatchewan farms over the five-year period, both in terms of the number of individuals using ATV's on the farm and the days per year of operation. ATV use is significantly more common on farms with livestock, among male farmers, and among younger farmers. Farmers with low back pain were also more likely to report ATV use. Qualitative content analysis of farmers' reported "most serious injury" on the farm revealed themes related to: (1) tasks undertaken with ATV's at the time of the incident (e.g., stock work and personal transport); (2) contributing factors (vehicle, environmental and driver); and (3) safety reflections. CONCLUSION: The apparent trends of increasing ATV use on Saskatchewan farms and serious nature of the injury incidents reported indicate that this is an issue worthy of further investigation. PMID- 28644734 TI - High-Throughput Phenotypic Screening of Kinase Inhibitors to Identify Drug Targets for Polycystic Kidney Disease. AB - Polycystic kidney disease (PKD) is a prevalent disorder characterized by renal cysts that lead to kidney failure. Various signaling pathways have been targeted to stop disease progression, but most interventions still focus on alleviating PKD-associated symptoms. The mechanistic complexity of the disease, as well as the lack of functional in vitro assays for compound testing, has made drug discovery for PKD challenging. To identify modulators of PKD, Pkd1-/- kidney tubule epithelial cells were applied to a scalable and automated 3D cyst culture model for compound screening, followed by phenotypic profiling to determine compound efficacy. We used this screening platform to screen a library of 273 kinase inhibitors to probe various signaling pathways involved in cyst growth. We show that inhibition of several targets, including aurora kinase, CDK, Chk, IGF 1R, Syk, and mTOR, but, surprisingly, not PI3K, prevented forskolin-induced cyst swelling. Additionally, we show that multiparametric phenotypic classification discriminated potentially undesirable (i.e., cytotoxic) compounds from molecules inducing the desired phenotypic change, greatly facilitating hit selection and validation. Our findings show that a pathophysiologically relevant 3D cyst culture model of PKD coupled to phenotypic profiling can be used to identify potentially therapeutic compounds and predict and validate molecular targets for PKD. PMID- 28644735 TI - Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. AB - INTRODUCTION: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a relatively rare but potentially lethal disease, leading to severe bleeding complications in 1 in 11.000 newborns. It is the leading cause of thrombocytopenia in healthy term-born neonates. Areas covered: This review summarizes the antenatal as well as postnatal treatment, thus creating a complete overview of all possible management strategies for FNAIT. Expert commentary: The optimal antenatal therapy in order to prevent bleeding complications in pregnancies complicated by FNAIT is non-invasive treatment with weekly intravenous immunoglobulin (IVIG). Based on risk stratification, weekly doses of IVIG of 0.5 or 1.0g/kg should be administered started early in the second in high risk cases or at the end of the second trimester in low risk cases. The optimal postnatal treatment depends on the platelet count and the clinical condition of the newborn. Prompt administration of compatible platelet transfusion is the first treatment of choice in case of severe thrombocytopenia or active bleeding. In case matched platelets are not directly available, random platelets can also be administered initially to gain time until matched platelets are available. In case of persistent thrombocytopenia despite transfusions, IVIG 1.0-2.0g/kg can be administered. PMID- 28644736 TI - Asymptomatic microscopic hematuria as a predictor of neoplasia in the urinary tract. AB - OBJECTIVE: The Danish hematuria guidelines were revised in January 2016. Before revision, it was recommended that asymptomatic microscopic hematuria in patients more than 40 years old should be routinely urologically investigated. In the revised guidelines, patients with asymptomatic microscopic hematuria are not recommended to be investigated, irrespective of age. The purpose of this study was to investigate whether asymptomatic microscopic hematuria was predictive of neoplasia of the urinary tract in a referred cohort of patients. METHODS: All patients older than 40 years referred from primary care to private clinics and public hospitals in the Central Denmark Region for evaluation of asymptomatic microscopic hematuria in a 2 year period from January 2014 to December 2015 were included retrospectively. All patients had been routinely investigated with computed tomography urography and outpatient flexible cystoscopy. Patients' age and gender were recorded and the final diagnosis after full investigation was retrieved. RESULTS: In total, 1305 patients (492 males and 813 females) were included. Eleven patients (0.8%) were diagnosed with neoplasia in the urinary tract, including non-invasive Ta bladder tumor (n = 6), benign tumors in the kidney (n = 2), invasive bladder cancer (n = 2) and carcinoma in situ in the urinary bladder (n = 1). None of the patients had renal cancer or upper urinary tract tumors as the final diagnosis. CONCLUSION: A minority of patients with malignancies or non-invasive tumors would have been missed based on the revised Danish hematuria referral pathways. PMID- 28644737 TI - Circulatory CNP Rescues Craniofacial Hypoplasia in Achondroplasia. AB - Achondroplasia is the most common genetic form of human dwarfism, characterized by midfacial hypoplasia resulting in occlusal abnormality and foramen magnum stenosis, leading to serious neurologic complications and hydrocephalus. Currently, surgery is the only way to manage jaw deformity, neurologic complications, and hydrocephalus in patients with achondroplasia. We previously showed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth of long bones and vertebrae and is also a potent stimulator in the craniofacial region, which is crucial for midfacial skeletogenesis. In this study, we analyzed craniofacial morphology in a mouse model of achondroplasia, in which fibroblast growth factor receptor 3 (FGFR3) is specifically activated in cartilage ( Fgfr3ach mice), and investigated the mechanisms of jaw deformities caused by this mutation. Furthermore, we analyzed the effect of CNP on the maxillofacial area in these animals. Fgfr3ach mice exhibited midfacial hypoplasia, especially in the sagittal direction, caused by impaired endochondral ossification in craniofacial cartilage and by premature closure of the spheno-occipital synchondrosis, an important growth center in craniomaxillofacial skeletogenesis. We crossed Fgfr3ach mice with transgenic mice in which CNP is expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP ( Fgfr3ach/SAP-Nppc-Tg mice). In the progeny, midfacial hypoplasia in the sagittal direction observed in Fgfr3ach mice was improved significantly by restoring the thickness of synchondrosis and promoting proliferation of chondrocytes in the craniofacial cartilage. In addition, the foramen magnum stenosis observed in Fgfr3ach mice was significantly ameliorated in Fgfr3ach/SAP-Nppc-Tg mice due to enhanced endochondral bone growth of the anterior intraoccipital synchondrosis. These results clearly demonstrate the therapeutic potential of CNP for treatment of midfacial hypoplasia and foramen magnum stenosis in achondroplasia. PMID- 28644738 TI - National survey and analysis of barriers to the utilisation of the 2005 mental capacity act by people with bipolar disorder in England and Wales. AB - BACKGROUND: The Mental Capacity Act (2005) (MCA) provides a legal framework for advance planning for both health and welfare in England and Wales for people if they lose mental capacity, for example, through mania or severe depression. AIMS: To determine the proportion of people with bipolar disorder (BD) who utilise advance planning, their experience of using it and barriers to its implementation. METHODS: National survey of people with clinical diagnosis of BD of their knowledge, use and experience of the MCA. Thematically analysed qualitative interviews with maximum variance sample of people with BD. RESULTS: A total of 544 respondents with BD participated in the survey; 18 in the qualitative study. 403 (74.1%) believed making plans about their personal welfare if they lost capacity to be very important. A total of 199 (36.6%) participants knew about the MCA. A total 54 (10%), 62 (11%) and 21 (4%) participants made advanced decisions to refuse treatment, advance statements and lasting power of attorney, respectively. Barriers included not understanding its different forms, unrealistic expectations and advance plans ignored by services. CONCLUSION: In BD, the demand for advance plans about welfare with loss of capacity was high, but utilisation of the MCA was low with barriers at service user, clinician and organisation levels. PMID- 28644739 TI - Treatment of hepatitis C with new fixed dose combinations. AB - INTRODUCTION: The advent of oral direct-acting antivirals (DAA) has revolutionized the hepatitis C virus (HCV) therapeutic landscape providing cure rates over 90%. However, a subset of patients remains at higher risk for treatment failure, including those infected with: i) genotype 3 and cirrhosis; ii) resistance-associated substitutions (RAS) occurring either as natural polymorphisms or selected after prior DAA failure; and iii) poor drug adherence associated with social disabilities (homeless, psychiatric illnesses, injection drug use, alcoholism, etc.). Whereas discovery of new DAA with increased antiviral activity across all genotypes and over RAS may enhance efficacy, development of fixed dose combinations (FDC) may be the best way to improve drug adherence in difficult-to-treat HCV populations. Areas covered: Three FDC regimens are in the last steps of clinical development for treating hepatitis C. Two distinct nucleotide analogues that inhibit the HCV polymerase, sofosbuvir and uprifosbuvir, are part of the FDC from Gilead and Merck, respectively. The AbbVie dual FDC does not include a polymerase inhibitor. All three new FDC include second-generation NS3 protease inhibitors and NS5A inhibitors active across all HCV genotypes and over common RAS. Expert opinion: Hepatitis C cure rates over 95% are expected with all three next-coming DAA, even in the most difficult-to treat and/or cure patient populations. These regimens would be particularly needed for the growing number of prior DAA failures. Co-formulations and 8-week shorter treatment lengths will help to overcome drug adherence challenges in certain populations. PMID- 28644740 TI - Efficacy of guided self-help behavioural activation and physical activity for depression: a randomized controlled trial. AB - Behavioural activation and physical activity have received empirical support that highlight their efficacy in reducing depression. Even though both behavioural activation and physical activity share the common goal of reactivating the individual, limited research has directly compared these interventions, and more research is required to evaluate their efficacy when offered in low-intensity formats. The present study involves a randomized controlled clinical trial comparing the efficacy of two guided self-help interventions for the treatment of depression: behavioural activation and physical activity. Fifty-nine participants presenting mild-to-moderate symptoms of depression were randomized either to a behavioural activation intervention (n = 20), a physical activity intervention (n = 19) or a wait-list control group (n = 20). All participants completed symptom measure pre-, mid- and post-intervention, as well as at a two-month follow-up. Mixed-model analyses of variance revealed that both interventions were significantly more efficacious in reducing depressive symptoms in comparison with the control group. Physical activity involved significantly less time-investment compared to the behavioural activation condition (less than half the amount of time). These results indicate that physical activity and behavioural activation both effectively reduce depressive symptoms and are favourably applicable in low intensity formats. Implications of these results and avenues for future research are discussed. PMID- 28644742 TI - New legal requirements for submission of product information to poisons centres in EU member states. AB - INTRODUCTION: In the past eight years, the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) has been intensively involved in a European Commission led process to develop EU legislation on the information of hazardous products that companies have to notify to EU Poisons Centres (or equivalent "appointed bodies"). As a result of this process, the Commission adopted Regulation (EU) No 2017/542, amending the CLP Regulation by adding an Annex on harmonised product submission requirements. Harmonised mixture information requirements: Detailed and consistent information on the composition of the hazardous product will become available to EU Poisons Centres (PC). The information will be submitted by companies to PCs (or equivalent "appointed bodies") using a web-based software application or in-house software. Two new important features are introduced. Firstly, to be able to rapidly identify the product formula, a Unique Formula Identifier (UFI) on the product label links to the submitted information. Secondly, for better comparability of reports on poisonings between EU member states, a harmonised Product Categorisation System will specify the intended use of a product. Rapid product identification and availability of detailed composition information will lead to timely and adequate medical intervention. This may lead to considerable reduction in healthcare costs. Additionally, for companies trading across the EU, costs of submission of this information will be reduced significantly. Next steps: From 2017, an implementation period has started, consisting of a three-year period for stakeholders to implement the new requirements, followed by a gradual applicability for consumer products (2020), professional products (2021) and industrial use-only products (2024). Technical tools to generate the electronic format and the UFI together with guidance documents are expected to be made available by the end of 2017 by the European Chemicals Agency (ECHA). Guidance on interpretation of legal text and ECHA helpdesk support are planned to be ready at the end of 2018. PMID- 28644741 TI - Ras Signaling Regulates Stem Cells and Amelogenesis in the Mouse Incisor. AB - The role of Ras signaling during tooth development is poorly understood. Ras proteins-which are activated by many upstream pathways, including receptor tyrosine kinase cascades-signal through multiple effectors, such as the mitogen activated protein kinase (MAPK) and PI3K pathways. Here, we utilized the mouse incisor as a model to study how the MAPK and PI3K pathways regulate dental epithelial stem cells and amelogenesis. The rodent incisor-which grows continuously throughout the life of the animal due to the presence of epithelial and mesenchymal stem cells-provides a model for the study of ectodermal organ renewal and regeneration. Utilizing models of Ras dysregulation as well as inhibitors of the MAPK and PI3K pathways, we found that MAPK and PI3K regulate dental epithelial stem cell activity, transit-amplifying cell proliferation, and enamel formation in the mouse incisor. PMID- 28644743 TI - Sarcocystis jamaicensis n. sp., from Red-Tailed Hawks (Buteo jamaicensis) Definitive Host and IFN-gamma Gene Knockout Mice as Experimental Intermediate Host. AB - Here, we report a new species of Sarcocystis with red-tailed hawk (RTH, Buteo jamaicensis) as the natural definitive host and IFN-gamma gene knockout (KO) mice as an experimental intermediate host in which sarcocysts form in muscle. Two RTHs submitted to the Carolina Raptor Center, Huntersville, North Carolina, were euthanized because they could not be rehabilitated and released. Fully sporulated 12.5 * 9.9-MUm sized sporocysts were found in intestinal scrapings of both hawks. Sporocysts were orally fed to laboratory-reared outbred Swiss Webster mice (SW, Mus musculus) and also to KO mice. The sporocysts were infective for KO mice but not for SW mice. All SW mice remained asymptomatic, and neither schizonts nor sarcocysts were found in any SW mice euthanized on days 54, 77, 103 (n = 2) or 137 post-inoculation (PI). The KO mice developed neurological signs and were necropsied between 52 to 68 days PI. Schizonts/merozoites were found in all KO mice euthanized on days 52, 55 (n = 3), 59, 61 (n = 2), 66, and 68 PI and they were confined to the brain. The predominant lesion was meningoencephalitis characterized by perivascular cuffs, granulomas, and necrosis of the neural tissue. The schizonts/merozoites were located in neural tissue and were apparently extravascular. Brain homogenates from infected KO mice were infective to KO mice by subcutaneous inoculation and when seeded on to CV-1 cells. Microscopic sarcocysts were found in skeletal muscles of 5 of 8 KO mice euthanized between 55-61 days PI. Only a few sarcocysts were detected. Sarcocysts were microscopic, up to 3.5 mm long. When viewed with light microscopy, the sarcocyst wall appeared thin (<1 MUm thick) and smooth. By transmission electron microscopy, the sarcocyst wall classified as "type 1j" (new designation). Molecular characterization using 18S rRNA, 28S rRNA, ITS-1, and cox1 genes revealed a close relationship with Sarcocystis microti and Sarcocystis glareoli; both species infect birds as definitive hosts. The parasite in the present study was biologically and molecularly different from species so far described in RTHs and we therefore propose a new species name, Sarcocystis jamaicensis n. sp. PMID- 28644744 TI - Add-on iguratimod as a therapeutic strategy to achieve remission in patients with rheumatoid arthritis inadequately responding to biological DMARDs: A retrospective study. AB - OBJECTIVES: In this study, iguratimod (IGU) was added to rheumatoid arthritis (RA) patients inadequately responding to 24-week or longer treatment with biological disease-modifying antirheumatic drug (bDMARDs), its effectiveness was assessed, and factors contributing to remission were evaluated. METHODS: RA patients who fulfilled the following criteria were included: (i) >= 24-week of bDMARDs; (ii) 2.6 < disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) < 5.1 or the presence of synovitis with a power Doppler (PD) score >=2 in at least 1 of the 28 joints on joint ultrasonography. Disease activity and joint ultrasound findings were evaluated at baseline and at 12 and 24 weeks. RESULTS: DAS assessing 28 joints with ESR (DAS28-ESR) decreased significantly from 3.45 +/- 0.92 at baseline to 2.85 +/- 1.13 at 24 weeks (p < .001). Overall, 38.3% achieved clinical remission (c-remission). The total PD score decreased significantly from 8.7 +/- 6.1 at baseline to 5.5 +/- 5.0 at 24 weeks (p < .001). A lower baseline DAS28-ESR was related to c-remission after 24 weeks (p =.002). Shorter duration of disease (p =.020) was related to ultrasound remission, in addition to a lower baseline DAS28-ESR (p < .001). CONCLUSIONS: IGU add-on therapy can be a therapeutic strategy to achieve remission in RA patients inadequately responding to >=24-week treatment with bDMARDs. PMID- 28644745 TI - Current views on Zika virus vaccine development. PMID- 28644746 TI - Conversations on Dying: A Palliative Care Pioneer Faces His Own Death. AB - Editor's Note The journal is delighted to continue a collaboration with the International Association for Hospice and Palliative Care (IAHPC) in publication of book reviews relevant to symptom control in advanced disease. These reviews are adapted from the work of Roger Woodruff, MD, FRACP, FAChPM, an internationally recognized oncologist and palliative care specialist physician from Australia. Dr. Woodruff's reviews appear concurrently or did so previously in the IAHPC Newsletter, which is accessible through the IAHPC Web site: http://hospicecare.com . PMID- 28644747 TI - Pain Management and Prescription Opioid-Related Harms: Exploring the State of the Evidence: Proceedings of a Workshop-In Brief. PMID- 28644748 TI - Paediatric Palliative Medicine, 2nd ed. AB - Editor's Note The journal is delighted to continue a collaboration with the International Association for Hospice and Palliative Care (IAHPC) in publication of book reviews relevant to symptom control in advanced disease. These reviews are adapted from the work of Roger Woodruff, MD, FRACP, FAChPM, an internationally recognized oncologist and palliative care specialist physician from Australia. Dr. Woodruff's reviews appear concurrently or did so previously in the IAHPC Newsletter, which is accessible through the IAHPC Web site: http://hospicecare.com . PMID- 28644749 TI - Breakfast, Lunch, and Dinner. PMID- 28644751 TI - Medical Cannabis for Pain: Anecdote or Evidence. PMID- 28644753 TI - A comparison of the neutrophil-lymphocyte, platelet-lymphocyte and monocyte lymphocyte ratios in schizophrenia and bipolar disorder patients - a retrospective file review. AB - Neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and monocyte lymphocyte ratio (MLR) have recently been used as indicators of inflammation. Higher MLR and PLR values have been determined in the euthymic and manic periods in patients with bipolar disorder compared to a control group. High NLR values were determined in the only study investigating this ratio in schizophrenia patients. The purpose of this study was to compare NLR, PLR and MLR values and complete blood count elements in patients receiving treatment and hospitalized due to schizophrenic psychotic episode and bipolar disorder manic episode. All patients meeting the inclusion criteria among subjects receiving treatment and hospitalized due to schizophrenia-psychotic episode and bipolar affective disorder-manic episode at the Ondokuz Mayis University Medical Faculty Psychiatry Department, Turkey, in 2012-2016 were included in our study. A total of 157 healthy donors were included as a control group. White blood cell (WBC), neutrophil, lymphocyte, platelet and monocyte numbers were noted retrospectively from complete blood counts at time of admission, and NLR, PLR and MLR were calculated from these. NLR, PLR and MLR values and platelet numbers in this study were higher and lymphocyte numbers were lower in bipolar disorder patients compared to the controls. Elevation in NLR, MLR and PLR values and neutrophil numbers and lower lymphocyte numbers were determined in schizophrenia patients compared to the controls. Higher NLR and MLR values were found in schizophrenia patients compared to bipolar disorder. Findings of our study supported the inflammation hypothesis for schizophrenia and bipolar disorder. PMID- 28644752 TI - Expression and purification of swine RAG2 in E. coli for production of porcine RAG2 polyclonal antibodies. AB - Recombination activating gene 2 (RAG2) is necessary for immature B cell differentiation. Antibodies to human and rabbit RAG2 are currently commercially available, but antibodies to swine RAG remain unavailable to date. In this study, the swine RAG2 genes sequence was synthesized and then cloned into a pET-28a vector. The recombinant fusion protein was successfully expressed in E. coli, purified through nickel column chromatography, and further digested with Tobacco Etch Virus protease. The cleaved protein was purified by molecular-exclusion chromatography and named pRAG2. We used pRAG2 to immunize rabbits, collected the serum and purified rabbit anti-pRAG2 polyclonal antibodies. The rabbit anti-pRAG2 polyclonal antibodies were tested via immunofluorescence on eukaryotic cells overexpressing pRAG2 and also able to recognize pig natural RAG2 and human RAG2 protein in western blotting. These results indicated that the prepared rabbit anti-pRAG2 polyclonal antibodies may serve as a tool to detect immature B cell differentiation of swine. PMID- 28644754 TI - Expression of enzymes related to glucose metabolism in non-small cell lung cancer and prognosis. AB - : Purpose/Aim: Cancer cells are addicted to glycolytic anaerobic pathways, in presence or in absence of a functional Krebs' cycle (phenomenon Warburg). This metabolic predilection relies on both extracellular (impaired vascularization and oxygenation) and intracellular (oncogenic activation of genes) causes. MATERIALS AND METHODS: We investigated the expression and prognostic relevance of enzymes involved in the glucose absorption and metabolism, monocarboxylate transporter (MCT) expression, MCT1 and MCT2, pentose pathway (Glucose-6-phospahte dehydrogenase G6PD), glycogene synthesis (glycogene synthase GYS1), glycolysis (Hexokinase HXKII, phosphofructokinase PFK1, fructose biphosphate aldolase), fate of pyruvate (pyruvate dehydrogenase PDH, phosphorylated pPDH, PDH kinase PDK1, lactate dehydrogenase LDH5 and LDH1) and key Kreb's cycle enzymes (citrate synthase CSynth and isocitrate dehydrogenase IDH). RESULTS: A strong overexpression of the above enzymes/proteins was noted in a varying percentage of cases examined. An interesting significant correlation between the enzymes involved in glycolysis and with the LDH5 was noted. Adenocarcinomas expressed higher levels of GLUT1 and MCT2 compared to other subtypes. Stage (p = 0.0001), aldolase (p = 0.004), LDH5 (p = 0.008), GLUT2 (p = 0.008), MCT2 (p = 0.009), GSYS1 (p = 0.04), and GLUT1 (p = 0.05) were significantly related with poor disease specific overall survival. In multivariate analysis stage (p = 0.001), LDH5 (p = 0.04), pPDH (p = 0.04), and aldolase (p = 0.04) were independent prognostic variables. CONCLUSION: It is concluded that an orchestrated activation of glucose absorption and metabolism towards anaerobic pathways characterize the majority of NSCLC, and this phenotype is strongly linked with an aggressive clinical behavior. This glycolytic addiction of lung cancer cell is revealed as a key therapeutic target. PMID- 28644755 TI - A Contemporary Examination of First and Second Permanent Molar Emergence. AB - The emergence of first permanent molars (FPMs) and second permanent molars (SPMs) is an important developmental milestone influencing caries risk and the timing of sealant placement. Emergence times have been shown to vary by sex and race/ethnicity, while recent reports suggest a positive association with adiposity. Amid the changing demographics of the US population and the rising rates of pediatric overweight/obesity, we sought to examine the association of body mass index (BMI) with FPM/SPM emergence in a representative sample of US children and adolescents. We used cross-sectional data from 3 consecutive cycles of the National Health and Nutrition Examination Survey (2009 to 2014). The FPM analysis included ages 4 to 8 y ( n = 3,102 representing ~20 million children), and the SPM analysis included ages 9 to 13 y ( n = 2,774 representing ~19 million children/adolescents). The Centers for Disease Control and Prevention's growth chart data were used to calculate age- and sex-specific BMI percentiles, as measures of adiposity. Initial data analyses relied on descriptive statistics and stratified analyses. We used multivariate methods, including survey linear and ordinal logistic regression and marginal effects estimation to quantify the association between pediatric overweight/obesity and FPM/SPM emergence, adjusting for age, sex, and race/ethnicity. Forty-eight percent of 6-y-olds and 98% of 8-y olds had all FPMs emerged, whereas SPM emergence varied more. Blacks (vs. whites) and females (vs. males) experienced earlier emergence of FPMs and SPMs. Overweight/obesity was associated with earlier FPM emergence, particularly among black females. Obesity but not overweight was associated with earlier SPM emergence. Overall, overweight/obesity accounted for 6 to 12 mo of dental acceleration. This study's results emanate from the most recent US-representative data and affirm that FPM/SPM emergence varies by race/ethnicity and sex and is positively influenced by BMI. Future research should further elucidate these associations with detailed eruption data and examine the implications of this variation for clinical care. PMID- 28644757 TI - Relationships Between Adipokine Profiles, Physique Index, and Severity of Bronchiolitis in Infancy. AB - INTRODUCTION: Relationships between adipokines, adiposity and severity of acute viral bronchiolitis in infancy have not been elucidated. MATERIALS AND METHODS: We investigated the relationships between three serum adipokines (leptin, adiponectin and TNF-alpha), physique index (Kaup index) and clinical severity in 13 bronchiolitis infants. Seven healthy infants were enrolled as the control group. We used Modified Pulmonary Index Score (MPIS) to evaluate bronchiolitis severity. RESULTS: No significant differences in adipokine levels were found between groups. In bronchiolitis infants, Kaup index negatively correlated with MPIS (r = -0.614, p = 0.03). A positive correlation was observed between the serum leptin/adiponectin ratio and MPIS (r = 0.618, p = 0.03), although correlations were not observed between respective serum adipokines levels and MPIS. Serum leptin and adiponectin had significantly negative correlations with age (r = 0.815, p = 0.001 and r = 0.566, p = 0.04, respectively), but not Kaup index. CONCLUSION: The severity of viral bronchiolitis in infancy may be related to the adipokine profile, but not adiposity. PMID- 28644758 TI - An independent shopping experience for wheelchair users through augmented reality and RFID. AB - People with physical and mobility impairments continue to struggle to attain independence in the performance of routine activities and tasks. For example, browsing in a store and interacting with products located beyond an arm's length may be impossible without the enabling intervention of a human assistant. This research article describes a study undertaken to design, develop, and evaluate potential interaction methods for motor-impaired individuals, specifically those who use wheelchairs. Our study includes a user-centered approach, and a categorization of wheelchair users based upon the severity of their disability and their individual needs. We designed and developed access solutions that utilize radio frequency identification (RFID), augmented reality (AR), and touchscreen technologies in order to help people who use wheelchairs to carry out certain tasks autonomously. In this way, they have been empowered to go shopping independently, free from reliance upon the assistance of others. A total of 18 wheelchair users participated in the completed study. PMID- 28644756 TI - Immunological effects of hypomethylating agents. AB - INTRODUCTION: Epigenetic changes resulting from aberrant methylation patterns are a recurrent observation in hematologic malignancies. Hypomethylating agents have a well-established role in the management of patients with high-risk myelodysplastic syndrome or acute myeloid leukemia. In addition to the direct effects of hypomethylating agents on cancer cells, there are several lines of evidence indicating a role for immune-mediated anti-tumor benefits from hypomethylating therapy. Areas covered: We reviewed the clinical and basic science literature for the effects of hypomethylating agents, including the most commonly utilized therapeutics azacitidine and decitabine, on immune cell subsets. We summarized the effects of hypomethylating agents on the frequency and function of natural killer cells, T cells, and dendritic cells. In particular, we highlight the effects of hypomethylating agents on expression of immune checkpoint inhibitors, leukemia-associated antigens, and endogenous retroviral elements. Expert commentary: In vitro and ex vivo studies indicate mixed effects on the function of natural killer, dendritic cells and T cells following treatment with hypomethylating agents. Clinical correlates of immune function have suggested that hypomethylating agents have immunomodulatory functions with the potential to synergize with immune checkpoint therapy for the treatment of hematologic malignancy, and has become an active area of clinical research. PMID- 28644759 TI - Virulence profile: Mark Thomas. PMID- 28644760 TI - Expression and characterization of soybean seed coat peroxidase in Escherichia coli BL21(DE3). AB - Soybean seed coat peroxidase (SBP) is a valuable enzyme having a broad variety of applications in analytical chemistry, biochemistry, and food processing. In the present study, the sscp gene (Gene ID: 548068) was optimized based on the preferred codon usage of Escherichia coli, synthesized, and expressed in E. coli BL21(DE3). SDS-PAGE and western blot analysis of this expressed protein revealed that its molecular weight is approximately 39 kDa. The effects of induction temperature, concentration of isopropyl-beta-D-thiogalactoside and hemin, induction time, expression time were optimized to enhance SBP production with a maximum activity of 11.23 U/mL (8.64 U/mg total protein). Furthermore, the kinetics of enzyme-catalyzed reactions of recombinant protein was determined. When 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) was used as substrate, optimum reaction temperature and pH of the enzyme were 85 degrees C and 5.0, respectively. The effects of metal ions on the enzymatic reaction were also further investigated. The SBP was successfully expressed in E. coli BL21(DE3) which would provide a more efficient production strategy for industrial applications of SBP. PMID- 28644762 TI - Continued Focus on Communities. PMID- 28644761 TI - Effectiveness of Satir-Informed Family-Therapy on the Codependency of Drug Dependents' Family Members in Iran: A Randomized Controlled Trial. AB - PURPOSE: Social workers in substance abuse treatment settings are responsible for involving families in treatment program to improve family functioning. The effectiveness of available interventions in treating codependency of family members of drug users in Iran is not well explored. We evaluated the effectiveness of the Satir communication family therapy (CFT) in healing codependency of drug dependents' family members in Tehran, Iran. METHODS: The intervention group participants (n = 27) received a seven-session social work intervention with CFT approach and the control group (n = 26) received treatment as usual. We used the Holyoake Codependency Index to measure participants' codependency at baselines, end of intervention, and 90 days post intervention. RESULTS: Codependents enrolled in the intervention had a significantly lower codependency score than controls at the end of intervention and 90 days post intervention. DISCUSSION: CFT is an effective strategy to reduce codependency in Iranian population and can be explored as a population-based strategy. PMID- 28644763 TI - Methyltransferase G9A Regulates Osteogenesis via Twist Gene Repression. AB - Here we investigate the role of epigenetic factors in controlling the timing of cranial neural crest cell differentiation. The gene coding for histone H3 lysine 9 methyltransferase G9A was conditionally deleted in neural crest cells with Wnt1 Cre. The majority of homozygous-null animals survived to birth but thereafter failed to thrive. Phenotypic analysis of postnatal animals revealed that the mutants displayed incomplete ossification and 20% shorter jaws as compared to their wild-type littermates. At E13.5, patterns of expression of the osteogenic transcription factor RUNX2 and the mesenchymal transcription factor TWIST are similar in controls and mutants; both overlap in areas of future intramembranous bone formation. At E14.5, the nonosteogenic mesenchyme expressed TWIST, whereas the ossification center had strong RUNX2 and osteopontin expression. In the mutants, TWIST protein was present in the osteogenic mesenchyme, while osteopontin was not expressed until E15.5. In addition, in mutants, small regions of TWIST-positive osteogenic mesenchyme were visible until E15.5. The delay in ossification and reduction in size of the ossification centers were correlated with an earlier decrease in proliferation. We used micromass cultures of the face to investigate the direct effects of G9A inhibition on skeletal differentiation. Addition of a small molecule inhibitor for G9A, BIX-01294, to wild-type cells upregulated Twist genes similar to what was observed in vivo. The inhibitor also caused decreases in several osteogenic markers. Chromatin immunoprecipitation analysis of primary osteogenic mesenchyme from calvaria revealed that Twist1 and Twist2 regulatory regions contain the repressive H3K9me2 marks catalyzed by G9A, which are removed when BIX-01294 is added. Our results establish a role for G9A and H3K9me2 in the regulation of Twist genes and provide novel insights into the significance of epigenetic mechanisms in controlling temporal and tissue-specific gene expression during development. PMID- 28644764 TI - Interventions to Improve Breastfeeding Self-Efficacy and Resultant Breastfeeding Rates: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Maternal breastfeeding self-efficacy (BSE) is reflective of a mother's confidence in breastfeeding and is a modifiable factor that may improve breastfeeding rates. Breastfeeding self-efficacy theory purports that women with higher BSE will have better breastfeeding outcomes. Research aim: The aim of this systematic review was to explore the theoretical link between BSE and breastfeeding outcomes by investigating (a) if interventions to improve BSE were successful and (b) if improvements in BSE resulted in improved breastfeeding rates. METHODS: The authors performed a systematic search of 10 databases for studies that investigated the effect of interventions for mothers of full-term infants on BSE and breastfeeding rates. They used an inverse-variance, random effects meta-analysis. RESULTS: Of 1,366 titles and abstracts identified, 58 full text articles were screened and 11 met the study criteria. Compared with mothers in control groups, mothers in intervention groups had significantly higher BSE, scoring 4.86 points higher, 95% confidence interval [3.11, 6.61], at 2 months postpartum. Mothers in the intervention groups were 1.56 and 1.66 times more likely to be breastfeeding at 1 month and 2 months postpartum, respectively. Interventions that were implemented in the postpartum period, used combined delivery settings, or were informed by BSE theory had the greatest influence on breastfeeding outcomes. Meta-regression indicated that for each 1-point increase in the mean BSE score between the intervention and control groups, the odds of exclusive breastfeeding increased by 10% in the intervention group. CONCLUSION: Breastfeeding self-efficacy is a modifiable factor that practitioners can target to improve breastfeeding rates in mothers of full-term infants. PMID- 28644765 TI - Radioactivity measurements and dosimetric evaluation in meat of wild birds. AB - The aim of this study was to determine the background activity concentration of natural radionuclides and 137Cesium (Cs) in meat of 14 migratory birds originating from central and northern Europe. This meat is largely consumed by the Italian population. 40K, 210Pb, and 137Cs were determined by gamma spectrometry and 210Po by alpha spectrometry. The mean 40K activity concentration detected was 490 +/- 117 Bq/kgdw. In all the samples, 210Pb was below the limit of detection (LOD), and therefore it was not possible to calculate the ratio 210Po/210Pb. The 210Po activity concentration ranged between 0.11 +/- 0.02 Bq/kgdw and 6.2 +/- 0.93 Bq/kgdw with a mean value of 1.03 +/- 1.75 Bq/kgdw. The 137Cs activity concentration was not detectable or near LOD except in two samples with 45 +/- 0.7 Bq/kgdw (wood pigeon, from Italy) and 139.1 +/- 1.9 Bq/kgdw (woodcock, from Sweden). The effective dose of 210Po ingested by consumption of wild birds meat accounts for only 0.01-0.6% of natural radiation exposure in Italy. These data indicate that the meat analyzed was safe. PMID- 28644766 TI - Independent Development of Imagination and Perception of Fitts' Law in Late Childhood and Adolescence. AB - Recent neurophysiological and behavioral research suggests perception-action systems are tightly coupled. Accordingly, Fitts' law has been observed when individuals execute, perceive, and imagine actions. Developmental research has found that (a) children demonstrate Fitts' law in imagined actions and (b) imagined movement time (MT) becomes closer to actual MT as age increases. However, action execution, imagination, and perception have yet to be assessed together in children. The authors investigated how imagined and perceived MTs related to actual MTs in children and adolescents. It was found that imagined MTs were longer than execution MTs were. Perception MTs were lower than execution MTs for children and more consistent with execution MTs for adolescents. These results suggest potential mechanistic differences in action imagination and perception. PMID- 28644767 TI - Blood lead levels and risk factors for lead exposure among pregnant women in western French Guiana: the role of manioc consumption. AB - Concerns regarding lead (Pb) poisoning in French Guiana first arose in 2011 following the discovery of excessively high levels of the metal amongst children in a small neighborhood without any apparent source of Pb. Since 2012, blood lead level (BLL) measurement has been proposed for all pregnant women in western French Guiana. The aim of this study was to determine BLL in pregnant women in this region and identify factors associated with elevated BLL. An observational study of a consecutive sample of women who delivered in the maternity ward of the hospital was conducted. Risk factors were investigated using a questionnaire administered postdelivery by midwives (N = 531). Approximately 25 and 5% of women displayed BLL of >=50 MUg/L and >=100 ug/L, respectively. The geometric mean was 32.6 MUg/L. Factors that were significantly associated with an elevated BLL after modeling (multivariate linear regression) included place of residence along the Maroni river, low level of education, daily consumption of manioc derivatives, weekly and daily consumption or personal preparation of manioc flour during pregnancy, and weekly consumption of wild game. This study provides insight into the regional and social disparities in BLL in French Guiana and potential sources of exposure. Evidence indicates that foods that are primarily produced and consumed in the Guiana Shield significantly affect BLL levels. Taken together with existing data, our results demonstrate that specific actions in terms of prevention, screening, and care are required to be adapted and put into place in order to reduce exposure. PMID- 28644768 TI - Error Feedback Frequency Affects Automaticity But Not Accuracy and Consistency After Extensive Motor Skill Practice. AB - Earlier studies addressed the effects of feedback frequency on movement accuracy and consistency. The authors additionally addressed the effects on motor automatization. High error feedback frequencies may induce attentional control processes and impede motor automatization. In a pre-post design, 42 participants were assigned to 2 groups with different feedback frequencies and practiced an arm movement sequence with 760 trials in 5 sessions. The 100% group practiced with feedback on 3 movement reversals of the sequence after each trial. The 14% group practiced with 14% frequency according to a fading schedule. Only the 14% group showed a decrease in dual-task costs indicating an increase in automaticity. Group differences in movement accuracy and consistency were not evident. PMID- 28644769 TI - Localization of the CAPRICE-ENHANCER OF TRY AND CPC1 chimera protein in Arabidopsis root epidermis. AB - The CAPRICE (CPC) encodes an R3-type MYB transcription factor, which promotes root-hair differentiation. Previously, we showed that the CPC protein moves from the non-hair cell to the neighboring cell and induces root-hair differentiation in Arabidopsis. In addition, we proposed two cell-to-cell movement signal sequences, S1 and S2, in CPC. However, an S1:2xGFP:S2 chimera protein did not move between root epidermal cells. Here, we show that the S1 and S2 sequences do not confer cell-to-cell movement or nuclear localization ability to a GFP protein. The ENHANCER OF TRY AND CPC1 (ETC1) gene encodes the CPC homolog R3 MYB; this protein does not possess cell-to-cell movement ability or the S1 sequence. To elucidate whether the S1 sequence can induce cell-to-cell movement ability in ETC1, CPCp:S1:ETC1:2xGFP was constructed and introduced into Arabidopsis. Our results indicate that the addition of the S1 sequence was not sufficient for ETC1 to acquire cell-to-cell movement ability. PMID- 28644770 TI - The impact of photovoltaic (PV) installations on downwind particulate matter concentrations: Results from field observations at a 550-MWAC utility-scale PV plant. AB - : With utility-scale photovoltaic (PV) projects increasingly developed in dry and dust-prone geographies with high solar insolation, there is a critical need to analyze the impacts of PV installations on the resulting particulate matter (PM) concentrations, which have environmental and health impacts. This study is the first to quantify the impact of a utility-scale PV plant on PM concentrations downwind of the project site. Background, construction, and post-construction PM2.5 and PM10 (PM with aerodynamic diameters <2.5 and <10 MUm, respectively) concentration data were collected from four beta attenuation monitor (BAM) stations over 3 yr. Based on these data, the authors evaluate the hypothesis that PM emissions from land occupied by a utility-scale PV installation are reduced after project construction through a wind-shielding effect. The results show that the (1) confidence intervals of the mean PM concentrations during construction overlap with or are lower than background concentrations for three of the four BAM stations; and (2) post-construction PM2.5 and PM10 concentrations downwind of the PV installation are significantly lower than the background concentrations at three of the four BAM stations. At the fourth BAM station, downwind post construction PM2.5 and PM10 concentrations increased marginally by 5.7% and 2.6% of the 24-hr ambient air quality standards defined by the U.S. Environmental Protection Agency, respectively, when compared with background concentrations, with the PM2.5 increase being statistically insignificant. This increase may be due to vehicular emissions from an access road near the southwest corner of the site or a drainage berm near the south station. The findings demonstrate the overall environmental benefit of downwind PM emission abatement from a utility scale PV installation in desert conditions due to wind shielding. With PM emission reductions observed within 10 months of completion of construction, post construction monitoring of downwind PM levels may be reduced to a 1-yr period for other projects with similar soil and weather conditions. IMPLICATIONS: This study is the first to analyze impact of a utility photovoltaic (PV) project on downwind particulate matter (PM) concentration in desert conditions. The PM data were collected at four beta attenuation monitor stations over a 3-yr period. The post construction PM concentrations are lower than background concentrations at three of four stations, therefore supporting the hypothesis of post-construction wind shielding from PV installations. With PM emission reductions observed within 10 months of completion of construction, postconstruction monitoring of downwind PM levels may be reduced to a 1-yr period for other PV projects with similar soil and weather conditions. PMID- 28644771 TI - Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer. AB - Purpose Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease ( P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months (95% CI, 4.1 to 7.0 months) and 1.4 months (95% CI, 1.4 to 2.7 months), respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema. Conclusion These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC. PMID- 28644772 TI - Risk Stratification for Second Primary Lung Cancer. AB - Purpose This study estimated the 10-year risk of developing second primary lung cancer (SPLC) among survivors of initial primary lung cancer (IPLC) and evaluated the clinical utility of the risk prediction model for selecting eligibility criteria for screening. Methods SEER data were used to identify a population based cohort of 20,032 participants diagnosed with IPLC between 1988 and 2003 and who survived >= 5 years after the initial diagnosis. We used a proportional subdistribution hazards model to estimate the 10-year risk of developing SPLC among survivors of lung cancer LC in the presence of competing risks. Considered predictors included age, sex, race, treatment, histology, stage, and extent of disease. We examined the risk-stratification ability of the prediction model and performed decision curve analysis to evaluate the clinical utility of the model by calculating its net benefit in varied risk thresholds for screening. Results Although the median 10-year risk of SPLC among survivors of LC was 8.36%, the estimated risk varied substantially (range, 0.56% to 14.3%) when stratified by age, histology, and extent of IPLC in the final prediction model. The stratification by deciles of estimated risk showed that the observed incidence of SPLC was significantly higher in the tenth-decile group (12.5%) versus the first decile group (2.9%; P < 10-10). The decision curve analysis yielded a range of risk thresholds (1% to 11.5%) at which the clinical net benefit of the risk model was larger than those in hypothetical all-screening or no-screening scenarios. Conclusion The risk stratification approach in SPLC can be potentially useful for identifying survivors of LC to be screened by computed tomography. More comprehensive environmental and genetic data may help enhance the predictability and stratification ability of the risk model for SPLC. PMID- 28644775 TI - How a Child With Cancer Moved From Vulnerability to Resilience. PMID- 28644773 TI - Mobilized Peripheral Blood Stem Cells Versus Unstimulated Bone Marrow As a Graft Source for T-Cell-Replete Haploidentical Donor Transplantation Using Post Transplant Cyclophosphamide. AB - Purpose T-cell-replete HLA-haploidentical donor hematopoietic transplantation using post-transplant cyclophosphamide was originally described using bone marrow (BM). With increasing use of mobilized peripheral blood (PB), we compared transplant outcomes after PB and BM transplants. Patients and Methods A total of 681 patients with hematologic malignancy who underwent transplantation in the United States between 2009 and 2014 received BM (n = 481) or PB (n = 190) grafts. Cox regression models were built to examine differences in transplant outcomes by graft type, adjusting for patient, disease, and transplant characteristics. Results Hematopoietic recovery was similar after transplantation of BM and PB (28 day neutrophil recovery, 88% v 93%, P = .07; 100-day platelet recovery, 88% v 85%, P = .33). Risks of grade 2 to 4 acute (hazard ratio [HR], 0.45; P < .001) and chronic (HR, 0.35; P < .001) graft-versus-host disease were lower with transplantation of BM compared with PB. There were no significant differences in overall survival by graft type (HR, 0.99; P = .98), with rates of 54% and 57% at 2 years after transplantation of BM and PB, respectively. There were no differences in nonrelapse mortality risks (HR, 0.92; P = .74) but relapse risks were higher after transplantation of BM (HR, 1.49; P = .009). Additional exploration confirmed that the higher relapse risks after transplantation of BM were limited to patients with leukemia (HR, 1.73; P = .002) and not lymphoma (HR, 0.87; P = .64). Conclusion PB and BM grafts are suitable for haploidentical transplantation with the post-transplant cyclophosphamide approach but with differing patterns of treatment failure. Although, to our knowledge, this is the most comprehensive comparison, these findings must be validated in a randomized prospective comparison with adequate follow-up. PMID- 28644774 TI - CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531. AB - Purpose Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO containing chemotherapy. Patients and Methods CD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children's Oncology Group AAML0531 trial. Results The rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript ( P < 1.0E-6) and with lower diagnostic leukemic cell surface CD33 intensity ( P < 1.0E-6). Patients with the CC genotype had significantly lower relapse risk in the GO arm than in the No-GO arm (26% v 49%; P < .001). However, in patients with the CT or TT genotype, exposure to GO did not influence relapse risk (39% v 40%; P = .85). Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% v 46%, respectively; P = .004), but this benefit of GO addition was not seen in patients with the CT or TT genotype. Conclusion Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to GO, making this a potential biomarker for the selection of patients with a likelihood of significant response to GO. PMID- 28644777 TI - Transitional Instability Predicts Polymorphous Distress in Emerging Adults. AB - The primary aim of this investigation is to determine the extent to which transitional instability can predict diverse markers of distress in emerging adults. Participants were 210 emerging adults, aged 18-25 who completed measures of distress that included loneliness, stress, problem drinking, and prescription medication use. One year later, they returned to complete these same measures of distress along with a measure of significant life transitions that they encountered during the past year in such domains as education, employment, residence, and relationships. Results of a structural equation modeling analysis showed that even after controlling for the potential reciprocal association between transitional instability and distress, the more transitional instability emerging adults experienced over the year, the higher their distress was at time 2. The results are consistent with models of transitional instability as a precipitant of distress in emerging adulthood. PMID- 28644776 TI - Eye Injuries in High School and Collegiate Athletes. AB - BACKGROUND: Although eye injuries constitute a small percentage of high school and college sports injuries, they have the potential to be permanently debilitating. HYPOTHESIS: Eye injury rates will vary by sport, sex, and between the high school and college age groups. STUDY DESIGN: Descriptive epidemiology study. LEVEL OF EVIDENCE: Level 3. METHODS: Data from eye injury reports in high school and college athletes were obtained from the National High School Sports Related Injury Surveillance System, High School Reporting Information Online (HS RIO) database over a 10-year span (2005-2006 through 2014-2015 school years) and the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) over an 11-year span (2004-2005 through 2014-2015 school years). Injury rates per 100,000 athlete-exposures (AEs), injury rate ratios (RRs), and 95% CIs were calculated. Distributions of eye injuries by diagnosis, mechanism, time loss, and surgery needs were also examined. RESULTS: A total of 237 and 273 eye injuries were reported in the HS RIO and the NCAA ISP databases, respectively. The sports with the highest eye injury rates (per 100,000 AEs) for combined high school and college athletes were women's basketball (2.36), women's field hockey (2.35), men's basketball (2.31), and men's wrestling (2.07). Overall eye injury rates at the high school and college levels were 0.68 and 1.84 per 100,000 AEs, respectively. Eye injury rates were higher in competition than practice in high school (RR, 3.47; 95% CI, 2.69-4.48) and college (RR, 3.13; 95% CI, 2.45-3.99). Most injuries were contusions (high school, 35.9%; college, 33.3%) and due to contact (high school, 89.9%; college, 86.4%). Only a small percentage of injuries resulted in time loss over 21 days (high school, 4.2%; college, 3.0%). CONCLUSION: Eye injury rates and patterns vary by sport, sex, and between the high school and college age groups. Although severe injuries do occur, most eye injuries sustained by high school and college athletes are minor, with limited time loss and full recovery. CLINICAL RELEVANCE: Additional focus needs to be placed on preventing eye injuries at the collegiate level in women's and men's basketball, women's field hockey, and men's wrestling. PMID- 28644778 TI - Impact of Economic Hardship and Financial Threat on Suicide Ideation and Confusion. AB - The present study tested the extent to which perceived economic hardship is associated with psychological distress (suicide ideation and confusion) after controlling for personal characteristics. It also explored whether perceived financial threat (i.e., fearful anxious-uncertainty about the stability and security of one's personal financial situation) mediates the relationship between economic hardship and psychological distress outcomes. The theoretical model was tested in a sample of Canadian students (n = 211) and was validated in a community sample of employed Portuguese adults (n = 161). In both samples, the fit of the model was good. Parameter estimates indicated that greater experience of economic hardship increased with financial threat, which in turn increased with levels of suicide ideation and confusion. We discuss the practical implications of these results, such as for programs aimed at alleviating the burden of financial hardship, in our concluding remarks. PMID- 28644779 TI - Cellular Light Scattering for the Identification of Bacteria and Its Application to the Identification of Staphylococcus. AB - Rapid identification of bacteria is critical in clinical and food safety applications. This paper describes a novel instrument and data analysis method for identifying bacteria based on the measurement of laser light scattering as the beam interacts with bacterial cells suspended in water. A description of the technology is followed by an identification performance study for a set of strains from the genus Staphylococcus (the inclusive target organisms) and a set of non-Staphylococcus strains (the exclusive organisms). Staphylococcus and non Staphylococcus cells were grown on sheep blood agar (SBA), tryptic soy agar, brain heart infusion (BHI) agar, or Luria-Bertani (LB) agar and identified based on how cells scattered light. Bacteria from the genus Staphylococcus grown on solid media were correctly identified more than 92% of the time. To determine whether the system could also identify bacteria grown in liquid culture, six different Staphylococcus strains and six different non-Staphylococcus strains were grown in tryptic soy broth, BHI broth, or LB broth. This system accurately identified all targeted Staphylococcus samples tested, and no misidentifications occurred. A single-blind identification experiment was also performed on human clinical isolates obtained from the Upper Peninsula Health System. Ninety blind coded clinical bacterial isolates on SBA were tested to determine whether they were from the genus Staphylococcus. All Staphylococcus were accurately identified, and no misidentifications occurred. This study demonstrated the proof of concept of a novel system that can rapidly and accurately identify bacteria from pure culture based on cellular light-scattering properties. PMID- 28644780 TI - Avoiding Racial Essentialism in Medical Science Curricula. AB - A wave of medical student activism is shining a spotlight on medical educators' sometimes maladroit handling of racial categories in teaching about health disparities. Coinciding with recent critiques, primarily by social scientists, regarding the imprecise and inappropriate use of race as a biological or epidemiological risk factor in genetics research, medical student activism has triggered new collaborations among students, faculty, and administrators to rethink how race is addressed in the medical curriculum. Intensifying critiques of racial essentialism are a crucial concern for educators since bioscientific knowledge grounds the authority of health professionals. Central ethical issues racial bias and social justice-cannot be properly addressed without confronting the epistemological problem of racial essentialism in bioscience teaching. Thus, educators now face an ethical imperative to improve academic capacities for robust interdisciplinary teaching about the conceptual apparatus of race and the recalibration of its use in teaching both genetics and the more pervasive and urgent social causes of health inequalities. PMID- 28644781 TI - Teaching Clinical Ethics at the Bedside: William Osler and the Essential Role of the Hospitalist. AB - As the field of hospital medicine celebrates its twenty-first anniversary, we believe it is time to expand its mission to play an even greater role in medical education. Given hospitalists' proximity to students and clinical material, members of this growing cohort of physicians are uniquely positioned to teach normative reasoning, professionalism, communication, and medical ethics in real time to trainees on the wards. But, to do so, we must reimagine the role of the hospitalist in graduate and postgraduate medical education. PMID- 28644782 TI - How Should Resident Physicians Respond to Patients' Discomfort and Students' Moral Distress When Learning Procedures in Academic Medical Settings? AB - In this scenario, a medical student, Lauren, experiences moral distress because she feels that learning to perform a procedure on a patient who requested not to be used for "practice" puts her own interests above the patient's. Lauren might also worry that the resident physician is misrepresenting her abilities. The resident physician could help alleviate Lauren's distress and align her interests with the patient's by more clearly explaining the training situation to the patient and seeking the patient's approval. Lauren might also manage the situation by assuring the patient of the resident's supervisory role. This article argues that trainees should have the opportunities to practice procedures and difficult conversations in simulated settings and that institutions should support a culture of "speaking up" to ensure patients' and learners' safety. PMID- 28644783 TI - How Should Integrity Preservation and Professional Growth Be Balanced during Trainees' Professionalization? AB - People can experience moral distress when they regard themselves as expected to pursue a course of action they believe to be morally wrong. However, beliefs that give rise to moral distress are sometimes underdeveloped. Experiences of moral distress are not uncommon for medical trainees, who are still in the process of forming their professional identities and whose identity-constituting beliefs might therefore be subject to ongoing revision. Thus, it is important for health professions training programs to incorporate case-based ethics education sessions into their structure to help identify and alleviate trainees' moral distress, provide ethics education, and create a "safe space" for trainees to talk openly about moral concerns related to clinical practice. Such opportunities are crucial to the professional growth of trainees. PMID- 28644784 TI - How Should Physicians Respond When the Best Treatment for an Individual Patient Conflicts with Practice Guidelines about the Use of a Limited Resource? AB - The case presents a physician's ethical conflict, due to limited resources, between his obligations to meet the needs of a community and those of his patient. Elements of the decision-making process (and who should make the decision) are discussed, including the limitations of what ethical reasoning can offer and risks of arbitrary outcomes. Additionally, potential benefits to physicians and their patients of discussing these conflicts, including reducing the physician's moral distress, are noted. I argue that physicians' abilities to make "right" decisions in such situations are limited, and I suggest ways in which physicians can try to preserve their relationships with patients. PMID- 28644785 TI - What Should Physicians Do When They Disagree, Clinically and Ethically, with a Surrogate's Wishes? AB - When patients' surrogates and physicians disagree about the appropriateness of aggressive treatment in intensive care units (ICUs), physicians can experience surrogates' demands as sources of moral distress. This article addresses the virtues and communication strategies needed to respond appropriately in such situations. Specifically, we offer a framework and language that rely on moral community to facilitate common ground and alleviate moral distress. PMID- 28644786 TI - Antecedents and Consequences of Medical Students' Moral Decision Making during Professionalism Dilemmas. AB - Medical students often experience professionalism dilemmas (which differ from ethical dilemmas) wherein students sometimes witness and/or participate in patient safety, dignity, and consent lapses. When faced with such dilemmas, students make moral decisions. If students' action (or inaction) runs counter to their perceived moral values-often due to organizational constraints or power hierarchies-they can suffer moral distress, burnout, or a desire to leave the profession. If moral transgressions are rationalized as being for the greater good, moral distress can decrease as dilemmas are experienced more frequently (habituation); if no learner benefit is seen, distress can increase with greater exposure to dilemmas (disturbance). We suggest how medical educators can support students' understandings of ethical dilemmas and facilitate their habits of enacting professionalism: by modeling appropriate resistance behaviors. PMID- 28644787 TI - Who Is Experiencing What Kind of Moral Distress? Distinctions for Moving from a Narrow to a Broad Definition of Moral Distress. AB - Moral distress, according to Andrew Jameton's highly influential definition, occurs when a nurse knows the morally correct action to take but is constrained in some way from taking this action. The definition of moral distress has been broadened, first, to include morally challenging situations that give rise to distress but which are not necessarily linked to nurses feeling constrained, such as those associated with moral uncertainty. Second, moral distress has been broadened so that it is not confined to the experiences of nurses. However, such a broadening of the concept does not mean that the kind of moral distress being experienced, or the role of the person experiencing it, is morally irrelevant. I argue that differentiating between categories of distress-e.g., constraint and uncertainty-and between groups of health professionals who might experience moral distress is potentially morally relevant and should influence the analysis, measurement, and amelioration of moral distress in the clinic. PMID- 28644788 TI - Initiatives for Responding to Medical Trainees' Moral Distress about End-of-Life Cases. AB - Moral distress frequently arises for medical trainees exposed to end-of-life cases. We review the small literature on best practices for reducing moral distress in such cases and propose two areas to target for moral distress reduction: medical education and organizational ethics programs. Students require training in end-of-life dialogues and truthful prognostication, which are not generally available without skilled mentors. But physician-mentors and teachers can suffer from lingering moral residue themselves, which can affect the teaching culture and student expectations. Finally, reducing unit moral distress that affects learners requires formal educational opportunities to debrief about difficult end-of-life cases and formal institutional mechanisms for effective clinical ethics consultation. PMID- 28644789 TI - What Is the Role of Ethics Consultation in the Moral Habitability of Health Care Environments? AB - Ethics consultation has traditionally focused on the provision of expert guidance to health care professionals when challenging quandaries arise in clinical cases. Its role, however, is expanding as demands on health care organizations are negatively impacting their moral habitability. A sign of this impact can be seen in the moral distress experienced by staff and administrators, such that some leave their positions and their organizations. Ethics consultation, more broadly conceived, can be a major asset in ensuring that ethical practice is meaningfully supported, that moral distress is mitigated, and that the organizational environment is morally habitable. PMID- 28644790 TI - Strategies for Promoting High-Quality Care and Personal Resilience in Palliative Care. AB - Palliative care (PC) clinicians are faced with ever-expanding pressures, which can make it difficult to fulfill their duties to self and others and lead to moral distress. Understanding the pressures that PC clinicians face and the resources that could be employed to ease their moral distress is crucial to maintaining a healthy PC workforce and to providing necessary PC services to patients. In this paper, we discuss recommendations related to two promising pathways for supporting PC clinicians in providing high-quality PC: (1) improving systemic PC delivery and (2) strategies to promote ethical practice environments and individual resilience. Enacting these recommendations holds promise for sustaining higher-quality and accessible PC and a more engaged PC workforce. PMID- 28644791 TI - Culture and Moral Distress: What's the Connection and Why Does It Matter? AB - Culture is learned behavior shared among members of a group and from generation to generation within that group. In health care work, references to "culture" may also function as code for ethical uncertainty or moral distress concerning patients, families, or populations. This paper analyzes how culture can be a factor in patient-care situations that produce moral distress. It discusses three common, problematic situations in which assumptions about culture may mask more complex problems concerning family dynamics, structural barriers to health care access, or implicit bias. We offer sets of practical recommendations to encourage learning, critical thinking, and professional reflection among students, clinicians, and clinical educators. PMID- 28644792 TI - What Moral Distress in Nursing History Could Suggest about the Future of Health Care. AB - The concept of moral distress was defined in 1984 as (a) the psychological distress of (b) being in a situation in which one is constrained from acting (c) on what one knows to be right. A substantial literature on the subject has developed, primarily in nursing ethics. The aforementioned elements of distress are applied here to areas of clinical and organizational significance: (a) distress from causing intimate pain during care of the dying, (b) constraints stemming from proximate and background challenges of health care organizations, and (c) changing perspectives on therapeutic technologies derived from global environmental perspectives. Although moral distress may be increasing in clinical settings, nursing advocates are developing positive ways to cope with it that can help clinicians in general. PMID- 28644793 TI - Dirty Laundry: Drug Formulary Exclusions. PMID- 28644794 TI - Electrocardiogram Signal Quality Assessment Based on Structural Image Similarity Metric. AB - OBJECTIVE: We developed an image-based electrocardiographic (ECG) quality assessment technique that mimics how clinicians annotate ECG signal quality. METHODS: We adopted the structural similarity measure (SSIM) to compare images of two ECG records that are obtained from displaying ECGs in a standard scale. Then, a subset of representative ECG images from the training set was selected as templates through a clustering method. SSIM between each image and all the templates were used as the feature vector for the linear discriminant analysis classifier. We also employed three commonly used ECG signal quality index (SQI) measures: baseSQI, kSQI, and sSQI to compare with the proposed image quality index (IQI) approach. We used 1926 annotated ECGs, recorded from patient monitors, and associated with six different ECG arrhythmia alarm types which were obtained previously from an ECG alarm study at the University of California, San Francisco (UCSF). In addition, we applied the templates from the UCSF database to test the SSIM approach on the publicly available PhysioNet Challenge 2011 data. RESULTS: For the UCSF database, the proposed IQI algorithm achieved an accuracy of 93.1% and outperformed all the SQI metrics, baseSQI, kSQI, and sSQI, with accuracies of 85.7%, 63.7%, and 73.8% respectively. Moreover, evaluation of our algorithm on the PhysioNet data showed an accuracy of 82.5%. CONCLUSION: The proposed algorithm showed better performance for assessing ECG signal quality than traditional signal processing methods. SIGNIFICANCE: A more accurate assessment of ECG signal quality can lead to a more robust ECG-based diagnosis of cardiovascular conditions. PMID- 28644795 TI - A Novel Short-Term Event Extraction Algorithm for Biomedical Signals. AB - In this paper, we propose a fast novel nonlinear filtering method named Relative Energy (Rel-En), for robust short-term event extraction from biomedical signals. We developed an algorithm that extracts short- and long-term energies in a signal and provides a coefficient vector with which the signal is multiplied, heightening events of interest. This algorithm is thoroughly assessed on benchmark datasets in three different biomedical applications, namely ECG QRS complex detection, EEG K-complex detection, and imaging photoplethysmography (iPPG) peak detection. Rel-En successfully identified the events in these settings. Compared to the state-of-the-art, better or comparable results were obtained on QRS-complex and K-complex detection. For iPPG peak detection, the proposed method was used as a preprocessing step to a fixed threshold algorithm that lead to a significant improvement in overall results. While easily defined and computed, Rel-En robustly extracted short-term events of interest. The proposed algorithm can be implemented by two filters and its parameters can be selected easily and intuitively. Furthermore, Rel-En algorithm can be used in other biomedical signal processing applications where a need of short-term event extraction is present. PMID- 28644797 TI - Spatiotemporal GMM for Background Subtraction with Superpixel Hierarchy. AB - We propose a background subtraction algorithm using hierarchical superpixel segmentation, spanning trees and optical flow. First, we generate superpixel segmentation trees using a number of Gaussian Mixture Models (GMMs) by treating each GMM as one vertex to construct spanning trees. Next, we use the -smoother to enhance the spatial consistency on the spanning trees and estimate optical flow to extend the -smoother to the temporal domain. Experimental results on synthetic and real-world benchmark datasets show that the proposed algorithm performs favorably for background subtraction in videos against the state-of-the-art methods in spite of frequent and sudden changes of pixel values. PMID- 28644796 TI - Design of an Autonomous Social Orienting Training System (ASOTS) for Young Children With Autism. AB - Social communication is among the core areas of impairment for children with Autism Spectrum Disorders (ASD). The training of social orientation is important for improving social communication of children with ASD. In recent years, technology-assisted ASD intervention had gained momentum due to its potential advantages in terms of precision, sustainability, flexibility and cost. In this paper, we propose a closed-loop autonomous computer system, named ASOTS, for training social orientation skills to young children with ASD. This system is designed to detect and track a child's attention in response to social orientation bids and help the child towards appropriate social orientation when needed. Response to name, an important social orientation skill, was used to demonstrate the functionality of the proposed system. Ten toddlers with ASD participated in a pilot user study to show whether the system could be used on young children who have been diagnosed with ASD. Another pilot user study with 10 TD infants tested whether this system has a potential to be applied for early detection for infants who were younger than the age when ASD diagnoses can be done. This was done intentionally to separately demonstrate utility and functionality for the clinical population of interest and to demonstrate functionality beyond current clinical identification capacity (i.e., infants). The results showed that the proposed system and the protocol were well tolerated by both groups, successfully captured young children's attention, and elicited the desired behavior. PMID- 28644798 TI - Joint Alignment of Multiple Point Sets with Batch and Incremental Expectation Maximization. AB - This paper addresses the problem of registering multiple point sets. Solutions to this problem are often approximated by repeatedly solving for pairwise registration, which results in an uneven treatment of the sets forming a pair: a model set and a data set. The main drawback of this strategy is that the model set may contain noise and outliers, which negatively affects the estimation of the registration parameters. In contrast, the proposed formulation treats all the point sets on an equal footing. Indeed, all the points are drawn from a central Gaussian mixture, hence the registration is cast into a clustering problem. We formally derive batch and incremental EM algorithms that robustly estimate both the GMM parameters and the rotations and translations that optimally align the sets. Moreover, the mixture's means play the role of the registered set of points while the variances provide rich information about the contribution of each component to the alignment. We thoroughly test the proposed algorithms on simulated data and on challenging real data collected with range sensors. We compare them with several state-of-the-art algorithms, and we show their potential for surface reconstruction from depth data. PMID- 28644799 TI - Hybrid CS-DMRI: Periodic Time-Variant Subsampling and Omnidirectional Total Variation Based Reconstruction. AB - Compressive sensing (CS) has been used to accelerate dynamic magnetic resonance imaging (DMRI). Currently, the online CS-DMRI is faster, whereas the offline CS DMRI provides higher accuracy for image reconstruction. To achieve good image reconstruction performance in terms of both speed and accuracy, we propose a hybrid CS-DMRI method using periodic time-variant subsampling for different frames. In each period, there is one reference frame that is sampled at a higher subsampling ratio. The two nearby reference frames with good reconstruction quality can be used to provide rough predictions of the other frames between them. To finely recover the current frame, one structural regularization in the optimization model for reconstruction is a 2-D omnidirectional total variation (OTV) for exploiting the sparsity of the difference between the predicted and estimated frames, and the other is a 3-D OTV as a regularization term for exploiting the bilateral spatio-temporal coherence between the forward reference frame, current frame, and backward reference frame. Compared with classical total variation, the proposed OTV fully utilizes the correlations of all the possible directions of the data. The formulated optimization model can be solved using iterative reweighted least squares with the pre-conditioned conjugate gradient method. Numerical experiments demonstrate that the proposed method has better reconstruction accuracy than all the existing methods and low computational complexity that is comparable to the existing online methods. PMID- 28644800 TI - Online Combination of EPID & Cherenkov Imaging for 3-D Dosimetry in a Liquid Phantom. AB - Online acquisition of Cherenkov and portal imaging data was combined with a reconstruction scheme called EC3-D, providing a full 3-D dosimetry of megavoltage X-ray beams in a water tank. The methodology was demonstrated and quantified in a single static beam. Furthermore, the dynamics and visualization of the 3-D dose reconstruction were demonstrated with a volumetric modulated arc therapy plan for TG-119 C-Shape geometry. The developed algorithm combines depth dose information, provided by Cherenkov images, with the lateral dose distribution, provided by the electronic portal imaging device. The strength of our approach lies in the acquisition of both imaging data streams with sub-millimeter theoretical resolution at 5-Hz frame-rate, which can be concurrently processed by the fast Fourier transform-based analysis, thus providing means for an efficient real-time 3-D dosimetry. PMID- 28644801 TI - Magnetic Particle Imaging for Quantification of Vascular Stenoses: A Phantom Study. AB - Magnetic particle imaging (MPI) is a promising new tomographic imaging method to detect the spatial distribution of superparamagnetic iron-oxide nanoparticles (SPIOs). The aim of this paper was to investigate the potential of MPI to quantify artificial stenoses in vessel phantoms. Custom-made stenosis phantoms (length 40 mm; inner diameter 8 mm) with different degrees of stenosis (0%, 25%, 50%, 75%, and 100%) were scanned in a custom-built MPI scanner (in-plane resolution: ~1-1.5 mm and field of view: 65 29 29 mm3). Phantoms were filled with diluted Feru-carbotran [SPIO agent, 5 mmol (Fe)/l]. Each measurement (overall acquisition time: 20 ms per image, 400 averages) was repeated ten times to assess reproducibility. The MPI signal was used for semi-automatic stenosis quantification. Two stenosis evaluation approaches were compared based on the signal intensity profile alongside the stenosis phantoms. Using a novel multi step image evaluation approach, MPI allowed for accurate quantification of different stenosis grades. While low grade stenoses were slightly over-estimated, high grade stenoses were slightly underestimated. In particular, the 0%, 25%, and 50% stenosis phantoms revealed a 6.2% +/- 0.8, 25.7% +/- 1.0, and 48.0% +/- 1.5 stenosis, respectively. The higher grade 75% stenosis phantom revealed a 73.3% +/ 2.8 and the 100% stenosis phantom a 95.8%+/- 1.9 stenosis. MPI accurately visualized and quantified different stenosis grades in vessel phantoms with high reproducibility demonstrating its great potential for fast and radiation-free preclinical cardiovascular imaging. PMID- 28644802 TI - Fully Nonlinear ${SP}_{3}$ Approximation Based Fluorescence Optical Tomography. AB - In fluorescence optical tomography, many works in the literature focus on the linear reconstruction problem to obtain the fluorescent yield or the linearized reconstruction problem to obtain the absorption coefficient. The nonlinear reconstruction problem, to reconstruct the fluorophore absorption coefficient, is of interest in imaging studies as it presents the possibility of better reconstructions owing to a more appropriate model. Accurate and computationally efficient forward models are also critical in the reconstruction process. The approximation to the radiative transfer equation (RTE) is gaining importance for tomographic reconstructions owing to its computational advantages over the full RTE while being more accurate and applicable than the commonly used diffusion approximation. This paper presents Gauss-Newton-based fully nonlinear reconstruction for the approximated fluorescence optical tomography problem with respect to shape as well as the conventional finite-element method-based representations. The contribution of this paper is the Frechet derivative calculations for this problem and demonstration of reconstructions in both representations. For the shape reconstructions, radial-basis-function represented level-set-based shape representations are used. We present reconstructions for tumor-mimicking test objects in scattering and absorption dominant settings, respectively, for moderately noisy data sets in order to demonstrate the viability of the formulation. Comparisons are presented between the nonlinear and linearized reconstruction schemes in an element wise setting to illustrate the benefits of using the former especially for absorption dominant media. PMID- 28644804 TI - Global Time-Delay Estimation in Ultrasound Elastography. AB - A critical step in quasi-static ultrasound elastography is the estimation of time delay between two frames of radio-frequency (RF) data that are obtained while the tissue is undergoing deformation. This paper presents a novel technique for time delay estimation (TDE) of all samples of RF data simultaneously, thereby exploiting all the information in RF data for TDE. A nonlinear cost function that incorporates similarity of RF data intensity and prior information of displacement continuity is formulated. Optimization of this function involves searching for TDE of all samples of the RF data, rendering the optimization intractable with conventional techniques given that the number of variables can be approximately one million. Therefore, the optimization problem is converted to a sparse linear system of equations, and is solved in real time using a computationally efficient optimization technique. We call our method GLobal Ultrasound Elastography (GLUE), and compare it to dynamic programming analytic minimization (DPAM) and normalized cross correlation (NCC) techniques. Our simulation results show that the contrast-to-noise ratio (CNR) values of the axial strain maps are 4.94 for NCC, 14.62 for DPAM, and 26.31 for GLUE. Our results on experimental data from tissue mimicking phantoms show that the CNR values of the axial strain maps are 1.07 for NCC, 16.01 for DPAM, and 18.21 for GLUE. Finally, our results on in vivo data show that the CNR values of the axial strain maps are 3.56 for DPAM and 13.20 for GLUE. PMID- 28644803 TI - Cardiac Strain Imaging With Coherent Compounding of Diverging Waves. AB - Current methods of cardiac strain imaging at high frame rate suffer from motion matching artifacts or poor lateral resolution. Coherent compounding has been shown to improve echocardiographic image quality while maintaining a high frame rate, but has never been used to image cardiac strain. However, myocardial velocity can have an impact on coherent compounding due to displacements between frames. The objective of this paper was to investigate the feasibility and performance of coherent compounding for cardiac strain imaging at a low and a high myocardial velocity. Left-ventricular contraction in short-axis view was modeled as an annulus with radial thickening and circumferential rotation. Simulated radio-frequency channel data with a cardiac phased array were obtained using three different beamforming methods: single diverging wave, coherent compounding of diverging waves, and conventional focusing. Axial and lateral displacements and strains as well as radial strains were estimated and compared to their true value. In vivo feasibility of cardiac strain imaging with coherent compounding was performed and compared to single diverging wave imaging. At low myocardial velocities, the axial, lateral, and radial strain relative error for nine compounded waves (16.3%, 40.4%, and 18.9%) were significantly lower than those obtained with single diverging wave imaging (19.9%, 80.3%, and 30.6%) and closer to that obtained with conventional focusing (16.7%, 43.7%, and 16%). In vivo left-ventricular radial strains exhibited higher quality with nine compounded waves than with single diverging wave imaging. These results indicate that cardiac strain can be imaged using coherent compounding of diverging waves with a better performance than with single diverging wave imaging while maintaining a high frame rate, and therefore, has the potential to improve diagnosis of myocardial strain-based cardiac diseases. PMID- 28644805 TI - Development of Real-Time 3-D Photoacoustic Imaging System Employing Spherically Curved Array Transducer. AB - Photoacoustic (PA) imaging is a promising imaging modality to visualize specific living tissues based on the light absorption coefficients without dyeing. In this paper, a real-time PA imaging system with a tunable laser was newly developed with an originally designed spherically curved array transducer. Five different series of experiments were conducted to validate the PA measurement system. The peak frequency of the transducer response was 17.7 MHz, and a volume-imaging rate of 3-D volume imaging was 10-20 volumes per second. The spatial resolution of imaging was 90- [Formula: see text] along both the axial and lateral directions. The developed imaging system could measure a difference on an absorption coefficient of gold nanorods. Additionally, the PA imaging could visualize the in vivo microvasculatures of a human hand. This PA imaging system with higher spatial-temporal resolution and the tunable laser further should enhance our understanding of not only basic properties of the photo acoustics but also clinical applications. PMID- 28644806 TI - Discriminative Deep Metric Learning for Face and Kinship Verification. AB - This paper presents a new discriminative deep metric learning (DDML) method for face and kinship verification in wild conditions. While metric learning has achieved reasonably good performance in face and kinship verification, most existing metric learning methods aim to learn a single Mahalanobis distance metric to maximize the inter-class variations and minimize the intra-class variations, which cannot capture the nonlinear manifold where face images usually lie on. To address this, we propose a DDML method to train a deep neural network to learn a set of hierarchical nonlinear transformations to project face pairs into the same latent feature space, under which the distance of each positive pair is reduced and that of each negative pair is enlarged. To better use the commonality of multiple feature descriptors to make all the features more robust for face and kinship verification, we develop a discriminative deep multi-metric learning method to jointly learn multiple neural networks, under which the correlation of different features of each sample is maximized, and the distance of each positive pair is reduced and that of each negative pair is enlarged. Extensive experimental results show that our proposed methods achieve the acceptable results in both face and kinship verification. PMID- 28644807 TI - Depth Image Inpainting: Improving Low Rank Matrix Completion With Low Gradient Regularization. AB - We address the task of single depth image inpainting. Without the corresponding color images, previous or next frames, depth image inpainting is quite challenging. One natural solution is to regard the image as a matrix and adopt the low rank regularization just as color image inpainting. However, the low rank assumption does not make full use of the properties of depth images. A shallow observation inspires us to penalize the nonzero gradients by sparse gradient regularization. However, statistics show that though most pixels have zero gradients, there is still a non-ignorable part of pixels, whose gradients are small but nonzero. Based on this property of depth images, we propose a low gradient regularization method in which we reduce the penalty for small gradients while penalizing the nonzero gradients to allow for gradual depth changes. The proposed low gradient regularization is integrated with the low rank regularization into the low rank low gradient approach for depth image inpainting. We compare our proposed low gradient regularization with the sparse gradient regularization. The experimental results show the effectiveness of our proposed approach. PMID- 28644808 TI - ESIM: Edge Similarity for Screen Content Image Quality Assessment. AB - In this paper, an accurate full-reference image quality assessment (IQA) model developed for assessing screen content images (SCIs), called the edge similarity (ESIM), is proposed. It is inspired by the fact that the human visual system (HVS) is highly sensitive to edges that are often encountered in SCIs; therefore, essential edge features are extracted and exploited for conducting IQA for the SCIs. The key novelty of the proposed ESIM lies in the extraction and use of three salient edge features-i.e., edge contrast, edge width, and edge direction. The first two attributes are simultaneously generated from the input SCI based on a parametric edge model, while the last one is derived directly from the input SCI. The extraction of these three features will be performed for the reference SCI and the distorted SCI, individually. The degree of similarity measured for each above-mentioned edge attribute is then computed independently, followed by combining them together using our proposed edge-width pooling strategy to generate the final ESIM score. To conduct the performance evaluation of our proposed ESIM model, a new and the largest SCI database (denoted as SCID) is established in our work and made to the public for download. Our database contains 1800 distorted SCIs that are generated from 40 reference SCIs. For each SCI, nine distortion types are investigated, and five degradation levels are produced for each distortion type. Extensive simulation results have clearly shown that the proposed ESIM model is more consistent with the perception of the HVS on the evaluation of distorted SCIs than the multiple state-of-the-art IQA methods. PMID- 28644809 TI - Structured Kernel Dictionary Learning With Correlation Constraint for Object Recognition. AB - In this paper, we propose a new discriminative non-linear dictionary learning approach, called correlation constrained structured kernel KSVD, for object recognition. The objective function for dictionary learning contains a reconstructive term and a discriminative term. In the reconstructive term, signals are implicitly non-linearly mapped into a space, where a structured kernel dictionary, each sub-dictionary of which lies in the span of the mapped signals from the corresponding class, is established. In the discriminative term, by analyzing the classification mechanism, the correlation constraint is proposed in kernel form, constraining the correlations between different discriminative codes, and restricting the coefficient vectors to be transformed into a feature space, where the features are highly correlated inner-class and nearly independent between-classes. The objective function is optimized by the proposed structured kernel KSVD. During the classification stage, the specific form of the discriminative feature is needless to be known, while the inner product of the discriminative feature with kernel matrix embedded is available, and is suitable for a linear SVM classifier. Experimental results demonstrate that the proposed approach outperforms many state-of-the-art dictionary learning approaches for face, scene, and synthetic aperture radar vehicle target recognition. PMID- 28644810 TI - Action Recognition Using 3D Histograms of Texture and A Multi-Class Boosting Classifier. AB - Human action recognition is an important yet challenging task. This paper presents a low-cost descriptor called 3D histograms of texture (3DHoTs) to extract discriminant features from a sequence of depth maps. 3DHoTs are derived from projecting depth frames onto three orthogonal Cartesian planes, i.e., the frontal, side, and top planes, and thus compactly characterize the salient information of a specific action, on which texture features are calculated to represent the action. Besides this fast feature descriptor, a new multi-class boosting classifier (MBC) is also proposed to efficiently exploit different kinds of features in a unified framework for action classification. Compared with the existing boosting frameworks, we add a new multi-class constraint into the objective function, which helps to maintain a better margin distribution by maximizing the mean of margin, whereas still minimizing the variance of margin. Experiments on the MSRAction3D, MSRGesture3D, MSRActivity3D, and UTD-MHAD data sets demonstrate that the proposed system combining 3DHoTs and MBC is superior to the state of the art. PMID- 28644812 TI - A Self-Adaptive Capacitive Compensation Technique for Body Channel Communication. AB - In wireless body area network, capacitive-coupling body channel communication (CC BCC) has the potential to attain better energy efficiency over conventional wireless communication schemes. The CC-BCC scheme utilizes the human body as the forward signal transmission medium, reducing the path loss in wireless body centric communications. However, the backward path is formed by the coupling capacitance between the ground electrodes (GEs) of transmitter (Tx) and receiver (Rx), which increases the path loss and results in a body posture dependent backward impedance. Conventional methods use a fixed inductor to resonate with the backward capacitor to compensate the path loss, while it's not effective in compensating the variable backward impedance induced by the body movements. In this paper, we propose a self-adaptive capacitive compensation (SACC) technique to address such a problem. A backward distance detector is introduced to estimate the distance between two GEs of Tx and Rx, and a backward capacitance model is built to calculate the backward capacitance. The calculated backward capacitance at varying body posture is compensated by a digitally controlled tunable inductor (DCTI). The proposed SACC technique is validated by a prototype CC-BCC system, and measurements are taken on human subjects. The measurement results show that 9dB-16 dB channel enhancement can be achieved at a backward path distance of 1 cm 10 cm. PMID- 28644813 TI - Sufficient Condition for the Existence of the Compact Set in the RBF Neural Network Control. AB - In this brief, sufficient conditions are proposed for the existence of the compact sets in the neural network controls. First, we point out that the existence of the compact set in a classical neural network control scheme is unsolved and its result is incomplete. Next, as a simple case, we derive the sufficient condition of the existence of the compact set for the neural network control of first-order systems. Finally, we propose the sufficient condition of the existence of the compact set for the neural-network-based backstepping control of high-order nonlinear systems. The theoretic result is illustrated through a simulation example. PMID- 28644811 TI - Applying Pattern Recognition to High-Resolution Images to Determine Cellular Signaling Status. AB - Two frequently used tools to acquire high- resolution images of cells are scanning electron microscopy (SEM) and atomic force microscopy (AFM). The former provides a nanometer resolution view of cellular features rapidly and with high throughput, while the latter enables visualizing hydrated and living cells. In current practice, these images are viewed by eye to determine cellular status, e.g., activated versus resting. Automatic and quantitative data analysis is lacking. This paper develops an algorithm of pattern recognition that works very effectively for AFM and SEM images. Using rat basophilic leukemia cells, our approach creates a support vector machine to automatically classify resting and activated cells. Ten-fold cross-validation with cells that are known to be activated or resting gives a good estimate of the generalized classification results. The pattern recognition of AFM images achieves 100% accuracy, while SEM reaches 95.4% for our images as well as images published in prior literature. This outcome suggests that our methodology could become an important and frequently used tool for researchers utilizing AFM and SEM for structural characterization as well as determining cellular signaling status and function. PMID- 28644814 TI - Learning Multimodal Parameters: A Bare-Bones Niching Differential Evolution Approach. AB - Most learning methods contain optimization as a substep, where the nondifferentiability and multimodality of objectives push forward the interplay of evolutionary optimization algorithms and machine learning models. The recently emerged evolutionary multimodal optimization (MMOP) technique enables the learning of diverse sets of effective parameters for the models simultaneously, providing new opportunities to the applications requiring both accuracy and diversity, such as ensemble, interactive, and interpretive learning. Targeting at locating multiple optima simultaneously in the multimodal landscape, this paper develops an efficient neighborhood-based niching algorithm. Bare-bones differential evolution is used as the baseline. Further, using Gaussian mutation with local mean and standard deviations, the neighborhoods capture niches that match well with the contours of peaks in the landscape. To increase diversity and enhance global exploration, the proposed algorithm embeds a diversity preserving operator to reinitialize converged or overlapped neighborhoods. The experimental results verify that the proposed algorithm has superior and consistent performance for a wide range of MMOP problems. Further, the algorithm has been successfully applied to train neural network ensembles, which validates its effectiveness and benefits of learning multimodal parameters. PMID- 28644815 TI - Landmark Image Retrieval by Jointing Feature Refinement and Multimodal Classifier Learning. AB - Landmark retrieval is to return a set of images with their landmarks similar to those of the query images. Existing studies on landmark retrieval focus on exploiting the geometries of landmarks for visual similarity matches. However, the visual content of social images is of large diversity in many landmarks, and also some images share common patterns over different landmarks. On the other side, it has been observed that social images usually contain multimodal contents, i.e., visual content and text tags, and each landmark has the unique characteristic of both visual content and text content. Therefore, the approaches based on similarity matching may not be effective in this environment. In this paper, we investigate whether the geographical correlation among the visual content and the text content could be exploited for landmark retrieval. In particular, we propose an effective multimodal landmark classification paradigm to leverage the multimodal contents of social image for landmark retrieval, which integrates feature refinement and landmark classifier with multimodal contents by a joint model. The geo-tagged images are automatically labeled for classifier learning. Visual features are refined based on low rank matrix recovery, and multimodal classification combined with group sparse is learned from the automatically labeled images. Finally, candidate images are ranked by combining classification result and semantic consistence measuring between the visual content and text content. Experiments on real-world datasets demonstrate the superiority of the proposed approach as compared to existing methods. PMID- 28644816 TI - Fast and Accurate Poisson Denoising With Trainable Nonlinear Diffusion. AB - The degradation of the acquired signal by Poisson noise is a common problem for various imaging applications, such as medical imaging, night vision, and microscopy. Up to now, many state-of-the-art Poisson denoising techniques mainly concentrate on achieving utmost performance, with little consideration for the computation efficiency. Therefore, in this paper we aim to propose an efficient Poisson denoising model with both high computational efficiency and recovery quality. To this end, we exploit the newly developed trainable nonlinear reaction diffusion (TNRD) model which has proven an extremely fast image restoration approach with performance surpassing recent state-of-the-arts. However, the straightforward direct gradient descent employed in the original TNRD-based denoising task is not applicable in this paper. To solve this problem, we resort to the proximal gradient descent method. We retrain the model parameters, including the linear filters and influence functions by taking into account the Poisson noise statistics, and end up with a well-trained nonlinear diffusion model specialized for Poisson denoising. The trained model provides strongly competitive results against state-of-the-art approaches, meanwhile bearing the properties of simple structure and high efficiency. Furthermore, our proposed model comes along with an additional advantage, that the diffusion process is well-suited for parallel computation on graphics processing units (GPUs). For images of size , our GPU implementation takes less than 0.1 s to produce state-of the-art Poisson denoising performance. PMID- 28644817 TI - Graphene-based humidity sensors: the origin of alternating resistance change. AB - The response of a graphene-based humidity sensor is considered as a function of film structures. Analysis of the resistance changes due to water molecule adsorption on the graphene or multi-layer graphene (MLG) surface is performed for films with different structures and resistivities from hundreds of ohms/sq to hundreds of kilo-ohms/sq. The results revealed possible increase, decrease and non-monotonous behavior of resistance with changes in film structure. Adsorption of water molecules at grain boundary defects is assumed to lead to an increase in film resistivity due to the donor property of water and the p-type conductivity of graphene. Another type of conductive center with a higher capture cross section is realized in the case of water molecule adsorption at edge defects in MLG films (the formation of conductive chains with ionic conductivity). If these chains form a continuous network the film resistivity decreases. The result of the competition between the opposite effects of the conductivity compensation and formation of the water-based conductive chains depends on the film structure and determines the response of humidity sensors. Sensor sensitivity is found to increase when only one type of defect determines water adsorption (edge defects or grain boundary defects). PMID- 28644818 TI - Fabrication and optical properties of nanostructured plasmonic Al2O3/Au Al2O3/Al2O3 metamaterials. AB - Discontinuous multilayer (DML) thin films, which consist of nano-granular metals (NGMs) embedded in a dielectric matrix, have attracted significant interest as engineered plasmonic metamaterials. In this study, a systematic layer-by-layer deposition of three-dimensional sub-wavelength periodic plasmonic DML structures via the radio frequency sputtering of a composite target has been reported. The overall optical response of the DML films composed of Au-Al2O3 NGM homogenous layers, which are periodically sandwiched between two amorphous Al2O3 layers, are studied using reflection spectroscopic ellipsometry and transmission spectroscopy techniques. By applying the analytical optical approaches based on multiple Gaussian oscillators, ambient DML sub-wavelength structures have been successfully modeled. As a result, the effects of the size and shape of the Au nanoparticles as well as of the surrounding and interfacial media on their localized surface plasmon resonance (LSPR) are elucidated, and the related films thickness and effective optical constants are determined. Interestingly, during the examination of resonance frequencies and dielectric functions, the obtained DML structures exhibit unusual characteristics that are different from those of their NGM constituents due to the electromagnetic interactions of the NGM layers with the LSPR, which represent metamaterial features. PMID- 28644819 TI - Quantifying the accuracy and precision of a novel real-time 6 degree-of-freedom kilovoltage intrafraction monitoring (KIM) target tracking system. AB - Target rotation can considerably impact the delivered radiotherapy dose depending on the tumour shape. More accurate tumour pose during radiotherapy treatment can be acquired through tracking in 6 degrees-of-freedom (6 DoF) rather than in translation only. A novel real-time 6 DoF kilovoltage intrafraction monitoring (KIM) target tracking system has recently been developed. In this study, we experimentally evaluated the accuracy and precision of the 6 DoF KIM implementation. Real-time 6 DoF KIM motion measurements were compared against the ground truth motion retrospectively derived from kV/MV triangulation for a range of lung and prostate tumour motion trajectories as well as for various static poses using a phantom. The accuracy and precision of 6 DoF KIM were calculated as the mean and standard deviation of the differences between KIM and kV/MV triangulation for each DoF, respectively. We found that KIM is able to provide 6 DoF motion with sub-degree and sub-millimetre accuracy and precision for a range of realistic tumour motion. PMID- 28644820 TI - Investigation of real tissue water equivalent path lengths using an efficient dose extinction method. AB - For proton therapy, an accurate conversion of CT HU to relative stopping power (RSP) is essential. Validation of the conversion based on real tissue samples is more direct than the current practice solely based on tissue substitutes and can potentially address variations over the population. Based on a novel dose extinction method, we measured water equivalent path lengths (WEPL) on animal tissue samples to evaluate the accuracy of CT HU to RSP conversion and potential variations over a population. A broad proton beam delivered a spread out Bragg peak to the samples sandwiched between a water tank and a 2D ion-chamber detector. WEPLs of the samples were determined from the transmission dose profiles measured as a function of the water level in the tank. Tissue substitute inserts and Lucite blocks with known WEPLs were used to validate the accuracy. A large number of real tissue samples were measured. Variations of WEPL over different batches of tissue samples were also investigated. The measured WEPLs were compared with those computed from CT scans with the Stoichiometric calibration method. WEPLs were determined within +/-0.5% percentage deviation (% std/mean) and +/-0.5% error for most of the tissue surrogate inserts and the calibration blocks. For biological tissue samples, percentage deviations were within +/-0.3%. No considerable difference (<1%) in WEPL was observed for the same type of tissue from different sources. The differences between measured WEPLs and those calculated from CT were within 1%, except for some bony tissues. Depending on the sample size, each dose extinction measurement took around 5 min to produce ~1000 WEPL values to be compared with calculations. This dose extinction system measures WEPL efficiently and accurately, which allows the validation of CT HU to RSP conversions based on the WEPL measured for a large number of samples and real tissues. PMID- 28644821 TI - Zirconium oxocluster/polymer hybrid nanoparticles prepared by photoactivated miniemulsion copolymerization. AB - The photoactivated free radical miniemulsion copolymerization of methyl methacrylate (MMA) and the zirconium oxocluster Zr4O2(methacrylate)12 is used as an effective and fast preparation method for polymer/inorganic hybrid nanoparticles. The oxoclusters, covalently anchored to the polymer network, act as metal-organic cross-linkers, thus improving the thermomechanical properties of the resulting hybrid nanoparticles. Benzoin carbonyl organic compounds were used as photoinitiators. The obtained materials are compared in terms of cross linking, effectiveness of cluster incorporation, and size distribution with the analogous nanoparticles produced by using conventional thermally induced free radical miniemulsion copolymerization. The kinetics of the polymerization process in the absence and in the presence of the oxocluster is also investigated. PMID- 28644822 TI - The effect of a lay-led, group-based self-management program for patients with chronic pain: a randomized controlled trial of the Danish version of the Chronic Pain Self-Management Programme. AB - The Stanford Chronic Pain Self-Management Programme (CPSMP) consists of 6 21/2 hour weekly workshops focusing on how to manage pain in daily life. The workshops are facilitated by 2 workshop leaders of whom at least 1 must suffer from a long term pain condition. The program is highly structured and manualized. Only few controlled trials testing the effect of CPSMP exist. Enrolled in the study were 424 adults from 19 Danish municipalities, (72% women; age: 25-93 years) with pain of any etiology and great variation in pain history (0-50 yrs). Of these, 216 were randomized to a lay-led version of the CPSMP. The primary outcome was pain related disability. Secondary outcomes were pain, pain catastrophizing, self efficacy, emotional distress, physical symptoms, and illness worry. Outcomes were measured before randomization, immediately after the CPSMP (response rate: 94%), and at 3-month follow-up (response rate: 92%). National register data on health expenditure were obtained to examine effects on health care use. ClinicalTrials.gov Identifier: NCT01306747. The CPSMP had no effect on the primary outcome pain-related disability or on health expenditure during intervention and follow-up period. Small positive effects on emotional distress and illness worry 3 months after CPSMP were observed. Lay-led CPSMP is not recommended as treatment for chronic pain-related disability. This heterogeneous group of patients with pain did not benefit from the CPSMP except for a small, but clinically insignificant improvement in psychological well-being. PMID- 28644823 TI - EEG Characteristics in Cooled and Rewarmed Periods in Post-cardiac Arrest Therapeutic Hypothermia Patients. AB - PURPOSE: Continuous video EEG is a tool to assess brain function in injuries, including cardiac arrest (CA). In post-CA therapeutic hypothermia (TH) studies, some EEG features are linked to poor prognosis, but the evolvement of EEG characteristics during two temperature phases and its significance is unclear. We systematically analyzed EEG characteristics in cooled and rewarmed phases of post CA therapeutic hypothermia patients and investigated their correlation to patient outcome. METHODS: This is a retrospective study of EEG analyses, from a single academic center, of 20 patients who underwent CA and therapeutic hypothermia. For each patient, three 30-minute EEG segments in cooled and rewarmed phases were analyzed for continuity, frequency, interictal epileptiform discharges, and seizures. Mortality at the time of discharge was used as outcome. RESULTS: Rewarming was associated with the emergence of interictal epileptiform discharges, 2.6 times as likely compared with the cooled period (P = 0.03), and was not affected by systemic factors. Continuity, frequency, and discrete seizures were unaffected by temperature and did not show variance within each temperature phase. There was a trend toward the emergence of interictal epileptiform discharges upon rewarming and mortality, but it was not statistically significant. CONCLUSIONS: Increased interictal epileptiform discharges with rewarming in post-CA therapeutic hypothermia patients may suggest poor prognosis, but a larger scale prospective study is needed. PMID- 28644824 TI - Mechanism Underlying Acupuncture-Ameliorated Depressive Behaviors by Enhancing Glial Glutamate Transporter in Chronic Unpredictable Mild Stress (CUMS) Rats. AB - BACKGROUND Major depressive disorder (MDD) is a recurrent mental illness worldwide. The glutamatergic neurotransmission system is now a target for antidepressant therapy because it takes part in synaptic plasticity and cognition in physical condition and has a potential excitatory neurotoxicity in pathological conditions. Glial glutamate transporter EAAT2 performs 90% of Glu neurotransmission. Therefore, the aim of the study was to evaluate the effect of acupuncture on depressive behaviors and EAAT2 in CUMS. MATERIAL AND METHODS We randomly divided 56 male SD rats into a normal group, a model group, an acupuncture group, and a riluzole group. Rats in the model group, acupuncture group, and riluzole group underwent chronic unpredictable mild stress (CUMS) exposure for 21 days. The acupuncture group received electro-acupuncture stimulation on LI4 and LR3 for 5 continuous days per week for 4 weeks, and rats in the riluzole group received 4 mg/kg of riluzole orally (Sanofi, J20140092) for 4 weeks after undergoing CUMS stimulation. RESULTS Rats showed significantly increased sucrose consumption in the sucrose preference test paradigm, and showed elevated food intake and shortened latency in the novelty-suppressed feeding test paradigm after undergoing acupuncture therapy and riluzole treatment. The amelioration of depressive behavioral actions was consistent with increasing number of positive cells, protein, and mRNA expression of glial glutamate transporter EAAT2 in the hippocampus and PFC. CONCLUSIONS The results suggest that acupuncture and riluzole are both effective in improving sucrose consumption, latency, and food intake in CUMS rats. However, acupuncture appears to achieve an antidepressant effect later than riluzole does because it might need accumulated stimulation by enhancing EAAT2 expression. Enhance glial glutamate transporter EAAT2 in the hippocampus and PFC is a mechanism underlying the antidepressant effect of acupuncture. PMID- 28644826 TI - Is there a relation between public investment and the prevention of metaxenic diseases in the North of Peru? PMID- 28644825 TI - Neuro-Behcet's disease in Peru: a case report and literature review. AB - Behcet's disease is a vasculitis that can cause inflammatory lesions in multiple organs or systems including the nervous system. Most cases worldwide have been reported along what is called the "Silk Route" from the Mediterranean region to Japan, so it is considered a rare disease in Latin American countries. The frequency of neurological involvement ranges from 5 to 13%. We present the case of a young adult woman with diagnostic criteria for Behcet's disease and manifestations of neurological disease, as well as a review of the literature. PMID- 28644827 TI - What drives cooperative breeding? AB - Cooperative breeding, in which more than a pair of conspecifics cooperate to raise young at a single nest or brood, is widespread among vertebrates but highly variable in its geographic distribution. Particularly vexing has been identifying the ecological correlates of this phenomenon, which has been suggested to be favored in populations inhabiting both relatively stable, productive environments and in populations living under highly variable and unpredictable conditions. Griesser et al. provide a novel approach to this problem, performing a phylogenetic analysis indicating that family living is an intermediate step between nonsocial and cooperative breeding birds. They then examine the ecological and climatic conditions associated with these different social systems, concluding that cooperative breeding emerges when family living is favored in highly productive environments, followed secondarily by selection for cooperative breeding when environmental conditions deteriorate and within-year variability increases. Combined with recent work addressing the fitness consequences of cooperative breeding, Griesser et al.'s contribution stands to move the field forward by demonstrating that the evolution of complex adaptations such as cooperative breeding may only be understood when each of the steps leading to it are identified and carefully integrated. PMID- 28644828 TI - A mutant of Chlamydomonas without LHCSR maintains high rates of photosynthesis, but has reduced cell division rates in sinusoidal light conditions. AB - The LHCSR protein belongs to the light harvesting complex family of pigment binding proteins found in oxygenic photoautotrophs. Previous studies have shown that this complex is required for the rapid induction and relaxation of excess light energy dissipation in a wide range of eukaryotic algae and moss. The ability of cells to rapidly regulate light harvesting between this dissipation state and one favoring photochemistry is believed to be important for reducing oxidative stress and maintaining high photosynthetic efficiency in a rapidly changing light environment. We found that a mutant of Chlamydomonas reinhardtii lacking LHCSR, npq4lhcsr1, displays minimal photoinhibition of photosystem II and minimal inhibition of short term oxygen evolution when grown in constant excess light compared to a wild type strain. We also investigated the impact of no LHCSR during growth in a sinusoidal light regime, which mimics daily changes in photosynthetically active radiation. The absence of LHCSR correlated with a slight reduction in the quantum efficiency of photosystem II and a stimulation of the maximal rates of photosynthesis compared to wild type. However, there was no reduction in carbon accumulation during the day. Another novel finding was that npq4lhcsr1 cultures underwent fewer divisions at night, reducing the overall growth rate compared to the wild type. Our results show that the rapid regulation of light harvesting mediated by LHCSR is required for high growth rates, but it is not required for efficient carbon accumulation during the day in a sinusoidal light environment. This finding has direct implications for engineering strategies directed at increasing photosynthetic productivity in mass cultures. PMID- 28644829 TI - Swapping the N- and C-terminal domains of human apolipoprotein E3 and AI reveals insights into their structure/activity relationship. AB - Apolipoprotein (apo) E3 and apoAI are exchangeable apolipoproteins that play a dominant role in regulating plasma lipoprotein metabolism. ApoE3 (299 residues) is composed of an N-terminal (NT) domain bearing a 4-helix bundle and a C terminal (CT) domain bearing a series of amphipathic alpha-helices. ApoAI (243 residues) also comprises a highly helical NT domain and a less structured CT tail. The objective of this study was to understand their structural and functional role by generating domain swapped chimeras: apoE3-NT/apoAI-CT and apoAI-NT/apoE-CT. The bacterially overexpressed chimeras were purified by affinity chromatography and their identity confirmed by immunoblotting and mass spectrometry. Their alpha-helical content was comparable to that of the parent proteins. ApoE3-NT/apoAI-CT retained the denaturation profile of apoE3 NT domain, with apoAI CT tail eliciting a relatively unstructured state; its lipid binding ability improved dramatically compared to apoE3 indicative of a significant role of apoAI CT tail in lipid binding interaction. The LDL receptor interaction and ability to promote ABCA1-mediated cholesterol efflux of apoE3-NT/apoAI-CT was comparable to that of apoE3. In contrast, apoAI-NT/apoE-CT elicited an unfolding pattern and lipid binding ability that were similar to that of apoAI. As expected, DMPC/apoAI-NT/apoE-CT discoidal particles did not elicit LDLr binding ability, and promoted SR-B1 mediated cellular uptake of lipids to a limited extent. However, apoAI-NT/apoE-CT displayed an enhanced ability to promote cholesterol efflux compared to apoAI, indicative of a significant role for apoE CT domain in mediating this function. Together, these results indicate that the functional attributes of apoAI and apoE3 can be conferred on each other and that NT-CT domain interactions significantly modulate their structure and function. PMID- 28644830 TI - Optimal chemotactic responses in stochastic environments. AB - Although the "adaptive" strategy used by Escherichia coli has dominated our understanding of bacterial chemotaxis, the environmental conditions under which this strategy emerged is still poorly understood. In this work, we study the performance of various chemotactic strategies under a range of stochastic time- and space-varying attractant distributions in silico. We describe a novel "speculator" response in which the bacterium compare the current attractant concentration to the long-term average; if it is higher then they tumble persistently, while if it is lower than the average, bacteria swim away in search of more favorable conditions. We demonstrate how this response explains the experimental behavior of aerobically-grown Rhodobacter sphaeroides and that under spatially complex but slowly-changing nutrient conditions the speculator response is as effective as the adaptive strategy of E. coli. PMID- 28644831 TI - Inflammatory and vascular placental lesions are associated with neonatal amplitude integrated EEG recording in early premature neonates. AB - INTRODUCTION: Placental histologic examination can assist in revealing the mechanism leading to preterm birth. Accumulating evidence suggests an association between intrauterine pathological processes, morbidity and mortality of premature infants, and their long term outcome. Neonatal brain activity is increasingly monitored in neonatal intensive care units by amplitude integrated EEG (aEEG) and indices of background activity and sleep cycling patterns were correlated with long term outcome. We hypothesized an association between types of placental lesions and abnormal neonatal aEEG patterns. OBJECTIVE: To determine the association between the placental lesions observed in extreme preterm deliveries, and their neonatal aEEG patterns and survival. PATIENTS AND METHODS: This prospective cohort study included extreme premature infants, who were born <= 28 weeks of gestation, their placentas were available for histologic examination, and had a continues aEEG, soon after birth)n = 34). Infants and maternal clinical data were collected. aEEG data was assessed for percentage of depressed daily activity in the first 3 days of life and for sleep cycling. Associations of placental histology with clinical findings and aEEG activity were explored using parametric and non-parametric statistics. RESULTS: Twenty two out of the 34 newborns survived to discharge. Preterm prelabor rupture of membranes (PPROM) or chorioamnionitis were associated with placental lesions consistent with fetal amniotic fluid infection (AFI) or maternal under perfusion (MUP) (P < 0.05). Lesions consistent with fetal response to AFI were associated with absence of SWC pattern during the 1st day of life. Fetal-vascular-thrombo-occlusive lesions of inflammatory type were negatively associated with depressed cerebral activity during the 1st day of life, and with aEEG cycling during the 2nd day of life (P<0.05). Placental lesions associated with MUP were associated with depressed neonatal cerebral activity during the first 3 days of life (P = 0.007). CONCLUSIONS: Depressed neonatal aEEG patterns are associated with placental lesions consistent with maternal under perfusion, and amniotic fluid infection of fetal type, but not with fetal thrombo-oclusive vascular disease of inflammatory type. Our findings highlight the association between the intrauterine mechanisms leading to preterm parturition and subsequent depressed neonatal cerebral function early after birth, which eventually may put premature infants at risk for abnormal neurodevelopmental outcome. PMID- 28644832 TI - Parent-child discrepancies in the report of adolescent emotional and behavioral problems in Taiwan. AB - The majority of studies on parent-child discrepancies in the assessment of adolescent emotional and behavioral problems have been conducted in Western countries. It is believed that parent-adolescent agreement would be higher in societies with a strong culture of familism. We examined whether parent adolescent discrepancies in the rating of adolescent emotional and behavioral problems are related to parental and family factors in Taiwan. Participants included 1,421 child-parent pairs of 7th-grade students from 12 middle schools in Northern Taiwan and their parents. We calculated Pearson's correlation coefficients to assess the relationship between parental (Child Behavior Checklist, CBCL) and adolescent (Youth Self Report, YSR) report of emotional/behavioral problem syndromes. Regression models were used to assess parent-adolescent differences in relation to parental psychopathology and family factors. We found that parent-adolescent agreement was moderate (r = 0.37). Adolescents reported higher symptom scores than their parents (Mean Total Problem Score: CBCL: 20.79, YSR: 33.14). Parental psychopathology was related to higher parental ratings and better informant agreement. Parents with higher socioeconomic status (SES) tended to report lower scores for adolescent problem syndromes, resulting in higher levels of disagreement. Greater maternal care was related to higher parent-adolescent agreement. Based on our study findings, we conclude that familism values do not seem to improve parent-child agreement in the assessment of adolescent problem syndromes. The finding that higher SES was related to increased discrepancies speaks to the need to explore the culture specific mechanisms giving rise to informant discrepancies. PMID- 28644833 TI - Quantifying the web browser ecosystem. AB - Contrary to the assumption that web browsers are designed to support the user, an examination of a 900,000 distinct PCs shows that web browsers comprise a complex ecosystem with millions of addons collaborating and competing with each other. It is possible for addons to "sneak in" through third party installations or to get "kicked out" by their competitors without user involvement. This study examines that ecosystem quantitatively by constructing a large-scale graph with nodes corresponding to users, addons, and words (terms) that describe addon functionality. Analyzing addon interactions at user level using the Personalized PageRank (PPR) random walk measure shows that the graph demonstrates ecological resilience. Adapting the PPR model to analyzing the browser ecosystem at the level of addon manufacturer, the study shows that some addon companies are in symbiosis and others clash with each other as shown by analyzing the behavior of 18 prominent addon manufacturers. Results may herald insight on how other evolving internet ecosystems may behave, and suggest a methodology for measuring this behavior. Specifically, applying such a methodology could transform the addon market. PMID- 28644834 TI - Automatic non-symbolic numerosity processing in preschoolers. AB - There has recently been an increasing focus on the development of automatic processing of numerical magnitude. However, little effort has been made to explore automatic access to non-symbolic numerical magnitude in preschool children. In experiment 1, we used a non-symbolic physical size comparison task in 3- to 6-year-olds to examine developmental changes and the effect of ratio and counting principle knowledge. Results showed that the existence of automatic non symbolic numerical processing began at age 3-4 years and size congruity effects tended to reduce with increasing age from 4 years old. The study also found that non-counting-principle knowers had a larger congruity effect, and in low ratio conditions the size congruity effect was more easily found. In addition, symbolic number comparison ability was negatively related to size congruity effect. In experiment 2, we explored the relationship between inhibition skill and size congruity effects, as well as interference and facilitatory components in children aged 4 years old. Results showed no correlation between inhibition skills and the size congruity effect and only interference effects were found. We also found a larger interference effect in low ratio conditions than in high ratio conditions. PMID- 28644835 TI - Physician assessments of drug seeking behavior: A mixed methods study. AB - BACKGROUND: Pain complaints are common, but clinicians are increasingly concerned about overuse of opioid pain medications. This may lead patients with actual pain to be stigmatized as "drug-seeking," or attempting to obtain medications they do not require medically. We assessed whether patient requests for specific opioid pain medication would lead physicians to classify them as drug-seeking and change management decisions. METHODS AND FINDINGS: Mixed-methods analysis of interviews with 192 office-based primary care physicians after viewing video vignettes depicting patients presenting with back pain. For each presentation physicians were randomly assigned to see either an active request for a specific medication or a more general request for help with pain. The main outcome was assignment by the physician of "drug-seeking" as a potential diagnosis among patients presenting with back pain. Additional outcomes included other actions the physician would take and whether the physician would prescribe the medication requested. A potential diagnosis of drug-seeking behavior was included by 21% of physicians seeing a specific request for oxycodone vs. 3% for a general request for help with back pain(p<0.001). In multivariable models an active request was most strongly associated with a physician-assigned diagnosis of drug-seeking behavior(OR 8.10; 95% CI 2.11-31.15;p = 0.002); other major patient and physician characteristics, including gender and race, did not have strong associations with drug-seeking diagnosis. Physicians described short courses of opioid medications as a strategy for managing patients with pain while avoiding opioid overuse. CONCLUSIONS: When patients make a specific request for opioid pain medication, physicians are far more likely to suspect that they are drug-seeking. Physician suspicion of drug-seeking behavior did not vary by patient characteristics, including gender and race. The strategies used to assess patients further varied widely. These findings indicate a need for the development of better clinical tools to support the evaluation and management of patients presenting with pain. PMID- 28644836 TI - Biliary drainage improves the predictive value of modified Glasgow Prognostic Scores in inoperable pancreatic cancer. AB - OBJECTIVE: To assess the influence of biliary drainage to cholangitis on modified Glasgow Prognostic Score (mGPS) in patients with pancreatic cancer. METHODS: mGPS was calculated before and after biliary drainage in 47 consecutive patients with inoperable pancreatic cancer who were receiving chemotherapy. Biliary drainage was indicated for malignant obstructive jaundice that prevented the administration of chemotherapy. To elucidate mGPS values, serum levels of CRP and albumin were measured at the time of diagnosis (before biliary drainage). Overall survival was evaluated and risk factors, which contribute to overall survival, were examined. RESULTS: Biliary drainage was performed in 15 patients. Using values obtained before biliary drainage, there were no significant differences in median survival time between patients with a mGPS of 0 and those with a mGPS of 1 or 2 (10.7 vs. 9.4 months; p = 0.757). However, using values obtained after biliary drainage, median survival time was significantly higher in patients with a mGPS of 0 than in those with a mGPS of 1 or 2 (11.4 vs. 4.7 months; p = 0.002). Multivariate analysis revealed that a mGPS of 1 or 2 (HR: 3.38; 95% CI: 1.35 8.46, p = 0.009), a carbohydrate antigen 19-9 >1000 U/mL (2.52; 1.22-5.23, p = 0.013), a performance status of 2 (7.68; 2.72-21.28, p = 0.001), carcinoembryonic antigen level >10 ng/mL (2.29; 1.13-4.61, p = 0.021) were independently associated with overall survival. CONCLUSION: mGPS values obtained after biliary drainage appear to be a more reliable indicator of overall survival in patients with inoperable pancreatic cancer. PMID- 28644837 TI - Real-world first-line treatment and overall survival in non-small cell lung cancer without known EGFR mutations or ALK rearrangements in US community oncology setting. AB - PURPOSE: To establish a baseline for care and overall survival (OS) based upon contemporary first-line treatments prescribed in the era before the introduction of immune checkpoint inhibitors, for people with metastatic non-small cell lung cancer (NSCLC) without common actionable mutations. METHODS: Using a nationally representative electronic health record data from the Flatiron dataset which included 162 practices from different regions in US, we identified patients (>=18 years old) newly diagnosed with stage IV NSCLC initiating first-line anticancer therapy (November 2012- January 2015, with follow-up through July 2015). Patients with documented epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) translocation were excluded. Anti-cancer drug therapy and overall survival were described overall, and by histology. RESULTS: A total of 2,014 patients with stage IV NSCLC without known EGFR or ALK genomic tumor aberrations initiated systemic anticancer therapy, 22% with squamous and 78% with nonsquamous histology. Their mean (SD) age was 67 (10) years, 55% were male, and 87% had a smoking history. In nonsquamous NSCLC, carboplatin plus pemetrexed either without (25.7%) or with bevacizumab (16%) were the most common regimens; 26.6% of nonsquamous patients receiving induction therapy also received continuation maintenance therapy. In squamous NSCLC, carboplatin plus paclitaxel (37.6%) or nab-paclitaxel (21.1%) were the most commonly used regimens. Overall median OS was 9.7 months (95% CI: 9.1, 10.3), 8.5 months (95% CI: 7.4, 10.0) for squamous, and 10.0 months (95% CI: 9.4, 10.8) for nonsquamous NSCLC. CONCLUSION: The results provide context for evaluating the effect of shifting treatment patterns of NSCLC treatments on patient outcomes, and for community oncology benchmarking initiatives. PMID- 28644838 TI - Characterization and utilization of an international neurofibromatosis web-based, patient-entered registry: An observational study. AB - The neurofibromatoses (neurofibromatosis type 1, neurofibromatosis type 2 and schwannomatosis) are rare disorders having clinical manifestations that vary greatly from patient to patient. The rarity and variability of these disorders has made it challenging for investigators to identify sufficient numbers of patients with particular clinical characteristics or specific germline mutations for participation in interventional studies. Similarly, because the natural history of all types of neurofibromatosis (NF) is variable and unique for each individual, it is difficult to identify meaningful clinical outcome measures for potential therapeutic interventions. In 2012, the Children's Tumor Foundation created a web-based patient-entered database, the NF Registry, to inform patients of research opportunities for which they fit general eligibility criteria and enable patients to contact investigators who are seeking to enroll patients in approved trials. Registrants were recruited through CTF-affiliated NF clinics and conferences, through its website, and by word-of-mouth and social media. Following online consent, demographic information and details regarding manifestations of NF were solicited on the Registry website. Statistical analyses were performed on data from a cohort of 4680 registrants (the number of registrants as of October 9, 2015) who met diagnostic criteria for one of the 3 NF conditions. The analyses support our hypothesis that patient-reported symptom incidences in the NF Registry are congruent with published clinician-sourced data. Between April 26, 2013 and July 8, 2016, the registry has been useful to investigators in recruitment, particularly for observational trials, especially those for development of patient-reported outcomes. PMID- 28644839 TI - Genomic introgression mapping of field-derived multiple-anthelmintic resistance in Teladorsagia circumcincta. AB - Preventive chemotherapy has long been practiced against nematode parasites of livestock, leading to widespread drug resistance, and is increasingly being adopted for eradication of human parasitic nematodes even though it is similarly likely to lead to drug resistance. Given that the genetic architecture of resistance is poorly understood for any nematode, we have analyzed multidrug resistant Teladorsagia circumcincta, a major parasite of sheep, as a model for analysis of resistance selection. We introgressed a field-derived multiresistant genotype into a partially inbred susceptible genetic background (through repeated backcrossing and drug selection) and performed genome-wide scans in the backcross progeny and drug-selected F2 populations to identify the major genes responsible for the multidrug resistance. We identified variation linking candidate resistance genes to each drug class. Putative mechanisms included target site polymorphism, changes in likely regulatory regions and copy number variation in efflux transporters. This work elucidates the genetic architecture of multiple anthelmintic resistance in a parasitic nematode for the first time and establishes a framework for future studies of anthelmintic resistance in nematode parasites of humans. PMID- 28644840 TI - Linking structure and activity in nonlinear spiking networks. AB - Recent experimental advances are producing an avalanche of data on both neural connectivity and neural activity. To take full advantage of these two emerging datasets we need a framework that links them, revealing how collective neural activity arises from the structure of neural connectivity and intrinsic neural dynamics. This problem of structure-driven activity has drawn major interest in computational neuroscience. Existing methods for relating activity and architecture in spiking networks rely on linearizing activity around a central operating point and thus fail to capture the nonlinear responses of individual neurons that are the hallmark of neural information processing. Here, we overcome this limitation and present a new relationship between connectivity and activity in networks of nonlinear spiking neurons by developing a diagrammatic fluctuation expansion based on statistical field theory. We explicitly show how recurrent network structure produces pairwise and higher-order correlated activity, and how nonlinearities impact the networks' spiking activity. Our findings open new avenues to investigating how single-neuron nonlinearities-including those of different cell types-combine with connectivity to shape population activity and function. PMID- 28644841 TI - Low-dimensional spike rate models derived from networks of adaptive integrate-and fire neurons: Comparison and implementation. AB - The spiking activity of single neurons can be well described by a nonlinear integrate-and-fire model that includes somatic adaptation. When exposed to fluctuating inputs sparsely coupled populations of these model neurons exhibit stochastic collective dynamics that can be effectively characterized using the Fokker-Planck equation. This approach, however, leads to a model with an infinite dimensional state space and non-standard boundary conditions. Here we derive from that description four simple models for the spike rate dynamics in terms of low dimensional ordinary differential equations using two different reduction techniques: one uses the spectral decomposition of the Fokker-Planck operator, the other is based on a cascade of two linear filters and a nonlinearity, which are determined from the Fokker-Planck equation and semi-analytically approximated. We evaluate the reduced models for a wide range of biologically plausible input statistics and find that both approximation approaches lead to spike rate models that accurately reproduce the spiking behavior of the underlying adaptive integrate-and-fire population. Particularly the cascade-based models are overall most accurate and robust, especially in the sensitive region of rapidly changing input. For the mean-driven regime, when input fluctuations are not too strong and fast, however, the best performing model is based on the spectral decomposition. The low-dimensional models also well reproduce stable oscillatory spike rate dynamics that are generated either by recurrent synaptic excitation and neuronal adaptation or through delayed inhibitory synaptic feedback. The computational demands of the reduced models are very low but the implementation complexity differs between the different model variants. Therefore we have made available implementations that allow to numerically integrate the low-dimensional spike rate models as well as the Fokker-Planck partial differential equation in efficient ways for arbitrary model parametrizations as open source software. The derived spike rate descriptions retain a direct link to the properties of single neurons, allow for convenient mathematical analyses of network states, and are well suited for application in neural mass/mean-field based brain network models. PMID- 28644842 TI - Investigation of discriminant metabolites in tamoxifen-resistant and choline kinase-alpha-downregulated breast cancer cells using 1H-nuclear magnetic resonance spectroscopy. AB - Metabolites linked to changes in choline kinase-alpha (CK-alpha) expression and drug resistance, which contribute to survival and autophagy mechanisms, are attractive targets for breast cancer therapies. We previously reported that autophagy played a causative role in driving tamoxifen (TAM) resistance of breast cancer cells (BCCs) and was also promoted by CK-alpha knockdown, resulting in the survival of TAM-resistant BCCs. There is no comparative study yet about the metabolites resulting from BCCs with TAM-resistance and CK-alpha knockdown. Therefore, the aim of this study was to explore the discriminant metabolic biomarkers responsible for TAM resistance as well as CK-alpha expression, which might be linked with autophagy through a protective role. A total of 33 intracellular metabolites, including a range of amino acids, energy metabolism related molecules and others from cell extracts of the parental cells (MCF-7), TAM-resistant cells (MCF-7/TAM) and CK-alpha knockdown cells (MCF-7/shCK-alpha, MCF-7/TAM/shCK-alpha) were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMRS). Principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) revealed the existence of differences in the intracellular metabolites to separate the 4 groups: MCF-7 cells, MCF-7/TAM cells, MCF-7-shCK-alpha cells, and MCF-7/TAM/shCK-alpha cells. The metabolites with VIP>1 contributed most to the differentiation of the cell groups, and they included fumarate, UA (unknown A), lactate, myo-inositol, glycine, phosphocholine, UE (unknown E), glutamine, formate, and AXP (AMP/ADP/ATP). Our results suggest that these altered metabolites would be promising metabolic biomarkers for a targeted therapeutic strategy in BCCs that exhibit TAM resistance and aberrant CK-alpha expression, which triggers a survival and drug resistance mechanism. PMID- 28644843 TI - A high-density genetic map and QTL analysis of agronomic traits in foxtail millet [Setaria italica (L.) P. Beauv.] using RAD-seq. AB - Foxtail millet (Setaria italica), a very important grain crop in China, has become a new model plant for cereal crops and biofuel grasses. Although its reference genome sequence was released recently, quantitative trait loci (QTLs) controlling complex agronomic traits remains limited. The development of massively parallel genotyping methods and next-generation sequencing technologies provides an excellent opportunity for developing single-nucleotide polymorphisms (SNPs) for linkage map construction and QTL analysis of complex quantitative traits. In this study, a high-throughput and cost-effective RAD-seq approach was employed to generate a high-density genetic map for foxtail millet. A total of 2,668,587 SNP loci were detected according to the reference genome sequence; meanwhile, 9,968 SNP markers were used to genotype 124 F2 progenies derived from the cross between Hongmiaozhangu and Changnong35; a high-density genetic map spanning 1648.8 cM, with an average distance of 0.17 cM between adjacent markers was constructed; 11 major QTLs for eight agronomic traits were identified; five co-dominant DNA markers were developed. These findings will be of value for the identification of candidate genes and marker-assisted selection in foxtail millet. PMID- 28644844 TI - Carbonic anhydrase inhibitor attenuates ischemia-reperfusion induced acute lung injury. AB - Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions including lung transplantation, cardiopulmonary bypass surgery, re-expansion of collapsed lung from pneumothorax or pleural effusion and etc. IR-induced ALI remains a challenge in the current treatment. Carbonic anhydrase has important physiological function and influences on transport of CO2. Some investigators suggest that CO2 influences lung injury. Therefore, carbonic anhydrase should have the role in ALI. This study was undertaken to define the effect of a carbonic anhydrase inhibitor, acetazolamide (AZA), in IR-induced ALI, that was conducted in a rat model of isolated-perfused lung with 30 minutes of ischemia and 90 minutes of reperfusion. The animals were divided into six groups (n = 6 per group): sham, sham + AZA 200 mg/kg body weight (BW), IR, IR + AZA 100 mg/kg BW, IR + AZA 200 mg/kg BW and IR+ AZA 400 mg/kg BW. IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, pulmonary hypertension, neutrophilic sequestration, and an increase in the expression of pro-inflammatory cytokines. Increases in carbonic anhydrase expression and perfusate pCO2 levels were noted, while decreased Na-K-ATPase expression was noted after IR. Administration of 200mg/kg BW and 400mg/kg BW AZA significantly suppressed the expression of pro-inflammatory cytokines (TNF-alpha, IL-1, IL-6 and IL-17) and attenuated IR-induced lung injury, represented by decreases in pulmonary hyper-permeability, pulmonary edema, pulmonary hypertension and neutrophilic sequestration. AZA attenuated IR-induced lung injury, associated with decreases in carbonic anhydrase expression and pCO2 levels, as well as restoration of Na-K-ATPase expression. PMID- 28644845 TI - Lipo-PGE1 suppresses collagen production in human dermal fibroblasts via the ERK/Ets-1 signaling pathway. AB - Dysregulation of collagen production contributes to various pathological processes, including tissue fibrosis as well as impaired wound healing. Lipo prostaglandin E1 (Lipo-PGE1), a lipid microsphere-incorporated prostaglandin E1, is used as a vasodilator for the treatment of peripheral vascular diseases. Lipo PGE1 was recently shown to enhance human dermal fibroblast (HDF) migration and in vivo wound healing. No published study has characterized the role of Lipo-PGE1 in collagen regulation in HDFs. Here, we investigated the cellular signaling mechanism by which Lipo-PGE1 regulates collagen in HDFs. Collagen production was evaluated by the Sircol collagen assay, Western blot analysis of type I collagen and real time PCR. Unexpectedly, Lipo-PGE1 decreased mRNA expression of collagen 1A1, 1A2, and 3A1. Lipo-PGE1 markedly inhibited type I collagen and total soluble collagen production. In addition, Lipo-PGE1 inhibited transforming growth factor beta-induced collagen expression via Smad2 phosphorylation. To further investigate whether extracellular signal-regulated kinase (ERK)/Ets-1 signaling, a crucial pathway in collagen regulation, is involved in Lipo-PGE1-inhibited collagen production, cells were pretreated with an ERK-specific inhibitor, PD98059, prior to the addition of Lipo-PGE1. Lipo-PGE1-inhibited collagen mRNA expression and total soluble collagen production were recovered by pretreatment with PD98059. Moreover, Lipo-PGE1 directly induced the phosphorylation of ERK. Furthermore, silencing of Ets-1 recovered Lipo-PGE1-inhibited collagen production and PD98059 blocked Lipo-PGE1-enhanced Ets-1 expression. The present study reveals an important role for Lipo-PGE1 as a negative regulator of collagen gene expression and production via ERK/Ets-1 signaling. These results suggest that Lipo-PGE1 could potentially be a therapeutic target in diseases with deregulated collagen turnover. PMID- 28644846 TI - The tree balance signature of mass extinction is erased by continued evolution in clades of constrained size with trait-dependent speciation. AB - The kind and duration of phylogenetic topological "signatures" left in the wake of macroevolutionary events remain poorly understood. To this end, we examined a broad range of simulated phylogenies generated using trait-biased, heritable speciation probabilities and mass extinction that could be either random or selective on trait value, but also using background extinction and diversity dependence to constrain clade sizes. In keeping with prior results, random mass extinction increased imbalance of clades that recovered to pre-extinction size, but was a relatively weak effect. Mass extinction that was selective on trait values tended to produce clades of similar or greater balance compared to random extinction or controls. Allowing evolution to continue past the point of clade size recovery resulted in erosion and eventual erasure of this signal, with all treatments converging on similar values of imbalance, except for very intense extinction regimes targeted at taxa with high speciation rates. Return to a more balanced state with extended post-extinction evolution was also associated with loss of the previous phylogenetic root in most treatments. These results further demonstrate that while a mass extinction event can produce a recognizable phylogenetic signal, its effects become increasingly obscured the further an evolving clade gets from that event, with any sharp imbalance due to unrelated evolutionary factors. PMID- 28644847 TI - Role of classic signs as diagnostic predictors for enteric fever among returned travellers: Relative bradycardia and eosinopenia. AB - BACKGROUND: The lack of characteristic clinical findings and accurate diagnostic tools has made the diagnosis of enteric fever difficult. We evaluated the classic signs of relative bradycardia and eosinopenia as diagnostic predictors for enteric fever among travellers who had returned from the tropics or subtropics. METHODS: This matched case-control study used data from 2006 to 2015 for culture proven enteric fever patients as cases. Febrile patients (>38.3 degrees C) with non-enteric fever, who had returned from the tropics or subtropics, were matched to the cases in a 1:3 ratio by age (+/-3 years), sex, and year of diagnosis as controls. Cunha's criteria were used for relative bradycardia. Absolute eosinopenia was defined as an eosinophilic count of 0/MUL. RESULTS: Data from 160 patients (40 cases and 120 controls) were analysed. Cases predominantly returned from South Asia (70% versus 18%, p <0.001). Relative bradycardia (88% versus 51%, p <0.001) and absolute eosinopenia (63% versus 38%, p = 0.008) were more frequent in cases than controls. In multivariate logistic regression analysis, return from South Asia (aOR: 21.6; 95% CI: 7.17-64.9) and relative bradycardia (aOR: 11.7; 95% CI: 3.21-42.5) were independent predictors for a diagnosis of enteric fever. The positive likelihood ratio was 4.00 (95% CI: 2.58-6.20) for return from South Asia, 1.72 (95% CI: 1.39-2.13) for relative bradycardia, and 1.63 (95%CI: 1.17 2.27) for absolute eosinopenia. The negative predictive values of the three variables were notably high (83-92%);. however, positive predictive values were 35-57%. CONCLUSIONS: The classic signs of relative bradycardia and eosinopenia were not specific for enteric fever; however both met the criteria for being diagnostic predictors for enteric fever. Among febrile returned travellers, relative bradycardia and eosinopenia should be re-evaluated for predicting a diagnosis of enteric fever in non-endemic areas prior to obtaining blood cultures. PMID- 28644848 TI - Exploring the differences between pet and non-pet owners: Implications for human animal interaction research and policy. AB - There is conflicting evidence about whether living with pets results in better mental and physical health outcomes, with the majority of the empirical research evidence being inconclusive due to methodological limitations. We briefly review the research evidence, including the hypothesized mechanisms through which pet ownership may influence health outcomes. This study examines how pet and non-pet owners differ across a variety of socio-demographic and health measures, which has implications for the proper interpretation of a large number of correlational studies that attempt to draw causal attributions. We use a large, population based survey from California administered in 2003 (n = 42,044) and find that pet owners and non-pet owners differ across many traits, including gender, age, race/ethnicity, living arrangements, and income. We include a discussion about how the factors associated with the selection into the pet ownership group are related to a range of mental and physical health outcomes. Finally, we provide guidance on how to properly model the effects of pet ownership on health to accurately estimate this relationship in the general population. PMID- 28644849 TI - Rapid development of cyanobacterial crust in the field for combating desertification. AB - Desertification is currently a major concern, and vast regions have already been devastated in the arid zones of many countries. Combined application of cyanobacteria with soil fixing chemicals is a novel method of restoring desertified areas. Three cyanobacteria, Nostoc sp. Vaucher ex Bornet & Flahault, Phormidium sp. Kutzing ex Gomont and Scytonema arcangeli Bornet ex Flahault were isolated and tested in this study. Tacki-SprayTM (TKS7), which consists of bio polysaccharides and tackifiers, was used as a soil fixing agent. In addition, superabsorbent polymer (SAP) was applied to the soil as a water-holding material and nutrient supplement. Application of cyanobacteria with superabsorbent polymer and TKS7 (CST) remarkably improved macro-aggregate stability against water and erodibility against wind after 12 months of inoculation when compared to the control soil. The mean weight diameter and threshold friction velocity of the CST treated soil were found to be 75% and 88% of those of the approximately 20-year old natural cyanobacterial crust (N-BSC), respectively, while these values were 68% and 73% of those of the N-BSC soil after a single treatment of cyanobacteria alone (CY). Interestingly, biological activities of CST were similar to those of CY. Total carbohydrate contents, cyanobacterial biomass, microbial biomass, soil respiration, carbon fixation and effective quantum yield of CST treated soil were enhanced by 50-100% of the N-BSC, while those of control soil were negligible. Our results suggest that combined application of cyanobacteria with soil fixing chemicals can rapidly develop cyanobacterial crust formation in the field within 12 months. The physical properties and biological activities of the inoculated cyanobacterial crust were stable during the study period. The novel method presented herein serves as another approach for combating desertification in arid regions. PMID- 28644850 TI - Visceral adiposity index predicts the conversion of metabolically healthy obesity to an unhealthy phenotype. AB - OBJECTIVE: Some individuals with metabolically healthy obesity (MHO) convert to metabolically unhealthy obesity (MUO) phenotype, and visceral adiposity is one of proposed mechanisms underlying such conversion. Visceral adipose index (VAI) is a novel mathematical model which estimates visceral adiposity based on anthropometric and lipid profiles. We aimed to determine the association of VAI estimated visceral adiposity with the MHO-to-MUO conversion and the predictive value of VAI in estimating such unfavorable outcomes. METHODS: A total of 2,204 Korean subjects with the MHO phenotype were enrolled and stratified by body mass index and metabolic health state according to Wildman criteria at baseline and last follow-up examinations. VAI was calculated at baseline. RESULTS: Over a median follow-up period of 41.1 months, 46.0% of subjects converted to MUO phenotype. Higher VAI quartiles were associated with a greater proportion of subjects who underwent MHO-to-MUO conversion, and also with increased odds ratios for such conversion even after multivariate analyses. The optimal VAI cut off value was around 1.00, and VAI had a greater power in the prediction of MHO-to MUO conversion than waist circumference in both genders. CONCLUSION: MHO phenotypes with high VAI values are associated with poor future metabolic outcomes. VAI-estimated visceral adiposity is well correlated with the prognosis of MHO subjects, and VAI has a good predictive value in determining the MHO-to MUO conversion. PMID- 28644852 TI - Comparisons of retinal vessel diameter and glaucomatous parameters between both eyes of subjects with clinically unilateral pseudoexfoliation syndrome. AB - PURPOSE: Pseudoexfoliation syndrome (PEX), the most common identifiable cause of open-angle glaucoma, might affect the retinal hemodynamics. To test this, we compared retinal vessel diameter and glaucoma-related parameters between eyes with pseudoexfoliation material (PE+) and fellow unaffected (PE-) eyes of patients with clinically unilateral PEX. METHODS: The medical records of 30 consecutive Japanese subjects were reviewed retrospectively. The retinal vessel diameters were measured and expressed as the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) using standardized software. During the chart review, we recorded glaucoma-related parameters including intraocular pressure (IOP), visual field mean deviation (MD) value, planimetrically measured vertical cup-to-disc (C/D) ratio, circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and macular inner retinal thickness (mIRT) measured by spectral-domain optical coherence tomography, anterior chamber flare (ACF), corneal endothelial cell density (CECD), and number of antiglaucoma medications. RESULTS: Compared with PE- eyes, the CRAE, CRVE, MD, cpRNFLT and mIRT, and CECD were significantly lower in PE+ eyes; the IOP, vertical C/D ratio, number of antiglaucoma medications, and ACF were significantly higher in PE+ eyes (P<0.0001 for all comparisons). The CRAE, cpRNFLT, and MD were correlated positively with each other (rho = 0.456-0.499, P<0.0001-0.0002) and negatively with the IOP (rho = -0.562- -0.432, P<0.0001-0.0006). The vertical C/D ratio was correlated positively with the IOP (rho = 0.483, P<0.0001) and negatively with the CRAE, cpRNFLT, and MD (rho = -0.745--0.479, P<0.0001-0.0001). CONCLUSIONS: Deposition of PE can cause retinal vessel narrowing in arterioles and venules. The roles and mechanisms of retinal vessel narrowing in glaucoma pathogenesis need clarification. PMID- 28644851 TI - Comorbidities in the diseasome are more apparent than real: What Bayesian filtering reveals about the comorbidities of depression. AB - Comorbidity patterns have become a major source of information to explore shared mechanisms of pathogenesis between disorders. In hypothesis-free exploration of comorbid conditions, disease-disease networks are usually identified by pairwise methods. However, interpretation of the results is hindered by several confounders. In particular a very large number of pairwise associations can arise indirectly through other comorbidity associations and they increase exponentially with the increasing breadth of the investigated diseases. To investigate and filter this effect, we computed and compared pairwise approaches with a systems based method, which constructs a sparse Bayesian direct multimorbidity map (BDMM) by systematically eliminating disease-mediated comorbidity relations. Additionally, focusing on depression-related parts of the BDMM, we evaluated correspondence with results from logistic regression, text-mining and molecular level measures for comorbidities such as genetic overlap and the interactome based association score. We used a subset of the UK Biobank Resource, a cross sectional dataset including 247 diseases and 117,392 participants who filled out a detailed questionnaire about mental health. The sparse comorbidity map confirmed that depressed patients frequently suffer from both psychiatric and somatic comorbid disorders. Notably, anxiety and obesity show strong and direct relationships with depression. The BDMM identified further directly co-morbid somatic disorders, e.g. irritable bowel syndrome, fibromyalgia, or migraine. Using the subnetwork of depression and metabolic disorders for functional analysis, the interactome-based system-level score showed the best agreement with the sparse disease network. This indicates that these epidemiologically strong disease-disease relations have improved correspondence with expected molecular level mechanisms. The substantially fewer number of comorbidity relations in the BDMM compared to pairwise methods implies that biologically meaningful comorbid relations may be less frequent than earlier pairwise methods suggested. The computed interactive comprehensive multimorbidity views over the diseasome are available on the web at Co=MorNet: bioinformatics.mit.bme.hu/UKBNetworks. PMID- 28644853 TI - The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia. AB - Philadelphia chromosome positive B cell acute lymphoblastic leukemia (Ph+ ALL) is an aggressive cancer of the bone marrow. The addition of tyrosine kinase inhibitors (TKIs) has improved outcomes but many patients still suffer relapse and novel therapeutic agents are needed. KPC34 is an orally available, novel phospholipid conjugate of gemcitabine, rationally designed to overcome multiple mechanisms of resistance, inhibit the classical and novel isoforms of protein kinase C, is able to cross the blood brain barrier and is orally bioavailable. KPC34 had an IC50 in the nanomolar range against multiple ALL cell lines tested but was lowest for Ph+ lines. In mice bearing either naive or resistant Ph+ ALL, KPC34 treatment resulted in significantly improved survival compared to cytarabine and gemcitabine. Treatment with KPC34 and doxorubicin was more effective than doxorubicin and cytarabine. Mice with recurrence of their ALL after initial treatment with cytarabine and doxorubicin saw dramatic improvements in hind limb paralysis after treatment with KPC34 demonstrating activity against established CNS disease. Consistent with this KPC34 was better than gemcitabine at reducing CNS leukemic burden. These promising pre-clinical results justify the continued development of KPC34 for the treatment of Ph+ALL. PMID- 28644854 TI - An independently reconfigurable dual-mode dual-band substrate integrated waveguide filter. AB - In this paper, a novel perturbation approach for implementing the independently reconfigurable dual-mode dual-band substrate integrated waveguide (SIW) filter is proposed. Dual-frequency manipulation is achieved by adding perturbation via holes (the first variable) and changing the lengths of the interference slot (the second variable) in each cavity. The independent control of the upper passband only depends on the second variable while the lower passband is independently tuned by combining the two variables. Using such a design method, a two-cavity dual-band SIW filter is designed and experimentally assessed with four via-holes and an interference slot in each cavity. The dual-band filter not only has a frequency ratio (fR) ranging from 1.14 to 1.58 but also can be considered as a single passband one with a tunable range of 40.5% from 1.26 GHz to 2.12 GHz. The scattering parameters |S11| and |S21| are in the range of -10.72 dB to -37.17 dB and -3.67 dB to -7.22 dB in the operating dual bands, respectively. All the simulated and measured results show an acceptable agreement with the predicted data. PMID- 28644855 TI - Comparison of the miRNA expression profiles in fresh frozen and formalin-fixed paraffin-embedded tonsillar tumors. AB - MicroRNAs are considered as promising prognostic and diagnostic biomarkers of human cancer since their profiles differ between tumor types. Most of the tumor profiling studies were performed on rarely available fresh frozen (FF) samples. Alternatively, archived formalin-fixed paraffin-embedded (FFPE) tissue samples are also well applicable to larger-scale retrospective miRNA profiling studies. The aim of this study was to perform systematic comparison of the miRNA expression profiles between FF and macrodissected FFPE tonsillar tumors using the TaqMan Low Density Array system, with the data processed by different software programs and two types of normalization methods. We observed a marked correlation between the miRNA expression profiles of paired FF and FFPE samples; however, only 27-38% of the differentially deregulated miRNAs overlapped between the two source systems. The comparison of the results with regard to the distinct modes of data normalization revealed an overlap in 58-67% of differentially expressed miRNAs, with no influence of the choice of software platform. Our study highlights the fact that for an accurate comparison of the miRNA expression profiles from published studies, it is important to use the same type of clinical material and to test and select the best-performing normalization method for data analysis. PMID- 28644856 TI - Estimating psychopathological networks: Be careful what you wish for. AB - Network models, in which psychopathological disorders are conceptualized as a complex interplay of psychological and biological components, have become increasingly popular in the recent psychopathological literature (Borsboom, et. al., 2011). These network models often contain significant numbers of unknown parameters, yet the sample sizes available in psychological research are limited. As such, general assumptions about the true network are introduced to reduce the number of free parameters. Incorporating these assumptions, however, means that the resulting network will lead to reflect the particular structure assumed by the estimation method-a crucial and often ignored aspect of psychopathological networks. For example, observing a sparse structure and simultaneously assuming a sparse structure does not imply that the true model is, in fact, sparse. To illustrate this point, we discuss recent literature and show the effect of the assumption of sparsity in three simulation studies. PMID- 28644857 TI - Beneficial effects of Hibiscus rosa-sinensis L. flower aqueous extract in pregnant rats with diabetes. AB - PURPOSE: The Hibiscus rosa-sinensis flower is widely used in Brazilian traditional medicine for the treatment of diabetes and has shown antifertility activity in female Wistar rats. However, there is no scientific confirmation of its effect on diabetes and pregnancy. The aim of this study was evaluate the effect of aqueous extract of H. rosa-sinensis flowers on maternal-fetal outcome in pregnant rats with diabetes. METHODS: Diabetes was induced by streptozotocin (STZ, 40 mg/kg) in virgin, adult, female Wistar rats. After diabetes induction, the rats were mated. The pregnant rats were distributed into four groups (n minimum = 11 animals/group): non-diabetic, non-diabetic treated, diabetic, and diabetic treated. Oral aqueous extract of Hibiscus rosa-sinensis was administered to rats in the treatment groups during pregnancy. At term pregnancy, maternal reproductive outcomes, fetal parameters, and biochemical parameters were analyzed. RESULTS: The non-diabetic treated group showed decreased high density lipoprotein cholesterol, increased atherogenic index (AI) and coronary artery risk index (CRI), and increased preimplantation loss rate compared to the non diabetic group. Although treatment with H. rosa-sinensis led to no toxicity, it showed deleterious effects on cardiac and reproductive functions. However, the diabetic treated group showed increased maternal and fetal weights, reduced AI and CRI, and reduced preimplantation loss rate compared to the untreated diabetic group. CONCLUSION: Our results demonstrate beneficial effects of this flower only in pregnant rats with diabetes and their offspring. Although these findings cannot be extrapolated to human clinical use, they show that the indiscriminate intake of H. rosa-sinensis may be harmful to healthy individuals and its use should be completely avoided in pregnancy. PMID- 28644858 TI - The flame retardant DE-71 (a mixture of polybrominated diphenyl ethers) inhibits human differentiated thyroid cell function in vitro. AB - BACKGROUND: Normal thyroid function is essential for general growth and metabolism, but can be affected by endocrine disrupting chemicals (EDCs). Polybrominated diphenyl ethers (PBDEs) have been used worldwide to reduce flammability in different materials and are suspected to be EDCs. The production of the commercial Penta- and OctaBDE mixtures is banned, but DecaBDEs and existing products may leak PBDEs into the environment. Our aim was to investigate the effect of the PentaBDE mixture DE-71 on human thyroid cells in vitro. MATERIALS AND METHODS: Primary human thyroid cells were obtained as paraadenomatous tissue and cultured in monolayers. The influence of DE-71 on cyclic adenosine monophosphate (cAMP) and thyroglobulin (Tg) production was examined in the culture medium by competitive radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Real-time quantitative PCR analysis of thyroid specific genes was performed on the exposed cell cultures. PBDE concentrations were determined in cellular and supernatant fractions of the cultures. RESULTS: DE-71 inhibited Tg-release from TSH-stimulated thyrocytes. At 50 mg/L DE-71, mean Tg production was reduced by 71.9% (range: 8.5-98.7%), and cAMP by 95.1% (range: 91.5-98.8%) compared to controls). Expression of mRNA encoding Tg, TPO and TSHr were significantly inhibited (p<0.0001, p = 0.0079, and p = 0.0002, respectively). The majority of DE-71 added was found in the cell fraction. No cytotoxicity was found. CONCLUSIONS: DE-71 inhibited differentiated thyroid cell functions in a two phase response manner and a concentration-dependent inhibition of Tg and cAMP production, respectively, as well as expression of mRNA encoding Tg, TPO and TSHr. Our findings suggest an inhibiting effect of PBDEs on thyroid cells. PMID- 28644859 TI - Grief interventions for people bereaved by suicide: A systematic review. AB - BACKGROUND: Adaption to the loss of a loved one due to suicide can be complicated by feelings of guilt, shame, responsibility, rejection, and stigmatization. Therefore people bereaved by suicide have an increased risk for developing complicated grief which is related to negative physical and mental disorders and an increased risk for suicidal behavior. Grief interventions are needed for this vulnerable population. The aim of this systematic review was to provide an overview of the current state of evidence concerning the effectiveness of interventions that focus on grief for people bereaved by suicide. METHODS: We conducted a systematic literature search using PubMed, Web of Science, and PsycINFO for articles published up until November 2016. Relevant papers were identified and methodological quality was assessed by independent raters. A narrative synthesis was conducted. RESULTS: Seven intervention studies met the inclusion criteria. Two interventions were based on cognitive-behavioral approaches, four consisted of bereavement groups, and one utilized writing therapy. As five of the seven interventions were effective in reducing grief intensity on at least one outcome measure, there is some evidence that they are beneficial. Bereavement groups tend to be effective in lowering the intensity of uncomplicated grief, as are writing interventions in lowering suicide-specific aspects of grief. Cognitive-behavioral programs were helpful for a subpopulation of people who had high levels of suicidal ideation. LIMITATION: On average, methodological quality was low so the evidence for benefits is not robust. The stability of treatment effects could not be determined as follow-up assessments are rare. Generalizability is limited due to homogeneous enrollments of mainly female, white, middle-aged individuals. CONCLUSIONS: People bereaved by suicide are especially vulnerable to developing complicated grief. Therefore, grief therapies should be adapted to and evaluated in this population. Prevention of complicated grief may be successful in populations of high risk individuals. PMID- 28644860 TI - Time dependent genetic analysis links field and controlled environment phenotypes in the model C4 grass Setaria. AB - Vertical growth of plants is a dynamic process that is influenced by genetic and environmental factors and has a pronounced effect on overall plant architecture and biomass composition. We have performed six controlled growth trials of an interspecific Setaria italica x Setaria viridis recombinant inbred line population to assess how the genetic architecture of plant height is influenced by developmental queues, water availability and planting density. The non destructive nature of plant height measurements has enabled us to monitor height throughout the plant life cycle in both field and controlled environments. We find that plant height is reduced under water limitation and high density planting and affected by growth environment (field vs. growth chamber). The results support a model where plant height is a heritable, polygenic trait and that the major genetic loci that influence plant height function independent of growth environment. The identity and contribution of loci that influence height changes dynamically throughout development and the reduction of growth observed in water limited environments is a consequence of delayed progression through the genetic program which establishes plant height in Setaria. In this population, alleles inherited from the weedy S. viridis parent act to increase plant height early, whereas a larger number of small effect alleles inherited from the domesticated S. italica parent collectively act to increase plant height later in development. PMID- 28644861 TI - Impact of Ki67 re-assessment at time of disease progression in patients with pancreatic neuroendocrine neoplasms. AB - BACKGROUND: Although re-assessment of proliferative activity by K67 evaluation during the course of neuroendocrine neoplasms (NENs) is recommended in selected patients, its impact on patients' management is not clear due to the lack of data supporting this practice. AIM: To investigate Ki67 change at time of progressive disease (PD) in entero-pancreatic NENs (EP-NENs). PATIENTS AND METHODS: Retrospective analysis of sporadic EP-NENs which received histological re assessment after PD once radiologically documented. RESULTS: Forty-three patients were evaluated, including 24 pancreatic NENs (PNENs), and 19 small intestine NENs (SI-NENs). At time of initial histological evaluation, 19 patients had grade 1 (G1) NETs (44.2%), and 24 grade 2 (G2) NETs (55.8%), overall median Ki67 being 3% (range 1%-20%). At time of PD, 13 patients had G1 NETs (30.2%), 26 G2 NETs (60.5%), and 4 had grade 3 (G3) NECs (9.3%), thus resulting in a significant median Ki67 increase (8%, range 1%-70%; p = 0.0006), and a G upgrading in 12 patients (27.9%). A statistically significant Ki67 increase and G grading change at time of PD was observed in PNENs (p = 0.0005 and p = 0.028, respectively). Conversely, no statistically significant change occurred in non-PNENs. CONCLUSIONS: In PNENs with documented PD, Ki67 increase occurs in a significant proportion of patients, providing useful information necessary to choose appropriate therapeutic options. PMID- 28644863 TI - A rule-based named-entity recognition method for knowledge extraction of evidence based dietary recommendations. AB - Evidence-based dietary information represented as unstructured text is a crucial information that needs to be accessed in order to help dietitians follow the new knowledge arrives daily with newly published scientific reports. Different named entity recognition (NER) methods have been introduced previously to extract useful information from the biomedical literature. They are focused on, for example extracting gene mentions, proteins mentions, relationships between genes and proteins, chemical concepts and relationships between drugs and diseases. In this paper, we present a novel NER method, called drNER, for knowledge extraction of evidence-based dietary information. To the best of our knowledge this is the first attempt at extracting dietary concepts. DrNER is a rule-based NER that consists of two phases. The first one involves the detection and determination of the entities mention, and the second one involves the selection and extraction of the entities. We evaluate the method by using text corpora from heterogeneous sources, including text from several scientifically validated web sites and text from scientific publications. Evaluation of the method showed that drNER gives good results and can be used for knowledge extraction of evidence-based dietary recommendations. PMID- 28644862 TI - High-intensity corneal collagen crosslinking with riboflavin and UVA in rat cornea. AB - Corneal collagen cross-linking (CXL) halts human corneal ectasias progression by increasing stromal mechanical stiffness. Although some reports describe that this procedure is effective in dealing with some infectious and immunologic corneal thinning diseases, there is a need for more animal models whose corneal thickness more closely resemble those occurring in these patients. To meet this need, we describe here high-intensity protocols that are safe and effective for obtaining CXL in rat corneas. Initially, a range of potentially effective UVA doses were evaluated based on their effectiveness in increasing tissue enzymatic resistance to dissolution. At UVA doses higher than a threshold level of 0.54 J/cm2, resistance to enzymatic digestion increased relative to that in non-irradiated corneas. Based on the theoretical threshold CXL dose, a CXL regimen was established in which the UVA tissue irradiance was 9 mW/cm2, which was delivered at doses of either 2.16, 2.7 or 3.24 J/cm2. Their dose dependent effects were evaluated on ocular surface morphological integrity, keratocyte apoptotic frequency, tissue thickness and endothelial cell layer density. Doses of 2.16 and 2.7 J/cm2 transiently decreased normal corneal transparency and increased thickness. These effects were fully reversed after 14 days. In contrast, 3.24 J/cm2 had more irreversible side effects. Three days after treatment, apoptotic frequency in the CXL-2.16 group was lower than that at higher doses. Endothelial cell losses remained evident only in the CXL-3.24 group at 42 days posttreatment. Stromal fiber thickening was evident in all the CXL-treated groups. We determined both the threshold UVA dose using the high-intensity CXL procedure and identified an effective dose range that provides optimal CXL with minimal transient side effects in the rat cornea. These results may help to provide insight into how to improve the CXL outcome in patients afflicted with a severe corneal thinning disease. PMID- 28644865 TI - Test designs and modeling under the general nominal diagnosis model framework. AB - Most psychological questionnaires face issues of response bias in respondent reported scales, inadequacy for criterion-reference testing, or difficulty in estimating a large number of latent traits. Situational tests together with the general nominal diagnosis model framework provide a viable alternative to alleviate these concerns. Under this framework, there are different ways to design situationally nominal items, which can offer more flexibility for test development. Any response bias remaining with respondent-reported questionnaires may be addressed with appropriate test designs. The saturated model subsumes different reduced forms that can help inform whether the test is designed as expected. Two simulation studies are presented to demonstrate the effectiveness of the models and designs. PMID- 28644864 TI - Overexpression and characterization of two types of nitrile hydratases from Rhodococcus rhodochrous J1. AB - Nitrile hydratase (NHase) from Rhodococcus rhodochrous J1 is widely used for industrial production of acrylamide and nicotinamide. However, the two types of NHases (L-NHase and H-NHase) from R. rhodochrous J1 were only slightly expressed in E. coli by routine methods, which limits the comprehensive and systematic characterization of the enzyme properties. We successfully expressed the two types of recombinant NHases in E. coli by codon-optimization, engineering of Ribosome Binding Site (RBS) and spacer sequences. The specific activity of the purified L-NHase and H-NHase were 400 U/mg and 234 U/mg, respectively. The molecular mass of L-NHase and H-NHase was identified to be 94 kDa and 504 kDa, respectively, indicating that the quaternary structure of the two types of NHases was the same as those in R. rhodochrous J1. H-NHase exhibited higher substrate and product tolerance than L-NHase. Moreover, higher activity and shorter culture time were achieved in recombinant E. coli, and the whole cell catalyst of recombinant E. coli harboring H-NHase has equivalent efficiency in tolerance to the high-concentration product relative to that in R. rhodochrous J1. These results indicate that biotransformation of nitrile by R. rhodochrous J1 represents a potential alternative to NHase-producing E. coli. PMID- 28644866 TI - The high tolerance to aluminium in crucian carp (Carassius carassius) is associated with its ability to avoid hypoxia. AB - It is well known that aluminium is the principle toxicant killing fish in acidified freshwater systems, and it has been shown that crucian carp (Carassius carassius) can survive exposures to aqueous aluminium levels toxic to most other freshwater fish species. The crucian carp has a remarkable ability to survive anoxic conditions, and the aim of the present study was to reveal if the tolerance to aluminium can be associated with the ability to survive prolonged anoxia. Crucian carps were exposed to either acidic Al-rich water (pH 5.8; 960 MUg Al/l), acidic Al-poor water (pH 5.8; 50 MUg Al/l) or untreated control water (pH 6.5; 50 MUg Al/l). Blood, muscle and gill samples were collected from exposed fish, and closed respirometry was performed to measure critical O2-tension an normoxic O2-consumption. The results show an increased gill surface area in Al exposed fish, while the critical O2-tension did not change. The normoxic O2 consumption was lower in Al-exposed fish and might be due to a reduced metabolic rate. The results suggest that crucian carp exposed to aluminium do not become hypoxic, since haematocrit, plasma lactate and blood ethanol did not differ from that of control fish after 14 days of exposure. We also observed an initial loss of plasma chloride and sodium, followed by a stabilisation of these ions at a lower level than in control fish. The decrease in plasma ions caused a transient increase in haematocrit and water content in muscle tissue, returning to control levels when the ion concentrations stabilised, suggesting that the water balance was restored. We conclude that the high tolerance to aluminium in crucian carp is associated with its ability to avoid hypoxia as well as an ability to counteract a continuous loss of plasma ions. PMID- 28644867 TI - Host-derived apolipoproteins play comparable roles with viral secretory proteins Erns and NS1 in the infectious particle formation of Flaviviridae. AB - Amphipathic alpha-helices of exchangeable apolipoproteins have shown to play crucial roles in the formation of infectious hepatitis C virus (HCV) particles through the interaction with viral particles. Among the Flaviviridae members, pestivirus and flavivirus possess a viral structural protein Erns or a non structural protein 1 (NS1) as secretory glycoproteins, respectively, while Hepacivirus including HCV has no secretory glycoprotein. In case of pestivirus replication, the C-terminal long amphipathic alpha-helices of Erns are important for anchoring to viral membrane. Here we show that host-derived apolipoproteins play functional roles similar to those of virally encoded Erns and NS1 in the formation of infectious particles. We examined whether Erns and NS1 could compensate for the role of apolipoproteins in particle formation of HCV in apolipoprotein B (ApoB) and ApoE double-knockout Huh7 (BE-KO), and non-hepatic 293T cells. We found that exogenous expression of either Erns or NS1 rescued infectious particle formation of HCV in the BE-KO and 293T cells. In addition, expression of apolipoproteins or NS1 partially rescued the production of infectious pestivirus particles in cells upon electroporation with an Erns deleted non-infectious RNA. As with exchangeable apolipoproteins, the C-terminal amphipathic alpha-helices of Erns play the functional roles in the formation of infectious HCV or pestivirus particles. These results strongly suggest that the host- and virus-derived secretory glycoproteins have overlapping roles in the viral life cycle of Flaviviridae, especially in the maturation of infectious particles, while Erns and NS1 also participate in replication complex formation and viral entry, respectively. Considering the abundant hepatic expression and liver-specific propagation of these apolipoproteins, HCV might have evolved to utilize them in the formation of infectious particles through deletion of a secretory viral glycoprotein gene. PMID- 28644869 TI - Status of chemistry lab safety in Nepal. AB - Chemistry labs can become a dangerous environment for students as the lab exercises involve hazardous chemicals, glassware, and equipment. Approximately one hundred thousand students take chemistry laboratory classes annually in Nepal. We conducted a survey on chemical lab safety issues across Nepal. In this paper, we assess the safety policy and equipment, protocols and procedures followed, and waste disposal in chemistry teaching labs. Significant population of the respondents believed that there is no monitoring of the lab safety in their lab (p<0.001). Even though many labs do not allow food and beverages inside lab and have first aid kits, they lack some basic safety equipment. There is no institutional mechanism to dispose lab waste and chemical waste is disposed haphazardly. Majority of the respondents believed that the safety training should be a part of educational training (p = 0.001) and they would benefit from short course and/or workshop on lab safety (p<0.001). PMID- 28644868 TI - Electrophysiological alterations in a murine model of chronic coxsackievirus B3 myocarditis. AB - INTRODUCTION: Coxsackievirus B3 (CVB3) is known to induce acute and chronic myocarditis. Most infections are clinically unapparent but some patients suffer from ventricular arrhythmias (VA) and sudden cardiac death (SCD). Studies showed that acute CVB3 infection may cause impaired function of cardiac ion channels, creating a proarrhythmic substrate. However, it is unknown whether low level CVB3+ expression in myocytes may cause altered cardiac electrophysiology leading to VA. METHODS: Cellular electrophysiology was used to analyze cellular action potentials (APs) and occurrence of afterdepolarizations from isolated cardiomyocytes of wildtype (WT) and transgenic CVB3DeltaVP0 (CVB3+) mice. Further, we studied surface ECGs, monophasic APs, ventricular effective refractory period (VERP) and inducibility of VAs in Langendorff-perfused whole hearts. All used cardiomyocytes and whole hearts originated from male mice. RESULTS: Cellular action potential duration (APD) in WT and CVB3+ myocytes was unchanged. No difference in mean occurrence or amplitude of afterdepolarizations in WT and CVB3+ myocytes was found. Interestingly, resting membrane potential in CVB3+ myocytes was significantly hyperpolarized (WT: -90.0+/-2.2 mV, n = 7; CVB3+: -114.1+/-3.0 mV, n = 14; p<0.005). Consistently, in Langendorff-perfused hearts, APDs were also not different between WT and CVB3+ whole hearts. Within both groups, we found a heart rate dependent shortening of ADP90 with increasing heart rate in Langendorff-perfused hearts. VERP was significantly prolonged in CVB3+ hearts compared to WT (WT: 36.0+/-2.7 ms, n = 5; CVB3+: 47.0+/-2.0 ms, n = 7; p = 0.018). Resting heart rate (HR) in Langendorff-perfused hearts was not significantly different between both genotypes. Electrical pacing protocols induced no VA in WT and CVB3+ hearts. CONCLUSION: In CVB3+ mice, prolonged ventricular refractoriness and hyperpolarized resting membrane potentials in presence of unchanged APD were observed, suggesting that low level CVB3 expression does not promote VA by altered cardiac electrophysiology in this type of chronic myocarditis. These findings may suggest that other mechanisms such as chronic myocardial inflammation or fibrosis may account for arrhythmias observed in patients with chronic enteroviral myocarditis. PMID- 28644870 TI - Effects of nicotine on corneal wound healing following acute alkali burn. AB - Epidemiological studies have indicated that smoking is a pivotal risk factor for the progression of several chronic diseases. Nicotine, the addictive component of cigarettes, has powerful pathophysiological properties in the body. Although the effects of cigarette smoking on corneal re-epithelialization have been studied, the effects of nicotine on corneal wound healing-related neovascularization and fibrosis have not been fully demonstrated. The aim of this study was to evaluate the effects of chronic administration of nicotine on corneal wound healing following acute insult induced by an alkali burn. BALB/C female mice randomly received either vehicle (2% saccharin) or nicotine (100 or 200 MUg/ml in 2% saccharin) in drinking water ad libitum. After 1 week, animals were re-randomized and the experimental group was subjected to a corneal alkali burn, and then nicotine was administered until day 14 after the alkali burn. A corneal alkali burn model was generated by placing a piece of 2 mm-diameter filter paper soaked in 1N NaOH on the right eye. Histopathological analysis and the expression level of the pro-angiogenic genes vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9) revealed that chronic nicotine administration enhanced alkali burn-induced corneal neovascularization. Furthermore, the mRNA expression of the pro-fibrogenic factors alpha-smooth muscle actin (alphaSMA), transforming growth factor-beta (TGF-beta), and collagen alpha1 (Col1) was enhanced in the high-concentration nicotine-treated group compared with the vehicle group after corneal injury. Immunohistochemical analysis also showed that the alphaSMA positive area was increased in chronic nicotine-treated mice after corneal alkali burn. An in vitro assay found that expression of the alpha3, alpha7, and beta1 nicotinic acetylcholine receptor (nAChR) subunits was significantly increased by chemical injury in human corneal fibroblast cells. Moreover, alkali-induced fibrogenic gene expression and proliferation of fibroblast cells were further increased by treatment with nicotine and cotinine. The proliferation of such cells induced by treatment of nicotine and cotinine was reduced by inhibition of the PI3K and PKC pathways using specific inhibitors. In conclusion, chronic administration of nicotine accelerated the angiogenic and fibrogenic healing processes in alkali-burned corneal tissue. PMID- 28644871 TI - Predicting the bounds of large chaotic systems using low-dimensional manifolds. AB - Predicting extrema of chaotic systems in high-dimensional phase space remains a challenge. Methods, which give extrema that are valid in the long term, have thus far been restricted to models of only a few variables. Here, a method is presented which treats extrema of chaotic systems as belonging to discretised manifolds of low dimension (low-D) embedded in high-dimensional (high-D) phase space. As a central feature, the method exploits that strange attractor dimension is generally much smaller than parent system phase space dimension. This is important, since the computational cost associated with discretised manifolds depends exponentially on their dimension. Thus, systems that would otherwise be associated with tremendous computational challenges, can be tackled on a laptop. As a test, bounding manifolds are calculated for high-D modifications of the canonical Duffing system. Parameters can be set such that the bounding manifold displays harmonic behaviour even if the underlying system is chaotic. Thus, solving for one post-transient forcing cycle of the bounding manifold predicts the extrema of the underlying chaotic problem indefinitely. PMID- 28644874 TI - Position and orientation inference via on-board triangulation. AB - This work proposes a new approach to determine the spatial location and orientation of an object using measurements performed on the object itself. The on-board triangulation algorithm we outline could be implemented in lieu of, or in addition to, well-known alternatives such as Global Positioning System (GPS) or standard triangulation, since both of these correspond to significantly different geometric pictures and necessitate different hardware and algorithms. We motivate the theory by describing situations in which on-board triangulation would be useful and even preferable to standard methods. The on-board triangulation algorithm we outline involves utilizing dumb beacons which broadcast omnidirectional single frequency radio waves, and smart antenna arrays on the object itself to infer the direction of the beacon signals, which may be used for onboard calculation of the position and orientation of the object. Numerical examples demonstrate the utility of the method and its noise tolerance. PMID- 28644872 TI - Helicobacter pylori gene silencing in vivo demonstrates urease is essential for chronic infection. AB - Helicobacter pylori infection causes chronic active gastritis that after many years of infection can develop into peptic ulceration or gastric adenocarcinoma. The bacterium is highly adapted to surviving in the gastric environment and a key adaptation is the virulence factor urease. Although widely postulated, the requirement of urease expression for persistent infection has not been elucidated experimentally as conventional urease knockout mutants are incapable of colonization. To overcome this constraint, conditional H. pylori urease mutants were constructed by adapting the tetracycline inducible expression system that enabled changing the urease phenotype of the bacteria during established infection. Through tight regulation we demonstrate that urease expression is not only required for establishing initial colonization but also for maintaining chronic infection. Furthermore, successful isolation of tet-escape mutants from a late infection time point revealed the strong selective pressure on this gastric pathogen to continuously express urease in order to maintain chronic infection. In addition to mutations in the conditional gene expression system, escape mutants were found to harbor changes in other genes including the alternative RNA polymerase sigma factor, fliA, highlighting the genetic plasticity of H. pylori to adapt to a changing niche. The tet-system described here opens up opportunities to studying genes involved in the chronic stage of H. pylori infection to gain insight into bacterial mechanisms promoting immune escape and life-long infection. Furthermore, this genetic tool also allows for a new avenue of inquiry into understanding the importance of various virulence determinants in a changing biological environment when the bacterium is put under duress. PMID- 28644873 TI - Circular RNA expression profiling of human granulosa cells during maternal aging reveals novel transcripts associated with assisted reproductive technology outcomes. AB - Circular RNAs (circRNAs) are a unique class of endogenous RNAs which could be used as potential diagnostic and prognostic biomarkers of many diseases. Our study aimed to investigate circRNA profiles in human granulosa cells (GCs) during maternal aging and to uncover age-related circRNA variations that potentially reflect decreased oocyte competence. CircRNAs in GCs from in vitro fertilization (IVF) patients with young age (YA, <= 30 years) and advanced age (AA, >= 38 years) were profiled by microarray, and validated in 20 paired samples. The correlation between circRNAs expression and clinical characteristics was analyzed in additional 80 samples. Chip-based analysis revealed 46 up-regulated and 11 down-regulated circRNAs in AA samples (fold change > 2.0). Specifically, circRNA_103829, circRNA_103827 and circRNA_104816 were validated to be up regulated, while circRNA_101889 was down-regulated in AA samples. After adjustment for gonadotropin treatment, only circRNA_103827 and circRNA_104816 levels were positively associated with maternal age (partial r = 0.332, P = 0.045; partial r = 0.473, P = 0.003; respectively). Moreover, circRNA_103827 and circRNA_104816 expressions in GCs were negatively correlated with the number of top quality embryos (r = -0.235, P = 0.036; r = -0.221, P = 0.049; respectively). Receiver operating characteristic (ROC) curve analysis indicated that the performance of circRNA_103827 for live birth prediction reached 0.698 [0.570 0.825], with 77.2% sensitivity and 60.9% specificity (P = 0.006), and that of circRNA_104816 was 0.645 [0.507-0.783] (P = 0.043). Bioinformatics analysis revealed that both circRNAs were potentially involved in glucose metabolism, mitotic cell cycle, and ovarian steroidogenesis. Therefore, age-related up regulation of circRNA_103827 and circRNA_104816 might be potential indicators of compromised follicular micro-environment which could be used to predict IVF prognosis, and improve female infertility management. PMID- 28644875 TI - Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB. AB - Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended. PMID- 28644876 TI - Effects of ploidy level and haplotype on variation of photosynthetic traits: Novel evidence from two Fragaria species. AB - To reveal the effects of ploidy level and haplotype on photosynthetic traits, we chose 175 genotypes of wild strawberries belonging to two haplotypes at two types of ploidy levels (diploidy and tetraploidy) and measured photosynthetic traits. Our results revealed that ploidy significantly affected the characteristics of light-response curves, CO2-response curves, and leaf gas exchange parameters, except intercellular CO2 concentration (Ci). Tetraploid species had a lower light saturation point (LSP) and CO2 saturation point (CSP), higher light compensation point (LCP), dark respiration (Rd), and CO2 compensation point (CCP) than diploid species. Furthermore, tetraploid species have lower photosynthetic capacity than diploid species, including net photosynthetic rate (Pn), stomatal conductivity (Gs), and transpiration rate (Tr). In addition, haplotype had a significant effect on LSP, CSP, Tr, and Ci as well as a significant interactive effect between ploidy and haplotype on the maximal photosynethic rate of the light response curve and Rd. Most of the variance existed within haplotypes among individuals. These results suggest that polyploidization was the main driver for the evolution of photosynthesis with increasing ploidy level (i.e. from diploidy to tetraploidy in Fragaria species), while the origin of a chromosome could also affect the photosynthetic traits and the polyploidization effect on photosynthetic traits. PMID- 28644877 TI - Patient-experienced burden of treatment in patients with multimorbidity - A systematic review of qualitative data. AB - OBJECTIVE: To synthesize existing qualitative literature on patient-experienced burden of treatment in multimorbid patients. METHODS: A literature search identified available qualitative studies on the topic of burden of treatment in multimorbidity and meta-ethnography was applied as method. The authors' original findings were preserved, but also synthesized to new interpretations to investigate the concept of the burden of treatment using the Cumulative Complexity Model. RESULTS: Nine qualitative studies were identified. The majority of the 1367 participants from 34 different countries were multimorbid. The treatment burden components, experienced by patients, were identified for each study. The components financial burden, lack of knowledge, diet and exercise, medication burden and frequent healthcare reminding patients of their health problem were found to attract additional attention from the multimorbid patients. In studies conducted in the US and Australia the financial burden and the time and travel burden were found most straining to patients with deprived socioeconomic status. The burden of treatment was found to be a complex concept consisting of many different components and factors interacting with each other. The size of the burden was associated to the workload of demands (number of conditions, number of medications and health status), the capacity (cognitive, physical and financial resources, educational level, cultural background, age, gender and employment conditions) and the context (structure of healthcare and social support). Patients seem to use strategies such as prioritizing between treatments to diminish the workload and mobilizing and coordinating resources to improve their ability to manage the burden of treatment. They try to routinize and integrate the treatment into their daily lives, which might be a way to maintain the balance between workload and capacity. CONCLUSIONS: Healthcare providers need to increase the focus on minimizing multimorbid patients' burden of treatment. Findings in this review suggest that the weight of the burden needs to be established in the individual patient and components of the burden must be identified. PMID- 28644878 TI - Tumor location as a novel high risk parameter for stage II colorectal cancers. AB - Current studies do not accurately evaluate the influence of tumor location on survival of colorectal cancer patients. This study aimed to explore whether tumor location could be identified as another high-risk factor in stage II colorectal cancer by using data identified from the Surveillance, Epidemiology, and End Results database. All colorectal cancer patients between 2004 and 2008 were grouped into three according to tumor location. Of 33,789 patients diagnosed with stage II colorectal cancer, 46.8% were right colon cancer, 37.5% were left colon cancer and 15.7% were rectal cancer. The 5-year cancer specific survivals were examined. Right colon cancer was associated with the female sex, older age (> 50), and having over 12 lymph nodes resected. Conversely, rectal cancer was associated with the male sex, patients younger than 50 years of age and insufficient lymph node resection. The characteristics of left colon cancer were between them and associated with Asian or Pacific Islander populations, T4 stage, and Grade II patients. The prognostic differences between three groups were significant and retained after stratification by T stage, histological grade, number of regional nodes dissected, age at diagnose, race and sex. Furthermore, the significant difference of location was retained as an independent high-risk parameter. Thus, stage II colorectal cancers of different locations have different clinic-pathological features and cancer-specific survivals, and tumor location should be recognized as another high-risk parameter in stage II colorectal cancer. PMID- 28644879 TI - Identification of a novel fungus, Trichoderma asperellum GDFS1009, and comprehensive evaluation of its biocontrol efficacy. AB - Due to its efficient broad-spectrum antimicrobial activity, Trichoderma has been established as an internationally recognized biocontrol fungus. In this study, we found and identified a novel strain of Trichoderma asperellum, named GDFS1009. The mycelium of T. asperellum GDFS1009 exhibits a high growth rate, high sporulation capacity, and strong inhibitory effects against pathogens that cause cucumber fusarium wilt and corn stalk rot. T. asperellum GDFS1009 secretes chitinase, glucanase, and protease, which can degrade the cell walls of fungi and contribute to mycoparasitism. The secreted xylanases are good candidates for inducing plant resistance and enhancing plant immunity against pathogens. RNA sequencing (RNA-seq) and gas chromatography-mass spectrometry (GC-MS) showed that T. asperellum GDFS1009 produces primary metabolites that are precursors of antimicrobial compounds; it also produces a variety of antimicrobial secondary metabolites, including polyketides and alkanes. In addition, this study speculated the presence of six antimicrobial peptides via ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF MS/MS). Future studies should focus on these antimicrobial metabolites for facilitating widespread application in the field of agricultural bio-control. PMID- 28644880 TI - O-GlcNAcylation mediates the control of cytosolic phosphoenolpyruvate carboxykinase activity via Pgc1alpha. AB - PGC1alpha is a coactivator of many transcription factors and cytosolic phosphoenolpyruvate carboxykinase (PCK1) is a key enzyme for gluconeogenesis. PGC1alpha interacts with the transcription factor PPARgamma to stimulate PCK1 expression and thus de novo glucose synthesis. These proteins are not only important for central energy metabolism but also for supplying intermediates for other metabolic pathways, including lipidogenesis and protein synthesis and might therefore be important factors in the ethiopathogenesis of metabolic disorders like diabetes but also in other pathologies like cancer. Since polymorphisms in these proteins have been related to some phenotypic traits in animals like pigs and PGC1alpha G482S polymorphism increases fat deposition in humans, we have investigated the molecular basis of such effects focusing on a commonly studied polymorphism in pig Pgc1alpha, which changes a cysteine at position 430 (WT) of the protein to a serine (C430S). Biochemical analyses show that Pgc1alpha WT stimulates higher expression of human PCK1 in HEK293T and HepG2 cells. Paradoxically, Pgc1alpha WT is less stable than Pgc1alpha p.C430S in HEK293T cells. However, the study of different post-translational modifications shows a higher O-GlcNAcylation level of Pgc1alpha p.C430S. This higher O-GlcNAcylation level significantly decreases the interaction between Pgc1alpha and PPARgamma demonstrating the importance of post-translational glycosylation of PGC1alpha in the regulation of PCK1 activity. This, furthermore, could explain at least in part the observed epistatic effects between PGC1alpha and PCK1 in pigs. PMID- 28644881 TI - Gestational diabetes mellitus and risk of type 2 diabetes 10 years after the index pregnancy in Sri Lankan women-A community based retrospective cohort study. AB - BACKGROUND: Women with a history of gestational diabetes mellitus (GDM) have an increased risk of type 2 diabetes mellitus (T2DM) later in life compared to women with no GDM. This study was aimed to determine the risk of developing T2DM 10 years after GDM in Sri Lankan women. METHODS: A retrospective cohort study was conducted in the Colombo district, Sri Lanka. 7205 women who delivered a child in 2005 were identified through Public Health Midwives in the field. Women with antenatal records were interviewed and relevant data were extracted from medical records to identify potential participants. One hundred and nineteen women who had GDM and 240 women who did not have GDM were recruited. Current diagnosis of diabetes was based on history, relevant medical records and blood reports within the past 1 year. RESULTS: The mean duration of follow up was 10.9 (SD = 0.35) years in the GDM group and 10.8 (SD = 0.31) years in the non-GDM group. The incidence density of diabetes in the GDM group was 56.3 per 1000 person years compared to 5.4 per 1000 person years in non GDM group giving a rate ratio of 10.42 (95% CI: 6.01-19.12). A woman having GDM in the index pregnancy was 10.6 times more likely to develop diabetes within 10 years compared to women with no GDM after controlling for other confounding variables. Delivering a child after 30 years, being treated with insulin during the pregnancy and delivering a baby weighing more than 3.5 Kg were significant predictors of development of T2DM after controlling for family history of diabetes mellitus (DM), GDM in previous pregnancies, parity and gestational age at delivery. CONCLUSIONS: Women with GDM had a 10-fold higher risk of developing T2DM during a 10-year follow up period as compared to women with no GDM after controlling for other confounding variables. PMID- 28644882 TI - A spatially explicit risk assessment approach: Cetaceans and marine traffic in the Pelagos Sanctuary (Mediterranean Sea). AB - Spatially explicit risk assessment is an essential component of Marine Spatial Planning (MSP), which provides a comprehensive framework for managing multiple uses of the marine environment, minimizing environmental impacts and conflicts among users. In this study, we assessed the risk of the exposure to high intensity vessel traffic areas for the three most abundant cetacean species (Stenella coeruleoalba, Tursiops truncatus and Balaenoptera physalus) in the southern area of the Pelagos Sanctuary, which is the only pelagic Marine Protected Area (MPA) for marine mammals in the Mediterranean Sea. In particular, we modeled the occurrence of the three cetacean species as a function of habitat variables in June by using hierarchical Bayesian spatial-temporal models. Similarly, we modelled the marine traffic intensity in order to find high risk areas and estimated the potential conflict due to the overlap with the cetacean home ranges. Results identified two main hot-spots of high intensity marine traffic in the area, which partially overlap with the area of presence of the studied species. Our findings emphasize the need for nationally relevant and transboundary planning and management measures for these marine species. PMID- 28644883 TI - Effects of dietary inclusion of high concentrations of crude glycerin on meat quality and fatty acid profile of feedlot fed Nellore bulls. AB - Crude glycerin, the main by-product of biodiesel production, can replace dietary energy sources, such as corn. The objective of this study was to evaluate the inclusion of up to 30% of crude glycerin in dry matter (DM) of the total diets, and its effects on meat quality parameters of feedlot Nellore bulls. Thirty animals (227.7 +/- 23.8 kg body weight; 18 months old) were housed in individual pens and fed 5 experimental diets, containing 0, 7.5, 15, 22.5 or 30% crude glycerin (DM basis). After 103 d (21 d adaptation) animals were slaughtered and the Longissimus muscle was collected. The characteristics assessed were chemical composition, fatty acid profile, cholesterol, shear force, pH, color, water holding capacity, cooking loss and sensory properties. The increasing inclusion of crude glycerin in the diets did not affect the chemical composition of the Longissimus muscle (P > 0.10). A quadratic effect was observed when levels of crude glycerin were increased, on the concentration of pentadecanoic, palmitoleic and eicosenoic fatty acids in meat (P < 0.05), and on the activity of the delta-9 desaturase 16 and delta-9 desaturase 18 enzymes (P < 0.05). The addition of crude glycerin increased the gamma linolenic fatty acid concentration (P < 0.01), and altered the monounsaturated fatty acids in Longissimus muscle of animals (Pquad. < 0.05). Crude glycerin decreased cholesterol content in meat (P < 0.05), and promoted higher flavor score and greasy intensity perception of the meat (P < 0.01). The inclusion of up to 30% crude glycerin in Nellore cattle bulls'diets (DM basis) improves meat cholesterol and sensory attributes, such as flavor, without affecting significantly the physical traits, the main fatty acid concentrations and the chemical composition. PMID- 28644885 TI - Organic anion transporting polypeptide 1B3 can form homo- and hetero-oligomers. AB - OATP1B3 is a 12 transmembrane domain protein expressed at the basolateral membrane of human hepatocytes where it mediates the uptake of numerous drugs and endogenous compounds. Previous western blot results suggest the formation of OATP1B3 multimers. In order to better understand the function of OATP1B3 under normal physiological conditions, we investigated its oligomerization status. We transiently transfected OATP1B3 with a C-terminal His-, FLAG- or HA-tag in HEK293 cells and used co-immunoprecipitation and a Proximity Ligation Assay to detect interactions between the different constructs. All three constructs retained similar transport rates as wild-type OATP1B3. Immunofluorescence experiments indicated that in contrast to wild-type, His- and FLAG-tagged OATP1B3, where the C-terminal end is on the cytoplasmic side of the membrane, the C-terminal end of HA-tagged OATP1B3 is extracellular. After cross-linking, anti-FLAG antibodies were able to pull down FLAG-tagged OATP1B3 (positive control) and co-transfected His- or HA-tagged OATP1B3, demonstrating the formation of homo-oligomers and suggesting that the C-terminal part is not involved in oligomer formation. We confirmed co-localization of His- and FLAG-tagged OATP1B3 in transfected HEK293 cells with the Proximity Ligation Assay. Transport studies with a non-functional OATP1B3 mutant suggest that the individual subunits and not the whole oligomer are the functional units in the homo-oligomers. In addition, we also detected OATP1B3-FLAG co-localization with OATP1B1-His or NTCP-His, suggesting that OATP1B3 also hetero-oligomerizes with other transport proteins. Using the Proximity Ligation Assay with transporter specific antibodies, we demonstrate close association of OATP1B3 with NTCP in frozen human liver tissue. These findings demonstrate that OATP1B3 can form homo- and hetero-oligomers and suggest a potential co-regulation of the involved transporters. PMID- 28644884 TI - Ligand-induced rapid skeletal muscle atrophy in HSA-Fv2E-PERK transgenic mice. AB - BACKGROUND: Formation of 43S and 48S preinitiation complexes plays an important role in muscle protein synthesis. There is no muscle-wasting mouse model caused by a repressed 43S preinitiation complex assembly. OBJECTIVE: The aim of the present study was to develop a convenient mouse model of skeletal muscle wasting with repressed 43S preinitiation complex assembly. MATERIAL AND METHODS: A ligand activatable PERK derivative Fv2E-PERK causes the phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), which inhibits 43S preinitiation complex assembly. Thus, muscle atrophic phenotypes, intracellular signaling pathways, and intracellular free amino acid profiles were investigated in human skeletal muscle alpha-actin (HSA) promoter-driven Fv2E-PERK transgenic (Tg) mice. RESULTS: HSA Fv2E-PERK Tg mice treated with the artificial dimerizer AP20187 phosphorylates eIF2alpha in skeletal muscles and leads to severe muscle atrophy within a few days of ligand injection. Muscle atrophy was accompanied by a counter regulatory activation of mTORC1 signaling. Moreover, intracellular free amino acid levels were distinctively altered in the skeletal muscles of HSA-Fv2E-PERK Tg mice. CONCLUSIONS: As a novel model of muscle wasting, HSA-Fv2E-PERK Tg mice provide a convenient tool for studying the pathogenesis of muscle loss and for assessing putative therapeutics. PMID- 28644886 TI - Complex I inhibition augments dichloroacetate cytotoxicity through enhancing oxidative stress in VM-M3 glioblastoma cells. AB - The robust glycolytic metabolism of glioblastoma multiforme (GBM) has proven them susceptible to increases in oxidative metabolism induced by the pyruvate mimetic dichloroacetate (DCA). Recent reports demonstrate that the anti-diabetic drug metformin enhances the damaging oxidative stress associated with DCA treatment in cancer cells. We sought to elucidate the role of metformin's reported activity as a mitochondrial complex I inhibitor in the enhancement of DCA cytotoxicity in VM M3 GBM cells. Metformin potentiated DCA-induced superoxide production, which was required for enhanced cytotoxicity towards VM-M3 cells observed with the combination. Similarly, rotenone enhanced oxidative stress resultant from DCA treatment and this too was required for the noted augmentation of cytotoxicity. Adenosine monophosphate kinase (AMPK) activation was not observed with the concentration of metformin required to enhance DCA activity. Moreover, addition of an activator of AMPK did not enhance DCA cytotoxicity, whereas an inhibitor of AMPK heightened the cytotoxicity of the combination. Our data indicate that metformin enhancement of DCA cytotoxicity is dependent on complex I inhibition. Particularly, that complex I inhibition cooperates with DCA-induction of glucose oxidation to enhance cytotoxic oxidative stress in VM-M3 GBM cells. PMID- 28644887 TI - Sarcopenia is a predictive factor for intestinal resection in admitted patients with Crohn's disease. AB - The relationship between skeletal muscle volume and the prognosis of patients with inflammatory bowel disease (IBD) remains undetermined. We conducted a retrospective study of 72 IBD patients who were admitted to the hospital due to disease exacerbation. We enrolled IBD patients who had undergone abdominal computed tomography and assessed the nutritional indices, such as the Onodera's prognostic nutritional index (O-PNI) and the controlling nutritional status (CONUT) index. The L3 skeletal muscle index (SMI), which is the ratio of the cross-sectional area of skeletal muscles at the level of the third lumbar (L3) vertebra to the height squared, was used to identify sarcopenia. Sarcopenia, defined as a low SMI, was observed in 42% of all IBD patients (37% with Crohn's disease (CD) and 48% with ulcerative colitis (UC)). In UC patients, the O-PNI and CONUT values, height, and albumin levels were significantly lower than in CD patients. The SMI strongly correlated with sex, body weight, albumin level, and O PNI in IBD patients. Multivariate analysis using the Cox regression model demonstrated that the presence of sarcopenia (P = 0.015) and disease type (CD or UC) (P = 0.007) were significant factors predicting intestinal resection. The cumulative operation-free survival rate was significantly lower for sarcopenic patients than in all IBD patients (P = 0.003) and a stratified analysis of CD patients (P = 0.001) using the Kaplan-Meier method and log-rank test. The L3 skeletal muscle area is a prognostic factor for intestinal resection in patients with CD. PMID- 28644888 TI - Fragmentation of the mitochondrial network in skin in vivo. AB - Mitochondria form dynamic networks which adapt to the environmental requirements of the cell. We investigated the aging process of these networks in human skin cells in vivo by multiphoton microscopy. A study on the age-dependency of the mitochondrial network in young and old volunteers revealed that keratinocytes in old skin establish a significantly more fragmented network with smaller and more compact mitochondrial clusters than keratinocytes in young skin. Furthermore, we investigated the mitochondrial network during differentiation processes of keratinocytes within the epidermis of volunteers. We observe a fragmentation similar to the age-dependent study in almost all parameters. These parallels raise questions about the dynamics of biophysical network structures during aging processes. PMID- 28644889 TI - Evaluation of different serological assays for early diagnosis of leptospirosis in Martinique (French West Indies). AB - BACKGROUND: Leptospirosis is a potentially life-threatening but curable zoonosis whose prognosis depends on accurate and timely diagnosis. Because of its non specific clinical presentation, laboratory testing is essential to confirm the diagnosis. Here, we aimed to assess the performance of two enzyme-linked immunosorbent assays (ELISAs) (ELISA Serion and ELISA-Hb Pasteur) and one immunodot (GenBio) using quantitative PCR (qPCR) as gold standard, instead of the traditional microscopic agglutination test, for the diagnosis of acute leptospirosis in an endemic area. METHODOLOGY/PRINCIPAL FINDINGS: Between January 2011 and December 2012, a total of 122 patients were diagnosed with leptospirosis, as confirmed by qPCR at the University Hospital of Martinique. Among them, 103 had at least one serum sample available for analysis. Performance of each serological assay was evaluated according to days' post onset of symptoms (DPO) and local species diversity (which included L. santarosai, L. interrogans, L. kirschneri, L. borgpetersenii, L. noguchii, and L. kmetyi). Several thresholds were tested to optimize accuracy. When considering the manufacturer's threshold, the sensitivity of ELISA Serion, ELISA-Hb Pasteur and GenBio immunodot was 75%, 67% and 64%, while specificity was 92%, 98% and 100%, respectively. Moreover, the threshold optimization allowed a significant improvement in specificity for the ELISA Serion from 92% to 99% (p<0.05). During the first 5 DPO, sensitivities were 35%, 30% and 42% for ELISA Serion, ELISA-Hb Pasteur and GenBio immunodot, respectively. However, between 6?10 DPO, these sensitivities dramatically increased to reach 86%, 76% and 67%, respectively. Performances of the three assays were not affected by the species studied. CONCLUSIONS/SIGNIFICANCE: All these serological assays showed the potential for diagnosing leptospirosis after (but not before) 6 days' post onset of symptoms. In a high prevalence setting, where highest specificities are needed, threshold optimizing should be performed for this purpose. PMID- 28644890 TI - Drivers of coral reef marine protected area performance. AB - Coral reefs are severely threatened and a principal strategy for their conservation is marine protected areas (MPAs). However the drivers of MPA performance are complex and there are likely to be trade-offs between different types of performance (e.g. conservation or welfare related outcomes). We compiled a global dataset from expert knowledge for 76 coral reef MPAs in 33 countries and identified a set of performance measures reflecting ecological and socio-economic outcomes, achievement of aims and reduction of threats, using spatial or temporal comparisons wherever possible. We wanted to test the extent to which distinct types of performance occurred simultaneously, understood as win-win outcomes. Although certain performance measures were correlated, most were not, suggesting trade-offs that limit the usefulness of composite performance scores. Hypotheses were generated as to the impact of MPA features, aims, location, management and contextual variables on MPA performance from the literature. A multivariate analysis was used to test hypotheses as to the relative importance of these "drivers" on eight uncorrelated performance measures. The analysis supported some hypotheses (e.g. benefit provision for the local community improved performance), but not others (e.g. higher overall budget and more research activity did not). Factors endogenous to the MPA (such as size of the no-take area) were generally more significant drivers of performance than exogenous ones (such as national GDP). Different types of performance were associated with different drivers, exposing the trade-offs inherent in management decisions. The study suggests that managers are able to influence MPA performance in spite of external threats and could inform adaptive management by providing an approach to test for the effects of MPA features and management actions in different contexts and so to inform decisions for allocation of effort or funds to achieve specific goals. PMID- 28644891 TI - The impact of changes in dietary knowledge on adult overweight and obesity in China. AB - Overweight and obesity are rapidly growing threats in China. Improvement in dietary knowledge can potentially prevent overweight and obesity, conditions which are receiving substantial attention from international organizations and governments. The purpose of this study was to investigate the impact of changes in dietary knowledge on adult overweight and obesity, using a balanced panel data consisting of 10,401 samples from the 2006, 2009, and 2011 iterations of the China Health and Nutrition Survey. Results indicate that overweight and obesity are becoming increasingly problematic in China, and the level of dietary knowledge among Chinese adults needs improvement. Moreover, the empirical results indicate that changes in dietary knowledge among adults has no significant influence on adult overweight and obesity, a likely result of lacking systematic dietary knowledge and having inadequate guidance on overweight/obesity-related behaviors. PMID- 28644893 TI - High speed rail and coastal tourism: Identifying passenger profiles and travel behaviour. AB - In this paper, we characterise tourists most likely to visit a coastal destination by high-speed rail (HSR). Our data came from a survey conducted among HSR passengers during 2014's high season (July and August) at Spain's Camp de Tarragona and Alicante Stations, each of which is near a mass tourism destination on the Mediterranean coast: the Costa Daurada and the Costa Blanca, respectively. We used responses to the survey, which presented binary discrete-choice situations, to construct a database necessary for a logistic regression model that allowed us to examine how passenger profile, trip characteristics, and stay conditions influenced the use of HSR services on visits to each coastal destination. Results highlighted significant differences in the profiles of tourists who arrived at each destination by HSR and, in turn, that no specific tourist profile is associated with HSR, even for two stations that serve sunny beach destinations. Among its implications, to analyse travellers that HSR can attract, it is vital to consider the specific characteristics of each destination and its current market. PMID- 28644892 TI - R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity. AB - Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes. PMID- 28644894 TI - Northward dispersal of sea kraits (Laticauda semifasciata) beyond their typical range. AB - Marine reptiles are declining globally, and recent climate change may be a contributing factor. The study of sea snakes collected beyond their typical distribution range provides valuable insight on how climate change affects marine reptile populations. Recently, we collected 12 Laticauda semifasciata (11 females, 1 male) from the waters around southern South Korea-an area located outside its typical distribution range (Japan, China including Taiwan, Philippines and Indonesia). We investigated the genetic origin of Korean specimens by analyzing mitochondrial cytochrome b gene (Cytb) sequences. Six individuals shared haplotypes with a group found in Taiwan-southern Ryukyu Islands, while the remaining six individuals shared haplotypes with a group encompassing the entire Ryukyu Archipelago. These results suggest L. semifasciata moved into Korean waters from the Taiwan-Ryukyu region via the Taiwan Warm Current and/or the Kuroshio Current, with extended survival facilitated by ocean warming. We highlight several contributing factors that increase the chances that L. semifasciata establishes new northern populations beyond the original distribution range. PMID- 28644895 TI - Floristic characteristics and affinities in Lao PDR, with a reference to the biogeography of the Indochina peninsula. AB - The flora of Laos is composed of 5,005 species in 1,373 genera and 188 families of seed plants. Floristic and geographical attributes of the flora were analyzed. Tropical floristic elements at the family and generic levels contributed a majority (62.23% of the families and 82.30% of the genera) of the flora, of which the dominant geographical elements were pantropical distribution (42.02% of families) and tropical Asian distribution (30.08% of genera). This revealed that the flora of Lao PDR is tropical in nature and has a conspicuously tropical Asian affinity. Compared with the neighbouring countries of the Indochina peninsula, the flora of Laos has similar floristic composition and geographical elements. The floras of these Indochinese countries have similarities of more than 77.84% at the generic level, which suggests that they compose an affiliated biogeographical region. However, the flora of Laos showed the highest similarity to the flora of Vietnam (92.13%), followed by Myanmar (86.01%) at the generic level, but has less East Asian and North Temperate elements than Vietnam, and less North Temperate elements than Myanmar. These differences among the compared countries could be explained by the extrusion of the Indochinese block with the uplift of the Himalayas. PMID- 28644896 TI - How fast is a collective bacterial state established? AB - Bacteria in a biofilm colony have the capacity to monitor the size and growth conditions for the colony and modify their phenotypical behaviour to optimise attacks, defence, migration, etc. The quorum sensing systems controlling this involve production and sensing of diffusive signal molecules. Frequently, quorum sensing systems carry a positive feedback loop which produces a switch at a threshold size of the colony. This all-or-none switch can be beneficial to create a sudden attack, leaving a host little time to establish a defence. The reaction diffusion system describing a basal quorum sensing loop involves production of signal molecules, diffusion of signal molecules, and detection of signal molecules. We study the ignition process in a numerical solution for a basal quorum sensor and demonstrate that even in a large colony the ignition travels through the whole colony in a less than a minute. The ignition of the positive feedback loop was examined in different approximations. As expected, in the exact calculation the ignition was found to be delayed compared to a calculation where the binding of signal molecules was quasistatic. The buffering of signal molecules is found to have little effect on the ignition process. Contrary to expectation, we find that the ignition does not start when the threshold is reached at the center-instead it allows for the threshold to be approached in the whole colony followed by an almost simultaneous ignition of the whole biofilm aggregate. PMID- 28644897 TI - TRPA1 and TRPV1 contribute to propofol-mediated antagonism of U46619-induced constriction in murine coronary arteries. AB - BACKGROUND: Transient receptor potential (TRP) ion channels have emerged as key components contributing to vasoreactivity. Propofol, an anesthetic is associated with adverse side effects including hypotension and acute pain upon infusion. Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofol-induced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs. METHODS: Hearts were excised from anesthetized mice and coronary arterioles were dissected from control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). Isolated microvessels were cannulated and secured in a temperature-controlled chamber and allowed to equilibrate for 1 hr. Vasoreactivity studies were performed in microvessels pre-constricted with U46619 to assess the dose-dependent relaxation effects of propofol on coronary microvascular tone. RESULTS: Propofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV /- mice. Furthermore, NOS inhibition with L-NAME or endothelium denuding abolished the proporfol-induced depressor response in pre-constricted vessels obtained from all mice. In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild type mice and to a lesser extent in vessels obtained from TRPV1-/-, mice with no effect in vessels obtained from TRPA1-/- or TRPAV-/- mice. CONCLUSIONS: TRPA1 and TRPV1 appear to contribute to the propofol-mediated antagonism of U46619-induced constriction in murine coronary microvessels that involves activation of NOS and BKCa. PMID- 28644898 TI - Spatio-temporal orientation of microtubules controls conical cell shape in Arabidopsis thaliana petals. AB - The physiological functions of epidermal cells are largely determined by their diverse morphologies. Most flowering plants have special conical-shaped petal epidermal cells that are thought to influence light capture and reflectance, and provide pollinator grips, but the molecular mechanisms controlling conical cell shape remain largely unknown. Here, we developed a live-confocal imaging approach to quantify geometric parameters of conical cells in Arabidopsis thaliana (A. thaliana). Through genetic screens, we identified katanin (KTN1) mutants showing a phenotype of decreased tip sharpening of conical cells. Furthermore, we demonstrated that SPIKE1 and Rho of Plants (ROP) GTPases were required for the final shape formation of conical cells, as KTN1 does. Live-cell imaging showed that wild-type cells exhibited random orientation of cortical microtubule arrays at early developmental stages but displayed a well-ordered circumferential orientation of microtubule arrays at later stages. By contrast, loss of KTN1 prevented random microtubule networks from shifting into well-ordered arrays. We further showed that the filamentous actin cap, which is a typical feature of several plant epidermal cell types including root hairs and leaf trichomes, was not observed in the growth apexes of conical cells during cell development. Moreover, our genetic and pharmacological data suggested that microtubules but not actin are required for conical cell shaping. Together, our results provide a novel imaging approach for studying petal conical cell morphogenesis and suggest that the spatio-temporal organization of microtubule arrays plays crucial roles in controlling conical cell shape. PMID- 28644899 TI - New insights in dehydration stress behavior of two maize hybrids using advanced distributed reactivity model (DRM). Responses to the impact of 24 epibrassinolide. AB - Proposed distributed reactivity model of dehydration for seedling parts of two various maize hybrids (ZP434, ZP704) was established. Dehydration stresses were induced thermally, which is also accompanied by response of hybrids to heat stress. It was found that an increased value of activation energy counterparts within radicle dehydration of ZP434, with a high concentration of 24 epibrassinolide (24-EBL) at elevated operating temperatures, probably causes activation of diffusion mechanisms in cutin network and may increases likelihood of formation of free volumes, large enough to accommodate diffusing molecule. Many small random effects were detected and can be correlated with micro disturbing in a space filled with water caused by thermal gradients, increasing capillary phenomena, and which can induce thermo-capillary migration. The influence of seedling content of various sugars and minerals on dehydration was also examined. Estimated distributed reactivity models indicate a dependence of reactivity on structural arrangements, due to present interactions between water molecules and chemical species within the plant. PMID- 28644900 TI - Suppression of chikungunya virus replication and differential innate responses of human peripheral blood mononuclear cells during co-infection with dengue virus. AB - Dengue and chikungunya are viral diseases transmitted to humans by infected Aedes spp. mosquitoes. With an estimated 390 million infected people per year dengue virus (DENV) currently causes the most prevalent arboviral disease. During the last decade chikungunya virus (CHIKV) has caused large outbreaks and has expanded its territory causing millions of cases in Asia, Africa and America. The viruses share a common mosquito vector and during the acute phase cause similar flu-like symptoms that can proceed to more severe or debilitating symptoms. The growing overlap in the geographical distribution of these mosquito-borne infections has led to an upsurge in reported cases of DENV/CHIKV co-infections. Unfortunately, at present we have little understanding of consequences of the co-infections to the human host. The overall aim of this study was to define viral replication dynamics and the innate immune signature involved in concurrent DENV and CHIKV infections in human peripheral blood mononuclear cells (PBMCs). We demonstrate that concomitant infection resulted in a significant reduction of CHIKV progeny and moderate enhancement of DENV production. Remarkably, the inhibitory effect of DENV on CHIKV infection occurred independently of DENV replication. Furthermore, changes in type I IFN, IL-6, IL-8, TNF-alpha, MCP-1 and IP-10 production were observed during concomitant infections. Notably, co-infections led to a significant increase in the levels of TNF-alpha and IL-6, cytokines that are widely considered to play a crucial role in the early pathogenesis of both viral diseases. In conclusion, our study reveals the interplay of DENV/CHIKV during concomitant infection and provides a framework to investigate viral interaction during co-infections. PMID- 28644901 TI - Vascular geometry as a risk factor for non-penetrating traumatic injuries of the aortic arch. AB - PURPOSE: To assess biomechanical factors in aortic arch geometry contributing to the development of non-penetrating aortic arch injury (NAAI) in multiply injured patients with an Injury Severity Score (ISS) >= 16. MATERIAL AND METHODS: 230 consecutive multiply injured trauma patients with an ISS >= 16 admitted to our Level-I trauma center during a consecutive 24-month period were prospectively included of whom 13 presented with NAAI (5.7%). Standardized whole-body CT in a 2x128-detector-row scanner included a head-and-neck CTA. Aortic arch diameters, width, height, angles and thoracic width and height were measured in individuals with NAAI and ISS-, sex-, age-, and trauma mechanism-matched controls. RESULTS: There was no difference between groups regarding sex, age, ISS, and aortic diameters. The aortic arch angle in individuals with NAAI (71.3 degrees +/- 14.9 degrees ) was larger than in healthy control (60.7 degrees +/- 8.6 degrees ; p*<0.05). In patients with NAAI, the distance between ascendent and descendent aorta was larger (5.2 cm +/- 1.9 cm) than in control (2.8 +/- 0.5 cm; ***p<0.001). The aortic arch is higher above tracheal bifurcation in NAAI (3.6 cm +/- 0.6 cm) than in matched control (2.4 cm +/- 0.3 cm; ***p<0.001). Accordingly, the area under the aortic arch, calculated as half of an eliptic shape, is significantly larger in patients with NAAI (15.0 cm2 +/- 6.5 cm2) when compared to age- and sex-matched controls without NAAI (5.5 cm2 +/- 1.3 cm2; ***p<0.001). CONCLUSION: Besides the magnitude of deceleration and direction of impact, width and height of the aortic arch are the 3rd and 4th factor directly contributing to the risk of developing traumatic NAAI in severely injured patients. PMID- 28644904 TI - Sustained Psoriasis Area and Severity Index, Dermatology Life Quality Index and EuroQol-5D response of biological treatment in psoriasis: 10 years of real-world data in the Swedish National Psoriasis Register. AB - BACKGROUND: Few studies have analysed the long-term effects of biological treatment in psoriasis. PsoReg, the Swedish national register for systemic psoriasis treatment, started in 2006 and now includes 10 years of real-world data on the effectiveness of biological treatment. OBJECTIVES: To analyse the long term real-world outcome data of patients who are biologically naive with moderate to-severe psoriasis after switching to biological treatment. METHODS: An observational study of patients who are biologically naive with at least one registration of outcome before switching to biological treatment while included in PsoReg and at least one follow-up visit. Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and EuroQol-5D (EQ-5D) values were analysed at 3-5 months, 6-11 months and at least once after >= 1 year, up to 9 years after the switch to biological treatment. RESULTS: In total, 583 patients fulfilled the inclusion criteria. Of these, 399, 395 and 373 patients had observed outcome data beyond 1 year on the PASI, DLQI and EQ-5D, respectively, and 164, 168 and 152, respectively, were observed in at least three time periods after the switch. Significant (P < 0.01) improvement in PASI, DLQI and EQ-5D scores was observed 3-5 months after the switch and sustained under the whole observation period. The mean PASI, DLQI and EQ-5D changed from 13.5 +/- 9.1, 9.0 +/- 8.1 and 0.74 +/- 0.22, respectively, before the switch, to 4.0 +/- 3.5, 3.7 +/- 4.7 and 0.79 +/- 0.21, respectively, 1-5 years after the switch. CONCLUSIONS: Biological treatment, as used in clinical practice, shows a stable long-term effectiveness in all the measured dimensions, PASI, DLQI and EQ-5D. PMID- 28644902 TI - Sirt6 alters adult hippocampal neurogenesis. AB - Sirtuins are pleiotropic NAD+ dependent histone deacetylases involved in metabolism, DNA damage repair, inflammation and stress resistance. SIRT6, a member of the sirtuin family, regulates the process of normal aging and increases the lifespan of male mice over-expressing Sirt6 by 15%. Neurogenesis, the formation of new neurons within the hippocampus of adult mammals, involves several complex stages including stem cell proliferation, differentiation, migration and network integration. During aging, the number of newly generated neurons continuously declines, and this is correlated with a decline in neuronal plasticity and cognitive behavior. In this study we investigated the involvement of SIRT6 in adult hippocampal neurogenesis. Mice over-expressing Sirt6 exhibit increased numbers of young neurons and decreased numbers of mature neurons, without affecting glial differentiation. This implies of an involvement of SIRT6 in neuronal differentiation and maturation within the hippocampus. This work adds to the expanding body of knowledge on the regulatory mechanisms underlying adult hippocampal neurogenesis, and describes novel roles for SIRT6 as a regulator of cell fate during adult hippocampal neurogenesis. PMID- 28644903 TI - Changes in remote myocardial tissue after acute myocardial infarction and its relation to cardiac remodeling: A CMR T1 mapping study. AB - OBJECTIVES: To characterize the temporal alterations in native T1 and extracellular volume (ECV) of remote myocardium after acute myocardial infarction (AMI), and to explore their relation to left ventricular (LV) remodeling. METHODS: Forty-two patients with AMI successfully treated with primary PCI underwent cardiovascular magnetic resonance after 4-6 days and 3 months. Cine imaging, late gadolinium enhancement, and T1-mapping (MOLLI) was performed at 1.5T. T1 values were measured in the myocardial tissue opposite of the infarct area. Myocardial ECV was calculated from native- and post-contrast T1 values in 35 patients, using a correction for synthetic hematocrit. RESULTS: Native T1 of remote myocardium significantly decreased between baseline and follow-up (1002 +/ 39 to 985 +/- 30ms, p<0.01). High remote native T1 at baseline was independently associated with a high C-reactive protein level (standardized Beta 0.32, p = 0.04) and the presence of microvascular injury (standardized Beta 0.34, p = 0.03). ECV of remote myocardium significantly decreased over time in patients with no LV dilatation (29 +/- 3.8 to 27 +/- 2.3%, p<0.01). In patients with LV dilatation, remote ECV remained similar over time, and was significantly higher at follow-up compared to patients without LV dilatation (30 +/- 2.0 versus 27 +/- 2.3%, p = 0.03). CONCLUSIONS: In reperfused first-time AMI patients, native T1 of remote myocardium decreased from baseline to follow-up. ECV of remote myocardium decreased over time in patients with no LV dilatation, but remained elevated at follow-up in those who developed LV dilatation. Findings from this study may add to an increased understanding of the pathophysiological mechanisms of cardiac remodeling after AMI. PMID- 28644905 TI - A realistic phantom for validating MRI-based synthetic CT images of the human skull. AB - PURPOSE: To introduce a new realistic human skull phantom for the validation of synthetic CT images of cortical bone from ultra-short echo-time (UTE) sequences. METHODS: A human skull of an adult female was utilized as a realistic representation of skull cortical bone. The skull was stabilized in a special acrylic container and was filled with contrast agents that have T1 and T2 relaxation times similar to human brain. The phantom was MR scanned at 3T with UTE and T2 -weighted sequences, followed by CT. A clustering approach was developed to extract the cortical bone signal from MR images. T2* maps of the skull were calculated. Synthetic CT images of the bone were compared to cortical bone signal extracted from CT images and confounding factors, such as registration errors, were analyzed. RESULTS: Dice similarity coefficient (DSC) of UTE-detected cortical bone was 0.84 and gradually decreased with decreasing number of spokes. DSC did not significantly depend on echo-time. Registration errors were found to be significant confounding factors, with 25% decrease in DSC for consistent 2 mm error at each axis. CONCLUSION: This work introduced a new realistic human skull phantom, specifically for the evaluation and analysis of synthetic CT images of cortical bone. PMID- 28644906 TI - Cholinesterases in normal and Alzheimer's disease primary olfactory gyrus. AB - AIMS: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and deposition of beta-amyloid (Abeta) plaques and tau neurofibrillary tangles (NFTs) in the brain. Olfactory abnormalities often precede cognitive symptoms in AD, indicating early involvement of pathology in olfactory structures. The cholinergic system is important not only in cognition but also in modulation of the olfactory system. The primary olfactory gyrus (POG) is comprised of the olfactory tract, anterior olfactory nucleus (AON) and olfactory area (OA). Because of the importance of the olfactory and cholinergic systems, we examined the anatomical and cholinergic organization of the POG in normal human brain and neuropathology in AD. METHODS: Cytoarchitecture of the POG was studied using Nissl staining in normal (n = 8) and AD (n = 6) brains. Distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined using histochemical methods. Abeta plaques and tau NFTs were detected using immunohistochemistry. Abundance of AD pathology was assessed using a semi quantitative approach. RESULT: Nissl staining showed pyramidal cells in the AON and paleocortical organization of the OA. AChE stained neurons and neuropil in the AON and OA, while BChE activity was noted in the olfactory tract and in AON and OA neurons. Pathology was frequent in the AD POG and the abundance of BChE associated AD pathology was greater than that associated with AChE. CONCLUSIONS: AChE and BChE activities in normal POG recapitulated their distributions in other cortical regions. Greater abundance of BChE-associated, in comparison to AChE associated, AD pathology in the POG suggests preferential involvement of BChE in olfactory dysfunction in AD. PMID- 28644907 TI - Optimal duration of fasting period after endoscopic submucosal dissection for gastric epithelial neoplasia: A prospective evaluation. AB - OBJECTIVE: There are currently no standardized guidelines for adequately determining the fasting period following gastric endoscopic submucosal dissection (ESD). The aim of this study was to determine the appropriate fasting period. METHODS: The enrolled patients were randomized into a short and a long-fasting group. In the short-fasting group, patients had fasted until the day after the ESD. In the long-fasting group, patients had fasted until 2 days after the ESD. A second-look endoscopy was performed immediately prior to starting to eat meals. The primary end-point was the measurement of discomfort-related ESD after starting meals such as epigastric pain, heartburn, regurgitation, nausea and vomiting. Secondary end-points included the bleeding rate after starting meals, hospital stay, patient satisfaction and hemostasis upon second-look endoscopy. RESULTS: We analyzed data from 101 of 110 randomized patients. Both groups demonstrated similar baseline characteristics. There were no significant differences in reports of epigastric pain, heartburn, regurgitation, nausea and vomiting after starting meals. Both groups demonstrated similar hemostasis rates upon second-look endoscopy (26% vs 31.4%, P = 0.551) and bleeding rate (4% vs 0%, P = 0.149). The duration of hospital stay was significantly shorter in the short fasting group (4.3 days vs 5.1 days, P < 0.001), and patient satisfaction was greater (P = 0.003) than in the long-fasting group. CONCLUSIONS: A short fasting protocol does not cause discomfort related to ESD or influence post-ESD bleeding. Moreover, the short fasting protocol results in shorter hospital stays and greater patient satisfaction. PMID- 28644908 TI - Photoactive Surface-Grafted Polymer Brushes with Phthalocyanine Bridging Groups as an Advanced Architecture for Light-Harvesting. AB - Surface-grafted polymer brushes of novel ladder-like architecture were proposed for inducing ordering of chromophores embedded therein. The brushes with acetylene side groups were obtained by surface-initiated photoiniferter-mediated polymerization. The acetylene moieties reacted then through a "click" process with an axially azide-bifunctionalized silicon phthalocyanine bridging the neighboring chains that inherently adopt extended conformations in dense brushes. FTIR, quartz crystal microbalance, and atomic force microscopy were used to study formation and structure of the photoactive brushes varying in grafting densities. Importantly, photophysical properties of the chromophores were virtually unaffected upon embedding them into the brushes, as evidenced by UV/Vis absorption and emission spectroscopy. Owing to the unique ordering of the chromophores, the proposed method may open new opportunities for the fabrication of light-harvesting systems suitable for photovoltaic or sensing applications. PMID- 28644909 TI - A Highly Efficient Synthesis of Z-Macrocycles Using Stereoretentive, Ruthenium Based Metathesis Catalysts. AB - A highly efficient, Z-selective ring-closing metathesis system for the formation of macrocycles using a stereoretentive, ruthenium-based catalyst supported by a dithiolate ligand is reported. The catalyst is remarkably active as observed in initiation experiments showing complete catalyst initiation at -20 degrees C within 10 minutes. Macrocyclization reactions generated Z-products from easily accessible diene starting materials bearing a Z-olefin moiety. This approach provides a more efficient and selective route to Z-macrocycles relative to previously reported systems. Reactions were completed within shorter reaction times, and turnover numbers of up to 100 could be achieved. Macrocyclic lactones ranging in size from twelve- to seventeen-membered rings were synthesized in moderate to high yields (67-79 %) with excellent Z-selectivity (95-99 %). PMID- 28644910 TI - Across state lines: Fulminant Babesia microti infection in a liver transplant recipient. AB - The potential for transmission of Babesia microti by blood transfusion is well recognized. Physicians may be unaware that products used for transfusion may be collected from geographically diverse regions. We describe a liver transplant recipient in South Carolina who likely acquired B. microti infection from a unit of blood collected in Minnesota. PMID- 28644911 TI - Interictal oscillations and focal epileptic disorders. AB - Neuronal network oscillations represent a main feature of the brain activity recorded in the EEG under normal and pathological conditions such as epilepsy. Specific oscillations occur between seizures in patients and in animal models of focal epilepsy, and thus, they are termed interictal. According to their shape and intrinsic signal frequency, interictal oscillations are classified as spikes and high-frequency oscillations (HFOs). Interictal spikes are recorded in the 'wideband' EEG signal and consist of large-amplitude events that usually last less than 1 s; HFOs, in contrast, are extracted by amplifying the appropriately filtered EEG signal and are usually categorized as ripples (80-200 Hz) and fast ripples (250-500 Hz). Interictal spikes and HFOs are used in clinical practice to localize the seizure onset zone in focal epileptic disorders, which is fundamental for performing successful surgical interventions in epileptic patients not responding to anti-epileptic drug therapy. Both types of interictal oscillations have been widely studied in animal models of focal epilepsy to identify the mechanisms underlying their generation as well as to establish their role in ictogenesis and epileptogenesis. In this review, we will address the cellular mechanisms underlying the generation of interictal spikes and HFOs in animal models of epileptiform synchronization and of focal epilepsy. Moreover, we will highlight in vitro and in vivo evidence indicating that these interictal oscillations mirror specific, dynamic changes in neuronal network excitability causing seizure generation (i.e. ictogenesis) and leading to a chronic epileptic condition (i.e. epileptogenesis). PMID- 28644912 TI - Biofilm formation and disinfectant resistance of Salmonella sp. in mono- and dual species with Pseudomonas aeruginosa. AB - AIMS: This study aimed to evaluate the biofilm formation and disinfectant resistance of Salmonella cells in mono- and dual-species biofilms with Pseudomonas aeruginosa, and to investigate the role of extracellular polymeric substances (EPS) in the protection of biofilms against disinfection treatment. METHODS AND RESULTS: The populations of Salmonella in mono- or dual-species biofilms with P. aeruginosa on stainless steel (SS) coupons were determined before and after exposure to commercial disinfectant, 50 MUg ml-1 chlorine or 200 MUg ml-1 Ecolab(r) WhisperTM V (a blend of four effective quaternary ammonium compounds (QAC)). In addition, EPS amount from biofilms was quantified and biofilm structures were observed using scanning electron microscopy (SEM). Antagonistic interactions between Salmonella and P. aeruginosa resulted in lower planktonic population level of Salmonella, and lower density in dual-species biofilms compared to mono-species biofilms. The presence of P. aeruginosa significantly enhanced disinfectant resistance of S. Typhimurium and S. Enteritidis biofilm cells for 2 days, and led to an average of 50% increase in polysaccharides amount in dual-species biofilms than mono-species biofilms of Salmonella. Microscopy observation showed the presence of large microcolonies covered by EPS in dual-species biofilms but not in mono-species ones. CONCLUSION: The presence of P. aeruginosa in dual-species culture inhibited the growth of Salmonella cells in planktonic phase and in biofilms, but protected Salmonella cells in biofilms from disinfection treatment, by providing more production of EPS in dual-species biofilms than mono-species ones. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides insights into inter-species interaction, with regard to biofilm population dynamics and disinfectant resistance. Thus, a sanitation protocol should be designed considering the protective role of secondary species to pathogens in biofilms on SS surface which has been widely used at food surfaces and manufacturers. PMID- 28644913 TI - Supplement 2 for the 2004 update of the AAPM Task Group No. 43 Report: Joint recommendations by the AAPM and GEC-ESTRO. AB - Since the publication of the 2004 update to the American Association of Physicists in Medicine (AAPM) Task Group No. 43 Report (TG-43U1) and its 2007 supplement (TG-43U1S1), several new low-energy photon-emitting brachytherapy sources have become available. Many of these sources have satisfied the AAPM prerequisites for routine clinical purposes and are posted on the Brachytherapy Source Registry managed jointly by the AAPM and the Imaging and Radiation Oncology Core Houston Quality Assurance Center (IROC Houston). Given increasingly closer interactions among physicists in North America and Europe, the AAPM and the Groupe Europeen de Curietherapie-European Society for Radiotherapy & Oncology (GEC-ESTRO) have prepared another supplement containing recommended brachytherapy dosimetry parameters for eleven low-energy photon-emitting brachytherapy sources. The current report presents consensus datasets approved by the AAPM and GEC ESTRO. The following sources are included: 125 I sources (BEBIG model I25.S17, BEBIG model I25.S17plus, BEBIG model I25.S18, Elekta model 130.002, Oncura model 9011, and Theragenics model AgX100); 103 Pd sources (CivaTech Oncology model CS10, IBt model 1031L, IBt model 1032P, and IsoAid model IAPd-103A); and 131 Cs (IsoRay Medical model CS-1 Rev2). Observations are included on the behavior of these dosimetry parameters as a function of radionuclide. Recommendations are presented on the selection of dosimetry parameters, such as from societal reports issuing consensus datasets (e.g., TG-43U1, AAPM Report #229), the joint AAPM/IROC Houston Registry, the GEC-ESTRO website, the Carleton University website, and those included in software releases from vendors of treatment planning systems. Aspects such as timeliness, maintenance, and rigor of these resources are discussed. Links to reference data are provided for radionuclides (radiation spectra and half-lives) and dose scoring materials (compositions and mass densities). The recent literature is examined on photon energy response corrections for thermoluminescent dosimetry of low-energy photon-emitting brachytherapy sources. Depending upon the dosimetry parameters currently used by individual physicists, use of these recommended consensus datasets may result in changes to patient dose calculations. These changes must be carefully evaluated and reviewed with the radiation oncologist prior to their implementation. PMID- 28644914 TI - The role of expectation in multisensory body representation - neural evidence. AB - Sensory events contribute to body ownership, the feeling that the body belongs to me. However, the encoding of sensory events is not only reactive, but also proactive in that our brain generates prediction about forthcoming stimuli. In previous studies, we have shown that prediction of sensory events is a sufficient condition to induce the sense of body ownership. In this study, we investigated the underlying neural mechanisms. Participants were seated with their right arm resting upon a table just below another smaller table. Hence, the real hand was hidden from the participant's view and a life-sized rubber model of a right hand was placed on the small table in front of them. Participants observed a wooden plank while approaching - without touching - the rubber hand. We measured the phenomenology of the illusion by means of questionnaire. Neural activity was recorded by means of near-infrared spectroscopy (fNIRS). Results showed higher activation of multisensory parietal cortices in the rubber hand illusion induced by touch expectation. Furthermore, such activity was correlated with the subjective feeling of owning the rubber hand. Our results enrich current models of body ownership suggesting that our multisensory brain regions generate prediction on what could be my body and what could not. This finding might have interesting implications in all those cases in which body representation is altered, anorexia, bulimia nervosa and obesity, among others. PMID- 28644915 TI - Mechanistic Insights on the Reduction of CO2 to Silylformates Catalyzed by Ir NSiN Species. AB - The hydrosilylation of CO2 with different silanes such as HSiEt3 , HSiMe2 Ph, HSiMePh2 , HSiMe(OSiMe3 )2 , and HSi(OSiMe3 )3 in the presence of catalytic ammounts of the iridium(III) complex [Ir(H)(CF3 CO2 )(NSiN*)(coe)] (1; NSiN*=fac bis-(4-methylpyridine-2-yloxy); coe=cis-cyclooctene) has been comparatively studied. The activity of the hydrosilylation catalytic system based on 1 depends on the nature of the reducing agent, where HSiMe(OSiMe3 )2 has proven to be the most active. The aforementioned reactions were found to be highly selective toward the formation of the corresponding silylformate. It has been found that using 1 as catalyst precursor above 328 K decreases the activity through a thermally competitive mechanistic pathway. Indeed, the reduction of the ancillary trifluoroacetate ligand to give the corresponding silylether CF3 CH2 OSiR3 has been observed. Moreover, mechanistic studies for the 1-catalyzed CO2 hydrosilylation reaction based on experimental and theoretical studies suggest that 1 prefers an inner-sphere mechanism for the CO2 reduction, whereas the closely related [Ir(H)(CF3 SO3 )(NSiN)(coe)] catalyst, bearing a triflate instead of trifluoroacetate ligand, follows an outer-sphere mechanism. PMID- 28644917 TI - An oxygen isotope chronometer for cellulose deposition: the successive leaves formed by tillers of a C4 perennial grass. AB - Multiannual time series of (palaeo)hydrological information can be reconstructed from the oxygen isotope composition of cellulose (delta18 OCel ) in biological archives, for example, tree rings, but our ability to temporally resolve information at subannual scale is limited. We capitalized on the short and predictable leaf appearance interval (2.4 d) of a perennial C4 grass (Cleistogenes squarrosa), to assess its potential for providing highly time resolved delta18 OCel records of vapour pressure deficit (VPD). Plants grown at low (0.63 kPa) or high (1.58 kPa) VPD were swapped between VPD environments and exposed to the new environment for 7 d with simultaneous 13 CO2 labelling. Then, leaves were sampled by age/position along individual tillers. Five leaves at different developmental stages were growing simultaneously. The period of most active leaf elongation, from 10 to 90% of final length, lasted 6.6 d, and ~80% of all carbon and oxygen incorporation in whole-leaf cellulose occurred within 7 d. Cellulose deposition stopped at (or shortly after) full leaf expansion. The direction of change, low-to-high or high-to-low VPD, had no differential effect on new oxygen and carbon incorporation in cellulose. Successive leaves produced by tillers of C. squarrosa provide a delta18 OCel record useful for reconstructions of short-term hydrological dynamics. PMID- 28644919 TI - Signaling and epigenetic mechanisms of intestinal stem cells and progenitors: insight into crypt homeostasis, plasticity, and niches. AB - The rapid turnover of intestinal epithelial cells is maintained by a small number of stem cells located in pocket-like gland structures called crypts. While our understanding of the identity and function of intestinal stem cells (ISCs) has rapidly progressed, epigenetic and transcriptional regulation in crypt stem cell and progenitor pools remains an active field of investigation. Surrounded by various types of cells in the stroma, crypt progenitors display high levels of plasticity, harboring the ability to interconvert in the face of epithelial damage. Recent studies analyzing epigenetic patterns of intestinal epithelial cells have provided evidence that plasticity is maintained by a broadly permissive epigenomic state, wherein cell-lineage specification is directed through activation of signaling pathways and transcription factor (TF) expression. New studies also have shown that the ISC niche, which is comprised of surrounding epithelial and mesenchymal tissues, plays a crucial role in supporting the maintenance and differentiation of stem cells by providing contextual information in the form of signaling cascades, such as Wnt, Notch, and Hippo. These cascades ultimately govern TF expression to promote early cell lineage decisions in both crypt stem cells and progenitors. Highlighting recent studies investigating signaling, transcriptional, and epigenetic mechanisms of intestinal epithelial cells, we will discuss the mechanisms underlying crypt homeostasis, plasticity, and niches. WIREs Dev Biol 2017, 6:e281. doi: 10.1002/wdev.281 For further resources related to this article, please visit the WIREs website. PMID- 28644920 TI - Genome-scale metabolic models applied to human health and disease. AB - Advances in genome sequencing, high throughput measurement of gene and protein expression levels, data accessibility, and computational power have allowed genome-scale metabolic models (GEMs) to become a useful tool for understanding metabolic alterations associated with many different diseases. Despite the proven utility of GEMs, researchers confront multiple challenges in the use of GEMs, their application to human health and disease, and their construction and simulation in an organ-specific and disease-specific manner. Several approaches that researchers are taking to address these challenges include using proteomic and transcriptomic-informed methods to build GEMs for individual organs, diseases, and patients and using constraints on model behavior during simulation to match observed metabolic fluxes. We review the challenges facing researchers in the use of GEMs, review the approaches used to address these challenges, and describe advances that are on the horizon and could lead to a better understanding of human metabolism. WIREs Syst Biol Med 2017, 9:e1393. doi: 10.1002/wsbm.1393 For further resources related to this article, please visit the WIREs website. PMID- 28644921 TI - Targeted Memory Reactivation During Sleep, But Not Wake, Enhances Sensorimotor Skill Performance: A Pilot Study. AB - The benefits of sleep on memory consolidation have been enhanced for declarative and motor sequence learning through replaying classically conditioned auditory stimuli during sleep, known as targeted memory reactivation (TMR). However, it is unknown if TMR can influence performance of a sensorimotor skill, in the absence of the cognitive requirements of sequence learning. Here, young adults performed a nondominant arm throwing task separated by a full night of sleep or a full day of wake, with half of all participants receiving TMR between sessions. Participants who received TMR during sleep demonstrated enhanced sensorimotor performance relative to all other groups. In conclusion, this pilot study indicates that it is feasible to influence sensorimotor skill performance through TMR during sleep and may serve as a future adjunct to physical rehabilitation. Future studies will aim to confirm the present results with a larger sample size as well as investigate the effects of TMR during sleep on older adults both with and without a history of stroke. PMID- 28644918 TI - Heterogeneous Microtesla SABRE Enhancement of 15 N NMR Signals. AB - The hyperpolarization of heteronuclei via signal amplification by reversible exchange (SABRE) was investigated under conditions of heterogeneous catalysis and microtesla magnetic fields. Immobilization of [IrCl(COD)(IMes)], [IMes=1,3 bis(2,4,6-trimethylphenyl), imidazole-2-ylidene; COD=cyclooctadiene] catalyst onto silica particles modified with amine linkers engenders an effective heterogeneous SABRE (HET-SABRE) catalyst that was used to demonstrate a circa 100 fold enhancement of 15 N NMR signals in 15 N-pyridine at 9.4 T following parahydrogen bubbling within a magnetic shield. No 15 N NMR enhancement was observed from the supernatant liquid following catalyst separation, which along with XPS characterization supports the fact that the effects result from SABRE under heterogeneous catalytic conditions. The technique can be developed further for producing catalyst-free agents via SABRE with hyperpolarized heteronuclear spins, and thus is promising for biomedical NMR and MRI applications. PMID- 28644922 TI - Hands Support and Postural Oscillation During Sit-to-Stand Movement in Children With Cerebral Palsy and Typical Children. AB - The authors aimed to compare the weight bearing on hands during sit-to-stand (STS) movement in children with cerebral palsy (CP) and typical children (TC), verify its effect on postural oscillation, and analyze the relationship between weight bearing on hands and postural oscillation. Twenty children with CP (Gross Motor Function Classification System levels I and II) and 35 TC performed STS with and without anterior hands support. Mann-Whitney test compared weight bearing between groups. Wilcoxon test investigated differences in postural oscillation between the conditions with and without anterior hand support for both groups. The Spearman correlation tested the relationship between weight bearing and postural oscillation during the hand support condition. Children with CP bore more weight on hands than TC to perform STS. The hand support reduced postural oscillation during the second phase of STS in both groups. In the CP group, greater weight bearing was related with lower postural oscillation in the beginning of STS. Although children with CP were able to perform STS without support, they bore more weight on their hands to perform the task than TC. Moreover, children with CP and TC use mechanical and somatosensory information to modulate their postural control during STS in different ways. PMID- 28644923 TI - Examining Transfer Effects of Dual-Task Training Protocols for a Complex Locomotor Task. AB - Training protocols designed to improve dual-task performance of an obstacle crossing and auditory Stroop task (OBS+Stroop) were tested. In Experiment 1 , following baseline collection of OBS+Stroop trials, proximally related walking training was performed, and participants were then retested on the OBS+Stroop test. After training, participants adopted a more cautious obstacle crossing strategy, indicating a potentially safer navigation strategy. Transfer effects from distally related training were then examined (Experiment 2 ); a computer game training paradigm was examined using the same testing protocol as Experiment 1 . Computer training demonstrated improved dual-task performance on some measures, but did not induce a more cautious stepping strategy. Results indicate that dual-task training needs to be similar to targeted tasks to yield reliable, positive training outcomes. PMID- 28644924 TI - Intravenous thrombolysis for acute ischemic stroke: a bridge between two centuries. AB - INTRODUCTION: Intravenous tissue-plasminogen activator (tPA) remains the only approved systemic reperfusion therapy suitable for most patients presenting timely with acute ischemic stroke. Accumulating real-word experience for over 20 years regarding tPA safety and effectiveness led to re-appraisal of original contraindications for intravenous thrombolysis (IVT). Areas covered: This narrative review focuses on fast yet appropriate selection of patients for safe administration of tPA per recently expanded indications. Novel strategies for rapid patient assessment will be discussed. The potential for mobile stroke units (MSU) that shorten onset-to-needle time and increase tPA treatment rates is addressed. The use of IVT in the era of non-vitamin K antagonist oral anticoagulants (NOACs) is highlighted. The continuing role of IVT in large vessel occlusion (LVO) patients eligible for mechanical thrombectomy (MT) is discussed with regards to 'drip and ship' vs. 'mothership' treatment paradigms. Promising studies of penumbral imaging to extend IVT beyond the 4.5-hour window and in wake up strokes are summarized. Expert commentary: This review provides an update on the role of IVT in specific conditions originally considered tPA contraindications. Novel practice challenges including NOAC's, MSU proliferation and bridging therapy (IVT&MT) for LVO patients, and the potential extension of IVT time-window using penumbral imaging are emerging as safe and potentially effective IVT applications. PMID- 28644925 TI - Does Low Body Mass Index Predict the Hospital Mortality of Adult Western or Asian Patients? AB - BACKGROUND: Some strategies for screening and assessment of malnutrition include a low but variable body mass index (BMI) cutoff, while others do not. The purpose of this systematic review was to investigate published data for Western and Asian hospital samples to determine how the prevalence of low BMI is associated with increased hospital mortality. METHOD: A PubMed search of the past 10 years (2006 2016) was conducted with the terms "BMI," "malnutrition," "adult," "outcome," and "hospital" or "ICU" for articles published in English. Studies that examined BMI levels among Western or Asian populations were included. Forest plots were constructed to determine the odds of hospital mortality in low versus normal BMI groups. RESULTS: Twenty studies met inclusion criteria. The prevalence of BMI <18.5 kg/m2 was greater in Asian (15%-20%) than Western (2%-7%) patient groups. In Western populations, BMI <18.5 kg/m2 was so rare that most studies lacked power to evaluate outcomes. Hospital mortality among ICU patients was greater for patients with BMI <18.5 than those with BMI of 18.5-24.9 kg/m2 (Western: odds ratio, 1.42 [95% CI, 1.33-1.50]; Asian: odds ratio = 1.78 [95% CI, 1.7-1.86]). RECOMMENDATIONS: BMI <18.5 kg/m2 is a possible screening variable for malnutrition. Since low BMI was associated with increased mortality in Western and Asian patient groups, we suggest that all populations at risk based on low BMI undergo a full nutrition assessment with a validated method. PMID- 28644926 TI - Gangnam-Style Plastic Surgery: The Science of Westernized Beauty in South Korea. AB - New beauty ideals and particular types of plastic surgery beauty have emerged in South Korea from the early twenty-first century. By defining Gangnam-style plastic surgery as a hybrid of old Westernized beauty ideals and a new science of beauty with variations and contradictions, I intend to twist the simplistic understanding of non-Western plastic surgery as an effort to resemble the white westerner's body. I also draw political implications from a case of monstrous Gangnam-style beauty made by excessive plastic surgery. PMID- 28644927 TI - Testing an Integrative Model of Affect Regulation and Avoidance in Non-Suicidal Self-Injury and Disordered Eating. AB - This research tested a model that integrates risk factors among non-suicidal self injury (NSSI) and eating disorder (ED) behaviors with the aim of elucidating possible shared and unique mechanisms underlying both behaviors. Emotional distress, limited access to emotion regulation (ER) strategies, experiential avoidance, and NSSI/ED frequency were examined in a sample of 230 female undergraduates. Structural equation modeling indicated that limited access to ER strategies and avoidance mediated relationship between emotional distress and avoidance, which in turn was associated with NSSI and ED behaviors. Results suggest NSSI and ED behaviors may serve similar emotion regulation functions, and specifically highlight the role of experiential avoidance in these behaviors. PMID- 28644930 TI - Trends in Open and Endoscopic Cubital Tunnel Release in the Medicare Patient Population. AB - BACKGROUND: Cubital tunnel syndrome (CUT) is the second most common peripheral neuropathy with an annual incidence of 24.7 per 100 000, affecting nearly twice as many men as women. With increasing focus on cost-effectiveness and cost containment in medicine, a critical understanding of utilization of health care resources for open and endoscopic approaches for cubital tunnel release is of value. The purpose of this study was to evaluate the costs and utilization trends of open and endoscopic cubital tunnel release. METHODS: We performed a retrospective review of a Medicare database within the PearlDiver Supercomputer (Warsaw, Indiana) for procedures performed from 2005 to 2012. Annual utilization, charges, reimbursement, demographic data, and compound annual growth rate were evaluated. RESULTS: Our query returned 262 104 patients with CUT, of which 69 378 (26.5%) and 4636 (1.8%) were surgically managed with open and endoscopic release respectively. Average charges were higher in endoscopic release ($3798) than open release ($3197) while reimbursements were higher in open releases ($1041) than endoscopic release, ($866). Both were performed most commonly in the <65 years age range. CONCLUSIONS: Despite the unexpectedly lower reimbursement rate with endoscopic release, endoscopy utilization is growing faster than open releases in the Medicare population. Lower reimbursement is likely related to lack of a dedicated current procedural terminology code for endoscopic cubital tunnel release. PMID- 28644931 TI - Quadrigia and Productivity. AB - Financial productivity in academic surgery is important and deserves great emphasis, yet it is but one of many vital elements of a healthy practice. Productivity must be carefully balanced with many other vital goals such as maximizing patient safety, maintaining excellent outcomes, optimizing resident and medical student education, and earning outstanding patient feedback. The following editorial explores this elusive balance and the importance of not swaying too far in the direction of revenue. PMID- 28644932 TI - Comment on the article "A Clinical Scoring System for Distinguishing Patients With Coincident Cubital Tunnel Syndrome Among Patients With Carpal Tunnel Syndrome". PMID- 28644929 TI - Short interpregnancy intervals, maternal folate levels, and infants born small for gestational age: a preliminary study in a Canadian supplement-using population. AB - Short interpregnancy intervals (SIPI) have been associated with increased risks for adverse neonatal outcomes including preterm delivery and infants small for gestational age (SGA). It has been suggested that mechanistically, adverse neonatal outcomes after SIPI arise due to insufficient recovery of depleted maternal folate levels prior to the second pregnancy. However, empirical data are lacking regarding physiological folate levels in pregnant women with SIPI and relationships between quantified physiological folate levels and outcomes like SGA. Therefore, we sought to test 2 hypotheses, specifically that compared with controls women with SIPI would: (i) have lower red blood cell folate (RBCF) levels and (ii) be more likely to have SGA infants (defined as <10th percentile). Using data collected in British Columbia, Canada, for a larger study on perinatal psychopathology, we documented supplementation use and compared prenatal RBCF levels and proportion of SGA infants between women with SIPI (second child conceived <=24 months after previous birth, n = 26) and matched controls (no previous pregnancies, or >24 months between pregnancies, n = 52). There were no significant differences in either mean RBCF levels (Welch's t test, p = 0.7) or proportion of SGA infants (Fisher's exact test, p = 0.7) between women with SIPI and matched controls. We report the first data about RBCF levels in the context of SIPI. If confirmed, our finding of no relationship between these variables in this population suggests that continued folic acid supplementation following an initial pregnancy mitigates folate depletion. We found no relationship between SIPI and SGA. PMID- 28644933 TI - Survey of Hand and Upper Extremity Injuries Among Rock Climbers. AB - BACKGROUND: Rock climbing first evolved as a sport in the late 18th century. With its growing popularity, the number of rock climbing-related injuries has potential to increase, spurring a rise in the number of articles associated with it. Despite the available literature, there remains a paucity of information about upper extremity injuries sustained by rock climbers, and no studies to date have focused on gender-specific injuries. METHODS: A 24-question online survey was distributed to rock climbers about upper extremity injuries sustained during rock climbing. Statistical analysis was used to study association between participants' demographics and injuries. RESULTS: A total of 397 participants responded to the survey. Mean age was 32.5 years with males comprising 85%. No significant differences in demographics or climbing behaviors were found between males and females. Ninety percent of participants reported sustaining an upper extremity injury. Fingers were the most common injury followed by shoulder/arm and elbow/forearm. Our study found females to be more likely to report a rock climbing-related injury, and more likely to undergo surgery for it. CONCLUSION: Female rock climbers were significantly more likely to report a shoulder/upper arm injury and were also more likely to report undergoing surgery compared with males, where these differences were not due to age or climbing behaviors. Further investigation is warranted into the association between shoulder injuries and female athletes to determine how the gender differences relate to extent of injury as well as health service utilization behaviors. PMID- 28644934 TI - Fingertip Injuries in Children: Epidemiology, Financial Burden, and Implications for Prevention. AB - BACKGROUND: Although fingertip injuries are common, there is limited literature on the epidemiology and hospital charges for fingertip injuries in children. This descriptive study reports the clinical features of and hospital charges for fingertip injuries in a large pediatric population treated at a tertiary medical center. METHODS: Our hospital database was queried using International Classification of Diseases, Revision 9 (ICD-9) codes, and medical records were reviewed. Frequency statistics were generated for 1807 patients with fingertip injuries who presented to the emergency department (ED) at Boston Children's Hospital (BCH) between 2005 and 2011. Billing records were analyzed for financial data. RESULTS: A total of 1807 patients were identified for this study; 59% were male, and the mean age at time of injury was 8 years. Most commonly, injuries occurred when a finger was crushed (n = 831, 46%) in a door or window. Average length of stay in the ED was 3 hours 45 minutes, 25% of cases needed surgery, and, on average, patients had more than 1 follow-up appointment. About one-third of patients were referred from outside institutions. The average ED charge for fingertip injuries was $1195 in 2014, which would amount to about $320 430 each year (in 2014 dollars) for fingertip injuries presenting to BCH. CONCLUSION: Fingertip injuries in children are common and result in significant burden, yet are mostly preventable. Most injuries occur at home in a door or window. Although these patients generally heal well, fingertip injuries pose a health, time, and financial burden. Increased awareness and education may help to avoid these injuries. PMID- 28644935 TI - Triquetrohamate Impaction Syndrome: An Unrecognized Cause of Ulnar-Sided Wrist Pain; Its Presentation Further Defined. AB - BACKGROUND: The aim of this review was to further define the clinical condition triquetrohamate (TH) impaction syndrome (THIS), an entity underreported and missed often. Its presentation, physical findings, and treatment are presented. METHODS: Between 2009 and 2014, 18 patients were diagnosed with THIS. The age, sex, hand involved, activity responsible for symptoms, and defining characteristics were recorded. The physical findings, along with ancillary studies, were reviewed. Delay in diagnosis and misdiagnoses were assessed. Treatment, either conservative or surgical, is presented. Follow-up outcomes are presented. RESULTS: There were 15 male and 3 females, average age of 42 years. Two-handed sports such as golf and baseball accounted for more than 60% of the cases, and these cases were the only ones that involved the lead nondominant hand, pain predominantly at impact. Delay in diagnosis averaged greater than 7 months, with triangular fibrocartilage (TFCC) and extensor carpi ulnaris (ECU) accounting for more than 50% of misdiagnoses. Physical findings of note included pain over the TH joint, worse with passive dorsiflexion and ulnar deviation. Radiographic findings are described. Instillation of lidocaine with the wrist in radial deviation under fluoroscopic imaging with relief of pain helped to confirm the diagnosis. Conservative treatment was successful in 9 of 18 patients (50%), whereas in the remaining, surgical intervention allowed approximately 80% return to full activities without limitation. CONCLUSION: Triquetrohamate impaction syndrome remains an underreported and often unrecognized cause of ulnar-sided wrist pain. In this report, the largest series to date, its presentation, defining characteristics, and treatment options are further elucidated. PMID- 28644936 TI - The Deltoid Lift: A Comparison Study of Exposure Area in Proximal Humeral Approaches. AB - BACKGROUND: Adequate exposure of the proximal humerus is necessary to address atypical or complex proximal humerus fractures and orthopedic tumors. Surgical management may be difficult through existing approaches due to their limited nature and the delicate neurovascular anatomy of the shoulder. The deltoid lift, a previously described extensile approach, can be incorporated into the surgeon's armamentarium as an alternative exposure to the proximal humerus. The objective of this study was to quantify and compare the humeral exposure achieved through the deltoid lift with the standard direct lateral deltoid-splitting, anterolateral acromial, and deltopectoral approaches in terms of surface area and exposure of key anatomic landmarks. METHODS: Each approach was performed a minimum of 8 times on 18 cadaveric specimens. After identifying landmarks, exposure area of exposed humerus was quantified using digital images and ImageJ software. RESULTS: The deltoid lift yielded an average exposure area of 46 cm2. Comparison of the exposure area for the deltoid lift against each of the other approaches yielded statistical significance ( P < .01). The exposure provided was 2-folds greater than that of the next most extensive approach. All anatomic landmarks were directly visible through the deltoid lift as compared with the remaining approaches, through which only 1 landmark was directly visualized and only 2 of the 3 remaining were palpable through the approach. CONCLUSIONS: The deltoid lift extensile surgical exposure to the proximal humerus provides the largest humeral exposure with the greatest visibility of landmarks relative to the 3 most widely utilized standard approaches. PMID- 28644937 TI - Predictors of Recurrence After Corticosteroid Injection for Trigger Digits. AB - BACKGROUND: We aimed to identify risk factors for recurrence of trigger digit following corticosteroid injection. METHODS: A retrospective review identified patients 18 years and older who presented to a single fellowship-trained hand surgeon with a symptomatic trigger digit during a 1-year period. Baseline demographic data were recorded. Patients with persistent trigger digit after a single injection were offered a second injection. Patients refusing a second injection were excluded from our analysis. Patients with persistent symptoms after 2 injections were offered surgery. For patients with diabetes mellitus, additional information regarding method of disease control and hemoglobin A1c level was recorded. RESULTS: The overall success of corticosteroid injection was 84% with 16% of patients requiring surgical release. Of the 240 patients successfully treated with injection, 99 (41%) required a second injection. Injections resulted in persistent triggering in 15% of patients with diabetes and 17% of patients without diabetes. A multivariate regression analysis revealed that the 2 strongest risk factors for requiring surgical release were patient age and patients whose fourth digit of the right hand was injected. Diabetes was not a risk factor for persistent triggering after corticosteroid injection. CONCLUSIONS: Our findings can be used to counsel patients prior to their initial injection and suggest that patients with diabetes can be managed with corticosteroid injection with equal efficacy compared with patients without diabetes. PMID- 28644938 TI - Preoperative Epoxy Embolization Facilitates the Safe and Effective Resection of Venous Malformations in the Hand and Forearm. AB - BACKGROUND: The standard of care for treatment of low-flow venous malformations (VMs) is percutaneous sclerotherapy. These lesions are seldom surgically resected, especially if the malformation is in an anatomically difficult location. Percutaneous sclerotherapy is safe and effective. However, the drawbacks to sclerotherapy are the need for repeated treatments and risks of skin ulceration, deep venous thrombosis, scarring/contractures, and nerve damage. Surgical resection can be difficult because of intraoperative bleeding, intraoperative lesional decompression, and difficulty in localization. METHODS: We describe our initial experience with 11 patients who underwent surgical resection of VMs located in the hand and forearm after preembolization of 27 total sites using n-butyl-cyanoacrylate or ethylene vinyl alcohol copolymer. RESULTS: Of the 11 patients treated, 5 had focal VMs, 3 had multifocal VMs, and 3 had diffuse VMs throughout the affected extremity. Four of the 5 patients with focal VMs were followed for at least 1 year, and no further treatment was required. All 3 of the patients with diffuse VMs have required ongoing treatment. No major functional impairments were reported, and there were no major procedure related complications. CONCLUSIONS: Overall, embolization of the malformation before surgical resection facilitated localization, demarcation, and removal of the lesion. PMID- 28644939 TI - An Economic Analysis of MAC Versus WALANT: A Trigger Finger Release Surgery Case Study. AB - BACKGROUND: There has been recent interest in wide awake hand surgery, also referred to as "wide awake local anesthesia with no tourniquet" (WALANT) surgery. Using a model of single trigger finger release (TFR) surgery, a hypothesis was made that WALANT would result in decreased hospital time and cost than patients receiving sedation with monitored anesthetic care (MAC). METHODS: Consecutive cases of single TFR surgery with MAC were compared with WALANT. All surgeries were performed in the same manner, at the same facility, and by the same surgeon. Total operating room (OR) time, surgical time, recovery time, and anesthesia costs were analyzed. RESULTS: There were 78 patients: 31 MAC and 47 WALANT. The MAC group averaged 27.2 minutes of OR time; the WALANT group averaged 25.2 minutes. The MAC group surgical time was 10.2 minutes versus WALANT of 10.4 minutes. Post-operatively, the MAC group averaged 72.3 minutes in the recovery room compared with WALANT group of 30.2 minutes. Each case performed under MAC had a minimum of excess charges from anesthesia of approximately $105. CONCLUSIONS: Patients undergoing single TFR surgery under WALANT trended toward less time in the OR, had similar surgical times, and spent significantly less time in the recovery room, compared with MAC, thereby resulting in less indirect costs. Each MAC case also had minimum direct excess anesthesia charges of $105, which knowingly underestimates overall charges as it excludes material and fixed costs associated with the delivery of anesthesia. Avoiding sedation for high volume procedures such as TFR may result in significant systemic savings to payers, and in the future with bundling and episode-based payments can become increasingly important to patients, facilities, and surgeons. PMID- 28644941 TI - The Use of the "Cup of Diogenes" and "OK Approach" for Carpal Tunnel Surgery. PMID- 28644940 TI - Percutaneous Treatment of Unstable Scaphoid Waist Fractures. AB - BACKGROUND: Percutaneous techniques have been described for the treatment of nondisplaced scaphoid fractures, although less information has been reported about outcomes for unstable, displaced fractures. The aim of this study was to evaluate the union and complication rates following manual closed reduction and percutaneous screw placement for a consecutive series of unstable, displaced scaphoid fractures. METHODS: A total of 28 patients (average age, 27 years; 22 male/6 female) were treated for isolated unstable displaced scaphoid waist fractures. Closed reduction and percutaneous headless, compression screw fixation was successfully performed in 14 patients (average age, 32 years; 10 male/4 female), and the remaining 14 patients required open reduction. Patients who underwent percutaneous treatment were followed for radiographic fracture union and clinical outcomes. RESULTS: Thirteen of 14 fractures (93%) had clinical and radiographic evidence of bone union at an average of 2.8 months postoperatively. Average visual analog pain score at the time of union was 0.9. The average Quick Disability of the Arm, Shoulder, and Hand score at 2.5 years follow-up (range, 1.5-8.3 years) was 9.6 (range, 0.0-27.3). Complications included 1 case of nonunion and 1 case of intraoperative Kirschner wire breakage. CONCLUSIONS: Manual closed reduction followed by percutaneous headless, compression screw fixation was possible in 50% of patients who presented with acute unstable, displaced scaphoid fractures. This technique appears to be a safe and effective method when a manual reduction is possible, and it may offer a less invasive option when compared with a standard open technique. PMID- 28644942 TI - Total Wrist Arthroplasty Versus Wrist Fusion: Utilization and Complication Rates as Reported by ABOS Part II Candidates. AB - BACKGROUND: The aim of this study was to assess national trends in the utilization and complication rates of total wrist arthroplasty (TWA) and total wrist fusion (WF) as identified via review of the American Board of Orthopedic Surgery (ABOS) Part II candidate database. METHODS: The ABOS Part II candidate database is a collection of cases reported by candidates of the ABOS Part II board certification oral exam. The ABOS database was queried for all TWA and WF cases performed from 2005 to 2014. Linear regression analyses were used to assess trends in procedure utilization. Treatment diagnoses, patient characteristics, and reported complications were also compared between the 2 treatment cohorts. RESULTS: No significant increases in the proportion of candidates performing TWA or WF, number of TWA or WF cases, nor the number of TWA or WF cases performed per candidate performing those procedures were noted during the study period. Significantly less TWA cases were performed when compared with WF cases (68 vs 327; P = .006). Patients undergoing TWA were significantly older ( P = .005), more likely female ( P < .001), and more likely to have a diagnosis of osteoarthritis ( P = .003) than patients undergoing WF. There were no significant differences in complication rates, including postoperative infection, nerve palsy, or rate of secondary surgery, between the TWA and WF cohorts. CONCLUSIONS: Utilization of both TWA and WF has remained unchanged among emerging career orthopedic surgeons. Although WF is performed nearly 5 times more frequently than TWA, our short-term findings suggest that TWA compares favorably with WF. PMID- 28644943 TI - Failure of Wrist Hemiarthroplasty. AB - BACKGROUND: Wrist hemiarthroplasty has emerged as a motion-sparing option for severe wrist arthritis. It is technically easy with advantages of limited bone resection and no risk of nonunion. Given the relative infancy of the procedure in clinical practice, there are limited data on patient outcomes. METHODS: Eleven patients were treated with wrist reconstructive hemiarthroplasty. Indications included 1 patient with scaphoid nonunion advanced collapse, 9 patients with scapholunate advanced collapse, and 1 patient with capitolunate arthritis. Average age was 63 years; average follow-up was 4 years. Objective parameters included Disabilities of the Arm Shoulder and Hand (DASH), grip strength, and range of motion. Implant failure defined by necessity of revision procedure. RESULTS: DASH scores initially improved postoperatively but were not statistically significant. Grip strength was 60% of contralateral side. Postoperative range of motion at 6 months was flexion 40.3 degrees , extension 39.3 degrees , supination 87.0 degrees , pronation 77.8 degrees , radial deviation 14.5 degrees , and ulnar deviation 13.8 degrees . A 45% failure rate was observed. Complications included failure with conversion to Total Wrist Arthroplasty (TWA; n = 2) or wrist fusion (n = 3) secondary to development of ulnar-sided wrist pain. One additional patient experienced severe wrist pain but declined additional surgery. CONCLUSIONS: Wrist hemiarthroplasty in our series had a significant failure rate. In each case of failure, the patient developed ulnar-sided wrist pain. In the presence of more reliable procedures, wrist hemiarthroplasty is not indicated in its current incarnation. PMID- 28644944 TI - Change in the Distance From the Axillary Nerve to the Glenohumeral Joint With Shoulder External Rotation or Abduction Position. AB - BACKGROUND: This study investigated whether axillary nerve (AN) distance to the inferior border of the humeral head and inferior glenoid would change while placing the glenohumeral joint in different degrees of external rotation and abduction. METHODS: A standard deltopectoral approach was performed on 10 fresh frozen cadaveric specimens. The distance between AN and the inferior border of the humeral head and inferior glenoid while placing the shoulder in 0 degrees , 45 degrees , and 90 degrees of external rotation or abduction was measured. Continuous variables for changes in AN position were compared with paired 2 tailed Student t test. RESULTS: The mean distance between the AN and the humeral head with the shoulder in 0 degrees , 45 degrees , and 90 degrees of external rotation and 0 degrees of abduction was 13.77 mm (SD 4.31), 13.99 mm (SD 4.12), and 16.28 mm (SD 5.40), respectively. The mean distance between the AN and glenoid with the shoulder in 0 degrees , 45 degrees , and 90 degrees of external rotation was 16.33 mm (SD 3.60), 15.60 mm (SD 4.19), and 16.43 (SD 5.35), respectively. The mean distance between the AN and the humeral head with the shoulder in 0 degrees , 45 degrees , and 90 degrees of abduction and 0 degrees of external rotation was 13.76 mm (SD 4.31), 10.68 mm (SD 4.19), and 3.81 mm (SD 3.08), respectively. The mean distance between the AN and glenoid with the shoulder in 0 degrees , 45 degrees , and 90 degrees of abduction was 16.33 mm (SD 3.60), 17.66 mm (SD 5.80), and 12.44 mm (SD 5.57), respectively. CONCLUSIONS: The AN position relative to the inferior aspect of the glenohumeral joint does not significantly change despite position of external rotation. Increasing shoulder abduction over 45 degrees decreases the distance from the glenohumeral joint to the AN and should be avoided. PMID- 28644945 TI - Complications and Cost of Syndactyly Reconstruction in the United States: Analysis of the Pediatric Health Information System. AB - BACKGROUND: Syndactyly is one of the most common congenital differences of the upper extremity and offers an exceptional opportunity to evaluate value-based care in pediatric orthopedic surgery. We designed a study to characterize complications and cost associated to syndactyly surgery among US pediatric hospitals. METHODS: A total of 2047 patients were identified for syndactyly surgery at 38 pediatric hospitals from 2009 to 2012 using the Pediatric Health Information System (PHIS) database. We examined costs as well as complication rates across hospitals stratified by patient and hospital variables. RESULTS: The postoperative complication rate was 1.9% (95% confidence interval [CI]: 1.3% 2.5%). Postoperative infection rate was 1.6% and surgical complication rate was 0.3%. Median adjusted standardized cost was $4112.5 (interquartile range: $2979 $6049). Patients with more than 1 diagnosis had 19 times higher risk of complications and were associated with 13% more hospital cost than those with syndactyly as single diagnosis ( P < .001). Finally, there was a wide variation in cost across hospitals; 8 (21%) yielded confidence limits above the benchmarked value. CONCLUSIONS: In the United States, it is important to recognize variations in practice of syndactyly surgery in hopes of developing quality improvement strategies in pediatric orthopedic surgery. PMID- 28644946 TI - Effectiveness of Corticosteroid Injections for Treatment of de Quervain's Tenosynovitis. AB - BACKGROUND: Although surgery can provide definitive treatment for de Quervain's tenosynovitis, nonoperative treatment could be preferable if symptoms are predictably relieved. We sought to determine the effectiveness of corticosteroid injections as treatment for de Quervain's tenosynovitis and to evaluate patient characteristics as predictors of treatment outcome. METHODS: A retrospective study was conducted using our institutional database International Classification of Disease, version 9 (ICD-9) code list for de Quervain's tenosynovitis. Treatment success was defined as relief of symptoms after 1 or 2 injections. Relief was defined as resolution or improvement to the extent that the patient did not seek further intervention. Failure was defined as a subsequent surgical release or a third injection. Logistic regression analyses were performed to look for univariate associations between patient demographics/comorbidities and risk of treatment failure. RESULTS: The treatment outcome of 222 limbs from 199 patients was studied. Of the 222 limbs, 73.4% (95% confidence interval [CI], 66.9%-79.1%) experienced treatment success within 2 injections, and 51.8% (95% CI, 45.0%-58.6%) experienced success after 1 injection. Body mass index (BMI) >30 and female sex were found to be significantly associated with treatment failure, with a 2.4-fold increase (95% CI, 1.02%-5.72%) in odds and 3.23 times greater (95% CI, 1.08%-9.67%) odds of failure, respectively. Although not reaching statistical significance, African American race, hypothyroidism, and carpal tunnel syndrome suggested increased odds of failure. CONCLUSIONS: This study indicates that corticosteroid injections are a useful treatment for de Quervain's tenosynovitis, leading to treatment success 73.4% of the time within 2 injections. This study also suggests that female sex and BMI >30 are associated with increased treatment failure. PMID- 28644947 TI - Acoustic Rhinometry for Evaluation of Velopharyngeal Function in Preschool Children Post Palatoplasty. AB - PURPOSE: To assess the feasibility of acoustic rhinometry for the evaluation of velopharyngeal function in preschool children by detecting changes in nasal cavity volume (NV) and minimal cross-sectional area (MCSA) after palatoplasty. MATERIALS AND METHODS: Sixty-one preschool children with incomplete cleft palate who underwent Sommerlad palatoplasty were examined by acoustic rhinometry. MCSA, distance of the MCSA from the nostril (DMCA), NV, and nasopharyngeal volume (NPV) were measured. Patients were grouped according to velopharyngeal state and lateral cephalographic findings. RESULTS: MCSA, NV, and NPV showed a meaningful difference between the experimental and control groups. DMCA in the experimental group (7.09 +/- 1.33 mm) was not markedly different between the 2 sides. NV, NPV, and MCSA in the velopharyngeal insufficiency (VPI) subgroup were obviously larger than those in the velopharyngeal competence (VPC) and marginal VPI subgroups. NV in the VPC group showed no relevant difference from that in the control group. No relevant difference in MCSA, DMCA, and NPV was observed among the 3 subgroups at radiographic evaluation. NV in the noncontact group was markedly larger than in the control group. The curve showed marked constriction in the anterior part but an elevation in the posterior part, especially at a distance of 7.09 cm. CONCLUSION: Acoustic rhinometry is a rapid, noninvasive, and reproducible method that can be used in lieu of lateral cephalography for quantitative evaluation of the NV and MCSA. It can be used to assess postoperative velopharyngeal function in children and has good adaptability. PMID- 28644948 TI - Traumatic Buccal Fat Pad Herniation in Young Children: A Systematic Review and Case Report. AB - PURPOSE: Traumatic herniation of a buccal fat pad, predominantly seen in young children, is a rare condition. Because of its rarity and clinical features that resemble tumors, clinicians are faced with challenges at the initial diagnosis. This report describes a case of buccal fat pad herniation with excellent long term prognosis after surgical relocation and conservative treatment and presents a systematic review of the literature on its management. MATERIALS AND METHODS: Through a PubMed search, 811 articles were initially identified. Case series, case reports, technical notes, case and review reports, and retrospective case series were included. After screening and manual review, the sample was narrowed to 35 reports (41 patients) based on eligibility criteria. Articles were included if the standard criteria for traumatic intraoral herniation of buccal fat pad were met. RESULTS: Patients' ages ranged from 4 months to 12 years, with no specific gender predilection. Management consisted of excision (82.9%), relocation (14.6%), and observation (2.4%). Follow-up ranged from 1 week to 4 months. No reports presented a follow-up longer than 4 months; hence, data on long-term prognosis were not reported. For the present case report, a 19-month old boy diagnosed with traumatic buccal fat pad herniation was successfully treated with surgical relocation and antibiotic support. Twelve-month follow-up showed no esthetic or functional disturbance or recurrence. CONCLUSION: Traumatic herniation of the buccal fat pad requires special attention at the initial diagnosis. Considering its clinical importance in young children and few studies have reported long-term postresection follow-up, surgical relocation can be regarded as an excellent and more conservative treatment option. PMID- 28644949 TI - Hematopoietic cell transplantation for acute lymphoblastic leukemia in adult patients. AB - Acute lymphoblastic leukemia (ALL) consists of precursor B ALL or T ALL phenotypes. In the pediatric population, ALL patients enjoy an 80% long-term survival with the current pediatric chemotherapy protocols as compared with 50% long-term survival in the adult population. In adults, complete remission rates are similar to those of pediatric patients; however, long-term survival is much lower with the majority of deaths attributable to relapsed disease. Postremission consolidation strategies in adults include chemotherapy, autologous, or allogeneic transplant. Pediatric-inspired chemotherapy protocols are being explored as a consolidation modality in adults. Assigning patients to either modality depends on patient and disease characteristics. Here, we review the literature on the use of hematopoietic cell transplantation as a consolidation modality in the treatment of adult ALL. PMID- 28644950 TI - Hematopoietic cell transplantation in Fanconi anemia and dyskeratosis congenita: A minireview. AB - Bone marrow failure syndrome is an epithet of bone marrow failure (all or single cell lineage) that is attributable to an underlying genetic aberration usually with a constellation of somatic abnormalities. Multiple inheritance patterns have been described in these disorders; many are transmitted in an autosomal recessive pattern, which may consequently lead to a higher prevalence of such illnesses in homogeneous societies such as Saudi Arabia, where consanguineous marriages are not uncommon. At King Faisal Specialist Hospital and Research Center, the most common entity referred for allogeneic hematopoietic cell transplantation (HCT) is Fanconi anemia, followed by pure red aplasia, and, less commonly, dyskeratosis congenita, congenital neutropenia, and others. Of all the congenital bone marrow failure syndromes, two of them-Fanconi anemia and dyskeratosis congenita represent a real challenge in terms of conditioning for HCT and require special attention. This minireview is a snapshot of the recent international and local experience of HCT in these two entities. PMID- 28644951 TI - Principles of Chemical Biology: From Sexy Fatty Acids and EBV probes to Anti-Acid Antibiotic via Post-Biotics and Host-Microbe Metabolic Complementarity. AB - This month: The role of fatty acids in sex determination; a probe to monitor and inhibit EBNA1 at the same time; a biological role for post-biotics; what happens when you mix microbes, hosts, and drugs; and an antibiotic that cross-protects with acid. PMID- 28644952 TI - ACSF3 and Mal(onate)-Adapted Mitochondria. AB - In this issue of Cell Chemical Biology, Bowman and colleagues show that the mitochondrial enzyme ACSF3 generates malonyl-CoA from malonate, in turn regulating metabolic flux and mitochondrial protein malonylation (Bowman et al., 2017). The study reveals a mechanism to generate mitochondrial malonyl-CoA and how this molecule impacts mitochondrial biology. PMID- 28644953 TI - Helping Induced hPSCs Clean Up Their Act. AB - Inhibition of the tumorigenic potential of human pluripotent stem cells (hPSCs) remains critically important for safe hPSC-based therapy. In this issue of Cell Chemical Biology, Kuang et al. (2017) reveal that the phospho-D-peptide D-3 efficiently induces death of residual hPSCs, but not of differentiated progenies, through high alkaline phosphatase activity in hPSCs. PMID- 28644954 TI - Bacteria and the Fate of Estrogen in the Environment. AB - In this issue of Cell Chemical Biology, Chen et al. (2017) report that 4 hydroxyestrone and pyridinestrone acid are intermediates in the 4,5-seco pathway of aerobic estrogen degradation by the bacterium Sphingomonas. The authors identify a gene for 4-hydroxyestrone 4,5-dioxygenase and find it to be widely distributed in diverse proteobacteria, suggesting that this pathway is environmentally significant. PMID- 28644955 TI - Turning-ON Proteasomes. AB - While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical Biology, in a study from the groups of Berkers and Ovaa (Leestemaker et al., 2017), a chemical screen was used to identify a p38 MAPK inhibitor as a proteasome activator. This compound furthermore enhanced clearance of protein aggregates, thereby implicating alternative chemotherapeutic options for treating neurodegenerative diseases. PMID- 28644956 TI - SIRT4 Is a Regulator of Insulin Secretion. AB - In a recent issue of Cell Metabolism, Anderson et al. (2017) report that SIRT4 regulates insulin sensitivity in the pancreas via activation of methylcrotonyl CoA carboxylase 1 (MCCC1) by removal of dicarboxyacyl-lysine modifications. Thus, SIRT4 activates leucine catabolism and causes decreased secretion of insulin from the pancreas. PMID- 28644957 TI - Chemical Probes for Visualizing Intact Animal and Human Brain Tissue. AB - Newly developed tissue clearing techniques can be used to render intact tissues transparent. When combined with fluorescent labeling technologies and optical sectioning microscopy, this allows visualization of fine structure in three dimensions. Gene-transfection techniques have proved very useful in visualizing cellular structures in animal models, but they are not applicable to human brain tissue. Here, we discuss the characteristics of an ideal chemical fluorescent probe for use in brain and other cleared tissues, and offer a comprehensive overview of currently available chemical probes. We describe their working principles and compare their performance with the goal of simplifying probe selection for neuropathologists and stimulating probe development by chemists. We propose several approaches for the development of innovative chemical labeling methods which, when combined with tissue clearing, have the potential to revolutionize how we study the structure and function of the human brain. PMID- 28644958 TI - Translating cancer epigenomics into the clinic: focus on lung cancer. AB - Epigenetic deregulation is increasingly being recognized as a hallmark of cancer. Recent studies have identified many new epigenetic biomarkers, some of which are being introduced into clinical practice for diagnosis, molecular classification, prognosis or prediction of response to therapies. O-6-methylguanine-DNA methyltransferase gene is the most clinically advanced epigenetic biomarker as it predicts the response to temozolomide and carmustine in gliomas. Therefore, epigenomics may represent a novel and promising tool for precision medicine, and in particular, the detection of epigenomic biomarkers in liquid biopsies will be of great interest for monitoring diseases in patients. Of particular relevance is the identification of epigenetic biomarkers in lung cancer, one of the most prevalent and deadly types of cancer. DNA methylation of SHOX2 and RASSF1A could be used as diagnostic markers to differentiate between normal and tumor samples. MicroRNA and long noncoding RNA signatures associated with lung cancer development or tobacco smoke have also been identified. In addition to the field of biomarkers, therapeutic approaches using DNA methylation and histone deacetylation inhibitors are being tested in clinical trials for several cancer types. Moreover, new DNA editing techniques based on zinc finger and CRISPR/Cas9 technologies allow specific modification of aberrant methylation found in oncogenes or tumor suppressor genes. We envision that epigenomics will translate into the clinical field and will have an impact on lung cancer diagnosis/prognosis and treatment. PMID- 28644960 TI - Improved simulation based HR-EBSD procedure using image gradient based DIC techniques. AB - Conventional HR-EBSD is attracting much interest due to its ability of measuring relative crystal misorientations and microstresses with great accuracy. However, this technique needs the use of simulated patterns in order to get absolute values of crystal orientation and stresses and thus expand its use to intergranular analyses. Simulation-based approaches have shown many limitations due to the poor correlation with the real patterns specially when Bragg simulations are considered. This paper presents an improved algorithm based on gradient-based correlation techniques that makes simulation-based HR-EBSD possible. Based on this new algorithm, a new pattern center calibration procedure is proposed and validated. Also, a new hybrid procedure that combines simulation based HR-EBSD with conventional HR-EBSD is presented that enables an absolute determination of both orientations and stresses with improved accuracy. The hybrid HR-EBSD is used to analyze the martensitic transformation induced by plastic deformation in an as-quenched Ti-12wt.%Mo alloy. PMID- 28644959 TI - Generation and characterization of aptamers targeting factor XIa. AB - BACKGROUND: The plasma protease factor XIa (FXIa) has become a target of interest for therapeutics designed to prevent or treat thrombotic disorders. METHODS: We used a solution-based, directed evolution approach called systematic evolution of ligands by exponential enrichment (SELEX) to isolate RNA aptamers that target the FXIa catalytic domain. RESULTS: Two aptamers, designated 11.16 and 12.7, were identified that bound to previously identified anion binding and serpin bindings sites on the FXIa catalytic domain. The aptamers were non-competitive inhibitors of FXIa cleavage of a tripeptide chromogenic substrate and of FXIa activation of factor IX. In normal human plasma, aptamer 12.7 significantly prolonged the aPTT clotting time. CONCLUSIONS: The results show that novel inhibitors of FXIa can be prepared using SELEX techniques. RNA aptamers can bind to distinct sites on the FXIa catalytic domain and noncompetitively inhibit FXIa activity toward its primary macromolecular substrate factor IX with different levels of potency. Such compounds can be developed for use as therapeutic inhibitors. PMID- 28644961 TI - Bisphenol A and other environmental risk factors for prostate cancer in Hong Kong. AB - BACKGROUND: Environmental exposures are contributing factors to prostate cancer etiology, but these remain unclear. We aimed to document the associations between environmental risk factors and prostate cancer in Chinese, with special reference to bisphenol A (BPA). METHODS: We recruited 431 newly diagnosed prostate cancer cases and 402 age-matched controls from Prince of Wales Hospital in Hong Kong. We obtained each participant's clinical data and epidemiological information on chronic BPA exposure and other environmental risk factors (e.g., dietary habits, occupation and shift work) using a standard questionnaire. A new assessment tool of environmental BPA exposure was developed and replicated. Multiple logistic regression analysis was performed to examine odds ratio (OR) and 95% confidence interval (95% CI) for the association of prostate cancer with a novel cumulative BPA exposure index (CBPAI) and other environmental risk factors. RESULTS: Weekly consumption of deep fried food (OR=1.85, 95% CI: 1.15-2.95) and pickled vegetable (OR=1.87, 95% CI: 1.07-3.28) was significantly associated with excessive prostate cancer risk. Prostate cancer was positively associated with nightshift work (OR=1.76, 95% CI: 1.07-2.89) and it was negatively associated with green tea drinking (OR=0.56, 95% CI: 0.34-0.91). There was a positive exposure-response relationship between CBPAI and prostate cancer, with the greatest and significant risk in the high versus reference category (OR=1.57, 95% CI: 1.01-2.44). CONCLUSIONS: Frequent consumption of deep fried food and pickled vegetable, non habitual green tea drinking and nightshift work are the contributing risk factors to prostate cancer in Hong Kong Chinese. More importantly, this study provides the first epidemiological evidence on carcinogenicity of BPA on the human prostate. PMID- 28644962 TI - Validity and reproducibility of the modified STarT Back Tool (Dutch version) for patients with neck pain in primary care. AB - OBJECTIVE: To evaluate the reliability and validity of the Dutch version of the STarT Back screening Tool (SBT), for patients with neck pain. METHODS: We modified the SBT to fit patients with neck pain. General practitioners and physiotherapists included patients who completed both a baseline and a follow-up questionnaire at 3 days and 3 months, respectively. The construct validity was assessed using Pearson's correlation between the SBT and the reference questionnaires. The reproducibility was assessed in the first week using the quadratic weighted kappa and the specific agreement. Predictive validity was assessed using a relative-risk ratio (RR) for, amongst others, persisting disability at 3 months. Content validity was analysed using both floor and ceiling effects. RESULTS: In total, 100 patients were included; 58% were categorised as being at "low risk" for persisting disability, 37% at "medium risk" and 5% at "high risk". As expected for the construct validity, we found a moderate to high correlation for all questions except for activity question 3. The reproducibility had a quadratic-weighted kappa of 0.58, and a specific agreement of 90.9% for "low-risk" and 66.7% for "medium-risk" patients. The RRs for persisting disability for "medium-risk" against "low-risk" patients were 1.5 (95% C.I. 0.9-2.4) and 1.5 (95% C.I. 0.5-4.1) for pain. The sample size for high risk patients was low. CONCLUSION: The original SBT is modified to fit patients with neck pain in Dutch primary care. The psychometric analysis indicates sufficiently reliable outcomes, although the predictive validity showed statistically insignificant results. PMID- 28644963 TI - Self-report and subjective history in the diagnosis of painful neck conditions: A systematic review of diagnostic accuracy studies. AB - : Rising healthcare costs and inherent risks with over-utilizing diagnostic imaging require a quality subjective examination to improve effectiveness and time management of physical examinations. This systematic review investigates the diagnostic accuracy of subjective history and self-report items to determine if there is significant alteration in the probability of identifying specific painful neck conditions. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. INCLUSION CRITERIA: 1) Written in the English language 2) Cervical pain with/without referred upper extremity or head pain 3) Subjective history or self-report items 4) Study designs that reported diagnostic statistics or allowed calculation of sensitivities, specificities, diagnostic odds ratios, and likelihood ratios 5) used a reference standard that has a sensitivity or specificity >=75% or a diagnostic tool that is strongly supported in the literature where this data is not available. Quality Assessment of Studies of Diagnostic Accuracy II was performed to evaluate risk of bias. Five studies with 830 total patients met the inclusion criteria. Conditions commonly reported in the literature included: cervical radiculopathy, cervical myelopathy, degenerative joint disease, and cervicogenic headache. Individual history questions show minimal diagnostic value in identifying cervical conditions without the physical examination. The value of the subjective history report is important and requires further investigation for specific neck conditions. Clustering symptoms may provide more insight than individual history items in future studies. The diagnostic value of history for neck conditions may be underrepresented due to the lack of studies that isolate subjective examination from the physical examination. LEVEL OF EVIDENCE: 3a. PMID- 28644964 TI - Determination of absolute material nonlinearity with air-coupled ultrasonic receivers. AB - Quantitative evaluation of the microstructural state of a specimen can be deduced from knowledge of the sample's absolute acoustic nonlinearity parameter, beta, making the measurement of beta a powerful tool in the NDE toolbox. However, the various methods used in the past to measure beta each suffer from significant limitations. Piezoelectric contact transducers are sensitive to nonlinear signals, cheap, and simple to use, but they are hindered by the variability of the interfacial contact between transducer and specimen surface. Laser interferometry provides non-contact detection, but requires carefully prepared specimens or complicated optics to maximize sensitivity to the higher harmonic components of a received waveform. Additionally, laser interferometry is expensive and relatively difficult to use in the field. Air-coupled piezoelectric transducers offer the strengths of both of these technologies and the weaknesses of neither, but are notoriously difficult to calibrate for use in nonlinear measurements. This work proposes a hybrid modeling and experimental approach to air-coupled transducer calibration and the use of this calibration in a model based optimization to determine the absolute beta parameter of the material under investigation. This approach is applied to aluminum and fused silica, which are both well-documented materials and provide a strong reference for comparison of experimental and modeling results. PMID- 28644965 TI - 3, 4-dihydroxybenzalacetone attenuates lipopolysaccharide-induced inflammation in acute lung injury via down-regulation of MMP-2 and MMP-9 activities through suppressing ROS-mediated MAPK and PI3K/AKT signaling pathways. AB - 3, 4-Dihydroxybenzalacetone (DBL) is a constituent of Phellinus linteus. This study demonstrated the protective effect of DBL on lipopolysaccharide (LPS) induced acute lung injuries in mice. Pretreatment with DBL significantly improved LPS-induced histological alterations in lung tissues. In addition, DBL markedly reduced the total cell number, the leukocytes, the protein concentrations, and decreased the release of nitrite, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6 and the activities of matrix metalloproteinase (MMP)-2 and -9 in the bronchoalveolar lavage fluid. DBL also inhibited the W/D ratio and myeloperoxidase activity in the lung tissues. Western blot analysis indicated DBL efficiently blocked the protein expressions of inducible nitric oxide synthase, cyclooxygenase-2, MMP-2, MMP-9, and the phosphorylation of mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase (PI3K), AKT, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-kappaB. Moreover, DBL enhanced the expression of anti-oxidant proteins, such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). Based on our results, DBL might be a potential target for attenuating tissue oxidative injuries and nonspecific pulmonary inflammation. PMID- 28644966 TI - An immunosuppressive function of interleukin-35 in chronic hepatitis C virus infection. AB - Interleukin (IL)-35, a newly identified member of the IL-12 cytokine family, has been reported to suppress inflammation and induce immunotolerance. However, little is known regarding the role of IL-35 during chronic hepatitis C virus (HCV) infection. Herein, we measured the serum IL-35 concentration of 73 patients with hepatitis C and 22 healthy individuals, as well as further investigated the modulatory function of IL-35 on CD4+CD25+CD127dim/- regulatory T cells (Tregs) and on hepatocytes infected with HCV in cell culture (HCVcc). IL-35 expression was significantly increased in patients with chronic hepatitis C and was positively correlated with the levels of HCV RNA. Inhibition of viral replication led to decreases in the serum levels of IL-35. IL-35 stimulation not only elevated the percentage of Tregs but also robustly inhibited cellular proliferation and up-regulated the production of anti-inflammatory cytokines (e.g., IL-10 and IL-35) in a HCV-specific and non-specific manner, which indicates enhancement of the suppressive function of Tregs. Although IL-35 did not exert anti-HCV activity in HCVcc-infected Huh7.5 cells, it reduced inflammatory cytokine secretion from Huh7.5 cells. This was probably via inhibition of the STAT1 and STAT3 signaling pathways, which could suppress subsequent liver damage due to chronic hepatitis C. The current data suggested that IL-35 contributes to persistent HCV infection by inhibiting antiviral immune activity. Moreover, IL-35 might also protect against HCV-induced liver injury by down-regulating the expression of proinflammatory cytokines. Thus, the immunosuppressive properties of IL-35 might play contradictory roles in maintaining viral persistence and reducing the inflammatory responses in chronic HCV infection. PMID- 28644967 TI - Tramadol may increase the efficacy of therapeutic plasma exchange in anti-NMDAR encephalitis. PMID- 28644968 TI - Serum lipoprotein-associated phospholipase A2 predicts the formation of carotid artery plaque and its vulnerability in anterior circulation cerebral infarction. AB - OBJECTIVE: Circulation inflammation markers such as high-sensitive C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) are considered as predictors of cerebral and cardiac vascular diseases. However, the role of hsCRP and Lp-PLA2 in the anterior circulation cerebral infarction (ACI) is to be elaborated. PATIENTS AND METHODS: We included 100 patients with acute anterior circulation cerebral infarction (AaCI group) and 50 non-infarction subjects (control group). Carotid artery was detected by color Doppler ultrasound. Subjects were grouped based on carotid intima-media thickness (IMT) and degree of stability of carotid atherosclerotic plaque. The levels of hsCRP and Lp-PLA2 were measured in corresponding groups and the association was analyzed. RESULTS: hsCRP and Lp-PLA2 levels were the risk factors for AaCI. With the increment of carotid IMT and degree of plaque instability, the level of hsCRP and Lp-PLA2 showed an elevating tendency. hsCRP and Lp-PLA2 levels were significantly higher in plaque formation group than in IMT normal group (P=0.002 and P=0.001, respectively). hsCRP and Lp-PLA2 levels were significantly higher in vulnerable plaque group than in mixed plaque group and stable plaque group (P=0.003, P<0.001 for hsCRP and P<0.001, P<0.001 for Lp-PLA2). Lp-PLA2 was finally included in the atherosclerotic plaque model (OR=1.019, 95% confidence interval (CI): 1.003-1.035, P=0.020) and vulnerable plaque model (OR=1.041, 95%CI: 1.017-1.065, P=0.001) by performing multivariate logistic regression analysis. The area under the ROC curve (AUC) of Lp-PLA2 levels for atherosclerotic plaque was 0.746 (95% CI: 0.628-0.865, P<0.001). The optimal cut off value for Lp-PLA2 level was 267.5ng/ml, and its sensitivity and specificity for diagnosis of atherosclerotic plaque were 70.8% and 67.1%, respectively. CONCLUSIONS: The current study demonstrates that hsCRP and Lp-PLA2 are among the risk factors for AaCI. Elevated hsCRP and Lp-PLA2 are associated with carotid plaque formation. Univariate and multivariate logistic regression analysis suggests that elevated Lp-PLA2 is the independent risk factor for carotid plaque and its vulnerability. PMID- 28644969 TI - Premotor symptoms and the risk of Parkinson's disease: A case-control study in Mexican population. AB - OBJECTIVES: To assess the prevalence of pre-motor symptoms and estimate the risk for developing Parkinson's disease in Mexican population. PATIENTS AND METHODS: A case-control study was carried out with consecutive subjects with Parkinson's disease from two different referral centers in Mexico. Gender- and age-matched controls were randomly selected from the participating hospitals. All subjects were assessed using a structured questionnaire for the assessment of pre-motor symptoms (hyposmia, depression, anxiety, constipation, and sleep disorders). Odds ratios (OR) were calculated using logistic regression analysis. RESULTS: A total of 430 subjects with PD and 430 healthy subjects were included. Premotor symptoms prevalence was 77.7% (n=334) for the PD group, compared to 41.3% (n=178) in the control group (p<0.001). After logistic multivariate analysis, previous history of hyposmia (OR 2.02 [95% CI 1.33-3.06]), depression (OR 2.52 [95% CI 1.67 3.84]), anxiety (OR 4.37 [95% CI 2.73-6.98]) and sleep disorders (OR 2.03 [95% CI 1.41-2.93]) were independently associated with Parkinson's disease. Overall prediction success of the model was 81.2% for controls and 61.2% for subjects with PD. CONCLUSION: All five premotor symptoms assessed were more commonly reported in PD subjects than healthy controls. The presence of non-motor symptoms yield a prediction success of 71.2% to discriminate between PD subjects and healthy controls. PMID- 28644970 TI - Overexpression of Populus*canescens isoprene synthase gene in Camelina sativa leads to alterations in its growth and metabolism. AB - Isoprene (2-methyl-1,3-butadiene) is a hemiterpene molecule. It has been estimated that the plant kingdom emits 500-750 million tons of isoprene in the environment, half of which results from tropical broadleaf trees and the remainder from shrubs. Camelina (Camelina sativa (L.) Crantz) is an emerging bioenergy plant for biodiesel. In this study, we characterized isoprene formation following a diurnal/nocturnal cycle in wild-type Camelina plants. To understand the potential effects of isoprene emission on this herbaceous plant, a gray poplar Populus*canescens isoprene synthase gene (PcISPS) was overexpressed in Camelina. Transgenic plants showed increased isoprene production, and the emissions were characterized by a diurnal/nocturnal cycle. Measurements of the expression of six genes of the plastidial 2-C-methyl-d-erythriol-4-phosphate (MEP) pathway revealed that the expression patterns of three key genes were associated with isoprene formation dynamics in the three genotypic plants. Conversely, dissimilar gene expression levels existed in different genotypes, indicating that dynamics and variations occurred among plants. Moreover, transgenic plants grew shorter and developed smaller leaves than the wild-type and empty vector control transgenic plants. Photosynthetic analysis showed that the CO2 assimilation rate, intracellular CO2 concentration, mesophyll conductance and contents of chlorophylls a and b were similar among PcISPS transgenic, empty vector control transgenic, and wild-type plants, indicating that the transgene did not negatively affect photosynthesis. Based on these results, we suggest that the reduced biomass was likely a trade-off consequence of the increased isoprene emission. PMID- 28644971 TI - Simultaneous silencing of GhFAD2-1 and GhFATB enhances the quality of cottonseed oil with high oleic acid. AB - Cottonseed oil has become an important source of edible oil due to its significant cost advantage. However, there is a growing concern over its fatty acid composition and nutritional value. In Gossypium hirsutum, GhFAD2-1 and GhFATB encoding the microsomal oleate desaturase and palmitoyl-acyl carrier protein thioesterase, respectively, play critical roles in regulating the proportions of saturated and polyunsaturated fatty acids in cottonseed lipids. In this study, RNAi technology was used to simultaneously inhibit the expression levels of GhFAD2-1 and GhFATB to improve the quality of cottonseed oil by increasing oleic acid content. Transgenic cotton plants with reduced levels of both target genes were successfully generated. In mature seed kernels of transgenic plants, the content of oleic acid was 38.25%, accordingly increasing by 156.96%, while the content of palmitic acid and linoleic acid was 19.15% and 36.68%, decreasing by 21.28% and 33.92%, respectively, compared with that of the control. The total oil content in transgenic and control kernels was 22.48% and 29.83%, respectively. The reduced oil level in transgenic seeds was accompanied by a reduction in seed index, thereby causing disadvantageous effects on seed germination potentiality and seed vigor, particularly under cool stress conditions. Our results demonstrated the feasibility of simultaneous manipulation of multiple genes using RNAi technology and showed the important role of oil content in seed development and vigor. Our findings provide insight into the physiological significance of the fatty acid composition in cottonseeds. PMID- 28644972 TI - Advantages of targeting B cell receptor complex to treat B-cell derived autoimmune diseases and lymphomas. AB - Antibodies produced by B-cells provide protection from infectious agents. However, impaired cell death signaling pathways in B-cells can lead to cancer, immunodeficiency or autoimmune diseases. B-cell signaling molecules such as CD20, CD19, Btk, and BAFF-R are targeted by therapeutic drugs and used to treat B-cell derived lymphomas or autoimmune diseases. Nevertheless, B-cells could develop resistance to these therapeutic drugs or the therapeutic drugs may have off target effects. For instance, repeated rituximab (anti-CD20 antibody) treatment may lead to the loss of its target cell surface molecule, CD20. In addition, in B cell malignancies, loss of CD19 expression has been observed. Another target molecule, Btk is expressed not only in B-cells but also in mast cells, macrophages, and dendritic cells. Thus, targeting Btk could negatively regulate the functions of innate immunity. The expression of BAFF-R is thought to be restricted to B-cells but it is also expressed on T-cells. Targeting BAFF-R, therefore, may lead to depletion of T-cells in addition to B-cells. B cell receptor (BCR) expression and signaling, however, are critically important for development, differentiation and survival of B-cells. Moreover, BCR is exclusively expressed on B-cells, which makes it an excellent target to avoid off target effects. PMID- 28644973 TI - IL-18/IL-15/IL-12 synergy induces elevated and prolonged IFN-gamma production by ex vivo expanded NK cells which is not due to enhanced STAT4 activation. AB - The synergistic effect of IL-18/IL-15/IL-12 stimulation potently activates NK cells, inducing high levels of IFN-gamma production. As a result of this potent stimulatory effect, NK cell pre-activation with IL-18/IL-15/IL-12 is being developed as a cancer immunotherapy. Ex vivo expansion of NK cells enables the efficient generation of large numbers of NK cells for wide-scale and repeated therapeutic use, and is thus an important source of NK cells for clinical application. However, the effects of IL-18/IL-15/IL-12 stimulation on ex vivo expanded NK cells have not yet been assessed. Thus, the present study assessed the effects of IL-18/IL-15/IL-12 stimulation on NK cells expanded ex vivo using K562-based artificial antigen presenting cells expressing membrane-bound IL-21. We report that ex vivo expanded NK cells stimulated with IL-18/IL-15/IL-12 produce high levels of IFN-gamma and TNFalpha, have potent cytotoxicity, and maintain prolonged IFN-gamma production following removal of stimulation. IL 18/IL-15/IL-12 stimulation induces a phenotypically unique IFN-gamma-producing population with reduced CD16 expression and greater CD25 expression as compared to stimulated IFN-gamma- NK cells and unstimulated NK cells. We elucidate that the mechanism of synergy for induction and maintenance of IFN-gamma production is not due to a further enhancement of STAT4 activation compared to stimulation with IL-12 alone. Furthermore, we demonstrate that the synergistic increase in IFN gamma is not solely under translational regulation, as elevated levels of IFN gamma mRNA contribute to the synergistic increase in IFN-gamma. Overall, this study characterizes the response of ex vivo expanded NK cells to IL-18/IL-15/IL 12 stimulation and supports the use of ex vivo expanded NK cells as a feasible and efficient source of IL-18/IL-15/IL-12 pre-activated NK cells for adoptive transfer in cancer immunotherapies. PMID- 28644974 TI - Immature human DCs efficiently translocate endocytosed antigens into the cytosol for proteasomal processing. AB - Cross-presentation of endocytosed antigen is essential for induction of CD8 effector T cell responses and a hallmark of dendritic cells (DCs). The mode of antigen processing in this context is controversial and some models imply translocation of the antigen from the endosomes into the cytosol. To test this hypothesis we made use of the pro-apoptotic properties of cytochrome c when in the cytosol, and confirmed that it indeed triggered apoptosis of human immature DCs but only at high concentrations. Proteasome inhibitors reduced the required concentration of cytochrome c thousand-fold, indicating that protein translocated into the cytosol is rapidly degraded by proteasomes. Mature DCs were also susceptible to cytochrome c-triggered apoptosis at high concentrations but proteasome inhibitors did not increase their sensitivity. Other cross-presenting cells such as B cells and monocytes were not sensitive to cytochrome c at all, indicating that they do not shuttle internalized antigen into the cytosol. Thus, processing of internalized antigens seems to follow different pathways depending on cell type and, in case of DCs, maturation state. Immature DCs appear to have a unique capacity to shuttle external antigen into the cytosol for proteasomal processing, which could explain their efficiency in antigen cross-presentation. PMID- 28644975 TI - A neural blood pressure marker for bioelectronic medicines for treatment of hypertension. AB - A novel therapeutic approach for treating resistant hypertension could be the use of bioelectronic medicines to achieve blood pressure (BP) control in implanted patients by closed-loop stimulation of the left vagus nerve (LVN). However, such a technology would require an implantable BP marker, which is not available yet. As it is known that the LVN conducts afferent BP-related signals, this study aimed to investigate if such signals could be recorded with implantable means and used to derive BP markers. The present experiments were performed in anesthetized pigs subjected to a transient or stable BP increase induced by adrenaline administration. The LVN signals recorded with cuff electrodes and the BP waves recorded with carotid catheters were ensemble averaged relative to the R-peaks of the electrocardiogram. Through this procedure, afferent BP-related neural profiles (BPnPs) were derived from the LVN signals. As the BPnPs represented accurate copies of the BP waves, the timing parameters of both waveforms were almost the same and the BPnP amplitude increased linearly with the diastolic, systolic and mean BP. These results indicate that the BPnPs comprise accurate BP information and that the BPnP amplitude could serve as a BP marker in implantable systems. PMID- 28644976 TI - Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs. AB - Mesenchymal stromal cells (MSCs) secrete paracrine factors that play crucial roles during tissue regeneration. Whether this paracrine function is influenced by the properties of biomaterials in general, and those used for cell delivery in particular, largely remains unexplored. Here, we investigated if three dimensional culture in distinct microenvironments - nanoporous hydrogels (mean pore size ~5 nm) and macroporous scaffolds (mean pore size ~120 MUm) - affects the secretion pattern of MSCs, and consequently leads to differential paracrine effects on target progenitor cells such as myoblasts. We report that compared to MSCs encapsulated in hydrogels, scaffold seeded MSCs show an enhanced secretion profile and exert beneficial paracrine effects on various myoblast functions including migration and proliferation. Additionally, we show that the heightened paracrine effects of scaffold seeded cells can in part be attributed to N cadherin mediated cell-cell interactions during culture. In hydrogels, this physical interaction between cells is prevented by the encapsulating matrix. Functionally blocking N-cadherin negatively affected the secretion profile and paracrine effects of MSCs on myoblasts, with stronger effects observed for scaffold seeded compared to hydrogel encapsulated cells. Together, these findings demonstrate that the therapeutic potency of MSCs can be enhanced by biomaterials that promote cell-cell interactions. PMID- 28644977 TI - Influenza Hemagglutinin and M2 ion channel priming by trypsin: Killing two birds with one stone. AB - Influenza A virus membrane fusion and disassembly, prerequisite processes for viral infectivity, depend on acidic pH. In a recent study, Zhirnov et al. reported an important finding-that influenza virions are not permeable to protons unless the hemagglutinin (HA) fusion protein is primed by trypsin cleavage. This raises the question of whether in the viral context the M2 ion channel requires priming prior to its activation by low pH. Here, it is hypothesized that both HA and M2 ion channel direct priming by trypsin is required for their sensitization by low pH. PMID- 28644978 TI - Immune activation in prolonged cART-suppressed HIV patients is comparable to that of healthy controls. AB - Sustained immune activation during chronic HIV infection is considered to augment co-morbidity and mortality. Effective combination antiretroviral therapy (cART) has shown to dampen immune activation especially during the first year cART, but the effects of long-term cART in patients without major comorbidities remains under-investigated. We performed a comprehensive analysis including cellular, intracellular and plasma biomarkers to study the effect of cART on immune parameters in 5 groups of 10 HIV patients. All patients were without major co morbidities and grouped based on cART duration (0, 1, 3, 5, and 10 years). We included 10 matched healthy controls for comparison. Our data show that after the first year of cART, no additional effect on the level of inflammatory markers is observed in HIV infected patients without major co morbidities. Residual immune activation status in well-treated HIV-infection is similar to levels observed in healthy controls. PMID- 28644980 TI - Making power visible: Doing theatre-based status work with nursing students. AB - As part of a senior leadership class in an undergraduate baccalaureate nursing program in the northeastern United States, we conducted an experiential, theater based workshop designed to increase student awareness of the micro-dynamics of power and the enactment of status in their day-to-day lives. These exercises allowed student participants to embody status and power and understand it in ways that they did not after simply completing assigned readings. At the conclusion of the workshop the participants were asked to reflect on their status habits and the consequences of these habits in a single hand-written page. The participants' reflections showed two interesting trends. The first is that a relatively short workshop dramatically increased participants' awareness of power and status as ever present, including a substantial normative move from seeing using power as being a generally bad thing that can be justified in the interests of the organization's mission to a more neutral stance that power and status are at work in all of our interactions. The second trend that emerged was the tendency for participants to focus on agency-based explanations of power dynamics. PMID- 28644979 TI - Intraoperative fast ripples independently predict postsurgical epilepsy outcome: Comparison with other electrocorticographic phenomena. AB - In the surgical management of epilepsy, the resection of cortex exhibiting interictal fast ripples (250-500Hz) on electrocorticography has been linked to postoperative seizure-freedom. Although fast ripples appear to accurately identify the epileptogenic zone-the minimum tissue that must be removed at surgery to achieve seizure-freedom-it has not been established that fast ripples are a superior biomarker in comparison with multimodal presurgical neuroimaging and other electrocorticography abnormalities. Hence, in the prediction of postoperative seizure-freedom, we compared the value of fast ripples with other intraoperative electocorticography abnormalities including focal slowing, paroxysmal fast activity, intermittent spike discharges, continuous epileptiform discharges, focal attenuation, and intraoperative seizures, as well as complete resection of the lesion defined by MRI and other neuroimaging. In a cohort of 60 children with lesional epilepsy and median postsurgical follow-up exceeding 4 years, who underwent resective epilepsy surgery with intraoperative electrocorticography, we evaluated the extent to which removal of each intraoperative electrocorticography abnormality impacts time to first postoperative seizure using the Kaplan-Meier method and Cox proportional hazards regression. Secondly, we contrasted the predictive value of resection of each competing electrocorticography abnormality using standard test metrics (sensitivity, specificity, positive predictive value, and negative predictive value). In contrast with all other intraoperative electrocorticography abnormalities, fast ripples demonstrated the most favorable combination of positive predictive value (100%) and negative predictive value (76%) in the prediction of postoperative seizures. Among all candidate electrocorticography features, time to first postoperative seizure was most strongly associated with incomplete resection of fast ripples (hazard ratio=19.8, p<0.001). In multivariate survival analyses, postoperative seizures were independently predicted by incomplete resection of cortex generating fast ripples (hazard ratio=25.4, 95%CI 6.71-96.0, p<0.001) and focal slowing (hazard ratio=5.79, 95%CI 1.76-19.0, p=0.004), even after adjustment for the impact of an otherwise complete resection. All children with incomplete resection of interictal FR generating cortex exhibited postoperative seizures within six months. Notably, this cohort included many patients with large resections and thus limited opportunity to exhibit unresected fast ripples. Future study in a cohort with small resection volume, or a clinical trial in which resection margins are guided by fast ripple distribution, would likely yield a more precise estimate of the risk posed by unresected fast ripples. With a high detection rate during brief intraoperative electrocorticography and favorable positive and negative predictive value, interictal fast ripple characterization during surgery is a feasible and useful adjunct to standard methods for epilepsy surgery planning, and represents a valuable spatially-localizing biomarker of the epileptogenic zone, without the need for prolonged extraoperative electrocorticography. PMID- 28644981 TI - Chemical profiling and antioxidant evaluation of Yangxinshi Tablet by HPLC-ESI-Q TOF-MS/MS combined with DPPH assay. AB - Yangxinshi Tablet (YXST) is a Chinese patent medicine commonly used to treat cardiovascular diseases. However, its detailed chemical basis and mechanisms of action have not been clarified. In this study, high performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOF-MS) was applied for comprehensive analysis of the chemical constituents in YXST. A total of 127 compounds, including 19 phenolic acids, 12 alkaloids, 51 flavanoids, 32 triterpenoids, 2 lignans, 2 phenylethanoid glycosides, 2 anthraquinones, 1 coumarin, and 6 other compounds, were identified or tentatively deduced by comparing their retention times and MS spectra with those of authentic standards or literature data. To further prove the antioxidant activity of YXST, its free radical scavenging capacity was assessed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) spectrophotometric assay and the antioxidants in YXST were rapidly screened by DPPH-HPLC experiment. Especially, salvianolic acid A and salvianolic acid B showed excellent DPPH scavenging activities with the IC50 of 151.9 and 275.6MUg/mL, respectively, which were stronger than that of l-ascorbic acid (positive control) with the IC50 of 297.1MUg/mL. Additionally, these two most potent antioxidants were detectable in rat plasma after oral administration. In conclusion, this study reported important clues for the further pharmacological and clinical studies of YXST. Meanwhile, it provided a practical strategy for rapid screening and identifying of in vivo antioxidant in traditional Chinese medicine preparations. PMID- 28644982 TI - Assessment of sublethal endpoints after chronic exposure of the nematode Caenorhabditis elegans to palladium, platinum and rhodium. AB - The aim of this study was to investigate chronic effects of the platinum-group elements (PGE) palladium (Pd), platinum (Pt) and rhodium (Rh) on the nematode Caenorhabditis elegans. Aquatic toxicity testing was carried out according to ISO 10872 by determining 96 h EC50 values for sublethal endpoints, including growth, fertility and reproduction. Single PGE standard solutions were used as metal source. Based on the EC50 values for Pt, reproduction (96 h EC50 = 497 MUg/L) was the most sensitive endpoint followed by fertility (96 h EC50 = 726 MUg/L) and growth (96 h EC50 = 808 MUg/L). For Pd, no precise EC50 values could be calculated due to bell-shaped concentration response curves, but the 96 h EC50 for reproduction ranged between 10 and 100 MUg/L. Pd and Pt had effects on all endpoints. With raising element concentrations reproduction was inhibited first. At a certain concentration, fertility was also affected, which in turn had an additional effect on reproduction. Growth inhibition can also lead to a loss of fertility if the worms do not reach an appropriate body size to become fertile. Rhodium showed no inhibition of any endpoint between concentrations of 100 to 10,000 MUg Rh/L. The results of this study allow the following order of PGE with respect to decreasing toxicity to C. elegans: Pd > Pt " Rh. PMID- 28644983 TI - Future heat waves due to climate change threaten the survival of Posidonia oceanica seedlings. AB - Extreme weather events are major drivers of ecological change, and their occurrence is likely to increase due to climate change. The transient increases in atmospheric temperatures are leading to a greater occurrence of heat waves, extreme events that can produce a substantial warming of water, especially in enclosed basins such as the Mediterranean Sea. Here, we tested the effects of current and predicted heat waves on the early stages of development of the seagrass Posidonia oceanica. Temperatures above 27 degrees C limited the growth of the plant by inhibiting its photosynthetic system. It suffered a reduction in leaf growth and faster leaf senescence, and in some cases mortality. This study demonstrates that the greater frequency of heat waves, along with anticipated temperature rises in coming decades, are expected to negatively affect the germination of P. oceanica seedlings. PMID- 28644984 TI - Current practice and recommendations in UK epilepsy monitoring units. Report of a national survey and workshop. AB - PURPOSE: Inpatient video-EEG monitoring (VEM) is an important investigation in patients with seizures or blackouts, and in the pre-surgical workup of patients with epilepsy. There has been an expansion in the number of Epilepsy Monitoring Units (EMU) in the UK offering VEM with a necessary increase in attention on quality and safety. Previous surveys have shown variation across centres on issues including consent and patient monitoring. METHOD: In an effort to bring together healthcare professionals in the UK managing patients on EMU, we conducted an online survey of current VEM practice and held a one-day workshop convened under the auspices of the British Chapter of the ILAE. The survey and workshop aimed to cover all aspects of VEM, including pre-admission, consent procedures, patient safety, drug reduction and reinstatement, seizure management, staffing levels, ictal testing and good data recording practice. RESULTS: This paper reports on the findings of the survey, the workshop presentations and workshop discussions. 32 centres took part in the survey and there were representatives from 22 centres at the workshop. There was variation in protocols, procedures and consent processes between units, and levels of observation of monitored patients. Nevertheless, the workshop discussion found broad areas of agreement on points. CONCLUSION: A survey and workshop of UK epilepsy monitoring units found that some variability in practice is inevitable due to different local arrangements and patient groups under investigation. However, there were areas of clear consensus particularly in relation to consent and patient safety that can be applied to most units and form a basis for setting minimum standards. PMID- 28644985 TI - Depressive-like behavior is elevated among offspring of parents exposed to dim light at night prior to mating. AB - Rates of major depressive disorder (MDD) have steadily increased over the past 50 years. Many factors have been implicated in the etiology of depressive disorders and environmental influences are being increasingly recognized. The increase in depression rates has coincided with increased artificial nighttime lighting. Exposure to light at night (LAN) has been associated with increased depressive like behavior in rodents and decreased mood in humans. However, relatively little is known on the multigenerational effects of dLAN on affect. In this study, we exposed adult male and female Siberian hamsters (Phodopus sungorus) to either DARK (0lx) or dim LAN (5lx) for 9 weeks, then paired animals in a full factorial design; all animals were thereafter housed in dark nights. Offspring were gestated and reared in dark nights, then tested in adulthood for depressive-like behaviors and hippocampal expression of glucocorticoid (GR) and melatonin (MT1) receptor expression. Maternal exposure to dLAN decreased sucrose preference, time to first float bout in the Porsolt swim test, and GR expression in the hippocampus. Paternal exposure to dLAN increased time spent floating, and increased hippocampal GR expression. Overall, our results suggest that chronic exposure of parents to light at night has multigenerational effects on offspring depressive-like behavior. If these results pertain to humans, then our data suggest that LAN may contribute to the rapidly rising rates of major depressive disorder in industrialized and developing countries. PMID- 28644987 TI - Thiophene/thiazole-benzene replacement on guanidine derivatives targeting alpha2 Adrenoceptors. AB - Searching for improved antagonists of alpha2-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6 311++G(p,d) computational level] confirming that thiophene and thiazole will be good 'ring equivalents' to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at alpha2-adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their alpha2-adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues. In the case of cycloakyl systems, thiophenes with 6-membered rings showed the largest affinities, while for the thiazoles the 5-membered analogue presented the strongest affinity. From all the compounds tested for noradrenergic activity, only one compound exhibited agonistic activity, while two compounds showed very promising antagonism of alpha2-adrenoceptors. PMID- 28644986 TI - Designing novel inhibitors against histone acetyltransferase (HAT: GCN5) of Plasmodium falciparum. AB - During active proliferation phase of intra-erythrocytic cycle, the genome of P. falciparum is regulated epigenetically and evolutionary conserved parasite specific histone proteins are extensively acetylated. The reversible process of lysine acetylation, causing transcriptional activation and its deacetylation, causing transcriptional repression is regulated by balanced activities of HATs and HDACs. They are also known to regulate antigenic variations and gametocytic conversion in P. falciparum. These histone modifying enzymes have been identified as potential targets for development of anitmalarials in literature. PfGCN5, a HAT family member of P. falciparum is predominantly involved in H3K9 acetylation. In this study, through comparative structure and sequence analysis, we elucidate differences in the catalytic pocket of PfGCN5 which can be exploited to design selective inhibitors. Through virtual screening of known antimalarials from ChEMBL bioassay database, we mapped 10 compounds with better affinity towards PfGCN5. Further, we identified 10 more novel compounds which showed remarkably better affinity towards the Plasmodium target from analogues of mapped inhibitors from ZINC database of commercially available compounds. Comparative molecular dynamics simulation study of one of the compounds (C14) complex with PfGCN5 and HsGCN5 suggested the possible reason for its selectivity. In vitro parasite growth assay in the presence of C14 showed IC50 value at lower nanomolar range (~ 225 nM). However, no effect in mammalian fibroblast cells was observed for C14 (up to 20 MUM). Further, reduced level of HAT activity of recombinant GCN5 and H3K9Ac was observed in the parasites treated with C14. Overall, this study reports 20 potential inhibitors of PfGCN5 and experimental validation of one molecule (C14) with antimalarial activity at low nanomolar range. PMID- 28644988 TI - Effect of marbling on volatile generation, oral breakdown and in mouth flavor release of grilled beef. AB - While the positive effect of intramuscular fat (IMF) on beef tenderness is well established, its role in flavor generation and flavor release is less defined. To increase understanding, real-time volatile generation was monitored during grilling of beefsteaks (grass and grain-fed Angus and grass-fed Wagyu) with different amounts of IMF by proton transfer reaction mass spectrometry. Volatile concentration increased significantly (p<0.001) when the IMF was >~10%, but did not differ (p>0.05) at lower IMF levels (5.2-10.2%). In vivo release of volatiles during consumption of grilled steaks was also measured using human subjects. Pre- and postswallow volatile release profiles varied according to marbling level and volatile fat solubility. In-mouth release of key hydrophilic volatiles was significantly greater (p<0.05) in high IMF grilled beef, consistent with more intense sensory flavor. Faster oral breakdown and higher peak saliva concentrations of non-volatile flavor compounds in high IMF grilled beef were consistent with higher tenderness and more intense flavor perception. PMID- 28644989 TI - Transcriptome analysis shows activation of the arginine deiminase pathway in Lactococcus lactis as a response to ethanol stress. AB - This paper describes the molecular response of Lactococcus lactis NZ9700 to ethanol. This strain is a well-known nisin producer and a lactic acid bacteria (LAB) model strain. Global transcriptome profiling using DNA microarrays demonstrated a bacterial adaptive response to the presence of 2% ethanol in the culture broth and differential expression of 67 genes. The highest up-regulation was detected for those genes involved in arginine degradation through the arginine deiminase (ADI) pathway (20-40 fold up-regulation). The metabolic responses to ethanol of wild type L. lactis strains were studied and compared to those of regulator-deletion mutants MG?argR and MG?ahrC. The results showed that in the presence of 2% ethanol those strains with an active ADI pathway reached higher growth rates when arginine was available in the culture broth than in absence of arginine. In a chemically defined medium strains with an active ADI pathway consumed arginine and produced ornithine in the presence of 2% ethanol, hence corroborating that arginine catabolism is involved in the bacterial response to ethanol. This is the first study of the L. lactis response to ethanol stress to demonstrate the relevance of arginine catabolism for bacterial adaptation and survival in an ethanol containing medium. PMID- 28644990 TI - Global transcriptional response of Escherichia coli MG1655 cells exposed to the oxygenated monoterpenes citral and carvacrol. AB - DNA microarrays were used to study the mechanism of bacterial inactivation by carvacrol and citral. After 10-min treatments of Escherichia coli MG1655 cells with 100 and 50ppm of carvacrol and citral, 76 and 156 genes demonstrated significant transcriptional differences (p<=0.05), respectively. Among the up regulated genes after carvacrol treatment, we found gene coding for multidrug efflux pumps (acrA, mdtM), genes related to phage shock response (pspA, pspB, pspC, pspD, pspF and pspG), biosynthesis of arginine (argC, argG, artJ), and purine nucleotides (purC, purM). In citral-treated cells, transcription of purH and pyrB and pyrI was 2 times higher. Deletion of several differentially expressed genes confirmed the role of ygaV, yjbO, pspC, sdhA, yejG and ygaV in the mechanisms of E. coli inactivation by carvacrol and citral. These results would indicate that citral and carvacrol treatments cause membrane damage and activate metabolism through the production of nucleotides required for DNA and RNA synthesis and metabolic processes. Comparative transcriptomics of the response of E. coli to a heat treatment, which caused a significant change of the transcription of 1422 genes, revealed a much weaker response to both individual constituents of essential oils (ICs)..Thus, inactivation by citral or carvacrol was not multitarget in nature. PMID- 28644991 TI - Glimpses into the blind spot: Social interaction and autism. AB - A primary feature of autism spectrum disorder (ASD) is marked difficulty in social interactions. Despite the centrality of social interaction differences to the clinical presentation of ASD, only a small portion of research in this field characterizes interaction in everyday social contexts. This theoretical paper reviews the growing corpus of interactional research on ASD, including discourse analysis (DA) and conversation analysis (CA) approaches. DA and CA are micro analytic methods aimed at understanding the organizational structure of, and actions pursued within, social encounters. These methods are aligned with enactive theories of social interaction. The bulk of current ASD research construes social interaction as involving isolated individuals who represent and/or theorize about the minds of an interlocutor. Enactive approaches posit that achieving intersubjectivity does not require theories of other minds, but instead a propensity for coordinating social actions with others. Through the complementary lenses of enactivism and interactional research, I offer an account of autistic social interaction as involving differences in interactional coordination, interactional priorities, and the enactment of meaning across conversational turns. This characterization challenges the explanatory role of cognitive processes such as Theory of Mind, and points to new avenues for conceptualizing, measuring, and supporting social interaction. PMID- 28644992 TI - Surface coating-modulated toxic responses to silver nanoparticles in Wolffia globosa. AB - With the omnipresence of silver nanoparticles (AgNPs) in our daily consumer products, their release has raised serious concerns. However, the biochemical mechanisms by which plants counteract the toxicity of nanoparticles are largely unknown. This study investigated the exposure of aquatic Wolffia globosa to ATP nAg (AgNPs coated with adenosine triphosphate), cit-nAg (AgNPs coated with citrate), and Ag+. Hill reaction activity was basically lost in W. globosa treated with 10mg/L ATP-nAg and Ag+, while the activity was still maintained at 38.7%-38.9% of the respective controls at 10mg/L cit-nAg. The reduction of amounts of chlorophyll and soluble protein were shown in response to the Ag stresses. This was accompanied by the accumulation of sugar in W. globosa treated with cit-nAg. By contrast, the depletion of sugar was recorded after 10mg/L ATP nAg and Ag+ treatments. The superoxide dismutase and peroxidase activities were significantly increased after exposure to 10mg/L ATP-nAg and Ag+, which did not occurred in W. globosa treated with cit-nAg. The ratio between NADPH/NADP+ was higher after cit-nAg and Ag+ stresses than the respective controls. The accumulation of Ag was found to increase in a concentration-dependent manner. Ag+ and ATP-nAg inhibited the uptake of P and K, and promoted the uptake of Fe and Cu. In contrast, cit-nAg only promoted the uptake of Cu. Our results implied that surface coating induced different physiological responses of W. globosa to AgNPs. Based on above results, we speculated that after exposure to cit-nAg, citrate possibly could serve as the substrate for the tricarboxylic acid cycle and accumulated sugar may promote pentose phosphate pathways. For ATP-nAg treatments, ATP would act as an exogenous energy source of plant metabolisms. Our findings demonstrate that surface coating regulates the physiological responses of plants to AgNPs through distinct mechanisms. PMID- 28644993 TI - Long-term toxicity of surface-charged polystyrene nanoplastics to marine planktonic species Dunaliella tertiolecta and Artemia franciscana. AB - Plastic pollution has been globally recognized as a critical issue for marine ecosystems and nanoplastics constitute one of the last unexplored areas to understand the magnitude of this threat. However, current difficulties in sampling and identifying nano-sized debris make hard to assess their occurrence in marine environment. Polystyrene nanoparticles (PS NPs) are largely used as nanoplastics in ecotoxicological studies and although acute exposures have been already investigated, long-term toxicity on marine organisms is unknown. Our study aims at evaluating the effects of 40nm PS anionic carboxylated (PS-COOH) and 50nm cationic amino-modified (PS-NH2) NPs in two planktonic species, the green microalga Dunaliella tertiolecta and the brine shrimp Artemia franciscana, respectively prey and predator. PS NP behaviour in exposure media was determined through DLS, while their toxicity to microalgae and brine shrimps evaluated through 72h growth inhibition test and 14 d long-term toxicity test respectively. Moreover, the expression of target genes (i.e. clap and cstb), having a role in brine shrimp larval growth and molting, was measured in 48h brine shrimp larvae. A different behaviour of the two PS NPs in exposure media as well as diverse toxicity to the two planktonic species was observed. PS-COOH formed micro-scale aggregates (Z-Average>1MUm) and did not affect the growth of microalgae up to 50MUg/ml or that of brine shrimps up to 10MUg/ml. However, these negatively charged NPs were adsorbed on microalgae and accumulated (and excreted) in brine shrimps, suggesting a potential trophic transfer from prey to predator. On the opposite, PS-NH2-formed nano-scale aggregates (Z-Average<200nm), caused inhibition of algal growth (EC50=12.97MUg/ml) and mortality in brine shrimps at 14 d (LC50=0.83MUg/ml). Moreover, 1MUg/ml PS-NH2 significantly induced clap and cstb genes, explaining the physiological alterations (e.g. increase in molting) previously observed in 48h larvae, but also suggesting an apoptotic pathway triggered by cathepsin L-like protease in brine shrimps upon PS-NH2 exposure. These findings provide a first insight into long-term toxicity of nanoplastics to marine plankton, underlining the role of the surface chemistry in determining the behaviour and effects of PS NPs, in terms of adsorption, growth inhibition, accumulation, gene modulation and mortality. The use of long-term end-point has been identified as valuable tool for assessing the impact of nanoplastics on marine planktonic species, being more predictable of real exposure scenarios for risk assessment purposes. PMID- 28644994 TI - Is the systematic circumferential tumor cavity shaving a representative sample for the remaining mammary gland? About 75 cases. AB - INTRODUCTION: The conservative surgery is more and more indicated for breast cancer. However, we still fear local recurrence which is mostly due to residual tumors?. Several techniques have been used to minimize theses residual tumors; one of them is the systematic circumferential tumor cavity shaving (SCTCS). METHODS: We sampled 75 female patients who had conservative surgery with positive shaved margins in the anatomopathology examination and to whom a complementary treatment with mastectomy have been decided. RESULTS: The median age was 48 years old. The median tumor size was 23 mm. In the histological examination of the tumors, 93% were invasive ductal carcinoma associated in 50% of the cases to the presence of ductal carcinoma in situ (DCIS) where all the lumpectomies had clear margin. For the SCTCS, 62,2% were DCIS and in 17,6% of the cases were invasive ductal carcinoma. A complementary treatment with mastectomy was indicated to all the patients. A residual tumor was detected in the remaining mammary gland in 47,7% of the cases out of which 50% were DCIS. Local recurrence happened in three patients (4,6%) after a median of follow up of 36 months. The overall survival and the disease free survival at five years were respectively 83,6% and 75,5%. CONCLUSION: Standardized lumpectomy cavity shaving provides a backup to lumpectomy margins in conservative breast surgery but it can also be used as a sample for the remaining breast, helping to detect the residual tumor, and decreasing the rates of local recurrence after BCT. PMID- 28644995 TI - Less is more. Breast conservation might be even better than mastectomy in early breast cancer patients. AB - During the recent years an increase of mastectomy rates in early breast cancer patients has been observed. Nevertheless, several large population-based studies reported a possible improved outcome after breast conserving therapy compared to radical surgery, after all the adjustments. We hereby summarize our opinion on this topic suggesting that these robust and consistent data might challenge the statement that breast conserving therapy is merely not inferior to radical surgery. PMID- 28644996 TI - Neural correlates of psychotic-like experiences during spiritual-trance state. AB - Recent studies indicate high levels of psychotic experiences in the general population. Here, we report a functional imaging study with 8 mentally healthy spiritual mediums and 8 matched controls. The mediums entered a mediumistic trance state using a standardized manner by closing their eyes and actively seeking to ignore external and internal stimuli to achieve a 'state of emptiness'; in a control condition, they were instructed to re-enact the same mediumistic experience that they had during the mediumistic-trance condition but in a non-trance state (imaginative-trance). Both mediums and controls took part in a resting state session. The results indicate stronger activation in the lateral occipital cortex, posterior cingulate cortex (PCC), temporal pole, middle temporal gyrus and orbitofrontal cortex during the mediumistic-trance state. We also observe increased functional connectivity within auditory and sensorimotor Resting State Networks (RSN) during mediumistic-trance compared to resting and imaginative-trance conditions. Comparing spiritual mediums and controls, no differences in RSN were found. These data show preserved engagement of prefrontal cortex and connectivity of the default-mode network that indicate maintained introspective control over non-pathological psychotic-like experiences. PMID- 28644997 TI - First episode psychosis moderates the effect of gray matter volume on cognition. AB - Patients with first episode psychosis (FEP) present with cognitive deficits and volume differences in certain brain areas. Brain volumetric information further correlates with cognitive testing, and multiple brain areas shows different strengths of correlation with the cognitive functions being tested. Traditionally, these cognitive functions are independently related to volumetric differences, but these functions share variance. Failing to account for this aspect of cognition hinders the proper representation of cognition in neuroimaging studies. We used modeling methods which account for this shared variance to investigate the differences of correlations between cognitive abilities and brain areas. A multiple-groups structured equation model (SEM) approach was used to design and test a model representing the relation between gray matter volumetric data and neuropsychological test scores in a sample of 100 Brazilian FEP patients and 94 controls. Models with a latent variable formed by neurological measures and reflecting cognitive measures performed better on fit tests. FEP moderated the relation between gray matter volumes and cognition by altering the profile of correlations between groups. This moderation had a large effect size. SEM provides a fine grained picture of the interdependence of structural brain changes and cognition. PMID- 28644999 TI - Diffusion tensor imaging of cingulum bundle and corpus callosum in schizophrenia vs. bipolar disorder. AB - Both schizophrenia and bipolar disorder show abnormalities of white matter, as seen in diffusion tensor imaging (DTI) analyses of major brain fibre bundles. While studies in each of the two conditions have indicated possible overlap in anatomical location, there are few direct comparisons between the disorders. Also, it is unclear whether phenotypically similar subgroups (e.g. patients with bipolar disorder and psychotic features) might share white matter pathologies or be rather similar. Using region-of-interest (ROI) analysis of white matter with diffusion tensor imaging (DTI) at 3 T, we analysed fractional anisotropy (FA), radial diffusivity (RD), and apparent diffusion coefficient (ADC) of the corpus callosum and cingulum bundle in 33 schizophrenia patients, 17 euthymic (previously psychotic) bipolar disorder patients, and 36 healthy controls. ANOVA analysis showed significant main effects of group for RD and ADC (both elevated in schizophrenia). Across the corpus callosum ROIs, there was not group effect on FA, but for RD (elevated in schizophrenia, lower in bipolar disorder) and ADC (higher in schizophrenia, intermediate in bipolar disorder). Our findings show similarities and difference (some gradual) across regions of the two major fibre tracts implicated in these disorders, which would be consistent with a neurobiological overlap of similar clinical phenotypes. PMID- 28644998 TI - Olfactory identification deficit predicts white matter tract impairment in Alzheimer's disease. AB - Olfactory identification deficit (OID) has been associated with both aging and Alzheimer's disease (AD). In the context of an amnestic disorders, OID predicts conversion to AD. Neuroanatomical correlates could increase specificity and sensitivity and elucidate the mechanistic differences between OID in AD and aging. Cross-sectional analysis of white matter microstructural changes was performed using diffusion tensor imaging (DTI) and tract-based-spatial-statistics in amnestic mild cognitive impairment (aMCI), AD and normal controls (NC) in 66 subjects (26 AD, 15 aMCI, 25 NC). DTI 3-Tesla MRI scans were analyzed and subject level means for fractional anisotropy (FA), mean diffusivity (MD), radial and axial diffusivity (lambda1D and lambda2,3D) were calculated. Linear regression models were applied using DTI markers as predictor and OID as outcome. OID was associated with increased lambda1D in aMCI and increased MD, lambda1D and lambda2,3D in AD. Voxel-wise analyses revealed widespread differences in all markers in AD. There were significant differences in lambda1D in aMCI, particularly in the olfactory tract. OID is correlated with microstructural white matter changes as early as in aMCI. This study may help elucidate the biological basis for olfactory impairment in Alzheimer's disease. Neuroanatomical correlates could help distinguish OID associated with AD and that associated with aging. PMID- 28645000 TI - Manipulating cues in mind wandering: Verbal cues affect the frequency and the temporal focus of mind wandering. AB - Our understanding of mind wandering (MW) has dramatically increased over the past decade. A key challenge still facing research is the identification of the processes and events that directly cause and control its occurrence. In the present study we sought to shed light on this question, by investigating the effects of verbal cues on the frequency and temporal focus of MW. To this aim, we experimentally manipulated the presence of irrelevant verbal cues during a vigilance task, in two independent groups (Verbal-cues group vs. No-cues group). We found that compared to the No-cues group, the Verbal-cues group reported a higher amount of MW, mostly triggered by the irrelevant cue-words, and a higher proportion of past-oriented MW compared to the other temporal orientations. These results demonstrate that task-irrelevant verbal stimulation increases the frequency of MW and steers its temporal orientation toward the past. Implications for the research on MW are discussed. PMID- 28645001 TI - A role for visceral feedback and interoception in feelings-of-knowing. AB - Guided by the framework that autonomic feedback shapes emotional experience and other feeling states, we asked whether feeling-of-knowing (FOK) judgments may be influenced by visceral information through interoception. Participants performed a FOK task for previously studied face-name pairs while changes in cardiovascular and facial muscle activity were recorded. Previously studied face cues for which the corresponding name could not be recalled elicited an increased cardiac rate relative to novel face cues. Critically, the relationship between this pattern of cardiovascular activity and FOK ratings was moderated by interoception, such that for individuals with high interoceptive sensitivity, relative increases in cardiac rate for old items were associated with larger corresponding differences in FOK. Consistent with a link between familiarity and positive affect, we also found that old items elicited less frowning, as reflected in muscle activity recorded from the corrugator muscle. These results provide psychophysiological evidence that visceral signals contribute to experiential metamemory processes. PMID- 28645002 TI - Synthesis of S-linked trisaccharide glycal of derhodinosylurdamycin A: Discovery of alkyl thiocyanate as an efficient electrophile for stereoselective sulfenylation of 2-deoxy glycosyl lithium. AB - Stereoselective synthesis of S-linked trisaccharide glycal of angucycline antitumor antibiotic derhodinosylurdamycin A is described. The synthesis has been accomplished employing our previously reported umpolung S-glycosylation strategy stereoselective sulfenylation of 2-deoxy glycosyl lithium. It was found that sugar-derived thiocyanate was a better electrophile than corresponding asymmetric disulfide in this type of stereoselective sulfenylation. PMID- 28645003 TI - Structure and gene cluster of the O-antigen of Enterobacter cloacae C4115. AB - An O-polysaccharide was isolated by mild acid degradation of the lipopolysaccharide of Enterobacter cloacae C4115 and studied by sugar analysis along with 1D and 2D 1H and 13C NMR spectroscopy. The following structure of the linear pentasaccharide repeating unit of the O-polysaccharide was established: >2)-alpha-l-Rhap-(1 -> 2)-alpha-l-Rhap-(1 -> 2)-alpha-l-Rhap-(1 -> 2)-alpha-d Galp-(1 -> 3)-alpha-d-FucpNAc-(1-> The O-antigen gene cluster of E. cloacae C4115 was sequenced. The gene functions were tentatively assigned by comparison with sequences in the available databases and found to be in consistence with the O polysaccharide structure. The O-antigen structure and gene cluster of E. cloacae C4115 are similar to those of E. cloacae G3421 studied by us earlier (Perepelov A.V. et al. Carbohydr. Res. 427 (2016) 55-59). PMID- 28645004 TI - Amplified detection of hepatitis B virus using an electrochemical DNA biosensor on a nanoporous gold platform. AB - In the present study, a nanoporous gold platform was applied for the amplified detection of Hepatitis B virus (HBV) by an electrochemical DNA biosensor. Ferrocene as a redox reporter was covalently attached to the DNA probe and its electrochemical signal was recorded as the biosensor response. For real samples, DNA was firstly extracted from blood of patients and then amplified by polymerase chain reaction (PCR) for 5cycles. Sensitivity of this biosensor was enhanced by using nanoporous gold electrode, therefore this sensor can discriminate the genome of HBV in real sample with low PCR cycles. By this strategy and signal amplification using nanoporous platform and covalently attached electroactive label, the biosensor can distinguish between healthy and HBV patients with limited PCR cycles. Moreover, the errors of PCR with large cycles can be disregarded. A linear dynamic range of 0.4 to 10nmol of mutant DNA was achieved, with reliable reproducibility (RSD) 8.9%. PMID- 28645006 TI - Study of intestinal anti-inflammatory activity of Phoenix loureiroi Kunth (Arecaceae) fruit. AB - Phoenix loureiroi Kunth belongs to the family Arecaceae, the fruits are widely consumed by Kurumba and Irula tribes of Tamil Nadu (India) and also used to cure intestinal related diseases in folklore medicine. Therefore, in vivo animal studies were evaluated to confirm the prevention of inflammatory bowel disease (IBD) with the treatment of this plant fruits. The IBD was studied in Wistar albino rats by indomethacin (s.c.), acetic acid (i.c.) and dextran sulfate sodium (DSS) induced models. The diseases parameters such as macroscopic, microscopic features, serum biomarkers levels, haematological profile, biochemical and antioxidant levels were determined. The fruit extract (50, 100 and 200mg/kg) treated enterocolitis rats significantly retain their body weight, organ weight, stool consistency, macroscopic score, histology, haematological parameters, antioxidative enzyme levels and also reduce the serum marker levels and myeloperoxidase (MPO) activity compared to prednisolone (2mg/kg) and sulfasalazine (50mg/kg) drugs. In conclusion, regular consumption of P. loureiroi fruit may prevent IBD and strongly support the folklore use of fruit in the treatment of intestinal ailments. PMID- 28645005 TI - Application of stem cell derived neuronal cells to evaluate neurotoxic chemotherapy. AB - The generation of induced pluripotent stem cells (iPSCs) and differentiation to cells composing major organs has opened up the possibility for a new model system to study adverse toxicities associated with chemotherapy. Therefore, we used human iPSC-derived neurons to study peripheral neuropathy, one of the most common adverse effects of chemotherapy and cause for dose reduction. To determine the utility of these neurons in investigating the effects of neurotoxic chemotherapy, we measured morphological differences in neurite outgrowth, cell viability as determined by ATP levels and apoptosis through measures of caspase 3/7 activation following treatment with clinically relevant concentrations of platinating agents (cisplatin, oxaliplatin and carboplatin), taxanes (paclitaxel, docetaxel and nab paclitaxel), a targeted proteasome inhibitor (bortezomib), an antiangiogenic compound (thalidomide), and 5-fluorouracil, a chemotherapeutic that does not cause neuropathy. We demonstrate differential sensitivity of neurons to mechanistically distinct classes of chemotherapeutics. We also show a dose dependent reduction of electrical activity as measured by mean firing rate of the neurons following treatment with paclitaxel. We compared neurite outgrowth and cell viability of iPSC-derived cortical (iCell(r) Neurons) and peripheral (Peri.4U) neurons to cisplatin, paclitaxel and vincristine. Goshajinkigan, a Japanese herbal neuroprotectant medicine, was protective against paclitaxel induced neurotoxicity but not oxaliplatin as measured by morphological phenotypes. Thus, we have demonstrated the utility of human iPSC-derived neurons as a useful model to distinguish drug class differences and for studies of a potential neuroprotectant for the prevention of chemotherapy-induced peripheral neuropathy. PMID- 28645007 TI - Activation of the PI3K-Akt pathway promotes neuroprotection of the delta-opioid receptor agonist against cerebral ischemia-reperfusion injury in rat models. AB - The central objective was to identify the role of the PI3K-Akt activation pathway on the neuroprotection of delta-opioid receptor agonist (DADLE) against cerebral ischemia-reperfusion (I/R) injury in a rat model. Fifty-five male Sprague-Dawley (SD) rats were included to establish a middle cerebral artery occlusion (MCAO) model which were then divided into the sham, MCAO, LY294002 (MCAO+DADLE+LY294002 [inhibitor of PI3K-Akt pathway]), DADLE (MCAO+DADLE) and DMSO (MCAO+DADLE+DMSO [dimethyl sulphoxide]) groups. The cerebral infarction (CI) volume and nerve cell apoptosis was determined using TTC and TUNEL staining. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry staining were applied for the expressions of Bad, Bax, Bcl-2 and cleaved caspase 3. The MCAO group showed higher CI volume, nerve cell apoptosis and cleaved caspase-3 expressions than the DADLE and DMSO groups, which were also higher in the LY294002 group than the DADLE group. Compared with the MCAO group, the mRNA and protein expressions of PI3K and Bcl-2, and the protein expressions of p-Akt and p-Bad were elevated, while the mRNA and protein expressions of Bax were decreased in the DADLE and DMSO groups. Decreased mRNA and protein expressions of PI3K and Bcl-2, reduced protein expressions of p-Akt and p-Bad and elevated mRNA and protein expressions of Bax exhibited in the LY294002 group than the DADLE group. These results indicate that activation of PI3K-Akt pathway promotes the neuroprotection of DADLE against cerebral I/R injury in a rat model by decreasing nerve cells apoptosis. PMID- 28645008 TI - Effect of microRNA-129-5p targeting HMGB1-RAGE signaling pathway on revascularization in a collagenase-induced intracerebral hemorrhage rat model. AB - BACKGROUND: This study aimed at exploring the effect of microRNA-129-5p (miR-129 5p) targeting high mobility group box-1 (HMGB1)-receptor for advanced glycation end-products (RAGE) signaling pathway on the revascularization in a collagenase induced intracerebral hemorrhage (ICH) rat model. METHODS: OX26-pGFAP-IL, an immunoliposome expressing miR-129-5p was constructed. The collagenase-induced ICH rat models were successfully established by 96 Sprague Dawley (SD) rats, which were categorized into the sham group, ICH group, miR-129-5p group, negative control (NC) group, ethyl pyruvate (EP, an inhibitor of HMGB1) group and N-benzyl 4-chloro-N-cyclohe-xylbenzamide (FPS-ZM1, a RAGE receptor antagonist) group. The miR-129-5p expression in the brain tissue homogenate was detected using the quantitative real-time polymerase chain reaction (qRT-PCR) and the protein expressions of HMGB1 and RAGE by Western blotting. Immunohistochemistry (IHC) was used for the detection of the vascular endothelial growth factor (VEGF). Microvessel density (MVD) was also detected. RESULTS: Compared to the sham group, the ICH, NC, EP and FPS-ZM1 groups had a decrease in miR-129-5p expressions, and an increase in the protein expressions of HMGB1, RAGE and VEGF and MVD. In comparison to the ICH, NC, EP and FPS-ZM1 groups the miR-129-5p group had an elevation in the miRNA-129-5p expressions. The miR-129-5p and EP groups had decreased HMGB1 protein expression and the miR-129-5p, EP and FPS-ZM1 groups had a reduced RAGE protein expression as compared to the ICH group. In comparison to the ICH group, the miR-129-5p, EP, FPS-ZM1 groups had a decline in the VEGF protein expression and MVD. CONCLUSION: Our study proved that up-regulation of miR-129-5p might suppress the HMGB1-RAGE signaling pathway to restrain the revascularization of rats with ICH. PMID- 28645009 TI - Case report of robotic dor fundoplication for scleroderma esophagus with aperistalsis on manometry. AB - Scleroderma is a systemic disease of collagen deposition resulting in fibrosis of small arteries and arterioles. It commonly affects the skin, lungs, and gastrointestinal tract. The most common site of GI tract involvement is the esophagus. We present the case report of a 44year old female with scleroderma esophagus and severe reflux which was successfully treated with robotic dor fundoplication. Because of the wide variety of symptoms with which this problem can present, a tailored approach taking into consideration the patient's symptomatology and findings during diagnostic work-up was implemented with good results. The patient exhibited complete resolution of symptoms at short term follow up. Robotic dor fundoplication is an effective option for patients with scleroderma esophagus and no evidence of hiatal hernia or esophageal shortening. PMID- 28645010 TI - A rare case of male pseudohermaphroditism-persistent mullerian duct syndrome with transverse testicular ectopia - Case report and review of literature. AB - INTRODUCTION: Persistent Mullerian duct syndrome (PMDS) is a rare type of male pseudohermaphroditism. Transverse testicular ectopia (TTE) is characterized by one testis moving to the opposite side and both testes traversing the same inguinal canal. CASE PRESENTATION: An 11-month-old boy presented with bilateral cryptorchidism. The left testis was not palpable; the right testis was canalicular with a right inguinal hernia. Ultrasound showed both testes located in the right inguinal canal. Right inguinal exploration revealed two testes with intact spermatic cords. A primitive uterus with fallopian tubes was also identified on opening the processus vaginalis. After herniotomy, bilateral orchidopexy was carried out (left orchidopexy through a trans-septal approach). Karyotyping confirmed a male gender (46XY). One year after the operation, ultrasound showed both testes to be in good condition. DISCUSSION: PMDS is caused by defects in the gene that encodes Antimullerian hormone(AMH). Treatment aims to correct cryptorchidism and ensure appropriate scrotal placement of the testes. Malignant transformation is as likely as the presence of abdominal testes in an otherwise normal man. Failing early surgical correction, gonadectomy must be offered to prevent malignancy. Division of the persistent mullerian duct structures is indicated only in patients where persistence interferes with orchidopexy. CONCLUSION: TTE should be suspected in patients presenting with inguinal hernia on one side and cryptorchidism on the other side. Herniotomy and bilateral orchidopexy is optimal. Removal of mullerian structures may injure the artery to vas deferens and is hence not recommended. Follow-up for fertility assessment in the latter years should be counselled. PMID- 28645011 TI - Transient portal venous gas associated with reversible non-occlusive mesenteric ischemia: A case report. AB - OBJECTIVES: To report the utility of abdominal ultrasonography (US) to identify the presence of portal venous gas (PVG) during non-occlusive mesenteric ischemia (NOMI), and to follow the disappearance of portal venous gas after resolution of the NOMI. DATA SOURCES: This was a clinical observation of a patient, with images of abdominal computed tomography (CT), and a video of portal venous gas identified by ultrasonography. DATA SYNTHESIS: We describe the case of an adult patient admitted to our ICU for NOMI developing 48h after cardiac surgery. Medical intensive care associated with jejunal resection and vacuum-assisted closure led to rapid recovery. Three weeks later, the patient presented acute pulmonary edema, and developed a new episode of NOMI that was suspected by identification of PVG on US, and then confirmed on abdominal CT. The patient rapidly improved after orotracheal intubation and treatment of pulmonary edema. A second US performed 9h later showed disappearance of PVG. The laparotomy performed 10h after the first US did not find evidence of small bowel or colon ischemia. The postoperative period was uneventful. CONCLUSIONS: US is a useful tool for the detection of PVG in critically ill patients, prompting suspicion of AMI. PVG can be observed at the early phase of AMI, even before irreversible transmural gut ischemia; transient PVG that disappears rapidly (within several hours) may suggest resolution of the NOMI. PMID- 28645012 TI - Associations between toxic and essential trace elements in maternal blood and fetal congenital heart defects. AB - Prenatal exposure to toxic trace elements, including heavy metals, is an important public health concern. Few studies have assessed if individual and multiple trace elements simultaneously affect cardiac development. The current study evaluated the association between maternal blood lead (Pb), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), and selenium (Se) levels and congenital heart defects (CHDs) in offspring. This hospital-based case-control study included 112 case and 107 control infants. Maternal peripheral blood draw was made during gestational weeks 17-40 and used to determine trace element levels by inductively coupled plasma mass spectrometry. Multivariable logistic regression was used to assess associations and interactions between individual and multiple trace elements and fetal CHDs, adjusted for maternal age, parity, education, newborn gender, migrant, folic acid or multivitamin intake, cigarette smoking, maternal prepregnancy body mass index, and time of sample collection. Control participants had medians of 2.61MUg/dL Pb, 1.76MUg/L Cd, 3.57MUg/L Cr, 896.56MUg/L Cu, 4.17MUg/L Hg, and 186.47MUg/L Se in blood. In a model including all measured trace elements and adjusted for confounders, high levels of maternal Pb (OR=12.09, 95% CI: 2.81, 51.97) and Se (OR=0.25, 95% CI: 0.08, 0.77) were harmful and protective predictors of CHDs, respectively, with positive and negative interactions suggested for Cd with Pb and Se with Pb, respectively. Similar associations were detected for subgroups of CHDs, including conotruncal defects, septal defects, and right ventricle outflow tract obstruction. Our results suggest that even under the current standard for protecting human health (10MUg/dL), Pb exposure poses an important health threat. These data can be used for developing interventions and identifying high-risk pregnancies. PMID- 28645014 TI - The association between serum ferritin levels and the risk of new-onset type 2 diabetes mellitus: A 10-year follow-up of the Chinese Multi-Provincial Cohort Study. AB - AIMS: To investigate the association of serum ferritin levels and ferritin level changes with the 10-year risk of new-onset type 2 diabetes mellitus (T2DM). METHODS: Among 2359 subjects without T2DM at baseline in 2002, 1956 subjects were re-examined in 2007, and 1660 subjects were invited to be re-examined in 2012. Serum ferritin (ng/ml) levels were measured by latex-enhanced turbidimetric immunoassay. Five-year serum ferritin changes were categorized into four groups using the median as the cut-off point. Multivariate logistic regression was performed to examine the independent association of serum ferritin levels and 5 year ferritin level changes with 10-year new-onset T2DM. RESULTS: At the 10-year follow-up, 205 (12.3%) subjects had developed new-onset T2DM. After adjusting for traditional risk factors and high-sensitivity C-reactive protein, 10-year new onset T2DM risk was significantly increased in subjects in the highest tertile of baseline serum ferritin levels [odds ratio (OR)=1.80, 95% confidence interval (CI): 1.17-2.79] and in subjects with high serum ferritin levels in both 2002 and 2007 (OR=1.54, 95% CI: 1.01-2.34). After adjusting for baseline fasting blood glucose, the effect was attenuated and became borderline or non-significant. CONCLUSIONS: Serum ferritin levels and ferritin level changes were associated with 10-year new-onset T2DM risk in the Chinese population, whereas the independent effect awaits validation from studies with larger sample sizes. PMID- 28645015 TI - Mid-infrared and near-infrared spectroscopy for rapid detection of Gardeniae Fructus by a liquid-liquid extraction process. AB - Gardeniae Fructus is widely used in the pharmaceutical industry, and many studies have confirmed its medical and economic value. In this study, samples collected from different liquid-liquid extraction batches of Gardeniae Fructus were detected by mid-infrared (MIR) and near-infrared (NIR) spectroscopy. Seven analytes, neochlorogenic acid (5-CQA), cryptochlorogenic acid (4-CQA), chlorogenic acid (3-CQA), geniposidic acid (GEA), deacetyl-asperulosidic acid methyl ester (DAAME), genipin-gentiobioside (GGB), and gardenoside (GA), were chosen as quality property indexes of Gardeniae Fructus. The two kinds of spectra were each used to build models by single partial least squares (PLS). Additionally, both spectral data were combined and modeled by multiblock PLS. For single spectroscopy modeling results, NIR had a better prediction for high concentration analytes (3-CQA, DAAME, GGB, and GA) whereas MIR performed better for low-concentration analytes (5-CQA, 4-CQA, and GEA). The multiblock methodology was found to be better compared to single spectroscopy models for all seven analytes. Specifically, the coefficients of determination (R2) of the NIR, MIR, and multiblock PLS calibration models of all seven components were higher than 0.95. Relative standard errors of prediction (RSEP) were all less than 7%, except for models of GGB, which were 10.36%, 13.24%, and 8.15% for the NIR-PLS, MIR-PLS, and multiblock models, respectively. These results indicate that MIR and NIR spectrographic techniques could provide a new choice for quality control in industrial production of Gardeniae Fructus. PMID- 28645013 TI - Per- and polyfluoroalkyl substances in human serum and urine samples from a residentially exposed community. AB - BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are considered chemicals of emerging concern, in part due to their environmental and biological persistence and the potential for widespread human exposure. In 2007, a PFAS manufacturer near Decatur, Alabama notified the United States Environmental Protection Agency (EPA) it had discharged PFAS into a wastewater treatment plant, resulting in environmental contamination and potential exposures to the local community. OBJECTIVES: To characterize PFAS exposure over time, the Agency for Toxic Substances and Disease Registry (ATSDR) collected blood and urine samples from local residents. METHODS: Eight PFAS were measured in serum in 2010 (n=153). Eleven PFAS were measured in serum, and five PFAS were measured in urine (n=45) from some of the same residents in 2016. Serum concentrations were compared to nationally representative data and change in serum concentration over time was evaluated. Biological half-lives were estimated for perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) using a one-compartment pharmacokinetic model. RESULTS: In 2010 and 2016, geometric mean PFOA and PFOS serum concentrations were elevated in participants compared to the general U.S. POPULATION: In 2016, the geometric mean PFHxS serum concentration was elevated compared to the general U.S. POPULATION: Geometric mean serum concentrations of PFOA, PFOS, and perfluorononanoic acid (PFNA) were significantly (p<=0.0001) lower (49%, 53%, and 58%, respectively) in 2016 compared to 2010. Half-lives for PFOA, PFOS, and PFHxS were estimated to be 3.9, 3.3, and 15.5years, respectively. Concentrations of PFOA in serum and urine were highly correlated (r=0.75) in males. CONCLUSIONS: Serum concentrations of some PFAS are decreasing in this residentially exposed community, but remain elevated compared to the U.S. general population. PMID- 28645016 TI - Quantitative analysis of a biopharmaceutical protein in cell culture samples using automated capillary electrophoresis (CE) western blot. AB - An effective control strategy is critical to ensure the safety, purity and potency of biopharmaceuticals. Appropriate analytical tools are needed to realize such goals by providing information on product quality at an early stage to help understanding and control of the manufacturing process. In this work, a fully automated, multi-capillary instrument is utilized for size-based separation and western blot analysis to provide an early readout on product quality in order to enable a more consistent manufacturing process. This approach aims at measuring two important qualities of a biopharmaceutical protein, titer and isoform distribution, in cell culture harvest samples. The acquired data for isoform distribution can then be used to predict the corresponding values of the final drug substance, and potentially provide information for remedy through timely adjustment of the downstream purification process, should the expected values fall out of the accepted range. PMID- 28645017 TI - Examining anxiety sensitivity as a mediator of the association between PTSD symptoms and suicide risk among women firefighters. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) symptoms are associated with increased suicide risk. Anxiety sensitivity (AS)-the fear of anxiety-related sensations-is both a vulnerability factor for and consequence of PTSD symptoms. AS also predicts suicide risk. To our knowledge, no study has examined whether AS concerns account for the association between PTSD symptoms and suicide risk. METHOD: A total of 254 women firefighters completed a web-based mental health survey. The Life Events Checklist for DSM-5 (LEC-5) was administered as a prelude to the PTSD Checklist for DSM-5 (PCL-5) to assess for exposure to a Criterion A event. The PCL-5, Anxiety Sensitivity Index-3 (ASI-3), and Suicidal Behaviors Questionnaire-Revised (SBQ-R) were utilized to assess PTSD symptoms, AS concerns, and suicide risk, respectively. Bootstrap mediation analyses were conducted, controlling for depression symptoms as measured by the Center for Epidemiologic Studies Depression Scale-Revised (CESD-R). RESULTS: Global and cognitive AS concerns, but neither physical nor social AS concerns, were statistically significant mediators of the relationship between PTSD symptoms (total score, re experiencing and numbing clusters) and suicide risk. Alternate mediation models testing PTSD symptoms as a mediator of the relationship between AS concerns and suicide risk were not statistically significant, supporting the specificity of our proposed model. CONCLUSIONS: Anxiety sensitivity concerns-specifically, cognitive AS concerns-account for the link between PTSD symptoms and suicide risk among women firefighters. Among firefighters with elevated PTSD symptoms, interventions that address cognitive AS concerns may thwart the trajectory to suicidal thoughts and behaviors. PMID- 28645018 TI - Take-over performance in evasive manoeuvres. AB - We investigated after effects of automation in take-over scenarios in a high-end moving-base driving simulator. Drivers performed evasive manoeuvres encountering a blocked lane in highway driving. We compared the performance of drivers 1) during manual driving, 2) after automated driving with eyes on the road while performing the cognitively demanding n-back task, and 3) after automated driving with eyes off the road performing the visually demanding SuRT task. Both minimum time to collision (TTC) and minimum clearance towards the obstacle disclosed a substantial number of near miss events and are regarded as valuable surrogate safety metrics in evasive manoeuvres. TTC proved highly sensitive to the applied definition of colliding paths, and we prefer robust solutions using lane position while disregarding heading. The extended time to collision (ETTC) which takes into account acceleration was close to the more robust conventional TTC. In line with other publications, the initial steering or braking intervention was delayed after using automation compared to manual driving. This resulted in lower TTC values and stronger steering and braking actions. Using automation, effects of cognitive distraction were similar to visual distraction for the intervention time with effects on the surrogate safety metric TTC being larger with visual distraction. However the precision of the evasive manoeuvres was hardly affected with a similar clearance towards the obstacle, similar overshoots and similar excursions to the hard shoulder. Further research is needed to validate and complement the current simulator based results with human behaviour in real world driving conditions. Experiments with real vehicles can disclose possible systematic differences in behaviour, and naturalistic data can serve to validate surrogate safety measures like TTC and obstacle clearance in evasive manoeuvres. PMID- 28645019 TI - Using network screening methods to determine locations with specific safety issues: A design consistency case study. AB - The Highway Safety Manual provides multiple methods that can be used to identify sites with promise (SWiPs) for safety improvement. However, most of these methods cannot be used to identify sites with specific problems. Furthermore, given that infrastructure funding is often specified for use related to specific problems/programs, a method for identifying SWiPs related to those programs would be very useful. This research establishes a method for Identifying SWiPs with specific issues. This is accomplished using two safety performance functions (SPFs). This method is applied to identifying SWiPs with geometric design consistency issues. Mixed effects negative binomial regression was used to develop two SPFs using 5 years of crash data and over 8754km of two-lane rural roadway. The first SPF contained typical roadway elements while the second contained additional geometric design consistency parameters. After empirical Bayes adjustments, sites with promise (SWiPs) were identified. The disparity between SWiPs identified by the two SPFs was evident; 40 unique sites were identified by each model out of the top 220 segments. By comparing sites across the two models, candidate road segments can be identified where a lack design consistency may be contributing to an increase in expected crashes. Practitioners can use this method to more effectively identify roadway segments suffering from reduced safety performance due to geometric design inconsistency, with detailed engineering studies of identified sites required to confirm the initial assessment. PMID- 28645020 TI - Do we see how they perceive risk? An integrated analysis of risk perception and its effect on workplace safety behavior. AB - While risk perception is a key factor influencing safety behavior, the academia lacks specific attention to the ways that workers perceive risk, and thus little is known about the mechanisms through which different risk perceptions influence safety behavior. Most previous research in the workplace safety domain argues that people tend to perceive risk based on rational formulations of risk criticality. However, individuals' emotions can be also useful in understanding their perceptions. Therefore, this research employs an integrated analysis concerning the rational and emotional perspectives. Specifically, it was expected that the identified three rational ways of perceiving risk, i.e., perceived probability, severity, and negative utility, would influence the direct emotional risk perception. Furthermore, these four risk perceptions were all expected to positively but differently influence safety behavior. The hypotheses were tested using a sample of 120 construction workers. It was found that all the three rational risk perceptions significantly influenced workers' direct perception of risk that is mainly based on emotions. Furthermore, safety behavior among workers relied mainly on emotional perception but not rational calculations of risk. This research contributes to workplace safety research by highlighting the importance of integrating the emotional assessment of risk, especially when workers' risk perception and behavior are concerned. Suggested avenues for improving safety behavior through improvement in risk perception include being aware of the possibility of different ways of perceiving risk, promoting experience sharing and accident simulation, and uncovering risk information. PMID- 28645021 TI - Development a validated highly sensitive LC-MS/MS method for simultaneous quantification of Ledipasvir, sofosbuvir and its major metabolite GS-331007 in human plasma: Application to a human pharmacokinetic study. AB - A highly sensitive and rapid LC-MS/MS method was developed, fully optimized and validated for the simultaneous determination of Ledipasvir (LED) and Sofosbuvir (SOF) in the presence of its major metabolite GS-331007 in human plasma using Daclatasvir as internal standard (IS). The extraction of analytes and IS from plasma was performed using liquid-liquid extraction with ethyl acetate. The chromatographic separation of these prepared samples was achieved on Xterra MS C8 column (4.6*50mm,5MUm) using gradient elution with a mobile phase of ammonium formate buffer (pH 3.5; 10mM), acetonitrile and methanol pumped at a flow rate 0.7mLmin-1.The detection was performed on API4000 triple quadrupole tandem mass spectrometer using multiple reaction monitoring (MRM) positive electrospray ionization interface. The method was validated according to FDA guidelines for bio-analytical methods with respect to linearity, accuracy, precision, selectivity, carry-over, stability and dilution integrity. Linearity was obtained over a concentration range of 0.1-1000, 0.3-3000 and 3.0-3000ngmL-1 for LED, SOF and GS-331007; respectively by applying weighted least-squares linear regression method (1/x2). The wider range of quantification in a shorter period of separation time less than 5.0min allowed monitoring the serum concentration of analytes up to 144h. The proposed method can be successfully applied for pharmacokinetic and bioequivalence studies in healthy human volunteers. PMID- 28645022 TI - Benzene and childhood acute leukemia in Oklahoma. AB - BACKGROUND: Although childhood cancer is a leading cause of childhood mortality in the US, evidence regarding the etiology is lacking. The goal of this study was to evaluate the association between benzene, a known carcinogen, and childhood acute leukemia. METHODS: We conducted a case-control study including cases diagnosed with acute leukemia between 1997 and 2012 (n = 307) from the Oklahoma Central Cancer Registry and controls matched on week of birth from birth certificates (n = 1013). We used conditional logistic regression to evaluate the association between benzene, measured with the 2005 National-Scale Air Toxics Assessment (NATA) at census tract of the birth residence, and childhood acute leukemia. RESULTS: We observed no differences in benzene exposure overall between cases and controls. However, when stratified by year of birth, cases born from 2005 to 2010 had a three-fold increased unadjusted odds of elevated exposure compared to controls born in this same time period (4th Quartile OR: 3.53, 95% CI: 1.35, 9.27). Furthermore, the estimates for children with acute myeloid leukemia (AML) were stronger than those with acute lymphoid leukemia, though not statistically significant. CONCLUSIONS: While we did not observe an association between benzene and childhood leukemia overall, our results suggest that acute leukemia is associated with increased benzene exposure among more recent births, and children with AML may have increased benzene exposure at birth. Using the NATA estimates allowed us to assess a specific pollutant at the census tract level, providing an advantage over monitor or point source data. Our study, however, cannot rule out the possibility that benzene may be a marker of other traffic-related exposures and temporal misclassification may explain the lack of an association among earlier births. PMID- 28645023 TI - Maternal serum PFOA concentration and DNA methylation in cord blood: A pilot study. AB - Perfluorooctanoic acid (PFOA), a perfluoroalkyl substance, is commonly detected in the serum of pregnant women and may impact fetal development via epigenetic re programming. In a pilot study, we explored associations between serum PFOA concentrations during pregnancy and offspring peripheral leukocyte DNA methylation at delivery in women with high (n = 22, range: 12-26ng/mL) and low (n = 22, range: 1.1-3.1ng/mL) PFOA concentrations. After adjusting for cell type, child sex, and income, we did not find differences in CpG methylation in the two exposure groups that reached epigenome-wide significance. Among the 20 CpGs with the lowest p-values we found that seven CpG sites in three genes differed by exposure status. In a confirmatory cluster analysis, these 20 CpGs clustered into two groups that perfectly identified exposure status. Future studies with larger sample sizes should confirm these findings and determine if PFOA-associated changes in DNA methylation underlie potential health effects of PFOA. PMID- 28645024 TI - Prevalence of depression: Comparisons of different depression definitions in population-based samples of older adults. AB - BACKGROUND: Depression prevalence in older adults varies largely across studies, which probably reflects methodological rather than true differences. This study aims to explore whether and to what extent the prevalence of depression varies when using different diagnostic criteria and rating scales, and various samples of older adults. METHODS: A population-based sample of 3353 individuals aged 60 104 years from the Swedish National Study on Aging and Care in Kungsholmen (SNAC K) were examined in 2001-2004. Point prevalence of depression was estimated by: 1) diagnostic criteria, ICD-10 and DSM-IV-TR/DSM-5; 2) rating scales, MADRS and GDS-15; and 3) self-report. Depression prevalence in sub-samples by dementia status, living place, and socio-demographics were compared. RESULTS: The prevalence of any depression (including all severity grades) was 4.2% (moderate/severe: 1.6%) for ICD-10 and 9.3% (major: 2.1%) for DSM-IV-TR; 10.6% for MADRS and 9.2% for GDS-15; and 9.1% for self-report. Depression prevalence was lower in the dementia-free sample as compared to the total population. Furthermore, having poor physical function, or not having a partner were independently associated with higher depression prevalence, across most of the depression definitions. LIMITATIONS: The response rate was 73.3% and this may have resulted in an underestimation of depression. CONCLUSION: Depression prevalence was similar across all depression definitions except for ICD-10, showing much lower figures. However, independent of the definition used, depression prevalence varies greatly by dementia status, physical functioning, and marital status. These findings may be useful for clinicians when assessing depression in older adults and for researchers when exploring and comparing depression prevalence across studies. PMID- 28645025 TI - Decreased functional connectivity and disrupted neural network in the prefrontal cortex of affective disorders: A resting-state fNIRS study. AB - BACKGROUND: Affective disorders (AD) have been conceptualized as neural network level diseases. In this study, we utilized functional near infrared spectroscopy (fNIRS) to investigate the spontaneous hemodynamic activities in the prefrontal cortex (PFC) of the AD patients with or without medications. METHODS: 42 optical channels were applied to cover the superior frontal gyrus (SFG), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG), which constitute one of the most important affective networks of the brain. We performed resting-state measurements on 28 patients who were diagnosed as having AD and 30 healthy controls (HC). Raw fNIRS data were preprocessed with independent component analysis (ICA) and a band-pass filter to remove artifacts and physiological noise. RESULTS: By systematically analyzing the intra-regional, intrahemispheric, and interhemispheric connectivities based on the spontaneous oscillations of Delta[HbO], our results indicated that patients with AD exhibited significantly reduced intra-regional and symmetrically interhemispheric connectivities in the PFC when compared to HC. More specifically, relative to HC, AD patients showed significantly lower locally functional connectivity in the right IFG, and poor long-distance connectivity between bilateral IFG. In addition, AD patients without medication presented more disrupted cortical organizations in the PFC, and the severity of self-reported symptoms of depression was negatively correlated with the strength of intra-regional and symmetrically interhemispheric connectivity in the PFC. LIMITATIONS: Regarding the measuring technique, fNIRS has restricted measurement depth and spatial resolution. During the study, the subgroups of AD, such as major depressive disorder, bipolar, comorbidity, or non comorbidity, dosage of psychotropic drugs, as well as different types of pharmacological responses were not distinguished and systematically compared. Furthermore, due to the limitation of the research design, it was still not very clear how pharmacological treatment affected the resting state cortical organization of the prefrontal lobe, and the degree of the effect in patients with AD. CONCLUSION: These results strongly supported that RSFC measured by fNIRS could be a useful and powerful way of delineating the neuropathology of AD. PMID- 28645026 TI - Measuring physical activity with accelerometers for individuals with intellectual disability: A systematic review. AB - BACKGROUND: Multiple studies have reported differing physical activity levels for individuals with intellectual disabilities when using accelerometers. One of the potential reasons for these differences may be due to how researchers measure physical activity. Currently there is a lack of understanding on measurement protocol of accelerometers. AIMS: The purpose of this study was to synthesize the current practice of using accelerometers to measure physical activity levels among individuals with intellectual disabilities. METHODS: A systematic search was conducted using multiple databases including Medline (1998-2015), Sport Discus (1992-2015), Web of Science (1965-2015), and Academic Research Premier (2004-2015). Seventeen articles were found that met the inclusion criteria. RESULTS: There is a lack of consistent research protocols for measuring physical activity levels with accelerometers. Issues with the amount of time participants wore the accelerometer was a challenge for multiple studies. Studies that employed external strategies to maximize wear time had higher compliance rates. CONCLUSION: There is a need to establish and standardize specific accelerometer protocols for measuring physical activity levels of individuals with intellectual disabilities for higher quality and more comparable data. PMID- 28645027 TI - Validity of the growth model of the 'computerized visual perception assessment tool for Chinese characters structures'. AB - Morphological awareness is the foundation for the important developmental skills involved with vocabulary, as well as understanding the meaning of words, orthographic knowledge, reading, and writing. Visual perception of space and radicals in two-dimensional positions of Chinese characters' morphology is very important in identifying Chinese characters. The important predictive variables of special and visual perception in Chinese characters identification were investigated in the growth model in this research. The assessment tool is the "Computerized Visual Perception Assessment Tool for Chinese Characters Structures" developed by this study. There are two constructs, basic stroke and character structure. In the basic stroke, there are three subtests of one, two, and more than three strokes. In the character structure, there are three subtests of single-component character, horizontal-compound character, and vertical compound character. This study used purposive sampling. In the first year, 551 children 4-6 years old participated in the study and were monitored for one year. In the second year, 388 children remained in the study and the successful follow up rate was 70.4%. This study used a two-wave cross-lagged panel design to validate the growth model of the basic stroke and the character structure. There was significant correlation of the basic stroke and the character structure at different time points. The abilities in the basic stroke and in the character structure steadily developed over time for preschool children. Children's knowledge of the basic stroke effectively predicted their knowledge of the basic stroke and the character structure. PMID- 28645029 TI - Phytoavailability of Cr in Silene vulgaris: The role of soil, plant genotype and bacterial rhizobiome. AB - Understanding the metal behavior at the soil-root interface is of utmost significance for a successful implementation of phytoremediation. In this study, we investigated the differences in chromium (Cr) uptake, chemical changes in soil solution and the shifts in rhizosphere bacterial communities of two genotypes of Silene vulgaris (SV21, SV38) with different tolerance to Cr. A greenhouse experiment was performed in two soils that differed on pH and organic matter (OM) content. An industrial sludge with high content in Cr was used as pollution source. The soil solution in the rhizosphere was sample by Rhizon Soil Moisture Samplers. The total concentration of Cr reached the highest values in soil solution samplers from calcareous soils with poor contents in OM. Plants grown in this soil also increased the Cr uptake in roots of both genotypes, but the concentration was higher in genotype SV-38 than in SV21. The clustering analysis of denaturing gradient gel electrophoresis (DGGE) of 16S rRNA fragments revealed major differences in bacterial community structure related to Cr pollution, followed by soil type and finally, plant genotype. Diversity indices based on DGGE profiles were the highest in alkaline soil, and between genotypes, values were significantly greater in SV38. Canonical correspondence analysis (CCA) showed that changes in bacterial community structure of rhizosphere were highly correlated with total Cr concentration and soil solution pH. The isolation and identification of S. vulgaris bacterial rhizosphere revealed a different composition according to soil type and plant genotype. Results suggested the potential role of Pseudomonas fluorescens on Cr mobilization and therefore, on enhanced metal bioavailability and may provide a starting point for further studies aimed at the combined use of tolerant plants and selected metal mobilizing rhizobacteria, in the microbial-assisted phytoremediation of Cr polluted soils. PMID- 28645030 TI - Uptake and tissue distributions of cadmium, selenium and zinc in striped marsh frog tadpoles exposed during early post-embryonic development. AB - Metals and metalloids released through anthropogenic activities can accumulate in aquatic organisms, resulting in adverse effects in sensitive species. We investigated the influence of feeding regime and exposure complexity (i.e., mixture) on bioaccumulation kinetics and body distribution of common metal(loid) pollutants in Limnodynastes peronii during early post-embryonic development. Tadpoles were exposed to radiolabelled 109Cd, 75Se and 65Zn alone and in a mixture for 4 days, followed by 3 days depuration in clean water. One group was fed directly in exposure aquaria, whereas a second group was transferred to clean water for feeding, to investigate the potential influence of sorption to food on uptake. Bioconcentration factor and retention was observed to be greatest for Se. Results demonstrate that tadpoles accumulated and retained half the amount of Cd when exposed in mixture, suggesting that Se and/or Zn may have antagonistic effects against Cd uptake. Additionally, tadpoles fed directly in exposure water accumulated 2-3-times more Cd and Zn compared to tadpoles fed in clean water, indicating that the presence of food particles is an important factor that may influence uptake. Interestingly, this had a negligible impact on Se uptake. The study reveals how exposure conditions can influence the bioaccumulation of metal(loid)s, highlighting experimental factors as important considerations for both controlled toxicity experiments and for understanding exposure risks for amphibian populations. PMID- 28645031 TI - Understanding the variation of microbial community in heavy metals contaminated soil using high throughput sequencing. AB - To improve the understanding of bacterial community in heavy metals contaminated soils, we studied the effects of environmental factors on the bacterial community structure in contaminated fields located in Shaanxi Province of China. Our results showed that microbial community structure varied among sites, and it was significantly affected by soil environmental factors such as pH, soil organic matter (SOM), Cd, Pb and Zn. In addition, Spearman's rank-order correlation indicated heavy metal sensitive (Ralstonia, Gemmatimona, Rhodanobacter and Mizugakiibacter) and tolerant (unidentified-Nitrospiraceae, Blastocatella and unidentified-Acidobacteria) microbial groups. Our findings are crucial to understanding microbial diversity in heavy metal polluted soils of China and can be used to evaluate microbial communities for scientific applications such as bioremediation projects. PMID- 28645028 TI - Lipid homeostasis and regulated cell death. AB - Modern lipidomics analysis paints a dynamic picture of membrane organizations, as changing and adapting lipid assemblies that play an active role in cellular function. This article highlights how the lipid composition of membranes determines specific organelle functions, how homeostatic mechanisms maintain these functions by regulating physical properties of membranes, and how cells disrupt lipid homeostasis to bring about regulated cell death (RCD). These are broad phenomena, and representative examples are reviewed here. In particular, the mechanisms of ferroptosis - a form of RCD brought about by lipid peroxidation - are highlighted, demonstrating how lipid metabolism drives cells' lipid composition toward states of increased sensitivity to lipid oxidation. An understanding of these interactions has begun to give rise to lipid-based therapies. This article reviews current successes of such therapies, and suggests directions for future developments. PMID- 28645032 TI - Physiological traits and antioxidant metabolism of leaves of tropical woody species challenged with cement dust. AB - Tropical woody species occurring in limestone outcrops are frequently exposed to particulate material from cement factories. The effects of 60-day cement dust exposure on physiological traits and enzymatic antioxidant system of young plant leaves of Guazuma ulmifolia Lam., Myracrodruon urundeuva Allemao and Trichilia hirta L. were investigated. Cement dust (2.5 or 5mgcm-2) was applied to the leaf surface or soil or both (leaf plus soil) and plants were maintained at greenhouse. Cement dust barely affected the mineral nutrient levels, except for iron whose content was decreased in leaves/leaflets of all species studied. The incident light was partly blocked in cement dust-treated leaves, regardless of the plant species, causing a decrease in the photosynthetic pigments in M. urundeuva. The chlorophyll b content, however, increased in G. ulmifolia and T. hirta leaves upon cement dust treatment. The potential quantum yield of photosystem II in challenged leaves of G. ulmifolia was 3.8% lower than that of control plants, while such trait remained unaffected in the leaves of the other species. No changes in leaf stomatal conductance and antioxidant enzymes activities were observed, except for M. urundeuva, which experienced a 31% increment in the superoxide dismutase activity upon 5mgcm-2 cement dust (leaf plus soil treatment), when compared with control plants. Overall, the mild changes caused by cement dust in the in physiological and biochemical traits of the species studied indicate that such species might be eligible for further studies of revegetation in fields impacted by cement factories. PMID- 28645033 TI - Acetic acid-assisted fabrication of hierarchical flower-like Bi2O3 for photocatalytic degradation of sulfamethoxazole and rhodamine B under solar irradiation. AB - With the assistance of acetic acid (CH3COOH), a novel 3D flower-like Bi2O3 was synthesized via hydrothermal process followed by calcination. For the first time, the role of CH3COOH as a capping agent in the formation of flower-like structure was investigated. The as-prepared flower-like Bi2O3 had a high activity on the degradation of sulfamethoxazole (SMX) under simulated solar light irradiation due to the narrow band gap of 2.69eV, high percentage of beta-Bi2O3 as well as high intensity of polar facets (120) and (200). Meanwhile, the photocatalytic degradation followed apparent pseudo-first-order kinetics. The rate constant (k) increased from 0.7*10-2 to 3.0*10-2min-1 with the catalyst loading varying from 0.5 to 2.0gL-1. Increasing pH values from 3 to 11 led to the decrease of k from 2.2*10-2 to 0.2*10-2min-1, which could be attributed to the electrostatic adsorption between SMX molecules and Bi2O3. The radical quenching experiments showed both direct (h+) and indirect oxidation (OH and O2-) happened in this process. PMID- 28645034 TI - Formation of hematite nanoparticle monolayers of controlled coverage and structure at polymeric microparticles. AB - The deposition of hematite nanoparticles (22nm and 29nm in diameter) on negatively charged polystyrene microspheres (820nm in diameter) was studied by micro-electrophoretic measurements and AFM. The influence of ionic strength, varied between 10-4 and 10-2M, was determined. Initially, the electrophoretic mobility change of microspheres upon the addition of controlled amount of hematite nanoparticles were measured. These dependencies were quantitatively interpreted in terms of the general electrokinetic model. This allowed to determine the coverage of nanoparticles on microspheres under in situ conditions, which increased with ionic strength attaining 0.35 for the ionic strength of 10 2M and 29 in diameter hematite particles. This effect, attributed to the decreasing range of lateral electrostatic repulsion among deposited particles, was accounted for by the random sequential adsorption model. However, the coverages attained for lower ionic strength exceeded the theoretical predictions. This effect was interpreted in terms of an additional electrostatic screening due to polymeric chains present at the microparticle surface. The acid base properties of the hematite monolayers were also acquired by applying thorough micro-electrophoretic measurements. The obtained results confirmed a feasibility of preparing hematite nanoparticle monolayers on polymeric carrier microspheres having well-defined coverage and structure. PMID- 28645035 TI - CTAB induced hierarchical bismuth microspheres for visible-light photocatalytic study. AB - Nanosheet constructed bismuth microspheres were prepared through an aqueous reduction approach in the presence of CTAB molecules, with initial formed BiOCl as the precursor and hydrazine hydrate as the reductant. The flower-like morphology and platelet units of BiOCl precursor determined the evolution of hierarchical Bi microspheres through a morphology-heredity process. Trisodium citrate was introduced to keep the Bi microspheres from oxidation, the high purity in composition are beneficial to eliminate the influence of bismuth oxides. Photocatalytic properties of the hierarchical Bi microspheres were investigated under visible-light irradiation by taking the degradation of rhodamine B (RhB) dye and colorless bisphenol A (BPA) as probe reactions. 99.7% of RhB and 47.4% of BPA degradation in 3h indicate good photocatalytic property of the hierarchical Bi microspheres. Results of storing detection and recycled experiments revealed good structure stability and photocatalytic stability of the Bi microspheres, these properties are vital for practical applications of the materials. The formation mechanism of Bi microspheres and relative degradation mechanism are also proposed on the basis of experimental data. PMID- 28645036 TI - Influence of surface states on blinking characteristics of single colloidal CdSe CdS/ZnS core-multishell quantum dot. AB - We carefully characterized the fluorescence blinking of single colloidal CdSe CdS/ZnS core-multishell quantum dots (QDs) with different surface modifications, including octadecylamine (ODA) coated QDs dispersed in chloroform, aqueous 3 mercaptopropionic acids (3MPA) coated QDs in HEPES solution treated by Ca2+ ions and ethylene glycol tetraacetic acid (EGTA, Ca2+ chelator), and aqueous 3MPA-QDs treated by glycerol. It was found that the on- and off-state probability density distributions displayed different rules. The off-state probability density distributions of all QDs complied well with the inverse power law, while the on state probability density distributions bended upwards in log-log scale, and the degree of the upwards-bending correlated strongly with QD surface modification and fluorescence brightness of the single QD. Further autocorrelation analysis revealed that the fluorescence time series of a single QD was more random when the single QD showed a stronger fluorescence. Realistic numerical simulations with input parameters from quantum mechanical calculations showed that the QD exciton was first generated by an excitation photon; It radiatively recombined to give QD's fluorescence response, i.e., the on-state, which displayed the upwards bended on-state probability density distribution profile; The electron and/or the hole of the photoexcited exciton in the QD core, after tunneling to the QD surface, randomly walked through the two-dimensional network of the QD surface states, resulting in the off-state probability density distribution profile of the inverse power law. Surface modification modified the QD surface-state network, in turn modifying the on/off probability density distribution profiles. Our findings provide us with a novel highway of applying colloidal QDs to study microscopic physical, and chemical, processes in many fields including in vivo and in vitro imaging, sensing and labelling. PMID- 28645037 TI - Slip-additive migration, surface morphology, and performance on injection moulded high-density polyethylene closures. AB - HYPOTHESIS: The amount and distribution of slip agents, erucamide, and behenamide, on the surface of high-density polyethene, is determined by integral characteristics of slip agent structure and polymer morphology. A suite of surface analysis techniques was applied to correlate physicochemical properties with slip-additive migration behaviour and their surface morphology. The migration, surface morphology and physicochemical properties of the slip additives, crystallinity and orientation of polyethene spherulites and interaction between slip additives and high-density polyethene influence the surface characteristics. EXPERIMENTAL: The high-density polyethene closures were produced with erucamide and behenamide separately and stored until they produced required torque. Surface composition was determined employing spectroscopy and gas chromatography. The distribution of additives was observed under optical, scanning electron and atomic force microscopes. The surface energy, crystallinity and application torque were measured using contact angle, differential scanning calorimeter and a torque force tester respectively. RESULTS AND DISCUSSION: Each slip additive produced a characteristic amide peak at 1645cm-1 in infrared spectroscopy and peaks of oxygen and nitrogen in X-ray photoelectron spectroscopy, suggesting their presence on the surface. The erucamide produced placoid scale-like structures and behenamide formed denticulate structures. The surface erucamide and behenamide responsible for reducing the torque was found to be 15.7ug/cm2 and 1.7ug/cm2. PMID- 28645038 TI - When attention wanders: Pupillometric signatures of fluctuations in external attention. AB - Attention is not always directed to events in the external environment. On occasion our thoughts wander to people and places distant from the here and now. Sometimes, this lack of external attention can compromise ongoing task performance. In the current study we set out to understand the extent to which states of internal and external attention can be determined using pupillometry as an index of ongoing cognition. In two experiments we found that periods of slow responding were associated with elevations in the baseline pupil signal over three and a half seconds prior to a behavioural response. In the second experiment we found that unlike behavioural lapses, states of off-task thought, particularly those associated with a focus on the past and with an intrusive quality, were associated with reductions in the size of the pupil over the same window prior to the probe. These data show that both states of large and small baseline pupil size are linked to states when attention is not effectively focused on the external environment, although these states have different qualities. More generally, these findings illustrate that subjective and objective markers of task performance may not be equivalent and underscore the importance of developing objective indicators that can allow these different states to be understood. PMID- 28645039 TI - Fundamental causes of accelerated declines in colorectal cancer mortality: Modeling multiple ways that disadvantage influences mortality risk. AB - BACKGROUND: Improvements in colorectal cancer (CRC) mortality reflect the distribution of effective preventions. Social inequalities often generate unequal diffusion of medical interventions, resulting in disparate outcomes while preventions are being disseminated throughout the population. This study used a novel method to examine whether Race (Black versus White) and SES influenced when rates of CRC mortality started to decline, and how rapidly they did so. METHOD: Mortality counts from 1968-2010 were derived from death certificates of U.S. residents aged 25 + years. Individuals' race, age, county of residence, and sex were collected from death certificates. County-level SES was measured using the decennial U.S. census. Layered joinpoint regression was used to model CRC mortality trends over time. Acceleration in rates of historical decline were used to indicate preventability within counties. RESULTS: Black race was associated with a 4.1-year delay in colonoscopy-attributable declines in CRC mortality and each standard deviation unit change in SES with a 5.7-year delay in such mortality. Following the onset of a decline, colonoscopy-attributable mortality change was slower by 0.5% among Blacks, and 2.0%/standard deviation in SES. Modifying the rapidity of colonoscopy uptake could have averted 12-14,000 and 83 86,000 deaths among Blacks and residents of lower SES counties, respectively. CONCLUSIONS: Successful interventions do not uniformly benefit the U.S. POPULATION: This study highlighted the notable impact that substantial delays in the provision of interventions, and in the relative rapidity of dissemination, and estimated the extent to which there was a preventable loss of life concentrated amongst the most disadvantaged. A more egalitarian delivery of life saving interventions could drastically reduce mortality by improving effectiveness of interventions while also addressing inequalities in health. PMID- 28645040 TI - Longitudinal effects of religious involvement on religious coping and health behaviors in a national sample of African Americans. AB - Many studies have examined associations between religious involvement and health, linking various dimensions of religion with a range of physical health outcomes and often hypothesizing influences on health behaviors. However, far fewer studies have examined explanatory mechanisms of the religion-health connection, and most have overwhelmingly relied on cross-sectional analyses. Given the relatively high levels of religious involvement among African Americans and the important role that religious coping styles may play in health, the present study tested a longitudinal model of religious coping as a potential mediator of a multidimensional religious involvement construct (beliefs; behaviors) on multiple health behaviors (e.g., diet, physical activity, alcohol use, cancer screening). A national probability sample of African Americans was enrolled in the RHIAA (Religion and Health In African Americans) study and three waves of telephone interviews were conducted over a 5-year period (N = 565). Measurement models were fit followed by longitudinal structural models. Positive religious coping decreased modestly over time in the sample, but these reductions were attenuated for participants with stronger religious beliefs and behaviors. Decreases in negative religious coping were negligible and were not associated with either religious beliefs or religious behaviors. Religious coping was not associated with change in any of the health behaviors over time, precluding the possibility of a longitudinal mediational effect. Thus, mediation observed in previous cross sectional analyses was not confirmed in this more rigorous longitudinal model over a 5-year period. However, findings do point to the role that religious beliefs have in protecting against declines in positive religious coping over time, which may have implications for pastoral counseling and other faith-based interventions. PMID- 28645042 TI - The changing health priorities of earthquake response and implications for preparedness: a scoping review. AB - OBJECTIVES: Earthquakes have substantial impacts on mortality in low- and middle income countries (LMIC). The academic evidence base to support Disaster Risk Reduction activities in LMIC settings is, however, limited. We sought to address this gap by identifying the health and healthcare impacts of earthquakes in LMICs and to identify the implications of these findings for future earthquake preparedness. STUDY DESIGN: Scoping review. METHODS: A scoping review was undertaken with systematic searches of indexed databases to identify relevant literature. Key study details, findings, recommendations or lessons learnt were extracted and analysed across individual earthquake events. Findings were categorised by time frame relative to earthquakes and linked to the disaster preparedness cycle, enabling a profile of health and healthcare impacts and implications for future preparedness to be established. RESULTS: Health services need to prepare for changing health priorities with a shift from initial treatment of earthquake-related injuries to more general health needs occurring within the first few weeks. Preparedness is required to address mental health and rehabilitation needs in the medium to longer term. Inequalities of the impact of earthquakes on health were noted in particular for women, children, the elderly, disabled and rural communities. The need to maintain access to essential services such as reproductive health and preventative health services were identified. Key preparedness actions include identification of appropriate leaders, planning and training of staff. Testing of plans was advocated within the literature with evidence that this is possible in LMIC settings. CONCLUSIONS: Whilst there are a range of health and healthcare impacts of earthquakes, common themes emerged in different settings and from different earthquake events. Preparedness of healthcare systems is essential and possible, in order to mitigate the adverse health impacts of earthquakes in LMIC settings. Preparedness is needed at the community, organisational and system levels. PMID- 28645041 TI - Behavioral and neural concordance in parent-child dyadic sleep patterns. AB - Sleep habits developed in adolescence shape long-term trajectories of psychological, educational, and physiological well-being. Adolescents' sleep behaviors are shaped by their parents' sleep at both the behavioral and biological levels. In the current study, we sought to examine how neural concordance in resting-state functional connectivity between parent-child dyads is associated with dyadic concordance in sleep duration and adolescents' sleep quality. To this end, we scanned both parents and their child (N=28 parent-child dyads; parent Mage=42.8years; adolescent Mage=14.9years; 14.3% father; 46.4% female adolescent) as they each underwent a resting-state scan. Using daily diaries, we also assessed dyadic concordance in sleep duration across two weeks. Our results show that greater daily concordance in sleep behavior is associated with greater neural concordance in default-mode network connectivity between parents and children. Moreover, greater neural and behavioral concordances in sleep is associated with more optimal sleep quality in adolescents. The current findings expand our understanding of dyadic concordance by providing a neurobiological mechanism by which parents and children share daily sleep behaviors. PMID- 28645043 TI - In vitro and in vivo behavior of DNA tetrahedrons as tumor-targeting nanocarriers for doxorubicin delivery. AB - Deoxyribonucleic acid (DNA) is a versatile material with high applicability and inherent biocompatibility. L-DNA, the perfect mirror form of the naturally occurring D-DNA, has been used in DNA nanotechnology. It has thermodynamically identical properties to D-DNA, is capable of self-assembly and bio-orthogonal base-pairing, and is resistant to nuclease activity. We previously constructed an L-DNA tetrahedron (L-Td) and found that this nanostructure has remarkably higher capacity for cell penetration than its natural counterpart (D-Td). L-Td molecules of two different sizes-one with 17-mer per side (L-Td17) and the other with 30 mer per side (L-Td30)-were prepared by assembling four L-DNA strands. In this study, cellular uptake of L-Td with different sizes was observed over time using a laser scanning confocal microscope (LSCM) equipped with a live cell chamber system. In addition, we conducted a pharmacokinetic study to examine the potential of L-Td as a carrier for in vivo tumor-targeted delivery of a low dose of doxorubicin (DOX). L-Td entered into the cells through endocytosis, and a specific DNA sequence of the L-Td ensures targeted entry into cancer cells. Compared with free DOX, DOX-loaded L-Td (DOX@L-Td) showed decreased clearance and increased initial concentration (C0), half-life, and area under the curve (AUC), indicating that DOX@L-Td circulated in the blood stream for longer than free DOX. L-Td17, in particular, had beneficial effects owing to its ability to enhance tumor accumulation of DOX and reduce the cardiotoxicity caused by it through administration of a low dose of the drug. PMID- 28645044 TI - Mussel-inspired nano-multilayered coating on magnesium alloys for enhanced corrosion resistance and antibacterial property. AB - Magnesium alloys are promising candidates for load-bearing orthopedic implants due to their biodegradability and mechanical resemblance to natural bone tissue. However, the high degradation rate and the risk of implant-associated infections pose grand challenges for their clinical applications. Herein, we developed a nano-multilayered coating strategy through polydopamine and chitosan assisted layer-by-layer assembly of osteoinductive carbonated apatite and antibacterial sliver nanoparticles on the surface of AZ31 magnesium alloys. The fabricated nano multilayered coating can not only obviously enhance the corrosion resistance but also significantly increase the antibacterial activity and demonstrate better biocompatility of magnesium alloys. PMID- 28645045 TI - Hydra amphiphiles: Using three heads and one tail to influence aggregate formation and to kill pathogenic bacteria. AB - Hydra amphiphiles mimic the morphology of the mythical multi-headed creatures for which they are named. Likewise, when faced with a pathogenic bacterium, some hydra derivatives are as destructive as their fabled counterparts were to their adversaries. This report focuses on eight new tricephalic (triple-headed), single tailed amphiphiles. Each amphiphile has a mesitylene (1,3,5-trimethylbenzene) core, two benzylic trimethylammonium groups and one dimethylalkylammonium group with a linear hydrophobe ranging from short (C8H17) to ultralong (C22H45). The logarithm of the critical aggregation concentration, log(CAC), decreases linearly with increasing tail length, but with a smaller dependence than that of ionic amphiphiles with fewer head groups. Tail length also affects antibacterial activity; amphiphiles with a linear 18 or 20 carbon atom hydrophobic chain are more effective at killing bacteria than those with shorter or longer chains. Comparison to a recently reported amphiphilic series with three heads and two tails allows for the development of an understanding of the relationship between number of tails and both colloidal and antibacterial properties. PMID- 28645046 TI - A paradigm shift for socioeconomic justice and health: from focusing on inequalities to aiming at sustainable equity. AB - OBJECTIVES: To measure the 'best possible health for all', incorporating sustainability, and to establish the magnitude of global health inequity. STUDY DESIGN: Observational, retrospective. METHODS: We identified countries with three criteria: (1) a healthy population-life expectancy above world average; (2) living conditions feasible to replicate worldwide-per-capita gross domestic product (GDP-pc) below the world average; and (3) sustainability-per-capita carbon dioxide emissions lower than the planetary pollution boundary. Using these healthy, feasible, and sustainable (HFS) countries as the gold standard, we estimated the burden of global health inequity (BGHiE) in terms of excess deaths, analyzing time-trends (1950-2012) by age, sex, and geographic location. Finally, we defined a global income 'equity zone' and quantified the economic gap needed to achieve global sustainable health equity. RESULTS: A total of 14 countries worldwide met the HFS criteria. Since 1970, there has been a BGHiE of ~17 million avoidable deaths per year (~40% of all deaths), with 36 life-years-lost per excess death. Young children and women bore a higher BGHiE, and, in recent years, the highest proportion of avoidable deaths occurred in Africa, India, and the Russian Federation. By 2012, the most efficient HFS countries had a GDP-pc/year of USD$2,165, which we proposed as the lower equity zone threshold. The estimated USD$2.58 trillion economic gap represents 3.6% of the world's GDP-twenty times larger than current total global foreign aid. CONCLUSIONS: Sustainable health equity metrics provide a benchmark tool to guide efforts toward transforming overall living conditions, as a means to achieve the 'best possible health for all.' PMID- 28645047 TI - Neurological condition assessed with the Hempel examination and cognition and behaviour at 4years. AB - AIM: To investigate associations between neurological condition, assessed with the Hempel examination, in terms of minor neurological dysfunction (MND) and neurological optimality, and cognition and behaviour at 4years. STUDY DESIGN: Cross-sectional analyses within a prospective, assessor-blinded follow-up study. SUBJECTS: Four-year-old singletons born to subfertile parents (n=235; 120 boys). OUTCOME MEASURES: Outcome parameters were complex minor neurological dysfunction (complex MND) and the neurological optimality score (NOS). Cognitive outcome was evaluated with the Kaufman Assessment Battery for Children, resulting in a total intelligence quotient (IQ). Behavioural outcome was evaluated with the Child Behavior Checklist, resulting in a total problem T-score. RESULTS: Fifty-seven (24.3%) children had complex MND. None of the children showed fine motor dysfunction, suggesting a ceiling effect of the Hempel assessment. Complex MND was not correlated with IQ or total problem T-score. Nevertheless, a higher NOS was correlated with a higher IQ and a lower total problem T-score (adjusted mean estimate [95% confidence interval]: cognition: 0.445 [0.026; 0.865], p=0.038; behaviour: -0.458 [-0.830; -0.087], p=0.016). INTERPRETATION: At age 4, complex MND assessed with the Hempel assessment was not associated with cognition and behaviour, presumably due to a ceiling effect in the Hempel domain of fine motor function. A more optimal neurological condition was associated with higher IQ and better behaviour. PMID- 28645048 TI - Phytolith carbon sequestration in global terrestrial biomes. AB - Terrestrial biogeochemical carbon (C) sequestration is coupled with the biogeochemical silicon (Si) cycle through mechanisms such as phytolith C sequestration, but the size and distribution of the phytolith C sink remain unclear. Here, we estimate phytolith C sequestration in global terrestrial biomes. We used biome data including productivity, phytolith and silica contents, and the phytolith stability factor to preliminarily determine the size and distribution of the phytolith C sink in global terrestrial biomes. Total phytolith C sequestration in global terrestrial biomes is 156.7+/-91.6TgCO2yr-1. Grassland (40%), cropland (35%), and forest (20%) biomes are the dominant producers of phytolith-based carbon; geographically, the main contributors are Asia (31%), Africa (24%), and South America (17%). Practices such as bamboo afforestation/reforestation and grassland recovery for economic and ecological purposes could theoretically double the above phytolith C sink. The potential terrestrial phytolith C sequestration during 2000-2099 under such practices would be 15.7-40.5PgCO2, equivalent in magnitude to the C sequestration of oceanic diatoms in sediments and through silicate weathering. Phytolith C sequestration contributes vitally to the global C cycle, hence, it is essential to incorporate plant-soil silica cycling in biogeochemical C cycle models. PMID- 28645049 TI - Gaseous elemental mercury in the marine boundary layer and air-sea flux in the Southern Ocean in austral summer. AB - Gaseous elemental mercury (GEM) in the marine boundary layer (MBL), and dissolved gaseous mercury (DGM) in surface seawater of the Southern Ocean were measured in the austral summer from December 13, 2014 to February 1, 2015. GEM concentrations in the MBL ranged from 0.4 to 1.9ngm-3 (mean+/-standard deviation: 0.9+/-0.2ngm 3), whereas DGM concentrations in surface seawater ranged from 7.0 to 75.9pgL-1 (mean+/-standard deviation: 23.7+/-13.2pgL-1). The occasionally observed low GEM in the MBL suggested either the occurrence of atmospheric mercury depletion in summer, or the transport of GEM-depleted air from the Antarctic Plateau. Elevated GEM concentrations in the MBL and DGM concentrations in surface seawater were consistently observed in the ice-covered region of the Ross Sea implying the influence of the sea ice environment. Diminishing sea ice could cause more mercury evasion from the ocean to the air. Using the thin film gas exchange model, the air-sea fluxes of gaseous mercury in non-ice-covered area during the study period were estimated to range from 0.0 to 6.5ngm-2h-1 with a mean value of 1.5+/-1.8ngm-2h-1, revealing GEM (re-)emission from the East Southern Ocean in summer. PMID- 28645050 TI - Land use affects total dissolved nitrogen and nitrate concentrations in tropical montane streams in Kenya. AB - African tropical montane forests are facing fast and dynamic changes in land use. However, the impacts of these changes on stream water quality are understudied. This paper aims at assessing the effect of land use and physical catchment characteristics on stream water concentrations of dissolved organic carbon (DOC), total dissolved nitrogen (TDN), nitrate (NO3-N) and dissolved organic nitrogen (DON) in the Mau Forest, the largest tropical montane forest in Kenya. We conducted five synoptic stream water sampling campaigns at the outlets of 13-16 catchments dominated by either natural forest, smallholder agriculture or commercial tea and tree plantations. Our data show a strong effect of land use on TDN and NO3-N, with highest concentrations in stream water of catchments dominated by tea plantations (1.80+/-0.50 and 1.62+/-0.60mgNl-1, respectively), and lowest values in forested catchments (0.55+/-0.15 and 0.30+/-0.08mgNl-1, respectively). NO3-N concentration increased with stream temperature and specific discharge, but decreased with increasing catchment area. DOC concentrations increased with catchment area and precipitation and decreased with specific discharge, drainage density and topographic wetness index. Precipitation and specific discharge were also strong predictors for DON concentrations, with an additional small positive effect of tree cover. In summary, land use affects TDN and NO3-N concentrations in stream water in the Mau Forest region in Kenya, while DOC and DON were more related to hydrologic regimes and catchment properties. The importance of land use for NO3-N and TDN concentrations emphasizes the risk of increased nitrogen export along hydrological pathways caused by intensified land use and conversion of land to agricultural uses, which might result in deterioration of drinking water quality and eutrophication in surface water in tropical Africa. PMID- 28645051 TI - Enantioselective disturbance of chiral herbicide dichlorprop to nitrogen metabolism of Arabidopsis thaliana: Regular analysis and stable isotope attempt. AB - As the most essential element, nitrogen play a pivotal role in plant physiological process, which is susceptible to contaminants. However, the enantioselective effects of chiral herbicides on nitrogen metabolism have not been comprehensively understood. In this study, effects of chiral herbicide dichlorprop (DCPP) on the nitrogen behaviors in Arabidopsis thaliana were investigated. The results revealed that the uptakes of inorganic nitrogen (NO3- and NH4+) were preferentially impacted by herbicidal active (R)-DCPP, where the transportation of beneficial NO3- was inhibited but the toxic NH4+ was accumulated. As for nitrogen assimilation, enantioselectivity was disappeared and reoccurred when NO3- was assimilated into NH4+. Furthermore, the pathways of NH4+ assimilation differed in Arabidopsis exposed to DCPP enantiomers, where (S)-DCPP remained almost the same to the control relying on GS-GOGAT cycle, but the dominant pathway in (R)-DCPP group was shifted to glutamate dehydrogenase route. Consequently, a profound enantioselectivity was also observed in the effects on amino acids synthesis. As for nitrogen stable isotope fractionation, (R)-DCPP led to more negative delta15N values than (S)-DCPP at 0.3MUM, indicating the selective uptake of toxic NH4+ and different discrimination of delta15N was also observed between DCPP enantiomers. Moreover, stable isotopic evidence also revealed the disturbance caused by DCPP to the balance of nitrogen demand and consumption in A. thaliana. All these results may contribute to the final enantioselective toxicity, providing a new sight into the better understanding the action mechanism of chiral herbicides. PMID- 28645053 TI - Assessment of imaging-in-flow system (FlowCAM) for systematic ballast water management. AB - Assessing the disinfection of ballast water and its compliance with international standards requires determining the size, viability, and concentration of planktonic organisms. The FlowCAM (Flow Cytometer and Microscope) is an Imaging Flow Cytometry designed to obtain the particle concentration, images, and quantitative morphologic information. The objective in this paper is to establish the basis for transforming the FlowCAM from being a laboratory analyzer into a tool for systematic monitoring of ballast water. The capacity of the FlowCAM was evaluated by analyzing artificial microbeads, phytoplankton monocultures, and real seawater samples. Microbead analyses reported high accuracy and precision in size and concentration measurements. Monoculture analyses showed the effect of disinfection treatments in cell appearance and growth. Low concentration and heterogeneity of particles in real seawater analyses require the comprehensive observation of images by experts. Additionally, some physical characteristics of the device must be improved. The optimization of device configuration enables the quick transferring of files and information between parties involved in ballast water management. FlowCAM may become a feasible technology for this after the device and protocols are adapted. PMID- 28645052 TI - Cardiorespiratory responses of air filtration: A randomized crossover intervention trial in seniors living in Beijing: Beijing Indoor Air Purifier StudY, BIAPSY. AB - In this Beijing Indoor Air Purifier StudY (BIAPSY), we conducted a randomized crossover intervention trial in a panel of 35 non-smoking senior participants with free-living, with and without chronic obstructive pulmonary disease (COPD). Portable air filtration units were randomly allocated to active-(filter in) for 2weeks and sham-mode (filter out) for 2weeks in the households. We examined the differences in indoor air pollutant concentrations in 20 study homes and a suite of cardio-respiratory biomarker levels in study participants between filtration modes, with and without adjustment for potential confounders. Following active filtration, we observed significant reductions from 60+/-45 to 24+/-15MUg/m3 in ten-day averages of indoor PM2.5 and reductions from 3.87+/-1.65 to 1.81+/-1.19m 1.10-5 in ten-day averages of indoor BC, compared to sham-mode filtration. The major components of indoor PM2.5, including water soluble organics, NO3-, SO42-, Zn2+, Pb2+ and K+, were also reduced significantly by 42% to 63%. However, following active filtration, we only observed significant reductions on systemic inflammation measured as of IL-8 at 58.59% (95% CI: -76.31, -27.64) in the total group of participants and 70.04% (95% CI: -83.05, -47.05) in the subset of COPD patients, with adjustments. We were not able to detect improvements on lung function, blood pressure, and heart rate variability, following short-term intervention of two-week active air filtration. In conclusion, our results showed that indoor air filtration produced clear improvement on indoor air quality, but no demonstrable changes in the cardio-respiratory outcomes of study interest observed in the seniors living with real-world air pollution exposures. PMID- 28645054 TI - Computational analysis of the ToxCast estrogen receptor agonist assays to predict vitellogenin induction by chemicals in male fish. AB - Endocrine disruptors, especially estrogen receptor (ER) agonists, have received considerable research attention. While there are several mechanistic endpoints for ER agonism in the Endocrine Disruptor Screening Program, there have been growing efforts to develop high-throughput screening assays and computational models to reduce testing cost, time, and animal use. For example, there are 16 ER agonist assays and an integrated computational model in ToxCast. In the present study, we examined the relationship between ToxCast ER agonist assays and model activity to male vitellogenin induction in the Fish-Short Term Reproduction Assay. It was found 15/16 of the assays significantly predicted potency ranks for 10 common ER agonists, and 7/16 of the assays had a significant linear correlation. The integrated model also provided comparable performance to most assays. Thus, the ToxCast ER agonist assays and model may be useful to identify endocrine disruptors and predict reproductive outcomes in fish. PMID- 28645055 TI - C-reactive protein and white blood cell levels in schizophrenia, bipolar disorders and depression - associations with mortality and psychiatric outcomes: a population-based study. AB - BACKGROUND: Mental disorders have been associated with increased levels of inflammatory markers, which can affect disease trajectories. We aimed to assess levels of C-reactive protein (CRP) and white blood cells (WBC) across individuals with schizophrenia, bipolar disorder, and depression, and to investigate associations with subsequent psychiatric admission and mortality. METHODS: We identified all adults in the Central Denmark Region during 2000-2012 with a first diagnosis of schizophrenia, bipolar disorder, or depression and a baseline measurement of CRP and/or WBC count. We followed these individuals until outcome of interest (psychiatric admission or death), emigration or December 31, 2012, using Cox regression analysis to estimate hazard ratios (HRs). RESULTS: Baseline median CRP differed significantly between mental disorders (P=0.01) being highest in individuals with bipolar disorder (3.5mg/L) (particularly during manic states, 3.9mg/L), followed by schizophrenia (3.1mg/L), and depression (2.8mg/L), while baseline WBC count did not differ (median 7.1*109/L). Elevated CRP levels were associated with increased all-cause mortality by adjusted HRs of 1.56 (95% CI: 1.02-2.38) for levels 3-10mg/L and 2.07 (95% CI: 1.30-3.29) for levels above 10mg/L compared to individuals with levels below 3mg/L. WBC counts were not associated with all-cause mortality. No association was observed between levels of the inflammatory markers and subsequent psychiatric admissions. CONCLUSIONS: People with severe mental disorders had increased inflammatory markers at first diagnosis, and elevated CRP levels were associated with increased mortality. Thorough screening for physical diseases is of utmost importance among individuals who are diagnosed with severe mental disorder. PMID- 28645056 TI - Serious delinquency and later schizophrenia: A nationwide register-based follow up study of Finnish pretrial 15- to 19-year-old offenders sent for a forensic psychiatric examination. AB - BACKGROUND: Aggressive and disruptive behaviors often precede the onset of schizophrenia. In this register-based follow-up study with a case-control design, we wanted to investigate if serious delinquency was associated with future diagnoses of schizophrenia or schizoaffective disorder (here, broadly defined schizophrenia) among a nationwide consecutive sample of 15- to 19-year-old Finnish delinquents sent for a forensic psychiatric examination in 1989-2010. METHODS: The sample comprised 313 delinquents with no past or current psychotic disorder. For each delinquent, four age-, gender- and place of birth -matched controls were randomly selected from the Central Population Register. Five controls (0.4%) had been treated for schizophrenia before their respective index dates and were thus excluded from further analysis, leaving us with a control population of 1247 individuals. The subjects were followed till death, emigration or the end of 2015, whichever occurred first. Diagnoses were obtained from the Care Register for Health Care. RESULTS: Forty (12.8%) of the delinquents and 11 (0.9%) of the controls were diagnosed with schizophrenia later in life (HR 16.6, 95% CI 8.53-32.39, P<0.001). Almost half of the pretrial adolescents with later schizophrenia were diagnosed within 5years of the forensic psychiatric examination, but latency was longer among the other half of the sample, reaching up to 20.5years. CONCLUSIONS: The study supports the previous research indicating a potential link between serious delinquency and later schizophrenia. Accurate psychiatric assessments should be made in correctional services but also later in life so that any possible psychotic symptoms can be detected in individuals with a history of serious delinquency even if there were no signs of psychosis before or at the time of the crime. Future research should explore which factors influence the delinquent's risk of developing later schizophrenia. PMID- 28645057 TI - Effects of salinity and short-term elevated atmospheric CO2 on the chemical equilibrium between CO2 fixation and photosynthetic electron transport of Stevia rebaudiana Bertoni. AB - The effect of water salinity on plant growth and photosynthetic traits of Stevia rebaudiana was investigated to determine its level and mechanisms of salinity tolerance. It was also attempted to assess how short-term elevated CO2 concentration would influence the boundaries and mechanisms of its photosynthetic capacity. The plants were grown in gravel/hydroponic system under controlled greenhouse conditions and irrigated with four different salinity levels (0, 25, 50 and 100 mol m-3NaCl). Low salinity did not significantly alter the plant fresh weight, which was substantially decreased by 67% at high salinity treatment. Salinity tolerance threshold was reached at 50 mol m-3 NaCl while C50 was between 50 and 100 mol m-3 NaCl, indicating that S. rebaudiana is a moderate salt tolerant species. Salt-induced growth reduction was apparently linked to a significant decline of about 47% in the photosynthetic rates (Anet) at high salinity treatment, leading consequently to a disequilibrium between CO2 assimilation and electron transport rates (indicated by enhanced ETRmax/Agross ratio). Elevated atmospheric CO2 enhanced CO2 assimilation rates by 65% and 80% for control and high-salt-stressed plants respectively, likely due to significant increases in intercellular CO2 concentration (indicated by enhanced Ci/Ca). The priority for Stevia under elevated atmospheric CO2 was not to save water but to maximize photosynthesis so that the PWUE was progressively improved and the threat of oxidative stress was diminished (decline in ETRmax/Agross). The results imply that elevated CO2 level could ameliorate some of the detrimental effects of salinity, conferring higher tolerance and survival of S. rebaudiana, a highlydesired feature with the forthcoming era of global changes. PMID- 28645058 TI - Promoting physical activity in high-poverty neighborhood parks: A cluster randomized controlled trial. AB - Although physical activity can help mitigate or prevent multiple chronic diseases, most people in the U.S., especially high-poverty minority groups, engage in insufficient levels of physical activity. To test ways to promote more physical activity in high-poverty area public parks we conducted a randomized controlled intervention trial. After completing baseline measures of park-based physical activity using systematic direct observation three times/day each month for six months and assessing preferences for park programming among 1445 residents living within 1 mile of study parks, we randomized 48 parks in high poverty neighborhoods in the City of Los Angeles, California during 2013-2014 to four study arms: 1) free physical activity classes over a 6-month period, 2) a frequent user program where participants could win prizes based upon the number of visits they made to the park, 3) both the programs, and 4) neither one (control condition). We re-measured park use in 2014-2015 using the same methods during the six months the intervention programs were in operation. A total of 2047 free park classes were offered attracting 16,718 participants. The frequent user programs enrolled 1452 individuals and prizes were awarded to 830. Residents in the two study arms with free classes were more likely to report being aware of and participating in park-based physical activity programs; however, overall observed park-based physical activity increased similarly across all study arms. The process evaluation uncovered several barriers to program implementation, including inconsistent scheduling of classes, partly due to safety concerns among instructors. Multiple social factors interfere with leisure time physical activity among low-income populations, suggesting modest interventions may be insufficient to overcome these issues. Although new park programs can attract users, new programs alone may be insufficient to increase overall park use in low income neighborhoods at times when the programs are not taking place. PMID- 28645059 TI - Association of elevated ambient temperature with death from cocaine overdose. AB - BACKGROUND: Ecologic data suggest that elevated outdoor temperature is correlated with mortality rates from cocaine overdose. Using non-aggregated death records, we studied the association of hot temperatures with risk of death from cocaine overdose. METHODS: We carried out a case-crossover study of all deaths from cocaine or other drug overdose between the months of May and September, from 2000 through 2013 in Quebec, Canada. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between maximum outdoor temperature and death from cocaine or other drug overdose. The main outcome measure was death from cocaine overdose as a function of maximum temperature the day of death and the days immediately preceding death. RESULTS: There were 316 deaths from cocaine overdose and 446 from other drug overdoses during the study. Elevated temperature the preceding week was associated with the likelihood of death from cocaine but not other drug overdose. Compared with 20 degrees C, a maximum weekly temperature of 30 degrees C was associated with an OR of 2.07 for death from cocaine overdose (95% CI 1.15-3.73), but an OR of 1.03 for other drug overdoses (95% CI 0.60-1.75). Associations for cocaine overdose were present with maximum daily temperature the day of and each of the three days preceding death. CONCLUSIONS: Elevated ambient temperature is associated with the risk of death from cocaine overdose. Public health practitioners and drug users should be aware of the added risk of mortality when cocaine is used during hot days. PMID- 28645060 TI - Young people who use drugs engaged in harm reduction programs in New York City: Overdose and other risks. AB - BACKGROUND: Little is known about the engagement of young people who use drugs (PWUD) in harm reduction programs (HRPs), and few studies have included non opioid users and non-injectors. While HRPs have effectively engaged PWUD, young people are under-represented in their services. METHODS: The Injection Drug Users Health Alliance Citywide Study (IDUCS) is the largest community-based study of PWUD in HRPs in the US. From 2014-2015, 2421 HRP participants across New York City (NYC) completed a cross-sectional survey. We investigated differences in socio-demographics, service utilization, and risk behaviors between young (aged 18-30) and older participants and examined factors associated with overdose among young participants. RESULTS: The study included 257 young participants. They were significantly more likely than older participants to be white, educated, uninsured, unstably housed or homeless, and have a history of incarceration and residential drug treatment. They were more likely to report recent overdose but less likely to report knowledge of naloxone. Young participants also had higher rates of alcohol, marijuana, benzodiazepine, and injection drug use, and related risk behaviors such as public injection. Factors associated with past year overdose among young participants included experiencing symptoms of psychological distress (AOR=9.71), being unstably housed or homeless (AOR=4.39), and utilizing detox (AOR=4.20). CONCLUSIONS: Young PWUD who access services at HRPs in NYC differ significantly from their older counterparts. New York City and other urban centers that attract young PWUD should consider implementing harm reduction oriented services tailored to the unique needs of young people. PMID- 28645062 TI - Acute and chronic alcohol use correlated with methods of suicide in a Swiss national sample. AB - OBJECTIVES: Chronic and acute alcohol use are highly associated risk factors for suicides worldwide. Therefore, we examined suicide cases with and without alcohol use disorder (AUD) using data from the SNSF project "Suicide in Switzerland: A detailed national survey". Our investigations focus on correlations between acute and chronic alcohol use with reference to suicide and potential interactions with the methods of suicide. METHODS: We used data from the SNSF project in which all cases of registered completed suicide in Switzerland reported to any of the seven Swiss institutes of legal and forensic medicine between 2000 and 2010 were collected. We extracted cases that were tested for blood alcohol to use in our analysis. We compared clinical characteristics, blood alcohol concentrations, and methods of suicide in cases with and without AUD. RESULTS: Out of 6497 cases, 2946 subjects were tested for acute alcohol use and included in our analysis. Of the latter, 366 (12.4%) persons had a medical history of AUD. Subjects with AUD significantly had higher blood alcohol concentrations and were more often in medical treatment before suicide. Drug intoxication as method of suicide was more frequent in cases with AUD compared to NAUD. CONCLUSION: Overall, we found a high incidence of acute alcohol use at the time of death in chronic alcohol misusers (AUD). The five methods of suicide most commonly used in Switzerland differed considerably between individuals with and without AUD. Blood alcohol concentrations varied across different methods of suicide independently from the medical history in both groups. PMID- 28645061 TI - The neurochemical consequences of methamphetamine self-administration in male and female rats. AB - BACKGROUND: Methamphetamine (METH) is an addictive substance that is used in both males and females. Few preclinical studies have focused on understanding sex differences in the neurochemical consequences of contingent METH. The purpose of the current study was to investigate potential sex-differences in the neurochemical consequences of METH self-administration. METHODS: Male and female adult rats were given extended access to METH or saline self-administration for 7d. Following self-administration, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine transporter (DAT) were assessed via western blotting. RESULTS: Male and female rats had similar METH intake. METH self administration reduced striatal DAT in both sexes, but only males that self administered METH had elevated hippocampal BDNF levels. CONCLUSIONS: Sex differences exist in the neurochemical consequences of METH self-administration. These differences may lead to sex-specific vulnerability to the toxic effects of METH. PMID- 28645063 TI - Assessing phosphatidylethanol (PEth) levels reflecting different drinking habits in comparison to the alcohol use disorders identification test - C (AUDIT-C). AB - In addition to monitoring problematic or harmful alcohol consumption, drinking experiments indicated the potential of phosphatidylethanols (PEth) in abstinence monitoring. To date, no profound evaluation of thresholds for the differentiation of abstinence from moderate drinking and for detection of excessive consumption based on PEth homologues exists. Investigations with a large group of healthy volunteers (n=300) were performed to establish PEth reference values reflecting different drinking habits. Blood samples were analyzed for PEth 16:0/18:1 and 16:0/18:2 by online-SPE-LC-MS/MS method. Results were compared to AUDIT-C questionnaires, to the amounts of alcohol consumed during the two-weeks prior to blood sampling, and were statistically evaluated. PEth concentrations were significantly correlated with self-reported alcohol consumption (r>0.69) and with AUDIT-C scores (r>0.65). 4.0% of 300 volunteers reported abstinence (AUDIT-C score: 0), no PEth was detectable in their blood. PEth 16:0/18:1 concentrations below the limit of detection of 10.0ng/mL match with abstinence and light drinking habits (<=10g pure alcohol/day). However, some volunteers classified as "excessive alcohol consumers" had negative PEth results. In the group of volunteers classified as "moderate drinkers" (AUDIT-C score: 1-3 (women) and 1-4 (men)), 95% of the test persons had PEth 16:0/18:1 ranging from not detected to 112ng/mL, and PEth 16:0/18:2 ranging from not detected to 67.0ng/mL. Combination of self-reported alcohol consumption and AUDIT-C score showed that negative PEth results match with abstinence or light drinking. Moderate alcohol consumption resulted in PEth 16:0/18:1 from 0 to 112ng/mL and for PEth 16:0/18:2 ranged from 0 to 67.0ng/mL. Higher PEth concentrations indicated excessive alcohol consumption. PMID- 28645064 TI - Heroin and saccharin demand and preference in rats. AB - BACKGROUND: Several recent studies have investigated the choice between heroin and a non-drug alternative reinforcer in rats. A common finding in these studies is that there are large individual differences in preference, with some rats preferring heroin and some preferring the non-drug alternative. The primary goal of the present study was to determine whether individual differences in how heroin or saccharin is valued, based on demand analysis, predicts choice. METHODS: Rats lever-pressed for heroin infusions and saccharin reinforcers on fixed-ratio schedules. The essential value of each reinforcer was obtained from resulting demand curves. Rats were then trained on a mutually exclusive choice procedure where pressing one lever resulted in heroin and pressing another resulted in saccharin. After seven sessions of increased access to heroin or saccharin, rats were reexposed to the demand and choice procedures. RESULTS: Demand for heroin was more elastic than demand for saccharin (i.e., heroin had lower essential value than saccharin). When allowed to choose, most rats preferred saccharin. The essential value of heroin, but not saccharin, predicted preference. The essential value of both heroin and saccharin increased following a week of increased access to heroin, but similar saccharin exposure had no effect on essential value. Preference was unchanged after increased access to either reinforcer. CONCLUSION: Heroin-preferring rats differed from saccharin preferring rats in how they valued heroin, but not saccharin. To the extent that choice models addiction-related behavior, these results suggest that overvaluation of opioids specifically, rather than undervaluation of non-drug alternatives, could identify susceptible individuals. PMID- 28645065 TI - Cross-validation of short forms of the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). AB - BACKGROUND: The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a 24-item assessment designed to assist in the prediction of aberrant drug-related behavior (ADB) among patients with chronic pain. Recent work has created shorter versions of the SOAPP-R, including a static 12-item short form and two computer-based methods (curtailment and stochastic curtailment) that monitor assessments in progress. The purpose of this study was to cross-validate these shorter versions in two new populations. METHODS: This retrospective study used data from patients recruited from a hospital-based pain center (n=84) and pain patients followed and treated at primary care centers (n=110). Subjects had been administered the SOAPP-R and assessed for ADB. In real data simulation, the sensitivity, specificity, and area under the curve (AUC) of each form were calculated, as was the mean test length using curtailment and stochastic curtailment. RESULTS: Curtailment reduced the number of items administered by 30% to 34% while maintaining sensitivity and specificity identical to those of the full-length SOAPP-R. Stochastic curtailment reduced the number of items administered by 45% to 63% while maintaining sensitivity and specificity within 0.03 of those of the full-length SOAPP-R. The AUC of the 12 item form was equal to that of the 24-item form in both populations. CONCLUSIONS: Curtailment, stochastic curtailment, and the 12-item short form have potential to enhance the efficiency of the SOAPP-R. PMID- 28645066 TI - Hydrothermal co-carbonization of sewage sludge and pinewood sawdust for nutrient rich hydrochar production: Synergistic effects and products characterization. AB - The aim of this study is to explore the synergistic effects of hydrothermal co carbonization of sewage sludge and pinewood sawdust on hydrochar production. Firstly, the effects of mixing ratios on hydrothermal carbonization were investigated, and then, the hydrochar was characterized by diverse analytical techniques. The mass balance results indicated that a significant synergistic enhancement occurred in terms of the increased hydrochar yield, organic and carbon retentions. By combining sewage sludge and pinewood sawdust at the mass ratio of 1:1, 58.11 +/- 0.91% of hydrochar yield was obtained with high synergistic coefficients (8.41% for hydrochar yield, 13.09% for carbon retention, and 14.92% for organics retention). The hydrochar properties of nutrients, such as nitrogen and phosphorus, and surface functional groups were improved by hydrothermal co-carbonization approach. The FT-IR spectra, CP-MAS 13C NMR and SEM results further indicated that hydrothermal co-carbonization promoted the development of aromaticity and surface structure. Our findings suggested that hydrothermal co-carbonization is a promising strategy to tailor high-performance hydrochar for different applications. PMID- 28645067 TI - Using a detailed inventory of a large wastewater treatment plant to estimate the relative importance of construction to the overall environmental impacts. AB - The aim of this work is to quantify the relative contribution to the overall environmental impact of the construction phase compared to the operational phase for a large conventional activated sludge wastewater treatment plant (WWTP). To estimate these environmental impacts, a systematic procedure was designed to obtain the detailed Life Cycle Inventories (LCI) for civil works and equipment, taking as starting point the construction project budget and the list of equipment installed at the Girona WWTP, which are the most reliable information sources of materials and resources used during the construction phase. A detailed inventory is conducted by including 45 materials for civil works and 1,240 devices for the equipment. For most of the impact categories and different life spans of the WWTP, the contribution of the construction phase to the overall burden is higher than 5% and, especially for metal depletion, the impact of construction reaches 63%. When comparing to the WWTP inventories available in Ecoinvent the share of construction obtained in this work is about 3 times smaller for climate change and twice higher for metal depletion. Concrete and reinforcing steel are the materials with the highest contribution to the civil works phase and motors, pumps and mobile and transport equipment are also key equipment to consider during life cycle inventories of WWTPs. Additional robust inventories for similar WWTP can leverage this work by applying the factors (kg of materials and energy per m3 of treated water) and guidance provided. PMID- 28645068 TI - Fracture, roughness and phase transformation in CAD/CAM milling and subsequent surface treatments of lithium metasilicate/disilicate glass-ceramics. AB - This paper studied surface fracture, roughness and morphology, phase transformations, and material removal mechanisms of lithium metasilicate/disilicate glass ceramics (LMGC/LDGC) in CAD/CAM-milling and subsequent surface treatments. LMGC (IPS e.max CAD) blocks were milled using a chairside dental CAD/CAM milling unit and then treated in sintering, polishing and glazing processes. X-ray diffraction was performed on all processed surfaces. Scanning electron microscopy (SEM) was applied to analyse surface fracture and morphology. Surface roughness was quantitatively characterized by the arithmetic average surface roughness Ra and the maximum roughness Rz using desktop SEM assisted morphology analytical software. The CAD/CAM milling induced extensive brittle cracks and crystal pulverization on LMGC surfaces, which indicate that the dominant removal mechanism was the fracture mode. Polishing and sintering of the milled LMGC lowered the surface roughness (ANOVA, p < 0.05), respectively, while sintering also fully transformed the weak LMGC to the strong LDGC. However, polishing and glazing of LDGC did not significantly improve the roughness (ANOVA, p > 0.05). In comparison of all applied fabrication process routes, it is found that CAD/CAM milling followed by polishing and sintering produced the smoothest surface with Ra = 0.12 +/- 0.08um and Rz = 0.89 +/- 0.26um. Thus, it is proposed as the optimized process route for LMGC/LDGC in dental restorations. This route enables to manufacture LMGC/LDGC restorations with cost effectiveness, time efficiency, and improved surface quality for better occlusal functions and reduced bacterial plaque accumulation. PMID- 28645069 TI - Controlled single bubble cavitation collapse results in jet-induced injury in brain tissue. AB - Multiscale damage due to cavitation is considered as a potential mechanism of traumatic brain injury (TBI) associated with explosion. In this study, we employed a TBI relevant hippocampal ex vivo slice model to induce bubble cavitation. Placement of single reproducible seed bubbles allowed control of size, number, and tissue location to visualize and measure deformation parameters. Maximum strain value was measured at 45 us after bubble collapse, presented with a distinct contour and coincided temporally and spatially with the liquid jet. Composite injury maps combined this maximum strain value with maximum measured bubble size and location along with histological injury patterns. This facilitated the correlation of bubble location and subsequent jet direction to the corresponding regions of high strain which overlapped with regions of observed injury. A dynamic threshold strain range for tearing of cerebral cortex was estimated to be between 0.5 and 0.6. For a seed bubble placed underneath the hippocampus, cavitation induced damage was observed in hippocampus (local), proximal cerebral cortex (marginal) and the midbrain/forebrain (remote) upon histological evaluation. Within this test model, zone of cavitation injury was greater than the maximum radius of the bubble. Separation of apposed structures, tissue tearing, and disruption of cellular layers defined early injury patterns that were not detected in the blast-exposed half of the brain slice. Ultrastructural pathology of the neurons exposed to cavitation was characterized by disintegration of plasma membrane along with loss of cellular content. The developed test system provided a controlled experimental platform to study cavitation induced high strain deformations on brain tissue slice. The goal of the future studies will be to lower underpressure magnitude and cavitation bubble size for more sensitive evaluation of injury. PMID- 28645070 TI - Passive smoking and mortality from aortic dissection or aneurysm. AB - BACKGROUND AND AIMS: Evidence on the association between passive smoking and risk of aortic dissection or aneurysm is limited. This study aimed to investigate whether passive smoking increases risk of mortality from aortic dissection or aneurysm. METHODS: The Japan Collaborative Cohort (JACC) Study is a prospective community-based cohort study begun in 1988-90 and followed up to the end of 2009. We examined 48,677 individuals (mean age, 56 years; women, 46%) without history of stroke, coronary heart disease, or cancer, who provided valid responses to a lifestyle questionnaire including questions on active and passive smoking. We used 3 categories (passive smoking out of home, passive smoking at home, and passive smoking out of or at home combined) to divide never-smokers into 3 exposure groups: low, intermediate, and high exposures, respectively. The endpoint was underlying cause of death from aortic dissection or aneurysm. RESULTS: During the median 19-year follow-up of 48,677 study participants, 66 died of aortic dissection, and 75 of aortic aneurysm. Multivariable hazard ratios (95% confidence intervals) for the high passive-smoking group as compared with the low passive-smoking group were 2.45 (1.02-5.88) out of home, 1.82 (0.84-3.96) at home, and 2.35 (1.09-5.09) out of or at home combined. The corresponding hazard ratios for current smokers as compared with the low passive-smoking group were 3.97 (2.14-7.39), 3.41 (1.84-6.32) and 4.09 (1.99-8.39), respectively. CONCLUSIONS: Out-of-home passive smoking and out-of- or at-home combined passive smoking were associated with increased mortality from aortic dissection or aneurysm. PMID- 28645071 TI - Television viewing and risk of mortality: Exploring the biological plausibility. AB - BACKGROUND AND AIMS: Television (TV) viewing is a major component of leisure sedentary time, and has been consistently associated with cardiovascular disease. We examined the extent to which metabolic biomarkers explain the association between TV viewing and mortality. METHODS: Participants (N = 8,451, aged 64.8 +/- 9.9 yrs) were drawn from The English Longitudinal Study of Ageing (ELSA), a national prospective cohort study of community-dwelling men and women living in England. The individual participant data were linked with death records from the National Health Service registries from 2008 to 2012. Cox proportional hazards models were used to estimate the risk of death according to time spent watching TV, with biomarkers added in a stepwise fashion to estimate potential mediation. RESULTS: Over an average follow up of 4 years (33,832 person years), there were 370 deaths. In models adjusted for comorbidities, psychosocial factors, and health behaviours including physical activity, there was an association between TV viewing and mortality (>=6 h per day vs. < 2 h per day [Ref]; hazard ratio = 1.98, 95% CI, 1.25, 3.15). Adjustment for inflammatory markers (C-reactive protein and fibrinogen) accounted for ~15.7% of the association between TV viewing and mortality, but metabolic risk factors (HDL-cholesterol, triglycerides, glycated haemoglobin) did not contribute. CONCLUSIONS: The association between TV viewing and mortality was partly mediated by inflammatory markers, although the relationship remains largely unexplained. PMID- 28645073 TI - Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene. AB - BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant disease with widespread global prevalence that partially accounts for the high prevalence of premature coronary heart disease. Although the majority of research on FH has focused on single heterozygous LDLR mutations, there have been limited reports of double LDLR mutations on the same chromosome. The aim of this study was to gain insight into the clinical consequences of the presence of multiple mutations in the LDLR gene. METHODS: DNA from two clinical homozygous FH patients and their relatives was analysed using targeted exome sequencing and DNA resequencing. Functional characterization of novel variants was performed by Western blot, flow cytometry and confocal microscopy. RESULTS: Proband 1 carried p.Q12X, NTDA (p.N276T and c.892delA) mutations in LDLR, and Proband 2 carried c.971delG, GSDN (p.G77S + D601N). Results showed that p.Q12X, c.892delA, and c.971delG are non-functional LDLR variants. Conversely, N276T and G77S are non pathogenic variants. Interestingly, while D601N alone only slightly diminishes LDLR activity, its co-presence with the non pathogenic p.G77S mutation results in a more strongly pathogenic variant with LDLR activity reduced by 40%. One of the double mutants, NTDA, is as non functional as c.892delA alone. The other double mutant, GSDN, is more severe than either of the component single mutants. CONCLUSIONS: An early gene screening and laboratory functional verification of LDLR activity is of vital importance to enable a definite FH diagnosis. Functional verification is also necessary for prenatal and postnatal care in patients with FH. PMID- 28645072 TI - Association of the serum myeloperoxidase/high-density lipoprotein particle ratio and incident cardiovascular events in a multi-ethnic population: Observations from the Dallas Heart Study. AB - BACKGROUND AND AIMS: Myeloperoxidase (MPO), a product of systemic inflammation, promotes oxidation of lipoproteins; whereas, high-density lipoprotein (HDL) exerts anti-oxidative effects in part via paraoxonase-1 (PON1). MPO induces dysfunctional HDL particles; however, the interaction of circulating levels of these measures in cardiovascular disease (CVD) has not been studied in humans. We tested whether serum levels of MPO indexed to HDL particle concentration (MPO/HDLp) are associated with increased CVD risk in a large multiethnic population sample, free of CVD at baseline. METHODS: Levels of MPO, HDL-C, and HDL particle concentration (HDLp) by NMR were measured at baseline in 2924 adults free of CVD. The associations of MPO/HDLp with incident ASCVD (first non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or CVD death) and total CVD were assessed in Cox proportional-hazards models adjusted for traditional risk factors. The median follow-up period was 9.4 years. RESULTS: Adjusted for sex and race/ethnicity, MPO/HDLp was associated directly with body mass index, smoking status, high-sensitivity C-reactive protein, and interleukin 18, and inversely with age, HDL-C levels, HDL size, and PON1 arylesterase activity, but not with cholesterol efflux. In fully adjusted models, the highest versus lowest quartile of MPO/HDLp was associated with a 74% increase in incident ASCVD (aHR, 1.74, 95% CI 1.12-2.70) and a 91% increase in total incident CVD (aHR, 1.91, 95% CI 1.27-2.85). CONCLUSIONS: Increased MPO indexed to HDL particle concentration (MPO/HDLp) at baseline is associated with increased risk of incident CVD events in a population initially free of CVD over the 9.4 year period. PMID- 28645074 TI - Relationship between inter-arm blood pressure difference and severity of coronary atherosclerosis. AB - BACKGROUND AND AIMS: A greater inter-arm blood pressure difference (IABPD) is associated with atherosclerosis, but its association with coronary artery disease is unknown. We investigated the relationship between IABPD and coronary atherosclerosis. METHODS: We retrospectively reviewed blood pressure (BP) data that was measured simultaneously in both arms of patients who underwent initial coronary angiography. Coronary atherosclerosis was assessed using the Gensini score, based on quantitative coronary angiography findings. To adjust for the effect of baseline BP, the percentages of systolic IABPD to higher mean BP (cIABPDsys), diastolic IABPD to higher mean BP (cIABPDdia), and mean IABPD to higher mean BP (cIABPDmean) were calculated as BP-adjusted IABPDs. RESULTS: We examined the records of 816 patients (516 males, mean age: 65.5 +/- 11.8 years). The mean Gensini score was 33.4 +/- 30.4, and the median was 25. All cIAPBDs had positive correlations with the Gensini score (cIABPDsys: r = 0.208, p < 0.001; cIABPDdia: r = 0.123, p < 0.001; cIABPDmean: r = 0.120, p = 0.001). Multiple regression analysis indicated that cIABPDsys was associated with the Gensini score, independently of age, gender, smoking, diabetes, hypertension and dyslipidemia (B = 0.031, p < 0.001). CONCLUSIONS: The BP-adjusted IABPD parameters are related to the severity of coronary artery disease. Further studies should investigate the use of the IABPD to improve management of coronary atherosclerosis. PMID- 28645076 TI - Does reflective functioning mediate the relationship between attachment and personality? AB - Mentalization, operationalized as reflective functioning (RF), can play a crucial role in the psychological mechanisms underlying personality functioning. This study aimed to: (a) study the association between RF, personality disorders (cluster level) and functioning; (b) investigate whether RF and personality functioning are influenced by (secure vs. insecure) attachment; and (c) explore the potential mediating effect of RF on the relationship between attachment and personality functioning. The Shedler-Westen Assessment Procedure (SWAP-200) was used to assess personality disorders and levels of psychological functioning in a clinical sample (N = 88). Attachment and RF were evaluated with the Adult Attachment Interview (AAI) and Reflective Functioning Scale (RFS). Findings showed that RF had significant negative associations with cluster A and B personality disorders, and a significant positive association with psychological functioning. Moreover, levels of RF and personality functioning were influenced by attachment patterns. Finally, RF completely mediated the relationship between (secure/insecure) attachment and adaptive psychological features, and thus accounted for differences in overall personality functioning. Lack of mentalization seemed strongly associated with vulnerabilities in personality functioning, especially in patients with cluster A and B personality disorders. These findings provide support for the development of therapeutic interventions to improve patients' RF. PMID- 28645077 TI - Increased blood BDNF in healthy individuals with a family history of depression. AB - The brain-derive neurotrophic factor (BDNF) may play an important role in the course of depression. We aimed to study the associations between peripheral whole blood BDNF levels in healthy individuals with and without a family history of depression. BDNF levels were significantly increased in healthy individuals with (n = 76), compared with healthy individuals without (n = 39) a family history of depression and persisted after adjustment for age and gender differences. Higher BDNF levels were associated with increasing age and seasonality. A family history of depression may contribute to an elevation of peripheral BDNF levels in healthy individuals. PMID- 28645075 TI - A prospective follow-up study of younger and older subjects with pathological gambling. AB - Pathological gambling (PG) is a common and costly public health problem associated with impaired quality of life and high suicide rates. Despite its frequency in the general population, PG course is poorly understood in older adults who are especially vulnerable to its devastating consequences. We enrolled 175 subjects in a longitudinal study of gambling behavior: our case group of 53 older adults with PG (>= 60 years), and two comparison groups including 72 younger adults with PG (< 40 years) and 50 older adults without PG (>= 60 years). Subjects with PG met lifetime criteria for DSM-IV PG and had a South Oaks Gambling Screen (SOGS) and National Opinion Research Center DSM Screen for Gambling Problems (NODS) scores >= 5. Subjects were evaluated at intake and reassessed every 6 months and drop outs were replaced. Follow-up lasted a mean (SD) of 2.6 (1.4) years. At intake older PGs were more likely to be female, Caucasian, divorced, and to have a lower level of education. Older and younger PGs were similar in gambling severity, but older PGs were more likely to have sought PG treatment. Older PGs had lower rates of lifetime drug use disorders, attention deficit/hyperactivity disorder, and obsessive-compulsive disorder. They preferred slots, were more likely to receive PG treatment, and were less likely to discontinue participation in the study. Week by week gambling activity levels showed a significant general downward movement for older and younger PGs, although there were no differences between the groups. Elders without PG had no change in their level of gambling activity. We conclude that younger and older PGs moved toward a reduced level of gambling activity during follow-up. Our data challenge the notion that PG is chronic and progressive. PMID- 28645078 TI - Facial affect recognition and social functioning among individuals with varying degrees of schizotypy. AB - Facial affect recognition (FAR) accuracy is impaired in schizophrenia and, to a lesser extent, in individuals at-risk for psychosis. Reduced reaction time and negative bias on FAR tasks are also evident in schizophrenia, though few studies have examined these measures in at-risk samples. Social dysfunction is associated with FAR deficits in schizophrenia and at-risk individuals. We aimed to elucidate the nature of FAR and social functioning among individuals from a non-clinical population reporting a range of schizotypal traits (i.e., risk for psychosis), and to examine whether FAR mediates the relationship between schizotypal traits and social functioning. Participants completed self-report measures assessing schizotypal traits and social functioning, and a computerized FAR task remotely via the Internet. High schizotypy individuals performed significantly worse than low schizotypy individuals on FAR total and neutral accuracy, demonstrated a negative bias, and reported significantly worse social functioning. Schizotypal traits were also negatively correlated with FAR performance and social functioning in the total sample. FAR accuracy did not mediate the direct relationship between schizotypal traits and social functioning. FAR may be an important social-cognitive endophenotype of psychosis risk with implications for understanding etiology of psychotic spectrum disorders, improving ways of identifying at-risk individuals, and developing preventive strategies. PMID- 28645079 TI - Desire thinking as a confounder in the relationship between mindfulness and craving: Evidence from a cross-cultural validation of the Desire Thinking Questionnaire. AB - Desire thinking and mindfulness have been associated with craving. The aim of the present study was to validate the French version of the Desire Thinking Questionnaire (DTQ) and to investigate the relationship between mindfulness, desire thinking and craving among a sample of university students. Four hundred and ninety six university students completed the DTQ and measures of mindfulness, craving and alcohol use. Results from confirmatory factor analyses showed that the two-factor structure proposed in the original DTQ exhibited suitable goodness of-fit statistics. The DTQ also demonstrated good internal reliability, temporal stability and predictive validity. A set of linear regressions revealed that desire thinking had a confounding effect in the relationship between mindfulness and craving. The confounding role of desire thinking in the relationship between mindfulness and craving suggests that interrupting desire thinking may be a viable clinical option aimed at reducing craving. PMID- 28645080 TI - Relationships between patients' attachment characteristics and views and use of psychiatric treatment. AB - This study explored the influence of attachment on psychiatric treatment by considering attitudes towards and the use of psychotropic medication and psychotherapy in patients with depressive and anxiety disorders. Adults referred to a psychiatrist completed self-report measures and participated in a diagnostic interview based on DSM-IV criteria. Those with depressive, anxiety or adjustment disorders were included (n = 124). Patients reported the types and dosage of current psychotropic medication as well as number of different psychiatrists and psychologists/counselors they had seen in the past 10 years. Multiple regression analyses were used to examine relationships between attachment anxiety and avoidance and the variables capturing treatment use and attitudes towards treatments. Attachment anxiety was positively associated with the number of current psychiatric medications and with both the number of psychiatrists and the number of psychologists/counselors seen. Attachment avoidance was negatively associated with the number of current psychotropic medications and beliefs about the efficacy of psychotherapy. The findings suggest that patients' attachment characteristics play a role in their views and choices regarding treatments. Developing treatments sensitive to the needs of insecurely attached individuals may lead to improved treatment outcomes. PMID- 28645082 TI - Local populations and inaccuracies: Determining the relevant mitochondrial haplotype distributions for North West European cats. AB - Typing of different portions of the feline mitochondrial control region has illustrated pronounced differences in haplotype distributions between cats from the Netherlands and other parts of the world. To gain a better understanding of the haplotype distribution of North West Continental Europe, 605bp of mitochondrial DNA was typed from randomly selected cats from the Netherlands (N=146), Belgium (N=64) and South West Germany (N=128). The genetic differences between these randomly sampled European populations correlate to the geographical distances, with the Dutch and the South West German populations furthest apart and the Belgian population as an intermediate (Fst values 0.01-0.03). Comparison of North West European mainland distributions to published feline mitochondrial haplotype distributions illustrated moderate to large genetic differentiation (Fst values 0.01-0.32). In this comparison, the correlation between geographical and genetic distance was absent, leading to founder effects and human impact on cat population structure and dispersion being considered as important parameters. When an accurate estimation of feline haplotype distribution is required in forensics, care should be taken when deciding whether extrapolating the frequency data from a certain source to a larger area (country/continent) is justified or whether additional typing of local populations is necessary. This may differ from case to case as local frequencies can be relevant, but can also be deceitful. To improve the applicability of forensic feline mitochondrial DNA studies, documentation and publishing of sampling strategies is advised, as is the implementation of measures to help eliminate potentially erroneous haplotypes. PMID- 28645081 TI - Loudness- and time-dependence of auditory evoked potentials is blunted by the NMDA channel blocker MK-801. AB - Amplitudes of auditory evoked potentials (AEP) increase with the intensity/loudness of sounds (loudness-dependence of AEP, LDAEP), and the time between adjacent sounds (time-dependence of AEP, TDAEP). Both, blunted LDAEP and blunted TDAEP are markers of altered auditory function in schizophrenia (SZ). However, while blunted LDAEP has been attributed to altered serotonergic function, blunted TDAEP has been linked to altered NMDA receptor function. Despite phenomenological similarities of the two effects, no common pharmacological underpinnings have been identified. To test whether LDAEP and TDAEP are both affected by NMDA receptor blockade, two rhesus macaques passively listened to auditory clicks of 5 different intensities presented with stimulus onset asynchronies ranging between 0.2 and 6.4s. 8 AEP components were analyzed, including the N85, the presumed human N1 homolog. LDAEP and TDAEP were estimated as the slopes of AEP amplitude with intensity and the logarithm of stimulus-onset asynchrony, respectively. On different days, AEPs were collected after systemic injection of MK-801 or vehicle. Both TDAEP and LDAEP of the N85 were blunted by the NMDA blocker MK-801 and recapitulate the SZ phenotype. In summary, LDAEP and TDAEP share important pharmacological commonalities that may help identify a common pharmacological intervention to normalize both electrophysiological phenotypes in SZ. PMID- 28645084 TI - Application of the combination index (CI)-isobologram equation to research the toxicological interactions of clothianidin, thiamethoxam, and dinotefuran in honeybee, Apis mellifera. AB - Due to complex pest control scenarios and the needs of agricultural production, different neonicotinoids may be used in certain agricultural applications. Consequently, honeybees may be exposed to these substances through distribution throughout plant tissues via the vascular system through several pathways, such as surface water, the exudates excreted from plants, and air pollution via drift of dust as well as contaminated pollen and nectar. In the current study, the single and combined toxicity of clothianidin, dinotefuran, and thiamethoxam to honeybees was examined after 48 h exposure by the acute oral method and combination index (CI)-isobologram equation. At the 48 h interval, our results showed that 1) the order of toxicities for the single insecticides was ranked as clothianidin > thiamethoxam > dinotefuran and that 2) all binary and ternary combinations showed synergism or additive effect at the effect (fa) 0.5. Therefore, our results not only provided meaningful guidelines in evaluating the safety risk of the mixtures of the three neonicotinoids towards honeybees but also suggested that there is a significant interest in the study of mixture toxicities of neonicotinoids against honeybees because risk assessment of neonicotinoids against honeybees conducted only in individual insecticides may underestimate the realistic toxicity. PMID- 28645083 TI - Graphene oxide nanosheets induce DNA damage and activate the base excision repair (BER) signaling pathway both in vitro and in vivo. AB - Graphene oxide (GO) has widespread concerns in the fields of biological sciences and medical applications. Currently, studies have reported that excessive GO exposure can cause cellular DNA damage through reactive oxygen species (ROS) generation. However, DNA damage mediated response of the base excision repair (BER) pathway due to GO exposure is not elucidated yet. Therefore, we exposed HEK293T cells and zebrafish embryos to different concentrations of GO for 24 h, and transcriptional profiles of BER pathway genes, DNA damage, and cell viability were analyzed both in vitro and in vivo. Moreover, the deformation of HEK293T cells before and after GO exposure was also investigated using atomic force microscopy (AFM) to identify the physical changes occurred in the cells' structure. CCK-8 and Comet assay revealed the significant decrease in cell viability and increase in DNA damage in HEK293T cells at higher GO doses (25 and 50 MUg/mL). Among the investigated genetic markers in HEK293T cells, BER pathway genes (APEX1, OGG1, CREB1, UNG) were significantly up-regulated upon exposure to higher GO dose (50 MUg/mL), however, low exposure concentration (5, 25 MUg/mL) failed to induce significant genetic induction except for CREB1 at 25 MUg/mL. Additionally, the viscosity of HEK293T cells decreased upon GO exposure. In zebrafish, the results of up-regulated gene expressions (apex1, ogg1, polb, creb1) were consistent with those in the HEK293T cells. Taken all together, the exposure to elevated GO concentration could cause DNA damage to HEK293T cells and zebrafish embryos; BER pathway could be proposed as the possible inner response mechanism. PMID- 28645085 TI - Extending the functionality of the slurry ferrihydrite-DGT method: Performance evaluation for the measurement of vanadate, arsenate, antimonate and molybdate in water. AB - The monitoring of oxyanions in waters, presents significant challenges due to their relatively low concentrations, and a characteristically changeable/unstable/reactive geochemistry with high spatial and temporal turnover. This results in a very heterogeneous pattern of mobility and bioavailability, which is difficult to capture reliably and in a cost effective manner. The diffusive gradients in thin-films (DGT) technique is a popular analytical tool for testing water quality, primarily because it provides a time integrated measurement. However, to date, the most widely used DGT configuration for oxyanion sampling, the slurry ferrihydrite binding layer (SF-DGT) has only been fully characterized for phosphate. Confirmatory testing of the functional range of ionic strengths, pH, deployment times and ionic competition effects, that the SF-DGT's operates within has not been carried out, but is addressed in this study for VV, AsV, SbV, and MoVI. In this study SF-DGT SbV measurements functioned over the largest range of conditions (ionic strength, 0.1-500 mM; pH 3.86-9.90), while ionic strengths above 100 and 500 mM were found to be problematic for AsV and MoVI, respectively. Low pH (below 4) caused inferences with VV, conversely AsV and MoVI determination faltered/deviated from predicted responses in pH conditions of ~9. SF-DGT measurements adequately predicted up to weeklong averaged in situ metal oxyanion concentrations in a freshwater river. This study concludes that the SF-DGT configuration is highly suitable for pollution monitoring applications in freshwater systems for key oxyanion species. PMID- 28645086 TI - Toddler exposure to flame retardant chemicals: Magnitude, health concern and potential risk- or protective factors of exposure: Observational studies summarized in a systematic review. AB - Endocrine disrupting flame retardant (FR) chemicals form a human health concern, that is investigated mostly from the perspective of adult- and early life exposure. No overview of studies on toddler exposure and health effects exist. However, toddlerhood is a critical developmental period and toddlers are at increased risk for exposure because of their age-specific behavior. This systematic review encompasses toddler FR exposure studies in three countries, associated health effects and potential environmental, demographic, or behavioral risk- or protective factors for toddler exposure. A systematic literature search in four databases (PubMed, Embase.com, The Cochrane Library (via Wiley) and Web of Science Core collection) resulted in the identification of ten publications representing seven unique studies that measured brominated and/or phosphorylated FRs in toddlers' (8-24 month-old) serum, urine, hand wipes and feces. This review showed that toddlers are exposed to a range of FRs, that thyroid hormone disruption is associated with FR exposure and that factors in the indoor environment, including products such as plastic toys, might increase FR exposure. Considering the limited amount of studies, and the variety of biological matrices, FRs, and risk- and protective factors, this review did not reveal a uniform pattern of toddler exposure across the different cohorts studied. More evidence is necessary and considering the feasibility of invasive sampling in young children, we suggest to emphasize research on non-invasive matrices. PMID- 28645087 TI - EP2 receptor agonist ONO-AE1-259-01 attenuates pentylenetetrazole- and pilocarpine-induced seizures but causes hippocampal neurotoxicity. AB - Epilepsy is a common and devastating neurological disease affecting more than 50 million people worldwide. Accumulating experimental and clinical evidence suggests that inflammatory pathways contribute to the development of seizures in various forms of epilepsy. In this context, while the activation of the PGE2 EP2 receptor causes early neuroprotective and late neurotoxic effects, the role of EP2 receptor in seizures remains unclear. We investigated whether the systemic administration of the highly selective EP2 agonist ONO-AE1-259-01 prevented acute pentylenetetrazole (PTZ)- and pilocarpine-induced seizures. The effect of ONO-AE1 259-01 on cell death in the hippocampal formation of adult male mice seven days after pilocarpine-induced status epilepticus (SE) was also evaluated. ONO-AE1-259 01 (10MUg/kg, s.c.) attenuated PTZ- and pilocarpine-induced seizures, evidenced by the increased latency to seizures, decreased number and duration of seizures episodes and decreased mean amplitude of electrographic seizures. ONO-AE1-259-01 and pilocarpine alone significantly increased the number of pyknotic cells per se in all hippocampal subfields. The EP2 agonist also additively increased pilocarpine-induced pyknosis in the pyramidal cell layer of CA1 but reduced pilocarpine-induced pyknosis in the granule cell layer of the dentate gyrus (DG). Although the systemic administration of ONO-AE1-259-01 caused a significant anticonvulsant effect in our assays, this EP2 agonist caused extensive cell death. These findings limit the likelihood of EP2 receptor agonists being considered as novel potential anticonvulsant drugs. PMID- 28645088 TI - Risk-based screening combined with a PCR-based test for group B streptococci diminishes the use of antibiotics in laboring women. AB - OBJECTIVE: To assess the performance of a polymerase chain reaction - group B streptococci test (PCR-GBS test) - in deciding antibiotic prophylaxis in term laboring women. STUDY DESIGN: In this observational study, we enrolled 902 unselected Danish term pregnant women. During labor, midwives obtained vaginal swabs that were used for both GBS cultures (reference standard) and for the PCR GBS test. Furthermore, we recorded the presence of risk factors for EOGBS (Early Onset Group B Streptococcal disease): (1) Bacteriuria during current pregnancy, (2) Prior infant with EOGBS (3) Temperature above 38.0 degrees C during labor, and (4) Rupture of membranes >=18h. RESULTS: The prevalence of GBS carriers was 12% (104 of 902), the sensitivity of the PCR-GBS test 83% (86 of 104), and the specificity 97% (774 of 798). Among the 108 with one or more EOGBS-risk factors, GBS was present in 23% (25 of 108), the sensitivity 92% (23 of 25), and the specificity 89% (74 of 83). CONCLUSION: In programs that aim to treat all laboring women with vaginal GBS-colonization (12% in the present study) with penicillin, the PCR-GBS will perform well (sensitivity 83% and specificity 97%). In programs aiming to treat only GBS-carriers among those with risk factors of EOGBS, a reduction of penicillin usage by two-thirds from 12% to 4% may be possible. PMID- 28645089 TI - Drug Resistance Mechanism of L10F, L10F/N88S and L90M mutations in CRF01_AE HIV-1 protease: Molecular dynamics simulations and binding free energy calculations. AB - HIV-1 protease plays a crucial role in viral replication and maturation, which makes it one of the most attractive targets for anti-retroviral therapy. The majority of HIV infections in developing countries are due to non-B subtype. Subtype AE is spreading rapidly and infecting huge population worldwide. The mutations in the active site of subtype AE directly impair the interactions with the inhibitor. The non-active site mutations influence the binding of the inhibitor indirectly and their resistance mechanism is not well understood. It is important to design new effective inhibitors that combat drug resistance in subtype AE protease. In this work, we examined the effect of non active site mutations L10F, L10F/N88S and L90M with nelfinavir using molecular dynamics simulation and binding free energy calculations. The simulations suggested that the L10F and L10F/N88S mutants decrease the binding affinity of nelfinavir, whereas the L90M mutant increases the binding affinity. The formation of hydrogen bonds between nelfinavir and Asp30 is crucial for effective binding. The benzamide moiety of nelfinavir shows large positional deviation in L10F and L10F/N88S complexes and the L10F/N88S mutation changes the hydrogen bond between the side chain atoms of 30th residue and the 88th residue. Consequently the hydrogen bond interaction between Asp30 and nelfinavir are destroyed leading to drug resistance. Our present study shed light on the resistance mechanism of the strongly linked mutation L10F/N88S observed experimentally in AE subtype. PMID- 28645090 TI - The impact of tidal and mesoscale eddy advection on the long term dispersion of 99Tc from Sellafield. AB - In the present work, numerical models are used to study the fate of the 99Tc discharges from Sellafield with a specific focus on the role of mesoscale eddy and tidal advection on the transport and dispersion of this radionuclide. Transport estimates are made with an ocean model that resolves a large part of the ocean mesoscale eddy field and also includes tides. Equivalent estimates are also computed with another model in which these processes are either absent or parametrized. Comparison with field observations shows that the coarse-resolution model can reproduce the general features of the observed time-space 99Tc distribution if the diffusivity in its eddy parametrization scheme is suitably chosen. However, the eddy-permitting simulations capture regional details better and show an overall higher prediction skill, with the model predictions agreeing with the observations within a factor of two to four. The importance of tidal advection is investigated by comparing transport in the eddy-permitting model when this is run either with tides included or with tides filtered out. The results point to systematic Lagrangian tidal drift in the Irish Sea and the North Sea that eventually impacts the 99Tc activity concentration levels also far downstream. PMID- 28645091 TI - A survey of natural terrestrial and airborne radionuclides in moss samples from the peninsular Thailand. AB - The aim of this study was to determine the activity concentrations of natural terrestrial radionuclides (238U, 226Ra, 232Th and 40K) and airborne radionuclides (210Pb, 210Pbex and 7Be) in natural terrestrial mosses. The collected moss samples (46) representing 17 species were collected from 17 sampling localities in the National Parks and Wildlife Sanctuaries of Thailand, situated in the mountainous areas between the northern and the southern ends of peninsular Thailand (~7-12 degrees N, 99-102 degrees E). Activity concentrations of radionuclides in the samples were measured using a low background gamma spectrometer. The results revealed non-uniform spatial distributions of all the radionuclides in the study area. Principal component analysis and cluster analysis revealed two distinct origins for the studied radionuclides, and furthermore, the Pearson correlations were strong within 226Ra, 232Th, 238U and 40K as well as within 210Pb and 210Pbex, but there was no significant correlation between these two groups. Also 7Be was uncorrelated to the others, as expected due to different origins of the airborne and terrestrial radionuclides. The radionuclide activities of moss samples varied by moss species, topography, geology, and meteorology of each sampling area. The observed abnormally high concentrations of some radionuclides probably indicate that the concentrations of airborne and terrestrial radionuclides in moss samples were directly related to local geological features of the sampling site, or that high levels of 7Be were most probably linked with topography and regional NE monsoonal winds from mainland China. PMID- 28645092 TI - Examining effectiveness of tailorable computer-assisted therapy programmes for substance misuse: Programme usage and clinical outcomes data from Breaking Free Online. AB - RATIONALE: When evaluating complex, tailorable digital behavioural interventions, additional approaches may be required alongside established methodologies such as randomised controlled trials (RCTs). Research evaluating a computer-assisted therapy (CAT) programme for substance misuse, Breaking Free Online (BFO), is informed by Medical Research Council (MRC) guidance recommending examination of 'mechanisms of action' of individual intervention strategies, which is relevant when evaluating digital interventions with content that may evolve over time. AIMS: To report findings from examination of mechanisms of action of tailoring advice within the BFO programme and outcomes from specific intervention strategies. METHODOLOGY: Analysis of covariance and linear regressions were used to assess intervention completion data, and psychometric and clinical outcomes, for 2311 service users accessing drug and alcohol treatment services across the UK. RESULTS: Tailoring advice provided to users appeared to prompt them to prioritise completion of intervention strategies associated with their areas of highest biopsychosocial impairment. Completion of specific intervention strategies within BFO were associated with specific clinical outcomes, with a dose response also being found. Mechanisms of action analyses revealed the primacy of cognitions, with cognitive restructuring strategies being associated with improvements in mental health, severity of substance dependence, quality of life and global biopsychosocial functioning. CONCLUSIONS: The MRC framework provides an evolved research paradigm within the field of digital behavioural change. By assessing baseline profiles of need, BFO can target the most appropriate clinical content for individual users. Mechanisms of action research can be used to inform modifications to BFO to continually update clinical content and the technology platform. PMID- 28645093 TI - Identification of key outcome measures when using the instrumented timed up and go and/or posturography for fall screening. AB - The Timed Up and Go (TUG) has been commonly used for fall risk assessment. The instrumented Timed Up and Go (iTUG) adds wearable sensors to capture sub movements and may be more sensitive. Posturography assessments have also been used for determining fall risk. This study used stepwise logistic regression models to identify key outcome measures for the iTUG and posturography protocols. The effectiveness of the models containing these measures in differentiating fallers from non-fallers were then compared for each: iTUG total time duration only, iTUG, posturography, and combined iTUG and posturography assessments. One hundred and fifty older adults participated in this study. The iTUG measures were calculated utilizing APDM Inc.'s Mobility Lab software. Traditional and non linear posturography measures were calculated from center of pressure during quiet-standing. The key outcome measures incorporated in the iTUG assessment model (sit-to-stand lean angle and height) resulted in a model sensitivity of 48.1% and max re-scaled R2 value of 0.19. This was a higher sensitivity, indicating better differentiation, compared to the model only including total time duration (outcome of the traditional TUG), which had a sensitivity of 18.2%. When the key outcome measures of the iTUG and the posturography assessments were combined into a single model, the sensitivity was approximately the same as the iTUG model alone. Overall the findings of this study support that the iTUG demonstrates greater sensitivity than the total time duration, but that carrying out both iTUG and posturography does not greatly improve sensitivity when used as a fall risk screening tool. PMID- 28645094 TI - Quality assessment of shoulder plyometric exercises: Examining the relationship to scapular muscle activity. AB - OBJECTIVES: The purpose of the study was to evaluate performance quality of shoulder plyometric exercises, and examine the relationship to scapular muscle activation during an intense exercise bout. DESIGN: Observational study. SETTING: University laboratory. PARTICIPANTS: 32 healthy university students (male/female: 14/18) volunteers. MAIN OUTCOME MEASURES: Subjects performed 10 plyometric exercises. Surface EMG of upper (UT), middle (MT) and lower (LT) trapezius and serratus anterior (SA) was registered. A quality assessment questionnaire was administered at the beginning and end of the exercise bout. Muscle activation at the beginning and end was evaluated by t-test. Mixed repeated measures ANOVA was conducted to test the effects of criterion-quality, time, muscles, exercises, and their interactions. RESULTS: Increased EMG activation was noted in 34/40 cases, (21/40 significant (p < 0.05) changes). Quality assessment revealed a decline in the ability to maintain initial position (43% of subjects), failure to keep a consistent and symmetrical arc of motion (62% of subjects), and performance with trick movements (48% of subjects). Inability to keep a consistent arc of motion was significant in 4 exercises. CONCLUSIONS: The novel questionnaire may aid quality assessment during plyometric exercises. Ability to keep a consistent arc of motion was the most sensitive marker of decline of performance quality. PMID- 28645095 TI - Tooth coronal index and pulp/tooth ratio in dental age estimation on digital panoramic radiographs-A comparative study. AB - BACKGROUND: Assessment of an age of an individual whether living or dead through teeth is one of the most reliable and simple method to calculate age than skeletal remains especially when they are in poor conditions. OBJECTIVES: The study was carried out with aim of (i) to evaluate reliability of dental age assessment through two different methods for adults i.e. tooth coronal index and pulp/tooth ratio using digital panoramic radiographs and (ii) to compare these methods for their accuracy in age determination. MATERIALS AND METHODS: The digital panoramic radiographs of 180 subjects of Chhattisgarh aged 15-70 years were selected for the study. The measurements were performed on the JPEG images of selected panoramic radiographs by using Adobe Acrobat 7.0 professional software. For tooth coronal index (TCI), height of the crown i.e. coronal height (CH) and the height of the coronal pulp cavity i.e. coronal pulp cavity height (CPCH) of mandibular second premolars and first molars was measured in millimeter (mm) and then TCI was calculated for each tooth and calculated age was compared with chronological age. For pulp/tooth ratio, the measurements of pulp chamber height (PCH) and crown root trunk height (CRTH) were performed on the mandibular first and second molar teeth, the pulp chamber crown root trunk height ratios (PCTHR) of selected tooth were calculated. The acquired data were subjected to Pearson correlation test, unpaired t test and Analysis of Variance (ANOVA) analysis. RESULTS: Results suggested that TCI (mandibular first molar r=-0.178), second premolar (r=-0.187) and PCTHR(mandibular first molar r=-0.921, second molar r=-0.901) correlated negatively with chronological age suggesting decrease in size of pulp cavity. Mandibular first molar was found to be most reliable tooth to estimate dental age. CONCLUSION: The study showed that both PCTHR and TCI have negative association with chronological age. PCTHR showed slightly higher negative correlation and proved as a better tool for age estimation than TCI. Statistically significant differences were observed between chronological and calculated age by both methods thus emphasizing the need for future clinical trials. PMID- 28645096 TI - Incidental focal uptake in the breast and axilla on FDG PET: Clinical considerations and differential diagnosis. AB - Incidental focal FDG uptake in the breast or axilla on PET/CT performed for evaluation of extra-mammary primary disease presents a diagnostic challenge. Radiologists must consider a broad differential diagnosis, assess clinical history, and judiciously employ other imaging modalities such as mammography, ultrasound and MRI in the pursuit of findings which help narrow the differential diagnosis. Tissue sampling may be reserved for nondiagnostic imaging scenarios. PMID- 28645097 TI - Raman spectroscopy differentiates between sensitive and resistant multiple myeloma cell lines. AB - Current methods for identifying neoplastic cells and discerning them from their normal counterparts are often nonspecific and biologically perturbing. Here, we show that single-cell micro-Raman spectroscopy can be used to discriminate between resistant and sensitive multiple myeloma cell lines based on their highly reproducible biomolecular spectral signatures. In order to demonstrate robustness of the proposed approach, we used two different cell lines of multiple myeloma, namely MM.1S and U266B1, and their counterparts MM.1R and U266/BTZ-R subtypes, resistant to dexamethasone and bortezomib, respectively. Then, micro-Raman spectroscopy provides an easily accurate and noninvasive method for cancer detection for both research and clinical environments. Characteristic peaks, mostly due to different DNA/RNA ratio, nucleic acids, lipids and protein concentrations, allow for discerning the sensitive and resistant subtypes. We also explored principal component analysis (PCA) for resistant cell identification and classification. Sensitive and resistant cells form distinct clusters that can be defined using just two principal components. The identification of drug-resistant cells by confocal micro-Raman spectroscopy is thus proposed as a clinical tool to assess the development of resistance to glucocorticoids and proteasome inhibitors in myeloma cells. PMID- 28645099 TI - Harnessing the natural diversity and in vitro evolution of Cas9 to expand the genome editing toolbox. AB - In the past few years, the Cas9 endonuclease from the type II CRISPR-Cas bacterial antiviral defense system has revolutionized the genome editing field. Guided by an RNA molecule, Cas9 can be reprogrammed to target almost any DNA sequence: the only limitation being the short nucleotide sequence in the vicinity of the target, termed the PAM, which is characteristic for each Cas9 protein. Streptococcus pyogenes Cas9 which recognizes the NGG PAM is currently most widely used for genome manipulation. However, Cas9 orthologues and engineered Cas9 variants offer expanded genome targeting capabilities, improved specificity and biochemical properties. PMID- 28645098 TI - The behavioral economics of social anxiety disorder reveal a robust effect for interpersonal traits. AB - Recent evidence suggests that reduced generosity among individuals with social anxiety disorder (SAD) in behavioral economic tasks may result from constraint in changing behavior according to interpersonal contingencies. That is, people with SAD may be slower to be more generous when the situation warrants. Conversely, more global effects on generosity may be related to interpersonal vindictiveness, a dimension only somewhat related to SAD. A total of 133 participants, 73 with the generalized form of SAD, completed self-report instruments and a behavioral economic task with simulated interpersonal (friend, romantic partner, stranger) interactions. In a separate visit, friends (n = 88) also came to the lab and rated participants on vindictiveness. Interpersonal vindictiveness was associated with reduced initial and overall giving to simulated friends. SAD predicted a lack of increased giving to a simulated friend, and attenuated an increase in giving to simulated known versus unknown players compared to participants without SAD. Friend-reported vindictiveness predicted in the same direction as diagnosis. However, the findings for SAD were less robust than those for vindictiveness. SAD is perhaps weakly related to behavioral constraint in economic tasks that simulate interpersonal interactions, whereas vindictiveness is strongly related to lower overall generosity as well as (via friend report) behavioral constraint. Further study is needed to better characterize the construct of vindictiveness. Our findings dovetail with the suggestion that SAD is related to impairment in the proposed affiliation and attachment system, but further suggest that direct study of that system may be more fruitful than focusing on disorders. PMID- 28645100 TI - Interferential effect of the over-erupted third molar on chewing movement. AB - OBJECTIVE: To clarify whether over-eruption of the mandibular third molar can disturb chewing movement. METHODS: Eighteen patients with a unilateral mandibular over-erupted third molar confirmed by both study cast observation and T-scan occlusal detection were selected from a sample of patients with complaints of temporomandibular disorder (TMD) symptoms. A unilateral gum-chewing trace was recorded separately for left and right side chewing by an electrognathography system. The average chewing pattern (ACP) was created based on segments from the recorded chewing trace to represent the chewing movement characteristics of each individual. Two factors, the TMD symptomatic side and the over-eruption side, were analysed for their effects on values of difference in the parameters (Deltavalue) regarding the ACP between chewing with right and left side. Three dimensional amplitudes of ACP and the cross point value of ACP with the vertical axis (termed the cross zero point value) which described the turning point of the chewing cycle from the balancing side to the working side, were compared between sides. RESULTS: The over-eruption side had an effect on the Deltavalue of the medial amplitude, the lateral amplitude, and the cross zero point (P<0.05), but the symptomatic side didn't (P>0.05). When chewing on the over-eruption side, the medial amplitude was shorter, the lateral amplitude was larger, and the cross zero point value was smaller than those when chewing on the other side (P<0.05). CONCLUSION: The present data indicate an effect of the over-erupted mandibular third molar on the chewing pattern while that from the symptom(s) is limited. PMID- 28645101 TI - Co-localization of endogenous Arf6 and its activator EFA6D in the granular convoluted tubule cells of mouse submandibular glands under normal conditions and when stimulated by isoproterenol, noradrenaline and carbachol. AB - OBJECTIVE: This study proposed to investigate the localization at light and electron microscopic levels of Arf6 and its activator EFA6D in the mouse submandibular gland (SMG) under normal conditions and when stimulated by adrenergic or cholinergic agonists. MATERIALS AND METHODS: SMGs of male adult mice were utilized for immunoblotting and immuno-light and -electron microscopic analyses. Isoproterenol and noradrenalin were used as adrenergics, while carbachol was used for the cholinergic stimulant. SMGs were examined at 15, 30, 60 and 120min after intraperitoneal injection of these agents. RESULTS: Immunoreactivities for both Arf6 and its activator EFA6D were similarly intense in the basolateral domain of GCTs, but no significant immunoreactivities were seen in the apical domain of GCT cells or any domain of acinar cells under normal conditions. In immuno-electron microscopy, the immunoreactive materials were mainly deposited on the basolateral plasma membranes and subjacent cytoplasm. Shortly after injection of isoproterenol and noradrenaline, but not carbachol, the immunoreactivities for both molecules were additionally seen on the apical plasmalemma of most, if not all, GCT cells, but not acinar cells. CONCLUSION: The present findings suggest that the direct involvement of Arf6/EFA6D in regulatory exocytosis at the apical plasma membrane of acinar and GCT cells is apparently to be smaller, if present, than that of endocytosis at the basolateral membranes of GCT cells under normal conditions. This also suggests that the two molecules function additionally at the apical membrane of GCT cells for modulation of saliva secretion under beta-adrenoceptor stimulation. PMID- 28645102 TI - Expression of p63 and CD44 in oral squamous cell carcinoma and correlation with clinicopathological parameters. AB - Squamous cell carcinoma (SCC) is the sixth most frequent malignant tumor of the head and neck region. Despite advances in therapeutic options over the last decades, the rate of mortality and morbidity has not been improved markedly. A small subset of cells, cancer stem cells (CSCs), with self-renewal properties have become a major focus of current cancer research. CD44 and p63 are identified as candidate stem cell markers in normal squamous epithelium and SCC. The role of these markers in oral squamous cell carcinoma (OSCC) is still debatable. The aim of this study was to evaluate immunohistochemical expression of these markers in OSCC samples and also correlates the expression of these markers with some clinicopathological parameters of prognostic significance including histological grading, TNM staging, overall survival (OS) rate as well as patients' age, gender, and tumor location. CD44 and p63 were expressed in all studied lesions with different degrees. Statistically significant difference was observed between CD44 and p63 expression with tumor grade and stage with higher expression in high grade and advanced OSCCs. No significant relationship was detected between markers immunoreactivity and patients age, gender, tumor location as well as OS. These markers can possibly advance our understanding of the initiating mechanisms and pathogenesis of OSCC and also result in novel therapeutic target in cancer treatment. PMID- 28645120 TI - Acute Abdomen Secondary to Ruptured Epithelial Ovarian Cancer during Pregnancy: The Relevance of Teamwork. AB - Acute abdomen secondary to epithelial ovarian cancer rupture during pregnancy is a rare event. Our aim is to present how the work of a coordinated multidisciplinary team in a case of ruptured epithelial ovarian cancer during pregnancy is feasible to obtain the best results possible. A 34-year-old woman during the 37th week of her first gestation presented with an acute abdomen. During laparotomy, a ruptured 16.5-cm left ovarian tumor was detected; the tumor was extirpated and sent to pathologic evaluation. In the meantime, a Kerr cesarean section was performed, and a healthy female neonate was born. The tumor was diagnosed as a cystadenocarcinoma; therefore, the family and the combined surgical team (obstetricians and a surgical oncologist) decided to complete a definitive radical ovarian cancer surgery: hysterectomy, right salpingo oophorectomy, lymphadenectomy, omentectomy and appendectomy. The patient's postoperative evolution was uneventful, and she was sent to adjuvant chemotherapy. PMID- 28645121 TI - Effect of Obesity on Gestational and Perinatal Outcomes. AB - Purpose To assess the impact of pre-pregnancy obesity (body mass index [BMI] >= 30 kg/m2) on the gestational and perinatal outcomes. Methods Retrospective cohort study of 731 pregnant women with a BMI >= 30 kg/m2 at the first prenatal care visit, comparing them with 3,161 women with a BMI between 18.5 kg/m2 and 24.9 kg/m2. Maternal and neonatal variables were assessed. Statistical analyses reporting the demographic features of the pregnant women (obese and normal) were performed with descriptive statistics followed by two-sided independent Student's t tests for the continuous variables, and the chi-squared (chi2) test, or Fisher's exact test, for the categorical variables. We performed a multiple linear regression analysis of newborn body weight based on the mother's BMI, adjusted by maternal age, hyperglycemic disorders, hypertensive disorders, and cesarean deliveries to analyze the relationships among these variables. All analyses were performed with the R (R Foundation for Statistical Computing, Vienna, Austria) for Windows software, version 3.1.0. A value of p < 0.05 was considered statistically significant. Results Obesity was associated with older age [OR 9.8 (7.8-12.2); p < 0.01], hyperglycemic disorders [OR 6.5 (4.8-8.9); p < 0.01], hypertensive disorders [OR 7.6 (6.1-9.5); p < 0.01], caesarean deliveries [OR 2.5 (2.1-3.0); p < 0.01], fetal macrosomia [OR 2.9 (2.3-3.6); p < 0.01] and umbilical cord pH [OR 2.1 (1.4-2.9); p < 0.01). Conversely, no association was observed with the duration of labor, bleeding during labor, Apgar scores at 1 and 5 minutes after birth, gestational age, stillbirth and early neonatal mortality, congenital malformations, and maternal and fetal injury. Conclusion We observed that pre-pregnancy obesity was associated with maternal age, hyperglycemic disorders, hypertension syndrome, cesarean deliveries, fetal macrosomia, and fetal acidosis. PMID- 28645122 TI - Survey on Aesthetic Vulvovaginal Procedures: What do Portuguese Doctors and Medical Students Think? AB - Objective To assess the medical doctors and medical students' opinion regarding the evidence and ethical background of the performance of vulvovaginal aesthetic procedures (VVAPs). Methods Cross-sectional online survey among 664 Portuguese medical doctors and students. Results Most participants considered that there is never or there rarely is a medical reason to perform: vulvar whitening (85.9% [502/584]); hymenoplasty (72.0% [437/607]); mons pubis liposuction (71.6% [426/595]); "G-spot" augmentation (71.0% [409/576]); labia majora augmentation (66.3% [390/588]); labia minora augmentation (58.3% [326/559]); or laser vaginal tightening (52.3% [313/599]). Gynecologists and specialists were more likely to consider that there are no medical reasons to perform VVAPs; the opposite was true for plastic surgeons and students/residents.Hymenoplasty raised ethical doubts in 51.1% (283/554) of the participants. Plastic surgeons and students/residents were less likely to raise ethical objections, while the opposite was true for gynecologists and specialists.Most considered that VVAPs could contribute to an improvement in self-esteem (92.3% [613/664]); sexual function (78.5% [521/664]); vaginal atrophy (69.9% [464/664]); quality of life (66.3% [440/664]); and sexual pain (61.4% [408/664]). Conclusions While medical doctors and students acknowledge the lack of evidence and scientific support for the performance of VVAPs, most do not raise ethical objections about them, especially if they are students or plastic surgeons, or if they have had or have considered having plastic surgery. PMID- 28645123 TI - [Drug safety in psychiatry]. PMID- 28645124 TI - [Paralytic ileus with fatal consequence under psychotropic medication]. AB - In the area of Bielefeld there occurred a striking accumulation of four cases of death as a consequence of a paralytic ileus within a period of two years. All four patients suffered from a psychotic disorder and had taken psychotropic medication for many years. After exclusion of other causes, the anticholinergic effect of the psychotropic medication must be taken as the cause of death. A review of literature and pharmacological receptor profiles are presented. Therapeutic consequences are described in order to prevent more cases of death. PMID- 28645125 TI - [Epidemiology of Parkinson's Disease and Current Concepts of Outpatient Care in Germany]. AB - The ambulatory care of patients with Parkinson's disease (PD) in Germany has been established for a long time. As the prevalence of Parkinson's disease continues to increase, the outpatient neurological sector is becoming more and more important and needs to adapt itself to current needs. This includes an optimization of the care structures for Parkinson's patients as well as adequate concepts for the execution of differentiated diagnostics and therapy. For many patients care is provided by non-specialized neurological practices or general practitioners, without exchange of views with neurologists or a specialized university outpatient clinic for movement disorders. A connective link between these care structures could be provided by a "practice with focus on Parkinson's disease", whose idea and conception is presented in this article. In addition to the necessity and usefulness of such an institution, structural prerequisites and basic principles for the treatment of Parkinsonian patients in a disease state centered manner will be presented but also current limitations of the concept are pointed out. This article presents the results of an expert workshop on Parkinson's disease, which took place in Frankfurt am Main on 21 November 2015. PMID- 28645126 TI - [ADHD in Adults and Comorbid Substance Use Disorder: Prevalence, Clinical Diagnostics and Integrated Therapy]. AB - Substance use disorders (SUD) are one of the most frequent mental disorders among adults. Attention-Deficit/Hyperactivity-Disorder (ADHD) is one of the most common mental health issues in childhood and adolescence, often persisting in adulthood. ADHD in childhood and adolescence is a robust predictor of tobacco, alcohol and illicit substance use in adulthood. Prevalence of comorbid ADHD in SUD patients is high. Nearly one quarter of these patients fulfill the DSM IV criteria for ADHD. Integrated concepts for treatment of SUD and ADHD are needed, but rare up to now. The aim of this review is to present and discuss recent scientific literature on the topic SUD and ADHD among adults and show its implications for clinical diagnostics and treatment. PMID- 28645127 TI - [High Prevalence of Antipsychotic Medication Use in Dementia Patients in German Neuropsychiatric Practices]. AB - Background The aim of the present study was to examine inpatients as well as patients living at home with respect to the frequency of antipsychotic medication use and to determine the factors leading to initial use of antipsychotics following dementia diagnosis. Methods This study included patients aged 60 years and over with an initial diagnosis of all-cause dementia (index date) by German psychiatrists in Disease Analyzer database (IMS Health). The main outcome measure was the proportion of patients who initially received an antipsychotic prescription after the index date. Kaplan-Meier analyses were performed for studying time to initiation of antipsychotic therapy as a function of age and residence in nursing homes. A Cox proportional hazards regression model was used to estimate the relation between the likelihood of therapy initiation and the predefined demographical/clinical variables. Results 14 915 patients with dementia (mean age 80.3 years, 34.7 % male, 53.3 % residents of nursing homes) were included in this study. Within two years after the index date, 47.7 % patients with dementia were treated with antipsychotics. Residing in nursing homes, private insurance status, higher age, private health insurance, exhibiting mental disorders due to known physiological condition, personality and behavioral disorders due to known physiological condition, vascular dementia, and symptoms and signs involving emotional state were positively associated with therapy initiation. Conclusion The prevalence of antipsychotic drug therapy in dementia patients, particularly in nursing homes, is very high. Further studies including qualitative research are required in order to understand and explain the reasons for this prescribing behavior. PMID- 28645128 TI - [Headache News]. AB - A review of the latest and most relevant information on different disorders of head and facial pain is presented. News from epidemiologic studies regarding the relationship between migraine and patent foramen ovale, the cardiovascular risk in migraine, and migraine behavior during menopause, and the development of white matter lesions or migraine genetics are presented. Regarding pathophysiology there are very recent insights regarding the role of the hypothalamus during prodromal phase and the interplay of brain-stem and hypothalamus during the attack. In the last year studies and metaanalysis generated new knowledge for the use of triptans in general as in menstrual related migraine and hemiplegic variants. Furthermore, new hope rises for the CGRP (calcitonin-gene related peptide)-antagonists, as the data for ubrogepant do not suggest hepatotoxicity but efficacy. In prophylactic migraine treatment the news are manly on how the new therapeutic approach with monoclonal antibodies against CGRP or its receptor is moving on. Additional newly generated data for already known prophylactic agents as for new approaches are compactly discussed. Although main developments in headache focus on migraine new data on trigemino-autonomic headache trigeminal neuralgia and new daily persistant headache became available. PMID- 28645129 TI - Clinical Scoring Systems in Thrombosis and Hemostasis. PMID- 28645131 TI - Osteochondral Autologous Transplantation Compared to Microfracture for Treating Osteochondral Defect: An Updated Meta-analysis of Randomized Controlled Trials. AB - Various techniques have proven to be effective for treating articular cartilage defect of the knee joint, but knowledge regarding which method is best still remains uncertain. Osteochondral autologous transplantation (OAT) provides hyaline or hyaline-like repair for articular defects, whereas microfracture (MF) provides fibrocartilage repair tissue. To compare the OAT with MF procedure for the treatment of articular cartilage defect, we present an update of previous meta-analysis of randomized controlled trials.We searched for the published results of relevant trials. Then, we pooled the outcome measures of the included trials for analysis. The outcome measures assessed in this study included the number of patients who reached excellent or good results, the patients returning to the activity, the International Cartilage Repair Society (ICRS) scores, the failure rate, and the osteoarthritis rate. Six studies and 294 patients were identified as eligible for data extraction and meta-analysis. The pooled result showed that there was no significant difference in the excellent or good results (relative risks [RRs], 1.27; 95% confidence intervals [CIs], 0.95 to 1.70; p = 0.11) and the rate of osteoarthritis (RRs, 0.64; 95% CIs, 0.37 to 1.13; p = 0.12). There were significant differences between the two groups in the scores of ICRS (mean differences [MDs], 12.51; 95% CIs, 10.55 to 14.47; p = 0.00001), the patients returning to activity (RRs, 2.04; 95% CIs, 1.36 to 3.07; p = 0.0006), and in the failure rate (RRs, 0.23; 95% CIs, 0.11 to 0.49; p = 0.0001). OAT has more advantages compared with MF procedure in referring to the index of return to activity, the scores of ICRS, and the rate of failure. However, the limitations restrict the generalizability of this study, and larger, sufficiently powered studies are necessary to evaluate the efficiency of OAT compared with MF procedure in the future. PMID- 28645130 TI - Sustained Release of Transforming Growth Factor-beta1 from Platelet-Rich Chondroitin Sulfate Glycosaminoglycan Gels. AB - Activated platelet-rich plasma (PRP), also referred to as platelet-rich fibrin (PRF), has been used to augment numerous techniques of cartilage repair in the knee but does not always result in superior quality of repair tissue. One possible reason that PRF does not consistently result in excellent cartilage regeneration is the transiency of growth factor provision with PRF. The objective of this study was to compare the release of transforming growth factor (TGF) beta1 from PRF and from PRP combined with a novel chondroitin sulfate glycosaminoglycan (CS-GAG) gel. PRP was prepared from nine healthy dogs and split into two aliquots: one activated with bovine thrombin and calcium chloride (CaCl2) to form PRF and the other aliquot was used to rehydrate a lyophilized CS GAG gel. Both PRF and the CS-GAG gels were incubated in media for 13 days and media were collected, stored, and replaced every 48 hours and the concentration of TGF-beta1 quantified in the media using an enzyme-linked immunosorbent assay. Concentrations of TGF-beta1 in the media were up to three times greater with the CS-GAG gels and were significantly (p < 0.05) greater than with PRF on days 3, 5, 7, 9, and 13. Furthermore, TGF-beta1 elution was still substantial at day 13 with the use of the CS-GAG gels. Additional in vitro work is warranted to characterize TGF-beta1 elution from this CS-GAG gel with human PRP and to determine whether the use of these CS-GAG gels can augment cartilage repair in vivo. PMID- 28645132 TI - Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis: A Review. PMID- 28645133 TI - [New Aspects in Treatment of Metastatic Prostate Cancer]. PMID- 28645135 TI - Osteotomies around the Knee-Part I. PMID- 28645134 TI - [Arterial Hyper- and Hypotension associated with psychiatric medications: a risk assessment based on the summaries of product characteristics (SmPCs)]. AB - Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure. Results According to the SmPCs, atomoxetine had the highest risk of arterial hypertension ("very frequent", > 10 %), and another 15 substances followed in the category "frequent" (> 1 %): duloxetine, milnacipran, venlafaxine, bupropion, citalopram, tranylcypromine (particularly with certain diets), reboxetine, methylphenidate, clozapine, paliperidone, risperidone, buprenorphine+naloxone, memantine, galantamine, and rivastigmine. Conversely, 7 substances, namely amitriptyline, tranylcypromine, chlorprothixen, flupentixol, levomepromazine, olanzapine and trimipramine had the highest reported risk of low blood pressure ("very frequent"), and another 25 substances had the risk "frequent". No risk of hypertension or hypotension was documented for many other substances. Incidentally, we observed that the reported effects on blood pressure for single substances (e. g. citalopram) markedly differed between the SmPCs from different manufacturers, rendering a clear risk assessment impossible for many medications. Discussion According to the German SmPc, many psychiatric medications are associated with the risk of arterial hypertension and, even more so, hypotension. We hardly observed substance group effects, such as high blood pressure with noradrenergic antidepressants. Commonly used tables summarising secondary causes of arterial hypertension should be revised in terms of psychiatric medications. Our rank orders of risk may aid choosing the best psychiatric medications in patients with known hypertension or at risk for syncope, as well as when blood pressure changes occur under psychiatric pharmacotherapy. A definitive risk assessment however requires controlled studies. PMID- 28645136 TI - Childhood traumatic experiences and the association with marijuana and cocaine use in adolescence through adulthood. AB - BACKGROUND AND AIMS: Examination of longitudinal relationships between childhood traumatic experiences and drug use across the life-course at the national level, with control of confounding by other forms of trauma, is needed. We aimed to estimate the prevalence of nine typologies of childhood traumas and the cumulative number experienced, correlation between traumas and associations between individual and cumulative number of traumas with drug use during adolescence, emerging adulthood and adulthood. DESIGN: Secondary data analysis using the National Longitudinal Study of Adolescent to Adult Health. SETTING: United States. PARTICIPANTS: A nationally representative sample of individuals in grades 7-12 (aged 11-21 years) during 1994-95, who were re-interviewed during emerging adulthood (2001-02; aged 18-28) and adulthood (2007-08; aged 24-34). The analytical sample comprised 12 288 participants with data at all three waves. MEASUREMENTS: Nine typologies of childhood traumas: neglect; emotional, physical and sexual abuse; parental incarceration and binge drinking; and witnessing, being threatened with and experiencing violence. Indicators of each were summed to measure cumulative dose. Outcomes were marijuana and cocaine use during adolescence, emerging adulthood and adulthood. FINDINGS: Approximately half experienced at least one childhood trauma; traumas were not highly correlated. We observed a dose-response relationship between the number of traumas and drug use in adolescence [marijuana, adjusted odds ratio (aOR) one trauma versus none = 1.65, 95% confidence interval (CI) = 1.42, 1.92; two traumas = 2.58, 95% CI = 2.17, 3.06; >= four traumas = 6.92, 95% CI = 5.17, 9.26; cocaine, aOR one trauma = 1.87, 95% CI = 1.23, 2.84; two traumas = 2.80, 95% CI = 1.74, 4.51; >= four traumas = 9.54, 95% CI = 5.93, 15.38]. Similar dose-response relationships with drug use were observed in emerging adulthood and adulthood. Each individual trauma was associated independently with either marijuana or cocaine use in adolescence, emerging adulthood and/or adulthood. CONCLUSIONS: Childhood trauma is prevalent in the United States, and individual types as well as the total number experienced are associated significantly with marijuana and cocaine use throughout the life-course. PMID- 28645137 TI - To take or not to take: the association between perceived addiction risk, expected analgesic response and likelihood of trying novel pain relievers in self identified chronic pain patients. AB - BACKGROUND AND AIMS: Probability discounting refers to the effect of outcome uncertainty on decision making. Using probability discounting, we examined the degree to which self-identified chronic pain patients (CPP) were likely to try a novel analgesic medication given increasing addiction risk. We postulated that propensity for opioid misuse, trait impulsivity and previous opioid experience would be associated positively with likelihood of risky medication use. DESIGN: This cross-sectional on-line study determined state/trait associations with addiction-related medication decisions in CPP. SETTING: US-based CPP participated via Amazon Mechanical Turk; data were collected and analyzed in Baltimore, Maryland. PARTICIPANTS: A total of 263 CPP (70.6% female) participated in the study from 12-13 December 2014. MEASUREMENTS: CPP responded to the Benefit versus Addiction Risk Questionnaire (BARQ) assessing likelihood of taking a hypothetical once-daily oral analgesic medication as a function of two factors: risk of addiction (0-50%) and duration of expected complete pain relief (3, 30 or 365 days). The primary outcome was the BARQ, quantified as area under the curve (AUC). Grouping of CPP at high or low risk for opioid misuse was based on the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Predictors included previous experience with opioids, as well as various measures of chronic pain and mental health. FINDINGS: Across hypothetical addiction risk assessed in the BARQ, the likelihood of taking a novel analgesic medication was elevated significantly in patients with high (>=18; n = 137) versus low (<18; n = 126) SOAPP-R scores [P < 0.001; 3-day: Cohen's d = 0.66, 95% confidence interval (CI) = 0.63, 0.69; 30-day: d = 0.74, 95% CI = 0.71, 0.78; 365-day: d = 0.75, 95% CI = 0.72, 0.79]. CONCLUSIONS: In the United States, self-identified chronic pain patients (CPP) at higher risk for opioid misuse were more likely to report willingness to try a novel analgesic despite increasing addiction risk than CPP with low risk of opioid misuse. PMID- 28645138 TI - Correction: Tumor growth suppressive effect of IL-4 through p21-mediated activation of STAT6 in IL-4Ralpha overexpressed melanoma models. PMID- 28645139 TI - Correction: CCR4 promotes metastasis via ERK/NF-kappaB/MMP13 pathway and acts downstream of TNF-alpha in colorectal cancer. PMID- 28645140 TI - Ruptured oesophageal haematoma caused by transoesophageal echocardiography. PMID- 28645141 TI - Does the seed bank contribute to the build-up of a genetic extinction debt in the grassland perennial Campanula rotundifolia? AB - Background and Aims: Habitat fragmentation threatens global biodiversity. Many plant species persist in habitat fragments via persistent life cycle stages such as seed banks, generating a species extinction debt. Here, seed banks are hypothesized to cause a temporal delay in the expected loss of genetic variation, which can be referred to as a genetic extinction debt, as a possible mechanism behind species extinction debts. Methods: Fragmented grassland populations of Campanula rotundifolia were examined for evidence of a genetic extinction debt, investigating if the seed bank contributed to the extinction debt build-up. The genetic make-up of 15 above- and below-ground populations was analysed in relation to historical and current levels of habitat fragmentation, both separately and combined. Key Results: Genetic diversity was highest in above ground populations, though below-ground populations contained 8 % of unique alleles that were absent above-ground. Above-ground genetic diversity and composition were related to historical patch size and connectivity, but not current patch characteristics, suggesting the presence of a genetic extinction debt in the above-ground populations. No such relationships were found for the below-ground populations. Genetic diversity measures still showed a response to historical but not present landscape characteristics when combining genetic diversity of the above- and below-ground populations. Conclusions: The fragmented C. rotundifolia populations exhibited a genetic extinction debt. However, the role of the seed banks in the build-up of this extinction debt is probably small, since the limited, unique genetic diversity of the seed bank alone seems unable to counter the detrimental effects of habitat fragmentation on the population genetic structure of C. rotundifolia. PMID- 28645143 TI - Fermentable Carbohydrates in IBD - Trouble Brewing? PMID- 28645142 TI - Polyphyly of Arundinoideae (Poaceae) and evolution of the twisted geniculate lemma awn. AB - Background and Aims: Subfamily Arundinoideae represents one of the last unsolved taxonomic mysteries in the grass family (Poaceae) due to the narrow and remote distributions of many of its 19 morphologically and ecologically heterogeneous genera. Resolving the phylogenetic relationships of these genera could have substantial implications for understanding character evolution in the grasses, for example the twisted geniculate awn - a hygroscopic awn that has been shown to be important in seed germination for some grass species. In this study, the phylogenetic positions of most arundinoid genera were determined using DNA from herbarium specimens, and their placement affects interpretation of this ecologically important trait. Methods: A phylogenetic analysis was conducted on a matrix of full-plastome sequences from 123 species in 107 genera representing all grass subfamilies, with 15 of the 19 genera in subfamily Arundinoideae. Parsimony and maximum likelihood mapping approaches were used to estimate ancestral states for presence of a geniculate lemma awn with a twisted column across Poaceae. Lastly, anatomical characters were examined for former arundinoid taxa using light microscopy and scanning electron microscopy. Key Results: Four genera traditionally included in Arundinoideae fell outside the subfamily in the plastome phylogeny, with the remaining 11 genera forming Arundinoideae sensu stricto . The twisted geniculate awn has originated independently at least five times in the PACMAD grasses, in the subfamilies Panicoideae, Danthonioideae/Chloridoideae and Arundinoideae. Morphological and anatomical characters support the new positions of the misplaced arundinoid genera in the phylogeny, but also highlight convergent and parallel evolution in the grasses. Conclusions: In placing the majority of arundinoid genera in a phylogenetic framework, our study answers one of the last remaining big questions in grass taxonomy while highlighting examples of convergent evolution in an ecologically important trait, the hygroscopic, twisted geniculate awn. PMID- 28645145 TI - Systematic procedures to promote U.S. HIV medication adherence via Photovoice. AB - Medication adherence is essential to promote the health of people living with HIV (PL-HIV) and prevent HIV transmission in the U.S. Novel medication health promotion interventions are needed that address patient-centeredness, understandability, and communication with providers. The aims of this article are to define the systematic stages we used to develop an effective health promotion intervention via the products (e.g. images and stories) of Photovoice. We designed an intervention to improve HIV adherence knowledge, attitudes, and communication with providers through Photovoice. 16 PL-HIV used Photovoice strategies to describe their experiences with medication via images and captions and create an intervention (10 adherence promotion posters) that integrated photo stories of their adherence motivators, journeys from sickness to health, and how they manage and counter HIV stigma. We outline the systematic process we used to adapt Photovoice to create the effective intervention for replication. The process included six stages: (i) identify scope of the project; (ii) create collaborative project team; (iii) design project materials; (iv) review and revise materials with team members; (v) disseminate materials; and (vi) evaluate materials. Photovoice is used traditionally as a social action research method. In this project, it was adapted to create patient-driven images and stories for health promotion posters. Poster viewers experienced improved self-efficacy for HIV medication adherence. Describing the adaptation of the Photovoice process in a deliberate and transparent way can support fidelity to the essence of the participant-driven method, while also allowing researchers and practitioners to replicate Photovoice as a successful health promotion intervention. PMID- 28645144 TI - Increased alignment sensitivity improves the usage of genome alignments for comparative gene annotation. AB - Genome alignments provide a powerful basis to transfer gene annotations from a well-annotated reference genome to many other aligned genomes. The completeness of these annotations crucially depends on the sensitivity of the underlying genome alignment. Here, we investigated the impact of the genome alignment parameters and found that parameters with a higher sensitivity allow the detection of thousands of novel alignments between orthologous exons that have been missed before. In particular, comparisons between species separated by an evolutionary distance of >0.75 substitutions per neutral site, like human and other non-placental vertebrates, benefit from increased sensitivity. To systematically test if increased sensitivity improves comparative gene annotations, we built a multiple alignment of 144 vertebrate genomes and used this alignment to map human genes to the other 143 vertebrates with CESAR. We found that higher alignment sensitivity substantially improves the completeness of comparative gene annotations by adding on average 2382 and 7440 novel exons and 117 and 317 novel genes for mammalian and non-mammalian species, respectively. Our results suggest a more sensitive alignment strategy that should generally be used for genome alignments between distantly-related species. Our 144-vertebrate genome alignment and the comparative gene annotations (https://bds.mpi-cbg.de/hillerlab/144VertebrateAlignment_CESAR/) are a valuable resource for comparative genomics. PMID- 28645147 TI - Corrigendum. PMID- 28645146 TI - Analysis of in vitro evolution reveals the underlying distribution of catalytic activity among random sequences. AB - The emergence of catalytic RNA is believed to have been a key event during the origin of life. Understanding how catalytic activity is distributed across random sequences is fundamental to estimating the probability that catalytic sequences would emerge. Here, we analyze the in vitro evolution of triphosphorylating ribozymes and translate their fitnesses into absolute estimates of catalytic activity for hundreds of ribozyme families. The analysis efficiently identified highly active ribozymes and estimated catalytic activity with good accuracy. The evolutionary dynamics follow Fisher's Fundamental Theorem of Natural Selection and a corollary, permitting retrospective inference of the distribution of fitness and activity in the random sequence pool for the first time. The frequency distribution of rate constants appears to be log-normal, with a surprisingly steep dropoff at higher activity, consistent with a mechanism for the emergence of activity as the product of many independent contributions. PMID- 28645148 TI - A soft environmental control effect of apatite doped with mineral traces in the fowl droppings. AB - Fowl-dropping apatite (Ca10-z[PO4]6-z[OH]2-z) synthesized from carbonized, incinerated fowl droppings contains PO4 and OH groups that are partially substituted by CO32- ions. It shows stronger ion conductivity than commercially available hydroxyapatite in a wide range of temperatures from 23 degrees C to 800 degrees C. Fowl-dropping apatite readily adsorbs NO2 and SO2 gases and, without re-releasing these gases, slowly decomposes them at room temperature under sunlight via ultraviolet-visible (UV-Vis) irradiation. A limited amount of minerals and organics contained in fowl droppings causes light-induced activities in fowl-dropping apatite with a crystal structure that has a developed c face; this initiates excitation-induced atomic transfer on the solid surface derived from PO4 exposed on the c face, which then advances the decomposition reaction. PMID- 28645149 TI - Structural determinants of APOBEC3B non-catalytic domain for molecular assembly and catalytic regulation. PMID- 28645150 TI - GfaPy: a flexible and extensible software library for handling sequence graphs in Python. AB - Summary: GFA 1 and GFA 2 are recently defined formats for representing sequence graphs, such as assembly, variation or splicing graphs. The formats are adopted by several software tools. Here, we present GfaPy, a software package for creating, parsing and editing GFA graphs using the programming language Python. GfaPy supports GFA 1 and GFA 2, using the same interface and allows for interconversion between both formats. The software package provides a simple interface for custom record types, which is an important new feature of GFA 2 (compared to GFA 1). This enables new applications of the format. Availability and implementation: GfaPy is available open source at https://github.com/ggonnella/gfapy and installable via pip. Contact: gonnella@zbh.uni-hamburg.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28645151 TI - The genetic architecture of heterochrony as a quantitative trait: lessons from a computational model. PMID- 28645152 TI - Erratum. PMID- 28645153 TI - Defective mitochondrial RNA processing due to PNPT1 variants causes Leigh syndrome. AB - Leigh syndrome is a severe infantile encephalopathy with an exceptionally variable genetic background. We studied the exome of a child manifesting with Leigh syndrome at one month of age and progressing to death by the age of 2.4 years, and identified novel compound heterozygous variants in PNPT1, encoding the polynucleotide phosphorylase (PNPase). Expression of the wild type PNPT1 in the subject's myoblasts functionally complemented the defects, and the pathogenicity was further supported by structural predictions and protein and RNA analyses. PNPase is a key enzyme in mitochondrial RNA metabolism, with suggested roles in mitochondrial RNA import and degradation. The variants were predicted to locate in the PNPase active site and disturb the RNA processing activity of the enzyme. The PNPase trimer formation was not affected, but specific RNA processing intermediates derived from mitochondrial transcripts of the ND6 subunit of Complex I, as well as small mRNA fragments, accumulated in the subject's myoblasts. Mitochondrial RNA processing mediated by the degradosome consisting of hSUV3 and PNPase is poorly characterized, and controversy on the role and location of PNPase within human mitochondria exists. Our evidence indicates that PNPase activity is essential for the correct maturation of the ND6 transcripts, and likely for the efficient removal of degradation intermediates. Loss of its activity will result in combined respiratory chain deficiency, and a classic respiratory chain-deficiency-associated disease, Leigh syndrome, indicating an essential role for the enzyme for normal function of the mitochondrial respiratory chain. PMID- 28645154 TI - ALG-5 is a miRNA-associated Argonaute required for proper developmental timing in the Caenorhabditis elegans germline. AB - Caenorhabditis elegans contains 25 Argonautes, of which, ALG-1 and ALG-2 are known to primarily interact with miRNAs. ALG-5 belongs to the AGO subfamily of Argonautes that includes ALG-1 and ALG-2, but its role in small RNA pathways is unknown. We analyzed by high-throughput sequencing the small RNAs associated with ALG-5, ALG-1 and ALG-2, as well as changes in mRNA expression in alg-5, alg-1 and alg-2 mutants. We show that ALG-5 defines a distinct branch of the miRNA pathway affecting the expression of genes involved in immunity, defense, and development. In contrast to ALG-1 and ALG-2, which associate with most miRNAs and have general roles throughout development, ALG-5 interacts with only a small subset of miRNAs and is specifically expressed in the germline where it localizes alongside the piRNA and siRNA machinery at P granules. alg-5 is required for optimal fertility and mutations in alg-5 lead to a precocious transition from spermatogenesis to oogenesis. Our results provide a near-comprehensive analysis of miRNA-Argonaute interactions in C. elegans and reveal a new role for miRNAs in the germline. PMID- 28645155 TI - Features of genomic organization in a nucleotide-resolution molecular model of the Escherichia coli chromosome. AB - We describe structural models of the Escherichia coli chromosome in which the positions of all 4.6 million nucleotides of each DNA strand are resolved. Models consistent with two basic chromosomal orientations, differing in their positioning of the origin of replication, have been constructed. In both types of model, the chromosome is partitioned into plectoneme-abundant and plectoneme-free regions, with plectoneme lengths and branching patterns matching experimental distributions, and with spatial distributions of highly-transcribed chromosomal regions matching recent experimental measurements of the distribution of RNA polymerases. Physical analysis of the models indicates that the effective persistence length of the DNA and relative contributions of twist and writhe to the chromosome's negative supercoiling are in good correspondence with experimental estimates. The models exhibit characteristics similar to those of 'fractal globules,' and even the most genomically-distant parts of the chromosome can be physically connected, through paths combining linear diffusion and inter segmental transfer, by an average of only ~10 000 bp. Finally, macrodomain structures and the spatial distributions of co-expressed genes are analyzed: the latter are shown to depend strongly on the overall orientation of the chromosome. We anticipate that the models will prove useful in exploring other static and dynamic features of the bacterial chromosome. PMID- 28645157 TI - Secretory IgA response against Pseudomonas aeruginosa in the upper airways and the link with chronic lung infection in cystic fibrosis. AB - We assessed the diagnostic ability of an enzyme-linked immunosorbent assay test for measurement of specific secretory IgA (sIgA) in saliva to identify cystic fibrosis (CF) patients with Pseudomonas aeruginosa chronic lung infection and intermittent lung colonization. A total of 102 Brazilian CF patients and 53 healthy controls were included. Specific serum IgG response was used as a surrogate to distinguish CF patients according to their P. aeruginosa colonization/infection status. The rate of sIgA positivity was 87.1% in CF chronically infected patients (median value = 181.5 U/mL), 48.7% in intermittently colonized patients (median value = 45.8 U/mL) and 21.8% in free of infection patients (median value = 22.1 U/mL). sIgA levels in saliva were significantly associated with serum P. aeruginosa IgG and microbiological culture results. The sensitivity, specificity, PPV and NPV for differentiation between presence and absence of chronic lung infection were 87%, 63%, 51% and 92%, respectively. Measurement of sIgA in saliva may be used for screening patients in risk of developing P. aeruginosa chronic lung infection in CF and possibly also for paranasal sinusitis, and, most importantly, to efficiently rule out chronic P. aeruginosa lung infection. PMID- 28645158 TI - The potential for co-evolution of CO2-concentrating mechanisms and Rubisco in diatoms. AB - Diatoms are a diverse group of unicellular algae that contribute significantly to global photosynthetic carbon fixation and export in the modern ocean, and are an important source of microfossils for paleoclimate reconstructions. Because of their importance in the environment, diatoms have been a focus of study on the physiology and ecophysiology of carbon fixation, in particular their CO2 concentrating mechanisms (CCMs) and Rubisco characteristics. While carbon fixation in diatoms is not as well understood as in certain model aquatic photoautotrophs, a greater number of species have been examined in diatoms. Recent work has highlighted a large diversity in the function, physiology, and kinetics of both the CCM and Rubisco between different diatom species. This diversity was unexpected since it has generally been assumed that CCMs and Rubiscos were similar within major algal lineages as the result of selective events deep in evolutionary history, and suggests a more recent co-evolution between the CCM and Rubisco within diatoms. This review explores our current understanding of the diatom CCM and highlights the diversity of both the CCM and Rubisco kinetics. We will suggest possible environmental, physiological, and evolutionary drivers for the co-evolution of the CCM and Rubisco in diatoms. PMID- 28645156 TI - REM Sleep Behavior Disorder and Cognitive Impairment in Parkinson's Disease. AB - Study Objectives: REM sleep behavior disorder (RBD) is a parasomnia affecting 33% to 46% of patients with Parkinson's disease (PD). The existence of a unique and specific impaired cognitive profile in PD patients with RBD is still controversial. We extensively assessed cognitive functions to identify whether RBD is associated with more severe cognitive deficits in nondemented patients with PD. Methods: One hundred sixty-two participants, including 53 PD patients with RBD, 40 PD patients without RBD, and 69 healthy subjects, underwent polysomnography, a neurological assessment and an extensive neuropsychological exam to assess attention, executive functions, episodic learning and memory, visuospatial abilities, and language. Results: PD patients with RBD had poorer and clinically impaired performance in several cognitive tests compared to PD patients without RBD and healthy subjects. These two latter groups were similar on all cognitive measures. Mild cognitive impairment (MCI) diagnosis frequency was almost threefold higher in PD patients with RBD compared to PD patients without RBD (66% vs. 23%, p < .001). Moreover, subjective cognitive decline was reported in 89% of PD patients with RBD compared to 58% of PD patients without RBD (p = .024). Conclusions: RBD in PD is associated with a more impaired cognitive profile and higher MCI diagnosis frequency, suggesting more severe and widespread neurodegeneration. This patient subgroup and their caregivers should receive targeted medical attention to better detect and monitor impairment and to enable the development of management interventions for cognitive decline and its consequences. PMID- 28645159 TI - Genomic characterization of two novel SAR11 isolates from the Red Sea, including the first strain of the SAR11 Ib clade. AB - The SAR11 clade (Pelagibacterales) is a diverse group that forms a monophyletic clade within the Alphaproteobacteria, and constitutes up to one third of all prokaryotic cells in the photic zone of most oceans. Pelagibacterales are very abundant in the warm and highly saline surface waters of the Red Sea, raising the question of adaptive traits of SAR11 populations in this water body and warmer oceans through the world. In this study, two pure cultures were successfully obtained from surface waters on the Red Sea: one isolate of subgroup Ia and one of the previously uncultured SAR11 Ib lineage. The novel genomes were very similar to each other and to genomes of isolates of SAR11 subgroup Ia (Ia pan genome), both in terms of gene content and synteny. Among the genes that were not present in the Ia pan-genome, 108 (RS39, Ia) and 151 genes (RS40, Ib) were strain specific. Detailed analyses showed that only 51 (RS39, Ia) and 55 (RS40, Ib) of these strain-specific genes had not reported before on genome fragments of Pelagibacterales. Further analyses revealed the potential production of phosphonates by some SAR11 members and possible adaptations for oligotrophic life, including pentose sugar utilization and adhesion to marine particulate matter. PMID- 28645160 TI - Chronic Pseudomonas aeruginosa biofilm infection impairs murine S100A8/A9 and neutrophil effector cytokines-implications for delayed wound closure? AB - The impact of Pseudomonas aeruginosa biofilm infections in chronic wounds and clinical implication for healing is receiving increased attention. However, the pathophysiology of host/pathogen interplay is not fully understood. By further revealing the mechanisms, necessary new treatment strategies may be identified. Since the background for chronic wounds is diverse, representative animal models are important. We assessed host response and spontaneous wound closure in the relatively resistant C3H/HeN and the susceptible BALB/c mouse strain. Full thickness burn wounds were inflicted in 108 mice. Pseudomonas aeruginosa biofilm (106 colony forming units) was injected subcutaneously in 72 mice, euthanised day 4, 7 or 10 days post-infection. Wounds were analysed for neutrophil host response markers: S100A8/A9, keratinocyte-derived chemokine and granulocyte-colony stimulating factor. Total peripheral blood leucocyte and polymorphonuclear count were assessed in parallel. Histopathology evaluated wound inflammatory burden. Photoplanimetry described macroscopical wound closure. Stable chronic wound infection was established in all challenged mice. Pseudomonas aeruginosa biofilm suppressed neutrophil host response in wounds. C3H/HeN mice achieved earlier systemic inflammatory control and healed faster than BALB/c mice. Pseudomonas aeruginosa biofilms perturb host defence thereby inducing a steady state of chronic infection which may impair wound healing. These results indicate therapeutic options for immune modulation of biofilm-infected wounds. PMID- 28645161 TI - LncRNA TUG1 influences papillary thyroid cancer cell proliferation, migration and EMT formation through targeting miR-145. AB - LncRNA TUG1, a tumor oncogene associated with various human cancers, has been reported to be involved in regulating various cellular processes, such as proliferation, apoptosis and invasion through targeting multiple genes. However, its biological function in thyroid cancer cells has not been elucidated. The aim of this study is to measure TUG1 expression level and evaluate its function in thyroid cancer cells. LncRNA TUG1 expression levels in thyroid cancer tissues and three thyroid cancer cell lines (the ATC cell lines SW1736 and KAT18 and the FTC cell line FTC133) were assessed by qRT-PCR and compared with that of the human normal breast epithelial cell HGC-27. MTT assay, colony formation assay, transwell assay and western blot analysis were performed to assess the effects of TUG1 on proliferation, metastasis and EMT formation in thyroid cancer cells in vitro. Rescue assay was performed to further confirm that TUG1 contributes to the progression of thyroid cancer cells through regulating miR-145/ZEB1 signal pathway. LncRNA TUG1 was found to be up-regulated in thyroid cancer tissues and thyroid cancer cells compared with that in the human normal breast epithelial cell HGC-27. Increased lncRNA TUG1 expression was found to significantly promote tumor cell proliferation, and facilitate cell invasion, while down-regulated TUG1 could obviously inhibit cell proliferation, migration/invasion and reverse EMT to MET. These results indicated that TUG1 may contribute to the progression of thyroid cancer cells by function as a ceRNA competitive sponging miR-145, and that lncRNA TUG1 is associated with tumor progression in thyroid cancer cells. PMID- 28645162 TI - Reply to Nejsum et al. PMID- 28645164 TI - Differences in Cardiac Structure and Function Between Black and White Patients: Another Step in the Evaluation of Cardiovascular Risk in Chronic Kidney Disease. PMID- 28645163 TI - Variations in chloroplast movement and chlorophyll fluorescence among chloroplast division mutants under light stress. AB - Chloroplasts divide to maintain consistent size, shape, and number in leaf mesophyll cells. Altered expression of chloroplast division proteins in Arabidopsis results in abnormal chloroplast morphology. To better understand the influence of chloroplast morphology on chloroplast movement and photosynthesis, we compared the chloroplast photorelocation and photosynthetic responses of a series of Arabidopsis chloroplast division mutants with a wide variety of chloroplast phenotypes. Chloroplast movement was monitored by red light reflectance imaging of whole plants under increasing intensities of white light. The accumulation and avoidance responses were differentially affected in different mutants and depended on both chloroplast number and morphological heterogeneity. Chlorophyll fluorescence measurements during 5 d light experiments demonstrated that mutants with large-chloroplast phenotypes generally exhibited greater PSII photodamage than those with intermediate phenotypes. No abnormalities in photorelocation efficiency or photosynthetic capacity were observed in plants with small-chloroplast phenotypes. Simultaneous measurement of chloroplast movement and chlorophyll fluorescence indicated that the energy dependent (qE) and long-lived components of non-photochemical quenching that reflect photoinhibition are affected differentially in different division mutants exposed to high or fluctuating light intensities. We conclude that chloroplast division mutants with abnormal chloroplast morphologies differ markedly from the wild type in their light adaptation capabilities, which may decrease their relative fitness in nature. PMID- 28645165 TI - MALT lymphoma of the conjunctiva. PMID- 28645166 TI - Epidemiological and Clinical Characteristics of Children and Adolescents with Leprosy Admitted Over 16 Years at a Rural Hospital in Ethiopia: A Retrospective Analysis. AB - Aim: To analyse differences in children and adolescents aged <=18 years admitted to the leprosy ward in a rural Ethiopian hospital >16 years. Methods: We retrospectively collected data from leprosy admission registry books on patients with leprosy who were admitted to a referral hospital from September 2000 to September 2016. Results: There were 2129 admissions for leprosy during the study period: 180 (8.4%) patients were s <= 18 years old. Of these, 98 (54.4%) were male and 82 (45.6%) were female. The proportion of new diagnoses in children and adolescents was 31.7%, significantly higher than in adults (11.7%; p < 0.001). There were also significant differences in the prevalence of lepromatous ulcers (46.9 vs. 61.7%), leprosy reaction (29.4 vs. 13.0%) and neuritis (16.9 vs.5.3%) between these age groups. Conclusions: There were more new diagnoses, leprosy reactions and neuritis, and fewer lepromatous ulcers, in children and adolescents compared with adults, with younger patients being referred more frequently to reference centres. PMID- 28645167 TI - "It's important, but...": Perceived Barriers and Situational Dependencies to Social Contact Preferences of Nursing Home Residents. AB - Background and Objectives: U.S. Nursing homes (NH) are shifting toward a person centered philosophy of care, where staff understand each residents preferences, goals and values, and seek to honor them throughout the care delivery process. Social interactions are a major component of life and while low rates of social interactions are typically found among NH residents, little research has examined resident preferences for specific types of social interactions. The purpose of this study is to explore, from the perspective of the NH resident, barriers to social contact preferences and situations when social preferences change. Research Design and Methods: Two interviews were conducted with 255 NH residents 3 months apart, recruited from 32 NHs using 13 social-contact items from the Preferences for Everyday Living Inventory-NH. Results: Content analysis of 1,461 spontaneous comments identified perceived barriers to preference fulfillment along with reasons why residents would change their mind about the importance of a preference (situational dependencies). Nearly 50% of social preferences for choosing a roommate, having regular contact with friends, giving gifts, and volunteering were associated with barriers. Social preferences were likely to change based upon the quality of the social interaction and the resident's level of interest. Discussion and Implications: Knowledge of barriers regarding social preferences can inform care efforts vital to advancing the delivery of person centered care. In addition, understanding the reasons why NH resident preferences change based upon context can help providers with staff training leading to individualized care and develop meaningful social programs that are in line with resident preferences. PMID- 28645170 TI - Non-compaction cardiomyopathy and incessant supraventricular tachycardia: an unusual first presentation. PMID- 28645168 TI - Genomic Reconstruction of the History of Native Sheep Reveals the Peopling Patterns of Nomads and the Expansion of Early Pastoralism in East Asia. AB - China has a rich resource of native sheep (Ovis aries) breeds associated with historical movements of several nomadic societies. However, the history of sheep and the associated nomadic societies in ancient China remains poorly understood. Here, we studied the genomic diversity of Chinese sheep using genome-wide SNPs, mitochondrial and Y-chromosomal variations in > 1,000 modern samples. Population genomic analyses combined with archeological records and historical ethnic demographics data revealed genetic signatures of the origins, secondary expansions and admixtures, of Chinese sheep thereby revealing the peopling patterns of nomads and the expansion of early pastoralism in East Asia. Originating from the Mongolian Plateau ~5,000-5,700 years ago, Chinese sheep were inferred to spread in the upper and middle reaches of the Yellow River ~3,000 5,000 years ago following the expansions of the Di-Qiang people. Afterwards, sheep were then inferred to reach the Qinghai-Tibetan and Yunnan-Kweichow plateaus ~2,000-2,600 years ago by following the north-to-southwest routes of the Di-Qiang migration. We also unveiled two subsequent waves of migrations of fat tailed sheep into northern China, which were largely commensurate with the migrations of ancestors of Hui Muslims eastward and Mongols southward during the 12th-13th centuries. Furthermore, we revealed signs of argali introgression into domestic sheep, extensive historical mixtures among domestic populations and strong artificial selection for tail type and other traits, reflecting various breeding strategies by nomadic societies in ancient China. PMID- 28645169 TI - Heterodimerization of Arabidopsis calcium/proton exchangers contributes to regulation of guard cell dynamics and plant defense responses. AB - Arabidopsis thaliana cation exchangers (CAX1 and CAX3) are closely related tonoplast-localized calcium/proton (Ca2+/H+) antiporters that contribute to cellular Ca2+ homeostasis. CAX1 and CAX3 were previously shown to interact in yeast; however, the function of this complex in plants has remained elusive. Here, we demonstrate that expression of CAX1 and CAX3 occurs in guard cells. Additionally, CAX1 and CAX3 are co-expressed in mesophyll tissue in response to wounding or flg22 treatment, due to the induction of CAX3 expression. Having shown that the transporters can be co-expressed in the same cells, we demonstrate that CAX1 and CAX3 can form homomeric and heteromeric complexes in plants. Consistent with the formation of a functional CAX1-CAX3 complex, CAX1 and CAX3 integrated into the yeast genome suppressed a Ca2+-hypersensitive phenotype of mutants defective in vacuolar Ca2+ transport, and demonstrated enzyme kinetics different from those of either CAX protein expressed by itself. We demonstrate that the interactions between CAX proteins contribute to the functioning of stomata, because stomata were more closed in cax1-1, cax3-1, and cax1-1/cax3-1 loss-of-function mutants due to an inability to buffer Ca2+ effectively. We hypothesize that the formation of CAX1-CAX3 complexes may occur in the mesophyll to affect intracellular Ca2+ signaling during defense responses. PMID- 28645171 TI - UpSetR: an R package for the visualization of intersecting sets and their properties. AB - Motivation: Venn and Euler diagrams are a popular yet inadequate solution for quantitative visualization of set intersections. A scalable alternative to Venn and Euler diagrams for visualizing intersecting sets and their properties is needed. Results: We developed UpSetR, an open source R package that employs a scalable matrix-based visualization to show intersections of sets, their size, and other properties. Availability and implementation: UpSetR is available at https://github.com/hms-dbmi/UpSetR/ and released under the MIT License. A Shiny app is available at https://gehlenborglab.shinyapps.io/upsetr/ . Contact: nils@hms.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28645174 TI - Adrenomedullin promotes the odontogenic differentiation of dental pulp stem cells through CREB/BMP2 signaling pathway. PMID- 28645173 TI - Spatially resolved metabolic analysis reveals a central role for transcriptional control in carbon allocation to wood. AB - The contribution of transcriptional and post-transcriptional regulation to modifying carbon allocation to developing wood of trees is not well defined. To clarify the role of transcriptional regulation, the enzyme activity patterns of eight central primary metabolism enzymes across phloem, cambium, and developing wood of aspen (Populus tremula L.) were compared with transcript levels obtained by RNA sequencing of sequential stem sections from the same trees. Enzymes were selected on the basis of their importance in sugar metabolism and in linking primary metabolism to lignin biosynthesis. Existing enzyme assays were adapted to allow measurements from ~1 mm3 sections of dissected stem tissue. These experiments provided high spatial resolution of enzyme activity changes across different stages of wood development, and identified the gene transcripts probably responsible for these changes. In most cases, there was a clear positive relationship between transcripts and enzyme activity. During secondary cell wall formation, the increases in transcript levels and enzyme activities also matched with increased levels of glucose, fructose, hexose phosphates, and UDP-glucose, emphasizing an important role for transcriptional regulation in carbon allocation to developing aspen wood. These observations corroborate the efforts to increase carbon allocation to wood by engineering gene regulatory networks. PMID- 28645172 TI - The biogenesis pathway of tRNA-derived piRNAs in Bombyx germ cells. AB - Transfer RNAs (tRNAs) function in translational machinery and further serves as a source of short non-coding RNAs (ncRNAs). tRNA-derived ncRNAs show differential expression profiles and play roles in many biological processes beyond translation. Molecular mechanisms that shape and regulate their expression profiles are largely unknown. Here, we report the mechanism of biogenesis for tRNA-derived Piwi-interacting RNAs (td-piRNAs) expressed in Bombyx BmN4 cells. In the cells, two cytoplasmic tRNA species, tRNAAspGUC and tRNAHisGUG, served as major sources for td-piRNAs, which were derived from the 5'-part of the respective tRNAs. cP-RNA-seq identified the two tRNAs as major substrates for the 5'-tRNA halves as well, suggesting a previously uncharacterized link between 5' tRNA halves and td-piRNAs. An increase in levels of the 5'-tRNA halves, induced by BmNSun2 knockdown, enhanced the td-piRNA expression levels without quantitative change in mature tRNAs, indicating that 5'-tRNA halves, not mature tRNAs, are the direct precursors for td-piRNAs. For the generation of tRNAHisGUG derived piRNAs, BmThg1l-mediated nucleotide addition to -1 position of tRNAHisGUG was required, revealing an important function of BmThg1l in piRNA biogenesis. Our study advances the understanding of biogenesis mechanisms and the genesis of specific expression profiles for tRNA-derived ncRNAs. PMID- 28645175 TI - Perturbation to Cholesterol at the Neuromuscular Junction Confers Botulinum Neurotoxin A Sensitivity to Neonatal Mice. AB - Botulinum neurotoxin A (BoNT/A) cleaves SNAP25 at the motor nerve terminals and inhibits stimulus evoked acetylcholine release. This causes skeletal muscle paralysis. However, younger neonatal mice (P7) mice. However, neonatal mice younger than 7 days-age remained unaffected by BoNT/A injection. Also, BoNT/A inhibited stimulus evoked acetylcholine release and stimulus-evoked twitch tension of diaphragm nerve muscle preparations (NMPs) of adult mouse and >P7 neonates but not that of P7. However, cholesterol depletion using methyl-beta-cyclodextrin (MbetaCD) sensitized 20 Gy were more likely to achieve obliteration (P = .001). Obliteration occurred earlier in patients who received a higher prescribed margin dose (P = .05) and maximum dose (P = .041). Post-SRS hemorrhage occurred in 8.8% (n = 18). Annual postgamma knife latency period hemorrhage was 1.5%. Radiation induced complications were radiologically evident in 35.6% (n = 73), symptomatic in 14.6% (n = 30), and permanent in 14.6% (n = 30, which included long-tract signs and new cranial nerve deficits). FO was achieved in 64.4% (n = 132). Predictors of an FO were a higher Virginia radiosurgery AVM scale score (P = .003), prior hemorrhage (P = .045), and a lower prescribed maximum dose (P = .006). CONCLUSION: SRS for bAVMs results in obliteration and avoids permanent complications in the majority of patients. PMID- 28645184 TI - Early Menarche and Menstrual Problems Are Associated with Sleep Disturbance in a Large Sample of Chinese Adolescent Girls. AB - Study Objectives: Little is known about the association between menstruation and sleep disturbance in adolescent girls. This study examined sleep duration, insomnia symptoms, and sleep quality in relation to age at menarche and menstrual problems in a large sample of Chinese adolescent girls. Methods: This report represents the baseline data of an ongoing longitudinal study of the Shandong Adolescent Behavior & Health Cohort in Shandong, China. A total of 5800 girls aged 12-18 years (mean age = 15.0, standard deviation = 1.4) participated in the baseline survey. A structured questionnaire was used to assess participants' age at menarche, menstrual cycle interval, menstrual flow length, period irregularity, period pain, body weight and height, and demographics. Internalizing and externalizing problems were measured by the Youth-Self Report of Child Behavioral Checklist. Sleep duration, insomnia symptoms, and sleep quality were assessed by the items adapted from the Pittsburgh Sleep Quality Index. Results: After adjusting for age, school, body mass index, internalizing and externalizing problems, and family covariates, irregular periods (odds ratio [OR] = 1.46, 95% confidence interval [CI] = 1.06-2.02), period pain (OR = 1.99, 95% CI = 1.44-2.76), and menstrual flow length >=7 days (OR = 1.21, 95% CI = 1.00 1.48) were significantly associated with insomnia symptoms. Irregular periods (OR = 1.72, 95% CI = 1.30-2.27) and period pain (OR = 1.78, 95% CI = 1.34-2.37) were significantly associated with poor sleep quality. Age at menarche <=11 years (OR = 1.62, 95% CI = 1.05-2.50) was significantly associated with insomnia symptoms in 12- to 14-year-old girls. Conclusions: Our results suggest that irregular periods and period pain appear to be associated with sleep disturbance and that early menarche may have short-term impact on sleep in adolescent girls. PMID- 28645183 TI - In defense of Bacillus thuringiensis, the safest and most successful microbial insecticide available to humanity - a response to EFSA. AB - The Bacillus cereus group contains vertebrate pathogens such as Bacillus anthracis and Bacillus cereus and the invertebrate pathogen Bacillus thuringiensis. Microbial biopesticides based on B. thuringiensis (Bt) are widely recognized as being among the safest and least environmentally damaging insecticidal products available. Nevertheless, a recent food poisoning incident prompted a European Food Safety Authority review which argued that B. thuringiensis poses a health risk equivalent to B. cereus, a causative agent of diarrhoea. However, a critical examination of available data, and this latest incident, provide no solid evidence that B. thuringiensis causes diarrhoea. Although relatively high levels of B. cereus-like spores can occur in foods, genotyping demonstrates that these are predominantly naturally-occurring strains rather than biopesticides. Moreover, MLST genotyping of > 2000 isolates show that biopesticide genotypes have never been isolated from any clinical infection. MLST data demonstrate that Bacillus cereus group is heterogeneous and formed of distinct clades with substantial differences in biology, ecology and host association. The group posing the greatest risk (the anthracis clade) is distantly related to the clade containing all biopesticides. These recent data support the long-held view that B. thuringiensis, and especially the strains used in Bt biopesticides, are very safe for humans. PMID- 28645186 TI - IGF-I Gene Therapy in Aging Rats Modulates Hippocampal Genes Relevant to Memory Function. AB - In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes underlie the hippocampal phenotype of aging but no studies on the effects of IGF-I on the hippocampal transcriptome of old rodents have been documented. Here, we assessed the effects of IGF-I gene therapy on spatial memory performance in old female rats and compared them with changes in the hippocampal transcriptome. In the Barnes maze test, experimental rats showed a significantly higher exploratory frequency of the goal hole than controls. Hippocampal RNA-sequencing showed that 219 genes are differentially expressed in 28-month-old rats intracerebroventricularly injected with an adenovector expressing rat IGF-I as compared with placebo adenovector-injected counterparts. From the differentially expressed genes, 81 were down and 138 upregulated. From those genes, a list of functionally relevant genes, concerning hippocampal IGF-I expression, synaptic plasticity as well as neuronal function was identified. Our results provide an initial glimpse at the molecular mechanisms underlying the neuroprotective actions of IGF-I in the aging brain. PMID- 28645185 TI - Soil prokaryotic communities in Chernobyl waste disposal trench T22 are modulated by organic matter and radionuclide contamination. AB - After the Chernobyl nuclear power plant accident in 1986, contaminated soils, vegetation from the Red Forest and other radioactive debris were buried within trenches. In this area, trench T22 has long been a pilot site for the study of radionuclide migration in soil. Here, we used 454 pyrosequencing of 16S rRNA genes to obtain a comprehensive view of the bacterial and archaeal diversity in soils collected inside and in the vicinity of the trench T22 and to investigate the impact of radioactive waste disposal on prokaryotic communities. A remarkably high abundance of Chloroflexi and AD3 was detected in all soil samples from this area. Our statistical analysis revealed profound changes in community composition at the phylum and OTUs levels and higher diversity in the trench soils as compared to the outside. Our results demonstrate that the total absorbed dose rate by cell and, to a lesser extent the organic matter content of the trench, are the principal variables influencing prokaryotic assemblages. We identified specific phylotypes affiliated to the phyla Crenarchaeota, Acidobacteria, AD3, Chloroflexi, Proteobacteria, Verrucomicrobia and WPS-2, which were unique for the trench soils. PMID- 28645187 TI - Salmonella virulence plasmid: pathogenesis and ecology. AB - A current view on the role of the Salmonella virulence plasmid in the pathogenesis of animal and human hosts is discussed; including the possible relevance in secondary ecological niches. Various strategies towards further studies in this respect are proposed within the One Health Concept. PMID- 28645188 TI - Temporal variation of the microbiome is dependent on body region in a wild mammal (Tamiasciurus hudsonicus). AB - Microbial communities are increasingly being recognized as important to host health in wild mammals, but how these communities are characterized can have important consequences on the results of these studies. Previous research has explored temporal variation in microbial communities in humans and lab mammals, but few have investigated how microbiomes fluctuate in wild populations and none have examined the temporal dynamics of these fluctuations in different body regions on a wild mammal. Using Illumina MiSeq sequencing of the V3-V4 16S rRNA gene regions, we characterized the buccal and gut microbiomes of wild North American red squirrels, Tamiasciurus hudsonicus, to measure changes in these two microbiomes over short (<2 weeks), medium (2-4 weeks) and long (>1 month) term sampling periods. While we observed short and medium temporal stability in the buccal microbiome, the gut microbiome varied between medium and long-term sampling periods. There was no evidence of intra-individual correlations between buccal and gut microbiome change, suggesting that temporal stability is dependent on the body region and factors affecting microbial stability may be specific to body sites. From these findings, we urge researchers to be cautious in interpreting results from single temporal sampling periods when quantifying characteristic microbiomes in wild mammals. PMID- 28645189 TI - The potential role of retinoic acid receptor alpha on glomerulosclerosis in rats and podocytes injury is associated with the induction of MMP2 and MMP9. AB - Retinoic acid receptor alpha (RARalpha) plays a crucial role in kidney disease. However, the underlying mechanisms in glomerulosclerosis (GS) is still not clear. The roles of RARalpha in an adriamycin (ADR)-induced GS rat model and in ADR induced podocyte injury in vitro were investigated. RARalpha was over-expressed in GS rats, and serum, urine and kidney samples were collected to detect the induction of the expression of the receptor. RARalpha expression was inhibited and/or over-expressed in cultured podocytes following injury, as demonstrated by morphometric assays, cell toxicity, and matrix metalloproteinase (MMP) enzymatic activity. RARalpha displayed a renoprotective role in GS rats, resulting in a lower GS index, podocyte foot process fusion, and proteinuria, reduced serum creatinine and blood urea nitrogen. Further experiments indicated that RARalpha inhibited the accumulation of TGF-beta1, alpha-smooth muscle actin, collagen IV, and fibronectin, while it induced MMP2 and MMP9 excessive expression in podocytes in vitro. RARalpha improved the renal function and attenuated the progression of GS that was associated with the over-expression of MMP2 and MMP9. PMID- 28645190 TI - Analysis of Ribosomal DNA Cannot Unequivocally Assign Ascaris to Species Level or Identify Hybrids. PMID- 28645192 TI - Frequent Sexual Activity Predicts Specific Cognitive Abilities in Older Adults. AB - Objectives: This study replicates and extends the findings of previous research (Wright, H., & Jenks, R. A. (2016). Sex on the brain! Associations between sexual activity and cognitive function in older age. Age and Ageing, 45, 313-317. doi:10.1093/ageing/afv197) which found a significant association between sexual activity (SA) and cognitive function in older adults. Specifically, this study aimed to generalize these findings to a range of cognitive domains, and to assess whether increasing SA frequency is associated with increasing scores on a variety of cognitive tasks. Methods: Seventy-three participants aged 50-83 years took part in the study (38.4% male, 61.6% female). Participants completed the Addenbrooke's Cognitive Examination-III (ACE-III) cognitive assessment and a questionnaire on SA frequency (never, monthly, or weekly), and general health and lifestyle. Results: Weekly SA was a significant predictor of total ACE-III, fluency, and visuospatial scores in regression models, including age, gender, education, and cardiovascular health. Discussion: Greater frequency of SA was associated with better overall ACE-III scores and scores on subtests of verbal fluency and visuospatial ability. Both of these tasks involve working memory and executive function, and links between sexual behavior, memory, and dopamine are discussed. The findings have implications for the maintenance of intimate relationships in later life. PMID- 28645191 TI - How Effective Is Algorithm-Guided Treatment for Depressed Inpatients? Results from the Randomized Controlled Multicenter German Algorithm Project 3 Trial. AB - Background: Treatment algorithms are considered as key to improve outcomes by enhancing the quality of care. This is the first randomized controlled study to evaluate the clinical effect of algorithm-guided treatment in inpatients with major depressive disorder. Methods: Inpatients, aged 18 to 70 years with major depressive disorder from 10 German psychiatric departments were randomized to 5 different treatment arms (from 2000 to 2005), 3 of which were standardized stepwise drug treatment algorithms (ALGO). The fourth arm proposed medications and provided less specific recommendations based on a computerized documentation and expert system (CDES), the fifth arm received treatment as usual (TAU). ALGO included 3 different second-step strategies: lithium augmentation (ALGO LA), antidepressant dose-escalation (ALGO DE), and switch to a different antidepressant (ALGO SW). Time to remission (21-item Hamilton Depression Rating Scale <=9) was the primary outcome. Results: Time to remission was significantly shorter for ALGO DE (n=91) compared with both TAU (n=84) (HR=1.67; P=.014) and CDES (n=79) (HR=1.59; P=.031) and ALGO SW (n=89) compared with both TAU (HR=1.64; P=.018) and CDES (HR=1.56; P=.038). For both ALGO LA (n=86) and ALGO DE, fewer antidepressant medications were needed to achieve remission than for CDES or TAU (P<.001). Remission rates at discharge differed across groups; ALGO DE had the highest (89.2%) and TAU the lowest rates (66.2%). Conclusions: A highly structured algorithm-guided treatment is associated with shorter times and fewer medication changes to achieve remission with depressed inpatients than treatment as usual or computerized medication choice guidance. PMID- 28645193 TI - IRF6 Regulates Alternative Activation by Suppressing PPARgamma in Male Murine Macrophages. AB - Aberrant proinflammatory and suppressed anti-inflammatory (alternative; M2) macrophage activation underlies the chronic inflammation associated with obesity and other metabolic disorders. This study demonstrates a critical role for interferon regulatory factor 6 (IRF6) in regulating macrophage M2 activation by suppressing peroxisome proliferator-activated receptor-gamma (PPARgamma) expression, a critical regulator of alternative macrophage polarization. The data demonstrate suppression of IRF6 in both M2 macrophages and obese adipose tissue macrophages. Using gain- and loss-of-function strategies, we confirmed that IRF6 knockdown enhanced M2 activation, whereas IRF6 overexpression dramatically attenuated M2 activation. Computational target prediction analysis coupled with chromatin immunoprecipitation indicated that IRF6 suppresses PPARgamma through binding IRF recognition sites located upstream of the PPARgamma coding region. Taken together, our results suggest that an IRF6/PPARgamma regulatory axis suppresses anti-inflammatory responses in bone marrow-derived macrophages and provides references for future study addressing dysregulated metabolic and immunologic homeostasis of obese adipose tissue. PMID- 28645194 TI - Predictors of Treatment Response and Survival Outcomes in Meningioma Recurrence with Atypical or Anaplastic Histology. AB - BACKGROUND: Recurrence rates for atypical and anaplastic meningiomas range between 9% and 50% after gross total resection and between 36% and 83% after subtotal resection. Optimal treatment of recurrent meningiomas exhibiting atypical/anaplastic histology is complicated because they are often refractory to both surgery and radiation. OBJECTIVE: To evaluate clinical determinants of recurrence and treatment-specific outcomes in patients with recurrent meningiomas exhibiting atypical/anaplastic histology at our institution. METHODS: A cohort study was conducted using clinical data of all patients treated for meningiomas with atypical/anaplastic histology at first recurrence between January 1985 and July 2014 at a tertiary cancer center. Predictors of second recurrence were analyzed using competing risks regression models. RESULTS: Nine hundred eighteen patients with meningioma were screened, of whom 60 (55% female) had recurrent disease with atypical/anaplastic histology at a median age of 58.1 yr at diagnosis. The median follow-up from the time of first recurrence was 36.7 mo, with 32 (53%) patients alive at last follow-up. There was no effect of extent of resection at first recurrence on time to a subsequent recurrence. Inclusion of radiation as primary or adjuvant therapy at first recurrence reduced the risk of progression or subsequent recurrence compared to surgery alone (P = .07). CONCLUSION: Treatment of recurrent meningiomas with atypical/anaplastic histology remains challenging. Our data, from one of the largest cohorts, suggest better tumor control with the addition of radiation and challenges the importance of extent of resection at first recurrence. A multicenter effort is needed to confirm these findings and propose treatment guidelines. PMID- 28645195 TI - Mutational Biases Influence Parallel Adaptation. AB - While mutational biases strongly influence neutral molecular evolution, the role of mutational biases in shaping the course of adaptation is less clear. Here we consider the frequency of transitions relative to transversions among adaptive substitutions. Because mutation rates for transitions are higher than those for transversions, if mutational biases influence the dynamics of adaptation, then transitions should be overrepresented among documented adaptive substitutions. To test this hypothesis, we assembled two sets of data on putatively adaptive amino acid replacements that have occurred in parallel during evolution, either in nature or in the laboratory. We find that the frequency of transitions in these data sets is much higher than would be predicted under a null model where mutation has no effect. Our results are qualitatively similar even if we restrict ourself to changes that have occurred, not merely twice, but three or more times. These results suggest that the course of adaptation is biased by mutation. PMID- 28645196 TI - Antagonistic regulation of cyclin expression by the bZIP transcription factors Pcr1 and Atf1 during G2/M transition. AB - The transcription factor Atf1 is known to promote cell survival during various stress conditions in Schizosaccharomyces pombe by activating the expression of appropriate genes. It can also activate transcription of other important genes responsible for cell cycle progression. An Atf1-dependent increase in the expression of cell division promoting genes will oppose activation of checkpoints necessary to ensure repairs and cell survival during stress. Hence, selective inhibition of the cell cycle-related functions of Atf1 would be indispensable for cellular survival during stress. Here we present evidence in favour of selective inhibition of Atf1's ability to activate cdc13+ transcription. We show that the transcription factor Pcr1 can specifically inhibit the recruitment of Atf1 on cdc13 promoter and thereby prevent Atf1-mediated mitotic acceleration. We also show that this opposition of Atf1 functions by Pcr1 extends to the G1-S transition event as well. Altogether these results suggest a previously unknown antagonistic function of Atf1 and Pcr1 in regulating Cdc13 expression during cell cycle progression. PMID- 28645197 TI - pHTbeta-promoted mobilization of non-conjugative resistance plasmids from Enterococcus faecium to Enterococcus faecalis. AB - Objectives: To analyse the recombination events associated with conjugal mobilization of two multiresistance plasmids, pRUM17i48 and pLAG (formerly named pDO1-like), from Enterococcus faecium 17i48 to Enterococcus faecalis JH2-2. Methods: The plasmids from two E. faecalis transconjugants (JH-4T, tetracycline resistant, and JH-8E, erythromycin resistant) and from the E. faecium donor (also carrying a pHTbeta-like conjugative plasmid, named pHTbeta17i48) were investigated by several methods, including PCR mapping and sequencing, S1-PFGE followed by Southern blotting and hybridization, and WGS. Results: Two locations of repApHTbeta were detected in both transconjugants, one on a ~50 kb plasmid (as in the donor) and the other on plasmids of larger sizes. In JH-4T, WGS disclosed an 88.6 kb plasmid resulting from the recombination of pHTbeta17i48 (~50 kb) and a new plasmid, named pLAG (35.3 kb), carrying the tet(M), tet(L), lsa(E), lnu(B), spw and aadE resistance genes. In JH-8E, a 75 kb plasmid resulting from the recombination of pHTbeta17i48 and pRUM17i48 was observed. In both cases, the cointegrates were apparently derived from replicative transposition of an IS1216 present in each of the multiresistance plasmids into pHTbeta17i48. The cointegrates could resolve to yield the multiresistance plasmids and a pHTbeta17i48 derivative carrying an IS1216 (unlike the pHTbeta17i48 of the donor). Conclusions: Our results completed the characterization of the multiresistance plasmids carried by the E. faecium 17i48, confirming the role of pHT plasmids in the mobilization of non-conjugative antibiotic resistance elements among enterococci. Results also revealed that mobilization to E. faecalis was associated with the generation of cointegrate plasmids promoted by IS1216-mediated transposition. PMID- 28645199 TI - Do Neurobiological Understandings of Smoking Influence Quitting Self-Efficacy or Treatment Intentions? AB - Introduction: Addiction is increasingly defined as a "brain disease" caused by changes to neurochemistry. While nicotine addiction has historically been excluded in the brain disease model of addiction (BDMA), it is beginning to be labeled a chronic brain disease. We investigated whether Australian smokers endorse brain-based explanations of smoking, and whether these beliefs are associated with quitting self-efficacy or treatment intentions. Method: Cross sectional study of Australian smokers (N = 1538) who completed a survey measuring their agreement with statements on the brain's role in smoking. Logistic regressions tested associations between these items and socio-demographic variables, quitting self-efficacy and intention to use cessation medications. Results: The majority (57.9%) agreed that smoking changed brain chemistry and 34.4% agreed that smoking was a brain disease. Younger participants and those with more education were more likely to endorse brain-based understandings of smoking. Participants who agreed smoking changed brain chemistry were more likely to report an intention to use cessation medicines (OR 1.5, 95% CI = 1.0-2.2) as were those who agreed that smoking was a brain disease (OR 1.5, 95% CI = 1.1 2.1). Self-efficacy did not differ between those who agreed and disagreed that smoking changed brain chemistry. However, those who agreed that smoking was a brain disease had higher self-efficacy than those who disagreed (OR 1.7, 95% CI = 1.3-2.3). Conclusion: A neurobiological view of smoking does not dominate public understandings of smoking in Australia. Endorsement of neurobiological explanations of smoking were associated with increased intention to use cessation aids, but were not associated with reduced self-efficacy. Implications: Explaining tobacco dependence in neurobiological terms is unlikely to induce feelings of fatalism in relation to smoking cessation. Those who endorse biomedical explanations of smoking may be more open to using cessation pharmacotherapies. Describing smoking in terms of alterations in brain chemistry may be more acceptable to smokers than labeling smoking a "brain disease" or "brain disorder." PMID- 28645198 TI - Diabetes-Specific and General Life Stress and Glycemic Outcomes in Emerging Adults With Type 1 Diabetes: Is Race/Ethnicity a Moderator? AB - Objective: This study examines whether race/ethnicity moderates relationships of (a) diabetes stress and general life stressors with (b) diabetes outcomes of glycemic control and diabetic ketoacidosis (DKA) among emerging adults (aged 18 25 years) with type 1 diabetes (T1D). Method: Using a T1D Exchange Registry sample of non-Hispanic White, African American, and Hispanic emerging adults (N = 3,440), multiple group analyses were used to determine whether race/ethnicity moderates the relationships between stress and diabetes outcomes. Results: The relationships between the two stress types and glycemic control did not differ between African American and non-Hispanic Whites. However, as compared with non Hispanic Whites, the association between higher diabetes-specific stress and poorer glycemic control was significantly stronger for Hispanics, and Hispanics had poorer glycemic control when they experienced a relatively fewer number of general life stressors than non-Hispanic Whites. The relationships between the type of stress (diabetes-specific and general stress) and DKA did not differ across racial/ethnic groups. Conclusions: Future research should evaluate possible mechanisms that contribute to the different relationships of stress with glycemic control among Hispanics compared with non-Hispanic Whites. PMID- 28645200 TI - Prognostic awareness, prognostic communication, and cognitive function in patients with malignant glioma. AB - Background: Malignant glioma (MG) is a devastating neuro-oncologic disease with almost invariably poor prognosis. Prognostic awareness (PA) is the awareness of incurable disease and shortened life expectancy (LE). Accurate PA is associated with favorable psychological outcomes at the end of life (EoL) for patients with cancer; however, little is known about PA or prognostic communication in MG. Moreover, research has yet to evaluate the impact of cognitive impairment on PA and preferred forms of communication. Methods: Fifty MG patients and 32 paired caregivers were evaluated in this exploratory study with a semi-structured PA assessment aimed to measure their awareness of MG incurability and LE. Full PA was defined as awareness of MG incurability and accurate estimate of LE. The assessment included a survey about preferences for prognostic communication (items from the Prognosis and Treatment Perceptions Questionnaire), neurocognitive assessment (Hopkins Verbal Learning Test-Revised, Trail Making Test Parts A and B, and the Controlled Oral Word Association Test), and measurements of mood (Hospital Anxiety and Depression Scale) and quality of life (Functional Assessment of Cancer Therapy-Brain [FACT-Br]). Results: Twenty (40%) patients and 22 (69%) caregivers had full PA. Thirty (60%) patients and 23 (72%) caregivers reported that prognostic information was extremely or very important, and 21 (42%) patients and 16 (50%) caregivers desired more prognostic information. Patients with memory impairment more frequently believed that prognostic information was important (P = 0.04, P = 0.03) and desired more information (P = 0.05, P = 0.003) as compared with those without impairment. Conclusions: Most MG patients were unaware of their LE. Memory impairment may influence preferences for prognostic information. PMID- 28645201 TI - Benznidazole treatment safety: the Medecins Sans Frontieres experience in a large cohort of Bolivian patients with Chagas' disease. AB - Background: Up to half of patients with Chagas' disease under benznidazole treatment present adverse drug reactions (ADRs) and up to one-third do not complete standard treatment. Objectives: To verify the incidence and possible factors associated with the suspension of benznidazole treatment in a large cohort of patients. Methods: We included 2075 patients treated with benznidazole during the projects managed by the medical humanitarian organization Doctors Without Borders (Medecins Sans Frontieres) in Bolivia from 2009 to 2013. Benznidazole treatment was provided two or three times per day for ~60 days at 5 7.5 mg/kg/day. A multiple logistic regression model was developed to evaluate the factors associated with permanent suspension of benznidazole treatment. Results: Permanent benznidazole treatment suspension occurred in 211 patients (10.2%) and the average time until permanent treatment suspension was 23 days. Multifactorial analysis revealed that female sex (adjusted OR = 1.70), moderate ADRs (adjusted OR = 10.57), mild ADRs (adjusted OR = 1.69) and skin disorders (adjusted OR = 4.18) were significantly associated with the permanent suspension of benznidazole treatment. Women with mild or moderate skin ADRs presented a probability of treatment interruption of 18.6% and 59.0%, respectively. Conclusions: Benznidazole treatment was safe and a large proportion of patients were able to complete a full course of benznidazole treatment under close treatment surveillance. Female sex, skin disorders and mild and moderate ADRs were independently associated with the permanent suspension of benznidazole treatment. In particular, women with moderate skin ADRs had the highest risk of benznidazole treatment interruption. PMID- 28645203 TI - Neurosurgical Randomized Controlled Trials-Distance Travelled. AB - BACKGROUND: The evidence base for many neurosurgical procedures has been limited. We performed a comprehensive and systematic analysis of study design, quality of reporting, and trial results of neurosurgical randomized controlled trials (RCTs). OBJECTIVE: To systematically assess the design and quality characteristics of neurosurgical RCTs. METHODS: From January 1961 to June 2016, RCTs with >5 patients assessing any 1 neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINE, Scopus, and Cochrane Library. RESULTS: The median sample size in the 401 eligible RCTs was 73 patients with a mean patient age of 49.6. Only 111 trials (27.1%) described allocation concealment, 140 (34.6%) provided power calculations, and 117 (28.9%) were adequately powered. Significant efficacy or trend for efficacy was claimed in 226 reports (56.4%), no difference between the procedures was found in 166 trials (41.4%), and significant harm was reported in 9 trials (2.2%). Trials with a larger sample size were more likely to report randomization mode, specify allocation concealment, and power calculations (all P < .001). Government funding was associated with better specification of power calculations (P = .008) and of allocation concealment (P = .026), while industry funding was associated with reporting significant efficacy (P = .02). Reporting of funding, specification of randomization mode and primary outcomes, and mention of power calculations improved significantly (all, P < .05) over time. CONCLUSION: Several aspects of the design and reporting of RCTs on neurosurgical procedures have improved over time. Better powered and accurately reported trials are needed in neurosurgery to deliver evidence-based care and achieve optimal outcomes. PMID- 28645202 TI - Effects of Mobility and Multimorbidity on Inpatient and Postacute Health Care Utilization. AB - Background: This study examines effects of mobility and multimorbidity on hospitalization and inpatient and postacute care (PAC) facility days among older men. Methods: Prospective study of 1,701 men (mean age 79.3 years) participating in Osteoporotic Fractures in Men (MrOS) Study Year 7 (Y7) examination (2007-2008) linked with their Medicare claims. At Y7, mobility ascertained by usual gait speed and categorized as poor, intermediate, or good. Multimorbidity quantified by applying Elixhauser algorithm to inpatient and outpatient claims and categorized as none, mild-moderate, or high. Hospitalizations and PAC facility stays ascertained during 12 months following Y7. Results: Reduced mobility and greater multimorbidity burden were independently associated with a higher risk of inpatient and PAC facility utilization, after accounting for each other and traditional indicators. Adjusted mean total facility days per year were 1.13 (95% confidence interval [CI] = 0.74-1.40) among men with good mobility increasing to 2.43 (95% CI = 1.17-3.84) among men with poor mobility, and 0.67 (95% CI = 0.38 0.91) among men without multimorbidity increasing to 2.70 (95% CI = 1.58-3.77) among men with high multimorbidity. Men with poor mobility and high multimorbidity had a ninefold increase in mean total facility days per year (5.50, 95% CI = 2.78-10.87) compared with men with good mobility without multimorbidity (0.59, 95% CI = 0.37-0.95). Conclusions: Among older men, mobility limitations and multimorbidity were independent predictors of higher inpatient and PAC utilization after considering each other and conventional predictors. Marked combined effects of reduced mobility and multimorbidity burden may be important to consider in clinical decision-making and planning health care delivery strategies for the growing aged population. PMID- 28645204 TI - When Homoplasy Is Not Homoplasy: Dissecting Trait Evolution by Contrasting Composite and Reductive Coding. AB - The conceptualization and coding of characters is a difficult issue in phylogenetic systematics, no matter which inference method is used when reconstructing phylogenetic trees or if the characters are just mapped onto a specific tree. Complex characters are groups of features that can be divided into simpler hierarchical characters (reductive coding), although the implied hierarchical relational information may change depending on the type of coding (composite vs. reductive). Up to now, there is no common agreement to either code characters as complex or simple. Phylogeneticists have discussed which coding method is best but have not incorporated the heuristic process of reciprocal illumination to evaluate the coding. Composite coding allows to test whether 1) several characters were linked resulting in a structure described as a complex character or trait or 2) independently evolving characters resulted in the configuration incorrectly interpreted as a complex character. We propose that complex characters or character states should be decomposed iteratively into simpler characters when the original homology hypothesis is not corroborated by a phylogenetic analysis, and the character or character state is retrieved as homoplastic. We tested this approach using the case of fruit types within subfamily Cinchonoideae (Rubiaceae). The iterative reductive coding of characters associated with drupes allowed us to unthread fruit evolution within Cinchonoideae. Our results show that drupes and berries are not homologous. As a consequence, a more precise ontology for the Cinchonoideae drupes is required. PMID- 28645205 TI - Aquaporin Positron Emission Tomography Differentiates Between Grade III and IV Human Astrocytoma. AB - BACKGROUND: Aquaporin (AQP) water channels play a significant role in mesenchymal microvascular proliferation and infiltrative growth. AQPs are highly expressed in malignant astrocytomas, and a positive correlation is observed between their expression levels and histological tumor grade. OBJECTIVE: To examine the utility of aquaporin positron emission tomography (PET) for differentiating between astrocytoma grade III and grade IV using the AQP radioligand [11C]TGN-020. METHODS: Fifteen astrocytoma patients, grade III (n = 7) and grade IV (n = 8), and 10 healthy volunteers underwent [11C]TGN-020 aquaporin PET imaging. Surgical tissues of astrocytoma patients were examined for histopathological grading using the WHO classification standard and expression of AQP1 and AQP4 immunohistochemically. RESULTS: Mean standardized uptake values of astrocytoma grade III and IV (0.51 +/- 0.11 vs 1.50 +/- 0.44, respectively) were higher than normal white matter (0.17 +/- 0.02, P < .001) for both tumor grades. Importantly, mean standardized uptake values of astrocytoma grade IV were significantly higher than grade III (P < .01). CONCLUSION: Our study demonstrated that [11C]TGN-020 aquaporin PET imaging differentiated between astrocytoma grades III and IV. We suggest its clinical application as a noninvasive diagnostic tool would lead to advancements in the management of these malignant brain tumors. PMID- 28645206 TI - Catheter-based renal denervation as therapy for chronic severe kidney-related pain. AB - Background: Loin pain haematuria syndrome (LPHS) and autosomal dominant polycystic kidney disease (ADPKD) are the most important non-urological conditions to cause chronic severe kidney-related pain. Multidisciplinary programmes and surgical methods have shown inconsistent results with respect to pain reduction. Percutaneous catheter-based renal denervation (RDN) could be a less invasive treatment option for these patients. Methods: Our aim was to explore the change in perceived pain and use of analgesic medication from baseline to 3, 6 and 12 months after RDN. Patients with LPHS or ADPKD, who experienced kidney-related pain >=3 months with a visual analogue scale (VAS) score >= 50/100 could be included. Percutaneous RDN was performed with a single electrode radiofrequency ablation catheter. Results: RDN was performed in 11 patients (6 with LPHS and 5 with ADPKD). Perceived pain declined in the whole group by 23 mm (P = 0.012 for the total group). In patients with LPHS and ADPKD, the median daily defined dosage of analgesic medication decreased from 1.6 [interquartile range (IQR) 0.7-2.3] and 1.4 (IQR 0.0-7.4) at baseline to 0.3 (IQR 0.0-1.9; P = 0.138) and 0.0 (IQR 0.0-0.8; P = 0.285) at 12 months, respectively. Mean estimated glomerular filtration rate decreased in the whole group by 5.4 mL/min/1.73 m 2 at 6 months compared with baseline (P = 0.163). Conclusions: These results suggest that percutaneous catheter-based RDN reduces pain complaints and the use of analgesic medication in patients with LPHS or ADPKD. The present results can serve as the rationale for a larger, preferably randomized (sham) controlled study. PMID- 28645207 TI - Development and validation of an electronic medical record (EMR)-based computed phenotype of HIV-1 infection. AB - Background: Electronic medical record (EMR) computed algorithms allow investigators to screen thousands of patient records to identify specific disease cases. No computed algorithms have been developed to detect all cases of human immunodeficiency virus (HIV) infection using administrative, laboratory, and clinical documentation data outside of the Veterans Health Administration. We developed novel EMR-based algorithms for HIV detection and validated them in a cohort of subjects in the Duke University Health System (DUHS). Methods: We created 2 novel algorithms to identify HIV-infected subjects. Algorithm 1 used laboratory studies and medications to identify HIV-infected subjects, whereas Algorithm 2 used International Classification of Diseases, Ninth Revision (ICD-9) codes, medications, and laboratory testing. We applied the algorithms to a well characterized cohort of patients and validated both against the gold standard of physician chart review. We determined sensitivity, specificity, and prevalence of HIV between 2007 and 2011 in patients seen at DUHS. Results: A total of 172 271 patients were detected with complete data; 1063 patients met algorithm criteria for HIV infection. In all, 970 individuals were identified by both algorithms, 78 by Algorithm 1 alone, and 15 by Algorithm 2 alone. The sensitivity and specificity of each algorithm were 78% and 99%, respectively, for Algorithm 1 and 77% and 100% for Algorithm 2. The estimated prevalence of HIV infection at DUHS between 2007 and 2011 was 0.6%. Conclusions: EMR-based phenotypes of HIV infection are capable of detecting cases of HIV-infected adults with good sensitivity and specificity. These algorithms have the potential to be adapted to other EMR systems, allowing for the creation of cohorts of patients across EMR systems. PMID- 28645210 TI - Minimally Invasive Autopsy: Welcoming a New Tool for Cause of Death Investigation in Children in Resource-constrained Countries. PMID- 28645209 TI - Genome-Wide Mapping of In Vivo ERalpha-Binding Sites in Male Mouse Efferent Ductules. AB - As an important nuclear hormone receptor, estrogen receptor alpha (ERalpha), which is encoded by the Esr1 gene, regulates the expression of hundreds of genes in a stimulus-specific, temporal, and tissue-specific fashion, mainly by binding to specific DNA sequences called estrogen response elements (EREs). As an important estrogen target tissue in males, the function of the efferent ductules relies on the presence of the ERalpha protein, but the underlying regulatory mechanisms are poorly illustrated. In this study, genome-wide ERalpha-binding sites in mouse efferent ductules were mapped by chromatin immunoprecipitation sequencing. In total, 12,105 peaks were identified, and a majority of them were located far from the annotated gene transcription start site. Motif analysis revealed that ~80% of the ERalpha-binding peaks harbored at least one ERE, whereas androgen response element-like sequences were the most overrepresented motif in the peaks without any EREs. A number of candidate transcription factor motifs adjacent to the EREs were significantly enriched, including AP2 and GRE, implying the involvement of these putative adjacent factors in the global regulation of ERalpha target genes. Unexpectedly, more than 50% of the ERalpha binding peaks in mouse efferent ductules overlapped with those binding peaks previously identified in mouse uterus, suggesting the conserved mechanism of ERalpha action in these two tissues. Cobinding of ERalpha target genes by androgen receptor was further confirmed for Slc9a3 gene, which was responsible for fluid resorption in the efferent ductules. Taken together, our study provides a useful reference set for future work aimed at exploring the mechanism of ERalpha action in physiological conditions. PMID- 28645212 TI - Google Searches for "Cheap Cigarettes" Spike at Tax Increases: Evidence from an Algorithm to Detect Spikes in Time Series Data. AB - Introduction: Online cigarette dealers have lower prices than brick-and-mortar retailers and advertise tax-free status.1-8 Previous studies show smokers search out these online alternatives at the time of a cigarette tax increase.9,10 However, these studies rely upon researchers' decision to consider a specific date and preclude the possibility that researchers focus on the wrong date. The purpose of this study is to introduce an unbiased methodology to the field of observing search patterns and to use this methodology to determine whether smokers search Google for "cheap cigarettes" at cigarette tax increases and, if so, whether the increased level of searches persists. Methods: Publicly available data from Google Trends is used to observe standardized search volumes for the term, "cheap cigarettes". Seasonal Hybrid Extreme Studentized Deviate and E Divisive with Means tests were performed to observe spikes and mean level shifts in search volume. Results: Of the twelve cigarette tax increases studied, ten showed spikes in searches for "cheap cigarettes" within two weeks of the tax increase. However, the mean level shifts did not occur for any cigarette tax increase. Conclusion: Searches for "cheap cigarettes" spike around the time of a cigarette tax increase, but the mean level of searches does not shift in response to a tax increase. The SHESD and EDM tests are unbiased methodologies that can be used to identify spikes and mean level shifts in time series data without an a priori date to be studied. SHESD and EDM affirm spikes in interest are related to tax increases. Implications: * Applies improved statistical techniques (SHESD and EDM) to Google search data related to cigarettes, reducing bias and increasing power * Contributes to the body of evidence that state and federal tax increases are associated with spikes in searches for cheap cigarettes and may be good dates for increased online health messaging related to tobacco. PMID- 28645211 TI - AKR1C3-Mediated Adipose Androgen Generation Drives Lipotoxicity in Women With Polycystic Ovary Syndrome. AB - Context: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS. Methods: We performed a human deep metabolic in vivo phenotyping study examining the systemic and intra-adipose effects of acute and chronic androgen exposure in 10 PCOS women, in comparison with 10 body mass index matched healthy controls, complemented by in vitro experiments. Results: PCOS women had increased intra-adipose concentrations of testosterone (P = 0.0006) and dihydrotestosterone (P = 0.01), with increased expression of the androgen activating enzyme aldo-ketoreductase type 1 C3 (AKR1C3) (P = 0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (P = 0.04). Mirroring this, nontargeted serum metabolomics revealed prolipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity, whereas androgen exposure increased adipocyte de novo lipid synthesis. Pharmacologic AKR1C3 inhibition in vitro decreased de novo lipogenesis. Conclusions: These findings define an intra-adipose mechanism of androgen activation that contributes to adipose remodeling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising therapeutic target in PCOS. PMID- 28645213 TI - Cohort Profile: The 'Bristol Cats Study' (BCS)-a birth cohort of kittens owned by UK households. PMID- 28645214 TI - Sodium Fluorescein Facilitates Guided Sampling of Diagnostic Tumor Tissue in Nonenhancing Gliomas. AB - BACKGROUND: Accurate tissue sampling in nonenhancing (NE) gliomas is a unique surgical challenge due to their intratumoral histological heterogeneity and absence of contrast enhancement as a guide for intraoperative stereotactic guidance. Instead, T2/fluid-attenuated inversion-recovery (FLAIR) hyperintensity on MRI is commonly used as an imaging surrogate for pathological tissue, but sampling from this region can yield nondiagnostic or underdiagnostic brain tissue. Sodium fluorescein is an intraoperative fluorescent dye that has a high predictive value for tumor identification in areas of contrast enhancement and NE in glioblastomas. However, the underlying histopathological alterations in fluorescent regions of NE gliomas remain undefined. OBJECTIVE: To evaluate whether fluorescein can identify diagnostic tissue and differentiate regions with higher malignant potential during surgery for NE gliomas, thus improving sampling accuracy. METHODS: Thirteen patients who presented with NE, T2/FLAIR hyperintense lesions suspicious for glioma received fluorescein (10%, 3 mg/kg intravenously) during surgical resection. RESULTS: Patchy fluorescence was identified within the T2/FLAIR hyperintense area in 10 of 13 (77%) patients. Samples taken from fluorescent regions were more likely to demonstrate diagnostic glioma tissue and cytologic atypia (P < .05). Fluorescein demonstrated a 95% positive predictive value for the presence of diagnostic tissue. Samples from areas of fluorescence also demonstrated greater total cell density and higher Ki-67 labeling than nonfluorescent biopsies (P < .05). CONCLUSION: Fluorescence in NE gliomas is highly predictive of diagnostic tumor tissue and regions of higher cell density and proliferative activity. PMID- 28645215 TI - Upper Extremity Trauma Resulting From Agricultural Accidents: Mechanism and Severity for Patients With and Without Upper Extremity Injury. AB - BACKGROUND: Farming remains the most dangerous occupation in the United States and upper extremity (UE) injuries occur frequently in agricultural accidents. The purpose of this study is to describe the injury mechanisms, severity, and health care costs of UE injuries resulting from agricultural accidents and to compare patients with and without injuries to the UE. METHODS: We performed a 6-year retrospective review of our level I trauma center registry from January 2006 to May 2013, identifying all patients injured in an agricultural accident. Data collection included baseline demographics, injury type and mechanism, costs and treatment. Patients with UE injuries were compared with those without UE injuries. RESULTS: Ninety-six of 273 patients (35%) sustained an UE injury with fractures of the phalanx and radius/ulna occurring most frequently. Patients with UE injuries were more likely to be injured from table saws ( P = .0003) and farm machinery ( P < .0001). Twenty-one percent with UE injuries sustained a mangled extremity. Patients with UE injuries were more likely to require surgery (68% vs 36%, P < .0001) and were more likely to be readmitted (17% vs 5%, P = .0007) with risk factors for readmission including age >18 years, falls from height, and surgery. Mean hospital charges were $95 147. CONCLUSIONS: Patients sustaining agricultural UE injuries have longer lengths of stay and more frequently require surgery despite similar hospital charges compared with non-UE injured patients. Hospital readmissions occur frequently for patients with UE injuries. Understanding injury mechanisms and the epidemiology of these potentially devastating and costly injuries may help guide agricultural injury prevention programs. PMID- 28645216 TI - iGlarLixi: A Fixed-Ratio Combination of Insulin Glargine 100 U/mL and Lixisenatide for the Treatment of Type 2 Diabetes. AB - OBJECTIVE: To review the safety and efficacy of iGlarLixi, a titratable fixed ratio combination of insulin glargine 100 U/mL (iGlar) and lixisenatide, a glucagon-like peptide-1 receptor agonist. DATA SOURCES: A literature search of MEDLINE for all English-language primary articles through June 2016, using the terms LixiLan, iGlarLixi and insulin glargine and lixisenatide, and a search of abstracts presented at the 2016 Scientific Sessions of the American Diabetes Association were performed. STUDY SELECTION AND DATA EXTRACTION: All studies assessing the efficacy and/or safety of iGlarLixi were evaluated. DATA SYNTHESIS: iGlarLixi has been approved in the United States for glycemic control in people with type 2 diabetes (T2D) inadequately controlled with basal insulin (<60 U/d) or lixisenatide. In clinical trials, iGlarLixi was associated with significantly greater reductions from baseline in glycated hemoglobin A1C (A1C) than iGlar or lixisenatide alone. Reductions in postprandial glucose were also greater with iGlarLixi than with iGlar or lixisenatide. iGlarLixi was weight neutral compared with the weight gain with iGlar and loss with lixisenatide alone, and there was no increase in hypoglycemia with iGlarLixi compared with iGlar despite the greater A1C reduction. Gastrointestinal events, frequently associated with lixisenatide, were less common with iGlarLixi. Potential drawbacks of iGlarLixi include reduced flexibility in dosing and the absence of long-term efficacy and safety data. CONCLUSIONS: iGlarLixi is a titratable fixed-ratio combination that shows improved efficacy and comparable or improved safety outcomes relative to its separate constituents, offering an alternative approach to intensification of therapy in T2D. PMID- 28645217 TI - Microtubule-Organizing Centers. AB - The organization of microtubule networks is crucial for controlling chromosome segregation during cell division, for positioning and transport of different organelles, and for cell polarity and morphogenesis. The geometry of microtubule arrays strongly depends on the localization and activity of the sites where microtubules are nucleated and where their minus ends are anchored. Such sites are often clustered into structures known as microtubule-organizing centers, which include the centrosomes in animals and spindle pole bodies in fungi. In addition, other microtubules, as well as membrane compartments such as the cell nucleus, the Golgi apparatus, and the cell cortex, can nucleate, stabilize, and tether microtubule minus ends. These activities depend on microtubule-nucleating factors, such as gamma-tubulin-containing complexes and their activators and receptors, and microtubule minus end-stabilizing proteins with their binding partners. Here, we provide an overview of the current knowledge on how such factors work together to control microtubule organization in different systems. PMID- 28645218 TI - Wide-Awake Anesthesia in the In-Office Procedure Room: Lessons Learned. AB - BACKGROUND: Wide-awake local anesthesia and no tourniquet (WALANT) has become more popular in hand surgery. Without a tourniquet, there is no need for preoperative testing or sedation. The use of lidocaine with epinephrine has allowed a larger variety of cases to be done safely in an outpatient setting instead of the hospital. "Minor field sterility," which uses fewer drapes and tools to accomplish the same procedures, is a concept that is also gaining recognition. METHODS: Investigation of hand surgeons performing a majority of cases using WALANT and minor field sterility was the beginning of seeing its potential at our institution. Administration was concerned about patient safety, cost-effectiveness, and patient satisfaction of the proposed changes. Analysis of our institution to determine location of these procedures was also imperative to using WALANT. RESULTS: An in-office procedure room was built to allow for WALANT and minor field sterility. The requirements and logistics of developing an in office procedure room for wide-awake surgery are reviewed in this article. CONCLUSIONS: The concurrent use of WALANT and minor field sterility has created a hand surgery practice that is cost-effective for the patient and the facility and resulted in excellent patient outcomes and satisfaction. PMID- 28645219 TI - Pullulan microbeads/Si-HPMC hydrogel injectable system for the sustained delivery of GDF-5 and TGF-beta1: new insight into intervertebral disc regenerative medicine. AB - Discogenic low back pain is considered a major health concern and no etiological treatments are today available to tackle this disease. To clinically address this issue at early stages, there is a rising interest in the stimulation of local cells by in situ injection of growth factors targeting intervertebral disc (IVD) degenerative process. Despite encouraging safety and tolerability results in clinic, growth factors efficacy may be further improved. To this end, the use of a delivery system allowing a sustained release, while protecting growth factors from degradation appears of particular interest. We propose herein the design of a new injectable biphasic system, based on the association of pullulan microbeads (PMBs) into a cellulose-based hydrogel (Si-HPMC), for the TGF-beta1 and GDF-5 growth factors sustained delivery. We present for the first time the design and mechanical characterization of both the PMBs and the called biphasic system (PMBs/Si-HPMC). Their loading and release capacities were also studied and we were able to demonstrate a sustained release of both growth factors, for up to 28 days. Noteworthy, the growth factors biological activity on human cells was maintained. Altogether, these data suggest that this PMBs/Si-HPMC biphasic system may be a promising candidate for the development of an innovative bioactive delivery system for IVD regenerative medicine. PMID- 28645221 TI - Obituary: Dr Dimitri Tassiopoulos. PMID- 28645220 TI - Comparison of Emla cream and topical lidocaine tape for pain relief of V-beam laser treatment. AB - The authors compared the analgesic effects of two topical applications; Emla(r) cream (Sato Pharmaceutical Co. Ltd., Tokyo, Japan) and 60% lidocaine tape (Penles(r) tape; Maruho, Osaka, Japan). The authors examined 20 outpatients with capillary malformations. Emla(r) cream or Penles(r) tape was applied 1 h before laser irradiation using V-Beam. After V-Beam irradiation, pain intensity was measured using Pain Vision(r) (NIPRO, Osaka, Japan), while subjective pain was converted into numerical values using the VAS system. In the assessment using Pain Vision(r), pain was significantly lower in patients who received Emla(r) cream (Welch test), whereas no difference was observed in VAS ratings between the two applications (student's t test). The objective system showed that Emla(r) cream had a significantly greater analgesic effect. We plan to evaluate the analgesic effects of these topical anesthetics by applying them to other anatomical areas. PMID- 28645222 TI - Dietary Fat and Risk of Cardiovascular Disease: Recent Controversies and Advances. AB - Health effects of dietary fats have been extensively studied for decades. However, controversies exist on the effects of various types of fatty acids, especially saturated fatty acid (SFA), on cardiovascular disease (CVD). Current evidence supports that different types of dietary fatty acids have divergent effects on CVD risk, and the effects also depend strongly on the comparison or replacement macronutrient. A significant reduction in CVD risk can be achieved if SFAs are replaced by unsaturated fats, especially polyunsaturated fatty acids. Intake of industrially produced trans fat is consistently associated with higher CVD risk. Both n-6 and n-3 polyunsaturated fatty acids are associated with lower CVD risk, although the effects of fish oil supplementation remains inconsistent. The 2015-2020 Dietary Guidelines for Americans place greater emphasis on types of dietary fat than total amount of dietary fat and recommend replacing SFAs with unsaturated fats, especially polyunsaturated fatty acids for CVD prevention. PMID- 28645223 TI - Decline in Literacy and Incident AD Dementia Among Community-Dwelling Older Persons. AB - OBJECTIVE: To quantify longitudinal change in financial and health literacy and examine the associations of declining literacy with incident Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI). METHOD: Data came from 799 participants of an ongoing cohort study. Literacy was measured using a battery of 32 questions. Clinical diagnoses were made annually following uniform structured procedures. The associations of declining literacy with incident AD dementia and MCI were tested using a joint model for longitudinal and time-to-event data. RESULTS: We observed an overall decline in total literacy score over up to 6 years of follow-up ( p < .001). Faster decline in literacy was associated with higher risks for incident AD dementia (hazard ratio = 4.526, 95% confidence interval = [2.993, 6.843], p < .001) and incident MCI (hazard ratio = 2.971, 95% confidence interval = [1.509, 5.849], p = .002). DISCUSSION: Declining literacy among community-dwelling older persons predicts adverse cognitive outcomes and serves as an early indicator of impending dementia. PMID- 28645225 TI - Medication Regimen Complexity and Low Adherence in Older Community-Dwelling Adults With Substantiated Self-Neglect. AB - OBJECTIVE: Determine whether medication regimen complexity predicts medication adherence levels in a sample of community-dwelling adults 65 years and older with Adult Protective Services-substantiated self-neglect. METHODS: A cross-sectional analysis of baseline data ( N = 31 participants) from a pilot intervention to increase medication adherence among the target group was performed. The Medication Regimen Complexity Index (MRCI) and the 8-item Morisky Medication Adherence Scale (MMAS-8)TM were the primary independent and dependent measures, respectively. A multivariable linear regression analysis, adjusting for potential confounders, was conducted to estimate the association between complexity and adherence. RESULTS: Regimen complexity was high (mean MRCI = 19.6) and adherence was low (mean MMAS = 5.1). Even after controlling for confounders, increased complexity was significantly associated with lower adherence. DISCUSSION: Older community-dwelling adults who self-neglect have complex medication regimens that contribute to low medication adherence. Medication regimen complexity may be a modifiable contributor to low adherence that can be targeted by future interventions to reduce self-neglect and its consequences. PMID- 28645226 TI - The Fragile Spell of Desire: A Functional Perspective on Changes in Sexual Desire Across Relationship Development. AB - The sexual behavioral system evolved to motivate reproductive acts by arousing sexual desire. Building on the idea that this system has also been "exploited" by evolutionary processes to promote enduring bonds between romantic partners, the present article introduces an integrative model that delineates the functional significance of sexual desire in relationship formation and maintenance. This model explains why individuals' sexual reaction to their partner is context dependent, clarifying how changes in the nature of interdependence over the course of relationships alter the ways in which specific predictors of sexual desire tend to promote (or inhibit) desire and thereby affect relationship depth and stability. The model postulates that although desire influences the development of attachment bonds, the contribution that it makes varies over the course of relationships. The model also provides new insight regarding fundamental but unresolved issues in human sexuality, such as the vulnerability of sexual desire and the desire-intimacy paradox. PMID- 28645224 TI - A Symphony of Cyclases: Specificity in Diguanylate Cyclase Signaling. AB - Cyclic diguanylate (c-di-GMP) is a near universal signaling molecule produced by diguanylate cyclases that can direct a variety of bacterial behaviors. A major area of research over the last several years has been aimed at understanding how a cell with dozens of diguanylate cyclases can deploy a given subset of them to produce a desired phenotypic outcome without undesired cross talk between c-di GMP-dependent systems. Several models have been put forward to address this question, including specificity of cyclase activation, tuned binding constants of effector proteins, and physical interaction between cyclases and effectors. Additionally, recent evidence has suggested that there may be a link between the catalytic state of a cyclase and its physical contact with an effector. This review highlights several key studies, examines the proposed global and local models of c-di-GMP signaling specificity in bacteria, and attempts to identify the most fruitful steps that can be taken to better understand how dynamic networks of sibling cyclases and effector proteins result in sensible outputs that govern cellular behavior. PMID- 28645228 TI - So this is it.... PMID- 28645227 TI - Diabetic and Obese Patient Clinical Outcomes Improve During a Care Management Implementation in Primary Care. AB - BACKGROUND: To address the increasing burden of chronic disease, many primary care practices are turning to care management and the hiring of care managers to help patients coordinate their care and self-manage their conditions. Care management is often, but not always, proving effective at improving patient outcomes, but more evidence is needed. METHODS: In this pair-matched cluster randomized trial, 5 practices implemented care management and were compared with 5 comparison practices within the same practice organization. Targeted patients included diabetic patients with a hemoglobin A1c >9% and nondiabetic obese patients. Clinical values tracked were A1c, blood pressure, low-density lipoprotein, microalbumin, and weight. RESULTS: Clinically important improvements were demonstrated in the intervention versus comparison practices, with diabetic patients improving A1c control and obese patients experiencing weight loss. There was a 12% relative increase in the proportion of patients meeting the clinical target of A1c <7% (95% CI, 3%-20%), and 26% of obese nondiabetic patients in chronic care management practices lost 5% or more of their body weight as compared with 10% of comparison patients (adjusted relative improvement, 15%; CI, 2%-28%). CONCLUSIONS: These findings add to the growing evidence-base for the effectiveness of care management as an effective clinical practice with regard to improving diabetes- and obesity-related outcomes. PMID- 28645229 TI - Cognitive function in early psychosis patients from a lower middle-income country. AB - OBJECTIVES: To establish evidence of cognitive changes in early psychosis (EP) patients compared to healthy controls (HC) in Pakistan. METHODS: Fifty-one participants with EP were recruited from psychiatric units in Karachi and Rawalpindi, Pakistan and matched with 51 HC. Neurocognitive domains were assessed using standardised neuropsychological tests [the Stroop test, block design, Matrix Reasoning, picture completion, object assembly, oral fluency, memory for design, Coughlan learning task (verbal and visual)]. RESULTS: EP patients had higher scores than controls for both Stroop tests (T1: EP = 122 HC = 65, p <.001; T2: EP = 190 HC = 153, p = .007) and memory for design test (EP = 10 HC = 3, p = .005). EP group had lower values for block design (EP = 4, HC = 11, p = .01), category fluency (EP = 18.9, HC = 26.1, p < .001), Coughlan verbal tasks (EP = 36.4 NC = 51.5, p < .001), matrix reasoning (EP = 4 NC = 10, p < .001), picture completion (EP = 4 NC = 6, p = .003) and object assembly (EP = 10.7, HC = 15.5, p = .002). There were limited significant associations between cognitive performance and PANSS scores. CONCLUSIONS: Reduced cognitive performance was found across multiple domains in Pakistani EP patients, which suggests that impaired cognitive performance is homogenous in patients with schizophrenia, regardless of ethnicity. PMID- 28645230 TI - Implementation in action: how Australian Exercise Physiologists approach exercise prescription for people with mental illness. AB - BACKGROUND: Accredited Exercise Physiologists (AEPs) are trained to deliver exercise and physical activity interventions for people with chronic and complex health conditions including those with mental illness. However, their views on exercise for mental illness, their exercise prescription practices, and need for further training are unknown. AIMS: To examine the way in which Australian AEPs prescribe exercise for people with mental illness. METHODS: Eighty-one AEPs (33.3 +/- 10.4 years) completed an online version of the Exercise in Mental Illness Questionnaire. Findings are reported using descriptive statistics. RESULTS: AEPs report a high level of knowledge and confidence in prescribing exercise for people with mental illness. AEPs rate exercise to be at least of equal value to many established treatments for mental illness, and frequently prescribe exercise based on current best-practice principles. A need for additional training was identified. The response rate was low (2.4%) making generalisations from the findings difficult. CONCLUSIONS: Exercise prescription practices utilised by AEPs are consistent with current best-practice guidelines and there is frequent consultation with consumers to individualise exercise based on their preferences and available resources. Further training is deemed important. PMID- 28645231 TI - Evolution of Hormone Signaling Networks in Plant Defense. AB - Studies with model plants such as Arabidopsis thaliana have revealed that phytohormones are central regulators of plant defense. The intricate network of phytohormone signaling pathways enables plants to activate appropriate and effective defense responses against pathogens as well as to balance defense and growth. The timing of the evolution of most phytohormone signaling pathways seems to coincide with the colonization of land, a likely requirement for plant adaptations to the more variable terrestrial environments, which included the presence of pathogens. In this review, we explore the evolution of defense hormone signaling networks by combining the model plant-based knowledge about molecular components mediating phytohormone signaling and cross talk with available genome information of other plant species. We highlight conserved hubs in hormone cross talk and discuss evolutionary advantages of defense hormone cross talk. Finally, we examine possibilities of engineering hormone cross talk for improvement of plant fitness and crop production. PMID- 28645232 TI - Interplay Between Innate Immunity and the Plant Microbiota. AB - The innate immune system of plants recognizes microbial pathogens and terminates their growth. However, recent findings suggest that at least one layer of this system is also engaged in cooperative plant-microbe interactions and influences host colonization by beneficial microbial communities. This immune layer involves sensing of microbe-associated molecular patterns (MAMPs) by pattern recognition receptors (PRRs) that initiate quantitative immune responses to control host microbial load, whereas diversification of MAMPs and PRRs emerges as a mechanism that locally sculpts microbial assemblages in plant populations. This suggests a more complex microbial management role of the innate immune system for controlled accommodation of beneficial microbes and in pathogen elimination. The finding that similar molecular strategies are deployed by symbionts and pathogens to dampen immune responses is consistent with this hypothesis but implies different selective pressures on the immune system due to contrasting outcomes on plant fitness. The reciprocal interplay between microbiota and the immune system likely plays a critical role in shaping beneficial plant-microbiota combinations and maintaining microbial homeostasis. PMID- 28645233 TI - Adaptation to the Host Environment by Plant-Pathogenic Fungi. AB - Many fungi can live both saprophytically and as endophyte or pathogen inside a living plant. In both environments, complex organic polymers are used as sources of nutrients. Propagation inside a living host also requires the ability to respond to immune responses of the host. We review current knowledge of how plant pathogenic fungi do this. First, we look at how fungi change their global gene expression upon recognition of the host environment, leading to secretion of effectors, enzymes, and secondary metabolites; changes in metabolism; and defense against toxic compounds. Second, we look at what is known about the various cues that enable fungi to sense the presence of living plant cells. Finally, we review literature on transcription factors that participate in gene expression in planta or are suspected to be involved in that process because they are required for the ability to cause disease. PMID- 28645234 TI - The Long Arm of Childhood in China: Early-Life Conditions and Cognitive Function Among Middle-Aged and Older Adults. AB - OBJECTIVE: This study examined the association between childhood conditions and cognitive function among middle-aged and older adults in China. METHOD: We analyzed data from the 2011 China Health and Retirement Longitudinal Study ( N = 11,868). Cognitive function was measured by word recall, a test of episodic memory. We examined the association between childhood conditions and cognitive function among the middle-aged (45-59 years) and the older (60 years and older) adults separately, using multilevel linear regressions. RESULTS: Indicators of childhood socioeconomic status (SES) and nutrition were significantly associated with memory performance among the middle-aged and the older adults in China. Adulthood SES, education in particular, accounted for some but not all the associations. The protective effect of childhood urban residence was stronger for middle-aged women than for middle-aged men. DISCUSSION: Childhood conditions are significantly associated with mid- to late-life cognitive function in China. The strengths of the associations may vary by gender and cohort. PMID- 28645235 TI - External Validity of the New York University Caregiver Intervention: Key Caregiver Outcomes Across Multiple Demonstration Projects. AB - PURPOSE OF THE STUDY: The Administration on Aging funded six New York University Caregiver Intervention (NYUCI) demonstration projects, a counseling/support intervention targeting dementia caregivers and families. Three sites (Georgia, Utah, Wisconsin) pooled data to inform external validity in nonresearch settings. This study (a) assesses collective changes over time, and (b) compares outcomes across sites on caregiver burden, depressive symptoms, satisfaction with social support, family conflict, and quality of life. DESIGN AND METHODS: Data included baseline/preintervention ( N = 294) and follow-up visits (approximately 4, 8, 12 months). RESULTS: Linear mixed models showed that social support satisfaction increased ( p < .05) and family conflict decreased ( p < .05; Cohen's d = 0.49 and 0.35, respectively). Marginally significant findings emerged for quality of life increases ( p = .05) and burden decreases ( p < .10). Depressive symptoms remained stable. Slopes did not differ much by site. IMPLICATIONS: NYUCI demonstrated external validity in nonresearch settings across diverse caregiver samples. PMID- 28645236 TI - A Quantitative Study of Empathy in Pakistani Medical Students: A Multicentered Approach. AB - OBJECTIVE: To examine the empathy level of undergraduate medical students in Pakistan. Three hypotheses are developed based on the literature review. (1) Female medical students have a higher level of empathy than do male students. (2) Empathy scores vary during the medical school years in Pakistani students. (3) Medical students interested in people-oriented specialties would score higher than the students interested in technology-oriented specialties. METHODS: This is a quantitative inquiry approach using a cross-sectional design of 1453 students from 8 Pakistani medical schools, both private and state. The sample consists of 41.1% (n = 597) male students and 58.9% (n = 856) female students. Empirical data are collected using the Jefferson Scale of Physician Empathy (JSPE), a well validated self-administered questionnaire. RESULTS: The mean empathy score among students is 4.77 with a standard deviation of 0.72. The results show that there is no statistically significant association between the empathy scores and gender, t(1342.36) = -0.053, P = .95). There is a statistically significant difference between the empathy scores and the years of medical school, F(14, 1448) = 4.95, P = .01. Concerning the specialty interests, there is no statistically significant difference between the empathy score and specialty interests. CONCLUSION: The findings of this study showed that in Western countries, medical students performed better than Pakistani medical students on the empathy scale. This finding has important implications for Pakistani medical educators to improve the interpersonal skills of medical students in the context of patient care. Inconsistent with our expectations and experiences, our findings do not support that female medical students scored better than their male counterparts on the empathy scale. Because of the nature of a cross-sectional study, it is impossible to argue the decline of empathy during medical school training. PMID- 28645237 TI - Homologous microscopic agglutinating antibodies after natural infection with leptospires - results from a long term follow up of a cohort living in an endemic area. PMID- 28645238 TI - New World Arenavirus Biology. AB - Hemorrhagic fevers caused by viruses were identified in the late 1950s in South America. These viruses have existed in their hosts, the New World rodents, for millions of years. Their emergence as infectious agents in humans coincided with changes in the environment and farming practices that caused explosions in their host rodent populations. Zoonosis into humans likely occurs because the pathogenic New World arenaviruses use human transferrin receptor 1 to enter cells. The mortality rate after infection with these viruses is high, but the mechanism by which disease is induced is still not clear. Possibilities include direct effects of cellular infection or the induction of high levels of cytokines by infected sentinel cells of the immune system, leading to endothelia and thrombocyte dysfunction and neurological disease. Here we provide a review of the ecology and molecular and cellular biology of New World arenaviruses, as well as a discussion of the current animal models of infection. The development of animal models, coupled with an improved understanding of the infection pathway and host response, should lead to the discovery of new drugs for treating infections. PMID- 28645239 TI - Cassava Mosaic and Brown Streak Diseases: Current Perspectives and Beyond. AB - Cassava is the fourth largest source of calories in the world but is subject to economically important yield losses due to viral diseases, including cassava brown streak disease and cassava mosaic disease. Cassava mosaic disease occurs in sub-Saharan Africa and the Asian subcontinent and is associated with nine begomovirus species, whereas cassava brown streak disease has to date been reported only in sub-Saharan Africa and is caused by two distinct ipomovirus species. We present an overview of key milestones and their significance in the understanding and characterization of these two major diseases as well as their associated viruses and whitefly vector. New biotechnologies offer a wide range of opportunities to reduce virus-associated yield losses in cassava for farmers and can additionally enable the exploitation of this valuable crop for industrial purposes. This review explores established and new technologies for genetic manipulation to achieve desired traits such as virus resistance. PMID- 28645240 TI - Engineered Expression of Broadly Neutralizing Antibodies Against Human Immunodeficiency Virus. AB - This review discusses recent progress made in developing a vaccine and novel treatments for human immunodeficiency virus (HIV). It highlights the shortcomings of the RV144 vaccination trial [ALVAC-HIV (vCP1521) and AIDSVAX B/E] and the current standard of care and proposes that engineered expression of broadly neutralizing antibodies (bNAbs) against HIV-1 could overcome these shortcomings. Current developments in three major lines of research on HIV prevention and treatment using bNAbs are reviewed: firstly, the use of sequential immunogens to activate B cells to express bNAbs; secondly, the delivery of novel and extremely potent bNAbs through passive administration; and finally, the use of gene transfer using adeno-associated viral vectors to deliver bNAbs. PMID- 28645241 TI - Long-term outcome after right ventricle to pulmonary artery conduit surgery and reintervention. AB - BACKGROUND: Reconstruction of the right ventricular outflow tract with a conduit is an established surgical procedure in congenital heart disease and reinterventions are common. OBJECTIVE: An increasing number of patients have a conduit, but there are few population-based studies of long-term outcomes after conduit surgery, reoperations, and transcatheter pulmonary valve replacement. METHODS: In April 2015, all adult patients with a conduit were identified in the Swedish National Registry for Congenital Heart Disease (SWEDCON). Data on patients who died before age of 16 years are not included in the registry and thus not included in the study. RESULTS: We found 574 patients with a mean age 36.1 years. The largest proportion had tetralogy of Fallot (45%). In total there were 762 operations and 50 transcatheter pulmonary valve replacements. Mean age at first conduit operation was 20.2 years. Long-term survival up to 48 years including perioperative mortality (<1%) was 93% at 20 years. The most common cause of death was cardiac-related. Higher age at first conduit operation was associated with increased mortality risk. Reintervention-free survival was 77% and 54% at 10 and 20 years, respectively. Conduit reinterventions were common. Ten-year reintervention-free survival after first conduit reintervention (n = 176) was significantly lower than after first conduit operation (70% vs 77% p = .04). Higher age at first conduit operation was associated with a reduced risk of reintervention, whereas male sex and complex malformations were associated with increased risk of reintervention. CONCLUSIONS: The mortality of repeated conduit reinterventions is low. The need for reintervention of conduits is considerable, and reintervention-free survival after the first conduit reintervention is poorer than after first conduit implantation. The findings in this study only applies for patients reaching 16 years of age. PMID- 28645242 TI - Factors Associated With Visual Impairment and Eye Care Utilization: The International Mobility in Aging Study. AB - OBJECTIVE: To examine factors associated with visual impairment (VI) and eye care in the International Mobility in Aging Study (IMIAS). METHOD: IMIAS data were analyzed ( N = 1,995 with ages 65-74). Outcomes were VI defined as presenting visual acuity worse than 6/18 in the better eye and eye care utilization assessed by annual visits to eye care professionals. The Hurt-Insult-Threaten-Scream (HITS) questionnaire requested information on domestic violence. RESULTS: Among men, VI varied from 24% in Manizales (Colombia) to 0.5% in Kingston (Canada); among women, VI ranged from 20% in Manizales to 1% in Kingston; lifetime exposure to domestic violence was associated with VI (odds ratio [OR] = 1.87; 95% confidence interval [CI] = [1.17, 3.00]). Eye care utilization varied from 72% in Kingston's men to 25% in Tirana's men; it was associated with domestic violence (prevalence ratio [PR] = 1.3; 95% CI = [1.1, 1.6]). DISCUSSION: VI is more frequent where eye care utilization is low. Domestic violence may be a risk factor for VI. PMID- 28645243 TI - Extended Periarterial Sympathectomy: Evaluation of Long-term Outcomes. AB - BACKGROUND: Periarterial sympathectomy is a proposed surgical treatment for patients with refractory Raynaud syndrome; however, there is debate regarding the indications and extent of dissection. Due to the segmental arterial sympathetic innervation, we favor an extended sympathectomy in concert with vein graft reconstruction of occluded vessels when necessary. The purpose of this study is to examine outcomes of extended periarterial sympathectomy in our patients. METHODS: A retrospective chart review was performed on 46 patients who underwent 58 periarterial sympathectomies (12 bilateral) since 1981. The data collected include demographics, comorbidities, previous therapy, operative details, and surgical outcomes. In addition, we contacted available patients for a phone survey. RESULTS: Of 58 cases, 68.9% were female, 29.3% were current smokers, and 58.6% had known connective tissue disease. Thirty-three vein graft reconstructions were performed with a long-term patency of 77.4%. Sustained improvement of ischemic pain was reported in 94.8% of cases, and 78% of patients with ulcers completely healed. For the most symptomatic fingertip, mean Semmes Weinstein monofilament measurements improved from 4.15 preoperatively to 3.29 postoperatively ( P <= .05). Mean follow-up was 3.97 years. Of 10 patients contacted by telephone, all reported a decrease in frequency and severity of Raynaud attacks, while 9 reported a long-term decrease in pain an average of 11.6 years after surgery. CONCLUSIONS: Extended periarterial sympathectomy is an effective and safe procedure for patients with refractory Raynaud syndrome. Our data demonstrate long-term improvement in ischemic pain and sensibility, along with a high rate of ulcer healing and patient satisfaction. PMID- 28645244 TI - Evolution of the vertebrate insulin receptor substrate (Irs) gene family. AB - BACKGROUND: Insulin receptor substrate (Irs) proteins are essential for insulin signaling as they allow downstream effectors to dock with, and be activated by, the insulin receptor. A family of four Irs proteins have been identified in mice, however the gene for one of these, IRS3, has been pseudogenized in humans. While it is known that the Irs gene family originated in vertebrates, it is not known when it originated and which members are most closely related to each other. A better understanding of the evolution of Irs genes and proteins should provide insight into the regulation of metabolism by insulin. RESULTS: Multiple genes for Irs proteins were identified in a wide variety of vertebrate species. Phylogenetic and genomic neighborhood analyses indicate that this gene family originated very early in vertebrae evolution. Most Irs genes were duplicated and retained in fish after the fish-specific genome duplication. Irs genes have been lost of various lineages, including Irs3 in primates and birds and Irs1 in most fish. Irs3 and Irs4 experienced an episode of more rapid protein sequence evolution on the ancestral mammalian lineage. Comparisons of the conservation of the proteins sequences among Irs paralogs show that domains involved in binding to the plasma membrane and insulin receptors are most strongly conserved, while divergence has occurred in sequences involved in interacting with downstream effector proteins. CONCLUSIONS: The Irs gene family originated very early in vertebrate evolution, likely through genome duplications, and in parallel with duplications of other components of the insulin signaling pathway, including insulin and the insulin receptor. While the N-terminal sequences of these proteins are conserved among the paralogs, changes in the C-terminal sequences likely allowed changes in biological function. PMID- 28645245 TI - Transcriptomic dynamics in soybean near-isogenic lines differing in alleles for an aphid resistance gene, following infestation by soybean aphid biotype 2. AB - BACKGROUND: Genetic resistance of soybean [Glycine max (L.) Merr] against Aphis glycines provides effective management of this invasive pest, though the underlying molecular mechanisms are largely unknown. This study aimed to investigate genome-wide changes in gene expressions of soybean near-isogenic lines (NILs) either with the Rag5 allele for resistance or the rag5 allele for susceptibility to the aphid following infestation with soybean aphid biotype 2. RESULTS: The resistant (R)-NIL responded more rapidly to aphid infestation than the susceptible (S)-NIL, with differential expressions of 2496 genes during first 12 h of infestation (hai), compared to the aphid-free control. Although the majority of the differentially expressed genes (DEGs) in the R-NIL also responded to aphid infestation in S-NIL, overall the response time was longer and/or the magnitude of change was smaller in the S-NIL. In addition, 915 DEGs in R-NIL continued to be regulated at all time points (0, 6, 12, and 48 hai), while only 20 DEGs did so in S-NIL. Enriched gene ontology of the 2496 DEGs involved in plant defense responses including primary metabolite catalysis, oxidative stress reduction, and phytohormone-related signaling. By comparing R- vs. S-NIL, a total of 556 DEGs were identified. Of the 13 genes annotated in a 120-kb window of the Rag5 locus, two genes (Glyma.13 g190200 and Glyma.13 g190600) were differentially expressed (upregulated in S- or R-NIL), and another gene (Glyma.13 g190500) was induced up to 4-fold in the R-NIL at 6 and 12 h following aphid infestation. CONCLUSIONS: This study strengthens our understanding of the defense dynamics in compatible and incompatible interactions of soybean and soybean aphid biotype 2. Several DEGs (e.g., Glyma.13 g190200, Glyma.13 g190500, and Glyma.13 g190600) near the Rag5 locus are strong candidate genes for further investigations. PMID- 28645246 TI - IgMk paraprotein from gammopathy patient can bind to cardiolipin and interfere with coagulation assay: a case report. AB - BACKGROUND: The monoclonal gammopathies are a group of plasma-cell proliferative disorders characterized by the secretion of monoclonal immunoglobulin (M protein or paraprotein). Some rare cases have revealed the specific affinity of paraprotein as autoantibody. Here we report a patient with monoclonal gammopathy of undetermined significance (MGUS) accompanied by a remarkable increase of anticardiolipin antibody (aCL) and an extensively decreased coagulation factor activity, however, without any clinical signs of antiphospholipid syndrome (APS) and bleeding. RESULTS: Our further investigation indicated that IgMkappa paraprotein of this patient possessed an antibody activity against phospholipids so as to bind to cardiolipin and interfere with coagulation assay in vitro. CONCLUSIONS: This case might be indicative that an abnormality of coagulation tests, disturbed by IgMkappa paraprotein, does not predict a risk of bleeding in this patient. PMID- 28645247 TI - The correlation between poor prognosis and increased yes-associated protein 1 expression in keratin 19 expressing hepatocellular carcinomas and cholangiocarcinomas. AB - BACKGROUND: The Hippo pathway plays a vital role in liver regeneration and development by determining cellular lineage and regulating cell proliferation and apoptosis. In this study, we aimed to assess the role of the Hippo pathway in hepatic carcinogenesis and morphogenesis by examining Yes-associated protein 1 (YAP1) expression in the spectrum of hepatic carcinomas based on cellular lineage. METHODS: We examined 913 primary hepatic carcinomas, including hepatocellular carcinomas (HCCs), combined hepatocellular and cholangiocarcinomas (cHC-CCAs), intrahepatic cholangiocarcinomas (IHCCAs) and perihilar extrahepatic bile duct carcinomas (EHBCAs). Our study group was categorized into 8 disease groups, based on histological diagnosis and cytokeratin 19 (CK19) expression, and immunohistochemistry was used to detect and compare YAP1 expression levels between the groups. The eight disease groups we identified were: 1) CK19(-) HCC, 2) CK19(-) scirrhous HCC, 3) CK19(+) HCC, 4) stem cell feature of cHC-CCA, 5) classical cHC-CCA, 6) cholangiolocellular IHCCA, 7) non-cholangiolocellular IHCCA, and 8) EHBCA. RESULTS: Positive rates of YAP1 were the highest in the EHBCA group (21%). CK19(+) HCC and non-cholangiolocellular IHCCA groups also showed high expression levels (10% -11%), while the CK19 (-) HCC, CK19 (-) scirrhous HCC, cHC-CCA, and cholangiolocellular IHCCA groups showed low expression levels, ranging between 0% and 5%. Survival analysis, restricted to pT1 stage HCCs and IHCCAs, showed poor overall survival for YAP1(+) IHCCA patients (39 +/- 17 vs. 109 +/- 10 months, mean +/- SD, log rank p-value 0.005). For HCCs, a trend of poor progression-free survival for YAP1(+) HCCs was observed (39 +/- 18 vs. 81 +/- 5 months, mean +/- SD, log rank p-value 0.205) CONCLUSIONS: YAP1 activation was more commonly found in CCAs than in pure HCCs. However, a differing pattern of YAP1 expression between cHC-CCAs and CK19(+) HCCs and the poor prognosis of YAP1 positive hepatic carcinomas suggests that YAP1 may have a preferential role in aggressive tumor behavior, rather than in the determination of cellular lineage in hepatic carcinomas. PMID- 28645249 TI - Comparative transcriptomic analysis of the evolution and development of flower size in Saltugilia (Polemoniaceae). AB - BACKGROUND: Flower size varies dramatically across angiosperms, representing innovations over the course of >130 million years of evolution and contributing substantially to relationships with pollinators. However, the genetic underpinning of flower size is not well understood. Saltugilia (Polemoniaceae) provides an excellent non-model system for extending the genetic study of flower size to interspecific differences that coincide with variation in pollinators. RESULTS: Using targeted gene capture methods, we infer phylogenetic relationships among all members of Saltugilia to provide a framework for investigating the genetic control of flower size differences via RNA-Seq de novo assembly. Nuclear concatenation and species tree inference methods provide congruent topologies. The inferred evolutionary trajectory of flower size is from small flowers to larger flowers. We identified 4 to 10,368 transcripts that are differentially expressed during flower development, with many unigenes associated with cell wall modification and components of the auxin and gibberellin pathways. CONCLUSIONS: Saltugilia is an excellent model for investigating covarying floral and pollinator evolution. Four candidate genes from model systems (BIG BROTHER, BIG PETAL, GASA, and LONGIFOLIA) show differential expression during development of flowers in Saltugilia, and four other genes (FLOWERING-PROMOTING FACTOR 1, PECTINESTERASE, POLYGALACTURONASE, and SUCROSE SYNTHASE) fit into hypothesized organ size pathways. Together, these gene sets provide a strong foundation for future functional studies to determine their roles in specifying interspecific differences in flower size. PMID- 28645250 TI - Labour-market marginalisation after mental disorders among young natives and immigrants living in Sweden. AB - BACKGROUND: The aim was to investigate the associations between mental disorders and three different measures of labour-market marginalisation, and differences between native Swedes and immigrants. METHODS: The study comprised 1,753,544 individuals, aged 20-35 years, and resident in Sweden 2004. They were followed 2005-2011 with regard to disability pension, sickness absence (>=90 days) and unemployment (>=180 days). Immigrants were born in Western countries (Nordic countries, EU, Europe outside EU or North-America/Oceania), or in non-Western countries (Africa, Asia or South-America). Mental disorders were grouped into seven subgroups based on a record of in- or specialised outpatient health care 2001-2004. Hazard ratios (HRs) with 95% confidence intervals (CIs) were computed by Cox regression models with both fixed and time-dependent covariates and competing risks. We also performed stratified analyses with regard to labour market attachment. RESULTS: Individuals with mental disorders had a seven times higher risk of disability pension, a two times higher risk of sickness absence, and a 20% higher risk of unemployment than individuals without mental disorders. Individuals with personality disorders and schizophrenia/non-affective psychoses had highest risk estimates for having disability pension and long-term sickness absence, while the risk estimates of long-term unemployment were similar among all subgroups of mental disorders. Among persons with mental disorders, native Swedes had higher risk estimates for disability pension (HR:6.6; 95%CI:6.4-6.8) than Western immigrants (4.8; 4.4-5.2) and non-Western immigrants (4.8; 4.4-5.1), slightly higher risk estimates for sickness absence (2.1;2.1-2.2) than Western (1.9;1.8-2.1), and non-Western (1.9;1.7-2.0) immigrants but lower risk estimates for unemployment (1.4;1.3-1.4) than Western (1.8;1.7-1.9) and non-Western immigrants (2.0;1.9-2.1). There were similar risk estimates among sub-regions within both Western and non-Western countries. Stratification by labour-market attachment showed that the risk estimates for immigrants were lower the more distant individuals were from gainful employment. CONCLUSIONS: Mental disorders were associated with all three measures of labour-market marginalisation, strongest with subsequent disability pension. Native Swedes had higher risk estimates for both disability pension and sickness absence, but lower risk estimates for unemployment than immigrants. Previous labour-market attachment explained a great part of the association between immigrant status and subsequent labour-market marginalisation. PMID- 28645248 TI - Characterizing the reproductive transcriptomic correlates of acute dehydration in males in the desert-adapted rodent, Peromyscus eremicus. AB - BACKGROUND: The understanding of genomic and physiological mechanisms related to how organisms living in extreme environments survive and reproduce is an outstanding question facing evolutionary and organismal biologists. One interesting example of adaptation is related to the survival of mammals in deserts, where extreme water limitation is common. Research on desert rodent adaptations has focused predominantly on adaptations related to surviving dehydration, while potential reproductive physiology adaptations for acute and chronic dehydration have been relatively neglected. This study aims to explore the reproductive consequences of acute dehydration by utilizing RNAseq data in the desert-specialized cactus mouse (Peromyscus eremicus). RESULTS: We exposed 22 male cactus mice to either acute dehydration or control (fully hydrated) treatment conditions, quasimapped testes-derived reads to a cactus mouse testes transcriptome, and then evaluated patterns of differential transcript and gene expression. Following statistical evaluation with multiple analytical pipelines, nine genes were consistently differentially expressed between the hydrated and dehydrated mice. We hypothesized that male cactus mice would exhibit minimal reproductive responses to dehydration; therefore, this low number of differentially expressed genes between treatments aligns with current perceptions of this species' extreme desert specialization. However, these differentially expressed genes include Insulin-like 3 (Insl3), a regulator of male fertility and testes descent, as well as the solute carriers Slc45a3 and Slc38a5, which are membrane transport proteins that may facilitate osmoregulation. CONCLUSIONS: These results suggest that in male cactus mice, acute dehydration may be linked to reproductive modulation via Insl3, but not through gene expression differences in the subset of other a priori tested reproductive hormones. Although water availability is a reproductive cue in desert-rodents exposed to chronic drought, potential reproductive modification via Insl3 in response to acute water limitation is a result which is unexpected in an animal capable of surviving and successfully reproducing year-round without available external water sources. Indeed, this work highlights the critical need for integrative research that examines every facet of organismal adaptation, particularly in light of global climate change, which is predicted, amongst other things, to increase climate variability, thereby exposing desert animals more frequently to the acute drought conditions explored here. PMID- 28645251 TI - Improving early detection initiatives: a qualitative study exploring perspectives of older people and professionals. AB - BACKGROUND: A wide range of initiatives on early detection and intervention have been developed to proactively identify problems related to health and wellbeing in (frail) older people, with the aim of supporting them to live independently for as long as possible. Nevertheless, it remains unclear what the best way is to design such initiatives and how older people's needs and preferences can be best addressed. This study aimed to address this gap in the literature by exploring: 1) older people's perspectives on health and living environment in relation to living independently at home; 2) older people's needs and preferences in relation to initiating and receiving care and support; and 3) professionals' views on what would be necessary to enable the alignment of early detection initiatives with older people's own needs and preferences. METHODS: In this qualitative study, we conducted semi-structured interviews with 36 older people and 19 professionals in proactive elderly care. Data were analysed using the framework analysis method. RESULTS: From the interviews with older people important themes in relation to health and living environment emerged, such as maintaining independence, appropriate housing, social relationships, a supporting network and a sense of purpose and autonomy. Older people preferred to remain self-sufficient, and they would rather not ask for help for psychological or social problems. However, the interviews also highlighted that they were not always able or willing to anticipate future needs, which can hinder early detection or early intervention. At the same time, professionals indicated that older people tend to over-estimate their self-reliance and therefore advocated for early detection and intervention, including social and psychological issues. CONCLUSION: Older people have a broad range of needs in different domains of life. Discrepancies exist between older people and professionals with regard to their views on timing and scope of early detection initiatives. This study aimed to reveal starting-points for better alignment between initiatives and older people's needs and preferences. Such starting points may support policy makers and care professionals involved in early detection initiatives to make more informed decisions. PMID- 28645252 TI - Statin use reduces cardiovascular events and all-cause mortality amongst Chinese patients with type 2 diabetes mellitus: a 5-year cohort study. AB - BACKGROUND: The benefit of statin on the management of Type 2 Diabetes Mellitus (T2DM) among Chinese patients in primary care is not clear nor fully implemented in clinical practice. This study aimed to evaluate and quantify the benefit of statin on the overall cardiovascular risk and all-cause mortality in patients with T2DM. METHODS: Uncomplicated diabetic patients with baseline low-density lipoprotein cholesterol (LDL-C) > 2.6 mmol/L and without statin use before baseline in 2010 were followed-up for 5 years for cardiovascular disease (CVD) events and all-cause mortality. Propensity score matching analysis was conducted to identify patients who were newly prescribed statin at baseline and then compared to non-statin users with similar baseline characteristics. Subgroup analysis was done within the statin group to detect any difference in outcomes between patients achieving target LDL-C of <2.6 mmol/L and not. Multivariable Cox proportional hazards regression with adjustment of all baseline covariates was used to evaluate the effect of statin on outcome events. Hazard ratio (HR) and its 95% confidence intervals were reported. RESULTS: 10,104 pairs of diabetic patients were propensity score matched. Statin users had an extra drop of 1.21 mmol/L in LDL-C than non-users. Statin group had a CVD incidence rate of 16.533 per 1000 person-years whereas comparison group had 32.387 per 1000 person-years (HR: 0.458) during a median follow-up period of 50.5 months. Statin group had a mortality rate of 8.138 deaths per 1000 person-years whereas comparison group had 19.603 deaths per 1000 person-years (HR: 0.378). For patients prescribed with statin, the HR was 0.491 for CVD and 0.487 for all-cause mortality if target of LDL-C < 2.6 mmol/L achieved compare to those not achieved. CONCLUSIONS: Use of statin was associated with a significant decrease in CVD risk and all-cause mortality among diabetic patients in primary care, and the risk reduction was most significant if the target of LDL-C less than 2.6 mmol/L was achieved. PMID- 28645253 TI - A case report of thoracolumbar paraspinal myopathy as the cause of camptocormia in a patient with atypical parkinsonism. AB - BACKGROUND: Camptocormia is severe flexion of the thoracolumbar spine, exaggerated during standing and walking but minimized in supine position. Even though camptocormia is a relatively common condition during the course of Parkinson's disease, there is ongoing controversy concerning its mechanisms. The most widely accepted and yet still disputed one is dystonia. However, based on myopathic changes observed in the paraspinal muscle biopsies of some PD patients with camptocormia, the attempt to attribute camptocormia to myopathy has continued. This case presents evidence for paraspinal myopathy as the cause of camptocormia in a patient with atypical parkinsonism. CASE PRESENTATION: A patient presented with a relatively acute onset of camptocormia and new-onset back pain. Upon examination, she had asymmetric parkinsonism. Magnetic resonance imaging of the lumbar spine revealed alterations in muscle signal intensity in the right paraspinal muscles at the L1-2 level. In the presence of persistent back pain, repeat imaging done two months later showed diffuse enlargement and patchy enhancement of the paraspinal muscles on T1-weighted imaging from T4 through sacrum bilaterally. About fifteen months after the onset of camptocormia, she underwent ultrasound-guided gun biopsy of the paraspinal muscles for evaluation of focal atrophy of the back muscles on the right. The biopsy revealed unmistakable myopathic changes, marked endomysial and perimysial fibrosis of the muscles, and merely mild infiltration of inflammatory cells but no clues regarding the cause of myopathy. On account of persistent back pain and MRI results indicative of ongoing inflammation, she was prescribed glucocorticoid, which she refused to take. Now merely two and a half years after the onset of camptocormia, she is in Hoehn and Yahr stage 4. CONCLUSIONS: The coincidence of back pain with the appearance of camptocormia and the imaging and pathology findings supportive of myopathy give strong evidence for paraspinal myopathy as the cause of the deformity in this patient. When a patient presents with a relatively acute onset of camptocormia accompanied by back pain, the clinician should not overlook the possibility of myopathy of paraspinal muscles, which may be one of the few treatable causes of camptocormia. PMID- 28645254 TI - Comparing self- and provider-collected swabbing for HPV DNA testing in female-to male transgender adult patients: a mixed-methods biobehavioral study protocol. AB - BACKGROUND: Cervical cancer, nearly all cases of which are caused by one of several high-risk strains of the human papillomavirus (hr-HPV), leads to significant morbidity and mortality in individuals with a cervix. Trans masculine (TM) individuals were born with female reproductive organs and identify as male, man, transgender man, or another diverse gender identity different from their female assigned sex at birth. Routine preventive sexual health screening of TM patients is recommended, including screening for cervical cancer and other sexually transmitted infections (STIs); however, as many as one in three TM patients are not up-to-date per recommended U.S. GUIDELINES: Among cisgender (non transgender) women, self-swab hr.-HPV DNA testing as a primary cervical cancer screening method and self-swab specimen collection for other STIs have high levels of acceptability. No study has yet been conducted to compare the performance and acceptability of self- and provider-collected swabs for hr.-HPV DNA testing and other STIs in TM patients. METHODS: This article describes the study protocol for a mixed-methods biobehavioral investigation enrolling 150 sexually active TM to (1) assess the clinical performance and acceptability of a vaginal self-swab for hr.-HPV DNA testing compared to provider cervical swab and cervical cytology, and (2) gather acceptability data on self-collected specimens for other STIs. Study participation entails a one-time clinical visit at Fenway Health in Boston, MA comprised of informed consent, quantitative assessment, venipuncture for syphilis testing and HIV (Rapid OraQuick) testing, randomization, collection of biological specimens/biomarkers, participant and provider satisfaction survey, and qualitative exit interview. Participants are compensated $100. The primary study outcomes are concordance (kappa statistic) and performance (sensitivity and specificity) of self-collected vaginal HPV DNA specimens vs provider-collected cervical HPV swabs as a gold standard. DISCUSSION: This study addresses critical gaps in current clinical knowledge of sexual health in TM patients, including comparing alternative strategies for screening and diagnosis of cervical cancer, hr.-HPV, and other STIs. Findings have implications for improving the delivery of sexual health screening to this often overlooked and underserved patient population. Less-invasive patient centered strategies may also generalize to other at-risk cisgender female populations that face barriers to timely and needed STI and cervical cancer screening. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02401867. PMID- 28645255 TI - Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa. AB - BACKGROUND: Anaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity. METHODS: Individual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models. RESULTS: Eight thousand eight hundred ninety-seven patients (77.0% <5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5's had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 MUl) than older subjects (2784 MUl). Baseline anaemia increased the risk of parasitological recurrence. Hb began to fall after treatment start. In under 5's the estimated nadir was ~35 h (range 29-48), with a drop of -12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15's, the mean Hb decline between day 0-3 was -4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach +13.8% compared to baseline. Severe anaemia (<5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28. There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia. CONCLUSION: On presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1-2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment. PMID- 28645256 TI - Socioeconomic status is associated with symptom severity and sickness absence in people with infectious intestinal disease in the UK. AB - BACKGROUND: The burden of infectious intestinal disease (IID) in the UK is substantial. Negative consequences including sickness absence are common, but little is known about the social patterning of these outcomes, or the extent to which they relate to disease severity. METHODS: We performed a cross-sectional analysis using IID cases identified from a large population-based survey, to explore the association between socioeconomic status (SES) and symptom severity and sickness absence; and to assess the role of symptom severity on the relationship between SES and absence. Regression modelling was used to investigate these associations, whilst controlling for potential confounders such as age, sex and ethnicity. RESULTS: Among 1164 cases, those of lower SES versus high had twice the odds of experiencing severe symptoms (OR 2.2, 95%CI;1.66 2.87). Lower SES was associated with higher odds of sickness absence (OR 1.8, 95%CI;1.26-2.69), however this association was attenuated after adjusting for symptom severity (OR 1.4, 95%CI;0.92-2.07). CONCLUSIONS: In a large sample of IID cases, those of low SES versus high were more likely to report severe symptoms, and sickness absence; with greater severity largely explaining the higher absence. Public health interventions are needed to address the unequal consequences of IID identified. PMID- 28645258 TI - Erratum to: Solitary plasmacytoma: population-based analysis of survival trends and effect of various treatment modalities in the USA. PMID- 28645257 TI - Relationship between nasopharyngeal and bronchoalveolar microbial communities in clinically healthy feedlot cattle. AB - BACKGROUND: The importance of upper airway structure in the susceptibility of the lower respiratory tract to colonization with potential pathogens is well established. With the advent of rapid, high throughput, next generation sequencing, there is a growing appreciation of the importance of commensal microbial populations in maintaining mucosal health, and a realization that bacteria colonize anatomical locations that were previously considered to be sterile. While upper respiratory tract microbial populations have been described, there are currently no published studies describing the normal microbial populations of the bovine lower respiratory tract. Consequently, we have little understanding of the relationship between upper and lower respiratory tract microbiota in healthy cattle. The primary objective of our study was to characterize the composition, structure and relationship of the lower and upper respiratory microbial communities in clinically healthy feedlot cattle. Nasopharyngeal swabs (NPS), and bronchoalveolar lavage (BAL) fluid, were collected from clinically healthy feedlot calves (n = 8). Genomic DNA from each sample was extracted, and the V3-V4 hypervariable region of the bacterial 16S rRNA gene was amplified and sequenced using Illumina Miseq platform. RESULTS: Across all samples, the most predominant phyla were Proteobacteria, Actinobacteria and Firmicutes. The most common genera were Rathayibacter, Mycoplasma, Bibersteinia and Corynebacterium. The microbial community structure was distinct between these two biogeographical sites. Most of the bacterial genera identified in the BAL samples were also present in the NPS, but biogeographical-specific genera were enriched in both the NPS (Rathayibacter) and BAL (Bibersteinia) samples. There were strong associations between the presence of certain taxa at each specific location, and strong correlations between the presence of specific taxa in both the NPS and BAL samples. CONCLUSIONS: The correlation between the presence of specific taxa in both the NPS and BAL samples, supports the notion of a mutualistic interrelationship between these microbial communities. Future studies, in large cohorts of animals, are needed to determine the role and clinical importance of the relationships of respiratory tract microbial communities with health, productivity, and susceptibility to the development of respiratory disease, in growing cattle. PMID- 28645259 TI - Adapted yoga to improve physical function and health-related quality of life in physically-inactive older adults: a randomised controlled pilot trial. AB - BACKGROUND: Yoga is a holistic therapy of expanding popularity, which has the potential to produce a range of physical, mental and social benefits. This trial evaluated the feasibility and effects of an adapted yoga programme on physical function and health-related quality of life in physically-inactive older adults. METHODS: In this randomised controlled pilot trial, 52 older adults (90% female; mean age 74.8 years, SD 7.2) were randomised 1:1 to a yoga programme or wait-list control. The yoga group (n = 25) received a physical activity education booklet and were invited to attend ten yoga sessions during a 12-week period. The control group (n = 27) received the education booklet only. Measures of physical function (e.g., Short Physical Performance Battery; SPPB), health status (EQ-5D) and mental well-being (Warwick-Edinburgh Mental Well-being Scale; WEMWBS) were assessed at baseline and 3 months. Feasibility was assessed using course attendance and adverse event data, and participant interviews. RESULTS: Forty seven participants completed follow-up assessments. Median class attendance was 8 (range 3 to 10). At the 3-month follow-up, the yoga group had a higher SPPB total score compared with the control group (mean difference 0.9, 95% confidence interval [CI] -0.3 to 2.0), a faster time to rise from a chair five times (mean difference - 1.73 s, 95% CI -4.08 to 0.62), and better performance on the chair sit-and-reach lower-limb flexibility test (mean difference 5 cm, 95% CI 0 to 10). The yoga group also had superior health status and mental well-being (vs. control) at 3 months, with mean differences in EQ-5D and WEMWBS scores of 0.12 (95% CI, 0.03 to 0.21) and 6 (95% CI, 1 to 11), respectively. The interviews indicated that participants valued attending the yoga programme, and that they experienced a range of benefits. CONCLUSIONS: The adapted yoga programme appeared to be feasible and potentially beneficial in terms of improving mental and social well-being and aspects of physical function in physically-inactive older adults. An appropriately-powered trial is required to confirm the findings of the present study and to determine longer-term effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT02663726 . PMID- 28645260 TI - Within-class differences in cancer risk for sulfonylurea treatments in patients with type 2 diabetes (ZODIAC-55) - a study protocol. AB - BACKGROUND: Patients with type 2 diabetes (T2D) are at increased risk for developing cancer. As approximately 8% of the world's population is living with T2D, even a slight increase in cancer risk could result in an enormous impact on the number of persons developing cancer. In addition, several glucose lowering drug classes for treating patients with T2D have been associated with a difference in risk of cancer overall, and especially for obesity related cancers. In what way and to what degree cancer risk is modified by the use of different sulfonylureas (SU) is unclear. The primary aim of this study will be to evaluate within-class SU differences in obesity related cancer risk. Secondary aims will be to investigate within-class SU differences in risk for all cancers combined and site-specific cancers separately (i.e. breast, colorectal, prostate, bladder and lung cancer) and to account for duration-response relationships between individual SU use and cancer risk. METHODS: Patients will be selected from a Dutch primary care cohort of patients with T2D linked with the Dutch Cancer Registration (ZODIAC-NCR). Within this cohort study annually collected clinical data (e.g. blood pressure, weight, HbA1c) and nationwide data on cancer incidence are available. Time-dependent cox proportional hazard analyses will be performed to evaluate SU cancer risk, adjusted for potential confounders. DISCUSSION: This study will be the first prospective cohort study investigating within-class SU differences in cancer risk and could contribute to improved decision making regarding the individual drugs within the class of SUs, and possibly improve quality of life and result in an increased cost-effectiveness of healthcare in patients with T2D. TRIAL REGISTRATION: Nederlands Trialregister ( NTR6166 ), 6 Jan 2017. PMID- 28645261 TI - Genome-wide analysis of UDP-glycosyltransferase super family in Brassica rapa and Brassica oleracea reveals its evolutionary history and functional characterization. AB - BACKGROUND: Glycosyltransferases comprise a highly divergent and polyphyletic multigene family that is involved in widespread modification of plant secondary metabolites in a process called glycosylation. According to conserved domains identified in their amino acid sequences, these glycosyltransferases can be classified into a single UDP-glycosyltransferase (UGT) 1 superfamily. RESULTS: We performed genome-wide comparative analysis of UGT genes to trace evolutionary history in algae, bryophytes, pteridophytes, and angiosperms; then, we further investigated the expansion mechanisms and function characterization of UGT gene families in Brassica rapa and Brassica oleracea. Using Hidden Markov Model search, we identified 3, 21, 140, 200, 115, 147, and 147 UGTs in Chlamydomonas reinhardtii, Physcomitrella patens, Selaginella moellendorffii, Oryza sativa, Arabidopsis thaliana, B. rapa, and B. oleracea, respectively. Phylogenetic analysis revealed that UGT80 gene family is an ancient gene family, which is shared by all plants and UGT74 gene family is shared by ferns and angiosperms, but the remaining UGT gene families were shared by angiosperms. In dicot lineage, UGTs among three species were classified into three subgroups containing 3, 6, and 12 UGT gene families. Analysis of chromosomal distribution indicates that 98.6 and 71.4% of UGTs were located on B. rapa and B. oleracea pseudo-molecules, respectively. Expansion mechanism analyses uncovered that whole genome duplication event exerted larger influence than tandem duplication on expansion of UGT gene families in B. rapa, and B. oleracea. Analysis of selection forces of UGT orthologous gene pairs in B. rapa, and B. oleracea compared to A. thaliana suggested that orthologous genes in B. rapa, and B. oleracea have undergone negative selection, but there were no significant differences between A. thaliana -B. rapa and A. thaliana -B. oleracea lineages. Our comparisons of expression profiling illustrated that UGTs in B. rapa performed more discrete expression patterns than these in B. oleracea indicating stronger function divergence. Combing with phylogeny and expression analysis, the UGTs in B. rapa and B. oleracea experienced parallel evolution after they diverged from a common ancestor. CONCLUSION: We first traced the evolutionary history of UGT gene families in plants and revealed its evolutionary and functional characterization of UGTs in B. rapa, and B. oleracea. This study provides novel insights into the evolutionary history and functional divergence of important traits or phenotype related gene families in plants. PMID- 28645262 TI - Acute myeloid leukemia and pregnancy: clinical experience from a single center and a review of the literature. AB - BACKGROUND: Acute myeloid leukemia (AML) accounts for more than two thirds of leukemia during pregnancy and has an incidence of 1 in 75,000 to 100,000. Its clinical management remains a challenging therapeutic task both for patient and medical team, given to the therapy-attributable risks for mother and fetus and the connected counseling regarding pregnancy continuation. METHODS: We provided a review of updated literature and a comprehensive description of five maternal/fetal outcomes of AML cases diagnosed concomitantly to pregnancy and treated at our Institution from 2006 to 2012. RESULTS: Median age at AML diagnosis was 32 years (31-39). One diagnosis was performed in first trimester and the patient asked for therapeutic abortion before starting chemotherapy. Three cases were diagnosed in second/third trimester; in one case leukemia was diagnosed concomitantly with intrauterine fetal death, while the remaining two patients continued pregnancy and delivered a healthy baby by cesarean section. In only one of these two cases chemotherapy was performed during pregnancy (at 24 + 5 weeks) and consisted of a combination of daunorubicine and cytarabine. Therapy was well tolerated and daily fetus monitoring was performed. After completion of 30 weeks of gestation a cesarean section was carried out; the newborn had an Apgar score of 5/1'-7/5'-9/10', oxygen therapy was temporarily given and peripheral counts displayed transient mild leukopenia. One patient had diagnosis of myelodysplastic syndrome rapidly progressed to AML after delivery. Four out of the 5 described women are currently alive and disease-free. Three children were born and long-term follow-up has shown normal growth and development. CONCLUSIONS: The treatment of AML occurring during pregnancy is challenging and therapeutic decisions should be taken individually for each patient. Consideration must be given both to the immediate health of mother and fetus and to long-term infant health. Our series confirmed the literature data: fetal toxicity of cytostatic therapy clusters during the first trimester; while chemotherapy can be administered safely during second/third trimester and combination of daunorubicin and cytarabine is recommended for induction. PMID- 28645263 TI - Microbiota-dependent metabolite and cardiovascular disease marker trimethylamine N-oxide (TMAO) is associated with monocyte activation but not platelet function in untreated HIV infection. AB - BACKGROUND: HIV infection is associated with increased risk of cardiovascular disease beyond that explained by traditional risk factors. Altered gut microbiota, microbial translocation, and immune activation have been proposed as potential triggers. The microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) predicts myocardial infarction (MI) in the general population and has recently been shown to induce platelet hyperreactivity. In the present study, we investigated if TMAO was associated with platelet function, microbial translocation, and immune activation in both untreated and combination anti retroviral therapy (cART) HIV infection. METHODS: TMAO and the pre-cursors betaine, choline, and carnitine were quantified by mass-spectrometry in plasma samples from a previously established cross-sectional cohort of 50 untreated and 50 cART treated HIV-infected individuals. Whole-blood impedance aggregometry, C reactive protein, sCD14, and lipopolysaccharide were assessed as measures of platelet function, inflammation, monocyte activation, and microbial translocation, respectively. RESULTS: TMAO was not associated with platelet aggregation response after stimulation with four different agonists, or with overall hypo- or hyperreactivity in untreated or treated HIV-infected individuals. In contrast, sCD14 a marker of both monocyte activation and microbial translocation was independently associated with TMAO in untreated HIV infection (R = 0.381, P = 0.008). Lower levels of carnitine [32.2 (28.4-36.8) vs. 38.2 (33.6-42.0), P = 0.001] and betaine [33.1 (27.3-43.4) vs.37.4 (31.5-48.7, P = 0.02], but similar TMAO levels [3.8 (2.3-6.1), vs. 2.9 MUM (1.9-4.8) P = 0.15] were found in cART treated compared to untreated HIV-infected individuals, resulting in higher ratios of TMAO/carnitine [0.12 (0.07-0.20) vs. 0.08 (0.05 0.11), P = 0.02] and TMAO/betaine [0.11 (0.07-0.17) vs. 0.08 (0.05-0.13), P 0.02]. CONCLUSIONS: In contrast to recent studies in HIV-uninfected populations, the present study found no evidence of TMAO-induced platelet hyperreactivity in HIV infected individuals. Microbial translocation and monocyte activation may affect TMAO levels in untreated individuals. Furthermore, the elevated ratios of TMAO/betaine and TMAO/carnitine in cART-treated individuals could possibly suggest a role of cART in TMAO metabolism. PMID- 28645264 TI - Molecular cloning, structure, phylogeny and expression analysis of the invertase gene family in sugarcane. AB - BACKGROUND: Invertases (INVs) are key enzymes regulating sucrose metabolism and are here revealed to be involved in responses to environmental stress in plants. To date, individual members of the invertase gene family and their expression patterns are unknown in sugarcane due to its complex genome despite their significance in sucrose metabolism. RESULTS: In this study, based on comparative genomics, eleven cDNA and twelve DNA sequences belonging to 14 non-redundant members of the invertase gene family were successfully cloned from sugarcane. A comprehensive analysis of the invertase gene family was carried out, including gene structures, phylogenetic relationships, functional domains, conserved motifs of proteins. The results revealed that the 14 invertase members from sugarcane could be clustered into three subfamilies, including 6 neutral/alkaline invertases (ShN/AINVs), and 8 acid invertases (ShAINVs). Faster divergence occurred in acid INVs than in neutral/alkaline INVs after the split of sugarcane and sorghum. At least a one-time gene duplication event was observed to have occurred in the four groups of acid INVs, whereas ShN/AINV1 and ShN/AINV2 in the beta8 lineage were revealed to be the most recently duplicated genes among their paralogous genes in the beta group of N/AINVs. Furthermore, comprehensive expression analysis of these genes was performed in sugarcane seedlings subjected to five abiotic stresses (drought, low temperature, glucose, fructose, and sucrose) using Quantitative Real-time PCR. The results suggested a functional divergence of INVs and their potential role in response to the five different treatments. Enzymatic activity in sugarcane seedlings was detected under five abiotic stresses treatments, and showed that the activities of all INVs were significantly inhibited in response to five different abiotic stresses, and that the neutral/alkaline INVs played a more prominent role in abiotic stresses than the acid INVs. CONCLUSIONS: In this study, we determined the INV gene family members of sugarcane by PCR cloning using sorghum as a reference, providing the first study of the INV gene family in sugarcane. Combining existing INV gene data from 7 plants with a comparative approach including a series of comprehensive analyses to isolate and identify INV gene family members proved to be highly successful. Moreover, the expression levels of INV genes and the variation of enzymatic activities associated with drought, low temperature, glucose, fructose, and sucrose are reported in sugarcane for the first time. The results offered useful foundation and framework for future research for understanding the physiological roles of INVs for sucrose accumulation in sugarcane. PMID- 28645265 TI - A pilot study: LASEK with the Triple-A profile of a MEL 90 for mild and moderate myopia. AB - BACKGROUND: To investigate the visual and refractive outcomes in patients with mild to moderate myopia after laser-assisted subepithelial keratectomy (LASEK) using the 500 Hz pulse rate of the Triple-A profile. METHODS: Thirty-six eyes of 20 patients (mean age, 27.5 +/- 4.6 years) were included in this prospective, consecutive study. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corneal topography, and corneal aberrations were measured preoperatively and 1 day, 1 week, 1, 3 and 6 months post-operation. RESULTS: At 1 week after surgery, UDVA was better than or equal to 20/25 in all eyes. At postoperative 6 months, the efficacy and safety index was 1.05 +/- 0.13 and 1.12 +/- 0.15, respectively; all eyes had a UDVA of 20/20 or better, and no eyes showed a loss in CDVA; 100% of the eyes were within +/-1.00 D of the attempted spherical equivalent (SE) correction. CONCLUSION: The postoperative results indicate that using the Triple-A ablation profile of the MEL 90 excimer laser with a 500 Hz pulse rate is a safe, efficient, and predictable method to correct mild to moderate myopia. PMID- 28645266 TI - Poorer outcomes among cancer patients diagnosed with Clostridium difficile infections in United States community hospitals. AB - BACKGROUND: Cancer predisposes patients to Clostridium difficile infection (CDI) due to health care exposures and medications that disrupt the gut microbiota or reduce immune response. Despite this association, the national rate of CDI among cancer patients is unknown. Furthermore, it is unclear how CDI affects clinical outcomes in cancer. The objective of this study was to describe CDI incidence and health outcomes nationally among cancer patients in the United States (U.S.). METHODS: Data for this study were obtained from the U.S. National Hospital Discharge Surveys from 2001 to 2010. Eligible patients included those at least 18 years old with a discharge diagnosis of cancer (ICD-9-CM codes 140-165.X, 170 176.X, 179-189.X, 190-209.XX). CDI was identified using ICD-9-CM code 008.45. Data weights were applied to sampled patients to provide national estimates. CDI incidence was calculated as CDI discharges per 1000 total cancer discharges. The in-hospital mortality rate and hospital length of stay (LOS) were compared between cancer patients with and without CDI using bivariable analyses. RESULTS: A total of 30,244,426 cancer discharges were included for analysis. The overall incidence of CDI was 8.6 per 1000 cancer discharges. CDI incidence increased over the study period, peaking in 2008 (17.2 per 1000 cancer discharges). Compared to patients without CDI, patients with CDI had significantly higher mortality (9.4% vs. 7.5%, p < 0.0001) and longer median LOS (9 days vs. 4 days, p < 0.0001). CONCLUSIONS: CDI incidence is increasing nationally among cancer patients admitted to U.S. community hospitals. CDI was associated with significantly increased mortality and hospital LOS. PMID- 28645267 TI - A rapid and quantitative method to detect human circulating tumor cells in a preclinical animal model. AB - BACKGROUND: As cancer metastasis is the deadliest aspect of cancer, causing 90% of human deaths, evaluating the molecular mechanisms underlying this process is the major interest to those in the drug development field. Both therapeutic target identification and proof-of-concept experimentation in anti-cancer drug development require appropriate animal models, such as xenograft tumor transplantation in transgenic and knockout mice. In the progression of cancer metastasis, circulating tumor cells (CTCs) are the most critical factor in determining the prognosis of cancer patients. Several studies have demonstrated that measuring CTC-specific markers in a clinical setting (e.g., flow cytometry) can provide a current status of cancer development in patients. However, this useful technique has rarely been applied in the real-time monitoring of CTCs in preclinical animal models. METHODS: In this study, we designed a rapid and reliable detection method by combining a bioluminescent in vivo imaging system (IVIS) and quantitative polymerase chain reaction (QPCR)-based analysis to measure CTCs in animal blood. Using the IVIS Spectrum CT System with 3D-imaging on orthotropic-developed breast-tumor-bearing mice. RESULTS: In this manuscript, we established a quick and reliable method for measuring CTCs in a preclinical animal mode. The key to this technique is the use of specific human and mouse GUS primers on DNA/RNA of mouse peripheral blood under an absolute qPCR system. First, the high sensitivity of cancer cell detection on IVIS was presented by measuring the luciferase carried MDA-MB-231 cells from 5 to 5x1011 cell numbers with great correlation (R2 = 0.999). Next, the MDA-MB-231 cell numbers injected by tail vein and their IVIS radiance signals were strongly corrected with qPCR calculated copy numbers (R2 > 0.99). Furthermore, by applying an orthotropic implantation animal model, we successfully distinguished xenograft tumor-bearing mice and control mice with a significant difference (p < 0.001), whereas IVIS Spectrum-CT 3D-visualization showed that blood of mice with lung metastasis contained more than twice the CTC numbers than ordinary tumor-bearing mice. We demonstrated a positive correlation between lung metastasis status and CTC numbers in peripheral mouse blood. CONCLUSION: Collectively, the techniques developed for this study resulted in the integration of CTC assessments into preclinical models both in vivo and ex vivo, which will facilitate translational targeted therapy in clinical practice. PMID- 28645268 TI - How can technology enhance cognitive behavioral therapy: the case of pediatric obsessive compulsive disorder. AB - Many children with mental health disorders do not receive adequate treatment due to the uneven dissemination of resources, and other barriers to treatment. In the case of pediatric obsessive compulsive disorder treatment progress is also hindered by partial or non-response to treatment in addition to poor compliance. This debate paper focuses on new technologies as a potential vehicle to address the challenges faced by traditional treatment, with special reference to cognitive behavioral therapy for pediatric obsessive compulsive disorder. We discuss the achievements and challenges that previous studies have faced, debate ways to overcome them, and we offer specific suggestions for further research in the area. PMID- 28645269 TI - Restricted posture in dentistry - a kinematic analysis of orthodontists. AB - BACKGROUND: This study aims at identifying orthodontic activities with the highest frequency of unfavorable/awkward and static postures held over a period of more than 4 s based on kinematic analysis. Moreover, a separate analysis of static postures for orthodontic and non-orthodontic activities serves to evaluate the duration for which these particular postures are assumed. METHODS: In total, 21 (13f/8 m) orthodontists (age: 31.5 +/- 3.8 years) participated in this study. CUELA, a personal measurement system, was used to collect kinematic data for all orthodontic activities in a working day. Angle values of the head and torso were evaluated in accordance with ergonomic standards. Only those postures that were held statically for 4 s and longer were selected for further analysis. Alongside the kinematic analysis, the activities performed on-site were also subject to a detailed computerized analysis. The synchronization of data collected from both measurements arranges the patterns of posture found chronologically and in conjunction with the orthodontic activities performed ((I) "treatment" (II) "office" and (III) "other activities"). RESULTS: For (I) we observed an anterior inclination of the head and torso area as well as a twist of the head and neck area to the right. We found anterior back inclination and lateral back torsion to the right for (II) and (III). If, furthermore, we differentiate the duration of static postures, there are primarily short to medium-term (4-30s) static postures identified for (I). Also, categories (II) and (III) predominantly demonstrate static back postures with a duration of up to 30 s. With regard to (II) we observed that the back is ventrally inclined for 10.1% of the total activity duration. CONCLUSIONS: During treatment static strains are observed in the entire head and torso area. On the contrary, static postures prevalent in the torso area are essential for activities of the other categories, particularly office work. These findings allow for a careful selection of unfavorable and static postures for each of the activities performed and help to develop specific preventive measures. PMID- 28645270 TI - Qualitative modification and development of patient- and caregiver-reported outcome measures for iron chelation therapy. AB - BACKGROUND: Compliance, palatability, gastrointestinal (GI) symptom, and treatment satisfaction patient- and observer-reported outcome (PRO, ObsRO) measures were developed/modified for patients with transfusion-dependent anemias or myelodysplastic syndrome (MDS) requiring iron chelation therapy (ICT). METHODS: This qualitative cross-sectional observational study used grounded theory data collection and analysis methods and followed PRO/ObsRO development industry guidance. Patients and caregivers of patients with transfusion-dependent anemias or MDS were individually interviewed face-to-face to cognitively debrief the Compliance, Palatability, GI Symptom Diary, and Modified Satisfaction with Iron Chelation Therapy (SICT) instruments presented electronically. Interviews were conducted in sets. Interviews began open-endedly to spontaneously elicit ICT experiences. Item modifications were debriefed during the later interviews. Interviews were audio recorded, transcribed, and coded. Data was analyzed using ATLAS.ti qualitative research software. RESULTS: Twenty-one interviews were completed (Set 1: 5 patients, 6 caregivers; Set 2: 6 patients, 4 caregivers) in 6 US cities. Mean age was 43 years for patients and 9 years for children of caregivers. Conditions requiring ICT use across groups included transfusion dependent anemias (85.7%) and MDS (14.3%). Concepts spontaneously reported were consistent with instruments debriefed. Interview analysis resulted in PRO and ObsRO versions of each instrument: Compliance (2 items), Palatability (4 items), GI Symptom Diary (6 items), and Modified SICT (PRO = 13, ObsRO = 17 items). CONCLUSION: Qualitative research data from cognitive interviews supports the content validity and relevance of the instruments developed/modified. Quantitative validation of these PRO and ObsRO measures is needed testing for validity, reliability, and responsiveness for future research use with new formulations of oral ICT. PMID- 28645271 TI - Association of stress, depression, and suicidal ideation with subjective oral health status and oral functions in Korean adults aged 35 years or more. AB - BACKGROUND: Oral health greatly affects well-being throughout the different stages of life from childhood to late adulthood. Loss of teeth due to poor oral health hinders mastication, leading to poor nutrition absorption, and affects pronunciation and aesthetics, leading to interpersonal difficulties. As social activities become limited, a sense of isolation and loneliness, stress, and depression grows while happiness decreases. This study aimed to examine the association of stress, depression, and suicidal ideation with oral health status and oral functions in a large nationwide sample of Korean adults aged 35 years or more. METHODS: The sample comprised 15,716 adults, selected using a rolling survey sampling method and data were extracted from the Fifth Korea National Health and Nutrition Examination Survey (KNHANES) (2010-2012). Participants were interviewed about their self-evaluation of health including oral health status and mental health, such as stress, depression, and suicidal ideation. Data from 11,347 adults were finally selected after excluding participants with missing answers. The dependent variables were stress, depression, and suicidal ideation. The independent variables were gender, age, household income, education, smoking, drinking, oral health perception, chewing, and speaking. Complex samples logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Participants met the criteria for stress (25.4%), depression (13.0%), and suicidal ideation (13.9%). Subjective oral health status was not significantly associated with stress, depression, and suicidal ideation. However, the presence of very uncomfortable chewing problems was significantly associated with stress (OR = 2.294, 95% CI = 1.41, 3.72), depression (OR = 3.232, 95% CI = 1.97, 5.31), and suicidal ideation (OR = 2.727, 95% CI = 1.58, 4.72). The presence of very uncomfortable speaking problems was significantly associated with stress (OR = 1.592, 95% CI = 1.13, 2.24) but not significantly associated with depression and suicidal ideation. CONCLUSIONS: Oral functional problems including chewing and speaking difficulties can be associated with mental health. It is necessary to develop oral health promotion programs for adults and help them maintain a good quality of life and mental health. PMID- 28645272 TI - Prosthetic joint infection caused by Granulicatella adiacens: a case series and review of literature. AB - BACKGROUND: Bone and joint infection involving Granulicatella adiacens is rare, and mainly involved in cases of bacteremia and infectious endocarditis. Here we report three cases of prosthetic joint infection involving G. adiacens that were successfully treated with surgery and prolonged antimicrobial treatment. We also review the two cases of prosthetic joint infection involving G. adiacens that are reported in the literature. CASE PRESENTATION: Not all five cases of prosthetic joint infection caused by G. adiacens were associated with bacteremia or infectious endocarditis. Dental care before the onset of infection was observed in two cases. The median time delay between arthroplasty implantation and the onset of infection was of 4 years (ranging between 2 and 10 years). One of our cases was identified with 16srRNA gene sequencing, one case with MALDI-TOF mass spectrometry, and one case with both techniques. Two literature cases were diagnosed by 16srRNA gene sequencing. All five cases were cured after surgery including a two-stage prosthesis exchange in three cases, a one-stage prosthesis exchange in one case, and debridement, antibiotics, irrigation, and retention of the prosthesis in one case, and prolonged antimicrobial treatment. CONCLUSION: Prosthetic joint infection involving G. adiacens is probably often dismissed due to difficult culture or misdiagnosis, in particular in the cases of polymicrobial infection. Debridement, antibiotics, irrigation, and retention of the prosthesis associated with prolonged antimicrobial treatment (>= 8 weeks) should be considered as a treatment strategy for prosthetic joint infection involving G. adiacens. PMID- 28645273 TI - Factors associated with diabetes-related distress over time among patients with T2DM in a tertiary hospital in Singapore. AB - BACKGROUND: Persistent diabetes-related distress (DRD) is experienced by patients with Type 2 Diabetes Mellitus. Knowing factors associated with persistent DRD will aid clinicians in prioritising interventions efforts. METHODS: A total of 216 patients were recruited from a tertiary hospital in Singapore, an Asian city state, and followed for 1.5 years (2011-2014). Data was collected by self completed questionnaires assessing DRD (measured by the Problem Areas in Diabetes score) and other psychosocial aspects such as social support, presenteeism, depression, health-related quality of life (HRQoL) and excessive daytime sleepiness (EDS) at three time points. Clinical data (body-mass-index and glycated haemoglobin) was obtained from medical records. Change score was calculated for each clinical and psychosocial variable to capture changes in these variables from baseline. Generalized Linear Model with Generalized Estimating Equation method was used to assess whether baseline and change scores in clinical and psychosocial are associated with DRD over time. RESULTS: Complete data was available for 73 patients, with mean age 44 (SD 12.5) years and 67% males. Persistent DRD was experienced by 21% of the patients. In the final model, baseline HRQoL (OR = 0.56, p < 0.05) and change score of EDS (OR = 1.22, p < 0.05) was significantly associated with DRD over time. CONCLUSIONS: EDS might be a surrogate marker for persistent DRD and should be explored in larger samples of population to confirm the findings from this study. PMID- 28645274 TI - Buccal mucosa micronuclei counts in relation to exposure to low dose-rate radiation from the Chornobyl nuclear accident and other medical and occupational radiation exposures. AB - BACKGROUND: Ionizing radiation is a well-known carcinogen. Chromosome aberrations, and in particular micronuclei represent an early biological predictor of cancer risk. There are well-documented associations of micronuclei with ionizing radiation dose in some radiation-exposed groups, although not all. That associations are not seen in all radiation-exposed groups may be because cells with micronuclei will not generally pass through mitosis, so that radiation induced micronuclei decay, generally within a few years after exposure. METHODS: Buccal samples from a group of 111 male workers in Ukraine exposed to ionizing radiation during the cleanup activities at the Chornobyl nuclear power plant were studied. Samples were taken between 12 and 18 years after their last radiation exposure from the Chornobyl cleanup. The frequency of binucleated micronuclei was analyzed in relation to estimated bone marrow dose from the cleanup activities along with a number of environmental/occupational risk factors using Poisson regression adjusted for overdispersion. RESULTS: Among the 105 persons without a previous cancer diagnosis, the mean Chornobyl-related dose was 59.5 mSv (range 0 748.4 mSv). There was a borderline significant increase in micronuclei frequency among those reporting work as an industrial radiographer compared with all others, with a relative risk of 6.19 (95% CI 0.90, 31.08, 2-sided p = 0.0729), although this was based on a single person. There was a borderline significant positive radiation dose response for micronuclei frequency with increase in micronuclei per 1000 scored cells per Gy of 3.03 (95% CI -0.78, 7.65, 2-sided p = 0.1170), and a borderline significant reduction of excess relative MN prevalence with increasing time since last exposure (p = 0.0949). There was a significant (p = 0.0388) reduction in MN prevalence associated with bone X-ray exposure, but no significant trend (p = 0.3845) of MN prevalence with numbers of bone X-ray procedures. CONCLUSIONS: There are indications of increasing trends of micronuclei prevalence with Chornobyl-cleanup-associated dose, and indications of reduction in radiation-associated excess prevalence of micronuclei with time after exposure. There are also indications of substantially increased micronuclei associated with work as an industrial radiographer. This analysis adds to the understanding of the long-term effects of low-dose radiation exposures on relevant cellular structures and methods appropriate for long-term radiation biodosimetry. PMID- 28645276 TI - Assessing the impact of health research on health policies: a study of the Dodowa Health Research Centre, Ghana. AB - BACKGROUND: The importance of assessing research impact is increasingly recognised. Ghana has a long tradition of research dating from the 1970s. In the Ghana Health Service there are three health research centres under the Research and Development Division. Dodowa Health Research Centre (DHRC) is the youngest in the country dating from the 1990s. The objective of this study is to analyse the influence of the research conducted in DHRC on national and local health policies. METHODS: The study used the Research Impact Framework. Six projects were selected based on a set of criteria. Thirteen interviews were conducted with researchers and policy makers using a semi-structured interview guide. RESULTS: DHRC had numerous policy impacts in terms of researchers participating in policy networks, increasing political capital and influencing policy documents. Factors identified to be associated with policy impact included collaboration with policy makers at the design stage, addressing health priorities, and communicating results mainly through the participation in annual review meetings. CONCLUSIONS: DHRC was successful in influencing health policies. Recommendations were made that could be included in the DHRC strategic planning to improve the research process and its policy impact. PMID- 28645275 TI - Rapid monocyte infiltration following retinal detachment is dependent on non canonical IL6 signaling through gp130. AB - BACKGROUND: Retinal detachment (RD) can lead to proliferative vitreoretinopathy (PVR), a leading cause of intractable vision loss. PVR is associated with a cytokine storm involving common proinflammatory molecules like IL6, but little is known about the source and downstream signaling of IL6 and the consequences for the retina. Here, we investigated the early immune response and resultant cytokine signaling following RD in mice. METHODS: RD was induced in C57BL/6 J and IL6 knockout mice, and the resulting inflammatory response was examined using immunohistochemistry and flow cytometry. Cytokines and signaling proteins of vitreous and retinas were quantified by multiple cytokine arrays and Western blotting. To attempt to block IL6 signaling, a neutralizing antibody of IL6 receptor alpha (IL6Ralpha) or IL6 receptor beta (gp-130) was injected intravitreally immediately after RD. RESULTS: Within one day of RD, bone marrow derived Cd11b + monocytes had extravasated from the vasculature and lined the vitreal surface of the retina, while the microglia, the resident macrophages of the retina, were relatively unperturbed. Cytokine arrays and Western blot analysis revealed that this sterile inflammation did not cause activation of IL6 signaling in the neurosensory retina, but rather only in the vitreous and aqueous humor. Monocyte infiltration was inhibited by blocking gp130, but not by IL6 knockout or IL6Ralpha blockade. CONCLUSIONS: Together, our results demonstrate that monocytes are the primary immune cell mediating the cytokine storm following RD, and that any resulting retinal damage is unlikely to be a direct result of retinal IL6 signaling, but rather gp130-mediated signaling in the monocytes themselves. These results suggest that RD should be treated immediately, and that gp130-directed therapies may prevent PVR and promote retinal healing. PMID- 28645277 TI - Dignity in people with frontotemporal dementia and similar disorders - a qualitative study of the perspective of family caregivers. AB - BACKGROUND: Frontotemporal dementia (FTD) constitutes on average 10-15% of dementia in younger persons (<=65 years old), but can also affect older people. These patients demonstrate a decline in social conduct, and/or language aphasias, apathy, and loss of insight that is gradual and progressive. Preservation of dignity seems to be highly relevant both before and after admission to different types of institutionalized care, but the research is scant. From the perspective of close relatives, this study aims to develop knowledge related to dignified or undignified care of patients with FTD and similar conditions. METHODS: A qualitative, descriptive, and explorative design were employed to address the aims of this study. We interviewed nine relatives of people with FTD and similar conditions living in nursing homes, and two relatives of people living at home but attending day center 5 days a week. RESULTS: Relatives described the transition from being a close relative to someone who had little influence or knowledge of what constituted the care and the daily life of their loved ones. According to relatives' descriptions, patients are deprived of dignity in various ways: through limited interaction with peers and close relatives, limited confirmation of identity through staff who know them well, lack of possibilities for making autonomous decisions or entertaining meaningful roles or activities. Examples provided from the day care centres show how dignity is maintained through identity-strengthening activities conducted in different places, under various kinds of supervision and care, and together with people representing different roles and functions. CONCLUSIONS: Maintaining a link with the world outside the institution, through closer cooperation between the institution and family members, and/or by the use of day care centres, seems to facilitate prevention of many of the factors that may threaten dignified care. PMID- 28645278 TI - The impact of mobile phone based messages on maternal and child healthcare behaviour: a retrospective cross-sectional survey in Bangladesh. AB - BACKGROUND: Mobile phones are gradually becoming an integral part of healthcare services worldwide. We assessed the association between Aponjon mobile phone based messaging services and practices regarding childbirth and care of mother and neonates in selected areas in Bangladesh. METHODS: In early 2014, 476 subscriber mothers whose last born child's age was between 3 and 18 months, were recruited to the study by Dnet from selected areas of Bangladesh. One group of mothers received the early warning messages from Aponjon during pregnancy (exposed; n = 210) while the other group of new mothers did not receive the messages during pregnancy as they had enrolled in the service after childbirth (non-exposed; n = 266). We undertook regression analyses to investigate the relationship between timing of exposure to Aponjon messages and socio-economic factors and outcomes of safe delivery, immediate breastfeeding post birth, delayed bathing of the neonate, and number of postnatal care (PNC) visits. RESULTS: Women reported delivering babies at home without a skilled birth attendant (SBA) (n = 58, 12%), at home with SBA (n = 111, 23%) and at health facilities (n = 307, 65%). Most (n = 443, 93%) women breastfed babies immediately post birth. Babies were bathed after 72 h (n = 294, 62%), between 48 and 72 (n = 100, 21%) and between 0 and 47 (n = 80, 17%) hours after birth. PNC frequencies were reported as none (n = 273, 57%), 1 (n = 79, 17%), 2 (n = 54, 11%), 3 (n = 34, 7%) and 4 (n = 36, 8%). There was no significant association between exposure to Aponjon messages during pregnancy and presence of a SBA at birth, breastfeeding practices, and postnatal care visits, although delayed bathing up to 48 h was significant at the 10% but not 5% level (RRR 1.7; 95% CI 0.93-3.0; p = 0.083). Women with higher education, from higher income, older in age, with birth order 1 or 2 were more likely to birth at health facilities. Facility based delivery was an independent factor for delayed bathing and having postnatal care visits. CONCLUSIONS: Low cost mobile phone messages may have the potential to positively influence maternal and child healthcare behaviours, such as delayed timing of first bath, in resource-poor settings. Further studies are needed, with adequate sample size to detect significant change. PMID- 28645280 TI - Erratum to: Multiscalar cellular automaton simulates in-vivo tumour-stroma patterns calibrated from in-vitro assay data. PMID- 28645279 TI - Diabetes care in a complex humanitarian emergency setting: a qualitative evaluation. AB - BACKGROUND: Evidence is urgently needed from complex emergency settings to support efforts to respond to the increasing burden of diabetes mellitus (DM). We conducted a qualitative study of a new model of DM health care (Integrated Diabetic Clinic within an Outpatient Department [IDC-OPD]) implemented by Medecins Sans Frontieres (MSF) in Mweso Hospital in eastern Democratic Republic of Congo (DRC). We aimed to explore patient and provider perspectives on the model in order to identify factors that may support or impede it. METHODS: We used focus group discussions (FGDs; two discussions, each with eight participants) and individual semi-structured qualitative interviews (seven patients and 10 staff) to explore experience of and perspectives on the IDC-OPD. Participants were recruited purposively to represent a range of DM disease severity and staff functions respectively, and to ensure the age and gender distribution was representative of the population of DM patients registered in the clinic. Data were coded in NVivo10(c) and analysed using an inductive thematic approach. RESULTS: There appears to be little awareness surrounding DM in patient communities, resulting in delays presenting to hospital. Patients describe their first reactions to symptoms as fear and confusion, often assuming symptoms are of another disease (e.g. HIV/AIDS). They often express disbelief that they could have DM (e.g. stating DM is a 'rich man's disease') and lack acceptance that there is no cure. Patients experienced difficulty travelling to appointments, exacerbated by flare-ups in the conflict. Providing psycho-social and sensitisation activities in a group setting appears to offer an opportunity for patients to support each other in their effort to adhere to drug treatment and follow-up appointments. All patients reported great difficulty in adhering to the recommended diet, which was viewed as unaffordable and unavailable, and fear that this would be the biggest obstacle to maintaining their drug treatment (as treatment must be taken with food). CONCLUSION: Our findings emphasize the importance of community awareness of DM and the value of treatment support, including psychosocial and educational support to DM patients and their families, and culturally sensitive, low-cost dietary advice, to ensuring the adoption and maintenance of DM treatment. PMID- 28645281 TI - Sex difference in the risk for exercise-induced albuminuria correlates with hemoglobin A1C and abnormal exercise ECG test findings. AB - BACKGROUND: Albuminuria is an established marker for endothelial dysfunction and cardiovascular risk in diabetes and prediabetes. Exercise induced albuminuria (EiA) appears earlier and may be a more sensitive biomarker for renal endothelial damage. We sought to examine the association between EiA, parameters of the metabolic syndrome, A1C levels, exercise ECG test results and sex related differences in a large cohort of healthy, pre-diabetic and diabetic subjects. METHODS: A total of 3029 participants from the Tel-Aviv Medical Center Inflammation Survey cohort (mean age 46 years, 73% men) were analyzed. Multiple physiologic and metabolic parameters including A1C were collected and albuminuria was measured in all subjects before and immediately after completing an exercise ECG test. RESULTS: Exercise increased urinary albumin to creatinine ratio (DeltaEiA) by 2.8 (0-13.6) mg/g for median (IQR) compared to rest albuminuria (p < 0.001). An increase in DeltaEiA was observed with accumulating parameters of the metabolic syndrome. DeltaEiA showed significant interaction with sex and A1C levels; i.e. women with A1C > 6.5% had an increased risk of higher DeltaEiA (p < 0.001). Using a cutoff of DeltaEiA > 13 mg/g (top quartile) we found that women with DeltaEiA > 13 mg/g were at greater risk for abnormal exercise ECG findings, (OR = 2.7, p = 0.001). CONCLUSION: Exercise promotes excessive urinary albumin excretion in dysmetabolic patients. In women, a significant correlation exists between DeltaEiA and A1C levels. A cutoff of DeltaEiA > 13 mg/g in women may be used to identify populations at risk for abnormal exercise ECG test findings and perhaps increased cardiovascular risk. Future studies will be needed to further validate the usefulness of DeltaEiA as a biomarker for cardiovascular risk in women with and without diabetes. PMID- 28645282 TI - Swiss National Research Programme "Opportunities and Risks of Nanomaterials" (NRP 64): key findings. PMID- 28645283 TI - Oocyte polarized light microscopy, assay of specific follicular fluid metabolites, and gene expression in cumulus cells as different approaches to predict fertilization efficiency after ICSI. AB - BACKGROUND: The complex relationship between oocyte morphology, specific follicular fluid metabolites, gene expression in cumulus granulosa cells, and oocyte competence toward fertilization and embryo development still needs further clarification. METHODS: Forty-six oocytes retrieved from the largest pre ovulatory follicle of patients undergoing intra-cytoplasmic sperm injection (ICSI) were considered assessing: (a) oocyte morphological characteristics at polarized light microscopy (PLM), (b) specific follicular fluid (FF) metabolites previously suggested to influence oocyte competence (AMH, markers of redox status and of cytotoxicity), (c) transcription of AMH and AMH type II receptor genes in cumulus cells. Data were analyzed using mono-parametric tests and multivariable logistic analysis in order to correlate morphological and biochemical data with fertilization. RESULTS: Comparing normally fertilized oocytes (n = 29, F group) with unfertilized (n = 17, nF group) we observed that: (a) the meiotic spindle area and major axis were significantly higher in nF group and in fertilized oocytes undergoing an early embryo development arrest; (b) AMH level in FF was comparable in F and nF groups; (c) the FF of nF group contained significantly higher levels of cytotoxicity (lactate dehydrogenase) and oxidative stress (Cu,Zn superoxide dismutase, catalase, 4-hydroxynonenal-protein conjugates) markers; (d) cumulus cells of nF group showed significantly higher AMH receptor type II gene expression. CONCLUSIONS: Taken together, these observations suggest that an excessive cytotoxicity level can alter AMH signal transduction within cumulus cells, in turn leading to partial inhibition of aromatase activity, altered cytoplasmic maturation and increased oxidative stress, factors able to impair oocyte fertilization competence and embryo growth. PMID- 28645284 TI - Healthcare expenditure on Indigenous and non-Indigenous Australians at high risk of cardiovascular disease. AB - BACKGROUND: In spite of bearing a heavier burden of death, disease and disability, there is mixed evidence as to whether Indigenous Australians utilise more or less healthcare services than other Australians given their elevated risk level. This study analyses the Medicare expenditure and its predictors in a cohort of Indigenous and non-Indigenous Australians at high risk of cardiovascular disease. METHODS: The healthcare expenditure of participants of the Kanyini Guidelines Adherence with the Polypill (GAP) pragmatic randomised controlled trial was modelled using linear regression methods. 535 adult (48% Indigenous) participants at high risk of cardiovascular disease (CVD) were recruited through 33 primary healthcare services (including 12 Aboriginal Medical Services) across Australia. RESULTS: There was no significant difference in the expenditure of Indigenous and non-Indigenous participants in non-remote areas following adjustment for individual characteristics. Indigenous individuals living in remote areas had lower MBS expenditure ($932 per year P < 0.001) than other individuals. MBS expenditure was found to increase with being aged over 65 years ($128, p = 0.013), being female ($472, p = 0.003), lower baseline reported quality of life ($102 per 0.1 decrement of utility p = 0.004) and a history of diabetes ($324, p = 0.001), gout ($631, p = 0.022), chronic obstructive pulmonary disease ($469, p = 0.019) and established CVD whether receiving guideline recommended treatment prior to the trial ($452, p = 0.005) or not ($483, p = 0.04). When controlling for all other characteristics, morbidly obese patients had lower MBS expenditure than other individuals (-$887, p = 0.002). CONCLUSION: The findings suggest that for the majority of participants, once individuals are engaged with a primary care provider, factors other than whether they are Indigenous determine the level of Medicare expenditure for each person. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN 126080005833347. PMID- 28645285 TI - Completeness and timeliness of notifiable disease reporting: a comparison of laboratory and provider reports submitted to a large county health department. AB - BACKGROUND: Most public health agencies expect reporting of diseases to be initiated by hospital, laboratory or clinic staff even though so-called passive approaches are known to be burdensome for reporters and produce incomplete as well as delayed reports, which can hinder assessment of disease and delay recognition of outbreaks. In this study, we analyze patterns of reporting as well as data completeness and timeliness for traditional, passive reporting of notifiable disease by two distinct sources of information: hospital and clinic staff versus clinical laboratory staff. Reports were submitted via fax machine as well as electronic health information exchange interfaces. METHODS: Data were extracted from all submitted notifiable disease reports for seven representative diseases. Reporting rates are the proportion of known cases having a corresponding case report from a provider, a faxed laboratory report or an electronic laboratory report. Reporting rates were stratified by disease and compared using McNemar's test. For key data fields on the reports, completeness was calculated as the proportion of non-blank fields. Timeliness was measured as the difference between date of laboratory confirmed diagnosis and the date the report was received by the health department. Differences in completeness and timeliness by data source were evaluated using a generalized linear model with Pearson's goodness of fit statistic. RESULTS: We assessed 13,269 reports representing 9034 unique cases. Reporting rates varied by disease with overall rates of 19.1% for providers and 84.4% for laboratories (p < 0.001). All but three of 15 data fields in provider reports were more often complete than those fields within laboratory reports (p <0.001). Laboratory reports, whether faxed or electronically sent, were received, on average, 2.2 days after diagnosis versus a week for provider reports (p <0.001). CONCLUSIONS: Despite growth in the use of electronic methods to enhance notifiable disease reporting, there still exists much room for improvement. PMID- 28645286 TI - The myths surrounding mild stimulation in vitro fertilization (IVF). AB - So-called mild controlled ovarian hyperstimulation (mCOH) has in recent years increased in popularity, claiming to be safer and more patient-friendly, while also improving in vitro fertilization (IVF) outcomes. We here challenge the International Society for Mild Approaches in Assisted Reproduction (ISMAAR) definition of mild stimulation, and especially address four fundamental issues, where our review found conventional COH (cCOH) advantageous over mCOH. They are: prevalence of severe ovarian hyperstimulation syndrome (OHSS), oocyte/embryo quality, pregnancy/live birth rates, and cost. We conclude that an objective review of the literature does not support the routine utilization of mCOH in assisted reproduction. PMID- 28645287 TI - Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial. AB - BACKGROUND: The effect of enzalutamide on health-related quality of life (HRQoL) in the PREVAIL trial in chemotherapy-naive men with metastatic castration resistant prostate cancer was analyzed using the generic EQ-5D instrument. METHODS: Patients received oral enzalutamide 160 mg/day (n = 872) or placebo (n = 845). EQ-5D index and EQ-5D visual analogue scale (EQ-5D VAS) scores were evaluated at baseline, week 13, and every 12 weeks until week 61 due to sample size reduction thereafter. Changes on individual dimensions were assessed, and Paretian Classification of Health Change (PCHC) and time-to-event analyses were conducted. RESULTS: With enzalutamide, EQ-5D index and EQ-5D VAS scores declined more slowly versus placebo and time to diverge from full health was prolonged. Average decline in EQ-5D index (-0.042 vs. -0.070; P < .0001) and EQ-5D VAS (-1.3 vs. -4.4; P < .0001) was significantly smaller with enzalutamide. There were significant (P < .05) between-group differences favoring enzalutamide in Pain/Discomfort to week 37, Anxiety/Depression at week 13, and Usual Activities at week 25, but no significant differences for Mobility and Self-care. The PCHC analysis showed more enzalutamide patients reporting improvement than placebo patients at weeks 13, 25, and 49 (all P < .05) and week 37 (P = .0512). Enzalutamide was superior (P <= .0003) to placebo for time to diverge from full health and time to first deterioration on Pain/Discomfort and Anxiety/Depression dimensions. CONCLUSIONS: This in-depth post hoc analysis showed that enzalutamide delayed HRQoL deterioration and had beneficial effects on several HRQoL domains, including Pain/Discomfort and the proportion of patients in full health, compared with placebo, and may help to support future analyses of this type. TRIAL REGISTRATION: NCT01212991. PMID- 28645288 TI - A cohort study of a general surgery electronic consultation system: safety implications and impact on surgical yield. AB - BACKGROUND: Electronic consultation (eConsult) systems have enhanced access to specialty expertise and enhanced care coordination among primary care and specialty care providers, while maintaining high primary care provider (PCP), specialist and patient satisfaction. Little is known about their impact on the efficiency of specialty care delivery, in particular surgical yield (percent of ambulatory visits resulting in a scheduled surgical case). METHODS: Retrospective cohort of a random selection of 150 electronic consults from PCPs to a safety-net general surgery clinic for the three most common general surgery procedures (herniorrhaphy, cholecystectomy, anorectal procedures) in 2014. Electronic consultation requests were reviewed for the presence/absence of consult domains: symptom acuity/severity, diagnostic evaluation, concurrent medical conditions, and attempted diagnosis. Logic regression was used to examine the association between completeness of consult requests and scheduling an ambulatory clinic visit. Surgical yield was also calculated, as was the percentage of patients requiring unanticipated healthcare visits. RESULTS: In 2014, 1743 electronic consultations were submitted to general surgery. Among the 150 abstracted, the presence of consult domains ranged from 49% to 99%. Consult completeness was not associated with greater likelihood of scheduling an ambulatory visit. Seventy-six percent of consult requests (114/150) were scheduled for a clinic appointment and surgical yield was 46%; without an eConsult system, surgical yield would have been 35% (p=0.07). Among patients not scheduled for a clinic visit (n=36), 4 had related unanticipated emergency department visits. CONCLUSION: Econsult systems can be used to safely optimize the surgical yield of a safety-net general surgery service. PMID- 28645289 TI - Degenerative changes of the canine cervical spine after discectomy procedures, an in vivo study. AB - BACKGROUND: Discectomies are a common surgical treatment for disc herniations in the canine spine. However, the effect of these procedures on intervertebral disc tissue is not fully understood. The objective of this study was to assess degenerative changes of cervical spinal segments undergoing discectomy procedures, in vivo. RESULTS: Discectomies led to a 60% drop in disc height and 24% drop in foraminal height. Segments did not fuse but showed osteophyte formation as well as endplate sclerosis. MR imaging revealed terminal degenerative changes with collapse of the disc space and loss of T2 signal intensity. The endplates showed degenerative type II Modic changes. Quantitative MR imaging revealed that over 95% of Nucleus Pulposus tissue was extracted and that the nuclear as well as overall disc hydration significantly decreased. Histology confirmed terminal degenerative changes with loss of NP tissue, loss of Annulus Fibrosus organization and loss of cartilage endplate tissue. The bony endplate displayed sclerotic changes. CONCLUSION: Discectomies lead to terminal degenerative changes. Therefore, these procedures should be indicated with caution specifically when performed for prophylactic purposes. PMID- 28645290 TI - Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis. AB - BACKGROUND: Metastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice. RESULTS: By using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice. CONCLUSIONS: Surgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies. PMID- 28645291 TI - The effect of zoledronic acid on type and volume of Modic changes among patients with low back pain. AB - BACKGROUND: Modic changes (MC) are associated with low back pain (LBP). In this study, we compared changes in size and type of MC, after a single intravenous infusion of 5 mg zoledronic acid (ZA) or placebo, among chronic LBP patients with MC on magnetic resonance imaging (MRI), and evaluated whether the MRI changes correlate with symptoms. METHODS: All patients (N = 19 in ZA, 20 in placebo) had MRI at baseline (0.23-1.5 T) and at one year (1.5-3 T). We evaluated the level, type and volume of all the MC. The MC were classified into M1 (M1 (100%)), predominating M1 (M1/2 (65:35%)) or predominating M2 (M1/2 (35:65%)), and M2 (M2 (100%)). The first two were considered M1-dominant, and the latter two M2 dominant. Volumes of M1 and M2 were calculated separately for the primary MC, which was assumed to cause the symptoms, and the other MC. We analysed the one year treatment differences in M1 and M2 volumes using analysis of covariance with adjustments for age, sex, body mass index, and smoking. The correlations between the MRI changes and the changes in LBP symptoms were analysed using Pearson correlations. RESULTS: In the ZA group, 84.2% of patients had M1-dominant primary MC at baseline, compared to 50% in the placebo group (p = 0.041). The primary MC in the ZA group converted more likely to M2-dominant (42.1% ZA, 15% placebo; p = 0.0119). The other MC (15 ZA, 8 placebo) were on average 42% smaller and remained largely M2-dominant. The M1 volume of the primary MC decreased in the ZA group, but increased in the placebo group (-0.83 cm3 vs 0.91 cm3; p = 0.21). The adjusted treatment difference for M1 volume was -1.9 cm3 (95% CI -5.0 to 1.2; p = 0.22) and for M2 volume 0.23 cm3 (p = 0.86). In the MC that remained M1-dominant, volume change correlated positively with increased symptoms in the placebo group, whereas the correlations were negative and weak in the ZA group. CONCLUSIONS: Zoledronic acid tended to speed up the conversion of M1-dominant into M2-dominant MC and decrease the volume of M1-dominant MC, although statistical significance was not demonstrated. TRIAL REGISTRATION: The registration number in ClinicalTrials.gov is NCT01330238 and the date of registration February 11, 2011. PMID- 28645292 TI - Implementation of tobacco cessation brief intervention in complementary and alternative medicine practice: qualitative evaluation. AB - BACKGROUND: This article presents findings from qualitative interviews conducted as part of a research study that trained Acupuncture, Massage, and Chiropractic practitioners' in Arizona, US, to implement evidence-based tobacco cessation brief interventions (BI) in their routine practice. The qualitative phase of the overall study aimed to assess: the impact of tailored training in evidence-based tobacco cessation BI on complementary and alternative medicine (CAM) practitioners' knowledge and willingness to implement BIs in their routine practice; and their patients' responses to cessation intervention in CAM context. METHODS: To evaluate the implementation of skills learned from a tailored training program, we conducted semi-structured qualitative interviews with 54 CAM practitioners in Southern Arizona and 38 of their patients. Interview questions focused on reactions to the implementation of tobacco cessation BIs in CAM practice. RESULTS: After participating in a tailored BI training, CAM practitioners reported increased confidence, knowledge, and motivation to address tobacco in their routine practice. Patients were open to being approached by CAM practitioners about tobacco use and viewed BIs as an expected part of wellness care. CONCLUSIONS: Tailored training motivated CAM practitioners in this study to implement evidence-based tobacco cessation BIs in their routine practice. Results suggest that CAM practitioners can be a valuable point of contact and should be included in tobacco cessation efforts. PMID- 28645293 TI - Prenatal screening of fetal ventriculoarterial connections: benefits of 4D technique in fetal heart imaging. AB - BACKGROUND: Identification of prenatal ventriculoarterial connections in fetuses with conotruncal anomalies (CTA) remains one of the greatest challenges for sonographers performing screening examinations. Herein, we propose a novel protocol of 4D volume analysis that identifies ventriculoarterial connections and evaluate its clinical utility in routine screenings. METHODS: Twenty-nine cases of transposition of the great arteries (TGA), 22 cases of double-outlet right ventricle (DORV), 36 cases of tetralogy of Fallot (TOF), 14 cases of truncus arteriosus (TCA), and randomly selected 70 normal fetuses were reviewed in this study. All cases were evaluated using 2D data alone (2D method), post-processing volumes with no exact algorithm (4D-1 method), or with the proposed algorithm (4D 2 method), or using the 2D and 4D data together (combined method). Comparisons were made to evaluate the detection rate of ventriculoarterial connections for these different methods. RESULTS: During 18-28 gestational weeks, the detection rate of 4D-2 modality was satisfactory. The detection rate of the combined method was significantly higher than 2D method in the identification of TGA, TOF, and TCA. The detection rate of 4D-1 method was significantly lower than 4D -2 modality for CTA fetuses. During late pregnancy, the detection rate for both 4D modalities was very low due to the poor quality of the 4D volumes. CONCLUSIONS: We proposed a detailed protocol, which allowed the examiner to identify fetal ventriculoarterial connections by 4D volumes. Inclusion of blood information into the volumes improved diagnosis. Our findings suggest that the incorporation of 4D STIC into routine screenings could improve the detection for TGA, TOF, and TCA. PMID- 28645294 TI - 3,5,4'-trihydroxy-6,7,3'-trimethoxyflavone protects against beta amyloid-induced neurotoxicity through antioxidative activity and interference with cell signaling. AB - BACKGROUND: Alzheimer's disease is a neurodegenerative disease, characterized by progressive decline in memory and cognitive functions, that results from loss of neurons in the brain. Amyloid beta (Abeta) protein and oxidative stress are major contributors to Alzheimer's disease, therefore, protecting neuronal cells against Abeta-induced toxicity and oxidative stress might form an effective approach for treatment of this disease. 3,5,4'-trihydroxy-6,7,3'-trimethoxyflavone (TTF) is a flavonoid we have purified from the plant Achillea fragrantissima; and the present study examined, for the first time, the effects of this compound on Abeta toxicity to neuronal cells. METHODS: Various chromatographic techniques were used to isolate TTF from the plant Achillea fragrantissima, and an N2a neuroblastoma cell line was used to study its activities. The cellular levels of total and phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and of total and phosphorylated extracellular signal-regulated kinase (ERK 1/2) were determined by enzyme-linked immunosorbent assay (ELISA). Intracellular reactive oxygen species (ROS) levels were measured by using 2',7' dichlorofluorescein diacetate (DCF-DA). Cytotoxicity and cell viability were assessed by using lactate dehydrogenase (LDH) activity in cell-conditioned media, or by crystal violet cell staining, respectively. RESULTS: TTF prevented the Abeta-induced death of neurons and attenuated the intracellular accumulation of ROS following treatment of these cells with Abeta. TTF also inhibited the Abeta induced phosphorylation of the signaling proteins SAPK/JNK and ERK 1/2, which belong to the mitogen-activated protein kinase (MAPK) family. CONCLUSION: TTF should be studied further as a potential therapeutic means for the treatment of Alzheimer's disease. PMID- 28645295 TI - Identification of the flotillin-1/2 heterocomplex as a target of autoantibodies in bona fide multiple sclerosis. AB - BACKGROUND: Autoantibodies, in particular those against aquaporin-4 and myelin oligodendrocyte glycoprotein (MOG), aid as biomarkers in the differential diagnosis of demyelination. Here, we report on discovery of autoantibodies against flotillin in patients with multiple sclerosis (MS). METHODS: The target antigen was identified by histo-immunoprecipitation using the patients' sera and cryosections of rat or pig cerebellum combined with mass spectrometrical analysis. Correct identification was ascertained by indirect immunofluorescence and neutralization tests using the target antigens recombinantly expressed in HEK293 cells. RESULTS: Serum and CSF of the index patient produced a fine granular IgG indirect immunofluorescence staining of the hippocampal and cerebellar molecular layers. Flotillin-1 and flotillin-2 were identified as target autoantigens. They also reacted with recombinant human flotillin-1/2 co expressed in HEK293 cells, but not with the individual flotillins in fixed- and live-cell assays. Moreover, neutralization using flotillin-1/2, but not the single flotillins, abolished the tissue reactivity of patient serum. Screening of 521 patients, for whom anti-aquaporin-4 testing was requested and negative, revealed 8 additional patients with anti-flotillin-1/2 autoantibodies. All eight were negative for anti-MOG. Six patients ex post fulfilled the revised McDonald criteria for MS. Vice versa, screening of 538 MS sera revealed anti-flotillin-1/2 autoantibodies in eight patients. The autoantibodies were not found in a cohort of 67 patients with other neural autoantibody-associated syndromes and in 444 healthy blood donors. CONCLUSIONS: Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, are present in 1-2% of patients with bona fide MS. PMID- 28645296 TI - MyD88-dependent pro-interleukin-1beta induction in dendritic cells exposed to food-grade synthetic amorphous silica. AB - BACKGROUND: Dendritic cells (DCs) are specialized first-line sensors of foreign materials invading the organism. These sentinel cells rely on pattern recognition receptors such as Nod-like or Toll-like receptors (TLRs) to launch immune reactions against pathogens, but also to mediate tolerance to self-antigens and, in the intestinal milieu, to nutrients and commensals. Since inappropriate DC activation contributes to inflammatory diseases and immunopathologies, a key question in the evaluation of orally ingested nanomaterials is whether their contact with DCs in the intestinal mucosa disrupts this delicate homeostatic balance between pathogen defense and tolerance. Here, we generated steady-state DCs by incubating hematopoietic progenitors with feline McDonough sarcoma-like tyrosine kinase 3 ligand (Flt3L) and used the resulting immature DCs to test potential biological responses against food-grade synthetic amorphous silica (SAS) representing a common nanomaterial generally thought to be safe. RESULTS: Interaction of immature and unprimed DCs with food-grade SAS particles and their internalization by endocytic uptake fails to elicit cytotoxicity and the release of interleukin (IL)-1alpha or tumor necrosis factor-alpha, which were identified as master regulators of acute inflammation in lung-related studies. However, the display of maturation markers on the cell surface shows that SAS particles activate completely immature DCs. Also, the endocytic uptake of SAS particles into these steady-state DCs leads to induction of the pro-IL-1beta precursor, subsequently cleaved by the inflammasome to secrete mature IL-1beta. In contrast, neither pro-IL-1beta induction nor mature IL-1beta secretion occurs upon internalization of TiO2 or FePO4 nanoparticles. The pro-IL-1beta induction is suppressed by pharmacologic inhibitors of endosomal TLR activation or by genetic ablation of MyD88, a downstream adapter of TLR pathways, indicating that endosomal pattern recognition is responsible for the observed cytokine response to food-grade SAS particles. CONCLUSIONS: Our results unexpectedly show that food grade SAS particles are able to directly initiate the endosomal MyD88-dependent pathogen pattern recognition and signaling pathway in steady-state DCs. The ensuing activation of immature DCs with de novo induction of pro-IL-1beta implies that the currently massive use of SAS particles as food additive should be reconsidered. PMID- 28645297 TI - Interleukin-1 receptor type 1 is overexpressed in neurons but not in glial cells within the rat superficial spinal dorsal horn in complete Freund adjuvant-induced inflammatory pain. AB - BACKGROUND: All known biological functions of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) are mediated by type 1 interleukin receptor (IL 1R1). IL-1beta-IL-1R1 signaling modulates various neuronal functions including spinal pain processing. Although the role of IL-1beta in pain processing is generally accepted, there is a discussion in the literature whether IL-1beta exerts its effect on spinal pain processing by activating neuronal or glial IL 1R1. To contribute to this debate, here we investigated the expression and cellular distribution of IL-1R1 in the superficial spinal dorsal horn in control animals and also in inflammatory pain. METHODS: Experiments were performed on rats and wild type as well as IL-1R1-deficient mice. Inflammatory pain was evoked by unilateral intraplantar injection of complete Freund adjuvant (CFA). The nociceptive responsiveness of control and CFA-treated animals were tested daily for withdrawal responses to mechanical and thermal stimuli before and after CFA injection. Changes in the expression of 48 selected genes/mRNAs and in the quantity of IL-1R1 protein during the first 3 days after CFA injection were measured with the TaqMan low-density array method and Western blot analysis, respectively. The cellular localization of IL-1R1 protein was investigated with single and double staining immunocytochemical methods. RESULTS: We found a six times and two times increase in IL-1R1 mRNA and protein levels, respectively, in the dorsal horn of CFA-injected animals 3 days after CFA injection, at the time of the summit of mechanical and thermal allodynia. Studying the cellular distribution of IL-1R1, we found an abundant expression of IL-1R1 on the somatodendritic compartment of neurons and an enrichment of the receptor in the postsynaptic membranes of some excitatory synapses. In contrast to the robust neuronal localization, we observed only a moderate expression of IL-1R1 on astrocytes and a negligible one on microglial cells. CFA injection into the hind paw caused a remarkable increase in the expression of IL-1R1 in neurons, but did not alter the glial expression of the receptor. CONCLUSION: The results suggest that IL-1beta exerts its effect on spinal pain processing primarily through neuronal IL-1R1, but it can also interact in some extent with IL-1R1 expressed by astrocytes. PMID- 28645298 TI - Neurodevelopmental profile of Fetal Alcohol Spectrum Disorder: A systematic review. AB - BACKGROUND: In an effort to improve the screening and diagnosis of individuals with Fetal Alcohol Spectrum Disorder (FASD), research has focused on the identification of a unique neurodevelopmental profile characteristic of this population. The objective of this review was to identify any existing neurodevelopmental profiles of FASD and review their classification function in order to identify gaps and limitations of the current literature. METHODS: A systematic search for studies published up to the end of December 2016 reporting an identified neurodevelopmental profile of FASD was conducted using multiple electronic bibliographic databases. The search was not limited geographically or by language of publication. Original research published in a peer-reviewed journal that involved the evaluation of the classification function of an identified neurodevelopmental profile of FASD was included. RESULTS: Two approaches have been taken to determine the pathognomonic neurodevelopmental features of FASD, namely the utilization of i) behavioral observations/ratings by parents/caregivers and ii) subtest scores from standardized test batteries assessing a variety of neurodevelopmental domains. Both approaches show some promise, with the former approach (which is dominated by research on the Neurobehavioral Screening Tool) having good sensitivity (63% to 98%), but varying specificity (42% to 100%), and the latter approach having good specificity (72% to 96%), but varying sensitivity (60% to 88%). CONCLUSIONS: The current review revealed that research in this area remains limited and a definitive neurodevelopmental profile of FASD has not been established. However, the identification of a neurodevelopmental profile will aid in the accurate identification of individuals with FASD, by adding to the armamentarium of clinicians. The full review protocol is available in PROSPERO ( http://www.crd.york.ac.uk/PROSPERO/ ); registration number CRD42016039326; registered 20 May 2016. PMID- 28645299 TI - Programming of mouse obesity by maternal exposure to concentrated ambient fine particles. AB - BACKGROUND: Many diseases including obesity may originate through alterations in the early-life environment that interrupts fetal development. Increasing evidence has shown that exposure to ambient fine particles (PM2.5) is associated with abnormal fetal development. However, its long-term metabolic effects on offspring have not been systematically investigated. RESULTS: To determine if maternal exposure to PM2.5 programs offspring obesity, female C57Bl/6j mice were exposed to filtered air (FA) or concentrated ambient PM2.5 (CAP) during pre-conception, pregnancy, and lactation, and the developmental and metabolic responses of offspring were assessed. The growth trajectory of offspring revealed that maternal exposure to CAP significantly decreased offspring birth weight but increased body weight of adult male but not female offspring, and the latter was expressed as increased adiposity. These adult male offspring had increased food intake, but were sensitive to exogenous leptin. Their hypothalamic expression of Socs3 and Pomc, two target genes of leptin, was not changed, and the hypothalamic expression of NPY, an orexigenic peptide that is inhibited by leptin, was significantly increased. These decreases in central anorexigenic signaling were accompanied by reduced plasma leptin and its expression in adipose tissues, the primary source of circulating leptin. In contrast, maternal exposure did not significantly change any of these indexes in adult female offspring. Pyrosequencing demonstrated that the leptin promoter methylation of adipocytes was significantly increased in CAP-exposed male but not female offspring. CONCLUSIONS: Our data indicate that maternal exposure to ambient PM2.5 programs obesity in male offspring probably through alterations in the methylation of the promoter region of the leptin gene. PMID- 28645300 TI - Bacterial ghosts as adjuvants: mechanisms and potential. AB - Bacterial ghosts (BG) are empty cell envelopes derived from Gram-negative bacteria. They contain many innate immunostimulatory agonists, and are potent activators of a broad range of cell types involved in innate and adaptive immunity. Several considerable studies have demonstrated the effectiveness of BG as adjuvants as well as their ability to induce proinflammatory cytokine production by a range of immune and non-immune cell types. These proinflammatory cytokines trigger a generalized recruitment of T and B lymphocytes to lymph nodes that maximize the chances of encounter with their cognate antigen, and subsequent elicitation of potent immune responses. The plasticity of BG has allowed for the generation of envelope-bound foreign antigens in immunologically active forms that have proven to be effective vaccines in animal models. Besides their adjuvant property, BG also effectively deliver DNA-encoded antigens to dendritic cells, thereby leading to high transfection efficiencies, which subsequently result in higher gene expressions and improved immunogenicity of DNA-based vaccines. In this review, we summarize our understanding of BG interactions with the host immune system, their exploitation as an adjuvant and a delivery system, and address important areas of future research interest. PMID- 28645301 TI - The Sternal Management Accelerated Recovery Trial (S.M.A.R.T) - standard restrictive versus an intervention of modified sternal precautions following cardiac surgery via median sternotomy: study protocol for a randomised controlled trial. AB - BACKGROUND: The routine implementation of sternal precautions to prevent sternal complications that restrict the use of the upper limbs is currently worldwide practice following a median sternotomy. However, evidence is limited and drawn primarily from cadaver studies and orthopaedic research. Sternal precautions may delay recovery, prolong hospital discharge and be overly restrictive. Recent research has shown that upper limb exercise reduces post-operative sternal pain and results in minimal micromotion between the sternal edges as measured by ultrasound. The aims of this study are to evaluate the effects of modified sternal precautions on physical function, pain, recovery and health-related quality of life after cardiac surgery. METHODS/DESIGN: This study is a phase II, double-blind, randomised controlled trial with concealed allocation, blinding of patients and assessors, and intention-to-treat analysis. Patients (n = 72) will be recruited following cardiac surgery via a median sternotomy. Sample size calculations were based on the minimal important difference (two points) for the primary outcome: Short Physical Performance Battery. Thirty-six participants are required per group to counter dropout (20%). All participants will be randomised to receive either standard or modified sternal precautions. The intervention group will receive guidelines encouraging the safe use of the upper limbs. Secondary outcomes are upper limb function, pain, kinesiophobia and health related quality of life. Descriptive statistics will be used to summarise data. The primary hypothesis will be examined by repeated-measures analysis of variance to evaluate the changes from baseline to 4 weeks post-operatively in the intervention arm compared with the usual-care arm. In all tests to be conducted, a p value <0.05 (two-tailed) will be considered statistically significant, and confidence intervals will be reported. DISCUSSION: The Sternal Management Accelerated Recovery Trial (S.M.A.R.T.) is a two-centre randomised controlled trial powered and designed to investigate whether the effects of modifying sternal precautions to include the safe use of the upper limbs and trunk impact patients' physical function and recovery following cardiac surgery via median sternotomy. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry identifier: ACTRN12615000968572 . Registered on 16 September 2015 (prospectively registered). PMID- 28645303 TI - Effect of physicochemical parameters on Anopheles and Culex mosquito larvae abundance in different breeding sites in a rural setting of Muheza, Tanzania. PMID- 28645302 TI - Untangling glycaemia and mortality in critical care. AB - BACKGROUND: Hyperglycaemia is associated with adverse outcomes in the intensive care unit, and initial studies suggested outcome benefits of glycaemic control (GC). However, subsequent studies often failed to replicate these results, and they were often unable to achieve consistent, safe control, raising questions about the benefit or harm of GC as well as the nature of the association of glycaemia with mortality and clinical outcomes. In this study, we evaluated if non-survivors are harder to control than survivors and determined if glycaemic outcome is a function of patient condition and eventual outcome or of the glycaemic control provided. METHODS: Clinically validated, model-based, hour-to hour insulin sensitivity (SI) and its hour-to-hour variability (%DeltaSI) were identified over the first 72 h of therapy in 145 patients (119 survivors, 26 non survivors). In hypothesis testing, we compared distributions of SI and %DeltaSI in 6-hourly blocks for survivors and non-survivors. In equivalence testing, we assessed if differences in these distributions, based on blood glucose measurement error, were clinically significant. RESULTS: SI level was never equivalent between survivors and non-survivors (95% CI of percentage difference in medians outside +/-12%). Non-survivors had higher SI, ranging from 9% to 47% higher overall in 6-h blocks, and this difference became statistically significant as glycaemic control progressed. %DeltaSI was equivalent between survivors and non-survivors for all 6-hourly blocks (95% CI of difference in medians within +/-12%) and decreased in general over time as glycaemic control progressed. CONCLUSIONS: Whereas non-survivors had higher SI levels, variability was equivalent to that of survivors over the first 72 h. These results indicate survivors and non-survivors are equally controllable, given an effective glycaemic control protocol, suggesting that glycaemia level and variability, and thus the association between glycaemia and outcome, are essentially determined by the control provided rather than by underlying patient or metabolic condition. PMID- 28645304 TI - Validation of an automated technique for ovarian cortex dissociation: isolation of viable ovarian cells and their qualification by multicolor flow cytometry. AB - BACKGROUND: Ovarian tissue cryopreservation is a technique for fertility preservation addressed to prepubertal girls or to patients for whom no ovarian stimulation is possible before initiation of gonadotoxic treatments. Autotransplantation of frozen-thawed ovarian tissue is the only available option for reuse but presents some limitations: ischemic tissue damages post-transplant and reintroduction of malignant cells in cases of cancer. It is therefore essential to qualify ovarian tissue before autograft on a functional and oncological point of view. Here, we aimed to isolate viable cells from human ovarian cortex in order to obtain an ovarian cell suspension analyzable by multicolor flow cytometry. METHODS: Ovarian tissue (fresh or frozen-thawed), from patients with polycystic ovarian syndrome (reference tissue) and from patients who underwent ovarian tissue cryopreservation, was used for dissociation with an automated device. Ovarian tissue-dissociated cells were analyzed by multicolor flow cytometry; the cell dissociation yield and viability were assessed. Two automated dissociation protocols (named laboratory and commercial protocols) were compared. RESULTS: The effectiveness of the dissociation was not significantly different between reference ovarian tissue (1.58 * 106 +/- 0.94 * 106 viable ovarian cells per 100 mg of ovarian cortex, n = 60) and tissue from ovarian tissue cryopreservation (1.70 * 106 +/- 1.35 * 106 viable ovarian cells, n = 18). However, the viability was slightly different for fresh ovarian cortex compared to frozen-thawed ovarian cortex whether we used reference tissue (p = 0.022) or tissue from ovarian cryopreservation (p = 0.018). Comparing laboratory and commercial protocols, it appeared that cell yield was similar but cell viability was significantly improved when using the commercial protocol (81.3% +/- 12.3% vs 23.9% +/- 12.5%). CONCLUSION: Both dissociation protocols allow us to isolate more than one million viable cells per 100 mg of ovarian cortex, but the viability is higher when using the commercial dissociation kit. Ovarian cortex dissociation is a promising tool for human ovarian cell qualification and for ovarian residual disease detection by multicolor flow cytometry. PMID- 28645305 TI - High expression of Collagen Triple Helix Repeat Containing 1 (CTHRC1) facilitates progression of oesophageal squamous cell carcinoma through MAPK/MEK/ERK/FRA-1 activation. AB - BACKGROUND: Oesophageal cancer is one of the most common malignancies worldwide,and oesophageal squamous cell carcinoma (ESCC) is the predominant histological type both globally and in China. Collagen triple helix repeat containing 1 (CTHRC1) has been found to be upregulated in ESCC. However, its role in tumourigenesis and progression of ESCC remains unclear. METHODS: Using our previous ESCC mRNA profiling data, we screened upregulated genes to identify those required for proliferation. Immunohistochemistry was performed to determine the level of CTHRC1 protein expression in 204 ESCC patients. Correlations between CTHRC1 expression and clinicopathological characteristics were assessed. In addition, pyrosequencing and 5-aza-dC treatment were performed to evaluate methylation status of CTHRC1 promoter. In vitro and in vivo analyses were also conducted to determine the role of CTHRC1 in ESCC cell proliferation, migration and invasion, and RNA sequencing and molecular experiments were performed to study the underlying mechanisms. RESULTS: Based on mRNA profiling data, CTHRC1 was identified as one of the most significantly upregulated genes in ESCC tissues (n = 119, fold change = 20.5, P = 2.12E-66). RNA interference screening also showed that CTHRC1 was required for cell proliferation. Immunohistochemistry confirmed markedly high CTHRC1 protein expression in tumour tissues, and high CTHRC1 expression was positively correlated with advanced T stage (P = 0.043), lymph node metastasis (P = 0.023), TNM stage (P = 0.024) and poor overall survival (P = 0.020). Promoter hypomethylation at cg07757887 may contribute to increased CTHRC1 expression in ESCC cells and tumours. Forced overexpression of CTHRC1 significantly enhanced cell proliferation, migration and invasion, whereas depletion of CTHRC1 suppressed these cellular functions in three ESCC cell lines and xenografts. CTHRC1 was found to activate FRA-1 (Fos-related antigen 1, also known as FOSL1) through the MAPK/MEK/ERK cascade, which led to upregulation of cyclin D1 and thus promoted cell proliferation. FRA-1 also induced snail1 mediated MMP14 (matrix metallopeptidase 14, also known as MT1-MMP) expression to facilitate ESCC cell invasion, migration, and metastasis. CONCLUSIONS: Our data suggest that CTHRC1 may act as an oncogenic driver in progression and metastasis of ESCC, and may serve as a potential biomarker for prognosis and personalized therapy. PMID- 28645306 TI - Excretory/secretory products of anisakid nematodes: biological and pathological roles. AB - Parasites from the family Anisakidae are widely distributed in marine fish populations worldwide and mainly nematodes of the three genera Anisakis, Pseudoterranova and Contracaecum have attracted attention due to their pathogenicity in humans. Their life cycles include invertebrates and fish as intermediate or transport hosts and mammals or birds as final hosts. Human consumption of raw or underprocessed seafood containing third stage larvae of anisakid parasites may elicit a gastrointestinal disease (anisakidosis) and allergic responses. Excretory and secretory (ES) compounds produced by the parasites are assumed to be key players in clinical manifestation of the disease in humans, but the molecules are likely to play a general biological role in invertebrates and lower vertebrates as well. ES products have several functions during infection, e.g. penetration of host tissues and evasion of host immune responses, but are at the same time known to elicit immune responses (including antibody production) both in fish and mammals. ES proteins from anisakid nematodes, in particular Anisakis simplex, are currently applied for diagnostic purposes but recent evidence suggests that they also may have a therapeutic potential in immune-related diseases. PMID- 28645307 TI - Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis. AB - BACKGROUND: Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist (Il1rn -/- mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn -/- mice. RESULTS: Using high-throughput 16S rRNA gene sequencing, we show that IL-1Ra critically maintains the diversity and regulates the composition of intestinal microbiota in mice. IL-1Ra deficiency reduced the intestinal microbial diversity and richness, and caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella. Notably, the aberrant intestinal microbiota in IL1rn -/- mice specifically potentiated IL-17 production by intestinal lamina propria (LP) lymphocytes and skewed the LP T cell balance in favor of T helper 17 (Th17) cells, an effect transferable to WT mice by fecal microbiota. Importantly, LP Th17 cell expansion and the development of spontaneous autoimmune arthritis in IL1rn -/- mice were attenuated under germ-free condition. Selective antibiotic treatment revealed that tobramycin-induced alterations of commensal intestinal microbiota, i.e., reduced Helicobacter, Flexispira, Clostridium, and Dehalobacterium, suppressed arthritis in IL1rn -/- mice. The arthritis phenotype in IL1rn -/- mice was previously shown to depend on Toll-like receptor 4 (TLR4). Using the ablation of both IL-1Ra and TLR4, we here show that the aberrations in the IL1rn -/- microbiota are partly TLR4-dependent. We further identify a role for TLR4 activation in the intestinal lamina propria production of IL-17 and cytokines involved in Th17 differentiation preceding the onset of arthritis. CONCLUSIONS: These findings identify a critical role for IL1Ra in maintaining the natural diversity and composition of intestinal microbiota, and suggest a role for TLR4 in mucosal Th17 cell induction associated with the development of autoimmune disease in mice. PMID- 28645308 TI - Neonatal AAV delivery of alpha-synuclein induces pathology in the adult mouse brain. AB - Abnormal accumulation of alpha-synuclein (alphasyn) is a pathological hallmark of Lewy body related disorders such as Parkinson's disease and Dementia with Lewy body disease. During the past two decades, a myriad of animal models have been developed to mimic pathological features of synucleinopathies by over-expressing human alphasyn. Although different strategies have been used, most models have little or no reliable and predictive phenotype. Novel animal models are a valuable tool for understanding neuronal pathology and to facilitate development of new therapeutics for these diseases. Here, we report the development and characterization of a novel model in which mice rapidly express wild-type alphasyn via somatic brain transgenesis mediated by adeno-associated virus (AAV). At 1, 3, and 6 months of age following intracerebroventricular (ICV) injection, mice were subjected to a battery of behavioral tests followed by pathological analyses of the brains. Remarkably, significant levels of alphasyn expression are detected throughout the brain as early as 1 month old, including olfactory bulb, hippocampus, thalamic regions and midbrain. Immunostaining with a phospho alphasyn (pS129) specific antibody reveals abundant pS129 expression in specific regions. Also, pathologic alphasyn is detected using the disease specific antibody 5G4. However, this model did not recapitulate behavioral phenotypes characteristic of rodent models of synucleinopathies. In fact no deficits in motor function or cognition were observed at 3 or 6 months of age. Taken together, these findings show that transduction of neonatal mouse with AAV alphasyn can successfully lead to rapid, whole brain transduction of wild-type human alphasyn, but increased levels of wildtype alphasyn do not induce behavior changes at an early time point (6 months), despite pathological changes in several neurons populations as early as 1 month. PMID- 28645309 TI - Herpes simplex virus-1 infects the olfactory bulb shortly following ocular infection and exhibits a long-term inflammatory profile in the form of effector and HSV-1-specific T cells. AB - BACKGROUND: Herpes simplex virus 1 (HSV-1) infection can result in a life threatening condition known as herpes simplex encephalitis (HSE). Trafficking patterns by which the virus reaches the central nervous system (CNS) following ocular infection are unresolved. We evaluated early viral dissemination pathways following ocular infection that involve trafficking to the olfactory bulb (OB). Additionally, we have characterized the capacity of HSV-1 to establish latency within OB tissue and profiled the local T lymphocyte response over the course of the acute infection into latency. METHODS: Scarified corneas of C57BL/6 or reporter-inducible Rosa mice (RosaTd/Tm) were inoculated with HSV-1 and assessed for viral dissemination into the peripheral nervous system (PNS) and CNS by RT PCR and confocal microscopy. T cells and the resident microglia activation signatures were analyzed by flow cytometry. T cell effector function in the form of IFN-gamma secretion was measured by T cells isolated from OB in comparison to T cells from other nervous system sites known to harbor HSV-1-specific memory T cells. RESULTS: Following ocular infection, HSV-1 viral titers from nasal secretions were detected as early as 48 h through 8 days post infection (8 DPI). HSV-1 gene expression was expressed as early as 2 days following ocular infection in the OB and was consistent with an enhanced expression in the ophthalmic, maxillary, and mandibular branch of the trigeminal nerve ganglia (TG). Rosa fluorescence protein expression (RFP+) representing HSV-1-infected cells from RosaTd/Tm mice was detected in the OB before other areas of the CNS (2 DPI). Additionally, during acute infection, most infected cells appeared to be anatomically distributed within the OB rather than other regions of the CNS. During latency (i.e., 30 DPI and beyond) despite no detectable infectious virus or lytic gene expression and low levels of latency associated transcripts, total effector (CD44+ CD62-) CD4+ T, CD8+ T, HSV-1-specific CD8+ T cells, and MHC class II positive resident microglia numbers continued to increase. CD4+ and CD8+ T cell populations isolated from the OB during latency were capable of responding to PMA/ionomycin in the production of IFN-gamma similar to T cells from other tissue that possess latent virus including the TG and brain stem. CONCLUSIONS: It is currently understood that HSV-1 traffics to the TG following ocular infection. We have identified a second conduit by which HSV-1 can directly access the CNS bypassing the brain stem. We have also recognized that the OB is unique in that during HSV-1 latency, latency-associated transcripts levels were marginally above uninfected controls. Despite these findings, the local immune response mimicked the phenotype of an active infection during latency. PMID- 28645310 TI - PTH monitoring after total parathyroidectomy with forearm auto-transplantation: potential for spuriously high levels from grafted forearm. AB - BACKGROUND: We have identified a cause of falsely elevated parathyroid hormone (PTH) levels after total parathyroidectomy with forearm auto-transplantation (TPT ATx). Our cases highlight the need to draw PTH samples remotely, away from forearm graft sites, to ensure accurate levels. CASE PRESENTATIONS: We report on four patients who were referred to our surgical team at an academic tertiary care center for what was perceived to be recurrent hyperparathyroidism 2-5 years following total parathyroidectomy with auto-transplantation. Further evaluation revealed highly discrepant results in these patients depending on where the blood was drawn, with spuriously high levels in blood drawn from the grafted arm (Range 337-3885 ng/l), and much lower levels when blood was drawn remotely away from the graft site (Range 9-242 ng/l). The difference in PTH level between the grafted forearm and remote site for these patients ranged between 328 and 3643 ng/l. Over the period these cases were accrued (2008-2012), 89 patients underwent TPT-ATx in our institution. Therefore, our case report series suggests that this phenomenon will be evident to a clinically important extent in at least 4% of patients. CONCLUSIONS: One can acquire spuriously high PTH levels from grafted forearms, leading to the false diagnosis of recurrent hyperparathyroidism. We recommend PTH levels be drawn remotely from graft sites to ensure accurate systemic levels are reflected. PMID- 28645312 TI - PHF21B overexpression promotes cancer stem cell-like traits in prostate cancer cells by activating the Wnt/beta-catenin signaling pathway. AB - BACKGROUND: PHF21B is newly identified to be involved in the tumor progression; however, its biological role and molecular mechanism in prostate cancer have not been defined. This study is aimed to study the role of PHF21B in the progression of prostate cancer. METHODS: Real-time PCR, immunohistochemistry and western blotting analysis were used to determine PHF21B expression in prostate cancer cell lines and clinical specimens. The role of PHF21B in maintaining prostate cancer stem cell-like phenotype was examined by tumor-sphere formation assay and expression levels of stem cell markers. Luciferase reporter assay, western blot analysis, enzyme-linked immunosorbent assay and ChIP assay were used to determine whether PHF21B activates the Wnt/beta-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2. RESULTS: Our results revealed that PHF21B was markedly upregulated in prostate cancer cell lines and tissues. High PHF21B levels predicted poorer recurrence-free survival in prostate cancer patients. Gain-of-function and loss-of-function studies showed that overexpression of PHF21B enhanced, while downregulation suppressed, the cancer stem cell-like phenotype in prostate cancer cells. Xenograft tumor model showed that silencing PHF21B decreased the ability of tumorigenicity in vivo. Notably, Wnt/beta-catenin signaling was hyperactivated in prostate cancer cells overexpressing PHF21B, and mediated PHF21B-induced cancer stem cell-like phenotype. Furthermore, PHF21B suppressed repressors of the Wnt/beta-catenin signaling cascade, including SFRP1 and SFRP2. These results demonstrated that PHF21B constitutively activated wnt/beta-catenin signaling by transcriptionally downregulating SFRP1 and SFRP2, which promotes prostate cancer stem cell-like phenotype. CONCLUSIONS: Our results revealed that PHF21B functions as an oncogene in prostate cancer, and may represent a promising prognostic biomarker and an attractive candidate for target therapy of prostate cancer. PMID- 28645311 TI - Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected. AB - The recent global outbreak of Zika virus (ZIKV) infection has been linked to severe neurological disorders affecting the peripheral and central nervous systems (PNS and CNS, respectively). The pathobiology underlying these diverse clinical phenotypes are the subject of intense research; however, even the principal neural cell types vulnerable to productive Zika infection remain poorly characterised. Here we used CNS and PNS myelinating cultures from wild type and Ifnar1 knockout mice to examine neuronal and glial tropism and short-term consequences of direct infection with a Brazilian variant of ZIKV. Cell cultures were infected pre- or post-myelination for various intervals, then stained with cell-type and ZIKV-specific antibodies. In bypassing systemic immunity using ex vivo culture, and the type I interferon response in Ifnar1 deficient cells, we were able to evaluate the intrinsic infectivity of neural cells. Through systematic quantification of ZIKV infected cells in myelinating cultures, we found that ZIKV infection is enhanced in the absence of the type I interferon responses and that CNS cells are considerably more susceptible to infection than PNS cells. In particular, we demonstrate that CNS axons and myelinating oligodendrocytes are especially vulnerable to injury. These results have implications for understanding the pathobiology of neurological symptoms associated with ZIKV infection. Furthermore, we provide a quantifiable ex vivo infection model that can be used for fundamental and therapeutic studies on viral neuroinvasion and its consequences. PMID- 28645313 TI - Molecular investigation and phylogeny of Anaplasmataceae species infecting domestic animals and ticks in Corsica, France. AB - BACKGROUNDS: Corsica is a French island situated in the Mediterranean Sea. The island provides suitable natural conditions to study disease ecology, especially tick-borne diseases and emerging diseases in animals and ticks. The family Anaplasmataceae is a member of the order Rickettsiales; it includes the genera Anaplasma, Ehrlichia, Neorickettsia and Wolbachia. Anaplasmosis and ehrlichiosis traditionally refer to diseases caused by obligate intracellular bacteria of the genera Anaplasma and Ehrlichia. The aim of this study was to identify and estimate the prevalence of Anaplasmataceae species infecting domestic animals and ticks in Corsica. METHODS: In this study, 458 blood samples from sheep, cattle, horses, goats, dogs, and 123 ticks removed from cattle, were collected in Corsica. Quantitative real-time PCR screening and genetic characterisation of Anaplasmataceae bacteria were based on the 23S rRNA, rpoB and groEl genes. RESULTS: Two tick species were collected in the present study: Rhipicephalus bursa (118) and Hyalomma marginatum marginatum (5). Molecular investigation showed that 32.1% (147/458) of blood samples were positive for Anaplasmataceae infection. Anaplasma ovis was identified in 42.3% (93/220) of sheep. Anaplasma marginale was amplified from 100% (12/12) of cattle and two R. bursa (2/123). Several potentially new species were also identified: Anaplasma cf. ovis, "Candidatus Anaplasma corsicanum", "Candidatus Anaplasma mediterraneum" were amplified from 17.3% (38/220) of sheep, and Anaplasma sp. marginale-like was amplified from 80% (4/5) of goats. Finally, one R. bursa tick was found to harbour the DNA of E. canis. All samples from horses and dogs were negative for Anaplasmataceae infection. CONCLUSIONS: To our knowledge, this study is the first epidemiological survey on Anaplasmataceae species infecting animals and ticks in Corsica and contributes toward the identification of current Anaplasmataceae species circulating in Corsica. PMID- 28645316 TI - Erratum to: A novel anatomic severity grading score for acute Type B aortic dissections and correlation to aortic reinterventions after thoracic endovascular aortic repair. PMID- 28645314 TI - Neuromuscular function during knee extension exercise after cold water immersion. AB - BACKGROUND: Human adaptability to cold environment has been focused on in the physiological anthropology and related research area. Concerning the human acclimatization process in the natural climate, it is necessary to conduct a research assessing comprehensive effect of cold environment and physical activities in cold. This study investigated the effect of cold water immersion on the exercise performance and neuromuscular function during maximal and submaximal isometric knee extension. METHODS: Nine healthy males participated in this study. They performed maximal and submaximal (20, 40, and 60% maximal load) isometric knee extension pre- and post-immersion in 23, 26, and 34 degrees C water. The muscle activity of the rectus femoris (RF) and vastus lateralis (VL) was measured using surface electromyography (EMG). The percentages of the maximum voluntary contraction (%MVC) and mean power frequency (MPF) of EMG data were analyzed. RESULTS: The post-immersion maximal force was significantly lower in 23 degrees C than in 26 and 34 degrees C conditions (P < 0.05). The post-immersion %MVC of RF was significantly higher than pre-immersion during 60% maximal exercise in 23 and 26 degrees C conditions (P < 0.05). In the VL, the post-immersion %MVC was significantly higher than pre-immersion in 23 and 26 degrees C conditions during 20% maximal exercise and in 26 degrees C at 40 and 60% maximal intensities (P < 0.05). The post-immersion %MVC of VL was significantly higher in 26 degrees C than in 34 degrees C at 20 and 60% maximal load (P < 0.05). The post-immersion MPF of RF during 20% maximal intensity was significantly lower in 23 degrees C than in 26 and 34 degrees C conditions (P < 0.05), and significantly different between three water temperature conditions at 40 and 60% maximal intensities (P < 0.05). The post-immersion MPF of VL during three submaximal trials were significantly lower in 23 and 26 degrees C than in 34 degrees C conditions (P < 0.05). CONCLUSIONS: The lower shift of EMG frequency would be connected with the decrease in the nerve and muscle fibers conduction velocity. To compensate for the impairment of each muscle fibers function, more muscle fibers might be recruited to maintain the working load. This might result in the greater amplitude of EMG after the cold immersion. PMID- 28645315 TI - Role of inhibitors of serine peptidases in protecting Leishmania donovani against the hydrolytic peptidases of sand fly midgut. AB - BACKGROUND: In vector-borne diseases such as leishmaniasis, the sand fly midgut is considered to be an important site for vector-parasite interaction. Digestive enzymes including serine peptidases such as trypsin and chymotrypsin, which are secreted in the midgut are one of the obstacles for Leishmania in establishing a successful infection. The presence of some natural inhibitors of serine peptidases (ISPs) has recently been reported in Leishmania. In the present study, we deciphered the role of these ISPs in the survival of Leishmania donovani in the hostile sand fly midgut environment. METHODS: In silico and co immunoprecipitation studies were performed to observe the interaction of L. donovani ISPs with trypsin and chymotrypsin. Zymography and in vitro enzyme assays were carried out to observe the inhibitory effect of purified recombinant ISPs of L. donovani (rLdISPs) on trypsin, chymotrypsin and the sand fly midgut peptidases. The expression of ISPs in the amastigote to promastigote transition stages were studied by semi-quantitative RT-PCR and Western blot. The role of LdISP on the survival of ISP overexpressed (OE) and ISP knocked down (KD) Leishmania parasites inside the sand fly gut was investigated by in vitro and in vivo cell viability assays. RESULTS: We identified two ecotin-like genes in L. donovani, LdISP1 and LdISP2. In silico and co-immunoprecipitation results clearly suggest a strong interaction of LdISP molecules with trypsin and chymotrypsin. Zymography and in vitro enzyme assay confirmed the inhibitory effect of rLdISP on trypsin, chymotrypsin and the sand fly midgut peptidases. The expression of LdISP2 was found to be strongly associated with the amastigote to promastigote phase transition. The activities of the digestive enzymes were found to be significantly reduced in the infected sand flies when compared to uninfected. To our knowledge, our study is the first report showing the possible reduction of chymotrypsin activity in L. donovani infected sand flies compared to uninfected. Interestingly, during the early transition stage, substantial killing was observed in ISP2 knocked down (ISP2KD) parasites compared to wild type (WT), whereas ISP1 knocked down (ISP1KD) parasites remained viable. Therefore, our study clearly indicates that LdISP2 is a more effective inhibitor of serine peptidases than LdISP1. CONCLUSION: Our results suggest that the lack of ISP2 is detrimental to the parasites during the early transition from amastigotes to promastigotes. Moreover, the results of the present study demonstrated for the first time that LdISP2 has an important role in the inhibition of peptidases and promoting L. donovani survival inside the Phlebotomus argentipes midgut. PMID- 28645317 TI - Facial soft tissue response to maxillo-mandibular advancement in obstructive sleep apnea syndrome patients. PMID- 28645318 TI - Detecting consistent patterns of directional adaptation using differential selection codon models. AB - BACKGROUND: Phylogenetic codon models are often used to characterize the selective regimes acting on protein-coding sequences. Recent methodological developments have led to models explicitly accounting for the interplay between mutation and selection, by modeling the amino acid fitness landscape along the sequence. However, thus far, most of these models have assumed that the fitness landscape is constant over time. Fluctuations of the fitness landscape may often be random or depend on complex and unknown factors. However, some organisms may be subject to systematic changes in selective pressure, resulting in reproducible molecular adaptations across independent lineages subject to similar conditions. RESULTS: Here, we introduce a codon-based differential selection model, which aims to detect and quantify the fine-grained consistent patterns of adaptation at the protein-coding level, as a function of external conditions experienced by the organism under investigation. The model parameterizes the global mutational pressure, as well as the site- and condition-specific amino acid selective preferences. This phylogenetic model is implemented in a Bayesian MCMC framework. After validation with simulations, we applied our method to a dataset of HIV sequences from patients with known HLA genetic background. Our differential selection model detects and characterizes differentially selected coding positions specifically associated with two different HLA alleles. CONCLUSION: Our differential selection model is able to identify consistent molecular adaptations as a function of repeated changes in the environment of the organism. These models can be applied to many other problems, ranging from viral adaptation to evolution of life-history strategies in plants or animals. PMID- 28645319 TI - Architectural frameworks: defining the structures for implementing learning health systems. AB - BACKGROUND: The vision of transforming health systems into learning health systems (LHSs) that rapidly and continuously transform knowledge into improved health outcomes at lower cost is generating increased interest in government agencies, health organizations, and health research communities. While existing initiatives demonstrate that different approaches can succeed in making the LHS vision a reality, they are too varied in their goals, focus, and scale to be reproduced without undue effort. Indeed, the structures necessary to effectively design and implement LHSs on a larger scale are lacking. In this paper, we propose the use of architectural frameworks to develop LHSs that adhere to a recognized vision while being adapted to their specific organizational context. Architectural frameworks are high-level descriptions of an organization as a system; they capture the structure of its main components at varied levels, the interrelationships among these components, and the principles that guide their evolution. Because these frameworks support the analysis of LHSs and allow their outcomes to be simulated, they act as pre-implementation decision-support tools that identify potential barriers and enablers of system development. They thus increase the chances of successful LHS deployment. DISCUSSION: We present an architectural framework for LHSs that incorporates five dimensions-goals, scientific, social, technical, and ethical-commonly found in the LHS literature. The proposed architectural framework is comprised of six decision layers that model these dimensions. The performance layer models goals, the scientific layer models the scientific dimension, the organizational layer models the social dimension, the data layer and information technology layer model the technical dimension, and the ethics and security layer models the ethical dimension. We describe the types of decisions that must be made within each layer and identify methods to support decision-making. CONCLUSION: In this paper, we outline a high level architectural framework grounded in conceptual and empirical LHS literature. Applying this architectural framework can guide the development and implementation of new LHSs and the evolution of existing ones, as it allows for clear and critical understanding of the types of decisions that underlie LHS operations. Further research is required to assess and refine its generalizability and methods. PMID- 28645320 TI - Acromegaly discovered during a routine out-patient surgical procedure: a case report. AB - BACKGROUND: Acromegaly is a rare syndrome in which there is unregulated hypersecretion of growth hormone. The anesthetic management of patients with this disorder is particularly challenging due to pre-existing cardiovascular and respiratory dysfunction, as well as recognized difficulties with airway management. Because of the insidious progression of the disease and the presence of nonspecific signs and symptoms, diagnosis is often made late when characteristic acromegalic features become apparent. CASE PRESENTATION: We report the management of a 35-year-old African American man with previously undiagnosed acromegaly, who underwent a general anesthetic for same day surgery. Subtle physical features and difficult endotracheal intubation raised our suspicion for the diagnosis of acromegaly. Following an uncomplicated postoperative course he underwent workup for the disease, which was confirmed. In addition, brain magnetic resonance imaging showed a pituitary adenoma. A subsequent transsphenoidal hypophysectomy was performed successfully. CONCLUSIONS: This case underscores the notable absence of recognizing the clinical presentation of acromegaly in this patient by his primary care physician, and the value of thorough history taking, vigilance, and observation in making a new diagnosis that has the potential to alter a patient's health care and mitigate impending morbidity and/or mortality. PMID- 28645322 TI - Erratum to: Trends in antimicrobial resistance and empiric antibiotic therapy of bloodstream infections at a general hospital in mid-Norway: a prospective observational study. PMID- 28645321 TI - Genome-wide analysis of DNA methylation in hypothalamus and ovary of Capra hircus. AB - BACKGROUND: DNA methylation is a frequently studied epigenetic modification due to its role in regulating gene expression and hence in biological processes and in determining phenotypic plasticity in organisms. Rudimentary DNA methylation patterns for some livestock species are publically available: among these, goat methylome deserves to be further explored. RESULTS: Genome-wide DNA methylation maps of the hypothalamus and ovary from Saanen goats were generated using Methyl CpG binding domain protein sequencing (MBD-seq). Analysis of DNA methylation patterns indicate that the majority of methylation peaks found within genes are located gene body regions, for both organs. Analysis of the distribution of methylated sites per chromosome showed that chromosome X had the lowest number of methylation peaks. The X chromosome has one of the highest percentages of methylated CpG islands in both organs, and approximately 50% of the CpG islands in the goat epigenome are methylated in hypothalamus and ovary. Organ-specific Differentially Methylated Genes (DMGs) were correlated with the expression levels. CONCLUSIONS: The comparison between transcriptome and methylome in hypothalamus and ovary showed that a higher level of methylation is not accompanied by a higher gene suppression. The genome-wide DNA methylation map for two goat organs produced here is a valuable starting point for studying the involvement of epigenetic modifications in regulating goat reproduction performance. PMID- 28645323 TI - Early response index: a statistic to discover potential early stage disease biomarkers. AB - BACKGROUND: Identifying disease correlated features early before large number of molecules are impacted by disease progression with significant abundance change is very advantageous to biologists for developing early disease diagnosis biomarkers. Disease correlated features have relatively low level of abundance change at early stages. Finding them using existing bioinformatic tools in high throughput data is a challenging task since the technology suffers from limited dynamic range and significant noise. Most existing biomarker discovery algorithms can only detect molecules with high abundance changes, frequently missing early disease diagnostic markers. RESULTS: We present a new statistic called early response index (ERI) to prioritize disease correlated molecules as potential early biomarkers. Instead of classification accuracy, ERI measures the average classification accuracy improvement attainable by a feature when it is united with other counterparts for classification. ERI is more sensitive to abundance changes than other ranking statistics. We have shown that ERI significantly outperforms SAM and Localfdr in detecting early responding molecules in a proteomics study of a mouse model of multiple sclerosis. Importantly, ERI was able to detect many disease relevant proteins before those algorithms detect them at a later time point. CONCLUSIONS: ERI method is more sensitive for significant feature detection during early stage of disease development. It potentially has a higher specificity for biomarker discovery, and can be used to identify critical time frame for disease intervention. PMID- 28645324 TI - BMI and recommended levels of physical activity in school children. AB - BACKGROUND: Physical activity (PA) and its health benefits are a continuous point of discussion. Recommendations for children's daily PA vary between guidelines. To better define the amount of PA necessary to prevent overweight and obesity in children, further research is needed. The present study investigates children's compliance to physical activity guidelines (PAGs) and the association between objectively measured PA and body mass index (BMI). METHODS: Participating children were 11 years old (n = 419) and part of the European CHOP trial, which was conducted in Germany, Belgium, Poland, Spain, Italy. At least 2 days of PA measurements were collected from each child using a SenseWearTM armband. BMI was calculated from children's height and weight. Thresholds of min.day-1 in PA needed to differentiate between normal and excess weight (overweight/obesity) were determined with Receiver Operator Characteristics (ROC) analysis. Additionally, adjusted linear and logistic regressions models were calculated for group differences and effects of a 5, 15 and 60 min.day-1 increases in PA on BMI. RESULTS: Median time spent in total PA was 462 min.day-1 (25th percentile; 75th percentile: 389; 534) and 75 min.day-1 (41; 115) in moderate to vigorous PA (MVPA). Girls spent 36 min.day-1 less in MVPA than boys and overweight/obese children 24 min.day-1 less than normal weight children (linear regression, p < 0.001). 63.2% of the children met PAGs of 60 min.day-1 in MVPA. The optimal threshold for min.day-1 in MVPA determined with ROC analysis was 46 min.day-1. Comparing 5, 15 and 60 min.day-1 increases in PA revealed that an additional 15 min.day-1 of vigorous PA had the same effect as 60 min.day-1 of MVPA. Sedentary time and light PA showed contrary associations to one another, with light PA being negatively and sedentary time being positively associated with excessive weight. CONCLUSIONS: Current PAGs are met by 2/3 of children and seem appropriate to prevent excess weight in children. An official recommendation of daily 15-20 min of vigorous PA and further reduction of sedentary time could help to fight youth overweight and thus be of potential public health importance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00338689 . Registered: June 19, 2006 (retrospectively registered). PMID- 28645325 TI - Performance characteristics of prostate-specific antigen density and biopsy core details to predict oncological outcome in patients with intermediate to high-risk prostate cancer underwent robot-assisted radical prostatectomy. AB - BACKGROUND: Many urologic surgeons refer to biopsy core details for decision making in cases of localized prostate cancer (PCa) to determine whether an extended resection and/or lymph node dissection should be performed. Furthermore, recent reports emphasize the predictive value of prostate-specific antigen density (PSAD) for further risk stratification, not only for low-risk PCa, but also for intermediate- and high-risk PCa. This study focused on these parameters and compared respective predictive impact on oncologic outcomes in Japanese PCa patients. METHODS: Two-hundred and fifty patients with intermediate- and high risk PCa according to the National Comprehensive Cancer Network (NCCN) classification, that underwent robot-assisted radical prostatectomy at a single institution, and with observation periods of longer than 6 months were enrolled. None of the patients received hormonal treatments including antiandrogens, luteinizing hormone-releasing hormone analogues, or 5-alpha reductase inhibitors preoperatively. PSAD and biopsy core details, including the percentage of positive cores and the maximum percentage of cancer extent in each positive core, were analyzed in association with unfavorable pathologic results of prostatectomy specimens, and further with biochemical recurrence. The cut-off values of potential predictive factors were set through receiver-operating characteristic curve analyses. RESULTS: In the entire cohort, a higher PSAD, the percentage of positive cores, and maximum percentage of cancer extent in each positive core were independently associated with advanced tumor stage >= pT3 and an increased index tumor volume > 0.718 ml. NCCN classification showed an association with a tumor stage >= pT3 and a Gleason score >=8, and the attribution of biochemical recurrence was also sustained. In each NCCN risk group, these preoperative factors showed various associations with unfavorable pathological results. In the intermediate-risk group, the percentage of positive cores showed an independent predictive value for biochemical recurrence. In the high-risk group, PSAD showed an independent predictive value. CONCLUSIONS: PSAD and biopsy core details have different performance characteristics for the prediction of oncologic outcomes in each NCCN risk group. Despite the need for further confirmation of the results with a larger cohort and longer observation, these factors are important as preoperative predictors in addition to the NCCN classification for a urologic surgeon to choose a surgical strategy. PMID- 28645326 TI - Improving visualization of 4D flow cardiovascular magnetic resonance with four dimensional angiographic data: generation of a 4D phase-contrast magnetic resonance CardioAngiography (4D PC-MRCA). AB - Magnetic Resonance Angiography (MRA) and Phase-Contrast MRA (PC-MRA) approaches used for assessment of cardiovascular morphology typically result in data containing information from the entire cardiac cycle combined into one 2D or 3D image. Information specific to each timeframe of the cardiac cycle is, however, lost in this process. This study proposes a novel technique, called Phase Contrast Magnetic Resonance CardioAngiography (4D PC-MRCA), that utilizes the full potential of 4D Flow CMR when generating temporally resolved PC-MRA data to improve visualization of the heart and major vessels throughout the cardiac cycle. Using non-rigid registration between the timeframes of the 4D Flow CMR acquisition, the technique concentrates information from the entire cardiac cycle into an angiographic dataset at one specific timeframe, taking movement over the cardiac cycle into account. Registration between the timeframes is used once more to generate a time-resolved angiography. The method was evaluated in ten healthy volunteers. Visual comparison of the 4D PC-MRCAs versus PC-MRAs generated from 4D Flow CMR using the traditional approach was performed by two observers using Maximum Intensity Projections (MIPs). The 4D PC-MRCAs resulted in better visibility of the main anatomical regions of the cardiovascular system, especially where cardiac or vessel motion was present. The proposed method represents an improvement over previous PC-MRA generation techniques that rely on 4D Flow CMR, as it effectively utilizes all the information available in the acquisition. The 4D PC-MRCA can be used to visualize the motion of the heart and major vessels throughout the entire cardiac cycle. PMID- 28645327 TI - Impact of growth matrix on pharmacodynamics of antimicrobial drugs for pig pneumonia pathogens. AB - BACKGROUND: The most widely used measure of potency of antimicrobial drugs is Minimum Inhibitory Concentration (MIC). MIC is usually determined under standardised conditions in broths formulated to optimise bacterial growth on a species-by-species basis. This ensures comparability of data between laboratories. However, differences in values of MIC may arise between broths of differing chemical composition and for some drug classes major differences occur between broths and biological fluids such as serum and inflammatory exudate. Such differences must be taken into account, when breakpoint PK/PD indices are derived and used to predict dosages for clinical use. There is therefore interest in comparing MIC values in several broths and, in particular, in comparing broth values with those generated in serum. For the pig pneumonia pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, MICs were determined for three drugs, florfenicol, oxytetracycline and marbofloxacin, in five broths [Mueller Hinton Broth (MHB), cation-adjusted Mueller Hinton Broth (CAMHB), Columbia Broth supplemented with NAD (CB), Brain Heart Infusion Broth (BHI) and Tryptic Soy Broth (TSB)] and in pig serum. RESULTS: For each drug, similar MIC values were obtained in all broths, with one exception, marbofloxacin having similar MICs for three broths and 4-5-fold higher MICs for two broths. In contrast, for both organisms, quantitative differences between broth and pig serum MICs were obtained after correction of MICs for drug binding to serum protein (fu serum MIC). Potency was greater (fu serum MIC lower) in serum than in broths for marbofloxacin and florfenicol for both organisms. For oxytetracycline fu serum:broth MIC ratios were 6.30:1 (P. multocida) and 0.35:1 (A. pleuropneumoniae), so that potency of this drug was reduced for the former species and increased for the latter species. The chemical composition of pig serum and broths was compared; major matrix differences in 14 constituents did not account for MIC differences. Bacterial growth rates were compared in broths and pig serum in the absence of drugs; it was concluded that broth/serum MIC differences might be due to differing growth rates in some but not all instances. CONCLUSIONS: For all organisms and all drugs investigated in this study, it is suggested that broth MICs should be adjusted by an appropriate scaling factor when used to determine pharmacokinetic/pharmacodynamic breakpoints for dosage prediction. PMID- 28645328 TI - Ocular manifestations as first signs of systemic T cell lymphoma in two cases. AB - BACKGROUND: Intraocular involvement of systemic T-cell lymphomas are uncommon and have been broadly regarded as markers of poor prognosis. We reported two cases of uveitis patients finally diagnosed as systemic T cell lymphoma. CASE PRESENTATION: Case one is a 19-year-old female presented with fever and liver dysfunction, and was diagnosed as EBV-associated chronic active hepatitis. Fourteen months later, she suffered from recurrent granulomatous anterior uveitis in both eyes, which failed to respond to steroid and immunosuppressant therapy. A mass on the left side of pharynx was found and the final diagnosis was pharynx T cell non-Hodgkin's lymphoma. After 13 cycles of chemotherapy, her systematic symptoms and uveitis relieved a lot, and eye condition is stable after cataract surgery. Case two is a 37-year-old male complaining bilateral blurred vision and recurrent abdominal pain. Panuveitis was diagnosed and anterior inflammation did not release after topical steroid. During the following days, the patient complained intermittent abdominal pain and fever, with rapidly progressive bilateral visual decrease. Final diagnosis was gallbladder type II enteropathy associated T-cell lymphoma. The patient died of multiple organ failure 4 days after operation that was only 26 days after presenting to our hospital. CONCLUSIONS: Ocular manifestations as first signs of systemic T cell lymphoma were rare. Diagnosis of lymphoma has to be suspected when patients have systemic manifestations including fever, fatigue, abdominal pain, EBV-associated liver disease, et al., and uveitis fails to respond to steroid therapy. PMID- 28645329 TI - Ticks and associated pathogens in dogs from Greece. PMID- 28645330 TI - Screen-based sedentary behavior during adolescence and pulmonary function in a birth cohort. AB - BACKGROUND: Adolescents spend many hours in sitting activities as television viewing, video game playing and computer use. The relationship between sedentary behavior and respiratory health remains poorly elucidated. To date there have been no studies evaluating the relationship between sedentary behavior and pulmonary function in young populations. The purpose of this study is to examine the association between the trajectory of screen-based sedentary behavior from 11 to 18 years and pulmonary function at 18 years in a Brazilian birth cohort. METHODS: Data from a longitudinal prospective study conducted among the participants of the 1993 Pelotas (Brazil) Birth Cohort. Time spent on television, video games, and computers during a weekday was self-reported at ages 11, 15 and 18 years. For each age, sedentary behavior was defined as the sum of time spent on these screen-based activities. To evaluate the sedentary behavior trajectory during adolescence group-based trajectory modeling was used. Outcome variables were three pulmonary function parameters: forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF), evaluated by spirometry, at 18 years expressed as z-scores. Crude and adjusted linear regressions, stratified by sex, were performed. RESULTS: The three-group trajectory of sedentary behavior was the best fitting model. The trajectory groups were: always high (representing 38.8% of the individuals), always moderate (54.1%), and always low (7.1%). In the adjusted analyses, boys in the always-low group for sedentary behavior had higher FVC at 18 years (beta = 0.177; 95% CI:0.027;0.327; p = 0.021) than boys in the always-high group. There were no differences for other pulmonary function parameters in boys. No significant association was found for girls. CONCLUSION: The trajectory of screen-based sedentary behavior throughout adolescence was not consistent associated with pulmonary function at 18 years. PMID- 28645331 TI - Circadian CLOCK gene polymorphisms in relation to sleep patterns and obesity in African Americans: findings from the Jackson heart study. AB - BACKGROUND: Circadian rhythms regulate key biological processes and the dysregulation of the intrinsic clock mechanism affects sleep patterns and obesity onset. The CLOCK (circadian locomotor output cycles protein kaput) gene encodes a core transcription factor of the molecular circadian clock influencing diverse metabolic pathways, including glucose and lipid homeostasis. The primary objective of this study was to evaluate the associations between CLOCK single nucleotide polymorphisms (SNPs) and body mass index (BMI). We also evaluated the association of SNPs with BMI related factors such as sleep duration and quality, adiponectin and leptin, in 2962 participants (1116 men and 1810 women) from the Jackson Heart Study. Genotype data for the selected 23 CLOCK gene SNPS was obtained by imputation with IMPUTE2 software and reference phase data from the 1000 genome project. Genetic analyses were conducted with PLINK RESULTS: We found a significant association between the CLOCK SNP rs2070062 and sleep duration, participants carriers of the T allele showed significantly shorter sleep duration compared to non-carriers after the adjustment for individual proportions of European ancestry (PEA), socio economic status (SES), body mass index (BMI), alcohol consumption and smoking status that reach the significance threshold after multiple testing correction. In addition, we found nominal associations of the CLOCK SNP rs6853192 with longer sleep duration and the rs6820823, rs3792603 and rs11726609 with BMI. However, these associations did not reach the significance threshold after correction for multiple testing. CONCLUSIONS: In this work, CLOCK gene variants were associated with sleep duration and BMI suggesting that the effects of these polymorphisms on circadian rhythmicity may affect sleep duration and body weight regulation in Africans Americans. PMID- 28645332 TI - Effects of air pollution and seasons on health-related quality of life of Mongolian adults living in Ulaanbaatar: cross-sectional studies. AB - BACKGROUND: Ulaanbaatar, Mongolia, is known as severely air-polluted city in the world due to increased coal consumption in the cold season. The health effects of air pollution in Mongolia such as mortality, morbidity and symptoms have been previously reported. However, the concept of health-related quality of life (HR QoL), which refers to the individual's perception of well-being, should also be included as an adverse health outcome of air pollution. METHODS: Surveys on the Mongolian people living in Ulaanbaatar were performed in the warm and cold seasons. Self-completed questionnaires on the subjects' HR-QoL, data from health checkups and pulmonary function tests by respiratory specialists were collected for Mongolian adults aged 40-79 years (n = 666). Ambient PM2.5 and PM10 were concurrently sampled and the components were analyzed to estimate the source of air pollution. RESULTS: In logistic regression analyses, respiratory symptoms and smoke-rich fuels were associated with reduced HR-QoL (> 50th percentile vs. <= 50th percentile). PM 2.5 levels were much higher in the cold season (median 86.4 MUg/m3 (IQR: 58.7-121.0)) than in the warm season (12.2 MUg/m3 (8.9-21.2). The receptor model revealed that the high PM2.5 concentration in the cold season could be attributed to solid fuel combustion. The difference in HR-QoL between subjects with and without ventilatory impairment was assessed after the stratification of the subjects by season and household fuel type. There were no significant differences in HR-QoL between subjects with and without ventilatory impairment regardless of household fuel type in the warm season. In contrast, subjects with ventilatory impairment who used smoke-rich fuel in the cold season had a significantly lower HR-QoL. CONCLUSIONS: Our study showed that air pollution in Ulaanbaatar worsened in the cold season and was estimated to be contributed by solid fuel combustion. Various aspects of HR-QoL in subjects with ventilatory impairment using smoke-rich fuels deteriorated only in the cold season while those with normal lung function did not. These results suggest that countermeasures or interventions by the policymakers to reduce coal usage would improve HR-QoL of the residents of Ulaanbaatar, especially for those with ventilatory impairment in the winter months. PMID- 28645334 TI - The Authors Respond. PMID- 28645335 TI - Early Mobilization After Mechanical Ventilation: A Question of Details and Time. PMID- 28645336 TI - Contextualizing the Role of Alcohol in Sexual Violence. PMID- 28645337 TI - The Visible Man: Gendering Health Care Services to Improve Young Men's Sexual Health. PMID- 28645333 TI - Sac-1004, a vascular leakage blocker, reduces cerebral ischemia-reperfusion injury by suppressing blood-brain barrier disruption and inflammation. AB - BACKGROUND: Blood-brain barrier (BBB) breakdown and inflammation are critical events in ischemic stroke, contributing to aggravated brain damage. The BBB mainly consists of microvascular endothelial cells sealed by tight junctions to protect the brain from blood-borne substances. Thus, the maintenance of BBB integrity may be a potential target for neuroprotection. Sac-1004, a pseudo-sugar derivative of cholesterol, enhances the endothelial barrier by the stabilization of the cortical actin ring. RESULTS: Here, we report on the protective effects of Sac-1004 on cerebral ischemia-reperfusion (I/R) injury. Treatment with Sac-1004 significantly blocked the interleukin-1beta-induced monolayer hyperpermeability of human brain microvascular endothelial cells (HBMECs), loss of tight junctions, and formation of actin stress fiber. Sac-1004 suppressed the expression of adhesion molecules, adhesion of U937 cells, and activation of nuclear factor kappaB in HBMECs. Using a rat model of transient focal cerebral ischemia, it was shown that Sac-1004 effectively ameliorated neurological deficits and ischemic damage. In addition, Sac-1004 decreased BBB leakage and rescued tight junction related proteins. Moreover, the staining of CD11b and glial fibrillary acidic protein showed that Sac-1004 inhibited glial activation. CONCLUSIONS: Taken together, these results demonstrate that Sac-1004 has neuroprotective activities through maintaining BBB integrity, suggesting that it is a great therapeutic candidate for stroke. PMID- 28645338 TI - Optic Nerve Gray Crescent. PMID- 28645339 TI - Purtscher's Retinopathy. PMID- 28645340 TI - Soemmering's Ring. PMID- 28645341 TI - Spinocerebellar Ataxia. PMID- 28645342 TI - Pleomorphic Adenoma of an Accessory Lacrimal Gland Masquerading as a Chalazion. PMID- 28645343 TI - Metastatic Lung Adenocarcinoma. PMID- 28645344 TI - Re: Merani et al.: Aqueous chlorhexidine for intravitreal injection antisepsis (Ophthalmology. 2016;123:2588-2594). PMID- 28645345 TI - Reply. PMID- 28645346 TI - Re: Khan et al.: Clinical and genetic features of choroideremia in childhood (Ophthalmology. 2016;123:2158-2165). PMID- 28645347 TI - Re: Niederer et al.: Predictors of long-term visual outcome in intermediate uveitis (Ophthalmology. 2017;124:393-398). PMID- 28645348 TI - Reply. PMID- 28645349 TI - Reply. PMID- 28645350 TI - Re: Haripriya et al.: Long-term posterior capsule opacification reduction with square-edge polymethylmethacrylate intraocular lens: randomized controlled study (Ophthalmology. 2017;124:295-302). PMID- 28645351 TI - Reply. PMID- 28645352 TI - ? AB - Steroid resistance syndrome (mineralocorticoids, glucocorticoids, estrogens, androgens) is a rare clinical disorder, androgen insensitivity syndrome being the most commonly described. Resistance syndromes are characterized by elevated steroid hormone levels, secondary to an impaired signal transduction and a lack of negative feedback, without any specific clinical signs of steroid excess. In most cases, steroid hormone resistance is generally caused by steroid receptor mutations. Several nonsense and missense mutations or deletions have already been described for all steroid receptors, except for the progesterone receptor. The number of reported mutations is extremely variable, depending on the steroid receptor, ranging from 3 for the estrogen receptor to more than 500 for the androgen receptor. Loss of function of others factors implicated on the steroid hormone signaling pathway, such as molecular chaperones or coactivators, might also be involved in the pathogenesis of steroid resistance. Therapy is essentially symptomatic, there is currently no pharmacological strategy enabling restoration of the impaired hormone signaling pathway. Identification of steroid resistance syndrome and their characterization should allow a better understanding of underlying molecular defects, opening new avenues for the development of novel alternative options for the disease management. PMID- 28645353 TI - ? AB - Diabetes insipidus is a syndrome that associates both hypotonic polyuria and polydipsia, due to insufficient or ineffective arginine vasopressin (AVP) synthesis, or to AVP resistance. The diagnosis between central/renal origin, or an abnormal thirst regulation (primary polydipsia) is required to organize an adapted management. Because water deprivation tests are not reliable, it's often based on medical history, response to treatment and MRI. Copeptin is an AVP precursor which could be very helpful for the diagnosis. Its basal dosage may identify nephrogenic DI whereas osmotic stimulated dosage would discriminate central DI and primary polydipsia. Central DI is quite frequent after pituitary surgeries or traumatic brain injuries, and often transient. In case of early diagnosis and familial history of DI, a mutation of AVP gene is suspected, most of the time autosomal dominant. MRI is required to identify the other causes, i.e. tumors and inflammatory diseases (sarcoidosis, histiocytosis, hypophysitis). An advanced evaluation is required before idiopathic DI be retained, especially if a thickening of pituitary stalk is observed. The treatment of central DI is mainly based on lyophilisate of desmopressin administration. PMID- 28645354 TI - [Acromegaly and Cushing's disease: Persistence of comorbidities after the control of hypersecretion]. AB - Acromegaly and Cushing's disease lead to common and distinct comorbidities. Currently available treatments lead to the control of hyper secretion in the majority of cases. However, the prevalence of the comorbidities does not always go back to the one of the normal population after remission. For instance, about 1/3 of acromegalic patients with diabetes and half of patients with Cushing's disease and diabetes will have normal blood glucose values after remission. In contrast, high blood pressure frequently recovers after remission in both diseases. In contrast, while patients with acromegaly improve their lipid profile, patients with Cushing's disease frequently remain hypertriglyceridemic. Many other comorbidities (cardiovascular disease, bone alterations, altered quality of life) may persist after the control of hyper secretion. The aim of this review is to focus on the outcome of patients with acromegaly and Cuhing's disease, and to suggest the optimal follow-up of such patients in a multidisciplinary approach. These points have been discussed during the 2016 European Congress of Endocrinology, notably by J.Romijn and E.Valassi. PMID- 28645355 TI - [Obesities: What's new in 2016?] AB - Since 1997, the World Health Organisation considered obesity, defined as an excess of fat mass, as a disease. Many plans have been set up to fight against obesity in industrialised countries. However, the prevalence of obesity is still increasing. The goal of this paper is to report some of the major scientific publications in terms of epidemiology, physiopathology or therapeutic in the field of obersity mainly published during year 2015-2016 or presented at ENDO meeting 2016. PMID- 28645356 TI - [Endocrine control of serum phosphate: from the discoveries of phosphatonins to novel therapies]. AB - Phosphate is absorbed through the gut, stored in the bone and reabsorbed through the proximal renal tubule. More importantly, PTH and FGF23 have been identified as the main phosphaturic factors that control the expression of the phosphate co transporters NaPi-IIa et IIc. By allowing the adjustment of the urinary phosphate reabsorption, these two phosphatonins play a major role in bone and tooth mineralization and growth. Recently, novel therapies have successfully targeted the FGF23 signaling pathway to treat the hypophosphatemia in patients affected with molecular defects of this pathway (mutations in the PHEX gene). PMID- 28645357 TI - Appreciating the Population-wide Impact of Copy Number Variants on Cognition. PMID- 28645358 TI - A Placenta-Specific Genetic Manipulation Reprograms Offspring Brain Development and Function. PMID- 28645359 TI - A Fragile Balance: Dendritic Spines, Learning, and Memory. PMID- 28645361 TI - Benefits of embedding researchers in a health service setting. PMID- 28645360 TI - Cognitive Deficits in Prematurely Born Adults Are Associated With Reduced Basal Forebrain Integrity. PMID- 28645362 TI - Measuring most informative titles (declarative titles) as a knowledge translation dissemination tool is possible using altmetrics. PMID- 28645363 TI - Response to letter Dr Gail. PMID- 28645364 TI - The prediction impact curve is proportional to the proportion of cases followed (letter commenting: J Clin Epidemiol 2016;69:361-363). PMID- 28645366 TI - Optimization of Native and Formaldehyde iPOND Techniques for Use in Suspension Cells. AB - The isolation of proteins on nascent DNA (iPOND) technique developed by the Cortez laboratory allows a previously unparalleled ability to examine proteins associated with replicating and newly synthesized DNA in mammalian cells. Both the original, formaldehyde-based iPOND technique and a more recent derivative, accelerated native iPOND (aniPOND), have mostly been performed in adherent cell lines. Here, we describe modifications to both protocols for use with suspension cell lines. These include cell culture, pulse, and chase conditions that optimize sample recovery in both protocols using suspension cells and several key improvements to the published aniPOND technique that reduce sample loss, increase signal to noise, and maximize sample recovery. Additionally, we directly and quantitatively compare the iPOND and aniPOND protocols to test the strengths and limitations of both. Finally, we present a detailed protocol to perform the optimized aniPOND protocol in suspension cell lines. PMID- 28645365 TI - Complexity of immune responses to AAV transgene products - Example of factor IX. AB - After two decades of research, in vivo gene transfer with adeno-associated viral (AAV) vectors has now resulted in successful treatments and even cures for several human diseases. However, the potential for immune responses against the therapeutic gene products remains one of the concerns as this approach is broadened to more patients, diverse diseases, and target organs. Immune responses following gene transfer of coagulation factor IX (FIX) for the treatment of the bleeding disorder hemophilia B has been extensively investigated in multiple animal models. Findings from these studies have not only influenced clinical trial design but have broader implications for other diseases. The impact of vector design and dose, as well as target organ/route of administration on humoral and cellular immune responses are reviewed. Furthermore, the potential for tolerance induction by hepatic gene transfer or combination with immune modulation is discussed. PMID- 28645367 TI - Base Excision Repair Variants in Cancer. AB - Base excision repair (BER) is a key genome maintenance pathway that removes endogenously damaged DNA bases that arise in cells at very high levels on a daily basis. Failure to remove these damaged DNA bases leads to increased levels of mutagenesis and chromosomal instability, which have the potential to drive carcinogenesis. Next-generation sequencing of the germline and tumor genomes of thousands of individuals has uncovered many rare mutations in BER genes. Given that BER is critical for genome maintenance, it is important to determine whether BER genomic variants have functional phenotypes. In this chapter, we present our in silico methods for the identification and prioritization of BER variants for further study. We also provide detailed instructions and commentary on the initial cellular assays we employ to dissect potentially important phenotypes of human BER variants and highlight the strengths and weaknesses of our approaches. BER variants possessing interesting functional phenotypes can then be studied in more detail to provide important mechanistic insights regarding the role of aberrant BER in carcinogenesis. PMID- 28645368 TI - Fluorescence-Based Reporters for Detection of Mutagenesis in E. coli. AB - Mutagenesis in model organisms following exposure to chemicals is used as an indicator of genotoxicity. Mutagenesis assays are also used to study mechanisms of DNA homeostasis. This chapter focuses on detection of mutagenesis in prokaryotes, which boils down to two approaches: reporter inactivation (forward mutation assay) and reversion of an inactivating mutation (reversion mutation assay). Both methods are labor intensive, involving visual screening, quantification of colonies on solid media, or determining a Poisson distribution in liquid culture. Here, we present two reversion reporters for in vivo mutagenesis that produce a quantitative output, and thus have the potential to greatly reduce the amount of test chemical and labor involved in these assays. This output is obtained by coupling a TEM beta lactamase-based reversion assay with GFP fluorescence, either by placing the two genes on the same plasmid or by fusing them translationally and interrupting the N-terminus of the chimeric ORF with a stop codon. We also describe a reporter aimed at facilitating the monitoring of continuous mutagenesis in mutator strains. This reporter couples two reversion markers, allowing the temporal separation of mutation events in time, thus providing information about the dynamics of mutagenesis in mutator strains. Here, we describe these reporter systems, provide protocols for use, and demonstrate their key functional features using error-prone Pol I mutagenesis as a source of mutations. PMID- 28645369 TI - Sequencing DNA for the Oxidatively Modified Base 8-Oxo-7,8-Dihydroguanine. AB - The DNA base guanine (G) can be oxidatively modified to 8-oxo-7,8-dihydroguanine (OG). Extraction of genomic DNA followed by nuclease digestion and mass spectrometry analysis has found OG is present at background levels of ~1 out of 106 Gs; however, this approach cannot determine the locations for the OGs in the genome. Thus, in this methods report, we outline three different methods (A, B, and C) for sequencing OG in DNA. Method A sequences OG by utilizing the base excision repair pathway to delete the OG nucleotide from the DNA that is then detected by Sanger sequencing as a deletion signature. Method B sequences OG by harnessing the base excision repair pathway to convert OG to an unnatural DNA base pair followed by Sanger sequencing to locate the unnatural base pair indicating where OG was located. Method C (i.e., OG-Seq) takes genomic DNA sheared to ~150bps followed by selectively biotinylating the OG-containing fragments for affinity purification and enrichment of the OG-modified strands. The OG-modified fragments are sequenced on a next-generation sequencing platform to locate OG on the genomic scale with a resolution of ~150bps. The methods outlined are then compared and contrasted allowing researchers to select the one that best suits their experimental goals. PMID- 28645370 TI - Xenopus laevis as Model System to Study DNA Damage Response and Replication Fork Stability. AB - Although many players of the DNA damage response and DNA repair have been identified in several systems their biochemical role is still poorly understood. The use of the Xenopus laevis egg extract cell-free system allowed biochemical dissection of DNA replication and cell cycle events in a complex biological context. The possibility of manipulating the protein content by using protein depletion procedures makes egg extract a powerful system to study proteins whose inactivation results in cellular lethality. The egg extract has been increasingly used to study DNA damage response and the coordination of DNA replication with DNA repair. The recent development of advanced imaging techniques based on electron microscopy has allowed the characterization of replication intermediates formed in the absence of essential DNA repair proteins. These studies have been important to understand how cells maintain genome stability under unchallenged and stressful conditions. Here, we present a collection of protocols that have been developed to recapitulate DNA damage response activated by chromosome breakage in egg extract and to isolate replication intermediates for electron microscopy analysis using sperm nuclei or more defined genomic substrates. PMID- 28645371 TI - Ensemble and Single-Molecule Analysis of Non-Homologous End Joining in Frog Egg Extracts. AB - Non-homologous end joining (NHEJ) repairs the majority of DNA double-strand breaks in human cells, yet the detailed order of events in this process has remained obscure. Here, we describe how to employ Xenopus laevis egg extract for the study of NHEJ. The egg extract is easy to prepare in large quantities, and it performs efficient end joining that requires the core end joining proteins Ku, DNA-PKcs, XLF, XRCC4, and DNA ligase IV. These factors, along with the rest of the soluble proteome, are present at endogenous concentrations, allowing mechanistic analysis in a system that begins to approximate the complexity of cellular end joining. We describe an ensemble assay that monitors covalent joining of DNA ends and fluorescence assays that detect joining of single pairs of DNA ends. The latter assay discerns at least two discrete intermediates in the bridging of DNA ends. PMID- 28645372 TI - Analysis of Structure-Selective Endonuclease Activities From Yeast and Human Extracts. AB - The efficient separation of two equal DNA masses to the daughter cells is an essential step in mitosis. This process is dependent upon the removal of any remaining recombination or replication intermediates that link sister chromatids, and a failure to resolve these intermediates leads to genome instability. Similarly, a failure to resolve meiotic recombination intermediates that link homologous chromosomes can cause chromosome nondisjunction and aneuploidy. Cleavage of these potentially toxic replication/recombination intermediates requires the Mus81 endonuclease, which is active upon flaps, forks, and more complex secondary structures in DNA such as Holliday junctions. Recent studies of Mus81 revealed that it is regulated throughout the cell cycle: Mus81 activity is controlled in S-phase to limit the cleavage of replication fork structures, whereas it is activated at G2/M to ensure the cleavage of recombination and late replication intermediates. In this chapter, we describe a simple method that can monitor the activity of Mus81, which involves the immunoprecipitation of epitope tagged Mus81 and use of an on-bead assay for nuclease activity. PMID- 28645373 TI - Strategies and Methods of Transcription-Coupled Repair Studies In Vitro and In Vivo. AB - Transcription-coupled repair (TCR) serves an important role in preserving genome integrity and maintaining fidelity of replication. Coupling transcription to DNA repair requires a coordinated action of several factors, including transcribing RNA polymerase and various transcription modulators and repair proteins. To study TCR in molecular detail, it is important to employ defined protein complexes in vitro and defined genetic backgrounds in vivo. In this chapter, we present methods to interrogate various aspects of TCR at different stages of repair. We describe promoter-initiated and nucleic acid scaffold-initiated transcription as valid approaches to recapitulate various stages of TCR, and discuss their strengths and weaknesses. We also outline an approach to study TCR in its cellular context using Escherichia coli as a model system. PMID- 28645375 TI - Current and Emerging Assays for Studying the Primer Synthesis Activities of DNA Primases. AB - Primases play a crucial role in the initiation of DNA synthesis during replication by de novo synthesis of short RNA or DNA "primers." In recent years, evidence has accumulated which expands the essential roles of primases to include, not only the initiation of replication but also other critical roles in DNA metabolism, including damage tolerance and repair. Despite the broadening roles for these enzymes, the methods used to identify and characterize primase activities are limited. Historically, biochemical analysis of primases has been based on the synthesis of radioactively labeled primers and their detection on denaturing polyacrylamide gels. In the last two decades, a number of alternative primase assays have been developed in an effort to supersede radioactive methods. However, the radioactive gel-based assay, which has not significantly changed since its conception in the late 1970s, remains the most widely used and favored method. In this chapter, we discuss the background to, and the advantages and disadvantages of, the current techniques used to characterize primase activity in vitro. Finally, we describe an alternative, gel-based, fluorescent primase assay, which we have successfully used in the characterization of a recently identified primase-polymerase, PrimPol. PMID- 28645374 TI - Reconstituted System for the Examination of Repair DNA Synthesis in Homologous Recombination. AB - In homologous recombination (HR), DNA polymerase delta-mediated DNA synthesis occurs within the displacement loop (D-loop) that is made by the recombinase Rad51 in conjunction with accessory factors. We describe in this chapter the reconstitution of the D-loop and repair DNA synthesis reactions using purified Saccharomyces cerevisiae HR (Rad51, RPA, and Rad54) and DNA replication (PCNA, RFC, and DNA polymerase delta) proteins and document the role of the Pif1 helicase in DNA synthesis via a migrating DNA bubble intermediate. These reconstituted systems are particularly valuable for understanding the conserved mechanism of repair DNA synthesis dependent on DNA polymerase delta and its cognate helicase in eukaryotic organisms. PMID- 28645376 TI - Proteomic Analyses of the Eukaryotic Replication Machinery. AB - DNA replication in a human cell involves hundreds of proteins that copy the DNA accurately and completely each cell division cycle. In addition to the core DNA copying machine (the replisome), accessory proteins work to respond to replication stress, correct errors, and repackage the DNA into appropriate chromatin structures. New proteomic tools have been invented in the past few years to facilitate the purification, identification, and quantification of the replication, chromatin maturation, and replication stress response machineries. These tools, including iPOND (isolation of proteins on nascent DNA) and NCC (nascent chromatin capture), have yielded discoveries of new proteins involved in these processes and insights into the dynamic regulatory processes ensuring genome and chromatin integrity. In this review, I will introduce these experimental approaches and examine how they have been utilized to define the replication fork proteome. PMID- 28645377 TI - Electrical Probes of DNA-Binding Proteins. AB - A DNA electrochemistry platform has been developed to probe proteins bound to DNA electrically. Here gold electrodes are modified with thiol-modified DNA, and DNA charge transport chemistry is used to probe DNA binding and enzymatic reaction both with redox-silent and redox-active proteins. For redox-active proteins, the electrochemistry permits the determination of redox potentials in the DNA-bound form, where comparisons to DNA-free potentials can be made using graphite electrodes without DNA modification. Importantly, electrochemistry on the DNA modified electrodes facilitates reaction under aqueous, physiological conditions with a sensitive electrical measurement of binding and activity. PMID- 28645378 TI - Preparation of Stable Nitrogen Mustard DNA Interstrand Cross-Link Analogs for Biochemical and Cell Biological Studies. AB - Nitrogen mustards (NMs) react with two bases on opposite strands of a DNA duplex to form a covalent linkage, yielding adducts called DNA interstrand cross-links (ICLs). This prevents helix unwinding, blocking essential processes such as replication and transcription. Accumulation of ICLs causes cell death in rapidly dividing cells, especially cancer cells, making ICL-forming agents like NMs valuable in chemotherapy. However, the repair of ICLs can contribute to chemoresistance through a number of pathways that remain poorly understood. One of the impediments in studying NM ICL repair mechanisms has been the difficulty of generating site-specific and stable NM ICLs. Here, we describe two methods to synthesize stable NM ICL analogs that make it possible to study DNA ICL repair. As a proof of principle of the suitability of these NM ICLs for biochemical and cell biological studies, we use them in primer extension assays with Klenow polymerase. We show that the NM ICL analogs block the polymerase activity and remain intact under our experimental conditions. PMID- 28645380 TI - Comet-FISH for Ultrasensitive Strand-Specific Detection of DNA Damage in Single Cells. AB - The genome integrity of living organisms is constantly threatened by endogenous cellular metabolic processes and environmental agents. To quantify these low, physiologically relevant levels of DNA damage, a single-cell gel electrophoresis (comet) combined with strand-specific fluorescence in situ hybridization (FISH) based approach has been developed. This approach enables the quantification of low levels of specific DNA lesions in each strand of the selected sequence at the single-molecule sensitivity, as well as in the genome overall in single cells. In this method, the percentage of DNA in the comet tail is used to quantify lesions in the genome overall. Lesions in the respective strands of the designated sequence are analyzed using strand-specific FISH probes. These probes targeting the 3' and 5' termini of the selected sequence are conjugated with two distinct fluorophores. Following the comet-FISH assay, the two termini of the designated sequence are visualized as two spots with different colors, under a fluorescence microscope. Separated spots indicate a damage strand, while adjacent or colocalized spots imply an intact strand. Any DNA lesions or DNA modifications, which can be converted into strand breaks enzymatically or chemically, can be quantified by this method. The comet-FISH approach described here can be applied to the study of the molecular mechanisms of various repair pathways, as well as in drug screening to develop inhibitors for specific repair pathways. PMID- 28645379 TI - DNA Fiber Analysis: Mind the Gap! AB - Understanding the mechanisms of replication stress response following genotoxic stress induction is rapidly emerging as a central theme in cell survival and human disease. The DNA fiber assay is one of the most powerful tools to study alterations in replication fork dynamics genome-wide at single-molecule resolution. This approach relies on the ability of many organisms to incorporate thymidine analogs into replicating DNA and is widely used to study how genotoxic agents perturb DNA replication. Here, we review different approaches available to prepare DNA fibers and discuss important limitations of each approach. We also review how DNA fiber analysis can be used to shed light upon several replication parameters including fork progression, restart, termination, and new origin firing. Next, we discuss a modified DNA fiber protocol to monitor the presence of single-stranded DNA (ssDNA) gaps on ongoing replication forks. ssDNA gaps are very common intermediates of several replication stress response mechanisms, but they cannot be detected by standard DNA fiber approaches due to the resolution limits of this technique. We discuss a novel strategy that relies on the use of an ssDNA-specific endonuclease to nick the ssDNA gaps and generate shorter DNA fibers that can be used as readout for the presence of ssDNA gaps. Finally, we describe a follow-up DNA fiber approach that can be used to study how ssDNA gaps are repaired postreplicatively. PMID- 28645382 TI - Preface. PMID- 28645381 TI - Examining DNA Double-Strand Break Repair in a Cell Cycle-Dependent Manner. AB - DNA double-strand breaks (DSBs) are deleterious DNA lesions that must be properly repaired to maintain genome stability. Agents, generated both exogenously (environmental radiation, dental X-rays, etc.) and endogenously (reactive oxygen species, DNA replication, V(D)J recombination, etc.), induce numerous DSBs every day. To counter these DSBs, there are two major repair pathways in mammalian cells, nonhomologous end joining (NHEJ) and homologous recombination (HR). NHEJ directly mediates the religation of the broken DNA molecule and is active in all phases of the cell cycle. HR directs repair via the use of a homologous DNA sequence as a template and is primarily active in only S/G2 phases owing to the availability of a DNA template via a sister chromatid. As NHEJ and HR are active in multiple cell cycle phases, there is significant interest in how a cell chooses between the two DSB repair pathways. Therefore, it is essential to utilize assays to study DSB repair that can distinguish between the two DSB repair pathways and the different phases of the cell cycle. In this chapter, we describe methods to measure the contribution of DNA repair pathways in different phases of the cell cycle. These methods are simple, can be applied to most mammalian cell lines, and can be used as a broad utility to monitor cell cycle dependent DSB repair. PMID- 28645383 TI - Importance of the immune system in mediating plasticity of the brain and behavior. PMID- 28645384 TI - Nonoperative Management of Appendicitis: A Paradigm Shift?: July 2017 Annals of Emergency Medicine Journal Club. PMID- 28645385 TI - Male Infant With Rapidly Progressive Skin Lesions. PMID- 28645386 TI - Pathophysiology of Primary Blast Injury. PMID- 28645387 TI - In reply. PMID- 28645388 TI - The Role that Health Care Coalitions Play in Support of Mass Casualty Response. PMID- 28645389 TI - Defining Quality and Outcome in Geriatric Emergency Care. PMID- 28645390 TI - In reply. PMID- 28645391 TI - Role of the State EMS Medical Director. PMID- 28645392 TI - Naloxone Access and Use for Suspected Opioid Overdoses. PMID- 28645393 TI - Drug "Take-Back" Programs. PMID- 28645394 TI - Physician Medical Direction of Emergency Medical Services Education Program. PMID- 28645395 TI - Tobacco and Nicotine Products: Public Policy Measures. PMID- 28645396 TI - Advanced Automatic Crash Notification and Intelligent Transportation Systems. PMID- 28645397 TI - Emergency Department Nurse Staffing. PMID- 28645398 TI - Screening Questions at Triage. PMID- 28645399 TI - Urgent Care Centers. PMID- 28645400 TI - Electronic Prescription Drug Monitoring Program. PMID- 28645401 TI - Alternative Methods to Vascular Access in the Emergency Department. PMID- 28645402 TI - Health Information Technology Standards. PMID- 28645403 TI - Nonbeneficial ("Futile") Emergency Medical Interventions. PMID- 28645404 TI - Confidentiality of Patient Information. PMID- 28645405 TI - Conflict of Interest. PMID- 28645406 TI - Antibiotics Only for Appendicitis? PMID- 28645409 TI - Guidelines for Emergency Physicians on the Interpretation of Physician Orders for Life-Sustaining Therapy (POLST). PMID- 28645408 TI - Disclosure of Medical Errors. PMID- 28645407 TI - Recording Devices in the Emergency Department. PMID- 28645410 TI - Elderly Woman With Fever and Abdominal Discomfort. PMID- 28645411 TI - Commentary. PMID- 28645413 TI - 76-Year-Old Man With Palpitations. PMID- 28645412 TI - Man With Hypertension and Heart Failure. PMID- 28645414 TI - Humanizing the Patient: A Lesson I Learned From Pumbaa. PMID- 28645415 TI - Pain and Empathy. PMID- 28645416 TI - The First Time. PMID- 28645417 TI - Female With Vaginal Spotting. PMID- 28645418 TI - Code of Ethics for Emergency Physicians. PMID- 28645419 TI - Elderly Man With Painless Vision Loss. PMID- 28645420 TI - Young Woman With Abdominal Pain and Distention. PMID- 28645421 TI - Code of Ethics for Emergency Physicians. PMID- 28645422 TI - Form of presentation, natural history and course of postoperative venous thromboembolism in patients operated on for pelvic and abdominal cancer. Analysis of the RIETE registry. AB - INTRODUCTION: Venous thromboembolism (VTE) represents a serious complication after oncologic surgery. Recent studies have shown that the risk of VTE persists several weeks after surgery. This study assesses the form of presentation and time course of VTE after abdominal and pelvic cancer surgery. METHODS: Prospective, multicenter, observational study that analyzes data from an international registry (RIETE) that includes consecutive patients with symptomatic VTE. Our study assesses the form and time of presentation of postoperative VTE, as well as main outcomes, in patients operated for abdominopelvic cancer 8 weeks prior to VTE diagnosis. Variables related to the presentation of VTE after hospital discharge are identified. RESULTS: Out of the 766 analyzed patients with VTE, 395 (52%) presented pulmonary embolism (PE). Most VTE cases (84%) were detected after the first postoperative week, and 38% after one month. Among patients with VTE in the first postoperative week, 70% presented PE. VTE presented after hospital discharge in 54% of cases. Colorectal, urologic, and gynecologic tumors, the use of radiotherapy, and blood hemoglobin levels were independently associated with VTE diagnosis after hospital discharge. Complications (thrombosis recurrence, bleeding, and death) occurred in 34% of patients with VTE detected before hospital discharge, compared to 24% in VTE after hospital discharge (P<0.01). CONCLUSIONS: VTE occurs after hospital discharge in most patients, particularly in those operated for colorectal, urologic, and gynecologic cancer. Pulmonary embolism is more frequent in patients who develop early VTE, who also have worse prognosis. PMID- 28645423 TI - A technique for extraction of the distal segment of a broken femoral nail using a flexible reamer. AB - INTRODUCTION: Extraction of broken femoral nails in peri-implant fractures is becoming an increasingly common problem faced by orthopaedic surgeons. Different closed and open techniques for removal of broken nails have been previously described but due to variations in equipment and fracture configurations these methods are not always easily reproducible. We describe an open surgical technique using simple equipment that can be utilised when other methods of extraction have failed. CASE PRESENTATION AND SURGICAL TECHNIQUE: We present a case of a peri-implant fracture secondary to non-union involving a short cephalomedullary nail where the broken distal segment of nail was significantly more distal to the femoral fracture site. After multiple failed attempts at extraction with previously described closed techniques a rectangular cortical window was created 2cm distal to the tip of the broken nail using a saw. An antegrade guide wire was passed through the nail and pulled out of the bony window. A flexible intramedullary reamer was subsequently passed in retrograde fashion over the guide wire and a simple pushout technique was used to push both segments of the broken nail through the original insertion site. An exchange nailing was performed and the cortical window was reattached using a cable. DISCUSSION: This is a simple technique that does not require any specialist equipment and does not require the fracture site to be disturbed. The use of a flexible reamer as a pushout device is ideal as there are multiple size options allowing the surgeon to match the size of the medullary canal with the reamer. Furthermore, the flexibility of the reamer allows easy access through a lateral bone window. CONCLUSION: Broken femoral nail extraction can be technically challenging and when other closed methods have failed we believe our technique offers a simple alternative that can be added to the armamentarium of solutions. PMID- 28645425 TI - We Are Teachers by Design; The Time Machine Approach-Time to Revisit. PMID- 28645424 TI - Occurrence of selected trace metals and their oral bioaccessibility in urban soils of kindergartens and parks in Bratislava (Slovak Republic) as evaluated by simple in vitro digestion procedure. AB - A total of eighty surface soil samples were collected from public kindergartens and urban parks in the city of Bratislava, and the <150um soil fraction was evaluated for total concentrations of five metals, Cd, Cu, Hg, Pb and Zn, their oral bioaccessibilities, non-carcinogenic and carcinogenic health risks to children, and lead isotopic composition. The mean metal concentrations in urban soils (0.29, 36.1, 0.13, 30.9 and 113mg/kg for Cd, Cu, Hg, Pb and Zn, respectively) were about two times higher compared with background soil concentrations. The order of bioaccessible metal fractions determined by Simple Bioaccessibility Extraction Test was: Pb (59.9%) > Cu (43.8%) > Cd (40.8%) > Zn (33.6%) > Hg (12.8%). Variations in the bioaccessible metal fractions were mainly related to the total metal concentrations in urban soils. A relatively wide range of lead isotopic ratios in urban soils (1.1598-1.2088 for 206Pb/207Pb isotopic ratio) indicated a combination of anthropogenic and geogenic sources of metals in the soils. Lower values of 206Pb/207Pb isotopic ratio in the city centre and similar spatial distribution of total metal concentrations, together with their increasing total concentrations in soils towards the city centre, showed that traffic and coal combustion in former times were likely the major sources of soil contamination. The non-carcinogenic and carcinogenic health risks to children due to exposure to metals in kindergarten and urban park soils were low, with hazard index and cancer risk values below the threshold values at all studied sites. PMID- 28645426 TI - Enhanced recovery in gynecologic oncology - A sea change in perioperative management. PMID- 28645427 TI - Antidiabetic medication, statins and the risk of endometrioid endometrial cancer in patients with type 2 diabetes. AB - OBJECTIVE: To gain further evidence of an association between the incidence of endometrial cancer (EC) and the use of metformin, other antidiabetic medication (ADM) and statins in women with type 2 diabetes (T2D). METHODS: A retrospective cohort of 92,366 women with newly diagnosed T2D was obtained from a diabetes register (FinDM). 590 endometrioid ECs were observed during the follow-up time. Poisson regression was utilized to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CIs) of the endometrioid EC in relation to the use of metformin, other oral ADM, insulin and statins. Nested case-control analyses were performed, where up to 20 controls were matched for age and duration of DM for each EC case. The HRs were estimated by conditional logistic regression for never/ever and cumulative use of different forms of ADM and statins. RESULTS: In the case-control analyses the use of metformin (HR 1.24, 95% CI 1.02-1.51) and other oral ADM (HR 1.25, 95% CI 1.04-1.50) was associated with an increased incidence of endometrioid EC compared to no ADM use. No difference was observed between metformin users and those using other oral ADMs. The use of statins was inversely related to the incidence of endometrioid EC (HR 0.78, 95% CI 0.65 0.94). Results from the full cohort analysis supported this finding. CONCLUSIONS: In our study the use of metformin or other oral forms of ADM was not associated with a lowered risk of endometrioid EC in women with T2D. Instead statins were observed to be inversely associated with endometrioid EC in this population. PMID- 28645429 TI - Coronary syndrome as the first manifestation of invasive thymoma. PMID- 28645428 TI - Cost-effectiveness of laparoscopy as diagnostic tool before primary cytoreductive surgery in ovarian cancer. AB - OBJECTIVE: To evaluate the cost-effectiveness of a diagnostic laparoscopy prior to primary cytoreductive surgery to prevent futile primary cytoreductive surgery (i.e. leaving >1cm residual disease) in patients suspected of advanced stage ovarian cancer. METHODS: An economic analysis was conducted alongside a randomized controlled trial in which patients suspected of advanced stage ovarian cancer who qualified for primary cytoreductive surgery were randomized to either laparoscopy or primary cytoreductive surgery. Direct medical costs from a health care perspective over a 6-month time horizon were analyzed. Health outcomes were expressed in quality-adjusted life-years (QALYs) and utility was based on patient's response to the EQ-5D questionnaires. We primarily focused on direct medical costs based on Dutch standard prices. RESULTS: We studied 201 patients, of whom 102 were randomized to laparoscopy and 99 to primary cytoreductive surgery. No significant difference in QALYs (utility=0.01; 95% CI 0.006 to 0.02) was observed. Laparoscopy reduced the number of futile laparotomies from 39% to 10%, while its costs were ? 1400 per intervention, making the overall costs of both strategies comparable (difference ? -80 per patient (95% CI -470 to 300)). Findings were consistent across various sensitivity analyses. CONCLUSION: In patients with suspected advanced stage ovarian cancer, a diagnostic laparoscopy reduced the number of futile laparotomies, without increasing total direct medical health care costs, or adversely affecting complications or quality of life. PMID- 28645430 TI - Thymic Stromal Lymphopoietin: A Promising Target in the Treatment of Asthma? PMID- 28645431 TI - Bronchocentric Granulomatosis in an Immunocompetent Patient. PMID- 28645432 TI - Inflammatory Myofibroblastic Tumor Diagnosed by Transbronchial Needle Aspiration. PMID- 28645433 TI - Medical Training after the Core Curriculum Model. PMID- 28645434 TI - Is There room for Theophylline in COPD? PMID- 28645435 TI - Reply to "Decisions after irreversible cardiopulmonary arrest: ends and opportunities". PMID- 28645436 TI - Sacubitril/valsartan in PARADIGM-HF. PMID- 28645437 TI - Sacubitril/valsartan in PARADIGM-HF. PMID- 28645438 TI - Sacubitril/valsartan in PARADIGM-HF. PMID- 28645439 TI - Sacubitril/valsartan in PARADIGM-HF - Authors' reply. PMID- 28645440 TI - The Pediatric Medical Student Research Forum: Fostering Interest in Pediatric Research. PMID- 28645441 TI - Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. PMID- 28645442 TI - Spinal Canal Involvement in Neuroblastoma. PMID- 28645443 TI - Once- or twice-daily non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: A meta-analysis of randomized controlled trials. AB - BACKGROUND/PURPOSE: Non-vitamin K antagonist oral anticoagulants (NOACs) have a half-life of around 12 h. We aimed to clarify if there was any effect modification by dosing (once- or twice-daily) regimens in Asian patients. METHODS: Phase III randomized controlled trials of NOACs compared with warfarin in Asian patients with atrial fibrillation (AF) were identified and extracted from PubMed, CENTRAL, and CINAHL databases through November 2016. Outcomes were pooled by dosing regimens with the Mantel-Haenszel fixed-effects model. The risk ratio (RR) and 95% confidence interval (CI) were calculated. Effect differences between once- and twice-daily NOACs were assessed with Bucher indirect comparisons using common estimates, once heterogeneity was low, and with the Bayesian method. RESULTS: From 6 trials, there was no effect modification by dosing regimens in the risk of stroke or systemic embolism across ethnicities (all interaction P > 0.05). Both dosing regimens were associated with a greater reduction in the risk of major bleeding in Asian patients (RR, 0.63 (95% CI, 0.47 0.85) and 0.57 (95% CI, 0.43-0.75), for once- and twice-daily NOACs, respectively). In Asian patients, risks of hemorrhagic stroke and intracranial hemorrhage were lower with once- (RR, 0.41 (95% CI, 0.21-0.80) and 0.29 (95% CI, 0.16-0.53)) and twice-daily NOACs (RR, 0.25 (95% CI, 0.12-0.51) and 0.38 (95% CI, 0.23-0.65)), compared with warfarin. There was no effect difference favoring any of NOAC regimens evaluated by Bucher and Bayesian methods. CONCLUSION: In Asian patients with AF, NOACs, regardless of dosing regimens, have a similar feature of preserved efficacy with improved safety compared with warfarin. PMID- 28645444 TI - NPM1 for MRD? Droplet Like It's Hot! AB - This commentary highlights the article by Mencia-Trinchant et al that describes a novel digital PCR assay for sensitive detection of minimal residual disease in NPM1 mutated acute myeloid leukemia. PMID- 28645445 TI - Fundamental Frequency and Formants Before and After Prolonged Voice Use in Teachers. AB - OBJECTIVES: This study aimed to describe and correlate the fundamental frequency behavior and the first four formants before and after exposure to usual and routinely prolonged voice use from teachers with over 4 years of experience in teaching. STUDY DESIGN: The study design is observational and transversal with quantitative and descriptive evaluations. METHODS: A total of 28 female teachers were subjected to the Screening Index for Voice Disorder (SIVD) and to recordings of the sustained vowel /a/ before and after exposure to prolonged voice use. Data were obtained about the fundamental frequency and the first four formants before and after voice use. Descriptive analysis and statistical processing were performed with P <= 0.05 for the general sample and in groups according to the outcome of the SIVD (normal and altered) and the evaluation period (morning or afternoon). RESULTS: The average exposure time to prolonged voice use was 176 minutes. There was no statistical difference in any of the variables studied. Correlations were positive and similar across all assessments before the class, something not observed in evaluations conducted after exposure to prolonged voice use. In the general sample, altered SIVD and afternoon period groups, the second formant from before-class measurements seems to interfere negatively in the fourth formant from after-class measurements. CONCLUSIONS: There were no changes in vocal behavior before and after exposure to prolonged voice use in the occupational environment. However, formants F1 and F2 measured before class correlated inversely with F4 after exposure to prolonged voice use. PMID- 28645446 TI - Cost-effectiveness analysis of two treatment strategies for chronic hepatitis C before and after access to direct-acting antivirals in Spain. AB - OBJECTIVE: To evaluate the cost-effectiveness of a strategy based on direct acting antivirals (DAAs) following the marketing of simeprevir and sofosbuvir (post-DAA) versus a pre-direct-acting antiviral strategy (pre-DAA) in patients with chronic hepatitis C, from the perspective of the Spanish National Health System. METHODS: A decision tree combined with a Markov model was used to estimate the direct health costs (?, 2016) and health outcomes (quality-adjusted life years, QALYs) throughout the patient's life, with an annual discount rate of 3%. The sustained virological response, percentage of patients treated or not treated in each strategy, clinical characteristics of the patients, annual likelihood of transition, costs of treating and managing the disease, and utilities were obtained from the literature. The cost-effectiveness analysis was expressed as an incremental cost-effectiveness ratio (incremental cost per QALY gained). A deterministic sensitivity analysis and a probabilistic sensitivity analysis were performed. RESULTS: The post-DAA strategy showed higher health costs per patient (?30,944 vs. ?23,707) than the pre-DAA strategy. However, it was associated with an increase of QALYs gained (15.79 vs. 12.83), showing an incremental cost-effectiveness ratio of ?2,439 per QALY. The deterministic sensitivity analysis and the probabilistic sensitivity analysis showed the robustness of the results, with the post-DAA strategy being cost-effective in 99% of cases compared to the pre-DAA strategy. CONCLUSIONS: Compared to the pre-DAA strategy, the post-DAA strategy is efficient for the treatment of chronic hepatitis C in Spain, resulting in a much lower cost per QALY than the efficiency threshold used in Spain (?30,000 per QALY). PMID- 28645447 TI - Colitis as a form of presentation of eosinophilic granulomatosis with polyangiitis. PMID- 28645448 TI - Takotsubo syndrome presenting as syncope in a patient with permanent pacemaker. AB - Takotsubo syndrome is an acute reversible heart failure syndrome triggered by physical or emotional stress, especially in postmenopausal women. Herein, we describe a case of a 31-year-old pacemaker dependent lady who presented with syncope after she was bereaved of her father. Electrocardiogram at admission revealed ventricular paced rhythm at 60/min, prolonged QT interval and frequent runs of torsades de pointes. Transthoracic echocardiogram and left ventriculogram revealed findings typical of Takotsubo syndrome. QT prolongation and torsade de pointes in the context of fixed-rate ventricular pacing imply direct catecholamine toxicity on the ventricular myocardium independent of heart rate. PMID- 28645449 TI - High incidence of ST-T changes in women during tilt-table testing. AB - INTRODUCTION: We have observed electrocardiographic (ECG) changes primarily in women during tilt table testing. METHODS: We reviewed 12 lead ECGs during tilt studies between 2012 and 2016 for changes in ST segments and T waves during tilt table testing. Patients with distinctly abnormal baseline ECGs were excluded. RESULTS: Of the 180 tilt studies, 117 (65%) were in women. There were 32 patients with ECG changes during tilting. Of these, 28 (87.5%) were in women with an average age of 45years. None had a history of CAD or exertional chest pain. Echocardiograms were available in 21 of the 28 women with tilt induced ECG changes and all were normal. ECG changes during tilt table testing were found in 4/64 (6.25%) of men. The occurrence of ST-T wave changes during tilt testing was significantly higher among women compared to men, with a p value of 0.008. Of the 28 women with ECG changes during tilt, 11 had T wave inversions alone. ST segment depression alone was noted in 7 women. There were 10 women who had both ST segment depression and T wave inversions. Changes occurred immediately upon tilting in 6. In the remaining, they occurred at an average of 4.8+/-4min after tilting. The slight increase in heart rate in patients with ECG changes was similar to that in the patients without new ECG changes. The ECG changes were not related to the presence of syncope. CONCLUSIONS: ECG changes during the testing was observed at a relatively high incidence primarily in women. The clinical significance of these repolarization changes during tilt testing is unknown. These ECG changes during tilt testing may correlate with the high incidence of false positive ECGs in women during exercise testing but do not necessarily indicate the presence of ischemic coronary disease. Additional research is needed to explain this phenomenon. PMID- 28645450 TI - Identification of a novel food allergen in lotus root. PMID- 28645451 TI - Differences in Outcomes of Patients Treated by Male vs Female Chiropractors. AB - OBJECTIVE: The purpose of this study was to compare treatment outcomes of low back pain patients depending on the sex of the treating doctor of chiropractic (DC). METHODS: For this study, 1095 adult patients with no manual therapy in the prior 3 months were recruited. Pretreatment pain levels (Numeric Rating Scale for pain [NRS]), Oswestry Disability Index (ODI), and patient demographic details were recorded. The NRS and Patient Global Impression of Change were assessed after 1 week and 1, 3, 6, and 12 months. The ODI was completed up to 3 months. The chi2 test compared sex of the DC with the proportion of patients "improved" at all time points and with baseline categorical variables. The unpaired t test compared changes in NRS and ODI scores between patients of male and female DCs. RESULTS: Female DCs saw proportionally more acute patients (P = .012). Patients of male DCs presented more often with radiculopathy (P = .007). There were no differences in NRS and ODI baseline scores between male and female DCs' patients. At 1 week and 3 and 12 months, significantly more patients of female DCs reported improvement and they had greater decreases in NRS and ODI scores at 1 week. Removing acute patients from the data, there were no longer differences in outcome. CONCLUSIONS: Significant differences in treatment outcome in favor of female DCs was no longer present on removal of the acute subgroup from the data. This suggests that patient outcome is influenced by other factors, such as chronicity, rather than sex of the treating DC. PMID- 28645453 TI - Choice of knee cartilage thickness change metric for different treatment goals in efficacy studies. AB - INTRODUCTION: In knee osteoarthritis, local increase and decrease in cartilage thickness has been observed over short time intervals. Hence, averaging cartilage change across large regions may not capture the complexity of structural alterations in disease progression. This study aims to examine the relative performance of different metrics of cartilage thickness change for different clinical studies scenarios. MATERIALS AND METHODS: Metrics for assessing cartilage thickness change were characterized by conventional measures of change versus absolute values (the magnitude) of change, and by different methods of summarizing change over (sub-) regions. Sample sizes for these metrics were derived for 6-24-month observation periods, and for different treatment efficacies. Treatment effects were derived from an observational trial with 6-, 12-, and 24-month follow-up, ranging from slowing cartilage loss to stimulating cartilage growth. RESULTS: Projected sample sizes ranged from 10 to >10,000 patients/arm (median = 164), depending on metric choice, treatment efficacy, and observation period. The smallest sample sizes for metrics using magnitude of change typically were half the size of those using conventional measures of change. Extreme values, e.g., minimum change or average of last four-ordered values of absolute change, required smaller sample sizes than metrics averaging over one or more regions. CONCLUSIONS: Metrics using extreme magnitudes of change were most efficient in detecting differences between treatment and placebo, i.e., involved the smallest sample sizes across different DMOAD study lengths and treatment efficacies. Ancillary metrics can be used to clarify whether differences between treatment and placebo indicate structural benefit when needed. PMID- 28645452 TI - Thrust Magnitudes, Rates, and 3-Dimensional Directions Delivered in Simulated Lumbar Spine High-Velocity, Low-Amplitude Manipulation. AB - OBJECTIVES: The purpose of this study was to measure faculty performance of simulated spinal manipulation on a mannequin to help identify teaching standards. METHODS: We measured 3-dimensional transmitted loads using a force plate mounted in the table. Thrusts were delivered through a compliant, jointed mannequin by faculty members along predefined "listings" as taught in lumbopelvic technique courses. RESULTS: Eleven chiropractic faculty members participated, delivering 9 thrusts at 3 loads (light, moderate, and heavy) along 9 different prone and side posture listings, totaling 81 thrusts per participant. Single-hand Gonstead-style thrusts had variability in magnitude across participants and loads: light thrusts averaged 365 N (95% confidence interval [CI] 327-402), moderate thrusts 454 N (421-487), and heavy thrusts 682 N (623-740). All faculty members could easily distinguish the loads within their performances, but there was some crossover of load levels between participants. Thrust rates averaged 3.55 N/ms (95% CI 3.29 3.82). The dominant vector of prone thrusts was in the z direction (vertically downward), but side-to-side and inferior-to-superior vector components occurred. CONCLUSION: Faculty member performance of simulated spinal manipulation indicated that they are able to control the thrust magnitude and rate as well as direction. In this sample, there was significant variability in peak loads between participants, which needs to be considered in student learning standards. These findings may be useful in translating the understanding of force characteristics to the technique teaching lab. PMID- 28645454 TI - Uterine Diverticulum With Fetal Leg Entrapment: A Case Report. AB - BACKGROUND: Uterine anomalies causing fetal complications are very rarely encountered in obstetric practice and thus pose a diagnostic dilemma. CASE: A multigravid patient attended the clinic for an ultrasound examination in the third trimester following a recent hospital admission for abdominal pain. Ultrasound imaging revealed a large uterine diverticulum in the right cornu of the uterus with evidence of fetal leg entrapment. Because of concerns of increased soft tissue edema in the entrapped leg, the patient was delivered at 35 weeks' gestation by elective CS. The CS was complicated by uterine rupture at the diverticular portion. The neonatal course was complicated by compartment syndrome of the leg, and the infant underwent surgery on post-delivery day one with good outcome. CONCLUSION: Uterine diverticula are rare anomalies, and once they are diagnosed, the possibility of entrapment of fetal parts or placenta in pregnancy should be considered. PMID- 28645455 TI - Kinematic chain reactions on trunk and dynamic postural steadiness in subjects with recurrent low back pain. AB - Although subjects with recurrent low back pain (LBP) demonstrate altered trunk control, the kinematic and kinetic responses of the trunk have not been carefully investigated. This study was conducted to compare the standing time, spine range of motion (ROM), and dynamic postural steadiness index (DPSI) based on visual condition between subjects with and without recurrent LBP during upright one leg standing. Sixty-three individuals participated in the study, including 34 control subjects and 29 subjects with recurrent LBP. The DPSI was a composite of the medio-lateral (MLSI), anterior-posterior (APSI), and vertical steadiness indices (VSI) on a force platform. The control group demonstrated longer standing time (s) during the eyes-open condition than the LBP group (26.82+/-6.03 vs. 19.87+/ 9.36; t=2.96, p=0.01). Regarding spine ROM, visual condition was significantly different between groups (F=7.09, p=0.01) and demonstrated interactions with spine region and group (F=5.53, p=0.02). For the kinetic measures, there was a significant interaction between visual conditions and indices (F=25.30, p=0.001). In the LBP group, the DPSI was significantly correlated with the MLSI (r=0.59, p=0.002), APSI (r=0.44, p=0.03), and VSI (r=0.98, p=0.01) in the eyes-closed condition. Overall, the results of this study indicated that the LBP group decreased thorax and lumbar spine rotations during the eyes-closed condition. The LBP group also demonstrated positive correlations with the kinetic indices, enhancing dynamic postural steadiness in the eyes-closed condition in order to possibly avoid pain or further injury. This dynamic postural steadiness strategy is necessary to improve kinetic and kinematic chain reactions in the LBP group. This compensatory pattern supports the development of optimal postural correction strategies to prevent LBP recurrence and might represent a chain reaction to protect trunk control without visual input. PMID- 28645456 TI - Andragogic Approaches to Continuing Medical Education. PMID- 28645457 TI - Diagnostic Medical Imaging in Pediatric Patients and Subsequent Cancer Risk. AB - The use of diagnostic medical imaging is becoming increasingly more commonplace in the pediatric setting. However, many medical imaging modalities expose pediatric patients to ionizing radiation, which has been shown to increase the risk of cancer development in later life. This review article provides a comprehensive overview of the available data regarding the risk of cancer development following exposure to ionizing radiation from diagnostic medical imaging. Attention is paid to modalities such as computed tomography scans and fluoroscopic procedures that can expose children to radiation doses orders of magnitude higher than standard diagnostic x-rays. Ongoing studies that seek to more precisely determine the relationship of diagnostic medical radiation in children and subsequent cancer development are discussed, as well as modern strategies to better quantify this risk. Finally, as cardiovascular imaging and intervention contribute substantially to medical radiation exposure, we discuss strategies to enhance radiation safety in these areas. PMID- 28645458 TI - Pulmonary 3He Magnetic Resonance Imaging Biomarkers of Regional Airspace Enlargement in Alpha-1 Antitrypsin Deficiency. AB - RATIONALE AND OBJECTIVES: Thoracic x-ray computed tomography (CT) and hyperpolarized 3He magnetic resonance imaging (MRI) provide quantitative measurements of airspace enlargement in patients with emphysema. For patients with panlobular emphysema due to alpha-1 antitrypsin deficiency (AATD), sensitive biomarkers of disease progression and response to therapy have been difficult to develop and exploit, especially those biomarkers that correlate with outcomes like quality of life. Here, our objective was to generate and compare CT and diffusion-weighted inhaled-gas MRI measurements of emphysema including apparent diffusion coefficient (ADC) and MRI-derived mean linear intercept (Lm) in patients with AATD, chronic obstructive pulmonary disease (COPD) ex-smokers, and elderly never-smokers. MATERIALS AND METHODS: We enrolled patients with AATD (n = 8; 57 +/- 7 years), ex-smokers with COPD (n = 8; 77 +/- 6 years), and a control group of never-smokers (n = 5; 64 +/- 2 years) who underwent thoracic CT, MRI, spirometry, plethysmography, the St. George's Respiratory Questionnaire, and the 6-minute walk test during a single 2-hour visit. MRI-derived ADC, Lm, surface-to volume ratio, and ventilation defect percent were generated for the apical, basal, and whole lung as was CT lung area <=-950 Hounsfield units (RA950), low attenuating clusters, and airway count. RESULTS: In patients with AATD, there was a significantly different MRI-derived ADC (P = .03), Lm (P < .0001), and surface to-volume ratio (P < .0001), but not diffusing capacity of carbon monoxide, residual volume or total lung capacity, or CT RA950 (P > .05) compared to COPD ex smokers with a significantly different St. George's Respiratory Questionnaire. CONCLUSIONS: In this proof-of-concept demonstration, we evaluated CT and MRI lung emphysema measurements and observed significantly worse MRI biomarkers of emphysema in patients with AATD compared to patients with COPD, although CT RA950 and diffusing capacity of carbon monoxide were not significantly different, underscoring the sensitivity of MRI measurements of AATD emphysema. PMID- 28645459 TI - [Hotline for Zika virus: experience of a tropical and travel medicine unit]. AB - The current outbreak of Zika virus has caused great social alarm, generated in part by the lack of information in the general population. In order to provide accurate and verified information, the Tropical and Travel Medicine Unit of Hospital Carlos III-La Paz (Madrid, Spain) established a hotline for Zika virus infection. We present the data concerning the first 6 months of operation of the telephone hotline. The predominant call profile consisted of women seeking information about the risk of acquiring the disease before travelling. Brazil, Mexico and Colombia were the destinations for which the most information was requested. Most of the consultations were resolved by providing information only. The implementation of call devices that provide confirmed and reliable information on diseases associated with great alarm are of significant public health interest, as they reduce the number of unnecessary medical consultations and save on medical costs. PMID- 28645461 TI - Yeast-based assays for detecting protein-protein/drug interactions and their inhibitors. AB - Understanding cellular processes at molecular levels in health and disease requires the knowledge of protein-protein interactions (PPIs). In line with this, identification of PPIs at genome-wide scale is highly valuable to understand how different cellular pathways are interconnected, and it eventually facilitates designing effective drugs against certain PPIs. Furthermore, investigating PPIs at a small laboratory scale for deciphering certain biochemical pathways has been demanded for years. In this regard, yeast two hybrid system (Y2HS) has proven an extremely useful tool to discover novel PPIs, while Y2HS derivatives and novel yeast-based assays are contributing significantly to identification of protein drug/inhibitor interaction at both large- and small-scale set-ups. These methods have been evolving over time to provide more accurate, reproducible and quantitative results. Here we briefly describe different yeast-based assays for identification of various protein-protein/drug/inhibitor interactions and their specific applications, advantages, shortcomings, and improvements. The broad range of yeast-based assays facilitates application of the most suitable method(s) for each specific need. PMID- 28645460 TI - Associations between timing of corticosteroid treatment initiation and clinical outcomes in Duchenne muscular dystrophy. AB - The long-term efficacy of corticosteroid treatment and timing of treatment initiation among Duchenne muscular dystrophy (DMD) patients is not well understood. We used data from a longitudinal, population-based DMD surveillance program to examine associations between timing of treatment initiation (early childhood [before or at age 5 years], late childhood [after age 5 years], and naive [not treated]) and five clinical outcomes (age at loss of ambulation; ages at onset of cardiomyopathy, scoliosis, and first fracture; and pulmonary function). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using survival analysis. DMD patients who initiated corticosteroid treatment in early childhood had a higher risk of earlier onset cardiomyopathy compared to cases who initiated treatment in late childhood (HR = 2.0, 95% CI = [1.2, 3.4]) or treatment naive patients (HR = 1.9, 95% CI = [1.1, 3.2]), and higher risk of suffering a fracture (HR = 2.3, 95% CI = [1.4, 3.7] and HR = 2.6, 95% CI = [1.6, 4.2], respectively). Patients with early childhood treatment had slightly decreased respiratory function compared with those with late childhood treatment. Ages at loss of ambulation or scoliosis diagnosis did not differ statistically among treatment groups. We caution that the results from our study are subject to several limitations, as they were based on data abstracted from medical records. Further investigations using improved reporting of disease onset and outcomes are warranted to obtain a more definitive assessment of the association between the timing of corticosteroid treatment and disease severity. PMID- 28645462 TI - Analgosedation Practices and the Impact of Sedation Depth on Clinical Outcomes Among Patients Requiring Mechanical Ventilation in the ED: A Cohort Study. AB - BACKGROUND: Analgesia and sedation are cornerstone therapies for mechanically ventilated patients. Despite data showing that early deep sedation in the ICU influences outcome, this has not been investigated in the ED. Therefore, ED-based sedation practices, and their influence on outcome, remain incompletely defined. This study's objectives were to describe ED sedation practices in mechanically ventilated patients and to test the hypothesis that ED sedation depth is associated with worse outcomes. METHODS: This was a cohort study of a prospectively compiled ED registry of adult mechanically ventilated patients at a single academic medical center. Hospital mortality was the primary outcome and hospital-, ICU-, and ventilator-free days were secondary outcomes. A backward stepwise multivariable logistic regression model evaluated the primary outcome as a function of ED sedation depth. Sedation depth was assessed with the Richmond Agitation-Sedation Scale (RASS). RESULTS: Four hundred fourteen patients were studied. In the ED, 354 patients (85.5%) received fentanyl, 254 (61.3%) received midazolam, and 194 (46.9%) received propofol. Deep sedation was observed in 244 patients (64.0%). After adjusting for confounders, a deeper ED RASS was associated with mortality (adjusted OR, 0.77; 95% CI, 0.63-0.94). CONCLUSIONS: Early deep sedation is common in mechanically ventilated ED patients and is associated with worse mortality. These data suggest that ED-based sedation is a modifiable variable that could be targeted to improve outcome. PMID- 28645464 TI - [Drug eruption with clomifene citrate in a bodybuilder]. PMID- 28645465 TI - Muscle Medicine-a Small Success Worth Celebrating. PMID- 28645463 TI - Etiologies of Chronic Cough in Pediatric Cohorts: CHEST Guideline and Expert Panel Report. AB - BACKGROUND: There is no published systematic review on the etiologies of chronic cough or the relationship between OSA and chronic cough in children aged <= 14 years. We thus undertook a systematic review based on key questions (KQs) using the Population, Intervention, Comparison, Outcome format. The KQs follow: Among children with chronic (> 4 weeks) cough (KQ 1) are the common etiologies different from those in adults? (KQ 2) Are the common etiologies age or setting dependent, or both? (KQ 3) Is OSA a cause of chronic cough in children? METHODS: We used the CHEST Expert Cough Panel's protocol and the American College of Chest Physicians (CHEST) methodological guidelines and Grading of Recommendations Assessment, Development, and Evaluation framework. Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus. RESULTS: Combining KQs 1 and 2, we found moderate-level evidence from 10 prospective studies that the etiologies of cough in children are different from those in adults and are setting dependent. Data from three studies found that common etiologies of cough in young children were different from those in older children. However, data relating sleep abnormalities to chronic cough in children were found only in case studies. CONCLUSIONS: There is moderate-quality evidence that common etiologies of chronic cough in children are different from those in adults and are dependent on age and setting. As there are few data relating OSA and chronic cough in children, the panel suggested that these children should be managed in accordance with pediatric sleep guidelines. PMID- 28645466 TI - The Scottish enhanced Staphylococcus aureus bacteraemia surveillance programme: the first 18 months of data in children. AB - BACKGROUND: National enhanced surveillance of Staphylococcus aureus bacteraemia (SAB) commenced on 1st October 2014 to gain a more in-depth understanding of the epidemiology of SAB in Scotland. Children under 16 years of age were analysed separately from adults because previous studies had demonstrated epidemiological differences. AIM: To identify risk factors and patient populations at greatest risk to enable the development of focused improvement plans. METHODS: All National Health Service (NHS) boards within NHS Scotland take part in the mandatory enhanced surveillance, with data collected by trained data collectors using nationally agreed definitions. FINDINGS: Analysis of the first 18 months of data showed that hospital-acquired SAB was mostly associated with neonates with device risk factors, whereas community-associated SAB was found in older children who had few, if any, risk factors and most presented with a bone or joint infection. CONCLUSION: The enhanced SAB data highlighted the difference in risk factors and entry points for the acquisition of SAB within the paediatric population. PMID- 28645467 TI - Citreoviridin induces triglyceride accumulation in hepatocytes through inhibiting PPAR-alpha in vivo and in vitro. AB - Citreoviridin (CIT) is a mycotoxin produced by Penicillum citreonigrum, Aspergillus terreus and Eupenicillium ochrosalmoneum. CIT occurs naturally in moldy rice and corn. CIT is associated with the development of atherosclerosis in the general population. Alteration in hepatic lipid metabolism is a pathogenic factor in atherosclerosis. However the effect and the underlying mechanism of CIT on hepatic lipid metabolism are largely unknown. In this study, we reported that CIT induced triglyceride accumulation in mice liver and human liver HepG2 cells as shown in oil red O staining. CIT (0.1 mg/kg-0.3 mg/kg) for 6 weeks elevated liver triglyceride contents in mice. CIT inhibited the transactivation activity of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in hepatocyte in vivo and in vitro, as shown by the reduced mRNA levels of PPAR-alpha target genes which play key roles in lipid metabolism in various aspects. PPAR-alpha agonist fenofibrate attenuated CIT-induced triglyceride accumulation in HepG2 cells. Furthermore, CIT increased serum total cholesterol/high-density lipoprotein cholesterol ratio, a strong risk factor for cardiovascular disease. In summary, we reported that CIT induced PPAR-alpha-dependent hepatic triglyceride accumulation and dyslipidemia. Our data will provide new mechanistic insights into CIT-induced lipid alterations. PMID- 28645468 TI - ALDHs in normal and malignant hematopoietic cells: Potential new avenues for treatment of AML and other blood cancers. AB - Multiple studies have demonstrated that ALDH1A1 is elevated in hematopoietic stem cells (HSCs). As a means to better characterize such cells, we previously developed the fluorescent ALDH1A1 substrate Aldefluor to facilitate HSC identification and isolation. This has proven useful for counting and isolating HSCs from human bone marrow, peripheral blood and cord blood as well as stem cells in other tissues and organisms. Given the high level expression of ALDH1A1, we explored its biology and that of other ALDHs in HSCs and found that ALDH1A1 and ALDH3A1 were important in metabolizing reactive aldehydes (RAlds) and reactive oxygen species (ROS). In murine models, loss of these two isoforms resulted in a variety of effects on HSC biology, increased DNA damage and predisposition to leukemia formation when combined with a genetic driver of HSC proliferation and self-renewal. Loss of ALDH activity may also predispose to marrow failure and AML in Fanconi's anemia (FA). ALDHs also have importance in mediating drug resistance in AML, may be useful in the identification of leukemia stem cells (LSCs) and ALDH activity levels may have prognostic significance. Together these findings suggest that further studying ALDH biology in AML and other blood cancers may provide important insights into malignant transformation and may point the way to the development of novel diagnostics and therapies. PMID- 28645469 TI - Transcatheter Mitral Valve Repair With MitraClip for Symptomatic Functional Mitral Valve Regurgitation. AB - Transcatheter edge-to-edge mitral valve repair (TMVr) with MitraClip has proved to be safe and effective for high-risk surgical patients with severe symptomatic degenerative mitral regurgitation. There is paucity of data regarding its use in functional mitral regurgitation (FMR). The objective of this study was to evaluate the use of MitraClip in patients with symptomatic moderate or severe FMR and a high surgical risk. Medical libraries were systematically searched for studies assessing the use of MitraClip for patients with symptomatic moderate or severe FMR and a high surgical risk. Studies reporting safety and efficacy outcomes at 12 months were included in the analysis. A total of 12 studies including 1,695 patients (age 73 [interquartile range [IQR] 70.5 to 74], 69.8% men, left ventricular ejection fraction 32.5% [IQR 29.5 to 36], New York Heart Association class II to IV) who underwent TMVr with MitraClip were included in the analysis. Acute procedural success was 89% (IQR 85.5 to 92). Ischemic cardiomyopathy was the most common cause of left ventricular dysfunction. Over 2/3 of patients had known coronary artery disease, 35% a previous myocardial infarction, and 38.5% had a previous cardiac surgery. Survival to hospital discharge was 98% (IQR 97 to 100) and 30-day survival 97% (IQR 96 to 98). Overall survival at 12 months was 82% (IQR 77 to 87). Mitral valve re-intervention at 12 months was infrequent (3%; IQR 2 to 6.5). In conclusion, our pooled analysis suggests that TMVr with MitraClip is feasible, safe, and carries a low rate of mitral valve re-intervention at 12 months in patients with symptomatic moderate or severe FMR and a high surgical risk. PMID- 28645470 TI - Significance of Atrial Fibrillation Complicating ST-Segment Elevation Myocardial Infarction. AB - The aim of the present study is to assess the clinical impact of atrial fibrillation (AF) in patients with ST-segment elevation myocardial infarction (STEMI) complicated by new-onset AF depending on STEMI location and timing of arrhythmia. We analyzed 4,363 consecutive STEMI patients treated invasively. Finally, 4,099 subjects were included into further analysis, as 264 patients were excluded because of previous AF history. In total, 1,800 (43.9%) subjects with anterior infarction were included into Group 1, whereas Group 2 encompassed 2,299 (56.1%) patients with nonanterior infarction. Subsequently, both groups were divided into patients with new-onset AF (AF Group 1 and 2, respectively) and without AF (Control Group 1 and 2). New-onset AF was recognized in 225 patients (5.5%): 96 (5.3%) with an anterior wall infarction (AF Group 1) and 129 (5.6%) with a nonanterior wall infarction (AF Group 2). The incidence of early-onset arrhythmia (within 24 hours after admission) was significantly higher in AF Group 2 than in AF Group 1: 71.3% versus 35.4% (p <0.001). In Group 1, both early- and late-onset AFs were associated with significantly increased in-hospital mortality compared with AF-free population (17.7% and 27.4%, respectively vs 6.3%; p <0.05), whereas in Group 2, in-hospital mortality was increased only in subjects with late-onset AF compared with AF-free population (13.5% vs 4.2%, p <0.05). New onset AF was the independent predictor of death only in Group 1 (hazard ratio 2.16) and this effect was stronger for late-onset AF (hazard ratio 2.86). In conclusion, 1 in 20 patients with STEMI treated invasively was affected by new onset AF. The predictive value of new-onset AF was strongly related with STEMI location and timing of arrhythmia. PMID- 28645471 TI - Association of Obstructive Sleep Apnea With Subclinical Cardiovascular Disease Predicted by Coronary Artery Calcium Score in Asymptomatic Subjects. AB - The aim of this study is to determine the association among various sleep parameters for obstructive sleep apnea (OSA) and subclinical cardiovascular disease measured by coronary artery calcium (CAC) score. A cross-sectional study was conducted among 461 patients who underwent both polysomnography (PSG) and coronary artery computed tomography to evaluate CAC score. For each participant, coronary artery computed tomography was conducted within 12 months of PSG. We evaluated the possible association among various PSG parameters by evaluating overnight-attended PSG and CAC. A univariate analysis with lowest SaO2 and stage 3 sleep % during sleep was significantly associated with CAC score (beta = 5.528, 95% confidence interval [CI] -9.179 to -1.777, p = 0.004 and beta = 8.658, 95% CI -16.461 to -0.855, p = 0.030, respectively). However, after adjustment for possible confounders, only the lowest SaO2 was independently associated with CAC score (beta = -5.234, 95% CI -9.215 to -1.253, p = 0.010). This association was stronger in participants aged >=60 years (beta = -26.966, 95% CI -41.874 to -12.058, p = 0.001). In a univariate analysis, apnea-hypopnea index, stage 3 sleep %, and moderate and severe OSA were significantly associated with CAC presence (odds ratio [OR] 1.010, p = 0.035; OR 0.949, p = 0.039; OR 2.186, p = 0.013; and OR 2.019, p = 0.020, respectively). However, after adjusting for possible confounders, there was no significant association. In conclusion, the patients with intermittent hypoxemia during sleep should be considered for evaluation of coronary artery calcification to detect cardiovascular disease in subclinical status. PMID- 28645472 TI - Bradycardia, Syncope, and Left Ventricular Noncompaction Cardiomyopathy. AB - A 55-year-old man with syncopal episodes was found to have sinus bradycardia at a rate of 37 beats/min, an episode of nonsustained ventricular tachycardia, and left ventricular noncompaction cardiomyopathy. After placement of a dual-chamber cardioverter defibrillator 4 years ago, he has had no further syncopal episodes, and there have been no defibrillator shocks. PMID- 28645473 TI - Efficacy and Safety of Rivaroxaban Versus Warfarin in Patients Taking Nondihydropyridine Calcium Channel Blockers for Atrial Fibrillation (from the ROCKET AF Trial). AB - Non-dihydropyridine calcium channel blockers (non-DHP CCBs) possess combined P glycoprotein and moderate CYP3A4 inhibition, which may lead to increased exposure of medications that are substrates for these metabolic pathways, such as rivaroxaban. We evaluated the use and outcomes of non-DHP CCBs in patients with atrial fibrillation (AF) in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). We assessed clinical outcomes in patients who received non-DHP CCBs and the impact on the efficacy and safety of rivaroxaban compared with warfarin. Stroke or noncentral nervous system (CNS) systemic embolism (SE), major or nonmajor clinically relevant (NMCR) bleeding, all-cause death, and major bleeding were compared according to non-DHP CCB use. At randomization, 1,308 patients (9.2%) were taking a non-DHP CCB. They were more likely to be women, have diabetes and COPD, and less likely to have heart failure and had a lower mean CHADS2 score (3.3 vs 3.5). Non-DHP CCB use was not associated with an increased risk of stroke/non-CNS SE (p = 0.11) or the composite outcome of NMCR or major bleeding (p = 0.087). Non-DHP CCB use was associated with an increased risk of major bleeding (adjusted hazard ratio 1.50, 95% CI 1.11 to 2.04) and intracranial hemorrhage (adjusted hazard ratio 2.84, 95% CI 1.53 to 5.29). No significant difference was observed in the primary efficacy (stroke or non-CNS SE; adjusted interaction p value = 0.38) or safety outcome (NMCR or major bleeding; adjusted interaction p value = 0.14) between rivaroxaban and warfarin with non-DHP CCB use. In conclusion, although the overall use of non DHP CCBs was associated with an increased risk of major bleeding and intracranial hemorrhage, the use was not associated with a significant change in the safety or efficacy of rivaroxaban compared with warfarin observed in ROCKET AF. PMID- 28645474 TI - Severe Mental Illness and Clinical Outcome After Primary Percutaneous Coronary Intervention. AB - The mechanisms behind the increased mortality in patients with acute myocardial infarction and co-existing severe mental illness (SMI) compared with non-SMI patients remain unclear. We studied 12,102 patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention, of whom 457 had SMI. The primary outcome was major adverse cardiac events (death, myocardial infarction, target vessel revascularization) at 30 days, 1 year, 2 years, and maximum follow-up. Patients with SMI were younger, more often women, had higher prevalence of active smoking and diabetes, and had a longer duration of symptoms than patients without SMI. There were no substantial differences in the in hospital treatment of patients with and without SMI. Fewer SMI patients were treated with the recommended medications during follow up; however, the absolute differences were modest. Compared with non-SMI patients, the cumulative risks of major adverse cardiac events after 1 year, 2 years, and maximum follow-up were higher among SMI patients [hazard ratio 1.27 (1.02 to 1.57), hazard ratio 1.32 (1.09 to 1.60), and hazard ratio 1.43 (1.25 to 1.65), respectively]. Even after adjustment for differences in baseline characteristics, the differences in outcome persisted. In conclusion, compared with patients without SMI, primary percutaneous coronary intervention treated patients with SMI had a worse baseline risk profile. No differences in in-hospital treatments were found. Although the absolute differences were small, SMI patients were less likely to receive recommended medical treatment during follow up and they face a worse prognosis, even after adjustment for differences in risk profile. This indicates that SMI per se is likely to have an adverse effect on the prognosis following ST elevation myocardial infarction. PMID- 28645476 TI - Relation of Coronary Artery Calcium Score and Risk of Cancer (from a Danish Population-Based Follow-up Study in Patients Who Underwent Cardiac Computed Tomography). AB - Evidence of a causal link between atherosclerosis and cancer is sparse and conflicting. Therefore, we examined the association between extent of coronary atherosclerosis determined by coronary artery calcium score (CACS) and risk of cancer. We conducted a historical population-based cohort study of 28,549 cancer free patients identified in the Western Denmark Heart Registry. All patients underwent cardiac computed tomography for measurement of CACS for suspected coronary artery disease. The outcome was an incident cancer diagnosis: total, tobacco-related, lung, prostate, breast, and colorectal. We used Cox proportional hazards regression analyses stratified by gender to estimate hazard ratios (HRs) for relations between CACS and cancer with 95% confidence intervals (95% CI). During follow-up, 455 men and 527 women had a cancer diagnosis. In a multivariable model (reference group: CACS 0), adjusted hazard ratios (95% confidence interval) for total cancer were as follows: CACS 1 to 99: 1.07 (0.83 to 1.39), CACS 100 to 399: 1.24 (0.94 to 1.63), CACS 400 to 999: 0.88 (0.62 to 1.25), CACS >=1,000: 0.96 (0.66 to 1.41) in men; and CACS 1 to 99: 0.96 (0.77 to 1.19), CACS 100 to 399: 0.99 (0.75 to 1.31), CACS 400 to 999: 1.11 (0.76 to 1.62), and CACS >=1,000: 1.16 (0.73 to 1.83) in women. We found no significant association between CACS and the specified outcomes for men or women, except for an increased risk of lung cancer among women with a high CACS. In conclusion, extent of coronary atherosclerosis determined by CACS was not associated with development of total, tobacco-related, lung, prostate, breast, or colorectal cancer. However, we did observe an association between CACS and risk of lung cancer in women. PMID- 28645477 TI - The overexpression of CPR and P450 3A4 in pancreatic cancer cells changes the metabolic profile and increases the cytotoxicity and pro-apoptotic activity of acridine antitumor agent, C-1748. AB - Drug resistance is one of the major causes of pancreatic cancer treatment failure. Thus, it is still imperative to develop new active compounds and novel approach to improve drug efficacy. Here we present 9-amino-1-nitroacridine antitumor agent, C-1748, developed in our laboratory, as a candidate for pancreatic cancer treatment. We examined (i) the cellular response of pancreatic cancer cell lines: Panc-1, MiaPaCa-2, BxPC-3 and AsPC-1, differing in expression levels of commonly mutated genes for this cancer type, to C-1748 treatment and (ii) the role of P450 3A4 isoenzyme and cytochrome P450 reductase (CPR) in the modulation of this response. C-1748 exhibited the highest cytotoxic activity against MiaPaCa-2, while AsPC-1 cells were the most resistant (IC50: 0.015, 0.075uM, respectively). A considerable amount of apoptosis was detected in Panc-1 and MiaPaCa-2 cells but only limited apoptosis was observed in AsPC-1 and BxPC-3 cells as indicated by morphological changes and biochemical markers. Furthermore, only AsPC-1 cells underwent senescence. Since AsPC-1 cells were the most resistant to C-1748 as evidenced by the lowest P450 3A4 and CPR protein levels, this cell line was subjected to transient transfection either with P450 3A4 or CPR gene. The overexpression of P450 3A4 or CPR changed the pro-apoptotic activity of C-1748 and sensitized AsPC-1 cells to this drug compared to wild-type cells. However, metabolism was changed significantly only for CPR overexpressing cells. In conclusion, the antitumor effectiveness of C-1748 would be improved by multi-drug therapy with chemotherapeutics, that are able to induce P450 3A4 and/or CPR gene expression. PMID- 28645475 TI - Usefulness of Early Treatment With Melatonin to Reduce Infarct Size in Patients With ST-Segment Elevation Myocardial Infarction Receiving Percutaneous Coronary Intervention (From the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty Trial). AB - Melatonin, an endogenously produced hormone, might potentially limit the ischemia reperfusion injury and improve the efficacy of mechanical reperfusion with primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI). This study was aimed to evaluate whether the treatment effect of melatonin therapy in patients with STEMI is influenced by the time to administration. We performed a post hoc analysis of the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty trial (NCT00640094), which randomized STEMI patients to melatonin (intravenous and intracoronary bolus) or placebo during pPCI. Randomized patients were divided into tertiles according to symptoms onset to balloon time: first tertile (136 +/- 23 minutes), second tertile (196 +/- 19 minutes), and third tertile (249 +/- 41 minutes). Magnetic resonance imaging was performed within 1 week after pPCI. A total of 146 patients presenting with STEMI within 360 minutes of chest pain onset were randomly allocated to intravenous and intracoronary melatonin or placebo during pPCI. In the first tertile, the infarct size was significantly smaller in the melatonin-treated subjects compared with placebo (14.6 +/- 14.2 vs 24.9 +/- 9.0%; p = 0.003). Contrariwise, treatment with melatonin was associated with a larger infarct size in the group of patients included in the third tertile (20.5 +/- 8.7% vs 11.2 +/- 5.2%; p = 0.001), resulting in a significant interaction (p = 0.001). In conclusion, the administration of melatonin in patients with STEMI who presented early after symptom onset was associated with a significant reduction in the infarct size after pPCI. PMID- 28645478 TI - A TSPO ligand prevents mitochondrial sterol accumulation and dysfunction during myocardial ischemia-reperfusion in hypercholesterolemic rats. AB - A major cause of cell death during myocardial ischemia-reperfusion is mitochondrial dysfunction. We previously showed that the reperfusion of an ischemic myocardium was associated with an accumulation of cholesterol into mitochondria and a concomitant strong generation of auto-oxidized oxysterols. The inhibition of mitochondrial accumulation of cholesterol abolished the formation of oxysterols and prevented mitochondrial injury at reperfusion. The aim of this study was to investigate the impact of hypercholesterolemia on sterol and oxysterol accumulation in rat cardiac cytosols and mitochondria and to analyse the effect of the translocator protein ligand 4'-chlorodiazepam on this accumulation and mitochondrial function. Hypercholesterolemic ZDF fa/fa rats or normocholesterolemic lean rats were submitted to 30min of coronary artery occlusion followed by 15min reperfusion where cardiac cytosols and mitochondria were isolated. Hypercholesterolemia increased the cellular cardiac concentrations of cholesterol, cholesterol precursors and oxysterols both in cytosol and mitochondria in non-ischemic conditions. It also amplified the accumulation of all these compounds in cardiac cells and the alteration of mitochondrial function with ischemia-reperfusion. Administration of 4'-chlorodiazepam to ZDF fa/fa rats had no effect on the enhancement of sterols and oxysterols observed in the cytosols but inhibited cholesterol transfer to the mitochondria. It also alleviated the mitochondrial accumulation of all the investigated sterols and oxysterols. This was associated with a restoration of oxidative phosphorylation and a prevention of mitochondrial transition pore opening. The inhibition of cholesterol accumulation with TSPO ligands represents an interesting strategy to protect the mitochondria during ischemia-reperfusion in hypercholesterolemic conditions. PMID- 28645479 TI - Impact of the NAP-1 strain on disease severity, mortality, and recurrence of healthcare-associated Clostridium difficile infection. AB - OBJECTIVES: Studies are conflicting regarding the association of the North American pulsed-field gel electrophoresis type 1 (NAP1) strain in Clostridium difficile infection (CDI) and outcomes. We evaluated the association of NAP1 with healthcare-associated CDI disease severity, mortality, and recurrence at our academic medical center. METHODS: Healthcare-associated CDI cases were identified from November 1, 2011 through January 31, 2013. Multivariable regression models were used to evaluate the associations of NAP1 with severe disease (based on the Hines VA severity score index), mortality, and recurrence. RESULTS: Among 5424 stool specimens submitted to the Clinical Microbiology Laboratory, 292 (5.4%) were positive for C. difficile by polymerase chain reaction (PCR) on or after hospital day 4; 70 (24%) of these specimens also tested positive for NAP1. During the study period, 247 (85%) patients had non-severe disease and 45 (15%) patients had severe disease. Among patients with non-severe disease, 65 (26%) had NAP1 and among patients with severe disease, 5 (11%) had NAP1. After controlling for potential confounders, NAP1 was not associated with an increased likelihood of severe disease (adjusted odds ratio [aOR] = 0.35; 95% confidence interval [CI], 0.13-0.93), in-hospital mortality (aOR = 1.02; 95% CI, 0.53-1.96), or recurrence (aOR = 1.16, 95% CI, 0.36-3.77). CONCLUSIONS: The NAP1 strain did not increase disease severity, mortality, or recurrence in this study, although the incidence of NAP1-positive healthcare associated-CDI was low. The role of strain typing in outcomes and treatment selection in patients with healthcare-associated CDI remains uncertain. PMID- 28645480 TI - Comparative performance of Aspergillus galactomannan ELISA and PCR in sputum from patients with ABPA and CPA. AB - OBJECTIVES: Galactomannan (GM) and Aspergillus DNA detection are useful tools for the diagnosis of invasive pulmonary aspergillosis (IPA), primarily in blood and bronchoscopy samples. This study aimed to evaluate the utility of both markers for detection of Aspergillus in sputum from patients with allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). METHODS: ABPA or CPA demographic patient data were retrieved. This retrospective observational audit included 159 patients with at least one sputum pair. 223 sputum sample pairs were analysed, as well as six control samples for GM only. Real time PCR was performed following sputum DNA extraction using the MycAssayTM Aspergillus kit and cycle thresholds were subtracted from 38 to give positive values (transformed Ct, TCt). RESULTS: The mean age of the patients was 61.81years (SD: +/-11.06; range 29-100). One hundred and twenty-six (79.2%) had CPA. Cultures were positive for fungi in 13.1% of the samples, and A. fumigatus was the commonest (11.9%) fungus isolated. Receiver operating characteristic (ROC curve) analysis of sputum GM comparing TCt of >0.0, and >2.0 to derive GMI cut off values showed a cut-off of 6.5. About 50% of sputa with strongly positive PCR values had GM values>6.5. Two of six (33%) control samples had GM indices>6.5. CONCLUSION: It is not clear that GM determinations in sputum are useful for diagnosis of either CPA or ABPA, or following therapy. PMID- 28645481 TI - Subcellular localization of glycolytic enzymes and characterization of intermediary metabolism of Trypanosoma rangeli. AB - Trypanosoma rangeli is a hemoflagellate protist that infects wild and domestic mammals as well as humans in Central and South America. Although this parasite is not pathogenic for human, it is being studied because it shares with Trypanosoma cruzi, the etiological agent of Chagas' disease, biological characteristics, geographic distribution, vectors and vertebrate hosts. Several metabolic studies have been performed with T. cruzi epimastigotes, however little is known about the metabolism of T. rangeli. In this work we present the subcellular distribution of the T. rangeli enzymes responsible for the conversion of glucose to pyruvate, as determined by epifluorescense immunomicroscopy and subcellular fractionation involving either selective membrane permeabilization with digitonin or differential and isopycnic centrifugation. We found that in T. rangeli epimastigotes the first six enzymes of the glycolytic pathway, involved in the conversion of glucose to 1,3-bisphosphoglycerate are located within glycosomes, while the last four steps occur in the cytosol. In contrast with T. cruzi, where three isoenzymes (one cytosolic and two glycosomal) of phosphoglycerate kinase are expressed simultaneously, only one enzyme with this activity is detected in T. rangeli epimastigotes, in the cytosol. Consistent with this latter result, we found enzymes involved in auxiliary pathways to glycolysis needed to maintain adenine nucleotide and redox balances within glycosomes such as phosphoenolpyruvate carboxykinase, malate dehydrogenase, fumarate reductase, pyruvate phosphate dikinase and glycerol-3-phosphate dehydrogenase. Glucokinase, galactokinase and the first enzyme of the pentose-phosphate pathway, glucose-6 phosphate dehydrogenase, were also located inside glycosomes. Furthermore, we demonstrate that T. rangeli epimastigotes growing in LIT medium only consume glucose and do not excrete ammonium; moreover, they are unable to survive in partially-depleted glucose medium. The velocity of glucose consumption is about 40% higher than that of procyclic Trypanosoma brucei, and four times faster than by T. cruzi epimastigotes under the same culture conditions. PMID- 28645482 TI - Proton Pump Inhibitors and Survival Outcomes in Patients With Metastatic Renal Cell Carcinoma. AB - INTRODUCTION: Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and can affect the optimal absorption of concomitant oral medications, such as vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs). The purpose of this study was to investigate the effect of PPI use on survival in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. MATERIALS AND METHODS: We conducted a pooled analysis of mRCC patients treated in phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS: We identified 2188 patients treated with sunitinib (n = 952), axitinib (n = 626) or sorafenib (n = 610), of whom 120 were PPI users. Overall, PPI users showed similar overall survival compared with non-PPI users (hazard ratio [HR], 1.051; 95% confidence interval [CI], 0.769-1.438; P = .754; median, 24.1 vs. 21.3 months). Similarly, progression-free survival (HR, 1.016; 95% CI, 0.793-1.301; P = .902; median, 5.5 vs. 8.0 months) and objective response rates (23.3% vs. 27.4%; P = .344) were not different between PPI users and nonusers. These findings were consistent across International mRCC Database Consortium risk groups and according to line of therapy. Adverse events were similar between PPI users and nonusers. CONCLUSION: We showed that PPI use does not appear to negatively affect the efficacy and safety of select VEGF-TKIs in patients with mRCC. Documentation of concomitant medications and patient education on potential drug interactions are critical for optimizing the use of oral cancer-targeting therapy. PMID- 28645483 TI - Chemosensitivity of Immature Teratoma in a Man. PMID- 28645484 TI - Immune Check Point Inhibition in Sarcomatoid Renal Cell Carcinoma: A New Treatment Paradigm. PMID- 28645485 TI - Eli Ruckenstein - A Rare Researcher, Teacher, and Mentor par Excellence. PMID- 28645486 TI - Adaptive Genetic Exchange: A Tangled History of Admixture and Evolutionary Innovation. AB - Genetic exchange between divergent evolutionary lineages, from introgressive hybridization between locally adapted populations to insertion of retroviral sequences into eukaryotic genomes, has now been documented. The detection of frequent divergence-with-gene-flow contrasts the neo-Darwinian paradigm of largely allopatric diversification. Nevertheless, of even greater significance is the growing wealth of data suggesting that the recipients of the transferred genomic material gain adaptive phenotypes from the donor lineages. This adaptive enrichment is reflected by changes in pathogenicity in viruses and bacteria, the transformation of ecological amplitude in eukaryotes, and adaptive radiations in extremely diverse lineages. Although genetic exchange may produce maladaptive consequences, most of the recently reported examples suggest increases in fitness, and many such adaptive trait transfers have been identified in our own species. PMID- 28645487 TI - Equipping the 22nd-Century Historical Ecologist. AB - Historical ecology provides information needed to understand contemporary conditions and make science-based resource management decisions. Gaps in historical records, however, can limit inquiries and inference. Unfortunately, the patchiness of data that poses challenges for today's historical ecologist may be similarly problematic for those in the future seeking to understand what are currently present-day conditions and trends, in part because of societal underinvestment in systematic collection and curation. We therefore highlight the generational imperative that contemporary scientists and managers individually have - especially in this era of tremendous global change - to ensure sufficient documentation of the past and current conditions of the places and resources to which they have access. PMID- 28645488 TI - Characterization and expression patterns of key ecdysteroid biosynthesis and signaling genes in a spider mite (Panonychus citri). AB - Ecdysteroids play a crucial role in regulating molting in the phylum of Arthropoda and much is known with members of the subphylum of Hexapoda including the Insecta. However, this is still unclear in key pests as spider mites belonging to the subphylum of Chelicerata that originated earlier in the Cambrian period. In this study, we investigated 14 key genes of ecdysteroid biosynthesis and signaling and their expression over the different developmental stages in the citrus red mite, Panonychus citri (Acari: Stigmaeidae). P. citri is an economically important and widespread pest of citrus crops and it has five developmental stages of egg, larva, protonymph, deutonymph and adult. Typically, the expression of the ecdysteroid-synthesizing Halloween gene Spook (PcSpo) followed a positive zigzag-like pattern with a peak in the first half of each developmental stage and a drop in the second half prior to the molting to the next stage. Similar to PcSpo, PcDib, PcSad, PcRXR2, PcE75 and PcHR38 showed a positive zigzag-like expression pattern, while that of PcE78, PcHR3 and PcFTZ-F1 was opposite that we called a negative zigzag-like pattern. Silencing of the PcSpo gene by RNAi showed that molting was inhibited. Interestingly, we could rescue these RNAi effects by supplementing ponasterone A (PonA) and not by 20E, which is indicative that mites use PonA rather than 20E as ecdysteroid hormone. Modeling of the ecdysteroid receptor (PcEcR) hormone binding cavity also predicted binding of PonA, but showed a steric hindrance for 20E. We believe our data provide insight into the evolution and expression patterns of key ecdysteroid biosynthesis and signaling genes in a distant, non-insect species, and can become a foundation to develop new targets for controlling important agricultural pests such as spider mites. PMID- 28645490 TI - Re: Radiation with or Without Antiandrogen Therapy in Recurrent Prostate Cancer. PMID- 28645489 TI - Effects of hypnotic bromovalerylurea on microglial BV2 cells. AB - An old sedative and hypnotic bromovalerylurea (BU) has anti-inflammatory effects. BU suppressed nitric oxide (NO) release and proinflammatory cytokine expression by lipopolysaccharide (LPS)-treated BV2 cells, a murine microglial cell line. However, BU did not inhibit LPS-induced nuclear translocation of nuclear factor kappaB and subsequent transcription. BU suppressed LPS-induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF1). The Janus kinase 1 (JAK1) inhibitor filgotinib suppressed the NO release much more weakly than that of BU, although filgotinib almost completely prevented LPS-induced STAT1 phosphorylation. Knockdown of JAK1, STAT1, or IRF1 did not affect the suppressive effects of BU on LPS-induced NO release by BV2 cells. A combination of BU and filgotinib synergistically suppressed the NO release. The mitochondrial complex I inhibitor rotenone, which did not prevent STAT1 phosphorylation or IRF1 expression, suppressed proinflammatory mediator expression less significantly than BU. BU and rotenone reduced intracellular ATP (iATP) levels to a similar extent. A combination of rotenone and filgotinib suppressed NO release by LPS-treated BV2 cells as strongly as BU. These results suggest that anti-inflammatory actions of BU may be attributable to the synergism of inhibition of JAK1/STAT1-dependent pathways and reduction in iATP level. PMID- 28645491 TI - Systematic Review of Immune Checkpoint Inhibition in Urological Cancers. AB - CONTEXT: In patients with advanced and metastatic urological cancers, clinical outcome may be improved by immune checkpoint inhibitors (ICIs). OBJECTIVE: To systematically review relevant literature on efficacy and safety of ICIs in patients with advanced and metastatic urothelial cell cancer (UCC), renal cell cancer (RCC), and prostate cancer. EVIDENCE ACQUISITION: Relevant databases, including Medline, Embase, and the Cochrane Library, were searched up to March 16, 2017. A narrative review of randomized clinical trials (RCTs) was performed. EVIDENCE SYNTHESIS: Six RCTs were included for the systematic review. In platinum pretreated UCC, efficacy of pembrolizumab was superior to chemotherapy, with longer median overall survival (OS; 10.3 vs 7.4 mo), a higher objective response rate (ORR; 21.1% vs 11.4%, p=0.001), and a lower adverse event rate (60.9% vs 90.2%). Three RCTs assessed the safety and efficacy of nivolumab in advanced RCC. The median OS (25.0 vs 19.6 mo) and the ORR (25% vs 5%) were higher in patients treated with nivolumab compared with second-line everolimus. In all three studies, the safety profile of nivolumab was favorable. In patients with metastatic castration-resistant prostate cancer, two RCTs were identified, which did not show significant benefits for ipilimumab over placebo. In UCC and RCC, there was no conclusive association between programmed cell death receptor ligand 1 (PD-L1) expression in tumor tissue and clinical outcome during pembrolizumab and nivolumab treatment, respectively. CONCLUSION: In metastatic UCC and RCC, pembrolizumab and nivolumab have superior efficacy and safety to second-line chemotherapy and everolimus, respectively. No beneficial effect of ipilimumab was observed in prostate cancer patients. PD-L1 expression status is currently not suitable as a predictive marker for treatment outcome. PATIENT SUMMARY: Immune checkpoint inhibitors are able to reactivate the immune system against tumor cells. In second-line setting, pembrolizumab and nivolumab are safe and confer survival benefit in advanced urothelial cell and renal cell cancer, respectively. PMID- 28645492 TI - Advances in stable isotope assisted labeling strategies with information science. AB - Stable-isotope (SI) labeling of proteins is an essential technique to investigate their structures, interactions or dynamics by nuclear magnetic resonance (NMR) spectroscopy. The assignment of the main-chain signals, which is the fundamental first step in these analyses, is usually achieved by a sequential assignment method based on triple resonance experiments. Independently of the triple resonance experiment-based sequential assignment, amino acid-selective SI labeling is beneficial for discriminating the amino acid type of each signal; therefore, it is especially useful for the signal assignment of difficult targets. Various combinatorial selective labeling schemes have been developed as more sophisticated labeling strategies. In these strategies, amino acids are represented by combinations of SI labeled samples, rather than simply assigning one amino acid to one SI labeled sample as in the case of conventional amino acid selective labeling. These strategies have proven to be useful for NMR analyses of difficult proteins, such as those in large complex systems, in living cells, attached or integrated into membranes, or with poor solubility. In this review, recent advances in stable isotope assisted labeling strategies will be discussed. PMID- 28645493 TI - Sprayable Carbopol hydrogel with soluble beta-1,3/1,6-glucan as an active ingredient for wound healing - Development and in-vivo evaluation. AB - Chronic wounds represent a significant health problem worldwide. There is a need for advanced- and cost-efficient wound healing products able to increase patient comfort and reduce the healing time. The aim of this study was to develop a sprayable hydrogel dressing with beta-glucan (betaG) as the active ingredient, targeting future application in the treatment of both chronic and burn wounds. The betaG was chosen as an active ingredient because of its promising wound healing capabilities, whereas Carbopol 971P NF (Carbopol) was chosen as the thickening agent in the formulation due to several attractive characteristics such as its low viscosity, low toxicity, high transparency and good ion tolerance. Four different hydrogel formulations were prepared with varying Carbopol concentrations. The higher Carbopol concentration, 0.5% (w/w), was used to prepare three formulations comprising the HighCP:NobetaG, HighCP:LowbetaG and the HighCP:MediumbetaG formulation, respectively. Lower Carbopol concentration, 0.25% (w/w), was used to prepare the LowCP:HighbetaG formulation. The content of betaG varied from 0.25% in the HighCP:LowbetaG, 0.5% in the HighCP:MediumbetaG and 1.0% (w/w) in the LowCP:HighbetaG formulation, respectively. The first part of the study focused on the rheological characterization of the hydrogels and the fluid affinity testing. All formulations were confirmed to be stable gels; the betaG was shown to augment the gel strength by increasing the yield strength of the gel in a dose dependent manner. The stability of the formulations containing either Carbopol alone or in a combination with betaG did not deteriorate over 26weeks, and the fluid donation and absorption study indicated a fluid donation profile, which favors healing of dry wounds. The in vivo efficacy of the formulations, evaluated in the modified diabetic male mice (db/db mice), showed that Carbopol alone was unable to induce improved healing and caused adverse reactions in some wounds. The inclusion of betaG increased the epithelialization and wound contraction in the db/db mice when given at high betaG:Carbopol ratio. The positive effect of betaG was, however, not sufficient to counteract the adverse effect of Carbopol, thus a more suitable thickening agent should be investigated for further development of a sprayable wound care product. PMID- 28645494 TI - Venous or arterial blood components trigger more brain swelling, tissue death after acute subdural hematoma compared to elderly atrophic brain with subdural effusion (SDE) model rats. AB - Acute subdural hematoma (ASDH) is a frequent complication of severe head injury, whose secondary ischemic lesions are often responsible for the severity of the disease. We focused on the differences of secondary ischemic lesions caused by the components, 0.4ml venous- or arterial-blood, or saline, infused in the subdural space, evaluating the differences in vivo model, using rats. The saline infused rats are made for elderly atrophic brain with subdural effusion (SDE) model. Our data showed that subdural blood, both venous- and arterial-blood, aggravate brain edema and lesion development more than SDE. This study is the first study, in which different fluids in rats' subdural space, ASDH or SDE are compared with the extension of early and delayed brain damage by measuring brain edema and histological lesion volume. Blood constituents started to affect the degree of ischemia underneath the subdural hemorrhage, leading to more pronounced breakdown of the blood-brain barrier and brain damage. This indicates that further strategies to treat blood-dependent effects more efficiently are in view for patients with ASDH. PMID- 28645495 TI - Validity and reliability of the myTemp ingestible temperature capsule. AB - OBJECTIVES: An accurate and non-invasive measurement of core body temperature (Tc) is of great importance to quantify exercise-induced increases in Tc in athletes or to assess changes in Tc in patient populations. The use of ingestible gastrointestinal telemetric temperature capsules is widely accepted as a surrogate marker for Tc, but widespread implementation is lacking due to the high costs of these disposable capsules. A new and cheaper temperature capsule system (i.e. myTemp) was recently introduced. The aim of present study is to determine the validity and test-retest reliability of the myTemp system. DESIGN: Ex-vivo experimental study. METHODS: Fifteen ingestible temperature capsules (myTemp, Nijmegen, Netherlands) were tested in a highly temperature controlled water bath, in which the water temperature gradually increased from 34 degrees C to 44 degrees C. The study protocol was performed twice for each temperature capsule. RESULTS: Mean difference between myTemp temperature and water bath temperature was -0.001+/-0.005 degrees C (Limit of Agreement (LOA): +/-0.011 degrees C) during Trial 1 (p=0.11) and -0.001+/-0.006 degrees C (LOA: +/-0.012 degrees C) during Trial 2 (p=0.039). Furthermore, an Intraclass Correlation Coefficient (ICC) of 1.00 was found for both trials. A systematic difference between Trials 1 and 2 of 0.004+/-0.008 degrees C (LOA: +/-0.015 degrees C) was found (p<0.001), whereas the ICC between both trials was 1.00 and the standard error of measurement was 0.005 degrees C. CONCLUSIONS: Although we found a systematic bias for the sensitivity (-0.001 degrees C) and reliability (0.004 degrees C), these values can be considered insignificant from a physiological and clinical perspective. Thus, the myTemp ingestible temperature capsule is a valid technique to measure (water) temperature under controlled circumstances. PMID- 28645496 TI - Determining the best percent-predicted equation for estimated VO2 peak by a 1-km moderate perceptually-regulated treadmill walk to predict mortality in outpatients with cardiovascular disease. AB - OBJECTIVES: To determine the prognostic ability of established percent-predicted equations of peak oxygen consumption (%PRED) estimated by a moderate submaximal walking test in a large cohort of outpatients with cardiovascular disease (CVD). DESIGN: Population-based prospective study. METHODS: A total of 1442 male patients aged 25-85 years at baseline, underwent a moderate perceptually regulated (11-13 on the 6-20 Borg scale) treadmill walk (1k-TWT) for peak oxygen consumption estimation (VO2 peak). %PRED was derived from ACSM, Ades et al, Morris et al, and the Wasserman/Hansen equations, and their prognostic performance was assessed. Overall mortality was the end point. Participants were divided into quartiles of %PRED, and mortality risk was estimated using a Cox regression model. RESULTS: During a median 8.2year follow-up, 167 all-cause deaths occurred. The Wasserman/Hansen equation provided the highest prognostic value. Mortality rate was lower across increasing quartiles of %PRED. Compared to the first quartile, after adjustment for confounders, the mortality risk decreased for the second, third, and fourth quartiles, with HRs of 0.75 (95% CI 0.44-1.29, p=0.29), 0.67 (95% CI 0.38-1.18, p=0.17), and 0.37 (95% CI 0.10-0.78, p=0.009), respectively (p for trend <0.0001). Each 1% increase in %PRED conferred a 4% improvement in survival. CONCLUSIONS: The percent-predicted VO2 peak determined by Wasserman/Hansen equations applied to the 1k-TWT is inversely and significantly related to survival in cardiac outpatients. The 1k-TWT is a simple and useful tool for stratifying mortality risk in patients participating in secondary prevention programs. PMID- 28645497 TI - An association between polymorphisms within the APOE gene and concussion aetiology in rugby union players. AB - OBJECTIVES: Concussion refers to changes in neurological function due to biomechanical forces transmitted to the head. The APOE epsilon4 allele is associated with brain injury severity. The objective was to determine if APOE gene variants are associated with concussion history and severity in rugby players. DESIGN: In total, 128 non-concussed controls and 160 previously concussed participants (all cases N=160; diagnosed N=139) were recruited from high school (junior, N=121), club (N=116) and professional rugby teams (N=51). METHODS: Participants were genotyped for rs405509 (G>T), rs429358 (T>C) and rs7412 (C>T) APOE variants. Statistical analyses were performed using the R environment. RESULTS: The rs405509 TT genotype was over-represented in controls compared to all cases (P=0.043; control: 29%, all cases: 18%; odds ratio: 0.55, 95% confidence interval 0.31-0.98). The APOE-epsilon isoform frequencies were not significantly different between groups (P>0.05). Additionally, the inferred APOE (rs405509-epsilon2/epsilon3/epsilon4) T-epsilon3 haplotype was over-represented in controls (41%) compared to diagnosed (32%, P=0.042). The G-epsilon3 haplotype was under-represented in controls (36%) compared to all cases (44%, P=0.019) and diagnosed (44%, P=0.021). The TT genotype was significantly associated with rapid recovery (P=0.048, <1 week: 51%, N=70, >=1 week: 36%, N=29; odds ratio: 0.55, 95% confidence interval 0.30-1.01). CONCLUSIONS: These findings support the further elucidation of the APOE gene or closely-related genes in concussion aetiology. Although similar preliminary results were found when juniors were separately analysed, the under-powered sample size for junior subgroup requires future investigation in larger cohorts of junior-level athletes. PMID- 28645498 TI - Pulmonary Artery Embolization after Blunt Trauma. PMID- 28645499 TI - An Ideal Opportunity for Interventional Radiologists to Advance Shared Decision Making. PMID- 28645500 TI - Percutaneous Anterior Ureterostomy for Double J Ureteral Stent Placement in an 18 Month-Old Patient. PMID- 28645501 TI - Bigger Is Better: Refinement of an Animal Model of Hepatocellular Carcinoma and Transfemoral Arterial Embolization. PMID- 28645502 TI - HydroCoil Embolization of an Infected Ascending Aortic Pseudoaneurysm. PMID- 28645503 TI - On-Site Fenestration of a Peripheral Covered Stent for the Treatment of a Complex Subclavian Artery Injury. PMID- 28645504 TI - Single-Session Endolymphatic Thoracic Duct Stent-Graft Placement for Recurrent Idiopathic Chylothorax. PMID- 28645505 TI - Treatment of Chylous Ascites in a Child after Wilms Tumor Resection with Intranodal Injection of N-Butyl Cyanoacrylate Glue. PMID- 28645506 TI - Preoperative Percutaneous Microwave Ablation of Long Bone Metastases Using a Parallel Medullary Approach for Reduction of Operative Blood Loss. PMID- 28645507 TI - The Role of Interventional Radiologists in the Use of Extracorporeal Membranous Oxygenation in the Catheter-Directed Treatment of Pulmonary Embolism. AB - Patients with pulmonary embolism who are in hemodynamically unstable condition present a special challenge to the interventionalist. When treating such patients, extracorporeal membranous oxygenation (ECMO) can help to stabilize these patients' condition; however, specific criteria for its use do not exist. Two patients are presented here to familiarize the reader with the use of ECMO and to demonstrate its utility for the interventional radiologist. PMID- 28645508 TI - Merkel cell carcinoma, melanoma, metastatic mimics of breast cancer. AB - Merkel cell carcinoma and melanoma can each occur primarily in breast skin, or metastasize to the breast. The breast is a rare site of metastasis of essentially any and every type of tumor, including carcinomas, sarcomas, and hematolymphoid neoplasms, and 10-30% of breast metastases may represent the initial presentation of disease. Although metastases generally recapitulate histologic features of the primary tumor, they are diagnostically challenging given their rarity and morphologic overlap with breast carcinoma, including special types of breast cancer. Histologic clues may include lack of carcinoma in situ, lack of central elastosis, pattern of infiltration around normal breast structures, yet none of these are specific. Careful correlation with clinical history and judicious use of immunostain panels is essential in approaching these cases. PMID- 28645510 TI - The nonlinear flexural response of a whole teleost fish: Contribution of scales and skin. AB - The scaled skin of fish is an intricate system that provides mechanical protection against hard and sharp puncture, while maintaining the high flexural compliance required for unhindered locomotion. This unusual combination of local hardness and global compliance makes fish skin an interesting model for bioinspired protective systems. In this work we investigate the flexural response of whole teleost fish, and how scales may affect global flexural stiffness. A bending moment is imposed on the entire body of a striped bass (Morone saxatilis). Imaging is used to measure local curvature, to generate moment curvature curves as function of position along the entire axis of the fish. We find that the flexural stiffness is the highest in the thick middle portion of the fish, and lowest in the caudal and rostral ends. The flexural response is nonlinear, with an initial soft response followed by significant stiffening at larger flexural deformations. Low flexural stiffness at low curvatures promotes efficient swimming, while higher stiffness at high curvatures enables a possible tendon effect, where the mechanical energy at the end of a stroke is stored in the form of strain energy in the fish skin. To assess the contribution of the scales to stiffening we performed flexural tests with and without scales, following a careful protocol to take in account tissue degradation and the effects of temperature. Our findings suggest that scales do not substantially increase the whole body flexural stiffness of teleost fish over ranges of deformations which are typical of swimming and maneuvering. Teleost scales are thin and relatively flexible, so they can accommodate large flexural deformations. This finding is in contrast to the bulkier ganoid scales which were shown in previous reports to have a profound impact of global flexural deformations and swimming in fish like gar or Polypterus. PMID- 28645509 TI - A fast and reliable method for daily quality assurance in spot scanning proton therapy with a compact and inexpensive phantom. AB - In a radiotherapy center, daily quality assurance (QA) measurements are performed to ensure that the equipment can be safely used for patient treatment on that day. In a pencil beam scanning (PBS) proton therapy center, spot positioning, spot size, range, and dose output are usually verified every day before treatments. We designed, built, and tested a new, reliable, sensitive, and inexpensive phantom, coupled with an array of ionization chambers, for daily QA that reduces the execution times while preserving the reliability of the test. The phantom is provided with 2 pairs of wedges to sample the Bragg peak at different depths to have a transposition on the transverse plane of the depth dose. Three "boxes" are used to check spot positioning and delivered dose. The box thickness helps spread the single spot and to fit a Gaussian profile on a low resolution detector. We tested whether our new QA solution could detect errors larger than our action levels: 1 mm in spot positioning, 2 mm in range, and 10% in spot size. Execution time was also investigated. Our method is able to correctly detect 98% of spots that are actually in tolerance for spot positioning and 99% of spots out of 1 mm tolerance. All range variations greater than the threshold (2 mm) were correctly detected. The analysis performed over 1 month showed a very good repeatability of spot characteristics. The time taken to perform the daily quality assurance is 20 minutes, a half of the execution time of the former multidevice procedure. This "in-house build" phantom substitutes 2 very expensive detectors (a multilayer ionization chamber [MLIC] and a strip chamber, reducing by 5 times the cost of the equipment. We designed, built, and validated a phantom that allows for accurate, sensitive, fast, and inexpensive daily QA procedures in proton therapy with PBS. PMID- 28645511 TI - Lamellae spatial distribution modulates fracture behavior and toughness of african pangolin scales. AB - Pangolin scales form a durable armor whose hierarchical structure offers an avenue towards high performance bio-inspired materials design. In this study, the fracture resistance of African pangolin scales is examined using single edge crack three-point bend fracture testing in order to understand toughening mechanisms arising from the structures of natural mammalian armors. In these mechanical tests, the influence of material orientation and hydration level are examined. The fracture experiments reveal an exceptional fracture resistance due to crack deflection induced by the internal spatial orientation of lamellae. An order of magnitude increase in the measured fracture resistance due to scale hydration, reaching up to ~ 25kJ/m2 was measured. Post-mortem analysis of the fracture samples was performed using a combination of optical and electron microscopy, and X-ray computerized tomography. Interestingly, the crack profile morphologies are observed to follow paths outlined by the keratinous lamellae structure of the pangolin scale. Most notably, the inherent structure of pangolin scales offers a pathway for crack deflection and fracture toughening. The results of this study are expected to be useful as design principles for high performance biomimetic applications. PMID- 28645512 TI - The RNA-seq analysis suggests a potential multi-component complement system in oyster Crassostrea gigas. AB - The complement system is one of the major effector mechanisms of immune system, playing essential roles in both the innate and adaptive immune responses. In the present study, the counterparts of vertebrate complement components were identified by screening the sequenced genome of Crassostrea gigas, resulting in the identification of 792 gene models containing complement-related domains. The transcriptome of haemocytes at 6, 12 and 24 h post lipopolysaccharides (LPS) stimulation showed differential expression of 77 C1q domain containing proteins, 53 C-type lectins and 42 fibrinogen-related proteins. mRNAs encoding 18 serine protease domain-containing (SPC) proteins, 4 MACPF-domain containing proteins and 11 C3 receptor-like proteins were up-regulated upon LPS stimulation, and CgC3 mRNA was significantly increased at 12 h. The presence of CgC3 was confirmed in cell free plasma and was present in three subunit chains as expected for the processed mature protein. The complement related PRRs with coiled coil regions and SPC proteins with CUB domains may function in the activation of CgC3, whereas, the C3-like receptors with integrin-alpha/beta domain mediated the phagocytosis of C3-labled pathogens. These PRRs appear to serve as opsonins to promote phagocytosis of opsonized pathogens. The overall results suggested the existence of a potential multi-component complement system in C. gigas. PMID- 28645513 TI - Atrial Fibrillation: Current Therapies. AB - A rate control, or a rhythm control, strategy can be applied to the management of atrial fibrillation. Rate control of atrial fibrillation consists of decreasing the ventricular response rate by limiting the number of supraventricular impulses that can travel through the atrioventricular node. The goal of decreasing heart rate in dogs with atrial fibrillation is usually achieved with a combination of the calcium channel blocker diltiazem and digoxin. Rhythm control of atrial fibrillation encompasses pharmacologic and nonpharmacologic methods to terminate the arrhythmia and restore sinus rhythm. Transthoracic synchronized electrical cardioversion is commonly used to stop atrial fibrillation. PMID- 28645514 TI - Bcl-xL deamidation and cancer: Charting the fame trajectories of legitimate child and hidden siblings. AB - Bcl-2 family proteins control programmed cell death through a complex network of interactions within and outside of this family, that are modulated by post translational modifications (PTM). Bcl-xL, an anti-apoptotic member of this family, is overexpressed in a number of cancers, plays an important role in tumorigenesis and is correlated with drug resistance. Bcl-xL is susceptible to a number of different PTMs. Here, we focus on deamidation. We will first provide an overview of protein deamidation. We will then review how the apoptotic and autophagic functions of Bcl-xL are modified by this PTM, and how this impacts on its oncogenic properties. Possible therapeutic outcomes will also be discussed. Finally, we will highlight how the specific case of Bcl-xL deamidation provides groundings to revisit some concepts related to protein deamidation in general. PMID- 28645516 TI - The Search Continues for Optimal Intensive Care Unit Glucose Management and Measurement. PMID- 28645517 TI - Glucose Control, Diabetes Status, and Mortality in Critically Ill Patients: The Continuum From Intensive Care Unit Admission to Hospital Discharge. AB - OBJECTIVE: To describe the relationships among glycemic control, diabetes mellitus (DM) status, and mortality in critically ill patients from intensive care unit (ICU) admission to hospital discharge. PATIENTS AND METHODS: This is a retrospective investigation of 6387 ICU patients with 5 or more blood glucose (BG) tests and 4462 ICU survivors admitted to 2 academic medical centers from July 1, 2010, through December 31, 2014. We studied the relationships among mean BG level, hypoglycemia (BG level <70 mg/dL [to convert to mmol/L, multiply by 0.0555]), high glucose variability (coefficient of variation >=20%), DM status, and mortality. RESULTS: The ICU mortality for patients without DM with ICU mean BG levels of 80 to less than 110, 110 to less than 140, 140 to less than 180, and at least 180 mg/dL was 4.50%, 7.30%, 12.16%, and 32.82%, respectively. Floor mortality for patients without DM with these BG ranges was 2.74%, 2.64%, 7.88%, and 5.66%, respectively. The ICU and floor mean BG levels of 80 to less than 110 and 110 to less than 140 mg/dL were independently associated with reduced ICU and floor mortality compared with mean BG levels of 140 to less than 180 mg/dL in patients without DM (odds ratio [OR] [95% CI]: 0.43 (0.28-0.66), 0.62 (0.45 0.85), 0.41 (0.23-0.75), and 0.40 (0.25-0.63), respectively) but not in patients with DM. Both ICU and floor hypoglycemia and increased glucose variability were strongly associated with ICU and floor mortality in patients without DM, and less so in those with DM. The independent association of dysglycemia occurring in either setting with mortality was cumulative in patients without DM. CONCLUSION: These findings support the importance of glucose control across the entire trajectory of hospitalization in critically ill patients and suggest that the BG target of 140 to less than 180 mg/dL is not appropriate for patients without DM. The optimal BG target for patients with DM remains uncertain. PMID- 28645515 TI - Adaptations in rod outer segment disc membranes in response to environmental lighting conditions. AB - The light-sensing rod photoreceptor cell exhibits several adaptations in response to the lighting environment. While adaptations to short-term changes in lighting conditions have been examined in depth, adaptations to long-term changes in lighting conditions are less understood. Atomic force microscopy was used to characterize the structure of rod outer segment disc membranes, the site of photon absorption by the pigment rhodopsin, to better understand how photoreceptor cells respond to long-term lighting changes. Structural properties of the disc membrane changed in response to housing mice in constant dark or light conditions and these adaptive changes required output from the phototransduction cascade initiated by rhodopsin. Among these were changes in the packing density of rhodopsin in the membrane, which was independent of rhodopsin synthesis and specifically affected scotopic visual function as assessed by electroretinography. Studies here support the concept of photostasis, which maintains optimal photoreceptor cell function with implications in retinal degenerations. PMID- 28645518 TI - Blood Gas Analyzer Accuracy of Glucose Measurements. AB - OBJECTIVE: To investigate the comparability of glucose levels measured with blood gas analyzers (BGAs) and by central laboratories (CLs). MATERIAL AND METHODS: Glucose measurements obtained between June 1, 2007, and March 1, 2016, at the Vanderbilt University Medical Center were reviewed. The agreement between CL and BGA results were assessed using Bland-Altman, consensus error grid (CEG), and surveillance error grid (SEG) analyses. We further analyzed the BGAs' performance against the US Food and Drug Administration (FDA) 2014 draft guidance and 2016 final guidance for blood glucose monitoring and the International Organization for Standardization (ISO) 15197:2013 standard. RESULTS: We analyzed 2671 paired glucose measurements, including 50 pairs of hypoglycemic values (1.9%). Bland Altman analysis yielded a mean bias of -3.1 mg/dL, with 98.1% of paired values meeting the 95% limits of agreement. In the hypoglycemic range, the mean bias was -0.8 mg/dL, with 100% of paired values meeting the 95% limits of agreement. When using CEG analysis, 99.9% of the paired values fell within the no risk zone. Similar results were found using SEG analysis. For the FDA 2014 draft guidance, our data did not meet the target compliance rate. For the FDA 2016 final guidance, our data partially met the target compliance rate. For the ISO standard, our data met the target compliance rate. CONCLUSION: In this study, the agreement for glucose measurement between common BGAs and CL instruments met the ISO 2013 standard. However, BGA accuracy did not meet the stricter requirements of the FDA 2014 draft guidance or 2016 final guidance. Fortunately, plotting these results on either the CEG or the SEG revealed no results in either the great or extreme clinical risk zones. PMID- 28645519 TI - The repellent efficacy of eleven essential oils against adult Dermacentor reticulatus ticks. AB - Dermacentor reticulatus ticks are among the most important arthropod vectors of zoonotic disease agents in Europe. Eleven essential oils, namely basil (Ocimum basilicum), bergamot (Citrus bergamia), clove bud (Syzygium aromaticum), citronella (Cymbopogon winterianus), creeping thyme (Thymus serpyllum), lavender (Lavandula angustifolia), lemon-scented gum (Corymbia citriodora), marjoram (Origanum majorana), peppermint (Mentha piperita), spearmint (M. spicata), and red thyme (Thymus vulgaris) were tested for repellency against adult D. reticulatus ticks at concentrations of 1 and 3%. Clove bud, creeping thyme and red thyme essential oils were the most efficient - repelling 83, 82 and 68% of ticks when diluted to 3%, respectively. The mixture of creeping thyme and citronella containing 1.5% of each showed higher repellency (91%) than individual essential oils at the concentration of 3%. PMID- 28645520 TI - Impact of birth weight on adult-onset diabetes mellitus in relation to current body mass index: The Japan Nurses' Health Study. AB - BACKGROUND: Although birth weight is considered as a fetal determinant of the development of adult-onset diabetes mellitus (DM), its public health importance relative to adult body mass index (BMI) remains unclear. We aimed to examine the association between adult-onset DM and birth weight in relation to adult BMI. METHODS: We conducted a self-administered questionnaire as a baseline survey of the Japanese Nurses' Health Study cohort between 2001 and 2007. Exclusion criteria were applied to the volunteer sample of 49,927 female nurses (age <30 years or unknown, current pregnancy, development of DM before the age of 30 years, unknown core variables), and data from 26,949 female nurses aged 30 years or older were used. The association between history of DM diagnosis and birth weight was analyzed using logistic regression. RESULTS: A linear inverse association was observed between birth weight and DM, after adjustment for age, BMI, and parental history of DM. The odds ratio for developing DM per 100 g increase in birth weight was 0.93 (95% confidence interval [CI], 0.90-0.96). The association was unchanged when birth weight was converted to percentile for gestational age. In the BMI-stratified analysis, the odds ratio for DM in the <2500 g birth weight group reached 4.75 (95% CI, 1.22-18.44, compared to the reference 3000-3499 g group) among women with normal low BMI (18.5-20.9). CONCLUSIONS: Birth weight and its percentile for gestational age were associated with adult-onset DM. Attention should be paid to the risk of DM among women born with low weight, even when their current BMI is normal. PMID- 28645521 TI - Platelet count and indoor cold exposure among elderly people: A cross-sectional analysis of the HEIJO-KYO study. AB - BACKGROUND: Excess mortality from cardiovascular disease during cold seasons is a worldwide issue. Although some physiologic studies suggests that platelet activation via cold exposure may cause an increased incidence of cardiovascular disease in winter, the influence of indoor cold exposure in real-life situations on platelet (PLT) count remains unclear. METHODS: A cross-sectional study was conducted among 1095 elderly individuals. After obtaining a venous sample in the morning, indoor temperature of participants' home was measured every 10 min for 48 h. The mean indoor temperature while the participants stayed at home was calculated. All measurement was conducted during cold seasons (October to April) from 2010 to 2014. RESULTS: The mean age of the 1095 participants was 71.9 years. They spent 87.3% of the day at home (20 h 27 min). A 1 degrees C lower daytime indoor temperature was associated with a significant increase in PLT count of 1.47 * 109/L (95% confidence interval, 0.39-2.56 * 109/L). Compared with the warmest tertile group (20.1 [standard deviation {SD}, 0.09] degrees C), the coldest group (11.7 [SD, 0.12] degrees C) showed a 5.2% higher PLT count (238.84 [SD, 3.30] vs. 226.48 [SD, 3.32] * 109/L; P = 0.01), even after adjusting for basic characteristics (age, gender, body weight, and smoking), antihypertensive medication, comorbidities (diabetes, estimated glomerular filtration rate), socioeconomic status (household income and education), day length, and outdoor temperature. CONCLUSIONS: We found a significant and independent association between lower indoor temperature and higher PLT count among elderly in winter. PMID- 28645522 TI - Acute effects of ambient temperature and particulate air pollution on fractional exhaled nitric oxide: A panel study among diabetic patients in Shanghai, China. AB - BACKGROUND: Epidemiological studies have shown the associations of ambient temperature and particulate matter (PM) air pollution with respiratory morbidity and mortality. However, the underlying mechanisms have not been well characterized. The aim of this study is to investigate the associations of temperature and fine and coarse PM with fractional exhaled nitric oxide (FeNO), a well-established biomarker of respiratory inflammation. METHODS: We conducted a longitudinal panel study involving six repeated FeNO tests among 33 type 2 diabetes mellitus patients from April to June 2013 in Shanghai, China. Hourly temperature and PM concentrations were obtained from a nearby fixed-site monitoring station. We then explored the associations between temperature, PM, and FeNO using linear mixed-effect models incorporated with distributed lag nonlinear models for the lagged and nonlinear associations. The interactions between temperature and PM were evaluated using stratification analyses. RESULTS: We found that both low and high temperature, as well as increased fine and coarse PM, were significantly associated with FeNO. The cumulative relative risk of FeNO was 1.75% (95% confidence interval [CI], 1.04-2.94) comparing 15 degrees C to the referent temperature (24 degrees C) over lags 0-9 days. A 10 MUg/m3 increase in fine and coarse PM concentrations were associated with 1.18% (95% CI, 0.18 2.20) and 1.85% (95% CI, 0.62-3.09) FeNO in lag 0-1 days, respectively. PM had stronger effects on cool days than on warm days. CONCLUSIONS: This study suggested low ambient temperature, fine PM, and coarse PM might elevate the levels of respiratory inflammation. Our findings may help understand the epidemiological evidence linking temperature, particulate air pollution, and respiratory health. PMID- 28645523 TI - Elevated Serum High-Mobility Group Box-1 Protein Level Is Associated with Poor Functional Outcome in Ischemic Stroke. AB - BACKGROUND: In experimental models, inhibition of high-mobility group box-1 (HMGB1) signaling has been reported to protect against the sequelae of ischemic stroke. Here, we determined the clinical significance of serum HMGB1 levels in patients with acute ischemic stroke. METHODS: We enrolled 183 patients (114 men, 69 women; mean age: 72.7 years) over 6 consecutive months. On admission and day 7, we recorded the National Institutes of Health Stroke Scale scores and measured serum high-sensitivity C-reactive protein (hs-CRP) and HMGB1 levels. Stroke volumes were estimated using diffusion-weighted magnetic resonance imaging performed on admission. One year later, clinical outcome was assessed using the modified Rankin Scale (mRS). RESULTS: Serum hs-CRP and HMGB1 levels in patients with ischemic stroke were increased relative to healthy controls (both P < .01). On day 7, hs-CRP, but not HMBG1, levels had increased significantly relative to levels at admission (P < .01 and .54, respectively). Higher HMGB1, but not hs CRP, levels at day 7 correlated with larger stroke volumes (P < .01 and .28, respectively). HMGB1 levels did not significantly differ between stroke subtypes. Multiple logistic regression analysis indicated that a serum HMGB1 level higher than 7.5 ng/mL was an independent risk factor for poor prognosis, defined as a 1 year mRS score of 3-6 (odds ratio, 2.34; 95% confidence interval, 1.02-5.38). CONCLUSIONS: Acute ischemic stroke is associated with elevated serum HMGB1 levels, and HMGB1 levels at admission independently predict poor outcome at 1 year. These results suggest that HMGB1 quantification provides more accurate prognostic information after ischemic stroke. PMID- 28645524 TI - Orientin Attenuates Cerebral Ischemia/Reperfusion Injury in Rat Model through the AQP-4 and TLR4/NF-kappaB/TNF-alpha Signaling Pathway. AB - BACKGROUND: Orientin has been reported to have extensive pharmaceutical effects of antioxidant, anti-inflammatory, antithrombosis, antiapoptosis, and so on. In the present study, we tried to investigate the protective effects of orientin on cerebral ischemia-reperfusion (I/R) injury and explored the possible mechanisms. METHODS: Middle cerebral artery occlusion rat model was established and then treated with low, middle, and high concentrations of orientin, respectively, with edaravone as a positive control. The treatment effect of orientin was evaluated by measuring the neurological deficit score, cerebral infarction, brain edema, oxidative stress, excitatory amino acids release, the expression levels of aquaporin-4 (AQP-4), and related inflammatory molecules using different methods including immunohistochemistry, enzyme-linked immunosorbent assay, real-time PCR, and western blot. Moreover, morphological and structural changes were also observed by hematoxylin-eosin staining and transmission electron microscope. RESULTS: Orientin provided a significant reduction on neurological deficits, cerebral infarction, cerebral edema, oxidative damage, and neurotoxicity of excitatory amino acids compared to model group (P < .05) in a dose-dependent manner. In addition, orientin substantially downregulated AQP-4 and inflammatory factors expression (P < .05) and improved cell morphology and structure in rats following I/R injury. CONCLUSION: Orientin was able to mediate noticeable protection against cerebral I/R injury through the attenuation of oxidative stress and neurotoxicity of amino acids and inhibiting the upregulation of AQP-4 and inflammatory cytokines. PMID- 28645525 TI - Placenta as alternative specimen to detect in utero cannabis exposure: A systematic review of the literature. AB - The use of cannabis during pregnancy and lactation is widely recognized as a health concern. The placenta is one of the several biological matrices that can be used to detect in utero drug exposure with the distinct advantage of easy and noninvasive collection. We conducted a PubMed search of selected literature published to June 30, 2016 to investigate the pharmacokinetics of cannabinoids, the active constituent of cannabis, in the placenta. The majority of the selected twelve papers was before 1990 and concerned animals at term gestation with great variability of experimental conditions. Only three were about human population and two of them reported equivocal findings on pre- term placenta. Our systematic review confirms that placental cannabis pharmacokinetics has been scarcely investigated and that further research is needed to determine advantages and disadvantages for monitoring maternal THC use or the degree of in utero exposure. PMID- 28645526 TI - Injury-induced gp130 cytokine signaling in peripheral ganglia is reduced in diabetes mellitus. AB - Neuropathy is a major diabetic complication. While the mechanism of this neuropathy is not well understood, it is believed to result in part from deficient nerve regeneration. Work from our laboratory established that gp130 family of cytokines are induced in animals after axonal injury and are involved in the induction of regeneration-associated genes (RAGs) and in the conditioning lesion response. Here, we examine whether a reduction of cytokine signaling occurs in diabetes. Streptozotocin (STZ) was used to destroy pancreatic beta cells, leading to chronic hyperglycemia. Mice were injected with either low doses of STZ (5*60mg/kg) or a single high dose (1*200mg/kg) and examined after three or one month, respectively. Both low and high dose STZ treatment resulted in sustained hyperglycemia and functional deficits associated with the presence of both sensory and autonomic neuropathy. Diabetic mice displayed significantly reduced intraepidermal nerve fiber density and sudomotor function. Furthermore, low and high dose diabetic mice showed significantly reduced tactile touch sensation measured with Von Frey monofilaments. To look at the regenerative and injury-induced responses in diabetic mice, neurons in both superior cervical ganglia (SCG) and the 4th and 5th lumbar dorsal root ganglia (DRG) were unilaterally axotomized. Both high and low dose diabetic mice displayed significantly less axonal regeneration in the sciatic nerve, when measured in vivo, 48h after crush injury. Significantly reduced induction of two gp130 cytokines, leukemia inhibitory factor and interleukin-6, occurred in diabetic animals in SCG 6h after injury compared to controls. Injury-induced expression of interleukin-6 was also found to be significantly reduced in the DRG at 6h after injury in low and high dose diabetic mice. These effects were accompanied by reduced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the gp130 signaling pathway. We also found decreased induction of several gp130-dependent RAGs, including galanin and vasoactive intestinal peptide. Together, these data suggest a novel mechanism for the decreased response of diabetic sympathetic and sensory neurons to injury. PMID- 28645527 TI - Inhibition of 17beta-hydroxysteroid dehydrogenase type 7 modulates breast cancer protein profile and enhances apoptosis by down-regulating GRP78. AB - 17beta-hydroxysteroid dehydrogenase type 7 (17beta-HSD7) promotes breast cancer cell growth via dual-catalytic activity by modulating estradiol and DHT. Here, we clarified the expression pattern of 17beta-HSD7 in postmenopausal luminal A type breast cancer with The Cancer Genome Atlas (TCGA) cohort. The impact of 17beta HSD7 inhibition on the proteome of MCF-7 cells was investigated and on cell apoptosis was revealed. MCF-7 cells were treated with an efficient inhibitor of 17beta-HSD7 (INH7) or with vehicle, and a differential proteomics study was performed using two-dimensional (2D) gel electrophoresis followed by mass spectrometry and ingenuity pathway analysis (IPA). Cell apoptosis was analyzed by flow cytometry, followed by reverse transcription quantitative real-time PCR (RT qPCR) and Western blot to investigate the expression of apoptosis-related genes. Our data showed 17beta-HSD7 is amplified in primary and progressive breast cancer, inhibition of 17beta-HSD7 in MCF-7 cells modulated 104 proteins primarily involved in cell death/survival, cell growth and DNA processing. The expression of 78kDa glucose-regulated protein (GRP78) and anti-apoptosis factor Bcl-2 were significantly suppressed via 17beta-HSD7 inhibition with INH7, consequently induced MCF-7 cell apoptosis. However, INH7 treatment of T47D, another widely used epithelial ER+ breast cancer cell line, led to an up-regulation of GRP78 expression, resulting in a limited increase in apoptosis. These results suggest cell-specific effects of INH7 in the breast cancer, which is interesting for further study. An combinatory effect on apoptosis by INH7 and Letrozole (aromatase inhibitor) was further demonstrated in MCF-7. Down-regulation of GRP78 via 17beta-HSD7 inhibition enhances cell apoptosis in response to Letrozole. This study highlights GRP78 as a key regulator related to 17beta-HSD7 inhibition and effect. Taken together, results from the present study suggest a hypothesis that inhibition of 17beta-HSD7 would be a complementary strategy to Letrozole by suppression of GRP78 in ER+ breast cancer. However, from a research perspective, further studies have to be carried out with more breast cancer cell lines as well as in vivo model to assess the efficacy of inhibitor combination. PMID- 28645528 TI - Long-term sustainable dendritic cell-specific depletion murine model for periodontitis research. AB - Dendritic cells (DCs) are specialized antigen-presenting cells that play a pivotal role in the pathogenesis of periodontitis. The use of animal models to study the role of DCs in periodontitis has been limited by lack of a method for sustained depletion of DCs. Hence, the objectives of this study were to validate the zDC-DTR knockin mouse model of conventional DCs (cDCs) depletion, as well as to investigate whether this depletion could be sustained long enough to induce alveolar bone loss in this model. zDC-DTR mice were treated with different dose regimens of diphtheria toxin (DT) to determine survival rate. A loading DT dose of 20ng/bw, followed and maintained with doses of 10ng/bm every 3days for up to 4weeks demonstrated 80% survival. Animals were weighed weekly and peripheral blood was obtained to confirm normal neutrophil counts. Five animals per group were euthanized at baseline, 24h, 1 and 4weeks. Bone marrow (BM), spleen (SP) and gingival tissue (GT) were harvested, and cells were isolated, separated and stained for Pre-DCs precursors (CD45R-MHCII+CD11c+Flt3+CD172a+) in BM, cDCs (CD11c+MHCII+CD209+) in spleen, and DCs in GT (CD45R+MHCII+CD11c+ DC SIGN/CD209+). Pre-DCs in BM were significantly depleted at 24h and depletion maintained for up to 4weeks, as compared to blank (PBS) controls. Circulating cDCs in spleen demonstrated a non-significant trend to deplete in 1week with high variability among mice. GT also showed a similar non-significant trend to deplete in 24h. The zDC-DTR model seems to be viable for evaluating the role of DCs immune homeostasis disruption and alveolar bone loss pathogenesis in response to long-term oral infection. PMID- 28645529 TI - Nanoparticle-Based Dressing: The Future of Wound Treatment? AB - Reconstructing functional skin after a wound remains a challenge due to the complexity of healing. In this regard, biocompatible nanoparticles (NPs) carrying and releasing bioactive drugs in a controlled and sustained manner may significantly improve the efficacy of wound therapies compared with current treatments. Topical administration of drug-loaded NPs allows optimal delivery to the dermis and improves product efficacy. Furthermore, associating NPs with scaffolds represents a new concept of 'dressing'. Experimental in vivo, ex vivo, and in vitro models have been developed in preclinical assays to evaluate the beneficial effects of nanoparticulate dressings. Drug-loaded NPs are promising tools for innovative wound healing treatment, especially with regard to their multifunctional properties. PMID- 28645530 TI - Recent Advances in Microbial Production of Aromatic Chemicals and Derivatives. AB - Along with the development of metabolic engineering and synthetic biology tools, various microbes are being used to produce aromatic chemicals. In microbes, aromatics are mainly produced via a common important precursor, chorismate, in the shikimate pathway. Natural or non-natural aromatics have been produced by engineering metabolic pathways involving chorismate. In the past decade, novel approaches have appeared to produce various aromatics or to increase their productivity, whereas previously, the targets were mainly aromatic amino acids and the strategy was deregulating feedback inhibition. In this review, we summarize recent studies of microbial production of aromatics based on metabolic engineering approaches. In addition, future perspectives and challenges in this research area are discussed. PMID- 28645532 TI - The Short Physical Performance Battery. PMID- 28645533 TI - Measuring two-point discrimination threshold with a caliper. PMID- 28645531 TI - New protein structures provide an updated understanding of phenylketonuria. AB - Phenylketonuria (PKU) and less severe hyperphenylalaninemia (HPA) constitute the most common inborn error of amino acid metabolism, and is most often caused by defects in phenylalanine hydroxylase (PAH) function resulting in accumulation of Phe to neurotoxic levels. Despite the success of dietary intervention in preventing permanent neurological damage, individuals living with PKU clamor for additional non-dietary therapies. The bulk of disease-associated mutations are PAH missense variants, which occur throughout the entire 452 amino acid human PAH protein. While some disease-associated mutations affect protein structure (e.g. truncations) and others encode catalytically dead variants, most have been viewed as defective in protein folding/stability. Here we refine this view to address how PKU-associated missense variants can perturb the equilibrium among alternate native PAH structures (resting-state PAH and activated PAH), thus shifting the tipping point of this equilibrium to a neurotoxic Phe concentration. This refined view of PKU introduces opportunities for the design or discovery of therapeutic pharmacological chaperones that can help restore the tipping point to healthy Phe levels and how such a therapeutic might work with or without the inhibitory pharmacological chaperone BH4. Dysregulation of an equilibrium of architecturally distinct native PAH structures departs from the concept of "misfolding", provides an updated understanding of PKU, and presents an enhanced foundation for understanding genotype/phenotype relationships. PMID- 28645534 TI - Too Fit To Fracture. PMID- 28645535 TI - Data Security and Privacy in Apps for Dementia: An Analysis of Existing Privacy Policies. AB - INTRODUCTION: Despite tremendous growth in the number of health applications (apps), little is known about how well these apps protect their users' health related data. This gap in knowledge is of particular concern for apps targeting people with dementia, whose cognitive impairment puts them at increased risk of privacy breaches. In this article, we determine how many dementia apps have privacy policies and how well they protect user data. METHODS: Our analysis included all iPhone apps that matched the search terms "medical + dementia" or "health & fitness + dementia" and collected user-generated content. We evaluated all available privacy policies for these apps based on criteria that systematically measure how individual user data is handled. RESULTS: Seventy-two apps met the above search teams and collected user data. Of these, only 33 (46%) had an available privacy policy. Nineteen of the 33 with policies (58%) were specific to the app in question, and 25 (76%) specified how individual-user as opposed to aggregate data would be handled. Among these, there was a preponderance of missing information, the majority acknowledged collecting individual data for internal purposes, and most admitted to instances in which they would share user data with outside parties. CONCLUSIONS: At present, the majority of health apps focused on dementia lack a privacy policy, and those that do exist lack clarity. Bolstering safeguards and improving communication about privacy protections will help facilitate consumer trust in apps, thereby enabling more widespread and meaningful use by people with dementia and those involved in their care. PMID- 28645536 TI - Imaging genetics of schizophrenia in the post-GWAS era. AB - Imaging genetics is a research methodology studying the effect of genetic variation on brain structure, function, behavior, and risk for psychopathology. Since the early 2000s, imaging genetics has been increasingly used in the research of schizophrenia (SZ). SZ is a severe mental disorder with no precise knowledge of its underlying neurobiology, however, new genetic and neurobiological data generate a climate for new avenues. The accumulating data of genome wide association studies (GWAS) continuously decode SZ risk genes. Global neuroimaging consortia produce collections of brain phenotypes from tens of thousands of people. In this context, imaging genetics will be strategically important both for the validation and discovery of SZ related findings. Thus, the study of GWAS supported risk variants as candidate genes to validate by neuroimaging is one trend. The study of epigenetic differences in relation to variations of brain phenotypes and the study of large scale multivariate analysis of genome wide and brain wide associations are other trends. While these studies hold a big potential for understanding the neurobiology of SZ, the problem of reproducibility appears as a major challenge, which requires standardizations in study designs and compensations of methodological limitations such as sensitivity and specificity. On the other hand, advancements of neuroimaging, optical and electron microscopy along with the use of genetically encoded fluorescent probes and robust statistical approaches will not only catalyze integrative methodologies but also will help better design the imaging genetics studies. In this invited paper, I will discuss the current perspective of imaging genetics and emerging opportunities of SZ research. PMID- 28645537 TI - CRISPR-Cas systems for genome engineering and investigation. PMID- 28645538 TI - Editorial. PMID- 28645539 TI - Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. AB - Heterotopic ossification (HO), acquired or hereditary, endochondral or intramembranous, is the formation of true bone outside the normal skeleton. Since perivascular Gli1+ progenitors contribute to injury induced organ fibrosis, and CD133 is expressed by a variety of populations of adult stem cells, this study utilized Cre-lox based genetic lineage tracing to test the contribution to endochondral HO of adult stem/progenitor cells that expressed either Gli1 or CD133. We found that both lineages contributed broadly to different normal tissues with distinct patterns, but that only Gli1-creERT labeled stem/progenitor cells contributed to all stages of endochondral HO in a BMP dependent, injury induced, transgenic mouse model. Hedgehog (Hh) signaling was abnormal at endochondral HO lesion sites with increased signaling surrounding the lesion but diminished signaling within it. Thus, local dysregulation of Hh signaling participates in the pathophysiology of endochondral HO. However, unlike a previous report of intramembranous HO, systemic inhibition of Hh signaling was insufficient to prevent the initiation of the endochondral HO process or to treat the existing endochondral HO, suggesting that Hh participates in, but is not essential for endochondral HO in this model. This could potentially reflect the underlying difference between intramembranous and endochondral HO. Nevertheless, identification of this novel stem/precursor cell population as a HO-contributing cell population provides a potential drugable target. PMID- 28645540 TI - Reply to "Chest ultrasound versus chest X-rays for detecting pneumonia in children: Why compare them each other if together can improve the diagnosis?" PMID- 28645541 TI - Comparison of the effect by which gastric plication and sleeve gastrectomy procedures alter metabolic and physical parameters in an obese type 2 diabetes rodent model. AB - BACKGROUND: Gastric plication (GP) and sleeve gastrectomy (SG) are 2 restrictive bariatric surgeries that are associated with weight loss and health improvement in patients with obesity. However, differences in how these procedures exert their effects have not been systematically evaluated and compared between techniques. OBJECTIVES: To investigate the effectiveness of GP and SG surgeries for obese patients with type 2 diabetes based on evaluation of energy metabolism, hormone metabolism, and gastrointestinal dynamics. SETTING: University medical center. METHODS: Zucker diabetic fatty rats (n = 30) were equally and randomly divided into 3 groups: sham, GP, and SG. Weight, food intake, fasting plasma glucose (FPG), and intraperitoneal glucose tolerance test (IPGTT) were measured in vivo before operation and at 2, 4, and 6 weeks postoperation. Whole-body metabolic parameters including activity, energy expenditure, and respiratory exchange rate (RER) were measured using metabolic cages 3 weeks postoperation. Blood samples were taken 2 weeks before operation and at 2, 4, and 6 weeks postoperation for the purpose of measuring the expression of serum ghrelin and glucagon-like peptide (GLP-1) by enzyme-linked immunosorbent assay. The residual gastric and intestinal propulsive movement were measured at 6 weeks postoperation after all animals were sacrificed. RESULTS: Compared with sham, the GP and SG procedures achieved near equivalent levels of efficacy as far as weight loss, reduced food intake, and decreased FBG and IPGTT in our rodent model. The GP and SG procedures also provided the same effectiveness as far as altering serum ghrelin and GLP-1 hormones. In addition, results showed that the GP and SG procedures can increase metabolic rate by consuming more energy and reducing activity. RERs in GP and SG animals were lower than in sham animals, which indicates that the energy mainly comes from adipose tissue. Moreover, the GP procedure showed lower gastric residual compared to sham, while the SG procedure did not appear to have this affect; the SG procedure resulted in deficiencies in intestinal propulsion function. CONCLUSIONS: The GP and SG procedures have the same effectiveness and can help improve diabetes control by regulating weight, glucose tolerance, and metabolic hormones and augmenting gastrointestinal dynamics. Therefore, these procedures have great potential as therapies for obesity and type 2 diabetes. PMID- 28645542 TI - Young children's inclusion decisions in moral and social-conventional group norm contexts. AB - Being a member of a peer group involves making decisions about whom to include in or exclude from the group. Sometimes these decisions are related to whether members of the group support or challenge the norms of the group. To examine how young children weigh concerns for group norms and group membership in both moral and social-conventional norm contexts, children (3- to 6-year-olds; N=73) were asked to decide between including an ingroup member who challenged the group's norm or an outgroup member who supported the norm. Groups held either moral (equal or unequal resource allocation) or social-conventional (traditional or nontraditional) norms. In the moral contexts, children were more likely to include the peer who advocated for the moral concern for equality regardless of the peer's group membership or their group's specific norm. In the social conventional contexts, however, children were more likely to include the peer who advocated for the conventional concern for maintaining traditions but only at the group-specific level. Furthermore, with age children increasingly based their inclusion decisions on normative concerns, rather than on group membership concerns, and differed in their inclusion decisions for ingroups and outgroups. Finally, children reasoned about their decisions by referencing concerns for fairness, group norms, and group membership, suggesting that preschool children weigh multiple concerns when deciding whom to include in their groups. Overall, the current study revealed differences in how preschool children weigh moral and social-conventional concerns in intergroup contexts. PMID- 28645543 TI - Mechanosensing in the Drosophila nervous system. AB - Neurons allocated to sense organs respond rapidly to mechanical signals dictating behavioral responses at the organism level. The receptors that transduce these signals, and underlie these senses, are mechanically gated channels. Research on mechanosensation over the past decade, employing in many cases Drosophila as a model, has focused in typifying these receptors and in exploring the different ways, depending on context, in which these mechanosensors are modulated. In this review, we discuss first what we have learned from Drosophila on these mechanisms and we describe the different mechanosensory organs present in the Drosophila larvae and adult. Secondly, we focus on the progress obtained by studying the fly on the characterization of the mechanosensory crosstalk underlying complex behaviors like motor coordination. Finally, turning to a cellular level, we summarize what is known on the mechanical properties and sensing capabilities of neural cells and how they may affect neural physiology and pathology. PMID- 28645544 TI - Diagnostic accuracy of EUS compared with MRCP in detecting choledocholithiasis: a meta-analysis of diagnostic test accuracy in head-to-head studies. AB - BACKGROUND AND AIMS: There is a wide range of reported sensitivity and specificity for EUS and MRCP in the diagnosis of choledocholithiasis, with lack of a proper meta-analysis of diagnostic test accuracy by using head-to-head comparison. Here, we aimed to compare the diagnostic accuracy of EUS and MRCP in detecting choledocholithiasis by using appropriate methodology recommended by the Cochrane Collaboration. METHODS: A comprehensive electronic literature search up to January 2017 was done by 2 reviewers for prospective cohort studies comparing EUS and MRCP to a reference standard for detecting choledocholithiasis. The acceptable reference standards were considered ERCP, intraoperative cholangiography, or clinical follow-up >3 months for negative cases. Quality of the included studies was measured by using the QUADAS-2 tool. A bivariate hierarchical model was used to perform the meta-analysis of diagnostic test accuracy. Summary receiver operating characteristics were developed and the area under the curve was calculated. RESULTS: A total of 5 of 32 studies were included. No study presented a high risk of bias. The pooled sensitivity and specificity were 0.97 (range, 0.91-0.99) and 0.90 (range, 0.83-0.94) for EUS and 0.87 (range, 0.80-0.93) and 0.92 (range, 0.87-0.96) for MRCP. The overall diagnostic odds ratio of EUS was significantly higher than the one with MRCP (162.5 vs 79.0, respectively; P = .008). Further analysis showed that this was mainly due to the significantly higher sensitivity of EUS as compared with that of MRCP (P = .006). The specificity was not significantly different between 2 modalities (P = .42). CONCLUSION: Both EUS and MRCP provide good diagnostic accuracy, with EUS providing statically better diagnostic accuracy and sensitivity, with comparable specificity. EUS should be incorporated in the diagnostic algorithm in patients suspected of choledocholithiasis whenever appropriate. PMID- 28645545 TI - "Updating the evolution of nursing research journals on journal citation report: 2009 to 2015": Author's reply. PMID- 28645546 TI - Post-sepsis cognitive impairment and associated risk factors: A systematic review. AB - INTRODUCTION: Post-sepsis cognitive impairment is one of the major sequelae observed in survivors of sepsis. This cognitive impairment can be global or may affect specific domains. A better understanding of these deficits and associated risk factors could influence the care of patients with sepsis. OBJECTIVE: To perform a systematic review to investigate the presence of cognitive impairment and its associated risk factors among patients who survived sepsis. METHODS: The search was conducted in MEDLINE (1966 to March 2017) and EMBASE (1988 to March 2017). We included studies with individuals who were 18 years or older with post sepsis cognitive impairment. RESULTS: We analysed 577 articles. Sixteen studies met the inclusion criteria. More than 74,000,000 patients were evaluated in the selected studies. Significant variation was observed in the definition of sepsis and cognitive impairment. Twelve studies used ACCP/SCCM criteria for sepsis, while cognitive impairment was defined per test used. Post-sepsis cognitive impairment was observed in 12.5 to 21% of survivors of sepsis. Attention, cognitive flexibility, processing speed, associative learning, visual perception, work memory, verbal memory, and semantic memory were the specific domains affected. Depressive symptoms, central nervous system infection, length of hospitalisation due to infection, and temporal proximity to the last period of infection were associated with cognitive impairment. CONCLUSION: The studies are heterogeneous, and there is urgent need for a common language, including definitions and neuropsychological tests, for the investigation of post-sepsis cognitive impairment. Despite this, there is mounting evidence for the clinical relevance of post-sepsis cognitive impairment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017054583 (www.crd.york.ac.uk/PROSPERO). PMID- 28645547 TI - An Alternative Strategy for Treatment of Distal Tibiofibular Syndesmotic Disruption: A Technical Note. AB - Metal screws are the most widely used in treating syndesmotic injuries; however, failure and the rigidity of the screws can threaten the success of the treatment and increase the cost of care. We performed open reduction and internal fixation of a fibula fracture followed by fixation of the tibiofibular joint with an olive wire and one half of an external fixator. We present a review of 1 patient treated with this material. We believe this method to be a physiologic fixation system with the advantage of being safe, inexpensive, adjustable, and effective; however, further clinical investigation and comparison to other methods is needed in order to better understand it clinical utility. PMID- 28645548 TI - Perioperative Complications and Initial Alignment of Lateral Approach Total Ankle Arthroplasty. AB - Total ankle replacement continues to become a more common treatment of end-stage ankle arthritis. A lateral approach total ankle implant system is an innovative approach for this treatment. We performed a retrospective review of 16 patients treated with lateral approach total ankle replacement. The implant was successful and retained in all cases during a follow-up period of 769 +/- 221.3 days (25.3 +/- 7.3 months). Initial satisfactory alignment was achieved in all cases. For patients in whom a frontal plane incongruent deformity was present preoperatively, a statistically significant correction was obtained (p = .0122). Three cases of delayed or nonunion of the fibula (18.8%) occurred, and one case of infection that led to removal of the fibular plate developed, for a total of 4 complications (25.0%) related to the fibular osteotomy. Our findings indicate that lateral approach total ankle replacement is effective with unique advantages and disadvantages for treating end-stage ankle arthritis. PMID- 28645549 TI - Staged Treatment of Infected Tibiotalar Fusion Using a Combination Antibiotic Spacer and Antibiotic-Coated Intramedullary Nail. AB - Pilon fractures are notoriously difficult injuries to treat. The current published data on salvage procedures after failed pilon fractures includes both total ankle arthroplasty (TAA) and tibiotalar fusion, each with its own specific indications. However, no acceptable treatment algorithm addressing the complications of these limb salvage procedures is available. We present the case of a 23-year-old patient, who sustained a complex pilon fracture after a motor vehicle accident. The patient was referred to our institution after an initial fixation attempt, followed by subsequent failed TAA, which was complicated by an infected fusion attempt. We describe a staged treatment approach to clearing the infection and obtaining the final fusion goals. PMID- 28645550 TI - Intermediate- to Long-Term Longevity and Incidence of Revision of the Modified Brostrom-Gould Procedure for Lateral Ankle Ligament Repair: A Systematic Review. AB - The Brostrom-Gould procedure is an effective procedure for chronic lateral ankle instability. However, long-term studies are limited, and the durability of this procedure remains unclear. A systematic review of the published data was undertaken to determine the outcomes and incidence of revision after long-term follow-up. Eleven studies involving 669 Brostrom-Gould procedures met the inclusion criteria. The revision rate was 1.2% at a weighted mean follow-up period of 8.4 years. Our systematic review of the available data revealed that the Brostrom-Gould procedure results in low revision rates for chronic lateral ankle instability. However, additional prospective comparative analyses are needed regarding this topic. PMID- 28645551 TI - Association between blood vitamin D and myocardial infarction: A meta-analysis including observational studies. AB - BACKGROUND: The association between blood vitamin D levels and the risk of myocardial infarction (MI) is controversial. This meta-analysis aimed to describe the relationship between MI risk and blood vitamin D levels. METHODS: Online databases were searched in PubMed, EMBASE and Web of science till February 2017 for observational studies in relation to reporting the vitamin D levels in MI cases and non-MI controls. The weighted mean difference (WMD) or odds ratio (OR), with 95% confidence interval (CI), were calculated to evaluate the relationship between MI risk and blood vitamin D levels. RESULTS: Eight observational studies with 9913 individuals, consisted of 3411 MI patients and 6502 non-MI controls, were included in our study. The pooled results revealed that blood vitamin D levels were significantly lower in MI patients when compared with non-MI controls (WMD=-3.40; 95% CI: -5.87 to -0.92, P=0.007). Subgroup analyses indicated MI patients were also associated with lower levels of blood vitamin D in America and Asia. Furthermore, when compared to non-MI controls, sufficient blood vitamin D appeared to protect against the occurrence of MI (OR=0.44; 95% CI: 0.25 to 0.76, P=0.004) in MI patients. Subgroup analyses also showed that sufficient blood 25(OH)D levels was a protective factor for MI in America and Asia. CONCLUSIONS: Present study suggested that the levels of blood 25(OH)D were significant lower in MI patients, especially in America and Asia, and sufficient blood vitamin D levels might protect against the occurrence of MI. PMID- 28645552 TI - Mortality following augmentation cystoplasty: A transitional urologist's viewpoint. AB - INTRODUCTION: Three complications have been hypothesized to increase patient mortality following enterocystoplasty: spontaneous bladder perforation, bladder neoplasia, and chronic renal failure (CRF). The present study examined risk of their occurrence and discussed ways to improve the quality of care. MATERIALS AND METHODS: The present transitional clinic followed 385 patients with a history of bladder augmentation using either ileal, sigmoid, or ascending colon. The median age was 37 years (range 16-71). Median follow-up interval after augmentation was 26 years (range 2-59). DISCUSSION: Spontaneous rupture of the bladder occurred in 3% (13/385), with one associated death (0.25%, 1/385). Spontaneous bladder rupture significantly correlated with substance abuse, non-compliance with catheterization, and mental/physical disabilities that required the use of surrogates to perform and monitor intermittent catheterization (P < 0.01). Of the 203 patients that were followed for >=10 years, 4% (8/203) developed a bladder tumor. In comparison, 2.5% (5/203) of an age-matched control population, managed by anticholinergics and intermittent catheterization, developed a bladder tumor. Therefore, enterocystoplasty cannot be associated with an increased risk of cancer development (P = 0.397). Chronic renal failure >= Stage 3 arose in 15% (58/385), and 1% (4/385) of the patients died as a result of this complication. Obese patients (BMI >=30) catheterizing per urethra were more likely to be non compliant with catheterization and develop CRF compared with obese patients with a continent catheterizable stoma (P > 0.001). These findings suggest that compliance with intermittent catheterization and renal preservation are enhanced by the presence of a catheterizable abdominal stoma. CONCLUSION: The individual's intellectual and physical capability to obey medical directives, refrain from high-risk habits, maintain a healthy weight, and comply with long-term follow-up visits were all critical to the enduring success of bladder augmentation. PMID- 28645553 TI - A mixed-methods evaluation of an Integrated Medication Management program and implications for implementation. AB - BACKGROUND: Improving medication adherence is a common and challenging issue. Taking medications as prescribed becomes particularly difficult for individuals with multiple chronic conditions. Poor adherence can lead to exacerbated health issues and prolonged disease severity. Medication Therapy Management is increasingly being used to help clinics improve medication adherence and reduce adverse events, but factors that enable implementation of such programs are not well identified. OBJECTIVE: To describe the factors associated with implementation of an innovative pharmacy program and to measure the impact of the intervention. METHODS: This mixed-methods cohort study in a federal qualified health center with its own pharmacy examined the implementation and the impact of a broad program including MTM. The intervention included appointments with pharmacists, communication between pharmacists and physicians, and, for some, monthly pre-packaged medications. Semi-structured interviews with patients and staff were recorded, transcribed, and analyzed for themes relating to implementation, satisfaction, and challenges. Quantitative methods using data collected by the pharmacists at each visit were used to compare the first visit to those at later visits and provided measures of impact on diabetes control, statin use, and medication-related problems (MRPs). RESULTS: Qualitative interviews identified enabling factors that contributed to successful implementation of this program, including: program factors such as data access, communication with patients, and dedicated staff; organizational factors such as culture of integration, leadership support, and staffing; and lastly, environmental factors such as the availability of 340B funding. Quantitative analyses were limited by poor retention and lack of a similarly-documented comparison group. Health outcomes were not found to be significantly better, though there was a significant decrease in some kinds of MRPs. This program was well received by patients and staff and demonstrated some clinical impact. CONCLUSION: The program's implementation was enabled by design as well as organizational and external factors. Financial and leadership support allowed for flexibility and creativity, which contributed to successful implementation. Alternative delivery models beyond fee-for-service payments may make this kind of program more feasible. PMID- 28645554 TI - Monocrotophos, an organophosphorus insecticide, disrupts the expression of HpNetrin and its receptor neogenin during early development in the sea urchin (Hemicentrotus pulcherrimus). AB - Netrins, chemotropic guidance cues, can guide the extension of serotonergic axons by binding to netrin receptors during neural development. However, little is known about whether disruption of netrin signaling is involved in the mechanisms by which organophosphorus pesticides affect serotonergic nervous system (SNS) development. In this study, we evaluated the effects of the pesticide monocrotophos (MCP) on the expression patterns of HpNetrin and its receptor neogenin as well as on the intracellular calcium ion (Ca2+) levels in Hemicentrotus pulcherrimus (sea urchin) by exposing fertilized embryos to 0, 0.01, 0.10, and 1.00mg/L MCP. The results showed that MCP disrupted HpNetrin and neogenin expression at different developmental stages in H. pulcherrimus and that Ca2+ appeared to be involved in the MCP-induced developmental neurotoxicity. Specifically, the lower concentrations of MCP elevated HpNetrin and neogenin transcription, resulting in higher intracellular Ca2+ levels during the early developmental stages in the sea urchin; this may affect netrin-directed cell migration/axon extension and subsequently disrupt serotonergic axon branching and synapse formation. In contrast, 1.00mg/L MCP exhibited an inhibitory effect on HpNetrin and neogenin transcription. This finding implies that the regulatory roles of these factors may be diminished during early development, thereby causing developmental defects in the sea urchin. Collectively, our results provide a basis for exploring the involvement of netrin and neogenin in the organophosphate-induced disruption of the SNS during development. PMID- 28645555 TI - Impact of intraoperative vascular occlusion during liver surgery on long-term outcomes: A systematic review and meta-analysis. AB - OBJECTIVE: To determine the impact of intraoperative vascular occlusion during liver surgery on postoperative long-term outcomes for hepatocellular carcinoma (HCC) patients using a meta-analysis. METHODS: A systematic literature search of PubMed, EMBASE, and Cochrane Central was conducted to discover relevant randomized controlled trials (RCTs) and observational studies. Studies that reported postoperative long-term outcomes; 1-, 3-, and 5-year overall survival (OS); and/or 1-, 3-, and 5-year recurrence-free survival (RFS) for both an observation group (vascular occlusion) and a control group (vascular non occlusion) were included. Forest plots were performed to calculate the difference between the 2 groups. The Q statistic and the I2 index statistic were used to assess heterogeneity. Publication bias was evaluated using Egger's test. RESULTS: Four observational studies containing 2917 patients were included in this meta analysis. The pooled estimation results indicated that intraoperative vascular occlusion would not shorten the postoperative OS (RR = 1.01; 95%CI: 0.98-1.03; P = 0.763) and would not increase the risk of HCC recurrence (RR = 0.99; 95%CI: 0.97-1.02; P = 0.320) with low heterogeneity (I2 = 0.0% and 12.7%, respectively). Furthermore, Egger's test did not reveal any publication bias (P = 0.405 and P = 0.269, respectively) in this research. CONCLUSIONS: Intraoperative vascular occlusion during liver surgery is safe for HCC patients. It does not affect the postoperative overall survival or increase the risk of HCC recurrence. PMID- 28645556 TI - Breast cancer liver metastases in a UK tertiary centre: Outcomes following referral to tumour board meeting. AB - INTRODUCTION: To assess the outcomes from multidisciplinary board meetings (MDM) for patients with breast cancer liver metastases (BCLM) and identify prognostic factors for survival. MATERIALS AND METHODS: A retrospective review of MDM records for patients referred with BCLM to a tertiary centre between 2005 and 2016. Patient demographics, clinicopathological factors and intervention type were analysed to find predictive factors for overall survival. RESULTS: 61 patients with BCLM were referred to the MDM. Treatment pathways included surgical resection (n = 23), radiofrequency ablation (RFA, n = 11), or chemotherapy (n = 27). Surgical resection patients had an improved median overall survival compared to chemotherapy (49 v 20mo; p < 0.001). RFA showed comparable survival benefit (37 v 20mo; p = 0.011). Resection and RFA showed no significant difference in survival over one another (49 v 37mo; p = 0.854). Survival analysis identified that resection (p = 0.002) and RFA (p = 0.001) were associated with improved overall survival compared to chemotherapy. Multivariate analysis identified extrahepatic disease (HR = 14.21; p = 0.044) and R0 resection (HR = 0.068; p = 0.023) as prognostic factors. CONCLUSIONS: Surgical resection of BCLM may improve the overall survival in selected patient groups. This study identifies a cohort of patients, without extrahepatic disease and responsive to chemotherapy, who may particularly benefit from surgery. PMID- 28645557 TI - Response to the letter: Students' participation in collaborative research should be recognised. PMID- 28645558 TI - Novel applications of agent-based modeling in emergency medicine research - A systematic literature review. PMID- 28645559 TI - Multicenter prevalence of opioid medication use as abortive therapy in the ED treatment of migraine headaches. AB - Despite a range of therapeutic options for treating acute migraine headaches, the use of opioids is still reported to be common practice. This study describes treatment practices in regards to migraines in the ED. It characterizes the prevalence of opioid orders during visits in three different settings, an academic medical center, a non-academic urban ED, and a community ED. Fourteen months of consecutive migraine visits were identified. All medications ordered were separated into first-line and rescue medications. Number of visits, length of stay, door to provider time, and total provider time were compared. A total of 1222 visits were identified. Opioids were ordered in 35.8% of these visits. By facility, opioids were ordered in 12.3% of academic medical center visits, 40.9% of urban ED visits, and 68.6% of community ED visits. This ranged from 6.9% of first-line therapies in the academic center to 69.9% of rescue therapies in the community ED. Of those who received opioids, 36.0% versus 25.1% required rescue medications. Patients who received opioids had more repeat visits, 1.79 versus 1.30. The academic center and urban ED both found greater than 30% decrease in length of stay in visits where opioids were not given. In the face of evidence against opioids for migraines, over one third of patients received them. There was a higher prevalence in the community setting. There were no significant benefits in overall throughput time, however, opioid visits required more rescue medications, increased length of stay, and resulted in more repeat visits. PMID- 28645560 TI - Sustained remission in patients with treatment-resistant depression receiving vagal nerve stimulation: A case series. PMID- 28645561 TI - BORIS up-regulates OCT4 via histone methylation to promote cancer stem cell-like properties in human liver cancer cells. AB - Accumulating evidence has revealed the importance of cancer stem cells (CSCs) in chemoresistance and recurrence. BORIS, a testes-specific CTCF paralog, has been shown to be associated with stemness traits of embryonic cancer cells and epithelial CSCs. We previously reported that BORIS is correlated with the expression of the CSC marker CD90 in hepatocellular carcinoma (HCC). These results encourage us to wonder whether BORIS exerts functions on CSC-like traits of human liver cancer cells. Here, we report that BORIS was enriched in HCC tissues. Exogenous overexpression of BORIS promoted CSC-like properties, including self-renewal, chemoresistance, migration and invasion in Huh7 and HCCLM3 cells. Conversely, BORIS knockdown suppressed CSC-like properties in SMMC 7721 and HepG2 cells and inhibited tumorigenicity in SMMC-7721 cells. Moreover, BORIS alteration did not affect the DNA methylation status of the minimal promoter and exon 1 region of OCT4. However, BORIS overexpression enhanced the amount of BORIS bound on the OCT4 promoter and increased H3K4me2, while reducing H3K27me3; BORIS depletion decreased BORIS and H3K4me2 on the OCT4 promoter, while increasing H3K27me3. These results revealed that BORIS is associated with the CSC like traits of human liver cancer cells through the epigenetic regulation of OCT4. PMID- 28645562 TI - Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients. AB - JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI 8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells. PMID- 28645563 TI - Bruceine D inhibits hepatocellular carcinoma growth by targeting beta catenin/jagged1 pathways. AB - Hepatocellular carcinoma (HCC) is known for high mortality and limited available treatments. Aberrant activation of the Wnt and Notch signaling pathways is critical to liver carcinogenesis and progression. Here, we identified a small molecule, bruceine D (BD), as a Notch inhibitor, using an RBP-Jkappa-dependent luciferase-reporter system. BD significantly inhibited liver tumor growth and enhanced the therapeutic effects of sorafenib in various murine HCC models. Mechanistically, BD promotes proteasomal degradation of beta-catenin and the depletion of its nuclear accumulation, which in turn disrupts the Wnt/beta catenin-dependent transcription of the Notch ligand Jagged1 in HCC. Our findings provide important information about a novel Wnt/Notch crosstalk inhibitor that is synergistic with sorafenib for treatment of HCC, and therefore have high clinical impact. PMID- 28645564 TI - Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome. AB - Monoallelic germline mutations in one of the DNA mismatch repair (MMR) genes cause Lynch syndrome, with a high lifetime risks of colorectal and endometrial cancer at adult age. Less well known, is the constitutional mismatch repair deficiency (CMMRD) syndrome caused by biallelic germline mutations in MMR genes. This syndrome is characterized by the development of childhood cancer. Patients with CMMRD are at extremely high risk of developing multiple cancers including hematological, brain and intestinal tumors. Mutations in MMR genes impair DNA repair and therefore most tumors of patients with CMMRD are hypermutated. These mutations lead to changes in the translational reading frame, which consequently result in neoantigen formation. Neoantigens are recognized as foreign by the immune system and can induce specific immune responses. The growing evidence on the clinical efficacy of immunotherapies, such as immune checkpoint inhibitors, offers the prospect for treatment of patients with CMMRD. Combining neoantigen based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. Neoantigen-based vaccines might also be a preventive treatment option in healthy biallelic MMR mutation carriers. Future studies need to reveal the safety and efficacy of immunotherapies for patients with CMMRD. PMID- 28645565 TI - From the outside, from within: Biological and therapeutic relevance of signal transduction in T-cell acute lymphoblastic leukemia. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from clonal expansion of transformed T-cell precursors. In this review we summarize the current knowledge on the external stimuli and cell intrinsic lesions that drive aberrant activation of pivotal, pro-tumoral intracellular signaling pathways in T-cell precursors, driving transformation, leukemia expansion, spread or resistance to therapy. In addition to their pathophysiological relevance, receptors and kinases involved in signal transduction are often attractive candidates for targeted drug development. As such, we discuss also the potential of T-ALL signaling players as targets for therapeutic intervention. PMID- 28645566 TI - Using straw hydrolysate to cultivate Chlorella pyrenoidosa for high-value biomass production and the nitrogen regulation for biomass composition. AB - Heterotrophic cultivation of Chlorella pyrenoidosa based on straw substrate was proposed as a promising approach in this research. The straw pre-treated by ammonium sulfite method was enzymatically hydrolyzed for medium preparation. The highest intrinsic growth rate of C. pyrenoidosa reached to 0.097h-1 in hydrolysate medium, which was quicker than that in glucose medium. Rising nitrogen concentration could significantly increase protein content and decrease lipid content in biomass, meanwhile fatty acids composition kept stable. The highest protein and lipid content in microalgal biomass reached to 62% and 32% under nitrogen excessive and deficient conditions, respectively. Over 40% of amino acids and fatty acids in biomass belonged to essential amino acids (EAA) and essential fatty acids (EFA), which were qualified for high-value uses. This research revealed the rapid biomass accumulation property of C. pyrenoidosa in straw hydrolysate medium and the effectiveness of nitrogen regulation to biomass composition at heterotrophic condition. PMID- 28645567 TI - Entrenched obesity in childhood: findings from a national cohort study. AB - PURPOSE: Given the high levels of obesity among U.S. children, we examine whether obesity in childhood is a passing phenomenon or remains entrenched into adolescence. METHODS: Data are from the prospective nationally representative Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999 (analytic sample = 6600). Anthropometrics were measured six times during 1998-2007. Overweight and obesity were defined using CDC cut-points. Entrenched obesity was defined as obesity between ages 5-9 coupled with persistent obesity at ages 11 and 14. RESULTS: Almost 30% of children experienced obesity at some point between ages 5.6 and 14.1 years; 63% of children who ever had obesity between ages 5.6 and 9.1 and 72% of those who had obesity at kindergarten entry experienced entrenched obesity. Children with severe obesity in kindergarten or who had obesity at more than 1 year during early elementary were very likely to experience obesity through age 14, regardless of their sex, race, or socioeconomic backgrounds. CONCLUSIONS: Prevention should focus on early childhood, as obesity at school entry is not often a passing phenomenon. Even one timepoint of obesity measured during the early elementary school years may be an indicator of risk for long-term obesity. PMID- 28645568 TI - Predictors of successful telephone follow-up in a multicenter study of infants with severe bronchiolitis. AB - PURPOSE: To identify the characteristics that predict successful telephone follow up with parents of infants with severe bronchiolitis. METHODS: We analyzed data from a 17-center, prospective cohort study of infants (age <1 year) hospitalized with bronchiolitis during three consecutive fall/winter seasons. Participant contact information and clinical data were collected during the index hospitalization. Parents were called at 6-month intervals (based on the child's age) after discharge to assess respiratory problems. The primary outcome was age 12-month telephone interview status. Participants were classified as unreachable after 28 days of unsuccessful attempts. RESULTS: 798 of 916 children (87%) completed the age 12-month telephone interview. In unadjusted analyses, factors associated with successful follow-up included: private health insurance, annual household income $60,000 or more, and residing in the Northeast, Midwest, or West. Follow-up was less common among non-Hispanic blacks, Hispanics, and households with 3 or more children. In multivariable analyses, follow-up was more likely among parents of females, and, compared with the South, in the Northeast and Midwest (all P < .05). Compared with non-Hispanic whites, non-Hispanic blacks and Hispanics remained less likely to complete the interview as did households with 3 or more children (all P < .05). CONCLUSION: Sociodemographic and geographic factors predict successful telephone follow-up, even among parents of infants with severe illness. PMID- 28645570 TI - Quantitative proteomics analysis by iTRAQ revealed underlying changes in thermotolerance of Arthrospira platensis. AB - : Growth temperature is a critical factor that affects cultivation of Arthrospira platensis which is a type of cyanobacterium widely known as Spirulina that has significant commercial value. To investigate the molecular mechanism underlying the thermotolerance of Spirulina, differential protein expression profiling was carried out using iTRAQ-based quantitative proteomic analysis. This study only analyzed changes in thylakoids. Among the 2085 proteins quantified, 43 differentially expressed proteins were selected based on the fold change cutoff scores of >=2 or <=0.5 for up-regulation or down-regulation, respectively. An analysis of these 43 proteins found that 23% of them are photosynthetic system proteins which include photosynthetic enzymes and pigment proteins. The dynamic change of these proteins indicates that photosynthetic system functions were profoundly affected under heat stress and the light-dependent reactions were probably the most sensitive to temperature changes. Meanwhile, to cope with the low energy production due to impaired photosynthesis there was a considerable down-shift in protein synthesis which is a very energy demanding process. The impaired photosynthesis led to low energy generation that was compensated by a down-shift in translation (the most energy-demanding process) and an up-shift of glycolysis. The reduction of many ribosome proteins may lead to a loss in translation efficiency; therefore, Spirulina may adopted a different mechanism to increase translational elongation under heat stress to compensate for this loss, such as elevate L7/L12 proteins. Changes were also found in the classical heat shock proteins, the ROS scavenging system, DNA-binding proteins, and some membrane proteins. In conclusion, this research demonstrate that heat stress induces profound changes in cellular physiology and shed light on the mechanism of the heat stress response and thermotolerance of Arthrospira platensis. BIOLOGICAL SIGNIFICANCE: Arthrospira platensis, widely known as Spirulina, is a type of cyanobacteria which is cultivated at large scale for it great commercial value. It has become a consensus that continually increasing temperature due to global warming is bringing serious threat to agriculture, including the Spirulina cultivation. High temperature not only limits biomass accumulation by Spirulina, but also changes the composition of nutrition. Therefore there is a greater need than ever before to understand how Spirulina tolerates and cope with high temperature. In this study, we for the first time applied the iTRAQ-based quantitative proteomic technology to investigate the thermotolerance of Spirulina. Our results showed that many biological processes were altered by heat stress. Most significantly, we found that heat stress harmed the photosynthesis ability and caused low energy production, and to deal with this situation, energy demanding processes like protein synthesis were down-shifted and the alternative energy metabolism process glycolysis was up-shifted. Our results also show other important proteins, like the classical heat shock proteins and some antioxidant proteins, are also increased. Thus our study sheds light to our understanding of the mechanism underlying the thermotolerance of Spirulina. PMID- 28645569 TI - Impact of end stage kidney disease on costs and outcomes of Clostridium difficile infection. AB - OBJECTIVES: To assess the impact of end stage kidney disease (ESKD) on the outcomes of Clostridium difficile infection (CDI), including complications of infection, length of hospital stay, overall mortality, and healthcare burden. METHODS: The National Inpatient Sample (NIS) database created by the Agency of Healthcare Research and Quality (AHRQ) was used, covering the years 2009 through 2013. Manufacturer-provided sampling weights were used to produce national estimates. RESULTS: All-cause unadjusted in-hospital mortality was significantly higher for patients with CDI and ESKD than for patients without ESKD (11.6% vs. 7.7%, p<0.001). The in-hospital mortality remained higher even after adjusting for age, sex, race, and Charlson index group using multivariate logistic regression (odds ratio 1.47, confidence interval 1.41-1.53). The median length of stay was found to be longer by 2days in the ESKD group (9 vs. 7 days, p<0.001). The average cost of hospitalization for patients with CDI and ESKD was also significantly higher compared to the non-ESKD group (USD $35 588 vs. $23 505, in terms of the 2013 value of the USD, p<0.001). CONCLUSIONS: The presence of end stage kidney disease in hospitalized patients with Clostridium difficile infection is associated with higher mortality, a longer length of stay, and a higher cost of hospitalization. PMID- 28645571 TI - A pooled analysis of combined liver and inferior vena cava resection for hepatic malignancy. AB - BACKGROUND: Limited data are currently available to address the safety and efficacy of combined resection of the liver and inferior vena cava (IVC) for hepatic malignancies. METHODS: A systematic review was performed to identify relevant studies. Pooled individual data were examined for the clinical outcome of combined resection of the liver and IVC for hepatic malignancies. RESULTS: A total of 258 patients were described in 38 articles eligible for inclusion. Resections were performed for colorectal liver metastasis (CLM) [n = 128 (50%)], intrahepatic cholangiocarcinoma (ICC) [n = 51 (20%)], hepatocellular carcinoma (HCC) [n = 48 (19%)], and other pathologies [n = 31 (11%)]. There were 14 (5%) perioperative deaths. The median survival duration was 34 months, and the 1-, 3- and 5-year overall survival (OS) rate was 79%, 46% and 33%, respectively. The 5 year OS rate was 26% for CLM, 37% for ICC, and 30% for HCC. CONCLUSION: Combined resection of the liver and IVC for hepatic malignancies is safe and applicable, and offers acceptable survival outcomes. PMID- 28645572 TI - Longitudinal associations between mental health conditions and overactive bladder in women veterans. AB - BACKGROUND: One in 5 recently deployed US women veterans report overactive bladder symptoms. Mental health conditions such as depression and anxiety commonly co-occur in women with overactive bladder, but temporal relationships between these outcomes have not been well studied, and the mechanism behind this association is unknown. The Women Veterans Urinary Health Study, a nationwide longitudinal study in recently deployed women veterans, was designed to better understand relationships between overactive bladder and mental health conditions. OBJECTIVE: We sought to estimate the 1-year incidence and remission of overactive bladder and to identify the impact of depression, anxiety, posttraumatic stress disorder, and prior sexual assault on 1-year overactive bladder incidence and remission rates. STUDY DESIGN: Participants of this 1-year prospective cohort study were female veterans separated from military service who had returned from Iraq or Afghanistan deployment within the previous 2 years. Eligible women were identified through the Defense Manpower Data Center and recruited by mail and telephone. Telephone screening confirmed participants were ambulatory, community dwelling veterans and excluded those with urinary tract fistula, congenital abnormality, or cancer; pelvic radiation; spinal cord injury; multiple sclerosis; Parkinson disease; stroke; or current/recent pregnancy. Data collection included computer-assisted telephone interviews performed at enrollment and 1 year later. The interview assessed demographic and military service characteristics; urinary symptoms and treatment; depression, anxiety, and posttraumatic stress disorder symptoms and treatment; and a lifetime history of sexual assault. Overactive bladder was identified if at least moderately bothersome urgency urinary incontinence and/or urinary frequency symptoms were reported on Urogenital Distress Inventory items. Exposures included depression, anxiety, posttraumatic stress disorder, and lifetime sexual assault, assessed at baseline using validated questionnaires (including the Patient Health Questionnaire and Posttraumatic Stress Disorder Checklist). Associations between exposures and overactive bladder incidence and remission were estimated using propensity score adjusted logistic regression models. RESULTS: In all, 1107 (88.0%) of 1258 eligible participants completed 1-year interviews. Median age was 29 (range 20 67) years and 53% were nulliparous. Overactive bladder was identified at baseline in 242 (22%), and 102 (9.2%), 218 (19.7%), 188 (17.0%), and 287 (25.9%) met criteria for baseline depression, anxiety, posttraumatic stress disorder, and lifetime sexual assault, respectively. At 1 year, overactive bladder incidence was 10.5% (95% confidence interval, 8.6-12.8%), and remission of overactive bladder was 36.9% (95% confidence interval, 30.8-43.4%). New overactive bladder occurred more often in women with baseline anxiety (21% vs 9%), posttraumatic stress disorder (19% vs 9%) and lifetime sexual assault (16% vs 9%) (all: P < .01). After adjustment, anxiety (odds ratio, 2.4; 95% confidence interval, 1.4 4.1) and lifetime sexual assault (odds ratio, 1.7; 95% confidence interval, 1.0 2.8) predicted 1-year incident overactive bladder. Overactive bladder remission occurred less often in those with baseline depression (19% vs 41%, P < .01) and anxiety (29% vs 42%, P = .03). After adjustment, depression decreased 1-year overactive bladder remission risk (odds ratio, 0.37; 95% confidence interval, 0.16-0.83). Overactive bladder treatment was uncommon and not associated with remission. CONCLUSION: Anxiety, depression, and prior sexual assault-common postdeployment problems for women veterans-influence the natural history of overactive bladder. Providers should screen for mental health conditions and sexual assault in women with newly diagnosed or persistent overactive bladder. PMID- 28645573 TI - Evidence that fetal death is associated with placental aging. AB - BACKGROUND: The risk of unexplained fetal death or stillbirth increases late in pregnancy, suggesting that placental aging is an etiological factor. Aging is associated with oxidative damage to DNA, RNA, and lipids. We hypothesized that placentas at >41 completed weeks of gestation (late-term) would show changes consistent with aging that would also be present in placentas associated with stillbirths. OBJECTIVE: We sought to determine whether placentas from late-term pregnancies and unexplained stillbirth show oxidative damage and other biochemical signs of aging. We also aimed to develop an in vitro term placental explant culture model to test the aging pathways. STUDY DESIGN: We collected placentas from women at 37-39 weeks' gestation (early-term and term), late-term, and with unexplained stillbirth. We used immunohistochemistry to compare the 3 groups for: DNA/RNA oxidation (8-hydroxy-deoxyguanosine), lysosomal distribution (lysosome-associated membrane protein 2), lipid oxidation (4-hydroxynonenal), and autophagosome size (microtubule-associated proteins 1A/1B light chain 3B, LC3B). The expression of aldehyde oxidase 1 was measured by real-time polymerase chain reaction. Using a placental explant culture model, we tested the hypothesis that aldehyde oxidase 1 mediates oxidative damage to lipids in the placenta. RESULTS: Placentas from late-term pregnancies show increased aldehyde oxidase 1 expression, oxidation of DNA/RNA and lipid, perinuclear location of lysosomes, and larger autophagosomes compared to placentas from women delivered at 37-39 weeks. Stillbirth-associated placentas showed similar changes in oxidation of DNA/RNA and lipid, lysosomal location, and autophagosome size to placentas from late-term. Placental explants from term deliveries cultured in serum-free medium also showed evidence of oxidation of lipid, perinuclear lysosomes, and larger autophagosomes, changes that were blocked by the G-protein-coupled estrogen receptor 1 agonist G1, while the oxidation of lipid was blocked by the aldehyde oxidase 1 inhibitor raloxifene. CONCLUSION: Our data are consistent with a role for aldehyde oxidase 1 and G-protein-coupled estrogen receptor 1 in mediating aging of the placenta that may contribute to stillbirth. The placenta is a tractable model of aging in human tissue. PMID- 28645574 TI - Department of Error. PMID- 28645575 TI - Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells. AB - Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events. Treatment with acetaminophen significantly elevated the levels of inflammatory cytokines by hES-HLCs. Moreover, three human immune cell lines, Jurkat, THP-1, and NK92MI, were activated when cultured in conditioned medium obtained from acetaminophen-treated hES-HLCs. To further validate, we tested thiazolidinedione (TZD) class, antidiabetic drugs, including troglitazone withdrawn from the market because of severe idiosyncratic drug hepatotoxicity. We found that TZD drug treatment to hES-HLCs resulted in the production of pro-inflammatory cytokines and eventually associated immune cell activation. In summary, our study demonstrates for the first time the potential of hES-HLCs as an in vitro model system for assessment of drug-induced as well as immune-mediated hepatotoxicity. PMID- 28645576 TI - Mechanisms of hepatocellular toxicity associated with new psychoactive synthetic cathinones. AB - Synthetic cathinones are a new class of psychostimulant substances. Rarely, they can cause liver injury but associated mechanisms are not completely elucidated. In order to increase our knowledge about mechanisms of hepatotoxicity, we investigated the effect of five frequently used cathinones on two human cell lines. Bupropion was included as structurally related drug used therapeutically. In HepG2 cells, bupropion, MDPV, mephedrone and naphyrone depleted the cellular ATP content at lower concentrations (0.2-1mM) than cytotoxicity occurred (0.5 2mM), suggesting mitochondrial toxicity. In comparison, methedrone and methylone depleted the cellular ATP pool and induced cytotoxicity at similar concentrations (>=2mM). In HepaRG cells, cytotoxicity and ATP depletion could also be demonstrated, but cytochrome P450 induction did not increase the toxicity of the compounds investigated. The mitochondrial membrane potential was decreased in HepG2 cells by bupropion, MDPV and naphyrone, confirming mitochondrial toxicity. Bupropion, but not the other compounds, uncoupled oxidative phosphorylation. Bupropion, MDPV, mephedrone and naphyrone inhibited complex I and II of the electron transport chain, naphyrone also complex III. All four mitochondrial toxicants were associated with increased mitochondrial ROS and increased lactate production, which was accompanied by a decrease in the cellular total GSH pool for naphyrone and MDPV. In conclusion, bupropion, MDPV, mephedrone and naphyrone are mitochondrial toxicants impairing the function of the electron transport chain and depleting cellular ATP stores. Since liver injury is rare in users of these drugs, affected persons must have susceptibility factors rendering them more sensitive for these drugs. PMID- 28645577 TI - Quantitative structure-skin permeability relationships. AB - This paper reviews in silico models currently available for the prediction of skin permeability. A comprehensive discussion on the developed methods is presented, focusing on quantitative structure-permeability relationships. In addition, the mechanistic models and comparative studies that analyse different models are discussed. Limitations and strengths of the different approaches are highlighted together with the emergent issues and perspectives. PMID- 28645578 TI - The electrophilic character of quinones is essential for the suppression of Bach1. AB - The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) is the most important cellular defense mechanisms against oxidative attack. BTB and CNC homology-1 (Bach1), like Kelch-like ECH-associated protein 1 (Keap1), is one of a negative regulator of Nrf2 that control antioxidant response elements (ARE) dependent gene expressions. In the current study, we found that quinones show greater capacity than hydroquinones in nuclear Bach1 export, as well as ubiquitin dependent Bach1 degradation in our experimental time frame. Consistently, quinones are easier than hydroquinones in Nrf2 activation and ARE-driven antioxidant protein expressions. Considering the redox cycling potential of quinone-hydroquinone couple, we investigated the effect of transit metal oxidation on the regulation of Nrf2 activity. As shown, Fe3+ enhanced hydroquinone-induced Nrf2 activation and ARE-driven gene expressions, suggesting quinones rather than hydroquinone activate Nrf2 through Bach1 arylation. Taking together, our investigation illustrated that the electrophilic character of quinones ensure their conjugation with Bach1, which is important for the downregulation of Bach1 and the upregulation of Nrf2 signaling. PMID- 28645579 TI - Anti-androgenic mechanisms of Bisphenol A involve androgen receptor signaling pathway. AB - We have shown Bisphenol A (BPA) acts as an androgen receptor (AR) antagonist in the previous study. However, the mechanisms underlying anti-androgenic effects of BPA remain unclear. The objective of this study was to explore whether the AR signaling was involved in AR antagonism of BPA. The Cell Counting Kit-8 (CCK-8) assay and Real-Time Cell Analysis (RTCA) iCELLigence system were applied to analyze the mouse Sertoli cell TM4 proliferation. The mammalian two-hybrid assays were performed to investigate the effects of BPA on the AR amino- and carboxyl terminal regions (N/C) interaction and the interactions of the AR with steroid receptor coactivator-1 (SRC-1), co-repressors including silencing mediator for thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (NCoR). BPA exposure resulted in decreased TM4 cell proliferation. BPA inhibited the AR N/C interaction significantly. Furthermore, BPA enhanced the interactions of AR-SMRT and AR-NCoR significantly. In conclusion, these data suggest BPA inhibits Sertoli cell proliferation due to its anti-androgenic actions. The mechanisms responsible for AR antagonism of BPA involve inhibiting the AR N/C interaction and enhancing the interactions of AR-SMRT and AR-NCoR. The data uncover novel anti-androgenic mechanisms by which BPA antagonizes AR signaling, contributing to Sertoli cell proliferation suppression and male reproductive toxicology. PMID- 28645580 TI - Chemostat studies of bacteriophage M13 infected Escherichia coli JM109 for continuous ssDNA production. AB - Steady state studies in a chemostat enable the control of microbial growth rate at defined reaction conditions. The effects of bacteriophage M13 infection on maximum growth rate of Escherichia coli JM109 were studied in parallel operated chemostats on a milliliter-scale to analyze the steady state kinetics of phage production. The bacteriophage infection led to a decrease in maximum specific growth rate of 15% from 0.74h-1 to 0.63h-1. Under steady state conditions, a constant cell specific ssDNA formation rate of 0.15+/-0.004 mgssDNA gCDW-1h-1 was observed, which was independent of the growth rate. Using the estimated kinetic parameters for E. coli infected with bacteriophage M13, the ssDNA concentration in the steady state could be predicted as function of the dilution rate and the glucose concentration in the substrate. Scalability of milliliter-scale data was approved by steady state studies on a liter-scale at a selected dilution rate. An ssDNA space-time yield of 5.7mgL-1h-1 was achieved with increased glucose concentration in the feed at a dilution rate of 0.3h-1, which is comparable to established fed-batch fermentation with bacteriophage M13 for ssDNA production. PMID- 28645581 TI - Improvement of isopropanol tolerance of Escherichia coli using adaptive laboratory evolution and omics technologies. AB - Isopropanol (IPA) is the secondary alcohol that can be dehydrated to yield propylene. To produce IPA using microorganisms, a significant issue is that the toxicity of IPA causes retardation or inhibition of cell growth, decreasing the yield. One possible strategy to overcome this problem is to improve IPA tolerance of production organisms. For the understanding of tolerance to IPA, we performed parallel adaptive laboratory evolution (ALE) of Escherichia coli under IPA stress. To identify the genotypic change during ALE, we performed genome re sequencing analyses of obtained tolerant strains. To verify which mutations were contributed to IPA tolerance, we constructed the mutant strains and quantify the IPA tolerance of the constructed mutants. From these analyses, we found that five mutations (relA, marC, proQ, yfgO, and rraA) provided the increase of IPA tolerance. To understand the phenotypic change during ALE, we performed transcriptome analysis of tolerant strains. From transcriptome analysis, we found that expression levels of genes related to biosynthetic pathways of amino acids, iron ion homeostasis, and energy metabolisms were changed in the tolerant strains. Results from these experiments provide fundamental bases for designing IPA tolerant strains for industrial purposes. PMID- 28645582 TI - Improved pFastBacTM donor plasmid vectors for higher protein production using the Bac-to-Bac(r) baculovirus expression vector system. AB - The Autographa californica multiple nucleopolyhedrovirus (AcMNPV)-based Bac-to Bac(r) expression system consists of a bacmid and five pFastBacTM donor transfer vectors. It has been widely used for eukaryotic gene expression in insect cells to elucidate gene function in biotechnology laboratories. The pFastBacTM vectors contain a 50bp AcMNPV polyhedrin (polh) promoter and a 127bp SV40 polyadenylation (pA) signal for cloning a gene of interest into the bacmid, resulting in unsolved lower gene expression levels than the wild type (wt) AcMNPV in insect cells. Therefore, the purpose of this research is to understand why the Bac-to-Bac system produces lower gene expression levels. Here, we determined that bacmids transposed with pFastBacTM vectors produced 3-4 fold lower levels of certain proteins than the wt AcMNPV. We found that an 80bp cis element 147bp upstream of the 50bp polh promoter and a 134bp polh pA signal are required in pFastBacTM to achieve bacmid protein expression levels equivalent to wt AcMNPV in High Five insect cells. Therefore, researchers currently using pFastBacTM vectors for protein expression can transfer their genes of interest into the improved vectors in this report to elevate protein expression yields in insect cells to reduce protein production costs. PMID- 28645583 TI - Societal constraints related to environmental remediation and decommissioning programmes. AB - The decisions related to decommissioning or environmental remediation projects (D/ER) cannot be isolated from the socio-political and cultural environment. Experiences of the IAEA Member States point out the importance of giving due attention to the societal aspects in project planning and implementation. The purpose of this paper is threefold: i) to systematically review societal constraints that some organisations in different IAEA Member States encounter when implementing D/ER programmes, ii) to identify different approaches to overcome these constraints and iii) to collect examples of existing practices related to the integration of societal aspects in D/ER programmes worldwide. The research was conducted in the context of the IAEA project Constraints to Decommissioning and Environmental Remediation (CIDER). The research results show that societal constraints arise mostly as a result of the different perceptions, attitudes, opinions and concerns of stakeholders towards the risks and benefits of D/ER programmes and due to the lack of stakeholder involvement in planning. There are different approaches to address these constraints, however all approaches have common points: early involvement, respect for different views, mutual understanding and learning. These results are relevant for all on-going and planned D/ER programmes. PMID- 28645584 TI - Effects of intranasal treatment with slow (GYY4137) and rapid (NaHS) donors of hydrogen sulfide in lipopolysaccharide-induced airway inflammation in mice. AB - We have investigated the effects of slow (GYY4137) and rapid (NaHS) hydrogen sulfide (H2S) releasing donors in lipopolysaccharide (LPS)-induced airway inflammation in mice. LPS (0.1 mg/ml) in 60 MUl PBS was administered by the intranasal (i.n.) route and control group received vehicle, whereas the subgroups of mice were treated with i.n. GYY4137 or NaHS. The tracheal reactivity, inflammatory cell count in bronchoalveolar lavage (BAL) fluid and lung histopathology were evaluated in all groups 48 h after LPS/PBS applications. 5 Hydroxytryptamine (5-HT)-induced contraction response in isolated tracheas was enhanced after LPS treatment but carbachol response was not altered. Incubation with atropine (10-6 M), 5-HT2A receptor antagonist ketanserin (10-9-10-7 M) and 5 HT3 receptor antagonist alosetron (10-8 and 10-7 M) prevented 5-HT-induced hyperreactivity whereas 5-HT4 receptor antagonist GR113808 (10-7 M, 10-6 M) did not have any effect in LPS-treated group. Electrical field stimulation (EFS) of isolated tracheas elicited frequency-dependent contractile response, which was not altered by LPS treatment alone but was enhanced in the presence of 5-HT (10-9 10-4 M). This data indicated that 5-HT2A and 5-HT3 receptors, and acetylcholine released from cholinergic nerves were contributing to 5-HT-induced hyperreactivity in the present experiments. The increase in neutrophil count along with cytokine (IL-1beta, TNF-alpha) levels in bronchoalveolar lavage (BAL) fluid and histopathological changes like paranchymal inflammation and interalveolar thickening were determined in LPS-treated mice. H2S production in lung homogenates were determined by the methylene blue assay, and found to be similar in both LPS and control groups. The experiments conducted after i.n. treatment with H2S donors has shown that only GYY4137 (1 mg/kg) inhibited 5-HT induced hyperreactivity, and both GYY4137 and NaHS (1 mg/kg) prevented the neutrophil increase in BAL fluid in LPS-induced airway inflammation. IL-1beta increase in BAL fluid was abolished by both GYY4137 and NaHS treatments whereas TNF-alpha levels remained unchanged. Furthermore, GYY4137 treatment did not have any effect in LPS-induced changes of lung pathology whereas NaHS prevented the paranchymal inflammation. The different H2S releasing pattern of these donors may explain the difference of their effects in this model. Compounds that provide stable H2S levels via local application may be a new therapeutic approach in airway inflammation. PMID- 28645585 TI - Thrombocytopenia and Neurosurgery: A Literature Review. AB - INTRODUCTION: The absence of evidence-based guidelines for platelet transfusion surrounding invasive neurosurgical procedures leads to uncertainty in management. Multiple studies have illuminated this lack of high quality data, and subsequent reliance on expert opinion. The generally accepted threshold for platelet transfusion has hovered around 100,000/MUL. METHODS: We have conducted a review of available clinical literature to identify any evidence that may support or refute these general guidelines, in an attempt to clarify the need for platelet transfusion in the patient requiring neurosurgical intervention. RESULTS: The available evidence is sparse and of low quality, but suggests that a platelet count <100,000/MUL is associated with increased risk of hemorrhagic complications. In addition, the acuity of thrombocytopenia, magnitude of decrease in platelet count, and responsiveness to platelet transfusions impact the risk of neurosurgical intervention, and should be taken into account when evaluating a patient's surgical candidacy. Higher quality, prospective studies on the subject are unlikely, given a general lack of clinical equipoise on the subject, and the ethical concerns such a study would present. PMID- 28645586 TI - Venous Sinus Stenting in the Management of Patients with Intracranial Hypertension Manifesting with Skull Base Cerebrospinal Fluid Leaks. AB - BACKGROUND: A subset of patients with skull base cerebrospinal fluid (CSF) leaks are found to have elevated intracranial pressure (ICP). In these patients, elevated ICP is thought to contribute to both the pathophysiology of the leak and postoperative leak recurrences. Current strategies for postoperative ICP control include medical therapy and shunting procedures. The aim of this study is to report the use of venous sinus stenting (VSS) in the management of patients with skull base CSF leaks caused by elevated ICP. METHODS: We performed a retrospective investigation of 2 patients who underwent surgical repair of skull base CSF leaks and were found to have elevated ICP associated with venous sinus stenosis and subsequently treated with VSS. RESULTS: Two patients underwent successful surgical repair of skull base CSF leaks with perioperative ICP monitoring via temporary lumbar catheters. Postoperative CSF pressure measurement demonstrated elevated ICP. Both patients were found to have venous sinus stenosis on further workup and subsequently underwent VSS for treatment of intracranial hypertension. Both patients had improvement in their symptoms with no evidence of recurrent CSF leak at follow-up. CONCLUSIONS: Patients with skull base CSF leaks of unknown etiology should undergo CSF pressure monitoring postoperatively and, if found to be elevated, be treated for intracranial hypertension. In patients unresponsive to, or intolerant of, medical therapy, VSS can provide an alternative option to medical and surgical shunting procedures for treatment of intracranial hypertension in patients with skull base CSF leaks and venous sinus stenosis. PMID- 28645587 TI - Dawn of an Even Newer Era: Mechanical Thrombectomy for Acute Ischemic Stroke Beyond 6 to 8 Hours. PMID- 28645588 TI - Long-Term Outcomes of Mechanical Thrombectomy for Treatment of Acute Ischemic Stroke. PMID- 28645589 TI - A Bug in the Brain and the Future of Neurosciences. PMID- 28645590 TI - Endoscopic Supracerebellar Transtentorial Approach to Atrium of Lateral Ventricle: Preliminary Surgical and Optical Considerations. AB - OBJECTIVE: We sought to report the operative techniques of the endoscopic supracerebellar transtentorial approach (ESTA) to the atrium of the lateral ventricle, especially focusing on the role of the endoscope and analyzing optically related issues. METHODS: A retrospective data review was performed on 5 patients with lesions in the atrium of the lateral ventricle undergoing the ESTA. The patients were positioned in the three quarters prone position, and a paramidline linear incision was used. After performing a suboccipital craniotomy extending immediately above the transverse sinus and tentorium incision with precisely neuronavigation, corticotomy in the posterior mediobasal temporal region created a corridor to the tumor. All of the procedures were performed with an endoscope in a pneumatic arm holder. The preoperative and postoperative perimetry test and diffusion tensor imaging fiber tracking of the optic radiations were compared and analyzed. RESULTS: Three patients had meningiomas, and 2 patients had high-grade gliomas in the atrium. The meningiomas were totally removed, and the gliomas were subtotally resected. One patient with glioblastoma died 2 months later after surgery because of the tumor progression; the remaining 4 patients had a visual field deficit without any other neurologic complications. The endoscope improved the surgical viewing angle, which was restricted by the microscope and slope of the tentorium. CONCLUSIONS: ESTA is an alternative route to the atrium of the lateral ventricle. However, the collateral sulcus, which is highly relied on in neuronavigation, is illegible in the limited area. And the visual field deficit remains the primary challenge with this approach. PMID- 28645591 TI - Surgical Repair of Iatrogenic Transverse-Sigmoid Sinus Laceration with a Dural Flap During Skull Base Tumor Surgery: A Technical Case Report. AB - BACKGROUND: Injury to cerebral venous sinuses during craniotomy procedures can cause significant blood loss or venous air embolism, potentially leading to serious morbidity or mortality. When iatrogenic sinus injuries occur, it is essential to promptly obtain hemostasis and repair the sinus defect. CASE DESCRIPTION: We report on a 43-year-old woman that sustained a transverse-sigmoid sinus injury during a retrosigmoid craniotomy for resection of a cerebellopontine angle meningioma. Sinus repair was performed using a reflected dural flap with excellent outcome. CONCLUSIONS: The use of a reflected dural flap for closure of a widely torn sinus proved to be an effective and straightforward sinus repair strategy, with postoperative imaging demonstrating persistent patency of the sinus. The described technique may be a useful addition to any neurosurgeon's armamentarium and should be considered during cases of complex sinus injuries. PMID- 28645592 TI - Enlarged Encephalo-Duro-Myo-Synangiosis Treatment for Moyamoya Disease in Young Children. AB - OBJECTIVE: To retrospectively evaluate the midterm therapeutic effect of enlarged encephalo-duro-myo-synangiosis (EDMS) for moyamoya disease (MMD) in young children. METHODS: Seventy-seven children diagnosed with MMD by digital subtraction angiography (DSA) or magnetic resonance angiography (MRA) were treated between January 2011 and December 2014 in our center. Their clinical features, imaging, and operative reports were analyzed. RESULTS: Four patients presented with intracerebral hemorrhage, whereas 73 presented with ischemic symptoms. Revascularization procedures were performed unilaterally on 11 left hemispheres and 9 right hemispheres, and 57 had bilateral surgeries. The average length of surgery was 143 +/- 24 minutes, with 28 +/- 9 mL of blood loss. The mean period of follow-up was 28.43 +/- 15.31 months. Cerebral blood flow increased 3 months after the operations in the previously affected regions. Collateralization from the deep temporal artery, superficial temporal artery, and the middle meningeal artery was found by DSA or MRA. In cases where single-photon emission computed tomography was obtained, it demonstrated better perfusion postoperatively. The ischemic symptoms were relieved in 118 (88.06%) hemispheres, and remained stable in 5 (3.73%) hemispheres. There were 12 radiographic cerebral infarctions (8.96%) within 1 month postoperatively. CONCLUSIONS: Enlarged EDMS is safe and effective for MMD in young children. Extensive and multilayered revascularization could significantly preserve neurologic function. The long-term effect on posterior circulation disease development needs further investigation. PMID- 28645593 TI - The Healthcare Landscape: Are Doctors Agents of Change or Impediments to Change? PMID- 28645594 TI - Publication Metrics in Neurosurgery. PMID- 28645595 TI - Transforaminal Endoscopic Decompression for Displaced End Plate Fracture After Lateral Lumbar Interbody Fusion: Technical Note. AB - Lateral lumbar interbody fusion is a minimally invasive approach to anterior spinal column fusion, deformity correction, and indirect decompression of the lumbar spine. A rarely reported possible complication of the procedure is end plate fracture, which has the potential for nerve root compression. Here we present a case of end plate fracture and nerve compression after stand-alone lateral lumbar interbody fusion, its diagnosis, and its subsequent successful treatment with transforaminal endoscopic spine surgery. The case highlights the possible role for minimally invasive endoscopic surgery as a rescue procedure after fusion complication. PMID- 28645596 TI - Endoscopic Removal of a Bullet That Migrated to the Third Ventricle Causing Hydrocephalus. AB - BACKGROUND: Hydrocephalus caused by an intraventricular bullet is a rare event. We report a case of endoscopic removal of an intraventricular bullet. CASE DESCRIPTION: A 66-year-old man was admitted with a gunshot wound to the head after a suicide attempt. The bullet migrated from the frontal parenchyma to the third ventricle day 4 of admission. On day 21 of admission, the patient developed hydrocephalus with obstruction of the cerebral aqueduct. The bullet was accessed through an endoscopic third ventriculostomy and removed using an endoscope. CONCLUSIONS: Hydrocephalus may develop in patients with intraventricular foreign objects. When such objects must be removed, the endoscopic approach is a safe, efficient, and minimally invasive procedure. To our knowledge, this is the first case in the literature of foreign object removal from the ventricle via a transcortical endoscopic approach. PMID- 28645597 TI - Spinal Arteriovenous Malformation Associated with Parkes Weber Syndrome: Report of Two Cases and Literature Review. AB - OBJECTIVE: To present 2 cases of Parkes Weber syndrome (PWS) with spinal arteriovenous malformation (AVM) and discuss the radiologic features and clinical treatment with literature review. METHODS: Clinical data on 2 patients with PWS with spinal AVM was acquired in a prospective follow-up investigation. Clinical manifestations, radiographic features, procedural results, and follow-up outcome were collected and reviewed together with a literature review. RESULTS: The first patient presented with limb weakness and urinary dysfunction and the second with repetitive subarachnoid hemorrhage followed by paraplegia. Limb hypertrophy, skin ulceration, and extensive microfistulas in the affected limb were observed in both patients. Spinal AVM was confirmed by digital subtraction angiography and endovascular embolization was performed. The first patient experienced limb amputation at 6-year follow-up as a result of chronic ulceration and the second did not have neurologic improvement. After literature review, 15 cases (male/female ratio, 5:10; mean age, 22+/-10.4 years) were included. The presentations comprised subarachnoid hemorrhage in 6, radicular pain in 5, myelopathy in 4, and asymptomatic in 1. Embolization was performed in 9 cases, solitary surgery in 2, and combined therapy in 4. Among 10 cases with known follow-up results, 6 achieved neurologic recovery after surgery and 1 died after solitary surgery. CONCLUSIONS: Awareness of the association between spinal AVM and PWS is essential for radiographic screening of spinal lesions with myelopathy or intracranial subarachnoid hemorrhage. Clinical therapeutic strategy should be multidisciplinary and individualized on the basis of vasculature and lesion behavior. PMID- 28645598 TI - Efficacy of Early Surgery for Neurological Improvement in Spinal Cord Injury without Radiographic Evidence of Trauma in the Elderly. AB - BACKGROUND: The optimal timing for surgery for patients with spinal cord injury without radiographic evidence of trauma (SCIWORET) remains unclear. This is especially true in the elderly, given that most studies are done with younger patients to avoid age-related comorbidities. We aimed to compare the efficacy of early (<24 hours postinjury) and late (>24 hours postinjury) surgery in patients with SCIWORET aged >=65 years. METHODS: We identified patients aged >=65 years who underwent surgery for SCIWORET between January 1995 and February 2016. The primary outcome was a change in the Japanese Orthopaedic Association (JOA) score at discharge, with a recovery of >50% defined as a favorable neurologic outcome. Logistic regression analysis was performed, and model fit was assessed using the Hosmer-Lemeshow test. RESULTS: Eighty patients aged >=65 years with SCIWORET underwent surgery were enrolled. Favorable neurologic outcomes were seen in 43.3% of those who underwent early surgery, but only in 18.0% of those who underwent late surgery. Logistic regression analysis, adjusted for age, sex, comorbidities (Charlson Comorbidity Index), and JOA score, revealed that early surgery independently predicted favorable outcomes (odds ratio, 4.06; 95% confidence interval, 1.25-13.20), with excellent calibration (Hosmer-Lemeshow, P = 0.857). CONCLUSIONS: The present study indicated that early surgery within 24 hours of injury for elderly patients with SCIWORET could lead to more favorable neurologic improvements. We believe that chronological age alone should not be considered sufficient justification to deny patients early surgical decompression for SCIWORET. PMID- 28645599 TI - Biplanar Fluoroscopy-Guided Percutaneous Lead Implantation for Spinal Cord Stimulation: Technical Note. AB - INTRODUCTION: The correct positioning of spinal cord stimulator leads is assessed radiographically during their percutaneous implantation for trial stimulation. Usually the C-arm is repositioned several times to allow imaging in different planes, which may extend the total duration of surgery. The study aimed to evaluate whether the concurrent intraoperative use of 2 C-arms could safely reduce the duration of surgery. MATERIALS: This retrospective study included cases of percutaneous implantation of a spinal cord stimulation (SCS) lead for trial neurostimulation between 2006 and 2011. The duration of the surgical intervention was recorded, along with the duration of the preparation stage in the operating room. In addition, total radiation exposure time per case was recorded. RESULTS: Ninety-four patients underwent percutaneous implantation of an SCS lead (72 thoracolumbar, 22 cervical). In 73 cases 2 C-arms were used, with 21 cases performed with a single C-arm. In both the cervical and thoracolumbar groups, a biplanar configuration was associated with significant reduction in the mean length of the surgical phase, by 29 minutes (P = 0.017) and 14 minutes, respectively (P = 0.016), albeit while increasing the duration of the preoperative preparation stage. There was no significant difference in the total duration in the operating room or in the total radiation exposure time between groups. CONCLUSIONS: Here we present a technical note on the use of a biplanar fluoroscopy configuration for percutaneous implantation of SCS leads. This arrangement correlated with a reduction in surgery duration without increasing total radiation exposure, representing a practical and safe adjustment to current practice. PMID- 28645600 TI - Newly Detected Cervical Spinal Dural Arteriovenous Fistula on Magnetic Resonance Angiography Causing Intracranial Subarachnoid Hemorrhage. AB - BACKGROUND: Although an asymptomatic spinal dural arteriovenous fistula (SDAVF) can sometimes be incidentally detected on magnetic resonance imaging (MRI), there are no previous reports showing the development of an SDAVF on MRI or magnetic resonance angiography (MRA). CASE DESCRIPTION: A 64-year old man with unruptured vertebral artery dissection (VAD) developed a subarachnoid hemorrhage (SAH) during regular follow-up. Emergent endovascular coil internal trapping for the VAD was performed; however, angiography after the endovascular treatment showed a lower cervical SDAVF. The SDAVF was considered the bleeding source based on subsequent spinal MRI, and endovascular embolization was performed. In this case, previous serial MRA examinations indicated that the SDAVF appeared for the first time during follow-up, and SAH occurred. CONCLUSIONS: This may be the first report in which serial MRA studies demonstrated the course of this condition, from the appearance of an SDAVF to the development of SAH. An abnormal vascular structure detected on MRA indicated abnormal enlargement of the perimedullary vein and the presence of a cervical SDAVF. A lower cervical SDAVF should be suspected if such an abnormal vascular structure is detected on MRA. PMID- 28645601 TI - A Cranial Trauma was the Cause of Death of Charles VIII of France (1470-1498). AB - This article summarizes the reign, life and death, of Charles VIII of France. Also we intend to investigate current views on his cause of death, contradictions and opinions of his biographers. Poisoning, disease, and injury are the possible causes of his death but, according to the literature, cranial trauma was the most probable cause of death of the King Charles VIII of France. PMID- 28645602 TI - Clinical Application of Insertion Force Sensor System for Coil Embolization of Intracranial Aneurysms. AB - INTRODUCTION: In endovascular embolization for intracranial aneurysms, it is important to properly control the coil insertion force. However, the force can only be subjectively detected by the subtle feedback experienced by neurointerventionists at their fingertips. The authors envisioned a system that would objectively sense and quantify that force. In this article, coil insertion force was measured in cases of intracranial aneurysm using this sensor, and its actual clinical application was investigated. METHODS: The sensor consists of a hemostatic valve (Y-connector). A little flexure was intentionally added in the device, and it creates a bend in the delivery wire. The sensor measures the change in the position of the bent wire depending on the insertion force and translates it into a force value. Using this, embolization was performed for 10 unruptured intracranial aneurysms. RESULTS: The sensor adequately recorded the force, and it reflected the operators' usual clinical experience. The presence of the sensor did not affect the procedures. The sensor enabled the operators to objectively note and evaluate the insertion force and better cooperative handling was possible. Additionally, other members of the intervention team shared the information. Force records demonstrated the characteristic patterns according to every stage of coiling (framing, filling, and finishing). CONCLUSIONS: The force sensor system adequately measured coil insertion force in intracranial aneurysm coil embolization procedures. The safety of this sensor was demonstrated in clinical application for the limited number of patients. This system is useful adjunct for assisting during coil embolization for an intracranial aneurysm. PMID- 28645603 TI - Robotic Transnasal Endoscopic Skull Base Surgery: Systematic Review of the Literature and Report of a Novel Prototype for a Hybrid System (Brescia Endoscope Assistant Robotic Holder). AB - BACKGROUND: Although robotics has already been applied to several surgical fields, available systems are not designed for endoscopic skull base surgery (ESBS). New conception prototypes have been recently described for ESBS. The aim of this study was to provide a systematic literature review of robotics for ESBS and describe a novel prototype developed at the University of Brescia. METHODS: PubMed and Scopus databases were searched using a combination of terms, including Robotics OR Robot and Surgery OR Otolaryngology OR Skull Base OR Holder. The retrieved papers were analyzed, recording the following features: interface, tools under robotic control, force feedback, safety systems, setup time, and operative time. A novel hybrid robotic system has been developed and tested in a preclinical setting at the University of Brescia, using an industrial manipulator and readily available off-the-shelf components. RESULTS: A total of 11 robotic prototypes for ESBS were identified. Almost all prototypes present a difficult emergency management as one of the main limits. The Brescia Endoscope Assistant Robotic holder has proven the feasibility of an intuitive robotic movement, using the surgeon's head position: a 6 degree of freedom sensor was used and 2 light sources were added to glasses that were therefore recognized by a commercially available sensor. CONCLUSIONS: Robotic system prototypes designed for ESBS and reported in the literature still present significant technical limitations. Hybrid robot assistance has a huge potential and might soon be feasible in ESBS. PMID- 28645604 TI - Posterior Paramedian Approach to Ventrally Located Spinal Meningioma. AB - BACKGROUND: To approach a ventral spinal pathology, a lateral viewing angle is often required. However, lateral approaches to the spine are usually more technically demanding and require a certain amount of surgical expertise. In this report, we describe a simple and easy technique to obtain the lateral viewing angle to the ventral spinal pathology. CASE DESCRIPTION: The technique is demonstrated in a ventrally located meningioma at the C2 level. Axial magnetic resonance imaging showed a square posterior shift of the spinal cord with little lateral space, which necessitated a more lateral viewing angle than the conventional posterior approach. With the patient in a prone position, we made a horizontal skin incision at the level of C2 and unilaterally exposed the right side of the C1 and C2 laminae. We then made a small perpendicular incision on the medial portion of the paravertebral muscles, which we retracted longitudinally. This approach provided an unobstructed lateral view toward the spinal cord. Following a gross total removal of the tumor with minimal cord retraction, the patient made an uneventful recovery. Her preoperative neurologic symptoms completely resolved in 2 months. No significant muscle atrophy was observed on postoperative magnetic resonance imaging at 3 months. There was no long-term complication related to the muscle incision at 1-year follow-up. CONCLUSION: The posterior paramedian approach is a simple and versatile technique to obtain lateral viewing angle to the spine and useful for approaching lesions residing ventral to the spinal cord. PMID- 28645605 TI - Emergency Reoperations in Cranial Neurosurgery. AB - BACKGROUND: Complications after neurosurgical procedures that lead to reoperation are associated with poor outcome and economic costs. Therefore the aim of our study was to establish predictors of reoperation due to complications after cranial neurosurgery. METHODS: We retrospectively analyzed 875 patients who underwent a cranial neurosurgical procedure. We used univariate and multivariate logistic regression analysis to determine the possible predictors of reoperation. RESULTS: A total of 78 (8.91%) patients underwent emergency reoperation. Those patients more often were operated due to brain tumor (50.65% vs. 38.43%; P = 0.036) and least often due to head trauma (22.08% vs. 32.99%; P = 0.049). Reoperated patients more often underwent frontal craniotomy (26.47% vs. 13.46%; P < 0.01) and least often had burr hole surgery (7.35% vs. 19.21%; P = 0.016). Patients who did not require reoperation were more often operated during a weekend (5.29% vs. 16.99%; P < 0.01). After adjustment for confounders, weekend surgeries (OR: 0.309; 95% CI: 0.111-0.861; P = 0.025) remained independently associated with reduced risk of reoperation and frontal craniotomy (OR: 1.355; 95% CI: 1.005-1.354; P = 0.046) and lower mean cell hemaglobin concentration (OR: 2.227; 95% CI: 1.230-4.033; P < 0.01) remained independently associated with higher risk of reoperation. CONCLUSIONS: Brain tumor surgery and frontal craniotomy are associated with a higher risk of emergency reoperation. Patients with head trauma, operated on during a weekend, and those who underwent burr hole surgery are less likely to be reoperated. Frontal craniotomy and lower mean cell hemoglobin concentration are independently associated with a higher risk of reoperation and operation during a weekend with lower risk of reoperation. PMID- 28645607 TI - The TCA cycle as a bridge between oncometabolism and DNA transactions in cancer. AB - Cancer cells exploit metabolic rearrangements for sustaining their high proliferation rate and energy demand. The TCA cycle is a central metabolic hub necessary for ATP production and for providing precursors used in many biosynthetic pathways. Thus, dysregulation of the TCA cycle flux is frequently observed in cancer. The identification of mutations in several enzymes of the TCA cycle in human tumours demonstrated a direct connection between this metabolic pathway and cancer occurrence. Moreover, changes in the expression/activity of these enzymes were also shown to promote metabolic adaptation of cancer cells. In this review, the main genetic and non-genetic alterations of TCA cycle in cancer will be described. Particular attention will be given to extrametabolic roles of TCA cycle enzymes and metabolites underlying the regulation of nuclear and mitochondrial DNA transactions. PMID- 28645606 TI - Presence of a Malignant Tumor as a Novel Predictive Factor for Repeated Recurrences of Chronic Subdural Hematoma. AB - BACKGROUND: Various risk factors for recurrence of chronic subdural hematomas (CSDHs) have been reported, including alcohol addiction and diabetes mellitus. However, the significance of malignant tumors with respect to CSDH recurrence remains unclear. METHODS: We retrospectively evaluated 281 patients with a first time CSDH from 2006 to 2016. The difference in the recurrence rate within 100 days postoperatively was compared between patients with a past or present extracranial malignant tumor and those with neither a past nor present extracranial malignant tumor at presentation. Patients in the former group were further divided into 2 subgroups: those with present tumors and those with past tumors. Statistical significance was defined as P < 0.05. RESULTS: A significantly greater repeated recurrence rate (>2 recurrences) was observed in patients with than without a past or present malignant tumor (8.5% vs. 1.7%, respectively; P = 0.01); no significant difference in the first recurrence rate was observed (19.1% vs. 16.2%, respectively; P = 0.63). Furthermore, patients with a present malignant tumor showed a marginally increased repeated recurrence rate than did patients with a past malignant tumor (20.0% vs. 3.1%, respectively; P = 0.053). In the multivariate analysis, a monolayer hematoma was the only risk factor for first recurrence (odds ratio, 3.16; P = 0.003), while a present malignant tumor was the only significant risk factor for repeated recurrences (odds ratio, 16.49; P = 0.002). CONCLUSIONS: The presence of a malignant tumor can be a novel predictive factor for repeated CSDH recurrences. Patients with malignant tumors should be carefully followed, and treatment options such as subcutaneous reservoir placement may be considered to prevent further recurrences. PMID- 28645608 TI - The role of losartan in preventing vascular remodeling in spontaneously hypertensive rats by inhibition of the H2O2/VPO1/HOCl/MMPs pathway. AB - Vascular peroxidase 1 (VPO1) has been proved to be associated with vascular endothelial cell apoptosis by producing reactive oxygen species. However, the contribution of VPO1 to the development of vascular remodeling (VR) remains to be fully characterized. We explored the role of VPO1 in VR in spontaneously hypertensive rats (SHRs) and the underlying mechanism of losartan in inhibiting VR. Compared to Wistar-Kyoto (WKY) rats, the SHR showed remodeling of their vascular walls. The level of VPO1 and the hydrogen peroxide (H2O2) concentration were increased in the SHRs. However, the SHRs pretreated with losartan showed significant inhibition of blood pressure and VR and decreased levels of VPO1 and H2O2 compared to the non-treated SHRs. Angiotensin II significantly increased the expressions of MMP-2, MMP-9 and the concentrations of H2O2 and hypochlorous acid (HOCl) in vascular smooth muscle cells (VSMCs). However, only the H2O2 level increased in VSMCs when transfected with VPO1 shRNA. These results support a critical but previously unrecognized role of VPO1 in VR and suggest that therapies to reduce VPO1 may be novel approaches for VR. PMID- 28645609 TI - Identification and characterization of a novel antimicrobial protein from the housefly Musca domestica. AB - Antimicrobial peptides/proteins are immune-related molecules that are widely distributed in bacteria, fungi, plants, invertebrates and higher animals. They have exhibited great potential to be developed into antimicrobial drugs. The housefly, Musca domestica, lives in a highly contaminated environment and has adapted a robust immune system against various pathogens. As an effort to search for new antimicrobial molecules in the housefly, we investigated the function of an uncharacterized gene firstly by confirming that its expression was induced by infection in M. domestica. The corresponding protein was then shown to have potent antimicrobial activity. Scanning Electron Microscopy data showed that treatment of C. albicans cells with the protein caused cell size decreasing and cell elongation. The results here suggest the protein a novel class of antimicrobial protein and provide new insights into the immunological mechanisms by which M. domestica combats invading C. albicans. PMID- 28645610 TI - Inhibition of mitochondrial translation effectively sensitizes renal cell carcinoma to chemotherapy. AB - The functional importance of mitochondrial protein translation has been recently documented in the context of various cancers but not renal cell carcinoma (RCC). In lines with these efforts, our work demonstrates that mitochondrial translation inhibition by tigecycline or depletion of EF-Tu mitochondrial translation factor effectively targets RCC and significantly sensitizes RCC response to chemotherapy. We show that antibiotic tigecycline inhibits multiple biological functions of RCC, including growth, colony formation and survival. It also significantly enhances in vitro and in vivo efficacy of paclitaxel in RCC. Tigecycline preferentially inhibits translation of mitochondrial DNA-encoded proteins, activities of mitochondrial respiratory complexes that contain mitochondrially encoded subunits. As a consequence of mitochondrial respiratory chain inhibition, decreased mitochondrial respiration is observed in RCC cells exposed to tigecycline. In contrast, tigecycline is ineffective in RCC rho0 cells that lack mitochondrial DNA and subsequent mitochondrial respiration, further confirm mitochondrial translation inhibition as the mechanism of tigecycline's action in RCC. Importantly, genetic inhibition of mitochondrial translation by EF Tu knockdown reproduced the inhibitory effects of tigecycline. Finally, we show the association between mitochondrial translation inhibition and suppression of PI3K/Akt/mTOR signaling pathway. Our work used pharmacological and genetic strategies to demonstrate the important roles of mitochondrial translation in RCC and emphasize the therapeutic value of sensitizing RCC to chemotherapy. PMID- 28645611 TI - Activation of central nesfatin-1/NucB2 after intraperitoneally administered cisplatin in rats. AB - Cisplatin, known as an anticancer drug, has been widely used; however, diverse disadvantageous side effects, including appetite loss, afflict patients. Nesfatin 1/NucB2, discovered as an anorexic neuropeptide, is broadly expressed in the central nervous system (CNS) and peripheral organ. In the present study, we examined the effects of intraperitoneally (i.p.) administered cisplatin on central nesfatin-1/NucB2. Saline, as control, or cisplatin (6 mg/kg dissolved in saline) was i.p. administered in adult male Wistar rats (180-220 g). Cumulative food intake was remarkably suppressed for at least 24 h and body weight was significantly smaller at 24 h after i.p. administration of cisplatin compared to control group. At 90 min after i.p. administration, they were perfused, followed by carrying out double-immunohistochemistry for Fos and nesfatin-1/NucB2. The percentage of nesfatin-1/NucB2 immunoreactive neurons expressing Fos was marked increased in the hypothalamus and brainstem after i.p. administration of cisplatin. Intracerebroventricularlly administered nesfatin-1/NucB2-antisense resulted in a significant attenuation of decreased food intake for 2 h after i.p. administration of cisplatin compared to nesfatin-1/NucB2-missense treated group. These results suggest that i.p. administration of cisplatin activated, at least in part, nesfatin-1/NucB2 neuron in the CNS and may exert anorexigenic effects in rats. PMID- 28645612 TI - IL-1beta induced methylation of the estrogen receptor ERalpha gene correlates with EMT and chemoresistance in breast cancer cells. AB - Inflammation has been recently acknowledged as a key participant in the physiopathology of oncogenesis and tumor progression. The inflammatory cytokine IL-1beta has been reported to induce the expression of markers associated with malignancy in breast cancerous cells through Epithelial-Mesenchymal Transition (EMT). Aggressive breast cancer tumors classified as Triple Negative do not respond to hormonal treatment because they lack three crucial receptors, one of which is the estrogen receptor alpha (ERalpha). Expression of ERalpha is then considered a good prognostic marker for tamoxifen treatment of this type of cancer, as the binding of this drug to the receptor blocks the transcriptional activity of the latter. Although it has been suggested that inflammatory cytokines in the tumor microenvironment could regulate ERalpha expression, the mechanism(s) involved in this process have not yet been established. We show here that, in a cell model of breast cancer cells (6D cells), in which the inflammatory cytokine IL-1beta induces EMT by activation of the IL-1beta/IL 1RI/beta-catenin pathway, the up regulation of TWIST1 leads to methylation of the ESR1 gene promoter. This epigenetic modification produced significant decrease of the ERalpha receptor levels and increased resistance to tamoxifen. The direct participation of IL-1beta in these processes was validated by blockage of the cytokine-induced signaling pathway by wortmannin inactivation of the effectors PI3K/AKT. These results support our previous reports that have suggested direct participation of the inflammatory cytokine IL-1beta in the transition to malignancy of breast cancer cells. PMID- 28645613 TI - Regulation of testicular steroidogenesis by Foxa3 via transcriptional modulation of ERalpha signaling in type 2 diabetes mellitus (T2DM). AB - Although both insulin and estrogen receptor alpha (ERalpha) are known to exert inhibitory effects on testicular steroidogenesis, it remains unknown whether these pathways regulate testosterone (T) production under certain pathological conditions [e.g., type 2 diabetes mellitus (T2DM)] in a coordinated manner. Here, we found that the expression of forkhead box protein A3 (Foxa3), an essential transcriptional regulator engaged in adipogenesis and energy metabolism, was significantly down-regulated in the Leydig cells (LCs) from T-deficient T2DM mice. Functionally, upon hCG stimulation, Foxa3 recruits to the Esr1 promoter and suppresses the transactivation of Esr1 gene. Disruption of this recruitment by T2DM-elicited hyperinsulinemia led to abnormal activation of ERalpha pathway, inhibited steroidogenic enzyme genes expression, and thus caused inadequate T production. Therapeutically, insulin-impaired and Foxa3 ablation-compromised steroidogenesis were effectively rescued by a pharmacological inhibitor of the ERalpha pathway. These findings reveal an obligatory coregulatory role of Foxa3 in the regulation of ERalpha expression and of the Foxa3/ERalpha cascade, at least in part, in the pathogenesis of androgen deficiency caused by T2DM. PMID- 28645614 TI - Site-1 protease, a novel metabolic target for glioblastoma. AB - Sterol regulatory element binding proteins (SREBPs) are transcriptional regulators of lipids which promote glioblastoma growth. Here, we investigate the effect of inhibiting expression of SREBP target genes in human glioblastoma cells. This was achieved by using PF-429242 to inhibit site-1 protease (S1P), an enzyme required for SREBP activation. Treatment with PF-429242 decreased glioblastoma cell viability, induced apoptosis and downregulated steroid, isoprenoid and unsaturated fatty acid biosynthetic pathways. Several pro inflammatory genes were upregulated. Collectively, these results demonstrate the potential of S1P as a target for glioblastoma therapy. PMID- 28645615 TI - An energy-efficient data transmission scheme for remote state estimation and applications to a water-tank system. AB - An energy-efficient data transmission scheme for remote state estimation is proposed and experimentally evaluated in this paper. This new transmission strategy is presented by proving an upper bound of the system performance. Stability of the remote estimator is proved under the condition that some of the observation measurements are lost in a random probability. An experimental platform of two coupled water tanks with a wireless sensor node is established to evaluate and verify the proposed transmission scheme. PMID- 28645616 TI - Epidemiological and sociodemographic factors associated with complicated alcohol withdrawal syndrome. AB - OBJECTIVES: To analyse the influence of epidemiological and sociodemographic factors in complicated alcohol withdrawal syndrome (AWS). MATERIAL AND METHODS: A multicentre, observational prospective study was conducted on consecutively added patients with AWS hospitalised in internal medicine departments. We recorded sociodemographic, epidemiological, clinical and progression data. Complicated AWS was defined as that which progressed with seizures or delirium tremens. RESULTS: We studied 228 episodes of AWS in 219 patients. The mean age was 54.5 years (SD, 11.5), and 90.8% were men. AWS was the cause for hospitalisation in 39.9% of the patients. Some 27.1% of the cases presented seizures, and 32.4% presented delirium tremens. The daily quantity of alcohol ingested was 17.8 standard drink units (SD, 21.4), with 16.6 years of dependence (SD, 11.3). The pattern of alcohol abuse was regular in 82.8% of the patients. Some 38.4% of the patients were married or had a partner, and 45.6% had children. Some 72.7% of the patients were unemployed or retired. Some 68.5% had only completed primary studies. Some 4.8% consumed cannabis, 5.2% consumed cocaine and 3% consumed opioids. The independent variables related to complicated AWS were consumption of a drug other than alcohol (OR, 5.3; 95% CI 1.5-18.7), low education level (OR, 3.4; 95% CI 1.6 7.3) and hospitalisation for AWS (OR, 2.9; 95% CI 1.5-5.6). The model's receiver operating characteristic area was 0.718 (95% CI 0.643-0.793). CONCLUSIONS: Concomitant drug abuse and a low educational level could help identify patients at risk of complicated AWS. PMID- 28645617 TI - Featuring: Asymptomatic adolescent varicoceles. PMID- 28645618 TI - Featuring: Distal ureteral diameter in the resolution of vesicoureteral reflux. PMID- 28645619 TI - Supporting and caring for transgender and gender nonconforming youth in the urology practice. AB - INTRODUCTION: Gender identity is a person's internal sense of gender, which may be different than the sex they were assigned at birth. Pediatric urologists are starting to see more transgender and gender non-conforming (TGN) youth and need to be able to provide culturally competent and appropriate care for these patients and their caregivers. This review will discuss common transgender terminology, specific health concerns and treatment options. METHODS AND MATERIALS: A systematic literature review was performed on Medline(r), PubMed(r), and Google ScholarTM for key words transgender, gender dysphoria and gender identity disorder. Original research articles and relevant reviews were examined as well as transgender treatment guidelines from several organizations. These studies and expert opinion are summarized in this review. RESULTS: In this rapidly growing area of medicine, there is very little literature and few evidence-based studies. Treatment guidelines are based on small studies and expert opinion. CONCLUSION: Transgender and gender nonconforming youth are at high risk for mental health concerns and other health disparities based on their gender identity. Pediatric urologists can create a safe and welcoming environment for these patients and their caregivers to discuss these matters. Providers who are able to provide competent care for TGN youth can improve outcomes for this group. PMID- 28645620 TI - Jean-Paul Amoureux: Having fun with quadrupolar nuclei. PMID- 28645622 TI - In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1G93A mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to loss of upper and lower motor neurons (MNs). The mechanisms of neuronal death are largely unknown, thus prejudicing the successful pharmacological treatment. One major cause for MN degeneration in ALS is represented by glutamate(Glu)-mediated excitotoxicity. We have previously reported that activation of Group I metabotropic Glu receptors (mGluR1 and mGluR5) at glutamatergic spinal cord nerve terminals produces abnormal Glu release in the widely studied SOD1G93A mouse model of ALS. We also demonstrated that halving mGluR1 expression in the SOD1G93A mouse had a positive impact on survival, disease onset, disease progression, and on a number of cellular and biochemical readouts of ALS. We generated here SOD1G93A mice with reduced expression of mGluR5 (SOD1G93AGrm5-/+) by crossing the SOD1G93A mutant mouse with the mGluR5 heterozigous Grm5-/+ mouse. SOD1G93AGrm5-/+ mice showed prolonged survival probability and delayed pathology onset. These effects were associated to enhanced number of preserved MNs, decreased astrocyte and microglia activation, reduced cytosolic free Ca2+ concentration, and regularization of abnormal Glu release in the spinal cord of SOD1G93AGrm5-/+ mice. Unexpectedly, only male SOD1G93AGrm5-/+ mice showed improved motor skills during disease progression vs. SOD1G93A mice, while SOD1G93AGrm5-/+ females did not. These results demonstrate that a lower constitutive level of mGluR5 has a significant positive impact in mice with ALS and support the idea that blocking Group I mGluRs may represent a potentially effective pharmacological approach to the disease. PMID- 28645621 TI - Two delta opioid receptor subtypes are functional in single ventral tegmental area neurons, and can interact with the mu opioid receptor. AB - The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA). Here we demonstrate that a majority of both dopaminergic and non-dopaminergic VTA neurons express combinations of functional DOR1, DOR2, and/or MOR, and that within a single VTA neuron, DOR1, DOR2, and MOR agonists can differentially couple to downstream signaling pathways. As reported for the MOR agonist DAMGO, DPDPE and deltorphin II produced either a predominant K+ dependent hyperpolarization or a Cav2.1 mediated depolarization in different neurons. In some neurons DPDPE and deltorphin II produced opposite responses. Excitation, inhibition, or no effect by DAMGO did not predict the response to DPDPE or deltorphin II, arguing against a MOR-DOR interaction generating DOR subtypes. However, in a subset of VTA neurons the DOR antagonist TIPP-Psi augmented DAMGO responses; we also observed DPDPE or deltorphin II responses augmented by the MOR selective antagonist CTAP. These findings directly support the existence of two independent, stable forms of the DOR, and show that MOR and DOR can interact in some neurons to alter downstream signaling. PMID- 28645624 TI - Response to Letter to the Editor. PMID- 28645623 TI - Identification of a coumarin-based antihistamine-like small molecule as an anti filoviral entry inhibitor. AB - Filoviruses, consisting of Ebola virus, Marburg virus and Cuevavirus, cause severe hemorrhagic fevers in humans with high mortality rates up to 90%. Currently, there is no approved vaccine or therapy available for the prevention and treatment of filovirus infection in humans. The recent 2013-2015 West African Ebola epidemic underscores the urgency to develop antiviral therapeutics against these infectious diseases. Our previous study showed that GPCR antagonists, particularly histamine receptor antagonists (antihistamines) inhibit Ebola and Marburg virus entry. In this study, we screened a library of 1220 small molecules with predicted antihistamine activity, identified multiple compounds with potent inhibitory activity against entry of both Ebola and Marburg viruses in human cancer cell lines, and confirmed their anti-Ebola activity in human primary cells. These small molecules target a late-stage of Ebola virus entry. Further structure-activity relationship studies around one compound (cp19) reveal the importance of the coumarin fused ring structure, especially the hydrophobic substituents at positions 3 and/or 4, for its antiviral activity, and this identified scaffold represents a favorable starting point for the rapid development of anti-filovirus therapeutic agents. PMID- 28645625 TI - Foreword for the special issue on the Tenth International Workshop on Low Energy Electron Microscopy and Photoemission Electron Microscopy. PMID- 28645626 TI - What makes an active public realm? Opportunities and challenges for research. PMID- 28645627 TI - Does higher education protect against obesity? Evidence using Mendelian randomization. AB - OBJECTIVES: The aim of this explorative study was to examine the effect of education on obesity using Mendelian randomization. METHODS: Participants (N=2011) were from the on-going nationally representative Young Finns Study (YFS) that began in 1980 when six cohorts (aged 30, 33, 36, 39, 42 and 45 in 2007) were recruited. The average value of BMI (kg/m2) measurements in 2007 and 2011 and genetic information were linked to comprehensive register-based information on the years of education in 2007. We first used a linear regression (Ordinary Least Squares, OLS) to estimate the relationship between education and BMI. To identify a causal relationship, we exploited Mendelian randomization and used a genetic score as an instrument for education. The genetic score was based on 74 genetic variants that genome-wide association studies (GWASs) have found to be associated with the years of education. Because the genotypes are randomly assigned at conception, the instrument causes exogenous variation in the years of education and thus enables identification of causal effects. RESULTS: The years of education in 2007 were associated with lower BMI in 2007/2011 (regression coefficient (b)=-0.22; 95% Confidence Intervals [CI]=-0.29, -0.14) according to the linear regression results. The results based on Mendelian randomization suggests that there may be a negative causal effect of education on BMI (b=-0.84; 95% CI=-1.77, 0.09). CONCLUSION: The findings indicate that education could be a protective factor against obesity in advanced countries. PMID- 28645628 TI - The association between socioeconomic status and subclinical atherosclerosis in a rural Bangladesh population. AB - BACKGROUND: In Bangladesh, CVD accounts for the majority of non-communicable mortality. The purpose of this study was to determine the role of socioeconomic status (SES) on subclinical atherosclerosis measured as carotid intima-media thickness (IMT) in a rural Bangladesh population. METHODS: Carotid IMT was measured between 2010 and 2011 in 1022 participants (average age 46, 40% male) randomly selected from the Health Effects of Arsenic Longitudinal Study (HEALS), a population-based prospective cohort study based in rural Bangladesh. SES was measured as occupation type, land ownership, educational attainment, and television ownership. RESULTS: Half of the participants received formal education (53%) and under half owned land (48%) and a television (44%). Women were primarily homemakers (95%) and men worked as factory workers (24%), laborers (18%), or in business (55%). In univariate analysis, those owning greater than one acre of land (p=0.03), owning a television (p=0.02), or laborers and business owners compared to factory workers had higher levels of carotid IMT (p<0.01). In multivariate analysis after adjustment for confounders, only men employed in the business sector had elevated carotid IMT compared to factory workers. The association was strongest in older men (58.7MUm, 95% CI 17.2-100.0, >=50years old) compared to younger men (13.7MUm, 95% CI -7.8-35.2, <50years old). CONCLUSION: Business sector employment was positively associated with subclinical atherosclerosis after adjustment for confounders. This finding is consistent with evidence from other developing nations suggesting that certain SES factors are independent predictors of CVD. PMID- 28645629 TI - Production and characterization of aluminium oxide nanoshells on spray dried lactose. AB - Atomic layer deposition (ALD) enables deposition of dense nanometer thick metal oxide nanoshells on powder particles with precise thickness control. This leads to products with low weight fraction coating, also when depositing on nano- or micron sized powder particles. This study aimed at investigating the aluminium oxide nanoshell thickness required to prevent moisture sorption. The nanoshells were produced with ALD on spray-dried lactose, which is amorphous and extremely hygroscopic. The particles were studied with dynamic vapor sorption between 0 and 50% RH, light scattering, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and polarized light microscopy. The ALD did not induce any recrystallization of the amorphous lactose. The dynamic vapor sorption indicated that the moisture sorption was almost completely inhibited by the nanoshell. Neat amorphous lactose rapidly recrystallized upon moisture exposure. However, only ca. 15% of the amorphous lactose particles recrystallized of a sample with 9% (by weight) aluminium oxide nanoshell at storage for six months upon 75% RH/40 degrees C, which indicate that the moisture sorption was completely inhibited in the majority of the particles. In conclusion, the aluminium oxide nanoshells prevented moisture sorption and dramatically improved the long term physical stability of amorphous lactose. This shows the potential of the ALD-technique to protect drug microparticles. PMID- 28645630 TI - Evolution of Cyclodextrin Nanosponges. AB - Cyclodextrin-based nanosponges (CD-NSs) are insoluble, highly cross-linked 3D network polymers used in several scientific and technological fields, the main area of investigation concerns the pharmaceutical applications, in which CD-NSs have been mostly employed as drug delivery systems. CD-NSs can be generally grouped into four consecutive generations, taking into account their chemical composition and properties. The 1st generation of NSs are plain nanosponges, subdivided into four main types: urethane, carbonate, ester and ether NSs, depending on the chemical nature of the functional group connecting the CD to the cross-linker. The 2nd generation of NSs are modified nanosponges characterized by specific properties, such as fluorescence and electric charge. The 3rd generation of NSs is represented by stimuli-responsive CD polymers, which are able to modulate their behavior according to external variations in the environment, such as pH and temperature gradients, oxidative/reducing conditions, and finally the 4th generation of NSs, a new family of molecularly imprinted CD polymers (MIPs), exhibiting a high selectivity towards specific molecules. The following review focuses on the evolution of cyclodextrin nanosponges, listing some examples of each generation. PMID- 28645631 TI - Outcomes of First-Generation EGFR-TKIs Against Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Post Hoc Analysis of the BE-POSITIVE Study. AB - BACKGROUND: Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a "real-life" Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study. PATIENTS AND METHODS: Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations. RESULTS: Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR-mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19. CONCLUSION: Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy. PMID- 28645632 TI - Adjuvant Chemotherapy Guided by Molecular Profiling and Improved Outcomes in Early Stage, Non-Small-Cell Lung Cancer. AB - INTRODUCTION: Many early stage non-small-cell lung cancer (NSCLC) patients who are not considered candidates for adjuvant treatment according to current guidelines do harbor occult metastasis, and have disease recurrence despite complete resection. Although National Comprehensive Cancer Network (NCCN) guidelines suggest clinicopathologic characteristics to identify high-risk patients for adjuvant intervention, molecular profiling more accurately predicts 5-year survival. Early evidence of clinical benefit from application of this molecular-based management strategy, however, has not been reported. PATIENTS AND METHODS: An internationally validated, prognostic, 14-gene quantitative polymerase chain reaction expression assay was used to stratify risk prospectively in 100 consecutive patients with stage IA, IB, and IIA nonsquamous NSCLC. Kaplan-Meyer estimates, log rank analysis, and Cox regression were used to compare disease-free survival (DFS) between high-risk patients who did or did not elect adjuvant chemotherapy. RESULTS: Forty-eight patients (48%) were deemed high risk according to molecular testing and 36 (36%) met NCCN high-risk criteria; risk designations were discordant in 34 (34%) of all patients. Estimated 5-year DFS was 48.9% among molecular high-risk patients who did not undertake adjuvant chemotherapy, 93.8% among untreated molecular low-risk patients, and 91.7% in molecular high-risk patients who did undergo chemotherapy (P = .004). In contrast, DFS was only 75.2% in untreated NCCN low-risk patients, and 61.9% in untreated NCCN high-risk patients (P = .183). CONCLUSION: This prospective, nonrandomized study provides initial evidence that high-risk designation according to the 14-gene prognostic assay also predicts benefit from adjuvant chemotherapy for very early stage NSCLC, and further supports the superiority of molecular stratification over current NCCN criteria at identifying high-risk patients. PMID- 28645633 TI - Portal blood pressure and hypoxemia: The 2 main mechanisms of liver regeneration? PMID- 28645634 TI - Hormonal behavior correlates with follicular recruitment at mid-gestation in the South American plains vizcacha, Lagostomus maximus (Rodentia, Caviomorpha). AB - In mammals, hormonal regulation during gestation is crucial for embryo implantation and pregnancy success. This regulation is controlled through the level of progesterone (P4) that blocks the activity of the hypothalamic hypophyseal-gonadal (HHG) axis. Previous studies in the pregnant South American plains vizcacha, Lagostomus maximus, have shown that the HHG axis activates around mid-gestation, promoting pre-ovulatory follicle formation. However, the characterization of the hormonal dynamics throughout gestation and its ovarian correlation has not been studied in depth. We studied the ovarian dynamics of L. maximus and its correlation with the hormonal profile during gestation, analyzing serum levels of P4, 17beta-estradiol (E2), 4Delta-androstenedione (A4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) as well as the ovarian distribution and expression of their receptors. Additionally, we have analyzed the folliculogenesis and accessory corpora lutea (ACL) formation. P4 showed two concentration peaks reaching its highest level at mid-gestation decreasing at 91-100days post-coitum. P4 decrease is followed by an increase of circulating levels of A4, E2, FSH and LH and with an elevated number of antral/pre-ovulatory follicles which express PGR, ESR1, ESR2, AR, LHR and FSHR. In addition, ACL with oocyte retention and cytoplasmic lipid droplets in luteal cells were detected at this time point. These results show that in L. maximus the decrease of P4 level from mid-gestation enables follicular recruitment until pre ovulatory stage and the development of functional ACL. PMID- 28645635 TI - Cytotoxicity of the coagulant Moringa oleifera lectin (cMoL) to B16-F10 melanoma cells. AB - Moringa oleifera seeds are used in alternative medicine to treat inflammation, tumors and bacterial and protozoan infections, for example. The seeds contain lectins, which are carbohydrate-binding proteins with several biological properties including cytotoxicity to cancer cells. In this work, we examined the cytotoxicity of the coagulant M. oleifera lectin (cMoL) on B16-F10 murine melanoma cells. cMoL cytotoxic effects were evaluated through trypan blue assay and flow cytometry analysis. Mitochondrial superoxide levels and activation of caspases 3, 8 and 9 were measured. cMoL (1.5-16MUM) reduced viability and caused cell death of B16-F10 cells with an IC50 of 9.72MUM. Flow cytometry analysis indicated induction of necrosis and suggested the presence of cells in late apoptosis. Specificity for tumor cells was observed since death of normal human fibroblasts (GN) was not higher than 20% in treatments with cMoL from 1.5 to 16MUM. Microscopy images revealed rounded shape and reduction of volume in B16 F10 cells treated with cMoL. cMoL increased mitochondrial ROS production and promoted caspases 3, 8 and 9 activation in B16-F10 cells, indicating the activation of apoptosis-related pathway. In conclusion, this study demonstrates that cMoL is cytotoxic to B16-F10 cells, which stimulates more investigation on the anticancer potential of this lectin. PMID- 28645636 TI - Theobromine does not affect postprandial lipid metabolism and duodenal gene expression, but has unfavorable effects on postprandial glucose and insulin responses in humans. AB - BACKGROUND & AIMS: Chocolate consumption is associated with a decreased risk for CVD. Theobromine, a compound in cocoa, may explain these effects as it favorably affected fasting serum lipids. However, long-term effects of theobromine on postprandial metabolism as well as underlying mechanisms have never been studied. The objective was to evaluate the effects of 4-week theobromine consumption (500 mg/day) on fasting and postprandial lipid, lipoprotein and glucose metabolism, and duodenal gene expression. METHODS: In a randomized, double-blind crossover study, 44 healthy men and women, with low baseline HDL-C concentrations consumed 500 mg theobromine or placebo daily. After 4-weeks, fasting blood was sampled and subjects participated in a 4-h postprandial test. Blood was sampled frequently for analysis of lipid and glucose metabolism. In a subgroup of 10 men, 5 h after meal consumption duodenal biopsies were taken for microarray analysis. RESULTS: 4 weeks theobromine consumption lowered fasting LDL-C (-0.21 mmol/L; P = 0.006), and apoB100 (-0.04 g/L; P = 0.022), tended to increase HDL-C (0.03 mmol/L; P = 0.088) and increased hsCRP (1.2 mg/L; P = 0.017) concentrations. Fasting apoA-I, TAG, FFA, glucose and insulin concentrations were unchanged. In the postprandial phase, theobromine consumption increased glucose (P = 0.026), insulin (P = 0.011) and FFA (P = 0.003) concentrations, while lipids and (apo)lipoproteins were unchanged. In duodenal biopsies, microarray analysis showed no consistent changes in expression of genes, pathways or gene sets related to lipid, cholesterol or glucose metabolism. CONCLUSIONS: It is not likely that the potential beneficial effects of cocoa on CVD can be ascribed to theobromine. Although theobromine lowers serum LDL-C concentrations, it did not change fasting HDL-C, apoA-I, or postprandial lipid concentrations and duodenal gene expression, and unfavorably affected postprandial glucose and insulin responses. This trial was registered on clinicaltrials.gov under study number NCT02209025. PMID- 28645637 TI - Antimicrobial and biological activity of leachate from light curable pulp capping materials. AB - OBJECTIVES: Characterization of a number of pulp capping materials and assessment of the leachate for elemental composition, antimicrobial activity and cell proliferation and expression. METHODOLOGY: Three experimental light curable pulp capping materials, Theracal and Biodentine were characterized by scanning electron microscopy, energy dispersive spectroscopy and X-ray diffraction. The elemental composition of the leachate formed after 24h was assessed by inductively coupled plasma (ICP). The antimicrobial activity of the leachate was determined by the minimum inhibitory concentration (MIC) against multispecies suspensions of Streptococcus mutans ATCC 25175, Streptococcus gordonii ATCC 33478 and Streptococcus sobrinus ATCC 33399. Cell proliferation and cell metabolic function over the material leachate was assessed by an indirect contact test using 3-(4,5 dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The hydration behavior of the test materials varied with Biodentine being the most reactive and releasing the highest amount of calcium ions in solution. All materials tested except the unfilled resin exhibited depletion of phosphate ions from the solution indicating interaction of the materials with the media. Regardless the different material characteristics, there was a similar antimicrobial activity and cellular activity. All the materials exhibited no antimicrobial activity and were initially cytotoxic with cell metabolic function improving after 3days. CONCLUSIONS: The development of light curable tricalcium silicate-based pulp capping materials is important to improve the bonding to the final resin restoration. Testing of both antimicrobial activity and biological behavior is critical for material development. The experimental light curable materials exhibited promising biological properties but require further development to enhance the antimicrobial characteristics. PMID- 28645638 TI - Genome-wide Targeted Mutagenesis in Rice Using the CRISPR/Cas9 System. PMID- 28645639 TI - Construction of a Genome-Wide Mutant Library in Rice Using CRISPR/Cas9. PMID- 28645640 TI - Communicating to promote informed decisions in the context of early pregnancy loss. AB - OBJECTIVE: To evaluate residents' ability to engage standardized patients in informed decision making during a pregnancy loss scenario. METHODS: Forty patient encounters between interns and standardized patients were coded to assess informed decision-making practices, exploration of unexpressed concerns, and support provision. RESULTS: Interns engaged in minimum informed decision making but did not address all of the communicative elements necessary for informed decisions, and most elements were only partially addressed. Patients in this study did not receive information about all management options, their concerns were not addressed, and there was limited support communicated for their decision. CONCLUSION: This study offers an initial assessment of a communicative approach to evaluate and improve decision making during early pregnancy loss. A comprehensive approach to making informed decisions must include discussion of all management options, exploration of patient preferences and concerns, and support for the patient's decision. PRACTICE IMPLICATIONS: Physicians could benefit from communication skills training to communicate more effectively with patients to help them make more informed decisions. PMID- 28645641 TI - Homogenizing bacterial cell factories: Analysis and engineering of phenotypic heterogeneity. AB - In natural habitats, microbes form multispecies communities that commonly face rapidly changing and highly competitive environments. Thus, phenotypic heterogeneity has evolved as an innate and important survival strategy to gain an overall fitness advantage over cohabiting competitors. However, in defined artificial environments such as monocultures in small- to large-scale bioreactors, cell-to-cell variations are presumed to cause reduced production yields as well as process instability. Hence, engineering microbial production toward phenotypic homogeneity is a highly promising approach for synthetic biology and bioprocess optimization. In this review, we discuss recent studies that have unraveled the cell-to-cell heterogeneity observed during bacterial gene expression and metabolite production as well as the molecular mechanisms involved. In addition, current single-cell technologies are briefly reviewed with respect to their applicability in exploring cell-to-cell variations. We highlight emerging strategies and tools to reduce phenotypic heterogeneity in biotechnological expression setups. Here, strain or inducer modifications are combined with cell physiology manipulations to achieve the ultimate goal of equalizing bacterial populations. In this way, the majority of cells can be forced into high productivity, thus reducing less productive subpopulations that tend to consume valuable resources during production. Modifications in uptake systems, inducer molecules or nutrients represent valuable tools for diminishing heterogeneity. Finally, we address the challenge of transferring homogeneously responding cells into large-scale bioprocesses. Environmental heterogeneity originating from extrinsic factors such as stirring speed and pH, oxygen, temperature or nutrient distribution can significantly influence cellular physiology. We conclude that engineering microbial populations toward phenotypic homogeneity is an increasingly important task to take biotechnological productions to the next level of control. PMID- 28645642 TI - NGS and blood group systems: State of the art and perspectives. AB - Molecular analysis, or genotyping, of genes involved in the expression of blood group antigens has been a standard strategy used in immunohaematology laboratories routinely. For the past ten years, next-generation sequencing (NGS), or second-generation sequencing, has become the reference method in genetics. Extensive study of distinct targets, large genomic regions, and even whole genome is henceforth possible by this approach at minimal cost. Blood group genotyping has thus taken advantage of this technological advent. A few preliminary studies have open the way to NGS in this field by studying one or several genes, in a wide range of samples (donors and patients) by using several different platforms. These works have helped in the identification of both the benefits and limitations of the technology. Other recently published studies have benefited from these preliminary data to improve the methodology, specificity and accuracy of output data. In parallel novel strategies, i.e. third-generation sequencing, which can sequence long DNA regions at the single-molecule level, have emerged and shown promise for the potential resolution of complex rearrangements involving genes of the Rh and MNS blood group systems respectively. As technological and methodological hurdles have been overcome, these approaches may be used in a clinical situation in a near future. PMID- 28645643 TI - Management of thrombotic thrombocytopenic purpura. AB - Daily therapeutic plasma exchange (TPE) transformed the historically fatal prognosis of acquired, anti-ADAMTS13 antibody-mediated thrombotic thrombocytopenic purpura (TTP), leading to the current overall survival rates of >80%. However, relapses occur in up to 40% of patients and refractory disease with fatal outcomes still occurs, typically within the first days of management. In this context, the introduction of rituximab has been the second major breakthrough in TTP management. Rituximab is now routinely recommended during the acute phase, typically in patients with a suboptimal response to treatment, and increasingly as frontline therapy, with high response rates in the following weeks. In more severe patients, salvage strategies typically include twice daily TPE, pulses of cyclophosphamide, as well as splenectomy in the more desperate cases. In this life-threatening and debilitating disease, relapses can be efficiently prevented in patients with a severe acquired ADAMTS13 deficiency and otherwise in remission with the use of rituximab. In the coming years, the TTP therapeutic landscape should be enriched by original strategies stemming from clinical experience and new agents that are currently being evaluated in large, international, clinical trials. Promising agents under evaluation include caplacizumab (an inhibitor of the glycoprotein-Ib/IX-Von-Willebrand factor axis), N-acetylcysteine, recombinant ADAMTS13, and anti-plasmocyte compounds. PMID- 28645644 TI - [Antiplatelet agents and transfusion]. AB - Antiplatelet agents are at risk for bleeding complications, the management of which differs depending on the clinical situation and on the antiplatelet agent itself. Neutralization of antiplatelets is sometimes necessary, most often leading to platelet transfusion, although the benefit of this strategy is poorly documented. In addition, if platelet transfusion corrects the platelet inhibition induced by aspirin and probably by clopidogrel and prasugrel, it does not neutralize ticagrelor, as a consequence of its pharmacological properties. The clinical benefit of platelet transfusion is limited, and the most recent studies are challenging it. However, it is indicated on a perioperative basis for surgeries with high hemorrhagic risk and is discussed in severe hemorrhages. The neutralization of ticagrelor is a concern and the antidote currently under development may be a solution. In all cases, other therapeutic solutions may be considered, such as administration of desmopressin, tranexamic acid or activated factor VII. PMID- 28645645 TI - Determinants of plasma donation: A review of the literature. AB - The major contribution of Human Sciences in the understanding of the whole blood donation behavior has been through the study of individuals' motivations and deterrents to donate. However, if whole blood donation has been very widely studied in the last sixty years, we still know very little about plasma donation in voluntary non-remunerated environments. Yet, the need for plasma-derived products has been strongly increasing for some years, and blood collection agencies have to adapt if they want to meet this demand. This article aims to review the main motivations and deterrents to whole blood donation, and to compare them with those that we already know concerning plasma donation. Current evidence shows similarities between both behaviors, but also differences that indicate a need for further research regarding plasma donation. PMID- 28645646 TI - Association of bullous pemphigoid with malignancy: A systematic review and meta analysis. AB - BACKGROUND: Studies evaluating whether malignancy rate is increased in patients with bullous pemphigoid (BP) have reached conflicting results. OBJECTIVE: We sought to determine whether BP is associated with malignancy. METHOD: Medline, EMBASE, the Cochrane library, and reference lists of included studies were searched for comparative studies that evaluated the relationship between BP and malignancy. Data were analyzed on the basis of study design: cross-sectional, case control, and cohort. A meta-analysis was performed by using a random effects model to estimate pooled odds ratio. RESULTS: The review included 8 studies. No association between BP and overall cancer was found for any of the study designs. Although a single cohort study reported an association with lymphoid leukemia and kidney and larynx cancer, a pooled analysis of case-control studies did not. A pooled analysis of cross-sectional studies found a significant association between BP and hematologic malignancies. LIMITATIONS: The paucity of well designed studies hindered the possibility of proving or disproving the BP-cancer association. CONCLUSION: We did not find an association of BP with overall malignancy, but a possible association with hematologic malignancy was observed. PMID- 28645647 TI - Racial disparity in mycosis fungoides: An analysis of 4495 cases from the US National Cancer Database. AB - BACKGROUND: Studies have shown contradictory results regarding the survival outcomes among white, African American, and Asian patients with mycosis fungoides (MF). OBJECTIVE: To evaluate the survival outcomes among white, African American, and Asian patients with MF and to determine other prognostic factors of the disease. METHODS: The US National Cancer Database was used to identify patients with histologically confirmed MF from 2004 to 2014. Clinicopathologic, socioeconomic, and treatment data were compared among the races by using the chi square test. Overall survival was evaluated by using the log-rank test, multivariable Cox proportional hazard regression, and propensity score-matched analysis. RESULTS: Of 4459 patients with MF, 77.7% were white, 19.2% were African American, and 3.2% were Asian. Older age, treatment received in a community facility, government insurance, higher Charlson-Deyo score, male sex, higher clinical stage, receipt of radiotherapy or chemotherapy, and African American race were predictors of poor overall survival on multivariate analysis (P < .001), whereas Asian race trended toward improved outcomes (P = .07). LIMITATIONS: Retrospective analysis. CONCLUSION: African American patients with MF demonstrated poorer survival than white patients after accounting for disease characteristics, socioeconomic factors, and types of treatment, warranting further investigation into the underlying biology of MF and prescribed treatment modalities. PMID- 28645648 TI - Promotion of iron nutrition and growth on peanut by Paenibacillus illinoisensis and Bacillus sp. strains in calcareous soil. AB - This study aimed to explore the effects of two siderophore-producing bacterial strains on iron absorption and plant growth of peanut in calcareous soil. Two siderophore-producing bacterial strains, namely, YZ29 and DZ13, isolated from the rhizosphere soil of peanut, were identified as Paenibacillus illinoisensis and Bacillus sp., respectively. In potted experiments, YZ29 and DZ13 enhanced root activity, chlorophyll and active iron content in leaves, total nitrogen, phosphorus and potassium accumulation of plants and increased the quality of peanut kernels and plant biomass over control. In the field trial, the inoculated treatments performed better than the controls, and the pod yields of the three treatments inoculated with YZ29, DZ13, and YZ29+DZ13 (1:1) increased by 37.05%, 13.80% and 13.57%, respectively, compared with the control. Based on terminal restriction fragment length polymorphism analysis, YZ29 and DZ13 improved the bacterial community richness and species diversity of soil surrounding the peanut roots. Therefore, YZ29 and DZ13 can be used as candidate bacterial strains to relieve chlorosis of peanut and promote peanut growth. The present study is the first to explore the effect of siderophores produced by P. illinoisensis on iron absorption. PMID- 28645649 TI - Evaluation of a selective chromogenic medium for detecting vancomycin-resistant enterococci. AB - Rapid identification of vancomycin-resistant enterococci (VRE) can assist in choosing the appropriate treatment and preventing VRE spread. The performance of chromIDTM VRE agar was evaluated using 184 clinical isolates of Enterococcus spp. and reference strains. The test had a sensitivity of 95.52% but a low specificity of 30%. PMID- 28645650 TI - Isolation, identification, and biocontrol of antagonistic bacterium against Botrytis cinerea after tomato harvest. AB - Tomato is one of the most important vegetables in the world. Decay after harvest is a major issue in the development of tomato industry. Currently, the most effective method for controlling decay after harvest is storage of tomato at low temperature combined with usage of chemical bactericide; however, long-term usage of chemical bactericide not only causes pathogen resistance but also is harmful for human health and environment. Biocontrol method for the management of disease after tomato harvest has great practical significance. In this study, antagonistic bacterium B-6-1 strain was isolated from the surface of tomato and identified as Enterobacter cowanii based on morphological characteristics and physiological and biochemical features combined with sequence analysis of 16SrDNA and ropB gene and construction of dendrogram. Effects of different concentrations of antagonistic bacterium E. cowanii suspension on antifungal activity after tomato harvest were analyzed by mycelium growth rate method. Results revealed that antifungal activity was also enhanced with increasing concentrations of antagonistic bacterium; inhibitory rates of 1*105 colony-forming units (cfu)/mL antagonistic bacterial solution on Fusarium verticillioides, Alternaria tenuissima, and Botrytis cinerea were 46.31%, 67.48%, and 75.67%, respectively. By using in vivo inoculation method, it was further confirmed that antagonistic bacterium could effectively inhibit the occurrence of B. cinerae after tomato harvest, biocontrol effect of 1*109cfu/mL zymotic fluid reached up to 95.24%, and antagonistic bacterium E. cowanii has biocontrol potential against B. cinerea after harvest of fruits and vegetables. PMID- 28645651 TI - Post-transplant cholangiopathy: Classification, pathogenesis, and preventive strategies. AB - Biliary complications are the most frequent cause of morbidity, re transplantation, and even mortality after liver transplantation. In general, biliary leakage and anastomotic and non-anastomotic biliary strictures (NAS) can be recognized. There is no consensus on the exact definition of NAS and different names and criteria have been used in literature. We propose to use the term post transplant cholangiopathy for the spectrum of abnormalities of large donor bile ducts, that includes NAS, but also intraductal casts and intrahepatic biloma formation, in the presence of a patent hepatic artery. Combinations of these manifestations of cholangiopathy are not infrequently found in the same liver and ischemia-reperfusion injury is generally considered the common underlying mechanism. Other factors that contribute to post-transplant cholangiopathy are biliary injury due to bile salt toxicity and immune-mediated injury. This review provides an overview of the various types of post-transplant cholangiopathy, the presumed pathogenesis, clinical implications, and preventive strategies. PMID- 28645654 TI - Epigenome dysregulation in cholangiocarcinoma. AB - Epigenomics is a fast-evolving field of research that has lately attracted considerable interest, mainly due to the reversibility of epigenetic marks. Clinically, among solid tumors, the field is still limited. In cholangiocarcinoma (CCA) it is well known that the epigenetic landscape is deregulated both during carcinogenesis and disease progression as a consequence of aberrant mechanisms leading to genome instability. In this article, we will briefly review the molecular alterations that have been described in the transformation of normal cholangiocytes into malignant derivatives, focusing on the role of non-coding RNA (ncRNA) interactions, DNA methylation, post-translational modifications (PTMs) of histones and chromatin remodeling complexes. PMID- 28645652 TI - Androgen inhibits key atherosclerotic processes by directly activating ADTRP transcription. AB - Low androgen levels are associated with an increased risk of coronary artery disease (CAD), thrombosis and myocardial infarction (MI), suggesting that androgen has a protective role. However, little is known about the underlying molecular mechanism. Our genome-wide association study identified the ADTRP gene encoding the androgen-dependent TFPI regulating protein as a susceptibility gene for CAD and MI. The expression level of ADTRP was regulated by androgen, but the molecular mechanism is unknown. In this study, we identified the molecular mechanism by which androgen regulates ADTRP expression and tested the hypothesis that androgen plays a protective role in cardiovascular disease by activating ADTRP expression. Luciferase assays with an ADTRP promoter luciferase reporter revealed that androgen regulated ADTRP transcription in a dose- and time dependent manner, and the effect was abolished by three different androgen inhibitors, including pyrvinium pamoate, bicalutamide, and cyproterone acetate. Chromatin-immunoprecipitation showed that the androgen receptor bound to a half androgen response element (ARE, TGTTCT) located at +324bp from the ADTRP transcription start site. The ARE is required for concentration-dependent transcriptional activation of ADTRP. HL-60 monocyte adhesion to EAhy926 endothelial cells (ECs) and transmigration across the EC layer, the two processes critical to development of CAD and MI, were inhibited by androgen, but the effect was rescued by ADTRP siRNA and exacerbated by overexpression of ADTRP and its downstream genes PIK3R3 and MIA3. These data suggest that one molecular mechanism by which androgen confers protection against CAD is stimulation of ADTRP expression. PMID- 28645653 TI - Catalase overexpression modulates metabolic parameters in a new 'stress-less' leptin-deficient mouse model. AB - Oxidative stress plays a key role in obesity by modifying the function of important biological molecules, thus altering obesogenic pathways such as glucose and lipid signaling. Catalase, is an important endogenous antioxidant enzyme that catabolizes hydrogen peroxide produced by the dismutation of superoxide. Recent studies have shown knockdown of catalase exacerbates insulin resistance and leads to obesity. We hypothesized that overexpressing catalase in an obese mouse will modulate obesogenic pathways and protect against obesity. Therefore, we bred catalase transgenic ([Tg(CAT)+/-] mice with Ob/Ob mice to generate the hybrid "Bob-Cat" mice. This newly generated "stress-less" mouse model had decreased oxidative stress (oxidized carbonylated proteins). ECHO-MRI showed lower fat mass but higher lean mass in "Bob-Cat" mice. Comprehensive Lab Animal Monitoring System (CLAMS) showed light and dark cycle increase in energy expenditure in Bob Cat mice compared to wild type controls. Circulating levels of leptin and resistin showed no change. Catalase mRNA expression was increased in key metabolic tissues (adipose, liver, intestinal mucosa, and brain) of the Bob-Cat mice. Catalase activity, mRNA and protein expression was increased in adipose tissue. Expression of the major adipokines leptin and adiponectin was increased while pro-inflammatory genes, MCP-1/JE and IL-1beta were lowered. Interestingly, sexual dimorphism was seen in body composition, energy expenditure, and metabolic parameters in the Bob-Cat mice. Overall, the characteristics of the newly generated "Bob-Cat" mice make it an ideal model for studying the effect of redox modulators (diet/exercise) in obesity. PMID- 28645655 TI - 5-Lipoxygenase in monocytes emerges as a therapeutic target for intimal hyperplasia in a murine wire-injured femoral artery. AB - Given the importance of leukotrienes in vascular inflammation induced by local tissue injury, this study investigated the role for 5-lipoxygenase (5-LO) in monocytes in the development of intimal hyperplasia. As a mechanistic study, the importance of monocyte 5-LO in monocyte-macrophage differentiation with subsequent infiltration in neointima was evaluated. In a mouse model of wire injured femoral artery, intimal hyperplasia started as early as 2wks after injury, and luminal area and blood flow were reduced due to increased neointima formation. Time-dependent increases in macrophage infiltration were observed in neointima and showed a positive relationship with neointima volume. In 5-LO deficient (KO) mice or wild-type (WT) mice treated with an inhibitor of 5-LO activating protein (MK886, 1 and 10mg/kg), intimal hyperplasia and macrophage infiltration into neointima were reduced, but monocyte adhesion to injured luminal surface was not inhibited, which suggested 5-LO participates in monocyte macrophage differentiation. In an in vitro study, monocyte-macrophage differentiation was found to be increased by high mobility group box 1 protein (HMGB1), but this effect was attenuated in cells isolated from 5-LO-KO mice. Furthermore, macrophage infiltration and intimal hyperplasia were more prominent in 5-LO-KO mice transplanted with monocytes from WT mice than in 5-LO-KO mice transplanted with monocytes from 5-LO-KO mice. Taken together, it was suggested that 5-LO in monocytes played a pivotal role in monocyte-macrophage differentiation and subsequent infiltration of macrophage in neointima, leading to vascular remodeling after vascular injury. PMID- 28645656 TI - Allochthonous carbon is a major driver of the microbial food web - A mesocosm study simulating elevated terrestrial matter runoff. AB - Climate change predictions indicate that coastal and estuarine environments will receive increased terrestrial runoff via increased river discharge. This discharge transports allochthonous material, containing bioavailable nutrients and light attenuating matter. Since light and nutrients are important drivers of basal production, their relative and absolute availability have important consequences for the base of the aquatic food web, with potential ramifications for higher trophic levels. Here, we investigated the effects of shifts in terrestrial organic matter and light availability on basal producers and their grazers. In twelve Baltic Sea mesocosms, we simulated the effects of increased river runoff alone and in combination. We manipulated light (clear/shade) and carbon (added/not added) in a fully factorial design, with three replicates. We assessed microzooplankton grazing preferences in each treatment to assess whether increased terrestrial organic matter input would: (1) decrease the phytoplankton to bacterial biomass ratio, (2) shift microzooplankton diet from phytoplankton to bacteria, and (3) affect microzooplankton biomass. We found that carbon addition, but not reduced light levels per se resulted in lower phytoplankton to bacteria biomass ratios. Microzooplankton generally showed a strong feeding preference for phytoplankton over bacteria, but, in carbon-amended mesocosms which favored bacteria, microzooplankton shifted their diet towards bacteria. Furthermore, low total prey availability corresponded with low microzooplankton biomass and the highest bacteria/phytoplankton ratio. Overall our results suggest that in shallow coastal waters, modified with allochthonous matter from river discharge, light attenuation may be inconsequential for the basal producer balance, whereas increased allochthonous carbon, especially if readily bioavailable, favors bacteria over phytoplankton. We conclude that climate change induced shifts at the base of the food web may alter energy mobilization to and the biomass of microzooplankton grazers. PMID- 28645657 TI - Gross pathology, physiological and toxicological responses in relation to metals and persistent organic pollutants (POPs) burden in tilapia species from Ogun River, Nigeria. AB - We have investigated gross pathology, physiological (steroid precursors) and toxicological responses (oxidative stress and phase II biotransformation) in relation to tissue contaminant burden in Tilapia species along the entire length (320 km) of Ogun River, Nigeria. The Ogun River is the longest and largest river in Southwestern Nigeria located along heavily industrialized cities and receives complex mixtures of effluents. A total of 1074 tilapias were collected from three sampling points (Abeokuta, Isheri and Ikorodu) and from an upstream control point (Igboho) and evaluated for gross pathological changes, hepatic transcript levels for oxidative stress and phase II biotransformation responses. Trace metal concentrations and POPs in muscle samples were analyzed using ICP-MS and GC-MS respectively. Evaluation of gross pathological changes showed a 50-, 33-, 17 and 0% prevalence of hepatic tumors at the Ikorodu, Abeokuta, Isheri and Igboho sites, respectively. Plasma concentrations of cholesterol and pregnenolone showed apparent significant decreases at downstream sites of the control point in both male and female fish (except for pregnenolone levels of male fish at Ikorodu). Inversely, gst, ugt-1, ZuCu-sod and sod significantly increased in fish collected from downstream sites, compared with the control site and these increases paralleled the significant increase in trace metal and POPs concentrations at these sites. PCA revealed a site related association between measured toxicological responses and contaminant burden, indicating a potential cause-and effect relationship. Thus, the possible adaptation of Ogun River Tilapia species to contaminants may have significant consequences on cellular, physiological and biochemical processes regulating metabolism, growth, development and reproduction, and also have serious human health consequences, since the Ogun River is used for fisheries and domestic water supply for surrounding neighborhoods. PMID- 28645658 TI - Spacer structure and hydrophobicity influences transfection activity of novel polycationic gemini amphiphiles. AB - Three novel polycationic gemini amphiphiles with different spacers were developed and evaluated in terms of their physiochemical properties and transfection efficiencies. Cationic liposomes formed by these amphiphiles and the helper lipid DOPE were able to successfully condense DNA, as shown by gel mobility shift and ethidium bromide intercalation assays. Transfection activity of the liposomes was superior to Lipofectamine(r) 2000 and was dependent on spacer structure, hydrophobicity, and nucleic acid type (pDNA or siRNA). We demonstrated that the cationic liposomes 2X6/DOPE and 2X7/DOPE are potential non-toxic vehicles for gene delivery. PMID- 28645659 TI - Synthesis, in vitro and in vivo giardicidal activity of nitrothiazole-NSAID chimeras displaying broad antiprotozoal spectrum. AB - We designed and synthesized five new 5-nitrothiazole-NSAID chimeras as analogues of nitazoxanide, using a DCC-activated amidation. Compounds 1-5 were tested in vitro against a panel of five protozoa: 2 amitochondriates (Giardia intestinalis, Trichomonas vaginalis) and 3 kinetoplastids (Leishmania mexicana, Leishmania amazonensis and Trypanosoma cruzi). All chimeras showed broad spectrum and potent antiprotozoal activities, with IC50 values ranging from the low micromolar to nanomolar order. Compounds 1-5 were even more active than metronidazole and nitazoxanide, two marketed first-line drugs against giardiasis. In particular, compound 4 (an indomethacin hybrid) was one of the most potent of the series, inhibiting G. intestinalis growth in vitro with an IC50 of 0.145MUM. Compound 4 was 38-times more potent than metronidazole and 8-times more active than nitazoxanide. The in vivo giardicidal effect of 4 was evaluated in a CD-1 mouse model obtaining a median effective dose of 1.709MUg/kg (3.53nmol/kg), a 321-fold and 1015-fold increase in effectiveness after intragastric administration over metronidazole and nitazoxanide, respectively. Compounds 1 and 3 (hybrids of ibuprofen and clofibric acid), showed potent giardicidal activities in the in vitro as well as in the in vivo assays after oral administration. Therefore, compounds 1-5 constitute promising drug candidates for further testing in experimental chemotherapy against giardiasis, trichomoniasis, leishmaniasis and even trypanosomiasis infections. PMID- 28645660 TI - Corrigendum to "Prevalence of mutations within major hydrophilic region of hepatitis B virus and their correlation with genotypes among chronically infected patients in Egypt" [Arab J Gastroenterol 17 (2016) 34-40]. PMID- 28645661 TI - Postoperative delirium in total joint arthroplasty patients. PMID- 28645662 TI - Development of a 3D printable maxillofacial silicone: Part II. Optimization of moderator and thixotropic agent. AB - STATEMENT OF PROBLEM: Conventionally, maxillofacial prostheses are fabricated by hand carving the missing anatomic defect in wax and creating a mold into which pigmented silicone elastomer is placed. Digital technologies such as computer numerical control milling and 3-dimensional (3D) printing have been used to prepare molds, directly or indirectly, into which a biocompatible pigmented silicone elastomer can be placed. PURPOSE: The purpose of this in vitro study was to develop a silicone elastomer that could be 3D printed directly without a mold to create facial or body prostheses by varying its composition. MATERIAL AND METHODS: The room temperature vulcanizing silicone composition was divided into 2 components which were mixed 1:1 to initiate polymerization in the printer before printing began. Different types of moderators and thixotropic agents were used, and the base composition was varied to obtain 11 formulations. The specimens were printed and polymerized from these formulations and tested for tear and tensile strength and hardness. Ten readings of the specimens were recorded for tear and tensile strength and 6 for hardness. Results were analyzed using ANOVA (alpha=.05). Visual assessment of uncured printed specimens was undertaken for 5 formulations to assess any differences in their ability to hold their shape after printing. RESULTS: The tear and tensile strength of the 11 formulations with varying moderators, thixotropic agents, and base compositions were statistically similar to each other (P>.05). Five of 11 formulations were chosen for the visual assessment as they had sufficient thixotropic agent to avoid slumping while printing. The specimens showed varied slumping behavior until they polymerized. The filler content was increased in the selected formulation, and the tear and tensile strength of the formulation was increased to 6.138 kNm-1 and 3.836 MPa; these increases were comparable to those of commercial silicones currently used for the fabrication of facial prostheses. CONCLUSIONS: The optimum combination of mechanical properties implies the use of one of the formulations as a suitable material for the 3D printing of facial prostheses. PMID- 28645663 TI - Failure torque of ceramic neck titanium implant. AB - STATEMENT OF PROBLEM: Dental implants are typically made of titanium. However, with the current systems on the market, the implant neck often shows through the gingival tissues as a black or dark gray line and/or as a grayish discoloration of the peri-implant soft tissue. PURPOSE: The purpose of this in vitro study was to test a new implant design. The key component of this design is the ceramic shell that covers the polished collar of the tissue-level titanium implant and masks its dark color to mimic natural dentition. The main purpose was to determine the maximum torque for fracturing the ceramic shell and compare it with clinical implant insertion torque value. MATERIAL AND METHODS: Type 4 commercially pure titanium endosseous implants of 3 different diameters (3.3, 4.1, and 4.8 mm) were used. Porcelain was applied in 0.5-mm thickness to the polished collar of each implant. An axial-torsional universal testing machine was used to twist the implants until failure. The data (n=10) were statistically analyzed by ANOVA and the Tukey honest significant difference test (alpha=.05). The maximum torque for each diameter group was also compared with the optimum clinical implant insertion torque value of 35 Ncm (control) using a 1-sample t test. RESULTS: None of the tested groups had a fractured ceramic shell. Instead, the implant carriers fractured at the maximum torque levels. Therefore, the fracture of the implant carriers was selected as the maximum (failure) torque value. A statistical difference was found for the failure torque between the 3.3 mm diameter and the other 2 diameters (P<.001) although no statistical differences were found between the 4.1-mm and 4.8-mm diameters (P=.106). A statistically significant difference was found between the failure torque of any one of the tested groups and the clinical insertion torque (P<.001). CONCLUSIONS: The ceramic shells did not fracture. Instead, the implant carriers fractured at certain torque levels. These levels were sufficiently higher than the clinical torque values. PMID- 28645664 TI - Muscle activity and masticatory efficiency with bilateral extension base removable partial dentures with different cusp angles. AB - STATEMENT OF PROBLEM: Whether masticatory efficiency and electromyographic activity are influenced by type of artificial teeth and food is unclear. PURPOSE: The purpose of this clinical study was to evaluate the influence of extension base removable partial dentures (RPDs) with different cusp angles: anatomic (33 degrees), semianatomic (20 degrees), and nonanatomic (0 degrees) teeth on masticatory efficiency and muscle activity during the mastication of test foods with different textures. MATERIAL AND METHODS: Twelve participants with RPDs were selected to perform masticatory efficiency and electromyographic tests. Surface electromyograms (EMGs) were used to record the activities of the masseter and temporalis muscles during the mastication of different types of test foods. The maximal voltage and duration were measured on the integrated EMG signal in each muscle during food mastication, and the mean reading of both sides was then recorded. Analysis of variance and the Tukey post hoc test were used to perform statistical analyses (alpha=.05). RESULTS: The masticatory efficiency of RPDs with nonanatomic teeth was significantly inferior to that of RPDs with anatomic and semianatomic teeth (P<.05). However, masticatory efficiency did not differ between anatomic and semianatomic teeth (P>.05). Also, muscle activity (according to EMG) with RPDs with NA teeth was significantly higher than that with anatomic and semianatomic teeth (P<.05). CONCLUSIONS: RPDs with NA teeth were associated with higher EMG muscle activity and reduced masticatory efficiency than anatomic or semianatomic teeth. PMID- 28645665 TI - Experimental evaluation of stress distribution with narrow diameter implants: A finite element analysis. AB - STATEMENT OF PROBLEM: Narrow diameter implants were developed to allow placement in narrow alveolar ridges. Clinicians may have concerns about the durability and function of such implants. PURPOSE: The purpose of this finite element study was to compare the stress values occurring on the implant and at the implant bone interface after the application of the static and dynamic forces on narrow diameter, titanium and titanium-zirconia implants in the maxillary and mandibular second premolar region. MATERIAL AND METHODS: Titanium (Ti) and titanium zirconium (Ti-Zr) narrow diameter implants (3.3 mm in diameter, 10 mm in length) were simulated in the maxillary and mandibular second premolar region, and metal ceramic crown restorations were designed. Forces of 100 N were applied to crowns in a vertical and oblique (45-degree angle to the long axis) direction. Maximum and minimum principal stresses in the cortical and trabecular bone and the von Mises stresses and fatigue strength of the implants were evaluated with 3 dimensional finite element analysis. RESULTS: In vertical and oblique static loading, Ti and Ti-Zr implants showed similar stress distribution within the same jaw models. However, the von Mises stresses in Ti-Zr implants were slightly higher than for Ti implants in all models. In oblique static and dynamic loading, all stresses were found higher than vertical loading, and fatigue failure results were found to be more critical than vertical forces. CONCLUSIONS: Based on a numerical simulation, Ti and Ti-Zr alloys can be used successfully as narrow diameter implants in the second premolar area. PMID- 28645666 TI - Color masking measurement for ceramic coating of titanium used for dental implants. AB - STATEMENT OF PROBLEM: Poor implant placement or thin gingival tissue and progressive bone resorption may lead to the dark metal color showing through the peri-implant soft tissue. Whether the dark color can be adequately masked is unclear. PURPOSE: The purpose of this in vitro study was to test the color masking effect of porcelain applied on titanium used in fabricating the polished collar of tissue level implants. MATERIAL AND METHODS: Type 4 commercially pure titanium disks and 5 porcelain dentin shades (A2, A3, B2, C2, and D3) were used. Ten titanium disk specimens per porcelain shade were airborne-particle abraded and ultrasonically cleaned. Porcelain was condensed directly on the specimens, fired, and finished (1200 grit SiC paper). The color (L*a*b* values) of the polished specimens was measured with a reflective spectrophotometer. The specimens were then ground and polished in 0.1 mm increments. Color was measured and DeltaE values were calculated at each increment until the thickness at which the DeltaE was greater than 3.3 was identified. The data (n=10) were statistically analyzed by ANOVA and the Tukey multiple-comparison test (alpha=.05). RESULTS: For ceramic thicknesses greater or equal to 0.5 mm for the A2, A3, B2, and C2 shades, the DeltaE was less than 3.3. This value was 0.4 mm for the D3 shade. CONCLUSIONS: The minimum ceramic thickness required to mask the underlying titanium color is 0.5 mm for all shades except D3, which only needs 0.4 mm. L* decreased with thickness increase. Redness and yellowness increased with thickness increase. PMID- 28645667 TI - Effect of different restorative crown and customized abutment materials on stress distribution in single implants and peripheral bone: A three-dimensional finite element analysis study. AB - STATEMENT OF PROBLEM: In recent years, the use of resin-matrix ceramics and polyetheretherketone (PEEK) abutments has been suggested to absorb excessive stresses on dental implants. However, only a few studies have evaluated the effect of these materials on stress distribution in implants and peripheral bone structure. PURPOSE: The purpose of this finite element analysis was to evaluate the biomechanical behaviors of resin-matrix ceramics and PEEK customized abutments in terms of stress distribution in implants and peripheral bone. MATERIAL AND METHODS: Three-dimensional (3D) models of a bone-level implant system and a titanium base abutment were created by using the standard tessellation language (STL) data of original implant components. An anatomic customized abutment and a maxillary right second premolar crown were then modeled over the titanium base abutment. A bone block representing the maxillary right premolar area was created, and the implant was placed in the bone block with 100% osseointegration. Six different models were created according to combinations of restoration materials (translucent zirconia [TZI], lithium disilicate glass ceramic [IPS], polymer-infiltrated hybrid ceramic [VTE]), and customized abutment materials (PEEK and zirconia). In each model, the implants were loaded vertically (200 N) and obliquely (100 N). The stress distribution in the crown, implant, and abutments was evaluated through the von Mises stress analysis, and the stress distribution in the peripheral bone was examined through the maximum and minimum principal stress analyses. RESULTS: The oblique load resulted in high stress values in the implant components, restorative crown, and cortical bone. Low stress values were observed in the VTE crowns. Zirconia customized abutments exhibited higher stress values than PEEK customized abutments. The stress distributions in the implant and peripheral bone were similar in all models. CONCLUSIONS: Changes in restoration and customized abutment material did not affect stress distribution in the implant and peripheral bone. PMID- 28645668 TI - Titration technique using endoscopy for an oral appliance treatment of obstructive sleep apnea. AB - The degree of mandibular protrusion for an oral appliance (OA) should be customized for each patient with obstructive sleep apnea (OSA). This article describes the mandibular titration technique for OAs to effectively treat OSA by using endoscopy to evaluate the change in the airway at the velopharynx. This technique may minimize the degree of mandible protrusion and contribute to both the efficacy of and compliance with OA therapy. PMID- 28645669 TI - Multidisciplinary approach to oral rehabilitation with dental implants after gunshot injury: A clinical report. AB - This clinical report describes a multidisciplinary approach to treat a patient with edentulism and a severe anatomic defect in the mandible caused by a gunshot injury by using an implant-fixed complete dental prosthesis. An immediate loading interim implant-fixed complete dental prosthesis in the mandible associated with a maxillary removable complete denture prosthesis was initially provided to restore the intermaxillary relation. Nasal floor elevation and maxillary sinus augmentation were subsequently performed to increase the maxillary bone volume. Definitive implant-fixed complete dental prostheses were placed in both arches in order to rehabilitate this initially compromised anatomic condition, which ensured patient satisfaction and improvement in masticatory function and esthetics. PMID- 28645670 TI - Fracture resistance of CAD-CAM monolithic ceramic and veneered zirconia molar crowns after aging in a mastication simulator. AB - STATEMENT OF PROBLEM: The demand for ceramic restorations has increased over the past years, and now various machinable materials can be used for chairside computer-aided design and computer aided manufacturing (CAD-CAM) systems. Limited studies of these new materials make it difficult to evaluate their mechanical performance, advantages, and limitations. PURPOSE: The purpose of this in vitro study was to investigate the fracture resistance of CAD-CAM monolithic ceramic and veneered zirconia molar crowns after thermomechanical aging. MATERIAL AND METHODS: A mandibular first molar tooth was prepared, and 12 different experimental groups were generated (n=10). An aging procedure was performed by subjecting the specimens to 12*105 mechanical cycles and 5000 thermocycles. Survival analysis was performed according to the thermomechanical aging. The fracture resistance (load at fracture) of all specimens was evaluated with 1-way analysis of variance after the means had been compared using the Tukey honest significant difference test and Weibull distributions of the experimental groups (alpha=.05). RESULTS: According to the results, the differences between the fracture resistance of the groups were found to be significant. Restorations in the dual network ceramic crown group fractured catastrophically during thermomechanical aging. In all groups, the highest value was found for monolithic zirconia, followed by monolithic lithium disilicate crowns (P<.05). Both of the monolithic crowns made of lithium disilicate derivates and zirconia crowns veneered with lithium disilicate ceramic showed no differences from each other (P>.05). The Weibull modulus (m) ranged from 4.22 to 8.58, and conventionally veneered and overpressed zirconia showed the lowest Weibull modulus values among the tested groups, indicating greater variation of the data. CONCLUSIONS: The highest fracture resistance was observed for yttria-stabilized zirconia crowns, followed by lithium disilicate derivates. Veneered zirconia restorations generally showed lower resistance than these ceramics. The dual network ceramic crowns fractured during thermomechanical aging. PMID- 28645671 TI - A proposal to improve health-care value in spine care delivery: the primary spine practitioner. PMID- 28645672 TI - Percutaneous pedicle screw placement under single dimensional fluoroscopy with a designed pedicle finder-a technical note and case series. AB - BACKGROUND CONTEXT: Minimally invasive spine surgery has become increasingly popular in clinical practice, and it offers patients the potential benefits of reduced blood loss, wound pain, and infection risk, and it also diminishes the loss of working time and length of hospital stay. However, surgeons require more intraoperative fluoroscopy and ionizing radiation exposure during minimally invasive spine surgery for localization, especially for guidance in instrumentation placement. In addition, computer navigation is not accessible in some facility-limited institutions. PURPOSE: This study aimed to demonstrate a method for percutaneous screws placement using only the anterior-posterior (AP) trajectory of intraoperative fluoroscopy. STUDY DESIGN: A technical report (a retrospective and prospective case series) was carried out. PATIENT SAMPLE: Patients who received posterior fixation with percutaneous pedicle screws for thoracolumbar degenerative disease or trauma comprised the patient sample. METHOD: We retrospectively reviewed the charts of consecutive 670 patients who received 4,072 pedicle screws between December 2010 and August 2015. Another case series study was conducted prospectively in three additional hospitals, and 88 consecutive patients with 413 pedicle screws were enrolled from February 2014 to July 2016. The fluoroscopy shot number and radiation dose were recorded. In the prospective study, 78 patients with 371 screws received computed tomography at 3 months postoperatively to evaluate the fusion condition and screw positions. RESULTS: In the retrospective series, the placement of a percutaneous screw required 5.1 shots (2-14, standard deviation [SD]=2.366) of AP fluoroscopy. One screw was revised because of a medialwall breach of the pedicle. In the prospective series, 5.8 shots (2-16, SD=2.669) were required forone percutaneous pedicle screw placement. There were two screws with a Grade 1 breach (8.6%), both at the lateral wall of the pedicle, out of 23 screws placed at the thoracic spine at T9-T12. Forthe lumbar and sacral areas, there were 15 Grade 1 breaches (4.3%), 1 Grade 2 breach (0.3%), and 1 Grade 3 breach (0.3%). No revision surgery was necessary. CONCLUSION: This method avoids lateral shots of fluoroscopy during screw placement and thus decreases the operation time and exposes surgeons to less radiation. At the same time, compared with the computer-navigated procedure, it is less facility-demanding, and provides satisfactory reliability and accuracy. PMID- 28645673 TI - Supra-acetabular line is better than supra-iliac line for coronal balance referencing-a study of perioperative whole spine X-rays in degenerative lumbar scoliosis and ankylosing spondylitis patients. AB - BACKGROUND CONTEXT: The aim of spinal deformity correction is to restore the spine's functional alignment by balancing it in both the sagittal and coronal planes. Regardless of posture, the ideal coronal profile is straight, and therefore readily assessable. PURPOSE: This study compares two radiological methods to determine which better predicts postoperative standing coronal balance. STUDY DESIGN/SETTING: We conducted a single-center, radiographic comparative study between 2011 and 2015. PATIENT SAMPLE: A total of 199 patients with a mean age of 55.1 years were studied. Ninety patients with degenerative lumbar scoliosis (DLS) and 109 ankylosing spondylitis (AS) were treated with posterior surgery during this period. OUTCOME MEASURES: Baseline clinical and radiographic parameters (sagittal and coronal) were recorded. Comparison was performed between the new supra-acetabular line (central sacral vertical line [CSVL1]) and conventional supra-iliac line (CSVL2) perpendicular methods of coronal balance assessment. These methods were also compared with the gold standard standing C7 plumb line. METHODS: Each patient underwent standardized operative procedures and had perioperative spine X-rays obtained for assessment of spinal balance. Adjusted multivariate analysis was used to determine predictors of coronal balance. RESULTS: Significant differences in baseline characteristics (age, gender, and radiographic parameters) were found between patients with DLS and AS. CSVL1, CSVL2, and C7 plumb line differed in all the perioperative measurements. These three radiological methods showed a mean right coronal imbalance for both diagnoses in all pre-, intra-, and postoperative radiographs. The magnitude of imbalance was the greatest for CSVL2 followed by CSVL1 and subsequently the C7 plumb line. A larger discrepancy between CSVL and C7 plumb line measurements intraoperatively than those postoperatively suggests a postural effect on these parameters, which is greater for CSVL2. Multivariate analysis identified that in DLS, the preoperative C7 plumb line was predictive of its postoperative value. CSVL1, but not CSVL2, was predictive of the postoperative C7 plumb line in patients with AS. CONCLUSIONS: The supra acetabular line (CSVL1) is better, although not ideal, as compared with the supra iliac line (CSVL2) in determining coronal balance. Because CSVL1 still cannot be relied on with a high predictive value, it is imperative that future studies continue to identify better intraoperative markers for achieving coronal balance. PMID- 28645674 TI - Does spinal deformity correction of non-dystrophic scoliosis in neurofibromatosis type I with one-stage posterior pedicle screw technique produce outcomes similar to adolescent idiopathic scoliosis? AB - BACKGROUND CONTEXT: The efficacy of one-stage posterior pedicle screw instrument used in the treatment of non-dystrophic scoliosis in neurofibromatosis type I (NF 1) is unknown. Also, there is no study that has directly compared the results of spinal deformity correction between non-dystrophic scoliosis in NF-1 and adolescent idiopathic scoliosis (AIS). PURPOSE: The objectives of this study were to study the efficacy of a one-stage posterior pedicle screw instrument used in the treatment of non-dystrophic scoliosis in NF-1 and to compare non-dystrophic scoliosis in NF-1 with matched AIS to illustrate the differences. STUDY DESIGN: This is a retrospective case control study. PATIENT SAMPLE: Fifteen patients with non-dystrophic scoliosis in NF-1 and 15 patients with AIS underwent a one-stage posterior surgery with the pedicle screw system. OUTCOME MEASURES: Preoperative and postoperative whole-spine radiographs were used to determine coronal and sagittal Cobb angles. Also, the distance between the C7 plumb line and the center sacral vertical line and the sagittal vertebral axis was measured to assess spinal balance. The Scoliosis Research Society (SRS)-22 questionnaire was used to evaluate functional outcomes. METHODS: We matched 15 patients with non-dystrophic scoliosis in NF-1 with patients with AIS (ratio, 1:1) for age, sex, and degree of major deformity. The overall mean age was 13.4+/-2.0 and 14.0+/-2.1 years, respectively. The NF-1 group consisted of 10 boys and 5 girls, and the AIS group consisted of 9 boys and 6 girls. The mean follow-up was 37.6+/-3.9 and 33.5+/-5.0 months, respectively. The AIS group underwent end vertebra (EV) or EV+1 fusion. The NF-1 group underwent EV+1, 2, or 3 fusion. Both coronal and sagittal Cobb angles, trunk balance, operative time, blood loss, fusion levels, length of stay, and scores on the SRS-22 questionnaire were compared between the two groups. The study was supported by the National Natural Science Foundation of China (Grant No. 81401760). There were no study-specific conflict of interest-associated biases. RESULTS: The preoperative main curve magnitude was similar between the two groups; however, the flexibility of the NF-1 group tended to be less than that of the AIS group. The rate of correction of the main curve obtained surgically (79.8% compared with 81.1%) was similar in the NF-1 and AIS groups. There were no significant differences in the loss of correction between the two groups (p>.05). Also, there were no significant differences between the groups in operative time, blood loss, fusion levels, screw number, length of stay, trunk balance, and scores on the SRS-22. There were no serious complications related to surgery in both groups. CONCLUSIONS: Despite the differences in preoperative flexibilities and fusion strategies, non-dystrophic scoliosis in NF-1 can be treated with a satisfied correction rate and progression rate similar to comparable AIS by using the one-stage posterior pedicle screw technique. Dural ectasia or thin pedicles in non-dystrophic scoliosis could make pedicle screw placement challenging. PMID- 28645675 TI - Anatomical considerations of the iliac crest on percutaneous endoscopic discectomy using a transforaminal approach. AB - BACKGROUND CONTEXT: Percutaneous endoscopic discectomy is a minimally invasive procedure for the surgical treatment of lumbar disc herniation (LDH). It can be performed under local anesthesia and requires a skin incision of only 8 mm, with minimal disruption of the spinal structures including ligaments and muscles. However, performing percutaneous endoscopic discectomy with a transforaminal approach (TF-PED) for the lower lumbar spine is associated with some anatomical problems, such as interference from the iliac crest. This study sought to assess the operability of TF-PED for the lower lumbar spine. PURPOSE: The purpose of this study was to assess a three-dimensional relationship between the trajectory of TF-PED and the iliac crest, and the operability of TF-PED at the lower lumbar disc levels (L4-L5 and L5-S1) using CT images. STUDY DESIGN: This is a retrospective study using 323 multiplanar abdominal computed tomography (CT) scans. PATIENT SAMPLE: We retrospectively reviewed contrast-enhanced multiplanar abdominal CT scans of 323 consecutive patients (203 male and 120 female) in our hospital from April 2009 to March 2013. The mean age was 66.5 (range 15-89) years old. OUTCOME MEASURES: The operability of the TF-PED was the outcome measure. MATERIALS AND METHODS: We defined the tangent line in the iliac crest and the superior articular process of the caudal spine as the trajectory line of TF-PED, and evaluated the maximum inclination angle of the trajectory of the TF-PED (alpha angle) at the L4-L5 and the L5-S1 disc levels. Assuming the use of an oblique viewing endoscope at 25 degrees , we defined alpha angle>=65 degrees as the operability of TF-PED. RESULTS: (1) Relationship between iliac crest and disc level: The trajectory of the TF-PED interfered with the iliac crest at L4-L5 in 40.2% (right) and 54.5% (left) of the subjects, and at L5-S1 in 99.7% and 100% of the subjects. (2) The maximum inclination angle of the trajectory of TF-PED: the alpha angles were 84.3 degrees and 82.3 degrees at the L4-L5, and 56.8 degrees and 55.2 degrees at L5-S1. (3) Laterality of the alpha angle: At both disc levels, the mean age of the subjects with a laterality of >=10 degrees was significantly higher than that of subjects with a laterality of <10 degrees . (4) Operability of TF-PED: At L4-L5, TF-PED could be performed in 94.4% and 90.4% of the subjects. In contrast, at L5-S1 the procedure could be performed in 24.1% and 19.2% of the subjects (male: 15.8% and 10.8%, female: 38.3% and 33.3%). CONCLUSIONS: From the results of this study, the trajectory of TF-PED can be limited by the surrounding anatomical structures. The maximum inclination angle indicated that treatment for the central type of LDH at the L5-S1 disc level was considered more difficult than that at the L4-L5 disc level because of the iliac crest. In the clinical setting, such anatomical particularities can be overcome by using a more perpendicular approach (hand-down technique) with the possible addition of a foraminoplasty. Moreover, we found that we must consider the laterality of the trajectory of TF-PED in terms of the patients' age or sex. PMID- 28645676 TI - A journey through growth plates: tracking differences in morphology and regulation between the spine and the long bones in a pig model. AB - BACKGROUND CONTEXT: The process of linear growth is driven by axial elongation of both long bones and vertebral bodies and is accomplished by enchondral ossification. Differences in regulation between the two skeletal sites are mirrored clinically by the age course in body proportions. Whereas long bone growth plates (GPs) can easily be discriminated, vertebral GPs are part of the cartilaginous end plate, which typically shows important species differences. PURPOSE: The objective of this study was to describe and compare histologic, histomorphometric, and regulatory characteristics in the GPs of the spine and the long bones in a porcine model. MATERIALS AND METHODS: Two- and six-week-old piglet GPs of three vertebral segments (cervical, thoracic, and lumbar) and eight long bones (proximal and distal radius, humerus, tibia, and femur) were analyzed morphometrically. Further, estrogen receptors, proliferation markers, and growth factor expressions were examined by immunohistochemistry. RESULTS: Individual vertebral GPs were smaller in width and contained fewer chondrocytes than long bone GPs, although their proliferation activity was similar. Whereas the expression pattern of growth hormone-associated factors such as insulin-like growth factor (IGF)-1 and IGF-1 receptor (IGF-1R) was similar, estrogen receptor (ER)-beta and IGF-2 were distinctly expressed in the vertebral samples. CONCLUSIONS: Vertebral GPs display differential growth, with measurements similar to the slowest-growing GPs of long bones. Further investigation is needed to decipher the molecular basis of the differential growth of the spine and the long bones. Knowledge on the distinct mechanism will ultimately improve the assessment of clinically essential characteristics of spinal growth, such as vertebral elongation potential and GP fusion. PMID- 28645677 TI - Dry eye and Meibomian gland dysfunction with meibography in patients with lamellar ichthyosis. AB - PURPOSE: To evaluate the dry eye findings and Meibomian gland dysfunction as demonstrated with meibography in patients with lamellar ichthyosis. METHODS: Twenty-four eyes of 12 patients with lamellar ichthyosis (Group 1) and twenty four eyes of 12 healthy individuals (Group 2) were enrolled. Comprehensive eye examination along with corneal and conjunctival fluorescein staining with Oxford scoring, tear film break-up time, Schirmer 1 test, ocular surface disease index (OSDI) score assessment, and evaluation of upper and lower eyelid Meibomian glands using infrared filter of slit-lamp biomicroscope (SL-D701, TOPCON, Tokyo, Japan) were performed. The Meibomian glands were graded from grade 0 (no loss of Meibomian glands) to grade 3 (gland dropout >2/3 of the total Meibomian glands). RESULTS: The mean ages of Group 1 and Group 2 were 25.3+/-15.6years (range, 9-61 years) and 25.3+/-13.3years (range, 9-52 years), respectively (p=0.997). No significant difference in terms of best-corrected visual acuity, Schirmer 1 test and Oxford scores were detected in between groups. Mean tear film break-up time was lower (p=0.013), and OSDI score, lower, upper and total (upper+lower) meiboscores were significantly higher in Group 1 as compared with Group 2 (p<0.001, p=0.001, p=0.001, p=0.001, respectively). CONCLUSION: Lamellar ichthyosis is associated with evaporative type dry eye disease with decreased tear film break-up time, normal Schirmer 1 values and Meibomian gland dysfunction that can objectively be demonstrated with meibography. For this reason, in order to prevent undesired complications, these patients should be examined and treated for dry eye disease especially targeting Meibomian gland dysfunction. PMID- 28645678 TI - Endolymphatic hydrops imaging: Differential diagnosis in patients with Meniere disease symptoms. AB - PURPOSE: The goal of this retrospective study was to investigate the differential diagnosis of endolymphatic hydrops in patients with Meniere's disease (MD) symptoms by using magnetic resonance imaging (MRI) with intravenous injection of gadolinium chelate and delayed acquisition. MATERIAL AND METHOD: Two hundred patients (133 women, 67 men; mean age=67.2+/-11 ([SD] years) with unilateral MD underwent MRI at 3-T, between 4.5 and 5.5hours after intravenous administration of gadoterate meglumine at a dose of 0.1mmol/kg. MR images were analyzed for the presence of saccular hydrops, perilymphatic fistulae, inner ear malformations, semicircular canal (SCC) abnormal enhancement and brain lesions. We also tested the potential relationship between past history of gentamicin intratympanic administration and perilymphatic fistula presence and SCC aspect. RESULTS: Saccular hydrops were found in 96/200 patients with MD (48%). Three patients (1.5%) had perilymphatic fistulas associated with saccular hydrops, as confirmed by surgery. There was a correlation between the presence of perilymphatic fistula and past history of intratympanic gentamicin administration (P=0.02). We detected inner ear malformations in 5 patients (2.5%), SCC local enhancement in 15 patients (7.5%) always on the same side than the clinical symptoms of MD. There was a correlation between the presence of SCC abnormal enhancement and past intratympanic gentamicin administration (P=0.001). Five patients (2.5%) had brain lesions along central cochleovestibular pathways. CONCLUSION: MRI may reveal brain lesions, SCC abnormalities and perilymphatic fistulae in patients with clinical MD. PMID- 28645679 TI - Percutaneous management of benign biliary disorders in children. AB - PURPOSE: The goal of this study was to analyze the outcomes of percutaneous transhepatic management of benign biliary disorders in pediatric patients. MATERIALS AND METHODS: This study included 11 pediatric patients who underwent percutaneous transhepatic biliary interventional procedures between September 2007 and December 2016. There were 3 males and 8 females with a mean age of 9.6+/ 5.4 (SD)years (range: 2-17years). Technical details, complications and outcome of the procedures were evaluated. RESULTS: The underlying pathologies were bile duct stones (n=2), bile leakage (n=4), choledochal cyst (n=3) and benign biliary stricture (n=2). The therapeutic interventional procedures were as follows; percutaneous stone removal in patients with bile duct stones, external biliary drainage in patients with choledochal cyst, bile diversion by internal-external percutaneous biliary drainage (IE-PBD) in patients with bile leakage, plastic stent placement, IE-PBD with balloon dilatation in patients with benign biliary stricture. The procedures were successful in all patients technically and clinically. One patient experienced intermittent fever. CONCLUSION: Percutaneous transhepatic biliary interventional procedure is an effective and safe approach for the treatment of pediatric patients with bile duct stones, bile leakage, symptomatic choledochal cyst and benign biliary stricture when endoscopic procedure is unavailable or fails. PMID- 28645680 TI - Collection, processing and freezing of equine bone marrow cells. AB - There is no consensus on aspects of equine bone marrow collection and processing. The study aimed to describe the collection of large volumes of bone marrow from horses of advanced age, with emphasis on bone marrow mononuclear cells (BMMCs) recovery and viability after cryopreservation. Fourteen horses, aged 3-24 years, were divided into three experiments. E1 studied the feasibility of collecting 200 mL from the sternums of horses of advanced age; E2 examined the number of cells obtained from the first and last syringe of each puncture; and E3 investigated the influence of heparin concentration on the prevention of cell aggregation, and cell viability after freezing in liquid nitrogen. Bone marrow aspirations were done with syringes pre-filled with Iscove's modified Dulbecco's medium and different concentrations of sodium heparin. BMMCs were counted, cell viability was determined, and samples were frozen. Bone marrow collection from the sternum is safe, even at large volumes and from horses of advanced age, and the number of cells recovered decreases with successive aspirations (p < 0.0001). Heparin concentration influenced cell aggregation, and recovered cells continued to be commercially viable after 150 days in frozen storage. PMID- 28645681 TI - Thermal thresholds of cardiovascular HL-1 cell destruction by cryothermal exposure. AB - The use of thermal based therapies for treatment of atrial fibrillation is increasing. While numerous reports are available in the literature regarding the efficacy of cryotherapy on pulmonary vein survival, there are no reports specifically at the cellular level that establish thermal thresholds and mechanisms of cellular destruction. The current article reports on the response of HL-1 cardiomyocytes to cooling rates and end temperatures during cryothermal exposure. The focus is on establishment of in vitro thresholds while also establishing mechanisms of action due to biophysical events (i.e. intracellular ice formation and water transport). PMID- 28645682 TI - Re: Subclinical thyroid dysfunction and mortality in type 2 diabetes. PMID- 28645683 TI - A single brain metastasis seen on 68Ga-PSMA PET/CT in recurrent breast cancer. PMID- 28645684 TI - Detection and quantification of 223Ra uptake in bone metastases of patients with castration resistant prostate carcinoma, with the aim of determining the absorbed dose in the metastases. AB - PURPOSES: To obtain the necessary acquisition and calibration parameters in order to evaluate the possibility of detecting and quantifying 223Ra uptake in bone metastases of patients treated for castration resistant prostate carcinoma. Furthermore, in the cases in which the activity can be quantified, to determine the absorbed dose. MATERIAL AND METHODS: Acquisitions from a Petri dish filled with 223Ra were performed in the gamma camera. Monte Carlo simulations were also performed to study the partial volume effect. Formulae to obtain the detection and quantification limits of 223Ra uptake were applied to planar images of two patients 7 days post-administration of 55kBq/kg of 223Ra. In order to locate the lesions in advance, whole-body scans and SPECT/CT images were acquired after injecting 99mTc-HDP. RESULTS: The optimal energy window was found to be at 82keV with a medium-energy collimator MEGP. Of the lesions found in the patients, only those that had been detected in both the AP and PA projections could be quantified. These lesions were those which had shown a higher 99mTc-HDP uptake. The estimated values of absorbed doses ranged between 0.7Gy and 7.8Gy. CONCLUSIONS: Of the lesions that can be detected, it is not possible to quantify the activity uptake in some of them, which means that the absorbed dose cannot be determined either. This does not mean that the absorbed dose in these lesions can be regarded as negligible. PMID- 28645686 TI - Relationship between cardiovascular disease and dental pathology. Systematic review. AB - BACKGROUND AND OBJECTIVE: The relationship between atherothrombotic cardiovascular disease (ATCD) and localised infections in teeth, including caries and chronic apical periodontitis (CAP) has not been studied much and is not well defined. METHOD: A systematic search was performed using the scientific databases PubMed and Medline from 1989 to 2016. RESULTS: A significant relationship was observed with ATCD in 10 out of 10 studies addressing the degree of oral hygiene, in 14 of 17 that included loss of teeth, in 6 of 12 that analysed caries and in 11 of 15 that included CAP. However, there was a huge methodological heterogeneity. CONCLUSIONS: It can be concluded that there is an association between CAP and ATCD. Patients with ATCD present a worse oral hygiene status and fewer teeth. PMID- 28645685 TI - Concordance between brain 18F-FDG PET and cerebrospinal fluid biomarkers in diagnosing Alzheimer's disease. AB - OBJECTIVES: Cortical posterior hypometabolism on PET imaging with 18F-FDG (FDG PET), and altered levels of Abeta1-42 peptide, total Tau (tTau) and phosphorylated Tau (pTau) proteins in cerebrospinal fluid (CSF) are established diagnostic biomarkers in Alzheimer's disease (AD). An evaluation has been made of the concordance and relationship between the results of FDG-PET and CSF biomarkers in symptomatic patients with suspected AD. MATERIAL AND METHODS: A retrospective review was carried out on 120 patients with cognitive impairment referred to our Cognitive Neurology Unit, and who were evaluated by brain FDG-PET and a lumbar puncture for CSF biomarkers. In order to calculate their Kappa coefficient of concordance, the result of the FDG-PET and the set of the three CSF biomarkers in each patient was classified as normal, inconclusive, or AD compatible. The relationship between the results of both methods was further assessed using logistic regression analysis, including the Abeta1-42, tTau and pTau levels as quantitative predictors, and the FDG-PET result as the dependent variable. RESULTS: The weighted Kappa coefficient between FDG-PET and CSF biomarkers was 0.46 (95% CI: 0.35-0.57). Logistic regression analysis showed that the Abeta1-42 and tTau values together were capable of discriminating an FDG-PET result metabolically suggestive of AD from one non-suggestive of AD, with a 91% sensitivity and 93% specificity at the cut-off line Abeta1-42=44+1.3*tTau. CONCLUSIONS: The level of concordance between FDG-PET and CSF biomarkers was moderate, indicating their complementary value in diagnosing AD. The Abeta1-42 and tTau levels in CSF help to predict the patient FDG-PET cortical metabolic status. PMID- 28645687 TI - Generalized rash and lymphocytosis as clinical onset adult T-cell leukemia/lymphoma. PMID- 28645688 TI - Pubertal Timing, Smoking, and Sexual Activity. PMID- 28645689 TI - Duration and timing of daily light exposure influence the rapid shifting of BALB/cJ mouse circadian locomotor rhythms. AB - Photic entrainment of the murine circadian system can typically be explained with a discrete model in which light exposures near dusk and dawn can either advance or delay free-running rhythms to match the external light cycle period. In most mouse strains, the magnitude of those phase shifts is limited to several hours per day; however, the BALB/cJ mouse can re-entrain to large (6-8hour) phase advances of the light/dark cycle. In this study, we demonstrate that the circadian responses of BALB/cJ mice are dependent on duration as well as timing of light exposure, with significantly larger phase shifts resulting from >6-hour light exposures, yet loss of entrainment to photoperiods of <2-3hours per day or to skeleton photoperiods. Intermittent light exposures of the same total duration but distributed differentially over the same period of time as that of a 6-hour phase advance of the light cycle yielded phase shifts of different magnitudes depending on the pattern of exposure. Both negative and positive masking responses to light and darkness, respectively, were exaggerated in BALB/cJ mice under a T7 light cycle, but were not responsible for their rapid re-entrainment to chronic phase shifting of the light dark cycle. These results collectively suggest that the innately jetlag-resistant BALB/cJ mouse circadian system provides an alternative murine model in which to elucidate the limitations of photic entrainment observed in other commonly used strains of mice. PMID- 28645690 TI - Beyond the social stereotypes of hormones. PMID- 28645691 TI - Maternal exposure to a mixture of persistent organic pollutants (POPs) affects testis histology, epididymal sperm count and induces sperm DNA fragmentation in mice. AB - Persistent organic pollutants (POPs) are widespread throughout the environment and some are suspected to induce reproductive toxicity. As animals and humans are exposed to complex mixtures of POPs, it is reasonable to assess how such mixtures could interact with the reproductive system. Our aim is to investigate how maternal exposure to a mixture of 29 different persistent organic pollutants, formulated to mimic the relative POP levels in the food basket of the Scandinavian population, could alter reproductive endpoints. Female mice were exposed via feed from weaning, during pregnancy and lactation in 3 exposure groups (control (C), low (L) and high (H)). Testicular morphometric endpoints, epididymal sperm concentration and sperm DNA integrity were assessed in adult male offspring. We found that the number of tubules, proportion of tubule compartments and epididymal sperm concentration significantly decreased in both POP exposed groups. Epididymal sperm from both POP exposed groups showed increased DNA fragmentation. It is concluded that maternal exposure to a defined POP mixture relevant to human exposure can affect testicular development, sperm production and sperm chromatin integrity. PMID- 28645692 TI - Clinical implementation of combined modulated electron and photon beams with conventional MLC for accelerated partial breast irradiation. AB - PURPOSE: To report the clinical implementation of a novel external beam radiotherapy technique for accelerated partial breast irradiation treatments based on combined electron and photon modulated beams radiotherapy (MERT+IMRT) with conventional MLC. MATERIALS AND METHODS: A group of patients was selected to test the viability of the technique. The prescribed dose was 38.5Gy, following a hypofractionated schema, and the structures were defined following the NSABP B39/RTOG-0413 protocol. The plans were calculated with an in-house Monte Carlo based planning system to consider explicitly the particle interactions with the MLC. An ad-hoc breast phantom was designed for a specific QA protocol. A reduced SSD was used for electron beams. Toxicity and cosmetic effects were assessed at every follow-up visit. RESULTS: All the plans achieved the dosimetric objectives and fulfilled the specific quality assurance protocol. Treatment delivery did not entail additional drawbacks for the clinical routine. Moderate or severe grade of toxicity was not reported, and the cosmetic results were comparable to those obtained with other APBI techniques. CONCLUSIONS: Results showed that MERT+IMRT with the MLC is a feasible and secure technique, and easy to be extended to other centers with the implementation of the adequate software for planning. PMID- 28645693 TI - Male mice ultrasonic vocalizations enhance female sexual approach and hypothalamic kisspeptin neuron activity. AB - Vocal communication in animals is important for ensuring reproductive success. Male mice emit song-like "ultrasonic vocalizations (USVs)" when they encounter female mice, and females show approach to the USVs. However, it is unclear whether USVs of male mice trigger female behavioral and endocrine responses in reproduction. In this study, we first investigated the relationship between the number of deliveries in breeding pairs for 4months and USVs syllables emitted from those paired males during 3min of sexual encounter with unfamiliar female mice. There was a positive correlation between these two indices, which suggests that breeding pairs in which males could emit USVs more frequently had more offspring. Further, we examined the effect of USVs of male mice on female sexual behavior. Female mice showed more approach behavior towards vocalizing males than devocalized males. Finally, to determine whether USVs of male mice could activate the neural system governing reproductive function in female mice, the activation of kisspeptin neurons, key neurons to drive gonadotropin-releasing hormone neurons in the hypothalamus, was examined using dual-label immunocytochemistry with cAMP response element-binding protein phosphorylation (pCREB). In the arcuate nucleus (Arc), the number of kisspeptin neurons expressing pCREB significantly increased after exposure to USVs of male as compared with noise exposure group. In conclusion, our results suggest that USVs of male mice promote fertility in female mice by activating both their approaching behavior and central kisspeptin neurons. PMID- 28645695 TI - [Pneumomediastinum: When asthma exacerbation does not improve]. PMID- 28645694 TI - [Comparative analysis: Effectiveness of nicotine addiction treatment in people with psychiatric comorbidity]. AB - OBJECTIVE: To determine whether or not nicotine addiction treatment was less effective in psychiatric than in the healthy population. MATERIAL AND METHODS: A retrospective, descriptive and comparative cohort study was conducted in Albacete University Hospital during years 2008-2012 on all patients that attended the Tobacco Cessation Unit. The statistical tests used were Chi-squared, likelihood ratio, and the Student t test. Statistical significance P<=.05. RESULTS: The study included a total of 1,484 patients, of which 48.6% were female. The mean age was 46.8 years, and the mean age of starting smoking was 17.6 years. The mean number of previous attempts to quit was 1.48, and mean number of cigarettes smoked was 25.39. They had a mean Fagerstrom score of 6.04, a Richmond score of 8.13, and a mean carbon monoxide level of 16.65ppm. Most patients were referred from Primary Care (38.7%) and Chest Diseases department (33%), and the type of tobacco smoked was "light" in 75.8%. There was 15% with chronic obstructive pulmonary disease, 8% with asthma, and 9.4% with obstructive sleep apnoea syndrome. Furthermore, there was respiratory disease in 28.7%, cardiovascular disease in 4.6%, and both in 3.5%. Hiatus hernia was present in 7.2%, thyroid disease in 3.8%, hypertension in 19%, diabetes in 10.7%, and dyslipidaemia in 29.4%, Drugs were used by 7.1%, and 12.6% consumed alcohol. There was 39.3% psychiatric comorbidity (PC), and were comparable except in gender, age of onset, Fagerstrom, Richmond, source of referral, asthma, hiatus hernia, thyroid disease, hypertension, as well as drugs and treatment. Drug treatment was completed by 22.3% in the PC group, with no significant difference. There were differences in success (P=.008), but not in failure and relapse rates. CONCLUSION: Anti-smoking treatment in psychiatric patients is effective. An increase in the probability of treatment success is observed in patients without psychiatric comorbidity. PMID- 28645696 TI - Exercise training improves functional status in hypertensive older adults under angiotensin converting enzymes inhibitors medication. AB - BACKGROUND: The study aims to analyze the effect of three types of treatment on functional status, and cardiovascular risk outcomes in hypertensive older adults with comorbidities. METHODS: Participants (n=418) underwent one of the following 3 conditions: i) multicomponent exercise training 3 times/week (MEX; n=116); ii) angiotensin converting enzyme inhibitors used mono-dose daily (ACEi; n=70); iii) combined exercise and ACEi drugs (ACEiMEX; n=232). The trial was completed by 82% of the participants (n=342): MEX (n=90); ACEi (n=66); ACEiMEX (n=186). Baseline and 2-year follow-up evaluations included the Senior Fitness Test battery, Short Form Health Survey 36 (SF-36), the health history questionnaires, anthropometric and hemodynamic profile. RESULTS: MEX and ACEiMEX groups improved all physical functional status outcomes, decreased systolic (SBP) and diastolic blood pressure (p<0.001) and augmented the physical functioning, role physical and physical component score (PCS) (p<0.05), but also bodily pain (p<0.05). The ACEi group reduced the upper body strength, upper and lower body flexibility and aerobic endurance (p<0.05); worsened the anthropometric profile, and SBP (p<0.001); and decreased general health and PCS (p<0.05). CONCLUSIONS: The improvement of the physical functioning and HRQoL in older hypertensive adults using ACEi medications only occur if they adopt an exercise training regimen, increasing also the management of the blood pressure and other cardiovascular risk factors. PMID- 28645697 TI - Clinical high-resolution mapping of the proteoglycan-bound water fraction in articular cartilage of the human knee joint. AB - PURPOSE: We applied our recently introduced Bayesian analytic method to achieve clinically-feasible in-vivo mapping of the proteoglycan water fraction (PgWF) of human knee cartilage with improved spatial resolution and stability as compared to existing methods. MATERIALS AND METHODS: Multicomponent driven equilibrium single-pulse observation of T1 and T2 (mcDESPOT) datasets were acquired from the knees of two healthy young subjects and one older subject with previous knee injury. Each dataset was processed using Bayesian Monte Carlo (BMC) analysis incorporating a two-component tissue model. We assessed the performance and reproducibility of BMC and of the conventional analysis of stochastic region contraction (SRC) in the estimation of PgWF. Stability of the BMC analysis of PgWF was tested by comparing independent high-resolution (HR) datasets from each of the two young subjects. RESULTS: Unlike SRC, the BMC-derived maps from the two HR datasets were essentially identical. Furthermore, SRC maps showed substantial random variation in estimated PgWF, and mean values that differed from those obtained using BMC. In addition, PgWF maps derived from conventional low resolution (LR) datasets exhibited partial volume and magnetic susceptibility effects. These artifacts were absent in HR PgWF images. Finally, our analysis showed regional variation in PgWF estimates, and substantially higher values in the younger subjects as compared to the older subject. CONCLUSIONS: BMC-mcDESPOT permits HR in-vivo mapping of PgWF in human knee cartilage in a clinically feasible acquisition time. HR mapping reduces the impact of partial volume and magnetic susceptibility artifacts compared to LR mapping. Finally, BMC-mcDESPOT demonstrated excellent reproducibility in the determination of PgWF. PMID- 28645698 TI - Radiological studies of fetal alcohol spectrum disorders in humans and animal models: An updated comprehensive review. AB - Fetal Alcohol Spectrum Disorders encompass a wide range of birth defects in children born to mothers who consumed alcohol during pregnancy. Typical mental impairments in FASD include difficulties in life adaptation and learning and memory, deficits in attention, visuospatial skills, language and speech disabilities, mood disorders and motor disabilities. Multimodal imaging methods have enabled in vivo studies of the teratogenic effects of alcohol on the central nervous system, giving more insight into the FASD phenotype. This paper offers an up-to-date comprehensive review of radiological findings in the central nervous system in studies of prenatal alcohol exposure in both humans and translational animal models, including Magnetic Resonance Imaging, Computed Tomography, Positron Emission Tomography, Single Photon Emission Tomography and Ultrasonography. PMID- 28645699 TI - The forgotten artist: Why to consider intentions and interaction in a model of aesthetic experience: Comment on "Move me, astonish me... delight my eyes and brain: The Vienna Integrated Model of top-down and bottom-up processes in Art Perception (VIMAP) and corresponding affective, evaluative, and neurophysiological correlates" by Matthew Pelowski et al. PMID- 28645700 TI - Antagonistic regulation of spermatogonial differentiation in zebrafish (Danio rerio) by Igf3 and Amh. AB - Fsh-mediated regulation of zebrafish spermatogenesis includes modulating the expression of testicular growth factors. Here, we study if and how two Sertoli cell-derived Fsh-responsive growth factors, anti-Mullerian hormone (Amh; inhibiting steroidogenesis and germ cell differentiation) and insulin-like growth factor 3 (Igf3; stimulating germ cell differentiation), cooperate in regulating spermatogonial development. In dose response and time course experiments with primary testis tissue cultures, Fsh up-regulated igf3 transcript levels and down regulated amh transcript levels; igf3 transcript levels were more rapidly up regulated and responded to lower Fsh concentrations than were required to decrease amh mRNA levels. Quantification of immunoreactive Amh and Igf3 on testis sections showed that Fsh increased slightly Igf3 staining but decreased clearly Amh staining. Studying the direct interaction of the two growth factors showed that Amh compromised Igf3-stimulated proliferation of type A (both undifferentiated [Aund] and differentiating [Adiff]) spermatogonia. Also the proliferation of those Sertoli cells associated with Aund spermatogonia was reduced by Amh. To gain more insight into how Amh inhibits germ cell development, we examined Amh-induced changes in testicular gene expression by RNA sequencing. The majority (69%) of the differentially expressed genes was down-regulated by Amh, including several stimulators of spermatogenesis, such as igf3 and steroidogenesis-related genes. At the same time, Amh increased the expression of inhibitory signals, such as inha and id3, or facilitated prostaglandin E2 (PGE2) signaling. Evaluating one of the potentially inhibitory signals, we indeed found in tissue culture experiments that PGE2 promoted the accumulation of Aund at the expense of Adiff and B spermatogonia. Our data suggest that an important aspect of Fsh bioactivity in stimulating spermatogenesis is implemented by restricting the different inhibitory effects of Amh and by counterbalancing them with stimulatory signals, such as Igf3. PMID- 28645701 TI - Effect of phosphate-solubilizing bacteria on phosphorus dynamics and the bacterial community during composting of sugarcane industry waste. AB - Sugarcane processing generates a large quantity of residues, such as filter cake and ashes, which are sometimes composted prior to their amendment in soil. However, important issues still have to be addressed on this subject, such as the description of bacterial succession that occurs throughout the composting process and the possibilities of using phosphate-solubilizing bacteria (PSB) during the process to improve phosphorus (P) availability in the compost end product. Consequently, this study evaluated the bacterial diversity and P dynamics during the composting process when inoculated with Pseudomonas aeruginosa PSBR12 and Bacillus sp. BACBR01. To characterize the bacterial community structure during composting, and to compare PSB-inoculated compost with non-inoculated compost, partial sequencing of the bacterial 16S rRNA gene and sequential P fractionation were used. The data indicated that members of the order Lactobacillales prevailed in the early stages of composting for up to 30 days, mostly due to initial changes in pH and the C/N ratio. This dominant bacterial group was then slowly replaced by Bacillales during a composting process of up to 60 days. In addition, inoculation of PSB reduced the levels of Ca-bound P by 21% and increased the labile organic P fraction. In PSB-inoculated compost, Ca-P compound solubilization occurred concomitantly with an increase of the genus Bacillus. The bacterial succession and the final community is described in compost from sugarcane residues and the possible use of these inoculants to improve P availability in the final compost is validated. PMID- 28645702 TI - Use of adipose tissue and stromal vascular fraction in hand surgery. AB - Adipose tissue is an abundant source of various cell types including not only adipocytes, but also progenitor and endothelial cells from thestroma. Interest in adipose tissue has surged since the identification in 2001 of adipose-derived stem cells (ADSCs) and of the stromal vascular fraction (SVF) obtained from adipose tissue by enzymatic digestion and centrifugation. SVF has been proven effective in ensuring tissue regeneration, thus improving tissue trophicityand vascularisation. These effects have generated strong interest among both physicians and surgeons, particularly in the field of hand surgery. Several applications have been developed and used, for instance to treat Dupuytren's contracture, systemic sclerosis-related hand lesions, and skin ageing at the hand. Other uses are being evaluated in clinical or animal studies. The objective of this article is to review the capabilities of adipose tissue and their current and potential applications in hand surgery. PMID- 28645703 TI - Mapping of the anterior tibial profile to identify accurate reference points for sagittal alignment of tibial component in total knee arthroplasty. AB - BACKGROUND: Although standard instrumentation is the procedure most frequently used to implant a Total Knee Arthroplasty (TKA), high rates of malalignment of tibial component are reported using this technique. Anatomical landmarks for sagittal alignment have been little investigated and the best reference axis, which parallels the mechanical axis, is yet to be established. HYPOTHESIS: Mapping the Anterior Tibial Profile (ATP) may allow the identification of segmental zones of the ATP parallel to the mechanical axis which can be used to align the extramedullary rod. METHODS: An intramedullary rod was positioned in line with the mechanical axis in 47 dried cadaveric tibiae. The rod was connected to a cutting jig and to an extramedullary rod. Digitalized images of lateral view radiographs were taken and the distance between the ATP and the extramedullary rod was measured at 10-mm intervals and at interpolated distances corresponding to every 2% of the tibial length. RESULTS: Segmental portions of the ATP exhibit an alignment parallel to the mechanical axis between points located at 58% and 90% and at 62% and 88% of the tibial length. Points placed at 50% of tibial length and 5mm proximal to the ankle joint generate the longer axis parallel to the mechanical axis. CONCLUSION: The orientation of sagittal tibial cut may be improved by aligning the extramedullary rod parallel to the ATP at definite points. Points placed at 50% of the tibial length and 5mm proximal to the ankle joint may be preferred since they generate the longer axis parallel to the mechanical axis and are more easily identified at surgery. PMID- 28645704 TI - Reconstruction of large diaphyseal bone defect by simplified bone transport over nail technique: A 7-case series. AB - : Reconstruction of large diaphyseal bone defect is complex and the complications rate is high. This study aimed to assess a simplified technique of segmental bone transport by monorail external fixator over an intramedullary nail.A prospective study included 7 patients: 2 femoral and 5 tibial defects. Mean age was 31years (range: 16-61years). Mean follow-up was 62 months (range: 46-84months). Defects were post-traumatic, with a mean length of 7.2cm (range: 4 to 9.5cm). For 3 patients, reconstruction followed primary failure. In 4 cases, a covering flap was necessary. Transport used an external fixator guided by an intramedullary nail, at a rate of 1mm per day. One pin was implanted on either side of the distraction zone. The external fixator was removed 1 month after bone contact at the docking site. Mean bone transport time was 11 weeks (range: 7-15 weeks). Mean external fixation time was 5.1months (range: 3.5 to 8months). Full weight-bearing was allowed 5.7months (range: 3.5-13months) after initiation of transport. In one patient, a pin had to be repositioned. In 3 patients, the transported segment re ascended after external fixatorablation, requiring repeat external fixation and resumption of transport. There was just 1 case of superficial pin infection. Reconstruction quality was considered "excellent" on the Paley-Marr criteria in 6 cases. The present technique provided excellent reconstruction quality in 6 of the 7 cases. External fixation time was shorter and resumption of weight-bearing earlier than with other reconstruction techniques, notably including bone autograft, vascularized bone graft or the induced membrane technique. Nailing facilitated control of limb axis and length. The complications rate was 50%, comparable to other techniques. This study raises the question of systematic internal fixation of the docking site, to avoid any mobilization of the transported segment. The bone quality, axial control and rapidity shown by the present technique make it well-adapted to reconstruction of diaphyseal bone defect. LEVEL OF EVIDENCE: Four-case series. PMID- 28645706 TI - Pilot Pharmacokinetic Study of High-Dose Daptomycin in Hemodialysis Patients With Infected Medical Devices. PMID- 28645707 TI - Syndemic Factors Mediate the Relationship between Sexual Stigma and Depression among Sexual Minority Women and Gender Minorities. AB - INTRODUCTION: Stigma and discrimination contribute to elevated depression risks among sexual minority women (SMW) and gender minority (GM) people who identify as lesbian, bisexual, or queer. Syndemics theory posits that adverse psychosocial outcomes cluster to negatively impact health and mental health outcomes among sexual minorities. We tested whether a syndemic condition composed of low social support, low self-rated health, low self-esteem, and economic insecurity mediated the relationship between sexual stigma and depressive symptoms among SMW/GM. METHODS: We implemented a cross-sectional, Internet-based survey with SMW and GM in Toronto, Canada. We conducted structural equation modeling using maximum likelihood estimation to test a conceptual model of pathways between sexual stigma, syndemic factors, and depressive symptoms. RESULTS: A total of 391 SMW/GM with a mean age of 30.9 (SD = 7.62) were included in the analysis. The model fit for a latent syndemics construct consisting of psychosocial variables (low social support, low self-rated health, low self-esteem, economic insecurity) was very good (chi2 = 6.022, df = 2, p = .049; comparative fit index = 0.973, Tucker-Lewis index = 0.918, root-mean square error of approximation = 0.072). In the simultaneous model, sexual stigma had a significant direct effect on depression. When the syndemic variable was added as a mediator, the direct path from sexual stigma to depression was no longer significant, suggesting mediation. The model fit the data well: chi2 = 33.50, df = 12, p = .001; comparative fit index = 0.951, Tucker-Lewis index = 0.915, root-mean square error of approximation = 0.068. CONCLUSIONS: Our results highlight the salience of considering both sexual stigma and syndemic factors to explain mental health disparities experienced by SMW and GM. Addressing sexual stigma in the context of co-occurring psychosocial factors and economic insecurity will be key to achieving optimal health for SMW and GM. PMID- 28645705 TI - Acid Load and Phosphorus Homeostasis in CKD. AB - BACKGROUND: The kidneys maintain acid-base homeostasis through excretion of acid as either ammonium or as titratable acids that primarily use phosphate as a buffer. In chronic kidney disease (CKD), ammoniagenesis is impaired, promoting metabolic acidosis. Metabolic acidosis stimulates phosphaturic hormones, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) in vitro, possibly to increase urine titratable acid buffers, but this has not been confirmed in humans. We hypothesized that higher acid load and acidosis would associate with altered phosphorus homeostasis, including higher urinary phosphorus excretion and serum PTH and FGF-23. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 980 participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. PREDICTORS: Net acid excretion as measured in 24-hour urine, potential renal acid load (PRAL) estimated from food frequency questionnaire responses, and serum bicarbonate concentration < 22 mEq/L. OUTCOME & MEASUREMENTS: 24-hour urine phosphorus and calcium excretion and serum phosphorus, FGF-23, and PTH concentrations. RESULTS: Using linear and log-linear regression adjusted for demographics, kidney function, comorbid conditions, body mass index, diuretic use, and 24-hour urine creatinine excretion, we found that 24-hour urine phosphorus excretion was higher at higher net acid excretion, higher PRAL, and lower serum bicarbonate concentration (each P<0.05). Serum phosphorus concentration was also higher with higher net acid excretion and lower serum bicarbonate concentration (each P=0.001). Only higher net acid excretion associated with higher 24-hour urine calcium excretion (P<0.001). Neither net acid excretion nor PRAL was associated with FGF-23 or PTH concentrations. PTH, but not FGF-23, concentration (P=0.2) was 26% (95% CI, 13%-40%) higher in participants with a serum bicarbonate concentration <22 versus >=22 mEq/L (P<0.001). Primary results were similar if stratified by estimated glomerular filtration rate categories or adjusted for iothalamate glomerular filtration rate (n=359), total energy intake, dietary phosphorus, or urine urea nitrogen excretion, when available. LIMITATIONS: Possible residual confounding by kidney function or nutrition; urine phosphorus excretion was included in calculation of the titratable acid component of net acid excretion. CONCLUSIONS: In CKD, higher acid load and acidosis associate independently with increased circulating phosphorus concentration and augmented phosphaturia, but not consistently with FGF-23 or PTH concentrations. This may be an adaptation that increases titratable acid excretion and thus helps maintain acid-base homeostasis in CKD. Understanding whether administration of base can lower phosphorus concentrations requires testing in interventional trials. PMID- 28645709 TI - Aquatic biodiversity in sedimentation ponds receiving road runoff - What are the key drivers? AB - Recently, increased attention has been paid to biodiversity conservation provided by blue-green solutions such as engineered ponds that are primarily established for water treatment and flood control. However, little research has been done to analyse the factors that affect biodiversity in such ponds. The purpose of this study was to evaluate the influence of environmental factors on aquatic biodiversity, mainly macroinvertebrate communities, in road sedimentation ponds in order to provide a foundation for recommendations on aquatic biodiversity conservation. Multivariate statistical methods, including unconstrained and constrained analysis, were applied to examine the relationships between organisms and the water quality as well as physical factors (including plant cover). Stepwise multiple regressions indicated that the most important variables governing the variation in the biological community composition were pond size, average annual daily traffic, metals, chloride, distance to the closest pond from study pond, dissolved oxygen, hydrocarbons, and phosphorus. The presence of most taxa was positively correlated with pond size and negatively correlated with metals. Small ponds with high pollutant loadings were associated with a low diversity and dominated by a few pollution tolerant taxa such as oligochaetes. A comprehensive understanding of impacts of various environmental factors on aquatic biodiversity is important to effectively promote and conserve aquatic biodiversity in such sedimentation ponds. Our results indicate that road sedimentation ponds should be designed large enough, because large ponds are likely to provide a more heterogeneous habitat and thus contain a species rich fauna. In addition, larger ponds seem to be less contaminated due to dilution compared to smaller ponds, thereby maintaining a higher biodiversity. Finally, creating some additional ponds in the vicinity of the sedimentation ponds in areas with few water bodies would increase the connectivity that facilitates the movement of invertebrates between ponds. PMID- 28645708 TI - Identification of major routes of HIV transmission throughout Mesoamerica. AB - BACKGROUND: Migration and travel are major drivers of the spread of infectious diseases. Geographic proximity and a common language facilitate travel and migration in Mesoamerica, which in turn could affect the spread of HIV in the region. METHODS: 6092 HIV-1 subtype B partial pol sequences sampled from unique antiretroviral treatment-naive individuals from Mexico (40.7%), Guatemala (24.4%), Honduras (19%), Panama (8.2%), Nicaragua (5.5%), Belize (1.4%), and El Salvador (0.7%) between 2011 and 2016 were included. Phylogenetic and genetic network analyses were performed to infer putative relationships between HIV sequences. The demographic and geographic associations with clustering were analyzed and viral migration patterns were inferred using the Slatkin-Maddison approach on 100 iterations of random subsets of equal number of sequences per location. RESULTS: A total of 1685/6088 (27.7%) of sequences linked with at least one other sequence, forming 603 putative transmission clusters (range: 2-89 individuals). Clustering individuals were significantly more likely to be younger (median age 29 vs 33years, p<0.01) and men-who-have-sex-with-men (40.4% vs 30.3%, p<0.01). Of the 603 clusters, 30 (5%) included sequences from multiple countries with commonly observed linkages between Mexican and Honduran sequences. Eight of the 603 clusters included >10 individuals, including two comprised exclusively of Guatemalans (52 and 89 individuals). Phylogenetic and migration analyses suggested that the Central and Southern regions of Mexico along with Belize were major sources of HIV throughout the region (p<0.01) with genetic flow southward from Mexico to the other nations of Mesoamerica. We also found evidence of significant viral migration within Mexico. CONCLUSION: International clusters were infrequent, suggesting moderate migration between HIV epidemics of the different Mesoamerican countries. Nevertheless, we observed important sources of transnational HIV spread in the region, including Southern and Central Mexico and Belize. PMID- 28645710 TI - Impact of upstream river inputs and reservoir operation on phosphorus fractions in water-particulate phases in the Three Gorges Reservoir. AB - The impoundment of the Three Gorges Reservoir (TGR) has changed water-sand transport regime, with inevitable effects on phosphorus transport behavior in the TGR. In this study, we measured phosphorus fractions in water and suspended particles transported from upstream rivers of the TGR (the Yangtze River, the Jialing River and the Wu River) to reservoir inner region over the full operation schedule of the TGR. The aim was to determine how phosphorus fractions in water and particulate phases varied in response to natural hydrological processes and reservoir operations. The results showed that total phosphorus concentration (TP) in water in the TGR inner region was 0.17+/-0.05mg/L, which was lower than that in the Yangtze River (0.21+/-0.04mg/L) and the Wu River (0.23+/-0.03mg/L), but higher than that in the Jialing River (0.12+/-0.07mg/L). In the TGR inner region, there was no clear trend of total dissolved phosphorus (TDP), but total particulate phosphorus (TPP) showed a decreasing trend from tail area to head area because of particle deposition along the TGR mainstream. In addition, the concentrations of TPP in water and particulate phosphorus in a unit mass of suspended particles (PP) in the TGR inner region were higher in October 2014 and January 2015 (the impounding period and high water level period) than that in July 2015 (the low water level period). The temporal variations of PP and TPP concentrations in the TGR may be linked to the change of particle size distribution of suspended particles in the TGR. The particle size tended to be finer due to large-size particle deposition under stable hydrodynamic conditions in the process of TGR impoundment, resulting in high adsorption capacities of phosphorus in suspended particles. The results implied that phosphorus temporal variations in the TGR could exert different impacts on water quality in the TGR tributaries. PMID- 28645712 TI - Blood transfusions in severe burn patients: Epidemiology and predictive factors: Methodological issues. PMID- 28645711 TI - Proteome dynamics during post-desiccation recovery reveal convergence of desiccation and gamma radiation stress response pathways in Deinococcus radiodurans. AB - Deinococcus radiodurans is inherently resistant to both ionizing radiation and desiccation. Fifteen months of desiccation was found to be the LD50 dose for D. radiodurans. Desiccated cells of D. radiodurans entered 6h of growth arrest during post-desiccation recovery (PDR). Proteome dynamics during PDR were mapped by resolving cellular proteins by 2-dimensional gel electrophoresis coupled with mass spectrometry. At least 41 proteins, represented by 51 spots on proteome profiles, were differentially expressed throughout PDR. High upregulation in expression was observed for DNA repair proteins involved in single strand annealing (DdrA and DdrB), nucleotide excision repair (UvrA and UvrB), homologous recombination (RecA) and other vital proteins that contribute to DNA replication, recombination and repair (Ssb, GyrA and GyrB). Expression of CRP/FNR family transcriptional regulator (Crp) remained high throughout PDR. Other pathways such as cellular detoxification, protein homeostasis and metabolism displayed both, moderately induced and repressed proteins. Functional relevance of proteomic modulations to surviving desiccation stress is discussed in detail. Comparison of our data with the published literature revealed convergence of radiation and desiccation stress responses of D. radiodurans. This is the first report that substantiates the hypothesis that the radiation stress resistance of D. radiodurans is incidental to its desiccation stress resistance. PMID- 28645713 TI - Propranolol kinetics in plasma from severely burned adults. AB - OBJECTIVES: The aim of this study was to determine the appropriate propranolol dosing strategy for reducing heart rate in severely burned adults. METHODS: A total of 26 patients (>=18 years) with burns covering >=30% of the total body surface area were included in this IRB-approved study. Plasma propranolol concentrations were determined in a placebo group (n=10) or following one of three dosing strategies: Q6 (n=4), Q8 (n=6), and Q24 (n=6). Blood was collected just before dosing and at regular intervals over two dosing periods with corresponding heart rate and blood pressure recordings. Statistical significance was determined by one-way ANOVA followed by the appropriate post-hoc test. RESULTS: Heart rate was 86+/-2 bpm for Q6, 93+/-3 bpm for Q8, and 90+/-4 bpm for Q24. The Q8 group had a significantly higher heart rate than the Q6 group (p=0.0001). Plasma propranolol concentrations were significantly higher in the Q6 dosing strategy than in the Q8 dosing strategy (p=0.02). CONCLUSIONS: Heart rate can be decreased to a similar degree with Q6 and Q24 dosing strategies, with the Q8 dosing strategy being less effective. Q6 dosing is recommended to maintain reduced heart rate throughout dosing periods. PMID- 28645714 TI - Retrospective analysis on thermal injuries in children-Demographic, etiological and clinical data of German and Austrian pediatric hospitals 2006-2015 Approaching the new German burn registry. AB - OBJECTIVE: The purpose of this observational, multi-center study was to reveal epidemiologic, etiological and clinical aspects of hospitalized children with thermal injuries in Germany and Austria and the workup of a renewed web-based pediatric burn registry. METHODS: From 2006 to 2015, comprehensive patient data of thermally injured children in Germany and Austria were collected prospectively. Retrospective analysis of age, gender, mechanism of injury, total body surface area burned, way of admission and length of stay was performed, followed by the comparative analysis between designated burn centers and other pediatric hospitals. RESULTS: 32 hospitals participated in the study including data of 13,460 thermally injured hospitalized children. The majority was 12-<36 months of age with a share of 48%. 56.5% were boys. The most frequent cause of injury was scalding representing 74.4%. Designated pediatric burn centers treated 82.2% of all patients. In relation to non-centers, no significant differences were seen concerning the affected total body surface area and the amount of patients <1 year of age in contrast to a significant difference regarding the amount of fire injuries, all being parameters indicating the severity of thermal injuries. Overall mortality was 0.1%. CONCLUSION: This study extends our knowledge about population characterization of thermally injured children, highlights risk factors and serves as a basis for the renewed pediatric burn registry from 2016 on. PMID- 28645715 TI - Agents, mechanisms and clinical features of non-scald burns in children: A prospective UK study. AB - AIMS: To inform childhood burn prevention by identifying demographics, clinical features and circumstances of unintentional non-scald burns. METHODS: A prospective cross-sectional study was conducted across Cardiff, Bristol and Manchester, including six emergency departments, three minor injury units and one burns unit between 13/01/2013-01/10/2015. Data collected for children aged <16 years with any burn (scald, contact, flame, radiation, chemical, electrical, friction) included: demographics, circumstances of injury and clinical features. Scalds and burns due to maltreatment were excluded from current analysis. RESULTS: Of 564 non-scald cases, 60.8% were boys, 51.1% were <3 years old, 90.1% (472/524) of burns affected one anatomical site. Contact burns accounted for 86.7% (489/564), 34.8% (137/394) of which were from objects placed at >0.6m and 76.5% (349/456) affected the hands. Hairstyling devices were the most common agent of contact burns (20.5%, 100/487); 34.1% (30/88) of hairstyling devices were on the floor. Of children aged 10-15 years, 63.7% (65/102), sustained contact burns of which 23.2% (13/56) were preparing food, and when burnt from hairstyling devices, 73.3% (11/15) were using them at the time of injury. CONCLUSIONS: Parents of toddlers must learn safe storage of hazardous items. Older children should be taught skills in safe cooking and hairstyling device use. PMID- 28645717 TI - Surveillance of pneumococcal colonization and invasive pneumococcal disease reveals shift in prevalent carriage serotypes in Massachusetts' children to relatively low invasiveness. AB - BACKGROUND: Following the introduction of pneumococcal conjugate vaccines (PCV), overall nasopharyngeal colonization rates have not changed significantly, however a dramatic and sustained decline in invasive pneumococcal disease (IPD) in children was observed in every setting where the PCVs were implemented. We aimed to describe the differences in invasive disease potential of serotypes that are common colonizers in pre- and post-vaccine eras in order to provide further insight in our understanding of dynamic epidemiology of pneumococcal diseases. METHODS: Using data from surveillance of nasopharyngeal carriage and enhanced surveillance for IPD, a serotype specific "invasive capacity (IC)" was computed by dividing the incidence of IPD due to serotype x by the carriage prevalence of that same serotype in children <7years of age in Massachusetts. We have evaluated the serotype specific invasive capacity in two periods; pre-PCV13 (2001/02, 2003/04, 2006/07, 2008/09) and post-PCV13 (2010/11 and 2013/14), and by age groups; <24monthsvs. >=24months. RESULTS: An approximate 50-fold variation in the point estimate was observed between the serotypes having the highest (7F, 38, 19A, 3, 33F) and the lowest (6C, 35B, 21, 11A, 23B and 23A) computed serotype specific invasive disease potential. In the post-PCV13 era (6C, 35B, 11A, 23B and 23A), 5 of the 7 most common serotypes colonizing the nasopharynx were serotypes with the lowest invasive capacity. Serotype specific invasive capacity trended down in older children for majority of the serotypes, and serotypes 3, 10A and 19A had significantly lower invasive capacity in children older than 24months of age compared to younger children. CONCLUSION: Invasive capacity differs among serotypes and likely by age. Point estimates of IC for most of the common serotypes colonizing children in Massachusetts in post-PCV13 era were low and likely explain the continued reduction in IPD from the pre-PCV era in the absence of specific protection against these serotypes. PMID- 28645716 TI - Guide to active vaccine safety surveillance: Report of CIOMS working group on vaccine safety - executive summary. AB - In 2013, the Council for International Organizations of Medical Sciences (CIOMS) created a Working Group on Vaccine Safety (WG) to address unmet needs in the area of vaccine pharmacovigilance. Generating reliable data about specific vaccine safety concerns is becoming a priority due to recent progress in the development and deployment of new vaccines of global importance, as well as novel vaccines targeting diseases specifically endemic to many resource-limited countries (RLCs), e.g. malaria, dengue. The WG created a Guide to Active Vaccine Safety Surveillance (AVSS) to assist national regulatory authorities and national immunization program officers in RLCs in determining the best course of action with regards to non-routine pharmacovigilance activities, when confronted with a launch of a new vaccine or a vaccine that is new to their country. Here we summarize the results of the WG, further detailed in the Guide, which for the first time provides a structured approach to identifying and analyzing specific vaccines safety knowledge gaps, while considering all available sources of information, in order to determine whether AVSS is an appropriate solution. If AVSS is confirmed as being the appropriate tool, the Guide provides additional essential information on AVSS, a detailed overview of common types of AVSS and practical implementation considerations. It also provides a framework for a well constructed and informative AVSS when needed, thus aiming to ensure the best possible safety of immunization in this new landscape. PMID- 28645718 TI - Optimizing adjuvants for intradermal delivery of MenC glycoconjugate vaccine. AB - Intradermal vaccine delivery is a promising alternative to the conventional intramuscular route. The skin layer is immunologically supported by a densely network of antigen presenting cells, while the skeletal muscle is loaded with a relatively sparse population of APCs. Nevertheless, the vaccine to be suitable for intradermal delivery needs a new formulation to facilitate either smaller injection volumes or the introduction into new delivery devises as micro-needles. This study presents a proof of concept for intradermal delivery of the MenC CRM197 glycoconjugate vaccine using a mouse model. Tangential flow filtration allowed obtaining a 20-fold concentrated vaccine formulation suitable for intradermal injection. Importantly the intradermal delivery of non-adjuvanted MenC glycoconjugate vaccine showed a quicker on-set and superiority in terms of immunogenicity compared to intramuscular administration of the respective vaccine and comparable immunogenicity to the aluminum adjuvanted vaccine formulation given intramuscular. Subsequently, the use of adjuvants allowed to further increase the immunogenicity and to modulate the quality of the immune response towards a more beneficial Th1 response. As adjuvants two Toll like receptor agonists (TLR4a and TLR7a), a mutant of the heat-labile enterotoxin from Escherichia coli (LT), a alpha-GalactosylCeramide analogue and an oil in water emulsion were investigated in order to target skin-resident antigen-presenting cells. This approach has the potential to be extended to other meningococcal serogroups, representing a promising strategy for the development of dermally administered multivalent glycoconjugate vaccines. PMID- 28645719 TI - Leadless Pacing System: Initial experience with a novel technology in Greece.